PMID- 25715822 TI - Models of bovine babesiosis including juvenile cattle. AB - Bovine Babesiosis in cattle is caused by the transmission of protozoa of Babesia spp. by ticks as vectors. Juvenile cattle (<9 months of age) have resistance to Bovine Babesiosis, rarely show symptoms, and acquire immunity upon recovery. Susceptibility to the disease varies between breeds of cattle. Models of the dynamics of Bovine Babesiosis transmitted by the cattle tick that include these factors are formulated as systems of ordinary differential equations. Basic reproduction numbers are calculated, and it is proved that if these numbers are below the threshold value of one, then Bovine Babesiosis dies out. However, above the threshold number of one, the disease may approach an endemic state. In this case, control measures are suggested by determining target reproduction numbers. The percentage of a particular population (for example, the adult bovine population) needed to be controlled to eradicate the disease is evaluated numerically using Columbia data from the literature. PMID- 25715823 TI - Controlled-release fertilizer prepared using a biodegradable aliphatic copolyester of poly(butylene succinate) and dimerized fatty acid. AB - The preparation and characterization of a controlled-release multicomponent (NPK) fertilizer with the coating layer consisting of a biodegradable copolymer of poly(butylene succinate) and a butylene ester of dilinoleic acid (PBS/DLA) is reported. The morphology and structure of the resulting polymer-coated materials and the thickness of the covering layers were examined using X-ray diffraction and scanning electron microscopy coupled with energy dispersive X-ray analysis. The mechanical properties of these materials were determined with a strength testing machine. Nutrient release was measured in water using spectrophotometry, potentiometry, and conductivity methods. The results of the nutrient release experiments from these polymer-coated materials were compared with the requirements for controlled-release fertilizers. A conceptual model is presented describing the mechanism of nutrient release from the materials prepared in this study. This model is based on the concentrations of mineral components inside the water-penetrated fertilizer granules, the diffusion properties of the nutrients in water, and a diffusion coefficient through the polymer layer. The experimental kinetic data on nutrient release were interpreted using the sigmoidal model equation developed in this study. PMID- 25715824 TI - The Central Role of Community-Practicing Pediatricians in Contemporary Concussion Care: A Case Study of Children's Healthcare of Atlanta's Concussion Program. PMID- 25715825 TI - Reach Out and Eat: Food and Beverages Depicted in Books for Preschoolers. AB - OBJECTIVE: To examine food and beverage depictions in books for preschoolers. METHODS: Books for preschoolers from Reach Out and Read (ROR; n = 42), public library (n = 27), and Publisher's Weekly booklists (n = 31) were examined for nutritive and empty-calorie food and beverage depictions. RESULTS: It was found that 66% of books depicted at least 1 food or beverage. More books depicted nutritive items than empty-calorie items (87.5% vs 54.7%, P < .001). There was a trend toward fewer empty-calorie depictions in ROR books than in other booklists. Yet nearly half of ROR books depicted at least 1 empty-calorie item. ROR books also accounted for 5 of 10 books with the most empty-calorie item depictions and 3 of 4 books with branding. With regard to messaging, approximately a third of books with the most empty-calorie depictions promoted unhealthy foods. CONCLUSIONS: When selecting books for ROR, it may be important to consider food and beverage depictions and messages. PMID- 25715826 TI - The Rhythmic, Sonorous and Melodic Components of Adult-Child-Object Interactions Between 2 and 6 Months Old. AB - Adults mediate the relationship between material reality and children, according to functional units of cultural relevance. This paper explores early development of semiotic systems in infants, analyzing rhythmic, sonorous and melodic components, which enable adult-child interaction with and about objects. The triads (with sonorous and non-sonorous objects) was studied longitudinally at age 2, 4 and 6 months. We propose that rhythmic, sonorous and melodic components conformed one of the basic semiotic systems upon the adult's action relies (through gestures and uses of objects) in order to segment and organize objects in the world. Likewise, children actively respond to these presentations and seek sounds for themselves when they are able to interact with the object more autonomously. PMID- 25715827 TI - A novel isolated Terrabacter-like bacterium can mineralize 2-aminopyrimidine, the principal metabolite of microbial sulfadiazine degradation. AB - Recently we showed that during the degradation of sulfadiazine (SDZ) by Microbacterium lacus strain SDZm4 the principal metabolite 2-aminopyrimidine (2 AP) accumulated to the same molar amount in the culture as SDZ disappeared (Tappe et al. Appl Environ Microbiol 79:2572-2577, 2013). Although 2-AP is considered a recalcitrant agent, long-term lysimeter experiments with (14)C-pyrimidine labeled SDZ ([(14)C]pyrSDZ) provided indications for substantial degradation of the pyrimidine moiety of the SDZ molecule. Therefore, we aimed to enrich 2-AP degrading bacteria and isolated a pure culture of a Terrabacter-like bacterium, denoted strain 2APm3. When provided with (14)C-labeled SDZ, M. lacus strain SDZm4 degraded [(14)C]pyrSDZ to [(14)C]2-AP. Resting cells of 2APm3 at a concentration of 5 * 10(6) cells ml(-1) degraded 62 uM [(14)C]2-AP to below the detection limit (0.6 uM) within 5 days. Disappearance of 2-AP resulted in the production of at least two transformation products (M1 and M2) with M2 being identified as 2-amino 4-hydroxypyrimidine. After 36 days, the transformation products disappeared and 83 % of the applied [(14)C]2-AP radioactivity was trapped as (14)CO2. From this we conclude that a consortium of two species should be able to almost completely degrade SDZ in soils. PMID- 25715828 TI - Improvement in inpatient glycemic care: pathways to quality. AB - The management of inpatient hyperglycemia is a focus of quality improvement projects across many hospital systems while remaining a point of controversy among clinicians. The association of inpatient hyperglycemia with suboptimal hospital outcomes is accepted by clinical care teams; however, the clear benefits of targeting hyperglycemia as a mechanism to improve hospital outcomes remain contentious. Glycemic management is also frequently confused with efforts aimed at intensive glucose control, further adding to the confusion. Nonetheless, several regulatory agencies assign quality rankings based on attaining specified glycemic targets for selected groups of patients (Surgical Care Improvement Project (SCIP) measures). The current paper reviews the data supporting the benefits associated with inpatient glycemic control projects, the components of a successful glycemic control intervention, and utilization of the electronic medical record in implementing an inpatient glycemic control project. PMID- 25715829 TI - Combined node and link partitions method for finding overlapping communities in complex networks. AB - Community detection in complex networks is a fundamental data analysis task in various domains, and how to effectively find overlapping communities in real applications is still a challenge. In this work, we propose a new unified model and method for finding the best overlapping communities on the basis of the associated node and link partitions derived from the same framework. Specifically, we first describe a unified model that accommodates node and link communities (partitions) together, and then present a nonnegative matrix factorization method to learn the parameters of the model. Thereafter, we infer the overlapping communities based on the derived node and link communities, i.e., determine each overlapped community between the corresponding node and link community with a greedy optimization of a local community function conductance. Finally, we introduce a model selection method based on consensus clustering to determine the number of communities. We have evaluated our method on both synthetic and real-world networks with ground-truths, and compared it with seven state-of-the-art methods. The experimental results demonstrate the superior performance of our method over the competing ones in detecting overlapping communities for all analysed data sets. Improved performance is particularly pronounced in cases of more complicated networked community structures. PMID- 25715830 TI - Quantity of lymph nodes correlates with improvement in lymphatic drainage in treatment of hind limb lymphedema with lymph node flap transfer in rats. AB - PURPOSE: This study was conducted to investigate the correlation between the number of vascularized lymph nodes (LN) transferred and resolution of hind limb lymphedema in a rat model. METHODS: Unilateral hind limb lymphedema was created in 18 male Sprague-Dawley rats following inguinal and popliteal LN resection and radiation. A para-aortic LN flap based on the celiac artery was subsequently transferred to the affected groin. The three study groups consisted of Group A (no LN transfer), Group B (transfer of a single vascularized LN), and Group C (transfer of three vascularized LNs). Volumetric analysis of bilateral hind limbs was performed using micro-CT imaging at 1, 2, and 3 months postoperatively. Lymphatic drainage was assessed with Tc(99) lymphoscintigraphy preoperatively and at 3 months postoperatively. RESULTS: A statistically significant volume reduction was seen in Groups B and C compared to Group A at all time points. Volume reduction of Group A vs.Group B at 1 month (8.6% +/- 2.0% vs. 2.7% +/- 2.6%, P < 0.05), 2 months (9.3% +/- 2.2% vs. -4.3% +/- 2.7%, P < 0.05), and 3 months (7.6% +/- 3.3% vs. -8.9% +/- 5.2%, P < 0.05). Volume reduction of Group A vs. Group C at 1 month (8.6% +/- 2.0% vs. -6.6% +/- 3.1%, P < 0.05), 2 months (9.3% +/- 2.2% vs. -10.2% +/- 4.6%, P < 0.05), and 3 months (7.6% +/- 3.3% vs. 9.1% +/- 3.1%, P < 0.05). Of note, comparison of Groups B and C demonstrated greater volume reduction in Group C at 1 (P < 0.02) and 2 (P = 0.07) months postoperatively. CONCLUSIONS: LN flap transfer is an effective procedure for the treatment of lymphedema. The number of vascularized LNs transferred correlates positively with the degree of volume reduction. PMID- 25715831 TI - Age-Period-Cohort approaches to back-calculation of cancer incidence rate. AB - A compartment model for cancer incidence and mortality is developed in which healthy subjects may develop cancer and subsequently die of cancer or another cause. In order to adequately represent the experience of a defined population, it is also necessary to allow for subjects who are diagnosed at death, as well as subjects who migrate and are subsequently lost to follow-up. Expressions are derived for the number of cancer deaths as a function of the number of incidence cases and vice versa, which allows for the use of mortality statistics to obtain estimates of incidence using survival information. In addition, the model can be used to obtain estimates of cancer prevalence, which is useful for health care planning. The method is illustrated using data on lung cancer among males in Connecticut. PMID- 25715832 TI - Investigation of the cytotoxicity of aluminum oxide nanoparticles and nanowires and their localization in L929 fibroblasts and RAW264 macrophages. AB - The biological responses of aluminum oxide (Al2 O3 ) nanoparticles (NPs) and nanowires (NWs) in cultured fibroblasts (L929) and macrophages (RAW264) were evaluated from their cytotoxicities and micromorphologic properties. Cultured cells were exposed to Al2 O3 NPs (13 nm diameter) and Al2 O3 NWs (2-6 * 200-400 nm). Cytotoxicity and genotoxicity were examined by immunostaining with fluorescence microscopy, and nanomaterial localization was studied by using scanning electron microscopy and transmission electron microscopy. The NPs were cytotoxic and genotoxic, whereas the NWs were not. The scanning electron microscopy images showed that the NPs aggregate more on the cell surface than do the NWs. The transmission electron microscopy images showed that the NPs were internalized into the vesicle and nuclei, for both cell types. In contrast, numerous solid NWs were observed as large aggregates in vesicles, but not in nuclei. Nuclear damage was confirmed by measuring cell viability and by immunostaining for NPs. The chemical changes induced by the NPs in the vesicles or cells may cause cell damage because of their large surface area per volume. The extent of NW entrapment was not sufficient to lower the viability of either cell type. PMID- 25715833 TI - Prolactin anterior pituitary expression and circulating levels are reduced in obese and diabetic rats: role of TGF-beta and TNF-alpha. AB - The levels of the hormone prolactin (PRL) are reduced in the circulation of patients with Type 2 diabetes and in obese children, and lower systemic PRL levels correlate with an increased prevalence of diabetes and a higher risk of metabolic syndrome. The secretion of anterior pituitary (AP) PRL in metabolic diseases may be influenced by the interplay between transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha), which inhibit and can stimulate AP PRL synthesis, respectively, and are known contributors to insulin resistance and metabolic complications. Here, we show that TGF-beta and TNF-alpha antagonize the effect of each other on the expression and release of PRL by the GH4C1 lactotrope cell line. The levels of AP mRNA and circulating PRL decrease in high-fat diet-induced obese rats in parallel with increased and reduced AP levels of TGF-beta and TNF-alpha mRNA, respectively. Likewise, AP expression and circulating levels of PRL are reduced in streptozotocin-induced diabetic rats and are associated with higher AP expression and protein levels of TGF-beta and TNF-alpha. The opposing effects of the two cytokines on cultured AP cells, together with their altered expression in the AP of obese and diabetic rats suggest they are linked to the reduced PRL production and secretion characteristics of metabolic diseases. PMID- 25715835 TI - Ammonia excretion in the Atlantic hagfish (Myxine glutinosa) and responses of an Rhc glycoprotein. AB - Hagfishes, the most ancient of the extant craniates, demonstrate a high tolerance for a number of unfavorable environmental conditions, including elevated ammonia. Proposed mechanisms of ammonia excretion in aquatic organisms include vesicular NH(4)(+) transport and release by exocytosis in marine crabs, and passive NH(3) diffusion, active NH(4)(+) transport, and paracellular leakage of NH3 or NH(4)(+) across the gills of fishes. Recently, an emerging paradigm suggests that Rhesus glycoproteins play a vital role in ammonia transport in both aquatic invertebrates and vertebrates. This study has identified an Rh glycoprotein ortholog from the gills of Atlantic hagfish. The hagfish Rhcg shares a 56-60% amino acid identity to other vertebrate Rhcg cDNAs. Sequence information was used to produce an anti-hagfish Rhcg (hRhcg) antibody. We have used hRhcg to localize protein expression to epithelial cells of the gill and the skin. In addition, we have quantified hRhcg expression following exposure to elevated plasma ammonia levels. Animals exposed to a 3 mmol/kg NH(4)Cl load resulted in significantly elevated plasma ammonia concentrations compared with controls for up to 4 h postinjection. This correlated with net ammonia excretion rates that were also significantly elevated for up to 4 h postinjection. Rhcg mRNA expression in both the gill and skin was significantly elevated by 15 min and 1 h, respectively, and hRhcg protein expression in gills was significantly elevated at 2, 4, and 8 h postinjection. These results demonstrate a potential role for Rhcg in the excretion of ammonia in the Atlantic hagfish. PMID- 25715834 TI - Cold-acclimation leads to differential regulation of the steelhead trout (Oncorhynchus mykiss) coronary microcirculation. AB - The regulation of vascular resistance in fishes has largely been studied using isolated large conductance vessels, yet changes in tissue perfusion/vascular resistance are primarily mediated by the dilation/constriction of small arterioles. Thus we adapted mammalian isolated microvessel techniques for use in fish and examined how several agents affected the tone/resistance of isolated coronary arterioles (<150 MUm ID) from steelhead trout (Oncorhynchus mykiss) acclimated to 1, 5, and 10 degrees C. At 10 degrees C, the vessels showed a concentration-dependent dilation to adenosine (ADE; 61 +/- 8%), sodium nitroprusside (SNP; 35 +/- 10%), and serotonin (SER; 27 +/- 2%) (all values maximum responses). A biphasic response (mild contraction then dilation) was observed in vessels exposed to increasing concentrations of epinephrine (EPI; 34 +/- 9% dilation) and norepinephrine (NE; 32 +/- 7% dilation), whereas the effect was less pronounced with bradykinin (BK; 12.5 +/- 3.5% constriction vs. 6 +/- 6% dilation). Finally, a mild constriction was observed after exposure to acetylcholine (ACh; 6.5 +/- 1.4%), while endothelin (ET)-1 caused a strong dose dependent increase in tone (79 +/- 5% constriction). Acclimation temperature had varying effects on the responsiveness of vessels. The dilations induced by EPI, ADE, SER, and SNP were reduced/eliminated at 5 degrees C and/or 1 degrees C as compared with 10 degrees C. In contrast, acclimation to 5 and 1 degrees C increased the maximum constriction induced by ACh and the sensitivity of vessels to ET-1 (but not the maximum response) at 1 degrees C was greater. Acclimation temperature had no effect on the response to NE, and responsiveness to BK was variable. PMID- 25715836 TI - Coextruded, aligned, and gradient-modified poly(epsilon-caprolactone) fibers as platforms for neural growth. AB - Polymeric fibers are of increasing interest to regenerative medicine, as materials made from these fibers are porous, allowing for cell infiltration, influx of nutrients, and efflux of waste products. Recently, multilayered coextrusion has emerged as a scalable and rapid fabrication method to yield microscale to submicron fibers. In this report, we describe the multilayered coextrusion of aligned poly(epsilon-caprolactone) (PCL) fibers, followed by a simple photochemical patterning to create surface-immobilized gradients onto the polymer fibers. PCL fibers were photochemically decorated with a linear gradient of propargyl benzophenone using a gradient photomask to control light source intensity. The pendant alkynes were then able to undergo the copper-catalyzed azide-alkyne cycloaddition reaction with an azide-modified IKVAV peptide to further functionalize the surface. Gradient-modified IKVAV fibers were evaluated for neural cell adhesion and neural differentiation, using PC-12 cells cultured onto the fibers. The aligned gradient fibers provided directional cues for neurite outgrowth and alignment of neural cells, as observed by cellular elongation, neurite differentiation, and orientation. The work presented herein describes a scalable fiber system combined with simple chemical patterning to generate aligned fibers with controlled surface gradients as cell-seeding scaffolds. PMID- 25715837 TI - Injuries to appendage extremities and digit tips: A clinical and cellular update. AB - BACKGROUND: The regrowth of amputated appendage extremities and the distal tips of digits represent models of tissue regeneration in multiple vertebrate taxa. In humans, digit tip injuries, including traumatic amputation and crush injuries, are among the most common type of injury to the human hand. Despite clinical reports demonstrating natural regeneration of appendages in lower vertebrates and human digits, current treatment options are suboptimal, and are complicated by the anatomical complexities and functions of the different tissues within the digits. RESULTS: In light of these challenges, we focus on recent advancements in understanding appendage regeneration from model organisms. We pay special attention to the cellular programs underlying appendage regeneration, where cumulative data from salamanders, fish, frogs, and mice indicate that regeneration occurs by the actions of lineage-restricted precursors. We focus on pathologic states and the interdependency that exists, in both humans and animal models, between the nail organ and the peripheral nerves for successful regeneration. CONCLUSIONS: The increased understanding of regeneration in animal models may open new opportunities for basic and translational research aimed at understanding the mechanisms that support limb regeneration, as well as amelioration of limb abnormalities and pathologies. PMID- 25715838 TI - Dynamic contrast-enhanced imaging of the wrist in rheumatoid arthritis: dedicated low-field (0.25-T) versus high-field (3.0-T) MRI. AB - OBJECTIVE: To compare the assessment of wrist synovitis severity, synovial volume and synovial perfusion parameters on a dedicated low-field (0.25-T) to that of a high-field (3-T) whole-body MR system in patients with rheumatoid arthritis (RA). METHODS: Twenty-one patients (mean age 50.0 +/- 9.8 years) with active RA were recruited prospectively. Dynamic contrast-enhanced MRI examination of the most severely affected wrist was performed at both 0.25 T and 3 T. Three MRI-derived parameters, synovitis severity (RAMRIS grade), synovial volume (ml(3)) and synovial perfusion indices (maximum enhancement and enhancement slope), were compared. RESULTS: Comparing 0.25- and 3-T MRI, there was excellent agreement for semiquantitative assessment (r: 0.80, p < 0.00001) of synovitis (RAMRIS) as well as quantitative assessment (r: 0.94, p < 0.00001) of synovial volume. Good agreement for synovial Emax (r: 0.6, p = 0.002) and fair agreement (r: 0.5, p = 0.02) for synovial Eslope was found. CONCLUSIONS: Imaging of the RA wrist at 0.25 T yields excellent correlation with 3 T with regard to the synovitis activity score (RAMRIS) and synovial volume measurement. Fair to good correlation between low- (0.25-T) and high-field (3-T) MR systems was found for perfusion parameters, being better for Emax than for Eslope. PMID- 25715839 TI - Endoscopic management of a choroid plexus cyst of the third ventricle: case report and documentation of dynamic behavior. AB - PURPOSE: The aim of this study is to document the dynamic behavior of a choroid plexus cyst of the third ventricle. Although these lesions may float freely within the ventricle leading to intermittent obstruction of the cerebrospinal fluid (CSF) circulation at variable points in a single patient, such a phenomenon has only been documented using cranial ultrasonography and was never observed intraoperatively. METHODS: We endoscopically treated a case of third ventricular choroid plexus cyst in a 9-year-old boy who presented with headaches and disturbed conscious level. He underwent a transventricular approach through a single burr hole. RESULTS: During the procedure, the cyst was noted to intermittently herniate into the lateral ventricle and recede back through the foramen of Monro. Endoscopic ablation of the cyst was achieved and followed by endoscopic third ventriculostomy (ETV). The patient made an excellent recovery after the procedure. CONCLUSIONS: We were able to endoscopically observe the dynamic behavior displayed by a choroid plexus cyst of the third ventricle. To the best of our knowledge, intraoperative documentation of the obstruction of the CSF pathway by a single choroid plexus cyst that intermittently herniates through the foramen of Monro and back into the third ventricular cavity has not been previously demonstrated neither microsurgically nor endoscopically. PMID- 25715840 TI - Frontal cranial modeling using endocranial resorbable plate fixation in 27 consecutive plagiocephaly and trigonocephaly patients. AB - INTRODUCTION: Premature ossification of coronal and metopic sutures is treated by fronto-orbital remodeling. Such operations require stable fixation of the reshaped cranial bones. Currently, biodegradable plating systems are used to provide sufficient stability over the time that takes for the osteotomies to ossify. Plates that are placed traditionally on the outer surface of the cranium are often palpable and even visible through the thin overlying skin, compromising the cosmetic results of these operations. Improved aesthetics could be achieved by placing the plates endocranially. PURPOSE: This study aimed to evaluate endocranial resorbable plate fixation and its clinical and radiographic results in frontal remodeling cranioplasty for plagiocephaly and trigonocephaly patients with follow-up sufficiently long for the plates to have been completely resorbed. METHODS: A poly(lactide-co-glycolide) (PLGA) resorbable plating system was used on the inner aspect of frontal bone in 27 patients treated for coronal and metopic craniosynostoses. The outcome was evaluated at follow-up visits. The mean follow-up was 79.2 months. RESULTS: Three patients had complications that required reoperations. None of these complications were related to the endocranial location of the plates. There were no problems with ossification of the osteotomy sites. All but one patient's outcome was judged as good or excellent. CONCLUSION: Placement of resorbable fixation on the endocranial surface of the calvarial bones is safe, stable, and results in satisfactory aesthetics without interfering with the ossification of the cranial bones. PMID- 25715841 TI - Cortical gluing and Ringer lactate solution inflation to avoid cortical mantle collapse and subdural fluid collections in pediatric neurosurgery: safety and feasibility. AB - INTRODUCTION: Subdural fluid collections following intraventricular and/or paraventricular procedures in pediatric neurosurgery are common and can be hard to treat. We describe our technique to close cortical defects by the aid of a fibrin adhesive and subsequent Ringer inflation with the aim to avoid cortical mantle collapse and to prevent the development of subdural fluid collections. MATERIALS AND METHODS: We report the preliminary results of a prospective study on a consecutive series of 29 children who underwent 37 transcortical or transcallosal surgical procedures since 2008 in our department. RESULTS: In 17 procedures, we performed a transcortical approach on lesions, and in other 19 operations, we operated by a transcallosal. In 5/17 transcortical approaches (29%) and in 3/20 transcallosal approaches (15%), we observed a 5-mm-thick subdural fluid collection of the 5 patients with subdural fluid collections in the transcortical group, 3 patients (17%) underwent surgery for symptomatic or progressive subdural fluid collections. Of the 3 patients in the transcallosal group, a subduro-peritoneal shunt was necessary only for 1 patient (5%). At the very end of the treatment (including chemotherapy and radiotherapy), it was possible to remove the subduro-peritoneal shunt in all these patients because of disappearance of the subdural fluid collections. CONCLUSION: In pediatric patients after transcortical or transcallosal procedures, the use of a fibrin adhesive to seal surgical opening and subsequent inflation of the residual cavity with Ringer lactate solution to avoid cortical mantle collapse seems safe and appears to prevent the development of subdural fluid collections. PMID- 25715842 TI - Neuroimaging findings in pediatric cerebral sinovenous thrombosis. AB - PURPOSE: Pediatric cerebral sinovenous thrombosis (CSVT) is a potentially life threatening condition which is usually diagnosed by MRI. We analyzed the signal changes of the thrombus over time and the role of diffusion-weighted/tensor imaging (DWI/DTI) in the diagnosis of CSVT. METHODS: Clinical histories were reviewed for risk factors for CSVT, neurologic manifestation, and interval from onset of symptoms related to CSVT to the neuroimaging diagnosis. MRI studies were retrospectively evaluated for the appearance of thrombi on T1- and T2-weighted, fluid-attenuated inversion recovery (FLAIR), DWI/DTI, susceptibility-weighted imaging (SWI), and magnetic resonance venography (MRV) images. RESULTS: Thirty three children with CSVT were included in this study. Seventy-seven thrombi were found. Seventy-four thrombi could be identified on T1- or T2-weighted images (96 %), 72 thrombi were seen on DWI/DTI (94 %) and 68 on FLAIR (88 %). DWI showed restricted diffusion in 29 thrombi (40 %). Thrombi older than 1 day were more likely to have a T1-hyperintense signal (p = 0.002). No additional correlation between signal intensity and age of the thrombi was found. Intraparenchymal changes secondary to CSVT were seen in 11 children. CONCLUSION: MR sequences individually are not sensitive enough to provide the diagnosis. DWI/DTI does not provide complementary diagnostic value. Approximation of the age of the thrombus is difficult because of poor correlation between signal intensity and age of the thrombi. PMID- 25715843 TI - Parasitic rachipagus twins; report of two cases. AB - BACKGROUND: Parasitic fetus is a kind of conjoined twin, in which one of the twins is resorbed and some parts of the body can remain attached to the other twin. In the spinal form of parasitic twin--the so-called parasitic rachipagus- an ectopic or accessory limb is attached to the back of a normal baby or only a mass of viable tissue may remain. METHOD: Here, we report two cases of rachipagus that one had a lower extremity on her back and the other had some tissues similar to genitalia and formed bony structures on his back. PMID- 25715845 TI - [Evaluating the learning curve for the transversus abdominal plane block: a prospective observational study]. AB - PURPOSE: Anesthesia is a medical specialty where a large number of technical skills need to be mastered with the learning curve for these skills depending on both the technique and the individual involved. The transversus abdominis plane (TAP) block has demonstrated its effectiveness especially in postoperative analgesia following midline laparotomy. It is usually described as a simple technique even though little is known about the learning curve for this block. The purpose of this study was to determine the learning curve for ultrasound guided TAP block in anesthesiologists who had no prior experience performing the block. METHODS: This was a prospective observational study performed in gynecological and general surgery patients at the University Hospital Center of Nancy (France) between November 2011 and June 2012. After a short theoretical training, sixresidents were asked to perform, 20 TAP blocks under the supervision of a senior staff physician. The success of the procedure involved the visualization and identification of the different muscle planes, the peritoneum, the tip of the needle, an evaluation of the effectiveness of the block (sensory block), the absence of intervention from the supervisor, the absence of complications, less than three attempts, and a satisfaction score by the supervisor > 7 on a 0-10 rating scale. A learning curve/cummulative summation (LC CUSUM) was generated. RESULTS: The six residents performed all 20 TAP blocks. All residents had already performed ultrasound-guided procedures. The procedure was considered mastered after performing 16 blocks on average for a 90% success rate. The average time (SD) to complete the block decreased from 6.8 (4.1 min) at the beginning to 2.8 (1.3) min at the end of the study. There was a decrease in the number of repositionings of the needle and in the number of interventions by the supervisor throughout the study. The LC-CUSUM analysis revealed that all residents had acquired the TAP block technique within 20 procedures. CONCLUSION: This study demonstrates that the TAP block can be rapidly mastered even if the learning curve varies due to inter-individual differences in dexterity and in the ease of obtaining the ultrasound images. PMID- 25715846 TI - [Acute coronary syndrome following a 100 ug carbetocin injection during an emergency Cesarean delivery]. AB - PURPOSE: Postpartum hemorrhage affects 5% of parturients. Its prevention relies mainly on the administration of oxytocin derivatives. Carbetocin is a newly available analogue of oxytocin but has a considerable incidence of side effects. CLINICAL FEATURES: We report the case of a woman with no cardiovascular risk factors experiencing an acute coronary syndrome with significant electrocardiogram changes perioperatively after a single injection of carbetocin during an emergency Cesarean delivery. Postoperative cardiac enzyme levels and transthoracic echocardiogram results were normal. CONCLUSION: A 2012 retrospective analysis of the use of carbetocin in our institution revealed an incidence rate for coronary events of 1/245 (0.34%), a rate similar to the ones reported in previous studies. We discuss the management of patients with angina during a Cesarean delivery as well as the plans to care for these patients in the future. PMID- 25715847 TI - Anesthetic considerations in organ procurement surgery: a narrative review. AB - PURPOSE: While a few publications specify the anesthetic implications of either brain or cardiac death, they lack detail on how to provide anesthesia during organ donation surgery. We provide a thorough description of important anesthetic considerations during organ donation surgery in patients with either brain or cardiac death. SOURCE: A thorough literature review was undertaken to locate all relevant articles that describe systemic effects of brain and cardiac death and their anesthetic implications. We searched PubMed, Pubget, and EMBASETM for relevant articles using the following search terms: anesthesia, management, donation cardiac death, donation brain death. In addition, we reviewed the relevant protocols at our own institution. PRINCIPAL FINDINGS: Highly specific intraoperative management by an anesthesiologist is required during organ procurement after brain death. To manage the heart-beating brain-dead donor, the anesthesiologist must incorporate knowledge of the effects of brain death on each organ system as well as the effects of the preoperative measures that the donor required in the intensive care unit. It is also important to know which organs are going to be procured in order to establish specific goals and implement strategies (e.g., lung-protective ventilation or intraoperative glycemic control) to optimize donor outcome. During organ procurement after cardiac death, an anesthesiologist's direct involvement is particularly important for lung donors. CONCLUSION: Anesthesiologist-guided physiological optimization of the brain-dead donor may be a factor in determining the outcome of the organ recipient. Additionally, anesthesiologists have an important role in helping to ensure that the highest quality and most appropriate care are rendered to non-heart-beating donors. This is achieved through establishing protocols in their hospitals for donation after cardiac death that maximize the number of available organs with the best chance for long-term graft viability. PMID- 25715848 TI - miRNA-dis: microRNA precursor identification based on distance structure status pairs. AB - MicroRNA precursor identification is an important task in bioinformatics. Support Vector Machine (SVM) is one of the most effective machine learning methods used in this field. The performance of SVM-based methods depends on the vector representations of RNAs. However, the discriminative power of the existing feature vectors is limited, and many methods lack an interpretable model for analysis of characteristic sequence features. Prior studies have demonstrated that sequence or structure order effects were relevant for discrimination, but little work has explored how to use this kind of information for human pre microRNA identification. In this study, in order to incorporate the structure order information into the prediction, a method called "miRNA-dis" was proposed, in which the feature vector was constructed by the occurrence frequency of the "distance structure status pair" or just the "distance-pair". Rigorous cross validations on a much larger and more stringent newly constructed benchmark dataset showed that the miRNA-dis outperformed some state-of-the-art predictors in this area. Remarkably, miRNA-dis trained with human data can correctly predict 87.02% of the 4022 pre-miRNAs from 11 different species ranging from animals, plants and viruses. miRNA-dis would be a useful high throughput tool for large scale analysis of microRNA precursors. In addition, the learnt model can be easily analyzed in terms of discriminative features, and some interesting patterns were discovered, which could reflect the characteristics of microRNAs. A user-friendly web-server of miRNA-dis was constructed, which is freely accessible to the public at the web-site on http://bioinformatics.hitsz.edu.cn/miRNA-dis/. PMID- 25715849 TI - Lack of consensus regarding pretensioning and preconditioning protocols for soft tissue graft reconstruction of the anterior cruciate ligament. AB - PURPOSE: Pretensioning and preconditioning of soft tissue grafts are often performed to obviate graft stress relaxation and elongation due to viscoelastic graft properties following anterior cruciate ligament (ACL) reconstruction. It was hypothesized that a consensus could be identified in the current literature regarding the biomechanical effects and clinical benefits of an optimal protocol. METHODS: A systematic electronic literature search was performed by two independent reviewers to identify relevant publications. Only studies describing and/or comparing pretensioning or preconditioning protocols of soft tissue grafts or equivalent animal research models were eligible for inclusion. Study design, graft type, and protocol, including method, magnitude, mode (cyclic and/or static loading), and duration of load application, were compared. Research results and clinical conclusions were also evaluated for each study. RESULTS: Five studies, including four in vitro biomechanical investigations and one histological analysis of patient tissue, met the predefined criteria for inclusion. Studies described numerous pretensioning and/or preconditioning protocols with varying force, time, and application modalities for multiple soft tissue graft types and animal models. The majority of studies (80 %) utilized at least one pretensioning or preconditioning protocol between 80 and 89 N, while only one study investigated substantially higher loads (500 N). CONCLUSIONS: Despite common trends demonstrating the effects of pretensioning and preconditioning, no clear consensus regarding an optimal protocol, magnitude, or modality could be identified within the currently available relevant literature. Further multidisciplinary research is required before an optimal or consensus protocol can be established for soft tissue ACL reconstruction. Regardless, the current biomechanical literature demonstrates the potential clinically beneficial effects of pretensioning and preconditioning, including reduced graft elongation and greater preservation of graft tension and stiffness following fixation. LEVEL OF EVIDENCE: Systematic review, Level II. PMID- 25715850 TI - Tibiotalocalcaneal arthrodesis using an intramedullary nail: a systematic review. AB - PURPOSE: Tibiotalocalcaneal arthrodesis is aimed to block the ankle joint motion in cases of severe osteoarthritis, avascular necrosis of the talus and/or failure of arthroplasty operations. This systematic review was carried out to evaluate the clinical outcome after tibiotalocalcaneal arthrodesis using intramedullary nail either open and arthroscopically assisted. Focus was on the success rate of the procedure in terms of union and complications and on the comparison between the techniques. METHODS: The databases PubMed (Medline), EMBASE and Cochrane Library were searched in order to retrieve relevant studies. All therapeutic level 1-4 studies involving humans with intramedullary nail fixation technique were included. Only studies written in English, Italian, French, Spanish and German were included. Data related to the type of surgery, complications and clinical outcomes were extracted and analysed. RESULTS: A total of 83 studies were identified, of which 32 studies were eligible for inclusion; 31 case series and one randomized controlled trial. The main reported outcome score was the American Orthopaedic Foot and Ankle Society scale. Almost, all the included studies reported higher than 50% union rates and a significant improvement in terms of the clinical and mechanical ankle function after treatment. CONCLUSIONS: Results suggest that satisfactory outcomes can be achieved by tibiotalocalcaneal arthrodesis using intramedullary nailing. Low complication rates contribute to make this a safe procedure. No comparison can be done between arthroscopic and open technique, due to the lack of scientific works on the first one. LEVEL OF EVIDENCE: IV. PMID- 25715851 TI - Protein phosphorylation profiling identifies potential mechanisms for direct immunotoxicity. AB - Signaling networks are essential elements that are involved in diverse cellular processes. One group of fundamental components in various signaling pathways concerns protein tyrosine kinases (PTK). Various toxicants have been demonstrated to exert their toxicity via modulation of tyrosine kinase activity. The present study aimed to identify common cellular signaling pathways that are involved in chemical-induced direct immunotoxicity. To this end, an antibody array-based profiling approach was applied to assess effects of five immunotoxicants, two immunosuppressive drugs and two non-immunotoxic control chemicals on the phosphorylation of 28 receptor tyrosine kinases and 11 crucial signaling nodes in Jurkat T-cells. The phosphorylation of ribosomal protein S6 (RPS6) and of kinases Akt, Src and p44/42 were found to be commonly regulated by immunotoxicants and/or immunosuppressive drugs (at least three compounds), with the largest effect observed upon RPS6. Flow cytometry and Western blotting were used to further examine the effect of the model immunotoxicant TBTO on the components of the mTOR p70S6K-RPS6 pathway. These analyses revealed that both TBTO and the mTOR inhibitor rapamycin inactivate RPS6, but via different mechanisms. Finally, a comparison of the protein phosphorylation data to previously obtained transcriptome data of TBTO-treated Jurkat cells resulted in a good correlation at the pathway level and indicated that TBTO affects ribosome biogenesis and leukocyte migration. The effect of TBTO on the latter process was confirmed using a CXCL12 chemotaxis assay. PMID- 25715852 TI - Reconstruction of organ dose for external radiotherapy patients in retrospective epidemiologic studies. AB - Organ dose estimation for retrospective epidemiological studies of late effects in radiotherapy patients involves two challenges: radiological images to represent patient anatomy are not usually available for patient cohorts who were treated years ago, and efficient dose reconstruction methods for large-scale patient cohorts are not well established. In the current study, we developed methods to reconstruct organ doses for radiotherapy patients by using a series of computational human phantoms coupled with a commercial treatment planning system (TPS) and a radiotherapy-dedicated Monte Carlo transport code, and performed illustrative dose calculations. First, we developed methods to convert the anatomy and organ contours of the pediatric and adult hybrid computational phantom series to Digital Imaging and Communications in Medicine (DICOM)-image and DICOM-structure files, respectively. The resulting DICOM files were imported to a commercial TPS for simulating radiotherapy and dose calculation for in-field organs. The conversion process was validated by comparing electron densities relative to water and organ volumes between the hybrid phantoms and the DICOM files imported in TPS, which showed agreements within 0.1 and 2%, respectively. Second, we developed a procedure to transfer DICOM-RT files generated from the TPS directly to a Monte Carlo transport code, x-ray Voxel Monte Carlo (XVMC) for more accurate dose calculations. Third, to illustrate the performance of the established methods, we simulated a whole brain treatment for the 10 year-old male phantom and a prostate treatment for the adult male phantom. Radiation doses to selected organs were calculated using the TPS and XVMC, and compared to each other. Organ average doses from the two methods matched within 7%, whereas maximum and minimum point doses differed up to 45%. The dosimetry methods and procedures established in this study will be useful for the reconstruction of organ dose to support retrospective epidemiological studies of late effects in radiotherapy patients. PMID- 25715853 TI - Current status of functional gastrointestinal evaluation in clinical practice. AB - Neurogastroenterology and motility disorders of the gastrointestinal (GI) tract encompass a broad spectrum of diseases involving the GI tract and central nervous system. They have varied pathophysiology, clinical presentation and management, and make up a substantial proportion of outpatient clinic visits. Typically, patients experience persistent symptoms referable to the GI tract despite normal endoscopic and radiologic findings. An appropriate evaluation is thus important in the patient's care. Advances in technology and understanding of the disease pathophysiology have provided better insight into the physiological basis of disease and a more rational approach to patient management. While technological advances serve to explain patients' persistent symptoms, they should be balanced against the costs of diagnostic tests. This review highlights the GI investigative modalities employed to evaluate patients with persistent GI symptoms in the absence of a structural lesion, with particular emphasis on investigative modalities available locally and the clinical impact of such tools. PMID- 25715854 TI - Clinics in diagnostic imaging. 159. Jejunal intussusception due to Peutz-Jeghers syndrome. AB - A 21-year-old woman presented with acute onset of upper abdominal pain. A diagnosis of Peutz-Jeghers syndrome (PJS) was made based on the clinical picture of perioral pigmentation with imaging findings of transient jejunojejunal intussusceptions and small bowel polyps, and confirmed by characteristic histopathological appearances of Peutz-Jeghers polyps. PJS is a rare hereditary condition characterised by unique hamartomatous polyps, perioral mucocutaneous pigmentations, and increased susceptibility to gastrointestinal and extraintestinal neoplasms. Patients usually present with recurrent abdominal pain due to intussusception caused by polyps. Other modes of presentations include rectal bleeding and melaena. We describe the imaging findings of PJS and provide a brief review of bowel polyposis syndromes. The latter are relatively rare disorders characterised by multiple polyps in the large or small intestine, with associated risk of malignancies and other extraintestinal manifestations. Awareness of the manifestations and early diagnosis of these syndromes is crucial to prevent further complications. PMID- 25715855 TI - Effectiveness of early cardiology undergraduate learning using simulation on retention, application of learning and level of confidence during clinical clerkships. AB - INTRODUCTION: This study aimed to assess the effectiveness of the use of a cardiopulmonary patient simulator in the teaching of second-year medical students. Effectiveness was measured in terms of the extent of knowledge retention and students' ability to apply the skills learned in subsequent real life patient contact. METHODS: In this study, ten third-year medical students who had previously undergone simulator training as part of their second-year curriculum underwent an objective structured clinical examination (OSCE) and a multiple-choice question (MCQ) test to assess their ability to apply the knowledge gained during the simulator training when dealing with real patients. The performance of this group of students was compared with that of a group of ten fourth-year medical students who did not undergo simulation training. RESULTS: Although the third-year medical students performed well in the OSCE, they were outperformed by the group of fourth-year medical students, who had an extra year of clinical exposure. The MCQ scores of the two groups of students were similar. Post-simulation training survey revealed that students were generally in favour of incorporating cardiopulmonary simulator training in the preclinical curriculum. CONCLUSION: Cardiopulmonary simulator training is a useful tool for the education of preclinical medical students. It aids the translation of preclinical knowledge into real-life clinical skills. PMID- 25715856 TI - Comparison of effectiveness and time-efficiency between multimedia and conventional counselling on metered-dose inhaler technique education. AB - INTRODUCTION: This study aimed to evaluate whether multimedia counselling (MC) using a touchscreen computer is as effective and time-efficient as conventional counselling (CC) in promoting correct metered-dose inhaler (MDI) technique, with or without the valved holding chamber (VHC). METHODS: Participants in the MDI only and MDI-with-VHC groups were randomly assigned to the MC group or CC group. No blinding was imposed. Inhalation technique was assessed using checklists before and after counselling. Time spent on counselling was determined for all participants, while time taken to perfect the technique was determined only for participants who achieved perfect technique within one hour. RESULTS: The CC group had more elderly participants than the MC group, but the difference was not significant. MDI-only and MDI-with-VHC users showed significant improvement in their inhaler technique after multimedia (44.5 +/- 28.0% and 44.1 +/- 14.4%, respectively) and conventional counselling (36.8 +/- 20.5% and 37.0 +/- 14.6%, respectively). No significant difference in MDI technique enhancement was found between the two groups. Although no significant difference was found between the MC and CC groups with regard to the time spent on counselling and the time taken to perfect the technique, the average time spent on counselling was longer for MDI-only users. MDI-only users had 13.5 times the odds of failing to achieve perfect technique compared to MDI-with-VHC users (95% confidence interval 1.50 121.32, p = 0.020). CONCLUSION: MC and CC significantly improved MDI technique. Both methods showed comparable short-term effectiveness and time-efficiency in MDI technique education. VHC was beneficial, especially for MDI-users with hand lung coordination problems. PMID- 25715857 TI - Cost of post-stroke outpatient care in Malaysia. AB - INTRODUCTION: This study aimed to investigate the direct cost of outpatient care for patients with stroke, as well as the relationship between the aforementioned cost and the sociodemographic and stroke characteristics of the patients. METHODS: This was a cross-sectional study involving patients with first-ever stroke who were attending outpatient stroke rehabilitation, and their family members. Participants were interviewed using a structured questionnaire designed to obtain information regarding the cost of outpatient care. Stroke severity was measured using the National Institute of Health Stroke Scale. RESULTS: This study comprised 49 patients (28 men, 21 women) with a mean age of 60.2 (range 35-80) years. The mean total cost incurred was USD 547.10 (range USD 53.50-4,591.60), of which 36.6% was spent on attendant care, 25.5% on medical aids, 15.1% on travel expenses, 14.1% on medical fees and 8.5% on out-of-pocket expenses. Stroke severity, age > 70 years and haemorrhagic stroke were associated with increased cost. The mean cost of attending outpatient therapy per patient was USD 17.50 per session (range USD 6.60-30.60), with travelling expenses (41.8%) forming the bulk of the cost, followed by medical fees (38.1%) and out-of-pocket expenses (10.9%). Multiple regression analysis showed that stroke severity was the main determinant of post-stroke outpatient care cost (p < 0.001). CONCLUSION: Post-stroke outpatient care costs are significantly influenced by stroke severity. The cost of attendant care was the main cost incurred during the first three months after hospital discharge, while travelling expenses was the main cost incurred when attending outpatient stroke rehabilitation therapy. PMID- 25715858 TI - Glucocorticoids for mitochondrial disorders. PMID- 25715859 TI - Intramedullary compression device for proximal ulna fracture. AB - Proximal ulna fractures account for 20% of all proximal forearm fractures. Many treatment options are available for such fractures, such as cast immobilisation, plate and screw fixation, tension band wiring and intramedullary screw fixation, depending on the fracture pattern. Due to the subcutaneous nature of the proximal forearm, it is vulnerable to open injuries over the dorsal aspect of the proximal ulna. This may in turn prove challenging, as it is critical to obtain adequate soft tissue coverage to reduce the risk of implant exposure and bony infections. We herein describe a patient with a Gustillo III-B open fracture of the proximal ulna, treated with minimally invasive intramedullary screw fixation using a 6.0 mm cannulated headless titanium compression screw (FusiFIX, Peronnas, France). PMID- 25715860 TI - Imaging features of an intraosseous arteriovenous malformation in the tibia. AB - Primary intraosseous arteriovenous malformations (AVMs) are rare and have only been occasionally reported. We herein report a histologically proven case of primary intraosseous AVM in the tibia, which mimicked a fibrous tumour on radiography. This presentation carries a risk of triggering acute large haemorrhage through unnecessary biopsy. In intraosseous AVM, the magnetic resonance (MR) imaging features typical of a soft tissue AVM are absent, making diagnosis difficult. In this report, peculiar MR features in the presence of a connecting vessel between the normal deep venous system of the lower extremity and the tumour provide a clue for the early diagnosis of primary intraosseous AVM. PMID- 25715861 TI - Cerebrovascular ischaemia after carbon monoxide intoxication. AB - Carbon monoxide intoxication is the most prevalent cause of death from carbon monoxide poisoning. We herein report the case of a 56-year-old man who was found unconscious and smelled of smoke after exposure to carbon monoxide from a heater. He scored 5 on the Glasgow Coma Scale, and had respiratory insufficiency and elevated troponin I, creatine kinase-MB fraction and carboxyhaemoglobin levels. He was treated by mechanical ventilation. After regaining consciousness, brain magnetic resonance imaging showed diffusion restriction in the left occipital lobe; there was a loss of vision (right temporal hemianopsia), which improved by the follow-up session. Carbon monoxide intoxication may cause neurologic and cardiac sequelae, and the initial treatment includes oxygen therapy. Acute carbon monoxide poisoning can cause serious injury to the brain, heart and other organs; the most severe damages that could be inflicted to the brain include cerebral ischaemia and hypoxia, oedema, and neural cell degeneration and necrosis. PMID- 25715862 TI - Spontaneous rupture of the ureter. AB - Spontaneous rupture of the ureter is a very rare condition and usually results from ureteral obstruction by a calculus. Only theoretical mechanisms have been proposed and no possible explanation has yet been reported in the literature. Intravenous contrast-enhanced computed tomography is the most informative study with high sensitivity. Treatment should be individualised, and depends on the state of the patient. Minimally invasive endourological procedures with double-J catheter placement and percutaneous drainage offer excellent results. Conservative management with analgesics and antibiotic coverage may be an alternative to surgery. Herein, we present a case of spontaneous rupture of the proximal ureter with no evidence of an underlying pathological condition. PMID- 25715863 TI - Not all unexplained hypoxia is pulmonary embolism. AB - Acute myocardial infarction is one of the conditions frequently managed in the emergency department. There are many complications associated with right ventricular infarction, and the incidence of right ventricular infarction associated with inferior myocardial infarction is as high as 51% based on electrocardiographic findings. We herein report the case of a 45-year-old Chinese man with inferior myocardial infarction complicated by right ventricular failure. He had hypoxaemia refractory to supplemental oxygen due to an acute right-to-left shunting through a patent foramen ovale (PFO). He underwent coronary angioplasty and closure of the PFO. It is crucial for the attending physician to consider the presence of a right-to-left shunt when there is persistent uncorrectable hypoxaemia despite maximal oxygen supplementation in the setting of right ventricular infarction, as there are clinical implications and certain clinical managing principles that should be applied. PMID- 25715864 TI - A droplet microchip with substance exchange capability for the developmental study of C. elegans. AB - The nematode Caenorhabditis elegans (C. elegans) has been widely used as a multicellular organism in developmental research due to its simplicity, short lifecycle, and its relevance to human genetics and biology. Droplet microfluidics is an attractive platform for the study of C. elegans in integrated mode with flexibility at the single animal resolution. However, it is still challenging to conduct the developmental study of worms within droplets initiating at the L1 larval stage, due to the small size, active movement, and the difficulty in achieving effective substance exchange within the droplets. Here, we present a multifunctional droplet microchip to address these issues and demonstrate the usefulness of this device for investigating post-embryonic development in individual C. elegans initiating at the larval L1 stage. The key components of this device consist of multiple functional units that enable parallel worm loading, droplet formation/trapping, and worm encapsulation in parallel. In particular, it exhibits superior functions in encapsulating and trapping individual larval L1 worms into droplets in a controlled way. Continuous food addition and expulsion of waste by mixing the static worm-in-droplet with moving medium plugs allows for the long-term culture of worms under a variety of conditions. We used this device to investigate the development processes of C. elegans in transgenic strains with deletion and overexpression of the hypoxia inducible factor (HIF-1), a highly conserved transcript factor in regulating an organism's response to hypoxia. This microdevice may be a useful tool for the high throughput analysis of individual worms starting at the larval stage, and facilitates the study of developmental worms in response to multiple drugs or environmental toxins. PMID- 25715865 TI - Accounting for repeat enrollments during an emergency clinical trial: the Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART). AB - OBJECTIVES: The objectives were to describe the frequency of repeat enrollment within a specific exception from informed consent trial testing benzodiazepine treatment of prehospital status epilepticus and to estimate the effect of repeat enrollments on the analysis of the primary outcome. METHODS: This was a secondary analysis of data collected as part of the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), a study comparing intramuscular midazolam to intravenous lorazepam given by paramedics to patients with prehospital status epilepticus. Subjects in RAMPART achieved a successful primary outcome if they had cessation of seizures by the time of emergency department arrival. Data were collected on all subjects, but only the first enrollment for each individual was used in the primary analysis. The patterns of repeat enrollment are described, along with the demographics of these subjects. In addition, an intraclass correlation coefficient (ICC) was estimated to assess the amount of within subject correlation and its effect on the estimated treatment effect when all enrollments are included in the analysis. RESULTS: A total of 1,023 enrollments occurred in RAMPART among 893 unique individuals (range of repeat enrollment observed = two to 14). The ICC for seizure cessation within individual was low at 0.119; when excluding subjects with benzodiazepine crossover, the ICC was 0.094. CONCLUSIONS: In clinical trials of emergency conditions with interval complete resolution, accounting for repeat enrollments is feasible. The RAMPART experience demonstrated that in this setting the within-subject correlation is low and can be accounted for at relatively low statistical cost. PMID- 25715866 TI - Flexibility and protection by design: imbricated hybrid microstructures of bio inspired armor. AB - Inspired by the imbricated scale-tissue flexible armor of elasmoid fish, we design hybrid stiff plate/soft matrix material architectures and reveal their ability to provide protection against penetration while preserving flexibility. Indentation and bending tests on bio-inspired 3D-printed prototype materials show that both protection and flexibility are highly tunable by geometrical parameters of the microstructure (plate inclination angle and volume fraction). We show that penetration resistance can be amplified by a factor of 40, while flexibility decreases in less than 5 times. Different deformation resistance mechanisms are found to govern flexibility (inter-plate matrix shear) versus penetration resistance (localized plate bending) for this microstructural architecture which, in turn, enables separation of these functional requirements in the material design. These experiments identify the tradeoffs between these typically conflicting properties as well as the ability to design the most protective material architecture for a required flexibility, providing new design guidelines for enhanced flexible armor systems. PMID- 25715867 TI - Growth impairment in children with pre-dialysis chronic kidney disease in Japan. AB - BACKGROUND: Growth impairment is a major complication of chronic kidney disease (CKD) in children. However, no cohort studies have examined the growth of Asian children with pre-dialysis CKD. METHODS: We sent cross-sectional surveys to 113 Japanese medical institutions that were treating 447 children with CKD stages 3-5 in 2010 and 2011. Of 447 children included in our survey conducted in 2010, height and CKD stage were evaluable for 297 children in 2011, and height standard deviation score (height SDS) was calculated in these children. RESULTS: Height SDS decreased with increasing CKD stage (P < 0.001) in boys and girls. Height SDS also decreased significantly with increasing CKD stage among patients with congenital anomalies of the kidney and urinary tract (P < 0.001). Risk factors for growth impairment included CKD stages 4 and 5 (relative to stage 3), being small-for-date, and asphyxia at birth. Among children with a height SDS <=-2.0, growth hormone was used in 19.5, 31.0, and 25.0 % of children with CKD stages 3, 4, and 5, respectively. CONCLUSIONS: This prospective cohort study revealed marked growth impairment in Japanese children with CKD stages 3-5 relative to healthy children. CKD-related risk factors for growth impairment included advanced CKD (stages 4 and 5), being small-for-date, and asphyxia at birth. Growth hormone was infrequently used in this cohort of children with pre-dialysis CKD. PMID- 25715868 TI - Association of arginine vasopressin surrogate marker urinary copeptin with severity of autosomal dominant polycystic kidney disease (ADPKD). AB - BACKGROUND: Experimental studies suggest a detrimental role for cyclic adenosine monophosphate (cAMP) and vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). It is unknown, however, whether urinary cAMP and copeptin concentration are associated with disease severity in patients with ADPKD. METHODS: Urinary cAMP (u-cAMP) and copeptin concentration (u-copeptin) were measured by immunoassay in ADPKD patients with CKD stage <=4. We compared our measurements with clinical parameters including estimated glomerular filtration rate (eGFR), total kidney volume (TKV), and height-adjusted TKV (htTKV). Logarithmic transformation of all variables was performed to fulfill the requirement of equal distribution of the residuals. RESULTS: We included 50 patients in this study (24 females and 26 males; mean age: 49.3 years). The median eGFR and TKV were 53.2 ml/min/1.73 m(2) (interquartile range: IQR; 29.4 68.45) and 1138.1 ml (IQR; 814.7-2065.0), respectively. The median u-copeptin level was 12.19 (IQR; 6.91-22.32) ng/ml. Although u-cAMP/u-Cr was not significantly correlated with TKV (R = -0.006, p = 0.967) and eGFR (R = 0.077, p = 0.602), urinary copeptin/u-Cr was statistically associated with the various markers of disease severity in ADPKD [positively with TKV (R = 0.351, p = 0.014), htTKV (R = 0.383, p = 0.008) and negatively with eGFR (R = -0.304, p = 0.036)]. CONCLUSIONS: In ADPKD subjects, a higher u-copeptin is associated with disease progression, suggesting that u-copeptin may be a new surrogate marker to predict renal prognosis in ADPKD. PMID- 25715869 TI - Immobilization of alcohol dehydrogenase onto metal-chelated cryogels. AB - In this presented work, poly(HEMA-GMA) cryogel was synthesized and used for the immobilization of alcohol dehydrogenase. For this, synthesized cryogels were functionalized with iminodiacetic acid and chelated with Zn(2+). This metal chelated cryogels were used for the alcohol dehydrogenase immobilization and their kinetic parameters were compared with free enzyme. Optimum pH was found to be 7.0 for both immobilized and free enzyme preparations, while temperature optima for free and immobilized alcohol dehydrogenase was 25 degrees C. Kinetic constants such as K(m), V(max), and k(cat) for free and immobilized form of alcohol dehydrogenase were also investigated. k(cat) value of free enzyme was found to be 3743.9 min(-1), while k(cat) for immobilized enzyme was 3165.7 min( 1). Thermal stability of the free and immobilized alcohol dehydrogenase was studied and stability of the immobilized enzyme was found to be higher than free form. Also, operational stability and reusability profile of the immobilized alcohol dehydrogenase were investigated. Finally, storage stability of the free and immobilized alcohol dehydrogenase was studied, and at the end of the 60 days storage, it was demonstrated that, immobilized alcohol dehydrogenase was exhibited high stability than that of free enzyme. PMID- 25715870 TI - Relieving the attentional blink in the amblyopic brain with video games. AB - Video game play induces a generalized recovery of a range of spatial visual functions in the amblyopic brain. Here we ask whether video game play also alters temporal processing in the amblyopic brain. When visual targets are presented in rapid succession, correct identification of the first target (T1) can interfere with identification of the second (T2). This is known as the "attentional blink". We measured the attentional blink in each eye of adults with amblyopia before and after 40 hours of active video game play, using a rapid serial visual presentation technique. After videogame play, we observed a ~40% reduction in the attentional blink (identifying T2 200 ms after T1) seen through the amblyopic eye and this improvement in performance transferred substantially to the untrained fellow sound eye. Our experiments show that the enhanced performance cannot be simply explained by eye patching alone, or to improved visual acuity, but is specific to videogame experience. Thus, videogame training might have important therapeutic applications for amblyopia and other visual brain disorders. PMID- 25715871 TI - Hemorrhagic stomatitis in a natural hybrid of Vipera ammodytes * Vipera berus due to inappropriate substrate in terrarium. AB - A natural hybrid of Vipera ammodytes * Vipera berus was presented having low body weight, seizures and generalized swelling of the cephalic region. Based on the history of the case and clinical examination, hemorrhagic stomatitis of traumatic origin was diagnosed. The snake was kept in a terrarium with wood chips as a substrate, and the material had induced trauma in the oral mucosa which was further complicated with Salmonella Arizonae and Morganella morganii co infection, abscessation and osteomyelitis. To the best of the authors' knowledge, this is the first reported case of bacterial infection in European snake hybrids and one of a few case reports in European snakes. Although wood chips are an inexpensive substrate, based on our findings, they should be avoided when keeping and breeding European vipers. PMID- 25715873 TI - Orthogonal femoral plating: a biomechanical study with implications for interprosthetic fractures. AB - OBJECTIVES: This study tests the biomechanical properties of adjacent locked plate constructs in a femur model using Sawbones. Previous studies have described biomechanical behaviour related to inter-device distances. We hypothesise that a smaller lateral inter-plate distance will result in a biomechanically stronger construct, and that addition of an anterior plate will increase the overall strength of the construct. METHODS: Sawbones were plated laterally with two large fragment locking compression plates with inter-plate distances of 10 mm or 1 mm. Small-fragment locking compression plates of 7-hole, 9-hole, and 11-hole sizes were placed anteriorly to span the inter-plate distance. Four-point bend loading was applied, and the moment required to displace the constructs by 10 mm was recorded. RESULTS: We found that a 1 mm inter-plate distance supported greater moments than a 10 mm distance in constructs with only lateral plates. Moments supported after the addition of a 9- or 11-hole anterior plate were greater for both 10 mm and 1 mm inter-plate distance, with the 11-hole anterior plate supporting a greater moment than a 9-hole plate. Femurs with a 7-hole anterior plate fractured regardless of lateral inter-plate distance size. CONCLUSION: This suggests that the optimal plate configuration is to minimise lateral inter-plate distance and protect it with an anterior plate longer than seven holes. Cite this article: Bone Joint Res 2015;4:23-8. PMID- 25715874 TI - SNORD76, a box C/D snoRNA, acts as a tumor suppressor in glioblastoma. AB - Glioblastoma (GBM) is associated with disproportionately high morbidity and mortality, reflecting the need to develop new diagnostic and therapeutic targets for this disease. Recently, accumulating evidence has suggested that small nucleolar RNAs (snoRNAs) are gaining prominence and are more actively involved in tumorigenesis than previously thought. However, no report concerning the implication of snoRNAs in glioma has been published to date. In our study, SNORD76 was first found to be inversely associated with Hox Transcript Antisense Intergenic RNA (HOTAIR) knockdown, and surprisingly, forcibly expressed SNORD76 inhibited proliferation and growth of glioma cells. Moreover, downregulation of SNORD76 led to a more malignant phenotype. The pleiotropy of SNORD76 overexpression could be achieved at least partially through inducing cell cycle arrest at S phase by affecting the Rb-associated cell cycle regulation. Enforced SNORD76 expression in orthotopic tumors resulted in decreased tumor growth and the reduction of tumor volume. Additionally, in surgically resected glioma tissues, SNORD76, not its host gene, was associated with the WHO classification and was selectively downregulated in GBM (WHO grade IV). Collectively, our study adds to a growing body of evidence for the participation of snoRNAs in gliomagenesis and is the first to implicate a snoRNA in glioblastoma. PMID- 25715875 TI - Comparative functional anatomy of hindlimb muscles and bones with reference to aquatic adaptation of the sea otter. AB - Although the sea otter (Enhydra lutris) is a complete aquatic species, spending its entire life in the ocean, it has been considered morphologically to be a semi aquatic animal. This study aimed to clarify the unique hindlimb morphology and functional adaptations of E. lutris in comparison to other Mustelidae species. We compared muscle mass and bone measurements of five Mustelidae species: the sea otter, Eurasian river otter (Lutra lutra), American mink (Neovison vison), Japanese weasel (Mustela itatsi) and Siberian weasel (M. sibirica). In comparison with the other 4 species, E. lutris possessed significantly larger gluteus, popliteus and peroneus muscles, but smaller adductor and ischiopubic muscles. The popliteus muscle may act as a medial rotator of the crus, and the peroneus muscle may act as an abductor of the fifth toe and/or the pronator of the foot. The bundles of the gluteus superficialis muscle of E. lutris were fused with those of the tensor fasciae latae muscle and gluteofemoralis muscles, and they may play a role in femur abduction. These results suggest that E. lutris uses the abducted femur, medially rotated crus, eversion of the ankle and abducted fifth digit or extended interdigital web as a powerful propulsion generator. Therefore, we conclude that E. lutris is a complete aquatic animal, possessing differences in the proportions of the hindlimb muscles compared with those in other semi-aquatic and terrestrial mustelids. PMID- 25715872 TI - Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective cohort study. AB - INTRODUCTION: The aim of this study was to investigate current mobilization practice, strength at ICU discharge and functional recovery at 6 months among mechanically ventilated ICU patients. METHOD: This was a prospective, multi centre, cohort study conducted in twelve ICUs in Australia and New Zealand. Patients were previously functionally independent and expected to be ventilated for >48 hours. We measured mobilization during invasive ventilation, sedation depth using the Richmond Agitation and Sedation Scale (RASS), co-interventions, duration of mechanical ventilation, ICU-acquired weakness (ICUAW) at ICU discharge, mortality at day 90, and 6-month functional recovery including return to work. RESULTS: We studied 192 patients (mean age 58.1 +/- 15.8 years; mean Acute Physiology and Chronic Health Evaluation (APACHE) (IQR) II score, 18.0 (14 to 24)). Mortality at day 90 was 26.6% (51/192). Over 1,351 study days, we collected information during 1,288 planned early mobilization episodes in patients on mechanical ventilation for the first 14 days or until extubation (whichever occurred first). We recorded the highest level of early mobilization. Despite the presence of dedicated physical therapy staff, no mobilization occurred in 1,079 (84%) of these episodes. Where mobilization occurred, the maximum levels of mobilization were exercises in bed (N = 94, 7%), standing at the bed side (N = 11, 0.9%) or walking (N = 26, 2%). On day three, all patients who were mobilized were mechanically ventilated via an endotracheal tube (N = 10), whereas by day five 50% of the patients mobilized were mechanically ventilated via a tracheostomy tube (N = 18). CONCLUSIONS: Early mobilization of patients receiving mechanical ventilation was uncommon. More than 50% of patients discharged from the ICU had developed ICU-acquired weakness, which was associated with death between ICU discharge and day-90. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01674608. Registered 14 August 2012. PMID- 25715876 TI - David Lloyd: wants to create a "Kaiser Harrow". PMID- 25715877 TI - In the performing art of medicine: the doctor as actor. PMID- 25715878 TI - Increased risk of revision of cementless stemmed total hip arthroplasty with metal-on-metal bearings. AB - BACKGROUND AND PURPOSE: Data from the national joint registries in Australia and England and Wales have revealed inferior medium-term survivorship for metal-on metal (MoM) total hip arthroplasty (THA) than for metal-on-polyethylene (MoP) THA. Based on data from the Nordic Arthroplasty Register Association (NARA), we compared the revision risk of cementless stemmed THA with MoM and MoP bearings and we also compared MoM THA to each other. PATIENTS AND METHODS: We identified 32,678 patients who were operated from 2002 through 2010 with cementless stemmed THA with either MoM bearings (11,567 patients, 35%) or MoP bearings (21,111 patients, 65%). The patients were followed until revision, death, emigration, or the end of the study period (December 31, 2011), and median follow-up was 3.6 (interquartile range (IQR): 2.4-4.8) years for MoM bearings and 3.4 (IQR: 2.0 5.8) years for MoP bearings. Multivariable regression in the presence of competing risk of death was used to assess the relative risk (RR) of revision for any reason (with 95% confidence interval (CI)). RESULTS: The cumulative incidence of revision at 8 years of follow-up was 7.0% (CI: 6.0-8.1) for MoM bearings and 5.1% (CI: 4.7-5.6) for MoP bearings. At 6 years of follow-up, the RR of revision for any reason was 1.5 (CI: 1.3-1.7) for MoM bearings compared to MoP bearings. The RR of revision for any reason was higher for the ASR (adjusted RR = 6.4, CI: 5.0-8.1), the Conserve Plus (adjusted RR = 1.7, CI: 1.1-2.5) and "other" acetabular components (adjusted RR = 2.4, CI: 1.5-3.9) than for MoP THA at 6 years of follow-up. INTERPRETATION: At medium-term follow-up, the survivorship for cementless stemmed MoM THA was inferior to that for MoP THA, and metal related problems may cause higher revision rates for MoM bearings with longer follow-up. PMID- 25715880 TI - Does ear keloid formation depend on the type of earrings or piercing jewellery? AB - The ear is one of the most common sites of keloid formation, usually associated with the wearing of earrings. However, although this is a small perforating lesion that is equal on both sides, keloids are bigger and more prevalent on the posterior surface. In this study, 141 keloids were evaluated, most of which were located on the posterior surface of the earlobe and caused by the piercing of the ear. Most of the earrings and piercing jewellery used had metallic backs. The more frequent occurrence of earlobe keloids on the posterior surface of the ear therefore may be associated with the exacerbation of local neurogenic inflammation caused by the metallic backs. PMID- 25715879 TI - Endogenous Retinoic Acid Required to Maintain the Epidermis Following Ultraviolet Light Exposure in SKH-1 Hairless Mice. AB - Ultraviolet light B (UVB) exposure induces cutaneous squamous cell carcinoma (cSCC), one of the most prevalent human cancers. Reoccurrence of cSCC in high risk patients is prevented by oral retinoids. But oral retinoid treatment causes significant side effects; and patients develop retinoid resistance. Exactly how retinoids prevent UVB-induced cSCC is currently not well understood. Retinoid resistance blocks mechanistic studies in the leading mouse model of cSCC, the UVB exposed SKH-1 hairless mouse. To begin to understand the role of retinoids in UVB induced cSCC we first examined the localization pattern of key retinoid metabolism proteins by immunohistochemistry 48 h after UVB treatment of female SKH-1 mice. We next inhibited retinoic acid (RA) synthesis immediately after UVB exposure. Acute UVB increased RA synthesis, signaling and degradation proteins in the stratum granulosum. Some of these proteins changed their localization; while other proteins just increased in intensity. In contrast, acute UVB reduced the retinoid storage protein lectin:retinol acyltransferase (LRAT) in the epidermis. Inhibiting RA synthesis disrupted the epidermis and impaired differentiation. These data suggest that repair of the epidermis after acute UVB exposure requires endogenous RA synthesis. PMID- 25715881 TI - Macular amyloidosis: a case report with scanning electron microscopy. PMID- 25715882 TI - No evidence in favor of a more deleterious impact of a major depressive episode on verbal memory in older patients with antidepressant response. AB - BACKGROUND: Older patients may be more vulnerable to the deleterious effect of depressive episodes on delayed narrative memory, a cognitive task which reflects hippocampal activity. We aimed to disentangle which factors could explain such increased vulnerability in the elderly, including the poorer response to treatment, a longer lifetime exposure to past depressive episodes, and lower baseline memory skills. METHODS: From an initial sample of 8,229 depressed outpatients, we focused on the 2,424 treatment responders, and compared older (65 years old and over, N = 233) to younger (N = 2,191) ones. These patients were included through general practitioners' assessment and tested for the Wechsler delayed paragraph recall index, a valid and sensitive test assessing verbal declarative memory (and a marker of the hippocampal function), at baseline and after six weeks of treatment. RESULTS: As expected, older patients after response to antidepressants showed decreased narrative memory abilities compared to younger ones. As baseline memory performance and residual depressive symptoms were also found in excess in this sample, they could act as confounders. Indeed, after controlling for these two factors, the role of age in memory performance after treatment response was ruled out. CONCLUSIONS: The potential "toxicity" of a depressive episode to cognitive functions related to the hippocampus may not be more critical in older patients compared to younger ones. Limiting remaining depressive symptoms in older depressed patients might be a way to counteract the observed worsening of memory functions in depressed patients. PMID- 25715883 TI - Trends in incidence of primary brain cancer in New Zealand, 1995 to 2010. AB - OBJECTIVE: Case-control studies have linked mobile phone use to an increased risk of glioma in the most exposed brain areas, the temporal and parietal lobes, although inconsistently. We examined time trends in the incidence rates of brain malignancies in New Zealand from 1995 to 2010. METHODS: Data from the New Zealand Cancer Registry was used to calculate incidence rates of primary brain cancer, by age, gender, morphology and anatomical site. Log-linear regression analysis was used to assess trends in the annual incidence of primary brain cancer; annual percentage changes and their 95% confidence intervals were estimated. RESULTS: No consistent increases in all primary brain cancer, glioma, or temporal or parietal lobe glioma were seen. At ages 10-69, the incidence of all brain cancers declined significantly. Incidence of glioma increased at ages over 70. CONCLUSION: In New Zealand, there has been no consistent increase in incidence rates of primary brain cancers. An increase in glioma at ages over 70 is likely to be due to improvements in diagnosis. As with any such studies, a small effect, or one with a latent period of more than 10 to 15 years, cannot be excluded. PMID- 25715885 TI - Electrical switch for smart pH self-adjusting system based on silver nanowire/polyaniline nanocomposite film. AB - A sensitive pH-triggered electrical switch is demonstrated by using a layer structured silver nanowire/polyaniline nanocomposite film fabricated via an easy vertical spinning method. The as-prepared nanocomposite film shows the high electrical conductivity of 1.03 * 10(4) S cm(-1) at the Ag-NW areal density of 0.84 mg cm(-2) and a good cycling stability. Particularly, because of the layered structure, the switch achieves a very high contrast ratio of ca. 9 * 10(8), which is 2-6 orders higher than that reported previously. The high electrical conductivity and the high switching ratio make the layer-structured nanocomposite film a sensitive switch candidate for pH-responsive systems. Finally, a smart pH self-adjusting switching system is successfully designed using the as-prepared layer-structured nanocomposite film. PMID- 25715884 TI - Does ketamine have anti-suicidal properties? Current status and future directions. AB - Ketamine, a widely used anesthetic agent, is currently being investigated as a novel therapeutic for depression and suicidality. Ketamine has garnered substantial attention from researchers, clinicians, media outlets, and patients alike, but numerous questions remain. One of the compelling features of ketamine is the rapidity of its antidepressant effects, which peak just 24 h after infusion, setting it apart from other existing treatments. Ketamine's rapid time course has inspired research efforts to explore its potential as a life-saving therapy for patients at imminent risk of suicide. In this article, we review current evidence supporting the rapid effects of ketamine on suicidal ideation in the context of unipolar and bipolar depression. We then discuss several future directions that are necessary before ketamine can be considered a viable treatment option for suicidality in clinical settings. These include: testing for a specific anti-suicidal effect-separate from overall antidepressant effects-to ascertain whether ketamine might hold promise for a broader class of suicidal patients; ensuring that acute benefits of ketamine can be prolonged over a clinically meaningful timeframe; and developing a better understanding of the mechanisms by which ketamine might reduce suicide risk. Such efforts will enable the field to more accurately assess the potential of ketamine, as well as its limitations, allowing for appropriate placement within the context of comprehensive clinical care for suicide prevention. PMID- 25715886 TI - Clinical diagnosis of rabies in a patient with schizophrenia. PMID- 25715887 TI - Guideline of Guidelines: Imaging of Localized Prostate Cancer. PMID- 25715888 TI - A Farm Transmission Model for Salmonella in Pigs, Applicable to E.U. Member States. AB - The burden of Salmonella entering pig slaughterhouses across the European Union is considered a primary food safety concern. To assist E.U. member states with the development of national control plans, we have developed a farm transmission model applicable to all member states. It is an individual-based stochastic susceptible-infected model that takes into account four different sources of infection of pigs (sows, feed, external contaminants such as rodents, and new stock) and various management practices linked to Salmonella transmission/protection (housing, flooring, feed, all-in-all-out production). A novel development within the model is the assessment of dynamic shedding rates. The results of the model, parameterized for two case study member states (one high and one low prevalence) suggest that breeding herd prevalence is a strong indicator of slaughter pig prevalence. Until a member state's' breeding herd prevalence is brought below 10%, the sow will be the dominant source of infection to pigs raised for meat production; below this level of breeding herd prevalence, feed becomes the dominant force of infection. PMID- 25715889 TI - Cation Effects on the Electron-Acceptor Side of Photosystem II. AB - The normal pathway of electron transfer on the electron-acceptor side of photosystem II (PSII) involves electron transfer from quinone A, QA, to quinone B, QB. It is possible to redirect electrons from QA(-) to water-soluble Co(III) complexes, which opens a new avenue for harvesting electrons from water oxidation by immobilization of PSII on electrode surfaces. Herein, the kinetics of electron transfer from QA(-) to [Co(III)(terpy)2](3+) (terpy = 2,2';6',2"-terpyridine) are investigated with a spectrophotometric assay revealing that the reaction follows Michaelis-Menten saturation kinetics, is inhibited by cations, and is not affected by variation of the QA reduction potential. A negatively charged site on the stromal surface of the PSII protein complex, composed of glutamic acid residues near QA, is hypothesized to bind cations, especially divalent cations. The cations are proposed to tune the redox properties of QA through electrostatic interactions. These observations may thus explain the molecular basis of the effect of divalent cations like Ca(2+), Sr(2+), Mg(2+), and Zn(2+) on the redox properties of the quinones in PSII, which has previously been attributed to long range conformational changes propagated from divalent cations binding to the Ca(II)-binding site in the oxygen-evolving complex on the lumenal side of the PSII complex. PMID- 25715890 TI - Predicting operative duration and implications for list planning: a retrospective analysis of data from 85 adults and 72 children undergoing tonsillectomy: Our Experience. PMID- 25715891 TI - [In Process Citation]. PMID- 25715892 TI - [Assessment of drinking water quality in Avellino (Italy) by multivariate analysis]. AB - The aim of this study was to assess the quality of the drinking water supply in the district of Avellino (Italy), by evaluating physico-chemical parameters and presence of contaminants. A multivariate approach was used to analyse data and to evaluate compliance to norms and standards. Study results indicate that statistical modeling is a powerful descriptive method to identify qualitative temporal trends in water quality and, if repeated in time, allows an evaluation of representativeness of the sampling points. PMID- 25715893 TI - [Evaluating the quality of organization of nursing care in a hospital in Turin (Italy): a pilot study]. AB - Evaluating the quality of organization of nursing activities is essential to improve hospital care delivery. The aim of this pilot study was to develop and test a tool for measuring this aspect of quality of care. A working group developed an assessment instrument by identifying thirteen items to be evaluated and their relevant criteria, indicators, standards and methods of evaluation. The instrument was tested in eight wards of the S. Giovanni Bosco Hospital in Turin (Italy) and, on the basis of assessment results, the working group designed interventions for improvement. The assessment instrument tested was found to be user -friendly and shown to be an effective tool for evaluating the organizational quality of care in a standardized and repeatable manner, and for highlighting areas of concern and identifying possible solutions for improvement. PMID- 25715894 TI - [Epidemiology of third molar extractions: the experience of the S.G.C. Fatebenefratelli Hospital in Rome (Italy)]. AB - The extraction of third molars (wisdom teeth) is one of the main surgical procedures performed in dentistry. The aim of this study was to describe the characteristics of patients undergoing the procedure in the SGC Fatebenefratelli Hospital, a large hospital in Rome (Italy), where about 20% of all third molar extractions in the Lazio Region are performed. Hospital discharge forms were analysed for patients discharged in the years 2010 and 2011 with a Diagnosis Related Group (DRG) code 169, used for the procedure. Study results indicate that the extraction of third molars is a relevant public health issue considering its frequency and associated yearly costs at the national level. The appropriateness of third molar extraction, especially when performed prophylactically in young persons, should be further explored. PMID- 25715895 TI - [The integration of behavioral, social and environmental interventions in active prevention programmes: the case of childhood obesity]. AB - Childhood obesity is one of the most important issues in Public Health so that the adoption of innovative preventive integrated approaches is increasingly needed. The presence of coordinated and integrated programmes, aimed at preventing childhood obesity and based on innovative large-scale approaches, was ascertained by means of a literature search. In Europe three programmes, with activities and staff characterized by common aims and active participation of different stakeholders, use such a community-based approach, which allowed changes in physical and social environment, resulting in new and innovative elements for lifestyle modifications. PMID- 25715896 TI - The private healtcare systems in europe. What can we learn from Russia? AB - The European healthcare system is characterized by different kinds of funding: public, insurance-based, and mixed. In Italy, the prolonged economic crisis and the need for a cost reduction in the public administrations make necessary a cut in expenditure, which has a significant impact also on the funding of the healthcare system. The comparison of different European healthcare systems may offer useful insights for a better definition of the European and / or national healthcare provision strategies, which would be economically and financially sustainable but also capable to protect the population health. In this regard, it is worth to analyze the Russian healthcare system, which in the last years has undergone significant changes in its structure and in the way healthcare services are supplied. The peculiarity of the Russian healthcare system, which is quite different from the European standards for both professional requirements and theoretical knowledge, makes Russia an absolutely interesting partner for a future joint venture research. This paper describes the Russian national healthcare system highlights the differences in the demographic and socio economic structures relatively to the Italian model. The paper supports a reflection on the sustainability of the health care systems and on the organizational forms that would guarantee the supply of better healthcare services in terms of quality, appropriateness and safety, compatibly with its economic sustainability. PMID- 25715897 TI - [Relaunching primary healthcaree]. AB - The health environment today is characterized by diffuse inequalities, the emergence of chronic diseases, and the introduction of new technologies, all of which, together with other factors are leading to a healthcare system that is becoming increasingly less sustainable from a financial point of view. Primary healthcare, public health and hospitals should work together to define a comprehensive healthcare delivery model characterized by continuity of care, information and management. The proposed model of disease management, in particular of chronic diseases, must reorganize health services around the needs of citizens and the community and involve patients and their families in the disease management process, by promoting self-help groups and patient organizations that cooperate with health services. In order to put this change into effect, evidence-based medicine and evidence-based practice need to be adopted. From an organizational point of view, it will be important to change wage rules, so as to implement a new payment system based upon performance. In this new contest, physicians specialized in hygiene and public health can play an important role that includes leadership, governance and coordination. By integrating the concepts of accountability, community intervention and training, we can acquire the tools to change the current hospital-based system to a new model of primary healthcare that works together with the community to move the focus from healthcare provider to patient. PMID- 25715898 TI - [Attitude and compliance towards influenza vaccination among health care workersin two Italian hospitals after a vaccination promotion campaign]. AB - In the season 2013-2014, a campaign to promote influenza vaccination among health care workers (HCWs) was conducted in two Italian hospitals, based on an educational toolkit and attitude and compliance towards vaccination were investigated. Overall, 36% of the HCWs get vaccinated almost once, 2.3% in 2013 14 season for the first time, 57% never, 7% do not know or not remember. The main reason for vaccination was reportedly to avoid taking sick-leave (29.7%); while refusal was guided by the low risk-perception associated with influenza (38.5%). Interventions based only on education and communication seem not to be sufficient; an integrated approach with multiple components is needed to achieve higher coverage rates and to ensure a successful vaccination campaign. PMID- 25715899 TI - Visibility and variability of pleural fissures on normal digital chest radiographs of 1,000 healthy adults. AB - PURPOSE: To investigate the visibility and variability of pleural fissures on digital chest radiographs. METHODS: Posteroanterior digital chest radiographs of 566 males and 434 females were retrospectively reviewed for the frequencies and/or appearances of various pleural fissures. RESULTS: The right only, left only and bilateral minor fissures were visible in 722 (72.2 %), 1 (0.1 %) and 7 (0.7 %) subjects, respectively. The right minor fissures were visible as more than one line in 219 (30.0 %) subjects, i.e., 2, 3 and 4 lines in 214 (29.3 %), 4 (0.5 %) and 1 (0.1 %), respectively. The 955 visible right minor fissures exhibited variable length (<1/3 of right hemithorax, 17.8 %; 1/3-2/3, 60.1 %; >2/3, 22.1 %), alignment (medial higher 40.9 %; lateral higher 54.2 %; horizontal 4.8 %) and contour (convex upward 68.6 %; convex downward 2.7 %; flat 24.9 %; sigmoid 3.8 %). Superolateral major fissures were visualized in 14.8 % (right only 3.0 %; left only 9.0 %; bilateral 2.8 %), superomedial major fissures in 0.3 % (right 0.1 %; left 0.2 %), vertical fissures in 0.5 % (right 0.2 %; left 0.3 %), inferior accessory fissures in 5.4 % (right 4.8 %; left 0.6 %), right superior accessory fissures in 1.2 % and azygos fissures in 0.2 %. CONCLUSION: The right minor fissure was most frequently visible and exhibited variable appearances. Other pleural fissures were occasionally seen. PMID- 25715900 TI - Incidence, management, and outcome of high-grade transformation of nodular lymphocyte predominant Hodgkin lymphoma: long-term outcomes from a 30-year experience. AB - Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare form of Hodgkin lymphoma that typically presents as early stage, indolent disease in young adult males. The relationship between NLPHL and DLBCL is incompletely understood, and there remains a paucity of data with regard the incidence and management of high grade transformation. We report the largest study to date describing the incidence, management and long-term outcome of 26 cases of high-grade transformation of NLPHL over a 30-year period. We report a transformation incidence of 17.0%. Bone marrow, splenic, and liver infiltration with DLBCL was frequent. Patients with an aa-IPI 2-3 have poorer OS and PFS (P = 0.034 and P = 0.009, respectively). Although the approach to treatment was somewhat variable, typically young, otherwise fit patients received anthracycline-based induction, platinum-based consolidation with stem cell harvesting, followed by autologous SCT with BEAM conditioning. Long-term (5 year) PFS was over 60% with this approach, and comparable to our de novo DLBCL historical age and time period matched cohort largely treated with CHOP-like chemotherapy alone. The transformation rate of 17.0% highlights the importance of accurate initial diagnosis, long-term follow-up, and re-biopsy at relapse. PMID- 25715901 TI - Educational Status, Anger, and Inflammation in the MIDUS National Sample: Does Race Matter? AB - BACKGROUND: Racial differences in anger frequency and expression styles have been found. Further, African Americans receive fewer health benefits from higher education than Whites. PURPOSE: This study seeks to investigate racial differences in how anger moderates the association between education and inflammation. METHODS: Midlife in the US participants (n = 1,200; 43.0 % male; 18.5 % African American) provided education and anger data via survey assessments. Interleukin-6 (IL-6) and fibrinogen were determined from a fasting blood sample following an overnight clinic visit. RESULTS: African Americans reported higher anger-out, IL-6, and fibrinogen and lower anger-control than Whites. Anger-out predicted higher IL-6 and fibrinogen among African Americans with higher education; whereas, trait anger and anger-out predicted lower fibrinogen among Whites with higher education. Anger-out marginally predicted higher IL-6 in less educated Whites. CONCLUSIONS: Findings underscore racial differences in the benefits and consequences of educational attainment, and how social inequities and anger are manifested in inflammatory physiology. PMID- 25715902 TI - A comparative efficacy evaluation of ultrasound-guided pulsed radiofrequency treatment in the gastrocnemius in managing plantar heel pain: a randomized and controlled trial. AB - OBJECTIVE: The treatment of plantar heel pain is highly challenging. We report ultrasound-guided pulsed radiofrequency treatment (UG-PRF) in the gastrocnemius to treat plantar heel pain and minimize the safety issues. DESIGN: This study compared UG-PRF with sham treatment in 100 patients with plantar heel pain. Primary outcome measures include the pain subscale of the Foot Health Status Questionnaire (FHSQ-pain) and "first step" pain as measured on a visual analogue scale (VAS-"first-step" pain). The secondary outcome measures include the FHSQ foot function and general foot health, and health related quality of life (assessed using the Short Form-36 questionnaire [SF-36]). All outcomes were measured at 3 and 6 months post-treatment. RESULTS: The results showed the efficacy of UG-PRF in terms of pain management, as reflected by higher FHSQ-pain score (increased by 20.0 (P < 0.0001) and 17.9 (P = 0.001) compared with the sham treatment at 3 or 6 months, respectively) and lower VAS-"first-step" pain (reduced by 26.1 (P < 0.0001) and 14.3 (P = 0.01) compared with the sham group at 3 or 6 months, respectively). The FHSQ-foot function and FHSQ-general foot health were increased by the UG-PRF (P < 0.05, vs sham treatment at 3 or 6 months). The SF-36 physical component score in the sham group was 10.8 (P = 0.042) and 10.4 (P = 0.044) lower than the UG-PRF group at 3 or 6 months, respectively. No severe complications were observed. CONCLUSIONS: We conclude that the UG-PRF is both safe and efficacious in managing plantar heel pain. PMID- 25715903 TI - Eating and Feeding at the Margins of the State: Barriers to Health Care for Undocumented Migrant Women and the "Clinical" Aspects of Food Assistance. AB - In this article, I examine the various meanings of Mexican and Central American migrant women's utilization of private food assistance programs. I present findings from 20 months of ethnographic fieldwork conducted between 2008 and 2011 with migrant women, public health workers, and staff and volunteers of food assistance programs in Santa Barbara County, California. I discuss the barriers undocumented women face in accessing formal health care and the social and moral obligations that underpin these women's role in feeding others. I also document the ways in which private food assistance programs are orienting toward a focus on health in service delivery, and how women depend on provisions from these programs to support feeding practices at home. I argue that these findings are significant for current engagement by critical medical anthropologists in studying framings of "the clinic" and cultural beliefs about "deservingness." PMID- 25715904 TI - Assessment of glutamate in striatal subregions in obsessive-compulsive disorder with proton magnetic resonance spectroscopy. AB - Glutamatergic signaling abnormalities in cortico-striatal circuits are hypothesized to lead to the repetitive thoughts and behaviors of obsessive compulsive disorder (OCD). To test this hypothesis, studies have used proton magnetic resonance spectroscopy (1H MRS) to measure glutamatergic compounds in the striatum of individuals with OCD. However, no studies have used methods that could measure glutamate minimally contaminated by glutamine and gamma aminobutyric acid (GABA) in striatal subregions. Therefore, in this study, a proton MRS imaging (1H MRSI) technique with relatively high spatial resolution at 3.0 T was used to measure minimally contaminated glutamate levels in three striatal subregions (i.e., dorsal caudate, dorsal putamen, and ventral striatum) in 15 unmedicated adults with OCD and 16 matched healthy control subjects. No significant group differences in glutamate levels were found in any of the three striatal subregions. In contrast, a study in unmedicated pediatric OCD patients that measured glutamatergic compounds in the dorsal caudate by MRS at 1.5 T found significant elevations. Further studies are warranted to assess whether these discrepant MRS findings are due to differences in subject age or MRS methodology, or potentially are associated with glutamatergic gene variants implicated in OCD. PMID- 25715905 TI - Assessing the anticoagulant effect of dabigatran in children: an in vitro study. AB - OBJECTIVES: Age-related changes in the hemostatic system result in variation in response to anticoagulants and coagulation assays over childhood. This study used in vitro methods to determine i) optimum coagulation assays for dabigatran in children and ii) anticoagulant effect of dabigatran across pediatric age groups. MATERIALS AND METHODS: Pooled plasma samples from healthy children aged 0 to <1, 1 to <5, 5 to <10, 10 to <17 years and adults were spiked with increasing concentrations of dabigatran and the effect was assessed in five coagulation assays. The samples were also assessed for overall hemostasis potential using a fibrin clot formation and lysis assay. RESULTS: In all five coagulation assays, there were no differences in responses to dabigatran over all pediatric age groups. The international normalized ratio was the least sensitive measure. Activated partial thromboplastin time showed moderate sensitivity and a nonlinear response curve. Thrombin time (TT), dilute TT (dTT) and ecarin clotting time were linearly correlated with dabigatran concentrations; however, the ecarin time and TT were overly sensitive. In the overall hemostasis potential assay, increasing dabigatran concentrations delayed the initiation of clot formation and reduced the time to 50% clot lysis. The responses to initiation of clot formation and clot lysis were consistent across all pediatric groups and comparable to responses in adults. CONCLUSION: The dTT is the most suitable assay for measuring dabigatran concentrations in children. Fibrin clot generation and lysis assay responses to dabigatran in children over all ages were consistent and comparable to those of adults. PMID- 25715906 TI - Reactions of cytotoxic metallodrugs with lysozyme in pure DMSO explored through UV-Vis absorption spectroscopy and ESI MS. AB - The reactions of four representative metallodrugs with the model protein HEWL were investigated within a non-aqueous environment-i.e. in pure DMSO- through UV Vis absorption spectroscopy and ESI MS analysis. Notably, formation of a variety of metallodrug-protein adducts was clearly documented. This is the first example for this kind of protein metalation reactions carried out within a pure organic solvent. It is shown that the applied solution conditions greatly affect the nature of the formed adducts, this being well accounted for by the fact that the overall protein conformation is greatly perturbed within pure DMSO; in addition, the activation profiles of the studied metallodrugs are also highly dependent on the nature of the solvent. The implications of these results are discussed. PMID- 25715907 TI - Design and photovoltaic characterization of dialkylthio benzo[1,2-b:4,5 b']dithiophene polymers with different accepting units. AB - Three dialkylthio benzo[1,2-b:4,5-b']dithiophene (S-BDT) based polymers have been developed using different accepting units to tune their bandgaps. The polymer:PC71BM solar cells achieved the highest power conversion efficiency (PCE) of 4.51% without any post-treatment (such as annealing and solvent additive) in conventional single-cell devices. Joint photophysical, electrical and computational studies on the polymer based solar cells revealed the considerable impact of molecular planarity on polymer design. The polymer:PC71BM devices processed with 1,8-diiodooctane for improving their morphology afforded an improved PCE value of 5.63%, with a Voc of 0.83, a Jsc of 10.24 mA cm(-2) and a FF of 66.3%. PMID- 25715908 TI - Adult neurogenesis: a substrate for experience-dependent change. AB - A rapidly growing body of literature indicates that adult neurogenesis in the hippocampus is sensitive to a variety of environmental factors. The effects of emotionally salient experiences, such as stress and physical exercise, have been characterized extensively with regard to both adult neurogenesis and behaviors associated with the hippocampus. Experience-dependent changes in the production and function of new neurons may serve as a means to fine-tune the hippocampus to the predicted environment. Here, we discuss this possibility along with the argument that more naturalistic experimental conditions may be a necessary step toward understanding the adaptive significance of neurons born in the adult brain. PMID- 25715909 TI - Slow digestion property of octenyl succinic anhydride modified waxy maize starch in the presence of tea polyphenols. AB - The in vivo slow digestion property of octenyl succinic anhydride modified waxy corn starch (OSA-starch) in the presence of tea polyphenols (TPLs) was studied. Using a mouse model, the experimental results showed an extended and moderate postprandial glycemic response with a delayed and significantly decreased blood glucose peak of OSA-starch after cocooking with TPLs (5% starch weight base). Further studies revealed an increased hydrodynamic radius of OSA-starch molecules indicating an interaction between OSA-starch and TPLs. Additionally, decreased gelatinization temperature and enthalpy and reduced viscosity and emulsifiability of OSA-starch support their possible complexation to form a spherical OSA-starch TPLs (OSAT) complex. The moderate and extended postprandial glycemic response is likely caused by decreased activity of mucosal alpha-glucosidase, which is noncompetitively inhibited by tea catechins released from the complex during digestion. Meanwhile, a significant decrease of malondialdehyde (MDA) and increased DPPH free radical scavenging activity in small intestine tissue demonstrated the antioxidative functional property of the OSAT complex. Thus, the complex of OSAT, acting as a functional carbohydrate material, not only leads to a flattened and prolonged glycemic response but also reduces the oxidative stress, which might be beneficial to health. PMID- 25715911 TI - Isolating the independent influence of body fat on thermoregulatory responses to exercise. PMID- 25715910 TI - The role of cannabinoids in regulation of nausea and vomiting, and visceral pain. AB - Marijuana derived from the plant Cannabis sativa has been used for the treatment of many gastrointestinal (GI) disorders, including anorexia, emesis, abdominal pain, diarrhea, and others. However, its psychotropic side effects have often limited its use. Several cannabinoid receptors, which include the cannabinoid receptor 1 (CB1), CB2, and possibly GPR55, have been identified throughout the GI tract. These receptors may play a role in the regulation of food intake, nausea and emesis, gastric secretion and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation, and cell proliferation in the gut. However, the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system has shed new knowledge in this field. Thus far, despite evidence of visceral sensitivity inhibition in animal models, data in irritable bowel syndrome (IBS) patients is scarce and not supportive. Furthermore, many compounds that either act directly at the receptor or increase (or reduce) ligand availability have the potential to affect other brain functions and cause side effects. Novel drug targets such as FAAH and monoacylglycerol lipase (MAGL) inhibitors appear to be promising in animal models, but more studies are necessary to prove their efficiency. The promise of emerging drugs that are more selective and peripherally acting suggest that, in the near future, cannabinoids will play a major role in managing an array of GI diseases. PMID- 25715912 TI - Response. PMID- 25715914 TI - Erratum to: variants within the MMP3 gene and patellar tendon properties in vivo in an asymptomatic population. PMID- 25715913 TI - Heart rate variability and critical flicker fusion frequency changes during and after parachute jumping in experienced skydivers. AB - PURPOSE: The purpose of this study was (1) to further explore the heart rate dynamics and assess a potential cardiovascular risk in response to 4000 m jumps in experienced skydivers; (2) to assess whether there is an impact of such jumps on skydivers' cortical arousal or not, which may impact their decision making processes. METHOD: 18 experienced skydivers performed successive jumps from a plane at 4000 m of height. Heart rate dynamics and cortical arousal were assessed by the use of heart rate variability and Critical Flicker Fusion Frequency (CFFF), respectively. RESULTS: CFFF did not differ between the three measurement time points (p > 0.05). Mean heart rate increased during the jump (p < 0.001) and came back to pre-jump values after the jump (p < 0.001). Percentage of the differences of successive NN intervals greater than 50 ms (pNN50) decreased during the jump (p < 0.001) and kept lower values after the jump compared to pre jump (p < 0.05). High-frequency power (HF) did not differ during the jump (p > 0.05) but decreased after the jump compared to both pre-jump (p < 0.01) and jump (p < 0.05). Sample entropy decreased during the jump (p < 0.001) and came back to pre-jump values after the jump (p > 0.05). CONCLUSION: These results confirm a vagal input reduction associated with a rise of the sympathetic tone during the jump and suggests that the experienced skydiver is not exposed to a high cardiovascular risk. This study also shows that environmental stresses induced by free fall could not hamper the perceptual vigilance of experienced skydivers. PMID- 25715917 TI - Localization of pacing and defibrillator leads using standard x-ray views is frequently inaccurate and is not reproducible. AB - PURPOSE: While the accuracy of roentography for evaluation of lead tip position compared with three-dimensional imaging techniques has been well described, there remains considerable variability in the interpretation of the reproducibility of standard x-ray for right ventricular (RV) and left ventricular (LV) lead position. The aim of this study was to evaluate the accuracy and reliability of right ventricular (RV) and left ventricular (LV) lead tip position as determined by board-certified cardiac electrophysiologists (EP) using standard x-ray views. METHODS: EP interpretations of RV and LV lead tip position using standard x-ray views (posterior-anterior, lateral, and left anterior oblique) were compared to thoracic computed tomography (CT). The accuracy of x-ray interpretation was compared to the reference CT location, and the reproducibility of x-ray interpretation was tested using the free-marginal Kappa statistic. RESULTS: A total of 58 EPs were invited to participate in the survey with a response rate of 43 % (25/58). The agreement between x-ray and CT lead tip position (accuracy) was 37 % for RV lead, 33 % for longitudinal LV lead, and 41 % for short axis LV lead. Reproducibility was 64 % for RV lead tip (k = 0.46), 58 % for longitudinal LV lead tip (k = 0.37), and 39 % for short axis LV lead tip (k = 0.24). CONCLUSIONS: Conventional roentography is limited in its ability to accurately and reliably determine pacing lead tip position. PMID- 25715916 TI - Biomarkers in electrophysiology: role in arrhythmias and resynchronization therapy. AB - Circulating biomarkers related to inflammation, neurohormones, myocardial stress, and necrosis have been associated with commonly encountered arrhythmic disorders such as atrial fibrillation (AF) and more malignant processes including ventricular arrhythmias (VA) and sudden cardiac death (SCD). Both direct and indirect biomarkers implicated in the heart failure cascade have potential prognostic value in patients undergoing cardiac resynchronization therapy (CRT). This review will focus on the role of biomarkers in AF, history of SCD, and CRT with an emphasis to improve clinical risk assessment for arrhythmias and patient selection for device therapy. Notably, information obtained from biomarkers may supplement traditional diagnostic and imaging techniques, thus providing an additional benefit in the management of patients. PMID- 25715918 TI - Cis-regulatory control of human GLI2 expression in the developing neural tube and limb bud. AB - BACKGROUND: GLI2, a zinc finger transcription factor, mediates Sonic hedgehog signaling, a critical pathway in vertebrate embryogenesis. GLI2 has been implicated in diverse set of embryonic developmental processes, including patterning of central nervous system and limbs. In humans, mutations in GLI2 are associated with several developmental defects, including holoprosencephaly and polydactyly. RESULTS: Here, we demonstrate in transient transgenic zebrafish assays, the potential of a subset of tetrapod-teleost conserved non-coding elements (CNEs) residing within human GLI2 intronic intervals to induce reporter gene expression at known regions of endogenous GLI2 transcription. The regulatory activities of these elements are observed in several embryonic domains, including neural tube and pectoral fin. Moreover, our data reveal an overlapping expression profile of duplicated copies of an enhancer during zebrafish evolution. CONCLUSIONS: Our data suggest that during vertebrate history GLI2 acquired a high level of complexity in the genetic mechanisms regulating its expression during spatiotemporal patterning of the central nervous system (CNS) and limbs. PMID- 25715919 TI - Antibacterial and dissolution ability of sodium hypochlorite in different pHs on multi-species biofilms. AB - OBJECTIVES: The aim of this study was to investigate whether variation in pH of sodium hypochlorite (NaOCl) increased its antibacterial and dissolution ability on polymicrobial biofilms formed in situ. MATERIALS AND METHODS: Fifty-six dentin blocks (eight/group) were intraorally infected for 48 h and incubated in BHI for 48 h to standardize the biofilm growth. The specimens were irrigated with 1 and 2.5% NaOCl with pH levels of 5, 7, and 12 for 20 min. The control group was irrigated with distilled water. The cell viability and the bacterial volume were measured at the pre- and post-irrigation procedures. Five random areas of each sample were chosen and analyzed with confocal laser scanning microscopy (CLSM). Statistical analysis was performed using the non-parametric Kruskal-Wallis and Dunn's tests (p < 0.05). RESULTS: All the experimental solutions were able to decrease the biomass (p < 0.05) except for the 1% NaOCl-pH 5 group. The antibacterial ability of the NaOCl was dependent on the concentration and acidification of the solution. CONCLUSIONS: The acidification of NaOCl improves its antibacterial ability, but the dissolution effect of the irrigant is decreased. CLINICAL RELEVANCE: Bacteria and their products are the main factors in development of apical periodontitis. The pH reduction in the NaOCl could enhance the reduction or elimination of the root canal bacterial colonies in comparison with the unaltered solution. PMID- 25715920 TI - Cartilage health in high tibial osteotomy using dGEMRIC: Relationships with joint kinematics. AB - PURPOSE: The aims of this study are to determine how opening-wedge high tibial osteotomy (HTO) affects cartilage health in the tibiofemoral (TF) joint and patella, and to explore relationships between TF and patellofemoral (PF) joint kinematics and cartilage health in HTO. METHODS: 14 knees (13 subjects) with medial TF osteoarthritis (OA) were examined before HTO and 6 and 12 months after HTO using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to evaluate cartilage health at the TF joint and patella. They were also examined using a validated 3D MR knee kinematics measurement to obtain 11 rotations and translations at both TF and PF joints. RESULTS: No statistically significant differences in overall TF or patellar dGEMRIC score were found at 6 or 12 months after HTO. However three subjects had large decreases (mean 105 ms) in TF dGEMRIC at 6 months that recovered at 12 months. Kinematics for these subjects were compared to subjects who did not have decreases in TF dGEMRIC at 6 months (n=5). Differences were observed between groups with HTO in anterior and proximal tibial translation (mean differences 3.05 mm and 1.35 mm), and patellar flexion (mean difference 3.65 degrees ). These changes were consistent between 6 and 12 months, despite recovery of TF dGEMRIC values. CONCLUSIONS: We did not find significant differences in TF or patellar dGEMRIC before and after HTO with all subjects, however there were differences in kinematics between subjects who had a decrease in TF dGEMRIC at 6 months and those who did not. This suggests a link between joint kinematics and cartilage health in HTO. CLINICAL RELEVANCE: The effect of opening-wedge high tibial osteotomy on cartilage GAG concentration may be linked to specific changes in knee kinematics following surgery. PMID- 25715921 TI - Effect of xylan structure on reactivity in graft copolymerization and subsequent binding to cellulose. AB - The grafting reactivities with glycidyl methacrylate (GMA) of five xylans from hardwood and cereal sources were compared. The structural property that best predicted the reactivities of xylans with GMA was the fraction of 4-O methylglucuronic acid (MeGlcA) substitution. A comparatively high level of arabinose substitution was also positively correlated to reactivity with GMA. The impact of MeGlcA and arabinose branching groups is likely attributed to the solubilizing effect of these substituents. Consistent with this prediction, low water solubility and high lignin content were found to hinder reactivity. Even though oligomeric substrates have the advantage of water solubility, modified xylo-oligosaccharides were difficult to purify. Accordingly, delignified and high molecular weight xylans that are soluble or dispersible in water are best suited for this type of backbone derivatization. Adsorption studies with a quartz crystal microbalance with dissipation indicated that grafting lowered the total adsorption of arabinoxylan but did not significantly affect the fraction of xylans adsorbed irreversibly on cellulose. PMID- 25715922 TI - Quantification of liver, pancreas, kidney, and vertebral body MRI-PDFF in non alcoholic fatty liver disease. AB - PURPOSE: The purpose of the present study was to determine liver, pancreas, kidney, and vertebral fat deposition in NAFLD patients by proton density fat fraction (PDFF) using magnetic resonance imaging (MRI) and to evaluate the relationships among them. METHODS: A total of 41 biopsy-proven NAFLD patients underwent MRI-PDFF with IDEAL-IQ. MRI protocol included T1-independent volumetric multi-echo gradient-echo imaging with T2* correction and spectral fat modeling. The MR examinations were performed on a 1.5 HDx MRI system. MRI-PDFF measurements were obtained from liver, pancreas, renal cortex and sinus, and vertebral body. Liver biopsy specimens were retrieved from the archives and evaluated by one pathologist according to NASH CRN. RESULTS: The median age of the patients was 47 years. The median interval between liver biopsy and MRI examination was 16 days. Mean liver, pancreas, renal cortex, renal sinus, T12 and L1 vertebral body MRI PDFFs were 18.7%, 5.7%, 1.7%, 51%, 43.2%, and 43.5%, respectively. No correlation between either liver MRI-PDFF or histological steatosis, and other organ MRI PDFFs was observed. A good correlation between pancreas and vertebral body MRI PDFFs, and pancreas and renal sinus MRI-PDFFs was observed. Diabetic patients had higher average pancreas MRI-PDFF compared to non-diabetics (12.2%, vs., 4.8%; P = 0.028). CONCLUSIONS: Pancreas and vertebral body MRI-PDFF is well correlated in NAFLD patients and both of them are higher in diabetic patients which may explain increased bone fractures in diabetics. MRI-PDFF can be used to demonstrate fat fractions of different organs and tissues and to understand fat metabolism. PMID- 25715923 TI - Tracking larvae with molecular markers reveals high relatedness and early seasonal recruitment success in a partially spawning marine bivalve. AB - The partial synchronized spawning strategy adopted by some marine invertebrate broadcast-spawners can lead to the production of many distinct pools of larvae within a single reproductive cycle. Following the fate of these larval groups from birth to settlement with molecular markers might shed light on mechanisms regulating their population recruitment. Larvae and recruits of Mya arenaria, a partially spawning marine bivalve, were monitored and collected over 13 consecutive weeks during an entire reproductive cycle. Each sampled individual (n = 218) was sorted according to size (early veligers, late veligers, post-larval recruits) and genotyped at seven microsatellite loci for comparisons among samples and with adult reference samples (n = 270). While traditional differentiation statistics (e.g., pairwise Delta(ST), allelic richness) suggested the absence of sweepstakes reproductive success, the level of relatedness found within and among larvae and recruit samples suggested otherwise. Four samples out of ten were observed to have higher within-sample relatedness values than randomly expected, including the very first group of early veligers produced in the season (E1) and the last group of post-larvae who survived recruitment (P10). E1 individuals were also found to be more related than randomly expected to individuals of more than 80% of all other samples including the last surviving recruits (P8 and P10). These results suggest that the first larvae produced in the season were the most successful to survive recruitment. Results also show direct evidence for larval retention and demonstrate for the first time larval and post-larval kin aggregation in a marine bivalve. PMID- 25715924 TI - Trade-offs between growth and maturation: the cost of reproduction for surviving environmental extremes. AB - Life-history trade-offs and the costs of reproduction are central concepts in evolution and ecology. Episodic climatic events such as drought and extreme temperatures provide strong selective pressures that can change the balance of these costs and trade-offs. We used size-structured matrix models parameterized from field and laboratory studies to examine the effect of periodic drought on two species of aquatic salamanders (greater siren, Siren lacertina; lesser siren, Siren intermedia) that differ in size at reproduction and maximum body size. Post drought body size distributions of the larger species (S. lacertina) are consistent with size-dependent mortality. Smaller individuals were extirpated from the population during each drought while large animals persisted, a pattern that contrasted with that seen in several ectotherms. This appears to be largely explained by estivation proficiency and a positive relationship between body size and estivation potential. Increased body size, however, may come at the cost of fecundity and maturation rate compared to a closely related congener. The cost of somatic allocation in this case may manifest itself via reduced per-capita competitive ability, which (at least in simulation studies) allows the smaller, fast-maturing species to outcompete the larger, slow-maturing species when drought is minimal or nonexistent. PMID- 25715925 TI - Influence of MC3T3-E1 preosteoblast culture on the corrosion of a T6-treated AZ91 alloy. AB - This study investigated the corrosion of artificially aged T6 heat-treated Mg 9%Al-1%Zn (AZ91) for biomedical applications. Corrosion tests and surface analysis were completed both with and without a monolayer of mouse preosteoblast MC3T3-E1 cells cultured on the sample. Electrochemical impedance spectroscopy (EIS) and inductively coupled plasma mass spectroscopy (ICPMS) were used to explore the corrosion processes after either 3 or 21 days of AZ91 incubation in cell culture medium (CCM). The EIS showed both the inner layer resistance (Rin ) and outer layer resistance (Rout ) were lower for samples without cells cultured on the surface at 3 days (Rin = 2.64 e4 Omega/cm(2) , Rout = 140 Omega/cm(2) ) compared to 21 days (Rin = 3.60 e4 Omega/cm(2) , Rout = 287 Omega/cm(2) ) due to precipitation of magnesium and calcium phosphates over time. Samples with preosteoblasts cultured on the surface had a slower initial corrosion (3 day, Rin = 1.88 e5 Omega/cm(2) , Rout = 1060 Omega/cm(2) ) which was observed to increase over time (21 day, Rin = 2.99 e4 Omega/cm(2) , Rout = 287 Omega/cm(2) ). Changes in the corrosion processes were thought to be related to changes in the coverage provided by the cell layer. Our results reveal that the presence of cells and biological processes are able to significantly influence the corrosion rate of AZ91. PMID- 25715926 TI - Setdb1 is required for myogenic differentiation of C2C12 myoblast cells via maintenance of MyoD expression. AB - Setdb1, an H3-K9 specific histone methyltransferase, is associated with transcriptional silencing of euchromatic genes through chromatin modification. Functions of Setdb1 during development have been extensively studied in embryonic and mesenchymal stem cells as well as neurogenic progenitor cells. But the role of Sedtdb1 in myogenic differentiation remains unknown. In this study, we report that Setdb1 is required for myogenic potential of C2C12 myoblast cells through maintaining the expressions of MyoD and muscle-specific genes. We find that reduced Setdb1 expression in C2C12 myoblast cells severely delayed differentiation of C2C12 myoblast cells, whereas exogenous Setdb1 expression had little effect on. Gene expression profiling analysis using oligonucleotide micro array and RNA-Seq technologies demonstrated that depletion of Setdb1 results in downregulation of MyoD as well as the components of muscle fiber in proliferating C2C12 cells. In addition, exogenous expression of MyoD reversed transcriptional repression of MyoD promoter-driven lucif-erase reporter by Setdb1 shRNA and rescued myogenic differentiation of C2C12 myoblast cells depleted of endogenous Setdb1. Taken together, these results provide new insights into how levels of key myogenic regulators are maintained prior to induction of differentiation. PMID- 25715927 TI - Metabolic engineering for resveratrol derivative biosynthesis in Escherichia coli. AB - We previously reported that the SbROMT3syn recombinant protein catalyzes the production of the methylated resveratrol derivatives pinostilbene and pterostilbene by methylating substrate resveratrol in recombinant E. coli. To further study the production of stilbene compounds in E. coli by the expression of enzymes involved in stilbene biosynthesis, we isolated three stilbene synthase (STS) genes from rhubarb, peanut, and grape as well as two resveratrol O methyltransferase (ROMT) genes from grape and sorghum. The ability of RpSTS to produce resveratrol in recombinant E. coli was compared with other AhSTS and VrSTS genes. Out of three STS, only AhSTS was able to produce resveratrol from p coumaric acid. Thus, to improve the solubility of RpSTS, VrROMT, and SbROMT3 in E. coli, we synthesized the RpSTS, VrROMT and SbROMT3 genes following codon optimization and expressed one or both genes together with the cinnamate/4 coumarate:coenzyme A ligase (CCL) gene from Streptomyces coelicolor. Our HPLC and LC-MS analyses showed that recombinant E. coli expressing both ScCCL and RpSTSsyn led to the production of resveratrol when p-coumaric acid was used as the precursor. In addition, incorporation of SbROMT3syn in recombinant E. coli cells produced resveratrol and its mono-methylated derivative, pinostilbene, as the major products from p-coumaric acid. However, very small amounts of pterostilbene were only detectable in the recombinant E. coli cells expressing the ScCCL, RpSTSsyn and SbROMT3syn genes. These results suggest that RpSTSsyn exhibits an enhanced enzyme activity to produce resveratrol and SbROMT3syn catalyzes the methylation of resveratrol to produce pinostilbene in E. coli cells. PMID- 25715928 TI - Interpretation of urine analysis for cocaine metabolites. PMID- 25715929 TI - Guidance document: management priorities in salicylate toxicity. PMID- 25715930 TI - Genital sensation in women with pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The objective was to compare vaginal and clitoral sensory thresholds in women with pelvic organ prolapse and women with normal pelvic anatomy. METHODS: Quantitative sensory thresholds for warm, cold, and vibratory sensations were measured at the vagina and clitoral area of women with pelvic organ prolapse, pelvic organ prolapse quantification (POP-Q) stage II or higher (study group) and of women without prolapse, POP-Q stage <= I (control group). The quantitative sensory tests were performed with a thermal and vibration Genito-Sensory Analyzer, at the distal third of the anterior and posterior vaginal wall and at the clitoral area. Warm stimuli were used to evaluate unmyelinated C-fibers; cold stimuli for thinly myelinated A-delta; and vibratory stimuli for large A-beta fibers. Independent Student's t test and Chi squared test of association were used for analysis of continuous and categorical parameters respectively. RESULTS: Overall, 66 women, 22 with median POP-Q stage III (range: II-IV) and 44 with POP-Q stage I (range: 0-I), participated in the study. There were no statistically significant differences between the two groups regarding the characteristics examined (health status, medical history, and age). In all regions examined, mean thresholds for vibratory and warm stimuli were significantly higher and mean thresholds for cold stimuli significantly lower in the group with prolapse. CONCLUSION: Women with pelvic organ prolapse exhibited lower sensitivity in the genital area to vibratory and thermal stimuli than did women without prolapse. Our findings suggest that a neuropathic sensory deficit in the area of the genitalia might be associated with prolapse. PMID- 25715931 TI - Patient and public involvement in urogynecology: a pause for reflection before taking a leap. PMID- 25715932 TI - Previous cesarean section and risk of urinary tract injury during laparoscopic hysterectomy: a meta-analysis. AB - INTRODUCTION AND HYPOTHESIS: Today laparoscopic hysterectomy (LH) can be performed safely and effectively, even for women with a previous history of cesarean section (CS). However, it is unclear whether the risk of urinary tract injury increases with previous CS during LH. METHODS: PubMed and Embase databases were searched for all studies on previous history of CS and risk of urinary tract injuries during and after LH. Reference lists of the identified studies, reviews, and other relevant publications were also searched. Urinary tract injuries or related complications were the outcomes of interest. Meta-analysis was conducted using an inverse-variance weighted random-effects model. RESULTS: A total of 7 studies including 3,191 patients were identified in the meta-analysis. Overall, the pooled relative risk (RR) and the corresponding 95 % confidence interval (CI) of urinary tract injury were 3.48 (1.86-6.50) for previous CS compared with no previous CS. However, only two studies reported sufficient data on ureteral injury, and the combined RR was 1.83 (95 % CI 0.19-17.26). All seven studies reported the outcomes of bladder injury, and the pooled RR was 3.75 (95 % CI 1.96 7.17). Stratified analyses showed a basically consistent result with the overall analysis except for that by 1-2 times of previous CS (RR 2.32, 95 % CI 0.56 9.56). CONCLUSIONS: Previous CS is significantly associated with development of bladder injury during LH. No significant association was found yet between previous CS and risk of ureteral injury. Given the limited number of studies, more future studies are required to confirm the associations. PMID- 25715933 TI - The S.A.C.S. (Satisfaction-Anatomy-Continence-Safety) score for evaluating pelvic organ prolapse surgery: a proposal for an outcome-based scoring system. AB - INTRODUCTION AND HYPOTHESIS: To date, there is no overall consensus on the definition of cure after surgery for pelvic organ prolapse (POP). The aim of the study was to design and test the scoring system S.A.C.S. (Satisfaction-Anatomy Continence-Safety) to assess and compare the outcomes of POP repair. METHODS: A total of 233 women underwent open sacrocolpopexy. The S.A.C.S. outcome scoring system was scheduled at 24 months of follow-up, and each component was detected according to: Satisfaction by mean of Patient Global Improvement Inventory scale, Anatomy by mean of POP Quantification system and bulge symptom, Continence by mean of pad use, and Safety by mean of the Clavien-Dindo classification of surgical complications. Each component produced a binary nominal categorical variable (1 or 0), with a total score of 4 representing cure. As a comparative tool, patients answered a simple yes/no question: "If you had to undergo surgery all over again, would you still do it?". The degree of concordance was estimated using Cohen's Kappa test. RESULTS: According to the S.A.C.S. scoring system, only 160 patients (68.6 %) reached the maximum score of cure. Sensitivity of the S.A.C.S. score was 74.1 %, specificity was 90 %, total diagnostic capacity was 75.5 %. The S.A.C.S. score internal consistency was good; the k-coefficient was higher for the satisfaction component of the score (k = 0.560). CONCLUSION: This study proposes an original, simple post-operative scoring system integrating satisfaction, anatomy, continence, and safety reports for patients undergoing surgery for POP, providing a complete, although perfectible, method to accurately report outcomes in all clinical scenarios. PMID- 25715935 TI - Chloroquine enhances replication of influenza A virus A/WSN/33 (H1N1) in dose-, time-, and MOI-dependent manners in human lung epithelial cells A549. AB - Anti-malaria drug, chloroquine, has been reported to be effective against influenza A virus (IAV) in vitro and used in in-vivo experiments and clinical trial for prevention or treatment of influenza. In this study, it has been shown by immunofluorescence, hemagglutination, and plaque assays that chloroquine enhanced A/WSN/33 (H1N1) replication with pronounced cytopathic effect in dose-, time-, and MOI-dependent manners in human lung epithelial cells A549. Time-of addition assay showed that inhibitory effect on virus replication by chloroquine pre-treatment was indistinctive, and virus productions were enhanced when the drug was applied after viral adsorption. The effectiveness of chloroquine as an anti-influenza drug is questioned, and caution in its use is recommended. PMID- 25715937 TI - Chronotropic incompetence presenting as sudden sinus slowing during exercise stress test: the pathophysiological mechanisms. PMID- 25715938 TI - Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension. AB - BACKGROUND: Sympathetic overactivity increases sodium retention and contributes to the pathophysiology of hypertension. Renal sympathetic denervation lowers blood pressure and reduces sympathetic activity in certain patients with resistant hypertension. METHODS AND RESULTS: This study aimed to assess the effect of renal denervation on urinary sodium excretion. 24-h urinary sodium excretion was estimated at baseline and after 6 months using the Kawasaki formula in 137 patients with resistant hypertension undergoing renal denervation. Sodium excretion was adjusted for cystatin C GFR and fractional sodium excretion was assessed. Mean office systolic blood pressure at baseline was 171 +/- 2 mmHg despite an intake of 5.2 +/- 0.1 antihypertensive drugs. Six months after renal denervation, systolic and diastolic BP decreased by 18 +/- 2 mmHg (p < 0.0001) and 10 +/- 1 mmHg (p < 0.001). 90 patients (65.7%) had SBP reductions >= 10 mmHg (responders). After 6 months, 24-h UNa increased by 13% compared to baseline (236 +/- 9 vs. 268 +/- 9 mmol/day, p < 0.003). This increase was most pronounced in patients with less response in BP. These findings were paralleled by a significant increase in fractional sodium excretion (1.19 +/- 0.11 vs. 1.64 +/- 0.14%, p < 0.0001) and were observed independently of the intake of antihypertensive drugs affecting sodium balance, such as mineralocorticoid receptor antagonists or diuretics. CONCLUSION: RDN lowered BP and increased estimated UNa and fractional sodium excretion in patients with resistant hypertension independently of renal function and antihypertensive therapy. PMID- 25715939 TI - Comparison of Vesikari and Clark scales regarding the definition of severe rotavirus gastroenteritis in children. AB - BACKGROUND: Two clinical severity scales, the Vesikari scale and the Clark scale, are commonly used to assess the efficacy of rotavirus vaccines. The results obtained using the two severity scales differ significantly and hamper comparisons. The aim of this study was to compare the Clark and Vesikari scales and to determine whether modified classifications would provide a better correlation between the two scales. METHODS: The severity of rotavirus gastroenteritis was assessed for each child using both the Vesikari and Clark scales. To make a statistical comparison between the two scales, the classifications were modified. RESULTS: In total, 200 children with rotavirus gastroenteritis were evaluated. Of these, 57% were classified as severe by the Vesikari scale, and only 1.5% by the Clark scale (p < 0.001). When the Clark three-category scale was transformed into a two-category scale by merging mild and moderate categories as non-severe, a good correlation with the Vesikari scale still could not be found. Using the median of the severity scores as the severity threshold did not provide a better correlation between the two scales. Transforming the Vesikari two-category scale into a three-category scale by further subdividing the severe category into two parts, as moderate and severe (>= 16), provided a better correlation between the two severity scales, but still did not achieve a good level of agreement. CONCLUSIONS: The Clark and Vesikari scales differ significantly in the definition of severe gastroenteritis. Even the attempts at reclassifying the scales did not achieve a good correlation. PMID- 25715940 TI - Height as a prognostic marker for survival during antituberculous therapy. PMID- 25715941 TI - Ten years of treating necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis is a soft tissue infection characterized by rapid progression and a high mortality rate. The objective of this study was to investigate diagnosis, causative microbial agents, comorbidities, antibiotic regimen and outcome regarding this disease at Skane University Hospital in Malmo, Sweden. METHODS: From medical records, we identified 33 patients treated from January 2003 to January 2013, 31 of whom could be included in our investigation. RESULTS: The infections were monomicrobial in 87% of the cases, and most were caused by group A streptococci. The rate of polymicrobial infections was lower than in other studies. In addition to blood and wound cultures, a rapid antigen detection test for group A streptococci was used in a majority of the cases as a supplement to other diagnostic tools. The time from onset of symptoms to surgery proved to be significantly shorter for patients infected with group A streptococci than for other patients. The mortality rate among all patients was 19%, which is lower than much of the historical material but in line with some more recent studies of this disease. CONCLUSIONS: Our results indicate that low mortality rates can be achieved by surgery, appropriate antibiotics and good supportive care. Furthermore, we show that the use of the rapid antigen detection test for group A streptococci, in this setting, helps to shorten the time to surgical intervention in patients suffering from necrotizing fasciitis. This also helps to guide the antibiotic treatment into a narrower spectrum. PMID- 25715942 TI - Characterization of molecular channel in photodissociation of SOCl2 at 248 nm: Cl2 probing by cavity ring-down absorption spectroscopy. AB - A primary elimination channel of the chlorine molecule in the one-photon dissociation of SOCl2 at 248 nm was investigated using cavity ring-down absorption spectroscopy (CRDS). By means of spectral simulation, the ratio of the vibrational population in the v = 0, 1, and 2 levels was evaluated to be 1 : (0.10 +/- 0.02) : (0.009 +/- 0.005), corresponding to a Boltzmann vibrational temperature of 340 +/- 30 K. The Cl2 molecular channel was obtained with a quantum yield of 0.4 +/- 0.2 from the X(1)A' ground state of SOCl2via internal conversion. The dissociation mechanism differs from a prior study where a smaller yield of <3% was obtained, initiated from the 2(1)A' excited state. Temperature dependence measurements of the Cl2 fragment turn out to support our mechanism. With the aid of ab initio potential energy calculations, two dissociation routes to the molecular products were found, including one synchronous dissociation pathway via a three-center transition state (TS) and the other sequential dissociation pathway via a roaming-mediated isomerization TS. The latter mechanism with a lower energy barrier dominates the dissociation reaction. PMID- 25715943 TI - Erratum to: 21st Annual Conference of the International Society for Quality of Life Research. PMID- 25715944 TI - Longitudinal associations between asthma control, medication adherence, and quality of life among adolescents: results from a cross-lagged analysis. AB - PURPOSE: It is not completely clear whether and how medication adherence, asthma control, and quality of life (QOL) predict each other over time. Therefore, the aim of the present study was to examine the longitudinal associations between asthma control, medication adherence, and quality of life among adolescents. METHODS: In this 3-wave longitudinal study, adolescents (N = 139, Mean age = 11.8) completed questionnaires about their medication adherence (Medication Adherence Report Scale for Asthma), asthma control (Asthma Control Questionnaire), and QOL (Adolescent Asthma Quality of Life Questionnaire) during home visits in the spring/summer of 2011, 2012, and 2013. Cross-lagged analyses examined temporal interrelations between the three variables over the course of 3 years. RESULTS: Higher QOL at baseline predicted increased medication adherence at follow-up (T2), but did not predict changes in asthma control over time. Medication adherence and asthma control did not predict changes in QOL over time. There were no associations between asthma control and medication adherence over time. CONCLUSIONS: Interventions could focus on increasing QOL to increase medication adherence in adolescents with asthma. PMID- 25715945 TI - Quality of life and patient preferences: identification of subgroups of multiple sclerosis patients. AB - PURPOSE: The aim of this study was to estimate preferences related to quality of life attributes in people with multiple sclerosis, by keeping heterogeneity of patient preference in mind, using the latent class approach. METHODS: A discrete choice experiment survey was developed using the following attributes: activities of daily living, instrumental activities of daily living, pain/fatigue, anxiety/depression and attention/concentration. Choice sets were presented as pairs of hypothetical health status, based upon a fractional factorial design. RESULTS: The latent class logit model estimated on 152 patients identified three subpopulations, which, respectively, attached more importance to: (1) the physical dimension; (2) pain/fatigue and anxiety/depression; and (3) instrumental activities of daily living impairments, anxiety/depression and attention/concentration. A posterior analysis suggests that the latent class membership may be related to an individual's age to some extent, or to diagnosis and treatment, while apart from energy dimension, no significant difference exists between latent groups, with regard to Multiple Sclerosis Quality of Life 54 scales. CONCLUSIONS: A quality of life preference-based utility measure for people with multiple sclerosis was developed. These utility values allow identification of a hierarchic priority among different aspects of quality of life and may allow physicians to develop a care programme tailored to patient needs. PMID- 25715947 TI - The cytoplasm as a radiation target: an in silico study of microbeam cell irradiation. AB - We performed in silico microbeam cell irradiation modelling to quantitatively investigate ionisations resulting from soft x-ray and alpha particle microbeams targeting the cytoplasm of a realistic cell model. Our results on the spatial distribution of ionisations show that as x-rays are susceptible to scatter within a cell that can lead to ionisations in the nucleus, soft x-ray microbeams may not be suitable for investigating the DNA damage response to radiation targeting the cytoplasm alone. In contrast, ionisations from an ideal alpha microbeam are tightly confined to the cytoplasm, but a realistic alpha microbeam degrades upon interaction with components upstream of the cellular target. Thus it is difficult to completely rule out a contribution from alpha particle hits to the nucleus when investigating DNA damage response to cytoplasmic irradiation. We find that although the cytoplasm targeting efficiency of an alpha microbeam is better than that of a soft x-ray microbeam (the probability of stray alphas hitting the nucleus is 0.2% compared to 3.6% for x-rays), stray alphas produce more ionisations in the nucleus and thus have greater potential for initiating damage responses therein. Our results suggest that observed biological responses to cytoplasmic irradiation include a small component that can be attributed to stray ionisations in the nucleus resulting from the stochastic nature of particle interactions that cause out-of-beam scatter. This contribution is difficult to isolate experimentally, thus demonstrating the value of the in silico approach. PMID- 25715946 TI - PROMIS((r)) pediatric self-report scales distinguish subgroups of children within and across six common pediatric chronic health conditions. AB - PURPOSE: To conduct a comparative analysis of eight pediatric self-report scales for ages 8-17 years from the National Institutes of Health (NIH) Patient Reported Outcomes Measurement Information System (PROMIS((r))) in six pediatric chronic health conditions, using indicators of disease severity. METHODS: Pediatric patients (N = 1454) with asthma, cancer, chronic kidney disease, obesity, rheumatic disease, and sickle cell disease completed items from the PROMIS pediatric mobility, upper extremity functioning, depressive symptoms, anxiety, anger, peer relationships, pain interference, and fatigue self-report scales. Comparisons within the six pediatric chronic health conditions were conducted by examining differences in groups based on the disease severity using markers of severity that were specific to characteristics of each disease. A comparison was also made across diseases between children who had been recently hospitalized and those who had not. RESULTS: In general, there were differences in self-reported health outcomes within each chronic health condition, with patients who had higher disease severity showing worse outcomes. Across health conditions, when children with recent hospitalizations were compared with those who had not been hospitalized in the past 6 months, we found significant differences in the expected directions for all PROMIS domains, except anger. CONCLUSIONS: PROMIS measures discriminate between different clinically meaningful subgroups within several chronic illnesses. Further research is needed to determine the responsiveness of the PROMIS pediatric scales to change over time. PMID- 25715948 TI - Highly stable and sensitive fluorescent probes (LysoProbes) for lysosomal labeling and tracking. AB - We report the design, synthesis and application of several new fluorescent probes (LysoProbes I-VI) that facilitate lysosomal pH monitoring and characterization of lysosome-dependent apoptosis. LysoProbes are superior to commercially available lysosome markers since the fluorescent signals are both stable and highly selective, and they will aid in characterization of lysosome morphology and trafficking. We predict that labeling of cancer cells and solid tumor tissues with LysoProbes will provide an important new tool for monitoring the role of lysosome trafficking in cancer invasion and metastasis. PMID- 25715949 TI - A lab-on-a-chip system with integrated sample preparation and loop-mediated isothermal amplification for rapid and quantitative detection of Salmonella spp. in food samples. AB - Foodborne disease is a major public health threat worldwide. Salmonellosis, an infectious disease caused by Salmonella spp., is one of the most common foodborne diseases. Isolation and identification of Salmonella by conventional bacterial culture or molecular-based methods are time consuming and usually take a few hours to days to complete. In response to the demand for rapid on line or on site detection of pathogens, in this study, we describe for the first time an eight chamber lab-on-a-chip (LOC) system with integrated magnetic bead-based sample preparation and loop-mediated isothermal amplification (LAMP) for rapid and quantitative detection of Salmonella spp. in food samples. The whole diagnostic procedures including DNA isolation, isothermal amplification, and real-time detection were accomplished in a single chamber. Up to eight samples could be handled simultaneously and the system was capable to detect Salmonella at concentration of 50 cells per test within 40 min. The simple design, together with high level of integration, isothermal amplification, and quantitative analysis of multiple samples in short time, will greatly enhance the practical applicability of the LOC system for rapid on-site screening of Salmonella for applications in food safety control, environmental surveillance, and clinical diagnostics. PMID- 25715950 TI - An ESIPT-based fluorescent probe for highly selective and ratiometric detection of mercury(II) in solution and in cells. AB - A novel ratiometric fluorescent Hg(2+) detecting system was rationally developed based on the typical excited state intramolecular proton transfer (ESIPT) characteristic of the latent fluorophore, 2-(1-(p-tolyl)-1H-phenanthro[9,10 d]imidazol-2-yl)phenol (Pol) and the Hg(2+)-mediated cleavage of the vinyl group. The probe responds selectively to Hg(2+) over various other metal ions with a larger bathochromic shift (~100 nm). The sensing mechanism was investigated in detail by fluorescence spectroscopy, NMR spectra and mass spectrometry. Taking advantage of the enhancement effect of dichloromethane on the ESIPT efficiency, a facile dichloromethane extraction was introduced in the process of detection of Hg(2+), which affords a high sensitivity for the probe with a detection limit of 7.8 * 10(-9) M for Hg(2+). By using the new strategy, the novel probe can be used for the detection of Hg(2+) in practical water samples with good recovery. Moreover, the probe was successfully applied to the fluorescence image of Hg(2+) in living cells. These results indicated that the probe and the proposed method have promising applications for Hg(2+) sensing in biological and environmental sciences. PMID- 25715951 TI - Multi-scale undulations in human aortic endothelial cell fibers. AB - Blood vessels often have an undulatory morphology, with excessive bending, kinking, and coiling occuring in diseased vasculature. The underlying physical causes of these morphologies are generally attributed, in combination, to changes in blood pressure, blood flow rate, and cell proliferation or apoptosis. However, pathological vascular morphologies often start during developmental vasculogenesis. At early stages of vasculogenesis, angioblasts (vascular endothelial cells that have not formed a lumen) assemble into primitive vessel like fibers before blood flow occurs. If loose, fibrous aggregates of endothelial cells can generate multi-cellular undulations through mechanical instabilities, driven by the cytoskeleton, new insight into vasculature morphology may be achieved with simple in vitro models of endothelial cell fibers. Here we study mechanical instabilities in vessel-like structures made from endothelial cells embedded in a collagen matrix. We find that endothelial cell fibers contract radially over time, and undulate at two dominant wavelengths: approximately 1cm and 1mm. Simple mechanical models suggest that the long-wavelength undulation is Euler buckling in rigid confinement, while the short-wavelength buckle may arise from a mismatch between fiber bending energy and matrix deformation. These results suggest a combination of fiber-like geometry, cystoskeletal contractions, and extracellular matrix elasticity may contribute to undulatory blood vessel morphology in the absence of a lumen or blood pressure. PMID- 25715952 TI - Simulated glass-forming polymer melts: dynamic scattering functions, chain length effects, and mode-coupling theory analysis. AB - We present molecular-dynamics simulations for a fully flexible model of polymer melts with different chain length N ranging from short oligomers (N = 4) to values near the entanglement length (N = 64). For these systems we explore the structural relaxation of the supercooled melt near the critical temperature T c of mode-coupling theory (MCT). Coherent and incoherent scattering functions are analyzed in terms of the idealized MCT. For temperatures T > T c we provide evidence for the space-time factorization property of the beta relaxation and for the time-temperature superposition principle (TTSP) of the alpha relaxation, and we also discuss deviations from these predictions for T ~ T c. For T larger than the smallest temperature where the TTSP holds we perform a quantitative analysis of the dynamics with the asymptotic MCT predictions for the late beta regime. Within MCT a key quantity, in addition to T c, is the exponent parameter lambda. For the fully flexible polymer models studied we find that lambda is independent of N and has a value (lambda = 0.735 ) typical of simple glass-forming liquids. On the other hand, the critical temperature increases with chain length toward an asymptotic value T c (infinity) . This increase can be described by T c (infinity) - T c(N) ~ 1/N and may be interpreted in terms of the N dependence of the monomer density rho, if we assume that the MCT glass transition is ruled by a soft-sphere-like constant coupling parameter Gamma c = rho c T c (-1/4), where rho c is the monomer density at T c. In addition, we also estimate T c from a Hansen-Verlet-like criterion and MCT calculations based on structural input from the simulation. For our polymer model both the Hansen-Verlet criterion and the MCT calculations suggest T c to decrease with increasing chain length, in contrast to the direct analysis of the simulation data. PMID- 25715953 TI - Sub-100 nm resolution microscopy based on proximity projection grating scheme. AB - Structured illumination microscopy (SIM) has been widely used in life science imaging applications. The maximum resolution improvement of SIM, compared to conventional bright field system is a factor of 2. Here we present an approach to structured illumination microscopy using the proximity projection grating scheme (PPGS), which has the ability to further enhance the SIM resolution without invoking any nonlinearity response from the sample. With the PPGS-based SIM, sub 100 nm resolution has been obtained experimentally, and results corresponding to 2.4 times resolution improvement are presented. Furthermore, it will be shown that an improvement of greater than 3 times can be achieved. PMID- 25715954 TI - Common variable immune deficiency in a Pomeranian with Pneumocystis carinii pneumonia. AB - A Pomeranian dog, 1 year- and 8 month-old neutered female, was presented with persistent respiratory distress and recurrent generalized demodicosis. Physical examination revealed cyanosis, rough respiratory sounds, multifocal alopecia and dermal erosions on the dorsal side of the forelimbs, perineal area and skin around the eyes. A severe diffuse interstitial lung pattern was observed on thoracic radiographs. The blood examination revealed neutrophilia and hypoglobulinemia. Serum immunoglobulin concentrations of IgG and IgA were low. Histopathological examination revealed severe diffuse interstitial pneumonia with Pneumocystis carinii infection. Severe lymphoid depletion was observed in the spleen and other organs with lymphoid follicles consisted mainly of CD3-positive T cells and few cells of B-cell lineage. B-cell hypoplasia with subsequent antibody deficiency was suspected. PMID- 25715955 TI - Laparoscopic cryptorchidectomy in standing bulls. AB - Laparoscopic cryptorchidectomy without insufflation was applied in 10 standing bulls aged 3 to 15 months. Nine bulls were preoperatively pointed out intra abdominal testes by computed tomography. Preoperative fasting for a minimum of 24 hr provided laparoscopic visualization of intra-abdominal area from the kidney to the inguinal region. Surgical procedure was interrupted by intra-abdominal fat and testis size. It took 0.6 to 1.5 hr in 4 animals weighing 98 to 139 kg, 0.8 to 2.8 hr in 4 animals weighing 170 to 187 kg, and 3 and 4 hr in 2 animals weighing 244 and 300 kg to complete the cryptorchidectomy. In conclusion, standing gasless laparoscopic cryptorchidectomy seems to be most suitable for bulls weighing from 100 to 180 kg. PMID- 25715956 TI - Effect of a single injection of gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) on testicular blood flow measured by color doppler ultrasonography in male Shiba goats. AB - Although color Doppler ultrasonography has been used to evaluate testicular blood flow in many species, very little has been done in goat. Eight male Shiba goats were exposed to a single intramuscular injection of either gonadotropin-releasing hormone (GnRH group; 1 ug/kg BW) or human chorionic gonadotropin (hCG group; 25 IU/kg BW). Plasma testosterone (T), estradiol (E2) and inhibin (INH) were measured just before (0 hr) and at different intervals post injection by radioimmunoassay. Testis volume (TV) and Doppler indices, such as resistive index (RI) and pulsatility index (PI) of the supratesticular artery, were measured by B mode and color Doppler ultrasonography, respectively. The results indicated an increase in testicular blood flow in both groups, as RI and PI decreased significantly (P<0.05), but this increase was significant higher and earlier in hCG group (1 hr) than in the GnRH group (2 hr). A high correlation was found for RI and PI with both T (RI, r= -0.862; PI, r= -0.707) and INH in the GnRH group (RI, r=0.661; PI, r=0.701). However, a significant (P<0.05) correlation was found between E2 and both RI (r= -0.610) and PI (r= -0.763) in hCG group. In addition, TV significantly increased and was highly correlated with RI in both groups (GnRH, r= -0.718; hCG, r= -0.779). In conclusion, hCG and GnRH may improve testicular blood flow and TV in Shiba goats. PMID- 25715957 TI - Comparison of amino acid profiles between rats subjected to forced running and voluntary running exercises. AB - It has been suspected that in comparison with glucose or fatty acids, the levels of amino acids may readily change with different forms of exercise. In the present study, we measured the concentrations of amino acids, glucose, triglycerides, total protein and total cholesterol in the blood and/or cerebrospinal fluid (CSF) of rats subjected to forced running exercise on a treadmill, and voluntary running exercise using a wheel, with a constant running distance of 440 m. Rats that performed no running and rats subjected to immobilization stress were used as controls. We observed a few significant changes in the levels of plasma glucose, triglycerides, total protein and total cholesterol in all groups. Whereas, plasma amino acid levels were significantly changed by exercise and stress, especially during the light period. The plasma levels of many amino acids were specifically increased by forced running; some were decreased by immobilization stress. Few amino acids showed similar changes in their levels as a result of voluntary running. In addition, there was a significant difference in the degree of amino acid imbalance between blood and CSF. These results provide the first information on changes in levels of amino acids in plasma and CSF resulting from forced and voluntary exercises. PMID- 25715958 TI - Emergency department quality improvement activity: an inventory from the American Board of Emergency Medicine Maintenance of Certification program. AB - OBJECTIVES: The American Board of Emergency Medicine (ABEM) Maintenance of Certification (MOC) program requires every ABEM-certified physician to attest to participating in a quality improvement (QI) activity every 5 years. Understanding the type and frequency of these QI activities could inform the emergency medicine community about the variety of QI activities in which emergency physicians (EPs) are involved. These QI activities could provide ideas for the development of additional quality measures. METHODS: This was a retrospective descriptive study of self-reported QI activity attestations from the ABEM MOC program during 2013. Attestations were provided by ABEM-certified EPs using the ABEM MOC website. The type, number, and cumulative frequency of activities are reported. RESULTS: ABEM received 9,380 attestations for QI activities in 91 different categories. The three most commonly reported activities were acute myocardial infarction percutaneous coronary intervention within 90 minutes of arrival (includes door-to balloon time), door-to-doctor times, and throughput time measures. These three activities comprised 36.4% of attestations. More than half (54.4%) of the attestations were captured by the five most frequently attested activities, 67.1% by the top seven categories, and 89.9% by the top 21 categories. Of these 21 categories, 10 involved clinical protocols, nine were time-centered measures, and two were patient-centered activities. CONCLUSIONS: This report demonstrates that diverse QI activities occur in emergency departments (EDs) across the United States. The majority of reported projects are nested in a few categories, following recognized areas of emphasis in emergency care, particularly in areas using time-sensitive metrics. PMID- 25715959 TI - Evaluation of membrane filtration system using The "Pore Diffusion" for eliminating viruses. AB - Here, we report a first study of virus removal by a novel membrane filtration system, named the "Pore Diffusion". The "Pore Diffusion" manipulated the direction of circulating flow from vertical to parallel to the membrane, thereby achieved to alter the trans-membrane pressure as low as possible. We compared the viral activity between before and after filtration by both infectivity assay and real-time reverse transcription-PCR. Among 4 "Pore Diffusion" modules tested, the big module with average pore size of 80 nm showed the highest log reduction value of viral activity. Our study shows the possibility of "The Pore Diffusion" to filtrate viruses from bioproducts without increasing the trans-membrane pressure, so that the filtration process can be carried out effectively and economically. PMID- 25715960 TI - Localization and dynamics of amylose-lipophilic molecules inclusion complex formation in starch granules. AB - Inclusion complex formation between lipophilic dye molecules and amylose polymers in starch granules is investigated using laser spectroscopy and microscopy. By combining confocal laser scanning microscopy (CLSM) with spatial resolved photoluminescence (PL) spectroscopy, we are able to discriminate the presence of amylose in the peripheral region of regular and waxy granules from potato and corn starch, associating a clear optical fingerprint with the interaction between starch granules and lipophilic dye molecules. We show in particular that in the case of regular starch the polar head of the lipophilic dye molecules remains outside the amylose helix experiencing a water-based environment. The measurements performed on samples that have been extensively washed provide a strong proof of the specific interaction between lipid dye molecules and amylose chains in regular starch. These measurements also confirm the tendency of longer amylopectin chains, located in the hilum of waxy starch granules, to form inclusion complexes with ligands. Through real-time recording of CLSM micrographs, within a time frame of tens of seconds, we measured the dynamics of occurrence of the inclusion process between lipids and amylose located at the periphery of starch granules. PMID- 25715961 TI - Antibiotic prescribing in primary care by international medical graduates and graduates from Swedish medical schools. AB - BACKGROUND: Studies of antibiotic prescribing related to diagnosis comparing prescribers trained abroad with those trained in Sweden are lacking. OBJECTIVES: To determine whether general practices (GPs) and GP residents trained abroad had different prescribing patterns for antibiotics for common infections than those trained in Sweden using retrospective data from electronic patient records from primary health care in Kalmar County, Sweden. METHODS: Consultations with an infection diagnosis, both with and without the prescription of antibiotics to 67 GPs and residents trained in Western Europe outside Sweden and other countries, were compared with a matched control group trained in Sweden. RESULTS: For 1 year, 44101 consultations of patients with an infection diagnosis and 16276 prescriptions of antibiotics were registered. Foreign-trained physicians had 20% more visits compared with physicians trained in Sweden. The prescription of antibiotics per visit and physician in the respective groups, and independent of diagnosis, did not significantly differ between groups, when scaled down from number of consultations to number of prescribing physicians. CONCLUSIONS: There were minor and non-significant differences in antibiotic prescribing comparing GPs and residents trained abroad and in Sweden, most likely the result of an adaptation to Swedish conditions. Nevertheless, no group prescribed antibiotics in accordance to national guidelines. The results suggest that interventions are needed to reduce irrational antibiotic prescribing patterns, targeting all physicians working in Swedish primary health care. PMID- 25715962 TI - Does patient experience of multimorbidity predict self-management and health outcomes in a prospective study in primary care? AB - BACKGROUND: There is a need to better understand the mechanisms which lead to poor outcomes in patients with multimorbidity, especially those factors that might be amenable to intervention. OBJECTIVE: This research aims to explore what factors predict self-management behaviour and health outcomes in patients with multimorbidity in primary care in the UK. METHODS: A prospective study design was used. Questionnaires were mailed out to 1460 patients with multimorbidity. Patients were asked to complete a range of self-report measures including measures of multimorbidity, measures of their experience of multimorbidity and service delivery and outcomes (three measures of self-management: behaviours, Self-monitoring and Insight and medication adherence; and a measure of self reported health). RESULTS: In total, 36% (n = 499) of patients responded to the baseline survey and 80% of those respondents completed follow-up. Self-management behaviour at 4 months was predicted by illness perceptions around the consequences of individual conditions. Self-monitoring and Insight at 4 months was predicted by patient experience of 'Hassles' in health services. Self reported medication adherence at 4 months was predicted by health status, Self monitoring and Insight and 'Hassles' in health services. Perceived health status at 4 months was predicted by age and patient experience of multimorbidity. CONCLUSIONS: This research shows that different factors, particularly around patients' experiences of health care and control over their treatment, impact on various types of self-management. Patient experience of multimorbidity was not a critical predictor of self-management but did predict health status in the short term. The findings can help to develop and target interventions that might improve outcomes in patients with multimorbidity. PMID- 25715963 TI - Direct-access to abdominal ultrasonic investigation from general practice-the role in earlier cancer diagnosis. AB - BACKGROUND: Abdominal ultrasound (US) is a safe and low-cost diagnostic tool for various abdominal symptoms. Direct-access to US from general practice has been suggested as a feasible option to promote earlier cancer diagnosis because abdominal cancer often presents with non-specific and vague symptoms, and the exact location may be difficult to identify on the basis of symptoms alone. OBJECTIVE: To describe patterns of use and cancer prevalence in referred patients when providing Danish GPs with direct-access to hospital-based US. METHODS: In an observational study, GPs were given the opportunity to either refer patients directly to US or through a waiting-list at Vejle Regional Hospital in Denmark; 701 patients were included between 1 August 2009 and 31 January 2010. Data were retrieved from the local Radiology Information System, GP referrals and the Danish Cancer Registry. RESULTS: GPs referred 60% of all patients to direct access US. Cancer was diagnosed in 19 (2.7%) of the referred patients within 6 months after the US investigation. US gave rise to the suspicion of cancer in 11 of these patients (57.9%); 10 of these had been referred to direct-access US. At least one non-malignant diagnosis resulted from US in 59.5% of the cases, while 37.8% of the cases had no final diagnosis. CONCLUSION: The findings in this study might indicate that GPs refer patients assessed to have a higher risk of cancer through direct-access US. The finding was statistically non-significant, and further research is required to confirm this result. PMID- 25715964 TI - Long-term survival benefits of thrombolysis: the Royal College of General Practitioners' myocardial infarction study. AB - OBJECTIVE: To investigate whether there is a long-term survival benefit from receipt of thrombolysis in routine care particularly pre-hospital thrombolysis, using 20 year mortality data from the RCGP myocardial infarction (MI) cohort study. METHODS: During 1991-92 the RCGP MI study assessed GP delivery of thrombolysis. Participants who received pre-hospital thrombolysis (n = 290), thrombolysis in hospital (n = 781) or no thrombolysis (n = 2021) were followed and mortality data collected to June 2012. The relationship between thrombolysis and survival time was analysed using Cox regression at 28 days, 1, 5, 10, 15 years post-AMI, and at end of follow-up (~20 years post-AMI). RESULTS: Compared to those who did not receive it, participants who received thrombolysis had a significant survival benefit at 28 days [adjusted hazard ratio (HR) 0.72, 95% confidence interval (CI): 0.58-0.90]; 1 year (adjusted HR 0.69, 95% CI: 0.57 0.83); 5 years (adjusted HR 0.76, 95% CI: 0.66-0.86); 10 years (adjusted HR 0.85, 95% CI: 0.77-0.95) and 15 years (adjusted HR 0.88, 95% CI: 0.80-0.96) post-AMI until end of follow-up (adjusted HR 0.92, 95% CI: 0.84-1.00). Pre versus in hospital thrombolysis did not appear beneficial, although there was evidence among the pre-hospital group that short symptom onset-to-needle times conferred greater benefit. CONCLUSIONS: We found substantial long-term survival benefits associated with thrombolysis when used in routine care. Although primary percutaneous coronary intervention (pPCI) is now the choice treatment, thrombolysis remains an important option when pPCI cannot be delivered within 120 minutes of diagnosis. PMID- 25715965 TI - Bronchiectasis. AB - INTRODUCTION: Bronchiectasis is usually a complication of previous lower respiratory infection and/or inflammation. It causes chronic cough, copious production of sputum (often purulent), and recurrent infections, and may cause airway obstruction bearing some similarities with that seen in COPD. It may complicate respiratory conditions such as asthma or COPD. It can be associated with primary ciliary dyskinesia, primary immunodeficiencies, certain systemic diseases such as inflammatory bowel disease and rheumatoid arthritis, and foreign body inhalation. Bronchiectasis can be due to cystic fibrosis but this is excluded from this review. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with non-cystic fibrosis (non-CF) bronchiectasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions. RESULTS: We found 23 studies that met our inclusion criteria. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: airway clearance techniques, corticosteroids (inhaled), exercise or physical training, hyperosmolar agents (inhaled), mucolytics, prolonged-use antibiotics, and surgery. PMID- 25715966 TI - Protection by genistein on cortical neurons against oxidative stress injury via inhibition of NF-kappaB, JNK and ERK signaling pathway. AB - CONTEXT: Genistein, one of the isoflavones derived from soybean seeds, has been reported to exert multiple bioactivities. However, the mechanism of its action on the central nervous system is not fully understood. OBJECTIVE: To investigate the cytoprotection of genistein and its molecular mechanism against H2O2-induced cell death in primary rat cortical neurons. MATERIALS AND METHODS: Genistein (0.01, 0.1, and 1 MUM) were added into the primary rat neurons 24 h before and co cultured with 500 MUM H2O2 for 1 h. Neuronal injury was assessed by MTT, lactate dehydrogenase (LDH) assay, and Hoechst33258 staining. Intracellular reactive oxygen species (ROS) generation induced by H2O2 was determined. Neuronal apoptosis was evaluated by Bcl-2/Bax ratio as well as by caspase-9 and caspase-3 activities. The protein levels and phosphorylation of NF-kappaB/p65, IkappaB, JNK, and ERK were detected by western blots. RESULTS: Genistein pretreatment attenuated H2O2-mediated neuronal viability loss, nuclear condensation, and ROS generation in a concentration-dependent manner. Genistein exerted anti-apoptotic effects by reversing the apoptotic factors Bcl-2 and Bax ratio, along with the suppression of caspase-9 and caspase-3 activities. In addition, genistein down regulated the expression of NF-kappaB/p65, and suppressed the phosphorylation of p65 and IkappaB. Genistein also inhibited H2O2-induced activation of the MAPK signaling pathway including JNK and ERK. DISCUSSION AND CONCLUSION: The results indicated that genistein effectively protects cortical neurons against oxidative stress at least partly via inactivation of NF-kappaB as well as MAPK-signaling pathways, and suggested the possibility of this antioxidant for the prevention and treatment of stroke. PMID- 25715967 TI - Activity cliff clusters as a source of structure-activity relationship information. AB - The activity cliff (AC) concept is widely applied in medicinal chemistry. ACs are formed by compounds with small structural changes having large differences in potency. Accordingly, ACs are a primary source of structure-activity relationship (SAR) information. Through large-scale compound data mining it has been shown that the vast majority of ACs are formed in a coordinated manner by groups of structurally analogous compounds with significant potency variations. In network representations coordinated ACs form clusters of varying size but frequently recurrent topology. Recently, computational methods have been introduced to systematically organize AC clusters and extract SAR information from them. AC clusters are widely distributed over compound activity classes and represent a rich source of SAR information. These clusters can be visualized in AC networks and isolated. However, it is challenging to extract SAR information from such clusters and make this information available to the practice of medicinal chemistry. Therefore, it is essential to go beyond subjective case-by-case analysis and design computational approaches to systematically access SAR information associated with AC clusters. PMID- 25715969 TI - The skin microbiome: Associations between altered microbial communities and disease. AB - A single square centimetre of the human skin can contain up to one billion microorganisms. These diverse communities of bacteria, fungi, mites and viruses can provide protection against disease, but can also exacerbate skin lesions, promote disease and delay wound healing. This review addresses the current knowledge surrounding the healthy skin microbiome and examines how different alterations to the skin microbial communities can contribute to disease. Current methodologies are considered, changes in microbial diversity and colonisation by specific microorganisms are discussed in the context of atopic dermatitis, psoriasis, acne vulgaris and chronic wounds. The recent impact of modern Westernised lifestyles on the human skin microbiome is also examined, as well as the potential benefits and pitfalls of novel therapeutic strategies. Further analysis of the human skin microbiome, and its interactions with the host immune system and other commensal microorganisms, will undoubtedly elucidate molecular mechanisms for disease and reveal gateways for novel therapeutic treatment strategies. PMID- 25715968 TI - Reed frog diversification in the Gulf of Guinea: overseas dispersal, the progression rule, and in situ speciation. AB - Oceanic islands accumulate endemic species when new colonists diverge from source populations or by in situ diversification of resident island endemics. The relative importance of dispersal versus in situ speciation in generating diversity on islands varies with a number of archipelago characteristics including island size, age, and remoteness. Here, we characterize interisland dispersal and in situ speciation in frogs endemic to the Gulf of Guinea islands. Using mitochondrial sequence and genome-wide single-nucleotide polymorphism data, we demonstrate that dispersal proceeded from the younger island (Sao Tome) to the older island (Principe) indicating that for organisms that disperse overseas on rafts, dispersal between islands may be determined by ocean currents and not island age. We find that dispersal between the islands is not ongoing, resulting in genotypically distinct but phenotypically similar lineages on the two islands. Finally, we demonstrate that in situ diversification on Sao Tome Island likely proceeded in allopatry due to the geographic separation of breeding sites, resulting in phenotypically distinct species. We find evidence of hybridization between the species where their ranges are sympatric and the hybrid zone coincides with a transition from agricultural land to primary forest, indicating that anthropogenic development may have facilitated secondary contact between previously allopatric species. PMID- 25715970 TI - Is a smoking ban in UK parks and outdoor spaces a good idea? PMID- 25715971 TI - Inpatient aggression in community hospitals. AB - Physical violence is a frequent occurrence in acute community psychiatry units worldwide. Violent acts by patients cause many direct injuries and significantly degrade quality of care. The most accurate tools for predicting near-term violence on acute units rely on current clinical features rather than demographic risk factors. The efficacy of risk assessment strategies to lower incidence of violence on acute units is unknown. A range of behavioral and psychopharmacologic treatments have been shown to reduce violence among psychiatric inpatients. PMID- 25715972 TI - The impact of violence against women on reproductive health and child mortality in Timor-Leste. AB - OBJECTIVES: To determine differences in reproductive health and infant and child mortality and health between abused and non-abused ever-married women in Timor Leste. METHODS: Secondary data analysis of Timor-Leste Demographic Health Survey (1,959 ever-married women aged 15-49 years). Associations with violence estimated using multinomial logistic regression adjusted for sociodemographic variables and age of first intercourse. RESULTS: Overall, 45% of ever-married women experienced violence: 34% reported physical only and 11% reported combined physical, sexual and/or emotional violence. Compared to non-abused women, women reporting physical violence only were more likely to use traditional contraception (AdjOR 2.35, 95%CI 1.05-5.26) or report: a sexually transmitted infection (AdjOR 4.46, 95%CI 3.27-6.08); a pregnancy termination (AdjOR 1.42, 95%CI 1.03-1.96); a child who had died (AdjOR 1.30, 95%CI 1.05-1.60), a low birth weight infant (AdjOR 2.08, 95%CI 1.64-2.64); and partially vaccinated children (AdjOR 1.35, 95%CI 1.05 1.74). Women who reported combined abuse were more likely to report: a sexually transmitted infection (AdjOR 3.51, 95%CI 2.26-5.44); a pregnancy termination (AdjOR 1.95, 95%CI 1.27-3.01); few antenatal visits (AdjOR 1.76 95%CI 1.21-2.55); and a child who had died (AdjOR 1.45, 95%CI 1.06-2.00). CONCLUSIONS: Violence exposes women to poor reproductive health, infant and child mortality and poor infant and child health. IMPLICATIONS: Preventing and reducing violence against women should improve women and children's health outcomes in Timor-Leste. PMID- 25715973 TI - Lung cancer CT screening is cost-effective but implementation matters. PMID- 25715974 TI - [Salvage surgery in esophageal cancer : Feasibility in patients after definitive radiochemotherapy (> 50 Gy)]. AB - BACKGROUND: Salvage surgery as an additional therapy option is currently discussed for an increasing number of patients with esophageal cancer after definitive radio(chemo)therapy after tumor progression, recurrence or on explicit request of the patient. OBJECTIVES: The objective of this study was an analysis of the surgical option of salvage esophagectomy after definitive radiation in patients with esophageal cancer. Additionally the current literature on this topic was evaluated. MATERIAL AND METHODS: A total of 92 patients with esophageal cancer from a prospective database were included in this study who underwent esophagectomy either after neoadjuvant radio(chemo)therapy (< 50 Gy) or definitive radio(chemo)therapy (> 50 Gy) between 2002 and 2012. The analysis was performed retrospectively. RESULTS: The median survival of the two groups of patients was not significantly different after initial diagnosis with 24.2 months (95 % CI 0.0-51.93) for patients undergoing definitive radio(chemo)therapy and 30.7 months (95 % CI 9.3-52.2) for patients after neoadjuvant therapy (p = 0.96). Both patient groups showed no differences in pretherapeutic characteristics and response to radio(chemo)therapy. Postoperative complications and perioperative mortality were not different. DISCUSSION: Salvage esophagectomy is now an additional treatment option after definitive radio(chemo)therapy in patients with esophageal cancer. In preselected patients with tumor recurrence, progression or with a strong wish for surgical therapy, salvage surgery should be discussed in interdisciplinary tumor boards after exclusion of distant metastases. PMID- 25715976 TI - Factors related to receipt of dental care in Eastern Iowa nursing facilities. AB - OBJECTIVE: To assess factors related to nursing facility residents' receipt of dental treatment when it was offered on site. METHODS: Screening forms that included demographic, general, and dental health information were obtained from residents of 10 nursing facilities in Eastern Iowa, and their dental procedure history for up to 7 years after screening was recorded. Residents were grouped as having received either no procedures; diagnostic procedures only; or nondiagnostic procedures. RESULTS: Of the 586 residents, the mean age was 83.8 years at screening and 31.3% were edentulous. The odds of receiving nondiagnostic procedures were lower among residents who were older (OR = 0.98, 95%CI 0.96-0.99) or edentulous (OR = 0.31, 95%CI 0.20-0.46), compared to those who received no dental procedures. CONCLUSIONS: Those who were older or edentulous had lower odds of receiving nondiagnostic dental procedures. Well-designed prospective cohort studies are needed to better evaluate barriers to receipt of dental treatment among the institutionalized elderly. PMID- 25715975 TI - Probabilistic Markov Model Estimating Cost Effectiveness of Methylphenidate Osmotic-Release Oral System Versus Immediate-Release Methylphenidate in Children and Adolescents: Which Information is Needed? AB - BACKGROUND: Incidence of attention deficit hyperactivity disorder (ADHD) in children and adolescents has been increasing. The disorder results in high societal costs. Policymakers increasingly use health economic evaluations to inform decisions on competing treatments of ADHD. Yet, health economic evaluations of first-choice medication of ADHD in children and adolescents are scarce and generally do not include broader societal effects. OBJECTIVES: This study presents a probabilistic model and analysis of methylphenidate osmotic release oral system (OROS) versus methylphenidate immediate-release (IR). We investigate and include relevant societal aspects in the analysis so as to provide cost-effectiveness estimates based on a broad societal perspective. METHODS: We enhanced an existing Markov model and determined the cost effectiveness of OROS versus IR for children and adolescents responding suboptimally to treatment with IR. Enhancements included screening of a broad literature base, updated utility values, inclusion of costs and effects on caregivers and a change of the model type from deterministic to probabilistic. RESULTS: The base case scenario resulted in lower incremental costs (?-5815) of OROS compared with IR and higher incremental quality-adjusted life-year (QALY) gains (0.22). Scenario analyses were performed to determine sensitivity to changes in transition rates, utility of caregivers, medical costs of caregivers and daily medication dose. CONCLUSIONS: The results indicate that, for children responding suboptimally to treatment with IR, the beneficial effect of OROS on compliance may be worth the additional costs of medication. The presented model adds to the health economic information available for policymakers and to considerations on a broader perspective in cost-effectiveness analyses. PMID- 25715977 TI - Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60-2770 in rabbit corpus cavernosum. AB - OBJECTIVE: To characterise the relaxation induced by the soluble guanylate cyclase (sGC) activator, BAY 60-2770 (4-({(4-carboxybutyl) [2- (5-fluoro-2-{[4' (trifluoromethyl) biphenyl-4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid) in rabbit corpus cavernosum (CC). MATERIAL AND METHODS: The penis from male New Zealand rabbits was removed and fours strips of CC were obtained. Concentration response curves to BAY 60-2770 were constructed in the absence and presence of inhibitors of nitric oxide synthase, N (G)-nitro-L- arginine methyl ester (L NAME, 100 MUm), sGC, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 MUm) and phosphodiesterase type 5 (PDE-5), tadalafil (0.1 MUm). The potency (pEC50 ) and maximal response (Emax ) values were determined. Then, electrical-field stimulation (EFS)-induced contraction or relaxation was tested in the absence and presence of BAY 60-2770 (0.1 or 1 MUm) alone or combined with ODQ (10 MUm). For EFS-induced relaxation two protocols were used: (i) ODQ (10 MUm) was first incubated for 20 min and then BAY 60-2770 (1 MUm) was added for another 20 min (ODQ + BAY 60-2770); (ii) in different CC strips, BAY 60-2770 was incubated for 20 min followed by another 20 min with ODQ (BAY 60-2770 + ODQ). The intracellular levels of cyclic guanosine monophosphate (cGMP) were also determined. RESULTS: BAY 60-2770 potently relaxed rabbit CC with mean (sem) pEC50 and Emax values of 7.58 (0.19) and 81 (4)%, respectively. The inhibitors ODQ (n = 7) or tadalafil (n = 7) produced 4.2- and 6.3-leftward shifts, respectively in BAY 60-2770-induced relaxation without interfering with the Emax values. The intracellular levels of cGMP were augmented after stimulation with BAY 60-2770 (1 MUm) alone, whereas its co-incubation with ODQ produced even higher levels of cGMP. The EFS-induced contraction was reduced in the presence of BAY 60-2770 (1 MUm) and this inhibition was even greater when BAY 60-2770 was co-incubated with ODQ. The nitrergic stimulation induced CC relaxation, which was abolished in the presence of ODQ. BAY 60-2770 alone increased the amplitude of relaxation. Co-incubation of ODQ and BAY 60-2770 did not alter the relaxation in comparison with ODQ alone. Interestingly, when BAY 60-2770 was incubated before ODQ, EFS-induced relaxation was partly restored in comparison with ODQ alone or ODQ + BAY 60-2770. CONCLUSIONS: The relaxation induced by the sGC activator, BAY 60-2770 was increased after sGC oxidation and unaltered in the absence of nitric oxide. Thus, this class of substances may have advantages over sGC stimulators or PDE-5 inhibitors for treating patients with erectile dysfunction and extensive endothelial damage. PMID- 25715978 TI - Post-remission intensive treatment after induction chemotherapy is feasible in selected elderly patients with acute myeloid leukemia and age >=75 years: a retrospective analysis of the Rete Ematologica Lombarda. PMID- 25715979 TI - Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting. AB - The impact of physical and chemical modifications of nanoparticles on their biological function has been systemically investigated and exploited to improve their circulation and targeting. However, the impact of nanoparticles' flexibility (i.e., elastic modulus) on their function has been explored to a far lesser extent, and the potential benefits of tuning nanoparticle elasticity are not clear. Here, we describe a method to synthesize polyethylene glycol (PEG) based hydrogel nanoparticles of uniform size (200 nm) with elastic moduli ranging from 0.255 to 3000 kPa. These particles are used to investigate the role of particle elasticity on key functions including blood circulation time, biodistribution, antibody-mediated targeting, endocytosis, and phagocytosis. Our results demonstrate that softer nanoparticles (10 kPa) offer enhanced circulation and subsequently enhanced targeting compared to harder nanoparticles (3000 kPa) in vivo. Furthermore, in vitro experiments show that softer nanoparticles exhibit significantly reduced cellular uptake in immune cells (J774 macrophages), endothelial cells (bEnd.3), and cancer cells (4T1). Tuning nanoparticle elasticity potentially offers a method to improve the biological fate of nanoparticles by offering enhanced circulation, reduced immune system uptake, and improved targeting. PMID- 25715980 TI - Assessment of the contralateral routing of signal system in unilateral cochlear implantation. AB - OBJECTIVES: The purpose of this study was to evaluate the contribution of a contralateral routing of signal (CROS) system in unilateral cochlear implants (CI) users. DESIGN: Single-centre prospective interventional study. SETTING: Tertiary referral centre. PARTICIPANTS: Eight unilateral cochlear implants patients with >30% speech perception in silence and >6 months' implantation. MAIN OUTCOME MEASURES: Free-field speech perception assessed by 'vowel-consonant vowel' pseudoword test and free-field spatial localisation by Fournier lists on five loudspeakers (in silence and in noise). Subjective benefit assessed on the abbreviated profile of hearing aid benefit (APHAB) questionnaire. These tests were performed on the 1st and 15th day of the trial (denoted by D1 and D15, respectively). RESULTS: Contralateral routing of signal-cochlear implants provided significant improvement in speech perception at D1 and D15 in silence (P, respectively, 0.03 and 0.025) and in noise (P 0.012 and 0.036). No improvement in spatial localisation was demonstrated. The abbreviated profile of hearing aid benefit quality of life questionnaire administered at D15 showed overall benefit and a significant difference in ease of communication with versus without contralateral routing of signal. By 6 months, however, 75% of the patients (6/8) had abandoned the system due to trouble in noise (5/6), trouble with the device's wiring (3/6) and onset of headache (4/6). CONCLUSION: Contralateral routing of signal-cochlear implants is an interesting novel option, restoring a binaural effect and providing improved speech perception and non negligible comfort of hearing in certain patients, without the medical and economic costs of bilateral cochlear implants. However, the drawbacks (especially the difficulty of modulating the signal-to-noise ratio) do not presently allow it to be an effective alternative to bilateral cochlear implants. PMID- 25715981 TI - Alcohol and burden of disease in Australia: the challenge in assessing consumption. AB - OBJECTIVE: Alcohol consumption is one of the major avoidable risk factors for disease, illness and injury in the Australian community. Population health scientists and economists use estimates of alcohol consumption in burden of disease frameworks to estimate the impact of alcohol on disease, illness and injury. This article highlights challenges associated with estimating alcohol consumption in these models and provides a series of recommendations to improve estimates. METHODS: Key challenges in measuring alcohol consumption at the population level are identified and discussed with respect to how they apply to burden of disease frameworks. RESULTS: Methodological advances and limitations in the estimation of alcohol consumption are presented with respect to use of survey data, population distributions of alcohol consumption, consideration of 'patterns' of alcohol use including 'bingeing', and capping exposure. Key recommendations for overcoming these limitations are provided. Implications and conclusion: Alcohol-related burden has a significant impact on the health of the Australian population. Improving estimates of alcohol related consumption will enable more accurate estimates of this burden to be determined to inform future alcohol policy by legislators. PMID- 25715982 TI - Identification of homozygous deletion in ACAN and other candidate variants in familial classical Hodgkin lymphoma by exome sequencing. PMID- 25715983 TI - Platelet-rich plasma for muscle injuries: game over or time out? AB - Muscle injuries are common and may be associated with impaired functional capacity, especially among athletes. The results of healing with conventional therapy including rest, ice, compression, and elevation (RICE) are often inadequate, generating substantial interest in the potential for emerging technologies such as platelet-rich plasma (PRP) to enhance the process of soft tissue healing and to decrease time to recovery. In vitro studies and animal research have suggested that PRP may have benefits associated with the increased release of cytokines and growth factors resulting from supraphysiological concentrations of platelets that facilitate muscle repair, regeneration, and remodeling. Despite the promise of basic science, there is a paucity of clinical data to support the theoretical benefits of PRP. The only double-blind controlled clinical trial was recently reported and showed no benefit of PRP in the time to resume sports activity among athletes with hamstring muscle injury. This review examines the current evidence and the theoretical framework for PRP and muscle healing. Scientific gaps and technological barriers are discussed that must be addressed if the potential promise of PRP as a therapeutic modality for muscle injury is to be realized. PMID- 25715985 TI - 2015 Carl W. Gottschalk Distinguished Lectureship of the American Physiological Society Renal Section. PMID- 25715984 TI - Recent advances in renal hemodynamics: insights from bench experiments and computer simulations. AB - It has been long known that the kidney plays an essential role in the control of body fluids and blood pressure and that impairment of renal function may lead to the development of diseases such as hypertension (Guyton AC, Coleman TG, Granger Annu Rev Physiol 34: 13-46, 1972). In this review, we highlight recent advances in our understanding of renal hemodynamics, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal: Renal Hemodynamics: Integrating with the Nephron and Beyond. PMID- 25715986 TI - Albumin impairs renal tubular tight junctions via targeting the NLRP3 inflammasome. AB - Proteinuria is, not only a hallmark of glomerular disease, but also a contributor to kidney injury. However, its pathogenic mechanism is still elusive. In the present study, the effects of albumin on renal tubular tight junctions and the potential molecular mechanisms of those effects were investigated. In mouse proximal tubular cells (mPTCs), albumin treatment resulted in a significant loss of the cellular tight junction proteins zonula occludens-1 (ZO-1) and claudin-1 in a time- and dose-dependent manner, indicating a severe impairment of the tight junctions. On the basis of our previous study showing that albumin stimulated NLRP3 [neuronal apoptosis inhibitor protein, major histocompatibility complex class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT); leucine-rich repeat (LRR); and pyrin domain (PYD) domains-containing protein 3] inflammasome activation in mPTCs, we pretreated mPTCs with NLRP3 siRNA (siNLRP3) and found that NLRP3 knockdown significantly blocked the downregulation of ZO-1 and claudin-1 induced by albumin. Similarly, in albumin-overloaded wild-type mice, both ZO-1 and claudin-1 were downregulated at the protein and mRNA levels in parallel with the impaired formation of the tight junctions on transmission electron microscopy and the abnormal renal tubular morphology on periodic acid-Schiff staining, which contrasted with the stimulation of NLRP3 in the renal tubules. In contrast, NLRP3 knockout (NLRP3(-/-)) mice preserved normal ZO-1 and claudin-1 expression as well as largely normal tight junctions and tubular morphology. More importantly, deletion of the NLRP3 pathway downstream component caspase-1 similarly blocked the albumin overload-induced downregulation of ZO-1 and claudin-1. Taken together, these findings demonstrated an important role of the albumin-NLRP3 inflammasome axis in mediating the impairment of renal tubular tight junctions and integrity. PMID- 25715988 TI - Excess prenatal corticosterone exposure results in albuminuria, sex-specific hypotension, and altered heart rate responses to restraint stress in aged adult mice. AB - Exposure to excess glucocorticoids programs susceptibility to cardiovascular and renal dysfunction in later life although the mechanisms have not been clearly elucidated. We administered corticosterone (CORT; 33 MUg.kg(-1).h(-1)) to pregnant mice for 60 h from embryonic day (E) 12.5. Prenatal CORT resulted in postnatal growth restriction and reduced nephron endowment at postnatal day 30 in both male and female offspring. The reduction in nephron number was associated with increased expression of apoptotic markers in the kidney at E14.5. In offspring of both sexes at 12 mo of age, there were no differences in kidney weights, urine output, or urinary sodium excretion; however, prenatal CORT exposure increased the urinary albumin/creatinine ratio and 24-h urinary albumin excretion. Surprisingly, at 12 mo male but not female offspring exposed to prenatal CORT were hypotensive, with mean arterial blood pressures ~10 mmHg lower than untreated controls (P < 0.001). Finally, we examined how offspring responded to a renal or cardiovascular challenge (saline load or restraint stress). When given 0.9% NaCl as drinking water for 7 days, there were no differences in blood pressures or urinary parameters between groups. Restraint stress (15 min) caused a tachycardic response in all animals; however the increase in heart rate was not sustained in male offspring exposed to CORT (P < 0.01), suggesting that autonomic control of cardiovascular function may be altered. These data demonstrate that excess prenatal CORT impairs kidney development and increases the risk of cardiovascular dysfunction especially in males. PMID- 25715987 TI - Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron. AB - Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (-7.9 +/- 0.2 mmHg) was blocked by furosemide (-0.4 +/- 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: -0.2 +/- 0.1 vs. furosemide+benzamil: -4.3 +/- 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 +/- 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: -1.1 +/- 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors. PMID- 25715989 TI - Discrepancies in describing pain: is there agreement between numeric rating scale scores and pain reduction percentage reported by patients with musculoskeletal pain after corticosteroid injection? AB - OBJECTIVE: Pain intensity is commonly rated on an 11-point Numerical Pain Rating Scale which can be expressed as a calculated percentage pain reduction (CPPR), or by patient-reported percentage pain reduction (PRPPR). We aimed to determine the agreement between CPPR and PRPPR in quantifying musculoskeletal pain improvement at short-term follow-up after a corticosteroid injection. DESIGN: Retrospective cohort study. SETTING: Urban, academic, physical medicine, and rehabilitation outpatient interventional musculoskeletal and spine center. METHODS: The agreement between CPPR and PRPPR was determined by concordance correlation coefficient (CCC) in subjects who had experienced improvement in musculoskeletal or radicular pain 3 weeks after a first-time injection at our clinic. Subjects who experienced unchanged pain (PRPPR = 0) were compared to CPPR with paired t test. RESULTS: We examined 197 subjects with greater than 3/10 pain who underwent first-time fluoroscopic-guided corticosteroid injections. Ninety-three subjects reported higher PRPPR than CPPR values, and 41 subjects reported higher CPPR values. The CCC between CPPR and PRPPR was 0.44 (95% CI 0.35-0.54), with a precision of 0.54 and an accuracy of 0.81, and 95% limits of agreement ranging between -41% and +73%. Values for CCC, precision, and accuracy were higher for males compared to females and were highest in the youngest age group (18-40) and lowest in the middle age group (41-60). CONCLUSIONS: PRPPR may not agree with CPPR at 3 week follow-up, as these individuals tend to report a higher estimated percentage improvement compared to the value calculated from their pain scores. PMID- 25715990 TI - SIMPLEr not to test implantable cardioverter defibrillators? PMID- 25715991 TI - Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). AB - BACKGROUND: Defibrillation testing by induction and termination of ventricular fibrillation is widely done at the time of implantation of implantable cardioverter defibrillators (ICDs). We aimed to compare the efficacy and safety of ICD implantation without defibrillation testing versus the standard of ICD implantation with defibrillation testing. METHODS: In this single-blind, randomised, multicentre, non-inferiority trial (Shockless IMPLant Evaluation [SIMPLE]), we recruited patients aged older than 18 years receiving their first ICD for standard indications at 85 hospitals in 18 countries worldwide. Exclusion criteria included pregnancy, awaiting transplantation, particpation in another randomised trial, unavailability for follow-up, or if it was expected that the ICD would have to be implanted on the right-hand side of the chest. Patients undergoing initial implantation of a Boston Scientific ICD were randomly assigned (1:1) using a computer-generated sequence to have either defibrillation testing (testing group) or not (no-testing group). We used random block sizes to conceal treatment allocation from the patients, and randomisation was stratified by clinical centre. Our primary efficacy analysis tested the intention-to-treat population for non-inferiority of no-testing versus testing by use of a composite outcome of arrhythmic death or failed appropriate shock (ie, a shock that did not terminate a spontaneous episode of ventricular tachycardia or fibrillation). The non-inferiority margin was a hazard ratio (HR) of 1.5 calculated from a proportional hazards model with no-testing versus testing as the only covariate; if the upper bound of the 95% CI was less than 1.5, we concluded that ICD insertion without testing was non-inferior to ICD with testing. We examined safety with two, 30 day, adverse event outcome clusters. The trial is registered with ClinicalTrials.gov, number NCT00800384. FINDINGS: Between Jan 13, 2009, and April 4, 2011, of 2500 eligible patients, 1253 were randomly assigned to defibrillation testing and 1247 to no-testing, and followed up for a mean of 3.1 years (SD 1.0). The primary outcome of arrhythmic death or failed appropriate shock occurred in fewer patients (90 [7% per year]) in the no-testing group than patients who did receive it (104 [8% per year]; HR 0.86, 95% CI 0.65-1.14; pnon inferiority <0.0001). The first safety composite outcome occurred in 69 (5.6%) of 1236 patients with no-testing and in 81 (6.5%) of 1242 patients with defibrillation testing, p=0.33. The second, pre-specified safety composite outcome, which included only events most likely to be directly caused by testing, occurred in 3.2% of patients with no-testing and in 4.5% with defibrillation testing, p=0.08. Heart failure needing intravenous treatment with inotropes or diuretics was the most common adverse event (in 20 [2%] of 1236 patients in the no-testing group vs 28 [2%] of 1242 patients in the testing group, p=0.25). INTERPRETATION: Routine defibrillation testing at the time of ICD implantation is generally well tolerated, but does not improve shock efficacy or reduce arrhythmic death. FUNDING: Boston Scientific and the Heart and Stroke Foundation (Ontario Provincial office). PMID- 25715992 TI - West African Ebola crisis and orphans. PMID- 25715993 TI - Health Literacy as a Social Determinant of Health in Asian American Immigrants: Findings from a Population-Based Survey in California. AB - BACKGROUND: Asian American immigrants have a lower level of health literacy than non-Latino whites, but their level of health literacy and its impact on health outcomes may differ among subgroups. OBJECTIVE: We investigated the level of health literacy across five subgroups of Asian American immigrants and explored the association between health literacy and self-rated health status and symptoms of depression. DESIGN: We utilized a cross-sectional survey research design and a population-based sampling strategy using the 2007 California Health Interview Survey (CHIS). PARTICIPANTS: We sampled 30,615 non-Latino whites and 3,053 Asian American immigrants (1,058 Chinese, 598 Koreans, 534 Filipinos, 416 South Asians, and 447 Vietnamese). MAIN MEASURES: We used two questions as proxy measures to assess the level of health literacy in non-Latino whites and in both aggregated and disaggregated Asian American immigrant groups. We then investigated the effect of health literacy on two main health outcomes: self-rated health status and depression symptoms. KEY RESULTS: The level of health literacy varied across the five subgroups of Asian American immigrants. Chinese, Korean, and Vietnamese groups had the lowest levels of health literacy, while Filipinos showed the highest level. Health literacy was positively correlated with health status in Chinese and Korean immigrants, and negatively correlated with depression symptoms in Korean and South Asian immigrants. CONCLUSION: We found heterogeneity in health literacy among Asian American immigrants and found that health literacy had varying associations with health outcomes. The aggregated Asian American immigrant group results may mask the true health disparities that each Asian American immigrant group faces. Koreans were the only group found to have a significant association between the proxy for health literacy and both health outcomes. Further research is needed to better understand the causes of heterogeneity and to investigate health literacy as a critical determinant of immigrant health. PMID- 25715994 TI - Comparison of Response of DRI Oxycodone Semiquantitative Immunoassay With True Oxycodone Values Determined by Liquid Chromatography Combined With Tandem Mass Spectrometry: Sensitivity of the DRI Assay at 100 ng/ml Cut-Off and Validity of Semiquantitative Value. AB - OBJECTIVE: Oxycodone is a widely used opioid for pain management and patient's compliance with therapy is often monitored by using oxycodone immunoassay. The performance of the DRI oxycodone immunoassay was compared with liquid chromatography combined with tandem mass spectrometry (LC/MS/MS) assay. MATERIALS AND METHODS: In 48 urine specimens collected from patients taking oxycodone, urinary oxycodone concentrations were determined using LC/MS/MS and the DRI oxycodone immunoassay for application on the Cobas c 501 analyzer (Roche Diagnostics, Indianapolis, IN). RESULTS: Out of 48 specimens, 14 specimens showed oxycodone value less than 100 ng/ml, seven specimens had low positive values (between 101 and 165 ng/ml) and all other specimens had values 165 to 1789 ng/ml using the LC/MS/MS assay. The DRI oxycodone assay successfully identified all oxycodone specimens with oxycodone concentrations over the 100 ng/ml. In addition, the DRI assay also showed positive response in 11 out of 14 specimens with oxycodone values less than 100 ng/ml. However, semiquantitative values obtained by the DRI assay did not match with true oxycodone and metabolite oxymorphone concentrations combined obtained by using LC/MS/MS. CONCLUSIONS: DRI oxycodone immunoassay at 100 ng/ml is a reliable immunoassay for analysis of oxycodone in urine. PMID- 25715995 TI - Prevalence of DSM-IV disorders in a population-based sample of 5- to 8-year-old children: the impact of impairment criteria. AB - This study determined the impact of impairment criteria on the prevalence and patterns of comorbidity of child DSM-IV disorders. The validity of these impairment criteria was tested against different measures of mental health care referral and utilization. We interviewed parents of 1,154 children aged 5-8 years in-depth using the Diagnostic Interview Schedule for Children in Rotterdam, the Netherlands, to establish DSM-IV diagnosis. These children were randomly selected or oversampled based on Child Behavior Checklist ratings from a large population based study (N = 6,172). Referral data were extracted from the psychiatric interview as well as from a follow-up questionnaire. The results showed an overall prevalence of DSM-IV disorders of 31.1 % when impairment was not considered. This rate declined to 22.9 % when mild impairment was required and declined even further, to 10.3 %, for more severe levels of impairment. Similarly, the overall comorbidity rate declined from 8.5 to 6.7 and 2.7 % when mild and severe impairment were required, respectively. Virtually all children who attained symptom thresholds for a specific disorder, and had been referred to a mental health care professional because of the associated symptoms, also had mild impairment. The requirement of severe impairment criteria significantly increased diagnostic thresholds, but for most disorders, this definition captured only half of the clinically referred cases. In conclusion, prevalence was highly dependent upon the criteria used to define impairment. If severe impairment is made a diagnostic requirement, many children with psychiatric symptoms and mild impairment seeking mental health care will be undiagnosed and possibly untreated. PMID- 25715996 TI - The discriminative capacity of CBCL/11/2-5-DSM5 scales to identify disruptive and internalizing disorders in preschool children. AB - This paper studies the discriminative capacity of CBCL/11/2-5 (Manual for the ASEBA Preschool-Age Forms & Profiles, University of Vermont, Research Center for Children, Youth, & Families, Burlington, 2000) DSM5 scales attention deficit and hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), anxiety and depressive problems for detecting the presence of DSM5 (DSM5 diagnostic and statistical manual of mental disorders, APA, Arlington, 2013) disorders, ADHD, ODD, Anxiety and Mood disorders, assessed through diagnostic interview, in children aged 3-5. Additionally, we compare the clinical utility of the CBCL/11/2 5-DSM5 scales with respect to analogous CBCL/11/2-5 syndrome scales. A large community sample of 616 preschool children was longitudinally assessed for the stated age group. Statistical analysis was based on ROC procedures and binary logistic regressions. ADHD and ODD CBCL/11/2-5-DSM5 scales achieved good discriminative ability to identify ADHD and ODD interview's diagnoses, at any age. CBCL/11/2-5-DSM5 Anxiety scale discriminative capacity was fair for unspecific anxiety disorders in all age groups. CBCL/11/2-5-DSM5 depressive problems' scale showed the poorest discriminative capacity for mood disorders (including depressive episode with insufficient symptoms), oscillating into the poor-to-fair range. As a whole, DSM5-oriented scales generally did not provide evidence better for discriminative capacity than syndrome scales in identifying DSM5 diagnoses. CBCL/11/2-5-DSM5 scales discriminate externalizing disorders better than internalizing disorders for ages 3-5. Scores on the ADHD and ODD CBCL/11/2-5-DSM5 scales can be used to screen for DSM5 ADHD and ODD disorders in general populations of preschool children. PMID- 25715997 TI - Determination of pharmacokinetics of chrysin and its conjugates in wild-type FVB and Bcrp1 knockout mice using a validated LC-MS/MS method. AB - Chrysin, a flavone found in many plants, is also available as a dietary supplement because of its reported anticancer activities. However, its bioavailability is very poor due to extensive phase II metabolism. The purpose of this study was to develop an UPLC-MS/MS method to simultaneously quantify chrysin and its phase II metabolites, and to determine its pharmacokinetics in FVB wild type and Bcrp knockout (Bcrp1 -/-) mice. In addition, the role of BCRP in chrysin phase II disposition was further investigated in Caco-2 cells. The results showed that our sensitive and reproducible UPLC-MS/MS method was successfully applied to the pharmacokinetic study of chrysin in wild-type and Bcrp1 (-/-) FVB mice after oral administration (20 mg/kg). Although there was no significant change in systemic exposure of chrysin and its metabolites, it was found that the Tmax for chrysin glucuronide was significantly shorter (p < 0.01) in Bcrp1-deficient mice. Furthermore, it was shown that inhibition of BCRP by Ko143 significantly reduced the efflux of chrysin sulfate in Caco-2 cells. In conclusion, BCRP had significant but less than expected impact on pharmacokinetics of chrysin and its conjugates, which were determined using a newly developed and validated LC-MS/MS method. PMID- 25715998 TI - Susceptibility of Aedes albopictus and Aedes aegypti to three imported Chikungunya virus strains, including the E1/226V variant in Taiwan. AB - BACKGROUND/PURPOSE: An E1/226V variant Chikungunya virus (CHIKV) efficiently transmitted by Aedes albopictus to humans poses a significant threat to public health for those areas with the presence of Aedes albopictus, including Taiwan. METHODS: We infected three imported CHIKV isolates including the E1/226V variant with Ae. albopictus and Aedes aegypti in the laboratory to understand the disease risk. Viral RNA was measured by real time reverse transcription polymerase chain reaction. RESULTS: The viral susceptibility varied by virus strain and mosquito species and strain. The Asian virus strain started to replicate at 5-6 days post infection (dpi) with the maximum virus yield, ranging from 10(3.63) to 10(3.87) at 5-10 dpi in both species. The variant CHIKV Central/East/South African (CESA) virus genotype replicated earlier at 1 dpi with the maximum virus yield ranging from 10(5.63) to 10(6.52) at 3-6 dpi in Ae. albopictus females while the nonvariant virus strain replicated at 1-2 dpi with the maximum virus yield ranging from 10(5.51) to 10(6.27) at 6-12 dpi. In Ae. aegypti, these viruses replicated at 1-2 dpi, with maximum yields at 4-5 dpi (range from 10(5.38) to 10(5.62)). CONCLUSION: We concluded that the risk of CHIKV in Taiwan is high in all distribution areas of Ae. aegypti and Ae. albopictus for the CESA genotype and that the E1/226V variant virus strain presents an even higher risk. PMID- 25715999 TI - The role of KCa3.1 channels in cardiac fibrosis induced by pressure overload in rats. AB - The intermediate-conductance Ca(2+)-activated K(+) (KCa3.1) channels play a pivotal role in the proliferation and collagen secretion of cardiac fibroblasts. However, their contribution in cardiac fibrosis remains unknown. This study was designed to investigate whether KCa3.1 channels mediate the development of cardiac fibrosis. Pressure-overloaded rats were induced by abdominal aortic constriction and treated without or with KCa3.1 blocker (TRAM-34) or angiotensin type 1 receptor blocker (losartan) for 2 weeks. Besides the increase of blood pressure, angiotensin (Ang) II level in the plasma and myocardium, left ventricle mass and hydroxyproline concentration, myocardial hypertrophy, as well as significant collagen deposition in the perivascular regions and interstitium of the myocardium were observed in pressure-overloaded rats. The expression of leukocyte differentiation antigens (CD45 and CD3), macrophage surface marker (F4/80), tumor necrosis factor alpha, and monocyte chemotactic protein-1 (MCP-1) also significantly increased. All these alterations were prevented by losartan and TRAM-34. TRAM-34 also reduced the increase of renin and angiotensinogen in the plasma and myocardium of pressure-overloaded rats. Ang II promoted the migration of monocytes through endothelial cells and the secretion of MCP-1 from human umbilical vein endothelial cells in vitro, which was inhibited by TRAM-34. In conclusion, the present study demonstrates that TRAM-34 alleviates cardiac fibrosis induced by pressure overload, which is related to its inhibitory action on KCa3.1 channels and Ang II level. Our findings indicate that the inhibition of KCa3.1 channels may represent a novel approach of preventing the progression of cardiac fibrosis, and also add to the already developing literature of promising targets for TRAM-34. PMID- 25716001 TI - Characterization of Amphora sp., a newly isolated diatom wild strain, potentially usable for biodiesel production. AB - Microalgae as feedstock for biofuel production have attracted serious consideration as an important sustainable source of energy. For biodiesel production with microalgae, a series of consecutive processes should be performed as selection of adequate microalgal strains, mass culture, cell harvesting, oil extraction and transesterification. The aim of this study was to investigate the growth and lipid accumulation of a new isolated marine microalgal strain by optimizing culture medium composition and applying different stressful culture conditions. Microalga CTM 20023 was isolated from the evaporating salt-ponds at Sfax, Tunisia, using serial-dilution technique from enriched cultures. Phylogenetic analysis based on SSU rDNA and rbcL-3P sequences attributed this isolate to a new species of the Amphora genus. This wild strain possesses rapid gravity sedimentation of 2.91 m h(-1), suitable for an easy and low-cost biomass harvest. The optimization of the composition of the culture medium through statistical experimental designs improved the specific growth rate of Amphora sp. from 0.149 to 0.262 day(-1) and increased its 15-day culture biomass production from 465 to 2200 mg L(-1) (dw) and its lipid content from 140 to 370 mg g(-1) (dw). Highest biomass productivity of 178 mg L(-1) day(-1) was achieved at the 10th day of culture. Highest lipid content of 530 mg g(-1) (dw) was obtained under phosphorus starvation and 64.34% of these lipids were saturated fatty acids. A first growth stage, in optimized condition, would thus offer the maximum productivity for an algal biomass feed stream, followed by second stressful stage for lipid accumulation, thus suitable for biodiesel production. PMID- 25716000 TI - Complement C1q-induced activation of beta-catenin signalling causes hypertensive arterial remodelling. AB - Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates beta-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of beta-catenin signalling in hypertensive arterial remodelling. Activation of beta-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of beta-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced beta-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of beta-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension. PMID- 25716002 TI - Management of segmental bone defects. AB - Segmental bone defects cause significant disability in patients. Modern orthopaedic surgical techniques have proved to be reliable for reconstruction of these defects. Autogenous bone graft remains the standard of care for reconstruction of small defects (<5 cm). Induced membrane technique and distraction osteogenesis are contemporary strategies of choice for reconstruction of larger bony defects. The use of vascularized fibular grafts has waned in popularity because of donor site morbidity and the success of alternative methods. Complications are ubiquitous with all methods of reconstruction for segmental bone defects but can be limited with careful surgical judgment and technique. In most cases, the rehabilitation period is prolonged, although some treatment options are shorter and enable a more active recovery than do others. PMID- 25716003 TI - AAOS Clinical Practice Guideline: Detection and Nonoperative Management of Pediatric Developmental Dysplasia of the Hip in Infants up to Six Months of Age. PMID- 25716004 TI - Instructional course lectures: the need for structural allograft biomechanical guidelines. PMID- 25716005 TI - Triazole-containing N-acyl homoserine lactones targeting the quorum sensing system in Pseudomonas aeruginosa. AB - In an attempt to devise new antimicrobial treatments for biofilm infections, the bacterial cell-cell communication system termed quorum sensing has emerged as an attractive target. It has proven possible to intercept the communication system by synthetic non-native ligands and thereby lower the pathogenesis and antibiotic tolerance of a bacterial biofilm. To identify the structural elements important for antagonistic or agonistic activity against the Pseudomonas aeruginosa LasR protein, we report the synthesis and screening of new triazole-containing mimics of natural N-acyl homoserine lactones. A series of azide- and alkyne-containing homoserine lactone building blocks was used to prepare an expanded set of 123 homoserine lactone analogues through a combination of solution- and solid-phase synthesis methods. The resulting compounds were subjected to cell-based quorum sensing screening assays, thereby revealing several bioactive compounds, including 13 compounds with antagonistic activity and 9 compounds with agonistic activity. PMID- 25716006 TI - Molecular features and toxicological properties of four common pesticides, acetamiprid, deltamethrin, chlorpyriphos and fipronil. AB - Structural features and selected physicochemical properties of four common pesticides: acetamiprid (neonicotinoid), chlorpyriphos (organophosphate insecticide), deltamethrin (pyrethroid) and fipronil (phenylpyrazole) have been investigated by Density Functional Theory quantum chemical calculations. The high flexible character of these insecticides is revealed by the numerous conformers obtained, located within a 20kJmol(-1) range in the gas phase. In line with this trend, a redistribution of the energetic minima is observed in water medium. Molecular electrostatic potential calculations provide a ranking of the potential interaction sites of the four insecticides. The theoretical studies reported in the present work are completed by comparative toxicological assays against three aphid strains. Thus, the same toxicity order for the two susceptible strains Myzus persicae 4106A and Acyrthosiphon pisum LSR1: acetamiprid>fipronil>deltamethrin>chlorpyriphos is revealed. In the resistant strain M. persicae 1300145, the toxicity order is modified: acetamiprid>fipronil>chlorpyriphos>deltamethrin. Interestingly, the strain 1300145 which is known to be resistant to neonicotinoids, is also less sensitive to deltamethrin, chlorpyriphos and fipronil. PMID- 25716007 TI - Structure activity studies of nociceptin/orphanin FQ(1-13)-NH2 derivatives modified in position 5. AB - Nociceptin/orphanin FQ (N/OFQ) is a heptadecapeptide acting as the endogenous ligand of the N/OFQ peptide receptor (NOP). N/OFQ(1-13)-NH2 is the shortest N/OFQ sequence maintaining the same potency and efficacy as the natural peptide. Thus N/OFQ(1-13)-NH2 was used as chemical template for investigating the structure activity relationship of threonine in position 5. 28 [X(5)]N/OFQ(1-13)-NH2 derivatives, in which Thr was substituted with natural and unnatural residues, were synthesized and characterized pharmacologically for their effects at the human NOP receptor. Two different functional assays were used: agonist stimulated [(35)S]GTPgammaS binding in cell membranes and calcium mobilization in whole cells co-expressing chimeric G proteins. All [X(5)]N/OFQ(1-13)-NH2 derivatives behaved as full NOP agonists showing large differences in their potency. There was an excellent correlation between the results obtained in the two assays. The results of this study suggest that: position 5 does not play a pivotal role in receptor activation; the secondary alcoholic function of Thr is not important for receptor binding; side chain size, lipo/hydrophilic balance as well as hydrogen bond capability are also not crucial for receptor binding; an aliphatic amino function positively charged with at least 3 carbon atom distance from the peptide backbone has a huge disrupting effect on receptor binding. In conclusion this study demonstrates that a simple ethyl side chain as in compound 23 is sufficient in N/OFQ position 5 for maintaining bioactivity. PMID- 25716008 TI - Goblet cell density association with tear function and ocular surface physiology. AB - PURPOSE: To determine the relationship of goblet cell density (GCD) with tear function and ocular surface physiology. METHODS: This was a cross-sectional study conducted in 35 asymptomatic subjects with mean age 23.8+/-3.6 years. Tear film assessment, conjunctiva and cornea examination were done in each subject. Conjunctival impression cytology was performed by applying Nitrocellulose Millipore MFTM-Membrane filter over the superior bulbar conjunctiva. The filter paper was than fixed with 96% ethanol and stained with Periodic Acid Schiff, Hematoxylin and Eosin. GCD was determined by optical microscopy. Relation between GCD and Schirmer score, tear break-up time (TBUT), bulbar redness, limbal redness and corneal staining was determined. RESULTS: The mean GCD was 151+/-122 cells/mm(2). GCD was found higher in eyes with higher Schirmer score but it was not significant (p=0.75). There was a significant relationship of GCD with TBUT (p=0.042). GCD was not correlated with bulbar redness (p=0.126), and limbal redness (p=0.054) as well as corneal staining (p=0.079). No relationship of GCD with age and gender of the subjects (p>0.05) was observed. CONCLUSION: GCD was found correlated with TBUT but no significant correlation was found with the aqueous portion of the tear, limbal as well as bulbar redness and corneal staining. PMID- 25716009 TI - In vitro and in vivo evaluation of strontium-containing nanostructured carbonated hydroxyapatite/sodium alginate for sinus lift in rabbits. AB - Various synthetic bone substitutes have been developed to reconstruct bone defects. One of the most prevalent ceramics in bone treatment is hydroxyapatite (HA) that is a useful material as bone substitute, however, with a low rate of biodegradation. Its structure allows isomorphic cationic and anionic substitutions to be easily introduced, which can alter the crystallinity, morphology, biocompatibility, and osteoconductivity. The objective of this study was to investigate the in vitro and in vivo biological responses to strontium containing nanostructured carbonated HA/sodium alginate (SrCHA) spheres (425=3 DT (P for trend = 0.01), and this significant relationship was observed even in those without periodontal pocket formation (P for trend = 0.03) or missing teeth (P for trend = 0.02). DT was significantly related to overweight/obesity and the MetS components of hypertension, dyslipidemia, and hyperglycemia, with adjusted ORs of 1.35 (95% CI, 1.19-1.53), 1.22 (95% CI, 1.07 1.39), 1.18 (95% CI, 1.03-1.34), and 1.33 (95% CI, 1.13-1.56), respectively. In addition, even in non-overweight/non-obese men, DT was found to be related to dyslipidemia and hyperglycemia, though with marginal significance (P < 0.05). CONCLUSIONS: Our findings suggest that having DT is related to MetS in early middle-aged Japanese men directly and through obesity and is independent of health behaviors, periodontal condition, and tooth loss. PMID- 25716057 TI - Interaction between curcumin and human serum albumin in the presence of excipients and the effect of binding on curcumin photostability. AB - Curcumin (Cur) is known to bind to human serum albumin (HSA) which may lead to a reduced phototoxic effect of the compound in the presence of serum or saliva. The influence of excipients on the Cur-HSA binding was studied by HSA florescence quenching and Cur absorption and emission spectroscopy in the presence and absence of the selected excipients. Photostabilty of Cur in the presence of HSA was evaluated, as well as the effect of excipients on HSA bound Cur photodegradation. Cyclodextrins (CDs) (2-hydroxypropyl-beta-cyclodextrin and 2 hydroxypropyl-gamma-cyclodextrin) and polymers (polyethylene glycol 400, PEG 400 and Pluronic F-127, PF-127) were selected for the study. CDs and PF-127 seem to decrease Cur binding to HSA, probably through competitive binding. Cur was still bound to HSA in polyethylene glycol (PEG) solutions at the highest investigated concentration (5% w/v). However, high PEG concentration appears to have effect on the protein conformation, as shown by the fluorescence quenching study. Low Cur photostability in the presence of HSA could be improved by the addition of hydroxylpropyl-gamma-cyclodextrin (HPgammaCD) to the samples, whereas PEG and PF 127 showed no effect. PMID- 25716058 TI - Effects of hexagonal boron nitride on dry compression mixture of Avicel DG and Starch 1500. AB - The objective of this study was to investigate the lubrication properties of hexagonal boron nitride (HBN) on a (1:1) binary mixture of Avicel DG and Starch 1500 after using the dry granulation-slugging method and compare it with conventional lubricants, such as magnesium stearate (MGST), glyceryl behenate (COMP) and stearic acid (STAC). MGST is one of the most commonly used lubricants in the pharmaceutical industry. However, it has several adverse effects on tablet properties. In our current study, we employed various methods to eradicate the work hardening phenomenon in dry granulation, and used HBN as a new lubricant to overcome the adverse effects of other lubricants on tablet properties. HBN was found to be as effective as MGST and did not show any significant adverse effects on the crushing strength or work hardening. From the scanning electron microscope (SEM) images, it was concluded that HBN distributed better than MGST. As well as showing better distribution, HBN's effect on disintegration was the least pronounced. Semi-quantitative weight percent distribution of B and N elements in the tablets was obtained using EDS (energy dispersive spectroscopy). Based on atomic force microscope (AFM) surface roughness images, formulations prepared with 1% HBN showed better plastic character than those prepared with MGST. PMID- 25716059 TI - Resampling (bootstrapping) the mean: A definite do. AB - There has been discussion lately about whether bootstrap versus permutations methods are the more appropriate in diagnostic psychophysiology, especially in the context of concealed information tests (CITs), also called guilty knowledge tests (GKTs). We review the use of bootstrapping in most published CIT/GKT studies (where means, or correlations, as opposed to peak amplitudes are estimated) and find them valid and reliable. When bootstrapping and permutations were applied to the same synthesized ERP datasets, they agreed 98.1% of the time, averaged over 24,000 iterations. PMID- 25716060 TI - Comparative pharmacokinetics of purified flaxseed and associated mammalian lignans in male Wistar rats. AB - Consumption of flaxseed lignans is associated with various health benefits; however, little is known about the bioavailability of purified lignans in flaxseed. Data on their bioavailability and hence pharmacokinetics (PK) are necessary to better understand their role in putative health benefits. In the present study, we conducted a comparative PK analysis of the principal lignan of flaxseed, secoisolariciresinol diglucoside (SDG), and its primary metabolites, secoisolariciresinol (SECO), enterodiol (ED) and enterolactone (EL) in rats. Purified lignans were intravenously or orally administered to each male Wistar rat. SDG and its primary metabolites SECO, ED and EL were administered orally at doses of 40, 40, 10 and 10 mg/kg, respectively, and intravenously at doses of 20, 20, 5 and 1 mg/kg, respectively. Blood samples were collected at 0 (pre-dose), 5, 10, 15, 20, 30 and 45 min, and at 1, 2, 4, 6, 8, 12 and 24 h post-dosing, and serum samples were analysed. PK parameters and oral bioavailability of purified lignans were determined by non-compartmental methods. In general, administration of the flaxseed lignans SDG, SECO and ED demonstrated a high systemic clearance, a large volume of distribution and short half-lives, whereas administration of EL at the doses of 1 mg/kg (intravenously) and 10 mg/kg (orally administered) killed the rats within a few hours of dosing, precluding a PK analysis of this lignan. PK parameters of flaxseed lignans exhibited the following order: systemic clearance, SDG < SECO < ED; volume of distribution, SDG < SECO < ED; half-life, SDG < ED < SECO. The percentage of oral bioavailability was 0, 25 and < 1 % for SDG, SECO and ED, respectively. PMID- 25716061 TI - Pixantrone: a novel anthracycline-like drug for the treatment of non-Hodgkin lymphoma. AB - INTRODUCTION: The current treatment approach of high-grade non-Hodgkin lymphoma (NHL) relies to a large extent on anthracycline-based regimens yielding cure rates in ~ 65 - 75% of patients. Despite being highly effective, these regimens are associated with significant long-term toxicity with a cumulative 10-year incidence of cardiovascular disease of 22%. Moreover, for the 25 - 35% of patients who fail first-line therapy there has been very little progress in terms of salvage regimens over the past 15 years. Re-treatment with anthracyclines based regimens was, until now, not an option given the extensive cardiac toxicity of these agents. Pixantrone dimaleate (Pixantrone) is a novel anthracycline-like drug that offers an interesting alternative for the treatment of aggressive NHL. AREAS COVERED: This article provides an overview of treatment-related cardiac toxicity in NHL, the pharmacology of Pixantrone and the evidence supporting its use in NHL. EXPERT OPINION: Pixantrone is a potential alternative agent with a favorable safety profile for the treatment of relapsed and refractory NHL patients. It might benefit from combinations strategies and further development in the elderly and frail population. PMID- 25716062 TI - The location of adipose tissue is important: epicardial fat in patients with chronic kidney disease. PMID- 25716064 TI - Incidence and prevalence of non-melanoma skin cancer in Australia: A systematic review. AB - Non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is the most common cancer occurring in people with fair skin. Australia has been reported to have the highest incidence of NMSC in the world. Using a systematic search of the literature in EMBASE and Medline, we identified 21 studies that investigated the incidence or prevalence of NMSC in Australia. Studies published between 1948 and 2011 were identified and included in the analysis. There were six studies that were conducted on national level, two at state level and 13 at the regional level. Overall, the incidence of NMSC had steadily increased over calendar-years in Australia. The incidence of NMSC per 100,000 person-years was estimated to be 555 in 1985; 977 in 1990; 1109 in 1995; 1170 in 2002 and 2448 in 2011. The incidence was higher for men than women and higher for BCC than SCC. Incidence varied across the states of Australia, with the highest in Queensland. The prevalence of NMSC was estimated to be 2% in Australia in 2002. The incidence and prevalence of NMSC still need to be accurately established at both national and state levels to determine the costs and burden of the disease on the public health system in Australia. PMID- 25716065 TI - The recommended interval for cervical cancer screening: Victorian women's attitudes to an extended interval. AB - AIM: To determine Victorian women's knowledge of the recommended Pap test screening interval and support for extending the interval from two years to three years, in light of possible changes to the National Cervical Screening Program. METHODS: A random sample of 2,360 women aged 18-69 was interviewed by telephone about their knowledge of the recommended interval, their willingness to change to three-yearly screening if recommended and reasons for their preference. RESULTS: More than 91% of women were aware of the current screening recommendation and nearly half (48.7%) indicated they would be willing to change to three-yearly screening. Women were less likely to support the change if they were up-to-date with screening (45.7%, p<0.01), of low socioeconomic status (43.8%, p<0.01) or aged 50-69 (44.4%, p<0.01). Dislike of having a Pap test was reason for some women to want a longer interval, but most needed to be confident a longer interval was safe to be willing to change. CONCLUSIONS AND IMPLICATIONS: A longer interval between screening tests would readily be accepted by some women, but others will need to be persuaded of the safety of a new recommendation. The current interval is widely known and a clear communication strategy will be needed explain the change and its rationale. PMID- 25716063 TI - Extra-thymically induced T regulatory cell subsets: the optimal target for antigen-specific immunotherapy. AB - Antigen-specific immunotherapy aims to selectively restore tolerance to innocuous antigens in cases of autoimmune or allergic disease, without the need for general immune suppression. Although the principle of antigen-specific immunotherapy was discovered more than a century ago, its clinical application to date is limited, particularly in the control of autoimmunity. This has resulted mainly from a lack of in-depth understanding of the underlying mechanism. More recently, the differentiation of extra-thymically induced T regulatory (Treg) cell subsets has been shown to be instrumental in peripheral tolerance induction. Two main types of inducible Treg cells, interleukin-10-secreting or Foxp3(+) , have now been described, each with distinct characteristics and methods of therapeutic induction. It is crucial, therefore, to identify the suitability of either subset in the control of specific immune disorders. This review explores their natural function, the known mechanisms of therapeutic differentiation of either subset as well as their in vivo functionality and discusses new developments that may aid their use in antigen-specific immunotherapy, with a focus on autoimmune disease. PMID- 25716066 TI - Differential expression of lipid metabolism-related genes and myosin heavy chain isoform genes in pig muscle tissue leading to different meat quality. AB - The aim of this study was to investigate the variations in meat quality, lipid metabolism-related genes, myosin heavy chain (MyHC) isoform genes and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) gene mRNA expressions in longissimus dorsi muscle (LM) of two different pig breeds. Six Rongchang and six Landrace barrows were slaughtered at 161 days of age. Subsequently, meat quality traits and gene expression levels in LM were observed. Results showed that Rongchang pigs not only exhibited greater pH, CIE a*24 h and intramuscular fat content but also exhibited lower body weight, carcass weight, dressing percentage, LM area and CIE b*24 h compared with Landrace pigs (P<0.05). Meanwhile, the mRNA expression levels of the lipogenesis (peroxisome proliferator activated receptor gamma, acetyl-CoA carboxylase and fatty acid synthase) and fatty acid uptake (lipoprotein lipase)-related genes were greater in the Rongchang (P<0.05), whereas the lipolysis (adipose triglyceride lipase and hormone sensitive lipase) and fatty acid oxidation (carnitine palmitoyltransferase-1B)-related genes were better expressed in the Landrace. Moreover, compared with the Landrace, the mRNA expression levels of MyHCI, MyHCIIa and MyHCIIx were greater, whereas the mRNA expression levels of MyHCIIb were lower in the Rongchang pigs (P<0.05). In addition, the mRNA expression levels of PGC-1alpha were greater in Rongchang pigs than in the Landrace (P<0.05), which can partly explain the differences in MyHC isoform gene expressions between Rongchang and Landrace pigs. Although the small number of samples does not allow to obtain a definitive conclusion, we can suggest that Rongchang pigs possess better meat quality, and the underlying molecular mechanisms responsible for the better meat quality in fatty pigs may be partly due to the higher mRNA expression levels of lipogenesis and fatty acid uptake related genes, as well as the oxidative and intermediate muscle fibers, and due to the lower mRNA expression levels of lipolysis and fatty acid oxidation-related genes, as well as the glycolytic muscle fibers. PMID- 25716067 TI - The association between the regular use of preventive labour induction and improved term birth outcomes: findings of a systematic review and meta-analysis. AB - BACKGROUND: Despite a lack of high-quality evidence, the use of 'non-indicated' term labour induction is increasingly restricted throughout the world. OBJECTIVES: To assess published associations between the regular use of modelled risk-based 'non-indicated' term labour induction (hereinafter 'preventive induction') and rates of common adverse birth outcomes. SEARCH STRATEGY: MEDLINE and PUBMED databases were searched electronically. SELECTION CRITERIA: Studies were identified that compared term birth outcomes following either the current standard approach with its emphasis on the expectant management of intermediate level risk or the regular use of preventive induction. DATA COLLECTION AND ANALYSIS: Four studies from four unique databases were identified. A meta analysis was performed using STATA IC12. MAIN RESULTS: Pregnancies exposed to the regular use of preventive induction (n = 1153), as compared with pregnancies receiving the current standard approach (n = 1865), experienced a lower caesarean delivery rate (5.7% versus 14.4%; relative risk 0.39, 95% CI 0.31-0.50; I(2) P = 0.21), a lower neonatal intensive care unit admission rate (2.9% versus 6.5%; relative risk 0.45, 95% CI 0.31-0.65; I(2) P = 0.57), and a lower weighted adverse outcome index score (2.8 versus 6.1). CONCLUSIONS: The regular use of preventive induction, as compared with the current standard approach, was associated with a more favourable pattern of birth outcomes. Other recently published meta-analyses have also determined that certain types of 'non indicated' labour induction are beneficial. Accordingly, the current broad restrictions on 'non-indicated' labour induction should be reconsidered. Adequately powered multi-site randomised clinical trials are needed to definitively study the risks and benefits of modelled risk-based 'non-indicated' (i.e. 'preventive') term labour induction. PMID- 25716069 TI - Treatment response in enteropathy associated T-cell lymphoma; survival in a large multicenter cohort. AB - Enteropathy-associated T-cell lymphoma (EATL) is a T-cell Non-Hodgkin Lymphoma which is highly associated with celiac disease. The prognosis of EATL has been considered poor and there are no standardized treatment protocols. Here, we evaluate treatment response and survival of EATL patients in a large multicenter cohort. A total of 61 patients diagnosed with EATL were analyzed. Various treatment regimens were applied in EATL during the past fifteen years including either monotherapy consisting of chemotherapy or resection, or combination therapy with both aforementioned regimens whether or not combined with stem-cell transplantation (SCT). Overall, 50/61 patients (82%) died after a median of 7.4 months. One- and five-year overall survival was 40 and 11%, respectively. Median follow-up in the survivors was 26 months. Patients treated with the most aggressive treatment, that is, resection, chemotherapy and autologous SCT, showed the most favourable outcome with complete remission in all patients, the lowest relapse rate and one- and five-year overall survival of 100 and 33%, respectively, although overall survival in this group was not significantly better as compared to patients treated with surgery and chemotherapy. This study indicates that combination treatment is superior compared to monotherapy. Whether or not consolidation therapy with autologous SCT may improve survival needs to be substantiated in a larger randomized international trial. PMID- 25716070 TI - Beyond yolk-shell nanoparticles: Fe3O4@Fe3C core@shell nanoparticles as yolks and carbon nanospindles as shells for efficient lithium ion storage. AB - To well address the problems of large volume change and dissolution of Fe3O4 nanomaterials during Li(+) intercalation/extraction, herein we demonstrate a one step in situ nanospace-confined pyrolysis strategy for robust yolk-shell nanospindles with very sufficient internal void space (VSIVS) for high-rate and long-term lithium ion batteries (LIBs), in which an Fe3O4@Fe3C core@shell nanoparticle is well confined in the compartment of a hollow carbon nanospindle. This particular structure can not only introduce VSIVS to accommodate volume change of Fe3O4 but also afford a dual shell of Fe3C and carbon to restrict Fe3O4 dissolution, thus providing dual roles for greatly improving the capacity retention. As a consequence, Fe3O4@Fe3C-C yolk-shell nanospindles deliver a high reversible capacity of 1128.3 mAh g(-1) at even 500 mA g(-1), excellent high rate capacity (604.8 mAh g(-1) at 2000 mA g(-1)), and prolonged cycling life (maintaining 1120.2 mAh g(-1) at 500 mA g(-1) for 100 cycles) for LIBs, which are much better than those of Fe3O4@C core@shell nanospindles and Fe3O4 nanoparticles. The present Fe3O4@Fe3C-C yolk-shell nanospindles are the most efficient Fe3O4-based anode materials ever reported for LIBs. PMID- 25716068 TI - Placental vitamin D receptor expression is decreased in human idiopathic fetal growth restriction. AB - Fetal growth restriction (FGR) affects up to 5 % of pregnancies worldwide, and trophoblast function plays a significant role on the outcome. An epidemiological study has linked vitamin D deficiency to adverse perinatal outcomes, which include decreased birth weight. The placenta as an important source of vitamin D regulates its metabolism through the vitamin D receptor (VDR), but the mechanism by which VDR regulates trophoblast function is poorly understood. Our study aimed at determining placental VDR expression in FGR and gestation-matched control (GMC) pregnancies and identifying the actions of VDR in trophoblast differentiation and apoptosis. Placentae were collected from a well-defined cohort of idiopathic FGR and GMC pregnancies. VDR mRNA and protein expressions were determined by PCR, immunohistochemistry and immunoblotting, while functional consequences of VDR inactivation in vitro were determined on BeWo cells by determining changes in differentiation, attachment and apoptosis. Significant decreases in VDR mRNA expression (p = 0.0005) and protein expression (p = 0.0003) were observed in the FGR samples, while VDR inactivation, which showed markers for differentiation, cell attachment and apoptosis, was significantly increased. Thus, decreased placental VDR may contribute to uncontrolled premature differentiation and apoptosis of trophoblasts that are characteristics of idiopathic FGR pregnancies. KEY MESSAGE: Fetal growth restriction (FGR) affects up to 5 % of all pregnancies worldwide. FGR is the second highest cause of perinatal mortality and morbidity. The placenta plays a pivotal role in vitamin D metabolism during pregnancy. Vitamin D deficiency is associated with adverse pregnancy outcomes. Placental vitamin D receptor expression is decreased in FGR. PMID- 25716071 TI - Aboriginal and Torres Strait Islander health: accuracy of patient self-report of screening for diabetes, high cholesterol and cervical cancer. AB - OBJECTIVE: To determine the accuracy and clinical utility of patient self reported screening history. METHODS: Aboriginal and Torres Strait Islander patients (>=18 years; n=587) were interviewed on their screening history according to recommended time intervals; these were matched to pathology data. RESULTS: The proportion of patients meeting screening guidelines were 32% (95%CI 26%-39%) for diabetes, 43% (95%CI 38%-47%) for cholesterol and 4.1% (95%CI 2.2% 7.3%) for cervical cancer. When patients reported having had the test, their accuracy (PPV) was low: 38% (95%CI 30%-46%) for diabetes, 47% (95%CI 42%-52%) for cholesterol, 6.5% (95%CI 3.0%-12%) for cervical cancer. However, for the minority of patients who had been screened, positive recall (sensitivity) was high: 94% (95%CI 85%-98%) for diabetes, 83% (95%CI 77%-88%) for cholesterol, 90% (95%CI 55% 98%) for cervical cancer. The accuracy of patient recall was good for those who reported not having been screened (NPV): 90% (95%CI 77%-97%) for diabetes, 70% (95%CI 61%-78%) for cholesterol, 99% (95%CI 95%-100%) for cervical cancer. CONCLUSIONS: The results indicate that reliance on self-report for patients' screening history is inappropriate due to missed opportunities for health gain. However, patients who report not being tested are sufficiently accurate to ensure that ordering the test in this group will involve only a small percentage of unnecessary assays. IMPLICATIONS: GPs often rely on self-report as a fast and inexpensive way to determine whether a patient requires screening. New strategies are needed to identify patients at risk. PMID- 25716073 TI - Prognostic significance of the Medical Research Council cytogenetic classification compared with the European LeukaemiaNet risk classification system in acute myeloid leukaemia. PMID- 25716074 TI - Inadvertent transmission of polycystic kidney disease in kidney transplantation. AB - BACKGROUND: Although organ donors are rigorously tested, occasionally an unidentified donor disease can be transmitted to the recipient. These conditions include malignancies, infections, and, rarely, congenital diseases. CASE REPORT: We report a case of an inadvertent transmission of polycystic kidney disease from a 40-year-old trauma victim to both kidney recipients. There was no family history of renal disease in the donor. The renal allografts gradually increased in size with the development of cysts and functioned for 10 and 14 years. CONCLUSIONS: We report a case of inadvertent transmission of polycystic kidney disease from an unsuspecting deceased donor to both the recipients through renal allograft. Both the grafts lasted long enough to suggest that polycystic kidneys from deceased donors can be considered for transplantation. PMID- 25716072 TI - TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes. AB - Extracellular (ex) HSP60 is increasingly recognized as an agent of cell injury. Previously, we reported that low endotoxin exHSP60 causes cardiac myocyte apoptosis. Our findings supported a role for Toll-like receptor (TLR) 4 in HSP60 mediated apoptosis. To further investigate the involvement of TLR4 in cardiac injury, we studied adult cardiac myocytes from C3H/HeJ (HeJ) mice, which have a mutant, nonfunctional TLR4, and compared the results with parallel studies using wild-type (WT) mice. Nuclear factor kappaB (NFkappaB) activation is an early step downstream of TLR4. NFkappaB was activated 1 h after treatment with HSP60 in WT, but not HeJ mouse myocytes. ExHSP60 caused apoptosis in cardiac myocytes from WT mice, but not in myocytes from the HeJ mutants. To further elucidate the importance of exHSP60 in cardiac myocyte injury, both WT and HeJ mutant isolated mouse adult cardiac myocytes were exposed to hypoxia/reoxygenation. Anti-HSP60 antibody treatment reduced apoptosis in the WT group, but had no effect on the HeJ mutant myocytes. Unexpectedly, necrosis was also decreased in the HeJ mutants. Necrosis after hypoxia/reoxygenation in WT cardiac myocytes was mediated in part by TLR2 and TLR4 through rapid activation of PKCalpha, followed by increased expression of Nox2, and this was ameliorated by blocking antibodies to TLR2/4. These studies provide further evidence that TLR4 mediates exHSP60 associated apoptosis and that exHSP60 has an important role in cardiac myocyte injury, both apoptotic and necrotic. PMID- 25716075 TI - Evaluation of a telementoring intervention for pain management in the Veterans Health Administration. AB - OBJECTIVE: Half of all Veterans experience chronic pain yet many face geographical barriers to specialty pain care. In 2011, the Veterans Health Administration (VHA) launched the Specialty Care Access Network-ECHO (SCAN-ECHO), which uses telehealth technology to provide primary care providers with case based specialist consultation and pain management education. Our objective was to evaluate the pilot SCAN-ECHO pain management program (SCAN-ECHO-PM). DESIGN AND SETTING: This was a longitudinal observational evaluation of SCAN-ECHO-PM in seven regional VHA healthcare networks. METHODS: We identified the patient panels of primary care providers who submitted a consultation to one or more SCAN-ECHO PM sessions. We constructed multivariable Cox proportional hazards models to assess the association between provider SCAN-ECHO-PM consultation and 1) delivery of outpatient care (physical medicine, mental health, substance use disorder, and pain medicine) and 2) medication initiation (antidepressants, anticonvulsants, and opioid analgesics). RESULTS: Primary care providers (N = 159) who presented one or more SCAN-ECHO-PM sessions had patient panels of 22,454 patients with chronic noncancer pain (CNCP). Provider consultation to SCAN-ECHO-PM was associated with utilization of physical medicine [hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.05-1.14] but not mental health (HR 0.99, 95% CI 0.93 1.05), substance use disorder (HR 0.93, 95% CI 0.84-1.03) or specialty pain clinics (HR 1.01, 95% CI 0.94-1.08). SCAN-ECHO-PM consultation was associated with initiation of an antidepressant (HR 1.09, 95% CI 1.02-1.15) or anticonvulsant medication (HR 1.13, 95% CI 1.06-1.19) but not an opioid analgesic (HR 1.05, 0.99-1.10). CONCLUSIONS: SCAN-ECHO-PM was associated with increased utilization of physical medicine services and initiation of nonopioid medications among patients with CNCP. SCAN-ECHO-PM may provide a novel means of building pain management competency among primary care providers. PMID- 25716076 TI - Main results of the 2012 joint Norwegian-Russian expedition to the dumping sites of the nuclear submarine K-27 and solid radioactive waste in Stepovogo Fjord, Novaya Zemlya. AB - This paper reports the main results of the 2012 joint Norwegian-Russian expedition to investigate the radioecological situation of the Stepovogo Fjord on the eastern coast of Novaya Zemlya, where the nuclear submarine K-27 and solid radioactive waste was dumped. Based on in situ gamma measurements and the analysis of seawater and sediment samples taken around the submarine, there was no indication of any leakage from the reactor units of K-27. With regard to the radioecological status of Stepovogo Fjord, activity concentrations of all radionuclides in seawater, sediment and biota in 2012 were in general lower than reported from the previous investigations in the 1990s. However in 2012, the activity concentrations of (137)Cs and, to a lesser extent, those of (90)Sr remained elevated in bottom water from the inner part of Stepovogo Fjord compared with surface water and the outer part of Stepovogo Fjord. Deviations from expected (238)Pu/(239,240)Pu activity ratios and (240)Pu/(239)Pu atom ratios in some sediment samples from the inner part of Stepovogo Fjord observed in this study and earlier studies may indicate the possibility of leakages from dumped waste from different nuclear sources. Although the current environmental levels of radionuclides in Stepovogo Fjord are not of immediate cause for concern, further monitoring of the situation is warranted. PMID- 25716077 TI - Molecular characterization of Acanthamoeba strains isolated from domestic dogs in Tenerife, Canary Islands, Spain. AB - The present study describes two cases of Acanthamoeba infections (keratitis and ascites/peritonitis) in small breed domestic dogs in Tenerife, Canary Islands, Spain. In both cases, amoebic trophozoites were observed under the inverted microscope and isolated from the infected tissues and/or fluids, without detecting the presence of other viral, fungal or bacterial pathogens. Amoebae were isolated using 2 % non-nutrient agar plates and axenified for further biochemical and molecular analyses. Osmotolerance and thermotolerance assays revealed that both isolates were able to grow up to 37 degrees C and 1 M of mannitol and were thus considered as potentially pathogenic. Moreover, the strains were classified as highly cytotoxic as they cause more than 75 % of toxicity when incubated with two eukaryotic cell lines. In order to classify the strains at the molecular level, the diagnostic fragment 3 (DF3) region of the 18S rDNA of Acanthamoeba was amplified and sequenced, revealing that both isolates belonged to genotype T4. In both cases, owners of the animals did not allow any further studies or follow-up and therefore the current status of these animals is unknown. Furthermore, the isolation of these pathogenic amoebae should raise awareness with the veterinary community locally and worldwide. PMID- 25716078 TI - Planned delivery at 37 weeks in twins: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the effects of planned delivery at 37 weeks in women with twin gestations compared to expectant management. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Searches were performed in electronic databases. We included all RCTs of uncomplicated early term twin gestations with intact membranes who were randomized to planned delivery at 37 weeks or control (i.e. expectant management until at least 38(0) weeks). The primary outcome was the rate of cesarean delivery. RESULTS: Two trials (271 women) were analyzed. Women with twin gestations who had planned delivery at 37 weeks had similar rates of cesarean delivery compared to controls [51.9 versus 49.3%; relative risk (RR): 1.05, 95% confidence interval (CI): 0.83-1.32]. Furthermore, no differences in all secondary outcomes were detected, except for a significantly lower rate of serious adverse infant outcomes in the women who had planned delivery at 37 weeks compared to controls (4.7 versus 12.2%; RR: 0.39, 95% CI: 0.20-0.76). CONCLUSIONS: Planned delivery at 37 weeks in twins is associated with a similar risk of cesarean delivery and lower risk of serious adverse infant outcomes, compared to expectant management until at least 38 weeks. PMID- 25716079 TI - Placental pathology in smoking and non-smoking preeclamptic women. AB - OBJECTIVE: To ascertain whether the protective effect of smoking during preeclampsia (PE) can be visualized in the placenta. METHODS: The study cohort consisted of placentas (n = 523) from pregnancies complicated by PE, delivered at Karolinska University Hospital in Stockholm during the period 2000-2009. Of the women included in the study, 488 were non-smokers and 35 were smokers at first visit to maternity care. Outcome variables were placental infarctions and decidual arteriopathy. RESULTS: Infarctions (affecting >=5% of the placental tissue) were found in 15.6% of the placentas from non-smokers and in 25.7% of the placentas from smokers (OR 1.88: CI 0.84-4.16, p = 0.12). Decidual arteriopathy was found in 27.5% of the placentas from non-smokers and in 40.0% of the placentas from smokers (1.76: CI 0.87-3.56, p = 0.12). When diagnosed histopathologically, placental abruption was found in 15.4% among non-smokers and in 17.1% among smokers (1.14: CI 0.46-2.84, p = 0.98). Those differences did not show any statistical significance. CONCLUSION: No significant differences concerning placental infarctions, decidual arteriopathy or abruption were found between preeclamptic placentas from non-smokers compared to smokers. PMID- 25716081 TI - Aging alters long-term potentiation--related gene networks and impairs synaptic protein synthesis in the rat hippocampus. AB - During aging, memory retention and persistence of long-term potentiation (LTP) are impaired, suggesting an aging-related deterioration in mechanisms regulating information storage. Late-phase LTP requires synthesis of proteins at synapses as well as integrated regulation of gene networks. Because aging diminishes the persistence of LTP, primarily by affecting the transition between early and late phases, we assessed whether this was reflected in perturbation of gene networks. Using DNA microarray analysis, we compared LTP-associated gene expression in young (5 months), middle-aged (15 months), and old (22 months) male Sprague Dawley rats. As expected, we found no significant difference in LTP measured 20 minutes postinduction; however, we found that overall more genes were regulated in the young group. Bioinformatics predicted not only dysregulation of activator protein-1 and nuclear factor kB transcription factor activity and epigenetic modifications but also dysregulation of protein synthesis. Notably, we confirmed an age-related impairment in metabotropic and ionotropic receptor-mediated synaptic protein synthesis. Together, these results demonstrate that LTP-specific gene expression is altered with aging and suggest that dysregulation of synaptic protein synthesis also contributes to the age-dependent reduction in LTP persistence. PMID- 25716080 TI - Plasma from human volunteers subjected to remote ischemic preconditioning protects human endothelial cells from hypoxia-induced cell damage. AB - Short repeated cycles of peripheral ischemia/reperfusion (I/R) can protect distant organs from subsequent prolonged I/R injury; a phenomenon known as remote ischemic preconditioning (RIPC). A RIPC-mediated release of humoral factors might play a key role in this protection and vascular endothelial cells are potential targets for these secreted factors. In the present study, RIPC-plasma obtained from healthy male volunteers was tested for its ability to protect human umbilical endothelial cells (HUVEC) from hypoxia-induced cell damage. 10 healthy male volunteers were subjected to a RIPC-protocol consisting of 4 * 5 min inflation/deflation of a blood pressure cuff located at the upper arm. Plasma was collected before (T0; control), directly after (T1) and 1 h after (T2) the RIPC procedure. HUVEC were subjected to 24 h hypoxia damage and simultaneously incubated with 5% of the respective RIPC-plasma. Cell damage was evaluated by lactate dehydrogenase (LDH)-measurements. Western blot experiments of hypoxia inducible factor 1 alpha (HIF1alpha), phosphorylated signal transducer and activator of transcription 5 (STAT5), protein kinase B (AKT) and extracellular signal-related kinase 1/2 (ERK-1/2) were performed. Furthermore, the concentrations of hVEGF were evaluated in the RIPC-plasma by sandwich ELISA. Hypoxia-induced cell damage was significantly reduced by plasma T1 (p = 0.02 vs T0). The protective effect of plasma T1 was accompanied by an augmentation of the intracellular HIF1alpha (p = 0.01 vs T0) and increased phosphorylation of ERK-1/2 (p = 0.03 vs T0). Phosphorylation of AKT and STAT5 remained unchanged. Analysis of the protective RIPC-plasma T1 showed significantly reduced levels of hVEGF (p = 0.01 vs T0). RIPC plasma protects endothelial cells from hypoxia-induced cell damage and humoral mediators as well as intracellular HIF1alpha may be involved. PMID- 25716083 TI - Comparative proteomic analysis of developing rhizomes of the ancient vascular plant Equisetum hyemale and different monocot species. AB - The rhizome is responsible for the invasiveness and competitiveness of many plants with great economic and agricultural impact worldwide. Besides its value as an invasive organ, the rhizome plays a role in the establishment and massive growth of forage, providing biomass for biofuel production. Despite these features, little is known about the molecular mechanisms that contribute to rhizome growth, development, and function in plants. In this work, we characterized the proteome of rhizome apical tips and elongation zones from different species using a GeLC-MS/MS (one-dimensional electrophoresis in combination with liquid chromatography coupled online with tandem mass spectrometry) spectral-counting proteomics strategy. Five rhizomatous grasses and an ancient species were compared to study the protein regulation in rhizomes. An average of 2200 rhizome proteins per species were confidently identified and quantified. Rhizome-characteristic proteins showed similar functional distributions across all species analyzed. The over-representation of proteins associated with central roles in cellular, metabolic, and developmental processes indicated accelerated metabolism in growing rhizomes. Moreover, 61 rhizome characteristic proteins appeared to be regulated similarly among analyzed plants. In addition, 36 showed conserved regulation between rhizome apical tips and elongation zones across species. These proteins were preferentially expressed in rhizome tissues regardless of the species analyzed, making them interesting candidates for more detailed investigative studies about their roles in rhizome development. PMID- 25716084 TI - The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple negative breast cancer. AB - Various guidelines recommend that women with triple-negative breast cancer should be tested for BRCA1 mutations, but the prevalence of mutations may vary with ethnic group and with geographic region, and the optimal cutoff age for testing has not been established. We estimated the frequencies of BRCA1 and BRCA2 (BRCA) mutations among 190 women with triple-negative breast cancer, unselected for family history, diagnosed at age 50 or less at a single hospital in Mexico City. Patients were screened for 115 recurrent BRCA mutations, which have been reported previously in women of Hispanic origin, including a common large rearrangement Mexican founder mutation (BRCA1 ex9-12del). A BRCA mutation was detected in 44 of 190 patients with triple-negative breast cancer (23 %). Forty-three mutations were found in BRCA1 and one mutation was found in BRCA2. Seven different mutations accounted for 39 patients (89 % of the total mutations). The Mexican founder mutation (BRCA1 ex9-12del) was found 18 times and accounted for 41 % of all mutations detected. There is a high prevalence of BRCA1 mutations among young triple-negative breast cancer patients in Mexico. Women with triple-negative breast cancer in Mexico should be screened for mutations in BRCA1. PMID- 25716086 TI - Baby on board: olfactory cues indicate pregnancy and fetal sex in a non-human primate. AB - Olfactory cues play an integral, albeit underappreciated, role in mediating vertebrate social and reproductive behaviour. These cues fluctuate with the signaller's hormonal condition, coincident with and informative about relevant aspects of its reproductive state, such as pubertal onset, change in season and, in females, timing of ovulation. Although pregnancy dramatically alters a female's endocrine profiles, which can be further influenced by fetal sex, the relationship between gestation and olfactory cues is poorly understood. We therefore examined the effects of pregnancy and fetal sex on volatile genital secretions in the ring-tailed lemur (Lemur catta), a strepsirrhine primate possessing complex olfactory mechanisms of reproductive signalling. While pregnant, dams altered and dampened their expression of volatile chemicals, with compound richness being particularly reduced in dams bearing sons. These changes were comparable in magnitude with other, published chemical differences among lemurs that are salient to conspecifics. Such olfactory 'signatures' of pregnancy may help guide social interactions, potentially promoting mother-infant recognition, reducing intragroup conflict or counteracting behavioural mechanisms of paternity confusion; cues that also advertise fetal sex may additionally facilitate differential sex allocation. PMID- 25716087 TI - Sex-dependent effects of nutrition on telomere dynamics in zebra finches (Taeniopygia guttata). AB - At a cellular level, oxidative stress is known to increase telomere attrition, and hence cellular senescence and risk of disease. It has been proposed that dietary micronutrients play an important role in telomere protection due to their antioxidant properties. We experimentally manipulated dietary micronutrients during early life in zebra finches (Taeniopygia guttata). We found no effects of micronutrient intake on telomere loss during chick growth. However, females given a diet high in micronutrients during sexual maturation showed reduced telomere loss; there was no such effect in males. These results suggest that micronutrients may influence rates of cellular senescence, but differences in micronutrient requirement and allocation strategies, probably linked to the development of sexual coloration, may underlie sex differences in response. PMID- 25716088 TI - Norway rats reciprocate help according to the quality of help they received. AB - Direct reciprocity, according to the decision rule 'help someone who has helped you before', reflects cooperation based on the principle of postponed benefits. A predominant factor influencing Homo sapiens' motivation to reciprocate is an individual's perceived benefit resulting from the value of received help. But hitherto it has been unclear whether other species also base their decision to cooperate on the quality of received help. Previous experiments have demonstrated that Norway rats, Rattus norvegicus, cooperate using direct reciprocity decision rules in a variant of the iterated Prisoner's Dilemma, where they preferentially help cooperators instead of defectors. But, as the quality of obtained benefits has not been varied, it is yet unclear whether rats use the value of received help as decision criterion to pay help back. Here, we tested whether rats distinguish between different cooperators depending purely on the quality of their help. Our data show that a rat's propensity to reciprocate help is, indeed, adjusted to the perceived quality of the partner's previous help. When cooperating with two conspecific partners expending the same effort, rats apparently rely on obtained benefit to adjust their level of returned help. PMID- 25716089 TI - Socioecological variables predict telomere length in wild spotted hyenas. AB - Telomeres are regarded as important biomarkers of ageing and serve as useful tools in revealing how stress acts at the cellular level. However, the effects of social and ecological factors on telomere length remain poorly understood, particularly in free-ranging mammals. Here, we investigated the influences of within-group dominance rank and group membership on telomere length in wild adult spotted hyenas (Crocuta crocuta). We found large effects of both factors; high ranking hyenas exhibited significantly greater mean telomere length than did subordinate animals, and group membership significantly predicted mean telomere length within high-ranking females. We further inquired whether prey availability mediates the observed effect of group membership on telomere length, but this hypothesis was not supported. Interestingly, adult telomere length was not predicted by age. Our work shows for the first time, to the best of our knowledge, the effects of social rank on telomere length in a wild mammal and enhances our understanding of how social and ecological variables may contribute to organismal senescence. PMID- 25716090 TI - Intergroup threat gates social attention in humans. AB - Humans shift their attention to follow another person's gaze direction, a phenomenon called gaze cueing. This study examined whether a particular social factor, intergroup threat, modulates gaze cueing. As expected, stronger responses of a particular in-group to a threatening out-group were observed when the in group, conditioned to perceive threat from one of two out-groups, was presented with facial stimuli from the threatening and non-threatening out-groups. These results suggest that intergroup threat plays an important role in shaping social attention. Furthermore, larger gaze-cueing effects were found for threatening out group faces than for in-group faces only at the 200 ms but not the 800 ms stimulus onset asynchrony (SOA); the specificity of the gaze-cueing effects at the short SOA suggests that threat cues modulate the involuntary component of gaze cueing. PMID- 25716091 TI - Gene expression, chromosome heterogeneity and the fast-X effect in mammals. AB - The higher rate of non-synonymous over synonymous substitutions (dN/dS) of the X chromosome compared with autosomes is often interpreted as a consequence of X hemizygosity. However, other factors, such as gene expression, are also known to vary between X and autosomes. Analysing 4800 orthologues in six mammals, we found that gene expression levels, associated with GC content, fully account for the variation in dN/dS between X and autosomes with no detectable effect of hemizygosity. We also report an extensive variance in dN/dS and gene expression between autosomes. PMID- 25716092 TI - Gender Specificity of a Genetic Variant of Androgen Receptor and Risk of Coronary Artery Disease. AB - BACKGROUND: Androgens are known to influence the risk of developing cardiovascular diseases. This study aims at investigating the possible association between G1733A polymorphism in the coding region of androgen receptor (AR) gene and premature coronary artery disease (CAD). METHODS: A total of 460 Greek subjects were investigated for the G1733A polymorphism. The patient group consisted of 250 CAD individuals, aged less than 58 years, while 210 healthy individuals served as controls. Genotyping was performed using the PCR-RFLP method. RESULTS: Significant differences in genotype distribution (P = 0.0067) and allele frequencies (P = 0.0060) have been observed between patients and controls in the women's subgroup. Conversely, the genotype/allele frequencies were similar between patients and controls in the subgroup of men. CONCLUSION: We may conclude that the G1733A polymorphism of AR gene could be a useful genetic marker for the assessment of a woman's risk for CAD in our Caucasian Greek population. PMID- 25716093 TI - Molecular characterization of whey protein hydrolysate fractions with ferrous chelating and enhanced iron solubility capabilities. AB - The ferrous (Fe2+) chelating capabilities of WPI hydrolysate fractions produced via cascade membrane filtration were investigated, specifically 1 kDa permeate (P) and 30 kDa retentate (R) fractions. The 1 kDa-P possessed a Fe2+ chelating capability at 1 g L(-1) equivalent to 84.4 MUM EDTA (for 30 kDa-R the value was 8.7 MUM EDTA). Fourier transformed infrared (FTIR) spectroscopy was utilized to investigate the structural characteristics of hydrolysates and molecular interactions with Fe2+. Solid-phase extraction was employed to enrich for chelating activity; the most potent chelating fraction was enriched in histidine and lysine. The solubility of ferrous sulfate solutions (10 mM) over a range of pH values was significantly (P<0.05) improved in dispersions of hydrolysate fraction solutions (10 g protein L(-1)). Total iron solubility was improved by 72% in the presence of the 1 kDa-P fraction following simulated gastrointestinal digestion (SGID) compared to control FeSO4.7H2O solutions. PMID- 25716094 TI - Osmotic stress represses strigolactone biosynthesis in Lotus japonicus roots: exploring the interaction between strigolactones and ABA under abiotic stress. AB - MAIN CONCLUSION: Strigolactone changes and cross talk with ABA unveil a picture of root-specific hormonal dynamics under stress. Strigolactones (SLs) are carotenoid-derived hormones influencing diverse aspects of development and communication with (micro)organisms, and proposed as mediators of environmental stimuli in resource allocation processes; to contribute to adaptive adjustments, therefore, their pathway must be responsive to environmental cues. To investigate the relationship between SLs and abiotic stress in Lotus japonicus, we compared wild-type and SL-depleted plants, and studied SL metabolism in roots stressed osmotically and/or phosphate starved. SL-depleted plants showed increased stomatal conductance, both under normal and stress conditions, and impaired resistance to drought associated with slower stomatal closure in response to abscisic acid (ABA). This confirms that SLs contribute to drought resistance in species other than Arabidopsis. However, we also observed that osmotic stress rapidly and strongly decreased SL concentration in tissues and exudates of wild type Lotus roots, by acting on the transcription of biosynthetic and transporter encoding genes and independently of phosphate abundance. Pre-treatment with exogenous SLs inhibited the osmotic stress-induced ABA increase in wild-type roots and down-regulated the transcription of the ABA biosynthetic gene LjNCED2. We propose that a transcriptionally regulated, early SL decrease under osmotic stress is needed (but not sufficient) to allow the physiological increase of ABA in roots. This work shows that SL metabolism and effects on ABA are seemingly opposite in roots and shoots under stress. PMID- 25716095 TI - Populus endo-beta-1,4-glucanases gene family: genomic organization, phylogenetic analysis, expression profiles and association mapping. AB - MAIN CONCLUSION: Extensive characterization of the poplar GH9 gene family provides new insights into GH9 function and evolution in woody species, and may drive novel progress for molecular breeding in trees. In higher plants, endo-beta 1,4-glucanases (cellulases) belonging to the glycosyl hydrolase family 9 (GH9) have roles in cell wall synthesis, remodeling and degradation. To increase the understanding of the GH9 family in perennial woody species, we conducted an extensive characterization of the GH9 family in the model tree species, Populus. We characterized 25 putative GH9 members in Populus with three subclasses (A, B, and C), using structures and bioinformatic analysis. Phylogenetic analyses of 114 GH9s from plant (dicot, monocot, and conifer) and bacterial species (outgroup) demonstrated that plant GH9s are monophyletic with respect to bacteria GH9s. Three subclasses, A, B, and C, of plant GH9 are formed before the divergence of angiosperms and gymnosperms. Chromosomal localization and duplications of GH9s in the Populus genome showed that eight paralogous pairs remained in conserved positions on segmental duplicated blocks, suggesting duplication of chromosomal segments has contributed to the family expansion. By examining tissue-specific expression profiles for all 25 members, we found that GH9 members exhibited distinct but partially overlapping expression patterns, while certain members have higher transcript abundance in mature or developing xylem. Based on our understanding of intraspecific variation and linkage disequilibrium of two KORRIGANs (PtoKOR1 and PtoKOR2) in natural population of Populus tomentosa, two non-synonymous SNPs in PtoKOR1 associated with fiber width and holocellulose content were obtained. Characterizations of the poplar GH9 family provide new insights into GH9 function and evolution in woody species, and may drive novel progress for molecular breeding in trees. PMID- 25716096 TI - Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer. AB - PURPOSE: Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patient's sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. METHODS: Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. FINDINGS: The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5 15% had pCR and were disease free after 2 years (excellent prognosis), 65-75% had no pCR but were disease free (good prognosis) and 15-30% had neither pCR nor 2yDFS (poor prognosis). INTERPRETATION: Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies. PMID- 25716097 TI - Exploring relationships between personality and anatomy performance. AB - There is increasing recognition in medicine of the importance of noncognitive factors, including personality, for performance, and for good medical practice. The personality domain of conscientiousness is a well-established predictor of performance in workplace and academic settings. This study investigates the relationships between the "Big Five" personality domains, the facets of conscientiousness and performance in a practical anatomy examination. First- and second-year undergraduate medical students (n = 85) completed a paper-based questionnaire, which included a 50-item measure of the Big Five personality domains (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) and a 60-item measure of the six conscientiousness facets (orderliness, dutifulness, achievement-striving, self-discipline, self-efficacy, and cautiousness) from the International Personality Item Pool (IPIP). In addition, routinely-collected academic performance scores from the end of semester anatomy practical examinations (spotters) were obtained. Anatomy examination performance correlated moderately with conscientiousness (r = 0.24, P = 0.03). Of the six facets of conscientiousness, a positive relationship was observed between anatomy examination performance and achievement striving (r = 0.22, P = 0.05). In conclusion, this study found that performance in an anatomy examination was related to higher levels of conscientiousness and, more specifically, to higher levels of achievement striving. The results have implications for selection and assessment in medicine. PMID- 25716098 TI - Dietary intake of carotenoids and risk of type 2 diabetes. AB - BACKGROUND AND AIMS: Carotenoids may reduce diabetes risk, due to their antioxidant properties. However, the association between dietary carotenoids intake and type 2 diabetes risk is still unclear. Therefore, the objective of this study was to examine whether higher dietary carotenoid intakes associate with reduced type 2 diabetes risk. METHODS AND RESULTS: Data from 37,846 participants of the European Prospective Investigation into Cancer and Nutrition- Netherlands study were analyzed. Dietary intakes of beta-carotene, alpha carotene, beta-cryptoxanthin, lycopene, lutein & zeaxanthin and the sum of these carotenoids were assessed using a validated food frequency questionnaire. Incident type 2 diabetes was mainly self-reported, and verified against general practitioner information. Mean +/-SD total carotenoid intake was 10 +/- 4 mg/day. During a mean +/-SD follow-up of 10 +/- 2 years, 915 incident cases of type 2 diabetes were ascertained. After adjustment for age, sex, diabetes risk factors, dietary intake, waist circumference and BMI, higher beta-carotene intakes associated inversely with diabetes risk [Hazard Ratio quartile 4 versus quartile 1 (HR(Q4)): 0.78 (95%CI:0.64,0.95), P-linear trend 0.01]. For alpha-carotene, a borderline significant reduced risk was observed, with a HR(Q4) of 0.85 (95%CI:0.70,1.03), and P-linear trend 0.05. beta-cryptoxanthin, lycopene, lutein & zeaxanthin, and the sum of all carotenoids did not associate with diabetes risk. CONCLUSIONS: This study shows that diets high in beta-carotene and alpha carotene are associated with reduced type 2 diabetes in generally healthy men and women. PMID- 25716099 TI - Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma. AB - The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined "Lynch-like syndrome" if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or "familial colorectal cancer type X" if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies. PMID- 25716100 TI - Targeting breast cancer with CDK inhibitors. AB - Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Re-establishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy. Three oral agents selectively targeting CDK4/6 have been developed: palbociclib, abemaciclib, and LEE011. Preclinical models show optimal activity in hormone receptor positive breast cancer, which may display biologic features suggesting particular dependence on the CDK4/cyclin D1/Rb interaction. Palbociclib has been studied in a randomized phase 2 clinical trial in metastatic hormone receptor positive breast cancer in which the combination of palbociclib and endocrine therapy significantly prolonged progression-free survival over endocrine therapy alone. The toxicity profile of palbociclib and the other CDK 4/6 inhibitors in early phase I and II trials has been predominantly hematologic, characterized by limited neutropenia, as well as variable gastrointestinal toxicity. Multiple phase II and III studies are ongoing with all three agents, and are designed to explore the role of CDK 4/6 inhibition in metastatic hormone receptor positive breast cancer. The next wave of studies will examine further clinical and scientific topics, including the role of CDK 4/6 inhibition in the neo/adjuvant setting, the combination of CDK 4/6 inhibitors with other targeted therapies, and the activity of CDK 4/6 inhibitors in the HER2 positive subset of breast cancer, as well as in other cancer subtypes. Should ongoing study confirm benefits and tolerability of CDK 4/6 inhibition, combination therapy with endocrine agents may become a new standard of care for hormone receptor positive breast cancer. PMID- 25716101 TI - Cross-sectional imaging of common and unusual complications after endoscopic retrograde cholangiopancreatography. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is currently a primarily therapeutic procedure that is extensively employed to treat several biliopancreatic disorders. Although widely considered a safe procedure, ERCP is associated with a non-negligible morbidity and occasional mortality. Due to the number and complexity of operative ERCPs performed, radiologists are increasingly faced with urgent requests for investigation of suspected post-procedural complications, which often have similar clinical and laboratory manifestations. This pictorial essay reviews the usual post-procedural CT findings, the clinical features and imaging appearances of common and unusual post-ERCP occurrences including interstitial oedematous and necrotising acute pancreatitis, haemorrhages, retroperitoneal and intraperitoneal duodenal perforations, infections and stent-related complications. Emphasis is placed on the pivotal role of multidetector CT, which is warranted after complex or prolonged ERCP procedures as it represents the most effective modality to detect and grade ERCP related complications and to monitor nonsurgically treated patients. Timely diagnosis and optimal management require a combination of clinical and laboratory data with imaging appearances; therefore, this article aims to provide an increased familiarity with interpretation of early post-ERCP studies, particularly to triage those occurrences that require interventional or surgical treatment. In selected patients MRI allows imaging pancreatitis and abnormal collections without the use of ionising radiation. Teaching Points * Endoscopic retrograde cholangiopancreatography (ERCP) allows treating many biliopancreatic disorders.* Due to the number and complexity of procedures, post-ERCP complications are increasingly encountered.* Main complications include acute pancreatitis, haemorrhages, duodenal perforation and infections.* Diagnosis and management of complications rely on combined clinical, laboratory and imaging data.* Multidetector CT is most effective to diagnose, categorise and monitor post-ERCP complications. PMID- 25716102 TI - A highly conspicuous mineralized composite photonic architecture in the translucent shell of the blue-rayed limpet. AB - Many species rely on diverse selections of entirely organic photonic structures for the manipulation of light and the display of striking colours. Here we report the discovery of a mineralized hierarchical photonic architecture embedded within the translucent shell of the blue-rayed limpet Patella pellucida. The bright colour of the limpet's stripes originates from light interference in a periodically layered zig-zag architecture of crystallographically co-oriented calcite lamellae. Beneath the photonic multilayer, a disordered array of light absorbing particles provides contrast for the blue colour. This unique mineralized manifestation of a synergy of two distinct optical elements at specific locations within the continuum of the limpet's translucent protective shell ensures the vivid shine of the blue stripes, which can be perceived under water from a wide range of viewing angles. The stripes' reflection band coincides with the spectral range of minimal light absorption in sea water, raising intriguing questions regarding their functional significance. PMID- 25716103 TI - What is "normal" in grief? AB - Research conducted over the past two decades has revealed that grief, a common phenomenon experienced by many people following the loss of a loved one, is rarely experienced as a steady progression from high acuity (intensity) to eventual resolution. Instead of this single "traditional" path, four distinct trajectories are supported by empirical data: resilience, chronic grief, depressed-improved, and chronic depression. Furthermore, a small subset of individuals never fully integrate the loss into their life, and continue to experience severe disruption in daily life many years after the loss event, a phenomenon known as Complicated Grief (CG). Continued empirical research will help further our understanding of the normative grief process and CG as a disorder. This information is crucial for informing clinicians of best practices when attending to those suffering from loss. PMID- 25716105 TI - Who can benefit from virtual reality to reduce experimental pain? A crossover study in healthy subjects. AB - BACKGROUND: The present study aimed to identify predicting factors affecting experimental pain stimuli reduction by using 'EyeToy', which is an Immersive Virtual Reality System (IVRS). METHODS: Sixty-two healthy subjects (31 M, 31 F) underwent a battery of pain tests to determine each participant's baseline sensitivity to nociceptive. The battery included thermal pain tests (hot and cold) as well as a paradigm to induce conditioned pain modulation (CPM). Later on, each subject participated in two study conditions in random order: (1) An exposure to tonic heat stimulation (46.5 degrees C/135 s) to the ankle while participating in VR environment which included an activity requiring limb movements; (2) Same heat stimulation with no exposure to VR. Six pain measures were taken during each study condition (baseline, test 1-5). RESULTS: An interaction of time * treatment was found (RM ANOVA, F(5, 305) = 24.33, p < 0.001, eta2 = 0.28). Specifically, the reduction in pain score between baseline and test 1 was significantly greater in VR condition than in control (p < 0.001). The maximal pain reduction in both conditions was between baseline and test 1. Hierarchical regression revealed gender and the extent of CPM as predictive factors for pain reduction in the VR condition (6.1% and 7.5%, respectively). CONCLUSIONS: It can be concluded that VR can serve as an effective manipulation for pain reduction in individuals with efficient CPM and in women. These findings constitute a promising platform for future research and hold potential for the improvement and facilitation of clinical treatment. PMID- 25716104 TI - Establishment of a simple model for hepatitis B virus infection status based on trait marker from quantitative measurement of serum markers. AB - The objectives of this study were to establish a simple model based on quantitative serum markers of hepatitis B virus (HBV) infection to understand the complex immune response to HBV. Patients samples were obtained from individuals with active HBV infection (alanine transaminase [ALT]-positive, aspartate aminotransferase [AST]-positive and HBsAg-positive), or patients who had recovered from infection (ALT-negative, AST-negative, anti-HBs-positive and either HBsAg, HBeAg, anti-HBe or anti-HBc positive). HBV quantitative markers, including HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc, were measured using a chemiluminescent microparticle immunoassay. Based on cut-off values, anti-HBs levels were converted to a ratio (sample value/cut-off value, RV). Anti-HBe and anti-HBc levels were determined using a competition method, resulting in the use of a ratio (cut-off value/sample value, RV) for determination of anti-HBe and anti-HBc values. The greater RV value in a patient was considered as a trait marker for HBV infection (TMHB) of this patient. Patients with TMHB including HBsAg or HBeAg were defined as TMHB-Ag; and patients with TMHB including anti HBs, anti-HBe, or anti-HBc TMHB were defined as TMHB-Ab. The percentage of patients determined to be TMHB-Ag was 96.3% in the HBV group. The percentage of patients determined to be TMHB-Ab was 94.7% in recovery group. TMHBs could be used to analyze different status of HBV infection. PMID- 25716106 TI - In situ growth of a polyphosphazene nanoparticle coating on a honeycomb surface: facile formation of hierarchical structures for bioapplication. AB - In combination with the breath-figure method, an in situ growth approach of polyphosphazenes was performed on a honeycomb surface resulting in a closely packed nanoparticle coating and a micro/nanoscale hierarchical structure. The hierarchically structured surfaces exhibited high biocompatibility, allowed good cellular adhesion and presented strong potential use as a cell scaffold. PMID- 25716107 TI - Validation of Single-Item Screening Measures for Provider Burnout in a Rural Health Care Network. AB - We validated three single-item measures for emotional exhaustion (EE) and depersonalization (DP) among rural physician/nonphysician practitioners. We linked cross-sectional survey data (on provider demographics, satisfaction, resilience, and burnout) with administrative information from an integrated health care network (1 academic medical center, 6 community hospitals, 31 clinics, and 19 school-based health centers) in an eight-county underserved area of upstate New York. In total, 308 physicians and advanced-practice clinicians completed a self-administered, multi-instrument questionnaire (65.1% response rate). Significant proportions of respondents reported high EE (36.1%) and DP (9.9%). In multivariable linear mixed models, scores on EE/DP subscales of the Maslach Burnout Inventory were regressed on each single-item measure. The Physician Work-Life Study's single-item measure (classifying 32.8% of respondents as burning out/completely burned out) was correlated with EE and DP (Spearman's rho = .72 and .41, p < .0001; Kruskal-Wallis chi(2) = 149.9 and 56.5, p < .0001, respectively). In multivariable models, it predicted high EE (but neither low EE nor low/high DP). EE/DP single items were correlated with parent subscales (Spearman's rho = .89 and .81, p < .0001; Kruskal-Wallis chi(2) = 230.98 and 197.84, p < .0001, respectively). In multivariable models, the EE item predicted high/low EE, whereas the DP item predicted only low DP. Therefore, the three single-item measures tested varied in effectiveness as screeners for EE/DP dimensions of burnout. PMID- 25716108 TI - A meta-analysis of margin size and local recurrence in oral squamous cell carcinoma. AB - OBJECTIVES: Excision margins for oral squamous cell carcinoma (OSCC) are poorly understood. Close (<5mm) and involved (<1mm) pathological margins are key indicators of the need for adjuvant treatment. This review aimed to assess the impact of pathological margin size on local recurrence rates. METHODS: MEDLINE and EMBASE were searched for studies that looked at local recurrence following excision of primary OSCC without adjuvant therapy. Five studies met the inclusion criteria. RESULTS: Recurrence rates were pooled to give a 21% absolute risk reduction (95% confidence interval 12-30%, p=<0.00001) in local recurrence with margins clear by more than 5mm. Unweighted pooled recurrence rates were 20% in patients with margins clear by more than 5mm. CONCLUSION: These findings suggest that a 5mm pathological margin is the minimum acceptable margin size in OSCC. PMID- 25716109 TI - Return to work and sporting activities after high tibial osteotomy. AB - PURPOSE: High tibial osteotomy (HTO) is a commonly used treatment to correct varus malalignment of the knee. The purpose of this study was, first, to determine, whether HTO allows return to pre-operative work, depending on the amount of work load. Second, the restoration of sports ability and a difference in sports activities pre- to postoperative should be analyzed. METHODS AND PATIENTS: Fifty-one patients were included in this study. Patients were divided into three groups dependent on work intensity. Sporting activity was evaluated by an activity score (Naal). Clinical examination includes Tegner-score, Lysholm score and visual analog pain scale. General health was assessed using the 36-Item Short Form Survey questionnaire. RESULTS: On an average of 16.7 +/- 15.6 weeks after surgery patients returned to work, and 93.8 % of the patients returned to pre-operative work load. The Tegner activity score did not show significant changes pre- and postoperatively. At the time of survey Lysholm score reached a value of 68.7 +/- 23.9 points on average. Postoperatively, patients remarked on decreased pain by VAS by an average of 2.6 +/- 2.3 points. CONCLUSIONS: In total, 92.3 % returned to pre-operative sports activities after surgery. A shift away from high impact activities to lower impact activities, a significant decrease of the duration of sports activities and number of sports disciplines was detected. In summary, HTO allows the young, active patient with medial osteoarthritis of the knee to return to work with the same work intensity and to return to sports. PMID- 25716110 TI - Comparison between the spatial subchondral support plate and the proximal humeral locking plate in the treatment of unstable proximal humeral fractures. AB - PURPOSE: The aim of our study was to evaluate the effect of the S3 (spatial subchondral support) humeral plate and to compare the clinical outcomes and complications after ORIF (open reduction and internal fixation) of proximal humeral fractures using either a S3 plate or a PHLP (proximal humeral locking plate). METHODS: A total of 144 patients with displaced unstable proximal humeral fractures were treated with either a S3 plate or a PHLP. Each patient had a follow-up at least for one year. We retrospectively collected the data and compared the shoulder functional outcome as well as complications of these two methods. RESULTS: During the one-year follow-up, the average Constant scores gradually improved for both groups. Patients treated with use of an S3 plate had better functional results at three and six months (P < 0.05). The one-year Constant score for all fracture types (Neer classified) were not significantly different between the S3 and PHLP group (P > 0.05). The complication rate was comparable between the two groups (P > 0.05). CONCLUSIONS: The treatment using an S3 plate for displaced unstable proximal humeral fractures resulted in a good union rate and functional outcome, which is comparable to the PHLP treatment. The S3 humerus plate can be considered as an effective implant for ORIF of displaced unstable proximal humeral fractures. PMID- 25716112 TI - Evaporation-induced self-assembling of few-layer graphene into a fractal-like conductive macro-network with a reduction of percolation threshold. AB - The transcription of nanoproperties to other dimensions in an efficient and simple way by the appropriate design of devices is a challenge, and conductive nanocarbon systems are considered here. The evaporation-induced self-assembling method is proposed to form branched, fractal-like "2D" conductive macrostructures from (nano) micro few-layer graphene flakes. The self-assembled conductive graphene networks reveal a reduction of percolation threshold compared to a random arrangement (a lower matter concentration is required to make a given substrate conductive and at a lower coverage), and become a promising matrix for conductive (transparent) films. The method is easy, cost-efficient and can potentially be applied on unlimited surfaces. PMID- 25716111 TI - The role of adipocytokines in the pathogenesis of knee joint osteoarthritis. AB - Osteoarthritis (OA) is one of the most common causes of musculoskeletal disability in the world. Traditionally, it has been thought that obesity contributes to the development and progression of OA by increased mechanical load of the joint structures. Nevertheless, studies have shown that adipose tissue derived cytokines (adipocytokines) are a possible link between obesity and OA. Furthermore, according to recent findings, not only articular cartilage may be the main target of these cytokines but also the synovial membrane, subchondral bone and infrapatellar fat pad may be encompassed in the process of degradation. This review presents the most recent reports on the contribution of adipocytokines to the knee joint cartilage degradation, osteophyte formation, infrapatellar fat pad alterations and synovitis. PMID- 25716114 TI - Impact of a new alcohol policy on homemade alcohol consumption and sales in Russia. AB - AIMS: To describe the effects of Russian policy since 2006 affecting price and availability on the consumption of recorded and unrecorded alcohol, with specific reference to homemade alcohol, and to investigate other factors affecting homemade alcohol consumption and purchasing. METHODS: Consumption and preferred beverage data were collected from RLMS-HSE nationwide panel surveys from 1994 to 2013, with a detailed analysis of 2012 data (18,221 respondents aged 16+ years). Official statistics on manufactured alcohol sales, regional price increase and real disposable income were used. RESULTS: Homemade distilled spirits (samogon) consumption decreased together with that of recorded and unrecorded manufactured spirits since 2000. The consumption of spirits was partially replaced by the consumption of beer and wine. These trends in alcohol consumption were interrupted in 2008-2013. The interruption was more likely affected by the economic crisis and recession than by the new alcohol policy. Social networks and availability of unrecorded alcohol were more important predictors of homemade alcohol consumption and purchasing than was a recorded alcohol price increase. CONCLUSIONS: Homemade alcohol consumption does not replace the declining market for recorded spirits in Russia. The effects of economic and social factors on homemade alcohol consumption are greater than are the short-term effects of the new alcohol policy. The very recent (2015) reduction of the minimum unit price of vodka may be premature. PMID- 25716113 TI - People with alcohol use disorders in specialized care in eight different European countries. AB - AIM: To provide a description of patients receiving alcohol treatment in eight different European countries, including the level of comorbidities and functional limitations. METHODS: Drinking behaviours, DSM-IV alcohol use disorder (AUD), mental and somatic comorbidities, disability and health services utilization of 1767 patients from various specialized treatment settings were assessed as representative for regions of eight European countries. Severity of alcohol dependence (AD) in terms of drinking level was compared with a large representative US sample. RESULTS: Patients in specialized care for AUDs showed high levels of consumption [average level of daily ethanol intake: 141.1 g, standard deviation (SD): 116.0 g], comorbidity [e.g. liver problems: 19.6%, 95% confidence interval (CI): 17.5-21.6%; depression: 43.2%, 95% CI: 40.7-45.8%; anxiety: 50.3%, 95% CI: 47.8-52.9%], disability and health services utilization (average number of nights spent in hospital(s) during the last 6 months: 8.8, SD: 19.5 nights). Severity of AD was similar to the US sample, but European men consumed on average more alcohol daily. CONCLUSIONS: High levels of consumption, somatic and mental comorbidities, disability and functional losses were found in this representative treatment sample, indicating that treatment was initiated only at severe stages of AUDs. Earlier initiation of treatment could help avoid some of the health and social burden. PMID- 25716115 TI - Increased facial attractiveness following moderate, but not high, alcohol consumption. AB - AIMS: Alcohol consumption is known to be associated with risky sexual behaviours, but this relationship may be complex and bidirectional. We explored whether alcohol consumption leads to the consumer being rated as more attractive than sober individuals. METHODS: Heterosexual social alcohol consumers completed an attractiveness-rating task, in which they were presented with pairs of photographs depicting the same individual, photographed while sober and after having consumed alcohol (either 0.4 or 0.8 g/kg), and required to decide which image was more attractive. RESULTS: Photographs of individuals who had consumed a low dose of alcohol (equivalent to 250 ml of wine at 14% alcohol by volume for a 70 kg individual) were rated as more attractive than photographs of sober individuals. This was not observed for photographs of individuals who had consumed a high dose of alcohol. CONCLUSION: In addition to perceiving others as more attractive, a mildly intoxicated alcohol consumer may also be perceived as more attractive by others. This in turn may play a role in the relationship between alcohol consumption and risky sexual behaviour. PMID- 25716117 TI - The use of subdissociative-dose ketamine for acute pain in the emergency department. AB - OBJECTIVES: Ketamine is a well-known anesthetic with its use trailing back to the 1960s. It has antagonistic effects at the N-methyl-d-aspartate receptor. There is emerging literature to suggest the use of subdissociative-dose ketamine (SDDK) for pain reduction. This evidence-based review evaluates the evidence regarding the use of SDDK for acute pain control in the emergency department (ED). METHODS: The MEDLINE and EMBASE databases were searched. Randomized controlled trials (RCTs) that described or evaluated the use of SDDK for acute pain in the ED were included. Literature was excluded if it was not published in English. Duplicate articles, unpublished reports, abstracts, and review articles were also excluded. Quality assessment and evaluation of literature were evaluated based on the GRADE criteria. The primary outcome of interest in this review was the difference in pain score from baseline to cutoff time as specified in the studies. Secondary outcome measures were the incidence of adverse events and reduction in the amount of adjuvant opioids consumed by patients who received SDDK. RESULTS: Four RCTs met the inclusion criteria, which enrolled a total of 428 patients. Three adult trials and one pediatric trial were identified. The level of evidence for the individual trials ranged from low to moderate. A significant reduction in pain scores was only found in two of the four trials. One trial found a significant reduction in mean pain scores when ketamine was compared to morphine (p < 0.05). Another trial reported a significant decrease in mean distress scores, favoring SDDK over fentanyl (1.0 vs. 2.7, p < 0.05). One trial found a significant reduction in the amount of morphine consumed, favoring ketamine over placebo (0.14 mg/kg, 95% confidence interval [CI] = 0.13 to 0.16 mg/kg vs. 0.2 mg/kg, 95% CI = 0.18 to 0.22 mg/kg; p < 0.001). An emergence phenomenon was reported in one trial. CONCLUSIONS: Four RCTs with methodologic limitations failed to provide convincing evidence to either support or refute the use of SDDK for acute pain control in the ED. PMID- 25716118 TI - Spin-current nano-oscillator based on nonlocal spin injection. AB - Nonlocal spin injection has been recognized as an efficient mechanism for creation of pure spin currents not tied to the electrical charge transfer. Here we demonstrate experimentally that it can induce coherent magnetization dynamics, which can be utilized for the implementation of novel microwave nano-sources for spintronic and magnonic applications. We show that such sources exhibit a small oscillation linewidth and are tunable over a wide frequency range by the static magnetic field. Spatially resolved measurements of the dynamical magnetization indicate a relatively large oscillation area, resulting in a high stability of the oscillation with respect to thermal fluctuations. We propose a simple quasilinear dynamical model that reproduces well the oscillation characteristics. PMID- 25716119 TI - Supramolecular Amphiphiles Based on Host-Guest Molecular Recognition Motifs. PMID- 25716120 TI - Attachment insecurity predicts responses to an interdisciplinary chronic pain rehabilitation program. AB - The aim of this study was to examine the hypothesis that attachment insecurity is associated with poorer responses to interdisciplinary treatment for chronic pain. Patients (n = 235) admitted to a 4-week interdisciplinary rehabilitation program were recruited. At pre-treatment, participants completed a battery of questionnaires assessing adult attachment styles and dimensions, as well as pain intensity, disability, self-efficacy, pain catastrophizing, and depressive symptoms. The latter measures were completed again at post-treatment. Nearly two thirds of participants (65.5 %) reported having an insecure attachment style. Attachment insecurity was unrelated to pre- and post-treatment reports of pain intensity and pain-related disability, but was significantly associated with most other clinical variables at both time points. Regression analyses controlling for pre-treatment functioning indicated that attachment insecurity was associated with less improvement in pain catastrophizing, pain self-efficacy, and depressive symptoms. Further research is warranted to investigate the processes by which attachment characteristics influence patients' responses to chronic pain rehabilitation. PMID- 25716121 TI - Lymphangiosarcoma with bone formation of the auricle in a dog. AB - A 12-year-old mixed-breed neutered female dog was referred with cutaneous tumors at the left auricle. Histologically, the cutaneous tumor located in the dermis comprised numerous clefts and cavernous channels lined by neoplastic endothelial cells with no erythrocytes. Bone tissue without direct contact with neoplastic cells was seen in the well-developed stromal connective tissue. The neoplastic endothelial cells exhibited mild to moderate atypia. Immunohistochemically, neoplastic cells were positive for vimentin and negative for cytokeratin and factor VIII-related antigen. Basement membrane around the neoplastic lumens was positive for laminin in a linear or granular pattern. Ultrastructural examination revealed discontinuous basement membrane beneath the tumor cells. Histopathological features of this case were consistent with lymphangiosarcoma, and stromal ossification was characteristic. PMID- 25716122 TI - The Use of Modafinil in the Intensive Care Unit. AB - As patients recover from their critical illness, the focus of intensive care unit (ICU) care becomes rehabilitation. Fatigue, excessive daytime somnolence (EDS), and depression can delay their recovery and potentially worsen outcomes. Psychostimulants, particularly modafinil (Provigil), have been shown to alleviate some of these symptoms in various patient populations, and as clinical trials are underway exploring this novel use of the drug, we present a case series of 3 patients in our institution's Thoracic Surgery Intensive Care Unit. Our 3 patients were chosen as a result of their fatigue, EDS, and/or depression, which prolonged their ICU stay and precluded them from participating in physical therapy, an integral component of the rehabilitative process. The patients were given 200 mg of modafinil each morning to increase patient wakefulness, encourage their participation, and enable a more restful sleep during the night. Although the drug was undoubtedly not the sole reason why our patients became more active, the temporal relationship between starting the drug and our patients' clinical improvement makes it likely that it contributed. Based on our observations with these patients, the known effects of modafinil, its safety profile, and the published experiences of others, we believe that modafinil has potential benefits when utilized in some critically ill patients and that the consequences of delayed patient recovery and a prolonged ICU stay may outweigh the risks of potential modafinil side effects. PMID- 25716124 TI - Design, synthesis and in vitro bactericidal/fungicidal screening of some vanadyl(IV)complexes with mono- and di-substituted ONS donor triazoles. AB - A new series of anti-bacterial and anti-fungal mono- and di-substituted triazoles (L(1))-(L(6)) have been synthesized and characterized on the basis of their physical, spectral and analytical data. The ligands (L(1))-(L(6)) on reaction with vanadyl(IV) sulphate led to the formation of vanadyl(IV) metal complexes (1) (4). The structure of the complexes has been established on the basis of their physical, spectral and elemental analyses data. The synthesized ligands and their vanadyl(IV) complexes have been screened in vitro for anti-bacterial activity against six bacterial species such as, Escherichia coli (ATCC 25922), Shigella flexneri (ATCC 12022), Pseudomonas aeruginosa (ATCC 27853), Salmonella typhi (ATCC 14028), Staphylococcus aureus (ATCC 25923) and Bacillus subtilis (ATCC 6051) and for in vitro anti-fungal activity against six fungal strains, Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata. The screening results showed the vanadyl complexes to be more bactericidal/fungicidal against one or more bacterial/fungal species. The synthesized compounds were also subjected to brine shrimp bioassay for scrutinizing their cytotoxicity. PMID- 25716125 TI - Synthesis and anti-cancer activity evaluation of new aurone derivatives. AB - In this study, we have synthesized 2-[3- or 4-(2-aryl-2 oxoethoxy)arylidene]benzofuran-3-one derivatives (D1-D38) and evaluated their anti-cancer activities. The final compounds were obtained in multistep synthesis reactions using benzofuranon-3-one derivatives (A1-A4, B) as starting materials which were gained in various synthetic ways. Aurone derivatives (C1-C10) were acquired with the condensation reaction of these starting materials and 3-/4 hydroxybenzaldehyde which were then reacted with alpha-bromoacetophenones to get final compounds. The anti-cancer activity of the selected compounds was performed by National Cancer Institute (NCI), USA against 60 human tumor cell lines derived from nine neoplastic diseases. Compounds exhibited anti-cancer activity in varying ratios. PMID- 25716126 TI - Comparison of Rhabdomyolysis Markers in Patients Undergoing Bariatric Surgery with Propofol and Inhalation-based Anesthesia. AB - BACKGROUND: Rhabdomyolysis is a relatively uncommon, severe complication of anesthesia and surgery in the morbidly obese. As the use of propofol-based anesthesia has been associated with an increased risk of rhabdomyolysis and metabolic acidosis, this pilot study was designed to assess the effect of propofol anesthesia on the incidence of rhabdomyolysis in morbidly obese patients undergoing bariatric surgery. METHODS: Thirty, morbidly obese patients (body mass index 43 +/- 3 kg/m(2)) scheduled for bariatric laparoscopic sleeve gastrectomy were randomized to receive either propofol (P) or inhalational anesthetic (I) based balanced general anesthesia. A sample of venous blood gas analysis including pH, bicarbonate concentrations, and calculated base excess was taken at the end of the operation. Creatine phosphokinase (CPK), troponin I, blood urea nitrogen, and creatinine plasma concentrations were measured at the end of the surgery and again 24 h later. RESULTS: All patients enrolled to the study completed it without significant complications. CPK, troponin I, blood urea nitrogen, and creatinine plasma concentrations at the end of the operation and at 24 h, as well as the bicarbonate concentration and the base excess at the end of the operation were not significantly different between the two study groups. A statistically significant mild respiratory acidosis was noted in the inhalational anesthetic group (pH 7.30 +/- 0.04 vs. 7.36 +/- 0.02 in the propofol group) CONCLUSIONS: This small-size pilot study may suggest that propofol-based anesthesia is not related to increased incidence of rhabdomyolysis in morbidly obese patients undergoing short, uncomplicated bariatric surgery. PMID- 25716127 TI - Endoscopic removal of partially migrated intragastric bands following surgical gastroplasty: a prospective case series. AB - BACKGROUND: The intragastric migration of a surgically placed adjustable gastric band is believed to occur slowly, over months to years. Band removal procedures necessitate surgical laparotomy, thus increasing the risk of complications. METHODS: The endoscopic technique for band removal described in this case-series provides a minimally invasive approach. RESULTS: Fifteen patients referred for endoscopic removal of a partially migrated intragastric band. The partially migrated intragastric bands were all successfully removed in a mean of 1.1 endoscopic sessions. No patient required subsequent surgical intervention, and there were no immediate or delayed adverse events including no infections, bleeding, or perforations. CONCLUSIONS: Endoscopic removal of partially migrated intragastric bands appears feasible, effective, safe, and is a minimally invasive alternative to repeat surgery. PMID- 25716129 TI - Anomalous diffusion process applied to magnetic resonance image enhancement. AB - Diffusion process is widely applied to digital image enhancement both directly introducing diffusion equation as in anisotropic diffusion (AD) filter, and indirectly by convolution as in Gaussian filter. Anomalous diffusion process (ADP), given by a nonlinear relationship in diffusion equation and characterized by an anomalous parameters q, is supposed to be consistent with inhomogeneous media. Although classic diffusion process is widely studied and effective in various image settings, the effectiveness of ADP as an image enhancement is still unknown. In this paper we proposed the anomalous diffusion filters in both isotropic (IAD) and anisotropic (AAD) forms for magnetic resonance imaging (MRI) enhancement. Filters based on discrete implementation of anomalous diffusion were applied to noisy MRI T2w images (brain, chest and abdominal) in order to quantify SNR gains estimating the performance for the proposed anomalous filter when realistic noise is added to those images. Results show that for images containing complex structures, e.g. brain structures, anomalous diffusion presents the highest enhancements when compared to classical diffusion approach. Furthermore, ADP presented a more effective enhancement for images containing Rayleigh and Gaussian noise. Anomalous filters showed an ability to preserve anatomic edges and a SNR improvement of 26% for brain images, compared to classical filter. In addition, AAD and IAD filters showed optimum results for noise distributions that appear on extreme situations on MRI, i.e. in low SNR images with approximate Rayleigh noise distribution, and for high SNR images with Gaussian or non central chi noise distributions. AAD and IAD filter showed the best results for the parametric range 1.2 < q < 1.6, suggesting that the anomalous diffusion regime is more suitable for MRI. This study indicates the proposed anomalous filters as promising approaches in qualitative and quantitative MRI enhancement. PMID- 25716128 TI - Use of Enoxaparin in Obese Adolescents During Bariatric Surgery--a Pilot Study. AB - BACKGROUND: Obese patients have a higher risk of venous thromboembolism when immobilized due to surgery. The objective of this study was to assess anti-factor Xa activity in adolescent bariatric surgical patients receiving prophylactic enoxaparin. METHODS: Four morbidly obese adolescents undergoing laparoscopic sleeve gastrectomy were enrolled. Enoxaparin was administered (40 mg subcutaneous (SC) if BMI <=50 kg/m(2) or 60 mg SC if BMI >50 kg/m(2)) for prevention of venous thromboembolism every 12 h starting after induction of anesthesia until discharge. Plasma anti-factor Xa activity was assessed over 12 h after the first dose and used as a surrogate marker for enoxaparin levels. Non-compartmental analysis of anti-factor Xa activity levels was performed and compared with previously published studies. RESULTS: Patients recruited were 16 to 18 years of age with a mean BMI of 52.6 +/- 5.8 kg/m(2) (>99th BMI percentile). Peak anti factor Xa activity ranged from 0.20 to 0.23 IU/mL in our study population, compared to 0.38 to 0.53 IU/mL in the cited lean comparator groups. CONCLUSIONS: Our current dosing practice of 40 mg SC for individuals with a BMI <=50 kg/m(2) and 60 mg for individuals with a BMI >=50 kg/m(2) resulted in anti-factor Xa activity that was sufficient for adequate thromboprophylaxis in adolescent bariatric surgical patients. Our data also demonstrates lower drug exposures in the obese when compared to lean patients. Therefore, randomized controlled efficacy and safety studies are urgently needed to guide the use of low-molecular weight heparins in the pediatric and adolescent obese population. PMID- 25716130 TI - Legal protections to promote response willingness among the local public health workforce. AB - OBJECTIVE: The legal environment may improve response willingness among local health department (LHD) workers. We examined whether 3 hypothetical legal protections influence LHD workers' self-reported response willingness for 4 emergency scenarios and whether specific demographic factors are associated with LHD workers' response willingness given these legal protections. METHODS: Our 2011-2012 survey included questions on demographics and about attitudes and beliefs regarding LHD workers' willingness to respond to 4 emergency scenarios given specific legal protections (i.e., ensuring priority health care for workers' families, granting workers access to mental health services, and guaranteeing access to personal protective equipment). Data were collected from 1238 LHD workers in 3 states. RESULTS: Across scenarios, between 60% and 83% of LHD workers agreed that they would be more willing to respond given the presence of 1 of the 3 hypothetical legal protections. Among the 3 legal protections, a guarantee of personal protective equipment elicited the greatest agreement with improved response willingness. CONCLUSIONS: Specific legal protections augment a majority of LHD workers' response willingness. Policymakers must, however, balance improved response willingness with other considerations, such as the ethical implications of prioritizing responders over the general public. (Disaster Med Public Health Preparedness. 2015;9:98-102). PMID- 25716132 TI - Facile synthesis of the Ti3+ self-doped TiO2-graphene nanosheet composites with enhanced photocatalysis. AB - This study developed a facile approach for preparing Ti(3+) self-doped TiO2 graphene photocatalyst by a one-step vacuum activation technology involved a relative lower temperature, which could be activated by the visible light owing to the synergistic effect among Ti(3+) doping, some new intersurface bonds generation and graphene oxide reduction. Compared with the traditional methods, the vacuum activation involves a low temperature and low-costing, which can achieve the reduction of GO, the self doping of Ti(3+) in TiO2 and the loading of TiO2 nanoparticles on GR surface at the same time. These resulting TiO2-graphene composites show the high photodegradation rate of MO, high hydrogen evolution activity and excellent IPCE in the visible light irradiation. The facile vacuum activation method can provide an effective and practical approach to improve the performance of TiO2-graphene and other metal oxides-graphene towards their practical photocatalytic applications. PMID- 25716133 TI - Rheological properties, molecular distribution, and microstructure of Fortunella margarita (Lour.) swingle polysaccharides. AB - Fortunella margarita polysaccharides (FMPS) are one of the main bioactive components of F. margarita. The activity is related to their rheological properties and structure. The objective of this study was to investigate the relationship between rheological properties, molecular distribution, and microstructure of crude FMPS (C-FMPS) and purified FMPS (P-FMPS). The results showed that both of solutions were shear-thinning pseudoplastic fluids with flow properties in line with the Power Law model. The pseudoplasticity of P-FMPS was stronger compared to C-FMPS. Additionally, the molecular weight and polydispersity of P-FMPS were greater, whereas the molecular radius was less compared to C-FMPS. The surface of C-FMPS was rough and dense whereas P-FMPS displayed a smooth network structure by environment scanning electron microscopy. According to confocal laser scanning microscopy, C-FMPS dispersed in the medium without connected network, whereas the network of P-FMPS was unevenly distributed in the medium and the shape was compact and smooth. The molecular distribution and microstructure of P-FMPS were attributed to the purification process while rearrangement and aggregation of polysaccharide molecules took place, which resulted in the significant difference of rheological properties between C-FMPS and P-FMPS. PMID- 25716134 TI - Factors associated with scoliosis in schoolchildren: a cross-sectional population based study. AB - BACKGROUND: The present study aimed to investigate the prevalence of scoliosis and to analyze the factors associated with scoliosis in schoolchildren aged between 7 and 17 years. METHODS: This is a cross-sectional and quantitative study with stratified random selection of public school students in the city of Santa Cruz, Brazil. The presence of scoliosis was examined, as well as the flexibility of the posterior muscle chain, socioeconomic characteristics, anthropometry, lifestyle habits, sexual maturation, and ergonomics of school furniture. In order to identify factors associated with scoliosis, the variables were divided in biological, socioeconomic, lifestyle, and ergonomic factors, and crude and adjusted prevalence ratios (PRs) were estimated by means of Poisson regression analysis. RESULTS: Two hundred and twelve pupils participated in this study (mean age 11.61 years, 58% female). The prevalence of scoliosis was 58.1% (n = 123) and associated with female sex (PR 2.54; 95% CI, 1.33-4.86) and age between 13 and 15 years (PR 5.35; 95% CI, 2.17-13.21). Sleeping in a hammock was inversely associated with scoliosis (PR 0.44; 95% CI, 0.23-0.81). CONCLUSIONS: Scoliosis seems to be positively associated with female sex and age between 13 and 15 years, whereas the habit of sleeping in a hammock is negatively associated with the onset of scoliosis. PMID- 25716135 TI - Clinical-pathological characteristics and prognosis of a cohort of oesophageal cancer patients: a competing risks survival analysis. AB - BACKGROUND: To determine the clinical course, follow-up strategies, and survival of oesophageal cancer patients using a competing risks survival analysis. METHODS: We conducted a retrospective and prospective follow-up study. The study included 180 patients with a pathological diagnosis of oesophageal cancer in A Coruna, Spain, between 2003 and 2008. The Kaplan-Meier methodology and competing risks survival analysis were used to calculate the specific survival rate. The study was approved by the Ethics Review Board (code 2011/372, CEIC Galicia). RESULTS: The specific survival rate at the first, third, and fifth years was 40.2%, 18.1%, and 12.4%, respectively. Using the Kaplan-Meier methodology, the survival rate was slightly higher after the third year of follow-up. In the multivariate analysis, poor prognosis factors were female sex (hazard ratio [HR] 1.94; 95% confidence interval [CI], 1.24-3.03), Charlson's comorbidity index (HR 1.17; 95% CI, 1.02-1.33), and stage IV tumours (HR 1.70; 95% CI, 1.11-2.59). The probability of dying decreased with surgical and oncological treatment (chemotherapy and/or radiotherapy) (HR 0.23; 95% CI, 0.12-0.45). The number of hospital consultations per year during the follow-up period, from diagnosis to the appearance of a new event (local recurrences, newly appeared metastasis, and newly appeared neoplasias) did not affect the probability of survival (HR 1.03; 95% CI, 0.92-1.15). CONCLUSIONS: The Kaplan-Meier methodology overestimates the survival rate in comparison to competing risks analysis. The variables associated with a poor prognosis are female sex, Charlson's comorbidity score and extensive tumour invasion. Type of follow-up strategy employed after diagnosis does not affect the prognosis of the disease. PMID- 25716136 TI - Healthcare costs and resource utilization of asthma in Germany: a claims data analysis. AB - INTRODUCTION: Asthma is associated with a substantial economic burden on the German Statutory Health Insurance. AIMS AND OBJECTIVES: To determine costs and resource utilization associated with asthma and to analyze the impact of disease severity on subgroups based on age and gender. METHODS: A claims database analysis from the statutory health insurance perspective was conducted. Patients with an ICD-10-GM code of asthma were extracted from a 10% sample of a large German sickness fund. Five controls for each asthma patient matched by age and gender were randomly selected from the same database. Costs and resource utilization were calculated for each individual in the asthma and control group. Incremental asthma-related costs were calculated as the mean cost difference. Based on prescribed asthma medication, patients were classified as intermittent or persistent. In addition, age groups of <= 5, 6-18, and >18 years were analyzed separately and gender differences were investigated. RESULTS: Overall, 49,668 individuals were included in the asthma group. On average, total annual costs per patient were ?753 higher (p = 0.000) compared to the control group (?2,168 vs. ?1,415). Asthma patients had significantly higher (p = 0.000) outpatient (?217), inpatient (?176), and pharmacy costs (?259). Incremental asthma-related total costs were higher for patients with persistent asthma compared to patients with intermittent asthma (?1,091 vs. ?408). Women aged >18 years with persistent asthma had the highest difference in costs compared to their controls (?1,207; p < 0.0001). Corresponding healthcare resource utilization was significantly higher in the asthma group (p = 0.000). CONCLUSIONS: The treatment of asthma is associated with an increased level of healthcare resource utilization and significantly higher healthcare costs. Asthma imposes a substantial economic burden on sickness funds. PMID- 25716138 TI - Origins of photoluminescence decay kinetics in CdTe colloidal quantum dots. AB - Recent experimental studies have identified at least two nonradiative components in the fluorescence decay of solutions of CdTe colloidal quantum dots (CQDs). The lifetimes reported by different groups, however, differed by orders of magnitude, raising the question of whether different types of traps were at play in the different samples and experimental conditions and even whether different types of charge carriers were involved in the different trapping processes. Considering that the use of these nanomaterials in biology, optoelectronics, photonics, and photovoltaics is becoming widespread, such a gap in our understanding of carrier dynamics in these systems needs addressing. This is what we do here. Using the state-of-the-art atomistic semiempirical pseudopotential method, we calculate trapping times and nonradiative population decay curves for different CQD sizes considering up to 268 surface traps. We show that the seemingly discrepant experimental results are consistent with the trapping of the hole at unsaturated Te bonds on the dot surface in the presence of different dielectric environments. In particular, the observed increase in the trapping times following air exposure is attributed to the formation of an oxide shell on the dot surface, which increases the dielectric constant of the dot environment. Two types of traps are identified, depending on whether the unsaturated bond is single (type I) or part of a pair of dangling bonds on the same Te atom (type II). The energy landscape relative to transitions to these traps is found to be markedly different in the two cases. As a consequence, the trapping times associated with the different types of traps exhibit a strikingly contrasting sensitivity to variations in the dot environment. Based on these characteristics, we predict the presence of a sub nanosecond component in all photoluminescence decay curves of CdTe CQDs in the size range considered here if both trap types are present. The absence of such a component is attributed to the suppression of type I traps. PMID- 25716137 TI - Adolescent over-general memory, life events and mental health outcomes: Findings from a UK cohort study. AB - Previous research suggesting that over-general memory (OGM) may moderate the effect of life events on depressive symptoms and suicidality has sampled older adolescents or adults, or younger adolescents in high-risk populations, and has been conducted over relatively short follow-up periods. The authors examined the relationship between OGM at age 13 and life events and mental health outcomes (depression, self-harm, suicidal ideation and planning) at age 16 years within a sample of 5792 adolescents participating in the Avon Longitudinal Study of Parents and Children (ALSPAC), approximately 3800 of whom had also provided data on depression and self-harm. There was no clear evidence of either direct or interactive effects of OGM at age 13 on levels of depression at age 16. Similarly there was no clear evidence of either direct or interactive effects of OGM on suicidal ideation and self-harm. Although there was some evidence that over general autobiographical memory was associated with reduced risk of suicidal planning and increased risk of self-harm, these associations were absent when confounding variables were taken into account. The findings imply that although OGM is a marker of vulnerability to depression and related psychopathology in high-risk groups, this cannot be assumed to generalise to whole populations. PMID- 25716139 TI - Progesterone and Tregs: emergence of a new paradigm? PMID- 25716140 TI - Seeing without knowing: task relevance dissociates between visual awareness and recognition. AB - We demonstrate that task relevance dissociates between visual awareness and knowledge activation to create a state of seeing without knowing-visual awareness of familiar stimuli without recognizing them. We rely on the fact that in order to experience a Kanizsa illusion, participants must be aware of its inducers. While people can indicate the orientation of the illusory rectangle with great ease (signifying that they have consciously experienced the illusion's inducers), almost 30% of them could not report the inducers' color. Thus, people can see, in the sense of phenomenally experiencing, but not know, in the sense of recognizing what the object is or activating appropriate knowledge about it. Experiment 2 tests whether relevance-based selection operates within objects and shows that, contrary to the pattern of results found with features of different objects in our previous studies and replicated in Experiment 1, selection does not occur when both relevant and irrelevant features belong to the same object. We discuss these findings in relation to the existing theories of consciousness and to attention and inattentional blindness, and the role of cognitive load, object based attention, and the use of self-reports as measures of awareness. PMID- 25716141 TI - Daily consumption of white tea (Camellia sinensis (L.)) improves the cerebral cortex metabolic and oxidative profile in prediabetic Wistar rats. AB - Diabetes mellitus (DM) is a major public health problem and its incidence is rising dramatically. The brain, particularly the cerebral cortex, is very susceptible to glucose fluctuations and hyperglycaemia-induced oxidative stress. Tea (Camellia sinensis (L.)) is widely consumed; however, the antidiabetic properties of white tea remain largely unexplored. In the present study, we investigated the effects of daily consumption of white tea on the cerebral cortex of prediabetic rats. The cerebral cortex metabolic profile was evaluated, and the expression levels of GLUT, phosphofructokinase-1, lactate dehydrogenase (LDH) and monocarboxylate transporter 4 were assessed. LDH activity was also determined. The cerebral cortex oxidative profile was determined by evaluating its antioxidant power, lipid peroxidation and protein oxidation levels. Catalase, glutathione, glutamate, N-acetylaspartate, aspartate, choline, gamma-aminobutyric acid, taurine and valine contents were determined. Daily consumption of white tea ameliorated glucose tolerance and insulin sensitivity. Moreover, white tea altered the cortex glycolytic profile, modulating GLUT expression and lactate and alanine contents. Finally, white tea consumption restored protein oxidation and lipid peroxidation levels and catalase expression, and improved antioxidant capacity. In conclusion, daily consumption of white tea improved the cerebral cortex metabolic and oxidative profile in prediabetic rats, suggesting it as a good, safe and inexpensive strategy to prevent DM-related effects in the cerebral cortex. PMID- 25716142 TI - Health literacy and the Internet: a study on the readability of Australian online health information. AB - OBJECTIVE: Almost 80% of Australian Internet users seek out health information online so the readability of this information is important. This study aimed to evaluate the readability of Australian online health information and determine if it matches the average reading level of Australians. METHODS: Two hundred and fifty-one web pages with information on 12 common health conditions were identified across sectors. Readability was assessed by the Flesch-Kincaid (F-K), Simple Measure of Gobbledygook (SMOG) and Flesch Reading Ease (FRE) formulas, with grade 8 adopted as the average Australian reading level. RESULTS: The average reading grade measured by F-K and SMOG was 10.54 and 12.12 respectively. The mean FRE was 47.54, a 'difficult-to-read' score. Only 0.4% of web pages were written at or below grade 8 according to SMOG. Information on dementia was the most difficult to read overall, while obesity was the most difficult among government websites. CONCLUSIONS AND IMPLICATIONS: The findings suggest that the readability of Australian health websites is above the average Australian levels of reading. A quantifiable guideline is needed to ensure online health information accommodates the reading needs of the general public to effectively use the Internet as an enabler of health literacy. PMID- 25716143 TI - Data linkage capabilities in Australia: practical issues identified by a Population Health Research Network 'Proof of Concept project'. AB - OBJECTIVE: To describe the practical issues that need to be overcome to conduct national data linkage projects in Australia and propose recommendations to improve efficiency. METHODS: Review of the processes, documentation and applications required to conduct national data linkage in Australia. RESULTS: The establishment of state and national data linkage centres in Australia has placed Australia at the forefront of research linking health-related administrative data collections. However, improvements are needed to reduce the clerical burden on researchers, simplify the process of obtaining ethics approval, improve data accessibility, and thus improve the efficiency of data linkage research. CONCLUSIONS: While a sound state and national data linkage infrastructure is in place, the current complexity, duplication and lack of cohesion undermines any attempts to conduct research involving national record linkage in a timely manner. IMPLICATIONS: Data linkage applications and Human Research Ethics Committee approval processes need to be streamlined and duplication removed, in order to reduce the administrative and financial burden on researchers if national data linkage research is to be viable. PMID- 25716144 TI - Changes in prokaryotic community composition accompanying a pronounced temperature shift of a shallow marine thermal brine pool (Panarea Island, Italy). AB - Hot Lake is a recently described thermal brine pool off Panarea Island (Eolian Islands, Italy) where emitted fluids are highly saline and rich in CO2 and H2S. The prokaryotic community composition in surface sediment samples was analyzed by high-throughput Illumina sequencing targeting the V3 region of the 16S rRNA at two time points that differed mainly with respect to temperature conditions, high temperature (94 degrees C, HT09) and low-temperature (28.5 degrees C, LT10). Bacterial richness and diversity were greater than those of Archaea under both temperature conditions. In contrast to Bacteria, diversity and evenness of Archaea greatly increased at LT10. While the phylogenetic analysis indicated the presence of members mostly affiliated with the same taxonomic groups, their relative abundances differed from HT09 to LT10, resulting in different bacterial and archaeal assemblages. Both HT09 and LT10 were dominated by members of the Epsilonproteobacteria. Within this subphylum, bacteria of the genus Sulfurimonas were most frequently detected at HT09, while Arcobacter prevailed at LT10. The abundance of other dominant taxonomic groups (>=1 % of Illumina reads) also correlated with temperature conditions. Members assigned to hyperthermophilic Euryarchaeota (Thermococci) or to thermophilic (Caldiserica) and thermoresistant (Firmicutes) bacterial taxa were dominant at HT09, while those related to non thermophilic Bacteroidetes, Fusobacteria and Actinobacteria were dominant at LT10. Several, probably photosynthetic, members of the Alphaproteobacteria, Chlorobi, Cyanobacteria and Chloroflexi were recovered under both temperature conditions. The co-occurrence of photosynthetic and chemolithotrophic microorganisms represents a unique feature of shallow vents such as Hot Lake. PMID- 25716145 TI - Moderately thermophilic, hydrocarbonoclastic bacterial communities in Kuwaiti desert soil: enhanced activity via Ca(2+) and dipicolinic acid amendment. AB - Pristine and oil-contaminated desert soil samples from Kuwait harbored between 10 and 100 cells g(-1) of hydrocarbonoclastic bacteria capable of growth at 50 degrees C. Enrichment by incubation of moistened soils for 6 months at 50 degrees C raised those numbers to the magnitude of 10(3) cells g(-1). Most of these organisms were moderately thermophilic and belonged to the genus Bacillus; they grew at 40-50 degrees C better than at 30 degrees C. Species belonging to the genera Amycolatopsis, Chelativorans, Isoptericola, Nocardia, Aeribacillus, Aneurinibacillus, Brevibacillus, Geobacillus, Kocuria, Marinobacter and Paenibacillus were also found. This microbial diversity indicates a good potential for hydrocarbon removal in soil at high temperature. Analysis of the same desert soil samples by a culture-independent method (combined, DGGE and 16S rDNA sequencing) revealed dramatically different lists of microorganisms, many of which had been recorded as hydrocarbonoclastic. Many species were more frequent in the oil contaminated than in the pristine soil samples, which may reflect their hydrocarbonoclastic activity in situ. The growth and hydrocarbon consumption potential of all tested isolates were dramatically enhanced by amendment of the cultures with Ca(2+) (up to 2.5 M CaSO4). This enhanced effect was even amplified when in addition 8 % w/v dipicolinic acid was amended. These novel findings are useful in suggesting biotechnologies for waste hydrocarbon remediation at moderately high temperature. PMID- 25716146 TI - Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem. AB - Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlusTM Oral Cavity Compartmental Absorption and Transit (OCCATTM) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo(r) sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C max, T max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F a_IO). The OCCATTM model captured the observed pharmacokinetics for Intermezzo(r) sublingual tablets (R (2) > 0.9). The predicted deviations (%) for C max, AUC0-inf, AUC0-20 min, and T max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F a_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD pH = 7.4). The novel physiologically based IO absorption OCCATTM model showed satisfactory performance and will be helpful to guide development of future intraoral formulations. PMID- 25716147 TI - Mesenchymal Stromal/Stem Cell and Minocycline-Loaded Hydrogels Inhibit the Growth of Staphylococcus aureus that Evades Immunomodulation of Blood-Derived Leukocytes. AB - Mesenchymal stromal/stem cells (MSCs) have demonstrated favorable wound healing properties in addition to their differentiation capacity. MSCs encapsulated in biomaterials such as gelatin and polyethylene glycol (PEG) composite hydrogels have displayed an immunophenotype change that leads to the release of cytokines and growth factors to accelerate wound healing. However, therapeutic potential of implanted MSC-loaded hydrogels may be limited by non-specific protein adsorption that facilitates adhesion of bacterial pathogens such as planktonic Staphylococcus aureus (SA) to the surface with subsequent biofilm formation resistant to immune cell recognition and antibiotic activity. In this study, we demonstrate that blood-derived primary leukocytes and bone marrow-derived MSCs cannot inhibit colony-forming abilities of planktonic or biofilm-associated SA. However, we show that hydrogels loaded with MSCs and minocycline significantly inhibit colony-forming abilities of planktonic SA while maintaining MSC viability and multipotency. Our results suggest that minocycline and MSC-loaded hydrogels may decrease the bioburden of SA at implant sites in wounds, and may improve the wound healing capabilities of MSC-loaded hydrogels. PMID- 25716148 TI - Liquid Chromatography-High Resolution Mass Spectrometry for Peptide Drug Quality Control. AB - A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed using three peptide drugs: salmon calcitonin, bivalirudin, and exenatide as model systems to assess the suitability of this approach for monitoring peptide drug product quality. Calcitonin and its related impurities displayed linear responses over the range from 0.1 to 10 MUM (R (2) values for calcitonin salmon, Glu(14)-calcitonin, and acetyl-calcitonin were 0.995, 0.996, and 0.993, respectively). Intra-assay precision in terms of relative standard deviation (%RSD) was less than 10% at all tested concentrations. The accuracy of the method was greater than 85% as measured by spiking 0.1, 0.3, and 1% of Glu(14)-calcitonin and acetyl-calcitonin into a stock calcitonin solution. Limits of detection for calcitonin, Glu(14)-calcitonin, and acetyl-calcitonin were 0.02, 0.03, and 0.04 MUM, respectively, indicating that an impurity present at less than 0.1% (0.1 MUM) of the drug product API concentration (107 MUM) could be detected. Method validation studies analyzing bivalirudin and exenatide drug products exhibited similar results to calcitonin salmon in regard to high selectivity, sensitivity, precision, and linearity. Added benefits of using LC HRMS-based methods are the ability to also determine amino acid composition, confirm peptide sequence, and quantify impurities, even when they are co-eluting, within a single experiment. LC-HRMS represents a promising approach for the quality control of peptides including the measurement of any peptide-related impurities. While the development work performed here is focus on peptide drug products, the principles could be adapted to peptide drug substance. PMID- 25716149 TI - Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products. AB - In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of beta-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size. PMID- 25716151 TI - The 'Best Practice Guide to Conservative Management of Patellofemoral Pain': incorporating level 1 evidence with expert clinical reasoning. AB - IMPORTANCE: Patellofemoral pain (PFP) is both chronic and prevalent; it has complex aetiology and many conservative treatment options. OBJECTIVE: Develop a comprehensive contemporary guide to conservative management of PFP outlining key considerations for clinicians to follow. DESIGN: Mixed methods. METHODS: We synthesised the findings from six high-quality systematic reviews to September 2013 with the opinions of 17 experts obtained via semistructured interviews. Experts had at least 5 years clinical experience with PFP as a specialist focus, were actively involved in PFP research and contributed to specialist international meetings. The interviews covered clinical reasoning, perception of current evidence and research priorities. RESULTS: Multimodal intervention including exercise to strengthen the gluteal and quadriceps musculature, manual therapy and taping possessed the strongest evidence. Evidence also supports use of foot orthoses and acupuncture. Interview transcript analysis identified 23 themes and 58 subthemes. Four key over-arching principles to ensure effective management included-(1) PFP is a multifactorial condition requiring an individually tailored multimodal approach. (2) Immediate pain relief should be a priority to gain patient trust. (3) Patient empowerment by emphasising active over passive interventions is important. (4) Good patient education and activity modification is essential. Future research priorities include identifying risk factors, testing effective prevention, developing education strategies, evaluating the influence of psychosocial factors on treatment outcomes and how to address them, evaluating the efficacy of movement pattern retraining and improving clinicians' assessment skills to facilitate optimal individual prescription. CONCLUSIONS AND RELEVANCE: Effective management of PFP requires consideration of a number of proven conservative interventions. An individually tailored multimodal intervention programme including gluteal and quadriceps strengthening, patellar taping and an emphasis on education and activity modification should be prescribed for patients with PFP. We provide a 'Best Practice Guide to Conservative Management of Patellofemoral Pain' outlining key considerations. PMID- 25716150 TI - Influence of P-Glycoprotein Inhibition or Deficiency at the Blood-Brain Barrier on (18)F-2-Fluoro-2-Deoxy-D-glucose ( (18)F-FDG) Brain Kinetics. AB - The fluorinated D-glucose analog (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) is the most prevalent radiopharmaceutical for positron emission tomography (PET) imaging. P-Glycoprotein's (P-gp, MDR1, and ABCB1) function in various cancer cell lines and tumors was shown to impact (18)F-FDG incorporation, suggesting that P gp function at the blood-brain barrier may also modulate (18)F-FDG brain kinetics. We tested the influence of P-gp inhibition using the cyclosporine analog valspodar (PSC833; 5 MUM) on the uptake of (18)F-FDG in standardized human P-gp-overexpressing cells (MDCKII-MDR1). Consequences for (18)F-FDG brain kinetics were then assessed using (i) (18)F-FDG PET imaging and suitable kinetic modelling in baboons without or with P-gp inhibition by intravenous cyclosporine infusion (15 mg kg(-1) h(-1)) and (ii) in situ brain perfusion in wild-type and P gp/Bcrp (breast cancer resistance protein) knockout mice and controlled D-glucose exposure to the brain. In vitro, the time course of (18)F-FDG uptake in MDR1 cells was influenced by the presence of valspodar in the absence of D-glucose but not in the presence of high D-glucose concentration. PET analysis revealed that P gp inhibition had no significant impact on estimated brain kinetics parameters K 1, k 2, k 3, V T , and CMRGlc. The lack of P-gp effect on in vivo (18)F-FDG brain distribution was confirmed in P-gp/Bcrp-deficient mice. P-gp inhibition indirectly modulates (18)F-FDG uptake into P-gp-overexpressing cells, possibly through differences in the energetic cell level state. (18)F-FDG is not a P-gp substrate at the BBB and (18)F-FDG brain kinetics as well as estimated brain glucose metabolism are influenced by neither P-gp inhibition nor P-gp/Bcrp deficiencies in baboon and mice, respectively. PMID- 25716152 TI - Preparticipation injury complaint is a risk factor for injury: a prospective study of the Moscow 2013 IAAF Championships. AB - OBJECTIVES: To determine the health status of athletes before the start of an international athletics championship and to determine whether preparticipation risk factors predicted in-championship injuries. METHODS: At the beginning of the 2013 International Association of Athletics Federations (IAAF) World Championships, all registered athletes (n=1784) were invited to complete a preparticipation health questionnaire (PHQ) on health status during the month preceding the championships. New injuries that occurred at the championships were prospectively recorded. RESULTS: The PHQ was completed by 698 (39%) athletes; 204 (29.2%) reported an injury complaint during the month before the championships. The most common mode of onset of preparticipation injury complaints was gradual (43.6%). Forty-nine athletes in the study reported at least one injury during the championships. Athletes who reported a preparticipation injury complaint were at twofold increased risk for an in-championship injury (OR=2.09; 95% CI 1.16 to 3.77); p=0.014). Those who reported a preparticipation gradual-onset injury complaint were at an almost fourfold increased risk for an in-championship time loss injury (OR=3.92; 95% CI 1.69 to 9.08); p=0.001). Importantly, the preparticipation injury complaint severity score was associated with the risk of sustaining an in-championship injury (OR=1.14; 95% CI 1.06 to 1.22); p=0.001). SUMMARY AND CONCLUSIONS: About one-third of the athletes participating in the study reported an injury complaint during the month before the championships, which represented a risk factor for sustaining an injury during the championship. This study emphasises the importance of the PHQ as a screening tool to identify athletes at risk of injuries before international championships. PMID- 25716154 TI - Educational interventions are effective in treating childhood obesity: (PEDro synthesis). PMID- 25716155 TI - Ankle: avoid another ankle sprain! PMID- 25716156 TI - Multimodal cardiac imaging of a postinfarction subvalvular left ventricular aneurysm. PMID- 25716157 TI - Coexisting ipsilateral right femoral hernia and incarcerated obturator hernia. AB - Obturator hernia (OH) is an uncommon cause of bowel obstruction and described in elderly females in the literature. The treatment has traditionally been laparotomy because of an acute nature of the condition. However, because of old age and comorbidities that OH is associated with, general anaesthesia may need to be avoided. In the current case, a transinguinal preperitoneal approach and management are presented after delayed preoperative diagnosis of bowel obstruction caused by a coexisting right incarcerated OH and ipsilateral non reducible femoral hernia. A 91-year-old woman had a 6-day history of nausea and vomiting. She was referred to surgery because of persisting vomiting, but without any abdominal pain. A CT scan showed a hernia in the right groin area but the diagnosis was delayed. The hernias were repaired using a preperitoneal transinguinal approach. Bowel resection was not needed. The obturator canal and the femoral ring were both covered by a Bard Polysoft patch. PMID- 25716158 TI - Mechanical tuning of the evaporation rate of liquid on crossed fibers. AB - We investigate experimentally the drying of a small volume of perfectly wetting liquid on two crossed fibers. We characterize the drying dynamics for the three liquid morphologies that are encountered in this geometry: drop, column, and a mixed morphology, in which a drop and a column coexist. For each morphology, we rationalize our findings with theoretical models that capture the drying kinetics. We find that the evaporation rate significantly depends upon the liquid morphology and that the drying of the liquid column is faster than the evaporation of the drop and the mixed morphology for a given liquid volume. Finally, we illustrate that shearing a network of fibers reduces the angle between them, changes the morphology toward the column state, and therefore, enhances the drying rate of a volatile liquid deposited on it. PMID- 25716159 TI - Synthetic cajanin stilbene acid derivatives inhibit c-MYC in breast cancer cells. AB - In the present study, we investigated the activity and modes of action of cajanin stilbene acid (CSA) and its derivatives in terms of cytotoxicity, gene expression profile, and transcription factor activity. XTT assays on MCF7 cells were performed upon treatment with CSA or derivatives. After the determination of IC50 values, gene expression profiling was performed with Agilent microarray experiments. Deregulated genes were determined with Chipster software, pathway and functional analyses were performed with Ingenuity pathway software. In order to identify the potential upstream regulators, MatInspector software was used to perform transcription factor binding motif search in the promoter regions of the deregulated genes. Molecular docking on MYC/MAX complex and reporter cell line experiments were performed to validate the MYC inhibitory activity of CSA and its derivatives. Two known MYC inhibitors: 10058-F4 and 10074-G5 were used as positive control. All compounds showed cytotoxicities in the micromolar range. Microarray analyses pointed to cell cycle, DNA damage, and DNA repair as mainly affected cellular functions. Promoter motif analysis of the deregulated genes further supported the microarray gene expression analysis results emphasizing the relevance of transcription factors regulating cell cycle and proliferation, with MYC as being the most pronounced one. Luciferase-based reporter cell line experiments and molecular docking studies yielded supportive results emphasizing the inhibitory activity of CSA and its derivatives on MYC. CSA and its derivatives are shown to be promising anticancer compounds with low toxicity. They inhibit MYC activity comparable to 10058-F4 and 10074-G5. Further studies are warranted to analyze the therapeutic applicability of these compounds in more detail. PMID- 25716160 TI - In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. AB - Steatosis, also known as fatty liver disease (FLD), is a disorder in which the lipid metabolism of the liver is disturbed, leading to the abnormal retention of lipids in hepatocytes. FLD can be induced by several drugs, and although it is mostly asymptomatic, it can lead to steatohepatitis, which is associated with liver inflammation and damage. Drug-induced liver injury is currently the major cause of postmarketing withdrawal of pharmaceuticals and discontinuation of the development of new chemical entities. Therefore, the potential induction of steatosis must be evaluated during preclinical drug development. However, robust human-relevant in vitro models are lacking. In the present study, we explore the applicability of hepatic cells (hSKP-HPCs) derived from postnatal skin precursors, a stem cell population residing in human dermis, to investigate the steatosis-inducing effects of sodium valproate (Na-VPA). Exposure of hSKP-HPC to sub-cytotoxic concentrations of this reference steatogenic compound showed an increased intracellular accumulation of lipid droplets, and the modulation of key factors involved in lipid metabolism. Using a toxicogenomics approach, we further compared Na-VPA-treated hSKP-HPC and Na-VPA-treated primary human hepatocytes to liver samples from patients suffering from mild and advanced steatosis. Our data show that in hSKP-HPC exposed to Na-VPA and liver samples of patients suffering from mild steatosis, but not in primary human hepatocytes, "liver steatosis" was efficiently identified as a toxicological response. These findings illustrate the potential of hSKP-HPC as a human-relevant in vitro model to identify hepatosteatotic effects of chemical compounds. PMID- 25716161 TI - Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses. AB - Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air-liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week old male Sprague-Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form of aerosol particles would induce an airway barrier injury via ROS, release fibrotic inflammatory cytokines, and trigger a wound healing response, leading to pulmonary fibrosis. A simultaneous state of tissue destruction and inflammation caused by PHMG-phosphate had whipped up a "perfect storm" in the respiratory tract. PMID- 25716162 TI - Working length of locking plates determines interfragmentary movement in distal femur fractures under physiological loading. AB - BACKGROUND: This study aimed to investigate the influence of the screw location and plate working length of a locking plate construct at the distal femur on interfragmentary movement under physiological loading. METHODS: To quantitatively analyse the influence of plate working length on interfragmentary movements in a locking plate construct bridging a distal femur fracture, a finite element model based on CT (computed tomography) data was physiologically loaded and fracture gap conditions were calculated. Four working lengths with eight screw variations each were systemically analysed. FINDINGS: Interfragmentary movements for axial (12-19%, p<0.001) and shear movements (-7.4-545%, p<0.001) at all tested nodes increased significantly with longer plate working length, whereas screw variations within the groups revealed no significant influence. The working length (defined by screw location) dominates the biomechanical fracture gap conditions. INTERPRETATION: The current finite element analysis demonstrates that plate working length significantly influences interfragmentary movements, thereby affecting the biomechanical consequences of fracture healing. PMID- 25716163 TI - Viable pigs with a conditionally-activated oncogenic KRAS mutation. AB - Oncogenic mutations of KRAS play a major role in human carcinogenesis. Here we describe viable gene-targeted pigs carrying a latent KRAS (G12D) mutant allele that can be activated by Cre recombination. These have been produced as part of a program to model human cancers in pigs by replicating genetic lesions known to initiate and drive human disease. Cre-activated KRAS (G12D) animals add to a growing set of gene-targeted pigs that includes a Cre-activated oncogenic mutant TP53, a Cre-responsive dual fluorescent reporter and two truncating mutations of APC (adenomatous polyposis coli). These alleles can be combined and activated in various tissues to produce new models for cancer research. PMID- 25716165 TI - Use of Opioid Analgesics in Older Australians. AB - OBJECTIVE: To identify potential medication management issues associated with opioid use in older Australians. DESIGN: Retrospective cross-sectional review of the utilization of analgesics in 19,581 people who underwent a medication review in Australia between 2010 and 2012. SUBJECTS: Australian residents living in the community deemed at risk for adverse medication outcomes or any resident living fulltime in an aged care facility. METHODS: Patient characteristics in those taking regularly dosed opioids and not and those taking opioid doses >120 mg and <=120 mg MEQ/day were compared. Multivariable binary logistic regression was used to analyze the association between regular opioid and high dose opioid usage and key variables. Additionally, medication management issues associated with opioids were identified. RESULTS: Opioids were taken by 31.8% of patients, with 22.1% taking them regularly. Several major medication management issues were identified. There was suboptimal use of multimodal analgesia, particularly a low use of non-opioid analgesics, in patients taking regular opioids. There was extensive use (45%) of concurrent anxiolytics/hypnotics among those taking regular opioid analgesics. Laxative use in those prescribed opioids regularly was low (60%). Additionally, almost 12% of patients were taking doses of opioid that exceeded Australian recommendations. CONCLUSIONS: A significant evidence to practice gap exists regarding the use of opioids amongst older Australians. These findings highlight the need for a quick reference guide to support prescribers in making appropriate decisions regarding pain management in older patients with persistent pain. This should also be combined with patient and caregiver education about the importance of regular acetaminophen to manage persistent pain. PMID- 25716167 TI - Heart failure in a patient with a pacemaker. PMID- 25716164 TI - Genetic basis and detection of unintended effects in genetically modified crop plants. AB - In January 2014, an international meeting sponsored by the International Life Sciences Institute/Health and Environmental Sciences Institute and the Canadian Food Inspection Agency titled "Genetic Basis of Unintended Effects in Modified Plants" was held in Ottawa, Canada, bringing together over 75 scientists from academia, government, and the agro-biotech industry. The objectives of the meeting were to explore current knowledge and identify areas requiring further study on unintended effects in plants and to discuss how this information can inform and improve genetically modified (GM) crop risk assessments. The meeting featured presentations on the molecular basis of plant genome variability in general, unintended changes at the molecular and phenotypic levels, and the development and use of hypothesis-driven evaluations of unintended effects in assessing conventional and GM crops. The development and role of emerging "omics" technologies in the assessment of unintended effects was also discussed. Several themes recurred in a number of talks; for example, a common observation was that no system for genetic modification, including conventional methods of plant breeding, is without unintended effects. Another common observation was that "unintended" does not necessarily mean "harmful". This paper summarizes key points from the information presented at the meeting to provide readers with current viewpoints on these topics. PMID- 25716168 TI - Telomere reverse transcriptase (TERT) rs2735940 increases cancer risk. AB - BACKGROUND: Telomerase reverse transcriptase (TERT) rs2735940 polymorphism was found to be associated with increased cancer risk. However, recent studies reported controversial results. The aim of our study was to detect its relationship with cancer risk. MATERIAL AND METHODS: EMBASE and PubMed databases were searched for all publications until October 2014. ORs and 95% CIs were applied to investigate the association in the random-effects model. RESULTS: Thirteen case-control studies with 19385 cases and 17558 controls were included in this study. We found a significant association between cancer risk and TERT rs2735940 polymorphism (OR=1.06, 95% CI 1.02-1.11, P=0.005). In the subgroup analysis by ethnicity, a marginal association was found in Caucasians (OR=1.05, 95% CI 1.00-1.10, P=0.05), but not in Asians (OR=1.01, 95% CI 0.82-1.24, P=0.93). In the subgroup analysis by cancer site, this polymorphism was significantly associated with lung cancer risk (OR=1.08, 95% CI 1.02-1.13, P=0.004). CONCLUSIONS: TERT rs2735940 polymorphism was significantly associated with cancer risk, especially lung cancer. PMID- 25716169 TI - The role of extracorporeal photopheresis in chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (GVHD) is the most important cause of late morbidity and mortality in recipients of allogeneic blood and marrow transplantation. Despite increased understanding of biology of chronic GVHD, treatment options remain limited and ineffective. While corticosteroids represent the backbone of initial chronic GVHD treatment, they have significant long-term toxicity and more than half of the patients require second-line therapy. Among the second-line treatments for chronic GVHD, extracorporeal photopheresis (ECP) is one of the most extensively studied modalities. While high quality studies establishing true value of ECP in chronic GVHD patients are lacking, its benefits in chronic GVHD are well documented. Its putative immunomodulatory, but not immunosuppressive, properties represent an attractive alternative to the other strategies leading to global immunosuppression and the resulting risks of opportunistic infections or malignancy relapse. PMID- 25716170 TI - Protective effects of erdosteine against nephrotoxicity caused by gamma radiation in male albino rats. AB - The aim of this study was focused on investigating the possible protective effect of erdosteine against gamma radiation-induced renal lesions in male albino rats. Twenty-eight albino rats were divided into four equal groups as follows: control group, irradiated group (animals subjected to whole-body gamma irradiation at a dose of 5 Gy), treated group (each rat received 100 mg/kg body weight once daily, orally by gastric tube, erdosteine for 1 week), and treated irradiated group (each rat received 100 mg/kg body weight once daily, orally by gastric tube, erdosteine for 1 week, then exposed to whole-body gamma irradiation at a dose of 5 Gy). The results revealed that the administration of erdosteine to rats before irradiation significantly ameliorated the changes occurred in kidney function (creatinine and urea) compared with irradiated group. Also the changes in serum tumor necrosis factor alpha, interleukin 1beta, and interleukin 6 activities were markedly improved compared with the corresponding values of irradiated group. Kidney catalase and glutathione peroxidase (GPx) activities and reduced glutathione concentration showed approximately normal level when compared with the irradiated group. The histopathological results showed distinctive pattern of renal lesions in irradiated group, while in treated irradiated group the renal tissues showed relatively well-preserved architecture. Erdosteine acts in the kidney as a potent scavenger of free radicals to prevent or ameliorate the toxic effects of gamma irradiation as shown in the biochemical and histopathological changes and might provide substantial protection against radiation-induced inflammatory damage. PMID- 25716171 TI - Distinct difference in absorption pattern in pigs of betaine provided as a supplement or present naturally in cereal dietary fiber. AB - The net absorption of betaine and choline was determined for 4 h after the first meal of the day in three experiments with porto-arterial catheterized pigs in which betaine was added as a supplement to a low-betaine diet (n=4 pigs) and compared to the net absorption of betaine and choline from high-fiber breads differing in amount and source of dietary fiber (two experiments, n=6 pigs each). Plasma betaine peaked after 30 min when betaine was fed as a supplement, whereas it peaked after 120-180 min when high-fiber breads were fed. Plasma betaine showed no diet*time interaction after feeding with high-fiber breads, indicating that the absorption kinetic did not differ between fiber sources. The net absorption of choline was not affected by the experimental diets. In conclusion, betaine in cereal sources has to be liberated from the matrix prior to absorption, causing delayed absorption. PMID- 25716172 TI - Performance Evaluation of CLIA for Treponema Pallidum Specific Antibodies Detection in Comparison with ELISA. AB - OBJECTIVES: In this study we aimed to evaluate the performance effects of chemiluminescence assay (CLIA) for Treponema pallidum specific antibodies detection, and to compare T. pallidum specific antibodies detection accuracy between CLIA and ELISA with TPPA (T. pallidum particle agglutination assay) as a confirmatory test. METHODS: A total of 865 samples from suspected syphilis patients and preoperative patients were included, in which T. pallidum specific antibodies were simultaneously detected by CLIA and ELISA. Among them, 457 samples were determined by TPPA. RESULTS: All coefficients of variation (CVs) of ELISA in high-, median-, and low-level samples were more than 5% and the maximum CV was 54.39% in the low-level sample. CVs of CLIA in different-level samples were all below 5%. Among the three assays the Spearman correlation and Kappa coefficients were 0.771 (P <= 0.001) and 0.854 (P <= 0.001, CLIA vs. ELISA), 0.806 (P <= 0.001) and 0.897 (P <= 0.001, ELISA vs. TPPA), 0.937 (P <= 0.001) and 0.967 (P <= 0.001, CLIA vs. TPPA), respectively. The area under the receiver operating characteristic curve (AUC) of CLIA was higher than that of ELISA (0.994 vs. 0.989) with TPPA as the confirmatory test. In 18 discrepant samples the consistency rate between CLIA and TPPA was elevated compared with that between ELISA and TPPA (72.22% vs. 27.78%, P = 0.008). In gray zone, the consistency rate of CLIA with TPPA was higher than that of ELISA with TPPA (90.91% vs. 41.67%, P = 0.027). CONCLUSIONS: Compared with ELISA, CLIA is more reliable, sensitive and accurate to detect serum T. pallidum specific antibodies. In the future it may be an alternative test with higher sensitivity to ELISA. PMID- 25716173 TI - Comparison of the China growth charts with the WHO growth standards in assessing malnutrition of children. AB - OBJECTIVES: To compare the difference between the China growth reference and the WHO growth standards in assessing malnutrition of children under 5 years. SETTINGS: The households selected from 31 provinces, autonomous regions and municipalities in mainland China (except Taiwan, Hong Kong and Macao). PARTICIPANTS: Households were selected by using a stratified, multistage probability cluster sampling. Children under 5 years of age in the selected households were recruited (n=15,886). PRIMARY AND SECONDARY OUTCOME MEASURES: Underweight, stunting, wasting, overweight and obesity. RESULTS: According to the China growth reference, the prevalence of underweight (8.7% vs 4.8%), stunting (17.2% vs 16.1%) and wasting (4.4% vs 3%) was significantly higher than that based on the WHO growth standards, respectively (p<0.001); the prevalence of overweight was lower than that based on the WHO growth standards (9.4% vs 10.2%, p<0.001). In most cases, the prevalence of undernutrition assessed by using the China growth reference was significantly higher. However, the prevalence of overweight was significantly lower by using China charts for boys aged 3-4, 6, 8, 10, 12-18 and 24 months. CONCLUSIONS: The WHO growth standards could be more conservative in undernutrition estimation and more applicable for international comparison for Chinese children. Future researches are warranted for using the WHO growth standards within those countries with local growth charts when there are distinct differences between the two. PMID- 25716174 TI - What do external consultants from private and not-for-profit companies offer healthcare commissioners? A qualitative study of knowledge exchange. AB - OBJECTIVES: The use of external consultants from private and not-for-profit providers in the National Health Service (NHS) is intended to improve the quality of commissioning. The aim of this study was to learn about the support offered to healthcare commissioners, how external consultants and their clients work together and the perceived impact on the quality of commissioning. SETTING: NHS commissioning organisations and private and not-for-profit providers. DESIGN: Mixed methods case study of eight cases. DATA COLLECTION: 92 interviews with external consultants (n=36), their clients (n=47) and others (n=9). Observation of 25 training events and meetings. Documentation, for example, meeting minutes and reports. ANALYSIS: Constant comparison. Data were coded, summarised and analysed by the research team with a coding framework to facilitate cross-case comparison. RESULTS: In the four contracts presented here, external providers offered technical solutions (eg, software tools), outsourcing and expertise including project management, data interpretation and brokering relationships with experts. In assessing perceived impact on quality of commissioning, two contracts had limited value, one had short-term benefits and one provided short and longer term benefits. Contracts with commissioners actively learning, embedding and applying new skills were more valued. Other elements of success were: (1) addressing clearly agreed problems of relevance to managerial and operational staff (2) solutions co-produced at all organisational levels (3) external consultants working directly with clients to interpret data outputs to inform locally contextualised commissioning strategies. Without explicit knowledge exchange strategies, outsourcing commissioning to external providers resulted in the NHS clients becoming dependent. CONCLUSIONS: NHS commissioning will be disadvantaged if commissioners both fail to learn in the short term from the knowledge of external providers and in the longer term lose local skills. Knowledge exchange mechanisms are a vital component of commissioning and should be embedded in external provider contracts. PMID- 25716176 TI - Early childhood measles vaccinations are not associated with paediatric IBD: a population-based analysis. AB - BACKGROUND: Early childhood vaccinations have been hypothesized to contribute to the emergence of paediatric inflammatory bowel disease [IBD] in developed countries. Using linked population-based administrative databases, we aimed to explore the association between vaccination with measles-containing vaccines and the risk for IBD. METHODS: This was a case-control study using the University of Manitoba IBD Epidemiology Database [UMIBDED]. The UMIBDED was linked to the Manitoba Immunization Monitoring System [MIMS], a population-based database of immunizations administered in Manitoba. All paediatric IBD cases in Manitoba, born after 1989 and diagnosed before March 31, 2008, were included. Controls were matched to cases on the basis of age, sex, and region of residence at time of diagnosis. Measles-containing vaccinations received in the first 2 years of life were documented, with vaccinations categorized as 'None' or 'Complete', with completeness defined according to Manitoba's vaccination schedule. Conditional logistic regression models were fitted to the data, with models adjusted for physician visits in the first 2 years of life and area-level socioeconomic status at case date. RESULTS: A total of 951 individuals [117 cases and 834 controls] met eligibility criteria, with average age of diagnosis among cases at 11 years. The proportion of IBD cases with completed vaccinations was 97%, compared with 94% of controls. In models adjusted for physician visits and area-level socioeconomic status, no statistically significant association was detected between completed measles vaccinations and the risk of IBD (adjusted odds ratio [AOR]: 1.5; 95% confidence interval [CI]: 0.5-4.4; p = 0.419]. CONCLUSIONS: No significant association between completed measles-containing vaccination in the first 2 years of life and paediatric IBD could be demonstrated in this population based study. PMID- 25716175 TI - Statin use and risk of haemorrhagic stroke in a community-based cohort of postmenopausal women: an observational study from the Women's Health Initiative. AB - OBJECTIVES: To determine whether statin treatment is associated with increased risk of haemorrhagic stroke (HS) in older women. A secondary objective was to evaluate HS risk in users of combined statin and antiplatelet treatment. DESIGN: Observational study: secondary data analysis from the Women's Health Initiative (WHI) clinical trials. SETTING: Women were recruited from 40 participating sites. PARTICIPANTS: Cohort of 68,132 women followed through 2005 (parent study) and for an additional 5 years in the extension study. MAIN OUTCOME MEASURES: Statin use was assessed at baseline and at follow-up visits (1, 3, 6 and 9 years). Women brought medications in original containers for inventory. Strokes were ascertained semiannually and centrally adjudicated. Risk of HS by statin use (time-varying covariate, with the 'no use' category as the referent) was estimated from Cox proportional hazard regression models adjusted for age (model 1); risk factors for HS (model 2); and possible confounders by indication (model 3). Prespecified subgroup analyses were conducted by use of antiplatelet medications. RESULTS: Final models included 67,882 women (mean age, 63+/-7 years). Over a mean follow-up of 12 years, incidence rates of HS were 6.4/10,000 person-years among statin users and 5.0/10,000 person-years among non-users (p=0.11). The unadjusted risk of HS in statin users was 1.21 (CI 0.96 to 1.53); after adjusting for age and HS risk factors the HR was 0.98 (CI 0.76 to 1.26). Risk of HS was higher among women on statins and antiplatelet agents versus women on antiplatelet medications alone (HR=1.59; CI 1.03 to 2.47); p for interaction=0.011. CONCLUSIONS: This retrospective analysis did not show an association between statin use and HS risk among older women. HS risk was higher among women taking statins with antiplatelet agents. These findings warrant further investigation, given potential implications for clinical decision-making. PMID- 25716177 TI - Ibrutinib is an effective treatment of autoimmune haemolytic anaemia in chronic lymphocytic leukaemia. PMID- 25716178 TI - The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. AB - The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5' CpG-island near the G4C2 repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2)n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles >50 repeats (97 %), while small (<22 repeats) or intermediate (22-90 repeats) alleles were completely unmethylated. The presence of (G4C2)n methylation does not separate the C9orf72-phenotypes (ALS vs. ALS/FTLD vs. FTLD), but has the potential to predict large vs. intermediate repeat length. Our results suggest that (G4C2)n -methylation might sometimes spread to the 5' upstream region, but not vice versa. It is stable over time, since (G4C2)n methylation was detected in carriers with a wide range of ages (24-74 years). It was identified in both blood and brain tissues for the same individual, implying its potential use as a biomarker. Furthermore, our findings may open up new perspectives for studying disease mechanisms, such as determining whether methylated and unmethylated repeats have the same ability to form a G-quadruplex configuration. PMID- 25716179 TI - The role of IL-17 in CNS diseases. AB - Cytokines of the IL-17 family are uniquely placed on the border between immune cells and tissue. Although IL-17 was originally found to induce the activation and mobilization of neutrophils to sites of inflammation, its tissue-specific function is not yet fully understood. The best-studied IL-17 family members, IL 17A and IL-17F, are both typically produced by immune cells such as Th17, gammadelta T cells and innate lymphoid cells group 3. However, the cells that respond to these cytokines are mostly found in inflamed tissue. As seen in psoriatic skin lesions or in joints of rheumatoid arthritis patients, high levels of IL-17 have been detected in the central nervous system (CNS) during inflammatory responses. Here, we provide a general review of the molecular function of IL-17 and its role in the CNS in particular. Of the different inflammatory conditions of the CNS, we found multiple sclerosis (MS) to be the one most associated with the presence of Th17 cells and IL-17. In particular, many studies using the murine model for MS, experimental autoimmune encephalomyelitis, found a clear association of Th17 and IL-17 with disease severity and progression. We summarize the recent advances made in correlating the presence of IL-17 with impaired blood-brain barrier integrity as well as the activation of astrocytes and microglia and the consequences for disease progression. There is also evidence that IL-17 plays a pathogenic role in the post-ischemic phase of stroke as well as its experimental model. We review the limited but promising data on the sources of post-stroke IL-17 production and its effects on CNS-resident target cells. In addition to MS and stroke, there is also evidence linking high levels of IL-17 to depression, as a frequent comorbidity of several inflammatory diseases, as well as to different types of infections of the CNS. The evidence we supply here suggests that inhibiting the function of the IL 17 cytokine family could have a beneficial effect on pathogenic conditions in the CNS. PMID- 25716180 TI - Psychiatric treatment outcomes of preschool children in a family day hospital. AB - This study describes the treatment outcomes of preschoolers with severe mental health problems who were treated at the child psychiatric family day hospital for preschool children in Munster, Germany. The eclectic multi-modal treatment combines behavioral and psychodynamic techniques for both parents and children in various settings within an intermittent attendance structure provided by a multi disciplinary team. This study evaluated 185 children with the Caregiver-Teacher Report Form (C-TRF/1.5-5), which was completed by therapists, and the Child Behavior Checklist (CBCL/1.5-5), which was completed by mothers, at admission and discharge. The mothers' ratings of their children were statistically adjusted for the distortion caused by their own psychopathology. After treatment, the patients showed significant improvement on the C-TRF/CBCL Total Problem score with an average Cohen's d = -0.50 based on therapists' ratings, d = -0.97 for the non adjusted maternal ratings, and d = -0.68 for the adjusted maternal ratings. We conclude that specialized family day hospitals may successfully treat preschool psychiatric patients. PMID- 25716181 TI - The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion. AB - Persistent neural activity, a sustained circuit output that outlasts the stimuli, underlies short-term or working memory, as well as various mental representations. Molecular mechanisms that underlie persistent activity are not well understood. Combining in situ whole-cell patch clamping and quantitative locomotion analyses, we show here that the Caenorhabditis elegans neuromuscular system exhibits persistent rhythmic activity, and such an activity contributes to the sustainability of basal locomotion, and the maintenance of acceleration after stimulation. The NALCN family sodium leak channel regulates the resting membrane potential and excitability of invertebrate and vertebrate neurons. Our molecular genetics and electrophysiology analyses show that the C. elegans NALCN, NCA, activates a premotor interneuron network to potentiate persistent motor circuit activity and to sustain C. elegans locomotion. Collectively, these results reveal a mechanism for, and physiological function of, persistent neural activity using a simple animal model, providing potential mechanistic clues for working memory in other systems. PMID- 25716182 TI - Ways of knowing: a guide to the journals a clinical discipline needs? PMID- 25716185 TI - Coupling human mobility and social ties. AB - Studies using massive, passively collected data from communication technologies have revealed many ubiquitous aspects of social networks, helping us understand and model social media, information diffusion and organizational dynamics. More recently, these data have come tagged with geographical information, enabling studies of human mobility patterns and the science of cities. We combine these two pursuits and uncover reproducible mobility patterns among social contacts. First, we introduce measures of mobility similarity and predictability and measure them for populations of users in three large urban areas. We find individuals' visitations patterns are far more similar to and predictable by social contacts than strangers and that these measures are positively correlated with tie strength. Unsupervised clustering of hourly variations in mobility similarity identifies three categories of social ties and suggests geography is an important feature to contextualize social relationships. We find that the composition of a user's ego network in terms of the type of contacts they keep is correlated with mobility behaviour. Finally, we extend a popular mobility model to include movement choices based on social contacts and compare its ability to reproduce empirical measurements with two additional models of mobility. PMID- 25716186 TI - Eyelashes divert airflow to protect the eye. AB - Eyelashes are ubiquitous, although their function has long remained a mystery. In this study, we elucidate the aerodynamic benefits of eyelashes. Through anatomical measurements, we find that 22 species of mammals possess eyelashes of a length one-third the eye width. Wind tunnel experiments confirm that this optimal eyelash length reduces both deposition of airborne particles and evaporation of the tear film by a factor of two. Using scaling theory, we find this optimum arises because of the incoming flow's interactions with both the eye and eyelashes. Short eyelashes create a stagnation zone above the ocular surface that thickens the boundary layer, causing shear stress to decrease with increasing eyelash length. Long eyelashes channel flow towards the ocular surface, causing shear stress to increase with increasing eyelash length. These competing effects result in a minimum shear stress for intermediate eyelash lengths. This design may be employed in creating eyelash-inspired protection for optical sensors. PMID- 25716187 TI - Quantifying the reliability of dispersal paths in connectivity networks. AB - Many biological systems, from fragmented landscapes to host populations, can be represented as networks of connected habitat patches. Links between patches in these connectivity networks can represent equally diverse processes, from individuals moving through the landscape to pathogen transmissions or successive colonization events in metapopulations. Any of these processes can be characterized as stochastic, with functional links among patches that exist with various levels of certainty. This stochasticity then needs to be reflected in the algorithms that aim to predict the dispersal routes in these networks. Here we adapt the concept of reliability to characterize the likelihood that a specific path will be used for dispersal in a probabilistic connectivity network. The most reliable of the paths that connect two patches will then identify the most likely sequence of intermediate steps between these patches. Path reliability will be sensitive to targeted disruptions of individual links that form the path, and this can then be used to plan the interventions aimed at either preserving or disrupting the dispersal along that path. The proposed approach is general, and can be used to identify the most likely dispersal routes in various contexts, such as predicting patterns of migrations, colonizations, invasions and epidemics. PMID- 25716188 TI - A compact and hand-held infection-screening system for use in rapid medical inspection at airport quarantine stations: system design and preliminary validation. AB - To conduct mass screening and thereby reduce the spread of infection, a compact (13.5 cm * 8.5 cm * 2.5 cm), highly-mobile and hand-held infection-screening system was developed for rapid medical inspection in mass gathering places such as airports. The system is capable of non-contact vital-sign monitoring using two integrated sensors: a 24-GHz microwave radar for measuring heart and respiration rates and a thermopile array for capturing facial temperature. Subsequently, the system detects infected individuals using a linear discriminant function (LDA) from the derived vital-signs data. The system was tested on 10 subjects under two conditions (resting as normal and exercising as pseudo-infected, i.e. a 10-min bicycle ergometer at 100 W exercise); the normal and pseudo-infected conditions were classified successfully via LDA for all subjects (p < 0.01; classification error rate < 5%). The proposed non-contact system can be applied for preventing secondary exposure of medical doctors at the outbreak of highly pathogenic infectious diseases such as the Ebola virus. PMID- 25716189 TI - Does working memory training have to be adaptive? AB - This study tested the common assumption that, to be most effective, working memory (WM) training should be adaptive (i.e., task difficulty is adjusted to individual performance). Indirect evidence for this assumption stems from studies comparing adaptive training to a condition in which tasks are practiced on the easiest level of difficulty only [cf. Klingberg (Trends Cogn Sci 14:317-324, 2010)], thereby, however, confounding adaptivity and exposure to varying task difficulty. For a more direct test of this hypothesis, we randomly assigned 130 young adults to one of the three WM training procedures (adaptive, randomized, or self-selected change in training task difficulty) or to an active control group. Despite large performance increases in the trained WM tasks, we observed neither transfer to untrained structurally dissimilar WM tasks nor far transfer to reasoning. Surprisingly, neither training nor transfer effects were modulated by training procedure, indicating that exposure to varying levels of task difficulty is sufficient for inducing training gains. PMID- 25716190 TI - Prevalence of depressive symptoms in patients with cleft lip and palate. AB - INTRODUCTION: Cleft lip and/or palate (CL/P) represent the most common congenital anomalies of the face. OBJECTIVE: To evaluate the prevalence of depressive symptoms in children and adolescents with nonsyndromic cleft lip and/or palate (nsCL/P). METHODS: We conducted an observational, case-control study, with a case study group composed of 61 patients with nsCL/P, aged 7-17 years, and a control group of 61 clinically normal patients. Both groups were selected at the same institution. RESULTS: Depressive symptoms were observed in the case group (nsCL/P), but there were no statistically significant differences compared to the control group. No association was found between the two groups (case and control) in relation to sociodemographic variables: gender, age and education. CONCLUSIONS: This study identified the prevalence of depressive symptoms in children and adolescents with nsCL/P from a localized geographic population, although the results were not statistically significant when compared to the control group, not justifying the use of CDI (Child Depression Inventory) as a screening instrument for depressive symptoms in the examined population. PMID- 25716191 TI - Seeking Information on Behalf of Others: An Analysis of Calls to a Spanish Language Radio Health Program. AB - OBJECTIVE: Spanish-monolingual Latinos account for 13% of U.S. residents and experience multiple barriers to effective health communication. Information intermediaries/proxies mediate between the linguistically isolated and health care providers. This study characterizes the information needs of surrogate callers and their subjects to a U.S.-based Spanish-language radio health program. METHOD: Content analysis of calls placed (N = 281 calls). RESULTS: Women made 70% of calls; 39.1% of calls were on behalf of children, 11.0% on behalf of parents/older adults, and 18.5% on behalf of spouses/siblings/contemporary adults. Most common topics were disease symptoms/conditions (19.6%), cancer (13.9%), and reproduction/sexuality (12.9%). Calls for children were more likely than those for parents/other adults to pertain to current illness symptoms or conditions; calls for parents were more likely to be about cancer/chronic conditions. Half of all calls sought clarification about a previous medical encounter. CONCLUSION: Information-seeking surrogates may represent a useful strategy for linguistic minorities to overcome structural and individual barriers to health information access. Results suggest that Latinos are willing to seek information on behalf of friends and family and highlight the need for improved, culturally and linguistically appropriate health communication sources. PRACTICE IMPLICATIONS: Leveraging Latinos' natural familial social networks/willingness to share information may improve dissemination of culturally and linguistically appropriate health information. Further implications for patient activation and doctor-patient communication are discussed. PMID- 25716192 TI - Cochrane corner: exercise for people with high cardiovascular risk. PMID- 25716194 TI - Quercetin Metabolites Up-Regulate the Antioxidant Response in Osteoblasts Isolated From Fetal Rat Calvaria. AB - Oxidative stress contributes to osteoporosis by suppressing differentiation of osteoblasts, suggesting the osteoblast antioxidant response may be a viable strategy for osteoporosis prevention. Quercetin, an antioxidant flavonol, up regulates the antioxidant response in many cell types, but studies are needed to understand the effects of quercetin plasma metabolites on the osteoblast antioxidant response. The first specific aim was to examine antioxidant response genes and proteins in osteoblasts exposed to plasma quercetin metabolites. The second specific aim was to identify potential signaling pathways in the osteoblast antioxidant response that mediate the effect of quercetin, specifically Nrf2, ERK1/2, and NFkappaB p65. Osteoblasts isolated from fetal rat calvaria were treated with doses up to 20 MUM of three different quercetin metabolites found in blood plasma after consumption of quercetin-rich foods or supplements: quercetin aglycone (QRC), isorhamnetin (ISO), or quercetin 3-O glucuronide (Q3G). Alternatively, some cells received a 2:1:1 mixture of all three metabolites (10 MUM Q3G: 5 MUM ISO: 5 MUM QRC) to evaluate synergistic effects. Antioxidant response genes and proteins known to be up-regulated by quercetin were analyzed along with Nrf2, ERK1/2, and NFkappaB proteins. Both QRC and ISO, but not Q3G, up-regulated heme oxygenase-1 (HO-1) and gamma-glutamate cysteine ligase catalytic subunit (GCLC) at the mRNA and protein level. Synergistic effects of metabolites were not observed. Up-regulation of HO-1 and GCLC was associated with suppression of phosphorylated ERK1/2 and NFkappaB, but no alterations in Nrf2 protein levels were observed. This study shows that the antioxidant response of osteoblasts is differentially stimulated by quercetin metabolites. PMID- 25716193 TI - Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson's disease models. AB - Nicotinamide adenine dinucleotide phosphate oxidase, a key superoxide-producing enzyme, plays a critical role in microglia-mediated chronic neuroinflammation and subsequent progressive dopaminergic neurodegeneration in Parkinson's disease. Although nicotinamide adenine dinucleotide phosphate oxidase-targeting anti inflammatory therapy for Parkinson's disease has been proposed, its application in translational research remains limited. The aim of this study was to obtain preclinical evidence supporting this therapeutic strategy by testing the efficacy of an ultra-low dose of the nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium in both endotoxin (lipopolysaccharide)- and 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using post-treatment regimens. Our data revealed that post-treatment with diphenyleneiodonium significantly attenuated progressive dopaminergic degeneration and improved rotarod activity. Remarkably, post-treatment with diphenyleneiodonium 10 months after lipopolysaccharide injection when mice had 30% loss of nigral dopaminergic neurons, showed high efficacy in protecting the remaining neuronal population and restoring motor function. Diphenyleneiodonium-elicited neuroprotection was associated with the inhibition of microglial activation, a reduction in the expression of proinflammatory factors and an attenuation of alpha-synuclein aggregation. A pathophysiological evaluation of diphenyleneiodonium-treated mice, including assessment of body weight, organs health, and neuronal counts, revealed no overt signs of toxicity. In summary, infusion of ultra-low dose diphenyleneiodonium potently reduced microglia-mediated chronic neuroinflammation by selectively inhibiting nicotinamide adenine dinucleotide phosphate oxidase and halted the progression of neurodegeneration in mouse models of Parkinson's disease. The robust neuroprotective effects and lack of apparent toxic side effects suggest that diphenyleneiodonium at ultra-low dose may be a promising candidate for future clinical trials in Parkinson's disease patients. PMID- 25716195 TI - Profiles of Community Violence Exposure Among African American Youth: An Examination of Desensitization to Violence Using Latent Class Analysis. AB - The current study employed latent class analysis (LCA) to identify distinct profiles of community violence exposure and their associations to desensitization outcomes in 241 African American early adolescents (M age = 12.86, SD = 1.28) in the sixth through eighth grade from under-resourced urban communities. Participants self-reported on their exposure to community violence, as well as on depressive and anxiety symptoms. The LCA revealed three distinct classes: a class exposed to low levels of violence (low exposure class), a class exposed to moderately high levels of victimization (victimization class), and a class exposed to high levels of all types of violence (high exposure class). Consistent with predictions, the high exposure class showed the lowest levels of depressive symptoms, suggesting a desensitization outcome. Gender and age were also examined in relation to the classes, and age was significantly associated with an increased risk of being a member of the high exposure class relative to the low exposure class. Using person-based analyses to examine desensitization outcomes provides useful information for prevention and intervention efforts, as it helps to identify a specific subgroup of youth that may be more likely to show desensitization outcomes in the context of community violence. PMID- 25716196 TI - Racial Disparities in Intimate Partner Violence Examined Through the Multiple Disadvantage Model. AB - This research adopted the perspective of the multiple disadvantage model to explore racial disparities in intimate partner violence (IPV) against women and IPV's links to social structural factors, social relationships, substance use, and health/mental health and access to related services. The study used data from 6,588 women who completed the National Violence Against Women Survey; linear regression was conducted separately for four ethnic groups. Results consistently showed physical assaults to increase with posttraumatic stress disorder symptoms. For African Americans, increases in assaults were linked to injury, disclosing IPV to friends/family as well as medical professionals, Medicaid use, and drug use; decreases, in turn, were linked to past assault by ex-partners. For Latinas, increases in assaults were associated with eight factors: being married, number of ex-partners, depression, disclosing IPV to friends/family and disclosing to mental-health professionals, drug use, alcohol abstinence, and partner's frequent alcohol use. For European Americans, increases in assaults were linked to number of ex-partners, injury, low income, Medicaid use, disclosing IPV to friends/family as well as mental-health professionals, and alcohol abstinence; decreases were associated with age and with other health insurance coverages. For women of other ethnicity, increases were linked to number of ex-partners, disclosing IPV to mental-health professionals, Medicaid use, drug use, and woman's own as well as partner's alcohol abstinence; decreases in this ethnicity category were linked to past assault by ex-partners. Intervention and policy implications are discussed. PMID- 25716198 TI - Enkephalin analog, cyclo[N(epsilon),N(beta)-carbonyl-D-Lys(2),Dap(5)] enkephalinamide (cUENK6), inhibits the ethanol withdrawal-induced anxiety-like behavior in rats. AB - An analog of enkephalin, cyclo[N(epsilon),N(beta)-carbonyl-D-Lys(2),Dap(5)] enkephalinamide (cUENK6), is predominantly a functional agonist of MU-opioid receptors (MOPr) and, to a lesser extent, of delta-opioid receptors (DOPr) in vitro. The aim of the present study was to determine whether cUENK6 could affect ethanol withdrawal-induced anxiety-like behavior in the elevated plus maze (EPM) test in rats. An anxiety-like effect of withdrawal was predicted to occur in the EPM test 24 h after the last ethanol administration (2 g/kg, intraperitoneally [i.p.]; 15% w/v once daily for 9 days). Ethanol withdrawal decreased the percent of time spent by rats in the open arms and the percent of open-arms entries. cUENK6 (0.25 nmol), given by intracerebroventricular (i.c.v.) injection, significantly reversed these anxiety-like effects of ethanol withdrawal and elevated the percent of time spent by rats in the open arms and the percent of open-arms entries. These effects of cUENK6 were significantly inhibited by the DOPr antagonist naltrindole (NTI) (5 nmol, i.c.v.), but not by the MOPr antagonist beta-funaltrexamine (beta-FNA) (5 nmol, i.c.v.). The preferential DOPr agonist [Leu(5)]-enkephalin (LeuEnk) (2.7 and 5.4 nmol, i.c.v.) and the MOPr agonist morphine (6.5 and 13 nmol, i.c.v.) reduced the anxiety-like effects of ethanol withdrawal. cUENK6 at the dose of 0.25 nmol did not disturb locomotor activity in the EPM, in contrast to cUENK6 at the dose of 0.5 nmol, and morphine at 6.5 and 13 nmol. However, similarly to LeuEnk, cUENK6 induced the anxiolytic like effects in naive rats. Thus, our study suggests that cUENK6 reduced ethanol withdrawal-induced anxiety-like behavior by activation of delta-opioid receptors rather than MU-opioid receptors. PMID- 25716197 TI - Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions. AB - The central amygdala is a critical brain region for many aspects of alcohol dependence. Much of the work examining the mechanisms by which the central amygdala mediates the development of alcohol dependence has focused on the interaction of acute and chronic ethanol with central amygdala corticotropin releasing factor signaling. This work has led to a great deal of success in furthering the general understanding of central amygdala neurocircuitry and its role in alcohol dependence. Much of this work has primarily focused on the hypothesis that ethanol utilizes endogenous corticotropin releasing factor signaling to upregulate inhibitory GABAergic transmission in the central amygdala. Work that is more recent suggests that corticotropin releasing factor also plays an important role in mediating anxiety-like behaviors via the enhancement of central amygdala glutamatergic transmission, implying that ethanol/corticotropin releasing factor interactions may modulate excitatory neurotransmission in this brain region. In addition, a number of studies utilizing optogenetic strategies or transgenic mouse lines have begun to examine specific central amygdala neurocircuit dynamics and neuronal subpopulations to better understand overall central amygdala neurocircuitry and the role of neuronal subtypes in mediating anxiety-like behaviors. This review will provide a brief update on this literature and describe some potential future directions that may be important for the development of better treatments for alcohol addiction. PMID- 25716200 TI - Macrophage immigration inhibitory factor promotes cell proliferation and inhibits apoptosis of cervical adenocarcinoma. AB - As a multifunctional cytokine, macrophage migration inhibitory factor (MIF) is associated with inflammation and tumorigenesis; however, the role of MIF in cervical adenocarcinoma (ADC) is not fully understood. In this study, we aimed to examine the expression of MIF in ADC and explore the mechanism of MIF in ADC progression. MIF expression was positively related to ADC clinicopathological features of carcinoma diameter and lymph node metastasis. MIF knockdown induced cell cycle arrest of G1/S transition in ADC cells, upregulation of the expressions of p21 and p27, and downregulation of the expressions of Cdk4, CyclinD2, and CyclinE2. In MIF knockdown cells, the expressions of proapoptotic proteins of Bax, caspase-3, cleaved caspase-3, and cleaved-PARP were upregulated, and the expressions of antiapoptotic proteins of Bcl-2, pAkt, and p53 were downregulated. It indicated that MIF knockdown inhibited cell proliferation and induced apoptosis in ADC cells. MIF might be a novel molecular marker in diagnosis and therapy of ADC. PMID- 25716199 TI - Three-dimensional topology of the SMC2/SMC4 subcomplex from chicken condensin I revealed by cross-linking and molecular modelling. AB - SMC proteins are essential components of three protein complexes that are important for chromosome structure and function. The cohesin complex holds replicated sister chromatids together, whereas the condensin complex has an essential role in mitotic chromosome architecture. Both are involved in interphase genome organization. SMC-containing complexes are large (more than 650 kDa for condensin) and contain long anti-parallel coiled-coils. They are thus difficult subjects for conventional crystallographic and electron cryomicroscopic studies. Here, we have used amino acid-selective cross-linking and mass spectrometry combined with structure prediction to develop a full-length molecular draft three-dimensional structure of the SMC2/SMC4 dimeric backbone of chicken condensin. We assembled homology-based molecular models of the globular heads and hinges with the lengthy coiled-coils modelled in fragments, using numerous high-confidence cross-links and accounting for potential irregularities. Our experiments reveal that isolated condensin complexes can exist with their coiled-coil segments closely apposed to one another along their lengths and define the relative spatial alignment of the two anti-parallel coils. The centres of the coiled-coils can also approach one another closely in situ in mitotic chromosomes. In addition to revealing structural information, our cross-linking data suggest that both H2A and H4 may have roles in condensin interactions with chromatin. PMID- 25716201 TI - MiR-129 regulates MMP9 to control metastasis of non-small cell lung cancer. AB - The molecular mechanism underlying activation of MMP9 in non-small cell lung cancer (NSCLC) cells, which controls cancer invasiveness and metastasis, remains elusive. Here, we reported significant decrease in miR-129 and significant increases in phosphorylated EGFR and MMP9 in the resected NSCLC from the patients, compared with adjacent normal tissue. Moreover, strong correlations were detected among these three factors, the relationship of which was examined in two human NSCLC lines, A549 and H460. We found that EGF-induced EGFR phosphorylation in A549 or H460 cells activated MMP9 and, consequently, cancer invasiveness. The EGF-induced activation of MMP9 was efficiently inhibited either by an EGFR inhibitor or by an Akt inhibitor. However, miR-129 level was not affected by EGF stimulation. In addition, overexpression of miR-129 antagonized EGF-induced MMP9 activation without affecting EGFR phosphorylation in A549 or H460 cells. Taken together, our data suggest that miR-129 inhibits EGFR signaling through PI3K signal transduction cascades to regulate MMP9 expression in NSCLC. Thus, miR-129, EGFR, and MMP9 appear to be promising therapeutic targets for preventing the metastasis of NSCLC. PMID- 25716202 TI - Galectin-9 predicts postoperative recurrence and survival of patients with clear cell renal cell carcinoma. AB - Galectin-9 (Gal-9), a member of animal lectin family with evolutionary conserved carbohydrate recognition domains, has been reported to exert a large variety of functional roles in tumorigenesis due to its beta-galactoside-binding affinity. The aim of this study is to evaluate the expression and prognostic significance of Gal-9 in patients with clear-cell renal cell carcinoma (ccRCC). The expression of Gal-9 was assessed by immunohistochemistry in 196 patients with ccRCC who underwent nephrectomy. In the cohort, 48 patients died and 61 patients suffered recurrence. Kaplan-Meier method with log-rank test was applied to compare survival curves. The authors employed univariate and multivariate Cox regression models to evaluate the prognostic value of Gal-9 expression in overall survival (OS) and recurrence-free survival (RFS). In patients with ccRCC, Gal-9 expression, which was positively associated with tumor size (P = 0.014), Fuhrman grade (P = 0.010), and necrosis (P = 0.025), was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 2.394; P = 0.005) and RFS (HR 2.096; P = 0.006). High expression of Gal-9 was associated with poor survival (P = 0.001) and early recurrence (P = 0.006). Furthermore, Gal-9 expression could significantly stratify the patients in early (grades I + II) tumor, node, and metastasis (TNM) stage (OS: P = 0.005; RFS: P = 0.041) and low (grades 1 + 2) Fuhrman grade (OS: P = 0.004; RFS: P = 0.006). The prognostic accuracy of TNM, SSIGN, and UISS prognostic models was improved when Gal-9 expression was added. Gal-9 expression is a potential independent prognostic factor for OS and RFS in patients with ccRCC. PMID- 25716203 TI - Clinicopathological significance and potential drug target of O6-methylguanine DNA methyltransferase in colorectal cancer: a meta-analysis. AB - Emerging evidence indicates that O(6)-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69-7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC. PMID- 25716204 TI - A strategy to design novel structure photochromic sensitizers for dye-sensitized solar cells. AB - Two sensitizers with novel structure were designed and synthetized by introducing photochromic bisthienylethene (BTE) group into the conjugated system. Thanks to the photochromic effect the sensitizers have under ultraviolet and visible light, the conjugated bridge can be restructured and the resulting two photoisomers showed different behaviors in photovoltaic devices. This opens up a new research way for the dye-sensitized solar cells (DSSCs). PMID- 25716205 TI - Severe non-traumatic bleeding, the answer is not in the blood. PMID- 25716207 TI - Content delivery to newly forming Weibel-Palade bodies is facilitated by multiple connections with the Golgi apparatus. AB - Weibel-Palade bodies (WPBs) comprise an on-demand storage organelle within vascular endothelial cells. It's major component, the hemostatic protein von Willebrand factor (VWF), is known to assemble into long helical tubules and is hypothesized to drive WPB biogenesis. However, electron micrographs of WPBs at the Golgi apparatus show that these forming WPBs contain very little tubular VWF compared with mature peripheral WPBs, which raises questions on the mechanisms that increase the VWF content and facilitate vesicle growth. Using correlative light and electron microscopy and electron tomography, we investigated WPB biogenesis in time. We reveal that forming WPBs maintain multiple connections to the Golgi apparatus throughout their biogenesis. Also by volume scanning electron microscopy, we confirmed the presence of these connections linking WPBs and the Golgi apparatus. From electron tomograms, we provided evidence that nontubular VWF is added to WPBs, which suggested that tubule formation occurs in the WPB lumen. During this process, the Golgi membrane and clathrin seem to provide a scaffold to align forming VWF tubules. Overall, our data show that multiple connections with the Golgi facilitate content delivery and indicate that the Golgi appears to provide a framework to determine the overall size and dimensions of newly forming WPBs. PMID- 25716206 TI - Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia. AB - The prognosis of acute myeloid leukemia (AML) is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear export receptor (exportin 1 [XPO1]) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances the antileukemic effects of selinexor. These effects could be mediated by the re-expression of a subset of TSs (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine- versus control-treated cells. Sequential treatment of decitabine followed by selinexor in an MV4-11 xenograft model significantly improved survival compared with selinexor alone. On the basis of these preclinical results, a phase 1 clinical trial of decitabine followed by selinexor in elderly patients with AML has been initiated. PMID- 25716208 TI - The problem of unrecognized acromegaly: surgeries patients undergo prior to diagnosis of acromegaly. AB - PURPOSE: To reveal the variety of symptoms experienced by patients before acromegaly diagnosis and to emphasize unneeded surgeries that patients undergo related to acromegaly prior to diagnosis of the disease. METHODS: In total, 490 consecutive adult patients with acromegaly who were treated at our institution between 1998 and 2014 were included in this cross-sectional study, of which 313 could be contacted. Participants were questioned about their complaints at initial consultation and at the time of diagnosis, the first medical professional who they consulted, interval between onset and diagnosis, and surgeries they had undergone. RESULTS: This study included 313 participants, of whom 181 were women. The mean age was 48.8 +/- 12.0 years. Patients most frequently presented with acral growth of hands and feet (32.6%) and headache (26.2%). Internists were the medical specialists who were most frequently first consulted (29.4%) then neurosurgeons (11.8%). Acromegaly was generally diagnosed by endocrinologists (55%), followed by neurosurgeons (23%). The median elapsed period prior to diagnosis was 24 months, interquartile range 6.0-48.0 months. Some 45.7% had undergone surgery; 35.2% were related to acromegaly symptoms: head and throat surgery (12.8%), nose surgery (9.3%), thyroidectomy (6.4%), carpal tunnel surgery (4.8%). The delay period for patients who had an operation prior to acromegaly diagnosis was significantly longer than for those who had no operations (p < 0.001). CONCLUSIONS: Acromegaly patients mostly present to internal medicine professionals. Surgeries related to acromegaly complications and symptoms before diagnosis cause a long delay period before diagnosis. Medical staff must be more aware of the clinical aspects of acromegaly. PMID- 25716209 TI - Effectiveness of using Grindr to increase syphilis testing among men who have sex with men in Darwin, Australia. PMID- 25716210 TI - The association of health status and providing consent to continued participation in an out-of-hospital cardiac arrest trial performed under exception from informed consent. AB - OBJECTIVES: Emergency medical research performed under federal regulation 21 S CFR 50.24 provides a means to protect human subjects and investigate novel time sensitive treatments. Although prospective individual consent is not required for studies conducted under this regulation, consent from a legally authorized representative (LAR) or the patient at the earliest feasible opportunity is required to obtain short- and long-term outcome data. The objective of this study was to determine which demographic, cardiac arrest, and patient outcome characteristics predicted the likelihood of obtaining informed consent following enrollment under exception from informed consent in a multicenter cardiac arrest study. METHODS: This investigation was an analysis of data collected during a multisite, randomized, controlled, out-of-hospital cardiac arrest clinical trial performed under 21 S CFR 50.24. Research personnel attempted to obtain informed consent from LARs and subjects for medical records review of primary outcome data, as well as consent for neurologic outcome assessments up to 1 year post cardiac arrest. Hospital discharge and neurologic status were obtained from public records and/or medical records up until the time consent was formally denied, in accordance with federal regulations and guidance. Local institutional review boards also allowed medical records review for cases where consent was neither obtained nor declined despite multiple consent attempts. Patient demographic, cardiac arrest, and clinical outcome characteristics were analyzed in univariate multinomial regression models, with consent status (obtained, denied, neither obtained nor denied) as the dependent variable. A multivariate multinomial logistic regression was then performed. An exploratory secondary analysis following the same process was performed after assigning patients who neither consented nor declined to the declined consent group. RESULTS: Among a total study population of 1,655 cardiac arrest subjects, 457 were transported and had consent attempted (27.6%). The survival status and neurologic function at the time of hospital discharge were known in 440 of 457 (96%) subjects. In the multivariate analysis, initial rhythm of ventricular fibrillation/ventricular tachycardia (VF/VT) and survival with good neurologic outcome were strong predictors of obtaining consent (odds ratio [OR] = 3.15, 95% confidence interval [CI] = 1.73 to 5.75; OR = 7.64, 95% CI = 2.28 to 25.63, respectively). The exploratory secondary analysis also showed initial rhythm of VF/VT and survival with good neurologic outcome as strong predictors of obtaining consent (OR = 1.86, 95% CI = 1.17 to 2.95; OR = 4.52, 95% CI = 2.21 to 9.26, respectively). CONCLUSIONS: Initial arrest rhythm and survival with good neurologic outcome were highly predictive of obtaining consent in this cardiac arrest trial. This phenomenon could result in underrepresentation of outcome data in the study arm with the worse outcome and represents a significant potential confounder in studies performed under 21 S CFR 50.24. Future revisions to the exception from informed consent regulations should allow access to critical survival data recorded as part of standard documentation, regardless of patient consent status. PMID- 25716211 TI - Are There Sex Differences in Knee Cartilage Composition and Walking Mechanics in Healthy and Osteoarthritis Populations? AB - BACKGROUND: Women are at a greater risk for knee osteoarthritis (OA), but reasons for this greater risk in women are not well understood. It may be possible that differences in cartilage composition and walking mechanics are related to greater OA risk in women. QUESTIONS/PURPOSES: (1) Do women have higher knee cartilage and meniscus T1rho than men in young healthy, middle-aged non-OA and OA populations? (2) Do women exhibit greater static and dynamic (during walking) knee loading than men in young healthy, middle-aged non-OA and OA populations? METHODS: Data were collected from three cohorts: (1) young active (<35 years) (20 men, 13 women); (2) middle-aged (>=35 years) without OA (Kellgren-Lawrence [KL] grade < 2) (43 men, 65 women); and (3) middle-aged with OA (KL>1) (18 men, 25 women). T1rho and T2 relaxation times for cartilage in the medial knee, lateral knee, and patellofemoral compartments and medial and lateral menisci were quantified with 3.0-T MRI. A subset of the participants underwent three-dimensional motion capture during walking for calculation of peak knee flexion and adduction moments, flexion and adduction impulses, and peak adduction angle. Differences in MR, radiograph, and gait parameters between men and women were compared in the three groups separately using multivariate analysis of variance. RESULTS: Women had higher lateral articular cartilage T1rho (men=40.5 [95% confidence interval {CI}, 38.8-42.3] ms; women=43.3 [95% CI, 41.9-44.7] ms; p=0.017) and patellofemoral T1rho (men=44.4 [95% CI, 42.6-46.3] ms; women=48.4 [95% CI, 46.9 50.0] ms; p=0.002) in the OA group; and higher lateral meniscus T1rho in the young group (men=15.3 [95% CI, 14.7-16.0] ms; women=16.4 [95% CI, 15.6-17.2] ms; p=0.045). The peak adduction moment in the second half of stance was lower in women in the middle-aged (men=2.05 [95% CI, 1.76-2.34] %BW*Ht; women=1.66 [95% CI, 1.44-1.89] %BW*Ht; p=0.037) and OA (men=2.34 [95% CI, 1.76-2.91] %BW*Ht; women=1.42 [95% CI, 0.89-1.94] %BW*Ht; p=0.022) groups. Static varus from radiographs was lower in women in the middle-aged (men=178 degrees [95% CI, 177 degrees -179 degrees ]; women=180 degrees [95% CI, 179 degrees -181 degrees ]; p=0.002) and OA (men=176 degrees [95% CI, 175 degrees -178 degrees ]; women=180 degrees [95% CI, 179 degrees -181 degrees ]; p<0.001) groups. Women had lower varus during walking in all three groups (young: men=4 degrees [95% CI, 3 degrees -6 degrees ]; women=2 degrees [95% CI, 0 degrees -3 degrees ]; p=0.013; middle-aged: men=2 degrees [95% CI, 1 degrees -3 degrees ]; women=0 degrees [95% CI, -1 degrees to 1 degrees ]; p=0.015; OA: men=4 degrees [95% CI, 2 degrees -6 degrees ]; women=0 degrees [95% CI, -2 degrees to 2 degrees ]; p=0.011). Women had a higher knee flexion moment (men=4.24 [95% CI, 3.58-4.91] %BW*Ht; women 5.40 [95% CI, 4.58-6.21] %BW*Ht; p=0.032) in the young group. CONCLUSIONS: These data demonstrate differences in cartilage composition and gait mechanics between men and women in young healthy, middle-aged healthy, and OA cohorts. Considering the cross-sectional nature of the study, longitudinal research is needed to investigate if these differences in cartilage composition and walking mechanics are associated with a greater risk of lateral tibiofemoral or patellofemoral OA in women. Future studies should also investigate the relative risk of lateral versus medial patellofemoral cartilage degeneration risk in women compared with men. LEVEL OF EVIDENCE: Level III, retrospective study. PMID- 25716212 TI - Do Secular Trends in Skeletal Maturity Occur Equally in Both Sexes? AB - BACKGROUND: Skeletal maturity assessment provides information on a child's physical development and expectations based on chronological age. Given recently recognized trends for earlier maturity in a variety of systems, most notably puberty, examination of sex-specific secular trends in skeletal maturation is important. For the orthopaedist, recent trends and changes in developmental timing can affect clinical management (eg, treatment timing) if they are currently based on outdated sources. QUESTIONS/PURPOSES: (1) Has the male or female pediatric skeleton experienced a secular trend for earlier maturation over the past 80 years? (2) Do all indicators of maturity trend in the same direction (earlier versus later)? METHODS: In this retrospective study, a total of 1240 children were examined longitudinally through hand-wrist radiographs for skeletal maturity based on the Fels method. All subjects participate in the Fels Longitudinal Study based in Ohio and were born between 1930 and 1964 for the "early" cohort and between 1965 and 2001 for the "recent" cohort. Sex-specific secular trends were estimated for (1) mean relative skeletal maturity through linear mixed models; and (2) median age of maturation for individual maturity indicators through logistic regression and generalized estimating equations. RESULTS: Overall relative skeletal maturity was significantly advanced in the recent cohort (maximum difference of 5 months at age 13 years for girls, 4 months at age 15 years for boys). For individual maturity indicators, the direction and magnitude of secular trends varied by indicator type and sex. The following statistically significant secular trends were found: (1) earlier maturation of indicators of fusion in both sexes (4 months for girls, 3 months for boys); (2) later maturation of indicators of projection in long bones in both sexes (3 months for girls, 2 months for boys); (3) earlier maturation of indicators of density (4 months) and projection (3 months) in carpals and density in long bones (6 months), for girls only; and (4) later maturation of indicators of long bone shape (3 months) for boys only. CONCLUSIONS: A secular trend has occurred in the tempo of maturation of individual components of the pediatric skeleton, and it has occurred in a sex-specific manner. The mosaic nature of this trend, with both earlier and later maturation of individual components of the skeletal age phenotype, calls for greater attention to specific aspects of maturation in addition to the overall skeletal age estimate. The Fels method is currently the most robust method for capturing these components, and future work by our group will deliver an updated, user-friendly version of the Fels assessment tool. CLINICAL RELEVANCE: Appreciation of sex-specific secular changes in maturation is important for clinical management, including treatment timing, of orthopaedic patients, because children today exhibit a different pattern of maturation than children on whom original maturity assessments were based (including Fels and Greulich-Pyle). PMID- 25716214 TI - Letter to the editor: on patient safety: how well do we police ourselves? PMID- 25716213 TI - What Host Factors Affect Aseptic Loosening After THA and TKA? AB - BACKGROUND: Aseptic loosening is the most common cause for revisions after lower extremity total joint arthroplasties, however studies differ regarding the degree to which host factors influence loosening. QUESTIONS/PURPOSE: We performed a systematic review to determine which host factors play a role in the development of clinical and/or radiographic failure from aseptic loosening after (1) THA and (2) TKA. METHODS: Two searches on THA and TKA, respectively, using four electronic databases (EMBASE, CINAHL Plus, PubMed, and Scopus) were conducted. We identified a total of 209 reports that encompassed nine potential host factors affecting aseptic loosening. Inclusion criteria for consideration of scientific clinical reports were that 20 or more patients were involved, with more than 1 year followup, with at least three studies pertaining to each factor, and at least six of the Methodological Index for Non-randomized Studies criteria met, and with raw data for odds ratio (OR) calculations. Twenty-one studies (16 THA studies with 45,779 hips and five TKA studies with 288 knees, respectively) were used to calculate weighted OR and CIs (using the random effects theory) and study heterogeneity for four different host factors in THAs (male sex, high activity level, obesity defined as BMI>=30 kg/m2, and current or former tobacco use) and one factor in TKA (BMI>=30 kg/m2), which were placed in a forest plot. RESULTS: For THA, male sex (OR, 1.39; 95% CI, 1.22-1.58; p=0.001) and high activity level (University of California Los Angeles [UCLA] activity score>=8 points; OR, 4.24; 95% CI, 2.46-7.31; p=0.001) were associated with aseptic loosening. However, obesity (OR, 1.01; 95% CI, 0.73-1.40; p=0.96), and tobacco use (OR, 1.96; 95% CI, 0.43-8.97; p=0.39) were not associated with an increased risk of aseptic loosening after THA with the numbers available. For TKA, we found no host factors associated with loosening. In particular, obesity (BMI>=30 kg/m2) was not associated with aseptic loosening with the numbers available (OR, 2.28; 95% CI, 0.60-8.62; p=0.22). CONCLUSIONS: Patients undergoing a lower-extremity total joint arthroplasty who engage in impact sports should be counseled regarding their potential increased risk of aseptic loosening; however, given the weak evidence available, we believe that higher-level studies are necessary to clearly define the risk factors, particularly with newer-generation constructs. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25716215 TI - Double-Deficit Hypothesis in a Clinical Sample: Extension Beyond Reading. AB - This study explored the double-deficit hypothesis (DDH) in a transparent orthography (Finnish) and extended the view from reading disabilities to comorbidity of learning-related problems in math and attention. Children referred for evaluation of learning disabilities in second through sixth grade (N = 205) were divided into four groups based on rapid automatized naming (RAN) and phonological awareness (PA) according to the DDH: the double-deficit group, the naming speed deficit-only group, the phonological deficit-only group, and the no deficit group. The results supported the DDH in that the prevalence and severity of reading disability were greatest in the double-deficit group. Despite the greater prevalence of reading disabilities in single-deficit groups compared to the no-deficit group, the means of reading measures in the single-deficit groups were similar to those of the no-deficit group. The PA single-deficit group was poorer in spelling than the no-deficit group and single-naming-deficit group. Deficits in RAN or PA were primarily linked to reading disabilities but not with math or attention problems. The results supported the DDH partially and indicate that deficits in RAN and PA are specific to reading disabilities. PMID- 25716216 TI - Improvement of sensitivity for Mycobacterium avium subsp. paratuberculosis (MAP) detection in bovine fecal samples by specific duplex F57/IC real-time and conventional IS900 PCRs after solid culture enrichment. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne's disease in ruminants and a probable pathogen of Crohn's disease in humans. Accurate, cost-effective, and time-relevant diagnostics are the basis for efficient control programs. This study was conducted as an attempt to re-evaluate MAP detection improvement by coupling solid media enrichment to a more specific IS900 conventional PCR and a very specific F57/IC real-time PCR. In a spiking experiment, we investigated the improvement of molecular-based MAP detection in feces after a culture-based enrichment step into Herrold's egg yolk media with mycobactin J (HEYM-MJ) for different time intervals, when compared to traditional culture. Detection limit of culture was 0.33 * 10(4) bacteria * g(-1) (33 CFU g( 1)), while that of IS900 PCR when coupled with an enrichment step for 2, 4, and 6 weeks was 0.33 * 10(5) (0.33 * 10(3) CFU g(-1)), 0.33 * 10(4) (33 CFU g(-1)), and 33 (>3.3 CFU g(-1)) bacteria * g(-1), respectively. Whereas the detection limits of F57/IC real-time PCR after the enrichment step for the same time intervals were 0.33 * 10(5) (0.33 * 10(3) CFU g(-1)), 0.33 * 10(3) (3.3 CFU g(-1)), and 33 (>3.3 CFU g(-1)) bacteria * g(-1), respectively. Altogether, enrichment of bovine fecal samples into solid media increased the sensitivity of specific molecular detection of MAP using IS900 conventional PCR and duplex F57/IC real-time PCR and offers an expedited and accurate alternative for MAP detection in bovine feces. Validation of these results is further recommended using field bovine fecal samples. PMID- 25716217 TI - Nellore cows and their calves during the lactation period: performance, intake, milk composition, and total apparent digestibility. AB - An experiment was conducted to evaluate intake and nutrient digestibility, performance, milk composition, and microbial efficiency of Nellore cows and their calves during lactation. Fifteen Nellore cows were fed corn silage and concentrate (85:15). After calving, calves were kept with their dams for 2 months then separated and housed in individual pens adjacent to their dams. Cows were milked every 15 days over 7 months to estimate milk intake of the calves. During lactation, nutrient intake decreased (P < 0.01) for cows, while nutrient digestibility increased (P < 0.001). Starting 2 months post-calving, calves were offered concentrate (5 g/kg body weight (BW)) and roughage. An increase in DM digestibility was observed for calves in the third month of age, probably due to an associative effect between milk, concentrate, and roughage, which increased DM digestibility without increasing DM intake. Average daily gain (ADG) of the calves increased (P < 0.001) during lactation period. Microbial efficiency (g mCP/kg total digestible nutrients (TDN)) did not change (P > 0.05) in either cows or their calves during lactation period. However, nutrient digestibility decreased for calves during this period. Nellore cows produced milk with average of 4.58 % lactose, 5.61 % fat, and with milk protein increasing from 3.6 to 4.0 % as lactation progressed. PMID- 25716218 TI - Thoracoabdominal impalement by a tree branch. PMID- 25716219 TI - Dietary protein derived from dried bonito fish improves type-2 diabetes mellitus induced bone frailty in Goto-Kakizaki rats. AB - Type-2 diabetes mellitus (T2DM) induces bone frailty. Protein and polyunsaturated fatty acids (PUFA) contained in fish can be effective in enhancing bone quality, but the bone developing effect of fish protein containing less PUFA has not been evaluated in young animals with T2DM. We prepared a bonito fish (BF) and defatted BF (DBF) and hypothesized that protein contained in BF and DBF would be effective for mitigating the effects of T2DM-induced bone frailty. We mainly evaluated the effect of dietary BF and DBF on bone and apparent calcium absorption in young Goto-Kakizaki (GK) rats with T2DM. GK rats were divided into 3 groups based on diets (casein, BF, and DBF) and fed with each diet for 6 wk. Wistar rats were fed with the casein diet as a non-T2DM control. Bone mass, bone strength, apparent calcium absorption, and serum biochemical parameters were determined. The dry weight and strength of the femurs were lower in the GK rats than in the Wistar rats fed with the casein diet. Dietary intake of the BF and DBF diets enhanced the maximum load and dry weight of the femurs and suppressed the serum alkaline phosphatase activity although the apparent calcium absorption was lower in the GK rats fed with the BF and DBF diets than in those fed with the casein diet. These parameters were not different between the rats fed with the BF and DBF diets. Our data suggest that protein contained in the BF and DBF diets improved T2DM-induced bone frailty. PMID- 25716220 TI - 3d single-ion magnets. AB - One of the determining factors in whether single-molecule magnets (SMMs) may be used as the smallest component of data storage, is the size of the barrier to reversal of the magnetisation, Ueff. This physical quantity depends on the magnitude of the magnetic anisotropy of a complex and the size of its spin ground state. In recent years, there has been a growing focus on maximising the anisotropy generated for a single 3d transition metal (TM) ion, by an appropriate ligand field, as a means of achieving higher barriers. Because the magnetic properties of these compounds arise from a single ion in a ligand field, they are often referred to as single-ion magnets (SIMs). Here, the synthetic chemist has a significant role to play, both in the design of ligands to enforce propitious splitting of the 3d orbitals and in the judicious choice of TM ion. Since the publication of the first 3d-based SIM, which was based on Fe(ii), many other contributions have been made to this field, using different first row TM ions, and exploring varied coordination environments for the paramagnetic ions. PMID- 25716221 TI - The Effect of beta-blockade on objectively measured physical fitness in patients with abdominal aortic aneurysms--A blinded interventional study. AB - BACKGROUND: Perioperative beta-blockade is widely used, especially before vascular surgery; however, its impact on exercise performance assessed using cardiopulmonary exercise testing (CPET) in this group is unknown. We hypothesized that beta-blocker therapy would significantly improve CPET-derived physical fitness in this group. METHODS: We recruited patients with abdominal aortic aneurysms (AAA) of <5.5 cm under surveillance. All patients underwent CPET on and off beta-blockers. Patients routinely prescribed beta-blockers underwent a first CPET on medication. Beta-blockers were stopped for one week before a second CPET. Patients not routinely taking beta-blockers underwent the first CPET off treatment, then performed a second CPET after commencement of bisoprolol for at least 48 h. Oxygen uptake (.VO2) at estimated lactate threshold and .VO2 at peak were primary outcome variables. A linear mixed-effects model was fitted to investigate any difference in adjusted CPET variables on and off beta-blockers. RESULTS: Forty-eight patients completed the study. No difference was observed in .VO2 at estimated lactate threshold and .VO2 at peak; however, a significant decrease in .VE/.VCO2 at estimated lactate threshold and peak, an increase in workload at estimated lactate threshold., O2 pulse and heart rate both at estimated lactate threshold and peak was found with beta-blockers. Patients taking beta-blockers routinely (chronic group) had worse exercise performance (lower .VO2 ). CONCLUSIONS: Beta blockade has a significant impact on CPET derived exercise performance, albeit without changing .VO2 at estimated lactate threshold and.VO2 at peak. This supports performance of preoperative CPET on or off beta-blockers depending on local perioperative practice. CLINICAL TRIAL REGISTRATION: NCT 02106286. PMID- 25716222 TI - Determining the influence of Itaipu Lake on thermal conditions for soybean development in adjacent lands. AB - Previous numerical simulations have suggested that the area adjacent to Itaipu Lake in Southern Brazil is significantly affecting the local thermal regime through development of a lake breeze. This has led to concerns that soybean growth and development, and consequently yield, has been affected by the creation of the artificial lake in this important agricultural region, but a systematic climatological study of the thermal effects of Itaipu Lake has not been conducted. The objectives of this study were to assess the spatial pattern of minimum and maximum air temperatures in a 10-km-wide area adjacent to Itaipu Lake as affected by distance from the water. Measurements were conducted over 3 years in seven transects along the shore of Itaipu Lake, with five weather stations placed in each transect. Phenological observations in soybean fields surrounding the weather stations were also conducted. Generalized additive models for location, scale, and shape (GAMLSS) analysis indicated no difference in the temperature time series as distance from water increased. Semivariograms showed that the random components in the air temperature were predominant and that there was no spatial structure to the signal. Wind direction measured over the three growing seasons demonstrated that, on average, the development of a lake breeze is limited to a few locations and a few hours of the day, supporting the temporal and spatial analysis. Phenological observations did not show differences in the timing of critical soybean stages. We suggest that the concerns that soybean development is potentially affected by the presence of Itaipu Lake are not supported by the thermal environment observed. PMID- 25716223 TI - A good Darwinian? Winwood Reade and the making of a late Victorian evolutionary epic. AB - In 1871 the travel writer and anthropologist W. Winwood Reade (1838-1875) was inspired by his correspondence with Darwin to turn his narrow ethnological research on West African tribes into the broadest history imaginable, one that would show Darwin's great principle of natural selection at work throughout the evolutionary history of humanity, stretching back to the origins of the universe itself. But when Martyrdom of Man was published in 1872, Reade confessed that Darwin would not likely find him a very good Darwinian, as he was unable to show that natural selection was anything more than a secondary law that arranges all details. When it came to historicising humans within the sweeping history of all creation, Reade argued that the primary law was that of development, a less contentious theory of human evolution that was better suited to Reade's progressive and teleological history of life. By focussing on the extensive correspondence between Reade and Darwin, this paper reconstructs the attempt to make an explicitly Darwinian evolutionary epic in order to shed light on the moral and aesthetic demands that worked to give shape to Victorian efforts to historicise humans within a vastly expanding timeframe. PMID- 25716225 TI - The effect of acetabular rim recession on anterior acetabular coverage: a cadaveric study using the false-profile radiograph. AB - BACKGROUND: The majority of rim recession for femoroacetabular impingement (FAI) is performed anteriorly and has traditionally been assessed by the lateral center edge (CE) angle, which correlates most closely with lateral coverage. The radiographic false-profile view permits measurement of anterior coverage via the anterior CE angle and more closely correlates with anterior coverage. PURPOSE: To answer the following questions: (1) How does incremental anterior rim recession change lateral and anterior CE angles? and (2) Can these changes be predicted by a formula? STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve cadaveric hips were dissected free of soft tissue to expose the anterior acetabular rim. Incremental resections of 2.5 mm (range, 0-10 mm) were performed from the 12- to 3-o'clock position using a Dremel rotary tool. Anteroposterior hip and false profile radiographs were obtained at each interval using a fluoroscopic C-arm. The lateral and anterior CE angles were measured by 3 orthopaedic surgeons. RESULTS: The average preresection lateral CE angle was 35.1 degrees , and the mean decrease in lateral CE angle from 0 to 10 mm was 9.9 degrees ; the average preresection anterior CE angle was 38.4 degrees and the mean decrease in anterior CE angle from 0 to 10 mm was 18.2 degrees . The anterior CE angle decreased by a factor of 1.9 when compared with the lateral CE angle (P = 2 * 10( 7)). The lateral CE angle decreased by approximately 1 degrees (1.0 degrees ) per millimeter of rim recessed. The anterior CE angle decreased by approximately 2 degrees (1.8 degrees ) per millimeter of rim recessed. CONCLUSION: The lateral CE angle should not be extrapolated to reflect anterior acetabular coverage. The anterior CE angle is a superior marker and predictably decreases with rim recession at double the rate of the lateral CE angle. CLINICAL RELEVANCE: The false-profile view is recommended in the perioperative workup for all patients undergoing arthroscopic treatment of pincer impingement. PMID- 25716226 TI - Platelet-Rich Plasma Increases Anti-inflammatory Markers in a Human Coculture Model for Osteoarthritis. AB - BACKGROUND: Platelet-rich plasma (PRP) has anti-inflammatory effects with potential applications in the treatment of osteoarthritis (OA). PURPOSE: To use an in vitro coculture model of OA in human cartilage and synovium to investigate the anti-inflammatory effects of 2 different PRP preparations. STUDY DESIGN: Controlled laboratory study. METHODS: A coculture system was created using osteoarthritic cartilage and synovium from 9 patients undergoing total knee arthroplasty. Interleukin-1beta (IL-1beta) was added to each coculture to induce inflammation. Two PRP preparations were obtained-one yielding low white blood cell and platelet concentrations (PRPLP) and one yielding high platelet and white blood cell concentrations (PRPHP). Either PRPLP, PRPHP, or medium was added to the coculture wells. Control wells contained OA cartilage and synovium but neither IL-1beta nor PRP. Normal, non-OA cartilage was obtained to establish baseline gene expression levels. Quantitative polymerase chain reaction was used to measure changes in markers of inflammation in the tissues (a disintegrin and metalloproteinase with thrombospondin motifs-5 [ADAMTS-5], tissue inhibitor of metalloproteinases-1 [TIMP-1], vascular endothelial growth factor [VEGF], aggrecan, and type I collagen) at 0, 24, 48, and 72 hours. RESULTS: Treatment with PRPLP or PRPHP significantly decreased expression of TIMP-1 and ADAMTS-5 in cartilage, increased aggrecan expression in cartilage, and decreased ADAMTS-5, VEGF, and TIMP-1 expression in synovium compared with control cocultures (P < .05). There was significantly less nitric oxide production in the PRPLP and PRPHP groups compared with controls (P < .05). There were significant differences in gene expression in the normal cartilage compared with all 4 groups of OA cartilage at all 4 time points. Treatment with either PRPLP or PRPHP returned some gene expression to the same levels in normal cartilage but not for all markers of inflammation. CONCLUSION: This coculture model assessed 2 different PRP preparations and their anti-inflammatory effects over time on human OA cartilage and synovium. Both had a significant anti-inflammatory effect on gene expression; however, there was no difference in the anti-inflammatory effect between the 2 preparations. CLINICAL RELEVANCE: Osteoarthritis is a leading cause of chronic disability, and less invasive treatment methods are needed. Study results suggest that PRP injections may be an effective alternative anti inflammatory agent in the treatment of OA. PMID- 25716228 TI - A note from the editor-in-chief, deputy editor, and managing editor. PMID- 25716227 TI - FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors. AB - The ability to escape apoptosis is a hallmark of cancer-initiating cells and a key factor of resistance to oncolytic therapy. Here, we identify FAM96A as a ubiquitous, evolutionarily conserved apoptosome-activating protein and investigate its potential pro-apoptotic tumor suppressor function in gastrointestinal stromal tumors (GISTs). Interaction between FAM96A and apoptotic peptidase activating factor 1 (APAF1) was identified in yeast two-hybrid screen and further studied by deletion mutants, glutathione-S-transferase pull-down, co immunoprecipitation and immunofluorescence. Effects of FAM96A overexpression and knock-down on apoptosis sensitivity were examined in cancer cells and zebrafish embryos. Expression of FAM96A in GISTs and histogenetically related cells including interstitial cells of Cajal (ICCs), "fibroblast-like cells" (FLCs) and ICC stem cells (ICC-SCs) was investigated by Northern blotting, reverse transcription-polymerase chain reaction, immunohistochemistry and Western immunoblotting. Tumorigenicity of GIST cells and transformed murine ICC-SCs stably transduced to re-express FAM96A was studied by xeno- and allografting into immunocompromised mice. FAM96A was found to bind APAF1 and to enhance the induction of mitochondrial apoptosis. FAM96A protein or mRNA was dramatically reduced or lost in 106 of 108 GIST samples representing three independent patient cohorts. Whereas ICCs, ICC-SCs and FLCs, the presumed normal counterparts of GIST, were found to robustly express FAM96A protein and mRNA, FAM96A expression was much reduced in tumorigenic ICC-SCs. Re-expression of FAM96A in GIST cells and transformed ICC-SCs increased apoptosis sensitivity and diminished tumorigenicity. Our data suggest FAM96A is a novel pro-apoptotic tumor suppressor that is lost during GIST tumorigenesis. PMID- 25716230 TI - Protective efficacy and pharmacokinetics of human/mouse chimeric anti-Stx1 and anti-Stx2 antibodies in mice. AB - In the United States, Shiga toxin (Stx)-producing Escherichia coli (STEC) is the most frequent infectious cause of hemorrhagic colitis. Hemolytic uremic syndrome (HUS) is a serious sequela that may develop after STEC infection that can lead to renal failure and death in up to 10% of cases. STEC can produce one or more types of Stx, Stx1 and/or Stx2, and Stx1 and Stx2 are responsible for HUS-mediated kidney damage. We previously generated two monoclonal antibodies (MAbs) that neutralize the toxicity of Stx1 or Stx2. In this study, we evaluated the protective efficacy of human/mouse chimeric versions of those monoclonal antibodies, named calphaStx1 and calphaStx2. Mice given an otherwise lethal dose of Stx1 were protected from death when injected with calphaStx1 either 1 h before or 1 h after toxin injection. Additionally, streptomycin-treated mice fed the mouse-lethal STEC strain B2F1 that produces the Stx2 variant Stx2d were protected when given a dose of 0.1 mg of calphaStx2/kg of body weight administered up to 72 h post-oral bacterial challenge. Since many STEC strains produce both Stx1 and Stx2 and since either toxin may lead to the HUS, we also assessed the protective efficacy of the combined MAbs. We found that both antibodies were required to protect mice from the presence of both Stx1 and Stx2. Pharmacokinetic studies indicated that calphaStx1 and calphaStx2 had serum half-lives (t1/2) of about 50 and 145 h, respectively. We propose that calphaStx1 and calphaStx2, both of which have been tested for safety in humans, could be used therapeutically for prevention or treatment early in the development of HUS. PMID- 25716231 TI - The Transforming Growth Factor beta1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival. AB - The transforming growth factor beta1/interleukin-31 (TGF-beta1/IL-31) pathway plays an important role in the process of cell injury and inflammation. The purpose of this work was to explore the role of the TGF-beta1/IL-31 pathway in the cytopathic process of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The quantitative serum levels of TGF-beta1, IL-9, IL-10, IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were analyzed among chronic hepatitis B (CHB) patients (n = 17), ACLF patients (n = 18), and normal control (NC) subjects (n = 18). Disease severity in patients with ACLF was assessed using the model for end-stage liver disease (MELD) and Child-Pugh scores. Serum TGF-beta1 levels were strongly positively correlated with IL-31 in all subjects, and both of them were positively correlated with IL-17, IL-22, and IL-33. In CHB and ACLF patients, serum levels of TGF-beta1 and IL-31 were both increased significantly compared with those in NC subjects and positively correlated with total bilirubin (TBil) and alpha-fetoprotein (AFP) levels. ACLF patients showed the highest levels of TGF-beta1 and IL-31, which were positively correlated with Child-Pugh scores. Furthermore, the recovery from the liver injury in CHB was accompanied by decreased TGF-beta1 and IL-31 levels. More importantly, serum levels of TGF-beta1 and IL-31 were markedly upregulated in ACLF nonsurvivors, and IL-31 displayed the highest sensitivity and specificity (85.7% and 100.0%, respectively) in predicting nonsurvival of ACLF patients. Increasing activity of the TGF-beta1/IL 31 pathway is well correlated with the extent of liver injury, disease severity, and nonsurvival of ACLF patients, while reducing activity is detected along the recovery from liver injury in CHB, suggesting its potential role in the pathogenesis of liver injury during chronic HBV infection. PMID- 25716233 TI - NSAIDs double risk of bleeding in patients taking antithrombotics after myocardial infarction, study finds. PMID- 25716232 TI - Coinfection with Blood-Stage Plasmodium Promotes Systemic Type I Interferon Production during Pneumovirus Infection but Impairs Inflammation and Viral Control in the Lung. AB - Acute lower respiratory tract infections (ALRTI) are the leading cause of global childhood mortality, with human respiratory syncytial virus (hRSV) being a major cause of viral ALRTI in young children worldwide. In sub-Saharan Africa, many young children experience severe illnesses due to hRSV or Plasmodium infection. Although the incidence of malaria in this region has decreased in recent years, there remains a significant opportunity for coinfection. Recent data show that febrile young children infected with Plasmodium are often concurrently infected with respiratory viral pathogens but are less likely to suffer from pneumonia than are non-Plasmodium-infected children. Here, we hypothesized that blood-stage Plasmodium infection modulates pulmonary inflammatory responses to a viral pathogen but does not aid its control in the lung. To test this, we established a novel coinfection model in which mice were simultaneously infected with pneumovirus of mice (PVM) (to model hRSV) and blood-stage Plasmodium chabaudi chabaudi AS (PcAS) parasites. We found that PcAS infection was unaffected by coinfection with PVM. In contrast, PVM-associated weight loss, pulmonary cytokine responses, and immune cell recruitment to the airways were substantially reduced by coinfection with PcAS. Importantly, PcAS coinfection facilitated greater viral dissemination throughout the lung. Although Plasmodium coinfection induced low levels of systemic interleukin-10 (IL-10), this regulatory cytokine played no role in the modulation of lung inflammation or viral dissemination. Instead, we found that Plasmodium coinfection drove an early systemic beta interferon (IFN beta) response. Therefore, we propose that blood-stage Plasmodium coinfection may exacerbate viral dissemination and impair inflammation in the lung by dysregulating type I IFN-dependent responses to respiratory viruses. PMID- 25716235 TI - Matrix site effects on vibrational frequencies of HXeCCH, HXeBr, and HXeI: a hybrid quantum-classical simulation. AB - The matrix shifts of the H-Xe stretching frequency of noble-gas hydrides, HXeCCH, HXeBr, and HXeI in various noble-gas matrices (in Ne, Ar, Kr, and Xe matrices) are investigated via the hybrid quantum-classical simulations. The order of the H Xe stretching frequencies is found to be nu(gas) < nu(Ne) < nu(Xe) < nu(Kr) < nu(Ar) for HXeCCH and HXeBr, while it is nu(gas) < nu(Ne) < nu(Xe) < nu(Ar) < nu(Kr) for HXeI. This order is anomalous with respect to the matrix dielectric constants, and the calculated results reproduce the experimentally observed shifts quite successfully. We also find that the matrix shifts from the gas-phase values are Deltanu(HXeCCH) ~ Deltanu(HXeCl) < Deltanu(HXeBr) < Deltanu(HXeI) in the same noble-gas matrix environments, which implies that the weakly bound molecules exhibit large matrix shifts. The local trapping site is analyzed in detail, and it is shown that a realistic modeling of the surrounding matrix environments is essential to describe the unusual matrix shifts accurately. PMID- 25716234 TI - CD235a (Glycophorin-A) Is the Most Predictive Value Among Different Circulating Cellular Microparticles in Thrombocytopenic Human Immunodeficiency Virus Type 1. AB - BACKGROUND: This study was conducted to assess different cellular microparticles (MPs) in thrombocytopenic human immunodeficiency virus type 1 and their significance as disease activity markers. METHODS: Thirty-five thrombocytopenic human immunodeficiency diseases and 25 healthy controls with matched age and sex were selected. Viral load was quantitated by COBAS real-time polymerase reaction (PCR) assessment of absolute T-cell subsets CD4, CD8 as a disease progress marker. Platelet MPs, platelet-derived monocyte MPs (CD42a, CD61), erythrocyte MP (CD235a), monocytic MP (CD14), and platelet activity MPs (CD62P, PAC-1) were assessed by multicolor flow cytometry FACSCalibur, while platelet functions were assessed by platelet function analyzer (PFA-100). CD42a, CD61, and platelet activity index represented by PAC-1 and CD62. RESULTS: P-selectin in HIV-infected patient samples were significantly greater (P < 0.001) than among controls. There was a negative correlation between the proportion of PAC-1 and CD62 P-selectin positive MPs and levels of CD4(+) T-cell counts (r = -0.403, P = 0.016; r = 0.438, P = 0.008), respectively. There was a negative correlation between collagen-ADP and levels of CD4(+) T-cell counts (r = -0.368, P = 0.03). There was a significant high expression level of CD14 monocyte MPs in patients than controls (P < 0.0001), overexpression of CD235a (P < 0.0001), and no correlation between CD14 and CD4, whereas there was a significant negative correlation with CD235a (r = -0.394, P = 0.019). A linear regression analysis of CD4 as a disease progression marker with other variable indicators in HIV patients showed that CD235a could be the most sensitive predictor similar to CD4. CONCLUSION: Different cellular MPs and platelets activated in HIV patients could have a role in thrombotic events in these patients. PMID- 25716274 TI - Radiation therapy for stage IIA and IIB testicular seminoma: peripheral dose calculations and risk assessments. AB - This study was conducted to calculate the peripheral dose to critical structures and assess the radiation risks from modern radiotherapy for stage IIA/IIB testicular seminoma. A Monte Carlo code was used for treatment simulation on a computational phantom representing an average adult. The initial treatment phase involved anteroposterior and posteroanaterior modified dog-leg fields exposing para-aortic and ipsilateral iliac lymph nodes followed by a cone-down phase for nodal mass irradiation. Peripheral doses were calculated using different modified dog-leg field dimensions and an extended conventional dog-leg portal. The risk models of the BEIR-VII report and ICRP-103 were combined with dosimetric calculations to estimate the probability of developing stochastic effects. Radiotherapy for stage IIA seminoma with a target dose of 30 Gy resulted in a range of 23.0-603.7 mGy to non-targeted peripheral tissues and organs. The corresponding range for treatment of stage IIB disease to a cumulative dose of 36 Gy was 24.2-633.9 mGy. A dose variation of less than 13% was found by altering the field dimensions. Radiotherapy with the conventional instead of the modern modified dog-leg field increased the peripheral dose up to 8.2 times. The calculated heart doses of 589.0-632.9 mGy may increase the risk for developing cardiovascular diseases whereas the testicular dose of more than 231.9 mGy may lead to a temporary infertility. The probability of birth abnormalities in the offspring of cancer survivors was below 0.13% which is much lower than the spontaneous mutation rate. Abdominoplevic irradiation may increase the lifetime intrinsic risk for the induction of secondary malignancies by 0.6-3.9% depending upon the site of interest, patient's age and tumor dose. Radiotherapy for stage IIA/IIB seminoma with restricted fields and low doses is associated with an increased morbidity. These data may allow the definition of a risk-adapted follow up scheme for long-term testicular cancer survivors. PMID- 25716275 TI - Management and diagnosis of fatty liver disease. AB - Nonalcoholic fatty liver disease is a common cause of chronic liver disease and has been an increasingly studied topic of research as the obesity epidemic has been growing. There is a significant morbidity and mortality with uncontrolled steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. The prevalence of this disease has been estimated to be roughly one third of the western population, thought to be largely due to diet and sedentary lifestyle. Several treatments have been studied including vitamin E, insulin sensitizing agents and ursodeoxycholic acid; however, the only treatment shown to improve the histologic changes of nonalcoholic fatty liver disease is weight loss. Given the proven benefit of weight loss, there may be reason to screen at risk populations; however, limited availability of other disease-modifying treatments may limit the cost-benefit ratios. A better understanding of the diagnosis and management of this condition is required to alter the course of this modifiable disease. PMID- 25716277 TI - Electronic-structure-based material descriptors: (in)dependence on self interaction and Hartree-Fock exchange. AB - Rational design of improved transition metal based materials mostly relies on their electronic structure descriptors, typically estimated by density functional theory and so unduly affected by self-interaction or static correlation errors. Here we show for all 30 transition metals that original or width-corrected d-band centers, and Hilbert transform highest peak descriptors are unaffected by self interaction, while poor treatment of static correlation by hybrid functionals leads to an unbalanced description. Thus, descriptors have a general validity unbiased by a specific computational method. PMID- 25716276 TI - Ethnic differences in postpartum weight retention: a Norwegian cohort study. AB - OBJECTIVE: To explore ethnic differences in weight retention 14 weeks postpartum. DESIGN: Population-based cohort study. SETTING: The STORK Groruddalen Study. POPULATION: A multi-ethnic cohort of healthy pregnant women attending primary antenatal care at three public Child Health Clinics, in Oslo, Norway (n = 642). METHODS: An explanatory linear regression was performed to model the relationship between ethnicity and postpartum weight retention. Forward selection of 12 explanatory factors was used to adjust for potential confounding factors, based on univariate analysis and adjusted R(2) . MAIN OUTCOME MEASURE: Postpartum weight retention. RESULTS: Unadjusted mean postpartum weight retention was 2.3 (4.9) kg for women from Western Europe and varied from 3.7 (3.5) to 6.3 (4.7) kg among the five ethnic minority groups. The proportion of women in the highest quintile (postpartum weight retention >8.5-24.4 kg) significantly differed by ethnicity (P < 0.01 for the proportion of women from South Asia, the Middle East and Africa compared with Western Europeans). Women from all ethnic minority groups had a higher relative increase in weight from pre-pregnancy to postpartum (P < 0.01) compared with Western Europeans. After adjustments for significant exposures, women from the Middle East retained 2.0 kg (95% CI: 1.0-3.0), South Asia 2.8 kg (91.9-3.6), and Africa 4.4 kg (3.1-5.8) more than Western Europeans (P < 0.01). CONCLUSIONS: Significantly more women with an ethnic origin from South Asia, the Middle East and Africa had high postpartum weight retention compared with Western European women. PMID- 25716278 TI - Back to basics: steps in pediatric dermatologic diagnosis. PMID- 25716279 TI - Rumen development process in goats as affected by supplemental feeding v. grazing: age-related anatomic development, functional achievement and microbial colonisation. AB - The aim of the present study was to describe age-related changes in anatomic, functional and microbial variables during the rumen development process, as affected by the feeding system (supplemental feeding v. grazing), in goats. Goats were slaughtered at seven time points that were selected to reflect the non rumination (0, 7 and 14 d), transition (28 and 42 d) and rumination (56 and 70 d) phases of rumen development. Total volatile fatty acid (TVFA) concentration (P= 0.002), liquid-associated bacterial and archaeal copy numbers (P< 0.01) were greater for supplemental feeding v. grazing, while rumen pH (P< 0.001), acetate molar proportion (P= 0.003) and solid-associated microbial copy numbers (P< 0.05) were less. Rumen papillae length (P= 0.097) and extracellular (P= 0.093) and total (P= 0.073) protease activity potentials in supplemented goats tended to be greater than those in grazing goats. Furthermore, from 0 to 70 d, irrespective of the feeding system, rumen weight, rumen wall thickness, rumen papillae length and area, TVFA concentration, xylanase, carboxymethylcellulase activity potentials, and microbial copy numbers increased (P< 0.01) with age, while the greatest amylase and protease activity potentials occurred at 28 d. Most anatomic and functional variables evolved progressively from 14 to 42 d, while microbial colonisation was fastest from birth to 28 d. These outcomes suggest that the supplemental feeding system is more effective in promoting rumen development than the grazing system; in addition, for both the feeding systems, microbial colonisation in the rumen is achieved at 1 month, functional achievement at 2 months, and anatomic development after 2 months. PMID- 25716280 TI - Risk profiles for endometriosis in Japanese women: results from a repeated survey of self-reports. AB - BACKGROUND: The prevalence and risk factors for endometriosis may differ according to diagnosis methodologies, such as study populations and diagnostic accuracy. We examined risk profiles in imaging-diagnosed endometriosis with and without surgical confirmation in a large population of Japanese women, as well as the differences in risk profiles of endometriosis based on history of infertility. METHODS: Questionnaires that included items on sites of endometriosis determined by imaging techniques and surgical procedure were mailed to 1025 women who self-reported endometriosis in a baseline survey of the Japan Nurses' Health Study (n = 15 019). RESULTS: Two hundred and ten women had surgically confirmed endometriosis (Group A), 120 had imaging-diagnosed endometriosis without a surgical procedure (Group B), and 264 had adenomyosis (Group C). A short menstrual cycle at 18-22 years of age and cigarette smoking at 30 years of age were associated with significantly increased risk of endometriosis (Group A plus Group B), while older age was associated with risk of adenomyosis (Group C). In women with a history of infertility, a short menstrual cycle was associated with a significantly increased risk of endometriosis in both Group A and Group B, but risk profiles of endometriosis were different between Group A and Group B in women without a history of infertility. CONCLUSIONS: Women with surgically confirmed endometriosis and those with imaging-diagnosed endometriosis without surgery have basically common risk profiles, but these risk profiles are different from those with adenomyosis. The presence of a history of infertility should be taken into consideration for evaluation of risk profiles. PMID- 25716281 TI - Pyogenic liver abscess correlates with increased risk of acute pancreatitis: a population-based cohort study. AB - BACKGROUND: The aim of this study was to explore whether there is a relationship between pyogenic liver abscess (PLA) and subsequent risk of acute pancreatitis in Taiwan. METHODS: Using inpatients claims data from the Taiwan National Health Insurance Program, we identified 30 866 subjects aged 20-84 years with the first attack of PLA from 2000 to 2010 as the PLA group and randomly selected 123 464 subjects without PLA as the non-PLA group. The incidence of the first attack of acute pancreatitis at the end of 2010 and the risk associated with PLA and other comorbidities were measured. RESULTS: The overall incidence of acute pancreatitis was 3.84-fold greater in the PLA group than in the non-PLA group (4.61 vs 1.19 events per 1000 person-years; 95% CI, 3.43-4.29). After controlling for potential confounding factors, the adjusted hazard ratio of acute pancreatitis was 3.00 (95% CI, 2.62-3.43) for the PLA group, as compared to the non-PLA group. Further analysis showed that compared to subjects with neither PLA nor comorbidities, patients with PLA and hypertriglyceridemia, biliary stones, alcoholism, or hepatitis C had greater risk of acute pancreatitis than those with PLA alone. CONCLUSIONS: PLA correlates with increased risk of subsequent acute pancreatitis. Comorbidities, including hypertriglyceridemia, biliary stones, alcoholism, and hepatitis C, may enhance the risk of developing acute pancreatitis. PMID- 25716282 TI - Dual effect of metformin on growth inhibition and oestradiol production in breast cancer cells. AB - Evidence has been accumulating for a role for metformin in reducing breast cancer risk in post-menopausal women. It inhibits growth of breast cancer cells via several mechanisms, primarily the AMPK/mTOR signalling pathway. Another possible protective mechanism may be the ability of metformin to inhibit aromatase activity. In the present study, we investigated the effects of metformin on the basal growth of MCF-7 cells, after oestradiol (E2) stimulation and after the inhibition of mTOR by rapamycin. Secondly, we investigated the effects of metformin on the activity of a number of steroidogenic enzymes and the mRNA expression of aromatase and steroid sulphatase (STS). High doses of metformin significantly inhibited both basal and oestrogen-stimulated cell division. Low dose rapamycin (10-10 M) did not inhibit growth, but the addition of metformin induced a significant reduction in growth. High-dose rapamycin (10-8 M) inhibited growth, and this was further attenuated by the addition of metformin. Exposure to low (10-7 M) and high (10-4 M) doses of metformin for 7-10 days significantly reduced the conversion of androstenedione (ANDRO) and testosterone (TESTO) (both requiring aromatase), but not the conversion of oestrone or oestrone sulphate (ES) via 17beta-hydroxysteroid dehydrogenase/sulphatase to E2. This attenuation was via a downregulation in the expression of total aromatase mRNA and promoter II, whilst the expression of sulphatase was unaffected by metformin. In conclusion, plasma levels of metformin have a dual therapeutic action, first by directly inhibiting cell proliferation which can be augmented by rapamycin analogues, and secondly, by inhibiting aromatase activity and reducing the local conversion of androgens to E2. PMID- 25716284 TI - [Femoral neck fracture]. AB - The incidence of femoral neck fractures increases exponentially with rising age. Young patients are rarely affected but when they are it is mostly due to high energy accidents, whereas older patients suffer from femoral neck fractures by low energy trauma due to osteoporotic changes of the bone mineral density. Treatment options have not essentially changed over the last few years. Non operative treatment may be a choice in non-dislocated and impacted fractures. Due to the high risk of secondary fracture displacement prophylactic screw osteosynthesis is recommended even in Garden type I fractures. Osteosynthetic fracture stabilization with cannulated screws or angle stable sliding screws, is usually applied in non-displaced fractures and fractures in younger patients. Older patients need rapid mobilization after surgery; therefore, total hip arthroplasty and hemiarthroplasty are commonly used with a low incidence of secondary complications. In addition to sufficient operative treatment a guideline conform osteoprosis therapy should be initiated for the prophylaxis of further fractures and patients should undertake a suitable rehabilitation. PMID- 25716285 TI - The unintended effects of the Medicare Part D low income subsidy. AB - OBJECTIVES: Medicare Part D is the voluntary program that provides insurance for prescription drugs to 37 million US elderly. This form of public insurance is delivered exclusively through a choice-based private insurance market, where Medicare pays various types of subsidies. The objective of this paper is to analyze how the subsidy paid to low income enrollees induces insurers to distort their plan premiums. METHODS: Combining both an analysis of the incentives created by the different regulations and empirical evidence obtained from plan level data for the years between 2006 and 2013, the paper evaluates the presence of premium distortions associated with insurers response to the low income subsidy. RESULTS: The findings indicate that insurers cluster premiums at the value that maximizes the rents they earn on enrollees receiving the low income subsidies. Moreover, insurers use the possibility of offering multiple insurance plans to manipulate the amount of the subsidy and increase further their rents. CONCLUSIONS: This study indicates the need to reform the subsidy system in Medicare Part D and offers guidance on the essential elements of the low income subsidy reform. PMID- 25716286 TI - Still serving hot soup? Two hundred years of a charitable food sector in Australia: a narrative review. AB - OBJECTIVE: Despite the importance of the charitable food sector for a proportion of the Australian population, there is uncertainty about its present and future contributions to wellbeing. This paper describes its nature and examines its scope for improving health and food security. METHODS: The review, using systematic methods for public health research, identified peer-reviewed and grey literature relevant to Australian charitable food programs (2002 to 2012). RESULTS: Seventy publications met the criteria and informed this paper. The sector includes food banks, more than 3,000 community agencies and 800 school breakfast programs. It provides food for up to two million people annually. The scope extends beyond emergency food relief and includes case management, advocacy and other support. Weaknesses include a food supply that is sub-optimal, resource limitations and lack of evidence to evaluate or support their work towards food security. CONCLUSIONS: The sector supports people experiencing disadvantage and involves multiple organisations, working in a variety of settings, to provide food for up to 8% of the population. The limits on the sector's capacity to address food insecurity by itself must be acknowledged so that civil society, government and the food industry can support sufficient, nutritious and affordable food for all. PMID- 25716287 TI - Sphingomyelin Regulates the Activity of Secretory Phospholipase A2 in the Plasma Membrane. AB - We examined the effect of the cellular sphingolipid level on the release of arachidonic acid (AA) and the activity of secretory phospholipase A2 (sPLA2 ) using two Chinese hamster ovary (CHO)-K1 cell mutants, LY-B and LY-A cells, deficient in sphingolipid synthesis. In LY-B cells, deficiency of sphingolipids enhanced the release of AA induced by bee venom sPLA2-III or human sPLA2-V. These alterations were reversed by replenishment of exogenous sphingomyelin (SM). In LY A cells, deficiency of SM increased the release of AA induced by sPLA2. In CHO-K1 cells, decrease and increase of SM level in the plasma membrane by pharmacological methods increased and inhibited the release of AA, respectively. SM inhibited the activity of sPLA2 in vitro. Niemann-Pick disease type C (NPC) is a lysosomal storage disorder caused by mutation of either the NPC1 or NPC2 gene, and is characterized by accumulation of cholesterol and sphingolipids including SM in late endosomes/lysosomes. Increased levels of AA and sPLA2 activity are involved in various neurodegenerative diseases. In CHO cells lacking NPC1 (A101 cells), SM level was lower in the plasma membrane, while it was higher in late endosomes/lysosomes. The release of AA induced by sPLA2 was increased in A101 cells than that in parental cells (JP17 cells), which was attenuated by adding exogenous SM. In addition, sPLA2 -III-induced cytotoxicity in A101 cells was much higher than that in JP17 cells. These results suggest that SM in the plasma membrane plays important roles in regulating sPLA2 activity and the enzyme induced cytotoxicity in A101 cells. PMID- 25716288 TI - Real-time PCR genotyping assay for feline erythrocyte pyruvate kinase deficiency and mutant allele frequency in purebred cats in Japan. AB - Erythrocyte pyruvate kinase (PK) deficiency is an inherited glycolytic erythroenzymopathy caused by mutations of the PKLR gene. A causative mutation of the feline PKLR gene was originally identified in Abyssinian and Somali cats in the U.S.A. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid genotyping and large-scale screening for this mutation. Furthermore, a genotyping survey was carried out in a population of four popular purebred cats in Japan to determine the current mutant allele frequency. The assay clearly displayed all genotypes of feline PK deficiency, indicating its suitability for large-scale survey as well as diagnosis. The survey demonstrated that the mutant allele frequency in Abyssinian and Somali cats was high enough to warrant measures to control and prevent the disease. The mutant allele frequency was relatively low in Bengal and American Shorthair cats; however, the testing should still be carried out to prevent the spread of the disease. In addition, PK deficiency should always be considered in the differential diagnosis of anemia in purebred cats in Japan as well as worldwide. PMID- 25716289 TI - Molecular epidemiology and phylogenetic analysis of diverse bovine astroviruses associated with diarrhea in cattle and water buffalo calves in China. AB - Astroviruses are the principal causative agents of gastroenteritis in humans and have been associated with diarrhea in other mammals as well as birds. However, astroviral infection of animals had been poorly studied. In the present study, 211 rectal swabs collected from cattle and water buffalo calves with mild to severe diarrhea were tested for bovine astrovirus (BAstV) by RT-PCR. Results: 92/211 (43.6%) samples were positive for BAstV, at a rate of 46.10% (71/154) in cattle and 36.84% (21/57) in water buffalo. Phylogenetic analysis based on the partial and full-length of 25 ORF2 amino acid sequences obtained in this study classified the Guangxi BAstVs isolates into five subgroups under the genus of Mamastrovirus, genotype MAstV33, which suggested that the water buffalo was a new host of this genogroup that previously included only cattle and roe deer. Despite the origin of the host, the Guangxi BAstV isolates were closely related to the BAstV Hong Kong isolates (B18/HK and B76-2/HK), but highly divergent from the BAstV NeuroS1 isolate previously associated with neurologic disease in cattle in the U.S.A. Nucleotide sequence-based characterization of the ORF1b/ORF2 junction and corresponding overlapping regions showed distinctive properties, which may be common to BAstVs. Our results suggested that cattle and water buffalo are prone to infection of closely related astroviruses, which probably evolved from the same ancestor. The current study described astroviruses in water buffalo for the first time and is thus far among the largest epidemiological investigations of BAstV infection in cattle conducted in China. PMID- 25716291 TI - Self-induced uniaxial strain in MoS2 monolayers with local van der Waals-stacked interlayer interactions. AB - Strain engineering is an effective method to tune the properties of electrons and phonons in semiconductor materials, including two-dimensional (2D) layered materials (e.g., MoS2 or graphene). External artificial stress (ExAS) or heterostructure stacking is generally required to induce strains for modulating semiconductor bandgaps and optoelectronic functions. For layered materials, the van der Waals-stacked interlayer interaction (vdW-SI) has been considered to dominate the interlayer stacking and intralayer bonding. Here, we demonstrate self-induced uniaxial strain in the MoS2 monolayer without the assistance of ExAS or heterostructure stacking processes. The uniaxial strain occurring in local monolayer regions is manifested by the Raman split of the in-plane vibration modes E2g(1) and is essentially caused by local vdW-SI within the single layer MoS2 due to a unique symmetric bilayer stacking. The local stacked configuration and the self-induced uniaxial strain may provide improved understanding of the fundamental interlayer interactions and alternative routes for strain engineering of layered structures. PMID- 25716290 TI - Differences in cisplatin-induced mechanical allodynia in male and female mice. AB - BACKGROUND: Chemotherapeutic agents, such as cisplatin, are known to induce a persistent polyneuropathy. The mechanisms underlying the development of this pain are complex, and have only been investigated rodent models using male animals, despite an equivalent presentation of neuropathy between the sexes, clinically. METHODS: Male and female C57Bl/6, Tlr3(-/-) Tlr4(-/-) , Myd88(-/-) , Trif(lps2) and Myd88(-/-) /Trif(lps2) mice received 6 i.p. injections of cisplatin (2.3 mg/kg/day) every other day over the course of 2 weeks. Changes in tactile threshold were monitored during this time, continuing through day 23, using von Frey filaments. RESULTS: Male WT mice develop a persistent tactile allodynia resulting from cisplatin administration. Female mice develop an initial allodynia, but thresholds return to baseline by day 23. Deletion of TLR3, TLR4, MyD88 and Trif/MyD88 protects animals from the development of cisplatin-induced polyneuropathy, and there are no sex differences. Trif(lps2) male mice show a persistent tactile allodynia following cisplatin administration, while female mice show a reduced allodynia, and remain higher in threshold than their male counterparts. On day 18, animals were given the analgesic gabapentin, and thresholds were tested 45 min after. Gabapentin was effective in transiently reversing mechanical allodynia in those mice with lowered thresholds. CONCLUSIONS: It is important to continue examining both sexes in various pain models, as a mononeuropathy and polyneuropathy show sex differences in pain development and the role of TLR signalling. PMID- 25716292 TI - Strong hydrophobizer: laterally chemisorbed low-molecular-weight polydimethylsiloxane. AB - We introduce a siloxane chain-based hydrophobizer that exhibits superior thermal and chemical stability compared to the conventional hydrophobizing silane agent under conditions of over 300 degrees C and pH 2-13. To demonstrate the capability of the siloxane chain-based hydrophobizer to serve as a highly robust chemical surface modifier, we present two applications: the formation of fine metal nanoparticles with a narrow size distribution by thermal aggregation of a metal thin film and the selective deposition of a ruthenium thin film by atomic layer deposition. PMID- 25716293 TI - beta-lactam and beta-lactamase inhibitor combinations in the treatment of extended-spectrum beta-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? AB - The spread of extended-spectrum beta-lactamase (ESBL) genes in Enterobacteriaceae such as Escherichia coli or Klebsiella spp is a major challenge to modern medical practice. Carbapenems are the treatment of choice for serious infections caused by ESBL producers; however, carbapenem resistance has increased globally. ESBL producers might be susceptible to beta-lactam-beta-lactamase inhibitor (BLBLI) combination antibiotics such piperacillin-tazobactam or amoxicillin-clavulanate. These drugs are frequently avoided in serious infections caused by ESBL producers because of the inoculum effect in-vitro (especially for piperacillin-tazobactam), animal data suggesting inferior efficacy when compared with carbapenems, concerns about pharmacokinetic-pharmacodynamic drug target attainment with standard doses, and poor outcomes shown in some observational studies. Prospective cohort data and a meta-analysis suggest that BLBLIs are non-inferior to carbapenems in the treatment of bloodstream infections caused by ESBL producers. We examine why BLBLIs are perceived as inferior in the treatment of infection with ESBL producers, and discuss data that suggest these concerns might not be strongly supported by clinical evidence. PMID- 25716294 TI - A New Animal Model of Brachial Plexus Neuralgia Produced by Injection of Cobra Venom into the Lower Trunk in the Rat. AB - BACKGROUND: To establish a new animal model for the study of neuropathic pain developed by administration of cobra venom to the brachial plexus (BP) lower trunk. METHODS: Fifty-eight adult male Sprague-Dawley rats were randomly divided into 5 groups. Under pentobarbital sodium anesthesia, cobra venom was injected into the lower trunk or sham operation was performed in the animals. On postoperative day 1 and day 12, pregabalin was administered intragastricly at 30 mg/kg in two groups. Mechanical withdrawal thresholds (MWT) were tested with von Frey filaments. Video recordings were used to analyze the spontaneous behaviors. Meanwhile, our model was confirmed by observing ultrastructural alterations of the BP and cervical cord (C8-T1) via electron microscope examination. RESULTS: In comparison to the blank and sham-operated group, cobra venom-treated rats showed a profound decrease in the MWT, exploratory and increase in grooming behaviors (P<0.05). The changes were long-lasting (up to 60 days), in both ipsilateral and contralateral paws. Furthermore, it was observed under microscopic examination that the myelin sheath was demyelinated in the BP and cervical cord (C8-T1) after injection of cobra venom to the lower trunk. Pregabalin group rats showed changes in MWT and spontaneous behaviors after pregabalin treatment at postoperative day 1 (P>0.05), compared with the control and sham-operated groups. In pregabalin test POD12 group, the decreased MWT and the increased grooming behavior were improved at 20 days after operation. However, pregabalin had no effect on exploratory activity. Results indicate that pregabalin effectively attenuates mechanical hyperalgesia in acute period. CONCLUSIONS: The cobra venom model can be used as a model to induce neuropathic pain and to enable study of the mechanism and treatment. PMID- 25716295 TI - Latent constructs model explaining the attachment-linked variation in autobiographical remembering. AB - In the current study, we proposed a latent constructs model to characterise the qualitative aspects of autobiographical remembering and investigated the structural relations in the model that may vary across individuals. Primarily, we focused on the memories of romantic relationships and argued that attachment anxiety and avoidance would be reflected in the ways that individuals encode, rehearse, or remember autobiographical memories in close relationships. Participants reported two positive and two negative relationship-specific memories and rated the characteristics for each memory. As predicted, the basic memory model yielded appropriate fit, indicating that event characteristics (EC) predicted the frequency of rehearsal (RC) and phenomenology at retrieval (PC). When attachment variables were integrated, the model showed that rehearsal mediated the link between anxiety and PC, especially for negative memories. On the other hand, for avoidance EC was the key factor mediating the link between avoidance and RC, as well as PC. Findings were discussed with respect to autobiographical memory functions emphasising a systematically, integrated framework. PMID- 25716296 TI - Acute diagnostic neurology: challenges and opportunities. PMID- 25716297 TI - Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning. AB - The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear. PMID- 25716298 TI - Impact of prenatal nicotine on the structure of midbrain dopamine regions in the rat. AB - In utero exposure of rats to nicotine (NIC) provides a useful animal model for studying the impact of smoking during pregnancy on human offspring. Certain sequelae of prenatal NIC exposure suggest an impact on the development of the midbrain dopamine (DA) system, which receives a robust cholinergic innervation from the mesopontine tegmentum. We therefore investigated whether prenatal NIC induced structural changes in cells and synapses within the midbrain that persisted into adulthood. Osmotic minipumps delivering either sodium bitartrate (vehicle; VEH) or NIC bitartrate at 2 mg/kg/day were implanted into nine timed pregnant dams at E4. At birth, rat pups were culled to litters of six males each, and the litters were cross-fostered. Plasma levels of NIC and cotinine from killed pups provided evidence of NIC exposure in utero. Pups separated from dams at weaning showed a trend toward reduced locomotor activity at this time point but not when tested again in adulthood. Adult rats were killed for anatomical studies. Estimates of brain size and volume did not vary with NIC treatment. Midbrain sections stained for Nissl or by immunoperoxidase for tyrosine hydroxylase and analyzed using unbiased stereology revealed no changes in volume or cell number in the substantia nigra compacta or ventral tegmental area as a result of NIC exposure. Within the ventral tegmental area, electron microscopic physical disector analysis showed no significant differences in the number of axon terminals or the number of asymmetric (putative excitatory) or symmetric (putative inhibitory) synapses. Although too infrequent to estimate by unbiased stereology, no obvious difference in the proportion of cholinergic axons was noted in NIC- versus VEH-treated animals. These data suggest that activation of nicotinic receptors during prenatal development induces no significant modifications in the structure of cells in the ventral midbrain when assessed in adulthood. PMID- 25716299 TI - A comparison of obesity related adipokine concentrations in knee and shoulder osteoarthritis patients. AB - OBJECTIVE: The ratio between the serum and knee synovial fluid (SF) adipokine level has been correlated to osteoarthritis (OA) severity. No study has examined the relative concentration of adipokines in shoulder OA. However, in this study, we document serum and SF concentrations, and serum/SF ratios, of leptin and adiponectin among individuals with end stage shoulder OA, and compare ratios with a sample of individuals with end stage knee OA. METHODS: Thirty-five patients with end stage knee and shoulder OA were surveyed prior to surgery for demographic data and body mass index (BMI). Synovial fluid (SF) and serum samples were analyzed for leptin and adiponectin. Serum/SF ratios were calculated and compared across cohorts. RESULTS: Knee and shoulder cohorts were matched, without clinical differences for age, gender, and BMI. Serum and SF leptin levels are consistently higher in knee OA patients as compared to shoulder OA patients. Further, serum/SF adiponectin ratios are greater than that for leptin across both joints. CONCLUSIONS: Our findings may help, in part, explain the findings that obesity has a stronger association to knee OA than shoulder OA. Whether this reflects a difference in local production of adipokines, capsular permeability, or both must be further studied. PMID- 25716300 TI - Neurodegenerative diseases and therapeutic strategies using iron chelators. AB - This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed. PMID- 25716301 TI - Give 'em 3 liters of hyperal. PMID- 25716303 TI - Searching for targets in visual working memory: investigating a dimensional feature bundle (DFB) model. AB - The human visual working memory (WM) system enables us to store a limited amount of task-relevant visual information temporally in mind. One actively debated issue in cognitive neuroscience centers around the question of how this WM information is maintained. The currently dominant views advocated by prominent WM models hold that the units of memory are configured either as independent feature representations, integrated bound objects, or a combination of both. Here, we approached this issue by measuring lateralized brain electrical activity during a retro-cue paradigm, in order to track people's ability to access WM representations as a function of the dimensional relation between WM items and task settings. Both factors were revealed to selectively influence WM access: whereas cross relative to intradimensional WM targets gave rise to enhanced contralateral delay activity (CDA) amplitudes, localization relative to identification task demands yielded speeded CDA and manual response times. As these dimension-based findings are not reconcilable with contemporary feature- and/or object-based accounts, an alternative view that is based on the hierarchical feature-bundle model is proposed. We argue that WM units may consist of three hierarchically structured levels of representations, with an intermediate dimensionally organized level that mediates between top-level object and lower-level feature representations. PMID- 25716302 TI - Colonoscopy: quality indicators. AB - Effective endoscopic screening for colorectal cancer (CRC), one of the few preventable cancers, is dependent on the adequate detection and removal of potentially precancerous lesions. However, observed variation in colonoscopy performance in practice and outcomes has highlighted the need for consistent quality measures. Quality indicators or measures are tools that help to quantify health-care processes and can aid in providing high-quality health care. The primary colonoscopy quality indicator is the adenoma detection rate (ADR), which is defined as the proportion of an endoscopist's screening colonoscopies in which one or more adenomas have been detected. The risk of post-colonoscopy CRC is inversely correlated with an endoscopist's ADR. However, ADR is dependent on other quality measures, including cecal intubation rates, withdrawal times, and quality of bowel preparation. Achieving suggested benchmarks for these other quality measures will aid the endoscopist in achieving the recently updated ADR benchmark of 25% in their practice. In addition, beyond ensuring adequate ADRs, endoscopists should have high compliance rates with guideline-recommended and evidence-based screening and surveillance intervals. Compliance with quality measures will ensure effective and safe CRC prevention and better patient outcomes. PMID- 25716304 TI - Illustrations of the HIV life cycle. AB - Illustrations of the HIV Life Cycle. The illustrations include proteins, nucleic acids and membranes; small molecules and water are omitted for clarity. Host cell molecules are shown in shades of blue and green and blood plasma proteins are shown in shades of tan and brown. HIV proteins are shown in red and magenta, HIV RNA is in yellow and HIV DNA is in yellow-green. The 3D model of the mature virion was generated using CellPACK by Graham Johnson Illustrations of the major steps of HIV life cycle are presented that integrate information from structural and biophysical studies. The illustrations depict HIV and its interaction with its cellular host at a magnification that reveals all macromolecules. This report describes the sources of scientific support for the structures and processes shown in the illustrations. PMID- 25716306 TI - Biomarkers of ecotoxicological oxidative stress in an urban environment: using evergreen plant in industrial areas. AB - Plants react to air pollution by increased production of reactive oxygene species and oxidative stress, which triggers multiple defense mechanisms. In this study, some parameters that serve as biomarkers for antioxidative defense, such as glutathione S-transferase (GST) activity, glutathione (GSH), malondialdehyde, chlorophyll and total soluble protein contents, were investigated on the needles of Cedrus libani (A. Rich.) grown around two industrial areas in Eskisehir. The measurements revealed that metabolism in needles of C. libani trees is largely directed towards defence against ROS, due to effects of air pollution in the sampling areas. We observed significant increases in all parameters, except chlorophyll contents, which were strongly decreased. However, these sharp changes were also prominent not only between sampling sites and control site, but also among the areas investigated, suggesting the quantitative influence of the extent of pollution. Together with total soluble protein contents, the correlation between GST activities and GSH contents suggests that damage due to oxidative stress was most probably reduced due to the increased antioxidant capacity. Therefore, we can suggest C. libani as a good model for biomonitoring atmospheric quality with the oxidative stress parameters providing an effective measure for early environmental assessment due to their sensitivities of even low levels of pollution. PMID- 25716305 TI - Mechanics of the brain: perspectives, challenges, and opportunities. AB - The human brain is the continuous subject of extensive investigation aimed at understanding its behavior and function. Despite a clear evidence that mechanical factors play an important role in regulating brain activity, current research efforts focus mainly on the biochemical or electrophysiological activity of the brain. Here, we show that classical mechanical concepts including deformations, stretch, strain, strain rate, pressure, and stress play a crucial role in modulating both brain form and brain function. This opinion piece synthesizes expertise in applied mathematics, solid and fluid mechanics, biomechanics, experimentation, material sciences, neuropathology, and neurosurgery to address today's open questions at the forefront of neuromechanics. We critically review the current literature and discuss challenges related to neurodevelopment, cerebral edema, lissencephaly, polymicrogyria, hydrocephaly, craniectomy, spinal cord injury, tumor growth, traumatic brain injury, and shaken baby syndrome. The multi-disciplinary analysis of these various phenomena and pathologies presents new opportunities and suggests that mechanical modeling is a central tool to bridge the scales by synthesizing information from the molecular via the cellular and tissue all the way to the organ level. PMID- 25716307 TI - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. AB - RATIONALE: While brain serotonin (5-HT) function is implicated in gene-by environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. OBJECTIVE: Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. RESULTS: Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2(-/-)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2(-/-) males displayed increased impulsivity and high aggressiveness. Tph2(-/-) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2(-/-) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. CONCLUSIONS: Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality. PMID- 25716308 TI - Altered spontaneous brain activity in heavy smokers revealed by regional homogeneity. AB - RATIONALE: Task-state and resting-state functional magnetic resonance imaging (fMRI) studies have revealed different brain responses in chronic cigarette smokers compared with healthy controls. However, little is known about the differences between chronic cigarette smokers and healthy subjects regarding the local synchronization of spontaneous brain activity in the resting state. OBJECTIVES: In this study, we used regional homogeneity (ReHo) analysis based on resting-state fMRI to investigate intrinsic brain activity in heavy smokers. METHODS: Thirty-one heavy smokers and 33 healthy non-smokers were included in this study. ReHo was used to measure spontaneous brain activity, and whole-brain voxel-wise comparisons of ReHo were performed to detect brain regions with altered spontaneous brain activity between groups. RESULTS: Compared with non smokers, heavy smokers showed decreased ReHo primarily in brain regions associated with the default-mode, frontoparietal attention, and inhibitory control networks; heavy smokers showed increased ReHo predominately in regions related to motor planning. CONCLUSIONS: Our results suggest that heavy smokers may have altered spontaneous brain activity in some brain regions that are associated with higher cognitive networks. Moreover, our study improves the understanding of the effects of chronic cigarette smoking on spontaneous brain activity and the pathophysiological mechanisms of nicotine dependence. PMID- 25716309 TI - Cardioprotective activity of iron oxide nanoparticles. AB - Iron oxide nanoparticles (IONPs) are chemically inert materials and have been mainly used for imaging applications and drug deliveries. However, the possibility whether they can be used as therapeutic drugs themselves has not yet been explored. We reported here that Fe2O3 nanoparticles (NPs) can protect hearts from ischemic damage at the animal, tissue and cell level. The cardioprotective activity of Fe2O3 NPs requires the integrity of nanoparticles and is not dependent upon their surface charges and molecules that were integrated into nanoparticles. Also, Fe2O3 NPs showed no significant toxicity towards normal cardiomyocytes, indicative of their potential to treat cardiovascular diseases. PMID- 25716310 TI - Postoperative complications affect long-term survival outcomes following hepatic resection for colorectal liver metastasis. AB - BACKGROUND: The impact of postoperative complications (POCs) on long-term survival outcomes following hepatic resection for colorectal liver metastasis (CRLM) is in controversy. The aim of the present meta-analysis was to systematically evaluate the POC effect on overall survival (OS) and disease-free survival (DFS) in patients undergoing hepatic resection for CRLM. METHODS: We conducted a systematic review and meta-analysis of all observational studies to evaluate the POC effect on OS and DFS in patients undergoing hepatic resection for CRLM. A search for all major databases and relevant journals from inception to January 2014 without restriction on languages or regions was performed. POCs were extracted and graded according to a validated system of classification. Outcome measures were postoperative 1-, 2-, 3-, and 10-year OSs and DFSs. Both random-effects and fixed-effect models were used to pool the hazard ratios (HRs) of the survival outcomes. Test of heterogeneity was performed with the Q statistic. RESULTS: A total of 2370 patients were included in the meta-analysis. Both 5- and 10-year postoperative OSs showed significant decreases in patients with POCs (HR = 1.52; 95 % CI 1.27-1.83; P < 0.001 and HR = 1.36; 95 % CI 1.18 1.58; P < 0.001, respectively). Similar outcomes were also observed in terms of DFSs, with the 5- and 10-year HRs found to be 1.37 (95 % CI 1.23-1.53; P < 0.001) and 1.34 (95 % CI 1.17-1.53; P < 0.001), respectively, compared to no POC group. CONCLUSIONS: POCs are strongly related to long-term oncologic outcomes following hepatic resection for CRLM. Further efforts to refine surgical technique and postoperative management to avoid complications may improve the long-term oncological outcomes of the selected patients. PMID- 25716311 TI - Diabetes and ischemic heart disease death in people age 25-54: a multiple-cause of-death analysis based on over 400 000 deaths from 1990 to 2008 in New York City. AB - BACKGROUND: Over the past decade, ischemic heart disease (IHD) mortality trends have been less favorable among adults age 25-54 than age >=55 years. HYPOTHESIS: Disorders associated with IHD such as diabetes, chronic inflammatory and infectious diseases, and cocaine use are important contributors to premature IHD mortality. METHODS: Multiple-cause-of-death analysis was performed using the New York City (NYC) Vital Statistics database. Frequencies of selected contributing causes on death records with IHD as the underlying cause for decedents age >=25 were assessed (n = 418,151; 1990-2008). Concurrent Telephone risk-factor surveys (NYC Community Health Survey, Centers for Disease Control Behavioral Risk Factor Survey in New York State) were analyzed. RESULTS: In sum, a prespecified contributing cause was identified on 13.6% of death certificates for IHD decedents age 25-54. Diabetes was reported more frequently for younger IHD decedents (15% of females and 10% of males age 25-54 vs 6% of both sexes age >= 55). In contrast, concurrent diabetes prevalence in New York State was 3.4% for those age 25-54 and 13.6% for those age >55 (P < 0.0001). Systemic lupus erythematosus, human immunodeficiency virus, and cocaine were also more likely to contribute to IHD death among younger than older people. CONCLUSIONS: Diabetes may be a potent risk factor for IHD death in young people, particularly young women, in whom it was reported on IHD death records at a rate 5* higher than local prevalence. The high frequency of reporting of studied contributing causes in younger IHD decedents may provide a focus for further IHD mortality-reduction efforts in younger adults. PMID- 25716313 TI - GSTO1*C/GSTO2*G haplotype is associated with risk of transitional cell carcinoma of urinary bladder. AB - PURPOSE: To clarify the role of genetic polymorphisms of GSTO1 (rs4925) and GSTO2 (rs156697) in individual susceptibility to urinary bladder cancer. METHODS: Case control study consisting of 187 patients with histologically confirmed transitional cell carcinoma (TCC) of urinary bladder and 140 age- and gender matched cancer-free controls was carried out. Genotyping of GSTO1 and GSTO2 was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: We found that carriers of mutant GSTO2*G/G genotype were at increased risk of the development of TCC (OR 2.6, 95% CI 1.2-5.8, p = 0.041), while GSTO1 rs4925 polymorphism was not significantly associated with TCC risk (p = 0.450). According to smoking status, smokers with GSTO2*G/G genotype had significantly higher risk of TCC of urinary bladder (OR 4.3, 95% CI 1.6-11.2, p = 0.003) compared to wild-type carriers with no smoking history. We further analyzed the effects of GSTO1/GSTO2 haplotypes on TCC risk, based on the linkage disequilibrium found for GSTO1 (rs4925) and GSTO2 (rs156697) (D' = 0.309, p = 0.001). The study subjects with GSTO1*C/GSTO2*G (GSTO1 wild-type/GSTO2 mutant) haplotype were at the highest risk of the development of transitional cell carcinoma of urinary bladder (OR 2.8, 95% CI 1.5-5.2, p = 0.002). CONCLUSIONS: Our results indicate that GSTO1*C/GSTO2*G haplotype is associated with increased risk of TCC. The modifying effect of GSTO2*G/G genotype on individual susceptibility to TCC is more pronounced, when associated with smoking. PMID- 25716314 TI - Misdiagnoses caused by use of indwelling urethral catheters in children with ureterovesical junction anomalies. AB - PURPOSE: Children commonly undergo vesicograms for diagnosing vesicoureteral reflux (VUR). This requires urethral catheterization with transurethral replacement. We report misdiagnosed or related complications due to indwelling urethral catheters unintentionally placed in the ureter. METHODS: From our computerized urology records over an 18-year period from January 1995 to May 2013, we retrospectively identified nine cases of 1850 vesicograms that had misdirection of a urethral catheter placed in a ureter. Foley catheters with inflating balloons were used to obtain the vesicograms. RESULTS: In all, 1850 vesicograms were performed (746 males, 1104 females; age 1 week to 14 years, mean age 3.8 years) using standard radiological techniques. Size 6-10 Fr indwelling urethral catheters were used, depending on the patient's age and gender. In nine cases (five females, four males), a misdirected urethral catheter was discovered in one of the ureters. The urethral catheter was in the left ureter in four patients and in the right ureter in five patients. Cystoscopic examination found ectopic ureteral openings in six patients: at the bladder neck in four and just below the bladder trigone in two. Three patients in this group with ectopic ureters were followed due a misdiagnosis of VUR. The remaining three patients had grade 3 or 4 VUR. In this group, the catheter passed into the ureter because of the enlarged ureterovesical junction. In one patient with VUR, intraparenchymal fluid leakage and transient hematuria occurred due to the rapid tension increase following the fast injection of contrast with liquid to one ureter. CONCLUSION: Although placing an indwelling urethral catheter is a relatively safe procedure, complications can occur, particularly in patients with ureterovesical anomalies, such as high-grade VUR or an ectopic ureter. Using catheters with inflating balloons can cause rapid increases in tension in the ureter, and related complications. PMID- 25716315 TI - Nitric oxide induction of Parkin translocation in PTEN-induced putative kinase 1 (PINK1) deficiency: functional role of neuronal nitric oxide synthase during mitophagy. AB - The failure to trigger mitophagy is implicated in the pathogenesis of familial Parkinson disease that is caused by PINK1 or Parkin mutations. According to the prevailing PINK1-Parkin signaling model, mitophagy is promoted by the mitochondrial translocation of Parkin, an essential PINK1-dependent step that occurs via a previously unknown mechanism. Here we determined that critical concentrations of NO was sufficient to induce the mitochondrial translocation of Parkin even in PINK1 deficiency, with apparent increased interaction of full length PINK1 accumulated during mitophagy, with neuronal nitric oxide synthase (nNOS). Specifically, optimum levels of NO enabled PINK1-null dopaminergic neuronal cells to regain the mitochondrial translocation of Parkin, which appeared to be significantly suppressed by nNOS-null mutation. Moreover, nNOS null mutation resulted in the same mitochondrial electron transport chain (ETC) enzyme deficits as PINK1-null mutation. The involvement of mitochondrial nNOS activation in mitophagy was further confirmed by the greatly increased interactions of full-length PINK1 with nNOS, accompanied by mitochondrial accumulation of phospho-nNOS (Ser(1412)) during mitophagy. Of great interest is that the L347P PINK1 mutant failed to bind to nNOS. The loss of nNOS phosphorylation and Parkin accumulation on PINK1-deficient mitochondria could be reversed in a PINK1-dependent manner. Finally, non-toxic levels of NO treatment aided in the recovery of PINK1-null dopaminergic neuronal cells from mitochondrial ETC enzyme deficits. In summary, we demonstrated the full-length PINK1-dependent recruitment of nNOS, its activation in the induction of Parkin translocation, and the feasibility of NO-based pharmacotherapy for defective mitophagy and ETC enzyme deficits in Parkinson disease. PMID- 25716316 TI - Oligomerization of the polycystin-2 C-terminal tail and effects on its Ca2+ binding properties. AB - Polycystin-2 (PC2) belongs to the transient receptor potential (TRP) family and forms a Ca(2+)-regulated channel. The C-terminal cytoplasmic tail of human PC2 (HPC2 Cterm) is important for PC2 channel assembly and regulation. In this study, we characterized the oligomeric states and Ca(2+)-binding profiles in the C terminal tail using biophysical approaches. Specifically, we determined that HPC2 Cterm forms a trimer in solution with and without Ca(2+) bound, although TRP channels are believed to be tetramers. We found that there is only one Ca(2+) binding site in the HPC2 Cterm, located within its EF-hand domain. However, the Ca(2+) binding affinity of the HPC2 Cterm trimer is greatly enhanced relative to the intrinsic binding affinity of the isolated EF-hand domain. We also employed the sea urchin PC2 (SUPC2) as a model for biophysical and structural characterization. The sea urchin C-terminal construct (SUPC2 Ccore) also forms trimers in solution, independent of Ca(2+) binding. In contrast to the human PC2, the SUPC2 Ccore contains two cooperative Ca(2+)-binding sites within its EF-hand domain. Consequently, trimerization does not further improve the affinity of Ca(2+) binding in the SUPC2 Ccore relative to the isolated EF-hand domain. Using NMR, we localized the Ca(2+)-binding sites in the SUPC2 Ccore and characterized the conformational changes in its EF-hand domain due to trimer formation. Our study provides a structural basis for understanding the Ca(2+)-dependent regulation of the PC2 channel by its cytosolic C-terminal domain. The improved methodology also serves as a good strategy to characterize other Ca(2+)-binding proteins. PMID- 25716317 TI - Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction. AB - The signaling pathway downstream of TNF receptor (TNFR) is involved in the induction of a wide range of cellular processes, including cell proliferation, activation, differentiation, and apoptosis. TNFR-associated factor 2 (TRAF2) is a key adaptor molecule in TNFR signaling complexes that promotes downstream signaling cascades, such as nuclear factor-kappaB (NF-kappaB) and mitogen activated protein kinase activation. TRAF-interacting protein (TRIP) is a known cellular binding partner of TRAF2 and inhibits TNF-induced NF-kappaB activation. Recent findings that TRIP plays a multifunctional role in antiviral response, cell proliferation, apoptosis, and embryonic development have increased our interest in exploring how TRIP can affect the TNFR-signaling pathway on a molecular level. In our current study, we demonstrated that TRIP is negatively involved in the TNF-induced inflammatory response through the down-regulation of proinflammatory cytokine production. Here, we demonstrated that the TRAF2-TRIP interaction inhibits Lys(63)-linked TRAF2 ubiquitination by inhibiting TRAF2 E3 ubiquitin (Ub) ligase activity. The TRAF2-TRIP interaction inhibited the binding of sphingosine 1-phosphate, which is a cofactor of TRAF2 E3 Ub ligase, to the TRAF2 RING domain. Finally, we demonstrated that TRIP functions as a negative regulator of proinflammatory cytokine production by inhibiting TNF-induced NF kappaB activation. These results indicate that TRIP is an important cellular regulator of the TNF-induced inflammatory response. PMID- 25716319 TI - Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype. AB - Hyaluronan (HA) promotes transforming growth factor (TGF)-beta1-driven myofibroblast phenotype. However, HA can also have disease-limiting activity. Bone morphogenetic protein-7 (BMP7) is an antifibrotic cytokine that antagonizes TGF-beta1, and isolated studies have demonstrated that HA can both mediate and modulate BMP7 responses. In this study, we investigated whether BMP7 can modulate HA in a manner that leads to prevention/reversal of TGF-beta1-driven myofibroblast differentiation in human lung fibroblasts. Results demonstrated that BMP7 prevented and reversed TGF-beta1-driven myofibroblast differentiation through a novel mechanism. BMP7 promoted the dissolution and internalization of cell-surface HA into cytoplasmic endosomes. Endosomal HA co-localized with the HA degrading enzymes, hyaluronidase-1 and hyaluronidase-2 (Hyal2). Moreover, BMP7 showed differential regulation of CD44 standard and variant isoform expression, when compared with TGF-beta1. In particular, BMP7 increased membrane expression of CD44v7/8. Inhibiting CD44v7/8 as well as blocking Hyal2 and the Na(+)/H(+) exchanger-1 at the cell-surface prevented BMP7-driven HA internalization and BMP7 mediated prevention/reversal of myofibroblast phenotype. In summary, a novel mechanism of TGF-beta1 antagonism by BMP7 is shown and identifies alteration in HA as critical in mediating BMP7 responses. In addition, we identify Hyal2 and CD44v7/8 as new potential targets for manipulation in prevention and reversal of fibrotic pathology. PMID- 25716318 TI - Munc18a does not alter fusion rates mediated by neuronal SNAREs, synaptotagmin, and complexin. AB - Sec1/Munc18 (SM) proteins are essential for membrane trafficking, but their molecular mechanism remains unclear. Using a single vesicle-vesicle content mixing assay with reconstituted neuronal SNAREs, synaptotagmin-1, and complexin 1, we show that the neuronal SM protein Munc18a/nSec1 has no effect on the intrinsic kinetics of both spontaneous fusion and Ca(2+)-triggered fusion between vesicles that mimic synaptic vesicles and the plasma membrane. However, wild type Munc18a reduced vesicle association ~50% when the vesicles bearing the t-SNAREs syntaxin-1A and SNAP-25 were preincubated with Munc18 for 30 min. Single molecule experiments with labeled SNAP-25 indicate that the reduction of vesicle association is a consequence of sequestration of syntaxin-1A by Munc18a and subsequent release of SNAP-25 (i.e. Munc18a captures syntaxin-1A via its high affinity interaction). Moreover, a phosphorylation mimic mutant of Munc18a with reduced affinity to syntaxin-1A results in less reduction of vesicle association. In summary, Munc18a does not directly affect fusion, although it has an effect on the t-SNARE complex, depending on the presence of other factors and experimental conditions. Our results suggest that Munc18a primarily acts at the prefusion stage. PMID- 25716320 TI - Sestrin 2 protein regulates platelet-derived growth factor receptor beta (Pdgfrbeta) expression by modulating proteasomal and Nrf2 transcription factor functions. AB - We recently identified the antioxidant protein Sestrin 2 (Sesn2) as a suppressor of platelet-derived growth factor receptor beta (Pdgfrbeta) signaling and Pdgfrbeta signaling as an inducer of lung regeneration and injury repair. Here, we identified Sesn2 and the antioxidant gene inducer nuclear factor erythroid 2 related factor 2 (Nrf2) as positive regulators of proteasomal function. Inactivation of Sesn2 or Nrf2 induced reactive oxygen species-mediated proteasomal inhibition and Pdgfrbeta accumulation. Using bacterial artificial chromosome (BAC) transgenic HeLa and mouse embryonic stem cells stably expressing enhanced green fluorescent protein-tagged Sesn2 at nearly endogenous levels, we also showed that Sesn2 physically interacts with 2-Cys peroxiredoxins and Nrf2 albeit under different reductive conditions. Overall, we characterized a novel, redox-sensitive Sesn2/Pdgfrbeta suppressor pathway that negatively interferes with lung regeneration and is up-regulated in the emphysematous lungs of patients with chronic obstructive pulmonary disease (COPD). PMID- 25716323 TI - Properties of gelatin film from horse mackerel (Trachurus japonicus) scale. AB - Optimal conditions for extracting gelatin and preparing gelatin film from horse mackerel scale, such as extraction temperature and time, as well as the protein concentration of film-forming solutions were investigated. Yields of extracted gelatin at 70 degrees C, 80 degrees C, and 90 degrees C for 15 min to 3 h were 1.08% to 3.45%, depending on the extraction conditions. Among the various extraction times and temperatures, the film from gelatin extracted at 70 degrees C for 1 h showed the highest tensile strength and elongation at break. Horse mackerel scale gelatin film showed the greatly low water vapor permeability (WVP) compared with mammalian or fish gelatin films, maybe due to its containing a slightly higher level of hydrophobic amino acids (total 653 residues per 1000 residues) than that of mammalian, cold-water fish and warm-water fish gelatins. Gelatin films from different preparation conditions showed excellent UV barrier properties at wavelength of 200 nm, although the films were transparent at visible wavelength. As a consequence, it can be suggested that gelatin film from horse mackerel scale extracted at 70 degrees C for 1 h can be applied to food packaging material due to its lowest WVP value and excellent UV barrier properties. PMID- 25716322 TI - Type I interferon controls propagation of long interspersed element-1. AB - Type I interferons (IFN) including IFNalpha and IFNbeta are critical for the cellular defense against viruses. Here we report that increased levels of IFNbeta were found in testes from mice deficient in MOV10L1, a germ cell-specific RNA helicase that plays a key role in limiting the propagation of retrotransposons including Long Interspersed Element-1 (LINE-1). Additional experiments revealed that activation of LINE-1 retrotransposons increases the expression of IFNbeta and of IFN-stimulated genes. Conversely, pretreatment of cells with IFN suppressed the replication of LINE-1. Furthermore, the efficacy of LINE-1 replication was increased in isogenic cell lines harboring inactivating mutations in diverse elements of the IFN signaling pathway. Knockdown of the IFN receptor chain IFNAR1 also stimulated LINE-1 propagation in vitro. Finally, a greater accumulation of LINE-1 was found in mice that lack IFNAR1 compared with wild type mice. We propose that LINE-1-induced IFN plays an important role in restricting LINE-1 propagation and discuss the putative role of IFN in preserving the genome stability. PMID- 25716321 TI - Synaptotagmin-1 is an antagonist for Munc18-1 in SNARE zippering. AB - In neuroexocytosis, SNAREs and Munc18-1 may consist of the minimal membrane fusion machinery. Consistent with this notion, we observed, using single molecule fluorescence assays, that Munc18-1 stimulates SNARE zippering and SNARE-dependent lipid mixing in the absence of a major Ca(2+) sensor synaptotagmin-1 (Syt1), providing the structural basis for the conserved function of Sec1/Munc18 proteins in exocytosis. However, when full-length Syt1 is present, no enhancement of SNARE zippering and no acceleration of Ca(2+)-triggered content mixing by Munc18-1 are observed. Thus, our results show that Syt1 acts as an antagonist for Munc18-1 in SNARE zippering and fusion pore opening. Although the Sec1/Munc18 family may serve as part of the fusion machinery in other exocytotic pathways, Munc18-1 may have evolved to play a different role, such as regulating syntaxin-1a in neuroexocytosis. PMID- 25716324 TI - Finite element modelling of human-seat interactions: vertical in-line and fore and-aft cross-axis apparent mass when sitting on a rigid seat without backrest and exposed to vertical vibration. AB - Biodynamic models representing distributed human-seat interactions can assist seat design. This study sought to develop a finite element (FE) model representing the soft tissues of the body supported by seating and the vertical in-line apparent mass and the fore-and-aft cross-axis apparent mass of the seated human body during vertical vibration excitation. The model was developed with rigid parts representing the torso segments, skeletal structures (pelvis and femurs) and deformable parts representing the soft tissues of the buttocks and the thighs. The model had three vibration modes at frequencies less than 15 Hz and provided reasonable vertical in-line apparent mass and fore-and-aft cross axis apparent mass. The model can be developed to represent dynamic interactions between the body and a seat over a seat surface (e.g. dynamic pressure distributions and variations in seat transmissibility over the seat surface). PRACTITIONER SUMMARY: The three-dimensional FE model of the human body represents the in-line apparent mass and cross-axis apparent mass measured on a seat. With deformable soft tissues it can assist seat design by representing dynamic human seat interactions, such as pressure distributions and variations in seat transmissibility over a seat surface. PMID- 25716325 TI - Muscle activity amplitudes and co-contraction during stair ambulation following anterior cruciate ligament reconstruction. AB - The purpose of this study was to compare muscle activity amplitudes and co contraction in those with anterior cruciate ligament (ACL) reconstruction to healthy controls during stair negotiation. Eighteen participants with unilateral ACL reconstruction and 17 healthy controls performed stair ascent and descent while surface electromyography was recorded from knee and hip musculature. During stair ascent, the ACL group displayed higher gluteus maximus activity (1-50% stance, p = 0.02), higher vastus lateralis:biceps femoris co-contraction (51-100% stance, p = 0.01), and higher vastus lateralis:vastus medialis co-contraction (51 100% stance, p = 0.05). During stair descent, the ACL group demonstrated higher gluteus maximus activity (1-50% stance, p = 0.01; 51-100% stance, p < 0.01), lower rectus femoris activity (1-50% stance, p = 0.04), higher semimembranosus activity (1-50% stance, p=0.01), higher gluteus medius activity (51-100% stance, p = 0.01), and higher vastus medialis:semimembranosus co-contraction (1-50% stance, p = 0.02). While the altered muscle activity strategies observed in the ACL group may act to increase joint stability, these strategies may alter joint loading and contribute to post-traumatic knee osteoarthritis often observed in this population. Our results warrant further investigation to determine the longterm effects of altered muscle activity on the knee joint following ACL reconstruction. PMID- 25716326 TI - Leg stiffness of older and younger individuals over a range of hopping frequencies. AB - The purpose of this study was to compare spring-mass behavior between older and younger individuals at a range of hopping frequencies. A total of 14 elderly and 14 young subjects performed in-place hopping in time with a metronome at frequencies of 2.2, 2.6, and 3.0 Hz. Using a spring-mass model, leg stiffness was calculated as the ratio of maximum ground reaction force to maximum center of mass displacement at the middle of the stance phase during ground contact. The lower extremities of both groups behaved like a simple spring-mass system at all three hopping frequencies. Further, statistical analysis revealed the existence of a significant interaction between hopping frequency and age group on leg stiffness. These results suggest that the sensitivity of leg stiffness to accommodate for variations in hopping frequency is likely to differ between elderly and young individuals. PMID- 25716328 TI - Luminescence in the fluoride-containing phosphate-based glasses: a possible origin of their high resistance to nanosecond pulse laser-induced damage. AB - Fusion power offers the prospect of an almost inexhaustible source of energy for future generations. It was reported that fusion fuel gains exceeding unity on the National Ignition Facility (NIF) were achieved, but so far great deal of scientific and engineering challenges have to be overcome for realizing fusion power generation. There is a bottleneck for color-separation gratings in NIF and other similar inertial confinement fusion (ICF) lasers. Here we show a series of high performance phosphate-based glasses that can transmit the third harmonic frequency (3omega) laser light with high efficiency meanwhile filter the fundamental (1omega) and the second harmonic frequency (2omega) laser lights through direct absorption, and especially they exhibit excellent damage threshold induced by nanosecond pulse laser compared with that of the fused silica used in NIF. Yellowish-orange fluorescence emits during the laser-material interaction process, and it can be tailored through regulating the glass structure. Study on its structural origin suggests that the fluorescence emission is a key factor that conduces to the high laser-induced damage resistance of these glasses. The results also indicated the feasibility of utilizing these high performance glasses in novel color separation optics, allowing novel design for the final optics assembly in ICF lasers. PMID- 25716327 TI - Differences in muscle activity patterns and graphical product quality in children copying and tracing activities on horizontal or vertical surfaces. AB - The observation that a given task, e.g. producing a signature, looks similar when created by different motor commands and different muscles groups is known as motor equivalence. Relatively little data exists regarding the characteristics of motor equivalence in children. In this study, we compared the level of performance when performing a tracing task and copying figures in two common postures: while sitting at a desk and while standing in front of a wall, among preschool children. In addition, we compared muscle activity patterns in both postures. Specifically, we compared the movements of 35 five- to six-year old children, recording the same movements of copying figures and path tracing on an electronic tablet in both a horizontal orientation, while sitting, and a vertical orientation, while standing. Different muscle activation patterns were observed between the postures, however no significant difference in the performance level was found, providing evidence of motor equivalence at this young age. The study presents a straightforward method of assessing motor equivalence that can be extended to other stages of development as well as motor disorders. PMID- 25716329 TI - Fabrication and In Vitro/In Vivo Performance of Mucoadhesive Electrospun Nanofiber Mats Containing alpha-Mangostin. AB - This study aimed to fabricate mucoadhesive electrospun nanofiber mats containing alpha-mangostin for the maintenance of oral hygiene and reduction of the bacterial growth that causes dental caries. Synthesized thiolated chitosan (CS SH) blended with polyvinyl alcohol (PVA) was selected as the mucoadhesive polymer. alpha-Mangostin was incorporated into the CS-SH/PVA solution and electrospun to obtain nanofiber mats. Scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and tensile strength testing were used to characterize the mats. The swelling degree and mucoadhesion were also determined. The nanofiber mats were further evaluated regarding their alpha mangostin content, in vitro alpha-mangostin release, antibacterial activity, cytotoxicity, in vivo performance, and stability. The results indicated that the mats were in the nanometer range. The alpha-mangostin was well incorporated into the mats, with an amorphous form. The mats showed suitable tensile strength, swelling, and mucoadhesive properties. The loading capacity increased when the initial amount of alpha-mangostin was increased. Rapid release of alpha-mangostin from the mats was achieved. Additionally, a fast bacterial killing rate occurred at the lowest concentration of nanofiber mats when alpha-mangostin was added to the mats. The mats were less cytotoxic after use for 72 h. Moreover, in vivo testing indicated that the mats could reduce the number of oral bacteria, with a good mouth feel. The mats maintained the amount of alpha-mangostin for 6 months. The results suggest that alpha-mangostin-loaded mucoadhesive electrospun nanofiber mats may be a promising material for oral care and the prevention of dental caries. PMID- 25716330 TI - Exploring Microstructural Changes in Structural Analogues of Ibuprofen-Hosted In Situ Gelling System and Its Influence on Pharmaceutical Performance. AB - The present work explores inner structuration of in situ gelling system consisting of glyceryl monooleate (GMO) and oleic acid (OA). The system under study involves investigation of microstructural changes which are believed to govern the pharmaceutical performance of final formulation. The changes which are often termed mesophasic transformation were analysed by small angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), rheology and plane polarised light (PPL) microscopy. The current work revealed transformation of blank system from W/O emulsion to reverse hexagonal structure upon addition of structural analogues of ibuprofen. Such transformations are believed to occur due to increased hydrophobic volume within system as probed by SAXS analysis. The findings of SAXS studies were well supported by DSC, rheology and PPL microscopy. The study established inverse relationship between log P value of structural analogues of ibuprofen and the degree of binding of water molecules to surfactant chains. Such relationship had pronounced effect on sol-gel transformation process. The prepared in situ gelling system showed sustained drug release which followed Higuchi model. PMID- 25716331 TI - The Design of Nanostructured Metronidazole-Loaded HPC/Oxide Xerogel Composites: Influence of the Formulation Parameters on In Vitro Characterisation. AB - In this study, oxide and polymer/oxide xerogels with metronidazole were prepared and examined as carriers of drug for the local application to the bone. The nanoporous SiO2-CaO-P2O5 and HPC-SiO2-CaO-P2O5 xerogel materials with different amounts of the polymer [hydroxypropyl cellulose (HPC)] were prepared using the sol-gel technology, and their physicochemical properties were characterised with respect to chemical structure [by Fourier transform infrared spectroscopy (FTIR)], porosity and the specific surface area of solids (BET), crystallinity [by X-ray powder diffraction (XRD)], morphology [by scanning electron microscope (SEM)] and the in vitro release of the metronidazole over time (by UV-vis spectroscopy, in the ultraviolet light region). HPC-modified oxide xerogels as the carriers of drug showed slower release of metronidazole, due to the structure and stronger interactions with drug as compared with the pure oxide xerogel. Kinetic analysis indicated diffusional mechanism of drug release from all xerogel carriers. HPC addition to the oxide material resulted in a decrease in the porosity and improved the bioactive properties of xerogels. Obtained results for xerogel composites suggest that the metronidazole-loaded xerogels could be attractive candidates for local delivery systems particularly to a bone. PMID- 25716332 TI - How many cancer deaths could New Zealand avoid if five-year relative survival ratios were the same as in Australia? AB - AIM: To determine how many Maori and non-Maori deaths might have been avoidable if cancer survival in New Zealand were as high as in Australia. METHODS: Age-sex tumour specific five-year relative survival ratios were calculated for cancer patients diagnosed with 27 tumour sites (representing about 92% of all cancers) in 2006-10. These were used to estimate the number of Maori, non-Maori and total deaths (and proportion of excess deaths) that would have been avoidable within five years of diagnosis had New Zealand's relative survival been equivalent to Australia's. RESULTS: A total of 3,631 cancer deaths (726/year; 13.4% of excess deaths) could have been avoidable. Among 25 tumours where ethnic-specific results were estimated, there were 851 potentially avoidable deaths in Maori (24.9%) and 2,758 in non-Maori (11.8%). Breast, bowel, lung and prostate tumours made up 64% of avoidable deaths. Those with the highest proportions of avoidable deaths were thyroid (44.7%), prostate (35.5%), breast (30.0%) and uterus (23.5%). More than 50% of Maori melanoma, prostate, testis and thyroid cancer deaths were avoidable. CONCLUSION: A significant number of cancer deaths could be avoidable if New Zealand achieved Australia's relative survival ratios. The proportion is much higher for Maori than for non-Maori. IMPLICATIONS: There is considerable scope to improve cancer outcomes in New Zealand. PMID- 25716333 TI - Insights into ALPPS. PMID- 25716335 TI - Cistus ladanifer L. Shrub is Rich in Saturated and Branched Chain Fatty Acids and their Concentration Increases in the Mediterranean Dry Season. AB - The Cistus ladanifer L. shrub is a widespread species of the Mediterranean region that is available as a feed source for ruminants all the year round, constituting a source of energy and nutrients when most of the vegetation is dry. However, there is no trustworthy information about the fatty acid composition of C. ladanifer, as well as no information about the seasonal and age related changes in their fatty acid composition. Thus, we collected the aerial parts of C. ladanifer plants of two age groups [young vs. older ones (2-6 years old)] during four consecutive seasons to characterize their fatty acid composition. The fatty acid composition of C. ladanifer is dominated by saturated fatty acids including the occurrence of two methyl branched chain fatty acids (BCFA), the iso-19:0 and iso-21:0, which as far as we know were detected for the first time in shrubs. Also, we demonstrated that several labdane type compounds might interfere with the fatty acid analysis of C. ladanifer. Marked seasonal changes in BCFA and polyunsaturated fatty acids (PUFA) were found, suggesting that BCFA can replace PUFA in plant lipids at high environmental temperatures. PMID- 25716334 TI - Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci. AB - The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 * 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart. Over 90% of these pairs are replicated (FDR<5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (P<0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states. PMID- 25716336 TI - Efficacy and Safety of Intravenous Thrombolysis for the Treatment of Acute Ischemic Stroke Patients with Saccular Intracranial Aneurysms of <=3 mm. AB - To explore the effectiveness and safety of intravenous thrombolysis (IVT) using recombinant tissue plasminogen activator in treating acute ischemic stroke patients with concomitant intracranial aneurysms (IA) of <=3 mm. Clinical data of patients who were treated in Tianjin Huanhu Hospital from June 2012 to September 2013 were retrospectively analyzed. Patients were divided into the following groups: (a) IVT group, in which there were 30 acute ischemic stroke patients with IA of <=3 mm and 30 patients without aneurysms; and (b) IA group, in which there were 30 patients who did not receive IVT and 30 patients who received IVT. The incidence of intracranial hemorrhage, case-fatality, and good outcome rate was compared within these two groups. Inside the IVT group, the incidence of systematic intracranial hemorrhage and case-fatality showed no significant differences between patients with concomitant IA and those without IA. The 3 month good outcome rate was also not significantly different (24 [80.0 %] vs. 27 [90 %]; P = 0.278). In IA group, patients who had received IVT showed significantly superior good outcome rate than those who had not received IVT (24 [80.0 %] vs. 16 [53.3 %]; P = 0.028).The incidence of intracranial hemorrhage and case-fatality rate were not significantly different between these two subgroups as well. IVT is effective and safe method for the treatment of acute ischemic stroke patients with saccular IA of <=3 mm. PMID- 25716337 TI - Recent Advances in the Diagnosis and Management of Bladder Cancer. AB - The most common malignancy of urinary tract is bladder cancer. It is one of the most widespread cancers of the world and ranks nine among frequent malignancies existing in world. The only solution to above burning problem is timely diagnosis at earlier stage, and the cancer research is being forwarded in this direction. There are various prominent gene modifications responsible for growth of bladder cancer. The present review is focused on recent advances in the field of cancer makers involving, genetic, urinary, pathological, etc., approaches to contain the deadly process of carcinogenesis. The present review provides an insight on the emerging biomarkers that could be developed to boost current bladder cancer detection strategies. This shall help timely diagnosis of this deadly disease at early stage, thereby, helping bladder cancer patients to fight against this iniquity of life. PMID- 25716338 TI - SOX9 Overexpression Promotes Glioma Metastasis via Wnt/beta-Catenin Signaling. AB - SOX9 gene encodes a transcription factor essential for a central role in the development and differentiation of multiple cell lineages, such as in neurogenesis, neural crest development, etc. Recent study reported that overexpression of SOX9 mRNA is closely associated with poor clinical outcome of patients with malignant gliomas. In the present study, we have explored the regulatory role of SOX9 in glioma metastasis. To investigate the role of SOX9 in glioma metastasis, SOX9 overexpressed in human glioma cell line U251 on cell migration and invasion was evaluated via wound scratch, Transwell assay without or with Matrigel. SOX9-induced changes in EMT process were evaluated by Western blot. Furthermore, the role of beta-catenin in the regulatory effect of SOX9 on cell migration and invasion, and EMT process was explored by suppressing beta catenin expression in SOX9-overexpressed U251 cells. SOX9 overexpression in U251 cells resulted in a significant increase in cell migration and invasion. SOX9 overexpression also markedly promoted the EMT process. More importantly, our results revealed that SOX9 stimulated metastasis through activating Wnt/beta catenin signaling. In summary, this study indicated that the promoting effect of SOX9 on glioma metastasis was, at least in part, through Wnt/beta-catenin signaling. The findings in this study highlight the effectiveness and therapeutic potential to utilize SOX9 targeted strategies in the treatment of glioma. PMID- 25716339 TI - Needs of caregivers of cancer patients: validation of the Mexican version of the Support Person Unmet Needs Survey (SPUNS-SFM). AB - PURPOSE: The purpose of this study was to validate the Mexican version of the Support Person Unmet Needs Survey (SPUNS-SFM). METHODS: A cross-sectional survey that included 826 primary caregivers of cancer patients was conducted from June to December 2013 at the Oncology Hospital of the Mexican Institute of Social Security in Mexico City. The validation procedure comprised (1) content validity through a group of experts; (2) construct validity through an exploratory factor analysis based on the polychoric correlation matrix; (3) internal consistency using Cronbach's alpha; (4) convergent validity between SPUNS-SFM and quality of life, anxiety-and-depression scales by calculating Spearman's rank correlation coefficient;( 5) discriminative validity through the Wilcoxon rank-sum test; and (6) test-retest reliability using intraclass correlation coefficient. RESULTS: SPUNS-SFM has 23 items with six factors accounting for 65 % of the total variance. The domains were concerns about the future, access and continuity of healthcare, information, work and finance, and personal and emotional needs. Cronbach's alpha values ranged from 0.70 to 0.88 among factors. SPUNS-SFM had moderate convergent validity compared with quality of life and depression-and anxiety scales and good discriminative validity, revealing high needs for younger caregivers and more emotional needs for caregivers of patients with advanced cancer stages. Intraclass correlation coefficient between SPUNS-SFM measurements was 0.78. CONCLUSION: SPUNS-SFM is a valid and reliable tool to identify needs of caregivers of cancer patients. PMID- 25716340 TI - Cognitive impairment in testicular cancer survivors 2 to 7 years after treatment. AB - PURPOSE: The aim of the present study was to determine the prevalence of cognitive impairment (CI) in a group of testicular (TC) survivors by comparing their neuropsychological test scores with normative data and to assess their performance in specific cognitive domains. METHODS: Seventy-two TC survivors were evaluated 2 to 7 years post-treatment with a neuropsychological test battery that assessed multiple cognitive domains-attention and working memory, processing speed, verbal fluency, learning and memory, and executive functioning. Test scores were compared with normative data, and CI status was calculated for each participant. RESULTS: In group-level analyses, survivors exhibited significantly impaired scores on a majority (9/12) of the neuropsychological outcomes (p < 0.01). In individual-level analyses, 62.5 % of the survivors were classified as having CI, significantly exceeding the expected normative frequency of 25 % (binomial test: p < 0.001). In particular, CI was observed in multiple outcomes related to verbal learning and memory (29 to 33 % of participants), visual learning and memory (14-28 %), processing speed (8-24 %), executive functioning (17 %), and attention and working memory (4-15 %). No association was found between treatment modality (surgery +/- chemotherapy) and CI. CONCLUSIONS: The prevalence of CI in TC survivors was unexpectedly high, with survivors performing significantly worse than expected on a majority of the neuropsychological outcomes. While the findings are preliminary in nature, they still have important implications for the diagnosis and treatment of CI in TC survivors. PMID- 25716341 TI - Medical comorbidity and psychotropic medication fills in older adults with breast or prostate cancer. AB - BACKGROUND: Previous research has shown that as people age, distress decreases despite an increase in prevalence of medical comorbidity. This could be due to increased use of psychotropic medications with comorbidity. We tested this hypothesis in older adults. METHODS: Information from medical records of older adults (65 to 99 years of age) in the following groups was collected: women with breast cancer (n = 2359), women without any cancer diagnosis (n = 27,161), men with prostate cancer (n = 2686), and men without any cancer diagnosis (n = 21,014). We collected fills of antidepressant or sedative medications, diagnosis of depression in the year of cancer diagnosis, and Charlson Comorbidity Index from the year before cancer. RESULTS: Women with breast cancer were more likely to fill psychotropic prescriptions (both ps < 0.02) or be diagnosed with depression (p < 0.001) than women without cancer. Men with prostate cancer were more likely to fill these prescriptions or receive a diagnosis of depression than men without cancer (ps < 0.05). Charlson was related to increased odds of filling both types of medication in women with breast cancer and men with prostate cancer (ps < 0.001). Comorbidity was related to greater odds of receiving a depression diagnosis in men with prostate cancer (p < 0.001) but not women with breast cancer (p > 0.15). CONCLUSIONS: Older adults with breast or prostate cancer are more likely to fill psychotropic medication prescriptions and receive a depression diagnosis than those without cancer. Comorbidity increased the likelihood of medication fills in older adults with cancer. As this population experiences polypharmacy, nonpharmacologic treatments for depression may need to be considered. PMID- 25716343 TI - In silico prediction of MOFs with high deliverable capacity or internal surface area. AB - Metal-organic frameworks (MOFs) offer unprecedented atom-scale design and structural tunability, largely due to the vast number of possible organic linkers which can be utilized in their assembly. Exploration of this space of linkers allows identification of ranges of achievable material properties as well as discovery of optimal materials for a given application. Experimental exploration of the linker space has to date been quite limited due to the cost and complexity of synthesis, while high-throughput computational studies have mainly explored MOF materials based on known or readily available linkers. Here an evolutionary algorithm for de novo design of organic linkers for metal-organic frameworks is used to predict MOFs with either high methane deliverable capacity or methane accessible surface area. Known chemical reactions are applied in silico to a population of linkers to discover these MOFs. Through this design strategy, MOF candidates are found in the ten symmetric networks acs, cds, dia, hxg, lvt, nbo, pcu, rhr, sod, and tbo. The correlation between deliverable capacities and surface area is network dependent. PMID- 25716342 TI - Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort. AB - Sporadic essential thrombocythaemia (ET) is rare in paediatrics, and the diagnostic and clinical approach to paediatric cases cannot be simply copied from experience with adults. Here, we assessed 89 children with a clinical diagnosis of ET and found that 23 patients (25.8%) had a clonal disease. The JAK2 V617F mutation was identified in 14 children, 1 child had the MPL W515L mutation, and 6 had CALR mutations. The monoclonal X-chromosome inactivation pattern was seen in six patients (two with JAK2 V617F and two with CALR mutations). The other 66 patients (74.2%) had persistent thrombocytosis with no clonality. There were no clinical or haematological differences between the clonal and non-clonal patients. The relative proportion of ET-specific mutations in the clonal children was much the same as in adults. The higher prevalence of non-clonal cases suggests that some patients may not have myeloproliferative neoplasms, with significant implications for their treatment. PMID- 25716344 TI - Synthesis of zinc phthalocyanine with large steric hindrance and its photovoltaic performance for dye-sensitized solar cells. AB - A zinc phthalocyanine (ZnPc) derivative (Zn-tri-PcNc-8) containing tri benzonaphtho-condensed porphyrazine with one carboxylic and six diphenylphenoxy peripheral substitutions was designed and synthesized as a sensitizer for dye sensitized solar cells (DSSCs). For the purpose of extending the absorption spectra while minimizing the formation of ZnPc molecular aggregates, bulky 2,6 diphenylphenoxy groups were used as electron donor moieties, and the carboxylic group as an anchoring group to graft the sensitizer onto the semiconductor. It was found that a TiO2-based solar cell sensitized by Zn-tri-PcNc-8 shows a maximum incident photon-to-current conversion efficiency in the red/near-IR light range (650-750 nm), and a solar cell sensitized at near room temperature (30 degrees C) for 48 h exhibits the best efficiency (3.01%). The efficiency was much higher than that (1.96%) for a solar cell sensitized by its analogue (Zn-tri-PcNc 2) having one carboxyl and three tert-butyl groups without chenodeoxycholic acid (CDCA), indicating that the introduction of six bulky diphenylphenoxy substitutions with large steric hindrance in the ZnPc macrocycle can effectively suppress the molecular aggregates, thus resulting in an improved conversion efficiency. The present results shed light on an effective solution to adjust the ZnPc property via chemical modification such as changing the "push-pull" effect and adding large steric hindrance substituents to further improve the efficiency of the phthalocyanine-sensitized solar cell. PMID- 25716345 TI - The EPR study of Mn(2+) ion doped KBr and VO(2+) ion doped KH2PO4 under high pressure. AB - In previous works under open atmosphere at various temperatures KBr host crystal never accepted paramagnetic Mn(2+) ion in its lattice, but KH2PO4 host crystal accepted VO(2+) ion in its lattice where K(+) ion substituted with VO(2+). In a series of works using high-pressure reactor at various pressures and temperatures under different gas atmospheres, Mn(2+) ion was inserted in KBr host, and VO(2+) ion was inserted in KH2PO4 host in sites different from those observed in previous works. The best results were obtained for Mn(2+) doped KBr at pressure of 100bars and 50 degrees C under Argon atmosphere, and for VO(2+) doped KH2PO4 at pressure of 100bars and temperature of 50 degrees C under oxygen atmosphere. The structural parameters of paramagnetic species formed were determined by EPR spectroscopy and optical transitions were determined by UV-Vis spectroscopy. PMID- 25716346 TI - Receptor tyrosine kinase inhibitors: Are they real tumor killers? AB - Inhibiting tumor growth by targeting the tumor vasculature was first proposed by Judah Folkman almost 40 years ago. Since then, different approaches and numerous drugs and agents have been developed to achieve this goal, either with the aim of inhibiting tumor neoangiogenesis or normalizing the tumor vasculature. Among the most promising therapeutic targets are receptor tyrosine kinases (RTKs), some of which are predominantly expressed on tumor endothelial cells, although they are sometimes also present on tumor cells. The majority of RTK inhibitors investigated over the past two decades competes with ATP at the active site of the kinase and therefore block the phosphorylation of intracellular targets. Some of these drugs have been approved for therapy, whereas others are still in clinical trials. Here, we discuss the scientific basis, current status, problems and future prospects of RTK inhibition in anti-tumor therapy. PMID- 25716347 TI - Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2. AB - Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid-induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERalpha, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. SIGNIFICANCE: We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERalpha-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer. PMID- 25716348 TI - Oral administration of dextran sodium sulphate induces a caecum-localized colitis in rabbits. AB - Trichuris suis ova (TSO) have shown promising results in the treatment of inflammatory bowel disease (IBD) but the mechanisms which underlies this therapeutic effect cannot be studied in mice and rats as T. suis fails to colonize the rodent intestine, whilst hatching in humans and rabbits. As a suitable rabbit IBD model is currently not available, we developed a rabbit colitis model by administration of dextran sodium sulphate (DSS). White Himalayan rabbits (n = 12) received 0.1% DSS in the daily water supply for five days. Clinical symptoms were monitored daily, and rabbits were sacrificed at different time points. A genomewide expression analysis was performed with RNA isolated from caecal lamina propria mononuclear cells (LPMC) and intestinal epithelial cells (IEC). The disease activity index of DSS rabbits increased up to 2.1 +/- 0.4 (n = 6) at day 10 (controls <0.5). DSS induced a caecum-localized pathology with crypt architectural distortion, stunted villous surface and inflammatory infiltrate in the lamina propria. The histopathology score reached a peak of 14.2 +/- 4.9 (n = 4) at day 10 (controls 7.7 +/- 0.9, n = 5). Expression profiling revealed an enrichment of IBD-related genes in both LPMC and IEC. Innate inflammatory response, Th17 signalling and chemotaxis were among the pathways affected significantly. We describe a reproducible and reliable rabbit model of DSS colitis. Localization of the inflammation in the caecum and its similarities to IBD make this model particularly suitable to study TSO therapy in vivo. PMID- 25716349 TI - Clinical care providers' perspectives on body size and weight management among long-term cancer survivors. AB - OBJECTIVE: To examine clinical care providers' perspectives on cancer survivors' body size and weight management. STUDY DESIGN: In-depth, semi-structured, qualitative interviews. METHODS: Interviews were conducted with 33 providers (eg. oncologists, surgeons, primary care providers, nurses, dietitians) across academic and community clinical settings. They were transcribed, coded, and analyzed thematically using constant comparative analysis. RESULTS: Providers conceptualized weight in relation to acute treatment, cancer outcomes, or overall health/comorbidities. These patterns were reflected in their reported framing of weight discussions, although providers indicated that they counsel patients on weight to varying extents. Perspectives differed based on professional roles and patient populations. Providers reported that survivors are motivated to lose weight, particularly due to comorbidity concerns, but face numerous barriers to doing so. CONCLUSION: Providers described survivor-level and capacity-level factors influencing survivors' weight management. Differences by provider type highlighted the role of provider knowledge, attitudes, and beliefs in clinical encounters. Opportunities for research and intervention include developing and disseminating evidence-based clinical resources for weight management among cancer survivors, addressing capacity barriers, and exploring communication strategies at interpersonal and population levels. PMID- 25716350 TI - Survey of Policies and Guidelines on Antioxidant Use for Cancer Prevention, Treatment, and Survivorship in North American Cancer Centers: What Do Institutions Perceive as Evidence? AB - BACKGROUND: Health care policies and guidelines that are clear and consistent with research evidence are important for maximizing clinical outcomes. To determine whether cancer centers in Canada and the United States had policies and/or guidelines about antioxidant use, and whether policies were aligned with the evidence base, we reviewed current research evidence in the field, and we undertook a survey of the policies and guidelines on antioxidant use at cancer institutions across North America. METHODS: A survey of policies and guidelines on antioxidant use and the development and communication of the policies and guidelines was conducted by contacting cancer institutions in North America. We also conducted a Website search for each institution to explore any online resources. RESULTS: Policies and guidelines on antioxidant use were collected from 78 cancer institutions. Few cancer institutions had policies (5%) but most provided guidelines (69%). Antioxidants from diet were generally encouraged at cancer institutions, consistent with the current research evidence. In contrast, specific antioxidant supplements were generally not recommended at cancer institutions. Policies and guidelines were developed using evidence-based methods (53%), by consulting another source (35%), or through discussions/conference (26%), and communicated mainly through online resources (65%) or written handouts (42%). For cancer institutions that had no policy or guideline on antioxidants, lack of information and lack of time were the most frequently cited reasons. CONCLUSIONS: Policies and guidelines on antioxidants from diet were largely consistent with the research evidence. Policies and guidelines on antioxidant supplements during treatment were generally more restrictive than the research evidence might suggest, perhaps due to the specificity of results and the inability to generalize findings across antioxidants, adding to the complexity of their optimal and safe use. Improved communication of comprehensive research evidence to cancer institutions may aid in the development of more evidence-based policies and guidelines. PMID- 25716351 TI - A Systematic Review of the Safety and Effect of Neurofeedback on Fatigue and Cognition. AB - BACKGROUND: Many cancer survivors continue to experience ongoing symptoms, such as fatigue and cognitive impairment, which are poorly managed and have few effective, evidence-based treatment options. Neurofeedback is a noninvasive, drug free form of brain training that may alleviate long-term symptoms reported by cancer patients. OBJECTIVE: The purpose of this systematic review of the literature was to describe the effectiveness and safety of neurofeedback for managing fatigue and cognitive impairment. METHODS: A systematic review of the literature was conducted using Joanna Briggs Institute (JBI) methodology. A comprehensive search of 5 databases was conducted: Medline, CINAHL, AMED, PsycInfo, and Embase. Randomized and nonrandomized controlled trials, controlled before and after studies, cohort, case control studies, and descriptive studies were included in this review. RESULTS: Twenty-seven relevant studies were included in the critical appraisals. The quality of most studies was poor to moderate based on the JBI critical appraisal checklists. Seventeen studies were deemed of sufficient quality to be included in the review: 10 experimental studies and 7 descriptive studies. Of these, only 2 were rated as high-quality studies and the remaining were rated as moderate quality. All 17 included studies reported positive results for at least one fatigue or cognitive outcome in a variety of populations, including 1 study with breast cancer survivors. Neurofeedback interventions were well tolerated with only 3 studies reporting any side effects. CONCLUSIONS: Despite issues with methodological quality, the overall positive findings and few reported side effects suggest neurofeedback could be helpful in alleviating fatigue and cognitive impairment. Currently, there is insufficient evidence that neurofeedback is an effective therapy for management of these symptoms in cancer survivors, however, these promising results support the need for further research with this patient population. More information about which neurofeedback technologies, approaches, and protocols could be successfully used with cancer survivors and with minimal side effects is needed. This research will have significance to nurses and physicians in oncology and primary care settings who provide follow-up care and counseling to cancer survivors experiencing debilitating symptoms in order to provide information and education related to evidence-based therapy options. PMID- 25716353 TI - "Fit note" is linked to fewer people taking long term sick leave, study finds. PMID- 25716352 TI - Psychological Impact of Predictive Genetic Testing in VCP Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia. AB - Inclusion Body Myopathy associated with Paget's disease of bone and Fronto temporal Dementia, also known as multisystem proteinopathy is an autosomal dominant, late onset neurodegenerative disorder caused by mutations in Valosin containing protein (VCP) gene. This study aimed to assess uptake and decision making for predictive genetic testing and the impact on psychological well-being. Individuals who had participated in the gene discovery study with a 50 % a priori risk of inheriting VCP disease were sent a letter of invitation offering genetic counseling and testing and were also invited to participate in this psychosocial study. A total of 102 individuals received an invitation and 33 individuals participated in genetic counseling and testing (32.3 %) with 29 completing baseline questionnaires. Twenty completed the follow-up post-test Hospital Anxiety and Depression Scale questionnaire including 13 of the 18 who had tested positive. Mean risk perception at baseline was 50.1 %. Reasons for testing included planning for the future, relieving uncertainty, informing children and satisfying curiosity. At baseline, one quarter of the participants had high levels of anxiety. However, scores were normal one year following testing. In this small cohort, one third of individuals at 50 % risk chose pre-symptomatic testing. Although one quarter of those choosing testing had high anxiety at baseline, this was not evident at follow-up. PMID- 25716354 TI - Subjective cognitive decline is related to CSF biomarkers of AD in patients with MCI. AB - OBJECTIVE: To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). METHODS: We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. RESULTS: Abnormal CSF beta-amyloid 1-42 (Abeta42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Abeta42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concerns, respectively. In addition, both SCD measures predicted risk of having a biomarker signature indicative of prodromal AD defined as presence of low CSF Abeta42 together with either high CSF tau or CSF phosphorylated tau 181 levels. CONCLUSIONS: In MCI, specific aspects of SCD severity and quality are related to CSF biomarkers indicative of AD. This extends findings in pre-MCI samples and calls for an improved operational assessment of SCD in MCI. This might be useful for sample enrichment strategies for increased likelihood of AD pathology. PMID- 25716355 TI - Spatially distinct atrophy is linked to beta-amyloid and tau in preclinical Alzheimer disease. AB - OBJECTIVES: To determine whether an MRI-based Alzheimer disease (AD) signature biomarker can detect tau-related neurodegeneration in preclinical AD, and to assess whether AD signature cortical thinning is associated with cognitive changes in cognitively normal (CN) older individuals. METHODS: In a large cohort of CN individuals (n = 188), we measured the hippocampal volume and cortical thickness within independently defined AD signature regions. We cross-sectionally assessed the associations between AD signature cortical thinning or hippocampal atrophy with CSF biomarkers of tau (increased tau) and beta-amyloid (Abeta) (decreased Abeta42). We also examined the impact of AD signature cortical thinning or other biomarker changes (i.e., hippocampal atrophy, reduced CSF Abeta42, or increased CSF tau) on cognitive performance in CN individuals. RESULTS: Elevated CSF tau was associated with AD signature cortical thinning but not hippocampal atrophy. In contrast, decreased CSF Abeta42 was associated with hippocampal loss but not AD signature cortical thinning. In addition, AD signature cortical thinning was associated with lower visuospatial performance. Reduced CSF Abeta42 was related to poorer performance on episodic memory. CONCLUSIONS: Spatially distinct neurodegeneration is associated with Abeta and tau pathology in preclinical AD. Abeta deposition and AD signature cortical atrophy independently affect cognition in CN older individuals. PMID- 25716356 TI - Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes. AB - OBJECTIVE: To gain insight into different cerebral amyloid angiopathy (CAA) phenotypes and mechanisms, we investigated cortical superficial siderosis (CSS), a new imaging marker of the disease, and its relation with APOE genotype in patients with pathologically proven CAA, who presented with and without intracerebral hemorrhage (ICH). METHODS: MRI scans of 105 patients with CAA pathologic confirmation and MRI were analyzed for CSS (focal, <=3 sulci; disseminates, >=4 sulci) and other imaging markers. We compared pathologic, imaging, and APOE genotype data between subjects with vs without ICH, and investigated associations between CSS and APOE genotype. RESULTS: Our cohort consisted of 54 patients with CAA with symptomatic lobar ICH and 51 without ICH. APOE genotype was available in 53 patients. More than 90% of pathology samples in both groups had neuritic plaques, whereas neurofibrillary tangles were more commonly present in the patients without ICH (87% vs 42%, p < 0.0001). There was a trend for patients with CAA with ICH to more commonly have APOE epsilon2 (48.7% vs 21.4%, p = 0.075), whereas patients without ICH were more likely to be APOE epsilon4 carriers (85.7% vs 53.9%, p = 0.035). Disseminated CSS was considerably commoner in patients with ICH (33.3% vs 5.9%, p < 0.0001). In logistic regression, disseminated CSS was associated with APOE epsilon2 (but not APOE epsilon4) (odds ratio 5.83; 95% confidence interval 1.49-22.82, p = 0.011). CONCLUSIONS: This neuropathologically defined CAA cohort suggests that CSS and APOE epsilon2 are related to the hemorrhagic expression of the disease; APOE epsilon4 is enriched in nonhemorrhagic CAA. Our study emphasizes the concept of different CAA phenotypes, suggesting divergent pathophysiologic mechanisms. PMID- 25716357 TI - Sleep duration and risk of fatal and nonfatal stroke: a prospective study and meta-analysis. AB - OBJECTIVE: To study the association between sleep duration and stroke incidence in a British population and to synthesize our findings with published results through a meta-analysis. METHODS: The prospective study included 9,692 stroke free participants aged 42-81 years from the European Prospective Investigation into Cancer-Norfolk cohort. Participants reported sleep duration in 1998-2000 and 2002-2004, and all stroke cases were recorded until March 31, 2009. For the meta analysis, we searched Ovid Medline, EMBASE, and the Cochrane Library for prospective studies published until May 2014, and pooled effect estimates using a weighted random-effect model. RESULTS: After 9.5 years of follow-up, 346 cases of stroke occurred. Long sleep was significantly associated with an increased risk of stroke (hazard ratio [HR] = 1.46 [95% confidence interval (CI) 1.08, 1.98]) after adjustment for all covariates. The association remained robust among those without preexisting diseases and those who reported sleeping well. The association for short sleep was smaller (and not statistically significant) (HR = 1.18 [95% CI 0.91, 1.53]). There was a higher stroke risk among those who reported persistently long sleep or a substantial increase in sleep duration over time, compared to those reporting persistently average sleep. These were compatible with the pooled HRs from an updated meta-analysis, which were 1.15 (1.07, 1.24) and 1.45 (1.30, 1.62) for short and long sleep duration, respectively. CONCLUSIONS: This prospective study and meta-analysis identified prolonged sleep as a potentially useful marker of increased future stroke risk in an apparently healthy aging population. PMID- 25716358 TI - Early-onset chronic axonal neuropathy, strokes, and hemolysis: inherited CD59 deficiency. AB - OBJECTIVE: To identify the underlying etiology of 3 patients in a multiplex family with strokes, chronic immune-mediated peripheral neuropathy, and hemolysis. All had onset in infancy. METHODS: We performed genome-wide linkage analysis followed by whole exome sequencing (WES) in the proband, Sanger sequencing, and segregation analysis of putative mutations. In addition, we conducted flow cytometry studies to assess CD59 expression. RESULTS: In a 2 generation-3-affected family with early-onset immune-mediated axonal neuropathy, cerebrovascular event both in the anterior and posterior circulation, and chronic Coombs-negative hemolysis, we detected CD59 deleterious mutation as the underlying cause. Linkage analysis and homozygosity mapping using single nucleotide polymorphism (SNP) microarrays in the family followed by WES in one index case allowed identification of a homozygous missense mutation in the CD59 gene (c.A146T:p.Asp49Val). Sanger sequencing validated the mutation, showing cosegregation with the disease phenotype. Flow cytometry using blood cells in the 3 patients showed a lack of CD59 expression at the cell membrane compared to control and CD55 labeling. CONCLUSION: We added to the knowledge base about inherited CD59 deficiency. PMID- 25716359 TI - Is sleep duration a risk factor for stroke? PMID- 25716360 TI - Quantifiable evaluation of cerebellar signs in children. AB - OBJECTIVE: To validate, examine the internal validity, and adapt to children the electronic version of the composite cerebellar functional severity (CCFS) score. METHODS: In this multicenter study, we compared the validated manual device with the new electronic version (n = 46) and analyzed its kinetics in 146 patients with Friedreich ataxia through the EFACTS (European Friedreich's Ataxia Consortium for Translational Studies) network, 77 patients with spinocerebellar ataxia, and 48 controls. We validated the CCFS in cerebellar ataxias in healthy children (n = 120) and children with Friedreich ataxia through the EFACTS network (n = 33). RESULTS: We showed that the electronic CCFS is a reliable replacement for the manual version (intraclass correlation coefficient: 0.98 [0.97-0.99]), and that the electronic CCFS is consistent when performed several times (0.92 [0.84-0.97]). Analysis of kinetics data showed an acceleration and irregularity that is not relevant compared with total speed. The CCFS was tested after modification in a population of patients with Friedreich ataxia between 8 and 19 years old, and showed similar values as adult patients with Friedreich ataxia (1.203 +/- 0.125 vs 1.228 +/- 0.167) and significantly higher values than controls of the same age (0.863 +/- 0.042). CONCLUSIONS: The electronic CCFS is a quantified measurement of cerebellar ataxia independent of age, usable in individuals aged from 7 to 80 years. The automated nature of the electronic test device makes it reproducible between operators and centers, as well as easy to use. PMID- 25716361 TI - Primary CNS lymphoma: a landmark trial and the next steps. PMID- 25716362 TI - Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. AB - OBJECTIVE: This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median follow-up of 81.2 months. METHODS: Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)-based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9. RESULTS: In the per-protocol population (n = 320), WBRT nonsignificantly prolonged progression-free survival (PFS) (median 18.2 vs 11.9 months, hazard ratio [HR] 0.83 [95% confidence interval (CI) 0.65-1.06], p = 0.14) and significantly PFS from last HDMTX (25.5 vs 12.0 months, HR 0.65 [95% CI 0.5-0.83], p = 0.001), but without OS prolongation (35.6 vs 37.1 months, HR 1.03 [95% CI 0.79-1.35], p = 0.82). In the intent-to-treat population (n = 410), there was a prolongation by WBRT of both PFS (15.4 vs 9.9 months, HR 0.79 [95% CI 0.64-0.98], p = 0.034) and PFS from last HDMTX (19.4 vs 11.9 months, HR 0.72 [95% CI 0.58-0.89], p = 0.003), but not of OS (32.4 vs 36.1 months, HR 0.98 [95% CI 0.79-1.26], p = 0.98). CONCLUSION: Although the statistical proof of noninferiority regarding OS was not given, our results suggest no worsening of OS without WBRT in primary therapy of PCNSL. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in PCNSL HDMTX-based chemotherapy followed by WBRT does not significantly increase survival compared to chemotherapy alone. The study lacked the precision to exclude an important survival benefit or harm from WBRT. PMID- 25716363 TI - Cortical superficial siderosis, APOE genotype, and hemorrhage risk in cerebral amyloid angiopathy. PMID- 25716364 TI - Functional and morphological myocardial changes in hepatitis C virus patients with end-stage liver disease. AB - BACKGROUND AND OBJECTIVES: Cardiovascular complications are common in liver transplant recipient. This study aims to evaluate functional and morphological myocardial changes in hepatitis C virus (HCV) patients with end-stage liver disease (ESLD) by cardiac magnetic resonance (CMR). METHODS: This cross-sectional study included 84 patients with HCV-related ESLD. They were subjected to 2D echocardiography and CMR. The presence, distribution, and percentage of delayed myocardial enhancement (DME) were estimated. RESULTS: The mean Model for End Stage Liver Disease score was 21.5 +/- 6.3. In CMR, all patients showed good global left ventricular (LV) systolic function (mean ejection fraction = 66.5 +/- 8.6%; range: 55-80) with normal wall thickness and motion. Left ventricle was mildly dilated in 25 patients (30%). Grade I and grade II diastolic dysfunction was detected in 81 patients (96.4%) with dilated left atrium in 25 patients (30%). Variable degrees of DME were detected in 70 patients (83.3%) with mean percentage of DME (%DME) being 19.5 +/- 16% (range: 4-52). A significant negative correlation was found between %DME and LV ejection fraction (r = -0.7; p < 0.001), cardiac output (r = -0.5; p = 0.013), cardiac index (r = -0.5; p = 0.02), and serum albumin level (r = -0.5; p = 0.01). The %DME >=19% was associated with 85.7% sensitivity and 85.7% specificity for detection of LV ejection fraction <60% as assessed by echocardiography (area under curve = 0.89; p = 0.001). CONCLUSION: DME with CMR is a common finding among patients with HCV-related ESLD. The extent of DME is significantly associated with global LV systolic function. PMID- 25716365 TI - Glycaemic index and glycaemic load of selected popular foods consumed in Southeast Asia. AB - The objective of the present study was to determine the glycaemic index (GI) and glycaemic load (GL) values of standard portion sizes of Southeast Asian traditional foods. A total of fifteen popular Southeast Asian foods were evaluated. Of these foods, three were soft drinks, while the other twelve were solid foods commonly consumed in this region. In total, forty-seven healthy participants (eighteen males and twenty-nine females) volunteered to consume either glucose at least twice or one of the fifteen test foods after a 10-12 h overnight fast. Blood glucose concentrations were analysed before consumption of the test food, and 15, 30, 45, 60, 90 and 120 min after food consumption, using capillary blood samples. The GI value of each test food was calculated by expressing the incremental area under the blood glucose response curve (IAUC) value of the test food as a percentage of each participant's average IAUC value, with glucose as the reference food. Among the fifteen foods tested, six belonged to low-GI foods (Ice Green Tea, Beehoon, Pandan Waffle, Curry Puff, Youtiao and Kaya Butter Toast), three belonged to medium-GI foods (Barley Drink, Char Siew Pau and Nasi Lemak), and the other six belonged to high-GI foods (Ice Lemon Tea, Chinese Carrot Cake, Chinese Yam Cake, Chee Cheong Fun, Lo Mai Gai and Pink Rice Cake). The GI and GL values of these traditional foods provide valuable information to consumers, researchers and dietitians on the optimal food choice for glycaemic control. Moreover, our dataset provides GI values of fifteen foods that were not previously tested extensively, and it presents values of foods commonly consumed in Southeast Asia. PMID- 25716366 TI - Editorial: recognition and reactivity at interfaces. PMID- 25716367 TI - External rib structure can be predicted using mathematical models: An anatomical study with application to understanding fractures and intercostal muscle function. AB - As ribs adapt to stress like all bones, and the chest behaves as a pressure vessel, the effect of stress on the ribs can be determined by measuring rib height and thickness. Rib height and thickness (depth) were measured using CT scans of seven rib cages from anonymized cadavers. A Finite Element Analysis (FEA) model of a rib cage was constructed using a validated approach and used to calculate intramuscular forces as the vectors of both circumferential and axial chest wall forces at right angles to the ribs. Nonlinear quadratic models were used to relate rib height and rib thickness to rib level, and intercostal muscle force to vector stress. Intercostal muscle force was also related to vector stress using Pearson correlation. For comparison, rib height and thickness were measured on CT scans of children. Rib height increased with rib level, increasing by 13% between the 3rd and 7th rib levels, where the 7th/8th rib was the widest part or "equator" of the rib cage, P < 0.001 (t-test). Rib thickness showed a statistically significant 23% increase between the 3rd and 7th ribs, P = 0.004 (t test). Intercostal muscle force was significantly related to vector stress, Pearson correlation r = 0.944, P = 0.005. The three nonlinear quadratic models developed all had statistically significant parameter estimates with P < 0.03. External rib morphology, in particular rib height and thickness, can be predicted using statistical mathematical models. Rib height is significantly related to the calculated intercostal muscle force, showing that environmental factors affect external rib morphology. PMID- 25716368 TI - Descriptive epidemiology of Kawasaki disease in Japan, 2011-2012: from the results of the 22nd nationwide survey. AB - BACKGROUND: The number of patients and incidence rate of Kawasaki disease (KD) are increasing in Japan. We have therefore characterized the latest epidemiological information on KD. METHODS: The 22nd nationwide survey of KD, which targeted patients diagnosed with KD in 2011 and 2012, was conducted in 2013 and included a total of 1983 departments and hospitals. In order to report on all patients with KD during the 2 survey years, we targeted hospitals of 100 beds or more with pediatric departments, or specialized pediatric hospitals. RESULTS: From a total of 1420 hospitals and departments (71.6% response rate), 26,691 KD patients were reported (12,774 in 2011 and 13,917 in 2012; 15,442 males and 11,249 females). The annual incidence rates were 243.1 per 100,000 population aged 0 to 4 years in 2011 and 264.8 in 2012. The number of cases of KD recorded in 2012 was the highest ever reported in Japan. The incidence rate of complete cases was also the highest ever reported in Japan and contributed to the increase in the rate of total cases in recent years. The number of patients diagnosed per month peaked in January, and additional peaks were noted during summer months, although these peaks were lower than those seen in winter. Age-specific incidence rate showed a monomodal distribution with a peak in the latter half of the year in which patients were born. CONCLUSIONS: The number of patients and the incidence rate of KD in Japan continue to increase. A similar trend has also been seen for patients with complete KD. PMID- 25716369 TI - Assessment of text documentation accompanying uncoded diagnoses in computerized health insurance claims in Japan. AB - BACKGROUND: Uncoded diagnoses in health insurance claims (HICs) may introduce bias into Japanese health statistics dependent on computerized HICs. This study's aim was to identify the causes and characteristics of uncoded diagnoses. METHODS: Uncoded diagnoses from computerized HICs (outpatient, inpatient, and the diagnosis procedure-combination per-diem payment system [DPC/PDPS]) submitted to the National Health Insurance Organization of Kumamoto Prefecture in May 2010 were analyzed. The text documentation accompanying the uncoded diagnoses was used to classify diagnoses in accordance with the International Classification of Diseases-10 (ICD-10). The text documentation was also classified into four categories using the standard descriptions of diagnoses defined in the master files of the computerized HIC system: 1) standard descriptions of diagnoses, 2) standard descriptions with a modifier, 3) non-standard descriptions of diagnoses, and 4) unclassifiable text documentation. Using these classifications, the proportions of uncoded diagnoses by ICD-10 disease category were calculated. RESULTS: Of the uncoded diagnoses analyzed (n = 363 753), non-standard descriptions of diagnoses for outpatient, inpatient, and DPC/PDPS HICs comprised 12.1%, 14.6%, and 1.0% of uncoded diagnoses, respectively. The proportion of uncoded diagnoses with standard descriptions with a modifier for Diseases of the eye and adnexa was significantly higher than the overall proportion of uncoded diagnoses among every HIC type. CONCLUSIONS: The pattern of uncoded diagnoses differed by HIC type and disease category. Evaluating the proportion of uncoded diagnoses in all medical facilities and developing effective coding methods for diagnoses with modifiers, prefixes, and suffixes should reduce number of uncoded diagnoses in computerized HICs and improve the quality of HIC databases. PMID- 25716370 TI - Perinatal outcome after first-trimester risk assessment in monochorionic and dichorionic twin pregnancies: a population-based register study. AB - OBJECTIVE: To evaluate the influence of chorionicity on outcome in twin pregnancies with two live fetuses at the nuchal translucency scan in the first trimester. DESIGN: Population-based register study. SETTING: Denmark. POPULATION: A cohort of 3621 twin pregnancies, 84.3% dichorionic (DC) pregnancies and 15.7% monochorionic (MC) pregnancies (15% diamniotic [MCDA] and 0.7% monoamniotic [MCMA]). METHODS: A cohort study based on data collected from the Danish Fetal Medicine Database from July 2008 to July 2011. MAIN OUTCOME MEASURES: Fetal loss rate before week 22, intrauterine death rate from week 22 to birth, and neonatal mortality. RESULTS: Significantly more DC than MC pregnancies resulted in at least one live born infant-98.2% versus 92.3% in MCDA (P < 0.05) and 66.7% in MCMA pregnancies (P < 0.05). The rates of spontaneous loss of both fetuses before week 22 were 0.9, 2.4, and 20.8% for DC, MCDA and MCMA twins, respectively (P < 0.05). The rate of intrauterine death of one fetus after week 22 was higher in MCDA twins than DC twins 1.7% versus 0.6% (P < 0.05). We found no significant difference in the rate of neonatal death. CONCLUSIONS: The risk of spontaneous loss of both fetuses before week 22 of gestation was significantly higher in MCMA and MCDA pregnancies than in DC pregnancies, and significantly higher in MCMA pregnancies than in MCDA pregnancies. After week 22 the risk of loss of one fetus after week 22 was significantly higher in MCDA pregnancies than in DC pregnancies. PMID- 25716371 TI - Diagnostic value of non stress test in latent phase of labor and maternal and fetal outcomes. AB - PURPOSE: The Non Stress Test (NST) is the one of the significant diagnostic fetal well being testes. The purpose of this study is to access diagnostic value of NST during latent phase of labor by considering maternal and neonatal outcomes. SUBJECTS: This case study control study was performed on 450 healthy pregnant women with gestational age between 38-42 weeks in AL-Zahra teaching hospital in Tabriz, Iran. All participants underwent NST after being admitted to labor during their latent phase of delivery. Participants were divided into groups including the study group which included 150 participants with non-reactive NST results whereas 300 subjects with reactive NST results assigned in the control group. Subjects in both groups were hospitalized for pregnancy termination because of the delivery time. In order to find out the importance of routine performance of NST during delivery, the relationship between NST results and maternal and fetal outcomes was evaluated. Several criteria including type of delivery, meconium defecation, descent arrest, bradicardia, Apgar score, and still birth were compared between two types. RESULTS: Finding of this study showed that descent arrest occurred in 2.7% of the subjects in the study group, whereas it occurred in 4.7% of the participants in the control group (p=0.44). Bradicardia found in 28% of the participants in study group and 3.3% of the control group (p<0.001). The low Apgar Score was found in 2.7% of case group however; no the low apgar score detected in the control group. Meconium defecation observed in 11.3% of the subjects in the study group and 9.7% of the participants in control group (p=0.62). The amount of stillbirth were found in control group. There was a significant difference between the results of both groups in terms of bradicardia, descent arrest, and the low Apgar score and cesarean section. CONCLUSION: Results of this study revealed that participants in study group with nonreactive NST results had more fetal complications than those with reactive NST results. NST was found to be a value diagnostic test for diagnosis of fetal distress during delivery in the latent phase. This findings of this study suggest that NST should be performed routinely as a valuable diagnostic test during the latent phase of delivery. PMID- 25716372 TI - Evaluation of limb load asymmetry using two new mathematical models. AB - Quantitative measurement of limb loading is important in orthopedic and neurological rehabilitation. In current practice, mathematical models such as Symmetry index (SI), Symmetry ratio (SR), and Symmetry angle (SA) are used to quantify limb loading asymmetry. Literatures have identified certain limitations with the above mathematical models. Hence this study presents two new mathematical models Modified symmetry index (MSI) and Limb loading error (LLE) that would address these limitations. Furthermore, the current mathematical models were compared against the new model with the goal of achieving a better model. This study uses hypothetical data to simulate an algorithmic preliminary computational measure to perform with all numerical possibilities of even and uneven limb loading that can occur in human legs. Descriptive statistics are used to interpret the limb loading patterns: symmetry, asymmetry and maximum asymmetry. The five mathematical models were similar in analyzing symmetry between limbs. However, for asymmetry and maximum asymmetry data, the SA and SR values do not give any meaningful interpretation, and SI gives an inflated value. The MSI and LLE are direct, easy to interpret and identify the loading patterns with the side of asymmetry. The new models are notable as they quantify the amount and side of asymmetry under different loading patterns. PMID- 25716373 TI - Informational support to family members of intensive care unit patients: the perspectives of families and nurses. AB - INTRODUCTION: The receiving information about the patients hospitalized in the intensive care unit is classified among the most important needs of the family members of such patients. Meeting the informational needs of families is a major goal for intensive care workers. Delivering honest, intelligible and effective information raises specific challenges in the stressful setting of the intensive care unit (ICU). The aim of this qualitative study was to explain perspectives of families of Intensive Care Unit patients and nurses about informational support. METHOD: Using a conventional content analysis approach, semi-structured interviews were conducted with participants to explore their perspectives of providing informational support to families of ICU patients. A purposeful sampling method was used to recruit nineteen family members of thirteen patients hospitalized in the ICU and twelve nurses from three teaching hospitals. In general, 31 persons participated in this study. Data collection continued to achieve data saturation. FINDINGS: A conventional content analysis of the data produced three categories and seven sub-categories. The three main categories were as followed, a) providing information, b) handling information and c) using information. Providing information had three sub-categories consisting of "receiving admission news", "receiving truthful and complete information" and receiving general information. Handling information had two sub-categories consisting "keeping information" and "gradual revelation". Lastly, using information has two sub-categories consisting of "support of patient" and "support of family members". CONCLUSION: The results of this study revealed perspectives of families of Intensive Care Unit patients and nurses about informational support. It also determines the nurses' need to know more about the influence of their supportive role on family's ICU patients informing. In addition, the results of present study can be used as a basis for further studies and for offering guidelines about informational support to the families of the patients hospitalized in the ICU. PMID- 25716374 TI - Self esteem and organizational commitment among health information management staff in tertiary care hospitals in Tehran. AB - BACKGROUND: Self esteem (SE) and organizational commitment (OC)? have significant impact on the quality of work life. AIM: This study aims to gain a better understanding of the relationships between SE and OC among health information management staff in tertiary care hospitals in Tehran (Iran). METHODS: This was a descriptive correlational and cross sectional study conducted on the health information management staff of tertiary care hospitals in Tehran, Iran. A total of 155 participants were randomly selected from 400 staff. Data were collected by two standard questionnaires. The SE and OC was measured using Eysenck SE scale and Meyer and Allen's three component model, respectively. The collected data were analyzed with the SPSS (version 16) using statistical tests of of independent T-test, Pearson Correlation coefficient, one way ANOVA and F tests. RESULTS: The OC and SE of the employees' were 67.8?, out of 120 (weak) and 21.0 out of 30 (moderate), respectively. The values for affective commitment, normative commitment, and continuance commitment were respectively 21.3 out of 40 (moderate), 23.9 out of 40 (moderate), and 22.7 out of 40 (moderate). The Pearson correlation coefficient test showed a significant OC and SE was statistically significant (P<0.05). The one way ANOVA test (P<0.05) did not show any significant difference between educational degree and work experience with SE and OC. CONCLUSION: This research showed that SE and OC ?are moderate. SE and OC have strong correlation with turnover, critical thinking, job satisfaction, and individual and organizational improvement. Therefore, applying appropriate human resource policies is crucial to reinforce these measures. PMID- 25716375 TI - Assessment of sick building syndrome and its associating factors among nurses in the educational hospitals of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. AB - BACKGROUND: Sick Building Syndrome is a diseases associated with indoor air quality accompanied with symptoms such as headache, dizziness, nausea, coughing and sneezing, irritation of eyes, throat and nose mucous membrane, and skin itching and inflammation. The purpose of this study was to investigate the symptoms of the syndrome and its related factors among nurses in teaching hospitals of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. METHODS: The study was conducted amongst nurses of three teaching hospitals of Shahid Sadoughi University of Medical Sciences, in Yazd. In this study the MM040EA questionnaire of sick building syndrome and indoor air quality was used and data extracted from the questionnaires were analyzed using the chi-square test and t test. RESULTS: The prevalence of sick building syndrome was 86.4%. The prevalence of the syndrome was in no association with age, gender, employment history and type of shift work .The most common symptoms reported by nurses included headache, fatigue and dry hands. Lack of sense of airflow, unpleasant odor in workplace (P<0.05( and also the amount of workload )P<0.001( were in relation with sick building syndrome. CONCLUSION: The high prevalence of sick building syndrome symptoms in the nursing environment was associated with factors of unpleasant odor and high workload of environment. So improvement of environmental conditions such as increasing the efficiency of the HVAC system, increasing fresh air flow in the sector, reducing the nurses workload as well as enhancing the quality of working life, will motivate the nurses and increase productivity in the workplace. PMID- 25716376 TI - The global relationship between the prevalence of diabetes mellitus and incidence of tuberculosis: 2000-2012. AB - BACKGROUND: The dual burden of tuberculosis (TB) and diabetes mellitus (DM) has increased over the past decade with DM prevalence increasing in countries already afflicted with a high burden of TB. The coexistence of the two conditions presents a serious threat to global public health. OBJECTIVE: The present study examines the global relationship between the prevalence of DM and the incidence of TB to evaluate their coexistence worldwide and their contribution to one another. METHODS: This is an ecological longitudinal study covering the period between years 2000 to 2012. We utilized data from the WHO and World Bank sources and International Diabetes Federation to estimate prevalence of DM (%) and the incidence of TB (per 100,000). Measures of central tendency and dispersion as well as the harmonic mean and linear regression were used for different WHO regions. The association between DM prevalence and TB incidence was examined by quartile of DM prevalence. RESULTS: The worldwide average (+/-S.D.) prevalence of DM within the study period was 6.6+/-3.8% whereas TB incidence was 135.0+/-190.5 per 100,000. DM prevalence was highest in the Eastern Mediterranean (8.3+/-4.1) and West Pacific (8.2+/-5.6) regions and lowest in the Africa (3.5+/-2.6). TB incidence was highest in Africa (313.1+/-275.9 per 100,000) and South-East Asia (216.7+/-124.9) and lowest in the European (46.5+/-68.6) and American (47.2+/ 52.9) regions. Only countries with high DM prevalence (>7.6%) showed a significant positive association with TB incidence (r=0.17, p=0.013). CONCLUSION: A positive association between DM and TB may exist in some - but not all - world regions, a dual burden that necessitates identifying the nature of this coexistence to assist in developing public health approaches that curb their rising burden. PMID- 25716377 TI - Participatory training in monitoring and evaluation for maternal and newborn health programmes. AB - In the context of slow progress towards Millennium Development Goals for child and maternal health, an innovative participatory training programme in the monitoring and evaluation (M&E) of Maternal and Newborn Health programmes was developed and delivered in six developing countries. The training, for health professionals and programme managers, aimed: (i) to strengthen participants' skills in M&E to enable more effective targeting of resources, and (ii) to build the capacity of partner institutions hosting the training to run similar courses. This review aims to assess the extent to which these goals were met and elicit views on ways to improve the training. An online survey of training participants and structured interviews with stakeholders were undertaken. Data from course reports were also incorporated. There was clearly a benefit to participants in terms of improved knowledge and skills. There is also some evidence that this translated into action through M&E implementation and tool development. Evidence of capacity-building at an institutional level was limited. Lessons for professional development training can be drawn from several aspects of the training programme that were found to facilitate learning, engagement and application. These include structuring courses around participant material, focussing on the development of practical action plans and involving multi disciplinary teams. The need for strengthening follow-up and embedding it throughout the training was highlighted to overcome the challenges to applying learning in the 'real world'. PMID- 25716378 TI - Exercise-induced asthma in asthmatic children of southern Iran. AB - BACKGROUND: Asthma is a common illness, especially among children. Exercise induced asthma is an important consideration, both as a factor, limiting physical activity of patients, and also as an indicator of poor long term control. We investigated pre-Valence of exercise-induced asthma in a group of asthmatic children living in southern Iran. METHODS: We conducted treadmill exercise challenge test in 40 young asthmatic patients aged 6 to 18. After 8 minutes exercise to achieve 80% of maximum heart rate predicted for age, patients were examined and spirometry values recorded at frequent intervals. We defined exercise-induced asthma as 10% or more decline in Forced Expiratory Volume in one second (FEV1) within 30 minutes after exercise challenge. RESULTS: Of 40 patients evaluated, 22 patients ( 55% of total ) met our criteria for exercise-induced asthma. Most positive responses (7 of 22, 31.8%) occurred at about 10 minutes after exercise. Cough was the most consistent sign (18 of 22 patients, 81%). In 2 patients (9%), FEV 1 decline did not accompany any symptom or sign. CONCLUSION: We concluded that Exercise- induced asthma occurs in a relatively smaller subset of southern Iranian asthmatic children. Also treadmill exercise challenge performed by a trained staff, following standard protocol and using enough monitoring and precautions is safe and diagnostic in children and adolescents. PMID- 25716379 TI - Do illness perceptions predict the attendance rate at diabetic outpatient clinic? AB - OBJECTIVE: The aim of this study was to identify predictors of non-attendance and to investigate the influence of illness perceptions on attendance at diabetic outpatient clinics. Research method and design: This is a descriptive study of 442 participants who were enrolled in a Diabetic Outpatient Clinic at Lerdsin Hospital, Thailand. Illness perceptions were derived from a Thai version of the IPQ-R questionnaire consisting of the same 3 sections as the original Illness perception- Revised with the distinction that it had 68 items. Test for validity was performed and the Cronbach's alpha reliability coefficient value was 0.87. Data were analysed by using independent t-tests. Binary logistic regression was used in order to assess the impact of illness perception scores on attendance among diabetic patients at the Outpatient Clinic. RESULTS: The results of the study were as follows: Demographic data showed that all respondents were of Thai ethnic origin and two-thirds of the respondents were women. The average age was 60 years. The majority of the participants had completed primary school (7-12 years old), was married and were Buddhist. The IPQ-R revealed the following findings: The illness perceptions at baseline and 6 months later showed that it illness perception had no effect on the participants' illness perception and attendance rate at the diabetic outpatient clinic. Participants who hold negative illness perceptions were more likely to attend diabetes clinics than those participants who had positive illness perceptions. A conceivable explanation for the non-significant findings in the study is the finding that during 6 month period there were some factors that have contributed to the failure of the participants to attend to their appointments. This is beyond the scope of the socio-demographic and illness perception factors. CONCLUSION: Thus, a plausible explanation for the non-significant findings in the study is that during 6 month period there were some factors that may have contributed to the appointment keeping among these patients beyond the scope of socio-demographic and illness perception factors. PMID- 25716380 TI - Determinants of use of insecticide treated bednets among caregivers of under five children in an urban local government area of Osun state, South-Western Nigeria. AB - In Sub Sahara Africa, the use of Insecticide Treated Nets (ITNs) is one of many strategies of Roll Back Malaria (RBM) initiatives to reduce malaria burden. This study therefore assessed the current use of insecticide treated nets and the determinants of its use among the caregivers of under five children in an urban local government area in Osun state, Nigeria. The study utilised a cross sectional design among caregivers of under- five children selected from households by multistage sampling technique. The study collected quantitative data using pretested semi structured, interviewer administered questionnaire while factors that determine the current use of ITN were identified using multi linear logistic regression. The study revealed that 54.4% caregivers of under five children were aware of ITNs as one of the malaria preventive measures, 49.1% had good knowledge of ITN and 38% agreed with the use of ITNs. Thirty four percent had access to ITNs, 32.3% owned at least one ITN with 30.3% reported been given free in the health care facilities. Thirty three percent had ever used and the foremost reasons for non-use are not readily available and expensive. Only 18.5% currently used ITNs and challenges faced were not easy to treat, difficult to set up and no place to keep it. Marital status, knowledge of ITN, attitude towards ITN, ownership of ITN and free ITN were factors that determined the use of ITNs amongst the respondents. There is a need to ensure intensive awareness on ITNs through campaigns and embark on its mass distribution to the public to enhance use. PMID- 25716381 TI - Assessment of health level and socio-economic characteristics of people working in the shipbuilding industry: a control group study. AB - INTRODUCTION: The health level of the population and the way people perceive it has been associated with their physical and mental health, as well as with their social and occupational characteristics. PURPOSE: The comparative assessment of mental and health level in shipbuilding industry workers and general population and its relationship to social and economic parameters. METHODS: A group of one hundred men working in the shipbuilding industry aged 51.8+/-8.2 years old and a control group of one hundred men of the general population aged 51.1+/-6.4 were studied. All participants completed the General Health Questionnaire - 28 and Fagerstrom test and a form with demographic, occupational and economic status characteristics. The statistical software SPSS 17.0 was used for data analysis. RESULTS: Twenty-six percent of the general population and 47% of men working in the shipbuilding industry assessed their health as moderate/poor. Higher median values of anxiety and depressive symptomatology were observed in individuals characterizing their health as moderate/poor (p<0.001), their work as physically too demanding and in individuals with high dependency on smoking (p<0.05). With regard to the parameter of physical complaints, people working in the shipbuilding industry, non-active employees and those with comorbidities were found more burdened in relation to the general population (p<0.05). Depressive disorders were more common in those stating that their economic situation had been significantly deteriorated and in individuals with chronic diseases, which also showed reduced social functioning (p<0.05). CONCLUSIONS: Health level and its individual dimensions are both associated with health self-assessment and occupational and economic status. The coexistence of chronic diseases and smoking dependence affects emotion and social functioning of individuals. PMID- 25716382 TI - Trauma in pregnancy and its consequences in Kermanshah, Iran from 2007 to 2010. AB - OBJECTIVE: Nowadays, with decreased mortality of pregnant women by obstetrical causes, trauma has become a leading cause of morbidity and mortality in pregnant women. This study was carried out to determine the frequency of trauma in pregnancy and related causes and selected consequences in pregnant women of Kermanshah, Iran from 2007 to 2010. METHODS: In this descriptive-analytical study, all pregnant women who suffered trauma and were admitted to Imam Reza, Taleghani, and Motazedi hospitals located in Kermanshah from 2007-2010 were studied. Sampling was done by census method and medical records of all eligible patients were studied. Data analysis was done by the SPSS software for Windows 9ver. 16.0). RESULTS: There were 102 cases of trauma in pregnancy registered in this time period. Mean age of the cases was 26 years. Most cases (43%) were in their third trimester of pregnancy upon admission. Most trauma cases were of blunt traumas (68%). In 68 cases (66.67%), trauma resulted in maternal injury (independent of pregnancy) and 13 cases (12.75%) resulted in obstetrical or fetal injuries. Maternal injuries showed significant difference (P= 0.02) in different years. Motor vehicle accidents with a frequency of 47% were the most common cause of trauma. CONCLUSION: Trauma in pregnancy can be a leading cause of injury and fatality in mother and fetus. The most common type of injury was motor vehicle accidents. Therefore, any strategy that can decrease the rate of motor vehicle accident in a community can decrease mortalities of women (even pregnant or non pregnant). PMID- 25716383 TI - Knowledge creation in nursing education. AB - In today's society, knowledge is recognized as a valuable social asset and the educational system is in search of a new strategy that allows them to construct their knowledge and experience. The purpose of this study was to explore the process of knowledge creation in nursing education. In the present study, the grounded theory approach was used. This method provides a comprehensive approach to collecting, organizing, and analyzing data. Data were obtained through 17 semi structured interviews with nursing faculties and nursing students. Purposeful and theoretical sampling was conducted. Based on the method of Strauss and Corbin, the data were analyzed using fragmented, deep, and constant-comparative methods. The main categories included striving for growth and reduction of ambiguity, use of knowledge resources, dynamism of mind and social factors, converting knowledge, and creating knowledge. Knowledge was converted through mind processes, individual and group reflection, praxis and research, and resulted in the creation of nursing knowledge. Discrete nursing knowledge is gained through disconformity research in order to gain more individual advantages. The consequence of this analysis was gaining new knowledge. Knowledge management must be included in the mission and strategic planning of nursing education, and it should be planned through operational planning in order to create applicable knowledge. PMID- 25716384 TI - Health-promoting behaviors and their association with certain demographic characteristics of nursing students of Tehran City in 2013. AB - BACKGROUND & OBJECTIVES: Nursing students provide health services and their behavior may affect the clinical services that they provide to clients. In addition, Health-promoting behaviors among nursing students may affect the quality of patient education. Therefore, the aim of this study was to determine the relationship between health-promoting behaviors and certain demographic characteristics of nursing students in Tehran. METHODS: This cross-sectional study was performed on 404 undergraduate nursing students (107 males and 297 females) of universities of Tehran who were selected through stratified random sampling procedure. The data collection tools were: demographic characteristics questionnaire and health-promoting lifestyle profile 2. This standard instrument has 6 subscales of nutrition, physical activity, spiritual growth, health responsibility, interpersonal relations, and stress management. In order to keep the weight of the expressions of the tool and subscale scores the mean were calculated. For this purpose, each expression was scored on a scale of 1 to 4. Internal consistency (Cronbach's Alpha) of this tool was a=0.86. Data was analyzed by using statistical tests of Chi Square, Independent T and ANOVA. RESULTS: According to the results, health-promoting behaviors among the students scored highly. The analysis of subscales of health-promoting lifestyle profile 2 showed that the highest mean belongs to the subscale of spiritual growth and the lowest mean belongs to the subscale of physical activity. The mean of health promoting behaviors among married students was higher than among single students. Moreover, as students advanced through academic years, health responsibility increased and stress management reduced. DISCUSSION: Undoubtedly, physical activity and stress management have a significant role in personal health and occupational satisfaction of students, which consequently help them provide better services to clients. Therefore, considering the low scores of students in these sections, nursing education managers, policymakers and planners should pay attention to these problems. PMID- 25716385 TI - Strategic planning, implementation, and evaluation processes in hospital systems: a survey from Iran. AB - BACKGROUND & AIM: Strategic planning has been presented as an important management practice. However, evidence of its deployment in healthcare systems in low-income and middle-income countries (LMICs) is limited. This study investigated the strategic management process in Iranian hospitals. METHODS: The present study was accomplished in 24 teaching hospitals in Tehran, Iran from September 2012 to March 2013. The data collection instrument was a questionnaire including 130 items. This questionnaire measured the situation of formulation, implementation, and evaluation of strategic plan as well as the requirements, facilitators, and its benefits in the studied hospitals. RESULTS: All the investigated hospitals had a strategic plan. The obtained percentages for the items "the rate of the compliance to requirements" and "the quantity of planning facilitators" (68.75%), attention to the stakeholder participation in the planning (55.74%), attention to the planning components (62.22%), the status of evaluating strategic plan (59.94%) and the benefits of strategic planning for hospitals (65.15%) were in the medium limit. However, the status of implementation of the strategic plan (53.71%) was found to be weak. Significant statistical correlations were observed between the incentive for developing strategic plan and status of evaluating phase (P=0.04), and between status of implementation phase and having a documented strategic plan (P=0.03). CONCLUSION: According to the results, it seems that absence of appropriate internal incentive for formulating and implementing strategies led more hospitals to start formulation strategic planning in accordance with the legal requirements of Ministry of Health. Consequently, even though all the investigated hospital had the documented strategic plan, the plan has not been implemented efficiently and valid evaluation of results is yet to be achieved. PMID- 25716386 TI - Cost effectiveness analysis of Avonex and CinnoVex in Relapsing Remitting MS. AB - INTRODUCTION: Multiple sclerosis is a chronic and degenerative neurological disease characterized by loss of myelin sheath of some neurons in brain and spinal cord. It is associated with high economic burden due to premature deaths and high occurrence of disabilities. The aim of the current study was to determine cost effectiveness of two major products of interferon 1a in patients with relapsing-remitting multiple sclerosis. METHOD AND MATERIALS: Altogether, 140 patients who have consumed Avonex and CinnoVex in Relapsing Remitting MS for at least two years were randomly selected (70 patients in each group). Health related quality of life (HRQoL) was assessed using the adopted MSQoL-54 instrument. Costs were measured and valued from Ministry of Health and Medical Education (MOHME) perspective. Two-way sensitivity analysis was used to check robustness of the results. RESULTS: Patients in CinnoVex group reported significantly higher scores in both physical (69.5 vs. 50.9, P<0.001) and mental (63.3 vs. 56.6, P=0.03) aspects of HRQoL than Avonex group. On the other hand, annual cost of CinnoVex and Avonex were 2410 US$ and 4515US$ per patient, respectively (P<0.001). CONCLUSIONS: The results showed that CinnoVex was dominant option over the study period. It is suggested that results of the current study should be considered in allocating resources to MS treatments in Iran. Of course, our findings should be interpreted with caution duo to short term horizon and lack of HRQoL scores at baseline (before the intervention). PMID- 25716387 TI - Measurement of microcystin -LR in water samples using improved HPLC method. AB - Microcystins are a group of toxic compounds produced by freshwater cyanobacteria and cause diseases. World Health Organization has recommended a concentration of 1 ug/l for Microcystin-LR (MC-LR) in potable water as guideline value. The high performance liquid chromatography (HPLC) followed by C18 analytical column and ultra violet detector for detection of MC-LR. In this regard, 5 different concentrations of MC-LR solutions were injected into HPLC. MC-LR was detected in 5.33 minute retention time and Calibration curve was achieved with R(2) = 0.988. Detection limit for this method was obtained by using acetonitrile solutions (32% and 55%) as a gradient run and a high silanol activity column equal to 0.02 ug /mL. Despite no acidic organic modifier being used in the mixture of solvents, the sensitivity of this method was appropriate for detection of MC-LR. Because of short retention time, reduction in number of solvents and high resolution and suitable sensitivity, this method is affordable and is fast for detection and determination of MC-LR in potable water. PMID- 25716388 TI - The effect of education and implementation of evidence-based nursing guidelines on infants' weight gaining in NICU. AB - BACKGROUND: Educating evidence-based guidelines influences increased quality of nursing cares effectively. Infant's weight gaining is one of the most important indicators for measuring quality of nursing care in NICU. The research is conducted with the aim of surveying the effect of education and implementation of educating evidence-based guidelines on infants' weight gaining in NICU. METHODS: This two-group clinical trial study was conducted in 2013 on one hundred infants in Baqiyatallah (AJ) hospital of Tehran. It was performed by using non-probable and convenient sampling. Data collection tools included; infants' demographic questionnaire and a researcher-made checklist to record infants' weight by using a weighing scale. Infants' weight was recorded before intervention and two months after implementation of the guidelines, then data were analyzed by using SPSS19 statistical software. FINDINGS: Mean weight of the infants in the control group on admission and on discharge was respectively; 1771(41.71) and 1712(42.68), and mean weight of the infants in intervention group on admission and on discharge was respectively; 1697(37.63) and 1793(40.71). After two months, infants' weight gaining in intervention group was more than control group and it was statistically significant (P = 0.001). CONCLUSION: results of the present study showed that implementation of evidence-based instruction an effective and economical method regarding infants' weight gaining. Therefore it is recommended to the authorities and managers of the hospitals and educational centers of the healthcare services to put education and implementation of educating evidence based instruction the priority of their work plans. PMID- 25716389 TI - The effect of pelvic muscle exercises on urinary incontinency and self-esteem of elderly females with stress urinary incontinency, 2013. AB - INTRODUCTION: Millions of women are afflicted with stress urinary incontinence. Urinary incontinence is mentioned as one of the geriatric syndromes, together with pressure ulcers, functional decline, falls, and low self-esteem. The aim of the present study was to determine the effect of pelvic muscle exercises on urinary incontinency and self- esteem of elderly females with stress urinary incontinency in Shiraz, Iran, 2013. MATERIAL AND METHOD: In this interventional study, 50 old females aged 60-74 years were chosen among the members of Jahandidegan center, and they were asked to sign the informed consent form and complete the demographic questionnaire. Then, Quid questionnaire was used for choosing the type of incontinence in the elderly females. Next, the participants completed the ICIQ and self-esteem questionnaires. Then, they were randomly assigned to case and control groups. Each participant took part in 8 training classes. Finally, the subjects filled the ICIQ and self-esteem questionnaires before and 2 months after the intervention. RESULT: The results is shown that after the intervention, ICIQ score has a significant difference between the two groups (P=0.001). Also, after the treatment, self-esteem average scores of studied unit indicated a significant statistical difference in experimental group. In other words, the training sessions improved the score of self-esteem in the experimental group (P<0.001) versus control group (P=0.08). CONCLUSION: Pelvic muscle exercises were an empowerment mechanism for incontinent women in improving their quality of life and self-esteem, so recommended that such these exercising programs be used in elderly health care centers as a factor to improve health promotion of elderlies 'that are suffering from urinary incontinence. PMID- 25716390 TI - A study of incivility in the Iranian nursing training system based on educators and students' experiences: a quantitative content analysis. AB - BACKGROUND: It is absolutely essential to know the negative impacts incivility in students and educators may have on the creation of a suitable teaching-learning environment. Better education of to-be nurses would improve their service to patients and society in the future. There has been no research in Iran so far on this particular case. This study examines the experiences of uncivil or disrespectful behavior from the standpoint of educators and students. METHODOLOGY & METHODS: A quantitative content analysis was carried out to study manuscripts presented in the form of open questionnaires. To this end, data produced from detailed answers from 640 students and educators were inputted into the computer and line-by-line and sentence-by-sentence coding was done. After that, implied codes were added, the categories were revealed, and finally counting frequency of code in categories was carried out. RESULTS: The most important categories that students considered uncivil behavior were waste of class time, distraction, incompetence in managing the class, discrimination, bad assessment, insult and threat on behalf of the educators. In contrast to their view, what the educators thought of as disrespectful included class disorder, humiliation of other students, irregular attendance of classes, bad sitting postures, non-observance of Islamic standards, and coming unprepared to the class by students. CONCLUSION: From the viewpoint of students and educators, incivility is present towards one another in the academic environment. This study determines the most important forms of the same from their stand point. Since disrespectful and threatening behavior has a significant impact on learning environment, we highly recommend a thorough examination to be carried out in future studies on the origin and the managing strategies of such behaviors. PMID- 25716391 TI - Growing up and role modeling: a theory in Iranian nursing students' education. AB - One of the key strategies in students' learning is being affected by models. Understanding the role-modeling process in education will help to make greater use of this training strategy. The aim of this grounded theory study was to explore Iranian nursing students and instructors' experiences about role modeling process. Data was analyzed by Glaserian's Grounded Theory methodology through semi-structured interviews with 7 faculty members, 2 nursing students; the three focus group discussions with 20 nursing students based on purposive and theoretical sampling was done for explaining role modeling process from four nursing faculties in Tehran. Through basic coding, an effort to comprehensive growth and excellence was made with the basic social process consisting the core category and through selective coding three phases were identified as: realizing and exposure to inadequate human and professional growth, facilitating human and professional growth and evolution. The role modeling process is taking place unconscious, involuntary, dynamic and with positive progressive process in order to facilitate overall growth in nursing student. Accordingly, the design and implementation of the designed model can be used to make this unconscious to conscious, active and voluntarily processes a process to help education administrators of nursing colleges and supra organization to prevent threats to human and professional in nursing students' education and promote nursing students' growth. PMID- 25716392 TI - The relationship between quality of work life and job satisfaction of faculty members in Zahedan University of Medical Sciences. AB - BACKGROUND: Quality of work life is one of the most important factors for human motivating and improving of job satisfaction. AIM: The current study was carried out aimed to determine the relationship between quality of work life and job satisfaction in faculty members of Zahedan University of Medical Sciences. METHOD: In this descriptive-analytic study, 202 faculty members of Zahedan University of Medical Sciences in 2012 were entered the study through census. The job satisfaction questionnaire of Smith and Kendall and Walton Quality of Work Life questionnaire were used for data collection. Validity and reliability of questionnaires were confirmed in previous studies. Data analysis was done using SPSS 18. The Pearson correlation coefficient and multiple regression tests were used for data analysis. RESULT: The mean score of quality of work life was 121/30+/-37/08 and job satisfaction was 135/98 +/-33/78. There was a significant and positive correlation between job satisfaction of faculty members and their quality of work life (P=0.003). In addition, two components of quality of work life "adequate and fair compensation" (beta=0.3) and "Social Integration" (beta=0.4) can predict job satisfaction of faculty members. CONCLUSION: According to correlation between job satisfaction and quality of work life in faculty members, job satisfaction can be improved through the changing and manipulating the components of quality of work life and in this way; the suitable environment for organization development should be provided. PMID- 25716393 TI - Postpartum contraception in adolescents: data from a single tertiary clinic in southeast of Turkey. AB - AIM: We aimed to evaluate the postpartum contraception preferences of adolescent women in this study. MATERIALS & METHOD: This descriptive study was prepared after a retrospective analysis of file records of primigravida women who had given birth at the Adiyaman University School of Medicine Training and Research Hospital Department of Obstetric and Gynecology between January 2010 and June 2012. More than 12 months had passed after birth. The adolescents who were included in the study and the control group women were called by phone and invited to our clinic. A total of 506 adolescents and 1,046 control group women came to the clinic and were evaluated. The control group was formed of women between the age of 20-35 years who gave given birth in our clinic during the same period and were randomly selected. Postpartum obstetric history, contraception methods and data of these patients were recorded. RESULTS: The mean age was 18.3+/-0.4 years and 28.2+/-4.9 years in the adolescent group and control group respectively. No contraception other than lactation amenorrhea was used by 256 women of the adolescent group (50.6%) and 345 women of the control group (33%). The most commonly used contraceptive method in both groups other than lactation amenorrhea was condoms (160 women (64%) and 230 women (32.8%) respectively). The annual contraceptive failure rate was 3.95% in the adolescent group and 1.72% in the control group. The highest failure rate was with lactation amenorrhea in both groups. DISCUSSION: Adolescent women mostly use contraceptive methods with low reliability such as lactation amenorrhea and the calendar method in the postpartum period. Providing adequate contraceptive education is therefore important. On the other hand, starting such training starting in the early postnatal period will prevent recurring adolescent pregnancies with a short pregnancy interval. PMID- 25716394 TI - Humanistic approach to nursing education: lived experiences of Iranian nursing students. AB - The nurse teachers tried to have a complete understanding of the educational contents, to transfer knowledge to nursing students better, and to facilitate the process of education. The purpose of this study was to explore the lived experiences of Iranian nursing students regarding the characteristics of academic nurse teachers. In this hermeneutic phenomenological study, data were collected via in-depth, semi-structured interviews with 12 Iranian nursing students and the audio-taped and transcribed interviews analyzed according to Van Manen's method. The main theme emerged during data analysis, was "humanistic approach to nursing education". The theme was extracted from 2 sub-themes including 'ethical necessities' and 'effective interaction'. The findings present greater understanding of humanistic approach to nursing education. PMID- 25716395 TI - Evaluation of work engagement and its determinants in Kermanshah hospitals staff in 2013. AB - OBJECTIVE: Work engagement is a new concept in the field of psychology and human resource management. Increased vitality and enthusiasm is a social phenomenon that brings work engagement for society. This study aimed to evaluate work engagement and its determinants in Kermanshah hospitals' staff. METHODS: This cross-sectional study was conducted on 387 hospital administrative, clinical, paraclinical, and service staff. The sample size was calculated using Krejcei Morgan table. The data were collected using a questionnaire including demographic characteristics and job engagement components. Then, the data were analyzed using descriptive statistics as well as independent sample t-test and one-way ANOVA. RESULTS: The participants' mean (SD) of age was 32.63+/-2.7 years and most of them were female (57.6%). The results revealed a significant relationship between work engagement and age group (P=0.01) and work experience (P=0.04). However, no significant relationship was found between work engagement and sex, education level, and job unit. CONCLUSION: The results of this study showed that only job experience and age were associated with work engagement. However, no significant relationship was found between work engagement and education level, sex, and job. Thus, further studies are suggested to investigate the cultural factors and personality traits associated with job enthusiasm among the hospital staff, especially nurses. PMID- 25716396 TI - Association between serum adiponectin and HDL-C in type II diabetic patients. AB - INTRODUCTION: Adiponectin has an important role in the metabolism of lipids and carbohydrates, and it also has a role in vascular biology. The aim of this study was to determine the association of adiponectin with HDL-C in type II diabetic patients and healthy individuals. METHODOLOGY: This was a case control study. After 12 hours of fasting, the patients' blood samples was taken, and the serum was separated in a centrifuge tube. The concentration of adiponectin in the serum was measured using ELISA kits. The same procedure also was performed for the members of the control group. FINDINGS: The adiponectin levels were signifcantly different between the two groups, i.e., the type II diabetic patients and the individuals in the control group who were healthy nondiabetics (P < 0.001) and (t = 5.93). There was a significant difference in the HDL-C values between the two groups (P < 0.001) and (t = 11.30). A significant relationship also was found between the amounts of adiponectin and HDL-C (P <= 0.001). CONCLUSIONS: The results of this study can be used to identify individuals at risk for type II diabetes, and to control the risk factors for type II diabetes and cardiovascular diseases by increasing the levels of adiponectin in the blood. PMID- 25716397 TI - Factors influencing development of professional values among nursing students and instructors: a systematic review. AB - INTRODUCTION: Professional values are standards of behavior for performance that provide a framework for appraising beliefs and attitudes that influence behavior. Development of professional values has been a continuous and long process and it is influenced by different factors. The aim of this study is "assessing different factors influencing development of professional values among nursing students and instructors". METHOD: In this systematic review, a broad research was performed to find articles from Persian and English databases: pub Med, Pro quest, Elsevier, SID, Google scholar, Ovid and Iran Doc; nursing student, instructors, ethics, professional value, ethical value and educators were used as the key words. Among 3205 achieved articles, by eliminating repeated ones, 22 articles were assessed during the period 1995-2013. Data achieved from the articles were summarized, categorized and analyzed based on the research question. RESULTS: In this study "education and achieving professional experiences", "Students and instructors' perspectives on professional values", "the role of culture in considering and developing professional special values" and "the effect of learners' individual characteristics" were extracted as the four main themes. CONCLUSION: Considering the effect of educational, cultural and individual factors in developing nurses' professional values; it is recommended to the educational and health centers to consider value-based cares in clinical environments for the patients in addition to considering the content of educational programs based on ethical values in the students' curriculum. PMID- 25716398 TI - Components of equity-oriented health care system: perspective of Iranian nurses. AB - Equity in health is one of key objectives in health care systems world wide. This study aimed to explain the perspective of Iranian nurses about equity in the health care system. A qualitative exploratory design with thematic analysis approach was used to collect and analyze data. Using a purposeful sampling helped the researchers to recruit 16 eligible participants. Data were collected via in depth semi-structured interviews. Five main categories were extracted through data analysis process including (1) inequity against the nurse, (2) the recommended patient, (3) no claim for equity-oriented care in health system, (4) physicians' dominancy system; and (5) the need to define criteria to measure equity-oriented care. All health care systems around the world struggle to establish equity-oriented care. In perspective of Iranian nurses, the reform of structures in the health system is possible through providing the context of equitable care for caregivers and care recipients. Health system should commit the flow of equity at all of its levels. It should utilize policies to claim equity and consider the interests of all beneficiaries. Furthermore, certain criteria should be defined for equity-oriented care in the health care system, and also provides the possibility to measure and monitor it. PMID- 25716399 TI - Body mass index and gonadotropin hormones (LH & FSH) associate with clinical symptoms among women with polycystic ovary syndrome. AB - To evaluate the relevance of body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and LH/FSH ratio with clinical symptoms in polycystic ovary syndrome (PCOS) women. METHODS: We reviewed the medical records of all women visited in the PCOS Clinic of Babol (Iran) from 2008 to 2012. A retrospective cross-sectional study was conducted on 175 PCOS women; aged 18-38 years diagnosed based on the Rotterdam criteria. Among the PCOs women, the prevalence of oligomenorrhea, acne, and hirsutism were found to be 92.0%, 31.4%, and 78.9%, respectively. Positive finding of polycystic ovaries was observed in 89.1% of PCOS women with by using sonography. A total of 69.2% overweight/obesity patients had polycystic ovary morphology on ultrasound image. Compared with non- overweight/obesity, the adjusted OR of PCOS women for sonographic view of polycystic ovaries was 4.33 (95% CI, 1.42-13.15, p=0.001), Nevertheless, the adjusted odds ratio (OR) showed no significant associations between LH, FSH, and LH/FSH ratio with clinical symptoms in these women. The findings of this study indicated that the overweight/obese women with PCOS are at an increased risk for sonographic view of polycystic ovaries. Therefore, it is suggested that successful weight loss is the most effective method of restoring ovulation, menstruation that should be used as major advice in obese PCOS patients. PMID- 25716400 TI - Implementation of OSCE test to develop appropriate tool to measure mothers' parenting skills. AB - INTRODUCTION: Parents play a vital role throughout a child's life. This role is very significant in the beginning years of a child's life. In this period, the child encounters new experiences and these experiences make him or her to learn and grow. These days, in order to help the parents build a bright future for their children, different parenting programs have been designed. These programs provide a great opportunity for parents to enhance positive parenting skills. The aim of this study was to design a reliable and valid instrument for assessing the mothers' parenting skills. METHODOLOGY: 44 mothers who had children aged 3 - 8 were invited to participate in this study. They took part in parenting-skills training sessions for more than two months. Then they were asked to attend the test center after six months to be tested on trained skills. In this study, mothers' parenting skills were measured by the OSCE test. The reliability of the test was determined with three methods including split half, Cronbach alpha, and correlation between assessors' scores in two similar stations. The construct validity of the test was determined with Explanatory Factor Analysis. RESULTS: The total Cronbach alpha coefficient obtained was 0.83 which indicated that the test had a high internal reliability. The Spearman correlation coefficient obtained for two halves of the test was 0.76. The results of Explanatory Factor Analysis showed that nine stations of OSCE were focused on two factors. The first factor was named positive positions and the second factor was named negative positions. CONCLUSION: The designed OSCE test has the suitable psychometric features to be used by researchers to assess mothers' parenting skills. PMID- 25716401 TI - Comparison of lifestyles of women with gestational diabetes and healthy pregnant women. AB - BACKGROUND: Gestational diabetes is the most common medical condition in pregnancy and can be a predisposing factor in incidence of type II diabetes in future. Incorrect lifestyles can predispose people to various diseases, including diabetes, which is a serious health risk. Therefore, this study was conducted to compare lifestyles of women with gestational diabetes and healthy pregnant women attending the health centers affiliated to Shahid Beheshti University of Medical Sciences (SBMU) in 2013. METHODS: A comparative-descriptive study was conducted on 100 pregnant women with definite diagnosis of gestational diabetes and 100 healthy pregnant women attending the health centers affiliated to SBMU. Data were collected by a researcher-made questionnaire about lifestyle during pregnancy. Informed consents were obtained, and sampling was performed using convenient multi-stage random sampling method. Data were analyzed using SPSS-18 software. RESULTS: Demographic and obstetrics variables were not significantly different in the two groups. However, two groups were significantly different regarding their lifestyles as the mean scores of pregnancy diet were 65.05 in the diabetic group and 74.12 in the healthy group (P<0.001), and the mean moderate physical activity scores in the two groups were 4.62 and 5.69, respectively (P=0.042), the mean pregnancy self-care scores were 71.9 and 81.87, respectively (P<0.001), the mean perceived social support in the two groups were 65.75 and 73.88, respectively (P<0.001), and the mean scores of perceived stress were 51.57 and 60.27, respectively (P<0.001). CONCLUSION: Women's lifestyles were different in some areas. This study further reveals the importance of women's diet, self-care, moderate physical activity, and perceived social support during pregnancy. Incidence of gestational diabetes can be prevented through increased awareness and education of pregnant women about having appropriate lifestyles during pregnancy and any intervention that would lead to improved lifestyle. PMID- 25716402 TI - The global perspective of nursing students in relation to college peers. AB - OBJECTIVE: The purpose of the present study was to assess the nursing students' global perspectives and compare it to a nationally normed reference group. BACKGROUND: An individual's global perspective impacts the extent to which the person perceives and knows the people and cultures within the world. Nursing care is expected to take a holistic perspective in providing care and respond in culturally appropriate ways to a diverse population through understanding the impact of cultural influences. METHODS: Participant nursing students completed the Global Perspective Inventory survey and information about their current global perspective taking and their perceptions of curricular and co-curricular experiences was collected and analyzed. RESULTS: Compared to the nationally normed reference group, nursing students expressed statistically significant lower intrapersonal affect average score. Although higher average scores were detected in most of the other scales, differences were not statistically significant. CONCLUSION: A global perspective approach to intercultural nursing education is an area that needs to be further developed and different options are to be examined. PMID- 25716403 TI - The relationship between the managerial skills and results of "performance evaluation "tool among nursing managers in teaching hospitals of Iran University of Medical Science. AB - Performance of different organizations, such as hospitals is mainly influenced by their managers' performance. Nursing managers have an important role in hospital performance and their managerial skills can improve the quality of the services. Hence, the present study was conducted in order to assess the relationship between the managerial skills and the results of their performance evaluation in Teaching Hospitals of Iran University of Medical Science in 2013. The research used the cross sectional method in 2013. It was done by distributing a managerial skills assessment questionnaire, with close-ended questions in 5 choice Likert scale, among 181 managers and head nurses of hospitals of Iran university of Medical Sciences; among which 131 answered the questions. Another data collection tools was a forms to record evaluation marks from the personnel records. We used Pearson and Spearman correlation tests and SPSS for analysis and description (frequency, mean and standard deviation). Results showed that the managerial skills of the nursing mangers were fair (2.57 out of 5) and the results of the performance evaluation were in a good condition (98.44). The mangers' evaluation results and the managerial skills scores were not in a meaningful correlation (r=0.047 np=0.856). The research showed no correlation between different domains of managerial skills and the performance evaluation marks: decision making skills (r=0.074 and p=0.399), leadership (correlation coefficient 0.028 and p=0.654), motivation (correlation coefficient 0.118 and p=0.163), communication (correlation coefficient 0.116 and p=0.122), systematic thinking (correlation coefficient 0.028 and p=0.828), time management (correlation coefficient 0.077 and p=0.401) and strategic thinking (correlation coefficient 0.041 and p=0.756). Lack of any correlation and relation between managers' managerial skills and their performance evaluation results shows need to a fundamental revision at managers' performance evaluation form. PMID- 25716404 TI - Effective strategies for global health research, training and clinical care: a narrative review. AB - The purpose of this narrative review was to synthesize the evidence on effective strategies for global health research, training and clinical care in order to identify common structures that have been used to guide program development. A Medline search from 2001 to 2011 produced 951 articles, which were reviewed and categorized. Thirty articles met criteria to be included in this review. Eleven articles discussed recommendations for research, 8 discussed training and 11 discussed clinical care. Global health program development should be completed within the framework of a larger institutional commitment or partnership. Support from leadership in the university or NGO, and an engaged local community are both integral to success and sustainability of efforts. It is also important for program development to engage local partners from the onset, jointly exploring issues and developing goals and objectives. Evaluation is a recommended way to determine if goals are being met, and should include considerations of sustainability, partnership building, and capacity. Global health research programs should consider details regarding the research process, context of research, partnerships, and community relationships. Training for global health should involve mentorship, pre-departure preparation of students, and elements developed to increase impact. Clinical care programs should focus on collaboration, sustainability, meeting local needs, and appropriate process considerations. PMID- 25716405 TI - Estimating the marginal effect of socioeconomic factors on the demand of specialty drugs. AB - Given the growing importance and role of drugs in the treatment of diseases, as well as replacement of them rather than expensive and often unsafe procedures, study of socioeconomicfactors affecting future demand for them seems necessary.we seek to examine the extent of to which socioeconomic factors affect specialty medicine use by the patients.using data from questionnaires completed by 280 patients with multiple sclerosis, hemophilia, thalassemia, and chronic kidney disease, we estimate marginal effect of significant variables in probit model.We found that the need for the patient(ME = 0.858), deterioration of the patient (ME = -0.001), household size (ME = 0.0004), House Ownership (ME = -0.002), gender (ME = -0.04), income (ME = -0.0007), education (ME = -0.0021) and job (ME = 0.0021) are significant variables affecting demand for specialty drugs. We conclude that it can be programmed to promote and protect the welfare of patients by specific factors such as income, and largely affect the demand of medication and medical services. Therefore economic aid to these patients should not be limited only to medical subsidies, especially in patients with MS, income and welfare can reduce drug demand. PMID- 25716406 TI - Nurse as a facilitator to professional communication: a qualitative study. AB - Nurses need to establish communication with other healthcare professionals to facilitate the process of care. Healthcare professionals have complementary roles in providing care to patients. As the key members of the healthcare team, nurses also have an important role in establishing communication among other healthcare professionals. The final outcome of professional communication is effective care and improved patient outcomes. The aim of this study was to explore nurses' role in establishing professional communications with other healthcare professionals. This was a descriptive qualitative study. The study was conducted by using the content analysis approach. A purposive sample of sixteen healthcare professionals was recruited from six teaching hospitals affiliated to Tehran University of Medical Sciences, Tehran, Iran. Study data were gathered by conducting personal face-to-face semi-structured interviews and were analyzed by using the qualitative content analysis approach. The three main themes of the study were 'Nurse as the mediator of communication', 'Nurse as the executor of others' duties, and 'Nurse as a scapegoat'. Study findings can be used by nurses, managers, and health policy-makers to develop effective strategies for exactly determining and clarifying nurses and other healthcare professionals' roles as well as for informing the public and other healthcare professionals about nurses' roles and importance. PMID- 25716407 TI - An overview of chronic disease models: a systematic literature review. AB - AIMS: The objective of our study was to examine various existing chronic disease models, their elements and their role in the management of Diabetes, Chronic Obstructive Pulmonary Disease (COPD), and Cardiovascular diseases (CVD). METHODS: A literature search was performed using PubMed and CINHAL during a period of January 2003- March 2011. Following key terms were used either in single or in combination such as "Chronic Disease Model" AND "Diabetes Mellitus" OR "COPD" OR "CVD". RESULTS: A total of 23 studies were included in the final analysis. Majority of the studies were US-based. Five chronic disease models included Chronic Care Model (CCM), Improving Chronic Illness Care (ICIC), and Innovative Care for Chronic Conditions (ICCC), Stanford Model (SM) and Community based Transition Model (CBTM). CCM was the most studied model. Elements studied included delivery system design and self-management support (87%), clinical information system and decision support (57%) and health system organization (52%). Elements including center care on the patient and family (13%), patient safety (4%), community policies (4%), built integrated health care (4%) and remote patient monitoring (4%) have not been well studied. Other elements including support paradigm shift, manage political environment, align sectoral policies for health, use healthcare personnel more effectively, support patients in their communities, emphasize prevention, identify patient specific concerns related to the transition process, and health literacy between visits and treatments have also not been well studied in the existing literature. CONCLUSIONS: It was unclear to what extent the results generated is applicable to different populations and locations and therefore is an area of future research. Future studies are also needed to test chronic disease models in settings where more racially and ethnically representative patients receive chronic care. Future program development should also include information on other barriers including transportation issues, finances and lack of services. PMID- 25716409 TI - Improvement critical care patient safety: using nursing staff development strategies, at Saudi Arabia. AB - Intensive care units (ICUs) provide lifesaving care for the critically ill patients and are associated with significant risks. Moreover complexity of care within ICUs requires that the health care professionals exhibit a trans disciplinary level of competency to improve patient safety. This study aimed at using staff development strategies through implementing patient safety educational program that may minimize the medical errors and improve patient outcome in hospital. The study was carried out using a quasi experimental design. The settings included the intensive care units at General Mohail Hospital and National Mohail Hospital, King Khalid University, Saudi Arabia. The study was conducted from March to June 2012. A convenience sample of all prevalent nurses at three shifts in the aforementioned settings during the study period was recruited. The program was implemented on 50 staff nurses in different ICUs. Their age ranged between 25-40 years. Statistically significant relation was revealed between safety climate and job satisfaction among nurses in the study sample (p=0.001). The years of experiences in ICU ranged between one year 11 (16.4) to 10 years 20 (29.8), most of them (68%) were working in variable shift, while 32% were day shift only. Improvements were observed in safety climate, teamwork climate, and nurse turnover rates on ICUs after implementing a safety program. On the heels of this improvement; nurses' total knowledge, skills and attitude were enhanced regarding patient safety dimensions. Continuous educational program for ICUs nursing staff through organized in-service training is needed to increase their knowledge and skills about the importance of improving patient safety measure. Emphasizing on effective collaborative system also will improve patient safety measures in ICUS. PMID- 25716408 TI - Randomized controlled trials: a systematic review of laparoscopic surgery and simulation-based training. AB - INTRODUCTION: This systematic review was conducted to analyze the impact and describe simulation-based training and the acquisition of laparoscopic surgery skills during medical school and residency programs. METHODS: This systematic review focused on the published literature that used randomized controlled trials to examine the effectiveness of simulation-based training to develop laparoscopic surgery skills. Searching PubMed from the inception of the databases to May 1, 2014 and specific hand journal searches identified the studies. This current review of the literature addresses the question of whether laparoscopic simulation translates the acquisition of surgical skills to the operating room (OR). RESULTS: This systematic review of simulation-based training and laparoscopic surgery found that specific skills could be translatable to the OR. Twenty-one studies reported learning outcomes measured in five behavioral categories: economy of movement (8 studies); suturing (3 studies); performance time (13 studies); error rates (7 studies), and global rating (7 studies). CONCLUSION: Simulation-based training can lead to demonstrable benefits of surgical skills in the OR environment. This review suggests that simulation-based training is an effective way to teach laparoscopic surgery skills, increase translation of laparoscopic surgery skills to the OR, and increase patient safety; however, more research should be conducted to determine if and how simulation can become apart of surgical curriculum. PMID- 25716410 TI - Regional disparities in the distribution of healthcare workers: evidence from Iran, Chaharmahal and Bakhtiari province. AB - A health care service is a prerequisite for sustainable development. This requires access to balanced health workers in different geographic areas. The first step is to identify inequality in access to health workers in different areas. This study is a descriptive study was carried out on the cities in Chaharmahal and Bakhtiari province. TOPSIS technique was used to rank the cities in terms of regional disparities in the distribution of health workers. The findings revealed that distinct disparities in the distribution of healthcare workers across Chaharmahal and Bakhtiari province. Shahrekord and Ardal cities were classified as 1st and 7th respectively. Policy makers should consider priority (regional planning, budget and resources allocation) according to the distribution of healthcare workers. PMID- 25716411 TI - Nursing students' views of nursing education quality: a qualitative study. AB - BACKGROUND: Nursing education is currently facing challenges related to the application of nursing knowledge in clinical environments and inability of students in application of nursing procedures in clinical settings. Nursing students themselves represent the best means of identifying these challenges. This study was conducted aimed to understand the nursing students' viewpoints and experiences concerning the challenges and deficiencies of the nursing education system. METHODS: This qualitative study that has been carried out adopting conventional qualitative content analysis approach, 40 senior nursing students with sufficient experience of educational situations participated through purposive sampling. Eight focus group discussions were done with volunteer nursing students from School of Nursing and Midwifery in Zahedan (Iran). All of the interviews and discussions were recorded and then analyzed using the conventional content analysis approach. RESULTS: Three themes were emerged from data analysis including theoretical education, clinical skills, and the gap between theoretical education and clinical skills. CONCLUSIONS: The students' views and experiences of nursing education quality (theoretical, clinical, and the gap between theoretical education and clinical skills) demonstrated a need to pay careful attention to the selection and recruitment of clinical teachers, and the assessment and control of their educational performance and clinical skills, as well as to determination of standards and validation of education quality. PMID- 25716412 TI - The effect of maternal employment on the elementary and junior high school students' mental health in Maku. AB - BACKGROUND & OBJECTIVE: Most experts view the childhood period as a foundation for shaping the individuals' fundamental future characteristics and behaviors. They believe that parents' personality and behavior quality exert a greater effect on the development of a child's personality than other factors. Given the mothers' role in children's mental health and considering the fact that children are a nation's future makers, the present study was designed to investigate the impact of maternal employment on students' mental health in Maku. MATERIALS & METHODS: The present study is descriptive and cross-sectional, and the population of the study encompasses all students in the fifth, sixth, and seventh grades (n=583) who are studying in 2013-2014 academic year in Maku. General Heath Questionnaire was employed for gathering data, and the SPSS software was used for analyzing the data. FINDINGS: The results of the study indicated that there was a significant difference between the mental health problems, somatic problems, social functioning, anxiety, and depression of the students with employed and non employed mothers. In other words, the students with non-working mothers experienced greater mental disorders than those with working mothers. CONCLUSION: According to the findings of this study, it can be concluded that children with working mothers showed a better mental health than non-working mothers' children. PMID- 25716413 TI - Evaluation of time management behaviors and its related factors in the senior nurse managers, Kermanshah-Iran. AB - BACKGROUND & OBJECTIVE: Time management is an extensive concept that is associated with promoting the performance of managers. The present study was carried out to investigate the time management behaviors along with its related factors among senior nurse mangers. MATERIALS AND METHODS: In this descriptive analytical study, 180 senior nurse managers were selected using census method. The instrument for data collection was a standard time behavior questionnaire. Data were analyzed by descriptive and analytical statistics. RESULTS: The findings showed that among the dimensions of time management behaviors, setting objectives and prioritization, and mechanics of time management dimensions obtained the highest and lowest frequency, respectively. Comparison of the mean scores of time management behaviors indicated a significant difference in the gender (p<0.05), age (p<0.001), education (p=0.015), job experience (p<0.001), managerial experience (p<0.001) and management rank management (p<0.029). CONCLUSION: On the whole, senior nurse managers enjoyed a favorable time management skill. Given the importance of time management behaviors, it seems that teaching these behaviors more seriously through regular educational programs can effectively promote the performance of senior nurse managers. PMID- 25716414 TI - Prevalence of self-medication among the elderly in Kermanshah-Iran. AB - INTRODUCTION: Self-medication is consumption of one or several medications without the physician's prescription. Given the risks of self-medication, this study was carried out to assess the prevalence of self-medication and its related factors among the elderly in Kermanshah-Iran METHOD: In this descriptive cross sectional study, 272 elderly visiting the private offices in Kermanshah were selected through convenience sampling method. The instrument for data collection was a researcher made self-medication questionnaire. Data were analyzed using descriptive and analytic statistical methods (Chi-Square and Fisher exact test). RESULTS: The prevalence of self-medication was 83%. The most common reasons for self-medication were certainty of its safety (93%), prior consumption of the drug (87.6%), busy offices of physicians (82%), non-seriousness of the illness (77.8%) and prior experience of the disease (73%).The most common drugs used for self medication were analgesics (92%), cold drugs (74%), vitamins (61%), digestive drugs (54%) and antibiotics (43%). There was a significant correlation between self-medication and gender (p=0.001), education level (p=008), drug information (p=0.01), marital status (p=0.002), and medical insurance (p=0.001) variables. CONCLUSION: considering the relatively high rates of self-medication among the elderly as well as its side effects, designing and performing educational programs are suggested for the elderly people. PMID- 25716415 TI - Comparing the effects of antenatal betamethasone on Doppler velocimetry between intrauterine growth restriction with and without preeclampsia. AB - Evaluation of the effects of betamethasone on patients with intrauterine growth restriction in couple with preeclampsia is not well studied. This study was designed to assess and compare the changes of Doppler flow in maternal, fetal and placental arteries in singleton pregnancies complicated by IUGR and preeclampsia which are at 24-34 weeks of gestation after betamethasone therapy. This prospective, longitudinal and multicenter study was conducted in 2013 on the 40 singleton pregnant women with IUGR fetuses and concerned over maternal or fetal well-being. Three Doppler measurements including absolutely before betamethasone, one day after betamethasone and 5 days after betamethasone administration were performed. Flow velocity waveforms were obtained from uterine arteries (UA), Umbilical (UM), and middle cerebral artery (MCA). The Systolic/Diastolic ratio (S/D), Resistance Index (RI), and Pulsatility Index (PI) were determined for waveforms. Comparison of baseline mean scores between IUGR with and without preeclampsia showed no statistically significant differences. The mean scores of UA, MCA-UM-RI, UM-S/D, UM-PI, and UM-RI did not differ statistically significant between three time points when compared trend between negative and positive preeclampsia subjects. However, UM-RI had close P value to the margin of statistical significance (P value = 0.055). In other words, in our study, UM-RI had a clear tendency to be significance. We can conclude that preeclampsia alone could not be major prognostic factor in pregnancies with IUGR. While, other prognostic factors such as gestational age, fetal weight, and fetal vascular Doppler flow may are more important for decision making about termination of preeclampsia. PMID- 25716416 TI - A consensus approach for estimating the predictive accuracy of dynamic models in biology. AB - Mathematical models that predict the complex dynamic behaviour of cellular networks are fundamental in systems biology, and provide an important basis for biomedical and biotechnological applications. However, obtaining reliable predictions from large-scale dynamic models is commonly a challenging task due to lack of identifiability. The present work addresses this challenge by presenting a methodology for obtaining high-confidence predictions from dynamic models using time-series data. First, to preserve the complex behaviour of the network while reducing the number of estimated parameters, model parameters are combined in sets of meta-parameters, which are obtained from correlations between biochemical reaction rates and between concentrations of the chemical species. Next, an ensemble of models with different parameterizations is constructed and calibrated. Finally, the ensemble is used for assessing the reliability of model predictions by defining a measure of convergence of model outputs (consensus) that is used as an indicator of confidence. We report results of computational tests carried out on a metabolic model of Chinese Hamster Ovary (CHO) cells, which are used for recombinant protein production. Using noisy simulated data, we find that the aggregated ensemble predictions are on average more accurate than the predictions of individual ensemble models. Furthermore, ensemble predictions with high consensus are statistically more accurate than ensemble predictions with large variance. The procedure provides quantitative estimates of the confidence in model predictions and enables the analysis of sufficiently complex networks as required for practical applications. PMID- 25716417 TI - Convergent Regulation of Candida albicans Aft2 and Czf1 in Invasive and Opaque Filamentation. AB - Candida albicans is the most common fungal pathogen of mucosal infections and invasive diseases in immuno-compromised humans. The abilities of yeast-hyphal growth and white-opaque switching affect C. albicans physiology and virulence. Here, we showed that C. albicans Aft2 regulator was required for embedded filamentous growth and opaque cell-type formation. Under low-temperature matrix embedded conditions, Aft2 functioned downstream of Czf1-mediated pathway and was required for invasive filamentation. Moreover, deletion of AFT2 significantly reduced opaque cell-type formation under N-acetylglucosamine (GlcNAc) inducing conditions. Ectopic expression of CZF1 slightly increased the white-opaque switching frequency in the aft2Delta/Delta mutant, but did not completely restore to wild-type levels, suggesting that Czf1 at least partially bypassed the essential requirement for Aft2 in response to opaque-inducing cues. In addition, multiple environmental cues altered AFT2 mRNA and protein levels, such as low temperature, physical environment and GlcNAc. Although the absence of Czf1 or Efg1 also increased the expression level of AFT2 gene, deletion of CZF1 remarkably reduced the stability of Aft2 protein. Furthermore, C. albicans Aft2 physically interacted with Czf1 under all tested conditions, whereas the interaction between Aft2 and Efg1 was barely detectable under embedded conditions, supporting the hypothesis that Aft2, together with Czf1, contributed to activate filamentous growth by antagonizing Efg1-mediated repression under matrix-embedded conditions. PMID- 25716418 TI - Differences between clinical and laboratory findings in patients with recent diagnosis of SLE according to the positivity of anti-dsDNA by the Crithidia luciliae method. AB - BACKGROUND: Of all anti-dsDNA antibody detection methods, the Crithidia luciliae immunofluorescence test (CLIF) is considered to have the highest specificity for systemic lupus erythematosus (SLE). OBJECTIVE: The objective of this report is to evaluate whether the presence of anti-dsDNA antibodies detected by the CLIF method is associated with a specific clinical phenotype in recently diagnosed SLE. METHODS: This retrospective cross-sectional study included all patients with newly diagnosed SLE between 1990 and 2011 and followed up in our institution. Demographic, clinical and laboratory findings were assessed. Correlations between positivity of anti-dsDNA by the CLIF method, clinical and laboratory data were analyzed. RESULTS: A total of 104 patients were included in the analysis. Patients who were positive for anti-dsDNA by the CLIF method at the time of diagnosis had (statistically) significantly higher titers of anti-dsDNA by the ELISA method, antinuclear (ANA) and anticardiolipin antibodies, lymphopenia and complement consumption compared with the other two groups. Also they presented significantly more musculoskeletal symptoms at baseline. CONCLUSION: The presence of anti-dsDNA by the CLIF method in newly diagnosed SLE was associated with certain markers of increased disease activity. Its use could be a useful biomarker for a specific clinical phenotype suggestive of a more severe involvement at the time of the diagnosis. PMID- 25716419 TI - Magnetic resonance imaging findings are useful for evaluating the three dimensional development and follow-up of linear lupus erythematosus profundus. AB - Lupus erythematosus profundus (LEP), which is a variant of chronic cutaneous lupus erythematosus (CLE), is seen in approximately 2~3% of CLE patients, and only 10% to 20% of LEP patients present with systemic LE (SLE). LEP shows subcutaneous nodules with or without discoid LE (DLE). Linear LEP, a very rare variant of LEP, was first reported in 1991 in Japanese and in 1998 in English. Since LEP sometimes leaves skin depressions or scars as a result of atrophy of adipose tissue, early and adequate treatments are necessary. Here, we introduce an LEP case in which magnetic resonance imaging (MRI) was quite effective in evaluating a lesion that had been considered to be linear DLE. PMID- 25716420 TI - SLE presenting as multiple hemorrhagic complications. AB - A 24 year old female with hereditary spastic paraplegia presented with intermittent headache for one year. She also had lower abdominal pain and vomiting for two months. She was pale, had icterus and mild splenomegaly. On diagnostic evaluation she was found to have hemolytic anemia, thrombocytopenia and bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages due to systemic lupus erythematosus (SLE). However, antiphospholipid syndrome (APS) antibodies were negative. Bilateral adrenal hemorrhage without associated APS is a rare phenomenon in SLE. We describe a case of SLE presenting with sequence of rare hemorrhagic complications in concert. PMID- 25716421 TI - Single high-concentration capsaicin application prevents c-Fos expression in spinothalamic and postsynaptic dorsal column neurons after surgical incision. AB - BACKGROUND: Allodynia and hyperalgesia present after surgical interventions are often a major complain of surgical patients. It is thought that both peripheral and central mechanisms contribute to these symptoms. In this study, the role of peripheral nerve fibres that express transient receptor potential vanilloid 1 (TRPV1) receptors in the activation of spinothalamic tract (STT) and postsynaptic dorsal column (PSDC) neurons was assessed in a model of surgical pain. METHODS: Spinothalamic tract and PSDC neurons retrogradely labelled from the thalamus and nucleus gracilis were used. Activation of these projection neurons was evaluated after plantar incision as expression of the early gene product, c-Fos protein, in the nuclei of these neurons. RESULTS: There was a robust increase in c-Fos immunopositivity in the STT and PSDC neurons, in the control animals after a plantar incision. This increase in c-Fos expression was significantly attenuated in animals in which a single high-concentration capsaicin injection was made intradermally at the incision site 24 h before the surgery. CONCLUSIONS: Our results suggest that activation of both STT and PSDC neurons is involved in development of pain states present after surgical incision and that TRPV1 containing peripheral nerve fibres are needed for c-Fos expression in these dorsal horn neurons after plantar incision. PMID- 25716422 TI - Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas-kidney transplantation. AB - Because microvascular disease is one of the most important drivers of diabetic complications, early monitoring of microvascular integrity may be of clinical value. By assessing profiles of circulating microRNAs (miRNAs), known regulators of microvascular pathophysiology, in healthy controls and diabetic nephropathy (DN) patients before and after simultaneous pancreas-kidney transplantation (SPK), we aimed to identify differentially expressed miRNAs that associate with microvascular impairment. Following a pilot study, we selected 13 candidate miRNAs and determined their circulating levels in DN (n = 21), SPK-patients (n = 37), healthy controls (n = 19), type 1 diabetes mellitus patients (n = 15) and DN patients with a kidney transplant (n = 15). For validation of selected miRNAs, 14 DN patients were studied longitudinally up to 12 months after SPK. We demonstrated a direct association of miR-25, -27a, -126, -130b, -132, -152, 181a, -223, -320, -326, -340, -574-3p and -660 with DN. Of those, miR-25, -27a, 130b, -132, -152, -320, -326, -340, -574-3p and -660 normalized after SPK. Importantly, circulating levels of some of these miRNAs tightly associate with microvascular impairment as they relate to aberrant capillary tortuosity, angiopoietin-2/angiopoietin-1 ratios, circulating levels of soluble thrombomodulin and insulin-like growth factor. Taken together, circulating miRNA profiles associate with DN and systemic microvascular damage, and might serve to identify individuals at risk of experiencing microvascular complications, as well as give insight into underlying pathologies. PMID- 25716423 TI - Hybrid organic/inorganic band-edge modulation of p-Si(111) photoelectrodes: effects of R, metal oxide, and Pt on H2 generation. AB - The efficient generation of dihydrogen on molecularly modified p-Si(111) has remained a challenge due to the low barrier heights observed on such surfaces. The band-edge and barrier height challenge is a primary obstruction to progress in the area of integration of molecular H2 electrocatalysts with silicon photoelectrodes. In this work, we demonstrate that an optimal combination of organic passivating agent and inorganic metal oxide leads to H2 evolution at photovoltages positive of RHE. Modulation of the passivating R group [CH3 -> Ph > Naph -> Anth -> Ph(OMe)2] improves both the band-edge position and DeltaV (Vonset - VJmax). Subsequent atomic layer deposition (ALD) of Al2O3 or TiO2 along with ALD-Pt deposition results in to our knowledge the first example of a positive H2 operating potential on molecularly modified Si(111). Mott-Schottky analyses reveal that the flat-band potential of the stable Ph(OMe)2 surface approaches that of the native (but unstable) hydride-terminated surface. The series resistance is diminished by the methoxy functional groups on the phenyl unit, due to its chemical and electronic connectivity with the TiO2 layer. Overall, judicious choice of the R group in conjunction with TiO2|Pt effects H2 generation on p-Si(111) photoelectrodes (Voc = 207 +/- 5.2 mV; Jsc = -21.7 mA/cm(2); ff = 0.22; etaH2 = 0.99%). These results provide a viable hybrid strategy toward the operation of catalysts on molecularly modified p-Si(111). PMID- 25716424 TI - On the measurement of dose in-air for small radiation fields: choice of mini phantom material. AB - The purpose of this work was to determine the effect of choice of mini-phantom material on the measurement and calculation of in-air output factors (Sc) in small fields. Monte Carlo simulations in conjunction with a theoretical determination of Sc were used to validate previously reported measurements. Options for alternative mini-phantom materials were compared. A 6 MV beam from a Varian Novalis linear accelerator operating in stereotactic (SRS) mode was modelled. Phase-space data were used to determine the theoretical value of Sc. To validate previously reported Sc measurements the data were used to model the fibre-optic detector and brass mini-phantom. The impact of mini-phantom material was investigated by comparing the energy spectra of electrons entering the detector volume as a function of field size, and comparing the simulated Sc measurement to the theoretical calculation. In order to determine factors leading to changes in Sc with field size, the origins of particles in the beam as incident on the mini-phantom were determined. Sc values derived from simulated measurements using a brass mini-phantom on a fibre-optic detector agreed with the measured Sc to within 0.7%. For simulation of measurement for all other mini phantom materials, Sc values agreed with the theoretically calculated values to within 0.6%. The dominant processes responsible for a decrease in Sc with field size is occlusion of the focal and primary collimator contributions, while the secondary scatter, from the flattening filter and cone collimators, has minimal effect. The secondary electron spectrum is affected by the choice of mini-phantom material, but is almost independent of field size. For cone-collimated small fields in the Novalis beam (<30 mm), the decrease in Sc with field size is primarily due to collimation of the focal radiation beam and scatter from the primary collimator. A fibre optic detector with either a brass, gold or lead mini phantom with at least d(max) equivalent height is suited to measure Sc for small SRS fields. The use of materials with higher electron/physical density can be used to reduce the size of the mini-phantom and reduce spatial averaging. PMID- 25716425 TI - A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer. AB - BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome. PMID- 25716426 TI - Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant. AB - The synthesis of proteins in the endoplasmic reticulum (ER) that exceeds the protein folding capacity of this organelle is a frequent cause of cellular dysfunction and disease. An example of such a disease is alpha-1-antitrypsin (A1AT) deficiency, caused by destabilizing mutations in this glycoprotein. It is considered that the mutant proteins are recognized in the ER by lectins and are subsequently degraded through the proteasome, leading to a deficiency in this enzyme in the afflicted patients. We previously established a Drosophila model of this disease by overexpressing the null Hong Kong (NHK) allele of this gene and found that the Drosophila lectin, ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2), can accelerate the degradation of A1AT when overexpressed. NHK is a rare allele, and in this study, we investigated in depth the mechanisms through which Drosophila EDEMs affect the degradation of the Z variant, which is the predominant disease allele. Specifically, we report that the Z allele does not activate ER stress signaling as prominently as the NHK allele, but similarly requires both Drosophila EDEM1 and EDEM2 for the degradation of the protein. We demonstrate that EDEMs are required for their ubiquitination, and without EDEMs, glycosylated A1AT mutants accumulate in cells. These results support the role of the EDEM-mediated ubiquitination of the alpha-1-antitrypsin Z (ATZ) allele, and establish a Drosophila model for the study of this protein and disease. PMID- 25716427 TI - A systematic review of parent and clinician views and perceptions that influence prescribing decisions in relation to acute childhood infections in primary care. AB - OBJECTIVES: To investigate the views of parents, clinicians, and children pertaining to prescribing decisions for acute childhood infection in primary care. METHODS: A systematic review of qualitative studies. Meta-ethnographic methods were used, with data drawn from the primary studies in an interpretive analysis. RESULTS: A total of 15 studies met the inclusion criteria. The literature was dominated by concerns about antibiotic over-prescription. Children's views were not reported. Clinicians prescribed antibiotics when they felt pressured by parents or others (e.g. employers) to do so, when they believed there was a clear clinical indication, but also when they felt uncertain of clinical or social outcomes they prescribed "just in case". Parents wanted antibiotics when they felt they would improve the current illness, and when they felt pressure from daycare providers or employers. Clinicians avoided antibiotics when they were concerned about adverse reactions or drug resistance, when certain they were not indicated, and when there was no perceived pressure from parents. Parents also wished to avoid adverse effects of antibiotics, and did not want antibiotics when they would not relieve current symptoms. Some parents preferred to avoid medication altogether. Within paediatric consultations, parents sought a medical evaluation and decision. Primary care clinicians want satisfied parents and short consultations. CONCLUSIONS: Antibiotic prescriptions for childhood infections in primary care often result from "just in case" prescribing. These findings suggest that interventions which reduce clinician uncertainty regarding social or clinical outcomes and provide strategies to meet parents' needs within a short consultation are most likely to reduce antibiotic prescribing. PMID- 25716428 TI - Pharmacokinetic difference of berberine between normal and chronic visceral hypersensitivity irritable bowel syndrome rats and its mechanism. AB - Berberine is one of active alkaloids from Rhizoma coptidis in traditional Chinese medicine. The pharmacokinetics of berberine in rat plasma were compared between normal and chronic visceral hypersensitivity irritable bowel syndrome rats (CVH IBS) established by mechanical colon irritation using angioplasty balloons for 2 weeks after oral administration of berberine hydrochloride (25 mg/kg) with the equivalent dose of 22 mg/kg for berberine according to body weight. Immunohistochemical analysis of c-fos and myosin light chain kinase (MLCK) and immunofluorescence analysis of MLCK in rat colon were conducted. Quantification of berberine in rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples were collected at 15 different points in time and the pharmacokinetic parameters were analyzed by WinNonlin software. The great different pharmacokinetic behavior of berberine was observed between normal and CVH-IBS model rats. Compared with normal group, T1/2 and AUC(0-t) of berberine in the model group were significantly increased, respectively (573.21 +/- 127.53 vs 948.22 +/- 388.57 min; 8,657.19 +/- 1,562.54 vs 11,415.12 +/- 1,670.72 min.ng/ml). Cl/F of berberine in the model group significantly decreased, respectively (13.89 +/- 1.69 vs 9.19 +/- 2.91 L/h/kg). Additionally, the expressions of c-fos and MLCK in model group were higher than those in normal group. The pharmacokinetic behavior of berberine was significantly altered in CVH IBS pathological conditions, which indicated the dosage modification of berberine hydrochloride in CVH-IBS were necessary. Especially, improved exposure to berberine in rat plasma in CVH-IBS model rats was attributed to increased the expression of MLCK. PMID- 25716430 TI - Quality evaluation of Perillae Folium by HPLC/PDA. AB - To establish a standard of quality control for Perillae Folium (Lamiaceae Family), four standard compounds including rosmarinic acid, elemicin, perillaldehyde, and dillapiole were evaluated by high-performance liquid chromatography (HPLC)/photodiode array (PDA). The four standards were analyzed with a Phenomenex Kinetex C18 (250 * 4.6 mm, 5 MUm) column by gradient elution using 0.1 % formic acid in water and methanol as the mobile phase. The standards were quantified by HPLC/PDA from Perillae Folium, which included the leaf and twig of Perilla frutescens L. Britton var. acuta (Thunb.) Kudo or Perilla frutescens Britton var. crispa Decne. The method was successfully used in the analysis of Perillae Folium, and the linearity, recovery, precision, accuracy, stability, and robustness were satisfactory according to the validation results. In Perillae Folium samples, the average contents (wt%) of rosmarinic acid, elemicin, perillaldehyde, and dillapiole were 0.540, 0.059, 0.050, and 0.056 %, respectively. The results indicate that the established HPLC/PDA method is suitable for the quantitation and quality evaluation of Perillae Folium. PMID- 25716429 TI - Inhibitory effects of quercetagetin 3,4'-dimethyl ether purified from Inula japonica on cellular senescence in human umbilical vein endothelial cells. AB - Cellular senescence contributes to tissue and organismal aging, tumor suppression and progress, tissue repair and regeneration, and age-related diseases. Thus, aging intervention might be beneficial for treatment and prevention of diverse age-related diseases. In the present study, we investigated whether four compounds purified from Inula japonica exert inhibitory activity against cellular senescence induced by adriamycin in human umbilical vein endothelial cells (HUVECs). Among them, compound 4 (quercetagetin 3,4'-dimethyl ether) showed inhibitory activity against cellular senescence, which was confirmed by senescence-associated beta-galactosidase (SA-beta-gal) activity, p53 and p21 protein levels, and intracellular ROS levels. Compound 4 also reduced SA-beta-gal activity in HUVECs under replicative senescence. These results suggest that compound 4 represses cellular senescence in HUVECs and might be useful for the development of dietary supplements or cosmetics that alleviate tissue aging or age-related diseases. PMID- 25716432 TI - Bilaspur sterilisation deaths: evidence of oppressive population control policy. PMID- 25716431 TI - Impact of a high-cholesterol diet on expression levels of Niemann-Pick C1-like 1 and intestinal transporters in rats and mice. AB - Niemann-Pick C1-like 1 (NPC1L1), ATP-binding cassette (ABC)G5, and ABCG8 are all involved in intestinal cholesterol absorption. It is unclear whether a high cholesterol (HC) diet affects the expression of these transporters in rats and mice as well as humans. We examined the effects of an HC diet on their expression in small intestine and the differences between rats and mice in the responsive of this expression to an HC diet. In addition to these transporters, alterations in six representative drug and nutrient transporters (multidrug resistance associated protein, breast cancer resistance protein, peptide transporter, sodium glucose linked transporter, glucose transporter, and L-type amino acid transporter) and transcriptional factors such as hepatocyte nuclear factor (HNF)4alpha, sterol regulatory element-binding protein (SREBP)2, and liver X receptor (LXR)alpha were determined. In rats and mice fed an HC diet for 7 days, the mRNA and protein levels of NPC1L1 in the small intestine were determined by real-time reverse transcription polymerase chain reaction and western blotting, respectively. The mRNA levels of ABCG5 and ABCG8, six representative transporters, and transcriptional factors such as HNF4alpha, SREBP2, and LXR were examined. Significant decreases in the expression levels of NPC1L1 were observed in mice, but not rats, fed the HC diet. The mRNA levels of ABCG5 and ABCG8 were significantly increased in HC rats but not in mice. Only minor changes in the mRNA levels of the other transporters were seen in HC rats and mice. Decreased mRNA levels of HNF4alpha and SREBP2 in mice could be involved in the reduction in NPC1L1 expression observed upon the introduction of an HC diet. These results indicate that the effects of an HC diet on the expression levels of NPC1L1, ABCG5, and ABCG8 differ between mice and rats. PMID- 25716433 TI - IJME Fifth National Bioethics Conference and the challenges ahead. PMID- 25716434 TI - Gender, mental illness and the Hindu Marriage Act, 1955. AB - INTRODUCTION: Section 5(ii) of The Hindu Marriage Act, 1955 (HMA) states that under certain circumstances, mental illness is accepted as a ground for the annulment of marriage, while Section 13(1) (iii) states that mental illness is a ground for divorce. There is little data on how this provision is used and applied in matrimonial petitions. This paper assesses judicial practices in divorce cases, exploring the extent to which gender and the diagnosis of mental illness affect the decision to grant annulment or divorce. METHODS: The paper analyses judgments related to annulment and divorce at the Family Court in Pune and at the High Courts in India. RESULTS: In the Family Court at Pune, 85% of the cases were filed by husbands, who alleged that their spouse was mentally ill. Medical evidence of mental illness was presented in only 36% of the cases and in many cases, divorce/nullity was granted even in the absence of medical evidence. In 14% of the cases, nullity/divorce was granted even when both spouses were not present. Of the Family Court cases reaching the High Court, 95% were filed by male petitioners. The High Courts reversed the lower courts' judgments in 50% of the cases. DISCUSSION: Our analysis highlights the need for standardised guidelines for lower courts on what constitutes adequate medical proof of mental illness when hearing a petition related to nullity or divorce under HMA. It also provides a critical review of Section 5(ii) of HMA. PMID- 25716435 TI - Reflections on discrimination and health in India. AB - This is a speculative paper on the structure of caste-based discrimination in India. It sketches the field by a) proposing four empirical and historical examples of discrimination in different medical situations; b) suggesting an analytical framework composed of domain, register, temporality and intensity of discrimination; c) proposing that in the Indian historical context, discrimination masks itself, hiding its character behind the veneer of secular ideas; d) arguing that discrimination is not some unfortunate residue of backwardness in modern society that will go away, but is the force of social hierarchy transforming itself into a fully modern capitalist culture. The paper then arrives at the understanding that discrimination is pandemic across India. The conclusion suggests that in India today, we need proposals, hypotheses and arguments that help us establish the ethical framework for meaningful empirical research that sociological studies of medical ethics and the epidemiology of discrimination can pursue. Its method is that of logical and speculative argument based on experience, with examples of different forms of discrimination to clarify the point being made. No specific research was undertaken for this purpose since the paper is not empirically based. PMID- 25716436 TI - What ails India's two-tiered healthcare system? A philosophical enquiry. AB - India's two-tiered healthcare system (viz the public and private sectors) has been suffering from various ailments, and each sector has been criticised for its own set of deficiencies. Against this backdrop, this article explores whether there is any possible commonality between the two sectors, and suggests that the "common logic", or common ground, is the model of biomedical knowledge, which forms the foundation of both sectors. It is to problems inherent in the "model of biomedical knowledge" that certain gaps in each sector can be traced. It is only when we have identified the lapses at the root of the structures of each sector that we can plug the gaps in healthcare. The author suggests that it would be best to analyse the gaps through a philosophical enquiry, and to offer a probable solution, turns to the methodologies of care ethics and feminist standpoint epistemology. PMID- 25716437 TI - (Mis)regulation--the case of commercial surrogacy. AB - In the most recent attempt to regulate commercial surrogacy, the Ministry of Home Affairs (MHA) has issued a notice altering the category of visa for foreign nationals entering into commercial surrogacy arrangements from "tourist" to "medical". Upon close scrutiny, it becomes clear that this measure is a far too hasty and unprincipled step. Given the varying laws across different countries, commercial surrogacy has been an area marked by a fair amount of legal ambiguity and conflict, for example, with respect to the citizenship status of the child and legally accepted parentage of commissioning parents. The MHA's step towards addressing some of the dilemmas is, however, grossly inadequate and discriminatory. In spite of its seeming advantages, of some administrative and legal oversight of the industry, the notice will impact the existing practices in questionable ways since its provisions remain to be vetted through the lens of medical ethics and social justice. The measures, which are supposed to ensure legality, disambiguation and some degree of security for the commercial surrogate, end up giving a clean chit to the industry for the time being. If the step taken by the MHA was meant to be urgent, one wonders at the lack of motivation to strengthen public debate and produce a piece of legislation that can address the various concerns and dilemmas generated by the assisted reproductive technologies (ARTs). This is especially with reference to legislation that ensures the health and democratic rights of those who are at a disadvantage due to the power imbalance in commercial surrogacy arrangements. PMID- 25716438 TI - Preventive lipostasis: spawning lipochondria. PMID- 25716439 TI - MTP Amendment Bill, 2014: towards re-imagining abortion care. AB - In India, the 1971 Medical Termination of Pregnancy Act, while allowing abortions under a broad range of circumstances, can be considered a conservative law from a feminist perspective. The Act allows healthcare providers rather than women seeking abortion to have the final say on abortion, and creates an environment within which women are made dependent on their healthcare providers. On October 29, 2014, the Ministry of Health and Family Welfare released a draft of the MTP (Amendment) Bill 2014, which proposes changes that could initiate a shift in the focus of the Indian abortion discourse from healthcare providers to women. Such a shift would decrease the vulnerability of women within the clinical setting and free them from subjective interpretations of the law. The Bill also expands the base of healthcare providers by including mid-level and non-allopathic healthcare providers. While the medical community has resisted this inclusion, the author is in favour of it, arguing that in the face of the high rates of unsafe abortion, such a step is both ethical and necessary. Additionally, the clause extending the gestational limit could trigger ethical debates on eugenic abortions and sex selective abortions. This paper argues that neither of these should be used to limit access to late-trimester termination, and should, instead, be dealt with separately and in a way that enquires into why such pregnancies are considered unwanted. PMID- 25716440 TI - Indiscriminate disposal of museum specimens--a case report. AB - The human body and its parts and organs are invariably used in medical teaching institutions for academic purposes. Legal provisions for the preservation of such specimens are made in anatomy Acts across the country. However, after they have been used, the specimens are not disposed of in a proper manner. This is a public menace and forces the authorities concerned to carry out unnecessary investigations. We report a case in which the bodies of two foetuses that were brought for medico-legal autopsy were later found to be formalin-preserved "museum specimens" that had been used for anatomical study. We wish to emphasise the need for guidelines for the proper disposal of anatomical museum specimens. PMID- 25716441 TI - Are we treating our geriatric population ethically?--Views of a resident doctor. AB - With the improvement in health services and continuing advancements in medicine, people are living longer all over the world. Thus the proportion of patients in the elderly age group is also increasing. How ethically are we treating our geriatric patients in India and what does the future hold for them? PMID- 25716442 TI - Catch-22 for the radiologist. PMID- 25716443 TI - Advance directives, palliative care and clinical bioethics committees. PMID- 25716444 TI - Reforming the Medical Council of India. PMID- 25716445 TI - Life insurance and clinical trial participants. PMID- 25716446 TI - Why Indian doctors are lethargic about active research. PMID- 25716447 TI - MLK. PMID- 25716449 TI - Differential immunodetection of toxin B from highly virulent Clostridium difficile BI/NAP-1/027. AB - We developed a simple immunoassay capable of differentially detecting toxin B from highly virulent strains of Clostridium difficile (BI/NAP-1/027) in stool. This assay can simultaneously confirm the presence of in vivo toxin production and provide strain-related information relevant to infection control epidemiology and disease prognosis. PMID- 25716450 TI - Acrophialophora, a poorly known fungus with clinical significance. AB - Acrophialophora fusispora is an emerging opportunistic fungus capable of causing human infections. The taxonomy of the genus is not yet resolved and, in order to facilitate identification of clinical specimens, we have studied a set of clinical and environmental Acrophialophora isolates by morphological and molecular analyses. This set included the available type strains of Acrophialophora species and similar fungi, some of which were considered by various authors to be synonyms of A. fusispora. Sequence analysis of the large subunit (LSU) and internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and a fragment of the beta-tubulin (Tub) gene revealed that Acrophialophora belongs in the family Chaetomiaceae and comprises three different species, i.e., A. fusispora, Acrophialophora levis, and Acrophialophora seudatica; the latter was previously included in the genus Ampullifera. The most prevalent species among clinical isolates was A. levis (72.7%), followed by A. fusispora (27.3%), both of which were isolated mostly from respiratory specimens (72.7%), as well as subcutaneous and corneal tissue samples. In general, of the eight antifungal drugs tested, voriconazole had the greatest in vitro activity, while all other agents showed poor in vitro activity against these fungi. PMID- 25716451 TI - Directionally hiding objects and creating illusions above a carpet-like device by reflection holography. AB - Realization of a perfect invisibility cloak still challenges the current fabricating technologies. Most experiments, if not all, are hence focused on carpet cloaks because of their relatively low requirements to material properties. Nevertheless, present invisibility carpets are used to hide beneath objects. Here, we report a carpet-like device to directionally conceal objects and further to create illusions above it. The device is fabricated through recording a reflection hologram of objects and is used to produce a time-reversed signal to compensate for the information of the objects and further to create light field of another object so as to realize both functions of hiding the objects and creating illusions, respectively. The carpet-like device can work for macroscopic objects at visible wavelength as the distance between objects and device is at decimeter scale. Our carpet-like device to realizing invisibility and creating illusions may provide a robust way for crucial applications of magic camouflaging and anti-detection etc. PMID- 25716452 TI - Child physical activity levels and associations with modifiable characteristics in centre-based childcare. AB - OBJECTIVE: To describe children's physical activity levels during childcare and associations with modifiable characteristics. METHODS: A cross-sectional study of 328 preschool children (43% girls; age 3-5 years) and 145 staff from 20 long day care centres in the Hunter Region of NSW, Australia. Pedometers assessed child physical activity levels. Centre characteristics and staff attitudes and behaviours towards children's physical activity were assessed using surveys, interviews and observational audit. Results were analysed using descriptive statistics and linear regression. RESULTS: Over the measurement period, average step count of children was 15.8 (SD=6.8) steps/minute. Four-year-olds had the highest step counts (16.4, SD=7.1, p=0.03) with no differences by sex. Step counts were significantly higher in centres that had a written physical activity policy (+3.8 steps/minute, p=0.03) and where staff led structured physical activity (+3.7 steps/minute, p<0.001) and joined in active play (+2.9 steps/minute, p=0.06). CONCLUSIONS: Written physical activity policy, structured staff-led physical activity and staff joining in active play were associated with higher levels of physical activity. IMPLICATIONS: Childcare physical activity interventions should consider including strategies to encourage written physical activity policies and support structured staff led physical activities. PMID- 25716454 TI - Lactate on emergency department arrival as a predictor of mortality and site-of care in pneumonia patients: a cohort study. AB - OBJECTIVE: To investigate the predictive performance of lactate, CURB-65, and a combination of lactate and CURB-65 (LAC-CURB-65) for mortality, hospitalisation and intensive care unit (ICU) admission in pneumonia patients in the emergency department (ED). METHODS: Consecutive adult patients with pneumonia presenting from January 2012 to May 2014 were divided into low-, moderate- and high-risk groups according to lactate (<2.0, 2.0-4.0, >4.0 mmol/L), CURB-65 (<=1, 2, >=3) and LAC-CURB-65 (patients with two low risks, any moderate risk, any high risk) values. Mortality, hospitalisation and ICU admission rates were compared between risk classes. RESULTS: Of 1641 patients, 861 (53%) were hospitalised (38% to a general ward, 15% to the ICU) while the remaining 780 (47%) were treated as outpatients or observed in the ED. 547/1641 (33%) patients died within 28 days. Lactate and CURB-65 were higher in patients who died, were hospitalised or were admitted to the ICU compared with patients who were not (p<0.001). Lactate and CURB-65 independently predicted outcomes. The performance of lactate in predicting 28-day mortality, hospitalisation and ICU admission was higher than that of CURB-65 (p<0.01). For LAC-CURB-65, patients at low or moderate risk had mortality rates of 2% and 14%, respectively, and hospitalisation rates of 15% and 40%, respectively, while none were admitted to ICU. Patients at high risk had the highest mortality (52%), hospitalisation (70%) and ICU admission rates (27%). CONCLUSIONS: Lactate is superior to CURB-65 in predicting mortality, hospitalisation and ICU admission in pneumonia patients in the ED. LAC-CURB-65 significantly improved the predictive value of CURB-65. PMID- 25716455 TI - Spouses and depressive symptoms in older adulthood. AB - Depressive symptoms may co-occur within couples and follow similar trajectories, but relatively little is known about this process in old age. This study thus examined the association between some spousal characteristics (spouse's depressive symptoms, age difference between spouses) and the trajectory of depressive symptoms in older adults. Participants >= 65 years old were drawn from the Health and Retirement Study (N = 12,010; Mean age = 70.60 and 69.16 for target husbands and wives, respectively). Depressive symptoms were measured with a short form of the Center for Epidemiological Studies Depression (CES-D) scale. Hierarchical Linear Modeling was used to model up to 9 assessments of depressive symptoms of target spouses (Mean number of CESD assessments per target spouse = 3, range 1-9). Depressive symptoms between spouses were correlated; convergence over time was modest. For both husbands and wives, having a younger spouse was associated with more depressive symptoms at age 65. These results suggest that there is concordance between spouses' depressive symptoms and that the age difference between spouses contribute to depressive symptoms as couples enter old age. The association between spouses' depressive symptoms is nearly as strong as the effect of each decade increase in age. PMID- 25716456 TI - Extended halogen bonding between fully fluorinated aromatic molecules. AB - Halogen bonding is a noncovalent interaction where an electrophilic cap on a halogen atom, the so-called sigma-hole, attracts a nucleophilic site on an adjacent molecule. The polarizability of halogens relates to the strength of the sigma-hole, and accordingly the halogen-halogen distance becomes shorter in the order of Cl, Br, and I. Fully fluoro-substituted aromatic molecules, on the contrary, are generally believed not to form halogen bonds due to the absence of a sigma-hole. Here, we study atomic-scale in-plane F-F contacts with high resolution force microscopy. Our ab initio calculations show that the attractive dispersion forces can overcome the electrostatic repulsion between the fluorine atoms, while the anisotropic distribution of the negative electrostatic potential leads the directional bond and even changes the gap. The coexistence of these two competing forces results in the formation of a "windmill" structure, containing three C-F...F bonds among neighboring molecules. While the sigma-hole is absent, the scheme of the C-F...F bonding has a high similarity to halogen bonding. PMID- 25716457 TI - Can and should carotid ultrasound be used in cardiovascular risk assessment?: the internist's perspective. AB - Cardiovascular risk management is a major and challenging task for internists. Risk scores using algorithms based on traditional risk factors are helpful in identifying patients in whom intensive prevention strategies are warranted. However there remains a need for more accurate screening tools to allow clinicians to individualize the primary prevention programs to their patients. Approximately 40-80% of apparently healthy, asymptomatic subjects exhibit increased thickness of the lamina intima-media of the carotid artery or have atherosclerotic carotid plaques. These abnormalities can be measured safely and at low cost by ultrasound. Subclinical carotid lesions are strongly associated with generalized atherosclerotic burden and the risk of future cardiovascular events. Although many cardiovascular risk management guidelines recommend the use of these parameters incorporation in clinical practice is still not commonplace. Based on the current literature it can be stated that in high risk patients there is no additional value of carotid ultrasound because even in the absence of carotid lesions these patients should receive an intensive risk reduction regime. In the large low-intermediate risk group however carotid ultrasound findings carry subtle but possibly clinically relevant information about cardiovascular risk profile. The effect of treatment decisions based on carotid ultrasound parameters has not been studied. Sequential measurements to monitor progression and evaluate treatment response on an individual basis are not sufficiently reproducible. We therefore recommend the use of carotid ultrasound in low to intermediate risk patients but emphasize the importance of interpreting the results in conjunction with all cardiovascular risk factors and avoid follow-up measurements. PMID- 25716458 TI - Archaeal viruses: living fossils of the ancient virosphere? AB - Studies on viruses parasitizing archaea reveal their specific nature and complete the tripartite division of the biosphere, indicating that each of the three domains of life-Archaea, Bacteria, and Eukarya-has its own set of associated DNA viruses. I argue that the remarkable morphotypical diversity of archaea-specific viruses could have originated from diverse viral archetypes that predated the divergence of the three domains of cellular life. It is possible that the descendants of many of these viral archetypes are able to parasitize extant archaea owing to their ability to evade archaea-specific defenses against virus infection, specifically the defenses linked to the evolution of cell envelope structure. PMID- 25716459 TI - A physical match of a metallic chip found on a bolt cutters' blade. AB - Bolt cutters are known as devices which are used for cutting hard objects and rigid materials such as padlocks and bars. They are commonly used in instances of forced entries. In this case study, a bolt cutter was found in the car of two suspects in a grocery burglary. This study indicates how the presence of a small metallic chip found on a suspected bolt cutter can prove that the tool was used in the crime scene. During the initial examination, a metallic chip from the cut shackle padlock was found stuck to one of the bolt cutters' blades. By comparing the metallic chip's microscopic edge and the breaking (fracture) line of the padlock's shackle, a full physical match was noticed. We wish to report here how residue, even the smallest, can be used to link burglary tools to a crime scene with a high level of certainty. PMID- 25716460 TI - The effect of thioctic acid on allodynia in a rat vincristine-induced neuropathy model. AB - OBJECTIVE: To investigate the antiallodynic effects of thioctic acid in vincristine-induced neuropathy in rats. METHODS: Neuropathy was induced in Sprague-Dawley rats via vincristine intraperitoneal injection. After 15 days, rats were investigated for the presence of mechanical and cold allodynia, and those with allodynia received intraperitoneal injection with normal saline or 1, 5, or 10 mg/kg thioctic acid. Mechanical and cold allodynia were assessed before treatment and at 15, 30, 60, 90, 150 and 180 min after treatment. RESULTS: Mechanical and cold allodynia were reduced by thioctic acid injection. The duration of effect increased with thioctic acid dose. CONCLUSION: Thioctic acid may be an effective treatment for vincristine-induced neuropathy. PMID- 25716461 TI - Treatment of invasive silent somatotroph pituitary adenoma with temozolomide. Report of a case and review of the literature. AB - Improved imaging techniques have contributed to increased diagnosis of pituitary tumors. These tumor types can be microadenomas or macroadenomas and can either be functional or non-functional. Atypical or aggressive pituitary adenomas are tumors that rapidly increase in size and may invade into the suprasellar or parasellar regions. They are characterized by a Ki-67 nuclear labeling index greater than 10 %. Management of these tumors is difficult, and many recur after surgery. Temozolomide, a second generation alkylating agent, has been showing promising results in the treatment of these tumors. The patient was a 39-year-old male diagnosed with an invasive silent somatotroph pituitary macroadenoma treated with temozolomide after surgery. We present the case along with the review of the literature of the therapeutic effects of temozolomide in somatotroph macroadenomas. PMID- 25716462 TI - Pre-exposure prophylaxis protects against HIV infection in real world setting, study finds. PMID- 25716464 TI - 70th birthday of professor Kiyokatsu Jinno. PMID- 25716463 TI - Treatment of pulmonary embolism with rivaroxaban: outcomes by simplified Pulmonary Embolism Severity Index score from a post hoc analysis of the EINSTEIN PE study. AB - OBJECTIVES: The objective was to assess adverse outcomes in relation to the simplified Pulmonary Embolism Severity Index (PESI) score in patients treated with rivaroxaban or standard therapy in the phase III EINSTEIN PE study and to evaluate the utility of the simplified PESI score to identify low-risk pulmonary embolism (PE) patients. METHODS: A post hoc analysis of EINSTEIN PE data was performed to assess the efficacy and safety of rivaroxaban in patients with a range of simplified PESI scores. Recurrent venous thromboembolism, fatal PE, all cause mortality, and major bleeding were stratified by simplified PESI scores of 0, 1, or >=2 and according to treatment period at 7, 14, 30, and 90 days and at the end of the full intended treatment period. RESULTS: Simplified PESI scores could be calculated in 4,831 of the 4,832 randomized patients; of those, 53.6, 36.7, and 9.7% had PESI scores of 0, 1, and >=2, respectively. Among patients with simplified PESI scores of 0 or 1, fatal PE, all-cause mortality, and other adverse outcomes were uncommon within the first 7, 14, and 30 days. Patients with simplified PESI scores of >=2 had more frequent adverse outcomes. Major bleeding was lower in the rivaroxaban group, particularly in those with simplified PESI scores of 1 or >=2. CONCLUSIONS: The findings support using risk stratification with the simplified PESI score to identify low-risk patients with PE. PMID- 25716465 TI - Progress in the development of immunoanalytical methods incorporating recombinant antibodies to small molecular weight biotoxins. AB - Rapid immunoanalytical screening of food and environmental samples for small molecular weight (hapten) biotoxin contaminations requires the production of antibody reagents that possess the requisite sensitivity and specificity. To date animal-derived polyclonal (pAb) and monoclonal (mAb) antibodies have provided the binding element of the majority of these assays but recombinant antibodies (rAb) isolated from in vitro combinatorial phage display libraries are an exciting alternative due to (1) circumventing the need for experimental animals, (2) speed of production in commonly used in vitro expression systems and (3) subsequent molecular enhancement of binder performance. Short chain variable fragments (scFv) have been the most commonly employed rAb reagents for hapten biotoxin detection over the last two decades but antibody binding fragments (Fab) and single domain antibodies (sdAb) are increasing in popularity due to increased expression efficiency of functional binders and superior resistance to solvents. rAb-based immunochromatographic assays and surface plasmon resonance (SPR) biosensors have been reported to detect sub-regulatory levels of fungal (mycotoxins), marine (phycotoxins) and aquatic biotoxins in a wide range of food and environmental matrices, however this technology has yet to surpass the performances of the equivalent mAb- and pAb-based formats. As such the full potential of rAb technology in hapten biotoxin detection has yet to be achieved, but in time the inherent advantages of engineered rAb are set to provide the next generation of ultra-high performing binder reagents for the rapid and specific detection of hapten biotoxins. PMID- 25716466 TI - Simultaneous determination of 148 pharmaceuticals and illicit drugs in sewage sludge based on ultrasound-assisted extraction and liquid chromatography-tandem mass spectrometry. AB - This paper describes the development and validation of a new method for the simultaneous determination of 148 substances in sewage sludge. The selected compounds belong to different classes of pharmaceuticals, including antibiotics, analgesic and/or anti-inflammatory drugs, antiepileptics, benzodiazepines, antipsychotics, and antidepressants, among others, and illicit drugs, including opiates, opioids, cocaine, amphetamines, cannabinoids, and their metabolites. As far as the authors are aware, this is the first method in the peer-reviewed literature covering such a large number of target drugs for determination in a complex matrix like sewage sludge. The method presented herein combines ultrasound-assisted extraction (USE) and liquid chromatography coupled to tandem mass spectrometry. Good analytical performance was achieved, with limit-of detection values below 10 ng g(-1) d.w. for 91% of the analytes and absolute recovery in the range 50-110% for more than 77% of the studied compounds. A combination of methanol and acidified water, also containing EDTA, proved to be the optimum solvent mixture to perform the extractions. An extra solid-phase extraction clean-up step was not required, substantially reducing sample preparation time and solvent consumption. Finally, the developed method was applied to the analysis of different sewage-sludge samples from five wastewater treatment plants of Santorini Island (Greece). Out of the 148 target compounds, 36 were detected. Several compounds, including acetylsalicylic acid, citalopram, and ciprofloxacin among others, had maximum concentrations above 100 ng g(-1) d.w. PMID- 25716467 TI - Preliminary study on suitability of ionic liquids as potential passive-sampling media of polyaromatic-hydrocarbon (PAH) analyses in water. AB - Recently, ionic liquids (ILs) have been regarded as an attractive water immiscible phase in liquid-liquid extraction. Because ILs have a wide range of polarity irrespective of their miscibility with water, the possibility of using them as an effective extraction phase for a broad range of contaminants means they are starting to be of particular interest. In this study we investigated a wide variety of ionic liquids, which are known to be hydrolytically stable and of a hydrophobic character, for their potential suitability as passive-sampling media for monitoring selected polyaromatic hydrocarbons. Preliminary research in this field has indicated very promising results using these novel extraction media. Because there is an enormous number of possible cation-anion combinations offering tuneable properties of ionic liquids with the potential for effective passive extraction, we hope this paper will encourage the scientific community to undertake further studies verifying the undoubted usefulness of these alternative solvents as passive samplers for many other groups of analytes. Additionally, because of the unusual solubility properties that have already been proved for ILs, it is very probable that it would soon be possible to deliver a very effective system able to extract analytes differing widely in polarity. PMID- 25716468 TI - Clinical biochemical and hormonal profiling in plasma: a promising strategy to predict growth hormone abuse in cattle. AB - Recombinant bovine somatotrophin (rbST) is widely used in some countries to increase milk production. Since 1994, both marketing and use of this substance have been prohibited within the European Union. In this context, the targeted plasma biochemical and hormonal profiling was assessed as a potential screening strategy to highlight rbST (ab)use in cattle. Twenty-one routinely measured clinical blood parameters, representative of main biological profiles (energetic, proteic, etc.), were measured in the plasma of six lactating cows before and after rbST treatment throughout a 23-day study period. Appropriate multivariate statistical analyses [principal component analysis (PCA) and orthogonal partial least square (OPLS)] enabled discriminating animal samples before and after treatment (days 0 vs. 2 to 9, P = 2.10(-9)) and highlighted the five most relevant blood parameters in this discrimination. Based on each five-analyte contribution, a simple mathematically weighted equation was suggested to predict the status of samples. A suspicious threshold was proposed, and the model was further tested with the status prediction of the supplementary samples from untreated (n = 20) and treated cows (n = 22). The calculated false-positive (10%) and false-negative (4.5%) rates were in accordance with the EU requirements for screening methods. Although the model needs to be further validated with additional samples, such targeted plasma biochemical and hormonal profiling already appears as a potential promising screening strategy to highlight rbST (ab)use in cattle. PMID- 25716469 TI - Laser ablation-ICP-MS depth profiling to study ancient glass surface degradation. AB - In general the analysis of archeological glass represents a challenge for a wide variety of objects because of the presence of physical and/or chemical damage on the surface of the artifact, also known as weathering or corrosion. To retrieve accurate bulk elemental information by laser ablation-inductively coupled plasma mass spectrometry (ICP-MS), the original, pristine glass needs to be "reached", thereby penetrating the alteration layer which is often more than 10 MUm thick. To study this alteration layer the laser was operated in the drilling mode, either with a low (1 Hz) or a high (10 Hz) pulse repetition rate for a period of 50 s yielding detailed spatial information for ca. 20 elements over a shallow depth (ca. 5 MUm) or less-detailed spatial information for 50-60 elements over a greater depth (ca. 50 MUm). Quantitative elemental depth profiles (in wt%) were obtained with the so-called sum normalization calibration protocol, based on summation of the elements as their oxides to 100 wt%. We were able to associate the increase of SiO2 (in wt%) in the alteration layer to the volumetric mass density change in the glass as a result of depletion of Na2O and K2O. Also the interaction of the number of laser shots with the alteration layer is shown experimentally via depth measurements using profilometry. Chemical and physical changes in four ancient glass artifacts, directly and indirectly measureable by laser drilling, were studied as a function of internal and external factors such as age, composition, and exposure conditions. PMID- 25716470 TI - CCR2-V64I genetic polymorphism: a possible involvement in HER2+ breast cancer. AB - Many tumor cells express chemokines and chemokine receptors, and these molecules can affect both tumor progression and anti-tumor immune response. Genetic polymorphisms of some chemokine receptors were found to be closely related to malignant tumors, especially in metastasis process, including breast cancer (BC). Considering this, it was investigated a possible role for CCR2-V64I (C-C chemokine receptor 2) and CCR5-Delta32 (C-C chemokine receptor 5) genetic variants in BC context. Patients were divided into subgroups according to immunohistochemical profile of estrogen (ER) and progesterone (PR) receptors and the human epidermal growth factor receptor 2 (HER2) overexpression. No significant associations were found in relation to susceptibility (CCR2-V64I: OR 1.32; 95 % CI 0.57-3.06; CCR5-?32: OR 1.04; 95 % CI 0.60-1.81), clinical outcome (tumor size, lymph nodes commitment and/or distant metastasis, TNM staging and nuclear grade) or therapeutic response (recurrence and survival). However, it was found a significant correlation between CCR2-V64I allelic variant and HER2 immunohistochemical positive samples (p = 0.026). All in all, we demonstrate, for the first time, a positive correlation between CCR2 receptor gene polymorphism and a subgroup of BC related to poor prognosis, which deserves further investigation in larger samples for validation. PMID- 25716471 TI - In vitro antiproliferative effect of trastuzumab (Herceptin((r))) combined with cetuximab (Erbitux((r))) in a model of human non-small cell lung cancer expressing EGFR and HER2. AB - Lung cancer is the leading cause of cancer death. For this reason, new therapies are needed for the treatment of this devastating disease. In this study, we investigated the effects of combining cetuximab and the trastuzumab on the growth of a model of human non-small cell lung carcinoma cell line (A549). The results were compared with those obtained from a human lung squamous carcinoma cell line (NCI-H226). Both cell lines were treated with cetuximab and trastuzumab, alone or in combination, at various concentrations, for 24, 48 and 72 h. Cell proliferation was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. EGFR and HER-2 mRNA expression was detected by reverse transcription polymerase chain reaction, and the gene amplification status of receptors was evaluated by fluorescence in situ hybridisation. The colorimetric proliferation assay showed that trastuzumab combined with cetuximab significantly inhibited A549 cells at a dose of 40 MUg/ml after 72 h of treatment (p < 0.05), while no time-dose dependent inhibition was observed in NCI-H226 cells. The combined treatment influenced both levels of EGFR and HER-2 mRNA in A549 cells and only EGFR mRNA levels in NCI-H226 cells. Fluorescence in situ hybridisation showed that both cell lines were aneuploid for the two genes with equally increased EGFR and CEN7 signals, as well as HER-2 and CEN17 signals, indicating a condition of polysomy without amplification. The preliminary results of this study encourage further investigations to elucidate the downstream events involved and to understand how these mechanisms influence non-small cell lung cancers growth. PMID- 25716472 TI - Toward the complete range separation of non-hybrid exchange-correlation functional. AB - In this study, we use a very simple scheme to achieve range separation of a total exchange-correlation functional. We have utilized this methodology to combine a short-range pure density functional theory (DFT) functional with a corresponding long-range pure DFT, leading to a "Range-separated eXchange-Correlation" (RXC) scheme. By examining the performance of a range of standard exchange-correlation functionals for prototypical short- and long-range properties, we have chosen B LYP as the short-range functional and PBE-B95 as the long-range counterpart. The results of our testing using a more diverse range of data sets show that, for properties that we deem to be short-range in nature, the performance of this prescribed RXC-DFT protocol does resemble that of B-LYP in most cases, and vice versa. Thus, this RXC-DFT protocol already provides meaningful numerical results. Furthermore, we envisage that the general RXC scheme can be easily implemented in computational chemistry software packages. This study paves a way for further refinement of such a range-separation technique for the development of better performing DFT procedures. PMID- 25716473 TI - TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. AB - Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor-bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8(+) T cells and reduced presence of CD4(+) T cells, the main source of the TH2 cytokine IL4 in mammary tumors. Selective depletion of CD4(+) T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8(+) T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8(+) T-cell-dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes. PMID- 25716478 TI - Mechanical rigidity of the Ortho-SUV frame compared to the Ilizarov frame in the correction of femoral deformity. AB - The Ortho-SUV frame (OSF) is a novel hexapod circular external fixator which draws upon the innovation of the Ilizarov method and the advantages of hexapod construction in the three-dimensional control of bone segments. Stability of fixation is critical to the success or failure of an external circular fixator for fracture or osteotomy healing. In vitro biomechanical modelling study was performed comparing the stability of the OSF under load in both original form and after dynamisation to the Ilizarov fixator in all zones of the femur utilising optimal frame configuration. A superior performance of the OSF in terms of resistance to deforming forces in both original and dynamised forms over that of the original Ilizarov fixator was found. The OSF shows higher rigidity than the Ilizarov in the control of forces acting upon the femur. This suggests better stabilisation of femoral fractures and osteotomies and thus improved healing with a reduced incidence of instability-related bone segment deformity, non-union and delayed union. PMID- 25716479 TI - Structural basis for self-assembly of a cytolytic pore lined by protein and lipid. AB - Pore-forming toxins (PFT) are water-soluble proteins that possess the remarkable ability to self-assemble on the membrane of target cells, where they form pores causing cell damage. Here, we elucidate the mechanism of action of the haemolytic protein fragaceatoxin C (FraC), a alpha-barrel PFT, by determining the crystal structures of FraC at four different stages of the lytic mechanism, namely the water-soluble state, the monomeric lipid-bound form, an assembly intermediate and the fully assembled transmembrane pore. The structure of the transmembrane pore exhibits a unique architecture composed of both protein and lipids, with some of the lipids lining the pore wall, acting as assembly cofactors. The pore also exhibits lateral fenestrations that expose the hydrophobic core of the membrane to the aqueous environment. The incorporation of lipids from the target membrane within the structure of the pore provides a membrane-specific trigger for the activation of a haemolytic toxin. PMID- 25716480 TI - Evaluation of carcinogenic potential of the herbicide glyphosate, drawing on tumor incidence data from fourteen chronic/carcinogenicity rodent studies. AB - Abstract Glyphosate, an herbicidal derivative of the amino acid glycine, was introduced to agriculture in the 1970s. Glyphosate targets and blocks a plant metabolic pathway not found in animals, the shikimate pathway, required for the synthesis of aromatic amino acids in plants. After almost forty years of commercial use, and multiple regulatory approvals including toxicology evaluations, literature reviews, and numerous human health risk assessments, the clear and consistent conclusions are that glyphosate is of low toxicological concern, and no concerns exist with respect to glyphosate use and cancer in humans. This manuscript discusses the basis for these conclusions. Most toxicological studies informing regulatory evaluations are of commercial interest and are proprietary in nature. Given the widespread attention to this molecule, the authors gained access to carcinogenicity data submitted to regulatory agencies and present overviews of each study, followed by a weight of evidence evaluation of tumor incidence data. Fourteen carcinogenicity studies (nine rat and five mouse) are evaluated for their individual reliability, and select neoplasms are identified for further evaluation across the data base. The original tumor incidence data from study reports are presented in the online data supplement. There was no evidence of a carcinogenic effect related to glyphosate treatment. The lack of a plausible mechanism, along with published epidemiology studies, which fail to demonstrate clear, statistically significant, unbiased and non-confounded associations between glyphosate and cancer of any single etiology, and a compelling weight of evidence, support the conclusion that glyphosate does not present concern with respect to carcinogenic potential in humans. PMID- 25716481 TI - Identification and preservation of the parathyroid gland during total thyroidectomy in dogs with bilateral thyroid carcinoma: a report of six cases. AB - Simultaneous removal of bilateral thyroid tumors was performed while preserving the parathyroid gland in six dogs. At least one external parathyroid gland was identified in all dogs. In five cases, the external parathyroid gland and its blood supply were preserved intact. In one dog, the vessels supplying the external parathyroid gland had been invaded by the tumor, and the gland was thus removed and reimplanted into the sternohyoid muscle. That dog required postoperative treatment with oral calcium gluconate and vitamin D3. Local tumor recurrence was not observed in any of the cases. The mean survival time was 920 days. We found that the external parathyroid gland could be identified and preserved in most dogs undergoing total thyroidectomy. PMID- 25716482 TI - Prevalence of and factors associated with Brucella sero-positivity in cattle in urban and peri-urban Gulu and Soroti towns of Uganda. AB - Brucellosis is a key zoonosis of major public health, animal welfare and economic significance, and is endemic in livestock in Uganda. A cross-sectional epidemiological study was carried out to estimate the sero-prevalence of brucellosis and identify factors associated with sero-positivity in cattle in urban and peri-urban Gulu and Soroti towns of Northern and Eastern Uganda, respectively. A total of 1007 sera and data on biologically plausible risk factors from 166 herds and their spatial locations, were collected from cattle reared in urban and peri-urban Gulu and Soroti towns of Uganda. The sera were analyzed using indirect ELISA and sero-positive reactors confirmed by competitive ELISA. Multivariable models were used to investigate for risk factors. The overall animal-level and herd-level sero-prevalence was 7.5% (76/1007, 95% Confidence Interval (CI): 6.15-9.4%) and 27.1% (45/166, 95% CI: 20.9-34.3%), respectively. Herd-level sero-prevalence was significantly (P<0.001) higher in Soroti than Gulu. In Gulu town, sero-positivity increased with an increase in herd size (P=0.03) and age (P=0.002), and was higher in cattle brought in from western Uganda (P<0.0001). In Soroti town, introduction of new cattle into a herd was significantly (P=0.027) associated with herd sero-positivity. There was a geographically differential risk (clustering) of Brucella sero- positivity in herds in Soroti, while sero-positivity was homogeneously distributed in Gulu. The data highlight brucellosis occurrence and major risk factors for its transmission in cattle in urban and peri-urban areas. PMID- 25716483 TI - The neuropsychiatric spectrum of motivational disorders. AB - Adaptive behavior requires neural systems that mediate the evaluation of stimuli in terms of the well-being of the organism and generate subsequent goal-directed behavior. The authors provide an overview of these systems, with an emphasis on those related to positive motivation/approach. The authors outline the contributions of various disciplines to the current understanding of these systems and discuss their dysfunction in the context of multiple neuropsychiatric disorders in terms of deficits, dysregulation, excess, and related syndromes. Illustrative examples are provided, with an emphasis on functional neuroimaging studies. This approach can provide a foundation for conceptualization, diagnosis, and targeted neuromodulatory therapeutics of neuropsychiatric disorders. PMID- 25716484 TI - The psychiatric and neuropsychiatric symptoms after subthalamic stimulation for Parkinson's disease. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for the motor symptoms of Parkinson's disease (PD). Nonmotor features of PD, however, may not improve with STN DBS, and a specific constellation of neuropsychiatric symptoms may emerge in the postoperative period. Mania, impulsivity, depression, and apathy may curtail the potential gains from surgery. In this paper, the authors discuss surgical candidacy, postoperative management of neuropsychiatric issues, and clinical dilemmas for the psychiatrist at the DBS center. A paradigm that considers stimulation effects and dopamine replacement therapy to be key drivers of postoperative neuropsychiatric problems is presented. PMID- 25716485 TI - Regional homogeneity of resting-state brain abnormalities in violent juvenile offenders: a biomarker of brain immaturity? AB - The authors investigated whether male violent juvenile offenders demonstrate any differences in local functional connectivity indicative of delayed maturation of the brain that may serve as a biomarker of violence. Twenty-nine violent juvenile offenders and 28 age-matched controls were recruited. Regional homogeneity (ReHo) method was used to analyze resting-state magnetic resonance images. Violent offenders showed significantly lower ReHo values in the right caudate, right medial prefrontal cortex, and left precuneus, and higher values in the right supramarginal gyrus than the controls. These regions had both high sensitivity and specificity in distinguishing between the two groups suggesting that dysfunction in these regions can be used to correctly classify those individuals who are violent. Dysfunction in the right medial prefrontal-caudate circuit may, therefore, represent an important biomarker of violence juvenile males. PMID- 25716486 TI - Irritability symptoms in Gilles de la Tourette syndrome. AB - Behavioral symptoms are known to be a prominent feature of Gilles de la Tourette syndrome (GTS), although little is known about irritability in this patient population. This study investigated the clinical correlates of irritability symptoms in 101 adult patients with GTS. We found that patients with more severe tics (especially vocal tics) report higher levels of irritability (r=0.37, p <0.001) Furthermore, irritability levels appear to be higher in those patients with comorbid attention-deficit and hyperactivity disorder, in whom poor impulse control is common. These findings prompt further research focusing on the possible link between irritability and impulse dyscontrol in GTS. PMID- 25716487 TI - Cannabis abuse effects on prepulse inhibition in patients with first episode psychosis in schizophrenia. AB - Deficits in prepulse inhibition (PPI) and cannabis abuse are consistently found in schizophrenia. The authors studied PPI deficits in first episode psychosis (FEP) with schizophrenia and cannabis abuse influence. Thirty-five patients with FEP and 22 control subjects were examined. Patients were divided into cannabis use disorder (CUD) (N=21) and non-CUD (N=14). Startle measures were as follows: PPI at 30, 60, and 120 msec. Patients with CUD and patients without CUD showed lower PPI at 30 msec than control subjects. At 60 msec, patients with CUD obtained higher %PPI than patients without CUD, and patients without CUD obtained lower levels than control subjects. These findings show that cannabis abuse may improve PPI in patients with FEP at some levels. PMID- 25716488 TI - Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies. AB - The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure. PMID- 25716489 TI - Catatonia: an unusual manifestation of Wilson's disease. AB - Wilson's disease, characterized by abnormal copper accumulation in the human body, may present with psychiatric manifestations in about one-fifth of patients. The authors report a patient with Wilson's disease who initially presented with acute psychosis and later developed catatonic symptoms. The atypical presentation led to a delay in diagnosis and institution of appropriate treatment. Wilson's disease can be ruled out in all young patients presenting with psychiatric symptoms for the first time by screening for a Kayser-Fleischer ring. PMID- 25716490 TI - Paliperidone palmitate for refractory and clozapine-resistant schizophrenia. AB - This is a report on two cases of refractory schizophrenia and two cases of clozapine-resistant schizophrenia successful treated with paliperidone palmitate. To the authors' knowledge, this is the first report of the successful use of paliperidone palmitate in such patients. PMID- 25716492 TI - Sudden unexpected death in epilepsy: some approaches to prevent it. AB - Mortality because of epilepsy is a major concern worldwide. People with epilepsy have a two to three times increased risk of death in comparison with the general population. Sudden unexplained death in epilepsy is a mysterious, rare condition, in which typically young or middle-aged people with epilepsy die without a clearly defined cause. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. In recent years, some significant risk factors have been recognized and strategies have been suggested that may be useful in prevention of sudden unexpected death in epilepsy (SUDEP). The present review provides some of the updates on new advances in prevention of SUDEP. PMID- 25716493 TI - A neural circuit framework for somatosensory amplification in somatoform disorders. AB - Although somatosensory amplification is theorized to serve a critical role in somatization, it remains poorly understood neurobiologically. In this perspective article, convergent visceral-somatic processing is highlighted, and neuroimaging studies in somatoform disorders are reviewed. Neural correlates of cognitive affective amplifiers are integrated into a neurocircuit framework for somatosensory amplification. The anterior cingulate cortex, insula, amygdala, hippocampal formation, and striatum are some of the identified regions. Clinical symptomatology in a given patient or group may represent dysfunction in one or more of these neurobehavioral nodes. Somatosensory amplification may, in part, develop through stress-mediated aberrant neuroplastic changes and the neuromodulatory effects of inflammation. PMID- 25716494 TI - Alive with the sound of music: a case series on patients presenting with musical hallucinations in a general hospital. AB - Musical hallucinations are a rare phenomenon that renders appropriate identification and treatment a challenge. This case series describes three women who presented with hearing complex, familiar melodies in the absence of external stimuli on a background of hearing impairment. PMID- 25716491 TI - Apathy is associated with lower inferior temporal cortical thickness in mild cognitive impairment and normal elderly individuals. AB - Apathy is a common neuropsychiatric symptom in Alzheimer's disease dementia and amnestic mild cognitive impairment and is associated with cortical atrophy in Alzheimer's disease dementia. This study investigated possible correlations between apathy and cortical atrophy in 47 individuals with mild cognitive impairment and 19 clinically normal elderly. Backward elimination multivariate linear regression was used to evaluate the cross-sectional relationship between scores on the Apathy Evaluation Scale and thickness of several cortical regions and covariates. Lower inferior temporal cortical thickness was predictive of greater apathy. Greater anterior cingulate cortical thickness was also predictive of greater apathy, suggesting an underlying reactive process. PMID- 25716495 TI - Aripiprazole-induced acute hiccups: a case report. PMID- 25716496 TI - Case report of clozapine-induced neutropenia and rechallenge. PMID- 25716497 TI - Successful treatment of idiopathic intractable hiccup with baclofen and supportive treatment: a case report. PMID- 25716498 TI - Gabapentin dependence in a patient with opioid dependence syndrome. PMID- 25716499 TI - Visual hallucinations: a treatment-emergent adverse effect of linezolid. PMID- 25716500 TI - Dengue fever-associated catatonia. PMID- 25716501 TI - Voltage-gated potassium channel antibody-associated encephalitis presenting as acute psychosis: case report. PMID- 25716502 TI - Tactile hallucination in a case of syringomyelia. PMID- 25716503 TI - Wernicke's encephalopathy in two different clinical settings: one after whipple surgery and the other due to alcohol abuse. PMID- 25716504 TI - Capgras syndrome as an initial manifestation in a patient with neurosyphilis. PMID- 25716505 TI - Subclavian steal syndrome presenting as a reversible dementia. PMID- 25716506 TI - Mirtazapine-induced restless legs syndrome treated with pramipexole. PMID- 25716507 TI - Persistent penile erection (priapism) associated with quetiapine and lithium. PMID- 25716508 TI - Early cues to detect atypical panthothenate kinase-associated neurodegeneration. PMID- 25716509 TI - Multiple tics in a patient with Adams-Oliver syndrome. PMID- 25716510 TI - Thalamic and thalamic reticular nucleus abnormalities in a patient with chromosome 22q11.2 deletion syndrome. PMID- 25716511 TI - Parkinsonism and Gorlin-Goltz syndrome: more than an incidental association? PMID- 25716512 TI - Stuck in the middle: Huntington's disease or not Huntington's disease? PMID- 25716513 TI - Childhood psychosis after H1N1 influenza. PMID- 25716514 TI - Rivastigmine treatment of Othello syndrome and post-ECT delirium in a patient with Parkinson's disease. PMID- 25716515 TI - Normal pressure hydrocephalus following Ekbom syndrome. PMID- 25716516 TI - Occupational exposure to solvents: neuropsychiatric and imaging features. PMID- 25716517 TI - A new inorganic-organic hybrid material Al-SBA-15-TPI/H6P2W18O62 catalyzed one pot, three-component synthesis of 2H-indazolo[2,1-b]phthalazine-triones. AB - A new inorganic-organic hybrid material Al-SBA-15-TPI/H6P2W18O62 was prepared and fully characterized by SEM, XRD, FT-IR, TGA-DTA, and UV-Vis spectroscopic techniques. Then, the prepared nanomaterial was used as a simple, cost-effective, and reusable heterogeneous catalyst for the synthesis of 2H-indazolo[2,1 b]phthalazine-1,6,11(13H)-trione derivatives by a one-pot, three-component condensation reaction of phthalhydrazide, cyclic diones, and aromatic aldehydes under solvent free conditions at 100 degrees C in a short time. This methodology has proven to be efficient and environmentally benign in terms of high yields and low reaction times and offers significant improvements with regard to the scope of transformation and simplicity of operation by avoiding expensive or corrosive catalysts. PMID- 25716518 TI - Colorectal Cancer Screening in US Seniors Ages 76-84 Years. AB - The US Preventive Services Task Force recommends patient-physician discussions about the appropriateness of colorectal cancer (CRC) screening among adults ages 76-84 years who have never been screened. In this study, we used data from the 2010 National Health Interview Survey to examine patterns of CRC screening and provider recommendation among seniors ages 76-84 years, and made some comparisons to younger adults. Nationally-representative samples of 1379 adults ages 76-84 years and 8797 adults ages 50-75 years responded to questions about CRC screening status, receipt of provider recommendation, and discussion of test options; 22.7% (95% CI 20.1-25.3) of seniors ages 76-84 had never been tested for CRC and therefore were not up-to-date with guidelines; 3.9% (95% CI 2.0-7.6) of these individuals reported a recent provider recommendation for screening. In multivariate analyses, the likelihood of never having been tested was significantly greater for seniors of other/multiple race or Hispanic ethnicity; with high school or less education; without private health insurance coverage; who had <= 1 doctor visit in the past year; without recent screening for breast, cervical, or prostate cancer; with no or unknown CRC family history; or with <= 1 chronic disease. Among the minority of respondents ages 50-75 and 76-84 reporting a provider recommendation, 73.2% indicated that the provider recommended particular tests, which was overwhelmingly colonoscopy (>= 89 %). Nearly one quarter of adults 76-84 have never been screened for CRC, and rates of provider recommendation in this group are very low. Greater attention to informed CRC screening discussions with screening-eligible seniors is needed. PMID- 25716519 TI - The cascade of care for Australians living with chronic hepatitis B: measuring access to diagnosis, management and treatment. AB - OBJECTIVE: To estimate the level of access to diagnosis, management and treatment for people living with chronic hepatitis B (CHB) in Australia, and to identify the gaps in clinical care for people living with CHB. METHODS: Analysis of publicly available population level data including infectious disease notifications, Medicare and Pharmaceutical Benefits Scheme utilisation data, census-based estimates of CHB prevalence and burden, and mathematical modelling. RESULTS: In 2012, of the estimated 218,567 Australians living with CHB, 57% had been diagnosed, 17,367 people (8%) received recommended HBV DNA viral load testing (without treatment) and 10,987 (5%) received antiviral therapy. CONCLUSIONS: This analysis reveals substantial gaps in the cascade of care for CHB in Australia, most notably in diagnosis (with 43% undiagnosed) and in recommended yearly monitoring (87% not in care). The number receiving therapy represents only one-third of those estimated to require treatment to prevent progressive liver disease and liver cancer. IMPLICATIONS: These findings demonstrate that the majority of those affected are not receiving guideline-based care; highlight the need for improvements in opportunistic screening, engagement in care, and access to therapy; and provide a method to assess the impact of public health and clinical interventions in response to CHB over time. PMID- 25716520 TI - Hole injection dynamics from two structurally related Ru-bipyridine complexes into NiO(x) is determined by the substitution pattern of the ligands. AB - The dyes bis[2,2'-bipyridine][4,4'-dicarboxy-2,2'-bipyridine]ruthenium(II) dihexafluorophosphate, [Ru(bpy)2dcb](PF6)2 (Ru1), and tris[4,4'-bis(ethylcarboxy) 2,2'-bipyridine]ruthenium(II) dihexafluorophosphate, [Ru(dceb)3](PF6)2 (Ru2), attached to NiOx nanoparticle films were investigated using transient absorption and luminescence spectroscopy. In acetonitrile solution the dyes reveal very similar physical and chemical properties, i.e. both dyes exhibit comparable ground state and long-lived, broad excited state absorption. However, when immobilized onto a NiOx surface the photophysical properties of the two dyes differ significantly. For Ru1 luminescence is observed, which decays within 18 ns and ultrafast transient absorption measurements do not show qualitative differences from the photophysics of Ru1 in solution. In contrast to this the luminescence of photoexcited Ru2 on NiOx is efficiently quenched and the ultrafast transient absorption spectra reveal the formation of oxidized nickel centres overlaid by the absorption of the reduced dye Ru2 with a characteristic time-constant of 18 ps. These findings are attributed to the different localization of the initially photoexcited state in Ru1 and Ru2. Due to the inductive effect (-I) of the carboxylic groups, the lowest energy excited state in Ru1 is localized on the dicarboxy-bipyridine ligand, which is bound to the NiOx surface. In Ru2, on the other hand, the initially populated excited state is localized on the ester-substituted ligands, which are not bound to the semiconductor surface. Hence, the excess charge density that is abstracted from the Ru-ion in the metal-to-ligand charge-transfer transition is shifted away from the NiOx surface, which ultimately facilitates hole transfer into the semiconductor. PMID- 25716521 TI - Erratum to: Distribution and ecotoxicological significance of polycyclic aromatic hydrocarbons in sediments from Iko River estuary mangrove ecosystem. PMID- 25716522 TI - Exploring the benefits of growing bioenergy crops to activate lead-contaminated agricultural land: a case study on sweet potatoes. AB - Phytoremediation is the most environmentally friendly remediation technology for heavy metal contaminated soil. However, the phytoremediation approach requires a long time to yield results, and the plants used must be economically profitable to maintain the sustainability of the process. Because high levels of bioethanol can be produced from sweet potatoes, an experiment was conducted by planting sweet potatoes in a lead-contaminated site to observe their growth and lead uptake capacity, thereby enabling the evaluation of the phytoremediation efficiency of sweet potatoes. The lead content in the soil was approximately 6000 mg kg(-1), and the phytoavailable Pb content was 1766 mg kg(-1). Three starch rich sweet potato varieties, Tainung No. 10 (TNG-10), Tainung No. 31 (TNG-31), and Tainung No. 57 (TNG-57), were used in the experiment. The results indicated that TNG-10, TNG-31, and TNG-57 had fresh root tuber yields of 94.5, 133.0, and 47.5 ton ha(-1) year(-1), produced 9450, 13,297, and 4748 L ha(-1) year(-1) of bioethanol, and removed 2.68, 7.73, and 3.22 kg ha(-1) year(-1) of lead, respectively. TNG-31 yielded the highest bioethanol production and the highest lead removal in the lead-contaminated site. Therefore, implementing phytoremediation by planting TNG-31 would decrease lead content and generate income, thereby rendering the sustainable and applicable activation of contaminated soil possible. PMID- 25716524 TI - A study on agricultural drought vulnerability at disaggregated level in a highly irrigated and intensely cropped state of India. AB - Drought is an important global hazard, challenging the sustainable agriculture and food security of nations. Measuring agricultural drought vulnerability is a prerequisite for targeting interventions to improve and sustain the agricultural performance of both irrigated and rain-fed agriculture. In this study, crop generic agricultural drought vulnerability status is empirically measured through a composite index approach. The study area is Haryana state, India, a prime agriculture state of the country, characterised with low rainfall, high irrigation support and stable cropping pattern. By analysing the multiyear rainfall and crop condition data of kharif crop season (June-October) derived from satellite data and soil water holding capacity and groundwater quality, nine contributing indicators were generated for 120 blocks (sub-district administrative units). Composite indices for exposure, sensitivity and adaptive capacity components were generated after assigning variance-based weightages to the respective input indicators. Agricultural Drought Vulnerability Index (ADVI) was developed through a linear combination of the three component indices. ADVI based vulnerability categorisation revealed that 51 blocks are with vulnerable to very highly vulnerable status. These blocks are located in the southern and western parts of the state, where groundwater quality is saline and water holding capacity of soils is less. The ADVI map has effectively captured the spatial pattern of agricultural drought vulnerability in the state. Districts with large number of vulnerable blocks showed considerably larger variability of de-trended crop yields. Correlation analysis reveals that crop condition variability, groundwater quality and soil factors are closely associated with ADVI. The vulnerability index is useful to prioritise the blocks for implementation of long term drought management plans. There is scope for improving the methodology by adding/fine-tuning the indicators and by optimising the weights. PMID- 25716523 TI - Source apportionment and seasonal variation of PM2.5 carbonaceous aerosol in the Beijing-Tianjin-Hebei region of China. AB - The seasonal variation of PM2.5 carbonaceous aerosol was investigated in Beijing and Tangshan cities of China. The characteristics of carbonaceous aerosol (e.g., organic carbon, OC and elemental carbon, EC) under different weather conditions and their source apportionment were also examined. The annual average PM2.5 concentration in the study area reached 95.6-197.3 MUg/m(3), showing seasonal and spatial variation. The carbonaceous materials accounted for 17.3-21.2 % of the PM2.5, and they had a much higher content under haze weather condition. It was found that the PM2.5 contained more OC than EC. Principal component analysis (PCA) results indicated that the carbonaceous components came from mixed emission sources of coal combustion, vehicle exhaust, and biomass burning. In Beijing, the vehicle emission made a contribution of 63.0 % to the carbonaceous components of PM2.5 in summer, which is higher than that in Tangshan. While in Tangshan, the coal combustion made a contribution of 30.3 %, which is much higher than that in Beijing. PMID- 25716525 TI - Use of mercury-based medical equipment and mercury content in effluents of tertiary care hospitals in India. AB - Environmental pollution due to mercury has raised serious concern over the last few decades. Various anthropogenic sources including the health sector play a vital role in increasing the mercury load on the environment. Mercury poses an important health issue because of its indiscriminate disposal into the environment. There are numerous mercury-containing devices being used in the health-care setup. The objective of the study was to obtain information on the procurement and consumption of mercury-containing items in the current year, the methods adopted for disposal and the contamination of the hospital effluents with mercury. A questionnaire-based study was conducted in government and corporate hospitals from different states of India, for the quantitative assessment of use of mercury-based items in tertiary care hospitals in India (n = 113). The results showed that mercury-containing items are still being used in India. The most common method adopted for disposal was collection in plastic bags and labeling them as hazardous waste. The hospital effluents contained mercury below the permissible limits. In view of the environmental pollution due to mercury and its adverse impact on health, efforts by the government are on for phasing out mercury-containing equipment from the health-care setup in India. PMID- 25716526 TI - Trend of blood lead, mercury, and cadmium levels in Korean population: data analysis of the Korea National Health and Nutrition Examination Survey. AB - This study was performed to assess the recent trends in lead, mercury, and cadmium levels in the blood among Korean adult population. The geometric means and 95 % confidence intervals (CIs) of blood lead, mercury, and cadmium concentrations were calculated using the data of the subjects from the third (2005, n = 1997), fourth (2008, n = 2005; 2009, n = 1991), and fifth (2010, n = 1989; 2011, n = 2014) Korea National Health and Nutrition Examination Survey. Blood lead levels in 2005, 2008, 2009, 2010, and 2011 declined to 2.61 MUg/dL (2.51-2.71), 2.32 MUg/dL (2.27-2.37), 2.29 MUg/dL (2.23-2.35), 2.09 MUg/dL (2.04 2.13), and 1.99 MUg/dL (1.94-2.05), respectively. Blood mercury levels were 4.19 MUg/L (3.99-4.39), 4.73 MUg/L (4.57-4.89), 4.25 MUg/L (4.09-4.41), 3.64 MUg/L (3.49-3.80), and 3.08 MUg/L (2.95-3.22), respectively, which indicated an increase in 2008 compared with those in 2005, and a clear downward trend from 2008 to 2011. Blood cadmium levels were 1.52 MUg/L (1.47-1.57), 0.93 MUg/L (0.89 0.97), 0.94 MUg/L (0.90-0.98), 0.89 MUg/L (0.87-0.92), 0.86 MUg/L (0.83-0.89), respectively, which indicated very high levels in 2005, but a downward trend since 2008. Although the lead, mercury, and cadmium levels in the blood of the Korean adult population are on the decline, they are still relatively high compared with those for the population of the USA, Canada, and Germany. Thus, continuous biological monitoring and measures to reduce these levels are needed in Korea. PMID- 25716527 TI - Concentrations, distribution, sources, and ecological risk assessment of heavy metals in agricultural topsoil of the Three Gorges Dam region, China. AB - Concentrations, distribution, sources, and ecological risk of seven heavy metals including chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), lead (Pb), cadmium (Cd), and mercury (Hg) in agricultural topsoil samples of the Three Gorges Dam region, China were investigated in this study. Among seven heavy metals, Zn had the highest mean concentration (149 mg kg(-1)) in the agricultural topsoil, followed by Cr (66 mg kg(-1)), Cu (52.2 mg kg(-1)), Pb (13.0 mg kg(-1)), Ni (8.5 mg kg(-1)), Cd (0.29 mg kg(-1)), and Hg (0.08 mg kg(-1)). Enrichment factor (EF) values of Zn, Cu, Cd, and Hg were higher than 1.5, indicating that Zn, Cu, Cd, and Hg were the major pollutants in this study area. The average potential ecological risk index (RI) value was 147, suggesting that heavy metals in the agricultural topsoil in the study area had a low ecological risk. The result of factor analysis (FA) and correlation analysis showed that long-term use of chemical fertilizer and pesticides, natural rock weathering, and atmospheric deposition were the several main sources of seven heavy metals in agricultural topsoil of the Three Gorges Dam region. Factor analysis-multiple linear regression (FA-MLR) results indicated that the most important source in this area was long-term use of chemical fertilizer and pesticides, which contributed 70 % for Cu and Zn, 62 % for Cd, and 72 % for Hg. More attention must be paid to the extensive use of chemical fertilizers and pesticides containing heavy metals which have been accumulated in the agricultural soil. PMID- 25716528 TI - Knowledge, attitude, and practice of Indonesian farmers regarding the use of personal protective equipment against pesticide exposure. AB - The use of synthetic pesticides in tropical countries has increased over the years, following the intensification of agriculture. However, awareness among farmers of the importance of protecting themselves from hazards associated with pesticide application is still lacking, especially in Indonesia. This paper reports results of an inventory on knowledge and attitudes regarding pesticide use by melon farmers of a village in Central Java, Indonesia. The importance of using personal protective equipment such as hats, masks, goggles, boots, and gloves on agricultural land is known and well understood by the farmers. However, in practice, only 3.8 % were wearing glasses and 1.9 % were using boots. In fact, the masks used only consisted of a part of their shirt tied around the mouth. The farmers were not wearing long pants and shirts with long sleeves and used the same clothes for more than 1 day without washing. Almost no farmers used personal protective equipment that was standard, in good condition, and complete. Based on the results of statistical analysis, no significant relationship was found between knowledge and attitude on the required practices on the one hand and the use of personal protective equipment in practice on the other hand. This shows that improved knowledge and attitudes are not enough to change the behavior of farmers to work in a healthy and safe way. The gap between knowledge and practice needs to be bridged by a more interactive and participatory training model. It is therefore of paramount importance to develop a special toolkit for pesticide risk reduction which is developed in a participatory manner involving the farmers as the main actors through a series of focus group discussions and field simulations. PMID- 25716529 TI - Beyond the usual suspects: using political science to enhance public health policy making. AB - That public health policy and practice should be evidence based is a seemingly uncontroversial claim. Yet governments and citizens routinely reject the best available evidence and prefer policies that reflect other considerations and concerns. The most common explanations of this paradox emphasise scientific disagreement, the power of 'politics', or the belief that scientists and policymakers live in two separate communities that do not communicate. However, another explanation may lie in the limits of the very notion of evidence-based policy making. In fact, the social science discipline of political science offers a rich body of theory and empirical evidence to explain the apparent gap between evidence and policy. This essay introduces this literature with a particular emphasis on a recent book by Katherine Smith, Beyond evidence-based policy in public health: the interplay of ideas. As the title suggests, Smith argues that what matters for public health policy is less scientific evidence and much more a more complex set of ideas. Based on detailed case studies of UK tobacco and health inequality policy, Smith offers a richly textured alternative account of what matters for policy making. This excellent book is part of a small but growing body of political science research on public health policy that draws on contemporary theories of policy change and governance more generally. This essay provides a window on this research, describes some examples, but emphasises that public health scholars and practitioners too often retain a narrow if not naive view of the policy-making process. PMID- 25716530 TI - Therapeutic effect of prenatal alkalization and PTC124 in Na(+)/HCO3(-) cotransporter 1 p.W516* knock-in mice. AB - We created Na(+)/HCO3(-) cotransporter 1 (NBCe1) p.W516* knock-in mice as a model of isolated proximal renal tubular acidosis showing early lethality associated with severe metabolic acidosis to investigate the therapeutic effects of prenatal alkalization or posttranscriptional control 124 (PTC124). NBCe1(W516*/W516*) mice were treated with non-alkalization (control, n=12), prenatal alkalization postcoitus (prenatal group, n=7) and postnatal alkalization from postnatal day 6 (postnatal group, n=12). Mutation-specific therapy, PTC124 (60 mg kg(-1)) or gentamicin (30 mg kg(-1)), was administered intraperitoneally from postnatal day 6. Blood and urine biochemistry, acid-base analysis, survival rate and renal histology were examined. NBCe1 protein, mRNA abundance and activity ex vivo were assessed after PTC124 and gentamicin treatment. Prenatal group mice had similar initial body weight to wild-type mice and achieved significant weight gain thereafter compared with controls. They had higher serum bicarbonate level (15.5 +/- 1.4 vs 5.5 +/- 0.1 mmol l(-1), P<0.05) on postnatal day 14 and better renal function, histology and survival rates (60.8 +/- 23.5 vs 41.1 +/- 15.8 days, P<0.05) than the postnatal group. Compared with the control and gentamicin therapies, PTC124 therapy significantly increased NBCe1 protein abundance despite unchanged mRNA transcription. Only PTC124 therapy significantly increased survival rate and partially rescued NBCe1 activity ex vivo. In NBCe1(W516*/W516*) mice, prenatal alkali therapy achieved higher survival rates and ameliorated organ dysfunction. PTC124 therapy for this nonsense mutation was partially effective in increasing NBCe1 expression and activity. PMID- 25716531 TI - Safety and angiogenic effects of systemic gene delivery of a modified erythropoietin. AB - Erythropoietin (EPO) is critical for red blood cell production and is also an effective neuroprotective agent. However, it may contribute to pathological angiogenesis. Here we investigate the angiogenic potential of EPO and a mutant form with attenuated erythropoietic activity, EPO-R76E, on primary human retinal microvascular endothelial cells (HRMECs) and in the adult retina. Assays of death, proliferation and tube formation were performed on HRMECs exposed to EPO, EPO-R76E or media alone. Postnatal day-9 wild-type mice were injected intramuscularly with adeno-associated virus vectors expressing either enhanced green fluorescent protein or EpoR76E. At 3 months, levels of EPO-R76E in the eye were quantified, and the health of the retinal vasculature was assessed by fluorescein angiography and isolectin immunolabeling. Immunohistochemistry, histology and electroretinogram (ERG) assessments were performed as measures of retinal health. Neither EPO nor EPO-R76E induced proliferation or tube formation in HRMECs under the conditions used. EPO-R76E decreased HRMEC death in a dose dependent manner. Long-term systemic gene delivery of EPO-R76E was safe in terms of retinal vasculature, histology and the ERG in vivo. Our results show that EPO R76E can block HRMEC death, consistent with its role in erythropoiesis and neuroprotection. In addition, long-term gene delivery of EPO-R76E is safe in the adult retina. PMID- 25716532 TI - The impact of HIV-1 genetic diversity on the efficacy of a combinatorial RNAi based gene therapy. AB - A hurdle for human immunodeficiency virus (HIV-1) therapy is the genomic diversity of circulating viruses and the possibility that drug-resistant virus variants are selected. Although RNA interference (RNAi) is a powerful tool to stably inhibit HIV-1 replication by the expression of antiviral short hairpin RNAs (shRNAs) in transduced T cells, this approach is also vulnerable to pre existing genetic variation and the development of viral resistance through mutation. To prevent viral escape, we proposed to combine multiple shRNAs against important regions of the HIV-1 RNA genome, which should ideally be conserved in all HIV-1 subtypes. The vulnerability of RNAi therapy to viral escape has been studied for a single subtype B strain, but it is unclear whether the antiviral shRNAs can inhibit diverse virus isolates and subtypes, including drug-resistant variants that could be present in treated patients. To determine the breadth of the RNAi gene therapy approach, we studied the susceptibility of HIV-1 subtypes A E and drug-resistant variants. In addition, we monitored the evolution of HIV-1 escape variants. We demonstrate that the combinatorial RNAi therapy is highly effective against most isolates, supporting the future testing of this gene therapy in appropriate in vivo models. PMID- 25716533 TI - Diet-animal fractionation of nitrogen stable isotopes reflects the efficiency of nitrogen assimilation in ruminants. AB - The natural abundance of 15N in animal proteins (delta15Nanimal) is greater than that in the diet consumed by the animals (delta15Ndiet), with a discrimination factor (Delta15N = delta15Nanimal - delta15Ndiet) that is known to vary according to nutritional conditions. The objectives of the present study were to test the hypothesis that Delta15N variations depend on the efficiency of nitrogen utilisation (ENU) in growing beef cattle, and to identify some of the physiological mechanisms responsible for this N isotopic fractionation in ruminants. Thus, we performed the regression of the Delta15N of plasma proteins obtained from thirty-five finishing beef cattle fed standard and non-conventional diets against different feed efficiency indices, including ENU. We also performed the regression of the Delta15N of different ruminant N pools (plasma and milk proteins, urine and faeces) against different splanchnic N fluxes obtained from multi-catheterised lactating dairy cows. The Delta15N of plasma proteins was negatively correlated with feed efficiency indices in beef cattle, especially ENU (body protein gain/N intake) and efficiency of metabolisable protein (MP) utilisation (body protein gain/MP intake). Although Delta15N obtained from different N pools in dairy cows were all negatively correlated with ENU, the highest correlation was found when Delta15N was calculated from plasma proteins. Delta15N showed no correlation with urea-N recycling or rumen NH3 absorption, but exhibited a strong correlation with liver urea synthesis and splanchnic amino acid metabolism, which points to a dominant role of splanchnic tissues in the present N isotopic fractionation study. PMID- 25716534 TI - Healthcare utilization associated with obesity and physical disabilities. AB - INTRODUCTION: Obesity incurs a substantial economic burden to healthcare systems. Little is known about the combined medical costs attributable to obesity among individuals with physical disabilities (PDs). PURPOSE: To estimate the annual healthcare utilization and expenditure associated with overweight and obesity among adults with and without PDs. METHODS: Weighted multivariate generalized linear models were used to estimate healthcare costs and utilization among adults with and without PDs, across standard BMI categories, using the 2002-2011 Medical Expenditure Panel Survey. The analyses, performed in 2013-2014, included a population representative sample of 215,107 individuals, aged >=18 years. Overall, 36,349 adults reported moderate or significant PDs. The primary outcomes were total healthcare costs, physician office visits, and hospitalization. RESULTS: After adjusting for sociodemographic variables, self-rated mental and physical health, physical activity, and year, adults with PDs incurred more than 1.96 times the adjusted total healthcare costs ($4,298, 95% CI=$3,980, $4,617) than adults without PDs. Obese individuals spent significantly more than those at normal weight ($726, p<0.001). Obese individuals with PDs spent 1.13 times more than normal-weight individuals with PDs ($1,107, p<0.001) and >2.2 times more than normal-weight individuals without PDs ($5,197, p<0.001). PDs plus obesity represents $23.9 billion/year, or roughly 50% of the total costs attributable to obesity in the U.S. CONCLUSIONS: Across BMI categories, there was significantly greater healthcare utilization and cost among adults with PDs, independent of age, race, education, and SES. Health policies need to identify behavioral interventions that address both healthy weight achievement/maintenance and functional independence among all adults. PMID- 25716535 TI - Should support for obesity interventions or perceptions of their perceived effectiveness shape policy? AB - OBJECTIVES: Most studies suggest the public locate responsibility for the 'obesity epidemic' with individuals themselves and support measures promoting greater personal responsibility in the belief these will reduce obesity prevalence. We compared estimates of policy support with estimates of perceived policy effectiveness to test this assumption. METHODS: In an on-line survey of 534 New Zealanders, we tested support for 15 potential measures to reduce overweight and obesity and compared this with estimates of the effectiveness of these policies, determined by a Best-Worst choice experiment. RESULTS: Respondents gave strongest support to measures encouraging people to undertake more exercise and adopt a better diet. However, they saw greater personal responsibility as less effective in reducing obesity than environmental interventions that reduced the costs of healthy food and exercise, and decreased the availability of unhealthy foods. CONCLUSIONS: Potentially important differences exist between the measures the general public say they support to address obesity, which favour personal responsibility and education, and those they believe will be effective, which include more environmental interventions. IMPLICATIONS: Simply measuring the popularity of measures to reduce obesity produces an incomplete picture of public opinion. Examining the perceived efficacy of different interventions offers a complementary perspective that policy makers should also consider. PMID- 25716536 TI - Effects of volatile vs. propofol-based intravenous anesthetics on the alveolar inflammatory responses to one-lung ventilation: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this meta-analysis is to compare the potential effects of inhalation anesthetics with total intravenous anesthetics on alveolar cytokine expression and lung-related clinical outcomes in patients undergoing one-lung ventilation (OLV) for thoracic surgery. METHODS: We retrieved the PubMed, EMBASE, and the Cochrane Library respectively to identify randomized controlled trials comparing different anesthetics (volatile anesthetics vs. intravenous anesthetics) on the pulmonary inflammatory response to OLV. The primary outcomes were the levels of alveolar concentrations of inflammatory cytokines. RESULTS: Eight randomized controlled trials that included 365 patients were screened. Overall, there were significant differences in the concentration of alveolar inflammatory mediators between volatile group and intravenous group, in which volatile group had lower levels of TNF-alpha (SMD -1.51; 95 % CI -2.15 to -0.87; p < 0.001), IL-6 (SMD -0.70; 95 % CI -0.99 to -0.41; p < 0.001) and IL-8 (SMD 1.32; 95 % CI -2.20 to -0.45; p = 0.003). The overall number of pulmonary complications in the volatile group was smaller (RR 0.42; 95 % CI 0.23-0.77; p = 0.005) and patients in that group had significantly abridged hospitalization stay (WMD -3.59 days; 95 % CI -5.70 to -1.48 days; p = 0.001). CONCLUSIONS: Inhalation anesthetics might be preferable in patients undergoing OLV for thoracic surgery and their protective effects might work via attenuating inflammatory responses. PMID- 25716537 TI - Factors influencing the opinion of patients concerning the functioning of the Polish hospital before and after ownership transformation. AB - Studies of satisfaction among patients are a popular and frequently obligatory tool used in improving the quality of medical services worldwide. Becoming familiar with the opinion of the patients enables to adjust the venue to their expectations, thus contributing to the increase in its competitiveness. We aimed to study patients' satisfaction understood as a tool used in increasing the quality of medical services; in addition, we assessed factors that affect a worse review patients gave about the functioning of this Polish hospital before and after its transformation into a commercial company. The study of satisfaction among patients was conducted using an anonymous questionnaire among 2702 respondents before and 2795 respondents after the hospital's transformation. Multivariate logistic regression analysis was applied to statistically analyze the collected empirical material, where the dependent variable was a worse evaluation of respondents concerning the functioning of the hospital. It was demonstrated that both before and after the hospital's transformation into a commercial company, it was education and conditions of housing of patients that determined their opinion about the functioning of the admission center and hospital wards. A higher level of education increases the risk of a worse evaluation of the admission center and hospital wards, whereas higher self evaluation of housing conditions lowered the discussed risk. Factors that influence the opinion of patients concerning the functioning of the hospital are education, age, marital status, housing conditions of the respondents and also the number of stays at a given hospital, and a conscious choice of the facility in which a patient wished to be treated. PMID- 25716538 TI - HPLC simultaneous determination of arbutin, chlorogenic acid and 6'-O caffeoylarbutin in different parts of Vaccinium dunalianum Wight. AB - Arbutin (1), chlorogenic acid (2) and 6'-O-caffeoylarbutin (3) are three major components in Vaccinium dunalianum Wight with various promising bioactivities. A reliable, reproducible and accurate method for simultaneous and quantitative determination of 1-3 is developed by RP-HPLC analysis. This method should be appropriate for the quality assurance of unprocessed and processed materials of V. dunalianum. The contents of 1-3 in different parts of V. dunalianum from different origins were analysed. The content of 3 was much higher than those of 1 and 2, accounting for up to 31.76% in the dried leaf buds. Moreover, the leaf buds, flower buds and leaves showed a tendency towards higher contents of 1-3 than the other plant parts. PMID- 25716539 TI - Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses. AB - Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4 mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti inflammatory effect during infections depending on the TLR primarily involved. PMID- 25716540 TI - The levator ani muscle during pregnancy and major levator ani muscle defects diagnosed postpartum: a three- and four-dimensional transperineal ultrasound study. AB - OBJECTIVE: To investigate associations between levator hiatus area and levator ani muscle function during pregnancy and major levator ani muscle defects postpartum. DESIGN: Observational prospective cohort study. SETTING: University hospital, Norway. SAMPLE: A cohort of 234 nulliparous women at 21 and 37 weeks of gestation, and at 6 weeks postpartum. METHODS: Ultrasound measurements of the levator hiatus at rest, during pelvic floor muscle contraction, and during the Valsalva manoeuvre were taken at 21 and 37 weeks of gestation. Levator ani muscle function was estimated as the percentage changes in levator ani muscle length from rest to contraction, and the level of muscle stretch during the Valsalva manoeuvre. Major levator ani muscle defects were diagnosed at 6 weeks postpartum using tomographic ultrasound imaging. MAIN OUTCOME MEASURES: Associations between ultrasound measurements antepartum and major levator ani muscle defects postpartum. RESULTS: Women with major levator ani muscle defects postpartum had significantly smaller levator hiatus area at rest and during the Valsalva manoeuvre at mid-pregnancy (mean difference 1.03 cm(2) , 95% CI 0.31-1.76; 2.92 cm(2) , 95% CI 1.77-4.07), and at 37 weeks of gestation (mean difference 1.47 cm(2) , 95% CI 0.62-2.32; 2.84 cm(2) , 95% CI 0.88-4.80), than women without such defects. They also had significantly less shortening of the levator ani muscle during contraction at 37 weeks of gestation. CONCLUSIONS: Smaller levator hiatus area at rest and during the Valsalva manoeuvre at mid and late pregnancy, and less shortening of the levator ani muscle during contraction at 37 weeks of gestation, are associated with major levator ani muscle defects postpartum. PMID- 25716541 TI - Voluntary activation of trunk extensors appears normal in young adults who have recovered from low back pain. AB - BACKGROUND: Low back pain (LBP) is associated with alterations in control of trunk movements and changes within central nervous system (CNS). Evidence shows that some of these alterations within the CNS are reversible when the symptoms are relieved, whereas other shows the opposite. Therefore, the purpose of the current study was to investigate whether alterations in voluntary activation (VA) of central neural drive, as assessed using twitch interpolation to measure VA, are present in subjects with a history of low back pain (HLBP), who are free from pain at the time of experiment. METHODS: Twelve adults with HLBP and 12 controls participated. Bilateral electromyographic recordings were obtained from erector spiane muscles at two vertebral levels (T12 and L4) and from rectus abdominis. Participants performed a series of brief isometric back extensions (50-100% maximum voluntary contraction) during which transcranial magnetic stimulation was delivered. The sizes of the evoked (superimposed) twitches were measured using dynamometry and VA was derived. The amplitude of motor evoked potentials (MEPs) and duration of cortical silent period (CSP) in erector spinae muscles were calculated; questionnaires were used to evaluate disability, levels of physical activity, quality of life and pain. RESULTS: The level of VA was not significantly different between HLBP and control groups. Additionally, there were no between-group differences in the time-to-peak amplitudes of the twitches, MEP amplitudes or duration of CSP. CONCLUSIONS: The ability to voluntarily activate back extensor muscles maximally does not appear to be impaired in subjects with a history of LBP during pain-free episodes. PMID- 25716542 TI - Three-dimensional virtual simulation and evaluation of the femoroacetabular impingement based on "black bone" MRA. AB - INTRODUCTION: Femoroacetabular impingement (FAI) is a recognised cause of secondary osteoarthritis of the hip. Several imaging methods have been used to analyse the pathologic signs. Because of the lack of precise pre- and intraoperative overview and the difficulty locating osseous pathologies, arthroscopic and minimal invasive treatment is still challenging, even for trained surgeons. This paper describes a procedure that is based on magnetic resonance arthrography (MRA) and is used to virtually verify the range of motion (ROM) of the hip. It enables the evaluation of FAI and the preoperative simulation of adequate surgical manoeuvres. METHODS: Each MRI was completed on a 3.0 T system using a flexible transmit/receive surface body coil with the patient in the supine position. An axial three-dimensional (3D) gradient-echo (VIBE, volume interpolated breathhold examination) sequence was performed. For the generation of 3D bone models, semiautomatic segmentation of the MRA data was accomplished using Amira((r)) visualisation software version 5.2. The self developed software "HipProject", written in C++, computes the maximal ROM of the hip. The virtual colliding regions were visualised for verification and simulation of osseous trimming. RESULTS: In addition, for necessary information about damage to the cartilage and labrum, "black bone" MRA was used to generate extremely precise 3D reconstructions of the hip joint to automatically calculate the preoperative osseous ROM. Furthermore, the acetabular and femoral locations of the impingement zone were individually visualised and quantified. CONCLUSIONS: The described procedure is a useful tool for the preoperative investigation of impinging hips. It enables appropriate planning of required surgical interventions. PMID- 25716543 TI - The significance of the pelvic collateral circulation in aorto-iliac disease. PMID- 25716544 TI - Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT 406) in patients with advanced cancer: results of a first-in-man study. AB - PURPOSE: To assess safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of DEBIO1143, an antagonist of inhibitor apoptosis proteins. METHODS: This first-in-man study in patients with advanced cancer used an accelerated dose titration design. DEBIO1143 was given orally once daily on days 1-5 every 2 or 3 weeks until disease progressed or patients dropped out. The starting dose of 5 mg was escalated by 100% in single patients until related grade 2 toxicity occurred. This triggered expansion to cohorts of three and subsequently six patients and reduction in dose increments to 50%. Maximum tolerated dose (MTD) was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). On days 1 and 5, PK and PD samples were taken. RESULTS: Thirty-one patients received doses from 5 to 900 mg. Only one DLT was reported at 180 mg. No MTD was found. Most common adverse drug reactions were fatigue (26%), nausea (23%), and vomiting (13%). Average t max and T 1/2 was about 1 and 6 h, respectively. Exposure increased proportionally with doses from 80 to 900 mg, without accumulation over 5 days. Plasma CCL2 increased at 3-6 h postdose and epithelial apoptosis marker M30 on day 5; cIAP-1 levels in PBMCs decreased at all doses >80 mg. Five patients (17%) had stable disease as the best treatment response. CONCLUSION: DEBIO1143 was well tolerated at doses up to 900 mg and elicited PD effects at doses greater 80 mg. Limited antitumor activity may suggest development rather as adjunct treatment. PMID- 25716545 TI - Correlation of myelodysplastic syndromes with i(17)(q10) and TP53 and SETBP1 mutations. PMID- 25716546 TI - Effects of partial neuromuscular blockade on lateral spread response monitoring during microvascular decompression surgery. AB - OBJECTIVE: We evaluated the effect of partial neuromuscular blockade (NMB) and no NMB on successful intraoperative monitoring of the lateral spread response (LSR) during microvascular decompression (MVD) surgery. METHODS: Patients were randomly allocated into one of three groups: the TOF group, the NMB was targeted to maintain two counts of train-of-four (TOF); the T1 group, maintain the T1/Tc (T1: amplitude of first twitch, Tc: amplitude of baseline twitch) ratio at 50%; and the N group, no relaxants after tracheal intubation. Successful LSR monitoring was defined as effective baseline establishment and maintenance of the LSR until dural opening. RESULTS: The success rate of LSR monitoring was significantly lower in the TOF group. But, there was no significant difference between T1 and N. The detection rate of spontaneous free-run electromyography (EMG) activity was significantly higher in the N group compared with the TOF and T1 groups. CONCLUSIONS: Partial NMB with a target of T1/Tc ratio at 50% allows good recording of LSR with same outcome as surgery without NMB, and reduced spontaneous EMG activity. SIGNIFICANCE: We suggested the availability of partial NMB for intraoperative LSR monitoring. PMID- 25716547 TI - Reframing landscape fragmentation's effects on ecosystem services. AB - Landscape structure and fragmentation have important effects on ecosystem services, with a common assumption being that fragmentation reduces service provision. This is based on fragmentation's expected effects on ecosystem service supply, but ignores how fragmentation influences the flow of services to people. Here we develop a new conceptual framework that explicitly considers the links between landscape fragmentation, the supply of services, and the flow of services to people. We argue that fragmentation's effects on ecosystem service flow can be positive or negative, and use our framework to construct testable hypotheses about the effects of fragmentation on final ecosystem service provision. Empirical efforts to apply and test this framework are critical to improving landscape management for multiple ecosystem services. PMID- 25716548 TI - Light-cleavable rapamycin dimer as an optical trigger for protein dimerization. AB - Rapamycin-induced protein heterodimerization of FKBP12 and FRB is one of the most commonly employed switches to conditionally control biological processes. We developed an optically activated rapamycin dimer that does not induce FKBP12-FRB dimerization until exposed to light, and applied it to control kinase, protease, and recombinase function. PMID- 25716549 TI - The cost of thromboembolic events in hospitalized patients with breast or prostate cancer in France. AB - AIMS: The aim of the present study was to determine the number of admissions and the cost of hospital management of venous thromboembolism (VTE) events occurring in patients with breast cancer (BC) or prostate cancer (PC). METHODS: The French national hospital database (PMSI) was analyzed to identify patients diagnosed with BC or PC in 2010 and followed for 2 years. The number of admissions for VTE (or with VTE occurring during hospitalization) and the corresponding number of patients hospitalized were determined using disease-specific International Classification of Diseases, 10th revision (ICD-10) codes. Associated hospital costs were estimated from the healthcare payer perspective, using the French official tariffs. RESULTS: 62,365 and 45,551 patients diagnosed with BC and PC, respectively, in 2010 were identified from PMSI data; 1,271 (2.0%) and 997 (2.2%) were hospitalized for or had VTE during hospitalization. During the 2 years of follow-up, 346 patients (15%) presented a recurrence of thrombosis requiring hospitalization. A total of 1,604 and 1,210 inpatient VTE-related admissions (stays) in the BC and PC cohorts, respectively, were analyzed. Pulmonary embolism (PE) was the most frequent diagnosis leading to hospital admission in those cancer patients, followed by deep venous thrombosis. Mean cost per admission was ?3,302 and ?2,916 for first event and recurrence, respectively, in BC patients (total cost ?1.98 million over 2 years) and ?3,611 and ?3,363 for first event and recurrence in PC patients (total cost ?1.43 million over 2 years). In patients who had at least one recurrence, mean hospitalization cost was ?5,545 and ?5,692 in BC and PC, respectively. CONCLUSION: The burden of VTE in cancer patients is important; costs should be reduced by decreasing the occurrence of thrombotic recurrences. In this respect, better prevention and follow-up measures may reduce recurrence and VTE costs. PMID- 25716550 TI - Age, fertility and reproductive behavior in cuban crocodiles, Crocodylus rhombifer, at the Smithsonian's National Zoological Park. AB - The Smithsonian's National Zoological Park (NZP) has a long history with Cuban crocodiles, Crocodylus rhombifer, beginning in 1900's when the first animals arrived at the NZP. Today, the Zoo has two breeding groups of C. rhombifer and has observed and analyzed reproductive behavior and fertility rates over the last three years. Fertility rates were determined initially by observing the formation of an opaque band that forms on the shell of a fertile egg, called banding. The fertility rates by banding were later compared to the observation made after opening the eggs to verify fertility. In addition to tracking fertility, nesting and agonistic behavior were also observed. Several notable observations were documented over the same period. These included a male predating a nesting female's eggs, increased aggression between two females housed together, the continued development of a partially banded egg, and the discovery of 19 additional egg shells post oviposition by both females in the enclosure. Here we discuss the nest phenology, fertility and behavior of the five exhibited C. rhombifer at the Smithsonian's National Zoological Park over a 3-year period. Zoo Biol. 34:278-284, 2015. (c) 2015 Wiley Periodicals Inc. PMID- 25716551 TI - Giant strain with ultra-low hysteresis and high temperature stability in grain oriented lead-free K0.5Bi0.5TiO3-BaTiO3-Na0.5Bi0.5TiO3 piezoelectric materials. AB - We synthesized grain-oriented lead-free piezoelectric materials in (K0.5Bi0.5TiO3 BaTiO3-xNa0.5Bi0.5TiO3 (KBT-BT-NBT) system with high degree of texturing along the [001]c (c-cubic) crystallographic orientation. We demonstrate giant field induced strain (~0.48%) with an ultra-low hysteresis along with enhanced piezoelectric response (d33 ~ 190pC/N) and high temperature stability (~160 degrees C). Transmission electron microscopy (TEM) and piezoresponse force microscopy (PFM) results demonstrate smaller size highly ordered domain structure in grain-oriented specimen relative to the conventional polycrystalline ceramics. The grain oriented specimens exhibited a high degree of non-180 degrees domain switching, in comparison to the randomly axed ones. These results indicate the effective solution to the lead-free piezoelectric materials. PMID- 25716552 TI - Genetic and environmental factors are associated with serum 25-hydroxyvitamin D concentrations in older African Americans. AB - BACKGROUND: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. OBJECTIVE: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. METHODS: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-MUg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. CONCLUSIONS: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans. PMID- 25716553 TI - Nutrient-induced stimulation of protein synthesis in mouse skeletal muscle is limited by the mTORC1 repressor REDD1. AB - BACKGROUND: In skeletal muscle, the nutrient-induced stimulation of protein synthesis requires signaling through the mechanistic target of rapamycin complex 1 (mTORC1). Expression of the repressor of mTORC1 signaling, regulated in development and DNA damage 1 (REDD1), is elevated in muscle during various atrophic conditions and diminished under hypertrophic conditions. The question arises as to what extent REDD1 limits the nutrient-induced stimulation of protein synthesis. OBJECTIVE: The objective was to examine the role of REDD1 in limiting the response of muscle protein synthesis and mTORC1 signaling to a nutrient stimulus. METHODS: Wild type REDD1 gene (REDD1(+/+)) and disruption in the REDD1 gene (REDD1(-/-)) mice were feed deprived for 16 h and randomized to remain feed deprived or refed for 15 or 60 min. The tibialis anterior was then removed for analysis of protein synthesis and mTORC1 signaling. RESULTS: In feed-deprived mice, protein synthesis and mTORC1 signaling were significantly lower in REDD1(+/+) than in REDD1(-/-) mice. Thirty minutes after the start of refeeding, protein synthesis in REDD1(+/+) mice was stimulated by 28%, reaching a value similar to that observed in feed-deprived REDD1(-/-) mice, and was accompanied by increased phosphorylation of mTOR (Ser2448), p70S6K1 (Thr389), and 4E-BP1 (Ser65) by 81%, 167%, and 207%, respectively. In refed REDD1(-/-) mice, phosphorylation of mTOR (Ser2448), p70S6K1 (Thr389), and 4E-BP1 (Ser65) were significantly augmented above the values observed in refed REDD1(+/+) mice by 258%, 405%, and 401%, respectively, although protein synthesis was not coordinately increased. Seventy-five minutes after refeeding, REDD1 expression in REDD1(+/+) mice was reduced (~15% of feed-deprived REDD1(+/+) values), and protein synthesis and mTORC1 signaling were not different between refed REDD1(+/+) mice and REDD1(-/-) mice. CONCLUSIONS: The results show that REDD1 expression limits protein synthesis in mouse skeletal muscle by inhibiting mTORC1 signaling during periods of feed deprivation and that a reduction in its expression is necessary for maximal stimulation of protein synthesis in response to refeeding. PMID- 25716555 TI - [The shoulder]. PMID- 25716554 TI - Dietary Marine n-3 PUFAs Do Not Affect Stress-Induced Visceral Hypersensitivity in a Rat Maternal Separation Model. AB - BACKGROUND: Although never evaluated for efficacy, n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS). OBJECTIVE: This study was designed to investigate, in a mast cell-dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment via peroxisome proliferator-activated receptor gamma (PPARG) activation. METHODS: Maternally separated rats were subjected to hypersensitivity inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil-supplemented diets [4% soy oil (SO) and 3% tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg . kg-1 . d-1). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor alpha (TNF-alpha) and beta hexosaminidase release. RESULTS: Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO-T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 +/- 4 vs. 128 +/- 12 (P < 0.05) vs. 115 +/- 14 and 82 +/- 5 vs. 127 +/- 16 (P < 0.01) vs. 113 +/- 19, respectively]. Comparison of SO-T7 with its control showed similar results [74 +/- 6 vs. 103 +/- 13 (P < 0.05) vs. 115 +/- 17 and 66 +/- 3 vs. 103 +/- 10 (P < 0.05) vs. 117 +/- 11, respectively]. Erythrocytes showed significant LCPUFA uptake in the absence of colonic PPARG activation. Rosiglitazone induced increased PPARG target gene expression, but did not prevent hypersensitivity. Mast cell degranulation never differed between groups. Rosiglitazone and LCPUFAs significantly reduced PMA/calcium ionophore-induced TNF alpha release but not degranulation of HMC-1 cells. CONCLUSION: Dietary LCPUFAs did not reverse stress-induced visceral hypersensitivity in maternally separated rats. Although further research is needed, claims concerning LCPUFAs as a treatment option in IBS cannot be confirmed at this point and should be regarded with caution. PMID- 25716556 TI - Assessment of a fast generated analytical matrix for rotating slat collimation iterative reconstruction: a possible method to optimize the collimation profile. AB - In SPECT imaging, improvement or deterioration of performance is mostly due to collimator design. Classical SPECT systems mainly use parallel hole or pinhole collimators. Rotating slat collimators (RSC) can be an interesting alternative to optimize the tradeoff between detection efficiency and spatial resolution. The present study was conducted using a RSC system for small animal imaging called CLiR. The CLiR system was used in planar mode only. In a previous study, planar 2D projections were reconstructed using the well-known filtered backprojection algorithm (FBP). In this paper, we investigated the use of the statistical reconstruction algorithm maximum likelihood expectation maximization (MLEM) to reconstruct 2D images with the CLiR system using a probability matrix calculated using an analytic approach. The primary objective was to propose a method to quickly generate a light system matrix, which facilitates its handling and storage, while providing accurate and reliable performance. Two other matrices were calculated using GATE Monte Carlo simulations to investigate the performance obtained using the matrix calculated analytically. The first matrix calculated using GATE took all the physics processes into account, where the second did not consider for the scattering, as the analytical matrix did not take this physics process into account either. 2D images were reconstructed using FBP and MLEM with the three different probability matrices. Both simulated and experimental data were used. A comparative study of these images was conducted using different metrics: the modulation transfert function, the signal-to-noise ratio and quantification measurement. All the results demonstrated the suitability of using a probability matrix calculated analytically. It provided similar results in terms of spatial resolution (about 0.6 mm with differences <5%), signal-to-noise ratio (differences <10%), or quality of image. PMID- 25716559 TI - Chromium content in the human hip joint tissues. AB - OBJECTIVE: Chromium has many important functions in the human body. For the osseous tissue, its role has not been clearly defined. This study was aimed at determining chromium content in hip joint tissues. METHODS: A total of 91 hip joint samples were taken in this study, including 66 from females and 25 from males. The sample tissues were separated according to their anatomical parts. The chromium content was determined by the AAS method. The statistical analysis was performed with U Mann-Whitney's non-parametric test, P<=0.05. RESULTS: The overall chromium content in tissues of the hip joint in the study subjects was as follows: 5.73 ug/g in the articular cartilage, 5.33 ug/g in the cortical bone, 17.86 ug/g in the cancellous bone, 5.95 ug/g in the fragment of the cancellous bone from the intertrochanteric region, and 1.28 ug/g in the joint capsule. The chromium contents were observed in 2 group patients, it was 7.04 ug/g in people with osteoarthritis and 12.59 ug/g in people with fractures. CONCLUSION: The observed chromium content was highest in the cancellous bone and the lowest in the joint capsule. Chromium content was significantly different between the people with hip joint osteoarthritis and the people with femoral neck fractures. PMID- 25716558 TI - Effects of baicalin on collagen Iota and collagen IotaIotaIota expression in pulmonary arteries of rats with hypoxic pulmonary hypertension. AB - The synthesis and accumulation of collagen play an important role in the formation and progression of hypoxic pulmonary hypertension. Baicalin has been reported to prevent bleomycin-induced pulmonary fibrosis. However, the role of baicalin in the treatment of pulmonary hypertension remains unknown. A disintegrin and metalloprotease with thrombospondin type-1 motif (ADAMTS-1) is a secreted enzyme that acts on a wide variety of extracellular matrix (ECM) substrates associated with vascular diseases. In this study, we aimed to investigate the effects of baicalin on the synthesis of collagen I in rats with pulmonary hypertension induced by hypoxia and the changes in ADAMTS-1 expression. A total of 24 Sprague Dawley rats were randomly assigned to 3 groups as follows: the control group (C), the hypoxia group (H) and the hypoxia + baicalin group (B). The rats in groups H and B were kept in a normobaric hypoxic chamber for 4 weeks, and the rats in group C were exposed to room air. We measured the hemodynamic indexes, including mean pulmonary artery pressure (mPAP), mean systemic (carotid) artery pressure (mSAP), and then calculated the mass ratio of right ventricle to left ventricle plus septum [RV/(LV + S)] to reflect the extent of right ventricular hypertrophy. We measured the mRNA and protein expression levels of type I collagen, type III collagen and ADAMTS-1 by hybridization in situ, and immunohistochemistry and western blot analysis, respectively. The results revealed that treatment with baicalin significantly reduced pulmonary artery pressure and attenuated the remodeling of the pulmonary artery under hypoxic conditions by increasing the expression of ADAMTS-1, so that the synthesis of type I collagen and its mRNA expression were inhibited. In conclusion, baicalin effectively inhibits the synthesis of collagen I in pulmonary arteries and this is associated with an increase in the expression of ADAMTS-1. Thus, treatment with baicalin may be an effective method for lowering pulmonary artery pressure and preventing pulmonary artery remodeling. PMID- 25716557 TI - Neutrophil gelatinase-associated lipocalin and innate immune responses to bacterial infections. AB - Neutrophil gelatinase-associated lipocalin (NGAL), an essential component of the antimicrobial innate immune system, is present in neutrophils and multiple other tissues. It prevents iron acquisition by microorganisms by sequestering iron loaded bacterial siderophores. NGAL also modulates neutrophil functions. Its production is inducible following Toll-like receptor 4 activation and release of pro-inflammatory cytokines. NGAL is employed clinically in the diagnosis of acute kidney injury and may be useful in general in the differential diagnosis of a bacterial-mediated infectious process. Elevated levels of NGAL have been detected in the blood of patients with bacterial urinary tract infection, community acquired pneumonia, sepsis, as well as in the cerebrospinal fluid and peritoneal fluid of patients with bacterial meningitis and peritonitis. Some bacteria have developed resistance to NGAL-mediated iron sequestration by production of modified siderophores that are not recognized by NGAL. PMID- 25716560 TI - Medium-Chain Triglyceride Activated Brown Adipose Tissue and Induced Reduction of Fat Mass in C57BL/6J Mice Fed High-fat Diet. AB - OBJECTIVE: To investigate activation of brown adipose tissue (BAT) stimulated by medium-chain triglyceride (MCT). METHODS: 30 Male C57BL/6J obese mice induced by fed high fat diet (HFD) were divided into 2 groups, and fed another HFD with 2% MCT or long-chain triglyceride (LCT) respectively for 12 weeks. Body weight, blood biochemical variables, interscapular brown fat tissue (IBAT) mass, expressions of mRNA and protein of beta 3-adrenergic receptors (beta3-AR), uncoupling protein-1 (UCP1), hormone sensitive lipase (HSL), protein kinase A (PKA), and adipose triglyceride lipase (ATGL) in IBAT were measured. RESULTS: Significant decrease in body weight and body fat mass was observed in MCT group as compared with LCT group (P<0.05) after 12 weeks. Greater increases in IBAT mass was observed in MCT group than in LCT group (P<0.05). Blood TG, TC, LDL-C in MCT group were decreased significantly, meanwhile blood HDL-C, ratio of HDL-C/LDL C and norepinephrine were increased markedly. Expressions of mRNA and protein of beta3-AR, UCP1, PKA, HSL, ATGL in BAT were greater in MCT group than in LCT group (P<0.05). CONCLUSION: Our results suggest that MCT stimulated the activation of BAT, possible via norepinephrine pathway, which might partially contribute to reduction of the body fat mass in obese mice fed high fat diet. PMID- 25716561 TI - Autophagy Accompanied with Bisdemethoxycurcumin-induced Apoptosis in Non-small Cell Lung Cancer Cells. AB - OBJECTIVE: To investigate the effects of bisdemethoxycurcumin (BDMC) on non-small cell lung cancer (NSCLC) cell line, A549, and the highly metastatic lung cancer 95D cells. METHODS: CCK-8 assay was used to assess the effect of BDMC on cytotoxicity. Flow cytometry was used to evaluate apoptosis. Western blot analysis, electron microscopy, and quantification of GFP-LC3 punctuates were used to test the effect of BDMC on autophagy and apoptosis of lung cancer cells. RESULTS: BDMC inhibited the viability of NSCLC cells, but had no cytotoxic effects on lung small airway epithelial cells (SAECs). The apoptotic cell death induced by BDMC was accompanied with the induction of autophagy in NSCLC cells. Blockage of autophagy by the autophagy inhibitor 3-methyladenine (3-MA) repressed the growth inhibitory effects and induction of apoptosis by BDMC. In addition, BDMC treatment significantly decreased smoothened (SMO) and the transcription factor glioma-associated oncogene 1 (Gli1) expression. Furthermore, depletion of Gli1 by siRNA and cyclopamine (a specific SMO inhibitor) induced autophagy. CONCLUSION: Aberrant activation of Hedgehog (Hh) signaling has been implicated in several human cancers, including lung cancers. The present findings provide direct evidence that BDMC-induced autophagy plays a pro-death role in NSCLC, in part, by inhibiting Hedgehog signaling. PMID- 25716562 TI - Ginsenoside Rg1 Attenuates Isoflurane-induced Caspase-3 Activation via Inhibiting Mitochondrial Dysfunction. AB - OBJECTIVE: The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rg1 is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rg1 can attenuate isoflurane induced caspase activation via inhibiting mitochondrial dysfunction. METHODS: We investigated the effects of ginsenoside Rg1 at concentrations of 12.5, 25, and 50 MUmol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naive and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein (APP) (H4-APP cells). For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore (mPTP) and adenosine-5'-triphosphate (ATP) levels. We employed Western blot analysis, chemiluminescence, and flowcytometry. RESULTS: Here we show that pretreatment with 50 umol/L ginsenoside Rg1 for 12 h attenuated isoflurane induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 umol/L ginsenoside Rg1 for 24 h attenuated isoflurane induced caspase-3 activation and mitochondrial dysfunction in both H4 naive and H4-APP cells. CONCLUSION: These data suggest that ginsenoside Rg1 may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rg1 in preventing and treating isoflurane-induced neurotoxicity. PMID- 25716563 TI - Pedestrian injuries and the relevant burden in shanghai, china: implications for control. AB - OBJECTIVE: To study the associations of pedestrian injuries with age, income and educational level in Shanghai and to analyze the relative disease burden. METHODS: Information on pedestrian-related cases and deaths were collected from 494 hospitals and mortality registry systems from 1992 to 2010, and a multistage cluster sampling survey conducted in 2006. Logistic regression model was used in the analyses. RESULTS: The age group of 5-9 had the highest mortality and morbidity among children. Mortality increased obviously among those aged 60 or above. Individuals with an educational level under the primary school and with the lower family average income were more likely to suffer pedestrian-related injuries. Multivariate Logistic analysis demonstrated that lower income and lower educational level increased the risk of pedestrian injuries with the odds ratio of 1.40 (95% CI: 1.15-1.71) and 1.70 (95% CI: 1.20-2-40), respectively. About 13.54% of the share of GDP for the healthcare, social security and welfare industries in Shanghai was occupied by the burden of pedestrian-related injuries in 2006. CONCLUSION: Pedestrian-related injury has inverse association with victims' income and educational level. Children of 5-9 years old and adults over 60 with lower educational level and lower monthly income are the target persons to be intervened. PMID- 25716564 TI - The Association between Folate Pathway Genes and Cleft Lip With or Without Cleft Palate in a Chinese Population. AB - NSCL/P is a common congenital defect and gene-environmental factors involve in this disorder. Periconceptional intake of folate may reduce the risk of NSCL/P. The present study investigated three SNPs (rs1801198, rs955516, and rs3733890) in three folate pathway genes, including TCN2, MTR, and BHMT among 481 patients and 558 healthy subjects. Rs955516 showed allelic association with NSCL/P. More patients carry rs955516 AA and rs3733890 AA genotypes. The gene-gene interaction test showed trans-phase combination effects for MTR and BHMT genes. Our study suggests that the interaction of MTR and BHMT genes play a vital role in the pathogenesis of NSCL/P in Chinese population. PMID- 25716565 TI - Intrauterine Exposure to Maternal Diabetes is Associated with Adiposity in Children at 6 Years of Age in China. AB - Children born to mothers with gestational diabetes mellitus (GDM) are more likely to exhibit congenital malformations, high birth weight, and obesity and have an increased risk of developing type 2 diabetes in later life. Children who are exposed to maternal diabetes in utero may be 'programmed' for later development of obesity at a critical period of development. Therefore, the purpose of the present study was to examine the associations among adiposity and systolic blood pressure in children and abnormal maternal glucose levels during pregnancy. A total of 856 mother-child pairs were included in the present retrospective study. Eligible pregnant women underwent a standard 75 g oral glucose tolerance test between 24 and 28 weeks' gestation. Anthropometric characteristics of their children were measured at 6 years of age, including body mass index, the sum of subscapular and tricep skinfold thickness, and systolic blood pressure. The result suggests that children exposed to GDM have higher adiposity; prevention of childhood obesity needs to begin early in life for these children. PMID- 25716566 TI - The Relationship between Working Conditions and Adverse Health Symptoms of Employee in Solar Greenhouse. AB - To determine the correlation between the working environment and the health status of employees in solar greenhouse, 1171 employees were surveyed. The results show the 'Greenhouse diseases' are affected by many factors. Among general uncomforts, the morbidity of the bone and joint damage is the highest and closely related to labor time and age. Planting summer squash and wax gourd more easily cause skin pruritus. Asthma-related cough, eye disease, and skin pruritus are significantly correlated with the cultivation of wax gourd. The application of inorganic fertilizer and fertigation dramatically induce the bone and joint damage. The smell of covering film greatly influence skin pruritus. Personal protection is badly scanty and normative occupational health and safety need to be completed. PMID- 25716567 TI - Protective effects of shikonin on brain injury induced by carbon ion beam irradiation in mice. AB - Radiation encephalopathy is the main complication of cranial radiotherapy. It can cause necrosis of brain tissue and cognitive dysfunction. Our previous work had proved that a natural antioxidant shikonin possessed protective effect on cerebral ischemic injury. Here we investigated the effects of shikonin on carbon ion beam induced radiation brain injury in mice. Pretreatment with shikonin significantly increased the SOD and CAT activities and the ratio of GSH/GSSG in mouse brain tissues compared with irradiated group (P<0.01), while obviously reduced the MDA and PCO contents and the ROS levels derived from of the brain mitochondria. The shikonin also noticeably improved the spatial memory deficits caused by carbon ion beam irradiation. All results demonstrated that shikonin could improve the irradiated brain injury which might resulted from its modulation effects on the oxidative stress induced by the 12C6+ ion beam. PMID- 25716568 TI - Follow-up Study of Retreatment TB Patients with Sputum Smear and/or Culture Positive Two Years after They were Declared Cured with First-line Anti-TB Drugs in Shandong Province. AB - This study aimed to learn the recurrence rate in the retreatment TB patients with sputum smear and/or culture positive (ss+ and/or c+) two years after they were declared cured, and to explore causes of recurrence in order to improve long-time treatment outcome. 5 cities were selected as research locations. Recurrence of TB was judged by chest X-ray examination together with sputum smear and culture examination. Questionnaire was carried out to collect data on treatment history, demographics and possible risk factors. Chi-square test and logistic regression were conducted using SPSS in this study. As the result, 99 active TB patients were identified and the recurrence rate was 16.67% and irregular medicine and smoking were the causes of the recurrence. The retreatment TB patients with sputum smear and/or culture positive in this study had higher recurrence rate and health education work on regular medication and smoking should be strengthened. PMID- 25716569 TI - Preparative resolution of gatifloxacin enantiomers with pre-column esterification strategy and comparing their enantioselectivity to bacteria and antibody. AB - Gatifloxacin (GFX) is a kind of chiral fluoroquinolones compound due to the methyl group at the C-3 position of the piperazine ring[1]. Although the enantiomers of GFX show similar levels of antimicrobial activity and pharmacokinetics[2], the other biological activities (i.e., toxicity or enantioselective recognition to various receptors in vivo) of GFX enantiomers have not yet been studied. With this in mind, we developed a rapid and cost effective high performance liquid chromatographic (HPLC) separation procedure for GFX enantiomers with a pre-column esterification strategy. With significant enhancement of drug solubility and optimization for chromatographic conditions, the proposed method was scaled up to preparative HPLC to obtain optical active S (-)- and R-(+)-GFX. The antibacterial activities of GFX enantiomers after preparative separation were further verified by measuring the Minimum Inhibitory Concentration (MIC) values against Escherichia coli ATCC 25922. In addition, the binding selectivity of GFX enantiomers to protein receptor were evaluated by antibody using enzyme-linked immunosorbent assay (ELISA) for the first time. PMID- 25716570 TI - Inaccuracy of Self-reported Low Sodium Diet among Chinese: Findings from Baseline Survey for Shandong & Ministry of Health Action on Salt and Hypertension (SMASH) Project. AB - This study was aimed to evaluate the agreement between the self-reported sodium intake level and 24-h urine sodium excretion level in Chinese. The 24-h urine collection was conducted among 2112 adults aged 18-69 years randomly selected in Shandong Province, China. The subjects were asked whether their sodium intake was low, moderate, or high. The weighted kappa statistics was calculated to assess the agreement between 24-h urine sodium excretion level and self-reported sodium intake level. One third of the subjects reported low sodium intake level. About 70% of the subjects had mean 24-h sodium excretion>9 g/d, but reported low or moderate sodium intake. The agreement between self-reported sodium intake level and 24-h urine sodium excretion level was low in both normotensive subjects and hypertensive subjects. These findings suggested that many subjects who reported low sodium intake had actual urine sodium excretion>9 g/d. Sodium intake is often underestimated in both hypertensive and normotensive participants in China. PMID- 25716571 TI - Effect of the Y chromosome on testis weight in mice. AB - We investigated the effect of the Y chromosome on testis weight in (B6.Cg-A(y) * Y-consomic mouse strain) F1 male mice. We obtained the following results: (1) Mice with the Mus musculus domesticus-type Y chromosome had significantly heavier testis than those with the M. m. musculus-type Y chromosome. (2) Variations in Usp9y and the number of CAG repeats in Sry were significantly associated with testes weight. The A(y) allele was correlated with a reduced testis weight, and the extent of this reduction was significantly associated with a CAG repeat number polymorphism in Sry. These results suggest that Y chromosome genes not only influence testis weight but also modify the effect of the A(y) allele in mediating this phenomenon. PMID- 25716572 TI - Forensic DNA Phenotyping: Predicting human appearance from crime scene material for investigative purposes. AB - Forensic DNA Phenotyping refers to the prediction of appearance traits of unknown sample donors, or unknown deceased (missing) persons, directly from biological materials found at the scene. "Biological witness" outcomes of Forensic DNA Phenotyping can provide investigative leads to trace unknown persons, who are unidentifiable with current comparative DNA profiling. This intelligence application of DNA marks a substantially different forensic use of genetic material rather than that of current DNA profiling presented in the courtroom. Currently, group-specific pigmentation traits are already predictable from DNA with reasonably high accuracies, while several other externally visible characteristics are under genetic investigation. Until individual-specific appearance becomes accurately predictable from DNA, conventional DNA profiling needs to be performed subsequent to appearance DNA prediction. Notably, and where Forensic DNA Phenotyping shows great promise, this is on a (much) smaller group of potential suspects, who match the appearance characteristics DNA-predicted from the crime scene stain or from the deceased person's remains. Provided sufficient funding being made available, future research to better understand the genetic basis of human appearance will expectedly lead to a substantially more detailed description of an unknown person's appearance from DNA, delivering increased value for police investigations in criminal and missing person cases involving unknowns. PMID- 25716573 TI - Excess intake of fat and sugar potentiates epinephrine-induced hyperglycemia in male rats. AB - AIMS: Over the past five decades, per capita caloric intake has increased significantly, and diet- and stress-related diseases are more prevalent. The stress hormone epinephrine stimulates hepatic glucose release during a stress response. The present experiment tested the hypothesis that excess caloric intake alters this ability of epinephrine to increase blood glucose. METHODS: Sprague Dawley rats were fed a high-energy cafeteria-style diet (HED). Weight gain during the first 5 days on the diet was used to divide the rats into an HED-lean group and HED-obese group. After 9 weeks, the rats were injected with epinephrine, and blood glucose was measured. RESULTS: HED-obese rats gained body and fat mass, and developed insulin resistance (IR) and hepatic steatosis. HED-lean and control rats did not differ. Epinephrine produced larger increases in blood glucose in the HED-obese rats than in the HED-lean and control rats. Removing the high energy components of the diet for 4 weeks reversed the potentiated effects of epinephrine on glucose and corrected the IR but not the steatosis or obesity. CONCLUSIONS: Consumption of a high-energy cafeteria diet potentiates epinephrine induced hyperglycemia. This effect is associated with insulin resistance but not adiposity or steatosis and is reversed by 4 weeks of standard chow. PMID- 25716574 TI - Mental health needs and availability of mental health care for children and adolescents with intellectual disability in Berlin. AB - BACKGROUND: The increased risk of mental health problems in children and adolescents with intellectual disability (ID) has been reported in several studies. However, almost no research has been conducted on parents' experiences with the general mental health system. We have investigated the prevalence of emotional and behavioural problems in children with ID as well as the availability and quality of mental health care from the parents' point of view. METHODS: Teachers of specialised schools for ID in Berlin were asked to complete the Teacher's Report Form (TRF) of the Child Behavior Checklist. Information was collected for 1226 children and adolescents aged 6-18 years with mild to profound ID (response 70.5%). The availability and quality of mental health care was assessed by a questionnaire given to parents who had already been seeking help for their children. A total of 330 parents completed the questionnaires (response 62.0%). In addition to univariate analysis, we conducted multiple logistic regressions regarding the psychopathology reported by teachers (TRF-syndrome scales) and difficulties concerning mental health care reported by parents for a paired sample of 308 children. RESULTS: Overall, 52.4% of the children and adolescents with ID had a total problem score on the TRF in the deviant range (47.1% when eliminating four items reflecting cognitive deficits). Compared with the general population normative sample of children, this is a three-time higher prevalence. The most striking problems were thought problems (schizoid and obsessive-compulsive), aggressive behaviour, attention problems and social problems. Parents whose children had more severe behavioural or emotional dysfunction reported more difficulties with the mental health system. From the parents' point of view, mental health professionals frequently did not feel responsible or were not sufficiently skilled for the treatment of children with ID. As a consequence, 96% of all parents were longing for specialised in- and outpatient services. CONCLUSIONS: This study confirms the findings from other studies regarding the high rate of co-occurrence of ID and mental health problems in youths. Results indicate that both are strongly requested by parents: specialised in- and outpatient services, as well as more professional general services and equitable treatment for all children, with and without ID. PMID- 25716575 TI - Metastatic Colorectal Cancer to the Liver: Involve the Surgeon Early and Often. PMID- 25716576 TI - Exception from informed consent: ethics and logistics. PMID- 25716577 TI - The impact of Daubert on the admissibility of forensic anthropology expert testimony. AB - Forensic anthropologists anticipated a significant impact from the 1993 Supreme Court Daubert decision, which addressed the standard of admissibility for expert testimony. In response, many forensic articles cited Daubert in the search for objective techniques or a critique of established subjective methods. This study examines challenges to forensic anthropological expert testimony to evaluate whether Daubert has actually affected the admissibility of such testimony. Thirty cases were identified that addressed the admissibility of the testimony, including 14 cases prior to Daubert and 16 after Daubert. Examination of these cases indicates that post-Daubert cases do not result in more exclusions. Yet, this lack of exclusions may instead be viewed as a manifestation of the field's overall surge toward more objective and quantifiable techniques in a self regulating response to Daubert. PMID- 25716578 TI - Quantification of the binding potential of cell-surface receptors in fresh excised specimens via dual-probe modeling of SERS nanoparticles. AB - The complete removal of cancerous tissue is a central aim of surgical oncology, but is difficult to achieve in certain cases, especially when the removal of surrounding normal tissues must be minimized. Therefore, when post-operative pathology identifies residual tumor at the surgical margins, re-excision surgeries are often necessary. An intraoperative approach for tumor-margin assessment, insensitive to nonspecific sources of molecular probe accumulation and contrast, is presented employing kinetic-modeling analysis of dual-probe staining using surface-enhanced Raman scattering nanoparticles (SERS NPs). Human glioma (U251) and epidermoid (A431) tumors were implanted subcutaneously in six athymic mice. Fresh resected tissues were stained with an equimolar mixture of epidermal growth factor receptor (EGFR)-targeted and untargeted SERS NPs. The binding potential (BP; proportional to receptor concentration) of EGFR - a cell surface receptor associated with cancer - was estimated from kinetic modeling of targeted and untargeted NP concentrations in response to serial rinsing. EGFR BPs in healthy, U251, and A431 tissues were 0.06 +/- 0.14, 1.13 +/- 0.40, and 2.23 +/ 0.86, respectively, which agree with flow-cytometry measurements and published reports. The ability of this approach to quantify the BP of cell-surface biomarkers in fresh tissues opens up an accurate new approach to analyze tumor margins intraoperatively. PMID- 25716580 TI - Epidemiology, population health, and health impact assessment. PMID- 25716581 TI - Early-life exposure to high-fat diet may predispose rats to gender-specific hepatic fat accumulation by programming Pepck expression. AB - Phosphoenolpyruvate carboxykinase (PEPCK) produces phosphoenolpyruvate during glyceroneogenesis. We previously demonstrated that a high-fat diet during pregnancy induced Pepck mRNA expression in neonatal rat pups, which is characterized by histone modifications in specific regions of the gene (Strakovsky RS, Zhang X, Zhou D, Pan YX. Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats. The Journal of Physiology 2011;589:2707 17). In the present study, we investigated whether these alterations persistent in adult offspring. Dams were fed either control or high-fat diet throughout gestation and lactation. Offspring were placed on control diet after weaning, generating C/C and HF/C groups. Liver was collected at 12 weeks of age. Hepatic nicotinamide adenine dinucleotide (reduced) (NADH) level was increased in both genders, but fat accumulation occurred only in liver of female offspring in HF/C group. This was accompanied by a significant increase of Pepck and fatty acid synthase (Fasn) mRNA expression in only female liver. The induction of Pepck gene expression in females was associated with increased dimethylated histone H3 lysine 4 level in multiple regions of the gene. Meanwhile, acetylated histone H3 and trimethylated histone H3 lysine 4 were induced at a specific coding region in HF/C, accompanied by decreased trimethylated histone H3 lysine 9 level at the promoter of female offspring. In conclusion, maternal high-fat diet programs Pepck expression through histone modifications in adult female offspring. Persistent Pepck induction in females may contribute to increased triglyceride synthesis, together with induced Fasn expression and NADH levels, which may lead to increased fat deposition in a gender-specific manner. PMID- 25716582 TI - Preparation and in vitro/in vivo evaluation of cyclosporin A-loaded nanodecorated ocular implants for subconjunctival application. AB - In terms of ocular drug delivery, biodegradable implant systems have several advantages including the ability to provide constant drug concentration at the target site, no necessity for surgical removal, and minimum systemic side effects. Cyclosporin A (CsA) is a neutral, hydrophobic, cyclic peptide of amino acids that frequently used for dry eye disease treatment. The aim of this study was to develop a nanoparticle-loaded implant system for sustained-release CsA delivery following subconjunctival implantation. Poly(lactide-co-glycolide) (85:15) or poly-epsilon-caprolactone (PCL) were used to prepare two different nanoparticle formulations. These nanoparticles loaded into PCL or poly(lactide-co caprolactone) implant formulations were prepared by two different methods, which were molding and electrospinning. Size and zeta potential of nanoparticles were determined and the morphology of the formulations were investigated by scanning electron microscopy. CsA-loading efficiencies were calculated and the in vitro degradation and in vitro release studies were performed. MTT test was also performed using L929 fibroblast cells to evaluate the cytotoxicity of the formulations. PCL-PCL-NP-I formulation was implanted to Swiss Albino mice with induced dry eye syndrome to evaluate the efficacy. In vitro release studies showed that the release from the formulations continues between 30 and 60 days, and the cell viability was found to be 77.4%-99.0%. In vivo studies showed that healing is significantly faster in the presence of the selected implant formulation. Results indicated that nanodecorated implants are promising ocular carriers for controlled-release CsA application. PMID- 25716583 TI - Fep1d: a script for the analysis of reaction coordinates. AB - The dynamics of complex systems with many degrees of freedom can be analyzed by projecting it onto one or few coordinates (collective variables). The dynamics is often described then as diffusion on a free energy landscape associated with the coordinates. Fep1d is a script for the analysis of such one-dimensional coordinates. The script allows one to construct conventional and cut-based free energy profiles, to assess the optimality of a reaction coordinate, to inspect whether the dynamics projected on the coordinate is diffusive, to transform (rescale) the reaction coordinate to more convenient ones, and to compute such quantities as the mean first passage time, the transition path times, the coordinate dependent diffusion coefficient, and so forth. Here, we describe the implemented functionality together with the underlying theoretical framework. PMID- 25716584 TI - Telling the story of mental health. PMID- 25716579 TI - The associations of month of birth with body mass index, waist circumference, and leg length: findings from the China Kadoorie Biobank of 0.5 million adults. AB - BACKGROUND: Season of birth (SoB) has been linked with various health outcomes. This study aimed to examine the associations between month of birth (MoB) and adult measures of leg length (LL), body mass index (BMI), and waist circumference (WC). METHODS: We analysed survey data from 10 geographically diverse areas of China obtained through the China Kadoorie Biobank. Analysis included 487 529 adults with BMI >= 18.5 kg/m(2). A general linear model was used to examine the associations between MoB and adult measures of LL, BMI, and WC, adjusted for survey site, sex, age, education level, smoking habit, alcohol consumption, physical activity level, sedentary leisure time, height (only for WC and LL), and hip circumference (only for LL). RESULTS: MoB was independently associated with both BMI and WC. Birth months in which participants had higher measures of adiposity were March-July for BMI and March-June for WC. The peak differences were 0.14 kg/m(2) for BMI and 0.47 cm for WC. The association between MoB and LL depended on survey site. Participants who were born in February-August in four sites (Harbin, Henan, Gansu, and Hunan) had the shortest LL (all P < 0.01). The peak difference in mean LL was 0.21 cm. No statistically significant association between MoB and LL was noted in the other sites (Qingdao, Suzhou, Sichuan, Zhejiang, Liuzhou, and Haikou). CONCLUSIONS: These findings suggest that MoB is associated with variations in adult adiposity measures and LL among Chinese adults. Low exposure to ultraviolet B radiation and subsequent reduced levels of vitamin D during the late second and early third trimesters may be involved in these phenomena. PMID- 25716585 TI - What doctors should know about the Trans-Pacific Partnership Agreement. PMID- 25716586 TI - Safety through reporting. PMID- 25716588 TI - Australian Early Psychosis Research Network: national collaboration, international competitive advantage. PMID- 25716589 TI - Whereto mental health reform in Australia: is anyone listening to our independent auditors? PMID- 25716590 TI - Choosing wisely: the message, messenger and method. PMID- 25716591 TI - Surveyors' perceptions of the impact of accreditation on patient safety in general practice. PMID- 25716592 TI - Surveyors' perceptions of the impact of accreditation on patient safety in general practice. PMID- 25716593 TI - First do no harm: a real need to deprescribe in older patients. PMID- 25716594 TI - Antibiotic prescribing in residential aged care facilities--health care providers' perspectives. PMID- 25716595 TI - Antibiotic prescribing practice in residential aged care facilities--health care providers' perspectives. PMID- 25716596 TI - A bowel cancer screening plan at last. PMID- 25716597 TI - Wasteful overinvestigation--ultrasound in groin hernias and groin pain. PMID- 25716598 TI - Severe glaucoma and vision loss due to cosmetic iris implants. PMID- 25716599 TI - Management of the acutely agitated patient in a remote location. PMID- 25716600 TI - Frequency and quality of mental health treatment for affective and anxiety disorders among Australian adults. AB - OBJECTIVES: To describe the frequency, type and quality of mental health treatment among Australian adults with past-year affective and/or anxiety disorders. DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of data for 8831 adults aged 16-85 years interviewed for the 2007 National Survey of Mental Health and Wellbeing, of whom 17% (n = 1517) met International Classification of Diseases, 10th revision (ICD-10) criteria for a past-year affective and/or anxiety disorder. MAIN OUTCOME MEASURES: Three levels of mental health treatment received in the past year: (1) any consultation with a health professional for mental health; (2) any evidence-based intervention (antidepressant medication, mood stabiliser medication, cognitive behaviour therapy and/or psychotherapy); and (3) minimally adequate treatment (a "dose" of an evidence-based intervention above a minimum threshold, consistent with treatment guidelines). RESULTS: Of participants with past-year affective and/or anxiety disorders, 39% sought professional help for mental health, 26% received an evidence-based treatment, and 16% received minimally adequate treatment. After controlling for clinical factors including type and severity of disorder, the odds of all levels of treatment were lower among younger adults (16-29 years) compared with middle-aged adults, and the odds of receiving an evidence-based treatment or minimally adequate treatment were lower among people who consulted a general practitioner only compared with a mental health professional. CONCLUSIONS: Closing the gap in treatment quality requires strategies to increase the use of evidence-based interventions, and to ensure these are delivered in sufficient doses. Research to elucidate why some patients are at increased risk of inadequate treatment, and the aspects of treatment that contribute to inadequate care, is indicated. PMID- 25716601 TI - Better access to mental health care and the failure of the Medicare principle of universality. AB - OBJECTIVES: To examine whether adult use of mental health services subsidised by Medicare varies by measures of socioeconomic and geographic disadvantage in Australia. DESIGN, SETTING AND PARTICIPANTS: A secondary analysis of national Medicare data from 1 July 2007 to 30 June 2011 for all mental health services subsidised by Better Access to Mental Health Care (Better Access) and Medicare - providers included general practitioners, psychiatrists, clinical psychologists and mental health allied health practitioners. MAIN OUTCOME MEASURES: Service use rates followed by measurement of inequity using the concentration curve and concentration index. RESULTS: Increasing remoteness was consistently associated with lower service activity; eg, per 1000 population, the annual rate of use of GP items was 79 in major cities and 25 and 8 in remote and very remote areas, respectively. Apart from GP usage, higher socioeconomic disadvantage in areas was typically associated with lower usage; eg, per 1000 population per year, clinical psychologist consultations were 68, 40 and 23 in the highest, middle and lowest advantaged quintiles, respectively; and non-Better Access psychiatry items were 117, 55 and 45 in the highest, middle and lowest advantaged quintiles, respectively. CONCLUSIONS: Our results highlight important socioeconomic and geographical disparities associated with the use of Better Access and related Medicare services. This can inform Australia's policymakers about these priority gaps and help to stimulate targeted strategies both nationally and regionally that work towards the universal and equitable delivery of mental health care for all Australians. PMID- 25716602 TI - Are Aboriginal people more likely to be diagnosed with more advanced cancer? AB - OBJECTIVE: To determine whether Aboriginal people in New South Wales were diagnosed with more advanced cancer than non-Aboriginal people. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of cancer cases, excluding lymphohaematopoietic cancers and cancers of unknown primary site, diagnosed in NSW in 2001-2007. MAIN OUTCOME MEASURE: Spread of disease at time of cancer diagnosis. RESULTS: Overall, 40.3% of 2039 cancers in Aboriginal people and 46.6% of 191 954 cancers in non-Aboriginal people were localised at diagnosis. After adjusting for age, sex, year of diagnosis, area of residence and socioeconomic status, Aboriginal people had significantly higher risks of regional or distant spread for head and neck cancer, relative to localised spread, than non Aboriginal people (regional: adjusted relative risk ratio [RRR], 1.89; 95% CI, 1.21-2.98; distant: adjusted RRR, 3.40; 95% CI, 1.85-6.05; P < 0.001). For breast, cervical and prostate cancers and melanoma, the risks of regional or distant spread were higher for Aboriginal people, but these differences were not statistically significant. For lung, colorectal, upper gastrointestinal tract, other gynaecological, and eye, brain and central nervous system cancers, the risks of regional, distant and unknown spread of cancer were similar for Aboriginal and non-Aboriginal people. CONCLUSION: Aboriginal people were more likely than non-Aboriginal people to be diagnosed with more advanced cancer for only a few cancer types, most notably head and neck cancers. Differences in spread of disease at diagnosis are unlikely to explain much of the survival differences observed across a wide range of cancers between Aboriginal and non Aboriginal people in NSW. PMID- 25716603 TI - Survival of Indigenous Australians receiving renal replacement therapy: closing the gap? AB - OBJECTIVES: To compare mortality rates for Indigenous and non-Indigenous Australians commencing renal replacement therapy (RRT) over time and by categories of remoteness of place of residence. DESIGN, SETTING AND PARTICIPANTS: An observational cohort study of Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data on Indigenous and non-Indigenous Australians registered with ANZDATA who commenced RRT from 1 January 1995 to 31 December 2009 and were followed until 31 December 2011. MAIN OUTCOME MEASURES: Five-year all cause mortality for Indigenous and non-Indigenous patients in three cohorts (1995 1999, 2000-2004 and 2005-2009) and five remoteness (of place of residence) categories. RESULTS: Indigenous patients were younger, more likely to have diabetes, be referred late and be from a more remote area than non-Indigenous patients. Age and comorbid conditions increased with successive cohorts for both groups. Unadjusted analysis (using the log-rank test) showed an increased risk of death for Indigenous patients in the 1995-1999 (P = 0.02) and 2000-2004 (P = 0.03) cohorts, but not for the 2005-2009 cohort (P = 0.7). However, a Cox proportional hazards model adjusted for covariates (age, sex, late referral and comorbid conditions [diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease, lung disease], and body mass index < 18.5 kg/m(2) and > 30 kg/m(2)) showed the following Indigenous:non-Indigenous hazard ratios (with 95% CIs) for major capital cities: 1995-1999, 1.47 (1.21-1.79); 2000 2004, 1.35 (1.12-1.63); and 2005-2009, 1.37 (1.14-1.66). CONCLUSIONS: Although unadjusted analysis suggests that the survival gap between Indigenous and non Indigenous patients receiving RRT has closed, there remains a significant disparity in survival after adjusting for the variables considered in our study. PMID- 25716604 TI - Are potential organ donors missed on general wards? A 6-month audit of hospital deaths. AB - OBJECTIVE: To determine whether potential organ donors are being missed on general wards by the DonateLife Audit, which concentrates on patients dying in emergency departments and intensive care units. DESIGN, SETTING AND PATIENTS: Six month (1 July to 31 December 2012) retrospective audit of patient deaths in a 700 bed metropolitan Australian tertiary referral and teaching hospital. MAIN OUTCOME MEASURE: Potential organ donor suitability as assessed by a panel of organ donation specialists. RESULTS: In total, 427 patients died, including nine neonates (2.1%) who were not further assessed and 175 patients (41.0%) who were excluded on the basis of age contraindicating organ donation (>= 80 years). Seventy-eight (18.3%) were excluded on the basis of active cancer or palliative care for cancer and 143 (33.5%) were deemed otherwise not medically suitable. Twelve (2.8%) had been referred to the DonateLife team for consideration for organ donation. Ten (2.3%) were submitted for panel review, and of these only three were considered to have "potential to develop brain death within 24 hours". These patients would have required mechanical ventilation if potential organ donation were to be realised. One additional potential candidate for donation after circulatory death was identified in the intensive care unit. CONCLUSION: We identified very few potential organ donors among patients who died outside the emergency department and intensive care unit. For these patients to have progressed to organ donation, medical interventions not in keeping with standard Australian practice would have been required. The DonateLife Audit appears to be a robust tool for identifying realistic potential organ donors. PMID- 25716605 TI - Domestically acquired hepatitis E successfully treated with ribavirin in an Australian liver transplant recipient. PMID- 25716606 TI - Chronic Q fever prosthetic valve endocarditis--an important cause of prosthetic valve dysfunction in Australia. PMID- 25716607 TI - Until the pips squeak. PMID- 25716609 TI - A new man. PMID- 25716610 TI - Metabolic Clinic Atlas: Organization of Care for Children with Inherited Metabolic Disease in Canada. AB - INTRODUCTION: Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. METHODS: Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. RESULTS: We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. CONCLUSIONS: The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial. PMID- 25716611 TI - Eye movements are primed toward the center of multiple stimuli even when the interstimulus distances are too large to generate saccade averaging. AB - Prior oculomotor research has established that saccades tend to land near the center of multiple saccade targets when they are near each other. This saccade averaging phenomenon (or global effect) has been ascribed to short-distance lateral excitation between neurons in the superior colliculus. Further, at greater inter-stimulus distances, eye movements tend toward the individual elements. This transition to control by local elements (individuation) with inter stimulus distance has been attributed to long-range lateral inhibition between neurons in winner-take-all models of oculomotor behavior. We hypothesized that the traditional method of requiring a saccade to an array of multiple, simultaneous targets may entail response ambiguity that intensifies with distance. We resolved the ambiguity by focussing on reaction time of our human participants to a single saccade target after one or more simultaneous priming stimuli. At a 50-ms prime-target interval, saccadic reaction time was shortest for targets closer to the center of the prime stimuli independent of the distance between the primes. This effect was gone at 400 ms. These findings challenge the typical inferences about the neural control of oculomotor behavior that have been derived from the boundary between saccade averaging and individuation and provide a new method to explore eye movements with lessened impact from decision processes. PMID- 25716612 TI - Agency elicits body-ownership: proprioceptive drift toward a synchronously acting external proxy. AB - Awareness of our own bodies (sense of body-ownership) and actions (sense of agency) is fundamental for self-consciousness. In the rubber hand illusion, watching a rubber hand being stroked synchronously as one's own unseen hand is also stroked causes the observer to attribute the rubber hand to their own body. The findings of the series of experiments reported here suggest that body ownership, measured using proprioceptive drift, is elicited by the external acting proxy that drives the sense of agency. While participants clasped and unclasped their left hand for 60 s, they focused on video feedback on a monitor in front of them. Proprioceptive drift was observed only under the conditions, including synchronized conditions, where the sense of agency for the acting proxy occurred, suggesting an essential interaction between body-ownership and agency. PMID- 25716613 TI - Coupling of postural activity with motion of a ship at sea. AB - On land, body sway during stance becomes coupled with imposed oscillations of the illuminated environment or of the support surface. This coupling appears to have the function of stabilizing the body relative to the illuminated or inertial environment. In previous research, the stimulus has been limited to motion in a single axis. Little is known about our ability to couple postural activity with complex, multi-axis oscillations. On a ship at sea, we evaluated postural activity using measures of body movement, as such, and we separately evaluated a direct measure of coupling between body movement and ship motion. Participants were tested while facing fore-aft and athwartship. We compared postural activity between participants who had been seasick at the beginning of the voyage and those who had not. Coupling of postural activity with ship motion differed between body axes as a function of body orientation relative to the ship. In addition, coupling differed between participants who had been seasick at the beginning of the voyage and those who had not. We discuss the results in terms of implications for general theories of postural control, and for prediction of susceptibility to seasickness in individuals. PMID- 25716614 TI - Predicting peptide vaccine candidates against H1N1 influenza virus through theoretical approaches. AB - Identification of potential epitopes that might activate the immune system has been facilitated by the employment of algorithms that use experimental data as templates. However, in order to prove the affinity and the map of interactions between the receptor (major histocompatibility complex, MHC, or T-cell receptor) and the potential epitope, further computational studies are required. Docking and molecular dynamics (MDs) simulations have been an effective source of generating structural information at molecular level in immunology. Herein, in order to provide a detailed understanding of the origins of epitope recognition and to select the best peptide candidate to develop an epitope-based vaccine, docking and MDs simulations in combination with MMGBSA free energy calculations and per-residue free energy decomposition were performed, taking as starting complexes those formed between four designed epitopes (P1-P4) from hemagglutinin (HA) of the H1N1 influenza virus and MHC-II anchored in POPC membrane. Our results revealed that the energetic contributions of individual amino acids within the pMHC-II complexes are mainly dictated by van der Waals interactions and the nonpolar part of solvation energy, whereas the electrostatic interactions corresponding to hydrogen bonds and salt bridges determine the binding specificity, being the most favorable interactions formed between p4 and MHC-II. Then, P1-P4 epitopes were synthesized and tested experimentally to compare theoretical and experimental results. Experimental results show that P4 elicited the highest strong humoral immune response to HA of the H1N1 and may induce antibodies that are cross-reactive to other influenza subtypes, suggesting that it could be a good candidate for the development of a peptide-based vaccine. PMID- 25716615 TI - Lower recurrence rate with full-thickness mesh fixation in incisional hernia repair. AB - PURPOSE: To share the lower recurrence rate achieved during long-term follow-up by repairing incisional hernias (IHs) with full-thickness fixation of onlay mesh. METHODS: We retrospectively analyzed 196 IH cases operated on by the same surgeon between 2002 and 2013. After exclusions (unrelated death, lack of follow-up), 154 cases were included. Abdominal examination findings, recurrence dates (if accessible), and imaging results were obtained from computer records and evaluated. Intraoperatively, all hernial sac adhesions were separated to reveal the anterior abdominal wall, and full-thickness suspension sutures were placed 6 8 cm lateral to the fascial edge at 2-cm intervals, excluding the peritoneum. The primary fasciae were closed, suspension sutures were passed through the mesh holes, and the mesh was fixed as an onlay, leaving no space between the fasciae. RESULTS: In total, 154 subjects with IHs were analyzed: 107 (69.5%) females and 47 (30.5%) males. The mean patient age was 52.60 years [standard deviation (SD) 11.24 years], and the mean fascial defect diameter was 77 cm(2). The average operation time was 128 min (SD 42.5 min), and the average patient follow-up time was 54 months (SD 22.8 months). Eight (5.2%) patients developed recurrences after full-thickness mesh fixation, and ten subjects (6.5%) had persistent pain in the operative area for longer than 3 months. CONCLUSIONS: Full-thickness mesh fixation mechanically supports the fascia, especially in the early postoperative period, and enables homogeneous fibrous healing in a wide area, preventing mesh migration; we believe that these attributes are crucial in reducing the IH recurrence rate. PMID- 25716616 TI - Isolation and the interaction between a mineral-weathering Rhizobium tropici Q34 and silicate minerals. AB - The purposes of this study were to isolate and evaluate the interaction between mineral-weathering bacteria and silicate minerals (feldspar and biotite). A mineral-weathering bacterium was isolated from weathered rocks and identified as Rhizobium tropici Q34 based on 16S rRNA gene sequence analysis. Si and K concentrations were increased by 1.3- to 4.0-fold and 1.1- to 1.7-fold in the live bacterium-inoculated cultures compared with the controls respectively. Significant increases in the productions of tartaric and succinic acids and extracellular polysaccharides by strain Q34 were observed in cultures with minerals. Furthermore, significantly more tartaric acid and polysaccharide productions by strain Q34 were obtained in the presence of feldspar, while better growth and more citric acid production of strain Q34 were observed in the presence of biotite. Mineral dissolution experiments showed that the organic acids and polysaccharides produced by strain Q34 were also capable of promoting the release of Si and K from the minerals. The results showed that the growth and metabolite production of strain Q34 were enhanced in the presence of the minerals and different mineral exerted distinct impacts on the growth and metabolite production. The bio-weathering process is probably a synergistic action of organic acids and extracellular polysaccharides produced by the bacterium. PMID- 25716617 TI - Linking ambient particulate matter pollution effects with oxidative biology and immune responses. AB - Exposure to combustion-related particulate matter (PM), at concentrations experienced by populations throughout the world, contributes to pulmonary and cardiac disease through multiple mechanistic pathways that are complex and interdependent. Current evidence supports an interactive chain of events linking pollution-induced pulmonary and systemic oxidative stress, inflammatory events, and translocation of particle constituents with an associated risk of vascular dysfunction, atherosclerosis, altered cardiac autonomic function, and ischemic cardiovascular and obstructive pulmonary diseases. Because oxidative stress is believed to play such an instrumental role in these pathways, the capacity of particulate pollution to cause damaging oxidative reactions (the oxidative potential) has been used as an effective exposure metric, identifying toxic components and sources within diverse ambient PM mixes that vast populations are subjected to-from traffic emissions on busy roads in urban areas to biomass smoke that fills homes in rural areas of the developing world. PMID- 25716618 TI - A facile room temperature iodination route to in situ fabrication of patterned copper-iodide/silicon quasi-bulk-heterojunction thin films for photovoltaic application. AB - Fabrication of a monocrystalline silicon based heterojunction film at room temperature in a time-efficient manner is desirable for energy and environmental considerations. In this report, a gas-solid phase direct elemental reaction (DER) route to realize this aim by firstly depositing an elemental copper layer on a monocrystalline silicon surface followed by a reaction with iodine vapor is described. The samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy, photoelectrochemical measurements, and the transient photovoltage (TPV) technique. The novelty of the current work lies in the following three aspects: (1) formation of an in situ CuI/Si quasi-bulk-heterojunction at room temperature is assisted by the infiltrated elemental copper layer being completely transformed into a gamma phase copper iodide (gamma-CuI) thin film; (2) the virgin monocrystalline silicon is pretreated to ensure a pyramidally patterned rough surface which facilitates the construction of quasi-bulk heterojunction thin films and enhances their chemical stability and mechanical stability; (3) the photovoltaic performance and mechanism of the resulting CuI/Si quasi-bulk-heterojunction based solar cell was detected and evaluated for the first time by a combination of photoelectrochemical and TPV techniques, which demonstrates that the intensity of the interface electric field as well as the open circuit potential can be adjusted by tuning the amount of CuI coated on the pyramidally patterned n-Si substrate. PMID- 25716620 TI - [Do Current German-Language Intelligence Tests Take into Consideration the Special Needs of Children with Disabilities?]. AB - Do Current German-Language Intelligence Tests Take into Consideration the Special Needs of Children with Disabilities? A review of 23 German intelligence test manuals shows that test-authors do not exclude the use of their tests for children with disabilities. However, these special groups play a minor role in the construction, standardization, and validation of intelligence tests. There is no sufficient discussion and reflection concerning the issue which construct irrelevant requirements may reduce the validity of the test or which individual test-adaptations are allowed or recommended. Intelligence testing of children with disabilities needs more empirical evidence on objectivity, reliability, and validity of the assessment-procedures employed. Future test construction and validation should systematically analyze construct-irrelevant variance in item format, the special needs of handicapped children, and should give hints for useful test-adaptations. PMID- 25716621 TI - [Relationship Between Age of School Entry and Behaviour Problems]. AB - Relationship Between Age of School Entry and Behaviour Problems Recent studies demonstrated that children who are relatively young within a school year show more behaviour problems, are at greater risk of being diagnosed with attention- eficit/hyperactivity disorder (ADHD) and treated with stimulants compared to their older classmates. In this paper we examine the association of age at school entry and behavioural problems for a German sample of elementary school children, who were enrolled in 2009 (N = 928). We used teacher ratings on the Strengths and Difficulties Questionnaire (SDQ) as well as the prevalence of ADHD diagnosis and medication. Our analyses showed that those children with a relatively younger age at school entry were judged more hyperactive than their older peers when sex was controlled for. After stratifying for sex, the effect of age at school entry on hyperactivity was now only significant for boys. No association with age at school entry could be found for the other SDQ-subscales as well as for ADHD diagnosis and medication. Although we could only partially demonstrate a significant relationship between age at school entry and behavioral problems in German elementary school-children, understanding these associations may help to consider children's maturity differences when evaluating the child's behavior. PMID- 25716622 TI - [Cognitive Profiles of Preschool Children with Developmental Coordination Disorders and ADHD]. AB - Cognitive Profiles of Preschool Children with Developmental Coordination Disorders and ADHD Studies confirm that developmental coordination disorders (DCD) are often accompanied by ADHD. It is important to know why children with combined disorders show a special profile in a common intelligence test (WPPSI III). For this purpose, the WPPSI-III results of a total of 125 children aged five to six years with diagnosed isolated DCD, isolated ADHD, combined disorders and a normative sample were compared. Children with isolated ADHD showed the best cognitive profile. Children of all three diagnosis subgroups presented significantly poorer abilities in all WPPSI-III scales than the normative sample. In comparison with preschoolers showing isolated ADHD, children with DCD and ADHD have a significant lower Processing Speed Quotient. PMID- 25716623 TI - [Father-Child-Contact and Well-being of the Children in Separated and Non Separated Families]. AB - Father-Child-Contact and Well-being of the Children in Separated and Non Separated Families This study investigated determinants of the contact between children and fathers after parental separation and the interplay of family status (non-separated vs. separated families), father-child relationship-quality and child's well-being. We compared 254 adolescents aged 15 to 19 years, from non separated and separated families, by administering an adaptation of the "Inventory of Life Quality in Children and Adolescents" (Mattejat u. Remschmidt, 1998) and the scale emotionality of the FPI-R (Fahrenberg, Hampel, Selg, 2000). Contact between fathers and children after parental separation was mainly associated with parental conflict and contact during and after the separation. No significant associations were found with age and gender of the child, maternal remarriage or paternal education. The relationship to the father mediated the effects of family arrangement on different measures of child well-being. In separated families children with little contact to their fathers showed worse relationships to them compared to children in intact families. Good father-child relationships were positively associated with different measures of children's well-being. A central conclusion of this study is, that the father-child relationship is an important source for child's well-being. PMID- 25716625 TI - [Test review]. PMID- 25716628 TI - The "Endura" of The Cathars' Heresy: Medieval Concept of Ritual Euthanasia or Suicide? AB - The aim of the study is to explore the medieval concepts on the voluntary death of severely sick people, as they emerge through the endura (endurance) of the heresy of the Cathars in France (twelfth to fourteenth centuries). The endura was the prerequisite act of repentance that would allow the fallen soul to return to heaven. The endura was a necessary act of repentance, after the performance of a ceremonial purification of the soul (consolamentum), and consisted of the patients' voluntary abstention from vital food. The consolamentum and endura could be performed in the final stage of a disease with the consent of the patients or their relatives. The role of the Cathar physician was only to determine the severity of the disease and the forthcoming death of the patient. The physician was not allowed to take steps that would deprive the life of the patient, and the performance of the ritual endura was duty of the spiritual leaders of the community. The modern ethical approach to this subject is dictated by the medieval belief on the salvation of the soul and tries to answer the question of whether the endura could be seen as a medieval concept of a ritual euthanasia or fell within the theological sin of suicide. PMID- 25716630 TI - ROLE OF INSULIN SENSITIZERS ON CARDIOVASCULAR RISK FACTORS IN POLYCYSTIC OVARIAN SYNDROME: A META-ANALYSIS. AB - OBJECTIVE: Polycystic ovarian syndrome (PCOS) is associated with an increase in cardiovascular (CV) risk factors such as insulin resistance, with accompanying hyperinsulinemia and hyperlipidemia, which are predisposing factors for type 2 diabetes mellitus and CV disease. The aim of this meta-analysis is to examine the effect of insulin sensitizers on clinical and biochemical features of PCOS and risk factors for CV disease. METHODS: A systematic literature review was conducted, and randomized controlled clinical trials were identified by a search of bibliographic databases: Medline database (from 1966 forward), EMBASE (January 1985 forward), and Cochrane Central Register of Controlled Trials. Reviews of reference lists further identified candidate trials. Data was independently abstracted in duplicate by 2 investigators using a standardized data-collection form. Articles without a comparison group and randomization allocation were excluded. Reviewers worked independently and in duplicate to determine the methodological quality of trials, then collected data on patient characteristics, interventions, and outcomes. RESULTS: Of 455 studies, 44 trials were eligible. A random effects model was used. Significant unadjusted results favoring treatment with insulin sensitizers were obtained for body mass index (BMI) (effect size [ES] of 0.58), waist to hip ratio (WHR) (ES of 0.02), low-density-lipoprotein cholesterol (LDL-C) (ES of 0.11), fasting insulin (ES of 2.82), fasting glucose (ES of 0.10), free testosterone (ES of 1.88), and androstenedione level (ES of 0.76). CONCLUSION: Treatment with insulin sensitizers in women with PCOS results in improvement in CV factors such as BMI, WHR, LDL-C, fasting insulin, glucose, free testosterone, and androstenedione. PMID- 25716629 TI - MEDULLARY THYROID CANCER THAT STAINS NEGATIVE FOR CA 19-9 HAS DECREASED METASTATIC POTENTIAL. AB - OBJECTIVE: Presently, no clinical tools are available to diagnose the metastatic potential of medullary thyroid cancer (MTC) at disease presentation. Surveillance with calcitonin (Ct) and carcinoembryonic antigen (CEA) is currently recommended for the observation and diagnosis of metastatic disease after initial treatment of MTC. Recently, carbohydrate antigen (CA)19-9 staining has been associated with aggressive forms of MTC and metastatic spread. This pilot study explored whether positive CA19-9 staining of MTC tissue is associated with its metastatic potential. METHODS: Sixteen cases of MTC were identified, and tissue specimens were immunostained for CA 19-9 and other MTC tumor markers. Clinical information about patients' MTC was collected through a retrospective chart review. RESULTS: Overall, 63% of the specimens stained positive for CA19-9. The median size of positively staining specimens was 2.6 cm (interquartile range [IQR] 1.2-3.2) compared to 0.7 cm (0.5-1.2) in negatively staining MTC specimens (P = .04). All specimens from patients diagnosed with stage IV MTC stained positive for CA19-9, compared to only 40% of cases that were classified as stages I to III (P = .03). Furthermore, 100% of the primary specimens that were documented to have metastatic spread stained positive for CA19-9. The sensitivity for ruling out stage IV MTC based on negative staining for CA 19-9 was 100%. CONCLUSION: Based on these results, we conclude that negative staining of MTC for CA19-9 may be associated with its decreased metastatic potential. PMID- 25716632 TI - ANTI-OBESITY PHARMACOTHERAPY AND THE POTENTIAL FOR PREVENTING PROGRESSION FROM PREDIABETES TO TYPE 2 DIABETES. AB - OBJECTIVE: Type 2 diabetes and its associated complications place heavy burdens on affected individuals, their caregivers, and society. The prevalence of type 2 diabetes is increasing worldwide. Attempts to combat this problem have been extended to the treatment of obesity and prevention of progression from prediabetes to type 2 diabetes. As such, weight loss is an important component of type 2 diabetes prevention. However, successful strategies for achieving sustained weight loss have remained elusive. Although lifestyle modification remains a cornerstone of this approach, it has become clear that changes to lifestyle alone will not suffice for many patients. A pragmatic approach includes consideration of pharmacotherapeutic options. METHODS: This review discusses the different pharmacotherapeutic options for the treatment of obesity and prediabetes. RESULTS: Approved anti-obesity therapies and antihyperglycemic agents associated with weight loss may prove effective earlier in the treatment paradigm, and other promising agents that are in clinical development for chronic weight management show promise for both weight reduction and a reduction in the risk of type 2 diabetes in high-risk individuals. CONCLUSION: Long-term evaluation of safety and efficacy is required for many of these agents before we can begin to optimize their use in clinical practice, but treatment choices for obese or prediabetic patients are increasing. PMID- 25716631 TI - ASSOCIATION OF PERIPHERAL 5-HYDROXYINDOLE-3-ACETIC ACID, A SEROTONIN DERIVATIVE, WITH METABOLIC SYNDROME AND LOW-GRADE INFLAMMATION. AB - OBJECTIVE: The constellation of metabolic abnormalities seen in metabolic syndrome (MetS) has been linked to atherosclerosis and adverse cardiovascular outcomes due to heightened inflammation. Accumulating evidence suggests that peripheral 5-hydroxyindole-3-acetic acid (5-HIAA), the derivative end-product of serotonin (5-HT), might be involved in the pathogenesis of obesity, and abnormal lipid and glucose metabolism. We examined the association between serum 5-HIAA concentrations and MetS and also highly sensitive C-reactive protein (hsCRP). METHODS: We assessed 180 healthy adults (110 males and 70 females) in a cross sectional setting. Anthropometric indices and blood pressure were measured, as were laboratory parameters including fasting 5-HIAA concentrations. The associations between 5-HIAA and individual components of MetS, as well as MetS as a single entity, were investigated with bivariate correlation and logistic regression analyses. RESULTS: Eighty-nine individuals (49.4%) were diagnosed with MetS. Significant correlations were found between 5-HIAA concentrations and age (r = 0.184), waist circumference (r = 0.415), high-density lipoprotein (HDL) cholesterol (r = -0.148), systolic blood pressure (r = 0.374), diastolic blood pressure (r = 0.355), homeostasis model assessment of insulin resistance (r = 0.201), and hsCRP (r = 0.453) were found (P<.05 in all tests). In logistic regression, 5-HIAA was significantly associated with 4 MetS components including central obesity, raised triglycerides, raised blood pressure, and raised fasting plasma glucose (FPG) (P<.05). Moreover, 5-HIAA was a predictor of MetS as a single entity, and the relationship persisted after adjusting for hsCRP (odds ratio [OR] = 4.41, 95% confidence interval [CI]: 2.58-7.67, P<.001). CONCLUSION: Elevated concentrations of 5-HIAA are seen in individuals with MetS. Increased 5 HIAA is also associated with hsCRP, a marker of chronic low-grade inflammation underlying MetS. PMID- 25716633 TI - PRIMARY ADRENAL LYMPHOMA: A SINGLE-CENTER EXPERIENCE. AB - OBJECTIVE: To describe the clinical presentation, biochemistry, imaging features, and treatment outcome of patients with primary adrenal lymphoma (PAL) presenting to a single tertiary care center. METHODS: We performed a retrospective analysis of case records of 7 patients diagnosed with PAL between January 2011 and May 2014 at our institution in Mumbai, India. RESULTS: Median age of presentation in our series was 48 years (range, 41 to 60 years), with a male to female ratio of 6:1. Bilateral adrenal involvement was seen in 4 of 7 patients (58%). Adrenal insufficiency (AI) was seen in 3 of the 4 patients with bilateral involvement (75%). Computed tomography showed slight to moderate contrast enhancement of adrenal masses in 4 of 5 patients (80%). Diffuse, large, B-cell lymphoma (DLBCL) was the most common immunophenotype (85%). One patient died due to rapid disease progression even before starting chemotherapy. Six patients were treated with chemotherapy and/or external beam radiotherapy. After 1 year, 2 more patients had died, whereas 4 patients were in remission. CONCLUSION: PAL should always be considered in differential diagnosis of bilateral adrenal mass with AI. DLBCL is the most common histologic subtype of PAL. Despite treatment, long-term prognosis of PAL remains poor. PMID- 25716634 TI - Pheochromocytoma and paraganglioma. AB - OBJECTIVE: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are neural crest cell tumors associated with catecholamine production and assessed by a metanephrine/methoxytyramine measurement. This review summarizes the genetics of these tumors. METHODS: Case presentation, review of the relevant literature, and bullet point conclusions. RESULTS: Genetic research over the past 10 years has led to a better understanding of the pathogenesis of these tumors, currently associated with 20 susceptibility genes (both somatic and germ-line mutations). Although most of these genes can be divided into two clusters (clusters 1 and 2), recent data suggest that all mutations converge on the hypoxia-inducible factor signaling pathway. Most of the susceptibility genes are well characterized and associated with specific clinical presentations, including biochemical phenotype, tumor location and behavior, as well as neoplasms or similar characteristics. Correct and early detection of hereditary PHEO/PGL is paramount, as early diagnosis leads to improved and focused treatment, along with better outcomes. However, missed or delayed diagnosis of hereditary PHEO/PGL forestalls proper treatment and results in multiple, recurrent, or metastatic tumors and avoidable complications in some patients. CONCLUSION: Early diagnosis allows prompt screening for potentially lethal cancers associated with specific gene mutations and makes genetic testing more readily available to first-degree and other relatives of an index patient. Thus, understanding the genetics of these tumors is an essential part of endocrinology. PMID- 25716635 TI - HOW PATIENTS WITH TYPE 1 DIABETES TRANSLATE CONTINUOUS GLUCOSE MONITORING DATA INTO DIABETES MANAGEMENT DECISIONS. AB - OBJECTIVE: To understand how patients use continuous glucose monitoring (CGM) data in their diabetes management. METHODS: We surveyed patients who regularly used CGM (>6 days per week), using 70 questions, many scenario-based. The survey had 6 sections: patient characteristics, general CGM use, hypoglycemia prevention and management, hyperglycemia prevention and management, insulin dosing adjustments (both for incidental hyperglycemia not at meals and at mealtimes), and real-time use versus retrospective analysis. RESULTS: The survey was completed by 222 patients with type 1 diabetes. In response to a glucose of 220 mg/dL, the average correction dose adjustment based on rate of change arrows varied dramatically. Specifically, when the CGM device showed 2 arrows up (glucose increasing >3 mg/dL/minute), respondents stated they would increase their correction bolus, on average, by 140% (range, 0 to 600%). Conversely, 2 arrows down (glucose decreasing >3 mg/dL/minute) caused respondents to reduce their dose by 42%, with 24% omitting their dose entirely. Furthermore, 59% of respondents stated they would delay a meal in response to rapidly rising glucose, whereas 60% would wait until after a meal to bolus in response to falling glucose levels. With a glucose value of 120 mg/dL and a falling glucose trend, 70% of respondents would prophylactically consume carbohydrates to avoid hypoglycemia. CONCLUSION: CGM users utilize CGM data to alter multiple aspects of their diabetes care, including insulin dose timing, dose adjustments, and in hypoglycemia prevention. The insulin adjustments are much larger than common recommendations. Additional studies are needed to determine appropriate insulin adjustments based on glucose trend data. PMID- 25716636 TI - KDIGO CATEGORIES OF GLOMERULAR FILTRATION RATE AND PARATHYROID HORMONE SECRETION IN PRIMARY HYPERPARATHYROIDISM. AB - OBJECTIVE: The recent Fourth Workshop on the Management of Asymptomatic primary hyperparathyroidism (PHPT) maintained the threshold of 60 mL/min for decreased renal function, below which surgery is recommended. This study investigated the relationship between different stages of renal insufficiency and parathyroid hormone (PTH) levels in an updated case series of PHPT patients. METHODS: This was a retrospective, cross-sectional study involving 379 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 (25[OH]D3) levels in the fasting state. Glomerular filtration rate (GFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Mean CKD-EPI estimated GFR was 81.9 +/- 20.3 mL/min/1.73 m(2), and median GFR was 84.0 mL/min/1.73 m(2) (interquartile range, 26.8 mL/min/1.73 m(2)). The patients were divided into 5 groups according to the Kidney Disease: Improving Global Outcomes 2012 guidelines: group 1 with normal or increased GFR (>90 mL/min/1.73 m(2)); group 2 with mild GFR decrease (60 to 89 mL/min/1.73 m(2)); group 3a with mild to moderate GFR decrease (45 to 59 mL/min/1.73 m(2)); group 3b with moderate to severe GFR decrease (30 to 44 mL/min/1.73 m(2)); and group 4 with severe GFR decrease (<30 mL/min/1.73 m(2)). Among the 5 groups of patients, serum calcium levels were different (P = .025), whereas 25(OH)D3 levels were not (P = .36). PTH levels were comparable across groups 1 through 3a, but they were significantly higher in groups 3b and 4 (P<.0001). CONCLUSION: In our series of PHPT patients, PTH levels did not rise as a result of renal impairment until GFR decreased below 45 mL/min/1.73 m(2). PMID- 25716638 TI - Effects of opioids on the endocrine system: should we be concerned? PMID- 25716637 TI - EFFECT OF HIGH-DOSE VITAMIN D REPLETION ON GLYCEMIC CONTROL IN AFRICAN-AMERICAN MALES WITH PREDIABETES AND HYPOVITAMINOSIS D. AB - OBJECTIVE: This double-blind, randomized, controlled trial evaluated whether 12 months of high-dose vitamin D2 supplementation improved insulin sensitivity and secretion and glycemic status. METHODS: African-American males (AAM) with prediabetes (glycosylated hemoglobin [A1C] 5.7-6.4%), hypovitaminosis D (25 hydroxyvitamin D [25OHD] 5-29 ng/mL), and prevalent medical problems were supplemented with vitamin D3 (400 IU/day) and then randomized to weekly placebo or vitamin D2 (50,000 IU). The primary outcome was the change in oral glucose insulin sensitivity (OGIS, from an oral glucose tolerance test [OGTT]) after 12 months of treatment. Secondary outcomes included other glycemic indices, A1C, and incident diabetes. RESULTS: Baseline characteristics were similar in vitamin D supplemented (n = 87) and placebo (n = 86) subjects completing the trial with average concentrations 14.4 ng/mL, 362 mL * min(-1) * m(-2), and 6.1% for 25OHD, OGIS and A1C, respectively. After 12 months, the vitamin D-supplemented group had a change in serum 25OHD +35 versus +6 ng/mL for placebo, P<.001; OGIS +7.8 versus -16.0 mL * min(-1) * m(-2) for placebo, P = .026; and A1C -0.01 versus +0.01% for placebo, P = .66. Ten percent of subjects in both groups progressed to diabetes. A posthoc analysis of participants with baseline impaired fasting glucose (IFG) showed that more subjects in the vitamin D subgroup (31.6%) than placebo (8.3%) returned to normal glucose tolerance, but the difference did not reach significance (P = .13). CONCLUSION: The trial does not provide evidence that 12 months of high-dose D2 repletion improves clinically relevant glycemic outcomes in subjects with prediabetes and hypovitaminosis D (NCT01375660). PMID- 25716639 TI - Visual vignette. PMID- 25716640 TI - PITUITARY GIGANTISM--EXPERIENCE OF A SINGLE CENTER FROM WESTERN INDIA. AB - OBJECTIVE: Limited data are available on pituitary gigantism, as it is a rare disorder. This study was carried out to assess the clinical, hormonal, and radiologic profiles and management outcomes of patients with pituitary gigantism. METHODS: We conduced a retrospective analysis of 14 patients with pituitary gigantism who presented to a single tertiary care institute from 1990 to 2014. RESULTS: Thirteen patients were male, and 1 was female. The mean age at diagnosis was 21.9 +/- 6.1 years, with a mean lag period of 6.5 +/- 5.6 years. The mean height SD score at the time of diagnosis was 3.2 +/- 0.6. Symptoms of tumor mass effect were the chief presenting complaint in the majority (50%) of patients, while 2 patients were asymptomatic. Six patients had hyperprolactinemia. At presentation, the nadir PGGH (postglucose GH) and insulin-like growth factor (IGF 1)-ULN (* upper limit of normal) were 63.2 +/- 94.9 ng/mL and 1.98 +/- 0.5, respectively. All (except 1 with mild pituitary hyperplasia) had pituitary macroadenoma. Six patients had invasive pituitary adenoma. Transsphenoidal surgery (TSS) was the primary modality of treatment in 13/14 patients, and it achieved remission in 4/13 (30.76%) patients without recurrence over a median follow-up of 7 years. Post-TSS radiotherapy (RT) achieved remission in 3/5 (60%) patients over a median follow-up of 3.5 years. None of the patients received medical management at any point of time. CONCLUSION: Gigantism is more common in males, and remission can be achieved in the majority of the patients with the help of multimodality treatment (TSS and RT). PMID- 25716641 TI - Evolution of the curbside consult commentary on transforming the endocrine consult: asynchronous provider consultations. PMID- 25716642 TI - Visual Vignette. PMID- 25716643 TI - Calciphylaxis in simultaneous liver-kidney transplantation. PMID- 25716645 TI - Transfusion interventions in critical bleeding requiring massive transfusion: a systematic review. AB - Critical bleeding (CB) requiring massive transfusion (MT) can occur in a variety of clinical contexts and is associated with substantial mortality and morbidity. In 2011, the Australian National Blood Authority (NBA) published patient blood management guidelines for CB and MT, which found limited high-quality evidence from which only 2 recommendations could be made. The aim of this systematic review (SR) was to update these guidelines and identify evidence gaps still to be addressed. A comprehensive search was performed for randomized controlled trials (RCTs) and SRs using MeSH index and free text terms in MEDLINE, the Cochrane Library (Issue 11, 2012), EMBASE, CINHAL, PUBMED, and the Transfusion Evidence Library up to July 15, 2014. The evidence was grouped according to 4 questions based on the original guideline relating to transfusion interventions: (1) effect of dose, timing, and ratio of red blood cells (RBCs) to component therapy on patient outcomes; (2) effect of RBC transfusion on patient outcomes; (3) effect of fresh frozen plasma, platelet, cryoprecipitate, fibrinogen concentrate, and prothrombin complex concentrate on patient outcomes; and (4) effect of recombinant activated factor VII (rFVIIa) on patient outcomes. From this search, 19 studies were identified: 6 RCTs and 13 SRs. Two of the RCTs were pilot/feasibility studies, 3 were investigating rFVIIa, and 1 compared restrictive versus liberal RBC transfusion in upper gastrointestinal hemorrhage. Overall, limited new evidence was identified and substantial evidence gaps remain, particularly with regard to the effect of component therapies, including ratio of RBC to component therapies, on patient outcomes. Clinical trials to address these questions are required. PMID- 25716644 TI - Comorbid condition care quality in cancer survivors: role of primary care and specialty providers and care coordination. AB - PURPOSE: The purpose of this study is to investigate provider specialty, care coordination, and cancer survivors' comorbid condition care. METHODS: This retrospective cross-sectional Surveillance, Epidemiology, and End Results (SEER) Medicare study included cancer survivors diagnosed in 2004, 2-3 years post-cancer diagnosis, in fee-for-service Medicare. We examined (1) provider specialties (primary care providers (PCPs), oncology specialists, other specialists) visited post-hospitalization, (2) role of provider specialties in chronic and acute condition management, and (3) an ambulatory care coordination measure. Outcome measures covered (1) visits post-hospitalization for nine conditions, (2) chronic disease management (lipid profile, diabetic eye exam, diabetic monitoring), and (3) acute condition management (electrocardiogram (EKG) for congestive heart failure (CHF), imaging for CHF, EKG for transient ischemic attack, cholecystectomy, hip fracture repair). RESULTS: Among 8661 cancer survivors, patients were more likely to visit PCPs than oncologists or other specialists following hospitalizations for 8/9 conditions. Patients visiting a PCP (vs. not) were more likely to receive recommended care for 3/3 chronic and 1/5 acute condition indicators. Patients visiting a nother specialist (vs. not) were more likely to receive recommended care for 3/3 chronic and 2/5 acute condition indicators. Patients visiting an oncology specialist (vs. not) were more likely to receive recommended care on 2/3 chronic indicators and less likely to receive recommended care on 1/5 acute indicators. Patients at greatest risk for poor coordination were more likely to receive appropriate care on 4/6 indicators. CONCLUSIONS: PCPs are central to cancer survivors' non-cancer comorbid condition care quality. Implications for Cancer Survivors PCP involvement in cancer survivors' care should be promoted. PMID- 25716646 TI - Exposure to 'healthy' fast food meal bundles in television advertisements promotes liking for fast food but not healthier choices in children. AB - Due to regulatory changes, fast food companies often depict healthy foods in their television advertisements to children. The present study examined how exposure to advertising for 'healthy' meal bundles to children influenced the selection of food in children. A total of fifty-nine children (thirty-seven males) aged 7-10 years (8.8 (SD 0.9) years) took part in the present study. The within-participant, counterbalanced design had two conditions: control (exposure to ten toy adverts across two breaks of five adverts each) and experimental (the middle advert in each break replaced with one for a McDonald's Happy Meal(r) depicting the meal bundle as consisting of fish fingers, a fruit bag and a bottle of mineral water). Following viewing of the adverts embedded in a cartoon, children completed a hypothetical menu task that reported liking for McDonald's food and fast food, in general. Nutritional knowledge, height and weight of the children were measured. There was no significant difference between the two advert conditions for the nutritional content of the meal bundles selected. However, children's liking for fast food, in general, increased after exposure to the food adverts relative to control (P= 0.004). Compared to children with high nutritional knowledge, those with low scores selected meals of greater energy content (305 kJ) after viewing the food adverts (P= 0.016). Exposure to adverts for 'healthy' meal bundles did not drive healthier choices in children, but did promote liking for fast food. These findings contribute to debates about food advertising to children and the effectiveness of related policies. PMID- 25716647 TI - Comparison of arteriosclerotic indicators in patients with ischemic stroke: ankle brachial index, brachial-ankle pulse wave velocity and cardio-ankle vascular index. AB - The ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) are surrogate markers of arteriosclerosis. However, their roles in patients with acute ischemic stroke remain unclear. From October 2003 to September 2011, we enrolled patients with arteriosclerotic ischemic stroke (AIS) exhibiting large infarcts attributed to large-artery atherosclerosis (LAA) or deep subcortical infarcts (mainly lacunar infarcts) attributed to small-artery disease (SAD). Outpatients without a history of stroke served as controls (CTL). We divided the study period into two terms and assessed patients using two different oscillometric devices (Form PWV/ABI, Omron Colin; and VaSera VS-1500, Fukuda Denshi) in each term. One-way analysis of variance and age- and sex-adjusted analysis of covariance were used to compare the three groups. We analyzed 842 patients. The ABI was significantly lower in the LAA (n = 102) group than in the SAD (n = 280) and CTL (n = 460) groups. The baPWV was significantly higher in the LAA and SAD groups than in the CTL group. The CAVI gradually increased in the order of CTL, SAD and LAA. The cutoff values of baPWV and CAVI for detection of AIS were 18.3 m s(-1) (odds ratio (OR): 6.09, 95% confidence interval (CI): 3.97-9.62, P < 0.01) and 9.5 (OR: 1.44, 95% CI: 1.24 1.70, P < 0.001), respectively. Among the three indicators, a lower ABI indicated advanced atherosclerosis associated with LAA, and an increased baPWV more closely indicated AIS. An increased CAVI may indicate the degree of vessel stiffness due to arteriosclerosis. PMID- 25716648 TI - Regulation of blood pressure, oxidative stress and AT1R by high salt diet in mutant human dopamine D5 receptor transgenic mice. AB - Humans have dopamine D5 receptors (hD5R) with single-nucleotide polymorphisms and a diminished function. We generated hD5(F173L) cDNA that has a decreased response to D5R agonist-mediated increase in cAMP production and increased production of reactive oxygen species, relative to wild-type hD5R (hD5(WT)) cDNA expressed in Chinese hamster ovary cells. To investigate the role of hD5(F173L) in the pathogenesis of salt-sensitive hypertension, we generated transgenic mice overexpressing hD5(F173L) or hD5(WT) and fed them normal (0.8% NaCl) or high (4% NaCl) salt diet. On normal salt diet, the blood pressure, and renal NADPH oxidase activity and angiotensin type 1 receptor (AT1R) expression were higher in hD5(F173L) than hD5(WT) transgenic mice. After 2 weeks on high salt diet, the blood pressure and renal NADPH oxidase activity, but not AT1R expression, were increased in hD5(F173L) but not in hD5(WT) transgenic mice. Candesartan, an AT1R antagonist, decreased the blood pressure and NADPH oxidase activity in hD5(F173L) but not in hD5(WT) transgenic mice. We suggest that the ability of the hD5R to negatively regulate the renal NADPH oxidase activity and AT1R function may have important implications in the pathogenesis of salt-sensitive blood pressure. However, the mechanisms involved in regulating the balance of renal D5R and AT1R function in the oxidative stress-mediated salt-sensitive blood pressure remain to be determined. PMID- 25716649 TI - Add-on effect of hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension uncontrolled with losartan 50 mg and amlodipine 5 mg. AB - This study assessed the antihypertensive efficacy of a triple combination, fixed dose therapy of losartan 50 mg (L50)/hydrochlorothiazide 12.5 mg (H12.5)/amlodipine 5 mg (A5) versus co-administration of L50 plus A5 (L50+A5) in Japanese subjects with uncontrolled essential hypertension. Initially, all subjects received single-blind treatment with L50+A5 for 8 weeks. Subjects whose blood pressure (BP) remained stable within pre-specified limits during the last 4 weeks of L50+A5 administration were randomized (n =3 27) to double-blind treatment with L50/H12.5/A5 or L50+A5 for 8 weeks. Primary and secondary efficacy endpoints were mean change from baseline to Week 8 in trough diastolic BP (DBP) and trough systolic BP (SBP), respectively. Safety was assessed throughout the study. The treatment difference for L50/H12.5/A5 versus L50+A5 in mean change from baseline in DBP at Week 8 was -1.1 mm Hg (95% confidence interval (CI) -2.7, 0.6; P = 0.205). However, the treatment difference in mean change from baseline in SBP at Week 8 was -3.2 mm Hg (95% CI: -5.7, -0.8; P=0.011). A chance imbalance in the change in DBP before randomization between groups was identified in a post hoc analysis as a major reason for the smaller-than-expected difference in DBP between groups. The overall safety profile was generally similar between groups. In conclusion, treatment with L50/H12.5/A5 for 8 weeks did not demonstrate a significant difference in DBP reduction, but demonstrated a nominally significant difference in SBP reduction, compared with L50+A5. L50/H12.5/A5 was well tolerated. (ClinicalTrials.gov identifier NCT01302691.). PMID- 25716650 TI - Effects of NAMPT polymorphisms and haplotypes on circulating visfatin/NAMPT levels in hypertensive disorders of pregnancy. AB - Dysregulation of adipocytokines may be associated with endothelial dysfunction in women with preeclampsia (PE), who are at increased risk of future cardiovascular disease. Visfatin, an adipocytokine with a potential cardiovascular role, is also known as nicotinamide phosphorybosil transferase (NAMPT). NAMPT gene polymorphisms affect circulating visfatin/NAMPT levels in obesity. Most findings provide evidence for increased visfatin/NAMPT circulating levels in PE. However, no previous study has tested the hypothesis that NAMPT polymorphisms affect visfatin/NAMPT levels in hypertensive disorders of pregnancy. We studied the effects of the NAMPT polymorphisms T>C (rs1319501) and A>G (rs3801266), and the haplotypes formed by them on visfatin/NAMPT levels and whether these genetic markers are associated with gestational hypertension (GH) and PE. We studied 212 healthy pregnant (HP), 181 patients with GH and 208 with PE. Genotypes were determined by Taqman allele discrimination assays. Plasma visfatin/NAMPT levels were measured by ELISA. No significant differences in visfatin/NAMPT levels were found among the groups. However, higher visfatin/NAMPT levels (P<0.05) were found in GH patients carrying the AG or the GG genotypes for the rs3801266 polymorphism or the 'T, G' haplotype. The TC and CC genotypes and the C allele for the rs1319501 polymorphism were more frequent in the HP than in the PE group (P<0.05). Moreover, the 'C, A' haplotype was also more frequent in the HP than in the PE group (P<0.01). Our findings suggest that although the rs3801266 polymorphism and the 'T, G' haplotype affect visfatin/NAMPT levels in GH, the rs1319501 polymorphism and the 'C, A' haplotype affect the susceptibility to PE. PMID- 25716651 TI - Aortic stiffness is associated with the central retinal arteriolar equivalent and retinal vascular fractal dimension in a population along the southeastern coast of China. AB - The objective of this study was to evaluate the association of the central retinal arteriolar equivalent (CRAE) and the retinal vascular fractal dimension, two quantitative parameters that reflect microcirculation, with aortic stiffness. In this cross-sectional study, we identified the cardiovascular risk factors in 2169 subjects using a health questionnaire, physical examinations and laboratory examinations. We evaluated the aortic stiffness using noninvasive brachial-ankle pulse wave velocity (baPWV) and assessed the microcirculatory alterations with CRAE and retinal vascular fractal dimension, which were measured using fundus photography and semiautomatic quantitative software, respectively. The increase in baPWV (Q1-Q4) correlated with an increased likelihood of the central retinal artery narrowing and a reduction in the retinal vascular fractal dimension. Further adjustment of the cardiovascular risk factors diminished the association between baPWV and CRAE, but increased the association between baPWV and retinal vascular fractal dimension. Elevated baPWV correlates with reduced CRAE and retinal vascular fractal dimension. Such a finding supports macrocirculation- and microcirculation-associated hypotheses. PMID- 25716652 TI - Decreased circulating anandamide levels in preeclampsia. AB - The endocannabinoid system has a key role in female reproduction, including implantation, decidualization and placentation. A growing number of studies indicate that placental and peripheral blood anandamide levels correlate closely with both spontaneous miscarriage and ectopic pregnancy. Anandamide has also been implicated in blood pressure regulation. In this study, we aimed to determine circulating anandamide levels in preeclampsia for the first time in the literature. Forty-three preeclamptic patients and 71 healthy pregnant women were involved in this case-control study. Serum anandamide concentrations were determined by high-performance liquid chromatography-mass spectrometry technique. Serum total soluble fms-like tyrosine kinase-1 (sFlt-1) and biologically active placental growth factor (PlGF) levels were measured by electrochemiluminescence immunoassay. For statistical analyses, nonparametric methods were applied. Serum levels of anandamide were significantly lower in preeclamptic patients than in healthy pregnant women (0.75 (0.44-1.03) ng ml(-1) vs. 1.30 (0.76-2.0) ng ml(-1), P<0.001). Preeclamptic patients had significantly higher sFlt-1 levels (12,121 (7963-18,316) pg ml(-1) vs. 2299 (1393-3179) pg ml(-1), P<0.001) and significantly lower PlGF concentrations (71.2 (39.2-86.4) pg ml(-1) vs. 256.8 (181.1-421.0) pg ml(-1), P<0.001) as compared with healthy pregnant women. Serum anandamide concentrations did not correlate with serum levels of sFlt-1 and PlGF in our healthy pregnant and preeclamptic groups. In conclusion, we demonstrated for the first time in the literature that serum anandamide concentrations are decreased in women with preeclampsia. However, the cause and consequence of this observation remain to be determined. PMID- 25716653 TI - Erratum: miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. PMID- 25716654 TI - Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers. AB - We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulatory region of HNRNPA0 associated with elevated cancer incidence in this family (Hazard ratio = 7.20, p = 0.0004). Whole genome sequencing identified a second rare protein changing mutation of WIF1 that interacted with the HNRNPA0 variant resulting in extremely high risk for cancer in carriers of mutations in both genes (p = 1.98 * 10(-13)). Analysis of downstream targets of the mutations in these two genes showed that the HNRNPA0 mutation affected expression patterns in the PI3 kinase and ERK/MAPK signaling pathways, while the WIF1 variant influenced expression of genes that play a role in NAD biosynthesis. This is a first report of variation in HNRNPA0 influencing common cancers or of a striking interaction between rare variants coexisting in an extended pedigree and jointly affecting cancer risk. PMID- 25716656 TI - A robust estimate of the number and characteristics of persons released from prison in Australia. AB - OBJECTIVE: To estimate the number and characteristics of adults released from prison in Australia. METHOD: We calculated ratios, stratified by age, sex and Indigenous status, by comparing the number of persons released from prison in New South Wales (NSW), with the number in NSW prisons on 30 June of the corresponding year. These stratified ratios were applied to Australia-wide prison data to estimate the number and characteristics of persons released annually. RESULTS: We estimated that in 2013, 38,576 persons were released from prison in Australia - 25.3% more than the daily prison population. Young people, Indigenous people and women were over-represented among those released. We estimated that 3.69 Indigenous women aged 18-24 were released annually for each equivalent person in prison; and 2.75 non-Indigenous women aged 18-24 were released annually for each equivalent person in prison. CONCLUSIONS: The annual 'flow' through Australia's prisons is well in excess of the daily number, but information on those moving through prison systems is not yet publicly available. The characteristics of those released from prison differ meaningfully from those of people in prison. Routine, national reporting of prison separations is critical to informing upscaling and targeting of Throughcare services for this profoundly vulnerable population. PMID- 25716655 TI - Development of DArT-based PCR markers for selecting drought-tolerant spring barley. AB - The tolerance of spring barley (Hordeum vulgare L.) cultivars to spring drought is an important agronomic trait affecting crop yield and quality in Poland. Therefore, breeders require new molecular markers to select plants with lower spring drought susceptibility. With the advent of genomic selection technology, simple molecular tools may still be applicable to screen material for markers of the most important traits and in-depth genome scanning. In previous studies, diversity arrays technology (DArT)-based genetic maps were constructed for F2 populations of Polish fodder and malt barley elite breeding lines, and 15 and 18 quantitative trait loci (QTLs) related to spring drought tolerance were identified, respectively. In this paper, we show the results of a conversion of 30 DArT markers corresponding to 11 QTLs into simple sequence repeat (SSR) and sequence tagged site (STS) markers. Twenty-two polymorphic markers were obtained, including 13 DArT-based SSRs. Additionally, 31 SSR markers, located in close proximity to the DArT markers, were selected from the GrainGenes database and tested. Further analyses of 24 advanced breeding lines with different drought tolerances confirmed that five out of the 30 converted markers, as well as three out of the 31 additional SSR markers, were effective in marker-assisted selection for drought tolerance. The possible function of clones related to these markers in drought tolerance is discussed. PMID- 25716657 TI - Understanding and addressing the Schoolies phenomenon. AB - OBJECTIVE: This study qualitatively explored Western Australian school leavers' alcohol-related experiences during the Schoolies period to generate insights for the purpose of intervention design. This is in the context of an impending change in the age of Western Australian students completing secondary school which, for the first time, will see around half being of legal age to purchase alcohol. METHOD: Fifty-four 18-21-year-olds provided reflections via an emailed introspection on their experiences in the immediate post-school period. This provided access to the views of those who chose to attend events and consume large amounts of alcohol, those who attended events but refrained from excessive alcohol consumption, and those who elected to either avoid Schoolies events or engage in alternative celebrations. The data were coded and analysed using NVivo10. RESULTS: Three primary themes were identified that related to the perceived role of alcohol during Schoolies, the range of associated rite-of passage rituals, and the strategies used by some Leavers to avoid alcohol and its consequences during the Schoolies period. CONCLUSION: Students and parents constitute important target groups for interventions designed to address alcohol related harms during Schoolies. In the WA context, legislation on secondary supply and controlled purchase, as recommended by health and police authorities, could reduce harms that are likely to result from the change in the age of school leavers. Suggestions for alternative pastimes to promote to school leavers are provided. PMID- 25716658 TI - Comparative efficacy of two oral treatments for dogs containing either afoxolaner or fluralaner against Rhipicephalus sanguineus sensu lato and Dermacentor reticulatus. AB - The present study compares the efficacy of two recent oral ectoparasiticides containing isoxazolines (NexGard((r)), containing afoxolaner and administered at a monthly regimen, and BravectoTM containing fluralaner and administered at a tri monthly regimen) against Rhipicephalus sanguineus sensu lato and Dermacentor reticulatus ticks on dogs. 24 dogs were randomly allocated to untreated control, NexGard((r)) treated, and BravectoTM treated groups. The treatments were administered on Days 0, 28 and 56 for afoxolaner and on Day 0 for fluralaner. Tick infestations were performed weekly with 50 unfed adult ticks per each species on each dog from Days 30 to 84 (with the exception of R. sanguineus on Day 63). Ticks were counted at 24h post-infestation. The dogs from both treated groups had statistically significantly (p<0.05) less R. sanguineus and D. reticulatus ticks compared to the untreated dogs on all assessment days. Percent efficacy against R. sanguineus ranged from 86.4% to 99.5% at 24h post-infestation for NexGard((r)) and from 65.7% to 100% for BravectoTM. Statistically significantly (p<0.05) less R. sanguineus ticks were recorded for NexGard((r)) treated dogs compared to BravectoTM treated dogs on Day 78. Percent efficacy against D. reticulatus ranged from 85.2% to 99.6% at 24h post-infestation for NexGard((r)) and from 63.4% to 99.1% for BravectoTM. Statistically significantly (p<0.05) less D. reticulatus ticks were recorded for NexGard((r)) treated dogs compared to BravectoTM treated dogs on Days 71, 78 and 85. PMID- 25716659 TI - Associations among pain, disability and psychosocial factors and the predictive value of expectations on returning to work in patients who undergo lumbar disc surgery. AB - PURPOSE: The aim of this study was to describe the associations among pain, disability and psychosocial factors preoperatively as well as 3 and 24 months later for patients who undergo first time discectomy and to analyse the predictive value of psychosocial factors on the outcome 24 months after surgery. METHODS: Fifty-nine patients, 41 % women, with a mean age of 40 years and without comorbidities were included, of whom 56 responded to the 24-month follow-up; at that point, they were divided into patients with complaints (C, n = 36) and patients without complaints (NC, n = 20). Correlations among the pain intensity, disability and psychosocial factors were analysed preoperatively, 3 and 24 months after discectomy, and regression analyses of psychosocial factors on the outcome at 24 months were performed. RESULTS: Psychosocial variables were weakly correlated with the pain intensity and disability preoperatively. High expectations on the return to work were predictive of both pain intensity (beta = 8.0, p = 0.03) and disability (beta = 9.1, p < 0.001) at 24 months. Associations between psychosocial variables and outcome variables were strengthened at the 3 month follow-up in the C group, and this association remained 24 months after surgery. Fear of movement was most strongly correlated with leg pain intensity (r (s) 0.64, p < 0.001) and the ability to decrease pain was the most correlated with disability (r (s) 0.78, p < 0.001). CONCLUSION: Having high expectations on the return to work after surgery was the strongest predictor for a favourable outcome. Therefore, low preoperative expectations on return to work convey an important prognostic signal. PMID- 25716660 TI - Intractable hiccups caused by syringobulbia and syringomyelia associated with intramedullary spinal hemangioblastoma. AB - INTRODUCTION: Hiccups caused by a neoplasm in the spinal cord are rare. MATERIALS AND METHODS: We report a case of intractable hiccups caused by syringobulbia and syringomyelia associated with cervical intramedullary spinal hemangioblastoma, which was successfully treated by surgical excision. A 60-year-old man was referred from the neurology department after presenting with hiccups for 1 year. The hiccups were aggravated 3 months ago and were sustained during eating or sleeping. Several doctors administered a muscle relaxant and an anticonvulsant, but they were ineffective. Spinal MRI revealed a huge syringomyelia from C2 to T2, associated with a highly enhancing intramedullary mass lesion at the C5 level. The hiccups were ceased after removal of the tumor through a right hemilaminectomy. The pathology of the specimen was hemangioblastoma. The size of the syringobulbia and syringomyelia decreased markedly on MRI checked 5 months after surgery. CONCLUSIONS: Intractable hiccups can be caused by syringobulbia associated with an intramedullary cord tumor in the cervical area and possible mechanisms of hiccups were reviewed. PMID- 25716661 TI - AOSpine subaxial cervical spine injury classification system. AB - PURPOSE: This project describes a morphology-based subaxial cervical spine traumatic injury classification system. Using the same approach as the thoracolumbar system, the goal was to develop a comprehensive yet simple classification system with high intra- and interobserver reliability to be used for clinical and research purposes. METHODS: A subaxial cervical spine injury classification system was developed using a consensus process among clinical experts. All investigators were required to successfully grade 10 cases to demonstrate comprehension of the system before grading 30 additional cases on two occasions, 1 month apart. Kappa coefficients (kappa) were calculated for intraobserver and interobserver reliability. RESULTS: The classification system is based on three injury morphology types similar to the TL system: compression injuries (A), tension band injuries (B), and translational injuries (C), with additional descriptions for facet injuries, as well as patient-specific modifiers and neurologic status. Intraobserver and interobserver reliability was substantial for all injury subtypes (kappa = 0.75 and 0.64, respectively). CONCLUSIONS: The AOSpine subaxial cervical spine injury classification system demonstrated substantial reliability in this initial assessment, and could be a valuable tool for communication, patient care and for research purposes. PMID- 25716662 TI - A new chromanone acid from the stem bark of Calophyllum teysmannii. AB - A new chromanone acid, namely caloteysmannic acid (1), along with three known compounds, calolongic acid (2), isocalolongic acid (3) and stigmasterol (4) were isolated from the stem bark of Calophyllum teysmannii. All these compounds were evaluated for their cytotoxic and antioxidant activities in the MTT and DPPH assays, respectively. The structure of compound 1 was determined by means of spectroscopic methods including 1D and 2D NMR experiments as well as HR-EIMS spectrometry. The stereochemical assignment of compound 1 was done based on the NMR results and X-ray crystallographic analysis. The preliminary assay results revealed that all the test compounds displayed potent inhibitory activity against HeLa cancer cell line, in particular with compound 1 which exhibited the highest cytotoxic activity comparable to the positive control used, cisplatin. However, no significant antioxidant activity was observed for all the test compounds in the DPPH radical scavenging capacity assay. PMID- 25716663 TI - Taking the long view: how well do patient activation scores predict outcomes four years later? AB - Patient activation is an important predictor of health outcomes and health care usage, yet we do not know how enduring the benefits of greater patient activation are. This study uses a large panel survey of people with chronic conditions (n = 4,865) to examine whether a baseline patient activation measure predicts outcomes 4 years later, and whether changes in patient activation measure scores are associated with changes in outcomes. The findings indicate that the benefits of health activation are enduring, yielding benefits in the form of better self management, improved functioning, and lower use of costly health care services over time. Furthermore, the findings indicate that when activation levels change, many outcomes change in the same direction. Patient activation seems to be an important and modifiable factor for influencing chronic disease outcomes; health care delivery systems can use this information to personalize and improve care. PMID- 25716664 TI - Amino acid residues in the laminin G domains of protein S involved in tissue factor pathway inhibitor interaction. AB - Protein S functions as a cofactor for tissue factor pathway inhibitor (TFPI) and activated protein C (APC). The sex hormone binding globulin (SHBG)-like region of protein S, consisting of two laminin G-like domains (LG1 and LG2), contains the binding site for C4b-binding protein (C4BP) and TFPI. Furthermore, the LG-domains are essential for the TFPI-cofactor function and for expression of full APC cofactor function. The aim of the current study was to localise functionally important interaction sites in the protein S LG-domains using amino acid substitutions. Four protein S variants were created in which clusters of surface exposed amino acid residues within the LG-domains were substituted. All variants bound normally to C4BP and were fully functional as cofactors for APC in plasma and in pure component assays. Two variants, SHBG2 (E612A, I614A, F265A, V393A, H453A), involving residues from both LG-domains, and SHBG3 (K317A, I330A, V336A, D365A) where residues in LG1 were substituted, showed 50-60 % reduction in enhancement of TFPI in FXa inhibition assays. For SHBG3 the decreased TFPI cofactor function was confirmed in plasma based thrombin generation assays. Both SHBG variants bound to TFPI with decreased affinity in surface plasmon resonance experiments. The TFPI Kunitz 3 domain is known to contain the interaction site for protein S. Using in silico analysis and protein docking exercises, preliminary models of the protein S SHBG/TFPI Kunitz domain 3 complex were created. Based on a combination of experimental and in silico data we propose a binding site for TFPI on protein S, involving both LG-domains. PMID- 25716665 TI - Incidental threat during visuospatial working memory in adolescent anxiety: an emotional memory-guided saccade task. AB - BACKGROUND: Pediatric anxiety disorders are among the most common psychiatric mental illnesses in children and adolescents, and are associated with abnormal cognitive control in emotional, particularly threat, contexts. In a series of studies using eye movement saccade tasks, we reported anxiety-related alterations in the interplay of inhibitory control with incentives, or with emotional distractors. The present study extends these findings to working memory (WM), and queries the interaction of spatial WM with emotional stimuli in pediatric clinical anxiety. METHODS: Participants were 33 children/adolescents diagnosed with an anxiety disorder, and 22 age-matched healthy comparison youths. Participants completed a novel eye movement task, an affective variant of the memory-guided saccade task. This task assessed the influence of incidental threat on spatial WM processes during high and low cognitive load. RESULTS: Healthy but not anxious children/adolescents showed slowed saccade latencies during incidental threat in low-load but not high-load WM conditions. No other group effects emerged on saccade latency or accuracy. CONCLUSIONS: The current data suggest a differential pattern of how emotion interacts with cognitive control in healthy youth relative to anxious youth. These findings extend data from inhibitory processes, reported previously, to spatial WM in pediatric anxiety. PMID- 25716666 TI - Levator avulsion is not associated with symptom bother of female pelvic organ prolapse. AB - PURPOSE: Both congenital and traumatic factors are likely to play a role in the etiology of female pelvic organ prolapse. We hypothesized that congenital prolapse may be less bothersome than traumatic prolapse related to vaginal childbirth. METHODS: This is a retrospective study using 482 archived data sets of patients seen for urodynamic testing. Patients had an interview, clinical and sonographic examination using 4D translabial ultrasound. Prolapse bother was determined by visual analog scale (VAS). RESULTS: A total of 463 patients were seen, of which 254 (55 %) suffered from symptoms of prolapse. The median bother attributable to these symptoms on VAS was 2 (0-10). Clinically significant prolapse was found in 81 % (cystocele 63 %, uterine prolapse 13 %, enterocele 5 %, rectocele 52 %). Evidence of major childbirth-related trauma, i.e., avulsion, was diagnosed in 118 (26 %), and it was bilateral in 9 %. On univariate analysis, clinical stage, maximal prolapse on ultrasound, levator avulsion, vaginal parity and hiatal area were significantly associated with prolapse bother. In a multivariate linear regression analysis, only prolapse extent remained a significant predictor (P < 0.0001), implying that evidence of traumatic prolapse etiology had no significant influence on prolapse bother. CONCLUSION: The presence of levator avulsion did not influence the degree of bother resulting from pelvic organ prolapse symptoms. Hence, increased prolapse bother does not seem to be associated with evidence of traumatic prolapse etiology. PMID- 25716667 TI - Association between osteocalcin and metabolic syndrome in postmenopausal women. AB - OBJECTIVES: Undercarboxylated osteocalcin (ucOC) has been proved as a regulator of glucose and fat mass in an animal model. This study examined the association between osteocalcin and metabolic syndrome (MetS) in postmenopausal women. METHODS: We selected 135 postmenopausal women and determined anthropometric values [waist-hip ratio (WHR), visceral fat area (VFA), body fat mass (BFM), and skeletal muscle mass (SMM)], the lipid profile, fasting plasma glucose (FPG), insulin, high-sensitivity C-reactive protein (hs-CRP), homeostasis model assessment of insulin resistance (HOMA-IR), serum leptin and adiponectin level, and serum tOC and ucOC level. RESULTS: There were 52 postmenopausal women in the MetS group. After adjusting for age and years since menopause, ucOC was negatively correlated with WHR, VFA, BFM, triglyceride, fasting insulin, HOMA-IR, and serum leptin and was positively correlated with serum adiponectin. The odds ratio for MetS was significantly lower in the highest quartile than the lowest quartile after adjusting for age, years since menopause, and BMI. In multiple regression analysis, serum leptin and HOMA-IR were the most important predictors of the independent variables that affect serum ucOC. CONCLUSION: ucOC showed an inverse correlation with markers of insulin resistance, central obesity, and the presence of MetS in postmenopausal women and appears to protect against MetS. Further large-scale clinical and experimental studies are needed to clarify the potential of ucOC as a predictor of MetS in postmenopausal women. PMID- 25716668 TI - Is open surgery the solution to avoid morcellation of uterine sarcomas? A systematic literature review on the effect of tumor morcellation and surgical techniques. AB - PURPOSE: Today's surgical standard of care for uterine leiomyomas is laparoscopic and/or vaginal surgery with larger specimens requiring morcellation to avoid open surgery. This is often associated with intra-abdominal dissemination of cellular material which in case of a uterine sarcoma might result in iatrogenic seeding of malignant tumor cells. The aim of this systematic literature review is to evaluate the surgical techniques and the impact of accidental tumor morcellation on the outcome of patients postoperatively diagnosed with malignant uterine sarcomas. METHODS: The National Library of Medicine database (pubmed) and Web of science were searched individually using three different search terms ('morcel* sarcoma', 'survival, sarcoma, treatment, Uter*', and 'disease free survival, sarcoma, treatment, uter*'). After excluding duplicates and screening for relevance, 16 articles were left for full-text review, resulting in seven case series with more than 5 patients. RESULTS: The case numbers range from 14 to 123 patients with the majority of cases being leiomyosarcomas. CONCLUSION: There is no reliable diagnostic tool to differentiate a fibroid from a uterine sarcoma preoperatively. Tumor morcellation occurs in various open and closed surgical techniques and is not limited to laparoscopic surgery only. There is an urgent need for a presurgical diagnostic parameter. PMID- 25716669 TI - Risk factors predicting an emergency cesarean delivery for the second twin after vaginal delivery of the first twin. AB - OBJECTIVE: To investigate obstetrical risk factors predicting failure of vaginal delivery and an emergency cesarean section (CS) for the second twin after vaginal delivery of the first twin. In addition, the study was aimed to define perinatal outcomes of the second twin. STUDY DESIGN: A retrospective study was conducted, comparing all deliveries of twins in which CS was performed for the second twin to those in which both twins were delivered vaginally during the years 1988-2010. Women with multiple gestations in which a CS was performed for both twins were excluded from the study. RESULTS: During the study period, 1966 vaginal deliveries of the first twin were recorded; 192 involved emergency CS for the second twin. Risk factors for emergency CS of the second twin were preterm delivery, previous CS, placental abruption and breech presentation of the second twin. Perinatal outcomes did not differ between the groups. CONCLUSION: Risk factors for emergency cesarean section of the second twin are preterm delivery, previous CS, placental abruption and breech presentation. Nevertheless, short term perinatal outcomes are comparable to twins delivered vaginally. PMID- 25716670 TI - Diagnostic accuracy of the soluble Fms-like tyrosine kinase-1/placental growth factor ratio for preeclampsia: a meta-analysis based on 20 studies. AB - PURPOSE: To investigate the accuracy of the soluble fms-like tyrosine kinase 1(sFlt-1)/placental growth factor (PlGF) ratio to predict preeclampsia (PE). METHODS: A search in the PubMed, Embase, and Cochrane Library was conducted for human studies without language restriction. We included the studies reported sufficient data to reconstruct the diagnostic 2 * 2 table of sFlt-1/PlGF with testing of PlGF and sFlt-1 in serum or plasma. Two reviewers independently screened the articles. Disagreements were resolved by a third reviewer. Unpublished data were requested from the authors of the study by email. RESULTS: Twenty studies with 28 groups of women with different gestational ages were included in our study. The pooled diagnostic sensitivity and specificity of sFlt 1/PlGF were 0.78 and 0.84 with the area under the SROC curve (AUC) of 0.88. In subgroup analyses, the diagnostic value of sFlt-1/PlGF for early-onset PE is highest with a pooled diagnostic odds ratio (DOR) of 241 and AUC of 0.98. CONCLUSIONS: The accuracy of sFlt-1/PlGF ratio for screening PE was moderate and was high for early-onset PE. High-quality studies are needed to confirm their usefulness in prediction of PE in clinical practice. PMID- 25716671 TI - Antenatal imaging of anomalies of the corpus callosum: a decade of experience. AB - PURPOSE: To assess the diagnostic accuracy of antenatal ultrasound and foetal magnetic resonance imaging (FMRI) over the past decade in the diagnosis of anomalies of the corpus callosum in a tertiary referral centre. METHODS: A single tertiary referral centre ultrasound database was searched for cases of suspected callosal anomalies between 2003 and 2012. All subsequent ultrasound scans, MRIs, neonatal imaging, postmortem investigations and birth records were reviewed. Callosal anomalies were classified into isolated or complex based on the presence or absence of accompanying congenital anomalies. RESULTS: Forty-three cases of callosal anomaly were detected; 60 % were investigated by FMRI revealing additional diagnoses in 23 %; half of which were anomalies of cortical development. Of those considered isolated who underwent FMRI, 21 % were diagnosed with additional anomalies, changing the classification to a complex callosal anomaly. CONCLUSION: In cases of callosal anomaly suspected on ultrasound, FMRI provides greater certainty and the potential to identify significant additional anomalies. The additional information may alter or clarify prognosis and help parents to better understand the pathology, allowing for informed decisions about the pregnancy to be made. However, some cases may still be diagnosed with additional anomalies after delivery and parents should be aware of such limitations of antenatal imaging. PMID- 25716672 TI - Uptake of non-invasive prenatal testing (NIPT) and impact on invasive procedures in a tertiary referral center. AB - PURPOSE: The introduction of non-invasive prenatal testing (NIPT) by isolation of cell-free fetal DNA from maternal blood is a new diagnostic option in prenatal care. The aim of the study was to investigate the algorithm of prenatal testing before and after the introduction of NIPT in a tertiary referral center and to investigate the influence of NIPT on the frequency of invasive procedures. METHODS: Retrospective data analysis was conducted of all singleton pregnancies that presented for first trimester screening 17 months before and after the introduction of NIPT (n = 2271). Women were categorized into three risk groups: low risk for trisomy 21 (<1:1000), intermediate risk (1:101-1:1000) and high risk (>=1:100). The choice of diagnostic testing after FTS was analyzed. RESULTS: 1093 (group 1) presented before and 1178 (group 2) after the introduction of NIPT. The rate of high-risk patients was equal in both groups (14.4 vs. 15.4 %). No differences were found with regard to invasive testing (11.6 vs. 11.3 %). NIPT was chosen by 3.7 % (44/1178) in group 2. Of those with NIPT, 72.7 % had a risk estimate of <1:100, but 90.9 % were >=35 years old. The rate of NIPT among high risk patients with a normal ultrasound examination was 25 %. CONCLUSION: At present, NIPT is chosen mainly for reassurance by patients not considered to be at high risk. In the high-risk group, NIPT can be offered if the ultrasound examination is normal and the risk is high due to maternal age or serum screening alone. The rate of invasive testing was not reduced in this selected population. PMID- 25716673 TI - Differential regulation of Th17 and T regulatory cell differentiation by aryl hydrocarbon receptor dependent xenobiotic response element dependent and independent pathways. AB - The aryl hydrocarbon receptor (AHR) is regarded as an environmental sensor and has been shown to link environmental stresses with chronic inflammatory and autoimmune diseases. The AHR can be activated to regulate both the X/DRE (xenobiotic or dioxin response elements) as well as a non-X/DRE mediated pathway. Selective AHR modulators (SAhRMs) are recently identified compounds that activate non-X/DRE mediated pathway without activating the X/DRE-driven responses. Here, we have used 3 classes of AHR ligands; agonist, antagonist, and a SAhRM, to delineate the role of these AHR-driven pathways in T helper 17 (Th17)/T regulatory (Treg) regulation. We show that Th17 differentiation is primarily dependent on X/DRE-driven responses, whereas Treg differentiation can be suppressed by inhibiting non-X/DRE pathway. Using a model of Citrobacter rodentium infection, we further show that AHR agonist enhances Th17 production and promoted resolution of infection, whereas a SAhRM inhibited Th17 mediated responses with reduced resolution of infection. These data indicate that Th17/Treg function may be differentially regulated by SAhRMs that differentially activate the X/DRE and non-X/DRE mediated pathways, and point to a therapeutic strategy to leverage AHR function in the treatment of chronic inflammatory and autoimmune disease. PMID- 25716674 TI - 1,3-dinitrobenzene induces age- and region-specific oxidation to mitochondria related proteins in brain. AB - Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve. This study investigates the role of age in the regional susceptibility of brain mitochondria-related proteins (MRPs) to oxidation following exposure to DNB. Male F344 rats (1 month old [young], 3 months old [adult], 18 months old [aged]) were exposed to 10 mg/kg DNB prior to mitochondrial isolation and histopathology experiments. Using a high-throughput proteomic approach, 3 important region- and age-related increases in DNB-induced MRP oxidation were determined: (1) brainstem mitochondria are *3 more sensitive to DNB-induced oxidation than cortical mitochondria; (2) oxidation of brainstem MRPs is significantly higher than in cortical counterparts; and (3) MRPs from the brainstems of older rats are significantly more oxidized than those from young or adult rats. Furthermore, lower levels of DNB cause signs of intoxication (ataxia, chromodacryorrhea) and vacuolation of the susceptible neuropil in aged animals, while neither is observed in DNB-exposed young rats. Additionally, methemoglobin levels increase significantly in DNB-exposed adult and aged animals, but not young DNB-exposed animals. This suggests that oxidation of key MRPs observed in brainstem of aged animals is necessary for DNB-induced signs of intoxication and lesion formation. These results provide compelling evidence that environmental chemicals such as DNB may aid in the acceleration of injury to specific brain regions by inducing oxidation of sensitive mitochondrial proteins. PMID- 25716675 TI - Prediction of Drug-Induced Liver Injury in Micropatterned Co-cultures Containing iPSC-Derived Human Hepatocytes. AB - Primary human hepatocytes (PHHs) are a limited resource for drug screening, their quality for in vitro use can vary considerably across different lots, and a lack of available donor diversity restricts our understanding of how human genetics affect drug-induced liver injury (DILI). Induced pluripotent stem cell-derived human hepatocyte-like cells (iPSC-HHs) could provide a complementary tool to PHHs for high-throughput drug screening, and ultimately enable personalized medicine. Here, we hypothesized that previously developed iPSC-HH-based micropatterned co cultures (iMPCCs) with murine embryonic fibroblasts could be amenable to long term drug toxicity assessment. iMPCCs, created in industry-standard 96-well plates, were treated for 6 days with a set of 47 drugs, and multiple functional endpoints (albumin, urea, ATP) were evaluated in dosed cultures against vehicle only controls to enable binary toxicity decisions. We found that iMPCCs correctly classified 24 of 37 hepatotoxic drugs (65% sensitivity), while all 10 non-toxic drugs tested were classified as such in iMPCCs (100% specificity). On the other hand, conventional confluent cultures of iPSC-HHs failed to detect several liver toxins that were picked up in iMPCCs. Results for DILI detection in iMPCCs were remarkably similar to published data in PHH-MPCCs (65% versus 70% sensitivity) that were dosed with the same drugs. Furthermore, iMPCCs detected the relative hepatotoxicity of structural drug analogs and recapitulated known mechanisms of acetaminophen toxicity in vitro. In conclusion, iMPCCs could provide a robust tool to screen for DILI potential of large compound libraries in early stages of drug development using an abundant supply of commercially available iPSC-HHs. PMID- 25716676 TI - Sildenafil in bronchopulmonary dysplasia: safe to use? PMID- 25716678 TI - Morphological and biomechanical analyses of the subchondral mineralized zone in human sacral facet joints: Application to improved diagnosis of osteoarthritis. AB - The anatomy of the facet joint subchondral mineralized zone (SMZ) is the main parameter used in diagnosing osteoarthritis. Usually, a single CT scan slice is used to measure the thickness, but the measurement is highly location-dependent. Bone mineral density (BMD) and porosity could be more reliable than thickness for detecting SMZ sclerosis, and linking them to stiffness can provide insights into the mechanism of osteoarthritis progression. The goal of this study was two-fold: (1) to assess spatial heterogeneity in thickness, BMD, and porosity within the non-pathological human facet joint SMZ; (2) to correlate these measurements with the static modulus of elasticity (MOEsta ). Four non-pathological facet joints were excised and imaged using micro-computed tomography (uCT) to measure SMZ thickness, BMD, and porosity. A total of eight parallelepiped SMZ samples were similarly analyzed and then mechanically tested. The mean SMZ BMD, porosity, and thickness (+/- Standard Deviation) of the whole facet joints were 611 +/- 35 mgHA/cc, 9.8 +/- 1.3%, and 1.39 +/- 0.41 mm, respectively. The mean BMD, porosity, and MOEsta of the eight SMZ samples were 479 +/- 23 mgHA/cc, 12 +/- 0.01%, and 387 +/- 138 MPa, respectively, with a positive rank correlation between BMD and porosity. BMD and porosity were more homogeneous within the facet joint than thickness and they could be more reliable parameters than thickness for detecting SMZ sclerosis. The values for the physiological SMZ and MOEsta of human facets joints obtained here were independent of BMD. SMZ BMD and porosity were related to each other. PMID- 25716677 TI - Ventilatory control and supplemental oxygen in premature infants with apparent chronic lung disease. AB - OBJECTIVES: Our goal was to evaluate changes in respiratory pattern among premature infants born at <29 weeks gestation who underwent a physiological challenge at 36 weeks postmenstrual age with systematic reductions in supplemental oxygen and inspired airflow. STUDY DESIGN: Subjects were all infants enrolled in the Prematurity and Respiratory Outcomes Project at St. Louis Children's Hospital and eligible for a physiological challenge protocol because they were receiving supplemental oxygen or augmented airflow alone as part of their routine care. Continuous recording of rib cage and abdominal excursion and haemoglobin oxygen saturation (SpO2%) were made in the newborn intensive care unit. RESULTS: 37 of 49 infants (75.5%) failed the challenge, with severe or sustained falls in SpO2%. Also, 16 of 37 infants (43.2%) who failed had marked increases in the amount of periodic breathing at the time of challenge failure. CONCLUSIONS: An unstable respiratory pattern is unmasked with a decrease in inspired oxygen or airflow support in many premature infants. Although infants with significant chronic lung disease may also be predisposed to more periodic breathing, these data suggest that the classification of chronic lung disease of prematurity based solely on clinical requirements for supplemental oxygen or airflow do not account for multiple mechanisms that are likely contributing to the need for respiratory support. PMID- 25716679 TI - [HDL cholesterol and high-sensitive troponin T as predictive biomarkers of atrial fibrillation after heart surgery]. AB - INTRODUCTION: Atrial fibrillation (AF) has an incidence rate of approximately 30% and is the most frequent arrhythmia following heart surgery. Factors such as inflammation, the presence of heart fibrosis, stress and cardiomyocyte apoptosis, have all been associated with AF. OBJECTIVES: We believe that atrial remodelling is a pre-existent process in patients with post-surgical AF. We have analyzed the factors related to the incidence of atrial fibrillation in the period after heart surgery. METHODS: We included consecutive, hemodynamically stable patients with a sinusal rhythm who were subjected to programmed heart surgery with extracorporeal circulation. An assessment was made of the fall in atrial fibrillation after surgery using prolonged electrocardiographic monitoring. RESULTS: A total of 100 patients were included in the study and were subjected to either coronary revascularisation surgery (59) or aortic valve substitution due to severe aortic stenosis (41). Postoperative AF occurred in 29 patients who received predominantly more valve surgery than coronary surgery. The following factors were predictive of postoperative AF in the multivariate analysis: Male sex; beta blocker therapy for chronic disease; the use of intraoperative; fibrinogen perfusion; low HDL cholesterol values; and high sensitive troponin T values, in the preoperative period. CONCLUSIONS: HDL cholesterol and high sensitive troponin T can be useful biomarkers to predict the occurrence of AF after surgery. The early identification of these patients who develop of FA allows us to take preventive measures to minimize the negative effects. PMID- 25716680 TI - Usp28 counteracts Fbw7 in intestinal homeostasis and cancer. AB - The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a "piggyback" interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28(DeltaIEC)) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7(DeltaIEC) mice. The aggressive intestinal tumor formation of APC(Min/+); Fbw7(DeltaIEC) mice was restrained when Usp28 was inactivated concomitantly. In both fibroblasts and intestinal cells, Usp28 deficiency corrected the accumulation of SCF(Fbw7) substrate proteins, including NICD1, c Jun, and c-Myc. These findings suggested that Usp28 function does not depend on the presence of Fbw7, but instead independently recognizes and deubiquitylates the same substrates as SCF(Fbw7). Fbw7 binds to a phosphorylated motif termed the phosphodegron and we found that Usp28 also interacted with this same motif, but only when it is unphosphorylated, offering a mechanistic explanation for identical substrate selection by Fbw7 and Usp28. Our results indicate an unusually direct antagonism between an E3 ligase and a deubiquitinase, Fbw7 and Usp28, in modulating intestinal homeostasis and cancer. PMID- 25716681 TI - Dietary microbes modulate transgenerational cancer risk. AB - Environmental factors are suspected in the increase of obesity and cancer in industrialized countries but are poorly understood. Here, we used animal models to test how future generations may be affected by Westernized diets. We discover long-term consequences of grandmothers' in utero dietary exposures, leading to high rates of obesity and frequent cancers of lung and liver in two subsequent generations of mice. Transgenerational effects were transplantable using diet associated bacteria communities alone. Consequently, feeding of beneficial microbes was sufficient to lower transgenerational risk for cancer and obesity regardless of diet history. Targeting microbes may be a highly effective population-based approach to lower risk for cancer. PMID- 25716683 TI - Influence of message error type on Korean adults' attitudes toward an individual who uses augmentative and alternative communication. AB - The aim of this study was to investigate the influence of types of message errors on the attitudes of Korean adults toward a person who uses AAC. The attitudes of 72 adults who speak native Korean were examined through attitude questionnaires completed after viewing videotaped conversations between a boy with cerebral palsy and an adult without disabilities. Each interaction video involved a message with one of six error types, including various types of syntactic, semantic, and pragmatic errors. The participants provided information on their attitude towards the person who used AAC, and ranked their preferences among the six messages. The results provide evidence that attitudes towards the individual using AAC were most positive (in comparison with other conditions) when a pragmatic error was observed. Messages containing a syntactic error were ranked most favorably. Spearman's correlation analyses revealed some relationship between attitudes rating and preferences ranking. Our results provide evidence that specific language and cultural contexts may play an important role in shaping attitudes toward those who use AAC. PMID- 25716684 TI - Breakdown of continuum fracture mechanics at the nanoscale. AB - Materials fail by the nucleation and propagation of a crack, the critical condition of which is quantitatively described by fracture mechanics that uses an intensity of singular stress field characteristically formed near the crack-tip. However, the continuum assumption basing fracture mechanics obscures the prediction of failure of materials at the nanoscale due to discreteness of atoms. Here, we demonstrate the ultimate dimensional limit of fracture mechanics at the nanoscale, where only a small number of atoms are included in a singular field of continuum stress formed near a crack tip. Surprisingly, a singular stress field of only several nanometers still governs fracture as successfully as that at the macroscale, whereas both the stress intensity factor and the energy release rate fail to describe fracture below a critically confined singular field of 2-3 nm, i.e., breakdown of fracture mechanics within the framework of the continuum theory. We further propose an energy-based theory that explicitly accounts for the discrete nature of atoms, and demonstrate that our theory not only successfully describes fracture even below the critical size but also seamlessly connects the atomic to macroscales. It thus provides a more universal fracture criterion, and novel atomistic insights into fracture. PMID- 25716682 TI - TWIST1-Induced miR-424 Reversibly Drives Mesenchymal Programming while Inhibiting Tumor Initiation. AB - Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis. PMID- 25716685 TI - Body mass dynamics in hand reared clouded leopard (Neofelis nebulosa) cubs from birth to weaning. AB - To study the dynamics of body mass changes in hand reared clouded leopards, we analyzed 3,697 weight data points during the first 3 months of life in 49 cubs from 24 zoo-born litters from 2003 through 2012. All cubs were fed the same formula mixture after a similar weaning protocol. The hand rearing process was divided into three periods based on feeding protocols: Stage 1: formula only (Days 1-28; Day 0 = day of birth); Stage 2, formula supplemented with protein (e.g., turkey baby food; Days 29-42); Stage 3, formula in decreasing amounts supplemented with meat (chicken and/or beef; Days 43-90). Weights at birth were 11.2% higher (P < 0.001) for males (n = 29) than females (n = 20). Daily weight gain was slowest (P < 0.05) during Stage 1 when cubs were fed straight formula only and fastest during Stage 3 when provided a mixture of formula and meat. Mean growth rate (+/- SD) during hand rearing differed (P < 0.05) by gender, being 34.6 +/- 1.4 g/day for male and 30.0 +/- 1.2 g/day for female cubs. Eighteen cubs (37%) exhibited mild to severe diarrhea during the study; however, palliative treatment resulted in similar (P > 0.05) growth and weaning weights compared to healthy counterparts. These are the first data documenting, on a large scale, the growth patterns for zoo born, hand reared clouded leopard cubs. Findings are valuable as an aid in managing this rare species, including for helping identify early onset of medical issues and further determining key factors regulating the first 3 months of development. PMID- 25716686 TI - Warfarin Treatment and Outcomes of Patients With Atrial Fibrillation in Rural and Urban Settings. AB - BACKGROUND: Warfarin is an effective agent in the prevention of stroke in patients with atrial fibrillation (AF). However, it requires close monitoring with regular visits to health care facilities. To date, it is unknown whether there is a difference in warfarin utilization and outcomes between urban and rural settings. METHODS: We used administrative databases to compare warfarin utilization patterns and stroke and major bleeding outcomes in rural and urban settings in a population-based cohort study of patients >= 65 years admitted to hospital with a diagnosis of AF in the province of Quebec, Canada, from 1999 to 2007. Patients' postal codes were used to differentiate between rural and urban settings. RESULTS: The cohort comprised 18,198 rural (21.8%) and 65,315 urban (78.2%) patients, with similar mean age of 79 years and a similar burden of comorbidities. Overall, there was marked underutilization of warfarin in both rural and urban settings. Warfarin-filled prescription rates were slightly higher in the rural setting (adjusted OR: 1.16, 95% CI: 1.12-1.20). In multivariable Cox regression analyses, the risk for stroke and major bleeding in rural settings was similar to that in urban settings (stroke: adjusted HR: 1.01, 95% CI: 0.95-1.09; major bleeding: adjusted HR: 1.03, 95% CI: 0.95-1.12). CONCLUSIONS: Patients in rural settings were slightly more likely to fill a prescription for warfarin, but they experienced similar stroke and major bleeding rates to their urban counterparts. PMID- 25716687 TI - Targeting G-quadruplex structures with extrinsic fluorogenic dyes: promising fluorescence sensors. AB - The research on the G-quadruplex DNAs has received much attention in recent years and numerous reports appeared probing their detection, structure, stability, reactivity, selectivity, etc. for the chemical intervention of their biological activity or sensor applications. This feature article provides an account of the recent reports from different research groups on the intriguing fluorescence properties showcased by certain fluorogenic dyes upon their binding to the G quadruplex DNAs. Aptly, these selective and sensitive emission features demonstrated with structure specific G-quadruplex DNAs have been turned into label-free fluorescence-based detection methods for various metal ions and small biomolecules, down to the pico molar range, having promising bio-analytical applications. While the in vivo formation of G-quadruplexes is dynamically sensitive to the cell cycle, in tandem with the in vitro applications, it is essential to understand the factors that affect chemical, biological and genetic roles of the G-quadruplex structures plausible along the human genome. Towards this, the recent findings on the quantitative visualization of the quadruplex structures in the human cells using immunofluorescent probes open up avenues to explore highly specific quadruplex responsive agents for diagnostic and therapeutic applications, especially to develop a clinically viable method for cancer treatment. PMID- 25716688 TI - [Diagnosis of overactive bladder (OAB)]. AB - Overactive bladder (OAB) is a symptom complex which is present in approximately 17% of the European population. It is observed in the presence or absence of incontinence (wet or dry) and is associated with a high degree of psychological stress as well as high costs for the healthcare system. Myogenic, urothelial and neurogenic factors lead to frequently unknown changes of muscular, neural and connective tissue. The diagnosis of OAB is empirical and can be used as a basis for initial treatment, while lower urinary tract symptoms have to be evaluated up front. As there are no established biomarkers for OAB, a definitive diagnosis is problematic. It is important to carry out routine diagnostics including a detailed medical history and if needed urodynamic evaluation of the patient. Therapy of OAB will be the topic of a further continuing medical education (CME) article entitled "Therapy of overactive bladder (OAB)". PMID- 25716689 TI - Cavitation-enhanced delivery of insulin in agar and porcine models of human skin. AB - Ultrasound-assisted transdermal insulin delivery offers a less painful and less invasive alternative to subcutaneous insulin injections. However, ultrasound based drug delivery, otherwise known as sonophoresis, is a highly variable phenomenon, in part dependent on cavitation. The aim of the current work is to investigate the role of cavitation in transdermal insulin delivery. Fluorescently stained, soluble Actrapid insulin was placed on the surface of human skin mimicking materials subjected to 265 kHz, 10% duty cycle focused ultrasound. A confocally and coaxially aligned 5 MHz broadband ultrasound transducer was used to detect cavitation. Two different skin models were used. The first model, 3% agar hydrogel, was insonated with a range of pressures (0.25-1.40 MPa peak rarefactional focal pressure-PRFP), with and without cavitation nuclei embedded within the agar at a concentration of 0.05% w/v. The second, porcine skin was insonated at 1.00 and 1.40 MPa PRFP. In both models, fluorescence measurements were used to determine penetration depth and concentration of delivered insulin. Results show that in agar gel, both insulin penetration depth and concentration only increased significantly in the presence of inertial cavitation, with up to a 40% enhancement. In porcine skin the amount of fluorescent insulin was higher in the epidermis of those samples that were exposed to ultrasound compared to the control samples, but there was no significant increase in penetration distance. The results underline the importance of instigating and monitoring inertial cavitation during transdermal insulin delivery. PMID- 25716690 TI - The proliferative effects of Pyropia yezoensis peptide on IEC-6 cells are mediated through the epidermal growth factor receptor signaling pathway. AB - For a number of years, seaweed has been used as a functional food in Asian countries, particularly in Korea, Japan and China. Pyropia yezoensis is a marine red alga that has potentially beneficial biological activities. In this study, we examined the mechanisms through which a Pyropia yezoensis peptide [PYP1 (1-20)] induces the proliferation of IEC-6 cells, a rat intestinal epithelial cell line, and the involvement of the epidermal growth factor receptor (EGFR) signaling pathway. First, cell viability assay revealed that PYP1 (1-20) induced cell proliferation in a concentration-dependent manner. Subsequently, we examined the mechanisms responsible for this induction of proliferation induced by PYP1 (1 20). EGFR is widely expressed in mammalian epithelial tissues, and the binding of this ligand affects a variety of cell physiological parameters, such as cell growth and proliferation. PYP1 (1-20) increased the expression of EGFR, Shc, growth factor receptor-bound protein 2 (Grb2) and son of sevenless (SOS). EGFR also induced the activation of the Ras signaling pathway through Raf, MEK and extracellular signal-regulated kinase (ERK) phosphorylation. In addition, cell cycle analysis revealed the expression of cell cycle-related proteins. The results demonstrated an increased number of cells in the G1 phase and an enhanced cell proliferation. In addition, the upregulation of cyclin D, cyclin E, Cdk2, Cdk4 and Cdk6 was observed accompanied by a decreased in p21 and p27 expression. These findings suggest that PYP1 (1-20) stimulates the proliferation of rat IEC-6 cells by activating the EGFR signaling pathway. Therefore, PYP1 (1-20) may be a potential source for the development of bio-functional foods which promotes the proliferation of intestinal epithelial cells. PMID- 25716691 TI - Real-time intraocular pressure measurement during phacoemulsification in dogs ex vivo. AB - This study was performed to evaluate changes in intraocular pressure (IOP) during standard coaxial phacoemulsification using 4 different bottle heights (BHs) and 2 different incision sizes. Coaxial phacoemulsification was performed with a venturi-based machine in 8 enucleated canine eyes through 3.0 and 3.2 mm clear corneal incisions (CCIs). A pressure transducer inserted in the peripheral cornea monitored the IOP in real-time. The surgery was subdivided into 4 stages: sculpt segment removal, irrigation/aspiration, capsular polishing and viscoelastic removal. The mean IOP and the difference between the maximum and minimum IOPs were calculated at each stage and compared. The ultrasound time and volume of irrigation fluid used were recorded. The mean IOP increased with an elevation in the BH. The mean IOP in the irrigation/aspiration stage was significantly higher than that in the sculpt-segment removal stage at the same BH. The difference between the maximum and minimum IOP at each stage was greater in the 3.2 mm than the 3.0 mm CCIs, although the mean IOP was lower with the 3.2 mm than the 3.0 mm CCIs. The ultrasound time and irrigation fluid volume were greater with the 3.2 mm than the 3.0 mm CCIs. Therefore, fluidic parameters during each stage could be reassessed and adjusted to reduce complications arising from an elevated IOP. Phacoemulsification with 3.0 mm CCIs at a lower BH might lead to less stress on the eye from IOP fluctuations, ultrasound energy and irrigation fluid. PMID- 25716692 TI - The prognostic significance of bromodomain PHD-finger transcription factor in colorectal carcinoma and association with vimentin and E-cadherin. AB - PURPOSE: Bromodomain PHD-finger transcription factor (BPTF) is a chromatin mediated regulation of transcription factor, playing an important role in embryogenesis and differentiation. Epithelial-mesenchymal transition (EMT) has a pivotal role in colorectal cancer (CRC) progression, sharing the similar characteristic with BPTF. Therefore, the aim of this study was to examine the expression and clinical value of BPTF and the correlation with EMT markers in patients with CRC. METHODS: Real-time PCR and Western blot were performed to evaluate the mRNA and protein expression levels of BPTF in 20 pairs of fresh frozen CRC and non-tumor adjacent tissues (NATs). The expressions of BPTF, vimentin and E-cadherin were examined by immunohistochemical staining in 105 cases of paraffin-embedded primary CRC specimens. In addition, the clinicopathological significance and the prognostic value of BPTF, vimentin and E cadherin expression were further determined. Then, the correlation of BPTF with vimentin and E-cadherin was also explored. RESULTS: BPTF mRNA and protein expression were significantly overexpressed in CRC tissues when compared with paired NATs (P < 0.01). The expression levels of BPTF and vimentin in CRC paraffin-embedded specimens were significantly higher than the expression in NATs (P < 0.01), while the expressions of E-cadherin in tumors were obviously lower than in NATs (P < 0.01). Tumors with high expression of BPTF and vimentin, as well as low expression of E-cadherin, were significantly correlated with various adverse clinicopathological factors (P < 0.05). The CRC patients with a high BPTF or vimentin expression had shorter overall survival than those with lower expression (P < 0.05). Furthermore, univariate analysis and multivariate analysis showed that high BPTF expression was an independent prognostic factor for patients with CRC. The last and more interesting Spearman rank correlation analysis and microscopic observation found that the expression of BPTF obviously correlated with the expression of EMT markers vimentin and E-cadherin. CONCLUSION: Our results strongly suggested that the high BPTF expression was significantly correlated with tumor progression and may be a potent prognostic marker of CRC. Moreover, BPTF expression was significantly associated with EMT markers vimentin and E-cadherin. PMID- 25716693 TI - Downregulation of growth hormone 1 gene in the cerebellum and prefrontal cortex of rats with depressive-like behavior. AB - Depressive-like behaviors in animals are usually assessed by standardized behavioral tests such as the forced swimming test (FST). However, individual variation in test performance may obscure group differences and thereby hinder the discovery of genes responsible for depression. Few reports have shown the influence of individual variability in identifying the genes associated with depressive-like behaviors. In this study, we conducted microarray analysis to identify genes differentially expressed in the prefrontal cortex (PFC) and cerebellum of rats stratified by FST immobility ratio (% immobility in 5 min) into a control group [immobility ratio: -1 to +1 standard deviation (SD) from the mean] and a depressive group (immobility ratio: +1 to +2 SDs above the mean). Genes differentially expressed in both the cerebellum and PFC of the depressive group were Alas2, Gh1, Hba-a2, Hbb, Hbb-b1, Hbe2, LOC689064, Mrps10, Mybpc, Olf6415, and Pfkb1. Ingenuity Pathway Analysis identified Gh1 as a hub gene in the networks of differentially expressed genes in both brain regions. This study indicates that the depressive-like behavior may be related to the decrease of Gh1 expression in the cerebellum and PFC. PMID- 25716694 TI - Caustic ingestion-a forensic overview. AB - The ingestion of corrosive substances may produce severe burns to the upper aerodigestive tract and stomach, particularly if the pH is greater than 12 or less than two. There is a biphasic age grouping with adult cases most often involving self-harm and pediatric cases accidental ingestion. Three cases are reported to demonstrate characteristic features following the ingestion of potassium hydroxide, glacial acetic acid and Lysol((r)) , respectively. All deaths were due to the effects of caustic burns to the upper aerodigestive tract, esophagus and stomach with perforation and/or hemorrhage. The extent of injuries in these cases depends on the nature, amount, and concentration of the agent and on the exposure time. A point to note at autopsy is that tissue damage may also occur from postmortem exposure. Typical injuries involve perioral, limb, and trunk burns, with extensive aerodigestive liquefactive/coagulative necrosis causing hemorrhage and perforation. PMID- 25716695 TI - Trade-off between constitutive and inducible resistance against herbivores is only partially explained by gene expression and glucosinolate production. AB - The hypothesis that constitutive and inducible plant resistance against herbivores should trade-off because they use the same resources and impose costs to plant fitness has been postulated for a long time. Negative correlations between modes of deployment of resistance and defences have been observed across and within species in common garden experiments. It was therefore tested whether that pattern of resistance across genotypes follows a similar variation in patterns of gene expression and chemical defence production. Using the genetically tractable model Arabidopsis thaliana and different modes of induction, including the generalist herbivore Spodoptera littoralis, the specialist herbivore Pieris brassicae, and jasmonate application, constitutive and inducibility of resistance was measured across seven A. thaliana accessions that were previously selected based on constitutive levels of defence gene expression. According to theory, it was found that modes of resistance traded-off among accessions, particularly against S. littoralis, in which accessions investing in high constitutive resistance did not increase it substantially after attack and vice-versa. Accordingly, the average expression of eight genes involved in glucosinolate production negatively predicted larval growth across the seven accessions. Glucosinolate production and genes related to defence induction on healthy and herbivore-damaged plants were measured next. Surprisingly, only a partial correlation between glucosinolate production, gene expression, and the herbivore resistance results was found. These results suggest that the defence outcome of plants against herbivores goes beyond individual molecules or genes but stands on a complex network of interactions. PMID- 25716696 TI - A cellular backline: specialization of host membranes for defence. AB - In plant-pathogen interactions, the host plasma membrane serves as a defence front for pathogens that invade from the extracellular environment. As such, the lipid bilayer acts as a scaffold that targets and delivers defence responses to the site of attack. During pathogen infection, numerous changes in plasma membrane composition, organization, and structure occur. There is increasing evidence that this facilitates the execution of a variety of responses, highlighting the regulatory role membranes play in cellular responses. Membrane microdomains such as lipid rafts are hypothesized to create signalling platforms for receptor signalling in response to pathogen perception and for callose synthesis. Further, the genesis of pathogen-associated structures such as papillae and the extra-haustorial membrane necessitates polarization of membranes and membrane trafficking pathways. Unlocking the mechanisms by which this occurs will enable greater understanding of how targeted defences, some of which result in resistance, are executed. This review will survey some of the changes that occur in host membranes during pathogen attack and how these are associated with the generation of defence responses. PMID- 25716697 TI - The song of lipids and proteins: dynamic lipid-protein interfaces in the regulation of plant cell polarity at different scales. AB - Successful establishment and maintenance of cell polarity is crucial for many aspects of plant development, cellular morphogenesis, response to pathogen attack, and reproduction. Polar cell growth depends on integrating membrane and cell-wall dynamics with signal transduction pathways, changes in ion membrane transport, and regulation of vectorial vesicle trafficking and the dynamic actin cytoskeleton. In this review, we address the critical importance of protein membrane crosstalk in the determination of plant cell polarity and summarize the role of membrane lipids, particularly minor acidic phospholipids, in regulation of the membrane traffic. We focus on the protein-membrane interface dynamics and discuss the current state of knowledge on three partially overlapping levels of descriptions. Finally, due to their multiscale and interdisciplinary nature, we stress the crucial importance of combining different strategies ranging from microscopic methods to computational modelling in protein-membrane studies. PMID- 25716698 TI - Clarification. PMID- 25716699 TI - Investigating young adults with chronic diarrhoea in primary care. PMID- 25716700 TI - Quality assurance of drugs used in clinical trials: proposal for adapting guidelines. PMID- 25716701 TI - Irritable bowel syndrome in adults in primary care: summary of updated NICE guidance. PMID- 25716702 TI - Blinded randomised controlled trial of low-dose Adjuvant Steroids in Adults admitted to hospital with Pandemic influenza (ASAP): a trial 'in hibernation', ready for rapid activation. AB - BACKGROUND: There are no completed randomised trials of the use of corticosteroids in patients with severe influenza infection. Corticosteroid use in influenza is widespread, non-systematic and marked by controversy. A recent meta-analysis of observational studies of adjuvant corticosteroids in influenza found an association with increased mortality but there were important concerns regarding the risks of bias. OBJECTIVES: To (1) evaluate whether or not low-dose corticosteroids given as an adjunct to standard treatment is beneficial in patients who are hospitalised with severe pandemic influenza and (2) develop an 'off-the-shelf' clinical trial that is ready to be activated in a future pandemic. DESIGN: Multicentre, pragmatic, blinded, randomised placebo-controlled trial. SETTING: Thirty to 40 hospitals in the UK. PARTICIPANTS: Adults (>= 16 years) admitted to hospital with an influenza-like illness during a pandemic. INTERVENTION: Five-day course of dexamethasone (Dexsol(r), Rosemont Pharmaceuticals Ltd) 6 mg daily, started within 24 hours of admission. MAIN OUTCOME MEASURE: Admission to Intensive Care Unit, or death, within 30 days of admission to hospital. RESULTS: This trial has not yet been activated. It is currently set up with full ethics and regulatory approvals in place, ready for rapid activation at the onset of the next pandemic. Hurdles to setting up a pandemic trial include planning for pandemic-level pressures on UK NHS resources and co-enrolment of patients to multiple pandemic studies, ensuring adequate geographical distribution of participating sites, maintaining long-term low-level engagement with site investigators, addressing future trial-specific training needs of local investigators and resilience planning in trial management. Identified threats to trial delivery include changes to research capabilities or policies during the hibernation phase, lack of staff resources during a pandemic and the influence of media at the time of a pandemic. A mismatch in the approach to informed consent required by current regulations to that preferred by patients and the public was identified. CONCLUSIONS: This study demonstrates that advance set-up of a trial to be conducted during a pandemic, with full regulatory approvals in place, is possible. Regular review during the hibernation phase will be required. This study serves as a model for the development of other 'off-the shelf' trials as part of preparedness planning for public health emergencies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72331452. European Union Drug Regulating Authorities Clinical Trials number: 2013-001051-12. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 16. See the NIHR Journals Library website for further project information. PMID- 25716703 TI - Prevalence and chemotherapy-induced reactivation of occult hepatitis B virus among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma: significance of hepatitis B core antibodies screening. AB - BACKGROUND: Occult hepatitis B infection (OBI) is characterized by negative hepatitis B surface antigen (HBsAg) and detectable hepatitis B virus (HBV)-DNA in the liver and/or serum, with or without hepatitis B core antibody (anti-HBc). Anti-HBc is the most sensitive marker of previous HBV. HBV reactivation in patients under immunosuppressive treatment is life-threatening, occurring in both overt and occult HBV especially in hematological malignancies. AIM OF THE WORK: To evaluate the prevalence and chemotherapy-induced reactivation of OBI among hepatitis B surface antigen negative patients with diffuse large B-cell lymphoma (DLBCL) patients and to determine the significance of anti-HBc screening among this group of patients before receiving chemotherapy. PATIENTS AND METHODS: This cross-sectional study included 72 DLBCL patients negative for HBsAg, HBsAb and hepatitis C virus antibodies (anti-HCV). Patients were subjected to investigations including anti-HBc. All patients underwent alanine transaminase (ALT) monitoring before each cycle of chemotherapy and monthly for 12 months after the end of chemotherapy. Patients with suspected OBI were tested for HBV DNA using real-time polymerase chain reaction (PCR). RESULTS: Anti-HBc was detected in 10 of 72 HBsAg negative sera (13.89%) (95% confidence interval 6.9 22.2%). Five of the 10 anti-HBc positive patients in this study had OBI reactivation. CONCLUSION: The study concluded that anti-HBc screening is mandatory before chemotherapy. HBsAg-negative/anti-HBc-positive patients should be closely observed for signs of HBV reactivation through the regular monitoring of ALT. Prophylaxis lamivudine is recommended for anti-HBc positive patients before chemotherapy. PMID- 25716704 TI - Surgical versus non-surgical interventions for treating patellar dislocation. AB - BACKGROUND: Patellar dislocation occurs when the patella disengages completely from the trochlear (femoral) groove. Following reduction of the dislocation, conservative (non-surgical) rehabilitation with physiotherapy may be used. Since recurrence of dislocation is common, some surgeons have advocated surgical intervention rather than non-surgical interventions. This is an update of a Cochrane review first published in 2011. OBJECTIVES: To assess the effects (benefits and harms) of surgical versus non-surgical interventions for treating people with primary or recurrent patellar dislocation. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group's Specialised Register, the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, AMED, CINAHL, ZETOC, Physiotherapy Evidence Database (PEDro) and a variety of other literature databases and trial registries. Corresponding authors were contacted to identify additional studies. The last search was carried out in October 2014. SELECTION CRITERIA: We included randomised and quasi randomised controlled clinical trials evaluating surgical versus non-surgical interventions for treating lateral patellar dislocation. DATA COLLECTION AND ANALYSIS: Two review authors independently examined titles and abstracts of each identified study to assess study eligibility, extract data and assess risk of bias. The primary outcomes we assessed were the frequency of recurrent dislocation, and validated patient-rated knee or physical function scores. We calculated risk ratios (RR) for dichotomous outcomes and mean differences MD) for continuous outcomes. When appropriate, we pooled data. MAIN RESULTS: We included five randomised studies and one quasi-randomised study. These recruited a total of 344 people with primary (first-time) patellar dislocation. The mean ages in the individual studies ranged from 19.3 to 25.7 years, with four studies including children, mainly adolescents, as well as adults. Follow-up for the full study populations ranged from two to nine years across the six studies. The quality of the evidence is very low as assessed by GRADE (Grading of Recommendations Assessment, Development and Evaluation Working Group) criteria, with all studies being at high risk of performance and detection biases, relating to the lack of blinding.There was very low quality but consistent evidence that participants managed surgically had a significantly lower risk of recurrent dislocation following primary patellar dislocation at two to five years follow-up (21/162 versus 32/136; RR 0.53 favouring surgery, 95% confidence interval (CI) 0.33 to 0.87; five studies, 294 participants). Based on an illustrative risk of recurrent dislocation in 222 people per 1000 in the non-surgical group, these data equate to 104 fewer (95% CI 149 fewer to 28 fewer) people per 1000 having recurrent dislocation after surgery. Similarly, there is evidence of a lower risk of recurrent dislocation after surgery at six to nine years (RR 0.67 favouring surgery, 95% CI 0.42 to 1.08; two studies, 165 participants), but a small increase cannot be ruled out. Based on an illustrative risk of recurrent dislocation in 336 people per 1000 in the non-surgical group, these data equate to 110 fewer (95% CI 195 fewer to 27 more) people per 1000 having recurrent dislocation after surgery.The very low quality evidence available from single trials only for four validated patient-rated knee and physical function scores (the Tegner activity scale, KOOS, Lysholm and Hughston VAS (visual analogue scale) score) did not show significant differences between the two treatment groups.The results for the Kujala patellofemoral disorders score (0 to 100: best outcome) differed in direction of effect at two to five years follow-up, which favoured the surgery group (MD 13.93 points higher, 95% CI 5.33 points higher to 22.53 points higher; four studies, 171 participants) and the six to nine years follow-up, which favoured the non-surgical treatment group (MD 3.25 points lower, 95% CI 10.61 points lower to 4.11 points higher; two studies, 167 participants). However, only the two to five years follow-up included the clear possibility of a clinically important effect (putative minimal clinically important difference for this outcome is 10 points).Adverse effects of treatment were reported in one trial only; all four major complications were attributed to the surgical treatment group. Slightly more people in the surgery group had subsequent surgery six to nine years after their primary dislocation (20/87 versus 16/78; RR 1.06, 95% CI 0.59 to 1.89, two studies, 165 participants). Based on an illustrative risk of subsequent surgery in 186 people per 1000 in the non-surgical group, these data equate to 11 more (95% CI 76 fewer to 171 more) people per 1000 having subsequent surgery after primary surgery. AUTHORS' CONCLUSIONS: Although there is some evidence to support surgical over non-surgical management of primary patellar dislocation in the short term, the quality of this evidence is very low because of the high risk of bias and the imprecision in the effect estimates. We are therefore very uncertain about the estimate of effect. No trials examined people with recurrent patellar dislocation. Adequately powered, multi-centre, randomised controlled trials, conducted and reported to contemporary standards, are needed. To inform the design and conduct of these trials, expert consensus should be achieved on the minimal description of both surgical and non-surgical interventions, and the anatomical or pathological variations that may be relevant to both choice of these interventions and the natural history of patellar instability. Furthermore, well-designed studies recording adverse events and long term outcomes are needed. PMID- 25716705 TI - Technical decision making with higher order structure data: higher order structure characterization during protein therapeutic candidate screening. AB - Protein therapeutics differ considerably from small molecule drugs because of the presence of higher order structure (HOS), post-translational modifications, inherent molecular heterogeneity, and unique stability profiles. At early stages of development, multiple molecular candidates are often produced for the same biological target. In order to select the most promising molecule for further development, studies are carried out to compare and rank order the candidates in terms of their manufacturability, purity, and stability profiles. This note reports a case study on the use of selected HOS characterization methods for candidate selection and the role of HOS data in identifying potential challenges that may be avoided by selecting the optimal molecular entity for continued development. PMID- 25716706 TI - Using Li(+) as the electrochemical messenger to fabricate an aqueous rechargeable Zn-Cu battery. AB - We propose an aqueous rechargeable Zn-Cu Daniell-type battery. In this system, Li(+) prefers to conduct currents rather than react with the electrodes, while the Zn-Cu electrode couples engage in their electrochemical reactions free from conducting currents. Here Li(+) performs like a messenger and thus could be called the electrochemical messenger. PMID- 25716707 TI - Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes. AB - Sustained viral response (SVR) is the optimal outcome of hepatitis C virus (HCV) therapy, yet more detailed data are required to confirm its clinical value. Individuals receiving treatment in 1996-2011 were identified using the Scottish HCV clinical database. We sourced data on 10 clinical events: liver, nonliver, and all-cause mortality; first hospitalisation for severe liver morbidity (SLM); cardiovascular disease (CVD); respiratory disorders; neoplasms; alcohol intoxication; drug intoxication; and violence-related injury (note: the latter three events were selected a priori to gauge ongoing chaotic lifestyle behaviours). We determined the association between SVR attainment and each outcome event, in terms of the relative hazard reduction and absolute risk reduction (ARR). We tested for an interaction between SVR and liver disease severity (mild vs. nonmild), defining mild disease as an aspartate aminotransferase-to-platelet ratio index (APRI) <0.7. Our cohort comprised 3,385 patients (mean age: 41.6 years), followed-up for a median 5.3 years (interquartile range: 3.3-8.2). SVR was associated with a reduced risk of liver mortality (adjusted hazard ratio [AHR]: 0.24; P < 0.001), nonliver mortality (AHR, 0.68; P = 0.026), all-cause mortality (AHR, 0.49; P < 0.001), SLM (AHR, 0.21; P < 0.001), CVD (AHR, 0.70; P = 0.001), alcohol intoxication (AHR, 0.52; P = 0.003), and violence-related injury (AHR, 0.51; P = 0.002). After 7.5 years, SVR was associated with significant ARRs for liver mortality, all-cause mortality, SLM, and CVD (each 3.0%-4.7%). However, we detected a strong interaction, in that ARRs were considerably higher for individuals with nonmild disease than for individuals with mild disease. CONCLUSIONS: The conclusions are 3-fold: (1) Overall, SVR is associated with reduced hazard for a range of hepatic and nonhepatic events; (2) an association between SVR and behavioral events is consistent with SVR patients leading healthier lives; and (3) the short-term value of SVR is greatest for those with nonmild disease. PMID- 25716708 TI - Is your department's quality good enough for your grandmother? Quality indicators for patients with dementia and delirium. PMID- 25716709 TI - Noncardiac chest pain: update on the diagnosis and management. AB - Noncardiac chest pain (NCCP) is defined as recurring, angina-like, retrosternal chest pain of noncardiac origin. Although patients with NCCP have excellent long term prognosis, most suffer persistently from their symptoms. Several pathophysiological mechanisms have been suggested, including gastroesophageal reflux disease (GERD), esophageal motility disorder, esophageal hypersensitivity, and psychological comorbidity. Among them, GERD is the most common cause of NCCP. Therefore, GERD should first be considered as the underlying cause of symptoms in patients with NCCP. Empirical proton pump inhibitor (PPI) treatment with a preferably double dose for more than 2 months could be cost-effective. PPI test can also be used for diagnosis of GERD-related NCCP, but it should be considered for patients with NCCP occurring at least weekly and its duration should be at least 2 weeks. However, upper endoscopy and esophageal pH monitoring are necessary when the diagnosis of GERD is uncertain. Esophageal impedance-pH monitoring could further improve the diagnostic yield. Patients with GERD-related NCCP should preferably be treated with a double dose PPI until symptoms remit (may require more than 2 months of therapy for optimal symptom control), followed by dose tapering to determine the lowest PPI dose that can control symptoms. However, treatment of patients with non-GERD-related NCCP is challenging. An empirical treatment of antidepressants could be considered. If there are specific esophageal motility disorders, smooth muscle relaxants or endoscopic treatment may be considered in selected cases. If none of these traditional treatments is effective, a psychology consultation for cognitive behavioral therapy should be considered. PMID- 25716710 TI - Prediction of the response to proton pump inhibitor treatment using wireless ambulatory pH monitoring in patients with globus sense. AB - BACKGROUND/AIMS: Globus is a persistent or intermittent non-painful sensation of a lump or foreign body in the throat and a commonly encountered clinical condition. We aim to evaluate the prevalence of gastroesophageal reflux disease (GERD) and to determine the parameters for predicting the response to treatment with proton pump inhibitor (PPI) using wireless pH monitoring in patients with globus sense. METHODS: We retrospectively reviewed the medical records of 37 patients with atypical GERD symptoms. A total of 27 patients with dominant globus sense were enrolled. Endoscopic examination and 48-hour wireless esophageal pH monitoring were performed, and the patients underwent a therapeutic trial of full dose PPIs daily over a period of 4 weeks. RESULTS: Both typical and atypical GERD symptoms co-existed in 14 patients (51.9%, 14/27). According to ROME III criteria, 19 patients (70.4%, 19/27) were diagnosed as GERD. Twelve patients (44.4%, 12/27) were PPI responders. A significant difference in the frequency of symptom index (+) or symptom associated probability (+) was observed between the PPI responder group and the non-responder group (p<0.01). CONCLUSIONS: In patients with globus sense, 70.4% were diagnosed with GERD. Symptom index/symptom associated probability in wireless ambulatory pH monitoring was a good objective parameter for PPI responder. PMID- 25716711 TI - [Additional polyp detection rate using colonoscopic retroflexion in right colon]. AB - BACKGROUND/AIMS: There have been several studies showing that retroflexion (RF) in the right colon (RC) could reduce the polyp miss rate of proximal colon during colonoscopy. This study was conducted to evaluate the additional benefit of RF technique in the RC. METHODS: Patients who underwent colonoscopy from May 2008 to April 2011 were enrolled in the study. Data were obtained by retrospectively reviewing the medical records. RF was attempted in every patients undergoing colonoscopy since May 2008 except in cases of small RC vault, co-morbidity, severe diverticulosis, failed RF despite two trials, complaints of severe abdominal pain, or time burden. At first, RC was examined under direct vision. It was then examined by RF to detect missed polyps during the initial observation. Finally, the RC was re-examined with direct view. RESULTS: The cumulative RF success rate in the RC was 78.84% (1,805 of 2,319). The RF success rate increased with the number of cases (50% at 160 cases, 70% at 400 cases, and reached near 90% over 1,000 cases). Few polyps (4.88%) were detected only with RF and the additional adenoma detection rate was 3.32%. The additional polyp/adenoma detection rates were higher in the old age group (p<0.01). There were no RF associated perforation or severe complication. CONCLUSIONS: Using RF examination, additional 4.88% of polyps could be detected in the RC. This technique could be a useful and safe method to detect hidden polyp during colonoscopy. PMID- 25716712 TI - Discordance between patients and parents regarding the perceived causes of clinical relapse in young inflammatory bowel disease patients. AB - BACKGROUND/AIMS: Relapse in inflammatory bowel disease (IBD) is not predictable, although several factors have been suggested. The aims of the current study were to assess and compare the possible causes of clinical relapse as perceived by patients and parents. METHODS: Of 107 young (<35 years old) IBD patients, 26 patients who experienced recent (<3 month) relapse and their parents completed a questionnaire at the same time. Baseline characteristics and clinical manifestations were reviewed and the most common causes of relapse as perceived by patients and parents were compared. RESULTS: Median patient age was 22.5 years and the male to female ratio was 17 : 9. Crohn's disease was diagnosed in 23 patients and ulcerative colitis in the other three patients. Mean disease duration was 39.8+/-30.3 months. Eighteen (69.2%) patients experienced stress before relapse. Fifteen (57.7%) parents thought that their children experienced stress before relapse. Agreement between patients and parents for non-adherence to medication and stress was 100% and 73.1%, respectively. Stress was considered the most likely cause of relapse in both groups. Discordance rate between parents and patients with respect to main causes of relapse was 40.4%. CONCLUSIONS: Stress was perceived to be the most common condition noted before clinical relapse in young IBD patients and their parents. However, the discordance rate between patients and parents with respect to the main causes of relapse was 40.4%. This result suggests a considerable difference in terms of disease understanding between young IBD patients and parents. PMID- 25716713 TI - [Prevalence, risk factors and clinical characteristics in patients with genotype 6 chronic hepatitis C: a single institute experience]. AB - BACKGROUND/AIMS: Hepatitis C genotypes 1 and 2 are widely distributed globally. In contrast, genotype 6 is found mainly in Southeast Asia, while genotype 6 is rare in Korea. This study aims to investigate the prevalence, risk factors and clinical characteristics of patients with genotype 6 chronic hepatitis C. METHODS: We retrospectively identified 133 HCV-infected patients who underwent HCV genotype analysis between January 2012 and December 2012, and analyzed the prevalence, risk factors and clinical characteristics of patients diagnosed with genotype 6 chronic hepatitis C. RESULTS: Among 133 patients, 53 patients (39.8%) were infected with genotype 1, 62 patients (46.6%) with genotype 2, 2 patients (1.5%) with genotype 3, 14 patients (10.5%) with genotype 6, and 2 patients (1.5%) with mixed genotypes (genotype 1 and 6). The risk factors associated with genotype 6 were acupuncture (n=4, 28.6%), intravenous drug use (n=3, 21.4%), tattoo (n=2, 14.3%), and transfusion (n=2, 14.3%). Of the 14 patients with genotype 6, 6 patients were treated with pegylated interferon and ribavirin. Five patients had reached the end of treatment. All patients reaching end of treatment for genotype 6 showed early virological response and sustained virological response. CONCLUSIONS: The prevalence of genotype 6 is 10.5% and mixed infections of genotype 1 and 6 are 1.5% in patients with chronic hepatitis C. A major potential risk factor is intravenous drug use and the treatment response rate to pegylated interferon plus ribavirin is high in patients with genotype 6 chronic hepatitis C. Large scale multicenter studies are needed. PMID- 25716714 TI - [A case of gastric leiomyosarcoma with multiple metastases]. AB - Leiomyosarcoma is an uncommon tumor that originates from various organs, including uterus, kidney, retroperitoneum, and soft tissues. In particular, leiomyosarcoma of the stomach is extremely rare. Only 9 cases have been reported worldwide since the discovery of KIT-activating mutation. A 48-year-old woman was admitted to our hospital with abdominal discomfort and generalized weakness. Upon detection of multiple nodules in both lung on chest posterior-anterior radiograph taken at the time of admission, chest CT was performed and it revealed multiple mass lesions in the lung, liver, and pancreas along with multiple lymph node metastases. On endoscopic examination, a 2.0 cm sized ulcerofungating mass lesion was found on the stomach body. Biopsy was performed and the mass lesion proved to be leiomyosarcoma confirmed by immunohistochemical staining. Chemotherapy was thus initiated, but the patient died after one year due to tumor progression. Our experience suggests that leiomyosarcoma can manifest aggressive behavior in its early stage. Herein, we report a case of gastric leiomyosarcoma with multiple metastases along with review of relevant literature. PMID- 25716715 TI - [Emphysematous gastritis with concomitant portal venous air]. AB - Emphysematous gastritis is a rare form of gastritis caused by infection of the stomach wall by gas forming bacteria. It is a very rare condition that carries a high mortality rate. Portal venous gas shadow represents elevation of intestinal luminal pressure which manifests as emphysematous gastritis or gastric emphysema. Literature reviews show that the mortality rate is especially high when portal venous gas shadow is present on CT scan. Until recently, the treatment of emphysematous gastritis has been immediate surgical intervention. However, there is a recent trend of avoiding surgery because of the frequent occurrence of post operative complications such as anastomosis leakage. In addition, aggressive surgical treatment has failed to show significant improvement in prognosis. Recently, the authors experienced a case of emphysematous gastritis accompanied by portal venous gas which was treated successfully by conservative treatment without immediate surgical intervention. Herein, we present a case of emphysematous gastritis with concomitant portal venous air along with literature review. PMID- 25716716 TI - Splenic rupture following colon polypectomy: a case report and review of literature. AB - Colonoscopy is a safe procedure performed routinely worldwide. Splenic rupture is a rare complication of colonoscopy with several reported cases since 1974. We report the first case of a complication in the Republic of Korea. The literature on this rare complication is also reviewed here, with focus on the analysis of risk, diagnosis, and treatment. A 77-year-old patient receiving oral aspirin underwent colonoscopy with polypectomy. After 24 hours, the patient experienced dizziness and hypotension. Colonoscopy was performed to exclude intestinal bleeding, which could be diagnosed with hemoperitoneum. A computed tomography scan showed copious abdominal free blood and a splenic rupture. An urgent splenectomy was performed, which was the recognized procedure of choice. Physicians should have greater awareness of the possibility of splenic rupture following colonoscopy in order to avoid delay of diagnosis and treatment for this life-threatening complication. PMID- 25716717 TI - [Appendiceal neuroendocrine tumor with lymph node metastasis in a teenager]. AB - Neuroendocrine tumor (NET) is a cancer-like tumor that occurs mostly in the gastrointestinal system. Within the gastrointestinal tract, NET most commonly occurs in the rectum whereas appendix is very rarely involved. In most cases of appendiceal NET, it is found at a relatively early stage compared to other NETs because appendiceal NET frequently presents with acute appendicitis because appendiceal NET frequently presents with acute appendicitis even when the size is smaller than 1 cm. Therefore, it is very rare for lymph node metastasis to occur in a young adult. Herein, we report a rare case of grade 1 appendiceal NET with lymph node metastasis which developed in a teenage male. PMID- 25716718 TI - Multi-fractal hierarchy of single-walled carbon nanotube hydrophobic coatings. AB - A hierarchical structure is an assembly with a multi-scale morphology and with a large and accessible surface area. Recent advances in nanomaterial science have made increasingly possible the design of hierarchical surfaces with specific and tunable properties. Here, we report the fractal analysis of hierarchical single walled carbon nanotube (SWCNT) films realized by a simple, rapid, reproducible, and inexpensive filtration process from an aqueous dispersion, then deposited by drytransfer printing method on several substrates, at room temperature. Furthermore, by varying the thickness of carbon nanotube random networks, it is possible tailoring their wettability due to capillary phenomena in the porous films. Moreover, in order to describe the wetting properties of such surfaces, we introduce a two-dimensional extension of the Wenzel-Cassie-Baxter theory. The hierarchical surface roughness of SWCNT coatings coupled with their exceptional and tunable optical and electrical properties provide an ideal hydrophobic composite surface for a new class of optoelectronic and nanofluidic devices. PMID- 25716719 TI - A Pediatric Bone Mass Scan has Poor Ability to Predict Peak Bone Mass: An 11-Year Prospective Study in 121 Children. AB - This 11-year prospective longitudinal study examined how a pre-pubertal pediatric bone mass scan predicts peak bone mass. We measured bone mineral content (BMC; g), bone mineral density (BMD; g/cm(2)), and bone area (cm(2)) in femoral neck, total body and lumbar spine by dual-energy X-ray absorptiometry in a population based cohort including 65 boys and 56 girls. At baseline all participants were pre-pubertal with a mean age of 8 years (range 6-9), they were re-measured at a mean 11 years (range 10-12) later. The participants were then mean 19 years (range 18-19), an age range that corresponds to peak bone mass in femoral neck in our population. We calculated individual BMC, BMD, and bone size Z scores, using all participants at each measurement as reference and evaluated correlations between the two measurements. Individual Z scores were also stratified in quartiles to register movements between quartiles from pre-pubertal age to peak bone mass. The correlation coefficients (r) between pre-pubertal and young adulthood measurements for femoral neck BMC, BMD, and bone area varied between 0.37 and 0.65. The reached BMC value at age 8 years explained 42 % of the variance in the BMC peak value; the corresponding values for BMD were 31 % and bone area 14 %. Among the participants with femoral neck BMD in the lowest childhood quartile, 52 % had left this quartile at peak bone mass. A pediatric bone scan with a femoral neck BMD value in the lowest quartile had a sensitivity of 47 % [95 % confidence interval (CI) 28, 66] and a specificity of 82 % (95 % CI 72, 89) to identify individuals who would remain in the lowest quartile at peak bone mass. The pre-pubertal femoral neck BMD explained only 31 % of the variance in femoral neck peak bone mass. A pre-pubertal BMD scan in a population-based sample has poor ability to predict individuals who are at risk of low peak bone mass. PMID- 25716720 TI - Horses fail to use social learning when solving spatial detour tasks. AB - Social animals should have plenty of opportunities to learn from conspecifics, but most studies have failed to document social learning in horses. This study investigates whether young Icelandic horses can learn a spatial detour task through observation of a trained demonstrator horse of either the same age (Experiments 1 and 2, n = 22) or older (Experiment 3, n = 24). Observer horses were allowed to observe the demonstrator being led three times through the detour route immediately before being given the opportunity to solve the task themselves. Controls were allowed only to observe the demonstrator horse eating at the final position, but not the demonstration of the route. Although we found a tendency towards better performance by observer horses in the second experiment, we were unable to repeat this result in a similar set-up with a new group of horses and older, dominant demonstrator horses. We conclude that horses exposed to prior demonstration did not perform better than control horses in solving spatial detour tasks. PMID- 25716721 TI - Innate immunity underlies symbiotic relationships. AB - Here, the modern data regarding interactions between normal microbiota and barrier tissues in plants, humans and animals are reviewed. The main homeostatic mechanisms responsible for interactions between epithelium and innate immune cells with symbiotic bacteria are described. A key step in this process is recognition of soluble microbial products by ligation to pattern-recognition receptors expressed on the host cells. As a result, epithelial cells secrete mucus, antibacterial peptides and immunoregulatory molecules. The main outcomes from immunological reactions towards symbiotic bacteria involve development of conditions for formation and maintenance of microbial biocenosis as well as providing safety for the host. Also, it is considered important to preserve and transfer beneficial bacteria to progeny. PMID- 25716722 TI - Neutrophil extracellular traps: mechanisms of formation and role in health and disease. AB - Recent insights into the specific type of cell death characteristic of neutrophils, called NETosis, are summarized. NETosis is a process of generation of Neutrophil Extracellular Traps (NETs), whose main components are DNA, granular antimicrobial peptides, and nuclear and cytoplasmic proteins. The structure of NETs determines their bactericidal, fungicidal, antiprotozoal, and antiviral properties. Therefore, NETs production by neutrophils is an essential immune response to infection. In addition to the antimicrobial function, NETosis is involved in many inflammatory and autoimmune disorders and participates in the regulation of noninfectious processes. The molecular mechanisms of NET formation, bactericidal effect, and involvement in some noninfectious, autoimmune, and inflammatory processes are discussed in detail in this review. PMID- 25716723 TI - Molecular barriers to processes of genetic reprogramming and cell transformation. AB - Genetic reprogramming by ectopic expression of transcription factor genes induces the pluripotent state in somatic cells. This technology provides an opportunity to establish pluripotent stem cells for each person, as well as to get better understanding of epigenetic mechanisms controlling cell state. Interestingly, some of the molecular processes that accompany somatic cell reprogramming in vitro are also characteristic for tumor manifestation. Thus, similar "molecular barriers" that control the stability of epigenetic state exist for both processes of pluripotency induction and malignant transformation. The reprogramming of tumor cells is interesting in two aspects: first, it will determine the contribution of epigenetic changes in carcinogenesis; second, it gives an approach to evaluate tumor stem cells that are supposed to form the entire cell mass of the tumor. This review discusses the key stages of genetic reprogramming, the similarity and difference between the reprogramming process and malignant transformation. PMID- 25716724 TI - Modern anti-cytokine therapy of autoimmune diseases. AB - The emergence of genetically engineered biological agents opened new prospects in the treatment of autoimmune and inflammatory diseases. Cytokines responsible for regulation of a wide range of processes during development of the normal immune response are among the most successful therapeutic targets. Studies carried out in recent decades and accompanied by rapid development of biotechnology have promoted establishing in detail the role and place of cytokines in autoimmune and inflammatory pathologies. Nevertheless, mechanisms that underlie anti-cytokine therapy are still not fully understood. This review examines the role of such cytokines as TNF, IL-1, and IL-6 in the development of inflammatory processes and the action mechanisms of their inhibitors. PMID- 25716725 TI - Plant cell death caused by fungal, bacterial, and viral elicitors: protective effect of mitochondria-targeted quinones. AB - Chitosan (partially deacetylated chitin), a component of fungal cell walls, caused epidermal cell (EC) death in the leaves of pea (Pisum sativum L.) and tobacco Nicotiana tabacum or Nicotiana benthamiana detected by destruction of cell nuclei. The mitochondria-targeted quinone SkQ1 prevented the destruction of EC nuclei induced by chitosan. Chitosan increased and SkQ1 suppressed the activity of protein kinases in N. benthamiana and P. sativum and eliminated the effect of chitosan. Chitosan induced the generation of reactive oxygen species (ROS) in the guard cells (GC) of pea plants. Treatment with chitosan or H2O2 did not cause destruction of GC nuclei; however, it resulted in disruption of the permeability barrier of the plasma membrane detected by propidium iodide fluorescence. Treatment with bacterial lipopolysaccharide but not peptidoglycan caused destruction of pea EC nuclei, which was prevented by SkQ1. Leaves of tobacco plants containing the N gene responsible for resistance to tobacco mosaic virus (TMV) were infiltrated with Agrobacterium tumefaciens cells. These cells contained a genetic construct with the gene of the helicase domain of TMV replicase (p50); its protein product p50 is a target for the N-gene product. As a result, the hypersensitive response (HR) was initiated. The HR manifested itself in the death of leaves and was suppressed by SkQ3. Treatment of tobacco epidermal peels with the A. tumefaciens cells for the p50 gene expression stimulated the destruction of EC nuclei, which was inhibited by SkQ1 or SkQ3. The p50-lacking A. tumefaciens cells did not induce the destruction of EC nuclei. The protective effect of mitochondria-targeted antioxidants SkQ1 and SkQ3 demonstrates the involvement of mitochondria and their ROS in programmed cell death caused by pathogen elicitors. PMID- 25716726 TI - Distinct biological activity of lipopolysaccharides with different lipid A acylation status from mutant strains of Yersinia pestis and some members of genus Psychrobacter. AB - Correlation between the chemical structure of lipid A from various Gram-negative bacteria and biological activity of their lipopolysaccharide (LPS) as an agonist of the innate immune receptor Toll-like receptor 4 was investigated. Purified LPS species were quantitatively evaluated by their ability to activate the production of tumor necrosis factor (TNF) by murine bone marrow-derived macrophages in vitro. Wild-type LPS from plague-causing bacteria Yersinia pestis was compared to LPS from mutant strains with defects in acyltransferase genes (lpxM, lpxP) responsible for the attachment of secondary fatty acid residues (12:0 and 16:1) to lipid A. Lipid A of Y. pestis double DeltalpxM/DeltalpxP mutant was found to have the chemical structure that was predicted based on the known functions of the respective acyltransferases. The structures of lipid A from two members of the ancient psychrotrophic bacteria of the genus Psychrobacter were established for the first time, and biological activity of LPS from these bacteria containing lipid A fatty acids with shorter acyl chains (C10-C12) than those in lipid A from LPS of Y. pestis or E. coli (C12-C16) was determined. The data revealed a correlation between the ability of LPS to activate TNF production by bone marrow derived macrophages with the number and the length of acyl chains within lipid A. PMID- 25716727 TI - Bacterial lipopolysaccharide activates CD57-negative human NK cells. AB - NK cells play an important regulatory role in sepsis by induction and augmentation of proinflammatory reactions in early stages of the septic process and by suppression of immune response in later stages of inflammation. The present work was aimed at the effect of bacterial lipopolysaccharide (LPS), the main pathogenic factor of sepsis development, on human NK cells ex vivo. We show that LPS activates immature CD57-negative NK cells, which typically constitute less than half of the normal NK cell population in human peripheral blood. Under conditions of NK cell stimulation with IL-2, addition of LPS provokes an increase in IFN-gamma production. However, LPS both increased and inhibited NK cell cytotoxic activity. It is important to note that the activation of NK cells on LPS addition was observed in the absence of TLR4 on the NK cell surface. These results confirm our previous data arguing for a direct interaction of LPS with NK cells and evidence an atypical mechanism of LPS-induced NK cell activation without the involvement of surface TLR4. PMID- 25716728 TI - Experimental models of arthritis in which pathogenesis is dependent on TNF expression. AB - Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by joint damage as well as systemic manifestations. The exact cause of RA is not known. Both genetic and environmental factors are believed to contribute to the development of this disease. Increased expression of tumor necrosis factor (TNF) has been implicated in the pathogenesis of RA. Currently, the use of anti-TNF drugs is one of the most effective strategies for the treatment of RA, although therapeutic response is not observed in all patients. Furthermore, due to non redundant protective functions of TNF, systemic anti-TNF therapy is often associated with unwanted side effects such as increased frequency of infectious diseases. Development of experimental models of arthritis in mice is necessary for studies on the mechanisms of pathogenesis of this disease and can be useful for comparative evaluation of various anti-TNF drugs. Here we provide an overview of the field and present our own data with two experimental models of autoimmune arthritis - collagen-induced arthritis and antibody-induced arthritis in C57Bl/6 and BALB/c mice, as well as in tnf-humanized mice generated on C57Bl/6 background. We show that TNF-deficient mice are resistant to the development of collagen-induced arthritis, and the use of anti-TNF therapy significantly reduces the disease symptoms. We also generated and evaluated a fluorescent detector of TNF overexpression in vivo. Overall, we have developed an experimental platform for studying the mechanisms of action of existing and newly developed anti-TNF drugs for the treatment of rheumatoid arthritis. PMID- 25716729 TI - Formation of compact aggregates of B-lymphocytes in lung tissue during mycobacterial infection in mice depends on TNF production by these cells and is not an element of the host's immunological protection. AB - Tumor necrosis factor (TNF) plays a pivotal role in the early control of Mycobacterium tuberculosis and M. avium infections by a host. It was previously shown that both phagocyte-derived and T-cell-derived TNF productions are critical for protective immunity against M. tuberculosis, but the role of TNF produced by B-cells remained unclear. By comparing mice with B-cell-specific TNF deletion to littermate control mice, here we show that TNF production by B-lymphocytes is essential for the formation of infection-specific aggregates of B-cells in the lung. It is likely that these compact foci represent a pathogenic feature of inflammatory response rather than an element of protective immunity, since the capacity to form aggregates has no influence on the severity of M. tuberculosis- and M. avium-triggered diseases. PMID- 25716730 TI - Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation. AB - Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the development of aGVHD in the maximal number of patients. PMID- 25716731 TI - Cytokine profile in children with inflammatory bowel disease. AB - Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by immune reactivity against microbial and auto-antigens. This work was designed to study the cytokine profile in blood serum and coproextracts of children with CD and UC. The studied patients consisted of 17 children with CD (group I), 17 children with UC (group II), and 18 controls with intestinal dysbiosis (group III). The diagnosis of UC and CD was based on accepted clinical and endoscopic criteria. The levels of 13 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-17A, TNF-alpha, TGF-beta, and IFN-gamma) were determined in blood sera and coproextracts of the patients and controls using the BioPlex technology. The level of IL-17A was significantly increased and that of TGF-beta was significantly decreased in the blood serum of the patients with IBDs. Changes in the cytokine profile in the coproextracts affected the wider spectrum of cytokines. The levels of proinflammatory cytokines (IL-2, IL-4, IL-6, IL-12p70, TNF-alpha, and IFN-gamma) were increased 6-9-fold, whereas the level of the anti-inflammatory cytokine IL-10 was increased 3-fold. The cytokine balance was shifted to the proinflammatory cytokines. The TGF-beta level was increased 9-fold and that of IL-17A was increased 3-fold. Thus, the cytokine profile in the coproextracts was more informative than that of the blood serum. The determination of cytokines in coproextracts is simple and noninvasive. PMID- 25716733 TI - Molecular analysis of heavy chain-only antibodies of Camelus bactrianus. AB - In this work, IgG content and structures of antigen-binding domains and hinge regions of different IgG subtypes of Camelus bactrianus were analyzed in detail for the first time. Our data demonstrate that C. bactrianus contains a very large amount of heavy chain-only antibodies that can be used as a source of VHH domain containing molecules. Despite some minor sequence differences identified in this study, C. bactrianus VHH domains possess principally the same unique features as those of C. dromedarius and the llama. These features are important for developing an efficient phage display-based antibody selection technology. We conclude that C. bactrianus is a very suitable animal to raise an immune response that serves as a source to identify antigen-specific VHHs selected after phage display. PMID- 25716732 TI - Novel recombinant anti-HER2/neu immunotoxin: design and antitumor efficiency. AB - The novel HER2/neu-specific recombinant immunotoxin 4D5scFv-PE40 consisting of 4D5scFv antibody (targeting module) and Pseudomonas exotoxin A fragment (effector module) combined in a single polypeptide chain via a flexible linker has been expressed and purified. This immunotoxin conserves specificity and affinity that are characteristics of the parental antibody 4D5scFv and exhibits selective and strong cytotoxic effect against cancer cells overexpressing HER2/neu receptor. The results of the experiments both in vitro (in cell cultures) and in vivo (in tumor-bearing animals) demonstrate high potential of 4D5scFv-PE40 for targeted therapy of tumors overexpressing HER2/neu. PMID- 25716734 TI - Highly specific hybrid protein DARPin-mCherry for fluorescent visualization of cells overexpressing tumor marker HER2/neu. AB - Here we propose a simple and reliable approach for detection of the tumor marker HER2/neu using the targeting fluorescent hybrid protein DARPin-mCherry. As a targeting module, we used DARPin9-29, which is a member of a novel class of non immunoglobulin targeting proteins that can highly selectively recognize the extracellular domain of the epidermal growth factor receptor HER2/neu. The red fluorescent protein mCherry was used as the detecting module. The hybrid protein DARPin-mCherry was prepared with high yield in a bacterial expression system and purified in one step by affinity chromatography. The purified protein is not prone to aggregation. The specificity of DARPin-mCherry binding with the HER2/neu tumor marker was demonstrated using confocal microscopy, flow cytofluorimetry, and surface plasmon resonance. The dissociation constant of the DARPin-mCherry protein complex with the HER2/neu receptor determined by surface plasmon resonance was calculated to be 4.5 nM. These characteristics of the hybrid protein DARPin-mCherry suggest it as a promising agent for immunofluorescent assay and an attractive alternative to antibodies and their fragments labeled with fluorescent dyes that are now used for this purpose. PMID- 25716735 TI - Epitope mapping of lymphocyte phosphatase-associated phosphoprotein. AB - Lymphocyte phosphatase-associated phosphoprotein (LPAP) is a transmembrane protein with unknown function. The available data on its close association with phosphatase CD45 and its phosphorylation depending on cell activation suggest that LPAP can play a significant role in the antigenic stimulation of lymphocytes. We have localized three antigenic epitopes of the LPAP molecule that can be detected using monoclonal antibodies prepared earlier. Experiments on reactions of antibodies with point mutants and shortened forms of the LPAP protein revealed regions of the amino acid sequence that correspond to the epitopes recognized by the antibodies. PMID- 25716736 TI - Upstream open reading frames regulate translation of the long isoform of SLAMF1 mRNA that encodes costimulatory receptor CD150. AB - More than 40% of human genes contain upstream open reading frames (uORF) in their 5'-untranslated regions (5'-UTRs) and at the same time express at least one truncated mRNA isoform containing no uORF. We studied translational regulation by four uORFs found in the 5'-UTR of full-length mRNA for SLAMF1, the gene encoding CD150 membrane protein. CD150 is a member of the CD2 superfamily, a costimulatory lymphocyte receptor, a receptor for measles virus, and a microbial sensor on macrophages. The SLAMF1 gene produces at least two mRNA isoforms that differ in their 5'-UTRs. In the long isoform of the SLAMF1 mRNA that harbors four uORFs in the 5'-UTR, the stop codon of uORF4 overlaps with the AUG codon of the main ORF forming a potential termination-reinitiation site UGAUG, while uORF2 and uORF3 start codons flank a sequence identical to Motif 1 from the TURBS regulatory element. TURBS was shown to be required for a coupled termination-reinitiation event during translation of polycistronic RNAs of some viruses. In a model cell system, reporter mRNA based on the 5'-UTR of SLAMF1 short isoform, which lacks any uORF, is translated 5-6 times more efficiently than the mRNA with 5'-UTR from the long isoform. Nucleotide substitutions disrupting start codons in either uORF2-4 result in significant increase in translation efficiency, while substitution of two nucleotides in TURBS Motif 1 leads to a 2-fold decrease in activity. These data suggest that TURBS-like elements can serve for translation control of certain cellular mRNAs containing uORFs. PMID- 25716737 TI - Mouse lymphomyeloid cells can function with significantly decreased expression levels of cytochrome C. AB - Cytochrome c is an indispensable electron carrier in the mitochondrial respiratory chain and also an important mediator of the internal pathway triggering apoptosis. Mice with a complete deficiency of the Cycs gene encoding the somatic cytochrome c die during the embryogenesis. Using the technology of LoxP-cre-dependent tissue-specific recombination, we obtained some mouse strains with significantly reduced expression of cytochrome c in certain cell types ("conditional genetic knockdown"). This knockdown was achieved by abrogation of the normal splicing of the Cycs locus pre-mRNA due to an additional acceptor site inside the stop-cassette neo(r). Previously, we observed embryonic lethality in homozygous mice with the same knockdown of cytochrome c in all cells of the organism. In the present work we studied two novel mouse strains with conditional knockdown of the Cycs gene in T lymphocytes and macrophages. Somewhat surprisingly, the mice of these two strains under normal conditions were not phenotypically different from the wild-type mice, either on the whole organism level or on the level of activity of individual target cells. Thus, the amount of cytochrome c in lymphomyeloid cells does not affect their development and normal functioning. PMID- 25716738 TI - Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage Using Cerebral Blood Flow Velocities and Cerebral Autoregulation Assessment. AB - BACKGROUND: The risk of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is associated with large cerebral artery vasospasm, but vasospasm is not a strong predictor for DCI. Assessment of cerebral autoregulation with transcranial Doppler (TCD) may improve the prediction of DCI. The aim of this prospective study was to assess the value of TCD-derived variables to be used alone or in combination for prediction of DCI. METHODS: We included consecutive patients with low-grade aneurysmal SAH within 4 days of aneurysm rupture. Cerebral autoregulation was evaluated using the moving correlation coefficient Mx calculated from spontaneous fluctuations of cerebral blood flow velocities and arterial blood pressure. Transcranial color-coded sonography was performed to assess large artery vasospasm. RESULTS: Thirty patients (19 women and 11 men; mean age +/- SD 44.7 +/- 12.1 years) were included. Twenty (66.7%) patients had vasospasm. DCI occurred in six (20%) patients after a median delay of 10 days (range 8-13 days). Cerebral autoregulation was impaired at baseline and at day 7 and then returned to normal at day 14. Neither cerebral autoregulation impairment nor large artery vasospasm alone was associated with DCI. In contrast, the combination of large artery vasospasm with worsening impairment of cerebral autoregulation from baseline to day 7 was significantly correlated to subsequent DCI (p = 0.007). CONCLUSIONS: Early deterioration of cerebral autoregulation was strongly predictive of DCI in patients with large artery vasospasm after low-grade SAH. Our results suggest that consideration to both cerebral blood flow velocities and cerebral autoregulation may improve the prediction of DCI. PMID- 25716739 TI - Gastrointestinal distress is common during a 161-km ultramarathon. AB - This study examined the incidence, severity, and timing of gastrointestinal (GI) symptoms in finishers and non-finishers of the 161-km Western States Endurance Run. A total of 272 runners (71.0% of starters) completed a post-race questionnaire that assessed the incidence and severity (none = 0, mild = 1, moderate = 2, severe = 3, very severe = 4) of 12 upper (reflux/heartburn, belching, stomach bloating, stomach cramps/pain, nausea, vomiting) and lower (intestinal cramps/pain, flatulence, side ache/stitch, urge to defecate, loose stool/diarrhoea, intestinal bleeding/bloody faeces) GI symptoms experienced during each of four race segments. GI symptoms were experienced by most runners (96.0%). Flatulence (65.9% frequency, mean value 1.0, s = 0.6 severity), belching (61.3% frequency, mean value 1.0, s = 0.6 severity), and nausea (60.3% frequency, mean value 1.0, s = 0.7 severity) were the most common symptoms. Among race finishers, 43.9% reported that GI symptoms affected their race performance, with nausea being the most common symptom (86.0%). Among race non-finishers, 35.6% reported that GI symptoms were a reason for dropping out of the race, with nausea being the most common symptom (90.5%). For both finishers and non-finishers, nausea was greatest during the most challenging and hottest part of the race. GI symptoms are very common during ultramarathon running, and in particular, nausea is the most common complaint for finishers and non-finishers. PMID- 25716740 TI - Prevalence of foot eczema and associated occupational and non-occupational factors in patients with hand eczema. AB - BACKGROUND: Foot eczema often occurs in combination with hand eczema. However, in contrast to the situation with hand eczema, knowledge about foot eczema is scarce, especially in occupational settings. OBJECTIVE: To evaluate the prevalence of foot eczema and associated factors in patients with hand eczema taking part in a tertiary individual prevention programme for occupational skin diseases. PATIENTS/MATERIALS/METHODS: In a retrospective cohort study, the medical records of 843 patients taking part in the tertiary individual prevention programme were evaluated. RESULTS: Seven hundred and twenty-three patients (85.8%) suffered from hand eczema. Among these, 201 patients (27.8%) had concomitant foot eczema, mainly atopic foot eczema (60.4%). An occupational irritant component was possible in 38 patients with foot eczema (18.9%). In the majority of patients, the same morphological features were found on the hands and feet (71.1%). The presence of foot eczema was significantly associated with male sex [odds ratio (OR) 1.78, 95% confidence interval (CI) 1.29-2.49], atopic hand eczema (OR 1.60, 95%CI: 1.15-2.22), hyperhidrosis (OR 1.73, 95%CI: 1.33-2.43), and the wearing of safety shoes/boots at work (OR 2.04, 95%CI: 1.46-2.87). Tobacco smoking was associated with foot eczema (OR 1.79, 95%CI: 1.25-2.57), in particular with the vesicular subtype. CONCLUSIONS: Foot eczema is common in patients with hand eczema, and is related to both occupational and non occupational factors. PMID- 25716741 TI - MERS CoV infection in two renal transplant recipients: case report. AB - Middle East Respiratory Syndrome Coronavirus (MERS CoV) infection has recently emerged as a cause of severe potentially fatal pneumonia. The clinical presentation ranges from asymptomatic infection to severe pneumonia and acute renal failure. Data on the clinical presentation in solid organ transplant recipients are lacking. We report two cases of MERS CoV infections in two renal transplant recipients with variable clinical presentations and outcomes. The first patient presented with progressive respiratory symptoms, acute renal failure and died. While the second patient presented with respiratory tract symptoms, remained stable and had an excellent clinical recovery despite recent reception of thymoglobulin induction. This is a rare report of MERS CoV infection in renal transplant recipients. Further data are needed to gain better understanding of the impact of anti-rejection immunosuppressive therapy on the clinical presentation, severity and outcome of MERS CoV infections in solid organ transplant recipients. PMID- 25716742 TI - Battery collection in municipal waste management in Japan: challenges for hazardous substance control and safety. AB - To clarify current collection rules of waste batteries in municipal waste management in Japan and to examine future challenges for hazardous substance control and safety, we reviewed collection rules of waste batteries in the Tokyo Metropolitan Area. We also conducted a field survey of waste batteries collected at various battery and small waste electric and electronic equipment (WEEE) collection sites in Tokyo. The different types of batteries are not collected in a uniform way in the Tokyo area, so consumers need to pay attention to the specific collection rules for each type of battery in each municipality. In areas where small WEEE recycling schemes are being operated after the enforcement of the Act on Promotion of Recycling of Small Waste Electrical and Electronic Equipment in Japan in 2013, consumers may be confused about the need for separating batteries from small WEEE (especially mobile phones). Our field survey of collected waste batteries indicated that 6-10% of zinc carbon and alkaline batteries discarded in Japan currently could be regarded as containing mercury. More than 26% of zinc carbon dry batteries currently being discarded may have a lead content above the labelling threshold of the EU Batteries Directive (2006/66/EC). In terms of safety, despite announcements by producers and municipalities about using insulation (tape) on waste batteries to prevent fires, only 2.0% of discarded cylindrical dry batteries were insulated. Our field study of small WEEE showed that batteries made up an average of 4.6% of the total collected small WEEE on a weight basis. Exchangeable batteries were used in almost all of mobile phones, digital cameras, radios, and remote controls, but the removal rate was as low as 22% for mobile phones. Given the safety issues and the rapid changes occurring with mobile phones or other types of small WEEE, discussion is needed among stakeholders to determine how to safely collect and recycle WEEE and waste batteries. PMID- 25716743 TI - A panchromatic hybrid crystal of iodoplumbate nanowires and J-aggregated naphthalene diimides with long-lived charge-separated states. AB - A panchromatic hybrid crystal of anionic iodoplumbate nanowires and J-aggregated protonated naphthalene diimides has been formed through charge-assisted anion-pi and lone pair-pi interactions, which exhibits unusually long-lived charge separated states even upon the irradiation of indoor lighting. PMID- 25716744 TI - Prediction of anaplastic transformation in low-grade oligodendrogliomas based on magnetic resonance spectroscopy and 1p/19q codeletion status. AB - The aim of this study was to assess whether combining multimodal magnetic resonance imaging (MRI) with the determination of the 1p/19q codeletion status could improve the ability to predict anaplastic transformation in low-grade oligodendrogliomas. Twenty patients with grade II oligodendrogliomas were followed-up using multimodal MR [proton MR spectroscopy (MRS), perfusion, and conventional MR imaging]. All patients diagnoses were histologically proven, and 1p/19q codeletion status was analyzed for all patients. Median follow-up was 30.5 +/- 11.4 months. Anaplastic transformation was observed in six patients. The only MRI feature that was associated with anaplastic transformation was an elevation of the choline/creatine ratio >2.4 which was observed in 4 out of 6 patients with anaplastic transformation versus 1 out of 14 patients without anaplastic transformation. In patients without 1p/19q codeletion, an elevation of the choline/creatine ratio >2.4 was associated with the occurrence of anaplastic transformation in all cases (4 out of 4 patients), with a mean time of 12 months. In contrast, in patients with a 1p/19q codeletion, no anaplastic transformation was observed in the patient who had an elevation of >2.4 of the choline/creatine ratio and two patients demonstrated an anaplastic transformation without any elevation of this ratio.Prospective validation in a larger series is needed, yet the present study suggests that combining data from in vivo proton MRS and genetic analysis could be a promising strategy to predict time to anaplastic transformation at the individual level in patients with low-grade oligodendrogliomas and may help deciding when chemotherapy and/or radiotherapy should be initiated in these tumors. PMID- 25716745 TI - What can blood biomarkers tell us about cardiovascular risk in obstructive sleep apnea? AB - BACKGROUND: Despite its high prevalence and frequent association with multiple comorbidities, including hypertension, heart disease, and stroke, obstructive sleep apnea (OSA) still lacks appropriate tools for cardiovascular risk assessment and stratification. Circulating biomarkers represent a safe, convenient, and inexpensive possibility, and several studies have been performed to define an ideal marker in this context. Additionally, biomarkers can provide insight into the pathological mechanisms of the disease and suggest new therapeutic approaches. METHODS: In the present review, the authors critically analyze the biomarkers of cardiovascular risk currently available and other potential markers, including brain natriuretic peptide, C-reactive protein, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), cysteine, homocysteine, free fatty acids, 8-isoprostane, gamma-glutamyl transferase, glycated hemoglobin, adipokines, and adhesion molecules. CONCLUSION: The results clearly demonstrate that the relationship between specific biomarkers and OSA is often influenced by age, gender or ethnicity, which has hindered the identification of a unique marker for the evaluation of all patients with OSA. Moreover, given the frequency of comorbidities in OSA, which, by themselves, increase the cardiovascular risk, all confounding factors must be considered in the evaluation of these biomarkers. PMID- 25716746 TI - Risk factors for automobile accidents caused by falling asleep while driving in obstructive sleep apnea syndrome. AB - PURPOSE: We examined the risk factors for automobile accidents caused by falling asleep while driving in subjects with obstructive sleep apnea syndrome (OSAS). METHODS: We asked licensed drivers with history of snoring and excessive daytime sleepiness who had undergone polysomnography (PSG) at the Department of Sleep Medicine/Sleep Disorders Center at Aichi Medical University Hospital to complete the questionnaires on accidents caused by falling asleep while driving. As a subjective measure of sleepiness, we used the Epworth sleepiness scale (ESS). Based on PSG results, 2387 subjects diagnosed with OSAS were divided into three groups according to apnea-hypopnea index (AHI): mild-to-moderate (5 <= AHI < 30), severe (30 <= AHI < 60), and very severe (AHI >= 60). We performed univariate and multivariate logistic regression on variables that might explain falling asleep at the wheel. RESULTS: We compared results between each group and simple snorers (394 subjects with AHI < 5) and found the group with very severe OSAS reported significantly higher rates of driving when drowsy and having accidents in the past 5 years due to falling asleep. CONCLUSIONS: Our multivariate analysis suggests that scores on the ESS and patient-reported frequency of feeling drowsy while regular driving and working are related to automobile accidents caused by falling asleep while driving. PMID- 25716748 TI - Correlation between premature ejaculation and female vaginal penetration difficulties. AB - Male and female sexual dysfunctions encompass biological, psychological and interpersonal aspects. Premature ejaculation (PE) and female vaginal penetration difficulties (VPD) are problems that may concurrently impair the couple's sexual relationship. We have studied the correlation between PE and VPD in the female partner, in a cross-sectional study of 125 heterosexual couples (male age 35.01+/ 10.63; female age 32.36+/-10.07). VPD included tampon insertion, gynecological examination, inserting self-finger or partner-finger and penile-vaginal intercourse. Female sexual function index (FSFI) and a validated PE questionnaire were used to measure the female sexual function and PE in their male partners. We found that female partners of men with anteportal ejaculation were found to experience significantly more VPDs, especially with regard to difficulties in penile penetration and tampon use. The intensity of pain in VPD was higher in females whose male partners presented anteportal ejaculation. No significant correlation was found between total male PE score and the total FSFI or separate domains of female sexual function. The results suggest that female VPD and male anteportal ejaculation are interrelated. Such severe couple sexual problems should be addressed in parallel. Further research is required to study the causation of PE and VPD. PMID- 25716749 TI - Increased intraindividual reaction time variability in persons with neuropsychiatric manifestations of systemic lupus erythematosus. AB - Systemic Lupus Erythematosus (SLE) can affect multiple organ systems, including the central (CNS) and/or peripheral nervous system. Individuals with nervous system involvement (termed Neuropsychiatric SLE or NPSLE) can present with nonspecific symptoms such as cognitive dysfunction. It is difficult to ascertain whether this is a direct consequence of lupus disease activity on the brain. Intraindividual variability, measured through trial-to-trial reaction time variation, has been proposed as a behavioral marker of CNS integrity. We compared 14 NPSLE, 20 non-NPSLE, and 27 age-matched healthy participants using multiple variability metrics. Variability was increased in NPSLE compared with non-NPSLE participants, and was increased throughout the distribution rather than there being a selective increase in extreme reaction times. Variability metrics were strongly intercorrelated providing convergent evidence that the different metrics are tapping similar processes. The results suggest that there is ongoing disruption to cognitive processing in NPSLE and may indicate small fluctuations in attention. PMID- 25716750 TI - Corrigendum: Duplication of a promiscuous transcription factor drives the emergence of a new regulatory network. PMID- 25716751 TI - Proposed changes to Medicare: undermining equity and outcomes in Australian primary health care? PMID- 25716752 TI - Critical Realism and Empirical Bioethics: A Methodological Exposition. AB - This paper shows how critical realism can be used to integrate empirical data and philosophical analysis within 'empirical bioethics'. The term empirical bioethics, whilst appearing oxymoronic, simply refers to an interdisciplinary approach to the resolution of practical ethical issues within the biological and life sciences, integrating social scientific, empirical data with philosophical analysis. It seeks to achieve a balanced form of ethical deliberation that is both logically rigorous and sensitive to context, to generate normative conclusions that are practically applicable to the problem, challenge, or dilemma. Since it incorporates both philosophical and social scientific components, empirical bioethics is a field that is consistent with the use of critical realism as a research methodology. The integration of philosophical and social scientific approaches to ethics has been beset with difficulties, not least because of the irreducibly normative, rather than descriptive, nature of ethical analysis and the contested relation between fact and value. However, given that facts about states of affairs inform potential courses of action and their consequences, there is a need to overcome these difficulties and successfully integrate data with theory. Previous approaches have been formulated to overcome obstacles in combining philosophical and social scientific perspectives in bioethical analysis; however each has shortcomings. As a mature interdisciplinary approach critical realism is well suited to empirical bioethics, although it has hitherto not been widely used. Here I show how it can be applied to this kind of research and explain how it represents an improvement on previous approaches. PMID- 25716753 TI - Analyzing internal fragmentation of electrosprayed ubiquitin ions during beam type collisional dissociation. AB - Gaseous fragmentation of intact proteins is multifaceted and can be unpredictable by current theories in the field. Contributing to the complexity is the multitude of precursor ion states and fragmentation channels. Terminal fragment ions can be re-fragmented, yielding product ions containing neither terminus, termed internal fragment ions. In an effort to better understand and capitalize upon this fragmentation process, we collisionally dissociated the high (13+), middle (10+), and low (7+) charge states of electrosprayed ubiquitin ions. Both terminal and internal fragmentation processes were quantified through step-wise increases of voltage potential in the collision cell. An isotope fitting algorithm matched observed product ions to theoretical terminal and internal fragment ions. At optimal energies for internal fragmentation of the 10+, nearly 200 internal fragments were observed; on average each of the 76 residues in ubiquitin was covered by 24.1 internal fragments. A pertinent finding was that formation of internal ions occurs at similar energy thresholds as terminal b- and y-ion types in beam-type activation. This large amount of internal fragmentation is frequently overlooked during top-down mass spectrometry. As such, we present several new approaches to visualize internal fragments through modified graphical fragment maps. With the presented advances of internal fragment ion accounting and visualization, the total percentage of matched fragment ions increased from approximately 40% to over 75% in a typical beam-type MS/MS spectrum. These sequence coverage improvements offer greater characterization potential for whole proteins with no needed experimental changes and could be of large benefit for future high-throughput intact protein analysis. PMID- 25716755 TI - Synthesis of indolines by copper-mediated intramolecular aromatic C-h amination. AB - A Cu(OAc)2-mediated intramolecular aromatic C-H amination proceeds with the aid of a picolinamide-type bidentate coordination group to deliver the corresponding indolines in good yields. The reaction occurs smoothly even under noble-metal free conditions, and in some cases the use of an MnO2 terminal oxidant renders the process catalytic in Cu. The mild oxidation aptitude of Cu(OAc)2 and/or MnO2 accommodates the formation of electron-rich thiophene- and indole-fused indoline analogues. The Cu-based system can provide an effective approach to various indolines of potent interest in pharmaceutical and medicinal chemistry. PMID- 25716754 TI - Identification of reduction-susceptible disulfide bonds in transferrin by differential alkylation using O(16)/O(18) labeled iodoacetic acid. AB - Stabilization of native three-dimensional structure has been considered for decades to be the main function of disulfide bonds in proteins. More recently, it was becoming increasingly clear that in addition to this static role, disulfide bonds are also important for many other aspects of protein behavior, such as regulating protein function in a redox-sensitive fashion. Dynamic disulfide bonds can be taken advantage of as candidate anchor sites for site-specific modification (such as PEGylation of conjugation to a drug molecule), but are also frequently implicated in protein aggregation (through disulfide bond scrambling leading to formation of intermolecular covalent linkages). A common feature of all these labile disulfide bonds is their high susceptibility to reduction, as they need to be selectively regulated by either specific local redox conditions in vivo or well-controlled experimental conditions in vitro. The ability to identify labile disulfide bonds in a cysteine-rich protein can be extremely beneficial for a variety of tasks ranging from understanding the mechanistic aspects of protein function to identification of troublesome "hot spots" in biopharmaceutical products. Herein, we describe a mass spectrometry (MS)-based method for reliable identification of labile disulfide bonds, which consists of limited reduction, differential alkylation with an O(18)-labeled reagent, and LC MS/MS analysis. Application of this method to a cysteine-rich protein transferrin allows the majority of its native disulfide bonds to be measured for their reduction susceptibility, which appears to reflect both solvent accessibility and bond strain energy. PMID- 25716756 TI - Alcohol policy impact on young risky drinkers and their support for proposed measures. AB - OBJECTIVE: To explore the impacts of existing policies on young Australian risky drinkers' access to alcohol and to gauge their support for proposed alcohol measures. METHODS: The 16-19 year old participants were recruited from three Australian states using non-random convenience sampling, for either a face-to face or online quantitative survey (N=958). The sample was deliberately selected to represent drinkers whose consumption placed them in the riskiest drinking 20 25% of their age bracket. RESULTS: Half (49%) the sample who were younger than the Australian legal purchase age reported it was 'easy' to buy alcohol from bottle stores, and 75% of those who had tried to purchase alcohol, said it was 'easy' the last time they tried. Half of those under 18, who had attempted to enter a licensed venue, reported they did not have their identification checked last time they gained access. Ninety per cent of all respondents drank within a private location at their last risky drinking session. Sixty-five per cent supported 'increasing the price of [alcohol by 20c] a standard drink if the extra 20c was used to support prevention and treatment of alcohol problems'. CONCLUSIONS: Age- or intoxication-based restrictions to alcohol were commonly bypassed. IMPLICATIONS: Point-of-sale alcohol controls require improvement to prevent under age access. Given that a significant proportion of drinking occasions for those under 18 were in private premises, prevention strategies need to target these locations. There were diverse levels of support for strategies to reduce harm, including potential community backing for an evidence-based proposed price policy. PMID- 25716757 TI - Multidisciplinary care in severe pediatric electrical oral burn. AB - Oral burns in pediatric patient are commonly due to electrical injuries, representing an important reconstructive issue even for functional than esthetic reason. Different classification, surgical management and even oral device were described to allow the best long-term result. In most case a multidisciplinary approach is necessary to achieve a satisfactory outcome. A severe case of pediatric oral burn with germinative teeth damage is presented, describing a multispecialist team approach that guarantee a satisfactory outcome by reconstructive surgery, careful progressive evaluation of dental and soft tissue healing and speech recovery. The use of acellular dermal substitute template within traditional reconstructive surgery had provided a good functional and esthetic result joint to valid preservation of germinative dental element as shown at long-term X-ray evaluation. Intensive rehabilitation speech program has also avoided phonetic impairment in an important speech develop period. It was so evident that the necessity of a multispecialist care in such difficult injury to achieve the best long-term result. PMID- 25716758 TI - Preliminary results in single-step wound closure procedure of full-thickness facial burns in children by using the collagen-elastin matrix and review of pediatric facial burns. AB - BACKGROUND: Management of full-thickness facial burns remains one of the greatest challenges. Controversy exists among surgeons regarding the use of early excision for facial burns. Unfortunately, delayed excision of deeper burns often results in more scarring and subsequent reconstruction becomes more difficult. A collagen elastin matrix is used to improve the quality of the reconstructed skin, to reduce scarring and to prevent wound contraction. It serves as a foundation for split thickness skin graft and enhances short and long-term results. AIM: We report the usage of a collagen-elastin matrix during single-step wound closure technique of severe full-thickness facial burns in 15 children with large burned body surface area, and also we review the literature about pediatric facial burns. RESULTS: There were 15 pediatric patients with severe facial burns, 8 girls and 7 boys ranging in age from 10 months to 12 years, mean age 7 years and 6 months old. The facial burn surface area (FBSA) among the patients includes seven patients with 100%, five with 75%, and three with 50%. The average total body surface area (TBSA) for the patients was 72%, ranging between 50 and 90%. 5 of the patients' admissions were late, more than four days after burns while the rest of the patients were admitted within the first four days (acute admission time). The burns were caused by flame in eight of the patients, bomb blast in four, and scalding in three. All patients were treated by the simultaneous application of the collagen-elastin matrix and an unmeshed split thickness skin graft at Turgut Ozal Medical Center, Pediatric Burn Center, Malatya, Turkey. After the treatment only two patients needed a second operation for revision of the grafts. All grafts transplanted to the face survived. The average Vancouver scar scales (VSS) were 2.55+/-1.42, ranging between one and six, in the first 10 of 15 patients at the end of 6 months postoperatively. VSS measurements of the last 5 patients were not taken since the 6 months postoperative period was not over. CONCLUSION: In regard to early results, graft quality was close to normal skin in terms of vascularity, elasticity, pliability, texture and color. Esthetic and functional results have been encouraging. This study shows us that the collagen-elastin matrix as a dermal substitute is a useful adjunct, which may result in quick healing with satisfying esthetic and functional results. It also may enhance short and long-term results in after burn facial wound closure in children. PMID- 25716759 TI - Experimental stem cell therapies on burn wound: do source, dose, timing and method matter? AB - Stem cell therapy has been introduced as a new and promising modality of wound covering in recent decade. It has been used for improvement of burn wound, post burn scar and saving stasis zone of burn with good results. However, there have been some differences between the various experimental burn wound trials in stem cell source, therapeutic dose, delivery method and timing of stem cell delivery. In our study, we aimed to review stem cell biology and investigate discrepancies in animal trials of use of stem cells in burn wound account for the variation in, stem cell source, therapeutic dose, delivery method and timing of stem cell delivery. PMID- 25716760 TI - Burns due to air freshener aerosol can explosion: a preventable accident. PMID- 25716761 TI - Incidences of malignancy in chronic burn scar ulcers: experience from Bangladesh. AB - Malignant transformation on any scar tissue is known as Marjolin's ulcer. Most cases of Marjolin's ulcer reported so far occur in post-burn scars but not all ulcers that occur in post-burn scar are malignant. One hundred and forty cases of chronic non-healing ulcers in post-burn scar were included in this prospective observational study. The study was conducted in the Department of Burn and Plastic Surgery Unit of Dhaka Medical College Hospital. Mean age of the patients was 40.63+/-18.44 with a range from 12 to 75 years. Two third of the patients were male. All patients underwent excision biopsy and coverage with either split thickness skin graft or flap. Histopathological analysis of the resected specimen revealed malignancy in 46 cases and pseudoepitheliomatous hyperplasia in four cases and verruca plantaris in one case. The rest of the cases were chronic non healing benign ulcers. All 46 cases of Marjolin's ulcer were squamous cell carcinoma with a mean latency period of 26.73 years. The commonest site of chronic ulcer was in the lower extremities (n-80, 57%), and malignancy was also found to be more common there (n-18). The most common type of burn was flame burn (68.57%). The Marjolin's ulcers were significantly larger in size than benign ulcers, and were mostly exophytic or ulcerative in appearance whereas benign ulcers were mostly flat. A non-healing ulcer in a post-burn scar should be addressed promptly because of its potential to develop into a malignant ulcer. Emphasis should be given to early surgical treatment of deep partial to full thickness burns to prevent scar formation, particularly over joints, and thus reduce the risk of development of Marjolin's ulcer. PMID- 25716762 TI - 3D photography is a reliable burn wound area assessment tool compared to digital planimetry in very young children. AB - BACKGROUND: Reliability and validity of 3D photography (3D LifeVizTM System) compared to digital planimetry (VisitrakTM) has been established in a compliant cohort of children with acute burns. Further research is required to investigate these assessment tools in children representative of the general pediatric burns population, specifically children under the age of three years. AIM: To determine if 3D photography is a reliable wound assessment tool compared to VisitrakTM in children of all ages with acute burns <=10% TBSA. METHOD: Ninety-six children (median age 1 year 9 months) who presented to the Royal Children's Hospital Brisbane with an acute burn <=10% TBSA were recruited into the study. Wounds were measured at the first dressing change using the VisitrakTM system and 3D photography. All measurements were completed by one investigator and level of agreement between wound surface area measurements was calculated. RESULTS: Wound surface area measurements were complete (i.e. participants had measurements from both techniques) for 75 participants. Level of agreement between wound surface area measurements calculated using an intra-class correlation coefficient (ICC) was excellent (ICC 0.96, 95% CI 0.93, 0.97). VisitrakTM tracings could not be completed in 19 participants with 16 aged less than two years. 3D photography could not be completed for one participant. Barriers to completing tracings were: excessive movement, pain, young age or wound location (e.g. face or perineum). CONCLUSION: This study has confirmed 3D photography as a reliable alternative to digital planimetry in children of all ages with acute burns <=10% TBSA. In addition, 3D photography is more suitable for very young children given its non invasive nature. PMID- 25716763 TI - Selective decontamination of the digestive tract ameliorates severe burn-induced insulin resistance in rats. AB - BACKGROUND: Severe burns often initiate the prevalence of hyperglycemia and insulin resistance, significantly contributing to adverse clinical outcomes. However, there are limited treatment options. This study was designed to investigate the role and the underlying mechanisms of oral antibiotics to selectively decontaminate the digestive tract (SDD) on burn-induced insulin resistance. MATERIALS AND METHODS: Rats were subjected to 40% of total body surface area full-thickness burn or sham operation with or without SDD treatment. Translocation of FITC-labeled LPS was measured at 4h after burn. Furthermore, the effect of SDD on post-burn quantity of gram-negative bacteria in gut was investigated. Serum or muscle LPS and proinflammatory cytokines were measured. Intraperitoneal glucose tolerance test and insulin tolerance test were used to determine the status of systemic insulin resistance. Furthermore, intracellular insulin signaling (IRS-1 and Akt) and proinflammatory related kinases (JNK and IKKbeta) were assessed by western blot. RESULTS: Burn increased the translocation of LPS from gut 4h after injury. SDD treatment effectively inhibited post-burn overgrowth of gram-negative enteric bacilli in gut. In addition, severe burns caused significant increases in the LPS and proinflammatory cytokines levels, activation of proinflammatory related kinases, and systemic insulin resistance as well. But SDD treatment could significantly attenuate burn-induced insulin resistance and improve the whole-body responsiveness to insulin, which was associated with the inhibition of gut-derived LPS, cytokines, proinflammatory related kinases JNK and IKKbeta, as well as activation of IRS-1 and Akt. CONCLUSIONS: SDD appeared to have an effect on proinflammatory signaling cascades and further reduced severe burn-induced insulin resistance. PMID- 25716764 TI - Photograph-based diagnosis of burns in patients with dark-skin types: the importance of case and assessor characteristics. AB - AIM: This study assessed whether photographs of burns on patients with dark-skin types could be used for accurate diagnosing and if the accuracy was affected by physicians' clinical background or case characteristics. METHOD: 21 South-African cases (Fitzpatrick grades 4-6) of varying complexity were photographed using a camera phone and uploaded on a web-survey. Respondents were asked to assess wound depth (3 categories) and size (in percentage). A sample of 24 burn surgeons and emergency physicians was recruited in South-Africa, USA and Sweden. Measurements of accuracy (using percentage agreement with bedside diagnosis), inter- (n=24), and intra-rater (n=6) reliability (using percentage agreement and kappa) were computed for all cases aggregated and by case characteristic. RESULTS: Overall diagnostic accuracy was 67.5% and 66.0% for burn size and depth, respectively. It was comparable between burn surgeons and emergency physicians and between countries of practice. However, the standard deviations were smaller, showing higher similarities in diagnoses for burn surgeons and South-African clinicians compared to emergency physicians and clinicians from other countries. Case characteristics (child/adult, simple/complex wound, partial/full thickness) affected the results for burn size but not for depth. Inter- and intra-rater reliability for burn depth was 55% and 77%. CONCLUSION: Size and depth of burns on patients with dark-skin types could be assessed at least as well using photographs as at bedside with 67.5% and 66.0% average accuracy rates. Case characteristics significantly affected the accuracy for burn size, but medical specialty and country of practice seldom did in a statistically significant manner. PMID- 25716765 TI - Intentional burns in Nepal: a comparative study. AB - AIMS: Intentional burns injuries are associated with high mortality rates, and for survivors, high levels of physical and psychological morbidity. This study provides a comprehensive assessment of intentional burn admissions to the adult Burns Unit at Bir Hospital, Kathmandu, Nepal, during the period 2002-2013. METHODS: A secondary data analysis of de-identified data of patients hospitalized at Bir Hospital, Kathmandu, with a burn during the period of 1 January 2002 to 31 August 2013. Socio-demographic, injury and psychosocial factors of patients with intentional and unintentional burns are described and compared. Chi-square tests, Fisher's exact test and Wilcoxon rank sum tests were used to determine statistical significance. RESULTS: There were a total of 1148 burn admissions of which 329 (29%) were for intentional burn, 293 (26%) were self-inflicted and 36 (3%) were due to assault. Mortality rates for intentional burns were approximately three times those for unintentional burns (60 vs. 22%). When compared to unintentional burns, patients with intentional burns were more likely to be female (79 vs. 48%), married (84 vs. 67%), younger (25 vs. 30 years), have more extensive burns (total body surface area, %: 55 vs. 25) and higher mortality (60 vs. 22%). Intentional burns were more likely to occur at home (95 vs. 67%), be caused by fire (96 vs. 77%), and kerosene was the most common accelerant (91 vs. 31%). A primary psychosocial risk factor was identified in the majority of intentional burn cases, with 60% experiencing adjustment problems/interpersonal conflict and 32% with evidence of a pre-existing psychological condition. A record of alcohol/substance abuse related to the patient or other was associated with a greater proportion of intentional burns when compared with unintentional burns (17 vs. 4%). CONCLUSIONS: The majority of intentional burn patients were female. Almost all intentional burns occurred in the home and were caused by fire, with kerosene the most common accelerant used. Underlying psychosocial risk factors were identified in most cases. Intentional burns resulted in severe burns with high mortality. Intentional burns are not only a serious medical issue; they represent significant public health and gender issues in Nepal. PMID- 25716767 TI - Photon upconversion nanomaterials. PMID- 25716766 TI - Therapy with proton pump inhibitors in patients with type 2 diabetes is independently associated with improved glycometabolic control. AB - AIMS: Experimental data demonstrated that gastrin has incretin-like stimulating actions on beta-cells, resulting in a promotion of glucose-induced insulin secretion. As proton pump inhibitors (PPIs) consistently increase plasma gastrin levels, a possible effect of this treatment on glucose-insulin homeostasis may be hypothesized. Therefore, the aim of this study was to evaluate the effect of chronic PPIs treatment on glycemic control in patients affected by type 2 diabetes. METHODS: This is an observational, retrospective study. A total of 548 consecutive patients with type 2 diabetes (mean age +/- SD: 67.1 +/- 10.9 years, M/F: 309/239, diabetes duration: 12.4 +/- 9.8 years) referring to our diabetes outpatient clinics were enrolled; among them, 45 %were treated with PPIs longer than 2 years for preventive/therapeutic purposes. Fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), serum lipids and transaminases were measured by standard laboratory methods. Major cardiovascular events and concomitant medications were recorded in all participants, and daily insulin requirement was calculated in insulin-treated subjects. RESULTS: PPIs-treated patients had significantly lower HbA1c (7.1 +/- 1.07 %-54.1 +/- 12 vs 7.4 +/- 1.4 %-57.4 +/- 8 mmol/mol, p = 0.011) and FPG (127 +/- 36.9 vs 147.6 +/- 49.4 mg/dl, p < 0.001) levels than those untreated. These differences increased in patients under insulin therapy and in those with concomitant PPIs + GLP-1-based therapy. The multivariate regression analysis demonstrated that the association between chronic PPIs treatment and HbA1c was independent from possible confounders (p = 0.01). CONCLUSIONS: PPIs treatment is associated with greater glycemic control in patients with type 2 diabetes, particularly in those on insulin- or GLP-1-based therapy. Our results suggest a role for PPIs in glucose-insulin homeostasis and may open a new scenario for diabetes therapy. PMID- 25716768 TI - Experimental investigation and histopathological identification of acute thermal damage in skeletal porcine muscle in relation to whole-body SAR, maximum temperature, and CEM43 degrees C due to RF irradiation in an MR body coil of birdcage type at 123 MHz. AB - PURPOSE: This study is an investigation of the relationship between several characteristic parameters and acute thermal damage in porcine skeletal muscle. MATERIAL AND METHODS: Fourteen pigs under injection anaesthesia were placed into a magnetic resonance body coil and exposed for different time durations to different specific energy absorption rate (SAR) levels at 123 MHz. Local temperatures were measured using four temperature sensors. Sensors 1-3 were placed in skeletal muscle and one sensor was placed in the rectum. Sensors 1 and 2 were placed in hot-spot areas and sensor 3 was placed at the periphery of the animals. The pigs were exposed to whole-body SAR (SAR-wb) between 2.5 W/kg and 5.2 W/kg for 30 or 60 min. Three animals received no SAR. After each experiment, muscle samples adjacent to the positions of sensors 1-3 were taken for frozen section analysis. Three characteristic parameters were chosen for investigation: SAR-wb, maximum sensor temperature (T-max), and cumulative equivalent minutes at 43 degrees C (CEM43 degrees C). RESULTS: Histopathological criteria were established to detect acute thermal tissue damage in frozen sections such as widening of intercellular space between the muscle fibres and loss of glycogen. Clear tissue damage thresholds were found for T-max and CEM43 degrees C, though not for SAR-wb. For all animals with high thermal exposure, damage was also found for muscle samples adjacent to the peripheral sensor 3. CONCLUSIONS: Both T-max and CEM43, are able to predict thermal damage in porcine muscle. However, CEM43 is the less ambiguous parameter. The reasons for the occurrence of the aforementioned damage at low local temperatures at the animals' periphery remain unclear and further investigations are needed. PMID- 25716769 TI - A new mechanism of thermal sensitivity for rapid drug release and low systemic toxicity in hyperthermia and thermal ablation temperature ranges. AB - PURPOSE: The aim of this paper was to introduce a new mechanism of thermal sensitivity in nanocarriers that results in a relatively low drug release at physiological temperature and rapid release of the encapsulated drug at hyperthermia and thermal ablation temperature range (40-60 degrees C). MATERIALS AND METHODS: The nanocarriers were synthesised by coating mesoporous silica nanoparticles with a thin layer of polyacrylamide. The low gelation temperature of the protective shell provides preferred routes for drug diffusion when the nanocarriers are heated within the hyperthermia temperature range. In order to determine the gelation point of polyacrylamide shell, differential scanning calorimetry was used. Various chemical, morphological, thermal, as well as drug loading capacities of these nanocarriers were characterised and their drug release behaviour was examined using magnetic resonance -guided focused ultrasound (MRgFUS). RESULTS: Drug release measurements at different temperatures using doxorubicin showed 11.5 +/- 2.4% leakage in aqueous solution at 37 degrees C after 30 min, while this value was significantly increased to 67.6 +/- 2.5% at 60 degrees C. A 39.2 +/- 2.2% release of doxorubicin was also obtained due to the sonication of drug-loaded nanoparticles for 5 * 20 s using MRgFUS. CONCLUSION: The nanocarriers developed do not exhibit a sharp transition temperature. However, a relatively high loading efficiency as well as rapid drug release at thermal ablation temperature range makes these nanostructures promising candidates for application as adjuvants to various thermal modalities such as radiofrequency and high intensity focused ultrasound. PMID- 25716770 TI - An overview of the influence of therapeutic ultrasound exposures on the vasculature: high intensity ultrasound and microbubble-mediated bioeffects. AB - It is well established that the interaction of ultrasound with soft tissues can induce a wide range of bioeffects. One of the most important and complex of these interactions in the context of therapeutic ultrasound is with the vasculature. Potential vascular effects range from enhancing microvascular permeability to inducing vascular damage and vessel occlusion. While aspects of these effects are broadly understood, the development of improved approaches to exploit these effects and gain a more detailed mechanistic understanding is ongoing and largely anchored in preclinical research. Here a general overview of this established yet rapidly evolving topic is provided, with a particular emphasis on effects arising from high-intensity focused ultrasound and microbubble-mediated exposures. PMID- 25716771 TI - Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula. AB - The safety and efficacy of warfarin in a large, unselected cohort of warfarin treated patients with high quality of care is comparable to that reported for non vitamin K antagonists. Warfarin is commonly used for stroke prevention in atrial fibrillation, as well as for treatment and prevention of venous thromboembolism. While reducing risk of thrombotic/embolic incidents, warfarin increases the risk of bleeding. The aim of this study was to elucidate risks of bleeding and thromboembolism for patients on warfarin treatment in a large, unselected cohort with rigorously controlled treatment. This was a retrospective, registry-based study, covering all patients treated with warfarin in the Swedish national anticoagulation register Auricula, which records both primary and specialised care. The study included 77,423 unselected patients with 100,952 treatment periods of warfarin, constituting 217,804 treatment years. Study period was January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68 %). The mean time in therapeutic range of the international normalised ratio (INR) 2.0-3.0 was 76.5 %. The annual incidence of severe bleeding was 2.24 % and of thromboembolism 2.65 %. The incidence of intracranial bleeding was 0.37 % per treatment year in the whole population, and 0.38 % among patients with atrial fibrillation. In conclusion, warfarin treatment where patients spend a high proportion of time in the therapeutic range is safe and effective, and will continue to be a valid treatment option in the era of newer oral anticoagulants. PMID- 25716772 TI - Drug-induced sleep endoscopy and simulated snoring in patients with sleep disordered breathing: agreement of anatomic changes in the upper airway. AB - Drug-induced sleep endoscopy (DISE) and simulated snoring (SimS) are performed as part of the diagnostic procedure in patients with suspected sleep-disordered breathing (SDB). Despite both techniques frequently performed, they have rarely been evaluated yet in terms of agreement of the obtained results. Both diagnostic procedures were performed consecutively in 40 patients with SDB and documented identically. The obtained data were analysed with respect to the agreement of both procedure at different levels of the oropharynx as well as different patterns of obstruction and vibration. The anterior-posterior collapsibility of the soft palate/uvula revealed a moderate agreement between SimS and DISE (kappa = 0.42; 95 % CI 0.22-0.63). The dorsal shift of the tongue base agreed moderate for patients with an AHI below 10 (kappa = 0.47) and above 25 (kappa = 0.44) between SimS ad DISE. The lateral and circular pharyngeal collapsibility at velum and tongue base level did not agree between SimS and DISE, was higher for DISE and could be partially reversed by mandibular protrusion. Collapse patterns of the soft palate and uvula can be induced by SimS and resemble the patterns induced by DISE. The dorsalization of the tongue base can be simulated to a lower extent by SimS. Lateral and circular patterns of collapse at the upper and lower oropharynx induced by DISE do not seem to be simulated by SimS. SimS seems to be an additional method to screen the collapsibility of the soft palate and uvula prior to DISE. PMID- 25716773 TI - Intensity-modulated radiotherapy for cervical esophageal squamous cell carcinoma: clinical outcomes and patterns of failure. AB - The objective of the study was to report clinical outcomes and patterns of failure for these patients with cervical esophageal squamous cell carcinoma (CESCC) treated with intensity-modulated radiotherapy (IMRT). A total of 64 patients with CESCC treated with definitive IMRT from May 2005 to March 2012 in our center were analyzed. Forty-two patients received radiotherapy alone and 22 patients received concurrent chemoradiotherapy. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. For all patients, the overall 2-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival rate was 74.5, 88.0, 66.6 and 42.5 %, respectively. Twenty-eight patients had developed treatment failure. Of the 28 patients, 14, 5, and 18 had developed local failure, regional failure, and distant metastasis, respectively. All of the 14 local failures were considered in field failures. Of the five regional failures, three were considered in-field failures and two were marginal failures. The most frequently observed acute toxicity was mainly Grade 1 or 2. The incidence of acute Grade 3 mucositis (including pharyngitis), skin reaction, and leukopenia was 4.7, 12.5 and 10.9 %, respectively. IMRT provides satisfactory locoregional control for CESCC. Distant metastasis remains the predominate pattern of failure and the predominate pattern of locoregional failures is in-field failure. PMID- 25716774 TI - Assay of ceftazidime and cefepime based on fluorescence quenching of carbon quantum dots. AB - A novel and sensitive method for the determination of ceftazidime and cefepime in an active pharmaceutical ingredient (API) has been developed based on the fluorescence quenching of poly(ethylene glycol) (PEG)2000-capped carbon quantum dots (CQDs) prepared using a chemical oxidation method. The quenching of fluorescence intensity is proportional to the concentration of ceftazidime and cefepime over the range of 0.33-3.30 and 0.24-2.40 ug/mL, respectively. The mode of interaction between PEG2000-capped CQDs and ceftazidime/cefepime in aqueous solutions was investigated using a fluorescence, UV/Vis and Fourier transform infrared spectrometry (FTIR) at physiological pH. UV/Vis and FTIR spectra demonstrated that ground state compounds were formed through hydrophobic interaction the fluorescence quenching of CQDs caused by ceftazidime and cefepime. The quenching constants decreased with increases in temperature, which was consistent with static quenching. PMID- 25716775 TI - Enantioselective cross-coupling of meso-epoxides with aryl halides. AB - The first enantioselective cross-electrophile coupling of aryl bromides with meso epoxides to form trans-beta-arylcycloalkanols is presented. The reaction is catalyzed by a combination of (bpy)NiCl2 and a chiral titanocene under reducing conditions. Yields range from 57 to 99% with 78-95% enantiomeric excess. The 30 examples include a variety of functional groups (ether, ester, ketone, nitrile, ketal, trifluoromethyl, sulfonamide, sulfonate ester), both aryl and vinyl halides, and five- to seven-membered rings. The intermediacy of a carbon radical is strongly suggested by the conversion of cyclooctene monoxide to an aryl [3.3.0]bicyclooctanol. PMID- 25716776 TI - Dopaminergic Modulation of Lateral Amygdala Neuronal Activity: Differential D1 and D2 Receptor Effects on Thalamic and Cortical Afferent Inputs. AB - BACKGROUND: In auditory fear conditioning, the lateral nucleus of the amygdala (LA) integrates a conditioned stimulus (CS) from the auditory thalamus (MGN) and the auditory association cortex (Te3) with an aversive unconditioned stimulus. The thalamic input provides a basic version of the CS, while the cortical input provides a processed representation of the stimulus. Dopamine (DA) is released in the LA under heightened arousal during the presentation of the CS. METHODS: In this study we examined how D1 or D2 receptor activation affects LA afferent driven neuronal firing using in vivo extracellular single-unit recordings with local micro-iontophoretic drug application in anesthetized rats. LA neurons that were responsive (~50%) to electrical stimulation in either the MGN or the Te3 were tested by iontophoresis of either the D1 agonist, SKF38393, or the D2 agonist, quinpirole. RESULTS: We found that most of the LA projection neurons exhibited either facilitatory or attenuating effects (changes in evoked probability >15% relative to baseline) on afferent input by activation of D1 or D2 receptors. In general, it required significantly higher stimulation current to evoke ~50% baseline responses to the cortical input. Activation of the D1 receptor showed no difference in modulation between the thalamic or cortical pathways. On the other hand, activation of the D2 receptor had a stronger inhibitory modulation of the cortical pathway, but a stronger excitatory modulation of the thalamic pathway. CONCLUSIONS: Our results suggest that there is a shift in balance favoring the thalamic pathway in response to DA acting via the D2 receptor. PMID- 25716777 TI - A placebo-controlled trial of dextromethorphan as an adjunct in opioid-dependent patients undergoing methadone maintenance treatment. AB - BACKGROUND: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). METHODS: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-alpha, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-beta1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. RESULTS: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-alpha was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. CONCLUSIONS: We provide evidence-decreased concomitant heroin use-of low-dose add on DM's efficacy for treating opioid-dependent patients undergoing MMT. PMID- 25716778 TI - Making sense of real-time functional magnetic resonance imaging (rtfMRI) and rtfMRI neurofeedback. AB - This review explains the mechanism of functional magnetic resonance imaging in general and specifically introduces real-time functional magnetic resonance imaging as a method for training self-regulation of brain activity. Using real time functional magnetic resonance imaging neurofeedback, participants can acquire control over their own brain activity. In patients with neuropsychiatric disorders, this control can potentially have therapeutic implications. In this review, the technical requirements are presented and potential applications and limitations are discussed. PMID- 25716779 TI - Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy nonobese humans. AB - BACKGROUND: Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [(11)C]-(+) PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. METHODS: Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [(11)C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. RESULTS: Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)= 0.93, P=.36). CONCLUSION: In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities. PMID- 25716780 TI - Postsynaptic adenosine A2A receptors modulate intrinsic excitability of pyramidal cells in the rat basolateral amygdala. AB - BACKGROUND: The basolateral amygdala plays a critical role in the etiology of anxiety disorders and addiction. Pyramidal neurons, the primary output cells of this region, display increased firing following exposure to stressors, and it is thought that this increase in excitability contributes to stress responsivity and the expression of anxiety-like behaviors. However, much remains unknown about the underlying mechanisms that regulate the intrinsic excitability of basolateral amygdala pyramidal neurons. METHODS: Ex vivo gramicidin perforated patch recordings were conducted in current clamp mode where hyper- and depolarizing current steps were applied to basolateral amygdala pyramidal neurons to assess the effects of adenosine A(2A) receptor modulation on intrinsic excitability. RESULTS: Activation of adenosine A(2A) receptors with the selective A(2A) receptor agonist CGS-21680 significantly increased the firing rate of basolateral amygdala pyramidal neurons in rat amygdala brain slices, likely via inhibition of the slow afterhyperpolarization potential. Both of these A(2A) receptor-mediated effects were blocked by preapplication of a selective A(2A) receptor antagonist (ZM-241385) or by intra-pipette infusion of a protein kinase A inhibitor, suggesting a postsynaptic locus of A(2A) receptors on basolateral amygdala pyramidal neurons. Interestingly, bath application of the A(2A) receptor antagonist alone significantly attenuated basolateral amygdala pyramidal cell firing, consistent with a role for tonic adenosine in the regulation of the intrinsic excitability of these neurons. CONCLUSIONS: Collectively, these data suggest that adenosine, via activation of A(2A) receptors, may directly facilitate basolateral amygdala pyramidal cell output, providing a possible balance for the recently described inhibitory effects of adenosine A1 receptor activation on glutamatergic excitation of basolateral amygdala pyramidal cells. PMID- 25716781 TI - Extensive gray matter volume reduction in treatment-resistant schizophrenia. AB - BACKGROUND: Approximately one-third of people with schizophrenia are treatment resistant and some do not achieve remission with clozapine, the gold-standard antipsychotic medication for treatment-resistant schizophrenia. This study compared global and regional brain volumes between treatment-respondent and treatment-resistant patients with schizophrenia, including a group of patients who were clozapine-resistant. METHODS: T1-weighted brain MRIs were obtained on a 3T scanner in 20 controls and 52 people with schizophrenia who were selected based on their symptomatic responses to antipsychotic medication: 18 responded well to first-line atypical antipsychotics (FLR), 19 were treatment-resistant but responsive to clozapine monotherapy (TR), and 15 were ultra-treatment-resistant and did not respond to clozapine (UTR). Treatment groups were matched for disease duration and current psychopathology. SIENAX and FSL-VBM were used to investigate differences in the global brain, gray matter (GM), white matter, ventricular cerebrospinal fluid volumes, and regional GM volumes. RESULTS: GM volume was significantly reduced in the TR and UTR groups compared with controls and the FLR group (p < 0.05). GM volume was significantly reduced in TR patients compared with FLRs in the superior, middle, and inferior temporal gyri, pre- and post central gyri, middle and superior frontal gyri, right supramarginal gyrus, and right lateral occipital cortex. UTR patients showed reduced GM compared with FLRs in their right parietal operculum and left cerebellum. No significant volume differences were observed between TR and UTR groups. CONCLUSIONS: These differences are unlikely to be solely due to medication effects, and reduced GM volume in treatment-resistant schizophrenia may represent an accelerated disease course or a different underlying pathology. PMID- 25716782 TI - Differences in Anxiety-Like Behavior within a Batch of Wistar Rats Are Associated with Differences in Serotonergic Transmission, Enhanced by Acute SRI Administration, and Abolished By Serotonin Depletion. AB - BACKGROUND: The anxiety-reducing effect of long-term administration of serotonin reuptake inhibitors is usually seen only in subjects with anxiety disorders, and such patients are also abnormally inclined to experience a paradoxical anxiety enhancing effect of acute serotonin reuptake inhibition. These unique responses to serotonin reuptake inhibitors in anxiety-prone subjects suggest, as do genetic association studies, that inter-individual differences in anxiety may be associated with differences in serotonergic transmission. METHODS: The one-third of the animals within a batch of Wistar rats most inclined to spend time on open arms in the elevated plus maze were compared with the one-third most inclined to avoid them with respect to indices of brain serotonergic transmission and how their behavior was influenced by serotonin-modulating drugs. RESULTS: "Anxious" rats displayed higher expression of the tryptophan hydroxylase-2 gene and higher levels of the tryptophan hydroxylase-2 protein in raphe and also higher levels of serotonin in amygdala. Supporting these differences to be important for the behavioral differences, serotonin depletion obtained by the tryptophan hydroxylase-2 inhibitor p-chlorophenylalanine eliminated them by reducing anxiety in "anxious" but not "non-anxious" rats. Acute administration of a serotonin reuptake inhibitor, paroxetine, exerted an anxiety-enhancing effect in "anxious" but not "non-anxious" rats, which was eliminated by long-term pretreatment with another serotonin reuptake inhibitor, escitalopram. CONCLUSIONS: Differences in an anxiogenic impact of serotonin, which is enhanced by acute serotonin reuptake inhibitor administration, may contribute to differences in anxiety-like behavior amongst Wistar rats. PMID- 25716783 TI - Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons. AB - BACKGROUND: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus. METHODS: Complete Freund's adjuvant-induced monoarthritis was used as inflammatory chronic pain model. alpha-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4 week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus. RESULTS: Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. alpha Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal regulated kinases 1/2 levels in the locus coeruleus. CONCLUSIONS: Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade. PMID- 25716784 TI - Adaptation to enemy shifts: rapid resistance evolution to local Vibrio spp. in invasive Pacific oysters. AB - One hypothesis for the success of invasive species is reduced pathogen burden, resulting from a release from infections or high immunological fitness of invaders. Despite strong selection exerted on the host, the evolutionary response of invaders to newly acquired pathogens has rarely been considered. The two independent and genetically distinct invasions of the Pacific oyster Crassostrea gigas into the North Sea represent an ideal model system to study fast evolutionary responses of invasive populations. By exposing both invasion sources to ubiquitous and phylogenetically diverse pathogens (Vibrio spp.), we demonstrate that within a few generations hosts adapted to newly encountered pathogen communities. However, local adaptation only became apparent in selective environments, i.e. at elevated temperatures reflecting patterns of disease outbreaks in natural populations. Resistance against sympatric and allopatric Vibrio spp. strains was dominantly inherited in crosses between both invasion sources, resulting in an overall higher resistance of admixed individuals than pure lines. Therefore, we suggest that a simple genetic resistance mechanism of the host is matched to a common virulence mechanism shared by local Vibrio strains. This combination might have facilitated a fast evolutionary response that can explain another dimension of why invasive species can be so successful in newly invaded ranges. PMID- 25716785 TI - A Miocene hyperdiverse crocodylian community reveals peculiar trophic dynamics in proto-Amazonian mega-wetlands. AB - Amazonia contains one of the world's richest biotas, but origins of this diversity remain obscure. Onset of the Amazon River drainage at approximately 10.5 Ma represented a major shift in Neotropical ecosystems, and proto-Amazonian biotas just prior to this pivotal episode are integral to understanding origins of Amazonian biodiversity, yet vertebrate fossil evidence is extraordinarily rare. Two new species-rich bonebeds from late Middle Miocene proto-Amazonian deposits of northeastern Peru document the same hyperdiverse assemblage of seven co-occurring crocodylian species. Besides the large-bodied Purussaurus and Mourasuchus, all other crocodylians are new taxa, including a stem caiman Gnatusuchus pebasensis-bearing a massive shovel-shaped mandible, procumbent anterior and globular posterior teeth, and a mammal-like diastema. This unusual species is an extreme exemplar of a radiation of small caimans with crushing dentitions recording peculiar feeding strategies correlated with a peak in proto Amazonian molluscan diversity and abundance. These faunas evolved within dysoxic marshes and swamps of the long-lived Pebas Mega-Wetland System and declined with inception of the transcontinental Amazon drainage, favouring diversification of longirostrine crocodylians and more modern generalist-feeding caimans. The rise and demise of distinctive, highly productive aquatic ecosystems substantially influenced evolution of Amazonian biodiversity hotspots of crocodylians and other organisms throughout the Neogene. PMID- 25716786 TI - New insights on postglacial colonization in western Europe: the phylogeography of the Leisler's bat (Nyctalus leisleri). AB - Despite recent advances in the understanding of the interplay between a dynamic physical environment and phylogeography in Europe, the origins of contemporary Irish biota remain uncertain. Current thinking is that Ireland was colonized post glacially from southern European refugia, following the end of the last glacial maximum (LGM), some 20 000 years BP. The Leisler's bat (Nyctalus leisleri), one of the few native Irish mammal species, is widely distributed throughout Europe but, with the exception of Ireland, is generally rare and considered vulnerable. We investigate the origins and phylogeographic relationships of Irish populations in relation to those across Europe, including the closely related species N. azoreum. We use a combination of approaches, including mitochondrial and nuclear DNA markers, in addition to approximate Bayesian computation and palaeo-climatic species distribution modelling. Molecular analyses revealed two distinct and diverse European mitochondrial DNA lineages, which probably diverged in separate glacial refugia. A western lineage, restricted to Ireland, Britain and the Azores, comprises Irish and British N. leisleri and N. azoreum specimens; an eastern lineage is distributed throughout mainland Europe. Palaeo-climatic projections indicate suitable habitats during the LGM, including known glacial refugia, in addition to potential novel cryptic refugia along the western fringe of Europe. These results may be applicable to populations of many species. PMID- 25716787 TI - Genome reorganization in F1 hybrids uncovers the role of retrotransposons in reproductive isolation. AB - Interspecific hybridization leads to new interactions among divergent genomes, revealing the nature of genetic incompatibilities having accumulated during and after the origin of species. Conflicts associated with misregulation of transposable elements (TEs) in hybrids expectedly result in their activation and genome-wide changes that may be key to species boundaries. Repetitive genomes of wild wheats have diverged under differential dynamics of specific long terminal repeat retrotransposons (LTR-RTs), offering unparalleled opportunities to address the underpinnings of plant genome reorganization by selfish sequences. Using reciprocal F1 hybrids between three Aegilops species, restructuring and epigenetic repatterning was assessed at random and LTR-RT sequences with amplified fragment length polymorphism and sequence-specific amplified polymorphisms as well as their methylation-sensitive counterparts, respectively. Asymmetrical reorganization of LTR-RT families predicted to cause conflicting interactions matched differential survival of F1 hybrids. Consistent with the genome shock model, increasing divergence of merged LTR-RTs yielded higher levels of changes in corresponding genome fractions and lead to repeated reorganization of LTR-RT sequences in F1 hybrids. Such non-random reorganization of hybrid genomes is coherent with the necessary repression of incompatible TE loci in support of hybrid viability and indicates that TE-driven genomic conflicts may represent an overlooked factor supporting reproductive isolation. PMID- 25716788 TI - Phylogenomic resolution of scorpions reveals multilevel discordance with morphological phylogenetic signal. AB - Scorpions represent an iconic lineage of arthropods, historically renowned for their unique bauplan, ancient fossil record and venom potency. Yet, higher level relationships of scorpions, based exclusively on morphology, remain virtually untested, and no multilocus molecular phylogeny has been deployed heretofore towards assessing the basal tree topology. We applied a phylogenomic assessment to resolve scorpion phylogeny, for the first time, to our knowledge, sampling extensive molecular sequence data from all superfamilies and examining basal relationships with up to 5025 genes. Analyses of supermatrices as well as species tree approaches converged upon a robust basal topology of scorpions that is entirely at odds with traditional systematics and controverts previous understanding of scorpion evolutionary history. All analyses unanimously support a single origin of katoikogenic development, a form of parental investment wherein embryos are nurtured by direct connections to the parent's digestive system. Based on the phylogeny obtained herein, we propose the following systematic emendations: Caraboctonidae is transferred to Chactoidea new superfamilial assignment: ; superfamily Bothriuroidea revalidated: is resurrected and Bothriuridae transferred therein; and Chaerilida and Pseudochactida are synonymized with Buthida new parvordinal synonymies: . PMID- 25716789 TI - Loss of Drosophila pheromone reverses its role in sexual communication in Drosophila suzukii. AB - The Drosophila pheromone cis-11-octadecenyl acetate (cVA) is used as pheromone throughout the melanogaster group and fulfils a primary role in sexual and social behaviours. Here, we found that Drosophila suzukii, an invasive pest that oviposits in undamaged ripe fruit, does not produce cVA. In fact, its production site, the ejaculatory bulb, is atrophied. Despite loss of cVA production, its receptor, Or67d, and cognate sensillum, T1, which are essential in cVA-mediated behaviours, were fully functional. However, T1 expression was dramatically reduced in D. suzukii, and the corresponding antennal lobe glomerulus, DA1, minute. Behavioural responses to cVA depend on the input balance of Or67d neurons (driving cVA-mediated behaviours) and Or65a neurons (inhibiting cVA-mediated behaviours). Accordingly, the shifted input balance in D. suzukii has reversed cVA's role in sexual behaviour: perfuming D. suzukii males with Drosophila melanogaster equivalents of cVA strongly reduced mating rates. cVA has thus evolved from a generic sex pheromone to a heterospecific signal that disrupts mating in D. suzukii, a saltational shift, mediated through offsetting the input balance that is highly conserved in congeneric species. This study underlines that dramatic changes in a species' sensory preference can result from rather 'simple' numerical shifts in underlying neural circuits. PMID- 25716790 TI - Rapid, generalized adaptation to asynchronous audiovisual speech. AB - The brain is adaptive. The speed of propagation through air, and of low-level sensory processing, differs markedly between auditory and visual stimuli; yet the brain can adapt to compensate for the resulting cross-modal delays. Studies investigating temporal recalibration to audiovisual speech have used prolonged adaptation procedures, suggesting that adaptation is sluggish. Here, we show that adaptation to asynchronous audiovisual speech occurs rapidly. Participants viewed a brief clip of an actor pronouncing a single syllable. The voice was either advanced or delayed relative to the corresponding lip movements, and participants were asked to make a synchrony judgement. Although we did not use an explicit adaptation procedure, we demonstrate rapid recalibration based on a single audiovisual event. We find that the point of subjective simultaneity on each trial is highly contingent upon the modality order of the preceding trial. We find compelling evidence that rapid recalibration generalizes across different stimuli, and different actors. Finally, we demonstrate that rapid recalibration occurs even when auditory and visual events clearly belong to different actors. These results suggest that rapid temporal recalibration to audiovisual speech is primarily mediated by basic temporal factors, rather than higher-order factors such as perceived simultaneity and source identity. PMID- 25716792 TI - Enalikter aphson is more likely an annelid than an arthropod: a comment to Siveter et al. (2014). PMID- 25716791 TI - Mechanical sensitivity reveals evolutionary dynamics of mechanical systems. AB - A classic question in evolutionary biology is how form-function relationships promote or limit diversification. Mechanical metrics, such as kinematic transmission (KT) in linkage systems, are useful tools for examining the evolution of form and function in a comparative context. The convergence of disparate systems on equivalent metric values (mechanical equivalence) has been highlighted as a source of potential morphological diversity under the assumption that morphology can evolve with minimal impact on function. However, this assumption does not account for mechanical sensitivity-the sensitivity of the metric to morphological changes in individual components of a structure. We examined the diversification of a four-bar linkage system in mantis shrimp (Stomatopoda), and found evidence for both mechanical equivalence and differential mechanical sensitivity. KT exhibited variable correlations with individual linkage components, highlighting the components that influence KT evolution, and the components that are free to evolve independently from KT and thereby contribute to the observed pattern of mechanical equivalence. Determining the mechanical sensitivity in a system leads to a deeper understanding of both functional convergence and morphological diversification. This study illustrates the importance of multi-level analyses in delineating the factors that limit and promote diversification in form-function systems. PMID- 25716793 TI - Ocean acidification with (de)eutrophication will alter future phytoplankton growth and succession. AB - Human activity causes ocean acidification (OA) though the dissolution of anthropogenically generated CO2 into seawater, and eutrophication through the addition of inorganic nutrients. Eutrophication increases the phytoplankton biomass that can be supported during a bloom, and the resultant uptake of dissolved inorganic carbon during photosynthesis increases water-column pH (bloom induced basification). This increased pH can adversely affect plankton growth. With OA, basification commences at a lower pH. Using experimental analyses of the growth of three contrasting phytoplankton under different pH scenarios, coupled with mathematical models describing growth and death as functions of pH and nutrient status, we show how different conditions of pH modify the scope for competitive interactions between phytoplankton species. We then use the models previously configured against experimental data to explore how the commencement of bloom-induced basification at lower pH with OA, and operating against a background of changing patterns in nutrient loads, may modify phytoplankton growth and competition. We conclude that OA and changed nutrient supply into shelf seas with eutrophication or de-eutrophication (the latter owing to pollution control) has clear scope to alter phytoplankton succession, thus affecting future trophic dynamics and impacting both biogeochemical cycling and fisheries. PMID- 25716796 TI - The series elastic shock absorber: tendon elasticity modulates energy dissipation by muscle during burst deceleration. AB - During downhill running, manoeuvring, negotiation of obstacles and landings from a jump, mechanical energy is dissipated via active lengthening of limb muscles. Tendon compliance provides a 'shock-absorber' mechanism that rapidly absorbs mechanical energy and releases it more slowly as the recoil of the tendon does work to stretch muscle fascicles. By lowering the rate of muscular energy dissipation, tendon compliance likely reduces the risk of muscle injury that can result from rapid and forceful muscle lengthening. Here, we examine how muscle tendon mechanics are modulated in response to changes in demand for energy dissipation. We measured lateral gastrocnemius (LG) muscle activity, force and fascicle length, as well as leg joint kinematics and ground-reaction force, as turkeys performed drop-landings from three heights (0.5-1.5 m centre-of-mass elevation). Negative work by the LG muscle-tendon unit during landing increased with drop height, mainly owing to greater muscle recruitment and force as drop height increased. Although muscle strain did not increase with landing height, ankle flexion increased owing to increased tendon strain at higher muscle forces. Measurements of the length-tension relationship of the muscle indicated that the muscle reached peak force at shorter and likely safer operating lengths as drop height increased. Our results indicate that tendon compliance is important to the modulation of energy dissipation by active muscle with changes in demand and may provide a mechanism for rapid adjustment of function during deceleration tasks of unpredictable intensity. PMID- 25716795 TI - Bypass of genetic constraints during mutator evolution to antibiotic resistance. AB - Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a beta lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness. PMID- 25716797 TI - Did shifting seawater sulfate concentrations drive the evolution of deep-sea methane-seep ecosystems? AB - The origin and evolution of the faunas inhabiting deep-sea hydrothermal vents and methane seeps have been debated for decades. These faunas rely on a local source of sulfide and other reduced chemicals for nutrition, which spawned the hypothesis that their evolutionary history is independent from that of photosynthesis-based food chains and instead driven by extinction events caused by deep-sea anoxia. Here I use the fossil record of seep molluscs to show that trends in body size, relative abundance and epifaunal/infaunal ratios track current estimates of seawater sulfate concentrations through the last 150 Myr. Furthermore, the two main faunal turnovers during this time interval coincide with major changes in seawater sulfate concentrations. Because sulfide at seeps originates mostly from seawater sulfate, variations in sulfate concentrations should directly affect the base of the food chain of this ecosystem and are thus the likely driver of the observed macroecologic and evolutionary patterns. The results imply that the methane-seep fauna evolved largely independently from developments and mass extinctions affecting the photosynthesis-based biosphere and add to the growing body of evidence that the chemical evolution of the oceans had a major impact on the evolution of marine life. PMID- 25716799 TI - Erratum. PMID- 25716798 TI - Closed form modeling of evolutionary rates by exponential Brownian functionals. AB - Accurate estimation of species divergence times from the analysis of genetic sequences relies on probabilistic models of evolution of the rate of molecular evolution. Importantly, while these models describe the sample paths of the substitution rates along a phylogenetic tree, only the (random) average rate can be estimated on each edge. For mathematical convenience, the stochastic nature of these averages is generally ignored. In this article we derive the probabilistic distribution of the average substitution rate assuming a geometric Brownian motion for the sample paths, and we investigate the corresponding error bounds via numerical simulations. In particular we confirm the validity of the gamma approximation proposed in Guindon (Syst Biol 62(1):22-34, 2013) for "small" values of the autocorrelation parameter. PMID- 25716800 TI - Solid variant type of serous cystadenocarcinoma of the pancreas: a case report and review of the literature. AB - Serous cystic neoplasms (SCN) of the pancreas are typically honeycombed microcystic masses, which are believed to be benign entity. This report describes a case of a 69-year-old man with a rare solid type of serous cystadenocarcinoma of the pancreas with liver metastases. A 6-cm well enhanced pancreatic tumor and multiple liver nodules were depicted with contrast medium on computed tomography scan. Distal pancreatectomy was performed at first operation. The cut surface of the tumor was solid and glossy appearance. Second operation of liver resection for all metastatic nodules was performed 27 months after the initial operation. The tumor cells in both the pancreas and the liver had cytoplasmic periodic acid Schiff positive granules, which were completely digested by diastase. Eleven cases of serous cystadenocarcinoma of the pancreas have been reported in the literature. To our knowledge, this is the first case of a solid type serous cystadenocarcinoma. PMID- 25716802 TI - Continuous colorimetric assay that enables high-throughput screening of N acetylamino acid racemases. AB - N-Acetyl amino acid racemases (NAAARs) have demonstrated their potential in the enzymatic synthesis of chiral amino acids, molecules of significant biotechnology interest. In order to identify novel activities and to improve these enzymes by engineering approaches, suitable screening methods are necessary. Previous engineering of the NAAAR from Amycolatopsis Ts-1-60 was achieved by relying on an in vivo selection system that linked the viability of an E. coli L-methionine auxotroph to the activity of the improved enzyme. However, this assay was only suitable for the screening of N-acetyl-D-methionine, therefore limiting the potential to evolve this enzyme toward other natural or non-natural acetylated amino acids. Here, we report the optimization and application of a spectrophotometric microtiter-plate-based assay for NAAAR. The assay is based on the detection of the amino acid reaction product formed by hydrolysis of the N acylated substrate by an L-amino acid acylase and its subsequent oxidation by an FAD-dependent L-amino acid oxidase (L-AAO). Cofactor recycling of the L-AAO leads to the formation of hydrogen peroxide which is easily monitored using horseradish peroxidase (HRP) and o-dianisidine. This method allowed for the determination of the kinetic parameters of NAAAR and led to the identification of N-acetyl-D naphthylalanine as a novel NAAAR substrate. This robust method is also suitable for the high-throughput screening of NAAAR mutant gene libraries directly from cell lysates. PMID- 25716801 TI - Induced pluripotent stem cells as a model for diabetes investigation. AB - Mouse and human induced pluripotent stem cells (iPSCs) may represent a novel approach for modeling diabetes. Taking this into consideration, the aim of this study was to generate and evaluate differentiation potential of iPSCs from lep(db/db) (db/db) mice, the model of diabetes type 2 as well as from patients with Maturity Onset Diabetes of the Young 3 (HNF1A MODY). Murine iPSC colonies from both wild type and db/db mice were positive for markers of pluripotency: Oct3/4A, Nanog, SSEA1, CDy1 and alkaline phosphatase and differentiated in vitro and in vivo into cells originating from three germ layers. However, our results suggest impaired differentiation of db/db cells into endothelial progenitor-like cells expressing CD34 and Tie2 markers and their reduced angiogenic potential. Human control and HNF1A MODY reprogrammed cells also expressed pluripotency markers: OCT3/4A, SSEA4, TRA-1-60, TRA-1-81, formed embryoid bodies (EBs) and differentiated into cells of three germ layers. Additionally, insulin expressing cells were obtained from those partially reprogrammed cells with direct as well as EB-mediated differentiation method. Our findings indicate that disease specific iPSCs may help to better understand the mechanisms responsible for defective insulin production or vascular dysfunction upon differentiation toward cell types affected by diabetes. PMID- 25716803 TI - Effect of partial covering of the visitor viewing area window on positioning and orientation of zoo orangutans: A preference test. AB - The window of the visitor viewing area adjacent to an animal platform in an orangutan enclosure was altered to produce three viewing treatments in a randomized controlled experiment. These treatments were window uncovered, left side of the window covered or right side of the window covered. Observations were conducted on the orangutans present on the platform, and on their location (left or right side), and orientation (towards or away from the window) while on the platform. The partial covering of the window had little effect on the proportion of time orangutans spent on the viewing platform, or on the direction they faced when on the platform. When the orangutans were facing towards the window, and the right side was uncovered, irrespective of whether the left side was covered, they spent about three quarters of the time on the right side, suggesting a preference for the right side of the platform. However, when the right side was covered and the left side uncovered, the animals facing towards the window spent only about a quarter of the time on the right side, that is, they spent more time on the uncovered side. The results suggest that the orangutans have a preference to position themselves to face the window of the visitor viewing area. PMID- 25716804 TI - Induction of PERV antigen in porcine peripheral blood mononuclear cells by human herpesvirus 1. AB - BACKGROUND: Xenotransplantation represents one of alternative candidates for allotransplantation due to the chronic shortage of suitable human tissues; however, many obstacles remain. Expression and release of endogenous retroviral antigens by porcine cells after transplantation may evoke adverse immune responses in human subjects. Here, we examined whether human herpesvirus 1 (HHV 1) could induce the production of porcine endogenous retrovirus (PERV) antigens in porcine peripheral blood mononuclear cells (PBMCs). METHODS: Porcine PBMCs were infected with HHV-1 and examined for the production of PERV Gag protein and HHV-1 using antigen-capture ELISA and quantitative real-time polymerase chain reaction (PCR), respectively. RESULTS: HHV-1 infection resulted in a 1.7- to 33.2 fold induction of PERV Gag relative to mock infection controls, compared to a 2.9 to 12.9-fold induction following treatment with PMA. Expression of PERV Gag was detected in porcine PBMCs and PK-15 cells after HHV-1 infection by double immunofluorescence staining of PERV Gag and HHV-1 antigen. The viability of HHV-1 infected porcine PBMCs was significantly lower than that of mock-infected cells. The HHV-1 level in the culture supernatant increased 5.2-fold relative to controls 24-h post-infection, indicative of active replication within these cells; decreased levels of HHV-1 were detected 72-h post-infection. CONCLUSIONS: These results suggest that HHV-1 may be capable of infecting transplanted porcine cells, resulting in strong direct induction of PERV antigen. PMID- 25716805 TI - [Current Topics on Vitamin D. Mechanism of molecular action of vitamin D via its nuclear receptor]. AB - Most of vitamin D actions mediate expression of target genes regulated by nuclear vitamin D receptor (VDR). Regulation of chromatin environment has emerged to underlie gene regulation by liganded VDR. Active state of chromatin is defined by specific combination of post-translational modification of histone proteins, and chromatin remodelers as nuclear complexes conduct dynamic shift of chromatin sate. Among histone modifications, methylations of specific lysine residues located in the N-terminal tails of histone H3 are known to play pivotal roles in directing chromatin state, and the methylated lysine 4 and 9 in the histone H3 (H3K4me and H3K9me) are widely used as indicators of chromatin state. The histone modifying enzymes and chromatin remodelers are thus regulators for chromatin environment, and overtly co-regulate transcriptional regulations of a particular set of target genes by nuclear receptors including VDR. In this review, the molecular mechanism of regulated chromatin configuration is described by illustrating modifications of histone proteins and rearrangements of nucleosome array and their regulators. PMID- 25716806 TI - [Current Topics on Vitamin D. Cross talks among vitamin D endocrine system, PTH and FGF23]. AB - 1,25-dihydroxyvitamin D and parathyroid hormone have been known to be essential for maintaining serum calcium and phosphate levels. In addition, fibroblast growth factor 23 was shown to work as a phosphotropic hormone. These hormones work through activating different intracellular signaling pathways, but regulate their productions each other directly or indirectly via changes in serum mineral levels. Fine regulation of these hormone actions seems to be essential for maintaining serum mineral levels. PMID- 25716807 TI - [Current Topics on Vitamin D. Evolution of animals and vitamin D]. AB - Vitamin D3 is already found in the early evolution of life, but essentially as inactive products of the photochemical reaction of 7-dehydrocholesterol. The full vitamin D endocrine system characterized by the specific vitamin D transport protein (DBP) , specific vitamin D-metabolizing CYP P450 enzymes, active vitamin D metabolites, 1alpha,25 (OH) 2D3, specific vitamin D nuclear receptor (VDR), and fibroblast growth factor 23 (FGF23) became essential for maintaining calcium and bone homeostasis in terrestrial animals cope with the challenging of higher gravity and calcium-poor environment. The present review describes the story about the evolution of animals and vitamin D. PMID- 25716808 TI - [Current Topics on Vitamin D. The effects of vitamin D on the immune system]. AB - Various kinds of immune cells-including macrophages, dendritic cells, T cells and B cells- express the vitamin D receptor and 1alpha-hydroxylase (CYP27B1), the enzyme necessary for the conversion of circulating 25-hydroxyvitamin D into its active form, 1,25-dihydroxyvitamin D. It suggests that vitamin D has a regulatory role on innate and adaptive immune responses. Vitamin D has been recently shown to promote antimicrobial responses through the production of antibacterial peptides, and stimulation of the autophagic activity in macrophages. Recent epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of several infectious diseases. Here, we review the essential roles of vitamin D in modulating the immune system and discuss the protective effects of vitamin D supplementation in diverse infections. PMID- 25716809 TI - [Current Topics on Vitamin D. The vitamin D functions in keratinocytes and its therapeutic applications]. AB - 1,25 (OH) 2D and calcium have been shown to promote epidermal keratinocyte differentiation and prevent proliferation. These prodifferentiation and antiproliferative effects of 1,25 (OH) 2D have led to its clinical use in the treatment of psoriasis. However, the mechanism of vitamin D action on keratinocytes remains largely unknown. While the actions of calcium and the vitamin D receptor signaling pathways on epidermal keratinocyte differentiation are redundant, their effects on the hair follicle are not. In this review, we discuss how the vitamin D and its receptor contribute to skin and hair follicle homeostasis. PMID- 25716810 TI - [Current Topics on Vitamin D. Anti-cancer effects of vitamin D]. AB - Epidemiological studies have revealed that vitamin D deficiency increases the risk of cancer development and is associated with its poor prognosis. In the classical view of calcium metabolism, vitamin D is activated by CYP27B1 in the kidney and promotes calcium absorption in the intestine as a hormone. Besides such a classical role, vitamin D is known to exert multiple extra-skeletal actions through CYP27B1 and vitamin D receptor (VDR) that is expressed in a wide variety of extra-renal tissues and cell types. As one of its "non-classical" actions, vitamin D has been shown to have anti-cancer activity by various mechanisms including inhibition of cellular proliferation, induction of apoptosis, stimulation of differentiation, suppression of tumor invasion, metastasis, and angiogenesis. Despite numerous promising results at the cellular and animal levels, clinical trials have so far failed to provide definitive evidence for anti-cancer effect of vitamin D. PMID- 25716811 TI - [Current Topics on Vitamin D. Influences of vitamin D on muscle cells and function]. AB - Vitamin D deficiency is associated with sarcopenia, which is characterized by the decrease in muscle mass and the muscle weakness. Active form of vitamin D binds to nuclear or non-nuclear vitamin D receptor (VDR) and regulates the proliferation and differentiation of myoblasts through its genomic or non-genomic actions. Clinical evidence showed the beneficial effects of vitamin D treatment on muscle mass and function in older people. Recent studies suggest that vitamin D is associated with the preservation of muscle function related to the interactions between bone and muscle. PMID- 25716812 TI - [Current Topics on Vitamin D. Protein interaction and biological action of active vitamin D compounds]. AB - To express its biological action, active vitamin D3 (1alpha,25-dihydroxyvitamin D3) interacts with three proteins : vitamin D binding protein (DBP), vitamin D receptor (VDR), and CYP24A1. This article explains how eldecalcitol interacts with these three proteins to achieve its mode of action. The main feature of eldecalcitol's molecular structure is the 3-hydroxypropyloxy group (3-HP group) at the 2beta-position. When interacting with DBP, eldecalcitol tightly binds to DBP via the 3-HP group and enhances systemic stability of eldecalcitol. By binding to VDR, the 3-HP group stabilizes the eldecalcitol-VDR complex, which leads to high efficacy. The 3-HP group also interferes with the binding to CYP24A1, which induces residence to CYP24A1 and liver metabolism. These protein interactions constitute the mode of action of eldecalcitol. PMID- 25716813 TI - [Current Topics on Vitamin D. The role of active forms of vitamin D in regulation of bone remodeling]. AB - Active forms of vitamin D3 have been widely used in the treatment of rickets, osteomalacia, and osteoporosis in order to stimulate bone mineralization and prevent bone loss. Meanwhile, the active form of vitamin D3, 1alpha, 25 dihydroxyvitamin D3 [1alpha, 25 (OH) 2D3], upregulates expression of receptor activator of nuclear factor-kappaB ligand (RANKL) in osteoblastic cells. Osteoclast formation requires RANKL and macrophage colony-stimulating factor (M CSF), which are expressed in osteoblastic cells. Recently, IL-34 was discovered as a cytokine functionally overlapping M-CSF. We found that administration of 1alpha, 25 (OH) 2D3 into mice enhanced IL-34 expression in spleen and bone. These results suggest that 1alpha, 25 (OH) 2D3 is a bone resorption-stimulating factor. However, daily administration of an active vitamin D3 analog (eldecalcitol, an osteoporotic therapeutic drug) for a month suppressed RANKL expression in osteoblasts, resulting in suppression of bone resorption. Here we discuss new findings and hypotheses to explain this contradictory effect of active vitamin D3 on bone remodeling. PMID- 25716814 TI - [Current Topics on Vitamin D. Nonsecosteroidal vitamin D mudulators and prospects for their thepapeutic application]. AB - Vitamin D is a secosteroid, in which the B ring of the steroid structure is ruptured. The active form of vitamin D, 1alpha, 25-dihydroxyvitamin D3 [1,25 (OH) 2D3], regulates numerous physiological and pharmacological processes, including bone and calcium homeostasis, cellular growth and differentiation, immunity, and cardiovascular function, through binding to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily. VDR ligands are promising in the treatment of bone and mineral disorders, cancer, autoimmune disease, and cardiovascular disease. However, the calcemic effect of vitamin D derivatives has limited their clinical application. Recently, nonsecosteroidal VDR modulators (VDRMs) have been developed. Several VDRMs have better therapeutic efficacy when compared to 1,25 (OH) 2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia. Analysis of crystal structures reveals that nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25 (OH) 2D3 and that hydrogen bond interactions between ligands and VDR are important for VDR transactivation. Pharmacokinetics of nonsecosteroidal VDRMs may be related to their less calcemic effect. Nonsecosteroidal VDRMs can induce VDR conformation distinct from that by 1,25 (OH) 2D3, likely leading to selective gene expression. Although the potential risk of unexpected adverse effects needs be considered, further development of nonsecosteroidal VDRMs should expand the possibility of VDR-targeted approaches. PMID- 25716815 TI - [Current Topics on Vitamin D. Vitamin D and chronic kidney disease]. AB - CKD-MBD is a new clinical concept which defines a systemic disorder of mineral and bone metabolism as a result of CKD. Although various mineral metabolic factors are involved in its pathogenesis, alteration in vitamin D metabolism plays a crucial role among them. Vitamin D receptor activators (VDRAs), which are traditionally considered a cardinal treatment of secondary hyperparathyroidism, have attracted lots of attention for their potential pleiotropic effects through the activation of the vitamin D receptor expressed in multiple organs. In recent years, the deficiency of vitamin D in CKD patients also has received growing interest. The serum 25 (OH) D levels are considered as a useful prognostic marker, and the significances of nutritional vitamin D supplementation are reviewed from a new perspective. PMID- 25716816 TI - [Current Topics on Vitamin D. Treatment of osteoporosis with eldecalcitol: Its therapeutic efficacy and adverse effect on renal function]. AB - Eldecalcitol, a newly developed active vitamin D3 analogue, has an inhibitory effect on bone resorption through disruption of osteoclast formation. In a double blind randomized controlled trial in Japanese patients with osteoporosis, eldecalcitol has been shown to increase bone mineral density and to decrease the incidence of vertebral fractures more effectively than alfacalcidol, an authentic active vitamin D3 analogue for treatment of osteoporosis. In general, long-term use of eldecalcitol seems to be safe ; however, it occasionally might develop hypercalcemia and serious renal impairment as does alfacalcidol. To prevent the adverse event, serum calcium and creatinine levels should be monitored routinely during the treatment with eldecalcitol. PMID- 25716817 TI - [Current Topics on Vitamin D. Combined therapy of anti-resorptive drug and active vitamin D]. AB - Combination therapy of oral bisphosphonate and vitamin D analogue showed superior anti-osteoporotic effect compare to bisphosphonate mono-therapy for post menopausal, male and glucocorticoid-induced osteoporosis. Furthermore, the degree of success of oral bisphosphonate therapy for osteoporotic patients should depend on the their vitamin D status. It is thought that we have to evaluate severity of osteoporosis and vitamin D status before started therapy. The combination therapy of these drugs will be more efficient for relatively patients with severe osteoporotic patients and with low vitamin D status. PMID- 25716818 TI - A rapidly enlarging swelling of the left orbit. PMID- 25716819 TI - Relationships between wheat grain physical characteristics studied through near isogenic lines with distinct puroindoline-b allele. AB - KEY MESSAGE: Genetic (different forms of puroindoline-b) and environment (through variations in vitreousness), have important effects on wheat grain mechanical properties. The two methods of hardness measurements (NIRS, SKCS) do not give the same information. Bread wheat near-isogenic lines differing in hardness, due to distinct puroindoline-b alleles (the wild type, Pinb-D1a, or the mutated forms, Pinb-D1b or Pinb-D1d), were grown for three years in seven sites and under two nitrogen fertilization levels, to study genetic and environmental effects on grain mechanical properties. Two methods, Near-Infrared Reflectance Spectroscopy (NIRS) and Single Kernel Characterization System (SKCS), currently used for grain hardness characterization, were carried out. Grain vitreousness, which is known to affect the grain mechanical behavior but is generally not studied, was also measured, as well as three other characters (Thousand Grain Weight, Test Weight and protein content). The relationships between the different characters were studied. Results revealed a clear effect of the different Pinb-D1 alleles on NIRS hardness, and a marked impact of the environmental conditions on vitreousness. SKCS hardness was influenced by both Pinb-D1 alleles and environmental conditions. The relationship between SKCS and NIRS hardness was strong when considering together soft and hard genotypes, but moderate within a class of genetical hardness. Vitreousness had only a weak effect on NIRS hardness, whereas vitreousness and SKCS values were strongly correlated, with two distinct regressions for soft and hard genotypes. Vitreousness was positively related to protein content, especially in the case of hard genotypes, which were able to reach high vitreousness values never observed for soft genotypes. PMID- 25716820 TI - Addition of rye chromosome 4R to wheat increases anther length and pollen grain number. AB - KEY MESSAGE: The research identified rye chromosome 4R arms associated with good pollinator traits, and demonstrated possible use of rye genetic resources to develop elite pollinators for hybrid wheat breeding. Bread wheat (Triticum aestivum) is a predominantly self-pollinating plant which has relatively small sized anthers and produces a low number of pollen grains. These features limit the suitability of most wheat lines as pollinators for hybrid seed production. One strategy for improving the pollination ability of wheat is to introgress cross-pollination traits from related species. One such species is rye (Secale cereale L.), which has suitable traits such as high anther extrusion, long anthers containing large amounts of pollen and long pollen viability. Therefore, introducing these traits into wheat is of great interest in hybrid wheat breeding. Here, we investigated wheat-rye chromosome addition lines for the effects of rye chromosomes on anther and pollen development in wheat. Using a single nucleotide polymorphism genotyping array, we detected 984 polymorphic markers that showed expected syntenic relationships between wheat and rye. Our results revealed that the addition of rye chromosomes 1R or 2R reduced pollen fertility, while addition of rye chromosome 4R increased anther size by 16% and pollen grain number by 33%. The effect on anther length was associated with increases in both cell size and the number of endothecium cells and was attributed to the long arm of chromosome 4R. In contrast, the effect on pollen grain number was attributed to the short arm of chromosome 4R. These results indicate that rye chromosome 4R contains at least two genetic factors associated with increased anther size and pollen grain number that can favourably affect pollination traits in wheat. PMID- 25716821 TI - Small subunit ribosomal RNA sequence links the myxospore stage of Henneguya mississippiensis n. sp. from channel catfish Ictalurus punctatus to an actinospore released by the benthic oligochaete Dero digitata. AB - There are more than 200 species of Henneguya described from fish. Of these, only three life cycles have been determined, identifying the actinospore and myxospore stages from their respective hosts. Two of these life cycles involve the channel catfish (Ictalurus punctatus) and the freshwater oligochaete Dero digitata. Herein, we molecularly confirm the life cycle of a previously undescribed Henneguya sp. by matching 18S ribosomal RNA (rRNA) gene sequence of the myxospore stage from channel catfish with the previously described actinospore stage (Aurantiactinomyxon mississippiensis) from D. digitata. Gill tissue from naturally infected channel catfish contained pseudocysts restricted to the apical end of the primary lamellae. Myxospores were morphologically consistent with Henneguya spp. from ictalurid fishes in North America. The spores measured 48.8 +/- 4.8 MUm (range = 40.7-61.6 MUm) in total spore length. The lanceolate spore body was 17.1 +/- 1.0 MUm (14.4-19.3 MUm) in length and 5.0 +/- 0.3 MUm (4.5-5.5 MUm) in width. The two polar capsules were 6.2 +/- 0.4 MUm (5.8-7.0 MUm) long and 5.0 +/- 0.3 MUm (4.5-5.5 MUm) wide. The polar capsule contained eight to nine coils in the polar filament. The two caudal processes were of equal length, measuring 31.0 +/- 4.1 MUm (22.9-40.6 MUm). The 1980-bp 18S rRNA gene sequence obtained from two excised cysts shared 99.4% similarity (100% coverage) to the published sequence of A. mississippiensis, an actinospore previously described from D. digitata. The sequence similarity between the myxospore from channel catfish and actinospore from D. digitata suggests that they are conspecific, representing alternate life stages of Henneguya mississippiensis n. sp. PMID- 25716823 TI - Cosmetic Surgery National Data Bank statistics. PMID- 25716822 TI - Ex vivo effectiveness of French over-the-counter products against head lice (Pediculus humanus capitis De Geer, 1778). AB - Head lice infestation is still a public health problem worldwide, with an intracountry and intercountry prevalence variation of 0.7 to 59%. There is a large variety of over-the-counter anti-louse products, but their efficacy is not always well assessed. Our objective was to test the pediculicidal and ovicidal efficacy of 21 over-the-counter head louse products, available in France during the period of 2008 to 2012. We tested children living in Tours City in central France and visiting preschools, primary schools, kindergarten, camps, and child care facilities, as well as children in their family houses, and were examined for the presence of lice. The products were collected from randomly selected pharmacies by covert investigators and then tested in the laboratory on an ex vivo sample of head lice and their eggs, collected from the hair of infested children. Living lice and unharmed eggs were collected from the scalps of 3-12 years old. The laboratory conditions for ex vivo testing mimicked the manufacturers' instructions for exposure time and application method. In 21 runs, 3919 living lice and 4321 undamaged living eggs were collected from the scalp of over 400 children. The 21 products were classified in three groups: 6 products in a group of potentially 100% pediculicidal activity and potentially 100% ovicidal activity, 8 products in a group of potentially 100% pediculicidal activity but insufficient ovicidal activity (including 2 products with claims of single application treatment), and 7 products in a group of insufficient pediculicidal activity and ovicidal activity. The pharmaceutical market for head lice products in France is swamped with poorly tested and ineffective products. Rigorous efficacy testing preregistration and periodic screening and testing of effectiveness in the post-registration period should be endorsed by the health authorities. PMID- 25716824 TI - Studies on Intramuscular Fat Percentage in Live Swine Using Real-time Ultrasound to Determine Pork Quality. AB - In the modern pork industry, selection of high intramuscular fat (IMF) in pigs is necessary to improve pork quality. Ultrasound has been used previously to predict subcutaneous fat thickness and IMF in the longissimus muscles of line pigs and Real-time ultrasound has also been reported as a reliable method for estimating IMF in live pigs. So we estimate the correlation between meat quality traits and IMF percentage to investigate the possibility of utilizing real-time ultrasound technology for predicting IMF percentage in line pigs to improve pork quality. The genetic and phenotypic correlations for chemical intramuscular fat (CIMF) and ultrasound intramuscular fat (UIMF) were estimated to be 0.75 and 0.76, respectively. These results suggest that genetic factors strongly influence meat quality. The genetic and phenotypic correlation between UIMF and CIMF were 0.75, 0.76, respectively. The heritability of UIMF and CIMF were 0.48 and 0.50, respectively. So we concluded that CIMF can be replaced with UIMF and Ultrasound machines can be used to test IMF in live swine. In future, UIMF can be utilized to improve pork quality as an alternative to CIMF. PMID- 25716825 TI - Erratum. PMID- 25716826 TI - Genome evolution in the primary endosymbiont of whiteflies sheds light on their divergence. AB - Whiteflies are important agricultural insect pests, whose evolutionary success is related to a long-term association with a bacterial endosymbiont, Candidatus Portiera aleyrodidarum. To completely characterize this endosymbiont clade, we sequenced the genomes of three new Portiera strains covering the two extant whitefly subfamilies. Using endosymbiont and mitochondrial sequences we estimated the divergence dates in the clade and used these values to understand the molecular evolution of the endosymbiont coding sequences. Portiera genomes were maintained almost completely stable in gene order and gene content during more than 125 Myr of evolution, except in the Bemisia tabaci lineage. The ancestor had already lost the genetic information transfer autonomy but was able to participate in the synthesis of all essential amino acids and carotenoids. The time of divergence of the B. tabaci complex was much more recent than previous estimations. The recent divergence of biotypes B (MEAM1 species) and Q (MED species) suggests that they still could be considered strains of the same species. We have estimated the rates of evolution of Portiera genes, synonymous and nonsynonymous, and have detected significant differences among-lineages, with most Portiera lineages evolving very slowly. Although the nonsynonymous rates were much smaller than the synonymous, the genomic dN/dS ratios were similar, discarding selection as the driver of among-lineage variation. We suggest variation in mutation rate and generation time as the responsible factors. In conclusion, the slow evolutionary rates of Portiera may have contributed to its long-term association with whiteflies, avoiding its replacement by a novel and more efficient endosymbiont. PMID- 25716827 TI - Insights on the emergence of Mycobacterium tuberculosis from the analysis of Mycobacterium kansasii. AB - By phylogenetic analysis, Mycobacterium kansasii is closely related to Mycobacterium tuberculosis. Yet, although both organisms cause pulmonary disease, M. tuberculosis is a global health menace, whereas M. kansasii is an opportunistic pathogen. To illuminate the differences between these organisms, we have sequenced the genome of M. kansasii ATCC 12478 and its plasmid (pMK12478) and conducted side-by-side in vitro and in vivo investigations of these two organisms. The M. kansasii genome is 6,432,277 bp, more than 2 Mb longer than that of M. tuberculosis H37Rv, and the plasmid contains 144,951 bp. Pairwise comparisons reveal conserved and discordant genes and genomic regions. A notable example of genomic conservation is the virulence locus ESX-1, which is intact and functional in the low-virulence M. kansasii, potentially mediating phagosomal disruption. Differences between these organisms include a decreased predicted metabolic capacity, an increased proportion of toxin-antitoxin genes, and the acquisition of M. tuberculosis-specific genes in the pathogen since their common ancestor. Consistent with their distinct epidemiologic profiles, following infection of C57BL/6 mice, M. kansasii counts increased by less than 10-fold over 6 weeks, whereas M. tuberculosis counts increased by over 10,000-fold in just 3 weeks. Together, these data suggest that M. kansasii can serve as an image of the environmental ancestor of M. tuberculosis before its emergence as a professional pathogen, and can be used as a model organism to study the switch from an environmental opportunistic pathogen to a professional host-restricted pathogen. PMID- 25716829 TI - The role of right anterior insula and salience processing in inhibitory control. PMID- 25716828 TI - Genome sequence, comparative analysis, and evolutionary insights into chitinases of entomopathogenic fungus Hirsutella thompsonii. AB - Hirsutella thompsonii (Ht) is a fungal pathogen of acarines and the primary cause of epizootics among mites. The draft genomes of two isolates of Ht (MTCC 3556: Ht3, 34.6 Mb and MTCC 6686: Ht6, 34.7 Mb) are presented and compared with the genomes of Beauveria bassiana (Bb) ARSEF 2860 and Ophiocordyceps sinensis (Os) CO18. Comparative analysis of carbohydrate active enzymes, pathogen-host interaction genes, metabolism-associated genes, and genes involved in biosynthesis of secondary metabolites in the four genomes was carried out. Reduction in gene family sizes in Ht3 and Os as compared with Ht6 and Bb is observed. Analysis of the mating type genes in Ht reveals the presence of MAT idiomorphs which is suggestive of cryptic sexual traits in Ht. We further identify and classify putative chitinases that may function as virulence factors in fungal entomopathogens due to their role in degradation of arthropod cuticle. PMID- 25716830 TI - Granger causality analysis in neuroscience and neuroimaging. PMID- 25716831 TI - beta-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a beta subunit-like fashion. AB - The beta-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1 deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a beta-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain. PMID- 25716832 TI - GABAergic projections from lateral hypothalamus to paraventricular hypothalamic nucleus promote feeding. AB - Lesions of the lateral hypothalamus (LH) cause hypophagia. However, activation of glutamatergic neurons in LH inhibits feeding. These results suggest a potential importance for other LH neurons in stimulating feeding. Our current study in mice showed that disruption of GABA release from adult LH GABAergic neurons reduced feeding. LH GABAergic neurons project extensively to the paraventricular hypothalamic nucleus (PVH), and optogenetic stimulation of GABAergic LH -> PVH fibers induced monosynaptic IPSCs in PVH neurons, and potently increased feeding, which depended on GABA release. In addition, disruption of GABA-A receptors in the PVH reduced feeding. Thus, we have identified a new feeding pathway in which GABAergic projections from the LH to the PVH promote feeding. PMID- 25716833 TI - Differential role of the proteasome in the early and late phases of BDNF-induced facilitation of LTP. AB - The neurotrophin brain-derived neurotrophic factor (BDNF) mediates activity dependent long-term changes of synaptic strength in the CNS. The effects of BDNF are partly mediated by stimulation of local translation, with consequent alterations in the synaptic proteome. The ubiquitin-proteasome system (UPS) also plays an important role in protein homeostasis at the synapse by regulating synaptic activity. However, whether BDNF acts on the UPS to mediate the effects on long-term synaptic potentiation (LTP) has not been investigated. In the present study, we show similar and nonadditive effects of BDNF and proteasome inhibition on the early phase of synaptic potentiation (E-LTP) induced by theta burst stimulation of rat hippocampal CA1 synapses. The effects of BDNF were blocked by the proteasome activator IU1, suggesting that the neurotrophin acts by decreasing proteasome activity. Accordingly, BDNF downregulated the proteasome activity in cultured hippocampal neurons and in hippocampal synaptoneurosomes. Furthermore, BDNF increased the activity of the deubiquitinating enzyme UchL1 in synaptoneurosomes and upregulated free ubiquitin. In contrast to the effects on posttetanic potentiation, proteasome activity was required for BDNF-mediated LTP. These results show a novel role for BDNF in UPS regulation at the synapse, which is likely to act together with the increased translation activity in the regulation of the synaptic proteome during E-LTP. PMID- 25716834 TI - Reactive astrogliosis causes the development of spontaneous seizures. AB - Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of beta1-integrin (Itgbeta1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted beta1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl(-) gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures. PMID- 25716835 TI - Peripheral nerve injury induces persistent vascular dysfunction and endoneurial hypoxia, contributing to the genesis of neuropathic pain. AB - Nerve injury is associated with microvascular disturbance; however, the role of the vascular system has not been well characterized in the context of neuropathic pain. Furthermore, ischemia is thought to play a role in a number of neuropathic pain conditions, and yet the role of hypoxia has also not been characterized in neuropathic pain conditions. In this study, we observed the presence of persistent endoneurial hypoxia in a mouse model of traumatic peripheral nerve injury, causing painful mononeuropathy. We attribute the ongoing hypoxia to microvascular dysfunction, endoneurial fibrosis, and increased metabolic requirements within the injured nerve. Increased lactate levels were observed in injured nerves, as well as increased oxygen consumption and extracellular acidification rates, suggesting that anaerobic glycolysis is required to maintain cellular ATP levels. Hypoxia causes a reduction in levels of the Na(+)/K(+) ATPase ion transporter in both cultured primary dorsal root ganglion neurons and injured peripheral nerve. A reduction of Na(+)/K(+) ATPase ion transporter levels likely contributes to the hyperexcitability of injured nerves. Physiological antagonism of hypoxia with hyperbaric oxygen alleviated mechanical allodynia in nerve-injured animals. These results suggest that hypoxia and the Na(+)/K(+) ATPase ion transporter may be a novel mechanistic target for the treatment of neuropathic pain. In addition, the findings support the possibility of using hypoxia activated pro-drugs to localize treatments for neuropathic pain and nerve injury to injured nerves. PMID- 25716836 TI - Activity in human visual and parietal cortex reveals object-based attention in working memory. AB - Visual attention enables observers to select behaviorally relevant information based on spatial locations, features, or objects. Attentional selection is not limited to physically present visual information, but can also operate on internal representations maintained in working memory (WM) in service of higher order cognition. However, only little is known about whether attention to WM contents follows the same principles as attention to sensory stimuli. To address this question, we investigated in humans whether the typically observed effects of object-based attention in perception are also evident for object-based attentional selection of internal object representations in WM. In full accordance with effects in visual perception, the key behavioral and neuronal characteristics of object-based attention were observed in WM. Specifically, we found that reaction times were shorter when shifting attention to memory positions located on the currently attended object compared with equidistant positions on a different object. Furthermore, functional magnetic resonance imaging and multivariate pattern analysis of visuotopic activity in visual (areas V1-V4) and parietal cortex revealed that directing attention to one position of an object held in WM also enhanced brain activation for other positions on the same object, suggesting that attentional selection in WM activates the entire object. This study demonstrated that all characteristic features of object-based attention are present in WM and thus follows the same principles as in perception. PMID- 25716837 TI - Layer-specific refinement of visual cortex function after eye opening in the awake mouse. AB - The laminar structure and conserved cellular organization of mouse visual cortex provide a useful model to determine the mechanisms underlying the development of visual system function. However, the normal development of many receptive field properties has not yet been thoroughly quantified, particularly with respect to layer identity and in the absence of anesthesia. Here, we use multisite electrophysiological recording in the awake mouse across an extended period of development, starting at eye opening, to measure receptive field properties and behavioral-state modulation of responsiveness. We find selective responses for orientation, direction, and spatial frequency at eye opening, which are similar across cortical layers. After this initial similarity, we observe layer-specific maturation of orientation selectivity, direction selectivity, and linearity over the following week. Developmental increases in selectivity are most robust and similar between layers 2-4, whereas layers 5 and 6 undergo distinct refinement patterns. Finally, we studied layer-specific behavioral-state modulation of cortical activity and observed a striking reorganization in the effects of running on response gain. During week 1 after eye opening, running increases responsiveness in layers 4 and 5, whereas in adulthood, the effects of running are most pronounced in layer 2/3. Together, these data demonstrate that response selectivity is present in all layers of the primary visual cortex (V1) at eye opening in the awake mouse and identify the features of basic V1 function that are further shaped over this early developmental period in a layer-specific manner. PMID- 25716838 TI - Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. AB - Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified receptor expressed on microglia and is thought to phagocytose damaged brain cells. The precise role of TREM2 during ischemic stroke has not been fully understood. We explore TREM2 in both in vitro and in vivo stroke models and identify a potential endogenous TREM2 ligand. TREM2 knockdown in microglia reduced microglial activation to an amoeboid phenotype and decreased the phagocytosis of injured neurons. Phagocytosis and infarcted brain tissue resorption was reduced in TREM2 knock-out (KO) mice compared with wild-type (WT) mice. TREM2 KO mice also had worsened neurological recovery and decreased viable brain tissue in the ipsilateral hemisphere. The numbers of activated microglia and phagocytes in TREM2 KO mice were decreased compared with WT mice, and foamy macrophages were nearly absent in the TREM2 KO mice. Postischemia, TREM2 was highly expressed on microglia and TREM2-Fc fusion protein (used as a probe to identify potential TREM2 binding partners) bound to an unknown TREM2 ligand that colocalized to neurons. Oxygen glucose deprivation-exposed neuronal media, or cellular fractions containing nuclei or purified DNA, but not cytosolic fractions, stimulated signaling through TREM2. TREM2-Fc fusion protein pulled down nucleic acids from ischemic brain lysate. These findings establish the relevance of TREM2 in the phagocytosis of the infarcted brain and emphasize its role in influencing neurological outcomes following stroke. Further, nucleic acids may be one potential ligand of TREM2 in brain ischemia. PMID- 25716839 TI - Migraine mutations impair hippocampal learning despite enhanced long-term potentiation. AB - To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the alpha1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity-response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatial memory deficits in contextual fear conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype-phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function. PMID- 25716840 TI - Microsaccade control signals in the cerebellum. AB - Microsaccades, the small saccades made when we try to keep the eyes still, were once believed to be inconsequential for vision, but recent studies suggest that they can precisely relocate gaze to tiny visual targets. Because the cerebellum is necessary for motor precision, we investigated whether microsaccades may exploit this neural machinery in monkeys. Almost all vermal Purkinje cells, which provide the eye-related output of the cerebellar cortex, were found to increase or decrease their simple spike firing rate during microsaccades. At both the single-cell and population level, microsaccade-related activity was highly similar to macrosaccade-related activity and we observed a continuous representation of saccade amplitude that spanned both the macrosaccade and microsaccade domains. Our results suggest that the cerebellum's role in fine tuning eye movements extends even to the oculomotor system's smallest saccades and add to a growing list of observations that call into question the classical categorical distinction between microsaccades and macrosaccades. PMID- 25716841 TI - Selective increase of intention-based economic decisions by noninvasive brain stimulation to the dorsolateral prefrontal cortex. AB - The intention behind another's action and the impact of the outcome are major determinants of human economic behavior. It is poorly understood, however, whether the two systems share a core neural computation. Here, we investigated whether the two systems are causally dissociable in the brain by integrating computational modeling, functional magnetic resonance imaging, and transcranial direct current stimulation experiments in a newly developed trust game task. We show not only that right dorsolateral prefrontal cortex (DLPFC) activity is correlated with intention-based economic decisions and that ventral striatum and amygdala activity are correlated with outcome-based decisions, but also that stimulation to the DLPFC selectively enhances intention-based decisions. These findings suggest that the right DLPFC is involved in the implementation of intention-based decisions in the processing of cooperative decisions. This causal dissociation of cortical and subcortical backgrounds may indicate evolutionary and developmental differences in the two decision systems. PMID- 25716842 TI - Ly6h regulates trafficking of alpha7 nicotinic acetylcholine receptors and nicotine-induced potentiation of glutamatergic signaling. AB - alpha7 nAChRs are expressed widely throughout the brain, where they are important for synaptic signaling, gene transcription, and plastic changes that regulate sensory processing, cognition, and neural responses to chronic nicotine exposure. However, the mechanisms by which alpha7 nAChRs are regulated are poorly understood. Here we show that trafficking of alpha7-subunits is controlled by endogenous membrane-associated prototoxins in the Ly6 family. In particular, we find that Ly6h reduces cell-surface expression and calcium signaling by alpha7 nAChRs. We detect Ly6h in several rat brain regions, including the hippocampus, where we find it is both necessary and sufficient to limit the magnitude of alpha7-mediated currents. Consistent with such a regulatory function, knockdown of Ly6h in rat hippocampal pyramidal neurons enhances nicotine-induced potentiation of glutamatergic mEPSC amplitude, which is known to be mediated by alpha7 signaling. Collectively our data suggest a novel cellular role for Ly6 proteins in regulating nAChRs, which may be relevant to plastic changes in the nervous system including rewiring of glutamatergic circuitry during nicotine addiction. PMID- 25716844 TI - Effector specificity in macaque frontal and parietal cortex. AB - Single neurons in the frontal eye fields (FEFs) and lateral intraparietal area (LIP) of macaques are preferentially activated by saccade- versus reach-related processes. fMRI studies focusing on saccade- and reach-specific activity in human cortex, however, provided conflicting evidence for effector specificity. To gain further insights into effector preferences throughout monkey cortex using the same technique as in humans, we performed a mixed block/event-related fMRI experiment in macaques. Within single fMRI runs, monkeys alternated between a visually guided saccade task, a visually guided arm movement task, and a fixation only task requiring no saccades or arm movements. The detection of a peripheral pop-out go cue initiating the required operant behavior and the identification of a target among distractors was identical in the arm and saccade tasks. We found saccade-related activity in parietal areas V6, V6A, LIP, and caudal intraparietal area and frontal areas FEF, 45a, 45b, and 46. Areas 45 and FEF even showed markedly decreased fMRI activity during arm movements relative to fixation only. Conversely, medial and anterior intraparietal areas (MIP and AIP), and parietal area PEip; somatosensory areas S1 and S2; and (pre)motor areas F1, F3, F5, and F6 showed increased arm movement-related activity. F1, F5, PEip, and somatosensory cortex also showed deactivations during saccades relative to fixation only. Control experiments showed that such deactivations in both operant-specific functional networks did not depend on training history or rapid task switching requiring active suppression of the unpreferred operant behavior. Therefore, although both tasks required divided attention to detect a pop-out go cue and target, two largely segregated and mainly effector-driven cortical networks were activated. PMID- 25716843 TI - Seasonal plasticity of precise spike timing in the avian auditory system. AB - Vertebrate audition is a dynamic process, capable of exhibiting both short- and long-term adaptations to varying listening conditions. Precise spike timing has long been known to play an important role in auditory encoding, but its role in sensory plasticity remains largely unexplored. We addressed this issue in Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii), a songbird that shows pronounced seasonal fluctuations in circulating levels of sex-steroid hormones, which are known to be potent neuromodulators of auditory function. We recorded extracellular single-unit activity in the auditory forebrain of males and females under different breeding conditions and used a computational approach to explore two potential strategies for the neural discrimination of sound level: one based on spike counts and one based on spike timing reliability. We report that breeding condition has robust sex-specific effects on spike timing. Specifically, in females, breeding condition increases the proportion of cells that rely solely on spike timing information and increases the temporal resolution required for optimal intensity encoding. Furthermore, in a functionally distinct subset of cells that are particularly well suited for amplitude encoding, female breeding condition enhances spike timing-based discrimination accuracy. No effects of breeding condition were observed in males. Our results suggest that high-resolution temporal discharge patterns may provide a plastic neural substrate for sensory coding. PMID- 25716845 TI - Norepinephrine activates dopamine D4 receptors in the rat lateral habenula. AB - The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function. PMID- 25716846 TI - Active avoidance requires a serial basal amygdala to nucleus accumbens shell circuit. AB - Freezing is a species-typical defensive reaction to conditioned threats. While the neural circuitry of aversive Pavlovian behavior has been extensively studied, less is known about the circuitry underlying more active responses to danger. Here we show that the flow of information between the basal amygdala (BA) and the nucleus accumbens (NAcc) is necessary for signaled active avoidance behavior. Rats trained to avoid shock by shuttling during an auditory conditioned stimulus showed increased expression of the activity-dependent protein c-Fos in the NAcc, specifically the shell subregion (NAccSh). Silencing neural activity in the NAccSh, but not in the adjacent NAcc core, disrupted avoidance behavior. Disconnection of the BA and the NAccSh was just as effective at disrupting avoidance behavior as bilateral NAccSh inactivations, suggesting learned avoidance behavior requires an intact BA-NAccSh circuit. Together, these data highlight an essential role for the amygdalar projection to the ventral striatum in aversively motivated actions. PMID- 25716847 TI - Shared neural markers of decision confidence and error detection. AB - Empirical evidence indicates that people can provide accurate evaluations of their own thoughts and actions by means of both error detection and confidence judgments. This study investigates the foundations of these metacognitive abilities, specifically focusing on the relationship between confidence and error judgments in human perceptual decision making. Electroencephalography studies have identified the error positivity (Pe)--an event-related component observed following incorrect choices--as a robust neural index of participants' awareness of their errors in simple decision tasks. Here we assessed whether the Pe also varies in a graded way with participants' subjective ratings of decision confidence, as expressed on a 6-point scale after each trial of a dot count perceptual decision task. We observed clear, graded modulation of the Pe by confidence, with monotonic reduction in Pe amplitude associated with increasing confidence in the preceding choice. This effect was independent of objective accuracy. Multivariate decoding analyses indicated that neural markers of error detection were predictive of varying levels of confidence in correct decisions, including subtle shifts in high-confidence trials. These results suggest that shared mechanisms underlie two forms of metacognitive evaluation that are often treated separately, with consequent implications for current theories of their neurocognitive basis. PMID- 25716848 TI - Neural mechanisms of human perceptual choice under focused and divided attention. AB - Perceptual decisions occur after the evaluation and integration of momentary sensory inputs, and dividing attention between spatially disparate sources of information impairs decision performance. However, it remains unknown whether dividing attention degrades the precision of sensory signals, precludes their conversion into decision signals, or dampens the integration of decision information toward an appropriate response. Here we recorded human electroencephalographic (EEG) activity while participants categorized one of two simultaneous and independent streams of visual gratings according to their average tilt. By analyzing trial-by-trial correlations between EEG activity and the information offered by each sample, we obtained converging behavioral and neural evidence that dividing attention between left and right visual fields does not dampen the encoding of sensory or decision information. Under divided attention, momentary decision information from both visual streams was encoded in slow parietal signals without interference but was lost downstream during their integration as reflected in motor mu- and beta-band (10-30 Hz) signals, resulting in a "leaky" accumulation process that conferred greater behavioral influence to more recent samples. By contrast, sensory inputs that were explicitly cued as irrelevant were not converted into decision signals. These findings reveal that a late cognitive bottleneck on information integration limits decision performance under divided attention, and places new capacity constraints on decision theoretic models of information integration under cognitive load. PMID- 25716849 TI - Distinct neural representation in the dorsolateral, dorsomedial, and ventral parts of the striatum during fixed- and free-choice tasks. AB - The striatum is a major input site of the basal ganglia, which play an essential role in decision making. Previous studies have suggested that subareas of the striatum have distinct roles: the dorsolateral striatum (DLS) functions in habitual action, the dorsomedial striatum (DMS) in goal-directed actions, and the ventral striatum (VS) in motivation. To elucidate distinctive functions of subregions of the striatum in decision making, we systematically investigated information represented by phasically active neurons in DLS, DMS, and VS. Rats performed two types of choice tasks: fixed- and free-choice tasks. In both tasks, rats were required to perform nose poking to either the left or right hole after cue-tone presentation. A food pellet was delivered probabilistically depending on the presented cue and the selected action. The reward probability was fixed in fixed-choice task and varied in a block-wise manner in free-choice task. We found the following: (1) when rats began the tasks, a majority of VS neurons increased their firing rates and information regarding task type and state value was most strongly represented in VS; (2) during action selection, information of action and action values was most strongly represented in DMS; (3) action-command information (action representation before action selection) was stronger in the fixed-choice task than in the free-choice task in both DLS and DMS; and (4) action-command information was strongest in DLS, particularly when the same choice was repeated. We propose a hypothesis of hierarchical reinforcement learning in the basal ganglia to coherently explain these results. PMID- 25716850 TI - Use-dependent activation of neuronal Kv1.2 channel complexes. AB - In excitable cells, ion channels are frequently challenged by repetitive stimuli, and their responses shape cellular behavior by regulating the duration and termination of bursts of action potentials. We have investigated the behavior of Shaker family voltage-gated potassium (Kv) channels subjected to repetitive stimuli, with a particular focus on Kv1.2. Genetic deletion of this subunit results in complete mortality within 2 weeks of birth in mice, highlighting a critical physiological role for Kv1.2. Kv1.2 channels exhibit a unique property described previously as "prepulse potentiation," in which activation by a depolarizing step facilitates activation in a subsequent pulse. In this study, we demonstrate that this property enables Kv1.2 channels to exhibit use-dependent activation during trains of very brief depolarizations. Also, Kv subunits usually assemble into heteromeric channels in the central nervous system, generating diversity of function and sensitivity to signaling mechanisms. We demonstrate that other Kv1 channel types do not exhibit use-dependent activation, but this property is conferred in heteromeric channel complexes containing even a single Kv1.2 subunit. This regulatory mechanism is observed in mammalian cell lines as well as primary cultures of hippocampal neurons. Our findings illustrate that use dependent activation is a unique property of Kv1.2 that persists in heteromeric channel complexes and may influence function of hippocampal neurons. PMID- 25716851 TI - Dopamine directly modulates GABAA receptors. AB - Dopamine is a critical neuromodulator that activates GPCRs in mammals or ligand gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10 mm) exerts novel, opposing effects on different populations of mammalian (rat) GABAA receptors. Using whole-cell patch-clamp electrophysiology, we observed direct dopamine-mediated inhibition of tonic-level (1 MUm) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing alpha1beta3 or alpha1beta2gamma2 subunits. Surprisingly, direct activation by dopamine was seen in the absence of GABA with alpha1beta2gamma2, alpha5beta3gamma2, or alpha1beta3gamma2 transfections. This activity was also present in alpha1beta3gamma2 receptors containing a mutant beta3 subunit (H267A [(Z)beta3]) insensitive to trace levels of inhibitory Zn(2+). Dopamine activation required beta and gamma subunits but not alpha subunits ((Z)beta3gamma2 EC50 value, 660 MUm). Dopamine activity was fully blocked by picrotoxin but not GABAA competitive antagonists, and was strongly correlated with spontaneous receptor activity. We also report opposing effects of bicuculline and gabazine, such that bicuculline surprisingly activated non-alpha-containing (beta3gamma2) GABAA receptors, whereas gabazine suppressed spontaneous activity in these receptors. Our results suggest that dopamine may directly inhibit GABAA receptors that are both immediately adjacent to dopamine release sites in the striatum and activated by tonic GABA. Furthermore, synaptic/phasic release of dopamine may directly enhance signaling at some spontaneously active noncanonical GABAA receptors that lack alpha subunits. PMID- 25716852 TI - Optogenetic stimulation of accumbens shell or shell projections to lateral hypothalamus produce differential effects on the motivation for cocaine. AB - Previous studies suggest that pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior. However, overexpression of CREB, which increases excitability of AcbSh neurons, enhances cocaine-seeking behavior while producing depression-like behavior in tests of mood. These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothalamus (LH), a target region known to influence addictive behavior and mood. Presently, it is unknown whether there is a causal link between altered activity in the AcbSh-LH pathway and changes in the motivation for cocaine. In this study, we used an optogenetics approach to either globally stimulate AcbSh neurons or to selectively stimulate AcbSh terminal projections in the LH, in rats self administering cocaine. We found that stimulation of the AcbSh-LH pathway enhanced the motivation to self-administer cocaine in progressive ratio testing, and led to long-lasting facilitation of cocaine-seeking behavior during extinction tests conducted after withdrawal from cocaine self-administration. In contrast, global AcbSh stimulation reduced extinction responding. We compared these opposing motivational effects with effects on mood using the forced swim test, where both global AcbSh neuron and selective AcbSh-LH terminal stimulation facilitated depression-like behavioral despair. Together, these findings suggest that the AcbSh neurons convey complex, pathway-specific modulation of addiction and depression-like behavior, and that these motivation and mood phenomenon are dissociable. PMID- 25716853 TI - Recency, repetition, and the multidimensional basis of recognition memory. AB - Recency and repetition are two factors that have large effects on human memory performance. One way of viewing the beneficial impact of these variables on recognition memory is to assume that both factors modulate a unidimensional memory trace strength. Although previous functional neuroimaging studies have indicated that recency and repetition may modulate similar brain structures, particularly in the region of the inferior parietal cortex, there is extensive behavioral evidence that human subjects can make independent and accurate recognition memory judgments about both an item's recency and its frequency. In the present study, we used fMRI to examine patterns of brain activity during recognition memory for auditory-verbal stimuli that were parametrically and orthogonally manipulated in terms of recency and number of repetitions. We found in a continuous recognition paradigm that the lateral inferior parietal cortex, a region that has previously been associated with recollective forms of memory, is highly sensitive to recency but not repetition. In a multivariate analysis of whole-brain activation patterns, we found orthogonal components that dissociated recency and repetition variables, indicating largely independent neural bases underlying these two factors. The results demonstrate that although both recency and repetition dramatically improve recognition memory performance, the neural bases for this improvement are dissociable, and thus are difficult to explain in terms of access to a unitary memory trace. PMID- 25716854 TI - Integration of canal and otolith inputs by central vestibular neurons is subadditive for both active and passive self-motion: implication for perception. AB - Traditionally, the neural encoding of vestibular information is studied by applying either passive rotations or translations in isolation. However, natural vestibular stimuli are typically more complex. During everyday life, our self motion is generally not restricted to one dimension, but rather comprises both rotational and translational motion that will simultaneously stimulate receptors in the semicircular canals and otoliths. In addition, natural self-motion is the result of self-generated and externally generated movements. However, to date, it remains unknown how information about rotational and translational components of self-motion is integrated by vestibular pathways during active and/or passive motion. Accordingly, here, we compared the responses of neurons at the first central stage of vestibular processing to rotation, translation, and combined motion. Recordings were made in alert macaques from neurons in the vestibular nuclei involved in postural control and self-motion perception. In response to passive stimulation, neurons did not combine canal and otolith afferent information linearly. Instead, inputs were subadditively integrated with a weighting that was frequency dependent. Although canal inputs were more heavily weighted at low frequencies, the weighting of otolith input increased with frequency. In response to active stimulation, neuronal modulation was significantly attenuated (~ 70%) relative to passive stimulation for rotations and translations and even more profoundly attenuated for combined motion due to subadditive input integration. Together, these findings provide insights into neural computations underlying the integration of semicircular canal and otolith inputs required for accurate posture and motor control, as well as perceptual stability, during everyday life. PMID- 25716855 TI - Mitochondrial ATP-Mg/Pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons. AB - Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca(2+) and Na(+) influx, activation of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca(2+) deregulation. Mitochondria undergo early changes in membrane potential during excitotoxicity, but their precise role in these events is still controversial. Using primary cortical neurons derived from mice, we show that NMDA exposure results in a rapid fall in mitochondrial ATP in neurons deficient in SCaMC-3/Slc25a23, a Ca(2+)-regulated mitochondrial ATP-Mg/Pi carrier. This fall is associated with blunted increases in respiration and a delayed decrease in cytosolic ATP levels, which are prevented by PARP-1 inhibitors or by SCaMC-3 activity promoting adenine nucleotide uptake into mitochondria. SCaMC-3 KO neurons show an earlier delayed Ca(2+) deregulation, and SCaMC-3-deficient mitochondria incubated with ADP or ATP-Mg had reduced Ca(2+) retention capacity, suggesting a failure to maintain matrix adenine nucleotides as a cause for premature delayed Ca(2+) deregulation. SCaMC-3 KO neurons have higher vulnerability to in vitro excitotoxicity, and SCaMC-3 KO mice are more susceptible to kainate-induced seizures, showing that early PARP-1-dependent fall in mitochondrial ATP levels, counteracted by SCaMC-3, is an early step in the excitotoxic cascade. PMID- 25716856 TI - Mouse model of OPRM1 (A118G) polymorphism increases sociability and dominance and confers resilience to social defeat. AB - A single nucleotide polymorphism (SNP) in the human MU-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in drug addiction, pain sensitivity, and, more recently, social behavior. The endogenous opioid system has been shown to regulate social distress and reward in a variety of animal models. However, mechanisms underlying the associations between the OPRM1 A118G SNP and these behaviors have not been clarified. We used a mouse model possessing the human equivalent nucleotide/amino acid substitution to study social affiliation and social defeat behaviors. In mice with the Oprm1 A112G SNP, we demonstrate that the G allele is associated with an increase in home-cage dominance and increased motivation for nonaggressive social interactions, similar to what is reported in human populations. When challenged by a resident aggressor, G-allele carriers expressed less submissive behavior and exhibited resilience to social defeat, demonstrated by a lack of subsequent social avoidance and reductions in anhedonia as measured by intracranial self stimulation. Protection from social defeat in G-allele carriers was associated with a greater induction of c-fos in a resilience circuit comprising the nucleus accumbens and periaqueductal gray. These findings led us to test the role of endogenous opioids in the A112G mice. We demonstrate that the increase in social affiliation in G carriers is blocked by pretreatment with naloxone. Together, these data suggest a mechanism involving altered hedonic state and neural activation as well as altered endogenous opioid tone in the differential response to aversive and rewarding social stimuli in G-allele carriers. PMID- 25716857 TI - Parkinson's disease iron deposition caused by nitric oxide-induced loss of beta amyloid precursor protein. AB - Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated beta-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP(-/-) mice develop iron dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD. PMID- 25716858 TI - A causal role for posterior medial frontal cortex in choice-induced preference change. AB - After a person chooses between two items, preference for the chosen item will increase and preference for the unchosen item will decrease because of the choice made. In other words, we tend to justify or rationalize our past behavior by changing our attitude. This phenomenon of choice-induced preference change has been traditionally explained by cognitive dissonance theory. Choosing something that is disliked or not choosing something that is liked are both cognitively inconsistent and, to reduce this inconsistency, people tend to change their subsequently stated preference in accordance with their past choices. Previously, human neuroimaging studies identified posterior medial frontal cortex (pMFC) as a key brain region involved in cognitive dissonance. However, it remains unknown whether the pMFC plays a causal role in inducing preference change after cognitive dissonance. Here, we demonstrate that 25 min, 1 Hz repetitive transcranial magnetic stimulation applied over the pMFC significantly reduces choice-induced preference change compared with sham stimulation or control stimulation over a different brain region, demonstrating a causal role for the pMFC. PMID- 25716859 TI - Revisiting the role of infralimbic cortex in fear extinction with optogenetics. AB - Previous rodent studies have implicated the infralimbic (IL) subregion of the medial prefrontal cortex in extinction of auditory fear conditioning. However, these studies used pharmacological inactivation or electrical stimulation techniques, which lack temporal precision and neuronal specificity. Here, we used an optogenetic approach to either activate (with channelrhodopsin) or silence (with halorhodopsin) glutamatergic IL neurons during conditioned tones delivered in one of two phases: extinction training or extinction retrieval. Activating IL neurons during extinction training reduced fear expression and strengthened extinction memory the following day. Silencing IL neurons during extinction training had no effect on within-session extinction, but impaired the retrieval of extinction the following day, indicating that IL activity during extinction tones is necessary for the formation of extinction memory. Surprisingly, however, silencing IL neurons optogenetically or pharmacologically during the retrieval of extinction 1 day or 1 week following extinction training had no effect. Our findings suggest that IL activity during extinction training likely facilitates storage of extinction in target structures, but contrary to current models, IL activity does not appear to be necessary for retrieval of extinction memory. PMID- 25716860 TI - Fast gamma oscillations are generated intrinsically in CA1 without the involvement of fast-spiking basket cells. AB - Information processing in neuronal networks relies on the precise synchronization of ensembles of neurons, coordinated by the diverse family of inhibitory interneurons. Cortical interneurons can be usefully parsed by embryonic origin, with the vast majority arising from either the caudal or medial ganglionic eminences (CGE and MGE). Here, we examine the activity of hippocampal interneurons during gamma oscillations in mouse CA1, using an in vitro model where brief epochs of rhythmic activity were evoked by local application of kainate. We found that this CA1 KA-evoked gamma oscillation was faster than that in CA3 and, crucially, did not appear to require the involvement of fast-spiking basket cells. In contrast to CA3, we also found that optogenetic inhibition of pyramidal cells in CA1 did not significantly affect the power of the oscillation, suggesting that excitation may not be essential for gamma genesis in this region. We found that MGE-derived interneurons were generally more active than CGE interneurons during CA1 gamma, although a group of CGE-derived interneurons, putative trilaminar cells, were strongly phase-locked with gamma oscillations and, together with MGE-derived axo-axonic and bistratified cells, provide attractive candidates for being the driver of this locally generated, predominantly interneuron-driven model of gamma oscillations. PMID- 25716862 TI - Melanin-concentrating hormone neurons release glutamate for feedforward inhibition of the lateral septum. AB - Melanin-concentrating hormone (MCH) regulates vital physiological functions, including energy balance and sleep. MCH cells are thought to be GABAergic, releasing GABA to inhibit downstream targets. However, there is little experimental support for this paradigm. To better understand the synaptic mechanisms of mouse MCH neurons, we performed neuroanatomical mapping and characterization followed by optogenetics to test their functional connectivity at downstream targets. Synaptophysin-mediated projection mapping showed that the lateral septal nucleus (LS) contained the densest accumulation of MCH nerve terminals. We then expressed channel rhodopsin-2 in MCH neurons and photostimulated MCH projections to determine their effect on LS activity. Photostimulation of MCH projections evoked a monosynaptic glutamate release in the LS. Interestingly, this led to a feedforward inhibition that depressed LS firing by a robust secondary GABA release. This study presents a circuit analysis between MCH and LS neurons and confirms their functional connection via monosynaptic and polysynaptic pathways. Our findings indicate that MCH neurons are not exclusively GABAergic and reveal a glutamate-mediated, feedforward mechanism that inhibits LS cells. PMID- 25716861 TI - Pharmacologically distinct nicotinic acetylcholine receptors drive efferent mediated excitation in calyx-bearing vestibular afferents. AB - Electrical stimulation of vestibular efferent neurons rapidly excites the resting discharge of calyx/dimorphic (CD) afferents. In turtle, this excitation arises when acetylcholine (ACh), released from efferent terminals, directly depolarizes calyceal endings by activating nicotinic ACh receptors (nAChRs). Although molecular biological data from the peripheral vestibular system implicate most of the known nAChR subunits, specific information about those contributing to efferent-mediated excitation of CD afferents is lacking. We sought to identify the nAChR subunits that underlie the rapid excitation of CD afferents and whether they differ from alpha9alpha10 nAChRs on type II hair cells that drive efferent mediated inhibition in adjacent bouton afferents. We recorded from CD and bouton afferents innervating the turtle posterior crista during electrical stimulation of vestibular efferents while applying several subtype-selective nAChR agonists and antagonists. The alpha9alpha10 nAChR antagonists, alpha-bungarotoxin and alpha-conotoxin RgIA, blocked efferent-mediated inhibition in bouton afferents while leaving efferent-mediated excitation in CD units largely intact. Conversely, 5-iodo-A-85380, sazetidine-A, varenicline, alpha-conotoxin MII, and bPiDDB (N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide) blocked efferent mediated excitation in CD afferents without affecting efferent-mediated inhibition in bouton afferents. This pharmacological profile suggested that calyceal nAChRs contain alpha6 and beta2, but not alpha9, nAChR subunits. Selective blockade of efferent-mediated excitation in CD afferents distinguished dimorphic from calyx afferents by revealing type II hair cell input. Dimorphic afferents differed in having higher mean discharge rates and a mean efferent mediated excitation that was smaller in amplitude yet longer in duration. Molecular biological data demonstrated the expression of alpha9 in turtle hair cells and alpha4 and beta2 in associated vestibular ganglia. PMID- 25716863 TI - Absence of plateau potentials in dLGN cells leads to a breakdown in retinogeniculate refinement. AB - The link between neural activity and the refinement of projections from retina to the dorsal lateral geniculate nucleus (dLGN) of thalamus is based largely on studies that disrupt presynaptic retinogeniculate activity. Postsynaptic mechanisms responsible for implementing the activity-dependent remodeling in dLGN remain unknown. We tested whether L-type Ca(2+) channel activity in the form of synaptically evoked plateau potentials in dLGN cells is needed for remodeling by using a mutant mouse that lacks the ancillary beta3 subunit and, as a consequence, has highly reduced L-type channel expression and attenuated L-type Ca(2+) currents. In the dLGNs of beta3-null mice, glutamatergic postsynaptic activity evoked by optic tract stimulation was normal, but plateau potentials were rarely observed. The few plateaus that were evoked required high rates of retinal stimulation, but were still greatly attenuated compared with those recorded in age-matched wild-type mice. While beta3-null mice exhibit normal stage II and III retinal waves, their retinogeniculate projections fail to segregate properly and dLGN cells show a high degree of retinal convergence even at late postnatal ages. These structural and functional defects were also accompanied by a reduction in CREB phosphorylation, a signaling event that has been shown to be essential for retinogeniculate axon segregation. Thus, postsynaptic L-type Ca(2+) activity plays an important role in mediating the refinement of the retinogeniculate pathway. PMID- 25716864 TI - Quantifying the microvascular origin of BOLD-fMRI from first principles with two photon microscopy and an oxygen-sensitive nanoprobe. AB - The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences. PMID- 25716865 TI - Anti-muscarinic adjunct therapy accelerates functional human oligodendrocyte repair. AB - Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a(+)O4(+) cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors. PMID- 25716867 TI - Monitoring of vacuolar-type H+ ATPase-mediated proton influx into synaptic vesicles. AB - During synaptic vesicle (SV) recycling, the vacuolar-type H(+) ATPase creates a proton electrochemical gradient (DeltaMUH(+)) that drives neurotransmitter loading into SVs. Given the low estimates of free luminal protons, it has been envisioned that the influx of a limited number of protons suffices to establish DeltaMUH(+). Consistent with this, the time constant of SV re-acidification was reported to be <5 s, much faster than glutamate loading (tau of ~ 15 s) and thus unlikely to be rate limiting for neurotransmitter loading. However, such estimates have relied on pHluorin-based probes that lack sensitivity in the lower luminal pH range. Here, we reexamined re-acidification kinetics using the mOrange2-based probe that should report the SV pH more accurately. In recordings from cultured mouse hippocampal neurons, we found that re-acidification took substantially longer (tau of ~ 15 s) than estimated previously. In addition, we found that the SV lumen exhibited a large buffering capacity (~ 57 mm/pH), corresponding to an accumulation of ~ 1200 protons during re-acidification. Together, our results uncover hitherto unrecognized robust proton influx and storage in SVs that can restrict the rate of neurotransmitter refilling. PMID- 25716868 TI - Divisive gain modulation of motoneurons by inhibition optimizes muscular control. AB - When using muscles, the precision with which force is delivered is as important as the delivery of force itself. Force is regulated by both the number of recruited motoneurons and their spike frequency. While it is known that the recruitment is ordered to reduce variability in force, it remains unclear whether the motoneuron gain, i.e., the slope of the transformation between synaptic input and spiking output, is also modulated to reduce variability in force. To address this issue, we use turtle hindlimb scratching as a model for fine motor control, since this behavior involves precise limb movement to rub the location of somatic nuisance touch. We recorded intracellularly from motoneurons in a reduced preparation where the limbs were removed to increase mechanical stability and the motor nerve activity served as a surrogate for muscle force. We found that not only is the gain of motoneurons regulated on a subsecond timescale, it is also adjusted to minimize variability. The modulation is likely achieved via an expansive nonlinearity between spike rate and membrane potential with inhibition having a divisive influence. These findings reveal a versatile mechanism of modulating neuronal sensitivity and suggest that such modulation is fundamentally linked to optimization. PMID- 25716869 TI - Retraction. Winton et al., Intraneuronal APP, not free Abeta peptides in 3xTg-AD mice: implications for Tau versus Abeta-mediated Alzheimer neurodegeneration. PMID- 25716866 TI - Persistent pain maintains morphine-seeking behavior after morphine withdrawal through reduced MeCP2 repression of GluA1 in rat central amygdala. AB - As long-term opioids are increasingly used for control of chronic pain, how pain affects the rewarding effect of opioids and hence risk of prescription opioid misuse and abuse remains a healthcare concern and a challenging issue in current pain management. In this study, using a rat model of morphine self administration, we investigated the molecular mechanisms underlying the impact of pain on operant behavior of morphine intake and morphine seeking before and after morphine withdrawal. We found that rats with persistent pain consumed a similar amount of daily morphine to that in control rats without pain, but maintained their level-pressing behavior of morphine seeking after abstinence of morphine at 0.2 mg/kg, whereas this behavior was gradually diminished in control rats. In the central nucleus of amygdala (CeA), a limbic structure critically involved in the affective dimension of pain, proteins of GluA1 subunits of glutamate AMPA receptors were upregulated during morphine withdrawal, and viral knockdown of CeA GluA1 eliminated the morphine-seeking behavior in withdrawn rats of the pain group. Chromatin immunoprecipitation analysis revealed that the methyl CpG binding protein 2 (MeCP2) was enriched in the promoter region of Gria1 encoding GluA1 and this enrichment was significantly attenuated in withdrawn rats of the pain group. Furthermore, viral overexpression of CeA MeCP2 repressed the GluA1 level and eliminated the maintenance of morphine-seeking behavior after morphine withdrawal. These results suggest direct MeCp2 repression of GluA1 function as a likely mechanism for morphine-seeking behavior maintained by long-lasting affective pain after morphine withdrawal. PMID- 25716870 TI - An ethanol root extract of Cynanchum wilfordii containing acetophenones suppresses the expression of VCAM-1 and ICAM-1 in TNF-alpha-stimulated human aortic smooth muscle cells through the NF-kappaB pathway. AB - The root of Cynanchum wilfordii (C. wilfordii) contains several biologically active compounds which have been used as traditional medicines in Asia. In the present study, we evaluated the anti-inflammatory effects of an ethanol root extract of C. wilfordii (CWE) on tumor necrosis factor (TNF)-alpha-stimulated human aortic smooth muscle cells (HASMCs). The inhibitory effects of CWE on vascular cell adhesion molecule (VCAM)-1 expression under an optimum extraction condition were examined. CWE suppressed the expression of VCAM-1 and ICAM-1 and the adhesion of THP-1 monocytes to the TNF-alpha-stimulated HASMCs. Consistent with the in vitro observations, CWE inhibited the aortic expression of ICAM-1 and VCAM-1 in atherogenic diet-fed mice. CWE also downregulated the expression of nuclear factor-kappaB (NF-kappaB p65) and its uclear translocation in the stimulated HASMCs. In order to identify the active components in CWE, we re extracted CWE using several solvents, and found that the ethyl acetate fraction was the most effective in suppressing the expression of VCAM-1 and ICAM-1. Four major acetophenones were purified from the ethyl acetate fraction, and two components, p-hydroxyacetophenone and cynandione A, potently inhibited the expression of ICAM-1 and VCAM-1 in the stimulated HASMCs. We assessed and determined the amounts of these two active components from CWE, and our results suggested that the root of C. wilfordii and its two bioactive acetophenones may be used for the prevention and treatment of atherosclerosis and vascular inflammatory diseases. PMID- 25716871 TI - Degenerative changes of the cranial cruciate ligament harvested from dogs with cranial cruciate ligament rupture. AB - Degenerative cranial cruciate ligament (CCL) rupture is characterized histologically by degenerating extracellular matrix (ECM) and chondroid metaplasia. Here, we describe the progression of chondroid metaplasia and the changes in the expression of ECM components in canine CCL rupture (CCLR). CCLs from 26 stifle joints with CCLR (CCLR group) and normal CCLs from 12 young beagles (control group) were examined histologically and immunohistochemically for expression of type I (COLI), type II (COLII), type III collagen (COLIII) and Sry-type HMG box 9 (SOX9). Cell density and morphology of CCLs were quantified using hematoxylin-eosin staining. The percentage of round cells was higher in the CCLR group than in controls. COLI-positive areas were seen extensively in the connecting fibers, but weakly represented in the cytoplasm of normal CCLs. In the CCLR group, there were fewer COLI-positive areas, but many COLI-positive cells. The percentages of COLII-, COLIII- and SOX9-positive cells were higher in the CCLR group than in controls. The number of spindle cells with perinuclear halo was high in the CCLR group, and most of these cells were SOX9-positive. Deposition of COLI, the main ECM component of ligaments, decreased with increased COLIII expression in degenerated CCL tissue, which shows that the deposition of the ECM is changed in CCLR. On the contrary, expression of SOX9 increased, which may contribute to the synthesis of cartilage matrix. The expression of COLII and SOX9 in ligamentocytes showed that these cells tend to differentiate into chondrocytes. PMID- 25716872 TI - Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4-phenylbutyrate. AB - Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a result of mutations in ABCB11 encoding bile salt export pump (BSEP), the canalicular bile salt export pump of hepatocyte. In some PFIC2 patients with missense mutations, BSEP is not detected at the canaliculus owing to mistrafficking of BSEP mutants. In vitro, chaperone drugs, such as 4-phenylbutyrate (4-PB), have been shown to partially correct mistrafficking. Four PFIC2 patients harboring at least one missense mutation (p.G982R, p.R1128C, and p.T1210P) were treated orally with 4-PB and followed prospectively. Patient mutations were reproduced in a Bsep/green fluorescent protein plasmid. Cellular localization of the resulting Bsep mutants was studied in a hepatocellular line (Can 10), and effects of treatment with 4-PB and/or ursodeoxycholic acid (UDCA) were assessed. In Can 10 cells, Bsep mutants were detected in the endoplasmic reticulum instead of at the canalicular membrane. Treatment with 4-PB and UDCA partially corrected Bsep mutant targeting. With 4-PB, we observed, in all patients, a decrease of pruritus and serum bile acid concentration (BAC) as well as an improvement of serum liver tests. Pathological liver injuries improved, and BSEP, which was not detected at the canalicular membrane before treatment, appeared at the canalicular membrane. Bile analyses showed an increase in BAC with 4-PB. Patient conditions remained stable with a median follow-up of 40 months (range, 3-53), and treatment tolerance was good. CONCLUSION: 4-PB therapy may be efficient in selected patients with PFIC2 owing to ABCB11 missense mutations affecting BSEP canalicular targeting. Bile secretion improvement may be a result of the ability of 4-PB to retarget mutated BSEP. PMID- 25716873 TI - Robot-assisted thoracoscopic esophagectomy with extensive mediastinal lymphadenectomy: experience with 114 consecutive patients with intrathoracic esophageal cancer. AB - The study aims to report the operative outcomes of robot-assisted thoracoscopic esophagectomy (RATE) with extensive mediastinal lymphadenectomy (ML) for intrathoracic esophageal cancer. We analyzed a prospective database of 114 consecutive patients who underwent RATE with lymph node dissection along recurrent laryngeal nerve (RLN) followed by cervical esophagogastrostomy. The study included 104 men with a mean age of 63.1 +/- 0.8 years. Of these, 110 (96.5%) had squamous cell carcinoma, and the location of the tumor was upper esophagus in 7 (6.1%), middle in 62 (54.4%), and lower in 45 (39.5%). Preoperative concurrent chemoradiation was performed in 15 patients (13.2%). All but one patient underwent successful RATE, and R0 resection was achieved in 111 patients (97.4%). Extended ML and total ML were performed in 24 (21.1%) and 90 (78.9%) patients, respectively. Total operation time was 419.6 +/- 7.9 minutes, and robot console time was 206.6 +/- 5.2 minutes. The mean number of total, mediastinal, and RLN nodes was 43.5 +/- 1.4, 24.5 +/- 1.0, and 9.7 +/- 0.7, respectively. The most common complication was RLN palsy (30, 26.3%), followed by anastomotic leakage (17, 14.9%) and pulmonary complications (11, 9.6%). Median hospital stay was 16 days, and 90-day mortality was observed in three patients (2.5%). On multivariate analysis, preoperative concurrent chemoradiation was a risk factor for pulmonary complications (odds ratio 7.42, 95% confidence interval 1.91-28.8, P = 0.004). RATE with extensive ML could be performed safely with acceptable postoperative outcomes. Long-term survival data should be followed in the future to verify the oncological outcome of the procedure. PMID- 25716874 TI - Influence of pig genetic type on sensory properties and consumer acceptance of Parma, San Daniele and Toscano dry-cured hams. AB - BACKGROUND: This study investigated the sensory properties and acceptability of different Protected Designation of Origin (PDO) dry-cured hams. For each PDO, two genotypes were selected: IL*LW (reference hybrid) and Goland (commercial hybrid). RESULTS: According to descriptive analysis, genetic variance affected few attributes describing Toscano and San Daniele ham sensory quality. The commercial hybrid Parma ham was distinct from the traditional one, the Goland genotype being significantly higher in red color, saltiness, dryness and hardness and showing a lower intensity of pork-meat odor/flavor and sweetness than the IL*LW genotype. Consumer acceptance was mainly influenced by the PDO technology. A genotype effect on acceptance was only observed in Toscano ham. Principal component regression analysis revealed that Toscano ham was the preferred sample. Considering that the consumers involved were from Tuscany, it is likely that Toscano ham was preferred owing to their higher familiarity with this product. CONCLUSION: Sensory properties of ham samples were better discriminated according to their PDO than their genotype. Likewise, consumer liking was more affected by the specific PDO technology than by genetic type. Toscano ham was the most preferred and most familiar product among Tuscan consumers, indicating that familiarity with the product was the best driver of dry-cured ham preference. PMID- 25716875 TI - Is the WBE model appropriate for semi-arid shrubs subjected to clear cutting? AB - It is crucial to understand the adaptive mechanisms of woody plants facing periodic drought to assess their vulnerability to the increasing climate variability predicted in the Sahel. Guiera senegalensis J.F.Gmel is a semi evergreen Combretaceae commonly found in Sahelian rangelands, fallows and crop fields because of its value as an agroforestry species. We compared canopy leafing, and allometric measurements of leaf area, stem area and stem length and their relationships with leaf water potential, stomatal conductance (gs) and soil to-leaf hydraulic conductance (KS-L), in mature and current-year resprouts of G. senegalensis in Sahelian Niger. In mature shrubs, seasonal drought reduced the ratio of leaf area to cross-sectional stem area (AL : AS), mainly due to leaf shedding. The canopy of the current-year resprouts remained permanently leafed as the shrubs produced leaves and stems continuously, and their AL : AS ratio increased throughout the dry season. Their KS-L increased, whereas gs decreased. West, Brown and Enquist's (WBE) model can thus describe allometric trends in the seasonal life cycle of undisturbed mature shrubs, but not that of resprouts. Annual clear cutting drives allometric scaling relationships away from theoretical WBE predictions in the current-year resprouts, with scaling exponents 2.5 times greater than those of mature shrubs. High KS-L (twice that of mature shrubs) supports this intensive regeneration process. The adaptive strategy described here is probably common to many woody species that have to cope with both severe seasonal drought and regular disturbance over the long term. PMID- 25716876 TI - Root resistance to cavitation is accurately measured using a centrifuge technique. AB - Plants transport water under negative pressure and this makes their xylem vulnerable to cavitation. Among plant organs, root xylem is often highly vulnerable to cavitation due to water stress. The use of centrifuge methods to study organs, such as roots, that have long vessels are hypothesized to produce erroneous estimates of cavitation resistance due to the presence of open vessels through measured samples. The assumption that roots have long vessels may be premature since data for root vessel length are sparse; moreover, recent studies have not supported the existence of a long-vessel artifact for stems when a standard centrifuge technique was used. We examined resistance to cavitation estimated using a standard centrifuge technique and compared these values with native embolism measurements for roots of seven woody species grown in a common garden. For one species we also measured vulnerability using single-vessel air injection. We found excellent agreement between root native embolism and the levels of embolism measured using a centrifuge technique, and with air-seeding estimates from single-vessel injection. Estimates of cavitation resistance measured from centrifuge curves were biologically meaningful and were correlated with field minimum water potentials, vessel diameter (VD), maximum xylem-specific conductivity (Ksmax) and vessel length. Roots did not have unusually long vessels compared with stems; moreover, root vessel length was not correlated to VD or to the vessel length of stems. These results suggest that root cavitation resistance can be accurately and efficiently measured using a standard centrifuge method and that roots are highly vulnerable to cavitation. The role of root cavitation resistance in determining drought tolerance of woody species deserves further study, particularly in the context of climate change. PMID- 25716877 TI - Environmental controls in the water use patterns of a tropical cloud forest tree species, Drimys brasiliensis (Winteraceae). AB - Trees from tropical montane cloud forest (TMCF) display very dynamic patterns of water use. They are capable of downwards water transport towards the soil during leaf-wetting events, likely a consequence of foliar water uptake (FWU), as well as high rates of night-time transpiration (Enight) during drier nights. These two processes might represent important sources of water losses and gains to the plant, but little is known about the environmental factors controlling these water fluxes. We evaluated how contrasting atmospheric and soil water conditions control diurnal, nocturnal and seasonal dynamics of sap flow in Drimys brasiliensis (Miers), a common Neotropical cloud forest species. We monitored the seasonal variation of soil water content, micrometeorological conditions and sap flow of D. brasiliensis trees in the field during wet and dry seasons. We also conducted a greenhouse experiment exposing D. brasiliensis saplings under contrasting soil water conditions to deuterium-labelled fog water. We found that during the night D. brasiliensis possesses heightened stomatal sensitivity to soil drought and vapour pressure deficit, which reduces night-time water loss. Leaf-wetting events had a strong suppressive effect on tree transpiration (E). Foliar water uptake increased in magnitude with drier soil and during longer leaf wetting events. The difference between diurnal and nocturnal stomatal behaviour in D. brasiliensis could be attributed to an optimization of carbon gain when leaves are dry, as well as minimization of nocturnal water loss. The leaf-wetting events on the other hand seem important to D. brasiliensis water balance, especially during soil droughts, both by suppressing tree transpiration (E) and as a small additional water supply through FWU. Our results suggest that decreases in leaf-wetting events in TMCF might increase D. brasiliensis water loss and decrease its water gains, which could compromise its ecophysiological performance and survival during dry periods. PMID- 25716878 TI - Conifer somatic embryogenesis: improvements by supplementation of medium with oxidation-reduction agents. AB - A major barrier to the commercialization of somatic embryogenesis technology in loblolly pine (Pinus taeda L.) is recalcitrance of some high-value crosses to initiate embryogenic tissue (ET) and continue early-stage somatic embryo growth. Developing initiation and multiplication media that resemble the seed environment has been shown to decrease this recalcitrance. Glutathione (GSH), glutathione disulfide (GSSG), ascorbic acid and dehydroascorbate analyses were performed weekly throughout the sequence of seed development for female gametophyte and zygotic embryo tissues to determine physiological concentrations. Major differences in stage-specific oxidation-reduction (redox) agents were observed. A simple bioassay was used to evaluate potential growth-promotion of natural and inorganic redox agents added to early-stage somatic embryo growth medium. Compounds showing statistically significant increases in early-stage embryo growth were then tested for the ability to increase initiation of loblolly pine. Low-cost reducing agents sodium dithionite and sodium thiosulfate increased ET initiation for loblolly pine and Douglas fir (Mirb) Franco. Germination medium supplementation with GSSG increased somatic embryo germination. Early-stage somatic embryos grown on medium with or without sodium thiosulfate did not differ in GSH or GSSG content, suggesting that sodium thiosulfate-mediated growth stimulation does not involve GSH or GSSG. We have developed information demonstrating that alteration of the redox environment in vitro can improve ET initiation, early-stage embryo development and somatic embryo germination in loblolly pine. PMID- 25716879 TI - Patient perspectives on physician conflict of interest in industry-sponsored clinical trials for multiple sclerosis therapeutics. AB - BACKGROUND: Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. OBJECTIVE: To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician-industry conflicts of interest created by clinical trials and how such disclosures may influence study participation METHODS: An anonymous online instrument was developed. RESULTS: 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients' decisions to participate in these studies. CONCLUSIONS: Findings from this study support a call for uniform guidelines regarding disclosure of physician-industry relationships to prospective research participants for industry-sponsored clinical trials. PMID- 25716880 TI - A randomized, controlled, single-blind, 6-month pilot study to evaluate the efficacy of MS-Line!: a cognitive rehabilitation programme for patients with multiple sclerosis. AB - BACKGROUND: MS-Line! was created to provide an effective treatment for cognitive impairment in multiple sclerosis (MS) patients. OBJECTIVE: To assess the efficacy of MS-Line!. METHODS: A randomized, controlled, single-blind, 6-month pilot study. Patients were randomly assigned to an experimental group (cognitive rehabilitation with the programme) or to a control group (no cognitive rehabilitation). Randomization was stratified by cognitive impairment level. Cognitive assessment included: selective reminding test, 10/36 spatial recall test (10/36 SPART), symbol digit modalities test, paced auditory serial addition test, word list generation (WLG), FAS test, subtests of WAIS-III, Boston naming test (BNT), and trail making test (TMT). RESULTS: Forty-three patients (22 in the experimental group, 21 in the control group) were analyzed. Covariance analysis showed significant differences in 10/36 SPART (P=0.0002), 10/36 SPART delayed recall (P=0.0021), WLG (P=0.0123), LNS (P=0.0413), BNT (P=0.0007) and TMT-A (P=0.010) scores between groups. CONCLUSIONS: The study showed a significant improvement related to learning and visual memory, executive functions, attention and information processing speed, and naming ability in those patients who received cognitive rehabilitation. The results suggest that MS-Line! is effective in improving cognitive impairment in MS patients. PMID- 25716881 TI - Neuromyelitis optica spectrum disorder as a paraneoplastic manifestation of lung adenocarcinoma expressing aquaporin-4. AB - BACKGROUND: The observations of neuromyelitis optica spectrum disorders (NMOSD) occurring in the setting of cancer suggest that aquaporin-4 (AQP4) autoimmunity may in some cases be paraneoplastic. RESULTS: We describe a 72-year-old patient who developed a longitudinally extensive transverse myelitis associated with AQP4 autoantibodies in the setting of a lung adenocarcinoma recurrence. AQP4 expression was demonstrated in tumor cells. IgG in patient's cerebrospinal fluid bound to tumor cells co-localizing with AQP4 immunoreactivity. CONCLUSIONS AND RELEVANCE: This case expands the spectrum of paraneoplastic AQP4 autoimmunity highlighting the importance of considering an oncological screening in patients with late-onset NMOSD. PMID- 25716882 TI - The best basic science paper in multiple sclerosis in 2014: important role for the choroid plexus in the central nervous system entry of leukocytes. PMID- 25716883 TI - UK DRAFFT: a randomised controlled trial of percutaneous fixation with Kirschner wires versus volar locking-plate fixation in the treatment of adult patients with a dorsally displaced fracture of the distal radius. AB - BACKGROUND: In high-income countries, 6% of all women will have sustained a fracture of the wrist (distal radius) by the age of 80 years and 9% by the age of 90 years. Advances in orthopaedic surgery have improved the outcome for patients: many such fractures can be treated in a plaster cast alone, but others require surgical fixation to hold the bone in place while they heal. The existing evidence suggests that modern locking-plate fixation provides improved functional outcomes, but costs more than traditional wire fixation. METHODS: In this multicentre trial, we randomly assigned 461 adult patients having surgery for an acute dorsally displaced fracture of the distal radius to either percutaneous Kirschner-wire fixation or locking-plate fixation. The primary outcome measure was the Patient-Rated Wrist Evaluation(c) (PRWE) questionnaire at 12 months after the fracture. In this surgical trial, neither the patients nor the surgeons could be blind to the intervention. We also collected information on complications and combined costs and quality-adjusted life-years (QALYs) to assess cost effectiveness. RESULTS: The baseline characteristics of the two groups were well balanced and over 90% of patients completed follow-up. Both groups of patients recovered wrist function by 12 months. There was no clinically relevant difference in the PRWE questionnaire score at 3 months, 6 months or 12 months [difference at 12 months: -1.3; 95% confidence interval (CI) -4.5 to 1.8; p=0.398]. There was no difference in the number of complications in each group and small differences in QALY gains (0.008; 95% CI -0.001 to 0.018); Kirschner wire fixation represents a cost-saving intervention (-L727; 95% CI -L588 to L865), particularly in younger patients. CONCLUSIONS: Contrary to the existing literature, and against the increasing use of locking-plate fixation, this trial shows that there is no difference between Kirschner wires and volar locking plates for patients with dorsally displaced fractures of the distal radius. A Kirschner-wire fixation is less expensive and quicker to perform. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31379280. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 17. See the NIHR Journals Library website for further project information. PMID- 25716884 TI - Core-shell hybrid upconversion nanoparticles carrying stable nitroxide radicals as potential multifunctional nanoprobes for upconversion luminescence and magnetic resonance dual-modality imaging. AB - Nitroxide radicals, such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and its derivatives, have recently been used as contrast agents for magnetic resonance imaging (MRI) and electron paramagnetic resonance imaging (EPRI). However, their rapid one-electron bioreduction to diamagnetic N-hydroxy species when administered intravenously has limited their use in in vivo applications. In this article, a new approach of silica coating for carrying stable radicals was proposed. A 4-carboxyl-TEMPO nitroxide radical was covalently linked with 3 aminopropyl-trimethoxysilane to produce a silanizing TEMPO radical. Utilizing a facile reaction based on the copolymerization of silanizing TEMPO radicals with tetraethyl orthosilicate in reverse microemulsion, a TEMPO radicals doped SiO2 nanostructure was synthesized and coated on the surface of NaYF4:Yb,Er/NaYF4 upconversion nanoparticles (UCNPs) to generate a novel multifunctional nanoprobe, PEGylated UCNP@TEMPO@SiO2 for upconversion luminescence (UCL) and magnetic resonance dual-modality imaging. The electron spin resonance (ESR) signals generated by the TEMPO@SiO2 show an enhanced reduction resistance property for a period of time of up to 1 h, even in the presence of 5 mM ascorbic acid. The longitudinal relaxivity of PEGylated UCNPs@TEMPO@SiO2 nanocomposites is about 10 times stronger than that for free TEMPO radicals. The core-shell NaYF4:Yb,Er/NaYF4 UCNPs synthesized by this modified user-friendly one-pot solvothermal strategy show a significant enhancement of UCL emission of up to 60 times more than the core NaYF4:Yb,Er. Furthermore, the PEGylated UCNP@TEMPO@SiO2 nanocomposites were further used as multifunctional nanoprobes to explore their performance in the UCL imaging of living cells and T1-weighted MRI in vitro and in vivo. PMID- 25716885 TI - Liposomal cytarabine in the prophylaxis and treatment of CNS lymphoma: toxicity analysis in a retrospective case series study conducted at Polish Lymphoma Research Group Centers. AB - Lymphomas with primary or secondary involvement of central nervous system (CNS) have poor prognosis despite specific treatment protocols which include whole brain radiotherapy and high-dose systemic and/or intrathecal chemotherapy. Toxicity of intrathecal liposomal cytarabine-based regimens collected between November 2006 and January 2012 was assessed retrospectively. Data from 120 adult lymphoma patients with, or at high risk of CNS involvement who received intrathecal liposomal cytarabine-based regimens at six Polish Lymphoma Research Group centres between November 2006 and January 2012 were assessed retrospectively. Patients were divided into three cohorts: A (high risk of CNS disease, n = 88), B (cerebrospinal fluid pleocytosis without neurological symptoms or pathological imaging findings, n = 7), and C (CNS disease/neurological involvement; n = 25). In all examined groups, toxicity of treatment was found to be acceptable (including the prophylactic setting). None of the patients in cohorts A or B who took intrathecal liposomal cytarabine 50 mg, repeated every 2-4 weeks (mean 3.8 doses) had experienced a CNS relapse at a median follow-up time of 3 years. Patients in cohort C had a 76 % overall neurological response rate (including a 40 % complete response rate) and median overall survival of 4.8 years. Regimens incorporating liposomal cytarabine seem to be safe and effective treatments for lymphomas with CNS involvement. PMID- 25716887 TI - p-Cyanophenylalanine and selenomethionine constitute a useful fluorophore quencher pair for short distance measurements: application to polyproline peptides. AB - The C=N stretching frequency and fluorescence quantum yield of p cyanophenylalanine are sensitive to environment. As such, this unnatural amino acid has found broad applications, ranging from studying how proteins fold to determining the local electric field of membranes. Herein, we demonstrate that the fluorescence of p-cyanophenylalanine can be quenched by selenomethionine through an electron transfer process occurring at short distances, thus further expanding its spectroscopic utility. Using this fluorophore-quencher pair, we are able to show that short polyproline peptides (1-4 prolines) are not rigid; instead, they sample a bimodal conformational distribution. PMID- 25716888 TI - Enterobacillus tribolii gen. nov., sp. nov., a novel member of the family Enterobacteriaceae, isolated from the gut of a red flour beetle, Tribolium castaneum. AB - Two novel Gram-stain negative facultative anaerobic, motile, rod-shaped bacterial strains IG-V01(T) and IG-V01b were isolated from the gut of red flour beetles, Tribolium castaneum. The 16S rRNA gene sequences of strains IG-V01(T) and IG-V01b were found to have their highest sequence similarity (96.5% and 96.4%) with Serratia nematodiphila DZ0503SBS1(T) (Enterobacteriaceae family) respectively. Strains IG-V01(T) and IG-V01b share 100% 16S rRNA gene sequence similarity and exhibit very similar phenotypic characteristics. In addition, they show 89.7% genomic relatedness (DNA-DNA hybridisation). Major fatty acids were identified to be C(16:0) (38.3%), C(17:0) cyclo (19.5-20%) and C(14:0) (11.2-11.3%). Cells contain phosphatidylethanolamine and diphosphatidylglycerol as predominant polar lipids. Genomic DNA G+C content (mol%) was determined to be 51.5-51.7. A polyphasic approach employing the study of morphological, physiological, chemotaxonomic, genomic and phylogenetic analysis revealed that the two newly isolated strains cannot be placed in any of the existing genera of the family Enterobacteriaceae. Therefore, it is proposed that strains IG-V01(T) and IG-V01b belong to a novel genus within the family Enterobacteriaceae, and represent a new species Enterobacillus tribolii gen. nov., sp. nov., with the type strain =IG V01(T) = KCTC 42159(T) = MCC 2532(T). PMID- 25716889 TI - Reduction in the use of potentially inappropriate drugs among old people living in geriatric care units between 2007 and 2013. AB - PURPOSE: The aims of this study were to investigate trends in the prevalence of potentially inappropriate drug use among old people living in geriatric care units in the county of Vasterbotten between 2007 and 2013 using six national quality indicators and to assess the impact of medication reviews on those quality indicators. METHODS: Data were collected concerning potentially inappropriate drug use, function in the activities of daily living (ADL) and cognitive function, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). A comparison was made between the years 2007 and 2013, comprising 2772 and 1902 people, respectively, living in geriatric care in the county of Vasterbotten, Sweden. We conducted a parallel investigation of a separate corresponding population in Vasterbotten County from 2012, where potentially inappropriate drug use was measured before and after 895 medication reviews which involved a clinical pharmacist. RESULTS: After controlling for age, sex, ADL and cognitive impairment, there was a significant improvement in five out of six quality indicators between 2007 and 2013. While 44% of the people were exposed to one or more potentially inappropriate medications in 2007, this number had declined to 26% by 2013. In the separate population from 2012, the frequency of potentially inappropriate drug use was significantly reduced amongst the people who had a medication review performed. CONCLUSION: The extent of potentially inappropriate drug use declined between 2007 and 2013 according to the quality indicators used. Medication reviews involving clinical pharmacists might be an important factor in reducing potentially inappropriate drug use and improving drug treatment among old people. PMID- 25716890 TI - Defining the cytosolic pathway of glutathione degradation in Arabidopsis thaliana: role of the ChaC/GCG family of gamma-glutamyl cyclotransferases as glutathione-degrading enzymes and AtLAP1 as the Cys-Gly peptidase. AB - Glutathione homoeostasis is critical to plant life and its adaptation to stress. The gamma-glutamyl cycle of glutathione biosynthesis and degradation plays a pre eminent role in glutathione homoeostasis. The genes encoding two enzymatic steps of glutathione degradation, the gamma-glutamyl cyclotransferase (GGCT; acting on gamma-glutamyl amino acids) and the Cys-Gly dipeptidase, have, however, lacked identification. We have investigated the family of GGCTs in Arabidopsis thaliana. We show through in vivo functional assays in yeast that all three members of the ChaC/GCG subfamily show significant activity towards glutathione but no detectable activity towards gamma-glutamyl methionine. Biochemical characterization of the purified recombinant enzymes GGCT2;2 and GGCT2;3 further confirmed that they act specifically to degrade glutathione to yield 5-oxoproline and Cys-Gly peptide and show no significant activity towards gamma-glutamyl cysteine. The Km for glutathione was 1.7 and 4.96 mM for GGCT2;2 and GGCT2;3 respectively and was physiologically relevant. Evaluation of representative members of other subfamilies indicates the absence of GGCTs from plants showing significant activity towards gamma-glutamyl-amino acids as envisaged in the classical gamma-glutamyl cycle. To identify the Cys-Gly peptidase, we evaluated leucine aminopeptidases (LAPs) as candidate enzymes. The cytosolic AtLAP1 (A. thaliana leucine aminopeptidase 1) and the putative chloroplastic AtLAP3 displayed activity towards Cys-Gly peptide through in vivo functional assays in yeast. Biochemical characterization of the in vitro purified hexameric AtLAP1 enzyme revealed a Km for Cys-Gly of 1.3 mM that was physiologically relevant and indicated that AtLAP1 represents a cytosolic Cys-Gly peptidase activity of A. thaliana. The studies provide new insights into the functioning of the gamma glutamyl cycle in plants. PMID- 25716891 TI - Idiosyncratic evolution of maternal effects in response to juvenile malnutrition in Drosophila. AB - Maternal effects often affect fitness traits, but there is little experimental evidence pertaining to their contribution to response to selection imposed by novel environments. We studied the evolution of maternal effects in Drosophila populations selected for tolerance to chronic larval malnutrition. To this end, we performed pairwise reciprocal F1 crosses between six selected (malnutrition tolerant) populations and six unselected control populations and assessed the effect of cross direction on larval growth and developmental rate, adult weight and egg-to-adult viability expressed under the malnutrition regime. Each pair of reciprocal crosses revealed large maternal effects (possibly including cytoplasmic genetic effects) on at least one trait, but the magnitude, sign and which traits were affected varied among populations. Thus, maternal effects contributed significantly to the response to selection imposed by the malnutrition regime, but these changes were idiosyncratic, suggesting a rugged adaptive landscape. Furthermore, although the selected populations evolved both faster growth and higher viability, the maternal effects on growth rate and viability were negatively correlated across populations. Thus, genes mediating maternal effects can evolve to partially counteract the response to selection mediated by the effects of alleles on their own carriers' phenotype, and maternal effects may contribute to evolutionary trade-offs between components of offspring fitness. PMID- 25716892 TI - Study the utilization and practice of ECT in south of Iran. PMID- 25716893 TI - EPOS 34th Annual Meeting. PMID- 25716895 TI - [Primary osteolytic intraosseous meningioma of the occipital bone]. AB - Primary intraosseous meningiomas are considered extradural meningiomas when no dural attachment is present. Most of them arise from the cranial bones and can present either as an osteoblastic or an osteolytic lesion. Osteolytic intraosseous meningiomas are the rarest and very few cases have been reported. Given that many of these may develop signs of malignancy, early histological confirmation is important in order to ensure appropriate treatment. The recommended therapy is surgery, with complete resection whenever possible. We present the case of a large primary intraosseous osteolytic meningioma within the occipital bone, which was completely excised five years ago, currently presenting no signs of recurrence. PMID- 25716897 TI - Corrigendum to Blood pressure normalization post-jugular venous balloon angioplasty. AB - Blood pressure normalization post-jugular venous balloon angioplasty,: by Zohara Sternberg, Prabhjot Grewal, Steven Cen, Frances DeBarge-Igoe, Jinhee Yu and Michael Arata, Phlebology 0268355513512824, first published on November 19, 2013 as Epub, DOI:10.1177/0268355513512824. The article also appears in this issue, Phlebology 2015; 30(4): 280-287. The authors would like to note the following corrections to their article: The article type for this paper is 'Retrospective Review' as opposed to 'Original Article'. Zohara Sternberg's affiliation was incorrectly listed. The correct affiliation is 'Synergy Health Concepts, Newport Beach, CA, USA'. The IRB protocol number for this retrospective review was omitted: Study name: Venous Obstruction in Neurodegenerative Disorders Research Registry Protocol Number: RESEARCH_REGISTRY. PMID- 25716896 TI - Optimization of the heme biosynthesis pathway for the production of 5 aminolevulinic acid in Escherichia coli. AB - 5-Aminolevulinic acid (ALA), the committed intermediate of the heme biosynthesis pathway, shows significant promise for cancer treatment. Here, we identified that in addition to hemA and hemL, hemB, hemD, hemF, hemG and hemH are also the major regulatory targets of the heme biosynthesis pathway. Interestingly, up-regulation of hemD and hemF benefited ALA accumulation whereas overexpression of hemB, hemG and hemH diminished ALA accumulation. Accordingly, by combinatorial overexpression of the hemA, hemL, hemD and hemF with different copy-number plasmids, the titer of ALA was improved to 3.25 g l(-1). Furthermore, in combination with transcriptional and enzymatic analysis, we demonstrated that ALA dehydratase (HemB) encoded by hemB is feedback inhibited by the downstream intermediate protoporphyrinogen IX. This work has great potential to be scaled-up for microbial production of ALA and provides new important insights into the regulatory mechanism of the heme biosynthesis pathway. PMID- 25716899 TI - Improvements in fundamental movement skill competency mediate the effect of the SCORES intervention on physical activity and cardiorespiratory fitness in children. AB - Numerous studies have identified a positive association between fundamental movement skill (FMS) competency and physical activity in children; however, the causal pathways have not been established. The aim of this study is to determine if changes in FMS competency mediated the effect of the Supporting Children's Outcomes using Rewards, Exercise and Skills (SCORES) intervention on physical activity and cardiorespiratory fitness in children. Eight primary schools (25 classes) and 460 children (aged 8.5 +/- 0.6, 54% girls) were randomised to the SCORES intervention or control group for the 12-month study. The outcomes were accelerometer-determined moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness. The hypothesised mediators were actual FMS competency and perceived sport competence. Mediation analyses were conducted using multilevel linear analysis in MPlus. From the original sample, 138 (30.0%) and 370 (80.4%) children provided useable physical activity and cardiorespiratory fitness data at post-test assessments. There were significant treatment effects for locomotor skills and overall FMSs. Changes in MVPA were associated with changes in object-control skills, overall FMSs and perceived competence. The overall FMSs had a significant mediating effect on MVPA (AB = 2.09, CI = 0.01 4.55). Overall FMSs (AB = 1.19, CI = 0.002-2.79) and locomotor skills (AB = 0.74, CI = 0.01-1.69) had a significant mediating effect on cardiorespiratory fitness. The results of this study conclude that actual but not perceived movement skill competency mediated the effect of the SCORES intervention on physical activity and cardiorespiratory fitness. PMID- 25716898 TI - Ischaemic stroke or TIA in older subjects associated with impaired dynamic blood pressure control in the absence of severe large artery stenosis. AB - BACKGROUND: older subjects may require higher baseline blood pressures to maintain cerebral perfusion. We investigated whether episodic hypotension is associated with tissue infarction in subjects with syncopal symptoms at stroke onset. METHODS: over 30 months, all acute strokes/TIAs were prospectively screened for symptoms of syncope or presyncope at stroke onset. Subjects with severe large vessel stenosis were excluded, while cases were referred for syncope unit investigation. All underwent 1.5 T MRI acutely, and suspected borderzone infarctions (BZI) were confirmed through Matlab-derived perfusion software. Case control comparison was derived from stroke controls with no prior syncope history. RESULTS: thirty-eight of 772 stroke patients described presyncope or syncope at stroke onset and had patent large vessels (4.9% of all strokes). Median age was 72 years (IQR 21.4). Twenty-two patients (58%) were prescribed antihypertensive agents at symptom onset. Twenty-six (68.4%) reported focal neurology <24 h in duration. 63.2% (n = 24) of cases reported prior syncope history, compared with 33% (N = 103) of controls, P < 0.001. Cases exhibited greater orthostatic BP drop than controls, P < 0.05 Twenty-four patients were diagnosed with vasovagal syncope through head-up tilt symptom reproduction, 9 with orthostatic hypotension, 4 with cardiac syncope and 1 with carotid sinus syndrome. Nineteen (50%) patients had an acute infarct on MRI, 14 of these were in the arterial borderzone (73.6%). The BZI group were significantly older than the non-BZI group, 79.2 yrs versus 63.3 yrs, P = 0.002. CONCLUSION: subjects reporting hypotensive symptoms at stroke onset have a higher prevalence of borderzone infarction, despite being normotensive or hypertensive at baseline. PMID- 25716901 TI - Radionuclides in the soil around the largest coal-fired power plant in Serbia: radiological hazard, relationship with soil characteristics and spatial distribution. AB - Primordial radionuclides, (238)U, (232)Th and (40)K were determined in soil samples collected at two depths (0-10 and 10-20 cm) in the vicinity of the largest coal-fired power plant in Serbia, and their spatial distribution was analysed using ordinary kriging. Mean values of activity concentrations for these depths were 50.7 Bq kg(-1) for (238)U, 48.7 Bq kg(-1) for (232)Th and 560 Bq kg( 1) for (40)K. Based on the measured activity concentrations, the radiological hazard due to naturally occurring radionuclides in soil was assessed. The value of the mean total absorbed dose rate was 76.3 nGy h(-1), which is higher than the world average. The annual effective dose due to these radionuclides ranged from 51.4 to 114.2 MUSv. Applying cluster analysis, correlations between radionuclides and soil properties were determined. The distribution pattern of natural radionuclides in the environment surrounding the coal-fired power plant and their enrichment in soil at some sampling sites were in accordance with dispersion models of fly ash emissions. From the results obtained, it can be concluded that operation of the coal-fired power plant has no significant negative impact on the surrounding environment with regard to the content of natural radionuclides. PMID- 25716900 TI - Influence of Rhizophagus irregularis inoculation and phosphorus application on growth and arsenic accumulation in maize (Zea mays L.) cultivated on an arsenic contaminated soil. AB - Southern Tuscany (Italy) is characterized by extensive arsenic (As) anomalies, with concentrations of up to 2000 mg kg soil(-1). Samples from the location of Scarlino, containing about 200 mg kg(-1) of As, were used to study the influence of the inoculation of an arbuscular mycorrhizal (AM) fungus (Rhizophagus irregularis, previously known as Glomus intraradices) and of phosphorus (P) application, separately and in combination, on As speciation in the rhizosphere of Zea mays on plant growth and As accumulation. Also, P distribution in plant parts was investigated. Each treatment produced a moderate rise of As(III) in the rhizosphere, increased As(III) and lowered As(V) concentration in shoots. P treatment, alone or in combination with AM, augmented the plant biomass. The treatments did not affect total As concentration in the shoots (with all the values <1 mg kg(-1) dry weight), while in the roots it was lowered by P treatment alone. Such decrease was probably a consequence of the competition between P and As(V) for the same transport systems, interestingly nullified by the combination with AM treatment. P concentration was higher with AM only in both shoots and roots. Therefore, the obtained results can be extremely encouraging for maize cultivation on a marginal land, like the one studied. PMID- 25716902 TI - The choice of the noninferiority margin in clinical trials was driven by baseline risk, type of primary outcome, and benefits of new treatment. AB - OBJECTIVES: To explore characteristics of clinical trials that influence the choice of the noninferiority margin (NIM) when planning the trial. STUDY DESIGN AND SETTING: We conducted an experimental survey among corresponding authors of randomized controlled trials indexed in MEDLINE. We described two hypothetical studies and asked the respondents' opinion on the largest loss of effectiveness that is clinically negligible (or the smallest lost of effectiveness that is clinically important in the superiority scenario). We randomly manipulated four study attributes in each vignette, using a factorial design. RESULTS: A total of 364 researchers participated. The values for NIMs were significantly lower than the differences to be detected in a superiority trial. The NIM was smaller when the primary outcome was mortality compared with treatment failure, when baseline risk in the control arm was lower, and when the advantage of the new treatment was a lower cost compared with having fewer side effects. In contrast, the population age group under study and the difficulty to recruit patients showed no effect on the choice of the NIM. CONCLUSION: In our experimental study, the factors associated with lower NIMs were mortality as a primary outcome, low baseline risk, and a less costly new treatment. PMID- 25716903 TI - Semantic primes theory may be helpful in designing questionnaires such as to prevent response shift. AB - OBJECTIVES: The purpose of randomized control trials (RCTs) can be the assessment of the direct effect of treatment on health-related quality of life (HRQL). Response shift (RS) theory considers that a change in HRQL scores observed over time cannot be explained solely by a direct effect of a medical condition, it may also result from a change in the way people appraise their HRQL. The RS effect is a potential bias that is liable to compromise efficient assessment of the effect of treatment on HRQL. STUDY DESIGN AND SETTING: We hypothesize a link between the RS effect on HRQL scores and the level of complexity of HRQL conceptualization. RESULTS: We discuss how the impact of reconceptualization on scores depends on the complexity of the linguistic definition of a subjective construct and how for reprioritization the impact depends on the dimensionality. The linguistic theory of semantic primes is used to help identify how subjective constructs can be classified according to the complexity of their definitions. CONCLUSION: Finally, we suggest that the impact of the RS effect on HRQL scores could be avoided (or lessened) if questionnaires were designed with a rule of "the least semantic and psychometric complexity" in mind. PMID- 25716904 TI - 99mTc-HYNIC-MPG: a novel SPECT probe for targeting mutated EGFR. AB - Mutated epidermal growth factor receptor (EGFR) is an important biomarker for cancer diagnosis and molecular target for many anticancer drugs. Localizing EGFR and evaluating EGFR mutational status can help to identify patients who are potentially the most suitable ones for targeted treatments. Hence, we developed a novel EGFR tyrosine kinase inhibitor labeled with (99m)Tc ((99m)Tc-HYNIC-MPG) and evaluated its EGFR binding capacity in vitro and in vivo. This molecular probe was synthesized by one-step method that is simple and highly efficient. Importantly, the uptake rate for (99m)Tc-HYNIC-MPG in the liver was as low as 28.44 +/- 0.15% (mean +/- SD, n=3). This finding presents for the first time that (99m)Tc-HYNIC-MPG can bind to mutated EGFR efficiently and thus provides a novel molecular tool to detect mutated EGFR and suppress tumorigenesis. PMID- 25716905 TI - Discovery of hydroxyaniline amides as selective Extracellular Regulated Kinase (Erk) inhibitors. AB - Starting from weak MUM hits identified through affinity based Automated Ligand Identification System (ALIS) screenings, double digit nM hydroxyaniline amide Erk inhibitors were discovered. This class of compounds had the unique dual mechanism of inhibiting activated and non-activated forms of Erk. They generally had high degree of selectivity in kinase panel tested. PMID- 25716906 TI - New quaternary arsenide oxides with square planar coordination of gold(I) - structure, (197)Au Mossbauer spectroscopic, XANES and XPS characterization of Nd10Au3As8O10 and Sm10Au3As8O10. AB - The quaternary gold(I) arsenide oxides Nd10Au3As8O10 and Sm10Au3As8O10 were synthesized in sealed quartz ampoules from the rare earth (RE) elements, their appropriate sesquioxides, arsenic, arsenic(III) oxide and finely dispersed gold at maximum annealing temperatures of 1223 K. Both structures were refined from X ray single crystal diffractometer data at room temperature and at 90 K. Nd10Au3As8O10 and Sm10Au3As8O10 crystallize with a new structure type that derives from the BaAl4 structure through distortions and formation of ordered vacancies. The structures consist of stacked polycationic [RE10O10](10+) layers with oxygen in tetrahedral rare earth coordination and polyanionic [Au(I)3(As2)4](10-) layers with gold in square planar or rectangular planar coordination of four arsenic dumbbells (255 pm As1-As2). In contrast to the well known ionic rare earth oxide layers, the gold arsenide layers rather show covalent bonding and account for the metallic nature of these two new arsenide oxides. This is confirmed by electronic structure calculations and resistivity measurements. The oxidation state of gold was investigated by (197)Au Mossbauer, X-ray absorption near edge structure (XANES) and photoelectron (XPS) spectroscopy. Due to missing comparative gold arsenide compounds, the monovalent gold phosphide oxides RE2AuP2O were measured for comparison. The XANES measurements additionally comprise monovalent gold arsenides REAuAs2. The XPS study contains BaAuAs as reference compound instead. Combination of all data clearly indicates Au(I), which was not observed in square planar coordination up to now. Temperature dependent magnetic susceptibility data show Curie-Weiss paramagnetism for Nd10Au3As8O10 and no magnetic ordering down to 2.5 K. Sm10Au3As8O10 shows the typical Van Vleck type paramagnetism for samarium compounds along with a transition to an antiferromagnetically ordered state at TN = 8.6 K. PMID- 25716907 TI - Triazolate-based 3D frameworks and a 2D layer with centrosymmetric Cu(II)7, Cu(II)5, Cu(II)4 clusters and tunable interlayer/interchain compactness: hydrothermal syntheses, crystal structures and magnetic properties. AB - Four 1,2,3-triazolate-based coordination polymers (CPs) with varied dimensionality, different nuclearity numbers and core topologies, [Cu4(MU-OH)(MU3 OH)(ta)2(btec)]n (1), {[Cu6(MU3-OH)2(ta)8(tp)].2.5H2O}n (2), {[Cu5(MU3 OH)2(ta)4(ip)2].2H2O}n (3) and {[Cu5(MU-OH)2(MU3-OH)2(ta)2(pa)2].2H2O}n (4) (ta = 1,2,3-triazolate, btec = 1,2,4,5-benzenetetracarboxylate, tp = terephthalate, ip = isophthalate and pa = phthalate), were hydrothermally synthesized by varying the numbers and positions of the carboxylate group appended on the phenyl tether, and structurally and magnetically characterized. The former three entities are three-dimensional (3D) robust frameworks with a (4(4).6(2))(4(11).6(5))2(4(13).6(10).8(5)) topological net containing centrosymmetric Cu(II)7 clusters, square-planar Cu(II)1 cores and tetratopic btec(4-) linkers for 1, a pillared-layered structure consisting of Cu(II)5 + Cu(II)1-based coplanar layers and ditopic tp(2-) pillars for 2 as well as a microporous architecture derived from Cu(II)5 clusters and directional ip(2-) connectors for 3. In contrast, complex exhibits an undulated two-dimensional (2D) layer with alternating Cu(II)4 + Cu(II)1 chains interconnected by anionic pa(2-) connectors. Crystallographically, the increment of the local nuclearity from Cu(II)4 up to Cu(II)7 in 1-4 benefits greatly from the synergistic co coordination of the hydroxyl group and the coplanar ta(-) ligand towards the metal ion, and the interlayer/interchain compactness is significantly tuned by the position isomerism of the dicarboxylate moieties. Due to the antiferromagnetic coupling in the local clusters and the asymmetric superexchange by MU3-ta(-) mediator, these complexes 4 exhibit different spin ground states (paramagnetic S = 1 and 1/2, ferrimagnetic S = 1/2 as well as spin canting) at low temperatures, which are informative for polynuclear-based magnetic materials. PMID- 25716908 TI - Radical aminooxygenation of alkenes with N-fluoro-benzenesulfonimide (NFSI) and TEMPONa. AB - Reaction of various alkenes with commercially available N fluorobenzenesulfonimide (NFSI) and TEMPONa provides the corresponding aminooxygenation products in moderate to good yields. Single electron transfer from readily generated TEMPONa to NFSI allows for clean generation of the corresponding bissulfonylamidyl radical along with TEMPO. N-radical addition to an alkene and subsequent TEMPO trapping provides the corresponding aminooxygenation product. PMID- 25716909 TI - The relationship between arterial stiffness and heart failure with preserved ejection fraction: a systemic meta-analysis. AB - The objective is to investigate the relationship between arterial stiffness measured by arterial tonometry and echocardiographic indices of diastolic dysfunction-a basis for the diagnosis of heart failure with preserved ejection fraction (HFpEF). OvidSP Medline, Embase and PubMed were systematically searched. Eligible articles correlated arterial stiffness measured by brachial-ankle pulse wave velocity (baPWV), carotid-femoral pulse wave velocity (cfPWV), augmentation index (AIx) or cardio-ankle vascular index (CAVI) with indices of diastolic dysfunction, E/A ratio, peak early mitral annular velocity (e') and E/e' ratio. Correlation coefficients were determined using a random-effects model. Twenty seven studies with 6,626 patients were included. baPWV was significantly correlated with E/A ratio (r = -0.434, 95 % CI -0.387 to -0.479), e' (r = -0.499, 95 % CI -0.448 to -0.548) and E/e' ratio (r = 0.372, 95 % CI 0.251-0.481). cfPWV was significantly correlated with E/A ratio (r = -0.391, 95 % CI -0.304 to 0.470) and E/e' ratio (r = 0.210, 95 % CI 0.300-0.116), but not e'. AIx was significantly correlated with E/A ratio (r = -0.356, 95 % CI -0.255 to -0.450), e' (r = -0.313, 95 % CI -0.195 to -0.423) and E/e' ratio (r = 0.321, 95 % CI 0.250-0.388). CAVI was significantly correlated with E/A ratio (r = -0.405, CI 0.324 to -0.481), e' (r = -0.449, 95 % CI -0.340 to -0.630), but not E/e'. baPWV showed significantly greater correlation with diastolic dysfunction compared to most other tonometric techniques. Arterial stiffness measured by arterial tonometry is an indicator of diastolic dysfunction with baPWV demonstrated the most consistent and strongest association. These data suggest a refocusing on the impact of arterial stiffness on the left ventricle as a potential causative factor leading to HFpEF. PMID- 25716910 TI - Genetic diversity of disease-associated loci in Turkish population. AB - Many consortia and international projects have investigated the human genetic variation of a large number of ethno-geographic groups. However, populations with peculiar genetic features, such as the Turkish population, are still absent in publically available datasets. To explore the genetic predisposition to health related traits of the Turkish population, we analyzed 34 genes associated with different health-related traits (for example, lipid metabolism, cardio-vascular diseases, hormone metabolism, cellular detoxification, aging and energy metabolism). We observed relevant differences between the Turkish population and populations with non-European ancestries (that is, Africa and East Asia) in some of the investigated genes (that is, AGT, APOE, CYP1B1, GNB3, IL10, IL6, LIPC and PON1). As most complex traits are highly polygenic, we developed polygenic scores associated with different health-related traits to explore the genetic diversity of the Turkish population with respect to other human groups. This approach showed significant differences between the Turkish population and populations with non-European ancestries, as well as between Turkish and Northern European individuals. This last finding is in agreement with the genetic structure of European and Middle East populations, and may also agree with epidemiological evidences about the health disparities of Turkish communities in Northern European countries. PMID- 25716911 TI - A new method for SMN1 and hybrid SMN gene analysis in spinal muscular atrophy using long-range PCR followed by sequencing. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by progressive loss of motor neurons in the spinal cord. Approximately 95% of SMA patients have a homozygous deletion of the survival motor neuron 1 (SMN1) gene, whereas 5% harbor compound heterozygous mutations such as an SMN1 deletion allele and an intragenic mutation in the other SMN1 allele. It is difficult to detect intragenic mutations in SMN1 because of the high degree of homology shared between SMN1 and SMN2. Current methods analyze a restricted region from exon 2a to exon 7 in SMN1. We propose a new, efficient long-range polymerase chain reaction (PCR) method for detecting intragenic mutations in SMN1 (exon 1-8) and hybrid SMN genes. We analyzed 20 unrelated SMA patients using SMN copy number analysis, and the new long-range PCR method followed by sequencing. We thus confirmed a novel mutation in SMN1 exon 1 (c.5C>T) in three patients with SMA type III who also had an SMN1 deletion allele. Moreover, we confirmed three hybrid SMN gene types in eight patients. We report a novel SMN1 mutation responsible for a relatively mild SMA phenotype and three hybrid SMN gene types in patients with SMA type III. PMID- 25716912 TI - Constructive rescue of TFIIH instability by an alternative isoform of XPD derived from a mutated XPD allele in mild but not severe XP-D/CS. AB - Mutations in XPD cause xeroderma pigmentosum (XP), XP and Cockayne syndrome (CS) crossover syndrome (XP/CS), trichothiodystrophy and cerebro-oculo-facio-skeletal syndrome (COFS). COFS represents the most severe end of the CS spectrum. This study reports two Japanese patients, COFS-05-135 and COFS-Chiba1, who died at ages of <1 year and exhibited typical COFS manifestations caused by XPD mutations p.[I619del];[R666W] and p.[G47R];[I619del], respectively. Two other cases of severe XP-D/CS (XP group D/CS), XP1JI (p.[G47R];[0]) and XPCS1PV (p.[R666W];[0]), died at ages <2 years. On the other hand, two cases of mild XP-D/CS, XP1NE (p.[G47R];[L461V;V716_R730del]) and XPCS118LV (p.[L461V;V716_R730del];[R666W]), lived beyond 37 years of age. p.I619Del and p.[L461V;V716_R730del] are functionally null; therefore, despite the differences in clinical manifestations, the functional protein in all of these patients was either p.G47R or p.R666W. To resolve the discrepancies in these XPD genotype-phenotype relationships, the p.[L461V;V716_R730del] allele was analyzed and we found that p.[L461V;A717G] was expressed from the same allele as p.[L461V;V716_R730del] by authentic splicing. Additionally, p.[L461V;A717G] could partially rescue the loss of XPD function, resulting in the milder manifestations observed in XP1NE and XPCS118LV. PMID- 25716913 TI - Detection of APC mosaicism by next-generation sequencing in an FAP patient. AB - Familial adenomatous polyposis (FAP) of the colon is characterized by multiple polyps in the intestine and extra-colonic manifestations. Most FAP cases are caused by a germline mutation in the tumor-suppressor gene APC, but some cases of adenomatous polyposis result from germline mutations in MUTYH, POLD1 or POLE. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic FAP patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. Whole-genome sequencing and subsequent deep sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in ~12% of his peripheral leukocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data implied that genetic analysis by next generation sequencing is an effective strategy to identify genetic mosaicism in hereditary diseases. PMID- 25716914 TI - WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period. AB - WWOX has been recently implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy (EOEE). By array comparative genomic hybridization, we identified a 0.6 Mb homozygous deletion in 16q23.1 in a fetus presenting with brain anomalies. His older sister who died at the age of 22 months from an EOEE was also homozygous for the copy number variations in 16q23.1. This deletion includes the first six exons of WWOX and results in a null genotype in homozygous patients. This family gives additional support for the implication of WWOX in severe EOEEs. We report for the first time prenatal ultrasound findings in a fetus with a WWOX-null genotype. Our study expands the range of brain abnormalities in WWOX-related EOEEs. This additional family confirms the genotype-phenotype correlation with WWOX-null alleles associated with the most severe form of WWOX-related epileptic encephalopathy with premature death. PMID- 25716915 TI - The juxtaposition of ribose hydroxyl groups: the root of biological catalysis and the RNA world? AB - We normally think of enzymes as being proteins; however, the RNA world hypothesis suggests that the earliest biological catalysts may have been composed of RNA. One of the oldest surviving RNA enzymes we are aware of is the peptidyl transferase centre (PTC) of the large ribosomal RNA, which joins amino acids together to form proteins. Recent evidence indicates that the enzymatic activity of the PTC is principally due to ribose 2'-OHs. Many other reactions catalyzed by RNA and/or in which RNA is a substrate similarly utilize ribose 2'-OHs, including phosphoryl transfer reactions that involve the cleavage and/or ligation of the ribose-phosphate backbone. It has recently been proposed by Yakhnin (2013) that phosphoryl transfer reactions were important in the prebiotic chemical evolution of RNA, by enabling macromolecules composed of polyols joined by phosphodiester linkages to undergo recombination reactions, with the reaction energy supplied by the phosphodiester bond itself. The almost unique juxtaposition of the ribose 2' hydroxyl and 3'-oxygen in ribose-containing polymers such as RNA, which gives ribose the ability to catalyze such reactions, may have been an important factor in the selection of ribose as a component of the first biopolymer. In addition, the juxtaposition of hydroxyl groups in free ribose: (i) allows coordination of borate ions, which could have provided significant and preferential stabilization of ribose in a prebiotic environment; and (ii) enhances the rate of permeation by ribose into a variety of lipid membrane systems, possibly favouring its incorporation into early metabolic pathways and an ancestral ribose-phosphate polymer. Somewhat more speculatively, hydrogen bonds formed by juxtaposed ribose hydroxyl groups may have stabilized an ancestral ribose-phosphate polymer against degradation (Bernhardt and Sandwick 2014). I propose that the almost unique juxtaposition of ribose hydroxyl groups constitutes the root of both biological catalysis and the RNA world. PMID- 25716916 TI - Novel applications of physical autocatalysis. AB - The autocatalytic self-reproduction of micelles and vesicles has been studied for several decades. These systems are vital components of certain protocell models and some models for how life may have begun from mixtures of simple chemicals. Here we discuss our recently described autocatalytic systems where self reproducing micelles are driven by bond-forming reactions. These systems generate increased complexity on both the molecular level, through covalent bond formation, and the supramolecular level, through spontaneous self-assembly into functional aggregates. This provides the conceptual basis for novel studies of the potential roles of self-reproducing lipid aggregates in the prebiotic world. PMID- 25716917 TI - Essentials in the Life Process Indicated by the Self-Referential Genetic Code. AB - The self-referential genetic encoding starts with glycine and serine, in the realm of one-carbon units of metabolism. It is proposed that the prototRNA dimer directed mechanism of protein synthesis and encoding promotes a sink dynamics that corresponds to the driving 'force' for the fixation of the supporting metabolic pathways. A succession of processes is delineated, ending up in reproduction, which accomplished the function of reinforcing the protein synthesis metabolic sink mechanism. PMID- 25716918 TI - Periodic Vesicle Formation in Tectonic Fault Zones--an Ideal Scenario for Molecular Evolution. AB - Tectonic fault systems in the continental crust offer huge networks of interconnected channels and cavities. Filled mainly with water and carbon dioxide (CO2), containing a wide variety of hydrothermal chemistry and numerous catalytic surfaces, they may offer ideal reaction conditions for prebiotic chemistry. In these systems, an accumulation zone for organic compounds will develop at a depth of approximately 1 km where CO2 turns sub-critical and dissolved components precipitate. At this point, periodic pressure changes caused for example by tidal influences or geyser activity may generate a cyclic process involving repeated phase transitions of carbon dioxide. In the presence of amphiphilic compounds, this will necessarily lead to the transient formation of coated water droplets in the gas phase and corresponding vesicular structures in the aqueous environment. During this process, the concentration of organic components inside the droplets and vesicles would be drastically increased, allowing for favorable reaction conditions and, in case of the vesicles generated, large trans-membrane concentration gradients. Altogether, the process of periodic formation and destruction of vesicles could offer a perfect environment for molecular evolution in small compartments and for the generation of protocells. The basic process of vesicle formation is reproduced experimentally with a lipid in a water/CO2 system. PMID- 25716919 TI - In situ imidazole activation of ribonucleotides for abiotic RNA oligomerization reactions. AB - The hypothesis that RNA played a significant role in the origin of life requires effective and efficient abiotic pathways to produce RNA oligomers. The most successful abiotic oligomerization reactions to date have utilized high-energy, modified, or pre-activated ribonucleotides to generate strands of RNA up to 50 mers in length. In spite of their success, these modifications and pre-activation reactions significantly alter the ribonucleotides in ways that are highly unlikely to have occurred on a prebiotic Earth. This research seeks to address this problem by exploring an aqueous based method for activating the canonical ribonucleotides in situ using 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and imidazole. The reactions were run with and without a montmorillonite clay catalyst and compared to reactions that used ribonucleotides that were pre activated with imidazole. The effects of pH and ribonucleotide concentration were also investigated. The results demonstrate the ability of in situ activation of ribonucleotides to generate linear RNA oligomers in solution, providing an alternative route to produce RNA for use in prebiotic Earth scenarios. PMID- 25716920 TI - Aldolase as a chirality intersection of L-amino acids and D-sugars. AB - Aldolase plays an important role in glycolysis and gluconeogenesis to produce D fructose-1,6-bisphosphate (D-FBP) from dihydroxyacetone phosphate (DHP) and D glyceraldehyde-3-phosphate (D-GAP). This reaction is stereoselective and retains the D-GAP 2R configuration and yields D-FBP (with the configuration: 3S, 4S, 5R). The 3- and 4-position carbons are the newly formed chiral carbons because the 5 position carbon of D-FBP comes from the 2-position of D-GAP. Although four diastereomeric products, (3S, 4R, 5R), (3R, 4R, 5R), (3R, 4S, 5R), (3S, 4S, 5R), are expected in the nonenzymatic reaction, only the (3S, 4S, 5R) diastereomer (D FBP) is obtained. Therefore, the chirality in the 3- and 4-positions is induced by the chirality of the enzyme composed of L-amino acid residues. D-Glucose-6 phosphate (D-G6P), which is generated from D-FBP in the gluconeogenesis pathway, produces D-ribose-5-phosphate (D-R5P) in the pentose phosphate pathway. D-R5P is converted to PRPP (5-phosphoribosyl-alpha-pyrophosphate), which is used for the de novo synthesis of nucleotides. Ribonucleic acid (RNA) uses the nucleotides as building blocks. The configurations of the 4R-carbon and of the 3S-carbon are retained. The stereochemical structure of RNA is based on 3S as well as 4R (D). The consideration above suggests that aldolase is a key enzyme that determines the 3S configuration in D-R5P. It is thus a chirality intersection between amino acids and sugars, because the sugar chirality is determined by the chiral environment of an L-amino acid protein, aldolase, to produce D-FBP. PMID- 25716922 TI - Secondary structure analysis of swine pasivirus (family Picornaviridae) RNA reveals a type-IV IRES and a parechovirus-like 3' UTR organization. AB - The potential RNA structures of the 5' and 3' untranslated regions (UTRs) and cis acting replication elements (CREs) of a novel pasivirus (PaV) genotype (family Picornaviridae) were analysed. PaV-A3 (KM259923) was identified in a faecal sample from a domestic pig in Hungary with posterior paraplegia of unknown etiology. Based on likely structural features of the 5' UTR, the pasiviruses were inferred to possess Hepacivirus/Pestivirus-like type-IV IRES. The pasivirus CRE was mapped to the 2B genome region, similar to Ljungan virus. The secondary RNA structure of the pasivirus 3' UTR was structurally similar to that of human parechoviruses. The genome, CRE, and 3' UTR of pasiviruses provide further evidence of the common origin of the members of the genera Parechovirus and Pasivirus, although their different 5' UTR IRES types suggest that a recombination event occurred during the divergence these viruses. PMID- 25716921 TI - Genome editing strategies: potential tools for eradicating HIV-1/AIDS. AB - Current therapy for controlling human immunodeficiency virus (HIV-1) infection and preventing acquired immunodeficiency syndrome (AIDS) progression has profoundly decreased viral replication in cells susceptible to HIV-1 infection, but it does not eliminate the low level of viral replication in latently infected cells, which contain integrated copies of HIV-1 proviral DNA. There is an urgent need for the development of HIV-1 genome eradication strategies that will lead to a permanent or "sterile" cure of HIV-1/AIDS. In the past few years, novel nuclease-initiated genome editing tools have been developing rapidly, including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas9 system. These surgical knives, which can excise any genome, provide a great opportunity to eradicate the HIV-1 genome by targeting highly conserved regions of the HIV-1 long terminal repeats or essential viral genes. Given the time consuming and costly engineering of target-specific ZFNs and TALENs, the RNA-guided endonuclease Cas9 technology has emerged as a simpler and more versatile technology to allow permanent removal of integrated HIV-1 proviral DNA in eukaryotic cells, and hopefully animal models or human patients. The major unmet challenges of this approach at present include inefficient nuclease gene delivery, potential off-target cleavage, and cell-specific genome targeting. Nanoparticle or lentivirus-mediated delivery of next generation Cas9 technologies including nickase or RNA-guided FokI nuclease (RFN) will further improve the potential for genome editing to become a promising approach for curing HIV-1/AIDS. PMID- 25716923 TI - Molecular characterization of a new begomovirus associated with leaf yellow mosaic disease of Jatropha curcas in India. AB - During a survey in June 2011, severe leaf yellow mosaic disease was observed on about 45 % plants of Jatropha curcas growing in the Katerniaghat wildlife sanctuary in India. An association of a begomovirus with disease was detected in 15 out of 20 samples by PCR using begomovirus genus-specific primers and total DNA isolated from symptomatic leaf samples. For identification of the begomovirus, the complete genome was amplified using a Phi-29 DNA-polymerase based rolling-circle amplification kit and total DNA from five representative samples and then digested with BamHI. The linearized RCA products were cloned and sequenced. Their GenBank accession numbers are JN698954 (SKRK1) and JN135236 (SKRK2). The sequences of the two begomovirus isolates were 97 % identical to each other and no more than 86 % to those of jatropha mosaic India virus (JMIV, HM230683) and other begomoviruses reported worldwide. In phylogenetic analysis, SKRK1 and SKRK2 clustered together and showed distant relationships to jatropha mosaic India virus, Jatropha curcas mosaic virus, Indian cassava mosaic virus, Sri Lankan cassava mosaic virus and other begomoviruses. Based on 86 % sequence identities and distant phylogenetic relationships to JMIV and other begomoviruses and the begomovirus species demarcation criteria of the ICTV (<89 % sequence identity of complete DNA-A genome), the begomovirus isolates associated with leaf yellow mosaic disease of J. curcas were identified as members of a new begomovirus species and provisionally designated as jatropha leaf yellow mosaic Katerniaghat virus (JLYMKV). Agroinfectious clones of the DNA molecule of the begomovirus isolate were also generated, and the fulfillment of Koch's postulates was demonstrated in J. curcas plants. PMID- 25716924 TI - Effects of acid-base variables and the role of carbonic anhydrase on oxalate secretion by the mouse intestine in vitro. AB - Hyperoxaluria is a major risk factor for calcium oxalate kidney stones and the intestine is recognized as an important extra-renal pathway for eliminating oxalate. The membrane-bound chloride/bicarbonate (Cl(-)/) exchangers are involved in the transcellular movement of oxalate, but little is understood about how they might be regulated. , CO2, and pH are established modulators of intestinal NaCl cotransport, involving Na(+)/H(+) and Cl(-)/ exchange, but their influence on oxalate transport is unknown. Measuring (14)C-oxalate and (36)Cl fluxes across isolated, short-circuited segments of the mouse distal ileum and distal colon we examined the role of these acid-base variables and carbonic anhydrase (CA) in oxalate and Cl(-) transport. In standard buffer both segments performed net oxalate secretion (and Cl(-) absorption), but only the colon, and the secretory pathway were responsive to and CO2. Ethoxzolamide abolished net oxalate secretion by the distal colon, and when used in tandem with an impermeant CA inhibitor, signaled an intracellular CA isozyme was required for secretion. There was a clear dependence on as their removal eliminated secretion, while at 42 mmol/L was also decreased and eradicated. Independent of pH, raising Pco2 from 28 to 64 mmHg acutely stimulated net oxalate secretion 41%. In summary, oxalate secretion by the distal colon was dependent on , CA and specifically modulated by CO2, whereas the ileum was remarkably unresponsive. These findings highlight the distinct segmental heterogeneity along the intestine, providing new insights into the oxalate transport mechanism and how it might be regulated. PMID- 25716925 TI - The blood pressure-elevating effect of Red Bull energy drink is mimicked by caffeine but through different hemodynamic pathways. AB - The energy drink Red Bull (RB) has recently been shown to elevate resting blood pressure (BP) and double product (reflecting increased myocardial load). However, the extent to which these effects can be explained by the drink's caffeine and sugar content remains to be determined. We compared the cardiovascular impact of RB to those of a comparable amount of caffeine, and its sugar-free version in eight young healthy men. Participants attended four experimental sessions on separate days according to a placebo-controlled randomized crossover study design. Beat-to-beat hemodynamic measurements were made continuously for 30 min at baseline and for 2 h following ingestion of 355 mL of either (1) RB + placebo; (2) sugar-free RB + placebo; (3) water + 120 mg caffeine, or (4) water + placebo. RB, sugar-free RB, and water + caffeine increased BP equally (3-4 mmHg) in comparison to water + placebo (P < 0.001). RB increased heart rate, stroke volume, cardiac output, double product, and cardiac contractility, but decreased total peripheral resistance (TPR) (all P < 0.01), with no such changes observed following the other interventions. Conversely, sugar-free RB and water + caffeine both increased TPR in comparison to the water + placebo control (P < 0.05). While the impact of RB on BP is the same as that of a comparable quantity of caffeine, the increase occurs through different hemodynamic pathways with RB's effects primarily on cardiac parameters, while caffeine elicits primarily vascular effects. Additionally, the auxiliary components of RB (taurine, glucuronolactone, and B-group vitamins) do not appear to influence these pathways. PMID- 25716926 TI - Regulation of soluble fms-like tyrosine kinase-1 production in response to placental ischemia/hypoxia: role of angiotensin II. AB - While soluble fms-like tyrosine-1 (sFlt-1) is implicated in the pathogenesis of hypertension during preeclampsia, the mechanisms leading to the enhanced sFlt-1 production remain unclear. A recent report suggests exogenous angiotensin II (ANGII) stimulates sFlt-1 production in pregnant rats, however, the role of endogenous ANGII in mediating the placental production of sFlt-1 in response to placental ischemia remains unknown. Therefore, the purpose of this study was to determine the role of endogenous ANGII in mediating the placental production of sFlt-1 in response to placental ischemia in pregnant Sprague-Dawley rats. To this end we compared sFlt-1 and ANGII levels from placental explants collected from normal pregnant (NP) and Reduced Uterine Perfusion Pressure (RUPP) rats. sFlt-1 (3271 +/- 264 vs. 2228 +/- 324 pg/mL, P < 0.05) and ANGII levels (43.2 +/- 2.8 vs. 26.7 +/- 1.9 pg/mL, P < 0.05) were higher in placental explants from RUPP rats versus NP rats. Administration of Losartan, an angiotensin type 1 (AT1) receptor antagonist, (10 mg/day for 5 days) to RUPP rats significantly reduced plasma levels of sFlt-1 (1432 +/- 255 pg/mL, P < 0.05) when compared with untreated control rats (3431 +/- 454 pg/mL). In addition, RUPP-induced hypertension was significantly reduced (113 +/- 2 mmHg vs. 139 +/- 2 mmHg, P < 0.05). In conclusion, placental sFlt-1 and ANGII production are significantly elevated in response to placental ischemia in pregnant rats. In addition, AT1 receptor activation, by endogenous ANGII, appears to play an important role in mediating the placental production of sFlt-1 in response to placental ischemia in pregnant rats. PMID- 25716927 TI - Effects of heat stress on carbohydrate and lipid metabolism in growing pigs. AB - Heat stress (HS) jeopardizes human and animal health and reduces animal agriculture productivity; however, its pathophysiology is not well understood. Study objectives were to evaluate the direct effects of HS on carbohydrate and lipid metabolism. Female pigs (57 +/- 5 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 20 degrees C) and were ad libitum fed. During period 2, pigs were exposed to: (1) constant HS conditions (32 degrees C) and fed ad libitum (n = 7), or (2) TN conditions and pair-fed (PFTN; n = 10) to minimize the confounding effects of dissimilar feed intake. All pigs received an intravenous glucose tolerance test (GTT) and an epinephrine challenge (EC) in period 1, and during the early and late phases of period 2. After 8 days of environmental exposure, all pigs were killed and tissue samples were collected. Despite a similar reduction in feed intake (39%), HS pigs tended to have decreased circulating nonesterified fatty acids (NEFA; 20%) and a blunted NEFA response (71%) to the EC compared to PFTN pigs. During early exposure, HS increased basal circulating C peptide (55%) and decreased the insulinogenic index (45%) in response to the GTT. Heat-stressed pigs had a reduced T3 to T4 ratio (56%) and hepatic 5'-deiodinase activity (58%). After 8 days, HS decreased or tended to decrease the expression of genes involved in oxidative phosphorylation in liver and skeletal muscle, and ATGL in adipose tissue. In summary, HS markedly alters both lipid and carbohydrate metabolism independently of nutrient intake. PMID- 25716928 TI - Molecular and metabolomic effects of voluntary running wheel activity on skeletal muscle in late middle-aged rats. AB - We examined the molecular and metabolomic effects of voluntary running wheel activity in late middle-aged male Sprague Dawley rats (16-17 months). Rats were assigned either continuous voluntary running wheel access for 8 weeks (RW+) or cage-matched without running wheel access (RW-). The 9 RW+ rats averaged 83 m/day (range: 8-163 m), yet exhibited both 84% reduced individual body weight gain (4.3 g vs. 26.3 g, P = 0.02) and 6.5% reduced individual average daily food intake (20.6 g vs. 22.0 g, P = 0.09) over the 8 weeks. Hindlimb muscles were harvested following an overnight fast. Muscle weights and myofiber cross-sectional area showed no difference between groups. Western blots of gastrocnemius muscle lysates with a panel of antibodies suggest that running wheel activity improved oxidative metabolism (53% increase in PGC1alpha, P = 0.03), increased autophagy (36% increase in LC3B-II/-I ratio, P = 0.03), and modulated growth signaling (26% increase in myostatin, P = 0.04). RW+ muscle also showed 43% increased glycogen phosphorylase expression (P = 0.04) and 45% increased glycogen content (P = 0.04). Metabolomic profiling of plantaris and soleus muscles indicated that even low-volume voluntary running wheel activity is associated with decreases in many long-chain fatty acids (e.g., palmitoleate, myristoleate, and eicosatrienoate) relative to RW- rats. Relative increases in acylcarnitines and acyl glycerophospholipids were also observed in RW+ plantaris. These data establish that even modest amounts of physical activity during late middle-age promote extensive metabolic remodeling of skeletal muscle. PMID- 25716929 TI - Frequency of dementia syndromes with a potentially treatable cause in geriatric in-patients: analysis of a 1-year interval. AB - In addition to neurodegenerative and vascular causes of dementia, in the differential diagnosis potentially reversible conditions of dementia also must be assessed. Routine laboratory parameters and neuroimaging, which are recommended for the differential diagnosis of suspected dementia by the German S3 Guideline "Dementia", were retrospectively studied in 166 geriatric patients with suspected dementia. Delirium was diagnosed in six patients (3.6%). These six patients were excluded from the study. Of the 160 remaining patients, there were 99 (59.6%) with an already known dementia. In this subgroup of patients, we found a potentially treatable cause of dementia in 18.2%. In the remaining 61 patients (36.8%), the newly diagnosed dementia syndrome was established according to ICD 10 criteria. Potentially reversible causes of the dementia syndrome were found in 19 of these patients (31.1%). The most common cause was depressive pseudodementia in eight patients followed by vitamin B12 deficiency in six patients. A significant amount of our patients showed laboratory or imaging changes suggestive of potentially reversible causes of the dementia syndrome upon admission. The results of our study indicate the importance of careful differential diagnosis of dementia based on the recommendations of guidelines. Although therapy of these potential causes is not always accompanied by a full recovery, the identification and therapy of treatable causes of cognitive deficits are possible even for general practitioners, who often are the primary contact persons of affected individuals. PMID- 25716930 TI - Prenatal Stress Alters the Development of Socioemotional Behavior and Amygdala Neuron Excitability in Rats. AB - Prenatal stress (PS) is a risk factor for neurodevelopmental disorders with diverse ages of onset and socioemotional symptoms. Some PS-linked disorders involve characteristic social deficits, such as autism spectrum disorders and schizophrenia, but PS also promotes anxiety disorders. We propose the diversity of symptoms following PS arises from perturbations to early brain development. To this end, we characterized the effects of PS on the developmental trajectory of physiology of the amygdala, a late-developing center for socioemotional control. We found that PS dampened socioemotional behavior and reduced amygdala neuron excitability in offspring during infancy (at postnatal days (P)10, 14, 17 and 21), preadolescence (day 28), and adulthood (day 60). PS offspring in infancy produced fewer isolation-induced vocalizations and in adulthood exhibited less anxiety-like behavior and deficits in social interaction. PS neurons had a more hyperpolarized resting membrane potential from infancy to adulthood and produced fewer action potentials. Moreover, adult amygdala neurons from PS animals expressed larger action potential afterhyperpolarizations and H-current relative to controls, further limiting excitability. Our results suggest that PS can suppress socioemotional behavior throughout development and produce age-specific alterations to amygdala physiology. PMID- 25716931 TI - Subclinical atherosclerosis in patients with rheumatoid arthritis. A meta analysis of literature studies. AB - We performed a systematic review with meta-analysis and meta-regression of literature studies evaluating the impact of rheumatoid arthritis (RA) on common carotid artery intima-media thickness (CCA-IMT) and on the prevalence of carotid plaques. Studies evaluating the relationship between RA and markers of cardiovascular (CV) risk (CCA-IMT and prevalence of carotid plaques) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. A total of 59 studies (4,317 RA patients and 3,606 controls) were included in the final analysis, 51 studies with data on CCA-IMT (52 data-sets on 3,600 RA patients and 3,020 controls) and 35 studies reporting on the prevalence of carotid plaques (2,859 RA patients and 2,303 controls). As compared to controls, RA patients showed a higher CCA-IMT (mean difference [MD]: 0.10 mm; 95 % confidence interval [CI]: 0.07, 0.12; p < 0.00001), and an increased prevalence of carotid plaques (odds ratio [OR]: 3.61; 95 %CI: 2.65, 4.93; p< 0.00001). Interestingly, when analysing studies on early RA, the difference in CCA-IMT among RA patients and controls was even higher (MD: 0.21 mm; 95 %CI: 0.06, 0.35; p=0.006), and difference in the prevalence of carotid plaques was entirely confirmed (OR: 3.57; 95 %CI: 1.69, 7.51; p=0.0008). Meta-regression models showed that male gender and a more severe inflammatory status [as expressed by disease activity score in 28 joints (DAS28), C-reactive protein (CRP) levels, and erythrocyte sedimentation rate (ESR)] significantly impacted on CCA-IMT. In conclusion, RA appears significantly associated with subclinical atherosclerosis and CV risk. These findings can be useful to plan adequate prevention strategies and therapeutic approaches. PMID- 25716932 TI - UK becomes first country to allow mitochondrial donation. PMID- 25716933 TI - A prospective study of positron emission tomography for evaluation of neck node response 6 weeks after radiotherapy in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate if a positron emission tomography (PET) scan, 6 weeks after radiotherapy (RT), adequately selects patients in whom a neck node dissection can be omitted. Primary endpoints were isolated neck recurrences and overall survival (OS). METHODS: One hundred five patients, mainly with oropharyngeal human papillomavirus (HPV)-positive tumors, with a positive PET scan before treatment, were evaluated regarding the neck response 6 weeks post-RT. The PET results determined the management of the neck: observation versus neck dissection. RESULTS: Median follow-up was 25 months. Positive predictive value (PPV) and negative predictive value (NPV) were 56% and 94%, respectively. Four isolated neck recurrences occurred. The 2-year OS rate was 86.3%. CONCLUSION: PET scans performed 6 weeks after RT have a high NPV and can obviate neck dissections but the PPV is insufficient. A later scheduled scan is recommended. (c) 2015 Wiley Periodicals (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E473-E479, 2016. PMID- 25716935 TI - Engrailed and tectum development. AB - The optic tectum is a visual center of nonmammalian vertebrates derived from the mesencephalon. In this review, function of Engrailed (En) in tectum development is reviewed. En plays crucial roles at three steps of tectum development. First, Engrailed is expressed in the mesencephalon and the metencephalon and essential for the regionalization of the mesencephalon. En is expressed in a gradient of caudal-to-rostral in the tectum primordial, and regulates the rostrocaudal polarity of the tectum. In the advanced stage of tectum development, En is expressed in a lamina-specific manner and it is suggested that En regulates cell migration in the tectal laminar formation. PMID- 25716934 TI - Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome. AB - BACKGROUND: Neurofilament light chain (NfL) represents a promising biomarker for axonal injury. We present the first exploratory study on serum NfL in patients with a clinically isolated syndrome (CIS) and healthy controls. METHODS: We investigated serum NfL levels in 100 patients with CIS with a short conversion interval to clinically definite multiple sclerosis (MS) (fast converters (FC), median (IQR) conversion time: 110 days (79-139)); 98 patients with non-converting CIS (non-converters (NC), follow-up: 6.5 years (5.3-7.9)); and 92 healthy controls. RESULTS: NfL levels were higher in FC (24.1 pg/mL (13.5-51.8)) and NC (19.3 pg/mL (13.6-35.2)) than in healthy controls (7.9 pg/mL (5.6-17.2)) (OR=5.85; 95% CI 2.63 to 13.02; p = 1.5 * 10(-5) and OR = 7.03; 95% CI 2.85 to 17.34; p = 2.3 * 10(-5), respectively). When grouping FC and NC, increased serum NfL concentration was also associated with increasing numbers of T2 hyperintense MRI lesions (OR = 2.36; 95% CI 1.21 to 4.59; p = 0.011), gadolinium-enhancing lesions (OR = 2.69; 95% CI 1.13 to 6.41; p=0.026) and higher disability scores (OR = 2.54; 95% CI 1.21 to 5.31; p = 0.013) at CIS diagnosis. CONCLUSIONS: If replicated in future studies, serum NfL may represent a reliable and easily accessible biomarker of early axonal damage in CIS and MS. PMID- 25716936 TI - Sympatric distribution of Plasmodium ovale curtisi and P. ovale wallikeri in India: implication for the diagnosis of malaria and its control. AB - BACKGROUND: We report the first evidence of sympatric distribution of Plasmodium ovale curtisi and P. ovale wallikeri from India. METHODS: Fingerprick blood samples were collected from fever cases in district Bastar, Chhattisgarh State for malaria screening by microscopy and PCR. RESULTS: Two cases of mono infection of P. ovale, and a fatal case of cerebral malaria with a mixed infection of P. vivax, P. falciparum and P. ovale were confirmed by PCR. Sequencing analysis revealed the presence of P. ovale curtisi and P. ovale wallikeri. CONCLUSIONS: This study highlights the need of molecular diagnosis of malaria cases in forested areas for treatment and control. PMID- 25716937 TI - Robot-assisted anterior wall extravesical ureteral reimplantation. AB - INTRODUCTION: Here we describe our technique for robot-assisted, extravesical, anterior wall ureteral reimplantation for select patients with obstructive megaureter or high grade VUR with paraureteral diverticulum. We performed anterior wall reimplantation, extrapolating our experience with anterior wall appendicovesicostomy [Famakinwa et al., Eur Urol 2013;64(5):831-6] METHODS: We applied this technique at our institution for a total of 6 patients: 4 pediatric, 2 adult. Amongst our pediatric patients, 3 underwent surgery for obstructive megaureter, and 1 for a paraureteral bladder diverticulum with high grade VUR. Our 2 adult patients opted for surgery in the setting of distal ureteral strictures. To avoid ureteral kinking, we perform detrusorotomy in alignment with the ureter, and take care to avoid ureteral laxity during reimplantation. RESULTS: Following surgery, each of our 6 patients continues to remain without evidence of obstruction, including ureteral kinking, with follow-up ranging from 3 months to 5 years. No procedural-related complications have been noted to date. CONCLUSION: We have found this approach to be technically straightforward, avoiding intravesical dissection and associated morbidity of bladder spasm, while achieving functional outcomes. PMID- 25716938 TI - High-resolution dynamic angiography using flat-panel volume CT: feasibility demonstration for neuro and lower limb vascular applications. AB - OBJECTIVE: This paper evaluates a prototype flat-panel volume CT (fpVCT) for dynamic in vivo imaging in a variety of neurovascular and lower limb applications. METHODS: Dynamic CTA was performed on 12 patients (neuro = 8, lower limb = 4) using an fpVCT with 120 kVp, 50 mA, rotation time varying from 8 to 19 s, and field of view of 25 * 25 * 18 cm(3). Four-dimensional data sets (i.e. 3D images over time) were reconstructed and reviewed. RESULTS: Dynamic CTA demonstrated sufficient spatio-temporal resolution to elucidate first-pass and recirculation dynamics of contrast bolus through neurovasclaur pathologies and phasic blood flow though lower-limb vasculature and grafts. The high spatial resolution of fpVCT resulted in reduced partial volume and metal beam-hardening artefacts. This facilitated assessment of vascular lumen in the presence of calcified plaque and evaluation of fractures, especially in the presence of fixation hardware. Evaluation of arteriovenous malformation using dynamic fpVCT angiography was of limited utility. CONCLUSIONS: Dynamic CTA using fpVCT can visualize time-varying phenomena in neuro and lower limb vascular applications and has suffcient diagnostic imaging quality to evaluate a number of pathologies affecting these regions. KEY POINTS: * CTA using fpVCT has sufficient spatial and temporal resolution to study phasic blood flow. * CTA using fpVCT reveals recurrence of aneurysms even after clipping/coiling. * fpVCT has reduced partial volume and metal beam-hardening artefacts. * fpVCT can show vessel lumen in the presence of calcified plaque. * CTA using fpVCT can demonstrate vascular supply to transplanted grafts. PMID- 25716940 TI - Wavelet-based calculation of cerebral angiographic data from time-resolved CT perfusion acquisitions. AB - OBJECTIVES: To evaluate a new approach for reconstructing angiographic images by application of wavelet transforms on CT perfusion data. METHODS: Fifteen consecutive patients with suspected stroke were examined with a multi-detector CT acquiring 32 dynamic phases (?t = 1.5s) of 99 slices (total slab thickness 99mm) at 80kV/200mAs. Thirty-five mL of iomeprol-350 was injected (flow rate = 4.5mL/s). Angiographic datasets were calculated after initial rigid-body motion correction using (a) temporally filtered maximum intensity projections (tMIP) and (b) the wavelet transform (Paul wavelet, order 1) of each voxel time course. The maximum of the wavelet-power-spectrum was defined as the angiographic signal intensity. The contrast-to-noise ratio (CNR) of 18 different vessel segments was quantified and two blinded readers rated the images qualitatively using 5pt Likert scales. RESULTS: The CNR for the wavelet angiography (501.8 +/- 433.0) was significantly higher than for the tMIP approach (55.7 +/- 29.7, Wilcoxon test p < 0.00001). Image quality was rated to be significantly higher (p < 0.001) for the wavelet angiography with median scores of 4/4 (reader 1/reader 2) than the tMIP (scores of 3/3). CONCLUSIONS: The proposed calculation approach for angiography data using temporal wavelet transforms of intracranial CT perfusion datasets provides higher vascular contrast and intrinsic removal of non-enhancing structures such as bone. KEY POINTS: * Angiographic images calculated with the proposed wavelet-based approach show significantly improved contrast-to-noise ratio. * CT perfusion-based wavelet angiography is an alternative method for vessel visualization. * Provides intrinsic removal of non-enhancing structures such as bone. PMID- 25716939 TI - Diagnostic performance of CT and MRI in distinguishing intraductal papillary neoplasm of the bile duct from cholangiocarcinoma with intraductal papillary growth. AB - OBJECTIVES: We aimed to evaluate the diagnostic performance of CT and MRI for distinguishing intraductal papillary neoplasm of the bile duct (IPNB) from cholangiocarcinoma (CC) with intraductal papillary growth (IPG). METHODS: Forty two patients with either IPNB or CC with IPG proven by histopathology were independently reviewed in retrospect. Strict criteria for diagnosis of IPNB included presence of the designated imaging features as follows: local dilatation of the bile duct, nodule within the dilated bile duct, growing along the interior wall of bile duct. Any lesion that was not consistent with the criteria was classified as CC with IPG. Sensitivity, specificity, positive and negative predictive values for characterization of IPNB were calculated, and k test was used to assess the level of agreement. RESULTS: Two imaging reviewers correctly identified 21 of 26 (80.8%) and 22 of 26 (84.6%) IPNB cases, respectively. Alternatively, they correctly identified 14 of 16 (87.5%) and 15 of 16 (93.8%) CC with IPG, respectively. Agreement between the two reviewers was perfect (k = 0.81) for the diagnosis of IPNB and differentiation from CC with IPG. CONCLUSIONS: By using our designated diagnostic criteria of CT and MRI, IPNB can be accurately identified and possible to be distinguished from CC with IPG. KEY POINTS: * IPNB can accurately be identified by using defined diagnostic criteria at CT/MRI. * IPNB has some characteristic CT and MR imaging features. * IPNB is a rare entity; up until now it might have been misdiagnosed. PMID- 25716941 TI - Robust, fully automatic delineation of the head contour by stereotactical normalization for attenuation correction according to Chang in dopamine transporter scintigraphy. AB - OBJECTIVES: Chang's method, the most widely used attenuation correction (AC) in brain single-photon emission computed tomography (SPECT), requires delineation of the outer contour of the head. Manual and automatic threshold-based methods are prone to errors due to variability of tracer uptake in the scalp. The present study proposes a new method for fully automated delineation of the head based on stereotactical normalization. The method was validated for SPECT with I-123 ioflupane. METHODS: The new method was compared to threshold-based delineation in 62 unselected patients who had received I-123-ioflupane SPECT at one of 3 centres. The impact on diagnostic power was tested for semi-quantitative analysis and visual reading of the SPECT images (six independent readers). RESULTS: The two delineation methods produced highly consistent semi-quantitative results. This was confirmed by receiver operating characteristic analyses in which the putamen specific-to-background ratio achieved highest area under the curve with negligible effect of the delineation method: 0.935 versus 0.938 for stereotactical normalization and threshold-based delineation, respectively. Visual interpretation of DVR images was also not affected by the delineation method. CONCLUSIONS: Delineation of the head contour by stereotactical normalization appears useful for Chang AC in I-123-ioflupane SPECT. It is robust and does not require user interaction. KEY POINTS: *Chang attenuation correction in brain SPECT requires delineation of the head contour. *Manual and threshold based methods are prone to errors. *The study proposes a fully-automated method for delineation based on stereotactical normalization. *The method is shown to work reliably in I-123-ioflupane SPECT. *It might improve the workflow of I-123 ioflupane SPECT in everyday patient care. PMID- 25716942 TI - Ultrasound evaluation of joints in systemic lupus erythematosus: a systematic review. AB - OBJECTIVES: The aim of this systematic review is to describe the scientific evidence regarding sonographic findings of joints in SLE patients. METHODS: Seven databases were searched (PubMed, ScienceDirect, Scopus, Cochrane, EMBASE, LILACS, and SciELO) for articles from 1950 to January 2015. The keywords used for selecting articles include "lupus", "ultrasound imaging", "ultrasonography", "synovitis", "tenosynovitis", and "arthritis". RESULTS: A total of 12 articles were included in the final analysis. In total, 610 SLE patients and 1,091 joints were studied. Most patients underwent bilateral joint examination by US. A total of 888 hands and wrists, 154 ankles/feet, and 56 knees were examined. Effusion was identified in 602 joints, synovitis in 213, tenosynovitis in 210, synovial hypertrophy in 150, and bone erosions in 73 cases. The majority of the studies demonstrated higher frequency of musculoskeletal abnormalities on US than those observed on physical examination. CONCLUSION: US seems to be a valuable tool to identify subclinical joint manifestations in SLE. Prospective studies are necessary to determine if those patients with subclinical joint abnormalities have a higher risk for the development of chronic deformities as those seen in Jaccoud's Arthropathy. KEY POINTS: * Musculoskeletal involvement occurs in more than 90% of SLE cases. * Arthralgia or tender/swollen joints found on physical examination showed more US findings. * Patients without joint symptoms or physical examinations changes showed musculoskeletal sonographic findings. * US became a useful tool for rheumatologists. * A substantial number of asymptomatic patients show abnormalities at musculoskeletal US. PMID- 25716943 TI - Rapid preparation of rare ginsenosides by acid transformation and their structure activity relationships against cancer cells. AB - The anticancer activities of ginsenosides are widely reported. The structure activity relationship of ginsenosides against cancer is not well elucidated because of the unavailability of these compounds. In this work, we developed a transformation method to rapidly produce rare dehydroxylated ginsenosides by acid treatment. The optimized temperature, time course, and concentration of formic acid were 120 degrees C, 4 h and 0.01%, respectively. From 100 mg of Rh1, 8.3 mg of Rk3 and 18.7 mg of Rh4 can be produced by acid transformation. Similarly, from 100 mg of Rg3, 7.4 mg of Rk1 and 15.1 mg of Rg5 can be produced. From 100 mg of Rh2, 8.3 mg of Rk2 and 12.7 mg of Rh3 can be generated. Next, the structure activity relationships of 23 ginsenosides were investigated by comparing their cytotoxic effects on six human cancer cells, including HCT-116, HepG2, MCF-7, Hela, PANC-1, and A549. The results showed that: (1) the cytotoxic effect of ginsenosides is inversely related to the sugar numbers; (2) sugar linkages rank as C-3 > C-6 > C-20; (3) the protopanaxadiol-type has higher activities; (4) having the double bond at the terminal C20-21 exhibits stronger activity than that at C20-22; and (5) 20(S)-ginsenosides show stronger effects than their 20(R) stereoisomers. PMID- 25716944 TI - Fitness impacts of tapeworm parasitism on wild gelada monkeys at Guassa, Ethiopia. AB - Parasitism is expected to impact host morbidity or mortality, although the fitness costs of parasitism have rarely been quantified for wildlife hosts. Tapeworms in the genus Taenia exploit a variety of vertebrates, including livestock, humans, and geladas (Theropithecus gelada), monkeys endemic to the alpine grasslands of Ethiopia. Despite Taenia's adverse societal and economic impacts, we know little about the prevalence of disease associated with Taenia infection in wildlife or the impacts of this disease on host health, mortality and reproduction. We monitored geladas at Guassa, Ethiopia over a continuous 61/2 year period for external evidence (cysts or coenuri) of Taenia-associated disease (coenurosis) and evaluated the impact of coenurosis on host survival and reproduction. We also identified (through genetic and histological analyses) the tapeworms causing coenurosis in wild geladas at Guassa as Taenia serialis. Nearly 1/3 of adult geladas at Guassa possessed >=1 coenurus at some point in the study. Coenurosis adversely impacted gelada survival and reproduction at Guassa and this impact spanned two generations: adults with coenuri suffered higher mortality than members of their sex without coenuri and offspring of females with coenuri also suffered higher mortality. Coenurosis also negatively affected adult reproduction, lengthening interbirth intervals and reducing the likelihood that males successfully assumed reproductive control over units of females. Our study provides the first empirical evidence that coenurosis increases mortality and reduces fertility in wild nonhuman primate hosts. Our research highlights the value of longitudinal monitoring of individually recognized animals in natural populations for advancing knowledge of parasite-host evolutionary dynamics and offering clues to the etiology and control of infectious disease. PMID- 25716946 TI - Is Mainland China ready to implement vocational rehabilitation to re-engage its people with schizophrenia in meaningful worker roles? PMID- 25716945 TI - Relation of murine thoracic aortic structural and cellular changes with aging to passive and active mechanical properties. AB - BACKGROUND: Maintenance of the structure and mechanical properties of the thoracic aorta contributes to aortic function and is dependent on the composition of the extracellular matrix and the cellular content within the aortic wall. Age related alterations in the aorta include changes in cellular content and composition of the extracellular matrix; however, the precise roles of these age related changes in altering aortic mechanical function are not well understood. METHODS AND RESULTS: Thoracic aortic rings from the descending segment were harvested from C57BL/6 mice aged 6 and 21 months. Thoracic aortic diameter and wall thickness were higher in the old mice. Cellular density was reduced in the medial layer of aortas from the old mice; concomitantly, collagen content was higher in old mice, but elastin content was similar between young and old mice. Stress relaxation, an index of compliance, was reduced in aortas from old mice and correlated with collagen fraction. Contractility of the aortic rings following potassium stimulation was reduced in old versus young mice. Furthermore, collagen gel contraction by aortic smooth muscle cells was reduced with age. CONCLUSIONS: These results demonstrate that numerous age-related structural changes occurred in the thoracic aorta and were related to alterations in mechanical properties. Aortic contractility decreased with age, likely because of a reduction in medial cell number in addition to a smooth muscle contractile deficit. Together, these unique findings provide evidence that the age-related changes in structure and mechanical function coalesce to provide an aortic substrate that may be predisposed to aortopathies. PMID- 25716947 TI - Distancing oneself from God among perpetrators of partner violence. PMID- 25716948 TI - Berberine regulates melanin synthesis by activating PI3K/AKT, ERK and GSK3beta in B16F10 melanoma cells. AB - Berberine, an isoquinoline alkaloid, has a wide range of beneficial properties, including anti-bacterial, anti-inflammatory, anti-cancer, and cholesterol lowering effects. Recently findings suggest that berberine improves glucose and lipid metabolism disorders. In the present study, we examined the mechanism underlying the inhibitory effect of berberine on alpha-melanocyte-stimulating hormone (alpha-MSH)-stimulated B16F10 melanoma cells. The results showed that berberine attenuated alpha-MSH induction of the microphthalmia-associated transcription factor (MITF) and tyrosinase in a dose-dependent manner. To elucidate the mechanism underlying the inhibitory effect of berberine, we examined the effect of alpha-MSH-stimulated phosphorylation of PI3K/AKT, ERK, and GSK3beta. The results showed that treatment with berberine resulted in a reduction in the phosphorylation of PI3K/AKT, ERK, and GSK3beta. Taken together, the results suggested that berberine inhibits melanin synthesis and tyrosinase activity by downregulating the expression of MITF and tyrosinase. Thus, these findings may contribute to the potential application of berberine in the prevention and treatment of skin pigmentation disorders. PMID- 25716950 TI - Exiguobacterium enclense sp. nov., isolated from sediment. AB - A Gram-stain-positive bacterium, designated strain NIO-1109(T), was isolated from a marine sediment sample from Chorao Island, Goa, India. Phenotypic and chemotaxonomic characteristics and data from phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NIO-1109(T) was related to the genus Exiguobacterium . Strain NIO-1109(T) exhibited >98.0% 16S rRNA gene sequence similarity with respect to Exiguobacterium indicum HHS 31(T) (99.5%) and Exiguobacterium acetylicum NCIMB 9889(T) (99.1%); the type strains of other species showed <98% similarity. Levels of DNA-DNA relatedness between strain NIO 1109(T) and E. acetylicum DSM 20416(T) and E. indicum LMG 23471(T) were less than 70% (33.0 +/- 2.0 and 37 +/- 3.2%, respectively). Strain NIO-1109(T) also differed from these two closely related species in a number of phenotypic traits. Based on phenotypic, chemotaxonomic and phylogenetic data, strain NIO-1109(T) is considered to represent a novel species of the genus Exiguobacterium , for which the name Exiguobacterium enclense sp. nov. is proposed. The type strain is NIO 1109(T) ( =NCIM 5457(T) =DSM 25128(T) = CCTCC AB 2011124(T)). PMID- 25716949 TI - Dense and nondense mammographic area and risk of breast cancer by age and tumor characteristics. AB - BACKGROUND: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER) negative status among women ages <55 years. To provide insight into these associations, we examined the components of PMD [dense area (DA) and nondense area (NDA)] with breast cancer subtypes. METHODS: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression. RESULTS: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; P(trend) <0.001] and NDA was associated with decreased risk [ORs for quartiles: 1.39, 1.00 (Ref), 0.88, 0.72; P(trend) <0.001] across all ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (P(trend) < 0.001) but no differences by nodal status. Among women <55 years, DA was more strongly associated with increased risk of ER(+) versus ER(-) tumors (P(het) = 0.02), while NDA was more strongly associated with decreased risk of ER(-) versus ER(+) tumors (P(het) = 0.03). CONCLUSIONS: DA and NDA have differential associations with ER(+) versus ER(-) tumors that vary by age. IMPACT: DA and NDA are important to consider when developing age- and subtype-specific risk models. PMID- 25716951 TI - Nocardioides deserti sp. nov., an actinobacterium isolated from desert soil. AB - A rod- or coccus-shaped, non-spore-forming actinobacterium, designated strain SC8A-24(T), was isolated from a soil sample collected from the rhizosphere of Alhagi sparsifolia on the southern edge of the Taklimakan desert, Xinjiang, China, and examined by a polyphasic approach to clarify its taxonomic position. This actinobacterium was Gram-staining-positive and aerobic. Substrate and aerial mycelia were not observed, and no diffusible pigments were observed on the media tested. Strain SC8A-24(T) grew optimally without NaCl at 28-30 degrees C and pH 7.0-8.0. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain SC8A-24(T) belonged to the genus Nocardioides and shared the highest 16S rRNA gene sequence similarity with Nocardioides salarius CL-Z59(T) (96.51%), N. pyridinolyticus OS4(T) (96.43%) and N. ginsengagri BX5-10(T) (96.37%). The DNA G+C content of strain SC8A-24(T) was 71 mol%. The cell-wall peptidoglycan contained ll-2,6-diaminopimelic acid, and MK-8(H4) was the predominant menaquinone. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, an unidentified glycolipid and an unidentified phospholipid. The major fatty acids were C17 : 1omega8c, 10-methyl C17 : 0 and C18 : 1omega9c. On the basis of phylogenetic analysis and phenotypic and chemotaxonomic characteristics, strain SC8A-24(T) represents a novel species of the genus Nocardioides , for which the name Nocardioides deserti sp. nov. is proposed. The type strain is SC8A-24(T) ( =DSM 26045(T) = CGMCC 4.7183(T)). PMID- 25716952 TI - Mameliella phaeodactyli sp. nov., a member of the family Rhodobacteraceae isolated from the marine algae Phaeodactylum tricornutum. AB - A novel Gram-staining-negative, aerobic, rod-shaped, non-motile, yellow bacterium designated strain KD53(T), was isolated from a culture of the alga Phaeodactylum tricornutum from Xiamen, Fujian Province, China. 16S rRNA gene sequence comparison showed that strain KD53(T) was a member of the Roseobacter clade within the family Rhodobacteraceae , forming a distinct lineage with species of the genus Mameliella . The 16S rRNA gene sequence similarities between strain KD53(T) and other strains examined were all less than 97.0%. Strain KD53(T) was found to grow optimally at 28 degrees C, at pH 7.5-8.0 and in the presence of 3% (w/v) NaCl. The dominant fatty acids of strain KD53(T) were C18 : 1omega6c and/or C18 : 1omega7c, C18 : 0 and C16 : 0. The major polar lipids were phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content was 65 mol% and the major respiratory quinone was ubiquinone 10 (Q 10). On the basis of phenotypic data and phylogenetic inference, strain KD53(T) represents a novel member of the genus Mameliella , then the name Mameliella phaeodactyli sp. nov. is proposed. The type strain is KD53(T) ( =MCCC 1K00273(T) =KCTC 42178(T)). PMID- 25716953 TI - Belliella aquatica sp. nov., isolated from a saline lake. AB - A Gram-staining-negative bacterium, strain TS-T86(T), was isolated from Lake Tuosu, a saline lake (salinity 5.4%, w/w) in Qaidam basin, China. Its taxonomic position was determined by using a polyphasic approach. Strain TS-T86(T) was strictly heterotrophic, aerobic and catalase- and oxidase-positive. Cells were non-spore-forming, non-motile rods, 0.4-0.6 um wide and 1.2-2.3 um long. Growth was observed in the presence of 0-9.0% (w/v) NaCl (optimum, 2.0%), at 4-35 degrees C (optimum, 25 degrees C) and at pH 7.0-10.5 (optimum, pH 8.5-9.0). Strain TS-T86(T) contained MK-7 as the predominant respiratory quinone. The major fatty acids (>10%) were iso-C15 : 1 G, iso-C15 : 0, iso-C17 : 1omega9c, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The polar lipids consisted of phosphatidylethanolamine, an unknown phospholipid, six unidentified aminolipids and two uncharacterized lipids. The DNA G+C content was 35 mol% (T m). Phylogenetic trees based on 16S rRNA gene sequences showed that strain TS-T86(T) was associated with the genus Belliella, and showed the highest sequence similarity to Belliella baltica BA134(T) (98.5 %) and then to Belliella kenyensis No.164(T) (95.7%) and Belliella pelovolcani CC-SAL-25(T) (95.3 %). DNA DNA relatedness of strain TS-T86(T) to Belliella baltica DSM 15883(T) was 32 +/- 3%. It is concluded that strain TS-T86(T) represents a novel species of the genus Belliella, for which the name Belliella aquatica sp. nov. is proposed. The type strain is TS-T86(T) ( = CGMCC 1.12479(T) = JCM 19468(T)). PMID- 25716955 TI - A 72 old woman with a painful leg after a fall. PMID- 25716954 TI - Metabolomic changes in grains of well-watered and drought-stressed transgenic rice. AB - BACKGROUND: Drought induces a number of physiological and biochemical responses in cereals. This study was designed to examine the metabolite changes in grains of drought-tolerant transgenic rice (Oryza sativa L.) that overexpresses AtCYP78A7 encoding cytochrome P450 protein using proton nuclear magnetic resonance ((1)H-NMR) and gas chromatography/mass spectrometry. RESULTS: Principal component analysis showed that the (1)H-NMR-based profile was clearly separated by soil water status of well-watered and water-deficit. A discrimination of metabolites between transgenic and non-transgenic grains appeared under both watering regimes. Variations in the levels of amino acids and sugars led to the discrimination of metabolites among genotypes. In particular, drought significantly enhanced the levels of gamma-aminobutyric acid (GABA, 244.6%), fructose (155.7%), glucose (211.0%), glycerol (57.2%), glycine (65.8%) and aminoethanol (192.4%) in the transgenic grains compared with the non-transgenic control grains. CONCLUSION: These changes in amounts of metabolites may assist in improving drought tolerance in transgenic rice by playing crucial roles in stress responsive pathways including GABA biosynthesis, sucrose metabolism and antioxidant defenses. PMID- 25716956 TI - Comparison of quality of life in people with partial foot and transtibial amputation: A pilot study. AB - BACKGROUND: Quality of life is often cited as a key influence in decisions about partial foot and transtibial amputations despite there being no studies comparing quality of life in these groups. OBJECTIVES: To compare quality of life in people with partial foot amputation or transtibial amputation secondary to peripheral vascular disease and determine factors influencing quality of life in these cohorts. STUDY DESIGN: Cross-sectional. METHODS: Mail-out, mail-back version of the SF-36v2 Health Survey and an adapted version of the demographic section of the Trinity Amputation and Prosthesis Experience Scales-Revised were sent to people recruited through a large metropolitan hospital. RESULTS: Both the SF-36v2 mental health component summary and physical component summary scores were comparable in the partial foot amputation (n = 10) and transtibial amputation (n = 23) cohorts. A multivariate linear regression showed that age, time with diabetes and the presence of retinopathy significantly influenced either the SF 36v2 mental health component summary or physical component summary whereas amputation level did not. DISCUSSION: Results support existing descriptive data that indicate quality of life is comparable in cohorts with partial foot and transtibial amputation. CONCLUSION: Our results suggest that quality of life need not to be a consideration when deciding between partial foot and transtibial amputation for persons with vascular disease. Surgeons and patients may wish to focus on other considerations, such as the relative risk of ulceration and subsequent amputation, when choosing between partial foot and transtibial amputation. CLINICAL RELEVANCE: The similarity in quality of life between people with partial foot and transtibial amputation helps inform difficult decisions about amputation surgery by focusing on surgery that will reduce the risk of complications and secondary amputation without fear of compromising quality of life. PMID- 25716957 TI - The effect of electromagnetic shielding on phantom limb pain: A placebo controlled double-blind crossover trial. AB - BACKGROUND: Environmental electromagnetic fields influence biological systems. Evidence suggests these have a role in the experience of phantom limb pain in patients with amputations. OBJECTIVES: This article followed a previous study to investigate the effect of electromagnetic field shielding with a specially designed prosthetic liner. STUDY DESIGN: Randomised placebo-controlled double blind crossover trial. METHODS: Twenty suitable participants with transtibial amputations, phantom pain at least 1 year with no other treatable cause or pathology were requested to record daily pain, well-being, activity and hours of prosthetic use on pre-printed diary sheets. These were issued for three 2-week periods (baseline, electromagnetic shielding (verum) and visually identical placebo liners - randomly allocated). RESULTS: Thirty-three per cent of the recruited participants were unable to complete the trial. The resulting N was therefore smaller than was necessary for adequate power. The remaining data showed that maximum pain and well-being were improved from baseline under verum but not placebo. More participants improved on all variables with verum than placebo. CONCLUSION: Electromagnetic field shielding produced beneficial effects in those participants who could tolerate the liner. It is suggested that this might be due to protection of vulnerable nerve endings from nociceptive effects of environmental electromagnetic fields. CLINICAL RELEVANCE: Electromagnetic field shielding with a suitable limb/prosthesis interface can be considered a useful technique to improve pain and well-being in patients with phantom limb pain. PMID- 25716958 TI - Effects of depression on the cytokine profile in drug naive first-episode psychosis. AB - Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naive patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNgamma, TNFalpha and IL-17) in FEP patients (n=55) versus healthy controls (n=57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFalpha in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFalpha levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described. PMID- 25716959 TI - Editorial overview: Emerging viruses: interspecies transmission. PMID- 25716960 TI - Saliva and oxidative stress in oral cavity and in some systemic disorders. AB - Saliva is a liquid environment of the oral ecosystem that to some extent reflects the local state of oral cavity or the general state of health of the human body. Since saliva reflects general health status of the human organism and is easy to collect, it can be used as a non-invasive diagnostic tool. In the present review the authors discuss and highlight the role of oxidant-antioxidant balance in the blood and saliva in human pathology. Particularly, the evaluation of oxidative stress status was proposed as an important factor in diagnosing the development and progress of such general diseases as periodontal disease, oral cancer, diabetes, rheumatoid arthritis, chronic renal failure, obstructive sleep apnea syndrome, and HIV. Moreover, the tryptophan metabolites via kynurenine pathway measured in the plasma and saliva are proposed as new and sensitive markers of oxidative stress status. It is concluded that measurement of oxidative stress in salivary fluid may provide a tool for diagnosing, monitoring and treatment of some systemic diseases as well as of local pathologic disturbances (e.g. periodontal disease). PMID- 25716961 TI - Peptidyl hormones of endocrine cells origin in the gut--their discovery and physiological relevance. AB - In 1902 William Bayliss and Ernest Starling discovered secretin and it was the beginning of general endocrinology as well as, endocrinology of gastrointestinal tract. Ernest Starling was also a first person who introduced a term hormone for the substances which serves to transfer the information between cells of organism. Subsequent years delivered discovery of successive hormones of the digestive tract. Gastrin was discovered in 1905; whereas cholecystokinin in 1928. Ghrelin and obestatin are last hormones determined in the gastrointestinal tract and they were found in 1999 and 2006, respectively. Both above hormones are originating from the common prohormone. In 60s of past century, the biochemical structure of the gastrointestinal tract hormones was determined for the first time. Substantial progress in endocrinology of the digestive tract took place when radioimmunoassay was employed to measure of hormones concentration. Subsequently, radiolabeled hormones were used to localize hormonal receptors. Next breakthrough in the gastrointestinal tract endocrinology happened after introduction to experimental methods the cloning of complementary DNA. This method has allowed, among the others, to establish the full structure of receptors as well as, a genes coding hormones and their receptors. Discovery of genes structure allowed subsequently introducing these genes into foreign cells, what gives a chance to obtain significant amount of recombined hormones possessing species specificity. This review is presenting a history of the gastrointestinal tract endocrinology, as well as a relevance of gastrointestinal tract hormones in the regulation of body physiological activity. PMID- 25716962 TI - Analysis of microRNA expression in canine mammary cancer stem-like cells indicates epigenetic regulation of transforming growth factor-beta signaling. AB - Cancer stem cells (CSCs) display both unique self-renewal ability as well as the ability to differentiate into many kinds of cancer cells. They are supposed to be responsible for cancer initiation, recurrence and drug resistance. Despite the fact that a variety of methods are currently employed in order to target CSCs, little is known about the regulation of their phenotype and biology by miRNAs. The aim of our study was to assess miRNA expression in canine mammary cancer stem like cells (expressing stem cell antigen 1, Sca-1; CD44 and EpCAM) sorted from canine mammary tumour cell lines (CMT-U27, CMT-309 and P114). In order to prove their stem-like phenotype, we conducted a colony formation assay that confirmed their ability to form colonies from a single cell. Profiles of miRNA expression were investigated using Agilent custom-designed microarrays. The results were further validated by real-time rt-PCR analysis of expression of randomly selected miRNAs. Target genes were indicated and analysed using Kioto Encyclopedia of Genes and Genomes (KEGG) and BioCarta databases. The results revealed 24 down regulated and nine up-regulated miRNAs in cancer stem-like cells compared to differentiated tumour cells. According to KEGG and BioCarta databases, target genes (n=240) of significantly down-regulated miRNAs were involved in transforming growth factor-beta signaling, mitogen-activated protein kinases (MAPK) signaling pathway, anaplastic lymphoma receptor tyrosine kinase (ALK) and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A) pathways. The analysis of single-gene overlapping with different pathways showed that the most important genes were: TGFBR1, TGFBR2, SOS1, CHUK, PDGFRA, SMAD2, MEF2A, MEF2C and MEF2D. All of them are involved in tumor necrosis factor-beta signaling and may indicate its important role in cancer stem cell biology. Increased expression of TGFBR2, SMAD2, MEF2A and MEF2D in canine mammary cancer stem-like cells was further confirmed by real-time-qPCR. The results of our study point at epigenetic differences between cancer stem-like cells and differentiated tumour cells, which may be important not only for veterinary medicine but also for comparative oncology. PMID- 25716963 TI - Superactive human leptin antagonist reverses leptin-induced excessive progesterone and testosterone secretion in porcine ovarian follicles by blocking leptin receptors. AB - Accumulating evidence indicates that leptin plays an important role in controlling reproductive function. At physiological levels, leptin stimulates steroidogenesis and follicle maturation, whereas supraphysiological concentrations of leptin have been suggested to be an independent risk factor for cyst formation. Since the discovery of the link between leptin and obesity, which is frequently associated with polycystic ovarian syndrome (PCOS), a number of leptin mutants exhibiting antagonistic properties have been developed, opening new avenues for leptin-related research. Here, using a superactive human leptin antagonist (SHLA), we sought to determine whether blocking leptin receptors can reverse the actions of leptin in ovarian follicles. Antral porcine ovarian follicles, collected from prepubertal and mature animals, were exposed to 100, 250 and 500 ng/ml SHLA for 24 hours, after which leptin receptor (ObR), leptin, CYP11A1 and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) levels in follicles were evaluated by Western blotting. Levels of secreted leptin, progesterone (P4), and testosterone (T) in the follicle incubation medium were measured using enzyme linked immunosorbent assays. The effects of SHLA on leptin-stimulated P4 and T secretion were also tested by exposing follicles to 40 ng/ml leptin in the presence and absence of SHLA. These experiments revealed that SHLA acted through inhibition of ObR expression and leptin expression and secretion decreased P4 and T secretion by ovarian follicles from both prepubertal and mature animals. Our data further suggest that the mechanism underlying this action of SHLA involves inhibition of CYP11A1 and 17beta-HSD protein expression. Importantly, SHLA reversed leptin-induced increases in P4 and T secretion. Collectively, these data indicate that, in addition to their potential application in novel therapeutic strategies in oncology, which has received considerable recent research attention, leptin receptors antagonists might also be beneficial in controlling reproduction. PMID- 25716964 TI - Dietary supplementation with dried chicory root triggers changes in the blood serum proteins engaged in the clotting process and the innate immune response in growing pigs. AB - The aim of the study was to characterize the systemic immune and metabolic alterations in the blood serum of growing pigs in response to a dietary supplementation with 4% of dried chicory roots. This was achieved by examining the influence of the experimental diet on serum protein changes especially these related with immunology and lipid metabolism. Serum proteins with the isoelectric point ranging from pH 3.0 to 10.0 were separated using high resolution two dimensional electrophoresis. As a result, we found that experimental diet triggered significant changes in 37 protein spots. Of these, 14 were up regulated, whereas 23 showed down-regulation. Of 37 significantly altered protein spots, 24 were successfully identified, representing 14 distinct gene products. Implementation of the dried chicory roots into the diet of growing pigs caused a significant down-regulation of apolipoprotein C-II complement component C6, C reactive protein, CD14 antigen, C4b binding protein alpha and beta chains, and fibrinogen. Piglets fed experimental diet had similar IgA, IgG and IgM concentrations, although the level of IgM tended to be lower compared to the control group. It is concluded that diet supplemented with 4% of dried chicory root may exert anti-inflammatory properties and affect lipid metabolism in growing pigs. PMID- 25716965 TI - Inflammatory response in visceral fat tissue and liver is prenatally programmed: experimental research. AB - To investigate the mechanisms of developmental programming we analyzed the effects of maternal stress and food intake on physiological activity of adipose tissue and hepatocellular organization in the offsprings. The experiments were conducted in nonlinear female rats (n=20) and their male offsprings (n=28). During their pregnancy female rats were exposed to social and emotional stress using Pratt's model, and nutritional insults: high sugar diet (HSD) with chronic access to 30% solution of saccharose in drinking water ad libitum, high fat diet (HFD) containing 45% calories from fat or their combination - high sugar and high fat diet (HSFD). The effects of maternal stress and nutrition on severity of visceral fat and liver changes were then examined in offsprings, along with changes in serum levels of the pro- and anti-inflammatory cytokines: IL-1b, IL-8 (in rats known as GRO/CINC-1), leptin and adiponectin, respectively. Maternal exposure to stress in combination with HSFD resulted in the most prominent changes in the offsprings: histological changes in the visceral fat tissue and liver with cell reorganization and signs of inflammation, 217% increase in IL 1beta level, 99% increase in GRO/CINC-1 level, 79% increase in leptin level and 41% decrease in adiponectin level. The leptin/adiponectin index was elevated in all study groups and reached 158% in HSD group, 138% in HFD group and was two times higher in HSFD group vs control. The rat model used in this study provides novel insight into development of nonalcoholic fatty liver disease. Expressed pro and anti-inflammatory cytokines may indicate early changes in liver and adipose tissue functioning and leptin/adiponectin index could be a novel non-invasive marker of metabolic-related liver alteration. Healthy nutrition and stress management during prenatal period may serve as a valid strategy to prevent liver and adipose tissue inflammation/alteration and metabolic disorders in adulthood. PMID- 25716966 TI - Atorvastatin enhanced nitric oxide release and reduced blood pressure, nitroxidative stress and rantes levels in hypertensive rats with diabetes. AB - Clinical trials have shown that atorvastatin benefits patients with diabetes even with normal baseline LDL levels. We hypothesized that atorvastatin improves endothelial cell (EC) function and reduces inflammation in hypertensive rats with diabetes. Non-diabetic and streptozotocin-induced type 2 diabetic male spontaneously hypertensive rats (SHR) were treated with atorvastatin at 20 mg/kg/day. After five weeks, nitric oxide (NO) and peroxynitrite (ONOO(-)) were measured in aortic and glomerular endothelial cells. A tandem of nanosensors was used to simultaneously measure NO and ONOO(-) concentration and their ratio [NO]/[ONOO(-)] was monitored with a time resolution better than 10 MUs and detection limit 1 nM. [NO]/[ONOO(-)] was applied as a marker of endothelial NO synthase (eNOS) uncoupling, endothelial dysfunction and nitroxidative stress. Glucose, cholesterol, blood pressure (BP), and the cytokine RANTES were also measured. Diabetic SHR rats had elevated glucose (355 +/- 38 mg/dL), mean BP (172 +/- 15 mmHg), and plasma RANTES (38.4 +/- 2.7 ng/mL), low endothelial NO bioavailability and high ONOO(-). Maximal NO release measured 267 +/- 29 nM in aortic endothelium of SHR rats and 214 +/- 20 nM for diabetic SHR rats; [NO]/[ONOO(-)] was 0.88 +/- 12 and 0.61 +/- 0.08, respectively. [NO]/[ONOO(-)] ratios below one indicate a high uncoupling of eNOS, endothelial dysfunction and high nitroxidative stress. Atorvastatin treatment partially restored endothelial function by increasing NO level by 98%, reducing ONOO(-) by 40% and favorably elevating [NO]/[ONOO(-)] to 1.1 +/- 0.2 for diabetic SHR rats and 1.6 +/- 0.3 for SHR rats. The effects of atorvastatin were similar in glomerular endothelial cells and were partially reproduced by modulators of eNOS or NADPH oxidase. Atorvastatin had no significant effect on fasting glucose or total cholesterol levels but reduced mean BP by 21% and 11% in diabetic and non-diabetic animals, respectively. Atorvastatin also reduced RANTES levels by 50%. Atorvastatin favorably increased the [NO]/[ONOO(-)] balance, enhanced endothelial cytoprotective NO, decreased cytotoxic ONOO(-) and reduced BP, inflammation and RANTES levels in diabetic, hypertensive rats without altering cholesterol levels. These findings provide insights into mechanisms of restoration of endothelial function and vascular protection by atorvastatin in diabetes and hypertension. PMID- 25716967 TI - Changes in intracellular calcium concentration influence beat-to-beat variability of action potential duration in canine ventricular myocytes. AB - The aim of the present work was to study the influence of changes in intracellular calcium concentration ([Ca(2+)]i) on beat-to-beat variability (short term variability, SV) of action potential duration (APD) in isolated canine ventricular cardiomyocytes. Series of action potentials were recorded from enzymatically isolated canine ventricular cells using conventional microelectrode technique. Drug effects on SV were evaluated as relative SV changes determined by plotting the drug-induced changes in SV against corresponding changes in APD and comparing these data to the exponential SV-APD function obtained with inward and outward current injections. Exposure of myocytes to the Ca(2+) chelator BAPTA-AM (5 MUM) decreased, while Ca(2+) ionophore A23187 (1 MUM) increased the magnitude of relative SV. Both effects were primarily due to the concomitant changes in APD. Relative SV was reduced by BAPTA-AM under various experimental conditions including pretreatment with veratridine, BAY K8644, dofetilide or E-4031. Contribution of transient changes of [Ca(2+)]i due to Ca(2+) released from the sarcoplasmic reticulum (SR) was studied using 10 MUM ryanodine and 1 MUM cyclopiazonic acid: relative SV was reduced by both agents. Inhibition of the Na(+)-Ca(2+) exchanger by 1 MUM SEA0400 increased relative SV. It is concluded that elevation of [Ca(2+)]i increases relative SV significantly. More importantly, Ca(2+) released from the SR is an important component of this effect. PMID- 25716968 TI - Acute anti-fibrillating and defibrillating potential of atorvastatin, melatonin, eicosapentaenoic acid and docosahexaenoic acid demonstrated in isolated heart model. AB - Cardioprotective compounds such as atorvastatin, melatonin, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exhibit antiarrhythmic potential in clinical and/or experimental conditions but underlying mechanisms are poorly understood. We have previously shown that protection from ventricular fibrillation (VF) due to prolonged treatment with these compounds was linked with modulation of myocardial connexin-43, which is responsible for myocardial electrical coupling and synchronisation. To elucidate further the antiarrhythmic potential of atorvastatin, melatonin, EPA and DHA we aimed to explore their acute anti fibrillating effects and defibrillating efficacy. Experiments were conducted on isolated perfused heart preparation of adult male and female hypertriglyceridemic (HTG) rats when using atorvastatin, EPA and DHA, while melatonin was examined in hearts of old male and female guinea pigs. VF inducibility was tested in hearts pre-treated for 10 min with atorvastatin, EPA or DHA (15 MUmol) or melatonin (50 MUmol) and compared with non-pre-treated hearts. Sustained VF was induced in all untreated HTG rat hearts. In contrast, its incidence was reduced to 30% and 60% by atorvastatin, 70% and 75% by EPA, 60% and 60% by DHA in male or female rat hearts respectively. Moreover, bolus (150 MUmol) of EPA and DHA administered directly to the fibrillating heart restored sinus rhythm in 6 of 6 hearts and atorvastatin in 4 of 6 hearts. Threshold to induce sustained VF was 21.7 +/- 3.8 mA in male and 38.3 +/- 2.9 mA in female guinea pig hearts. However, sustained VF was not possible to induce even by the strongest (50 mA) stimulus in the heart pre-treated with melatonin regardless the sex. In conclusion, atorvastatin, melatonin, EPA and DHA exhibit clear cut acute anti-fibrillating efficacy. Findings challenge to investigate expression of connexin-43, especially its phosphorylated status associated with connexin channel function, in acute conditions. PMID- 25716969 TI - Glucocorticoid receptor mediates the expansion of splenic late erythroid progenitors during chronic psychological stress. AB - Stress evokes an integrated neuroendocrine response perturbing the homeostasis of different physiological systems. In contrast to well established physiologica linteractions between neuroendocrine and immune systems during chronic stress, there has been relatively little information on the effects of psychological stress on erythroid cells. Since stress-induced erythropoiesis occurs predominantly in the spleen, in the current study, we investigated the influence of chronic psychological stress on splenic erythroid progenitors and examined a role of glucocorticoid receptor (GR) in observed effect using a mouse model of restraint. The adult male mice were subjected to 2 hours daily restraint stress for 7 or 14 consecutive days and the role of GR in erythropoietic response to stress was assessed by pretreatment of mice with GR antagonist mifepristone 60 min prior to restraint. The results showed that chronic restraint stress induced an increase in spleen weight as well as in the cellularity of red pulp, as compared to controls. Furthermore, 7 and 14 days of restraint stress resulted in markedly increased number of both splenic early (BFU-E) and late (CFU-E) erythroid progenitors. Blockade of GR with mifepristone did not affect the number of BFU-E in stressed mice, but it completely abolished the effect of repeated psychological stress on CFU-E cells. Additionally, plasma corticosterone concentration was enhanced whereas the GR expression was significantly decreased within splenic red pulp after one and two weeks of stress exposure. Obtained findings suggest for the first time an indispensable role for GR in the expansion of CFU-E progenitors in the spleen under conditions of chronic psychological stress. PMID- 25716970 TI - N-acetylcysteine effectively diminished meconium-induced oxidative stress in adult rabbits. AB - Since inflammation and oxidative stress are fundamental in the pathophysiology of neonatal meconium aspiration syndrome (MAS), various anti-inflammatory drugs have been used in experimental and clinical studies on MAS. This pilot study evaluated therapeutic potential of N-acetylcysteine in modulation of meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated adult rabbits were intratracheally given 4 ml/kg of meconium (25 mg/ml) or saline (Sal, n = 6). Thirty minutes later, meconium-instilled animals were treated with intravenous N acetylcysteine (10 mg/kg, Mec + NAC, n=6) or were non-treated (Mec, n = 6). All animals were oxygen-ventilated for additional 5 hours. Total and differential blood leukocyte counts were determined at baseline, and at 1, 3 and 5 h of the treatment. After sacrificing animals, left lung was saline-lavaged and total and differential cell counts in the bronchoalveolar lavage fluid were determined. Right lung was used for biochemical analyses and for estimation of wet-dry weight ratio. In lung tissue homogenate, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation (LPO) products, and total antioxidant status (TAS) were detected. In isolated lung mitochondria, TBARS, dityrosine, lysine-LPO products, thiol group content, conjugated dienes, and activity of cytochrome c oxidase were estimated. To evaluate systemic effects of meconium instillation and NAC treatment, TBARS and TAS were determined also in plasma. To evaluate participation of eosinophils in the meconium-induced inflammation, eosinophil cationic protein (ECP) was detected in plasma and lung homogenate. Meconium instillation increased oxidation markers and ECP in the lung and decreased TAS (all P<0.05). NAC treatment reduced ECP and oxidation markers (all P<0.05, except of dityrosine in homogenate and conjugated dienes in mitochondria) and prevented a decrease in TAS (P<0.01) in lung homogenate compared to Mec group. In plasma, NAC decreased TBARS (P<0.001) and ECP, and increased TAS (both P<0.05) compared to Mec group. Concluding, N-acetylcysteine diminished meconium-induced inflammation and oxidative lung injury. PMID- 25716971 TI - Anti-inflammatory effects of atorvastatin treatment in chronic obstructive pulmonary disease. A controlled pilot study. AB - Observational studies have suggested that statins may have beneficial effects on outcomes in chronic obstructive pulmonary disease (COPD) patients. These effects may be mediated through an anti-inflammatory effect of statins. The purpose of this pilot-study was to determine whether statins have an anti-inflammatory effect on the lungs of COPD patients. We conducted randomized, controlled, parallel group pilot-study to compare the effects of atorvastatin (n=12) or placebo (n=6) on lung inflammation in patients with mild to moderate COPD. The primary endpoint was change in CD45+ cells expression measured by immunohistochemistry and changes in expression of genes measured using microarrays in lung biopsy (TBB) samples before and after 12 weeks of treatment with atorvastatin 40 mg/day. All subjects had spirometry, lung volumes, diffusing capacity of the lungs for carbon monoxide (DLCO), St George's Respiratory Questionnaire (SGRQ), 6 minute walk distance (6 MWD), serum lipids, hs-CRP, induced sputum (IS), bronchoscopy and TBB carried out at baseline and after treatment. TBB specimens were processed for histology, immunohistochemistry and genome-wide association studies (GWAS) profiling. Seventeen subjects completed the study. There was a significant improvement in SGRQ with mean SGRQ decreased by 12 points after treatment with atorvastatin (P=0.012). Atorvastatin treatment produced a significant 34% reduction in sputum neutrophil count, and a 57% reduction in CD45+ cells in lung biopsies (expressed as integrated optical density -IOD; median IOD 62.51% before, 27.01% after atorvastatin treatment, P=0.008). In patients' lung tissue atorvastatin treatment produced downregulation of key genes involved in inflammatory processes, immune response, and leukocyte activation. These data demonstrate the pulmonary anti-inflammatory effects of atorvastatin in COPD patients with the potential for beneficial clinical effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01748279. PMID- 25716972 TI - Effect of subacute poisoning with bifenthrin on locomotor activity, memory retention, haematological, biochemical and histopathological parameters in mice. AB - Bifenthrin (BIF) is a pyrethroid (PYR) insecticide. The target point for PYR's toxic action are voltage sensitive sodium channels in the central nervous system (CNS). Intoxication with PYRs results in motor activity impairment and death in insects. Although PYRs are considered to be safe for mammals, there were numerous cases of pyrethroid poisoning in humans, animals and pets described. The general population is chronically exposed to PYRs via grain products, dust and indoor air. Therefore new questions arise: whether PYRs act in a dose-additive fashion in the course of subacute poisoning, are there other target organs (but brain) for BIF and if there is one common mechanism of its' toxic action in different organs. The objective of this work was to characterize the effect of BIF at the doses of 4 or 8 mg/kg injected intraperitoneally (i.p.) daily for 28 consecutive days on memory and motor activity, hematological, biochemical and histopathological parameters in mice. BIF at the doses of 8 mg/kg or 4 mg/kg of body mass was administered i.p. daily to the mice for 28 consecutive days. Motor function was measured on day 1, 7, 14 and 28 and memory retention was tested in a passive avoidance task on day 2, 7, 14 and 28. BIF significantly impaired memory retention on day 2. BIF decreased locomotor activity at every stage of the experiment in a single dose depending manner. No behavioral cumulative effect was observed. Subacute poisoning with the higher dose of BIF caused anaemia, elevated white blood cell count (WBC), elevated alanine transaminase (ALT), superoxide dismuthase (SOD), and decreased glutathione peroxidase (GPx) activity. Lymphocyte infiltrates were visualized in the livers. IN CONCLUSION: subacute poisoning with BIF decreases locomotor activity in a single dose proportionate manner. BIF damages also the liver and alters blood morphology. The possible common mechanism of these effects can be oxidative stress. PMID- 25716973 TI - Cytological assessment of the epithelial cells of the nasal mucous membrane after local fluticasone therapy. AB - The majority of cytological studies concern the influence of glucocorticosteroids on cells involved in creating and sustaining inflammation, such as eosinophils or neutrophils. Much less attention is devoted to epithelial cells. It should also be noticed that glucocorticosteroid drugs administered nasally for local action can significantly change the cytological image of the nasal mucous membrane. Therefore, the purpose of this research was to cytologically assess the influence of topical fluticasone therapy on the nasal mucous membrane cells, with special attention for the changes in the morphology of epithelial cells. The research samples were taken from patients with symptoms of chronic rhinitis and suspected allergies. The research was a two-step process. In the first step, a smear was taken from the surface of the nasal mucous membrane of the above-mentioned patients before the start of therapy and the obtained cytological image was compared with a control image of the nasal mucous of healthy people. Step two involved the cytology of the same patients after 4 weeks of fluticasone therapy, applied as a nasal aerosol in two doses of 50 MUg to each nostril once per day, in the combined daily dose of 200 MUg (for adults and children aged 12 or more). Children aged between 4 and 12 were given a single dose of 50 MUg to each nostril once per day, in a daily dose of 100 MUg. Based on smears stained according to the Papanicolaou and Pappenheim method, a qualitative and quantitative analysis of changes in the mucous membrane of nasal cells was performed. The cytological assessment of nasal mucous membrane stains of patients with chronic rhinitis before fluticasone treatment enabled a diagnosis of chronic infectious rhinitis, compared through the presence of numerous neutrophils and bacteria. The studied samples did not show significant changes in the morphology of epithelial cells, only a few cells with mild vacuolation changes of the cytoplasm were found. The use of fluticasone, however, caused a significant decrease in the neutrophilia and the appearance of numerous epithelial cells with intensified cytoplasm vacuolation in the sample. The results obtained allow us to conclude that standard fluticasone therapy as administered nasally in aerosol form to patients with diagnosed nonallergic nasal mucous membrane inflammation caused a significant reduction in the inflammation without showing cytological characteristics of damage to the epithelium of the nasal mucous membrane. The intensified vacuolation observed in the cytoplasm of epithelial cells, most prominently in the columnar cells, might suggest the stimulation of autophagic processes. PMID- 25716974 TI - Evaluation of the saliva cortisol levels in patients under prosthetic treatment due to functional disorders of the masticatory organ. AB - One of the main etiological factors of the stomatognathic system dysfunction is stress and psychoemotional disorders. During stressful situations, there is an increase in the level of cortisol, the so-called stress hormone. Literature data indicate the existence of a correlation between blood cortisol levels and its amount in the saliva. This spurred an inspiration to undertake open, non randomised studies, the objective of which was to conduct a comparative assessment of the saliva cortisol levels in patients with functional disorders of the masticatory system and in healthy volunteers, as well as to compare the results of cortisol levels with the results of survey-based tests with the use of Endler and Parker's CISS survey. Cortisol level was assessed due to its association with stress present in the body as one of the primary etiological factors of the stomatognathic system dysfunction, and hence the association of elevated cortisol levels assessed in the morning with the occurrence of dysfunctions of the stomatognathic system. The subject of the study is a group of 30 patients, of both sexes, aged between 20 and 46, who reported to the Dental Prosthetic Out-Patient Clinic of the Institute of Dentistry, Jagiellonian University in Cracow, for prosthetic treatment due to the painful form of functional masticatory organ disorders. The control group consisted of 30 subjects, aged between 19 and 41, in whom dysfunctions of the stomatognathic system were excluded. Collection of saliva for testing was performed at a fixed hour (9 am) into plastic test tubes with a stopper. Immediately after collection, the saliva was frozen at the temperature of -18 degrees C. The assessment of the cortisol levels was conducted by the high performance liquid chromatography (HPLC) with UV detection at the Department of Analytical Chemistry, Faculty of Pharmacy, Department of Laboratory Medicine of the Gdansk Medical University. Moreover, a 20-minute psychological test was conducted with the use of the CISS (coping inventory for stressful situations) survey in order to assess the patients in terms of their abilities to cope with stressful situations. The results obtained were submitted to a statistical analysis based on the conventional calculation procedures. The test group revealed significantly higher cortisol levels compared with the results obtained by the control group. The findings of the CISS survey confirmed the predominance of the emotion-focused strategy of coping with stressful situations in the test group. The results support the view that the psychoemotional factor is, to a considerable extent, conducive to the development of functional disorders. The elevated cortisol levels in patients with psychological disorders concur with the findings by other authors. The results obtained confirm that psychoemotional disorders may be one of the etiological factors of the stomatognathic system dysfunctions. The CISS survey, which was not used in similar studies before, makes it possible to obtain information on the subject's method of coping with stress, thus allowing for the initiation of a relevant psychological therapy aiding the prosthetic treatment. PMID- 25716975 TI - Development of a CERT START Domain-Ceramide HTRF Binding Assay and Application to Pharmacological Studies and Screening. AB - Sphingomyelin (SM) metabolism deregulation was recently associated with cell metastasis and chemoresistance, and several pharmacological strategies targeting SM metabolism have emerged. The ceramide (Cer) generated in the endoplasmic reticulum (ER) is transferred to the Golgi apparatus to be transformed into SM. CERamide Transfer (CERT) protein is responsible for the nonvesicular trafficking of Cer to Golgi. Blocking the CERT-mediated ER-to-Golgi Cer transfer is an interesting antioncogenic therapeutic approach. Here, we developed a protein lipid interaction assay for the identification of new CERT-Cer interaction inhibitors. Frequently used for protein-protein interaction by enzymatic and analyte dosage assays, homogeneous time-resolved fluorescence technology was adapted for the first time to a lipid-protein binding assay. This test was developed for high-throughput screening, and a library of 672 molecules was screened. Seven hits were identified, and their inhibitory effect quantified by EC50 measurements showed binding inhibition three orders of magnitude more potent than that of HPA12, the unique known CERT antagonist to date. Each compound was tested on an independent test, confirming its high affinity and pharmacological potential. PMID- 25716976 TI - Research and practice in a multidimensional world: a commentary on the contribution of the third dimension of the Haddon matrix to injury prevention. PMID- 25716977 TI - Transapical perfusion for peri-arrest salvage during transcutaneous aortic valve implantation. AB - An 80-year-old man developed severe haemodynamic instability during a transapical aortic valve implantation. He was not suitable for a conventional surgical approach due to comorbidities and patent aortocoronary bypass grafts also limited further stabilizing actions. As a bail-out procedure, we demonstrate the feasibility of transapical arterial cannulation by crossing a newly implanted TAVI valve in order to establish an emergency bypass circuit. PMID- 25716978 TI - Soft shoulders ahead: spurious signatures of soft and partial selective sweeps result from linked hard sweeps. AB - Characterizing the nature of the adaptive process at the genetic level is a central goal for population genetics. In particular, we know little about the sources of adaptive substitution or about the number of adaptive variants currently segregating in nature. Historically, population geneticists have focused attention on the hard-sweep model of adaptation in which a de novo beneficial mutation arises and rapidly fixes in a population. Recently more attention has been given to soft-sweep models, in which alleles that were previously neutral, or nearly so, drift until such a time as the environment shifts and their selection coefficient changes to become beneficial. It remains an active and difficult problem, however, to tease apart the telltale signatures of hard vs. soft sweeps in genomic polymorphism data. Through extensive simulations of hard- and soft-sweep models, here we show that indeed the two might not be separable through the use of simple summary statistics. In particular, it seems that recombination in regions linked to, but distant from, sites of hard sweeps can create patterns of polymorphism that closely mirror what is expected to be found near soft sweeps. We find that a very similar situation arises when using haplotype-based statistics that are aimed at detecting partial or ongoing selective sweeps, such that it is difficult to distinguish the shoulder of a hard sweep from the center of a partial sweep. While knowing the location of the selected site mitigates this problem slightly, we show that stochasticity in signatures of natural selection will frequently cause the signal to reach its zenith far from this site and that this effect is more severe for soft sweeps; thus inferences of the target as well as the mode of positive selection may be inaccurate. In addition, both the time since a sweep ends and biologically realistic levels of allelic gene conversion lead to errors in the classification and identification of selective sweeps. This general problem of "soft shoulders" underscores the difficulty in differentiating soft and partial sweeps from hard-sweep scenarios in molecular population genomics data. The soft shoulder effect also implies that the more common hard sweeps have been in recent evolutionary history, the more prevalent spurious signatures of soft or partial sweeps may appear in some genome-wide scans. PMID- 25716981 TI - Ethylene polymerisation and ethylene/norbornene copolymerisation by using aryloxo modified vanadium(V) complexes containing 2,6-difluoro-, dichloro-phenylimido complexes. AB - Aryloxo-modified vanadium(V) dichloride complexes containing a dichloro- or difluoro-phenylimido ligand of the type, V(N-2,6-X2C6H3)Cl2(O-2,6-R2C6H3) [X = Cl (1), F (2); R = Me (a), F (b)], showed remarkable catalytic activity in ethylene polymerisation and the copolymerisation with norbornene (NBE) in the presence of Et2AlCl; the activities were higher than that of V(N-2,6-Me2C6H3)Cl2(O-2,6 Me2C6H3) reported previously. Complex 1a is a suitable catalyst precursor in terms of not only the activity, but also synthesis of high molecular weight copolymers with both unimodal molecular weight distributions and uniform compositions. PMID- 25716979 TI - The Mps1 kinase modulates the recruitment and activity of Cnn1(CENP-T) at Saccharomyces cerevisiae kinetochores. AB - Kinetochores are conserved protein complexes that bind the replicated chromosomes to the mitotic spindle and then direct their segregation. To better comprehend Saccharomyces cerevisiae kinetochore function, we dissected the phospho-regulated dynamic interaction between conserved kinetochore protein Cnn1(CENP-T), the centromere region, and the Ndc80 complex through the cell cycle. Cnn1 localizes to kinetochores at basal levels from G1 through metaphase but accumulates abruptly at anaphase onset. How Cnn1 is recruited and which activities regulate its dynamic localization are unclear. We show that Cnn1 harbors two kinetochore localization activities: a C-terminal histone-fold domain (HFD) that associates with the centromere region and a N-terminal Spc24/Spc25 interaction sequence that mediates linkage to the microtubule-binding Ndc80 complex. We demonstrate that the established Ndc80 binding site in the N terminus of Cnn1, Cnn1(60-84), should be extended with flanking residues, Cnn1(25-91), to allow near maximal binding affinity to Ndc80. Cnn1 localization was proposed to depend on Mps1 kinase activity at Cnn1-S74, based on in vitro experiments demonstrating the Cnn1-Ndc80 complex interaction. We demonstrate that from G1 through metaphase, Cnn1 localizes via both its HFD and N-terminal Spc24/Spc25 interaction sequence, and deletion or mutation of either region results in anomalous Cnn1 kinetochore levels. At anaphase onset (when Mps1 activity decreases) Cnn1 becomes enriched mainly via the N-terminal Spc24/Spc25 interaction sequence. In sum, we provide the first in vivo evidence of Cnn1 preanaphase linkages with the kinetochore and enrichment of the linkages during anaphase. PMID- 25716980 TI - Periodontal Defects in the A116T Knock-in Murine Model of Odontohypophosphatasia. AB - Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl (-/-)) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl (-/-) mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl(+/A116T) mice to validate this model. Alpl(+/A116T) mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl(+/A116T) versus wild-type mice. The postcranial skeleton of Alpl(+/A116T) mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl(+/A116T) mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl(+/A116T) mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies. PMID- 25716982 TI - Roche perspectives on Tamiflu. PMID- 25716983 TI - Issues experienced while administering care to patients with dementia in acute care hospitals: a study based on focus group interviews. AB - OBJECTIVE: Dementia is a major public health problem. More and more patients with dementia are being admitted to acute care hospitals for treatment of comorbidities. Issues associated with care of patients with dementia in acute care hospitals have not been adequately clarified. This study aimed to explore the challenges nurses face in providing care to patients with dementia in acute care hospitals in Japan. METHODS: This was a qualitative study using focus group interviews (FGIs). The setting was six acute hospitals with surgical and medical wards in the western region of Japan. Participants were nurses in surgical and internal medicine wards, excluding intensive care units. Nurses with less than 3 years working experience, those without experience in dementia patient care in their currently assigned ward, and head nurses were excluded from participation. FGIs were used to collect data from February to December 2008. Interviews were scheduled for 1-1.5 h. The qualitative synthesis method was used for data analysis. RESULTS: In total, 50 nurses with an average experience of 9.8 years participated. Eight focus groups were formed. Issues in administering care to patients with dementia at acute care hospitals were divided into seven groups. Three of these groups, that is, problematic patient behaviors, recurrent problem, and problems affecting many people equally, interact to result in a burdensome cycle. This cycle is exacerbated by lack of nursing experience and lack of organization in hospitals. In coping with this cycle, the nurses develop protection plans for themselves and for the hospital. CONCLUSIONS: The two main issues experienced by nurses while administering care to patients with dementia in acute care hospitals were as follows: (a) the various problems and difficulties faced by nurses were interactive and caused a burdensome cycle, and (b) nurses do their best to adapt to these conditions despite feeling conflicted. PMID- 25716984 TI - Solid-Phase Extraction Followed by Dispersive Liquid-Liquid Microextraction Based on Solidification of Floating Organic Drop for the Determination of Parabens. AB - A dispersive liquid-liquid microextraction based on solidification of floating organic drop method combined with solid-phase extraction (500-mg C18 sorbent) was developed for preconcentration and determination of some parabens. The experimental parameters influencing the extraction efficiency such as the type of extraction and disperser solvents, as well as their volumes, breakthrough volume, flow rate and salt addition were studied and optimized. The optimum experimental conditions found included: sample volume, 100 mL; KCl concentration, 1% (w/v); extraction solvent (1-undecanol) volume, 20 uL and disperser solvent (acetone) volume, 250 uL. Under the optimum experimental conditions, calibration graphs were linear in the range of 1-200 ug L(-1) with limits of detection ranged from 0.3 to 1.7 ug L(-1). The relative standard deviations were in the range of 1.2 3.1% (n = 5). The enrichment factors and absolute recoveries of parabens in different matrices were 245-1886 and 9.0-69.8%, respectively. The method was applied to the simultaneous determination of parabens in different matrices. The relative recoveries from water, shampoo and mouth rinse samples, which have been spiked at different levels of parabens, were 87.83-112.25%, 82.80-108.40% and 90.10-97.60%, respectively. PMID- 25716985 TI - Epigenetics and depressive disorders: a review of current progress and future directions. AB - BACKGROUND: Several broad lines of evidence support the involvement of epigenetic processes in neurodevelopment and psychiatric disorders. Epigenetic disruption also provides a potential mechanism to account for the numerous gene-environment interactions that have been reported in association with neuropsychiatric phenotypes. METHODS: A review of the literature was performed with keywords 'depression', 'depressive disorder' or 'antidepressants' and 'DNA methylation', or 'epigenetics' in humans. Citations were limited to those written in English and published prior to July 2014. RESULTS: We present a summary of results to date. Most studies have focused on DNA methylation in various CNS or peripheral tissue, with almost universally small sample sizes. Although seven epigenome-wide association studies have now been reported, the majority of studies have used a candidate-gene approach. Three genes (SLC6A4, BDNF, NR3C1) have been investigated in more than one study, but replication of findings is generally lacking. CONCLUSIONS: Recent evidence provides insights to epigenetic processes in psychiatric disorders; however, replication is lacking and care must be taken in the interpretation of current findings. This applies to epigenetic epidemiology generally, which is subject to various limitations that no single approach can address in isolation. Due to limited focus of most depression studies to date, placing the findings within the broader context of mood disorder pathophysiology may prove challenging. However, identifying peripheral biomarkers for depressive disorder remains a tantalising possibility, especially given the potential for carefully-designed longitudinal studies with multiple biospecimens and ongoing advances in epigenetic technologies. PMID- 25716987 TI - Low recurrence rate after nodal reentrant tachycardia cryoablation with an 8-mm tip catheter and prolonged applications. PMID- 25716986 TI - Relationship between school dropout and teen pregnancy among rural South African young women. AB - BACKGROUND: Sexual activity may be less likely to occur during periods of school enrolment because of the structured and supervised environment provided, the education obtained and the safer peer networks encountered while enrolled. We examined whether school enrolment was associated with teen pregnancy in South Africa. METHODS: Using longitudinal demographic surveillance data from the rural Agincourt sub-district, we reconstructed the school enrolment status from 2000 through 2011 for 15 457 young women aged 12-18 years and linked them to the estimated conception date for each pregnancy during this time. We examined the effect of time-varying school enrolment on teen pregnancy using a Cox proportional hazard model, adjusting for: age; calendar year; household socioeconomic status; household size; and gender, educational attainment and employment of household head. A secondary analysis compared the incidence of pregnancy among school enrolees by calendar time: school term vs school holiday. RESULTS: School enrolment was associated with lower teen pregnancy rates [adjusted hazard ratio (95% confidence interval): 0.57 (0.50, 0.65)].This association was robust to potential misclassification of school enrolment. For those enrolled in school, pregnancy occurred less commonly during school term than during school holidays [incidence rate ratio (95% confidence interval): 0.90 (0.78, 1.04)]. CONCLUSIONS: Young women who drop out of school may be at higher risk for teen pregnancy and could likely benefit from receipt of accessible and high quality sexual health services. Preventive interventions designed to keep young women in school or addressing the underlying causes of dropout may also help reduce the incidence of teen pregnancy. PMID- 25716988 TI - Paced Tachycardia by Biventricular Pacemaker. PMID- 25716989 TI - Renal, endothelial function, warfarin management, and the CHADS2, CHA2DS2VASc and HAS-BLED scores inpredicting MACE in AF. PMID- 25716990 TI - Heterobimetallic metallation studies of N,N-dimethylphenylethylamine (DMPEA): benzylic C-H bond cleavage/dimethylamino capture or intact DMPEA complex. AB - Reaction of the sodium monoamido-bisalkylzincate [(TMEDA)Na(TMP)(Bu(t))Zn(Bu(t))] (TMEDA is N,N,N',N'-tetramethylethylenediamine; TMP is 2,2,6,6 tetramethylpiperidide) and the related lithium zincate [(PMDETA)Li(TMP)Zn(Bu(t))2] (PMDETA is N,N,N',N'',N'' pentamethyldiethylenetriamine) with the sensitive bio-relevant scaffold N,N dimethylphenylethylamine, DMPEA, afforded the crystalline complexes [(TMEDA)Na(TMP)(NMe2)Zn(Bu(t))] and [(PMDETA)Li(NMe2)Zn(Bu(t))2], respectively, both of which have been characterized by NMR spectroscopic and X-ray crystallographic studies. Made by reaction of a LiTMP-(TMP)Al(Bu(i))2 mixture with DMPEA, a third dimethylamino-containing crystalline complex, the aluminate [(THF)Li(TMP)(NMe2)Al(Bu(i))2] has been similarly characterized. All three complexes can be regarded as products of cleave and capture chemistry whereby metallation at the benzylic position of DMPEA has led to a beta-elimination of an anionic Me2N fragment that has been captured by a charge balancing cationic heterobimetallic entity. While a metallated intermediate prior to the elimination has proved elusive in all of these reactions, DMPEA has been captured fully intact in the novel Lewis acid-Lewis base crystalline complex [DMPEA.Li(TMP)Zn(Me)2], which has also been characterized by the aforementioned techniques. PMID- 25716991 TI - Epicardial catheter ablation of ventricular tachycardia in no entry left ventricle: mechanical aortic and mitral valves. AB - BACKGROUND: In patients with mechanical aortic and mitral valves and left ventricular tachycardia, catheter ablation may be prevented by limited access to the left ventricle. METHODS AND RESULTS: In our series of 6 patients, 2 patients underwent direct surgical ablation and 4 underwent epicardial catheter ablation via a pericardial window. All patients had abnormal low voltage areas with fractionated or delayed isolated potentials on the apical epicardium. Most of the ventricular tachycardias were targeted by pace mapping. Sites with a good pace match or abnormal electrograms were ablated using an irrigated radiofrequency ablation catheter. A microscopic pathological evaluation of the resected tissue from 2 of the open-heart ablation patients revealed dense fibrosis on the epicardium compared with the endocardium, supporting the feasibility of an epicardial ablation for the ventricular tachycardia. CONCLUSIONS: Epicardial catheter ablation of ventricular tachycardia is a potentially useful therapy in patients who have mechanical aortic and mitral valves. PMID- 25716992 TI - A meta-analytic review of moral licensing. AB - Moral licensing refers to the effect that when people initially behave in a moral way, they are later more likely to display behaviors that are immoral, unethical, or otherwise problematic. We provide a state-of-the-art overview of moral licensing by conducting a meta-analysis of 91 studies (7,397 participants) that compare a licensing condition with a control condition. Based on this analysis, the magnitude of the moral licensing effect is estimated to be a Cohen's d of 0.31. We tested potential moderators and found that published studies tend to have larger moral licensing effects than unpublished studies. We found no empirical evidence for other moderators that were theorized to be of importance. The effect size estimate implies that studies require many more participants to draw solid conclusions about moral licensing and its possible moderators. PMID- 25716994 TI - Ultraviolet radiation signaling through TLR4/MyD88 constrains DNA repair and plays a role in cutaneous immunosuppression. AB - UV radiation (UVR) induces DNA damage, leading to the accumulation of mutations in epidermal keratinocytes and immunosuppression, which contribute to the development of nonmelanoma skin cancer. We reported previously that the TLR4 MyD88 signaling axis is necessary for UV-induced apoptosis. In the dinitrofluorobenzene contact hypersensitivity model, UV-irradiated MyD88 deficient (MyD88(-/-)) C57BL/6 mice had intact ear swelling, exaggerated inflammation, and higher levels of dinitrofluorobenzene-specific IgG2a compared with wild-type (WT) mice. Even with normal UV-induced, dendritic cell migration, DNA damage in the local lymph nodes was less pronounced in MyD88(-/-) mice compared with WT mice. Cultured, UV-irradiated WT APCs showed cleavage (inactivation) of the DNA damage-recognition molecule PARP, whereas PARP persisted in MyD88(-/-) and TLR4(-/-) APCs. Epidermal DNA from in vivo UV irradiated MyD88(-/-) mice had an increased resolution rate of cyclobutane pyrimidine dimers. Both in vitro treatment of MyD88(-/-) APCs with and intradermal in vivo injections of PARP inhibitor, PJ-34, caused WT-level cyclobutane pyrimidine dimer repair. Lymphoblasts deficient in DNA repair (derived from a xeroderma pigmentosum group A patient) failed to augment DNA repair after MyD88 knockdown after UVR, in contrast to lymphoblasts from a healthy control. These data suggest that interference with the TLR4/MyD88 pathway may be a useful tool in promoting DNA repair and maintaining immune responses following UVR-induced damage. PMID- 25716993 TI - MAPK phosphatase 7 regulates T cell differentiation via inhibiting ERK-mediated IL-2 expression. AB - Members of the MAPK phosphatase (MKP) protein family play critical roles in immune responses through differential regulation of MAPK activation. In this study, we show that MKP7, also known as dual-specificity phosphatase 16, was required for CD4(+) T cell responses in vivo. Mkp7(-/-) CD4(+) T cells exhibited enhanced ERK and JNK activation, and produced increased amount of IL-2 compared with Mkp7(+/+) cells upon activation. Mkp7(-/-) CD4(+) T cells were selectively defective in Th17 differentiation in vitro, which was rescued by blocking IL-2 or inhibition of ERK activation. Furthermore, mice carrying Mkp7(-/-) T cells were deficient in generation of Th17 and T follicular helper cells in vivo, and were resistant to autoimmune experimental encephalomyelitis. Our results thus demonstrate an essential role of MKP7 in effector T cell function. PMID- 25716995 TI - Alcohol-induced miR-27a regulates differentiation and M2 macrophage polarization of normal human monocytes. AB - Alcohol abuse is a leading cause of liver disease characterized by liver inflammation, fatty liver, alcoholic hepatitis, or liver cirrhosis. Immunomodulatory effects of alcohol on monocytes and macrophages contribute to alcoholic liver disease. Alcohol use, an independent risk factor for progression of hepatitis C virus (HCV) infection-mediated liver disease, impairs host defense and alters cytokine production and monocyte/macrophage activation. We hypothesized that alcohol and HCV have synergistic effects on the phenotype and function of monocytes. Our data show that acute alcohol binge drinking in healthy volunteers results in increased frequency of CD16(+) and CD68(+) and M2-type (CD206(+), dendritic cell [DC]-SIGN(+)-expressing and IL-10-secreting) circulating CD14(+) monocytes. Expression of HCV-induced CD68 and M2 markers (CD206 and DC-SIGN) in normal monocytes was further enhanced in the presence of alcohol. The levels of microRNA (miR)-27a was significantly upregulated in monocytes cultured in the presence of alcohol or alcohol and HCV as compared with HCV alone. The functional role of miR-27a in macrophage polarization was demonstrated by transfecting monocytes with an miR-27a inhibitor that resulted in reduced alcohol- and HCV- mediated monocyte activation (CD14 and CD68 expression), polarization (CD206 and DC-SIGN expression), and IL-10 secretion. Overexpression of miR-27a in monocytes enhanced IL-10 secretion via activation of the ERK signaling pathway. We found that miR-27a promoted ERK phosphorylation by downregulating the expression of ERK inhibitor sprouty2 in monocytes. Thus, we identified that sprouty2 is a target of miR-27a in human monocytes. In summary, our study demonstrates the regulatory role of miR-27a in alcohol-induced monocyte activation and polarization. PMID- 25716996 TI - Retina-specific T regulatory cells bring about resolution and maintain remission of autoimmune uveitis. AB - Experimental autoimmune uveitis (EAU) induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein (IRBP) is a model of human autoimmune uveitis. We examined whether T regulatory cells (Tregs) found in uveitic eyes are IRBP specific, functionally suppressive, and play a role in natural resolution of disease and in maintenance of remission. Progressive increase of Foxp3(+) Treg to T effector cell (Teff) ratio in uveitic eyes correlated with resolution of disease. At peak disease, up to 20% of Tregs (CD4(+)Foxp3(+)) and up to 60% of Teffs (CD4(+)Foxp3(-)) were IRBP specific, whereas in lymphoid organs retina-specific T cells were undetectable. Tregs isolated from eyes of mice with EAU efficiently suppressed IRBP-specific responses of Teffs from the same eyes. Importantly, systemic depletion of Tregs at peak disease delayed resolution of EAU, and their depletion after resolution triggered a relapse. This could be partially duplicated by depletion of Tregs locally within the eye. Thus, the T cell infiltrate in uveitic eyes of normal mice with a polyclonal T cell repertoire is highly enriched in IRBP-specific Tregs and Teffs. Unlike what has been reported for Tregs in other inflammatory sites, Tregs from uveitic eyes appear unimpaired functionally. Finally, Foxp3(+) Tregs play a role in the natural resolution of uveitis and in the maintenance of remission, which occurs at least in part through an effect that is local to the eye. PMID- 25716997 TI - Buprenorphine decreases the CCL2-mediated chemotactic response of monocytes. AB - Despite successful combined antiretroviral therapy, ~ 60% of HIV-infected people exhibit HIV-associated neurocognitive disorders (HAND). CCL2 is elevated in the CNS of infected people with HAND and mediates monocyte influx into the CNS, which is critical in neuroAIDS. Many HIV-infected opiate abusers have increased neuroinflammation that may augment HAND. Buprenorphine is used to treat opiate addiction. However, there are few studies that examine its impact on HIV neuropathogenesis. We show that buprenorphine reduces the chemotactic phenotype of monocytes. Buprenorphine decreases the formation of membrane projections in response to CCL2. It also decreases CCL2-induced chemotaxis and mediates a delay in reinsertion of the CCL2 receptor, CCR2, into the cell membrane after CCL2 mediated receptor internalization, suggesting a mechanism of action of buprenorphine. Signaling pathways in CCL2-induced migration include increased phosphorylation of p38 MAPK and of the junctional protein JAM-A. We show that buprenorphine decreases these phosphorylations in CCL2-treated monocytes. Using DAMGO, CTAP, and Nor-BNI, we demonstrate that the effect of buprenorphine on CCL2 signaling is opioid receptor mediated. To identify additional potential mechanisms by which buprenorphine inhibits CCL2-induced monocyte migration, we performed proteomic analyses to characterize additional proteins in monocytes whose phosphorylation after CCL2 treatment was inhibited by buprenorphine. Leukosialin and S100A9 were identified and had not been shown previously to be involved in monocyte migration. We propose that buprenorphine limits CCL2 mediated monocyte transmigration into the CNS, thereby reducing neuroinflammation characteristic of HAND. Our findings underscore the use of buprenorphine as a therapeutic for neuroinflammation as well as for addiction. PMID- 25716999 TI - Extracellular vesicles derived from Gram-negative bacteria, such as Escherichia coli, induce emphysema mainly via IL-17A-mediated neutrophilic inflammation. AB - Recent evidence indicates that Gram-negative bacteria-derived extracellular vesicles (EVs) in indoor dust can evoke neutrophilic pulmonary inflammation, which is a key pathology of chronic obstructive pulmonary disease (COPD). Escherichia coli is a ubiquitous bacterium present in indoor dust and secretes nanometer-sized vesicles into the extracellular milieu. In the current study, we evaluated the role of E. coli-derived EVs on the development of COPD, such as emphysema. E. coli EVs were prepared by sequential ultrafiltration and ultracentrifugation. COPD phenotypes and immune responses were evaluated in C57BL/6 wild-type (WT), IFN-gamma-deficient, or IL-17A-deficient mice after airway exposure to E. coli EVs. The present study showed that indoor dust from a bed mattress harbors E. coli EVs. Airway exposure to E. coli EVs increased the production of proinflammatory cytokines, such as TNF-alpha and IL-6. In addition, the repeated inhalation of E. coli EVs for 4 wk induced neutrophilic inflammation and emphysema, which are associated with enhanced elastase activity. Emphysema and elastase activity enhanced by E. coli EVs were reversed by the absence of IFN gamma or IL-17A genes. In addition, during the early period, lung inflammation is dependent on IL-17A and TNF-alpha, but not on IFN-gamma, and also on TLR4. Moreover, the production of IFN-gamma is eliminated by the absence of IL-17A, whereas IL-17A production is not abolished by IFN-gamma absence. Taken together, the present data suggest that E. coli-derived EVs induce IL-17A-dependent neutrophilic inflammation and thereby emphysema, possibly via upregulation of elastase activity. PMID- 25716998 TI - OSCAR is a receptor for surfactant protein D that activates TNF-alpha release from human CCR2+ inflammatory monocytes. AB - Surfactant protein D (SP-D) is critical for maintenance of lung homeostasis and provides a first line of defense to pathogens at mucosal surfaces. Polymorphisms in the SP-D-encoding gene SFTPD have been associated with chronic obstructive pulmonary disease and ulcerative colitis. Identification of the immunoreceptors that bind SP-D is essential for understanding its contribution to lung homeostasis and mucosal defense. We located a putative binding motif for the osteoclast-associated receptor (OSCAR) within the SP-D collagenous domain. An OSCAR-Fc fusion protein specifically bound to the collagenous region of recombinant SP-D and captured native SP-D from human bronchoalveolar lavage. OSCAR localized in an intracellular compartment of alveolar macrophages together with SP-D. Moreover, we found OSCAR on the surface of interstitial lung and blood CCR2(+) inflammatory monocytes, which secreted TNF-alpha when exposed to SP-D in an OSCAR-dependent fashion. OSCAR and SP-D did not exclusively colocalize in lung, as they were also highly expressed in atherosclerotic plaques of human aorta, supporting a role for this interaction in atherosclerosis. Our results identify the OSCAR:SP-D interaction as a potential therapeutic target in chronic inflammatory diseases of the lung as well as other diseases involving tissue accumulation of SP-D, infiltration of inflammatory monocytes, and release of TNF alpha. PMID- 25717000 TI - WNT-inflammasome signaling mediates NOD2-induced development of acute arthritis in mice. AB - In addition to its role in innate immunity, the intracellular pathogen sensor nucleotide-binding oligomerization domain 2 (NOD2) has been implicated in various inflammatory disorders, including the development of acute arthritis. However, the molecular mechanisms involved in the development of NOD2-responsive acute arthritis are not clear. In this study, we demonstrate that NOD2 signals to a cellular protein, Ly6/PLAUR domain-containing protein 6, in a receptor interacting protein kinase 2-TGF-beta-activated kinase 1-independent manner to activate the WNT signaling cascade. Gain- or loss-of-function of the WNT signaling pathway in an in vivo experimental mouse arthritis model or in vitro systems established the role for WNT-responsive X-linked inhibitor of apoptosis during the development of acute arthritis. Importantly, WNT-stimulated X-linked inhibitor of apoptosis mediates the activation of inflammasomes. The subsequent caspase-1 activation and IL-1beta secretion together contribute to the phenotypic character of the inflammatory condition of acute arthritis. Thus, identification of a role for WNT-mediated inflammasome activation during NOD2 stimulation serves as a paradigm to understand NOD2-associated inflammatory disorders and develop novel therapeutics. PMID- 25717001 TI - The golgin GMAP-210 is required for efficient membrane trafficking in the early secretory pathway. AB - Golgins are coiled-coil proteins that participate in membrane-tethering events at the Golgi complex. Golgin-mediated tethering is thought to be important for vesicular trafficking and Golgi organization. However, the degree to which individual golgins contribute to these processes is poorly defined, and it has been proposed that golgins act in a largely redundant manner. Previous studies on the golgin GMAP-210 (also known as TRIP11), which is mutated in the rare skeletal disorder achondrogenesis type 1A, have yielded conflicting results regarding its involvement in trafficking. Here, we re-investigated the trafficking role of GMAP 210, and found that it is indeed required for efficient trafficking in the secretory pathway. GMAP-210 acts at both the endoplasmic reticulum (ER)-to-Golgi intermediate compartment (ERGIC) and Golgi complex during anterograde trafficking, and is also required for retrograde trafficking to the ER. Using co depletion experiments, we also found that GMAP-210 acts in a partially redundant manner with the golgin GM130 to ensure efficient anterograde cargo delivery to the cis-Golgi. In summary, our results indicate a role for GMAP-210 in several trafficking steps at the ER-Golgi interface, some of which are partially redundant with another golgin, namely GM130 (also known as GOLGA2). PMID- 25717002 TI - MicroRNA-mediated regulation of p21 and TASK1 cellular restriction factors enhances HIV-1 infection. AB - MicroRNAs (miRNAs) are short non-coding RNAs that play a central role in the regulation of gene expression by binding to target mRNAs. Several studies have revealed alterations in cellular miRNA profiles following HIV-1 infection, mostly for miRNAs involved in inhibiting viral infection. These miRNA expression modifications might also serve to block the innate HIV-1 inhibition mechanism. As a result, it is expected that during HIV-1 infection miRNAs target genes that hinder or prevent the progression of the HIV-1 replication cycle. One of the major sets of genes known to inhibit the progression of HIV-1 infection are cellular restriction factors. In this study, we identified a direct miRNA target gene that modulates viral spread in T-lymphocytes and HeLa-CCR5 cell lines. Following infection, let-7c, miR-34a or miR-124a were upregulated, and they targeted and downregulated p21 and TASK1 (also known as CDKN1A and KCNK3, respectively) cellular proteins. This eventually led to increased virion release and higher copy number of viral genome transcripts in infected cells. Conversely, by downregulating these miRNAs, we could suppress viral replication and spread. Our data suggest that HIV-1 exploits the host miRNA cellular systems in order to block the innate inhibition mechanism, allowing a more efficient infection process. PMID- 25717003 TI - Self-organization of core Golgi material is independent of COPII-mediated endoplasmic reticulum export. AB - The Golgi is a highly organized and dynamic organelle that receives and distributes material from and to the endoplasmic reticulum (ER) and the endocytic pathway. One open question about Golgi organization is whether it is solely based on ER-to-Golgi transport. Here, we analyzed the kinetics of Golgi breakdown in the absence of COPII-dependent ER export with high temporal and spatial resolution using quantitative fluorescence microscopy. We found that Golgi breakdown occurred in two phases. While Golgi enzymes continuously redistributed to the ER, we consistently observed extensive Golgi fragmentation at the beginning of the breakdown, followed by microtubule-dependent formation of a Golgi remnant structure (phase 1). Further Golgi disintegration occurred less uniformly (phase 2). Remarkably, cisternal Golgi morphology was lost early in phase 1 and Golgi fragments instead corresponded to variably sized vesicle clusters. These breakdown intermediates were devoid of COPI-dependent recycling material, but contained typical 'core' Golgi components. Furthermore, Golgi breakdown intermediates were able to disassemble and reassemble following cell division, indicating that they retained important regulatory capabilities. Taken together, these findings support the view that Golgi self-organization exists independently of ER-to-Golgi transport. PMID- 25717005 TI - An uninformed methodology. PMID- 25717004 TI - An active role for basement membrane assembly and modification in tissue sculpting. AB - Basement membranes are a dense, sheet-like form of extracellular matrix (ECM) that underlie epithelia and endothelia, and surround muscle, fat and Schwann cells. Basement membranes separate tissues and protect them from mechanical stress. Although traditionally thought of as a static support structure, a growing body of evidence suggests that dynamic basement membrane deposition and modification instructs coordinated cellular behaviors and acts mechanically to sculpt tissues. In this Commentary, we highlight recent studies that support the idea that far from being a passive matrix, basement membranes play formative roles in shaping tissues. PMID- 25717006 TI - Life cycle of Ornithodoros rostratus (Acari: Argasidae) ticks feeding on mice under laboratory conditions. AB - Ornithodoros rostratus Aragao is an argasid tick found in Bolivia, Paraguay, Argentina and Brazil. Only limited studies about O. rostratus have been conducted and several aspects of their life cycle differ among studies or remain unexplored. In order to better elucidate the biology of O. rostratus, the present work describes its life cycle when feeding on mice under laboratory conditions. To complete their life cycle on mice, O. rostratus goes through a larval stage, 3 6 nymphal instars (nymph 1-6) and adult male and female. Adults can be originated from nymph 3-6. Nymphs 4 with higher weight after feeding tend to originate adults. Adults originated from early instars tended to be lighter. Females tended to be heavier than males. Larvae needed on average 2.7 days to complete their blood meal whereas other instars ranged from 17.3 to 78.3 min. The capacity to ingest blood was higher in larvae and females in comparison to males. The preecdysis period ranged from 5 to 12.5 days. After one blood meal, females remain on average 15.2 +/- 5.8 days laying 276.8 +/- 137.2.9 eggs. Females originated from nymph 4 had similar oviposition time, egg incubation and conversion ingested blood/number of eggs produced, but presented lower initial weigh and weigh gain, generating fewer eggs. Our results added novel information on O. rostratus biology and was discussed considering the variability of argasid populations and in context with the differences about their life cycle described in previous works. PMID- 25717007 TI - Dominance of Dermacentor reticulatus over Ixodes ricinus (Ixodidae) on livestock, companion animals and wild ruminants in eastern and central Poland. AB - The most common tick species parasitizing animals in Poland are Ixodes ricinus and Dermacentor reticulatus. These tick species differ in their distribution, habitats, seasonal activity and host specificity. Ixodes ricinus is the most prevalent and widely distributed, whereas the range of D. reticulatus is limited to eastern and central parts of the country with several new foci in the middle west and the west. However, as in many central European countries, the range of D. reticulatus is expanding, and some authors have correlated this expansion with an increasing number of available hosts. The aim of the present study was to determine the tick fauna on domestic and livestock animals in two areas endemic for I. ricinus and D. reticulatus and to compare the risk of infestation with different tick species in open and forest areas. Over a 14 month period, 732 ticks were collected from five host species including domestic animals (dogs and cats), livestock (cows and horses) and wildlife (European bison) in two areas, central and NE Poland, endemic for D. reticulatus. Three tick species were recorded: D. reticulatus (623 individuals; 85.1% of all collected ticks), I. ricinus (106 individuals; 14.5%) and three females of Ixodes hexagonus (0.4%) from a dog. Dermacentor reticulatus was the dominant tick species found on four host species and constituted 86, 81, 97 and 100% of all ticks from dogs, horses, cows and bison, respectively, and was collected from animals throughout the year, including during the winter. The common tick, I. ricinus, was the dominant tick collected from cats (94%). Fully-engorged, ready-for-reproduction females of D. reticulatus were collected from all host species. In May 2012, questing ticks were collected by dragging in forest or open habitats. The density of adult marsh ticks in open areas was around 2 ticks/100 m(2) in the majority of locations, with a maximum of 9.5 ticks/100 m(2). The density of adult I. ricinus was much lower in its typical habitat (forests: range 0.8-2.2 ticks/100 m(2)) between three and seven times lower than the density of D. reticulatus in its typical habitat. In regions endemic for marsh ticks, this tick species constitutes the main risk of tick infestation for livestock and dogs throughout the year. Livestock and companion animals are competent hosts for D. reticulatus, enabling the completion of the tick's life cycle. Anti-tick treatment should be adjusted to marsh tick seasonal activity and drug sensitivity. PMID- 25717008 TI - Identification of potential plant extracts for anti-tick activity against acaricide resistant cattle ticks, Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - To develop an eco-friendly tick control method, seven plant extracts were prepared using 50 and 95% ethanol and evaluated for acaricidal activity against cattle tick, Rhipicephalus (Boophilus) microplus. The adult immersion test was adopted for testing different extracts. Based on 72 h screening criterion, 95% ethanolic extracts of Datura metel fruits and Argemone mexicana whole plant were found effective showing more than 50% mortality of treated ticks. The 95% ethanolic extracts of D. metel fruits and A. mexicana whole plant exhibited acaricidal and reproductive inhibitory effects on treated ticks. The LC90 values of D. metel and A. mexicana extracts were determined as 7.13 and 11.3%, respectively. However, although both the extracts were found efficacious against deltamethrin-resistant IVRI-4 and multi-acaricide resistant IVRI-5 lines of R. (B.) microplus, they caused less mortality than treated ticks of the reference IVRI-I line. Phytochemical studies indicated the presence of alkaloids and glucosides in D. metel fruits and alkaloids, terpenoids, flavonoids and phenolics in A. mexicana whole plant extracts. The results indicated that these botanicals may play an important role in reducing the use of chemicals for tick control and possibly to manage resistant tick population in environment friendly manner. PMID- 25717009 TI - Ticks (Acari: Argasidae, Ixodidae) parasitizing bats in the central Balkans. AB - Ticks parasitizing bats have been largely understudied, especially in the central part of the Balkan Peninsula, where the last data from the field research date from almost 25 years ago. Bats are hosts to a large number of ectoparasites, including ticks, which can act as vectors of zoonotic agents. For this reason, it is important to identify the distribution of ticks and their relationship to different hosts, including wild animals, bats in particular. The present research was conducted at 16 localities throughout Serbia, Montenegro, Bosnia and Herzegovina, and Former Yugoslav Republic of Macedonia (FYROM). We examined 475 individuals of bats belonging to 13 species. A total of three tick species were identified, I. simplex being the most numerous and widespread, followed by I. vespertilionis and A. vespertilionis. To the best of our knowledge, the presented data include the first records of I. simplex in Serbia and Montenegro, I. vespertilionis for Montenegro and A. vespertilionis in FYROM. Also, we identify a new possible host/parasite association between I. simplex and Rhinolophus euryale. PMID- 25717010 TI - There Are No Nonresponders to Resistance-Type Exercise Training in Older Men and Women. AB - OBJECTIVE: To assess the proposed prevalence of unresponsiveness of older men and women to augment lean body mass, muscle fiber size, muscle strength, and/or physical function following prolonged resistance-type exercise training. DESIGN/SETTING/PARTICIPANTS: A retrospective analysis of the adaptive response to 12 (n = 110) and 24 (n = 85) weeks of supervised resistance-type exercise training in older (>65 years) men and women. MEASUREMENTS: Lean body mass (DXA), type I and type II muscle fiber size (biopsy), leg strength (1-RM on leg press and leg extension), and physical function (chair-rise time) were assessed at baseline, and after 12 and 24 weeks of resistance-type exercise training. RESULTS: Lean body mass increased by 0.9 +/- 0.1 kg (range: -3.3 to +5.4 kg; P < .001) from 0 to 12 weeks of training. From 0 to 24 weeks, lean body mass increased by 1.1 +/- 0.2 kg (range: -1.8 to +9.2 kg; P < .001). Type I and II muscle fiber size increased by 324 +/- 137 MUm(2) (range: -4458 to +3386 MUm(2); P = .021), and 701 +/- 137 MUm(2) (range: -4041 to +3904 MUm(2); P < .001) from 0 to 12 weeks. From 0 to 24 weeks, type I and II muscle fiber size increased by 360 +/- 157 MUm(2) (range: -3531 to +3426 MUm(2); P = .026) and 779 +/- 161 MUm(2) (range: -2728 to +3815 MUm(2); P < .001). The 1-RM strength on the leg press and leg extension increased by 33 +/- 2 kg (range: -36 to +87 kg; P < .001) and 20 +/ 1 kg (range: -22 to +56 kg; P < .001) from 0 to 12 weeks. From 0 to 24 weeks, leg press and leg extension 1-RM increased by 50 +/- 3 kg (range: -28 to +145 kg; P < .001) and 29 +/- 2 kg (range: -19 to +60 kg; P < .001). Chair-rise time decreased by 1.3 +/- 0.4 seconds (range: +21.6 to -12.5 seconds; P = .003) from 0 to 12 weeks. From 0 to 24 weeks, chair-rise time decreased by 2.3 +/- 0.4 seconds (range: +10.5 to -23.0 seconds; P < .001). Nonresponsiveness was not apparent in any subject, as a positive adaptive response on at least one training outcome was apparent in every subject. CONCLUSIONS: A large heterogeneity was apparent in the adaptive response to prolonged resistance-type exercise training when changes in lean body mass, muscle fiber size, strength, and physical function were assessed in older men and women. The level of responsiveness was strongly affected by the duration of the exercise intervention, with more positive responses following more prolonged exercise training. We conclude that there are no nonresponders to the benefits of resistance-type exercise training on lean body mass, fiber size, strength, or function in the older population. Consequently, resistance-type exercise should be promoted without restriction to support healthy aging in the older population. PMID- 25717011 TI - Elevated Hospitalization Risk of Assisted Living Residents With Dementia in Alberta, Canada. AB - OBJECTIVES: Assisted living (AL) is an increasingly used residential option for older adults with dementia; however, lower staffing rates and service availability raise concerns that such residents may be at increased risk for adverse outcomes. Our objectives were to determine the incidence of hospitalization over 1 year for dementia residents of designated AL (DAL) facilities, compared with long-term care (LTC) facilities, and identify resident- and facility-level predictors of hospitalization among DAL residents. METHODS: Participants were 609 DAL (mean age 85.7 +/- 6.6 years) and 691 LTC (86.4 +/- 6.9 years) residents with dementia enrolled in the Alberta Continuing Care Epidemiological Studies. Research nurses completed a standardized comprehensive assessment of residents and interviewed family caregivers at baseline (2006-2008) and 1 year later. Standardized administrator interviews provided facility level data. Hospitalization was determined via linkage with the provincial Inpatient Discharge Abstract Database. Multivariable Cox proportional hazards models were used to identify predictors of hospitalization. RESULTS: The cumulative annual incidence of hospitalization was 38.6% (34.5%-42.7%) for DAL and 10.3% (8.0% 12.6%) for LTC residents with dementia. A significantly increased risk for hospitalization was observed for DAL residents aged 90+ years, with poor social relationships, less severe cognitive impairment, greater health instability, fatigue, high medication use (11+ medications), and 2+ hospitalizations in the preceding year. Residents from DAL facilities with a smaller number of spaces, no chain affiliation, and from specific health regions showed a higher risk of hospitalization. CONCLUSIONS: DAL residents with dementia had a hospitalization rate almost 4-fold higher than LTC residents with dementia. Our findings raise questions about the ability of some AL facilities to adequately address the needs of cognitively impaired residents and highlight potential clinical, social, and policy areas for targeted interventions to reduce hospitalization risk. PMID- 25717012 TI - Potential for a "Memory Gym" Intervention to Delay Conversion of Mild Cognitive Impairment to Dementia. PMID- 25717013 TI - Hospice in the nursing homes: perspectives of a medical director. PMID- 25717014 TI - Avoiding depression, dementia, and frailty: do you feel lucky? PMID- 25717015 TI - Effect of deoxynivalenol (DON) mycotoxin on in vivo and in vitro porcine circovirus type 2 infections. AB - Deoxynivalenol (DON) is a mycotoxin produced by Fusarium spp and is a common contaminant of grains in North America. Among farm animals, swine are the most susceptible to DON because it markedly reduces feed intake and decreases weight gain. Porcine circovirus type 2 (PCV2) is the main causative agent of several syndromes in weaning piglets collectively known as porcine circovirus-associated disease (PCVAD). The objectives of this study were to investigate the impact of DON on PCV2 replication in NPTr permissive cell line, and to determine eventual potentiating effects of DON on PCV2 infection in pigs. Noninfected and infected cells with PCV2 were treated with increasing concentrations of DON (0, 70, 140, 280, 560, 1200 ng/mL) and cell survival and virus titer were evaluated 72 h postinfection. Thirty commercial piglets were randomly divided into 3 experimental groups of 10 animals based on DON content of served diets (0, 2.5 and 3.5 mg/kg DON). All groups were further divided into subgroups of 6 pigs and were inoculated with PCV2b virus. The remaining pigs (control) were sham inoculated with PBS. In vitro results showed that low concentrations of DON could potentially increase PCV2 replication depending on virus genotype. In vivo results showed that even though viremia and lung viral load tend to be higher in animal ingesting DON contaminated diet at 2.5 mg/kg, DON had no significant effect on clinical manifestation of PCVAD in PCV2b infected animals. DON has neither in vitro nor in vivo clear potentiating effects in the development of porcine circovirus infection despite slight increases in viral replication. PMID- 25717016 TI - Low-expressed testis-specific calcium-binding protein CBP86-IV (CABYR) is observed in idiopathic asthenozoospermia. AB - OBJECTIVES: To investigate the expression level of testis-specific calcium binding protein CBP86-IV in normal and asthenozoospermic human sperm. METHODS: The total RNA was extracted from human sperm, and target cDNA was obtained by reverse transcription-polymerase chain reaction. Then the cDNA was used for quantitative PCR analysis and cloned into the prokaryotic expression vector pET 28a, respectively. The fusion protein was induced and expressed as inclusion body which was used to produce the polyclonal antibody against TSCBP86-IV. The protein expression level of TSCBP86-IV from normal human sperm and idiopathic asthenozoospermic samples was detected by the purified antibody. RESULTS: The experimental results showed that the protein expression of TSCBP86-IV was reduced in idiopathic asthenozoospermia and consistent with the transcriptional changing tendency which was detected by quantitative PCR analysis. CONCLUSIONS: The stable and reliable change of TSCBP86-IV may be taken as a new molecular marker for clinical diagnosis of idiopathic asthenozoospermia. PMID- 25717017 TI - Novel mutation in the alpha-myosin heavy chain gene is associated with sick sinus syndrome. AB - BACKGROUND: Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding alpha-myosin heavy chain (alpha-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown. METHODS AND RESULTS: We screened 9 genotype-negative probands with sick sinus syndrome families for mutations in MYH6 and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 alpha-MHC to myosin-binding protein C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with alpha-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 alpha-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 alpha-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type alpha-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by coexpressed wild-type human alpha-MHC but not by delE933 alpha-MHC. CONCLUSIONS: The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial sick sinus syndrome. PMID- 25717018 TI - A virtual caravan--A metaphor for home-internationalization through social media: A qualitative content analysis. AB - BACKGROUND: An internationalized curriculum in nursing education was created in response to the rise of globalization and the need to provide nursing care to people of diverse cultures. Through technology, internationalization at home can facilitate intercultural experiences for more nursing students. OBJECTIVES: The aim of this study is to explore and describe how a virtual course in intercultural communication between students of two universities, through internationalization at home, can support the development of cultural competence. DESIGN: Qualitative research PARTICIPANTS: Junior year nursing students METHOD: Qualitative content analysis of transcribed written and oral presentations during a course on intercultural communication. RESULTS: Four major themes, which are not mutually exclusive, were identified. CONCLUSION: Through this intercultural experience, without leaving home, students uncovered their cultural selves and others based on their own reflective understanding and collaborative discourse with each other and the use of social media for communication. Through experiential intercultural encounters beyond textbook and online materials, they learned to appreciate each other as people with cultural differences yet with much in common, and to recognize their assumptions and the value of subtleties and nuances. They were able to explore solutions within an unfamiliar context through their own efforts and with the support of peers and teachers. This led to a deeper understanding of cultural sensitivity and competence. PMID- 25717020 TI - Nanocrystals of XTiO3 (X=Ba, Sr, Ni, BaxTi(1-x)) materials obtained through a rapid one-step methodology at 50 degrees C. AB - Titanate-based perovskite (XTiO3; Ba, Sr, Ni, Ba0.6Sr0.4) nanocrystals were synthesized through a unified sonochemical methodology based on the reaction between XCl2 and TiCl4. The effects of the preparation conditions such as ultrasonication time and ultrasonication temperature were studied. XTiO3 nanocrystals were characterized by field-emission scanning electron microscopy (FE-SEM), X-Ray diffractometry and high-resolution transmission electron microscopy techniques. XTiO3 nanocrystals were synthesized at a relatively low temperature of 50 degrees C while were free from any by-product such as XCO3 (carbonate by-products). Characterization of the morphological characteristics and particle size distribution of the obtained powders indicated that the powder products consist of somewhat regularly shaped and relatively spherical particles with a narrow size distribution. The method described here, is simple, rapid, cost-effective and useful for large-scale production purposes. PMID- 25717019 TI - Low-frequency magnetic fields do not aggravate disease in mouse models of Alzheimer's disease and amyotrophic lateral sclerosis. AB - Low-frequency magnetic fields (LF-MF) generated by power lines represent a potential environmental health risk and are classified as possibly carcinogenic by the World Health Organization. Epidemiological studies indicate that LF-MF might propagate neurodegenerative diseases like Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). We conducted a comprehensive analysis to determine whether long-term exposure to LF-MF (50 Hz, 1 mT) interferes with disease development in established mouse models for AD and ALS, namely APP23 mice and mice expressing mutant Cu/Zn-superoxide dismutase (SOD1), respectively. Exposure for 16 months did not aggravate learning deficit of APP23 mice. Likewise, disease onset and survival of SOD1(G85R) or SOD1(G93A) mice were not altered upon LF-MF exposure for ten or eight months, respectively. These results and an extended biochemical analysis of protein aggregation, glial activation and levels of toxic protein species suggests that LF-MF do not affect cellular processes involved in the pathogenesis of AD or ALS. PMID- 25717021 TI - Prevalence and distribution of beta-lactamase coding genes in third-generation cephalosporin-resistant Enterobacteriaceae from bloodstream infections in Cambodia. AB - Resistance to third-generation cephalosporins in Gram-negative bacteria is emerging in Asia. We report the prevalence and distribution of extended-spectrum beta-lactamase (ESBL), AmpC beta-lactamase and carbapenemase-coding genes in cefotaxime-resistant Enterobacteriaceae isolates from bloodstream infections (BSI) in Cambodia. All Enterobacteriaceae isolated from BSI in adult patients at Sihanouk Hospital Centre of HOPE, Phnom Penh, Cambodia (2007-2010) were assessed. Antimicrobial susceptibility testing was carried out by disc diffusion and MicroScan according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Screening for ESBL, plasmidic AmpC and carbapenemase-coding genes was performed by multiplex polymerase chain reaction (PCR) sequencing assays. Identification of the ST131 clone was performed in all CTX-M-positive Escherichia coli, using PCR targeting the papB gene. Out of 183 Enterobacteriaceae, 91 (49.7 %) isolates (84 BSI episodes) were cefotaxime-resistant: E. coli (n = 68), Klebsiella pneumoniae (n = 17) and Enterobacter spp. (n = 6). Most episodes were community-acquired (66/84; 78.3 %). ESBLs were present in 89/91 (97.8 %) cefotaxime-resistant isolates: 86 (96.6 %) were CTX-M, mainly CTX-M-15 (n = 41) and CTX-M-14 (n = 21). CTX-M of group 1 were frequently associated with TEM and/or OXA-1/30 coding genes and with phenotypic combined resistance to ciprofloxacin, sulphamethoxazole-trimethoprim and gentamicin (39/50, 78.0 %). Plasmidic AmpC (CMY-2 and DHA-1 types) were found alone (n = 2) or in combination with ESBL (n = 4). Eighteen E. coli isolates were identified as B2-ST131-O25B: 11 (61.1 %) carried CTX-M-14. No carbapenemase-coding genes were detected. ESBL among Enterobacteriaceae from BSI in Cambodia is common, mainly associated with CTX-M-15 and CTX-M-14. These findings warrant urgent action for the containment of antibiotic resistance in Cambodia. PMID- 25717022 TI - Ureaplasma parvum and Ureaplasma urealyticum detected with the same frequency among women with and without symptoms of urogenital tract infection. AB - There is mounting evidence stating that Ureaplasma urealyticum causes non gonococcal urethritis in males, whereas Ureaplasma parvum does not seem to be of clinical significance. However, the clinical role of U. parvum and U. urealyticum in lower urogenital tract infections in females remains unclear. The aim of the study was to determine the frequency of U. parvum and U. urealyticum among 145 Ureaplasma spp. culture-positive women with symptoms of lower urogenital tract infection (n = 75) and those without (n = 70), and to determine possible associations between the detection of U. parvum and U. urealyticum with selected characteristics. Endocervical, urethral, and vaginal swabs, and first voided urine were obtained. Polymerase chain reaction (PCR) was performed to differentiate ureaplasmas. No significant association between the detection of U. parvum or U. urealyticum and symptom status was found. Significantly more women aged 25 years and younger were infected with U. urealyticum (23.4 %) compared to those aged above 25 years (9.2 %) [odds ratio (OR) 3.0 (1.1; 8.1); p = 0.03] and significantly less women aged 25 years and younger (83.5 %) were infected with U. parvum compared to those aged above 25 years (95.5 %) [OR 0.2 (0.1; 0.9); p = 0.03]. The detection of Chlamydia trachomatis was significantly associated to both U. parvum and U. urealyticum (p = 0.021), and to U. parvum alone with borderline significance (p = 0.063). Although neither U. parvum nor U. urealyticum seem to cause symptoms in females, their role in the female urogenital tract remains unknown, taking into account their ubiquity, possible augmentation of the urogenital microenvironment, and ascending capability to the sterile upper reproductive tract. PMID- 25717023 TI - Echocardiography has minimal yield and may not be warranted in Staphylococcus aureus bacteremia without clinical risk factors for endocarditis. AB - Current guidelines recommend performing echocardiography in all patients with Staphylococcus aureus bacteremia (SAB), but patients at very low risk of endocarditis may not benefit from this investigation. This study seeks to identify patients at very low risk of endocarditis. A retrospective single-center consecutive case series of patients with SAB was examined. Microbiological and echocardiographic data were used to identify patients with community onset, prolonged bacteremia, and intracardiac prosthetic devices. The diagnostic performance of these criteria for endocarditis as measured against transesophageal echocardiography (TEE) was calculated. 593 episodes of SAB were examined over a period of 6 years. 10 % were excluded from analysis due to death or discharge less than 48 h after the first positive blood culture or no admission to hospital, leaving 532 episodes for analysis. 64 % of the included episodes were investigated with echocardiography: 39 % with TEE and 26 % with transthoracic echocardiography (TTE) only. 16 % of the episodes investigated with echocardiography were demonstrated to have endocarditis. The rate of endocarditis was higher for episodes undergoing TEE (24 %) than TTE only (5 %). There were no instances of endocarditis amongst the 23 episodes investigated with TEE where none of the three risk factors were present. This group represented 57 % of the nosocomial (non-community-onset) episodes investigated with TEE. Patients with none of the three criteria examined in this study have a very low rate of endocarditis and may fall below the test threshold for echocardiography. PMID- 25717024 TI - Short-term efficacy of subthreshold micropulse yellow laser (577-nm) photocoagulation for chronic central serous chorioretinopathy. AB - PURPOSE: To investigate the short-term efficacy of subthreshold micropulse yellow laser photocoagulation in the treatment of chronic central serous chorioretinopathy (CSC). METHODS: A retrospective case series study was performed from April 2012 to June 2014 at Nune Eye Hospital. A total of ten eyes of ten chronic or chronic recurrent CSC patients received subthreshold micropulse yellow laser photocoagulation with a 15 % duty cycle at a reduced energy level from the micropulse laser test burn. Laser exposure time was 20 ms, and the spot diameter was 100 MUm. Patients were followed up at the authors' hospital for at least 3 months. RESULTS: Mean age of patients was 43.9 years. The baseline best-corrected visual acuity was 0.21 +/- 0.21 logarithm of the minimum angle of resolution (logMAR), which was improved to 0.055 +/- 0.093 logMAR (p = 0.020) at the 3 month follow-up and 0.035 +/- 0.063 logMAR (p = 0.012) at final follow-up. Central macular thickness at baseline was 349.2 +/- 53.2 MUm, which was changed to 250.7 +/- 28.8 MUm (p = 0.009) at the 3-month follow-up and 261.2 +/- 38.31 MUm (p = 0.009) at final follow-up. CONCLUSIONS: Subthreshold micropulse yellow laser photocoagulation showed short-term efficacy in treating chronic CSC without retinal damage. However, prospective, randomized, and comparative large-scale studies are needed to evaluate the efficacy and safety of this treatment. PMID- 25717025 TI - A case of progressively transformed germinal center-type IgG4-related lymphadenopathy. AB - Progressively transformed germinal centers (PTGC), a lymph node process unfamiliar to most otolaryngologists, is a morphological variant of reactive lymphofollicular hyperplasia of lymph nodes. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a newly identified condition, characterized by hyper-IgG4 gamma-globulinemia and mass-forming or hypertrophic lesions associated with infiltration of IgG4(+) plasma cells in the affected organs. Recently, a case study of PTGC was reported that fulfilled the diagnostic criteria of IgG4-RD (IgG4(+) PTGC) [1]. A 68-year-old male was referred to our hospital with swelling in the left submandibular region. Palpation revealed swollen lymph nodes, the largest of which measured 5cm in diameter. (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography identified lymphadenopathy with high (18)F-FDG uptake in the left submandibular region. We strongly suspected malignant lymphoma, and excisional biopsy of the submandibular lymph node was performed under general anesthesia. Pathological findings were consistent with IgG4(+) PTGC, and serological examination demonstrated elevated levels of IgG4. These findings were consistent with IgG4-RD. The patient did not have systemic lesions; therefore, he has not undergone corticosteroid therapy. IgG4(+) PTGC should be considered as a differential diagnosis for cervical lymphadenopathy by otolaryngologists as well as pathologists. PMID- 25717027 TI - People do not want cuts made to other public services to protect NHS, survey finds. PMID- 25717026 TI - Closure of tracheoesophageal puncture with pedicled fascia flap of the sternocleidomastoid muscle. AB - OBJECTIVE: Closure of a tracheoesophageal puncture (TEP) formed during voice prosthesis implantation may sometimes be required. We report a new method of closure that we have termed the RESET method. METHODS: We used the RESET method for four patients. An initial incision was made at the mucocutaneous junction of the tracheostoma, and the trachea and esophagus were separated. The TEP was sectioned, and the tracheal and esophageal sides were sutured into separate layers. A pedicled fascia flap lifted from the sternocleidomastoid muscle was sandwiched between the trachea and the esophagus, and subsequently secured. RESULTS: The TEP was closed in all patients, and no complications were observed. CONCLUSION: The RESET method, using a pedicled fascia flap with stable perfusion, is a simple, reliable method of TEP closure. PMID- 25717028 TI - Combination of amikacin and doxycycline against multidrug-resistant and extensively drug-resistant tuberculosis. AB - The objective of this study was to assess the activity of amikacin in combination with doxycycline against clinical strains of Mycobacterium tuberculosis in the search for new strategies against multidrug-resistant (MDR) and extensively drug resistant (XDR) tuberculosis. The study included 28 clinical M. tuberculosis strains, comprising 5 fully susceptible, 1 isoniazid-resistant, 17 MDR, 1 poly resistant (streptomycin/isoniazid), 1 rifampicin-resistant and 3 XDR isolates, as well as the laboratory strain M. tuberculosis H37Rv. Minimum inhibitory concentrations (MICs) were determined using a modified chequerboard methodology in a BACTECTM MGITTM 960 System. Fractional inhibitory concentration indices (FICIs) were calculated, and synergy, indifference or antagonism was assessed. Whole-genome sequencing was performed to investigate the genetic basis of synergy, indifference or antagonism. The MIC50 and MIC90 values (MICs that inhibit 50% and 90% of the isolates, respectively) were, respectively, 0.5 mg/L and 1.0 mg/L for amikacin and 8 mg/L and 16 mg/L for doxycycline. The combination of amikacin and doxycycline showed a synergistic effect in 18 of the 29 strains tested and indifference in 11 strains. Antagonism was not observed. A streptomycin resistance mutation (K43R) was associated with indifference. In conclusion, the benefit of addition of doxycycline to an amikacin-containing regimen should be explored since in vitro results in this study indicate either synergy or indifference. Moreover, doxycycline also has immunomodulatory effects. PMID- 25717029 TI - Flow cytometric analysis of the graft-versus-Leukemia-effect after hematopoietic stem cell transplantation in mice. AB - Acute Graft-versus-Host-Disease (aGvHD) is one of the major complications following allogeneic hematopoietic stem cell transplantation (HSCT). Although rather helpful, the use of conventional immunosuppressive drugs leads to general immunosuppression and is toxic. The effects of CD4(+) T-cells, in respect to the development of aGvHD, can be altered by administration of antihuman CD4 monoclonal antibodies, here MAX.16H5 IgG1 . This approach must be tested for possible interference with the Graft-versus-Leukemia-Effect (GvL). Thus, in vitro experiments were conducted, exposing P815 leukemic cells to bone marrow and splenocytes from cd4(-/-) -C57Bl/6 mice transgenic for human CD4 and HLA-DR3 (triple transgenic mice, [TTG]) as well as previously irradiated splenocytes from Balb/c(wt) mice. Using flow cytometry, the vitality of the various malignant and graft cells was analyzed over the course of 4 days. The survival rate of P815 cells did not change significantly when exposed to MAX.16H5 IgG1 , neither did the viability of the graft cells. This provides evidence that MAX.16H5 IgG1 does not impair the GvL effect in vitro. Additionally, P815-Balb/c(wt) leukemic mice were transplanted with P815(GFP) cells, bone marrow, and splenocytes from TTG mice with and without MAX.16H5 IgG1 . Without transplantation, P815(GFP) leukemic cells could be detected by flow cytometry in the liver, the bone marrow, and the spleen of recipients. The antibodies prevented aGvHD while leaving the GvL effect intact. These findings indicate no negative effect of MAX.16H5 IgG1 on the GvL effect in vitro and in vivo after HSCT in a murine model. PMID- 25717030 TI - Specific and efficient electrochemical selection of Geoalkalibacter subterraneus and Desulfuromonas acetoxidans in high current-producing biofilms. AB - Two different saline sediments were used to inoculate potentiostatically controlled reactors (a type of microbial bioelectrochemical system, BES) operated in saline conditions (35 gNaCl l(-1)). Reactors were fed with acetate or a mixture of acetate and butyrate at two pH values: 7.0 or 5.5. Electroactive biofilm formation lag-phase, maximum current density production and coulombic efficiency were used to evaluate the overall performance of reactors. High current densities up to 8.5 A m(-2) were obtained using well-defined planar graphite electrodes. Additionally, biofilm microbial communities were characterized by CE-SSCP and 454 pyrosequencing. As a result of this procedure, two anode-respiring bacteria (ARB) always dominated the anodic biofilms: Geoalkalibacter subterraneus and/or Desulfuromonas acetoxidans. This suggests that a strong electrochemically driven selection process imposed by the applied potential occurs in the BES system. Moreover, the emergence of Glk. subterraneus in anodic biofilms significantly contributes to broaden the spectrum of high current producing microorganisms electrochemically isolated from environmental samples. PMID- 25717031 TI - eIF4E and eIF4GI have distinct and differential imprints on multiple myeloma's proteome and signaling. AB - Accumulating data indicate translation plays a role in cancer biology, particularly its rate limiting stage of initiation. Despite this evolving recognition, the function and importance of specific translation initiation factors is unresolved. The eukaryotic translation initiation complex eIF4F consists of eIF4E and eIF4G at a 1:1 ratio. Although it is expected that they display interdependent functions, several publications suggest independent mechanisms. This study is the first to directly assess the relative contribution of eIF4F components to the expressed cellular proteome, transcription factors, microRNAs, and phenotype in a malignancy known for extensive protein synthesis multiple myeloma (MM). Previously, we have shown that eIF4E/eIF4GI attenuation (siRNA/Avastin) deleteriously affected MM cells' fate and reduced levels of eIF4E/eIF4GI established targets. Here, we demonstrated that eIF4E/eIF4GI indeed have individual influences on cell proteome. We used an objective, high throughput assay of mRNA microarrays to examine the significance of eIF4E/eIF4GI silencing to several cellular facets such as transcription factors, microRNAs and phenotype. We showed different imprints for eIF4E and eIF4GI in all assayed aspects. These results promote our understanding of the relative contribution and importance of eIF4E and eIF4GI to the malignant phenotype and shed light on their function in eIF4F translation initiation complex. PMID- 25717033 TI - Nature of charge transport and p-electron ferromagnetism in nitrogen-doped ZrO2: an ab initio perspective. AB - Zirconium dioxide provides an exceptional prototype material for studying the redistribution of the polaron holes and its magnetic coupling with their nearby anions owning to the difference oxygen binding behavior in the monoclinic phase. Here, we perform a comprehensive study of the p-electron magnetism in the nitrogen doped 2 * 2 * 2 monoclinic ZrO2 based on spin-polarized density functional theory. Nitrogen substitutions make the system display half-metallic properties, and the origin of room temperature ferromagnetism ascribes to the p-p coupling interaction between N 2p and the host 2p states. The charge density difference and Mulliken population analyses provide evidences of charge redistributions. Our results reveal that the polaron transfer may alter the magnetic properties and it is greatly facilitated ferromagnetic coupling if the polaron holes are localized around a single anion dopant. PMID- 25717032 TI - Activation of NRF2 by p62 and proteasome reduction in sphere-forming breast carcinoma cells. AB - Cancer stem cells (CSCs) express high levels of drug efflux transporters and antioxidant genes, and are therefore believed to be responsible for cancer recurrence following chemo/radiotherapy intervention. In this study, we investigated the role of NF-E2-related factor 2 (NRF2), a master regulator of antioxidant gene expression, in the growth and stress resistance of CSC-enriched mammosphere. The MCF7 mammospheres expressed significantly higher levels of the NRF2 protein and target gene expression compared to the monolayer. As underlying mechanisms, we observed that proteolytic activity and expression of the proteasome catalytic subunits were decreased in the mammospheres. Additionally, mammospheres retained a high level of p62 and the silencing of p62 was observed to attenuate NRF2 activation. NRF2 increase was confirmed in sphere-cultures of the colon and ovarian cancer cells. The functional implication of NRF2 was demonstrated in NRF2-knockdown mammospheres. NRF2-silenced mammospheres demonstrated increased cell death and retarded sphere growth as a result of target gene repression. Moreover, unlike the control mammospheres, NRF2-knockdown mammospheres did not develop anticancer drug resistance. Collectively, these results indicated that altered proteasome function and p62 expression caused NRF2 activation in CSC-enriched mammospheres. In addition, NRF2 appeared to play a role in CSC survival and anticancer drug resistance. PMID- 25717034 TI - Diastereoselective cyclization of an aminobenzoic acid derivative and chiroptical properties of triple-stranded helical bis(phenylethynyl)benzene. AB - The diastereoselective cyclization of 2,5-dibromo-4-hexylaminobenzoic acid was achieved by the microwave-assisted condensation using SiCl4. Moreover, the triple stranded helical structure of bis(phenylethynyl)benzene units embedded in the cyclic tri(benzamide) scaffold was obtained by a Sonogashira-Hagihara coupling reaction. Two optically active enantiomers that do not racemize even at the elevated temperature were separated by chiral HPLC. The chiral helical topology was revealed by the spectroscopic data and theoretical calculation. PMID- 25717035 TI - Turnip mosaic virus moves systemically through both phloem and xylem as membrane associated complexes. AB - Plant viruses move systemically in plants through the phloem. They move as virions or as ribonucleic protein complexes, although it is not clear what these complexes are made of. The approximately 10-kb RNA genome of Turnip mosaic virus (TuMV) encodes a membrane protein, known as 6K2, that induces endomembrane rearrangements for the formation of viral replication factories. These factories take the form of vesicles that contain viral RNA (vRNA) and viral replication proteins. In this study, we report the presence of 6K2-tagged vesicles containing vRNA and the vRNA-dependent RNA polymerase in phloem sieve elements and in xylem vessels. Transmission electron microscopy observations showed the presence in the xylem vessels of vRNA-containing vesicles that were associated with viral particles. Stem-girdling experiments, which leave xylem vessels intact but destroy the surrounding tissues, confirmed that TuMV could establish a systemic infection of the plant by going through xylem vessels. Phloem sieve elements and xylem vessels from Potato virus X-infected plants also contained lipid-associated nonencapsidated vRNA, indicating that the presence of membrane-associated ribonucleic protein complexes in the phloem and xylem may not be limited to TuMV. Collectively, these studies indicate that viral replication factories could end up in the phloem and the xylem. PMID- 25717036 TI - CO2-responsive CONSTANS, CONSTANS-like, and time of chlorophyll a/b binding protein Expression1 protein is a positive regulator of starch synthesis in vegetative organs of rice. AB - A unique CO2-Responsive CONSTANS, CONSTANS-like, and Time of Chlorophyll a/b Binding Protein1 (CCT) Protein (CRCT) containing a CCT domain but not a zinc finger motif is described, which is up-regulated under elevated CO2 in rice (Oryza sativa). The expression of CRCT showed diurnal oscillation peaked at the end of the light period and was also increased by sugars such as glucose and sucrose. Promoter beta-glucuronidase analysis showed that CRCT was highly expressed in the phloem of various tissues such as leaf blade and leaf sheath. Overexpression or RNA interference knockdown of CRCT had no appreciable effect on plant growth and photosynthesis except that tiller angle was significantly increased by the overexpression. More importantly, starch content in leaf sheath, which serves as a temporary storage organ for photoassimilates, was markedly increased in overexpression lines and decreased in knockdown lines. The expressions of several genes related to starch synthesis, such as ADP-glucose pyrophospholylase and alpha-glucan phospholylase, were significantly changed in transgenic lines and positively correlated with the expression levels of CRCT. Given these observations, we suggest that CRCT is a positive regulator of starch accumulation in vegetative tissues, regulating coordinated expression of starch synthesis genes in response to the levels of photoassimilates. PMID- 25717037 TI - Lotus japonicus clathrin heavy Chain1 is associated with Rho-Like GTPase ROP6 and involved in nodule formation. AB - Mechanisms underlying nodulation factor signaling downstream of the nodulation factor receptors (NFRs) have not been fully characterized. In this study, clathrin heavy chain1 (CHC1) was shown to interact with the Rho-Like GTPase ROP6, an interaction partner of NFR5 in Lotus japonicus. The CHC1 gene was found to be expressed constitutively in all plant tissues and induced in Mesorhizobium loti infected root hairs and nodule primordia. When expressed in leaves of Nicotiana benthamiana, CHC1 and ROP6 were colocalized at the cell circumference and within cytoplasmic punctate structures. In M. loti-infected root hairs, the CHC protein was detected in cytoplasmic punctate structures near the infection pocket along the infection thread membrane and the plasma membrane of the host cells. Transgenic plants expressing the CHC1-Hub domain, a dominant negative effector of clathrin-mediated endocytosis, were found to suppress early nodulation gene expression and impair M. loti infection, resulting in reduced nodulation. Treatment with tyrphostin A23, an inhibitor of clathrin-mediated endocytosis of plasma membrane cargoes, had a similar effect on down-regulation of early nodulation genes. These findings show an important role of clathrin in the leguminous symbiosis with rhizobia. PMID- 25717038 TI - Establishment of monitoring methods for autophagy in rice reveals autophagic recycling of chloroplasts and root plastids during energy limitation. AB - Autophagy is an intracellular process leading to vacuolar or lysosomal degradation of cytoplasmic components in eukaryotes. Establishment of proper methods to monitor autophagy was a key step in uncovering its role in organisms, such as yeast (Saccharomyces cerevisiae), mammals, and Arabidopsis (Arabidopsis thaliana), in which chloroplastic proteins were found to be recycled by autophagy. Chloroplast recycling has been predicted to function in nutrient remobilization for growing organs or grain filling in cereal crops. Here, to develop our understanding of autophagy in cereals, we established monitoring methods for chloroplast autophagy in rice (Oryza sativa). We generated transgenic rice-expressing fluorescent protein (FP) OsAuTophaGy8 (OsATG8) fusions as autophagy markers. FP-ATG8 signals were delivered into the vacuolar lumen in living cells of roots and leaves mainly as vesicles corresponding to autophagic bodies. This phenomenon was not observed upon the addition of wortmannin, an inhibitor of autophagy, or in an ATG7 knockout mutant. Markers for the chloroplast stroma, stromal FP, and FP-labeled Rubisco were delivered by a type of autophagic body called the Rubisco-containing body (RCB) in the same manner. RCB production in excised leaves was suppressed by supply of external sucrose or light. The release of free FP caused by autophagy-dependent breakdown of FP labeled Rubisco was induced during accelerated senescence in individually darkened leaves. In roots, nongreen plastids underwent both RCB-mediated and entire organelle types of autophagy. Therefore, our newly developed methods to monitor autophagy directly showed autophagic degradation of leaf chloroplasts and root plastids in rice plants and its induction during energy limitation. PMID- 25717039 TI - Evolution of a double amino acid substitution in the 5-enolpyruvylshikimate-3 phosphate synthase in Eleusine indica conferring high-level glyphosate resistance. AB - Glyphosate is the most important and widely used herbicide in world agriculture. Intensive glyphosate selection has resulted in the widespread evolution of glyphosate-resistant weed populations, threatening the sustainability of this valuable once-in-a-century agrochemical. Field-evolved glyphosate resistance due to known resistance mechanisms is generally low to modest. Here, working with a highly glyphosate-resistant Eleusine indica population, we identified a double amino acid substitution (T102I+P106S [TIPS]) in the 5-enolpyruvylshikimate-3 phosphate synthase (EPSPS) gene in glyphosate-resistant individuals. This TIPS mutation recreates the biotechnology-engineered commercial first generation glyphosate-tolerant EPSPS in corn (Zea mays) and now in other crops. In E. indica, the naturally evolved TIPS mutants are highly (more than 180-fold) resistant to glyphosate compared with the wild type and more resistant (more than 32-fold) than the previously known P106S mutants. The E. indica TIPS EPSPS showed very high-level (2,647-fold) in vitro resistance to glyphosate relative to the wild type and is more resistant (600-fold) than the P106S variant. The evolution of the TIPS mutation in crop fields under glyphosate selection is likely a sequential event, with the P106S mutation being selected first and fixed, followed by the T102I mutation to create the highly resistant TIPS EPSPS. The sequential evolution of the TIPS mutation endowing high-level glyphosate resistance is an important mechanism by which plants adapt to intense herbicide selection and a dramatic example of evolution in action. PMID- 25717040 TI - Anticipating divine protection? Reminders of god can increase nonmoral risk taking. AB - Religiosity and participation in religious activities have been linked with decreased risky behavior. In the current research, we hypothesized that exposure to the concept of God can actually increase people's willingness to engage in certain types of risks. Across seven studies, reminders of God increased risk taking in nonmoral domains. This effect was mediated by the perceived danger of a risky option and emerged more strongly among individuals who perceive God as a reliable source of safety and protection than among those who do not. Moreover, in an eighth study, when participants were first reminded of God and then took a risk that produced negative consequences (i.e., when divine protection failed to materialize), participants reported feeling more negatively toward God than did participants in the same situation who were not first reminded of God. This research contributes to an understanding of the divergent effects that distinct components of religion can exert on behavior. PMID- 25717041 TI - Aggressive-antisocial boys develop into physically strong young men. AB - Young men with superior upper-body strength typically show a greater proclivity for physical aggression than their weaker male counterparts. The traditional interpretation of this phenomenon is that young men calibrate their attitudes and behaviors to their physical formidability. Physical strength is thus viewed as a causal antecedent of aggressive behavior. The present study is the first to examine this phenomenon within a developmental framework. We capitalized on the fact that physical strength is a male secondary sex characteristic. In two longitudinal cohorts of children, we estimated adolescent change in upper-body strength using the slope parameter from a latent growth model. We found that males' antisocial tendencies temporally precede their physical formidability. Boys, but not girls, with greater antisocial tendencies in childhood attained larger increases in physical strength between the ages of 11 and 17. These results support sexual selection theory, indicating an adaptive congruence between male-typical behavioral dispositions and subsequent physical masculinization during puberty. PMID- 25717042 TI - Impact of x-ray screening programmes for active tuberculosis in homeless populations: a systematic review of original studies. AB - BACKGROUND: Tuberculosis prevalence is generally low in industrialized countries, but many cities now operate surveillance programmes to actively screen for tuberculosis in known risk groups including homeless people. While several studies have reported on individual screening programmes, this study is the first known systematic review specifically looking at chest x-ray screening programmes for tuberculosis in homeless populations. METHODS: Systematic review of relevant studies published in the last 20 years using the PRISMA checklist. RESULTS: Fourteen studies were reviewed: 12 cross-sectional studies, 1 retrospective cohort study and 1 'data-linkage' study. The studies were heterogenous in terms of the objectives, measured outcomes and methodological quality. Active tuberculosis prevalence was found to be higher in homeless populations and screening programmes appear to identify tuberculosis earlier, reduce prevalence and transmission, and increase treatment compliance. CONCLUSIONS: Active x-ray surveillance programmes in homeless communities appear to be cost-effective in reducing prevalence within the homeless population particularly in related strains and may have some benefits over passive finding. While there is a need for high-quality research to further assess the impact of these programmes, this study has outlined the benefits and limitations of existing programmes and included recommendations to achieve maximum coverage, uptake and cost-benefit. PMID- 25717043 TI - Public risk perception and attitudes towards live poultry markets before and after their closure due to influenza A(H7N9), Hong Kong, January-February 2014. AB - BACKGROUND: The study investigated public risk perception regarding influenza A(H7N9) and attitudes towards closure of live poultry markets (LPMs) before and after LPMs closed in Hong Kong. METHODS: Two population-based surveys were conducted before and after LPMs closed in January-February 2014, respectively. Adults were recruited using random digital dialing. RESULTS: In total, 670 and 1011 respondents completed the survey before and after closure of LPMs, respectively. Perceived susceptibility to H7N9 infection was low across surveys. Among respondents who completed the survey after LPMs closed, only 14.6% agreed that temporary closure of LPMs caused inconvenience to the daily life; 38.7% valued the Chinese tradition of live poultry consumption more than controlling the risk of avian influenza; 54.6% recognized greater risk of influenza epidemic associated with LPMs. Support for permanent closure of LPMs which was comparably low across surveys was strongly associated with perceived risk of avian influenza related to LPMs, the effectiveness of LPM closure in control of avian influenza and the inconvenience caused by closure. CONCLUSIONS: Risk communication that promotes people's perceived risk of avian influenza associated with LPMs and the effectiveness of LPM closure in control of avian influenza outbreaks may improve support for permanent closure of LPMs. PMID- 25717045 TI - Pretreatment with antiplatelet drugs in invasively managed patients with coronary artery disease in the contemporary era: review of the evidence and practice guidelines. PMID- 25717044 TI - Doppler-derived intracoronary physiology indices predict the occurrence of microvascular injury and microvascular perfusion deficits after angiographically successful primary percutaneous coronary intervention. AB - BACKGROUND: A total of 40% to 50% of patients with ST-segment-elevation myocardial infarction develop microvascular injury (MVI) despite angiographically successful primary percutaneous coronary intervention (PCI). We investigated whether hyperemic microvascular resistance (HMR) immediately after angiographically successful PCI predicts MVI at cardiovascular magnetic resonance and reduced myocardial blood flow at positron emission tomography (PET). METHODS AND RESULTS: Sixty patients with ST-segment-elevation myocardial infarction were included in this prospective study. Immediately after successful PCI, intracoronary pressure-flow measurements were performed and analyzed off-line to calculate HMR and indices derived from the pressure-velocity loops, including pressure at zero flow. Cardiovascular magnetic resonance and H2 (15)O PET imaging were performed 4 to 6 days after PCI. Using cardiovascular magnetic resonance, MVI was defined as a subendocardial recess of myocardium with low signal intensity within a gadolinium-enhanced area. Myocardial perfusion was quantified using H2 (15)O PET. Reference HMR values were obtained in 16 stable patients undergoing coronary angiography. Complete data sets were available in 48 patients of which 24 developed MVI. Adequate pressure-velocity loops were obtained in 29 patients. HMR in the culprit artery in patients with MVI was significantly higher than in patients without MVI (MVI, 3.33+/-1.50 mm Hg/cm per second versus no MVI, 2.41+/-1.26 mm Hg/cm per second; P=0.03). MVI was associated with higher pressure at zero flow (45.68+/-13.16 versus 32.01+/-14.98 mm Hg; P=0.015). Multivariable analysis showed HMR to independently predict MVI (P=0.04). The optimal cutoff value for HMR was 2.5 mm Hg/cm per second. High HMR was associated with decreased myocardial blood flow on PET (myocardial perfusion reserve <2.0, 3.18+/-1.42 mm Hg/cm per second versus myocardial perfusion reserve >=2.0, 2.24+/-1.19 mm Hg/cm per second; P=0.04). CONCLUSIONS: Doppler-flow-derived physiological indices of coronary resistance (HMR) and extravascular compression (pressure at zero flow) obtained immediately after successful primary PCI predict MVI and decreased PET myocardial blood flow. CLINICAL TRIAL REGISTRATION URL: http://www.trialregister.nl. Unique identifier: NTR3164. PMID- 25717046 TI - Usefulness of the controlled attenuation parameter for detecting liver steatosis in health checkup examinees. AB - BACKGROUND/AIMS: The controlled attenuation parameter (CAP) implemented in FibroScan(r) is reported to be a noninvasive means of detecting steatosis (>10% steatosis). We aimed to evaluate the usefulness of CAP in detecting steatosis among health checkup examinees and to assess its correlation with ultrasonography (US). METHODS: Consecutive CAP results were retrospectively collected. A total of 280 subjects were included. RESULTS: Fatty liver was detected in 119 subjects (42.5%) by US, whereas it was detected in 160 subjects (57.1%) by the CAP. The numbers of subjects with S0S1S2S3 steatosis according to the CAP value were 120595843, respectively. The mean CAP values were 203.34+/-28.39 dB/m for S0, 248.83+/-6.14 dB/m for S1, 274.33+/-8.53 dB/m for S2, and 322.35+/-22.20 dB/m for S3. CAP values were correlated with body weight (r=0.404, p<0.001), body mass index (r=0.445, p<0.001), and the fatty liver grade by US (r=0.472, p<0.001). Among the 161 subjects with normal US findings, steatosis was detected in 65 subjects (40.4%) using the CAP. CONCLUSIONS: The CAP seems to be useful for detecting very low-grade hepatic steatosis in health checkup examinees. Its role in predicting subjects with a risk of metabolic derangement needs to be evaluated. PMID- 25717047 TI - Secreted Phosphoprotein 1 Promoter Genetic Variants Are Associated with the Response to Pegylated Interferon alpha Plus Ribavirin Combination Therapy in Egyptian Patients with Chronic Hepatitis C Virus Infection. AB - BACKGROUND/AIMS: The T-helper 1 (TH1) immune reaction is essential for the eradication of hepatitis C virus (HCV) during pegylated interferon alpha (PEG-IFN alpha)- and ribavirin (RBV)-based therapy in chronic HCV patients. Secreted phosphoprotein 1 (SPP1) was shown to be a crucial cytokine for the initiation of a TH1 immune response. We aimed to investigate whether SPP1 single nucleotide polymorphisms (SNPs) may influence sustained virological response (SVR) rates. METHODS: Two SNPs in the promoter region of SPP1 at the -443 C>T and -1748 G>A loci were genotyped in 100 patients with chronic HCV genotype 4 infection using a TaqMan SNP genotyping assay. RESULTS: Sixty-seven patients achieved a SVR, and 33 patients showed no SVR. Patients carrying the T/T genotype at the -443 locus showed a significantly higher SVR rate than those carrying the C/T or C/C genotype (83.67% vs. 50.98%, p<0.001). At the -1748 locus, the SVR rate was significantly higher in patients with the G/G genotype than in those with the A/A genotype (88.89% vs. 52.63%, p=0.028) and in patients with the G/A genotype than in those with the A/A genotype (85.29% vs. 52.63%, p=0.001). CONCLUSIONS: SPP1 SNPs at -443 C>T and -1748 G>A loci may be useful markers for predicting the response to PEG-IFN-alpha-2b plus RBV therapy in Egyptian patients with chronic HCV genotype 4 infection. PMID- 25717048 TI - Endoscopic management of bile leakage after liver transplantation. AB - BACKGROUND/AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) can be an effective treatment for bile leakage after liver transplantation. We evaluated the efficacy of endoscopic treatment in liver transplantation in patients who developed bile leaks. METHODS: Forty-two patients who developed bile leaks after liver transplantation were included in the study. If a bile leak was observed on ERCP, a sphincterotomy was performed, and a nasobiliary catheter was then inserted. If a bile leak was accompanied by a bile duct stricture, either the stricture was dilated with balloons, followed by nasobiliary catheter insertion across the bile duct stricture, or endoscopic retrograde biliary drainage was performed. RESULTS: In the bile leakage alone group (22 patients), endoscopic treatment was technically successful in 19 (86.4%) and clinically successful in 17 (77.3%) cases. Among the 20 patients with bile leaks with bile duct strictures, endoscopic treatment was technically successful in 13 (65.0%) and clinically successful in 10 (50.0%) cases. Among the 42 patients who underwent ERCP, technical success was achieved in 32 (76.2%) cases and clinical success was achieved in 27 (64.3%) cases. CONCLUSIONS: ERCP is an effective and safe therapeutic modality for bile leaks after liver transplantation. ERCP should be considered as an initial therapeutic modality in post-liver transplantation patients. PMID- 25717049 TI - Hepatitis B Surface Antigen Quantification across Different Phases of Chronic Hepatitis B Virus Infection Using an Immunoradiometric Assay. AB - BACKGROUND/AIMS: Quantification of hepatitis B surface antigen (HBsAg) is an emerging serologic test and may be useful for identifying treatment strategies for chronic hepatitis B (CHB). This study aimed to evaluate HBsAg titers during the natural course of CHB and identify correlations between HBsAg titers and hepatitis B virus (HBV) DNA concentrations across different CHB phases measured using an immunoradiometric assay (IRMA). METHODS: CHB phases were defined on the basis of HBV DNA concentrations, the presence of hepatitis B e antigen/antibody (HBeAg/Ab) and serum alanine aminotransferase levels. Serum HBsAg titers and paired HBV DNA concentrations in the different phases of CHB were compared using 627 serum samples. RESULTS: Mean HBsAg titers were significantly higher in the immunotolerant (IT) phase and immunoreactive (IR) HBeAg-positive phase than in the low-replicative (LR) and HBeAg-negative CHB (ENH) states. The correlation between HBsAg titers and HBV DNA concentrations was modest in the IT (n=36, r=0.804, p<0.001) and IR (n=48, r=0.773, p<0.001) phases, and it was poor in the LR state (n=116, r=0.289, p=0.002); however, no significant correlation was observed in the ENH state (n=67, r=0.146, p=0.237) or in the oral nucleos(t)ide analogue-treated group (n=267). CONCLUSIONS: HBsAg quantification using IRMA might be useful for discriminating different CHB phases and different stages of chronic liver disease. PMID- 25717050 TI - Causes, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China. AB - BACKGROUND/AIMS: Drug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited. METHODS: All 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied. RESULTS: A total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs. 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs. 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs. 18/39, p=0.031). CONCLUSIONS: Most cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable. PMID- 25717052 TI - Flying over uneven moving terrain based on optic-flow cues without any need for reference frames or accelerometers. AB - Two bio-inspired guidance principles involving no reference frame are presented here and were implemented in a rotorcraft, which was equipped with panoramic optic flow (OF) sensors but (as in flying insects) no accelerometer. To test these two guidance principles, we built a tethered tandem rotorcraft called BeeRotor (80 grams), which was tested flying along a high-roofed tunnel. The aerial robot adjusts its pitch and hence its speed, hugs the ground and lands safely without any need for an inertial reference frame. The rotorcraft's altitude and forward speed are adjusted via two OF regulators piloting the lift and the pitch angle on the basis of the common-mode and differential rotor speeds, respectively. The robot equipped with two wide-field OF sensors was tested in order to assess the performances of the following two systems of guidance involving no inertial reference frame: (i) a system with a fixed eye orientation based on the curved artificial compound eye (CurvACE) sensor, and (ii) an active system of reorientation based on a quasi-panoramic eye which constantly realigns its gaze, keeping it parallel to the nearest surface followed. Safe automatic terrain following and landing were obtained with CurvACE under dim light to daylight conditions and the active eye-reorientation system over rugged, changing terrain, without any need for an inertial reference frame. PMID- 25717051 TI - Changes in the Expression and Distribution of Claudins, Increased Epithelial Apoptosis, and a Mannan-Binding Lectin-Associated Immune Response Lead to Barrier Dysfunction in Dextran Sodium Sulfate-Induced Rat Colitis. AB - BACKGROUND/AIMS: This animal study aimed to define the underlying cellular mechanisms of intestinal barrier dysfunction. METHODS: Rats were fed 4% with dextran sodium sulfate (DSS) to induce experimental colitis. We analyzed the sugars in 24-hour urine output by high pressure liquid chromatography. The expression of claudins, mannan-binding lectin (MBL), and MBL-associated serine proteases 2 (MASP-2) were detected in the colonic mucosa by immunohistochemistry; and apoptotic cells in the colonic epithelium were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method assay. RESULTS: The lactulose and sucralose excretion levels in the urine of rats with DSS-induced colitis were significantly higher than those in the control rats. Mannitol excretion was lower and lactulose/mannitol ratios and sucralose/mannitol ratios were significantly increased compared with those in the control group (p<0.05). Compared with the controls, the expression of sealing claudins (claudin 3, claudin 5, and claudin 8) was significantly decreased, but that of claudin 1 was increased. The expression of pore-forming claudin 2 was upregulated and claudin 7 was downregulated in DSS-induced colitis. The epithelial apoptotic ratio was 2.8%+/-1.2% in controls and was significantly increased to 7.2%+/-1.2% in DSS-induced colitis. The expression of MBL and MASP-2 in the intestinal mucosa showed intense staining in controls, whereas there was weak staining in the rats with colitis. CONCLUSIONS: There was increased intestinal permeability in DSS-induced colitis. Changes in the expression and distribution of claudins, increased epithelial apoptosis, and the MASP-2-induced immune response impaired the intestinal epithelium and contributed to high intestinal permeability. PMID- 25717053 TI - Rape Survivors' Experiences of the Silent Protest: Implications for Promoting Healing and Resilience. AB - This article examines the experiences of nine rape survivors who participated in the Silent Protest, an annual protest march at Rhodes University that aims to highlight the sexual abuse of women, validate the harm done, and foster solidarity among survivors. Participants responded to a semi-structured interview focusing on the context of their rape and its impact, and their experiences of participation in the Protest In the first phase of data analysis, synoptic case narratives were written. In the second, themes from participants' experience were identified using interpretative phenomenological analysis. In the third, the data were examined in light of questions around the extent to which participation contributed to healing. Participants reported experiences of validation and empowerment but the majority were suffering from posttraumatic stress disorder. In some cases, participation had exacerbated self-blame and avoidant coping. Recommendations are made about the provision of psychoeducation and counseling at such events. PMID- 25717054 TI - Case ascertainment of heat illness in the British Army: evidence of under reporting from analysis of Medical and Command notifications, 2009-2013. AB - BACKGROUND: Heat illness in the Armed Forces is considered preventable. The UK military relies upon dual Command and Medical reporting for case ascertainment, investigation of serious incidents and improvement of preventive practices and policy. This process could be vulnerable to under-reporting. OBJECTIVES: To establish whether heat illness in the British Army has been under-reported, by reviewing concordance of reporting to the Army Incident Notification Cell (AINC) and the Army Health Unit (AHU) and to characterise the burden of heat illness reported by these means. METHODS: Analysis of anonymised reporting databases held by the AHU and AINC, for the period 2009-2013. RESULTS: 565 unique cases of heat illness were identified. Annual concordance of reporting ranged from 9.6% to 16.5%. The overall rate was 13.3%. July was the month with the greatest number of heat illness reports (24.4% of total reporting) and the highest concordance rate (30%). Reports of heat illness from the UK (n=343) exceeded overseas notifications (n=221) and showed better concordance (17.1% vs 12.8%). The annual rate of reported heat illness varied widely, being greater in full-time than reservist personnel (87 vs 23 per100 000) and highest in full-time untrained personnel (223 per100 000). CONCLUSIONS: The risk of heat illness was global, year-round and showed dynamic local variation. Failure to dual-report casualties impaired case ascertainment of heat illness across Command and Medical chains. Current preventive guidance, as applied in training and on operations, should be critically evaluated to ensure that risk of heat illness is reduced as low as possible. Clear procedures for casualty notification and surveillance are required in support of this and should incorporate communication within and between the two reporting chains. PMID- 25717055 TI - Synthesis of bio-inspired multilayer polarizers and their application to anti counterfeiting. AB - Some insects, such as Papilio blumei and Suneve coronata, are known for exhibiting polarization effects on light such as color contrast or geometrical polarization rotation by reflection on their wing scales. The photonic structures found on these species that show these properties are multilayered spherical cavities or triangular grooves which polarize the light due to multiple inner reflections. These polarization effects, in addition to the intrinsic color mixing properties of these photonic structures, are of interest in the anti counterfeiting field due to their invisibility to the naked eye. In this paper, we report micro-fabrication techniques to produce bio-inspired cylindrical grooves (C-grooves) and triangular grooves (V-grooves) that demonstrate the same properties. Theoretical analyses were carried out by using multi-scale simulation (MS) as well as by finite-difference time-domain (FDTD) in order to compare the polarization capability of both structures. The V-grooves show greater polarization contrast than the C-grooves, but the spectrum is specular. The C grooves exhibit lower polarization effects but have a dispersive spectrum. In both cases, the structures show additional optical properties, such as diffraction, macroscopic color contrast under a polarizer, and contrast inversion due to geometries which contribute to their uniqueness. PMID- 25717056 TI - Functional loss of yeast detectors parallels transition to herbivory. PMID- 25717057 TI - Factors mediating plastid dependency and the origins of parasitism in apicomplexans and their close relatives. AB - Apicomplexans are a major lineage of parasites, including causative agents of malaria and toxoplasmosis. How such highly adapted parasites evolved from free living ancestors is poorly understood, particularly because they contain nonphotosynthetic plastids with which they have a complex metabolic dependency. Here, we examine the origin of apicomplexan parasitism by resolving the evolutionary distribution of several key characteristics in their closest free living relatives, photosynthetic chromerids and predatory colpodellids. Using environmental sequence data, we describe the diversity of these apicomplexan related lineages and select five species that represent this diversity for transcriptome sequencing. Phylogenomic analysis recovered a monophyletic lineage of chromerids and colpodellids as the sister group to apicomplexans, and a complex distribution of retention versus loss for photosynthesis, plastid genomes, and plastid organelles. Reconstructing the evolution of all plastid and cytosolic metabolic pathways related to apicomplexan plastid function revealed an ancient dependency on plastid isoprenoid biosynthesis, predating the divergence of apicomplexan and dinoflagellates. Similarly, plastid genome retention is strongly linked to the retention of two genes in the plastid genome, sufB and clpC, altogether suggesting a relatively simple model for plastid retention and loss. Lastly, we examine the broader distribution of a suite of molecular characteristics previously linked to the origins of apicomplexan parasitism and find that virtually all are present in their free-living relatives. The emergence of parasitism may not be driven by acquisition of novel components, but rather by loss and modification of the existing, conserved traits. PMID- 25717058 TI - Activities worth living for: call to action beyond prognosis. PMID- 25717060 TI - Role of isolated and clustered DNA damage and the post-irradiating repair process in the effects of heavy ion beam irradiation. AB - Clustered DNA damage is a specific type of DNA damage induced by ionizing radiation. Any type of ionizing radiation traverses the target DNA molecule as a beam, inducing damage along its track. Our previous study showed that clustered DNA damage yields decreased with increased linear energy transfer (LET), leading us to investigate the importance of clustered DNA damage in the biological effects of heavy ion beam radiation. In this study, we analyzed the yield of clustered base damage (comprising multiple base lesions) in cultured cells irradiated with various heavy ion beams, and investigated isolated base damage and the repair process in post-irradiation cultured cells. Chinese hamster ovary (CHO) cells were irradiated by carbon, silicon, argon and iron ion beams with LETs of 13, 55, 90 and 200 keV um(-1), respectively. Agarose gel electrophoresis of the cells with enzymatic treatments indicated that clustered base damage yields decreased as the LET increased. The aldehyde reactive probe procedure showed that isolated base damage yields in the irradiated cells followed the same pattern. To analyze the cellular base damage process, clustered DNA damage repair was investigated using DNA repair mutant cells. DNA double-strand breaks accumulated in CHO mutant cells lacking Xrcc1 after irradiation, and the cell viability decreased. On the other hand, mouse embryonic fibroblast (Mef) cells lacking both Nth1 and Ogg1 became more resistant than the wild type Mef. Thus, clustered base damage seems to be involved in the expression of heavy ion beam biological effects via the repair process. PMID- 25717059 TI - Activities of daily living and outcomes in heart failure. AB - BACKGROUND: Chronic disease can contribute to functional disability, which can degrade quality of life. However, the prevalence of functional disability and its association with outcomes among patients with heart failure requires further study. METHODS AND RESULTS: Southeastern Minnesota residents with heart failure were enrolled from September 2003 through January 2012 into a cohort study with follow-up through December 2012. Difficulty with 9 activities of daily living (ADLs) was assessed by a questionnaire. Patients were divided into 3 categories of ADL difficulty (no/minimal, moderate, severe). The associations of ADL difficulty with mortality and hospitalization were assessed using Cox and Andersen-Gill models. Among 1128 patients (mean age, 74.7 years; 49.2% female), a majority (59.4%) reported difficulty with one or more ADLs at enrollment, with 272 (24.1%) and 146 (12.9%) experiencing moderate and severe difficulty, respectively. After a mean (SD) follow-up of 3.2 (2.4) years, 614 patients (54.4%) had died. Mortality increased with increasing ADL difficulty; the hazard ratio (95% confidence interval) for death was 1.49 (1.22-1.82) and 2.26 (1.79 2.86) for those with moderate and severe difficulty, respectively, compared to those with no/minimal difficulty (Ptrend<0.001). Patients with moderate and severe difficulty were at an increased risk for all-cause and noncardiovascular hospitalization. In a second assessment, 17.7% of survivors reported more difficulty with ADLs and patients with persistently severe or worsening difficulty were at an increased risk for death (hazard ratio, 2.10; 95% confidence interval, 1.71-2.58; P<0.001) and hospitalization (hazard ratio, 1.51; 95% confidence interval, 1.31-1.74; P<0.001). CONCLUSIONS: Functional disability is common in patients with heart failure, can progress over time, and is associated with adverse prognosis. PMID- 25717061 TI - Identification of Early-Onset Preeclampsia-Related Genes and MicroRNAs by Bioinformatics Approaches. AB - BACKGROUND: Early-onset preeclampsia (EOPET), resulting in intrauterine growth restriction, has serious impact on maternal, perinatal, and neonatal livability worldwide. The current study conducted bioinformatics analyses to screen key genes and microRNAs (miRNAs) involved in EOPET and thus to explore the molecular mechanisms of EOPET. METHODS: The microarray data set GSE44711 containing 8 EOPET placentas and 8 gestational age-matched controls was obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened and subjected to gene ontology functional enrichment analysis. Then, Human Protein Reference Database was used to construct protein-protein interaction (PPI) network of DEGs. Besides, we predicted EOPET-associated miRNAs and built the miRNA regulatory network. RESULTS: A total of 150 DEGs including 26 upregulated and 124 downregulated genes were obtained. Corticotropin releasing hormone (CRH) and vitronectin (VTN) was the most significantly upregulated and downregulated genes, respectively. The DEGs were mainly related to the biological process (BP) of pregnancy, hormone-involved process, and formation of extracellular region. Analysis of PPI network revealed that fibronectin 1(FN1), FBJ murine osteosarcoma viral oncogene homolog (FOS), CD247 molecule (CD247), VTN, and interleukin 2 receptor, beta (IL2RB) were the top 5 DEGs with highest node degree. Furthermore, many EOPET-associated miRNAs were identified and miR 142-3p was the most significant one. Additionally, multiple miRNAs, such as miR 200b/c and miR-27a/b, were predicted to regulate the expression of several key DEGs. CONCLUSION: The current study identified several regulators in EOPET, which may contribute to interpret the molecular mechanism of EOPET and develop novel biomarkers and therapeutic targets for EOPET. PMID- 25717062 TI - Uric Acid Determination in Gestational Hypertension: Is it as Effective a Delineator of Risk as Proteinuria in High-Risk Women? AB - We asked, is uric acid as effective as proteinuria at identifying perinatal risk in high-risk women with gestational hypertension? Uric acid was measured in samples obtained ~4.6 weeks predelivery in 259 women with prior preeclampsia from the National Institute of Child Health and Human Development network study of low dose aspirin to prevent preeclampsia. Participants were grouped according to the presence/absence of gestational hypertension (H), proteinuria (P), and hyperuricemia (U). Adverse perinatal outcomes were not different between H or U and women with normal values (normal blood pressure, urinary protein, and uric acid [NNN]). Preterm birth was greater in hypertension and proteinuria (HP) and hypertension and hyperuricemia (HU) compared to NNN (relative risk [RR] = 2.4, P = .03 and 3.8, P < .01), respectively. In addition, in HU women, delivery was earlier (36.6 +/- 3.4 vs 38.4 +/- 2.3 weeks, P < .001) and small for gestational age infants =16 years, using the last available plasma creatinine, 22.5% had an eGFR>=90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15 29, and <15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P<0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size <10 cm in patients aged >=16 years (4.39 [2.00 to 9.62]; P<0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P<0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR<60 ml/min per 1.73 m(2) (2.7 [1.5 to 5.1]; P=0.001). CONCLUSIONS: CKD and high BP occur frequently in patients with cystinuria and should be routinely screened. PMID- 25717072 TI - Plasma Urate and Risk of a Hospital Stay with AKI: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND AND OBJECTIVES: Higher urate levels are associated with higher risk of CKD, but the association between urate and AKI is less established. This study evaluated the risk of hospitalized AKI associated with urate concentrations in a large population-based cohort. To explore whether urate itself causes kidney injury, the study also evaluated the relationship between a genetic urate score and AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 11,011 participants from the Atherosclerosis Risk in Communities study were followed from 1996-1998 (baseline) to 2010. The association between baseline plasma urate and risk of hospitalized AKI, adjusted for known AKI risk factors, was determined using Cox regression. Interactions of urate with gout and CKD were tested. Mendelian randomization was performed using a published genetic urate score among the participants with genetic data (n=7553). RESULTS: During 12 years of follow up, 823 participants were hospitalized with AKI. Overall, mean participant age was 63.3 years, mean eGFR was 86.3 ml/min per 1.73 m(2), and mean plasma urate was 5.6 mg/dl. In patients with plasma urate >5.0 mg/dl, there was a 16% higher risk of hospitalized AKI for each 1-mg/dl higher urate (adjusted hazard ratio, 1.16; 95% confidence interval, 1.10 to 1.23; P<0.001). When stratified by history of gout, the association between higher urate and AKI was significant only in participants without a history of gout (P for interaction=0.02). There was no interaction of CKD and urate with AKI, nor was there an association between genetic urate score and AKI. CONCLUSIONS: Plasma urate >5.0 mg/dl was independently associated with risk of hospitalized AKI; however, Mendelian randomization did not provide evidence for a causal role of urate in AKI. Further research is needed to determine whether lowering plasma urate might reduce AKI risk. PMID- 25717073 TI - Estimating GFR in adult patients with hematopoietic cell transplant: comparison of estimating equations with an iohexol reference standard. AB - BACKGROUND AND OBJECTIVES: Formal evaluation of kidney function before and after hematopoietic cell transplant is important to determine conditioning regimens, type of transplant, and medication dosing. Serum creatinine and estimating equations may not accurately assess kidney function. DESIGN, STUDY, PARTICIPANTS, & MEASUREMENTS: Existing estimating equations for GFR were compared with an iohexol measure of GFR in a prospective cohort study of 50 patients undergoing hematopoietic cell transplant and subsequent care at the Fred Hutchinson Cancer Research Institute from 2009 to 2013. Patients underwent iohexol GFR, serum creatinine, and cystatin C determination at baseline and day 100 posthematopoietic cell transplant. Iohexol GFR measurements were compared with the CKD Epidemiology Collaboration, Inker CKD Epidemiology Collaboration cystatin C with and without serum creatinine, Modification of Diet in Renal Disease, and Cockcroft-Gault estimating equations using Bland-Altman analysis and McNemar's test. The iohexol measurements were also compared with blood samples collected simultaneously on filter paper. RESULTS: Mean differences between iohexol GFR and eGFR on the basis of Bland-Altman analyses ranged from -20.6 to +15.4 ml/min per 1.73 m(2) at baseline and -12.7 to +12.9 ml/min per 1.73 m(2) at day 100. The CKD Epidemiology Collaboration and Modification of Diet in Renal Disease estimating equations classified 64% of patients with a GFR<90 at baseline compared with 38% by iohexol GFR (P=0.003 and P<0.01, respectively). No statistically significant differences were seen at day 100. The filter paper GFR had a mean difference of 0 at baseline and 5.9 at day 100. Additionally, 21%-37% and 57%-89% of eGFRs were within 10% and 30%, respectively, of the iohexol GFR at baseline, and 16%-34% and 72%-84% were within 10% and 30%, respectively, of the iohexol GFR at day 100; 98% of the filter paper estimates at baseline were within 30%, and 46% were within 10% of iohexol GFR. CONCLUSIONS: The estimating equations are neither accurate nor precise in the hematopoietic cell transplant population, and clinical decision may require measurement of GFR. PMID- 25717074 TI - When you smile, the world smiles at you: ERP evidence for self-expression effects on face processing. AB - Current models of emotion simulation propose that intentionally posing a facial expression can change one's subjective feelings, which in turn influences the processing of visual input. However, the underlying neural mechanism whereby one's facial emotion modulates the visual cortical responses to other's facial expressions remains unknown. To understand how one's facial expression affects visual processing, we measured participants' visual evoked potentials (VEPs) during a facial emotion judgment task of positive and neutral faces. To control for the effects of facial muscles on VEPs, we asked participants to smile (adopting an expression of happiness), to purse their lips (incompatible with smiling) or to pose with a neutral face, in separate blocks. Results showed that the smiling expression modulates face-specific visual processing components (N170/vertex positive potential) to watching other facial expressions. Specifically, when making a happy expression, neutral faces are processed similarly to happy faces. When making a neutral expression or pursing the lips, however, responses to neutral and happy face are significantly different. This effect was source localized within multisensory associative areas, angular gyrus, associative visual cortex and somatosensory cortex. We provide novel evidence that one's own emotional expression acts as a top-down influence modulating low level neural encoding during facial perception. PMID- 25717075 TI - Predictors of acculturative hassles among Vietnamese refugees in Norway: Results from a long-term longitudinal study. AB - We investigated acculturative hassles in a community cohort of Vietnamese refugees in Norway (n = 61), exploring cross-sectional data and longitudinal predictors of acculturative hassles using data from their arrival in Norway in 1982 (T1), with follow up in 1985 (T2) and in 2005-2006 (T3). To our knowledge, this is the first longitudinal study of predictors of acculturative hassles in a refugee population. Results indicated that more communication problems and less Norwegian language competence were related to most hassles at T3. Higher psychological distress, lower quality of life, lower self-reported state of health, and less education at T3 were associated with higher levels of hassles at T3. More psychological distress at T2 and less education at arrival (T1) were significant predictors for more acculturative hassles at T3. These data suggest that addressing psychological distress during the early phase in a resettlement country may promote long-term refugee adjustment and, in particular, reduce exposure to acculturative hassles. PMID- 25717081 TI - Pigment Deposition in the Rat Retina. AB - Incidental findings in the rat eye are not uncommon in acute and long-term toxicological studies. These findings can be associated with a number of causes unrelated to treatment with the test article, including congenital malformation, trauma, infection, metabolic disease, genetic predisposition, and age-related changes. The occurrence of pigment deposition in the retina of Wistar Hannover (Crl:WI (Han)) rats in a 4-week toxicity study is reported in this communication. The microscopic examination of the eyes in the 4-week toxicity study revealed focal yellow-brown pigment deposits in the retina, mainly located in the ganglion cell layer. The retinal pigment deposits were randomly distributed in the control and treated groups and were considered incidental. The deposits were clearly positive for ferric iron in the Perls' stain but not for lipofuscin by the Schmorl's and Long Ziehl-Neelsen methods. The iron-containing pigment is likely to represent hemosiderin accumulation after retinal micro-hemorrhage or could be indicative of the normal intraretinal iron transport and turnover. PMID- 25717082 TI - Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides. AB - Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies. PMID- 25717083 TI - The effects of particle size, milling method, and thermal treatment of feed on performance, apparent ileal digestibility, and pH of the digesta in laying hens. AB - Various milling methods result in different particle size distributions and, in combination with mash and thermal treatment (expandate) of the feed, may have an impact on nutrient digestibility, pH of the digesta and subsequently the performance of an animal. Since this aspect has not been widely considered in laying hens, the objective of the present study was to investigate the effects of milling method, expansion, and particle size of feed on performance, apparent ileal nutrient digestibility, and pH of digesta in laying hens. Twelve variants of the same diet were produced. Four different milling techniques (hammer mill, roller mill, disc mill, and wedge-shaped disc mill) were used to grind the feed cereals. Coarse feed was obtained from all four mills. Additionally, fine feed was obtained from the hammer mill and the roller mill. Each of the six feed variants was offered as mash or expandate, resulting in a total of 12 treatments. The duration of the experimental period was 21 days. A total of 576 layers, each 19 weeks of age, were used in eight replicates. The statistical analysis for the four milling methods and two thermal treatments was performed using a 4*2 factorial arrangement. The effect of particle size was investigated using a 2*2*2 factorial arrangement including the coarse and fine particle sizes that were produced with the hammer mill and the roller mill as well as the mash and expandate. The animal performance and the pH of the digesta were not affected by the treatments. Ileal digestibility of starch was significantly improved by feeding mash compared to expandate (P=0.013) and by feeding coarse compared to fine feed (P=0.028). Based on this study, the tested milling methods can be used for the production of feed for laying hens without affecting performance and digestibility of nutrients. PMID- 25717084 TI - Robustness to chronic heat stress in laying hens: a meta-analysis. AB - Chronic heat is a major stress factor in laying hens and many studies on the effect of heat stress have been published. It remains difficult, however, to draw general conclusions about the effect of chronic heat stress on performance and its relationship with genetic and environmental factors, as these studies have been done under varying experimental conditions and using various experimental designs. A meta-analysis enabled us to make a quantitative review of the results from 131 published papers. The relative effects of four factors (genotype, age, group size, and amplitude of temperature variation) and their interactions with temperature were analyzed for 13 traits. After pre-correcting the data for a random study effect, the best model for each trait was selected in a stepwise procedure based on its residual sum of squares. Shell strength, daily feed intake, egg mass, and hen-day egg production were found to be more sensitive to heat stress than the other traits as they dropped by 9.0 to 22.6% between thermo neutrality (15 to 20 degrees C) and heat stress (30 to 35 degrees C) while yolk and albumen proportions or Haugh units showed nearly no variation with temperature (<1.2% between thermo-neutrality and heat stress). Many interactions (17) were found between temperature and one or more factors in the 13 traits studied here, which reinforces the interest of using a meta-analysis to summarize data from the literature. This study highlighted that the impact of heat stress in laying hens depends on the genotype, age, and group size, some of which have rarely been investigated. PMID- 25717086 TI - Potential of fructooligosaccharide prebiotics in alternative and nonconventional poultry production systems. AB - Fructooligosaccharide and inulin prebiotics are carbohydrate-based polymers derived from natural sources that can be utilized by certain gastrointestinal tract bacteria but not by the host animal. They are attractive as feed additives for nonconventional poultry production systems because they select for beneficial microorganisms that are thought to promote nutritional benefits to the bird and potentially limit foodborne pathogen establishment. There have been numerous studies conducted with prebiotic supplements to assess their impact in humans, animals, and conventionally raised poultry but only limited research has been conducted with birds grown under nonconventional production conditions. Much remains unknown about the specific mechanism(s) associated with their impact on the host as well as the gastrointestinal tract microflora. Utilization of several recently developed approaches such as microbiome and metabolomic analyses should offer more insight on how dietary prebiotic additives influence the development of the gastrointestinal tract microbiota and these subsequent changes correspond with alterations in a bird's physiology as it matures. As more detailed and precise studies are done with nonconventional poultry, it is likely that structurally distinct prebiotics will influence not only the gastrointestinal tract microbiota differently, but potentially interact directly and/or indirectly with the bird host in distinguishable patterns as well. These functions will be important to delineate if further applications are to be developed for specific prebiotics in nonconventional poultry production systems. PMID- 25717085 TI - Comparative study of DL-selenomethionine vs sodium selenite and seleno-yeast on antioxidant activity and selenium status in laying hens. AB - The aim of this study was to compare the effect of DL-selenomethionine (SM) with 2 routinely used Se sources, sodium selenite (SS) and seleno-yeast (SY), on relative bioavailability based on antioxidant activity and tissue Se content. Six hundred thirty 131-day-old brown laying hens were randomly assigned to 7 treatments for 168 d (24 wks) with 6 replicates of 15 hens per replicate. The SS and SY animals were supplemented a cornmeal and soybean diet that supplied a total Se 0.3 mg/kg whereas SM was added at 4 different levels to the total Se at 0.1, 0.3, 0.5 and 0.7 mg/kg. All hens fed the Se-supplemented diet showed higher glutathione peroxidase (GSH-Px) activity (P < 0.01), higher superoxide dismutase (SOD) activity (P < 0.05), lower malondialdehyde (MDA) content (P < 0.05) in plasma, and greater Se contents in egg yolks, albumen, leg muscle, breast muscle, liver, and plasma compared with those fed the control diet (P < 0.01). The organic sources (SY and SM) exhibited a greater ability to increase the GSH-Px activity (P < 0.01) and Se content in albumen (P < 0.01), leg, and breast muscles (P = 0.0099 and P = 0.0014, respectively) than the SS that was added at 0.3 mg Se/kg. The higher SM added levels increased the GSH-Px activity until the dose of 0.5mg Se/kg (P < 0.01).The greater Se concentrations in albumen, muscle and liver appeared in the higher SM-added level, as well as above the dose of 0.1 mg Se/kg (P < 0.01). In addition, hens fed the diet with SM accumulated more Se in albumen, leg, and breast muscle than those fed diets with SY (P < 0.05). These results confirmed the higher ability of organic Se sources to increase the antioxidant activity and Se deposition in egg albumen, leg, and breast muscles compared with SS, and demonstrated a significantly better efficiency of SM compared with SY for albumen and muscle Se enrichment. PMID- 25717087 TI - Effects of Clostridium butyricum on growth performance, antioxidation, and immune function of broilers. AB - To investigate the effects of Clostridium butyricum on growth performance, antioxidation, and immune function of broilers, 320 one-day-old Arbor Acres commercial male chicks were assigned to one of 5 treatments with 8 replicates in a completely randomized design for 42 d. The 5 treatments were basal diet (control), basal diet supplemented with 2.5*10(8) cfu C. butyricum/kg (CB1), basal diet supplemented with 5*10(8) cfu C. butyricum/kg (CB2), basal diet supplemented with 1*10(9) cfu C. butyricum/kg (CB3), and basal diet supplemented with 150 mg aureomycin/kg (antibiotic). The results showed that all C. butyricum supplemented groups during d 1 to 21 and the CB2 group during d 22 to 42 had higher ADG compared with the control (P<0.05). Chicks fed the CB3 diet had higher glutathione S-transferase (GST) activity (P<0.05), and chicks fed the CB2 diet had a higher glutathione (GSH) concentration in duodenal and ileal mucosa at 21 d of age than those in the control group (P<0.05). Chicks fed the CB3 diet had a lower malondialdehyde (MDA) concentration in duodenal mucosa than those in the control and CB1 groups (P<0.05). Chicks fed the CB2, CB3, and antibiotic diets had a lower MDA concentration in ileal mucosa than those in the control and CB1 groups (P<0.05). Broilers fed the CB3 diet had greater superoxide dismutase (SOD) activity in the ileal mucosa on d 21 and in jejunal mucosa on d 42 than those in the other groups (P<0.05). Chicks fed the CB2, CB3, and antibiotic diets had a higher GSH concentration in duodenal and jejunal mucosa on d 42 than those in the control group (P<0.05). Broilers fed the CB2 and CB3 diets had a lower MDA concentration in the jejunal mucosa on d 42 than those in the control and CB1 groups. Chicks fed diets supplemented with C. butyricum had a higher IgM concentration than those in the control group at 21 and 42 d of age (P<0.05). The results indicate that C. butyricum improves broilers' growth performance, antioxidation, and immune function. PMID- 25717088 TI - The effects of environmental enrichment and beak-trimming during the rearing period on subsequent feather damage due to feather-pecking in laying hens. AB - This experiment investigated effects of environmental enrichment and beak trimming during the rearing period on behavior in rearing and plumage damage later in life. Treatments were applied in a 2 * 2 factorial arrangement. Half of the birds were beak-trimmed at 1 d of age using an infra-red laser. A follow-up light-trim was performed at 11 wk of age with a hot blade. Environmental enrichment consisted of pecking strings, whole oats in the litter, and greater litter depth. Sixteen pens of 50 ISA Brown laying hens were used. Four pullets were selected from each pen as focal birds and observed in their home pens between 3 and 14 wk of age. Plumage damage was scored at the end of the experiment in wk 43. Beak-trimmed birds performed less ground-pecking (P = 0.003), less severe feather-pecking (P = 0.021) and more gentle feather-pecking (P = 0.018) than their non-trimmed counterparts during the rearing period. These birds also exhibited less feather damage in wk 43 (P < 0.001). The results indicate that gentle feather-pecking during rearing is not related to plumage damage when older. Additionally, higher rates of ground-pecking and severe feather-pecking during rearing may be predictive of plumage damage later in life. There was no effect of enrichment on plumage damage. It was concluded that while there was no effect on enrichment, beak-trimming appeared to be effective in reducing plumage damage in wk 43. PMID- 25717089 TI - Effects of glucocorticoid-induced stress on absorption of glycylsarcosine in jejunum of broilers. AB - This study was conducted to investigate the effects of stress on the absorption of glycylsarcosine in the jejunum of broilers, as well as the underlying mechanisms. A glucocorticoid analogue, dexamethasone (DEX), was chosen to simulate the effects of endogenous glucocorticoids. Two hundred 21-day-old male Arbor Acre broilers were randomly allotted to 4 groups with 5 replicates in each group and 10 birds per replicate by a completely randomized assignment involving a single factorial arrangement of injection dose DEX. The broilers were injected with 1-mL DEX (0.1-, 0.5-, and 2.5-mg/kg BW) or saline subcutaneously in the abdomen 1*/d for 7 d. The broilers were weighed, killed, and sampled at 28 days old. The results showed that DEX dose-dependently reduced growth and endogenous corticosterone content in the plasma of the broilers (P<0.05). DEX decreased absorption of glycylsarcosine by jejunum brush border membrane vesicles and gut sacs (P<0.05). DEX treatment increased the crypt depth of the jejunum, decreased the villus height, absorption area, and ratio of villus height to crypt depth (P<0.05). Effect of dexamethasone on villus width was not obvious (P>0.05). It was concluded that DEX reduced the absorption of glycylsarcosine in the jejunum of broilers. PMID- 25717090 TI - Meat quality, oxidative stability and blood parameters from Graylag geese offered alternative fiber sources in growing period. AB - The effects of dietary fiber sources on the meat quality, oxidative stability, and blood parameters of growing Graylag geese (28-112d) were investigated. The birds were randomly allocated into 4 treatments, of which dietary fiber was mainly from corn straw silage (CSS), steam-exploded corn straw (SECS), steam exploded wheat straw (SEWS), and steam-exploded rice straw (SERS). No influence (P>0.05) on the basic chemical components, oxidative stability, or organoleptic traits of muscle were observed, except that birds fed SECS had a higher (P<0.05) protein proportion than those fed CSS or SERS, and CSS increased (P<0.01) the cholesterol content when compared to SEWS or SERS. Regarding fatty acid profile in meat, CSS and SECS increased (P<0.01) the proportion of C18:2n6t and decreased that of C21:0 and C22:0 when compared to the others. The birds fed SERS had a higher (P<0.05) proportion of C20:0 and C22:0 than the others, a higher proportion of C20:5n3, n-3 fatty acids, Delta-9 desaturase (18) index compared to those fed CSS or SECS, and a lower (P<0.01) proportion of C20:1n9 than those fed SECS or SEWS. Additionally, SEWS resulted in a higher (P<0.01) proportion of C20:2 when compared to the others. In conclusion, these fibers affect just the protein proportion, cholesterol content, and fatty acid profile of breast muscle, along with the concentration of TG and MDA in blood, but not the other characteristics. No superior fiber source exists with respect to meat quality, suggesting that Graylag geese feeding should make the most economically of the convenient fiber source with appropriate pretreatment. PMID- 25717091 TI - II. Evaluation of the impact of alternative light technology on male broiler chicken stress. AB - This study evaluates the impact of light-emitting diodes (LEDs), cold cathode fluorescent lamps (CCFLs), and incandescent lamps on broiler welfare in response to recent interest in the agriculture industry to transition to more energy efficient lighting technologies. Male Ross 708 broilers (n=672) were raised to 6 wk age in 8 light-tight modified large colony houses under identical intermittent lighting conditions using 4 unique types of lamps, which were gradually dimmed throughout the study. Incandescent lamps served as the control; experimental technologies tested were a CCFL, and 2 different LED lamps. Each technology was tested in duplicate for each of the 4 trials (8 replications total per technology) conducted across the course of one year to account for seasonal variance. Birds were removed from each house at days 7, 14, 35, and 42 to be humanely euthanized and weighed for necropsy evaluation and comparison of body mass. Blood collection via cardiac puncture was performed to obtain heterophil to lymphocyte (H:L) ratios for evaluation of environmental stress. Birds raised under CCFLs had significantly lower body weights (2,871 g+/-53) than the control (3,000+/-33 g) by 42 d. Birds raised under CCFLs additionally had significantly higher H:L ratios (0.68+/-0.06) than the control (0.53+/-0.03), indicating that these birds may have been chronically stressed (P=0.03). There were not significant differences in the H:L ratio between LED technologies at alpha=0.05. A significant age and seasonal correlation in H:L ratios was observed across all technologies, along with significant differences among birds raised under the experimental technologies. This study indicates that variation in broiler body weight and stress may be attributed in part to lighting technologies implemented in broiler houses. PMID- 25717092 TI - Cauda equina syndrome due to intravascular lymphoma: diagnosis by nasal biopsy. PMID- 25717093 TI - Venous thromboembolic event prevention in acute stroke: update on evidence and recommendations. AB - Venous thromboembolic events are a major cause of morbidity and mortality in patients with acute stroke and their prevention presents a significant challenge. This article outlines the clinical trial evidence for prevention of venous thromboembolic events in acute stroke, and the current UK clinical practice recommendations. PMID- 25717094 TI - Tuberculosis vaccines: time for a global strategy. PMID- 25717095 TI - Paying for innovation: reimbursement incentives for antibiotics. PMID- 25717096 TI - Financing translation: analysis of the NCATS rare-diseases portfolio. AB - The portfolio of the National Center for Advancing Translational Sciences (NCATS) rare-diseases therapeutic development program comprises 28 research projects initiated at the preclinical stage. Historical data reveal substantially lower costs and higher success rates but longer preclinical timelines for the NCATS projects relative to the industry averages for early-stage translational medical research and development (R&D) typically cited in literature. Here, we evaluate the potential risks and rewards of investing in a portfolio of rare-disease therapeutics. Using a "megafund" financing structure, NCATS data, and valuation estimates from a panel of industry experts, we simulate a hypothetical megafund in which senior and junior debt yielded 5 and 8%, respectively. The simulated expected return to equity was 14.7%, corresponding to a modified internal rate of return of 21.6%. These returns and the likelihood of private-sector funding can be enhanced through third-party funding guarantees from philanthropies, patient advocacy groups, and government agencies. PMID- 25717097 TI - Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. AB - To gain insights into the interrelationships among childhood undernutrition, the gut microbiota, and gut mucosal immune/barrier function, we purified bacterial strains targeted by immunoglobulin A (IgA) from the fecal microbiota of two cohorts of Malawian infants and children. IgA responses to several bacterial taxa, including Enterobacteriaceae, correlated with anthropometric measurements of nutritional status in longitudinal studies. The relationship between IgA responses and growth was further explained by enteropathogen burden. Gnotobiotic mouse recipients of an IgA(+) bacterial consortium purified from the gut microbiota of undernourished children exhibited a diet-dependent enteropathy characterized by rapid disruption of the small intestinal and colonic epithelial barrier, weight loss, and sepsis that could be prevented by administering two IgA targeted bacterial species from a healthy microbiota. Dissection of a culture collection of 11 IgA-targeted strains from an undernourished donor, sufficient to transmit these phenotypes, disclosed that Enterobacteriaceae interacted with other consortium members to produce enteropathy. These findings indicate that bacterial targets of IgA responses have etiologic, diagnostic, and therapeutic implications for childhood undernutrition. PMID- 25717098 TI - Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. AB - Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint kappa receptor excision circles (sjKRECs), and intron recombination signal sequence-K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor beta (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function. PMID- 25717099 TI - Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. AB - Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. We show that subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) to cats with NPC disease ameliorated hepatic disease, but doses sufficient to reduce neurological disease resulted in pulmonary toxicity. However, direct administration of HPbetaCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near-normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPbetaCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. These studies in a feline animal model have provided critical data on efficacy and safety of drug administration directly into the central nervous system that will be important for advancing HPbetaCD into clinical trials. PMID- 25717100 TI - Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. AB - Airway mucus in cystic fibrosis (CF) is highly elastic, but the mechanism behind this pathology is unclear. We hypothesized that the biophysical properties of CF mucus are altered because of neutrophilic oxidative stress. Using confocal imaging, rheology, and biochemical measures of inflammation and oxidation, we found that CF airway mucus gels have a molecular architecture characterized by a core of mucin covered by a web of DNA and a rheological profile characterized by high elasticity that can be normalized by chemical reduction. We also found that high levels of reactive oxygen species in CF mucus correlated positively and significantly with high concentrations of the oxidized products of cysteine (disulfide cross-links). To directly determine whether oxidation can cross-link mucins to increase mucus elasticity, we exposed induced sputum from healthy subjects to oxidizing stimuli and found a marked and thiol-dependent increase in sputum elasticity. Targeting mucin disulfide cross-links using current thiol amino structures such as N-acetylcysteine (NAC) requires high drug concentrations to have mucolytic effects. We therefore synthesized a thiol-carbohydrate structure (methyl 6-thio-6-deoxy-alpha-D-galactopyranoside) and found that it had stronger reducing activity than NAC and more potent and fast-acting mucolytic activity in CF sputum. Thus, oxidation arising from airway inflammation or environmental exposure contributes to pathologic mucus gel formation in the lung, which suggests that it can be targeted by thiol-modified carbohydrates. PMID- 25717101 TI - Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes. AB - A major hurdle to killing Epstein-Barr virus (EBV)-infected tumor cells using oncolytic therapy is the presence of a substantial fraction of EBV-infected cells that does not support the lytic phase of EBV despite exposure to lytic cycle promoting agents. To determine the mechanism(s) underlying this refractory state, we developed a strategy to separate lytic from refractory EBV-positive (EBV(+)) cells. By examining the cellular transcriptome in separated cells, we previously discovered that high levels of host STAT3 (signal transducer and activator of transcription 3) curtail the susceptibility of latently infected cells to lytic cycle activation signals. The goals of the present study were 2-fold: (i) to determine the mechanism of STAT3-mediated resistance to lytic activation and (ii) to exploit our findings to enhance susceptibility to lytic activation. We therefore analyzed our microarray data set, cellular proteomes of separated lytic and refractory cells, and a publically available STAT3 chromatin immunoprecipitation sequencing (ChIP-Seq) data set to identify cellular PCBP2 [poly(C)-binding protein 2], an RNA-binding protein, as a transcriptional target of STAT3 in refractory cells. Using Burkitt lymphoma cells and EBV(+) cell lines from patients with hypomorphic STAT3 mutations, we demonstrate that single cells expressing high levels of PCBP2 are refractory to spontaneous and induced EBV lytic activation, STAT3 functions via cellular PCBP2 to regulate lytic susceptibility, and suppression of PCBP2 levels is sufficient to increase the number of EBV lytic cells. We expect that these findings and the genome-wide resources that they provide will accelerate our understanding of a longstanding mystery in EBV biology and guide efforts to improve oncolytic therapy for EBV associated cancers. IMPORTANCE: Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV(+) cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies. PMID- 25717102 TI - Infection history determines the differentiation state of human CD8+ T cells. AB - After the resolution of the acute phase of infection, otherwise quiescent antigen experienced CD8(+) T cells confer rapid protection upon reinfection with viral pathogens or, in the case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8(+) T cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses to immediate effector functions for persistent viruses. We here show that both the differentiation stage, defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28, and CD27, and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8(+) T cells. Furthermore, virus-specific CD8(+) T cells targeting different respiratory syncytial virus-, influenza A virus-, Epstein-Barr virus (EBV)-, human cytomegalovirus (hCMV)-, and HIV-1-specific epitopes adopt distinct T-bet and Eomes expression patterns that appear to be installed early during the primary response. Importantly, the associations between surface phenotype, T-bet/Eomes expression levels, and the expression of markers that predict CD8(+) T-cell function change according to viral infection history, particularly against the background of HIV-1 and, to lesser extent, of human cytomegalovirus and/or Epstein-Barr virus infection. Thus, the functionality of human antigen-experienced CD8(+) T cells follows at least two dimensions, one outlined by the surface phenotype and another by the T-bet/Eomes expression levels, which are determined by previous or persistent viral challenges. IMPORTANCE: Functional human CD8(+) T-cell subsets have been defined using surface markers like CD45RA, CCR7, CD28, and CD27. However, the induction of function-defining traits, like granzyme B expression, is controlled by transcription factors like T-bet and Eomes. Here, we describe how T-bet and Eomes levels distinctly relate to the expression of molecules predictive for CD8(+) T cell function in a surface phenotype-independent manner. Importantly, we found that central memory and effector memory CD8(+) T-cell subsets differentially express T-bet, Eomes, and molecules predictive for function according to viral infection history, particularly so in the context of HIV-1 infection and, to lesser extent, of latent EBV- and/or hCMV-infected, otherwise healthy adults. Finally, we show that the distinct phenotypes and T-bet/Eomes levels of different virus-specific CD8(+) T-cell populations are imprinted early during the acute phase of primary infection in vivo. These findings broaden our understanding of CD8(+) T-cell differentiation. PMID- 25717104 TI - Prominent amphibian (Xenopus laevis) tadpole type III interferon response to the frog virus 3 ranavirus. AB - Ranaviruses (Iridoviridae) are posing an increasing threat to amphibian populations, with anuran tadpoles being particularly susceptible to these viral infections. Moreover, amphibians are the most basal phylogenetic class of vertebrates known to possess both type I and type III interferon (IFN)-mediated immunity. Moreover, little is known regarding the respective roles of the IFN mediators in amphibian antiviral defenses. Accordingly, we transcriptionally and functionally compared the amphibian Xenopus laevis type I (IFN) and III (IFN lambda) IFNs in the context of infections by the ranavirus frog virus 3 (FV3). X. laevis IFN and IFN-lambda displayed distinct tissue expression profiles. In contrast to our previous findings that X. laevis tadpoles exhibit delayed and modest type I IFN responses to FV3 infections compared to the responses of adults, here we report that tadpoles mount timely and robust type III IFN gene responses. Recombinant forms of these cytokines (recombinant X. laevis IFN [rXlIFN] and rXlIFN-lambda) elicited antiviral gene expression in the kidney derived A6 cell line as well as in tadpole leukocytes and tissues. However, rXlIFN-lambda was less effective than rXlIFN in preventing FV3 replication in A6 cells and tadpoles and inferior at promoting tadpole survival. Intriguingly, FV3 impaired A6 cell and tadpole kidney type III IFN receptor gene expression. Furthermore, in A6 cultures rXlIFN-lambda conferred equal or greater protection than rXlIFN against recombinant viruses deficient for the putative immune evasion genes, the viral caspase activation and recruitment domain (vCARD) or a truncated vIF-2alpha gene. Thus, in contrast to previous assumptions, tadpoles possess intact antiviral defenses reliant on type III IFNs, which are overcome by FV3 pathogens. IMPORTANCE: Anuran tadpoles, including those of Xenopus laevis, are particularly susceptible to infection by ranavirus such as FV3. We investigated the respective roles of X. laevis type I and type III interferons (IFN and IFN lambda, respectively) during FV3 infections. Notably, tadpoles mounted timely and more robust IFN-lambda gene expression responses to FV3 than adults, contrasting with the poorer tadpole type I IFN responses. However, a recombinant X. laevis IFN-lambda (rXlIFN-lambda) conferred less protection to tadpoles and the A6 cell line than rXlIFN, which may be explained by the FV3 impairment of IFN-lambda receptor gene expression. The importance of IFN-lambda in tadpole anti-FV3 defenses is underlined by the critical involvement of two putative immune evasion genes in FV3 resistance to IFN- and IFN-lambda-mediated responses. These findings challenge the view that tadpoles have defective antiviral immunity and suggest, rather, that their antiviral responses are predominated by IFN-lambda responses, which are overcome by FV3. PMID- 25717103 TI - Human Papillomavirus 16 Oncoprotein Expression Is Controlled by the Cellular Splicing Factor SRSF2 (SC35). AB - High-risk human papillomaviruses (HR-HPV) cause anogenital cancers, including cervical cancer, and head and neck cancers. Human papillomavirus 16 (HPV16) is the most prevalent HR-HPV. HPV oncogenesis is driven by two viral oncoproteins, E6 and E7, which are expressed through alternative splicing of a polycistronic RNA to yield four major splice isoforms (E6 full length, E6*I, E6*II, E6*X). The production of multiple mRNA isoforms from a single gene is controlled by serine/arginine-rich splicing factors (SRSFs), and HPV16 infection induces overexpression of a subset of these, SRSFs 1, 2, and 3. In this study, we examined whether these proteins could control HPV16 oncoprotein expression. Small interfering RNA (siRNA) depletion experiments revealed that SRSF1 did not affect oncoprotein RNA levels. While SRSF3 knockdown caused some reduction in E6E7 expression, depletion of SRSF2 resulted in a significant loss of E6E7 RNAs, resulting in reduced levels of the E6-regulated p53 proteins and E7 oncoprotein itself. SRSF2 contributed to the tumor phenotype of HPV16-positive cervical cancer cells, as its depletion resulted in decreased cell proliferation, reduced colony formation, and increased apoptosis. SRSF2 did not affect transcription from the P97 promoter that controls viral oncoprotein expression. Rather, RNA decay experiments showed that SRSF2 is required to maintain stability of E6E7 mRNAs. These data show that SRSF2 is a key regulator of HPV16 oncoprotein expression and cervical tumor maintenance. IMPORTANCE: Expression of the HPV16 oncoproteins E7 and E6 drives HPV-associated tumor formation. Although increased transcription may yield increased levels of E6E7 mRNAs, it is known that the RNAs can have increased stability upon integration into the host genome. SR splicing factors (SRSFs) control splicing but can also control other events in the RNA life cycle, including RNA stability. Previously, we demonstrated increased levels of SRSFs 1, 2, and 3 during cervical tumor progression. Now we show that SRSF2 is required for expression of E6E7 mRNAs in cervical tumor but not nontumor cells and may act by inhibiting their decay. SRSF2 depletion in W12 tumor cells resulted in increased apoptosis, decreased proliferation, and decreased colony formation, suggesting that SRSF2 has oncogenic functions in cervical tumor progression. SRSF function can be targeted by known drugs that inhibit SRSF phosphorylation, suggesting a possible new avenue in abrogating HPV oncoprotein activity. PMID- 25717105 TI - Gammaherpesvirus Tegument Protein ORF33 Is Associated With Intranuclear Capsids at an Early Stage of the Tegumentation Process. AB - Herpesvirus nascent capsids, after assembly in the nucleus, must acquire a variety of tegument proteins during maturation. However, little is known about the identity of the tegument proteins that are associated with capsids in the nucleus or the molecular mechanisms involved in the nuclear egress of capsids into the cytoplasm, especially for the two human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), due to a lack of efficient lytic replication systems. Murine gammaherpesvirus 68 (MHV-68) is genetically related to human gammaherpesviruses and serves as an excellent model to study the de novo lytic replication of gammaherpesviruses. We have previously shown that open reading frame 33 (ORF33) of MHV-68 is a tegument protein of mature virions and is essential for virion assembly and egress. However, it remains unclear how ORF33 is incorporated into virions. In this study, we first show that the endogenous ORF33 protein colocalizes with capsid proteins at discrete areas in the nucleus during viral infection. Cosedimentation analysis as well as an immunoprecipitation assay demonstrated that ORF33 is associated with both nuclear and cytoplasmic capsids. An immunogold labeling experiment using an anti-ORF33 monoclonal antibody revealed that ORF33-rich areas in the nucleus are surrounded by immature capsids. Moreover, ORF33 is associated with nucleocapsids prior to primary envelopment as well as with mature virions in the cytoplasm. Finally, we show that ORF33 interacts with two capsid proteins, suggesting that nucleocapsids may interact with ORF33 in a direct manner. In summary, we identified ORF33 to be a tegument protein that is associated with intranuclear capsids prior to primary envelopment, likely through interacting with capsid proteins in a direct manner. IMPORTANCE: Morphogenesis is an essential step in virus propagation that leads to the generation of progeny virions. For herpesviruses, this is a complicated process that starts in the nucleus. Although the process of capsid assembly and genome packaging is relatively well understood, how capsids acquire tegument (the layer between the capsid and the envelope in a herpesvirus virion) and whether the initial tegumentation process takes place in the nucleus remain unclear. We previously showed that ORF33 of MHV 68 is a tegument protein and functions in both the nuclear egress of capsids and final virion maturation in the cytoplasm. In the present study, we show that ORF33 is associated with intranuclear capsids prior to primary envelopment and identify novel interactions between ORF33 and two capsid proteins. Our work provides new insights into the association between tegument proteins and nucleocapsids at an early stage of the virion maturation process for herpesviruses. PMID- 25717106 TI - Cellular transformation of mouse embryo fibroblasts in the absence of activator E2Fs. AB - The E2F family of transcription factors, broadly divided into activator and repressor E2Fs, regulates cell cycle genes. Current models indicate that activator E2Fs are necessary for cell cycle progression and tumorigenesis and are also required to mediate transformation induced by DNA tumor viruses. E2Fs are negatively regulated by the retinoblastoma (RB) family of tumor suppressor proteins, and virus-encoded oncogenes disrupt the RB-E2F repressor complexes. This results in the release of activator E2Fs and induction of E2F-dependent genes. In agreement, expression of large tumor T antigens (TAg) encoded by polyomaviruses in mammalian cells results in increased transcriptional levels of E2F target genes. In addition, tumorigenesis induced by transgenic expression of simian virus 40 (SV40) TAg in choroid plexus or intestinal villi requires at least one activator E2F. In contrast, we show that SV40 TAg-induced transformation in mouse embryonic fibroblasts is independent of activator E2Fs. This work, coupled with recent studies showing that proliferation in stem and progenitor cells is independent of activator E2Fs, suggests the presence of parallel pathways governing cell proliferation and tumorigenesis. IMPORTANCE: The RB-E2F pathway is altered in many cancers and is also targeted by DNA tumor viruses. Viral oncoprotein action on RBs results in the release of activator E2Fs and upregulation of E2F target genes; thus, activator E2Fs are considered essential for normal and tumorigenic cell proliferation. However, we have observed that SV40 large T antigen can induce cell proliferation and transformation in the absence of activator E2Fs. Our results also suggest that TAg action on pRBs regulates both E2F-dependent and -independent pathways that govern proliferation. Thus, specific cell proliferation pathways affected by RB alterations in cancer may be a factor in tumor behavior and response to therapy. PMID- 25717107 TI - A novel endogenous betaretrovirus in the common vampire bat (Desmodus rotundus) suggests multiple independent infection and cross-species transmission events. AB - The Desmodus rotundus endogenous betaretrovirus (DrERV) is fixed in the vampire bat D. rotundus population and in other phyllostomid bats but is not present in all species from this family. DrERV is not phylogenetically related to Old World bat betaretroviruses but to betaretroviruses from rodents and New World primates, suggesting recent cross-species transmission. A recent integration age estimation of the provirus in some taxa indicates that an exogenous counterpart might have been in recent circulation. PMID- 25717108 TI - Activation of NF-kappaB by human papillomavirus 16 E1 limits E1-dependent viral replication through degradation of E1. AB - NF-kappaB is a family of transcription factors that regulate gene expression involved in many processes, such as the inflammatory response and cancer progression. Little is known about associations of NF-kappaB with the human papillomavirus (HPV) life cycle. We have developed a tissue culture system to conditionally induce E1-dependent replication of the human papillomavirus 16 (HPV16) genome in human cervical keratinocytes and found that expression of HPV16 E1, a viral helicase, results in reduction of IkappaBalpha and subsequent activation of NF-kappaB in a manner dependent on helicase activity. Exogenous expression of a degradation-resistant mutant of IkappaBalpha, which inhibits the activation of NF-kappaB, enhanced E1-dependent replication of the viral genome. Wortmannin, a broad inhibitor of phosphoinositide 3-kinases (PI3Ks), and, to a lesser extent, VE-822, an ATR kinase inhibitor, but not KU55933, an ATM kinase inhibitor, suppressed the activation of NF-kappaB and augmented E1-dependent replication of the HPV16 genome. Interestingly, the enhancement of E1-dependent replication of the viral genome was associated with increased stability of E1 in the presence of wortmannin as well as the IkappaBalpha mutant. Collectively, we propose that expression of E1 induces NF-kappaB activation at least in part through the ATR-dependent DNA damage response and that NF-kappaB in turn limits E1-dependent replication of HPV16 through degradation of E1, so that E1 and NF kappaB may constitute a negative feedback loop. IMPORTANCE: A major risk factor in human papillomavirus (HPV)-associated cancers is persistent infection with high-risk HPVs. To eradicate viruses from infected tissue, it is important to understand molecular mechanisms underlying the establishment and maintenance of persistent infection. In this study, we obtained evidence that human papillomavirus 16 (HPV16) E1, a viral DNA helicase essential for amplification of the viral genomes, induces NF-kappaB activation and that this limits E1-dependent genome replication of HPV16. These results suggest that NF-kappaB mediates a negative feedback loop to regulate HPV replication and that this feedback loop could be associated with control of the viral copy numbers. We could thus show for the first time that NF-kappaB activity is involved in the establishment and maintenance of persistent HPV infection. PMID- 25717109 TI - Oropouche virus infection and pathogenesis are restricted by MAVS, IRF-3, IRF-7, and type I interferon signaling pathways in nonmyeloid cells. AB - Oropouche virus (OROV) is a member of the Orthobunyavirus genus in the Bunyaviridae family and a prominent cause of insect-transmitted viral disease in Central and South America. Despite its clinical relevance, little is known about OROV pathogenesis. To define the host defense pathways that control OROV infection and disease, we evaluated OROV pathogenesis and immune responses in primary cells and mice that were deficient in the RIG-I-like receptor signaling pathway (MDA5, RIG-I, or MAVS), downstream regulatory transcription factors (IRF 3 or IRF-7), beta interferon (IFN-beta), or the receptor for type I IFN signaling (IFNAR). OROV replicated to higher levels in primary fibroblasts and dendritic cells lacking MAVS signaling, the transcription factors IRF-3 and IRF-7, or IFNAR than in wild-type (WT) cells. In mice, deletion of IFNAR, MAVS, or IRF-3 and IRF 7 resulted in uncontrolled OROV replication, hypercytokinemia, extensive liver damage, and death, whereas WT congenic animals failed to develop disease. Unexpectedly, mice with a selective deletion of IFNAR on myeloid cells (CD11c Cre(+) Ifnar(f/f) or LysM Cre(+) Ifnar(f/f)) did not sustain enhanced disease with OROV or a selective (flox/flox) deletion La Crosse virus, a closely related encephalitic orthobunyavirus. In bone marrow chimera studies, recipient irradiated Ifnar(-/-) mice reconstituted with WT hematopoietic cells sustained high levels of OROV replication and liver damage, whereas WT mice reconstituted with Ifnar(-/-) bone marrow were resistant to disease. Collectively, these results establish a dominant protective role for MAVS, IRF-3 and IRF-7, and IFNAR in restricting OROV infection and tissue injury and suggest that IFN signaling in nonmyeloid cells contributes to the host defense against orthobunyaviruses. IMPORTANCE: Oropouche virus (OROV) is an emerging arthropod-transmitted orthobunyavirus that causes episodic outbreaks of a debilitating febrile illness in humans in countries of South and Central America. The continued expansion of the range and number of its arthropod vectors increases the likelihood that OROV will spread into new regions. At present, the pathogenesis of OROV in humans or other vertebrate animals remains poorly understood. To define cellular mechanisms of control of OROV infection, we performed infection studies in a series of primary cells and mice that were deficient in key innate immune genes involved in pathogen recognition and control. Our results establish that a MAVS-dependent type I IFN signaling pathway has a dominant role in restricting OROV infection and pathogenesis in vivo. PMID- 25717110 TI - A role for 3-O-sulfated heparan sulfate in promoting human cytomegalovirus infection in human iris cells. AB - Human cytomegalovirus (HCMV) has emerged as a clinically opportunistic pathogen that targets multiple types of ocular cells and tissues, including the iris region of the uveal tract during anterior uveitis. In this report, we used primary cultures of human iris stroma (HIS) cells derived from human eye donors to investigate HCMV entry. The following lines of evidence suggested the role of 3-O-sulfated heparan sulfate (3-OS HS) during HCMV-mediated entry and cell-to cell fusion in HIS cells. First, 3-O-sulfotransferase-3 (3-OST-3) expression in HIS cells promoted HCMV internalization, while pretreatment of HIS cells with heparinase enzyme or with anti-3-OS HS (G2) peptide significantly reduced the HCMV-mediated formation of plaques/foci. Second, coculture of the HCMV-infected HIS cells with CHO-K1 cells expressing 3-OS HS significantly enhanced cell fusion. Finally, a similar trend of enhanced fusion was observed with cells expressing HCMV glycoproteins (gB, gO, and gH-gL) cocultured with 3-OS HS cells. Taken together, these results highlight the role of 3-OS HS during HCMV plaque formation and cell-to-cell fusion and identify a novel target for future therapeutic interventions. PMID- 25717112 TI - Five-year relative survival rate of brain and other nervous system cancer in the USA, Europe and Japan. PMID- 25717113 TI - Public health research in China: some recent findings and implications. PMID- 25717111 TI - Anti-APOBEC3G activity of HIV-1 Vif protein is attenuated in elite controllers. AB - HIV-1-infected individuals who control viremia to below the limit of detection without antiviral therapy have been termed elite controllers (EC). Functional attenuation of some HIV-1 proteins has been reported in EC. The HIV-1 accessory protein Vif (virion infectivity factor) enhances viral infectivity through anti retroviral factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) degradation; however, little is known regarding Vif function in EC. Here, the anti-APOBEC3G activities of clonal, plasma HIV RNA-derived Vif sequences from 46 EC, 46 noncontrollers (NC), and 44 individuals with acute infection (AI) were compared. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped viruses were generated by cotransfecting 293T cells with expression plasmids encoding patient-derived Vif, human APOBEC3G, VSV-G, and a vif/env deficient luciferase-reporter HIV-1 proviral DNA clone. Viral stocks were used to infect 293T cells, and Vif anti-APOBEC3G activity was quantified in terms of luciferase signal. On average, the anti-APOBEC3G activities of EC-derived Vif sequences (median log10 relative light units [RLU], 4.54 [interquartile range {IQR}, 4.30 to 4.66]) were significantly lower than those of sequences derived from NC (4.75 [4.60 to 4.92], P < 0.0001) and AI (4.74 [4.62 to 4.94], P < 0.0001). Reduced Vif activities were not associated with particular HLA class I alleles expressed by the host. Vif functional motifs were highly conserved in all patient groups. No single viral polymorphism could explain the reduced anti APOBEC3G activity of EC-derived Vif, suggesting that various combinations of minor polymorphisms may underlie these effects. These results further support the idea of relative attenuation of viral protein function in EC-derived HIV sequences. IMPORTANCE: HIV-1 elite controllers (EC) are rare individuals who are able to control plasma viremia to undetectable levels without antiretroviral therapy. Understanding the pathogenesis and mechanisms underpinning this rare phenotype may provide important insights for HIV vaccine design. The EC phenotype is associated with beneficial host immunogenetic factors (such as HLA-B*57) as well as with functions of attenuated viral proteins (e.g., Gag, Pol, and Nef). In this study, we demonstrated that HIV-1 Vif sequences isolated from EC display relative impairments in their ability to counteract the APOBEC3G host restriction factor compared to Vif sequences from normal progressors and acutely infected individuals. This result extends the growing body of evidence demonstrating attenuated HIV-1 protein function in EC and, in particular, supports the idea of the relevance of viral factors in contributing to this rare HIV-1 phenotype. PMID- 25717114 TI - Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation. AB - Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases. PMID- 25717115 TI - Volumizing viaducts of the midface: defining the Beut techniques. AB - BACKGROUND: In nonsurgical facial rejuvenation, autologous fat and dermal fillers have become an effective method to achieve symmetry and balance of the midface. Nonsurgical techniques that target the dynamic anatomical relationships existing in the midface can improve rejuvenation outcomes in this commonly augmented region. OBJECTIVES: The authors described techniques for fat compartment and potential space volumization of the midface via a standardized and reproducible technique. They placed emphasis on access to anatomical spaces and compartments within the midface. METHODS: In 11 hemifacial cadavers, hyaluronic acid filler homogenized with red dye was injected via 3 midfacial ports that were anatomically designed to access the superficial fat compartments, deep fat compartments, or traverse the prezygomatic space. Specimens were dissected in a layered fashion to analyze relationships between the injected filler and midfacial anatomy. We have described 4 site-specific procedural techniques and created a video containing anatomical renderings of each targeted viaduct accompanied by technique demonstrations. RESULTS: We found that Beut techniques 1 through 4 can be performed through 3 midfacial viaducts. Port placement 1.5 cm inferolateral to the alar base in the nasolabial crease created a medial midface viaduct, suitable for access to the deep medial cheek fat, medial superficial fat compartment, premaxillary space, and adjacent superior nasolabial cheek compartment. Port placement within the nasojugal groove provided a middle midface viaduct to access the middle superficial fat compartment and medial suborbicularis oculi fat (SOOF). Port placement 1.5 cm inferolateral to the lateral canthus created a lateral midface viaduct to approach the pre-periosteal fat, prezygomatic space, lateral SOOF, and infraorbital fat compartment. CONCLUSIONS: Our findings indicate that anterior and lateral cheek projection, V deformity correction, rhytid softening, and tear trough effacement can be achieved through the midfacial viaducts. Systematic assessment and site-specific nonsurgical rejuvenation of the midface may lead to increased safety, accuracy, and technique reproducibility in this commonly injected region. PMID- 25717117 TI - Aesthetic surgery of female external genitalia. AB - Aesthetic surgery of the external genitalia in women encompasses many procedures and may address the labia minora, clitoral hood, labia majora, mons pubis, or vaginal opening. During the initial evaluation, the surgeon should consider all aspects of the external genitalia to develop an appropriate surgical plan. It may be necessary to perform 2 or more procedures during the same surgical session to achieve the desired aesthetic result. In this continuing medical education (CME) article, we review the literature and summarize the available cosmetic techniques for female external genitalia. Resection of the labia minora has been described in several peer-reviewed reports. We also discuss the procedures and modifications to direct resection, wedge resection, and deepithelialization of the labia minora. Aesthetic surgery of the clitoral hood may involve straight line resection, extended wedge resection, or inverted V hoodoplasty. The mons pubis may be treated with mons pubis pexy, wedge resection, or lipomodeling. The labia majora can be managed with direct resection or lipomodeling, and hymenoplasty may be performed to correct a wide vaginal opening. PMID- 25717116 TI - Ten-year results from the Natrelle 410 anatomical form-stable silicone breast implant core study. AB - BACKGROUND: Silicone breast implants have long been used for breast augmentation and reconstruction. During this time, these medical devices have gone through a number of modifications to improve their safety, quality, and clinical outcome performance. OBJECTIVES: The authors conducted a 10-year study to determine the safety and effectiveness of Natrelle 410 silicone breast implants. METHODS: This prospective, multicenter study enrolled 941 subjects who were undergoing either augmentation, augmentation revision, reconstruction, or reconstruction revision. Data on complications, reoperations, explantations, and subject satisfaction were collected at annual clinic visits, and one-third of subjects underwent biennial magnetic resonance imaging (MRI) to screen for implant rupture. The authors used the Kaplan-Meier estimator to calculate risk rates for local complications, reoperations, and explantations. RESULTS: Capsular contracture rates increased approximately 1% per year from the previously reported 6-year rates. The rates were significantly lower than those from the Natrelle round gel core study. The overall rate of confirmed ruptured implants in subjects who underwent MRI was 5.7%. Eleven late seromas were reported. The most common reason for explantation was a subject requesting a size or style change. Satisfaction rates remained high through 10 years, with most subjects saying they were somewhat or definitely satisfied with their implants. CONCLUSIONS: This 10-year prospective trial demonstrated the long-term safety and effectiveness of Natrelle 410 anatomical form-stable implants. The complication rates were low and the satisfaction rates were high. LEVEL OF EVIDENCE 1: Therapeutic. PMID- 25717118 TI - Barbed sutures and wound complications in plastic surgery: an analysis of outcomes. AB - BACKGROUND: Barbed sutures may expedite dermal approximation and improve tissue support while requiring less time and material than conventional sutures. Several types of barbed sutures are available, each with unique advantages. OBJECTIVES: The authors sought to determine whether the incidence of complications differed after wound approximation in plastic surgery when various brands of barbed vs nonbarbed traditional sutures were employed. METHODS: The authors conducted a retrospective review of outcomes in body contouring, free flap, and breast reconstruction. Suture type and closure method were noted for each case. The number of complications after traditional 2-layer closure with nonbarbed sutures was compared with the number of complications after closure via 1- and 2-layer techniques with several brands of barbed sutures, and the brands of barbed sutures were compared with each other. RESULTS: A total of 1011 unique surgical procedures, including 298 procedures with barbed sutures and 713 procedures with nonbarbed sutures, were performed by 5 members of the plastic surgery faculty. The 2-layer technique with barbed sutures was associated with significantly higher rates of wound separation than traditional methods. Excessive erythema along the incision site was significantly more frequent with Quill barbed sutures than with V-Loc barbed sutures. CONCLUSIONS: Barbed sutures were associated with significantly higher rates of minor wound complications, specifically when the 2 layer closure technique was performed. Significantly higher rates of erythema were associated with Quill barbed sutures than with V-Loc barbed sutures. LEVEL OF EVIDENCE 4: Risk. PMID- 25717119 TI - Absence of bacterial or fungal growth in vials of reconstituted botulinum toxin type A after storage. AB - BACKGROUND: Botulinum toxin type A (BTX-A; Botox) is supplied as individual freeze-dried preparations that should be administered within 24 hours after reconstitution. To avoid wasting this expensive drug, some physicians have resorted to storing vials of reconstituted BTX-A beyond the recommended duration. However, there is insufficient evidence to indicate that the sterility of previously reconstituted BTX-A is maintained during storage. OBJECTIVES: The authors sought to determine whether bacterial and/or fungal proliferation occurred in vials of reconstituted BTX-A and subsequent storage of the remaining solution under refrigeration for 4 weeks. METHODS: A portion of the contents of 88 consecutive 100-U vials of BTX-A was administered aseptically to 108 patients for essential blepharospasm, hemifacial spasm, or facial rejuvenation. The vials were then stored for 4 weeks in a refrigerator, after which the contents were transferred to various media (blood agar, chocolate agar, Sabouraud agar, brain heart infusion medium, and thioglycolate broth) and assessed for bacterial and/or fungal growth by standard methods. RESULTS: None of the BTX-A vials contained detectable bacterial or fungal contamination after 4 weeks of storage. CONCLUSIONS: Storing vials of reconstituted BTX-A for 4 weeks after administration to patients was not associated with detectable growth of bacteria or fungi. PMID- 25717120 TI - Characterization of adipose tissue for autologous fat grafting. AB - Fat grafting is a common procedure in aesthetic and reconstructive plastic surgery, but variable graft retention limits its utility. Unpredictable clinical outcomes with fat grafting can be explained in part by the lack of standardized protocols for harvesting, processing, and transplanting adipose tissue (AT). Historically, plastic surgeons have relied on trial and error and their clinical experience to develop fat grafting protocols. Optimization of fat grafting protocols requires systematic assessment of the impact that key variables have on the quality of the AT preparation at each step of the procedure. In this article, we review recent findings regarding the composition and quality of AT prepared for fat grafting and the strengths and limitations of existing AT characterization assays. We discuss the need for an assessment of the viability of intact AT (ie, conventionally harvested AT that has not been disrupted further) by means of an operator-independent, quantitative assay that can be performed in real time and generates reproducible data. Promising assays for the characterization of cell product quality have been developed for other therapeutic applications, such as transplantation of pancreatic islet cells. The development or adaptation of a gold-standard assay to determine the quality of an AT preparation may help to standardize fat grafting protocols and improve clinical outcomes. PMID- 25717121 TI - Doppler ultrasound imaging for detection of deep vein thrombosis in plastic surgery outpatients: a prospective controlled study. AB - BACKGROUND: Venous thromboembolism is a serious surgical complication. Risk stratification does not reliably predict which patients will be affected, and anticoagulants introduce additional risks. The Doppler ultrasound scan is the definitive test for the detection of deep vein thrombosis. OBJECTIVES: This prospective, controlled study was undertaken to determine the feasibility of Doppler ultrasound imaging as a screening tool for deep vein thromboses in plastic surgery outpatients. METHODS: Doppler ultrasound screening was offered to 100 consecutive outpatients undergoing a variety of cosmetic plastic surgeries. Total intravenous anesthesia was administered by propofol infusion, and a laryngeal mask airway was inserted. SAFE (spontaneous breathing, avoid gas, face up, and extremities mobile) principles were observed. No patient received anticoagulants. Ultrasound scans were performed before surgery, 1 day after surgery, and approximately 1 week after surgery. Deep veins of the lower extremities, including the calf veins, were analyzed by compression, color Doppler imaging, and Doppler waveform analyses. Twenty-five control participants who did not undergo surgery were evaluated with ultrasonography. A survey was administered to all participants after the scans. RESULTS: No thromboses were detected in the outpatient or control group. Few survey respondents reported discomfort during the scan, and most indicated that ultrasound scans are a valuable screening tool for blood clots. CONCLUSIONS: Doppler ultrasound imaging of the lower extremities is a valuable, noninvasive method for detecting deep venous thromboses in plastic surgery outpatients. Additional study of this modality is warranted. LEVEL OF EVIDENCE 2: Diagnostic. PMID- 25717122 TI - Preparing for retirement: reflections on mistakes made and lessons learned. PMID- 25717123 TI - An anatomic study of nipple position and areola size in Asian men. AB - BACKGROUND: In planning gender-reassignment surgery for biological women and treating men with gynecomastia, surgeons must have a thorough understanding of anatomically correct nipple positions and appropriate areola sizes in men. OBJECTIVES: The authors sought to determine whether body height or body mass index (BMI) affects nipple position or areola size in men. METHODS: Anatomic measurements of the nipples and areolae of 50 Japanese men were obtained. A relative coordinate system was defined, where the medial-lateral and superior inferior positions of the nipple were quantitatively indicated by distance ratios between anatomic landmarks. Nipple positions were evaluated for each patient by referring to this coordinate system, and the positions were compared between groups categorized by body height or BMI. RESULTS: Nipple position was not significantly affected by body height. However, the nipple tended to be located more laterally in participants with higher BMI. The vertical nipple position differed between standing and supine positions. Tall men had larger areolae than short men; however, areola size did not differ with respect to BMI. CONCLUSIONS: Nipple position and areola size vary by body shape. Consideration of the differences is recommended when performing procedures such as female-to-male gender-reassignment surgery or correction of gynecomastia. PMID- 25717124 TI - A useful device for easy blunt dissection of abdominoplasty flaps. PMID- 25717125 TI - Preventing the problems of postoperative pressure alopecia. PMID- 25717126 TI - Response to "preventing the problems of postoperative pressure alopecia". PMID- 25717127 TI - Comments on "breast striae after cosmetic augmentation". PMID- 25717128 TI - Response to "comments on 'breast striae after cosmetic augmentation'". PMID- 25717129 TI - Corrigendum. PMID- 25717130 TI - Sex differences in pre-diagnosis concerns for children later diagnosed with autism spectrum disorder. AB - In the absence of intellectual impairment, girls are diagnosed with autism spectrum disorder significantly less and later than boys. This study explored potential reasons for why autism spectrum disorder may be more difficult to identify in girls, based on carer concerns during the pre-diagnosis period. Carers of 92 boys and 60 girls diagnosed with autism spectrum disorder from school age completed an online survey addressing concerns regarding the child's development during the pre-school years (pre-diagnosis). Significant sex differences were evident in key early concerns, as well as the strategies used to navigate pre-school social situations, and the types of restricted interests. Findings suggest, from carer perspective, that girls who went on to be diagnosed with autism spectrum disorder presented differently when compared to boys, providing insight into why the diagnosis of autism spectrum disorder may be more difficult to make with cognitively able girls. PMID- 25717131 TI - Feasibility of an empirically based program for parents of preschoolers with autism spectrum disorder. AB - This article reports on the feasibility of implementing an existing empirically based program, The Incredible Years, tailored to parents of young children with autism spectrum disorder. Parents raising preschool-aged children (aged 3-6 years) with autism spectrum disorder (N = 17) participated in a 15-week pilot trial of the intervention. Quantitative assessments of the program revealed fidelity was generally maintained, with the exception of program-specific videos. Qualitative data from individual post-intervention interviews reported parents benefited most from child emotion regulation strategies, play-based child behavior skills, parent stress management, social support, and visual resources. More work is needed to further refine the program to address parent self-care, partner relationships, and the diverse behavioral and communication challenges of children across the autism spectrum. Furthermore, parent access and retention could potentially be increased by providing in-home childcare vouchers and a range of times and locations in which to offer the program. The findings suggest The Incredible Years is a feasible intervention for parents seeking additional support for child- and family-related challenges and offers guidance to those communities currently using The Incredible Years or other related parenting programs with families of children with autism spectrum disorder. PMID- 25717132 TI - Studies of aging. PMID- 25717141 TI - The case for cryonics. AB - Cryonics is the low temperature preservation of people who can no longer be sustained by contemporary medicine in the hope that future medicine will make it possible to revive them and restore their health. A speculative practice at the outer edge of science, cryonics is often viewed with suspicion. In this paper I defend two theses. I first argue that there is a small, yet non-negligible, chance that cryonics is technically feasible. I make the case for this by reference to what we know about death and cryobiology, and what we can expect of future nanorobotics. I further argue that insofar as the alternatives to cryonics are burial or cremation, and thus certain, irreversible death, even small chances for success can be sufficient to make opting for cryonics a rational choice. Finally, I reply to five objections. PMID- 25717142 TI - Trends in animal use at US research facilities. AB - Minimising the use of animals in experiments is universally recognised by scientists, governments and advocates as an ethical cornerstone of research. Yet, despite growing public opposition to animal experimentation, mounting evidence that animal studies often do not translate to humans, and the development of new research technologies, a number of countries have reported increased animal use in recent years. In the USA--one of the world's largest users of animals in experiments--a lack of published data on the species most commonly used in laboratories (eg, mice, rats and fish) has prevented such assessments. The current study aimed to fill this gap by analysing the use of all vertebrate animals by the top institutional recipients of National Institutes of Health research funds over a 15-year period. These data show a statistically significant 72.7% increase in the use of animals at these US facilities during this time period-driven primarily by increases in the use of mice. Our results highlight a need for greater efforts to reduce animal use. We discuss technical, institutional, sociological and psychological explanations for this trend. PMID- 25717143 TI - Reforming the politics of animal research. AB - An unfortunate tension exists between the biomedical research and animal welfare/rights communities. We believe that despite the mistrust between these groups, there are individuals on both sides of the controversy who seek to better understand the other. We recommend an update of institutional policies that will better inform the public about the use of non-human animals in biomedical research and improve a dialogue on such use between concerned individuals who either support or oppose non-human animal-based biomedical research. Such interactions may well determine the longevity of using non-human animals as experimental subjects. PMID- 25717144 TI - Technical Advance: Transcription factor, promoter, and enhancer utilization in human myeloid cells. AB - The generation of myeloid cells from their progenitors is regulated at the level of transcription by combinatorial control of key transcription factors influencing cell-fate choice. To unravel the global dynamics of this process at the transcript level, we generated transcription profiles for 91 human cell types of myeloid origin by use of CAGE profiling. The CAGE sequencing of these samples has allowed us to investigate diverse aspects of transcription control during myelopoiesis, such as identification of novel transcription factors, miRNAs, and noncoding RNAs specific to the myeloid lineage. We further reconstructed a transcription regulatory network by clustering coexpressed transcripts and associating them with enriched cis-regulatory motifs. With the use of the bidirectional expression as a proxy for enhancers, we predicted over 2000 novel enhancers, including an enhancer 38 kb downstream of IRF8 and an intronic enhancer in the KIT gene locus. Finally, we highlighted relevance of these data to dissect transcription dynamics during progressive maturation of granulocyte precursors. A multifaceted analysis of the myeloid transcriptome is made available (www.myeloidome.roslin.ed.ac.uk). This high-quality dataset provides a powerful resource to study transcriptional regulation during myelopoiesis and to infer the likely functions of unannotated genes in human innate immunity. PMID- 25717146 TI - Purinergic signaling modulates human visceral adipose inflammatory responses: implications in metabolically unhealthy obesity. AB - Obesity is accompanied by chronic inflammation of VAT, which promotes metabolic changes, and purinergic signaling has a key role in a wide range of inflammatory diseases. Therefore, we addressed whether fat inflammation could be differentially modulated by this signaling pathway in the MUO and in individuals who remain MHO. Our results show that the necrotized VAT of both groups released greater levels of ATP compared with lean donors. Interestingly, MUO tissue SVCs showed up-regulation and engagement of the purinergic P2X7R. The extracellular ATP concentration is regulated by an enzymatic process, in which CD39 converts ATP and ADP into AMP, and CD73 converts AMP into adenosine. In VAT, the CD73 ectoenzyme was widely distributed in immune and nonimmune cells, whereas CD39 expression was restricted to immune CD45PAN+ SVCs. Although the MUO group expressed the highest levels of both ectoenzymes, no difference in ATP hydrolysis capacity was found between the groups. As expected, MUO exhibited the highest NLRP3 inflammasome expression and IL-1beta production. MUO SVCs also displayed up regulation of the A2AR, allowing extracellular adenosine to increase IL-1beta local secretion. Additionally, we demonstrate that metabolic parameters and BMI are positively correlated with purinergic components in VAT. These findings indicate that purinergic signaling is a novel mechanism involved in the chronic inflammation of VAT underlying the metabolic changes in obesity. Finally, our study reveals a proinflammatory role for adenosine in sustaining IL-1beta production in this tissue. PMID- 25717147 TI - Prostaglandins produced during class A scavenger receptor-mediated macrophage adhesion differentially regulate cytokine production. AB - Inflammation is associated with modification of the extracellular environment, changes in cytokine expression, and the accumulation of immune cells. Such modifications create ligands that support SR-A-mediated macrophage adhesion and retention. This may be particularly important in settings, such as atherosclerosis and diabetes, as modified lipoproteins and gluc-collagen are ligands for SR-A. SR-A-mediated adhesion requires the PLA2-dependent generation of AA and its metabolism by 12/15 LOX. In contrast, the inhibition of the COX dependent conversion of AA to PG had no effect on SR-A-mediated adhesion. In this study, macrophages were isolated from SR-A+/+ and SR-A-/- mice and plated on gluc collagen to test the hypothesis that COX-derived PGs are produced during SR-A mediated adhesion and regulate macrophage function. SR-A-mediated binding to gluc collagen induced a rapid but transient increase in PG production, which required the activation of PLA2 and Src kinase but not PI3K. SR-A+/+ macrophages cultured on gluc-collagen for 24 h secreted a similar amount of TNF-alpha and 2.5-fold more IL-10 than SR-A-/- macrophages. The inhibition of COX substantially increased TNF-alpha production but reduced IL-10 levels in SR-A+/+ macrophages. These effects of COX inhibition were reversed by exogenous PGE2 and mimicked by specific antagonism of the EP4 receptor. Thus, in addition to the enhancement of macrophage adhesion, SR-A binding to gluc-collagen stimulates PG production, which in turn, differentially regulates the expression of inflammatory cytokines. PMID- 25717148 TI - Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury. AB - Accumulating evidence suggest that platelets play an important role in regulating neutrophil recruitment in septic lung injury. Herein, we hypothesized that platelet-derived CCL5 might facilitate sepsis-induced neutrophil accumulation in the lung. Abdominal sepsis was induced by CLP in C57BL/6 mice. CLP increased plasma levels of CCL5. Platelet depletion and treatment with the Rac1 inhibitor NSC23766 markedly reduced CCL5 in the plasma of septic mice. Moreover, Rac1 inhibition completely inhibited proteasePAR4-induced secretion of CCL5 in isolated platelets. Immunoneutralization of CCL5 decreased CLP-induced neutrophil infiltration, edema formation, and tissue injury in the lung. However, inhibition of CCL5 function had no effect on CLP-induced expression of Mac-1 on neutrophils. The blocking of CCL5 decreased plasma and lung levels of CXCL1 and CXCL2 in septic animals. CCL5 had no effect on neutrophil chemotaxis in vitro, suggesting an indirect effect of CCL5 on neutrophil recruitment. Intratracheal challenge with CCL5 increased accumulation of neutrophils and formation of CXCL2 in the lung. Administration of the CXCR2 antagonist SB225002 abolished CCL5-induced pulmonary recruitment of neutrophils. Isolated alveolar macrophages expressed significant levels of the CCL5 receptors CCR1 and CCR5. In addition, CCL5 triggered significant secretion of CXCL2 from isolated alveolar macrophages. Notably, intratracheal administration of clodronate not only depleted mice of alveolar macrophages but also abolished CCL5-induced formation of CXCL2 in the lung. Taken together, our findings suggest that Rac1 regulates platelet secretion of CCL5 and that CCL5 is a potent inducer of neutrophil recruitment in septic lung injury via formation of CXCL2 in alveolar macrophages. PMID- 25717149 TI - TRACEY AND RESPECT FOR AUTONOMY: WILL THE PROMISE BE DELIVERED? AB - The central issue of the Court of Appeal decision in R (Tracey) v Cambridge University Hospitals NHS Foundation Trust & Ors [2014] EWCA Civ 822 concerned whether competent adults should be involved in the decision-making process for Do Not Attempt Cardio-Pulmonary Resuscitation (DNACPR) decisions. These are sensitive decisions made on the basis that cardio-pulmonary resuscitation would be futile, or that efforts to resuscitate would not be in the best clinical interests of the person concerned. The Court held that patient involvement in DNACPR decisions should be the presumption, even if clinicians sincerely believed that resuscitation would be futile, unless that involvement would cause actual psychological or physical harm. This case commentary explores the potential implications of this decision in the context of contemporary healthcare. PMID- 25717145 TI - Neutrophils in host defense: new insights from zebrafish. AB - Neutrophils are highly motile phagocytic cells that play a critical role in the immune response to infection. Zebrafish (Danio rerio) are increasingly used to study neutrophil function and host-pathogen interactions. The generation of transgenic zebrafish lines with fluorescently labeled leukocytes has made it possible to visualize the neutrophil response to infection in real time by use of optically transparent zebrafish larvae. In addition, the genetic tractability of zebrafish has allowed for the generation of models of inherited neutrophil disorders. In this review, we discuss several zebrafish models of infectious disease, both in the context of immunocompetent, as well as neutrophil-deficient hosts and how these models have shed light on neutrophil behavior during infection. PMID- 25717150 TI - A novel electronic assessment strategy to support applied Drosophila genetics training in university courses. AB - The advent of "omic" technologies has revolutionized genetics and created a demand to focus classical genetics on its present-day applications (Redfield, 2012, PLoS Biol 10: e1001356). This demand can be met by training students in Drosophila mating scheme design, which is an important problem-solving skill routinely applied in many modern research laboratories. It promotes a thorough understanding and application of classical genetics rules and introduces to transgenic technologies and the use of model organisms. As we show here, such training can be implemented as a flexible and concise module (~1-day home study, ~8-hour course time) on university courses by using our previously published training package designed for fly researchers (Roote and Prokop, 2013, G3 (Bethesda) 3: 353-358). However, assessing this training to make it an accredited course element is difficult, especially in large courses. Here, we present a powerful assessment strategy based on a novel hybrid concept in which students solve crossing tasks initially on paper and then answer automatically marked questions on the computer (1.5 hours total). This procedure can be used to examine student performance on more complex tasks than conventional e-assessments and is more versatile, time-saving, and fairer than standard paper-based assignments. Our evaluation shows that the hybrid assessment is effective and reliably detects varying degrees of understanding among students. It also may be applicable in other disciplines requiring complex problem solving, such as mathematics, chemistry, physics, or informatics. Here, we describe our strategies in detail and provide all resources needed for their implementation. PMID- 25717151 TI - Genetic mapping of natural variation in schooling tendency in the threespine stickleback. AB - Although there is a heritable basis for many animal behaviors, the genetic architecture of behavioral variation in natural populations remains mostly unknown, particularly in vertebrates. We sought to identify the genetic basis for social affiliation in two populations of threespine sticklebacks (Gasterosteus aculeatus) that differ in their propensity to school. Marine sticklebacks from Japan school strongly whereas benthic sticklebacks from a lake in Canada are more solitary. Here, we expanded on our previous efforts to identify quantitative trait loci (QTL) for differences in schooling tendency. We tested fish multiple times in two assays that test different aspects of schooling tendency: 1) the model school assay, which presents fish with a school of eight model sticklebacks; and 2) the choice assay, in which fish are given a choice between the model school and a stationary artificial plant. We found low-to-moderate levels of repeatability, ranging from 0.1 to 0.5, in schooling phenotypes. To identify the genomic regions that contribute to differences in schooling tendency, we used QTL mapping in two types of crosses: benthic * marine backcrosses and an F2 intercross. We found two QTL for time spent with the school in the model school assay, and one QTL for number of approaches to the school in the choice assay. These QTL were on three different linkage groups, not previously linked to behavioral differences in sticklebacks. Our results highlight the importance of using multiple crosses and robust behavioral assays to uncover the genetic basis of behavioral variation in natural populations. PMID- 25717152 TI - Two coincident cases of easily curable 'refractory sprue'. PMID- 25717153 TI - Postnatal overexpression of the human ARMS2 gene does not induce abnormalities in retina and choroid in transgenic mouse models. PMID- 25717154 TI - Author Response: Postnatal Overexpression of the Human ARMS2 Gene Does Not Induce Abnormalities in Retina and Choroid in Transgenic Mouse Models. PMID- 25717155 TI - The effect of force feedback delay on stiffness perception and grip force modulation during tool-mediated interaction with elastic force fields. AB - During interaction with objects, we form an internal representation of their mechanical properties. This representation is used for perception and for guiding actions, such as in precision grip, where grip force is modulated with the predicted load forces. In this study, we explored the relationship between grip force adjustment and perception of stiffness during interaction with linear elastic force fields. In a forced-choice paradigm, participants probed pairs of virtual force fields while grasping a force sensor that was attached to a haptic device. For each pair, they were asked which field had higher level of stiffness. In half of the pairs, the force feedback of one of the fields was delayed. Participants underestimated the stiffness of the delayed field relatively to the nondelayed, but their grip force characteristics were similar in both conditions. We analyzed the magnitude of the grip force and the lag between the grip force and the load force in the exploratory probing movements within each trial. Right before answering which force field had higher level of stiffness, both magnitude and lag were similar between delayed and nondelayed force fields. These results suggest that an accurate internal representation of environment stiffness and time delay was used for adjusting the grip force. However, this representation did not help in eliminating the bias in stiffness perception. We argue that during performance of a perceptual task that is based on proprioceptive feedback, separate neural mechanisms are responsible for perception and action-related computations in the brain. PMID- 25717156 TI - Role of intraglomerular circuits in shaping temporally structured responses to naturalistic inhalation-driven sensory input to the olfactory bulb. AB - Olfaction in mammals is a dynamic process driven by the inhalation of air through the nasal cavity. Inhalation determines the temporal structure of sensory neuron responses and shapes the neural dynamics underlying central olfactory processing. Inhalation-linked bursts of activity among olfactory bulb (OB) output neurons [mitral/tufted cells (MCs)] are temporally transformed relative to those of sensory neurons. We investigated how OB circuits shape inhalation-driven dynamics in MCs using a modeling approach that was highly constrained by experimental results. First, we constructed models of canonical OB circuits that included mono and disynaptic feedforward excitation, recurrent inhibition and feedforward inhibition of the MC. We then used experimental data to drive inputs to the models and to tune parameters; inputs were derived from sensory neuron responses during natural odorant sampling (sniffing) in awake rats, and model output was compared with recordings of MC responses to odorants sampled with the same sniff waveforms. This approach allowed us to identify OB circuit features underlying the temporal transformation of sensory inputs into inhalation-linked patterns of MC spike output. We found that realistic input-output transformations can be achieved independently by multiple circuits, including feedforward inhibition with slow onset and decay kinetics and parallel feedforward MC excitation mediated by external tufted cells. We also found that recurrent and feedforward inhibition had differential impacts on MC firing rates and on inhalation-linked response dynamics. These results highlight the importance of investigating neural circuits in a naturalistic context and provide a framework for further explorations of signal processing by OB networks. PMID- 25717157 TI - Weak orientation and direction selectivity in lateral geniculate nucleus representing central vision in the gray squirrel Sciurus carolinensis. AB - Classic studies of lateral geniculate nucleus (LGN) and visual cortex (V1) in carnivores and primates have found that a majority of neurons in LGN exhibit a center-surround organization, while V1 neurons exhibit strong orientation selectivity and, in many species, direction selectivity. Recent work in the mouse and the monkey has discovered previously unknown classes of orientation- and direction-selective neurons in LGN. Furthermore, some recent studies in the mouse report that many LGN cells exhibit pronounced orientation biases that are of comparable strength to the subthreshold inputs to V1 neurons. These results raise the possibility that, in rodents, orientation biases of individual LGN cells make a substantial contribution to cortical orientation selectivity. Alternatively, the size and contribution of orientation- or direction-selective channels from LGN to V1 may vary across mammals. To address this question, we examined orientation and direction selectivity in LGN and V1 neurons of a highly visual diurnal rodent: the gray squirrel. In the representation of central vision, only a few LGN neurons exhibited strong orientation or direction selectivity. Across the population, LGN neurons showed weak orientation biases and were much less selective for orientation compared with V1 neurons. Although direction selectivity was weak overall, LGN layers 3abc, which contain neurons that express calbindin, exhibited elevated direction selectivity index values compared with LGN layers 1 and 2. These results suggest that, for central visual fields, the contribution of orientation- and direction-selective channels from the LGN to V1 is small in the squirrel. As in other mammals, this small contribution is elevated in the calbindin-positive layers of the LGN. PMID- 25717158 TI - Midline section of the medulla abolishes inspiratory activity and desynchronizes pre-inspiratory neuron rhythm on both sides of the medulla in newborn rats. AB - Each half of the medulla contains respiratory neurons that constitute two generators that control respiratory rhythm. One generator consists of the inspiratory neurons in the pre-Botzinger complex (preBotC); the other, the pre inspiratory (Pre-I) neurons in the parafacial respiratory group (pFRG), rostral to the preBotC. We investigated the contribution of the commissural fibers, connecting the respiratory rhythm generators located on the opposite side of the medulla to the generation of respiratory activity in brain stem-spinal cord preparation from 0- to 1-day-old rats. Pre-I neuron activity and the facial nerve and/or first lumbar (L1) root activity were recorded as indicators of the pFRG driven rhythm. Fourth cervical ventral root (C4) root and/or hypoglossal (XII) nerve activity were recorded as indicators of preBotC-driven inspiratory activity. We found that a midline section that interrupted crossed fibers rostral to the obex irreversibly eliminated C4 and XII root activity, whereas the Pre-I neurons, facial nerve, and L1 roots remained rhythmically active. The facial and contralateral L1 nerve activities were synchronous, whereas right and left facial (and right and left L1) nerves lost synchrony. Optical recordings demonstrated that pFRG-driven burst activity was preserved after a midline section, whereas the preBotC neurons were no longer rhythmic. We conclude that in newborn rats, crossed excitatory interactions (via commissural fibers) are necessary for the generation of inspiratory bursts but not for the generation of rhythmic Pre-I neuron activity. PMID- 25717160 TI - The magnitude of the somatosensory cortical activity is related to the mobility and strength impairments seen in children with cerebral palsy. AB - The noted disruption of thalamocortical connections and abnormalities in tactile sensory function has resulted in a new definition of cerebral palsy (CP) that recognizes the sensorimotor integration process as central to the motor impairments seen in these children. Despite this updated definition, the connection between a child's motor impairments and somatosensory processing remains almost entirely unknown. In this investigation, we explored the relationship between the magnitude of neural activity within the somatosensory cortices, the strength of the ankle plantarflexors, and the gait spatiotemporal kinematics of a group of children with CP and a typically developing matched cohort. Our results revealed that the magnitude of somatosensory cortical activity in children with CP had a strong positive relationship with the ankle strength, step length, and walking speed. These results suggest that stronger activity within the somatosensory cortices in response to foot somatosensations was related to enhanced ankle plantarflexor strength and improved mobility in the children with CP. These results provide further support for the notion that children with CP exhibit, not only musculoskeletal deficits, but also somatosensory deficits that potentially contribute to their overall functional mobility and strength limitations. PMID- 25717161 TI - Functional topographic organization of the motor reticulothalamic pathway. AB - The thalamic reticular nucleus (TRN) is a thin layer of GABAergic cells lying rostral and lateral to the dorsal thalamus, and its projection to thalamic relay cells (i.e., the reticulothalamic pathway) strongly inhibits these cells. In an attempt to extend earlier studies of reticulothalamic connections to sensory thalamic nuclei, we used laser-scanning photostimulation to study the reticulothalamic projections to the main motor thalamic relays, the ventral anterior and lateral (VA and VL) nuclei, as well as to the nearby central lateral (CL) thalamic nucleus. VA/VL and the earlier studied somatosensory thalamic nuclei are considered "core" nuclei with topographic thalamocortical projections, whereas CL is thought to be a "matrix" nucleus with diffuse thalamocortical projections. We found that the TRN input footprints to VA/VL and CL are spatially localized and topographic and generally conform to the patterns established earlier for the TRN projections to sensory thalamic relays. These remarkable similarities suggest similar organization of reticulothalamic pathways and TRN regulation of thalamocortical communication for motor and sensory systems and perhaps also for core and matrix thalamus. Furthermore, we found that VA/VL and CL shared overlapping TRN input regions, suggesting that CL may also be involved in the relay of motor information. PMID- 25717159 TI - Lempel-Ziv complexity of cortical activity during sleep and waking in rats. AB - Understanding the dynamics of brain activity manifested in the EEG, local field potentials (LFP), and neuronal spiking is essential for explaining their underlying mechanisms and physiological significance. Much has been learned about sleep regulation using conventional EEG power spectrum, coherence, and period amplitude analyses, which focus primarily on frequency and amplitude characteristics of the signals and on their spatio-temporal synchronicity. However, little is known about the effects of ongoing brain state or preceding sleep-wake history on the nonlinear dynamics of brain activity. Recent advances in developing novel mathematical approaches for investigating temporal structure of brain activity based on such measures, as Lempel-Ziv complexity (LZC) can provide insights that go beyond those obtained with conventional techniques of signal analysis. Here, we used extensive data sets obtained in spontaneously awake and sleeping adult male laboratory rats, as well as during and after sleep deprivation, to perform a detailed analysis of cortical LFP and neuronal activity with LZC approach. We found that activated brain states-waking and rapid eye movement (REM) sleep are characterized by higher LZC compared with non-rapid eye movement (NREM) sleep. Notably, LZC values derived from the LFP were especially low during early NREM sleep after sleep deprivation and toward the middle of individual NREM sleep episodes. We conclude that LZC is an important and yet largely unexplored measure with a high potential for investigating neurophysiological mechanisms of brain activity in health and disease. PMID- 25717162 TI - Dissociable effects of local inhibitory and excitatory theta-burst stimulation on large-scale brain dynamics. AB - Normal brain function depends on a dynamic balance between local specialization and large-scale integration. It remains unclear, however, how local changes in functionally specialized areas can influence integrated activity across larger brain networks. By combining transcranial magnetic stimulation with resting-state functional magnetic resonance imaging, we tested for changes in large-scale integration following the application of excitatory or inhibitory stimulation on the human motor cortex. After local inhibitory stimulation, regions encompassing the sensorimotor module concurrently increased their internal integration and decreased their communication with other modules of the brain. There were no such changes in modular dynamics following excitatory stimulation of the same area of motor cortex nor were there changes in the configuration and interactions between core brain hubs after excitatory or inhibitory stimulation of the same area. These results suggest the existence of selective mechanisms that integrate local changes in neural activity, while preserving ongoing communication between brain hubs. PMID- 25717163 TI - Distinct neuronal organizations of the caudal cingulate motor area and supplementary motor area in monkeys for ipsilateral and contralateral hand movements. AB - The caudal cingulate motor area (CMAc) and the supplementary motor area (SMA) play important roles in movement execution. The present study aimed to characterize the functional organization of these regions during movement by investigating laterality representations in the CMAc and SMA of monkeys via an examination of neuronal activity during a button press movement with either the right or left hand. Three types of movement-related neuronal activity were observed: 1) with only the contralateral hand, 2) with only the ipsilateral hand, and 3) with either hand. Neurons in the CMAc represented contralateral and ipsilateral hand movements to the same degree, whereas neuronal representations in the SMA were biased toward contralateral hand movement. Furthermore, recording neuronal activities using a linear-array multicontact electrode with 24 contacts spaced 150 MUm apart allowed us to analyze the spatial distribution of neurons exhibiting particular hand preferences at the submillimeter scale. The CMAc and SMA displayed distinct microarchitectural organizations. The contralateral, ipsilateral, and bilateral CMAc neurons were distributed homogeneously, whereas SMA neurons exhibiting identical hand preferences tended to cluster. These findings indicate that the CMAc, which is functionally organized in a less structured manner than the SMA is, controls contralateral and ipsilateral hand movements in a counterbalanced fashion, whereas the SMA, which is more structured, preferentially controls contralateral hand movements. PMID- 25717164 TI - Brain-mediated antidiabetic, anorexic, and cardiovascular actions of leptin require melanocortin-4 receptor signaling. AB - We previously demonstrated that leptin has powerful central nervous system (CNS) mediated antidiabetic actions. In this study we tested the importance of melanocortin-4 receptors (MC4Rs) for leptin's ability to suppress food intake, increase blood pressure (BP) and heart rate (HR), and normalize glucose levels in insulin-dependent diabetes. MC4R knockout (MC4R-KO) and control wild-type (WT) rats were implanted with intracerebroventricular (ICV) cannula and BP and HR were measured 24 h/day by telemetry. After 5-day control period, an injection of streptozotocin (50 mg/kg, ip) was used to induce diabetes. Eight days after injection, an osmotic pump was implanted subcutaneously and connected to the ICV cannula to deliver leptin (15 MUg/day) for 7 days. At baseline, MC4R-KO rats were hyperphagic and 40% heavier than WT rats. Despite obesity, BP was similar (112 +/ 2 vs. 111 +/- 2 mmHg) and HR was lower in MC4R-KO rats (320 +/- 6 vs. 347 +/- 5 beats/min). Induction of diabetes increased food intake (30%) and reduced BP (~17 mmHg) and HR (~61 beats/min) in WT rats, while food intake, BP, and HR were reduced by ~10%, 7 mmHg, and 33 beats/min, respectively, in MC4R-KO rats. Leptin treatment normalized blood glucose (437 +/- 10 to 136 +/- 18 mg/dl), reduced food intake (40%), and increased HR (+60 beats/min) and BP (+9 mmHg) in WT rats. Only modest changes in blood glucose (367 +/- 16 to 326 +/- 23 mg/dl), food intake (5%), HR (+16 beats/min) and BP (+4 mmHg) were observed in MC4R-KO rats. These results indicate that intact CNS MC4R signaling is necessary for leptin to exert its chronic antidiabetic, anorexic, and cardiovascular actions. PMID- 25717165 TI - Hand placement near the visual stimulus improves orientation selectivity in V2 neurons. AB - Often, the brain receives more sensory input than it can process simultaneously. Spatial attention helps overcome this limitation by preferentially processing input from a behaviorally-relevant location. Recent neuropsychological and psychophysical studies suggest that attention is deployed to near-hand space much like how the oculomotor system can deploy attention to an upcoming gaze position. Here we provide the first neuronal evidence that the presence of a nearby hand enhances orientation selectivity in early visual processing area V2. When the hand was placed outside the receptive field, responses to the preferred orientation were significantly enhanced without a corresponding significant increase at the orthogonal orientation. Consequently, there was also a significant sharpening of orientation tuning. In addition, the presence of the hand reduced neuronal response variability. These results indicate that attention is automatically deployed to the space around a hand, improving orientation selectivity. Importantly, this appears to be optimal for motor control of the hand, as opposed to oculomotor mechanisms which enhance responses without sharpening orientation selectivity. Effector-based mechanisms for visual enhancement thus support not only the spatiotemporal dissociation of gaze and reach, but also the optimization of vision for their separate requirements for guiding movements. PMID- 25717166 TI - Differential Purkinje cell simple spike activity and pausing behavior related to cerebellar modules. AB - The massive computational capacity of the cerebellar cortex is conveyed by Purkinje cells onto cerebellar and vestibular nuclei neurons through their GABAergic, inhibitory output. This implies that pauses in Purkinje cell simple spike activity are potentially instrumental in cerebellar information processing, but their occurrence and extent are still heavily debated. The cerebellar cortex, although often treated as such, is not homogeneous. Cerebellar modules with distinct anatomical connectivity and gene expression have been described, and Purkinje cells in these modules also differ in firing rate of simple and complex spikes. In this study we systematically correlate, in awake mice, the pausing in simple spike activity of Purkinje cells recorded throughout the entire cerebellum, with their location in terms of lobule, transverse zone, and zebrin identified cerebellar module. A subset of Purkinje cells displayed long (>500-ms) pauses, but we found that their occurrence correlated with tissue damage and lower temperature. In contrast to long pauses, short pauses (<500 ms) and the shape of the interspike interval (ISI) distributions can differ between Purkinje cells of different lobules and cerebellar modules. In fact, the ISI distributions can differ both between and within populations of Purkinje cells with the same zebrin identity, and these differences are at least in part caused by differential synaptic inputs. Our results suggest that long pauses are rare but that there are differences related to shorter intersimple spike intervals between and within specific subsets of Purkinje cells, indicating a potential further segregation in the activity of cerebellar Purkinje cells. PMID- 25717167 TI - The kinematics of far-near re-fixation saccades. AB - We have analyzed the three-dimensional spatiotemporal characteristics of saccadic refixations between far and near targets in three behaviorally trained rhesus monkeys. The kinematics underlying these rapid eye movements can be accurately described by rotations of the eyes in four different planes, namely, first disconjugate rotations in the horizontal plane of regard converging the eyes toward the near target, followed by rotations in each eye's vertical direction plane, and finally, disconjugate rotations in a common frontoparallel plane. This compounded rotation of the eye was underlying an initially fast-rising variable torsion that typically overshot the final torsion, which the eyes attained at the time of target acquisition. The torsion consisted of a coarse, widely varying component of opposite polarity in the two eyes, which contained a more robust, much smaller modulation that sharply increased toward the end of saccades. The reorientation of the eyes in torsion depended on each eye's azimuth, elevation, and target distance. We conclude that refixation saccades are generated by motor commands that control ocular torsion in concert with the saccade generator, which operates in Donders-Listing kinematics underlying Listing's law. PMID- 25717168 TI - Inhibition during response preparation is sensitive to response complexity. AB - Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors. PMID- 25717169 TI - A surprising range of modified-methionyl S-adenosylmethionine analogues support bacterial growth. AB - S-Adenosyl-l-methionine (AdoMet) is an essential metabolite, serving in a very wide variety of metabolic reactions. The enzyme that produces AdoMet from l methionine and ATP (methionine adenosyltransferase, MAT) is thus an attractive target for antimicrobial agents. We previously showed that a variety of methionine analogues are MAT substrates, yielding AdoMet analogues that function in specific methyltransfer reactions. However, this left open the question of whether the modified AdoMet molecules could support bacterial growth, meaning that they functioned in the full range of essential AdoMet-dependent reactions. The answer matters both for insight into the functional flexibility of key metabolic enzymes, and for drug design strategies for both MAT inhibitors and selectively toxic MAT substrates. In this study, methionine analogues were converted in vitro into AdoMet analogues, and tested with an Escherichia coli strain lacking MAT (DeltametK) but that produces a heterologous AdoMet transporter. Growth that yields viable, morphologically normal cells provides exceptionally robust evidence that the analogue functions in every essential reaction in which AdoMet participates. Overall, the S-adenosylated derivatives of all tested l-methionine analogues modified at the carboxyl moiety, and some others as well, showed in vivo functionality sufficient to allow good growth in both rich and minimal media, with high viability and morphological normality. As the analogues were chosen based on incompatibility with the reactions via which AdoMet is used to produce acylhomoserine lactones (AHLs) for quorum sensing, these results support the possibility of using this route to selectively interfere with AHL biosynthesis without inhibiting bacterial growth. PMID- 25717170 TI - Late morbidity and mortality in patients with Hodgkin's lymphoma treated during adulthood. AB - BACKGROUND: Survivors of Hodgkin's lymphoma (HL) treated as adults are at risk for late effects of therapy. However, the burden of late morbidity and mortality among adults treated for HL remains incompletely characterized. METHODS: Vital status and, for deceased, cause of death were determined for 746 adults treated on a first-line trial at a single center from 1975 to 2000. Survivors completed a detailed survey describing their physical and mental health. A severity score (grades 1-4, ranging from mild to life-threatening or disabling) was assigned to self-reported conditions. RESULTS: At a median follow-up of 22 years, 227 of patients (30.4%) had died, 107 (47.1%) from HL, 120 (52.9%) from other causes, including second primary malignancies (SPMs) (n = 52) and cardiovascular disease (n = 27). Across the duration of follow-up, all-cause and SPM-specific risk of death remained higher than predicted by normative data. Among survivors, late morbidity survey data are available for 238 patients (45.9%). Ninety-four-point one percent of respondents reported at least one morbidity, and 47.5% reported at least one grade 3 or 4 morbidity; 20.2% reported two or more grade 3 morbidities. Commonly reported morbidities included cardiovascular (54.6%), endocrine (68.5%), pulmonary disease (21.4%), and nonfatal second malignancy (23.1%). Anxiety, depression, and fear of recurrence were frequently reported. CONCLUSIONS: Among a large cohort of patients treated for HL with extensive follow-up, risk of late mortality from causes other than HL and prevalence of late medical morbidity are high. Guidelines for prevention, screening, and management of late effects in adult survivors of HL are needed. PMID- 25717171 TI - RE: How many etiological subtypes of breast cancer: two, three, four, or more? PMID- 25717172 TI - Response. PMID- 25717173 TI - RE: How many etiological subtypes of breast cancer: two, three, four, or more? PMID- 25717175 TI - Can a vascular smooth muscle-derived foam-cell really change its spots? PMID- 25717174 TI - Atherosclerosis. PMID- 25717176 TI - Genome editing of a CArG element in the mouse genome establishes its role in gene expression. PMID- 25717177 TI - A critical role of platelet glycoprotein Ibalpha in arterial remodeling. PMID- 25717179 TI - Correction. PMID- 25717178 TI - Clinical experience with the new oral anticoagulants for treatment of venous thromboembolism. AB - Four non-vitamin K antagonist oral anticoagulants, apixaban, dabigatran, edoxaban, and rivaroxaban, have been evaluated in phase III clinical trials for the treatment of acute venous thromboembolism, and all except edoxaban have also been studied for extended secondary prophylaxis after venous thromboembolism. Rivaroxaban, and recently also dabigatran, has been approved for this indication, and it is therefore timely to review the characteristics, efficacy, and safety of these drugs with emphasis on patients with venous thromboembolism. This review focuses on the clinical results from the phase III trials, separately for each of the drugs as compared with vitamin K antagonists. We also address the results from meta-analyses that were published recently. Finally, the results in some special groups of interest-renal impairment, elderly patients, and patients with cancer-are reviewed, although they only comprised small minorities of the study populations. All 4 drugs demonstrated noninferiority against vitamin K antagonists in the acute treatment and clear superiority against placebo in the extended treatment (not performed with edoxaban). The risk of bleeding was generally lower with non-vitamin K antagonist oral anticoagulants, and the reduction of risk of intracranial hemorrhage seems to mirror the experience from atrial fibrillation trials. In conclusion, during the past 30 years we have moved from a week of hospitalization and intravenous heparin therapy, via low-molecular weight heparin injections subcutaneously and early discharge from the hospital, to the possibility of only oral outpatient therapy without coagulation monitoring, yet safe for patients with acute venous thromboembolism. PMID- 25717180 TI - Correction. PMID- 25717181 TI - UNC-87 isoforms, Caenorhabditis elegans calponin-related proteins, interact with both actin and myosin and regulate actomyosin contractility. AB - Calponin-related proteins are widely distributed among eukaryotes and involved in signaling and cytoskeletal regulation. Calponin-like (CLIK) repeat is an actin binding motif found in the C-termini of vertebrate calponins. Although CLIK repeats stabilize actin filaments, other functions of these actin-binding motifs are unknown. The Caenorhabditis elegans unc-87 gene encodes actin-binding proteins with seven CLIK repeats. UNC-87 stabilizes actin filaments and is essential for maintenance of sarcomeric actin filaments in striated muscle. Here we show that two UNC-87 isoforms, UNC-87A and UNC-87B, are expressed in muscle and nonmuscle cells in a tissue-specific manner by two independent promoters and exhibit quantitatively different effects on both actin and myosin. Both UNC-87A and UNC-87B have seven CLIK repeats, but UNC-87A has an extra N-terminal extension of ~190 amino acids. Both UNC-87 isoforms bind to actin filaments and myosin to induce ATP-resistant actomyosin bundles and inhibit actomyosin motility. UNC-87A with an N-terminal extension binds to actin and myosin more strongly than UNC-87B. UNC-87B is associated with actin filaments in nonstriated muscle in the somatic gonad, and an unc-87 mutation causes its excessive contraction, which is dependent on myosin. These results strongly suggest that proteins with CLIK repeats function as a negative regulator of actomyosin contractility. PMID- 25717182 TI - Modulation of phosphatidylinositol 4-phosphate levels by CaBP7 controls cytokinesis in mammalian cells. AB - Calcium and phosphoinositide signaling regulate cell division in model systems, but their significance in mammalian cells is unclear. Calcium-binding protein-7 (CaBP7) is a phosphatidylinositol 4-kinaseIIIbeta (PI4KIIIbeta) inhibitor required during cytokinesis in mammalian cells, hinting at a link between these pathways. Here we characterize a novel association of CaBP7 with lysosomes that cluster at the intercellular bridge during cytokinesis in HeLa cells. We show that CaBP7 regulates lysosome clustering and that PI4KIIIbeta is essential for normal cytokinesis. CaBP7 depletion induces lysosome mislocalization, extension of intercellular bridge lifetime, and cytokinesis failure. These data connect phosphoinositide and calcium pathways to lysosome localization and normal cytokinesis in mammalian cells. PMID- 25717183 TI - Crucial role for the LSP1-myosin1e bimolecular complex in the regulation of Fcgamma receptor-driven phagocytosis. AB - Actin cytoskeleton remodeling is fundamental for Fcgamma receptor-driven phagocytosis. In this study, we find that the leukocyte-specific protein 1 (LSP1) localizes to nascent phagocytic cups during Fcgamma receptor-mediated phagocytosis, where it displays the same spatial and temporal distribution as the actin cytoskeleton. Down-regulation of LSP1 severely reduces the phagocytic activity of macrophages, clearly demonstrating a crucial role for this protein in Fcgamma receptor-mediated phagocytosis. We also find that LSP1 binds to the class I molecular motor myosin1e. LSP1 interacts with the SH3 domain of myosin1e, and the localization and dynamics of both proteins in nascent phagocytic cups mirror those of actin. Furthermore, inhibition of LSP1-myosin1e and LSP1-actin interactions profoundly impairs pseudopodial formation around opsonized targets and their subsequent internalization. Thus the LSP1-myosin1e bimolecular complex plays a pivotal role in the regulation of actin cytoskeleton remodeling during Fcgamma receptor-driven phagocytosis. PMID- 25717184 TI - Dynamic actin filaments control the mechanical behavior of the human red blood cell membrane. AB - Short, uniform-length actin filaments function as structural nodes in the spectrin-actin membrane skeleton to optimize the biomechanical properties of red blood cells (RBCs). Despite the widespread assumption that RBC actin filaments are not dynamic (i.e., do not exchange subunits with G-actin in the cytosol), this assumption has never been rigorously tested. Here we show that a subpopulation of human RBC actin filaments is indeed dynamic, based on rhodamine actin incorporation into filaments in resealed ghosts and fluorescence recovery after photobleaching (FRAP) analysis of actin filament mobility in intact RBCs (~25-30% of total filaments). Cytochalasin-D inhibition of barbed-end exchange reduces rhodamine-actin incorporation and partially attenuates FRAP recovery, indicating functional interaction between actin subunit turnover at the single filament level and mobility at the membrane-skeleton level. Moreover, perturbation of RBC actin filament assembly/disassembly with latrunculin-A or jasplakinolide induces an approximately twofold increase or ~60% decrease, respectively, in soluble actin, resulting in altered membrane deformability, as determined by alterations in RBC transit time in a microfluidic channel assay, as well as by abnormalities in spontaneous membrane oscillations (flickering). These experiments identify a heretofore-unrecognized but functionally important subpopulation of RBC actin filaments, whose properties and architecture directly control the biomechanical properties of the RBC membrane. PMID- 25717185 TI - Ultrafast superresolution fluorescence imaging with spinning disk confocal microscope optics. AB - Most current superresolution (SR) microscope techniques surpass the diffraction limit at the expense of temporal resolution, compromising their applications to live-cell imaging. Here we describe a new SR fluorescence microscope based on confocal microscope optics, which we name the spinning disk superresolution microscope (SDSRM). Theoretically, the SDSRM is equivalent to a structured illumination microscope (SIM) and achieves a spatial resolution of 120 nm, double that of the diffraction limit of wide-field fluorescence microscopy. However, the SDSRM is 10 times faster than a conventional SIM because SR signals are recovered by optical demodulation through the stripe pattern of the disk. Therefore a single SR image requires only a single averaged image through the rotating disk. On the basis of this theory, we modified a commercial spinning disk confocal microscope. The improved resolution around 120 nm was confirmed with biological samples. The rapid dynamics of micro-tubules, mitochondria, lysosomes, and endosomes were observed with temporal resolutions of 30-100 frames/s. Because our method requires only small optical modifications, it will enable an easy upgrade from an existing spinning disk confocal to a SR microscope for live-cell imaging. PMID- 25717186 TI - The CD20 homologue MS4A4 directs trafficking of KIT toward clathrin-independent endocytosis pathways and thus regulates receptor signaling and recycling. AB - MS4A family members differentially regulate the cell cycle, and aberrant, or loss of, expression of MS4A family proteins has been observed in colon and lung cancer. However, the precise functions of MS4A family proteins and their mechanistic interactions remain unsolved. Here we report that MS4A4 facilitates trafficking of the receptor tyrosine kinase KIT through endocytic recycling rather than degradation pathways by a mechanism that involves recruitment of KIT to caveolin-1-enriched microdomains. Silencing of MS4A4 in human mast cells altered ligand-induced KIT endocytosis pathways and reduced receptor recycling to the cell surface, thus promoting KIT signaling in the endosomes while reducing that in the plasma membrane, as exemplified by Akt and PLCgamma1 phosphorylation, respectively. The altered endocytic trafficking of KIT also resulted in an increase in SCF-induced mast cell proliferation and migration, which may reflect altered signaling in these cells. Our data reveal a novel function for MS4A family proteins in regulating trafficking and signaling, which could have implications in both proliferative and immunological diseases. PMID- 25717187 TI - Microtubule-dependent transport and dynamics of vimentin intermediate filaments. AB - We studied two aspects of vimentin intermediate filament dynamics-transport of filaments and subunit exchange. We observed transport of long filaments in the periphery of cells using live-cell structured illumination microscopy. We studied filament transport elsewhere in cells using a photoconvertible-vimentin probe and total internal reflection microscopy. We found that filaments were rapidly transported along linear tracks in both anterograde and retrograde directions. Filament transport was microtubule dependent but independent of microtubule polymerization and/or an interaction with the plus end-binding protein APC. We also studied subunit exchange in filaments by long-term imaging after photoconversion. We found that converted vimentin remained in small clusters along the length of filaments rather than redistributing uniformly throughout the network, even in cells that divided after photoconversion. These data show that vimentin filaments do not depolymerize into individual subunits; they recompose by severing and reannealing. Together these results show that vimentin filaments are very dynamic and that their transport is required for network maintenance. PMID- 25717188 TI - Musashi-1 maintains blood-testis barrier structure during spermatogenesis and regulates stress granule formation upon heat stress. AB - In mouse testes, Musashi-1 (Msi-1) was predominantly expressed in the cytoplasm and nuclei of Sertoli cells. Here we demonstrate that knockdown of Msi-1 in Sertoli cells altered the levels and distribution of blood-testis barrier (BTB) associated proteins. Moreover, Msi-1 knockdown in vivo disrupted BTB functional structure and spermatogenesis. In addition, we report a novel role of Msi-1 in regulating Sertoli cells survival following heat-induced injury. Endogenous Msi-1 protein in heat-treated Sertoli cells was recruited to stress granules. The formation of stress granules was considerably disrupted, and apoptosis was significantly up-regulated in Msi-1-knockdown Sertoli cells after heat treatment. p-ERK1/2 acted downstream of stress granule formation, and inhibition of p-ERK1/2 signaling triggered Sertoli cell apoptosis upon heat stress. In conclusion, we demonstrate that Msi-1 is critical for constructing a functional BTB structure and maintaining spermatogenesis. We also note a role for Msi-1 in regulating Sertoli cell fate following heat-induced injury, likely through the induction of stress granule formation and subsequent activation of p-ERK1/2 signaling. PMID- 25717189 TI - rSeqNP: a non-parametric approach for detecting differential expression and splicing from RNA-Seq data. AB - High-throughput sequencing of transcriptomes (RNA-Seq) has become a powerful tool to study gene expression. Here we present an R package, rSeqNP, which implements a non-parametric approach to test for differential expression and splicing from RNA-Seq data. rSeqNP uses permutation tests to access statistical significance and can be applied to a variety of experimental designs. By combining information across isoforms, rSeqNP is able to detect more differentially expressed or spliced genes from RNA-Seq data. AVAILABILITY AND IMPLEMENTATION: The R package with its source code and documentation are freely available at http://www personal.umich.edu/~jianghui/rseqnp/. CONTACT: jianghui@umich.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717190 TI - Detection of significant protein coevolution. AB - MOTIVATION: The evolution of proteins cannot be fully understood without taking into account the coevolutionary linkages entangling them. From a practical point of view, coevolution between protein families has been used as a way of detecting protein interactions and functional relationships from genomic information. The most common approach to inferring protein coevolution involves the quantification of phylogenetic tree similarity using a family of methodologies termed mirrortree. In spite of their success, a fundamental problem of these approaches is the lack of an adequate statistical framework to assess the significance of a given coevolutionary score (tree similarity). As a consequence, a number of ad hoc filters and arbitrary thresholds are required in an attempt to obtain a final set of confident coevolutionary signals. RESULTS: In this work, we developed a method for associating confidence estimators (P values) to the tree-similarity scores, using a null model specifically designed for the tree comparison problem. We show how this approach largely improves the quality and coverage (number of pairs that can be evaluated) of the detected coevolution in all the stages of the mirrortree workflow, independently of the starting genomic information. This not only leads to a better understanding of protein coevolution and its biological implications, but also to obtain a highly reliable and comprehensive network of predicted interactions, as well as information on the substructure of macromolecular complexes using only genomic information. AVAILABILITY AND IMPLEMENTATION: The software and datasets used in this work are freely available at: http://csbg.cnb.csic.es/pMT/. CONTACT: pazos@cnb.csic.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717191 TI - GeNOSA: inferring and experimentally supporting quantitative gene regulatory networks in prokaryotes. AB - MOTIVATION: The establishment of quantitative gene regulatory networks (qGRNs) through existing network component analysis (NCA) approaches suffers from shortcomings such as usage limitations of problem constraints and the instability of inferred qGRNs. The proposed GeNOSA framework uses a global optimization algorithm (OptNCA) to cope with the stringent limitations of NCA approaches in large-scale qGRNs. RESULTS: OptNCA performs well against existing NCA-derived algorithms in terms of utilization of connectivity information and reconstruction accuracy of inferred GRNs using synthetic and real Escherichia coli datasets. For comparisons with other non-NCA-derived algorithms, OptNCA without using known qualitative regulations is also evaluated in terms of qualitative assessments using a synthetic Saccharomyces cerevisiae dataset of the DREAM3 challenges. We successfully demonstrate GeNOSA in several applications including deducing condition-dependent regulations, establishing high-consensus qGRNs and validating a sub-network experimentally for dose-response and time-course microarray data, and discovering and experimentally confirming a novel regulation of CRP on AscG. AVAILABILITY AND IMPLEMENTATION: All datasets and the GeNOSA framework are freely available from http://e045.life.nctu.edu.tw/GeNOSA. CONTACT: syho@mail.nctu.edu.tw SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717192 TI - Guidance for RNA-seq co-expression network construction and analysis: safety in numbers. AB - MOTIVATION: RNA-seq co-expression analysis is in its infancy and reasonable practices remain poorly defined. We assessed a variety of RNA-seq expression data to determine factors affecting functional connectivity and topology in co expression networks. RESULTS: We examine RNA-seq co-expression data generated from 1970 RNA-seq samples using a Guilt-By-Association framework, in which genes are assessed for the tendency of co-expression to reflect shared function. Minimal experimental criteria to obtain performance on par with microarrays were >20 samples with read depth >10 M per sample. While the aggregate network constructed shows good performance (area under the receiver operator characteristic curve ~0.71), the dependency on number of experiments used is nearly identical to that present in microarrays, suggesting thousands of samples are required to obtain 'gold-standard' co-expression. We find a major topological difference between RNA-seq and microarray co-expression in the form of low overlaps between hub-like genes from each network due to changes in the correlation of expression noise within each technology. CONTACT: jgillis@cshl.edu or sballouz@cshl.edu SUPPLEMENTARY INFORMATION: Networks are available at: http://gillislab.labsites.cshl.edu/supplements/rna-seq-networks/ and supplementary data are available at Bioinformatics online. PMID- 25717193 TI - Normalization and noise reduction for single cell RNA-seq experiments. AB - A major roadblock towards accurate interpretation of single cell RNA-seq data is large technical noise resulted from small amount of input materials. The existing methods mainly aim to find differentially expressed genes rather than directly de noise the single cell data. We present here a powerful but simple method to remove technical noise and explicitly compute the true gene expression levels based on spike-in ERCC molecules. AVAILABILITY AND IMPLEMENTATION: The software is implemented by R and the download version is available at http://wanglab.ucsd.edu/star/GRM. CONTACT: wei-wang@ucsd.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717194 TI - Fast, accurate, and reliable molecular docking with QuickVina 2. AB - MOTIVATION: The need for efficient molecular docking tools for high-throughput screening is growing alongside the rapid growth of drug-fragment databases. AutoDock Vina ('Vina') is a widely used docking tool with parallelization for speed. QuickVina ('QVina 1') then further enhanced the speed via a heuristics, requiring high exhaustiveness. With low exhaustiveness, its accuracy was compromised. We present in this article the latest version of QuickVina ('QVina 2') that inherits both the speed of QVina 1 and the reliability of the original Vina. RESULTS: We tested the efficacy of QVina 2 on the core set of PDBbind 2014. With the default exhaustiveness level of Vina (i.e. 8), a maximum of 20.49-fold and an average of 2.30-fold acceleration with a correlation coefficient of 0.967 for the first mode and 0.911 for the sum of all modes were attained over the original Vina. A tendency for higher acceleration with increased number of rotatable bonds as the design variables was observed. On the accuracy, Vina wins over QVina 2 on 30% of the data with average energy difference of only 0.58 kcal/mol. On the same dataset, GOLD produced RMSD smaller than 2 A on 56.9% of the data while QVina 2 attained 63.1%. AVAILABILITY AND IMPLEMENTATION: The C++ source code of QVina 2 is available at (www.qvina.org). CONTACT: aalhossary@pmail.ntu.edu.sg SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717195 TI - An event-driven approach for studying gene block evolution in bacteria. AB - MOTIVATION: Gene blocks are genes co-located on the chromosome. In many cases, gene blocks are conserved between bacterial species, sometimes as operons, when genes are co-transcribed. The conservation is rarely absolute: gene loss, gain, duplication, block splitting and block fusion are frequently observed. An open question in bacterial molecular evolution is that of the formation and breakup of gene blocks, for which several models have been proposed. These models, however, are not generally applicable to all types of gene blocks, and consequently cannot be used to broadly compare and study gene block evolution. To address this problem, we introduce an event-based method for tracking gene block evolution in bacteria. RESULTS: We show here that the evolution of gene blocks in proteobacteria can be described by a small set of events. Those include the insertion of genes into, or the splitting of genes out of a gene block, gene loss, and gene duplication. We show how the event-based method of gene block evolution allows us to determine the evolutionary rateand may be used to trace the ancestral states of their formation. We conclude that the event-based method can be used to help us understand the formation of these important bacterial genomic structures. AVAILABILITY AND IMPLEMENTATION: The software is available under GPLv3 license on http://github.com/reamdc1/gene_block_evolution.git. Supplementary online material: http://iddo-friedberg.net/operon-evolution PMID- 25717196 TI - Automated benchmarking of peptide-MHC class I binding predictions. AB - MOTIVATION: Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non trivial for the end-user to select which tool to use for a given task. To provide a solid basis on which to compare different prediction tools, we here describe a framework for the automated benchmarking of peptide-MHC class I binding prediction tools. The framework runs weekly benchmarks on data that are newly entered into the Immune Epitope Database (IEDB), giving the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding capability. Upon experimental binding validation, these peptides entered the benchmark study. RESULTS: The benchmark has run for 15 weeks and includes evaluation of 44 datasets covering 17 MHC alleles and more than 4000 peptide-MHC binding measurements. Inspection of the results allows the end-user to make educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. AVAILABILITY AND IMPLEMENTATION: Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto_bench/mhci/weekly. All prediction tool developers are invited to participate in the benchmark. Sign-up instructions are available at http://tools.iedb.org/auto_bench/mhci/join. CONTACT: mniel@cbs.dtu.dk or bpeters@liai.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717197 TI - RepExplore: addressing technical replicate variance in proteomics and metabolomics data analysis. AB - High-throughput omics datasets often contain technical replicates included to account for technical sources of noise in the measurement process. Although summarizing these replicate measurements by using robust averages may help to reduce the influence of noise on downstream data analysis, the information on the variance across the replicate measurements is lost in the averaging process and therefore typically disregarded in subsequent statistical analyses.We introduce RepExplore, a web-service dedicated to exploit the information captured in the technical replicate variance to provide more reliable and informative differential expression and abundance statistics for omics datasets. The software builds on previously published statistical methods, which have been applied successfully to biomedical omics data but are difficult to use without prior experience in programming or scripting. RepExplore facilitates the analysis by providing a fully automated data processing and interactive ranking tables, whisker plot, heat map and principal component analysis visualizations to interpret omics data and derived statistics. AVAILABILITY AND IMPLEMENTATION: Freely available at http://www.repexplore.tk CONTACT: enrico.glaab@uni.lu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25717198 TI - A new method to improve network topological similarity search: applied to fold recognition. AB - MOTIVATION: Similarity search is the foundation of bioinformatics. It plays a key role in establishing structural, functional and evolutionary relationships between biological sequences. Although the power of the similarity search has increased steadily in recent years, a high percentage of sequences remain uncharacterized in the protein universe. Thus, new similarity search strategies are needed to efficiently and reliably infer the structure and function of new sequences. The existing paradigm for studying protein sequence, structure, function and evolution has been established based on the assumption that the protein universe is discrete and hierarchical. Cumulative evidence suggests that the protein universe is continuous. As a result, conventional sequence homology search methods may be not able to detect novel structural, functional and evolutionary relationships between proteins from weak and noisy sequence signals. To overcome the limitations in existing similarity search methods, we propose a new algorithmic framework-Enrichment of Network Topological Similarity (ENTS)-to improve the performance of large scale similarity searches in bioinformatics. RESULTS: We apply ENTS to a challenging unsolved problem: protein fold recognition. Our rigorous benchmark studies demonstrate that ENTS considerably outperforms state-of-the-art methods. As the concept of ENTS can be applied to any similarity metric, it may provide a general framework for similarity search on any set of biological entities, given their representation as a network. AVAILABILITY AND IMPLEMENTATION: Source code freely available upon request CONTACT: : lxie@iscb.org. PMID- 25717200 TI - Inpatient and outpatient pharmacy monitoring of oral antineoplastic medications. PMID- 25717199 TI - Morality, Intentionality, and Intergroup Attitudes. AB - Morality is at the core of what it means to be social. Moral judgments require the recognition of intentionality, that is, an attribution of the target's intentions towards another. Most research on the origins of morality has focused on intragroup morality, which involves applying morality to individuals in one's own group. Yet, increasingly, there has been new evidence that beginning early in development, children are able to apply moral concepts to members of an outgroup as well, and that this ability appears to be complex. The challenges associated with applying moral judgments to members of outgroups includes understanding group dynamics, the intentions of others who are different from the self, and having the capacity to challenge stereotypic expectations of others who are different from the ingroup. Research with children provides a window into the complexities of moral judgment and raises new questions, which are ripe for investigations into the evolutionary basis of morality. PMID- 25717201 TI - Normal saline storage practices. PMID- 25717202 TI - Let's Target This "Dirty Dozen" for Improvement During 2015; Caution: "Per Liter" Content on Manufacturers' IV Bag Labels. AB - These medication errors have occurred in health care facilities at least once. They will happen again-perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site (www.ismp.org), by calling 800-FAIL-SAFE, or via e mail at ismpinfo@ismp.org. ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications. PMID- 25717203 TI - Pemetrexed long-term maintenance treatment leading to multiple finger amputation; cardiovascular complications after energy drink consumption; compartment syndrome due to extravasation of intravenous contrast; blue-gray mucocutaneous discoloration with ezogabine. AB - The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's Med Watch program and Temple University School of Pharmacy. ISMP is an FDA Med Watch partner. PMID- 25717204 TI - Gemcitabine and Carboplatin (renally dosed) regimen for bladder cancer. AB - The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID- 25717205 TI - The role of subcutaneous ketorolac for pain management. AB - This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu. PMID- 25717206 TI - Optimizing smart pump technology by increasing critical safety alerts and reducing clinically insignificant alerts. AB - BACKGROUND: Alerts generated by intravenous (IV) infusion pump safety software prevent life-threatening situations that might otherwise go unnoticed. However, when alerts are often clinically insignificant, health care workers may become desensitized and discount their importance, resulting in potentially dangerous situations. Little research has been devoted to visual alert desensitization. METHOD: This paper describes how the Carolinas HealthCare System decreased the number of nonclinically relevant infusion pump alerts by analyzing alert data that were formatted into scatter plots. This in turn enabled the identification of the medications associated with the most meaningful alerts and those associated with the least meaningful alerts. CONCLUSION: By revising drug library limits for specific medications, it was possible to decrease the number of less clinically meaningful alerts, reduce alert fatigue, and thereby increase the effectiveness of the smart infusion pumps. This added another layer of safety to patient care. PMID- 25717207 TI - Near-miss transcription errors: a comparison of reporting rates between a novel error-reporting mechanism and a current formal reporting system. AB - PURPOSE: The medication use process comprises several steps. In institutions without full implementation of computerized prescriber order entry (CPOE), transcription is a critical step in this process. As focus is increasingly placed on identifying near-miss errors, this study aimed to compare near-miss transcription error (NMTE) reporting rates between an institution's formal reporting system and an NMTE reporting mechanism. METHODS: Two NMTE reporting mechanisms were assessed for 3 months. These mechanisms included the institution's formal error-reporting system and a specific transcription error queue within the institution's order imaging software. Date, patient-care unit, and type of transcription error were recorded for each order image in the transcription error queue and for each transcription error reported formally. Following data collection, reporting rates for both systems were compared. RESULTS: Data collection spanned 92 days and an estimated 460,000 medication orders. In total, 1,563 NMTEs were reported using the transcription error queue and 12 errors were reported via the formal reporting mechanism. Of the 1,563 errors identified via the transcription error queue, 325 (20.79%) were of an unknown type. Reporting rates (with unknown errors removed) were 0.27% and 0.0026% for the novel system and formal reporting system, respectively (P < .001). CONCLUSION: Significantly more NMTEs were reported utilizing the novel system compared with the formal reporting system. PMID- 25717208 TI - Application and interview features used to assess applicant qualifications for residency training. AB - PURPOSE: To determine what factors residency program directors (RPDs) consider and what methods they use to assess applicants. METHODS: Respondents ranked the importance of 27 applicant features within domains: academics/credentials, application features/program fit, involvement, professional experience, research/ teaching experience, and postgraduate year 1 (PGY-1) residency experience. Rank was assigned in an ordinal fashion (1 = most important feature). The domains were characterized by their importance (mean % +/- SD) in selecting candidates for interviews. Participants characterized their screening process according to 8 application and 6 interview features and the corresponding applicant dimensions evaluated. RPDs rated the importance of 14 methods applicants used to communicate with the program and 3 methods by which references were obtained. A Likert scale was used for rating (4 = crucial features). The approaches the program used to evaluate 12 application features or interpersonal interactions were reported. RESULTS: The most important application domain was application features/program fit (26.28 +/- 19.11). The highest ranked application feature was program fit (2.04 +/- 1.17). The applicant's cover letter, recommendation letters, curriculum vitae, and interview meal were commonly used to assess communication and interpersonal skills, knowledge base, and experience. The most important communication venue was the on-site interview (3.95 +/- 0.23). Recommendations solicited by RPDs (3.42 +/- 0.69) were most important. Programs formally evaluated the interview (89%) and recommendation letters (84%). CONCLUSION: Understanding the importance that RPDs place on application and interview features, as well as the process used to assess communication skills and interpersonal interactions, should allow residency candidates to become more competitive residency prospects. PMID- 25717209 TI - Implementation of a 24-hour pharmacy service with prospective medication review in the emergency department. AB - BACKGROUND: It is reported that more than 128 million patients are seen in emergency departments (EDs) annually. Patient overcrowding had been associated with an increased occurrence of medication errors. PURPOSE: Due to increased patient volume and the need for improved patient safety, a 24-hour pharmacy service was established for our institution's ED. The purpose of the study is to quantify and demonstrate the impact of a 24-hour pharmacy service in an urban ED. METHODS: This was a retrospective descriptive study conducted at a regional level 1 trauma center. The study period occurred between December 2012 and July 2013. The following variables were quantified and analyzed: number of medication orders reviewed, number of intravenous medications compounded, and number of clinical interventions that were recommended by the ED pharmacy team (EDPT) and accepted by ED clinicians. RESULTS: A total of 3,779 medication orders were reviewed by the EDPT. Of these orders, 3,482 (92%) were prospectively reviewed. A total of 3,068 (81.2%) and 711 (18.8%) orders were reviewed for the adult and pediatric ED, respectively. During the study period, the EDPT procured 549 intravenous admixtures and conducted 642 clinical interventions. Most of the interventions involved providing drug information for physicians and nurses (45.9%), adjusting drug dosages (21.1%), and recommending antimicrobial therapy (15.1%). CONCLUSION: The implementation of a 24-hour pharmacy service at our institution was an innovative practice that increased the role of pharmacists in the ED. The EDPT conducted prospective medication review, procured intravenous admixtures from a sterile environment, and provided therapeutic recommendations for the ED interdisciplinary team. PMID- 25717210 TI - Ferric citrate. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The February 2015 monograph topics are netupitant/palonosetron, naltrxone SR/bupropion SR, nintedanib, pirfenidone, and ivabradine. The Safety MUE is on netupitant/palonosetron. PMID- 25717211 TI - Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals. AB - This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at danial.baker@wsu.edu. PMID- 25717212 TI - Issues facing pharmacy leaders in 2015: suggestions for pharmacy strategic planning. AB - Issues facing pharmacy leaders in 2015 include practice model growth and the role of pharmacy students, clinical privileging of health-system pharmacists and provider status, medication error prevention, and specialty pharmacy services. The goal of this article is to provide practical approaches to 4 issues facing pharmacy leaders in 2015 to help them focus their department's goals. This article will address (1) advances in the pharmacy practice model initiative and the role of pharmacy students, (2) the current thinking of pharmacists being granted clinical privileges in health systems, (3) updates on preventing harmful medication errors, and (4) the growth of specialty pharmacy services. The sample template of a strategic plan may be used by a pharmacy department in 2015 in an effort to continue developing patient-centered pharmacy services. PMID- 25717213 TI - Is it time for the customizable infobutton? AB - Infobuttons are intended to provide links to context-sensitive information in online resources to support clinical decision making. In this issue, we discuss challenges that impact the maximal effective use of Infobuttons. We also suggest methods to facilitate the role of Infobuttons as a tool to support optimal use of medications. PMID- 25717214 TI - Finite Mixtures for Simultaneously Modelling Differential Effects and Non-Normal Distributions. AB - Regression mixture models have been increasingly applied in the social and behavioral sciences as a method for identifying differential effects of predictors on outcomes. While the typical specification of this approach is sensitive to violations of distributional assumptions, alternative methods for capturing the number of differential effects have been shown to be robust. Yet, there is still a need to better describe differential effects that exist when using regression mixture models. The current study tests a new approach that uses sets of classes (called differential effects sets) to simultaneously model differential effects and account for non-normal error distributions. Monte Carlo simulations are used to examine the performance of the approach. The number of classes needed to represent departures from normality is shown to be dependent on the degree of skew. The use of differential effects sets reduced bias in parameter estimates. Applied analyses demonstrated the implementation of the approach for describing differential effects of parental health problems on adolescent body mass index using differential effects sets approach. Findings support the usefulness of the approach which overcomes the limitations of previous approaches for handling non-normal errors. PMID- 25717215 TI - NEONATAL VISUAL INFORMATION PROCESSING IN COCAINE-EXPOSED AND NON-EXPOSED INFANTS. AB - This study investigated early neonatal visual preferences in 267 poly drug exposed neonates (131 cocaine-exposed and 136 non-cocaine exposed) whose drug exposure was documented through interviews and urine and meconium drug screens. Infants were given four visual recognition memory tasks comparing looking time to familiarized stimuli of lattices and rectangular shapes to novel stimuli of a schematic face and curved hourglass and bull's eye forms. Cocaine-exposed infants performed more poorly, after consideration of confounding factors, with a relationship of severity of cocaine exposure to lower novelty score found for both self-report and biologic measures of exposure, Findings support theories which link prenatal cocaine exposure to deficits in information processing entailing attentional and arousal organizational systems. Neonatal visual discrimination and attention tasks should be further explored as potentially sensitive behavioral indicators of teratologic effects. PMID- 25717216 TI - Media and technology use predicts ill-being among children, preteens and teenagers independent of the negative health impacts of exercise and eating habits. AB - The American Academy of Pediatrics recommends no screen time for children under the age of 2 and limited screen time for all children. However, no such guidelines have been proposed for preteens and teenagers. Further, research shows that children, preteens, and teenagers are using massive amounts of media and those with more screen time have been shown to have increased obesity, reduced physical activity, and decreased health. This study examined the impact of technology on four areas of ill-being-psychological issues, behavior problems, attention problems and physical health-among children (aged 4-8), preteens (9 12), and teenagers (13-18) by having 1030 parents complete an online, anonymous survey about their own and their child's behaviors. Measures included daily technology use, daily food consumption, daily exercise, and health. Hypothesis 1, which posited that unhealthy eating would predict impaired ill-being, was partially supported, particularly for children and preteens. Hypothesis 2, which posited that reduced physical activity would predict diminished health levels, was partially supported for preteens and supported for teenagers. Hypothesis 3, that increased daily technology use would predict ill-being after factoring out eating habits and physical activity, was supported. For children and preteens, total media consumption predicted illbeing while for preteens specific technology uses, including video gaming and electronic communication, predicted ill-being. For teenagers, nearly every type of technological activity predicted poor health. Practical implications were discussed in terms of setting limits and boundaries on technology use and encouraging healthy eating and physical activity at home and at school. PMID- 25717217 TI - Effects of Web-Mediated Professional Development Resources on Teacher-Child Interactions in Pre-Kindergarten Classrooms. AB - As the workforce in state-funded pre-kindergarten programs continues to grow in the United States, the promise of these and other early education opportunities (e.g., Head Start) depends in large part on in-service professional development and training in key instructional and interaction skills. In this paper, we describe effects of MyTeachingPartner (MTP), a web-based system of professional development resources, that include video exemplars and web-mediated consultation on specific dimensions of interactions with children for 113 teachers in a state funded pre-k program. Teachers assigned to receive on-line consultation and feedback targeted to their interactions showed significantly greater increases in independent ratings of the quality of interactions than did those only receiving access to a website with video clips. The positive effects of consultation were particularly evident in classrooms with higher proportions of children who experienced economic risks. Implications of these findings for models of professional development and widespread needs for teacher access and support are discussed in relation to the effectiveness of early education. PMID- 25717218 TI - Variation in children's classroom engagement throughout a day in preschool: Relations to classroom and child factors. AB - This study examined sources of variability in preschool children's positive and negative engagement with teachers, peers, and tasks, and how that variability was related to both classroom activity settings (e.g., teacher-structured time, outdoor time, transitions) and child factors (age, gender). Participants were 283 socioeconomically and linguistically diverse children drawn from 84 classrooms, 34 to 63 months old (M = 50.8, SD = 6.5). Each child's engagement was observed and rated multiple times within a single day. Results suggested that children's engagement varied significantly across the preschool day. Activity settings that provided children with a greater degree of choice (free choice and outdoor time) were associated with more positive engagement with peers and tasks, while teacher structured activities were associated with more positive engagement with teachers. Transitions emerged as a difficult part of the day, associated with less positive engagement with teachers and tasks. Older children were rated higher on peer and task engagement. These findings, together with previous research, suggest that both characteristics of the classroom setting and child factors are associated with children's classroom engagement throughout a day in preschool. PMID- 25717219 TI - Cancer statistics: updated cancer burden in China. PMID- 25717220 TI - Annual report on status of cancer in China, 2011. AB - OBJECTIVE: The National Central Cancer Registry (NCCR) collected population-based cancer registration data in 2011 from all cancer registries. National cancer incidence and mortality were compiled and cancer incident new cases and cancer deaths were estimated. METHODS: In 2014, there were 234 cancer registries submitted cancer incidence and deaths occurred in 2011. All datasets were checked and evaluated based on the criteria of data quality from NCCR. Total 177 registries' data were qualified and compiled for cancer statistics in 2011. The pooled data were stratified by area (urban/rural), gender, age group (0, 1-4, 5 9, 10-14...85+) and cancer type. Cancer incident cases and deaths were estimated using age-specific rates and national population in 2011. All incidence and death rates are age-standardized to the 2000 Chinese standard population and Segi's population expressed per 100,000 persons. RESULTS: All 177 cancer registries (77 in urban and 100 in rural areas) covered 175,310,169 populations (98,341,507 in urban and 76,968,662 in rural areas). The morphology verified cases (MV%) accounting for 70.14% and 2.44% of incident cases were identified through death certifications only (DCO%) with mortality to incidence ratio of 0.63. The estimates of new cancer incident cases and cancer deaths were 3,372,175 and 2,113,048 in 2011, respectively. The incidence rate was 250.28/100,000 (males 277.77/100,000, females 221.37/100,000), and the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 186.34/100,000 and 182.76/100,000 with the cumulative incidence rate (0-74 years old) of 21.20%. The cancer incidence and ASIRC in urban areas were 261.38/100,000 and 189.89/100,000 compared to 238.60/100,000 and 182.10/100,000 in rural areas, respectively. The cancer mortality was 156.83/100,000 (194.88/100,000 in males and 116.81/100,000 in females), the age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 112.88/100,000 and 111.82/100,000, and the cumulative mortality rate (0-74 years old) was 12.69%. The cancer mortality and ASMRC were 154.37/100,000 and 108.20/100,000 in urban areas, and 159.42/100,000 and 117.97/100,000 in rural areas, respectively. Cancers of lung, female breast, stomach, liver, colon and rectum, esophageal, cervix, uterus, prostate and ovary were the most common cancers, accounting for about 75% of all cancer new cases. Lung cancer, liver cancer, stomach cancer, esophageal cancer, colorectal cancer, female breast cancer, pancreatic cancer, brain tumor, cervical cancer and leukemia were the leading causes of cancer death, accounting for about 80% of all cancer deaths. The cancer incidence, mortality and spectrum showed difference between urban and rural areas, males and females. CONCLUSIONS: The coverage of cancer registration population had a greater increase than that in the last year. The data quality and representativeness are gradually improved. As the basic work of cancer prevention and control, cancer registry is playing an irreplaceable role. The disease burden of cancer is increasing, and the health department has to take effective measures to contain the increased cancer burden in China. PMID- 25717221 TI - Population-based cancer incidence analysis in Beijing, 2008-2012. AB - OBJECTIVE: To analyze the incidence of cancer during 2008-2012 in Beijing, China, and compare the cancer spectrum with that during 1998-1999. METHODS: Data from the Beijing Cancer Registry (BCR), which covered 12 million residents and 16 administrative regions in Beijing, were checked and evaluated on basis of the criteria of data quality from the National Central Cancer Registry (NCCR) of China. Incidences were calculated stratified by cancer type, sex, areas (urban/rural), and age. The Chinese census population in 1982 and the world Segi's population were used for calculating the age-standardized incidences. RESULTS: A total of 177,101 new cancer cases were diagnosed in Beijing between 2008 and 2012. The crude incidence rate (CR) of all cancers was 282.64/100,000 (290.71/100,000 in males and 274.45/100,000 in females). The age-standardized rates by Chinese standard population (ASR-China) and by world standard population (ASR-world) were 124.46/100,000 and 161.18/100,000, respectively. Female breast cancer was the most common cancer, followed by lung cancer, colorectal cancer, liver cancer, and stomach cancer, with the CR of 59.87/100,000, 59.21/100,000, 32.49/100,000, 19.81/100,000 and 17.96/100,000, respectively. In urban areas, female breast cancer (68.50/100,000) was still the most common cancer, followed by lung cancer (61.23/100,000), colorectal cancer (37.23/100,000), prostate cancer (20.49/100,000) and stomach cancer (20.07/100,000). In rural areas, lung cancer (55.94/100,000) was the most common cancer, followed by female breast cancer (45.87/100,000), colorectal cancer (24.77/100,000), liver cancer (20.68/100,000) and stomach cancer (14.52/100,000). Great changes of the cancer spectrum were found from the period of 1998-1999 to the period of 2011-2012 in Beijing. CONCLUSIONS: The cancer burden in Beijing was heavier than the national average level. Cancer prevention and control strategies, especially for lung, colorectal, prostate and female thyroid cancers, should be enhanced. PMID- 25717222 TI - Incidence and mortality of colorectal cancer in China, 2011. AB - OBJECTIVE: Colorectal cancer is the third most common type of cancer and the fourth leading cause of cancer-related death in the world. This article provides the most up-to-date overview of colorectal cancer burden in China. METHODS: Totally 234 cancer registries submitted data of 2011 to the National Central Cancer Registry (NCCR). Qualified data from 177 registries was pooled and analyzed. The crude incidence and mortality rates of colorectal cancer were calculated by age, gender and geographic area. The numbers of new cases and deaths were estimated using the 5-year age-specific cancer incidence/mortality rates and the corresponding populations. China census in 2000 and Segi's world population were applied for age standardized rates. RESULTS: The estimate of new cases diagnosed with colorectal cancer of China in 2011 was 310,244 (178,404 for males and 131,840 for females, 195,117 in urban areas and 115,128 in rural areas), accounting for 9.20% of overall new cancer cases. The crude incidence of colorectal cancer ranked fourth in all cancer sites with rate of 23.03/100,000 (25.83/100,000 for males and 20.08/100,000 for female, 28.25/100,000 in urban areas and 17.54/100,000 in rural areas). The age-standardized rates by China population and by World population were 16.79/100,000 and 16.52/100,000, respectively. The estimated number of colorectal cancer deaths of China in 2011 was 149,722 (86,427 for males and 63,295 for females, 91,682 in urban areas and 58,040 in rural areas), accounting for 7.09% of overall cancer deaths. The crude mortality rate for colorectal cancer ranked fifth leading cause of cancer-related death in all cancer sites with rate of 11.11/100,000 (12.51/100,000 for males and 9.64/100,000 for female, 13.27/100,000 in urban areas and 8.84/100,000 in rural areas). The age-standardized rates by China population and by World population for mortality were 7.77/100,000 and 7.66/100,000, respectively. For both of incidence and mortality, the rates of colorectal cancer were much higher in males than in females, and in rural areas than in urban areas. The rate of colorectal cancer increased greatly with age, especially after 40 or 45 years old. CONCLUSIONS: Colorectal cancer is a relative common cancer in China, especially for males in urban areas. Targeted prevention and early detection programs should be carried out. PMID- 25717223 TI - Pancreatic cancer incidence and mortality patterns in China, 2011. AB - OBJECTIVE: The National Central Cancer Registry (NCCR) collected population-based cancer registration data in 2011 from all cancer registries in China. The incidence and mortality rates for pancreatic cancer were compiled and pancreatic cancer incident new cases and deaths were estimated. METHODS: A total of 234 cancer registries submitted cancer data to NCCR. Data from 177 cancer registries were qualified and compiled for cancer statistics in 2011. Pancreatic cancer cases were extracted and analyzed from the national database. The pooled data were stratified by area (urban/rural), gender and age group (0, 1-4, 5-9, 10 14...85+). Pancreatic cancer incident cases and deaths were estimated using age specific rates and national population in 2010. The national census in 2000 and Segi's population were used for age-standardized rates. RESULTS: All 177 cancer registries (77 in urban and 100 in rural areas) covered 175,310,169 populations (98,341,507 in urban and 76,968,662 in rural areas). The morphology verified pancreatic cancer cases (MV%) accounting for 40.52% and 4.33% of pancreatic cancer incident cases were identified through death certifications only (DCO%) with mortality to incidence ratio (M/I) of 0.91. The estimated number of newly diagnosed pancreatic cancer cases and deaths were 80,344 and 72,723 in 2011, respectively. The crude incidence rate was 5.96/100,000 (males 6.57/100,000, females 5.32/100,000). The age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 4.27/100,000 and 4.23/100,000 respectively, ranking 10(th) among all cancers. Pancreatic cancer incidence rate and ASIRC were 7.03/100,000 and 4.94/100,000 in urban areas whereas they were 4.84/100,000 and 3.56/100,000 in rural areas. The incidence rate of pancreatic cancer of 33 cancer registries increased from 3.24/100,000 in 2003 to 3.59/100,000 in 2011 with an annual percentage change (APC) of 1.44. The pancreatic cancer mortality rate was 5.40/100,000 (males 5.88/100,000, females 4.89/100,000), ranking 6(th) among all cancers. The age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 3.81/100 000 and 3.79/100 000. The pancreatic cancer mortality and ASMRC were 6.47/100,000 and 4.48/100,000 in urban areas, and 4.27/100,000 and 3.08/100,000 in rural areas, respectively. The mortality rates of pancreatic cancer showed an approximately 1.14-fold increase, from 2.85/100,000 in 2003 to 3.26/100,000 in 2011, with an APC of 1.68. CONCLUSIONS: The burden of pancreatic cancer is increasing in China. Identification of high-risk population and adequate treatment and prevention are important. PMID- 25717224 TI - Ovary cancer incidence and mortality in China, 2011. AB - OBJECTIVE: To evaluate and analyze ovary cancer incidence and mortality in China in 2011 using ovary cancer data from population-based cancer registration in China, and to provide scientific information for its control and prevention. METHODS: Invasive cases of ovary cancer were extracted and analyzed from the overall Chinese cancer database in 2011, which were based on data from 177 population-based cancer registries distributing in 28 provinces. The crude, standardized, and truncated incidences and mortalities et al. were calculated and new and deaths cases from ovary cancer throughout China and in different regions in 2011 were estimated using Chinese practical population. RESULTS: The estimates of new ovary cancer cases and deaths were 45,223 and 18,430, respectively, in China in 2011. The crude incidence rate, age-standardized rate by Chinese standard population (ASR-C) and age-standardized rate by world standard population (ASR-W) incidence were 6.89/100,000, 5.35/100,000 and 5.08/100,000, respectively; the crude, ASR-C and ASR-W mortalities were 2.81/100,000, 2.01/100,000 and 1.99/100,000, respectively. The incidence and mortality in urban areas were higher than those in rural areas. The age-specific incidence and mortality increased rapidly from age 35-39 and peaked at age 60-64 or 75-79 years. After age 45 or 55, the age-specific incidence and death rates in urban were much higher than those in rural areas. CONCLUSIONS: Compared with GLOBOCAN 2012 data, the ovary cancer incidence in China in 2011 was at middle level, but its mortality was at low level worldwide. PMID- 25717225 TI - Oral cancer incidence and mortality in China, 2011. AB - OBJECTIVE: To descript the incidence and mortality rates of oral cancer among Chinese population in 2011, and provide valuable data for oral cancer prevention and research. METHODS: Data from 177 population-based cancer registries distributed in 28 provinces were accepted for this study after evaluation based on quality control criteria, covering a total of 175,310,169 populations and accounting for 13.01% of the overall national population in 2011. Incidence and mortality rates were calculated by area, gender and age groups. The numbers of new cases and deaths were estimated using the 5-year age-specific cancer incidence/mortality rates and the corresponding populations. The Chinese population in 2000 and World Segi's population were used for age-standardized rates. RESULTS: The estimate of new cases diagnosed with oral cancer was 39,450 including 26,160 males and 13,290 females. The overall crude incidence rate for oral cancer was 2.93/100,000. The age-standardized rates by China (ASRCN) population and by World population (ASRwld) were 2.22/100,000 and 2.17/100,000, respectively. Among subjects aged 0-74 years, the cumulative incidence rate was 0.25%. The estimated number of oral cancer deaths of China in 2011 was 16,933, including 11,794 males and 5,139 females. The overall crude mortality rate was 1.26/100,000, accounting for 0.80% of all cancer deaths. The ASRCN and ASRwld for mortality were 0.90/100,000 and 0.89/100,000, respectively. Among subjects aged 0 74 years, the cumulative mortality rate was 0.10%. The incidence and mortality rates of oral cancer were much higher in males and urban areas than in females and rural areas. In addition, the incidence and mortality rates were increased by the raising of ages. CONCLUSIONS: Results in the study may have important roles for oral cancer prevention and research. Although oral cancer burden of China is not high, we must pay attention to this malignancy as well. In addition, further researches need to be done for primary and secondary prevention research of oral cancer, especially for the high risk population. PMID- 25717226 TI - Incidence and mortality of laryngeal cancer in China, 2011. AB - OBJECTIVE: Laryngeal cancer is the common cancer of the upper aerodigestive tract. We aimed to use the national cancer registration data in 2011 to estimate the incidence and mortality of laryngeal cancer within China. METHODS: Comparable, high-quality data from 177 population-based cancer registries were qualified for analysis. The pooled data were stratified by area, sex and age group. National new cases and deaths of laryngeal cancer were estimated using age specific rates and national population in 2010. All incidence and death rates were age-standardized to the 2000 Chinese standard population and Segi's population, which were expressed per 100,000 populations. RESULTS: All 177 cancer registries covered a total of 175,310,169 population (98,341,507 in urban and 76,968,662 in rural areas), accounting for 13.01% of the national population. The data quality indicators of proportion of morphological verification (MV%), percentage of cancer cases identified with death certification only (DCO%) and mortality to incidence ratio (M/I) were 77.98%, 2.62% and 0.55, respectively. Estimated 20,875 new cases of laryngeal cancer were diagnosed and 11,488 deaths from laryngeal cancer occurred in China in 2011. The crude incidence rate of laryngeal cancer was 1.55/100,000 (2.69/100,000 in males and 0.35/100,000 in females). Age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 1.13/100,000 and 1.14/100,000, respectively. Laryngeal cancer is much rarer in females than in males. The incidence rate was higher in urban areas than that in rural areas. The crude mortality rate of laryngeal cancer was 0.85/100,000 (1.42/100,000 in males and 0.25/100,000 in females). Age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were both 0.61/100,000. The mortality rate in males was much higher than that in females. There was no definite difference in mortality rates of laryngeal cancer between urban and rural areas. CONCLUSIONS: Larynx is a specialized area and cancer of larynx significantly affects the quality of life for the patients. Comprehensive measures should be carried out to prevent the ascent of laryngeal cancer. PMID- 25717227 TI - Population attributable risks of cigarette smoking for deaths of all causes, all cancers and other chronic diseases among adults aged 40-74 years in urban Shanghai, China. AB - OBJECTIVE: To evaluate the population attributable risks (PARs) between cigarette smoking and deaths of all causes, all cancers, lung cancer and other chronic diseases in urban Shanghai. METHODS: In total, 61,480 men aged 40-74 years from 2002 to 2006 and 74,941 women aged 40-70 years from 1997 to 2000 were recruited to undergo baseline surveys in urban Shanghai, with response rates of 74.0% and 92.3%, respectively. A Cox proportional hazards regression model was used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) of deaths associated with cigarette smoking. PARs and 95% CIs for deaths were estimated from smoking exposure rates and the estimated RRs. RESULTS: Cigarette smoking was responsible for 23.9% (95% CI: 19.4-28.3%) and 2.4% (95% CI: 1.6-3.2%) of all deaths in men and women, respectively, in our study population. Respiratory disease had the highest PAR in men [37.5% (95% CI: 21.5-51.6%)], followed by cancer [31.3% (95% CI: 24.6-37.7%)] and cardiovascular disease (CVD) [24.1% (95% CI: 16.7-31.2%)]. While the top three PARs were 12.7% (95% CI: 6.1-19.3%), 4.0% (95% CI: 2.4-5.6%), and 1.1% (95% CI: 0.0-2.3%), for respiratory disease, CVD, and cancer, respectively in women. For deaths of lung cancer, the PAR of smoking was 68.4% (95% CI: 58.2-76.5%) in men. CONCLUSIONS: In urban Shanghai, 23.9% and 2.4% of all deaths in men and women could have been prevented if no people had smoked in the area. Effective control programs against cigarette smoking should be strongly advocated to reduce the increasing smoking-related death burden. PMID- 25717228 TI - Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis. AB - OBJECTIVE: The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation (AHSCT) in the treatment of lymphoblastic lymphoma (LL). METHODS: We retrospectively analyzed the data from 41 patients with chemotherapy sensitive LL who underwent hematopoietic stem cell transplantation (HSCT) from December 1989 to December 2009 in a single institution. RESULTS: HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months (range, 24.6-173.1 months). The 5-year overall survival (OS) and event-free survival (EFS) rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow (BM) involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. CONCLUSIONS: These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission (CR1). PMID- 25717229 TI - Preclinical characterization and validation of a dual-labeled trastuzumab-based imaging agent for diagnosing breast cancer. AB - OBJECTIVE: The combination of both nuclear and fluorescent reporters provides unique opportunities for noninvasive nuclear imaging with subsequent fluorescence image-guided resection and pathology. Our objective was to synthesize and optimize a dual-labeled trastuzumab-based imaging agent that can be used to validate an optical imaging agent with potential use in identifying tumor metastases in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. METHODS: [(111)In]-DTPA-trastuzumab-IRDye 800 was synthesized by a three-step procedure. Purity, stability, immunoreactivity, internalization and biodistribution were explored in HER2+ SKBR-3 cells. Biodistribution of [(111)In] DTPA-trastuzumab-IRDye 800 was performed in a SKBR-3 xenograft model. RESULTS: [(111)In]-DTPA-trastuzumab-IRDye 800 demonstrated high purity by both chemical and fluorometric determinations. Both flow cytometry and the Lindmo assay demonstrated a high binding affinity of [(111)In]-DTPA-trastuzumab-IRDye 800 to HER2-overexpressing cells. The dual-labeled conjugate was stable in PBS, but not in serum after 24 h at 37 degrees C. Larger molecules (>150 kD) were seen after a 24 h-incubation in human serum. Biodistribution studies revealed tumor-specific accumulation of [(111)In]-DTPA-trastuzumab-IRDye 800 in SKBR-3 tumors, and tumor uptakes at 24 and 48 h were (12.42+/-1.72)% and (9.96+/-1.05)%, respectively, following intravenous administration. The tumor-to-muscle ratio was 9.13+/-1.68 at 24 h, and increased to 12.79+/-2.13 at 48 h. Liver and kidney showed marked uptake of the dual-labeled imaging agent. CONCLUSIONS: [(111)In]-DTPA-trastuzumab IRDye 800 is an effective diagnostic biomarker that can be used to validate dual labeled, molecularly targeted imaging agents and can allow these agents to be translated into clinical practice for identifying HER2+ lesions. PMID- 25717230 TI - Evaluation of contrast-enhanced ultrasound for diagnosis of dysplastic nodules with a focus of hepatocellular carcinoma in liver cirrhosis patients. AB - OBJECTIVE: To compare the enhancement features of dysplastic nodules with a focus of hepatocellular carcinoma (DN-HCC) versus HCC and regenerative nodules (RN) in cirrhotic patients. METHODS: One hundred and ninety-three cirrhotic patients were enrolled in this study; they had 215 focal liver lesions, 1.0-3.5 cm in size, which were examined using contrast-enhanced ultrasound (CEUS) with SonoVue((r)) and diagnosed as HCC, RN or DN-HCC by biopsy. Samples were obtained using 18 gauge needles in the different enhanced areas. The enhancement features of DN HCC, HCC and RN were evaluated. RESULTS: There were 86 HCC lesions, 102 RN lesions, and 27 DN-HCC lesions diagnosed by biopsy. Of 86 HCC lesions, 87.2% (75/86) showed complete enhancement during the arterial phase, and 12.8% (11/86) had inhomogeneous enhancement, with no enhancement in the central area during the arterial phase; 100% (86/86) exhibited washout during the late phase. Of 102 RN lesions, 95.1% (97/102) had delayed or simultaneous enhancement during the arterial phase, and 4.9% (5/102) displayed slight enhancement during the arterial phase; 26.5% (27/102) exhibited washout and 73.5% (75/102) exhibited no washout during the late phase. In 27 DN-HCC lesions, only part of the lesions enhanced during the arterial phase and washed out during the late phase; the other areas had delayed or simultaneous enhancement during the arterial phase, and 29.6% (8/27) exhibited slight washout in the late phase. In 86 HCCs, the pathological feature was HCC in the enhanced area of 75 lesions, hepatocellular fatty degeneration in the slightly enhanced area of 7 lesions, and hepatocellular necrosis in the unenhanced area and HCC in the enhanced area of 4 lesions. In 102 RNs, the pathological diagnosis was hepatocyte proliferation with or without fatty degeneration. In 27 DN-HCCs, the pathological feature was HCC in the enhanced area and hepatocyte regeneration in the unenhanced area. CONCLUSIONS: CEUS is useful for the diagnosis of focal liver lesions in cirrhotic patients. CEUS can help determine the progression from RN to DN-HCC to HCC by analyzing the hemodynamics. CEUS can promote the diagnostic accuracy of a biopsy by providing more accurate information on the site of the biopsy. PMID- 25717231 TI - Recent advances in uniportal video-assisted thoracoscopic surgery. AB - Thanks to the recent improvements in video-assisted thoracoscopic techniques (VATS) and anesthetic procedures, a great deal of complex lung resections can be performed avoiding open surgery. The experience gained through VATS techniques, enhancement of the surgical instruments, improvement of high definition cameras and avoidance of intubated general anesthesia have been the greatest advances to minimize the trauma to the patient. Uniportal VATS for major resections has become a revolution in the treatment of lung pathologies since initially described 4 years ago. The huge number of surgical videos posted on specialized websites, live surgery events and experimental courses has contributed to the rapid learning of uniportal major thoracoscopic surgery during the last years. The future of the thoracic surgery is based on evolution of surgical procedures and anesthetic techniques to try to reduce the trauma to the patient. Further development of new technologies probably will focus on sealing devices for all vessels and fissure, refined staplers and instruments, improvements in 3D systems or wireless cameras, and robotic surgery. As thoracoscopic techniques continue to evolve exponentially, we can see the emergence of new approaches in the anesthetical and the perioperative management of these patients. Advances in anesthesia include lobectomies performed without the employment of general anesthesia, through maintaining spontaneous ventilation, and with minimally sedated patients. Uniportal VATS resections under spontaneous ventilation probably represent the least invasive approach to operate lung cancer. PMID- 25717232 TI - Physical scientists research biomedicine: a call for caution. PMID- 25717233 TI - Injury-associated reacquiring of intestinal stem cell function. AB - Epithelial layer of the intestine relies upon stem cells for maintaining homeostasis and regeneration. Two types of stem cells are currently defined in intestinal crypts: the cycling crypt base columnar cells and quiescent cells. Though several candidate markers and regulators of rapidly cycling and quiescent stem cells have been identified so far, the exact nature of quiescent cells is still questionable since investigations mainly focused on candidate markers rather than the label-retaining population itself. Recent results, however, have strengthened the argument for functional plasticity. Using a lineage tracing strategy label-retaining cells (LRCs) of the intestinal epithelium were marked, then followed by a pulse-chase analysis it was found that during homeostasis, LRCs were Lgr5-positive and were destined to become Paneth and neuroendocrine cells. Nevertheless, it was demonstrated that LRCs are capable of clonogenic growth by recall to the self-renewing pool of stem cells in case of epithelial injury. These new findings highlight on the hierarchical and spatial organization of intestinal epithelial homeostasis and the important plasticity of progenitors during tissue regeneration, moreover, provide a motivation for studying their role in disorders like colorectal cancer. PMID- 25717234 TI - Gene expression profiling of MYC-driven tumor signatures in porcine liver stem cells by transcriptome sequencing. AB - AIM: To identify the genes induced and regulated by the MYC protein in generating tumors from liver stem cells. METHODS: In this study, we have used an immortal porcine liver stem cell line, PICM-19, to study the role of c-MYC in hepatocarcinogenesis. PICM-19 cells were converted into cancer cells (PICM-19 CSCs) by overexpressing human MYC. To identify MYC-driven differential gene expression, transcriptome sequencing was carried out by RNA sequencing, and genes identified by this method were validated using real-time PCR. In vivo tumorigenicity studies were then conducted by injecting PICM-19-CSCs into the flanks of immunodeficient mice. RESULTS: Our results showed that MYC overexpressing PICM-19 stem cells formed tumors in immunodeficient mice demonstrating that a single oncogene was sufficient to convert them into cancer cells (PICM-19-CSCs). By using comparative bioinformatics analyses, we have determined that > 1000 genes were differentially expressed between PICM-19 and PICM-19-CSCs. Gene ontology analysis further showed that the MYC-induced, altered gene expression was primarily associated with various cellular processes, such as metabolism, cell adhesion, growth and proliferation, cell cycle, inflammation and tumorigenesis. Interestingly, six genes expressed by PICM-19 cells (CDO1, C22orf39, DKK2, ENPEP, GPX6, SRPX2) were completely silenced after MYC-induction in PICM-19-CSCs, suggesting that the absence of these genes may be critical for inducing tumorigenesis. CONCLUSION: MYC-driven genes may serve as promising candidates for the development of hepatocellular carcinoma therapeutics that would not have deleterious effects on other cell types in the liver. PMID- 25717235 TI - Negative impact of bone-marrow-derived mesenchymal stem cells on dextran sulfate sodium-induced colitis. AB - AIM: To investigate the effects of mesenchymal stem cells (MSCs) on dextran sulfate sodium-induced inflammatory bowel disease (IBD). METHODS: C57BL/6 mice were fed 3.5% (g/L) dextran sulfate sodium. On day seven, the mice received intraperitoneal injections of 1*10(6) MSCs. The survival rate, disease activity index values, and body weight, were monitored daily. On day ten, colon lengths and histopathologic changes were assessed. In addition, immunoregulatory changes following MSC administration were evaluated by determining the levels of effector T cell responses in the spleen and mesenteric lymph nodes, and the expression levels of inflammatory cytokines in homogenized colons. RESULTS: Intraperitoneal administration of MSCs did not prevent development of colitis and did not reduce the clinicopathologic severity of IBD. No significant difference was evident in either survival rate or disease activity index score between the control and MSC treated group. Day ten-sacrificed mice exhibited no significant difference in either colon length or histopathologic findings. Indeed, the MSC-treated group exhibited elevated levels of interleukin (IL)-6 and transforming growth factor beta, and a reduced level of IL-10, in spleens, mesenteric lymph nodes, and homogenized colons. The IL-17 level was lower in the mesenteric lymph nodes of the MSC-treated group (P=0.0126). In homogenized colons, the IL-17 and tumor necrosis factor-alpha (P=0.0092) expression levels were also lower in the treated group. CONCLUSION: MSC infusion provided no significant histopathologic or clinical improvement, thus representing a limited therapeutic approach for IBD. Functional enhancement of MSCs is needed in further study. PMID- 25717236 TI - Depletion of the IKBKAP ortholog in zebrafish leads to hirschsprung disease-like phenotype. AB - AIM: To investigate the role of IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) in the development of enteric nervous system (ENS) and Hirschsprung disease (HSCR). METHODS: In this study, we injected a morpholino that blocked the translation of ikbkap protein to 1-cell stage zebrafish embryos. The phenotype in the ENS was analysed by antibody staining of the pan-neuronal marker HuC/D followed by enteric neuron counting. The mean numbers of enteric neurons were compared between the morphant and the control. We also studied the expressions of ret and phox2bb, which are involved in ENS development, in the ikbkap morpholino injected embryos by quantitative reverse transcriptase polymerase chain reaction and compared them with the control. RESULTS: We observed aganglionosis (chi2, P<0.01) and a reduced number of enteric neurons (38.8+/-9.9 vs 50.2+/-17.3, P<0.05) in the zebrafish embryos injected with ikbkap translation-blocking morpholino (morphant) when compared with the control embryos. Specificity of the morpholino was confirmed by similar results obtained using a second non-overlapping morpholino that blocked the translation of ikbkap. We further studied the morphant by analysing the expression levels of genes involved in ENS development such as ret, phox2bb and sox10, and found that phox2bb, the ortholog of human PHOX2B, was significantly down-regulated (0.51+/-0.15 vs 1.00+/-0, P<0.05). Although we also observed a reduction in the expression of ret, the difference was not significant. CONCLUSION: Loss of IKBKAP contributed to HSCR as demonstrated by functional analysis in zebrafish embryos. PMID- 25717237 TI - Impact of high glucose on metastasis of colon cancer cells. AB - AIM: To investigate the possible mechanism of how glucose promotes invasion and metastasis of colon cancer cells. METHODS: CT-26 rat colorectal cancer cells were cultured in different concentrations of glucose environments (10, 20, and 30 mmol/L). Wound healing assay and transwell chamber invasion assay were utilized to test the migration and invasion, respectively. In order to understand the role of signal transducer and activator of transcription 3 (STAT3) in the process, STAT3 inhibitors, including Stattic (an STAT3 specific inhibitor) and small interfering RNA targeting STAT3, were used to block STAT3 function to evaluate their impact on CT-26 cell motion. To verify whether STAT3 and matrix metalloproteinase-9 (MMP-9) protein expression is associated with glucose-induced cell movement, Western blot was used to compare the differences in the expression of MMP-9 and STAT3 in cells incubated with and without STAT3 inhibitors in high glucose condition. RESULTS: In both wound healing and invasion assays, the migration and invasion of CT-26 cells increased gradually with the increase in glucose concentration. However, the glucose-induced migration and invasion were obviously inhibited by STAT3 inhibitors (P<0.05). Similarly, in Western blot assessment, both MMP-9 and STAT3 expression increased under a high glucose environment and the highest expression was achieved when 30 mmol/L glucose was used. However, in cells treated with 30 mmol/L mannitol, either MMP-9 or STAT3 expression did not increase (P>0.05). When STAT3 inhibitors were added in the 30 mM glucose group, not only STAT3 but also MMP-9 expression decreased significantly (P<0.05). CONCLUSION: Our study provides evidence that glucose can promote both migration and invasion of CT-26 cells, and that the STAT3-induced MMP-9 signal pathway is involved in this process. PMID- 25717238 TI - Mechanism of action of gypenosides on type 2 diabetes and non-alcoholic fatty liver disease in rats. AB - AIM: To explore the mechanism of action of gypenosides (GPs) on type 2 diabetes mellitus and non-alcoholic fatty liver disease (T2DM-NAFLD) in rats. METHODS: Sixty rats were randomly divided into a healthy group, an untreated disease model group and GP-treatment groups. The study involved the evaluation of biochemical parameters, including serum aspartate transaminase (AST), alanine transferase (ALT), blood glucose (BG), triglycerides (TG) and total cholesterol (TC). Additionally, the protective effect of the treatments were confirmed histopathologically and the expression of TNF-alpha and NF-kappaB in the rat liver was analyzed using immunohistochemistry. The expression of proliferator activated receptor gamma (PPARgamma) and cytochrome P450 (CYP450) 1A1 mRNA was determined by quantitative RT-PCR. RESULTS: GP treatments at oral doses of 200, 400, and 800 mg/kg per day significantly decreased the levels of serum AST and ALT (P<0.05, P<0.01), especially at the dose of 800 mg/kg per day. To a similar extent, GP at 800 mg/kg per day reduced the levels of BG (4.19+/-0.47, P<0.01), TG (80.08+/-10.05, P<0.01), TC (134.38+/-16.39, P<0.01) and serum insulin (42.01+/-5.04, P<0.01). The expression of TNF-alpha and NF-kappaB measured by immunohistochemistry was significantly reduced by GPs in a dose-dependent manner, and the expression of PPARgamma and CYP4501A1 mRNA, as measured using quantitative real-time PCR, were significantly down-regulated by GPs. Moreover, GPs decreased the infiltration of liver fats and reversed the histopathological changes in a dose-dependent manner. CONCLUSION: This study suggests that GPs have a protective effect against T2DM-NAFLD by down-regulating the expression of TNF alpha and NF-kappaB proteins, and PPARgamma and CYP4501A1 mRNAs. PMID- 25717239 TI - Increased inspiratory esophagogastric junction pressure in systemic sclerosis: an add-on to antireflux barrier. AB - AIM: To investigate crural diaphragm (CD) function in systemic sclerosis (SSc) using high-resolution manometry and standardized inspiratory maneuvers. METHODS: Eight SSc volunteers (average age, 40.1 years; one male) and 13 controls (average age, 32.2 years; six males) participated in the study. A high-resolution manometry/impedance system measured the esophagus and esophagogastric junction (EGJ) pressure profile during swallows and two respiratory maneuvers: sinus arrhythmia maneuver (SAM; the average of six EGJ peak pressures during 5-s deep inhalations) and threshold maneuver (TM; the EGJ peak pressures during forced inhalation under 12 and 24 cmH2O loads). Inspiratory diaphragm lowering (IDL) was taken as the displacement of the EGJ high-pressure zone during the SAM. RESULTS: SSc patients had lower mean lower esophageal sphincter pressure than controls during normal breathing (19.7+/-2.8 mmHg vs 32.2+/-2.7 mmHg, P=0.007). Sinus arrhythmia maneuver pressure was higher in SSc patients than in controls (142.6+/ 9.4 mmHg vs 104.6+/-13.8 mmHg, P=0.019). Sinus arrhythmia maneuver pressure normalized to IDL was also higher in SSc patients than in controls (83.8+/-13.4 mmHg vs 37.5+/-6.9 mmHg, P=0.005). Threshold maneuver pressures normalized to IDL were also greater in SSc patients than in controls (TM 12 cmH2O: 85.1+/-16.4 mmHg vs 43.9+/-6.3 mmHg, P=0.039; TM 24 cmH2O: 85.2+/-16.4 mmHg vs 46.2+/-6.6 mmHg, P=0.065). Inspiratory diaphragm lowering in SSc patients was less than in controls (2.1+/-0.3 cm vs 3+/-0.2 cm, P=0.011). CONCLUSION: SSc patients had increased inspiratory EGJ pressure. This is an add-on to EGJ pressure and indicates that the antireflux barrier can be trained. PMID- 25717240 TI - Chronic hepatitis B in children with or without malignancies: a 13-year follow up. AB - AIM: To evaluate the outcome of chronic hepatitis B (CHB) in children with or without malignancies. METHODS: Twenty four children (15 boys and 9 girls) with malignancies, followed up by the pediatric gastroenterology outpatient clinic for CHB between January 2000 and December 2013, were enrolled in the study (Group 1). Group 2 was formed with twenty five children (11 girls and 14 boys) diagnosed with CHB without malignancies. The data from the patients' records were compared between the two groups. RESULTS: Hepatitis B e antigen (HBeAg)/antiHBe seroconversion was observed in 3 patients (12.5%) in group 1 and 15 patients (60%) in group 2, with annual seroconversion rates of 1.61% and 16.6%, respectively, and the difference was significant (P<0.01). One patient (6.6%) in Group 1 and 9 patients (53%) in Group 2 showed HBeAg/antiHBe seroconversion after treatment and the difference between the two groups was significant (P<0.06) Loss of hepatitis B surface antigen was observed in one patient in each of group 1 and 2. No clinical, laboratory and imaging findings of liver disease were observed in any of the patients at the end of the study. CONCLUSION: HBeAg/antiHBe seroconversion rate was lower in patients who had recovered from cancer. PMID- 25717241 TI - Clinical significance and usefulness of soluble heparin binding-epidermal growth factor in gastric cancer. AB - AIM: To evaluate the clinical usefulness of soluble heparin-binding epidermal growth factor (sHB-EGF) as a serum biomarker for gastric cancer (GC). METHODS: Serum sHB-EGF levels were measured by a commercially available human HB-EGF ELISA Kit and compared among 60 normal controls, 30 high-risk patients, 37 early gastric cancer (EGC), and 30 advanced gastric cancer (AGC) through ANOVA test. Correlations between serum sHB-EGF and clinicopathological features of GC were analyzed through Spearman's correlation. The diagnostic performance of serum sHB EGF for GC was evaluated through receiver operating characteristic (ROC) curve and logistic regression analysis. RESULTS: Serum sHB-EGF levels were significantly higher in AGC group (314.4+/-127.5 pg/mL) than EGC (165.3+/-123.2 pg/mL), high-risk (98.7+/-67.3 pg/mL), and control (94.7+/-83.6 pg/mL) groups (post-hoc Bonferroni, all P<0.001), respectively. Serum sHB-EGF levels were also significantly higher in EGC group than high-risk (P=0.049) and control (P=0.006) groups. Clinicopathologically, serum sHB-EGF levels closely correlated with depth of invasion (T-stage, gammas=0.669, P<0.001), lymph node metastasis (N-stage, gammas=0.407, P=0.001), and distant metastasis (M-stage, gammas=0.261, P=0.030). ROC curve and logistic regression analysis demonstrated a remarkable diagnostic potential of serum sHB-EGF. CONCLUSION: Serum sHB-EGF is closely correlated with advanced stage GC and can be a promising serological biomarker for GC. PMID- 25717242 TI - Natural YMDD-motif mutants affect clinical course of lamivudine in chronic hepatitis B. AB - AIM: To investigate the prevalence of nature tyrosine-methionine-aspartic acid aspartic acid motif mutations in chronic hepatitis B (CHB) patients and to evaluate the efficacy of lamivudine. METHODS: A total of 1268 CHB patients were recruited from the outpatient and inpatient departments of six centers. Tyrosine methionine-aspartic acid-aspartic acid (YMDD) mutations were analyzed using the hepatitis B virus (HBV) drug resistance line probe assay. Forty voluntary patients were selected from those with positive or negative natural YMDD mutations to undergo treatment with lamivudine. RESULTS: YMDD mutations were detected in 288 (22.71%) of the 1268 CHB patients. Multivariate analysis revealed that the patients' HBV DNA level (P=0.0282) and hepatitis B e antigen status (P=0.0133) were also associated with natural YMDD mutations. The rates of normalization of alanine aminotransferase levels and HBV DNA nondetection at 6, 24, 36, and 48 wk were compared between the patients with natural YMDD mutations and those without, and the differences were not significant. However, there was a significant difference in the cumulative emergence rates of virological breakthrough at 48 wk in the patients with natural YMDD mutations and those without (32.5% vs 12.5%, P=0.032). CONCLUSION: Naturally occurring YMDD mutations are detectable in a large proportion of CHB patients; breakthrough hepatitis tended to occur in patients with natural YMDD mutations. PMID- 25717243 TI - FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma. AB - AIM: To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma. METHODS: Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory to first-line therapy consisting of gemcitabine plus oxaliplatin-based first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI [irinotecan (180 mg/m2 i.v. over 90 min) concurrently with folinic acid (400 mg/m2 i.v. over 120 min) followed by fluorouracil (400 mg/m2 i.v. bolus) then fluorouracil 2400 mg/m2 intravenous infusion over 46 h] and bevacizumab (5 mg/kg) every 2 wk. Tumor response was evaluated by computed tomography scan every 4 cycles. RESULTS: The best tumor responses using response evaluation criteria in solid tumor criteria were: complete response for 1 patient, partial response for 4 patients, and stable disease for 6 patients after 6 mo of follow-up. The response rate was 38.4% (95%CI: 12.5-89) and the disease control rate was 84.5% (95%CI: 42-100). Seven deaths occurred at the time of analysis, progression free survival was 8 mo (95%CI: 7-16), and median overall survival was 20 mo (95%CI: 8-48). No grade 4 toxic events were observed. Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred. An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity, and a delay in chemotherapy cycles was required for 3 patients. CONCLUSION: FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy. PMID- 25717244 TI - Liver resection for the treatment of post-cholecystectomy biliary stricture with vascular injury. AB - AIM: To report experience with liver resection in a select group of patients with postoperative biliary stricture associated with vascular injury. METHODS: From a prospective database of patients treated for benign biliary strictures at our hospital, cases that underwent liver resections were reviewed. All cases were referred after one or more attempts to repair bile duct injuries following cholecystectomy (open or laparoscopic). Liver resection was indicated in patients with Strasberg E3/E4 (hilar stricture) bile duct lesions associated with vascular damage (arterial and/or portal), ipsilateral liver atrophy/abscess, recurrent attacks of cholangitis, and failure of previous hepaticojejunostomy. RESULTS: Of 148 patients treated for benign biliary strictures, nine (6.1%) underwent liver resection; eight women and one man with a mean age of 38.6 years. Six patients had previously been submitted to open cholecystectomy and three to laparoscopic surgery. The mean number of surgical procedures before definitive treatment was 2.4. All patients had Strasberg E3/E4 injuries, and vascular injury was present in all cases. Eight patients underwent right hepatectomy and one underwent left lateral sectionectomy without mortality. Mean time of follow up was 69.1 mo and after long-term follow up, eight patients are asymptomatic. CONCLUSION: Liver resection is a good therapeutic option for patients with complex postoperative biliary stricture and vascular injury presenting with liver atrophy/abscess in which previous hepaticojejunostomy has failed. PMID- 25717245 TI - Endocytoscopic narrow-band imaging efficiency for evaluation of inflammatory activity in ulcerative colitis. AB - AIM: To assess the efficacy of endocytoscopic narrow-band imaging (EC-NBI) for evaluating the severity of inflammation in ulcerative colitis (UC). METHODS: This retrospective study was conducted at a single tertiary care referral center. We included UC patients who underwent colonoscopy with endocytoscopy from July 2010 to December 2013. EC-NBI was performed, and the images were evaluated by assessing visibility, increased vascularization, and the increased calibers of capillaries and were classified as Obscure, Visible or Dilated. Obscure was indicative of inactive disease, while Visible and Dilated were indicative of acute inflammation. This study received Institutional Review Board approval. The primary outcome measures included the diagnostic ability of EC-NBI to distinguish between active and inactive UC on the basis of histological activity. The conventional endoscopic images were classified according to the Mayo endoscopic score. A score of 0 or 1 indicated inactive disease, whereas a score of 2 indicated active disease. RESULTS: Fifty-two patients were enrolled. There was a strong correlation between the EC-NBI findings and the histological assessment (r=0.871, P<0.01). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EC-NBI for diagnosing acute inflammation were 84.0%, 100%, 87.1%, 100%, and 92.3%, respectively, while those for the Mayo endoscopic score were 100%, 40.7%, 100%, 61.0%, and 69.2%, respectively. Compared with conventional endoscopy, EC-NBI was superior in diagnostic specificity, negative predictive value, and accuracy (P<0.001, P=0.001 and P=0.047, respectively). CONCLUSION: The EC-NBI finding of capillaries in the rectal mucosa was strongly correlated with histological inflammation and aided in the differential diagnosis between active and inactive UC. PMID- 25717246 TI - Predictors of kidney tubular dysfunction induced by adefovir treatment for chronic hepatitis B. AB - AIM: To investigate the predictors of proximal kidney tubular dysfunction (PKTD) induced by adefovir dipivoxil (ADV) treatment for chronic hepatitis B. METHODS: Seventy-nine patients (age at the evaluation of PKTD: 56.9+/-10.7 years) with chronic hepatitis B undergoing long-term oral antiviral nucleos(t)ide analogue treatment were consecutively recruited. PKTD was defined by the presence of at least two of the following five abnormalities: phosphate diabetes, nondiabetic glucosuria, metabolic acidosis, beta2-microglobulinuria, or renal hypouricemia. The single-nucleotide polymorphisms (SNPs) in the SLC22A6 gene encoding human organic anion transporter 1 (hOAT1) and ABCC2 encoding multidrug resistance protein 2 (MRP2) were analyzed using the TaqMan Allelic Discrimination Demonstration Kit. RESULTS: Nine (30.0%) of the 30 ADV-treated patients were diagnosed with PKTD, while no patients without ADV developed PKTD (P<0.001). Three patients with ADV were diagnosed with symptomatic osteomalacia. Among the patients who took ADV, those with PKTD were of higher age at initiation, had significantly longer treatment duration, and had a significantly lower body mass index than those without PKTD. The incidence of PKTD dramatically increased after 96 mo from the start of ADV administration. In contrast, the SNPs were not correlated with PKTD. Logistic regression analysis extracted older age at initiation (OR=5.0, 95%CI: 1.1-23.4; P=0.040) and longer treatment duration (OR=3.2, 95%CI: 1.2-8.6; P=0.020) as significant factors associated with PKTD. CONCLUSION: Our results suggest that the tubular function of the kidney of older patients undergoing long-term ADV treatment should be carefully evaluated. PMID- 25717247 TI - Repeat hepatic resection in patients with colorectal liver metastases. AB - AIM: To investigate the survival outcomes of secondary hepatectomy for recurrent colorectal liver metastases (CRLM). METHODS: From October 1994 to December 2009, patients with CRLM who underwent surgical treatment with curative intent were investigated. Patients were divided into two groups: patients who underwent primary hepatectomy (Group 1) and those who underwent secondary hepatectomy for recurrent CRLM (Group 2). RESULTS: Survival and prognostic factors were analyzed. A total of 461 patients were included: 406 patients in Group 1 and 55 patients in Group 2. After a median 39-mo (range, 3-195 mo) follow-up, there was a significant difference between Groups 1 and 2 in terms of disease-free survival (P=0.029) although there was no significant difference in overall survival (P=0.206). Secondary hepatectomy was less effective in patients with multiple recurrent CRLM than primary hepatectomy for initial CRLM (P=0.008). Multiple CRLM and radiofrequency ablation therapy were poor prognostic factors of secondary hepatectomy in multivariate Cox regression analysis (P=0.006, P=0.004, respectively). CONCLUSION: Secondary hepatectomy for single recurrent CRLM is as effective as primary surgical treatment for single recurrent CRLM. However, secondary hepatectomy for multiple recurrent CRLM is less effective than that for single recurrent CRLM. PMID- 25717248 TI - Determination of surgical priorities in appendicitis based on the probability of undetected appendiceal perforation. AB - AIM: To identify risk factors of actual appendiceal perforation when computed tomography (CT) scans suggest nonperforated appendicitis and accordingly determine surgical priority. METHODS: We collected database of 1362 patients who underwent an appendectomy for acute appendicitis between 2006 and 2013. A single radiologist selected 1236 patients whose CT scans were suggestive of nonperforated appendicitis. Patients were divided into 2 groups: actual nonperforation group and actual perforation group according to intraoperative and pathologic features. Comparison of the 2 groups were made using binary logistic regression. RESULTS: Of 1236 patients, 90 (7.3%) were found to have actual appendiceal perforation. Four risk factors related with actual appendiceal perforation were identified: body temperature>=37.6 degrees C (HR=1.912, 95%CI: 1.161-3.149; P=0.011), out-of-hospital symptom duration>=72 h (HR=2.454, 95%CI: 1.292-4.662; P=0.006), age>=35 years (HR=3.358, 95%CI: 1.968-5.728; P<0.001), and appendiceal diameter on CT scan>=8 mm (HR=4.294, 95%CI: 1.034-17.832; P=0.045). Actual appendiceal perforation group showed longer operation time, later initiation of diet, longer use of parenteral narcotics, longer hospital stay, and higher incidence of postoperative complications (P<0.05). CONCLUSION: We proposed here new criteria to select patients with adverse clinical outcomes after appendectomy among the patients with radiologically nonperforated appendicitis. Surgical appendectomy outcomes could be improved by determining the surgical priority according to our criteria. PMID- 25717249 TI - Endoscopic measurement of variceal diameter. AB - AIM: To measure in vitro diameter of imitational varices using a self-made endoscopic scale and confirm its accuracy and clinical feasibility. METHODS: A catheter was introduced into the endoscope accessory channel and attached to a zebra wire guide that was used as a stylet. The wire guide was fixed onto the tip of the catheter by a soft and thin string. By gently advancing the stylet into the catheter, the width of the opening loop at the tip of the endoscope approximated the diameter of the imitational varices. Measurements performed in vitro using this self-made endoscopic ruler were compared to measurements of simulative varices. RESULTS: At the handle, the sleeve moving distance ranged from 5 to 14 mm. There was no obvious proportional relationship between the sleeve movement distance and endoscopic measurement ruler. The results indicated that the gap between the endoscopic measurement and actual measurement of the object size tended to close. The in vitro measurement of the diameter of the simulative varices showed that the two kinds of measuring methods were not significantly different with respect to their accuracy (P=0.8499). CONCLUSION: In vitro experiments confirmed that using a self-designed endoscopic ruler to measure the diameter of simulative varices was objective, accurate and feasible. PMID- 25717250 TI - Is intraoperative cholangiography necessary during laparoscopic cholecystectomy for cholelithiasis? AB - AIM: To determine the efficacy and safety benefits of performing intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC) to treat symptomatic cholelithiasis. METHODS: Patients admitted to the Minimally Invasive Surgery Center of Tianjin Nankai Hospital between January 2012 and January 2014 for management of symptomatic cholelithiasis were recruited for this prospective randomized trial. Study enrollment was offered to patients with clinical presentation of biliary colic symptoms, radiological findings suggestive of gallstones, and normal serum biochemistry results. Study participants were randomized to receive either routine LC treatment or LC+IOC treatment. The routine LC procedure was carried out using the standard four-port technique; the LC+IOC procedure was carried out with the addition of meglumine diatrizoate (1:1 dilution with normal saline) injection via a catheter introduced through a small incision in the cystic duct made by laparoscopic scissors. Operative data and postoperative outcomes, including operative time, retained common bile duct (CBD) stones, CBD injury, other complications and length of hospital stay, were recorded for comparative analysis. Inter-group differences were statistically assessed by the chi2 test (categorical variables) and Fisher's exact test (binary variables), with the threshold for statistical significance set at P<0.05. RESULTS: A total of 371 patients were enrolled in the trial (late-adolescent to adult, age range: 16-70 years), with 185 assigned to the routine LC group and 186 to the LC+IOC group. The two treatment groups were similar in age, sex, body mass index, duration of symptomology, number and size of gallstones, and clinical symptoms. The two treatment groups also showed no significant differences in the rates of successful LC (98.38% vs 97.85%), CBD stone retainment (0.54% vs 0.00%), CBD injury (0.54% vs 0.53%) and other complications (2.16% vs 2.15%), as well as in duration of hospital stay (5.10+/-1.41 d vs 4.99+/-1.53 d). However, the LC+IOC treatment group showed significantly longer mean operative time (routine LC group: 43.00+/-4.15 min vs 52.86+/-4.47 min, P<0.01). There were no cases of fatal complications in either group. At the one-year follow-up assessment, one patient in the routine LC group reported experiencing diarrhea for three months after the LC and one patient in the LC+IOC group reported on-going intermittent epigastric discomfort, but radiological examination provided no abnormal findings. CONCLUSION: IOC addition to the routine LC treatment of symptomatic cholelithiasis does not improve rates of CBD stone retainment or bile duct injury but lengthens operative time. PMID- 25717251 TI - Establishing an integrated gastroenterology service between a medical center and the community. AB - AIM: To combine community and hospital services in order to enable improvements in patient management, an integrated gastroenterology service (IGS) was established. METHODS: Referral patterns to specialist clinics were optimized; open access route for endoscopic procedures (including esophago-gastro duodenoscopy, sigmoidoscopy and colonoscopy) was established; family physicians' knowledge and confidence were enhanced; direct communication lines between experts and primary care physicians were opened. Continuing education, guidelines and agreed instructions for referral were promoted by the IGS. Six quality indicators were developed by the Delphi method, rigorously designed and regularly monitored. Improvement was assessed by comparing 2010, 2011 and 2012 indicators. RESULTS: An integrated delivery system in a specific medical field may provide a solution to a fragmented healthcare system impaired by a lack of coordination. In this paper we describe a new integrated gastroenterology service established in April 2010. Waiting time for procedures decreased: 3 mo in April 30th 2010 to 3 wk in April 30th 2011 and stayed between 1-3 wk till December 30th 2012. Average cost for patient's visit decreased from 691 to 638 NIS (a decrease of 7.6%). Six health indicators were improved significantly comparing 2010 to 2012, 2.5% to 67.5%: Bone densitometry for patients with inflammatory bowel disease, preventive medications for high risk patients on aspirin/NSAIDs, colonoscopy following positive fecal occult blood test, gastroscopy in Barrett's esophagus, documentation of family history of colorectal cancer, and colonoscopy in patients with a family history of colorectal cancer. CONCLUSION: Establishment of an IGS was found to effectively improve quality of care, while being cost-effective. PMID- 25717252 TI - ARID1A expression in gastric adenocarcinoma: clinicopathological significance and correlation with DNA mismatch repair status. AB - AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas. METHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables. RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6+/-9.2 vs 60.4+/-11.7, P<0.001), a female sex (55.3% vs 31.3%, P=0.004), an antral location (44.7% vs 25.7%, P=0.021), and a differentiated histology (57.9% vs 39.7%, P=0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P=0.022) and lymph node metastasis (83.5% vs 73.7%, P=0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P<0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR=1.36, 95%CI: 1.01-1.84; P=0.040). CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas. PMID- 25717253 TI - Preliminary study of a new pathological evolution-based clinical hepatolithiasis classification. AB - AIM: To investigate clinical features, treatment strategies and outcomes of patients with hepatolithiasis (HL) undergoing surgical treatment, using a new clinical classification. METHODS: Sixty-eight HL patients were hospitalized and treated surgically from August 2011 to December 2012 and they were classified into four HL types according to pathological evolution of the disease. These four HL types included type I primary type (defined as no previous biliary tract surgery), type II inflammatory type (with previous biliary tract surgery and cholangitis), type III mass-forming type (HL complicated by hepatic mass-forming lesion), and type IV terminal type (with secondary biliary cirrhosis and resultant portal hypertension). The perioperative data including general information, imaging data, postoperative complications, and immediate and final stone clearance rate were obtained and analyzed. RESULTS: In all 68 patients, the proportion of HL type I-IV was 50% (34/68), 36.8% (25/68), 10.3% (7/68) and 2.8% (2/68), respectively. Abdominal pain was the main clinical manifestation in type I (88.2%), fever was predominant in type II (52.0%), the malignancy rate in type III was high (71.4%), and portal hypertension and spleen enlargement were common in type IV (2/2, 100.0%). Liver resection rate for types I-III was 79.4%, 72.0% and 71.4%, respectively. The overall incidence of postoperative complications was 23.5% (16/68). There were no perioperative deaths. The average length of hospital stay was 12.7+/-7.3 d. Immediate and final stone clearance rate was 73.5% (50/68) and 89.7% (61/68), respectively. Fifty-nine of 68 patients (86.8%) were followed- up for >1 year after surgery, and 96.6% of these patients (57/59) had a good quality of life according to a criterion recommended for postoperative evaluation of quality of life. CONCLUSION: The pathological evolution-based clinical classification of HL has a role in optimizing treatment strategy, and patients can benefit from this classification when it is used properly. PMID- 25717254 TI - Measurement system that improves the accuracy of polyp size determined at colonoscopy. AB - AIM: To assess the accuracy of polyp size using an endoscopic lesion measurement system (ELMS). METHODS: The accuracy of polyp size assessment was compared among measurements acquired by visual estimation, disposable graduated biopsy forceps (DGBF; used as a "scale-plate") and the ELMS. RESULTS: There were 192 polyps from 166 cases included in this study. The mean diameter of the post polypectomy measurement was 0.85+/-0.53 cm (range: 0.2-3.0 cm). The mean diameter by visual estimation was 1.10+/-0.53 cm, which was significantly different compared to the actual size of the polyp (P<0.001). The mean diameters obtained using DGBF (0.87+/-0.54 cm) and ELMS (0.85+/-0.53 cm) did not significantly differ from the actual size of the polyp. The difference between the measurements from the ELMS and DGBF was not significant. CONCLUSION: Unlike visual estimations at colonoscopy, endoscopic graduated biopsy forceps and the endoscopic lesion measurement system are accurate methods to estimate polyp size. PMID- 25717255 TI - MicroRNA profiling of the intestine during hypothermic circulatory arrest in swine. AB - AIM: To perform a profiling analysis of changes in intestinal microRNA (miRNA) expression during hypothermic circulatory arrest (HCA). METHODS: A total of eight piglets were randomly divided into HCA and sham operation (SO) groups. Under general anesthesia, swine in the HCA group were subjected to hypothermic cardiopulmonary bypass at 24 degrees C followed by 80 min of circulatory arrest, and the reperfusion lasted for 180 min after cross-clamp removal. The counterparts in the SO group were only subjected to median sternotomy. Histopathological analysis was used to detect mucosal injury, and Pick-and-Mix custom miRNA real-time polymerase chain reaction (PCR) panels containing 306 unique primer sets were utilized to assay unpooled intestinal samples harvested from the two groups. RESULTS: The intestinal mucosa of the animals that were subjected to 24 degrees C HCA exhibited representative ischemic reperfusion injury of grade 2 or 3 according to the Chiu score. Such intestinal mucosal injuries, with the subepithelial space and epithelial layer lifting away from the lamina propria, were accompanied by shortened and irregular villi. On the contrary, the intestinal mucosa remained normal in the sham-operated animals. In total, twenty-five miRNAs were differentially expressed between the two groups (15 upregulated and 10 downregulated in the HCA group). Among these, eight miRNAs (miR-122, miR-221-5p, miR-31, miR-421-5p, miR-4333, miR-499-3p, miR-542 and let 7d-3p) were significantly dysregulated (four higher and four lower). The expression of miR-122 was significantly (5.37-fold) increased in the HCA group vs the SO group, indicating that it may play a key role in HCA-induced mucosal injury. CONCLUSION: Exposure to HCA caused intestinal miRNA dysregulation and barrier dysfunction in swine. These altered miRNAs might be related to the protection or destruction of the intestinal barrier. PMID- 25717256 TI - Semaphorin 4D and hypoxia-inducible factor-1alpha overexpression is related to prognosis in colorectal carcinoma. AB - AIM: To investigate semaphorin 4D (Sema4D) and hypoxia-inducible factor-1alpha (HIF-1alpha) expression in colorectal carcinoma and evaluate their clinicopathological and prognostic significance. METHODS: Eighty-six curatively resected colorectal carcinoma patients at different stages of disease were randomly selected from the group of patients who underwent surgery, and none of them received preoperative radiochemotherapy. Normal proximal adjacent bowel tissue, which served as an internal control, was obtained from 52 randomly selected patients. Immunohistochemistry was performed to analyze the expression of Sema4D and the tumor angiogenesis-related protein HIF-1alpha in normal colorectal tissues and colorectal carcinoma tissues. The relationships between the expression and clinical characters and prognosis were analyzed. RESULTS: HIF 1alpha and Sema4D were positively expressed in 58% and 60% of colorectal carcinoma tissues, respectively. Significantly lower expression levels were observed in normal mucosa (8% and 12%, respectively). HIF-1alpha and Sema4D expression was closely correlated with histological tumor type, tumor-node metastasis (TNM) stage, and lymphatic metastasis (P<0.05), but not with age or tumor size (P>0.05). HIF-1alpha and Sema4D protein expression was significantly correlated with prognosis of colorectal carcinoma, as determined by Spearman rank correlation analysis (r=0.567; P<0.01). Multivariate Cox analysis revealed that only Sema4D expression played a significant role in predicting patient prognosis (P<0.05). CONCLUSION: These findings suggest that HIF-1alpha and Sema4D expression correlates with histological tumor type, TNM stage, and lymphatic metastasis in colorectal carcinoma and that Sema4D is a prognostic indicator of colorectal carcinoma. PMID- 25717257 TI - New cancer suppressor gene for colorectal adenocarcinoma: filamin A. AB - AIM: To determine the expression and significance of filamin A (FLNa) in colorectal adenocarcinoma tissue. METHODS: The expression of FLNa in 46 colorectal cancer tissues and normal tissues was detected by immunohistochemistry, reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, and its relationship with clinical parameters and prognosis was analyzed. RESULTS: The positive expression of FLNa in cancer tissues was lower than that in normal mucosa, and the difference was statistically significant. The expression of FLNa correlated with liver metastasis, lymph node metastasis and rectal invasion depth, regardless of sex, age, tumor location, tumor size, gross shape and histological type of colorectal carcinoma. Multivariate analysis showed that FLNa was an independent risk factor for postoperative survival of patients with colorectal adenocarcinoma. Moreover, survival analysis showed that the expression level of FLNa was closely related with survival of patients with colorectal adenocarcinoma. The results of RT-PCR and Western blotting were consistent with those of immunohistochemistry. CONCLUSION: FLNa showed low expression in colorectal adenocarcinoma, high correlation with the incidence and development of colorectal cancer, and was considered an indicator of prognosis. PMID- 25717258 TI - Lymphangitic spread from the appendiceal adenocarcinoma to the ileocecal valve, mimicking Crohn's disease. AB - Due to the anatomical peculiarity of the appendix, diagnosis of tumors arising from this area can be challenging by clinicoradiologic means. We report a case of a rare primary appendiceal signet ring carcinoma with an uncommon presentation. An 86-year-old woman was admitted to our hospital with subacute epigastric pain. Computed tomography demonstrated bowel wall thickening with fat stranding in the ileocecal region. The leading diagnostic consideration was inflammatory bowel disease. Upon colonoscopy, a swollen, distorted ileocecal valve was identified. The remaining colon was otherwise unremarkable. Extensive biopsy sampling of the ileocecal region and colon was performed. A lymphangitic signet ring carcinoma within the ileocecal region was diagnosed on biopsy; there was no dysplasia or carcinoma of the remaining biopsies. By cytomorphology and immunoprofile, a lymphangitic signet ring carcinoma of appendiceal origin was the primary consideration, further confirmed upon subsequent laparotomy. This case represents an unusual pattern of appendiceal tumor spread with localized, lymphangitic involvement, creating a milieu which closely simulates Crohn's disease on imaging modalities. PMID- 25717259 TI - Human papillomavirus-related squamous cell carcinoma of the anal canal with papillary features. AB - Human papillomavirus (HPV) related squamous cell carcinoma (SCC) involving the anal canal is a well-known carcinoma associated with high-risk types of HPV. HPV related SCC with papillary morphology (papillary SCC) has been described in the oropharynx. We describe, for the first time, a case of anal HPV-related squamous carcinoma with papillary morphology. The tumor arose from the anal mucosa. The biopsies revealed a superficially invasive SCC with prominent papillary features and associated in situ carcinoma. The tumor cells were positive for p16 and were also positive for high-risk types of HPV using chromogenic in situ hybridization. The findings are consistent with a HPV-related SCC of the anal canal with papillary features. This tumor shows histologic features similar to a papillary HPV-related SCC of the oropharynx. Additional studies are needed to characterize these lesions. PMID- 25717260 TI - Combined glucocorticoid and antiviral therapy of hepatitis B virus-related liver failure. AB - Acute hepatic failure due to hepatitis B virus (HBV) can occur both during primary infection as well as after reactivation of chronic infection. Guidelines recommend considering antiviral therapy in both situations, although evidence supporting this recommendation is weak. Since HBV is not directly cytopathic, the mechanism leading to fulminant hepatitis B is thought to be primarily immune mediated. Therefore, immunosuppression combined with antiviral therapy might be a preferred therapeutic intervention in acute liver failure in hepatitis B. Here we report our favourable experience in three hepatitis B patients with fulminant hepatic failure who were treated by combining high-dose steroid therapy with standard antiviral treatment, which resulted in a rapid improvement of clinical and liver parameters. PMID- 25717261 TI - Resection of multiple rectal carcinoids with transanal endoscopic microsurgery: case report. AB - Multiple rectal carcinoids are rare. Due to the unreliability of endoscopic polypectomy in treating these submucosal lesions, a laparotomy is usually performed. We present a case report on multiple rectal carcinoids with three carcinoid foci<10 mm in diameter located in the mid-rectum. Preoperative examination showed the lesions to be confined to the submucosal layer with no perirectal nodal involvement. A transanal endoscopic microsurgery was successfully performed to remove the three lesions with accurate full-thickness resection followed by secured suture closure. The postoperative pathology revealed neuroendocrine tumors G1 (carcinoids) located within the submucosal layer without lymphatic or vessel infiltration. Both the deep and lateral surgical margins were completely free of tumor cells. The patient recovered quickly and uneventfully. No tumor recurrence was observed at the six-month follow-up. For the multiple small rectal carcinoids without muscularis propria or lymphatic invasion, transanal endoscopic microsurgery offers a reliable and efficient alternative approach to traditional laparotomy for select patients, with the added advantages of minimally invasive surgery. PMID- 25717262 TI - Gastroduodenal intussusception due to gastric schwannoma treated by Billroth II distal gastrectomy: one case report. AB - Schwannomas are rarely observed in the gastrointestinal tract. The most common symptoms of a gastric schwannoma are abdominal pain or dyspepsia, gastrointestinal bleeding, and an abdominal mass. Many gastric schwannomas are asymptomatic and are discovered incidentally or at postmortem. The diagnosis of a schwannoma is based on immunohistochemical positivity for S-100 protein. We present a case report of a rare complication of gastric schwannoma causing gastroduodenal intussusception that was successfully managed by a Billroth II distal gastrectomy. In this rare case, the patient had intermittent, colicky abdominal pain, nausea, and vomiting for over 4 wk accompanied by a weight loss. A diagnosis of gastric intussusception was made by computed tomography. A Billroth II distal gastrectomy was then performed, and complete en bloc removal (R0 resection) was achieved. Pathology confirmed a gastric schwannoma through positive immunohistochemical staining for S-100 protein. PMID- 25717263 TI - Portal hypertension induced by congenital hepatic arterioportal fistula: report of four clinical cases and review of the literature. AB - Intrahepatic arterioportal fistula (IAPF) can be caused by many secondary factors. We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic arterioportal fistula. The clinical manifestations included ascites, variceal hemorrhage and hepatic encephalopathy. Computed tomography scans from all of the patients revealed the early enhancement of the portal branches in the hepatic arterial phase. All patients were diagnosed using digital subtraction angiography (DSA). DSA before embolization revealed an arteriovenous fistula with immediate filling of the portal venous radicles. All four patients were treated with interventional embolization. The four patients remained in good condition throughout follow-up and at the time of publication. IAPF is frequently misdiagnosed due to its rarity; therefore, clinicians should consider IAPF as a potential cause of non-cirrhotic portal hypertension. PMID- 25717264 TI - Autoimmune hepatitis-primary biliary cirrhosis concurrent with biliary stricture after liver transplantation. AB - Although the development of de novo autoimmune liver disease after liver transplantation (LT) has been described in both children and adults, autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome has rarely been seen in liver transplant recipients. Here, we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis. His liver function tests became markedly abnormal 8 years after LT. Standard autoimmune serological tests were positive for anti-nuclear and anti mitochondrial antibodies, and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus. Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis, which confirmed the diagnosis of AIH-PBC overlap syndrome. We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome; a novel type of autoimmune overlap syndrome. PMID- 25717265 TI - Gastric myeloid sarcoma without acute myeloblastic leukemia. AB - Myeloid sarcomas (MS) involve extramedullary blast proliferation from one or more myeloid lineages that replace the original tissue architecture, and these neoplasias are called granulocytic sarcomas, chloromas or extramedullary myeloid tumors. Such tumors develop in lymphoid organs, bones (e.g., skulls and orbits), skin, soft tissue, various mucosae, organs, and the central nervous system. Gastrointestinal (GI) involvement is rare, while the occurrence of myeloid sarcomas in patients without leukemia is even rare. Here, we report a case of a 38-year-old man who presented with epigastric pain and progressive jaundice. An upper GI endoscopy had shown extensive multifocal hyperemic fold thickening and the spread of nodular lesions in the body of the stomach. Biopsies from the gastric lesions indicated myeloid sarcoma of the stomach. However, concurrent peripheral blood and bone marrow examinations showed no evidence of acute myeloid leukemia. For diagnosis, the immunohistochemical markers must be checked when evaluating a suspected myeloid sarcoma case. Accurate MS diagnosis determines the appropriate therapy and prognosis. PMID- 25717266 TI - Stent displacement in endoscopic pancreatic pseudocyst drainage and endoscopic management. AB - A pancreatic pseudocyst (PPC) is a collection of pancreatic fluid enclosed by a non-epithelialized, fibrous or granulomatous wall. Endoscopic pancreatic pseudocyst drainage (PPD) has been widely used clinically to treat PPCs. The success and complications of endoscopic PPD are comparable with surgical interventions. Stent displacement is a rare complication after endoscopic PPD. Almost all the complications of endoscopic PPD have been managed surgically, and there is rare report involving the endoscopic treatment of intraperitoneal stent displacement. We report here a case of stent displacement after endoscopic ultrasound- and fluoroscopy-guided PPD in a 41-year-old female patient with a PPC in the tail of the pancreas. The endoscopic treatment was successfully performed to remove the displaced stent. The clinical course of the patient was unremarkable. The cyst had significantly reduced and disappeared by 12 wk. We found that both endoscopic ultrasound and fluoroscopy should be used during endoscopic PPD to avoid stent displacement. The displaced stent can be successfully treated by endoscopic removal. PMID- 25717267 TI - Mixed adenoneuroendocrine carcinoma of the ampulla: two case reports. AB - Mixed adenoneuroendocrine carcinoma (MANEC) is a malignant tumor with adenocarcinoma and neuroendocrine components, with >=30% of each component required. MANEC of the ampulla is rare. To the best of our knowledge, only 15 cases of MANEC of the ampulla have been reported in the English-language literature. Here, we report two cases of MANEC of the ampulla in two women aged 43 and 60 years, which was confirmed by histology after pancreaticoduodenectomy. These tumors contained neuroendocrine and adenocarcinoma components. The neuroendocrine components were positive for chromogranin A (CgA), synaptophysin (Syn) and CD56 by immunostaining. The adenocarcinoma components were negative for CgA, Syn and CD56. Both cases were T3N0M0 (Stage IIIA). They survived for 15 and 20 mo after surgery, respectively. A brief discussion about the histopathological features, clinical behavior and treatment of MANEC of ampulla, and review of the relevant literature are presented. PMID- 25717268 TI - Adalimumab-induced interstitial pneumonia in a patient with Crohn's disease. AB - There are several reports of anti-tumor necrosis factor (TNF)-induced lung disease, especially in patients with rheumatologic diseases. Adalimumab is an anti-TNF drug used to induce and maintain remission in patients with immune mediated diseases, such as Crohn's disease. Although pulmonary disorders could be an extra-intestinal manifestation of inflammatory bowel disease, biologic therapy could also be a cause of lung injury. Only few cases of adalimumab-induced lung toxicity have been reported, and the majority of them were in patients with rheumatologic diseases. Lung injury secondary to anti-TNF therapy should, after ruling out other etiologies, be considered in patients who have a temporal association between the onset of respiratory symptoms and the exposure to these drugs. A compatible pattern in the biopsy and the clinical improvement after discontinuation of the anti-TNF drug would strongly support the diagnosis. PMID- 25717269 TI - Hepatitis B reactivation and timing for prophylaxis. AB - It is known that immunotherapy and cancer chemotherapy may cause hepatitis B virus (HBV) reactivation in hepatitis B surface antigen carriers and inactive chronic hepatitis B patients. Guidelines recommend antiviral prophylaxis regardless of HBV DNA levels to prevent reactivation. We read from the article written by Liu et al that Lamivudine was given inadequate time for antiviral prophylaxis. PMID- 25717270 TI - Reducing environmental risks to modify lifestyle behaviors. PMID- 25717271 TI - Unrealistic optimism, sex, and risk perception of type 2 diabetes onset: implications for education programs. AB - This study examined links among unrealistic optimism, sex, and risk perception of type 2 diabetes onset in college students. Participants included 660 college students who consented to complete a questionnaire. The results showed significant differences between students who perceived that they were at risk for type 2 diabetes onset and those who thought their peers were the ones at risk. A higher prevalence of participants thought their peers were the ones at risk for type 2 diabetes. Women were more likely than men to report a higher risk perception, indicating that their peers were at lower risk for diabetes onset. PMID- 25717272 TI - Exercise as medicine for diabetes: prescribing appropriate activities and avoiding potential pitfalls: preface. PMID- 25717273 TI - Guest editor. PMID- 25717274 TI - Moving beyond cardio: the value of resistance training, balance training, and other forms of exercise in the management of diabetes. AB - IN BRIEF Traditionally, aerobic training has been a central focus of exercise promotion for diabetes management. However, people with diabetes have much to gain from other forms of exercise. This article reviews the evidence and recommendations on resistance, balance, and flexibility training, as well as other, less traditional, forms of exercise such as yoga and Tai Chi. PMID- 25717275 TI - Exercise strategies to optimize glycemic control in type 2 diabetes: a continuing glucose monitoring perspective. AB - IN BRIEF The introduction of continuous glucose monitoring (CGM) several years ago enabled researchers to investigate the impact of exercise strategies on 24 hour glycemic control. Such unique information on the glucoregulatory properties of exercise will ultimately lead to more effective exercise programs to prevent and treat type 2 diabetes. This article reviews the role of exercise and physical activity in the treatment of type 2 diabetes, complemented by recent data obtained by CGM. PMID- 25717276 TI - Exercise strategies for hypoglycemia prevention in individuals with type 1 diabetes. AB - IN BRIEF Fear of hypoglycemia is one of the main barriers to physical activity for individuals with type 1 diabetes. Recent studies indicate that anaerobic forms of exercise (i.e., resistance exercise/weight lifting, sprints, and high intensity intervals) can attenuate exercise-related declines in blood glucose both during and after exercise in young, healthy adults with type 1 diabetes. These responses might vary based on age, sex, and fitness level and in the general safety of relying on them to prevent hypoglycemia. PMID- 25717277 TI - Effectiveness and safety of high-intensity interval training in patients with type 2 diabetes. AB - IN BRIEF Recent research has shown that high-intensity interval training (HIIT) can promote improvements in glucose control and cardiovascular health in individuals with type 2 diabetes. This article summarizes the evidence and highlights the ways in which HIIT might be safely implemented as an adjunct to more traditional exercise approaches. PMID- 25717278 TI - High-tech tools for exercise motivation: use and role of technologies such as the internet, mobile applications, social media, and video games. AB - IN BRIEF The majority of patients with type 2 diabetes are not active at recommended levels, and many do not have access to behavior change programs to support lifestyle change. Thus, tools and programs designed to promote the adoption and maintenance of physical activity using technology may be helpful. This article reviews the evidence regarding the use of technology tools such as the Internet, mobile applications, social media, and video games and provides suggestions for evaluating the potential benefit of such tools for behavior change. PMID- 25717280 TI - Medication and exercise interactions: considering and managing hypoglycemia risk. PMID- 25717279 TI - Prevention of exercise-associated dysglycemia: a case study-based approach. PMID- 25717281 TI - A novel approach to adolescents with type 1 diabetes: the team clinic model. PMID- 25717282 TI - Observations of Children's Interactions with Teachers, Peers, and Tasks across Preschool Classroom Activity Settings. AB - This descriptive study examined classroom activity settings in relation to children's observed behavior during classroom interactions, child gender, and basic teacher behavior within the preschool classroom. 145 children were observed for an average of 80 minutes during 8 occasions across 2 days using the inCLASS, an observational measure that conceptualizes behavior into teacher, peer, task, and conflict interactions. Findings indicated that on average children's interactions with teachers were higher in teacher-structured settings, such as large group. On average, children's interactions with peers and tasks were more positive in child-directed settings, such as free choice. Children experienced more conflict during recess and routines/transitions. Finally, gender differences were observed within small group and meals. The implications of these findings might encourage teachers to be thoughtful and intentional about what types of support and resources are provided so children can successfully navigate the demands of particular settings. These findings are not meant to discourage certain teacher behaviors or imply value of certain classroom settings; instead, by providing an evidenced-based picture of the conditions under which children display the most positive interactions, teachers can be more aware of choices within these settings and have a powerful way to assist in professional development and interventions. PMID- 25717283 TI - Experimental Evaluation of a Deformable Registration Algorithm for Motion Correction in PET-CT Guided Biopsy. AB - Positron emission tomography computed tomography (PET-CT) images are increasingly being used for guidance during percutaneous biopsy. However, due to the physics of image acquisition, PET-CT images are susceptible to problems due to respiratory and cardiac motion, leading to inaccurate tumor localization, shape distortion, and attenuation correction. To address these problems, we present a method for motion correction that relies on respiratory gated CT images aligned using a deformable registration algorithm. In this work, we use two deformable registration algorithms and two optimization approaches for registering the CT images obtained over the respiratory cycle. The two algorithms are the BSpline and the symmetric forces Demons registration. In the first optmization approach, CT images at each time point are registered to a single reference time point. In the second approach, deformation maps are obtained to align each CT time point with its adjacent time point. These deformations are then composed to find the deformation with respect to a reference time point. We evaluate these two algorithms and optimization approaches using respiratory gated CT images obtained from 7 patients. Our results show that overall the BSpline registration algorithm with the reference optimization approach gives the best results. PMID- 25717284 TI - Ribonucleic acid (RNA) biosynthesis in human cancer. AB - In many respects, the most remarkable chemical substances within the genome of eukaryotic cells are remarkable proteins which are the critical structural and functional units of living cells. The specifications for everything that goes in the cell are natural digital-to-digital decoding process in an archive sequence by deoxyribonucleic acid (DNA) and an articulate construction by ribonucleic acid (RNA). The products of DNA transcription are long polymers of ribonucleotides rather than deoxyribonucleotides and are termed ribonucleic acids. Certain deoxyribonucleotide sequences, or genes, give rise to transfer RNA (tRNA) and other ribosomal RNA (rRNA) when transcribed. The ribonucleotide sequences fold extensively and rRNA is associated with specific proteins to yield the essential cell components, ribosomes. Transcription of other special sequences yields messenger RNAs (mRNAs) that contain ribonucleotide sequences that will be ultimately translated into new types of amino acid sequences of functional cellular protein molecules. This switch to a different variety of cellular molecular sequences is complex, but each sequence of the three ribonucleotides specifies the insertion of one particular amino acid into the polypeptide chain under production. Whilst mRNA is considered the vehicle by which genetic information is transmitted from the genome and allocated in the appropriate cytoplasmic sites for translation into protein via cap-dependent mechanism, the actual translation depends also on the presence of other so-called household and luxury protein molecules. Recent evidence suggests RNA species are required at initiation, because treatment of cells with antibiotics or drugs that inhibit RNA synthesis cause a decrease in protein synthesis. The rRNA is necessary as a structural constituent of the ribosomes upon which translation takes place, whereas tRNA is necessary as an adaptor in amino acid activation and elongation protein chains to ribosomes. In this article, we review malignant tumor, with stem like properties, and recent technical advances into the phenomenon of micro particles and micro-vesicles containing cell-free nucleic acids that circulate plasma. New areas of research have been opened into screening tumor telomerase progression, prognosis of aptamers targeting cell surface, monitoring the efficacy of anticancer therapies, oncogenic transformation of host cell, and RNA polymerases role in the cell cycle progression and differentiation. PMID- 25717285 TI - Orphan nuclear receptor NR4A2 induces transcription of the immunomodulatory peptide hormone prolactin. AB - BACKGROUND: Nuclear receptor 4A2 (NR4A2) is an orphan nuclear receptor and constitutively active transcription factor expressed at elevated levels in inflamed joint tissues from patients with arthritis. Inflammatory mediators rapidly and potently induce NR4A2 expression in resident joint cells and infiltrating immune cells. This receptor promotes synovial hyperplasia by increasing proliferation of synoviocytes and inducing transcription of matrix degrading enzymes and pro-inflammatory mediators. In order to further elucidate the molecular mechanisms of NR4A2, we conducted a gene expression screen to identify novel transcriptional targets of NR4A2 that may contribute to arthritis progression. METHODS: NR4A2 was over-expressed in human synoviocytes by lentiviral transduction and gene expression changes were measured using qPCR arrays specific for inflammation, proliferation, adhesion, and migration pathways. Subsequent analysis focused on the most potently induced gene prolactin (PRL). Messenger RNA levels of PRL and PRL receptor (PRL-R) were measured by RT qPCR and protein levels were measured by ELISA. PRL promoter studies were conducted in synoviocytes transiently transfected with NR4A2 and PRL reporter constructs. Molecular responses to PRL in synoviocytes were addressed using qPCR arrays specific for JAK/STAT signaling pathways. RESULTS: PRL was the most potently induced gene on the qPCR arrays, exhibiting a 68-fold increase in response to ectopic NR4A2. This gene encodes an immunomodulatory peptide hormone with roles in autoimmune diseases and inflammation. Induction of PRL mRNA and secreted protein by NR4A2 was confirmed in subsequent experiments, with increases of 300-fold and 18-fold respectively. Depletion of endogenous NR4A receptors with shRNA reduced basal and PGE2-induced PRL levels by 95%. At the transcriptional level, NR4A2 requires a functional DNA binding domain to transactivate the distal PRL promoter. Deletional analysis indicates that NR4A2 targets a region of the distal PRL promoter spanning -270 to -32 bp. In synoviocytes, recombinant PRL regulates several genes involved in inflammation, proliferation, and cell survival, suggesting that NR4A2 induced PRL may also impact these pathways and contribute to arthritis progression. CONCLUSIONS: These results provide the first evidence for transcriptional regulation of the immunomodulatory peptide hormone PRL by NR4A2 in synoviocytes, and highlight a novel molecular pathway in inflammatory arthritis. PMID- 25717286 TI - Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism - the J-EINSTEIN DVT and PE program. AB - BACKGROUND: The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban. METHODS: We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5-2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding. RESULTS: Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, 3.4-23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group. CONCLUSIONS: The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01516840 and NCT01516814. PMID- 25717287 TI - Improving the estimation of the burden of risk factors: an illustrative comparison of methods to measure smoking-attributable mortality. AB - BACKGROUND: Prevention efforts are informed by the numbers of deaths or cases of disease caused by specific risk factors, but these are challenging to estimate in a population. Fortunately, an increasing number of jurisdictions have increasingly rich individual-level, population-based data linking exposures and outcomes. These linkages enable multivariable approaches to risk assessment. We demonstrate how this approach can estimate the population burden of risk factors and illustrate its advantages over often-used population-attributable fraction methods. METHODS: We obtained risk factor information for 78,597 individuals from a series of population-based health surveys. Each respondent was linked to death registry (568,997 person-years of follow-up, 6,399 deaths).Two methods were used to obtain population-attributable fractions. First, the mortality rate difference between the entire population and the population of non-smokers was divided by the total mortality rate. Second, often-used attributable fraction formulas were used to combine summary measures of smoking prevalence with relative risks of death for select diseases. The respective fractions were then multiplied to summary measures of mortality to obtain smoking-attributable mortality. Alternatively, for our multivariable approach, we created algorithms for risk of death, predicted by health behaviors and various covariates (age, sex, socioeconomic position, etc.). The burden of smoking was determined by comparing the predicted mortality of the current population with that of a counterfactual population where smoking is eliminated. RESULTS: Our multivariable algorithms accurately predicted an individual's risk of death based on their health behaviors and other variables in the models. These algorithms estimated that 23.7% of all deaths can be attributed to smoking in Ontario. This is higher than the 20.0% estimated using population-attributable risk methods that considered only select diseases and lower than the 35.4% estimated from population attributable risk methods that examine the excess burden of all deaths due to smoking. CONCLUSIONS: The multivariable algorithms presented have several advantages, including: controlling for confounders, accounting for complexities in the relationship between multiple exposures and covariates, using consistent definitions of exposure, and using specific measures of risk derived internally from the study population. We propose the wider use of multivariable risk assessment approach as an alternative to population-attributable fraction methods. PMID- 25717288 TI - Economic well-being among elderly couples in marriage and cohabitation in Mexico. AB - In Latin America, the proportion of people in middle and late age who are cohabiting is higher than in industrialized countries. Some scholars consider cohabitation as an "incomplete" institution, where couples fare worse in economic and social well-being compared to marriage. The paper's goal is to analyze whether cohabiting couples in old age face a different economic situation than married couples, and whether this difference is due to the fact that cohabiters might be a selected group from the general population. The analysis focuses on Mexican couples where at least one of the partners was older than 49, by using the first wave of the Mexican Health and Aging Survey (MHAS) 2001 dataset, and part of the 2003 second wave. After controlling for compositional variables (related to selection into consensual unions), the paper finds no significant difference in net worth, change in net worth (from 2001 to 2003), and perceived financial situation between married and cohabiting couples, but there is on the likelihood of owning a house. PMID- 25717289 TI - Resting-state functional connectivity and pitch identification ability in non musicians. AB - Previous studies have used task-related fMRI to investigate the neural basis of pitch identification (PI), but no study has examined the associations between resting-state functional connectivity (RSFC) and PI ability. Using a large sample of Chinese non-musicians (N = 320, with 56 having prior musical training), the current study examined the associations among musical training, PI ability, and RSFC. Results showed that musical training was associated with increased RSFC within the networks for multiple cognitive functions (such as vision, phonology, semantics, auditory encoding, and executive functions). PI ability was associated with RSFC with regions for perceptual and auditory encoding for participants with musical training, and with RSFC with regions for short-term memory, semantics, and phonology for participants without musical training. PMID- 25717290 TI - The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer's disease. AB - We previously demonstrated that, in the early stages of tau processing in Alzheimer's disease, the N-terminal part of the molecule undergoes a characteristic cascade of phosphorylation and progressive misfolding of the proteins resulting in a structural conformation detected by Alz-50. In this immunohistochemical study of AD brain tissue, we have found that C-terminal truncation of tau at Asp-421 was an early event in tau aggregation and analyzed the relationship between phospho-dependent tau epitopes located at the C-terminus with truncation at Glu-391. The aim of this study was to determine whether C terminal truncation may trigger events leading to the assembly of insoluble PHFs from soluble tau aggregates present in pre-tangle cells. Our findings suggest that there is a complex interaction between phosphorylated and truncated tau species. A model is presented here in which truncated tau protein represents an early neurotoxic species while phosphorylated tau species may provide a neuroprotective role in Alzheimer's disease. PMID- 25717291 TI - Acoustic change responses to amplitude modulation: a method to quantify cortical temporal processing and hemispheric asymmetry. AB - OBJECTIVE: Sound modulation is a critical temporal cue for the perception of speech and environmental sounds. To examine auditory cortical responses to sound modulation, we developed an acoustic change stimulus involving amplitude modulation (AM) of ongoing noise. The AM transitions in this stimulus evoked an acoustic change complex (ACC) that was examined parametrically in terms of rate and depth of modulation and hemispheric symmetry. METHODS: Auditory cortical potentials were recorded from 64 scalp electrodes during passive listening in two conditions: (1) ACC from white noise to 4, 40, 300 Hz AM, with varying AM depths of 100, 50, 25% lasting 1 s and (2) 1 s AM noise bursts at the same modulation rate. Behavioral measures included AM detection from an attend ACC condition and AM depth thresholds (i.e., a temporal modulation transfer function, TMTF). RESULTS: The N1 response of the ACC was large to 4 and 40 Hz and small to the 300 Hz AM. In contrast, the opposite pattern was observed with bursts of AM showing larger responses with increases in AM rate. Brain source modeling showed significant hemispheric asymmetry such that 4 and 40 Hz ACC responses were dominated by right and left hemispheres respectively. CONCLUSION: N1 responses to the ACC resembled a low pass filter shape similar to a behavioral TMTF. In the ACC paradigm, the only stimulus parameter that changes is AM and therefore the N1 response provides an index for this AM change. In contrast, an AM burst stimulus contains both AM and level changes and is likely dominated by the rise time of the stimulus. The hemispheric differences are consistent with the asymmetric sampling in time hypothesis suggesting that the different hemispheres preferentially sample acoustic time across different time windows. SIGNIFICANCE: The ACC provides a novel approach to studying temporal processing at the level of cortex and provides further evidence of hemispheric specialization for fast and slow stimuli. PMID- 25717292 TI - Spinal metaplasticity in respiratory motor control. AB - A hallmark feature of the neural system controlling breathing is its ability to exhibit plasticity. Less appreciated is the ability to exhibit metaplasticity, a change in the capacity to express plasticity (i.e., "plastic plasticity"). Recent advances in our understanding of cellular mechanisms giving rise to respiratory motor plasticity lay the groundwork for (ongoing) investigations of metaplasticity. This detailed understanding of respiratory metaplasticity will be essential as we harness metaplasticity to restore breathing capacity in clinical disorders that compromise breathing, such as cervical spinal injury, motor neuron disease and other neuromuscular diseases. In this brief review, we discuss key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output; particularly after pre-conditioning with intermittent hypoxia. Progress in this area has led to the realization that similar mechanisms are operative in other spinal motor networks, including those governing limb movement. Further, these mechanisms can be harnessed to restore respiratory and non-respiratory motor function after spinal injury. PMID- 25717293 TI - The brain adjusts grip forces differently according to gravity and inertia: a parabolic flight experiment. AB - In everyday life, one of the most frequent activities involves accelerating and decelerating an object held in precision grip. In many contexts, humans scale and synchronize their grip force (GF), normal to the finger/object contact, in anticipation of the expected tangential load force (LF), resulting from the combination of the gravitational and the inertial forces. In many contexts, GF and LF are linearly coupled. A few studies have examined how we adjust the parameters-gain and offset-of this linear relationship. However, the question remains open as to how the brain adjusts GF regardless of whether LF is generated by different combinations of weight and inertia. Here, we designed conditions to generate equivalent magnitudes of LF by independently varying mass and movement frequency. In a control experiment, we directly manipulated gravity in parabolic flights, while other factors remained constant. We show with a simple computational approach that, to adjust GF, the brain is sensitive to how LFs are produced at the fingertips. This provides clear evidence that the analysis of the origin of LF is performed centrally, and not only at the periphery. PMID- 25717294 TI - The cooking task: making a meal of executive functions. AB - Current standardized neuropsychological tests may fail to accurately capture real world executive deficits. We developed a computer-based Cooking Task (CT) assessment of executive functions and trialed the measure with a normative group before use with a head-injured population. Forty-six participants completed the computerized CT and subtests from standardized neuropsychological tasks, including the Tower and Sorting Tests of executive function from the Delis-Kaplan Executive Function System (D-KEFS) and the Cambridge prospective memory test (CAMPROMPT), in order to examine whether standardized executive function tasks, predicted performance on measurement indices from the CT. Findings showed that verbal comprehension, rule detection and prospective memory contributed to measures of prospective planning accuracy and strategy implementation of the CT. Results also showed that functions necessary for cooking efficacy differ as an effect of task demands (difficulty levels). Performance on rule detection, strategy implementation and flexible thinking executive function measures contributed to accuracy on the CT. These findings raise questions about the functions captured by present standardized tasks particularly at varying levels of difficulty and during dual-task performance. Our preliminary findings also indicate that CT measures can effectively distinguish between executive function and Full Scale IQ abilities. Results of the present study indicate that the CT shows promise as an ecologically valid measure of executive function for future use with a head-injured population and indexes selective executive function's captured by standardized tests. PMID- 25717295 TI - Nicotine receptors mediating sensorimotor gating and its enhancement by systemic nicotine. AB - Prepulse inhibition (PPI) of startle occurs when intensity stimuli precede stronger startle-inducing stimuli by 10-1000 ms. PPI deficits are found in individuals with schizophrenia and other psychiatric disorders, and they correlate with other cognitive impairments. Animal research and clinical studies have demonstrated that both PPI and cognitive function can be enhanced by nicotine. PPI has been shown to be mediated, at least in part, by mesopontine cholinergic neurons that project to pontine startle neurons and activate muscarinic and potentially nicotine receptors (nAChRs). The subtypes and anatomical location of nAChRs involved in mediating and modulating PPI remain unresolved. We tested the hypothesis that nAChRs that are expressed by pontine startle neurons contribute to PPI. We also explored whether or not these pontine receptors are responsible for the nicotine enhancement of PPI. While systemic administration of nAChR antagonists had limited effects on PPI, PnC microinfusions of the non-alpha7nAChR preferring antagonist TMPH, but not of the alpha7nAChR antagonist MLA, into the PnC significantly reduced PPI. Electrophysiological recordings from startle-mediating PnC neurons confirmed that nicotine affects excitability of PnC neurons, which could be antagonized by TMPH, but not by MLA, indicating the expression of non-alpha7nAChR. In contrast, systemic nicotine enhancement of PPI was only reversed by systemic MLA and not by TMPH or local microinfusions of MLA into the PnC. In summary, our data indicate that non-alpha7nAChRs in the PnC contribute to PPI at stimulus intervals of 100 ms or less, whereas activation of alpha7nAChRs in other brain areas is responsible for the systemic nicotine enhancement of PPI. This is important knowledge for the correct interpretation of behavioral, preclinical, and clinical data as well as for developing drugs for the amelioration of PPI deficits and the enhancement of cognitive function. PMID- 25717296 TI - Evidence for altered upper extremity muscle synergies in chronic stroke survivors with mild and moderate impairment. AB - Previous studies indicate that motor coordination may be achieved by assembling task-dependent combinations of a few muscle synergies, defined here as fixed patterns of activation across a set of muscles. Our recent study of severely impaired chronic stroke survivors showed that some muscle synergies underlying isometric force generation at the hand are altered in the affected arm. However, whether similar alterations are evident in stroke survivors with lesser impairment remains unclear. Accordingly, we examined muscle synergies underlying spatial patterns of elbow and shoulder muscle activation recorded during an isometric force target matching protocol performed by 16 chronic stroke survivors, evenly divided across mild and moderate impairment levels. We applied non-negative matrix factorization to identify the muscle synergies and compared their structure across groups, including previously collected data from six age matched control subjects and eight severely impaired stroke survivors. For all groups, EMG spatial patterns were well explained by task-dependent combinations of only a few (typically 4) muscle synergies. Broadly speaking, elbow-related synergies were conserved across stroke survivors, regardless of impairment level. In contrast, the shoulder-related synergies of some stroke survivors with mild and moderate impairment differed from controls, in a manner similar to severely impaired subjects. Cluster analysis of pooled synergies for the 30 subjects identified seven distinct clusters (synergies). Subsequent analysis confirmed that the incidences of three elbow-related synergies were independent of impairment level, while the incidences of four shoulder-related synergies were systematically correlated with impairment level. Overall, our results suggest that alterations in the shoulder muscle synergies underlying isometric force generation appear prominently in mild and moderate stroke, as in most cases of severe stroke, in an impairment level-dependent manner. PMID- 25717297 TI - Enhanced Neuroactivation during Working Memory Task in Postmenopausal Women Receiving Hormone Therapy: A Coordinate-Based Meta-Analysis. AB - BACKGROUND AND AIM: Hormone therapy (HT) has long been thought beneficial for controlling menopausal symptoms and human cognition. Studies have suggested that HT has a positive association with working memory, but no consistent relationship between HT and neural activity has been shown in any cognitive domain. The purpose of this meta-analysis was to assess the convergence of findings from published randomized control trials studies that examined brain activation changes in postmenopausal women. METHODS: A systematic search for fMRI studies of neural responses during working memory tasks in postmenopausal women was performed. Studies were excluded if they were not treatment studies and did not contain placebo or blank controls. For the purpose of the meta-analysis, 8 studies were identified, with 103 postmenopausal women taking HT and 109 controls. RESULTS: Compared with controls, postmenopausal women who took HT increased activation in the left frontal lobe, including superior frontal gyrus (BA 8), right middle frontal gyrus (BA 9), anterior lobe, paracentral lobule (BA 7), limbic lobe, and anterior cingulate (BA 32). Additionally, decreased activation is noted in the right limbic lobe, including parahippocampal gyrus (BA 28), left parietal lobe, and superior parietal lobule (BA 7). All regions were significant at p <= 0.05 with correction for multiple comparisons. CONCLUSION: Hormone treatment is associated with BOLD signal activation in key anatomical areas during fMRI working memory tasks in healthy hormone-treated postmenopausal women. A positive correlation between activation and task performance suggests that hormone use may benefit working memory. PMID- 25717298 TI - Basic perceptual changes that alter meaning and neural correlates of recognition memory. AB - It is difficult to pinpoint the border between perceptual and conceptual processing, despite their treatment as distinct entities in many studies of recognition memory. For instance, alteration of simple perceptual characteristics of a stimulus can radically change meaning, such as the color of bread changing from white to green. We sought to better understand the role of perceptual and conceptual processing in memory by identifying the effects of changing a basic perceptual feature (color) on behavioral and neural correlates of memory in circumstances when this change would be expected to either change the meaning of a stimulus or to have no effect on meaning (i.e., to influence conceptual processing or not). Abstract visual shapes ("squiggles") were colorized during study and presented during test in either the same color or a different color. Those squiggles that subjects found to resemble meaningful objects supported behavioral measures of conceptual priming, whereas meaningless squiggles did not. Further, changing color from study to test had a selective effect on behavioral correlates of priming for meaningful squiggles, indicating that color change altered conceptual processing. During a recognition memory test, color change altered event-related brain potential (ERP) correlates of memory for meaningful squiggles but not for meaningless squiggles. Specifically, color change reduced the amplitude of frontally distributed N400 potentials (FN400), implying that these potentials indicated conceptual processing during recognition memory that was sensitive to color change. In contrast, color change had no effect on FN400 correlates of recognition for meaningless squiggles, which were overall smaller in amplitude than for meaningful squiggles (further indicating that these potentials signal conceptual processing during recognition). Thus, merely changing the color of abstract visual shapes can alter their meaning, changing behavioral and neural correlates of memory. These findings are relevant to understanding similarities and distinctions between perceptual and conceptual processing as well as the functional interpretation of neural correlates of recognition memory. PMID- 25717299 TI - Strengths and weakness of neuroscientific investigations of childhood poverty: future directions. AB - The neuroscientific study of child poverty is a topic that has only recently emerged. In comparison with previous reviews (e.g., Hackman and Farah, 2009; Lipina and Colombo, 2009; Hackman et al., 2010; Raizada and Kishiyama, 2010; Lipina and Posner, 2012), our perspective synthesizes findings, and summarizes both conceptual and methodological contributions, as well as challenges that face current neuroscientific approaches to the study of childhood poverty. The aim of this effort is to identify target areas of study that could potentially help build a basic and applied research agenda for the coming years. PMID- 25717300 TI - Contagious itch: what we know and what we would like to know. AB - All humans experience itch in the course of their life. Even a discussion on the topic of itch or seeing people scratch can evoke the desire to scratch. These events are coined "contagious itch" and are very common. We and others have shown that videos showing people scratching and pictures of affected skin or insects can induce itch in healthy persons and chronic itch patients. In our studies, patients with atopic dermatitis (AD) were more susceptible to visual itch cues than healthy. Also, personality traits like agreeableness and public self consciousness were associated with induced scratching in skin patients, while neuroticism correlated with induced itch in healthy subjects. The underlying course of contagious itch is not yet fully understood. It is hypothesized that there are human mirror neurons that are active when we imitate actions and/or negative affect. Until now, there has been only limited data on the mechanisms of brain activation in contagious itch though. We have barely begun to understand the underlying physiological reactions and the triggering factors of this phenomenon. We summarize what we currently know about contagious itch and provide some suggestions what future research should focus on. PMID- 25717301 TI - A self-organizing model of perisaccadic visual receptive field dynamics in primate visual and oculomotor system. AB - We propose and examine a model for how perisaccadic visual receptive field dynamics, observed in a range of primate brain areas such as LIP, FEF, SC, V3, V3A, V2, and V1, may develop through a biologically plausible process of unsupervised visually guided learning. These dynamics are associated with remapping, which is the phenomenon where receptive fields anticipate the consequences of saccadic eye movements. We find that a neural network model using a local associative synaptic learning rule, when exposed to visual scenes in conjunction with saccades, can account for a range of associated phenomena. In particular, our model demonstrates predictive and pre-saccadic remapping, responsiveness shifts around the time of saccades, and remapping from multiple directions. PMID- 25717302 TI - Dynamics of receptor-operated Ca(2+) currents through TRPC channels controlled via the PI(4,5)P2-PLC signaling pathway. AB - Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable, nonselective cation channels that carry receptor-operated Ca(2+) currents (ROCs) triggered by receptor-induced, phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction, and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5)P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5)P2 and the possible role of PI(4,5)P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5)P2 using a model simulation that could explain the complicated effects of PI(4,5)P2 on different ROCs. PMID- 25717304 TI - A method for a categorized and probabilistic analysis of the surface electromyogram in dynamic contractions. AB - The human motor system permits a wide variety of complex movements. Thereby, the inter-individual variability as well as the biomechanical aspects of the performed movement itself contribute to the challenge of the interpretation of sEMG signals in dynamic contractions. A procedure for the systematic analysis of sEMG recordings during dynamic contraction was introduced, which includes categorization of the data in combination with the analysis of frequency distributions of the sEMG with a probabilistic approach. Using the example of elbow flexion and extension the procedure was evaluated with 10 healthy subjects. The recorded sEMG signals of brachioradialis were categorized into a combination of constant and variable movement factors, which originate from the performed movement. Subsequently, for each combination of movement factors cumulative frequency distributions were computed for each subject separately. Finally, the probability of the difference of muscular activation in varying movement conditions was assessed. The probabilistic approach was compared to a deterministic analysis of the same data. Both approaches observed a significant change of muscular activation of brachioradialis during concentric and eccentric contractions exclusively for flexion and extension angles exceeding 30 degrees . However, with the probabilistic approach additional information on the likelihood that the tested effect occurs can be provided. Especially for movements under uncontrollable boundary conditions, this information to assess the confidence of the detected results is of high relevance. Thus, the procedure provides new insights into the quantification and interpretation of muscular activity. PMID- 25717305 TI - Computational analysis of the electromechanical consequences of short QT syndrome. PMID- 25717303 TI - The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy. AB - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal epilepsy with attacks typically arising in the frontal lobe during non-rapid eye movement (NREM) sleep. It is characterized by clusters of complex and stereotyped hypermotor seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs). This is consistent with the widespread expression of these receptors, particularly the alpha4beta2(*) subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal epilepsy is far from being straightforward because of the complexity of the cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR role in prefrontal regions as well as the studies carried out in murine models of ADNFLE. Functional evidence points to alterations in prefrontal GABA release, and the synaptic unbalance probably arises during the cortical circuit maturation. Although most of the available functional evidence concerns mutations on nAChR subunit genes, other genes have been recently implicated in the disease, such as KCNT1 (coding for a Na(+)-dependent K(+) channel), DEPD5 (Disheveled, Egl-10 and Pleckstrin Domain-containing protein 5), and CRH (Corticotropin-Releasing Hormone). Overall, the uncertainties about both the etiology and the pathogenesis of ADNFLE point to the current gaps in our knowledge the regulation of neuronal networks in the cerebral cortex. PMID- 25717306 TI - Neurological soft signs in aging, mild cognitive impairment, and Alzheimer's disease - the impact of cognitive decline and cognitive reserve. AB - OBJECTIVES: Neurological soft signs (NSS), i.e., minor motor and sensory changes, are a common feature in severe psychiatric disorders. We sought to establish the frequency of NSS in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) on basis of a large population-based sample and to identify their neuropsychological correlates including cognitive reserve. METHODS: Neurological soft signs were examined using an abbreviated version of the Heidelberg NSS Scale in 221 "old" participants born between 1930 and 1932 (63 with MCI, 15 with AD, 143 healthy old controls) and 256 healthy "young" participants (born between 1950 and 1952) of the population-based interdisciplinary longitudinal study of aging. Subjects received thorough neuropsychological testing; years of school education were used as a proxy for cognitive reserve. RESULTS: Neurological soft signs scores were significantly (p < 0.001) higher in the AD patients (5.6 +/- 3.11) than in the healthy old controls (2.8 +/- 1.90) and in the MCI patients (3.0 +/- 1.96). This result was confirmed after years of school education, which were inversely correlated (r = -0.25; p < 0.001) with NSS were entered as a covariate. In the patients, but not in the controls, NSS were significantly correlated with deficits in executive functioning and visuospatial functioning. Comparison of NSS scores between "old" (2.84 +/- 1.9) and "young" (2.46 +/- 1.97) controls yielded only minor, non-significant differences after education (13.86 +/- 3.0 vs. 14.61 +/- 2.48 years, respectively) was controlled for. CONCLUSION: Our results demonstrate that NSS are frequently found in mild AD, but not in MCI. NSS refer to frontal-executive deficits and visuospatial dysfunction rather than age per se and can be partly compensated for by cognitive reserve. PMID- 25717307 TI - A matter of time: improvement of visual temporal processing during training induced restoration of light detection performance. AB - The issue of how basic sensory and temporal processing are related is still unresolved. We studied temporal processing, as assessed by simple visual reaction times (RT) and double-pulse resolution (DPR), in patients with partial vision loss after visual pathway lesions and investigated whether vision restoration training (VRT), a training program designed to improve light detection performance, would also affect temporal processing. Perimetric and campimetric visual field tests as well as maps of DPR thresholds and RT were acquired before and after a 3 months training period with VRT. Patient performance was compared to that of age-matched healthy subjects. Intact visual field size increased during training. Averaged across the entire visual field, DPR remained constant while RT improved slightly. However, in transition zones between the blind and intact areas (areas of residual vision) where patients had shown between 20 and 80% of stimulus detection probability in pre-training visual field tests, both DPR and RT improved markedly. The magnitude of improvement depended on the defect depth (or degree of intactness) of the respective region at baseline. Inter individual training outcome variability was very high, with some patients showing little change and others showing performance approaching that of healthy controls. Training-induced improvement of light detection in patients with visual field loss thus generalized to dynamic visual functions. The findings suggest that similar neural mechanisms may underlie the impairment and subsequent training-induced functional recovery of both light detection and temporal processing. PMID- 25717308 TI - Cultural stereotypes as gatekeepers: increasing girls' interest in computer science and engineering by diversifying stereotypes. AB - Despite having made significant inroads into many traditionally male-dominated fields (e.g., biology, chemistry), women continue to be underrepresented in computer science and engineering. We propose that students' stereotypes about the culture of these fields-including the kind of people, the work involved, and the values of the field-steer girls away from choosing to enter them. Computer science and engineering are stereotyped in modern American culture as male oriented fields that involve social isolation, an intense focus on machinery, and inborn brilliance. These stereotypes are compatible with qualities that are typically more valued in men than women in American culture. As a result, when computer science and engineering stereotypes are salient, girls report less interest in these fields than their male peers. However, altering these stereotypes-by broadening the representation of the people who do this work, the work itself, and the environments in which it occurs-significantly increases girls' sense of belonging and interest in the field. Academic stereotypes thus serve as gatekeepers, driving girls away from certain fields and constraining their learning opportunities and career aspirations. PMID- 25717309 TI - Toward a general psychological model of tension and suspense. AB - Tension and suspense are powerful emotional experiences that occur in a wide variety of contexts (e.g., in music, film, literature, and everyday life). The omnipresence of tension and suspense suggests that they build on very basic cognitive and affective mechanisms. However, the psychological underpinnings of tension experiences remain largely unexplained, and tension and suspense are rarely discussed from a general, domain-independent perspective. In this paper, we argue that tension experiences in different contexts (e.g., musical tension or suspense in a movie) build on the same underlying psychological processes. We discuss key components of tension experiences and propose a domain-independent model of tension and suspense. According to this model, tension experiences originate from states of conflict, instability, dissonance, or uncertainty that trigger predictive processes directed at future events of emotional significance. We also discuss possible neural mechanisms underlying tension and suspense. The model provides a theoretical framework that can inform future empirical research on tension phenomena. PMID- 25717310 TI - Filling the blanks in temporal intervals: the type of filling influences perceived duration and discrimination performance. AB - In this work we investigate how judgments of perceived duration are influenced by the properties of the signals that define the intervals. Participants compared two auditory intervals that could be any combination of the following four types: intervals filled with continuous tones (filled intervals), intervals filled with regularly-timed short tones (isochronous intervals), intervals filled with irregularly-timed short tones (anisochronous intervals), and intervals demarcated by two short tones (empty intervals). Results indicate that the type of intervals to be compared affects discrimination performance and induces distortions in perceived duration. In particular, we find that duration judgments are most precise when comparing two isochronous and two continuous intervals, while the comparison of two anisochronous intervals leads to the worst performance. Moreover, we determined that the magnitude of the distortions in perceived duration (an effect akin to the filled duration illusion) is higher for tone sequences (no matter whether isochronous or anisochronous) than for continuous tones. Further analysis of how duration distortions depend on the type of filling suggests that distortions are not only due to the perceived duration of the two individual intervals, but they may also be due to the comparison of two different filling types. PMID- 25717311 TI - Developmental changes in reading do not alter the development of visual processing skills: an application of explanatory item response models in grades K 2. AB - Visual processing has been widely studied in regard to its impact on a students' ability to read. A less researched area is the role of reading in the development of visual processing skills. A cohort-sequential, accelerated-longitudinal design was utilized with 932 kindergarten, first, and second grade students to examine the impact of reading acquisition on the processing of various types of visual discrimination and visual motor test items. Students were assessed four times per year on a variety of reading measures and reading precursors and two popular measures of visual processing over a 3-year period. Explanatory item response models were used to examine the roles of person and item characteristics on changes in visual processing abilities and changes in item difficulties over time. Results showed different developmental patterns for five types of visual processing test items, but most importantly failed to show consistent effects of learning to read on changes in item difficulty. Thus, the present study failed to find support for the hypothesis that learning to read alters performance on measures of visual processing. Rather, visual processing and reading ability improved together over time with no evidence to suggest cross-domain influences from reading to visual processing. Results are discussed in the context of developmental theories of visual processing and brain-based research on the role of visual skills in learning to read. PMID- 25717312 TI - Psychometric properties of the multidimensional assessment of interoceptive awareness (MAIA) in a Chilean population. AB - The multidimensional assessment of interoceptive awareness (MAIA) is an instrument designed to assess interoceptive awareness. The aim of this study was to adapt the original MAIA scale to Spanish and to analyze its psychometric properties in a Chilean population. The MAIA was administered to 470 adults, aged 18-70 years, 76.6% women and 23.4% men, residents of the provinces of Valparaiso and Concepcion, Chile. Exploratory factor analysis reduced the scale from 32 to 30 items. Confirmatory factor analysis supports a structure of eight interrelated factors (Noticing, Not-Distracting, Not-Worrying, Attention Regulation, Emotional Awareness, Self- Regulation, Body Listening, and Trusting), similar to the original scale (chi(2) (371) = 659.78, p = 0.0001; CFI = 0.92, TLI = 0.91, RMSEA = 0.056 and SRMR = 0.059). The Spanish version showed appropriate indicators of construct validity and reliability, with a Cronbach's alpha of 0.90 for the total scale, and values between 0.40 and 0.86 for the different subscales. Similar to previous studies, low reliability was observed in two of the eight scales (Not Distracting and Not-Worrying), thus further revision of these subscales is suggested. The Spanish version of MAIA proved to be a valid and reliable tool to investigate interoceptive awareness in the Chilean population. PMID- 25717313 TI - Prediction of attendance at fitness center: a comparison between the theory of planned behavior, the social cognitive theory, and the physical activity maintenance theory. AB - In the processes of physical activity (PA) maintenance specific predictors are effective, which differ from other stages of PA development. Recently, Physical Activity Maintenance Theory (PAMT) was specifically developed for prediction of PA maintenance. The aim of the present study was to evaluate the predictability of the future behavior by the PAMT and compare it with the Theory of Planned Behavior (TPB) and Social Cognitive Theory (SCT). Participation rate in a fitness center was observed for 101 college students (53 female) aged between 19 and 32 years (M = 23.6; SD = 2.9) over 20 weeks using a magnetic card. In order to predict the pattern of participation TPB, SCT and PAMT were used. A latent class zero-inflated Poisson growth curve analysis identified two participation patterns: regular attenders and intermittent exercisers. SCT showed the highest predictive power followed by PAMT and TPB. Impeding aspects as life stress and barriers were the strongest predictors suggesting that overcoming barriers might be an important aspect for working out on a regular basis. Self-efficacy, perceived behavioral control, and social support could also significantly differentiate between the participation patterns. PMID- 25717314 TI - The climate change problem: promoting motivation for change when the map is not the territory. PMID- 25717315 TI - Route-planning and the comparative study of future-thinking. PMID- 25717316 TI - Investigating the neural architecture of handedness. PMID- 25717317 TI - Improving outcomes in cerebral palsy with early intervention: new translational approaches. PMID- 25717318 TI - Tweaking the structure to radically change the function: the evolution of transthyretin from 5-hydroxyisourate hydrolase to triiodothyronine distributor to thyroxine distributor. AB - Often, we elucidate evolutionary processes backwards, starting with eutherian mammals and gradually climbing down the evolutionary tree to those species who have survived since long before mammals evolved. This is also true for elucidating the evolution of specific proteins, in this case, the protein currently known as "transthyretin" (TTR). TTR was first described in eutherian mammals and was known as a thyroxine (T4) binding protein. However, mammals are the exception among vertebrates in respect to the function of TTR, as in teleost fish, amphibians, reptiles and birds TTR preferentially binds triiodothyronine (T3), which is the active form of thyroid hormone (TH). The TTR gene possibly arose as a duplication of the transthyretin-like protein (TLP) gene, around the stage of the agnathans. Some vertebrate species have both the TTR and TLP genes, while others have "lost" the TLP gene. TLP genes have been found in all kingdoms. The TLPs analyzed to date do not bind THs or their analogs, but are enzymes involved in uric acid metabolism; specifically, they are 5-hydroxyisourate hydrolases. A Salmonella TLP knock-out strain demonstrated that TLP was essential for the bacteria's survival in the high uric acid environment of the chicken alimentary tract. Many other TLPs are yet to be characterized for their function although several have been confirmed as 5-hydroxyisourate hydrolases. This review describes the evolution of TLP/TTR and how subtle changes in gene structure or amino acid substitution can drastically change the function of this protein, without altering its overall 3D conformation. PMID- 25717319 TI - Gram-positive phage-host interactions. PMID- 25717320 TI - Ascorbic acid-dependent gene expression in Streptococcus pneumoniae and the activator function of the transcriptional regulator UlaR2. AB - In this study, we have explored the impact of ascorbic acid on the transcriptome of Streptococcus pneumoniae D39. The expression of several genes and operons, including the ula operon (which has been previously shown to be involved in ascorbic acid utilization), the AdcR regulon (which has been previously shown to be involved in zinc transport and virulence) and a PTS operon (which we denote here as ula2 operon) were altered in the presence of ascorbic acid. The ula2 operon consists of five genes, including the transcriptional activator ulaR2. Our beta-galactosidase assay data and transcriptome comparison of the ulaR2 mutant with the wild-type demonstrated that the transcriptional activator UlaR2 in the presence of ascorbic acid activates the expression of the ula2 operon. We further predict a 16-bp regulatory site (5'-ATATTGTGCTCAAATA-3') for UlaR2 in the Pula2. Furthermore, we have explored the effect of ascorbic acid on the expression of the AdcR regulon. Our ICP-MS analysis showed that addition of ascorbic acid to the medium causes zinc starvation in the cell which leads to the activation of the AdcR regulon. PMID- 25717321 TI - Influence of growth rate on the physiological response of marine Synechococcus to phosphate limitation. AB - Phosphate (P) is an important nutrient potentially limiting for primary productivity, yet, we currently know little about the relationship between growth rate and physiological response to P limitation in abundant marine Cyanobacteria. Thus, the aim of this research was to determine how variation in growth rate affected the physiology of marine Synechococcus WH8102 and CC9311 when growing under high N:P conditions. Experiments were carried out in chemostats with a media input N:P of 441 and we estimated the half saturation concentration for growth under P limiting conditions (K s,p ) and cellular C:N:P ratios. The K s,p values were the lowest measured for any phytoplankton and on par with ambient P concentrations in oligotrophic regions. We also observed that both strains were able draw down P below 3 nM. Both K s,p and drawdown concentration were lower for the open ocean vs. coastal Synechococcus strain, which may be linked to differences in P acquisition genes in these strains. Cellular C:P and N:P ratios were significantly higher in relation to the Redfield ratio for both Synechococcus strains but we saw no difference in these ratios among growth rates or strains. These results demonstrate that Synechococcus can proliferate under very low P conditions and also that genetically different strains have unique physiological responses to P limitation. PMID- 25717322 TI - Agroforestry leads to shifts within the gammaproteobacterial microbiome of banana plants cultivated in Central America. AB - Bananas (Musa spp.) belong to the most important global food commodities, and their cultivation represents the world's largest monoculture. Although the plant associated microbiome has substantial influence on plant growth and health, there is a lack of knowledge of the banana microbiome and its influencing factors. We studied the impact of (i) biogeography, and (ii) agroforestry on the banana associated gammaproteobacterial microbiome analyzing plants grown in smallholder farms in Nicaragua and Costa Rica. Profiles of 16S rRNA genes revealed high abundances of Pseudomonadales, Enterobacteriales, Xanthomonadales, and Legionellales. An extraordinary high diversity of the gammaproteobacterial microbiota was observed within the endophytic microenvironments (endorhiza and pseudostem), which was similar in both countries. Enterobacteria were identified as dominant group of above-ground plant parts (pseudostem and leaves). Neither biogeography nor agroforestry showed a statistically significant impact on the gammaproteobacterial banana microbiome in general. However, indicator species for each microenvironment and country, as well as for plants grown in Coffea intercropping systems with and without agri-silvicultural production of different Fabaceae trees (Inga spp. in Nicaragua and Erythrina poeppigiana in Costa Rica) could be identified. For example, banana plants grown in agroforestry systems were characterized by an increase of potential plant-beneficial bacteria, like Pseudomonas and Stenotrophomonas, and on the other side by a decrease of Erwinia. Hence, this study could show that as a result of legume-based agroforestry the indigenous banana-associated gammaproteobacterial community noticeably shifted. PMID- 25717323 TI - Cell wall staining with Trypan blue enables quantitative analysis of morphological changes in yeast cells. AB - Yeast cells are protected by a cell wall that plays an important role in the exchange of substances with the environment. The cell wall structure is dynamic and can adapt to different physiological states or environmental conditions. For the investigation of morphological changes, selective staining with fluorescent dyes is a valuable tool. Furthermore, cell wall staining is used to facilitate sub-cellular localization experiments with fluorescently-labeled proteins and the detection of yeast cells in non-fungal host tissues. Here, we report staining of Saccharomyces cerevisiae cell wall with Trypan Blue, which emits strong red fluorescence upon binding to chitin and yeast glucan; thereby, it facilitates cell wall analysis by confocal and super-resolution microscopy. The staining pattern of Trypan Blue was similar to that of the widely used UV-excitable, blue fluorescent cell wall stain Calcofluor White. Trypan Blue staining facilitated quantification of cell size and cell wall volume when utilizing the optical sectioning capacity of a confocal microscope. This enabled the quantification of morphological changes during growth under anaerobic conditions and in the presence of chemicals, demonstrating the potential of this approach for morphological investigations or screening assays. PMID- 25717324 TI - Proteomic analysis reveals metabolic and regulatory systems involved in the syntrophic and axenic lifestyle of Syntrophomonas wolfei. AB - Microbial syntrophy is a vital metabolic interaction necessary for the complete oxidation of organic biomass to methane in all-anaerobic ecosystems. However, this process is thermodynamically constrained and represents an ecosystem-level metabolic bottleneck. To gain insight into the physiology of this process, a shotgun proteomics approach was used to quantify the protein landscape of the model syntrophic metabolizer, Syntrophomonas wolfei, grown axenically and syntrophically with Methanospirillum hungatei. Remarkably, the abundance of most proteins as represented by normalized spectral abundance factor (NSAF) value changed very little between the pure and coculture growth conditions. Among the most abundant proteins detected were GroEL and GroES chaperonins, a small heat shock protein, and proteins involved in electron transfer, beta-oxidation, and ATP synthesis. Several putative energy conservation enzyme systems that utilize NADH and ferredoxin were present. The abundance of an EtfAB2 and the membrane bound iron-sulfur oxidoreductase (Swol_0698 gene product) delineated a potential conduit for electron transfer between acyl-CoA dehydrogenases and membrane redox carriers. Proteins detected only when S. wolfei was grown with M. hungatei included a zinc-dependent dehydrogenase with a GroES domain, whose gene is present in genomes in many organisms capable of syntrophy, and transcriptional regulators responsive to environmental stimuli or the physiological status of the cell. The proteomic analysis revealed an emphasis on macromolecular stability and energy metabolism by S. wolfei and presence of regulatory mechanisms responsive to external stimuli and cellular physiological status. PMID- 25717325 TI - The Pho4 transcription factor mediates the response to arsenate and arsenite in Candida albicans. AB - Arsenate (As (V)) is the dominant form of the toxic metalloid arsenic (As). Microorganisms have consequently developed mechanisms to detoxify and tolerate this kind of compounds. In the present work, we have explored the arsenate sensing and signaling mechanisms in the pathogenic fungus Candida albicans. Although mutants impaired in the Hog1 or Mkc1-mediated pathways did not show significant sensitivity to this compound, both Hog1 and Mkc1 became phosphorylated upon addition of sodium arsenate to growing cells. Hog1 phosphorylation upon arsenate challenge was shown to be Ssk1-dependent. A screening designed for the identification of transcription factors involved in the arsenate response identified Pho4, a transcription factor of the myc-family, as pho4 mutants were susceptible to As (V). The expression of PHO4 was shortly induced in the presence of sodium arsenate in a Hog1-independent manner. Pho4 level affects Hog1 phosphorylation upon As (V) challenge, suggesting an indirect relationship between Pho4 activity and signaling in C. albicans. Pho4 also mediates the response to arsenite as revealed by the fact that pho4 defective mutants are sensitive to arsenite and Pho4 becomes phosphorylated upon sodium arsenite addition. Arsenite also triggers Hog1 phosphorylation by a process that is, in this case, independent of the Ssk1 kinase. These results indicate that the HOG pathway mediates the response to arsenate and arsenite in C. albicans and that the Pho4 transcription factor can differentiate among As (III), As (V) and Pi, triggering presumably specific responses. PMID- 25717326 TI - Distinct Transcriptomic Features are Associated with Transitional and Mature B Cell Populations in the Mouse Spleen. AB - Splenic transitional B-cells (T1 and T2) are selected to avoid self-reactivity and to safeguard against autoimmunity, then differentiate into mature follicular (FO-I and FO-II) and marginal zone (MZ) subsets. Transcriptomic analysis by RNA seq of the five B-cell subsets revealed T1 cell signature genes included RAG suggesting a potential for receptor revision. T1 to T2 B-cell differentiation was marked by a switch from Myb to Myc, increased expression of the PI3K adapter DAP10 and MHC class II. FO-II may be an intermediate in FO-I differentiation and may also become MZ B-cells as suggested by principle component analysis. MZ B cells possessed the most distinct transcriptome including down-regulation of CD45 phosphatase-associated protein (CD45-AP/PTPRC-AP), as well as upregulation of IL 9R and innate molecules TLR3, TLR7, and bactericidal Perforin-2 (MPEG1). Among the endosomal TLRs, stimulation via TLR3 further enhanced Perforin-2 expression exclusively in MZ B-cells. Using gene-deleted and overexpressing transgenic mice we show that IL-9/IL-9R interaction resulted in rapid activation of STAT1, 3, and 5, primarily in MZ B-cells. Importantly, CD45-AP mutant mice had reduced transitional and increased mature MZ and FO B-cells, suggesting that it prevents premature entry of transitional B-cells to the mature B-cell pool or their survival and proliferation. Together, these findings suggest, developmental plasticity among splenic B-cell subsets, potential for receptor revision in peripheral tolerance whereas enhanced metabolism coincides with T2 to mature B cell differentiation. Further, unique core transcriptional signatures in MZ B cells may control their innate features. PMID- 25717327 TI - Downregulation of immunosuppressive environment in patients with chronic HBV hepatitis on maintained remission. PMID- 25717328 TI - Generation of Human B-Cell Lines Dependent on CD40-Ligation and Interleukin-4. PMID- 25717329 TI - Environment, autoantibodies, and autoimmunity. PMID- 25717330 TI - Control of fire blight (Erwinia amylovora) on apple trees with trunk-injected plant resistance inducers and antibiotics and assessment of induction of pathogenesis-related protein genes. AB - Management of fire blight is complicated by limitations on use of antibiotics in agriculture, antibiotic resistance development, and limited efficacy of alternative control agents. Even though successful in control, preventive antibiotic sprays also affect non-target bacteria, aiding the selection for resistance which could ultimately be transferred to the pathogen Erwinia amylovora. Trunk injection is a target-precise pesticide delivery method that utilizes tree xylem to distribute injected compounds. Trunk injection could decrease antibiotic usage in the open environment and increase the effectiveness of compounds in fire blight control. In field experiments, after 1-2 apple tree injections of either streptomycin, potassium phosphites (PH), or acibenzolar-S methyl (ASM), significant reduction of blossom and shoot blight symptoms was observed compared to water injected control trees. Overall disease suppression with streptomycin was lower than typically observed following spray applications to flowers. Trunk injection of oxytetracycline resulted in excellent control of shoot blight severity, suggesting that injection is a superior delivery method for this antibiotic. Injection of both ASM and PH resulted in the significant induction of PR-1, PR-2, and PR-8 protein genes in apple leaves indicating induction of systemic acquired resistance (SAR) under field conditions. The time separating SAR induction and fire blight symptom suppression indicated that various defensive compounds within the SAR response were synthesized and accumulated in the canopy. ASM and PH suppressed fire blight even after cessation of induced gene expression. With the development of injectable formulations and optimization of doses and injection schedules, the injection of protective compounds could serve as an effective option for fire blight control. PMID- 25717331 TI - Defending the leaf surface: intra- and inter-specific differences in silicon deposition in grasses in response to damage and silicon supply. AB - Understanding interactions between grasses and their herbivores is central to the conservation of species-rich grasslands and the protection of our most important crops against pests. Grasses employ a range of defenses against their natural enemies; silicon-based defenses have been shown to be one of the most effective. Silicon (Si) is laid down on the leaf surface as spines and other sharp bodies, known as phytoliths, making grasses abrasive and their foliage indigestible to herbivores. Previous studies on Si defenses found that closely related species may have similar levels of Si in the leaves but differ markedly in abrasiveness. Here we show how the number, shape and distribution of Si-rich phytoliths and spines differ within and between different grass species and demonstrate that species also differ in their ability to change the deposition and distribution of these defenses in response to damage or increases in Si supply. Specifically, we tested the response of two genotypes of Festuca arundinacea known to differ in their surface texture and three different grass species (F. ovina, F. rubra, and Deschampsia cespitosa) differing in their abrasiveness to combined manipulation of leaf damage and Si supply. F. arundinacea plants with a harsh leaf surface had higher Si content and more spines on their leaf surface than soft varieties. F. ovina and D. cespitosa plants increased their leaf Si concentration and produced an increase in the number of leaf spines and phytoliths on the leaf surface in response to Si addition. F rubra also increased leaf Si content in response to treatments, particularly in damaged leaves, but did not deposit this in the form of spines or increased densities of phytoliths. We discuss how the form in which grasses deposit Si may affect their anti-herbivore characteristics and consider the ecological and agricultural implications of the differences in allocation to Si-based defenses between grass species. PMID- 25717332 TI - Comparative analysis of fruit aroma patterns in the domesticated wild strawberries "Profumata di Tortona" (F. moschata) and "Regina delle Valli" (F. vesca). AB - Strawberry is one of the most valued fruit worldwide. Modern cultivated varieties (Fragaria * ananassa) exhibit large fruits, with intense color and prolonged shell life. Yet, these valuable traits were attained at the cost of the intensity and the variety of the aroma of the berry, two characteristics highly appreciated by consumers. Wild species display smaller fruits and reduced yield compared with cultivated varieties but they accumulate broader and augmented blends of volatile compounds. Because of the large diversity and strength of aromas occurring in natural and domesticated populations, plant breeders regard wild strawberries as important donors of novel scented molecules. Here we report a comprehensive metabolic map of the aroma of the wild strawberry Profumata di Tortona (PdT), an ancient clone of F. moschata, considered as one of the most fragrant strawberry types of all. Comparison with the more renowned woodland strawberry Regina delle Valli (RdV), an aromatic cultivar of F. vesca, revealed a significant enrichment in the total level of esters, alcohols and furanones and a reduction in the content of ketones in in the aroma of PdT berries. Among esters, particularly relevant was the enhanced accumulation of methyl anthranilate, responsible for the intensive sweetish impression of wild strawberries. Interestingly, increased ester accumulation in PdT fruits correlated with enhanced expression of the Strawberry Alcohol Acyltransferase (SAAT) gene, a key regulator of flavor biogenesis in ripening berries. We also detected a remarkable 900-fold increase in the level of mesifurane, the furanone conferring the typical caramel notes to most wild species. PMID- 25717334 TI - Do ectomycorrhizal and arbuscular mycorrhizal temperate tree species systematically differ in root order-related fine root morphology and biomass? AB - While most temperate broad-leaved tree species form ectomycorrhizal (EM) symbioses, a few species have arbuscular mycorrhizas (AM). It is not known whether EM and AM tree species differ systematically with respect to fine root morphology, fine root system size and root functioning. In a species-rich temperate mixed forest, we studied the fine root morphology and biomass of three EM and three AM tree species from the genera Acer, Carpinus, Fagus, Fraxinus, and Tilia searching for principal differences between EM and AM trees. We further assessed the evidence of convergence or divergence in root traits among the six co-occurring species. Eight fine root morphological and chemical traits were investigated in root segments of the first to fourth root order in three different soil depths and the relative importance of the factors root order, tree species and soil depth for root morphology was determined. Root order was more influential than tree species while soil depth had only a small effect on root morphology All six species showed similar decreases in specific root length and specific root area from the 1st to the 4th root order, while the species patterns differed considerably in root tissue density, root N concentration, and particularly with respect to root tip abundance. Most root morphological traits were not significantly different between EM and AM species (except for specific root area that was larger in AM species), indicating that mycorrhiza type is not a key factor influencing fine root morphology in these species. The order-based root analysis detected species differences more clearly than the simple analysis of bulked fine root mass. Despite convergence in important root traits among AM and EM species, even congeneric species may differ in certain fine root morphological traits. This suggests that, in general, species identity has a larger influence on fine root morphology than mycorrhiza type. PMID- 25717333 TI - Post-transcriptional and post-translational regulations of drought and heat response in plants: a spider's web of mechanisms. AB - Drought and heat tolerance are complex quantitative traits. Moreover, the adaptive significance of some stress-related traits is more related to plant survival than to agronomic performance. A web of regulatory mechanisms fine-tunes the expression of stress-related traits and integrates both environmental and developmental signals. Both post-transcriptional and post-translational modifications contribute substantially to this network with a pivotal regulatory function of the transcriptional changes related to cellular and plant stress response. Alternative splicing and RNA-mediated silencing control the amount of specific transcripts, while ubiquitin and SUMO modify activity, sub-cellular localization and half-life of proteins. Interactions across these modification mechanisms ensure temporally and spatially appropriate patterns of downstream gene expression. For key molecular components of these regulatory mechanisms, natural genetic diversity exists among genotypes with different behavior in terms of stress tolerance, with effects upon the expression of adaptive morphological and/or physiological target traits. PMID- 25717335 TI - There and back again: consequences of biofilm specialization under selection for dispersal. AB - Experimental evolution paired with modern sequencing can be a powerful approach to identify the mechanisms by which bacteria adapt to discrete environmental conditions found in nature or during infections. We used this approach to identify mechanisms enabling biofilm specialists of the opportunistic respiratory pathogen Burkholderia cenocepacia to regain planktonic fitness. Seven mutants producing wrinkly (W) small-colony variants by mutations in the wrinkly-spreader operon (wsp) cluster, but with varying duration of biofilm adaptation, served as ancestors of this experiment. Following planktonic growth, each W ancestor produced smooth (S) mutants with distinct fitness effects across planktonic, biofilm, and dispersal-phase environments. The causes of the S phenotype traced to mutations in three gene clusters: wsp, Bcen2424_1436, an uncharacterized two component transcriptional regulator which appears to be critical for wsp signaling, and a cohort of genes involved in polysaccharide synthesis. The genetic pathway from W to S also associated with evolutionary history in the biofilm environment. W mutants isolated from long-term biofilm selection usually produced S types via secondary wsp mutations, whereas S types evolved from less adapted W ancestors by a wider scope of mutations. These different genetic pathways to suppress the W phenotype suggest that prolonged biofilm adaptation limits routes to subsequent planktonic adaptation, despite common initial mechanisms of biofilm adaptation. More generally, experimental evolution can be used as a nuanced screen for gain-of-function mutations in multiple conditions that illustrate tensions that bacteria may face in changing environments or hosts. PMID- 25717336 TI - Comparing decision-support systems in adopting sustainable intensification criteria. AB - Sustainable intensification (SI) is a multifaceted concept incorporating the ambition to increase or maintain the current level of agricultural yields while reduce negative ecological and environmental impacts. Decision-support systems (DSS) that use integrated analytical methods are often used to support decision making processes in agriculture. However, DSS often consist of set of values, objectives, and assumptions that may be inconsistent or in conflict with merits and objectives of SI. These potential conflicts will have consequences for adoption and up-take of agricultural research, technologies and related policies and regulations such as genetic technology in pursuit of SI. This perspective paper aimed at comparing a number of frequently used socio-economic DSS with respect to their capacity in incorporating various dimensions of SI, and discussing their application to analyzing farm animal genetic resources (FAnGR) policies. The case of FAnGR policies was chosen because of its great potential in delivering merits of SI. It was concluded that flexible DSS, with great integration capacity with various natural and social sciences, are needed to provide guidance on feasibility, practicality, and policy implementation for SI. PMID- 25717338 TI - Integrating multi-omic features exploiting Chromosome Conformation Capture data. AB - The representation, integration, and interpretation of omic data is a complex task, in particular considering the huge amount of information that is daily produced in molecular biology laboratories all around the world. The reason is that sequencing data regarding expression profiles, methylation patterns, and chromatin domains is difficult to harmonize in a systems biology view, since genome browsers only allow coordinate-based representations, discarding functional clusters created by the spatial conformation of the DNA in the nucleus. In this context, recent progresses in high throughput molecular biology techniques and bioinformatics have provided insights into chromatin interactions on a larger scale and offer a formidable support for the interpretation of multi omic data. In particular, a novel sequencing technique called Chromosome Conformation Capture allows the analysis of the chromosome organization in the cell's natural state. While performed genome wide, this technique is usually called Hi-C. Inspired by service applications such as Google Maps, we developed NuChart, an R package that integrates Hi-C data to describe the chromosomal neighborhood starting from the information about gene positions, with the possibility of mapping on the achieved graphs genomic features such as methylation patterns and histone modifications, along with expression profiles. In this paper we show the importance of the NuChart application for the integration of multi-omic data in a systems biology fashion, with particular interest in cytogenetic applications of these techniques. Moreover, we demonstrate how the integration of multi-omic data can provide useful information in understanding why genes are in certain specific positions inside the nucleus and how epigenetic patterns correlate with their expression. PMID- 25717339 TI - Effects of Inorganic Fillers on the Thermal and Mechanical Properties of Poly(lactic acid). AB - Addition of filler to polylactic acid (PLA) may affect its crystallization behavior and mechanical properties. The effects of talc and hydroxyapatite (HA) on the thermal and mechanical properties of two types of PLA (one amorphous and one semicrystalline) have been investigated. The composites were prepared by melt blending followed by injection molding. The molecular weight, morphology, mechanical properties, and thermal properties have been characterized by gel permeation chromatography (GPC), scanning electron microscope (SEM), instron tensile tester, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). It was found that the melting blending led to homogeneous distribution of the inorganic filler within the PLA matrix but decreased the molecular weight of PLA. Regarding the filler, addition of talc increased the crystallinity of PLA, but HA decreased the crystallinity of PLA. The tensile strength of the composites depended on the crystallinity of PLA and the interfacial properties between PLA and the filler, but both talc and HA filler increased the toughness of PLA. PMID- 25717337 TI - Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis), multiple telangiectases and arteriovenous malformations (AVMs) in major organs. Mutations in Endoglin (ENG or CD105) and Activin receptor-like kinase 1 (ACVRL1 or ALK1) genes of the TGF-beta superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic-angiostatic balance in the affected tissues. Hence, anti angiogenic therapies that target the abnormal vessels and restore the angiogenic angiostatic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease. PMID- 25717340 TI - Pilgrims and MERS-CoV: what's the risk? AB - The risk of Middle East Respiratory Syndrome Coronavirus spreading globally is worrying, given the annual mass gathering of the Hajj and the year-long influx of pilgrims undertaking the Umrah. Based on the incidence in Saudi Arabia since June 2012, the most likely scenario given recent pilgrim numbers is estimated to be one case per Hajj, and three Umrah pilgrims per year, but which could plausibly reach seven and ten pilgrims respectively. In addition to the 2015 Hajj, national surveillance systems should be on the alert for the low but long-lasting risk of infected pilgrims returning from the Umrah throughout the year. PMID- 25717341 TI - Temperature tolerance of different larval stages of the spider crab Hyas araneus exposed to elevated seawater PCO2. AB - INTRODUCTION: Exposure to elevated seawater PCO2 limits the thermal tolerance of crustaceans but the underlying mechanisms have not been comprehensively explored. Larval stages of crustaceans are even more sensitive to environmental hypercapnia and possess narrower thermal windows than adults. RESULTS: In a mechanistic approach, we analysed the impact of high seawater CO2 on parameters at different levels of biological organization, from the molecular to the whole animal level. At the whole animal level we measured oxygen consumption, heart rate and activity during acute warming in zoea and megalopa larvae of the spider crab Hyas araneus exposed to different levels of seawater PCO2. Furthermore, the expression of genes responsible for acid-base regulation and mitochondrial energy metabolism, and cellular responses to thermal stress (e.g. the heat shock response) was analysed before and after larvae were heat shocked by rapidly raising the seawater temperature from 10 degrees C rearing temperature to 20 degrees C. Zoea larvae showed a high heat tolerance, which decreased at elevated seawater PCO2, while the already low heat tolerance of megalopa larvae was not limited further by hypercapnic exposure. There was a combined effect of elevated seawater CO2 and heat shock in zoea larvae causing elevated transcript levels of heat shock proteins. In all three larval stages, hypercapnic exposure elicited an up regulation of genes involved in oxidative phosphorylation, which was, however, not accompanied by increased energetic demands. CONCLUSION: The combined effect of seawater CO2 and heat shock on the gene expression of heat shock proteins reflects the downward shift in thermal limits seen on the whole animal level and indicates an associated capacity to elicit passive thermal tolerance. The up regulation of genes involved in oxidative phosphorylation might compensate for enzyme activities being lowered through bicarbonate inhibition and maintain larval standard metabolic rates at high seawater CO2 levels. The present study underlines the necessity to align transcriptomic data with physiological responses when addressing mechanisms affected by an interaction of elevated seawater PCO2 and temperature extremes. PMID- 25717342 TI - Tobacco smoke particles and indoor air quality (ToPIQ-II) - a modified study protocol and first results. AB - BACKGROUND: Environmental tobacco smoke (ETS)-associated particulate matter (PM) has to be seen as an independent health hazard and needs to be discussed separately from the already well-known toxic and carcinogenic compounds contained in cigarette smoke. We believe that brand-specific amounts of PM are of public interest and should be investigated. METHODS: An automatic environmental tobacco smoke emitter was developed and placed into a glass-chamber to generate cigarette smoke as reliably as possible. Cigarettes were smoked automatically according to a standardized protocol. Mean concentrations (Cmean) and area under the curve (AUC) of PM2.5 released by the brands P&S, Virginia (without filter) and the 3R4F standard research cigarette of the University of Kentucky, USA, were measured and compared with each other. RESULTS: Cmean PM2.5 of 3R4F reference was 1,725 MUg/m(3), for P&S: 1,982 MUg/m(3) and for Virginia without filter: 1,525 MUg/m(3). AUC PM2.5 for 3R4F reference was: 527,644 MUg/m(3)*sec, for P&S: 606,171 MUg/m(3)*sec, and for Virginia without filter: 464,788 MUg/m(3)*sec. CONCLUSIONS: Our modified ToPIQ-II study protocol shows significant brand specific differences in the amounts of PM2.5 released by cigarettes into the environment, when compared to 3R4F reference cigarettes. We believe that information about PM-release of all relevant brands in relation to reference cigarettes should be published. In the light of PM as an independent risk factor for morbidity and mortality, this may serve as a basis for further epidemiologic investigations. PMID- 25717343 TI - Polar electrostatic forces drive poleward chromosome motions. AB - Recent experiments revealing nanoscale electrostatic force generation at kinetochores for chromosome motions have prompted models for interactions between positively charged molecules in kinetochores and negative charge at and near the plus ends of microtubules. A clear picture of how kinetochores and centrosomes establish and maintain a dynamic coupling to microtubules for force generation during the complex motions of mitosis remains elusive. The molecular cell biology paradigm requires that specific molecules, or molecular geometries, for polar force generation be identified. While progress has been made regarding explanations of kinetochore-based chromosome motility, molecular machinery for chromosome poleward movements at centrosomes has yet to be identified. The present work concerns polar generation of poleward force in terms of experimentally known electric charge distributions at microtubule minus ends and centrosomes interacting over nanometer distances. PMID- 25717344 TI - Synthesis of a new class of carbon-bonded anionic sigma complexes with 1,3 dimethyl-2,6-dioxo-5-(2,4,6-trinitrophenyl)-1,2,3,6-tetrahydropyrimidin-4-olate moiety as insensitive high energy density materials -- implications from impact sensitivity and thermal testings. AB - BACKGROUND: Poly nitro aromatic compounds are high energy density materials. Carbon-bonded anionic sigma complexes derived from them have remarkable thermal stability. At present there is a strong requirement for thermally stable insensitive high energy density materials (IHEDMs) in the energetic field which necessitates the present investigation. RESULTS: Three new carbon-bonded anionic sigma complexes were synthesized from 2-chloro-1,3,5-trinitrobenzene, 1,3 dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (1,3-dimethylbarbituric acid) and bases such as triethanolamine, pyridine and N,N-diethylaniline, characterized by UV VIS, IR, (1)H NMR, (13)C NMR and elemental analysis data. Their molecular structures were further ascertained through single crystal X-ray diffraction studies. TGA/DTA testings were undertaken at four different heating rates (5, 10, 20 and 40 K/min) and energy of activation was determined employing Ozawa and Kissinger plots. CONCLUSIONS: The reported carbon-bonded anionic sigma complexes were prepared through single pot synthesis in good yield with high purity. These complexes are molecular salts comprise of cation and anion moieties. Because of the salt-like nature, they are highly stable upto 300 degrees C and decompose in two stages on further heating. They are stable towards impact of 2 kg mass hammer upto height limit (160 cm) of the instrument. The delocalization of the negative charge and various hydrogen bonds noticed in their crystals are the added factors of their thermal stability. The new insensitive high energy density materials of the present findings may receive attention in the field of energetics in future. Graphical AbstractA new class of carbon-bonded anionic sigma complexes as insensitive high energy density materials. PMID- 25717345 TI - Characterization of cell wall components of wheat bran following hydrothermal pretreatment and fractionation. AB - BACKGROUND: Pretreatments are a prerequisite for enzymatic hydrolysis of biomass and production of ethanol. They are considered to open up the plant cell wall structure by altering, moving or solubilizing lignin and hydrolyzing a proportion of hemicellulosic moieties. However, there is little information concerning pretreatment-induced changes on wheat bran cell wall polymers and indeed on changes in cell wall phenolic esters in bran or other lignocellulosic biomass. Here, we evaluate polymeric changes (chemical and physical) as a result of selected hydrothermal pretreatment conditions on destarched wheat bran using controlled polymer extraction methods. Quantification of cell wall components together with soluble oligosaccharides, the insoluble residues and ease of extractability and fractionation of biomass residues were conducted. RESULTS: Pretreatment solubilized selected arabinoxylans and associated cross-linking ferulic and diferulic acids with a concomitant increase in lignin and cellulosic glucose. The remaining insoluble arabinoxylans were more readily extractable in alkali and showed considerable depolymerization. The degree of arabinose substitution was less in xylans released by higher concentrations of alkali. The recalcitrant biomass which remained after pretreatment and alkali extraction contained mostly cellulosic glucose and Klason lignin. Pretreatment generated small but insignificant amounts of yeast-inhibiting compounds such as furfural and hydroxymethyl furfural. As such, simultaneous saccharification and fermentation of the hydrothermally pretreated bran resulted in increased ethanol yields compared to that of the control (97.5% compared to 63% theoretical). CONCLUSION: Hydrothermal pretreatment of destarched wheat bran resulted in degradation and depolymerization of the hemicellulosic arabinoxylans together with some breakdown of cellulosic glucose. This was accompanied by a significant reduction in the cross-linking phenolic acids such as ferulic and diferulic acids. The results suggest that hydrothermal pretreatment enhances enzymatic digestibility of the cellulose not only by depolymerization and solubilization of the hemicelluloses but by breakdown of interpolymeric phenolic cross-links between the remaining insoluble polymers. This allows easier access of hydrolytic enzymes by opening or loosening of the cell wall thus resulting in enhanced saccharification of cellulose and subsequent fermentation to ethanol. The reduction in cinnamic acids by selected breeding or biotechnological approaches could provide a useful basis for improved saccharification and fractionation of wheat bran polysaccharides. PMID- 25717346 TI - Data-driven identification of structural alerts for mitigating the risk of drug induced human liver injuries. AB - BACKGROUND: The use of structural alerts to de-prioritize compounds with undesirable features as drug candidates has been gaining in popularity. Hundreds of molecular structural moieties have been proposed as structural alerts. An emerging issue is that strict application of these alerts will result in a significant reduction of the chemistry space for new drug discovery, as more than half of the oral drugs on the market match at least one of the alerts. To mitigate this issue, we propose to apply a rigorous statistical analysis to derive/validate structural alerts before use. METHOD: To derive human liver toxicity structural alerts, we retrieved all small-molecule entries from LiverTox, a U.S. National Institutes of Health online resource for information on human liver injuries induced by prescription and over-the-counter drugs and dietary supplements. We classified the compounds into hepatotoxic, nonhepatotoxic, and possible hepatotoxic classes, and performed detailed statistical analyses to identify molecular structural fragments highly enriched in the hepatotoxic class beyond random distribution as structural alerts for human liver injuries. RESULTS: We identified 12 molecular fragments present in multiple marketed drugs that one can consider as common "drug-like" fragments, yet they are strongly associated with drug-induced human liver injuries. Thus, these fragments may be considered as robust hepatotoxicity structural alerts suitable for use in drug discovery screening programs. CONCLUSIONS: The use of structural alerts has contributed to the identification of many compounds with potential toxicity issues in modern drug discovery. However, with a large number of structural alerts published to date without proper validation, application of these alerts may restrict the chemistry space and prevent discovery of valuable drugs. To mitigate this issue, we showed how to use statistical analyses to develop a small, robust, and broadly applicable set of structural alerts. Graphical abstractHepatotoxic-specific filters for flagging high risk compounds. PMID- 25717347 TI - Prevalence of metabolic syndrome and pre-metabolic syndrome in health professionals: LATINMETS Brazil study. AB - BACKGROUND: The metabolic syndrome (MS) is characterized by several cardiovascular risk factors and is associated with an increased incidence of diabetes, cardiovascular events and mortality. The prevalence of MS is increasing in epidemic proportions worldwide. The present study aimed to investigate the prevalence of MS and its components in health professionals in the municipality of Vicosa, Brazil. METHODS: Cross-sectional observational study in the frame of the LATIN America METabolic Syndrome (LATINMETS) multicenter study. The study sample consisted of 226 healthcare personnel (20-59 years). Weight, height, waist circumference and hip circumference were determined. The following anthropometric indices were calculated: body mass index (BMI), waist/hip ratio, waist/height ratio, body adiposity index (BAI) and conicity index. Body composition was assessed by tetrapolar bioelectrical impedance. The lipid profile, fasting glucose, insulin, uric acid, high-sensitive C-reactive protein (hs-CRP) and complement C3 were measured in fasting conditions. Insulin resistance was assessed by the Homeostasis Model Assessment Index of Insulin Resistance (HOMA IR). RESULTS: Of the 226 healthcare individuals included in the study, 74.3% were female, 77.0% graduated and 23.0% students of the last two years of courses in health area, with a median age of 27 years. The overall prevalence of MS was 4.5%, and increased with age (20 to 29 years: 1.3%; 30 to 39 years: 5.6%; >= 40 years: 26.3%) (P < 0.01). The presence of pre-MS and MS was associated with several measures of adiposity, total cholesterol/HDL-c and LDL-c/HDL-c ratios and serum complement C3 concentrations. CONCLUSIONS: The LATINMETS Brazil study reported an association between MS prevalence and age, especially in those over 40 years. The presence of MS is associated with an increased prevalence of several cardiovascular risk factors. PMID- 25717348 TI - Association of chronic diabetes and hypertension in sural nerve morphometry: an experimental study. AB - BACKGROUND: Prospective studies have shown incidence rates of hypertension in diabetes mellitus to be three times that of subjects without diabetes mellitus. The reverse also applies, with the incidence of diabetes two to three times higher in patients with hypertension. Despite this common clinical association, the contribution of each isolated entity in the development of a neuropathy is still not well understood. The aims of the present study were to investigate the presence of peripheral neuropathy in spontaneously hypertensive rats (SHR) and SHR with chronically induced diabetes, using a morphological and morphometric study of the sural nerves. METHODS: Female SHR and normotensive Wistar rats (WR), 8 weeks old, received a single intravenous injection of streptozotocin (STZ) through the tail vein. Controls from both strains received vehicle. Twelve weeks after the injection, sural nerves were dissected and prepared for light microscopy. Morphometry of sural nerve fascicles and myelinated fibers was performed with the aid of computer software. RESULTS: The sural nerve myelinated fibers were highly affected by experimental diabetes in normotensive rats, causing mainly the reduction of the fiber size. Hypertensive rats showed characteristics of small fiber neuropathy and a severe reduction of the number and density or Schwann cells. The association between diabetes and hypertension caused an increase on the average size of the myelinated fibers, pointing to a small fiber loss, associated to axonal atrophy. CONCLUSIONS: Our study gives morphological support to the existence of a neuropathy due to hypertension, which is among one of the most common risk factors for diabetic neuropathy. The association between the two neuropathies showed to be a complex alteration, involving and including both, large and small fibers neuropathy. Hypertension caused, indeed, an exacerbation of the alterations already observed in experimental models of diabetic neuropathy. PMID- 25717349 TI - Neural correlates of visual hallucinations in dementia with Lewy bodies. AB - INTRODUCTION: The aim of this study was to investigate the association between visual hallucinations in dementia with Lewy bodies (DLB) and brain perfusion using single-photon emission computed tomography. METHODS: We retrospectively included 66 patients with DLB, 36 of whom were having visual hallucinations (DLB hallu) and 30 of whom were not (DLB-c). We assessed visual hallucination severity on a 3-point scale of increasing severity: illusions, simple visual hallucinations and complex visual hallucinations. We performed voxel-level comparisons between the two groups and assessed correlations between perfusion and visual hallucinations severity. RESULTS: We found a significant decrease in perfusion in the left anterior cingulate cortex, the left orbitofrontal cortex and the left cuneus in the DLB-hallu group compared with the DLB-c group. We also found a significant correlation between decreased bilateral anterior cingulate cortex, left orbitofrontal cortex, right parahippocampal gyrus, right inferior temporal cortex and left cuneus perfusion with the severity of hallucinations. CONCLUSIONS: Visual hallucinations seem to be associated with the impairment of anterior and posterior regions (secondary visual areas, orbitofrontal cortex and anterior cingulate cortex) involved in a top-down and bottom-up mechanism, respectively. Furthermore, involvement of the bilateral anterior cingulate cortex and right parahippocampal gyrus seems to lead to more complex hallucinations. PMID- 25717350 TI - The monoaminergic footprint of depression and psychosis in dementia with Lewy bodies compared to Alzheimer's disease. AB - INTRODUCTION: Depression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies between both neurodegenerative conditions, given the lack of an efficient pharmacological treatment until present. METHODS: Eleven behaviorally relevant brain regions of the left frozen hemisphere of 10 neuropathologically confirmed AD patients with/without depression (AD + D/-D; 5 were psychotic within AD + D), 10 confirmed DLB patients, all of whom were depressed (DLB + D; 5 psychotic patients), and, finally, 10 confirmed control subjects were regionally dissected. All patients were retrospectively assessed before death using the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) and Cornell Scale for Depression in Dementia amongst others. The concentrations of dopamine (DA), serotonin (5-HT), (nor)adrenaline and respective metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 5-hydroxy-3-indoleacetic acid (5-HIAA), and, 3-methoxy-4 hydroxyphenylglycol (MHPG), were determined using reversed-phase high-performance liquid chromatography with electrochemical detection. RESULTS: DLB subjects had the overall lowest monoamine and metabolite concentrations regarding 33 out of 41 significant monoaminergic group alterations. Moreover, MHPG levels were significantly decreased in almost 8 out of 11 brain regions of DLB- compared to AD patients. We also observed the lowest 5-HT and 5-HIAA levels, and 5-HIAA/5-HT turnover ratios in DLB + D compared to AD + D subjects. Additionally, a 4- and 7 fold increase of DOPAC/DA and HVA/DA turnover ratios, and, a 10-fold decrease of thalamic DA levels in DLB + D compared to AD + D patients and control subjects was noticed. Regarding psychosis, hippocampal DA levels in the overall DLB group significantly correlated with Behave-AD AB scores. In the total AD group, DA levels and HVA/DA ratios in the amygdala significantly correlated with Behave-AD AB scores instead. CONCLUSIONS: Monoaminergic neurotransmitter alterations contribute differently to the pathophysiology of depression and psychosis in DLB as opposed to AD, with a severely decreased serotonergic neurotransmission as the main monoaminergic etiology of depression in DLB. Similarly, psychosis in DLB might, in part, be etiologically explained by dopaminergic alterations in the hippocampus, whereas in AD, the amygdala might be involved. PMID- 25717352 TI - Exercise training in the management of patients with resistant hypertension. AB - Hypertension is a very prevalent risk factor for cardiovascular disease. The prevalence of resistant hypertension, i.e., uncontrolled hypertension with 3 or more antihypertensive agents including 1 diuretic, is between 5% and 30% in the hypertensive population. The causes of resistant hypertension are multifactorial and include behavioral and biological factors, such as non-adherence to pharmacological treatment. All current treatment guidelines highlight the positive role of physical exercise as a non-pharmacological tool in the treatment of hypertension. This paper draws attention to the possible role of physical exercise as an adjunct non-pharmacological tool in the management of resistant hypertension. A few studies have investigated it, employing different methodologies, and taken together they have shown promising results. In summary, the available evidence suggests that aerobic physical exercise could be a valuable addition to the optimal pharmacological treatment of patients with resistant hypertension. PMID- 25717351 TI - Chronic alcohol consumption potentiates the development of diabetes through pancreatic beta-cell dysfunction. AB - Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic beta-cell and the exact mechanisms associated with ethanol-mediated beta-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic beta-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic beta-cell dysfunction and metabolic syndrome. PMID- 25717354 TI - Percutaneous left atrial appendage closure: Technical aspects and prevention of periprocedural complications with the watchman device. AB - Transcatheter closure of the left atrial appendage has been developed as an alternative to chronic oral anticoagulation for stroke prevention in patients with atrial fibrillation, and as a primary therapy for patients with contraindications to chronic oral anticoagulation. The promise of this new intervention compared with warfarin has been supported by several, small studies and two pivotal randomized trial with the Watchman Device. The results regarding risk reduction for stroke have been favourable although acute complications were not infrequent. Procedural complications, which are mainly related to transseptal puncture and device implantation, include air embolism, pericardial effusions/tamponade and device embolization. Knowledge of nature, management and prevention of complications should minimize the risk of complications and allow transcatheter left atrial appendage closure to emerge as a therapeutic option for patients with atrial fibrillation at risk for cardioembolic stroke. PMID- 25717353 TI - Cardiac remodeling and physical training post myocardial infarction. AB - After myocardial infarction (MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of renin-angiotensin aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re infarction. PMID- 25717357 TI - Pulmonary arterial dissection in a post-partum patient with patent ductus arteriosus: Case report and review of the literature. AB - Pulmonary arterial dissection is an uncommon but usually a deadly complication of chronic pulmonary hypertension. A 26-year-old female patient was admitted to our clinics with sudden dyspnea and chest discomfort one hour after giving birth to twins by vaginal delivery. An echocardiography was performed with a pre-diagnosis of pulmonary embolism. However, echocardiographic examination revealed a dilated main pulmonary artery and a dissection flap extending from main pulmonary artery to left pulmonary artery. In summary, in this report, we described a very rare case of pulmonary artery dissection in a pregnant patient with a previously un diagnosed patent ductus arteriosus without an obvious rise in pulmonary artery pressure and reviewed the relevant literature. PMID- 25717355 TI - Flecainide: Current status and perspectives in arrhythmia management. AB - Flecainide acetate is a class IC antiarrhythmic agent and its clinical efficacy has been confirmed by the results of several clinical trials. Nowadays, flecainide is recommended as one of the first line therapies for pharmacological conversion as well as maintenance of sinus rhythm in patients with atrial fibrillation and/or supraventricular tachycardias. Based on the Cardiac Arrhythmia Suppression Trial study results, flecainide is not recommended in patients with structural heart disease due to high proarrhythmic risk. Recent data support the role of flecainide in preventing ventricular tachyarrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia associated both with ryanodine receptor and calsequestrin mutations. We herein review the current clinical data related to flecainide use in clinical practice and some concerns about its role in the management of patients with coronary artery disease. PMID- 25717356 TI - Cardiac and non-cardiac causes of T-wave inversion in the precordial leads in adult subjects: A Dutch case series and review of the literature. AB - AIM: To describe the electrocardiographic (ECG) phenomena characterized by T-wave inversion in the precordial leads in adults and to highlight its differential diagnosis. METHODS: A retrospective chart review of 8 adult patients who were admitted with ECG T-wave inversion in the anterior chest leads with or without prolongation of corrected QT (QTc) interval. They had different clinical conditions. Each patient underwent appropriate clinical assessment including investigation for myocardial involvement. Single and multimodality non-invasive, semi-invasive and invasive diagnostic approach were used to ascertain the diagnosis. The diagnostic assessment included biochemical investigation, cardiac and abdominal ultrasound, cerebral and chest computed tomography, nuclear medicine and coronary angiography. RESULTS: Eight adult subjects (5 females) with a mean age of 66 years (range 51 to 82) are analyzed. The etiology of T-wave inversion in the precordial leads were diverse. On admission, all patients had normal blood pressure and the ECG showed sinus rhythm. Five patients showed marked prolongation of the QTc interval. The longest QTc interval (639 ms) was found in the patient with pheochromocytoma. Giant T-wave inversion (>= 10 mm) was found in pheochromocytoma followed by electroconvulsive therapy and finally ischemic heart disease. The deepest T-wave was measured in lead V3 (5 *). In 3 patients presented with mild T-wave inversion (patients 1, 5 and 4 mm), the QTc interval was not prolonged (432, 409 and 424 msec), respectively. CONCLUSION: T wave inversion associated with or without QTc prolongation requires meticulous history taking, physical examination and tailored diagnostic modalities to reach rapid and correct diagnosis to establish appropriate therapeutic intervention. PMID- 25717358 TI - Coronary stenting with cardiogenic shock due to acute ascending aortic dissection. AB - A 65-year-old man developed chest pain under cardiogenic shock. Coronary angiography revealed severe stenosis from the ostium of the left main coronary artery (LMCA) to the left anterior descending artery (LAD). Intravascular ultrasound (IVUS) identified a large hematoma that originated from the aorta and extended into the LAD, thereby compressing the true lumen. Type A aortic dissection (TAAD) that involved the LMCA was diagnosed by IVUS. Coronary stenting was performed via the LMCA to the proximal LAD, which resulted in coronary blood flow restoration and no further propagation of dissection. Elective surgical aortic repair was performed 2 wk after the stenting. LMCA stenting under IVUS guidance is effective for prompt diagnosis and precise stent deployment in patients with cardiogenic shock due to TAAD with LMCA dissection. PMID- 25717359 TI - Studying the active-site loop movement of the Sao Paolo metallo-beta-lactamase 1?Electronic supplementary information (ESI) available: Procedures for protein expression and purification, 19F-labelling, crystallisation, data collection, and structure determination, table of crystallographic data, table of crystallographic parameters and refinement statistics, figures showing binding mode and distances, procedures for mass spectrometry measurements, differential scanning fluorimetry measurements, stopped-flow measurements and other kinetics measurements. See DOI: 10.1039/c4sc01752hClick here for additional data file. AB - Metallo-beta-lactamases (MBLs) catalyse the hydrolysis of almost all beta-lactam antibiotics. We report biophysical and kinetic studies on the Sao Paulo MBL (SPM 1), which reveal its Zn(ii) ion usage and mechanism as characteristic of the clinically important di-Zn(ii) dependent B1 MBL subfamily. Biophysical analyses employing crystallography, dynamic 19F NMR and ion mobility mass spectrometry, however, reveal that SPM-1 possesses loop and mobile element regions characteristic of the B2 MBLs. These include a mobile alpha3 region which is important in catalysis and determining inhibitor selectivity. SPM-1 thus appears to be a hybrid B1/B2 MBL. The results have implications for MBL evolution and inhibitor design. PMID- 25717361 TI - Voluntary acceptance and consumption of two oral ciclosporin formulations in dogs: two randomised, controlled studies. AB - BACKGROUND: Atopic dermatitis (AD) is the most common canine allergic skin disease and can significantly affect the quality of life of affected dogs. Treating canine AD with ciclosporin has been a subject of great interest in recent years. Many studies have provided substantial evidence of ciclosporin efficacy and safety in canine AD management, and for several years ciclosporin has been recognised as a major component of canine AD multimodal therapy. As a chronic condition, canine AD requires life-long medical management and treatment success relies in large part on product ease of administration. Two studies were conducted to assess the comparative voluntary acceptance and consumption of Cyclavance(r) (Virbac), a new oral liquid formulation of ciclosporin, and Atopica(r) (Novartis) either added to a small quantity of kibbles (study 1) or administered directly into the dog's mouth (study 2). RESULTS: Over the course of the two studies 70 dogs assessed each of the ciclosporin formulations and 320 individual tests were performed for each tested product. Immediate prehension (in less than 2 seconds) occurred significantly more often with Cyclavance(r) (90.6% of the tests) than with Atopica(r) (14.4% of the tests) when products were mixed with 30 grams of dry food (p < 0.001). Moreover, Cyclavance(r) was significantly more often easily accepted than Atopica(r) (99.3% vs 27.1% of the tests, respectively) when products were administered directly into the dogs' mouth (p < 0.0001). Cyclavance(r) was also more often totally consumed (98.3% of the tests) than Atopica(r) (2.2% of the tests) when mixed with a small amount of food (p < 0.001). However, both products were totally consumed once administered directly into the dogs' mouth. CONCLUSIONS: By facilitating cicloporin administration and consumption, Cyclavance(r) liquid formulation offers an interesting alternative to capsules that may improve dosing compliance and therefore the ability to benefit from the therapeutic effects in the long-term treatment of canine AD. PMID- 25717360 TI - Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function. AB - BACKGROUND: Ca(2+) influx through CaV1.1 is not required for skeletal muscle excitation-contraction coupling, but whether Ca(2+) permeation through CaV1.1 during sustained muscle activity plays a functional role in mammalian skeletal muscle has not been assessed. METHODS: We generated a mouse with a Ca(2+) binding and/or permeation defect in the voltage-dependent Ca(2+) channel, CaV1.1, and used Ca(2+) imaging, western blotting, immunohistochemistry, proximity ligation assays, SUnSET analysis of protein synthesis, and Ca(2+) imaging techniques to define pathways modulated by Ca(2+) binding and/or permeation of CaV1.1. We also assessed fiber type distributions, cross-sectional area, and force frequency and fatigue in isolated muscles. RESULTS: Using mice with a pore mutation in CaV1.1 required for Ca(2+) binding and/or permeation (E1014K, EK), we demonstrate that CaV1.1 opening is coupled to CaMKII activation and refilling of sarcoplasmic reticulum Ca(2+) stores during sustained activity. Decreases in these Ca(2+) dependent enzyme activities alter downstream signaling pathways (Ras/Erk/mTORC1) that lead to decreased muscle protein synthesis. The physiological consequences of the permeation and/or Ca(2+) binding defect in CaV1.1 are increased fatigue, decreased fiber size, and increased Type IIb fibers. CONCLUSIONS: While not essential for excitation-contraction coupling, Ca(2+) binding and/or permeation via the CaV1.1 pore plays an important modulatory role in muscle performance. PMID- 25717362 TI - Deletion of ENTPD3 does not impair nucleotide hydrolysis in primary somatosensory neurons or spinal cord. AB - Ectonucleotidases are membrane-bound or secreted proteins that hydrolyze extracellular nucleotides. Recently, we identified three ectonucleotidases that hydrolyze extracellular adenosine 5'-monophosphate (AMP) to adenosine in primary somatosensory neurons. Currently, it is unclear which ectonucleotidases hydrolyze ATP and ADP in these neurons. Ectonucleoside triphosphate diphosphohydrolases (ENTPDs) comprise a class of enzymes that dephosphorylate extracellular ATP and ADP. Here, we found that ENTPD3 (also known as NTPDase3 or CD39L3) was located in nociceptive and non-nociceptive neurons of the dorsal root ganglion (DRG), in the dorsal horn of the spinal cord, and in free nerve endings in the skin. To determine if ENTPD3 contributes directly to ATP and ADP hydrolysis in these tissues, we generated and characterized an Entpd3 knockout mouse. This mouse lacks ENTPD3 protein in all tissues examined, including the DRG, spinal cord, skin, and bladder. However, DRG and spinal cord tissues from Entpd3 (-/-) mice showed no reduction in histochemical staining when ATP, ADP, AMP, or UTP were used as substrates. Additionally, using fast-scan cyclic voltammetry (FSCV), adenosine production was not impaired in the dorsal spinal cord of Entpd3 (-/-) mice when the substrate ADP was applied. Further, Entpd3 ( /-) mice did not differ in nociceptive behaviors when compared to wild-type mice, although Entpd3 (-/-) mice showed a modest reduction in beta-alanine-mediated itch. Taken together, our data indicate that deletion of Entpd3 does not impair ATP or ADP hydrolysis in primary somatosensory neurons or in dorsal spinal cord. Moreover, our data suggest there could be multiple ectonucleotidases that act redundantly to hydrolyze nucleotides in these regions of the nervous system. PMID- 25717363 TI - High-Performance Mixed Models Based Genome-Wide Association Analysis with omicABEL software. AB - To raise the power of genome-wide association studies (GWAS) and avoid false positive results in structured populations, one can rely on mixed model based tests. When large samples are used, and when multiple traits are to be studied in the 'omics' context, this approach becomes computationally challenging. Here we consider the problem of mixed-model based GWAS for arbitrary number of traits, and demonstrate that for the analysis of single-trait and multiple-trait scenarios different computational algorithms are optimal. We implement these optimal algorithms in a high-performance computing framework that uses state-of the-art linear algebra kernels, incorporates optimizations, and avoids redundant computations, increasing throughput while reducing memory usage and energy consumption. We show that, compared to existing libraries, our algorithms and software achieve considerable speed-ups. The OmicABEL software described in this manuscript is available under the GNU GPL v. 3 license as part of the GenABEL project for statistical genomics at http: //www.genabel.org/packages/OmicABEL. PMID- 25717364 TI - Directed evolution induces tributyrin hydrolysis in a virulence factor of Xylella fastidiosa using a duplicated gene as a template. AB - Duplication of genes is one of the preferred ways for natural selection to add advantageous functionality to the genome without having to reinvent the wheel with respect to catalytic efficiency and protein stability. The duplicated secretory virulence factors of Xylella fastidiosa (LesA, LesB and LesC), implicated in Pierce's disease of grape and citrus variegated chlorosis of citrus species, epitomizes the positive selection pressures exerted on advantageous genes in such pathogens. A deeper insight into the evolution of these lipases/esterases is essential to develop resistance mechanisms in transgenic plants. Directed evolution, an attempt to accelerate the evolutionary steps in the laboratory, is inherently simple when targeted for loss of function. A bigger challenge is to specify mutations that endow a new function, such as a lost functionality in a duplicated gene. Previously, we have proposed a method for enumerating candidates for mutations intended to transfer the functionality of one protein into another related protein based on the spatial and electrostatic properties of the active site residues (DECAAF). In the current work, we present in vivo validation of DECAAF by inducing tributyrin hydrolysis in LesB based on the active site similarity to LesA. The structures of these proteins have been modeled using RaptorX based on the closely related LipA protein from Xanthomonas oryzae. These mutations replicate the spatial and electrostatic conformation of LesA in the modeled structure of the mutant LesB as well, providing in silico validation before proceeding to the laborious in vivo work. Such focused mutations allows one to dissect the relevance of the duplicated genes in finer detail as compared to gene knockouts, since they do not interfere with other moonlighting functions, protein expression levels or protein-protein interaction. PMID- 25717365 TI - An object oriented implementation of the Yeadon human inertia model. AB - We present an open source software implementation of a popular mathematical method developed by M.R. Yeadon for calculating the body and segment inertia parameters of a human body. The software is written in a high level open source language and provides three interfaces for manipulating the data and the model: a Python API, a command-line user interface, and a graphical user interface. Thus the software can fit into various data processing pipelines and requires only simple geometrical measures as input. PMID- 25717366 TI - Breaking a Guinness World Record on Hand Sanitizing Relay, initiating a call for vital research in overcoming campaign fatigue for hand hygiene. AB - Hand hygiene has been shown to be effective in significantly reducing hospital acquired infections for many years. However it is difficult to maintain and enhance compliance with hand hygiene guidelines. In Hong Kong, we previously reported a strategy to counter campaign fatigue from 50%-55% in 2009-11 to 83% in 2012. Here we report a creative activity that we used to sustain and enhance hand hygiene compliance. In May 2014 we broke the first Guinness World Record for a Hand Sanitizing Relay. A total of 277 participants performed hand hygiene before two official and approved witnesses. Following this team-directed strategy, an increase in hand hygiene compliance was identified in two clinical areas with previously poor compliance. The longer term impact of this strategy remains to be determined. More broadly, further research is urgently needed on meeting the challenge of campaign fatigue, and maintaining and enhancing compliance with hand hygiene guidelines. PMID- 25717367 TI - Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions. AB - Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The ability of this AH to bind to other host proteins is disrupted by a neutralizing antibody derived from a human survivor of the 1995 Kikwit outbreak, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such 'hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the 'largest Ebola epidemic, affecting multiple countries in West Africa' ( http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html). PMID- 25717369 TI - Case Report: A case report of Moyamoya disease in a 36 year old African American woman. AB - Moyamoya is a rare idiopathic progressive vaso-occlusive disease characterized by irreversible condition of main blood vessels to the brain as they enter into the skull. We present a case of 36 year old African American female presenting to the Out Patient Clinic with headache which were on and off for 4-6 months and did not relieve on routine medical therapy. It was associated with weakness on right side for last few days. The patient was investigated with CT Angiogram, diagnosed as Moyamoya disease and operated. She has been followed up for the last 5 years and the patient has not complained of any headaches or focal neurological symptoms. PMID- 25717370 TI - Detection of Burkholderia pseudomallei in Sputum using Selective Enrichment Broth and Ashdown's Medium at Kampong Cham Provincial Hospital, Cambodia. AB - Melioidosis infection, caused by Burkholderia pseudomallei, is increasingly reported in Cambodia. We hypothesized that implementation of an enhanced sputum testing protocol in a provincial hospital diagnostic microbiology laboratory would increase detection of B. pseudomallei. We tested 241 sputum specimens that were deemed acceptable for culture, comparing culture in selective enrichment broth followed by sub-culture on Ashdown's medium to standard culture methods. Two specimens (0.8%) were positive for B. pseudomallei using the enhanced protocol whereas one specimen (0.4%) was positive using standard methods. These findings demonstrate that B. pseudomallei is rarely detected in sputum at this hospital. The low frequency of B. pseudomallei in sputum specimens precludes drawing any conclusions about the relative benefits of an enhanced sputum testing protocol at this site. Promoting clinician awareness of the infection and encouraging utilization of diagnostic microbiology services are likely to be important factors in facilitating identification of melioidosis. PMID- 25717371 TI - Case Report: Urgent endovascular treatment of subclavian artery injury after blunt trauma. AB - Subclavian arterial injury is rare and potentially life-threatening, particularly when it leads to arterial occlusion, causing limb ischemia, retrograde thromboembolization and cerebral infarction within hours after injury. Here we report a blunt trauma case with subclavian arterial injury, upper extremity ischemia, and the need for urgent treatment to salvage the limb and prevent cerebral infarction. A 41-year-old man had a left, open, mid-shaft clavicle fracture and left subclavian artery injury accompanied by a weak pulse in the left radial artery, decreased blood pressure of the left arm compared to the right, and left hand numbness. Urgent debridement and irrigation of the open clavicle fracture was followed by angiography for the subclavian artery injury. The left distal subclavian artery had a segmental dissection with a thrombus. Urgent endovascular treatment using a self-expanding nitinol stent successfully restored the blood flow and blood pressure to the left upper extremity. Endovascular treatment is a viable option for cases of subclavian artery injury where there is a risk of extremity ischemia and cerebral infarction. PMID- 25717372 TI - Strain-specific and pooled genome sequences for populations of Drosophila melanogaster from three continents. AB - To contribute to our general understanding of the evolutionary forces that shape variation in genome sequences in nature, we have sequenced genomes from 50 isofemale lines and six pooled samples from populations of Drosophila melanogaster on three continents. Analysis of raw and reference-mapped reads indicates the quality of these genomic sequence data is very high. Comparison of the predicted and experimentally-determined Wolbachia infection status of these samples suggests that strain or sample swaps are unlikely to have occurred in the generation of these data. Genome sequences are freely available in the European Nucleotide Archive under accession ERP009059. Isofemale lines can be obtained from the Drosophila Species Stock Center. PMID- 25717368 TI - Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis. AB - The interpretation of genomic variants has become one of the paramount challenges in the post-genome sequencing era. In this review we summarize nearly 20 years of research on the applications of information theory (IT) to interpret coding and non-coding mutations that alter mRNA splicing in rare and common diseases. We compile and summarize the spectrum of published variants analyzed by IT, to provide a broad perspective of the distribution of deleterious natural and cryptic splice site variants detected, as well as those affecting splicing regulatory sequences. Results for natural splice site mutations can be interrogated dynamically with Splicing Mutation Calculator, a companion software program that computes changes in information content for any splice site substitution, linked to corresponding publications containing these mutations. The accuracy of IT-based analysis was assessed in the context of experimentally validated mutations. Because splice site information quantifies binding affinity, IT-based analyses can discern the differences between variants that account for the observed reduced (leaky) versus abolished mRNA splicing. We extend this principle by comparing predicted mutations in natural, cryptic, and regulatory splice sites with observed deleterious phenotypic and benign effects. Our analysis of 1727 variants revealed a number of general principles useful for ensuring portability of these analyses and accurate input and interpretation of mutations. We offer guidelines for optimal use of IT software for interpretation of mRNA splicing mutations. PMID- 25717373 TI - Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection. AB - The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established. PMID- 25717375 TI - Design of thiol-ene photoclick hydrogels using facile techniques for cell culture applications?Electronic supplementary information (ESI) available. See DOI: 10.1039/c4bm00187gClick here for additional data file. AB - Thiol-ene 'click' chemistries have been widely used in biomaterials applications, including drug delivery, tissue engineering, and controlled cell culture, owing to their rapid, cytocompatible, and often orthogonal reactivity. In particular, hydrogel-based biomaterials formed by photoinitiated thiol-ene reactions afford spatiotemporal control over the biochemical and biomechanical properties of the network for creating synthetic materials that mimic the extracellular matrix or enable controlled drug release. However, the use of charged peptides functionalized with cysteines, which can form disulfides prior to reaction, and vinyl monomers that require multistep syntheses and contain ester bonds, may lead to undesired inhomogeneity or degradation under cell culture conditions. Here, we designed a thiol-ene hydrogel formed by the reaction of allyloxycarbonyl functionalized peptides and thiol-functionalized poly(ethylene glycol). Hydrogels were polymerized by free radical initiation under cytocompatible doses of long wavelength ultraviolet light in the presence of water-soluble photoinitiators (lithium acylphosphinate, LAP, and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2 methyl-1-propanone, Irgacure 2959). Mechanical properties of these hydrogels were controlled by varying the monomer concentration to mimic a range of soft tissue environments, and hydrogel stability in cell culture medium was observed over weeks. Patterns of biochemical cues were created within the hydrogels post formation and confirmed through the incorporation of fluorescently-labeled peptides and Ellman's assay to detect free thiols. Human mesenchymal stem cells remained viable after encapsulation and subsequent photopatterning, demonstrating the utility of the monomers and hydrogels for three-dimensional cell culture. This facile approach enables the formation and characterization of hydrogels with well-defined, spatially-specific properties and expands the suite of monomers available for three-dimensional cell culture and other biological applications. PMID- 25717376 TI - Effect of providing risk information on undergoing cervical cancer screening: a randomized controlled trial. AB - BACKGROUND: In Japan, the cervical cancer screening rate is extremely low. Towards improving the cervical cancer screening rate, encouraging eligible people to make an informed choice, which is a decision-making process that relies on beliefs informed by adequate information about the possible benefits and risks of screening, has attracted increased attention in the public health domain. However, there is concern that providing information on possible risks of screening might prevent deter from participating. METHODS: In total, 1,912 women aged 20-39 years who had not participated in screening in the fiscal year were selected from a Japanese urban community setting. Participants were randomly divided into 3 groups. Group A received a printed reminder with information about the possible benefits of screening, group B received a printed reminder with information about possible benefits and risks, and group C received a printed reminder with simple information only (control group). RESULTS: Out of 1,912 participants, 169 (8.8%) participated in cervical cancer screening. In the intervention groups, 137 (10.9%) participated in cervical cancer screening, compared to only 32 (4.9%) of the control group (p < 0.001). In addition, logistic regression analysis revealed that there was no significant difference in screening rate between group A and group B (p = 0.372). CONCLUSIONS: Providing information on the possible risks of screening may not prevent people from taking part in cervical cancer screening among a Japanese non-adherent population. PMID- 25717374 TI - A review of 40 years of enteric antimicrobial resistance research in Eastern Africa: what can be done better? AB - The emergence and persistence of antimicrobial resistance is driven by varied factors including the indiscriminate use of antibiotics and variable drug efficacy and presents a major threat to the control of infectious diseases. Despite the high burden of disease in sub-Saharan Africa and the potential health and economic consequences, the level of research on antimicrobial resistance in the region remains unknown. Little data exists to quantify the contribution of different factors to the current levels of antimicrobial resistance. To identify the factors that contribute most to the emergence, amplification, persistence and dissemination of antimicrobial resistance in humans and animals, we used the PRISMA 2009 guidelines to conduct a systematic review of studies on antibiotic resistant enteric bacteria in Eastern Africa. We searched PubMed and Google Scholar databases and identified 2,155 probable articles, of which 89 studies on humans and 28 on animals remained after full-text review. These were articles from Kenya, Tanzania, Uganda, Ethiopia, Rwanda and Burundi, published between 1974 and 2013, that reported resistance in Salmonella, Shigella, Escherichia coli and Vibrio sp. The majority (98%) of human studies were based on hospital- (rather than community-wide) sampling and although they report high levels of antimicrobial resistance in the region, study design and methodological differences preclude conclusions about the magnitude and trends of antimicrobial resistance. To remedy this, we discuss and propose minimum reporting guidelines for the level of detail that should be explicitly provided for antimicrobial resistance study designs, testing of samples and reporting of results that would permit comparative inferences and enable meta-analyses. Further, we advocate for increased focus on community- rather than hospital-based sampling to provide a better indication of population-wide trends in antimicrobial resistance. This approach, together with the establishment of a robust regional surveillance network, should over time build a pool of evidence-based data useful for policy decisions and interventions aimed at controlling antimicrobial resistance. PMID- 25717377 TI - Self-assembled micelles of amphiphilic PEGylated rapamycin for loading paclitaxel and resisting multidrug resistant cancer cells?Electronic supplementary information (ESI) available: Chemicals and reagents, detailed experimental procedures for materials synthesis, characterization, cellular evaluations and supporting figures and tables. See DOI: 10.1039/c4tb01633eClick here for additional data file. AB - Self-assembled micelles of amphiphilic PEG-rapamycin conjugates loaded with paclitaxel have been developed for co-delivery and simultaneous intracellular release of paclitaxel and rapamycin, bypassing the cancer cell drug resistant mechanism and maximising the synergy of dual-drug combinational therapy. This novel nanomedicine offers 20-fold improved potency over free paclitaxel against a model multidrug resistant human breast cancer cell. PMID- 25717378 TI - Biosynthesis of planet friendly bioplastics using renewable carbon source. AB - Plastics are uniquely flexible materials that offer considerable benefits as a simple packing to complex engineering material. Traditional synthetic polymers (often called plastics), such as polypropylene and polyethylene have been derived from non-renewable petrochemicals and known to cause environmental concerns due to their non-biodegradable nature. The enormous use of petroleum-based plastic compounds emphasized a need for sustainable alternatives derived from renewable resources. Bioplastics have attracted widespread attention, as eco-friendly and eco-tolerable alternative. But they have got certain limitations as well, such as high cost of production and unsatisfactory mechanical properties. In this study we have found agriculture waste (AW) as low-cost and renewable substrate for the production of bioplastics in bacterial fermentation. Improvement in tensile properties of produced bioplastic film has also been documented upon blending with Cellulose Acetate Butyrate (CAB). PMID- 25717379 TI - Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids from a common intermediate through regiocontrolled cyclizations by Staudinger reactions?Electronic supplementary information (ESI) available: Experimental details and procedures, compound characterization data, copies of 1H and 13C NMR spectra for new compounds. See DOI: 10.1039/c4qo00312hClick here for additional data file. AB - Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids bearing distinctive core structures were achieved through Staudinger reactions using a common intermediate. In the key cyclization step, water functioned like a switch to control which core structure to produce. The chemistry allowed for selective syntheses of the group of alkaloids from a simple intermediate through straightforward chemical operations. PMID- 25717380 TI - Therapeutic Opportunities for Targeting microRNAs in Cancer. AB - MicroRNAs (miRNAs) are small noncoding RNAs that can function as either powerful tumor promoters or suppressors in numerous types of cancer. The ability of miRs to target multiple genes and biological signaling pathways has created intense interest in their potential clinical utility as predictive and diagnostic biomarkers, and as innovative therapeutic agents. Recently, accumulating preclinical studies have illustrated the feasibility of slowing tumor progression by either overexpressing tumor suppressive miRNAs, or by neutralizing the activities of oncogenic miRNAs in cell- and animal-based models of cancer. Here we highlight prominent miRNAs that may represent potential therapeutic targets in human malignancies, as well as review current technologies available for inactivating or restoring miRNA activity in clinical settings. PMID- 25717381 TI - The wrong white crystals: not salt but sugar as aetiological in hypertension and cardiometabolic disease. AB - Cardiovascular disease is the leading cause of premature mortality in the developed world, and hypertension is its most important risk factor. Controlling hypertension is a major focus of public health initiatives, and dietary approaches have historically focused on sodium. While the potential benefits of sodium-reduction strategies are debatable, one fact about which there is little debate is that the predominant sources of sodium in the diet are industrially processed foods. Processed foods also happen to be generally high in added sugars, the consumption of which might be more strongly and directly associated with hypertension and cardiometabolic risk. Evidence from epidemiological studies and experimental trials in animals and humans suggests that added sugars, particularly fructose, may increase blood pressure and blood pressure variability, increase heart rate and myocardial oxygen demand, and contribute to inflammation, insulin resistance and broader metabolic dysfunction. Thus, while there is no argument that recommendations to reduce consumption of processed foods are highly appropriate and advisable, the arguments in this review are that the benefits of such recommendations might have less to do with sodium-minimally related to blood pressure and perhaps even inversely related to cardiovascular risk-and more to do with highly-refined carbohydrates. It is time for guideline committees to shift focus away from salt and focus greater attention to the likely more-consequential food additive: sugar. A reduction in the intake of added sugars, particularly fructose, and specifically in the quantities and context of industrially-manufactured consumables, would help not only curb hypertension rates, but might also help address broader problems related to cardiometabolic disease. PMID- 25717383 TI - Open Communication and Discussion Facilitate Reconciliation: The Maimonides Approach to Publication of Manduca's Letter in The Lancet. PMID- 25717382 TI - Standard medical care of patients with systemic lupus erythematosus (SLE) in large specialised centres: data from the Russian Federation, Ukraine and Republic of Kazakhstan (ESSENCE). AB - OBJECTIVES: To describe disease characteristics and treatment regimens for adult patients with systemic lupus erythematosus (SLE) with autoantibody positive disease in three countries (the Russian Federation, Ukraine and Republic of Kazakhstan). METHODS: The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) study was a 1-year, retrospective, multicentre, observational study. Data included patients' characteristics, disease activity and severity, and healthcare resource use in 2010. RESULTS: Twelve centres enrolled 436 eligible patients: 232 in Russia, 110 in Kazakhstan and 94 in Ukraine. Mean age ranged from 36 to 42 years and median SLE duration from 3 to 6.8 years. According to study definitions, 69.2% of patients in Russia, 72.7% in Kazakhstan and 55.4% in Ukraine had severe disease at diagnosis. SLE activity (Nasonova classification, 1972) decreased from diagnosis to the last visit in 2010 in all countries. At the last visit, mean (SD) Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index score was 13.8 (10.5) in Russia, 19.4 (16.9) in Kazakhstan and 7.2 (6.8) in Ukraine, and Systemic Lupus International Collaborative Clinics/American College of Rheumatology damage index was 2.0 (2.2), 3.3 (3.2) and 2.2 (2.0), respectively. Treatment regimens included predominantly glucocorticoids (96.7 99.1%), immunosuppressants or cytotoxic drugs, for example, azathioprine and cyclophosphamide (20.7-53.2%), and antimalarial drugs (18.3-40.8%). CONCLUSIONS: The study provides reliable insight into the SLE clinical profiles in the referenced countries. Patients were 4-10 years younger in the study and had 3-7 years shorter SLE duration than in Western European countries and both SLE activity and severity were higher with higher rate of hospitalisations, but decreased during treatment. Local and international scales demonstrated correlation in SLE activity and organ damage evaluation. There were differences in clinical characteristics and healthcare features across the countries. PMID- 25717384 TI - Geopolitical issues and responsibilities of medical and scientific journals. PMID- 25717385 TI - Academic Debate: Publications Which Promote Political Agendas Have no Place in Scientific and Medical Journals, and Academics Should Refrain from Publishing in Such Journals. AB - This paper presents the full debate held on October 1, 2014, which focused on the following resolution: "Publications which promote political agendas have no place in scientific and medical journals, and academics should refrain from publishing in such journals." The debate moderator was Professor Shimon Glick. Taking the pro stance was Professor A. Mark Clarfield; the con stance was held by Professor Rael D. Strous. Following the first part of the debate, Dr Richard Horton, Editor in-Chief of The Lancet, gave his thoughts on the topic. This was followed by the opportunity for rebuttal by Professors Clarfield and Strous. The debate was summarized and closed by Professor Glick. This paper provides a slightly edited text of the debate, for ease of reading. PMID- 25717386 TI - Adoptive T cell immunotherapy for cancer. AB - Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. In recent years, there has been an increased interest in optimizing this technology in order to make it a clinically feasible treatment. One of the main treatment modalities within cancer immunotherapy has been adoptive T cell therapy (ACT). Using this approach, tumor specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. In the current review, we revisit some of the major successes of ACT, the major hurdles that have been overcome to optimize ACT, the remaining challenges, and future approaches to make ACT widely available. PMID- 25717387 TI - The Significance of Normal Pretreatment Levels of CA125 (<35 U/mL) in Epithelial Ovarian Carcinoma. AB - OBJECTIVE: To assess the association between normal CA125 levels at diagnosis of epithelial ovarian carcinoma (EOC) with prognostic factors and with outcome. METHODS: The study group consisted of histologically confirmed EOC patients with normal pretreatment CA125 levels, and the controls consisted of EOC patients with elevated (>=35 U/mL) pretreatment CA125 levels, diagnosed and treated between 1995 and 2112. Study and control group patients fulfilled the following criteria: 1) their pretreatment CA125 levels were assessed; 2) they had full standard primary treatment, i.e. cytoreductive surgery and cisplatin-based chemotherapy; and 3) they were followed every 2-4 months during the first two years and every 4 6 months thereafter. RESULTS: Of 114 EOC patients who fulfilled the inclusion criteria, 22 (19.3%) had normal pretreatment CA125 levels. The control group consisted of the remaining 92 patients with >=35 U/mL serum CA125 levels pretreatment. The proportion of patients with early-stage and low-grade disease, with optimal cytoreduction, and with platin-sensitive tumors was significantly higher in the study group than in the control group. The progression-free survival (PFS) and overall survival (OS) were significantly higher in the study group than in the control group on univariate analysis but not on multivariate analysis. CONCLUSION: It seems that a normal CA125 level at diagnosis in EOC may also be of prognostic significance for the individual patient. PMID- 25717388 TI - Effect of ozone on intestinal epithelial homeostasis in a rat model. AB - BACKGROUND: The positive effects of ozone therapy have been described in many gastrointestinal disorders. The mechanisms of this positive effect of ozone therapy are poorly understood. The purpose of the present study was to investigate whether the use of ozone may potentiate the gut intestinal mucosal homeostasis in a rat model. METHODS: Adult rats weighing 250-280 g were randomly assigned to one of three experimental groups of 8 rats each: 1) Control rats were given 2 mL of water by gavage and intraperitoneally (IP) for 5 days; 2) O3-PO rats were treated with 2 mL of ozone/oxygen mixture by gavage and 2 mL of water IP for 5 days; 3) O3-IP rats were treated with 2 mL of water by gavage and 2 mL of ozone/oxygen mixture IP for 5 days. Rats were sacrificed on day 6. Bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, and cell proliferation and apoptosis were evaluated following sacrifice. RESULTS: The group of O3-IP rats demonstrated a greater jejunal and ileal villus height and crypt depth, a greater enterocyte proliferation index in jejunum, and lower enterocyte apoptosis in ileum compared to control animals. Oral administration of the ozone/oxygen mixture resulted in a less significant effect on cell turnover. CONCLUSIONS: Treatment with an ozone/oxygen mixture stimulates intestinal cell turnover in a rat model. Intraperitoneal administration of ozone resulted in a more significant intestinal trophic effect than oral administration. PMID- 25717389 TI - Rituals in death and dying: modern medical technologies enter the fray. AB - In the absence of immortality, the human species has over the millennia developed rites and rituals to help in the passing of life to honor the person who is dying or has died or in some way demonstrate their "courage" and perseverance as well as duty even in the face of almost certain death. The centuries-old traditions of the gathering of loved ones, the chanting of prayers, the ritual religious blessings are in the process of being replaced by the "miracles" of modern medical technology. PMID- 25717390 TI - Dr. Otto heinrich warburg-survivor of ethical storms. AB - Otto Heinrich Warburg (1883-1970; not to be confused with the Zionist of the same name) was a member of an illustrious Jewish family, known for some five centuries. From humble beginnings, the family became prominent in the world for their contributions to all aspects of society. The son of a German mother and a Jewish (converted) father, Otto H. Warburg became a major contributor to medical science in the field of cancer research. Considered for Nobel Prize more than once, he finally received it in 1931 for his discovery of the nature and mode of action of the cellular respiratory enzyme. Warburg's personality was controversial: he was intolerant of opposing scientific views yet tolerant toward Nazi abuses. Accused of collaboration under the Nazi regime, Otto H. Warburg was nevertheless readmitted to the global scientific community after World War II. His contribution to cancer research remains influential to this day and has been superseded by discoveries that have built upon his work. PMID- 25717391 TI - Scurvy on sea and land: political economy and natural history, c. 1780-c. 1850. AB - From the late eighteenth century, the ways in which scurvy was understood changed in consequence of the abandonment of humoral pathology and the adoption of a new causal framework informed by nervous physiology. Although there was some narrowing of the etiological framework around dietary deficiency in the wake of the navy's success with the issue of citrus juices, this was rarely to the exclusion of predisposing causes such as fatigue, weather and flagging spirits. Within the navy, the persistence of a multi-factoral framework was relatively unproblematic, for the standard issue of citrus juices and improvements in victualling occurred at the same time as other important reforms in naval health. But outside the navy it was a different matter. In other institutional settings, the continuing belief in the importance of factors other than diet created tensions between medical officers and administrators who found such inclusive views politically inconvenient. After a brief survey of the principal changes in the physiology of scurvy, this article examines how the problem of scurvy was understood, not only in the navy but also in the armies of the East India Company and in British prisons. These were not the only contexts in which scurvy caused concern, but they serve to illustrate the fact that it remained a complex and controversial disease. The article shows how different medical cultures and institutional imperatives took the natural history of scurvy in different directions. PMID- 25717392 TI - EHR-based phenome wide association study in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is one of the most common causes of cancer-related deaths in the United States, it is difficult to detect early and typically has a very poor prognosis. We present a novel method of large-scale clinical hypothesis generation based on phenome wide association study performed using Electronic Health Records (EHR) in a pancreatic cancer cohort. METHODS: The study population consisted of 1,154 patients diagnosed with malignant neoplasm of pancreas seen at The Froedtert & The Medical College of Wisconsin academic medical center between the years 2004 and 2013. We evaluated death of a patient as the primary clinical outcome and tested its association with the phenome, which consisted of over 2.5 million structured clinical observations extracted out of the EHR including labs, medications, phenotypes, diseases and procedures. The individual observations were encoded in the EHR using 6,617 unique ICD-9, CPT-4, LOINC, and RxNorm codes. We remapped this initial code set into UMLS concepts and then hierarchically expanded to support generalization into the final set of 10,164 clinical concepts, which formed the final phenome. We then tested all possible pairwise associations between any of the original 10,164 concepts and death as the primary outcome. RESULTS: After correcting for multiple testing and folding back (generalizing) child concepts were appropriate, we found 231 concepts to be significantly associated with death in the study population. CONCLUSIONS: With the abundance of structured EHR data, phenome wide association studies combined with knowledge engineering can be a viable method of rapid hypothesis generation. PMID- 25717393 TI - Drug-drug interaction data source survey and linking. AB - As an initial step towards the goal of a common data model for potential drug drug interactions, we surveyed the data elements provided by the publicly available sources. Our analysis found that there is very little overlap between or across publicly available resources and that the information provided is very heterogeneous. PMID- 25717394 TI - Selective model averaging with bayesian rule learning for predictive biomedicine. AB - Accurate disease classification and biomarker discovery remain challenging tasks in biomedicine. In this paper, we develop and test a practical approach to combining evidence from multiple models when making predictions using selective Bayesian model averaging of probabilistic rules. This method is implemented within a Bayesian Rule Learning system and compared to model selection when applied to twelve biomedical datasets using the area under the ROC curve measure of performance. Cross-validation results indicate that selective Bayesian model averaging statistically significantly outperforms model selection on average in these experiments, suggesting that combining predictions from multiple models may lead to more accurate quantification of classifier uncertainty. This approach would directly impact the generation of robust predictions on unseen test data, while also increasing knowledge for biomarker discovery and mechanisms that underlie disease. PMID- 25717395 TI - Generalized linear models for identifying predictors of the evolutionary diffusion of viruses. AB - Bioinformatics and phylogeography models use viral sequence data to analyze spread of epidemics and pandemics. However, few of these models have included analytical methods for testing whether certain predictors such as population density, rates of disease migration, and climate are drivers of spatial spread. Understanding the specific factors that drive spatial diffusion of viruses is critical for targeting public health interventions and curbing spread. In this paper we describe the application and evaluation of a model that integrates demographic and environmental predictors with molecular sequence data. The approach parameterizes evolutionary spread of RNA viruses as a generalized linear model (GLM) within a Bayesian inference framework using Markov chain Monte Carlo (MCMC). We evaluate this approach by reconstructing the spread of H5N1 in Egypt while assessing the impact of individual predictors on evolutionary diffusion of the virus. PMID- 25717396 TI - Heterogeneity within and across Pediatric Pulmonary Infections: From Bipartite Networks to At-Risk Subphenotypes. AB - Although influenza (flu) and respiratory syncytial virus (RSV) infections are extremely common in children under two years and resolve naturally, a subset develop severe disease resulting in hospitalization despite having no identifiable clinical risk factors. However, little is known about inherent host specific genetic and immune mechanisms in this at-risk subpopulation. We therefore conducted a secondary analysis of statistically significant, differentially-expressed genes from a whole genome-wide case-control study of children less than two years of age hospitalized with flu or RSV, through the use of bipartite networks. The analysis revealed three clusters of cases common to both types of infection: core cases with high expression of genes in the network core implicated in hyperimmune responsiveness; periphery cases with lower expression of the same set of genes indicating medium-responsiveness; and control like cases with a gene signature resembling that of the controls, indicating normal-responsiveness. These results provide testable hypotheses for at-risk subphenotypes and their respective pathophysiologies in both types of infections. We conclude by discussing alternate hypotheses for the results, and insights about how bipartite networks of gene expression across multiple phenotypes can help to identify complex patterns related to subphenotypes, with the translational goal of identifying targeted therapeutics. PMID- 25717397 TI - Use of RxNorm and NDF-RT to normalize and characterize participant-reported medications in an i2b2-based research repository. AB - The MURDOCK Study is longitudinal, large-scale epidemiological study for which participants' medication use is collected as free text. In order to maximize utility of drug data, while minimizing cost due to manual expert intervention, we have developed a generalizable approach to automatically coding medication data using RxNorm and NDF-RT and their associated application program interfaces (APIs). Of 130,273 entries, we were able to accurately map 122,523 (94%) to RxNorm concepts, and 106,135 (85%) of those drug concepts to nodes under the Drug by VA Class branch of NDF-RT. This approach has enabled use of drug data in combination with other complementary information for cohort identification within an i2b2-based participant registry. The method may be generalized to other projects requiring coding of medication data from free-text. PMID- 25717398 TI - Capturing cancer initiating events in OncoCL, a cancer cell ontology. AB - We have developed an ontology, OncoCL, to classify cancer cells and provide a framework for consistent annotation of cancer-associated data from conventional surgical pathology and cancer molecular biology for the purpose of access, comparison, and analysis. The cell type ontology, CL, describes normal cell types and was not designed to capture the pathology of cancer cells. OncoCL builds upon CL, as a canonical cell (represented in CL) undergoes oncogenic change and tumorigenesis with the acquisition of the cancer hallmarks described by Hanahan and Weinberg. PMID- 25717399 TI - Automatic gene prioritization in support of the inflammatory contribution to Alzheimer's disease. AB - This research seeks to extend the process of novel therapeutic gene target discovery for the treatment of Alzheimer's disease (AD). Gene-gene and gene pathway annotation tools as well as human analysis are used to explore likely connections between potential gene targets and biochemical mechanisms of AD and associated genes. Rule-based annotation systems, such as GeneRanker, can be applied to the continuously growing volume of literature to extract relevant gene lists. The subsequent challenge is to abstract biological significance from associated genes to aid in discovery of novel therapeutic gene targets. Automatic annotation of genes deemed significant by data-driven assays and knowledge-driven analysis is limited. Therefore, human analysis is still crucial to exploring novel gene targets and new disease models. This research illustrates a method of analysis of an extracted gene list which lead to the discovery of KNG1 as a possible therapeutic target, suggests a connection between inflammation and AD pathogenesis. PMID- 25717400 TI - Categorizing the Relationships between Structurally Congruent Concepts from Pairs of Terminologies for Semantic Harmonization. AB - In this paper, we are using "structurally congruent concepts" in pairs of terminologies to suggest methods for harmonizing the terminologies. Two concepts are structurally congruent if they are children of the same more general concept and parents of the same more specific concept in two different terminologies. We show that structurally congruent concepts can be interpreted in six useful ways, e.g., as new synonyms. All structurally congruent concepts were found for six terminologies from the UMLS, each paired with SNOMED CT. In total, 1384 concept pairs were discovered. Concepts from a sample of 241 pairs were analyzed by a human expert. It was found that 59.3% indicated alternative classifications of the same general concept. This discovery allows an ontology designer to make existing, implicit knowledge explicit. Another 14.5% were newly discovered synonyms, 23.6% suggested the import of a concept into a terminology and 2.5% indicated errors in a terminology. PMID- 25717401 TI - Automated, quantitative analysis of histopathological staining in nuclei. AB - Technological advances have allowed the generation of high-throughput imaging of tissue sections. However, the analysis of these samples is typically still performed manually by one or multiple pathologists. We present a novel statistical model for the automated, quantitative analysis of these images. Our approach requires minimal tuning and allows recapitulation of estimates of staining strength in the nuclei of tumor cells as estimated by the gold standard. Besides, it compares favorably to other quantitative approaches available in the public domain. PMID- 25717402 TI - Automated Tools for Clinical Research Data Quality Control using NCI Common Data Elements. AB - Clinical research data generated by a federation of collection mechanisms and systems often produces highly dissimilar data with varying quality. Poor data quality can result in the inefficient use of research data or can even require the repetition of the performed studies, a costly process. This work presents two tools for improving data quality of clinical research data relying on the National Cancer Institute's Common Data Elements as a standard representation of possible questions and data elements to A: automatically suggest CDE annotations for already collected data based on semantic and syntactic analysis utilizing the Unified Medical Language System (UMLS) Terminology Services' Metathesaurus and B: annotate and constrain new clinical research questions though a simple-to-use "CDE Browser." In this work, these tools are built and tested on the open-source LimeSurvey software and research data analyzed and identified to contain various data quality issues captured by the Comprehensive Research Informatics Suite (CRIS) at the University of Arkansas for Medical Sciences. PMID- 25717403 TI - An author topic analysis of tobacco regulation investigators. AB - To facilitate the implementation of the Family Smoking Prevention and Tobacco Control Act of 2009, the Federal Drug Agency (FDA) Center for Tobacco Products (CTP) has identified research priorities under the umbrella of tobacco regulatory science (TRS). As a newly introduced field, the current landscape of TRS research is unclear. In this work, we conducted a bibliometric study of TRS research by applying author topic modeling on MEDLINE citations published by currently-funded TRS principle investigators. Our initial results show that author topic modeling can address the issue of research interests reasonably. Furthermore, a network involving authors, topics and words can be established for more detailed bibliometric analysis. This network may also be useful to grantees and funding administrators in suggesting potential collaborators or identifying those that share common research interests for data harmonization or other purposes. PMID- 25717404 TI - Developing Governance for Federated Community-based EHR Data Sharing. AB - Bi-directional translational pathways between scientific discoveries and primary care are crucial for improving individual patient care and population health. The Data QUEST pilot project is a program supporting data sharing amongst community based primary care practices and is built on a technical infrastructure to share electronic health record data. We developed a set of governance requirements from interviewing and collaborating with partner organizations. Recommendations from our partner organizations included: 1) partner organizations can physically terminate the link to the data sharing network and only approved data exits the local site; 2) partner organizations must approve or reject each query; 3) partner organizations and researchers must respect local processes, resource restrictions, and infrastructures; and 4) partner organizations can be seamlessly added and removed from any individual data sharing query or the entire network. PMID- 25717405 TI - Facilitating post-surgical complication detection through sublanguage analysis. AB - Identification of postsurgical complications is the first step towards improving patient safety and health care quality as well as reducing heath care cost. Existing NLP-based approaches for retrieving postsurgical complications are based on search strategies. Here, we conduct a sublanguage analysis study using free text reports available for a cohort of patients with postsurgical complications identified manually to compare the keywords identified by subject matter experts with words/phrases automatically identified by sublanguage analysis. The results suggest that search-based approaches may miss some cases and the sublanguage analysis results can be used as a base to develop an information extraction system or support search-based NLP approaches by augmenting search queries. PMID- 25717406 TI - New genetic variants improve personalized breast cancer diagnosis. AB - Recent large-scale genome-wide association studies (GWAS) have identified a number of new genetic variants associated with breast cancer. However, the degree to which these genetic variants improve breast cancer diagnosis in concert with mammography remains unknown. We conducted a case-control study and collected mammography features and 77 genetic variants which reflect the state of the art GWAS findings on breast cancer. A naive Bayes model was developed on the mammography features and these genetic variants. We observed that the incorporation of the genetic variants significantly improved breast cancer diagnosis based on mammographic findings. PMID- 25717407 TI - Phonetic spelling filter for keyword selection in drug mention mining from social media. AB - Social media postings are rich in information that often remain hidden and inaccessible for automatic extraction due to inherent limitations of the site's APIs, which mostly limit access via specific keyword-based searches (and limit both the number of keywords and the number of postings that are returned). When mining social media for drug mentions, one of the first problems to solve is how to derive a list of variants of the drug name (common misspellings) that can capture a sufficient number of postings. We present here an approach that filters the potential variants based on the intuition that, faced with the task of writing an unfamiliar, complex word (the drug name), users will tend to revert to phonetic spelling, and we thus give preference to variants that reflect the phonemes of the correct spelling. The algorithm allowed us to capture 50.4 - 56.0 % of the user comments using only about 18% of the variants. PMID- 25717408 TI - tranSMART: An Open Source Knowledge Management and High Content Data Analytics Platform. AB - The tranSMART knowledge management and high-content analysis platform is a flexible software framework featuring novel research capabilities. It enables analysis of integrated data for the purposes of hypothesis generation, hypothesis validation, and cohort discovery in translational research. tranSMART bridges the prolific world of basic science and clinical practice data at the point of care by merging multiple types of data from disparate sources into a common environment. The application supports data harmonization and integration with analytical pipelines. The application code was released into the open source community in January 2012, with 32 instances in operation. tranSMART's extensible data model and corresponding data integration processes, rapid data analysis features, and open source nature make it an indispensable tool in translational or clinical research. PMID- 25717409 TI - Natural language processing methods for enhancing geographic metadata for phylogeography of zoonotic viruses. AB - Zoonotic viruses represent emerging or re-emerging pathogens that pose significant public health threats throughout the world. It is therefore crucial to advance current surveillance mechanisms for these viruses through outlets such as phylogeography. Despite the abundance of zoonotic viral sequence data in publicly available databases such as GenBank, phylogeographic analysis of these viruses is often limited by the lack of adequate geographic metadata. However, many GenBank records include references to articles with more detailed information and automated systems may help extract this information efficiently and effectively. In this paper, we describe our efforts to determine the proportion of GenBank records with "insufficient" geographic metadata for seven well-studied viruses. We also evaluate the performance of four different Named Entity Recognition (NER) systems for automatically extracting related entities using a manually created gold-standard. PMID- 25717410 TI - Creation and Validation of an EMR-based Algorithm for Identifying Major Adverse Cardiac Events while on Statins. AB - Statin medications are often prescribed to ameliorate a patient's risk of cardiovascular events due in part to cholesterol reduction. We developed and evaluated an algorithm that can accurately identify subjects with major adverse cardiac events (MACE) while on statins using electronic medical record (EMR) data. The algorithm also identifies subjects experiencing their first MACE while on statins for primary prevention. The algorithm achieved 90% to 97% PPVs in identification of MACE cases as compared against physician review. By applying the algorithm to EMR data in BioVU, cases and controls were identified and used subsequently to replicate known associations with eight genetic variants. We replicated 6/8 previously reported genetic associations with cardiovascular diseases or lipid metabolism disorders. Our results demonstrated that the algorithm can be used to accurately identify subjects with MACE and MACE while on statins. Consequently, future e studies can be conducted to investigate and validate the relationship between statins and MACE using real-world clinical data. PMID- 25717411 TI - Efficiently mining Adverse Event Reporting System for multiple drug interactions. AB - Efficiently mining multiple drug interactions and reactions from Adverse Event Reporting System (AERS) is a challenging problem which has not been sufficiently addressed by existing methods. To tackle this challenge, we propose a FCI-fliter approach which leverages the efforts of UMLS mapping, frequent closed itemset mining, and uninformative association identification and removal. By applying our method on AERS, we identified a large number of multiple drug interactions with reactions. By statistical analysis, we found most of the identified associations have very small p-values which suggest that they are statistically significant. Further analysis on the results shows that many multiple drug interactions and reactions are clinically interesting, and suggests that our method may be further improved with the combination of external knowledge. PMID- 25717412 TI - Adapting a natural language processing tool to facilitate clinical trial curation for personalized cancer therapy. AB - The design of personalized cancer therapy based upon patients' molecular profile requires an enormous amount of effort to review, analyze and integrate molecular, pharmacological, clinical and patient-specific information. The vast size, rapid expansion and non-standardized formats of the relevant information sources make it difficult for oncologists to gather pertinent information that can support routine personalized treatment. In this paper, we introduce informatics tools that assist the retrieval and curation of cancer-related clinical trials involving targeted therapies. Particularly, we adapted and extended an existing natural language processing tool, and explored its applicability in facilitating our annotation efforts. The system was evaluated using a gold standard of 539 curated clinical trials, demonstrating promising performance and good generalizability (81% accuracy in predicting genotype-selected trials and an average recall of 0.85 in predicting specific selection criteria). PMID- 25717413 TI - Towards personalized medicine: leveraging patient similarity and drug similarity analytics. AB - The rapid adoption of electronic health records (EHR) provides a comprehensive source for exploratory and predictive analytic to support clinical decision making. In this paper, we investigate how to utilize EHR to tailor treatments to individual patients based on their likelihood to respond to a therapy. We construct a heterogeneous graph which includes two domains (patients and drugs) and encodes three relationships (patient similarity, drug similarity, and patient drug prior associations). We describe a novel approach for performing a label propagation procedure to spread the label information representing the effectiveness of different drugs for different patients over this heterogeneous graph. The proposed method has been applied on a real-world EHR dataset to help identify personalized treatments for hypercholesterolemia. The experimental results demonstrate the effectiveness of the approach and suggest that the combination of appropriate patient similarity and drug similarity analytics could lead to actionable insights for personalized medicine. Particularly, by leveraging drug similarity in combination with patient similarity, our method could perform well even on new or rarely used drugs for which there are few records of known past performance. PMID- 25717414 TI - Automated physician order recommendations and outcome predictions by data-mining electronic medical records. AB - The meaningful use of electronic medical records (EMR) will come from effective clinical decision support (CDS) applied to physician orders, the concrete manifestation of clinical decision making. CDS development is currently limited by a top-down approach, requiring manual production and limited end-user awareness. A statistical data-mining alternative automatically extracts expertise as association statistics from structured EMR data (>5.4M data elements from >19K inpatient encounters). This powers an order recommendation system analogous to commercial systems (e.g., Amazon.com's "Customers who bought this..."). Compared to a standard benchmark, the association method improves order prediction precision from 26% to 37% (p<0.01). Introducing an inverse frequency weighted recall metric demonstrates a quantifiable improvement from 3% to 17% (p<0.01) in recommending more specifically relevant orders. The system also predicts clinical outcomes, such as 30 day mortality and 1 week ICU intervention, with ROC AUC of 0.88 and 0.78 respectively, comparable to state-of-the-art prognosis scores. PMID- 25717415 TI - Considerations for using research data to verify clinical data accuracy. AB - Collected to support clinical decisions and processes, clinical data may be subject to validity issues when used for research. The objective of this study is to examine methods and issues in summarizing and evaluating the accuracy of clinical data as compared to primary research data. We hypothesized that research survey data on a patient cohort could serve as a reference standard for uncovering potential biases in clinical data. We compared the summary statistics between clinical and research datasets. Seven clinical variables, i.e., height, weight, gender, ethnicity, systolic and diastolic blood pressure, and diabetes status, were included in the study. Our results show that the clinical data and research data had similar summary statistical profiles, but there are detectable differences in definitions and measurements for individual variables such as height, diastolic blood pressure, and diabetes status. We discuss the implications of these results and confirm the important considerations for using research data to verify clinical data accuracy. PMID- 25717416 TI - How essential are unstructured clinical narratives and information fusion to clinical trial recruitment? AB - Electronic health records capture patient information using structured controlled vocabularies and unstructured narrative text. While structured data typically encodes lab values, encounters and medication lists, unstructured data captures the physician's interpretation of the patient's condition, prognosis, and response to therapeutic intervention. In this paper, we demonstrate that information extraction from unstructured clinical narratives is essential to most clinical applications. We perform an empirical study to validate the argument and show that structured data alone is insufficient in resolving eligibility criteria for recruiting patients onto clinical trials for chronic lymphocytic leukemia (CLL) and prostate cancer. Unstructured data is essential to solving 59% of the CLL trial criteria and 77% of the prostate cancer trial criteria. More specifically, for resolving eligibility criteria with temporal constraints, we show the need for temporal reasoning and information integration with medical events within and across unstructured clinical narratives and structured data. PMID- 25717417 TI - Modeling clinical context: rediscovering the social history and evaluating language from the clinic to the wards. AB - Social, behavioral, and cultural factors are clearly linked to health and disease outcomes. The medical social history is a critical evaluation of these factors performed by healthcare providers with patients in both inpatient and outpatient care settings. Physicians learn the topics covered in the social history through education and practice, but the topics discussed and documented in real-world clinical narrative have not been described at scale. This study applies large scale automated topic modeling techniques to discover common topics discussed in social histories, to compare those topics to the medical textbook representation of those histories, and to compare topics between clinical settings to illustrate differences of clinical context on narrative content. Language modeling techniques are used to consider the extent to which inpatient and outpatient social histories share in their language use. Our findings highlight the fact that clinical context and setting are distinguishing factors for social history documentation, as the language of the hospital wards is not the same as that of the ambulatory clinic. Moreover, providers receive little feedback on the quality of their documentation beyond that needed for billing processes. The findings in this study demonstrate a number of topics described in textbooks - schooling, religion, alternative health practices, stressors, for example - do not appear in social histories in either clinical setting. PMID- 25717418 TI - Longitudinal analysis of new information types in clinical notes. AB - It is increasingly recognized that redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous, significant, and may negatively impact the secondary use of these notes for research and patient care. We investigated several automated methods to identify redundant versus relevant new information in clinical reports. These methods may provide a valuable approach to extract clinically pertinent information and further improve the accuracy of clinical information extraction systems. In this study, we used UMLS semantic types to extract several types of new information, including problems, medications, and laboratory information. Automatically identified new information highly correlated with manual reference standard annotations. Methods to identify different types of new information can potentially help to build up more robust information extraction systems for clinical researchers as well as aid clinicians and researchers in navigating clinical notes more effectively and quickly identify information pertaining to changes in health states. PMID- 25717419 TI - YKL-40 is a Protective Biomarker for Fatty Liver in World Trade Center Particulate Matter-Exposed Firefighters. AB - BACKGROUND: Serum biomarkers of metabolic syndrome predict abnormal lung function in World Trade Center particulate matter (WTC-PM)-exposed Fire Department of New York (FDNY) rescue workers. In animal models, exposure to ambient PM induces non alcoholic fatty liver disease (NAFLD), a well-known comorbidity of metabolic syndrome. YKL-40 is an inflammatory biomarker for both liver and lung disease. We tested if YKL-40 is a biomarker for NAFLD in this dust-exposed cohort. METHODS: Using a nested case-control design, we studied 131 FDNY personnel who had Computer Tomography performed within 5 years post 9/11. NAFLD was defined by a liver/spleen attenuation ratio of <=1. Serum biomarkers, lipid panel and liver function were measured in serum that had been drawn within 6 months of September 11, 2001. YKL-40 and chitotriosidase were assayed by ELISA. We tested biomarker and NAFLD association using logistic regression adjusted for age, BMI, and post 911 lung function. RESULTS: NAFLD was present in 29/131 (22%) of the cohort. In a multivariable model increasing YKL-40 was protective while increasing triglyceride and alkaline phosphatase were risk factors for NAFLD. CONCLUSIONS: Increased YKL-40 is a protective biomarker in non-alcoholic fatty liver disease. Further studies may reveal a link between PM-induced lung and liver diseases. PMID- 25717420 TI - Verification of Meso-Zeaxanthin in Fish. AB - BACKGROUND/OBJECTIVES: The carotenoids lutein (L), zeaxanthin (Z), and meso zeaxanthin (MZ) accumulate in the central retina (the macula), where they are collectively known as macular pigment (MP). MP has been shown to enhance visual function in both diseased and non-diseased retinae, and therefore an understanding and confirmation of, the origins of these carotenoids is needed. Studies have shown that L and Z are present in many foodstuffs found in a typical Western diet (e.g. spinach, kale, peppers, yellow corn and eggs). It has been shown that MZ is generated from L in the primate retina and earlier reports suggested that MZ was present in some fish species. Recently, however, one research group reported that MZ is not present in fish and suggested that the earlier reports showing MZ in these marine species were a methodological artefact. The current study was designed to investigate the reason for the contradiction, and test for the presence of MZ in fish and some other foods. METHODS: Raw fruits, vegetables and fish were extracted for carotenoid analysis by high performance liquid chromatography. RESULTS: MZ was not detected in any of the fruits or vegetables tested in our study. However, using retention time matching, absorption spectrum comparison, and sample spiking, we verified the presence of MZ in salmon skin, sardine skin, trout skin and trout flesh. CONCLUSION: This study confirmed the presence MZ in nature, and in the human food chain. PMID- 25717421 TI - Special requirements for electronic medical records in neurology. AB - Electronic medical records (EMRs) are being rapidly adapted in the United States with goals of improving patient care, increasing efficiency, and reducing costs. Neurologists must become knowledgeable about the utility and effectiveness of the important parts of these systems specifically needed for care of neurology patients. The field of neurology encompasses complex disorders whose diagnosis and management heavily relies on detailed medical documentation of history and physical examination, and often on specialty-specific ancillary tests and extensive neuroimaging. Small discrepancies in documentation or absence of an in hand ancillary test result can drastically change the current workup or treatment decision of a complex patient with neurologic disease. We describe current models and opportunities for improvements to EMRs that provide utility and efficiency in the care of neurology patients. PMID- 25717422 TI - Immobilization of Xanthate Agent on Titanium Dioxide and Surface Initiated RAFT Polymerization. AB - Surface modification of titanium dioxide (TiO2) nanoparticle is essential to control its surface properties, thereby to enhance its cell penetration capability, reduce its cytotoxicity, or improve its biocompatibility. In order to graft polyvinyl acetate onto TiO2 nanoparticles, xanthate was chemically immobilized on the surface of TiO2 by acylation followed by nucleophilic substitution with a carbodithioate salt. Reversible addition fragmentation chain transfer polymerization was conducted to graft vinyl acetate onto the surface of TiO2. Both the TiO2-xanthate and TiO2-polyvinyl acetate hybrids were characterized by UV-Vis spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. The chemical immobilization of xanthate on the surface of TiO2 and the subsequent controlled polymerization provide useful insight for decoration and modification of TiO2 and other nanoparticles. PMID- 25717423 TI - Early Outcome of Prostate Intensity Modulated Radiation Therapy (IMRT) Incorporating a Simultaneous Intra-Prostatic MRI Directed Boost. AB - This study assessed the feasibility and outcomes of treating prostate cancer with intensity modulated radiotherapy (IMRT) incorporating a Magnetic Resonance Imaging (MRI) directed boost. Seventy-eight men received IMRT for localized prostate cancer. The entire prostate received 77.4Gy in 43 fractions and simultaneous intra-prostatic boosts (SIB) of 83Gy were administered to increase the dose to the MRI identified malignancy. In 16 (21%) patients, the MRI didn't detect a neoplasm and these patients received an SIB of 81Gy to the posterior prostate. Androgen Deprivation Therapy (ADT) was also administered to 32 (41%) patients. The 3-year rates of biochemical control, local control, distant control, and survival were 92%, 98%, 95%, and 95% respectively. While grade 1-2 toxicities were common, there were only 2 patients who suffered grade 3 toxicity. These patients developed strictures which were dilated resulting in improvement in symptoms such that both had grade 1-2 toxicity at last follow up examination. The results of this program of IMRT incorporating a MRI directed intra-prostatic boost suggest this technique is feasible and well tolerated. This technique appears to shift the therapeutic index favorably by boosting the malignancy to the highest dose without increasing the doses administered to the bladder and rectum. PMID- 25717424 TI - Energy saving for OpenFlow switch on the NetFPGA platform based on queue engineering. AB - Data centers play an important role in our daily activities. The increasing demand on data centers in both scale and size has led to huge energy consumption that rises the cost of data centers. Besides, environmental impacts also increase considerably due to a large amount of carbon emissions. In this paper, we present a design aimed at green networking by reducing the power consumption for routers and switches. Firstly, we design the Balance Switch on the NetFPGA platform to save consumed energy based on Queue Engineering. Secondly, we design the test-bed system to precisely measure the consumed energy of our switches. Experimental results show that energy saving of our switches is about 30% - 35% of power consumption according to variation of input traffic compared with normal Openflow Switch. Finally, we describe performance evaluations. PMID- 25717425 TI - Laparoscopic resection of a rare gastrointestinal stromal tumor in children. AB - INTRODUCTION: Gastrointestinal stromal tumors (GIST) are uncommon mesenchymal tumors of the gastrointestinal (GI) tract, accounting for 0.1% to 3% of all GI malignancies. Paediatric GIST have an annual incidence of 0.02 per million children, have a female predisposition, are usually located in the stomach (50 60%) and in up to 85% of cases CD117-cKit or PDGFRA mutation is absent, resulting in a decreased efficacy of the target therapy. CASE DESCRIPTION: We report the case of an incidentally diagnosed gastric GIST in a 14-year-old boy with multiple malformations. Genetic tests and Kariotype resulted negative. Recently, an abdominal US visualized an hypoechoic heterogeneous abdominal mass. The common tumor markers resulted negative and the abdominal CT-scan confirmed the presence of a solid round lesion (42*36mm) in contact with the stomach and the pancreas. Laparoscopy allowed the recognition and the removal of the nodular mass at the posterior margin of the stomach. The histopathologic and the molecular biology findings were consistent with a kit-wilde type GIST. Surgical margins were microscopically free of tumor cells. These results justify the decision not to add other surgical or medical therapy. However, for high risk of recurrence and metastasis, a close follow-up was started. DISCUSSION AND EVALUATION: GIST are asymptomatic in 10% to 30% of patients or present nonspecific symptoms and signs. These tumors present usually irregular, lobulated and ulcerated. CT-scan of the abdomen and pelvis or magnetic resonance imaging (MRI) are mandatory in the diagnostic work-up. The final diagnosis is based on histology and immunohistochemistry. Surgery is the first-line treatment in patients with localized disease. CONCLUSION: Guidelines for the management of pediatric GIST are not presently available for the paucity of reports and data. However it is widely accepted that surgery is the first-line treatment and gross resection with negative microscopic margins can be considered therapeutic and lead to full remission of the pathology. Laparoscopy is a safe surgical approach for the exploration of the abdominal cavity, the evaluation of the disease and the complete removal of the tumor. PMID- 25717426 TI - High throughput molecular dynamics for drug discovery. AB - Molecular dynamics simulations hold the promise to be an important tool for biological research and drug discovery. Historically, however, there were several obstacles for it to become a practical research tool. Limitations in computer hardware had previously made it difficult to simulate for long enough to see interesting biological processes. Recent improvements in hardware and algorithms have largely removed this issue, leaving data analysis as the main obstacle. Advances in Markov state modeling appear to be on the way to remove this obstacle. We outline these advances here and discuss numerous recent studies that demonstrate that molecular dynamics simulations will start to be an important tool for pharmaceutical research. PMID- 25717427 TI - The influence of life events on first and recurrent admissions in bipolar disorder. AB - BACKGROUND: Life events play an important role in the onset and course of bipolar disorder. We will test the influence of life events on first and recurrent admissions in bipolar disorder and their interaction to test the kindling hypothesis. METHODS: We collected information about life events and admissions across the life span in 51 bipolar patients. We constructed four models to explore the decay of life event effects on admissions. To test their interaction, we used the Andersen-Gill model. RESULTS: The relationship between life events and admissions was best described with a model in which the effects of life events gradually decayed by 25% per year. Both life event load and recurrent admissions significantly increased the risk of both first and subsequent admissions. No significant interaction between life event load and number of admissions was found. CONCLUSIONS: Life events increase the risk of both first and recurrent admissions in bipolar disorder. We found no significant interaction between life events and admissions, but the effect of life events on admissions decreases after the first admission which is in line with the kindling hypothesis. PMID- 25717428 TI - Unexplained infertility, the controversial matter in management of infertile couples. PMID- 25717429 TI - Expression Patterns of VEGF and Flk-1 in Human Endometrium during the Menstrual Cycle. AB - BACKGROUND: The VEGF is essential in the process of tissue remodeling and angiogenesis. Limited data is available on the expression and regulation of VEGF and its receptors in the human endometrium. The aim of this study was evaluation of expression patterns of VEGF and Flk-1 in human endometrium during the menstrual cycle. METHODS: Sixty paraffin-embedded blocks of endometrial tissues from the patients with normal menstrual cycles were obtained. Tissue samples were assembled into tissue microarray slides and classified by histological dating into five phases: the proliferative (n = 14), peri-ovulatory (n = 9), early secretory (n = 12), mid-secretory (n = 11) and late-secretory (n = 14) phases. Immunohistochemical staining was performed using VEGF or Flk-1 monoclonal antibodies. The intensity of immunostaining was evaluated by the semi quantitative scoring method (HSCORE). Kruskal-Wallis one-way analysis of variance and Scheff's post-hoc test were used for statistical analysis. A p-value of <0.05 was considered statistically significant. RESULTS: VEGF and Flk-1 were expressed in the three components of the endometrium at various phases of the menstrual cycle. In the stroma, the expression of VEGF varied among the phases (p < 0.05). The expression of Flk-1 in the luminal and glandular epithelium revealed stronger intensity of immunostaining as compared with the stroma at the different phases (p < 0.05). The level of Flk-1 expression also showed significant differences among the phases in the glandular epithelium with greatest expression at late secretory phase (p < 0.05). CONCLUSION: Temporal and spatial distribution of VEGF and Flk-1 expression in the three components of human endometrium during menstrual cycle suggests the functional role of angiogenesis in the remodeling process of endometrial tissue. PMID- 25717430 TI - Effects of Anethum graveolens L. (dill) on Oocyte and Fertility of Adult Female Rats. AB - BACKGROUND: Our previous studies revealed Anethum graveolens L. caused some changes in female reproductive system that induced infertility. Therefore, in this study, oocyte changes as one of probable reasons of infertility were investigated. METHODS: In this study, 59 adult female rats were divided into 3 groups of control, low dose (0.5 g/kg) and high dose (5 g/kg) of dill seed aqueous extract (LDE and HDE) treated groups that were gavaged with 1 ml of each dose for 10 days (2 estrous cycles). Vaginal smears were prepared daily. Oocytes of superovulated animals were extracted and their morphometrical changes were measured (n = 5). Oocyte cell membrane glycoconjugates were stained with UEA, PNA, and DBA-FITC lectins (n = 5). Ultrastructural studies of oocytes were performed using TEM (n = 5). The number, weight, and crown-rump length of newborns were examined in three groups after mating with untreated males (n = 5). Data were analyzed using SPSS software. RESULTS: Results demonstrated that the duration of the estrous cycle, the diestrus phase and progesterone concentration in the experimental groups increased significantly compared to the control group (p < 0.05). Granulosa cells of corpus luteum in HDE-treated group were larger and clearer. The intensity reactions of galactose/Nacetylgalactoseamine terminal sugar of oocyte decreased insignificantly in experimental groups compared to the control group p > 0.05. Duration of mating to pregnancy increased and the weight and crown-rump length of newborns decreased in experimental groups significantly (p < 0.05). CONCLUSION: Dill seed aqueous extract can induce infertility without any effect on oocyte structure. PMID- 25717431 TI - Can hyaluronan binding assay predict the outcome of intrauterine insemination in couples with unexplained or mild male factor infertility? AB - BACKGROUND: The purpose of this study was to evaluate the prognostic effect of Hyaluronan Binding Assay (HBA) which has been used as a method of sperm selection for intracytoplasmic sperm injection procedure, on the outcome of intrauterine insemination (IUI) in couples with unexplained or mild male factor infertility. METHODS: 77 infertile couples were enrolled in our study. On the day of IUI procedure, HBA test was performed by using fresh semen samples, and the rates of sperm binding to HBA were calculated. HBA values and semen parameters were compared. Fisher exact test was used to evaluate the relationship between HBA ratio and pregnancy status. Mann-Whitney U test was used to compare quantitative variables between pregnant and non-pregnant groups. The p < 0.05 was considered statistically significant. RESULTS: In this study, HBA ratio was 69(29.25%) and pregnancy rate was 14.29%. A significant positive correlation between HBA and total motile sperm count, inseminating sperm count, progressive motility, morphology, and sperm concentration (p < 0.001, p < 0.001, p:0.007, p < 0.003, p:0.003 respectively) was observed. Although HBA values in pregnant group were higher than those in non-pregnant group, this result did not reach the statistically significant level (HBA: 67(20%) for non-pregnant group, 80.5(21.3%) for pregnant group). Also, no relationship between HBA values and pregnancy status was found. Moreover, there was no significant correlation between pregnancy status and HBA ratios based on the suggested cut-off value of 60 in literature (p = 0.425). CONCLUSION: HBA does not predict the IUI outcome in couples with unexplained infertility or mild male factor infertility, but it can be used together with semen parameters to verify sperm quality. PMID- 25717432 TI - Induction and determination of apoptotic and necrotic cell death by cadmium chloride in testis tissue of mouse. AB - BACKGROUND: Cadmium chloride which is potentially toxic is currently used in industry. The toxic effects of cadmium on testes have been reported to range from apoptosis to necrosis, with different effects on fertility. This research aimed to study the effect of different doses of cadmium on testicular tissues at acute stage by light and electron microscopy. METHODS: Cadmium chloride was injected into mature Balb/c mice intraperitoneally in 7 doses. Five mice were studied in each group. After 48 hr, the testes were extracted and prepared for light microscopy. Then two concentrations (15 and 25 uM/kg) of them were selected for electron microscopic study based on histological changes. The cellular changes of luminal epithelium of seminiferous tubules were studied under an electron microscope. Histological and ultrastructural changes were reported. RESULTS: The absence of sperm in the tubules was observed at 20 uM/kg concentration. At 25 uM/kg, histological destruction and epithelial damages were observed. Histological changes were not remarkable at 5 and 10 uM/kg. However, ultrastructural changes of seminiferous tubules at 20 uM/kg included spermatogonial cell death. At 25 uM/kg, vacuolation of Sertoli cells and death of spermatids as well as spermatocytes were observed. Cell death in the tubules was limited to germ cells. However, Sertoli cells exhibited architectural alterations without any cell death. CONCLUSION: Both apoptosis and necrosis occurred in testicular tissue by exposure to cadmium in a concentration-dependent manner. Gonadal cells were sensitive to cadmium administration. Supportive cells such as Sertoli cells in seminiferous tubules did not exhibit sensitivity to cadmium. PMID- 25717433 TI - Comparison of letrozole versus tamoxifen effects in clomiphen citrate resistant women with polycystic ovarian syndrome. AB - BACKGROUND: The objective of this prospective randomized study was to make a comparison between the effects of letrozole and tamoxifen (TMX) in ovulation induction in clomiphene (CC)-resistant women with polycystic ovarian syndrome (PCOS). METHODS: The study comprised a total of 60 infertile women (180 cycles) with CCresistant PCOS selected from the clinics affiliated to the Department of Obstetrics and Gynecology of Tanta University. Patients were randomized to treatment with 2.5 mg of letrozole daily (30 patients, 90 cycles) or 20 mg of TMX daily (30 patients, 90 cycles) for 5 days from day 5 of menses and 10000 IU hCG when mature follicles become =18 mm in diameter. The chi-square and t-test were used for comparing two groups and p < 0.05 was considered significant. RESULTS: The total number of follicles (=18 mm) in the letrozole group was more than TMX group. The endometrial thickness at the time of hCG administration was significantly higher (p < 0.05, at 95% CI) in the letrozole group than that of TMX group (10.2+/-0.7 vs. 9.1+/-0.2 mm). Ovulation occurred in 23.33% of cycles in the letrozole group and in 8.89% in the TMX group, whereas pregnancy occurred in 5.56% of the letrozole group and 2.22% of the TMX group. CONCLUSION: Both letrozole and TMX should be considered as optional therapies for CC-resistant women. In addition, letrozole was superior to TMX in achieving a higher pregnancy and ovulation rate and also lesser side effects in comparison to tamoxifen. PMID- 25717434 TI - Attitudes about Sex Selection and Sex Preference in Iranian Couples Referred for Sex Selection Technology. AB - BACKGROUND: Gender preference is prevalent in some communities and using medical techniques to choose the baby's sex may cause the gender discrimination and gender imbalance in communities. Therefore, evaluating the gender preferences and attitudes towards using sex selection technologies seems to be necessary. METHODS: This cross-sectional study was conducted in Avicenna Fertility Center. Participants were 100 women with one child who were referred for sex selection. Data were collected through self-developed questionnaires. The questions were designed by the researchers at the experts' panel. To determine the validity of the questionnaire, the viewpoints of professors specialized in these issues were obtained. The statistical analysis of the data was performed using SPSS software (Version 11.5), and p < 0.05 was considered significant. RESULTS: Tendency toward the male was more than female sex (55.5% male, 15.5% female and 28.5% no tendency). Majority of participants agreed with sex selection with medical reason and sex selection in order to balance the family. Women's level of education had positive effect on agreements to fetal sex selection with medical and non-medical reasons (p < 0.001). CONCLUSION: Although gender preferences were toward the male sex but this preference was not very strong. Most participants agreed with non medical sex selection for balancing the sex composition of their children. It doesn't seem that non-medical sex selection for family balancing causes severe sex imbalance in Iran. PMID- 25717435 TI - Sexual and Reproductive Behaviors among Undergraduate University Students in Mashhad, a City in Northeast of Iran. AB - BACKGROUND: The incidence of sexual transmitted infections (STIs) and HIV/AIDS is globally higher in young people. This study evaluated the prevalence of sexual reproductive behaviors among undergraduate students of Mashhad, Iran. METHODS: The study was conducted on 605 students in twelve non-medical faculties of a great university of Mashhad. A self-administered questionnaire was completed on demographic information, sexual contact in the lifetime and during the last three months, and age of first sex. Kaplan-Meier statistic was used to calculate the mean age of initiation of sex. A p < 0.05 was considered statistically significant. RESULTS: After exclusion of individuals over 25 years of age, among 590 students with a mean age of 20.8+/-1.5 years included in the analysis, 71.4% were female and 85.3% were single. Prevalence of at least one sexual contact in life was 15.1% and 35.3% of single sexually experienced students reported to have sex in the last three months. The lifetime prevalence of sexual relationship in males was significantly higher than females (32.9% vs. 7.6%, p < 0.001). The mean age of first sexual experience was 23.7 years with a significant difference between both sexes (p < 0.001). In single sexually experienced students, the mean age at first sex was 17.6+/-3.3 years, 24% started sexual activity at <15 years, 34.3% had at least 3 partners and only 40.6% stated using condom in their last sex. CONCLUSION: Although very small proportion of females reported premarital sex, a significant minority of male students experienced sexual and risky behaviors. Therefore, the use of educational programs on related issues to reduce the risk of STIs/HIV among youth including university students seems to be a necessity. PMID- 25717436 TI - A rare case of bilateral ectopic pregnancy and differential diagnosis of gestational trophoblastic disease. AB - BACKGROUND: Bilateral ectopic pregnancy is a rare condition and is divided in two subgroups, primary and secondary, based on history of assisted reproductive technology. CASE PRESENTATION: A 30 year old primigravid woman with history of infertility and ovulation induction presented to a hospital in Kashan in year 2013. She had vaginal bleeding, abdominal pain and ultrasound findings suggested early pregnancy. Due to high titer of beta-HCG, gestational trophoblastic disease was proposed and D8C was done in referral and admission to gyneco-oncology ward in Tehran. Repeat sonography suggested ectopic pregnancy in left side and repeat beta-HCG level showed an increase of 19435 mIU/ml. Laparotomy findings revealed bilateral ampullary ectopic pregnancy. Bilateral salpingostomy followed by one course of methotrexate was prescribed. CONCLUSION: Bilateral ectopic gestation should be considered as a rare differential diagnosis for ectopic pregnancy. In this study, bigger size and rupture in left side was observed. PMID- 25717437 TI - Replacement Therapy for Gaucher Disease during Pregnancy: A Case Report. AB - BACKGROUND: Gaucher disease is a lysosomal storage disorder due to deficiency of glucocerebrosidase enzyme. In this study, a case of enzyme-treated woman during her pregnancy was reported. CASE PRESENTATION: A 27-year old woman with type I Gaucher disease was managed for pregnancy until delivery. She underwent elective splenectomy at age 26 years and was treated with 19-38 units/kg of imiglucerase. A conservative approach with close monitoring of both mother and baby was planned. RESULTS: In the 39th week of pregnancy, a healthy male baby of 3180 g was delivered via cesarean section. CONCLUSION: Apart from mild hematological complications, the pregnancy, the delivery and the puerperium were uneventful. In this case report, the issue of therapy and risk assessment in pregnancy in patients with type I Gaucher disease was discussed. PMID- 25717438 TI - The Secret Role of microRNAs in Cancer Stem Cell Development and Potential Therapy: A Notch-Pathway Approach. AB - MicroRNAs (miRNAs) have been implicated in the development of some if not all cancer types and have been identified as attractive targets for prognosis, diagnosis, and therapy of the disease. miRNAs are a class of small non-coding RNAs (20-22 nt in length) that bind imperfectly to the 3'-untranslated region of target mRNA regulating gene expression. Aberrantly expressed miRNAs in cancer, sometimes known as oncomiRNAs, have been shown to play a major role in oncogenesis, metastasis, and drug resistance. Amplification of oncomiRNAs during cancer development correlates with the silencing of tumor suppressor genes; on the other hand, down-regulation of miRNAs has also been observed in cancer and cancer stem cells (CSCs). In both cases, miRNA regulation is inversely correlated with cancer progression. Growing evidence indicates that miRNAs are also involved in the metastatic process by either suppressing or promoting metastasis-related genes leading to the reduction or activation of cancer cell migration and invasion processes. In particular, circulating miRNAs (vesicle-encapsulated or non-encapsulated) have significant effects on tumorigenesis: membrane-particles, apoptotic bodies, and exosomes have been described as providers of a cell-to-cell communication system transporting oncogenic miRNAs from tumors to neighboring cells and distant metastatic sites. It is hypothesized that miRNAs control cancer development in a traditional manner, by regulating signaling pathways and factors. In addition, recent developments indicate a non-conventional mechanism of cancer regulation by stem cell reprograming via a regulatory network consisting of miRNAs and Wnt/beta-catenin, Notch, and Hedgehog signaling pathways, all of which are involved in controlling stem cell functions of CSCs. In this review, we focus on the role of miRNAs in the Notch-pathway and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of the Notch-pathway. PMID- 25717439 TI - Successful Treatment of Intracranial Hemorrhage with Recombinant Activated Factor VII in a Patient with Newly Diagnosed Acute Myeloid Leukemia: A Case Report and Review of the Literature. AB - Intracranial hemorrhage (ICH) is a common complication in acute myeloid leukemia (AML) patients with an incidence rate of 6.3% (1). Bleeding disorders related to disseminated intravascular coagulation (DIC) are common complications in AML cases (2). Recombinant activated Factor VII [rFVIIa (NovoSeven((r)))] is approved for the treatment of bleeding complications with FVIII or FIX inhibitors in patients with congenital FVII deficiency. Use of rFVIIa for the treatment of acute hemorrhage in patients without hemophilia has been successful (3, 4). Herein, we describe the successful use of rFVIIa in a patient with acute ICH in the setting of newly diagnosed AML. PMID- 25717440 TI - Characterization of interactions between inclusion membrane proteins from Chlamydia trachomatis. AB - Chlamydiae are obligate intracellular pathogens of eukaryotes. The bacteria grow in an intracellular vesicle called an inclusion, the membrane of which is heavily modified by chlamydial proteins called Incs (Inclusion membrane proteins). Incs represent 7-10% of the genomes of Chlamydia and, given their localization at the interface between the host and the pathogen, likely play a key role in the development and pathogenesis of the bacterium. However, their functions remain largely unknown. Here, we characterized the interaction properties between various Inc proteins of C. trachomatis, using a bacterial two-hybrid (BACTH) method suitable for detecting interactions between integral membrane proteins. To validate this approach, we first examined the oligomerization properties of the well-characterized IncA protein and showed that both the cytoplasmic domain and the transmembrane region independently contribute to IncA oligomerization. We then analyzed a set of Inc proteins and identified novel interactions between these components. Two small Incs, IncF, and Ct222, were found here to interact with many other Inc proteins and may thus represent interaction nodes within the inclusion membrane. Our data suggest that the Inc proteins may assemble in the membrane of the inclusion to form specific multi-molecular complexes in an hierarchical and temporal manner. These studies will help to better define the putative functions of the Inc proteins in the infectious process of Chlamydia. PMID- 25717442 TI - Urinary biomarker N-acetyl-beta-D-glucosaminidase can predict severity of renal damage in diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy is a clinical diagnosis where proteinuria is present in a patient with diabetes. Early intervention can significantly improve the prognosis. However, imprecision of the currently available biomarkers have impaired effective therapies in a timely manner. Urinary N-acetyl-beta-D glucosaminidase (NAG) is excreted in abnormally high amounts in many renal diseases. The aim of this study was to evaluate urinary NAG as an early biomarker in detection of diabetic nephropathy and whether it parallels the severity of kidney damage in different stages of diabetic nephropathy. METHODS: Fifty patients with type 2 DM were classified into 3 groups (normoalbuminurea, microalbuminurea and macroalbuminurea) and 10 healthy subjects served as a control group. Urinary NAG, albumin and creatinine were measured. Blood urea, serum creatinine, serum albumin, total proteins, serum cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting and postprandial blood glucose, HbA1c and creatinine clearance were measured for all subjects. RESULTS: All diabetic patients had a significantly higher level of urinary NAG compared to control. NAG value increased in parallel with the severity of renal involvement. CONCLUSION: Urinary NAG expresses the degree of renal impairment in diabetic nephropathy. PMID- 25717441 TI - Streptococcus pyogenes biofilms-formation, biology, and clinical relevance. AB - Streptococcus pyogenes (group A streptococci, GAS) is an exclusive human bacterial pathogen. The virulence potential of this species is tremendous. Interactions with humans range from asymptomatic carriage over mild and superficial infections of skin and mucosal membranes up to systemic purulent toxic-invasive disease manifestations. Particularly the latter are a severe threat for predisposed patients and lead to significant death tolls worldwide. This places GAS among the most important Gram-positive bacterial pathogens. Many recent reviews have highlighted the GAS repertoire of virulence factors, regulators and regulatory circuits/networks that enable GAS to colonize the host and to deal with all levels of the host immune defense. This covers in vitro and in vivo studies, including animal infection studies based on mice and more relevant, macaque monkeys. It is now appreciated that GAS, like many other bacterial species, do not necessarily exclusively live in a planktonic lifestyle. GAS is capable of microcolony and biofilm formation on host cells and tissues. We are now beginning to understand that this feature significantly contributes to GAS pathogenesis. In this review we will discuss the current knowledge on GAS biofilm formation, the biofilm-phenotype associated virulence factors, regulatory aspects of biofilm formation, the clinical relevance, and finally contemporary treatment regimens and future treatment options. PMID- 25717443 TI - Posttraumatic hemicerebral infarction in a four-year-old girl. AB - INTRODUCTION: Brain infarction after trauma is uncommon. Injury of the carotid and vertebrobasilar arteries can cause brain infarction due to occlusion of brain blood flow. CASE PRESENTATION: Emergency medical service (EMS) brought a 4-year old girl involved in a car accident to the emergency room. She had had seizure controlled by diazepam. She was unconscious and her Glasgow coma scale (GCS) score was eight. Early vital signs were stable. Her first brain CT scan showed a subdural hematoma (SDH). One day after admission to ICU, her GCS decreased to five; hence, a control brain CT was performed. The brain CT scan showed a brain infarction. Six days after admission, her status worsened and her GCS dropped to three and her pupils became dilated bilaterally and unresponsive to light; she was pronounced dead. DISCUSSION: We present an uncommon case of posttraumatic brain infarction and synchronous SDH. PMID- 25717444 TI - Survey of 2582 cases of acute orthopedic trauma. AB - BACKGROUND: Orthopedic injuries are among the most common causes of mortality, morbidity, hospitalization, and economic burden in societies. OBJECTIVES: In this research, we study the prevalence of different types of trauma requiring orthopedic surgery. PATIENTS AND METHODS: We conducted a cross-sectional study on 2582 patients with acute orthopedic injuries admitted to the orthopedic emergency ward at the Poursina Hospital (a referral center in Guilan province (northern Iran), during December 2010 through September 2011. Patients were examined and the data collection form was filled for each patient. Data were analyzed by SPSS software version 19 and were listed in tables. RESULTS: Of 2582 included cases, 1940 were male and 642 were female, with a mean age of 34.5 years. Most injuries were seen in the 25 to 44 year age group from rural areas. The highest frequency of trauma related to falls. On the other hand, bicycling and shooting had the lowest frequencies. There were 18 cases with limb amputation. Overall, 66.5% of patients had fractures, 5% had soft tissue lacerations, and 10% had dislocations. CONCLUSIONS: Identification of risk factors and methods of prevention is one of the most important duties of healthcare systems. Devising plans to minimize these risk factors and familiarizing people with them is prudent. PMID- 25717445 TI - The pattern of fracture of endodontically treated teeth. PMID- 25717446 TI - Midterm results of treating femoral head osteonecrosis with autogenous corticocancellous bone grafting. AB - BACKGROUND: Appropriate treatment of osteonecrosis of femoral head (ONFH) remains challenging. OBJECTIVES: Here, we report the results of treating these patients with auto-corticocancellous bone graft from iliac crest to overcome the need for early total hip arthroplasty (THA). PATIENTS AND METHODS: There were 132 hips (96 patients) with ONFH. Association Research Circulation Osseous (ARCO) type II and III underwent auto-corticocancellous bone grafting from the iliac crest in the current prospective study. Before the operation and in the final postoperative visit, the pain intensity using visual analogue scale (VAS), range of hip motions and Harris hip score (HHS) were determined and compared. Patients were followed for 48.5 +/- 17.9 months. RESULTS: The shape of head and the joint space were preserved in 120 hips (90.9%). There were 12 hips in which the disease progressed to grade IV and resulted in THA in 10 of them. The pain intensity significantly decreased (6.3 +/- 4.1 vs. 1.4 +/- 2) and HHS (35.8 +/- 15.3 vs. 79.5 +/- 16.2) and range of motion (ROM) significantly improved after the operation (P < 0.001). CONCLUSIONS: Necrotic bone removal and filling the femoral head cavity with auto corticocancellous bone graft from iliac crest is an effective femoral head preserving method in treating patients with precollapse stages of ONFH and preventing the need for early THA, especially in young active populations. PMID- 25717447 TI - Imaging-based diagnosis of wernicke encephalopathy: a case report. AB - INTRODUCTION: Wernicke encephalopathy (WE) is a medical emergency characterized by ataxia, confusion, nystagmus and ophthalmoplegia resulting from thiamin deficiency. Alcoholism is the common cause for this disease. CASE PRESENTATION: A 41 year old man was brought to our emergency department (ED) complaining of confusion. One week earlier he had started to experience severe nausea and vomiting followed by diplopia, dysarthria and also dysphagia. One day later he had experienced gait disturbance and progressive ataxia accompanied with confusion, apathy and disorientation. He had no history of alcoholism, drug abuse or previous surgery but had history of untreated Crohn disease. Just before arrival to our emergency department, he had been hospitalized in another center for about a week but all investigations had failed to provide a conclusive diagnosis. Upon admission to our ED, he was dysarthric and replied with inappropriate answers. On physical examination, bilateral horizontal nystagmus in lateral gaze, left abducens nerve palsy and upward gaze palsy were seen. Gag reflex was absent and plantar reflexes were upwards bilaterally. After reviewing all the previously performed management measures, MRI was performed and was consistent with the diagnosis of WE. Treatment with thiamine led to partial resolution of his upward gaze palsy and nystagmus on the first day. At the end of the third day of treatment, except for gate ataxia, all other symptoms completely resolved and he was fully conscious. After the fifth day his gait became normal and after one week he was discharged in good general condition. DISCUSSION: After reviewing the current literature, it seems that brain MRI can be helpful in the diagnosis of WE in patients with the classic clinical trial in the absence of clear risk factors. PMID- 25717448 TI - Ultrasonographic diagnosis of suspected hemopneumothorax in trauma patients. AB - BACKGROUND: Bleeding and trapped air in the pleural space are called hemothorax and pneumothorax, respectively. In cases where there are delays in diagnosis and treatment, the mortality rates due to hemopneumothorax can be significant. Hemopneumothorax is characterized by decreased lung sounds or chest percussion and subcutaneous emphysema. Diagnosis of pneumothorax and hemothorax can be achieved by portable chest X-ray (CXR), computed tomography (CT) scan, or ultrasonography. Portable CXR and CT-scans have their individual drawbacks. CXR creates a high percentage of false negative results, and a CT-scan is time consuming and less cost-effective; in addition, both modalities expose patients to radiation. Therefore, the introduction of ultrasonography as an easily available and highly accurate diagnostic modality has particular importance. OBJECTIVES: The aim of this study was to evaluate the sensitivity and specificity of ultrasonography in the diagnosis of pneumothorax and hemothorax in comparison with the other two methods, namely portable CXR and CT-scan. PATIENTS AND METHODS: Patients (163) with multiple trauma who were suspected of having chest injuries, and who had indications for a chest CT-scan according to ATLS algorithms, were included in the study. All patients underwent portable CXR, CT scan, and ultrasonography. RESULTS: In total, 163 patients were included in this study; 29 patients had a pneumothorax, 24 patients had a hemothorax, and 23 patients had a hemopneumothorax confirmed. The study revealed that ultrasonography had a sensitivity of 96.15%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 98%, in the diagnosis of pneumothorax. The sensitivity for ultrasonography in the diagnosis of a hemothorax was 82.97%, with a specificity of 98.05%, a positive predictive value of 90%, and a negative predictive value of 92.66%. Portable CXR for pneumothorax detection had a sensitivity of 34.61%, a specificity of 97.95%, a positive predictive value of 90%, and a negative predictive value of 73.84%. In the detection of hemothorax, CXR had a sensitivity of 25.53%, a specificity of 95.14%, a positive predictive value of 70.58%, and a negative predictive value of 73.68%. CONCLUSIONS: Ultrasonography sensitivity and specificity for diagnosis of hemopneumothorax was high. The sensitivity of portable CXR was low despite its high specificity for the detection of hemothorax and pneumothorax. PMID- 25717449 TI - Prevalence of low back pain among nurses: predisposing factors and role of work place violence. AB - BACKGROUND: Ergonomic factors predispose nurses to low back pain (LBP). Few studies have clarified the role of workplace violence in LBP occurrence. OBJECTIVES: The present study was designed to investigate acute and chronic LBP in Iranian nurses and its association with exposure to physical violence as well as its personal and ergonomic risk factors. MATERIALS AND METHODS: In this analytic cross sectional study, the rate of acute and chronic LBP and contributing factors were investigated among 1246 nurses using a validated questionnaire. Statistical analysis was performed by chi square, student t-test, and logistic regression, to determine the association between independent variables and LBP. RESULTS: In total, 1246 nurses, consisting of 576 (46.23%) males and 670 (53.77%) females, were included. The mean age and the mean years of employment were 31.23 +/- 5.33 and 16.18 +/- 7.05, respectively. Both acute low back pain (ALBP) and chronic low back pain (CLBP) were associated with physical violence experience. Moreover, acute and chronic LBP were predicted by positive past history of LBP as well as two ergonomic factors, frequent bending and frequent carrying of patients. CONCLUSIONS: Besides a history of low back pain and ergonomic factors, physical violence may be considered a contributing factor for acute low back injuries. Special attention to all personal, occupational, and psychological risk factors is recommended. PMID- 25717450 TI - Endoscopic carpal tunnel release: a 5-year experience. AB - BACKGROUND: Endoscopic carpal tunnel release (ECTR) has gained recognition as an alternative to the current gold standard, the open carpal tunnel release (OCTR). Detailed technical points for the ECTR have not been explained in the literature, especially for surgeons who are considering trying this technique. OBJECTIVES: In this paper, we present our 5-year experience with the ECTR and special emphasis will be placed on less frequently discussed technical points, such as the optimal site to make the skin incision and the signs to look for in a completely divided retinaculum. PATIENTS AND METHODS: In this prospective nonrandomized clinical trial, 176 patients with carpal tunnel syndrome who underwent surgical operation using the Agee uni-portal endoscopic carpal tunnel release technique, over a period of 5 years, were included. The "Hand Questionnaire", a standard questionnaire for hand surgery, was used to evaluate the patients at one, three, six and twelve month post-operative time points. Pain and scar tenderness were measured using the visual analog scale system. We propose the 'most proximally present wrist crease' for the skin incision and the 'proximal to distal sequential division of the retinaculum' as our methods of choice. Two signs, named 'railroad' and 'drop in', are proposed and these will be discussed in detail as hallmarks of complete retinaculum release. RESULTS: Of the 176 patients who underwent the ECTR operation, 164 cases (93.2%) had no or very little pain at the one year postoperative visit, and nearly all of the patients reported no relapse of symptoms at the previously mentioned postoperative time points. Patient satisfaction and functional recovery was comparable to other published ECTR studies, and showed better short-term results of this technique over the OCTR. One deep seated infection, three cases of transient index finger paresthesia due to scope pressure on the median nerve, and one case of median nerve branch transection, were observed. Scar complications, including; tenderness, redness and pain, were significantly lower in the proximally placed incision in comparison with the distally placed incision (P < 0.005). CONCLUSIONS: The 'most proximally present wrist crease' and the 'distal to proximal division of the retinaculum' using the two signs of 'railroad' and 'drop in' to confirm a complete division of retinaculum are proposed techniques that should be considered in order to produce good outcomes in ECTR. The 'railroad' sign is the parallel standing of the retinaculum edges, and the 'drop in' sign is the dropping of the retinaculum edge into the scope denote a completely divided retinaculum. PMID- 25717451 TI - Electrical burn injury: a five-year survey of 682 patients. AB - BACKGROUND: Electrical burn is less prevalent in comparison to other forms of burn injuries, however this type of injury is considered as one of the most devastating due to high morbidity and mortality. Understanding the epidemiologic pattern of electrical burns helps determine the contributing factors leading to this type of injury. OBJECTIVES: Epidemiologic studies on electrical burn are scarce in Iran. This study was conducted to evaluate electrical burn injury at our center. MATERIALS AND METHODS: Demographic data, etiology, burn percentage and other measures related to electrical burn injury of 682 electrical burn patients treated from 2007 to 2011 were collected and analyzed. RESULTS: We assessed 682 electrical burn patients (~10.8% of all burn patients); the mean age was 29.4 years and 97.8% were males. The mean hospital stay was 18.5 days and the mean burn extent was 14.43%. Severe morbidities caused 17 (2.5%) deaths. Amputation was performed in 162 cases. The most common amputation site was the fingers (35%). Most victims were workers and employees and 68.5% of electrical burns occurred at their workplace; 72% of electrical burns were due to high voltage electrical current (more than 1000 V). There was a correlation between voltage and amputation (P = 0.001) and also between voltage and fasciotomy (P = 0.033), but there was no correlation between voltage and mortality (P = 0.131). CONCLUSIONS: Electrical burn injuries are still amongst the highest accident related morbidities and mortalities. Educating the population about the dangers and hazards associated with improper use of electrical devices and instruments is imperative. PMID- 25717452 TI - National getaways for the weary trauma surgeon; part 1: kish island. PMID- 25717453 TI - Burn Survivors' Experience of Core Outcomes during Return to Life: a Qualitative Study. AB - INTRODUCTION: Burn is one of the main and common health problems that face the victims with significant challenges in their lives. The main purpose of caring and rehabilitating these people is returning them to their previous life situation. Thus, the present study was conducted with the purpose of determining the experience of burn survivors with regard to returning to life in order to be able to obtain new concepts of acceptable implications in the present cultural and religious context. METHODS: The present study is a qualitative study that was conducted using qualitative content analysis and in-depth unstructured interviews with 15 burn survivors in 2012 and 2013 in Tabriz. RESULTS: During the process of qualitative analysis, the content of the category "balance", as the core essence of the experience of participants, was extracted according to three sub categories: a- the physical integration (physiological stability, saving the affected limb), b-connecting to the life stream (self-care, getting accustomed, normalization), and c- return to the existence (sense of inner satisfaction and excellence). CONCLUSION: The results of this study confirmed the physical, psychological and social scales introduced by other studies. Also proposed the concept "return to the existence", that can be measured by the emergence of a sense of inner satisfaction and excellence in the individual, as one of the key and determinant scales in returning the victims of burn to life. PMID- 25717454 TI - The status of social well-being in Iranian nurses: a cross- sectional study. AB - INTRODUCTION: Social well-being is one of the important aspects of individual's health. However, the social aspect of health, or social well-being, has not been attended to as equally as the other aspects. Social well-being is people's perceptions and experiences in social circumstances as well as the degree of successful responses to social challenges. The aim of the study was to investigate the social well-being of a sample of Iranian nurses. METHODS: This study was a cross- sectional conducted in 2013. The study population consisted of all 1200 staff nurses working in all hospitals located in Ardabil, Iran. We invited a random sample of 281 practicing nurses to respond to the 33-item Keyes's Social Well-Being Questionnaire and the possible range of the total score is 33-165. Higher score reflect better SWB. The quantitative analysis of this study used the Statistical Package for Social Science SPSS version 13.0. RESULTS: The results showed that Participants' mean score of social well-being was 105.45 (15.87). Social well-being was significantly related to participants' age, gender, work experience, satisfaction with working in hospital and with income, familiarity with nursing prior to entering it, official position, and type of employment. However, there was no significant relationship between nurses' social well-being and their marital status, their parents and spouses' educational status, as well as the type of hospital. CONCLUSION: Nurses' social well-being deserves special attention. Effective well-being promotion strategies should be executed for promoting their social well-being particularly in areas of social integration and social acceptance. Moreover, nurses, particularly female nurses, need strong financial, emotional, informational, and social support for ensuring their social well-being. PMID- 25717455 TI - Assessing the quality of life in elderly people and related factors in tabriz, iran. AB - INTRODUCTION: Elderly people may suffer from the multiple health disorders due to the vulnerability for many physical and mental disturbances. Quality of life in elderly population can be affected by many environmental factors. The aim of this study was aimed to examine the quality of life in elderly people in Tabriz, Iran in 2012. METHODS: This cross-sectional study was carried out on 184 elderly people (male=97; female=87) with age >= 60 years. The participants surveyed in this study were elderly people who were living in the community and come voluntarily to the daily care centers. Validated Persian self-reported version of World Health Organization Quality of Life-BRIEF (WHOQOL-BRIEF) questionnaire including 26 broad and comprehensive questions were used to determine the quality of life in elderly people. Independent t-test and Pearson correlation were used to compare differences and correlation between the total score of quality of life and influential factors. RESULTS: Total score the quality of life in both genders was 90.75 (13.37) (range between 26-130). Male elderly had slightly high score in the quality of life; however, these differences were not significant. A significant difference was observed between having cardiovascular diseases, respiratory and gastrointestinal diseases, hearing and visual impairments with total score in the quality of life. Also, there was no significant difference between gender and age variables with total score in the quality of life. CONCLUSION: Policies and programs should be considered for improving the quality of life. Future studies are needed for assessing other influential factors on the quality of life in elderly population. PMID- 25717456 TI - Barriers to and Facilitators of Research Utilization among Iranian Nurses: a Literature Review. AB - INTRODUCTION: Research utilization (RU), is an important strategy to promote the quality of patient care. The aim of this study was to present a comprehensive literature review describing barriers and facilitators of RU among Iranian nurses. METHODS: Literature review was undertaken using the international databases including Pub Med/Medline, Scopus, Science Direct, and Google Scholar. Also, Persian electronic databases such as Magiran, SID and Iran Medex were searched up to May 2014. The search was limited to articles in the English and Persian languages that evaluate the barriers or facilitators of RU among Iranian nurses. RESULTS: A total of 11 articles were in the final dataset. The most important barriers to RU among Iranian nurses were related to the organization factors such as inadequate facilities; insufficient time on the job, lack of authority, physician cooperation, and administrative support. The most frequent facilitators of RU were education in enhancing nurses knowledge and skills in research evaluation, support from knowledgeable nursing colleagues and nursing faculty in the clinical setting, access to an expert committee for clinical appraisal, improving skills in English language and searching for articles, sufficient economic resources to carry out research, and having access to more facilities such as internet. CONCLUSION: Iranian nurses encounter with the same difficulties as to other countries regarding RU; while setting related barriers were the predominant obstacles to RU among them. Therefore, health managers are expected to plan appropriate strategies to smooth the progress of RU by nurses in their practice. PMID- 25717458 TI - Investigation of Seclusion in one of the Psychiatric Wards in Razi Teaching Hospital of Tabriz. AB - Seclusion is one of the methods in controlling violent behavior of inpatients in psychiatric wards. In current descriptive analytic study, data collection instrument included the seclusion list of inpatients by considering individual, social and clinical characteristics in one of the psychiatry wards In the Razi teaching hospital of Tabriz in the first six months of 2012. Among 264 admitted patients, 24 patients (9.1%) had been secluded and a total of 29 isolated incidents were recorded. Most of secluded incidents occurred on weekdays (75.9%), first week of inpatient (87.7%), and during the evening shifts (48.3%). The results obtained in this study demonstrate that in 55.2% cases, the duration of isolation was two hours and the most common cause of seclusion was aggressive behaviors. Most of secluded patients (66.7%) were diagnosed with mood disorders. PMID- 25717457 TI - The Relationship between Cognitive Appraisal and Adherence to Medical Regimens in Type 2 Diabetic Patients. AB - INTRODUCTION: Non-adherence to medical regimen has remained a challenge to the medical profession as well as to social sciences. To achieve positive results, the factors negatively impacting patient adherence to medical regimens (i.e., diet, drug and exercise regimen) must be scrutinized in detail. The objective of this research was to explore the relationship between cognitive appraisal and adherence to medical regimens in type 2 diabetic patients. METHODS: In this correlational study, 218 type 2 diabetes patients receiving treatment at the Diabetes Clinic affiliated with Gonabad University of Medical Sciences were selected through non-probability (convenience) sampling from April 2012 to May 2013. Two valid and reliable questionnaires of cognitive appraisal and adherence to medical regimens were completed by each patient. The data were analyzed using SPSS ver 13. RESULTS: A relationship was observed between perceived cognitive and adherence to some aspects of medical regimen. Also direct relationship was observedbetween perceived cognitive in form challenge and adherence of diet in patients with diabetes. There was no statistically significant relationship between aspects of cognitive appraisal and adherence to the drug regimen. CONCLUSION: The results suggest that interventions undertaken to improve adherence to medical regimen, particularly to drug regimen in patients with type 2 diabetes, should be focused on enriching cognitive appraisal. Nurses need to help patients perceive diabetes as less of a threat and in fact should empower them, so as to look upon it as more of a challenge. PMID- 25717459 TI - Head and neck malignant tumours in gombe, northeast Nigeria. AB - BACKGROUND: Head and neck cancer is the 10(th) most common cancer in the world constituting 5-8% of total cancer burden in Europe and America. However, it is difficult to appreciate the burden in Nigeria because of inadequate data. This retrospective study analysed the clinicopathological variables of head and neck malignancies seen over a 10-year period at a northeastern Nigerian referral centre. MATERIAL AND METHODS: The demographics and clinical findings of the patients were obtained from the case files while histology reports were retrieved from the histopathology department of the hospital. Malignancies involving the eye, brain and thyroid were excluded. RESULTS: One hundred and ninety five cases of head and neck malignancies were recorded over the ten year study period. The mean age of the patients was 38.3years (+20 SD) while a male: female ratio of 1.3:1 was recorded for all cases. The neck was the most frequent site of tumours, accounting for 57(29%) cases. While epithelial malignancies were 56.9% of all cases, lymphomas constituted 21.5%, sarcomas constituted 10.3% and others malignancies accounted for 11.3%. There was no sex predilection for carcinomas (1:1), but there were slightly more lymphomas 26(23%) in males than 16(19%) in females. Carcinomas were more prevalent in those above 51years of age; sarcomas were most common within the 21-30year age group while 42.8% of cases of lymphoma were in the 2(nd) and 3(rd) decades of life. CONCLUSION: While malignant head and neck tumours showed no sex predilection, carcinomas remained the most frequent head and neck malignancies in this study. PMID- 25717460 TI - Effectiveness of heat moisture exchangers (hmes) in preventing perioperative hypothermia among adult patients undergoing abdominal surgery under general endotracheal anaesthesia. AB - BACKGROUND: Heat Moisture Exchangers (HMEs) conserve heat and moisture during expiration and make this available to inspired gases during subsequent inspiration. We sought to evaluate the effectiveness of HMEs in the prevention of perioperative hypothermia in patients scheduled for abdominal surgery under general anaesthesia relaxant technique with endotrachael intubation (GART.) SETTING: Lagos University Teaching Hospital, in Modular theatre, Anaesthesia unit. STUDY DESIGN: The study was a randomized, controlled, longitudinal, interventional study Methods: 100 ASA I, II and III patients aged 18 to 65 years scheduled for abdominal surgery under GART were randomly assigned to 2 groups, groups H and C. Group H had HMEs, while group C served as controls. Core temperature measured using tympanic probe was every 10 minutes till end of anaesthesia Data from total 99 patients, 49 in group H and 50 in group C were eventually analysed. Although patients in both groups developed hypothermia in the course of anaesthesia, core temperature was significantly lower p< 0.05 after one hour in the control group than the intervention group. CONCLUSION: The use of HMEs during general anaesthesia with endotrachael intubation did not prevent hypothermia but resulted in higher core temperature and should be part of a multimodal approach in the prevention of perioperative hypothermia. KEYWORDS: Heat Moisture Exchangers, General endotracheal anaesthesia, Hypothermia, abdominal surgery. PMID- 25717461 TI - Awareness and screening for retinopathy of prematurity among paediatricians in Nigeria. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina which occurs in premature babies due to defective vasculogenesis. There are established screening guidelines to enhance its early identification and prompt treatment. The aim of the study was to determine the level of awareness of the screening protocols for retinopathy of prematurity (ROP) among paediatricians in Nigeria. METHODS: A questionnaire was administered to paediatricians and residents in paediatrics attending a continuous professional development (CPD) course in Benin City, Nigeria. Information on their knowledge of risk factors, screening guidelines and treatment modalities for ROP was obtained. RESULTS: There were a total of 48 participants. The mean age of the participants was 34.5 +/- 4.5 years of which 25 (52.1%) were females. A majority, 46 (95.8%) knew some risk factors for ROP. Fourteen (29.2%) participants knew the ROP screening guidelines while 10 (20.8%) had partial knowledge of these guidelines. Knowledge on the use of laser as a treatment modality of ROP was shown by 18 (37.5%) participants. The major reason given for not screening for ROP was being unaware of a referral centre in Nigeria in 43 (89.6%) participants. CONCLUSION: The majority of paediatricians attending a CPD course in Nigeria though aware of retinopathy of prematurity, are currently poorly informed on the management of this condition and the need for screening. There is need to enlighten paediatricians in Nigeria on retinopathy of prematurity in order to prevent this treatable cause of blindness in children. PMID- 25717462 TI - Evaluation of the effectiveness of computed tomography in the diagnosis of orbital tumours in ibadan, southwest Nigeria. AB - BACKGROUND: The orbit is a bony cavity within the skull that is composed of many structures which may undergo neoplastic transformation. Failure to diagnose the tumour and determine its extent may lead to high morbidity and mortality. The aim of this study was to evaluate the role of computed tomography in the diagnosis of orbital tumours in our centre. MATERIALS AND METHODS: Computed Tomography images acquired from a multi-sliced CT machine, tissue diagnoses obtained from histopathology reports and patients' clinical records were reviewed. The data were analyzed and presented using frequency tables, percentages and charts as appropriate. RESULTS: Sixty six patients made up of 34 (51.6%) males and 32 (48.4%) females were studied. The ages ranged between 1 and 80 years with a mean of 35 years. Majority (50%) of the patients were in their 4th - 6th decades of life. While secondary orbital tumours were seen in 42 (63.6%) patients, primary tumours occurred in 23 (34.8%) cases. Metastatic deposit was seen in 1 (1.6%) patient. Bone was the most commonly affected orbital tissue. The CT diagnoses of benign and malignant tumours were accurate when compared with histopathological diagnoses in 80.6% and 96.7 % of the cases respectively. CONCLUSION: Computed Tomography is useful in characterizing the nature, precise location of a lesion within the orbit and to demonstrate the extension of the orbital lesion into contiguous structures. This study showed that Computed tomography is also a useful imaging technique in the diagnosis of orbital tumours with high concordance rate when compared with histological diagnoses. PMID- 25717463 TI - Outpatient flexible urethrocystoscopy - initial experience at university of ilorin teaching hospital. AB - BACKGROUND: Endourology has revolutionized urological practices worldwide. This is not so in many urological centers in the West African sub-region. Although, some centers have made progress in the level of urological services that they offer; many of such centers provide rigid urethrocystoscopy services and only a few centers provide flexible urethrocystoscopy services. Flexible urethrocystoscopy has the advantage of being convenient as daycare procedure with no requirement for invasive forms of anaesthesia or the need for lithotomy position. In addition, skill transfer and acquisition is good. AIM & OBJECTIVES: We present our 2 year experience with outpatient flexible cystoscopy at the University of Ilorin Teaching Hospital, Ilorin. PATIENTS & METHODS: A review of the records of patients who had flexible cystoscopy at our outpatient endoscopy unit over a 2 year period was carried out. RESULTS: There were 39 patients (36 males and 3 females) with the age range of 25 -84 years and a mean of 58.5 years. The indications were both diagnostic and therapeutic. All the procedures were done under topical anesthesia. There were no complications noted. Consultants performed 80% of the cases while the remaining was performed by a senior registrar. The year 2 registrars from surgery and Obstetrics & Gyneacology assisted in most cases. CONCLUSION: Outpatient flexible urethrocystoscopy has positively improved endourological services in this centre with less invasive anesthesia, less morbidity and improved patient satisfaction. It has also enhanced training of residents doctors in lower urinary tract endoscopy. PMID- 25717464 TI - Fournier'S gangrene in cotonou, benin republic. AB - BACKGROUND: Gangrene of the male genitalia called Fournier's gangrene is not an uncommon surgical condition in the urological service at Cotonou, Benin Republic; it is associated with high mortality and morbidity. PATIENTS & METHODS: This is a retrospective, descriptive study conducted at the Teaching Clinic of Urology and Andrology at the National and Hospitable Center CNHU- Hubert Koutoukou MAGA in Cotonou, Benin Republic. The study is on patients managed for Fournier's gangrene from January 2002 to December 2012. The demographics, clinical presentation, management and outcome were recorded in a proforma and the data obtained were analyzed using SPSS 10.0 software. RESULTS: Fournier's gangrene represented 1.8% of hospitalizations with an annual average of 5 cases. The mean age was 52 years with range of 21 - 85 years. 77.7% of patients were 40 - 59 years and; while 22.3% were 60 years and above. About 28% had a predisposing factor (diabetis, HIV, leukaemia, high blood pressure). Etiological factors were urogenital (42.5%), anorectal (22.5%), and cutaneous (17.5%). In 17.5% of cases, no etiologic factor was found. The diagnosis was clinically obvious because of late presentation, 95% of patients were admitted in the acute phase. CONCLUSION: Fournier's gangrene mostly affects young males and the diagnosis was clinical. It is a disease with high morbidity and mortality in Benin Republic. PMID- 25717465 TI - Abdomino-Perineal Resection for Low Rectal and Anal Malignancies in Ibadan, SOUTHWEST NIGERIA. AB - BACKGROUND: Colonic tumours are the third most common tumours in the Nigerian cancer registry after breast and cervical carcinoma. Tumours involving the distal rectum and anus are increasingly a significant portion of all colorectal and anal malignancies in Nigeria. The patients frequently present with advanced disease. Abdomino-Perineal resection (APR), is thus an essential modality of treatment alongside chemo-radiation. The aim of the study was to review the surgical outcomes of APR done for low rectal and anal malignancies in a resource poor setting in sub-Saharan Africa. MATERIALS AND METHODS: The demographic data, clinical features, management offered and outcomes of all patients who had had abdomino-perineal resection for colonic and anal malignancies at the University College Hospital, Ibadan, Nigeria between 2007 and 2013 were included in this study. RESULTS: Over the 6-year period, 61 patients had abdomino-perineal resection for low colonic and anal malignancies in our institution. The indications were primary rectal carcinoma in 46 (75.4%) patients and anal carcinoma in 15 (24.6%) patients. The age ranged from 19-77 years with a mean of 48 years and median of 54 years. Majority were males in 33 (54.1%) patients. A fifth (20%) of the patients presented as emergency with large bowel obstruction that necessitated initial colostomy. Bleeding per rectum in 45 patients (73.8%), Weight loss in 26 patients (42.6%) and Tenesmus in 16 patients (26.2%) patients were the predominant complaints. All the patients were at stage AJCC 2A-3C (Duke Stage C or D) at presentation. Almost a third (66%) of the patients was incontinent of feaces. Palliative surgery was done for all the patients. The duration of follow up was between 3-36 months with a mean of 22 months. A total of 53 (86.9%) patients are alive after an average post-operative duration of 24 months, with 14 pts (23%) having local recurrence, and 22(36.1%) patients with hepatic metastases. Lymph nodal involvement was statistically significantly related to the survival status of the patients. Neo-adjuvant and adjuvant chemo radiation did not affect outcomes in terms of local recurrence and survival. CONCLUSION: Abdomino-perineal resection is still the option of treatment in this environment for low rectal and anal malignancies in this environment. Early presentation and effective treatment shall improve the outcome. PMID- 25717466 TI - Mooren'S ulcer in ibadan, southwest Nigeria. AB - BACKGROUND: Mooren's ulcer has been described as an idiopathic, painful, relentless, peripheral, chronic ulcerative keratitis that progresses circumferentially and centrally, with an unusual geographical presentation and distribution. AIM: To review the demographic and clinical characteristics of patients with Mooren's ulcer at University College Hospital, Ibadan, Nigeria over seven years, and, the outcome of treatment. STUDY DESIGN: A retrospective case series. METHODS: Medical records of all patients with Mooren's ulcer seen in the Eye Clinic, University College Hospital, Ibadan, South-west Nigeria between January 2007 and December 2013 were reviewed. RESULTS: Thirty-one eyes of 23 patients, (18 males, overall mean age of all patients 30.9 +/-16.6 years) were affected with Mooren's ulcer. The right eye was involved in nine (39.1%) patients while eight (34.8%) patients had bilateral lesions. Most common presenting symptoms were redness and pain, with an average of 6.8 clock hour-limbal involvement. All patients received topical and systemic steroids, while eight patients with severe disease, or poor response to treatment with steroids, received systemic methotrexate or cyclophosphamide. Surgical treatment with conjunctivectomy and cryotherapy was undertaken in 14 (60.9%) patients (21 eyes) who had a minimum follow-up period of eight weeks, while those presenting with perforation also had scleral patch graft or direct repair. The ulcer healed with varying degrees of corneal opacity in 18 (85.7%) of the 21 eyes, while the remaining three eyes developed descemetocele, anterior staphyloma or corneal perforation. Large proportion (76.2%) of eyes maintained their presenting acuity. CONCLUSION: Mooren's ulcer remains an uncommon disease in Ibadan, South-west Nigeria, and the clinical presentation is as recorded in other parts of the West African sub-region. Systemic immunosuppression with methotrexate and scleral patch graft appear to give good outcome in patients presenting with severe ulceration and/or perforation. PMID- 25717467 TI - Dexmedetomidine and fentanyl exhibit temperature dependent effects on human respiratory cilia. AB - BACKGROUND: Dexmedetomidine (dex) is commonly used in intensive care due to its effective sedation and analgesia with few adverse effects and minimal respiratory depression. However, we recently observed that exposing mouse epithelial respiratory cells to dex decreased ciliary beat frequency (CBF), suggesting dex may pose pulmonary risk. OBJECTIVE: The purpose of this study is to determine the effects of dex at clinically relevant doses on CBF in human respiratory epithelia. METHODS: Human nasal epithelial cilia were obtained from the inferior nasal turbinate with a rhinoprobe and placed in culture medium at 15 degrees C and 37 degrees C. At 5 and 30 min, video-microscopy was used to assess CBF, either without (control) or with different concentrations (1, 5, and 10 nM) of dex, fentanyl (fen), and dex + fen combination. RESULTS: At 15 degrees C, CBF was lower in the dex group compared to controls at 5 and 30 min. At 37 degrees C, there was a significant increase in CBF with dex at 5 and 30 min, except for dex at 5 nM after 5 min, which showed a significant decrease. At 15 degrees C the combination of dex + fen showed a positive interaction, causing less ciliary inhibition as expected. In contrast, no interaction between drugs was seen between dex and fen at 37 degrees C. CONCLUSION: At low temperatures, dex reduces CBF in human respiratory epithelia, whereas dex increases CBF at physiologic temperature in vitro. Whether these effects translate into clinical consequences during hypothermia, as with cardiopulmonary bypass surgery will require further studies. PMID- 25717469 TI - Aspects of Sustainability: Cooperation, Job Satisfaction, and Burnout among Swiss Psychiatrists. AB - PURPOSE: Greater sustainability in mental health services is frequently demanded but seldom analyzed. Levels of cooperation, job satisfaction, and burnout are indicators of social sustainability in this field and are of particular importance to medical staff. Because registered psychiatrists play a central role, we assessed the status quo and interactions between these three factors among registered psychiatrists in Switzerland. METHOD: A postal survey with three standardized questionnaires about cooperation, job satisfaction, and burnout was conducted among all registered psychiatrists in the German-speaking part of Switzerland (n = 1485). Addresses were provided by the Swiss Medical Association. RESULTS: Response rate was 23.7% (n = 352), yielding a largely male sample (62.8%; n = 218) aged 55.5 +/- 8.7 years old. Quantity (47 +/- 56.2 contacts over 3 months) and duration (91.1 +/- 101.6 min per week) of cooperation was found to be diverse depending on the stakeholder. Quality of cooperation was greatest in general practitioners (81.5%) while it was worst in community mental health providers (54.9%). Overall job satisfaction was assessed rather high (3.7 +/- 0.8), and burnout rates were below crucial values (Emotional Exhaustion, 2.9 +/- 0.8; Depersonalization, 1.9 +/- 0.5). Both were positively influenced by cooperation. The strongest correlation was found between job satisfaction and burnout, and both had significant inverse relationships in all dimensions. CONCLUSION: To foster sustainability in outpatient mental health care regarding cooperation, job satisfaction, and burnout, personal aspects such and age or years of registration, organizational aspects, such as networking and practice setting, as wells as supportive aspects such as psychotherapy, and self-help groups, must be considered. Quality of cooperation should be reinforced in particular. Because Integrated and Managed Care models cover several of these factors, the models should be more strongly embedded in health care systems. PMID- 25717468 TI - Review of literature: genes related to postaxial polydactyly. AB - BACKGROUND: Postaxial polydactyly (PAP) is one of the commonest congenital malformations and usually is associated to several syndromes. There is no primary investigational strategy for PAP cases with single gene disorder in literature. PAP cases with single gene disorder can be classified according to common pathways and molecular basis. Molecular classification may help in diagnostic approach. MATERIALS AND METHODS: All single gene disorders associated with PAP reported on PubMed and OMIM are analyzed and classified according to molecular basis. RESULTS: Majority of genes related to cilia structure and functions are associated with PAP, so we classified them as ciliopathies and non-ciliopathies groups. Genes related to Shh-Gli3 pathway was the commonest group in non ciliopathies. CONCLUSION: Genes related to cilia are most commonly related to PAP due to their indirect relationship to Shh-Gli3 signaling pathway. Initially, PAP may be the only clinical finding with ciliopathies so those cases need follow up. Proper diagnosis is helpful for management and genetic counseling. Molecular approach may help to define pleiotropy. PMID- 25717470 TI - Scope of algae as third generation biofuels. AB - An initiative has been taken to develop different solid, liquid, and gaseous biofuels as the alternative energy resources. The current research and technology based on the third generation biofuels derived from algal biomass have been considered as the best alternative bioresource that avoids the disadvantages of first and second generation biofuels. Algal biomass has been investigated for the implementation of economic conversion processes producing different biofuels such as biodiesel, bioethanol, biogas, biohydrogen, and other valuable co-products. In the present review, the recent findings and advance developments in algal biomass for improved biofuel production have been explored. This review discusses about the importance of the algal cell contents, various strategies for product formation through various conversion technologies, and its future scope as an energy security. PMID- 25717472 TI - Deep Reduced PEDOT Films Support Electrochemical Applications: Biomimetic Color Front. AB - Most of the literature accepts, despite many controversial results, that during oxidation/reduction films of conducting polymers (CPs) move from electronic conductors to insulators. Thus, engineers and device's designers are forced to use metallic supports to reoxidize the material for reversible device work. Electrochromic front experiments appear as main visual support of the claimed insulating nature of reduced CPs. Here, we present a different design of the biomimetic electrochromic front that corroborates the electronic and ionic conducting nature of deep reduced films. The direct contact PEDOT metal/electrolyte and film/electrolyte was prevented from electrolyte contact until 1 cm far from the metal contact with protecting Parafilm((r)). The deep reduced PEDOT film supports the flow of high currents promoting reaction induced electrochromic color changes beginning 1 cm far from the metal-polymer electrical contact and advancing, through the reduced film, toward the metal contact. Reverse color changes during oxidation/reduction always are initiated at the film/electrolyte contact advancing, under the protecting film, toward the film/metal contact. Both reduced and oxidized states of the film demonstrate electronic and ionic conductivities high enough to be used for electronic applications or, as self-supported electrodes, for electrochemical devices. The electrochemically stimulated conformational relaxation model explains those results. PMID- 25717471 TI - On the relative relevance of subject-specific geometries and degeneration specific mechanical properties for the study of cell death in human intervertebral disk models. AB - Capturing patient- or condition-specific intervertebral disk (IVD) properties in finite element models is outmost important in order to explore how biomechanical and biophysical processes may interact in spine diseases. However, disk degenerative changes are often modeled through equations similar to those employed for healthy organs, which might not be valid. As for the simulated effects of degenerative changes, they likely depend on specific disk geometries. Accordingly, we explored the ability of continuum tissue models to simulate disk degenerative changes. We further used the results in order to assess the interplay between these simulated changes and particular IVD morphologies, in relation to disk cell nutrition, a potentially important factor in disk tissue regulation. A protocol to derive patient-specific computational models from clinical images was applied to different spine specimens. In vitro, IVD creep tests were used to optimize poro-hyperelastic input material parameters in these models, in function of the IVD degeneration grade. The use of condition-specific tissue model parameters in the specimen-specific geometrical models was validated against independent kinematic measurements in vitro. Then, models were coupled to a transport-cell viability model in order to assess the respective effects of tissue degeneration and disk geometry on cell viability. While classic disk poro mechanical models failed in representing known degenerative changes, additional simulation of tissue damage allowed model validation and gave degeneration dependent material properties related to osmotic pressure and water loss, and to increased fibrosis. Surprisingly, nutrition-induced cell death was independent of the grade-dependent material properties, but was favored by increased diffusion distances in large IVDs. Our results suggest that in situ geometrical screening of IVD morphology might help to anticipate particular mechanisms of disk degeneration. PMID- 25717473 TI - Biochemical insight into the prion protein family. AB - Prion protein family comprises proteins, which share not only similarity in their primary structure, but also similarity in their fold. These two groups of similarity presume a parceling in their respective biological function through the common biochemical properties. In this review, biochemical and structural similarities of PrP and two other proteins, Doppel and Shadoo, are evocated. Some evidence demonstrating respectively similarity between PrP N-terminal and C terminal domain with respectively Shadoo and Doppel is presented. We extended primary structure similarity analysis to the other PrP subdomain as 166-176 polyNQ domain and compare it to proteins using aggregation as a support for structural information transference and structural epigenetic. Finally, we questioned if prion protein family have conserved the PrP structural bistability, which should be at the origin of Prion phenomenon and if Prion pathology is not, ultimately, an exaptation of the physiological propensity of PrP to undergo a structural switch and polymerize. PMID- 25717474 TI - The biocompatibility of degradable magnesium interference screws: an experimental study with sheep. AB - Screws for ligament reconstruction are nowadays mostly made of poly-L-lactide (PLLA). However, magnesium-based biomaterials are gathering increased interest in this research field because of their good mechanical property and osteoanabolic influence on bone metabolism. The aim of this pilot study was to evaluate the biocompatibility of an interference screw for ligament reconstruction made of magnesium alloy W4 by diecasting and milling and using different PEO-coatings with calcium phosphates. PLLA and titanium screws were used as control samples. The screws were implanted in the femur condyle of the hind leg of a merino sheep. The observation period was six and twelve weeks and one year. Histomorphometric, immunohistochemical, immunofluorescence, and molecular biological evaluation were conducted. Further TEM analysis was done. In all magnesium screws a clinically relevant gas formation in the vicinity of the biomaterial was observed. Except for the PLLA and titanium control samples, no screw was fully integrated in the surrounding bone tissue. Regarding the fabrication process, milling seems to produce less gas liberation and has a better influence on bone metabolism than diecasting. Coating by PEO with calcium phosphates could not reduce the initial gas liberation but rather reduced the bone metabolism in the vicinity of the biomaterial. PMID- 25717475 TI - Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease. AB - Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation. PMID- 25717476 TI - Revisiting Metal Toxicity in Neurodegenerative Diseases and Stroke: Therapeutic Potential. AB - Excessive accumulation of pro-oxidant metals, observed in affected brain regions, has consistently been implicated as a contributor to the brain pathology including neurodegenerative diseases and acute injuries such as stroke. Furthermore, the potential interactions between metal toxicity and other commonly associated etiological factors, such as misfolding/aggregation of amyloidogenic proteins or genomic damage, are poorly understood. Decades of research provide compelling evidence implicating metal overload in neurological diseases and stroke. However, the utility of metal toxicity as a therapeutic target is controversial, possibly due to a lack of comprehensive understanding of metal dyshomeostasis-mediated neuronal pathology. In this article, we discuss the current understanding of metal toxicity and the challenges associated with metal targeted therapies. PMID- 25717477 TI - Spherical Topic Models for Imaging Phenotype Discovery in Genetic Studies. AB - In this paper, we use Spherical Topic Models to discover the latent structure of lung disease. This method can be widely employed when a measurement for each subject is provided as a normalized histogram of relevant features. In this paper, the resulting descriptors are used as phenotypes to identify genetic markers associated with the Chronic Obstructive Pulmonary Disease (COPD). Features extracted from images capture the heterogeneity of the disease and therefore promise to improve detection of relevant genetic variants in Genome Wide Association Studies (GWAS). Our generative model is based on normalized histograms of image intensity of each subject and it can be readily extended to other forms of features as long as they are provided as normalized histograms. The resulting algorithm represents the intensity distribution as a combination of meaningful latent factors and mixing co-efficients that can be used for genetic association analysis. This approach is motivated by a clinical hypothesis that COPD symptoms are caused by multiple coexisting disease processes. Our experiments show that the new features enhance the previously detected signal on chromosome 15 with respect to standard respiratory and imaging measurements. PMID- 25717478 TI - [From the editor]. PMID- 25717479 TI - [Stem cell research and its growing impact on contemporary psychiatry]. AB - The expanding field of stem cell research is now beginning to help with the problems of modern psychiatry. On the one hand, induced pluripotent stem cells (iPSCs) can now be used to generate neural cell lines from patients suffering from psychiatric disorders, which can then serve as models for studying changes in gene expression pattern involved in the pathogenesis of these diseases. These artificially generated neural cells are also employed in studying the efficacy of newly developed antipsychotic treatments. On the other hand, evidence has accumulated that not only monocytes, which can be microglia precursors, but also certain other adult bone marrow-derived cells may cross the blood-brain barrier and affect biological processes in brain tissue. Along with evidence of circulating and brain-infiltrating cells, there are well-studied factors (e.g., chemokines, phosphosphingolipids, and complement-cleavage fragments) that modulate trafficking of these cells between bone marrow and neural tissue. These observations may help to shed new light on the pathogenesis of psychotic disorders and, in the future, perhaps help to develop more effective treatments. PMID- 25717480 TI - [The association between cognitive deficits and different outcomes of schizophrenia]. AB - AIM: Schizophrenia is a disorder with different outcomes. Besides the positive and negative symptoms, cognitive impairment is an important core feature of schizophrenia and often pre-dates the disorder. Cognition has consistently been related to outcome in schizophrenia. Given this finding and the fact that diagnosing and treating schizophrenia as early as possible has better outcome chances, the current study investigated the hypothesis that cognitive performance is associated with two seemingly opposite outcomes: clinical remission and forced hospitalization three years after first assessment. METHODS: Subjects in the current study were schizophrenia patients not in an active psychosis during cognitive testing (N = 321). The results of the cognitive tests were used as predictor variables for the status of remission or the occurrence of a forced hospitalization in the three years following the cognitive testing. The cognitive tests included were WAIS-III subtests (Digit symbol, Information, Arithmetic, Block Design), Benton Facial Recognition task, Hinting task and the Rey Auditory Verbal Learning task. Besides these cognitive predictors, several relevant covariates (gender, age, education, number of psychotic episodes, duration of illness and amphetamine, cannabis or cocaine intoxication) were analyzed. Two multinomial logistic regression and analyses were conducted with the cognitive tests as independent variables and remission and forced hospitalization as dependent variables in separate models. RESULTS: The results showed that better performance on the verbal tasks (WAIS-III arithmetic score (b=0.17) and the WAIS III information score (b=0.22)) and less psychotic episodes (b=-0.64) was associated with remission status. Worse performance on the memory task (b=-0.20) and more psychotic episodes (b=0,85) was related to forced hospitalization. CONCLUSIONS: This three-year longitudinal study showed that higher verbal IQ is a protective factor and poor memory and higher number of psychotic episodes are risk factors of the outcome of schizophrenia. This suggests that future research on prediction tools for the outcome of schizophrenia should include assessment of verbal IQ and verbal memory. PMID- 25717481 TI - [Cognitive dysfunctions in depression - underestimated symptom or new dimension?]. AB - Cognitive deficits constitute an integral part of clinical picture of depression, but often not enough attention has been paid to these deficits, mainly because of the presumption that they are secondary to typical depressive symptoms. It is considered that cognitive impairment is one of the main causes of depressive patients' poor functioning. Cognitive deficits are observed already in the first depressive episode. They may correlate with the severity of depression, with the patient's age and level of education. They may persist regardless of the improvement of depression during treatment. Cognitive deficits in depression are divided into "cold" which are not related to emotions, and "hot" - related to emotions. The "cold" deficits are supposed not to respond to antidepressants and seem to persist even in clinical remission. Vortioxetine is a novel antidepressant with a unique mechanism of action: it acts through the serotonine reuptake inhibition, but works also as 5HT(1A) agonist, as well as partial agonist of the 5HT(1B) receptor and antagonist of the 5HT(1D), 5HT(3) and 5HT(7) receptors. In preclinical studies vortioxetine showed the normalization of serotoninergic, noradrenergic, and dopaminergic transmission, additionally through GABA-ergic and glutaminergic effects. It has antidepressive property, it proved to be efficacious in various types of depression (severe, depression with anxiety, and depression in elderly); it also proved to be efficacious in those patients who did not respond sufficiently to SSRIs and SNRIs treatment. Vortioxetine is also beneficial for cognitive functions in depressed patients. PMID- 25717482 TI - [Homocysteine and cognitive functions in bipolar depression]. AB - AIM: The aim of the study was to evaluate a relationship between concentrations of hoocysteine (HCY), vitamin B12 and folic acid and disturbances of cognitive functions during acute episode of bipolar depression. METHODS: 116 patients were studied (93 women, 23 men), aged 20-78 (mean 51+/-13) years during acute episode of bipolar depression. Depression was evaluated by the 17-item Hamilton's Depression Rating Scale (HDRS). The following tests measuring cognitive functions were applied: Trail Making Test, Wisconsin Card Sorting Test, Stroop Test and Wechsler Adult Intelligence Scale-Revised. In all patients, the measurements of serum homocysteine, vitamin B12 and folic acid were carried out. RESULTS: Hyperhomocystemia (HCY>15MUM/l) was detected in 41 patients (35%), more frequently in men (52%) than in women (31%). Patients with hyperhomocysteinemia achieved worse results in sub-tests of WAIS-R (verbal understanding and perceptional organization). In men, negative correlation was found between HCY concentration and number of errors in Stroop Test, and WCST (total errors and non perseverative errors). In women with bipolar disorder, type II, negative correlation between HCY concentration and time of Stroop Test, and between vitamin B12 concentration and number of errors in Stroop Test, were demonstrated. In the whole group and in men, there was positive correlation between higher folic acid concentration and the number of errors in Stroop Test. CONCLUSIONS: The results obtained show higher HCY concentration in considerable proportion of patients with bipolar depression, especially in men. They also confirm a connect between high homocysteine concentration and worse performance in some neuropsychological tests. Such relationship was more marked in men. PMID- 25717483 TI - [Staging of unipolar affective illness]. AB - In this article, a concept of staging of unipolar affective illness (recurrent depression) is presented. In respective subchapters, three most important aspects of this issue have been discussed: 1) staging of unipolar affective illness; 2) staging of treatment-resistant depression; and 3) conversion of unipolar into bipolar affective illness. The evidence for so called neuroprogression of the illness, accumulated in recent years, has allowed for a classification of staging based on a concept of allostasis and allostatic load. In the course of illness, changes in neuroendocrine system (mainly hypothalamic pituitary-adrenal (HPA) axis), immunological system, mechanisms of oxidative stress, neurotransmitters, neurotrophic factors as well as structural and functional changes of the brain occur. In their paper of 2007, Fava and Tossani elaborated a concept of staging of unipolar affective illness presenting a continuum model of five consecutive stages with specific clinical features. In the present paper, a concept of treatment-resistant depression and staging of treatment resistance is presented in the context of several models. An important determinant of treatment-resistant depression is so called subthreshold bipolarity which is connected with worse efficacy of antidepressant drugs. In the course of illness, there is a possibility of changing diagnosis from recurrent depression into bipolar affective illness. The studies on this issue show that frequency of such diagnostic conversion is 1,5% of depressed patients per year. PMID- 25717484 TI - [Convergence insufficiency with unilateral exophoria at near in schizophrenia and bipolar disorder - a preliminary study]. AB - OBJECTIVES: The study describes an abnormal convergence symptom, i.e. unilateral exophoria at near, in patients with schizophrenia (SZ) and bipolar disorder (BD). The aim of this paper is to present the symptom and discuss its possible explanations. METHODS: 29 patients with SZ, 15 patients with BD and 20 healthy controls (HC) took part in the study. The neurological assessment was done with International Co-operative Ataxia Rating Scale (ICARS) and Neurological Evaluation Scale (NES). RESULTS: The abnormal vergence pattern was observed in 12 patients with SZ, 1 patient with BD and 0 HC. Symptom appeared statistically more often in SZ patients than in BD patients and HC. SZ patients with vergence symptom performed significantly worst in oculomotor and dysarthia subscores of ICARS. CONCLUSIONS: The symptom can be linked to disruptions in cortico-ponto cerebellar network and midbrain. It was the only neurological symptom that differed SZ and BD groups, thus it might be used in differential diagnosis. Further research is needed to obtain a full clinical description of the symptom. PMID- 25717485 TI - [Tardive dyskinesia in patients with schizophrenia treated with olanzapine - results from a 20-month, prospective, open study under naturalistic conditions]. AB - OBJECTIVES: The objective of the study was to assess the prevalence and incidence of tardive dyskinesia in patients treated with olanzapine during the follow-up period of 20 months. METHODS: It was a prospective, observational, non interventional study under naturalistic conditions, without a control group. The evaluation of the severity and presence of tardive dyskinesia was performed with the Abnormal Involuntary Movement Scale and research criteria by Schooler and Kane. RESULTS: The study included 573 patients (woman 43,3%) with the diagnosis of schizophrenia (ICD-10), the mean age of 41.8 (+/- 12) years. The mean dose of olanzapine was 15.9 (+/- 4.2) mg. The prevalence of tardive dyskinesia was 16.4%. The cumulative incidence assessed in the group of 479 patients was 6.47%. The annual incidence was 3.9%. An increased risk of tardive dyskinesia was observed in smokers - RR of 1.99 (CI 0.88-4.49), those taking higher doses of olanzapine 1.57 (CI 0.91-2.7) and in those who used polytherapy: 3.55 (CI 1.43-8.82). Only in the case of polytherapy a multidimensional analysis confirmed that this factor had a significant influence on the risk of tardive dyskinesia (p=0.006). CONCLUSIONS: The study demonstrated high (16,4%) prevalence of tardive dyskinesia, and the annual incidence (3,9%) comparable to the results of a meta analysis by Corell et al. In the case of olanzapine in monotherapy the annual incidence was lower (1.96%) but the use of antipsychotics in polytherapy more than tripled the risk of tardive dyskinesia. PMID- 25717486 TI - [New prospects for antipsychotic treatment - the role of the kynurenine pathway]. AB - The mechanism of action of antipsychotic drugs is mainly associated with changes in dopaminergic system. The application of antipsychotic agents simultaneously produces changes in concentrations of metabolites (e.g. kynurenic acid - KYNA, 3 hydroxykynurenine - 3-OHKYN, kynurenine - KYN) of the kynurenine pathway, the pathway engaged in glutamatergic transmission. The increase in KYNA levels in certain areas of the central nervous system results in inhibition of glutamatergic transmission. Pharmacologically induced elevation of KYNA levels produces effects similar to those observed after administering ketamine or phencyclidine (the noncompetitive NMDA receptor antagonist), concerning increased activity of mesolimbic dopamine neurons, as well as reduction in dopamine release from the prefrontal cortex. Recent research results confirm the predictive value of changes in concentrations of kynurenine pathway metabolites for assessment of effectiveness of antipsychotic treatment. Significant relationships were found 1) in schizophrenia between the reduction of psychopathological symptoms and variations in 3-OHKYN levels as well as changes in KYNA/3-OHKYN and KYN/KYNA ratios, 2) in mania between varying tryptophan concentrations and the reduction in manic symptoms achieved with antipsychotic treatment. The research as well presented the possibilities of kynurenine pathway modifications, raising high hopes for their future application as target points for the action of novel antipsychotic agents. PMID- 25717487 TI - [Cognitive rehabilitation for people living with schizophrenia - the newest interventions]. AB - The article reviews the latest interventions in cognitive rehabilitation for patients with schizophrenia. Studies referring to cognitive rehabilitation for people with schizophrenia from the last three years, found in the PubMed database, are presented. The authors categorised cognitive rehabilitation trainings in terms of targeted cognitive spheres - neurocognitive training, social cognition training, emotion perception training and combined training - and present current trends within this approaches. Cognitive function improvements after cognitive remediation are specific to the rehabilitation target and there are no clear differences between training types in the way they influence other cognitive domains or symptoms. There is a need to heighten transfer of gained / enhanced cognitive skills to functional ones. Therefore new methods of cognitive remediation are explored . The future direction in cognitive rehabilitation is to enhance benefits by combining various forms of cognitive remediation and by emphasizing patient specificity in planning and conducting cognitive interventions. PMID- 25717488 TI - [The assessment of chosen psychometric features of B-CATS test battery in schizophrenia - preliminary report]. AB - AIM: The assessment of cognitive impairment in schizophrenia proves helpful in the diagnosis of disease, identification of individuals at risk for adverse outcome and choosing the most adequate treatment. It is also a valuable complement of the psychiatric diagnosis. For this reason, there is a great need for a practical well-validated instrument to measure cognitive deficits that can be administered and interpreted easily in a clinical setting. The aim of the study was to verify the reliability, validity and practicality of the Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) in a clinical setting. METHODS: 68 psychotic patients were included in the study during their stay in a psychiatric ward. A double measurement was conducted. Test-retest assessment included tests of B-CATS battery (TMT part B, Category Fluency, Digit Symbol Test). To evaluate the intensity of psychopathological symptoms the PANSS was performed. SLOF, GAF, GARF, SOFAS were used to assess functioning of the subjects. RESULTS: The B-CATS is characterized by a satisfactory relative stability. The absolute stability should be seen as sufficient in case of one test: Fluency. The diagnostic validity of the battery is satisfactory. B-CATS is easy to administer and "friendly" for the patient. CONCLUSIONS: B-CATS is a brief and practical instrument that can provide clinicians with meaningful data regarding the global cognitive functioning of the psychotic subjects. PMID- 25717489 TI - [Stigmatization on the way to recovery in mental illness - the factors associated with social functioning]. AB - Persons with mental disorders often experience stigmatization. There is a number of social factors that may affect the process of recovery and at the same time, in certain circumstances, could be a source of stigma. Mentally ill may find strength in themselves to fight against the disease or the opposite - can internalize the negative attitudes of the society and become self-stigmatized. The patient's family, on the one hand, is often the only source of social support, on the other hand, can experience a destructive influence of courtesy stigma. Mentally ill have to face social reluctance which is reinforced by stereotypical media coverage of mental disorders. The social network of patients is poor and often limited to a family system. Negative views about persons diagnosed with mental illness are most visible in the labour market. Patients experience many types of discrimination at work,have lower employment rates and lower mean wages than healthy ones. Structural discrimination is a form of stigma which is revealed in underfunded and inefficient system of mental health care. All the social factors mentioned above are necessary for recovery (positive stimulation of functioning), but can also increase stigma and become a significant barrier in the recovery of psychiatric patients. This paper highlights the complex and ambiguous nature of the relationship between social factors and the recovery of the mentally ill basing on the data from the literature. PMID- 25717490 TI - [Significance of psychiatrists' personal variables in treatment of persons suffering from schizophrenia]. AB - AIM: The aim of the study is to investigate the significance of psychiatrists' personal variables in treatment and functioning of persons suffering from schizophrenia. METHODS: 150 patients with schizophrenia indicated by 30 psychiatrists were included in the study. Data was collected during single interview with the use of Dyadic Questionnaire of the Therapist-Patient Relationship, Questionnaire of Pharmacological Treatment Assessment, Life Satisfaction Scale, Emotion Control Scale, Life Orientation Test, Overall Self Efficacy Scale, Social Functioning Scale and Sociodemographic Questionnaire. Stepwise regression was used to determine the psychiatrist's related variables which explain variables associated with a patient. RESULTS: Psychiatrists' personal variables explained up to 20% of variance in social functioning of the patients with schizophrenia. Variables describing psychiatrists were most significant in explaining assessment of psychiatrist's professionalism and rejection of a psychiatrist by a patient. The abilities to identify medication symptoms and adherence to pharmacotherapy were only slightly explained by patient - psychiatrist collaboration length. CONCLUSIONS: Results indicate that psychiatrists' personal characteristics are significant for the development of the relationship between persons with schizophrenia and their psychiatrists. PMID- 25717491 TI - [The perception of authorship in schizophrenia - the analysis of activity patterns in autonarrations]. AB - AIM: The paper presents the study of narrations of schizophrenic patients focused on the description of activities characteristics. The aim is to answer the question of how experiencing of psychotic crisis influences the perception of their authorship. Do the inherent characteristics of the activity differ with reference to the period of life which they relate to: the time before getting sick, or after falling ill with schizophrenia? METHODS: The material consisted of narrations of 26 people with schizophrenia about their life prior to the illness and after the psychotic crisis. Linguistic categories that make up the patterns of activity have been distinguished. The frequency of the occurrence was compared in both narrations. RESULTS: Self-descriptions after falling ill are more saturated with patterns of avoidance, motivation internally localized connected with attempts of coping with the disease and externally localized action control connected with a decreased sense of authorship in relation to experiencing symptoms and reduction of social competence. CONCLUSIONS: The change of self image after psychotic experience concerns the deeper planes of narrative, i.e. the patterns of activity hidden in connection between the content and narrative form. The research showed the decrease of the sense of agency associated with the disease experience. PMID- 25717493 TI - [Characteristics of groups after the suicide attempt. Cluster analysis of National Comorbidity Survey (NCS) 1990-1992]. AB - AIM: Identification of specific groups with increased risk of suicidal behavior. METHODS: Latent class analysis, (LCA) data from the National Comorbidity Survey (NCS) 1990-1992, conducted in the representative sample of 5977 Americans aged 15 54 years. RESULTS: Seven clusters of persons were identified: (C1) young adults with at least 5 psychiatric diagnoses in lifetime, with sever anxiety, somatic illnesses and low income;(C2) alcohol dependent with depressive mood, and with at least 4 psychiatric diagnoses in lifetime; (C3) persons without mental disorders and persons with one or two mental disorders, in fourth decade of life; (C4) nearly only women suffering from depression with other comorbid mental disorders, often with anxiety disorders; (C5) young persons with variety of mental disorders, and with abuse of alcohol and other psychoactive substances, with suicidal attempt in past, currently not in relationship; (C6) nearly only men, in fourth decade of life, abusing alcohol and drugs, with depressive mood; majority of them with dissocial personality disorder and with at least three psychiatric diagnoses; (C7) young persons without mental disorders or with 1 or 2 mental disorders, strongly emotionally dependent. CONCLUSIONS: Cluster analysis let to identify and relatively well describe 7 groups of persons with increased risk of suicidal behavior. PMID- 25717492 TI - [Group psychoeducation in bipolar mood disorders - the influence on the cognitive representation of the illness. The results of the program "Taming the bipolar affective disorder"]. AB - OBJECTIVES: To assess the influence of group psychoeducation in bipolar disorder on selected aspects of cognitive representation of illness. METHODS: 51 patients with bipolar diagnosis were included in the study, and 24 were included in the final statistical analysis. The participants took part in 8 meetings of group psychoeducation. The assessment of selected aspects of cognitive representation of illness, i.e. acceptance of illness, health locus of control, generalized self efficiency, hope for success, therapeutic compliance, beliefs about bipolar disorder was conducted with validated questionnaires before, after, and 18 months after receiving psychoeducation to register possible changes. RESULTS: Statistically significant increase in acceptance of illness, perceived self efficiency, hope for success, therapeutic compliance, and positive modification of beliefs about bipolar disorder were detected. The observed change occurred right after the intervention, but it was not sustained during the follow-up. CONCLUSIONS: Psychoeducation may exert a positive influence on virtually important cognitive variables, which seem to be clinically important. This influence may disappear with time, thus the interventions should either be repeated or the duration of intervention should be prolonged. The study shows new possible research directions in the field of searching for the mechanism of action of psychoeducation in bipolar disorder, as well as of its active components. PMID- 25717494 TI - [Semantic differential in the study on the stereotype of mentally ill people - comparative study 10 years later]. AB - OBJECTIVES: This article examines how mentally ill people are perceived by psychology students. It was inspired by a study on stereotypical perception of mentally ill people carried out 10 years ago, which was published in Polish Psychiatry (2000). METHODS: A modified version of the semantic differential, which was used 10 years ago, was applied. The version consisted of: subject selection of 30 pairs of adjectives which describe mentally ill people, marking on a scale the extent a given object possesses a feature, describing what percentage of the mentally ill possess a feature as well as describing the level of certainty (%) of the respondent on the feature intensity. RESULTS: Compared to a similar group of subjects studied ten years ago, the examined 152 students (F 138, M 14), on average aged 21.8, received results showing higher maturity and lesser weight of stereotypical thinking regarding the mentally ill. The subjects currently studied stated lower certainty (71%) than the previously studied group (79%), in most mentally ill people having problems in contact with others as well as with themselves. They perceive mentally ill people in a wider perspective (11 differential categories in 2000 compared to 19 differential categories in 2010. CONCLUSIONS: The studies on stereotyping of the mentally ill show beneficial changes in awareness among psychology students. New psychology teaching programmes sensitizing to mental problems, the complexity of illness processes, likely impact of social advertising, and fostering social support for the mentally ill, contributed to the positive changes in results. PMID- 25717495 TI - [Contemporary requirements electroconvulsive therapy]. PMID- 25717496 TI - Analysis of fast channel blockage: revealing substrate binding in the microsecond range. AB - For an antibiotic to be effective, it needs to cross the outer membrane barrier and reach the target inside the cell. Hydrophilic antibiotics, e.g.beta-lactams, use porin channels to cross the outer membrane and accumulate in the periplasm. Experimental determination of antibiotic interactions with porin is performed by using electrophysiology on a single channel level by noise analysis or single event analysis methods. We report a novel framework for analyzing the ion-current noise, taking into account the corrections due to the analogous filter and the sampling procedure, with the goal of extending the time resolution to a range previously inaccessible by event analysis or by conventional noise analysis. The new method allows one to analyse fast binding events and/or the case when the single channel is not completely blocked by the substrate. We demonstrate the power of this approach by using as an example the interactions of meropenem, an antibiotic of the carbapenem family, with the OmpF porin that is considered to be one of the main pathways for antibiotics to enter Escherichia coli. The presence of meropenem in OmpF is detected by ion current blockages, and the on and off rates are estimated from the concentration dependence of the average ion current and of its power spectral density. The obtained average residence time of the antibiotic inside the channel is in the range of a few microseconds, i.e. more than 50 times smaller than the inverse cut-off frequency of the analogous filter. PMID- 25717497 TI - Rapid detection of sugar alcohol precursors and corresponding nitrate ester explosives using direct analysis in real time mass spectrometry. AB - This work highlights the rapid detection of nitrate ester explosives and their sugar alcohol precursors by direct analysis in real time mass spectrometry (DART MS) using an off-axis geometry. Demonstration of the effect of various parameters, such as ion polarity and in-source collision induced dissociation (CID) on the detection of these compounds is presented. Sensitivity of sugar alcohols and nitrate ester explosives was found to be greatest in negative ion mode with sensitivities ranging from hundreds of picograms to hundreds of nanograms, depending on the characteristics of the particular molecule. Altering the in-source CID potential allowed for acquisition of characteristic molecular ion spectra as well as fragmentation spectra. Additional studies were completed to identify the role of different experimental parameters on the sensitivity for these compounds. Variables that were examined included the DART gas stream temperature, the presence of a related compound (i.e., the effect of a precursor on the detection of a nitrate ester explosive), incorporation of dopant species and the role of the analysis surface. It was determined that each variable affected the response and detection of both sugar alcohols and the corresponding nitrate ester explosives. From this work, a rapid and sensitive method for the detection of individual sugar alcohols and corresponding nitrate ester explosives, or mixtures of the two, has been developed, providing a useful tool in the real-world identification of homemade explosives. PMID- 25718355 TI - Impact of clinical presentation on ischaemic and bleeding outcomes in patients receiving 6- or 24-month duration of dual-antiplatelet therapy after stent implantation: a pre-specified analysis from the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial. AB - AIMS: We investigated if acute coronary syndrome (ACS) rather than stable coronary artery disease (SCAD) presentation is an outcome modifier with respect to the duration of dual-antiplatelet therapy (DAPT) in patients undergoing coronary stenting. METHODS AND RESULTS: In the Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia (PRODIGY) trial, a total of 1465 (74.3%) patients presented ACS whereas 505 (25.7%) had SCAD and were randomized to 6- or 24-month DAPT. At 24 months, the composite of death, myocardial infarction (MI), or cerebrovascular accident (CVA) did not differ between the long- and short-term DAPT arms in both ACS (11.1 vs. 11.7%; P = 0.67) and SCAD (7.5 vs. 4.8%; P = 0.21) patients, respectively. Long-term DAPT was associated with a 75% increase of Bleeding Academic Research Consortium (BARC) class 2, 3, or 5 bleeding in ACS [7.1 vs. 4.1%; hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.11-2.74, P = 0.015; number needed to treat for harm (NNTH): 33.3] and a five-fold increase in SCAD (8.2 vs. 1.6%; HR 5.37, 95% CI 1.84-15.74, P = 0.002; NNTH: 15.1) patients, with a borderline quantitative interaction (PINT = 0.056). As a result, net adverse cardiovascular events (death, MI, CVA, BARC class 2, 3, or 5 bleeding) were more than doubled in SCAD patients receiving 24-month DAPT, whereas they did not differ in ACS patients (PINT = 0.024). CONCLUSIONS: This analysis suggests that clinical presentation may be a treatment modifier with respect to DAPT duration after stenting consistent with the hypothesis that SCAD-but not ACS-patients are exposed to a significant increase in bleeding and net adverse clinical events when treated with 24-month compared with 6-month therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00611286. http://clinicaltrials.gov/ct2/show/NCT00611286?term=prodigy&rank=2. PMID- 25718356 TI - Abstracts of the Annual meeting of the American Academy of Otorhinolaryngology, September 9-12, 2012 , Washington DC, USA. PMID- 25719176 TI - Atherosclerosis and CAD. PMID- 25719177 TI - The Cochrane Collaboration: twenty-first century encyclopedistes? PMID- 25719178 TI - Animal studies with the Carmat bioprosthetic total artificial heart. AB - OBJECTIVES: The Carmat bioprosthetic total artificial heart (TAH) contains bioprosthetic blood-contacting surfaces, and is designed for orthotopic cardiac replacement. In preparation for clinical studies, we evaluated the TAH performance and its effects on end-organ function in an animal model. METHODS: Twelve female Charolais calves, 2-3 months of age and weighing 102-122 kg, were implanted with the TAH through a mid-sternotomy to ensure an adequate anatomic fit. The intended support duration was 4-10 days. Haematological values, creatinine, bilirubin and lactate levels were measured and mean arterial and central venous pressure, central venous oxygen saturation and TAH parameters were monitored. RESULTS: The calves were placed in a cage immediately postoperatively, and extubated on postoperative day 1 in most cases. Average support duration was 3 days, with 4 of 12 calves supported for 4, 4, 8 and 10 days. The initial procedures were used to refine surgical techniques and postoperative care. Pump output ranged from 7.3 to 10 l/min. Haemodynamic parameters and blood analysis were within acceptable ranges. No device failures occurred. No anticoagulation was used in the postoperative phase. The calves were euthanized in case of discomfort compromising the animal well-being, such as respiratory dysfunction, severe blood loss and cerebral dysfunction. Device explant analysis showed no thrombus formation inside the blood cavities. Histological examination of kidneys showed isolated micro-infarction in 2/12 animals; brain histology revealed no thromboembolic depositions. CONCLUSION: The Carmat bioprosthetic TAH implanted in calves up to 10 days provided adequate blood flow to organs and tissues. Low levels of haemolysis and no visible evidence of thromboembolic depositions in major organs and device cavities, without the use of anticoagulation, may indicate early-phase haemocompatibility of the TAH. PMID- 25719179 TI - A rare case for gas in the heart: diagnosis and treatment. PMID- 25719180 TI - In vivo comparison between cardiac allograft vasculopathy and native atherosclerosis using near-infrared spectroscopy and intravascular ultrasound. AB - AIMS: The aim was to compare cardiac allograft vasculopathy to native atherosclerosis by near-infrared spectroscopy-intravascular ultrasound (NIRS IVUS). METHODS AND RESULTS: Twenty-seven atherosclerotic (non-transplant) patients and 28 heart transplant recipients undergoing routine surveillance coronary angiography underwent NIRS-IVUS imaging of the left anterior descending coronary artery. In each proximal, middle, and distal coronary artery segment, the maxLCBI4mm [4-mm long segment with maximum lipid core burden index (LCBI)] and corresponding IVUS parameters were compared. MaxLCBI4mm was significantly greater among atherosclerotic patients than the transplant patients in both proximal and middle coronary artery segments, but not in the distal segment. There was a positive linear correlation between maxLCBI4mm and maximum plaque burden in both groups, but atherosclerotic patients demonstrated a smaller maxLCBI4mm than transplant recipients among segments with plaque burden <40%. Among segments with a maximum plaque burden >=40%, native-atherosclerosis patients had a greater maxLCBI4mm compared with transplant patients (P = 0.015). Calcification was present in 72.9% of native atherosclerosis and 14.7% of transplant segments (P< 0.001). Among the 165 analysed segments, prevalence of lipid-rich plaque (LRP) with superficial attenuation (30.9 vs. 1.2%, P < 0.001) or calcified LRP (13.6 vs. 2.4%, P = 0.03) was significantly greater in native atherosclerosis compared with transplant patients. Conversely, the proportion of segments with non-LRP (46.4 vs. 11.1%, P < 0.001) was higher in transplant patients. CONCLUSION: NIRS-IVUS imaging demonstrated early and accelerated lipid accumulation with smaller plaque burden and less calcium in patients after heart transplant when compared with patients with native atherosclerosis. PMID- 25719181 TI - Quantification of coronary flow reserve in patients with ischaemic and non ischaemic cardiomyopathy and its association with clinical outcomes. AB - AIMS: Patients with left ventricular systolic dysfunction frequently show abnormal coronary vascular function, even in the absence of overt coronary artery disease. Moreover, the severity of vascular dysfunction might be related to the aetiology of cardiomyopathy.We sought to determine the incremental value of assessing coronary vascular dysfunction among patients with ischaemic (ICM) and non-ischaemic (NICM) cardiomyopathy at risk for adverse cardiovascular outcomes. METHODS AND RESULTS: Coronary flow reserve (CFR, stress/rest myocardial blood flow) was quantified in 510 consecutive patients with rest left ventricular ejection fraction (LVEF) <=45% referred for rest/stress myocardial perfusion PET imaging. The primary end point was a composite of major adverse cardiovascular events (MACE) including cardiac death, heart failure hospitalization, late revascularization, and aborted sudden cardiac death.Median follow-up was 8.2 months. Cox proportional hazards model was used to adjust for clinical variables. The annualized MACE rate was 26.3%. Patients in the lowest two tertiles of CFR (CFR <= 1.65) experienced higher MACE rates than those in the highest tertile (32.6 vs. 15.5% per year, respectively, P = 0.004), irrespective of aetiology of cardiomyopathy. CONCLUSION: Impaired coronary vascular function, as assessed by reduced CFR by PET imaging, is common in patients with both ischaemic and non ischaemic cardiomyopathy and is associated with MACE. PMID- 25719182 TI - Steroid-induced metamorphosis of the heart: a case of cardiac sarcoidosis. PMID- 25719195 TI - The gut bacterium Bacteroides thetaiotaomicron influences the virulence potential of the enterohemorrhagic Escherichia coli O103:H25. AB - Enterohemorrhagic E. coli (EHEC) is associated with severe gastrointestinal disease. Upon entering the gastrointestinal tract, EHEC is exposed to a fluctuating environment and a myriad of other bacterial species. To establish an infection, EHEC strains have to modulate their gene expression according to the GI tract environment. In order to explore the interspecies interactions between EHEC and an human intestinal commensal, the global gene expression profile was determined of EHEC O103:H25 (EHEC NIPH-11060424) co-cultured with B. thetaiotaomicron (CCUG 10774) or grown in the presence of spent medium from B. thetaiotaomicron. Microarray analysis revealed that approximately 1% of the EHEC NIPH-11060424 genes were significantly up-regulated both in co-culture (30 genes) and in the presence of spent medium (44 genes), and that the affected genes differed between the two conditions. In co-culture, genes encoding structural components of the type three secretion system were among the most affected genes with an almost 4-fold up-regulation, while the most affected genes in spent medium were involved in chemotaxis and were more than 3-fold up-regulated. The operons for type three secretion system (TTSS) are located on the Locus of enterocyte effacement (LEE) pathogenicity island, and qPCR showed that genes of all five operons (LEE1-LEE5) were up-regulated. Moreover, an increased adherence to HeLa cells was observed in EHEC NIPH-11060424 exposed to B. thetaiotaomicron. Expression of stx2 genes, encoding the main virulence factor of EHEC, was down regulated in both conditions (co-culture/spent medium). These results show that expression of EHEC genes involved in colonization and virulence is modulated in response to direct interspecies contact between cells, or to diffusible factors released from B. thetaiotaomicron. Such interspecies interactions could allow the pathogen to recognize its predilection site and modulate its behaviour accordingly, thus increasing the efficiency of colonization of the colon mucosa, facilitating its persistence and increasing its virulence potential. PMID- 25719196 TI - Whole genome sequencing based characterization of extensively drug-resistant Mycobacterium tuberculosis isolates from Pakistan. AB - Improved molecular diagnostic methods for detection drug resistance in Mycobacterium tuberculosis (MTB) strains are required. Resistance to first- and second- line anti-tuberculous drugs has been associated with single nucleotide polymorphisms (SNPs) in particular genes. However, these SNPs can vary between MTB lineages therefore local data is required to describe different strain populations. We used whole genome sequencing (WGS) to characterize 37 extensively drug-resistant (XDR) MTB isolates from Pakistan and investigated 40 genes associated with drug resistance. Rifampicin resistance was attributable to SNPs in the rpoB hot-spot region. Isoniazid resistance was most commonly associated with the katG codon 315 (92%) mutation followed by inhA S94A (8%) however, one strain did not have SNPs in katG, inhA or oxyR-ahpC. All strains were pyrazimamide resistant but only 43% had pncA SNPs. Ethambutol resistant strains predominantly had embB codon 306 (62%) mutations, but additional SNPs at embB codons 406, 378 and 328 were also present. Fluoroquinolone resistance was associated with gyrA 91-94 codons in 81% of strains; four strains had only gyrB mutations, while others did not have SNPs in either gyrA or gyrB. Streptomycin resistant strains had mutations in ribosomal RNA genes; rpsL codon 43 (42%); rrs 500 region (16%), and gidB (34%) while six strains did not have mutations in any of these genes. Amikacin/kanamycin/capreomycin resistance was associated with SNPs in rrs at nt1401 (78%) and nt1484 (3%), except in seven (19%) strains. We estimate that if only the common hot-spot region targets of current commercial assays were used, the concordance between phenotypic and genotypic testing for these XDR strains would vary between rifampicin (100%), isoniazid (92%), flouroquinolones (81%), aminoglycoside (78%) and ethambutol (62%); while pncA sequencing would provide genotypic resistance in less than half the isolates. This work highlights the importance of expanded targets for drug resistance detection in MTB isolates. PMID- 25719197 TI - Deep mRNA sequencing of the Tritonia diomedea brain transcriptome provides access to gene homologues for neuronal excitability, synaptic transmission and peptidergic signalling. AB - BACKGROUND: The sea slug Tritonia diomedea (Mollusca, Gastropoda, Nudibranchia), has a simple and highly accessible nervous system, making it useful for studying neuronal and synaptic mechanisms underlying behavior. Although many important contributions have been made using Tritonia, until now, a lack of genetic information has impeded exploration at the molecular level. RESULTS: We performed Illumina sequencing of central nervous system mRNAs from Tritonia, generating 133.1 million 100 base pair, paired-end reads. De novo reconstruction of the RNA Seq data yielded a total of 185,546 contigs, which partitioned into 123,154 non redundant gene clusters (unigenes). BLAST comparison with RefSeq and Swiss-Prot protein databases, as well as mRNA data from other invertebrates (gastropod molluscs: Aplysia californica, Lymnaea stagnalis and Biomphalaria glabrata; cnidarian: Nematostella vectensis) revealed that up to 76,292 unigenes in the Tritonia transcriptome have putative homologues in other databases, 18,246 of which are below a more stringent E-value cut-off of 1x10-6. In silico prediction of secreted proteins from the Tritonia transcriptome shotgun assembly (TSA) produced a database of 579 unique sequences of secreted proteins, which also exhibited markedly higher expression levels compared to other genes in the TSA. CONCLUSIONS: Our efforts greatly expand the availability of gene sequences available for Tritonia diomedea. We were able to extract full length protein sequences for most queried genes, including those involved in electrical excitability, synaptic vesicle release and neurotransmission, thus confirming that the transcriptome will serve as a useful tool for probing the molecular correlates of behavior in this species. We also generated a neurosecretome database that will serve as a useful tool for probing peptidergic signalling systems in the Tritonia brain. PMID- 25719199 TI - Evaluation of wheat chromosome translocation lines for high temperature stress tolerance at grain filling stage. AB - High temperature (HT, heat) stress is detrimental to wheat (Triticum aestivum L.) production. Wild relatives of bread wheat may offer sources of HT stress tolerance genes because they grow in stressed habitats. Wheat chromosome translocation lines, produced by introgressing small segments of chromosome from wild relatives to bread wheat, were evaluated for tolerance to HT stress during the grain filling stage. Sixteen translocation lines and four wheat cultivars were grown at optimum temperature (OT) of 22/14 degrees C (day/night). Ten days after anthesis, half of the plants were exposed to HT stress of 34/26 degrees C for 16 d, and other half remained at OT. Results showed that HT stress decreased grain yield by 43% compared with OT. Decrease in individual grain weight (by 44%) was the main reason for yield decline at HT. High temperature stress had adverse effects on leaf chlorophyll content and Fv/Fm; and a significant decrease in Fv/Fm was associated with a decline in individual grain weight. Based on the heat response (heat susceptibility indices, HSIs) of physiological and yield traits to each other and to yield HSI, TA5594, TA5617, and TA5088 were highly tolerant and TA5637 and TA5640 were highly susceptible to HT stress. Our results suggest that change in Fv/Fm is a highly useful trait in screening genotypes for HT stress tolerance. This study showed that there is genetic variability among wheat chromosome translocation lines for HT stress tolerance at the grain filling stage and we suggest further screening of a larger set of translocation lines. PMID- 25719198 TI - Metabolic phenotypes in pancreatic cancer. AB - INTRODUCTION: The aim of present study was to profile the glucose-dependent and glutamine- dependent metabolism in pancreatic cancer. METHODS: We performed Immunohistochemical staining of GLUT1, CAIX, BNIP3, p62, LC3, GLUD1, and GOT1. Based on the expression of metabolism-related proteins, the metabolic phenotypes of tumors were classified into two categories, including glucose- and glutamine dependent metabolism. There were Warburg type, reverse Warburg type, mixed type, and null type in glucose-dependent metabolism, and canonical type, non-canonical type, mixed type, null type in glutamine-dependent metabolism. RESULTS: Longer overall survival was associated with high expression of BNIP3 in tumor (p = 0.010). Shorter overall survival was associated with high expression of GLUT1 in tumor (P = 0.002) and GOT1 in tumor (p = 0.030). Warburg type of glucose dependent metabolism had a highest percentage of tumors with nerve infiltration (P = 0.0003), UICC stage (P = 0.0004), and activated autophagic status in tumor (P = 0.0167). Mixed type of glucose-dependent metabolism comprised the highest percentage of tumors with positive marginal status (P<0.0001), lymphatic invasion (P<0.0001), and activated autophagic status in stroma (P = 0.0002). Mixed type and Warburg type had a significant association with shorter overall survival (P = 0.018). Non-canonical type and mixed type of glutamine-dependent metabolism comprised the highest percentage of tumors with vascular invasion (p = 0.0073), highest percentage of activated autophagy in tumors (P = 0.0034). Moreover, these two types of glutamine-dependent metabolism were significantly associated with shorter overall survival (P<0.001). Further analysis suggested that most of tumors were dependent on both glucose- and glutamine-dependent metabolism. After dividing the tumors according to the number of metabolism, we found that the increasing numbers of metabolism subtypes inversely associated with survival outcome. CONCLUSION: Warburg type, non-canonical type and mixed types of glucose- and glutamine-dependent metabolism comprised of more metabolically active, biologically aggressive and poor prognostic tumors. Moreover, the increasing subtypes and categories of the metabolism in each tumor significantly associated with poor prognosis. PMID- 25719201 TI - Technological advancement in the treatment of diabetes-ignoring psychosocial impact at our peril. PMID- 25719200 TI - Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts. AB - Ocular coloboma results from abnormal embryonic development and is often associated with additional ocular and systemic features. Coloboma is a highly heterogeneous disorder with many cases remaining unexplained. Whole exome sequencing from two cousins affected with dominant coloboma with microcornea, cataracts, and skeletal dysplasia identified a novel heterozygous allele in MAB21L2, c.151 C>G, p.(Arg51Gly); the mutation was present in all five family members with the disease and appeared de novo in the first affected generation of the three-generational pedigree. MAB21L2 encodes a protein similar to C. elegans mab-21 cell fate-determining factor; the molecular function of MAB21L2 is largely unknown. To further evaluate the role of MAB21L2, zebrafish mutants carrying a p.(Gln48Serfs*5) frameshift truncation (mab21l2Q48Sfs*5) and a p.(Arg51_Phe52del) in-frame deletion (mab21l2R51_F52del) were developed with TALEN technology. Homozygous zebrafish embryos from both lines developed variable lens and coloboma phenotypes: mab21l2Q48Sfs*5 embryos demonstrated severe lens and retinal defects with complete lethality while mab21l2R51_F52del mutants displayed a milder lens phenotype and severe coloboma with a small number of fish surviving to adulthood. Protein studies showed decreased stability for the human p.(Arg51Gly) and zebrafish p.(Arg51_Phe52del) mutant proteins and predicted a complete loss-of function for the zebrafish p.(Gln48Serfs*5) frameshift truncation. Additionally, in contrast to wild-type human MAB21L2 transcript, mutant p.(Arg51Gly) mRNA failed to efficiently rescue the ocular phenotype when injected into mab21l2Q48Sfs*5 embryos, suggesting this allele is functionally deficient. Histology, immunohistochemistry, and in situ hybridization experiments identified retinal invagination defects, an increase in cell death, abnormal proliferation patterns, and altered expression of several ocular markers in the mab21l2 mutants. These findings support the identification of MAB21L2 as a novel factor involved in human coloboma and highlight the power of genome editing manipulation in model organisms for analysis of the effects of whole exome variation in humans. PMID- 25719202 TI - Perturbation of parentally biased gene expression during interspecific hybridization. AB - Interspecific hybridization often induces epigenetic remodeling that leads to transposon activation, gene expression changes, and loss of imprinting. These genomic changes can be deleterious and contribute to postzygotic hybrid incompatibility. In Arabidopsis, loss of genomic imprinting of PHERES1 and presumed failure of Polycomb Repressive Complex contributes to seed inviability observed in A. thaliana X A. arenosa interspecific hybrids. We used this species pair to further analyze the relationship between parentally biased gene expression and postzygotic hybrid incompatibility using two A. thaliana accessions, Col-0 and C24, with differential seed survival. We found that parentally biased expression was perturbed to a similar degree in both A. thaliana hybrids for PHERES1, HDG3, and six other normally paternally expressed genes. We propose that early genome remodeling and loss of imprinting of seed development genes induces lethality in both compatible and incompatible hybrids. PMID- 25719203 TI - Effects of low-level laser therapy on changes in inflammation and in the activity of osteoblasts in the expanded premaxillary suture in an ovariectomized rat model. AB - BACKGROUND AND OBJECTIVE: Osteoporosis is a progressive systemic skeletal disease characterized by reduced bone mass/density and microarchitectural deterioration of bone tissue. Bone formation initially exceeds bone resorption, but by the third decade, such formation is reversed, resulting in a net loss of bone mass. This resorption, in turn, increases bone fragility and susceptibility to fracture. This study aimed to evaluate the effects of low-level laser therapy (LLLT) on bone regeneration in the expanded premaxillary suture in an ovariectomized rat model. METHODS: Thirty-two 12-week-old female Wistar albino rats were used in the experiment. All of the animals underwent ovariectomy 3 months before the experiment. Expansion appliances were affixed to the maxillary incisors for the expansion of premaxillary sutures. The premaxillary sutures of the laser group were exposed to 5 J/cm(2) laser energy, and no treatment was performed for the controls. All the rats in both groups were euthanized on either the 7th day (n=8) [end of expansion period; Laser Group 1(LG1) and Control Group 1 (CG1)] or the 17th day (n=8) [end of retention period; Laser Group 2 (LG2) and Control Group 2 (CG2)], respectively, for histological assessment. RESULTS: Histological findings indicated that the LG1 group showed a significantly higher number of osteoblasts than did the CG1 group (p=0.028). The CG1 and CG2 groups showed a significantly higher number of osteoclasts than did the LG1 and LG2 groups, respectively (p=0.005), (p=0.032). The LG2 group exhibited a capillary increase similar to that of the other groups, without statistically significant differences. CONCLUSIONS: On the basis of our methodology and results, we conclude that low-level laser associated with rapid maxillary expansion influences bone regeneration in sutures, thereby accelerating healing, even in ovariectomized rats. We found that LLLT decreased osteoclastic activity in the ovariectomized rats. Therefore, preventing osteoporosis necessitates further investigations to clarify the effect of LLLT on postmenopausal patients. PMID- 25719204 TI - Contrasting taxonomic and phylogenetic diversity responses to forest modifications: comparisons of taxa and successive plant life stages in South African scarp forest. AB - The degradation of natural forests to modified forests threatens subtropical and tropical biodiversity worldwide. Yet, species responses to forest modification vary considerably. Furthermore, effects of forest modification can differ, whether with respect to diversity components (taxonomic or phylogenetic) or to local (alpha-diversity) and regional (beta-diversity) spatial scales. This real world complexity has so far hampered our understanding of subtropical and tropical biodiversity patterns in human-modified forest landscapes. In a subtropical South African forest landscape, we studied the responses of three successive plant life stages (adult trees, saplings, seedlings) and of birds to five different types of forest modification distinguished by the degree of within forest disturbance and forest loss. Responses of the two taxa differed markedly. Thus, the taxonomic alpha-diversity of birds was negatively correlated with the diversity of all plant life stages and, contrary to plant diversity, increased with forest disturbance. Conversely, forest disturbance reduced the phylogenetic alpha-diversity of all plant life stages but not that of birds. Forest loss neither affected taxonomic nor phylogenetic diversity of any taxon. On the regional scale, taxonomic but not phylogenetic beta-diversity of both taxa was well predicted by variation in forest disturbance and forest loss. In contrast to adult trees, the phylogenetic diversity of saplings and seedlings showed signs of contemporary environmental filtering. In conclusion, forest modification in this subtropical landscape strongly shaped both local and regional biodiversity but with contrasting outcomes. Phylogenetic diversity of plants may be more threatened than that of mobile species such as birds. The reduced phylogenetic diversity of saplings and seedlings suggests losses in biodiversity that are not visible in adult trees, potentially indicating time-lags and contemporary shifts in forest regeneration. The different responses of taxonomic and phylogenetic diversity to forest modifications imply that biodiversity conservation in this subtropical landscape requires the preservation of natural and modified forests. PMID- 25719205 TI - Ten simple rules for lifelong learning, according to Hamming. PMID- 25719206 TI - Coupled two-dimensional main-chain torsional potential for protein dynamics II: performance and validation. AB - The accuracy of force fields is of utmost importance in molecular modeling of proteins. Despite successful applications of force fields for about the past 30 years, some inherent flaws lying in force fields, such as biased secondary propensities and fixed atomic charges, have been observed in different aspects of biomolecular research; hence, a correction to current force fields is desirable. Because of the simplified functional form and the limited number of parameters for main chain torsion (MCT) in traditional force fields, it is not easy to propose an exquisite force field that is well-balanced among various conformations. Recently, AMBER-compatible force fields with coupled MCT term have been proposed, which show some improvement over AMBER03 and AMBER99SB force fields. In this work, further calibration of the torsional parameters has been conducted by changing the solvation model in quantum mechanical calculation and minimizing the deviation from the nuclear magnetic resonance experiments for some benchmark model systems and a folded protein. The results show that the revised force fields give excellent agreement with experiments in J coupling, chemical shifts, and secondary structure populations. In addition, the polarization effect is found to be crucial for the systems with ordered secondary structures. PMID- 25719207 TI - Deconstructing the DGAT1 enzyme: membrane interactions at substrate binding sites. AB - Diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in the triacylglyceride synthesis pathway. Bovine DGAT1 is an endoplasmic reticulum membrane-bound protein associated with the regulation of fat content in milk and meat. The aim of this study was to evaluate the interaction of DGAT1 peptides corresponding to putative substrate binding sites with different types of model membranes. Whilst these peptides are predicted to be located in an extramembranous loop of the membrane-bound protein, their hydrophobic substrates are membrane-bound molecules. In this study, peptides corresponding to the binding sites of the two substrates involved in the reaction were examined in the presence of model membranes in order to probe potential interactions between them that might influence the subsequent binding of the substrates. Whilst the conformation of one of the peptides changed upon binding several types of micelles regardless of their surface charge, suggesting binding to hydrophobic domains, the other peptide bound strongly to negatively-charged model membranes. This binding was accompanied by a change in conformation, and produced leakage of the liposome entrapped dye calcein. The different hydrophobic and electrostatic interactions observed suggest the peptides may be involved in the interactions of the enzyme with membrane surfaces, facilitating access of the catalytic histidine to the triacylglycerol substrates. PMID- 25719208 TI - C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings. AB - OBJECTIVE: The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. DESIGN: Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naive adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). METHODS: We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-gamma), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-alpha), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. RESULTS: Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. CONCLUSION: Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators. PMID- 25719209 TI - Hox genes control vertebrate body elongation by collinear Wnt repression. AB - In vertebrates, the total number of vertebrae is precisely defined. Vertebrae derive from embryonic somites that are continuously produced posteriorly from the presomitic mesoderm (PSM) during body formation. We show that in the chicken embryo, activation of posterior Hox genes (paralogs 9-13) in the tail-bud correlates with the slowing down of axis elongation. Our data indicate that a subset of progressively more posterior Hox genes, which are collinearly activated in vertebral precursors, repress Wnt activity with increasing strength. This leads to a graded repression of the Brachyury/T transcription factor, reducing mesoderm ingression and slowing down the elongation process. Due to the continuation of somite formation, this mechanism leads to the progressive reduction of PSM size. This ultimately brings the retinoic acid (RA)-producing segmented region in close vicinity to the tail bud, potentially accounting for the termination of segmentation and axis elongation. PMID- 25719211 TI - The unforeseen challenge: from genotype-to-phenotype in cell populations. AB - Biological cells present a paradox, in that they show simultaneous stability and flexibility, allowing them to adapt to new environments and to evolve over time. The emergence of stable cell states depends on genotype-to-phenotype associations, which essentially reflect the organization of gene regulatory modes. The view taken here is that cell-state organization is a dynamical process in which the molecular disorder manifests itself in a macroscopic order. The genome does not determine the ordered cell state; rather, it participates in this process by providing a set of constraints on the spectrum of regulatory modes, analogous to boundary conditions in physical dynamical systems. We have developed an experimental framework, in which cell populations are exposed to unforeseen challenges; novel perturbations they had not encountered before along their evolutionary history. This approach allows an unbiased view of cell dynamics, uncovering the potential of cells to evolve and develop adapted stable states. In the last decade, our experiments have revealed a coherent set of observations within this framework, painting a picture of the living cell that in many ways is not aligned with the conventional one. Of particular importance here, is our finding that adaptation of cell-state organization is essentially an efficient exploratory dynamical process rather than one founded on random mutations. Based on our framework, a set of concepts underlying cell-state organization exploration evolving by global, non-specific, dynamics of gene activity-is presented here. These concepts have significant consequences for our understanding of the emergence and stabilization of a cell phenotype in diverse biological contexts. Their implications are discussed for three major areas of biological inquiry: evolution, cell differentiation and cancer. There is currently no unified theoretical framework encompassing the emergence of order, a stable state, in the living cell. Hopefully, the integrated picture described here will provide a modest contribution towards a physics theory of the cell. PMID- 25719210 TI - The transcriptional response to tumorigenic polarity loss in Drosophila. AB - Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. The polarity regulators of the Drosophila Scribble (Scrib) module are potent tumor suppressors and provide a model for mechanistic investigation. RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. Prominent among these is upregulation of cytokine-like Unpaired (Upd) ligands, which drive tumor overgrowth. We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive. PMID- 25719212 TI - Bone morphogenetic protein-2 nonviral gene therapy in a goat iliac crest model for bone formation. AB - Treatment and reconstruction of large bone defects, delayed unions, and nonunions is challenging and has resulted in an ongoing search for novel tissue-engineered therapies. Bone morphogenetic protein-2 (BMP-2) gene therapy is a promising strategy to provide sustained production of BMP-2 locally. Alginate polymer-based nonviral gene therapy with BMP-2 plasmid DNA (pBMP-2) in constructs with multipotent mesenchymal stromal cells (MSCs) has resulted in prolonged gene expression and bone formation in vivo. To further translate this technology toward larger animal models, important issues remain to be investigated, such as the necessity of seeded cells as a target for gene therapy. For that purpose, a large animal-screening model in an orthotopic location, with fully separated chambers, was investigated. Four cylinder-shaped implants were placed in the iliac crests of ten goats. Polycaprolactone tubes around each implant allowed bone ingrowth from the underlying bone and bone marrow and ensured separation of the experimental conditions. An empty tube showed low levels of spontaneous bone ingrowth, and implantation of autologous bone indicated proper bone function with respect to remodeling and resorption. Control ceramic scaffolds were compared to scaffolds containing pBMP-2 either or not combined with seeded MSCs. Fluorochrome incorporation evaluated at 3, 6, and 9 weeks and histomorphometry at 12 weeks after implantation revealed clear differences between the groups, with pBMP-2 combined with MSCs being the most effective. The BMP-2 was demonstrated in a variety of bone-residing cells through immunohistochemistry. Further analysis indicated that multinucleated giant cells might have an important role in transgene expression. Taken together, this work introduces a large animal model for studying bone formation at multiple sites simultaneously in an orthotopic location. The model appeared robust, showed no neighboring effects, and demonstrated effectivity of combined cell and gene therapy. PMID- 25719213 TI - Main group tellurium heterocycles anchored by a P(2)(V)N(2) scaffold and their sulfur/selenium analogues. AB - A comprehensive investigation of reactions of alkali-metal derivatives of the ditelluro dianion [TePV(NtBu)(MU-NtBu)]22- (L2-, E = Te) with p-block element halides produced a series of novel heterocycles incorporating P2VN2 rings, tellurium, and group 13-16 elements. The dianion engages in Te,Te'-chelation to the metal center in Ph2Ge and R2Sn (R = tBu, nBu, Ph) derivatives; similar behavior was noted for group 14 derivatives of L2- (E = S, Se). In the case of group 13 trihalides MCl3 (M = Ga, In), neutral spirocyclic complexes (L)M[NtBu(Te)PV(MU-NtBu)2PIIIN(H)tBu)] (M = Ga, In) comprised of a Te,Te' chelated ligand L2- and a N,Te-bonded ligand resulting from loss of Te and monoprotonation were obtained. In reactions with RPCl2 (R = tBu, Ad, iPr2N) a significant difference was observed between Se- and S-containing systems. In the former case, Se,Se'-chelated derivatives were formed in high yields, whereas the N,S-chelated isomers predominated for sulfur. All complexes were characterized by multinuclear (1H, 31P, 77Se, 119Sn, and 125Te) NMR spectroscopy; this technique was especially useful in the analysis of the mixture of (L)(Se) and (L)(SeSe) obtained from the reaction of Se2Cl2 with L2- (E = Te). Single-crystal X-ray structures were obtained for the spirocyclic In complex (9), (L)GePh2 (E = Te, 10), (L)SntBu2 (E = Te, 12a); E = Se, 12aSe, E = S, 12aS) and (L)(MU-SeSe) (E = Te, 16). PMID- 25719214 TI - Perceived availability of culturally and demographically diverse photographs for health education materials, Colorado, 2010. AB - An online survey was conducted with health educators in Colorado to ascertain their needs and ability to access relevant stock art photographs for their print and electronic educational media. Health educators were dissatisfied with the cultural and demographic diversity of photographs available from their own sources or from commercial stock art websites. There was a perceived need for more photographs that would better represent their target populations. The health educators believed, furthermore, that representative visual images can help improve their message effectiveness. PMID- 25719215 TI - Diet quality and history of gestational diabetes mellitus among childbearing women, United States, 2007-2010. AB - INTRODUCTION: Women with a history of gestational diabetes mellitus (GDM) have elevated risk of developing type 2 diabetes. Diet quality plays an important role in the prevention of type 2 diabetes. We compared diet quality among childbearing women with a history of GDM with the diet quality of childbearing women without a history of GDM. METHODS: We used data from the National Health and Nutrition Examination Survey for 2007 through 2010. We included women without diabetes aged 20 to 44 years whose most recent live infant was born within the previous 10 years and who completed two 24-hour dietary recalls. The Healthy Eating Index (HEI)-2010 estimated overall and component diet quality. Multivariable linear regression models estimated the association between a history of GDM and current diet quality, adjusting for age, education, smoking status, and health risk for diabetes. RESULTS: A history of GDM was reported by 7.7% of women. Compared with women without a history of GDM, women with a history of GDM had, on average, 3.4 points lower overall diet quality (95% confidence interval [CI], -6.6 to -0.2) and 0.9 points lower score for consumption of green vegetables and beans (95% CI, -1.4 to -0.4). Other dietary component scores did not differ by history of GDM. CONCLUSION: In the United States, women with a history of GDM have lower diet quality compared with women who bore a child and do not have a history of GDM. Improving diet quality may be a strategy for preventing type 2 diabetes among childbearing women. PMID- 25719216 TI - Community cardiovascular disease risk from cross-sectional general practice clinical data: a spatial analysis. AB - INTRODUCTION: Cardiovascular disease (CVD) continues to be a leading cause of illness and death among adults worldwide. The objective of this study was to calculate a CVD risk score from general practice (GP) clinical records and assess spatial variations of CVD risk in communities. METHODS: We used GP clinical data for 4,740 men and women aged 30 to 74 years with no history of CVD. A 10-year absolute CVD risk score was calculated based on the Framingham risk equation. The individual risk scores were aggregated within each Statistical Area Level One (SA1) to predict the level of CVD risk in that area. Finally, the pattern of CVD risk was visualized to highlight communities with high and low risk of CVD. RESULTS: The overall 10-year risk of CVD in our sample population was 14.6% (95% confidence interval [CI], 14.3%-14.9%). Of the 4,740 patients in our study, 26.7% were at high risk, 29.8% were at moderate risk, and 43.5% were at low risk for CVD over 10 years. The proportion of patients at high risk for CVD was significantly higher in the communities of low socioeconomic status. CONCLUSION: This study illustrates methods to further explore prevalence, location, and correlates of CVD to identify communities of high levels of unmet need for cardiovascular care and to enable geographic targeting of effective interventions for enhancing early and timely detection and management of CVD in those communities. PMID- 25719217 TI - State socioeconomic indicators and self-reported hypertension among US adults, 2011 behavioral risk factor surveillance system. AB - INTRODUCTION: Hypertension is the leading cause of chronic disease and premature death in the United States. To date, most risk factors for hypertension have been identified at the individual (micro) level. The association of macro-level (area) socioeconomic factors and hypertension prevalence rates in the population has not been studied extensively. METHODS: We used the 2011 Behavioral Risk Factor Surveillance System to examine whether state socioeconomic status (SES) indicators predict the prevalence of self-reported hypertension. Quintiles of state median household income, unemployment rate among the population aged 16 to 64 years, and the proportion of the population under the national poverty line were used as the proxy for state SES. Hypertension status was determined by the question "Have you ever been told by a doctor, nurse, or other health professional that you have high blood pressure?" Logistic regression was used to assess the relationship between state SES and hypertension with adjustment for individual covariates (demographic and socioeconomic factors and lifestyle behaviors). RESULTS: States with a median household income of $43,225 or less (odds ratio [95% confidence interval] = 1.16 [1.08-1.25]) and states with 18.7% or more of residents living below the poverty line (odds ratio [95% confidence interval] = 1.14 [1.04-1.24]) had a higher prevalence of hypertension than states with the most residents in the most advantageous quintile of the indicators. CONCLUSION: The observed state SES-hypertension association indicates that area SES may contribute to the burden of hypertension in community-dwelling adults. PMID- 25719219 TI - The response to dietary threonine in laying-type pullets during growth. AB - 1. This study aimed to provide information on the response of laying-type pullets to dietary threonine (THR) during three periods of growth prior to the onset of lay. Different batches of Dekalb White pullets were used in three separate trial periods (from 4 to 6, 8 to 11 and 13 to 16 weeks of age) using 8 dietary THR concentrations in each period, using a completely randomised design, and with each treatment being replicated 6 times, using 15 birds per replication in period 1 and 8 birds in periods 2 and 3. In period 1 the THR content (THRc) ranged from 2.3 to 7.6 mg/g, in period 2 from 1.7 to 5.5 mg/g, and in period 3 from 1.4 to 4.7 mg THR/g feed. 2. Body weight gain, food intake and the deposition of protein and lipid in the feather-free body and in the feathers were measured in each period. Linear regressions were fitted to all data falling below the break point defined by the broken stick regression, to estimate the efficiency of utilisation of THR. The maximum protein growth rate was 4.0 +/- 0.2, 5.3 +/- 0.4 and 3.5 +/- 0.5 g/d in periods 1, 2 and 3, respectively. 3. The efficiency of utilisation of dietary THR for THR deposition in each period was the same, at 0.85 +/- 0.1 mg/mg. As dietary THRc decreased, the amount of body lipid deposition increased. 4. With this information, it is possible to determine the daily requirement for THR for the potential growth of body and feather protein in growing pullets. PMID- 25719218 TI - Radioresistance in a human laryngeal squamous cell carcinoma cell line is associated with DNA methylation changes and topoisomerase II alpha. AB - Accumulating evidence suggests that changes in methylation patterns may help mediate the sensitivity or resistance of cancer cells to ionizing radiation. The present study provides evidence for the involvement of radioresistance-induced DNA methylation changes in tumor radioresistance. We established radioresistant laryngeal cancer cells via long-term fractionated irradiation, and examined differences in DNA methylation between control and radioresistant laryngeal cancer cells. Interestingly, we found that the promoter-CpG islands of 5 previously identified radioresistance-related genes (TOPO2A, PLXDC2, ETNK2, GFI1, and IL12B) were significantly altered in the radioresistant laryngeal cancer cells. Furthermore, the demethylation of these gene promoters with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) increased their transcription levels. Treatment with 5-aza-2'-deoxycytidine also sensitized the radioresistant laryngeal cancer cells to irradiation, indicating that changes in DNA methylation contributed to their radioresistance. Of the tested genes, the expression and activity levels of TOPO2A were tightly associated with the radioresistant phenotype in our system, suggesting that the hypermethylation of TOPO2A might be involved in this radioresistance. Collectively, our data suggest that radiation-induced epigenetic changes can modulate the radioresistance of laryngeal cancer cells, and thus may prove useful as prognostic indicators for radiotherapy. PMID- 25719220 TI - Diagnostic potential of peritoneal fluid biomarkers of endometriosis. AB - Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus, in different parts of the peritoneal cavity. It affects up to 10% of reproductive-age women and up to 50% of women with infertility. Surgical diagnosis of endometriosis is still the gold standard, with no diagnostic biomarkers available. Medical therapies target the symptoms and not the disease itself, and surgical treatment cannot prevent recurrence. As peritoneal fluid reflects the altered peritoneal microenvironment of endometriosis patients, it can provide a wealth of information on pathophysiological processes and potential biomarkers. This report reviews the molecular biomarkers identified in peritoneal fluid over the last 5 years and discusses their potential applications for diagnosis, prognosis and drug therapy. PMID- 25719221 TI - Safety, reliability, and operability of cochlear implant electrode arrays coated with biocompatible polymer. AB - CONCLUSION: Polymer-coated electrodes can reduce surgically-induced trauma associated with the insertion of a cochlear implant (CI) electrode array. OBJECTIVES: To evaluate if insertion trauma in CI surgery can be reduced by using electrode arrays coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer. METHODS: We analyzed characteristics of the Contour Advance electrode arrays coated with MPC polymer. To assess surgical trauma during electrode insertion, polymer-coated or uncoated (n = 5 each) animal electrode arrays were implanted in guinea pig cochleae and operability and electrophysiological and histological changes were assessed. RESULTS: Under light and scanning electron microscopy, polymer-coated electrodes did not appear different from uncoated electrodes, and no change was observed after mechanical stressing of the arrays. Electrode insertion was significantly easier when polymer-coated electrodes were used. Auditory brainstem response (ABR) thresholds did not differ between groups, but p1-n1 amplitudes of the coated group were larger compared with the uncoated group at 32 kHz at 28 days after surgery. The survival of outer hair cells and spiral ganglion cells was significantly greater in the polymer-coated group. PMID- 25719222 TI - Endoscopic retrograde cholangiopancreatography versus intraoperative cholangiography for diagnosis of common bile duct stones. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) and intraoperative cholangiography (IOC) are tests used in the diagnosis of common bile duct stones in people suspected of having common bile duct stones. There has been no systematic review of the diagnostic accuracy of ERCP and IOC. OBJECTIVES: To determine and compare the accuracy of ERCP and IOC for the diagnosis of common bile duct stones. SEARCH METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov to September 2012. To identify additional studies, we searched the references of included studies and systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects (DARE)), Health Technology Assessment (HTA), Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included studies that provided the number of true positives, false positives, false negatives, and true negatives for ERCP or IOC. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct, or symptom-free follow-up for at least six months for a negative test as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones; with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors screened abstracts and selected studies for inclusion independently. DATA COLLECTION AND ANALYSIS: Two authors independently collected data from each study. We used the bivariate model to summarise the sensitivity and specificity of the tests. MAIN RESULTS: We identified five studies including 318 participants (180 participants with and 138 participants without common bile duct stones) that reported the diagnostic accuracy of ERCP and five studies including 654 participants (125 participants with and 529 participants without common bile duct stones) that reported the diagnostic accuracy of IOC. Most studies included people with symptoms (participants with jaundice or pancreatitis) suspected of having common bile duct stones based on blood tests, ultrasound, or both, prior to the performance of ERCP or IOC. Most studies included participants who had not previously undergone removal of the gallbladder (cholecystectomy). None of the included studies was of high methodological quality as evaluated by the QUADAS-2 tool (quality assessment tool for diagnostic accuracy studies). The sensitivities of ERCP ranged between 0.67 and 0.94 and the specificities ranged between 0.92 and 1.00. For ERCP, the summary sensitivity was 0.83 (95% confidence interval (CI) 0.72 to 0.90) and specificity was 0.99 (95% CI 0.94 to 1.00). The sensitivities of IOC ranged between 0.75 and 1.00 and the specificities ranged between 0.96 and 1.00. For IOC, the summary sensitivity was 0.99 (95% CI 0.83 to 1.00) and specificity was 0.99 (95% CI 0.95 to 1.00). For ERCP, at the median pre-test probability of common bile duct stones of 0.35 estimated from the included studies (i.e., 35% of people suspected of having common bile duct stones were confirmed to have gallstones by the reference standard), the post-test probabilities associated with positive test results was 0.97 (95% CI 0.88 to 0.99) and negative test results was 0.09 (95% CI 0.05 to 0.14). For IOC, at the median pre-test probability of common bile duct stones of 0.35, the post-test probabilities associated with positive test results was 0.98 (95% CI 0.85 to 1.00) and negative test results was 0.01 (95% CI 0.00 to 0.10). There was weak evidence of a difference in sensitivity (P value = 0.05) with IOC showing higher sensitivity than ERCP. There was no evidence of a difference in specificity (P value = 0.7) with both tests having similar specificity. AUTHORS' CONCLUSIONS: Although the sensitivity of IOC appeared to be better than that of ERCP, this finding may be unreliable because none of the studies compared both tests in the same study populations and most of the studies were methodologically flawed. It appears that both tests were fairly accurate in guiding further invasive treatment as most people diagnosed with common bile duct stones by these tests had common bile duct stones. Some people may have common bile duct stones in spite of having a negative ERCP or IOC result. Such people may have to be re tested if the clinical suspicion of common bile duct stones is very high because of their symptoms or persistently abnormal liver function tests. However, the results should be interpreted with caution given the limited quantity and quality of the evidence. PMID- 25719223 TI - Ultrasound versus liver function tests for diagnosis of common bile duct stones. AB - BACKGROUND: Ultrasound and liver function tests (serum bilirubin and serum alkaline phosphatase) are used as screening tests for the diagnosis of common bile duct stones in people suspected of having common bile duct stones. There has been no systematic review of the diagnostic accuracy of ultrasound and liver function tests. OBJECTIVES: To determine and compare the accuracy of ultrasound versus liver function tests for the diagnosis of common bile duct stones. SEARCH METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov to September 2012. We searched the references of included studies to identify further studies and systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects, Health Technology Assessment, Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included studies that provided the number of true positives, false positives, false negatives, and true negatives for ultrasound, serum bilirubin, or serum alkaline phosphatase. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test result, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct, or symptom-free follow-up for at least six months for a negative test result as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones, with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors screened abstracts and selected studies for inclusion independently. DATA COLLECTION AND ANALYSIS: Two authors independently collected data from each study. Where meta-analysis was possible, we used the bivariate model to summarise sensitivity and specificity. MAIN RESULTS: Five studies including 523 participants reported the diagnostic accuracy of ultrasound. One studies (262 participants) compared the accuracy of ultrasound, serum bilirubin and serum alkaline phosphatase in the same participants. All the studies included people with symptoms. One study included only participants without previous cholecystectomy but this information was not available from the remaining studies. All the studies were of poor methodological quality. The sensitivities for ultrasound ranged from 0.32 to 1.00, and the specificities ranged from 0.77 to 0.97. The summary sensitivity was 0.73 (95% CI 0.44 to 0.90) and the specificity was 0.91 (95% CI 0.84 to 0.95). At the median pre-test probability of common bile duct stones of 0.408, the post-test probability (95% CI) associated with positive ultrasound tests was 0.85 (95% CI 0.75 to 0.91), and negative ultrasound tests was 0.17 (95% CI 0.08 to 0.33).The single study of liver function tests reported diagnostic accuracy at two cut-offs for bilirubin (greater than 22.23 MUmol/L and greater than twice the normal limit) and two cut-offs for alkaline phosphatase (greater than 125 IU/L and greater than twice the normal limit). This study also assessed ultrasound and reported higher sensitivities for bilirubin and alkaline phosphatase at both cut offs but the specificities of the markers were higher at only the greater than twice the normal limit cut-off. The sensitivity for ultrasound was 0.32 (95% CI 0.15 to 0.54), bilirubin (cut-off greater than 22.23 MUmol/L) was 0.84 (95% CI 0.64 to 0.95), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.92 (95% CI 0.74 to 0.99). The specificity for ultrasound was 0.95 (95% CI 0.91 to 0.97), bilirubin (cut-off greater than 22.23 MUmol/L) was 0.91 (95% CI 0.86 to 0.94), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.79 (95% CI 0.74 to 0.84). No study reported the diagnostic accuracy of a combination of bilirubin and alkaline phosphatase, or combinations with ultrasound. AUTHORS' CONCLUSIONS: Many people may have common bile duct stones in spite of having a negative ultrasound or liver function test. Such people may have to be re-tested with other modalities if the clinical suspicion of common bile duct stones is very high because of their symptoms. False-positive results are also possible and further non-invasive testing is recommended to confirm common bile duct stones to avoid the risks of invasive testing.It should be noted that these results were based on few studies of poor methodological quality and the results for ultrasound varied considerably between studies. Therefore, the results should be interpreted with caution. Further studies of high methodological quality are necessary to determine the diagnostic accuracy of ultrasound and liver function tests. PMID- 25719224 TI - Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones. AB - BACKGROUND: Endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) are tests used in the diagnosis of common bile duct stones in patients suspected of having common bile duct stones prior to undergoing invasive treatment. There has been no systematic review of the accuracy of EUS and MRCP in the diagnosis of common bile duct stones using appropriate reference standards. OBJECTIVES: To determine and compare the accuracy of EUS and MRCP for the diagnosis of common bile duct stones. SEARCH METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov until September 2012. We searched the references of included studies to identify further studies and of systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included studies that provided the number of true positives, false positives, false negatives, and true negatives for EUS or MRCP. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct or symptom free follow-up for at least six months for a negative test, as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones, with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors independently screened abstracts and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently collected the data from each study. We used the bivariate model to obtain pooled estimates of sensitivity and specificity. MAIN RESULTS: We included a total of 18 studies involving 2366 participants (976 participants with common bile duct stones and 1390 participants without common bile duct stones). Eleven studies evaluated EUS alone, and five studies evaluated MRCP alone. Two studies evaluated both tests. Most studies included patients who were suspected of having common bile duct stones based on abnormal liver function tests; abnormal transabdominal ultrasound; symptoms such as obstructive jaundice, cholangitis, or pancreatitis; or a combination of the above. The proportion of participants who had undergone cholecystectomy varied across studies. Not one of the studies was of high methodological quality. For EUS, the sensitivities ranged between 0.75 and 1.00 and the specificities ranged between 0.85 and 1.00. The summary sensitivity (95% confidence interval (CI)) and specificity (95% CI) of the 13 studies that evaluated EUS (1537 participants; 686 cases and 851 participants without common bile duct stones) were 0.95 (95% CI 0.91 to 0.97) and 0.97 (95% CI 0.94 to 0.99). For MRCP, the sensitivities ranged between 0.77 and 1.00 and the specificities ranged between 0.73 and 0.99. The summary sensitivity and specificity of the seven studies that evaluated MRCP (996 participants; 361 cases and 635 participants without common bile duct stones) were 0.93 (95% CI 0.87 to 0.96) and 0.96 (95% CI 0.90 to 0.98). There was no evidence of a difference in sensitivity or specificity between EUS and MRCP (P value = 0.5). From the included studies, at the median pre-test probability of common bile duct stones of 41% the post test probabilities (with 95% CI) associated with positive and negative EUS test results were 0.96 (95% CI 0.92 to 0.98) and 0.03 (95% CI 0.02 to 0.06). At the same pre-test probability, the post-test probabilities associated with positive and negative MRCP test results were 0.94 (95% CI 0.87 to 0.97) and 0.05 (95% CI 0.03 to 0.09). AUTHORS' CONCLUSIONS: Both EUS and MRCP have high diagnostic accuracy for detection of common bile duct stones. People with positive EUS or MRCP should undergo endoscopic or surgical extraction of common bile duct stones and those with negative EUS or MRCP do not need further invasive tests. However, if the symptoms persist, further investigations will be indicated. The two tests are similar in terms of diagnostic accuracy and the choice of which test to use will be informed by availability and contra-indications to each test. However, it should be noted that the results are based on studies of poor methodological quality and so the results should be interpreted with caution. Further studies that are of high methodological quality are necessary to determine the diagnostic accuracy of EUS and MRCP for the diagnosis of common bile duct stones. PMID- 25719225 TI - A new biomimetic route to engineer enzymatically active mechano-responsive materials. AB - Using modified beta-galactosidase covalently linked to cross-linked polyelectrolyte multilayers (PEM), catalytically active materials have been designed. Their enzymatic activity can be modulated, partially in a reversible way, simply by stretching. This strategy, based on enzyme conformational changes, constitutes a new tool for the development of biocatalytic mechano-responsive materials. PMID- 25719226 TI - Measurements of long-range interactions between protein-functionalized surfaces by total internal reflection microscopy. AB - Understanding the interaction between protein-functionalized surfaces is an important subject in a variety of protein-related processes, ranging from coatings for biomedical implants to targeted drug carriers and biosensors. In this work, utilizing a total internal reflection microscope (TIRM), we have directly measured the interactions between micron-sized particles decorated with three types of common proteins concanavalin A (ConA), bovine serum albumin (BSA), lysozyme (LYZ), and glass surface coated with soy proteins (SP). Our results show that the protein adsorption greatly affects the charge property of the surfaces, and the interactions between those protein-functionalized surfaces depend on solution pH values. At pH 7.5-10.0, all these three protein-functionalized particles are highly negatively charged, and they move freely above the negatively charged SP-functionalized surface. The net interaction between protein functionalized surfaces captured by TIRM was found as a long-range, nonspecific double-layer repulsion. When pH was decreased to 5.0, both protein-functionalized surfaces became neutral and double-layer repulsion was greatly reduced, resulting in adhesion of all three protein-functionalized particles to the SP functionalized surface due to the hydrophobic attraction. The situation is very different at pH = 4.0: BSA-decorated particles, which are highly charged, can move freely above the SP-functionalized surfaces, while ConA- and LYZ-decorated particles can only move restrictively in a limited range. Our results quantify these nonspecific kT-scale interactions between protein-functionalized surfaces, which will enable the design of surfaces for use in biomedical applications and study of biomolecular interactions. PMID- 25719227 TI - The influence of gender and age on the association between "fat-talk" and disordered eating: an examination in men and women from their 20s to their 50s. AB - Fat-talk is a common experience in college-aged women, yet little is known about fat-talk in men and across the lifespan. Exposure to fat-talk was compared in a large sample of men (n = 819) and women (n = 1,696) across four age cohorts. Greater exposure to fat-talk was associated with increased disordered eating for men and women. Men experienced less fat-talk than women. Age was negatively associated with fat-talk in women but not in men. Weaker associations between fat talk and disordered eating were found in men compared to women and in older individuals compared to younger individuals. Nonetheless, the positive association between fat-talk and disordered eating in men and women from late adolescence to midlife and beyond indicates a need to extend intervention programs to target fat-talk in men and women across the lifespan. PMID- 25719228 TI - Outcomes: Trabeculectomy Bleb Needle Revision With 5-Fluorouracil. AB - PURPOSE: To evaluate outcomes of trabeculectomy bleb needle revision with 5 fluorouracil augmentation performed in the operating theater. METHODS: Retrospective study of all patients undergoing trabeculectomy bleb needle revisions in the operating theater performed by a single surgeon in a metropolitan hospital in Australia. A total of 51 needle revisions were performed on 33 eyes over a mean follow-up time of 1.81+/-1.56 years. RESULTS: A total of 29% achieved intraocular pressure (IOP) <=20 mm Hg off all glaucoma medications, and an additional 39% achieved qualified success with the addition of glaucoma medications, giving overall success of 68%. Analyzing success rate for target IOP<=16 mm Hg, 24% achieved target off all glaucoma medications, 35% achieved qualified success with the addition of glaucoma medications, giving an overall success rate of 59%. There was a statistically significant improvement in IOP, as compared with preoperative levels, at all timepoints postoperatively (P<0.05). However, number of glaucoma medications remained unchanged (P>0.05) contributing to the high percentage of qualified successes. Visual acuity remained unchanged and there were no major postoperative complications. The Kaplan-Meier survival shows a survival rate of 60% with IOP<=20 mm Hg and 40% for IOP<=16 mm Hg at 5 years. CONCLUSIONS: Trabeculectomy needle revision is a useful option for the management of elevated IOP in the presence of a failed or failing trabeculectomy bleb. However, as with trabeculectomy, there tends to be a failure rate over time. This often leads to reinstitution of glaucoma medications and/or further needle revisions to maintain IOPs at target level. The procedure itself is minimally invasive with an acceptable safety profile. PMID- 25719229 TI - Use of Autologous Scleral Graft in Ahmed Glaucoma Valve Surgery. AB - PURPOSE: To compare the efficacy of an autoscleral free-flap graft versus an autoscleral rotational flap graft in Ahmed glaucoma valve (AGV) surgery. PATIENTS AND METHODS: Medical records (2005 to 2012) of 51 consecutive patients (51 eyes) who underwent AGV surgery with the use of either an autoscleral free-flap graft or an autoscleral rotational flap graft to cover the external tube at the limbus were retrieved for review. The main outcome measure was the incidence of tube exposure associated with each surgical approach. RESULTS: Twenty-seven consecutive patients (27 eyes) received a free-flap graft and 24 consecutive patients (24 eyes) received a rotational flap graft. The mean follow-up time was 55.6 +/- 18.3 months for the former and 24.2+/- 5 .0 months for the latter (P<0.0001). Two patients in the free-flap group (8.9%) developed tube exposure at 24 and 55 months postoperatively compared with none of the patients in the rotational flap group. Graft thinning without evidence of conjunctival erosion was observed in 15 patients (55%) in the free-flap group and in 7 patients (29.1%) in the rotational flap group. CONCLUSIONS: The use of an autoscleral rotational flap graft is an efficacious technique for primary tube patch grafting in routine AGV surgery, and yielded better results than an autoscleral free-flap graft. Its main advantages over donor graft material are availability and lower cost. PMID- 25719230 TI - Long-term results of Ahmed glaucoma valve in association with intravitreal bevacizumab in neovascular glaucoma. AB - PURPOSE: Evaluate the long-term results of the Ahmed glaucoma valve (AGV) surgery in association with bevacizumab (Avastin) in neovascular glaucoma (NVG) patients. DESIGN AND METHODS: This retrospective institutional study reviewed 39 eyes of 34 patients with NVG who underwent AGV implantation. The intravitreal bevacizumab (IVB) group included 19 eyes that received an injection of IVB 7 days preoperatively, whereas the no-IVB group included 20 eyes that did not receive any antivascular endothelial growth factor therapy. Findings such as intraocular pressure (IOP), number of antiglaucoma medications, best-corrected visual acuity (BCVA), and surgical outcomes were reviewed over a period of 5 years. RESULTS: There were no significant differences in the preoperative characteristics between the 2 groups. At last follow-up visit, IOP was 16.37+/-5.72 mm Hg in the IVB group and 20.05+/-9.75 mm Hg in the no-IVB group (P=0.16). The number of postoperative antiglaucoma medications was significantly lower in the IVB group (P=0.02). Last visit's mean BCVA was 2.34+/-1.00 logMAR in the IVB group and 2.66+/-1.04 logMAR in the control group (P=0.33). Hyphema was significantly less observed in the IVB group (P=0.02). The probability of success was 63.2% in the IVB group and 70.0% in the control group (P=0.37). CONCLUSIONS: Preoperative IVB before AGV was not associated with a better surgical success, IOP control, or BCVA. Its administration significantly decreased postoperative hyphema and number of last visit's antiglaucoma medications. PMID- 25719231 TI - Retinal Blood Vessel Distribution Correlates With the Peripapillary Retinal Nerve Fiber Layer Thickness Profile as Measured With GDx VCC and ECC. AB - PURPOSE: Aim of the present study was to evaluate whether there is a correlation between retinal blood vessel density (RVD) and the peripapillary retinal nerve fiber layer (RNFL) thickness profile. METHODS: RNFL thickness of 106 healthy subjects was measured using scanning laser polarimetry, GDx variable corneal compensation (VCC), and GDx enhanced corneal compensation (ECC). A proprietary software was developed in MATLAB to measure the peripapillary retinal vessels using scanning laser ophthalmoscopy fundus images, centered on the optic disc measured by Cirrus spectral domain optical coherence tomography. The individual retinal vessel positions and thickness values were integrated in a 64-sector RVD profile and intrasubject and intersubject correlations were calculated. RESULTS: The mean R value+/-SD for intrasubject correlation between RVD and RNFL thickness measured with GDx VCC and GDx ECC was 0.714+/-0.157 and 0.629+/-0.140, with 105 of 106 subjects presenting significant correlations. In the intersubject linear regression analysis for GDx VCC, 33 of 64 (52%) sectors presented a significant Pearson correlation coefficient between RNFL thickness and RVD values, with a mean R value of 0.187+/-0.135 (P<0.05). CONCLUSIONS: Peripapillary RNFL thickness profiles correlate with the RVD over 50% of the sectors and might explain up to 26% of the interindividual variance of the peripapillary RNFL thickness values as measured with GDx VCC. To our opinion, taking into account RVD might reduce interindividual variation in peripapillary RNFL thickness profiles measured with scanning laser polarimetry. PMID- 25719232 TI - Pattern of Macular Ganglion Cell-Inner Plexiform Layer Defect Generated by Spectral-Domain OCT in Glaucoma Patients and Normal Subjects. AB - PURPOSE: To elucidate patterns of macular ganglion cell-inner plexiform layer (GCIPL) defects by Cirrus optical coherence tomography (OCT) and examine the spatial relationship between GCIPL defect and visual field (VF) defect patterns. METHODS: A total of 116 eyes of 116 normal subjects and 111 eyes of 111 glaucoma patients were included. The 227 study subjects underwent Cirrus OCT imaging in macular cube mode and reliable standard VF testing. Two ophthalmologists blindly classified GCIPL defect patterns and VF defects. The frequency distribution of GCIPL defect patterns and spatial relationships between GCIPL defects and VF defects were investigated. RESULTS: GCIPL defect patterns were classified as minimal, inner, outer, diffuse mild, diffuse severe, inferior confined, inferior dominant, superior confined, and superior dominant defects in normal controls (71.6%, 7.8%, 4.3%, 1.7%, 0%, 10.3%, 1.7%, 1.7%, and 0.9%, respectively) and in glaucoma patients (11.7%, 3.6%, 4.5%, 7.2%, 21.6%, 22.5%, 18.0%, 4.5%, and 6.3%, respectively). In mild and moderate glaucoma patients, the inferior confined type was most frequent (21.9% and 50.0%, respectively). However, the diffuse severe type was most frequent (59.1%) in advanced glaucoma patients. The locations of the VF defects corresponded to the locations of the GCIPL defects in glaucoma patients (P=0.012). CONCLUSIONS: Glaucomatous damage of the macula was common and more frequent in the inferior retina. GCIPL defect patterns as determined by SD OCT imaging corresponded well with central VF defects. It seems macular GCIPL analysis may be useful for evaluating glaucomatous optic neuropathy. PMID- 25719233 TI - The Effect of Trabeculectomy on Astigmatism. AB - PURPOSE: To investigate the change in corneal astigmatism after trabeculectomy. PATIENTS AND METHODS: Between January and April 2012, patients who underwent a primary trabeculectomy were enrolled in this prospective study. We measured the visual acuity, automated keratorefractometry, and the intraocular pressure preoperatively and postoperatively at 1, 3, and 6 months. Changes in astigmatism were quantified using the vector analysis described by Cravy. A Friedman test and a linear model for longitudinal measures were used to compare changes in the refraction and the intraocular pressure. A binomial test was used to compare the proportion of eyes with a shift in astigmatism with or against-the-rule. RESULTS: A total of 47 eyes (47/48 patients) were included for analysis. The mean (+/-SD) intraocular pressure decreased from 17.5 +/- 5.4 mmHg preoperatively to 9.8 +/- 4.0 mmHg after 6 months (P<0.001). At this time-point, 32/47 eyes showed a shift in astigmatism with-the-rule (P=0.02), with a median difference in cylinder of +0.50 D (range, 0 to 4 D) (P=0.004). The mean (+/-SD) axis of the positive cylinder changed from 169 +/- 148 to 135 +/- 146 degrees after 6 months (P=0.12) and the mean (+/-SD) spherical equivalent changed from -0.47 +/- 2.27 to -0.07 +/ 1.93 D (P=0.15). The mean (+/-SD) logMAR was 0.17 +/- 0.22 preoperatively and 0.14 +/- 0.14 after 6 months (P=0.9). CONCLUSIONS: Trabeculectomy induced a small but statistically significant shift in astigmatism with-the-rule after 6 months. The spherical equivalent did not change compared with the preoperative value. Most often, glasses will not need to be changed after trabeculectomy. PMID- 25719234 TI - Structure-Function Correlation Using Confocal Laser Ophthalmoscope in Primary Open-Angle Glaucoma and Pseudoexfoliative Glaucoma. AB - PURPOSE: To compare Heidelberg Retina Tomograph (HRT) optic disc parameters and structure-function correlation between primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG). DESIGN: Prospective, observation case series. PATIENTS AND METHODS: A total of 54 POAG and 33 PEXG cases, consecutively recruited from a University Glaucoma Service, underwent a comprehensive ophthalmic examination, including HRT optic disc imaging. Glaucoma definition required the presence of both structural and functional damage. One eye per subject was included in the analysis. T test, Mann-Whitney U test, and analysis of covariance were used to compare HRT parameters between POAG and PEXG, adjusting for age, mean deviation (MD) in the visual field, intraocular pressure, and disc area. The correlation between HRT and MD was assessed in each group. RESULTS: Cup area (P=0.048), height variation contour (P=0.016), and cup/disc area ratio (P=0.023) were higher in POAG, whereas the mean retinal nerve fiber layer thickness (P=0.048), retinal nerve fiber layer cross-section area (P=0.044), and rim area (P=0.048) were lower in POAG, compared with PEXG. The correlation of HRT parameters with MD was significant only in the POAG group. CONCLUSIONS: At a similar level of functional damage, POAG subjects presented with more pronounced structural damage than PEXG subjects. The correlation between HRT and visual field parameters was more evident in POAG, compared with PEXG. PMID- 25719235 TI - Effectiveness of Single-Digit IOP Targets on Decreasing Global and Localized Visual Field Progression After Filtration Surgery in Eyes With Progressive Normal Tension Glaucoma. AB - PURPOSE: To examine the effectiveness of achieving single-digit intraocular pressure (IOP) targets with filtration surgery on decreasing global and localized visual field (VF) progression in eyes with progressive normal-tension glaucoma (NTG). METHODS: A retrospective chart review was conducted to identify NTG patients who underwent trabeculectomy with mitomycin C between 2006 and 2010 for progressive VF loss with preoperative IOP<=15 mm Hg during the 12 months before surgery. All eyes had glaucomatous optic neuropathy and progressive VF loss, uncontrolled IOP on maximum therapy, and a minimum of 2 baseline preoperative and 4 postoperative VF examinations. VF progression was assessed using Guided Progression Analysis (GPA) and Progressor software. RESULTS: Fifteen eyes of 14 patients (mean age 71.8+/-7.5 y) were enrolled with mean follow-up of 71+/-26 months. Mean postoperative IOP (8.5+/-3.5 mm Hg) was significantly (P<0.001) reduced compared with preoperatively (13.1+/-1.5 mm Hg). The probability of achieving an IOP goal <=10 mm Hg was 66% at 4 years' follow-up. The overall rate of postoperative VF progression using any method was 13.3% (1 eye using Progressor; 1 eye using GPA and Progressor). Average postoperative slope of MD ( 0.25+/-0.86 dB/y) and pattern SD (0.49+/-0.83 dB/y) were improved (P=0.05 and 0.07) compared with the preoperative slopes (-1.05+/-0.66 and 1.21+/-0.71 dB/y). CONCLUSIONS: Achieving single-digit IOP targets with filtration surgery has a beneficial effect on reducing global and localized rates of VF progression in NTG eyes with progression at low IOP. PMID- 25719236 TI - Evaluation of Dimensional and Flow Properties of ExPress Glaucoma Drainage Devices. AB - PURPOSE: ExPress devices are available as P50 and P200 models, the numbers related to their luminal diameters in MUm. We compared their Poiseuille's Law based theoretical resistance values with experimental values and correlated these with their luminal dimensions derived from electron microscopy. METHODS: Scanning electron microscopy was performed on P50 and P200 devices. Bench-top flow studies were performed to find the resistances of the devices. Devices were also incorporated into a perfused, ex vivo porcine sclera model to test and compare their control of pressure, with and without overlying scleral flaps, and with trabeculectomies. RESULTS: The luminal dimensions of the P200 device were 206.4+/ 3.3 and 204.5+/-0.9 MUm at the subconjunctival space and anterior chamber ends, respectively. Those of the P50 device were 205.0+/-5.8 and 206.9+/-3.7 MUm, respectively. There were no significant differences between the P200 and P50 devices (all P>0.05). The resistances of the P200 and P50 devices were 0.010+/ 0.001 and 0.054+/-0.002 mm Hg/MUL/min, respectively (P<0.05). Equilibrium pressures with overlying scleral flaps were 17.81+/-3.30 mm Hg for the P50, 17.31+/-4.24 mm Hg for the P200, and 16.28+/-6.67 mm Hg for trabeculectomies (P=0.850). CONCLUSIONS: The luminal diameters of both devices are externally similar. The effective luminal diameter of the P50 is much larger than 50 MUm. Both devices have low resistance values, making them unlikely to prevent hypotony on their own. They lead to similar equilibrium pressures as the trabeculectomy procedure when inserted under the scleral flap. PMID- 25719237 TI - Clinical Outcomes of Ahmed Glaucoma Valve Implantation With or Without Intravitreal Bevacizumab Pretreatment for Neovascular Glaucoma: A Systematic Review and Meta-Analysis. AB - PURPOSE: To evaluate the efficacy and tolerability of Ahmed glaucoma valve (AGV) implantation with intravitreal bevacizumab injection (IVB) pretreatment in the treatment of neovascular glaucoma (NVG). METHODS: A comprehensive literature search was performed according to the Cochrane collaboration methodology to identify controlled clinical trials comparing AGV implantation with (IVB group) or without IVB (control group) pretreatment for NVG. The main outcome measures were the weighted mean differences (WMDs) for intraocular pressure reduction, a reduction in glaucoma medications, odds ratio (OR) for complete success rates, and qualified success rates. Tolerability estimates were measured by OR for adverse events. RESULTS: The WMD of the intraocular pressure reduction when comparing the IVB group with the control group was 3.30 (-1.21 to 7.80). The IVB group was associated with numerically greater but nonsignificant IOP lowering efficacy compared with the control group (P=0.152). Both groups were comparable in the reduction of glaucoma medication, with a WMD of 0.28 (-0.03 to 0.59) at the follow-up endpoint (P=0.077). The IVB group was associated with significant greater complete success rates compared with the control group, with a pooled OR of 3.18 (1.41 to 7.19). However, it did not show a significant difference for the qualified success rate between them, with a pooled OR of 2.00 (0.95 to 4.21). The IVB group was associated with a significantly lower frequency of hyphema than the control group, with a pooled OR of 0.15 (0.07 to 0.32). CONCLUSION: The use of IVB pretreatment for NVG is a safe and effective additional step during AGV implantation surgery. PMID- 25719238 TI - Association of Pigmentary Glaucoma and Nonsenile Nuclear Cataracts. AB - PURPOSE: To describe a new association between nonsenile nuclear cataracts and pigmentary glaucoma in patients with controlled intraocular pressure (IOP). DESIGN: Retrospective consecutive case series of nonsenile nuclear cataracts seen in patients with pigmentary glaucoma with controlled IOP in a single glaucoma specialist practice. Eight eyes of 7 patients with pigmentary glaucoma and visually significant cataract who underwent cataract removal were reviewed. RESULTS: Patients with pigmentary glaucoma developed rapidly progressing, nonsenile nuclear cataracts, with resulting myopic shifts between 4 and 13 D from baseline in <2 years. The patients had controlled IOP and there were no associations between medication use and cataract development. CONCLUSIONS: A new association between pigmentary glaucoma and nonsenile nuclear cataracts is described. In these patients, the IOP remains controlled and no association is seen between the cataract and medication use. The cataract is rapidly progressive and can cause a myopic shift between 4 and 13 D. Awareness of the purely nuclear cataract and its' clinical presentation can assist the clinician when approaching the patient with pigment dispersion and decreasing vision. To the best of our knowledge, this is a new association and warrants further investigation. PMID- 25719239 TI - Vascular Endothelial Growth Factor is Increased in Aqueous Humor of Acute Primary Angle-Closure Eyes. AB - PURPOSE: To measure and compare the levels of vascular endothelial growth factor (VEGF) in the aqueous humor of patients with acute primary angle closure (APAC), primary angle-closure glaucoma (PACG), and normal cataract (controls). METHODS: Aqueous humor samples were prospectively collected from 38 APAC eyes, 36 PACG eyes, and 25 nonglaucomatous cataract control eyes. The levels of aqueous humor VEGF were measured using enzyme-linked immunoassays. The clinical characteristics of participants were also collected for correlation analysis. RESULTS: VEGF was detected in aqueous humor samples of 35 of 38 APAC patients (mean+/-SE of the mean, 935+/-258 pg/mL), 30 of 36 PACG patients (165+/-37.5 pg/mL), and 16 of 25 cataract controls (69.5+/-13.5 pg/mL). The mean concentration of VEGF in APAC eyes was 13.5 and 5.7 times higher than that in controls and PACG eyes, respectively, and these differences were statistically significant (both P<0.0167). In the correlation analysis that included all participants, the aqueous humor VEGF level was found to correlate negatively with axial length (rho=-0.342, P=0.001), and positively with intraocular pressure (rho=0.434, P<0.001). CONCLUSIONS: VEGF was significantly increased in aqueous humor of APAC eyes. An increase in aqueous humor VEGF may be the result of the characteristic ocular ischemia and hypoxia observed in APAC eyes as a consequence of sudden excessive increases in intraocular pressure during the acute episode. PMID- 25719240 TI - Comparison of Optical Coherence Tomography Findings in Patients With Primary Open angle Glaucoma and Parkinson Disease. AB - PURPOSE: To evaluate the peripapillary retinal nerve fiber layer (RNFL), ganglion cell complex, and macular thickness as well as their correlation with the severity of diseases. MATERIALS AND METHODS: This is a cross-sectional study and comparing both eyes of 26 patients with primary open-angle glaucoma, 25 patients with Parkinson disease (PD), and 23 healthy subjects. RNFL, ganglion cell complex, and macular thickness were measured and analyzed with optical coherence tomography (OCT) in all cases and correlation with severity of the disease was assessed in PD group. RESULTS: The mean RNFL of PD was significantly thinner compared with controls (P=0.002). In glaucoma group, the mean RNFL was significantly thinner (96.28+/-12.49 MUm) than PD (105.43+/-13.45 MUm) and the controls (113.75+/-8.53 MUm) (P<0.001; P<0.001, respectively). The global loss volume (GLV) rates in the glaucoma and PD group were significantly higher than controls, respectively (P=0.006; P<0.001/P=0.002, P=0.013). However, the GLV rate was significantly lower in PD group compared with glaucoma group (P=0.001). There was no significant correlation between OCT measurements and disease duration or severity in the PD patients. CONCLUSIONS: Although RNFL thickness and GLV changes may show the ganglion cell loss in both disease but none of the OCT parameters are correlated with the severity of PD. OCT may help to reveal the ganglion cell damage but may not help in determination of severity during the clinical follow up of PD patients. PMID- 25719242 TI - TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression. PMID- 25719241 TI - Different normalization strategies might cause inconsistent variation in circulating microRNAs in patients with hepatocellular carcinoma. AB - BACKGROUND: Circulating microRNA (miRNA) are promising biomarkers for diagnosing and prognosticating numerous diseases. Reports have demonstrated controversial or even contradictory conclusions in studies on circulating microRNA. This study aimed to evaluate the potential bias of using different reference genes for analyzing circulating microRNAs in the same malignant digestive diseases. MATERIAL AND METHODS: We measured plasma concentrations of U6-snRNA, let-7a, miRNA-21, miRNA-106a, miRNA-155, miRNA-219, miRNA-221, and miRNA-16 in patients with hepatocellular carcinoma (HCC), gastric carcinoma (GC), hepatic cirrhosis, hepatitis B, and healthy volunteers using quantitative real-time polymerase chain reaction (qPCR). The GeNorm, Normfinder, BestKeeper, and Comparative DeltaCq algorithms integrated in RefFinder were used to screen the most suitable reference genes from the candidates. The 4 commonly used statistical evaluation software packages provided different results regarding the stability of the candidate reference genes. RESULTS: RefFinder revealed miRNA-106a and miRNA-21 as the most stably expressed reference genes, with comprehensive stability values of 1.189 and 1.861, respectively. U6-snRNA was the most unstable nucleic acid in our data. When 5 normalization strategies were compared using U6-snRNA, serum volume, miRNA-106a, miRNA-21, or the mean value of miRNA-106a and miRNA-21, obvious expression bias was detected in almost all target microRNAs. Intriguingly, all these normalization strategies indicated that circulating miRNA-155 is greatly upregulated in patients with HCC and GC, but downregulated in benign hepatic disease. CONCLUSIONS: Single reference genes used without justification in plasma microRNAs produce significant analysis bias or even erroneous results. Circulating miRNA-155 may be a promising non-invasive biomarker for discriminating malignant digestive tumors from the corresponding benign diseases. PMID- 25719243 TI - The calcineurin/NFAT pathway is activated in diagnostic breast cancer cases and is essential to survival and metastasis of mammary cancer cells. AB - Nuclear factor of activated T cells 1 (NFAT1) expression has been associated with increased migratory/invasive properties of mammary tumor-derived cell lines in vitro. It is unknown, however, if NFAT activation actually occurs in breast cancer cases and whether the calcineurin/NFAT pathway is important to mammary tumorigenesis. Using a cohort of 321 diagnostic cases of the major subgroup of breast cancer, we found Cn/NFAT pathway activated in ER(-)PR(-)HER2(-) triple negative breast cancer subtype, whereas its prevalence is less in other subgroups. Using a small hairpin RNA-based gene expression silencing approach in murine mammary tumor cell line (4T1), we show that not only NFAT1 but also NFAT2 and their upstream activator Cn are essential to the migratory and invasive properties of mammary tumor cells. We also demonstrate that Cn, NFAT1 and NFAT2 are essential to the tumorigenic and metastatic properties of these cells in mice, a phenotype which coincides with increased apoptosis in vivo. Finally, global gene expression analyses identified several NFAT-deregulated genes, many of them being previously associated with mammary tumorigenesis. In particular, we identified the gene encoding a disintegrin and metalloproteinase with thrombonspondin motifs 1, as being a potential direct target of NFAT1. Thus, our results show that the Cn/NFAT pathway is activated in diagnostic cases of breast cancers and is essential to the tumorigenic and metastatic potential of mammary tumor cell line. These results suggest that pharmacological inhibition of the Cn/NFAT pathway at different levels could be of therapeutical interest for breast cancer patients. PMID- 25719244 TI - Akt phosphorylates Prohibitin 1 to mediate its mitochondrial localization and promote proliferation of bladder cancer cells. AB - Bladder cancer (BC) is very common and associated with significant morbidity and mortality, though the molecular underpinnings of its origination and progression remain poorly understood. In this study, we demonstrate that Prohibitin 1 (PHB) was overexpressed in human BC tissues and that PHB upregulation was associated with poor prognosis. We also found that PHB was necessary and sufficient for BC cell proliferation. Interestingly, the overexpressed PHB was primarily found within mitochondria, and we provide the first direct evidence that phosphorylation by Akt at Thr258 of PHB induces this mitochondrial localization. Inhibiton of Akt reverses these effects and inhibited the proliferation of BC cells. Finally, the phosphorylation of PHB was required for BC cell proliferation, further implicating the importance of the Akt in BC. Taken together, these findings identify the Akt/PHB signaling cascade as a novel mechanism of cancer cell proliferation and provide the scientific basis for the establishment of PHB as a new prognostic marker and treatment target for BC. PMID- 25719245 TI - Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush. AB - Neuritin 1 (Nrn1) is an extracellular glycophosphatidylinositol-linked protein that stimulates axonal plasticity, dendritic arborization and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized retinal ganglion cells (RGCs) in vitro and on the in vivo optic nerve crush (ONC) mouse model. Axotomized cultured RGCs treated with recombinant hNRN1 significantly increased survival of RGCs by 21% (n=6-7, P<0.01) and neurite outgrowth in RGCs by 141% compared to controls (n=15, P<0.05). RGC transduction with AAV2-CAG-hNRN1 prior to ONC promoted RGC survival (450%, n=3-7, P<0.05) and significantly preserved RGC function by 70% until 28 days post crush (dpc) (n=6, P<0.05) compared with the control AAV2-CAG-green fluorescent protein transduction group. Significantly elevated levels of RGC marker, RNA binding protein with multiple splicing (Rbpms; 73%, n=5-8, P<0.001) and growth cone marker, growth-associated protein 43 (Gap43; 36%, n=3, P<0.01) were observed 28 dpc in the retinas of the treatment group compared with the control group. Significant increase in Gap43 (100%, n=5-6, P<0.05) expression was observed within the optic nerves of the AAV2 hNRN1 group compared to controls. In conclusion, Nrn1 exhibited neuroprotective, regenerative effects and preserved RGC function on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases. PMID- 25719246 TI - p53 is active in murine stem cells and alters the transcriptome in a manner that is reminiscent of mutant p53. AB - Since it was found that p53 is highly expressed in murine embryonic stem cells, it remained a mystery whether p53 is active in this cell type. We show that a significant part of p53 is localised in the nucleus of murine embryonic stem cells and that the majority of this nuclear p53 is bound to DNA. According to its nuclear localisation, we show that p53 alters the transcriptional program of stem cells. Nevertheless, the anti-proliferative activity of p53 is compromised in stem cells, and this control is due, at least in part, to the high amount of MdmX that is present in embryonic stem cells and bound to p53. Instead of the anti proliferative activity that p53 has in differentiated cells, p53 controls transcription of pro-proliferative genes in embryonic stem cells including c-myc and c-jun. The impeded anti-proliferative activity of p53 and the induction of certain proto-oncogenes by p53 in murine embryonic stem cells can explain why stem cells proliferate efficiently despite having high levels of p53. PMID- 25719247 TI - Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation. AB - Mitochondrial fission and fusion are essential processes in the maintenance of the skeletal muscle function. The contribution of these processes to muscle development has not been properly investigated in vivo because of the early lethality of the models generated so far. To define the role of mitochondrial fission in muscle development and repair, we have generated a transgenic mouse line that overexpresses the fission-inducing protein Drp1 specifically in skeletal muscle. These mice displayed a drastic impairment in postnatal muscle growth, with reorganisation of the mitochondrial network and reduction of mtDNA quantity, without the deficiency of mitochondrial bioenergetics. Importantly we found that Drp1 overexpression activates the stress-induced PKR/eIF2alpha/Fgf21 pathway thus leading to an attenuated protein synthesis and downregulation of the growth hormone pathway. These results reveal for the first time how mitochondrial network dynamics influence muscle growth and shed light on aspects of muscle physiology relevant in human muscle pathologies. PMID- 25719248 TI - Mitochondrial DNA copy number is regulated by DNA methylation and demethylation of POLGA in stem and cancer cells and their differentiated progeny. AB - Mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation so that cells with a high requirement for ATP generated through oxidative phosphorylation have high mtDNA copy number, whereas those with a low requirement have few copies. Using immunoprecipitation of DNA methylation on 5 methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), which distinguish between de novo DNA methylation and demethylation, respectively, we set out to determine whether DNA methylation at exon 2 of the human mtDNA-specific polymerase (DNA polymerase gamma A (POLGA)) regulates cell-specific mtDNA copy number in highly proliferative and terminally differentiated cells. Highly proliferative cancer and pluripotent and multipotent cells possessed low mtDNA copy number and were highly methylated at exon 2 of POLGA in contrast to post mitotic cells. Unlike neural stem cells, cancer cells were unable to differentiate and remained extensively DNA methylated at exon 2 of POLGA. However, mtDNA depletion of cancer cells reduced DNA methylation at exon 2 of POLGA as they replenished mtDNA to form tumours in mice. Glioblastoma cells treated with the DNA demethylation agent 5-azacytidine over 28 days of astrocyte induced differentiation demethylated exon 2 of POLGA leading to increased mtDNA copy number and expression of the astrocyte endpoint marker glial fibrillary acidic protein (GFAP). However, the demethylation agent vitamin C (VitC) was unable to sustain increased mtDNA copy number and differentiation, as was the case when VitC was withdrawn after short-term treatment. These data demonstrate that DNA demethylation of POLGA is an essential regulator of mtDNA copy number and cellular fate and that cancer cells are only able to modulate DNA methylation of POLGA and mtDNA copy number in the presence of a DNA demethylation agent that inhibits de novo methyltransferase 1 activity. PMID- 25719249 TI - Low expression of long noncoding RNA PANDAR predicts a poor prognosis of non small cell lung cancer and affects cell apoptosis by regulating Bcl-2. AB - Recently, a novel class of transcripts, long noncoding RNAs (lncRNAs), is involved in diseases including cancer. Here, we investigated the the role of lncRNA PANDAR in the progression of non-small cell lung carcinoma (NSCLC). PANDAR, interacting with NF-YA, was generally downregulated in NSCLC tissues. In a cohort of 140 NSCLC patients, decreased PANDAR expression was negatively correlated with greater tumor size (P<0.001) and advanced TNM stage (P=0.002). Moreover, PANDAR could serve as an independent predictor for overall survival in NSCLC (P=0.015). Further experiments demonstrated that PANDAR expression was induced by p53, and chromatin immunoprecipitation (ChIP) assays confirmed that PANDAR was a direct transcriptional target of p53 in NSCLC cells. PANDAR overexpression significantly repressed the proliferation in vitro and in vivo. We also showed that PANDAR-mediated growth regulation is in part due to the transcriptional modulation of Bcl-2 by interacting with NF-YA, thus affecting NSCLC cell apoptosis. To our knowledge, this is the first report which showed the role of PANDAR in the progression of NSCLC. The p53/PANDAR/NF-YA/Bcl-2 interaction might serve as targets for NSCLC diagnosis and therapy. PMID- 25719251 TI - Mitomycin C-associated scleral stromalysis after pterygium surgery. AB - PURPOSE: To describe complications after use of mitomycin C (MMC) as a surgical adjuvant in pterygium surgery. METHODS: This is a retrospective chart review of patients presenting to a tertiary referral center over a 7-year period with a diagnosis of scleral stromalysis after previous pterygium removal. RESULTS: Sixteen eyes of 15 patients were identified with scleral stromalysis after pterygium surgery with the use of adjuvant MMC. Three eyes were excluded because of insufficient chart information or previous beta-irradiation treatment. Twelve of 13 eyes underwent surgical treatment for primary pterygium, and 1 eye was treated for recurrent pterygium. Time from initial pterygium surgery to presentation ranged from 1 month to 10 years. Dosage and routes of MMC administration included 0.02% intraoperative application to either the bare sclera or Tenon capsule with a range of 30 seconds to 3 minutes or topical administration 4 times daily for 2 weeks. In some cases, the dose and route of MMC administration were unknown. Four of 13 patients (31%) required a scleral patch graft with 1 patient (8%) requiring multiple patch grafts. CONCLUSIONS: Use of MMC in various forms and concentrations can cause devastating complications including scleral stromalysis. Scleral stromalysis may present anywhere from months to years after application. We suggest that MMC should be used with extreme caution when used as a surgical adjuvant for pterygium surgery. Patients must be urged to continue long-term follow-up after MMC use because of the potential for future anterior segment complications. PMID- 25719250 TI - Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation. AB - Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects. PMID- 25719252 TI - Comparison of 4 specular microscopes in healthy eyes and eyes with cornea guttata or corneal grafts. AB - PURPOSE: The aim of this study was to compare 4 noncontact specular microscopes for the assessment of the corneal endothelium in a heterogeneous sample of eyes. METHODS: This prospective study included 22 healthy eyes, 16 eyes with cornea guttata and 31 eyes that had undergone penetrating keratoplasty or Descemet stripping automated endothelial keratoplasty. Corneal endothelial cell parameters of all eyes were assessed with the CellChek XL (Konan Medical, Hyogo, Japan), Perseus (Bon Optic, Lubeck, Germany), EM-3000 (Tomey, Nagoya, Japan), and CEM-530 (Nidek Co, Ltd, Gamagori, Japan) in a randomized order. Bland-Altman plots of interdevice agreement were produced. The time taken for data entry, scanning, and automated image analysis was recorded, and instrument repeatability was analyzed. RESULTS: The mean age was 61 +/- 19 years (range, 24-88). The measurement success rate was 100% in healthy corneas, ranged between 64.5% and 93.5% in eyes with corneal grafts, and between 0% and 18.8% in eyes with cornea guttata. Comparative analysis of endothelial cell parameters revealed significant differences in endothelial cell density readings in the total study population and in subgroups (P < 0.01). CONCLUSIONS: The CEM-530 and Perseus were extremely fast, showed highly repeatable measurements, and are recommendable for screening purposes. The CellChek XL device was slower, but extensive postprocessing options and an exportable database make this instrument suitable for compromised corneas and for research purposes. The EM-3000 device ranged between the fast devices and the CellChek XL and comes with reliable automated cell-counting software. However, careful interpretation of results from automated image analysis software is mandatory. PMID- 25719253 TI - Oral omega-3 fatty acid treatment for dry eye in contact lens wearers. AB - PURPOSE: The aim of this study was to evaluate the effect of dietary omega-3 fatty acid (O3FA) supplementation on dry eye symptoms, tear film tests, and conjunctival impression cytology in patients with contact lens wear-associated dry eye. METHODS: In this randomized, double-blind, multicentric trial, contact lens wearers (n = 496) were randomized to receive either O3FAs or placebo capsules (corn oil) twice daily for 6 months. Subjects underwent examinations at baseline, 3 months, and 6 months. At each visit, a questionnaire of dry eye symptoms and lens wear comfort was administered. Subjects further underwent measurement of tear film break-up time (TBUT) and a Schirmer test. Conjunctival impression cytology was performed by the transfer method. Improvement in symptoms and lens wear comfort were primary outcome measures. Changes from baseline in TBUT, Schirmer, and Nelson grade at 6 months were secondary outcome measures. RESULTS: The mean improvement in symptom score in the O3FA group was 4.7 +/- 2 (2.0) as compared with 0.5 +/- 2 (0.9) in the placebo group (P < 0.0001). Lens wear comfort levels improved significantly (P < 0.0001) from baseline. There was a significant increase in TBUT [3.3 +/- 2 (1.5)] and Nelson grade [0.7 +/- 2 (0.6)] in the O3FA group (P < 0.0001) as compared with 0.3 +/- 2 (0.6) and 0.1 +/ 2 (0.4) in the placebo group (P = 0.164 and 0.094, respectively). However, the magnitude of increase in Schirmer score [2.0 +/- 2 (1.5)] was relatively small (P = 0.08). CONCLUSIONS: The results of this study point toward benefits of orally administered O3FAs in alleviating dry eye symptoms, improving lens wear comfort, and cytological changes in contact lens wearers. PMID- 25719254 TI - Tear osmolarity in ocular graft-versus-host disease. PMID- 25719255 TI - Harmonizing the assessment of biodiversity effects from land and water use within LCA. AB - Addressing biodiversity impacts in life cycle assessment (LCA) has recently been significantly improved. Advances include the consideration of several taxa, consideration of vulnerability of species and ecosystems, global coverage and spatial differentiation. To allow a comparison of biodiversity impacts of different stressors (e.g., land and water use), consistent approaches for assessing and aggregating biodiversity impacts across taxa are needed. We propose four different options for aggregating impacts across taxa and stressors: equal weight for species, equal weight for taxa and two options with special consideration of species' vulnerability. We apply the aggregation options to a case study of coffee, tea and sugarcane production in Kenya for the production of 1 kg of crop. The ranking between stressors (land vs water use) within each crop and also of the overall impact between crops (coffee>sugarcane>tea) remained the same when applying the different aggregation options. Inclusion of the vulnerability of species had significant influence on the magnitude of results, and potentially also on the spatial distribution of impacts, and should be considered. PMID- 25719256 TI - Diffusion-facilitated direct determination of intrinsic parameters for rapid photoinduced bimolecular electron-transfer reactions in nonpolar solvents. AB - Bimolecular fluorescence-quenching reactions involving electron-transfer between electronically excited 5,10,15,20-tetraphenyl-21H,23H-porphine (TPP*) and 1,4 benzoquinone (BQ) or 1,4-naphthoquinone (NQ) were investigated using a set of alkane solvents that enabled the rapid reaction kinetics to be probed over a wide viscosity range, while minimizing changes in other relevant solvent parameters. Relative diffusion coefficients and reaction distances were recovered directly from analysis of fluorescence decay curves measured on a nanosecond time scale. The electron transfer from TPP* to BQ requires reactant contact, consistent with tightly associated exciplex formation in these nonpolar solvents. In contrast, electron transfer from TPP* to NQ displays a clear distance dependence, indicative of reaction via a much looser noncontact exciplex. This difference is attributed to the greater steric hindrance associated with contact between the TPP*/NQ pair. The diffusion coefficients recovered from fluorescence decay curve analysis are markedly smaller than the corresponding measured bulk relative diffusion coefficients. Classical hydrodynamics theory was found to provide a satisfactory resolution of this apparent discrepancy. The calculated hydrodynamic radii of TPP and NQ correlate very well with the van der Waals values. The hydrodynamic radius obtained for BQ is a factor of 6 times smaller than the van der Waals value, indicative of a possible tight cofacial geometry in the (TPP(+)/BQ(-))* exciplex. The present work demonstrates the utility of a straightforward methodology, based on widely available instrumentation and data analysis, that is broadly applicable for direct determination of kinetic parameter values for a wide variety of rapid bimolecular fluorescence quenching reactions in fluid solution. PMID- 25719257 TI - Attenuation of acute rat renal allograft rejection by apolipoprotein E-mimetic Peptide. AB - BACKGROUND: In addition to its well-described role in lipid metabolism, apolipoprotein E (ApoE) exerts immunomodulatory functions. A protective role of ApoE and ApoE-mimetic peptide (ApoE(133-149)) application was documented in several inflammatory disorders. In this study, we test the hypothesis that ApoE(133-149) promotes renal allograft survival. METHODS: Dark Agouti, Brown Norway, and Fischer 344 kidneys were transplanted to Lewis rats to investigate fatal and reversible acute rejection. Apolipoprotein E expression was assessed in intravascular leukocytes of renal grafts, in graft tissue and in recipient blood plasma. Recipients of Brown Norway kidneys were treated with ApoE(133-149), and graft survival was monitored until day 100. Graft infiltration, cytokine, and chemokine production were analyzed. RESULTS: Intravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression was reduced or remained unchanged. Animals treated with ApoE(133-149) showed prolonged allograft survival, which was associated with a reduced infiltration of CD8 and alpha/beta T-cell receptor-expressing cells, diminished Granzyme B mRNA expression, and decreased caspase-3 activation. CONCLUSIONS: Endogenous ApoE overexpression and exogenous application of ApoE(133-149) seem to protect renal allografts from fatal acute rejection. This effect was associated with a reduced influx of cytotoxic T cells. PMID- 25719258 TI - Live Donor Renal Anatomic Asymmetry and Posttransplant Renal Function. AB - BACKGROUND: Relationship between live donor renal anatomic asymmetry and posttransplant recipient function has not been studied extensively. METHODS: We analyzed 96 live kidney donors, who had anatomical asymmetry (>10% renal length and/or volume difference calculated from computerized tomography angiograms) and their matching recipients. Split function differences (SFD) were quantified with technetium-dimercaptosuccinic acid renography. Implantation biopsies at time 0 were semiquantitatively scored. A comprehensive model using donor renal volume adjusted to recipient weight (Vol/Wgt), SFD, and biopsy score was used to predict recipient estimated glomerular filtration rate (eGFR) at 1 year. Primary analysis consisted of a logistic regression model of outcome (odds of developing eGFR>60 mL/min/1.73 m(2) at 1 year), a linear regression model of outcome (predicting recipient eGFR at one-year, using the chronic kidney disease-epidemiology collaboration formula), and a Monte Carlo simulation based on the linear regression model (N=10,000 iterations). RESULTS: In the study cohort, the mean Vol/Wgt and eGFR at 1 year were 2.04 mL/kg and 60.4 mL/min/1.73 m(2), respectively. Volume and split ratios between 2 donor kidneys were strongly correlated (r = 0.79, P < 0.001). The biopsy scores among SFD categories (<5%, 5% 10%, >10%) were not different (P = 0.190). On multivariate models, only Vol/Wgt was significantly associated with higher odds of having eGFR > 60 mL/min/1.73 m (odds ratio, 8.94, 95% CI 2.47-32.25, P = 0.001) and had a strong discriminatory power in predicting the risk of eGFR less than 60 mL/min/1.73 m(2) at 1 year [receiver operating curve (ROC curve), 0.78, 95% CI, 0.68-0.89]. CONCLUSIONS: In the presence of donor renal anatomic asymmetry, Vol/Wgt appears to be a major determinant of recipient renal function at 1 year after transplantation. Renography can be replaced with CT volume calculation in estimating split renal function. PMID- 25719259 TI - Natural Killer Cells Mediate Long-term Kidney Allograft Injury. AB - BACKGROUND: Chronic allograft injury remains the leading cause of late kidney graft loss despite improvements in immunosuppressive drugs and a reduction in acute T cell-mediated rejection. We have recently demonstrated that natural killer (NK) cells are cytotoxic to tubular epithelial cells and contribute to acute kidney ischemia-reperfusion injury. The role of NK cells in kidney allograft rejection has not been studied. METHODS: A "parent to F1" kidney transplant model was used to study NK cell-mediated transplant rejection. RESULTS: The C57BL/6 kidneys were transplanted into fully nephrectomized CB6F1 (C57BL/6 x BALB/c) mice. Serum creatinine levels increased from baseline (18.8 +/ 5.0 MUmol/L to 37.2 +/- 5.9 MUmol/L, P < 0.001) at 60 days after transplantation. B6Rag-to-CB6F1Rag (B6RagxBALB/cRag) recipients, which lack T and B cells but retain NK cells, showed similar levels of kidney dysfunction 65 days after transplantation (creatinine, 33.8 +/- 7.9 MUmol/L vs 17.5 +/- 5.1 MUmol/L in nontransplant Rag mice, P < 0.05). Importantly, depletion of NK cells in Rag1 recipients inhibited kidney injury (24.6 +/- 5.5 MUmol/L, P < 0.05). Osteopontin, which can activate NK cells to mediate tubular epithelial cell death in vitro, was highly expressed in 60 days kidney grafts. Osteopontin null kidney grafts had reduced injury after transplantation into CB6F1 mice (17.7 +/- 3.1 MUmol/L, P < 0.001). CONCLUSIONS: Collectively, these data demonstrate for the first time that independent of T and B cells, NK cells have a critical role in mediating long term transplant kidney injury. Specific therapeutic strategies that target NK cells in addition to conventional immunosuppression may be required to attenuate chronic kidney transplant injury. PMID- 25719260 TI - The Relationship of the Severity and Category of Acute Rejection With Intimal Arteritis Defined in Banff Classification to Clinical Outcomes. AB - BACKGROUND: It is unclear if the category of acute rejection with intimal arteritis (ARV) is relevant to short- and long-term clinical outcomes and if the graft outcomes are affected by the severity of intimal arteritis. METHODS: One hundred forty-eight ARV episodes were reviewed and categorized according to the 2013 Banff criteria of AMR: T cell-mediated rejection with intimal arteritis (v) lesion (TCMRV; n = 78), total antibody-mediated rejection with v lesion (AMRV), which were further divided into suspicious AMRV (n = 37) and AMRV (n = 33). The Banff scores of intimal arteritis (v1, v2 and v3) represented low, moderate, and high ARV severity. RESULTS: The grafts with TCMRV, suspicious AMRV (sAMRV), and AMRV showed similar responses to antirejection therapy, whereas the grafts with v2- or v3-ARV responded significantly poorer compared to those with v1-ARV. The 8 year death-censored graft survival (DCGS) rate was 56.8% of TCMRV versus 34.1% of total AMRV (Log rank, P = 0.03), but the 1- and 5-year DCGS rates were comparable between the 2 groups; moreover, the 1-, 5-, and 8-year DCGS rates of v1-ARV were evidently higher than v2- and v3-ARV (each pairwise comparison to v1-AVR yields P < 0.01); in contrast, the DCGS rates were similar between sAMRV and AMRV. The existing donor-specific antibodies or moderate microvascular inflammation or C4d positive staining or intensive tubulointerstitial inflammation played a less significant role on the long-term graft survival. CONCLUSIONS: Compared to the category, the ARV severity is more closely associated with the initial response to antirejection therapy and long-term graft failure. The sAMRV and AMRV might represent a spectrum of the same disorder. PMID- 25719261 TI - Controlled Attenuation Parameter and Liver Stiffness Measurements for Steatosis Assessment in the Liver Transplant of Brain Dead Donors. AB - BACKGROUND: One of the main selection criteria of the quality of a liver graft is the degree of steatosis, which will determine the success of the transplantation. The aim of this study was to evaluate the ability of FibroScan and its related methods Controlled Attenuation Parameter and Liver Stiffness to assess objectively steatosis and fibrosis in livers from brain-dead donors to be potentially used for transplantation. METHODS: Over a period of 10 months, 23 consecutive brain dead donors screened for liver procurement underwent a FibroScan and a liver biopsy. RESULTS: The different predictive models of liver retrievability using liver biopsy as the gold standard have led to the following area under receiver operating characteristic curve: 76.6% (95% confidence intervals [95% CIs], 48.2%-100%) when based solely on controlled attenuation parameter, 75.0% (95% CIs, 34.3%-100%) when based solely on liver stiffness, and 96.7% (95% CIs, 88.7%-100%) when based on combined indices. CONCLUSIONS: Our study suggests that a preoperative selection of brain-dead donors based on a combination of both Controlled Attenuation Parameter and Liver Stiffness obtained with FibroScan could result in a good preoperative prediction of the histological status and degree of steatosis of a potential liver graft. PMID- 25719262 TI - Effect of Absent Immune Cell Expression of Vitamin D Receptor on Cardiac Allograft Survival in Mice. AB - INTRODUCTION: Vitamin D (VD) has immunomodulatory properties, but whether immune cell expression of the VD receptor (VDR) impacts costimulatory blockade induced cardiac allograft survival is not known. METHODS: To localize effects of VDR deficiency to hematopoietic cells and to avoid the metabolic consequences of systemic VDR deficiency, we produced bone marrow (BM)-chimeric mice by transplanting lethally irradiated C57BL/6 mice with congenic VDR or wild type BM. After reconstitution, we characterized baseline immune profiles and transplanted chimeras with heterotopic cardiac allografts with or without costimulatory blockade using anti-CD154 (MR1) or CTLA4Ig, the latter approved for use in human kidney transplant recipients. RESULTS: Immune reconstitution occurred equivalently in chimeras with wild type and VDR BM. Untreated animals rejected class II disparate and fully allogeneic cardiac transplants with similar kinetics. Compared to untreated controls, treatment with either MR1 or CTLA4Ig induced significant and equivalent prolongation of graft survival in both groups of chimeric recipients. We observed no differences in induced antidonor cellular or humoral alloimmunity between groups. CONCLUSIONS: Our findings support the conclusion that absent immune cell VDR expression (a) does not impact the strength, phenotype, or kinetics of heart transplant rejection in mice and (b) does not impact the graft-prolonging effects of costimulatory blockade including that induced by clinically used CTLA4Ig. PMID- 25719264 TI - Hospital-based active shooter incidents: sanctuary under fire. PMID- 25719265 TI - Electrically conductive polypropylene nanocomposites with negative permittivity at low carbon nanotube loading levels. AB - Polypropylene (PP)/carbon nanotubes (CNTs) nanocomposites were prepared by coating CNTs on the surface of gelated/swollen soft PP pellets. The electrical conductivity (sigma) studies revealed a percolation threshold of only 0.3 wt %, and the electrical conductivity mechanism followed a 3-d variable range hopping (VRH) behavior. At lower processing temperature, the CNTs formed the network structure more easily, resulting in a higher sigma. The fraction of gamma-phase PP increased with increasing the pressing temperature. The CNTs at lower loading (0.1 wt %) served as nucleating sites and promoted the crystallization of PP. The CNTs favored the disentanglement of polymer chains and thus caused an even lower melt viscosity of nanocomposites than that of pure PP. The calculated optical band gap of CNTs was observed to increase with increasing the processing temperature, i.e., 1.55 eV for nanocomposites prepared at 120 degrees C and 1.70 eV prepared at 160 and 180 degrees C. Both the Drude model and interband transition phenomenon have been used for theoretical analysis of the real permittivity of the nanocomposites. PMID- 25719266 TI - Impact of an Interactive On-line Tool on Therapeutic Decision-Making for Patients with Advanced Non-Small-Cell Lung Cancer. AB - BACKGROUND: Treatment guidelines provide recommendations but cannot account for the wide variability in patient-tumor characteristics in individual patients. We developed an on-line interactive decision tool to provide expert recommendations for specific patient scenarios in the first-line and maintenance settings for advanced non-small-cell lung cancer. We sought to determine how providing expert feedback would influence clinical decision-making. METHOD: Five lung cancer experts selected treatment for 96 different patient cases based on patient and/or tumor-specific features. These data were used to develop an on-line decision tool. Participant physicians entered variables for their patient scenario with treatment choices, and then received expert treatment recommendations for that scenario. To determine the impact on decision-making, users were asked whether the expert feedback impacted their original plan. RESULTS: A total of 442 individual physicians, of which 88% were from outside the United States, entered 653 cases, with report on impact in 389 cases. Expert feedback affected treatment choice in 73% of cases (23% changed and 50% confirmed decisions). For cases with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion, all experts selected targeted therapy whereas 51% and 58% of participants did not. Greater variability was seen between experts and participants for cases involving EGFR or ALK wild-type tumors. Participants were 2.5-fold more likely to change to expert recommended therapy for ALK fusions than for EGFR mutations (p = 0.017). CONCLUSION: This online tool for treatment decision-making resulted in a positive influence on clinician's decisions. This approach offers opportunities for improving quality of care and meets an educational need in application of new therapeutic paradigms. PMID- 25719267 TI - Synthesis of 6-(arylthio)phenanthridines by copper-catalyzed tandem reactions of 2-biaryl isothiocyanates with diaryliodonium salts. AB - A novel copper-catalyzed tandem C-S/C-C bond-forming reaction of 2-biaryl isothiocyanates with diaryliodonium salts was developed. This is the first general approach to synthesize phenanthridines from 2-biaryl isothiocyanates. This methodology has been successfully applied to the synthesis of trisphaeridine. PMID- 25719268 TI - Surgical models of Roux-en-Y gastric bypass surgery and sleeve gastrectomy in rats and mice. AB - Bariatric surgery is the only definitive solution currently available for the present obesity pandemic. These operations typically involve reconfiguration of gastrointestinal tract anatomy and impose profound metabolic and physiological benefits, such as substantially reducing body weight and ameliorating type II diabetes. Therefore, animal models of these surgeries offer unique and exciting opportunities to delineate the underlying mechanisms that contribute to the resolution of obesity and diabetes. Here we describe a standardized procedure for mouse and rat models of Roux-en-Y gastric bypass (80-90 min operative time) and sleeve gastrectomy (30-45 min operative time), which, to a high degree, resembles operations in humans. We also provide detailed protocols for both pre- and postoperative techniques that ensure a high success rate in the operations. These protocols provide the opportunity to mechanistically investigate the systemic effects of the surgical interventions, such as regulation of body weight, glucose homeostasis and gut microbiome. PMID- 25719269 TI - Site-specific protein modification using immobilized sortase in batch and continuous-flow systems. AB - Transpeptidation catalyzed by sortase A allows the preparation of proteins that are site-specifically and homogeneously modified with a wide variety of functional groups, such as fluorophores, PEG moieties, lipids, glycans, bio orthogonal reactive groups and affinity handles. This protocol describes immobilization of sortase A on a solid support (Sepharose beads). Immobilization of sortase A simplifies downstream purification of a protein of interest after labeling of its N or C terminus. Smaller batch and larger-scale continuous-flow reactions require only a limited amount of enzyme. The immobilized enzyme can be reused for multiple cycles of protein modification reactions. The described protocol also works with a Ca(2+)-independent variant of sortase A with increased catalytic activity. This heptamutant variant of sortase A (7M) was generated by combining previously published mutations, and this immobilized enzyme can be used for the modification of calcium-senstive substrates or in instances in which low temperatures are needed. Preparation of immobilized sortase A takes 1-2 d. Batch reactions take 3-12 h and flow reactions proceed at 0.5 ml h(-1), depending on the geometry of the reactor used. PMID- 25719270 TI - Statistical analysis of cell migration in 3D using the anisotropic persistent random walk model. AB - Cell migration through 3D extracellular matrices (ECMs) is crucial to the normal development of tissues and organs and in disease processes, yet adequate analytical tools to characterize 3D migration are lacking. The motility of eukaryotic cells on 2D substrates in the absence of gradients has long been described using persistent random walks (PRWs). Recent work shows that 3D migration is anisotropic and features an exponential mean cell velocity distribution, rendering the PRW model invalid. Here we present a protocol for the analysis of 3D cell motility using the anisotropic PRW model. The software, which is implemented in MATLAB, enables statistical profiling of experimentally observed 2D and 3D cell trajectories, and it extracts the persistence and speed of cells along primary and nonprimary directions and an anisotropic index of migration. Basic computer skills and experience with MATLAB software are recommended for successful use of the protocol. This protocol is highly automated and fast, taking <30 min to analyze trajectory data per biological condition. PMID- 25719271 TI - Production of an acetone-butanol-ethanol mixture from Clostridium acetobutylicum and its conversion to high-value biofuels. AB - Clostridium acetobutylicum is a bacterial species that ferments sugar to a mixture of organic solvents (acetone, butanol and ethanol). This protocol delineates a methodology to combine solventogenic clostridial fermentation and chemical catalysis via extractive fermentation for the production of biofuel blendstocks. Extractive fermentation of C. acetobutylicum is operated in fed batch mode with a concentrated feed solution (500 grams per liter glucose and 50 grams per liter yeast extract) for 60 h, producing in excess of 40 g of solvents (acetone, butanol and ethanol) between the completely immiscible extractant and aqueous phases of the bioreactor. After distillation of the extractant phase, the acetone, butanol and ethanol mixture is upgraded to long-chain ketones over a palladium-hydrotalcite (Pd-HT) catalyst. This reaction is generally carried out in batch with a high-pressure Q-tube for 20 h at 250 degrees C. Following this protocol enables the production of ~0.5 g of high-value biofuel precursors from a 1.7-g portion of fermentation solvents. PMID- 25719272 TI - Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors. AB - Plasmepsins (Plms) are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress has been achieved in the development of inhibitors of plasmepsin using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity versus the human Asp proteases cathepsins and renin and activity in cell-based assays. By use of SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity versus cathepsins are not always taken into account. A combination of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for future design cycles. PMID- 25719273 TI - Synthesis, characterisation and analytical application of Fe3O4@SiO2@polyaminoquinoline magnetic nanocomposite for the extraction and pre concentration of Cd(II) and Pb(II) in food samples. AB - This work describes a novel Fe3O4@SiO2@polyaminoquinoline magnetic nanocomposite and its application in the pre-concentration of Cd(II) and Pb(II) ions. The parameters affecting the pre-concentration procedure were optimised by a Box Behnken design through response surface methodology. Three variables (extraction time, magnetic sorbent amount and pH) were selected as the main factors affecting the sorption step, while four variables (type, volume and concentration of the eluent, and elution time) were selected as main factors in the optimisation study of the elution step. Following the sorption and elution of analytes, the ions were quantified by flame atomic absorption spectrometry (FASS). The limits of detection were 0.1 and 0.7 ng ml(-1) for Cd(II) and Pb(II) ions, respectively. All the relative standard deviations were less than 7.6%. The sorption capacities of this new sorbent were 57 mg g(-)(1) for Cd(II) and 73 mg g(-1) for Pb(II). Ultimately, this nanocomposite was successfully applied to the rapid extraction of trace quantities of these heavy metal ions from seafood and agricultural samples and satisfactory results were obtained. PMID- 25719274 TI - Metrics for biogeophysical climate forcings from land use and land cover changes and their inclusion in life cycle assessment: a critical review. AB - The regulation by vegetation of heat, momentum, and moisture exchanges between the land surface and the atmosphere is a major component in Earth's climate system. By altering surface biogeophysics, anthropogenic land use activities often perturb these exchanges and thereby directly affect climate. Although long recognized scientifically as being important, biogeophysical climate forcings from land use and land cover changes (LULCC) are rarely included in life cycle assessment (LCA). Here, I review climate metrics for characterizing biogeophysical climate forcings from LULCC, focusing mostly on those that do not require coupled land-atmosphere climate models to compute. I discuss their merits, highlight their pros and cons in terms of their compatibility with the LCA framework, outline near-term practical guidelines and solutions for their integration, and point to areas of longer term research needs in both the climate science and LCA research communities. PMID- 25719275 TI - Vascular Repair by Tissue-Resident Endothelial Progenitor Cells in Endotoxin Induced Lung Injury. AB - Vascular disruption is one of the pathological hallmarks in acute respiratory distress syndrome. Bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) and lung tissue-resident EPCs have been considered to play a pivotal role in pulmonary vascular repair; however, which population is predominant in local pulmonary vasculogenesis remains to be clarified. We therefore examined the origin of EPCs participating in the regenerative process of pulmonary vascular endothelial cells (PVECs) in experimental acute respiratory distress syndrome. Lung samples from mice administered LPS intratracheally were investigated for cell dynamics and EPC functions. Quantitative flow cytometric analysis demonstrated that the number of PVECs decreased by roughly 20% on Day 1 and then recovered on Day 7 of LPS challenge. Bromodeoxyuridine-incorporation assays and immunofluorescence microscopy demonstrated that proliferating PVECs preferentially located in the capillary vessels. Experiments using BM chimera mice revealed that most of the regenerating PVECs were tissue-resident cells, and BM-derived cells hardly engrafted as PVECs. The population of circulating putative phenotypical EPCs decreased during the first week after LPS challenge. The regenerating PVECs were characterized by high colony-forming and vasculogenic capacities, intracellular reactive oxygen species scavenging and aldehyde dehydrogenase activites, and enhanced gene expression of Abcb1b (a drug-resistant gene), suggesting that the population of PVECs included tissue-resident EPCs activated during regenerative process of PVECs. The proliferating PVECs expressed CD34, Flk-1/KDR, and c-kit more strongly and Prom1/CD133 less strongly on the surface than nonproliferating PVECs. Our findings indicated that lung tissue resident EPCs predominantly contribute to pulmonary vascular repair after endotoxin-induced injury. PMID- 25719276 TI - Cobalt-catalyzed asymmetric hydroboration of aryl ketones with pinacolborane. AB - The highly enantioselective cobalt-catalyzed hydroboration reaction of aryl ketones with HBpin was developed using iminopyridine oxazoline ligands. Halides, amines, ethers, sulfides, esters and amides are well tolerated under the mild reaction conditions, demonstrating its synthetic advantage. Substituted diaryl ketones could also be hydroborated with high enantioselectivity. PMID- 25719277 TI - Evaluation of the social and economic burden of road traffic noise-attributed myocardial infarction in Bulgarian urban population. AB - Road traffic noise is a widely studied environmental risk factor for ischaemic heart disease and myocardial infarction in particular. Given that myocardial infarction is a leading disability and mortality cause in Bulgaria and that a significant proportion of the urban population is exposed to high noise levels, quantification of the burden of disease attributable to traffic noise is essential for environmental health policy making and noise control engineering. This study aimed at estimating the burden of the myocardial infarction cases attributable to road traffic noise in the Bulgarian urban population. We used the methodology for estimating the burden of disease attributable to environmental noise outlined by the World Health Organization. Risk data were extracted from a recently published meta-analysis providing updated exposure-response relationship between traffic noise and the risk for myocardial infarction. Based on these data we calculated the fraction of myocardial infarction cases attributable to traffic noise, loss of quality-adjusted life-years (QALYs), and the economic burden, assuming ? 12,000 per QALY. About 2.9 % or 101 of all myocardial infarction cases could be attributed to road traffic noise. Fifty-five of these were fatal. Nine hundred and sixty-eight QALYs were lost to these cases. The monetary value of these QALYs was about ? 11.6 million. Although the measures used in this study are crude and give only an approximation of the real burden of disease from road traffic noise, they are indicative of the important social and economic aspect of noise pollution in Bulgaria. Hopefully, these results will direct the attention of epidemiologists, environmental hygienists, and health economists to this pivotal environmental issue. PMID- 25719278 TI - Quantitative biomechanical comparison of ankle fracture casting methods. AB - The incidence of ankle fractures is increasing rapidly due to the ageing demographic. In older patients with compromised distal circulation, conservative treatment of fractures may be indicated. High rates of malunion and complications due to skin fragility motivate the design of novel casting systems, but biomechanical stability requirements are poorly defined. This article presents the first quantitative study of ankle cast stability and hypothesises that a newly proposed close contact cast (CCC) system provides similar biomechanical stability to standard casts (SC). Two adult mannequin legs transected at the malleoli, one incorporating an inflatable model of tissue swelling, were stabilised with casts applied by an experienced surgeon. They were cyclically loaded in torsion, measuring applied rotation angle and resulting torque. CCC stiffness was equal to or greater than that of SC in two measures of ankle cast resistance to torsion. The effect of swelling reduction at the ankle site was significantly greater on CCC than on SC. The data support the hypothesis that CCC provides similar biomechanical stability to SC and therefore also the clinical use of CCC. They suggest that more frequent re-application of CCC is likely required to maintain stability following resolution of swelling at the injury site. PMID- 25719279 TI - Treatment of arrhythmias by external charged particle beams: a Langendorff feasibility study. AB - Hadron therapy has already proven to be successful in cancer therapy, and might be a noninvasive alternative for the ablation of cardiac arrhythmias in humans. We present a pilot experiment investigating acute effects of a 12C irradiation on the AV nodes of porcine hearts in a Langendorff setup. This setup was adapted to the requirements of charged particle therapy. Treatment plans were computed on calibrated CTs of the hearts. Irradiation was applied in units of 5 and 10 Gy over a period of about 3 h until a total dose of up to 160 Gy was reached. Repeated application of the same irradiation field helped to mitigate motion artifacts in the resulting dose distribution. After irradiation, PET scans were performed to verify accurate dose application. Acute AV blocks were identified. No other acute effects were observed. Hearts were kept in sinus rhythm for up to 6 h in the Langendorff setup. We demonstrated that 12C ions can be used to select a small target in the heart and, thereby, influence the electrical conduction system. Second, our pilot study seems to suggest that no adverse effects have to be expected immediately during heavy ion irradiation in performing subsequent experiments with doses of 30-60 Gy and intact pigs. PMID- 25719280 TI - Adhesion of human mesenchymal stem cells can be controlled by electron beam microstructured titanium alloy surfaces during osteogenic differentiation. AB - Several studies focusing on bone tissue engineering demonstrated that given microstructuring of an implant surface has a strong effect on its interaction with cells, and their adhesion and differentiation. In the present study, geometrically structured titanium alloy surfaces are shown to be able to guide cell adhesion during differentiation in vitro. For this reason, using an electron beam texturing technique, TiAl6V4 surfaces were selectively targeted in the micrometer range. The effect of such textured titanium alloy surfaces on cell adhesion during osteogenic differentiation was analyzed for human mesenchymal stem cells (MSC), the natural precursor cells of bone tissue. Cytotoxicity, cell viability and differentiation were analyzed. Immunofluorescence stainings demonstrated that in contrast to MSC in an expansion medium, MSC in an osteogenic induction medium produce adhesion proteins such as beta3-integrins and thereby connect in an oriented way to the generated microstructures on titanium alloy surfaces. These results are of relevance for developing tailored titanium alloy implant surfaces which exhibit an improved cell response. PMID- 25719281 TI - Insulinoma--rare, but important clinical problem. Analysis of a series of 530 patients who underwent surgical treatment for the pancreatic tumor. AB - Insulinomas are rare tumors, accounting for 1-2% of all neoplasms of the pancreas. Usually their treatment is not associated with any problems; however there is a small subset of problematic clinical cases. The authors present their own clinical experience with surgical treatment of insulinomas of the pancreas. The aim of the study was to conduct a retrospective analysis of patients with insulinomas of the pancreas who underwent surgical treatment at Department of General and Transplant Surgery Medical University in Lodz. MATERIAL AND METHODS: The study included all patients who underwent surgical treatment at the Department between 2007 and 2013 for the tumor of the pancreas. Further retrospective analysis included all patients with tumors of the insulinoma type. The data was obtained from medical records, surgical protocols and histopathology reports. RESULTS: The analysis included 530 patients who underwent surgical treatment for the tumor of the pancreas. Insulinoma was found in 10 (1.88%) patients (8 females, 2 males). An average age of patients who underwent surgical treatment was 47.5+/-13.8 years. An average size of the tumor was 1.6+/-0.5 cm. Six patients underwent extirpation of the insulinoma, while the other patients underwent distal resection of the pancreas. All patients underwent "an open surgical procedure". The average duration of the surgical procedure was 55+/-45 minutes. Duration of the hospitalization in the analyzed group of patients was 7+/-5 days. Incidence of postoperative pancreatic fistulas was 10%. All insulinomas were benign. CONCLUSIONS: Insulinomas were rare among patients who underwent surgical treatment at the Department. They were benign and their treatment was unproblematic. However, there is a small group of cases that can be associated with problematic clinical situations. Thus treatment of patients with insulinomas should be conducted at specialist centers. Correct diagnostic and therapeutic management, involving close cooperation between multiple medical specialists, results in complete curing of majority of patients. PMID- 25719282 TI - Physician as an infective vector at a department of surgery. AB - This study was designed to assess the degree of risk of bacterial transmission from physician to patient through hands, equipment and enclosing surfaces (shoe soles). MATERIAL AND METHODS: The study was conducted in the Clinical Department of General and Oncological Surgery UM in Lodz. In days 16.10.2013, 17.10.2013, 18.10.2013 there were done swabs from hands, stethoscopes and soles of shoes from the same group of physicians before and after doctor's rounds. The presence of alert-pathogens in swabs was regarded as positive result. RESULTS: Isolates included mostly aerobic saprophytic bacilli and Staphylococcus species coagulase negative. There were detected a singly cases of Acinetobacter Baumani and Escherichia coli. Alert-pathogens were found in 4 (16%) swabs taken from hand before doctor's rounds and in 7 (28%) swabs taken after rounds. Stetoscopes were contaminated by alert-pathogens in 3 (12%) cases before doctor's rounds and in 3 (12%) cases taken after doctor's rounds. Soles of shoes were contaminated by alert-pathogens in 14 (56%) cases taken before and 16 (65%) cases taken after doctor's rounds. CONCLUSIONS: 1. Physicians are important factor of bacterial transmission in hospital. 2. Hands, stetoscopes and particularly soles of shoes of medical staff is the source of infection. PMID- 25719283 TI - The role of apolipoprotein (a) in pathogenesis and clinical course of deep venous thrombosis. AB - Deep venous thrombosis is widespread disease, which complications, like: pulmonary embolism and postphlebitis syndrome areimportant social problem. There are many well-known and accurately described risk factors, though in many cases etiology remains unexplained. Further research into causes of deep venous thrombosis seem to be fully justified. The aim of the study was the evaluation of the influence of apolipoprotein (a) serum level in patients with deep venous thrombosis and the changes of its concentration during the treatment. MATERIALS AND METHODS: 26 patients with newly diagnosed deep venous thrombosis (DVT) were enrolled to the study. Diagnosis of DVT was established by use of physical examination and duplex Doppler. Measurements of apolipoprotein (a) and D-dimers serum level were recorded on the following days, starting from the day of the initial diagnosis: 1, 7, 14 and 84. RESULTS: Statistically significant increase of the level of serum apolipoprotein (a) has been found during properly conducted treatment. CONCLUSIONS: Alterations of the concentration of serum apoliprotein (a) during the deep venous thrombosis treatment, indicates the involvement of apolipoprotein (a) in pathogenesis of deep venous thrombosis. PMID- 25719284 TI - Peritoneal adhesions as a cause of mechanical small bowel obstruction based on own experience. AB - Bowel obstruction is a condition which has been known for many years. As time goes by, the problem is still often encountered at surgical emergency rooms. More than 20% of emergency surgical interventions are performed because of symptoms of digestive tract obstruction with the disease mostly situated in the small bowel. Rates of causative factors of the disease have changed over recent years and there have been increasingly more cases of small bowel obstruction caused by peritoneal adhesions, i.e., adhesive small bowel obstruction (ASBO). The aim of the study to analyse the reasons and incidence of adhesive small bowel obstruction during two periods of time (1990-1995 and 2005-2010). MATERIAL AND METHODS: We performed a retrospective analysis of medical records of patients hospitalized at the 1st Department of General Surgery and Surgical Oncology of the Provincial Polyclinic Hospital in Plock between 1990 and 1995. The outcomes were compared with another period of 2005-2010. RESULTS: We found that the incidence of adhesive small bowel obstruction increased from 58 cases in the first period to 215 cases in the second one, and the outcomes improved. The proportion of patients who underwent surgery diminished from 38% to 13%. The mean hospitalization time shortened and was 11.3 days and 6.95 days during 1990-1995 and 2005-2010 periods of time, respectively. In the first group, patients who had a surgery were hospitalized for 17.8 days and those who were treated conservatively for 8.08 days. In the second group, the mean hospital stay decreased to 15.6 days and 5.7 days in the case of surgical and conservative treatment, respectively. The age of onset declined from 56.63 years in the first period to 52.54 years in the other one. CONCLUSIONS: Analysed data show an increasing number of patients with adhesive small bowel obstruction. The highest risk of the disease was associated with operations on the large bowel and gynaecological procedures. PMID- 25719285 TI - Efficacy of lift (ligation of intersphincteric fistula tract) for complex and recurrent anal fistulas--a single-center experience and a review of the literature. AB - Ligation of intersphincteric fistula tract in treatment of anal fistulas (LIFT) is being said to have satisfactory results in short and long follow up, with low risk of complications. This study was designed to evaluate the results in patients with complex and recurrent fistulas in comparison with simple transsphincteric anal fistulas. The aim of the study was to present a single center experience in LIFT procedure in treatment of both simple and complex anal fistulas, including recurrent fistulas, in comparison with a review of current literature. MATERIAL AND METHODS: A series of 17 patients were qualified to LIFT procedure. 5 patients were treated for simple transsphincteric, 6 for complex fistulas, 6 with fistulas recurrent after fistulotomy. Median age was 47, most of the patients were male (16/17). Mean follow up was 11 months. RESULTS: Mean operating time was 55 minutes counting from surgical site disinfection to final dressing of the wound. Of the 17 patients the overall success rate was 53%. As expected, best results were achieved in patients with simple fistulas (80% success rate), then complex (50%), and recurrent fistulas (only 33%). There were no early nor late complications of the surgery. CONCLUSION: As expected, in simple transsphincteric fistulas the results were satisfactory, taking into account low complication rate. Complex and recurrent fistulas seem to be risk factors of LIFT failure. The results are consistent with data published by other authors, based on the review of the current literature, and it seems there is still room for improvement, so further research is required. PMID- 25719286 TI - Liver resection for non-colorectal, non-endocrine liver metastasis. PMID- 25719287 TI - Increased hospital admissions associated with extreme-heat exposure in King County, Washington, 1990-2010. AB - Increased morbidity and mortality have been associated with extreme heat events, particularly in temperate climates. Few epidemiologic studies have considered the impact of extreme heat events on hospitalization rates in the Pacific Northwest region. This study quantifies the historic (May to September 1990-2010) heat morbidity relationship in the most populous Pacific Northwest County, King County, Washington. A relative risk (RR) analysis was used to explore the association between heat and all non-traumatic hospitalizations on 99th percentile heat days, whereas a time series analysis using a piecewise linear model approximation was used to estimate the effect of heat intensity on hospitalizations, adjusted for temporal trends and day of the week. A non statistically significant 2% [95% CI: 1.02 (0.98, 1.05)] increase in hospitalization risk, on a heat day vs. a non-heat day, was noted for all-ages and all non-traumatic causes. When considering the effect of heat intensity on admissions, we found a statistically significant 1.59% (95% CI: 0.9%, 2.29%) increase in admissions per degree increase in humidex above 37.4 degrees C. Admissions stratified by cause and age produced statistically significant results with both relative risk and time series analyses for nephritis and nephrotic syndromes, acute renal failure, and natural heat exposure hospitalizations. This study demonstrates that heat, expressed as humidex, is associated with increased hospital admissions. When stratified by age and cause of admission, the non elderly age groups (<85 years) experience significant risk for nephritis and nephrotic syndromes, acute renal failure, natural heat exposure, chronic obstructive pulmonary disease, and asthma hospitalizations. PMID- 25719288 TI - Assessing exposure of young children to common endocrine-disrupting chemicals in the home environment: a review and commentary of the questionnaire-based approach. AB - BACKGROUND: Although infants and young children are particularly vulnerable to endocrine disrupting chemical (EDC) exposure, there is an absence of comprehensive exposure data for this age group. As young children spend the majority of their time indoors, improved methods of exposure assessment are needed to characterise the health risks from exposures in the home environment. Biologic assessment, which has been considered the gold standard for exposure assessment in recent years, is difficult to conduct in young children. Questionnaires are an alternative and indirect method of predicting exposure, which may overcome some of the limitations of direct exposure assessment. RESEARCH PROBLEM: The feasibility of using a questionnaire-based approach to predict exposure of young children to EDCs in the home has yet to be comprehensively reviewed. Moreover, there is no one questionnaire that has been validated for predicting the exposure of infants to common EDCs in the home. AIMS AND OBJECTIVES: The aim of this review is to discuss the use and validation of the questionnaire-based approach to predict exposure of children to chemicals from three common classes of EDCs in the home, namely, plasticisers, flame retardants, and insecticides. We discuss the strengths and weaknesses of the questionnaire-based approach as well as the important pathways of exposure in the home environment, by which to guide the design and validation of future exposure questionnaires. RESULTS: The findings from our review indicate that the questionnaire-based approach is a valuable tool in the prediction of exposure to persistent organic pollutants, as well as to toxicants that have consistent patterns of exposure. With improvements to the design and validation process, the questionnaire-based approach may also prove to be a reliable instrument in predicting exposure to EDCs with short-half lives, including bisphenol A, phthalates, and pyrethroid and organophosphate insecticides. PMID- 25719289 TI - Surfactant with and without bronchoalveolar lavage in an experimental model of meconium aspiration syndrome. AB - OBJECTIVES: To assess the effect of surfactant administration, preceded or not by bronchoalveolar lavage (BAL) with dilute surfactant, on pulmonary function in experimental severe meconium aspiration syndrome. METHODS: Twenty-one newborn pigs received 20% meconium in saline intratracheally and were randomly allocated to one of three groups: I, control; II, surfactant only (poractant alfa, 200 mg/kg); or III, dilute surfactant BAL followed by 125 mg/kg surfactant. Arterial blood gases (ABGs), lung compliance, and resistance were assessed. RESULTS: Thirty minutes after treatment, mean PaO2 (mm Hg) increased to 72 in group I, to 106 in group II and to 172 in group III (P=0.01). After 3 h, mean PaO2 (mm Hg) was 70 in group I, 95 in group II and 198 in group III (P<0.01). After 6 h, it was 79 in group I, 110 in group II, and 217 in group III (P=0.01). From the 30 min point onward, there were significant differences among treatment groups in all other parameters and at every point of assessment, except for compliance and resistance 3 h after treatment. CONCLUSIONS: BAL with dilute surfactant, followed by an additional dose of surfactant, produced significant improvements in ABGs and pulmonary mechanics as compared with a single dose of surfactant. PMID- 25719290 TI - Predicting neonatal respiratory morbidity by lamellar body count and gestational age. AB - AIMS: To develop a predictive model for assessing the risk of developing neonatal respiratory morbidity using lamellar body counts (LBCs) and gestational age (GA) to provide a more patient-specific assessment. METHODS: Retrospective cohort study of patients' >=32 weeks' gestation who received amniocentesis with LBC analysis over a 9-year period. Respiratory morbidity was defined as respiratory distress syndrome, transient tachypnea of the newborn or oxygen requirement for >24 h. Logistic regression analyses were used to predict the absolute risk and odds of respiratory morbidity as a function of GA and lamellar body count. RESULTS: Two hundred and sixty-seven mother-infant pairs included in the analysis with 32 cases (12.0%) of respiratory morbidity. When compared to those without respiratory morbidity, neonates with respiratory morbidity had amniocentesis performed at an earlier median GA, had lower mean birthweight and had lower median LBC (P<0.01). The GA specific absolute risks and odds ratios for the presence of respiratory morbidity were calculated. The predicted absolute risks of neonatal respiratory morbidity ranged from 38% at 32 weeks to 6% at 40 weeks when LBC were 35,000/MUL. CONCLUSION: GA specific predicted risk of neonatal respiratory morbidity using LBC provides a statistical model, which can aid clinicians in individually counseling patients regarding the absolute risk of their neonate developing respiratory morbidity. PMID- 25719291 TI - American medical education: the evolution of excellence. PMID- 25719292 TI - Pregnancy outcomes among renal transplant recipients and patients with end-stage renal disease on dialysis. AB - AIM: The purpose of our study is to compare pregnancy outcomes between women with a functioning renal transplant and women with end-stage renal disease (ESRD). METHODS: We carried out a population-based retrospective cohort study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database from 2006 to 2011. Logistic regression analysis was used to estimate the age-adjusted effect of functioning renal transplant vs. ESRD requiring dialysis on pregnancy outcomes. RESULTS: We identified 264 birth records to women with a functional renal transplant and 267 birth records to women with ESRD on dialysis among 5,245,452 births. As compared to women with ESRD on dialysis, renal transplant recipients were less likely to have placental abruption [odds ratio, OR 0.23 (95% confidence interval, CI 0.08-0.70)], to receive blood transfusions [OR 0.17 (95% CI 0.09-0.30)], and to have growth-restricted and small-for-gestational-age babies [OR 0.45 (95% CI 0.23-0.85)]. Renal transplant recipients were more likely to have an instrumental delivery [OR 15.38 (95% CI 1.92-123.3)]. Among renal transplant women, there was a trend towards delivery by cesarean section as compared to patients with ESRD [OR 1.31 (95% CI 0.93-1.85)]. However, these results were not statistically significant. Fetal deaths were less likely to occur in women with a renal transplant [OR 0.41 (95% CI 0.17-0.96)]. There were four maternal deaths among patients with ESRD on dialysis and no maternal deaths among renal transplant patients. CONCLUSION: Patients with a functional renal graft had an overall lower rate of morbidity and adverse pregnancy complications when compared to patients with ESRD on dialysis. PMID- 25719293 TI - Obstetrical Doppler: the evidence today. PMID- 25719294 TI - Internal resilience, peer victimization, and suicidal ideation among adolescents. AB - PURPOSE: Our goal was to examine the association between peer victimization (PV) and suicidal ideation (SI), and the degree to which internal resilience moderates this association. MATERIALS AND METHODS: We examined the independent associations between PV frequency and type (verbal, cyber, physical, and relational), internal resilience, and the risk of SI within the last 12 months among 9th and 11th grade students participating in the California Healthy Kids Survey (CHKS) (n=42,594; 55.2% female; 72.2% non-white). RESULTS: Odds ratios (OR) of SI associated with very low- (at least 1 PV type 1 time, but none more than 1 time), low- (at least 1 PV type 2-3 times, but none more than 2-3 times), and moderate/high- (at least 1 PV type 4 times or more) frequency PV compared with no PV were 1.30 (95% CI=1.15-1.45), 1.70 (95% CI=1.51-1.90) and 2.47 (95% CI=1.23-2.73), respectively. Any exposure to physical (OR=1.31; 95% CI=1.19-1.44), relational (OR=1.26; 95% CI=1.15-1.38), verbal (OR=1.38; 95% CI=1.27-1.50), or cyber (OR=1.26; 95% CI=1.15 1.39) PV was associated with increased odds of SI compared with no PV. Internal resilience was associated with lower odds of SI (OR=0.98, 95% CI=0.98-0.99), regardless of PV exposure. The slope between internal resilience and SI was significantly steeper for those subjects who experienced verbal PV (OR interaction=0.99; 95% CI=0.98-1.00). CONCLUSION: Even infrequent PV was found to be associated with increased risk for SI. Internal resilience was associated with reduced SI, particularly for verbal forms of PV. Our results suggested that efforts to decrease SI among adolescents should be directed toward both preventing PV and strengthening internal resilience. PMID- 25719295 TI - Practices and perceptions of adolescent girls regarding the impact of dysmenorrhea on their routine life: a comparative study in the urban, rural, and slum areas of Chandigarh. AB - To estimate the prevalence, to compare the impact of dysmenorrhea on routine life among adolescent girls, to compare the practices and perceptions regarding Dysmenorrhea and to ascertain the reason for difference if any, a cross-sectional study was conducted in urban, rural and slum areas of Chandigarh, India. 300 girls in age group of 11-18 years, who had attained menarche were included in the study. A questionnaire including the Demographic and Family profile, menstrual history, Symptoms of Dysmenorrhea, Effect of pain on daily activities, Faces scale, Practices regarding Dysmenorrhea, Beliefs about menstruation was used. Analysis was done by percentage and chi square prevalance of dysmenorrhea was 61.33%. Sickness absenteeism due to dysmenorrhea was reported in 24.45% girls. Most common symptom experienced by the girls was stomach ache which was experienced by 139 girls; others symptoms experienced during menstruation were backache (107), and general body pain (80). Only 11.63% of the girls ever visited physician due to pain during menstruation. During menstruation only 10 girls use hot water bottle, 71 skip meal. Due to poor knowledge the practices were not optimal for pain management, which affected their school attendance. Formal as well as informal channels of communication, such as mothers and peers, need to be emphasized for the delivery of such information particularly linking instructions on menstrual hygiene to an expanded programme of health education in schools. PMID- 25719296 TI - Should radioiodine be the first-line treatment for paediatric Graves' disease? AB - BACKGROUND: Debate exists regarding the optimal treatment strategy for paediatric Graves' disease with radioiodine (RAI), and surgery, usually reserved for failure of medical therapy. We present our own experience to introduce a review of the published literature focussing on the predictors of remission after antithyroid drug (ATD) therapy from diagnosis, and discuss whether RAI should be considered as a first-line therapy. METHOD: A retrospective analysis of all diagnosed cases of paediatric Graves' disease presenting to a large District General Hospital. RESULTS: Thirteen patients were diagnosed with Graves' disease between February 2004 and May 2013. The median age at diagnosis was 13.7 years (range 7.2-17.1 years) with a female:male ratio of 11:2. Some nine patients completed a 2-year course of carbimazole out of which 8 relapsed after a mean duration of 0.82 years (range 0.08-1.42 years); the ninth currently remains in remission. Of the eight patients who relapsed, three have undergone RAI treatment. Two patients failed to tolerate carbimazole treatment, one of whom received RAI treatment because surgery was contraindicated and one patient with severe autism proceeded to RAI treatment due to poor compliance and persistent hyperthyroidism. LITERATURE REVIEW: Prognostic factors at presentation predicting a low likelihood of remission following ATD treatment include younger age, non-Caucasian ethnicity, and severe clinical and/or biochemical markers of hyperthyroidism. Psycho-social factors including compliance also influence management decisions. CONCLUSION: In specifically selected patients presenting with paediatric Graves' disease, the benefits and risks of radioactive iodine as a potential first-line therapy should be communicated allowing families to make informed decisions. PMID- 25719297 TI - Resistin and right ventricular function in children with recently diagnosed type 1 diabetes mellitus: a case control study. AB - BACKGROUND: Resistin is an adipocyte-derived signaling polypeptide described in adipose tissue, which acts as a metabolic link between inflammation and atherosclerosis. This study aimed to assess the relation between right ventricular (RV) function assessed by echocardiography and resistin levels in recently diagnosed type-1 diabetic children. METHODS: The study was conducted as a prospective cohort study and it included 30 children with type-1 diabetes mellitus as a patient group and 30 healthy children matched for age and sex as controls. It evaluated RV functions by tissue Doppler imaging, speckle tracking imaging, and real-time three-dimensional echocardiography (RT3DE), as well as assessing resistin serum level using enzyme-linked immunosorbent assay. RESULTS: The left ventricle (LV) showed no significant difference between the two groups in E/A ratio across the mitral valve, ejection fraction, and S wave mitral annulus. However, it showed significant decrease in the E'/A' wave of mitral annulus, impairment of LV myocardial performance index (MPI), and decrease in LV EF measured by RT3DE in diabetic patients compared to the control group. Significant differences in the mean value of tricuspid annular systolic excursion (TASE), pulmonary artery pressure, longitudinal systolic strain (RV LSS), MPI, and RV ejection fraction were observed between the studied groups. Yet, no significant differences in E/A ratio and S value were observed between the two groups. Significant positive correlation of resistin level with age of studied group and significant negative correlation of resistin with both TASE and RV LSS values were also observed. CONCLUSION: We confirmed the presence of subclinical RV systolic and diastolic dysfunction in type-1 diabetic children with positive correlation between resistin level and RV dysfunction among them. PMID- 25719298 TI - Associations between IGF-I, IGF-binding proteins and bone turnover markers in prepubertal obese children. AB - OBJECTIVE: To assess the relationships between components of the growth hormone axis, body composition, and bone markers in obese children. METHODS: We determined the levels of bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), insulin-like growth factor-I (IGF-I), and IGF-binding proteins (IGFBPs) by immunoenzymatic methods, and body composition by dual-energy X-ray absorptiometry in 45 obese and 20 non-obese children. RESULTS: IGF-I and functional IGFBP-3 levels, IGF-I/total IGFBP-3, and functional IGFBP-3/total IGFBP-3 molar ratios were significantly higher in obese patients than in controls. Multivariate regression analysis in obese patients showed significant associations of BALP with IGF-I (p=0.047) and percent of body fat mass (p=0.002). CONCLUSION: The relationship of IGF-I and functional IGFBP-3 to BALP may support the concept of IGF-I influence on accelerated bone formation process in obesity. Moreover, IGF-I and percentage of body fat mass may be significant predictors of BALP in obese during the prepubertal period. PMID- 25719299 TI - Effect of GnRHa 3.75 mg subcutaneously every 6 weeks on adult height in girls with idiopathic central precocious puberty. AB - OBJECTIVE: To evaluate the long-term efficacy of triptorelin 3.75 mg subcutaneously every 6 weeks on the final height in girls with idiopathic central precocious puberty (ICPP). METHODS: Forty females with ICPP received triptorelin 3.75 mg every 6 weeks subcutaneously in our hospital from 2002 to December 2010 and reached their final heights were enrolled. These patients were treated with triptorelin alone (group A, n=17) or triptorelin+recombinant human growth hormone (rhGH) (group B, n=23). Height, weight, annual growth velocity (GV), sexual development, predicted adult height (PAH), and adverse effects were observed. Bone age (BA) and height standard deviation score (SDS) were monitored yearly. RESULTS: Final adult heights (FAHs) were 159.81+/-1.20 cm and 161.01+/-1.02 cm in group A vs. group B, which exceeded target height (THt) by 1.51+/-1.04 cm, 4.86+/ 0.94 cm, respectively. The values of (FAH-THt), (FAH-PAH posttreatment) showed significant difference between the two groups (p<0.05). FAH was positively correlated with Ht SDS-BA at the end of treatment, THt, course of rhGH treatment, and age of menarche (r2=0.66). Body mass index (BMI) increased after treatment in group B. However, there was no significant tendency of increase compared with healthy children at the same age. Ages of menarche and time to menarche from discontinuation were 11.74+/-0.16 vs. 12.18+/-0.15 years and 17.41+/-1.69 vs. 14.71+/-1.04 months in two groups. CONCLUSION: The FAH was improved effectively by triptorelin 3.75 mg subcutaneously every 6 weeks, and more height gain could be achieved when rhGH was used concomitantly. BMI maintained steadily and ovarian function restored quickly after treatment discontinuation with the age of menarche similar to that of normal children. Neither significant side effect nor polycystic ovary syndrome was observed. PMID- 25719300 TI - Assessment of human cartilage glycoprotein 39 (YKL-40), preptin, and nitric oxide in adolescent patients with type 1 diabetes and its relation to cardiorenal affection. AB - AIM: To evaluate new biomarkers such as YKL-40, preptin, and nitric oxide (NO) in patients with diabetes and to assess its relation to cardiorenal injury. PATIENTS AND METHODS: The study included 62 patients with type 1 diabetes and 30 healthy volunteers. Blood sample was taken for assessment of glycosylated hemoglobin, lipid profile, YKL-40, preptin, and NO. Also, urine sample was taken for analysis of albumin/creatinine ratio. Echocardiography was also done. RESULTS: NO was lower, whereas YKL-40, preptin, and albumin/creatinine ratio were significantly higher in patients with diabetes. NO had a significant negative correlation with LVEDD, LVESD, PWT, LV mass, YKL-40, preptin, and albumin/creatinine ratio. YKL-40 had a significant positive correlation with waist/height ratio, preptin and negative correlation with E/A ratio. Stepwise multiple regression revealed that E/A ratio is the only parameter related to YKL-40. On the contrary, NO and systolic blood pressure are related to preptin. CONCLUSION: A significant reduction of NO and elevation of YKL-40 and preptin was found in patients with diabetes. A decrease in NO is associated with diastolic dysfunction, LV hypertrophy, and renal impairment, whereas YKL-40 is associated with diastolic dysfunction. An increase in preptin level was associated with hypertension. PMID- 25719301 TI - A patient developing anaphylaxis and sensitivity to two different GnRH analogues and a review of literature. AB - Gonadotropin-releasing hormone analogues are used in the treatment of prostate cancer, breast cancer, endometriosis, and uterine leiomyomas in adults and often in the treatment of precocious puberty in children. Many adverse effects have been reported for gonadotropin-releasing hormone analogues, but anaphylaxis is rarely reported as an adverse effect. Frequent cross-reactions, particularly during childhood, and diversity of the time of onset of anaphylactic manifestations complicate the diagnosis. A patient who exhibited anaphylactic allergic reactions to two different agents used in the treatment of central precocious puberty presented here because the case has an atypical course and is the first in the literature. PMID- 25719302 TI - 17alpha-Hydroylase/17,20-lyase deficiency related to P.Y27*(c.81C>A) mutation in CYP17A1 gene. AB - 17alpha-Hydroxylase/17-20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. Genetic defects causing combined 17OHD lead to the impaired production of cortisol and sex steroids, accumulation of mineralocorticoids, and compensatory overproduction of pituitary adrenocorticotropic hormone. Consequently, individuals with this enzymatic defect present with both adrenal cortical hyperplasia and variable degrees of hypertension, hypokalemia, and sexual immaturity. The patient was aged 15 years and 3 months and she was diagnosed with 17OHD while she was being evaluated for complaints of delayed puberty. In the present case, p.Y27*(c.81C>A) mutation was revealed in the sequence analysis of the CYP17A1 gene. The same mutation was reported in a 20 year-old Turkish girl in Germany, who was investigated for delayed puberty in 2005. The previous case was reported to be normotensive and normokalemic. The presence and differences in the severity of hypertension in cases with the same mutation and total enzymatic deficiency may indicate that genes predisposed to hypertension, obesity due to genetic and environmental factors, and some other factors may play a role in the clinical presentation of hypertension. PMID- 25719303 TI - Plant-derived natural medicines for the management of depression: an overview of mechanisms of action. AB - Depression is a serious widespread psychiatric disorder that affects approximately 17% of people all over the world. Exploring the neurological mechanisms of the antidepressant activity of plant-derived agents could have a crucial role in developing natural drugs for the management of depression. The aim of the present study is to review the neurological mechanisms of action of antidepressant plants and their constituents. For this purpose, electronic databases, including PubMed, Science Direct, Scopus, and Cochrane Library, were searched from 1966 to October 2013. The results showed that several molecular mechanisms could be proposed for the antidepressant activity of medicinal plants and their constituents. Hypericum species could normalize brain serotonin level. Liquiritin and isoliquiritin from Glycyrrhiza uralensis rhizome act via the noradrenergic system. Rosmarinus officinalis and curcumin from Curcuma longa interact with D1 and D2 receptors as well as elevate the brain dopamine level. Sida tiagii and Aloysia gratissima involve gamma-aminobutyric acid and N-methyl-D aspartate receptors, respectively. Fuzi polysaccharide-1 from Aconitum carmichaeli could affect brain-derived neurotrophic factor signaling pathways. Psoralidin from Psoralea corylifolia seed modulate the hypothalamic-pituitary adrenal axis. The total glycosides of Paeonia lactiflora demonstrate an inhibitory effect on both subtypes of monoamine oxidase. 3,6'-Di-o-sinapoyl sucrose and tenuifoliside A from Polygala tenuifolia exhibit cytoprotective effects on neuronal cells. Further preclinical and clinical trials evaluating their safety, bioefficacy, and bioavailability are suggested to prove the valuable role of natural drugs in the management of depressive disorders. PMID- 25719304 TI - Peripheral nerve hyperexcitability syndromes. AB - Peripheral nerve hyperexcitability (PNH) syndromes can be subclassified as primary and secondary. The main primary PNH syndromes are neuromyotonia, cramp fasciculation syndrome (CFS), and Morvan's syndrome, which cause widespread symptoms and signs without the association of an evident peripheral nerve disease. Their major symptoms are muscle twitching and stiffness, which differ only in severity between neuromyotonia and CFS. Cramps, pseudomyotonia, hyperhidrosis, and some other autonomic abnormalities, as well as mild positive sensory phenomena, can be seen in several patients. Symptoms reflecting the involvement of the central nervous system occur in Morvan's syndrome. Secondary PNH syndromes are generally seen in patients with focal or diffuse diseases affecting the peripheral nervous system. The PNH-related symptoms and signs are generally found incidentally during clinical or electrodiagnostic examinations. The electrophysiological findings that are very useful in the diagnosis of PNH are myokymic and neuromyotonic discharges in needle electromyography along with some additional indicators of increased nerve fiber excitability. Based on clinicopathological and etiological associations, PNH syndromes can also be classified as immune mediated, genetic, and those caused by other miscellaneous factors. There has been an increasing awareness on the role of voltage-gated potassium channel complex autoimmunity in primary PNH pathogenesis. Then again, a long list of toxic compounds and genetic factors has also been implicated in development of PNH. The management of primary PNH syndromes comprises symptomatic treatment with anticonvulsant drugs, immune modulation if necessary, and treatment of possible associated dysimmune and/or malignant conditions. PMID- 25719305 TI - An evaluation of the links between microRNA, autophagy, and epilepsy. AB - Epilepsy is a serious chronic neurologic disorder characterized by recurrent unprovoked seizures resulting from abnormal and highly synchronous neuronal discharges within the brain. Small noncoding RNAs, called microRNAs, play vital roles in epileptogenesis, with potential contributions as valuable biomarkers and targets for the treatment of epilepsy. To maintain cellular homeostasis, cellular components, such as organelles, proteins, protein complexes/oligomers, and pathogens, are delivered to the lysosome for degradation through a process called autophagy, which plays either a protective or a harmful role under epileptic stress. Several autophagic mechanisms have been implicated in epileptogenesis, including the mammalian target of rapamycin pathway, aberrant substrate accumulation, and the formation of epileptic networks. In addition, the regulation of autophagy through microRNAs (miRNAs) represents a novel posttranscriptional regulatory mechanism through 'autophagamiRNAs'. The correlation between autophagy and miRNA has increased our understanding of the underlying pathogenesis of human diseases. Here, we review the current findings regarding the correlations between miRNA, autophagy, and epilepsy to provide a solid foundation for further examination of the miRNA-autophagy pathway involved in epilepsy pathophysiology. PMID- 25719306 TI - How does spreading depression spread? Physiology and modeling. AB - Spreading depression (SD) is a wave phenomenon in gray matter tissue. Locally, it is characterized by massive redistribution of ions across cell membranes. As a consequence, there is sustained membrane depolarization and tissue polarization that depress any normal electrical activity. Despite these dramatic events, SD remains difficult to observe in humans noninvasively, which, for long, has slowed advances in this field. The growing appreciation of its clinical importance in migraine and stroke is therefore consistent with an increasing need for computational methods that tackle the complexity of the problem at multiple levels. In this review, we focus on mathematical tools to investigate the question of spread and its two complementary aspects: What are the physiological mechanisms and what is the spatial extent of SD in the cortex? This review discusses two types of models used to study these two questions, namely, Hodgkin Huxley type and generic activator-inhibitor models, and the recent advances in techniques to link them. PMID- 25719307 TI - Pharmacogenetics of drug oxidation via cytochrome P450 (CYP) in the populations of Denmark, Faroe Islands and Greenland. AB - Denmark, the Faroe Islands and Greenland are three population-wise small countries on the northern part of the Northern Hemisphere, and studies carried out here on the genetic control over drug metabolism via cytochrome P450 have led to several important discoveries. Thus, CYP2D6 catalyzes the 2-hydroxylation, and CYP2C19 in part catalyzes the N-demethylation of imipramine. The phenomenon of phenocopy with regard to CYP2D6 was first described when Danish patients changed phenotype from extensive to poor metabolizers during treatment with quinidine. It was a Danish extensive metabolizer patient that became a poor metabolizer during paroxetine treatment, and this was due to the potent inhibition of CYP2D6 by paroxetine, which is also is metabolized by this enzyme. Fluoxetine and norfluoxetine are also potent inhibitors of CYP2D6, and fluvoxamine is a potent inhibitor of both CYP1A2 and CYP2C19. The bioactivation of proguanil to cycloguanil is impaired in CYP2C19 poor metabolizers. The O-demethylation of codeine and tramadol to their respective my-opioid active metabolites, morphine and (+)-O-desmethyltramadol was markedly impaired in CYP2D6 poor metabolizers compared to extensive metabolizers, and this impairs the hypoalgesic effect of the two drugs in the poor metabolizers. The frequency of CYP2D6 poor metabolizers is 2%-3% in Greenlanders and nearly 15% in the Faroese population. The frequency of CYP2C19 poor metabolizers in East Greenlanders is approximately 10%. A study in Danish mono and dizygotic twins showed that the non-polymorphic 3-N demethylation of caffeine catalyzed by CYP1A2 is subject to approximately 70% genetic control. PMID- 25719308 TI - In vitro assessment of anticholinesterase and NADH oxidase inhibitory activities of an edible fern, Diplazium esculentum. AB - BACKGROUND: Diplazium esculentum is the most commonly consumed edible fern throughout Asia and Oceania. Several studies have been performed so far to determine different functional properties of this plant, but there have been no reports on the anticholinesterase and nicotinamide adenine dinucleotide (NADH) oxidase inhibitory activities of this plant. Therefore, the present study was conducted to determine the anticholinesterase and NADH oxidase inhibitory activities of 70% methanolic extract of D. esculentum. METHODS: The D. esculentum extract was investigated for its acetylcholinesterase and NADH oxidase inhibitory activities as well as its free radical scavenging and total antioxidant activities in the linoleic acid system. The free radical scavenging activity of the extract was determined by the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) method. The total antioxidant activity of the extract was evaluated by ferric thiocyanate (FTC) and thiobarbituric acid (TBA) methods. RESULTS: The D. esculentum extract inhibited acetylcholinesterase and NADH oxidase in a dose-dependent manner, with IC50 values of 272.97+/-19.38 and 265.81+/-21.20 MUg/mL, respectively. The extract also showed a potent DPPH radical scavenging activity with an IC50 value of 402.88+/-12.70 MUg/mL. Moreover, the extract showed 27.41% and 33.22% of total antioxidant activities determined by FTC and TBA methods, respectively. CONCLUSIONS: Results indicated that 70% methanolic extract of D. esculentum effectively inhibited the enzymes acetylcholinesterase and NADH oxidase and acted as a potent antioxidant and free radical scavenger. These in vitro assays indicate that this plant extract is a significant source of natural antioxidants, which may be helpful in preventing the progression of various neurodegenerative disorders associated with oxidative stress. PMID- 25719310 TI - Enhancers, enhancers - from their discovery to today's universe of transcription enhancers. AB - Transcriptional enhancers are short (200-1500 base pairs) DNA segments that are able to dramatically boost transcription from the promoter of a target gene. Originally discovered in simian virus 40 (SV40), a small DNA virus, transcription enhancers were soon also found in immunoglobulin genes and other cellular genes as key determinants of cell-type-specific gene expression. Enhancers can exert their effect over long distances of thousands, even hundreds of thousands of base pairs, either from upstream, downstream, or from within a transcription unit. The number of enhancers in eukaryotic genomes correlates with the complexity of the organism; a typical mammalian gene is likely controlled by several enhancers to fine-tune its expression at different developmental stages, in different cell types and in response to different signaling cues. Here, I provide a personal account of how enhancers were discovered more than 30 years ago, and also address the amazing development of the field since then. PMID- 25719309 TI - Thymoquinone ameliorates NLRP3-mediated inflammation in the pancreas of albino Wistar rats fed ethanol and high-fat diet. AB - BACKGROUND: Inflammasomes are protein complexes that mediate the process of inflammation and tissue injury by regulating the level of cytokine production. Pancreatitis is a major gastrointestinal disorder characterized by painful inflammation in the pancreas. The aim of this study was to evaluate whether thymoquinone (TQ) exerts anti-inflammatory activity by influencing the expression of the apoptosis-associated speck-like protein (ASC) complex of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes in rats subjected to experimental pancreatitis. METHODS: Male albino Wistar rats were randomly separated into four groups. Rats in groups 1 and 2 were fed with a normal diet for 90 days, and rats in groups 3 and 4 were administered with ethanol (EtOH) 8-12 g/kg/day orally and fed with a high-fat diet (HFD) for 90 days. In addition, rats in groups 2 and 4 were administered with 100 mg/kg body weight of TQ from the 31st day. The serum lipase (L)/amylase (A) ratio; the oxidative stress markers; the GSH/GSSG ratio; the mRNA expression of ASC, caspase-1, IL-1beta, IL-18, and TNF-alpha; and the protein expression of ASC and caspase-1 in the pancreas were assessed. RESULTS: We observed a significant increase in the serum L/A ratio and oxidative stress, a decrease in the GSH/GSSG ratio, and a GST activity in EtOH- and HFD-fed rats. The mRNA expression of IL-1beta, IL-18, and TNF-alpha was significantly reduced in TQ coadministered rats than that in EtOH- and HFD-fed rats. The upregulation of mRNA and the protein expression of ASC and caspase-1 were significantly reduced in TQ coadministered rats. CONCLUSIONS: TQ exerts the anti-inflammatory activity probably by downregulating the ASC expression to minimize the maturation of proinflammatory cytokines. PMID- 25719311 TI - Downregulation of sphingosine 1-phosphate (S1P) receptor 1 by dexamethasone inhibits S1P-induced mesangial cell migration. AB - Sphingosine 1-phosphate (S1P) is generated by sphingosine kinase (SK)-1 and -2 and acts mainly as an extracellular ligand at five specific receptors, denoted S1P1-5. After activation, S1P receptors regulate important processes in the progression of renal diseases, such as mesangial cell migration and survival. Previously, we showed that dexamethasone enhances SK-1 activity and S1P formation, which protected mesangial cells from stress-induced apoptosis. Here we demonstrate that dexamethasone treatment lowered S1P1 mRNA and protein expression levels in rat mesangial cells. This effect was abolished in the presence of the glucocorticoid receptor antagonist RU-486. In addition, in vivo studies showed that dexamethasone downregulated S1P1 expression in glomeruli isolated from mice treated with dexamethasone (10 mg/kg body weight). Functionally, we identified S1P1 as a key player mediating S1P-induced mesangial cell migration. We show that dexamethasone treatment significantly lowered S1P-induced migration of mesangial cells, which was again reversed in the presence of RU-486. In summary, we suggest that dexamethasone inhibits S1P-induced mesangial cell migration via downregulation of S1P1. Overall, these results demonstrate that dexamethasone has functional important effects on sphingolipid metabolism and action in renal mesangial cells. PMID- 25719312 TI - SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A. AB - Lung cancer has been the most prolific cancer in China - as in the rest of the world - with a high death rate and low 5-year survival rate. Previous evidence showed that JMJD2A is over-expressed in human non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues, and that high level of JMJD2A predicts poor overall and disease-free survival. However, the mechanism by which JMJD2A is regulated in human NSCLC is not fully understood. In the present study, we identified that the SIRT2 as an anti-oncogenic protein in NSCLC was down regulated. JMJD2A as a target of SIRT2 was negatively correlated with SIRT2 level in NSCLC. SIRT2 bound to the promoter region of JMJD2A and negatively regulated JMJD2A expression. In addition, we found that SIRT2 inhibited NSCLC cells proliferation, colony formation and tumor growth in vitro and in vivo in a JMJD2A dependent manner. In summary, our findings implicate that SIRT2 suppresses non small cell lung cancer growth through targeting JMJD2A and SIRT2 activator may serve as candidate drug for NSCLC therapy. PMID- 25719313 TI - Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways. AB - The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by sphingolipid cancer research. Many studies have shown that ceramide generation in response to cytotoxic agents is central to tumor cell death. Ceramide can be generated either via hydrolysis of cell-membrane sphingomyelin by sphingomyelinases, hydrolysis of cerebrosides, or via de novo synthesis by ceramide synthases. Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the acid ceramidase can lead to the formation of sphingosine 1-phosphate, which then antagonizes ceramide signaling by initiating a pro-survival signaling pathway. Furthermore, ceramide glycosylation catalyzed by glucosylceramide synthase converts ceramide to glucosylceramide, thus eliminating ceramide and consequently protecting cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents. PMID- 25719314 TI - A universal mechanism for transport and regulation of CPA sodium proton exchangers. AB - Recent studies performed on a series of Na+/H+ exchangers have led us to postulate a general mechanism for Na+/H+ exchange in the monovalent cation/proton antiporter superfamily. This simple mechanism employs a single binding site for which both substrates compete. The developed kinetic model is self-regulatory, ensuring down-regulation of transport activity at extreme pH, and elegantly explains the pH-dependent activity of Na+/H+ exchangers. The mechanism was experimentally verified and shown to describe both electrogenic and electroneutral exchangers. Using a small number of parameters, exchanger activity can be modeled under different conditions, providing insights into the physiological role of Na+/H+ exchangers. PMID- 25719315 TI - Recent advances and concepts in substrate specificity determination of proteases using tailored libraries of fluorogenic substrates with unnatural amino acids. AB - Substrate specificity of proteases can be determined using several methods among which the most frequently used are positional scanning library, proteomics and phage display. Classic approaches can deliver information about preferences for natural amino acids in binding pockets of virtually all proteases. However, recent studies demonstrate the ability to obtain much more information by application of unnatural amino acids to positional scanning library approaches. This knowledge can be used for the design of more active and specific substrates, inhibitors and activity based probes. In this minireview we describe recent strategies and concepts for the design and application of fluorogenic substrates library tailored for exopeptidases and endopeptidases. PMID- 25719317 TI - Lithium chloride improves the efficiency of induced pluripotent stem cell-derived neurospheres. AB - Induced pluripotent stem cell (iPSC)-derived neurospheres, which consist mainly of neural progenitors, are considered to be a good source of neural cells for transplantation in regenerative medicine. In this study, we have used lithium chloride, which is known to be a neuroprotective agent, in an iPSC-derived neurosphere model, and examined both the formation rate and size of the neurospheres as well as the proliferative and apoptotic status of their contents. Our results showed that lithium enhanced the formation and the sizes of the iPSC derived neurospheres, increased the number of Ki67-positive proliferating cells, but reduced the number of the TUNEL-positive apoptotic cells. This increased number of Ki67 proliferating cells was secondary to the decreased apoptosis and not to the stimulation of cell cycle entry, as the expression of the proliferation marker cyclin D1 mRNA did not change after lithium treatment. Altogether, we suggest that lithium enhances the survival of neural progenitors and thus the quality of the iPSC-derived neurospheres, which may strengthen the prospect of using lithium-treated pluripotent cells and their derivatives in a clinical setting. PMID- 25719318 TI - Incidence and physiological relevance of protein thiol switches. AB - A few small-molecule oxidants, most notably hydrogen peroxide, can act as messengers in signal transduction. They trigger so-called 'thiol switches', cysteine residues that are reversibly oxidized to transiently change the functional properties of their host proteins. The proteome-wide identification of functionally relevant 'thiol switches' is of significant interest. Unfortunately, prediction of redox-active cysteine residues on the basis of surface accessibility and other computational parameters appears to be of limited use. Proteomic thiol labeling approaches remain the most reliable strategy to discover new thiol switches in a hypothesis-free manner. We discuss if and how genomic knock-in strategies can help establish the physiological relevance of a 'thiol switch' on the organismal level. We conclude that surprisingly few attempts have been made to thoroughly verify the physiological relevance of thiol-based redox switches in mammalian model organisms. PMID- 25719319 TI - Team work at its best - TAPL and its two domains. AB - The transporter associated with antigen processing (TAPL, ABCB9) is a homodimeric ABC transporter, shuttling cytosolic polypeptides into the lumen of lysosomes energized by ATP hydrolysis. Here we give a short overview of the superfamily of ABC transporters and summarize the current state of knowledge on TAPL in detail. The architecture of TAPL and its substrate specificity are described and we discuss the function of an extra N-terminal transmembrane domain, called TMD0, in respect of subcellular targeting and interaction with proteins, contributing to long-term stability. As TAPL shows - besides a ubiquitous basal expression - an elevated expression in antigen presenting cells, we present models of TAPL function in adaptive immunity. PMID- 25719320 TI - Mining of hospital laboratory information systems: a model study defining age- and gender-specific reference intervals and trajectories for plasma creatinine in a pediatric population. AB - BACKGROUND: The knowledge of physiological fluctuation and variation of even commonly used biochemical quantities in extreme age groups and during development is sparse. This challenges the clinical interpretation and utility of laboratory tests in these age groups. To explore the utility of hospital laboratory data as a source of information, we analyzed enzymatic plasma creatinine as a model analyte in two large pediatric hospital samples. METHODS: Plasma creatinine measurements from 9700 children aged 0-18 years were obtained from hospital laboratory databases and partitioned into high-resolution gender- and age-groups. Normal probability plots were used to deduce parameters of the normal distributions from healthy creatinine values in the mixed hospital datasets. Furthermore, temporal trajectories were generated from repeated measurements to examine developmental patterns in periods of changing creatinine levels. RESULTS: Creatinine shows great age dependence from birth throughout childhood. We computed and replicated 95% reference intervals in narrow gender and age bins and showed them to be comparable to those determined in healthy population studies. We identified pronounced transitions in creatinine levels at different time points after birth and around the early teens, which challenges the establishment and usefulness of reference intervals in those age groups. CONCLUSIONS: The study documents that hospital laboratory data may inform on the developmental aspects of creatinine, on periods with pronounced heterogeneity and valid reference intervals. Furthermore, part of the heterogeneity in creatinine distribution is likely due to differences in biological and chronological age of children and should be considered when using age-specific reference intervals. PMID- 25719321 TI - The influence of excipients commonly used in freeze drying on whole blood coagulation dynamics assessed by rotational thromboelastometry. AB - BACKGROUND: Lyophilized reagents are used on a daily basis in coagulation diagnostics. They often contain a number of excipients in addition to the active compound. Some of these excipients may, however, influence coagulation dynamics. METHODS: Besides from plasmatic coagulation bulking agents may influence platelet properties. We therefore studied the influence of a variety of bulking agents (glycine, mannitol, sucrose and trehalose) as well as a surfactant (Tween(r) 80) on whole blood coagulation using thromboelastometry (ROTEM(r)) and platelet function analysis (ROTEM(r) platelet). RESULTS: Both disaccharides as well as Tween(r) 80 did not influence whole blood coagulation in the concentration range investigated. The addition of glycine and mannitol solutions to the ROTEM(r) measurement leads to an impaired clot formation as well as overall clot strength while clotting initiation remained barely influenced. Hypertonic glycine and mannitol solutions exhibit different clot formation impairment when correlated to their osmolar concentration and compared to equally osmolar NaCl-solutions. The effect of glycine was assigned to fibrin formation impairment identified with the FIBTEM assay. Platelet function analysis revealed that hypertonic glycine solutions do not alter platelet function but hypertonic mannitol and NaCl solutions do. CONCLUSIONS: While the influence observed for glycine may be due to fibrinogen precipitation, the mechanism of mannitol appears to be more complex as platelet function as well as fibrin-based clot formation are influenced. This study therefore demonstrates the necessity to check for coagulation impairment due to compounds contained in lyophilized reagents. PMID- 25719322 TI - Performance criteria and quality indicators for the pre-analytical phase. AB - The definition, implementation and monitoring of valuable analytical quality specifications have played a fundamental role in improving the quality of laboratory services and reducing the rates of analytical errors. However, a body of evidence has been accumulated on the relevance of the extra-analytical phases, namely the pre-analytical steps, their vulnerability and impact on the overall quality of the laboratory information. The identification and establishment of valueable quality indicators (QIs) represents a promising strategy for collecting data on quality in the total testing process (TTP) and, particularly, for detecting any mistakes made in the individual steps of the pre-analytical phase, thus providing useful information for quality improvement projects. The consensus achieved on the developed list of harmonized QIs is a premise for the further step: the identification of achievable and realistic performance targets based on the knowledge of the state-of-the-art. Data collected by several clinical laboratories worldwide allow the classification of performances for available QIs into three levels: optimum, desirable and minimum, in agreement with the widely accepted proposal for analytical quality specifications. PMID- 25719323 TI - Assessing quality on the Sigma scale from proficiency testing and external quality assessment surveys. AB - BACKGROUND: There is a need to assess the quality being achieved for laboratory examinations that are being utilized to support evidence-based clinical guidelines. Application of Six Sigma concepts and metrics can provide an objective assessment of the current analytical quality of different examination procedures. METHODS: A "Sigma Proficiency Assessment Chart" can be constructed for data obtained from proficiency testing and external quality assessment surveys to evaluate the observed imprecision and bias of method subgroups and determine quality on the Sigma scale. RESULTS: Data for hemoglobin A1c (HbA1c) from a 2014 survey by the College of American Pathologists (CAP) demonstrates that approximately two-thirds of the examination subgroups provide only two-Sigma quality when evaluated against the CAP requirement of an allowable total error of 6.0%. The weighted averages were 1.46 Sigma for a survey sample with an assigned value of 6.49% Hb (average bias 2.31%, CV 2.87%), 1.45 Sigma at 6.97% Hb (average bias 2.29%, CV 2.81%), and 1.75 at 9.65% Hb (average bias 1.55%, CV 2.71%). Maximum biases for examination subgroups were 5.7%, 5.8%, and 4.1%, respectively. CONCLUSIONS: Assessment of quality on the Sigma scale provides evidence of the analytical performance that is being achieved relative to requirements for intended use and should be useful for identifying and prioritizing improvements that are needed in the analytical quality of laboratory examinations. In spite of global and national standardization programs, bias is still a critical limitation of current HbA1c examination procedures. PMID- 25719324 TI - A new integrated tool for assessing and monitoring test comparability and stability. PMID- 25719325 TI - S100B protein concentration measurement according to two different immunoassays. PMID- 25719326 TI - Glycation rate of haemoglobins S, C, D, E, J and G, and analytical interference on the measurement of HbA1c with affinity chromatography and capillary electrophoresis. PMID- 25719327 TI - Two novel genomic rearrangements identified in suicide subjects using a-CGH array. PMID- 25719328 TI - Quantitative detection of amyloid-beta peptides by mass spectrometry: state of the art and clinical applications. AB - Alzheimer's disease (AD) is the most common form of dementia in humans, and a major public health concern with 35 million of patients worldwide. Cerebrospinal fluid (CSF) biomarkers being early diagnostic indicators of AD, it is essential to use the most efficient analytical methods to detect and quantify them accurately. These biomarkers, and more specifically amyloid-beta (Abeta) peptides, are measured in routine clinical practice using immunoassays. However, there are several limits to this immunodetection in terms of specificity and multiplexing of the multiple isoforms of the Abeta peptides. To overcome these issues, the quantification of these analytes by mass spectrometry (MS) represents an interesting alternative, and several assays have been described over the past years. This article reviews the different Abeta peptides quantitative MS-based approaches published so far, compares their pre-analytical phase, and the different quantitative strategies implemented that might be suitable for clinical applications. PMID- 25719329 TI - Defining analytical performance specifications: Consensus Statement from the 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine. PMID- 25719330 TI - Combining antibody tests and taking into account antibody levels improves serologic diagnosis of celiac disease. AB - BACKGROUND: The European Society for Pediatric Gastroenterology and Nutrition states that if IgA anti-tissue transglutaminase (tTG) exceeds 10 times the upper limit of normal (ULN), there is the possibility to diagnose celiac disease (CD) without duodenal biopsy, if supported by anti-endomysium testing and human leukocyte antigen (HLA) typing. We aimed to evaluate whether combining IgA tTG and IgG anti-deamidated gliadin peptide (DGP) antibody testing and taking into account the antibody levels improves clinical interpretation. METHODS: We calculated likelihood ratios for various test result combinations using data obtained from newly diagnosed CD patients (n=156) [13 children <2 years, 45 children between 2 and 16 years, and 98 adults (>16 years)] and 974 disease controls. All patients and controls underwent duodenal biopsy. IgA anti-tTG and IgG anti-DGP assays were from Thermo Fisher and Inova. RESULTS: Likelihood ratios for CD markedly increased with double positivity and increasing antibody levels of IgA anti-tTG and IgG anti-DGP. Patients with double positivity and high antibody levels (>3 times, >10 times ULN) had a high probability for having CD (likelihood ratio >=649 for >3 times ULN and infinity for >10 times ULN). The fraction of CD patients with double positivity and high antibody levels was 59% 67% (depending on the assay) for >3 ULN and 33%-36% (depending on the assay) for >10 ULN, respectively. This fraction was significantly higher in children with CD than in adults. CONCLUSIONS: Combining IgG anti-DGP with IgA anti-tTG and defining thresholds for antibody levels improves the serologic diagnosis of CD. PMID- 25719331 TI - Application of a point of care creatinine device for trend monitoring in kidney transplant patients: fit for purpose? AB - BACKGROUND: The StatSensor(r) Xpress-iTM, a point-of-care system for blood creatinine measurement, offers patients the possibility of self-monitoring creatinine. In this study, the analytical performance of the StatSensor(r) for both detecting current renal function and monitoring renal (dys)function in kidney transplant patients was examined. METHODS: Accuracy of the StatSensor(r) with capillary and venous whole blood was evaluated and compared to an isotopic dilution mass spectrometry (IDMS)-traceable enzymatic creatinine test in venous serum (n=138). Twenty Li-heparin samples were compared to the IDMS reference method performed by a Joint Committee for Traceability in Laboratory Medicine (JCTLM)-listed reference laboratory (RfB, Bonn, Germany). To evaluate StatSensor(r)'s suitability to monitor kidney function, both venous and capillary samples were obtained in 20 hospitalized transplantation patients. Venous samples were analyzed with an IDMS-traceable enzymatic test, capillary samples were measured using the StatSensor(r). For all 2-day intervals, percentage change in creatinine was compared between both methods. RESULTS: The StatSensor(r) did not meet total allowable error criterion of 6.9%. Average overall CVa for the StatSensor(r) was 10.4% and 5.2% for capillary and venous whole blood results, respectively. Overall CVa for the central laboratory serum creatinine method was <1.5%. For monitoring renal (dys)function, total agreement of the StatSensor(r) with an IDMS-traceable enzymatic test was 68% using a 10% Delta change. No significant differences were found between the changes observed by both methods. CONCLUSIONS: Capillary blood testing with the StatSensor(r) is not advisable for determining current renal function with a single creatinine measurement in kidney transplant patients, mainly due to excessive analytical imprecision. However, our results suggest that capillary blood testing with the StatSensor(r) can be used for daily trend monitoring of kidney function after renal transplantation. PMID- 25719332 TI - Methods to identify saline-contaminated electrolyte profiles. AB - BACKGROUND: With providers becoming more selective in ordering daily chemistry profiles, it is critical that profiles ordered are accurate. Contaminated electrolyte profiles are an overlooked and potentially dangerous source of inaccurate clinical data. This study aimed to develop a method to accurately identify electrolyte profiles contaminated with normal saline to prevent reporting of erroneous measurements. METHODS: We conducted a retrospective cohort study of 76,497 electrolyte profiles from 5032 patients in a deidentified clinical database of all patients in the electronic medical record at Vanderbilt University Medical Center. Five methods to identify errors in quantification based on either deviations from observed concentration distributions or expected numerical changes from saline contamination were developed and tested. Potentially contaminated measurements were validated based on changes in electrolyte concentrations observed in the subsequent sample. RESULTS: Identification of erroneous electrolyte profiles based on absolute and percent deviations from normal variation rarely resulted in >50% of identified samples validated as contaminated. A targeted methodology based on expected changes in calcium and chloride concentrations due to saline contamination validated approximately 80% of identified samples when higher thresholds for changes in electrolyte concentration were used and 50% of identified samples when lower thresholds were used. CONCLUSIONS: Targeted methodology based on changes in chloride and calcium successfully identified electrolyte profiles suspicious for contamination. Implementation of this methodology could prevent misinterpretation of a patient's clinical course, inappropriate interventions, and unwarranted changes in treatment strategy. PMID- 25719333 TI - Hormones and the blood-brain barrier. AB - Hormones exert many actions in the brain, and brain cells are also hormonally active. To reach their targets in brain structures, hormones must overcome the blood-brain barrier (BBB). The BBB is a unique device selecting desired/undesired molecules to reach or leave the brain, and it is composed of endothelial cells forming the brain vasculature. These cells differ from other endothelial cells in their almost impermeable tight junctions and in possessing several membrane structures such as receptors, transporters, and metabolically active molecules, ensuring their selection function. The main ways how compounds pass through the BBB are briefly outlined in this review. The main part concerns the transport of major classes of hormones: steroids, including neurosteroids, thyroid hormones, insulin, and other peptide hormones regulating energy homeostasis, growth hormone, and also various cytokines. Peptide transporters mediating the saturable transport of individual classes of hormones are reviewed. The last paragraph provides examples of how hormones affect the permeability and function of the BBB either at the level of tight junctions or by various transporters. PMID- 25719335 TI - Melatonin counteracts changes in hypothalamic gene expression of signals regulating feeding behavior in high-fat fed rats. AB - BACKGROUND: Previous studies indicate that the administration of melatonin caused body weight and abdominal visceral fat reductions in rodent models of hyperadiposity. The objective of the present study performed in high-fat fed rats was to evaluate the activity of melatonin on gene expression of some medial basal hypothalamus (MBH) signals involved in feeding behavior regulation, including neuropeptide Y (NPY), proopiomelanocortin (POMC), prolactin-releasing peptide (PrRP), leptin- and insulin-receptors (R) and insulin-R substrate (IRS)-1 and -2. Blood levels of leptin and adiponectin were also measured. METHODS: Adult Wistar male rats were divided into four groups (n=16 per group): (i) control diet (3% fat); (ii) high-fat (35%) diet; (iii) high-fat diet+melatonin; (iv) control diet+melatonin. Rats had free access to high-fat or control chow and one of the following drinking solutions: (a) tap water; (b) 25 MUg/mL of melatonin. RESULTS: After 10 weeks, the high-fat fed rats showed augmented MBH mRNA levels of NPY, leptin-R, PrRP, insulin-R, IRS-1 and IRS-2. The concomitant administration of melatonin counteracted this increase. Feeding of rats with a high-fat diet augmented expression of the MBH POMC gene through an effect insensitive to melatonin treatment. The augmented levels of circulating leptin and adiponectin seen in high-fat fed rats were counteracted by melatonin as was the augmented body weight: melatonin significantly attenuated a body weight increase in high fat fed rats without affecting chow or water consumption. Melatonin augmented plasma leptin and adiponectin in control rats. CONCLUSIONS: The results indicate that an effect on gene expression of feeding behavior signals at the central nervous system (CNS) may complement a peripheral rise of the energy expenditure produced by melatonin to decrease body weight in high-fat fed rats. PMID- 25719334 TI - The role of perivascular adipose tissue in vasoconstriction, arterial stiffness, and aneurysm. AB - Since the "rediscovery" of brown adipose tissue in adult humans, significant scientific efforts are being pursued to identify the molecular mechanisms to promote a phenotypic change of white adipocytes into brown-like cells, a process called "browning". It is well documented that white adipose tissue (WAT) mass and factors released from WAT influence the vascular function and positively correlate with cardiac arrest, stroke, and other cardiovascular complications. Similar to other fat depots, perivascular adipose tissue (PVAT) is an active endocrine organ and anatomically surrounds vessels. Both brown-like and white like PVAT secrete various adipokines, cytokines, and growth factors that either prevent or promote the development of cardiovascular diseases (CVDs) depending on the relative abundance of each type and their bioactivity in the neighboring vasculature. Notably, pathophysiological conditions, such as obesity, hypertension, or diabetes, induce the imbalance of PVAT-derived vasoactive products that promote the infiltration of inflammatory cells. This then triggers derangements in vascular smooth muscle cells and endothelial cell dysfunction, resulting in the development of vascular diseases. In this review, we discuss the recent advances on the contribution of PVAT in CVDs. Specifically, we summarize the current proposed roles of PVAT in relationship with vascular contractility, endothelial dysfunction, neointimal formation, arterial stiffness, and aneurysm. PMID- 25719336 TI - Obesity and cancer. AB - The incidence of obesity in the Western world has increased dramatically during the recent decades. Epidemiological data suggest that obesity is associated with an increased risk of several but not all types of cancers, with clear sex specific differences. The underlying mechanisms are still a matter of debate. In this review, we discuss the potential factors linking obesity to cancer, with a focus on hormone-dependent cancer types. Current experimental evidence suggests that insulin resistance and a chronic, subclinical inflammation in the visceral fat are the major metabolic events, causing alterations in the levels of insulin, glucose, free fatty acids, insulin-like growth factor-1 and -2, adipose tissue derived proinflammatory factors (tumor necrosis factor-alpha and interleukin-1, 6, -12, and -23), and other bioactive molecules such as adipokines (adiponectin and leptin), vascular endothelial growth factor, sex hormones, gut microbiota, and secondary bile acids. All these factors may act directly or indirectly on the tumor microenvironment to drive tumor progression via the stimulation of cell survival/antiapoptosis, cell proliferation, angiogenesis, and invasion/metastasis of cancer cells. Therapeutic strategies (including bariatric surgery) that target dysfunctional or inflamed fat have been shown to benefit patients, whereas other cell- or hormone-directed interventions (such as the conversion of visceral fat macrophages to an anti-inflammatory M2 phenotype or the pharmacological modulation of serum adipokine levels) are still theoretical and need to be clinically evaluated for their ability to successfully treat or prevent obesity related cancers. PMID- 25719337 TI - A survey of computational methods in transcriptome-wide alternative splicing analysis. AB - Alternative splicing is widely recognized for its roles in regulating genes and creating gene diversity. Consequently the identification and quantification of differentially spliced transcripts is pivotal for transcriptome analysis. Here, we review the currently available computational approaches for the analysis of RNA-sequencing data with a focus on exon-skipping events of alternative splicing and discuss the novelties as well as challenges faced to perform differential splicing analyses. In accordance with operational needs we have classified the software tools, which may be instrumental for a specific analysis based on the experimental objectives and expected outcomes. In addition, we also propose a framework for future directions by pinpointing more extensive experimental validation to assess the accuracy of the software predictions and improvements that would facilitate visualizations, data processing, and downstream analyses along with their associated software implementations. PMID- 25719338 TI - The human beta-amyloid precursor protein: biomolecular and epigenetic aspects. AB - Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates beta amyloid (Abeta) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age <65 years old). However, these mutations in FAD represent a very small percentage of cases (~1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age >65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APP-mRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments. PMID- 25719339 TI - Conditional transformation models for survivor function estimation. AB - In survival analysis, the estimation of patient-specific survivor functions that are conditional on a set of patient characteristics is of special interest. In general, knowledge of the conditional survival probabilities of a patient at all relevant time points allows better assessment of the patient's risk than summary statistics, such as median survival time. Nevertheless, standard methods for analysing survival data seldom estimate the survivor function directly. Therefore, we propose the application of conditional transformation models (CTMs) for the estimation of the conditional distribution function of survival times given a set of patient characteristics. We used the inverse probability of censoring weighting approach to account for right-censored observations. Our proposed modelling approach allows the prediction of patient-specific survivor functions. In addition, CTMs constitute a flexible model class that is able to deal with proportional as well as non-proportional hazards. The well-known Cox model is included in the class of CTMs as a special case. We investigated the performance of CTMs in survival data analysis in a simulation that included proportional and non-proportional hazard settings and different scenarios of explanatory variables. Furthermore, we re-analysed the survival times of patients suffering from chronic myelogenous leukaemia and studied the impact of the proportional hazards assumption on previously published results. PMID- 25719340 TI - Translation and evaluation of the Cultural Awareness Scale for Korean nursing students. AB - BACKGROUND: To evaluate the effectiveness of a curriculum for achieving high levels of cultural competence, we need to be able to assess education intended to enhance cultural competency skills. We therefore translated the Cultural Awareness Scale (CAS) into Korean (CAS-K). The purpose of this study was to evaluate the cross-cultural applicability and psychometric properties of the CAS K, specifically its reliability and validity. METHODS: A cross-sectional descriptive design was used to conduct the evaluation. A convenience sample of 495 nursing students was recruited from four levels of nursing education within four universities in the city of Daejeon, South Korea. RESULTS: This study provided beginning evidence of the validity and reliability of the CAS-K and the cross-cultural applicability of the concepts underlying this instrument. Cronbach's alpha ranged between 0.59 and 0.86 (overall 0.89) in the tests of internal consistency. Cultural competency score prediction of the experience of travel abroad (r=0.084) and the perceived need for cultural education (r=0.223) suggested reasonable criterion validity. Five factors with eigenvalues >1.0 were extracted, accounting for 55.58% of the variance; two retained the same items previously identified for the CAS. CONCLUSION: The CAS-K demonstrated satisfactory validity and reliability in measuring cultural awareness in this sample of Korean nursing students. The revised CAS-K should be tested for its usability in curriculum evaluation and its applicability as a guide for teaching cultural awareness among groups of Korean nursing students. PMID- 25719341 TI - Using "think aloud" to capture clinical reasoning during patient simulation. AB - Think Aloud (TA), a strategy in which subjects are instructed to verbalize thoughts as they occur while completing an assigned task, was integrated into a study of clinical reasoning during high fidelity patient simulation by baccalaureate nursing students. TA methods in nursing education research with patient simulation have not previously been reported. Concurrent TA (verbalization of thoughts in short-term memory) and retrospective TA (reflective thoughts verbalized during an immediate post-simulation interview) methods facilitated the collection of rich and meaningful data. Students demonstrated distinct patterns in verbalization during concurrent TA, including public and private thoughts, narration of care, and the use of the pause to facilitate clinical reasoning. Retrospective TA data provided rich descriptions of reflection-on-action. TA provides a rich source of data regarding clinical reasoning as experienced by the baccalaureate nursing student during high fidelity patient simulation. PMID- 25719342 TI - Inferring bi-directional interactions between circadian clock genes and metabolism with model ensembles. AB - There has been much interest in reconstructing bi-directional regulatory networks linking the circadian clock to metabolism in plants. A variety of reverse engineering methods from machine learning and computational statistics have been proposed and evaluated. The emphasis of the present paper is on combining models in a model ensemble to boost the network reconstruction accuracy, and to explore various model combination strategies to maximize the improvement. Our results demonstrate that a rich ensemble of predictors outperforms the best individual model, even if the ensemble includes poor predictors with inferior individual reconstruction accuracy. For our application to metabolomic and transcriptomic time series from various mutagenesis plants grown in different light-dark cycles we also show how to determine the optimal time lag between interactions, and we identify significant interactions with a randomization test. Our study predicts new statistically significant interactions between circadian clock genes and metabolites in Arabidopsis thaliana, and thus provides independent statistical evidence that the regulation of metabolism by the circadian clock is not uni directional, but that there is a statistically significant feedback mechanism aiming from metabolism back to the circadian clock. PMID- 25719343 TI - Study of triplet periodicity differences inside and between genomes. AB - Triplet periodicity (TP) is a distinctive feature of the protein coding sequences of both prokaryotic and eukaryotic genomes. In this work, we explored the TP difference inside and between 45 prokaryotic genomes. We constructed two hypotheses of TP distribution on a set of coding sequences and generated artificial datasets that correspond to the hypotheses. We found that TP is more similar inside a genome than between genomes and that TP distribution inside a real genome dataset corresponds to the hypothesis which implies that a common TP pattern exists for the majority of sequences inside a genome. Additionally, we performed gene classification based on TP matrixes. This classification showed that TP allows identification of the genome to which a given gene belongs with more than 85% accuracy. PMID- 25719344 TI - The effect of ginger (Zingiber officinale) on glycemic markers in patients with type 2 diabetes. AB - BACKGROUND: Ginger (Zingiber officinale) is one of the functional foods which contains biological compounds including gingerol, shogaol, paradol and zingerone. Ginger has been proposed to have anti-cancer, anti-thrombotic, anti-inflammatory, anti-arthritic, hypolipidemic and analgesic properties. Here, we report the effect of ginger supplementation on glycemic indices in Iranian patients with type 2 diabetes. METHODS: A double-blind, placebo-controlled, randomized clinical trial was conducted on 20-60 -year-old patients with type 2 diabetes who did not receive insulin. Participants in the intervention and control groups were received 3 g of powdered ginger or placebo (lactose) (in capsules) daily for 3 months. Glycemic indices, total antioxidant capacity (TAC), malondialdehyde (MDA), C-reactive protein (CRP), serum paraoxonase, dietary intake and physical activity were measured at the beginning and end of the study, and after 12 h fasting. RESULTS: Comparison of the indices after 3 months showed that the differences between the ginger and placebo groups were statistically significant as follows: serum glucose (-19.41 +/- 18.83 vs. 1.63 +/- 4.28 mg/dL, p < 0.001), HbA1c percentage (-0.77 +/- 0.88 vs. 0.02 +/- 0.16%, p < 0.001), insulin (-1.46 +/- 1.7 vs. 0.09 +/- 0.34 MUIU/mL, p < 0.001), insulin resistance (-16.38 +/- 19.2 vs. 0.68 +/- 2.7, p < 0.001), high-sensitive CRP (-2.78 +/- 4.07 vs. 0.2 +/- 0.77 mg/L, p < 0.001), paraoxonase-1 (PON-1) (22.04 +/- 24.53 vs. 1.71 +/- 2.72 U/L, p < 0.006), TAC (0.78 +/- 0.71 vs. -0.04 +/- 0.29 uIU/mL, p < 0.01) and MDA (-0.85 +/- 1.08 vs. 0.06 +/- 0.08 umol/L, p < 0.001) were significantly different. CONCLUSIONS: This report shows that the 3 months supplementation of ginger improved glycemic indices, TAC and PON-1 activity in patients with type 2 diabetes. PMID- 25719345 TI - Ayurveda in changing scenario of diabetes management for developing safe and effective treatment choices for the future. AB - Ayurveda described diabetes mellitus (DM) as Madhumeha. This ancient evidence based system of medicine enumerated various herbs and formulations for its management, which needs scientific validation. Whereas translational "bedside to bench" approach in biomedical research is an upcoming concept, its application in traditional and complementary medicine can be interesting. The intersecting concepts in the field Ayurveda and translational research needs "omics" approach. The Ayurvedic biology concepts about DM have its close relations with present systems biology approach. Metabolic changes causing tissue damage connected with genetic and immunological irregularities leading to insulin resistance coincide with ancient knowledge. Combinatorial therapy according to Prakriti type as elucidated by Ayurgenomics should be carried on for further research. "Bedside to bench" approaches in research utilizing metabolomics and pharmacogenomics approach can be a major step towards changing the therapeutic strategy towards diabetes. Prameha which is described as the pre-diabetic state is a novel concept in Ayurvedic etiopathogenesis, while metabolomic parameters like lipid level in urine can be a thrust area of research to have a pre-diabetic screening method in high-risk populations. This tradition-guided research paradigm can open up novel opportunities in traditional knowledge-inspired systems biology and drug discovery against diabetes. PMID- 25719346 TI - Lesions involving the jugular foramen: clinical characteristics and surgical management. AB - CONCLUSION: Lesions involving the jugular foramen (JF) present as various diagnoses. Pulsatile tinnitus is more common in glomus jugulare (GJ) tumors, whereas otalgia and facial nerve paresis are more prevalent in temporal bone malignancies (TBMs). Preoperative facial nerve electroneurography (ENoG) was significantly correlated with postoperative facial nerve function. OBJECTIVE: To describe the diagnosis and surgical management of lesions involving the JF. METHODS: The charts were reviewed for 38 patients who had lesions involving the JF, including 14 patients with TBMs, 11 with GJ tumors, 7 with cholesteatomas, 2 with facial nerve schwannomas, 2 with JF schwannomas, and 2 with cholesterol granulomas. The follow-up data were recorded. RESULTS: The most frequent symptoms included hearing loss (89.47%), followed by otorrhea (47.37%) and pulsatile tinnitus (39.47%). With respect to TBMs, 57.14% of patients complained of otorrhea and otalgia, and 50.00% presented with facial nerve paresis. Among the 13 patients with facial nerve paresis, 53.85% were diagnosed with TBMs. Regarding GJ tumors, 81.82% had pulsatile tinnitus and hearing loss. Among the 25 patients with normal preoperative facial nerve function, the mean facial nerve ENoG reduction was 29.48 +/- 29.15%, and the mean postoperative facial nerve score was 77.48 +/- 33.13. The correlation coefficient was -0.973 (p = 0.000). PMID- 25719347 TI - Hot baths and cold minds: neuroscience, mind reading, and mind misreading. AB - The idea-the possibility-of reading the mind, from the outside or indeed even from the inside, has exercised humanity from the earliest times. If we could read other minds both prospectively, to discern intentions and plans, and retrospectively, to discover what had been "on" those minds when various events had occurred, the implications for morality and for law and social policy would be immense. Recent advances in neuroscience have offered some, probably remote, prospects of improved access to the mind, but a different branch of technology seems to offer the most promising and the most daunting prospect for both mind reading and mind misreading. You can't have the possibility of the one without the possibility of the other. This article tells some of this story. PMID- 25719348 TI - Guest editorial: wither philosophical bioethics? PMID- 25719349 TI - What do you think of philosophical bioethics? AB - This article provides an overview of approaches to bioethics-practical and theoretical, philosophical and nonphilosophical. It is argued that those who yearn for pragmatism and real-life relevance would do well to concentrate on politics, legislation, social policy, and lobbying. Those, on the other hand, who seek knowledge about our moral thought might be interested in philosophical bioethics-in the explication of concepts, arguments, views, and normative statements. PMID- 25719350 TI - Get to the point! Philosophical bioethics and the struggle to remain relevant. AB - This article argues that practicality is currently overemphasized in philosophical contributions to bioethics. The inclinations to aim at relevance, to ground normativity on common morality, and to involve many academic disciplines in ethical discussions is understandable, but they are all poorly founded. When answers to difficult questions are already known at the outset, these endeavors can help decisionmakers in gaining the acceptance of the general public. Wider theoretical analyses, in which philosophers could excel, however, tend to be lost in these practical enterprises. PMID- 25719351 TI - Toward critical bioethics. AB - This article deals with the question as to what makes bioethics a critical discipline. It considers different senses of criticism and evaluates their strengths and weaknesses. A primary method in bioethics as a philosophical discipline is critical thinking, which implies critical evaluation of concepts, positions, and arguments. It is argued that the type of analytical criticism that restricts its critical role to critical thinking of this type often suffers from other intellectual flaws. Three examples are taken to demonstrate this: premature criticism, uncritical self-understanding of theoretical assumptions, and narrow framing of bioethical issues. Such flaws can lead both to unfair treatment of authors and to uncritical discussion of topics. In this context, the article makes use of Hayry's analysis of different rationalities in bioethical approaches and argues for the need to recognize the importance of communicative rationality for critical bioethics. A radically different critical approach in bioethics, rooted in social theory, focuses on analyses of power relations neglected in mainstream critical thinking. It is argued that, although this kind of criticism provides an important alternative in bioethics, it suffers from other shortcomings that are rooted in a lack of normative dimensions. In order to complement these approaches and counter their shortcomings, there is a need for a bioethics enlightened by critical hermeneutics. Such hermeneutic bioethics is aware of its own assumptions, places the issues in a wide context, and reflects critically on the power relations that stand in the way of understanding them. Moreover, such an approach is dialogical, which provides both a critical exercise of speech and a normative dimension implied in the free exchange of reasons and arguments. This discussion is framed by Hedgecoe's argument that critical bioethics needs four elements: to be empirically rooted, theory challenging, reflexive, and politely skeptical. PMID- 25719352 TI - Philosophical feminist bioethics: past, present, and future. AB - The end of the last century was a particularly vibrant period for feminist bioethics. Almost two decades on, we reflect on the legacy of the feminist critique of bioethics and investigate the extent to which it has been successful and what requires more attention yet. We do this by examining the past, present, and future: we draw out three feminist concerns that emerged in this period abstraction, individualism, and power-and consider three feminist responses relationality, particularity, and justice-and we finish with some thoughts about the future. PMID- 25719353 TI - Toward a postmodern bioethics. AB - In this article, postmodernism is presented as posing a challenge to the role of philosophy within bioethics. It is argued that any attempt to develop a postmodern bioethics must respond to arguments concerning power, relational responsibility, and violence. Contemporary work on the topic of relational autonomy and naturalized bioethics is interpreted as engaging with the postmodern challenge. This article proposes that the role of philosophy in bioethics should be not to provide moral guidance but rather to adopt a critical approach to the possible consequences of privileging any position or understanding over others. PMID- 25719354 TI - The role of philosophy in global bioethics: introducing four trends. AB - This article examines the relationship between philosophy and culture in global bioethics. First, it studies what is meant by the term "global" in global bioethics. Second, the author introduces four different types, or recognizable trends, in philosophical inquiry in bioethics today. The main argument is that, in order to make better sense of the complexity of the ethical questions and challenges we face today across the globe, we need to embrace the universal nature of self-critical and analytical philosophical analysis and argumentation, rather than using seemingly philosophical approaches to give unjustified normative emphasis on different cultural approaches to bioethics. PMID- 25719355 TI - The grand leap of the whale up the Niagara Falls: converting philosophical conclusions into policy prescriptions. AB - This article analyzes a neat conjuring trick employed in bioethics, that is, the immediate conversion of a philosophical conclusion into a policy prescription, and compares it to the "grand leap of the whale up the Niagara Falls" mentioned by Benjamin Franklin. It is shown that there is no simple and easy way to achieve the conversion, by considering arguments falling under four headings: (1) reasonable disagreement about values and theories, (2) general jurisprudential arguments, (3) the differences between policymaking and philosophy, and (4) the messy world of implementation. The particular issue used to illustrate the difficulties in moving from philosophical conclusion to policy description is infanticide of healthy infants, but the analysis is general, and the conclusion that the immediate move to policy is illegitimate is quite general. PMID- 25719356 TI - The evolving idea of social responsibility in bioethics: a welcome trend. AB - This article discusses the notion of social responsibility for personal health and well-being in bioethics. Although social responsibility is an intrinsic aspect of bioethics, and its role is increasingly recognized in certain areas, it can still be claimed that bioethics in general is committed to an individualistic theoretical framework that disregards the social context in which decisions, health, and well-being are situated. The philosophical premises of this framework regard individuals as rational decisionmakers who can be held accountable for their health conditions and who should be the primary objects of intervention in attempts to reduce lifestyle-associated chronic diseases. There are, however, social determinants of health that challenge this conclusion. Because their impact can be controlled, to a certain extent, by social and public policy decisions, their existence shows the inadequacy of the purely individualistic approach. I suggest, accordingly, that bioethics would benefit, both academically and societally, from a more social perspective. Bioethical studies that acknowledge, from the start, the social determinants of health would be more amenable to constructive multi- and interdisciplinarity, and a more balanced account of responsibility would further the contribution of sound bioethical work to sensible public policies. PMID- 25719357 TI - Your morality, my mortality: conscientious objection and the standard of care. AB - Recently the scope of protections afforded those healthcare professionals and institutions that refuse to provide certain interventions on the grounds of conscience have expanded, in some instances insulating providers (institutional and individual) from any liability or sanction for harms that patients experience as a result. With the exponential increase in the penetration of Catholic affiliated healthcare across the country, physicians and nurses who are not practicing Catholics are nevertheless required to execute documents pledging to conform their patient care to the Ethical and Religious Directives for Health Care Services as a condition of employment or medical staff privileges. In some instances, doing so may result in patient morbidity or mortality or violate professional standards for respecting advance directives or surrogate decisionmaking. This article challenges the ethical propriety of such institutional mandates and argues that legal protections for conscientious refusal must provide redress for patients who are harmed by care that falls below the prevailing clinical standards. PMID- 25719358 TI - Why is therapeutic misconception so prevalent? AB - Therapeutic misconception (TM)-when clinical research participants fail to adequately grasp the difference between participating in a clinical trial and receiving ordinary clinical care-has long been recognized as a significant problem in consent to clinical trials. We suggest that TM does not primarily reflect inadequate disclosure or participants' incompetence. Instead, TM arises from divergent primary cognitive frames. The researchers' frame places the clinical trial in the context of scientific designs for assessing intervention efficacy. In contrast, most participants have a cognitive frame that is personal and focused primarily on their medical problems. To illustrate this, we draw on interview material from both clinical researchers and participants in clinical trials. We suggest that reducing TM requires encouraging subjects to adjust their frame, not just add information to their existing frame. What is necessary is a scientific reframing of participation in a clinical trial. PMID- 25719359 TI - Vitiligo in the Koolen-de Vries or 17q21.31 microdeletion syndrome. PMID- 25719360 TI - Developing a laddered algorithm for the management of intractable epistaxis: a risk analysis. AB - IMPORTANCE: For patients with epistaxis in whom initial interventions, such as anterior packing and cauterization, had failed, options including prolonged posterior packing, transnasal endoscopic sphenopalatine artery ligation (TESPAL), and embolization are available. However, it is unclear which interventions should be attempted and in which order. While cost-effectiveness analyses have suggested that TESPAL is the most responsible use of health care resources, physicians must also consider patient risk to maintain a patient-centered decision-making process. OBJECTIVE: To quantify the risk associated with the management of intractable epistaxis. DESIGN AND SETTING: A risk analysis was performed using literature-reported probabilities of treatment failure and adverse event likelihoods in an emergency department and otolaryngology hospital admissions setting. The literature search included articles from 1980 to May 2014. The analysis was modeled for a 50-year-old man with no other medical comorbidities. Severities of complications were modeled based on Environmental Protection Agency recommendations, and health state utilities were monetized based on a willingness to pay $22 500 per quality-adjusted life-year. Six management strategies were developed using posterior packing, TESPAL, and embolization in various sequences (P, T, and E, respectively). MAIN OUTCOMES AND MEASURES: Total risk associated with each algorithm quantified in US dollars. RESULTS: Algorithms involving posterior packing and TESPAL as first-line interventions were found to be similarly low risk. The lowest-risk approaches were P-T-E ($2437.99 [range, $1482.83-$6976.40]), T-P-E ($2840.65 [range, $1136.89-$8604.97]), and T-E-P ($2867.82 [range, $1141.05-$9833.96]). Embolization as a first-line treatment raised the total risk significantly owing to the risk of cerebrovascular events (E-T-P, $11 945.42 [range, $3911.43-$31 847.00]; and E-P-T, $11 945.71 [range, $3919.91-$31 767.66]). CONCLUSIONS AND RELEVANCE: Laddered approaches using TESPAL and posterior packing appear to provide the lowest risk. Combining risk and cost-effectiveness perspectives, we recommend a laddered approach to intractable epistaxis with TESPAL first, followed by either embolization or posterior packing. PMID- 25719361 TI - Batch-specific discrimination using nuclear quadrupole resonance spectroscopy. AB - In this paper, we report on the identification of batches of analgesic paracetamol (acetaminophen) tablets using nitrogen-14 nuclear quadrupole resonance spectroscopy ((14)N NQR). The high sensitivity of NQR to the electron charge distribution surrounding the quadrupolar nucleus enables the unique characterization of the crystal structure of the material. Two hypothesis were tested on batches of the same brand: the within the same batch variability and the difference between batches that varied in terms of their batch number and expiry date. The multivariate analysis of variance (MANOVA) did not provide any within-batches variations, indicating the natural deviation of a medicine manufactured under the same conditions. Alternatively, the statistical analysis revealed a significant discrimination between the different batches of paracetamol tablets. Therefore, the NQR signal is an indicator of factors that influence the physical and chemical integrity of the material. Those factors might be the aging of the medicine, the manufacturing, or storage conditions. The results of this study illustrate the potential of NQR as promising technique in applications such as detection and authentication of counterfeit medicines. PMID- 25719362 TI - Polycyclic aromatic hydrocarbons (PAHs) in indoor dusts of Guizhou, southwest of China: status, sources and potential human health risk. AB - Polycyclic aromatic hydrocarbons (PAHs) were analyzed for 136 indoor dust samples collected from Guizhou province, southwest of China. The ?18PAHs concentrations ranged from 2.18 MUg*g-1 to 14.20 MUg*g-1 with the mean value of 6.78 MUg*g-1. The highest Sigma18PAHs concentration was found in dust samples from orefields, followed by city, town and village. Moreover, the mean concentration of Sigma18PAHs in indoor dust was at least 10% higher than that of outdoors. The 4-6 rings PAHs, contributing more than 70% of ?18PAHs, were the dominant species. PAHs ratios, principal component analysis with multiple linear regression (PCA MLR) and hierarchical clustering analysis (HCA) were applied to evaluate the possible sources. Two major origins of PAHs in indoor dust were identified as vehicle emissions and coal combustion. The mean incremental lifetime cancer risk (ILCR) due to human exposure to indoor dust PAHs in city, town, village and orefield of Guizhou province, China was 6.14*10-6, 5.00*10-6, 3.08*10-6, 6.02*10 6 for children and 5.92*10-6, 4.83*10-6, 2.97*10-6, 5.81*10-6 for adults, respectively. PMID- 25719363 TI - Nutritional manipulation for the primary prevention of gestational diabetes mellitus: a meta-analysis of randomised studies. AB - INTRODUCTION: The rise in gestational diabetes (GDM), defined as first onset or diagnosis of diabetes in pregnancy, is a global problem. GDM is often associated with unhealthy diet and is a major contributor to adverse outcomes maternal and fetal outcomes. Manipulation of nutrition has the potential to prevent GDM. METHODS: We assessed the effects of nutritional manipulation in pregnancy on GDM and relevant maternal and fetal outcomes by a systematic review of the literature. We searched MEDLINE, EMBASE, and Cochrane Database from inception to March 2014 without any language restrictions. Randomised controlled trials (RCT) of nutritional manipulation to prevent GDM were included. We summarised dichotomous data as relative risk (RR) and continuous data as standardised mean difference (SMD) with 95% confidence interval (CI). RESULTS: From 1761 citations, 20 RCTs (6,444 women) met the inclusion criteria. We identified the following interventions: diet-based (n = 6), mixed approach (diet and lifestyle) interventions (n = 13), and nutritional supplements (myo-inositol n = 1, diet with probiotics n = 1). Diet based interventions reduced the risk of GDM by 33% (RR 0.67; 95% CI 0.39, 1.15). Mixed approach interventions based on diet and lifestyle had no effect on GDM (RR 0.95; 95% CI 0.89, 1.22). Nutritional supplements probiotics combined with diet (RR 0.40; 95% CI 0.20, 0.78) and myo inositol (RR 0.40; 95% CI 0.16, 0.99) were assessed in one trial each and showed a beneficial effect. We observed a significant interaction between the groups based on BMI for diet-based intervention. The risk of GDM was reduced in obese and overweight pregnant women for GDM (RR 0.40, 95% CI 0.18, 0.86). CONCLUSIONS: Nutritional manipulation in pregnancy based on diet or mixed approach do not appear to reduce the risk of GDM. Nutritional supplements show potential as agents for primary prevention of GDM. PMID- 25719365 TI - Correction: the avian head induces cues for sound localization in elevation. PMID- 25719364 TI - Transcriptome sequencing of Codonopsis pilosula and identification of candidate genes involved in polysaccharide biosynthesis. AB - BACKGROUND: Codonopsis pilosula (Franch.) Nannf. is one of the most widely used medicinal plants. Although chemical and pharmacological studies have shown that codonopsis polysaccharides (CPPs) are bioactive compounds and that their composition is variable, their biosynthetic pathways remain largely unknown. Next generation sequencing is an efficient and high-throughput technique that allows the identification of candidate genes involved in secondary metabolism. PRINCIPAL FINDINGS: To identify the components involved in CPP biosynthesis, a transcriptome library, prepared using root and other tissues, was assembled with the help of Illumina sequencing. A total of 9.2 Gb of clean nucleotides was obtained comprising 91,175,044 clean reads, 102,125 contigs, and 45,511 unigenes. After aligning the sequences to the public protein databases, 76.1% of the unigenes were annotated. Among these annotated unigenes, 26,189 were assigned to Gene Ontology categories, 11,415 to Clusters of Orthologous Groups, and 18,848 to Kyoto Encyclopedia of Genes and Genomes pathways. Analysis of abundance of transcripts in the library showed that genes, including those encoding metallothionein, aquaporin, and cysteine protease that are related to stress responses, were in the top list. Among genes involved in the biosynthesis of CPP, those responsible for the synthesis of UDP-L-arabinose and UDP-xylose were highly expressed. SIGNIFICANCE: To our knowledge, this is the first study to provide a public transcriptome dataset prepared from C. pilosula and an outline of the biosynthetic pathway of polysaccharides in a medicinal plant. Identified candidate genes involved in CPP biosynthesis provide understanding of the biosynthesis and regulation of CPP at the molecular level. PMID- 25719366 TI - Assessing the permeability of landscape features to animal movement: using genetic structure to infer functional connectivity. AB - Human-altered environments often challenge native species with a complex spatial distribution of resources. Hostile landscape features can inhibit animal movement (i.e., genetic exchange), while other landscape attributes facilitate gene flow. The genetic attributes of organisms inhabiting such complex environments can reveal the legacy of their movements through the landscape. Thus, by evaluating landscape attributes within the context of genetic connectivity of organisms within the landscape, we can elucidate how a species has coped with the enhanced complexity of human altered environments. In this research, we utilized genetic data from eastern chipmunks (Tamias striatus) in conjunction with spatially explicit habitat attribute data to evaluate the realized permeability of various landscape elements in a fragmented agricultural ecosystem. To accomplish this we 1) used logistic regression to evaluate whether land cover attributes were most often associated with the matrix between or habitat within genetically identified populations across the landscape, and 2) utilized spatially explicit habitat attribute data to predict genetically-derived Bayesian probabilities of population membership of individual chipmunks in an agricultural ecosystem. Consistency between the results of the two approaches with regard to facilitators and inhibitors of gene flow in the landscape indicate that this is a promising new way to utilize both landscape and genetic data to gain a deeper understanding of human-altered ecosystems. PMID- 25719368 TI - Oncocytic Adenocarcinoma of the Orbit. AB - Oncocytic adenocarcinoma of the orbit is a rare tumor, with 1 case of nonlacrimal sac, nonlacrimal gland origin, and a poor outcome previously reported. An 85-year old man with a 2-month history of left-sided epiphora, enlarging eyelid nodules, and diplopia in left gaze was found on imaging to have a poorly circumscribed, nodular mass of uniform radiodensity in the inferomedial orbit. Incisional biopsy revealed morphologic and immunohistochemical features of oncocytic adenocarcinoma with origin in the caruncle suspected, and CT of the neck, chest, abdomen, and pelvis showed no metastases or remote primary tumor source. Based on multidisciplinary consensus, orbital exenteration with adjuvant radiation therapy was performed, and there was no evidence of residual or recurrent tumor 2 years after treatment. PMID- 25719367 TI - Multi-timescale modeling of activity-dependent metabolic coupling in the neuron glia-vasculature ensemble. AB - Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID- 25719369 TI - Lateral Canthal Position Following Lateral Orbitotomy and the Influence of Ocular Proptosis. AB - PURPOSE: Anecdotal evidence suggests that detachment of the lateral canthal tendon during lateral orbitotomy results in shortening of the horizontal palpebral aperture (HPA) and rounding of the lateral canthal angle (LCA). This study investigated the change in HPA and LCA following lateral orbitotomy and the effect of proptosis on the HPA. METHODS: Retrospective, single surgeon, review of all cases undergoing lateral orbitotomy, comprising of a canthotomy and cantholysis and reconstruction of the lateral canthus using a single suture. The HPA and lateral canthal height (LCH) were measured on pre- and postoperative photographs using ImageJ software. Changes in the LCA and degree of proptosis were also investigated. Exclusion criteria included previous eyelid surgery, acute trauma, and less than 6 months' follow up. RESULTS: There were 41 cases of lateral orbitotomy in 27 patients, 67% female, average age 51 years. Twenty patients had thyroid eye disease of which 14 underwent bilateral surgery; the other 7 patients had a variety of orbital pathologies. Thirteen patients underwent unilateral orbitotomy with the contralateral eye serving as a control. Average follow up was 23 months. Overall, the HPA and proptosis were reduced by 0.6 mm (p = 0.143) and 3.4 mm (p < 0.001), respectively. A 0.2-mm reduction in HPA was observed for every 1-mm reduction in proptosis. A difference in post orbitotomy HPA was observed between cases and their matched controls (p = 0.016). No rounding of the LCA or significant change in LCH was observed following lateral orbitotomy. CONCLUSIONS: The described technique of lateral orbitotomy and simple reconstruction do not appear to cause lateral canthal drift or rounding. There was no significant change in HPA or LCH. The degree of change of proptosis does appear to influence the change of HPA. PMID- 25719370 TI - Novel Hormone Receptors Present in Apocrine Cystadenoma of the Eyelid. AB - A 53-year-old woman presented with an apocrine cystadenoma of the right upper eyelid. Histologic examination revealed proliferating epithelial cells with apocrine snouts and occasional mitotic figures. Immunohistochemical analysis revealed a Ki-67 index of 15% and positive staining for synaptophysin, chromogranin, estrogen receptor, progesterone receptor, gross cystic disease fluid protein (GCDFP)-15, and mammoglobin. The complement of positive immunomarkers in this case reinforces the importance of total excision and careful histologic assessment. PMID- 25719371 TI - Cytokeratin-Negative Undifferentiated (Lymphoepithelial) Carcinoma of the Lacrimal Sac. AB - Epstein-Barr virus-associated undifferentiated (lymphoepithelial) carcinoma is a malignancy that most commonly arises in the nasopharynx but can also occur in other locations including the lacrimal sac. Generally, this tumor strongly expresses cytokeratin, making the diagnosis straightforward. In the absence of confirmatory immunohistochemistry, the diagnosis can be problematic, particularly for tumors arising in unusual locations. Only 3 cases arising in the lacrimal sac in association with Epstein-Barr virus have been reported in the English literature, and all showed typical pathologic findings. The authors report a fourth case, unique in that it showed negative immunostaining for all cytokeratins tested. The clue to the nature of the tumor came from identification of Epstein-Barr virus by in-situ hybridization and demonstration of tonofilaments by electron microscopy. This case demonstrates that a multimodal approach may be needed in the diagnosis of Epstein-Barr virus-associated carcinoma, especially when occurring in uncommon locations. PMID- 25719372 TI - A modification to the Hughes tarsoconjunctival flap for a challenging case of recurrent lower eyelid retraction. AB - PURPOSE: To present a modification of the Hughes tarsoconjunctival flap to correct a case of refractory lower eyelid retraction. METHODS: The authors report a 49-year-old man with cicatricial right lower eyelid retraction that failed multiple surgical interventions, including ear cartilage grafts to the posterior lamella, tarsal strip, alloplastic implant, and Sub-Orbicularis Oculi Fat (SOOF) lift. A modified Hughes tarsoconjunctival flap was used for repair of a nonmarginal defect of the lower eyelid. A marginal defect was purposely created with a full-thickness blepharotomy that compensated for the amount of lower eyelid retraction. The posterior lamellar defect was filled with the tarsoconjunctival-Muller's flap and the anterior lamella defect covered with a full-thickness retroauricular skin graft. Mueller's muscle was included in the flap to increase the vascular supply to the reconstructed eyelid. Likewise, the authors waited 9 weeks to divide the flap because of concerns that the vascular supply of the surrounding eyelid might be compromised from multiple previous surgeries. RESULTS: A single case of cicatricial right lower eyelid retraction status after multiple failed surgical interventions successfully completed a full thickness blepharotomy with a modified Hughes tarsoconjunctival flap. Two months after the procedure, the patient had good cosmesis and function with resolution of his signs and symptoms of exposure keratopathy. CONCLUSIONS: The Hughes tarsoconjunctival flap combined with a full-thickness blepharotomy may be a useful technique in selected patients for repair of nonmarginal defects of the lower eyelid when other standard techniques have failed. PMID- 25719373 TI - Ocular Penetration Secondary to Cocaine-Induced Midline Destructive Lesion. AB - Herein, the authors present a retrospective case report of a patient with ocular penetration due to cocaine-induced midline destructive lesion. To their knowledge, this is the first documented case of ocular penetration secondary to cocaine insufflation. PMID- 25719374 TI - Observations on Prostaglandin Orbitopathy. AB - PURPOSE: To present the various orbital soft-tissue changes that can result from the use of topical prostaglandin analogs. METHODS: A case series of patients seen in a referral oculoplastic practice with presumed prostaglandin orbitopathy. RESULTS: Thirty-five patients were found to have a variety of disorders, including deepening of the superior sulci (24/35), hypertrichosis (32/35), periocular erythema (24/35), and meibomian gland dysfunction (18/35). Marginal eyelid thinning with posterior migration of the lash line was commonly present (34/35). Increased eyelid margin tension with horizontal eyelid shortening (32/35) was often associated with lateral canthal deformity or displacement (15/35). Lower eyelid retraction (18/35) seemed to contribute to ptosis in some patients, secondary to apparent tethering at the lateral canthus. Functional conditions resulting from the above structural abnormalities included tractional ptosis (n = 4), cicatricial entropion (n = 3), cicatricial ectropion (n = 2), trichiasis (n = 2), eyelid subluxation (n = 1), and chalazia (n = 1). CONCLUSIONS: While topical prostaglandin analogs are well-tolerated by many patients with glaucoma, some individuals using these medications develop structural changes of the orbital soft tissue resulting in a variety of cosmetic and functional eyelid disorders. The eyelid margins can thin, causing posterior migration of the lashes. Increased horizontal tension of the eyelids may result in acquired blepharophimosis and upper or lower eyelid malposition. These orbital changes may be partially reversible in some patients. When possible, it is reasonable to withhold the prostaglandin and allow a period of observation before proceeding with surgical correction. PMID- 25719375 TI - Comparison of Fasanella-Servat and Small-Incision Techniques for Involutional Ptosis Repair. AB - PURPOSE: To compare the results of the classic Fasanella-Servat internal approach to the newer, small-incision external approach in the repair of involutional ptosis. METHODS: Retrospective review identified 93 patients (104 surgical procedures) at Northwestern Ophthalmology from June 2005 until October 2011 who underwent either the Fasanella-Servat or the small-incision approaches for involutional ptosis repair. Change in vertical palpebral fissure measurement, change in marginal reflex distance 1 (MRD1) measurement, patient satisfaction, surgical complications, operating time, and postoperative pain were compared between groups. RESULTS: Of the 93 patients, most were female with an average age of 69 years. Of the procedures, 48% were small incision and 52% were Fasanella Servat approaches. Average postoperative follow up was 34.0 days. Vertical palpebral fissure height increased an average of 3.36 mm (+/-1.15) in the Fasanella-Servat group and 2.74 mm (+/-1.18) in the small-incision group (p = 0.003). Preoperative vertical palpebral fissure height was lower in the Fasanella Servat group, but postoperative vertical palpebral fissure height was similar between the 2 groups (p=0.3). MRD1 increased an average of 3.42 mm (+/-0.86) in the Fasanella-Servat group and 2.68 mm (+/-0.93) in the small-incision group (p < 0.01). Preoperative MRD1 was lower in the Fasanella-Servat group, but postoperative MRD1 was similar between the 2 groups (p = 0.15). Average operating time was 53 minutes (+/-16) in the small-incision group and 27 minutes (+/-6) in the Fasanella-Servat group (p < 0.01). There were no surgical complications in either group with equivalent patient satisfaction between the 2 groups. More patients reported postoperative pain in the Fasanella-Servat group (p < 0.0001). CONCLUSIONS: Both the Fasanella-Servat and small-incision approaches lead to good surgical outcomes with equivalent patient satisfaction, although the Fasanella Servat approach provides a shorter average operating time with satisfactory postoperative MRD1. PMID- 25719376 TI - Stop Blaming the Septum. AB - PURPOSE: To identify if isolated surgical violation of the orbital septum predisposes to "middle lamellar" scarring and subsequent postblepharoplasty lower eyelid retraction. METHODS: A retrospective review of patients who underwent transconjunctival blepharoplasty in either a postseptal (orbital septum undisturbed) or preseptal (septal incision required) plane was performed. Patients undergoing skin excision, orbicularis muscle plication, and canthal suspension were excluded. The presence of clinically apparent postoperative lower eyelid retraction and limitation of forced superior eyelid excursion (forced traction testing) were assessed. RESULTS: Two hundred eighty-eight patients (576 eyelids) were evaluated. One hundred fifty-eight patients (316 eyelids, 55%) had transconjunctival blepharoplasty performed in a postseptal plane and 130 patients (260 eyelids, 45%) in a preseptal plane. Two hundred two patients (404 eyelids, 70%) had forced traction testing performed postoperatively. After surgery, there were no patient complaints of change in lower eyelid position, subjective physician assessment of clinically apparent lower eyelid retraction, and only 1 case (0.5%) of a positive forced traction test in a patient with conjunctival scarring after significant postoperative infection. CONCLUSIONS: Lower eyelid scars leading to eyelid retraction after blepharoplasty are not likely related to "isolated" orbital septal scars (middle lamellar scars). Their designation as a "multilamellar scar" is more appropriate. PMID- 25719377 TI - The Effect of Socio-Economic Status on Severity of Periocular Basal Cell Carcinoma at Presentation. AB - PURPOSE: To evaluate the influence of socio-economic factors on size of periocular basal cell carcinoma at presentation. METHODS: All periocular basal cell carcinoma cases receiving treatment from the oculoplastics team in South Glasgow Hospitals NHS Trust, Glasgow, between 1999 and 2009, were identified retrospectively. Information collected included demographic details of patients, side and site of lesions, type of lesions, and size of lesions. The size of lesion was defined as small for any dimension not exceeding 5 mm, medium for dimensions between 6 mm and 10 mm, and large for dimensions exceeding 11 mm. Home address was used to determine the Scottish Index of Multiple Deprivation rank. The demographics, size of lesion, and Scottish Index of Multiple Deprivation rank were investigated using the general linear regression modelling. RESULTS: Of the 67 cases, 24 were men and 43 were women. The mean age was 71.5 years. There were a total of 67 identified cases, of which 38 presented with small-size lesions, 24 with medium-size lesions, and 5 with large-size lesions. Scottish Index of Multiple Deprivation is related to the presenting incidence of basal cell carcinoma, with the lower ranks presenting more frequently. CONCLUSIONS: Socio economic deprivation is associated with larger and more frequent presentation of periocular basal cell carcinoma. This highlights the importance of raising awareness among populations of the more deprived areas of the significance of lumps and bumps within the periocular regions. PMID- 25719378 TI - Dynamic Analysis of Muller's Muscle Response to Phenylephrine. AB - PURPOSE: To characterize in vivo response of Muller's muscle to phenylephrine about time and diurnal variation. METHODS: A nonrandomized trial of adults without (n = 20, 40 eyes) and with ptosis (n = 5, 5 eyes) measured for response of marginal reflex distance-1 (MRD1) to topical phenylephrine (2.5%) every 15 seconds in the morning (6-10 AM) and evening (6-10 PM). Mean MRD1 was plotted over time, and morning and evening MRD1 were compared with the Spearman correlation coefficient (r) and paired t test. RESULTS: Regardless of the time of day, subjects with and without ptosis had maximal response to phenylephrine within 2 minutes, with persistence of response at 30 minutes. There was good correlation (r = 0.92), with no statistically significant difference in rate or amount of change of MRD1 between morning and evening time points. CONCLUSIONS: Maximal response to phenylephrine occurs within 2 minutes of instillation with persistence of response at 30 minutes; there appears to be no diurnal variation in phenylephrine testing. PMID- 25719379 TI - Unusual Eyelid Dermal Keratinous Cysts of Pilosebaceous Origin. AB - PURPOSE: To describe 2 types of previously unrecognized dermal keratinous cysts of the eyelids-2 single sebaceous duct cysts derived from the glands of Zeis and 2 cases of multiple eruptive vellus hair cysts, both types associated with the pilosebaceous apparatus. METHODS: Clinical records and paraffin sections subjected to hematoxylin and eosin and acid-fast staining were critically reviewed from each case, and additional sections were immunoreacted for cytokeratins (CKs) 7, 14, and 17. RESULTS: Two patients had a slowly enlarging solitary sebaceous duct keratinous cyst at the eyelid margin where the glands of Zeis are located. The squamous cell lining displayed a corrugated squamous membrane manifesting an eosinophilic, refractile, surface cuticle. Either a sebaceous gland or a hair was proximate to the cyst. The squamous lining was CK7, CK14, and CK17. Two other patients developed over 2 and 10 years a different condition consisting of unilateral or bilateral clusters, respectively, of small papules of the upper eyelids. These were lined by keratinizing squamous epithelium without a cuticular membrane. Numerous small vellus hairs along with keratin in the lumens were discovered with acid-fast staining. The epithelium was also CK7, CK14, and CK17. CONCLUSIONS: Histopathologic and immunohistochemical studies can separate these 2 disparate new eyelid entities from the more common keratinous epidermoid cyst of the surface epidermis or the upper hair follicle (CK7, CK14, and CK17). Simple local excision of the anterior lamella of the eyelid is appropriate for the sebaceous duct keratinous cysts of Zeis, but the multiple vellus hair cysts are comparatively refractory to treatment. Both superficial types of cysts are totally unrelated to the deeper Meibomian keratinous cyst, which is not associated with a hair structure and is situated in the tarsus rather than the dermis of the eyelids. PMID- 25719380 TI - Axial Globe Position Measurement: A Prospective Multicenter Study by the International Thyroid Eye Disease Society. AB - PURPOSE: Identify a reproducible measure of axial globe position (AGP) for multicenter studies on patients with thyroid eye disease (TED). METHODS: This is a prospective, international, multicenter, observational study in which 3 types of AGP evaluation were examined: radiologic, clinical, and photographic. In this study, CT was the modality to which all other methods were compared. CT AGP was measured from an orthogonal line between the anterior lateral orbital rims to the cornea. All CT measurements were made at a single institution by 3 individual clinicians. Clinical evaluation was performed with exophthalmometry. Three clinicians from each clinical site assessed AGP with 3 different exophthalmometers and horizontal palpebral width using a ruler. Each physician made 3 separate measurements with each type of exophthalmometer not in succession. All photographic measurements were made at a single institution. AGP was measured from lateral photographs in which a standard marker was placed at the anterior lateral orbital rim. Horizontal and vertical palpebral fissure were measured from frontal photographs. Three trained readers measured 3 separate times not in succession. Exophthalmometry and photography method validity was assessed by agreement with CT (mean differences calculation, intraclass correlation coefficients [ICCs], Bland-Altman figures). Correlation between palpebral fissure and CT AGP was assessed with Pearson correlation. Intraclinician and interclinician reliability was evaluated using ICCs. RESULTS: Sixty-eight patients from 7 centers participated. CT mean AGP was 21.37 mm (15.96 28.90 mm) right and 21.22 mm (15.87-28.70 mm) left (ICC 0.996 and 0.995). Exophthalmometry AGP fell between 18 mm and 25 mm. Intraclinician agreement across exophthalmometers was ideal (ICC 0.948-0.983). Agreement between clinicians was greater than 0.85 for all upright exophthalmometry measurements. Photographic mean AGP was 20.47 mm (10.92-30.88 mm) right and 20.30 mm (8.61 28.72 mm) left. Intrareader and interreader agreement was ideal (ICC 0.991 0.989). All exophthalmometers' mean differences from CT ranged between -0.06 mm (+/-1.36 mm) and 0.54 mm (+/-1.61 mm); 95% confidence interval fell within 1 mm. Magnitude of AGP did not affect exophthalmometry validity. Oculus best estimated CT AGP but differences from other exophthalmometers were not clinically meaningful in upright measurements. Photographic AGP (right ICC = 0.575, left ICC = 0.355) and palpebral fissure do not agree with CT. CONCLUSIONS: Upright clinical exophthalmometry accurately estimates CT AGP in TED. AGP measurement was reliably reproduced by the same clinician and between clinicians at multiple institutions using the protocol in this study. These findings allow reliable measurement of AGP that will be of considerable value in future outcome studies. PMID- 25719381 TI - Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948-2008. AB - Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948-2008. The cohort of Mayak Production Association (PA) workers in Russia offers a unique opportunity to study the effects of prolonged low dose rate external gamma exposures and exposure to plutonium in a working age population. We examined radiation effects on the risk of mortality from solid cancers excluding sites of primary plutonium deposition (lung, liver, and bone surface) among 25,757 workers who were first employed in 1948-1982. During the period 1948-2008, there were 1,825 deaths from cancers other than lung, liver and bone. Using colon dose as a representative external dose, a linear dose response model described the data well. The excess relative risk per Gray for external gamma exposure was 0.16 (95% CI: 0.07 - 0.26) when unadjusted for plutonium exposure and 0.12 (95% CI 0.03 - 0.21) when adjusted for plutonium dose and monitoring status. There was no significant effect modification by sex or attained age. Plutonium exposure was not significantly associated with the group of cancers analyzed after adjusting for monitoring status. Site-specific risks were uncertainly estimated but positive for 13 of the 15 sites evaluated with a statistically significant estimate only for esophageal cancer. Comparison with estimates based on the acute exposures in atomic bomb survivors suggests that the excess relative risk per Gray for prolonged external exposure in Mayak workers may be lower than that for acute exposure but, given the uncertainties, the possibility of equal effects cannot be dismissed. PMID- 25719382 TI - Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes. AB - Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis. PMID- 25719383 TI - An essential role of the arginine vasotocin system in mate-guarding behaviors in triadic relationships of medaka fish (Oryzias latipes). AB - To increase individual male fitness, males of various species remain near a (potential) mating partner and repel their rivals (mate-guarding). Mate-guarding is assumed to be mediated by two different types of motivation: sexual motivation toward the opposite sex and competitive motivation toward the same sex. The genetic/molecular mechanisms underlying how mate presence affects male competitive motivation in a triadic relationship has remained largely unknown. Here we showed that male medaka fish prominently exhibit mate-guarding behavior. The presence of a female robustly triggers male-male competition for the female in a triadic relationship (2 males and 1 female). The male-male competition resulted in one male occupying a dominant position near the female while interfering with the other male's approach of the female. Paternity testing revealed that the dominant male had a significantly higher mating success rate than the other male in a triadic relationship. We next generated medaka mutants of arginine-vasotocin (avt) and its receptors (V1a1, V1a2) and revealed that two genes, avt and V1a2, are required for normal mate-guarding behavior. In addition, behavioral analysis of courtship behaviors in a dyadic relationship and aggressive behaviors within a male group revealed that avt mutant males displayed decreased sexual motivation but showed normal aggression. In contrast, heterozygote V1a2 mutant males displayed decreased aggression, but normal mate guarding and courtship behavior. Thus, impaired mate-guarding in avt and V1a2 homozygote mutants may be due to the loss of sexual motivation toward the opposite sex, and not to the loss of competitive motivation toward rival males. The different behavioral phenotypes between avt, V1a2 heterozygote, and V1a2 homozygote mutants suggest that there are redundant systems to activate V1a2 and that endogenous ligands activating the receptor may differ according to the social context. PMID- 25719385 TI - Correction: quantitative and qualitative assessment of yttrium-90 PET/CT imaging. PMID- 25719384 TI - Brown adipose tissue in cetacean blubber. AB - Brown adipose tissue (BAT) plays an important role in thermoregulation in species living in cold environments, given heat can be generated from its chemical energy reserves. Here we investigate the existence of BAT in blubber in four species of delphinoid cetacean, the Pacific white-sided and bottlenose dolphins, Lagenorhynchus obliquidens and Tursiops truncates, and Dall's and harbour porpoises, Phocoenoides dalli and Phocoena phocoena. Histology revealed adipocytes with small unilocular fat droplets and a large eosinophilic cytoplasm intermingled with connective tissue in the innermost layers of blubber. Chemistry revealed a brown adipocyte-specific mitochondrial protein, uncoupling protein 1 (UCP1), within these same adipocytes, but not those distributed elsewhere throughout the blubber. Western blot analysis of extracts from the inner blubber layer confirmed that the immunohistochemical positive reaction was specific to UCP1 and that this adipose tissue was BAT. To better understand the distribution of BAT throughout the entire cetacean body, cadavers were subjected to computed tomography (CT) scanning. Resulting imagery, coupled with histological corroboration of fine tissue structure, revealed adipocytes intermingled with connective tissue in the lowest layer of blubber were distributed within a thin, highly dense layer that extended the length of the body, with the exception of the rostrum, fin and fluke regions. As such, we describe BAT effectively enveloping the cetacean body. Our results suggest that delphinoid blubber could serve a role additional to those frequently attributed to it: simple insulation blanket, energy storage, hydrodynamic streamlining or contributor to positive buoyancy. We believe delphinoid BAT might also function like an electric blanket, enabling animals to frequent waters cooler than blubber as an insulator alone might otherwise allow an animal to withstand, or allow animals to maintain body temperature in cool waters during sustained periods of physical inactivity. PMID- 25719386 TI - Eye morphogenesis driven by epithelial flow into the optic cup facilitated by modulation of bone morphogenetic protein. AB - The hemispheric, bi-layered optic cup forms from an oval optic vesicle during early vertebrate eye development through major morphological transformations. The overall basal surface, facing the developing lens, is increasing, while, at the same time, the space basally occupied by individual cells is decreasing. This cannot be explained by the classical view of eye development. Using zebrafish (Danio rerio) as a model, we show that the lens-averted epithelium functions as a reservoir that contributes to the growing neuroretina through epithelial flow around the distal rims of the optic cup. We propose that this flow couples morphogenesis and retinal determination. Our 4D data indicate that future stem cells flow from their origin in the lens-averted domain of the optic vesicle to their destination in the ciliary marginal zone. BMP-mediated inhibition of the flow results in ectopic neuroretina in the RPE domain. Ultimately the ventral fissure fails to close resulting in coloboma. PMID- 25719387 TI - The role of corpus size and syntax in deriving lexico-semantic representations for a wide range of concepts. AB - One of the most significant recent advances in the study of semantic processing is the advent of models based on text and other corpora. In this study, we address what impact both the quantitative and qualitative properties of corpora have on mental representations derived from them. More precisely, we evaluate models with different linguistic and mental constraints on their ability to predict semantic relatedness between items from a vast range of domains and categories. We find that a model based on syntactic dependency relations captures significantly less of the variability for all kinds of words, regardless of the semantic relation between them or their abstractness. The largest difference was found for concrete nouns, which are commonly used to assess semantic processing. For both models we find that limited amounts of data suffice in order to obtain reliable predictions. Together, these findings suggest new constraints for the construction of mental models from corpora, both in terms of the corpus size and in terms of the linguistic properties that contribute to mental representations. PMID- 25719388 TI - Epigenetic biomarkers in the blood of patients with urological malignancies. AB - In the era of personalized medicine, there is an urgent need for non-invasive biomarkers to optimize the individual treatment of cancer patients. Epigenetic alterations, including DNA methylation and non-coding RNAs, are a hallmark of malignant tumors. The detection of many of these epigenetic conditions is feasible in bodily fluids, that is, blood plasma and serum, and may therefore be used for liquid biopsy. In this review, we summarize and discuss the current state of research on circulating epigenetic alterations (DNA methylation, miRNA and long non-coding RNA) in serum and plasma of patients with bladder cancer, prostate cancer, renal cell carcinoma and testicular germ cell cancer. PMID- 25719389 TI - Attention and other constructs: evolution or revolution? AB - This article provides a review of the construct of attention from a non traditional standpoint. Attention is conceptualized by focusing on the categorical concept of the diagnosis of attention-deficit hyperactivity disorder, large-scale brain network models of functional neuroanatomy, and implications for understanding lateralized hemispheric brain organization. Cortical systems are multifunctional, with certain degrees of specialization, but no cortical region or network supports only one, specific, isolated cognitive process, such as attention. Future implications for clinical practice must focus on connectivity patterns rather than the idea of "domains" or "constructs" when considering attention and other cognitive processes. This has significant implications for the future of neuropsychological assessment and intervention. PMID- 25719390 TI - Promoted decomposition of NOx in automotive diesel-like exhausts by electro catalytic honeycombs. AB - NO and NO2 (collectively called NOx) are major air pollutants in automotive emissions. More effective and easier treatments of NOx than those achieved by the present methods can offer better protection of human health and higher fuel efficiency that can reduce greenhouse gas emissions. However, currently commercialized technologies for automotive NOx emission control cannot effectively treat diesel-like exhausts with high NOx concentrations. Thus, exhaust gas recirculation (EGR) has been used extensively, which reduces fuel efficiency and increases particulate emission considerably. Our results show that the electro-catalytic honeycomb (ECH) promotes the decomposition of NOx to nitrogen and oxygen, without consuming reagents or other resources. NOx can be converted to nitrogen and oxygen almost completely. The ECHs are shown to effectively remove NOx from gasoline-fueled diesel-like exhausts. A very high NO concentration is preferred in the engine exhaust, especially during engine cold start. Promoted NOx decomposition (PND) technology for real-world automotive applications is established in this study by using the ECH. With PND, EGR is no longer needed. Diesel-like engines can therefore achieve superior fuel efficiency, and all major automotive pollutants can be easily treated due to high concentration of oxygen in the diesel-like exhausts, leading to zero pollution. PMID- 25719391 TI - Prevalence of myopia and its risk factors in urban school children in Delhi: the North India Myopia Study (NIM Study). AB - PURPOSE: Assess prevalence of myopia and identify associated risk factors in urban school children. METHODS: This was a cross-sectional study screening children for sub-normal vision and refractive errors in Delhi. Vision was tested by trained health workers using ETDRS charts. Risk factor questionnaire was filled for children with vision <6/9.5, wearing spectacles and for a subset (10%) of randomly selected children with normal vision. All children with vision <6/9.5 underwent cycloplegic refraction. The prevalence of myopia <-0.5 diopters was assessed. Association of risk factors and prevalence of myopia was analyzed for children with myopia and randomly selected non myopic children and adjusted odds ratio values for all risk factors were estimated. RESULTS: A total number of 9884 children were screened with mean age of 11.6 + 2.2 years and 66.8% boys. Prevalence of myopia was 13.1% with only 320 children (24.7%) wearing appropriate spectacles. Mean myopic spherical error was -1.86 + 1.4 diopters. Prevalence of myopia was higher in private schools compared to government schools (p<0.001), in girls vs. boys (p = 0.004) and among older (> 11 years) children (p<0.001). There was a positive association of myopia with studying in private schools vs. government schools (p<0.001), positive family history (p< 0.001) and higher socio economic status (p = 0.037). Positive association of presence of myopia was observed with children studying/reading > 5 hours per day (p < 0.001), watching television > 2 hours / day (p < 0.001) and with playing computer/video/mobile games (p < 0.001). An inverse association with outdoor activities/playing was observed with children playing > 2 hours in a day. CONCLUSION: Myopia is a major health problem in Indian school children. It is important to identify modifiable risk factors associated with its development and try to develop cost effective intervention strategies. PMID- 25719392 TI - Quad-barrel multifunctional electrochemical and ion conductance probe for voltammetric analysis and imaging. AB - The fabrication and use of a multifunctional electrochemical probe incorporating two independent carbon working electrodes and two electrolyte-filled barrels, equipped with quasi-reference counter electrodes (QRCEs), in the end of a tapered micrometer-scale pipet is described. This "quad-probe" (4-channel probe) was fabricated by depositing carbon pyrolytically into two diagonally opposite barrels of a laser-pulled quartz quadruple-barrelled pipet. After filling the open channels with electrolyte solution, a meniscus forms at the end of the probe and covers the two working electrodes. The two carbon electrodes can be used to drive local electrochemical reactions within the meniscus while a bias between the QRCEs in the electrolyte channels provides an ion conductance signal that is used to control and position the meniscus on a surface of interest. When brought into contact with a surface, localized high resolution amperometric imaging can be achieved with the two carbon working electrodes with a spatial resolution defined by the meniscus contact area. The substrate can be an insulating material or (semi)conductor, but herein, we focus mainly on conducting substrates that can be connected as a third working electrode. Studies using both aqueous and ionic liquid electrolytes in the probe, together with gold and individual single walled carbon nanotube samples, demonstrate the utility of the technique. Substrate generation-dual tip collection measurements are shown to be characterized by high collection efficiencies (approaching 100%). This hybrid configuration of scanning electrochemical microscopy (SECM) and scanning electrochemical cell microscopy (SECCM) should be powerful for future applications in electrode mapping, as well as in studies of insulating materials as demonstrated by transient spot redox titration measurements at an electrostatically charged Teflon surface and at a pristine calcite surface, where a functionalized probe is used to follow the immediate pH change due to dissolution. PMID- 25719395 TI - Water nanodroplet thermodynamics: quasi-solid phase-boundary dispersivity. AB - It has long been puzzling that water nanodroplets undergo simultaneously "supercooling" at freezing and "superheating" at melting. Recent progress (Sun et al. J. Phys. Chem. Lett. 2013, 4, 2565, 3238) enables us to resolve this anomaly from the perspective of hydrogen bond (O:H-O) specific heat disparity. A superposition of the specific heat etax(T) curves for the H-O bond (x = H) and the O:H nonbond (x = L) defines two intersecting temperatures that form the ice/quasi-solid/liquid phase boundaries. Molecular undercoordination (with fewer than four nearest neighbors in the bulk) stretches the etaH(T) curve by raising the Debye temperature ThetaDH through H-O bond shortening and phonon stiffening. The etaH(T) stretching is coupled with the etaL(T) depressing because of the Coulomb repulsion between electron pairs on oxygen ions. The extent of dispersion varies with the size of a droplet that prefers a core-shell structure configuration-the bulk interior and the skin. Understandings may open an effective way of dealing with the thermodynamic behavior of water droplets and bubbles from the perspective of O:H-O bond cooperativity. PMID- 25719393 TI - Carboxyl-terminal truncations alter the activity of the human alpha-galactosidase A. AB - Fabry disease is an X-linked inborn error of glycolipid metabolism caused by deficiency of the human lysosomal enzyme, alpha-galactosidase A (alphaGal), leading to strokes, myocardial infarctions, and terminal renal failure, often leading to death in the fourth or fifth decade of life. The enzyme is responsible for the hydrolysis of terminal alpha-galactoside linkages in various glycolipids. Enzyme replacement therapy (ERT) has been approved for the treatment of Fabry disease, but adverse reactions, including immune reactions, make it desirable to generate improved methods for ERT. One approach to circumvent these adverse reactions is the development of derivatives of the enzyme with more activity per mg. It was previously reported that carboxyl-terminal deletions of 2 to 10 amino acids led to increased activity of about 2 to 6-fold. However, this data was qualitative or semi-quantitative and relied on comparison of the amounts of mRNA present in Northern blots with alphaGal enzyme activity using a transient expression system in COS-1 cells. Here we follow up on this report by constructing and purifying mutant enzymes with deletions of 2, 4, 6, 8, and 10 C terminal amino acids (Delta2, Delta4, Delta6, Delta8, Delta10) for unambiguous quantitative enzyme assays. The results reported here show that the kcat/Km approximately doubles with deletions of 2, 4, 6 and 10 amino acids (0.8 to 1.7 fold effect) while a deletion of 8 amino acids decreases the kcat/Km (7.2-fold effect). These results indicate that the mutated enzymes with increased activity constructed here would be expected to have a greater therapeutic effect on a per mg basis, and could therefore reduce the likelihood of adverse infusion related reactions in Fabry patients receiving ERT treatment. These results also illustrate the principle that in vitro mutagenesis can be used to generate alphaGal derivatives with improved enzyme activity. PMID- 25719396 TI - Taming chlorine azide: access to 1,2-azidochlorides from alkenes. AB - The in situ preparation and trapping of chlorine azide provided a versatile one pot method for the azidochlorination of alkenes. Gaseous ClN3 generated from sodium azide, hypochlorite, and acetic acid can be explosive if isolation is attempted. Instead, we generated the reagent in biphasic media in the presence of olefinic compounds dissolved in the organic layer or evenly emulsified throughout the solution in the absence of organic solvent. Under these conditions, ClN3 is created slowly and trapped immediately at the aqueous-organic interface. The resulting safe and reliable procedure provided 1,2-azidochloride derivatives of a variety of substrates, with evidence for both polar and radical mechanisms. Minor impurities characterized in the product mixtures indicated the presence of alternative reaction pathways deriving primarily from radical intermediates. PMID- 25719394 TI - Antinociceptive activity of the ethanolic extract, fractions, and aggregatin D isolated from Sinningia aggregata tubers. AB - The present study investigated the effects of the ethanolic extract (ESa), fractions, and compounds isolated from Sinningia aggregata in male Swiss mice on carrageenan-induced paw edema, neutrophil migration, mechanical hyperalgesia, formalin-induced nociception, and lipopolysaccharide-induced fever. The ESa did not alter edema, neutrophil migration, or fever at any of the doses tested. However, the ESa reduced phase II of formalin-induced nociception and carrageenan induced mechanical hyperalgesia. The petroleum ether (PE) and ethyl acetate (EA) fractions and aggregatin D (AgD; isolated from the EA fraction) reduced formalin induced nociception. Anthraquinones from the PE fraction were ineffective. AgD also inhibited carrageenan-induced mechanical hyperalgesia. Neither the ESa nor AgD altered thermal nociception or motor performance. Local administration of AgD also reduced hyperalgesia induced by carrageenan, bradykinin, tumor necrosis factor-alpha, interleukin-1beta, cytokine-induced neutrophil chemoattractant, prostaglandin E2, and dopamine but not hyperalgesia induced by forskolin or dibutyryl cyclic adenosine monophosphate. The positive control dipyrone reduced the response induced by all of the stimuli. Additionally, glibenclamide abolished the analgesic effect of dipyrone but not the one induced by AgD. AgD did not change lipopolysaccharide-induced nitric oxide production by macrophages or the nociception induced by capsaicin, cinnamaldehyde, acidified saline, or menthol. These results suggest that the ESa has important antinociceptive activity, and this activity results at least partially from the presence of AgD. AgD reduced mechanical hyperalgesia induced by several inflammatory mediators through mechanisms that are different from classic analgesic drugs. PMID- 25719397 TI - Eating disorder therapists' personal eating disorder history and professional ethics: an interpretive description. AB - This qualitative study sought to explore and understand eating disorder (ED) therapists' perceptions of whether and how their personal ED histories had professional ethical relevance. Analysis of multiple interviews with 11 therapist participants indicated that they perceived their personal ED histories as having substantial ethical relevance in their day-to-day practice with ED clients. The major categories of ethics experiences that emerged were: boundaries, therapist wellness, helpfulness of personal ED history, and openness regarding therapists' personal ED histories. The findings have practical utility for the education, training, and continuing education of ED-historied practitioners. PMID- 25719398 TI - Arterial stiffness and cardiac functions in patients with chronic venous disease. AB - AIM: Although the venous system is in direct continuity with the heart and the arterial system, it is not known whether chronic venous disease (CVD) has any impact on either of these. The aims of this study were to investigate the global functions of the left and right heart, and also arterial stiffness parameters in patients with CVD. METHODS: Forty-eight patients with primary stage C4-C6 CVD were enrolled into the study. The control group consisted of 39 age/sex and Body Mass Index matched healthy volunteers. All of the patients underwent detailed echocardiographic examination with further focus on Doppler and tissue Doppler (TD) parameters of the left and right ventricle. Arterial stiffness was evaluated via applanation tonometry in each patient. RESULTS: The left atrial area (LAA) and interventricular septum thickness were slightly increased in patients with CVD. Regarding Doppler and tissue Doppler measurements of the LV, all of the parameters were similar among the groups, while RV tissue Doppler systolic velocity and TAPSE were higher in patients with CVD. Among the arterial stiffness parameters, central aortic pressure, augmentation index, and pulse wave velocity were slightly higher in patients with CVD. CONCLUSION: The results of this study indicated that CVD may be associated with a subclinical disease state in the arterial system and also in the heart. Further studies are needed to confirm this association and to describe the possible mechanisms. PMID- 25719399 TI - The current status of robotic vascular surgery in the abdominal cavity. AB - BACKGROUND: Robotically assisted procedures have emerged within vascular surgery as an alternative to open procedures for the treatment of arterial aneurysms and arterial occlusive diseases. METHODS: A thorough literature search was conducted to retrieve studies reporting the use of robotic systems for the management of aneurysms and arterial obstructive diseases. RESULTS: Eleven studies included data about abdominal aortic aneurysms (AAA) or aortoiliac occlusive disease (AIOD) related conditions. Among 260 patients, the reported aortic clamping time in AAA repairs ranged from 39 to 113 minutes, whilst the time needed for the anastomosis varied between 21.5-43 minutes for AAA and AIOD treatment. The conversion rates also ranged between 0-2% respectively, whilst patient hospital stay varied between 1.5 to 12.2 days. CONCLUSION: Despite the relatively small number of relevant studies, the results are promising. However randomised control trials will help elucidate further the potential superiority of robotic mediated procedures in vascular surgery. PMID- 25719400 TI - Can the tandem measurement of age adjusted D-dimer and tissue plasminagen activator improve the clinical utility of a conventional D-dimer in the pulmonary embolism diagnosis? AB - BACKGROUND: The aim of this study was to evaluate if a sequential measurement of age adjust D-dimer (ADD) and tissue plasminogen activator (tPA) could increase the clinical utility in patients with suspected pulmonary embolism (PE) compared to a conventional D-dimer. METHODS: We measured a conventional D-dimer (CDD), an ADD alone and a sequential combination ADD and tPA (ADD/tPA combination) in a prospective sample of 127 outpatients with PE suspected. Diagnosis of PE was based on a strict protocol. Plasma sample to measure levels of tPA and D-dimer was obtained at enrollment, and CDD, ADD and tPA were assessed at the end of study. For CDD the cut-off value was 500 ng/mL and for ADD the cut-off value was defined as (patient's age x10) ng/mL in patients aged >50. We compared the sensitivity, specificity and clinical utility obtained for CDD, ADD alone, and ADD/tPA combination. RESULTS: PE was confirmed in 41 patients (32%). The sensitivity, specificity and clinical utility for CDD were 95%, 36% and 28%, respectively. The ADD/tPA combination and ADD alone demonstrated an increased in specificity of +29% and +12% respectively, and increased in clinical utility of +20% and +8%, respectively, compared to CDD, and this was obtained without loss of sensitivity. CONCLUSION: The ADD/tPA combination substantially increased the clinical utility in the PE diagnosis compared with conventional D-dimer, without reducing the security. The ADD/tPA combination could decrease the need for pulmonary vascular imaging for the PE diagnosis in nearly the half. These promising results should be validated prospectively. PMID- 25719401 TI - Electrical muscle stimulation with Veinoplus(r) device in the treatment of venous ulcers. AB - AIM: The aim of the study was to analyze the results of the electrical muscle stimulation (EMS) usage in patients with venous ulcers developed on top of a post thrombotic syndrome (PTS). METHODS: Sixty patients (60 legs) with active venous ulcer (C6EsAsdpPr according to CEAP classification) were divided into two groups. In addition to the background therapy consisting of a standardized compression with ULCER X and intake of micronized purified flavonoid fraction (MPFF 1000 mg daily), all the patients in the main group underwent EMS with Veinoplus(r) V.I. for at least 3 times a day. Follow-up examinations were performed on days 30, 60 and 90. These included pain severity assessment with 100-mm Visual Analogue Scale (VAS), disease severity measurement with VCSS (Venous Clinical Severity Score) and ankle circumference above malleolus, as well as recording number of healed venous ulcers. RESULTS: At day 90 pain severity was reduced in both main and control groups. However, according to VAS pain reduction rates were significantly higher in patients of the main group (from 8.7 +/- 0.6 to 1.9 +/- 0.3 in the main group and 8.4 +/- 0.6 to 3.9 +/- 0.5 in the control group). At the end of the study, ankle circumference decreased from 270.9 +/- 4.6 mm to 257.1 +/- 4.2 mm in the main and from 269.7 +/- 5.3 mm to 263.4 +/- 5.2 in the control group. VCSS before treatment was 7.3 +/- 0.6 in the main group and 6.8 +/- 0.5 in the control group. By day 90 VCSS significantly decreased to 2.3 +/- 0.4 and 4.6 +/- 0.5 in the main and control groups respectively. Healing rates were significantly higher in the main group. On day 90, the number of open venous ulcers in the main group was 3 times lower than in the control group (4 vs. 12). CONCLUSION: EMS demonstrated high efficacy and good tolerability and provided significant reduction in pain severity, VCSS score and ankle edema, as well as a 3-fold increase in the number of healed venous ulcers. PMID- 25719402 TI - Chronic activation of FXR in transgenic mice caused perinatal toxicity and sensitized mice to cholesterol toxicity. AB - The nuclear receptor farnesoid X receptor (FXR) (nuclear receptor subfamily 1, group H, member 4, or NR1H4) is highly expressed in the liver and intestine. Previous reports have suggested beneficial functions of FXR in the homeostasis of bile acids, lipids, and glucose, as well as in promoting liver regeneration and inhibiting carcinogenesis. To investigate the effect of chronic FXR activation in vivo, we generated transgenic mice that conditionally and tissue specifically express the activated form of FXR in the liver and intestine. Unexpectedly, the transgenic mice showed several intriguing phenotypes, including partial neonatal lethality, growth retardation, and spontaneous liver toxicity. The transgenic mice also displayed heightened sensitivity to a high-cholesterol diet-induced hepatotoxicity but resistance to the gallstone formation. The phenotypes were transgene specific, because they were abolished upon treatment with doxycycline to silence the transgene expression. The perinatal toxicity, which can be rescued by a maternal vitamin supplement, may have resulted from vitamin deficiency due to low biliary bile acid output as a consequence of inhibition of bile acid formation. Our results also suggested that the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a member of the proinflammatory TNF family, is a FXR-responsive gene. However, the contribution of Fn14 induction in the perinatal toxic phenotype of the transgenic mice remains to be defined. Because FXR is being explored as a therapeutic target, our results suggested that a chronic activation of this nuclear receptor may have an unintended side effect especially during the perinatal stage. PMID- 25719403 TI - Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes. AB - Although the cardioprotective effects of glucagon-like peptide-1 and its analogs have been reported, the exact mechanisms of the glucagon-like peptide-1 receptor (GLP-1R) signaling pathway in the heart are still unclear. Activation of the GLP 1R has been shown to increase cAMP levels, thus eliciting protein kinase A- and exchange protein activated by cAMP (Epac)-dependent signaling pathways in pancreatic beta-cells. However, which pathway plays an important role in the antioxidant and antiapoptotic effects of GLP-1R activation in the heart is not known. In this study, we demonstrated that stimulation of GLP-1Rs with exendin-4 attenuated H2O2-induced reactive oxygen species production and increased the synthesis of antioxidant enzymes, catalase, glutathione peroxidase-1, and manganese superoxide dismutase that is dependent on Epac. Additionally, exendin-4 has an antiapoptotic effect by decreasing a number of apoptotic cells, inhibiting caspase-3 activity, and enhancing the expression of antiapoptotic protein B-cell lymphoma 2, which is mediated through both protein kinase A- and Epac-dependent pathways. These data indicate a critical role for Epac in GLP-1R-mediated cardioprotection. PMID- 25719404 TI - The effect of adaptation on the tuning curves of rat auditory cortex. AB - Repeated stimulus causes a specific suppression of neuronal responses, which is so-called as Stimulus-Specific Adaptation (SSA). This effect can be recovered when the stimulus changes. In the auditory system SSA is a well-known phenomenon that appears at different levels of the mammalian auditory pathway. In this study, we explored the effects of adaptation to a particular stimulus on the auditory tuning curves of anesthetized rats. We used two sequences and compared the responses of each tone combination in these two conditions. First sequence consists of different pure tone combinations that were presented randomly. In the second one, the same stimuli of the first sequence were presented in the context of an adapted stimulus (adapter) that occupied 80% of sequence probability. The population results demonstrated that the adaptation factor decreased the frequency response area and made a change in the tuning curve to shift it unevenly toward the higher thresholds of tones. The local field potentials and multi-unit activity responses have indicated that the neural activities strength of the adapted frequency has been suppressed as well as with lower suppression in neighboring frequencies. This aforementioned reduction changed the characteristic frequency of the tuning curve. PMID- 25719405 TI - Comparison of Ahmed glaucoma valve implantation and trabeculectomy for glaucoma: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the efficacy and safety of Ahmed glaucoma valve implantation (AGV) with trabeculectomy in the management of glaucoma patients. METHODS: A comprehensive literature search (PubMed, Embase, Google, and the Cochrane library) was performed, including a systematic review with meta-analysis of controlled clinical trials comparing AGV versus trabeculectomy. Efficacy estimates were the weighted mean differences (WMDs) for the percentage intraocular pressure reduction (IOPR %) from baseline to end-point, the reduction in glaucoma medications, and the odds ratios (ORs) for complete and qualified success rates. Safety estimates were the relative risks (RRs) for adverse events. All outcomes were reported with a 95% confidence interval (CI). Statistical analysis was performed using the RevMan 5.0 software. RESULTS: Six controlled clinical trials were included in this meta-analysis. There was no significant difference between the AGV and trabeculectomy in the IOPR% (WMD = -3.04, 95% CI: 8.36- 2.26; P = 0.26). The pooled ORs comparing AGV with trabeculectomy were 0.46 (0.22, 0.99) for the complete success rate (P = 0.05) and 0.97 (0.78-1.20) for the quantified success rate (P = 0.76). No significant difference in the reduction in glaucoma medicines was observed (WMD = 0.24; 95% CI: -0.27-0.76; P = 0.35). AGV was found to be associated with a significantly lower frequency of all adverse events (RR = 0.71; 95%CI: 1.14-0.97; p = 0.001) than trabeculectomy, while the most common complications did not differ significantly (all p> 0.05). CONCLUSION: AGV was equivalent to trabeculectomy in reducing the IOP, the number of glaucoma medications, success rates, and rates of the most common complications. However, AGV was associated with a significantly lower frequency of overall adverse events. PMID- 25719406 TI - Quantifying two-dimensional filamentous and invasive growth spatial patterns in yeast colonies. AB - The top-view, two-dimensional spatial patterning of non-uniform growth in a Saccharomyces cerevisiae yeast colony is considered. Experimental images are processed to obtain data sets that provide spatial information on the cell-area that is occupied by the colony. A method is developed that allows for the analysis of the spatial distribution with three metrics. The growth of the colony is quantified in both the radial direction from the centre of the colony and in the angular direction in a prescribed outer region of the colony. It is shown that during the period of 100-200 hours from the start of the growth of the colony there is an increasing amount of non-uniform growth. The statistical framework outlined in this work provides a platform for comparative quantitative assays of strain-specific mechanisms, with potential implementation in inferencing algorithms used for parameter-rate estimation. PMID- 25719407 TI - Early investigational TNF receptor antagonists for the treatment of ulcerative colitis. AB - INTRODUCTION: Ulcerative colitis (UC) is a life-long, immunologically mediated condition that results from an inappropriate activation of the mucosal immune system by intestinal luminal antigens in genetically susceptible individuals. TNF alpha is a pro-inflammatory cytokine central to UC pathogenesis. AREAS COVERED: This review examines the evidence for the use of the anti-TNF (alphaTNF) medications infliximab, adalimumab, certolizumab and golimumab in the management of UC. It highlights the newer biosimilar agents that are becoming available and the early stage investigation of an orally administered alphaTNF agent. EXPERT OPINION: alphaTNF therapy is effective but only in a proportion of UC patients. As there is now strong evidence that UC is not just a single disease but a series of phenotypes with distinct genetic, serological and environmental aspects, understanding the heterogeneity of the innate immunological response in UC could allow for better targeted patient management. Identifying differences in the efficacy of the various alphaTNF agents is difficult as there are no head-to-head studies, but only infliximab has proven clinical efficacy in the management of acute severe colitis. Biosimilars to the alphaTNF agents are now available and with the added competition, medications costs should fall allowing for greater patient access. PMID- 25719408 TI - You have my word: reciprocity expectation modulates feedback-related negativity in the trust game. AB - Promise is one of the most powerful tools producing trust and facilitating cooperation, and sticking to the promise is deemed as a key social norm in social interactions. The present study explored the extent to which promise would influence investors' decision-making in the trust game where promise had no predictive value regarding trustees' reciprocation. In addition, we examined the neural underpinnings of the investors' outcome processing related to the trustees' promise keeping and promise breaking. Consistent with our hypothesis, behavioral results indicated that promise could effectively increase the investment frequency of investors. Electrophysiological results showed that, promise induced larger differentiated-FRN responses to the reward and non-reward discrepancy. Taken together, these results suggested that promise would promote cooperative behavior, while breach of promise would be regarded as a violation of the social norm, corroborating the vital role of non-enforceable commitment in social decision making. PMID- 25719409 TI - Evaluation of approaches to monitor Staphylococcus aureus virulence factor expression during human disease. AB - Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize S. aureus isolates recovered from infected patients and also to investigate approaches for examining expression of S. aureus vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed S. aureus wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage S. aureus isolates were recovered and characterized for genotypic diversity. S. aureus antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. S. aureus nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable S. aureus triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the S. aureus virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine. PMID- 25719410 TI - Synergistic antimicrobial activity of Camellia sinensis and Juglans regia against multidrug-resistant bacteria. AB - Synergistic combinations of antimicrobial agents with different mechanisms of action have been introduced as more successful strategies to combat infections involving multidrug resistant (MDR) bacteria. In this study, we investigated synergistic antimicrobial activity of Camellia sinensis and Juglans regia which are commonly used plants with different antimicrobial agents. Antimicrobial susceptibility of 350 Gram-positive and Gram-negative strains belonging to 10 different bacterial species, was tested against Camellia sinensis and Juglans regia extracts. Minimum inhibitory concentrations (MICs) were determined by agar dilution and microbroth dilution assays. Plant extracts were tested for synergistic antimicrobial activity with different antimicrobial agents by checkerboard titration, Etest/agar incorporation assays, and time kill kinetics. Extract treated and untreated bacteria were subjected to transmission electron microscopy to see the effect on bacterial cell morphology. Camellia sinensis extract showed higher antibacterial activity against MDR S. Typhi, alone and in combination with nalidixic acid, than to susceptible isolates." We further explore anti-staphylococcal activity of Juglans regia that lead to the changes in bacterial cell morphology indicating the cell wall of Gram-positive bacteria as possible target of action. The synergistic combination of Juglans regia and oxacillin reverted oxacillin resistance of methicillin resistant Staphylococcus aureus (MRSA) strains in vitro. This study provides novel information about antimicrobial and synergistic activity of Camellia sinensis and Juglans regia against MDR pathogens. PMID- 25719411 TI - The Gulf of Mexico: a "hot zone" for neglected tropical diseases? PMID- 25719413 TI - Five years of stable disease with maintenance therapy using bevacizumab and tamoxifen in a patient with metastatic breast cancer. AB - Bevacizumab and Tamoxifen are valid therapeutic options for metastatic breast cancer (mBC) patients. In this report, we describe a 47 year old woman with mBC successfully treated with a maintenance therapy with Bevacizumab+Tamoxifen. A maintenance approach using 2 different drugs with different targets and mechanism of action, such as anti-angiogenic and anti-hormonal treatment is particularly intriguing because they affect different pathways involved in mBC progression. Further studies including a large number of patients are needed, in order to select women who could benefit from this maintenance approach. PMID- 25719412 TI - New insights into flavivirus evolution, taxonomy and biogeographic history, extended by analysis of canonical and alternative coding sequences. AB - To generate the most diverse phylogenetic dataset for the flaviviruses to date, we determined the genomic sequences and phylogenetic relationships of 14 flaviviruses, of which 10 are primarily associated with Culex spp. mosquitoes. We analyze these data, in conjunction with a comprehensive collection of flavivirus genomes, to characterize flavivirus evolutionary and biogeographic history in unprecedented detail and breadth. Based on the presumed introduction of yellow fever virus into the Americas via the transatlantic slave trade, we extrapolated a timescale for a relevant subset of flaviviruses whose evolutionary history, shows that different Culex-spp. associated flaviviruses have been introduced from the Old World to the New World on at least five separate occasions, with 2 different sets of factors likely to have contributed to the dispersal of the different viruses. We also discuss the significance of programmed ribosomal frameshifting in a central region of the polyprotein open reading frame in some mosquito-associated flaviviruses. PMID- 25719416 TI - Self-Lubricity of WSex Nanocomposite Coatings. AB - Transition metal chalcogenides with lamellar structure are known for their use in tribological applications although limited to vacuum due to their easy degradation in the presence of oxygen and/or moisture. Here we present a tailored WSex coating with low friction (0.07) and low wear rates (3*10(-7) mm3 Nm(-1)) even in ambient air. To understand the low friction behavior and lower chemical reactivity a tribological study is carried out in a high-vacuum tribometer under variable pressure (atmospheric pressure to 1*10(-8) mbar). A detailed investigation of the film nanostructure and composition by advanced transmission electron microscopy techniques with nanoscale resolution determined that the topmost layer is formed by nanocrystals of WSe2 embedded in an amorphous matrix richer in W, a-W(Se). After the friction test, an increased crystalline order and orientation of WSe2 lamellas along the sliding direction were observed in the interfacial region. On the basis of high angle annular dark field, scanning transmission electron microscopy, and energy dispersive X-ray analysis, the release of W atoms from the interstitial basal planes of the a-W(Se) phase is proposed. These W atoms reaching the surface, play a sacrificial role preventing the lubricant WSe2 phase from oxidation. The increase of the WSe2 crystalline order and the buffer effect of W capturing oxygen atoms would explain the enhanced chemical and tribological response of this designed nanocomposite material. PMID- 25719414 TI - The ionic charge of copper-64 complexes conjugated to an engineered antibody affects biodistribution. AB - The development of biomolecules as imaging probes requires radiolabeling methods that do not significantly influence their biodistribution. Sarcophagine (Sar) chelators form extremely stable complexes with copper and are therefore a promising option for labeling proteins with (64)Cu. However, initial studies using the first-generation sarcophagine bifunctional chelator SarAr to label the engineered antibody fragment ch14.18-DeltaCH2 (MW 120 kDa) with (64)Cu showed high tracer retention in the kidneys, presumably because the high local positive charge on the Cu(II)-SarAr moiety resulted in increased binding of the labeled protein to the negatively charged basal cells of the glomerulus. To test this hypothesis, ch14.18-DeltaCH2 was conjugated with a series of Sar derivatives of decreasing positive charge and three commonly used macrocyclic polyaza polycarboxylate (PAC) bifunctional chelators (BFC). The immunoconjugates were labeled with (64)Cu and injected into mice, and PET/CT images were obtained at 24 and 48 h postinjection (p.i.). At 48 h p.i., ex vivo biodistribution was assessed. In addition, to demonstrate the potential of metastasis detection using (64)Cu-labeled ch14.18-DeltaCH2, a preclinical imaging study of intrahepatic neuroblastoma tumors was performed. Reducing the positive charge on the Sar chelators decreased kidney uptake of Cu-labeled ch14.18-DeltaCH2 by more than 6 fold, from >45 to <6% ID/g, whereas the uptake in most other tissues, including liver, was relatively unchanged. However, despite this dramatic decrease, the renal uptake of the PAC BFCs was generally lower than that of the Sar derivatives, as was the liver uptake. Uptake of (64)Cu-labeled ch14.18-DeltaCH2 in neuroblastoma hepatic metastases was detected using PET. PMID- 25719417 TI - Transformation between inverse bicontinuous cubic phases of a lipid from diamond to primitive. AB - I studied the transformation between inverse bicontinuous cubic phases (QII) from diamond (QII(D)) to primitive (QII(P)) in a single-crystal region of monoolein. X ray diffraction data reveal that the crystallographic orientation of QII(P) rotates 55 degrees around the [011] axis from QII(D). This indicates that one direction of the four-branched water channels in the QII(D) phase is preserved in the six-branched water channels of the QII(P) phase. I therefore built a transformation model that would keep the direction of the water channels fixed in both phases and cause the water channels along other direction in QII(D) to shrink and disappear. PMID- 25719419 TI - Hearing preservation using topical dexamethasone alone and associated with hyaluronic acid in cochlear implantation. AB - CONCLUSION: Topical dexamethasone associated with hyaluronic acid in cochlear implant surgery demonstrated a statistically significant difference in the preservation of low-frequency thresholds when compared with topical dexamethasone alone and a control group. Topical dexamethasone alone was not superior in hearing preservation when compared to the control group. OBJECTIVE: To compare the effects of topical dexamethasone alone and associated with hyaluronic acid intraoperatively in hearing preservation in cochlear implantation. METHODS: Eighteen severely to profoundly hearing-impaired adult patients with measurable hearing were divided into three groups preoperatively: cochlear implantation as a control group (group 1), cochlear implantation using topical dexamethasone intraoperatively (group 2), and cochlear implantation using topical dexamethasone associated with hyaluronic acid intraoperatively (group 3). Preimplant and postimplant low-frequency pure-tone averages (PTAs) were calculated from unaided audiograms at 125, 250, and 500 Hz. RESULTS: The mean changes in the low frequency PTA comparing postoperative against preoperative thresholds were 28.03 +/- 6.77 dB in group 1, 30 +/- 14.53 dB in group 2, and 7.23 +/- 6.12 dB in group 3. There was statistical difference when comparing group 3 with groups 1 and 2 using one-way ANOVA (p = 0.002) followed by Scheffe post hoc test. PMID- 25719418 TI - Aberrant lymphatic endothelial progenitors in lymphatic malformation development. AB - Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133- cells isolated from LM fluids. CD133- LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133- LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs. PMID- 25719420 TI - Influence of carbon source on nutrient removal performance and physical-chemical characteristics of aerobic granular sludge. AB - The impact of carbon source variation on the physical and chemical characteristics of aerobic granular sludge and its biological nutrient (nitrogen and phosphorus) removal performance was investigated. Two identical sequencing batch reactors, R1 and R2, were set up. Granular biomass was cultivated to maturity using acetate-based synthetic wastewater. After mature granules in both reactors with simultaneous chemical oxygen demand (COD), ammonium and phosphorus removal capability were achieved, the feed of R2 was changed to municipal wastewater and R1 was continued on synthetic feed as control. Biological phosphorus removal was completely inhibited in R2 due to lack of readily biodegradable COD; however, the biomass maintained high ammonium and COD removal efficiencies. The disintegration of the granules in R2 occurred during the first two weeks after the change of feed, but it did not have significant impacts on settling properties of the sludge. Re-granulation of the biomass in R2 was then observed within 30 d after granules' disintegration when the biomass acclimated to the new substrate. The granular biomass in R1 and R2 maintained a Sludge Volume Index close to 60 and 47 mL g(-1), respectively, during the experimental period. It was concluded that changing the carbon source from readily biodegradable acetate to the more complex ones present in municipal wastewater did not have significant impacts on aerobic granular sludge characteristics; it particularly did not affect its settling properties. However, sufficient readily biodegradable carbon would have to be provided to maintain simultaneous biological nitrate and phosphorus removal. PMID- 25719422 TI - High interfacial lithium storage capability of hollow porous Mn2O3 nanostructures obtained from carbonate precursors. AB - The preparation of porous Mn2O3 boxes has been developed via a carbonate precursor route. As a Li-ion battery anode, it delivers a high reversible capacity of 1442 mA h g(-1) over 600 cycles at 800 mA g(-1), and 65% of the capacity originates from the gradually emerging interfacial storage contribution. PMID- 25719424 TI - Electrophysiological change in the tensor veli palatini muscle after radiotherapy. AB - CONCLUSION: Electromyography of the tensor veli palatine (TVP) was abnormal and showed mainly myogenic impairment in patients with nasopharyngeal carcinoma (NPC) with secretory otitis media (SOM) after radiotherapy. The diseased ears showed impairment in opening functions of the eustachian tubes (ETs). OBJECTIVES: To characterize electrophysiology of the TVP muscle using electromyography (EMG) in patients with SOM after radiotherapy of NPC. METHODS: Twenty healthy volunteers and 20 patients with NPC and SOM after radiotherapy were chosen for assessment of EMG of the TVP during swallowing. RESULTS: The measurements of average duration and amplitude of action potential, swallowing contraction duration, and peak voltage in NPC patients with both SOM (n = 25) and healthy ears (n = 6) were significantly lower than those of ears (n = 38) in healthy controls (p < 0.01). In patients with NPC, the average action potential duration and swallowing contraction duration in ears with SOM were lower than those of subjects with healthy ears (p < 0.05), whereas no significant difference was found in average amplitude of action potential and peak voltage between them. PMID- 25719423 TI - Ovariectomy shortens the life span of female mice. AB - This study shows that lack of ovarian activity has a negative impact on the life span of female mice. The extent to which this phenomenon could be associated with the anti-inflammatory effect of estrogens was analyzed in metabolic organs and aorta, by quantitative analysis of mRNAs encoding proteins in the inflammatory cascade. We demonstrate that the TNFalpha, IL-1beta, MCP-1, MIP-2 and IL-6 mRNA contents are increased in the liver, adipose tissue and aorta 7 months after ovariectomy (ovx) and this increased basal inflammation is maintained as the mice aged. In contrast, the extent of inflammatory gene expression is directly proportional to age in sham-operated mice. As a consequence, at 22 months, most of the inflammatory parameters examined were higher in the sham-operated group compared with the ovx group. These observations led us to propose that the decreased longevity of ovx mice may be due to an acceleration of the basal state of inflammation in metabolic organs, which is likely driven by the combination of a lack of estrogen-mediated anti-inflammatory activity and the loss of gonadal control of energy metabolism. PMID- 25719425 TI - Bilateral absence of the ulna in 4q terminal deletion syndrome: evidence for a critical region. PMID- 25719427 TI - Synthetic biology approaches to fluorinated polyketides. AB - The catalytic diversity of living systems offers a broad range of opportunities for developing new methods to produce small molecule targets such as fuels, materials, and pharmaceuticals. In addition to providing cost-effective and renewable methods for large-scale commercial processes, the exploration of the unusual chemical phenotypes found in living organisms can also enable the expansion of chemical space for discovery of novel function by combining orthogonal attributes from both synthetic and biological chemistry. In this context, we have focused on the development of new fluorine chemistry using synthetic biology approaches. While fluorine has become an important feature in compounds of synthetic origin, the scope of biological fluorine chemistry in living systems is limited, with fewer than 20 organofluorine natural products identified to date. In order to expand the diversity of biosynthetically accessible organofluorines, we have begun to develop methods for the site selective introduction of fluorine into complex natural products by engineering biosynthetic machinery to incorporate fluorinated building blocks. To gain insight into how both enzyme active sites and metabolic pathways can be evolved to manage and select for fluorinated compounds, we have studied one of the only characterized natural hosts for organofluorine biosynthesis, the soil microbe Streptomyces cattleya. This information provides a template for designing engineered organofluorine enzymes, pathways, and hosts and has allowed us to initiate construction of enzymatic and cellular pathways for the production of fluorinated polyketides. PMID- 25719428 TI - Nickel-catalyzed direct thioetherification of beta-C(sp(3))-H bonds of aliphatic amides. AB - The nickel-catalyzed beta-thioetherification of unactivated C(sp(3))-H bond of propionamides is established with the assistance of 8-aminoquinoline auxiliary, leading to the beta-thio carboxylic acid derivatives. A broad range of functional groups is compatible with this thioetherfication reaction. The process represents the first successful example of metal-catalyzed C-S bond formation from unactivated C(sp(3))-H bonds. PMID- 25719429 TI - Randomized trial of glucosamine and chondroitin supplementation on inflammation and oxidative stress biomarkers and plasma proteomics profiles in healthy humans. AB - BACKGROUND: Glucosamine and chondroitin are popular non-vitamin dietary supplements used for osteoarthritis. Long-term use is associated with lower incidence of colorectal and lung cancers and with lower mortality; however, the mechanism underlying these observations is unknown. In vitro and animal studies show that glucosamine and chondroitin inhibit NF-kB, a central mediator of inflammation, but no definitive trials have been done in healthy humans. METHODS: We conducted a randomized, double-blind, placebo-controlled, cross-over study to assess the effects of glucosamine hydrochloride (1500 mg/d) plus chondroitin sulfate (1200 mg/d) for 28 days compared to placebo in 18 (9 men, 9 women) healthy, overweight (body mass index 25.0-32.5 kg/m2) adults, aged 20-55 y. We examined 4 serum inflammatory biomarkers: C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor receptors I and II; a urinary inflammation biomarker: prostaglandin E2-metabolite; and a urinary oxidative stress biomarker: F2-isoprostane. Plasma proteomics on an antibody array was performed to explore other pathways modulated by glucosamine and chondroitin. RESULTS: Serum CRP concentrations were 23% lower after glucosamine and chondroitin compared to placebo (P = 0.048). There were no significant differences in other biomarkers. In the proteomics analyses, several pathways were significantly different between the interventions after Bonferroni correction, the most significant being a reduction in the "cytokine activity" pathway (P = 2.6 x 10-16), after glucosamine and chondroitin compared to placebo. CONCLUSION: Glucosamine and chondroitin supplementation may lower systemic inflammation and alter other pathways in healthy, overweight individuals. This study adds evidence for potential mechanisms supporting epidemiologic findings that glucosamine and chondroitin are associated with reduced risk of lung and colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01682694. PMID- 25719430 TI - Patient sharing and quality of care: measuring outcomes of care coordination using claims data. AB - BACKGROUND: With the goal of improving clinical efficiency and effectiveness, programs to enhance care coordination are a major focus of health care reform. OBJECTIVE: To examine whether "care density"--a claims-based measure of patient sharing by office-based physicians--is associated with measures of quality. Care density is a proxy measure that may reflect how frequently a patient's doctors collaborate. RESEARCH DESIGN: Cohort study using administrative databases from 3 large commercial insurance plans. SUBJECTS: A total of 1.7 million adult patients; 31,675 with congestive heart failure, 78,530 with chronic obstructive pulmonary disease, and 240,378 with diabetes. MEASURES: Care density was assessed in 2008. Prevention Quality Indicators (PQIs), 30-day readmissions, and Healthcare Effectiveness Data and Information Set quality indicators were measured in the following year. RESULTS: Among all patients, we found that patients with the highest care density density--indicating high levels of patient sharing among their office-based physicians--had significantly lower rates of adverse events measured as PQIs compared with patients with low-care density (odds ratio=0.88; 95% confidence interval, 0.85-0.92). A significant association between care density and PQIs was also observed for patients with diabetes mellitus but not congestive heart failure or chronic obstructive pulmonary disease. Diabetic patients with higher care density scores had significantly lower odds of 30-day readmissions (odds ratio=0.68, 95% confidence interval, 0.48 0.97). Significant associations were observed between care density and Healthcare Effectiveness Data and Information Set measures although not always in the expected direction. CONCLUSION: In some settings, patients whose doctors share more patients had lower odds of adverse events and 30-day readmissions. PMID- 25719431 TI - Statin use after acute myocardial infarction by patient complexity: are the rates right? AB - BACKGROUND: Guidelines suggest statin use after acute myocardial infarction (AMI) should be close to universal in patients without safety concerns yet rates are much lower than recommended, decline with patient complexity, and display substantial geographic variation. Trial exclusions have resulted in little evidence to guide statin prescribing for complex patients. OBJECTIVE: To assess the benefits and risks associated with higher rates of statin use after AMI by baseline patient complexity. RESEARCH DESIGN: Sample includes Medicare fee-for service patients with AMIs in 2008-2009. Instrumental variable estimators using variation in local area prescribing patterns by statin intensity as instruments were used to assess the association of higher statin prescribing rates by statin intensity on 1-year survival, adverse events, and cost by patient complexity. RESULTS: Providers seem to have individualized statin use across patients based on potential risks. Higher statin rates for noncomplex AMI patients were associated with increased survival rates with little added adverse event risk. Higher statin rates for complex AMI patients were associated with tradeoffs between higher survival rates and higher rates of adverse events. CONCLUSIONS: Higher rates of statin use for noncomplex AMI patients are associated with outcome rate changes similar to existing evidence. For the complex patients in our study, who were least represented in existing trials, higher statin-use rates were associated with survival gains and higher adverse event risks not previously documented. Policy interventions promoting higher statin-use rates for complex patients may need to be reevaluated taking careful consideration of these tradeoffs. PMID- 25719432 TI - Disability status, mortality, and leading causes of death in the United States community population. AB - OBJECTIVE: We examined the effect of functional disability on all-cause mortality and cause-specific deaths among community-dwelling US adults. METHODS: We used data from 142,636 adults who participated in the 1994-1995 National Health Interview Survey-Disability Supplement eligible for linkage to National Death Index records from 1994 to 2006 to estimate the effects of disability on mortality and leading causes of death. RESULTS: Adults with any disability were more likely to die than adults without disability (19.92% vs. 10.94%; hazard ratio=1.51, 95% confidence interval, 1.45-1.57). This association was statistically significant for most causes of death and for most types of disability studied. The leading cause of death for adults with and without disability differed (heart disease and malignant neoplasms, respectively). CONCLUSIONS: Our results suggest that all-cause mortality rates are higher among adults with disabilities than among adults without disabilities and that significant associations exist between several types of disability and cause specific mortality. Interventions are needed that effectively address the poorer health status of people with disabilities and reduce the risk of death. PMID- 25719433 TI - Is Traumatic Brain Injury Associated with Reduced Inter-Hemispheric Functional Connectivity? A Study of Large-Scale Resting State Networks following Traumatic Brain Injury. AB - Traumatic brain injury (TBI) often has long-term debilitating sequelae in cognitive and behavioral domains. Understanding how TBI impacts functional integrity of brain networks that underlie these domains is key to guiding future approaches to TBI rehabilitation. In the current study, we investigated the differences in inter-hemispheric functional connectivity (FC) of resting state networks (RSNs) between chronic mild-to-severe TBI patients and normal comparisons (NC), focusing on two externally oriented networks (i.e., the fronto parietal network [FPN] and the executive control network [ECN]), one internally oriented network (i.e., the default mode network [DMN]), and one somato-motor network (SMN). Seed voxel correlation analysis revealed that TBI patients displayed significantly less FC between lateralized seeds and both homologous and non-homologous regions in the opposite hemisphere for externally oriented networks but not for DMN or SMN; conversely, TBI patients showed increased FC within regions of the DMN, especially precuneus and parahippocampal gyrus. Region of interest correlation analyses confirmed the presence of significantly higher inter-hemispheric FC in NC for the FPN (p < 0.01), and ECN (p < 0.05), but not for the DMN (p > 0.05) or SMN (p > 0.05). Further analysis revealed that performance on a neuropsychological test measuring organizational skills and visuo-spatial abilities administered to the TBI group, the Rey-Osterrieth Complex Figure Test, positively correlated with FC between the right FPN and homologous regions. Our findings suggest that distinct RSNs display specific patterns of aberrant FC following TBI; this represents a step forward in the search for biomarkers useful for early diagnosis and treatment of TBI-related cognitive impairment. PMID- 25719434 TI - Impact of Cosmetics on the Surface Properties of Silicone Hydrogel Contact Lenses. AB - PURPOSE: This study evaluated the impact of various cosmetics on the surface properties of silicone hydrogel (SiHy) contact lens materials. METHODS: In this in vitro experiment, 7 SiHy contact lens materials were coated with 1 of 9 cosmetics, including common hand creams (3), eye makeup removers (3), and mascaras (3). Dark-field microscopy images were taken to determine pixel brightness (PB) after cosmetic exposure, which describes the visible surface deposition (n=6 for each lens type), with a higher PB indicating increased deposition. The sessile drop technique was used to determine the advancing contact angle (CA). Measurements were repeated for both methods after a single peroxide-based cleaning cycle. RESULTS: Pixel brightness was significantly higher for mascara-coated lenses compared with the other cosmetic products (P<0.01). The peroxide-based lens care solution removed most deposits from the nonwaterproof mascara for 4 lens types, whereas deposits remained relatively unchanged for 1 waterproof mascara (P>0.05). Hand creams and makeup remover had minimal impact on PB. Changes in CA measurements after cosmetic application were highly lens dependent. Hand creams caused primarily a decrease in CA for 5 of the 7 lens types, whereas 1 of the waterproof mascaras caused a significant increase of 30 to 50 degrees for 3 lens types. CONCLUSION: Some mascara-lens combinations resulted in increased CA and PB, which could have an impact on in vivo lens performance. Nonwaterproof mascara was mostly removed after a cleaning cycle. Further research is needed to understand the clinical implications for SiHy lens wearers using cosmetics. PMID- 25719436 TI - Postnatal quality of life, depressive symptoms, and social support among women in southern India. AB - Evaluation of postnatal quality of life (QOL) has remained a poorly researched area in India. The present cross-sectional study assessed postnatal QOL, using the Mother Generated Index (MGI) and its associated risk factors, and was conducted during January-March 2013 among 274 mothers, 6-8 weeks postnatally. A semi-structured questionnaire was used to evaluate sociodemographic and obstetric characteristics and social support. Depressive symptoms were assessed by the Patient Health Questionnaire (PHQ-9) and QOL using the MGI. The vast majority (90.1 percent) of respondents in our study had a primary MGI score <5, those with significantly higher prevalence of physical problems and psychological distress. A total of 39.8 percent of respondents were screened as having other (not major) depressive symptoms and 4.7 percent as having major depressive symptoms. Multiple regression analysis revealed that age (beta = 0.033, p = .018) and socioeconomic status (beta = 0.156, p < .001) were significantly positively associated with QOL, while increased depressive symptom scores (beta = -0.075, p < .001) were significantly negatively associated with QOL. A wide spectrum of QOL aspects were reported, including physical, emotional, social, and economic concerns by the mothers. Prevention, evaluation, and treatment of postnatal depressive symptoms and impaired QOL are warranted, taking into account the role of various biopsychosocial risk factors and specific concerns raised by the mothers. PMID- 25719435 TI - Microfluidic multiculture assay to analyze biomolecular signaling in angiogenesis. AB - Angiogenesis (the formation of blood vessels from existing blood vessels) plays a critical role in many diseases such as cancer, benign tumors, and macular degeneration. There is a need for cell culture methods capable of dissecting the intricate regulation of angiogenesis within the microenvironment of the vasculature. We have developed a microscale cell-based assay that responds to complex pro- and antiangiogenic soluble factors with an in vitro readout for vessel formation. The power of this system over traditional techniques is that we can incorporate the whole milieu of soluble factors produced by cells in situ into one biological readout (vessel formation), even if the identity of the factors is unknown. We have currently incorporated macrophages, endothelial cells, and fibroblasts into the assay, with the potential to include additional cell types in the future. Importantly, the microfluidic platform is simple to operate and multiplex to test drugs targeting angiogenesis in a more physiologically relevant context. As a proof of concept, we tested the effect of an enzyme inhibitor (targeting matrix metalloproteinase 12) on vessel formation; the triculture microfluidic assay enabled us to capture a dose-dependent effect entirely missed in a simplified coculture assay (p < 0.0001). This result underscores the importance of cell-based assays that capture chemical cross-talk occurring between cell types. The microscale dimensions significantly reduce cell consumption compared to conventional well plate platforms, enabling the use of limited primary cells from patients in future investigations and offering the potential to screen therapeutic approaches for individual patients in vitro. PMID- 25719437 TI - Molecular CHEVREL-like clusters [(RhPPh3)6(MU3-Se)8] and [Pd6(MU3-Te)8](4-). AB - [(RhPPh3)6(MU3-Se)8].0.5en (1; en = ethane-1,2-diamine), obtained by the reaction of [Pb2Se3](2-) anions with [Rh(PPh3)3Cl] in en, represents the first compound comprising a molecular [Rh6] octahedron with all faces capped by Se atoms. Analogous treatment of [Pb2Te3](2-) with [Pd(PPh3)2Cl2] yielded [Li4(en)10][Pd6(MU3-Te)8] (2), the first compound exhibiting a molecular, chalcogen-capped [Pd6] aggregate. Besides syntheses and structures of the title compounds, we report quantum-chemical calculations to understand the electronic properties of these molecular CHEVREL-like complexes. PMID- 25719438 TI - Origin of the regioselective reduction of chlorins. AB - The reduction of a free-base chlorin generally forms a bacteriochlorin (BC), while the reduction of the corresponding metallochlorin forms a metalloisobacteriochlorin (M-iBC). This regioselectivity has been long known but was never fully rationalized. In the free-base case, this regioselectivity can be explained using resonance arguments, but the explanations for the regioselectivity in the metallochlorin reactions requires a more sophisticated approach. A combination of DFT-calculated average local ionization energies (ALIEs), thermodynamics of the products, and the transition-state trajectories of reduction reactions of meso-tetraaryl- and beta-octaethylchlorins, as their free bases and zinc complexes, now fully delineate the theoretical basis of the reduction regioselectivity. The reactions are kinetically controlled. Steric effects originating in the conformational flexibility of the chlorin macrocycle direct the reactions toward the formation of iBCs. Only when electronic effects are strong enough to override the steric effects are BCs formed. Depending on the substituents present on the chlorin, this regioselectivity may change, but ALIE calculations provide reliable guidelines to predict this. The practical value of this work lies in the presentation of a simple predictive method toward synthetic tetrahydroporphyrins by reduction of chlorins. PMID- 25719439 TI - CAPS-1 promotes fusion competence of stationary dense-core vesicles in presynaptic terminals of mammalian neurons. AB - Neuropeptides released from dense-core vesicles (DCVs) modulate neuronal activity, but the molecules driving DCV secretion in mammalian neurons are largely unknown. We studied the role of calcium-activator protein for secretion (CAPS) proteins in neuronal DCV secretion at single vesicle resolution. Endogenous CAPS-1 co-localized with synaptic markers but was not enriched at every synapse. Deletion of CAPS-1 and CAPS-2 did not affect DCV biogenesis, loading, transport or docking, but DCV secretion was reduced by 70% in CAPS 1/CAPS-2 double null mutant (DKO) neurons and remaining fusion events required prolonged stimulation. CAPS deletion specifically reduced secretion of stationary DCVs. CAPS-1-EYFP expression in DKO neurons restored DCV secretion, but CAPS-1 EYFP and DCVs rarely traveled together. Synaptic localization of CAPS-1-EYFP in DKO neurons was calcium dependent and DCV fusion probability correlated with synaptic CAPS-1-EYFP expression. These data indicate that CAPS-1 promotes fusion competence of immobile (tethered) DCVs in presynaptic terminals and that CAPS-1 localization to DCVs is probably not essential for this role. PMID- 25719441 TI - Effect of Omeprazole on the Pharmacokinetics of Rosuvastatin in Healthy Male Volunteers. AB - The current study aimed at the evaluation of, in vivo, the effect of omeprazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Omeprazole is an acid suppressant and CYP2C9, CYP3A4, and CYP2C19 substrate and inhibitor, as well as inhibitor of transporters (like P-gp). This was a randomized, open-label, 2-period, crossover study. Healthy male volunteers (N = 20), divided into 2 groups, were given single oral doses of rosuvastatin 40 mg either alone (treatment period I) or concomitantly with omeprazole 40-mg capsule (treatment period II). Plasma concentrations of rosuvastatin (rosuva) and its metabolite N-desmethyl rosuvastatin (NDM-rosuva) were quantified by a validated liquid chromatography-tandem mass spectrometry method developed in our laboratory. An insignificant decrease (P > 0.05) has been observed in the values of maximum plasma concentrations, clearance, and half-life of rosuva, whereas an insignificant increase (P > 0.05) has been observed in the area under the plasma concentration-time curves from zero time to the last measurable concentration(Equation is included in full-text article.), that extrapolated to infinity (Equation is included in full-text article.), and mean residence time values after concomitant administration with omeprazole. Although omeprazole concomitant administration altered the pharmacokinetics of NDM-rosuva metabolite significantly, rosuva's very little metabolism (10%) suggests that these changes are of no clinical significance. Concomitant administration of omeprazole with rosuva did not alter the pharmacokinetics of rosuva in healthy volunteers. These data are consistent with other reported studies, indicating that rosuva is not a good candidate for metabolism-based drug-drug interactions. Therefore, rosuva can be administered safely along with omeprazole. PMID- 25719440 TI - The small molecule ISRIB reverses the effects of eIF2alpha phosphorylation on translation and stress granule assembly. AB - Previously, we identified ISRIB as a potent inhibitor of the integrated stress response (ISR) and showed that ISRIB makes cells resistant to the effects of eIF2alpha phosphorylation and enhances long-term memory in rodents (Sidrauski et al., 2013). Here, we show by genome-wide in vivo ribosome profiling that translation of a restricted subset of mRNAs is induced upon ISR activation. ISRIB substantially reversed the translational effects elicited by phosphorylation of eIF2alpha and induced no major changes in translation or mRNA levels in unstressed cells. eIF2alpha phosphorylation-induced stress granule (SG) formation was blocked by ISRIB. Strikingly, ISRIB addition to stressed cells with pre formed SGs induced their rapid disassembly, liberating mRNAs into the actively translating pool. Restoration of mRNA translation and modulation of SG dynamics may be an effective treatment of neurodegenerative diseases characterized by eIF2alpha phosphorylation, SG formation, and cognitive loss. PMID- 25719442 TI - Controversial Effects of Exogenous Testosterone on Cardiovascular Diseases. AB - The use of testosterone (T) among men aged 40 years or older was increased more than 3 times from 0.81% in 2001 to 2.91% in 2011. Until recently, the majority of the studies did not show any increased cardiovascular (CV) risk by using T in male patients with hypogonadism. What is more, some studies had observed a protective effect of using T against CV diseases. However, in 2010, a randomized clinical trial (RCT) was intended to study the advantage of T gel in older men with limitations in mobility; the study was stopped due to unexpected high prevalence of CV adverse outcome. These findings were confirmed by 2 other studies published in November of 2013 and January of 2014. Consequently, the Food and Drug Administration (FDA) had announced in January 2014 that it will reassess the safety of those treatments. Meanwhile, the agency had not reached to a definitive conclusion that FDA-approved testosterone therapy raises the risk of stroke, heart attack, or death. A report released in the broadcast of the NBC Nightly News in September of this year that the FDA says "there's little evidence that T boosting drugs taken by millions of American men are actually effective." NBC notes that the agency also pointed out that it was not convinced that they carry serious risk either. "The condition has been marketed as low 'T', and the medications are offered to help with low sex drive and fatigue among some men," notes NBC. The European Medicines Agency EMA's Pharmacovigilance Risk Assessment Committee has also responded to the concern of potential CV adverse outcomes associated with the use of T, and they have concluded in their October meeting of this year that the use of T in men who do not produce enough T raises the risk of heart diseases. In our review, we highlighted the association between exogenous T and major adverse CV outcomes. Additionally, we focused on the interplay between exogenous T and some endocrine abnormalities such as diabetes mellitus type 2, metabolic syndrome, dyslipidemia, and obesity. PMID- 25719443 TI - Weak encoding of faces predicts socially influenced judgments of facial attractiveness. AB - Conforming to the majority can be seen as a heuristic type of judgment, as it allows the individual to easily choose the most accurate or most socially acceptable type of behavior. People who process the currently to-be-judged items in a superficial, heuristic way should tend to conform to group judgment more than people processing these items in a systematic and elaborate way. We investigated this hypothesis using electroencephalography (EEG), analyzing whether the strength of neural encoding of faces was related to the tendency to adopt a group's evaluative judgments regarding these faces. As expected, we found that the amplitude of the N170, a specific neural correlate of face encoding, was inversely related to conformity across participants: The weaker the faces were encoded, the more the majority response regarding the faces' attractiveness was adopted instead of relying on the actual qualities of the faces. Applying neurophysiological methodology, we thus provide support for previous claims, based on behavioral data and theorizing, that social conformity is a heuristic type of judgment. We propose that weak encoding of judgment-relevant information is a typical, possibly even necessary, precursor of socially adjusted judgments, irrespective of one's current motivational goal (i.e., to be accurate or accepted). PMID- 25719444 TI - Effect of the Addition of Ketamine to Sevoflurane Anesthesia on Seizure Duration in Electroconvulsive Therapy. AB - OBJECTIVES: We evaluated the effects of a subanesthetic dose of ketamine, which was administered as an adjunct to sevoflurane, on duration of seizure activity, hemodynamic profile, and recovery times during electroconvulsive therapy in patients with major depression. METHODS: Patients were randomly allocated to a group receiving either sevoflurane-ketamine (group SK) or sevoflurane-saline (group SS). Sevoflurane was initiated in both groups at 8% for anesthesia induction until loss of consciousness was achieved, at which point it was discontinued. After loss of consciousness, ketamine was administered to the group SK in the form of a 0.5-mg/kg intravenous bolus. Patients in the group SS received saline in the same manner. Mean arterial pressure (MAP) and heart rate were recorded before anesthetic induction (T1); after anesthetic induction (T2); as well as 0, 1, 3, and 10 minutes after the seizure had ended (T3, T4, T5, and T6, respectively). Motor and electroencephalogram seizure durations were recorded. RESULTS: Motor and electroencephalogram seizure durations in the group SS were similar to those observed for the group SK. The heart rate increased significantly during T2 to T6 in both group SS and group SK compared with the baseline. The MAP increased in the group SS during the period between T3 and T6 as well as in the group SK during the same period compared with the baseline. The MAP increased more in the group SK, in comparison with the group SS, during T2 (P < 0.05). CONCLUSIONS: The addition of ketamine at subanesthetic doses, for the purposes of anesthetic induction with sevoflurane, yielded results similar to those in the control group in terms of both seizure duration and hemodynamic stability. PMID- 25719445 TI - Virus-like particles activate type I interferon pathways to facilitate post exposure protection against Ebola virus infection. AB - Ebola virus (EBOV) causes a severe hemorrhagic disease with high fatality. Virus like particles (VLPs) are a promising vaccine candidate against EBOV. We recently showed that VLPs protect mice from lethal EBOV infection when given before or after viral infection. To elucidate pathways through which VLPs confer post exposure protection, we investigated the role of type I interferon (IFN) signaling. We found that VLPs lead to accelerated induction of IFN stimulated genes (ISGs) in liver and spleen of wild type mice, but not in Ifnar-/- mice. Accordingly, EBOV infected Ifnar-/- mice, unlike wild type mice succumbed to death even after VLP treatment. The ISGs induced in wild type mice included anti viral proteins and negative feedback factors known to restrict viral replication and excessive inflammatory responses. Importantly, proinflammatory cytokine/chemokine expression was much higher in WT mice without VLPs than mice treated with VLPs. In EBOV infected Ifnar-/- mice, however, uninhibited viral replication and elevated proinflammatory factor expression ensued, irrespective of VLP treatment, supporting the view that type I IFN signaling helps to limit viral replication and attenuate inflammatory responses. Further analyses showed that VLP protection requires the transcription factor, IRF8 known to amplify type I IFN signaling in dendritic cells and macrophages, the probable sites of initial EBOV infection. Together, this study indicates that VLPs afford post-exposure protection by promoting expeditious initiation of type I IFN signaling in the host. PMID- 25719446 TI - Antimicrobial characterization of site-directed mutagenesis of porcine beta defensin 2. AB - Porcine beta defensin 2 (pBD2) is a small, cationic and amphiphilic antimicrobial peptide. It has broad antimicrobial activities against bacteria and plays an important role in host defense. In order to enhance its antimicrobial activity and better understand the effect of positively charged residues on its activity, we substituted eight amino acid residues with arginine or lysine respectively. All mutants were cloned and expressed in BL21 (DE3) plysS and the mutant proteins were then purified. These mutant versions had higher positive charges but similar structural configurations compared to the wild-type pBD2. Moreover, these mutant proteins showed different antimicrobial activities against E. coli and S. aureus. The mutant I4R of pBD2 had the highest antimicrobial activity. In addition, all the mutants showed low hemolytic activities. Our results indicated that the positively charged residues were not the only factor that influenced antimicrobial activity, but other factors such as distribution of these residues on the surface of defensins might also contribute to their antimicrobial potency. PMID- 25719448 TI - Changes in mangrove species assemblages and future prediction of the Bangladesh Sundarbans using Markov chain model and cellular automata. AB - The composition and assemblage of mangroves in the Bangladesh Sundarbans are changing systematically in response to several environmental factors. In order to understand the impact of the changing environmental conditions on the mangrove forest, species composition maps for the years 1985, 1995 and 2005 were studied. In the present study, 1985 and 1995 species zonation maps were considered as base data and the cellular automata-Markov chain model was run to predict the species zonation for the year 2005. The model output was validated against the actual dataset for 2005 and calibrated. Finally, using the model, mangrove species zonation maps for the years 2025, 2055 and 2105 have been prepared. The model was run with the assumption that the continuation of the current tempo and mode of drivers of environmental factors (temperature, rainfall, salinity change) of the last two decades will remain the same in the next few decades. Present findings show that the area distribution of the following species assemblages like Goran (Ceriops), Sundari (Heritiera), Passur (Xylocarpus), and Baen (Avicennia) would decrease in the descending order, whereas the area distribution of Gewa (Excoecaria), Keora (Sonneratia) and Kankra (Bruguiera) dominated assemblages would increase. The spatial distribution of projected mangrove species assemblages shows that more salt tolerant species will dominate in the future; which may be used as a proxy to predict the increase of salinity and its spatial variation in Sundarbans. Considering the present rate of loss of forest land, 17% of the total mangrove cover is predicted to be lost by the year 2105 with a significant loss of fresh water loving mangroves and related ecosystem services. This paper describes a unique approach to assess future changes in species composition and future forest zonation in mangroves under the 'business as usual' scenario of climate change. PMID- 25719447 TI - Reduction in subventricular zone-derived olfactory bulb neurogenesis in a rat model of Huntington's disease is accompanied by striatal invasion of neuroblasts. AB - Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies. PMID- 25719449 TI - Airway hyper-responsiveness and small airway function in children with well controlled asthma. AB - BACKGROUND: Airway hyper-responsiveness (AHR) and small airway function are critical to children with asthma. Little is known about the role of the small airway in well-controlled subjects with AHR. We aimed to evaluate AHR and small airway function in children with well-controlled asthma, and to investigate the association between them. METHODS: We studied 116 cases of children with well controlled asthma (group A), 46 cases healthy children as controls (group C). Spirometry, impulse oscillometry (IOS), and methacholine challenge test (MCT) were conducted on all the children. RESULTS: (i) Group A and group C had no differences in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) ratio (P > 0.05). Forced expiratory flow between 25 and 75% of vital capacity (FEF25-75) and reactance at 5 Hz (X5) in group A were significantly lower than those in group C. (ii) One hundred and five cases (90.5%) of group A proved positive to MCT. (iii) FEF25-75 in group A proved positive to MCT but were lower than those proved negative (P < 0.05). CONCLUSION: AHR persisted in majority of children with well-controlled asthma. Among children with well-controlled asthma, small airway function was lower in those with AHR than those without AHR. PMID- 25719450 TI - The relationship between dietary patterns, body mass index percentile, and household food security in young urban children. AB - BACKGROUND: The relationship between food insecurity and child obesity is unclear. Few studies have examined dietary patterns in children with regard to household food security and weight status. The aim of this study was to examine the association between household food security, dietary intake, and BMI percentile in low-income, preschool children. METHODS: Low-income caregivers (n=222) with children ages 2-4 years were enrolled in a primary-care-based obesity prevention/reversal study (Steps to Growing Up Healthy) between October 2010 and December 2011. At baseline, demographic data, household food security status (US Household Food Security Instrument) and dietary intake (Children's Dietary Questionnaire; CDQ) were collected. BMI percentile was calculated from anthropometric data. RESULTS: Participating children were primarily Hispanic (90%), Medicaid insured (95%), 50% female, 35+/-8.7 months of age (mean+/ standard deviation), 19% overweight (BMI 85th-94th percentile), and 29% obese (>=95th percentile). Thirty-eight percent of interviews were conducted in Spanish. Twenty-five percent of households reported food insecurity. There was no association between household food insecurity and child BMI percentile. Dietary patterns of the children based on the CDQ did not differ by household food security status. Food group subscale scores (fruit and vegetable, fat from dairy, sweetened beverages, and noncore foods) on the CDQ did not differ between normal weight and overweight/obese children. Maternal depression and stress did not mediate the relationship between household food insecurity and child weight status. Hispanic children were more likely to be overweight or obese in both food secure and food-insecure households. CONCLUSIONS: Household food insecurity was not associated with child BMI percentile in this study. Dietary intake patterns of children from food-insecure households were not different compared to those from food-secure households. PMID- 25719451 TI - As required versus fixed schedule analgesic administration for postoperative pain in children. AB - BACKGROUND: Acute postoperative pain occurs as a result of tissue damage following surgery. Administering the appropriate analgesia to children is a complex process and it is unclear whether children's postoperative pain is more successfully treated by using 'as required' (when pain occurs) (termed 'pro re nata' or PRN) or (irrespective of pain at the time of administration). OBJECTIVES: To assess the efficacy of as required versus fixed schedule analgesic administration for the management of postoperative pain in children under the age of 16 years. SEARCH METHODS: On 2 July 2014, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL databases. We reviewed the bibliographies of all included studies and of reviews, and searched two clinical trial databases, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform, to identify additional published or unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing PRN versus ATC analgesic administration for postoperative pain in children under the age of 16 years who had undergone any surgical procedure requiring postoperative pain relief, in any setting. DATA COLLECTION AND ANALYSIS: Two review authors (AH, PW) independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias as recommended in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included three RCTs (four reports) of 246 children aged under 16 years undergoing tonsillectomy. Children were given weight-appropriate doses of the study medication, either PRN or ATC, by a parent or carer at home for up to four days following surgery. We did not identify any studies assessing the management of postoperative pain in children in any other setting (i.e. as an inpatient). All studies included in this review were based on the use of paracetamol, and an opioid was added to paracetamol in two studies. Analgesics were administered either orally (tablet or elixir) or rectally (suppository). Reporting quality was poor and there were fewer than 50 children in each arm. Mean pain intensity scores decreased over time, as did medication use. However, children were still reporting pain at the final assessment, suggesting that no administration schedule provided adequate analgesia. There were no significant differences in pain intensity scores at any time point. The studies reported adverse events that may have been related to the study medication, such as nausea and vomiting, and constipation, but no statistically significant differences were noted between the groups. There were too few data from only three small studies and meta-analysis was not possible. One study reported that a higher amount of analgesics was consumed in the ATC group compared with the PRN group: it would have been helpful to show that the higher volume in the ATC group led to better analgesia but we were not able to demonstrate this. AUTHORS' CONCLUSIONS: There was limited evidence available to draw any conclusions about the efficacy of PRN versus ATC analgesic administration for the management of postoperative pain in children. PMID- 25719452 TI - A novel mechanism of bacterial toxin transfer within host blood cell-derived microvesicles. AB - Shiga toxin (Stx) is the main virulence factor of enterohemorrhagic Escherichia coli, which are non-invasive strains that can lead to hemolytic uremic syndrome (HUS), associated with renal failure and death. Although bacteremia does not occur, bacterial virulence factors gain access to the circulation and are thereafter presumed to cause target organ damage. Stx was previously shown to circulate bound to blood cells but the mechanism by which it would potentially transfer to target organ cells has not been elucidated. Here we show that blood cell-derived microvesicles, shed during HUS, contain Stx and are found within patient renal cortical cells. The finding was reproduced in mice infected with Stx-producing Escherichia coli exhibiting Stx-containing blood cell-derived microvesicles in the circulation that reached the kidney where they were transferred into glomerular and peritubular capillary endothelial cells and further through their basement membranes followed by podocytes and tubular epithelial cells, respectively. In vitro studies demonstrated that blood cell derived microvesicles containing Stx undergo endocytosis in glomerular endothelial cells leading to cell death secondary to inhibited protein synthesis. This study demonstrates a novel virulence mechanism whereby bacterial toxin is transferred within host blood cell-derived microvesicles in which it may evade the host immune system. PMID- 25719453 TI - Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: week 48 results of the ARIEL trial. AB - BACKGROUND: ARIEL (Darunavir in treatment-experienced pediatric population) was a phase II, open-label study assessing safety and antiviral activity of darunavir/ritonavir twice daily with an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected pediatric patients (3 to <6 years, weighing 10 to <20 kg). METHODS: The study consisted of an initial 4-week screening period, 48 weeks of treatment and a 4-week follow-up period. Patients initially received darunavir/ritonavir 20/3 mg/kg twice-daily for 2 weeks. Following review of pharmacokinetic, safety and antiviral data, the doses of darunavir/ritonavir were adjusted to 25/3 mg/kg twice-daily for patients <15 kg, and 375/50 mg twice daily for patients 15 to <20 kg. RESULTS: Of the 34 patients screened, 21 were treated (median treatment duration 48.6 weeks). Darunavir plus an OBR was well tolerated over 48 weeks, with no new safety concerns, and a comparable safety profile to that seen in older children and adults. All treatment-emergent lipid related and glucose-related laboratory abnormalities were grade 1 or 2. At week 48, 17 of 21 patients (81.0%) had a confirmed virologic response (intent-to treat, time-to-loss of virologic response). Improvements in height and weight were seen during the study. CONCLUSIONS: No new safety concerns were observed over a 48 week period. These results led to lowering the age to 3 years at which darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients. This study also established doses of darunavir to use in treatment experienced, HIV-1-infected patients aged 3 to <6 years. A high virologic response was observed with this dose. No development of resistance was observed in patients who experienced virologic failure. PMID- 25719454 TI - Quantification of vaccine-induced antipertussis toxin secretory IgA antibodies in breast milk: comparison of different vaccination strategies in women. AB - BACKGROUND: Pertussis vaccination during pregnancy or immediately after delivery is a strategy that is increasingly being recommended to protect young infants from disease. Breast milk contains disease-specific antibodies that can contribute to the protection of young infants. The composition of breast milk could be altered by vaccination during pregnancy or near delivery. However, the quantification of these antibodies in breast milk lacks standardization. METHODS: In this paper, sample preparation procedures and detection methods for total and antipertussis toxin (anti-PT) secretory immunoglobulin (sIg) A are proposed that can be accurately repeated and are in accordance with European Medicines Agency and Food and Drug Administration requirements. Both antibody analytes were measured in breast milk samples of lactating women obtained 8-9 weeks postpartum to compare different maternal pertussis vaccination strategies: vaccination during pregnancy, shortly after or at delivery (cocoon), less than 5 years before delivery or more than 5 years before delivery. RESULTS: The validated immunoassays could quantitatively detect total and anti-PT sIgA in the processed breast milk samples. Significantly higher levels of anti-PT sIgA were measured in breast milk after pertussis vaccination during pregnancy or at delivery [geometric mean concentration (GMC): 2.56 and 2.15 IU/mg] in contrast to mothers with no recent (>5 years) pertussis vaccination (GMC: 0.96 IU/mg; P = 0.014 and P = 0.028). CONCLUSION: Vaccination against pertussis in the second/third trimester of pregnancy or immediately postpartum significantly increased the levels of anti PT sIgA in breast milk. PMID- 25719455 TI - Mass spectrometry in leukemia research and treatment. AB - Mass spectrometry (MS) is a complex analytical chemistry tool that allows qualitative and quantitative assessments of the components of complex chemical compounds. Applications of MS in medicine include the identification and quantification of drugs and metabolites; identification of proteins, biopolymers and disease markers and investigation of differential protein expression and proteins altered by mutations and/or post-translational changes. A variety of MS methods and technologies now play valuable and expanding roles in the diagnosis and monitoring of acute leukemia, as well as in identification of therapeutic targets and biomarkers, drug discovery, and other important areas of leukemia research. The objective of this review is to present a clinically oriented review of the roles of MS in the research, diagnosis and therapy of acute leukemia. PMID- 25719456 TI - Towards a formal genealogical classification of the Lezgian languages (North Caucasus): testing various phylogenetic methods on lexical data. AB - A lexicostatistical classification is proposed for 20 languages and dialects of the Lezgian group of the North Caucasian family, based on meticulously compiled 110-item wordlists, published as part of the Global Lexicostatistical Database project. The lexical data have been subsequently analyzed with the aid of the principal phylogenetic methods, both distance-based and character-based: Starling neighbor joining (StarlingNJ), Neighbor joining (NJ), Unweighted pair group method with arithmetic mean (UPGMA), Bayesian Markov chain Monte Carlo (MCMC), Unweighted maximum parsimony (UMP). Cognation indexes within the input matrix were marked by two different algorithms: traditional etymological approach and phonetic similarity, i.e., the automatic method of consonant classes (Levenshtein distances). Due to certain reasons (first of all, high lexicographic quality of the wordlists and a consensus about the Lezgian phylogeny among Caucasologists), the Lezgian database is a perfect testing area for appraisal of phylogenetic methods. For the etymology-based input matrix, all the phylogenetic methods, with the possible exception of UMP, have yielded trees that are sufficiently compatible with each other to generate a consensus phylogenetic tree of the Lezgian lects. The obtained consensus tree agrees with the traditional expert classification as well as some of the previously proposed formal classifications of this linguistic group. Contrary to theoretical expectations, the UMP method has suggested the least plausible tree of all. In the case of the phonetic similarity-based input matrix, the distance-based methods (StarlingNJ, NJ, UPGMA) have produced the trees that are rather close to the consensus etymology-based tree and the traditional expert classification, whereas the character-based methods (Bayesian MCMC, UMP) have yielded less likely topologies. PMID- 25719457 TI - The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. AB - Two proalpha1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proalpha2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance. PMID- 25719458 TI - Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population. AB - PURPOSE: This study was designed to delineate genetic contributions, if any, to sporadic forms of mild to moderate sensorineural hearing loss (SNHL) not related to GJB2 mutations (DFNB1) in a pediatric population. METHODS: We recruited 11 non DFNB1 simplex cases of mild to moderate SNHL in children. We applied whole-exome sequencing to all 11 probands. We used a filtering strategy assuming that de novo variants of known autosomal dominant (AD) deafness genes, biallelic mutations in autosomal recessive (AR) genes, monoallelic mutations in X chromosome genes for males, and digenic inheritance could be associated. Candidate variants first were prioritized with allele frequency in public databases and confirmed by a phase or a segregation test in each family. Additional information from the literature or public databases was used to identify strong candidate variants. RESULTS: Strong candidate variants were detected in 5 of 11 probands (45.4%). A diverse mode of inheritance implicated the sporadic occurrence of the phenotype. AR mutations in OTOGL and SERPINB6 and digenic inheritance involving two deafness genes, GPR98 and PDZ7, were detected. A de novo AD mutation also was detected in TECTA and MYH14. No syndromic feature was detected in individuals with GPR98/PDZ7 or MYH14 variants in our cohort at this moment. CONCLUSION: Mild to moderate pediatric SNHL, even if sporadic, features a strong genetic etiology and can manifest via diverse modes of inheritance. In addition, a multidisciplinary approach should be used for a correct diagnosis. PMID- 25719459 TI - The number of divergent purging behaviors is associated with histories of trauma, PTSD, and comorbidity in a national sample of women. AB - The number of different types of purging behaviors (NPB) of subjects with bulimia nervosa (BN) has been associated with greater severity of illness and psychiatric comorbidity. No studies have examined the association between the NPB used (vomiting, laxative abuse, diuretic abuse), histories of trauma, and post traumatic stress disorder (PTSD). A national, representative sample of 3,006 adult women (>=18 years) completed a structured telephone interview including screenings for victimization experiences, PTSD, BN, major depression (MD), alcohol abuse (AA), and alcohol dependence (AD). Significant relationships were found between the NPB used and lifetime rates of victimization, PTSD, MD, AA, AD, and total comorbid disorders (p <= .001, chi(2)). PMID- 25719460 TI - Clinical predictors of abnormal magnetic resonance imaging findings in patients with asymmetric sensorineural hearing loss. AB - IMPORTANCE: Asymmetric sensorineural hearing loss (ASNHL) is commonly encountered in an otolaryngologic clinical practice. Determining what factors are associated with abnormal magnetic resonance imaging (MRI) findings will help with diagnostic workup. OBJECTIVE: To evaluate the association between clinical and audiometric factors and abnormal MRI findings in patients with ASNHL. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review from an urban, tertiary referral center of 451 patients with ASNHL who underwent MRI testing between January 2005 and December 2011. MAIN OUTCOMES AND MEASURES: Medical records were reviewed for audiometric parameters as well as clinical presentation and compared with MRI results, which were categorized as abnormal, normal, or incidental. Data analysis included chi2 tests, logistic regression analysis, and multivariate analysis. RESULTS: A total of 48 patients (10.6%) had abnormal MRI findings. Only 21 patients (4.7%) had a mass of the cerebellopontine angle/internal auditory canal on MRI, making up 40% of all abnormal MRI findings. The next most common MRI finding was labyrinthitis (n = 13; 25%). Vertigo/dizziness (n = 20; P = .01), tinnitus (n = 18; P = .02), sudden hearing loss (n = 15; P = .054), and 15-dB asymmetry at 3 kHz (n = 39; P = .01) were associated with abnormal MRI findings. Loud noise exposure was associated with normal MRI findings. Logistic regression analysis showed that vertigo/dizziness (odds ratio [OR], 2.14; 95% CI, 1.15-3.96; P = .02), unilateral tinnitus (OR, 2.15; 95% CI, 1.14-4.03; P = .02), and 15-dB asymmetry at 3 kHz (OR, 2.62; 95% CI, 1.24-5.57; P = .01) were significantly associated with abnormal MRI findings. Multivariate analysis showed that only 15 dB asymmetry at 3 kHz (OR, 2.42; 95% CI, 1.07-5.50; P = .03) was significantly associated with an abnormal MRI finding. CONCLUSIONS AND RELEVANCE: This study found that asymmetry of 15 dB at 3 kHz on audiometry was associated with higher positive yield on use of MRI in evaluating patients with ASNHL. We recommend that patients who present with ASNHL with this audiometric characteristic undergo MRI as part of their diagnostic workup. PMID- 25719461 TI - A systematic review and meta-analysis of the effects of extreme weather events and other weather-related variables on Cryptosporidium and Giardia in fresh surface waters. AB - Global climate change is expected to impact drinking water quality through multiple weather-related phenomena. We conducted a systematic review and meta analysis of the relationship between various weather-related variables and the occurrence and concentration of Cryptosporidium and Giardia in fresh surface waters. We implemented a comprehensive search in four databases, screened 1,228 unique citations for relevance, extracted data from 107 relevant articles, and conducted random-effects meta-analysis on 16 key relationships. The average odds of identifying Cryptosporidium oocysts and Giardia cysts in fresh surface waters was 2.61 (95% CI = 1.63-4.21; I2 = 16%) and 2.87 (95% CI = 1.76-4.67; I2 = 0%) times higher, respectively, during and after extreme weather events compared to baseline conditions. Similarly, the average concentration of Cryptosporidium and Giardia identified under these conditions was also higher, by approximately 4.38 oocysts/100 L (95% CI = 2.01-9.54; I(2) = 0%) and 2.68 cysts/100 L (95% CI = 1.08 6.55; I2 = 48%). Correlation relationships between other weather-related parameters and the density of these pathogens were frequently heterogeneous and indicated low to moderate effects. Meta-regression analyses identified different study-level factors that influenced the variability in these relationships. The results can be used as direct inputs for quantitative microbial risk assessment. Future research is warranted to investigate these effects and potential mitigation strategies in different settings and contexts. PMID- 25719462 TI - Removal of cadmium ion from wastewater by carbon-based nanosorbents: a review. AB - A green environment and a healthy life are dream projects of today's science and technology to save the world. Heavy metal ions in water affect both environment and human health. Cadmium has been identified as one of the heavy metals that causes acute or chronic toxic effects if ingested. Increasing use of cadmium in different technological fields has raised concern about its presence and removal from water/wastewater. Researchers have made many systematic efforts to remove heavy metals from water to reduce their impact on human beings and the environment. Adsorption is one of the best methods to remove heavy metals from water among the different proposed methods. This study explores carbon-based nanosorbents which have been proved as effective adsorbents for removal of cadmium ions from water. The adsorption efficiency of carbon-based nanosorbents is the main criterion to rank and select them for removal of cadmium ions from water. Toxicity, reusability and environmentally friendly characteristics of sorbents are also taken considered while ranking the suitable carbon-based nanosorbents for removal of cadmium ions from water. PMID- 25719463 TI - Methods for microbiological quality assessment in drinking water: a comparative study. AB - The present study aimed to compare several methods for quantifying and discriminating between the different physiological states of a bacterial population present in drinking water. Flow cytometry (FCM), solid-phase cytometry (SPC), epifluorescence microscopy (MSP) and culture method performances were assessed by comparing the results obtained for different water samples. These samples, including chlorinated and non-chlorinated water, were collected in a drinking water treatment plant. Total bacteria were quantified by using SYBR Green II (for FCM) and 4',6'-diamino-2-phenylindole (DAPI) (for MSP), viable and non-viable bacteria were distinguished by using SYBR Green II and propidium iodide dual staining (for FCM), and active cells were distinguished by using CTC (for MSP) and Chemchrome V6 (for FCM and SPC). In our conditions, counts using microscopy and FCM were significantly correlated regarding total bacteria and active cells. Conversely, counts were not significantly similar using solid-phase and FCM for active bacteria. Moreover, the R2A medium showed that bacterial culturability could be recovered after chlorination. This study highlights that FCM appears to be a useful and powerful technique for drinking water production monitoring. PMID- 25719464 TI - The effect of pyrite on Escherichia coli in water: proof-of-concept for the elimination of waterborne bacteria by reactive minerals. AB - We present proof-of-concept results for the elimination of waterborne bacteria by reactive minerals. We exposed Escherichia coli MG1655 suspended in water to the reactive mineral pyrite (FeS2) at room temperature and ambient light. This slurry eliminates 99.9% of bacteria in fewer than 4 hours. We also exposed Escherichia coli to pyrite leachate (supernatant liquid from slurry after 24 hours), which eliminates 99.99% of bacteria over the same time-scale. Unlike SOlar water DISinfection (SODIS), our results do not depend on the presence of ultraviolet (UV) light. We confirmed this by testing proposed SODIS additive and known photo catalyst anatase (TiO2) for antibacterial properties and found that, in contrast to pyrite, it does not eliminate E. coli under our experimental conditions. Previous investigations of naturally antibiotic minerals have focused on the medical applications of antibiotic clays, and thus have not been conducted under experimental conditions resembling those found in water purification. In our examination of the relevant literature, we have not found previously reported evidence for the use of reactive minerals in water sanitization. The results from this proof-of-concept experiment may have important implications for future directions in household water purification research. PMID- 25719465 TI - Developmental effects and genotoxicity of 10 water disinfection by-products in zebrafish. AB - Disinfection by-products are contaminants produced during drinking water disinfection. Several DBPs have been implicated in a variety of toxic effects, mainly carcinogenic and genotoxic effects. Moreover, DBPs exposure has also been associated with an increased risk of developmental effects. In this study, the developmental toxicity and genotoxicity of 10 DBPs (four trihalomethanes [THMs], five haloacetic acids [HAAs] and sodium bromate) in the zebrafish embryo model were evaluated. Embryos exposed for 72 hours were observed for different endpoints such as growth, hatching success, malformations and lethality. THMs exposure resulted in adverse developmental effects and a significant reduced tail length. Two HAAs, tribromoacetic acid and dichloroacetic acid, along with sodium bromate were found to cause a significant increase in malformation rate. Chloroform, chlorodibromomethane and sodium bromate produced a weak induction of DNA damage to whole embryos. However, developmental effects occurred at a range of concentrations (20-100 MUg/mL) several orders of magnitude above the levels that can be attained in fetal blood in humans exposed to chlorinated water. In conclusion, the teratogenic and genotoxic activity observed by some DBPs in zebrafish reinforce the view that there is a weak capacity of disinfection products to cause developmental effects at environmentally relevant concentrations. PMID- 25719466 TI - Multiparametric comparison of chromogenic-based culture methods used to assess the microbiological quality of drinking water and the mFC method combined with a molecular confirmation procedure. AB - MI agar and Colilert((r)), as well as mFC agar combined with an Escherichia coli specific molecular assay (mFC + E. coli rtPCR), were compared in terms of their sensitivity, ease of use, time to result and affordability. The three methods yielded a positive E. coli signal for 11.5, 10.8, and 11.5% of the 968 well water samples tested, respectively. One hundred and thirty-six (136) samples gave blue colonies on mFC agar and required confirmation. E. coli-specific rtPCR showed false-positive results in 23.5% (32/136) of cases. In terms of ease of use, Colilert was the simplest method to use while the MI method provided ease of use comparable to all membrane filtration methods. However, the mFC + E. coli rtPCR assay required highly trained employees for confirmation purposes. In terms of affordability, and considering contamination rate of well water samples tested, the Colilert method and the mFC + E. coli rtPCR assay were at least five times more costly than the MI agar method. Overall, compared with the other two methods tested, the MI agar method offers the most advantages to assess drinking water quality. PMID- 25719467 TI - Removal of bromide and bromate from drinking water using granular activated carbon. AB - Granular activated carbon (GAC) was used to remove bromide (Br-) and bromate (BrO(3)(-)) from drinking water in both bench- and pilot-scale experiments. The present study aims to minimize BrO(3)(-) formation and eliminate BrO(3)(-) generated during the ozonation of drinking water, particularly in packaged drinking water. Results show that the Br- and BrO(3)(-) levels in GAC-treated water decreased in both bench- and pilot-scale experiments. In the bench-scale experiments, when the empty bed contact time (EBCT) was 5 min, the highest reduction rates of Br(-) in the mineral and ultrapure water were found to be 74.9% and 91.2%, respectively, and those of BrO(3)(-) were 94.4% and 98.8%, respectively. The GAC capacity for Br- and BrO(3)(-) removal increased with the increase in EBCT. Reduction efficiency was better in ultrapure water than in mineral water. In the pilot-scale experiments, the minimum reduction rates of Br- and BrO(3)(-) were 38.5% and 73.2%, respectively. PMID- 25719468 TI - Accuracy, precision, usability, and cost of free chlorine residual testing methods. AB - Chlorine is the most widely used disinfectant worldwide, partially because residual protection is maintained after treatment. This residual is measured using colorimetric test kits varying in accuracy, precision, training required, and cost. Seven commercially available colorimeters, color wheel and test tube comparator kits, pool test kits, and test strips were evaluated for use in low resource settings by: (1) measuring in quintuplicate 11 samples from 0.0-4.0 mg/L free chlorine residual in laboratory and natural light settings to determine accuracy and precision; (2) conducting volunteer testing where participants used and evaluated each test kit; and (3) comparing costs. Laboratory accuracy ranged from 5.1-40.5% measurement error, with colorimeters the most accurate and test strip methods the least. Variation between laboratory and natural light readings occurred with one test strip method. Volunteer participants found test strip methods easiest and color wheel methods most difficult, and were most confident in the colorimeter and least confident in test strip methods. Costs range from 3.50-444 USD for 100 tests. Application of a decision matrix found colorimeters and test tube comparator kits were most appropriate for use in low-resource settings; it is recommended users apply the decision matrix themselves, as the appropriate kit might vary by context. PMID- 25719469 TI - A compact point-of-use water purification cartridge for household use in developing countries. AB - Simple, low-cost household interventions are known to be effective in lowering the incidence of waterborne diseases in developing countries. However, high costs along with operational and maintenance issues have prevented the successful adoption of these interventions among the affected communities. To address these limitations, a cost-effective, gravity-driven water purification cartridge has been developed by employing the synergistic disinfection action of low concentrations of silver and chlorine on bacteria and viruses. The silver and chlorine treatment components within the cartridge have been developed using inexpensive materials and integrated with a life indicator and auto-shut-off mechanism within a compact form factor. The antibacterial as well as antiviral performance of the cartridge was tested by using ground water spiked with Escherichia coli and MS2 bacteriophage. The results show that, although individually, the silver and chlorine treatment systems were unable to inactivate the test strains, the integrated cartridge inactivates both bacteria as well as viruses up to the log reduction requirement of the USEPA guide standard for microbiological water purifiers over its designated life of 2,000 liters. PMID- 25719470 TI - Characterization of bacterial pathogens in rural and urban irrigation water. AB - The study aimed to compare the bacteriological quality of an urban and rural irrigation water source. Bacterial counts, characterization, identification and diversity of aerobic bacteria were determined. Escherichia coli isolated from both sites was subjected to antibiotic susceptibility testing, virulence gene (Stx1/Stx2 and eae) determination and (GTG)5 Rep-PCR fingerprinting. Low mean monthly counts for aerobic spore formers, anaerobic spore formers and Staphylococcus aureus were noted although occasional spikes were observed. The most prevalent bacterial species at both sites were Bacillus spp., E. coli and Enterobacter spp. In addition, E. coli and Bacillus spp. were most prevalent in winter and summer respectively. Resistance to at least one antibiotic was 84% (rural) and 83% (urban). Highest resistance at both sites was to cephalothin and ampicillin. Prevalence of E. coli possessing at least one virulence gene (Stx1/Stx2 and eae) was 15% (rural) and 42% (urban). All (rural) and 80% (urban) of E. coli possessing virulence genes showed antibiotic resistance. Complete genetic relatedness (100%) was shown by 47% of rural and 67% of urban E. coli isolates. Results from this study show that surface irrigation water sources regardless of geographical location and surrounding land-use practices can be reservoirs of similar bacterial pathogens. PMID- 25719471 TI - Disinfection of an advanced primary effluent using peracetic acid or ultraviolet radiation for its reuse in public services. AB - The disinfection of a continuous flow of an effluent from an advanced primary treatment (coagulation-flocculation-sedimentation) with or without posterior filtration, using either peracetic acid (PAA) or ultraviolet (UV) radiation was studied. We aimed to obtain bacteriological quality to comply with the microbiological standard established in the Mexican regulations for treated wastewater reuse (NOM-003-SEMARNAT-1997), i.e., less than 240 MPN (most probable number) FC/100 mL. The concentrations of PAA were 10, 15, and 20 mg/L, with contact times of 10, and 15 min. Fecal coliforms (FC) inactivation ranged from 0.93 up to 6.4 log units, and in all cases it reached the limits set by the mentioned regulation. Water quality influenced the PAA disinfection effectiveness. An efficiency of 91% was achieved for the unfiltered effluent, as compared to 99% when wastewater was filtered. UV radiation was applied to wastewater flows of 21, 30 and 39 L/min, with dosages from 1 to 6 mJ/cm2. This treatment did not achieve the bacteriological quality required for treated wastewater reuse, since the best inactivation of FC was 1.62 log units, for a flow of 21 L/min of filtered wastewater and a UV dosage of 5.6 mJ/cm2. PMID- 25719472 TI - Nosocomial pseudo-outbreak of Mycobacterium gordonae associated with a hospital's water supply contamination: a case series of 135 patients. AB - Nontuberculous mycobacteria (NTM) are opportunistic pathogens found in natural and human-engineered waters. In 2009, a relative increase in the isolation of Mycobacterium gordonae from pulmonary samples originating from General Hospital Zabok was noted by the National Mycobacteria Reference Laboratory. An epidemiological survey revealed a contamination of the cold tap water with M. gordonae and guidelines regarding sputum sample taking were issued. In addition, all incident cases of respiratory infection due to NTM reported from 2007 to 2012 at General Hospital Zabok were included in a retrospective review. Out of 150 individual NTM isolates, M. gordonae was the most frequently isolated species (n = 135; 90%) and none of the cases met the criteria of the American Thoracic Society for pulmonary NTM disease. While concomitant Mycobacterium tuberculosis infection was confirmed in only 6 (4%) patients, anti-tuberculosis treatment was initiated for a significant portion of patients (n = 64; 42.6%) and unnecessary contact tracing was performed. This study points out the need to enhance the knowledge about NTM in our country and indicates the importance of faster NTM identification, as well as the importance of good communication between laboratory personnel and physicians when evaluating the significance of the isolated NTM. PMID- 25719473 TI - Evaluation of quantitative polymerase chain reaction assays targeting Mycobacterium avium, M. intracellulare, and M. avium subspecies paratuberculosis in drinking water biofilms. AB - Mycobacterium avium (MA), Mycobacterium intracellulare (MI), and Mycobacterium avium subsp. paratuberculosis (MAP) are difficult to culture due to their slow growing nature. A quantitative polymerase chain reaction (qPCR) method for the rapid detection of MA, MI, and MAP can be used to provide data supporting drinking water biofilms as potential sources of human exposure. The aim of this study was to characterize two qPCR assays targeting partial 16S rRNA gene sequences of MA and MI and use these assays, along with two previously reported MAP qPCR assays (IS900 and Target 251), to investigate Mycobacterium occurrence in kitchen faucet biofilms. MA and MI qPCR assays demonstrated 100% specificity and sensitivity when evaluated against 18 non-MA complex, 76 MA, and 17 MI isolates. Both assays detected approximately 1,000 cells from a diluted cell stock inoculated on a sampling swab 100% of the time. DNA analysis by qPCR indicated that 35.3, 56.9 and 11.8% of the 51 kitchen faucet biofilm samples collected contained MA, MI, and MAP, respectively. This study introduces novel qPCR assays designed to specifically detect MA and MI in biofilm. Results support the use of qPCR as an alternative to culture for detection and enumeration of MA, MI, and MAP in microbiologically complex samples. PMID- 25719474 TI - Bacterial composition in a metropolitan drinking water distribution system utilizing different source waters. AB - We investigated the bacterial composition of water samples from two service areas within a drinking water distribution system (DWDS), each associated with a different primary source of water (groundwater, GW; surface water, SW) and different treatment process. Community analysis based on 16S rRNA gene clone libraries indicated that Actinobacteria (Mycobacterium spp.) and alpha Proteobacteria represented nearly 43 and 38% of the total sequences, respectively. Sequences closely related to Legionella, Pseudomonas, and Vibrio spp. were also identified. In spite of the high number of sequences (71%) shared in both areas, multivariable analysis revealed significant differences between the GW and SW areas. While the dominant phylotypes where not significantly contributing in the ordination of samples, the populations associated with the core of phylotypes (1-10% in each sample) significantly contributed to the differences between both service areas. Diversity indices indicate that the microbial community inhabiting the SW area is more diverse and contains more distantly related species coexisting with local assemblages as compared with the GW area. The bacterial community structure of SW and GW service areas were dissimilar, suggesting that their respective source water and/or water quality parameters shaped by the treatment processes may contribute to the differences in community structure observed. PMID- 25719475 TI - Parental decisions, child health and valuation of avoiding arsenic in drinking water in rural Bangladesh. AB - Arsenic contamination of groundwater in Bangladesh is a widespread public health hazard. Water sources without high arsenic levels are scarce, affecting people's availability for work and other activities when they have to seek safe water to drink. While children are particularly susceptible to chronic arsenic exposure, limited information and heavy constraints on resources may preclude people in developing countries from taking protective actions. Since parents are primary decision-makers for children, a model of stochastic decision-making analytically linking parent health and child health is used to frame the valuation of avoiding arsenic exposure using an averting behavior model. The results show that safe drinking water programs do work and that people do take protective actions. The results can help guide public health mitigation policies, and examine whether factors such as child health and time required for remediation have an effect on mitigation measures. PMID- 25719476 TI - Outbreak of acute gastroenteritis caused by contamination of drinking water in a factory, the Basque Country. AB - On 18 September 2013, the Gipuzkoa Epidemiology Unit was notified of an outbreak of acute gastroenteritis (AGE) among employees at a domestic appliance factory. The first signs of the outbreak had emerged at the end of June and at the time of the notification 30 workers were on sick leave for gastroenteritis. Some employees had had more than one episode and the main symptoms were diarrhoea and vomiting. An investigation began to identify the causative agent, assess exposure and determine the route of transmission. Data collected by a questionnaire identified 302 episodes of AGE among 238 people affected between June and September 2013. The source of water consumed was found to be a risk factor associated with the appearance of symptoms both in the crude and the adjusted analysis: odds ratio 1.8 (0.8-4.2) and 6.4 (4.2-9.8), respectively. Microbiological analysis of stool samples and of water confirmed the presence of norovirus and rotavirus. The environmental study detected a connection between an industrial use water system and drinking water at the factory. It was concluded that the outbreak was caused by mixed viral infections, due to contamination of drinking water. PMID- 25719477 TI - Application of risk-based assessment and management to riverbank filtration sites in India. AB - This is the first reported study of a riverbank filtration (RBF) scheme to be assessed following the Australian Guidelines for Managed Aquifer Recharge. A comprehensive staged approach to assess the risks from 12 hazards to human health and the environment has been undertaken. Highest risks from untreated ground and Ganga River water were identified with pathogens, turbidity, iron, manganese, total dissolved solids and total hardness. Recovered water meets the guideline values for inorganic chemicals and salinity but exceeds limits for thermotolerant coliforms frequently. A quantitative microbial risk assessment undertaken on the water recovered from the aquifer indicated that the residual risks of 0.00165 disability-adjusted life years (DALYs) posed by the reference bacteria Escherichia coli O157:H7 were below the national diarrhoeal incidence of 0.027 DALYs and meet the health target in this study of 0.005 DALYs per person per year, which corresponds to the World Health Organization (WHO) regional diarrhoeal incidence in South-East Asia. Monsoon season was a major contributor to the calculated burden of disease and final DALYs were strongly dependent on RBF and disinfection pathogen removal capabilities. Finally, a water safety plan was developed with potential risk management procedures to minimize residual risks related to pathogens. PMID- 25719478 TI - Molecular characterisation of clinical and environmental isolates of Mycobacterium kansasii isolates from South African gold mines. AB - Mycobacterium kansasii (M. kansasii) is a major cause of non-tuberculous mycobacterial pulmonary disease in the South African gold-mining workforce, but the source of infection and molecular epidemiology are unknown. This study investigated the presence of M. kansasii in gold and coal mine and associated hostel water supplies and compared the genetic diversity of clinical and environmental isolates of M. kansasii. Five M. kansasii and ten other potentially pathogenic mycobacteria were cultured mainly from showerhead biofilms. Polymerase chain reaction-restriction analysis of the hsp65 gene on 196 clinical and environmental M. kansasii isolates revealed 160 subtype I, eight subtype II and six subtype IV strains. Twenty-two isolates did not show the typical M. kansasii restriction patterns, suggesting that these isolates may represent new subtypes of M. kansasii. In contrast to the clonal population structure found amongst the subtype I isolates from studies in other countries, DNA fingerprinting of 114 clinical and three environmental subtype I isolates demonstrated genetic diversity amongst the isolates. This study demonstrated that showerheads are possible sources of M. kansasii and other pathogenic non-tuberculous mycobacterial infection in a gold-mining region, that subtype I is the major clinical isolate of M. kansasii strain and that this subtype exhibits genetic diversity. PMID- 25719479 TI - Evaluation of corrosion and scaling tendency indices in a drinking water distribution system: a case study of Bandar Abbas city, Iran. AB - Corrosion and scaling is a major problem in water distribution systems, thus evaluation of water corrosivity properties is a routine test in water networks. To evaluate water stability in the Bandar Abbas water distribution system, the network was divided into 15 clusters and 45 samples were taken. Langelier, Ryznar, Puckorius, Larson-Skold (LS) and Aggressive indices were determined and compared to the marble test. The mean parameters included were pH (7.8 +/- 0.1), electrical conductivity (1,083.9 +/- 108.7 MUS/cm), total dissolved solids (595.7 +/- 54.7 mg/L), Cl (203.5 +/- 18.7 mg/L), SO4(174.7 +/- 16.0 mg/L), alkalinity (134.5 +/- 9.7 mg/L), total hardness (156.5 +/- 9.3 mg/L), HCO3(137.4 +/- 13.0 mg/L) and calcium hardness (71.8 +/- 4.3 mg/L). According to the Ryznar, Puckorius and Aggressive Indices, all samples were stable; based on the Langelier Index, 73% of samples were slightly corrosive and the rest were scale forming; according to the LS index, all samples were corrosive. Marble test results showed tested water of all 15 clusters tended to scale formation. Water in Bandar Abbas is slightly scale forming. The most appropriate indices for the network conditions are the Aggressive, Puckorius and Ryznar indices that were consistent with the marble test. PMID- 25719480 TI - Cyclospora cayetanensis travels in tap water on Italian trains. AB - Tap water samples from the toilets of an Italian national railway train were collected over a period of 10 months and tested for the presence of Cyclospora cayetanensis (C. cayetanensis) using EvaGreen(r) real-time polymerase chain reaction (RT-PCR) assay coupled with high resolution melting (HRM) analysis for protozoan detection and oocyst quantification. C. cayetanensis positive samples were detected in March, April, and May 2013, with the number of oocysts of 4, 5, and 11 per liter, respectively. This is the first finding of C. cayetanensis in water samples in Italy. The findings call for an improvement of hygiene and water safety by the Italian national railway company. PMID- 25719481 TI - A probabilistic assessment of the contribution of wastewater-irrigated lettuce to Escherichia coli O157:H7 infection risk and disease burden in Kumasi, Ghana. AB - Wastewater use for vegetable production is widespread across the cities of many developing countries. Studies on the microbial health risks associated with the practice have largely depended on faecal indicator organisms with potential underestimation or overestimation of the microbial health risks and disease burdens. This study assessed the Escherichia coli O157:H7 infection risk and diarrhoeal disease burden measured in disability-adjusted life years (DALYs) associated with the consumption of wastewater-irrigated lettuce in Kumasi, Ghana using data on E. coli O157:H7 in ready-to-harvest, wastewater-irrigated lettuce. Two exposure scenarios - best case and worst case - associated with a single consumption of wastewater-irrigated lettuce were assessed. The assessment revealed wastewater-irrigated lettuce is contributing to the transmission of E. coli O157:H7 in Kumasi, Ghana. The mean E. coli O157:H7 infection risk and DALYs in the wet and dry seasons, irrespective of the exposure scenario, were above the World Health Organization tolerable daily infection risk of 2.7 * 10-7 per person per day and 10-6 DALYs per person per year. It is recommended that legislation with clear monitoring indicators and penalties is implemented to ensure that farmers and food sellers fully implement risk mitigating measures. PMID- 25719482 TI - Risk behaviors and self-reported illnesses among Pacific Northwest surfers. AB - Although surfers have high incidental exposure to marine waters, no studies have investigated if surfer risk behaviors (such as surfing during advisories, near an outfall, during a rain event, or use of personal protective equipment) increase or decrease the risk of acquiring waterborne illnesses. We used a web-based survey to assess the association between risk-based behaviors and self-reported illnesses among Pacific Northwest surfers. Commonly reported illnesses include: ear infection or discharge (38%), sore throat or a cough (28%), diarrhea (16%), fever (10.5%), and vomiting (7%). Surfing often during rain events was associated with an increased likelihood of diarrhea (OR = 2.7; 95% CI: 1.4-5.47), sore throat (OR = 1.26; 95% CI: 1.01-2.05), and ear infection (OR = 1.39; 95% CI: 1.01 2.32). Surfing during a health advisory was associated with increased likelihood of diarrhea (OR = 1.94; 95% CI: 1.03-4.64) and sore throat (OR = 2.32; 95% CI: 1.23-4.40). Other behaviors associated with increased illnesses include body surfing, surfing near an outfall, frequency of surfing, and use of ear plugs. Approximately 40% of surfers were unaware if they had surfed during an active health advisory and 29% knowingly surfed during advisories, suggesting the need to engage this population about potential harm and behaviors that may increase health risk. PMID- 25719483 TI - Comparing the microbial risks associated with household drinking water supplies used in peri-urban communities of Phnom Penh, Cambodia. AB - Most Cambodians lack access to a safe source of drinking water. Piped distribution systems are typically limited to major urban centers in Cambodia, and the remaining population relies on a variety of surface, rain, and groundwater sources. This study examines the household water supplies available to Phnom Penh's resettled peri-urban residents through a case-study approach of two communities. A quantitative microbial risk assessment is performed to assess the level of diarrheal disease risk faced by community members due to microbial contamination of drinking water. Risk levels found in this study exceed those associated with households consuming piped water. Filtered and boiled rain and tank water stored in a kettle, bucket/cooler, bucket with spigot or a 500 mL bottle were found to provide risk levels within one order-of-magnitude to the piped water available in Phnom Penh. Two primary concerns identified are the negation of the risk reductions gained by boiling due to prevailing poor storage practices and the use of highly contaminated source water. PMID- 25719484 TI - Risk of diarrhoea from shallow groundwater contaminated with enteropathogens in the Kathmandu Valley, Nepal. AB - Shallow groundwater is the main water source among many alternatives in the Kathmandu Valley, Nepal, which has a rapidly growing population and intermittent piped water supply. Although human pathogens are detected in groundwater, its health effects are unclear. We estimated risk of diarrhoea from shallow groundwater use using quantitative microbial risk assessment. Escherichia coli, Giardia cyst and Cryptosporidium oocyst levels were analysed in dug and tube wells samples. E. coli concentrations were converted to those of enteropathogenic E. coli (EPEC). Risks from EPEC in dug wells and from Cryptosporidium and Giardia in both dug and tube wells were higher than the acceptable limit (<10-4 infections/person-year) for both drinking and bathing exposures. Risk from protozoan enteropathogens increased the total risk 10,000 times, indicating that ignoring protozoans could lead to serious risk underestimation. Bathing exposure considerably increased risk, indicating that it is an important pathway. Point-of use (POU) water treatment decreased the risk six-fold and decreased risk overestimation. Because removal efficiency of POU water treatment has the largest impact on total risk, increasing the coverage and efficiency of POU water treatment could be a practical risk management strategy in the Kathmandu Valley and similar settings. PMID- 25719485 TI - Monitoring of chlorination disinfection by-products and their associated health risks in drinking water of Pakistan. AB - This study reports the baseline data of chlorination disinfection by-products such as trihalomethanes (THMs) and their associated health risks in the water distribution network of Islamabad and Rawalpindi, Pakistan. THM monitoring was carried out at 30 different sampling sites across the twin cities for 6 months. The average concentration of total trihalomethanes (TTHMs) and chloroform ranged between 575 and 595 MUg/L which exceeded the permissible US (80 MUg/L) and EU (100 MUg/L) limits. Chloroform was one of the major contributors to the TTHMs concentration (>85%). The occurrence of THMs was found in the following order: chloroform, bromodichloromethane > dibromochloromethane > bromoform. Lifetime cancer risk assessment of THMs for both males and females was carried out using prediction models via different exposure routes (ingestion, inhalation, and dermal). Total lifetime cancer risk assessment for different exposure routes (ingestion, inhalation, and skin) was carried out. The highest cancer risk expected from THMs seems to be from the inhalation route followed by ingestion and dermal contacts. The average lifetime cancer risk for males and females was found to be 0.51 * 10-3 and 1.22 * 10-3, respectively. The expected number of cancer risks per year could reach two to three cases for each city. PMID- 25719486 TI - The imaging of neuroendocrine tumors using single photon emission computed tomography/computed tomography. AB - There have been several advances in technology over the past decade with the advent of hybrid imaging having a large impact on nuclear medicine, first with PET/CT and then more recently with SPECT/CT. Initial SPECT/CT systems used low dose but very low quality CT and except for attenuation correction offered no great advantage over reviewing SPECT and CT images side by side. More recently hybrid machines have become available and a series of studies have shown improved accuracy compared to SPECT alone with resulting changes in patient management. This has been true not only with somatostatin analogue imaging but also for demonstrating amine uptake using MIBG. Whilst PET/CT may be seen as the ideal, this may be less accessible due to the high cost and limited availability. In this case hybrid SPECT/CT offers hope for providing high quality and accurate imaging of neuroendocrine tumors. PMID- 25719487 TI - GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon like peptide-1 analogues: past, present and future. AB - Glucagon-like peptide 1 (GLP-1) receptors expression has been found on many types of cancer cells. In case of benign insulinoma the density of those receptors is even higher than the density of somatostatin receptors. This article presents the results of clinical trials proving the utility of GLP-1 receptors imaging. Scintigraphy or positron emission tomography with the use of GLP-1 analogues labelled with appropriate radioisotopes (111In, 99mTc, 68Ga, 18F or 64Cu) seem to be superior compared with other available techniques in diagnosis of hardly detectable benign insulinoma. While surgery is the only effective therapy for insulinoma patients, therefore proper preoperative localization of the tumor allows sparing operation. Glucagon-like peptide 1 receptors might become also a target for imaging of other tumors such as gastrinoma, pheochromocytoma and medullary thyroid cancer (MTC), which also were shown to overexpress this type of receptors. However, studies with larger groups of patients are required to prove the clinical usefulness of this indication. Moreover GLP-1 receptor imaging seems to be a potential tool to evaluate pancreatic beta cell mass (BCM). It may be useful in the early diagnosis of beta cell loss in preclinical phases of diabetes. The panceratic beta cells imaging may influence the prophylaxis of diabetes and management of diabetic patients. Presented results of clinical trials prove that glucagon-like peptide 1 receptor imaging might become helpful diagnostic strategy particularly in case of patients with benign insulinoma tumors, but also patients with gastrinoma, pheochromocytoma, medullary thyroid cancer and diabetes. PMID- 25719488 TI - Supercharging with m-nitrobenzyl alcohol and propylene carbonate: forming highly charged ions with extended, near-linear conformations. AB - The effectiveness of the supercharging reagents m-nitrobenzyl alcohol (m-NBA) and propylene carbonate at producing highly charged protein ions in electrospray ionization is compared. Addition of 5% m-NBA or 15% propylene carbonate increases the average charge of three proteins by ~21% or ~23%, respectively, when these ions are formed from denaturing solutions (water/methanol/acetic acid). These results indicate that both reagents are nearly equally effective at supercharging when used at their optimum concentrations. A narrowing of the charge state distribution occurs with both reagents, although this effect is greater for propylene carbonate. Focusing the ion signal into fewer charge states has the advantage of improving sensitivity. The maximum charge state of ubiquitin formed with propylene carbonate is 21+, four charges higher than previously reported. Up to nearly 30% of all residues in a protein can be charged, and the collisional cross sections of the most highly charged ions of both ubiquitin and cytochrome c formed with these supercharging reagents were measured for the first time and found to be similar to those calculated for theoretical highly extended, linear or near-linear conformations. Under native supercharging conditions, m-NBA is significantly more effective at producing high charge states than propylene carbonate. PMID- 25719490 TI - Human height is positively related to interpersonal dominance in dyadic interactions. AB - Across cultures, taller stature is linked to increased social status, but the potential reasons why this should be are unclear. One potential explanation is that taller individuals are more likely to win a dyadic confrontation with a competitor (i.e., they are more dominant), which leads to higher social rank. Although some previous studies have shown that perceptions of status or dominance are related to height, and are therefore consistent with such an explanation, there is surprisingly little research testing whether height actually has any influence on the behavioural outcomes in real-life social interactions. Here, we present three naturalistic observational studies demonstrating that height predicts interpersonal dominance during brief dyadic interactions. Study 1 investigated the likelihood of giving way in a narrow passage (N = 92); Study 2 investigated giving way in a busy shopping street, plus the likelihood of colliding with another individual (N = 1,108); and Study 3 investigated the likelihood of maintaining a linear path while walking, and potentially entering another individual's personal space (N = 1,056). We conclude that human height is positively related to interpersonal dominance, and may well contribute to the widely observed positive association between height and social status. PMID- 25719491 TI - How to write a presubmission inquiry. PMID- 25719489 TI - A novel bacterial pathogen of Biomphalaria glabrata: a potential weapon for schistosomiasis control? AB - BACKGROUND: Schistosomiasis is the second-most widespread tropical parasitic disease after malaria. Various research strategies and treatment programs for achieving the objective of eradicating schistosomiasis within a decade have been recommended and supported by the World Health Organization. One of these approaches is based on the control of snail vectors in endemic areas. Previous field studies have shown that competitor or predator introduction can reduce snail numbers, but no systematic investigation has ever been conducted to identify snail microbial pathogens and evaluate their molluscicidal effects. METHODOLOGY/PRINCIPAL FINDINGS: In populations of Biomphalaria glabrata snails experiencing high mortalities, white nodules were visible on snail bodies. Infectious agents were isolated from such nodules. Only one type of bacteria, identified as a new species of Paenibacillus named Candidatus Paenibacillus glabratella, was found, and was shown to be closely related to P. alvei through 16S and Rpob DNA analysis. Histopathological examination showed extensive bacterial infiltration leading to overall tissue disorganization. Exposure of healthy snails to Paenibacillus-infected snails caused massive mortality. Moreover, eggs laid by infected snails were also infected, decreasing hatching but without apparent effects on spawning. Embryonic lethality was correlated with the presence of pathogenic bacteria in eggs. CONCLUSIONS/SIGNIFICANCE: This is the first account of a novel Paenibacillus strain, Ca. Paenibacillus glabratella, as a snail microbial pathogen. Since this strain affects both adult and embryonic stages and causes significant mortality, it may hold promise as a biocontrol agent to limit schistosomiasis transmission in the field. PMID- 25719492 TI - Potential involvement of nicotinamide N-methyltransferase in the pathogenesis of metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is a complex disorder characterized by the presence of insulin resistance (IR), type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), or impaired fasting glucose (IFG), plus at least two of the following conditions--hypertension, hyperlipidemia, obesity, and microalbuminuria. Metabolic syndrome exposes patients to a greater risk of developing cardiovascular disease (CVD) and is often associated with elevated levels of homocysteine (Hcy). In the current work, we analyzed the expression of nicotinamide N-methyltransferase (NNMT). Because NNMT is involved in Hcy metabolism and participates in the regulation of the cellular and plasma levels of this compound, we explored the role played by the enzyme in metabolic syndrome. METHODS: Real-time PCR, immunohistochemistry, western blot analysis, and catalytic activity assay were performed to evaluate NNMT expression levels in adipose tissue from 10 Wistar Ottawa Karlsburg W (WOKW) rats, which are an animal model for metabolic syndrome, and from 10 Dark Agouti (DA) rats as the disease resistant control strain. RESULTS: NNMT mRNA, protein, and activity levels were significantly higher in adipose tissue obtained from WOKW rats compared with those observed in adipose tissue of DA rats. CONCLUSION: Data reported in this study represent the first evidence supporting the hypothesis that NNMT could play an important role in the pathogenesis of metabolic syndrome and could have a potential for the development of a targeted therapy. PMID- 25719494 TI - Coping with spatial heterogeneity and temporal variability in resources and risks: adaptive movement behaviour by a large grazing herbivore. AB - Movement is a key mean for mobile species to cope with heterogeneous environments. While in herbivorous mammals large-scale migration has been widely investigated, fine-scale movement responses to local variations in resources and predation risk remain much less studied, especially in savannah environments. We developed a novel approach based on complementary movement metrics (residence time, frequency of visits and regularity of visits) to relate movement patterns of a savannah grazer, the blue wildebeest Connochaetes taurinus, to fine-scale variations in food availability, predation risk and water availability in the Kruger National Park, South Africa. Wildebeests spent more time in grazing lawns where the grass is of higher quality but shorter than in seep zones, where the grass is of lower quality but more abundant. Although the daily distances moved were longer during the wet season compared to the dry season, the daily net displacement was lower, and the residence time higher, indicating a more frequent occurrence of area-concentred searching. In contrast, during the late dry season the foraging sessions were more fragmented and wildebeests moved more frequently between foraging areas. Surprisingly, predation risk appeared to be the second factor, after water availability, influencing movement during the dry season, when resources are limiting and thus expected to influence movement more. Our approach, using complementary analyses of different movement metrics, provided an integrated view of changes in individual movement with varying environmental conditions and predation risk. It makes it possible to highlight the adaptive behavioral decisions made by wildebeest to cope with unpredictable environmental variations and provides insights for population conservation. PMID- 25719495 TI - Hydration of hyaluronan: effects on structural and thermodynamic properties. AB - Hyaluronan (HA) is a frequently occurring biopolymer with a large variety of functions in nature. During the past 60 years, there have been numerous reports on structural and dynamic behavior of HA in water. Nevertheless, studies covering a wider concentration range are still lacking. In this work, we use isothermal scanning sorption calorimetry for the first time to investigate hydration-induced transitions in HA (sodium hyaluronate, 17 kDa). From this method, we obtain the sorption isotherm and the enthalpy and the entropy of hydration. Thermotropic events are evaluated by differential scanning calorimetry (DSC), and structure analysis is performed with X-ray scattering (SWAXS) and light and scanning electron microscopy. During isothermal hydration, HA exhibits a glass transition, followed by crystallization and subsequent dissolution of HA crystals and formation of a one-phase solution. Structural analysis reveals that the crystal may be indexed on an orthorhombic unit cell with space group P212121. Crystallization of HA was found to occur either through endothermic or exothermic processes, depending on the temperature and water content. We propose a mechanism of crystallization that explains this phenomenon based on the interplay between the hydrophobic effect and strengthening of hydrogen bonds during formation of crystals. The combined results were used to construct a binary phase diagram for the HA-water system. PMID- 25719496 TI - Attention: an evolving construct. AB - We review the implications of large-scale brain systems on the construct of attention by first focusing on significant theories and discoveries during the previous 150 years and then considering how the comparatively recent discovery of large-scale brain systems may render previous conceptualizations of attention outdated. Seven functional brain networks are briefly reviewed and the implications of emerging principles of brain functioning for test construction and neuropsychological evaluation are considered. To remain a relevant discipline moving into the 21st century, the field of neuropsychology needs to apply the principles that have been discovered about brain networks to better inform our understanding of attention as well as our ever-refining evaluation of this construct. PMID- 25719497 TI - Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies. AB - Inadequate delivery of therapeutics into tumors has been suggested as a reason for poor response. We hypothesize that bevacizumab, an antibody to vascular endothelial growth factor (VEGF), can improve cetuximab uptake in squamous cell carcinoma tumors. Athymic nude mice were implanted with OSC19 and SCC1 human cancer lines in a subcutaneous flank model. Mice were imaged daily for 14 days after intravenous tail vein injections of the following groups: IgG-IRDye800 (Control), cetuximab-IRDye800 (CTX800 Only), bevacizumab-IRDye800 (BVZ800 Only), cetuximab-IRDye800 + bevacuzimuab-IRDye800 (Simultaneous), and unlabeled bevacizumab followed by cetuximab-IRDye800 3 days later (Neoadjuvant). Within single-agent groups, the CTX800 Only tumor-specific uptake (TSU) was significantly higher than BVZ800 Only at Day 13 (TSU 8.6 vs 2.8, P < 0.001). The Simultaneous treatment with BVZ800 and CTX800 demonstrated no increase in antibody delivery. However, administration of unlabeled bevacizumab 3 days prior to CTX800 (Neoadjuvant group) resulted in significantly higher tumor specific delivery than administration of both antibodies at the same time (11.8 vs Simultaneous 5.0, P < 0.001). This difference can be attributed to a slower decline in tumor fluorescence intensity (-6.8% vs. Simultaneous -11.5% per day, respectively). Structural changes in pericyte coverage and functional vessel changes demonstrating decreased proliferation and tumor growth corroborate these fluorescence results. Although simultaneous administration of bevacizumab with cetuximab failed to increase antibody delivery to the tumor, pretreatment with bevacizumab improved TSU reflecting an increase in tumor-specific uptake of cetuximab as a result of vessel normalization. PMID- 25719499 TI - One year in review: novelties in the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic disease characterised by inflammation of the synovial tissue in joints, which can lead to joint destruction. The primary aim of the treatment is to control pain and inflammation, reduce joint damage and disability, and maintain or improve physical function and quality of life. In this article, we provide a critical analysis of the recent literature on the novelties in the treatment of RA, with a particular focus on the most relevant studies published over the last two years. PMID- 25719498 TI - Selective inhibition of deactivated mitochondrial complex I by biguanides. AB - Biguanides are widely used antihyperglycemic agents for diabetes mellitus and prediabetes treatment. Complex I is the rate-limiting step of the mitochondrial electron transport chain (ETC), a major source of mitochondrial free radical production, and a known target of biguanides. Complex I has two reversible conformational states, active and de-active. The deactivated state is promoted in the absence of substrates but is rapidly and fully reversed to the active state in the presence of NADH. The objective of this study was to determine the relative sensitivity of active/de-active complex I to biguanide-mediated inhibition and resulting superoxide radical (O2(*-)) production. Using isolated rat heart mitochondria, we show that deactivation of complex I sensitizes it to metformin and phenformin (4- and 3-fold, respectively), but not to other known complex I inhibitors, such as rotenone. Mitochondrial O2(*-) production by deactivated complex I was measured fluorescently by NADH-dependent 2 hydroxyethidium formation at alkaline pH to impede reactivation. Superoxide production was 260.4% higher than in active complex I at pH 9.4. However, phenformin treatment of de-active complex I decreased O2(*-) production by 14.9%, while rotenone increased production by 42.9%. Mitochondria isolated from rat hearts subjected to cardiac ischemia, a condition known to induce complex I deactivation, were sensitized to phenformin-mediated complex I inhibition. This supports the idea that the effects of biguanides are likely to be influenced by the complex I state in vivo. These results demonstrate that the complex I active and de-active states are a determinant in biguanide-mediated inhibition. PMID- 25719500 TI - Patients' perceptions of vocal problems: results from a survey in the Tokyo area. AB - Laryngoscopy in cases of sulcus vocalis reveals bowed vocal folds, resulting in a spindle-shaped chink with glottal incompetence. The anatomic and functional problems and resulting incomplete glottal closure during phonation lead to the presenting symptoms of breathy hoarseness, decrease in maximum phonation time (MPT), and vocal fatigue. These symptoms, however, have been reported from the physician's viewpoint, not the patient's. Furthermore, no standardized guidelines for the treatment of sulcus vocalis have been established. Because the general attitude toward sulcus vocalis appears to have become 'It is only a vocal problem and does not significantly affect the patient's well-being,' knowledge of sulcus vocalis has decreased and knowledge about choices of therapy remain limited. We therefore conducted an epidemiological questionnaire survey on this pathological condition in voice clinics in seven hospitals in the Tokyo area to establish preliminary guidelines for the management of sulcus vocalis, in reference to the opinion of the patients. Here we report the summary of our preliminary study 'a survey for sulcus vocalis' and suggest guidelines for the management of such pathological conditions. Although these management guidelines may result in improvement in the symptoms of sulcus vocalis, patients and physicians should be aware that treatment of this condition is difficult and improvement is not guaranteed. PMID- 25719501 TI - Scarce metals in conventional passenger vehicles and end-of-life vehicle shredder output. AB - Concurrent with the demand for cleaner, lighter, and more efficient vehicles, many scarce metals (SMs) are used in passenger vehicles because of their unique physical and chemical properties. To explore the recycling potential of these metals, it is important to understand their distribution in the vehicles as well as their fate at the vehicles' end-of-life. However, this information remains very scattered and sparse. In this paper, we present a study investigating the distribution of 31 SMs in selected electrical and electronic (EE) components of conventional passenger vehicles and in the end-of-life vehicle shredder fractions from a shredder plant in Switzerland. The results of the chemical analyses show that the mass fractions of Co, Sn, Sr, Ta, Y, and Zr were dominant with >20,000 g/t in the selected EE components and Ag, Ga, Mo, Sb, Sn, Sr, and Zr with >50 g/t in the analyzed shredder fractions. The largest masses of 17 SMs were found in the shredder light fraction, which is incinerated in municipal waste treatment plants mainly in Switzerland; thus, these SMs are currently not recovered. The SM mass fractions in both the EE components and the shredder fractions were projected to their total masses in 100 hypothetical midrange passenger vehicles. The resulting mass balance showed a mismatch of >50% for 23 metals, which indicates other important SM sources such as alloys. PMID- 25719505 TI - An oral redox-sensitive self-immolating prodrug strategy. AB - We report a novel oral prodrug approach where a solubilizing polymer conjugated to the drug is designed to be released by the action of an exogenously administered agent in the intestine. A redox-sensitive self-immolating design was implemented, and the reconversion kinetics were studied for three reducible prodrugs. PMID- 25719506 TI - Bilateral cochlear implants with large asymmetries in electrode insertion depth: implications for the study of auditory plasticity. AB - CONCLUSION: The human frequency-to-place map may be modified by experience, even in adult listeners. However, such plasticity has limitations. Knowledge of the extent and the limitations of human auditory plasticity can help optimize parameter settings in users of auditory prostheses. OBJECTIVES: To what extent can adults adapt to sharply different frequency-to-place maps across ears? This question was investigated in two bilateral cochlear implant users who had a full electrode insertion in one ear, a much shallower insertion in the other ear, and standard frequency-to-electrode maps in both ears. METHODS: Three methods were used to assess adaptation to the frequency-to-electrode maps in each ear: (1) pitch matching of electrodes in opposite ears, (2) listener-driven selection of the most intelligible frequency-to-electrode map, and (3) speech perception tests. Based on these measurements, one subject was fitted with an alternative frequency-to-electrode map, which sought to compensate for her incomplete adaptation to the standard frequency-to-electrode map. RESULTS: Both listeners showed remarkable ability to adapt, but such adaptation remained incomplete for the ear with the shallower electrode insertion, even after extended experience. The alternative frequency-to-electrode map that was tested resulted in substantial increases in speech perception for one subject in the short insertion ear. PMID- 25719508 TI - Buffering municipal wastewater pollution using urban wetlands in sub-Saharan Africa: a case of Masaka municipality, Uganda. AB - In many sub-Saharan Africa municipalities and cities, wastewater is discharged with limited or no treatment at all, thus creating public and environmental health risks. This study assessed the performance of a conventional municipal wastewater treatment plant (WWTP), based on effluent pollution flux, in Masaka Municipality, Uganda. Also, the downstream pollution attenuation through a natural wetland was analysed to ascertain its role in buffering the WWTP performance deficits. Generally, there was deficiency in WWTP performance, with 100% failure over a five-year assessment period, for example, the mean effluent biochemical oxygen demand (BOD)5 and chemical oxygen demand (COD) concentrations (mg l(-1)) were found to be 316 +/- 15 and 582 +/- 28 compared with 50 and 100 maximum permissible environment discharge limits, respectively. Despite these deficits in WWTP performance, the wetland buffer effectively reduced pollutant loads for suspended solids (73%), organic matter (BOD5, 88% and COD, 75%), nutrients (total nitrogen, 74% and total phosphorus, 83%) and pathogens (faecal coliforms, 99%). These findings underpin the challenge of managing municipal wastewater using centralized mechanical WWTPs in the region. However, the wetland buffer system demonstrated a critical role these ecosystems play in abating both pulse and intermittent pollution loads from urban environments of sub-Saharan Africa whose sanitation systems are defective and inadequate. Therefore, it was concluded that integrating wetland ecosystems in urban planning as natural landscape features to enhance municipal wastewater management and pollution control is paramount. PMID- 25719507 TI - An assessment of heavy ion irradiation mutagenesis for reverse genetics in wheat (Triticum aestivum L.). AB - Reverse genetic techniques harnessing mutational approaches are powerful tools that can provide substantial insight into gene function in plants. However, as compared to diploid species, reverse genetic analyses in polyploid plants such as bread wheat can present substantial challenges associated with high levels of sequence and functional similarity amongst homoeologous loci. We previously developed a high-throughput method to identify deletions of genes within a physically mutagenized wheat population. Here we describe our efforts to combine multiple homoeologous deletions of three candidate disease susceptibility genes (TaWRKY11, TaPFT1 and TaPLDbeta1). We were able to produce lines featuring homozygous deletions at two of the three homoeoloci for all genes, but this was dependent on the individual mutants used in crossing. Intriguingly, despite extensive efforts, viable lines possessing homozygous deletions at all three homoeoloci could not be produced for any of the candidate genes. To investigate deletion size as a possible reason for this phenomenon, we developed an amplicon sequencing approach based on synteny to Brachypodium distachyon to assess the size of the deletions removing one candidate gene (TaPFT1) in our mutants. These analyses revealed that genomic deletions removing the locus are relatively large, resulting in the loss of multiple additional genes. The implications of this work for the use of heavy ion mutagenesis for reverse genetic analyses in wheat are discussed. PMID- 25719509 TI - Surface modification of Pt(100) for electrocatalytic nitrate reduction to dinitrogen in alkaline solution. AB - Nitrate reduction on a Pt(100) electrode modified by Cu (Cu/Pt(100)) and Rh (Rh/Pt(100)) adatoms have been studied in alkaline media by means of cyclic voltammetry and in situ online electrochemical mass spectrometry (OLEMS). According to the cyclic voltammograms, nitrate reduction is catalyzed by both Cu/Pt(100) and Rh/Pt(100). Ammonia is the main product on the Rh/Pt(100) electrode in alkaline media. On Cu/Pt(100), the selective conversion from NO3(-) to N2 may be achieved. The Cu sites catalyze the reduction of NO3(-) to NO2(-), and the Pt(100) sites catalyze the reduction of NO2(-) to N2, though in different potential windows. PMID- 25719510 TI - The fermi paradox is neither Fermi's nor a paradox. AB - The so-called Fermi paradox claims that if technological life existed anywhere else, we would see evidence of its visits to Earth--and since we do not, such life does not exist, or some special explanation is needed. Enrico Fermi, however, never published anything on this topic. On the one occasion he is known to have mentioned it, he asked "Where is everybody?"--apparently suggesting that we do not see extraterrestrials on Earth because interstellar travel may not be feasible, but not suggesting that intelligent extraterrestrial life does not exist or suggesting its absence is paradoxical. The claim "they are not here; therefore they do not exist" was first published by Michael Hart, claiming that interstellar travel and colonization of the Galaxy would be inevitable if intelligent extraterrestrial life existed, and taking its absence here as proof that it does not exist anywhere. The Fermi paradox appears to originate in Hart's argument, not Fermi's question. Clarifying the origin of these ideas is important, because the Fermi paradox is seen by some as an authoritative objection to searching for evidence of extraterrestrial intelligence--cited in the U.S. Congress as a reason for killing NASA's SETI program on one occasion. But evidence indicates that it misrepresents Fermi's views, misappropriates his authority, deprives the actual authors of credit, and is not a valid paradox. PMID- 25719511 TI - A cross-sectional study of breath acetone based on diabetic metabolic disorders. AB - Breath acetone is a known biomarker for diabetes mellitus in breath analysis. In this work, a cross-sectional study of breath acetone based on clinical metabolic disorders of type 2 diabetes mellitus (T2DM) was carried out. Breath acetone concentrations of 113 T2DM patients and 56 apparently healthy individuals were measured at a single time point. Concentrations varied from 0.22 to 9.41 ppmv (mean 1.75 ppmv) for T2DM, which were significantly higher than those for normal controls (ranged from 0.32 to 1.96 ppmv, mean 0.72 ppmv, p = 0.008). Observations in our work revealed that breath acetone concentrations elevated to different degrees, along with the abnormality of blood glucose, glycated hemoglobin (HbA1c), triglyceride and cholesterol. Breath acetone showed obviously positive correlations with blood ketone and urine ketone. Possible metabolic relations between breath acetone and diabetic disorders were also discussed. This work aimed at giving an overall assessment of breath acetone from the perspective of clinical parameters for type 2 diabetes. PMID- 25719513 TI - Electrochemical stability and postmortem studies of Pt/SiC catalysts for polymer electrolyte membrane fuel cells. AB - In the presented work, the electrochemical stability of platinized silicon carbide is studied. Postmortem transmission electron microscopy and X-ray photoelectron spectroscopy were used to document the change in the morphology and structure upon potential cycling of Pt/SiC catalysts. Two different potential cycle aging tests were used in order to accelerate the support corrosion, simulating start-up/shutdown and load cycling. On the basis of the results, we draw two main conclusions. First, platinized silicon carbide exhibits improved electrochemical stability over platinized active carbons. Second, silicon carbide undergoes at least mild oxidation if not even silicon leaching. PMID- 25719512 TI - Neuromuscular blockade improves first-attempt success for intubation in the intensive care unit. A propensity matched analysis. AB - RATIONALE: The use of neuromuscular blocking agents (NMBAs) has been shown to be valuable in improving successful tracheal intubation in the operating room and emergency department. However, data on NMBA use in critically ill intensive care unit (ICU) patients are lacking. Furthermore, there are no data on NMBA use with video laryngoscopy. OBJECTIVES: To evaluate the effect of NMBA use on first attempt success (FAS) with tracheal intubation in the ICU. METHODS: Single-center observational study of 709 consecutive patients intubated in the medical ICU of a university medical center from January 1, 2012 to June 30, 2014. Data were collected prospectively through a continuous quality improvement program on all patients intubated in the ICU over the study period. Data relating to patient demographics, intubation, and complications were analyzed. We used propensity score (propensity to use an NMBA) matching to generate 5,000 data sets of cases (failed first intubation attempts) matched to controls (successful first attempts) and conditional logistic regression to analyze the results. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in patient demographics, except median total difficult airway characteristics were higher in the non-NMBA group (2 vs. 1, P < 0.001). There were significant differences in the sedative used between groups and the operator level of training. More patients who were given NMBAs received etomidate (83 vs. 35%) and more patients in the non-NMBA group received ketamine (39 vs. 9%) (P < 0.001). The FAS for NMBA use was 80.9% (401/496) compared with 69.6% (117/168) for non-NMBA use (P = 0.003). The summary odds ratio for FAS when an NMBA was used from the propensity matched analyses was 2.37 (95% confidence interval, 1.36-4.88). In the subgroup of patients intubated with a video laryngoscope, propensity-adjusted odds of FAS with the use of an NMBA was 2.50 (1.43-4.37; P < 0.001). There were no differences in procedurally related complications between groups. CONCLUSIONS: After controlling for potential confounders, this propensity-adjusted analysis demonstrates improved odds of FAS at intubation in the ICU with the use of an NMBA. This improvement in FAS is seen even with the use of a video laryngoscope. PMID- 25719514 TI - Sulfonate derived phosphoramidates as active intermediates in the enzymatic primer-extension of DNA. AB - Novel unnatural 5'-phosphoramidate nucleosides, capable of being processed as substrates by DNA polymerases for multiple nucleotide incorporations, have been designed. The mimics feature metabolites such as taurine and a broad range of aliphatic sulfonates coupled through a P-N bond to the 5'-phosphate position of deoxynucleotides, to allow binding interactions in the enzyme active site. The utility of all of the analogues as pyrophosphate mimics was demonstrated for the chain elongation of DNA, using both thermophilic and mesophilic microbial polymerases. PMID- 25719515 TI - Copy, edit, and paste: natural product approaches to biomaterials and neuroengineering. AB - Progress in the chemical sciences has formed the world we live in, both on a macroscopic and on a nanoscopic scale. The last century witnessed the development of high performance materials that interact with humans on many layers, from clothing to construction, from media to medical devices. On a molecular level, natural products and their derivatives influence many biological processes, and these compounds have enormously contributed to the health and quality of living of humans. Although coatings of stone materials with oils or resins (containing natural products) have led to improved tools already millennia ago, in contrast today, natural product approaches to designer materials, that is, combining the best of both worlds, remain scarce. In this Account, we will summarize our recent research efforts directed to the generation of natural product functionalized materials, exploiting the strategy of "copy, edit, and paste with natural products". Natural products embody the wisdom of evolution, and only total synthesis is able to unlock the secrets enshrined in their molecular structure. We employ total synthesis ("copy") as a scientific approach to address problems related to molecular structure, the biosynthesis of natural products, and their bioactivity. Additionally, the fundamental desire to investigate the mechanism of action of natural products constitutes a key driver for scientific inquiry. In an emerging area of relevance to society, we have prepared natural products such as militarinone D that can stimulate neurite outgrowth and facilitate nerve regeneration. This knowledge obtained by synthetic organic chemistry on complex natural products can then be used to design structurally simplified compounds that retain the biological power of the parent natural product ("edit"). This process, sometimes referred to as function-oriented synthesis, allows obtaining derivatives with better properties, improving their chemical tractability and reducing the step count of the synthesis. Along these lines, we have demonstrated that militarinone D can be truncated to yield structurally simplified analogs with improved activity. Finally, with the goal of designing bioactive materials, we have immobilized functionally optimized, neuritogenic natural products ("paste"). These materials could facilitate nerve regeneration, act as nerve guidance conduits, or lead to new approaches in neuroengineering. Based on the surface-adhesive properties of electron-deficient catecholates and the knowledge gathered on neuritogenic natural product derivatives, two mechanistically different design principles have been applied to generate neuritogenic materials. In conclusion, natural products, and their functionally optimized analogs, present a large, mostly untapped reservoir of powerful modulators of biological systems, and their hybridization with materials can lead to new approaches in various fields, from biofilm prevention to neuroengineering. PMID- 25719516 TI - Palladium-catalyzed coupling of azoles or thiazoles with aryl thioethers via C H/C-S activation. AB - Palladium-catalyzed cross-coupling via the C(sp(2))-S bond activation of aryl thioethers and the C-H bond activation of azoles or thiazoles was carried out. Electron-deficient and -rich aryl methyl thioethers and diaryl thioethers can be employed as the coupling partners and the reaction tolerates a range of functional groups including MeO, CF3, CN, PhCO, CONEt2, and Py groups. PMID- 25719518 TI - Expectancies and hypnotic responsiveness: an experimental-design flaw revealed. AB - Recent research suggests that expectancies about being hypnotized have a determinant role in the hypnotic experience. The authors analyzed the relationship between expectancies and the phenomenology of hypnosis using the Phenomenology of Consciousness Inventory and Hypnotic Assessment Procedure. Participants (115) were assigned either to the imagination (hypnosis labeled as imagination) or the hypnosis conditions. Results revealed only a minor influence of expectancies and none on the label "hypnosis" across all variables. These findings indicate that the methodology commonly used to study the influence of expectancies on hypnotic responsiveness and phenomenology might represent a flaw in favor of a causal relationship between expectancies and hypnotic experience. PMID- 25719517 TI - Health care system-level factors associated with performance on Medicare STAR adherence metrics in a large, integrated delivery system. AB - BACKGROUND: The Centers for Medicare and Medicaid Services provide significant incentives to health plans that score well on Medicare STAR metrics for cardiovascular disease risk factor medication adherence. Information on modifiable health system-level predictors of adherence can help clinicians and health plans develop strategies for improving Medicare STAR scores, and potentially improve cardiovascular disease outcomes. OBJECTIVE: To examine the association of Medicare STAR adherence metrics with system-level factors. RESEARCH DESIGN: A cross-sectional study. SUBJECTS: A total of 129,040 diabetes patients aged 65 years and above in 2010 from 3 Kaiser Permanente regions. MEASURES: Adherence to antihypertensive, antihyperlipidemic, and oral antihyperglycemic medications in 2010, defined by Medicare STAR as the proportion of days covered >= 80%. RESULTS: After controlling for individual-level factors, the strongest predictor of achieving STAR-defined medication adherence was a mean prescribed medication days' supply of > 90 days (RR=1.61 for antihypertensives, oral antihyperglycemics, and statins; all P < 0.001). Using mail order pharmacy to fill medications > 50% of the time was independently associated with better adherence with these medications (RR = 1.07, 1.06, 1.07; P < 0.001); mail order use had an increased positive association among black and Hispanic patients. Medication copayments <= $10 for 30 days' supply (RR = 1.02, 1.02, 1.02; P < 0.01) and annual individual out-of-pocket maximums <= $2000 (RR = 1.02, 1.01, 1.02; P < 0.01) were also significantly associated with higher adherence for all 3 therapeutic groupings. CONCLUSIONS: Greater medication days' supply and mail order pharmacy use, and lower copayments and out-of-pocket maximums, are associated with better Medicare STAR adherence. Initiatives to improve adherence should focus on modifiable health system-level barriers to obtaining evidence based medications. PMID- 25719519 TI - Pain perception and hypnosis: findings from recent functional neuroimaging studies. AB - Hypnosis modulates pain perception and tolerance by affecting cortical and subcortical activity in brain regions involved in these processes. By reviewing functional neuroimaging studies focusing on pain perception under hypnosis, the authors aimed to identify brain activation-deactivation patterns occurring in hypnosis-modulated pain conditions. Different changes in brain functionality occurred throughout all components of the pain network and other brain areas. The anterior cingulate cortex appears to be central in modulating pain circuitry activity under hypnosis. Most studies also showed that the neural functions of the prefrontal, insular, and somatosensory cortices are consistently modified during hypnosis-modulated pain conditions. Functional neuroimaging studies support the clinical use of hypnosis in the management of pain conditions. PMID- 25719520 TI - Diurnal variations in hypnotic responsiveness: is there an optimal time to be hypnotized? AB - With a sample of nearly 700 undergraduate students, the authors found support for diurnal variations in hypnotic responsiveness. Administering the Harvard Group Scale of Hypnotic Susceptibility, Form A (HGSHS:A) in the morning or evening resulted in higher average scores than from afternoon sessions. The authors replicated this finding using a second independent sample. In the primary study, participants indicated the time of day that they are most alert. Matching self reported preferred time of the day with HGSHS:A administration time did not improve hypnotic responsiveness. Considering this as well as past research, the authors argue that mid-morning may be the optimal time to be hypnotized and afternoon the least favorable. PMID- 25719521 TI - Paradoxical response to an emotional task: trait characteristics and heart-rate dynamics. AB - The present study evaluated the heart-rate dynamics of subjects reporting decreased (responders) or paradoxically increased relaxation (nonresponders) at the end of a threatening movie. Heart-rate dynamics were characterized by indices extracted through recurrence quantification analysis (RQA) and detrended fluctuation analysis (DFA). These indices were studied as a function of a few individual characteristics: hypnotizability, gender, absorption, anxiety, and the activity of the behavioral inhibition and activation systems (BIS/BAS). Results showed that (a) the subjective experience of responsiveness is associated with the activity of the behavioral inhibition system and (b) a few RQA and DFA indices are able to capture the influence of cognitive-emotional traits, including hypnotizability, on the responsiveness to the threatening task. PMID- 25719522 TI - Are hypnosis and dissociation related? New evidence for a connection. AB - The authors revisit the question of the existence of a relationship between hypnotizability and dissociative capacity. In the present study, the State Scale of Dissociation (SSD) replaced the commonly employed Dissociative Experiences Scale (DES) as a measure of dissociation, due to the latter capturing primarily pathological aspects of dissociation. Relationships between the Harvard Scale of Hypnotic Susceptibility, Form A (HGSHS:A), the SSD, and the Phenomenology of Consciousness Inventory (PCI) were assessed in the context of hypnosis. Robust results were found when comparing pre- to post-SSD scores, suggesting heightened nonpathological forms of dissociation are indeed related to hypnotizability. The appropriateness of the DES and similar trait-based measures for evaluating hypnotic phenomena is discussed as well as the relationships between PCI and SSD subscales. PMID- 25719523 TI - Feature-based coding system: a new way of characterizing hypnosis styles. AB - In this pilot study, the authors introduce a new system to assess hypnosis style. The Feature-Based Coding System (FBCS) comprises 24 standard individual hypnosis sessions, which were videotaped and coded according to both a previous and the new coding system. In addition, both subjects and hypnotists filled the Archaic Involvement Measure (AIM), the Phenomenology of Consciousness Inventory (PCI), and the Dyadic Interactional Harmony Questionnaire (DIH). The interrater agreement of FBCS was good and the construct Maternal-Paternal Axis had a good internal consistency (alpha = .95). Construct validity was also supported by the findings. Based on these results, a larger scale study is warranted to further establish the reliability and usefulness of this tool. PMID- 25719524 TI - Hypnotherapy of a pain disorder: a clinical case study. AB - Hypnotherapy's effectiveness in improving and controlling chronic pain of various etiologies has been demonstrated by studies; the mechanism by which hypnosis does this is more complex than a simple induction of muscle relaxation. This study reveals, in addition to this mechanism, a deeper dimension of hypnotherapy from the vantage of a patient with a medical-surgical background, diagnosed with a pain disorder and major severe depressive disorder in addition to incurable painful symptoms, through treatment associated with hypnoanalysis. Following psychotherapy, which included some elements of cognitive-behavioral therapy, a complete remission of the anxious-depressive mood and the painful symptoms was achieved. PMID- 25719525 TI - Correction to: Mechanisms of Hypnosis: Toward the Development of a Biopsychosocial Model. PMID- 25719526 TI - Insights into the Staphylococcus aureus-host interface: global changes in host and pathogen gene expression in a rabbit skin infection model. AB - Staphylococcus aureus is an important cause of human skin and soft tissue infections (SSTIs) globally. Notably, 80% of all SSTIs are caused by S. aureus, of which ~63% are abscesses and/or cellulitis. Although progress has been made, our knowledge of the host and pathogen factors that contribute to the pathogenesis of SSTIs is incomplete. To provide a more comprehensive view of this process, we monitored changes in the S. aureus transcriptome and selected host proinflammatory molecules during abscess formation and resolution in a rabbit skin infection model. Within the first 24 h, S. aureus transcripts involved in DNA repair, metabolite transport, and metabolism were up-regulated, suggesting an increase in the machinery encoding molecules involved in replication and cell division. There was also increased expression of genes encoding virulence factors, namely secreted toxins and fibronectin and/or fibrinogen-binding proteins. Of the host genes tested, we found that transcripts encoding IL-8, IL1beta, oncostatin M-like, CCR1, CXCR1 (IL8RA), CCL4 (MIP-1beta) and CCL3 (MIP1alpha)-like proteins were among the most highly up-regulated transcripts during S. aureus abscess formation. Our findings provide additional insight into the pathogenesis of S. aureus SSTIs, including a temporal component of the host response. These results serve as a springboard for future studies directed to better understand how/why mild or moderate SSTIs progress to invasive disease. PMID- 25719527 TI - The Femininity Ideology Scale (FIS): dimensions and its relationship to anxiety and feminine gender role stress. AB - The purpose of this study was to conduct a confirmatory factor analytic investigation of the Femininity Ideology Scale (FIS) and to assess whether feminine gender role stress mediated the relationship between femininity ideology and anxiety. During the 2010-2011 academic year, a convenience sample of 606 college women were recruited from three universities and one college. Confirmatory factor analysis supported a four- versus the hypothesized five factor model, resulting in the elimination of the Dependency/Deference factor. Mediation analysis using structural equation modeling indicated no direct relationship between Femininity Ideology and Anxiety, although an indirect one was observed, mediated through Feminine Gender Role Stress. The results are discussed in terms of possible changes in contemporary notions of femininity, and the utility of using the FIS in applied therapeutic settings. PMID- 25719528 TI - A study evaluating the bidirectional relationship between inflammatory bowel disease and self-reported non-celiac gluten sensitivity. AB - BACKGROUND: Non-celiac gluten sensitivity and the associated use of a gluten-free diet (GFD) are perceived to belong to the spectrum of irritable bowel syndrome (IBS). However, recent reports suggest substantial use of a GFD in inflammatory bowel disease (IBD). We assessed the bidirectional relationship between IBD and self-reported non-celiac gluten sensitivity (SR-NCGS). METHODS: A cross-sectional questionnaire screened for SR-NCGS and the use of a GFD in 4 groups: ulcerative colitis (n = 75), Crohn's disease (n = 70), IBS (n = 59), and dyspeptic controls (n = 109). We also assessed diagnostic outcomes for IBD in 200 patients presenting with SR-NCGS. RESULTS: The prevalence of SR-NCGS was 42.4% (n = 25/59) for IBS, followed by 27.6% (n = 40/145) for IBD, and least among dyspeptic controls at 17.4% (n = 19/109); P = 0.015. The current use of a GFD was 11.9% (n = 7/59) for IBS, 6.2% (n = 9/145) for IBD, and 0.9% (1/109) for dyspeptic controls; P = 0.02. No differences were established between ulcerative colitis and Crohn's disease. However, Crohn's disease patients with SR-NCGS were significantly more likely to have stricturing disease (40.9% versus 18.9%, P = 0.046), and higher mean Crohn's Disease Activity Index score (228.1 versus 133.3, P = 0.002), than those without SR-NCGS. Analysis of 200 cases presenting with SR NCGS suggested that 98.5% (n = 197) could be dietary-related IBS. However, 1.5% (n = 3) were found to have IBD; such patients had associated alarm symptoms, and/or abnormal blood parameters, prompting colonic investigations. CONCLUSIONS: SR-NCGS is not only exclusive to IBS but also associated with IBD, where its presence may be reflecting severe or stricturing disease. Randomized studies are required to further delineate the nature of this relationship and clarify whether a GFD is a valuable dietetic intervention in selected IBD patients. PMID- 25719529 TI - Can we improve on the "see one, do one, teach one" paradigm in training fellows to care for patients with inflammatory bowel disease? PMID- 25719530 TI - Pyrazine-based organometallic complex: synthesis, characterization, and supramolecular chemistry. AB - The design, synthesis, and characterization of a new pyrazine-based ditopic platinum(II) organometallic complex are reported. The molecular structure of the organoplatinum pyrazine dipod was determined by single-crystal X-ray crystallography. The potential utility of this organometallic ditopic acceptor as a building block in the construction of neutral metallasupramolecular macrocycles containing the pyrazine motif was explored. Pyrazine motifs containing supramolecules were characterized by multinuclear NMR (including (1)H DOSY), mass spectrometry, and elemental analysis. The geometry of each supramolecular framework was optimized by employing the PM6 semiempirical molecular orbital method to predict its shape and size. The ability of the pyrazine-based organoplatinum complex to act as a host for nitroaromatic guest (2,4 dinitrotoluene and PA) molecules was explored by isothermal titration calorimetry (ITC). The binding stoichiometry and thermodynamic parameters of these host-guest complexation reactions were evaluated using ITC. Theoretical calculations were performed to obtain insight into the binding pattern between the organometallic host and nitroaromatic guests. The preferable binding propensity of the binding sites of complex 1 for both nitroaromatics (PA and 2,4-dinitrotoluene) determined by molecular simulation studies corroborates well with the experimental results as obtained by ITC experiments. PMID- 25719531 TI - Approach to Antihypertensive Therapy. AB - Antihypertensive agents are commonly prescribed by physicians to prevent the long term mortality from chronic hypertension. They are also given to improve survival in a number of conditions (eg, heart failure, coronary artery disease), independent of the effect on blood pressure. Several classes of antihypertensives are available with unique pharmacologic characteristics and adverse effects. Not all agents in the same class have identical effects, and careful selection of drugs based on the comorbid conditions is recommended. PMID- 25719532 TI - Chemoselective synthesis of beta-ketophosphonates using lithiated alpha (trimethylsilyl)methylphosphonate. AB - A highly chemoselective synthesis of beta-ketophosphonates from pentafluorophenyl esters and lithiated methyl alpha-(trimethylsilyl)methylphosphonate has been developed. This mild lithiated phosphonate reagent allows the synthesis of functionalized beta-ketophosphonates in the presence of unactivated esters with high yields. This method has been compared with the standard lithiated methylphosphonate reagent. PMID- 25719534 TI - Outcomes of a pilot hand hygiene randomized cluster trial to reduce communicable infections among US office-based employees. AB - OBJECTIVE: To determine the effectiveness of an office-based multimodal hand hygiene improvement intervention in reducing self-reported communicable infections and work-related absence. METHODS: A randomized cluster trial including an electronic training video, hand sanitizer, and educational posters (n = 131, intervention; n = 193, control). Primary outcomes include (1) self reported acute respiratory infections (ARIs)/influenza-like illness (ILI) and/or gastrointestinal (GI) infections during the prior 30 days; and (2) related lost work days. Incidence rate ratios calculated using generalized linear mixed models with a Poisson distribution, adjusted for confounders and random cluster effects. RESULTS: A 31% relative reduction in self-reported combined ARI-ILI/GI infections (incidence rate ratio: 0.69; 95% confidence interval, 0.49 to 0.98). A 21% nonsignificant relative reduction in lost work days. CONCLUSIONS: An office-based multimodal hand hygiene improvement intervention demonstrated a substantive reduction in self-reported combined ARI-ILI/GI infections. PMID- 25719533 TI - Exposure Reconstruction and Risk Analysis for Six Semiconductor Workers With Lymphohematopoietic Cancers. AB - OBJECTIVE: To investigate whether workplace exposures to recognized lymphohematopoietic carcinogens were possibly related to cancers in six semiconductor-manufacturing workers. METHODS: A job-exposure matrix was developed for chemical and physical process agents and anticipated by-products. Potential cumulative occupational exposures of the six cases were reconstructed. The role of workplace exposures in cancer was evaluated through quantitative risk assessment and by comparison with epidemiological literature. RESULTS: Two workers were potentially exposed to agents capable of causing their diagnosed cancers. Reconstructed exposures were similar to levels in outdoor environments and lower than exposures associated with increased risks in epidemiological studies. Cancer risks were estimated to be less than 1 in 10,000 persons. CONCLUSIONS: The development of cancer among the six workers was unlikely to be explained by occupational exposures to recognized lymphohematopoietic carcinogens. PMID- 25719535 TI - Traditional Birth Attendants in Rural Northern Uganda: Policy, Practice, and Ethics. AB - The current emphasis on skilled attendants as a means to reduce maternal mortality contributes to a discouraging policy environment for traditional birth attendants (TBAs). They continue to attend a significant number of births, however, such that their role and the policies and practices affecting their work remain important to understanding maternity health care and maternal health in the global South. In this article, I examine the policies and practices governing community elders practicing as TBAs in rural northern Uganda. This discussion is relevant to health workers in developing countries and to scholars in fields such as women's studies, sociology, and public health. PMID- 25719536 TI - Ultra-strong coupling of molecular materials: spectroscopy and dynamics. AB - We report here a study of light-matter strong coupling involving three molecules with very different photo-physical properties. In particular we analyze their emission properties and show that the excitation spectra are very different from the static absorption of the coupled systems. Furthermore we report the emission quantum yields and excited state lifetimes, which are self-consistent. The above results raise a number of fundamental questions that are discussed and these demonstrate the need for further experiments and theoretical studies. PMID- 25719537 TI - Mechanisms of recovery of visual function in adult amblyopia through a tailored action video game. AB - Amblyopia is a deficit in vision that arises from abnormal visual experience early in life. It was long thought to develop into a permanent deficit, unless properly treated before the end of the sensitive period for visual recovery. However, a number of studies now suggest that adults with long-standing amblyopia may at least partially recover visual acuity and stereopsis following perceptual training. Eliminating or reducing interocular suppression has been hypothesized to be at the root of these changes. Here we show that playing a novel dichoptic video game indeed results in reduced suppression, improved visual acuity and, in some cases, improved stereopsis. Our relatively large cohort of adults with amblyopia, allowed us, for the first time, to assess the link between visual function recovery and reduction in suppression. Surprisingly, no significant correlation was found between decreased suppression and improved visual function. This finding challenges the prevailing view and suggests that while dichoptic training improves visual acuity and stereopsis in adult amblyopia, reduced suppression is unlikely to be at the root of visual recovery. These results are discussed in the context of their implication on recovery of amblyopia in adults. PMID- 25719538 TI - If we offer it, will children buy it? Sales of healthy foods mirrored their availability in a community sport, commercial setting in Alberta, Canada. AB - BACKGROUND: Community sports settings are often sources of unhealthy foods for children. Many managers in these settings are reluctant to increase availability of healthy food options because they perceive that healthy foods are not profitable. This study assessed the independent contribution of increased availability of healthy foods to their sales in a community sport, commercial context. Change in revenues per patron was also examined. METHODS: The availability of healthy items was increased from 9.1% at baseline (35 days) to 25.0% during the intervention period (40 days), returning to 9.1% postintervention (6 days). Purchases of all patrons who bought foods/beverages (n=17,262 items sold) from two concessions at an outdoor community pool were assessed from baseline to postintervention. Chi-square analyses assessed differences in the proportion of healthy and unhealthy items sold, as well as in the proportion of total revenues per patron across periods. A trained observer also recorded qualitative observations pertaining to a subset of patrons' (n=221) dietary behaviors and activities. RESULTS: Healthy items represented 7.7%, 22.7%, and 9.8% of sales during the preintervention, intervention, and postintervention periods, respectively (p<0.01). Sales of healthy beverages exceeded sales of all other product types. The proportion of total revenues per patron did not differ by period. CONCLUSIONS: Food availability was an important environmental determinant of food purchasing behaviors in this community commercial context, given that sales of healthy foods closely mirrored their availability. Increased availability of healthy foods in community and commercial settings is important because concurrent changes within multiple environments will be required to improve children's dietary behaviors. PMID- 25719539 TI - Clinical profiles, disease outcome and co-morbidities among T. b. rhodesiense sleeping sickness patients in Uganda. AB - BACKGROUND: The acute form of Human African Trypanosomiasis (HAT, also known as Sleeping sickness) caused by Trypanosoma brucei rhodesiense has been shown to have a wide spectrum of focus specific clinical presentation and severity in East and Southern Africa. Indeed HAT occurs in regions endemic for other tropical diseases, however data on how these co-morbidities might complicate the clinical picture and affect disease outcome remains largely scanty. We here describe the clinical presentation, presence of co-infections, and how the latter impact on HAT prognosis. METHODS AND FINDINGS: We carried out a retrospective analysis of clinical data from 258 sleeping sickness patients reporting to Lwala hospital between 2005 and 2012. The mean patient age was 28.6 years with a significant number of cases below 18 years (p< 0.0001). About 93.4% of the cases were diagnosed as late stage (p< 0.0001). The case fatality rate was 10.5% with post treatment reactive encephalopathys reported in 7.9% of the cases, of whom 36.8% eventually died. Fever was significantly (p = 0.045) higher in patients under 18 years. Of the early stage patients, 26.7% and 6.7% presented with late stage signs of sleep disorder and mental confusion respectively. Among the co infections, malaria was significantly more prevalent (28.9%; p< 0.0001) followed by urinary tract infections (4.2%). Co-infections were present in 14.3% of in hospital deaths, 38.5% of which were recorded as Malaria. Malaria was significantly more common in patients under 18 years (45.5%; p< 0.02), and was reported in 60% of the fatal cases in this age group. CONCLUSIONS: We show a wide spectrum of sleeping sickness clinical presentation and disease outcome that was apparently not significantly influenced by concurrent infections. It would thus be interesting to determine the host and/or parasite factors that might be responsible for the observed diverse clinical presentation. PMID- 25719540 TI - First clinical experience of intra-operative high intensity focused ultrasound in patients with colorectal liver metastases: a phase I-IIa study. AB - BACKGROUND: Surgery is the only curative treatment in patients with colorectal liver metastases (CLM), but only 10-20% of patients are eligible. High Intensity Focused Ultrasound (HIFU) technology is of proven value in several indications, notably prostate cancer. Its intra-operative use in patients with CLM has not previously been studied. Preclinical work suggested the safety and feasibility of a new HIFU device capable of ablating volumes of up to 2cm x 2cm in a few seconds. METHODS: We conducted a prospective, single-centre phase I-IIa trial. HIFU was delivered immediately before scheduled hepatectomy. To demonstrate the safety and efficacy of rapidly ablating liver parenchyma, ablations were performed on healthy tissue within the areas scheduled for resection. RESULTS: In total, 30 ablations were carried out in 15 patients. These ablations were all generated within 40 seconds and on average measured 27.5mm x 21.0mm. The phase I study (n = 6) showed that use of the HIFU device was feasible and safe and did not damage neighbouring tissue. The phase IIa study (n = 9) showed both that the area of ablation could be precisely targeted on a previously implanted metallic mark (used to represent a major anatomical structure) and that ablations could be undertaken deliberately to avoid such a mark. Ablations were achieved with a precision of 1-2 mm. CONCLUSION: HIFU was feasible, safe and effective in ablating areas of liver scheduled for resection. The next stage is a phase IIb study which will attempt ablation of small metastases with a 5 mm margin, again prior to planned resection. TRIAL REGISTRATION: ClinicalTrials.govNCT01489787. PMID- 25719541 TI - Follow-up of chronic coughers improves tuberculosis case finding: results from a community-based cohort study in southern Ethiopia. AB - BACKGROUND: Untreated smear-positive tuberculosis (TB) patients are the primary source of infection; however, a large number of TB cases have not been identified and are untreated in many sub-Saharan African countries, including Ethiopia. This study determined whether or not a community-based follow-up of chronic coughers improves detection of TB cases and the risk factors for death among such cases. METHODS: We conducted a census in six rural communities in Sidama, southern Ethiopia. Based on interview and sputum investigation, we identified 724 TB smear negative chronic coughers, and did a cohort study of these chronic coughers and 1448 neighbourhood controls. For both chronic coughers and neighbourhood controls, we conducted a TB screening interview and performed sputum microscopy, as required, at 4, 7 and 10 months. Between September 2011 and June 2012, we followed chronic coughers and neighbourhood controls for 588 and 1,204 person years of observation, respectively. RESULTS: Of the chronic coughers, 23 developed smear-positive TB (incidence rate = 3912/105 person-years) compared to three neighbourhood controls who developed smear-positive TB (incidence rate = 249/105 person-years). The male-to-female ratio of smear-positive TB was 1:1. We demonstrated that chronic coughers (adjusted hazards ratio [aHR], 13.5; 95% CI, 4.0-45.7) and the poor (aHR, 2.6; 95% CI, 1.1-5.8) were at high-risk for smear positive TB. Among the study cohort, 15 chronic coughers and two neighbourhood controls died (aHR, 14.0; 95% CI, 3.2-62.4). CONCLUSION: A community-based follow up of chronic coughers is helpful in improving smear-positive TB case detection, it benefits socioeconomically disadvantaged people in particular; in rural settings, chronic coughers had a higher risk of death. PMID- 25719543 TI - Contemporary proteomic strategies for clinical epigenetic research and potential impact for the clinic. AB - Novel proteomic methods are revealing the intricacy of the epigenetic landscape affecting gene regulation and improving our knowledge of the pathogenesis of complex diseases. Despite the enormous amount of data regarding epigenetic modifications present in DNA and histones, deciphering their biological relevance in the context of the disease and health is currently still an ongoing process. Here, we consider the relationship between epigenetic research in tumorigenesis and the prospect of knowledge transfer to clinical use, focusing primarily on the epigenetic histone post-translational modifications, which could be used as biomarkers. We additionally focus on the use of proteomic techniques in research and evaluate their usefulness in clinical setting. PMID- 25719542 TI - Molecular and functional analyses of a maize autoactive NB-LRR protein identify precise structural requirements for activity. AB - Plant disease resistance is often mediated by nucleotide binding-leucine rich repeat (NLR) proteins which remain auto-inhibited until recognition of specific pathogen-derived molecules causes their activation, triggering a rapid, localized cell death called a hypersensitive response (HR). Three domains are recognized in one of the major classes of NLR proteins: a coiled-coil (CC), a nucleotide binding (NB-ARC) and a leucine rich repeat (LRR) domains. The maize NLR gene Rp1 D21 derives from an intergenic recombination event between two NLR genes, Rp1-D and Rp1-dp2 and confers an autoactive HR. We report systematic structural and functional analyses of Rp1 proteins in maize and N. benthamiana to characterize the molecular mechanism of NLR activation/auto-inhibition. We derive a model comprising the following three main features: Rp1 proteins appear to self associate to become competent for activity. The CC domain is signaling-competent and is sufficient to induce HR. This can be suppressed by the NB-ARC domain through direct interaction. In autoactive proteins, the interaction of the LRR domain with the NB-ARC domain causes de-repression and thus disrupts the inhibition of HR. Further, we identify specific amino acids and combinations thereof that are important for the auto-inhibition/activity of Rp1 proteins. We also provide evidence for the function of MHD2, a previously uncharacterized, though widely conserved NLR motif. This work reports several novel insights into the precise structural requirement for NLR function and informs efforts towards utilizing these proteins for engineering disease resistance. PMID- 25719544 TI - Mask ventilation with two different face masks in the delivery room for preterm infants: a randomized controlled trial. AB - BACKGROUND: If an infant fails to initiate spontaneous breathing after birth, international guidelines recommend a positive pressure ventilation (PPV). However, PPV by face mask is frequently inadequate because of leak between the face and mask. Despite a variety of available face masks, none have been prospectively compared in a randomized fashion. We aimed to evaluate and compare leak between two commercially available round face masks (Fisher & Paykel (F&P) and Laerdal) in preterm infants <33 weeks gestational age in the delivery room. METHODS: Infants born at the Royal Alexandra Hospital from April to September 2013 at <33 weeks gestational age who received mask PPV in the delivery room routinely had a flow sensor placed between the mask and T-piece resuscitator. Infants were randomly assigned to receive PPV with either a F&P or Laerdal face mask. All resuscitators were trained in the use of both face masks. We compared mask leak, airway pressures, tidal volume and ventilation rate between the two groups. RESULTS: Fifty-six preterm infants (n=28 in each group) were enrolled; mean+/-s.d. gestational age 28+/-3 weeks; birth weight 1210+/-448 g; and 30 (52%) were male. Apgar scores at 1 and 5 min were 5+/-3 and 7+/-2, respectively. Infants randomized to the F&P face mask and Laerdal face mask had similar mask leak (30 (25-38) versus 35 (24-46)%, median (interquartile range), respectively, P=0.40) and tidal volume (7.1 (4.9-8.9) versus 6.6 (5.2-8.9) ml kg(-1), P=0.69) during PPV. There were no significant differences in ventilation rate, inflation time or airway pressures between groups. CONCLUSION: The use of either face mask during PPV in the delivery room yields similar mask leak in preterm infants <33 weeks gestational age. PMID- 25719545 TI - Evaluation of the performance of the insulin-like growth factor-binding protein 1/alpha-fetoprotein test in diagnosing ruptured fetal membranes in pregnant women. AB - OBJECTIVE: The objective of this study was to evaluate the efficacy of IGFBP 1/AFP (insulin-like growth factor-binding protein-1/alpha-fetoprotein) immunoassay (Amnioquick Duo+) in diagnosing rupture of membranes (ROM). STUDY DESIGN: A prospective, observational study was performed in pregnant women with a history of fluid leakage from the vagina. The IGFBP-1/AFP immunoassay and conventional methods were used to diagnose ROM. The obstetricians were blinded to the results of the IGFBP-1/AFP immunoassay. The diagnosis of ROM was finally confirmed by reviewing the medical records after delivery. RESULT: One hundred patients were recruited into this study. The mean gestational age was 37.6 weeks (range 25 to 41 weeks). Twenty-six percent were preterm and 74% were at term. IGFBP-1/AFP immunoassay had a sensitivity of 94.1%, specificity of 87.5%, positive predictive value of 97.5%, negative predictive value of 73.7% and accuracy of 93% in diagnosing ROM. CONCLUSION: IGFBP-1/AFP immunoassay is a rapid immunoassay test for diagnosing ROM with a high sensitivity and specificity. This test can be used as an alternative method for diagnosis of ROM. PMID- 25719546 TI - Does chronic oxygen dependency in preterm infants with bronchopulmonary dysplasia at NICU discharge predict respiratory outcomes at 3 years of age? AB - OBJECTIVE: To determine whether chronic oxygen dependency at the time of discharge from the neonatal intensive care unit (NICU) in infants with bronchopulmonary dysplasia (BPD) predicts respiratory outcomes at 3 years. STUDY DESIGN: Preterm infants ?1250 g without BPD, BPD and BPD with chronic oxygen dependency were identified from the Southern Alberta Perinatal Follow-up clinic database (1995-2007). Respiratory outcomes at 4, 8, 18 and 36 months corrected age following NICU discharge were examined. Univariate analyses were done. RESULTS: Out of 1563 infants admitted to the NICU, 1212 survived. Complete follow up data at 36 months were available for 1030 (85%) children. Children with BPD with or without chronic oxygen dependency had significantly (P<0.001) lower birth weights and gestational ages, and greater post-natal steroid use, compared with those with no BPD. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen were both significantly higher in the BPD infants with chronic oxygen dependency group compared with the no-BPD group and BPD group. At 36 months, children in the BPD with chronic oxygen dependency group were more likely to use respiratory medications and supplemental oxygen vs the no BPD or the BPD groups. At 4, 8 and 36 months of age, more children in the BPD with chronic oxygen dependency group had post-neonatal chronic lung disease (PNCLD) than children in the other groups, but at 36 months the difference was significant only for the BPD with chronic oxygen dependency vs no-BPD group (P<0.001). CONCLUSIONS: At 36 months, children diagnosed with BPD with chronic oxygen dependency at NICU discharge were more likely to need respiratory medications and supplemental oxygen in the previous 12 months, as compared with no-BPD or BPD groups. They were also more likely to require frequent physician visits and have PNCLD at 3 years, as compared with the no-BPD group. PMID- 25719547 TI - Endogenous endophthalmitis with iris abscess after routine dental cleaning. PMID- 25719549 TI - Bottom-up and middle-down proteomics have comparable accuracies in defining histone post-translational modification relative abundance and stoichiometry. AB - Histone proteins are key components of chromatin. Their N-terminal tails are enriched in combinatorial post-translational modifications (PTMs), which influence gene regulation, DNA repair, and chromosome condensation. Mass spectrometry (MS)-based middle-down proteomics has emerged as a technique to analyze co-occurring PTMs, as it allows for the characterization of intact histone tails (>50 aa) rather than short (<20 aa) peptides analyzed by bottom-up. However, a demonstration of its reliability is still lacking. We compared results obtained with the middle-down and the bottom-up strategy in calculating PTM relative abundance and stoichiometry. Since bottom-up was proven to have biases in peptide signal detection such as uneven ionization efficiency, we performed an external correction using a synthetic peptide library with known peptide relative abundance. Corrected bottom-up data were used as reference. Calculated abundances of single PTMs showed similar deviations from the reference when comparing middle down and uncorrected bottom-up results. Moreover, we show that the two strategies provided similar performance in defining accurate PTM stoichiometry. Collectively, we evidenced that the middle-down strategy is at least equally reliable to bottom-up in quantifying histone PTMs. PMID- 25719550 TI - Swiss physicians' perspectives on advance directives in elective cardiovascular surgery. AB - BACKGROUND: When patients are incompetent, advance directives (AD) can help physicians take crucial medical decisions. However, prevalence remains low. The objective was to investigate physicians' perspectives and attitudes towards AD in order to determine potential targets for improvement. METHODS: Observational study by self-administered questionnaires to general practitioners and specialists potentially involved in the care of patients scheduled for major cardiovascular surgery in a Swiss canton. RESULTS: One-hundred and sixty-four 164 (40%) questionnaires were completed. Men: 116 (71%). Specialties: Internists: 73 (45%); General Practitioners: 50 (31%); Intensivists: 22 (13%); Cardiologists: 18 (12%). Eighty-five percent (138/162) physicians thought that AD were useful and 124/161 (77%) were ready to help patients write AD (to allow them to decide on their fate [115/124 {93%}] and to increase their ease in expressing their wishes [108/124 {87%}]). Men and cardiologists were least likely to do so. Factors associated with lower interest in promoting AD were not logistical but personal such as "the topic can induce fear (21/34 [62%]) or unease (16/34 [47%]), and lack of knowhow (15/34 [44])". 22/160 (14%) physicians had never heard about AD, especially men. CONCLUSION: Not all physicians knew the concept of AD. The majority thought that AD were useful and would help patients write them, in order to respect their autonomy. Personal-related factors such as feelings of inducing fear or harm patients were more important than logistic factors in impeding the promotion of AD. Emphasizing AD during medical school might present a potential target to increase AD prevalence, particularly in the preoperative setting. PMID- 25719551 TI - The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms. AB - BACKGROUND: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation--JAK2 V617F--suggesting a potential role for environmental mutagens. METHODS: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921-1968 and residing in the area between 2000-2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. RESULTS: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3-5 fold increased risk. CONCLUSIONS: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs. PMID- 25719552 TI - Low pH-induced changes of antioxidant enzyme and ATPase activities in the roots of rice (Oryza sativa L.) seedlings. AB - Soil acidification is the main problem in the current rice production. Here, the effects of low pH on the root growth, reactive oxygen species metabolism, plasma membrane functions, and the transcript levels of the related genes were investigated in rice seedlings (Oryza sativa L.) in a hydroponic system at pH 3.5, 4.5, and 5.5. There were two hybrid rice cultivars in this trial, including Yongyou 12 (YY12, a japonica hybrid) and Zhongzheyou 1 (ZZY1, an indica hybrid). Higher H+ activity markedly decreased root length, the proportion of fine roots, and dry matter production, but induced a significant accumulation of hydrogen peroxide (H2O2), and led to serious lipid peroxidation in the roots of the two varieties. The transcript levels of copper/zinc superoxide dismutase 1 (Cu/Zn SOD1), copper/zinc superoxide dismutase 2 (Cu/Zn SOD2), catalase A (CATA) and catalase B (CATB) genes in YY12 and ZZY1 roots were significantly down-regulated after low pH exposure for two weeks. Meanwhile, a significant decrease was observed in the expression of the P-type Ca2+-ATPases in roots at pH 3.5. The activities of antioxidant enzymes (SOD, CAT) and plasma membrane (PM) Ca2+-ATPase in the two varieties were dramatically inhibited by strong rhizosphere acidification. However, the expression levels of ascorbate peroxidase 1 (APX1) and PM H+-ATPase isoform 7 were up-regulated under H+ stress compared with the control. Significantly higher activities of APX and PM H+-ATPase could contribute to the adaptation of rice roots to low pH. PMID- 25719553 TI - Adoptive cell transfer in autoimmune hepatitis. AB - Adoptive cell transfer is an intervention in which autologous immune cells that have been expanded ex vivo are re-introduced to mitigate a pathological process. Tregs, mesenchymal stromal cells, dendritic cells, macrophages and myeloid derived suppressor cells have been transferred in diverse immune-mediated diseases, and Tregs have been the focus of investigations in autoimmune hepatitis. Transferred Tregs have improved histological findings in animal models of autoimmune hepatitis and autoimmune cholangitis. Key challenges relate to discrepant findings among studies, phenotypic instability of the transferred population, uncertain side effects and possible need for staged therapy involving anti-inflammatory drugs. Future investigations must resolve issues about the purification, durability and safety of these cells and consider alternative populations if necessary. PMID- 25719554 TI - Recommendations for individual participant data meta-analyses on work stressors and health outcomes: comments on IPD-Work Consortium papers. AB - The IPD-Work (individual-participant data meta-analysis of working populations) Consortium has published several papers on job strain (the combination of low job control and high job demands) based on Karasek's demand-control model (1) and health-related outcomes including cardiovascular disease (CVD), cancer, obesity, diabetes as well as health-related behaviors, utilizing meta-analyses of a pooled database of study participants from 17 European cohorts. An IPD approach has some advantages over typical meta-analyses, eg, having access to all the data for each individual allows for additional analyses, compared to typical meta-analyses. However, such an approach, like other meta-analyses, is not free from errors and biases (2-6) when it is not conducted appropriately. In our review of the IPD Work Consortium's (hereafter called the Consortium) publications of the last two years, we have identified and pointed out several conceptual and methodological errors, as well as unsubstantiated conclusions and inappropriate recommendations for worksite public health policies (6-15). However, the Consortium has not yet appropriately addressed many of the issues we have raised. Also several major errors and biases underlying the Consortium IPD meta-analysis publications have not been presented in a comprehensive way, nor have they been discussed widely among work stress researchers. We are concerned that the same errors and biases could be repeated in future IPD Consortium meta-analysis publications as well as by other researchers who are interested in meta-analyses on work stressors and health outcomes. It is possible that the inappropriate interpretations in the Consortium publications, which remained uncorrected to date, may have a negative impact on the international efforts of the work stress research community to improve the health of working populations. Recently, Dr. Tores Theorell, a principal investigator of the Consortium, responded in this journal (16) to some of our criticisms on the Consortium papers (17, 18). The purpose of this article is to discuss the methodological and substantive issues that remain to be resolved and how they could be addressed in future analyses. We provide recommendations for future IPD or typical meta-analyses on work stressors and health outcomes. Finally, we discuss the inappropriate conclusions and recommendations in the Consortium publications and provide alternative recommendations, including a comprehensive perspective on worksite intervention studies. PMID- 25719556 TI - Exploring Photoinduced Excited State Evolution in Heterobimetallic Ru(II)-Co(III) Complexes. AB - Quantum chemical calculations provide detailed theoretical information concerning key aspects of photoinduced electron and excitation transfer processes in supramolecular donor-acceptor systems, which are particularly relevant to fundamental charge separation in emerging molecular approaches for solar energy conversion. Here we use density functional theory (DFT) calculations to explore the excited state landscape of heterobimetallic Ru-Co systems with varying degrees of interaction between the two metal centers, unbound, weakly bound, and tightly bound systems. The interplay between structural and electronic factors involved in various excited state relaxation processes is examined through full optimizations of multiple charge/spin states of each of the investigated systems. Low-energy relaxed heterobimetallic states of energy transfer and excitation transfer character are characterized in terms of energy, structure, and electronic properties. These findings support the notion of efficient photoinduced charge separation from a Ru(II)-Co(III) ground state, via initial optical excitation of the Ru-center, to low-energy Ru(III)-Co(II) states. The strongly coupled system has significant involvement of the conjugated bridge, qualitatively distinguishing it from the other two weakly coupled systems. Finally, by constructing potential energy surfaces for the three systems where all charge/spin state combinations are projected onto relevant reaction coordinates, excited state decay pathways are explored. PMID- 25719555 TI - Downregulation of phosphoglycerate dehydrogenase inhibits proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma cells by regulating Bcl 2 and caspase-3. AB - Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis. Previous reports have demonstrated that PHGDH plays an important role in some malignancies. However, the biological role of PHGDH in human cervical adenocarcinoma has not been explored. We examined the expression of PHGDH in 54 cervical adenocarcinoma samples by immunohistochemistry and evaluated the association with clinicopathological parameters and prognosis. We performed shRNA transfection to knock down PHGDH gene expression in HeLa cells. A cell proliferation test, cisplatin cytotoxicity test and apoptosis test examined the HeLa cell line after PHGDH knockdown in vitro. In vivo tumorigenesis was assessed using a mouse xenograft model. Moreover, we examined the effects on Bcl-2 and cleaved caspase-3 expression after knockdown of PHGDH and treatment of cisplatin for 48h by Western blot. In this study, we demonstrated that elevated PHGDH expression was found in cervical adenocarcinoma and was associated with tumor size and prognosis. Knocking down PHGDH in HeLa cells significantly inhibited cell proliferation and increased cisplatin chemotherapy sensitivity. Silencing PHGDH resulted in inhibition of tumorigenesis in vivo. Furthermore, PHGDH knockdown reduced Bcl-2 and increased cleaved caspase-3 expression. Collectively, our study indicates the novel roles of PHGDH in cervical adenocarcinoma and identifies PHGDH as a new anticancer target. PMID- 25719557 TI - The use of a two-tiered testing strategy for the simultaneous detection of small EGFR mutations and EGFR amplification in lung cancer. AB - Lung cancer is the leading cause of cancer-related death worldwide. Recent progress in lung cancer diagnosis and treatment has been achieved due to a better understanding the molecular mechanisms of the disease and the identification of biomarkers that allow more specific cancer treatments. One of the best known examples of personalized therapy is the use of tyrosine kinase inhibitors, such as gefitinib and erlotinib, for the successful treatment of non-small-cell lung cancer patients selected based on the specific EGFR mutations. Therefore, the reliable detection of mutations is critical for the application of appropriate therapy. In this study, we tested a two-tiered mutation detection strategy using real-time PCR assays as a well-validated high-sensitivity method and multiplex ligation-dependent probe amplification (MLPA)-based EGFRmut+ assay as a second tier standard-sensitivity method. One additional advantage of the applied MLPA method is that it allows the simultaneous detection of EGFR mutations and copy number alterations (i.e., amplifications) in EGFR, MET and ERBB2. Our analysis showed high concordance between these two methods. With the use of this two-tier strategy, we reliably determined the frequency of EGFR mutations and EGFR, MET and ERBB2 amplifications in over 200 lung cancer samples. Additionally, taking advantage of simultaneous copy number and small mutation analyses, we showed a very strong correlation between EGFR mutations and EGFR amplifications and a mutual exclusiveness of EGFR mutations/amplifications with MET and ERBB2 amplifications. Our results proved the reliability and usefulness of the two tiered EGFR testing strategy. PMID- 25719558 TI - Minipool caprylic acid fractionation of plasma using disposable equipment: a practical method to enhance immunoglobulin supply in developing countries. AB - BACKGROUND: Immunoglobulin G (IgG) is an essential plasma-derived medicine that is lacking in developing countries. IgG shortages leave immunodeficient patients without treatment, exposing them to devastating recurrent infections from local pathogens. A simple and practical method for producing IgG from normal or convalescent plasma collected in developing countries is needed to provide better, faster access to IgG for patients in need. METHODOLOGY/PRINCIPAL FINDINGS: IgG was purified from 10 consecutive minipools of 20 plasma donations collected in Egypt using single-use equipment. Plasma donations in their collection bags were subjected to 5%-pH5.5 caprylic acid treatment for 90 min at 31 degrees C, and centrifuged to remove the precipitate. Supernatants were pooled, then dialyzed and concentrated using a commercial disposable hemodialyzer. The final preparation was filtered online by gravity, aseptically dispensed into storage transfusion bags, and frozen at <-20 degrees C. The resulting preparation had a mean protein content of 60.5 g/L, 90.2% immunoglobulins, including 83.2% IgG, 12.4% IgA, and 4.4% IgM, and residual albumin. There was fourfold to sixfold enrichment of anti-hepatitis B and anti rubella antibodies. Analyses of aggregates (<3%), prekallicrein (5-7 IU/mL), plasmin (26.3 mU/mL), thrombin (2.5 mU/mL), thrombin-like activity (0.011 U/g), thrombin generation capacity (< 223 nM), and Factor XI (<0.01 U/mL) activity, Factor XI/XIa antigen (2.4 ng/g) endotoxin (<0.5 EU/mL), and general safety test in rats showed the in vitro safety profile. Viral validation revealed >5 logs reduction of HIV, BVDV, and PRV infectivity in less than 15 min of caprylic acid treatment. CONCLUSIONS/SIGNIFICANCE: 90% pure, virally-inactivated immunoglobulins can be prepared from plasma minipools using simple disposable equipment and bag systems. This easy-to-implement process could be used to produce immunoglobulins from local plasma in developing countries to treat immunodeficient patients. It is also relevant for preparing hyperimmune IgG from convalescent plasma during infectious outbreaks such as the current Ebola virus episode. PMID- 25719559 TI - Can Teleneuropsychology Help Meet the Neuropsychological Needs of Western Africans? The Case of Ghana. AB - In Ghana, the services of psychologists, particularly clinical psychologists and neuropsychologists, remain largely inaccessible to a large proportion of those in need. Emphasis has been placed on "physical wellness" even among patients with cognitive and behavioral problems needing psychological attention. The small number of clinical psychologists and neuropsychologists, the deplorable nature of road networks and transport systems, geopolitical factors, and a reliance on the face-to-face method in providing neuropsychological services have further complicated the accessibility problem. One way of expanding and making neuropsychological services available and accessible is through the use of information communication technology to provide these services, and this is often termed teleneuropsychology. Drawing on relevant literature, this article discusses how computerized neurocognitive assessment and videoconferencing could help in rendering clinical neuropsychological services to patients, particularly those in rural, underserved, and disadvantaged areas in Ghana. The article further proposes recommendations on how teleneuropsychology could be made achievable and sustainable in Ghana. PMID- 25719560 TI - The molecular clock of neutral evolution can be accelerated or slowed by asymmetric spatial structure. AB - Over time, a population acquires neutral genetic substitutions as a consequence of random drift. A famous result in population genetics asserts that the rate, K, at which these substitutions accumulate in the population coincides with the mutation rate, u, at which they arise in individuals: K = u. This identity enables genetic sequence data to be used as a "molecular clock" to estimate the timing of evolutionary events. While the molecular clock is known to be perturbed by selection, it is thought that K = u holds very generally for neutral evolution. Here we show that asymmetric spatial population structure can alter the molecular clock rate for neutral mutations, leading to either Ku. Our results apply to a general class of haploid, asexually reproducing, spatially structured populations. Deviations from K = u occur because mutations arise unequally at different sites and have different probabilities of fixation depending on where they arise. If birth rates are uniform across sites, then K <= u. In general, K can take any value between 0 and Nu. Our model can be applied to a variety of population structures. In one example, we investigate the accumulation of genetic mutations in the small intestine. In another application, we analyze over 900 Twitter networks to study the effect of network topology on the fixation of neutral innovations in social evolution. PMID- 25719562 TI - Being discharged from hospice alive: the lived experience of patients and families. AB - BACKGROUND: Approximately 259,000 patients were discharged alive from U.S. hospices in 2010. There is a paucity of research describing the experiences of these individuals and their family members. OBJECTIVE: The study objective was to explore the experiences of adults discharged from a hospice program due to decertification related to ineligibility or extended prognosis, from the perspective of the individual and his or her adult family members. Research questions were, How do participants perceive and describe (1) the experience of being discharged alive from hospice, and (2) their quality of life after a live hospice discharge? METHODS: A transcendental phenomenological design guided this study. Purposive, snowball sampling was used to recruit 12 volunteers, aged 35-92 years, who had experienced live hospice discharge due to decertification. Data collection included open-ended interviews and journals. RESULTS: Findings included two primary themes: suffering "AS..." and the paradox of hospice discharge. These primary themes were supported by 12 subthemes: abandonment, unanswered questions, loss of security, loneliness, uncertainty, anger and frustration, physical decline, bearing exhaustive witness, having and needing support, mixed feelings, not dying fast enough, and hospice equals life. CONCLUSION: Understanding this experience may enhance understanding and aid health care providers to anticipate the unique needs of the hospice population. PMID- 25719561 TI - Is there an association between traumatic dental injury and social capital, binge drinking and socioeconomic indicators among schoolchildren? AB - OBJECTIVES: Traumatic dental injury is defined as trauma caused by forces on a tooth with variable extent and severity. The aim of the present study was to investigate the prevalence of traumatic dental injury and its association with overjet, lip protection, sex, socioeconomic status, social capital and binge drinking among 12-year-old students. RESEARCH DESIGN AND METHOD: A cross sectional study was conducted with a sample of 633 12-year-old students. Data were collected through a clinical exam and self-administered questionnaires. Socioeconomic status was determined based on mother's schooling and household income. The Social Capital Questionnaire for Adolescent Students and Alcohol Use Disorders Identification Test (AUDIT-C) were used to measure social capital and binge drinking, respectively. RESULTS: The prevalence of traumatic dental injury was 29.9% (176/588). Traumatic dental injury was more prevalent among male adolescents (p = 0.010), those with overjet greater than 5 mm (p < 0.001) and those with inadequate lip protection (p < 0.001). In the multiple logistic regression analysis, overjet [OR = 3.80 (95% CI: 2.235-6.466), p < 0.0001], inadequate lip protection [OR = 5.585 (95% CI: 3.654-8.535), p < 0.0001] and binge drinking [OR = 1.93 (95% CI: 1.21-3.06), p = 0.005] remained significantly associated with traumatic dental injury. CONCLUSIONS: The present findings suggest that a high level of total social capital and trust are not associated with TDI in adolescents, unlike binge drinking. The effects of social and behavioral factors on TDI are not well elucidated. Therefore, further research involving other populations and a longitudinal design is recommended. PMID- 25719564 TI - Multiple C-H borylation of phenylhydrazones to boron-nitrogen analogues of benzopentalene. AB - One-pot multiple borylation of phenylhydrazones to a series of novel boron nitrogen analogues of benzopentalene by the cleavage of C-H bonds with PhBBr2 mediated by NEt3 has been established. The resulting BN benzopentalenes feature unique electronic structures and are luminescent both in solution and the solid state. PMID- 25719563 TI - Associations of collectivism with relationship commitment, passion, and mate preferences: opposing roles of parental influence and family allocentrism. AB - In collectivist cultures, families tend to be characterized by respect for parental authority and strong, interdependent ties. Do these aspects of collectivism exert countervailing pressures on mate choices and relationship quality? In the present research, we found that collectivism was associated with greater acceptance of parental influence over mate choice, thereby driving relationship commitment down (Studies 1 and 2), but collectivism was also associated with stronger family ties (referred to as family allocentrism), which drove commitment up (Study 2). Along similar lines, Study 1 found that collectivists' greater acceptance of parental influence on mate choice contributed to their reduced relationship passion, whereas Study 2 found that their greater family allocentrism may have enhanced their passion. Study 2 also revealed that collectivists may have reported a smaller discrepancy between their own preferences for mates high in warmth and trustworthiness and their perception of their parents' preferences for these qualities because of their stronger family allocentrism. However, their higher tolerance of parental influence may have also contributed to a smaller discrepancy in their mate preferences versus their perceptions of their parents' preferences for qualities signifying status and resources. Implications for the roles of collectivism, parental influence, and family allocentrism in relationship quality and mate selection will be discussed. PMID- 25719565 TI - The water footprint of California's energy system, 1990-2012. AB - California's energy and water systems are interconnected and have evolved in recent decades in response to changing conditions and policy goals. For this analysis, we use a water footprint methodology to examine water requirements of energy products consumed in California between 1990 and 2012. We combine energy production, trade, and consumption data with estimates of the blue and green water footprints of energy products. We find that while California's total annual energy consumption increased by just 2.6% during the analysis period, the amount of water required to produce that energy grew by 260%. Nearly all of the increase in California's energy-related water footprint was associated with water use in locations outside of California, where energy products that the state consumes were, and continue to be, produced. We discuss these trends and the implications for California's future energy system as it relates to climate change and expected water management challenges inside and outside the state. Our analysis shows that while California's energy policies have supported climate mitigation efforts, they have increased vulnerability to climate impacts, especially greater hydrologic uncertainty. More integrated analysis and planning are needed to ensure that climate adaptation and mitigation strategies do not work at cross purposes. PMID- 25719566 TI - Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B. AB - The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets. 13 represents an excellent chemical probe for functional studies of the BAZ2 bromodomains in vitro and in vivo. PMID- 25719568 TI - Synthesis of pyrazoles from 1,3-diols via hydrogen transfer catalysis. AB - 1,3-Diols engage in ruthenium-catalyzed hydrogen transfer in the presence of alkyl hydrazines to provide 1,4-disubstituted pyrazoles. Regioselective synthesis of unsymmetrical pyrazoles from beta-hydroxy ketones is also described. PMID- 25719567 TI - Body mass index and mortality among Korean elderly in rural communities: Kangwha Cohort Study. AB - BACKGROUND: The relationship between body mass index (BMI) and mortality may differ by ethnicity, but its exact nature remains unclear among Koreans. The study aim was to prospectively examine the association between BMI and mortality in Korean. METHODS: 6166 residents (2636 men; 3530 women) of rural communities (Kangwha County, Republic of Korea) aged 55 and above were followed up for deaths from 1985-2008. The multivariable-adjusted hazard ratios were calculated using the Cox proportional hazards model. RESULTS: During the 23.8 years of follow-up (an average of 12.5 years in men and 15.7 years in women), 2174 men and 2372 women died. Men with BMI of 21.0-27.4 and women with BMI of 20.0-27.4 had a minimal risk for all-cause mortality. A lower BMI as well as a higher BMI increased the hazard ratio of death. For example, multivariable-adjusted hazard ratios associated with BMI below 16, and with BMI of 27.5 and above, were 2.4 (95% CI = 1.6-3.5) and 1.5 (95% CI = 1.1-1.9) respectively, in men, compared to those with BMI of 23.0-24.9. This reverse J-curve association was maintained among never smokers, and among people with no known chronic diseases. Higher BMI increased vascular mortality, while lower BMI increased deaths from vascular diseases, cancers, and, especially, respiratory diseases. Except for cancers, these associations were generally weaker in women than in men. CONCLUSIONS: A reverse J-curve association between BMI and all-cause mortality may exist. BMI of 21-27.4 (rather than the range suggested by WHO of 18.5-23 for Asians) may be considered a normal range with acceptable risk in Koreans aged 55 and above, and may be used as cut points for interventions. More concern should be given to people with BMI above and below a BMI range with acceptable risk. Further studies are needed to determine ethnicity-specific associations. PMID- 25719569 TI - Cultivating a Culture of Medication Safety in Prelicensure Nursing Students. AB - Safety education in nursing has traditionally focused at the level of individual nurse-patient interactions. Students and novice clinicians lack clinical experience to create context and understand the complexity of the health care system and safety science. Using the Quality and Safety Education for Nurses quality and safety competency as a framework, the objective of this education project was to design comprehensive, engaging, learner-centered, online modules that increase knowledge, skills, and attitudes about medication safety. PMID- 25719570 TI - Interprofessional Education at a Pediatric Optometry Clinic. PMID- 25719571 TI - Implementing Collaborative Learning in Prelicensure Nursing Curricula: Student Perceptions and Learning Outcomes. AB - This study evaluated learning outcomes and student perceptions of collaborative learning in an undergraduate nursing program. Participants in this 3-phase action research study included students enrolled in a traditional and an accelerated nursing program. The number of students who passed the unit examination was not significantly different between the 3 phases. Students had positive and negative perceptions about the use of collaborative learning. PMID- 25719572 TI - Plagiarism Prevention and Detection: A Challenge. PMID- 25719573 TI - Characteristics of paranasal sinus osteoma and treatment outcomes. AB - CONCLUSION: The incidence of paranasal sinus (PNS) osteoma was 6.4%. The most common site of PNS osteoma was the ethmoid sinus. All surgically treated patients underwent endoscopic surgery, and there was no recurrence in any patient. Technical improvements, including an image guidance system, extended the indications for endoscopic surgery for PNS osteomas, especially in the frontal sinus region. OBJECTIVE: The purpose of this study was to investigate the incidence and location of PNS osteomas detected by computed tomography (CT) scan at our hospital, and to describe our experience in the surgical treatment of PNS osteomas. METHODS: This study was performed on 1724 patients undergoing CT scans because of suspected sinus disease between 2004 and 2013. Endoscopic surgery was performed in 34 symptomatic patients. Medical records of the patients were reviewed, and clinical findings and treatment outcomes were investigated. RESULTS: PNS osteomas were detected in 110 patients (6.4%). Triple osteomas were detected in two patients. Double osteomas were detected in seven patients. In total, 121 lesions were identified as PNS osteomas. The ethmoid sinus was the most commonly affected site (57.0%), followed by the frontal sinus (25.6%), frontal recess (9.1%), maxillary sinus (5.0%), olfactory fissure (1.7%), and sphenoid sinus (1.7%) in descending order of frequency. Thirty-three patients were surgically treated for PNS osteomas through a purely endoscopic approach, and one patient with a frontal sinus osteoma underwent combined endoscopic surgery and frontal trephination. Image-guided surgery was performed in nine patients with involvement of the orbit and skull base, including the frontal sinus/recess. There were no major surgical complications and there was no tumor recurrence. PMID- 25719574 TI - Human and murine erythropoiesis. AB - PURPOSE OF REVIEW: Research into the fundamental mechanisms of erythropoiesis has provided critical insights into inherited and acquired disorders of the erythrocyte. Studies of human erythropoiesis have primarily utilized in-vitro systems, whereas murine models have provided insights from in-vivo studies. This report reviews recent insights into human and murine erythropoiesis gained from transcriptome-based analyses. RECENT FINDINGS: The availability of high throughput genomic methodologies has allowed attainment of detailed gene expression data from cells at varying developmental and differentiation stages of erythropoiesis. Transcriptome analyses of human and murine reveal both stage and species-specific similarities and differences across terminal erythroid differentiation. Erythroid-specific long noncoding RNAs exhibit poor sequence conservation between human and mouse. Genome-wide analyses of alternative splicing reveal that complex, dynamic, stage-specific programs of alternative splicing program are utilized during terminal erythroid differentiation. Transcriptome data provide a significant resource for understanding mechanisms of normal and perturbed erythropoiesis. Understanding these processes will provide innovative strategies to detect, diagnose, prevent, and treat hematologic disease. SUMMARY: Understanding the shared and different mechanisms controlling human and murine erythropoiesis will allow investigators to leverage the best model system to provide insights in normal and perturbed erythropoiesis. PMID- 25719575 TI - World Birth Defects Day. Towards a national registry for birth defects in Saudi Arabia. PMID- 25719576 TI - The impact of maternal iron deficiency and iron deficiency anemia on child's health. AB - Iron deficiency anemia is extremely common, particularly in the developing world, reaching a state of global epidemic. Iron deficiency during pregnancy is one of the leading causes of anemia in infants and young children. Many women go through the entire pregnancy without attaining the minimum required intake of iron. This review aims to determine the impact of maternal iron deficiency and iron deficiency anemia on infants and young children. Extensive literature review revealed that iron deficiency is a global nutritional problem affecting up to 52% of pregnant women. Many of these women are symptomatic. Lack of proper weight gain during pregnancy is an important predictor of iron deficiency. PMID- 25719577 TI - Current understanding of the relationship between periodontal and systemic diseases. AB - Periodontal disease (PD) is among the most common infectious diseases affecting humans. While the burden of periodontal disease on oral health has been extensively investigated, a possible specific relationship between the disease and systemic health is a relatively new area of interest. More recently it has been suggested that PD has an etiological role in the development of atherosclerotic cardiovascular disease, diabetes mellitus, and preterm low-birth weight, among others. In this review, we critically evaluate the current knowledge on the relation between PD and systemic diseases overall, and specifically with cardiovascular diseases. The best available evidence today suggests that the infection and inflammatory reaction associated with PD may contribute toward systemic disease. It is critical that dentists and physicians are well informed of the potential general health impact of periodontal disease so that they are in a position to knowledgeably counsel patients. PMID- 25719578 TI - Laparoscopic permanent sigmoid stoma creation through the extraperitoneal route versus transperitoneal route. A meta-analysis of stoma-related complications. AB - OBJECTIVES: To compare laparoscopic extraperitoneal colostomy with transperitoneal colostomy for construction of a permanent stoma by measuring the incidence of parastomal hernia, and other postoperative complications related to colostomy. METHODS: The meta-analysis was carried out in the General Surgery Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China in 2014. A literature search of Medline, EMBASE, Cochrane database, and the Chinese Biomedical Literature Database (CBM) from the years 1990 to 2014 was performed. The literature searches were carried out using medical subject headings and free-text words: extraperitoneal colostomy, transperitoneal colostomy, laparoscopic extraperitoneal colostomy, rectal cancer, laparoscopic abdominoperineal resection, parastomal hernia, permanent stoma, and colostomy-related complications. Two different reviewers carried out the search and evaluated studies independently. RESULTS: One randomized controlled trial and 6 retrospective studies were included. A total of 378 patients (209 extraperitoneal colostomy and 169 transperitoneal colostomy) were identified. Our analysis showed that there was a significantly lower rate of parastomal hernia (odds ratio 0.10; 95% confidence interval 0.03-0.29, p<0.0001) in the extraperitoneal colostomy group. However, the other stoma-related complications were not significantly different between the 2 groups. CONCLUSION: Colostomy construction via the extraperitoneal route using a laparoscopic approach can largely reduce the incidence of parastomal hernia. Laparoscopic permanent sigmoid stoma creation through the extraperitoneal route should be the first choice after laparoscopic abdominoperineal resection. PMID- 25719579 TI - Efficacy of Xuebijing for coagulopathy in patients with sepsis. AB - OBJECTIVES: To provide evidence of the clinical efficacy of Xuebijing (XBJ) on blood coagulation in patients with sepsis. METHODS: We conducted this meta analysis in The People's Hospital of Liaoning Province, Shenyang, China between December 2013 and May 2014. We searched a number of databases for relevant randomized controlled trials (RCTs) published before December 2013 using the keywords 'Xuebijing', 'coagulation' and 'sepsis'. Statistical analysis was performed with Review Manager 5.2 from the Cochrane Collaboration. RESULTS: Fourteen RCTs involving 867 patients were included. Compared with placebo, XBJ injection significantly improved platelets (mean differences [MD] = 42.14, 95% confidence interval [CI]: 22.42 - 61.86, p<0.00001), shortened the activated partial thromboplastin time (MD = -4.81, 95% CI: -7.86 - [-1.76], p=0.002), shortened the prothrombin time (MD = -2.33, 95% CI: -4.15 - [-0.51], p=0.01), and shortened the thrombin time (MD = -2.05, 95% CI: -3.52 - [-0.58], p=0.006). However, no significant difference was found between the XBJ injection and the placebo group for fibrinogen (MD = 0.21, 95% CI: -0.38 - 0.81, p=0.48). CONCLUSION: Xuebijing injection may improve coagulopathy in patients with sepsis. High-quality and large sample clinical trials are needed for confirmation. PMID- 25719580 TI - Prognostic significance and clinicopathological features of hypoxic inducible factor-2alpha expression in hepatocellular carcinoma. AB - OBJECTIVES: To assess the association between hypoxic inducible factor-2alpha (HIF-2alpha) and hepatocellular carcinoma (HCC) by meta-analysis. METHODS: This study was carried out at Anhui Province Hospital, Hefei, Anhui, China in February 2014. We searched various databases for studies published in English or Chinese up to February 28, 2014. The hazard ratio for overall survival and analyzed odds ratio were combined to evaluate the clinicopathological features of HIF-2alpha expression in HCC. RESULTS: A total of 7 eligible studies comprising 1066 patients with HCC were identified after our full assessment according to inclusion criteria. All of the patients came from China. The results indicated that the association between HIF-2alpha expression and prognostic values in HCC was inconspicuous, while the expression of HIF-2alpha was significantly associated with capsule infiltration, vein invasion, and histological grade. CONCLUSION: Expression of HIF-2alpha was associated with invasion and metastasis in HCC, but did not have a distinct significance in prognosis, according to the limited evidence. However, high quality, large sample size, and controlled trials are required. PMID- 25719581 TI - Angiotensin-converting enzyme gene insertion/deletion polymorphism in Saudi patients with rheumatic heart disease. AB - OBJECTIVES: To investigate the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and rheumatic heart disease (RHD) in Saudi patients. METHODS: A case-control study was conducted in Saudi RHD patients. Genomic DNA was isolated from 99 RHD patients attending the Pediatric Cardiology Clinic at the Maternity and Children Hospital, Al-Madinah, Saudi Arabia from March 2013 to June 2014, and from 145 age- and gender-matched controls. Patient clinical records were reviewed to report major and minor modified Jones' criteria for diagnosis. The diagnosis was confirmed by echocardiography. The ACE I/D polymorphism was identified by polymerase chain reaction. RESULTS: A significant difference in ACE D allele carriage (DD+ID) distribution between RHD cases and controls was identified (p=0.02, odds ratio = 3.6, 95% confidence interval: 1.2-10.8). The D allele carriage was significantly associated with development of mitral valve lesions alone (p=0.03). CONCLUSION: The ACE I/D polymorphism is associated with an increased risk of RHD in the Saudi population. Further studies are needed to confirm our findings and to understand the molecular mechanisms underlying this association. PMID- 25719582 TI - Prevalence, clinical characteristics, and predictors of obesity hypoventilation syndrome in a large sample of Saudi patients with obstructive sleep apnea. AB - OBJECTIVES: To assess the prevalence, clinical characteristics, and predictors of obesity hypoventilation syndrome (OHS) in a large sample of Saudi patients with obstructive sleep apnea (OSA). METHODS: This prospective observational study consisted of 1693 patients who were diagnosed to have sleep-disordered breathing using type I attended polysomnography (PSG) between January 2002 and December 2012 in the University Sleep Disorders Center (USDC) at King Saud University Hospital, Riyadh, Kingdom of Saudi Arabia. RESULTS: Out of 1693 OSA patients, OHS was identified in 144 (8.5%) (women 66.7%). Compared with the pure OSA patients, the OHS patients were significantly older (57.4+/-13.4 years versus 46.8+/-13.7 years), had a higher body mass index (44.6+/-10.8 versus 35.7+/-9.2 kg/m2), a higher daytime partial pressure of carbon dioxide (PaCO2) (56.5+/-12.7 versus 41.6+/-6.7 mmHg), a longer duration of nocturnal oxygen saturation (nSaO2) <90% (71.0+/-34.3 versus 10.5+/-20.5 minutes), and a higher apnea hypopnea index (68.2+/-47.1 versus 46.5+/-34.1 events/hour). A multivariate logistic regression analysis showed that serum bicarbonate (odds ratio [OR]=1.17, p=0.0001, confidence interval [CI]=1.10-1.25), and duration of nSaO2 <90% (OR=1.05, p=0.0001, CI=1.04-1.06) were predictors of OHS. CONCLUSION: Obesity hypoventilation syndrome is common among Saudi OSA patients referred to the Sleep Disorders Center. Serum bicarbonate and duration of nSaO2 <90% are independent predictors of OHS among patients with OSA. PMID- 25719583 TI - Comparison of outcomes after bilateral simultaneous total knee arthroplasty using posterior-substituting versus cruciate-retaining prostheses. AB - OBJECTIVES: To compare the effectiveness and safety of posterior-substituting (PS) with cruciate-retaining (CR) total knee prostheses after the elimination of confounding variables. METHODS: Between January 2008 and June 2012, a total of 32 subjects who had bilateral arthritis of the knees agreed to have one knee replaced with a PS total knee design and the other with a CR design. In addition to postoperative complications, clinical outcomes (Knee Society Score, Range of Motion, Western Ontario and McMaster Universities Arthritis Index, as well as radiographic findings) were evaluated preoperatively, and at 2-week, 3-month, 12 month, and 24-month follow-up. RESULTS: At the 24-month follow-up interval, no benefit of CR design was observed over PS design regarding functional assessment, patient satisfaction, or postoperative complication. However, the PS total knee design did display statistically significant improvements in range of motion as compared with the CR design. CONCLUSION: While comparable regarding supporting good clinical outcomes, the PS design does appear to support significantly improved postoperative range of motion when compared with the CR design. PMID- 25719584 TI - Effect of tactile kinesthetic stimulation on preterm infants' weight and length of hospital stay in Khartoum, Sudan. AB - OBJECTIVES: To determine the effect of 7 days tactile kinesthetic stimulation (TKS) on preterm infants' weight and hospital stays in Khartoum State, Sudan. METHODS: This is a quasi-experimental study, it was conducted in 4 hospitals between January and June 2013, Khartoum, Sudan, and it involved 160 preterm infants randomly assigned into the case and control groups (80 neonates in each). Preterm infants in the control group received routine nursing care, while preterm infants in the case group received TKS for 3 periods, 15 minute per day for 7 constitutive days, in addition to routine care. Data was collected using a structured self-designed and validated questionnaire, checklist, and weighting scale. Weight gain and hospital stay were compared between the 2 groups. RESULTS: Over the constitutive 7 days, the case group gained significantly more weight (1071 gm versus 1104 gm) compared with the control group (1077 gm versus 1084 gm) (1084.55+/-90.74) who gained only 6.9 gm within the same 7 days without TKS treatment. The mean difference in weight gain was significant (p=0.00). The hospital stay for preterm infants in the case group was significantly shorter (18.05+/-9.36 versus 25.47+/-10.25; p=0.00). CONCLUSION: Tactile kinesthetic stimulation for preterm infants has a beneficial effect on weight gain and earlier discharge from hospital, which are sequentially efficient and cost effective. PMID- 25719585 TI - Fibrinolytic changes in pregnant women on highly active antiretroviral therapy. AB - OBJECTIVES: To report on the changes in fibrinolytic activity in human immunodeficiency virus (HIV) infected pregnant women who are undergoing highly active antiretroviral therapy (HAART). METHODS: Blood was collected from 50 HIV positive women on HAART (test subjects), and 50 HIV positive women not on HAART (controls). These women were attending the prevention of mother to child clinic (PMTCT) of the University of Benin Teaching Hospital, Benin City, Nigeria from January to June 2014. Standard manual techniques were used to estimate plasma fibrinogen concentration (PFC), euglobulin lysis time (ELT), packed cell volume (PCV), and plasma viscosity (PV). RESULTS: The mean +/- standard error of mean (SEM) of PFC was 4.02+/-0.13 g/l and ELT from the test subjects was 378+/-15 mins was significantly higher (p<0.05) compared with the control subjects (PFC 3.46+/ 0.12 g/l and ELT 267+/-9.0 mins). The PCV or hematocrit values in the test subject was 29.1+/-0.38%, which was significantly lower (p<0.05) compared with the control subject (31.3+/-0.43%). The PV in the test subject was 1.76+/-0.02 mPa/s, while the control subjects was higher (1.73+/-0.02 mPa/s). This increase was not statistically significant (p>0.05). There were differences in the various parameters investigated when the various trimesters were compared. These differences did not, however, follow a particular pattern. CONCLUSION: Highly active antiretroviral therapy can cause changes in fibrinolytic activity that may predispose pregnant women to hyperfibrinogenemia and anemia. PMID- 25719586 TI - Restless legs syndrome among Saudi end-stage renal disease patients on hemodialysis. AB - OBJECTIVES: To determine the prevalence of restless legs syndrome (RLS) in Saudi patients with end-stage renal disease (ESRD) on hemodialysis. METHODS: A cross sectional study was carried out in 3 hemodialysis centers in Jeddah, Saudi Arabia, between June 2012 and September 2013. All patients were individually interviewed and data was collected on the following: demographic features, medical history, laboratory test, the International Restless Legs Syndrome Study Group questionnaire, Epworth Sleepiness Scale (ESS), and Berlin Questionnaire. RESULTS: Three hundred and fifty-five patients were recruited. The prevalence of RLS among ESRD patients was 19.4%, with most patients having moderate to severe disease. The RLS was significantly associated with obstructive sleep apnea (p<0.0001) and excessive daytime sleepiness based on the ESS (p=0.009). The RLS showed no correlation with hemodialysis adequacy, chronicity, frequency per week, and hemodialysis duration per session; however, there was a weak negative relation between adequacy of hemodialysis and RLS severity. None of the comorbidities showed any association with RLS. The odds of developing RLS increased significantly with an increasing body mass index (p=0.001). Administration of aspirin (p=0.037) and anticoagulants (p=0.035) were also associated with increased risk of RLS. CONCLUSION: Restless legs syndrome is common in ESRD patients on hemodialysis, and it is an important source of sleep disruption. In addition to body mass index, Aspirin and anticoagulants may be important risk factors. PMID- 25719587 TI - Combined effect of a mixture of tetracycline, acid, and detergent, and nisin against Enterococcus faecalis and Actinomyces viscosus biofilms. AB - OBJECTIVES: To evaluate the combined effect of a mixture of tetracycline, acid, and detergent (MTAD) and Nisin against Enterococcus faecalis (E. faecalis) and Actinomyces viscosus (A. viscosus) biofilms. METHODS: This study was conducted between June and December 2013 in collaboration with Dental Caries Research Chair, College of Dentistry, King Saud University, Riyadh, Saudi Arabia. Single species biofilms (n=9/species/observation period) were generated on membrane filter discs and subjected to 5, 10, or 15 minute incubation with MTADN (MTAD with 3% Nisin), 5.25% sodium hypochlorite (NaOCl), or normal saline. The colony forming units were counted using the Dark field colony counter. RESULTS: A 100% bactericidal effect of 5.25% NaOCl was noted during the 3 observation periods; a significant reduction (p=0.000) in mean survival rates of E. faecalis (77.3+13.6) and A. viscosus (39.6+12.6) was noted after 5 minutes exposure to MTADN compared with normal saline (78000000+5291503) declining to almost no growth after 10 and 15 minutes. The survival rates of the E. faecalis and A. viscosus biofilm were no different after treatment with MTADN and 5.25% NaOCl at the 3 observation periods (p=1.000). CONCLUSION: A combination of MTAD and Nisin was as effective as NaOCl against E. faecalis and A. viscosus biofilms. PMID- 25719588 TI - Frequency and associated risk factors of recurrent diabetic ketoacidosis among Saudi adolescents with type 1 diabetes mellitus. AB - OBJECTIVES: To explore the frequency and associated risk factors of recurrent diabetic ketoacidosis (RDKA) among Saudi adolescents with type 1 diabetes mellitus (T1DM). METHODS: A cross-sectional study was conducted among 103 T1DM adolescents (aged 13-18 years, 57 males) who were hospitalized for diabetic ketoacidosis (DKA) between January 2013 and May 2014 at Prince Sultan Military Medical City (PSMMC), Riyadh, Kingdom of Saudi Arabia. The respondents were purposively, conveniently selected, and interviewed using a structured Arabic questionnaire including clinical information and demographics. RESULTS: Fifty-six participants had experienced one episode of DKA, 41 had 2 episodes, and 6 had >=3 episodes. Compared with adolescents who had hemoglobin A1c (HbA1c) <=9, mean difference in RDKA was found among adolescents with >9 HbA1c. Similarly, adolescents who stopped insulin and those with lipodystrophy at the injection site had a higher frequency of RDKA. Discontinuing insulin (67%) was the major reason for RDKA followed by infection (31%). Among adolescents who discontinued insulin treatment, 31 (46.3%) gave no reason for stopping, 25 (37.3%) reported feeling sick, 7 (10.4%) gave a combination of reasons, and 4 (6%) reported a lack of supplies or other reasons. Regression analysis revealed that a higher HbA1c level and the presence of lipodystrophy were independent risk factors for RDKA. CONCLUSION: The frequency of RDKA was significantly greater in the T1DM adolescents with a higher HbA1c level, lipodystrophy, and those who had discontinued insulin treatment. Comprehensive multidisciplinary diabetes education should be offered to control modifiable risk factors in these patients. PMID- 25719589 TI - Adherence to the American Diabetes Association standards of care among patients with type 2 diabetes in primary care in Saudi Arabia. AB - OBJECTIVES: To assess adherence to 11 American Diabetes Association (ADA) standards of diabetic care. METHODS: We conducted this one-year historical prospective study between October 2010 and September 2011 on 450 adult type 2 diabetes patients in a primary care center in Saudi Arabia. We used the definitions of the 2010 ADA standards of diabetic care processes and targets. RESULTS: Four-hundred and fifty medical files were valid. The adherence to ADA process standards of measurement of glycated hemoglobin (HbA1c) was 68.7%, 92.9% for blood pressure, and 80.2% for serum lipids. Screening was lowest for nephropathy (35.6%), and highest for diabetic foot (72%). Adherence to medications ranged between 82.2% for antiplatelets, and 92.4% for dyslipidemia. For outcome standards, 24.2% of the patients had an HbA1c <7%, and 32.2% had controlled blood pressure (<130/80 mm Hg); and 58.5% achieved targeted low density lipoproteins (LDL). Only 7.2% had glycemic control in addition to controlled blood pressure and targeted LDL level. An increasing trend of patients achieving glycemic control (<7%) was shown throughout follow-up (p=0.003). CONCLUSIONS: We found suboptimal adherence with many ADA standards of diabetic care among patients with type 2 diabetes treated at a primary care center in Saudi Arabia. The achievement of outcome standards, either singly or combined, is lower than the adherence rates. However, the figures show improvement in adherence during the follow-up period. PMID- 25719590 TI - Large eruption complex odontome in a Saudi patient. AB - Odontomas are odontogenic tumors formed of various dental tissues. They are classified into: central odontomas that are common, eruption odontomas that are rare with only 23 cases reported to date, and peripheral odontomas that are also rare. We present a case of a large complex eruption odontome in a 24-year-old Saudi male. PMID- 25719591 TI - Fanconi anemia associated with moyamoya disease in Saudi Arabia. AB - We report a 10-year-old Saudi girl who has Fanconi anemia (FA) and was admitted due to acute hemiplegia, of the right side. She had a previous attack of left side hemiplegia that resolved spontaneously. The brain magnetic resonance angiography showed a cerebrovascular pattern of moyamoya disease. She underwent partially matched related donor stem cell transplantation (SCT), but unfortunately died 3 months later with post SCT complications. The association of moyamoya disease with FA is uncommon, and is rarely reported in the literature. Although this condition may be acquired, it is considered a truly congenital defect in FA, and to identify the etiology of this association furthermore genetic mutation analysis is needed. PMID- 25719592 TI - A solitary fibrous tumor of the upper limb. AB - Solitary fibrous tumors (SFT) of the upper limb are extremely rare, and we report this tumor in the arm of a 30-year-old male. He is presented with a 22 cm painless mass. Complete surgical excision was performed. The histological diagnosis of SFT was based on the presence of ectatic blood vessels and positive staining for CD34 and vimentin. He remains disease-free at the 3-year follow-up interval. The report aims to increase the awareness of the criteria for the histological diagnosis of SFT, as well as the principles of their surgical excision and follow-up. PMID- 25719593 TI - Type-B lactic acidosis associated with progressive multiple myeloma. AB - We report a 64-year-old lady with stage II, Immunoglobulin-G lambda multiple myeloma (MM) (standard risk), who presented with type-B lactic acidosis (LA), and multi-organ dysfunction associating myeloma progression, and ending in imminent death. In the context of literature review of all previously reported similar cases, this report highlights and discusses the association of type-B LA and MM (especially progressive disease), and also emphasizes the poor outcome. Early recognition of this condition with intensive supportive care, and treatment of multiple myeloma may improve outcomes. PMID- 25719594 TI - Euthyroid sick syndrome in children with diabetic ketoacidosis. AB - OBJECTIVES: To investigate characteristics of euthyroid sick syndrome (ESS) in children with diabetic ketoacidosis (DKA). METHODS: This retrospective study was carried out between May 2010 and April 2013 at the Pediatric Department of Shandong Provincial Hospital, Shandong University, Shandong, China. Diabetic ketoacidosis children were divided into 2 groups: euthyroidism (group one, n=30) and ESS (group 2, n=40). C-peptide, glycosylated hemoglobin (HbA1c), bicarbonate, anion gap (AG), free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) levels were measured before and after 7 days of insulin treatment. Daily blood glucose (BG) profiles were recorded. RESULTS: Glycosylated hemoglobin, AG, the mean daily BG, and fasting blood glucose levels were higher, and bicarbonate, FT3, FT4, and TSH levels were lower in group 2 than in group one (all p<0.05). Free triiodothyronine (r=-0.593, p<0.001) and FT4 (r=-0.402, p=0.001) were negatively correlated with HbA1c. Free triiodothyronine (r=-0.438, p<0.001) and FT4 (r=-0.505, p<0.001) were negatively correlated with AG, and FT3 (r=0.503, p<0.001) and FT4 (r=0.448, p<0.001) were positively correlated with bicarbonate. CONCLUSION: Diabetic ketoacidosis children with ESS have poor diabetic control. Free thyroid hormones are associated with the severity of DKA. PMID- 25719595 TI - Molecular investigation of mixed malaria infections in southwest Saudi Arabia. AB - OBJECTIVE: To investigate the incidence of mixed-species (MS) malaria infection, and compare the results with microscopically confirmed cases of malaria. METHODS: During 2010, blood spots collected from 371 clinically suspected cases of malaria were microscopically examined in a cross-sectional study. The DNA was extracted from the samples, and a nested polymerase chain reaction (PCR) was performed. The results obtained by the 2 methods were compared. RESULTS: From the microscopic analysis it was determined that 369 samples (99.5%) were positive for Plasmodium falciparum (P. falciparum) and 2 were Plasmodium vivax (P. vivax) mono infections. There were no mixed malaria infections. The PCR analysis, however, showed that in 7 cases (1.9%) the infection was caused by MS malaria comprising of P. falciparum and P. vivax, 2 of these representing the cases that were microscopically diagnosed as P. vivax mono-infections. All cases were negative for Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. CONCLUSION: Mixed malaria infections are currently overlooked when using microscopy. The PCR assays are essential complementary techniques that should be used with microscopic examination of blood smears. PMID- 25719596 TI - Colonic bezoar caused by cracked-wheat consumption. PMID- 25719597 TI - Knowledge of Saudi female university students regarding cervical cancer and acceptance of the human papilloma virus. PMID- 25719598 TI - Thermally induced conformational transitions in nascent branched amphiphilic peptide capsules. AB - Branched amphiphilic peptide capsules (BAPCs) are biocompatible, bilayer delimited polycationic nanospheres that spontaneously form at room temperature through the coassembly of two amphiphilic branched peptides: bis(FLIVI)-K-K4 and bis(FLIVIGSII)-K-K4. BAPCs are readily taken up by cells in culture, where they escape and/or evade the endocytic pathway and accumulate in the perinuclear region, persisting there without apparent degradation or extravasation. Drugs, small proteins, and solutes as well as alpha particle emitting radionuclides are stably encapsulated for extended periods of time. BAPC formation at room temperature proceeds via a fusogenic process and after 48 h a range of BAPCs sizes are observed, from 50 nm to a few microns in diameter. It was previously reported that cooling BAPCs from 25 to 4 degrees C and then back to 25 degrees C eliminated their fusogenic property. In this report, biophysical techniques reveal that BAPCs undergo thermosensitive conformational transitions as a function of both time and temperature and that the properties of BAPCs vary based on the temperature of assembly. The solvent dissociation properties of BAPCs were studied as well as the contributions of specific amino acid residues to the observed conformations. The roles of the potential stabilizing forces present within the bilayer that bestow the unusal stability of the BAPCs are discussed. Ultimately this study presents revised assembly protocols for preparing BAPCs with discrete sizes and solvent-induced extravasation properties. PMID- 25719600 TI - Erratum. PMID- 25719599 TI - Grape seed proanthocyanidins ameliorates cadmium-induced renal injury and oxidative stress in experimental rats through the up-regulation of nuclear related factor 2 and antioxidant responsive elements. AB - Cadmium (Cd) preferentially accumulates in the kidney, the major target for Cd related toxicity. Cd-induced reactive oxygen species (ROS) have been considered crucial mediators for renal injury. The biologically significant ionic form of cadmium (Cd(+)) binds to many bio-molecules, and these interactions underlie the toxicity mechanisms of Cd. The present study was hypothesized to explore the protective effect of grape seed proanthocyanidins (GSP) on Cd-induced renal toxicity and to elucidate the potential mechanism. Male Wistar rats were treated with Cd as cadmium chloride (CdCl2, 5 mg.kg(-1) bw, orally) and orally pre administered with GSP (100 mg.kg(-1) bw) 90 min before Cd intoxication for 4 weeks to evaluate renal damage of Cd and antioxidant potential of GSP. Serum renal function parameters (blood urea nitrogen and creatinine) levels in serum and urine, renal oxidative stress (lipid peroxidation, protein carbonylation, enzymatic, and non-enzymatic antioxidants), inflammatory (NF-kappaB p65, NO, TNF alpha, IL-6), apoptotic (caspase-3, caspase-9, Bax, Bcl-2), membrane bound ATPases, and Nrf2 (HO-1, keap1, gamma-GCS, and MU-GST) markers were evaluated in Cd-treated rats. Pretreatment with GSP revealed a significant improvement in renal oxidative stress markers in kidneys of Cd-treated rats. In addition, GSP treatment decreases the amount of iNOS, NF-kappaB, TNF-alpha, caspase-3, and Bax and increases the levels Bcl-2 protein expression. Similarly, mRNA and protein analyses substantiated that GSP treatment notably normalizes the renal expression of Nrf2/Keap1 and its downstream regulatory proteins in the Cd-treated rats. Histopathological and ultra-structural observations also demonstrated that GSP effectively protects the kidney from Cd-induced oxidative damage. These findings suggest that GSP ameliorates renal dysfunction and oxidative stress through the activation of Nrf2 pathway in Cd-intoxicated rats. PMID- 25719601 TI - Measuring biomass and carbon stock in resprouting woody plants. AB - Resprouting multi-stemmed woody plants form an important component of the woody vegetation in many ecosystems, but a clear methodology for reliable measurement of their size and quick, non-destructive estimation of their woody biomass and carbon stock is lacking. Our goal was to find a minimum number of sprouts, i.e., the most easily obtainable, and sprout parameters that should be measured for accurate sprout biomass and carbon stock estimates. Using data for 5 common temperate woody species, we modelled carbon stock and sprout biomass as a function of an increasing number of sprouts in an interaction with different sprout parameters. The mean basal diameter of only two to five of the thickest sprouts and the basal diameter and DBH of the thickest sprouts per stump proved to be accurate estimators for the total sprout biomass of the individual resprouters and the populations of resprouters, respectively. Carbon stock estimates were strongly correlated with biomass estimates, but relative carbon content varied among species. Our study demonstrated that the size of the resprouters can be easily measured, and their biomass and carbon stock estimated; therefore, resprouters can be simply incorporated into studies of woody vegetation. PMID- 25719603 TI - 'There's only one enabler; come up, help us': staff perspectives of barriers and enablers to continuous quality improvement in Aboriginal primary health-care settings in South Australia. AB - This paper presents the findings from a qualitative study, which sought to investigate the barriers and enablers to implementation of a continuous quality improvement (CQI) program by health-care professionals in Aboriginal primary health-care services in South Australia. Eighteen semi-structured interviews across 11 participating services were conducted alongside CQI implementation activities. Multiple barriers exist, from staff perspectives, which can be categorised according to different levels of the primary health-care system. At the macro level, barriers related to resource constraints (workforce issues) and access to project support (CQI coordinator). At the meso level, barriers related to senior level management and leadership for quality improvement and the level of organisational readiness. At the micro level, knowledge and attitudes of staff (such as resistance to change; lack of awareness of CQI) and lack of team tenure were cited as the main barriers to implementation. Staff identified that successful and sustained implementation of CQI requires both organisational systems and individual behaviour change. Improvements through continuing regional level collaborations and using a systems approach to develop an integrated regional level CQI framework, which includes building organisational and clinic team CQI capacity at the health centre level, are recommended. Ideally, this should be supported at the broader national level with dedicated funding. PMID- 25719602 TI - Characterization of the interaction between Rfa1 and Rad24 in Saccharomyces cerevisiae. AB - Maintaining the integrity of the genome requires the high fidelity duplication of the genome and the ability of the cell to recognize and repair DNA lesions. The heterotrimeric single stranded DNA (ssDNA) binding complex Replication Protein A (RPA) is central to multiple DNA processes, which are coordinated by RPA through its ssDNA binding function and through multiple protein-protein interactions. Many RPA interacting proteins have been reported through large genetic and physical screens; however, the number of interactions that have been further characterized is limited. To gain a better understanding of how RPA functions in DNA replication, repair, and cell cycle regulation and to identify other potential functions of RPA, a yeast two hybrid screen was performed using the yeast 70 kDa subunit, Replication Factor A1 (Rfa1), as a bait protein. Analysis of 136 interaction candidates resulted in the identification of 37 potential interacting partners, including the cell cycle regulatory protein and DNA damage clamp loader Rad24. The Rfa1-Rad24 interaction is not dependent on ssDNA binding. However, this interaction appears affected by DNA damage. The regions of both Rfa1 and Rad24 important for this interaction were identified, and the region of Rad24 identified is distinct from the region reported to be important for its interaction with Rfc2 5. This suggests that Rad24-Rfc2-5 (Rad24-RFC) recruitment to DNA damage substrates by RPA occurs, at least partially, through an interaction between the N terminus of Rfa1 and the C terminus of Rad24. The predicted structure and location of the Rad24 C-terminus is consistent with a model in which RPA interacts with a damage substrate, loads Rad24-RFC at the 5' junction, and then releases the Rad24-RFC complex to allow for proper loading and function of the DNA damage clamp. PMID- 25719604 TI - Direct asymmetric amination of alpha-branched cyclic ketones catalyzed by a chiral phosphoric acid. AB - Here we report the direct asymmetric amination of alpha-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantioenriched alpha-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical. PMID- 25719605 TI - Susceptibility-weighted angiography visualizes hypoxia in cerebral veins. AB - OBJECTIVES: The objective of this study was to evaluate the influence of short- and long-term hypoxia on the depiction of cerebral veins in the susceptibility weighted angiography (SWAN) sequence. MATERIALS AND METHODS: In the context of a study on brain adaptation mechanisms to hypoxia, 16 healthy men (aged 20-28 years) were studied through magnetic resonance imaging (MRI) under room air conditions, short-term-hypoxia (7 minutes before and during the MRI scan), and long-term hypoxia (8.5 hours before and during the MRI scan). Oxygen saturation was continuously measured using a finger-mounted pulse oximeter. Two independent blinded readers compared the 3 scans of each participant and graded the SWAN source images and minimum intensity projections according to the size, number, and signal intensity of the cerebral veins. Signal intensities of deep cerebral veins were measured, and signal intensity proportions of deep cerebral veins to different parenchymal brain regions were calculated. RESULTS: Nine subjects could be included in the study. In all of them, both readers correctly distinguished the 2 hypoxia scans from the baseline scan, grading the SWAN images acquired under hypoxic conditions as visualizing cerebral veins more prominently. Signal intensities of the deep cerebral veins and signal intensity proportions were significantly lower in the hypoxia scans. No significant differences between short-term and long-term hypoxia were found on visual inspections and signal intensity measurements. This correlated with the results of the pulse oximetry: mean O2 saturation values were 97.9% +/- 1.2% (baseline), 84.1% +/- 3.8% (short term hypoxia), and 82.8% +/- 4.4% (long-term hypoxia), respectively. CONCLUSIONS: Hypoxia leads to visible and measurable changes in cerebral veins as depicted through SWAN. Possible clinical implications of this finding include stroke and tumor imaging and need further investigation. PMID- 25719606 TI - Clinical applications of correlational vestibular autorotation test. AB - CONCLUSION: The correlational vestibular autorotation test (VAT) system has the advantages of good test-retest reliability and calibrations of absolute degrees of eye movement are unnecessary when acquiring a cross correlation coefficient (CCC). The approach is able to efficiently detect peripheral vestibulopathies. OBJECTIVE: A VAT has some drawbacks including poor test-retest reliability and slippage of sensor. This study aimed to develop a correlational VAT system and to evaluate the reliability and applicability of this system. METHODS: Twenty healthy participants and 10 vertiginous patients were enrolled. Vertical and horizontal autorotations from 0 to 3 Hz with either closed or open eyes were performed. A small sensor and a wireless transmission technique were used to acquire the electro-ocular graph and head velocity signals. The two signals were analyzed using CCCs to assess the functioning of the vestibular ocular reflex (VOR). RESULTS: The results showed a significantly greater CCC for open-eye versus closed-eye of head autorotations. The CCCs also increased significantly with head rotational frequencies. Moreover, the CCCs significantly correlated with the VOR gains at autorotation frequencies >=1.0 Hz. The test-retest reliability was good (intraclass correlation coefficients >=0.85). The vertiginous participants had significantly lower individual CCCs and overall average CCC than age- and-gender matched controls. PMID- 25719607 TI - Structurally Complex Organization of Repetitive DNAs in the Genome of Cobia (Rachycentron canadum). AB - Repetitive DNAs comprise the largest fraction of the eukaryotic genome. They include microsatellites or simple sequence repeats (SSRs), which play an important role in the chromosome differentiation among fishes. Rachycentron canadum is the only representative of the family Rachycentridae. This species has been focused on several multidisciplinary studies in view of its important potential for marine fish farming. In the present study, distinct classes of repetitive DNAs, with emphasis on SSRs, were mapped in the chromosomes of this species to improve the knowledge of its genome organization. Microsatellites exhibited a diversified distribution, both dispersed in euchromatin and clustered in the heterochromatin. The multilocus location of SSRs strengthened the heterochromatin heterogeneity in this species, as suggested by some previous studies. The colocalization of SSRs with retrotransposons and transposons pointed to a close evolutionary relationship between these repetitive sequences. A number of heterochromatic regions highlighted a greater complex organization than previously supposed, harboring a diversity of repetitive elements. In this sense, there was also evidence of colocalization of active genetic regions and different classes of repetitive DNAs in a common heterochromatic region, which offers a potential opportunity for further researches regarding the interaction of these distinct fractions in fish genomes. PMID- 25719608 TI - Research activity and the association with mortality. AB - INTRODUCTION: The aims of this study were to describe the key features of acute NHS Trusts with different levels of research activity and to investigate associations between research activity and clinical outcomes. METHODS: National Institute for Health Research (NIHR) Comprehensive Clinical Research Network (CCRN) funding and number of patients recruited to NIHR Clinical Research Network (CRN) portfolio studies for each NHS Trusts were used as markers of research activity. Patient-level data for adult non-elective admissions were extracted from the English Hospital Episode Statistics (2005-10). Risk-adjusted mortality associations between Trust structures, research activity and, clinical outcomes were investigated. RESULTS: Low mortality Trusts received greater levels of funding and recruited more patients adjusted for size of Trust (n = 35, 2,349 L/bed [95% CI 1,855-2,843], 5.9 patients/bed [2.7-9.0]) than Trusts with expected (n = 63, 1,110 L/bed, [864-1,357] p<0.0001, 2.6 patients/bed [1.7-3.5] p<0.0169) or, high (n = 42, 930 L/bed [683-1,177] p = 0.0001, 1.8 patients/bed [1.4-2.1] p<0.0005) mortality rates. The most research active Trusts were those with more doctors, nurses, critical care beds, operating theatres and, made greater use of radiology. Multifactorial analysis demonstrated better survival in the top funding and patient recruitment tertiles (lowest vs. highest (odds ratio & 95% CI: funding 1.050 [1.033-1.068] p<0.0001, recruitment 1.069 [1.052-1.086] p<0.0001), middle vs. highest (funding 1.040 [1.024-1.055] p<0.0001, recruitment 1.085 [1.070-1.100] p<0.0001). CONCLUSIONS: Research active Trusts appear to have key differences in composition than less research active Trusts. Research active Trusts had lower risk-adjusted mortality for acute admissions, which persisted after adjustment for staffing and other structural factors. PMID- 25719609 TI - Teletherapy delivery of caregiver behavior training for children with attention deficit hyperactivity disorder. AB - BACKGROUND: Preliminary studies suggest that videoteleconferencing (VTC) may be an effective means to deliver behavioral interventions to families. Subjects consisted of a subsample of children (n=37) and caregivers who participated in the Children's Attention-Deficit Hyperactivity Disorder (ADHD) Telemental Health Treatment Study (CATTS) (n=223), a randomized trial testing the effectiveness of delivering treatments for ADHD to families residing in their home communities using distant technologies. Families randomized to the CATTS intervention arm received pharmacotherapy and caregiver behavior training. MATERIALS AND METHODS: Thirty-seven families from the CATTS intervention arm participated. All families received pharmacotherapy through VTC. Twelve families received the caregiver behavior training through VTC, or teletherapy, and 25 received the intervention in-person. We assessed children's outcomes at 25 weeks with the Vanderbilt ADHD Parent Rating Scale and the Columbia Impairment Scale. We assessed caregivers' outcomes using measures of distress in caring for a child with ADHD, including depression, stress, strain, and empowerment. We used analysis of covariance to assess outcomes from baseline to 25 weeks. RESULTS: Families in the two conditions showed comparable attendance at sessions and satisfaction with their care. Caregivers in both conditions reported comparable outcomes for their children's ADHD-related behaviors and functioning, but caregivers in the teletherapy group did not report improvement in their own distress. CONCLUSIONS: Findings support the feasibility, acceptability, and effectiveness of treating children with ADHD through teletherapy. Future work should investigate how teletherapy may improve caregivers' distress. Teletherapy is a promising modality for delivering behavioral interventions for children with ADHD. PMID- 25719610 TI - Effects of different ventilation strategies on exhaled nitric oxide in geriatric abdominal surgery. AB - Exhaled nitric oxide (eNO) has been suggested to be a marker of small airway injury. We investigated the effects of different ventilation strategies on eNO. Sixty-nine patients who received elective open abdominal surgery under general anesthesia with more than 2 h of surgery duration were randomly divided into three groups: high tidal volume of 10-12 ml kg(-1) predicted body weight (PBW) with zero end-expiratory pressure (ZEEP) (high VT + ZEEP group); low tidal volume of 6-8 ml kg(-1) PBW with 8 cm H2O positive end-expiratory pressure (PEEP) (low VT + PEEP group); and low tidal volume of 6-8 ml kg(-1) PBW with 8 cm H2O PEEP and recruitment maneuvers (low VT + PEEP + RMs group). eNO, respiratory system compliance (Crs), oxygenation index, inflammatory mediators tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8, prostaglandin E2 (PGE2) and PGF2a as well as pulmonary function were measured during the perioperative period. The postoperative eNO decreased in 78.3% of patients in the high VT + ZEEP group and low VT + PEEP group, and increased in 56.5% of patients in the low VT + PEEP + RMs group (P = 0.016). The Crs level in the high VT + ZEEP group significantly decreased with time but significantly increased in the low VT + PEEP + RMs group (P < 0.05). The oxygenation index, inflammatory mediators and pulmonary function did not statistically differ among the three groups. Compared with the low VT + PEEP + RMs group, the decreasing rate of postoperative eNO in the high VT + ZEEP and low VT + PEEP groups was higher, which may imply small airway injury during geriatric abdominal surgery. PMID- 25719611 TI - Manganese- and cobalt-based coordination networks as promising heterogeneous catalysts for olefin epoxidation reactions. AB - We demonstrate the synthesis of Mn(2+)- and Co(2+)-based coordination networks using two Co(3+)-based metalloligands differing by the position of the appended arylcarboxylate groups. The structural analyses reveal topologically distinct networks with pores of variable dimensions allowing facile diffusion of substrates and/or reagents. All four networks function as heterogeneous catalysts for the olefin epoxidation reactions using tert-butyl-hydroperoxide without any requirement of solvent or additive. Control and optimization experiments illustrate recyclable network-based catalysts that make them attractive candidates for the "greener" oxidation chemistry processes. PMID- 25719612 TI - A multi-target approach for pain treatment: dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis. AB - The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA. PMID- 25719613 TI - Cold and L-menthol-induced sensitization in healthy volunteers--a cold hypersensitivity analogue to the heat/capsaicin model. AB - Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 +/- 0.6 years). Cold stimulation of 5 degrees C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity. PMID- 25719614 TI - Inhibitory regulation of the pain gate and how its failure causes pathological pain. PMID- 25719615 TI - Growth mixture models and knee arthroplasty outcomes: Reply. PMID- 25719616 TI - Changes in and predictors of pain characteristics in patients with head and neck cancer undergoing radiotherapy. AB - Pain is a common symptom in patients with head and neck cancer (HNC) that is associated with significant decrements in physical and psychological functioning. Only 4 studies have evaluated for changes in and predictors of different pain characteristics in these patients. In this longitudinal study of patients with HNC, changes in pain intensity (i.e., average pain, worst pain), pain interference with function, and pain relief were evaluated from the initiation of radiotherapy and through the following 6 months. Hierarchical linear modeling was used to evaluate for changes over time in these 4 pain characteristics, as well as to identify predictors of interindividual variability in each characteristic. Overall, pain intensity and interference with function scores were in the mild-to moderate range, while pain relief scores were in the moderate range. The occurrence of pain, as well as scores for each pain characteristic, increased from the initiation to the completion of radiotherapy, followed by a gradual decrease to near pretreatment levels at 6 months. However, interindividual variability existed in patients' ratings of each pain characteristic. Predictors of more severe pain characteristic scores were more comorbidities, worse physical functioning, not having surgery before radiotherapy, difficulty swallowing, mouth sores, sleep disturbance, fatigue, more energy, and less social support. Patients with more depressive symptoms had better pain relief. Although some of the predictors cannot be modified (e.g., rrence of surgery), other predictors (e.g., symptoms) can be treated. Therefore, information about these predictors may result in decreased pain in patients with HNC. PMID- 25719617 TI - Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial. AB - Monotherapy with first-line drugs for neuropathic pain often fails to provide sufficient pain relief or has unacceptable side effects because of the need for high doses. The aim of this trial was to test whether the combination of imipramine and pregabalin in moderate doses would relieve pain more effectively than monotherapy with either of the drugs. This was a randomized, double-blind, placebo-controlled, crossover, multicenter trial consisting of four 5-week treatment periods in patients with painful polyneuropathy. Treatment arms were imipramine 75 mg/d vs pregabalin 300 mg/d vs combination therapy vs placebo. Patients with polyneuropathy and symptoms for more than 6 months, age 20 to 85 years, pain intensity >=4 on a 0- to 10-point numeric rating scale (NRS) and pain at least 4 days a week were included in the trial. A total of 262 patients were screened for participation, 73 patients were randomized, and 69 patients were included in the data analysis. The effect on average pain in comparison with placebo was: combination (-1.67 NRS points, P < 0.001), imipramine (-1.08 NRS points, P < 0.001), and pregabalin (-0.48 NRS points, P = 0.03). The combination therapy had significantly lower pain scores than both monotherapies: combination vs imipramine (P = 0.009), combination vs pregabalin (P < 0.001). During combination therapy, the dropout rate was higher and the patients reported a higher rate and severity of side effects. Combination of moderate doses of the tricyclic antidepressant imipramine and pregabalin could be considered as an alternative to high-dosage monotherapy. However, the trial also emphasized that balance between efficacy and safety is an issue. PMID- 25719618 TI - Applying a developmental perspective to the study of pain. PMID- 25719619 TI - Improved neuropathic pain treatment in developing countries--a critical review of WHO essential list. PMID- 25719620 TI - Comparing the DN4 tool with the IASP grading system for chronic neuropathic pain screening after breast tumor resection with and without paravertebral blocks: a prospective 6-month validation study. AB - Investigating protective strategies against chronic neuropathic pain (CNP) after breast cancer surgery entails using valid screening tools. The DN4 (Douleur Neuropathique en 4 questions) is 1 tool that offers important research advantages. This prospective 6-month follow-up study seeks to validate the DN4 and assess its responsiveness in screening for CNP that satisfies the International Association for the Study of Pain (IASP) definition and fulfills its grading system criteria after breast tumor resection with and without paravertebral blocks (PVBs). We randomized 66 females to standardized general anesthesia and sham subcutaneous injections, or PVB and total intravenous anesthesia. The 6-month CNP risk was assessed using the IASP grading system and the DN4 screening tools. We evaluated the DN4 sensitivity, specificity, and responsiveness in capturing the impact of PVB on the CNP risk relative to the IASP grading system. Data from 64 patients showed similar demographic characteristics in both groups. Twenty patients in both groups met the grading system CNP criteria; among these, 18 patients also met the DN4 CNP criteria. Furthermore, 15 patients in both groups did not meet the grading system CNP criteria; among these, 9 patients also did not meet the DN4 CNP criteria. Therefore, the sensitivity and specificity of the DN4 were estimated at 90% and 60%, respectively. Both screening tools suggested that PVB reduced the 6-month CNP risk. Our results suggest that the DN4 can reliably identify CNP at 6 months after breast tumor resection and detect the preincisional PVB effect on the risk of developing such pain. PMID- 25719621 TI - Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life threatening. AB - The aim of this study was to evaluate the most common adverse events (AEs) linked to everolimus therapy, a mammalian target of rapamycin (mTOR) inhibitor, in children and adolescents with tuberous sclerosis complex (TSC) hospitalized in one medical center. The study group included 18 patients with a diagnosis of subependymal giant cell astrocytoma or renal angiomyolipoma related to TSC. The median duration of therapy was 15 months. All clinical symptoms and laboratory abnormalities including complete blood count, fasting lipid profile, glucose level, and liver and kidney function tests were analyzed as potential AEs. The most common AEs of everolimus therapy were laboratory abnormalities (100% of patients) and infection complications (83 episodes in 15 patients). Infectious episodes of pharyngitis (67%), diarrhea (44%), stomatitis (39%), and bronchitis (39%) were the most common infections. They were mostly mild or moderate in severity (grade 1-2). In two cases, life-threatening conditions related to mTOR inhibitor treatment were encountered. The first was classified as grade 4 pleuropneumonia and Streptococcus pneumoniae sepsis, whereas the second was classified as death related to AE (grade 5) Escherichia coli sepsis. The most common laboratory abnormalities were hypercholesterolemia (13/18 patients - 72%) and hypertriglyceridemia (12/18 patients - 66%). Neutropenia (12/18 patents - 66%) and anemia (8/18 patients - 44%) were the most common hematologic toxicities. Everolimus treatment in TSC patients may lead to life-threatening outcomes, including sepsis and death. Long-lasting effects of everolimus treatment in the context of high incidences of different laboratory abnormalities found in TSC patients are another subject that should be researched further. PMID- 25719623 TI - Extraction of oil from oil sands using thermoresponsive polymeric surfactants. AB - Several thermoresponsive block copolymers constituted of a poly(ethylene glycol) (PEG) and a poly(2-(2-methoxyethoxy) ethyl methacrylate) (PMEO2MA) block were prepared by atom transfer radical polymerization (ATRP) and their ability to extract oil from oil sands was evaluated. The chemical composition of the PEG113 b-PMEO2MAX block copolymers was determined by (1)H NMR and gel permeation chromatography (GPC) with X-values ranging between 48 and 80. Aqueous solutions of block copolymers showed a cloud point of 34 +/- 1 degrees C as determined by turbidimetry and dynamic light scattering (DLS) measurements. DLS experiments indicated that these polymers formed stable block copolymer micelles due to association of the PMEO2MA blocks at temperatures greater than 45 degrees C with a unimodal distribution of hydrodynamic diameters. Since characterization of the block copolymer solutions as a function of temperature indicated the formation of hydrophobic domains in water for T > 45 degrees C, extractions of oil from oil sands with the block copolymers were conducted at T = 45 and 50 degrees C. At these temperatures, 15 mL of a 1 mg/mL PEG113-b-PMEO2MA77 aqueous solution extracted 100% of the oil trapped in 1 g of oil sand if 60 mg of toluene was added to the mixture. When the extraction was conducted under the same experimental conditions without block copolymer, a poor oil recovery of less than 30% was achieved. Starting with a 1 mg/mL block copolymer concentration, the block copolymer aqueous solution could be recycled up to five successive extractions while maintaining satisfying oil recovery. Each extraction cycle led to a 22% mass loss of block copolymer, certainly due to association with the toluene, oil, and sand particles. Together these experiments demonstrate that thermoresponsive block copolymers can be powerful aids to enhance the oil recovery of oil sands. PMID- 25719624 TI - Evaluation of a primary care intervention on body mass index: the Maine Youth Overweight Collaborative. AB - BACKGROUND: We evaluated the impact of a brief primary-care-based intervention, The Maine Youth Overweight Collaborative (MYOC), on BMI (kg/m(2)) z-score change among participants with obesity (BMI >=95th percentile for age and sex), overweight (BMI >=85th and <95th percentile), and healthy weight (>=50th and <85th percentile). METHODS: A quasi-experimental field trial with nine intervention and nine control sites in urban and rural areas of Maine, MYOC focused on improvements in clinical decision support, charting BMI percentile, identifying patients with obesity, appropriate lab tests, and counseling families/patients. Retrospective longitudinal record reviews assessed BMI z scores preintervention (from 1999 through October 2004) and one postintervention time point (between December 2006 and March 2008). Participants were youth ages 5 18 having two visits before the intervention with weight percentile greater than or equal to 95% (N=265). Secondary analyses focused on youths who are overweight (N=215) and healthy weight youth (N=506). RESULTS: Although the MYOC intervention demonstrated significant provider and office system improvements, we found no significant changes in BMI z-scores in intervention versus control youth pre- to postintervention and significant flattening of upward trends among both intervention and control sites (p<0.001). CONCLUSIONS: This brief office-based intervention was associated with no significant improvement in BMI z-scores, compared to control sites. An important avenue for obesity prevention and treatment as part of a multisector approach in communities, this type of primary care intervention alone may be unlikely to impact BMI improvement given the limited dosage-an estimated 4-6 minutes for one patient contact. PMID- 25719625 TI - The relationship between coagulation state and inflammatory bowel disease: current understanding and clinical implications. AB - Inflammatory bowel disease (IBD) is associated with a hypercoagulable state and subsequently with an increased risk for venous thromboembolism (VTE). VTE in IBD is characterized by a high recurrence rate and is associated with the disease activity. Acquired endothelial dysfunction, abnormalities of platelets, activation of coagulation system and impaired fibrinolysis are the main changes in the coagulation state in IBD. The development of VTE in IBD has been considered to be the result of multiple interactions between acquired and inherited risk factors. The treatment of VTE in IBD patients is recommended to be similar and to follow the same protocols as for non-IBD patients. In the clinical practice, the management of IBD patients and especially the hospitalized patients should include thromboprophylaxis. PMID- 25719626 TI - When right beats might. PMID- 25719627 TI - A sore thing. PMID- 25719628 TI - No strings. PMID- 25719629 TI - Focus on political Islamic groups to boost science. PMID- 25719641 TI - Wanted: 80,000 British babies. PMID- 25719642 TI - Biology powerhouse raises railway alarm. PMID- 25719643 TI - DeepMind algorithm beats people at classic video games. PMID- 25719644 TI - Researchers seek definition of head-trauma disorder. PMID- 25719646 TI - Dwarf planets: a tale of two missions. PMID- 25719647 TI - Planetary science: The Pluto siblings. PMID- 25719648 TI - Neuroscience in court: The painful truth. PMID- 25719653 TI - Antibodies: Validate recombinants too. PMID- 25719649 TI - Data sharing: Make outbreak research open access. PMID- 25719654 TI - Biochar: Bring on the sewage. PMID- 25719655 TI - Education: Gear students up for big medical data. PMID- 25719656 TI - Antibodies: The solution is validation. PMID- 25719657 TI - Environment: Polluters migrate to China's poor areas. PMID- 25719658 TI - Biochar: Pros must outweigh cons. PMID- 25719659 TI - Robert A. Berner (1935-2015). PMID- 25719660 TI - Artificial intelligence: Learning to see and act. PMID- 25719661 TI - Biodiversity: The benefits of traditional knowledge. PMID- 25719662 TI - Cosmology: A giant in the young Universe. PMID- 25719664 TI - Quantum physics: Teleportation for two. PMID- 25719665 TI - Molecular biology: RNA modification does a regulatory two-step. PMID- 25719667 TI - An ultraluminous quasar with a twelve-billion-solar-mass black hole at redshift 6.30. AB - So far, roughly 40 quasars with redshifts greater than z = 6 have been discovered. Each quasar contains a black hole with a mass of about one billion solar masses (10(9) M Sun symbol). The existence of such black holes when the Universe was less than one billion years old presents substantial challenges to theories of the formation and growth of black holes and the coevolution of black holes and galaxies. Here we report the discovery of an ultraluminous quasar, SDSS J010013.02+280225.8, at redshift z = 6.30. It has an optical and near-infrared luminosity a few times greater than those of previously known z > 6 quasars. On the basis of the deep absorption trough on the blue side of the Lyman-alpha emission line in the spectrum, we estimate the proper size of the ionized proximity zone associated with the quasar to be about 26 million light years, larger than found with other z > 6.1 quasars with lower luminosities. We estimate (on the basis of a near-infrared spectrum) that the black hole has a mass of ~1.2 * 10(10) M Sun symbol, which is consistent with the 1.3 * 10(10) M Sun symbol derived by assuming an Eddington-limited accretion rate. PMID- 25719668 TI - Quantum teleportation of multiple degrees of freedom of a single photon. AB - Quantum teleportation provides a 'disembodied' way to transfer quantum states from one object to another at a distant location, assisted by previously shared entangled states and a classical communication channel. As well as being of fundamental interest, teleportation has been recognized as an important element in long-distance quantum communication, distributed quantum networks and measurement-based quantum computation. There have been numerous demonstrations of teleportation in different physical systems such as photons, atoms, ions, electrons and superconducting circuits. All the previous experiments were limited to the teleportation of one degree of freedom only. However, a single quantum particle can naturally possess various degrees of freedom--internal and external- and with coherent coupling among them. A fundamental open challenge is to teleport multiple degrees of freedom simultaneously, which is necessary to describe a quantum particle fully and, therefore, to teleport it intact. Here we demonstrate quantum teleportation of the composite quantum states of a single photon encoded in both spin and orbital angular momentum. We use photon pairs entangled in both degrees of freedom (that is, hyper-entangled) as the quantum channel for teleportation, and develop a method to project and discriminate hyper entangled Bell states by exploiting probabilistic quantum non-demolition measurement, which can be extended to more degrees of freedom. We verify the teleportation for both spin-orbit product states and hybrid entangled states, and achieve a teleportation fidelity ranging from 0.57 to 0.68, above the classical limit. Our work is a step towards the teleportation of more complex quantum systems, and demonstrates an increase in our technical control of scalable quantum technologies. PMID- 25719669 TI - Dynamically reconfigurable complex emulsions via tunable interfacial tensions. AB - Emulsification is a powerful, well-known technique for mixing and dispersing immiscible components within a continuous liquid phase. Consequently, emulsions are central components of medicine, food and performance materials. Complex emulsions, including Janus droplets (that is, droplets with faces of differing chemistries) and multiple emulsions, are of increasing importance in pharmaceuticals and medical diagnostics, in the fabrication of microparticles and capsules for food, in chemical separations, in cosmetics, and in dynamic optics. Because complex emulsion properties and functions are related to the droplet geometry and composition, the development of rapid, simple fabrication approaches allowing precise control over the droplets' physical and chemical characteristics is critical. Significant advances in the fabrication of complex emulsions have been made using a number of procedures, ranging from large-scale, less precise techniques that give compositional heterogeneity using high-shear mixers and membranes, to small-volume but more precise microfluidic methods. However, such approaches have yet to create droplet morphologies that can be controllably altered after emulsification. Reconfigurable complex liquids potentially have great utility as dynamically tunable materials. Here we describe an approach to the one-step fabrication of three- and four-phase complex emulsions with highly controllable and reconfigurable morphologies. The fabrication makes use of the temperature-sensitive miscibility of hydrocarbon, silicone and fluorocarbon liquids, and is applied to both the microfluidic and the scalable batch production of complex droplets. We demonstrate that droplet geometries can be alternated between encapsulated and Janus configurations by varying the interfacial tensions using hydrocarbon and fluorinated surfactants including stimuli-responsive and cleavable surfactants. This yields a generalizable strategy for the fabrication of multiphase emulsions with controllably reconfigurable morphologies and the potential to create a wide range of responsive materials. PMID- 25719670 TI - Human-level control through deep reinforcement learning. AB - The theory of reinforcement learning provides a normative account, deeply rooted in psychological and neuroscientific perspectives on animal behaviour, of how agents may optimize their control of an environment. To use reinforcement learning successfully in situations approaching real-world complexity, however, agents are confronted with a difficult task: they must derive efficient representations of the environment from high-dimensional sensory inputs, and use these to generalize past experience to new situations. Remarkably, humans and other animals seem to solve this problem through a harmonious combination of reinforcement learning and hierarchical sensory processing systems, the former evidenced by a wealth of neural data revealing notable parallels between the phasic signals emitted by dopaminergic neurons and temporal difference reinforcement learning algorithms. While reinforcement learning agents have achieved some successes in a variety of domains, their applicability has previously been limited to domains in which useful features can be handcrafted, or to domains with fully observed, low-dimensional state spaces. Here we use recent advances in training deep neural networks to develop a novel artificial agent, termed a deep Q-network, that can learn successful policies directly from high-dimensional sensory inputs using end-to-end reinforcement learning. We tested this agent on the challenging domain of classic Atari 2600 games. We demonstrate that the deep Q-network agent, receiving only the pixels and the game score as inputs, was able to surpass the performance of all previous algorithms and achieve a level comparable to that of a professional human games tester across a set of 49 games, using the same algorithm, network architecture and hyperparameters. This work bridges the divide between high-dimensional sensory inputs and actions, resulting in the first artificial agent that is capable of learning to excel at a diverse array of challenging tasks. PMID- 25719666 TI - Whole genomes redefine the mutational landscape of pancreatic cancer. AB - Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded. PMID- 25719673 TI - Spontaneous adsorption of coiled-coil model peptides K and E to a mixed lipid bilayer. AB - A molecular description of the lipid-protein interactions underlying the adsorption of proteins to membranes is crucial for understanding, for example, the specificity of adsorption or the binding strength of a protein to a bilayer, or for characterizing protein-induced changes of membrane properties. In this paper, we extend an automated in silico assay (DAFT) for binding studies and apply it to characterize the adsorption of the model fusion peptides E and K to a mixed phospholipid/cholesterol membrane using coarse-grained molecular dynamics simulations. In addition, we couple the coarse-grained protocol to reverse transformation to atomistic resolution, thereby allowing to study molecular interactions with high detail. The experimentally observed differential binding of the peptides E and K to membranes, as well as the increased binding affinity of helical over unstructered peptides, could be well reproduced using the polarizable Martini coarse-grained (CG) force field. Binding to neutral membranes is shown to be dominated by initial binding of the positively charged N-terminus to the phospholipid headgroup region, followed by membrane surface-aligned insertion of the peptide at the interface between the hydrophobic core of the membrane and its polar headgroup region. Both coarse-grained and atomistic simulations confirm a before hypothesized snorkeling of lysine side chains for the membrane-bound state of the peptide K. Cholesterol was found to be enriched in peptide vicinity, which is probably of importance for the mechanism of membrane fusion. The applied sequential multiscale method, using coarse-grained simulations for the slow adsorption process of peptides to membranes followed by backward transformation to atomistic detail and subsequent atomistic simulations of the preformed peptide-lipid complexes, is shown to be a versatile approach to study the interactions of peptides or proteins with biomembranes. PMID- 25719671 TI - N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. AB - RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBMs). However, RBMs can be buried within their local RNA structures, thus inhibiting RNA-protein interactions. N(6) methyladenosine (m(6)A), the most abundant and dynamic internal modification in eukaryotic messenger RNA, can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs, but how m(6)A achieves its wide ranging physiological role needs further exploration. Here we show in human cells that m(6)A controls the RNA-structure-dependent accessibility of RBMs to affect RNA-protein interactions for biological regulation; we term this mechanism 'the m(6)A-switch'. We found that m(6)A alters the local structure in mRNA and long non-coding RNA (lncRNA) to facilitate binding of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing. Combining photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m(6)A immunoprecipitation (MeRIP) approaches enabled us to identify 39,060 m(6)A switches among HNRNPC-binding sites; and global m(6)A reduction decreased HNRNPC binding at 2,798 high-confidence m(6)A-switches. We determined that these m(6)A switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m(6)A switches on gene expression and RNA maturation. Our results illustrate how RNA binding proteins gain regulated access to their RBMs through m(6)A-dependent RNA structural remodelling, and provide a new direction for investigating RNA modification-coded cellular biology. PMID- 25719674 TI - The Application of Entrustable Professional Activities to Inform Competency Decisions in a Family Medicine Residency Program. AB - Assessing entrustable professional activities (EPAs), or carefully chosen units of work that define a profession and are entrusted to a resident to complete unsupervised once she or he has obtained adequate competence, is a novel and innovative approach to competency-based assessment (CBA). What is currently not well described in the literature is the application of EPAs within a CBA system. In this article, the authors describe the development of 35 EPAs for a Canadian family medicine residency program, including the work by an expert panel of family physician and medical education experts from four universities in three Canadian provinces to identify the relevant EPAs for family medicine in nine curriculum domains. The authors outline how they used these EPAs and the corresponding templates that describe competence at different levels of supervision to create electronic EPA field notes, which has allowed educators to use the EPAs as a formative tool to structure day-to-day assessment and feedback and a summative tool to ground competency declarations about residents. They then describe the system to compile, collate, and use the EPA field notes to make competency declarations and how this system aligns with van der Vleuten's utility index for assessment (valid, reliable, of educational value, acceptable, cost effective). Early outcomes indicate that preceptors are using the EPA field notes more often than they used the generic field notes. EPAs enable educators to evaluate multiple objectives and important but unwieldy competencies by providing practical, manageable, measurable activities that can be used to assess competency development. PMID- 25719675 TI - Dimensions of Diversity and Perception of Having Learned From Individuals From Different Backgrounds: The Particular Importance of Racial Diversity. AB - PURPOSE: Selective higher education institutions that take race into account in admissions decisions must be able to demonstrate that their policy is justified by a compelling governmental interest, is narrowly tailored, and is the least restrictive means for achieving that interest. The authors thus investigate whether, among medical students, the association between racial diversity (as distinct from other forms of diversity) and learning from individuals from different backgrounds is unique. METHOD: The authors examined six dimensions of diversity, including racial/ethnic diversity, among the 2010, 2011, and 2012 cohorts of fourth-year medical students in the United States. They also examined students' responses to two Medical Student Graduation Questionnaire items pertaining to learning from individuals from different backgrounds. They modeled the association between each of the school-level dimensions of diversity and the student-level responses to having learned from others with different backgrounds, and they assessed whether associations vary across different groups of students. RESULTS: Racial/ethnic diversity is unique in its very strong association with student perceptions of having learned from others who are different. The association between racial/ethnic diversity and student perceptions of having learned from others who are different is especially strong for members of historically underrepresented minority groups. CONCLUSIONS: Compared with other forms of diversity, racial/ethnic diversity has a unique association with students' perceptions of learning from others who are different. This association is of particular relevance to admissions and diversity policies in an era of strict scrutiny of these policies. PMID- 25719676 TI - Transmission of hepatitis C virus associated with surgical procedures - New Jersey 2010 and Wisconsin 2011. AB - Incidents of health care-associated hepatitis C virus (HCV) transmission that resulted from breaches in injection safety and infection prevention practices have been previously documented. During 2010 and 2011, separate, unrelated, occurrences of HCV infections in New Jersey and Wisconsin associated with surgical procedures were investigated to determine sources of HCV and mechanisms of HCV transmission. Molecular analyses of HCV strains and epidemiologic investigations indicated that transmission likely resulted from breaches of infection prevention practices. Health care and public health professionals should consider health care-associated transmission when evaluating acute HCV infections. PMID- 25719677 TI - CDC grand rounds: preventing youth violence. AB - Youth violence occurs when persons aged 10-24 years, as victims, offenders, or witnesses, are involved in the intentional use of physical force or power to threaten or harm others. Youth violence typically involves young persons hurting other young persons and can take different forms. Examples include fights, bullying, threats with weapons, and gang-related violence. Different forms of youth violence can also vary in the harm that results and can include physical harm, such as injuries or death, as well as psychological harm. Youth violence is a significant public health problem with serious and lasting effects on the physical, mental, and social health of youth. In 2013, 4,481 youths aged 10-24 years (6.9 per 100,000) were homicide victims. Homicide is the third leading cause of death among persons aged 10-24 years (after unintentional injuries and suicide) and is responsible for more deaths in this age group than the next seven leading causes of death combined. Males and racial/ethnic minorities experience the greatest burden of youth violence. Rates of homicide deaths are approximately six times higher among males aged 10-24 years (11.7 per 100,000) than among females (2.0). Rates among non-Hispanic black youths (27.6 per 100,000) and Hispanic youths (6.3) are 13 and three times higher, respectively, than among non Hispanic white youths (2.1). The number of young persons who are physically harmed by violence is more than 100 times higher than the number killed. In 2013, an estimated 547,260 youths aged 10-24 years (847 per 100,000) were treated in U.S. emergency departments for nonfatal physical assault-related injuries. PMID- 25719678 TI - Rapid intervention to reduce Ebola transmission in a remote village - Gbarpolu County, Liberia, 2014. AB - As late as September 14, 2014, Liberia's Gbarpolu County had reported zero cases of Ebola virus disease (Ebola). On October 25, the Bong County Health Team, a local health department in the Liberian Ministry of Health and Social Welfare (MOHSW), received confirmation of Ebola in a man who had recently left Geleyansiesu, a remote village of approximately 800 residents, after his wife and daughter had died of illnesses consistent with Ebola. MOHSW requested assistance from CDC, the World Health Organization, and other international partners to investigate and confirm the outbreak in Geleyansiesu and begin interventions to interrupt transmission. A total of 22 cases were identified, of which 18 (82%) were laboratory confirmed by real-time polymerase chain reaction. There were 16 deaths (case-fatality rate = 73%). Without road access to or direct telecommunications with the village, interventions had to be tailored to the local context. Public health interventions included 1) education of the community about Ebola, transmission of the virus, signs and symptoms, the importance of isolating ill patients from family members, and the potential benefits of early diagnosis and treatment; 2) establishment of mechanisms to alert health authorities of possibly infected persons leaving the village to facilitate safe transport to the closest Ebola treatment unit (ETU); 3) case investigation, contact tracing, and monitoring of contacts; 4) training in hygienic burial of dead bodies; 5) active case finding and diagnosis; and 6) isolation and limited no-touch treatment in the village of patients unwilling or unable to seek care at an ETU. The findings of this investigation could inform interventions aimed at controlling focal outbreaks in difficult-to-reach communities, which has been identified as an important component of the effort to eliminate Ebola from Liberia. PMID- 25719679 TI - Community quarantine to interrupt Ebola virus transmission - Mawah Village, Bong County, Liberia, August-October, 2014. AB - On September 30, 2014, the Bong County health officer notified the county Ebola task force of a growing outbreak of Ebola virus disease (Ebola) in Mawah, a village of approximately 800 residents. During September 9-16, household quarantine had been used by the community in response to a new Ebola infection. Because the infection led to a local outbreak that grew during September 17-20, county authorities suggested community quarantine be considered, and beginning on approximately September 20, the Fuamah District Ebola Task Force (Task Force) engaged Mawah leaders to provide education about Ebola and to secure cooperation for the proposed measures. On September 30, Bong County requested technical assistance to develop strategies to limit transmission in the village and to prevent spread to other areas. The county health team, with support from the Task Force and CDC, traveled to Mawah on October 1 and identified approximately two dozen residents reporting symptoms consistent with Ebola. Because of an ambulance shortage, 2 days were required, beginning October 1, to transport the patients to an Ebola treatment unit in Monrovia. Community quarantine measures, consisting of restrictions on entering or leaving Mawah, regulated river crossings, and market closures, were implemented on October 1. Local leaders raised concerns about availability of medical care and food. The local clinic was reopened on October 11, and food was distributed on October 12. The Task Force reported a total of 22 cases of Ebola in Mawah during September 9-October 2, of which 19 were fatal. During October 3-November 21, no new cases were reported in the village. Involving community members during planning and implementation helped support a safe and effective community quarantine in Mawah. PMID- 25719680 TI - Implementation of Ebola case-finding using a village chieftaincy taskforce in a remote outbreak - Liberia, 2014. AB - On October 16, 2014, a woman aged 48 years traveled from Monrovia, Liberia, to the Kayah region of Rivercess County, a remote, resource-poor, and sparsely populated region of Liberia, and died on October 21 with symptoms compatible with Ebola virus disease (Ebola). She was buried in accordance with local tradition, which included grooming, touching, and kissing the body by family and other community members while it was being prepared for burial. During October 24 November 12, eight persons with probable and 13 with confirmed Ebola epidemiologically linked to the deceased woman had onset of symptoms. Nineteen of the 21 persons lived in five nearby villages in Kayah region; two, both with probable cases, lived in neighboring Grand Bassa County (Figure). Four of the confirmed cases in Kayah were linked by time and location, although the source case could not be determined because the patients had more than one exposure. PMID- 25719681 TI - Update: Ebola virus disease epidemic - West Africa, February 2015. AB - CDC is assisting ministries of health and working with other organizations to end the ongoing epidemic of Ebola virus disease (Ebola) in West Africa. The updated data in this report were compiled from situation reports from the Guinea Interministerial Committee for Response Against the Ebola Virus, the Liberia Ministry of Health and Social Welfare, the Sierra Leone Ministry of Health and Sanitation, and the World Health Organization. PMID- 25719683 TI - Revised device labeling for the Cepheid Xpert MTB/RIF assay for detecting Mycobacterium tuberculosis. AB - The Food and Drug Administration (FDA) has cleared the Xpert MTB/RIF Assay (Cepheid; Sunnyvale, California) with an expanded intended use that includes testing of either one or two sputum specimens as an alternative to examination of serial acid-fast stained sputum smears to aid in the decision of whether continued airborne infection isolation (AII) is warranted for patients with suspected pulmonary tuberculosis. This change reflects the outcome of a recent multicenter international study demonstrating that negative Xpert MTB/RIF Assay results from either one or two sputum specimens are highly predictive of the results of two or three negative acid-fast sputum smears. PMID- 25719682 TI - Rapid response to Ebola outbreaks in remote areas - Liberia, July-November 2014. AB - West Africa is experiencing its first epidemic of Ebola virus disease (Ebola). As of February 9, Liberia has reported 8,864 Ebola cases, of which 3,147 were laboratory-confirmed. Beginning in August 2014, the Liberia Ministry of Health and Social Welfare (MOHSW), supported by CDC, the World Health Organization (WHO), and others, began systematically investigating and responding to Ebola outbreaks in remote areas. Because many of these areas lacked mobile telephone service, easy road access, and basic infrastructure, flexible and targeted interventions often were required. Development of a national strategy for the Rapid Isolation and Treatment of Ebola (RITE) began in early October. The strategy focuses on enhancing capacity of county health teams (CHT) to investigate outbreaks in remote areas and lead tailored responses through effective and efficient coordination of technical and operational assistance from the MOHSW central level and international partners. To measure improvements in response indicators and outcomes over time, data from investigations of 12 of 15 outbreaks in remote areas with illness onset dates of index cases during July 16 November 20, 2014, were analyzed. The times to initial outbreak alerts and durations of the outbreaks declined over that period while the proportions of patients who were isolated and treated increased. At the same time, the case fatality rate in each outbreak declined. Implementation of strategies, such as RITE, to rapidly respond to rural outbreaks of Ebola through coordinated and tailored responses can successfully reduce transmission and improve outcomes. PMID- 25719684 TI - Notes from the field: cryptosporidiosis associated with consumption of unpasteurized goat milk - Idaho, 2014. AB - On August 27, 2014, the Idaho Department of Health and Welfare's Division of Public Health (DPH) was notified of two cases of cryptosporidiosis in siblings aged <3 years. Idaho's Southwest District Health (SWDH) investigated and found that both children had consumed raw (unpasteurized) goat milk produced at a dairy licensed by the Idaho State Department of Agriculture (ISDA) and purchased at a retail store. Milk produced before August 18, the date of illness onset, was unavailable for testing from retail stores, the household, or the dairy. Samples of raw goat milk produced on August 18, 21, 25, and 28, taken from one opened container from the siblings' household, one unopened container from the retailer, and two unopened containers from the dairy, all tested positive for Cryptosporidium by real-time polymerase chain reaction (PCR) at a commercial laboratory. On August 30, ISDA placed a hold order on all raw milk sales from the producer. ISDA and SWDH issued press releases advising persons not to consume the raw milk; SWDH issued a medical alert, and Idaho's Central District Health Department issued an advisory to health care providers about the outbreak. PMID- 25719685 TI - The chemopreventive effect of the dietary compound kaempferol on the MCF-7 human breast cancer cell line is dependent on inhibition of glucose cellular uptake. AB - Our aim was to investigate the effect of several dietary polyphenols on glucose uptake by breast cancer cells. Uptake of (3)H-deoxy-D-glucose ((3)H-DG) by MCF-7 cells was time-dependent, saturable, and inhibited by cytochalasin B plus phloridzin. In the short-term (26 min), myricetin, chrysin, genistein, resveratrol, kaempferol, and xanthohumol (10-100 uM) inhibited (3)H-DG uptake. Kaempferol was found to be the most potent inhibitor of (3)H-DG uptake [IC50 of 4 uM (1.6-9.8)], behaving as a mixed-type inhibitor. In the long-term (24 h), kaempferol (30 uM) was also able to inhibit (3)H-DG uptake, associated with a 40% decrease in GLUT1 mRNA levels. Interestingly enough, kaempferol (100 uM) revealed antiproliferative (sulforhodamine B and (3)H-thymidine incorporation assays) and cytotoxic (extracellular lactate dehydrogenase activity determination) properties, which were mimicked by low extracellular (1 mM) glucose conditions and reversed by high extracellular (20 mM) glucose conditions. Finally, exposure of cells to kaempferol (30 uM) induced an increase in extracellular lactate levels over time (to 731 +/- 32% of control after a 24 h exposure), due to inhibition of MCT1-mediated lactate cellular uptake. In conclusion, kaempferol potently inhibits glucose uptake by MCF-7 cells, apparently by decreasing GLUT1 mediated glucose uptake. The antiproliferative and cytotoxic effect of kaempferol in these cells appears to be dependent on this effect. PMID- 25719687 TI - Discussion: Tissue-engineered breast reconstruction with Brava-assisted fat grafting: a 7-year, 488-patient, multicenter experience. PMID- 25719686 TI - Tissue-engineered breast reconstruction with Brava-assisted fat grafting: a 7 year, 488-patient, multicenter experience. AB - BACKGROUND: The ability of autologous fat transfer to reconstruct an entire breast is not established. The authors harnessed the regenerative capabilities of external expansion and autologous fat transfer to completely reconstruct breasts. METHODS: The authors performed 1877 Brava plus autologous fat transfer procedures on 616 breasts in 488 women to reconstruct 99 lumpectomies, 87 immediate breast reconstructions, and 430 delayed total breast reconstructions. After 2 to 4 weeks of Brava expansion, which increased volume by 100 to 300 percent, the authors diffusely grafted the breasts with 100 to 400 ml (225 ml average) of 15 g sedimented, manually harvested lipoaspirate. The procedure was repeated every 8 to 14 weeks until completion. The authors compared costs of this reconstruction with established deep inferior epigastric artery perforator/transverse rectus abdominis musculocutaneous flaps and implant procedures. RESULTS: Follow-up ranged from 6 months to 7 years (mean, 2.5 years), with 0.5 percent locoregional recurrence. Four hundred twenty-seven women completed the reconstruction, whereas 12.5 percent dropped out (2.5 percent medical, 10 percent personal reasons). Completion required 2.7 procedures for nonirradiated and 4.8 procedures for irradiated mastectomies. Patients recovered soft, natural appearing breasts with nearly normal sensation. Complications included five pneumothoraces and 20 ulcerative infections. Radiographically recognized benign palpable masses were observed in 12 percent of nonirradiated and 37 percent of irradiated breasts. The cost of Brava plus autologous fat transfer is 47 percent and 66 percent that of current reconstruction alternatives. CONCLUSION: Brava plus autologous fat transfer is a minimally invasive, incisionless, safe, economic, and effective alternative for breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719688 TI - Defining the relationship between patient decisions to undergo breast reconstruction and contralateral prophylactic mastectomy. AB - BACKGROUND: Recent studies suggest that the decisions to undergo breast reconstruction and contralateral prophylactic mastectomy are closely related. In this article, the relationship between method of reconstruction and decision to undergo contralateral prophylactic mastectomy is described. Recent trends in contralateral use in the context of literature questioning its oncologic benefit are also evaluated. METHODS: Female patients with unilateral breast cancer were identified and data extracted from the Surveillance, Epidemiology, and End Results database from 2000 through 2010. Logistic regression analyses were performed to study the relationship between having contralateral prophylactic mastectomy and key demographic, oncologic, and reconstructive factors among women with unilateral breast cancer. RESULTS: A total of 157,042 patients with unilateral breast cancer were included. The contralateral prophylactic mastectomy rate increased from 7.7 percent to 28.3 percent during the study period, and the proportion of reconstructed patients who underwent contralateral prophylactic mastectomy increased from 19 percent to 46 percent. Reconstruction was associated with higher odds of contralateral prophylactic mastectomy (OR, 2.79; 95 percent CI, 2.70 to 2.88; p < 0.0001). Among women who had reconstruction, implant-based reconstruction was associated with significantly higher odds of contralateral prophylactic mastectomy than autologous tissue reconstruction (OR, 1.38; p < 0.0001). CONCLUSIONS: This study confirms that reconstruction and the decision to undergo contralateral prophylactic mastectomy are closely related, with implant reconstruction dominating in these patients. Given the close relationship between reconstruction and the choice for contralateral prophylactic mastectomy, plastic surgeons should play an active role in educating patients to avoid decisions made based on inaccurate information. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 25719689 TI - The impact of breast mass on outcomes of total skin-sparing mastectomy and immediate tissue expander-based breast reconstruction. AB - BACKGROUND: Larger breast size has been viewed as a relative contraindication for nipple/areola preservation with mastectomy. Few studies have directly evaluated the effect of quantified breast size on postoperative outcomes. METHODS: The authors reviewed and assessed 325 total skin-sparing mastectomy cases performed in 224 patients with immediate tissue expander placement that had documented mastectomy specimen mass. Cases were divided into two groups based on having larger (>352 grams) or smaller (<=352 grams) breast mass. RESULTS: Patients in the larger group had a mean body mass index that was 3.6 kg/m2 greater (p < 0.001). Overall, the larger group had an 8.1 percent increase in risk of superficial nipple necrosis (adjusted relative risk 4.0; 95 percent CI, 1.5 to 10.3). There were non-significant trends toward a 4.3 percent increase in risk of minor skin necrosis (adjusted relative risk 2.0; 95 percent CI, 0.7 to 6.4) and a 4.4 percent increase in risk of wound breakdown (adjusted relative risk 1.8; 95 percent CI, 0.8 to 3.7) with larger breast mass. Stratifying by radiation exposure, there was a non-significant trend toward a 5.4 percent increase in risk of wound breakdown (adjusted relative risk 2.9; 95 percent CI, 0.9 to 8.8) with larger breast mass in the stratum without radiation exposure. CONCLUSIONS: Larger breast mass was associated with an increased risk of superficial nipple necrosis and trends toward increased risks of minor skin necrosis and wound breakdown. Larger breast mass was not associated with an increased risk of nipple or skin flap necrosis requiring operative management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 25719690 TI - The use of mesh versus primary fascial closure of the abdominal donor site when using a transverse rectus abdominis myocutaneous flap for breast reconstruction: a cost-utility analysis. AB - BACKGROUND: During breast reconstruction using the transverse rectus abdominis myocutaneous (TRAM) flap, the use of mesh for abdominal donor-site closure provides for a technology that potentially offers clinical benefit yet incurs an added cost. The authors' goal was to determine whether it is cost effective to use mesh during abdominal donor-site closure when performing a TRAM flap for breast reconstruction. METHODS: A literature review was conducted to identify and collect published hernia and bulge rates at abdominal TRAM flap donor sites closed either primarily or with mesh. A decision tree analysis was performed. Outcome probabilities, costs of complications, and expert utility estimates were populated into the decision tree model to evaluate the cost-utility of using mesh in TRAM abdominal donor-site closure. One-way sensitivity analyses were performed to verify the robustness of the results. RESULTS: The authors' literature review resulted in 10 articles describing 1195 patients who had TRAM abdominal donor site closure primarily and 696 patients who had donor-site closure performed with mesh. Pooled hernia/bulge complication rates for these two groups were 7.87 percent and 4.45 percent, respectively. The use of mesh was more clinically effective based on total quality-adjusted life-years gained of 30.53 compared with 30.41 when performing primary fascial closure alone. The incremental additional cost incurred by the mesh arm when running the decision tree model was $693.14. This difference in cost, divided by the difference in clinical efficacy (0.12), results in an incremental cost-utility ratio value of $5776.17 per quality-adjusted life-year gained when using mesh, making it cost effective (when using a willingness-to-pay threshold of $50,000). One-way sensitivity analysis revealed the following: (1) using mesh was a cost effective option, provided that the price of mesh was less than or equal to $5970; (2) mesh was cost effective when its use led to a hernia/bulge rate less than or equal to 7.25 percent; and (3) primary facial closure was cost effective when its use led to a hernia/bulge rate less than or equal to 4.75 percent. CONCLUSION: The use of mesh when repairing the abdominal donor site during a pedicled or free TRAM flap breast reconstruction is cost effective compared with primary fascial closure alone. PMID- 25719691 TI - Total envelope fat grafting: a novel approach in breast reconstruction. AB - Fat grafting is an effective technique to correct specific deformities of the breast following reconstruction; however, results are plagued by thin mastectomy skin flaps. In this study, the authors describe and evaluate their experience with total envelope fat grafting to restore thickness to the entire skin envelope during two-stage implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719692 TI - The efficacy and safety of liquid-type botulinum toxin type A for the management of moderate to severe glabellar frown lines. AB - BACKGROUND: Botulinum toxin type A has been widely used to correct unwanted hyperfunctional facial lines. Most forms of botulinum toxin type A currently used require reconstitution, which is very inconvenient for users. The authors compared the efficacy and safety of a newly developed liquid-type botulinum toxin type A (MT10109L) and onabotulinumtoxinA (Botox) for moderate to severe glabellar lines. METHODS: A double-blind, randomized, active drug-controlled, phase III study with 168 enrolled subjects was performed. The primary efficacy endpoint was the improvement rate at maximum frown at week 4 by the investigators' live assessment. The secondary efficacy endpoint included the improvement rate at maximum frown at week 16 and at rest at weeks 4 and 16 by live assessment, and the improvement rate at maximum frown and at rest based on photographic assessment at week 4. Self-assessment and self-satisfaction with glabellar line improvement were also evaluated. RESULTS: The improvement rate at maximum frown by live assessment was not significantly different between the MT10109L and Botox groups. In addition, the improvement rate of glabellar lines at rest based on the investigators' live assessment and photographic assessment was similar in both treatment groups. However, the improvement rate at maximum frown by live assessment at week 16 was significantly higher in the MT10109L group compared with the Botox group. There were no severe adverse events. CONCLUSIONS: The efficacy and safety of MT10109L were comparable to those of Botox for the management of glabellar frown lines. MT10109L provides greater convenience because it does not require dilution and has long-lasting effects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25719693 TI - Perforation of viscera, a dramatic complication of liposuction: a review of 19 cases evaluated by experts in France between 2000 and 2012. AB - BACKGROUND: Perforation of one or several intraperitoneal organs during a liposuction procedure is an exceptional but underestimated complication. Knowledge of this complication is essential because of frequent delay in diagnosis and possible dramatic consequences. METHODS: Nineteen cases were evaluated by experts and are presented in a retrospective analysis. Sixteen women and three men, aged 24 to 72 years, were operated on in France between July of 2001 and January of 2012. Abdominal liposuction (200 to 2400 ml) was performed in combination or not with an abdominoplasty. RESULTS: Uncommon pain and an intestinal obstruction were present in all of the patients. The peritonitis was never frank, replaced frequently by infraclinic peritonitis with septic and/or hypovolemic shock. Diagnosis, performed by abdominal scan between days 1 and 7, revealed intraperitoneal gas or liquid. Perforation, unique or multiple, because of the intraperitoneal passage of the cannula, often in the umbilical region and promoted by the presence of a hernia, involved the following organs: ileum (14 cases), jejunum (two cases), spleen (two cases), transverse colon (one case), cecum (one case), and sigmoid (one case). Death occurred in three cases, between days 2 and 11. Eleven patients had temporary ileostomy or colostomy. Associated complications were abdominal wall cellulitis, necrotizing fasciitis, thrombophlebitis, lung collection, and late subobstructive syndrome. CONCLUSIONS: Visceral perforation during liposuction, a severe and sometimes fatal complication with late and difficult diagnosis, is not often reported. Careful technique, particularly if an umbilical approach is used, should avoid this dramatic complication. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719694 TI - The no-drain, no-quilt abdominoplasty: a single-surgeon series of 271 patients. AB - BACKGROUND: Recent innovations in abdominoplasty include progressive tension "quilting" sutures or Scarpa fascia preservation to limit the risk of seromas and hematomas. No-drain abdominoplasty with progressive tension sutures has been well documented. The authors describe outcomes in patients undergoing abdominoplasty with a modified surgical technique (including sub-Scarpa fascia fat preservation) and no use of drains or progressive tension sutures-the "no-drain, no-quilt" abdominoplasty. METHODS: A retrospective, single-surgeon (A.A.Q.), single-site analysis of all abdominoplasty patients from 2003 to 2012 was performed. Data were extracted from paper case notes. All patients underwent surgery carried out under general anesthesia. The operative technique and postoperative regimen are described. RESULTS: Two hundred seventy-one patients were identified over the 10 year period. Patients had a mean age of 45 years and mean body mass index of 27, and 98 percent were women. Concomitant abdominal liposuction was undertaken in 61 percent of all patients (165 of 271). Twenty-one patients (7.7 percent) had a seroma and five patients (1.8 percent) had a hematoma. Seven patients (2.6 percent) required a return to the operating room to manage complications, and 24 (8.9 percent) required elective revision. Patients were admitted for an average of 1.7 days, and mean follow-up was 6.2 months. CONCLUSIONS: Abdominoplasty can be performed safely without drains or quilting sutures/progressive tension sutures. Benefits are discussed in terms of the potential for reduced intraoperative time (compared with progressive tension sutures), and reduced patient discomfort and inpatient stay (compared with drain use). The authors demonstrate low complication and elective revision rates in their series. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719695 TI - Lower body lift after massive weight loss: autoaugmentation versus no augmentation. AB - BACKGROUND: Lower body lift procedures have increased in popularity to treat massive weight loss patients with redundant tissues of the buttocks. To date, no studies have specifically compared outcomes related to autoaugmentation versus no augmentation, complications, or patient satisfaction between these groups. METHODS: A retrospective review of 97 patients was performed to examine age, body mass index, length of stay, and complications. Patient satisfaction was assessed with a phone survey, and a blinded physician survey was used to assess aesthetics. RESULTS: Forty-two patients underwent autoaugmentation and 55 did not. The mean age of the patients was 46.1 years in the augmented group and 47.3 years in the nonaugmented group (p = 0.55); mean maximum body mass index was 52.1 versus 50.6 kg/m2, respectively (p = 0.42); mean current body mass index was 29.1 versus 27.7 kg/m2, respectively (p = 0.10); and mean change in body mass index was 23.1 versus 22.7 kg/m2, respectively (p = 0.81). Eighteen augmented patients (42.5 percent) had complications postoperatively compared with 11 nonaugmented patients (20 percent) (p = 0.012). Both groups would undergo the same procedure again and recommend it to a friend. Physicians repeatedly rated aesthetics of augmented buttocks higher than of nonaugmented buttocks (p <= 0.032). CONCLUSIONS: Autoaugmentation in lower body lift procedures has a higher rate of complications, primarily because of dehiscence. Despite physicians rating aesthetics higher for autoaugmented patients, patient satisfaction is similar between the groups; thus, fully informed patients should be able to decide between procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25719696 TI - Vaginal labiaplasty: current practices and a simplified classification system for labial protrusion. AB - BACKGROUND: Vaginal labiaplasty has been described for the management of functional and aesthetic problems associated with protrusion of the labia minora. Despite increasing numbers of procedures performed, there is a paucity of data to guide treatment paradigms. This systematic review aims to establish a simple, unifying classification scheme for labial protrusion and summarize current labiaplasty techniques and practices. METHODS: A systematic literature review was performed using the PubMed database. Additional articles were selected after reviewing references of identified articles. RESULTS: The search returned 247 articles. After applying inclusion criteria to identify prospective and retrospective studies evaluating different techniques, outcomes, complications, and patient satisfaction, 19 articles were selected. Labiaplasty of the labia minora was described in 1949 patients. Seven different surgical techniques were used for labiaplasty, including deepithelialization, direct excision, W-shaped resection, wedge resection, composite reduction, Z-plasty, and laser excision. Patient satisfaction rates for each technique ranged from 94 to 100 percent. The most common postoperative complication for all techniques was wound dehiscence (4.7 percent). Key areas for perioperative patient management were defined. CONCLUSIONS: Labiaplasty is safe and carries a high satisfaction rate. However, current practices remain exceedingly diverse. The authors propose a simplified classification system based on the distance of the lateral edge of the labia minora from that of the labia majora, rather than from the introitus. Key areas for perioperative patient management include patient anesthesia, resection technique used, wound closure, and postoperative care. Further randomized studies using a standardized classification system are required to better compare different techniques and establish best practices. PMID- 25719697 TI - Discussion: Vaginal labiaplasty: current practices and a simplified classification system for labial protrusion. PMID- 25719698 TI - Quality and safety outcomes of ambulatory plastic surgery facilities in California. AB - BACKGROUND: Although most cosmetic surgery procedures are performed at outpatient surgery facilities, there is little published literature on the quality and safety of such facilities. Furthermore, regulation of such facilities varies widely and may leave room for poor outcomes. The authors sought to determine whether all outpatient surgery facilities that are licensed by the California Department of Public Health have similar rates of postoperative complications. METHODS: A retrospective review was performed of all data collected from 2005 to 2010 by the California Office of Statewide Health Planning and Development. All outpatient surgery facilities licensed by the Department of Public Health must report encounter-level data to that office. Patients' subsequent inpatient admissions and emergency department visits were identified. Several cosmetic procedures were studied. Outcomes analyzed were the 30-day venous thromboembolism, hospital admission, and emergency department visit rates. RESULTS: A total of 160,847 patients and 635 facilities were included. By facility, the range for 30-day venous thromboembolism rates was 0 to 3.4 percent, the range for 30-day admission rates was 0 to 7.7 percent, and the range for 30 day emergency department visits was 0 to 22.8 percent. CONCLUSIONS: Analysis showed a significant variability in the rate of 30-day venous thromboembolism incidents, admissions, and emergency department visits. Some facilities had complication rates that were a significant deviation from the mean, whereas others had no complications. To ensure optimal quality and patient safety, it is necessary to analyze why outliers exist and identify ways to improve on the current system of licensure and outcomes reporting. PMID- 25719699 TI - The role and regulation of osteoclasts in normal bone homeostasis and in response to injury. AB - Bone is a dynamic tissue, with a range of diverse functions, including locomotion, protection of internal organs, and hematopoiesis. Optimum treatment of fractures and/or bone defects requires knowledge of the complex cellular interactions involved with bone healing and remodeling. Emerging data have underscored the importance of osteoclasts in this process, playing a key role both in normal bone turnover and in facilitating bone regeneration. In this review, the authors discuss the basic principles of osteoclast biology, including its cellular origins, its function, and key regulatory mechanisms, in addition to conditions that arise when osteoclast function is altered. PMID- 25719700 TI - Pearls and pitfalls of needle aponeurotomy in Dupuytren's disease. AB - BACKGROUND: Dupuytren's disease is a benign, progressive, fibroproliferative disease, and despite advances in basic science and technology, there remains no cure. To date, open fasciectomy procedures remain the criterion standard for the treatment of Dupuytren's disease despite a significant complication rate and recovery time. Needle aponeurotomy, a less invasive treatment, is associated with reduced complications and quicker recovery. METHODS: A literature review and a compilation of over 700 procedures was performed to highlight the clinical relevance of needle aponeurotomy. A step-by-step description of the author's technique for needle aponeurotomy is presented, emphasizing the pearls and pitfalls of the procedure. RESULTS: Recurrence rates for open fasciectomy are 5 to 10 percent per year compared with rates for needle aponeurotomy, which are 10 to 20 percent per year. Overall complication rates are much less frequent with needle aponeurotomy, with skin tears being the most common (3 percent). Needle aponeurotomy is cost effective compared with open fasciectomy. Recurrent proximal interphalangeal joint flexion contractures remain the most problematic in terms of correction. CONCLUSIONS: Needle aponeurotomy has been shown to be an extremely useful adjunct available to the surgeon in the treatment of Dupuytren's disease. This procedure can be performed easily in an outpatient setting or office and carries with it dramatic results. Needle aponeurotomy has a lower complication rate and quicker recovery when compared with open fasciectomy and is therefore offered to patients as a first-line treatment. PMID- 25719701 TI - Methicillin-resistant Staphylococcus aureus infection in the hand. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus has become an increasingly common cause of skin and soft-issue infections. The purpose of this study was to review and summarize the most recent literature on methicillin resistant S. aureus infections of the hand. METHODS: The English-language literature related to methicillin-resistant S. aureus infections of the hand was reviewed, and information related to the history, epidemiology, clinical presentation, and treatment of methicillin-resistant S. aureus infections of the hand was summarized. RESULTS: Community-acquired methicillin-resistant S. aureus hand infections have increased rapidly in prevalence over the past two decades. The prevalence varies markedly around the world, but in the United States, community-acquired methicillin-resistant S. aureus now causes the majority of purulent hand infections. CONCLUSIONS: Purulent hand infections should be treated with surgical drainage. When antibiotics are indicated, empiric coverage for community-acquired methicillin-resistant S. aureus should be provided if local prevalence rates exceed 10 to 15 percent. PMID- 25719702 TI - Microsurgical scalp reconstruction in the elderly: a systematic review and pooled analysis of the current data. AB - BACKGROUND: Microvascular reconstruction is the mainstay of treatment in complex scalp defects. The rate of elderly patients requiring scalp reconstruction is increasing, but outcomes in elderly patients are unclear. The purpose of this study was to systematically review the literature pertaining to free tissue transfer for scalp reconstruction in patients older than 65 years to compare outcomes among different free flaps and determine the safety profile of treatment. METHODS: A systematic review of the available literature of patients undergoing microvascular scalp reconstruction was completed. Details for patients 65 years and older were extracted and reviewed for data analysis. RESULTS: A total of 45 articles (112 patients) were included for analysis. Mean age of the patients was 73.3 +/- 6.3 years (men, 69.4 percent; women, 23.4 percent; not reported, 7.2 percent). Mean flap size was 598 cm2 (range, 81 to 2500 cm2). The mean age of patients developing a complication was 72.8 +/- 6.4 years and patients that did not develop a complication was 73.4 +/- 5.5 years (p = 0.684). Overall, periprocedural mortality was 0.9 percent. Flap failures occurred in two cases (1.8 percent). The overall complication rate was 22.3 percent (n = 25). Complications by flap type varied without reaching statistical significance. CONCLUSIONS: Microvascular reconstruction in complex scalp defects is associated with successful outcomes, and chronologic age does not increase mortality or catastrophic flap complications. The most common flaps used to repair scalp defects are anterolateral thigh and latissimus dorsi, but a superior flap type could not be identified. PMID- 25719703 TI - Analysis of the surgical treatments of 63 keloids on the cartilaginous part of the auricle: effectiveness of the core excision method. AB - BACKGROUND: Treatments for keloids on the cartilaginous part of the auricle (i.e., the upper part of the ear excluding the earlobe) include surgical excision, cryosurgery, postoperative radiation therapy, steroid injection, taping stabilization, and pressure therapy. However, to date, there is no universally accepted treatment strategy for auricle keloids. METHODS: In this retrospective cohort study, the 63 primary auricle keloids in all 57 patients who underwent surgery from 2006 to 2012 were included. Mild scars such as hypertrophic scars were excluded. All 63 scars were treated with surgery, namely, total excision or intralesional excision (core excision method), and postoperative adjuvant radiation therapy and self-managed scar stabilization with surgical tape. The postsurgical radiation therapy consisted of 15 Gy administered in three fractions over 3 days. The recurrence rates associated with the two surgical methods over 18 months of follow-up were recorded. RESULTS: Of the 57 patients, 91.2 percent were women. Of the 63 lesions, 95.2 percent and 4.8 percent were caused by piercing and trauma, respectively. All were primary keloids. Before 2009, all lesions (n = 37) were treated by total excision. After 2009, all lesions (n = 26) were treated by core excision. These methods were associated with recurrence rates of 8.1 percent and 0 percent, respectively, although this difference did not achieve statistical significance (p > 0.05). The overall recurrence rate was 4.8 percent. Complications such as wound dehiscence and pigmentation during the 18-month follow-up period were not observed. CONCLUSION: Auricle keloids can be treated by customized plans consisting of appropriate surgical modalities, postoperative radiotherapy, and self-management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25719704 TI - Do adjunctive flap-monitoring technologies impact clinical decision making? An analysis of microsurgeon preferences and behavior by body region. AB - BACKGROUND: Multiple perfusion assessment technologies exist to identify compromised microvascular free flaps. The effectiveness, operability, and cost of each technology vary. The authors investigated surgeon preference and clinical behavior with several perfusion assessment technologies. METHODS: A questionnaire was sent to members of the American Society for Reconstructive Microsurgery concerning perceptions and frequency of use of several technologies in varied clinical situations. Demographic information was also collected. Adjusted odds ratios were calculated using multinomial logistic regression accounting for clustering of similar practices within institutions/regions. RESULTS: The questionnaire was completed by 157 of 389 participants (40.4 percent response rate). Handheld Doppler was the most commonly preferred free flap-monitoring technology (56.1 percent), followed by implantable Doppler (22.9 percent) and cutaneous tissue oximetry (16.6 percent). Surgeons were significantly more likely to opt for immediate take-back to the operating room when presented with a concerning tissue oximetry readout compared with a concerning handheld Doppler signal (OR, 2.82; p < 0.01), whereas other technologies did not significantly alter postoperative management more than simple handheld Doppler. Clinical decision making did not significantly differ by demographics, training, or practice setup. CONCLUSIONS: Although most surgeons still prefer to use standard handheld Doppler for free flap assessment, respondents were significantly more likely to opt for immediate return to the operating room for a concerning tissue oximetry reading than an abnormal Doppler signal. This suggests that tissue oximetry may have the greatest impact on clinical decision making in the postoperative period. PMID- 25719705 TI - Discussion: Do adjunctive flap-monitoring technologies impact clinical decision making? An analysis of microsurgeon preferences and behavior by body region. PMID- 25719706 TI - Scarless wound healing: chasing the holy grail. AB - Over 100 million patients acquire scars in the industrialized world each year, primarily as a result of elective operations. Although undefined, the global incidence of scarring is even larger, extending to significant numbers of burn and other trauma-related wounds. Scars have the potential to exert a profound psychological and physical impact on the individual. Beyond aesthetic considerations and potential disfigurement, scarring can result in restriction of movement and reduced quality of life. The formation of a scar following skin injury is a consequence of wound healing occurring through reparative rather than regenerative mechanisms. In this article, the authors review the basic stages of wound healing; differences between adult and fetal wound healing; various mechanical, genetic, and pharmacologic strategies to reduce scarring; and the biology of skin stem/progenitor cells that may hold the key to scarless regeneration. PMID- 25719707 TI - Looking at plastic surgery through Google Glass: part 1. Systematic review of Google Glass evidence and the first plastic surgical procedures. AB - BACKGROUND: Google Glass has the potential to become a ubiquitous and translational technological tool within clinical plastic surgery. Google Glass allows clinicians to remotely view patient notes, laboratory results, and imaging; training can be augmented via streamed expert master classes; and patient safety can be improved by remote advice from a senior colleague. This systematic review identified and appraised every Google Glass publication relevant to plastic surgery and describes the first plastic surgical procedures recorded using Google Glass. METHODS: A systematic review was performed using PubMed National Center for Biotechnology Information, Ovid MEDLINE, and the Cochrane Central Register of Controlled Trials, following modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Key search terms "Google" and "Glass" identified mutually inclusive publications that were screened for inclusion. RESULTS: Eighty-two publications were identified, with 21 included for review. Google Glass publications were formal articles (n = 3), editorial/commentary articles (n = 7), conference proceedings (n = 1), news reports (n = 3), and online articles (n = 7). Data support Google Glass' positive impact on health care delivery, clinical training, medical documentation, and patient safety. Concerns exist regarding patient confidentiality, technical issues, and limited software. The first plastic surgical procedure performed using Google Glass was a blepharoplasty on October 29, 2013. CONCLUSIONS: Google Glass is an exciting translational technology with the potential to positively impact health care delivery, medical documentation, surgical training, and patient safety. Further high-quality scientific research is required to formally appraise Google Glass in the clinical setting. PMID- 25719708 TI - First impression followed by rational reasoning. PMID- 25719710 TI - Does breast reconstruction after mastectomy for breast cancer affect overall survival? Long-term follow-up of a retrospective population-based cohort. AB - BACKGROUND: This study compared overall and breast cancer-specific survival using long-term follow-up data among women diagnosed with invasive breast cancer undergoing mastectomy or breast reconstruction. METHODS: Retrospective study using population-based data from Ontario Cancer Registry (1980 to 1990) including women receiving breast reconstruction within 5 years after mastectomy and controls of age- and cancer histology-matched women with mastectomy alone. We compared overall and breast cancer-specific survival using an extended Cox hazards model. Secondary analysis examined conditional survival across early, intermediate, and late follow-up. RESULTS: Seven hundred fifty-eight matched pairs formed the cohort, with a median follow-up of 23.4 years (interquartile range, 1.1 to 33.0 years). Fewer breast reconstruction patients died overall or from breast cancer compared with controls (overall survival, 44.5 percent versus 56.7 percent, p < 0.0001; breast cancer-specific survival, 31.8 percent versus 42.6 percent, p = 0.0002, respectively). Breast reconstruction was associated with a 17 percent reduced risk of death and a 19 percent reduced risk of breast cancer death, after adjustment (overall survival hazard ratio, 0.83; 95 percent CI, 0.72 to 0.96; breast cancer-specific survival hazard ratio, 0.81; 95 percent CI, 0.68 to 0.99). Among 885 women (58 percent) surviving 20 or more years, there was no difference in risk of death from breast cancer (hazard ratio, 0.59; 95 percent CI, 0.31 to 1.10). CONCLUSION: In a large cohort with invasive breast cancer followed over 20 years, there is no evidence that breast reconstruction is associated with worse survival outcomes compared with mastectomy alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25719711 TI - Discussion: Does breast reconstruction after mastectomy for breast cancer affect overall survival? Long-term follow-up of a retrospective population-based cohort. PMID- 25719712 TI - Patient-reported outcome measures in reconstructive breast surgery: is there a role for generic measures? AB - BACKGROUND: Patient-reported outcomes provide an invaluable tool in the assessment of outcomes in plastic surgery. Traditionally, patient-reported outcomes have consisted of either generic or ad hoc measures; however, more recently, there has been interest in formally constructed and validated questionnaires that are specifically designed for a particular patient population. The purpose of this systematic review was to determine whether generic measures still have a role in the evaluation of breast reconstruction outcomes, given the recent popularity and push for use of specific measures. METHODS: A systematic review was performed to identify all articles using patient reported outcomes in the assessment of postmastectomy breast reconstruction. Frequency of use was tabulated and the most frequently used tools were assessed for success of use, using criteria described previously by the Medical Outcomes Trust. RESULTS: To date, the most frequently used measures are still generic measures. The 36-Item Short-Form Health Survey was the most frequently used and most successfully applied showing evidence of responsiveness in multiple settings. Other measures such as the Hospital Anxiety and Depression Scale, the Hopwood Body Image Scale, and the Rosenberg Self-Esteem Scale were able to show responsiveness in certain settings but lacked evidence as universal tools for the assessment of outcomes in reconstructive breast surgery. CONCLUSIONS: Despite the recent advent of measures designed specifically to assess patient-reported outcomes in the breast reconstruction population, there still appears to be a role for the use of generic instruments. Many of these tools would benefit from undergoing formal validation in the breast reconstruction population. PMID- 25719713 TI - Indocyanine green laser angiography improves deep inferior epigastric perforator flap outcomes following abdominal suction lipectomy. AB - BACKGROUND: The reliability of deep inferior epigastric artery perforator (DIEP) flap reconstruction following abdominal liposuction is controversial. The authors' early cases were technically successful; however, they experienced high partial flap loss and fat necrosis rates. The authors sought to compare DIEP flap outcomes in the setting of prior liposuction after the use of intraoperative indocyanine green angiography compared to when flaps were assessed on clinical grounds alone. METHODS: A retrospective review of a consecutive series of DIEP flaps following liposuction at a single institution was performed, comparing those evaluated on clinical grounds alone and those in which indocyanine green angiography was used intraoperatively. Outcomes measured included anastomotic complications, total flap loss, partial flap loss, fat necrosis, and postoperative abdominal wounds. RESULTS: Thirteen DIEP flaps following prior liposuction were performed on 11 patients from July of 2003 through January of 2014. All patients had preoperative imaging with duplex ultrasound or computed tomographic angiography to analyze perforator suitability before surgical exploration. Seven flaps were evaluated intraoperatively on clinical grounds alone. Six flaps were assessed and modified based on indocyanine green angiography. All flaps were successful; however, partial flap loss and fat necrosis rates dropped from 71.4 percent to 0 percent when indocyanine green angiography was used intraoperatively (p = 0.02). CONCLUSIONS: Indocyanine green angiography is an excellent vascular imaging modality for intraoperative use to assess flap perfusion, and improves outcomes in DIEP flaps when harvested after prior abdominal suction lipectomy. PMID- 25719714 TI - Risks and benefits of using an absorbable mesh in one-stage immediate breast reconstruction: a comparative study. AB - BACKGROUND: Complete implant coverage by pectoralis major muscle in immediate breast reconstruction prevents implant exposure but restricts implant volume, increases the risk of a high-riding implant, and prevents natural ptosis. The authors hypothesized that extension of the subpectoral pocket with Vicryl mesh may produce more satisfactory results. The safety and efficiency of this technique were assessed by comparing complication rates and clinical results of the two reconstruction techniques: with and without mesh. METHODS: The authors reviewed 161 immediate breast reconstructions in 139 patients from 2002 to 2010. A complete submuscular pocket was performed in 46 breasts and a partial submuscular pocket with Vicryl mesh extension was performed in 115 breasts. Complications, surgical revisions rates, implant size, and contralateral breast procedures were compared between the two groups. RESULTS: Early and late surgical revisions were similar between the mesh and nonmesh groups (11.6 percent versus 4.3 percent at 90 days, p = 0.09; and 34.3 percent versus 41.4 percent at 5 years, p = 0.41). There were fewer revisions for implant malposition in the mesh group (8.9 percent versus 21.7 percent, p = 0.05). Patients with mesh could have a larger implant in comparison with those without mesh (329 g versus 284 g, p = 0.01) and had fewer contralateral mastopexies (12 percent versus 30 percent, p = 0.01). CONCLUSIONS: Larger implants and perhaps better control of implant position were possible using the Vicryl mesh extension without increasing complications. Because the mesh technique also recreates a slightly ptotic breast, fewer contralateral mastopexies were needed. The Vicryl mesh extension is a low-cost alternative to biological matrices or tissue expanders. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25719715 TI - Secondary upper lid blepharoplasty: a clinical series using the tarsal fixation technique. AB - BACKGROUND: One hundred consecutive secondary upper lid blepharoplasties were reviewed retrospectively to determine the lid characteristics of patients undergoing secondary blepharoplasty and the outcomes of all the procedures, which were performed using a tarsal fixation technique performed by one surgeon. METHODS: The median age of the patients was 54 years, and 99 percent of the patients were women. The median time since primary blepharoplasty was 8.7 years (range, 2 to 22 years). At surgery, no additional skin was removed in 37 percent, and the median amount excised in the remainder was only 2 mm. Revision surgery was performed in 13 percent, mainly for incomplete correction of asymmetry (5 percent) or ptosis (4 percent). Nonsurgical complications were mainly ocular (8 percent). There were no cases of persistent postoperative lagophthalmos or dry eyes. RESULTS: The term "postblepharoplasty look" was introduced to describe the different aging changes that follow primary blepharoplasty, mainly dermatochalasis (70 percent), with a high or absent and often poorly defined lid fold, with fat distribution irregularities. The tarsal fixation technique is advantageous in secondary blepharoplasty, as its benefit does not depend on further skin removal, minimizing the risk of lagophthalmos and dry eye syndrome. Lipoinfiltration for volume contouring is another major advance. The higher revision rate in secondary blepharoplasty reflects the incidence of asymmetry, lid ptosis, and scar from the original blepharoplasty, and from ongoing aging. CONCLUSIONS: The postblepharoplasty look of patients undergoing secondary upper lid blepharoplasty differs from the lid appearance of patients presenting for primary blepharoplasty. Tarsal fixation and lipoinfiltration are major advances in secondary upper lid blepharoplasty. PMID- 25719716 TI - Transareolar-perinipple (areolar omega) zigzag incision for augmentation mammaplasty. AB - BACKGROUND: Optimal augmentation mammaplasty results not only from proper implant size and breast shape, but also from the minimization of postoperative scarring, especially in patients prone to hypertrophic scars. In this context, the authors present a transareolar-perinipple (areolar omega) zigzag approach. METHODS: Between March of 2003 and June of 2012, a total of 613 patients underwent augmentation mammaplasty using a transareolar-perinipple incision. Among them, 45 patients received a classic (straight line) transareolar-perinipple incision, whereas 568 patients received a modified zigzag transareolar-perinipple incision. RESULTS: Patients' ages ranged from 21 to 60 years. Areola size varied from 2.3 to 4.5 cm in diameter. Follow-up duration ranged from 1 to 10 years, with an average of 2 years 7 months. Postoperative complications included capsular contracture, which occurred in 16 patients (2.6 percent). Nine patients (1.5 percent) had Baker class II and seven patients (1.1 percent) had Baker class III capsular contracture. Mild inferior displacement of the implant occurred in four patients (0.6 percent). The prevalence of areolar distortion was 3.4 percent. Nipple hypesthesia was found in approximately 70 percent of the patients, which returned to normal after 2 to 3 months. Based on third-party observers, 74.7 percent of patients who received zigzag transareolar-perinipple incision had excellent to good scarring results. CONCLUSIONS: The transareolar-perinipple (areolar omega) zigzag incision resulted in satisfactory postoperative scarring and surgical results in Asian patients. This method increases the opening of the areolar incision and can be performed in patients with small (<3.5 cm) areolas. This approach can be an alternative in patients who are prone to hypertrophic scarring. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25719717 TI - Evaluation of abdominal cutaneous sensibility following abdominoplasty. AB - BACKGROUND: Cutaneous hypesthesia is an undesirable postoperative outcome following abdominoplasty. The purpose of this study was to evaluate postabdominoplasty cutaneous sensibility using clinical, quantitative, and reproducible methods. METHODS: Thirty patients who underwent abdominoplasty were divided into three groups: 0 to 12 months (short-term follow-up), 12 to 24 months (intermediate-term follow-up), and greater than 24 months (long-term follow-up) following abdominoplasty. Abdominal skin was divided into 12 areas, and superficial tactile sensibility was assessed subjectively using a patient questionnaire and objectively using Semmes-Weinstein monofilaments. Statistical analysis was performed using the t test, with significance defined as p <= 0.05. RESULTS: Seventeen patients (56.7 percent) subjectively reported the presence of any abdominal cutaneous sensibility change postoperatively. Of those, 82.4 percent reported indifference toward this outcome. The greatest degree of objective sensibility loss was noted in area 8 (infraumbilical), followed by areas 5 (supraumbilical) and 11 (midline infraincisional). In these areas, there were statistically significant decreases in the average cutaneous pressure thresholds between the short-term and intermediate-term follow-up groups, the intermediate-term and long-term follow-up groups, and the short-term and long term follow-up groups. CONCLUSIONS: Postabdominoplasty cutaneous sensibility losses improve over time. These findings may enable plastic surgeons to better inform their patients regarding the risk of sensibility loss and the longitudinal outcome of such changes postoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719718 TI - Volumetric and functional evaluation of the gluteus maximus muscle after augmentation gluteoplasty using silicone implants. AB - BACKGROUND: The gluteal muscles have been very important throughout the evolution of mankind for the adoption of the bipedal posture. Over the past 15 years, the intramuscular technique has become popular and has been improved, with enhanced results and reduced levels of postoperative complications. The insertion of gluteal implants within the musculature may be an intrinsic compression factor of these muscles. The objective of the present study was to evaluate the gluteus maximus function and its variation over a 12-month period after the insertion of the implant. METHODS: This was a prospective, controlled, clinical study. All subjects were female patients, with anthropometric characteristics and body mass index within preset limits to establish similar groups. Isokinetic test gluteus computed tomographic scans and clinical nutritional assessment were conducted in four stages during the study period: preoperatively and 3, 6, and 12 months after surgery. RESULTS: The study group presented 6.14 percent muscle atrophy to the left and 6.43 percent muscle atrophy to the right after the procedure. Muscle strength presented differences in hip flexion and adduction tests. CONCLUSIONS: The gluteus maximus muscle presents atrophy secondarily to gluteal augmentation surgery with implants. Variations in gluteus maximus muscle strength should not be attributed primarily to the surgical procedure or to the implants; physiologic and multifactorial variations should also be considered. Strength and volume variations did not show a significant correlation. Gluteal augmentation with implants was effective in improving the waist-to-hip ratio and in changing the anthropometric pattern from android to gynoid. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25719719 TI - The discordant histology of grafted fat: a systematic review of the literature. AB - BACKGROUND: All combinations of harvesting, processing, and injection have been attempted to maximize fat graft take following transplantation. Two theories behind fat transplantation have been proposed: cell survival and host replacement. Although the cell survival theory states that fat cells survive and undergo neovascularization following transfer, host replacement theory predicts adipocyte necrosis and replacement of cells by host tissues. Whether or not transferred fat survives, proliferates, or is replaced by fibrous tissue is relevant for the investment of future resources into this thriving field of research. METHODS: A literature search of the MEDLINE and Cochrane databases was performed for studies focusing on the histology of grafted fat after transplantation up to December of 2013. Histologic examinations of grafted fat were reviewed and compared in humans and animals. RESULTS: Sixty-six articles met inclusion criteria, and eight of them were human studies. There was widespread diversity in the method of fat harvest and transfer among the studies, and the date of examination after transfer. Many studies reported the presence of viable adipocytes, although an extensive amount of fibrosis and inflammatory infiltration was also seen, depending on the period of examination. CONCLUSIONS: Free fat grafts show a variable response following transplantation, with significant disagreement in the reported evidence. Although neovascularization and preservation of adipocyte architecture appear possible, other fat grafts are completely replaced by necrotic ghost cells and fibrotic ingrowth. Adipocyte survival likely contributes to volume maintenance, but fibrosis may also play a role. PMID- 25719720 TI - The angiogenic and adipogenic modes of adipose tissue after free fat grafting. AB - BACKGROUND: The major drawback of adipose grafting is its clinical unpredictability, which leads to surgeon and patient dissatisfaction. The mechanisms underlying angiogenesis and regeneration of the graft tissue are still unclear. METHODS: Mouse adipose tissue was processed using two different methods (fragmental and integral) and was used to identify the mode of angiogenesis of the graft. Cross-grafting of tissue from normal mice and transgenic mice expressing green fluorescent protein was used to observe the origin of cells during the adipose regeneration. RESULTS: Almost all the CD31 endothelial cells of the new vessels were derived from the recipient. The new vessels in the graft were mainly formed through recipient vessels growing into the graft rather than the reassembly of donor endothelial cells or the reconnection of recipient and donor vessels. Angiogenesis depends largely on recipient-site environment. The retention of donor-derived tissue dropped to only 10 percent 8 weeks after grafting, and the majority of the key regeneration cells, the CD34 cells, came from the recipient during adipogenesis (p < 0.05). In total, the retention of the recipient-derived tissue was up to 73 percent in the fragmental group and 47.5 percent in the integral group. CONCLUSIONS: The angiogenesis of the graft occurs by the classic "vessel branching" mode, in which the recipient plays a dominant role. The mode of graft tissue retention primarily involves CD34 adipose precursor cells derived from the recipient. PMID- 25719721 TI - Evaluation of a stepwise surgical approach to camptodactyly. AB - BACKGROUND: Camptodactyly is common, but its treatment remains controversial. Multiple deforming forces have been implicated in its pathogenesis. This study evaluates a logical clinical assessment and corresponding stepwise surgical plan. METHODS: Eighteen consecutive fingers (12 children) had surgery to treat camptodactyly of the proximal interphalangeal joint at a mean age of 8 years (range, 9 months to 15 years). The little (n = 13), ring (n = 2), and middle fingers (n = 3) were involved. Mean preoperative flexion contracture was 57 degrees (range, 35 to 75 degrees). All digits had moderate to severe contracture with functional impairment and were offered surgery. Preoperative and postoperative active range of motion was recorded. The sequential treatment steps correspond to the clinical examination and potentially involve volar skin release with flap, fascial release, flexor digitorum superficialis tenotomy, sliding volar plate release, extension lag correction, and Fowler extensor tenotomy. RESULTS: Mean postoperative flexion contracture resolved to 3 degrees (range, 0 to 25 degrees) at a mean follow-up of 11 months (range, 3 to 32 months). Mean proximal interphalangeal joint flexion was 88 degrees (range, 50 to 100 degrees). Fifteen of 18 fingers achieved full active proximal interphalangeal joint extension. The remaining digits had residual contractures of 5, 20, and 25 degrees. All digits had soft-tissue release with flap and flexor digitorum superficialis tenotomy, 16 had volar plate release, two had intrinsic transfers, and three had Fowler tenotomy release performed. CONCLUSIONS: This stepwise surgical approach effectively treats severe camptodactyly and appears to confirm the authors' suspected pathogenesis of the disorder. Lumbricals and interossei were not involved. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719722 TI - The newborn butterfly project: a shortened treatment protocol for ear molding. AB - BACKGROUND: Secondary to circulating maternal estrogens, a baby's ear cartilage is unusually plastic during the first few weeks of life, providing an opportunity to correct ear deformities by molding. If molding is initiated during the first days of life with a more rigid molding system than previously described in the literature, the authors hypothesized that treatment time would be reduced and the correction rate would increase. METHODS: An interdisciplinary team identified and assessed all infants born with ear deformities at New York-Presbyterian Hospital/Weill Cornell Medical Center. The authors conducted a prospective, institutional review board-approved study on the first consecutive 100 infants identified. Parents were surveyed initially, immediately after treatment, and at 6 and 12 months. RESULTS: One hundred fifty-eight ears in 96 patients underwent ear molding using the EarWell Infant Ear Correction System. Eighty-two percent of the children had the device placed in the newborn nursery and 95 percent had it placed before 2 weeks of life. Average treatment time was 14 days, and 96 percent of the deformities were corrected. Complications were limited to mild pressure ulcerations. Ninety-nine percent of parents stated that they would have the procedure repeated. CONCLUSIONS: The molding period can be reduced from 6 to 8 weeks to 2 weeks by initiating molding during the first weeks of life and using a more secure and rigid device. Through an interdisciplinary approach, the authors were able to identify patients and to correct the deformity earlier and faster than has been previously published, eliminating the need for surgical correction in many children. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719723 TI - A new mucosal propeller flap (deep lingual artery axial propeller): the renaissance of lingual flaps. AB - BACKGROUND: Lingual flaps provide ideal mucosal coverage for intraoral defects but traditionally require two surgical stages. The authors present an axial mucosal propeller flap for single-stage intraoral reconstruction. The flap includes the mucosa of the lateral side of the tongue, islanded on the deep lingual vessels. METHODS: Between 2011 and 2013, 23 patients underwent intraoral mucosal reconstruction with a deep lingual artery axial propeller flap after cancer resection in the cheek (n = 16), floor of the mouth (n = 2), retromolar trigone (n = 2), hard palate (n = 2), and soft palate (n = 1). Mean defect size was 19.5 cm. Preoperative and postoperative intraoral function was evaluated with the Functional Intraoral Glasgow Scale. RESULTS: The authors always achieved one stage reconstruction with primary donor-site closure. The only complications were an infection treated conservatively and a late oronasal fistula caused by radiotherapy. All patients resumed an oral diet after 1 week and none required surgical revision. Mean 12-month postoperative Functional Intraoral Glasgow Scale score was better than the preoperative score (13.5 versus 12.8). CONCLUSIONS: The deep lingual artery axial propeller flap combines the advantages of the traditional lingual flap (i.e., reliable axial vascularization and like-with-like reconstruction) with those of a propeller flap (i.e., one-stage transfer of like tissue and extreme mobility) and has wider indications than a conventional lingual flap. The technique is fast and has low morbidity and good functional results, and the authors recommend it as a first-choice technique to reconstruct moderate to large intraoral defects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25719724 TI - Evidence to support controversy in microsurgery. AB - Microsurgery practice, including preoperative patient selection, intraoperative technique, and anesthetic considerations, varies from institution to institution and from surgeon to surgeon. Many surgeons' practices are driven by "conventional wisdom," which is handed down from mentors to fellows and residents. In this article, the authors explore the oxymoron that there is evidence to support controversy in microsurgery. Indeed, if there was convincing evidence to support varying microsurgery practices, there would be no controversy. The authors conducted a review with a focus on evidence-based medicine to support microsurgery practice. PMID- 25719725 TI - Prospective randomized comparison of scar appearances between cograft of acellular dermal matrix with autologous split-thickness skin and autologous split thickness skin graft alone for full-thickness skin defects of the extremities. AB - BACKGROUND: The purpose of this study was to evaluate the clinical outcomes of cografting of acellular dermal matrix with autologous split-thickness skin and autologous split-thickness skin graft alone for full-thickness skin defects on the extremities. METHODS: In this prospective randomized study, 19 consecutive patients with full-thickness skin defects on the extremities following trauma underwent grafting using either cograft of acellular dermal matrix with autologous split-thickness skin graft (nine patients, group A) or autologous split-thickness skin graft alone (10 patients, group B) from June of 2011 to December of 2012. The postoperative evaluations included observation of complications (including graft necrosis, graft detachment, or seroma formation) and Vancouver Scar Scale score. RESULTS: No statistically significant difference was found regarding complications, including graft necrosis, graft detachment, or seroma formation. At week 8, significantly lower Vancouver Scar Scale scores for vascularity, pliability, height, and total score were found in group A compared with group B. At week 12, lower scores for pliability and height and total scores were identified in group A compared with group B. CONCLUSIONS: For cases with traumatic full-thickness skin defects on the extremities, a statistically significant better result was achieved with cograft of acellular dermal matrix with autologous split-thickness skin graft than with autologous split-thickness skin graft alone in terms of Vancouver Scar Scale score. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 25719726 TI - The best of tendon and nerve transfers in the upper extremity. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Identify the prerequisite conditions to perform a tendon or a nerve transfer. 2. Detail some of the current nerve and tendon transfer options in upper extremity peripheral nerve injuries. 3. Understand the advantages and disadvantages of tendon and nerve transfers used in isolation and in combination. 4. Appreciate the controversies that surround the nerve/tendon transfers. 5. Realize the treatment outcomes of peripheral nerve injuries. SUMMARY: Traditional treatment of a Sunderland fourth- or fifth-degree peripheral nerve injury has been direct neurorrhaphy, nerve grafting, or tendon transfers. With increasing knowledge of nerve pathophysiology, additional treatment options such as nerve transfers have become increasingly popular. With an array of choices for treating peripheral nerve injuries, there is debate as to whether tendon transfers and/or nerve transfers should be performed to restore upper extremity function. Often, tendon and nerve transfers are used in combination as opposed to one in isolation to obtain the most normal functioning extremity without unacceptable donor deficits. The authors tend to prefer reconstructive techniques that have proven long-term efficacy to restore function. Nerve transfers are becoming more common practice, with excellent results; however, the authors are wary of using nerve transfers that sacrifice possible secondary tendon reconstruction should the nerve transfer fail. PMID- 25719727 TI - Evolution of practice patterns in plastic surgery using Current Procedural Terminology mapping: a 9-year analysis of cases submitted by primary and recertification candidates to the American Board of Plastic Surgery. AB - BACKGROUND: Understanding plastic surgery practice patterns allows the specialty to detect subtle shifts in the market and develop proactive strategies to maintain market share. METHODS: Current Procedural Terminology codes from American Board of Plastic Surgery recertification and primary certification candidates from 2003 to 2011 were examined. Statistical analyses identified significant changes (p < 0.05) in the percentage of surgeons performing each type of procedure and trends in average case volume per surgeon. RESULTS: The overall number of procedures decreased from 2003 to 2011. There was a statistically significant (p < 0.05) decrease in the percentage of recertification and primary certification candidates performing facial cosmetic and facial malignancy procedures. Both groups also experienced statistically significant decrease in facial plastic surgery case volume. The percentage of surgeons performing breast reconstruction remained stable for the recertification group and increased significantly for primary certification surgeons. Breast reconstruction volume increased significantly for both groups. Craniofacial surgery remained stable in the percentage of surgeons performing the cases and case volume. Hand surgery experienced a significant loss of recertification surgeons performing hand surgery; however, hand surgery case volume remained stable for both groups. CONCLUSION: From 2003 to 2011, plastic surgery lost market share in facial cosmetic, facial malignancy, and hand surgery and maintained market share in breast and craniofacial surgery. CPT mapping enables us to analyze these trends to better train plastic surgeons to adapt to changing pressures both from economic recovery and from competing specialties seeking to benefit from redistribution of case loads. PMID- 25719728 TI - RACK1 predicts poor prognosis and regulates progression of esophageal squamous cell carcinoma through its epithelial-mesenchymal transition. AB - BACKGROUND: RACK1 is known to be involved in tumor progression, and its prognostic value on many kinds of tumors has been identified. However, there are limited studies about the functional role of RACK1 in esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: RACK1 expression was examined in 100 ESCC tissue samples using immunohistochemistry staining. RACK1 was knocked-down in ESCC cell lines by shRNA. The effects on cell proliferation, invasion and migration were examined in ESCC cell lines and nude mouse model. Vimentin and E cadherin were introduced to further study the association between RACK1 and EMT. RESULTS: RACK1 expression was significantly associated with the tumor length (P = 0.012), diameter<3 cm (P = 0.047), T stage (P = 0.032), and lymph node metastasis (P = 0.038), respectively. Kaplan-Meier survival analysis and Cox analyses revealed RACK1 expression was an independent predictor for OS (P = 0.030) and DFS (P = 0.027) in ESCC. Down-regulation of RACK1 inhibited cell proliferation, along with invasion and migration in vitro and in vivo. A significant positive correlation between RACK1 expression and vimentin (P = 0.0190) and an inverse correlation between RACK1 expression and E-cadherin (P = 0.0047) were found. CONCLUSIONS: RACK1 predicted poor prognosis in ESCC, promoted tumor progression, and was involved in EMT of ESCC. PMID- 25719729 TI - Determination of bleb capsule porosity with an experimental glaucoma drainage device and measurement system. AB - IMPORTANCE: Control of intraocular pressure after implantation of a glaucoma drainage device (GDD) depends on the porosity of the capsule that forms around the plate of the GDD. OBJECTIVE: To compare capsular porosity after insertion of 2 different GDDs using a novel implant and measurement system. DESIGN, SETTING, AND SUBJECTS: We performed an experimental interventional study at an eye research facility in a tertiary eye care center. Testing was performed on 22 adult New Zealand white rabbits that received the experimental GDD or an existing GDD. INTERVENTIONS: A new experimental GDD, the Center for Eye Research Australia (CERA) implant, was created using computer-aided design and a 3-dimensional printer. The CERA GDDs were implanted in the eyes of rabbits randomized into 1 of the following 3 groups: with no connection to the anterior chamber (n = 7), with connection to the anterior chamber for 1 week (n = 5), and with connection to the anterior chamber for 4 weeks (n = 5). In a control group (n = 5), a pediatric GDD was implanted without connection to the anterior chamber. We measured the capsular porosity using a pressure-gated picoliter pump at a driving pressure of 12 mm Hg. The animals were killed humanely for histologic study. MAIN OUTCOMES AND MEASURES: Porosity of the fibrous capsule around the implant. RESULTS: We found no difference in mean (SEM) capsular porosity between the CERA (3.39 [0.76; 95% CI, 1.43-5.48] uL/min) and pediatric (4.52 [0.52; 95% CI, 3.19-5.95] uL/min) GDDs (P = .28, unpaired t test) at 4 weeks without aqueous exposure. Mean (SEM) capsular porosity of CERA GDDs connected to the anterior chamber at 1 week was 2.46 (0.36; 95% CI, 1.55-3.44) uL/min but decreased to 0.67 (0.07; 95% CI, 0.49 0.86) uL/min at 4 weeks (P = .001, unpaired t test). CONCLUSIONS AND RELEVANCE: Our experimental method permits direct measurement of capsular porosity of an in situ GDD. In a comparison between an experimental (CERA) and an existing GDD, no differences were identified in capsular porosity or histologic reaction between the implants. These results suggest that the CERA GDD model can be used to test key components of glaucoma surgery and implant design. PMID- 25719730 TI - Sensitive detection of a tumor marker, alpha-fetoprotein, with a sandwich assay on a plasmonic chip. AB - Two types of plasmonic silver- and gold-coated grating biosensor chips (plasmonic chip) were applied in the detection of alpha-fetoprotein (AFP) with a sandwich imunoassay and surface plasmon field-enhanced fluorescence. On the plasmonic chip, unlabeled marker in the sandwich immunoassay was first quantitatively detected over a wide range between 10(-12) and 10(-8) g/mL. The affinity constants between AFP and anti-AFP antibody, which were obtained by fitting the experimental data to the Langmuir isotherm adsorption curve, were 1 * 10(8) g(-1) mL regardless of the kind of metal in the plasmonic chips. Although the fluorescence intensity on the silver plasmonic chip was 5 times larger than that on the gold plasmonic chip, the limit of detection (LOD) was on the order of 10( 11) g/mL and not improved with a silver plasmonic chip. Herein, we used a new setup that generated less dispersions of both the fluorescence intensity for nonspecific adsorption and the background (optical blank) signal and improved the LOD of AFP to 4 pg/mL (55 fM) with the silver plasmonic chip. With the highly sensitive detection in the sandwich immunoassay, the development of a plasmonic chip for clinical diagnosis by a blood test is promising. PMID- 25719732 TI - Having Their Say: Sex Workers Discuss Their Needs and Resources. AB - In many countries where HIV/AIDS is prevalent, social, cultural, and economic factors often mitigate the adoption of healthy reproductive behaviors and practices. One group that is particularly susceptible to mitigating influences is women who work in the sex trade. In this article, we utilize a culture-centered approach to determine how a population of sex workers in Nairobi, Kenya, perceives their individual, social, and structural needs and resources in relation to the public, their families, friends, and peers. We conclude the article with next steps regarding collaboration with media representatives and policymakers. PMID- 25719731 TI - Phenotypic population screen identifies a new mutation in bovine DGAT1 responsible for unsaturated milk fat. AB - Selective breeding has strongly reduced the genetic diversity in livestock species, and contemporary breeding practices exclude potentially beneficial rare genetic variation from the future gene pool. Here we test whether important traits arising by new mutations can be identified and rescued in highly selected populations. We screened milks from 2.5 million cows to identify an exceptional individual which produced milk with reduced saturated fat content, and improved unsaturated and omega-3 fatty acid concentrations. The milk traits were transmitted dominantly to her offspring, and genetic mapping and genome sequencing revealed a new mutation in a previously unknown splice enhancer of the DGAT1 gene. Homozygous carriers show features of human diarrheal disorders, and may be useful for the development of therapeutic strategies. Our study demonstrates that high-throughput phenotypic screening can uncover rich genetic diversity even in inbred populations, and introduces a novel strategy to develop novel milks with improved nutritional properties. PMID- 25719733 TI - Diblock copolymer micelles and supported films with noncovalently incorporated chromophores: a modular platform for efficient energy transfer. AB - We report generation of modular, artificial light-harvesting assemblies where an amphiphilic diblock copolymer, poly(ethylene oxide)-block-poly(butadiene), serves as the framework for noncovalent organization of BODIPY-based energy donor and bacteriochlorin-based energy acceptor chromophores. The assemblies are adaptive and form well-defined micelles in aqueous solution and high-quality monolayer and bilayer films on solid supports, with the latter showing greater than 90% energy transfer efficiency. This study lays the groundwork for further development of modular, polymer-based materials for light harvesting and other photonic applications. PMID- 25719735 TI - Short-term effect of gastric resection on circulating levels of ghrelin, peptide YY3-36 and obestatin in patients with early gastric cancer. AB - The short-term responses of gut hormones and the compensative interaction during a one-week period after subtotal gastrectomy in early gastric cancer (EGC) patients were assessed. Previous studies have reported gut hormonal changes after Roux-en-Y gastric bypass surgery. Blood samples were collected from 40 patients with EGC preoperatively, at 1 h after gastric resection, and on postoperative day (POD) 1, 3, and 7. Levels of active ghrelin, total ghrelin, obestatin, and PYY3 36 were measured. Total ghrelin level rapidly reached a nadir of 69.1%, while active ghrelin level had increased to 135.5% at 1 h after resection. Then, both returned to preoperative level. On the contrary, active/total ghrelin reached its nadir quickly at 1 h after resection and had returned to the preoperative level by POD 3. The nadir PYY3-36 level was 71.4% on POD 1, followed by a gradual recovery, and had increased to 116.5% by POD 7. The same pattern was observed for obestatin. Active ghrelin/obestatin showed an increase on POD 1 while total ghrelin/obestatin showed a decrease on POD 3. Then, both returned to preoperative level. These results suggest that a rapid interactive compensatory mechanism of gut hormones does exist in the remnant gastrointestinal tract after abrupt changes in the production reservoir in nonobese people. PMID- 25719734 TI - A quantitative and dynamic model of the Arabidopsis flowering time gene regulatory network. AB - Various environmental signals integrate into a network of floral regulatory genes leading to the final decision on when to flower. Although a wealth of qualitative knowledge is available on how flowering time genes regulate each other, only a few studies incorporated this knowledge into predictive models. Such models are invaluable as they enable to investigate how various types of inputs are combined to give a quantitative readout. To investigate the effect of gene expression disturbances on flowering time, we developed a dynamic model for the regulation of flowering time in Arabidopsis thaliana. Model parameters were estimated based on expression time-courses for relevant genes, and a consistent set of flowering times for plants of various genetic backgrounds. Validation was performed by predicting changes in expression level in mutant backgrounds and comparing these predictions with independent expression data, and by comparison of predicted and experimental flowering times for several double mutants. Remarkably, the model predicts that a disturbance in a particular gene has not necessarily the largest impact on directly connected genes. For example, the model predicts that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC1) mutation has a larger impact on APETALA1 (AP1), which is not directly regulated by SOC1, compared to its effect on LEAFY (LFY) which is under direct control of SOC1. This was confirmed by expression data. Another model prediction involves the importance of cooperativity in the regulation of APETALA1 (AP1) by LFY, a prediction supported by experimental evidence. Concluding, our model for flowering time gene regulation enables to address how different quantitative inputs are combined into one quantitative output, flowering time. PMID- 25719736 TI - Disorders of Sex Development: Lessons to be Learned from Studies of Spina Bifida and Craniofacial Conditions. AB - The purpose of this review is to discuss research methods and clinical management strategies employed with other conditions (i. e., spina bifida and craniofacial conditions) and how these methods and strategies could be applied to youth with disorders of sex development (DSD). The review focuses specifically on the potential overlap between DSD and these other conditions across the following 3 areas: (1) developmentally-oriented theories that underlie the research base for chronic physical conditions; (2) research designs and methodological features that have proved fruitful in these areas; and (3) the potential applicability to DSD of clinical management practices for youth with craniofacial conditions. PMID- 25719737 TI - Use of a modified Liverpool care pathway in a tertiary Asian hospital: is there still a role for it? AB - BACKGROUND: In 2007, the Care of the Dying clinical coordinated Pathway (CDP) was adapted from the United Kingdom Liverpool Care Pathway (LCP) and implemented in a tertiary hospital in Singapore to improve care in oncology and subsequently renal patients. With concerns about its use after the Neuberger review, an audit of patients on the CDP was performed to determine if the use of such a pathway should be continued locally. METHODS: A two-year retrospective audit of CDP use was conducted. Aspects of communication, initiation of CDP, patient monitoring, medications, nutrition, and hydration were assessed. RESULTS: In the 111 patient records reviewed, there were documented extent of care discussions with 94% of caregivers and 29% of patients before CDP initiation. Of the 88% of CDPs initiated within office hours, 90% fulfilled the inclusion criteria. All patients were monitored at least every eight hours. Seventy-three patients (66%) were prescribed opioids or sedatives and subsequently monitored appropriately, albeit 56% had no documented prior discussion with caregivers regarding medication use. Indications for opioid use were documented for all patients and only one patient had documentation of excessive sedation. Oral feeding and parenteral hydration were continued in 85% and 74% of patients, respectively. CONCLUSION: There was no documented compromise in medication safety, clinical monitoring, and provision of nutrition and hydration for patients on the CDP. However, documentation of important end-of-life decisions and conversations remain poor. Development of an alternative care tool encouraging systematic discussion and documentation of individualized end-of-life care plans should be considered. PMID- 25719738 TI - Corrigendum to: Changes in the Serum Level of Vitamin D During Healing of Tibial and Femoral Shaft Fractures [Published in Trauma Mon. 2014 February; 19(1): e10946]. AB - [This corrects the article DOI: 10.5812/traumamon.10946.]. PMID- 25719739 TI - Synthesis and disinfection effect of the pyridine-4-aldoxime based salts. AB - A set of new quaternary ammonium compounds based on pyridine-4-aldoxime was synthesized, characterized with analytical data (NMR, EA, HPLC, MS) and tested for in vitro antimicrobial activity (antibacterial, antifungal) and cytotoxicity. Quaternary pyridinium-4-aldoxime salts with length of alkyl side chain from C8 to C20 and belonging to the group of cationic surfactants were investigated in this work. An HPLC experimental protocol for characterization of mixtures of all homologues has been found. Antimicrobial evaluation found that yeast-type fungi were most sensitive towards C14 and C16 analogues, whereas the C16 analogue was completely ineffective against filamentous fungi. Antibacterial assessment showed versatility of C14 and relatively high efficacy of C16 against G+ strains and C14 against G- strains. Notably, none of the studied compounds exceeded the efficacy and versatility of the benzalkonium C12 analogue, and benzalkonium analogues also exhibited lower cytotoxicity in the cell viability assay. PMID- 25719740 TI - Bioassay-guided fractionation of Melastoma malabathricum Linn. leaf solid phase extraction fraction and its anticoagulant activity. AB - The aims of this study were to examine the bioactive component(s) responsible for the anticoagulant activity of M. malabathricum Linn. leaf hot water crude extract via bioassay-guided fractionation and to evaluate the effect of bioactive component(s) on the intrinsic blood coagulation pathway. The active anticoagulant fraction of F3 was subjected to a series of chromatographic separation and spectroscopic analyses. Furthermore, the effect of the bioactive component(s) on the intrinsic blood coagulation pathway was studied through immediate and time incubation mixing studies. Through Activated Partial Thromboplastin Time (APTT) assay-guided fractionation, Subfraction B was considered the most potent anticoagulant fraction. Characterisation of Subfraction B indicated that anticoagulant activity could partly be due to the presence of cinnamic acid and a cinnamic acid derivative. APTT assays for both the immediate and time incubation mixing were corrected back into normal clotting time range (35.4-56.3 s). In conclusion, cinnamic acid and cinnamic acid derivative from Subfraction B were the first such compounds to be discovered from M. malabathricum Linn. leaf hot water crude extract that possess anticoagulant activity. This active anticoagulant Subfraction B prolonged blood clotting time by causing factor(s) deficiency in the intrinsic blood coagulation pathway. PMID- 25719741 TI - In vitro and in vivo evaluation of novel cross-linked saccharide based polymers as bile acid sequestrants. AB - Bile acid sequestrants (BAS) represent a therapeutic approach for the management of hypercholesterolemia that relies on the cationic polymeric nature of BAS to selectively bind negatively charged bile acids. We hypothesized that the cross linking of beta-cyclodextrin (beta-CD) and saccharides such as starch or dextrin with divinyl sulfone (DVS) yields homo- and hetero-polymeric materials with the ability to trap sterols. Our hypothesis was put to test by synthesizing a library of 22 polymers that were screened to evaluate their capability to sequester both cholesterol (CHOL) and cholic and deoxycholic acids (CA and DCA). Three polymers synthesized in high yield were identified as promising. Two were neutral hetero polymers of beta-CD and starch or dextrin and the third was a weakly cationic homo-polymer of starch, highlighting the importance of the cavity effect. They were tested in hypercholesterolemic male Wistar rats and their ability to regulate hypercholesterolemia was similar to that for the reference BAS cholestyramine, but with two additional advantages: (i) they normalized the TG level and (ii) they did not increase the creatinine level. Neither hepatotoxicity nor kidney injury was detected, further supporting them as therapeutical candidates to manage hypercholesterolemia. PMID- 25719742 TI - Dose-dependent cytotoxic effects of boldine in HepG-2 cells-telomerase inhibition and apoptosis induction. AB - Plant metabolites are valuable sources of novel therapeutic compounds. In an anti telomerase screening study of plant secondary metabolites, the aporphine alkaloid boldine (1,10-dimethoxy-2,9-dihydroxyaporphine) exhibited a dose and time dependent cytotoxicity against hepatocarcinoma HepG-2 cells. Here we focus on the modes and mechanisms of the growth-limiting effects of this compound. Telomerase activity and expression level of some related genes were estimated by real-time PCR. Modes of cell death also were examined by microscopic inspection, staining methods and by evaluating the expression level of some critically relevant genes. The growth inhibition was correlated with down-regulation of the catalytic subunit of telomerase (hTERT) gene (p < 0.01) and the corresponding reduction of telomerase activity in sub-cytotoxic concentrations of boldine (p < 0.002). However, various modes of cell death were stimulated, depending on the concentration of boldine. Very low concentrations of boldine over a few passages resulted in an accumulation of senescent cells so that HepG-2 cells lost their immortality. Moreover, boldine induced apoptosis concomitantly with increasing the expression of bax/bcl2 (p < 0.02) and p21 (p < 0.01) genes. Boldine might thus be an interesting candidate as a potential natural compound that suppresses telomerase activity in non-toxic concentrations. PMID- 25719743 TI - Purification and immobilization of the recombinant Brassica oleracea Chlorophyllase 1 (BoCLH1) on DIAION(r)CR11 as potential biocatalyst for the production of chlorophyllide and phytol. AB - Recombinant Brassica oleracea chlorophyllase 1 (BoCLH1) with a protein molecular weight of 38.63 kDa was successfully expressed in E. coli and could catalyze chlorophyll (Chl) hydrolysis to chlorophyllide and phytol in vitro. In this study, we used DIAION(r)CR11, a highly porous cross-linked polystyrene divinylbenzene-based metal chelator, for purifying and immobilizing the poly (His)-tagged enzyme. The Cu(II) showed the highest protein adsorption (9.2 +/- 0.43 mg/g gel) and enzyme activity (46.3 +/- 3.14 U/g gel) for the immobilization of the poly (His)-tagged recombinant BoCLH1 compared with other metal chelators. Biochemical analysis of the immobilized enzyme showed higher chlorophyllase activity for Chl a hydrolysis in a weak base environment (pH 8.0), and activity above 70% was in a high-temperature environment, compared with the free enzyme. In addition, compared with free BoCLH1, the enzyme half-life (t1/2) of the immobilized BoCLH1 increased from 25.42 to 54.35 min (approximately two-fold) at 60 degrees C. The immobilized enzyme retained a residual activity of approximately 60% after 17 cycles in a repeated-batch operation. Therefore, DIAION(r)CR11Cu(II)-immobilized recombinant BoCLH1 can be repeatedly used to lower the cost and is potentially useful for the industrial production of chlorophyllide and phytol. PMID- 25719744 TI - Visible-light-controlled homo- and copolymerization of styrenes by a bichromophoric Ir-Pd catalyst. AB - Visible-light-controlled polymerization was achieved by a bichromophoric organopalladium catalyst which possesses a naphthyl-substituted cyclometallated Ir(III) light-absorbing moiety. The complex was highly active toward styrene polymerization upon visible-light irradiation, and its photoactivity toward polymerization and dimerization was switchable. On the basis of the switching activity, controlled copolymerization of styrene and vinyl ether was achieved upon photo-irradiation to give the corresponding copolymers. PMID- 25719745 TI - Natural colloidal P and its contribution to plant P uptake. AB - Phosphorus (P) bioavailability depends on its concentration and speciation in solution. Andisols and Oxisols have very low soil solution concentration of free orthophosphate, as they contain high concentrations of strongly P-sorbing minerals (Al/Fe oxyhydroxides, allophanes). Free orthophosphate is the form of P taken up by plants, but it is not the only P species present in the soil solution. Natural colloidal P (P associated with Al, Fe, and organic matter of sizes ranging from 1 to 1000 nm) constitutes an important fraction of soil solution P in these soils; however, its availability has not been considered. We measured the uptake of P by wheat (Triticum aestivum) from radiolabeled nonfiltered (colloid-containing) and 3-kDa filtered (nearly colloid-free) soil water extracts from Andisols and Oxisols. In the Andisol extracts, P uptake was up to 5-fold higher from the nonfiltered solutions than the corresponding 3-kDa filtered solutions. In the Oxisol extract, no difference in P uptake between both solutions was observed. Also the diffusional flux of P as measured with the DGT technique was larger in the nonfiltered than in the 3-kDa filtered solutions. Our results suggest that colloidal P from Andisols is not chemically inert and contributes to plant uptake of P. PMID- 25719747 TI - Correction to Tetra-substituted pyridinylimidazoles as dual inhibitors of p38alpha mitogen-activated protein kinase and c-Jun N-terminal kinase 3 for potential treatment of neurodegenerative diseases. PMID- 25719748 TI - DWFS: a wrapper feature selection tool based on a parallel genetic algorithm. AB - Many scientific problems can be formulated as classification tasks. Data that harbor relevant information are usually described by a large number of features. Frequently, many of these features are irrelevant for the class prediction. The efficient implementation of classification models requires identification of suitable combinations of features. The smaller number of features reduces the problem's dimensionality and may result in higher classification performance. We developed DWFS, a web-based tool that allows for efficient selection of features for a variety of problems. DWFS follows the wrapper paradigm and applies a search strategy based on Genetic Algorithms (GAs). A parallel GA implementation examines and evaluates simultaneously large number of candidate collections of features. DWFS also integrates various filtering methods that may be applied as a pre processing step in the feature selection process. Furthermore, weights and parameters in the fitness function of GA can be adjusted according to the application requirements. Experiments using heterogeneous datasets from different biomedical applications demonstrate that DWFS is fast and leads to a significant reduction of the number of features without sacrificing performance as compared to several widely used existing methods. DWFS can be accessed online at www.cbrc.kaust.edu.sa/dwfs. PMID- 25719749 TI - Rapid differentiation of commercial juices and blends by using sugar profiles obtained by capillary zone electrophoresis with indirect UV detection. AB - A method for the determination of sugars in several fruit juices and nectars by capillary zone electrophoresis with indirect UV-vis detection has been developed. Under optimal conditions, commercial fruit juices and nectars from several fruits were analyzed, and the sugar and cyclamate contents were quantified in less than 6 min. A study for the detection of blends of high-value juices (orange and pineapple) with cheaper alternatives was also developed. For this purpose, different chemometric techniques, based on sugar content ratios, were applied. Linear discriminant analysis showed that fruit juices can be distinguished according to the fruit type, juice blends also being differentiated. Multiple linear regression models were also constructed to predict the adulteration of orange and pineapple juices with grape juice. This simple and reliable methodology provides a rapid analysis of fruit juices of economic importance, which is relevant for quality control purposes in food industries and regulatory agencies. PMID- 25719750 TI - Whole heart coronary imaging with flexible acquisition window and trigger delay. AB - Coronary magnetic resonance imaging (MRI) requires a correctly timed trigger delay derived from a scout cine scan to synchronize k-space acquisition with the quiescent period of the cardiac cycle. However, heart rate changes between breath held cine and free-breathing coronary imaging may result in inaccurate timing errors. Additionally, the determined trigger delay may not reflect the period of minimal motion for both left and right coronary arteries or different segments. In this work, we present a whole-heart coronary imaging approach that allows flexible selection of the trigger delay timings by performing k-space sampling over an enlarged acquisition window. Our approach addresses coronary motion in an interactive manner by allowing the operator to determine the temporal window with minimal cardiac motion for each artery region. An electrocardiogram-gated, k space segmented 3D radial stack-of-stars sequence that employs a custom rotation angle is developed. An interactive reconstruction and visualization platform is then employed to determine the subset of the enlarged acquisition window for minimal coronary motion. Coronary MRI was acquired on eight healthy subjects (5 male, mean age = 37 +/- 18 years), where an enlarged acquisition window of 166 220 ms was set 50 ms prior to the scout-derived trigger delay. Coronary visualization and sharpness scores were compared between the standard 120 ms window set at the trigger delay, and those reconstructed using a manually adjusted window. The proposed method using manual adjustment was able to recover delineation of five mid and distal right coronary artery regions that were otherwise not visible from the standard window, and the sharpness scores improved in all coronary regions using the proposed method. This paper demonstrates the feasibility of a whole-heart coronary imaging approach that allows interactive selection of any subset of the enlarged acquisition window for a tailored reconstruction for each branch region. PMID- 25719751 TI - Patterned sensory nerve stimulation enhances the reactivity of spinal Ia inhibitory interneurons. AB - Patterned sensory nerve stimulation has been shown to induce plastic changes in the reciprocal Ia inhibitory circuit. However, the mechanisms underlying these changes have not yet been elucidated in detail. The aim of the present study was to determine whether the reactivity of Ia inhibitory interneurons could be altered by patterned sensory nerve stimulation. The degree of reciprocal Ia inhibition, the conditioning effects of transcranial magnetic stimulation (TMS) on the soleus (SOL) muscle H-reflex, and the ratio of the maximum H-reflex amplitude versus maximum M-wave (H(max)/M(max)) were examined in 10 healthy individuals. Patterned electrical nerve stimulation was applied to the common peroneal nerve every 1 s (100 Hz-5 train) at the motor threshold intensity of tibialis anterior muscle to induce activity changes in the reciprocal Ia inhibitory circuit. Reciprocal Ia inhibition, the TMS-conditioned H-reflex amplitude, and H(max)/M(max) were recorded before, immediately after, and 15 min after the electrical stimulation. The patterned electrical nerve stimulation significantly increased the degree of reciprocal Ia inhibition and decreased the amplitude of the TMS-conditioned H-reflex in the short-latency inhibition phase, which was presumably mediated by Ia inhibitory interneurons. However, it had no effect on H(max)/M(max). Our results indicated that patterned sensory nerve stimulation could modulate the activity of Ia inhibitory interneurons, and this change may have been caused by the synaptic modification of Ia inhibitory interneuron terminals. These results may lead to a clearer understanding of the spinal cord synaptic plasticity produced by repetitive sensory inputs. PMID- 25719752 TI - Ancient and contemporary DNA reveal a pre-human decline but no population bottleneck associated with recent human persecution in the kea (Nestor notabilis). AB - The impact of population bottlenecks is an important factor to consider when assessing species survival. Population declines can considerably limit the evolutionary potential of species and make them more susceptible to stochastic events. New Zealand has a well documented history of decline of endemic avifauna related to human colonization. Here, we investigate the genetic effects of a recent population decline in the endangered kea (Nestor notabilis). Kea have undergone a long-lasting persecution between the late 1800s to 1970s where an estimated 150,000 kea were culled under a governmental bounty scheme. Kea now number 1,000-5,000 individuals in the wild and it is likely that the recent population decline may have reduced the genetic diversity of the species. Comparison of contemporary (n = 410), historical (n = 15) and fossil samples (n = 4) showed a loss of mitochondrial diversity since the end of the last glaciation (Otiran Glacial) but no loss of overall genetic diversity associated with the cull. Microsatellite data indicated a recent bottleneck for only one population and a range-wide decline in Ne dating back some 300 - 6,000 years ago, a period predating European arrival in NZ. These results suggest that despite a recent human persecution, kea might have experienced a large population decline before stabilizing in numbers prior to human settlement of New Zealand in response to Holocene changes in habitat distribution. Our study therefore highlights the need to understand the respective effects of climate change and human activities on endangered species dynamics when proposing conservation guidelines. PMID- 25719753 TI - Temperature stress mediates decanalization and dominance of gene expression in Drosophila melanogaster. AB - The regulatory architecture of gene expression remains an area of active research. Here, we studied how the interplay of genetic and environmental variation affects gene expression by exposing Drosophila melanogaster strains to four different developmental temperatures. At 18 degrees C we observed almost complete canalization with only very few allelic effects on gene expression. In contrast, at the two temperature extremes, 13 degrees C and 29 degrees C a large number of allelic differences in gene expression were detected due to both cis- and trans-regulatory effects. Allelic differences in gene expression were mainly dominant, but for up to 62% of the genes the dominance swapped between 13 and 29 degrees C. Our results are consistent with stabilizing selection causing buffering of allelic expression variation in non-stressful environments. We propose that decanalization of gene expression in stressful environments is not only central to adaptation, but may also contribute to genetic disorders in human populations. PMID- 25719754 TI - Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold. AB - RATIONALE: A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea (OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA. OBJECTIVES: We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected patients with OSA. METHODS: Subjects were studied on two separate nights in a randomized crossover design. Fifteen unselected subjects with OSA (AHI >= 10/h) underwent a standard polysomnogram plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100 mg) and placebo, with 1 week between conditions. The arousal threshold was calculated as the nadir pressure before electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the non-REM arousal threshold (-20.3 vs. -19.3 cm H2O, P = 0.51) compared with placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P = 0.052) and had an accompanying reduction in arousal index, whereas nonresponders were not observed to have a change in sleep parameters. CONCLUSIONS: These findings suggest that trazodone could be effective therapy for patients with OSA without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical trial registered with www.clinicaltrials.gov (NCT 01817907). PMID- 25719755 TI - Can we treat knee osteoarthritis with photomedicine? PMID- 25719757 TI - Preoperative Use of Dexamethasone in Rhinoplasty: A Randomized, Double-blind, Placebo-Controlled Clinical Trial. AB - IMPORTANCE: Postoperative edema and ecchymosis following rhinoplasty are a cause of anxiety for both patients and physicians and can affect the cosmetic results. Corticosteroids have been used to reduce these events. OBJECTIVE: To determine whether preoperative use of dexamethasone sodium phosphate alters the occurrence of edema and ecchymosis following rhinoplasty. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trial at an institutional referral center among a sample of individuals with rhinomegaly. INTERVENTIONS: Patients were randomized into 2 groups. In group 1, dexamethasone was intravenously injected before surgery. In group 2, normal saline solution was intravenously injected before surgery. MAIN OUTCOMES AND MEASURES: When patients returned at 1 week after surgery, standardized photographs were obtained. The photographs were analyzed by 5 plastic surgeons who were blinded as to whether dexamethasone or normal saline solution had been injected. The plastic surgeons rated the degree of edema and ecchymosis. RESULTS: Forty-two patients participated in the study. Randomization by lottery resulted in 20 patients in group 1 and 22 patients in group 2. Group 1 showed lower rates of postoperative ecchymosis than group 2; the difference of 0.62 (P = .02) reflects less perceived ecchymosis when dexamethasone was administered. Group 1 also showed lower rates of postoperative edema than group 2; the difference of 0.68 (P = .01) reflects less perceived edema when dexamethasone was administered. CONCLUSIONS AND RELEVANCE: Preoperative use of dexamethasone reduced edema and ecchymosis at 7 days after rhinoplasty. Rigorous methods in this trial demonstrate the beneficial effect of preoperative corticosteroid administration in this surgical procedure. LEVEL OF EVIDENCE: 1. PMID- 25719756 TI - Oocyte mitochondrial function and reproduction. AB - PURPOSE OF REVIEW: Mitochondria are cellular organelles that are required for energy production. Emerging evidence demonstrates their role in oocyte development and reproduction. In this review, we examine recent animal and clinical studies on the role of mitochondria in fertility. We also analyse the impact of assisted reproductive techniques (ARTs) on mitochondrial function and discuss the future clinical implications of mitochondrial nutrients and mitochondrial replacement. RECENT FINDINGS: Mitochondria affect all aspects of mammalian reproduction. They are essential for optimal oocyte maturation, fertilization and embryonic development. Mitochondrial dysfunction causes a decrease in oocyte quality and interferes with embryonic development. ART procedures affect mitochondrial function, while mitochondrial nutrients may increase mitochondrial performance in oocytes. New mitochondrial replacement procedures using mitochondria obtained from polar bodies or from the patient's own oogonial stem cells are promising and may address concerns related to the induction of high-levels of heteroplasmy, which could potentially result in negative long-term health effects. SUMMARY: Optimal energy production is required for oocyte and embryo development, and mitochondrial abnormalities have devastating reproductive consequences. Improvement of oocyte mitochondrial function via intake of compounds that boost mitochondrial activity may have clinical benefits, and mitochondrial replacement could potentially be used for the prevention of mitochondrial diseases. PMID- 25719758 TI - Regulation of macrophage motility by the water channel aquaporin-1: crucial role of M0/M2 phenotype switch. AB - The water channel aquaporin-1 (AQP1) promotes migration of many cell types. Although AQP1 is expressed in macrophages, its potential role in macrophage motility, particularly in relation with phenotype polarization, remains unknown. We here addressed these issues in peritoneal macrophages isolated from AQP1 deficient mice, either undifferentiated (M0) or stimulated with LPS to orientate towards pro-inflammatory phenotype (classical macrophage activation; M1). In non stimulated macrophages, ablation of AQP1 (like inhibition by HgCl2) increased by 2-3 fold spontaneous migration in a Src/PI3K/Rac-dependent manner. This correlated with cell elongation and formation of lamellipodia/ruffles, resulting in membrane lipid and F4/80 recruitment to the leading edge. This indicated that AQP1 normally suppresses migration of resting macrophages, as opposed to other cell types. Resting Aqp1-/- macrophages exhibited CD206 redistribution into ruffles and increased arginase activity like IL4/IL13 (alternative macrophage activation; M2), indicating a M0-M2 shift. In contrast, upon M1 orientation by LPS in vitro or peritoneal inflammation in vivo, migration of Aqp1-/- macrophages was reduced. Taken together, these data indicate that AQP1 oppositely regulates macrophage migration, depending on stimulation or not by LPS, and that macrophage phenotypic and migratory changes may be regulated independently of external cues. PMID- 25719759 TI - Comparison of the transcriptomes of mouse skin derived precursors (SKPs) and SKP derived fibroblasts (SFBs) by RNA-Seq. AB - Skin-derived precursors (SKPs) from dermis possess the capacities of self-renewal and multipotency. In vitro and in vivo studies demonstrated that they can differentiate into fibroblasts. However, little is known about the molecular mechanism of the differentiation of SKPs into fibroblasts. Here we compare the transcriptomes of mouse SKPs and SKP-derived fibroblasts (SFBs) by RNA-Seq analysis, trying to find differences in gene expression between the two kinds of cells and then elucidate the candidate genes that may play important roles in the differentiation of SKPs into fibroblasts. A total of 1971 differentially expressed genes (DEGs) were identified by RNA-Seq, which provided abundant data for further analysis. Gene Ontology enrichment analysis revealed that genes related to cell differentiation, cell proliferation, protein binding, transporter activity and membrane were significantly enriched. The most significantly up regulated genes Wnt4, Wisp2 and Tsp-1 and down-regulated genes Slitrk1, Klk6, Agtr2, Ivl, Msx1, IL15, Atp6v0d2, Kcne1l and Thbs4 may play important roles in the differentiation of SKPs into fibroblasts. KEGG analysis showed that DEGs were significantly enriched in the TGF-beta signaling pathway, Wnt signaling pathway and Notch signaling pathway, which have been previously proven to regulate the differentiation and self-renewal of various stem cells. These identified DEGs and pathways could facilitate further investigations of the detailed molecular mechanisms, making it possible to take advantage of the potential therapeutic applications of SKPs in skin regeneration in the future. PMID- 25719761 TI - Molecular interaction forces generated during protein adsorption to well-defined polymer brush surfaces. AB - The molecular interaction forces generated during the adsorption of proteins to surfaces were examined by the force-versus-distance (f-d) curve measurements of atomic force microscopy using probes modified with appropriate molecules. Various substrates with polymer brush layers bearing zwitterionic, cationic, anionic, and hydrophobic groups were systematically prepared by surface-initiated atom transfer radical polymerization. Surface interaction forces on these substrates were analyzed by the f-d curve measurements using probes with the same polymer brush layer as the substrate. Repulsive forces, which decreased depending on the ionic strength, were generated between cationic or anionic polyelectrolyte brush layers; these were considered to be electrostatic interaction forces. A strong adhesive force was detected between hydrophobic polymer brush layers during retraction; this corresponded to the hydrophobic interaction between two hydrophobic polymer layers. In contrast, no significant interaction forces were detected between zwitterionic polymer brush layers. Direct interaction forces between proteins and polymer brush layers were then quantitatively evaluated by the f-d curve measurements using protein-immobilized probes consisting of negatively charged albumin and positively charged lysozyme under physiological conditions. In addition, the amount of protein adsorbed on the polymer brush layer was quantified by surface plasmon resonance measurements. Relatively large amounts of protein adsorbed to the polyelectrolyte brush layers with opposite charges. It was considered that the detachment of the protein after contact with the polymer brush layer hardly occurred due to salt formation at the interface. Both proteins adsorbed significantly on the hydrophobic polymer brush layer, which was due to hydrophobic interactions at the interface. In contrast, the zwitterionic polymer brush layer exhibited no significant interaction force with proteins and suppressed protein adsorption. Taken together, our results suggest that to obtain the protein-repellent surfaces, the surface should not induce direct interaction forces with proteins after contact with them. PMID- 25719760 TI - Design of high-throughput screening assays and identification of a SUMO1-specific small molecule chemotype targeting the SUMO-interacting motif-binding surface. AB - Protein-protein interactions are generally challenging to target by small molecules. To address the challenge, we have used a multidisciplinary approach to identify small-molecule disruptors of protein-protein interactions that are mediated by SUMO (small ubiquitin-like modifier) proteins. SUMO modifications have emerged as a target with importance in treating cancer, neurodegenerative disorders, and viral infections. It has been shown that inhibiting SUMO-mediated protein-protein interactions can sensitize cancer cells to chemotherapy and radiation. We have developed highly sensitive assays using time-resolved fluorescence resonance energy transfer (TR-FRET) and fluorescence polarization (FP) that were used for high-throughput screening (HTS) to identify inhibitors for SUMO-dependent protein-protein interactions. Using these assays, we have identified a nonpeptidomimetic small molecule chemotype that binds to SUMO1 but not SUMO2 or 3. NMR chemical shift perturbation studies have shown that the compounds of this chemotype bind to the SUMO1 surface required for protein protein interaction, despite the high sequence similarity of SUMO1 and SUMO2 and 3 at this surface. PMID- 25719762 TI - Pharmacists' views on implementing a disease state management program for low back pain. AB - Pharmacists have the potential to take a lead role in the primary care management of people with acute low back pain. The aim of this study was to investigate pharmacists' views on implementing a care program for people with acute low back pain in the community pharmacy. Recruitment of pharmacists for this study took place between July 2012 and March 2013. A convenience sample of 30 pharmacists who collaborated in recruiting participants for a low back pain clinical trial in Sydney (n=15 pharmacist recruiters and n=15 non-recruiters) completed an open ended questionnaire. There was no marked variation in responses between the two groups. Participating pharmacists were receptive to the idea of implementing a care program for people with low back pain, highlighting the need for adequate reimbursement and adequate training of staff to ensure it is successful. Pharmacists identified that the follow up of people receiving such a service is dependent on several factors such as effective reminder systems and the proximity of patients to the pharmacy. PMID- 25719763 TI - A retrospective study of dual-energy CT for clinical detecting of metastatic cervical lymph nodes in laryngeal and hypopharyngeal squamous cell carcinoma. AB - CONCLUSION: After the reconstruction of imaging in dual-energy CT gemstone spectral imaging, the ratio of the two slopes curves, the target lymph node and primary lesion, respectively, might contribute to the clinical diagnosis of cervical lymph nodes in laryngeal and hypopharyngeal squamous carcinoma. OBJECTIVE: To investigate the value of the dual-energy CT gemstone spectral imaging for clinical detecting of metastatic cervical lymph nodes in laryngeal and hypopharyngeal squamous carcinoma. METHODS: Forty-seven cases who were suffering from laryngeal or hypopharyngeal squamous carcinoma and had complete clinical and pathological data were included, and 79 cervical lymph nodes were studied retrospectively (including 31 metastatic nodes and 48 non-metastatic nodes). Contrast-enhanced energy spectral imaging and reconstruction were performed. After the reconstruction, the slope of the curve in the target lymph node and the lesion were calculated. The ratio of the two slopes was studied. The pathological data of cervical lymph node and primary lesion were also collected. RESULTS: The ratios were 1.20 +/- 0.09 and 0.82 +/- 0.12 in metastatic and non metastatic lymph nodes, respectively. The difference was statistically significant (p < 0.05). The ratio was positively correlated to the stasis of lymph nodes only, rather than their morphological appearance, the pathological classification, or the individual difference (p < 0.05). PMID- 25719764 TI - Foreword. Interest for food and nutrition population studies. PMID- 25719765 TI - Consensus document and conclusions. Methodology of dietary surveys, studies on nutrition, physical activity and other lifestyles. PMID- 25719766 TI - Controversies about population, clinical or basic research studies related with food, nutrition, physical activity and lifestyle. AB - Nutritional studies including food and beverage consumption assessment are needed for different purposes in the field of nutrition, food supply monitoring, toxicology or in the context of intervention strategies that include changes in eating behaviors. Different methods have been used, each with strengths, weaknesses, biases and limitations that must be considered when choosing the most appropriate in each case. The development of new technologies offers exciting developments to improve the validity and accuracy of these methods, as well as their efficiency and commodity. The characteristics of the individuals under study, its environment and the resources available should be considered as well. PMID- 25719767 TI - Historical overview of diet assessment and food consumption surveys in Spain: assessment methods and applications. AB - The food consumption assessment methods are used in nutrition and health population surveys and are the basis for the development of guidelines, nutritional recommendations and health plans, The study of these issues is one of the major tasks of the research and health policy in developed countries. Major advances nationally in this area have been made since 1940, both in the reliability of the data and in the standardization of studies, which is a necessary condition to compare changes over time. In this article the history and application of different dietary surveys, dietary history and food frequency records are analyzed. Besides information from surveys conducted at a national level, the main data currently available for public health planning in nutrition comes from nutritional analysis of household budget surveys and food balance sheets, based on data provided by the Ministry of Agriculture. PMID- 25719768 TI - Sources of information on food consumption in Spain and Europe. AB - Estimation of food consumption and nutrient intake is a topic of growing interest. Currently, both in Europe and in Spain, there are numerous sources of information on food consumption, that we provide information on different levels: national, household and individual, all of them are useful, but including some limitations, mainly arising from the lack of accurate data on food purchased but not consumed. The data obtained allow, among other things, meet dietary habits, explore the food quality, study the energy and nutrient intake and / or assessing exposure to food risks. Among the existing sources in Spain can highlight two surveys especially useful: the Household Budget Survey of the National Statistics Institute (INE) and Food Consumption Panel Ministry of Agriculture, Food and Environment (MAGRAMA). Both provide for many years food consumption but, lately, only in households. Both European and Spanish would be necessary to improve the usefulness of the data, standardize the type of survey used and could be comparable between them. PMID- 25719769 TI - Dietary assessment methods: dietary records. AB - Dietary records or food diaries can be highlighted among dietary assessment methods of the current diet for their interest and validity. It is a prospective, open-ended survey method collecting data about the foods and beverages consumed over a previously specified period of time. Dietary records can be used to estimate current diet of individuals and population groups, as well as to identify groups at risk of inadequacy. It is a dietary assessment method interesting for its use in epidemiological or in clinical studies. High validity and precision has been reported for the method when used following adequate procedures and considering the sufficient number of days. Thus, dietary records are often considered as a reference method in validation studies. Nevertheless, the method is affected by error and has limitations due mainly to the tendency of subjects to report food consumption close to those socially desirable. Additional problems are related to the high burden posed on respondents. The method can also influence food behavior in respondents in order to simplify the registration of food intake and some subjects can experience difficulties in writing down the foods and beverages consumed or in describing the portion sizes. Increasing the number of days observed reduces the quality of completed diet records. It should also be considered the high cost of coding and processing information collected in diet records. One of the main advantages of the method is the registration of the foods and beverages as consumed, thus reducing the problem of food omissions due to memory failure. Weighted food records provide more precise estimates of consumed portions. New Technologies can be helpful to improve and ease collaboration of respondents, as well as precision of the estimates, although it would be desirable to evaluate the advantages and limitations in order to optimize the implementation. PMID- 25719770 TI - What and how much do we eat? 24-hour dietary recall method. AB - Diet, along with lifestyle factors, is an important determinant of the health status of an individual and of a community. Dietary assessment at the population level provides us with key information on the frequency and distribution of possible inadequate diets and/or nutritional status. It is also useful as input into the elaboration of food and nutrition policies aiming to improve dietary habits and the health status of a community. This article reviews the characteristics, advantages and limitations of the 24-hour dietary recall method (24hDR), which is one of the most widely used tools in nutrition epidemiology to identify food, energy and nutrient intake in national nutrition surveys, cross sectional studies, clinical trials and cohort studies as well as in the evaluation of individual dietary intake and Total Diet assessment. To reduce the key factors associated with bias, the importance of previously trained interviewers is highlighted, as well as the role of support materials and the contribution of novel technologies. PMID- 25719771 TI - Food frequency questionnaires. AB - Food Frequency Questionnaires are dietary assessment tools widely used in epidemiological studies investigating the relationship between dietary intake and disease or risk factors since the early '90s. The three main components of these questionnaires are the list of foods, frequency of consumption and the portion size consumed. The food list should reflect the food habits of the study population at the time the data is collected. The frequency of consumption may be asked by open ended questions or by presenting frequency categories. Qualitative Food Frequency Questionnaires do not ask about the consumed portions; semi quantitative include standard portions and quantitative questionnaires ask respondents to estimate the portion size consumed either in household measures or grams. The latter implies a greater participant burden. Some versions include only close-ended questions in a standardized format, while others add an open section with questions about some specific food habits and practices and admit additions to the food list for foods and beverages consumed which are not included. The method can be self-administered, on paper or web-based, or interview administered either face-to-face or by telephone. Due to the standard format, especially closed-ended versions, and method of administration, FFQs are highly cost-effective thus encouraging its widespread use in large scale epidemiological cohort studies and also in other study designs. Coding and processing data collected is also less costly and requires less nutrition expertise compared to other dietary intake assessment methods. However, the main limitations are systematic errors and biases in estimates. Important efforts are being developed to improve the quality of the information. It has been recommended the use of FFQs with other methods thus enabling the adjustments required. PMID- 25719772 TI - Diet history: Method and applications. AB - The diet history is a traditional method of analysis of food intake. In its traditional structure consists of three components that provide an overall information of the usual food consumption pattern of the individual and also detailed information on certain foods. The information is collected in an interview and requires highly experienced qualified interviewers. The quality of information depends largely on the skills of the interviewer. It is mostly used in clinical practice. It has also been used in studies of diet and health relationship to investigate the usual diet in the past. The high cost and long duration of the interview limit their usefulness in large epidemiological studies. PMID- 25719773 TI - Assessment of beverage intake and hydration status. AB - Water is the main constituent of the human body. It is involved in practically all its functions. It is particularly important for thermoregulation and in the physical and cognitive performance. Water balance reflects water intake and loss. Intake of water is done mainly through consumption of drinking water and beverages (70 to 80%) plus water containing foods (20 to 30%). Water loss is mainly due to excretion of water in urine, faeces and sweat. The interest in the type and quantity of beverage consumption is not new, and numerous approaches have been used to assess beverage intake, but the validity of these approaches has not been well established. There is no standardized questionnaire developed as a research tool for the evaluation of water intake in the general population. Sometimes, the information comes from different sources or from different methodological characteristics which raises problems of the comparability. In the European Union, current epidemiological studies that focus exclusively on beverage intake are scarce. Biomarkers of intake are able to objectively assess dietary intake/status without the bias of self-reported dietary intake errors and also overcome the problem of intra-individual diet variability. Furthermore, some methods of measuring dietary intake used biomarkers to validate the data it collects. Biological markers may offer advantages and be able to improve the estimates of dietary intake assessment, which impact into the statistical power of the study. There is a surprising paucity of studies that systematically examine the correlation of beverages intake and hydration biomarker in different populations. A pilot investigation was developed to evaluate the comparative validity and reliability of newly developed interactive multimedia (IMM) versions compared to validated paper-administered (PP) versions of the Hedrick et al. beverage questionnaire. The study showed that the IMM appears to be a valid and reliable measure to assess habitual beverage intake. Similar study was developed in China, but in this case, the use of Smartphone technology was employed for beverage assessment. CONCLUSION: The methodology for measuring beverage intake in population studies remains controversial. There are few validated and reproducible studies, so there is still lacking an ideal method (ie, short, easy to administer, inexpensive and accurate) in this regard. Clearly, this is an area of scientific interest that is still in development and seems to be very promising for improving health research. PMID- 25719774 TI - Consumption estimation of non alcoholic beverages, sodium, food supplements and oil. AB - The interest in the type and quantity of non alcoholic beverage, sodium, food supplements and oil consumption is not new, and numerous approaches have been used to assess beverage intake, but the validity of these approaches has not been well established. The need to intake liquids varies depending on the diet, the physical activity carried out, the environmental temperature, the humidity, etc. The variety of beverages in the diet can contribute to increasing the micro nutrient intake: vitamins, antioxidants, minerals. Risks associated to high sodium consumption are: an increase in high blood pressure, vascular endothelial deterioration, bone demineralisation, kidney disease, stomach cancer. Progress in health, investigation, education, etc. are leading to an increase in food supplement consumption. Olive oil represents one of the basic pillars of the Mediterranean diet and its normal presence in nutrition guarantees an adequate content of some important nutrients; not only oleic acid and linoleic acid but also tocopherols, phytoesterols and phenolic compounds. Biomarkers of intake are able to objectively assess dietary intake/status without the bias of self reported dietary intake errors and also overcome the problem of intra-individual diet variability. Furthermore, some methods of of measuring dietary intake used biomarkers to validate the data it collects. Biological markers may offer advantages and be able to improve the estimates of dietary intake assessment, which impact into the statistical power of the study. There is a surprising paucity of studies that systematically examine the correlation of beverages intake and hydration biomarker in different populations. CONCLUSION: There is no standardized questionnaire developed as a research tool for the evaluation of non alcoholic beverages, sodium, food supplements and oil intake in the general population. Sometimes, the information comes from different sources or from different methodological characteristics which raises problems of the comparability. In the European Union, current epidemiological studies are scarce. PMID- 25719775 TI - Dietary assessment in children and adolescents: issues and recommendations. AB - The assessment of dietary intake in children and adolescents is of great interest for different purposes. The characteristics of each developmental stage and associated cognitive abilities are two factors that influence the ability of children to provide valid and reliable information on food consumption. The ability to remember, limitations of vocabulary or the ability to identify different foods are some of the relevant aspects. In addition, often parents or caregivers provide surrogate information and their degree of knowledge depends on the time they spend with the child and on whether they share meals. As children grow they become more independent and increasingly spend more time away from their parents. Children also have limitations to recognize food models and photographs and associate them with different amounts of food consumed. On the other hand, often children and adolescents perceive long interviews or self administered questionnaires they as long and boring. The use of new technologies is contributing to the development of new tools adapting dietary assessment the methods to the cognitive abilities of children, introducing gaming environments and narrative structures that attract their interest and improve the quality of information they report.. PMID- 25719776 TI - Special considerations for nutritional studies in elderly. AB - The elderly population is increasing and it is well documented that may present some health problems related to nutritional intake. Both mental and physical impairments in the elderly may need specific adaptations to dietary assessment methods. But all self-report approaches include systematic and random errors, and under-reporting of dietary energy intake is common. Biomarkers of protein intake, as 24 hours urinary Nitrogen, may not be useful in elderly patients because of incontinence problems. Some micronutrients, like vitamin B12, have special importance in the elderly population. Also, measurement of fluid intake is also critical because elderly population is prone to dehydration. A detailed malnutrition status assessment should be included in the geriatric dietary history, and assessment. Body mass index (BMI) is not useful in the elderly, and it is important to evaluate functional status. Gait speed, handgrip strength using hand dynamometry can be used. Body Shape Index (ABSI) appears to be an accurate measure of adiposity, and is associated with total mortality. Further research is needed to clarify the best and simple methods to accurately estimate food and beverage fluid intake in the elderly population, and to evaluate nutritional and hidration status. PMID- 25719777 TI - Screeners and brief assessment methods. AB - In the last two decades easy-to-use simple instruments have been developed and validated to assess specific aspects of the diet or a general profile that can be compared with a reference dietary pattern as the Mediterranean Diet or with the recommendations of the Dietary Guidelines. Brief instruments are rapid, simple and easy to use tools that can be implemented by unskilled personnel without specific training. These tools are useful both in clinical settings and in Primary Health Care or in the community as a tool for triage, as a screening tool to identify individuals or groups of people at risk who require further care or even they have been used in studies to investigate associations between specific aspects of the diet and health outcomes. They are also used in interventions focused on changing eating behaviors as a diagnostic tool, for self-evaluation purposes, or to provide tailored advice in web based interventions or mobile apps. There are some specific instruments for use in children, adults, elderly or specific population groups. PMID- 25719778 TI - Energy balance, a new paradigm and methodological issues: the ANIBES study in Spain. AB - Energy Balance (EB) is an important topic to understand how an imbalance in its main determinants (energy intake and consumption) may lead to inappropriate weight gain, considered to be "dynamic"and not "static". There are no studies to evaluate EB in Spain and new technologies reveal as key tools to solve the common problems to precisely quantify energy consumption and expenditure at population level. Within this context, the increasing complexity of the diet, but also the common problems of under and over reporting in nutrition surveys have to be taken into account. The overall purpose of the ANIBES ("Anthropometry, Intake and Energy Balance in Spain") Study was to carry out an accurate updating of foods and beverages intake, dietary habits/ behaviour and anthropometric data of the Spanish population as well as the energy expenditure and physical activity patterns, by the use of new tested instruments (i.e. tablet device to assess energy intake and accelerometer to evaluate physical activity). This new ANIBES Study will contribute to a better knowledge of the different key factors contributing to EB in Spain. PMID- 25719779 TI - Biases and adjustments in nutritional assessments from dietary questionnaires. AB - In nutritional epidemiology, it is essential to use Food Consumption Assessment Methods that have been validated and accepted by the international community for estimating food consumption of individuals and populations. This assessment must be made with the highest quality possible so as to avoid, as far as possible, sources of error and confusion in the processes. The qualities that are required in a measurement method are validity and accuracy; validity being the main factor. Lack of validity produces biases, or systematic errors. These can reside in the process of subject selection, or processes of information gathering where the lack of accuracy produces random errors. For many nutrients, the intra individual variances are due to many factors such as day-of-the-week or season, and could create problems in the data analyses. Adjustments are needed to minimize these effects. Confounding factors may over- or under-state the real magnitude of the observed association, or even alter the direction of the real association. Total energy intake can be a confounding variable when studying a relationship between nutrient intake and disease risk. To control for this effect several approximations are proposed such as nutrient densities, standard multivariate models and the nutrient residual model. PMID- 25719780 TI - Misreporting in nutritional surveys: methodological implications. AB - The reliability of the information collected in dietary assessment can be affected by different factors. One of the main sources of error in dietary assessment is misreporting which encompass under- and overreporting. Underreporting of food intake is one of the major problems in the assessment of habitual dietary intake. Physical and psychosocial characteristics that are related to energy underreporting include sex, age, weight, BMI, fear of negative evaluation and dieting among others. At present, diverse reference methods are employed to verify the results of dietary assessment and double labelled water is used as the gold standard method. Underreporting affects the estimation of nutrient intake and also alters associations between diet and disease assessed in epidemiological studies. Therefore, underreporting has to be considered and addressed by researchers through development and improvement of dietary intake adjustment methods, and taking advantage of the new technologies for assessing dietary intake in order to minimize underreporting bias. PMID- 25719781 TI - Indicators for the evaluation of diet quality. AB - The role of diet quality and physical activity in reducing the progression of chronic disease is becoming increasingly important. Dietary Quality Indices or Indicators (DQIs) are algorithms aiming to evaluate the overall diet and categorize individuals according to the extent to which their eating behaviour is "healthy". Predefined indexes assess dietary patterns based on current nutrition knowledge and they have been developed primarily for nutritional epidemiology to assess dietary risk factors for non-communicable diseases. There are many different types of DQIs. There are three major categories of DQIs: a) nutrient based indicators; b) food/food group based indicators; and c) combination indexes, the vast majority of DQIs, which often include a measure of diet variety within and across food groups, a measure of adequacy i.e. nutrients (compared to requirements) or food groups (quantities or servings), a measure of nutrients/foods to consume in moderation, and an overall balance of macronutrients. The Healthy Eating Index (HEI), the Diet Quality Index (DQI), the Healthy Diet Indicator (HDI) and the Mediterranean Diet Score (MDS) are the four 'original' diet quality scores that have been referred to and validated most extensively. Several indexes have been adapted and modified from those originals. In particular, many variations on the MDS have been proposed, included different alternate MDS and Mediterranean Diet Adherence Screener (MEDAS). Primary data source of DQI's are individual dietary data collection tools, namely 24 h quantitative intake recalls, dietary records and food frequency questionnaires. Nutrients found in many scores are total fat, saturated fatty acids or the ratio of monounsaturated fatty acids to saturated fatty acids or the latter SFA to polyunsaturated fatty acids. Cholesterol, protein content and quality, complex carbohydrates, mono- and disaccharides, dietary fibre and sodium are also found in various scores. All DQIs, except those that only contain nutrients, include the components fruits and vegetables; additional attributes are legumes or pulses, nuts and seeds. Meat and meat products, namely red and processed meat, poultry, and milk and dairy products are also included in many scores. Other foods contained in some DQIs e.g. MDS are olive oil and fish. Nowadays, there is interest in defining more than DQIs, healthy life indices (HLIs), which give information on behaviours associated with specific patterns and beyond dietary habits they include physical activity, rest and selected socio-cultural habits. The Mediterranean Lifestyle (MEDLIFE) index has been recently created based on the current Spanish Mediterranean food guide pyramid and it includes both the assessment of food consumption directly related to the Mediterranean diet, physical activity and rest and other relevant cultural information. However, a global HLI should consider, based on the Iberoamerican Nutrition Foundation (FINUT) Pyramid of Healthy Lifestyles, in addition to food groups and nutrients, selected items on food safety e.g. consumption rate of proceed foods, food handling, preparation and storage and access to drinking water, selected food habits, including alcoholic beverage and salt consumption patterns, purchase of seasonal and local foods, home cooking and conviviality, as well as patterns of physical activity, sedentary and rest habits and some selected sociocultural habits, particularly those related to food selection, religious beliefs and socializing with friends. PMID- 25719782 TI - Immunonutrition: methodology and applications. AB - Immunonutrition is an emergent and interdisciplinary subject, since it comprises several aspects related to Nutrition, Immunity, Infection, Inflammation, and Injury or tissue damage, what is known as Nutrition and 4 "Is". Within these interactions the endocrine, nervous and immune systems are involved, microbiota being a part of the last one. Nowadays, gut microbiota has been shown to play an essential role, not only in the gastrointestinal tract but also into the nervous system, because of its bilateral connection. There are several methods to study Immunonutrition, which allow measuring different immunological biomarkers to provide information about the nutritional status. However, it should be taken into account that there is not a single gold standard parameter to evaluate the cause- effect relationship between nutrition and the immune system. On the contrary, a combination of biomarkers have to be assessed depending on the different nutritional situations. Since Immunonutrition is a multidisciplinary matter as mentioned above, the study on the interactions between nutrition and the immune system has not been exclusively focused as such, but bearing in mind other systems of the organisms as well as a wide range of confounding factors and determinants coming from idiosyncratic features, genes and lifestyle of each individual. Therefore, Immunonutrition allows to study the following research fields: 1) Evaluation of nutritional status in presumably healthy people with risk of malnutrition (children, adolescents, adults, pregnant women, elderly, and sportspeople); 2) Assessment of the evolution and progress of patients with nutrition and immune-related diseases, such as food allergies, eating and metabolic disorders; 3) Evaluation of the effects of nutrients, bioactive compounds and both conventional and functional foods on the immune system; 4) Evaluation of impact of lifestyle determinants on the immune system, such as diet, food behaviour, physical activity, sedentariness, sleep quality and quantity, and as a key factor, stress. PMID- 25719783 TI - Dietary intake and anthropometric reference values in population studies. AB - In nutritional epidemiology it is essential to have reference values for nutrition and anthropometry in order to compare individual and population data. With respect to reference nutritional intake, the new concept of Dietary Reference Intakes is generated based more on the prevention of chronic diseases than on covering nutritional deficiencies, as would occur in the early Recommendations. As such, the more relevant international organizations incorporated new concepts in their tables, such as the Adequate Intake levels or the Tolerable Upper Intake levels. Currently, the EURRECA recommendations (EURopean micronutrient RECommendations Aligned) are generating reference values for Europe in a transparent, systematic and scientific manner. Using the DRI, health-care authorities formulated nutritional objectives for countries or territories and Dietary Guides to disseminate the dietary advice to the population. Anthropometric assessment continues to be one of the most-used methods for evaluating and monitoring health status, nutritional state and growth in children, not only individuals but also communities. Different organizations have established anthropometric reference patterns of body mass index (BMI) with cut-off points to define overweight and obesity. In children, growth curves have been revised and adapted to the characteristics of healthy children in order to obtain anthropometric reference standards that better reflect optimum growth in children. The Growth Standards for children below 5 years of age of the WHO are a response to these principles, and are widely accepted and used worldwide. PMID- 25719784 TI - Intake of energy and nutrients; harmonization of Food Composition Databases. AB - Food composition databases (FCDBs) provide detailed information about the nutritional composition of foods. The conversion of food consumption into nutrient intake need a Food composition database (FCDB) which lists the mean nutritional values for a given food portion. The limitations of FCDBs are sometimes little known by the users. Multicentre studies have raised several methodology challenges which allow to standardize nutritional assessments in different populations and geographical areas for food composition and nutrient intake. Differences between FCDBs include those attributed to technical matters, such as description of foods, calculation of energy and definition of nutrients, analytical methods, and principles for recipe calculation. Such differences need to be identified and eliminated before comparing data from different studies, especially when dietary data is related to a health outcome. There are ongoing efforts since 1984 to standardize FCDBs over the world (INFOODS, EPIC, EuroFIR, etc.). Food composition data can be gathered from different sources like private company analysis, universities, government laboratories and food industry. They can also be borrowed from scientific literature or even from the food labelling. There are different proposals to evaluate the quality of food composition data. For the development of a FCDB it is fundamental document in the most detailed way, each of the data values of the different components and nutrients of a food. The objective of AECOSAN (Agencia Espanola de Consumo Seguridad Alimentaria y Nutricion) and BEDCA (Base de Datos Espanola de Composicion de Alimentos) association was the development and support of a reference FCDB in Spain according to the standards to be defined in Europe. BEDCA is currently the only FCDB developed in Spain with compiled and documented data following EuroFIR standards. PMID- 25719785 TI - Biomarkers: background, classification and guidelines for applications in nutritional epidemiology. AB - One of the main problems in nutritional epidemiology is to assess food intake as well as nutrient/food component intake to a high level of validity and reliability. To help in this process, the need to have good biomarkers that more objectively allow us to evaluate the diet consumed in a more standardized, valid and precise way has often been commented upon. There are various definitions of biomarkers and also different classifications of the same. In general a biomarker can be defined as a characteristic that can objectively measure different biological samples and that can be evaluated as an exposure marker of normal or pathogenic biological processes or of responses to a certain intervention. The biological samples most commonly used in nutritional epidemiology are blood, red blood cells, plasma, serum, urine, nails, saliva, faeces and samples of different tissues. Exposure biomarkers (dietary intake), biomarkers of effects and biomarkers of disease status can be determined from these samples. In turn, exposure biomarkers can be temporarily categorized into markers of acute, medium term or chronic effects. Many difficulties arise in identifying good biomarkers. Currently, advances in omics are opening up new possibilities for obtaining new biomarkers of various kinds, using genomics, epigenomics, transcriptomics, lipidomics, proteomics and metabolomics. We shall review the present situation of biomarkers in nutritional epidemiology as well as the future trends of the new omic biomarkers. PMID- 25719786 TI - The identification, impact and management of missing values and outlier data in nutritional epidemiology. AB - When performing nutritional epidemiology studies, missing values and outliers inevitably appear. Missing values appear, for example, because of the difficulty in collecting data in dietary surveys, leading to a lack of data on the amounts of foods consumed or a poor description of these foods. Inadequate treatment during the data processing stage can create biases and loss of accuracy and, consequently, misinterpretation of the results. The objective of this article is to provide some recommendations about the treatment of missing and outlier data, and orientation regarding existing software for the determination of sample sizes and for performing statistical analysis. Some recommendations about data collection are provided as an important previous step in any nutritional research. We discuss methods used for dealing with missing values, especially the case deletion method, simple imputation and multiple imputation, with indications and examples. Identification, impact on statistical analysis and options available for adequate treatment of outlier values are explained, including some illustrative examples. Finally, the current software that totally or partially addresses the questions treated is mentioned, especially the free software available. PMID- 25719787 TI - Assessment of nutritional status in the healthcare setting in Spain. AB - Early identification of undernourished patients in the healthcare setting, and their nutritional treatment, are essential if the harmful effects of poor nourishment are to be avoided and care costs kept down. The aim of assessing nutritional status is to determine the general health of a patient from a nutritional viewpoint. All hospitalised patients should undergo nutritional screening within 24-48 h of admission, as should any patient who shows signs of being malnourished when visiting any healthcare centre. The infrastructure and resources available, the possibilities of automisation, and the healthcare setting in which such assessment must be performed, etc., determine which method can be used. The European Society of Parenteral and Enteral Nutrition (ESPEN) recommends the use of the Nutritional Risk Screening-2002 (NRS-2002) method for hospitalised patients, the Malnutrition Universal Screening Tool (MUST) in the community healthcare setting, and the first part of the Mini-Nutritional Assessment (MNA) for elderly patients. In centres where screening can be computerised, the CONUT(r) or INFORNUT(r) methods can be used. A nutritional diagnosis is arrived at using the patient's medical history, a physical examination (including anthropometric assessment), biochemical analysis, and functional tests. No single variable allows a diagnosis to be made. The Subjective Global Assessment (SGA) and MNA tests are useful in nutritional assessment, but they are not universally regarded as the gold standard. At our hospital, and at many other centres in the Spanish health system, the Nutritional Status Assessment (NSA) method (in Spanish Valoracion del Estado Nutricional) is used, which involves the SGA method, the taking of anthropometric measurements, and biochemical analysis. After making a nutritional diagnosis, which should be included in the patient's medical history adhering to International Classification of Diseases code 9 (ICD- 9), and prescribing a nutritional treatment, the patient should be followed up. No single marker can be used to monitor progress; interpretations will once again require examination of the patient's medical history, the taking of anthropometric measurements and laboratory tests. Depending on whether a patient is ambulatory or hospitalised, the follow-up assessment times and variables measured will differ. PMID- 25719788 TI - Physical activity assessment in the general population; validated self-report methods. AB - Self-reported questionnaires have been commonly used to assess physical activity levels in large cohort studies. As a result, strong and convincing evidences that physical activity can protect health are widely recognized. However, validation studies using objective measures of physical activity or energy expenditure (double labelled water, accelerometers, pedometers, etc.) indicate that the accuracy and precision of survey techniques are limited. Physical activity questionnaires could fail in estimating particularly non-vigorous physical activity. They have a disproportionate focus on volitional type exercise (i.e. biking, jogging, and walking), while not capturing the activities of daily living and low to moderate intensity movements. Energy expenditure estimates from these data are not recommended. On the other hand, despite objective tools should be the measurement of choice to assess PA level, self-reported questionnaires remain valid, and have many advantages. i.e. low costs. These kind of recalls are designed and validated for different age groups and provide value and important information, mainly about physical activity pattern. Future studies will require more precision and accuracy in physical activity measurement than those provided by traditional survey methods. We can conclude that probably a mixed approach that combines both the objective and subjective techniques involving novel devices and electronic capture of physical activity questionnaires will be more effective. PMID- 25719789 TI - Physical activity assessment in the general population; instrumental methods and new technologies. AB - The objective measurement of human movement and the quantification of energy expenditure due to physical activity is an identified need in both research and the clinical setting. Validated and well-defined reference methods (double labelled water, direct calorimetry, indirect calorimetry) are expensive and mostly limited to the laboratory setting. Therefore, in the last years, several objective measurement devices have been developed which are appropriate for field studies and clinical settings. There is no gold standard among them, as all have limitations. Pedometers are small, non-expensive, count the steps taken and give information on total physical activity, but not about physical activity patterns and behaviour. Accelerometers are expensive, save information about frequency and intensity of physical activity, but not about type of physical activity. Both pedometers and accelerometers only save information about lower body movement, but reliability about the estimation of energy expenditure is limited. Heart rate monitoring relates intensity to energy expenditure, but gives no information about physical activity. GPS watches are portable, relatively inexpensive, non invasive and provide distance, speed, and elevation with exact time and location, but are maybe limited for the assessment of brief higher speed movement and energy expenditure. Combined motion sensors combine accelerometry with the measurement of physiological variables and share advantages of single devices and are more precise. Manufacturer software which applies activity-specific algorithms for the calculation of energy expenditure can affect energy expenditure results. Most of the devices estimate energy expenditure more accurately at light to moderate intensities; underestimation increases at very light and higher intensity activities. PMID- 25719790 TI - Evaluation of nutritional status and energy expenditure in athletes. AB - Continuous physical exercise leads the athlete to maintain an unstable balance between dietary intake, energy expenditure and the additional demands of a high amount of physical activity. Thus, an accurate assessment of nutritional status is essential to optimize the performance, since it affects health, body composition, and the recovery of the athlete. Specific aspects like the type of sport, specialty or playing position, training schedule and competition calendar, category, specific objectives, which differ from the general population, must be considered. A biochemical assessment can give us a general idea of the nutritional status, lipid profile, liver or kidney function, if diet is too high in proteins or fats, as well as possible nutritional deficiencies and the need for supplementation. Sport kinanthropometry has great utility that enables the assessment of body mass, height, length, diameter, perimeter and skinfolds, where information is processed by applying different equations, obtaining information on somatotype, body composition, and the proportionality of different parts of the body. To give proper nutritional counselling, energy needs of the athlete must be known. If objective measurement is not possible, there are tables including theoretically established energy requirements of different sports. Dietary assessment should include information about food consumption and nutrient intake to establish the relationship between diet, health status and athlete's performance. On the other hand, an adequate hydration status in athletes is essential to maintain adequate performance. Hence, the knowledge of fluid intake by the athlete is a matter of the utmost importance. Dehydration can cause harmful effects on athletes' health. As there is no gold standard, urine gravidity and urine colour are the most extended methods for analyzing hydration status. There is consensus that due to complexity, the combination of different methods assures an effective data collection which will be useful to proceed in dietary and nutritional intervention.. PMID- 25719791 TI - Biomarkers of physical activity and exercise. AB - Traditionally, biomarkers have been of interest in sports in order to measure performance, progress in training and for identifying overtraining. During the last years, growing interest is set on biomarkers aiming at evaluating health related aspects which can be modulated by regular physical activity and sport. The value or concentration of a biomarker depends on many factors, as the training status of the subject, the degree of fatigue and the type, intensity and duration of exercise, apart from age and sex. Most of the biomarkers are measured in blood, urine and saliva. One of the main limitations for biochemical biomarkers is that reference values for blood concentration of biomarkers specifically adapted to physically active people and athletes are lacking. Concentrations can differ widely from normal reference ranges. Therefore, it is important to adapt reference values as much as possible and to control each subject regularly, in order to establish his/her own reference scale. Other useful biomarkers are body composition (specifically muscle mass, fat mass, weight), physical fitness (cardiovascular capacity, strength, agility, flexibility), heart rate and blood pressure. Depending on the aim, one or several biomarkers should be measured. It may differ if it is for research purpose, for the follow up of training or to prevent risks. For this review, we will get deeper into the biomarkers used to identify the degree of physical fitness, chronic stress, overtraining, cardiovascular risk, oxidative stress and inflammation. PMID- 25719792 TI - Resting energy expenditure; assessment methods and applications. AB - The energetic expense daily total of an individual (EEDT) represents the energy that the organism consumes. It is constituted by the sum of: metabolic basal rate (MBR), termogenesis endogenous (TE) and energetic expense linked to the physical activity (EEPA). The determination of the EEDT considering the physical activity and the state of health of a person, it is very important to fit the calculation of the nutritional need for every individual. The MBR is the minimal quantity of energy that an organism needs to be alive. It constitutes a from 60 to 70 % of the EEPA in the majority of the sedentary adults, while, in the physically very active individuals it is of approximately 50 %. It changes depending on the corporal composition, specially on the corporal lean mass. The basal metabolism expressed as MRB, it is different from the metabolic rate in rest (MRR) or Resting energy expenditure (REE); the latter is obtained when the determination is done in rest and in the conditions described for the MRB but not in fasting, including therefore the energy used for the biological utilization of the food. Habitually, the REE decides by means of different technologies as the indirect calorimetry, the electrical bioimpedancy, the doubly marked water, the predictive equations, between others. These methods are used in the clinical practice and in scientific studies. Nevertheless, due to the inconsistency of the results of these researches, still there is no a consensus with regard to his applicability though the evidence indicates that the measurement of the consumption of oxygen, it is the method of major precision. AIMS: This review has as aim expose the components of the energetic expense in rest, as well as the technologies for its determination and estimation, indicating its advantages, limitations and practical applications. RESULTS: Part of the technologies of evaluation of the energetic expense described in this review, they remain relegated, for its complexity and cost to the area of the investigation. For a long time the indirect calorimetry, she remained also restricted to this field. Nevertheless, the technological advances have allowed the development of precise light and attainable equipments that allow that at present it should be a very useful method in the clinical space of the determination of the REE. PMID- 25719793 TI - Methodology for the estimation of use of tobacco, alcohol and other drugs. AB - The objective of this article is to revise the methods used for the assessment of the use of tobacco, alcohol and other drugs. Analysing the advantages of using one method or the other, as well as the most frequent methodological difficulties and problems in medication and classification of each one of these indicators. The main sources of information available from European, National and Madrid Autonomous Community levels have been consulted to estimate the most relevant aspects of these forms of substance abuse. PMID- 25719794 TI - Quality of life, dependency and mental health scales of interest to nutritional studies in the population. AB - Quality of life, dependency and mental health are multidimensional constructs that cannot be observed directly yet can be deduced in an indirect manner through indicators or profiles generated from questionnaires. These questionnaires are based on the validity of information transmitted by the respondents about perceptions, feelings and attitudes. For this reason, the information is difficult to contrast with and translate to a measuring system. The use of questionnaires or rapid quality of life and mental health evaluation scales involve a process directed towards an early identification of specific problems so as to establish medical treatment. This work will review the most commonly used scales or questionnaires in determining these variables and their relationship with the nutritional status of the population. PMID- 25719795 TI - Household food insecurity access scale (HFIAS). AB - In 1996, the World Food Summit reaffirmed the inalienable right that each person across the globe has to access safe, adequate and nutritious food. At that time a goal was established to reduce by half the number of undernourished persons worldwide by 2015, in other words the year that we are now commencing. Different countries and organisations considered the necessity of reaching consensus and developing indicators for measuring household food insecurity. The availability of a simple but evidence-based measurement method to identify nutritionally at risk population groups constitutes an essential instrument for implementing strategies that effectively address relevant key issues. PMID- 25719796 TI - Methods for monitoring the functional status of the circadian system in dietary surveys studies: application criteria and interpretation of results. AB - To evaluate the circadian system status of the subject may be of special interest in nutrition. Particularly for those studies related to the assessment of diseases related to malnutrition, as it is the case of most of the degenerative diseases such as obesity, cancer, or cardiovascular diseases. For this purpose, one of the approaches consists to measure a) the external synchronizers of the internal clock, such as light intensity, and changes from fasting to eating and from resting to activity. Indeed, "chronodisruptors" have been defined as "exogenous and endogenous exposures or effectors which are chronobiologically active and can thus disrupt the timing and order. Another approach to assess the circadian system health is to measure the b) outputs of the internal clock (circadian marker rhythms). Among such outputs, the rhythm of body temperature, motor activity, melatonin, cortisol and clock gene expression are the most commonly used. From the genetic perspective, we are now able to measure failures in the internal clock, in order to assess c) the genetics of the molecular clock. Indeed, new nutrigenetics techniques are giving us the opportunity to measure the association between different genetic variants of our clock genes and several illnesses such as obesity, cardiovascular diseases, diabetes or cancer. In addition to these techniques, self-reported questionnaires based in the morning evening preferences have been developed as complementary procedures to assess human chronotypes. PMID- 25719797 TI - Uses and applications of the results from food surveys, physical activity estimates and other lifestyle related surveys at a population level. AB - The results and conclusions of well design nutrition studies, using the appropriate methods to achieve the intended aims with the best validity and precision possible are of great value for nutritional, food and toxicological surveillance systems; also in the planning, follow-up and evaluation of nutrition and health policies and providing high value information for the formulation of recommended reference intakes, nutritional objectives and food based dietary guidelines. PMID- 25719798 TI - Journal of aquatic animal health: guide for authors 2015. PMID- 25719799 TI - Probing the topological properties of complex networks modeling short written texts. AB - In recent years, graph theory has been widely employed to probe several language properties. More specifically, the so-called word adjacency model has been proven useful for tackling several practical problems, especially those relying on textual stylistic analysis. The most common approach to treat texts as networks has simply considered either large pieces of texts or entire books. This approach has certainly worked well-many informative discoveries have been made this way but it raises an uncomfortable question: could there be important topological patterns in small pieces of texts? To address this problem, the topological properties of subtexts sampled from entire books was probed. Statistical analyses performed on a dataset comprising 50 novels revealed that most of the traditional topological measurements are stable for short subtexts. When the performance of the authorship recognition task was analyzed, it was found that a proper sampling yields a discriminability similar to the one found with full texts. Surprisingly, the support vector machine classification based on the characterization of short texts outperformed the one performed with entire books. These findings suggest that a local topological analysis of large documents might improve its global characterization. Most importantly, it was verified, as a proof of principle, that short texts can be analyzed with the methods and concepts of complex networks. As a consequence, the techniques described here can be extended in a straightforward fashion to analyze texts as time-varying complex networks. PMID- 25719801 TI - Nanoscale conductive pattern of the homoepitaxial AlGaN/GaN transistor. AB - The gallium nitride (GaN)-based buffer/barrier mode of growth and morphology, the transistor electrical response (25-310 degrees C) and the nanoscale pattern of a homoepitaxial AlGaN/GaN high electron mobility transistor (HEMT) have been investigated at the micro and nanoscale. The low channel sheet resistance and the enhanced heat dissipation allow a highly conductive HEMT transistor (Ids > 1 A mm(-1)) to be defined (0.5 A mm(-1) at 300 degrees C). The vertical breakdown voltage has been determined to be ~850 V with the vertical drain-bulk (or gate bulk) current following the hopping mechanism, with an activation energy of 350 meV. The conductive atomic force microscopy nanoscale current pattern does not unequivocally follow the molecular beam epitaxy AlGaN/GaN morphology but it suggests that the FS-GaN substrate presents a series of preferential conductive spots (conductive patches). Both the estimated patches density and the apparent random distribution appear to correlate with the edge-pit dislocations observed via cathodoluminescence. The sub-surface edge-pit dislocations originating in the FS-GaN substrate result in barrier height inhomogeneity within the HEMT Schottky gate producing a subthreshold current. PMID- 25719803 TI - Single-crystal-to-single-crystal metalation of a metal-organic framework: a route toward structurally well-defined catalysts. AB - Metal-organic frameworks featuring ligands with open chelating groups are versatile platforms for the preparation of a diverse set of heterogeneous catalysts through postsynthetic metalation. The crystalline nature of these materials allows them to be characterized via X-ray diffraction, which provides valuable insight into the structure of the metal sites that facilitate catalysis. A highly porous and thermally robust zirconium-based metal-organic framework, Zr6O4(OH)4(bpydc)6 (bpydc(2-) = 2,2'-bipyridne-5,5'-dicarboxylate), bears open bipyridine sites that readily react with a variety of solution- and gas-phase metal sources to form the corresponding metalated frameworks. Remarkably, Zr6O4(OH)4(bpydc)6 undergoes a single-crystal-to-single-crystal transformation upon metalation that involves a change in space group from Fm3m to Pa3. This structural transformation leads to an ordering of the metalated linkers within the framework, allowing structural characterization of the resulting metal complexes. Furthermore, Zr6O4(OH)4(bpydc)6 yields an active heterogeneous catalyst for arene C-H borylation when metalated with [Ir(COD)2]BF4 (COD = 1,5 cyclooctadiene). These results highlight the unique potential of metal-organic frameworks as a class of heterogeneous catalysts that allow unparalleled structural characterization and control over their active sites. PMID- 25719800 TI - Cerebrospinal fluid (CSF) CD8+ T-cells that express interferon-gamma contribute to HIV associated neurocognitive disorders (HAND). AB - BACKGROUND: HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis. METHODS: To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNgamma, IL-2, TNFalpha) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART. RESULTS: Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFalpha, IL 2, IFNgamma and CD8+T-cells: IL-2 and IFNgamma. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNgamma expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNgamma and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/MUl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNgamma expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF. CONCLUSIONS: Presence of IFNgamma expressing CD8+ T-cells, absence of cytolytic CD8+ T-cells, high myeloid activation, and failure of ART to suppress HIV replication in CSF contribute to increased risk of HAND. PMID- 25719802 TI - Diagnostic value of SFRP1 as a favorable predictive and prognostic biomarker in patients with prostate cancer. AB - Growing genetic and molecular biological evidence suggests that the disruption of balance between Secreted Frizzled-Related Protein-1 (SFRP1) and beta-catenin plays an important role in the initiation and development of multiple cancers. The aim of this study was to examine whether the expression of SFRP1 and beta catenin is associated with the clinical-pathologic features of patients with prostate cancer (PCa), and to evaluate their potential roles as predictive and prognostic biomarkers. In this study, a total of 61 patients with PCa and 10 patients with benign prostatic hyperplasia were included, and we showed that the expression of SFRP1 and beta-catenin was correlated with the Gleason score, survival rate and response for endocrine therapy of PCa. The survival rates of PCa patients with low SFRP1 expression (P = 0.016) or high beta-catenin expression (P = 0.004) were significantly poorer. A negative correlation (r = 0.275, P = 0.032) between SFRP1 and beta-catenin was observed by Chi-square test. Multivariate analysis suggested that SFRP1 (hazard ratio, 0.429; 95% confidence intervals, 0.227-0.812; P = 0.009) may serve as an independent predictive and prognostic factor for PCa. We also showed that the protein and mRNA levels of SFRP1 in androgen-dependent PCa cell line LNCaP were significantly higher than those in androgen-independent PCa cell lines DU145 and PC3. However, the protein level of beta-catenin in LNCaP cells was significantly lower than that in DU145 and PC3 cells, and no significant difference of beta-catenin mRNA level was observed in LNCaP, DU145 and PC3 cells. Bisulfite sequencing PCR assay revealed significantly lower methylation level of SFRP1 promoter in LNCaP cells than that in DU145 and PC3 cells. Taken together, these findings suggest that SFRP1, which expression inversely correlates with that of beta-catenin, is a favorable predictive and prognostic biomarker. PMID- 25719804 TI - Risk Model for Distal Gastrectomy When Treating Gastric Cancer on the Basis of Data From 33,917 Japanese Patients Collected Using a Nationwide Web-based Data Entry System. AB - OBJECTIVE: To establish a risk model for distal gastrectomy in Japanese patients with gastric cancer. BACKGROUND: Risk stratification for distal gastrectomy in Japanese patients with gastric cancer improves surgical outcomes. METHODS: The National Clinical Database was constructed for risk determination in gastric cancer-related gastrectomy among Japanese individuals. Data from 33,917 gastric cancer cases (1737 hospitals) were used. The primary outcomes were 30-day and operative mortalities. Data were randomly assigned to risk model development (27,220 cases) and test validation (6697 cases) subsets. Stepwise selection was used for constructing 30-day and operative mortality logistic models. RESULTS: The 30-day, in-hospital, and operative mortality rates were 0.52%, 1.16%, and 1.2%, respectively. The morbidity was 18.3%. The 30-day and operative mortality models included 17 and 21 risk factors, respectively. Thirteen variables overlapped: age, need for total assistance in activities of daily living preoperatively or within 30 days after surgery, cerebrovascular disease history, more than 10% weight loss, uncontrolled ascites, American Society of Anesthesiologists score (>= class 3), white blood cell count more than 12,000/MUL or 11,000/MUL, anemia (hemoglobin: males, <13.5 g/dL; females, <12.5 g/dL; or hematocrit: males, <37%; females <32%), serum albumin less than 3.5 or 3.8 g/dL, alkaline phosphatase more than 340 IU/L, serum creatinine more than 1.2 mg/dL, serum Na less than 135 mEq/L, and prothrombin time-international normalized ratio more than 1.25 or 1.1. The C-indices for the 30-day and operative mortalities were 0.785 (95% confidence interval, 0.705-0.865; P < 0.001) and 0.798 (95% confidence interval, 0.746-0.851; P < 0.001), respectively. CONCLUSIONS: The risk model developed using nationwide Japanese data on distal gastrectomy in gastric cancer can predict surgical outcomes. PMID- 25719806 TI - Reply to Letter: "Considerations on the Selection Process for Cytoreductive Surgery and HIPEC for Colorectal Carcinomatosis". PMID- 25719807 TI - Reply to Letter: Trainee Involvement and Outcomes in Emergency General Surgery: Smoke With No Fire? PMID- 25719808 TI - Warming to 39 degrees C but Not to 37 degrees C Ameliorates the Effects on the Monocyte Response by Hypothermia. AB - OBJECTIVE: To investigate whether warming to normal body temperature or to febrile range temperature (39 degrees C) is able to reverse the detrimental effects of hypothermia. BACKGROUND: Unintentional intraoperative hypothermia is a well-described risk factor for surgical site infections but also sepsis. We have previously shown that hypothermia prolongs the proinflammatory response whereas normothermia and especially febrile range temperature enhance the anti inflammatory response. METHODS: Primary human monocytes were isolated from healthy volunteers. After stimulation with LPS (Lipopolysaccharide), the monocytes were exposed to 32 degrees C for 3 hours or 6 hours and then warmed at either 37 degrees C or 39 degrees C for the remaining 33 hours or 36 hours, respectively. Tumor necrosis factor alpha, interleukin 10, and the expression of miR-155 and miR-101 were assessed at 24 hours and 36 hours. RESULTS: Warming to 37 degrees C does not normalize monocyte cytokine secretion within 36 hours, whereas warming to 39 degrees C partially reverses the effects of hypothermia on monocyte function. Both miR-155 and miR-101 were suppressed after the warming episode. However, 39 degrees C had a stronger suppressive effect than 37 degrees C. The duration of hypothermia and the warming temperature seem to be critical for a full reversibility of the effects of hypothermia. CONCLUSION: Warming to normal body temperature (37 degrees C) does not restore normal monocyte function in vitro. These data suggest that hypothermic patients should be warmed to febrile range temperatures. Furthermore, febrile range temperatures should be investigated as a means to modulate the inflammatory response in patients with systemic infections. PMID- 25719809 TI - Comparison of Binary Predictive Scoring Systems of Posthepatectomy Liver Failure. PMID- 25719810 TI - Simultaneous Resection of High-risk Liver Tumors and Pulmonary Metastases in Children. PMID- 25719811 TI - Vascular Surgery in World War II: The Shift to Repairing Arteries. AB - Vascular surgery in World War II has long been defined by DeBakey and Simeone's classic 1946 article describing arterial repair as exceedingly rare. They argued ligation was and should be the standard surgical response to arterial trauma in war. We returned to and analyzed the original records of World War II military medical units housed in the National Archives and other repositories in addition to consulting published accounts to determine the American practice of vascular surgery in World War II. This research demonstrates a clear shift from ligation to arterial repair occurring among American military surgeons in the last 6 months of the war in the European Theater of Operations. These conclusions not only highlight the role of war as a catalyst for surgical change but also point to the dangers of inaccurate history in stymieing such advances. PMID- 25719812 TI - Getting Clearer About Surgical Innovation: A New Definition and a New Tool to Support Responsible Practice. AB - OBJECTIVES: This article presents an original definition of surgical innovation and a practical tool for identifying planned innovations. These will support the responsible introduction of surgical innovations. BACKGROUND: Frameworks developed for the safer introduction of surgical innovations rely upon identifying cases of innovation; oversight cannot occur unless innovations are identified. However, there is no consensus among surgeons about which interventions they consider innovative; existing definitions are vague and impractical. METHODS: Using conceptual analysis, this article synthesizes findings from relevant literature, and from qualitative research with surgeons, to develop an original definition of surgical innovation and a tool for prospectively identifying planned surgical innovations. The tool has been developed in light of feedback from health care professionals, surgeons, and policy makers. RESULTS: This definition of innovation distinguishes between variations, introduction of established interventions, and innovations in surgical techniques or use of devices. It can be applied easily and consistently, is sensitive to the key features of innovation (newness and degree of change), is prospective, and focuses on features relevant to safety and evaluation. The accompanying tool is deliberately broad so that appropriate supports may, if necessary, be provided each time that a surgeon does something "new." CONCLUSIONS: The definition presented in this article overcomes a number of practical challenges. The definition and tool will be of value in supporting responsible surgical innovation, in particular, through the prospective identification of planned innovations. PMID- 25719813 TI - Determination of nanoparticles using UV-Vis spectra. AB - Nanoparticles (NPs) are increasingly being used in different branches of science and in industrial applications; however, their rapid detection and characterization at low concentration levels have remained a challenge; more specifically, there is no single technique that can characterize the physicochemical properties of NPs (e.g. composition and size). In this work we have developed a colorimetric sensor array for defining the physicochemical properties of NPs in aqueous solution with ultra-low concentrations (e.g. 10(-7) g ml(-1) for gold NPs). Various NPs were readily identified using a standard chemometric approach (i.e. hierarchical clustering analysis), with no misclassifications over 400 trials. PMID- 25719814 TI - Health literacy and computer-assisted instruction: usability and patient preference. AB - The authors investigated the feasibility of using computer-assisted instruction in patients of varying literacy levels by examining patients' preferences for learning and their ability to use 2 computer-based educational programs. A total of 263 participants 50-74 years of age with varying health literacy levels interacted with 1 of 2 educational computer programs as part of a randomized trial of a colorectal cancer screening decision aid. A baseline and postprogram evaluation survey were completed. More than half (56%) of the participants had limited health literacy. Regardless of literacy level, doctors were the most commonly used source of medical information-used frequently by 85% of limited and adequate literacy patients. In multivariate logistic regression, only those with health insurance (OR = 2.35, p = .06) and computer use experience (OR = 0.39, p = .03) predicted the ability to complete the programs without assistance compared with those without health insurance or prior computer use, respectively. Although patients with limited health literacy had less computer experience, the majority completed the programs without any assistance and stated that they learned more than they would have from a brochure. Future research should investigate ways that computer-assisted instruction can be incorporated in medical care to enhance patient understanding. PMID- 25719815 TI - Development of a Medication Safety and Quality Survey for Small Rural Hospitals. AB - PURPOSE: We summarize the development and initial implementation of a survey tool to assess medication safety in small rural hospitals. SUMMARY: As part of an ongoing rural hospital medication safety improvement program, we developed a survey tool in all 13 critical access hospitals (CAHs) in Florida. The survey was compiled from existing medication safety assessments and standards, clinical practice guidelines, and published literature. Survey items were selected based on considerations regarding practicality and relevance to the CAH setting.The final survey instrument included 134 items representing 17 medication safety domains. Overall hospital scores ranged from 41% to 95%, with a median of 59%. Most hospitals showed large variation in scores across domains, with 5 hospitals having at least 1 domain with scores less than 10%. Highest scores across all facilities were seen for safety procedures concerning high-alert or look-alike medications and the assembly of emergency carts. The lowest median scores included availability and consistent use of standardized order sets and the effective implementation of medication safety committees. Most hospitals used the survey results to identify and prioritize quality improvement activities. CONCLUSIONS: The survey can be used to conduct a short medication safety assessment specific to a limited number of areas and services in CAHs. It showed good ability to discriminate medication safety levels across participating sites and highlighted opportunities for improvement. It may need modification if case mix or services differ in other states or if the status quo of medication safety in CAHs or related standards advance. The described process of survey development might be helpful to support such modifications. PMID- 25719816 TI - Prescriptions for Bedtime Sedatives After the Introduction of a General Admission Order Set at an Academic Health Center: The Potential and Pitfalls of Order Sets. AB - OBJECTIVE: This study describes the impact of modifications to a general admission order set on physician prescribing of 2 as-needed or pro re nata (PRN) bedtime sedatives. METHODS: The hospitalists at our institution have used a general medical admission order set since 2005. Zolpidem was the only as-needed (PRN) bedtime sedative option on the order set until trazodone was added in December 2008. Trazodone is preferred over zolpidem in the geriatric population. We identified patients admitted by the hospitalists between January 2007 and August 2013 who were prescribed with either zolpidem or trazodone as a PRN sedative. Patient demographics, date and time of the order, and number of sedative doses administered during the hospitalization were recorded. Orders placed within 12 hours of admission were attributed to admission orders. RESULTS: Between 2007 and 2013, the number of patients admitted by the hospitalists with an order for PRN trazodone on admission increased by 18-fold. During the same period, the number of admissions by the hospitalists increased by 2.3 times. Zolpidem orders exceeded those for trazodone in all age groups until 2008. After the addition of trazodone, its use exceeded that of zolpidem. Almost half (48%) of all patients did not have a dose of the PRN trazodone administered. CONCLUSIONS: Although order sets can be leveraged to align practitioners with established guidelines, the expediency of using medications on an order set may overcome physicians' clinical judgment. The content of an order set therefore deserves careful scrutiny before implementation. PMID- 25719817 TI - Shoulder Dystocia Documentation: An Evaluation of a Documentation Training Intervention-Observations. PMID- 25719818 TI - High Rate of Implementation of Proposed Actions for Improvement With the Healthcare Failure Mode Effect Analysis Method: Evaluation of 117 Analyses. AB - OBJECTIVES: The aims of this study were to investigate what kind of impact the Healthcare Failure Mode Effect Analysis (HFMEA) had on the organization in 1 county council in Sweden and to evaluate the method of working for multidisciplinary teams performing HFMEA. Three main outcome measures were used: the quality of the documentation from the HFMEAs, fulfillment of the primary goal of the HFMEA, and, finally, whether proposed actions for improvement were implemented. METHODS: The study involved retrospective analysis of the documentation from 117 performed HFMEAs from 3 hospitals in the county council of Ostergotland, Sweden, and interviews or questionnaires with team leaders and managers between 2006 and 2010. RESULTS: A proposed change in the organizational structure was the most common issue in the analyses. Eighty-nine percent of the written reports were of high quality. A median of 10 serious risks were detected, and 10 proposed actions (median) were made. In 78% of the HFMEAs, all or a large part of these had been implemented a few years afterward. We were unable to find factors that promoted the rate of implementation of proposed actions. Seventy eight percent of the managers were completely satisfied with the results of the HFMEA. The mean cost per risk analysis was &OV0556;1909. CONCLUSIONS: Most of the proposed actions were implemented. The use of HFMEA can be improved using fewer team leaders but with more experience. The work involved in writing a report can be reduced without loss of impact on the organization. PMID- 25719819 TI - Bacterial Misidentification in a Resource-Limited Microbiology Laboratory Setting and Quality Improvement Strategies. PMID- 25719820 TI - Direct visualization of lead corona and its nanomolar colorimetric detection using anisotropic gold nanoparticles. AB - The study presents dithiothreitol (DTT) functionalized anisotropic gold nanoparticles (GNP) based colorimetric sensor for detection of toxic lead ions in water. Our results demonstrate the selectivity and sensitivity of the developed sensor over various heavy metal ions with detection limit of ~9 nM. The mechanism of sensing is explained on the basis of unique corona formation around the DTT functionalized anisotropic GNP. PMID- 25719821 TI - Identification of mycobacterial species by PCR restriction enzyme analysis of the hsp65 gene-an Indian experience. AB - Nowadays, nontuberculous mycobacteria (NTM) often cause pulmonary and extrapulmonary disease. Species identification of NTM determines the line of treatment and management of the disease. The routine diagnostic methods, i.e., smear microscopy and biochemical identification, of nontuberculous mycobacteria are tedious and time consuming and not all laboratories can perform these tests on a routine basis. A PCR targeting the hsp65 gene was implemented using standard strains and was applied to 109 clinical isolates. The PCR-amplified product was subjected to restriction enzyme analysis using BstEII and HaeIII. The results obtained were compared with that of biochemical tests. Of 109 NTM, 107 were identified to species level. PCR plus restriction enzyme analysis (PRA) identified 12 types of NTM. Common species identified were Mycobacterium chelonae (32), a rapid growing NTM, and Mycobacterium avium complex (21), among the slow growing NTM. PRA and biochemical identification showed 95.32% (102/107) concordant results. PRA is fast, cheap, and accurate for identification of potentially pathogenic NTM. PMID- 25719822 TI - miRNAs in inflammatory skin diseases and their clinical implications. AB - miRNAs are a class of non-coding RNA molecules that modulate gene expression post transcriptionally. They have a major impact on several physiological and pathological cellular processes including modulation of the innate and the adaptive immune system. The role of miRNAs in skin biology is still incomplete; however, it is known that miRNAs are implicated in various cellular processes of both normal and diseased skin. Some miRNAs appear to be consistently deregulated in several different inflammatory skin diseases, including psoriasis and atopic dermatitis, indicating a common role in fundamental biological processes. The clinical implications of miRNAs are intriguing, both from a diagnostic and a therapeutic perspective. Accordingly, there is emerging evidence for the clinical potential of miRNAs as both biomarkers and possible therapeutic targets in skin diseases. Future studies will hopefully establish the biological significance of miRNAs in skin biology, paving the way for new miRNA-based diagnostic and therapeutic applications in dermatology. PMID- 25719824 TI - dSysMap: exploring the edgetic role of disease mutations. PMID- 25719825 TI - The fickle P value generates irreproducible results. PMID- 25719826 TI - Probes: paths to photostability. PMID- 25719827 TI - Determining the epigenome using DNA alone. PMID- 25719828 TI - Switch to maraviroc/raltegravir dual therapy leads to an unfavorable immune profile with low-level HIV viremia. AB - Immunovirological consequences of a switch to a maraviroc/raltegravir dual therapy were analyzed in 16 HIV-infected patients with persistent viral load below 50 copies/ml. At 26-week postswitch, the CD4/CD8 ratio decreased and the CD8 T-cell activation increased. A decrease in classical monocytes was associated with a shift toward a proinflammatory monocyte profile and negatively correlated with ultrasensitive viral load. Thus, this therapeutic switch induced a proinflammatory profile probably driven by a slight loss of virus control. PMID- 25719829 TI - hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma. AB - BACKGROUND: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. METHODS: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (alpha-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL Kras(G12D/+),LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled alpha-hERG1-MoAb. RESULTS: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the alpha-hERG1-MoAb could detect PDAC in vivo. CONCLUSIONS: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo. PMID- 25719830 TI - Androgen receptor expression in circulating tumour cells from castration resistant prostate cancer patients treated with novel endocrine agents. AB - BACKGROUND: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in CTCs in patients treated with enzalutamide and abiraterone. METHODS: CTCs were captured and characterised using the CellSearch system. An automated algorithm to identify CTCs and quantify AR expression was employed. The primary aim was to evaluate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide. RESULTS: AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients. We observed large intra patient heterogeneity of AR expression in CTCs. Prior exposure to abiraterone or enzalutamide was not associated with a change in CTCs AR expression (median intensity and distribution of AR-positive classes). In support of this, we also confirmed maintained nuclear AR expression in tissue samples collected after progression on abiraterone. AR staining also identified additional AR-positive CD45-negative circulating cells that were CK-negative/weak and therefore missed using standard protocols. The number of these events correlated with traditional CTCs and was associated with worse outcome on univariate analysis. CONCLUSIONS: We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome. PMID- 25719831 TI - Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM. AB - BACKGROUND: Better biomarkers must be found to develop clinically useful urine tests for bladder cancer. Proteomics can be used to identify the proteins released by cancer cell lines and generate candidate markers for developing such tests. METHODS: We used shotgun proteomics to identify proteins released into culture media by eight bladder cancer cell lines. These data were compared with protein expression data from the Human Protein Atlas. Epidermal growth factor receptor (EGFR) was identified as a candidate biomarker and measured by ELISA in urine from 60 noncancer control subjects and from 436 patients with bladder cancer and long-term clinical follow-up. RESULTS: Bladder cancer cell lines shed soluble EGFR ectodomain. Soluble EGFR is also detectable in urine and is highly elevated in some patients with high-grade bladder cancer. Urinary EGFR is an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, P<0.001). In multivariable models including both urinary EGFR and EpCAM, both biomarkers are predictive of bladder cancer-specific survival and have prognostic value over and above that provided by standard clinical observations. CONCLUSIONS: Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of patients with the most aggressive bladder cancers. PMID- 25719832 TI - Who are the cancer survivors? A nationwide study in Denmark, 1943-2010. AB - BACKGROUND: No nationwide studies on social position and prevalence of comorbidity among cancer survivors exist. METHODS: We performed a nationwide prevalence study defining persons diagnosed with cancer 1943-2010 and alive on the census date 1 January 2011 as cancer survivors. Comorbidity was compared by social position with the non-cancer population. RESULTS: Cancer survivors composed 4% of the Danish population. Somatic comorbidity was more likely among survivors (OR 1.59, 95% CI 1.57-1.60) and associated with higher age, male sex, short education, and living alone among survivors. CONCLUSIONS: Among cancer survivors, comorbidity is common and highly associated with social position. PMID- 25719833 TI - DNA hypermethylation analysis in sputum for the diagnosis of lung cancer: training validation set approach. AB - BACKGROUND: Lung cancer has the highest mortality of all cancers. The aim of this study was to examine DNA hypermethylation in sputum and validate its diagnostic accuracy for lung cancer. METHODS: DNA hypermethylation of RASSF1A, APC, cytoglobin, 3OST2, PRDM14, FAM19A4 and PHACTR3 was analysed in sputum samples from symptomatic lung cancer patients and controls (learning set: 73 cases, 86 controls; validation set: 159 cases, 154 controls) by quantitative methylation specific PCR. Three statistical models were used: (i) cutoff based on Youden's J index, (ii) cutoff based on fixed specificity per marker of 96% and (iii) risk classification of post-test probabilities. RESULTS: In the learning set, approach (i) showed that RASSF1A was best able to distinguish cases from controls (sensitivity 42.5%, specificity 96.5%). RASSF1A, 3OST2 and PRDM14 combined demonstrated a sensitivity of 82.2% with a specificity of 66.3%. Approach (ii) yielded a combination rule of RASSF1A, 3OST2 and PHACTR3 (sensitivity 67.1%, specificity 89.5%). The risk model (approach iii) distributed the cases over all risk categories. All methods displayed similar and consistent results in the validation set. CONCLUSIONS: Our findings underscore the impact of DNA methylation markers in symptomatic lung cancer diagnosis. RASSF1A is validated as diagnostic marker in lung cancer. PMID- 25719836 TI - Learning to listen. PMID- 25719834 TI - The neutrophil-lymphocyte ratio and its utilisation for the management of cancer patients in early clinical trials. AB - BACKGROUND: Inflammation is critical to the pathogenesis and progression of cancer, with a high neutrophil-lymphocyte ratio (NLR) associated with poor prognosis. The utility of studying NLR in early clinical trials is unknown. METHODS: This retrospective study evaluated 1300 patients treated in phase 1 clinical trials between July 2004 and February 2014 at the Royal Marsden Hospital (RMH), UK. Data were collected on patient characteristics and baseline laboratory parameters. RESULTS: The test cohort recruited 300 patients; 53% were female, 35% ECOG 0 and 64% ECOG 1. RMH score was 0-1 in 66% and 2-3 in 34%. The median NLR was 3.08 (IQR 2.06-4.49). Median OS for the NLR quartiles was 10.5 months for quartile-1, 10.3 months for quartile-2, 7.9 months for quartile-3 and 6.5 months for quartile-4 (P<0.0001). Univariate analysis identified RMH score (HR=0.55, P<0.0001), ECOG (HR=0.62, P=0.002) and neutrophils (HR=0.65, P=0.003) to be associated with OS. In multivariate analysis, adjusting for RMH score, ECOG, neutrophils and tumour type, NLR remained significantly associated with OS (P=0.002), with no association with therapeutic steroid use. These results were validated in a further 1000 cancer patients. In the validation cohort, NLR was able to discriminate for OS (P=0.004), as was the RMH score. This was further improved on in the RMH score+NLR50 and RMH score+Log10NLR models, with an optimal NLR cutoff of 3.0. CONCLUSIONS: NLR is a validated independent prognostic factor for OS in patients treated in phase 1 trials. Combining the NLR with the RMH score improves the discriminating ability for OS. PMID- 25719837 TI - The bycatch of trap-neuter-vaccinate-return. PMID- 25719838 TI - Why the AVMA's Council on Education should be an independent entity. PMID- 25719839 TI - Conflicted by conflicts of interest. PMID- 25719840 TI - What is your diagnosis? Comminuted compression fracture of the last (free) thoracic vertebra. PMID- 25719841 TI - Pathology in practice. Mycotic dermatitis and gout in an American alligator. PMID- 25719842 TI - Pathology in practice. Canine distemper virus disease in a dog. PMID- 25719843 TI - Tips for providing P-12 students career day-type presentations about the veterinary profession. PMID- 25719846 TI - A randomized controlled trial of factors influencing fire occurrence during laser surgery of cadaveric rodents under simulated mask anesthesia. AB - OBJECTIVE: To determine whether face mask fit during anesthesia affects the occurrence of fire episodes during laser surgery in nonintubated cadaveric rodents under volatile anesthesia. DESIGN: Adaptive single-center randomized controlled trial with an interim analysis. SAMPLE: 100 dead rats intended for animal consumption. PROCEDURES: Rat carcasses were randomly allocated to undergo simulated anesthetic procedures with 2 face masks: open mask versus tight-fitting mask. Under volatile anesthesia, 4 cutaneous surgeries were performed (skin biopsies at 3 different sites and resection of a pinna) by means of a diode laser on each carcass. A single interim analysis of 50 rats was planned a priori to drop an arm of the study in the case of a highly significant difference in the incidence of fire events. Surgeries would have continued with the other face mask until completion of the study. Univariate and multivariate analyses were performed. RESULTS: Overall, 25 surgeries were performed with open face masks and 75 with tight-fitting masks. During 400 surgical procedures on 100 rat carcasses, 11 (11%; 95% confidence interval, 5.62% to 18.83%) fire events occurred. Ten fire events occurred with the open masks, and 1 fire event occurred with the tight fitting masks (relative risk, 30.0; 95% confidence interval, 4.0 to 222.8). All of the fire events occurred on different carcasses when cheek skin biopsy was performed. Procedure time, body weight, and surgeon did not significantly concur in the prediction of fire events. CONCLUSIONS AND CLINICAL RELEVANCE: Modification of open masks by the addition of a latex diaphragm significantly reduced the occurrence of fire ignition during laser surgery. Results suggested that open masks should not be used for laser surgery of nonintubated rodents during volatile anesthesia. Additionally, results indicated that surgical lasers should be avoided for facial surgery of nonintubated anesthetized rodents, even if tight-fitting masks are used. PMID- 25719847 TI - Application of fast-track surgery principles to evaluate effects of atipamezole on recovery and analgesia following ovariohysterectomy in cats anesthetized with dexmedetomidine-ketamine-hydromorphone. AB - OBJECTIVE: To evaluate the effects of atipamezole hydrochloride on recovery and analgesia following ovariohysterectomy in cats anesthetized with a dexmedetomidine hydrochloride, ketamine hydrochloride, and hydromorphone hydrochloride combination, in accordance with fast-track surgery principles. DESIGN: Prospective, randomized, clinical trial. ANIMALS: 44 cats. PROCEDURES: Cats were anesthetized with a combination of dexmedetomidine (15 MUg/kg [6.8 MUg/lb]), ketamine (5 mg/kg [2.3 mg/lb]), and hydromorphone (0.05 mg/kg [0.023 mg/lb]), IM, supplemented with isoflurane in oxygen. Immediately after ovariohysterectomy, cats received meloxicam (0.2 mg/kg [0.09 mg/lb]) SC and either atipamezole (75 MUg/kg [34.1 MUg/lb]) or an equivalent volume of saline (0.9% NaCl) solution IM. Pain and sedation were scored at baseline (prior to surgery) and at predetermined intervals after surgery. Time to sternal recumbency was recorded. RESULTS: The atipamezole group recovered to sternal recumbency faster (median, 15 minutes; range, 5 to 60 minutes) than the saline solution group (median, 60 minutes; range, 15 to 90 minutes]). Pain scores did not differ between groups or at any time, compared with baseline, and were below the intervention threshold for most cats. Sedation scores were significantly greater in the saline solution group (median, 0; range, 0 to 2) at 2 hours after surgery, compared with the atipamezole group (median, 0; range, 0 to 0). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that administration of atipamezole, compared with saline solution, allowed for a faster recovery from anesthesia with dexmedetomidine-ketamine-hydromorphone in cats following ovariohysterectomy without compromising analgesia. These findings have implications for the provision of appropriate postoperative analgesia following ovariohysterectomy in cats. PMID- 25719848 TI - Effect of tooth extraction on stomatitis in cats: 95 cases (2000-2013). AB - OBJECTIVE: To evaluate long-term response of cats with stomatitis to tooth extraction. DESIGN: Retrospective case series. ANIMALS: 95 cats with stomatitis. PROCEDURES: Medical records of cats with stomatitis that was treated with tooth extraction during a 14-year period were reviewed. Demographic information and diagnostic results were recorded as well as surgical procedure, including full mouth extraction (FME) versus partial-mouth extraction (PME), and specifics of medical management. Patients were categorized according to response to treatment. RESULTS: Median postoperative follow-up time was 231 days (range, 33 to 2,655 days). Of 95 cats, 6 (6.3%) had no improvement and 25 (26.3%) had little improvement in stomatitis following tooth extraction and extended medical management (EMM). Following tooth extraction, 37 (39.0%) cats had substantial clinical improvement and 27 (28.4%) cats had complete resolution of stomatitis; of these 64 cats, 44 (68.8%) required EMM for a finite period to achieve positive outcomes. Extent of tooth extraction (PME vs FME) was not associated with overall response to treatment. At initial recheck examination, a better long-term response to tooth extraction was observed in patients with resolution of abnormal behavior (OR, 7.2), decrease in oral inflammation (OR, 3.5), and lack of need for follow-up medical management with antimicrobials (OR, 3.7). CONCLUSIONS AND CLINICAL RELEVANCE: Extraction of teeth in areas of oral inflammation provided substantial improvement or complete resolution of stomatitis in more than two thirds of affected cats. Full-mouth extraction did not appear to provide additional benefit over PME. Most cats with stomatitis may require EMM to achieve substantial clinical improvement or complete resolution. PMID- 25719849 TI - Association of catastrophic biaxial fracture of the proximal sesamoid bones with bony changes of the metacarpophalangeal joint identified by standing magnetic resonance imaging in cadaveric forelimbs of Thoroughbred racehorses. AB - OBJECTIVE: To compare bony changes in the metacarpophalangeal joint (MCPJ) of racehorses with (cases) and without (controls) biaxial proximal sesamoid bone (PSB) fracture as determined by 2 grading scales applied to images of cadaveric forelimbs obtained by means of standing MRI (sMRI). DESIGN: Case-control study. SAMPLE: Forelimbs from 74 Thoroughbred racehorses (21 cases and 53 controls) that were euthanized at a Florida racetrack. PROCEDURES: Both forelimbs were harvested from cases and controls. Each forelimb underwent sMRI to obtain images of the MCPJ. Two grading scales were described and used for image evaluation; one assessed the density of the PSBs, and the other assessed the integrity of the subchondral bone (SCB) plate at the distopalmar aspect of the third metacarpal bone (MC3). Logistic regression was used to compare the grades between case and control limbs. RESULTS: Biaxial PSB fracture was associated with a total PSB grade (sum of lateral and medial PSB grades) >= 5 for the fractured limb, total MC3 SCB grade (sum of lateral and medial MC3 SCB grades) >= 5 for the contralateral limb, and the presence of orthopedic disease in the contralateral MC3. CONCLUSIONS AND CLINICAL RELEVANCE: For cases with biaxial PSB fracture, the density of the PSBs in the affected limb was greater and the MC3 of the contralateral limb was more likely to have orthopedic disease, compared with those for controls. Further evaluation of sMRI as a screening tool for identification of racehorses at risk of biaxial PSB fracture is warranted. PMID- 25719850 TI - Treatment of a maxillary fibrosarcoma in an adult alpaca. AB - CASE DESCRIPTION: An approximately 5-year-old sexually intact male alpaca was evaluated because of a right-sided maxillary mass that had recurred after previous surgical debulking. CLINICAL FINDINGS: Clinical, radiographic, and CT examination revealed an approximately 1.5-cm-diameter soft tissue mass associated with expansile osteolysis of the maxillary alveolar bone, beginning at the level of the right maxillary third premolar tooth extending caudally to the level of the rostral roots of the second molar tooth. TREATMENT AND OUTCOME: Right partial maxillectomy was performed, and histologic examination revealed an incompletely excised fibrosarcoma with osseous metaplasia. External beam radiation therapy to the tumor bed was initiated 1 month after surgery. Computerized planning was performed, and a total radiation dose of 48 Gy was prescribed in eleven 4.4-Gy fractions. Follow-up CT evaluations 6 and 58 weeks after radiation therapy was completed revealed no evidence of tumor recurrence. No clinical evidence of tumor recurrence was detected through 110 weeks after radiation therapy. CLINICAL RELEVANCE: The oral fibrosarcoma in the alpaca described here was successfully treated with surgical excision and adjuvant radiation therapy, resulting in excellent quality of life of the treated animal. PMID- 25719852 TI - Molecular diagnostic methods for invasive fungal disease: the horizon draws nearer? AB - Rapid, accurate diagnostic laboratory tests are needed to improve clinical outcomes of invasive fungal disease (IFD). Traditional direct microscopy, culture and histological techniques constitute the 'gold standard' against which newer tests are judged. Molecular diagnostic methods, whether broad-range or fungal specific, have great potential to enhance sensitivity and speed of IFD diagnosis, but have varying specificities. The use of PCR-based assays, DNA sequencing, and other molecular methods including those incorporating proteomic approaches such as matrix-assisted laser desorption ionisation-time of flight mass spectroscopy (MALDI-TOF MS) have shown promising results. These are used mainly to complement conventional methods since they require standardisation before widespread implementation can be recommended. None are incorporated into diagnostic criteria for defining IFD. Commercial assays may assist standardisation. This review provides an update of molecular-based diagnostic approaches applicable to biological specimens and fungal cultures in microbiology laboratories. We focus on the most common pathogens, Candida and Aspergillus, and the mucormycetes. The position of molecular-based approaches in the detection of azole and echinocandin antifungal resistance is also discussed. PMID- 25719851 TI - Crosslinks and replication: the show must go on. PMID- 25719853 TI - Molecular methods for detecting and typing of Clostridium difficile. AB - Since the early 2000s, Clostridium difficile has emerged as a major international pathogen. Recently, strains of C. difficile in circulation appear to be changing, with greater diversity, leading to challenges for diagnostics and surveillance. Currently molecular diagnostic methods are favoured for their high sensitivity and rapid processing times; however, a number of issues still exist with molecular tests, in particular high cost, low clinical specificity and failure to detect some variant C. difficile strains. Molecular typing methods are used to determine the continually evolving epidemiology of C. difficile infection. Typing methods including PCR ribotyping and pulsed field gel electrophoresis are currently popular in Europe and North America, respectively, while high throughput next-generation sequencing is likely to become more widely used in years to come. This review discusses current molecular detection and typing techniques for C. difficile. PMID- 25719854 TI - Molecular diagnostics for tuberculosis. AB - The phenotypic methods of smear microscopy, culture and indirect drug susceptibility testing (DST) remain the 'gold standard' diagnostics for tuberculosis (TB) in 2015. However, this review demonstrates that genotypic methods are in the ascendancy. Current-generation nucleic acid amplification tests (NAATs) are important supplementary tests for the rapid direct detection of (multidrug-resistant) TB in specific clinical settings. Genotypic detection is already the preferred method of detecting rifampicin and pyrazinamide resistance. Next-generation NAATs able to detect about 10 colony forming units/mL of sputum could replace culture as the initial test for detecting TB. Whole genome sequencing could also plausibly replace phenotypic DST but much work is required in method standardisation, database development and elucidation of all resistance gene determinants. The challenge then will be to rollout these increasingly complex and expensive diagnostics in the low-income countries where TB is prevalent. PMID- 25719855 TI - Molecular testing for viral and bacterial enteric pathogens: gold standard for viruses, but don't let culture go just yet? AB - Contemporary diagnostic microbiology is increasingly adopting molecular methods as front line tests for a variety of samples. This trend holds true for detection of enteric pathogens (EP), where nucleic acid amplification tests (NAAT) for viruses are well established as the gold standard, and an increasing number of commercial multi-target assays are now available for bacteria and parasites. NAAT have significant sensitivity and turnaround time advantages over traditional methods, potentially returning same-day results. Multiplex panels offer an attractive 'one-stop shop' that may provide workflow and cost advantages to laboratories processing large sample volumes. However, there are a number of issues which need consideration. Reflex culture is required for antibiotic susceptibility testing and strain typing when needed for food safety and other epidemiological investigations. Surveillance systems will need to allow for differences in disease incidence due to the enhanced sensitivity of NAAT. Laboratories should be mindful of local epidemiology when selecting which pathogens to include in multiplex panels, and be thoughtful regarding which pathogens will not be detected. Multiplex panels may not be appropriate in certain situations, such as hospital-onset diarrhoea, where Clostridium difficile testing might be all that is required, and laboratories may wish to retain the flexibility to run single tests in such situations. The clinical impact of rapid results is also likely to be relatively minor, as infective diarrhoea is a self limiting illness in the majority of cases. Laboratories will require strategies to assist users in the interpretation of the results produced by NAAT, particularly where pathogens are detected at low levels with uncertain clinical significance. These caveats aside, faecal NAAT are increasingly being used and introduce a new era of diagnosis of gastrointestinal infection. PMID- 25719856 TI - Strabismus surgical subspecialization: a population-based analysis. AB - IMPORTANCE: The growing complexity of medical and surgical care has resulted in increasing subspecialization. To date, data have been lacking regarding the degree to which subspecialization has affected the provision of strabismus surgical services. This gap is important to address given the implications for health care human resources planning and educational programs. OBJECTIVE: To investigate the effect of subspecialization on the provision of strabismus surgery services. DESIGN, SETTING, AND PARTICIPANTS: Population-based study in Ontario, Canada, which provides universal health care coverage to the provincial population. Participants included all ophthalmologists in Ontario and the provincial population of approximately 12 million persons from January 1, 1994, through December 31, 2011. MAIN OUTCOMES AND MEASURES: Surgeon-level rates of strabismus surgery. RESULTS: From January 1, 1994, through December 31, 2011, the percentage of ophthalmologists who provided strabismus surgery decreased from 37.7% (156 of 414 surgeons) to 12.5% (54 of 432 surgeons; difference, 25.2%; 95% CI, 19.3%-30.9%; P < .001), a 66.8% decline from the baseline level. Of ophthalmologists who provided strabismus surgery during the same period, the mean number of strabismus procedures per surgeon grew from 16.2 to 55.3 per year, a 241.4% increase (95% CI, 20.4%-461.6%; P < .001). These trends occurred at all career stages. CONCLUSIONS AND RELEVANCE: Strabismus surgery has evolved into a subspecialized field of ophthalmology during the past 15 years. These findings may have important implications for health care professionals and health care system leaders, including the need to account for subspecialization in physician human resources decisions to ensure access to quality strabismus surgery across regions. Furthermore, residency education programs and their governing organizations may need to account for strabismus subspecialization when designing curriculum and accreditation requirements. PMID- 25719858 TI - MRI and unilateral NMR study of reindeer skin tanning processes. AB - The study of arctic or subarctic indigenous skin clothing material, known for its design and ability to keep the body warm, provides information about the tanning materials and techniques. The study also provides clues about the culture that created it, since tanning processes are often specific to certain indigenous groups. Untreated skin samples and samples treated with willow (Salix sp) bark extract and cod liver oil are compared in this study using both MRI and unilateral NMR techniques. The two types of samples show different proton spatial distributions and different relaxation times, which may also provide information about the tanning technique and aging behavior. PMID- 25719857 TI - Widespread presence of the pathogenic fungus Batrachochytrium dendrobatidis in wild amphibian communities in Madagascar. AB - Amphibian chytridiomycosis, an emerging infectious disease caused by the fungus Batrachochytrium dendrobatidis (Bd), has been a significant driver of amphibian declines. While globally widespread, Bd had not yet been reported from within Madagascar. We document surveys conducted across the country between 2005 and 2014, showing Bd's first record in 2010. Subsequently, Bd was detected in multiple areas, with prevalence reaching up to 100%. Detection of Bd appears to be associated with mid to high elevation sites and to have a seasonal pattern, with greater detectability during the dry season. Lineage-based PCR was performed on a subset of samples. While some did not amplify with any lineage probe, when a positive signal was observed, samples were most similar to the Global Panzootic Lineage (BdGPL). These results may suggest that Bd arrived recently, but do not exclude the existence of a previously undetected endemic Bd genotype. Representatives of all native anuran families have tested Bd-positive, and exposure trials confirm infection by Bd is possible. Bd's presence could pose significant threats to Madagascar's unique "megadiverse" amphibians. PMID- 25719859 TI - Helicity-resolved Raman scattering of MoS2, MoSe2, WS2, and WSe2 atomic layers. AB - The two-fold valley degeneracy in two-dimensional (2D) semiconducting transition metal dichalcogenides (TMDCs) (Mo,W)(S,Se)2 is suitable for "valleytronics", the storage and manipulation of information utilizing the valley degree of freedom. The conservation of luminescent photon helicity in these 2D crystal monolayers has been widely regarded as a benchmark indicator for charge carrier valley polarization. Here we perform helicity-resolved Raman scattering of the TMDC atomic layers. In drastic contrast to luminescence, the dominant first-order zone center Raman bands, including the low energy breathing and shear modes as well as the higher energy optical phonons, are found to either maintain or completely switch the helicity of incident photons. In addition to providing a useful tool for characterization of TMDC atomic layers, these experimental observations shed new light on the connection between photon helicity and valley polarization. PMID- 25719860 TI - Response to "Brain magnetic resonance imaging in influenza A (H1N1) 2009 associated encephalopathy". PMID- 25719861 TI - Brain magnetic resonance imaging in influenza A (H1N1) 2009-associated encephalopathy. PMID- 25719862 TI - Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide. AB - The P140 peptide, a 21-mer linear peptide (sequence 131-151) generated from the spliceosomal SNRNP70/U1-70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired. PMID- 25719863 TI - New lower-limb gait asymmetry indices based on a depth camera. AB - BACKGROUND: Various asymmetry indices have been proposed to compare the spatiotemporal, kinematic and kinetic parameters of lower limbs during the gait cycle. However, these indices rely on gait measurement systems that are costly and generally require manual examination, calibration procedures and the precise placement of sensors/markers on the body of the patient. METHODS: To overcome these issues, this paper proposes a new asymmetry index, which uses an inexpensive, easy-to-use and markerless depth camera (Microsoft KinectTM) output. This asymmetry index directly uses depth images provided by the KinectTM without requiring joint localization. It is based on the longitudinal spatial difference between lower-limb movements during the gait cycle. To evaluate the relevance of this index, fifteen healthy subjects were tested on a treadmill walking normally and then via an artificially-induced gait asymmetry with a thick sole placed under one shoe. The gait movement was simultaneously recorded using a KinectTM placed in front of the subject and a motion capture system. RESULTS: The proposed longitudinal index distinguished asymmetrical gait (p < 0.001), while other symmetry indices based on spatiotemporal gait parameters failed using such KinectTM skeleton measurements. Moreover, the correlation coefficient between this index measured by KinectTM and the ground truth of this index measured by motion capture is 0.968. CONCLUSION: This gait asymmetry index measured with a KinectTM is low cost, easy to use and is a promising development for clinical gait analysis. PMID- 25719864 TI - Photocatalytic CO2 reduction by a mixed metal (Zr/Ti), mixed ligand metal-organic framework under visible light irradiation. AB - Postsynthetic exchange (PSE) of Ti(IV) into a Zr(IV)-based MOF enabled photocatalytic CO2 reduction to HCOOH under visible light irradiation with the aid of BNAH and TEOA. Use of a mixed-ligand strategy enhanced the photocatalytic activity of the MOF by introducing new energy levels in the band structure of the MOF. PMID- 25719865 TI - Corrigendum: Metagenomic and whole-genome analysis reveals new lineages of gokushoviruses and biogeographic separation in the sea. AB - [This corrects the article on p. 404 in vol. 4, PMID: 24399999.]. PMID- 25719866 TI - Isotope fractionation associated with the direct photolysis of 4-chloroaniline. AB - Compound-specific isotope analysis is a useful approach to track transformations of many organic soil and water pollutants. Applications of CSIA to characterize photochemical processes, however, have hardly been explored. In this work, we systematically studied C and N isotope fractionation associated with the direct photolysis of 4-Cl-aniline used as a model compound for organic micropollutants that are known to degrade via photochemical processes. Laboratory experiments were carried out at an irradiation wavelength of 254 nm over the pH range 2.0 to 9.0 as well as in the presence of Cs(+) as a quencher of excited singlet 4-Cl aniline at pH 7.0 and 9.0. We observed considerable variation of C and N isotope enrichment factors, epsilonC and epsilonN, between -1.2 +/- 0.20/00 to -2.7 +/- 0.20/00 for C and -0.6 +/- 0.20/00 to -9.1 +/- 1.60/00 for N, respectively, which could not be explained by the speciation of 4-Cl-aniline alone. In the presence of 1 M Cs(+), we found a marked increase of apparent (13)C-kinetic isotope effects ((13)C-AKIE) and decrease of 4-Cl-aniline fluorescence lifetimes. Our data suggest that variations of C and N isotope fractionation originate from heterolytic dechlorination of excited triplet and singlet states of 4-Cl-aniline. Linear correlations of (13)C-AKIE vs (15)N-AKIE were distinctly different for these two reaction pathways and may be explored further for the identification of photolytic aromatic dechlorination reactions. PMID- 25719867 TI - Recent Advances in Supramolecular Analytical Chemistry Using Optical Sensing. PMID- 25719868 TI - The Hippo Pathway and YAP/TAZ-TEAD Protein-Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment. AB - The Hippo pathway is an important organ size control signaling network and the major regulatory mechanism of cell-contact inhibition. Yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. Defects in the pathway can result in overgrowth phenotypes due to deregulation of stem-cell proliferation and apoptosis; members of the pathway are directly involved in cancer development. The pharmacological regulation of the pathway might be useful in cancer prevention, treatment, and regenerative medicine applications; currently, a few compounds can selectively modulate the pathway. In this review, we present an overview of the Hippo pathway, the sequence and structural analysis of YAP/TAZ, the known pharmacological modulators of the pathway, especially those targeting YAP/TAZ-TEAD interaction. PMID- 25719869 TI - Appropriateness of diagnostic coronary angiography as a measure of cardiac ischemia testing in non-emergency patients - a retrospective cross-sectional analysis. AB - BACKGROUND: Adequate application of guidelines concerning non-invasive ischemia testing (NIIT) could avoid inappropriate invasive testing in non-emergency situations. Hardly any data exists regarding frequency and appropriateness of diagnostic coronary angiography (CA). The aim of this study was to evaluate the proportion and predictors of patients without NIIT prior to elective purely diagnostic CA without therapeutic intervention. METHODS: Retrospective cross sectional analysis of insurance claims data from 2012 and 2013. Patients <18 years, acute cardiac ischemia and emergency procedures and patients insured in a managed care model were excluded from analysis. The proportion of patients with NIIT procedures (stress-ECG, transthoracic echocardiography, stress echocardiography, scintigraphy, computer tomography, heart MRI) undertaken within two months before diagnostic CA was assessed. Multiple logistic regression analysis was applied to investigate independent determinants for receiving NIIT. FINDINGS: 2714 patients were included for analysis. 37.5% (1018) did not receive any NIIT before CA. When high risk patients (patients having received therapeutic cardiac intervention within one month after or 18 months prior to diagnostic CA, n = 766) were excluded 34.3% (669) did not receive NIIT before CA. High risk status as well as >6 chronic comorbidities were independently associated with a lower proportion of NIIT (p<0.0001, OR 0.607 and p = 0.0041, OR 0.648), when additionally controlled for age, sex, language area, insurance coverage, inpatient treatment, cardiovascular medication and lower number of chronic comorbidities. Age (p<0.05, OR 1.009) and intake of oral antiplatelet therapy (p<0.0001, OR 1.914) were independently associated with a higher proportion of NIIT when controlled for the mentioned cofactors. CONCLUSIONS: Our data show that despite the existence of guidelines a substantial overuse of a potentially harmful and inappropriate diagnostic intervention is performed suggesting the need for improvement of diagnostic pathways prior to invasive testing. PMID- 25719870 TI - Consumer education needed on norovirus prevention and control: findings from a nationally representative survey of U.S. adults. AB - Noroviruses (NoVs) are the leading cause of foodborne disease in the United States; however, little is known about consumers' knowledge of NoV infection and their understanding of how to prevent and control associated illness. A nationally representative Web-enabled panel survey of U.S. adults (n = 1,051) was conducted to collect information on consumers' awareness and knowledge of NoVs. Respondents who had heard of NoVs were asked 22 true-and-false questions on the transmission, prevention, and control of NoVs. Forty-seven percent of respondents reported awareness of NoVs, and 85% of respondents had heard of the terms "cruise ship virus," "the stomach bug," or "the stomach flu," which are commonly used to describe NoVs. Of those respondents who had previously heard of NoV or other terms used by consumers to describe NoV (n = 948), 36% correctly answered 11 or more of the 22 true-and-false questions, suggesting that consumers have limited knowledge on how to prevent and control NoV infection. Most consumers do not understand that the primary mode of transmission for NoV infection is fecal to oral, and many have the misperception that meat and poultry are sources of NoV infection. There is the need to educate consumers about how to prevent and control NoV infection. Although there is a proliferation of food safety education materials available, most focus on foodborne bacteria rather than viruses. The survey results will be used to revise existing consumer food safety educational materials to include information on NoV prevention and control. PMID- 25719871 TI - Fate of Salmonella enterica in a mixed ingredient salad containing lettuce, cheddar cheese, and cooked chicken meat. AB - Food service and retail sectors offer consumers a variety of mixed ingredient salads that contain fresh-cut vegetables and other ingredients such as fruits, nuts, cereals, dairy products, cooked seafood, cooked meat, cured meats, or dairy products obtained from external suppliers. Little is known about the behavior of enteric bacterial pathogens in mixed ingredient salads. A model system was developed to examine the fate of Salmonella enterica (inoculum consisting of S. enterica serovars Agona, Typhimurium, Enteritidis, Brandenberg, and Kentucky) on the surface of romaine lettuce tissues incubated alone and in direct contact with Cheddar cheese or cooked chicken. S. enterica survived but did not grow on lettuce tissues incubated alone or in contact with Cheddar cheese for 6 days at either 6 or 14 degrees C. In contrast, populations increased from 2.01 +/- 0.22 to 9.26 +/- 0.22 CFU/cm(2) when lettuce washed in water was incubated in contact with cooked chicken at 14 degrees C. Populations on lettuce leaves were reduced to 1.28 +/- 0.14 CFU/cm(2) by washing with a chlorine solution (70 ppm of free chlorine) but increased to 8.45 +/- 0.22 CFU/cm(2) after 6 days at 14 degrees C. Experimentation with a commercial product in which one third of the fresh-cut romaine lettuce was replaced with inoculated lettuce revealed that S. enterica populations increased by 4 log CFU/g during storage for 3 days at 14 degrees C. These findings indicate that rapid growth of bacterial enteric pathogens may occur in mixed ingredient salads; therefore, strict temperature control during the manufacture, distribution, handling, and storage of these products is critical. PMID- 25719872 TI - Salmonella in beef and produce from honduras. AB - Salmonella continues to cause a considerable number of foodborne illnesses worldwide. The sources of outbreaks include contaminated meat and produce. The purpose of this study was to establish an initial investigation of the burden of Salmonella in produce and beef from Honduras by sampling retail markets and abattoirs. Retail produce samples (cantaloupes, cilantro, cucumbers, leafy greens, peppers, and tomatoes; n = 573) were purchased in three major cities of Honduras, and retail whole-muscle beef (n = 555) samples were also purchased in four major cities. Additionally, both hide and beef carcass (n = 141) samples were collected from two Honduran abattoirs. Whole-muscle beef samples were obtained using a sponge hydrated with buffered peptone water, and 10 ml of the buffered peptone water rinsate of each produce sample was collected with a dry sponge and placed in a bag to be transported back to the United States. Salmonella was detected using a commercially available, closeplatform PCR system, and positive samples were subjected to culture on selective media to obtain isolates. Overall, the prevalence of Salmonella-positive samples, based on PCR detection in Honduras (n = 555) retail beef was 10.1% (95% confidence interval = 7.8, 12.9), whereas 7.8% (n = 141) of beef carcass and hides samples were positive in both beef plants. The overall Salmonella prevalence for all produce samples (n = 573) collected was 2.1% (95% confidence interval = 1.2, 3.6). The most common serotypes identified in Honduras were Salmonella Typhimurium followed by Derby. These results provide an indication of Salmonella contamination of beef and produce in Honduras. Developing a Salmonella baseline for Latin America through an initial investigation like the one presented here contributes to a broader global understanding of the potential exposure through food, thus providing insight into the needs for control strategies. PMID- 25719873 TI - Efficacy of antimicrobial compounds on surface decontamination of seven Shiga toxin-producing Escherichia coli and Salmonella inoculated onto fresh beef. AB - Several antimicrobial compounds have been used in commercial meat processing plants for decontamination of pathogens on beef carcasses, but there are many commercially available, novel antimicrobial compounds that may be more effective and suitable for use in beef processing pathogen-reduction programs. Sixty-four prerigor beef flanks (cutaneous trunci) were used in a study to determine whether hypobromous acid, neutral acidified sodium chlorite, and two citric acid-based antimicrobial compounds effectively reduce seven Shiga toxin-producing Escherichia coli (STEC) serogroups and Salmonella on the surface of fresh beef. Two cocktail mixtures were inoculated onto prerigor beef flank surfaces. Cocktail mixture 1 was composed of STEC serogroups O26, O103, O111, O145, and O157; and cocktail mixture 2 was composed of STEC serogroups O45, O121, and O157 and Salmonella. The inoculated fresh beef flanks were subjected to spray treatments with four antimicrobial compounds. Following antimicrobial treatments, both control and treated fresh beef samples were either enumerated immediately or were stored for 48 h at 4 degrees C before enumeration. All four antimicrobial compounds caused 0.7- to 2.0-log reductions of STEC, Salmonella, aerobic plate counts, and Enterobacteriaceae. Results also indicated that the four antimicrobial compounds were as effective at reducing the six non-O157 STEC strains as they were at reducing E. coli O157:H7 on the surfaces of fresh beef. The recovery of all seven STEC strains and Salmonella in a low-inoculation study indicated that none of the four antimicrobial compounds eliminated all of the tested pathogens. PMID- 25719874 TI - Antimicrobial interventions for O157:H7 and non-O157 Shiga toxin-producing Escherichia coli on beef subprimal and mechanically tenderized steaks. AB - Non-O157 Shiga toxin-producing Escherichia coli (STEC) is an emerging risk for food safety. Although numerous postharvest antimicrobial interventions have been effectively used to control E. coli O157:H7 during beef harvesting, research regarding their effectiveness against non-O157 STEC is scarce. The objectives of this study were (i) to evaluate effects of the spray treatments-ambient water, 5% lactic acid (LA), 200 ppm of hypobromous acid (HA), and 200 ppm of peroxyacetic acid (PA)-on the reduction of O157:H7 or non-O157 STEC (O26, O103, O111, and O145) with high (10(6) log CFU/50 cm(2)) or low (10(2) log CFU/50 cm(2)) levels on beef subprimals after vacuum storage for 14 days and (ii) to evaluate the association of the antimicrobial treatments and cooking (50 or 70 degrees C) on the reduction of the pathogens in blade-tenderized steaks. The treatment effects were only observed (P = 0.012) on samples taken immediately after spray intervention treatment following inoculation with a high level of O157:H7. The LA and PA treatments significantly reduced low-inoculated non-O157 STEC after spray intervention; further, the LA and HA treatments resulted in significant reductions of non-O157 STEC on the low-inoculated samples after storage. Although cooking effectively reduced the detection of pathogens in internal steak samples, internalized E. coli O157:H7 and non-O157 STEC were able to survive in steaks cooked to a medium degree of doneness (70 degrees C). This study indicated that the reduction on surface populations was not sufficient enough to eliminate the pathogen's detection following vacuum storage, mechanical tenderization, and cooking. Nevertheless, the findings of this study emphasize the necessity for a multihurdle approach and further investigations of factors that may influence thermal tolerance of internalized pathogenic STEC. PMID- 25719875 TI - Transmission of Escherichia coli O157:H7 to internal tissues and its survival on flowering heads of wheat. AB - Escherichia coli O157:H7 is a human pathogen that can cause bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. E. coli O157:H7 illnesses are mainly associated with undercooked beef; however, in recent years, outbreaks have been linked to fresh produce, such as spinach, lettuce, and sprouts. In 2009, flour was implicated as the contamination source in an outbreak involving consumption of raw cookie dough that resulted in 77 illnesses. The objectives of this research were to determine (i) whether E. coli O157:H7 could be translocated into the internal tissues of wheat (Triticum aestivum) seedlings from contaminated seed, soil, or irrigation water and (ii) whether the bacterium could survive on flowering wheat heads. The levels of contamination of kanamycin resistant E. coli O157:H7 strains in seed, soil, and irrigation water were 6.88 log CFU/g, 6.60 log CFU/g, and 6.76 log CFU/ml, respectively. One hundred plants per treatment were sown in pot trays with 50 g of autoclaved soil or purposely contaminated soil, watered every day with 5 ml of water, and harvested 9 days postinoculation. In a fourth experiment, flowering wheat heads were spray inoculated with water containing 4.19 log CFU/ml E. coli O157:H7 and analyzed for survival after 15 days, near the harvest period. To detect low levels of internalization, enrichment procedures were performed and Biotecon real-time PCR detection assays were used to determine the presence of E. coli O157:H7 in the wheat, using a Roche Applied Science LightCycler 2.0 instrument. The results showed that internalization was possible using contaminated seed, soil, and irrigation water in wheat seedlings, with internalization rates of 2, 5, and 10%, respectively. Even though the rates were low, to our knowledge this is the first study to demonstrate the ability of this strain to reach the phylloplane in wheat. In the head contamination experiment, all samples tested positive, showing the ability of E. coli O157:H7 to survive on the wheat head. PMID- 25719876 TI - Validation of a novel rinse and filtration method for efficient processing of fresh produce samples for microbiological indicator enumeration. AB - Several methods have been described to prepare fresh produce samples for microbiological analysis, each with its own advantages and disadvantages. The aim of this study was to compare the performance of a novel combined rinse and membrane filtration method to two alternative sample preparation methods for the quantification of indicator microorganisms from fresh produce. Decontaminated cantaloupe melons and jalapeno peppers were surface inoculated with a cocktail containing 10(6) CFU/ml Escherichia coli, Salmonella Typhimurium, and Enterococcus faecalis. Samples were processed using a rinse and filtration method, homogenization by stomacher, or a sponge-rubbing method, followed by quantification of bacterial load using culture methods. Recovery efficiencies of the three methods were compared. On inoculated cantaloupes, the rinse and filtration method had higher recovery of coliforms (0.95 log CFU/ml higher recovery, P = 0.0193) than the sponge-rubbing method. Similarly, on inoculated jalapenos, the rinse and filtration method had higher recovery for coliforms (0.84 log CFU/ml higher, P = 0.0130) and E. coli (1.46 log CFU/ml higher, P < 0.0001) than the sponge-rubbing method. For jalapenos, the rinse and filtration method outperformed the homogenization method for all three indicators (0.79 to 1.71 log CFU/ml higher, P values ranging from 0.0075 to 0.0002). The precision of the three methods was also compared. The precision of the rinse and filtration method was similar to that of the other methods for recovery of two of three indicators from cantaloupe (E. coli P = 0.7685, E. faecalis P = 0.1545) and was more precise for recovery of two of three indicators from jalapeno (coliforms P = 0.0026, E. coli P = 0.0243). Overall, the rinse and filtration method performed equivalent to, and sometimes better than, either of the compared methods. The rinse and filtration method may have logistical advantages when processing large numbers of samples, improving sampling efficiency and facilitating microbial detection. PMID- 25719877 TI - Microbial inactivation and physicochemical properties of ultrasound processed pomegranate juice. AB - The effects of ultrasound treatment at various amplitudes (50, 75, and 100%) and times (0, 6, 12, 18, 24, and 30 min) on Escherichia coli ATCC 25922 (a surrogate for E. coli O157:H7) and Saccharomyces cerevisiae ATCC 2366 levels and physicochemical characteristics (monomeric anthocyanins, color values, total phenolics, pH, and soluble solids) were determined in pomegranate juice. More than a 5-log inactivation of E. coli ATCC 25922 and a 1.36-log inactivation of S. cerevisiae ATCC 2366 were achieved after 30 min of ultrasound treatment at 100% amplitude. The log-linear and Weibull models were successfully used to estimate the microbial inactivation as a function of ultrasound treatment time (R(2) > 0.97). No significant changes were observed in total phenolics, pH, and soluble solids of the treated juice (P > 0.05). The ultrasound treatment for up to 30 min resulted in more than 92 and 89% anthocyanin retention at 75 and 100% amplitude, respectively. The redness (a*) of the juice did not change significantly after the ultrasound treatment at amplitudes of 75 and 100% for up to 24 and 12 min, respectively. No significant changes in L* and b* values were observed after ultrasound treatment at all amplitudes and after up to 30 min of treatment for 50 and 75% amplitudes. Small differences in juice color were noted based on total color difference scores. PMID- 25719878 TI - Differentiation of different mixed Listeria strains and also acid-injured, heat injured, and repaired cells of Listeria monocytogenes using fourier transform infrared spectroscopy. AB - Fourier transform infrared (FT-IR) spectroscopy was used to differentiate mixed strains of Listeria monocytogenes and mixed strains of L. monocytogenes and Listeria innocua. FT-IR spectroscopy was also applied to investigate the hypothesis that heat-injured and acid-injured cells would return to their original physiological integrity following repair. Thin smears of cells on infrared slides were prepared from cultures for mixed strains of L. monocytogenes, mixed strains of L. monocytogenes and L. innocua, and each individual strain. Heat-injured and acid-injured cells were prepared by exposing harvested cells of L. monocytogenes strain R2-764 to a temperature of 56 +/- 0.2 degrees C for 10 min or lactic acid at pH 3 for 60 min, respectively. Cellular repair involved incubating aliquots of acid-injured and heat-injured cells separately in Trypticase soy broth supplemented with 0.6% yeast extract for 22 to 24 h; bacterial thin smears on infrared slides were prepared for each treatment. Spectral collection was done using 250 scans at a resolution of 4 cm(-1) in the mid-infrared wavelength region. Application of multivariate discriminant analysis to the wavelength region from 1,800 to 900 cm(-1) separated the individual L. monocytogenes strains. Mixed strains of L. monocytogenes and L. monocytogenes cocultured with L. innocua were successfully differentiated from the individual strains when the discriminant analysis was applied. Different mixed strains of L. monocytogenes were also successfully separated when the discriminant analysis was applied. A data set for injury and repair analysis resulted in the separation of acid-injured, heat-injured, and intact cells; repaired cells clustered closer to intact cells when the discriminant analysis (1,800 to 600 cm(-1)) was applied. FT IR spectroscopy can be used for the rapid source tracking of L. monocytogenes strains because it can differentiate between different mixed strains and individual strains of the pathogen. PMID- 25719879 TI - Effect of electrolyzed oxidizing water treatment on the reduction of nitrite levels in fresh spinach during storage. AB - Leafy vegetables are the major source of nitrite intake in the human diet, and technological processing to control nitrite levels in harvested vegetables is necessary. In the current work, the effect of electrolyzed oxidizing water (EOW) on the nitrite and nitrate levels in fresh spinach during storage was studied. EOW treatment, including slightly acidic electrolyzed water and acidic electrolyzed water, was found to effectively reduce nitrite levels in fresh spinach during storage; levels in the late period were 30 to 40% lower than that of the control. However, the nitrate levels in fresh spinach during storage were not influenced by EOW treatment. The reduction of nitrite levels in EOW-treated fresh spinach during storage can be attributed to the inactivation of nitrate reductase directly and to the reduction of bacterial populations. Our results suggest that treatment with slightly acidic electrolyzed water may be a better choice to control nitrite levels in fresh vegetables during storage. This study provided a useful method to reduce nitrite levels in fresh spinach. PMID- 25719880 TI - Concentrations and profiles of polycyclic aromatic hydrocarbons in some popular fish species in Nigeria. AB - The concentrations and profiles of polycyclic aromatic hydrocarbons (PAHs) in 10 popular fish species in the Nigerian market were determined with a view to providing information on the health hazards associated with the consumption of these fish species. The concentrations of PAHs were measured by gas chromatography-mass spectrometry after extraction by ultrasonication with acetone dichloromethane and clean up. The concentration ranges of the Sigma16 PAHs were 20 to 39.6 MUg kg(-1) for Parachanna obscura (African snake head), 6.8 to 532.3 MUg kg(-1) for Oreochromis niloticus (tilapia), 7.4 to 91.1 MUg kg(-1) for Gymnarchus niloticus (Asa), 13.1 to 34.1 MUg kg(-1) for Sebastes fasciatus (red fish), 11.2 to 80.0 MUg kg(-1) for Gadus morhua (cod), 23.9 to 34.6 MUg kg(-1) for Chrysicthys nigrodigitatus (silver cat fish), 63.4 to 131.4 MUg kg(-1) for Sardinella aurita (sardine), 22 to 52.9 MUg kg(-1) for Trachurus trachurus (Atlantic horse mackerel), 21.0 to 63.7 MUg kg(-1) for Scomber scombrus (mackerel), and 27.7 to 44.5 MUg kg(-1) for Pseudotolithus senegalensis (croaker). Benzo[a]pyrene occurred in 23% of these fish samples at concentrations above the European Union permissible limit of 2.0 MUg kg(-1). The calculated margins of exposure based on the indicators for occurrence and effects of PAHs were greater than 10,000 indicating no potential risk for the consumers of the species evaluated in this study. PMID- 25719881 TI - Distribution of radioactive cesium ((134)Cs plus (137)Cs) in rice fractions during polishing and cooking. AB - We investigated the distribution of cesium-134 ((134)Cs) and cesium-137 ((137)Cs) during polishing and cooking of rice to obtain their processing factors (Pf) and food processing retention factors (Fr) to make the information available for an adequate understanding of radioactive Cs dynamics. Polishing brown rice resulted in a decreased radioactive Cs concentration of the polished rice, but the bran and germ (outer layers) exhibited higher concentrations than brown rice. The Pf values for 100% polished rice and outer layers ranged from 0.47 to 0.48 and 6.5 to 7.8, respectively. The Fr values for 100% polished rice and outer layers were 0.43 and 0.58 to 0.60, respectively. The distribution of radioactive Cs in polished rice and outer layers was estimated at approximately 40 and 60%, respectively. On the other hand, cooked rice showed significantly lower levels of radioactive Cs than polished rice, and transfer of radioactive Cs into wash water was observed. The Pf and Fr values for cooked rice were 0.28 and 0.65 to 0.66, respectively. From these results, we can calculate that if the radioactive Cs concentration in brown rice is 100 Bq/kg, the concentrations of Cs in polished rice and cooked rice will be 47 to 48 Bq/kg and 13 Bq/kg, respectively. PMID- 25719882 TI - Fresh steam-flaked corn in cattle feedlots is an important site for fecal coliform contamination by house flies. AB - House flies are a common pest at food animal facilities, including cattle feedlots. Previously, house flies were shown to play an important role in the ecology of Escherichia coli O157:H7; house flies in cattle feedlots carried this zoonotic pathogen and were able to contaminate cattle through direct contact and/or by contamination of drinking water and feed. Because house flies aggregate in large numbers on fresh ( # 6 h) steam-flaked corn (FSFC) used in cattle feed, the aim of this study was to assess FSFC in a cattle feedlot as a potentially important site of fecal coliform contamination by house flies. House flies and FSFC samples were collected, homogenized, and processed for culturing of fecal coliforms on membrane fecal coliform agar. Selected isolates were identified by 16S rRNA gene sequencing, and representative isolates from each phylogenetic group were genotyped by pulsed-field gel electrophoresis. Fecal coliforms were undetectable in FSFC shortly (0 h) after flaking; however, in summer, after 4 to 6 h, the concentrations of fecal coliforms ranged from 1.9 * 10(3) to 3.7 * 10(4) CFU/g FSFC (mean, 1.1 +/- 3.0 * 10(4) CFU/g). House flies from FSFC carried between 7.6 * 10(2) and 4.1 * 10(6) CFU of fecal coliforms per fly (mean, 6.0 +/- 2.3 * 10(5) CFU per fly). Fecal coliforms were represented by E. coli (85.1%), Klebsiella spp. (10.6%), and Citrobacter spp. (4.3%). Pulsed-field gel electrophoresis demonstrated clonal matches of E. coli and Klebsiella spp. between house flies and FSFC. In contrast, in winter and in the absence of house flies, the contamination of corn by fecal coliforms was significantly (~10-fold) lower. These results indicate that FSFC is an important site for bacterial contamination by flies and possible exchange of E. coli and other bacteria among house flies. Further research is needed to evaluate the potential use of screens or blowers to limit the access of house flies to FSFC and therefore their effectiveness in preventing bacterial contamination. PMID- 25719883 TI - Oral salmonella challenge and subsequent uptake by the peripheral lymph nodes in calves. AB - Previous attempts to infect peripheral lymph nodes (PLNs) with Salmonella via oral inoculation have been inconsistent. Therefore, we performed a series of experiments to determine whether multiple exposures to an oral challenge would result in Salmonella-positive PLN in cattle. In each of three experiments, calves were inoculated with Salmonella Montevideo. In the first experiment, calves were challenged with either no Salmonella (control), a single oral dose (~10(10); PCON), or 10 consecutive doses in water (~10(3); WAT). The positive control treatment resulted in an increase (P < 0.05) in the percentage of Salmonella positive PLNs, compared with the WAT-treated and control animals. Experiments 2 and 3 were designed to additionally determine if the stress associated with feed and water deprivation influences the systemic spread of Salmonella from the gastrointestinal tract to PLNs. Following 14 days of oral inoculation (average 7.1 * 10(4) CFU/day) in experiment 1, Salmonella was recovered from one subiliac and one superficial cervical lymph node of calves that were deprived of feed and water (72 h). No treatment differences (P > 0.05) were observed between control and deprived calves. Based on the poor recovery of Salmonella from the PLNs in WAT-challenged calves in experiments 1 and 2, a higher challenge dose (average 1.2 * 10(7) CFU) was used in experiment 3. The increased dose resulted in the recovery of the challenge strain of Salmonella from the PLNs (70.8 and 75.0% of control and deprived calves, respectively). However, no treatment differences (P > 0.05) were observed between control and deprived calves. Results of this research demonstrated that a substantial oral challenge is required to produce Salmonella-positive PLNs. However, as the challenge periods examined herein were considerably shorter compared with the normal time spent by cattle in feedlots, increased exposure time to lower doses may produce the same effect observed in experiment 3. PMID- 25719884 TI - Fecal shedding of thermophilic Campylobacter in a dairy herd producing raw milk for direct human consumption. AB - Factors affecting the fecal shedding of thermophilic Campylobacter in Italian dairy farms were investigated in a 12-month longitudinal study performed on a dairy farm authorized to sell raw milk in Italy. Fifty animals were randomly selected from 140 adult and young animals, and fecal samples were collected six times at 2-month intervals. At each sampling time, three trough water samples and two trough feed samples also were collected for both adult and young animals. Samples were analyzed with real-time PCR assay and culture examination. Overall, 33 samples (9.7%) were positive for thermophilic Campylobacter by real-time PCR: 26 (9.2%) of 280 fecal samples, 6 (16.6%) of 36 water samples, and 1 (4.2%) of 24 feed samples. Campylobacter jejuni was isolated from 6 of 280 samples; no other Campylobacter species was isolated. A higher (but not significantly) number of positive fecal samples were found in younger animals (11.33 versus 6.92% of adult animals), and a significantly higher number of positive water samples were collected from the water troughs of young animals. A distinct temporal trend was observed during the study period for both cows and calves, with two prevalence peaks between November and December and between May and July. Several factors such as calving, housing practices, herd size, management practices forcing together a higher number of animals, and variations in feed or water sources (previously reported as a cause of temporal variation in different farming conditions) were excluded as the cause of the two seasonal peaks in this study. The factors affecting the seasonality of Campylobacter shedding in the dairy herds remain unclear and warrant further investigation. The results of the present study indicate that special attention should be paid to farm hygiene management on farms authorized to produce and sell raw milk, with increased surveillance by the authorities at certain times of the year. PMID- 25719885 TI - Evaluation of the effects of a mixture of organic acids and duration of storage on the survival of salmonella on turkey carcasses. AB - Samples from turkey carcasses previously inoculated with Salmonella Enteritidis 33/66 were subjected to the effect of various mixtures of equal parts of organic acid solutions (acetic, ascorbic, citric, lactic, and tartaric acids). The first part of the study concerned analysis of the influence of the mixtures of organic acids over 15 or 30 min on Salmonella Enteritidis on turkey carcasses. Turkey breast samples were inoculated with Salmonella Enteritidis at 3.7, 2.7, 1.7, 0.7, and 0.07 log CFU. The antibacterial effectiveness of the organic acids differed depending on the initial population of Salmonella on the turkey carcasses. Salmonella was most sensitive to mixtures of equal parts of 1% ascorbic, 1% citric, and 1% tartaric acids. The second part of the study involved determining the influence the organic acid mixtures had on survival of Salmonella Enteritidis on turkey meat stored at 4 degrees C for 2, 4, or 6 days. The level of Salmonella was determined using a most-probable-number method. Salmonella Enteritidis was inoculated into a nutrient broth, incubated at 37 degrees C for 24 h, and then added to the diluent in which the turkey breast samples were immersed for 5 min. The initial Salmonella level of the control samples of turkey breast following immersion was determined in each analysis. After storage at 4 degrees C, turkey samples were transferred to the organic acid solutions for 15 min. Stainless steel templates were used to swab 50 cm(2) of the turkey breast samples. During storage at 4 degrees C, the Salmonella level in the meat samples decreased. The largest decrease occurred at 4 degrees C after 6 days with equal parts of 1% acetic acid, 1% lactic acid, and 1% tartaric acid. Thus, treatment of raw turkey breasts with a mixture of organic acids is a promising option for reducing the risk of the presence of Salmonella. PMID- 25719886 TI - Spore prevalence and toxigenicity of Bacillus cereus and Bacillus thuringiensis isolates from U.S. retail spices. AB - Recent incidents of foodborne illness associated with spices as the vehicle of transmission prompted this examination of U.S. retail spices with regard to Bacillus cereus. This study focused on the levels of aerobic-mesophilic spore forming bacteria and B cereus spores associated with 247 retail spices purchased from five states in the United States. Samples contained a wide range of aerobic mesophilic bacterial spore counts (< 200 to 8.3 * 10(7) CFU/g), with 19.1% of samples at levels above 10(5) CFU/g. For examples, paprika, allspice, peppercorns, and mixed spices had high levels of aerobic spores (> 10(7) CFU/g). Using a novel chromogenic agar, B. cereus and B. thuringiensis spores were isolated from 77 (31%) and 11 (4%) samples, respectively. Levels of B. cereus were <3 to 1,600 MPN/g. Eighty-eight percent of B. cereus isolates and 91% of B. thuringiensis isolates possessed at least one type of enterotoxin gene: HBL (hemolysin BL) or nonhemolytic enterotoxin (NHE). None of the 88 isolates obtained in this study possessed the emetic toxin gene (ces). Using commercially available immunological toxin detection kits, the toxigenicity of the isolates was confirmed. The NHE enterotoxin was expressed in 98% of B. cereus and 91% of B. thuringiensis isolates that possessed the responsible gene. HBL enterotoxin was detected in 87% of B. cereus and 100% of B. thuringiensis PCR-positive isolates. Fifty-two percent of B. cereus and 54% of B. thuringiensis isolates produced both enterotoxins. Ninety-seven percent of B. cereus isolates grew at 12 degrees C, although only two isolates grew well at 9 degrees C. The ability of these spice isolates to form spores, produce diarrheal toxins, and grow at moderately abusive temperatures makes retail spices an important potential vehicle for foodborne illness caused by B. cereus strains, in particular those that produce diarrheal toxins. PMID- 25719887 TI - Ochratoxin A in stored U.S. barley and wheat. AB - Ochratoxin A (OTA) is a mycotoxin of significant health concern that is present in a variety of cereal grains and other foods around the world. Although OTA contamination can occur prior to harvest, it is largely considered a storage issue that can be controlled through the implementation of proper storage practices. Barley, durum, and hard red spring wheat samples that had been stored for various lengths of time were collected (n = 262) over a period of 2 years by multiple commercial grain companies located in the northwestern and northern Great Plains regions of the United States. Samples were analyzed for OTA concentration using high-performance liquid chromatography with fluorescence detection. OTA was detected in 12.2% of the samples, and of those samples, 81.3% had been stored for >=6 months. One sample of barley and four samples of wheat exceeded 5 ng/g of OTA. PMID- 25719888 TI - Cross-sectional survey of indicator and pathogenic bacteria on vegetables sold from Asian vendors at farmers' markets in northern California. AB - A cross-sectional survey was conducted during summer 2013 to determine the occurrence of Escherichia coli, fecal coliforms (FCs), E. coli O157:H7, and Salmonella on raw vegetable commodities common to Asian cuisine from 21 vendors or farmers at six farmers' markets in northern California. Based on 242 samples from six commodities (basil, yardlong beans, bitter squash, okra, squash stems and leaves, cilantro), 100% of samples had detectable FCs and 20% had detectable E. coli. The mean concentrations were 0.67 log CFU/g and 1.26 log CFU per bundle for E. coli and 4.00 log CFU/g and 6.26 log CFU per bundle for FCs. Vegetables irrigated with ground versus surface water contained lower concentrations of FCs, but this difference was not observed for E. coli. Yardlong beans, bitter squash, and okra had lower levels of FCs compared with basil, cilantro, and squash stems and leaves. Sixteen (6.6%) samples had detectable levels of Salmonella serovars (Newport, Enteritidis, Agona, and Worthington), with the majority of positives found in cilantro and squash stems and leaves. There was a twofold higher probability of Salmonella contamination in samples from growers or vendors who stated that they used organic farming practices compared with samples from those using conventional farming practices. Lastly, the concentrations of FC and E. coli bacteria were significantly associated with Salmonella contamination: for each additional 100 CFU/g or bundle, the probability of Salmonella contamination increased by ~15 and ~30%, respectively. None of the samples had detectable E. coli O157:H7. PMID- 25719889 TI - Presence and correlation of some enteric indicator bacteria, diarrheagenic Escherichia coli pathotypes, and Salmonella serotypes in alfalfa sprouts from local retail markets in Pachuca, Mexico. AB - Data on the presence of diarrheagenic Escherichia coli pathotypes (DEPs) in alfalfa sprouts and correlations between the presence of coliform bacteria (CB), fecal coliforms (FC), E. coli, DEPs, and Salmonella in alfalfa sprouts are not available. The presence of and correlations between CB, FC, E. coli, DEPs, and Salmonella in alfalfa sprouts were determined. One hundred sprout samples were collected from retail markets in Pachuca, Hidalgo State, Mexico. The presence of indicator bacteria and Salmonella was determined using conventional culture procedures. DEPs were identified using two multiplex PCR procedures. One hundred percent of samples were positive for CB, 90% for FC, 84% for E. coli, 10% for DEPs, and 4% for Salmonella. The populations of CB ranged from 6.2 up to 8.6 log CFU/g. The FC and E. coli concentrations were between , 3 and 1,100 most probable number (MPN)/g. The DEPs identified included enterotoxigenic E. coli (ETEC; 2%), enteropathogenic E. coli (EPEC; 3%), and Shiga toxin-producing E. coli (STEC; 5%). No E. coli O157:H7 strains were detected in any STEC-positive samples. In samples positive for DEPs, the concentrations ranged from 210 to 240 MPN/g for ETEC, 28 to 1,100 MPN/g for EPEC, and 3.6 to 460 MPN/g for STEC. The Salmonella isolates identified included Salmonella enterica serotype Typhimurium in three samples and Salmonella enterica serotype Enteritidis in one. STEC and Salmonella Typhimurium were identified together in one sample. Positive correlations were observed between FC and E. coli, between FC and DEPs, and between E. coli and DEPs. Negative correlations occurred between CB and DEPs and between CB and Salmonella. Neither FC nor E. coli correlated with Salmonella in the sprout samples. To our knowledge, this is the first report of ETEC, EPEC, and STEC isolated from alfalfa sprouts and the first report of correlations between different indicator groups versus DEPs and Salmonella. PMID- 25719890 TI - Prevalence of bacteria and absence of anisakid parasites in raw and prepared fish and seafood dishes in Spanish restaurants. AB - This study evaluated the presence of bacteria and anisakid parasites in 45 samples of raw anchovies in vinegar, a dish widely eaten in Spain, and in 227 samples of cooked fish and cephalopods served in Spanish food service establishments. Our analysis showed that, according to European and Spanish regulation, 14 to 30% of the prepared fish and cephalopod dishes exceeded the maximum allowable level for mesophilic aerobic counts, and 10 to 40% of these samples exceeded the allowable levels for Enterobacteriaceae. None of the studied samples showed evidence of anisakid parasites, Escherichia coli, Staphylococcus aureus, Salmonella, or Listeria monocytogenes. These results indicate that application of hazard analysis and critical control points, food safety training courses, and routine inspections in compliance with current European and Spanish legislation help protect consumer health. PMID- 25719891 TI - Bacterial contamination in Saeng-go-gi, a ready-to-eat fresh raw beef dish sold in restaurants in South Korea. AB - This study investigated the bacterial contamination levels in ready-to-eat fresh raw beef, Saeng-go-gi in Korean, sold in restaurants. A total of 462 samples were analyzed by performing an aerobic bacterial plate count, a coliform count, and an Escherichia coli O157:H7 count. Aerobic bacterial plate counts of fresh raw beef obtained from Seoul, Cheonan, Daegu, Gunsan, and Gwangju retail store restaurants were 6.46, 6.89, 6.39, 6.58, and 6.67 log CFU/g, respectively, and coliforms were 4.05, 4.97, 4.76, 3.62, and 3.32 log CFU/g, respectively. Among the 462 assessed samples, suspected E. coli O157:H7 colonies were found in 32, 24, 20, 22, and 16 samples obtained from Seoul, Cheonan, Daegu, Gunsan, and Gwangju, respectively. The identity of these isolated colonies was further assessed by using a latex agglutination kit. The agglutination assay data showed that the isolates were not E. coli O157:H7. The data from this study could be used to design better food handling practices for reducing foodborne illnesses linked to fresh raw beef consumption. PMID- 25719892 TI - Assessment of formaldehyde levels in local and imported fresh fish in Ghana: a case study in the Tamale Metropolis of Ghana. AB - Fish is an important source of protein all over the world, including in Ghana. The fishery sector plays a major role in meeting the domestic need of animal protein and also contributes greatly in foreign exchange earnings. The domestic supply of fish does not meet the demand, so Ghana imports fish and fish products from other countries. Media reports in Ghana have alleged the use of formaldehyde to preserve fish for increased shelf life and to maintain freshness. This research, therefore, sought to establish the levels of formaldehyde in imported and local fresh fish in the Tamale Metropolis by using a ChemSee formaldehyde and formalin detection test kit. Positive and negative controls were performed by using various concentrations of formalin (1, 10, 30, 50, 100, and 300 ppm) and sterile distilled water, respectively. Three times over a 6-month period, different fish species were obtained from five wholesale cold stores (where fish are sold in cartons) and some local sales points (where locally caught fish are sold). A total of 32 samples were taken during three different sampling sessions: 23 imported fish (mackerel, herring, horse mackerel, salmon, and redfish) and 9 local tilapia. The fish were cut, and 50 g was weighed and blended with an equal volume (50 ml) of sterile distilled water. Samples were transferred to test tubes and centrifuged. A test strip was dipped into the supernatant and observed for a color change. A change in color from white to pink or purple indicated the presence of formaldehyde in fish. The study showed that no formaldehyde was present in the imported and local fish obtained. The appropriate regulatory agencies should carry out this study regularly to ensure that fish consumed in Ghana is safe for consumption. PMID- 25719893 TI - Single-Laboratory Ruggedness Testing and Validation of a Modified QuEChERS Approach To Quantify 185 Pesticide Residues in Salmon by Liquid Chromatography- and Gas Chromatography-Tandem Mass Spectrometry. AB - In this study, we successfully applied a previously modified version of the QuEChERS approach to quantify pesticide residues in samples of fresh salmon. Analysis was performed using a combination of liquid and gas chromatography tandem mass spectrometry (LC-MS/MS and GC-MS/MS). The validated QuEChERS method used ethyl acetate for the extraction solvent and involved two freezing steps and a C18 dispersive solid phase extraction for removal of lipids. Of the 228 pesticides initially screened, only 185 passed the method validation criteria (103 on LC-MS/MS and 82 on GC-MS/MS). In a quantitative validation, acceptable performances were achieved with overall recoveries of 70-120% and <20% RSD for 179 analytes (n = 7) over the course of five different extractions at 2 times the limit of quantification. Over 12 months, this method was used in the analysis of 708 salmon samples collected as part of the U.S. Department of Agriculture's Pesticide Data Program. Ruggedness testing conducted throughout the entire study showed this method to be robust and suitable for long-term use. PMID- 25719894 TI - Transcriptional profile of muscle following acute induction of symptoms in a mouse model of Kennedy's disease/spinobulbar muscular atrophy. AB - BACKGROUND: Kennedy's disease/Spinobulbar muscular atrophy (KD/SBMA) is a degenerative neuromuscular disease affecting males. This disease is caused by polyglutamine expansion mutations of the androgen receptor (AR) gene. Although KD/SBMA has been traditionally considered a motor neuron disease, emerging evidence points to a central etiological role of muscle. We previously reported a microarray study of genes differentially expressed in muscle of three genetically unique mouse models of KD/SBMA but were unable to detect those which are androgen dependent or are associated with onset of symptoms. METHODOLOGY/PRINCIPAL FINDINGS: In the current study we examined the time course and androgen dependence of transcriptional changes in the HSA-AR transgenic (Tg) mouse model, in which females have a severe phenotype after acute testosterone treatment. Using microarray analysis we identified differentially expressed genes at the onset and peak of muscle weakness in testosterone-treated Tg females. We found both transient and persistent groups of differentially expressed genes and analysis of gene function indicated functional groups such as mitochondrion, ion and nucleotide binding, muscle development, and sarcomere maintenance. CONCLUSIONS/SIGNIFICANCE: By comparing the current results with those from the three previously reported models we were able to identify KD/SBMA candidate genes that are androgen dependent, and occur early in the disease process, properties which are promising for targeted therapeutics. PMID- 25719896 TI - Photodynamic therapy in endodontics: a literature review. AB - Recently, several in vitro and in vivo studies demonstrated promising results about the use of photodynamic therapy during root canal system disinfection. However, there is no consensus on a standard protocol for its incorporation during root canal treatment. The purpose of this study was to summarize the results of research on photodynamic therapy in endodontics published in peer reviewed journals. A review of pertinent literature was conducted using the PubMed database, and data obtained were categorized into sections in terms of relevant topics. Studies conducted in recent years highlighted the antimicrobial potential of photodynamic therapy in endodontics. However, most of these studies were not able to confirm a significant improvement in root canal disinfection for photodynamic therapy as a substitute for current disinfection methods. Its indication as an excellent adjunct to conventional endodontic therapy is well documented, however. Data suggest the need for protocol adjustments or new photosensitizer formulations to enhance photodynamic therapy predictability in endodontics. PMID- 25719897 TI - Determination of anabolic agents in dietary supplements by liquid chromatography high-resolution mass spectrometry. AB - A sensitive method for the identification and quantification of anabolic steroids and clenbuterol at trace levels in dietary supplements by liquid chromatography high-resolution mass spectrometry (LC-HRMS) in atmospheric pressure ionisation (APCI) mode using a single-stage Orbitrap analyser operating at a resolution power of 100 000 full width at half maximum (FWHM) was developed and validated. A total of 1 g of dietary supplement was added with testosterone-d3 as internal standard, dissolved in methanol, evaporated to dryness, diluted in sodium hydroxide solution and extracted with a mixture of pentane/ethyl ether 9:1. The extract was directly injected into the LC-HRMS system. The method was fully validated. Limits of detection (LODs) obtained for anabolic androgenic steroids (AASs) varied from 1 to 25 ng g(-1) and the limit of quantitation (LOQ) was 50 ng g(-1) for all analytes. The calibration was linear for all compounds in the range from the LOQ to 2000 ng g(-1), with correlation coefficients always higher than 0.99. Accuracy (intended as %E) and repeatability (%CV) were always lower than 15%. Good values of matrix effect and recovery were achieved. The ease of the sample preparation together with a fast run time of only 16 min permitted rapid identification of the analytes. The method was applied to the analysis of 30 dietary supplements in order to check for the presence of anabolic agents not labelled as being present in these supplements. Many AASs were often detected in the same sample: indeed, androstenedione was detected in nine supplements, 5 androsten-3beta-ol-17-one (DHEA) in 12, methandienone in three, stanozolol in one, testosterone in seven and testosterone esters in four of them. A retrospective analysis of suspected compounds not included at the beginning of the method development was also possible by means of the full acquisition spectra obtained with the HRMS technique. PMID- 25719899 TI - Changing paradigms in organ preservation and resuscitation. AB - PURPOSE OF REVIEW: Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions. RECENT FINDINGS: Flow and pressure based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPS XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation. SUMMARY: Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs. PMID- 25719895 TI - Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk. AB - RATIONALE: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered. OBJECTIVES: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women. METHODS: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use. MEASUREMENTS AND MAIN RESULTS: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures. CONCLUSIONS: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population. PMID- 25719900 TI - Donation after circulatory death: the current state and technical approaches to organ procurement. AB - PURPOSE OF REVIEW: In this review, we discuss the current state of donation after circulatory death (DCD). We define the DCD donor and describe the current protocols in management of the DCD patient. We then discuss current techniques in organ procurement of the lung and abdominal organs. RECENT FINDINGS: Although donation after brain death is preferable to DCD, recent data have demonstrated acceptable early outcomes in both thoracic and abdominal organ transplant. In spite of advancements in surgical techniques and organ preservation, much has yet to be learned to minimize warm ischemia time and reperfusion injury in the DCD population. SUMMARY: In light of the continually growing disparity between organ supply and demand, DCD has regained traction as a means to increase the donor pool. PMID- 25719902 TI - A school based cluster randomised health education intervention trial for improving knowledge and attitudes related to Taenia solium cysticercosis and taeniasis in Mbulu district, northern Tanzania. AB - Taenia solium causes significant economic and public health impacts in endemic countries. This study determined effectiveness of a health education intervention at improving school children's knowledge and attitudes related to T. solium cysticercosis and taeniasis in Tanzania. A cluster randomised controlled health education intervention trial was conducted in 60 schools (30 primary, 30 secondary) in Mbulu district. Baseline data were collected using a structured questionnaire in the 60 schools and group discussions in three other schools. The 60 schools stratified by baseline knowledge were randomised to receive the intervention or serve as control. The health education consisted of an address by a trained teacher, a video show and a leaflet given to each pupil. Two post intervention re-assessments (immediately and 6 months post-intervention) were conducted in all schools and the third (12 months post-intervention) was conducted in 28 secondary schools. Data were analysed using Bayesian hierarchical log-binomial models for individual knowledge and attitude questions and Bayesian hierarchical linear regression models for scores. The overall score (percentage of correct answers) improved by about 10% in all schools after 6 months, but was slightly lower among secondary schools. Monitoring alone was associated with improvement in scores by about 6%. The intervention was linked to improvements in knowledge regarding taeniasis, porcine cysticercosis, human cysticercosis, epilepsy, the attitude of condemning infected meat but it reduced the attitude of contacting a veterinarian if a pig was found to be infected with cysticercosis. Monitoring alone was linked to an improvement in how best to raise pigs. This study demonstrates the potential value of school children as targets for health messages to control T. solium cysticercosis and taeniasis in endemic areas. Studies are needed to assess effectiveness of message transmission from children to parents and the general community and their impacts in improving behaviours facilitating disease transmission. PMID- 25719901 TI - Immunogenicity and protective efficacy of a Vero cell culture-derived whole-virus H7N9 vaccine in mice and guinea pigs. AB - BACKGROUND: A novel avian H7N9 virus with a high case fatality rate in humans emerged in China in 2013. We evaluated the immunogenicity and protective efficacy of a candidate Vero cell culture-derived whole-virus H7N9 vaccine in small animal models. METHODS: Antibody responses induced in immunized DBA/2J mice and guinea pigs were evaluated by hemagglutination inhibition (HI), microneutralization (MN), and neuraminidase inhibition (NAi) assays. T-helper cell responses and IgG subclass responses in mice were analyzed by ELISPOT and ELISA, respectively. Vaccine efficacy against lethal challenge with wild-type H7N9 virus was evaluated in immunized mice. H7N9-specific antibody responses induced in mice and guinea pigs were compared to those induced by a licensed whole-virus pandemic H1N1 (H1N1pdm09) vaccine. RESULTS: The whole-virus H7N9 vaccine induced dose-dependent H7N9-specific HI, MN and NAi antibodies in mice and guinea pigs. Evaluation of T helper cell responses and IgG subclasses indicated the induction of a balanced Th1/Th2 response. Immunized mice were protected against lethal H7N9 challenge in a dose-dependent manner. H7N9 and H1N1pdm09 vaccines were similarly immunogenic. CONCLUSIONS: The induction of H7N9-specific antibody and T cell responses and protection against lethal challenge suggest that the Vero cell culture-derived whole-virus vaccine would provide an effective intervention against the H7N9 virus. PMID- 25719903 TI - Closing the gap between knowledge and clinical application: challenges for genomic translation. AB - Despite early predictions and rapid progress in research, the introduction of personal genomics into clinical practice has been slow. Several factors contribute to this translational gap between knowledge and clinical application. The evidence available to support genetic test use is often limited, and implementation of new testing programs can be challenging. In addition, the heterogeneity of genomic risk information points to the need for strategies to select and deliver the information most appropriate for particular clinical needs. Accomplishing these tasks also requires recognition that some expectations for personal genomics are unrealistic, notably expectations concerning the clinical utility of genomic risk assessment for common complex diseases. Efforts are needed to improve the body of evidence addressing clinical outcomes for genomics, apply implementation science to personal genomics, and develop realistic goals for genomic risk assessment. In addition, translational research should emphasize the broader benefits of genomic knowledge, including applications of genomic research that provide clinical benefit outside the context of personal genomic risk. PMID- 25719904 TI - Critical reflexivity in client-centred therapeutic relationships. AB - AIM/OBJECTIVES: This paper explores how a particular form of reflection--critical reflexivity--can support clinicians in developing a more nuanced understanding of therapeutic relationships, and work to advance the goal of client-centred practice. METHODS: A critical autobiographical narrative was written, and critical reflexivity adopted, as methods to critically examine the therapeutic relationship. FINDINGS: Critically reflexive stories have the potential to advance client-centred therapeutic relationships by inspiring the (re )consideration of practices, and by interrogating interpretive systems. DISCUSSION: Understandings and practices that potentially limit the extent to which therapeutic relationships are client centred include (i) Dichotomous thinking, (ii) Objectification, (iii) The economic imperative, and (iv) Knowledge generation. CONCLUSION: The critical autobiographical account points to ways in which critical reflexivity on the therapeutic relationship has the potential to foster critical questioning, interrogate interpretive systems, attune to subjectivities, contribute to practice-based knowledge, resist violation, foster compassionate practice, and develop new understandings of relevance to client centred practice. SIGNIFICANCE: This critical examination of the therapeutic relationship supports occupational therapists in more fully realizing the profession's core value of client-centred practice. PMID- 25719905 TI - Is there a role for pharmacists in multidisciplinary health-care teams at community outreach events for the homeless? AB - Homelessness is a significant public health problem. It is well-documented that people experiencing homelessness exhibit more serious illnesses and have poorer health than the general population. The provision of services and interventions by health-care professionals, including pharmacists, may make a simple yet important contribution to improved health outcomes in those experiencing homelessness, but evidence of roles and interventions is limited and variable. In Australia, the Queensland University of Technology Health Clinic connects with the homeless community by taking part in community outreach events. This paper provides details of one such event, as well as the roles, interventions and experiences of pharmacists. Participation and inclusion of pharmacists in a multidisciplinary health-care team approach at homeless outreach events should be supported and encouraged. PMID- 25719906 TI - One-year follow-up of conduction disturbances following transcatheter aortic valve implantation. AB - AIMS: To describe the postprocedural and 1-year follow-up incidence of heart conduction disturbances in patients with severe symptomatic aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). METHODS: Ninety-five patients were enrolled from 2008 to 2011 (mean age 81.8 +/- 7.2 years, 63.1% women). Clinical and ECG data were recorded at admission, discharge, and 3, 6 and 12 months following TAVI. RESULTS: Fifty-seven Edwards SAPIEN (31 transapical, 26 transfemoral) and 38 transfemoral CoreValve implants were used. Two (2.1%) patients died during the procedure and 11 (11.6%) patients received a pacemaker prior to discharge (7 CoreValve, 3 transapical, 1 transfemoral SAPIEN; P = 0.18). Among the surviving patients not receiving a pacemaker, TAVI increased the PQ interval (176 +/- 29 vs. 188 +/- 36 ms; P = 0.001), QRS width (90 +/- 15 vs. 108 +/- 26 ms; P < 0.001), and first-grade atrioventricular block (17 vs. 29%; P < 0.001). Postprocedural complete left bundle branch block was reported most in transapical (from 10 to 36%; P = 0.01) and CoreValve (from 8 to 64%; P < 0.001) recipients compared to the transfemoral SAPIEN group. At the 12-month follow-up, 24 (25.3%) patients had died [two (2.1%) sudden deaths] and four (4.2%) required pacemaker implantation. Among the survivors not receiving a pacemaker at the 1 year follow-up, the PQ interval (178 +/- 27 vs. 188 +/- 36 ms; P = 0.39) remained unchanged in the ECG, whereas the QRS width (100 +/- 22 vs. 108 +/- 26 ms; P = 0.008) decreased compared to measurements taken at discharge. CONCLUSION: Conduction disturbances following TAVI primarily develop during hospitalization and subsequently stabilize. However, the small percentage of patients suffering sudden death or pacemaker implantation requires attention. PMID- 25719908 TI - The chorda tympani degenerates during chronic otitis media: an electron microscopy study. AB - CONCLUSION: Chorda tympani nerve specimens from ears with chronic inflammatory middle ear disease exhibit structural signs of degeneration. These correlate well with taste disturbance. Simultaneously, they exhibit signs of regeneration, which may explain the ability for taste recovery. OBJECTIVES: The chorda tympani, the major taste nerve, runs uncovered through the middle ear cavity. This situation exposes it to various forms of middle ear pathology. A difference has been noticed regarding taste symptoms pre- and postoperatively between inflammatory and non-inflammatory diseases. The present study aimed to investigate ultrastructural changes of chorda tympani in different forms of inflammatory middle ear disease, such as chronic suppurative otitis media and cholesteatoma, as compared with normal. METHODS: Five chorda tympani specimens were collected from healthy middle ears of patients subjected to surgery for acoustic neuroma, to be used as normal controls, and five from middle ears with chronic otitis media or cholesteatoma, where the nerve could not be saved during the operation. Light and electron microscopy were performed. RESULTS: For all five nerves from diseased ears, microscopy showed a higher percentage of axon and myelin sheath degeneration than in the normal controls. Furthermore, three of the five also exhibited sprouting. PMID- 25719907 TI - Combining a Clostridial enzyme exhibiting unusual active site plasticity with a remarkably facile sigmatropic rearrangement: rapid, stereocontrolled entry into densely functionalized fluorinated phosphonates for chemical biology. AB - Described is an efficient stereocontrolled route into valuable, densely functionalized fluorinated phosphonates that takes advantage of (i) a Clostridial enzyme to set the absolute stereochemistry and (ii) a new [3,3]-sigmatropic rearrangement of the thiono-Claisen variety that is among the fastest sigmatropic rearrangements yet reported. Here, a pronounced rate enhancement is achieved by distal fluorination. This rearrangement is completely stereoretentive, parlaying the enzymatically established beta-C-O stereochemistry in the substrate into the delta-C-S stereochemistry in the product. The final products are of interest to chemical biology, with a platform for Zn-aminopeptidase A inhibitors being constructed here. The enzyme, Clostridium acetobutylicum (CaADH), recently expressed by our group, reduces a spectrum of gamma,delta-unsaturated beta-keto alpha,alpha-difluorophosphonate esters (93-99% ee; 10 examples). The resultant beta-hydroxy-alpha,alpha-difluorophosphonates possess the "L"-stereochemistry, opposite to that previously observed for the CaADH-reduction of omega-keto carboxylate esters ("D"), indicating an unusual active site plasticity. For the thiono-Claisen rearrangement, a notable structure-reactivity relationship is observed. Measured rate constants vary by over 3 orders of magnitude, depending upon thiono-ester structure. Temperature-dependent kinetics reveal an unusually favorable entropy of activation (DeltaS(?) = 14.5 +/- 0.6 e.u.). Most notably, a 400-fold rate enhancement is seen upon fluorination of the distal arene ring, arising from favorable enthalpic (DeltaDeltaH(?) = -2.3 kcal/mol) and entropic (DeltaDeltaS(?) = 4 e.u., i.e. 1.2 kcal/mol at rt) contributions. The unusual active site plasticity seen here is expected to drive structural biology studies on CaADH, while the exceptionally facile sigmatropic rearrangement is expected to drive computational studies to elucidate its underlying entropic and enthalpic basis. PMID- 25719909 TI - Nanodiamonds for field emission: state of the art. AB - The aim of this review is to highlight the recent advances and the main remaining challenges related to the issue of electron field emission (FE) from nanodiamonds. The roadmap for FE vacuum microelectronic devices envisages that nanodiamonds could become very important in a short time. The intrinsic properties of the nanodiamond materials indeed meet many of the requirements of cutting-edge technologies and further benefits can be obtained by tailored improvements of processing methodologies. The current strategies used to modulate the morphological and structural features of diamond to produce highly performing emitting systems are reported and discussed. The focus is on the current understanding of the FE process from nanodiamond-based materials and on the major concepts used to improve their performance. A short survey of non-conventional microsized cold cathodes based on nanodiamonds is also reported. PMID- 25719911 TI - Novel synthesis strategy for composite hydrogel of collagen/hydroxyapatite microsphere originating from conversion of CaCO3 templates. AB - Inspired by coralline-derived hydroxyapatite, we designed a methodological route to synthesize carbonated-hydroxyapatite microspheres from the conversion of CaCO3 spherulite templates within a collagen matrix under mild conditions and thus constructed the composite hydrogel of collagen/hydroxyapatite-microspheres. Fourier transform infrared spectroscopy (FTIR) and x-ray diffraction (XRD) were employed to confirm the successful generation of the carbonated hydroxyapatite phase originating from CaCO3, and the ratios of calcium to phosphate were tracked over time. Variations in the weight portion of the components in the hybrid gels before and after the phase transformation of the CaCO3 templates were identified via thermogravimetric analysis (TGA). Scanning electron microscopy (SEM) shows these composite hydrogels have a unique multiscale microstructure consisting of a collagen nanofibril network and hydroxyapatite microspheres. The relationship between the hydroxyapatite nanocrystals and the collagen fibrils was revealed by transmission electron microscopy (TEM) in detail, and the selected area electron diffraction (SAED) pattern further confirmed the results of the XRD analyses which show the typical low crystallinity of the generated hydroxyapatite. This smart synthesis strategy achieved the simultaneous construction of microscale hydroxyapatite particles and collagen fibrillar hydrogel, and appears to provide a novel route to explore an advanced functional hydrogel materials with promising potentials for applications in bone tissue engineering and reconstruction medicine. PMID- 25719912 TI - Psychological Strategies Included by Strength and Conditioning Coaches in Applied Strength and Conditioning. AB - This study provided the basis by which professional development needs can be addressed and add to the applied sport psychology literature from an underresearched sport domain. This study endeavored to use qualitative methods to explore the specific techniques applied by the strength and conditioning professional. Eighteen participants were recruited for interview, through convenience sampling, drawn from a previously obtained sample. Included in the study were 10 participants working within the United Kingdom, 3 within the United States, and 5 within Australia offering a cross section of experience from ranging sport disciplines and educational backgrounds. Participants were interviewed using semistructured interviews. Thematic clustering was used by interpretative phonological analysis to identify common themes. The practitioners referred to a wealth of psychological skills and strategies that are used within strength and conditioning. Through thematic clustering, it was evident that a significant emphasis is on the development or maintenance of athlete self confidence specifically with a large focus on goal setting. Similarly, albeit to a lesser extent, there was a notable attention on skill acquisition and arousal management strategies. The strategies used by the practitioners consisted of a combination of cognitive strategies and behavioral strategies. It is important to highlight the main psychological strategies that are suggested by strength and conditioning coaches themselves to guide professional development toward specific areas. Such development should strive to develop coaches' awareness of strategies to develop confidence, regulate arousal, and facilitate skill and technique development. PMID- 25719913 TI - Muscle Strength, Power, and Morphologic Adaptations After 6 Weeks of Compound vs. Complex Training in Healthy Men. AB - The aim of the study was to compare the effects of compound vs. complex resistance training on strength, high-speed movement performance, and muscle composition. Eighteen young men completed compound (strength and power sessions on alternate days) or complex training (strength and power sets within a single session) 3 times per week for 6 weeks using bench press, leg press, Smith machine box squat, and jumping exercises. Pre- and posttraining, jumping and throwing performance and maximum bench press, leg press, and Smith machine box squat strength were evaluated. The architecture of vastus lateralis and gastrocnemius muscle was assessed using ultrasound imaging. Vastus lateralis morphology was assessed from muscle biopsies. Jumping (4 +/- 3%) and throwing (9 +/- 8%) performance increased only with compound training (p < 0.02). Bench press (5 vs. 18%), leg press (17 vs. 28%), and Smith machine box squat (27 vs. 35%) strength increased after both compound and complex training. Vastus lateralis thickness and fascicle angle and gastrocnemius fascicle angle were increased with both compound and complex training. Gastrocnemius fascicle length decreased only after complex training (-11.8 +/- 9.4%, p = 0.006). Muscle fiber cross-sectional areas increased only after complex training (p <= 0.05). Fiber type composition was not affected by either intervention. These results suggest that short-term strength and power training on alternate days is more effective for enhancing lower-limb and whole-body power, whereas training on the same day may induce greater increases in strength and fiber hypertrophy. PMID- 25719914 TI - Determination of contraction-induced changes in elbow flexor cross-sectional area for evaluating muscle size-strength relationship during contraction. AB - The aims of this study were to determine contraction-induced changes in the elbow flexor cross-sectional area (CSA) and to examine whether the maximal CSA during a high-intensity contraction is more closely related to the strength than that at rest in the elbow flexors. Fourteen young male subjects participated in this study. The elbow flexor CSAs were measured at sites from 1 cm proximal to 6 cm distal to the reference site (60% of the upper arm length from the acromial process of the scapula to the lateral epicondyle of the humerus) (every 1 cm; 8 sampling sites) using magnetic resonance imaging, at rest and during 10, 20, 40, 60, and 80% of maximal voluntary contraction (MVC) of isometric elbow flexion. The elbow flexor CSA changed greatly during low-intensity contractions, and this contraction-induced change was small over 60%MVC. Compared with at rest, greater CSA around the muscle belly and smaller CSA in the distal portion of the elbow flexors were found in contracted conditions. The MVC strength was significantly correlated with the maximal CSAs at rest and each contraction level, but stepwise multiple regression analysis selected only that during 80%MVC as a significant contributor for estimating the MVC strength. These results suggest that, in the elbow flexors, the contraction-induced change in the CSA reaches its peak under high contractile level and that the maximal CSA during 80%MVC is more closely related to the MVC strength than that at rest. PMID- 25719915 TI - Muscle fiber type, Achilles tendon length, potentiation, and running economy. AB - The purpose of this investigation was to develop a potential model for how muscle fiber type, Achilles tendon length, stretch-shortening cycle potentiation (SSCP), and leg strength interact with running economy. Twenty trained male distance runners 24-40 years of age served as subjects. Running economy (net oxygen uptake) was measured while running on a treadmill. Leg press SSCP(force) and SSCP(velocity) were determined by measuring the difference in velocity between a static leg press throw and a countermovement leg press throw. Vertical jump SSCP was determined by measuring the difference in jump height between a static jump and a drop jump from a 20.3-cm bench. Tendon length was measured by magnetic resonance imaging, and muscle fiber type was made from a vastus lateralis muscle biopsy. Type IIx muscle fiber percent (r = 0.70, p < 0.001) and leg strength (r = 0.95, p < 0.001) were positively and independently related to late eccentric force development. Achilles tendon length (r = 0.42, p <= 0.05) and late eccentric force during stretch-shortening cycle (r = 0.76, p < 0.001) were independently related to SSCP(force). SSCP(force) was related to SSCP(velocity), which in turn was related to running economy (r = 0.61, p < 0.01). These results suggest that longer Achilles tendon length, type II fiber, and muscular leg strength may enhance the potential for SSCP, running economy, and physiological effort while running. PMID- 25719916 TI - Effects of Three Different Conditioning Activity Volumes on the Optimal Recovery Time for Potentiation in College Athletes. AB - This study examined the effect of 3 postactivation potentiation (PAP) protocols, differentiated by volume and with controlled intensity, on the recovery time required to observe enhanced jumping performance in recreationally trained college athletes. Following a randomized controlled order, 11 participants, 7 men and 4 women (age 25.4 +/- 2.1 years, height 176.2 +/- 7.7 cm, body mass 77.6 +/- 7.7 kg), performed a countermovement jump (CMJ) at baseline and at 15 seconds, 1, 2, 3, 5, 8, and 12 minutes after the 3 treatment conditions: low volume (LV, parallel squat [PS] with 80%, 1 repetition [rep]), moderate volume (MV, PS with 80%, 1 set of 3 reps), and high volume (HV, PS with 80%, 3 sets of 3 reps). Significantly lower CMJ heights were measured at 3 and 5 minutes from LV to HV (p = 0.048) and MV (p = 0.005) conditions, respectively. No significant differences were determined when comparing the 8 tested time points within each of the assessed volume protocols. However, effect size analysis indicated that higher CMJ performances displayed from 1 to 8 minutes with respect to both baseline and 15-second performance for MV (d = 0.91-3.18) and HV (d = 0.79) conditions. In conclusion, MV and HV protocols seem to be more effective to elicit potentiation compared with the LV. However, no relationship between the volume of conditioning activity (CA) and the optimal time point to obtain the maximum potentiation effect was determined. Strength and conditioning professionals are advised to analyze individual PAP responses in terms of the optimal recovery time with regard to different CA configurations. PMID- 25719917 TI - Relationships between lower-extremity flexibility, asymmetries, and the Y balance test. AB - Joint flexibility, bilateral asymmetries in flexibility, and bilateral asymmetries in performance of the Y Balance Test have been associated with injuries. However, relationships among these attributes are unclear. The goal of this investigation was to examine how flexibility and flexibility asymmetries relate to the Y Balance Test. Twenty healthy active young adults (9 men and 11 women; mean +/- SD: age = 21.9 +/- 2.6 years; height = 171 +/- 8.8 cm; mass = 67.2 +/- 1.9 kg) performed 9 different lower extremity active range of motion (AROM) tests and the Y Balance Test in a single visit. Significant correlations (p <= 0.05) existed between bilateral average AROM measures and bilateral average Y Balance Test scores at the ankle and hip. Specifically, ankle dorsiflexion AROM at 0 degrees knee flexion significantly correlated with Anterior, Posterolateral, and Composite directional scores of the Y Balance Test (r = 0.497 0.736). Significant correlations in ankle dorsiflexion AROM at 90 degrees knee flexion also existed with Anterior, Posterolateral, Posteromedial, and Composite directional scores (r = 0.472-0.795). Hip flexion AROM was significantly correlated with Posterolateral, Posteromedial, and Composite directional scores (r = 0.457-0.583). Significant correlations between asymmetries in AROM and asymmetries in the Y Balance Test existed only in ankle plantarflexion with Anterior, Posterolateral, and Composite directional scores of the Y Balance Test (r = 0.520-0.636). Results suggest that when used with recreationally active healthy adults, the Y Balance Test may help identify lower-extremity flexibility deficits and flexibility asymmetries in the ankle and hip regions but may need to be used in conjunction with additional tests to understand a broader picture of functional movement and injury risk. PMID- 25719918 TI - Integration of the functional movement screen into the National Hockey League Combine. AB - The sport of ice hockey requires coordination of complex skills involving musculoskeletal and physiological abilities while simultaneously exposing players to a high risk for injury. The Functional Movement Screen (FMS) was developed to assess fundamental movement patterns that underlie both sport performance and injury risk. The top 111 elite junior hockey players from around the world took part in the 2013 National Hockey League Entry Draft Combine (NHL Combine). The FMS was integrated into the comprehensive medical and physiological fitness evaluations at the request of strength and conditioning coaches with affiliations to NHL teams. The inclusion of the FMS aimed to help develop strategies that could maximize its utility among elite hockey players and to encourage or inform further research in this field. This study evaluated the outcomes of integrating the FMS into the NHL Combine and identified any links to other medical plus physical and physiological fitness assessment outcomes. These potential associations may provide valuable information to identify elements of future training programs that are individualized to athletes' specific needs. The results of the FMS (total score and number of asymmetries identified) were significantly correlated to various body composition measures, aerobic and anaerobic fitness, leg power, timing of recent workouts, and the presence of lingering injury at the time of the NHL Combine. Although statistically significant correlations were observed, the implications of the FMS assessment outcomes remain difficult to quantify until ongoing assessment of FMS patterns, tracking of injuries, and hockey performance are available. PMID- 25719919 TI - Relationship between functional movement screen scores, core strength, posture, and body mass index in school children in Moldova. AB - The assessment of functionality should include parameters that consider postural control, limb asymmetries, range of motion limitations, proprioceptive deficits, and pain. An increasingly popular battery of tests, the Functional Movement Screen (FMS), is purported to assess the above named parameters. The purpose of our study was twofold: (a) to report differences in total FMS scores in children, provide preliminary normative reference values of each of the 7 individual FMS scores for both genders and report on asymmetries and (b) to evaluate the relationship between total FMS scores, age, body mass index (BMI), core strength/stability, and postural angles to explore the possibility of using the FMS in the assessment of children's functional fitness. Descriptive data on 77 children aged 8-11 years were collected. The children performed core strength/stability exercises. Photographs were taken from a lateral view for later calculation of postural angles. The children performed the FMS while being videotaped for later review. The average total FMS score (of 21) was 14.9 (+1.9), and BMI was 16.4 (+2.2). Static posture is not related to results of the FMS. Core strength was positively correlated to the total FMS score (r = 0.31; p = 0.006). Over 60% demonstrated at least 1 asymmetry. The individual test scores indicate that none of the test items is too difficult for the children. Based on the screen's correlation to core strength, and the fact that it identifies areas of asymmetry, we suggest to further investigate its possible use in the assessment of children's functional fitness. PMID- 25719920 TI - Roles of an Upper-Body Compression Garment on Athletic Performances. AB - Compression garments (CGs) have been previously shown to enhance proprioception; however, this benefit has not been previously shown to transfer to improved performance in sports skills. The purpose of this study was to assess whether enhanced proprioception and comfort can be manifested in improved sports performance of high-level athletes. Eleven Division I collegiate pitchers (age: 21.0 +/- 2.9 years; height: 181.0 +/- 4.6 cm; weight: 89.0 +/- 13.0 kg; body fat: 12.0 +/- 4.1%) and 10 Division I collegiate golfers (age: 20.0 +/- 1.3 years; height: 178.1 +/- 3.9 cm; weight: 76.4 +/- 8.3 kg; body fat: 11.8 +/- 2.6%) participated in the study. A counterbalanced within-group design was used. Subjects performed the respective baseball or golf protocol wearing either typical noncompressive (NC) or the experimental CG. Golfers participated in an assessment of driving distance and accuracy, as well as approach shot, chipping, and putting accuracy. Pitchers were assessed for fastball accuracy and velocity. In pitchers, there was a significant (p <= 0.05) improvement in fastball accuracy (NC: 0.30 +/- 0.04 vs. CG: 0.21 +/- 0.07 cm). There were no differences in pitching velocity. In golfers, there were significant (p <= 0.05) improvements in driving accuracy (NC: 86.7 +/- 30.6 vs. CG: 68.9 +/- 18.5 feet), as well as approach shot accuracy (NC: 26.6 +/- 11.9 vs. CG: 22.1 +/- 8.2 feet) and chipping accuracy (NC: 2.9 +/- 0.6 vs. CG: 2.3 +/- 0.6 inch). There was also a significant (p <= 0.05) increase in comfort for the golfers (NC: 3.7 +/- 0.8 vs. CG: 4.5 +/- 1.0). These results demonstrate that comfort and performance can be improved with the use of CGs in high-level athletes being most likely mediated by improved proprioceptive cues during upper-body movements. PMID- 25719921 TI - Coordination Motor Skills of Military Pilots Subjected to Survival Training. AB - Survival training of military pilots in the Polish Army gains significance because polish pilots have taken part in more and more military missions. Prolonged exercise of moderate intensity with restricted sleep or sleep deprivation is known to deteriorate performance. The aim of the study was thus to determine the effects of a strenuous 36-hour exercise with restricted sleep on selected motor coordination and psychomotor indices. Thirteen military pilots aged 30-56 years were examined twice: pretraining and posttraining. The following tests were applied: running motor adjustment (15-m sprint, 3 * 5-m shuttle run, 15-m slalom, and 15-m squat), divided attention, dynamic body balance, handgrip strength differentiation. Survival training resulted in significant decreases in maximum handgrip strength (from 672 to 630 N), corrected 50% max handgrip (from 427 to 367 N), error 50% max (from 26 to 17%), 15-m sprint (from 5.01 to 4.64 m.s), and 15-m squat (2.20 to 1.98 m.s). The training improvements took place in divided attention test (from 48.2 to 57.2%). The survival training applied to pilots only moderately affected some of their motor adjustment skills, the divided attention, and dynamic body balance remaining unaffected or even improved. Further studies aimed at designing a set of tests for coordination motor skills and of soldiers' capacity to fight for survival under conditions of isolation are needed. PMID- 25719922 TI - Predictors of Speed Using Off-Ice Measures of College Hockey Players. AB - The purpose of this study was to examine the relationship between commonly employed dry-land performance tests and skating speed in male collegiate ice hockey players. Forty male National Collegiate Athletic Association Division I hockey players were tested on the following performance variables: vertical jump (VJ), standing broad jump, 40-yard dash, and maximal back squat (SQT). The subjects also performed 3 skating tests: the 90-ft forward acceleration test, the 90-ft backward acceleration test, and the 50-ft flying top speed test (F50). Pearson correlation coefficients were applied to compare the strength of association between each selected off-ice measure and each on-ice measure. Three multiple regression equations were then used to compare the weighted strengths of association between predictor and criterion variables. Only VJ showed significance in relation to skating speed (p = 0.011). These results suggest that meaningful performance testing in ice hockey players should occur mainly on the ice. PMID- 25719923 TI - Protein functionalized carbon nanotubes-based smart lab-on-a-chip. AB - A label-free impedimetric lab on a chip (iLOC) is fabricated using protein (bovine serum albumin) and antiapolipoprotein B functionalized carbon nanotubes nickel oxide (CNT-NiO) nanocomposite for low-density lipoprotein (LDL) detection. The antiapolipoprotein B (AAB) functionalized CNT-NiO microfluidic electrode is assembled with polydimethylsiloxane rectangular microchannels (cross section: 100 * 100 MUm). Cytotoxicity of the synthesized CNTs, NiO nanoparticles, and CNT-NiO nanocomposite has been investigated in the presence of lung epithelial cancer A549 cell line using MTT assay. The CNT-NiO nanocomposite shows higher cell viability at a concentration of 6.5 MUg/mL compared to those using individual CNTs. The cell viability and proliferation studies reveal that the toxicity increases with increasing CNTs concentration. The X-ray photoelectron spectroscopy studies have been used to quantify the functional groups present on the CNT-NiO electrode surface before and after proteins functionalization. The binding kinetic and electrochemical activities of CNT-NiO based iLOC have been conducted using chronocoulometry and impedance spectroscopic techniques. This iLOC shows excellent sensitivity of 5.37 kOmega (mg/dL)(-1) and a low detection limit of 0.63 mg/dL in a wide concentration range (5-120 mg/dL) of LDL. The binding kinetics of antigen-antibody interaction of LDL molecules reveal a high association rate constant (8.13 M(-1) s(-1)). Thus, this smart nanocomposite (CNT NiO) based iLOC has improved stability and reproducibility and has implications toward in vivo diagnostics. PMID- 25719925 TI - Erratum. PMID- 25719924 TI - Polarity engineering of conjugated polymers by variation of chemical linkages connecting conjugated backbones. AB - The fine tuning of the dominant polarity in polymer semiconductors is a key issue for high-performance organic complementary circuits. In this paper, we demonstrate a new methodology for addressing this issue in terms of molecular design. In an alternating conjugated donor-acceptor copolymer system, we systematically engineered the chemical linkages that connect the aromatic units in donor moieties. Three donor moieties, thiophene-vinylene-thiophene (TVT), thiophene-acetylene-thiophene (TAT), and thiophene-cyanovinylene-thiophene (TCNT), were combined with an acceptor moiety, thienoisoindigo (TIID), and finally, three novel TIID-based copolymers were synthesized: PTIID-TVT, PTIID TAT, and PTIID-TCNT. We found that the vinylene, acetylene, and cyanovinylene linkages decisively affect the energy structure, molecular orbital delocalization, microstructure, and, most importantly, the dominant polarity of the polymers. The vinylene-linked PTIID-TVT field-effect transistors (FETs) exhibited intrinsic hole and electron mobilities of 0.12 and 1.5 * 10(-3) cm(2) V(-1 )s(-1), respectively. By contrast, the acetylene-linked PTIID-TAT FETs exhibited significantly improved intrinsic hole and electron mobilities of 0.38 and 0.03 cm(2) V(-1) s(-1), respectively. Interestingly, cyanovinylene-linked PTIID-TCNT FETs exhibited reverse polarity, with hole and electron mobilities of 0.07 and 0.19 cm(2) V(-1) s(-1). As a result, the polarity balance, which is quantified as the electron/hole mobility ratio, was dramatically tuned from 0.01 to 2.7. Our finding demonstrates a new methodology for the molecular design of high-performance organic complementary circuits. PMID- 25719926 TI - A role of Candida albicans CDC4 in the negative regulation of biofilm formation. AB - The CDC4 gene is nonessential in Candida albicans and plays a role in suppressing filamentous growth, in contrast to its homologues, which are involved in the G1-S transition of the cell cycle. While characterizing the function of C. albicans CDC4 (CaCDC4), we found that the loss of CaCDC4 resulted in a reduction in cell flocculation, indicating a possible role for CaCDC4 in biofilm formation. To elucidate the role of CaCDC4 in biofilm formation, Cacdc4 null mutant strains were constructed by using the mini-Ura-blaster method. To create a CaCDC4 rescued strain, the plasmid p6HF-ACT1p-CaCDC4 capable of constitutively expressing CaCDC4 was introduced into the Cacdc4 homozygous null mutant. To determine the biofilm formation ability, an in vitro XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-5 [(phenylamino)carbonyl]-2H-tetrazolium-5-carboxanilide) reduction assay was used. Compared with the parental auxotrophic strain BWP17, the Cacdc4 homozygous null mutant was able to enhance biofilm formation significantly. This enhancement of biofilm formation in the Cacdc4 homozygous null mutant could be reversed by constitutively expressing CaCDC4. We conclude that CaCDC4 has a role in suppressing biofilm formation in C. albicans. PMID- 25719927 TI - Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions. AB - Aneurysmal subarachnoid hemorrhage is the most devastating form of stroke. Many pathological mechanisms ensue after cerebral aneurysm rupture, including hydrocephalus, apoptosis of endothelial cells and neurons, cerebral edema, loss of blood-brain barrier, abnormal cerebral autoregulation, microthrombosis, cortical spreading depolarization and macrovascular vasospasm. Although studied extensively through experimental and clinical trials, current treatment guidelines to prevent delayed cerebral ischemia is limited to oral nimodipine, maintenance of euvolemia, induction of hypertension if ischemic signs occur and endovascular therapy for patients with continued ischemia after induced hypertension. Future investigations will involve agents targeting vasodilation, anticoagulation, inhibition of apoptosis pathways, free radical neutralization, suppression of cortical spreading depolarization and attenuation of inflammation. PMID- 25719929 TI - Effects of continuous positive airway pressure therapy on glycaemic control, insulin sensitivity and body mass index in patients with obstructive sleep apnoea and type 2 diabetes: a systematic review and meta-analysis. AB - BACKGROUND: Evidence suggests that 15-30% of individuals with obstructive sleep apnoea (OSA) have type 2 diabetes mellitus (T2DM), and that OSA is an independent risk factor for T2DM. There is considerable interest in ascertaining whether OSA treatment improves glycaemic control and insulin sensitivity in patients with OSA and T2DM. AIMS: To assess the effects of continuous positive airway pressure (CPAP) therapy on glycosylated haemoglobin (HbA1c) level, insulin sensitivity and body mass index (BMI) in patients with OSA and T2DM. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched to identify prospective studies involving patients with OSA and T2DM who had received CPAP, and data on primary outcome (change in HbA1c) and/or secondary outcomes (changes in insulin sensitivity and BMI) were reported. All relevant studies published before 31 January 2014 were included. RESULTS: Six studies were included in the systematic review and meta analysis. The numbers of patients ranged from 9 to 44 (total=128), and mean age ranged from 50.7 to 66.1 years. For the change in HbA1c (six studies, 128 patients), the combined standardised paired difference revealed no significant effect of CPAP (-0.071, 95% confidence interval (CI)=-0.245, 0.103; P=0.421). Similarly, there was no significant effect of CPAP on the change in BMI (-0.102, 95% CI=-0.296, 0.092; P=0.302; five studies, 103 patients). In contrast, there was a significant effect of CPAP on the change (improvement) in insulin sensitivity (0.330, 95% CI=0.001, 0.658; P=0.049; three studies, 39 patients). CONCLUSION: The limited available evidence from randomised controlled trials and prospective observational studies suggests that CPAP does not decrease HbA1c level or BMI in patients with OSA and T2DM but may improve insulin sensitivity. PMID- 25719930 TI - Variation in glucose homeostasis traits associated with P2RX7 polymorphisms in mice and humans. AB - CONTEXT: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. OBJECTIVE: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. DESIGN: In humans, we mined genome wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose homeostasis. In mice, we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background. RESULTS: Variants in five genes were associated with glycemic traits and in three genes with diabetes risk. In the Prevalence, Prediction, and Prevention of Diabetes in Botnia study, the minor allele in the missense functional variant rs1718119 (A348T) in P2RX7 was associated with increased insulin sensitivity and secretion, consistent with its known effect on increased pore function. Both male and female P2x7-C57 mice demonstrated impaired glucose tolerance compared with matched P2x7-129 mice. Insulin tolerance testing showed that P2x7-C57 mice were also less responsive to insulin than P2x7-129 mice. CONCLUSIONS: We show association of the purinergic signaling pathway in general and hypofunctioning P2X7 variants in particular with impaired glucose homeostasis in both mice and humans. PMID- 25719931 TI - PTHrP-mediated hypercalcemia: causes and survival in 138 patients. AB - CONTEXT: Hypercalcemia is a common complication of cancer with PTHrP an important mediator. Literature on the underlying causes of PTHrP-mediated hypercalcemia, in both malignant and benign conditions, is limited to small case series and case reports. OBJECTIVE: The purpose of this study was to systematically identify a large series of cases of PTHrP-mediated hypercalcemia and to document differences in demographics and the clinical course between malignant and benign etiologies. DESIGN, SETTING, AND PATIENTS: This was a hospital-based, retrospective case series that identified subjects from 1999 to 2010 from the public hospital system in Queensland, Australia. Included subjects were 18 years and older and had persistent hypercalcemia with simultaneously elevated PTHrP. RESULTS: A total of 138 cases were identified. Solid organ malignancies made up 82.6% (n = 114) of cases, with squamous cell carcinoma (28.2% of total) and adenocarcinomas (27.5%) almost equally as common. Hematological malignancy and benign conditions made up 8.7% (n = 12) each. Squamous cell carcinoma of the lung was the single most commonly identified etiology (10.9%). Causes not previously identified included myxoid sarcoma, plasma cell leukemia, duodenal adenocarcinoma, metastatic Merkel cell carcinoma, and epithelioid hemangioendothelioma. Median survival was different among the groups (52 days [interquartile range, 21-132 days] for solid organ malignancy, 362 days [18-652 days] for hematological malignancy, and 906 days [16 days to undefined] for the apparently benign group; P < .0001). There were no differences in PTHrP among the groups. Although the mean corrected calcium level was lower in the benign group (3.03 mmol/L [2.80-3.29 mmol/L]) compared with that in the solid organ (3.11 mmol/L [2.89-3.46 mmol/L]) and hematological malignancy groups (3.60 mmol/L [3.01-3.79 mmol/L]) groups (P = .046), it was not a useful discriminator of etiology. CONCLUSION: PTHrP-mediated hypercalcemia is most frequently caused by solid organ malignancy, and it portends a poor prognosis. Although the solid organ malignancy group had the shortest survival, the hematological malignancy and apparently benign causes groups still had relatively short overall survival. PMID- 25719932 TI - A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations. AB - CONTEXT: Antibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited. OBJECTIVE: The purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease. DESIGN, SETTING, AND PARTICIPANTS: We studied European ancestry participants of 3 independent prospective population based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887). EXPOSURE: Single nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined. MAIN OUTCOMES: The main outcomes were TPOAb concentrations and positivity, thyroid hormone concentrations (TSH, free T4), and clinical thyroid diseases (subclinical and overt hypothyroidism and goiter). RESULTS: Significantly associated single nucleotide polymorphisms (P < 5 . 10(-8)) mapped into 4 genomic regions not previously implicated for TPOAbs (RERE, extended HLA region) and into 5 previously described loci. A higher Genetic Risk Score (GRS) based on these 9 SNPs showed strong and graded associations with higher TPOAb, TSH, and lower free T4 concentrations (P < .001). Compared with individuals in the lowest GRS quartile, those in the highest quartile had 1.80-fold higher odds of subclinical hypothyroidism (95% confidence interval, 1.27-2.55) and 1.89-fold higher odds of overt hypothyroidism (95% confidence interval, 1.24-2.87). CONCLUSION: The identification of 4 novel genetic loci associated with TPOAb concentrations and positivity gives further insight into the genetic underpinnings of hypothyroidism. A GRS showed strong and graded associations with markers of thyroid function and disease in independent population-based studies. PMID- 25719933 TI - Serum 25 hydroxyvitamin D, bone mineral density and fracture risk across the menopause. AB - CONTEXT: Low levels of serum 25 Hydroxyvitamin D [25(OH)D] have been linked to greater fracture risk in older women. OBJECTIVE: This study aimed to determine whether higher 25(OH)D is associated with slower loss of bone mineral density (BMD) and lower fracture risk during the menopausal transition. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study at five clinical centers in the United States. Mean age was 48.5 +/- 2.7 years. The fracture analysis included 124 women with an incident traumatic fracture, 88 with incident nontraumatic fracture, and 1532 women without incident fractures; average followup was 9.5 years. BMD analysis included 922 women with a documented final menstrual period. MAIN OUTCOME MEASURES: Serum 25(OH)D was measured by liquid chromatography tandem mass spectrometry at the third annual clinic visit. BMD was measured and incident fractures ascertained at each annual visit. RESULTS: The mean 25(OH)D was 21.8 ng/mL; seven-hundred two (43%) of the women had 25(OH)D values <20 ng/mL. There was no significant association between 25(OH)D and traumatic fractures. In multivariate adjusted hazards models, the hazard ratio (HR) for nontraumatic fractures (95% confidence interval [CI]) was 0.72 (0.54 0.96) for each 10-ng/mL increase in 25(OH)D. Comparing women whose 25(OH)D was >=20 vs <20 ng/mL, the HR (95% CI) for fracture was 0.54 (0.32-0.89). Changes in lumbar spine and femoral neck bone mineral density across menopause were not significantly associated with serum 25(OH)D level. CONCLUSION: Serum 25(OH)D levels are inversely associated with nontraumatic fracture in mid-life women. Vitamin D supplementation is warranted in midlife women with 25(OH)D levels <20 ng/mL. PMID- 25719934 TI - Associations of serum adipocyte fatty acid binding protein with body composition and fat distribution in nondiabetic Chinese women. AB - CONTEXT: Previous studies have demonstrated evidence of a positive relationship between serum adipocyte fatty acid binding protein (A-FABP) and obesity. However, associations of A-FABP with body composition and ectopic fat accumulation remain unclear. OBJECTIVE: This study aimed to elucidate the effect of body composition, visceral fat area (VFA), and subcutaneous fat area (SFA) on serum A-FABP levels in a cohort of Chinese women without diabetes mellitus. DESIGN, SETTING, AND PARTICIPANTS: A total of 2108 women without diabetes (760 premenopausal and 1348 postmenopausal women; age, 20-78 y) selected from the Shanghai Obesity Study were enrolled. MAIN OUTCOME MEASURES: VFA and SFA were measured by magnetic resonance imaging, and body composition was determined by bioelectrical impedance analysis. A high VFA was defined as >= 80 cm(2). A high SFA was defined as that above the 75th percentile cutoff point of the menopause-specific population, respectively. RESULTS: Serum A-FABP levels were higher in postmenopausal than premenopausal women (P < .001). Both premenopausal and postmenopausal women with an isolated high VFA had higher A-FABP levels than did those with an isolated high SFA (P = .017 and .002, respectively). In both body mass index (BMI) groups (< 25 and >= 25 kg/m(2)), women with a high VFA had higher serum A-FABP levels regardless of their menopausal status. Multiple stepwise regression analysis showed that A-FABP was independently associated with fat mass (Standardized beta = 0.417 and 0.252 for premenopausal and postmenopausal status, respectively, both P < .001). Moreover, VFA was identified as an independent risk factor for A-FABP in postmenopausal women (Standardized beta = 0.114, P = .001). Application of the same regression analyses model to the two BMI groups produced similar results in both BMI categories. CONCLUSIONS: Serum A-FABP levels were associated with fat mass, and were also influenced by VFA after menopause in Chinese women without diabetes mellitus. PMID- 25719935 TI - Crossroads of stress responses, development and flowering regulation--the multiple roles of Cyclic Nucleotide Gated Ion Channel 2. AB - The Arabidopsis autoimmune mutant, defense-no death 1 (dnd1) is a null mutant of CYCLIC NUCLEOTIDE-GATED ION CHANNEL2 (AtCNGC2). dnd1 exhibits constitutive pathogen resistance responses including higher levels of endogenous salicylic acid (SA), which is an important signaling molecule for pathogen defense responses. Recently we have reported that dnd1 exhibits a significantly delayed flowering phenotype, indicating the involvement of AtCNGC2 in flowering transition. However, since SA has been known to influence flowering timing as a positive regulator, the delayed flowering phenotype in dnd1 was unexpected. In this study, we have asked whether SA is involved in the dnd1-mediated delayed flowering phenotype. In addition, in order to gain insight into the involvement of SA and CNGCs in flowering transition, we analyzed the flowering transition of cpr22, another CNGC mutant with a similar autoimmune phenotype as dnd1 (including high SA accumulation), and null mutants of several other CNGCs. Our data suggest that dnd1 does not require SA or SA signaling for its delayed flowering phenotype, while SA was responsible for the early flowering phenotype of cpr22. None of the other CNGC mutants besides AtCNGC4 (1) displayed an alteration in flowering transition. This indicates that AtCNGC2 and AtCNGC4 have a unique role controlling flowering timing and this function is independent from its role in pathogen defense. PMID- 25719936 TI - Chronic myeloid leukemia diagnosed in a patient with uncontrolled proliferative diabetic retinopathy. AB - PURPOSE: To report a case of uncontrolled proliferative diabetic retinopathy as an initial manifestation of chronic myeloid leukemia. METHODS: Case report. PATIENTS: A 55-year-old man with moderate nonproliferative diabetic retinopathy who rapidly developed proliferative retinopathy and bilateral neovascular glaucoma despite good glycemic control. CONCLUSION: Other pathologies should be excluded in diabetic patients with a rapid and severe progression in their retinopathy despite adequate metabolic control. These patients should be treated promptly and aggressively until systemic disease is stable. PMID- 25719937 TI - Risk factors associated with intraocular pressure increase in patients with uveitis treated with the fluocinolone acetonide implant. AB - IMPORTANCE: Elevated intraocular pressure (IOP) is a well-known adverse event associated with the fluocinolone acetonide implant (FAI), but no data are available regarding factors associated with increased risk of IOP elevation in patients treated with the FAI. OBJECTIVE: To report risk factors that may predispose patients to elevated IOP after treatment with the FAI. DESIGN, SETTING, AND PARTICIPANTS: Data from 3 multicenter, 3-year, prospective, randomized, phase 2b/3 clinical trials evaluating the safety and efficacy of the FAI were pooled and analyzed. Patients had no underlying glaucoma and at least one eye with a history of recurrent noninfectious uveitis affecting the posterior segment. Patients were treated with 1 or more of the following: systemic therapy (corticosteroids or other immunosuppressive drugs) for at least 3 months before enrollment, 2 or more sub-Tenon capsule corticosteroid injections for uveitis management during the 6 months before enrollment, or systemic corticosteroid or sub-Tenon capsule corticosteroid injection therapy required for at least 2 separate recurrences within 6 months before enrollment. MAIN OUTCOMES AND MEASURES: Factors evaluated as risk factors for IOP elevation included age, sex, lens status, uveitis severity at enrollment, and location of uveitis. RESULTS: Data analyses were based on 641 eyes. A total of 351 eyes did not receive the FAI, whereas 290 eyes had the 0.59-mg FAI placed. An increase in IOP of 10 mm Hg or elevation to 30 mm Hg was seen in 60 untreated eyes (17.1%) and 188 treated eyes (65.1%) (hazard ratio, 5.80; 95% CI, 4.28-7.70; P < .001). A total of 8 untreated eyes (2.3%) required surgical intervention for elevated IOP compared with 93 treated eyes (32.1%) (hazard ratio, 16.48; 95% CI, 8.24-32.96; P < .001). In patients with the FAI, younger age, male sex, and phakic lens status were associated with higher risk of IOP elevation and the need for glaucoma surgery (P = .003, P < .001, and P < .001, respectively). CONCLUSIONS AND RELEVANCE: Patients receiving the FAI are at higher risk of developing an IOP increase of 10 mm Hg or an absolute IOP of 30 mm Hg when compared with patients without the FAI. Patients who are male, younger, and phakic are at an even higher risk for elevated IOP and possibly glaucoma surgery. PMID- 25719938 TI - Top-down MALDI-in-source decay-FTICR mass spectrometry of isotopically resolved proteins. AB - An accurate mass measurement of a known protein provides information on potential amino acid deletions and post-translational modifications. Although this field is dominated by strategies based on electrospray ionization, mass spectrometry (MS) methods using matrix-assisted laser desorption/ionization (MALDI) have the advantage of yielding predominantly singly charged precursor ions, thus avoiding peak overlap from different charge states of multiple species. Such MALDI-MS methods require mass measurement at ultrahigh resolution, which is provided by Fourier transform ion cyclotron resonance (FTICR) mass analyzers. Recently, using a MALDI-FTICR-MS platform equipped with a 15 T magnet, we reported on the mass analysis of intact human serum peptides and small proteins with isotopic resolution up to ~15 kDa and identified new proteoforms from an accurate measurement of mass distances. In the current study, we have used this FTICR system after an upgrade with a novel dynamically harmonized ICR cell, i.e., ParaCell, for mapping isotopically resolved intact proteins up to about 17 kDa and performed top-down MALDI in-source decay (ISD) analysis. Standard proteins myoglobin (m/z-value 16,950) and ribonuclease B (m/z-value 14,900) were measured with resolving powers of 62,000 and 61,000, respectively. Furthermore, it will be shown that (singly charged) MALDI-ISD fragment ions can be measured at isotopic resolution up to m/z-value 12,000 (e.g., resolving power 39,000 at m/z-value 12,000) providing more reliable identifications. Moreover, examples are presented of pseudo-MS(3) experiments on ISD fragment ions from RNase B by collisional induced dissociation (CID). PMID- 25719939 TI - Redox sorting of carbon nanotubes. AB - This work expands the redox chemistry of single-wall carbon nanotubes (SWCNTs) by investigating its role in a number of SWCNT sorting processes. Using a polyethylene glycol (PEG)/dextran (DX) aqueous two-phase system, we show that electron-transfer between redox molecules and SWCNTs triggers reorganization of the surfactant coating layer, leading to strong modulation of nanotube partition in the two phases. While the DX phase is thermodynamically more favored by an oxidized SWCNT mixture, the mildly reducing PEG phase is able to recover SWCNTs from oxidation and extract them successively from the DX phase. Remarkably, the extraction order follows SWCNT bandgap: semiconducting nanotubes of larger bandgap first, followed by semiconducting nanotubes of smaller bandgap, then nonarmchair metallic tubes of small but nonvanishing bandgap, and finally armchair metallic nanotubes of zero bandgap. Furthermore, we show that redox induced surfactant reorganization is a common phenomenon, affecting nanotube buoyancy in a density gradient field, affinity to polymer matrices, and solubility in organic solvents. These findings establish redox modulation of surfactant coating structures as a general mechanism for tuning a diverse range of SWCNT sorting processes and demonstrate for the first time that armchair and nonarmchair metallic SWCNTs can be separated by their differential response to redox. PMID- 25719940 TI - Chemography of natural product space. AB - We present the application of the generative topographic map algorithm to visualize the chemical space populated by natural products and synthetic drugs. Generative topographic maps may be used for nonlinear dimensionality reduction and probabilistic modeling. For compound mapping, we represented the molecules by two-dimensional pharmacophore features (chemically advanced template search descriptor). The results obtained suggest a close resemblance of synthetic drugs with natural products in terms of their pharmacophore features, despite pronounced differences in chemical structure. Generative topographic map-based cluster analysis revealed both known and new potential activities of natural products and drug-like compounds. We conclude that the generative topographic map method is suitable for inferring functional similarities between these two classes of compounds and predicting macromolecular targets of natural products. PMID- 25719941 TI - Protective effect of tetrahydrocurcumin against cisplatin-induced renal damage: in vitro and in vivo studies. AB - The adverse effects of anticancer drugs can prompt patients to end their treatment despite the efficacy. Cisplatin is a platinum-based molecule widely used to treat various forms of cancer, but frequent and long-term use of cisplatin is limited due to severe nephrotoxicity. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin on cisplatin-induced kidney damage, oxidative stress, and inflammation to evaluate its possible use in renal damage. Cisplatin-induced LLC-PK1 renal cell damage was significantly reduced by tetrahydrocurcumin treatment. Additionally, the protective effect of tetrahydrocurcumin on cisplatin-induced oxidative renal damage was investigated in rats. Tetrahydrocurcumin was orally administered every day at a dose of 80 mg/kg body weight for ten days, and a single dose of cisplatin was administered intraperitoneally (7.5 mg/kg body weight) in 0.9 % saline on day four. The creatinine clearance levels, which were markers of renal dysfunction, in cisplatin-treated rats were recovered nearly back to normal levels after administration of tetrahydrocurcumin. Moreover, tetrahydrocurcumin exhibited protective effects against cisplatin-induced oxidative renal damage in rats by inhibiting cyclooxygenase-2 and caspase-3 activation. These results collectively provide therapeutic evidence that tetrahydrocurcumin ameliorates renal damage by regulating inflammation and apoptosis. PMID- 25719942 TI - Similarity between Flavonoid Biosynthetic Enzymes and Flavonoid Protein Targets Captured by Three-Dimensional Computing Approach. AB - Natural products are made by nature through interaction with biosynthetic enzymes. They also exert their effect as drugs by interaction with proteins. To address the question "Do biosynthetic enzymes and therapeutic targets share common mechanisms for the molecular recognition of natural products?", we compared the active site of five flavonoid biosynthetic enzymes to 8077 ligandable binding sites in the Protein Data Bank using two three-dimensional based methods (SiteAlign and Shaper). Virtual screenings efficiently retrieved known flavonoid targets, in particular protein kinases. A consistent performance obtained for variable site descriptions (presence/absence of water, variable boundaries, or small structural changes) indicated that the methods are robust and thus well suited for the identification of potential target proteins of natural products. Finally, our results suggested that flavonoid binding is not primarily driven by shape, but rather by the recognition of common anchoring points. PMID- 25719943 TI - Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway. AB - Glioblastomas multiforme (GBM) are the most frequently occurring malignant brain cancers. Treatment for GBM consists of surgical resection and subsequent adjuvant radiation therapy and chemotherapy. Despite this, GBM patient survival is limited to 12-15 months, and researchers are continually trying to develop improved therapy options. Insulin-like growth factor 2 mRNA-binding protein 2 (Imp2) is known to be upregulated in many cancers and is known to regulate the signaling activity of insulin-like growth factor 2 (IGF2). However, relatively little is known about its role in malignant development of GBM. In this study, we first found Imp2 is upregulated in GBM tissues by using clinical samples and public database search. Studies with loss and gain of Imp2 expression in in vitro GBM cell culture system demonstrated the role of Imp2 in promoting GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT). Additionally, our results show that Imp2 regulates the activity of IGF2, which further activates PI3K/Akt signaling, thereby to promote GBM malignancy. Inhibition of Imp2 was also found to sensitize GBM to temozolomide treatment. These observations add to the current knowledge of GBM biology, and may prove useful in development of more effective GBM therapy. PMID- 25719945 TI - A novel Co@Au structure formed in bimetallic core@shell nanoparticles. AB - Core@shell Co@Au nanoparticles of around 8 nm have been produced by the inert gas condensation method, revealing for the first time that most of the nanoparticles exhibit an icosahedral shape in agreement with the theoretical prediction. Additionally, we report the existence of a novel morphology which consists of a Co icosahedron surrounded by fcc Au facets, reported here for the first time. PMID- 25719946 TI - Correction: Amassing Efforts against Alien Invasive Species in Europe. PMID- 25719944 TI - Immunological features of the non-structural proteins of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is currently one of the most important viruses affecting the swine industry worldwide. Despite the large number of papers published each year, the participation of non-structural proteins (nsps) in the immune response is not completely clear. nsps have been involved in the host innate immune response, specifically, nsp1alpha/beta, nsp2, nsp4 and nsp11 have been associated with the immunomodulation capability of the virus. To date, only participation by nsp1, nsp2, nsp4 and nsp7 in the humoral immune response has been reported, with the role of other nsps being overlooked. Furthermore, nsp1, nsp2, nsp5, nsp7 nsp9, nsp10, nsp11 have been implicated in the induction of IFN-gamma and probably in the development of the cell-mediated immune response. This review discusses recent reports involving the participation of nsps in the modulation of the innate immune response and their role in the induction of both the humoral and cellular immune responses. PMID- 25719947 TI - Temperature dependence of the photochemical formation of hydroxyl radical from dissolved organic matter. AB - The temperature dependence of the photochemical production of the hydroxyl radical (*OH) from dissolved organic matter (DOM) was investigated by measuring the apparent temperature dependence of the quantum yield (Phia) for this process. Temperature dependent Phia values were analyzed using the Arrhenius equation. Apparent activation energies obtained for DOM isolates purchased from the International Humic Substances Society ranged from 16 to 34 kJ mol(-1). Addition of 40 units mL(-1) catalase, used to hinder the hydrogen peroxide (H2O2) dependent pathway to *OH, did not impact the observed activation energy. However, an increase in activation energy was observed in lower molecular weight DOM obtained by size fractionation. We also measured the temperature dependence of p benzoquionone photolysis as a model compound for DOM and observed no temperature dependence (slope p = 0.41) for the formation of phenol from oxidation of benzene (the *OH probe used), but a value of about 10 kJ mol(-1) for p-benzoquinone loss, which is consistent with formation of a quinone-water exciplex. These data provide insight into DOM photochemistry as well as provide parameters useful for modeling steady state *OH concentrations in natural systems. PMID- 25719948 TI - Levels of tetrabromobisphenol A, tribromobisphenol A, dibromobisphenol A, monobromobisphenol A, and bisphenol a in Japanese breast milk. AB - The levels of bisphenol A (BPA) and tetrabromobisphenol A (TeBBPA) were determined in breast milk samples from 19 Japanese mothers. BPA and TeBBPA levels were 36 ng/g lipid (range: 1.4-380 ng/g lipid) and 1.9 ng/g lipid (range: N.D. - 8.7 ng/g lipid), respectively. Tribromobisphenol A (TriBBPA) was similarly detected in all samples (mean: 5.5 ng/g lipid). We investigated the alteration of BPA-related compounds in breast milk over a period of three months. No trend could be observed for time-dependent changes in TeBBPA levels. High levels of TriBBPA were detected in breast milk samples with a high concentration of TeBBPA. We further examined concentration changes in BPA-related compounds in the breast milk of two donors over a period of 24 h. The results suggested that TriBBPA was a debrominated metabolite of TeBBPA, which had been ingested via food consumption and immediately transferred to the breast milk. On the basis of the present results, we estimated and compared the daily intake of BPA, TriBBPA, and TeBBPA from breast milk for infants. The estimated average intake of TriBBPA was 4 times higher than TeBBPA, at 48 and 12 ng/kg/day, respectively. The level of TeBBPA in breast milk was low, suggesting a low risk of causing adverse health effects. In conclusion, the concentration of both TriBBPA and TeBBPA must be determined in breast milk to accurately clarify the exposure of these compounds to infants. PMID- 25719949 TI - New drugs 2015, part 1. PMID- 25719951 TI - Comparison of positive-pressure, passive ultrasonic, and laser-activated irrigations on smear-layer removal from the root canal surface. AB - OBJECTIVE: The purpose of this study was to compare the efficacy of three irrigation techniques for smear-layer removal with 17% EDTA. BACKGROUND DATA: Cleaning and shaping the root canal system during endodontic treatment produces a smear layer and hard tissue debris. Three irrigation techniques were tested for solution infiltration of this layer: positive-pressure irrigation, passive ultrasonic irrigation, and laser-activated irrigation. MATERIALS AND METHODS: Sixty extracted teeth were divided into six equal groups; 17% EDTA was used for 60 sec irrigation of five of the groups. The groups were as follows: Group 1, treated only with ProTaperTM F3 Ni-Ti files; Group 2, positive-pressure irrigation, with a syringe; Group 3, passive ultrasonic irrigation, inserted 1 mm short of the working length; Group 4, passive ultrasonic irrigation, inserted in the upper coronal third of the root; Group 5, Er:YAG laser-activated irrigation, inserted 1 mm short of the working length; and Group 6, Er:YAG laser-activated irrigation, inserted in the upper coronal third of the root. RESULTS: Scanning electron microscopy showed that the smear layer is removed most efficiently using laser-activated irrigation at low energy with 17% EDTA, inserted either at the working length or only in the coronal upper third of the root. Amounts of Ca, P, and O were not significantly different on all treated dentin surfaces. CONCLUSIONS: Smear-layer removal was most effective when the root canals were irrigated using Er:YAG laser at low energy with 17% EDTA solution. Interestingly, removal of the smear layer along the entire canal was similar when the laser was inserted in the upper coronal third and at 1 mm short of the working length of the root canal. This effect was not observed with the ultrasonic and positive pressure techniques. PMID- 25719950 TI - The Effect of High Rates of Bacterial Sexually Transmitted Infections on HIV Incidence in a Cohort of Black and White Men Who Have Sex with Men in Atlanta, Georgia. AB - Data reporting sexually transmitted infection (STI) incidence rates among HIV negative U.S. men who have sex with men (MSM) are lacking. In addition, it is difficult to analyze the effect of STI on HIV acquisition given that sexual risk behaviors confound the relationship between bacterial STIs and incident HIV. The InvolveMENt study was a longitudinal cohort of black and white HIV-negative, sexually active MSM in Atlanta who underwent routine screening for STI and HIV and completed behavioral questionnaires. Age-adjusted incidence rates were calculated for urethral and rectal Chlamydia (CT), gonorrhea (GC), and syphilis, stratified by race. Propensity-score-weighted Cox proportional hazards models were used to estimate the effect of STI on HIV incidence and calculate the population attributable fraction (PAF) for STI. We included 562 HIV-negative MSM with 843 person-years of follow-up in this analysis. High incidence rates were documented for all STIs, particularly among black MSM. Having a rectal STI was significantly associated with subsequent HIV incidence in adjusted analyses (aHR 2.7; 95% CI 1.2, 6.4) that controlled for behavioral risk factors associated with STI and HIV using propensity score weights. The PAF for rectal STI was 14.6 (95% CI 6.8, 31.4). The high incidence of STIs among Atlanta MSM and the association of rectal STI with HIV acquisition after controlling for behavioral risk underscore the importance of routine screening and treatment for STIs among sexually active MSM. Our data support targeting intensive HIV prevention interventions, such as preexposure chemoprophylaxis (PrEP), for Atlanta MSM diagnosed with rectal STIs. PMID- 25719952 TI - Stemness enhancement of human neural stem cells following bone marrow MSC coculture. AB - Rapid loss of stemness capacity in purified prototype neural stem cells (NSCs) remains a serious challenge to basic and clinical studies aiming to repair the central nervous system. Based on the essential role of mesodermal guidance in the process of neurulation, we hypothesized that coculture of human NSCs (hNSCs) with human bone marrow-derived mesenchymal stromal stem cells (hMSCs) could enhance the stemness of hNSCs through Notch-1 signaling. We have now tested the hypothesis by assessing behaviors of hNSCs and hMSCs under systematically designed coculture conditions relative to monocultures, with or without Notch-1 manipulation in vitro. Our data demonstrate that expression levels of Notch-1 and Hes-1 as determined by immunocytochemistry are significantly higher in hNSCs cocultured with hMSCs than those of controls. Furthermore, coculturing significantly increases immunoreactivity of CD15, a neural stemness marker, but decreases CD24, a marker of neural/neuronal commitment in hNSCs. The effect is independent from the physical status of cell growth since coculture and notch signaling actually promotes hNSC adhesion. Importantly, coculture with hMSCs markedly augments hNSC proliferation rate (e.g., higher yield in G2/M phase subpopulation in a notch-dependent manner detected by flow cytometry) without diminishing their lineage differentiation capabilities. The results suggest that coculture of hNSCs with hMSCs enhances stemness biology of hNSCs partially via activation of Notch-1 signal transduction. Our finding sheds new light on mesoderm-ectoderm cell fate determination via contact-based hMSC-hNSC interactions and provides mechanistic leads for devising effective regimens to sustain and augment stemness of in vitro established hNSC and hMSC lines for basic science, translational and clinical applications. PMID- 25719953 TI - A rapid liquid chromatography determination of free formaldehyde in cod. AB - A rapid method for the determination of free formaldehyde in cod is described. It uses a simple water extraction of formaldehyde which is then derivatised with 2,4 dinitrophenylhydrazine (DNPH) to form a sensitive and specific chromophore for high-performance liquid chromatography (HPLC) detection. Although this formaldehyde derivative has been widely used in past tissue analysis, this paper describes an improved derivatisation procedure. The formation of the DNPH formaldehyde derivative has been shortened to 2 min and a stabilising buffer has been added to the derivative to increase its stability. The average recovery of free formaldehyde in spiked cod was 63% with an RSD of 15% over the range of 25 200 mg kg(-1) (n = 48). The HPLC procedure described here was also compared to a commercial qualitative procedure - a swab test for the determination of free formaldehyde in fish. Several positive samples were compared by both methods. PMID- 25719954 TI - Impact of a new practice guideline on antibiotic use with pediatric tonsillectomy. AB - IMPORTANCE: More than 500,000 children undergo tonsillectomy each year in the United States. Although prior studies suggest that most patients received perioperative antibiotics, practice varies across centers. In 2011, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published a practice guideline recommending against perioperative antibiotic use for pediatric tonsillectomy. The impact of this recommendation has not been thoroughly examined. OBJECTIVE: To determine the impact of the AAO-HNS guideline on the use of perioperative antibiotics and patient outcomes for pediatric tonsillectomy. DESIGN, SETTING, AND PARTICIPANTS: This was a quasi-experimental study including 9265 children who underwent routine tonsillectomy from January 2009 through August 2012 within a large pediatric health care network containing hospital based and ambulatory surgical facilities. Data were collected from a shared electronic health record and validated through manual medical record review. We used an interrupted time series analysis with segmented logistic regression and a nonequivalent dependent variable (tympanoplasty) to assess acute changes and differences in trends over time relative to guideline publication. INTERVENTIONS: Publication of the AAO-HNS clinical practice guideline. MAIN OUTCOMES AND MEASURES: The primary outcome was antibiotic administration on the day of surgery. Secondary outcomes included otolaryngology clinic encounters, emergency department encounters, hospital admissions, and surgical procedures for bleeding in the 30 days following tonsillectomy. RESULTS: Of 9265 tonsillectomies during the study period, 5359 met inclusion criteria. Immediately after guideline publication, perioperative antibiotic use dropped by 86.5% (P < .001) and was sustained throughout the postintervention period. Rates of otolaryngology clinic encounters, emergency department encounters, and hospital admissions did not change significantly over time. There was a small but statistically significant increase in surgical procedures for bleeding following the intervention from 1.35% (95% CI, 0.57%-2.14%) to 3.48% (95% CI, 1.85%-5.10%). CONCLUSIONS AND RELEVANCE: AAO-HNS guideline publication decreased perioperative antibiotic use for pediatric tonsillectomy across a large pediatric health care network. Although there were no changes in otolaryngology clinic visits, emergency department visits, or admissions, we found a small but significant increase in surgery for bleeding following guideline publication. Additional studies are necessary to verify this unexpected association. PMID- 25719955 TI - Role of infection in exacerbations of chronic obstructive pulmonary disease. AB - PURPOSE OF REVIEW: In this review, we present the latest findings on the cause, pathogenesis and management of patients with chronic obstructive pulmonary disease (COPD) and an infective phenotype. RECENT FINDINGS: More than half of COPD exacerbations are infective. Bacteria are isolated in 70% of them, but viruses also play an important role, both alone and in combination with bacteria. Furthermore, in many cases, viral infection can be followed by bacterial infection in patients with COPD but not in individuals with normal lung function. Viral infection may produce changes in the lung microbiome that may precipitate subsequent bacterial infection. Research on the lung microbiome is providing new insight into the pathogenesis of infection in healthy and diseased lungs. SUMMARY: COPD patients have alterations in their lung microbiome that may result in chronic infection with potentially pathogenic microorganisms (PPMs) even in periods of clinical stability and associated with a higher frequency of bacterial exacerbations. Patients with this infective phenotype may require a personalized approach to therapy with the use of short-term or long-term antibiotic treatment in addition to the usual treatment for COPD. PMID- 25719956 TI - Networks of triboelectric nanogenerators for harvesting water wave energy: a potential approach toward blue energy. AB - With 70% of the earth's surface covered with water, wave energy is abundant and has the potential to be one of the most environmentally benign forms of electric energy. However, owing to lack of effective technology, water wave energy harvesting is almost unexplored as an energy source. Here, we report a network design made of triboelectric nanogenerators (TENGs) for large-scale harvesting of kinetic water energy. Relying on surface charging effect between the conventional polymers and very thin layer of metal as electrodes for each TENG, the TENG networks (TENG-NW) that naturally float on the water surface convert the slow, random, and high-force oscillatory wave energy into electricity. On the basis of the measured output of a single TENG, the TENG-NW is expected to give an average power output of 1.15 MW from 1 km(2) surface area. Given the compelling features, such as being lightweight, extremely cost-effective, environmentally friendly, easily implemented, and capable of floating on the water surface, the TENG-NW renders an innovative and effective approach toward large-scale blue energy harvesting from the ocean. PMID- 25719957 TI - Clinical factors indicating the presence of malignant lymphoma before lymph node dissection. AB - CONCLUSION: Lymph node swelling in the neck is one of the initial symptoms of malignant lymphoma (ML). The present study showed that clinical factors including higher age, higher level of maximum standardized uptake value (SUV-max) of positron-emission tomography, elevated serum lactate dehydrogenase (LDH), and elevated serum soluble interleukin-2 receptor (sIL-2R) were all useful indicators to suggest the diagnosis of ML, so may be helpful in the selection of patients for lymph node dissection. OBJECTIVE: Lymph node dissection is essential for the diagnosis of ML. The factors important for the diagnosis of ML were investigated, to establish surgical indicators. METHODS: Preoperative data including age, number and side of lymph nodes, SUV-max, serum LDH, serum sIL-2R, and size of lymph nodes were obtained from medical records. The cut-off level for each factor was calculated using the Youden Index for logistic regression analysis. RESULTS: Multivariate logistic regression analysis showed that the following factors were associated with ML: higher age (>= 53 years), higher level of SUV-max (>= 9.0), elevated serum LDH (>= 203 U/L), elevated serum sIL-2R (>= 2590 U/ml), with odds ratios of 3.7, 4.9, 3.7, and 11.9, respectively. PMID- 25719958 TI - Molecular cloning and functional analysis of the goose FSHbeta gene. AB - The objective of this investigation was to clone goose FSHbeta-subunit cDNA and to construct a FSH fusion gene to identify the function of FSHbeta mRNA during stages of the breeding cycle. The FSHbeta gene was obtained by reverse transcription-PCR, and the full-length FSHbeta mRNA sequence was amplified by rapid-amplification of cDNA ends. FSHbeta mRNA expression was detected in reproductive tissues at different stages (pre-laying, laying period, and broody period). Additionally, the expression of 4 genes known to be involved in reproduction (FSHbeta, GnRH, GH, and BMP) were evaluated in COS-7 cells expressing the fusion gene (pVITRO2-FSHalphabeta-CTP). The results show that the FSHbeta gene consists of a 16 base pair (bp) 5'-untranslated region (UTR), 396 bp open reading frame, and alternative 3'-UTRs at 518 bp and 780 bp, respectively. qPCR analyses revealed that FSHbeta mRNA is highly transcribed in reproductive tissues, including the pituitary, hypothalamus, ovaries, and oviduct. FSHbeta mRNA expression increased and subsequently decreased in the pituitary, ovaries, and oviduct during the reproductive stages. Stable FSH expression was confirmed using enzyme-linked immunosorbent assays after transfection with the pVITRO2 FSHalphabeta-CTP plasmid. FSHbeta, GnRH, and BMP expression increased significantly 36 h and 48 h after transfection with the fusion gene in COS-7 cells. The results demonstrate that the FSHbeta subunit functions in the goose reproductive cycle and provides a theoretical basis for future breeding work. PMID- 25719960 TI - Estimated dopamine D2 receptor occupancy and remission in schizophrenia. Analysis of the CATIE data: erratum. PMID- 25719959 TI - Barriers to and facilitators of interventions to counter publication bias: thematic analysis of scholarly articles and stakeholder interviews. AB - BACKGROUND: When the nature and direction of research results affect their chances of publication, a distortion of the evidence base - termed publication bias - results. Despite considerable recent efforts to implement measures to reduce the non-publication of trials, publication bias is still a major problem in medical research. The objective of our study was to identify barriers to and facilitators of interventions to prevent or reduce publication bias. METHODS: We systematically reviewed the scholarly literature and extracted data from articles. Further, we performed semi-structured interviews with stakeholders. We performed an inductive thematic analysis to identify barriers to and facilitators of interventions to counter publication bias. RESULTS: The systematic review identified 39 articles. Thirty-four of 89 invited interview partners agreed to be interviewed. We clustered interventions into four categories: prospective trial registration, incentives for reporting in peer-reviewed journals or research reports, public availability of individual patient-level data, and peer review/editorial processes. Barriers we identified included economic and personal interests, lack of financial resources for a global comprehensive trial registry, and different legal systems. Facilitators identified included: raising awareness of the effects of publication bias, providing incentives to make data publically available, and implementing laws to enforce prospective registration and reporting of clinical trial results. CONCLUSIONS: Publication bias is a complex problem that reflects the complex system in which it occurs. The cooperation amongst stakeholders to increase public awareness of the problem, better tailoring of incentives to publish, and ultimately legislative regulations have the greatest potential for reducing publication bias. PMID- 25719961 TI - Two cases of human cutaneous anthrax in Bosnia and Herzegovina, September 2014. PMID- 25719962 TI - The impact of a national routine immunisation programme initiated in 1999 on Hepatitis A incidence in Israel, 1993 to 2012. PMID- 25719963 TI - Spatial distribution and cluster analysis of a leishmaniasis outbreak in the south-western Madrid region, Spain, September 2009 to April 2013. PMID- 25719964 TI - Comparative safety evaluation of 7-valent and 13-valent pneumococcal vaccines in routine paediatric vaccinations in four Italian regions, 2009 to 2011. PMID- 25719965 TI - Assessment of human influenza pandemic scenarios in Europe. PMID- 25719966 TI - Ammonia synthesis by hydrogenolysis of titanium-nitrogen bonds using proton coupled electron transfer. AB - The catalytic hydrogenolysis of the titanium-amide bond in (eta(5) C5Me4SiMe3)2Ti(Cl)NH2 to yield free ammonia is described. The rhodium hydride, (eta(5)-C5Me5)(py-Ph)RhH (py-Ph = 2-phenylpyridine), serves as the catalyst and promotes N-H bond formation via hydrogen atom transfer. The N-H bond dissociation free energies of ammonia ligands have also been determined for titanocene and zirconocene complexes and reveal a stark dependence on metal identity and oxidation state. In all cases, the N-H BDFEs of coordinated NH3 decreases by >40 kcal/mol from the value in the free gas phase molecule. PMID- 25719967 TI - Superior canal dehiscence reveals concomitant unilateral utricular loss (UUL). AB - CONCLUSION: We report enhanced symmetrical cervical vestibular evoked myogenic potential (cVEMP) but asymmetrical ocular VEMP (oVEMP) responses in a patient with CT-verified bilateral superior semicircular canal dehiscence (SCD) but with acute vestibular syndrome. This implies that absence of unilateral utricular macula function alone is sufficient to cause symptoms of acute vertigo. Acute vertigo should not automatically be presumed to originate from semicircular canal dysfunction. OBJECTIVES: To identify the cause of an acute vertigo attack in a patient with bilateral SCD. METHODS: The functional state of all peripheral vestibular sense organs was tested using the video head impulse test (vHIT) for all semicircular canals and VEMPs to air-conducted sound (ACS) or bone-conducted vibration (BCV) to test all otolith organs. The cVEMP tested mainly saccular function and the oVEMP mainly utricular function. RESULTS: All semicircular canals showed normal function. The cVEMPs showed enhanced, but symmetrical saccular function. In contrast, oVEMPs showed an enhanced but asymmetric n10 component - it was greatly reduced beneath the left eye, implying decreased function in the right utricular macula. That result was confirmed using very high frequency stimuli which are effective in SCD: 4000 Hz BCV stimuli showed that oVEMP n10 was present beneath the right eye but absent beneath the left eye. PMID- 25719968 TI - Grief and growth of bereaved siblings as related to attachment style and flexibility. AB - This study examined the relationship between attachment style, coping flexibility, military/non-military cause of death, levels of grief reactions and posttraumatic growth (PTG), in 150 bereaved adult siblings in Israel. Insecurely attached participants, 72% of the sample, reported more grief and less PTG than did securely attached ones. Highly avoidant individuals exhibited the least amount of PTG. Securely attached siblings were more flexible and flexibly coping participants reported less grief and higher PTG. Cause of death was not related to grief and PTG. Discussion of these findings yields conditions enabling PTG after a sibling loss. PMID- 25719970 TI - Predictive modeling of subsurface shoreline oil encounter probability from the Exxon Valdez oil spill in Prince William Sound, Alaska. AB - To better understand the distribution of remaining lingering subsurface oil residues from the Exxon Valdez oil spill (EVOS) along the shorelines of Prince William Sound (PWS), AK, we revised previous modeling efforts to allow spatially explicit predictions of the distribution of subsurface oil. We used a set of pooled field data and predictor variables stored as Geographic Information Systems (GIS) data to generate calibrated boosted tree models predicting the encounter probability of different categories of subsurface oil. The models demonstrated excellent predictive performance as evaluated by cross-validated performance statistics. While the average encounter probabilities at most shoreline locations are low across western PWS, clusters of shoreline locations with elevated encounter probabilities remain in the northern parts of the PWS, as well as more isolated locations. These results can be applied to estimate the location and amount of remaining oil, evaluate potential ongoing impacts, and guide remediation. This is the first application of quantitative machine-learning based modeling techniques in estimating the likelihood of ongoing, long-term shoreline oil persistence after a major oil spill. PMID- 25719969 TI - Material properties of biofilms-a review of methods for understanding permeability and mechanics. AB - Microorganisms can form biofilms, which are multicellular communities surrounded by a hydrated extracellular matrix of polymers. Central properties of the biofilm are governed by this extracellular matrix, which provides mechanical stability to the 3D biofilm structure, regulates the ability of the biofilm to adhere to surfaces, and determines the ability of the biofilm to adsorb gases, solutes, and foreign cells. Despite their critical relevance for understanding and eliminating of biofilms, the materials properties of the extracellular matrix are understudied. Here, we offer the reader a guide to current technologies that can be utilized to specifically assess the permeability and mechanical properties of the biofilm matrix and its interacting components. In particular, we highlight technological advances in instrumentation and interactions between multiple disciplines that have broadened the spectrum of methods available to conduct these studies. We review pioneering work that furthers our understanding of the material properties of biofilms. PMID- 25719971 TI - Chemical and structural evolution in the Th-SeO3(2-)/SeO4(2-) system: from simple selenites to cluster-based selenate compounds. AB - While extensive success has been gained in the structural chemistry of the U-Se system, the synthesis and characterization of Th-based Se structures are widely unexplored. Here, four new Th-Se compounds, alpha-Th(SeO3)2, beta-Th(SeO3)2, Th(Se2O5)2, and Th3O2(OH)2(SeO4)3, have been obtained from mild hydrothermal or low-temperature (180-220 degrees C) flux conditions and were subsequently structurally and spectroscopically characterized. The crystal structures of alpha Th(SeO3)2 and beta-Th(SeO3)2 are based on ThO8 and SeO3 polyhedra, respectively, featuring a three-dimensional (3D) network with selenite anions filling in the Th channels along the a axis. Th(Se2O5)2 is a 3D framework composed of isolated ThO8 polyhedra interconnected by [Se2O5](2-) dimers. Th3O2(OH)2(SeO4)3 is also a 3D framework constructed by octahedral hexathorium clusters [Th6(MU3-O)4(MU3 OH)4](12+), which are interlinked by selenate groups SeO4(2-). The positions of the vibrational modes associated with both Se(IV)O3(2-) and Se(VI)O4(2-) units, respectively, were determined for four compounds, and the Raman spectra of alpha- and beta-Th(SeO3)2 are compared and discussed in detail. PMID- 25719974 TI - Clinical Efficacy of Percutaneous Kyphoplasty at the Hyperextension Position for the Treatment of Osteoporotic Kummell Disease. AB - SUMMARY OF BACKGROUND DATA: Percutaneous kyphoplasty might be effective for osteoporotic Kummell disease. OBJECTIVE: To investigate the clinical efficacy of percutaneous kyphoplasty in hyperextension for osteoporotic Kummell disease. STUDY DESIGN: Retrospective study. METHODS: A retrospective analysis was carried out on data from downstream balloon kyphoplasty treatments in hyperextension for 18 patients with osteoporotic Kummell disease. All cases were single-segment disease affecting T5 (1 case), T7 (1 case), T8 (2 cases), T11 (6 cases), T12 (4 cases), L1 (2 cases), L2 (1 case), or L4 (1 case). Dual-energy x-ray absorptiometry bone mineral density values ranged from -2.8 to -5.8 SD. The sagittal Cobb angle of the involved segment was measured before and after the operation and the final follow-up also included a visual analog pain score (VAS) and the Oswestry Disability Index (ODI) after comprehensive efficacy assessment. RESULTS: All patients were followed up for 12-36 months, with an average of 15.8 months. Patients showed lower back pain relief and improvement in daily life activities. The kyphosis Cobb angle improved from 32.60+/-3.82 degrees before surgery to 7.60+/-1.68 degrees after surgery, and VAS and ODI scores significantly improved from 8.7+/-0.96 points and 88.6+/-3.76% to 2.6+/-0.32 points and 28.6+/-2.67%, respectively. The last follow-up for the kyphosis Cobb angle yielded a value of 9.60+/-2.06 degrees, and VAS and ODI averaged 2.2+/-0.26 points and 26.4+/-2.46%, respectively. Compared with 2 days postoperatively, the differences were not statistically significant. Intervertebral cement leakage occurred in 1 case, but no symptom was observed and no treatment was performed. CONCLUSION: Percutaneous balloon kyphoplasty in the hyperextension position is an effective method for osteoporosis in Kummell disease. PMID- 25719972 TI - On the lag phase in amyloid fibril formation. AB - The formation of nanoscale amyloid fibrils from normally soluble peptides and proteins is a common form of self-assembly phenomenon that has fundamental connections with biological functions and human diseases. The kinetics of this process has been widely studied and exhibits on a macroscopic level three characteristic stages: a lag phase, a growth phase and a final plateau regime. The question of which molecular events take place during each one of these phases has been a central element in the quest for a mechanism of amyloid formation. In this review, we discuss the nature and molecular origin of the lag-phase in amyloid formation by making use of tools and concepts from physical chemistry, in particular from chemical reaction kinetics. We discuss how, in macroscopic samples, it has become apparent that the lag-phase is not a waiting time for nuclei to form. Rather, multiple parallel processes exist and typically millions of primary nuclei form during the lag phase from monomers in solution. Thus, the lag-time represents a time that is required for the nuclei that are formed early on in the reaction to grow and proliferate in order to reach an aggregate concentration that is readily detected in bulk assays. In many cases, this proliferation takes place through secondary nucleation, where fibrils may present a catalytic surface for the formation of new aggregates. Fibrils may also break (fragmentation) and thereby provide new ends for elongation. Thus, at least two - primary nucleation and elongation - and in many systems at least four - primary nucleation, elongation, secondary nucleation and fragmentation - microscopic processes occur during the lag phase. Moreover, these same processes occur during all three phases of the macroscopic aggregation process, albeit at different rates as governed by rate constants and by the concentration of reacting species at each point in time. PMID- 25719976 TI - Clinical assessment of speech correlates well with lung function during induced bronchoconstriction. AB - Clinical assessment of asthma often includes a crude assessment of speech, for example whether the patient can speak in full sentences. To date, this statement, despite appearing in national asthma guidelines, has not been related to lung function testing in asthma exacerbation. Seven asthmatics underwent a bronchial challenge and were then recorded reading a standardised text for 1 min. The recordings were played to 88 healthcare professionals who were asked to estimate FEV1% predicted. Health care professionals' estimations showed moderate correlation to FEV1% predicted (rho=0.61 P<0.01). There were no significant differences between professionals grouped by seniority or speciality. Speech can intuitively be estimated by health care professionals with moderate accuracy. This gives an evidence basis for the assessment in speech in acute asthma and may provide a new avenue for monitoring. PMID- 25719977 TI - Lipid profile and statin use: the paradox of survival after acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: A paradoxical association between cholesterol level and clinical outcome has been suggested, yet never previously established, in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: The authors sought to investigate the interaction between long-term survival, lipid profile and statin use in patients after acute exacerbation of COPD (AECOPD). METHODS: A retrospective study evaluating demographic, clinical and laboratory data of 615 consecutive patients admitted for AECOPD over a mean follow-up period of 24.8 months. Kaplan-Meier survival curves and multivariate analysis were used to identify independent prognostic predictors for all-cause mortality. RESULTS: Mean +/- standard deviation (SD) age of the study population was 71.8 +/- 11.4 years. Unexpectedly, mean serum cholesterol +/- SD levels were significantly higher in survivors (N = 340) versus nonsurvivors (N = 275): 181.5 +/- 43.6 versus 171.6 +/ 57.2 mg/dL, respectively, (P = 0.0043). Median survival for patients with cholesterol levels <150 and >200 mg/dL were 16.0 and 64.4 months, respectively (P = 0.0173). On multivariate analysis, cholesterol level <150 mg/dL was an independent predictor of mortality, irrespective of cardiovascular risk factors (hazard ratio [HR] = 1.8430, 95% confidence interval [CI] = 1.2547-2.7072, P = 0.0019). Statin use had an independent protective effect, regardless of cholesterol level (HR = 0.4924, 95% CI = 0.2924-0.8292, P = 0.0080). CONCLUSIONS: Low cholesterol levels are significantly associated with increased mortality after AECOPD. Nonetheless, as statin treatment was associated with reduced mortality over the entire range of cholesterol levels, its use should be considered in all COPD patients. PMID- 25719978 TI - Continuous Renal Replacement Therapy for Pheochromocytoma Crisis With Multiple Organ Failure. AB - Pheochromocytoma crisis is a feared and potentially lethal complication associated with excess release of catecholamine from the tumor, which might lead to multiple organ failure (MOF). The definitive treatment for pheochromocytoma is surgical resection. To safely proceed with surgery, hemodynamic stabilization in the acute phase is indispensable, but it might be extremely challenging in case of pheochromocytoma crisis with MOF even if the sufficient pharmacological drugs would be administered. Catecholamine is a dialyzable substance and is removed by renal replacement therapy. In this report, we described 2 cases of pheochromocytoma crisis with MOF, in which we succeeded in controlling acute unstable hemodynamics by means of catecholamine removal with continuous renal replacement therapy. These cases suggest that continuous renal replacement therapy may be effective to manage unstable hemodynamics because of massive catecholamine excretion in patients with pheochromocytoma crisis and MOF. PMID- 25719979 TI - Aberrant Hypermethylation at Sites -86 to 226 of DAB2 Gene in Non-Small Cell Lung Cancer. AB - BACKGROUND: Lung cancer is now the leading cause of malignant tumor-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Human Disabled-2 (DAB2) was reported to act as a tumor suppressor gene and was found downregulated in numerous cancer types. However, the expression of DAB2 in NSCLC and the mechanism of DAB2 expression regulation remain unclear. METHODS: DAB2 expression was analyzed by quantitative real-time polymerase chain reaction (PCR) and Western blot in 20 paired primary NSCLC tissues and corresponding normal lung tissues. Immunohistochemistry assay was performed in paired NSCLC tissues from another 20 patients. Methylation status of DAB2 promoter was analyzed using bisulfite sequencing polymerase chain reaction. RESULTS: DAB2 messenger RNA level was significantly lower in NSCLC tissues than normal tissues in 95.0% of the group of patients under investigation. In addition, NSCLC tissues showed a significant reduction in DAB2 protein when compared with normal tissues. Importantly, 85% of NSCLC tissues (17/20) had high methylation in DAB2 promoter when compared with normal tissues. CONCLUSIONS: DAB2 expression is decreased in NSCLC, and the frequent methylation event at sites -86 to 226 of the DAB2 gene could contribute to the downregulation of DAB2. PMID- 25719980 TI - Pathological Fracture Caused by Vascular Endothelial Cell Hemangioma-like Hyperplasia in POEMS Syndrome. PMID- 25719981 TI - Role of D-dimer Assays in the Diagnostic Evaluation of Pulmonary Embolism. AB - The diagnosis of pulmonary embolism (PE) remains challenging despite the evolution of well-validated clinical algorithms over the past few decades, largely because of nonspecific clinical features altering clinician suspicion. D dimer is a simple noninvasive test that is an essential part of the diagnostic algorithm but is often deemed to be of little value in patients who are elderly or have other comorbidities. We describe a case of an elderly man who presented with clinical features and initial imaging consistent with pneumonia and a positive D-dimer test. Adherence to the suggested diagnostic algorithm and obtaining chest imaging, however, prevented what could have been a catastrophic missed diagnosis of PE. We review existing evidence on the importance of suspecting PE in the presence of alternative diagnosis and explore the literature on the association between the magnitude of D-dimer and the diagnosis of PE. PMID- 25719983 TI - INNOVATIVE MULTIPLANAR RECONSTRUCTION AND VOLUME-RENDERED COMPUTED TOMOGRAPHY IN THE ASSESSMENT OF SCLERAL BUCKLE-RELATED COMPLICATIONS. AB - PURPOSE: To describe the role of multiplanar reconstruction and three-dimensional volume-rendered imaging in the assessment of silicon-based scleral buckle (SB) related complications. METHODS: Five eyes of five patients with SB-related complications where the history, surgical notes, and clinical examination proved inconclusive were included. Unenhanced axial orbital computed tomography images of all patients were acquired parallel to orbitomeatal line, and images were reviewed in orthogonal planes. The volume rendition of the imaged volume was evaluated in various tilts, with special reference to the spatial relationship of the band-buckle to the globe and bony orbit. All patients underwent imaging assisted SB removal. RESULTS: Imaging assisted in in vivo localization of the obscure band or buckle in all five eyes. Band was seen as hyperdense structure encircling whole of the globe, whereas buckle was seen as segmental, broad, hyperdense structure with scleral indentation. Presence of SB was identified in three patients, and globe integrity was shown in the other two. Abnormal anterior displacement of band and buckle was demonstrated in three cases on volume rendered imaging in relation to lateral orbital rim. Focal exuberant soft-tissue proliferation around the buckle was present in all patients, suggesting chronic inflammation and infection. Successful removal of band and buckle could be achieved, and all patients were relieved of their preoperative complaints. No complication occurred during intraoperative and postoperative period. CONCLUSION: Use of multiplanar reconstruction and three-dimensional volume-rendered computed tomography imaging played a pivotal role in surgical success. PMID- 25719984 TI - RELATIONSHIP BETWEEN VISUAL PROGNOSIS AND DELAY OF INTRAVITREAL INJECTION OF RANIBIZUMAB WHEN TREATING AGE-RELATED MACULAR DEGENERATION. AB - BACKGROUND: In age-related macular degeneration, various factors in clinical practice cause delays to arise between the time exudative change is observed and the time anti-vascular endothelial growth factor drugs are actually injected. We investigated the influence of injection delay on prognosis. METHODS: Subjects were 50 eyes (50 patients from 2 hospitals) that were administered ranibizumab monotherapy for age-related macular degeneration for 1 year since exudative change was first observed. We investigated the mean number of delay days for each injection. RESULTS: Mean injection delay was between 0 and 104 days. Significant prognostic factors for visual acuity were initial best-corrected visual acuity (P < 0.01) and mean injection delay (P = 0.03). We estimated that for an initial best-corrected visual acuity of 0.40 logMAR unit (20/50 Snellen equivalent), the respective best-corrected visual acuity values after 1 year for mean injection delays of 0, 7, 14, 28, and 56 days would be 0.22 (20/33), 0.24 (20/35), 0.26 (20/37), 0.31 (20/40), and 0.39 (20/49). For an initial best-corrected visual acuity of 0.097 (20/25), the respective values would be 0.054 (20/23), 0.075 (20/24), 0.10 (20/25), 0.14 (20/28), and 0.22 (20/33). CONCLUSION: Long-term visual acuity prognosis worsened when scheduling problems delayed intravitreal injection of anti-vascular endothelial growth factor drugs. PMID- 25719985 TI - SYMPATHETIC OPHTHALMIA: Clinicopathologic Correlation in a Consecutive Case Series. AB - PURPOSE: To correlate the clinical course of sympathetic ophthalmia with the histological and immunohistochemical characteristics of the enucleated inciting eye. METHODS: A consecutive case series with baseline clinical features and subsequent histopathologic findings. RESULTS: Evaluation of the 16 enucleated inciting eyes (blind and painful) disclosed that 9 of the 16 had typical histology, fulfilling the criteria for sympathetic ophthalmia of diffuse granulomatous inflammation. Among the 16, 11 sustained previous penetrating trauma, 4 underwent previous eye surgery, and 1 patient presented with an unknown etiology. Patients with atypical histology (7 of 7) were taking corticosteroids at the time of enucleation. Only 2 of 9 patients with typical histology were taking corticosteroids at the time of enucleation. At 6 months after enucleation of the inciting eye, 4 of the 7 patients with atypical histology had a visual acuity of >=20/40 compared with 8 of 8 patients (100%) with typical histology. On a 4-point scale (0-3+), the choroidal infiltrate of the 9 histopathologically typical eyes showed an average of 2.5+ CD68 (macrophages), 2.5+ CD20 (B cells), and 1.5+ CD3 (T cells). CONCLUSION: Histopathologic findings had minimal correlation with the clinical course of sympathetic ophthalmia. Corticosteroid treatment before enucleation may influence the pathologic confirmation of sympathetic ophthalmia. The predominance of B lymphocytes and macrophages over T lymphocytes may represent different stages of the disease process. PMID- 25719986 TI - THREE-YEAR RESULTS OF POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH PHOTODYNAMIC THERAPY: Retrospective Study and Systematic Review. AB - PURPOSE: To evaluate the 3-year outcome in eyes with polypoidal choroidal vasculopathy (PCV) treated with photodynamic therapy with verteporfin. METHODS: Retrospective study and review of the literature. We performed a retrospective study of patients with PCV who were treated with photodynamic therapy between January 2007 and December 2008. Patients were excluded if they had received photodynamic therapy before the study period, but those who received previous treatment with other modalities (thermal laser or intravitreal therapies) were allowed. The main outcome measures were best-corrected visual acuity, repeat photodynamic therapy, and recurrence of PCV at the end of Years 1, 2, and 3. We further conducted a systematic review of the literature using the terms "polypoidal choroidal vasculopathy" and "photodynamic therapy" and compared the visual outcome of studies over 3 years using meta-analytical methods. RESULTS: The retrospective study included 68 eyes. The mean best-corrected visual acuity was 0.73 +/- 0.56 logMAR (20/107, Snellen equivalent) at baseline, 0.73 +/- 0.70 logMAR (20/107, Snellen equivalent) at 1 year, 0.96 +/- 0.76 logMAR (20/182, Snellen equivalent) at 2 years, and 1.07 +/- 0.81 logMAR (20/235, Snellen equivalent) at 3 years. The cumulative recurrence rates of PCV were 16.1% (1 year), 34.9% (2 years), and 52.7% (3 years) and eyes with recurrence were more likely to suffer >=3 lines loss compared with eyes without recurrence (63.2 vs. 17.6%, P = 0.006). The systematic review summarized results from 48 published studies and our retrospective study. The pooled analysis from 29 studies (316 eyes reporting the 3-year visual outcome) reported mean best-corrected visual acuity improvement of 0.115 logMAR at 1 year (n = 1,669), 0.066 logMAR at 2 years (n = 701), and 0.027 logMAR at 3 years (n = 316). Reported recurrence rates were 5.9% to 50.0% after 1 year, 9.1% to 83.3% after 2 years, and 40.0% to 78.6% after 3 years or longer of follow-up. CONCLUSION: The visual outcome in eyes with PCV was stable until 2 years, but the outcome at 3 years worsened, particularly in eyes that experienced recurrence. PMID- 25719987 TI - PROSPECTIVE EVALUATION OF VISUAL ACUITY AGREEMENT BETWEEN STANDARD EARLY TREATMENT DIABETIC RETINOPATHY STUDY CHART AND A HANDHELD EQUIVALENT IN EYES WITH RETINAL PATHOLOGY. AB - PURPOSE: To evaluate the visual acuity agreement between a standard back illuminated Early Treatment Diabetic Retinopathy Study (ETDRS) chart and a handheld internally illuminated ETDRS chart. METHODS: Two-center prospective study. Seventy patients (134 eyes) with retinal pathology were enrolled between October 2012 and August 2013. Visual acuity was measured using both the ETDRS chart and the handheld device by masked independent examiners after best protocol refraction. Examination was performed in the same room under identical illumination and testing conditions. RESULTS: The mean number of letters seen was 63.0 (standard deviation: 19.8 letters) and 61.2 letters (standard deviation: 19.1 letters) for the ETDRS chart and handheld device, respectively. Mean difference per eye between the ETDRS and handheld device was 1.8 letters. A correlation coefficient (r) of 0.95 demonstrated a positive linear correlation between ETDRS chart and handheld device measured acuities. Intraclass correlation coefficient was performed to assess the reproducibility of the measurements made by different observers measuring the same quantity and was calculated to be 0.95 (95% confidence interval: 0.93-0.96). Agreement was independent of retinal disease. CONCLUSION: The strong correlation between measured visual acuity using the ETDRS and handheld equivalent suggests that they may be used interchangeably, with accurate measurements. Potential benefits of this device include convenience and portability, as well as the ability to assess ETDRS visual acuity without a dedicated testing lane. PMID- 25719988 TI - SUBTHRESHOLD MICROPULSE YELLOW LASER VERSUS SUBTHRESHOLD MICROPULSE INFRARED LASER IN CENTER-INVOLVING DIABETIC MACULAR EDEMA: Morphologic and Functional Safety. AB - BACKGROUND: To evaluate and compare in vivo retinal and choroidal morphologic changes and macular function in patients treated with yellow (Y-MPL) or infrared (IR-MPL) subthreshold micropulse laser in center-involving diabetic macular edema. METHODS: Prospective, randomized, single institution, comparative 6-month pilot study of 53 eyes (53 patients with diabetes). Inclusion criteria were previously untreated center-involving diabetic macular edema with central retinal thickness <=400 MUm (mild diabetic macular edema). Y-MPL or IR-MPL treatment was performed in a standardized pattern, using in both cases the lowest duty cycle (5%). Morphologic outcomes were the visibility of laser spots (on color fundus photographs [COL], fundus autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography), retinal thickness and volume changes, foveal choroidal thickness changes, and integrity and reflectivity of the outer retinal layers. Visual function outcomes were variation in mean 4 degrees and 12 degrees retinal sensitivity and best-corrected visual acuity. RESULTS: Twenty six eyes were treated with Y-MPL and 27 eyes with IR-MPL. No visible laser spots on the retina were found on COL, fundus autofluorescence, and fluorescein angiography in both treatment groups at 3 months and 6 months of follow-up. Central retinal thickness, macular volume, foveal choroidal thickness, and best corrected visual acuity were not significantly different at any follow-up visit between the two treatment groups. There were no changes in the integrity of the external limiting membrane or inner segment/outer segment junction in both treatment groups. Mean central 4 degrees retinal sensitivity increased in both treatment groups at 6 months (P = 0.01 and P = 0.04, respectively). Mean central 12 degrees retinal sensitivity increased in the Y-MPL group only (P = 0.047). But, there was no significant difference in mean 4 degrees and 12 degrees retinal sensitivity between the 2 treatment groups at any follow-up visit. CONCLUSION: No clinically visible or invisible scars in the macula were found after Y-MPL or IR-MPL treatment. Both Y-MPL and IR-MPL with the lowest duty cycle (5%) and fixed power parameters seem to be safe from the morphologic and visual function points of view in mild center-involving diabetic macular edema. PMID- 25719989 TI - ANALYSIS OF CHANGES IN CHARACTERISTICS OF SEVERE RETINOPATHY OF PREMATURITY PATIENTS AFTER SCREENING GUIDELINES WERE ISSUED IN CHINA. AB - PURPOSE: To describe the changes in the characteristics of infants treated for severe retinopathy of prematurity (ROP) in a tertiary referral unit in China after screening guidelines were issued in 2004 and to evaluate the effectiveness of the current criteria. METHODS: Information on consecutive infants referred to a single eye department for treatment of Stage 3 (Type 1 pretheshold and threshold disease), Stage 4, and Stage 5 ROP between January 2001 and May 2012 was retrieved from medical records. RESULTS: The mean gestational age was 29.98 +/- 2.13 weeks (range 26-34 weeks), and the mean birth weight was 1,414.32 +/- 343.18 g (range 742-2,087 g). The proportion of infants with Stage 4 and Stage 5 ROP decreased statistically significantly over time (P = 0.026 and P < 0.001, respectively) after screening guidelines for ROP were issued in 2004. The median postmenstrual age when patients first visited the study hospital was 48.32 weeks (range 30-602 weeks); later presentation was significantly associated with more advanced ROP (P < 0.001). In addition, the postmenstrual age of first presentation showed a significant decrease over time (P < 0.001) after the screening guidelines were issued. The current Chinese screening guidelines cover 99.63% of infants while 9.07% of infants exceeded the U.K. screening criteria and 35.77% of infants exceeded the U.S. criteria. CONCLUSION: After the government issued guidelines on ROP screening, the birth weight and gestational age of severe ROP patients remain similar. Big infants got severe ROP as before. But the awareness of ROP increased, the proportion of infants with retinal detachment caused by ROP decreased, and the infants received more timely treatment. The current ROP screening criteria are very effective. PMID- 25719990 TI - Improved efficacy of ocriplasmin for vitreomacular traction release and transient changes in optic disk morphology. AB - PURPOSE: To determine the efficacy and safety of ocriplasmin for vitreomacular traction (VMT) resolution and to study changes in optic disk and peripapillary region. METHODS: Retrospective, single-center, observational case series. In 38 eyes with VMT (10 with concomitant full-thickness macular hole), determined by optical coherence tomography, a single intravitreal injection of ocriplasmin was administered. Baseline ocular characteristics included the presence/absence of epiretinal membrane, lens status, and vitreomacular adhesion size. Spectral domain optical coherence tomography and Heidelberg retinal tomography were performed at baseline and follow-up visits. RESULTS: A total of 71.1% of eyes treated with ocriplasmin had VMT resolution, improving to 83.9% after applying MIVI-TRUST selection criteria. A total of 90% of eyes with full-thickness macular hole showed VMT resolution, with 40% of those achieving full-thickness macular hole closure. Subretinal fluid in the macular region was observed in 36.8% of eyes 1 day after injection, and all cleared spontaneously by Day 42. A significant difference was observed in cup/disk area ratio between patients who achieved VMT resolution and patients who did not. CONCLUSION: Careful patient selection improves ocriplasmin efficacy. Transient optic disk morphology changes such as decreased cup/disk area ratio may occur in patients without VMT resolution. PMID- 25719992 TI - Regioselective iodoazidation of alkynes: synthesis of alpha,alpha-diazidoketones. AB - Aryl alkyl alkynes reacted with N-iodosuccinimide (NIS) and trimethylsilyl azide (TMSN3), leading to alpha,alpha-diazidoketones via the regioselective addition of IN3 to alkynes. Huisgen cyclization of alpha,alpha-diazidoketones generated bis triazole compounds. PMID- 25719993 TI - [Individual and Contextual Reasons for Drop-outs in Vocational Retraining]. AB - BACKGROUND AND AIMS: The study focusses on the explanation of the individual, process-driven, and institutional factors and their interplay, and on the subjective accounts for the high drop-out rates in vocational retraining which are reported by the German statutory pension insurance scheme. METHODS: 454 participants of 2-year lasting vocational retraining schemes in 3 vocational promotion centers and 3 education providers took part in the questionnaire survey. Furthermore, experts, dropouts and participants were interviewed and group discussions with experts and participants were conducted. RESULTS: Drop-out is not a definite term. Instead, it consists of different dimensions. 3 personal factors for predicting a drop-out could be identified: suffering from depression, negative health assessment and lack of social support. Generally speaking, drop out of vocational retraining is a complex and mainly situational process which can hardly be predicted by personal factors, job-biographies or foregoing unemployment. PMID- 25719991 TI - Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. AB - IMPORTANCE: For the management of retinal disease, the use of intravitreous injections of anti-vascular endothelial growth factor has increased. Recent reports have suggested that this therapy may cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease. OBJECTIVE: To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS: An exploratory analysis was conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20, 2007, to December 17, 2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment. MAIN OUTCOMES AND MEASURES: The cumulative probability of sustained IOP elevation, defined as IOP of at least 22 mm Hg and an increase of at least 6 mm Hg from baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up. RESULTS: The mean (SD) baseline IOP in both treatment groups was 16 (3) mm Hg (range, 5-24 mm Hg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5% for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4% for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1% [99% CI, -0.2% to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P = .01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group. CONCLUSIONS AND RELEVANCE: In eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti-vascular endothelial growth factor for the treatment of diabetic macular edema. PMID- 25719994 TI - [Ways to psychosomatic rehabilitation--differential treatment selection between psychosomatic acute care and rehabilitation]. AB - Consecutive admissions to the psychosomatic departments of 5 hospital units in southwest Germany registered between October 2012 and October 2013 were asked to participate in a study investigating the treatment selection process for psychosomatic rehabilitation. 527 patients were included in the study, 269 outpatients and 258 inpatients at the end of their inpatient treatment. 52 patients (10.1%) received the recommendation for rehabilitation. 47 (90.4%) could be followed up 3 months later. 22 patients had applied for a rehabilitation treatment, 11 (50%) had obtained an approval for their rehabilitation, 5 had still no answer and for 6 patients the request was refused. 4 of the latter had objected their refusal and were still waiting for an answer. Only one patient was already admitted to a rehabilitation center. Possible reasons for the low permeability at the interface between hospital care and rehabilitation are discussed. PMID- 25719995 TI - ["Active in rehab": development and formative evaluation of a patient education program to increase health literacy of patients with chronic illness]. AB - OBJECTIVE: The aim of the article is to describe the development, the process of manualisation and results from the formative evaluation of a patient-oriented patient education program to increase health literacy of patients with chronic illness ("Active in rehab"). METHODS: Themes of the patient education program were extracted from 17 focus groups. An expert meeting was conducted to validate the content of the patient education program. The formative evaluation was based on a questionnaire (N(max) = 295 patients and N(max) = 39 trainers). RESULTS: The patient education program includes 4 modules with 3 themes (bio-psycho-social model, rehabilitation goals, communication competencies). The evaluation of the modules was good to very good. An analysis of free texts and a follow-up survey among trainers helped us to infer important improvements to the patient education program. CONCLUSION: RESULTS from the formative evaluation show that the patient education program meets patients and trainers needs and is accepted. PMID- 25719996 TI - Suvorexant (Belsomra) for insomnia. PMID- 25719997 TI - Ceftolozane/Tazobactam (Zerbaxa)--a new intravenous antibiotic. PMID- 25719998 TI - An inhaled insulin (Afrezza). PMID- 25719999 TI - Tavaborole topical solution (Kerydin) for onychomycosis. PMID- 25720000 TI - Stochastic modeling of mouse motor activity under deep brain stimulation: the extraction of arousal information. AB - In the present paper, we quantify, with a rigorous approach, the nature of motor activity in response to Deep Brain Stimulation (DBS), in the mouse. DBS is currently being used in the treatment of a broad range of diseases, but its underlying principles are still unclear. Because mouse movement involves rapidly repeated starting and stopping, one must statistically verify that the movement at a given stimulation time was not just coincidental, endogenously-driven movement. Moreover, the amount of activity changes significantly over the circadian rhythm, and hence the means, variances and autocorrelations are all time varying. A new methodology is presented. For example, to discern what is and what is not impacted by stimulation, velocity is classified (in a time-evolving manner) as being zero-, one- and two-dimensional movement. The most important conclusions of the paper are: (1) (DBS) stimulation is proven to be truly effective; (2) it is two-dimensional (2-D) movement that strongly differs between light and dark and responds to stimulation; and, (3) stimulation in the light initiates a manner of movement, 2-D movement, that is more commonly seen in the (non-stimulated) dark. Based upon these conclusions, it is conjectured that the above patterns of 2-D movement could be a straightforward, easy to calculate correlate of arousal. The above conclusions will aid in the systematic evaluation and understanding of how DBS in CNS arousal pathways leads to the activation of behavior. PMID- 25720001 TI - An enhanced fuzzy min-max neural network for pattern classification. AB - An enhanced fuzzy min-max (EFMM) network is proposed for pattern classification in this paper. The aim is to overcome a number of limitations of the original fuzzy min-max (FMM) network and improve its classification performance. The key contributions are three heuristic rules to enhance the learning algorithm of FMM. First, a new hyperbox expansion rule to eliminate the overlapping problem during the hyperbox expansion process is suggested. Second, the existing hyperbox overlap test rule is extended to discover other possible overlapping cases. Third, a new hyperbox contraction rule to resolve possible overlapping cases is provided. Efficacy of EFMM is evaluated using benchmark data sets and a real medical diagnosis task. The results are better than those from various FMM-based models, support vector machine-based, Bayesian-based, decision tree-based, fuzzy based, and neural-based classifiers. The empirical findings show that the newly introduced rules are able to realize EFMM as a useful model for undertaking pattern classification problems. PMID- 25720002 TI - Scaling up graph-based semisupervised learning via prototype vector machines. AB - When the amount of labeled data are limited, semisupervised learning can improve the learner's performance by also using the often easily available unlabeled data. In particular, a popular approach requires the learned function to be smooth on the underlying data manifold. By approximating this manifold as a weighted graph, such graph-based techniques can often achieve state-of-the-art performance. However, their high time and space complexities make them less attractive on large data sets. In this paper, we propose to scale up graph-based semisupervised learning using a set of sparse prototypes derived from the data. These prototypes serve as a small set of data representatives, which can be used to approximate the graph-based regularizer and to control model complexity. Consequently, both training and testing become much more efficient. Moreover, when the Gaussian kernel is used to define the graph affinity, a simple and principled method to select the prototypes can be obtained. Experiments on a number of real-world data sets demonstrate encouraging performance and scaling properties of the proposed approach. It also compares favorably with models learned via l1 -regularization at the same level of model sparsity. These results demonstrate the efficacy of the proposed approach in producing highly parsimonious and accurate models for semisupervised learning. PMID- 25720003 TI - Dimension selective self-organizing maps with time-varying structure for subspace and projected clustering. AB - Subspace clustering is the task of identifying clusters in subspaces of the input dimensions of a given dataset. Noisy data in certain attributes cause difficulties for traditional clustering algorithms, because the high discrepancies within them can make objects appear too different to be grouped in the same cluster. This requires methods specially designed for subspace clustering. This paper presents our second approach to subspace and projected clustering based on self-organizing maps (SOMs), which is a local adaptive receptive field dimension selective SOM. By introducing a time-variant topology, our method is an improvement in terms of clustering quality, computational cost, and parameterization. This enables the method to identify the correct number of clusters and their respective relevant dimensions, and thus it presents nearly perfect results in synthetic datasets and surpasses our previous method in most of the real-world datasets considered. PMID- 25720004 TI - Neural network-based finite horizon stochastic optimal control design for nonlinear networked control systems. AB - The stochastic optimal control of nonlinear networked control systems (NNCSs) using neuro-dynamic programming (NDP) over a finite time horizon is a challenging problem due to terminal constraints, system uncertainties, and unknown network imperfections, such as network-induced delays and packet losses. Since the traditional iteration or time-based infinite horizon NDP schemes are unsuitable for NNCS with terminal constraints, a novel time-based NDP scheme is developed to solve finite horizon optimal control of NNCS by mitigating the above-mentioned challenges. First, an online neural network (NN) identifier is introduced to approximate the control coefficient matrix that is subsequently utilized in conjunction with the critic and actor NNs to determine a time-based stochastic optimal control input over finite horizon in a forward-in-time and online manner. Eventually, Lyapunov theory is used to show that all closed-loop signals and NN weights are uniformly ultimately bounded with ultimate bounds being a function of initial conditions and final time. Moreover, the approximated control input converges close to optimal value within finite time. The simulation results are included to show the effectiveness of the proposed scheme. PMID- 25720005 TI - Neural network-based finite-horizon optimal control of uncertain affine nonlinear discrete-time systems. AB - In this paper, the finite-horizon optimal control design for nonlinear discrete time systems in affine form is presented. In contrast with the traditional approximate dynamic programming methodology, which requires at least partial knowledge of the system dynamics, in this paper, the complete system dynamics are relaxed utilizing a neural network (NN)-based identifier to learn the control coefficient matrix. The identifier is then used together with the actor-critic based scheme to learn the time-varying solution, referred to as the value function, of the Hamilton-Jacobi-Bellman (HJB) equation in an online and forward in-time manner. Since the solution of HJB is time-varying, NNs with constant weights and time-varying activation functions are considered. To properly satisfy the terminal constraint, an additional error term is incorporated in the novel update law such that the terminal constraint error is also minimized over time. Policy and/or value iterations are not needed and the NN weights are updated once a sampling instant. The uniform ultimate boundedness of the closed-loop system is verified by standard Lyapunov stability theory under nonautonomous analysis. Numerical examples are provided to illustrate the effectiveness of the proposed method. PMID- 25720006 TI - Maintaining the integrity of sources in complex learning systems: intraference and the correlation preserving transform. AB - The correlation preserving transform (CPT) is introduced to perform bivariate component analysis via decorrelating matrix decompositions, while at the same time preserving the integrity of original bivariate sources. Specifically, unlike existing bivariate uncorrelating matrix decomposition techniques, CPT is designed to preserve both the order of the data channels within every bivariate source and their mutual correlation properties. We introduce the notion of intraference to quantify the effects of interchannel mixing artifacts within recovered bivariate sources, and show that the integrity of separated sources is compromised when not accounting for the intrinsic correlations within bivariate sources, as is the case with current bivariate matrix decompositions. The CPT is based on augmented complex statistics and involves finding the correct conjugate eigenvectors associated with the pseudocovariance matrix, making it possible to maintain the physical meaning of the separated sources. The benefits of CPT are illustrated in the source separation and clustering scenarios, for both synthetic and real-world data. PMID- 25720007 TI - Exponential synchronization of complex networks of linear systems and nonlinear oscillators: a unified analysis. AB - A unified approach to the analysis of synchronization for complex dynamical networks, i.e., networks of partial-state coupled linear systems and networks of full-state coupled nonlinear oscillators, is introduced. It is shown that the developed analysis can be used to describe the difference between the state of each node and the weighted sum of the states of those nodes playing the role of leaders in the networks, thus making it feasible to consider the error dynamics for the whole network system. Different from the other various methods given in the existing literature, the analysis employed in this paper is demonstrated successfully in not only providing the consistent convergence analysis with much simpler form, but also explicitly specifying the convergence rate. PMID- 25720008 TI - Spatio-temporal learning with the online finite and infinite echo-state Gaussian processes. AB - Successful biological systems adapt to change. In this paper, we are principally concerned with adaptive systems that operate in environments where data arrives sequentially and is multivariate in nature, for example, sensory streams in robotic systems. We contribute two reservoir inspired methods: 1) the online echostate Gaussian process (OESGP) and 2) its infinite variant, the online infinite echostate Gaussian process (OIESGP) Both algorithms are iterative fixed budget methods that learn from noisy time series. In particular, the OESGP combines the echo-state network with Bayesian online learning for Gaussian processes. Extending this to infinite reservoirs yields the OIESGP, which uses a novel recursive kernel with automatic relevance determination that enables spatial and temporal feature weighting. When fused with stochastic natural gradient descent, the kernel hyperparameters are iteratively adapted to better model the target system. Furthermore, insights into the underlying system can be gleamed from inspection of the resulting hyperparameters. Experiments on noisy benchmark problems (one-step prediction and system identification) demonstrate that our methods yield high accuracies relative to state-of-the-art methods, and standard kernels with sliding windows, particularly on problems with irrelevant dimensions. In addition, we describe two case studies in robotic learning-by demonstration involving the Nao humanoid robot and the Assistive Robot Transport for Youngsters (ARTY) smart wheelchair. PMID- 25720009 TI - Bayesian nonparametric adaptive control using Gaussian processes. AB - Most current model reference adaptive control (MRAC) methods rely on parametric adaptive elements, in which the number of parameters of the adaptive element are fixed a priori, often through expert judgment. An example of such an adaptive element is radial basis function networks (RBFNs), with RBF centers preallocated based on the expected operating domain. If the system operates outside of the expected operating domain, this adaptive element can become noneffective in capturing and canceling the uncertainty, thus rendering the adaptive controller only semiglobal in nature. This paper investigates a Gaussian process-based Bayesian MRAC architecture (GP-MRAC), which leverages the power and flexibility of GP Bayesian nonparametric models of uncertainty. The GP-MRAC does not require the centers to be preallocated, can inherently handle measurement noise, and enables MRAC to handle a broader set of uncertainties, including those that are defined as distributions over functions. We use stochastic stability arguments to show that GP-MRAC guarantees good closed-loop performance with no prior domain knowledge of the uncertainty. Online implementable GP inference methods are compared in numerical simulations against RBFN-MRAC with preallocated centers and are shown to provide better tracking and improved long-term learning. PMID- 25720010 TI - Generalization performance of radial basis function networks. AB - This paper studies the generalization performance of radial basis function (RBF) networks using local Rademacher complexities. We propose a general result on controlling local Rademacher complexities with the L1 -metric capacity. We then apply this result to estimate the RBF networks' complexities, based on which a novel estimation error bound is obtained. An effective approximation error bound is also derived by carefully investigating the Holder continuity of the lp loss function's derivative. Furthermore, it is demonstrated that the RBF network minimizing an appropriately constructed structural risk admits a significantly better learning rate when compared with the existing results. An empirical study is also performed to justify the application of our structural risk in model selection. PMID- 25720011 TI - Novelty detection using level set methods. AB - This paper presents a level set boundary description (LSBD) approach for novelty detection that treats the nonlinear boundary directly in the input space. The proposed approach consists of level set function (LSF) construction, boundary evolution, and termination of the training process. It employs kernel density estimation to construct the LSF of the initial boundary for the training data set. Then, a sign of the LSF-based algorithm is proposed to evolve the boundary and make it fit more tightly in the data distribution. The training process terminates when an expected fraction of rejected normal data is reached. The evolution process utilizes the signs of the LSF values at all training data points to decide whether to expand or shrink the boundary. Extensive experiments are conducted on benchmark data sets to evaluate the proposed LSBD method and compare it against four representative novelty detection methods. The experimental results demonstrate that the novelty detector modeled with the proposed LSBD can effectively detect anomalies. PMID- 25720012 TI - A simplified adaptive neural network prescribed performance controller for uncertain MIMO feedback linearizable systems. AB - In this paper, the problem of deriving a continuous, state-feedback controller for a class of multiinput multioutput feedback linearizable systems is considered with special emphasis on controller simplification and reduction of the overall design complexity with respect to the current state of the art. The proposed scheme achieves prescribed bounds on the transient and steady-state performance of the output tracking errors despite the uncertainty in system nonlinearities. Contrary to the current state of the art, however, only a single neural network is utilized to approximate a scalar function that partly incorporates the system nonlinearities. Furthermore, the loss of model controllability problem, typically introduced owing to approximation model singularities, is avoided without attaching additional complexity to the control or adaptive law. Simulations are performed to verify and clarify the theoretical findings. PMID- 25720013 TI - Convergence analysis of the FOCUSS algorithm. AB - Focal Underdetermined System Solver (FOCUSS) is a powerful and easy to implement tool for basis selection and inverse problems. One of the fundamental problems regarding this method is its convergence, which remains unsolved until now. We investigate the convergence of the FOCUSS algorithm in this paper. We first give a rigorous derivation for the FOCUSS algorithm by exploiting the auxiliary function. Following this, we further prove its convergence by stability analysis. PMID- 25720014 TI - Neural network-based adaptive dynamic surface control for permanent magnet synchronous motors. AB - This brief considers the problem of neural networks (NNs)-based adaptive dynamic surface control (DSC) for permanent magnet synchronous motors (PMSMs) with parameter uncertainties and load torque disturbance. First, NNs are used to approximate the unknown and nonlinear functions of PMSM drive system and a novel adaptive DSC is constructed to avoid the explosion of complexity in the backstepping design. Next, under the proposed adaptive neural DSC, the number of adaptive parameters required is reduced to only one, and the designed neural controllers structure is much simpler than some existing results in literature, which can guarantee that the tracking error converges to a small neighborhood of the origin. Then, simulations are given to illustrate the effectiveness and potential of the new design technique. PMID- 25720015 TI - A unified approach to universal prediction: generalized upper and lower bounds. AB - We study sequential prediction of real-valued, arbitrary, and unknown sequences under the squared error loss as well as the best parametric predictor out of a large, continuous class of predictors. Inspired by recent results from computational learning theory, we refrain from any statistical assumptions and define the performance with respect to the class of general parametric predictors. In particular, we present generic lower and upper bounds on this relative performance by transforming the prediction task into a parameter learning problem. We first introduce the lower bounds on this relative performance in the mixture of experts framework, where we show that for any sequential algorithm, there always exists a sequence for which the performance of the sequential algorithm is lower bounded by zero. We then introduce a sequential learning algorithm to predict such arbitrary and unknown sequences, and calculate upper bounds on its total squared prediction error for every bounded sequence. We further show that in some scenarios, we achieve matching lower and upper bounds, demonstrating that our algorithms are optimal in a strong minimax sense such that their performances cannot be improved further. As an interesting result, we also prove that for the worst case scenario, the performance of randomized output algorithms can be achieved by sequential algorithms so that randomized output algorithms do not improve the performance. PMID- 25720017 TI - Low-Dimensional Non-Rigid Image Registration Using Statistical Deformation Models From Semi-Supervised Training Data. AB - Accurate and robust image registration is a fundamental task in medical image analysis applications, and requires non-rigid transformations with a large number of degrees of freedom. Statistical deformation models (SDMs) attempt to learn the distribution of non-rigid deformations, and can be used both to reduce the transformation dimensionality and to constrain the registration process. However, high-dimensional SDMs are difficult to train given orders of magnitude fewer training samples. In this paper, we utilize both a small set of annotated imaging data and a large set of unlabeled data to effectively learn an SDM of non-rigid transformations in a semi-supervised training (SST) framework. We demonstrate results applying this framework towards inter-subject registration of skull stripped, magnetic resonance (MR) brain images. Our approach makes use of 39 labeled MR datasets to create a set of supervised registrations, which we augment with a set of over 1200 unsupervised registrations using unlabeled MRIs. Through leave-one-out cross validation, we show that SST of a non-rigid SDM results in a robust registration algorithm with significantly improved accuracy compared to standard, intensity-based registration, and does so with a 99% reduction in transformation dimensionality. PMID- 25720016 TI - Ultrasound-Based Characterization of Prostate Cancer Using Joint Independent Component Analysis. AB - OBJECTIVE: This paper presents the results of a new approach for selection of RF time series features based on joint independent component analysis for in vivo characterization of prostate cancer. METHODS: We project three sets of RF time series features extracted from the spectrum, fractal dimension, and the wavelet transform of the ultrasound RF data on a space spanned by five joint independent components. Then, we demonstrate that the obtained mixing coefficients from a group of patients can be used to train a classifier, which can be applied to characterize cancerous regions of a test patient. RESULTS: In a leave-one-patient out cross validation, an area under receiver operating characteristic curve of 0.93 and classification accuracy of 84% are achieved. CONCLUSION: Ultrasound RF time series can be used to accurately characterize prostate cancer, in vivo without the need for exhaustive search in the feature space. SIGNIFICANCE: We use joint independent component analysis for systematic fusion of multiple sets of RF time series features, within a machine learning framework, to characterize PCa in an in vivo study. PMID- 25720018 TI - Design and Characterization of a Fabric-Based Softness Display. AB - To enable a realistic tactile interaction with remote or virtual objects, softness information represents a fundamental property to be rendered via haptic devices. What is challenging is to reduce the complexity of such an information as it arises from contact mechanics and to find suitable simplifications that can lead an effective development of softness displays. A possible approach is to surrogate detailed tactile cues with information on the rate of spread of the contact area between the object and the finger as the contact force increases, i.e. force/area relation. This paradigm is called contact area spread rate. In this paper we discuss how such a paradigm has inspired the design of a tactile device (hereinafter referred to as Fabric Yielding Display, FYD-2), which exploits the elasticity of a fabric to mimic different levels of stiffness, while the contact area on the finger indenting the fabric is measured. In this manner, the FYD-2 can be controlled to reproduce force-area characteristics. In this work, we describe the FYD-2 architecture and report a psychophysical characterization. FYD-2 is shown to be able to accurately reproduce force-area curves of typical objects and to enable a reliable softness discrimination in human users. PMID- 25720019 TI - Kinesthetic Force Feedback and Belt Control for the Treadport Locomotion Interface. AB - This paper describes an improved control system for the Treadport immersive locomotion interface, with results that generalize to any treadmill that utilizes an actuated tether to enable self-selected walking speed. A new belt controller is implemented to regulate the user's position; when combined with the user's own volition, this controller also enables the user to naturally self-select their walking speed as they would when walking over ground. A new kinesthetic-force feedback controller is designed for the tether that applies forces to the user's torso. This new controller is derived based on maintaining the user's sense of balance during belt acceleration, rather than by rendering an inertial force as was done in our prior work. Based on the results of a human-subjects study, the improvements in both controllers significantly contribute to an improved perception of realistic walking on the Treadport. The improved control system uses intuitive dynamic-system and anatomical parameters and requires no ad hoc gain tuning. The control system simply requires three measurements to be made for a given user: the user's mass, the user's height, and the height of the tether attachment point on the user's torso. PMID- 25720020 TI - FLS-Based Adaptive Synchronization Control of Complex Dynamical Networks With Nonlinear Couplings and State-Dependent Uncertainties. AB - This paper is concerned with the problem of synchronization control of complex dynamical networks (CDN) subject to nonlinear couplings and uncertainties. An fuzzy logical system-based adaptive distributed controller is designed to achieve the synchronization. The asymptotic convergence of synchronization errors is analyzed by combining algebraic graph theory and Lyapunov theory. In contrast to the existing results, the proposed synchronization control method is applicable for the CDN with system uncertainties and unknown topology. Especially, the considered uncertainties are allowed to occur in the node local dynamics as well as in the interconnections of different nodes. In addition, it is shown that a unified controller design framework is derived for the CDN with or without coupling delays. Finally, simulations on a Chua's circuit network are provided to validate the effectiveness of the theoretical results. PMID- 25720021 TI - Iceland: health system review. AB - This analysis of the Icelandic health system reviews the developments in its organization and governance, health financing, health care provision, health reforms and health system performance. Life expectancy at birth is high and Icelandic men and women enjoy longer life in good health than the average European. However, Icelanders are putting on weight, more than half of adult Icelanders were overweight or obese in 2004, and total consumption of alcohol has increased considerably since 1970. The health care system is a small, state centred, publicly funded system with universal coverage, and an integrated purchaser provider relationship in which the state as payer is also the owner of most organizations providing health care services. The country's centre of clinical excellence is the University Hospital, Landspitali, in the capital Reykjavik, which alone accounts for 70 percent of the total national budget for general hospital services. However, since 1990, the health system has become increasingly characterized by a mixed economy of care and service provision, in which the number and scope of private non profit and private for profit providers has increased. While Iceland's health outcomes are some of the best among OECD countries, the health care system faces challenges involving the financial sustainability of the current system in the context of an ageing population, new public health challenges, such as obesity, and the continued impact of the country's financial collapse in 2008. The most important challenge is to change the pattern of health care utilization to steer it away from the most expensive end of the health services spectrum towards more cost efficient and effective alternatives. To a large degree, this will involve renewed attempts to prioritize primary care as the first port of call for patients, and possibly to introduce a gatekeeping function for GPs in order to moderate the use of specialist services. PMID- 25720022 TI - Vacuoles protect plants from high magnesium stress. PMID- 25720023 TI - Mycotoxicoses in children. AB - Mycotoxicoses are acute and chronic poisonings caused by mould toxins called mycotoxins. Although acute mycotoxicoses, caused by high mycotoxin levels in food are rare nowadays, they need to be described in order to inform physicians and other health care workers about their symptoms. Children are more sensitive to mycotoxins because of their lower body mass, higher metabolic rate, and underdeveloped organ functions and detoxication mechanisms. Some mycotoxicoses appear only in children, and some are more pronounced in children than in adults. Acute mycotoxicoses in children are reported poorly, mostly because they occur in the tropical regions with poor healthcare coverage. In developed countries healthcare authorities are more concerned about child exposure to low levels of mycotoxins with immunotoxic, genotoxic or carcinogenic properties. PMID- 25720024 TI - Alkaline disinfection of urban wastewater and landfill leachate by wood fly ash. AB - Wood fly ash is an industrial by-product of the combustion of different wood materials and is mostly disposed of as waste on landfills. In our preliminary experiments, wood ash exhibited antibacterial activity against urban wastewater bacteria and we focused on wood fly ash as a potential substrate for wastewater disinfection. The addition of ash at a concentration of 10 g L-1 (1%) caused an instant increase of pH in urban wastewater and landfill leachate. High pH (10.1 12.7) inactivated bacterial populations in the wastewater and the removal of faecal coliforms and intestinal enterococci after 6 h of contact was 100% (below the detection limit; <1 CFU per mL) with the most efficient ash sample (ash from combustion of beech) both in urban wastewater and landfill leachate. Properly chosen wood fly ash, i.e. one that tends to increase the pH to the greatest extent, proved to be a very effective disinfection substrate. Considering that water treated with wood ash has a high pH and needs to be neutralised before discharge, ash would be suitable for disinfection of leachates when smaller volumes are treated. PMID- 25720025 TI - In vivo changes in carbonic anhydrase activity and histopathology of gill and liver tissues after acute exposure to chlorpyrifos in rainbow trout. AB - Chlorpyrifos is an organophosphate pesticide widely used in agriculture and aquaculture. This study investigated its effects on carbonic anhydrase (CA) enzyme activity and histopathology of rainbow trout gill and liver. The fish were exposed to 2.25 (25% of 96 h LC50), 4.5 (50% of 96 h LC50), and 6.75 MUg L-1 (75% of 96 h LC50) of chlorpyrifos for 24, 48, 72, and 96 h. CA activity was measured in liver and gills and histopathological changes were examined by light microscopy. The most common liver changes at most of the chlorpyrifos concentrations were hyperaemia and degenerative changes. Gill tissues were characterised by lamellar hyperaemia, lamellar oedemas, clumping, cellular degeneration, hyperplasia, and lamellar atrophy. CA enzyme activity in the gills decreased at all concentrations at 48, 72, and 96 h after exposure to chlorpyrifos (p<0.05). Similarly, there was a time-dependent decrease in CA activity at all of the concentrations in liver tissues (p<0.05). The present study indicated that chlorpyrifos inhibits CA enzyme activity and causes histopathological damage in gill and liver tissues. PMID- 25720026 TI - Sex-, tissue-, and exposure duration-dependent effects of imidacloprid modulated by piperonyl butoxide and menadione in rats. Part I: oxidative and neurotoxic potentials. AB - Earlier research has evidenced the oxidative and neurotoxic potential of imidacloprid, a neonicotinoid insecticide, in different animal species. The primary aim of this study was to determine how metabolic modulators piperonyl butoxide and menadione affect imidacloprid's adverse action in the liver and kidney of Sprague-Dawley rats of both sexes. The animals were exposed to imidacloprid alone (170 mg kg-1) or in combination with piperonyl butoxide (100 mg kg-1) or menadione (25 mg kg-1) for 12 and 24 h. Their liver and kidney homogenates were analysed spectrophotometrically for glutathione peroxidase, glutathione S-transferase, catalase, total cholinesterase specific activities, total glutathione, total protein content, and lipid peroxidation levels. Imidacloprid displayed its prooxidative and neurotoxic effects predominantly in the kidney of male rats after 24 h of exposure. Our findings suggest that the observed differences in prooxidative and neurotoxic potential of imidacloprid could be related to differences in its metabolism between the sexes. Co-exposure (90-min pre-treatment) with piperonyl butoxide or menadione revealed tissue specific effect of imidacloprid on total cholinesterase activity. Increased cholinesterase activity in the kidney could be an adaptive response to imidacloprid-induced oxidative stress. In the male rat liver, co-exposure with piperonyl butoxide or menadione exacerbated imidacloprid toxicity. In female rats, imidacloprid+menadione co-exposure caused prooxidative effects, while no such effects were observed with imidacloprid alone or menadione alone. In conclusion, sex-, tissue-, and duration-specific effects of imidacloprid are remarkable points in its toxicity. PMID- 25720027 TI - Antihaemolytic activity of thirty herbal extracts in mouse red blood cells. AB - Reactive oxygen species (ROS) can lead to haemolysis and eventually to diseases such as thalassemia and sickle cell anaemia. Their action can be counteracted by the antihaemolytic activity of therapeutic agents. The aim of our study was to identify plants that most efficiently counteract ROS-caused haemolysis. From ten plants known for their antioxidant activity (Orobanche orientalis G. Beck, Cucumis melo L., Albizzia julibrissin Durazz, Galium verum L., Scutellaria tournefortii Benth, Crocus caspius Fischer & Meyer, Sambucus ebulus L., Danae racemosa L., Rubus fruticsos L., and Artemisia absinthium L.) we prepared 30 extracts using three extraction methods (percolation, Soxhlet, and ultrasound assisted extraction) to see whether the extraction method affects antihaemolytic efficiency, and one extraction method (polyphenol extraction) to see how much of this action is phenol-related. Extract antihaemolytic activity was determined in mice red blood cells and compared to that of vitamin C as a known antioxidant. Nine of our extracts were more potent than vitamin C, of which G. verum (aerial parts/percolation) and S. tournefortii (aerial parts/polyphenol) extracts were the most potent, with an IC50 of 1.32 and 2.08 MUg mL-1, respectively. Haemolysis inhibition depended on extract concentration and the method of extraction. These plants could provide accessible sources of natural antioxidants to the pharmaceutical industry. PMID- 25720028 TI - Half-century archives of occupational medical data on French nuclear workers: a dusty warehouse or gold mine for epidemiological research? AB - This article discusses the availability and completeness of medical data on workers from the AREVA NC Pierrelatte nuclear plant and their possible use in epidemiological research on cardiovascular and metabolic disorders related to internal exposure to uranium. We created a computer database from files on 394 eligible workers included in an ongoing nested case-control study from a larger cohort of 2897 French nuclear workers. For each worker, we collected records of previous employment, job positions, job descriptions, medical visits, and blood test results from medical history. The dataset counts 9,471 medical examinations and 12,735 blood test results. For almost all of the parameters relevant for research on cardiovascular risk, data completeness and availability is over 90%, but it varies with time and improves in the latest time period. In the absence of biobanks, collecting and computerising available good-quality occupational medicine archive data constitutes a valuable alternative for epidemiological and aetiological research in occupational health. Biobanks rarely contain biological samples over an entire worker's carrier and medical data from nuclear industry archives might make up for unavailable biomarkers that could provide information on cardiovascular and metabolic diseases. PMID- 25720029 TI - Pericardial effusion as the first manifestation of occupational tuberculosis in a health care worker. AB - Tuberculosis (TB) is an infectious disease and, apart from protecting patients, attention must be given to protecting the persons who come in contact with them, especially nurses and medical practitioners. A 43-year-old immunocompetent male nurse developed occupationally disseminated TB after contact with patients affected by active TB (culture positive) while working in a psychiatric hospital. The first manifestation of the disease was exudative pericarditis with Mycobacterium tuberculosis (MT) confirmed two months after pericardiocentesis and evacuation of 1200 mL of pericardial effusion. Many lymph nodes showed histologic findings of granulomatous inflammation with necrosis. Treatment with antituberculosis drugs caused complications, including transient short-term medication-induced toxic hepatitis, prolonged fever, left pleural nonspecific effusion, and mononeuritis of the right peroneus nerve. The treatment lasted 14 months and led to permanent consequences, including fibrothorax with restrictive ventilation disorders and reduced diffusion of the alveolar-capillary membrane. This case highlights the need to improve the protection of health care workers who are in contact with TB patients, as well as the usefulness of the tuberculin skin test and QuantiFERON-TB test, which can be used to identify early latent TB. PMID- 25720030 TI - A survey of professional satisfaction among anaesthesiologists in Serbia. PMID- 25720031 TI - Volume of confidence ellipsoid: a technique for quantifying trunk sway during stance. AB - The position of the trunk can be negatively affected by many diseases. This work focuses on a noninvasive method of quantifying human postural stability and identifying defects in balance and coordination as a result of the nervous system pathology. We used a three-degree-of-freedom orientation tracker (Xsens MTx unit) placed on a patient's trunk and measured three-dimensional (3-D) data (pitch, roll, and yaw) during quiet stance. The principal component analysis was used to analyze the data and to determine the volume of 3-D 95% confidence ellipsoid. Using this method, we were able to model the distribution of the measured 3-D data (pitch, roll, and yaw). Eight patients with degenerative cerebellar disease and eight healthy subjects in this study were measured during stance, with eyes open and eyes closed, and statistical analysis was performed. The results of the new method based on the 3-D confidence ellipsoid show that the volumes related to the patients are significantly larger than the volumes related to the healthy subjects. The concept of confidence ellipsoid volume, although known to the biomechanics community, has not been used before to study the postural balance problems. The method can also be used to study, for example, head and pelvis movements or alignments during stance. PMID- 25720032 TI - The Intra-Cochlear Impedance-Matrix (IIM) test for the Nucleus(r) cochlear implant. AB - OBJECTIVE: To describe the principles and operation of a new telemetry-based function test for the Nucleus(r) cochlear implant, known as the CS19 Intra Cochlear Impedance Matrix (IIM) and to present results from a multicentre clinical study to establish reproducibility (test-retest reliability) and normative ranges. METHOD: The IIM test measures bipolar impedances between all electrode pairs and employs a normalization procedure based on common ground impedances in order to identify abnormal current paths among electrodes. Six European clinics collected IIM data from a total of 192 devices. RESULTS: Reproducibility was high between initial and repeat measurements. The normative analysis demonstrated narrow ranges among devices after normalization of impedance data. The IIM is able to identify abnormal current paths that are not evident from standard impedance telemetry and may otherwise only be found utilising average electrode voltage measurements (AEV). CONCLUSIONS: The IIM test was found to be straightforward to perform clinically and demonstrated reproducible data with narrow ranges in normally-functioning devices. Because this test uses a very low stimulation level the IIM test is well suited for children or multiply handicapped CI users who cannot reliably report on their auditory percepts. The new algorithms show potential to improve implant integrity testing capabilities if implemented in future clinical software. PMID- 25720033 TI - Numerical evaluation of blood viscosity affecting pulse wave propagation in a fluid-structure interaction model. AB - High blood viscosity often causes cardiovascular diseases, such as hypertension, atherosclerosis and thrombosis. It is proven that blood viscosity plays an important role in cardiovascular functions. In this paper, pulse wave characteristics with normal and high blood viscosities are presented in detail to evaluate how blood viscosity affects pulse wave propagation. A fluid-structure interaction is employed to solve for pulse wave characteristics. The results show that increased blood viscosity does not change the time delay of wave propagation. However, high viscosity reduces the velocity amplitude, while it enhances the pressure level. This study provides physical insight for evaluating blood viscosity leading potentially to pulse wave changes. PMID- 25720034 TI - Comparative analysis of breast cancer detection in mammograms and thermograms. AB - In this paper, we present a system based on feature extraction techniques for detecting abnormal patterns in digital mammograms and thermograms. A comparative study of texture-analysis methods is performed for three image groups: mammograms from the Mammographic Image Analysis Society mammographic database; digital mammograms from the local database; and thermography images of the breast. Also, we present a procedure for the automatic separation of the breast region from the mammograms. Computed features based on gray-level co-occurrence matrices are used to evaluate the effectiveness of textural information possessed by mass regions. A total of 20 texture features are extracted from the region of interest. The ability of feature set in differentiating abnormal from normal tissue is investigated using a support vector machine classifier, Naive Bayes classifier and K-Nearest Neighbor classifier. To evaluate the classification performance, five-fold cross-validation method and receiver operating characteristic analysis was performed. PMID- 25720035 TI - Evaluation of the adequacy of reference charts for the accurate identification of fetuses with bone length below the 5th percentile. AB - AIM: To identify reference charts for femoral and humeral lengths enabling appropriate identification of fetuses <5th percentile in one population. METHODS: Two samples of fetuses aged 14-40 weeks were selected from our institution's ultrasonographic database. Regression analysis was used to construct reference charts of femoral and humeral lengths based on the local population (n=901). Femur and humerus length measurements from a second sample (n=1240) were transformed into Z-scores using local and previously published equations. Z-score distributions were used to assess the appropriateness of reference curves for our population. Fetuses aged 18-24 weeks with measurements <5th percentile were identified using each reference equation. RESULTS: For femoral length, one equation other than the local equation yielded Z-score values within the standard normal distribution (P=0.10), but the histogram was skewed to the right. All Z score distributions for humeral length fell within the normal distribution (P>0.05), but one was skewed to the right. The numbers of fetuses with femoral and humeral lengths <5th percentile in second-trimester ultrasound examinations varied widely among reference equations used. CONCLUSION: Most reference charts assessed underestimated the number of fetuses with long bone lengths <5th percentile in second-trimester ultrasound examinations and were thus unfit for interpretations of biometric data from the study population. PMID- 25720036 TI - Experiences of 6 years quality assurance in obstetrics in Nigeria - a critical review of results and obstacles. AB - OBJECTIVE: The objective of this study was to monitor the maternal mortality ratio (MMR) in 19 general hospitals after introducing quality assurance in four states in Nigeria. METHODS: Data collection with a structured maternity record book started in 2008 in ten rural hospitals in Kano and Kaduna State. In 2011, five hospitals from Federal Capital Territory Abuja were added, whilst in 2013 four hospitals were added from Ondo State. The routine data collection was conducted by experienced midwives and supervised by obstetricians from each of the states. However, the data from all four states were collated centrally at Aminu Kano Teaching Hospital for analysis. RESULTS: From 2008 to 2013, 121,808 deliveries were evaluated; MMR fell from 1380 to 360/100,000 in Kaduna State, whilst for Kano State there was a gradual reduction of MMR from 2100/100,000 in 2008 to 1070/100,000 in 2011, and then it increased to 2150/100,000 in 2013. Ondo state had the lowest MMR of 180/100,000 in 2013 followed by Abuja with 240/100,000. The median cesarean section rate was 8.19%, (range 0.97-22.53%), eclampsia/preeclampsia was 4.43% (range 0-56.55%), and postpartum hemorrhage was 3.36% (range 0.81-11.4%). CONCLUSIONS: Quality assurance in rural hospitals generates the awareness necessary to improve maternal health and lead to reduction of MMR. PMID- 25720037 TI - Single center experience in selective feticide in high-order multiple pregnancy: clinical and ethical issues. AB - OBJECTIVE: This paper describes the 20-year experience with selective feticide (SF) of high-order multiple quadruplet and higher pregnancies in a single center. METHODS: The paper describes protocols, procedures, management, outcomes, and ethical issues. RESULTS: SF was performed in 49 pregnancies with 244 fetuses, with median gestational age of 12+2 weeks. The initial number was nine (one case), eight (one case), seven (three cases), six (11 cases), five (eight cases), and four (27 cases). Nuchal translucency was utilized prior to the procedure starting in 1996. The technique was transabdominal ultrasound-guided and intrathoracic injection of potassium chloride. One pregnancy (with seven fetuses) was reduced to three, 42 to two, and four (starting with four fetuses) to singletons. There were ten pregnancy losses (20.4%). A decreasing trend in losses was evident over the 20-year time period: 7/23 (30.4%) from 1994 to 2004 down to 3/26 (11.5%) for 2004-2014. No chromosomal abnormalities were present in any of the survivors. The ethical issues focus on the justification of SF in high-order multifetal pregnancies. CONCLUSION: In this series, pregnancy loss decreased with operator experience. Excellent outcomes can be achieved with the ethically justified use of feticide in high-order multiple pregnancies. PMID- 25720038 TI - Cervical sonoelastography for improving prediction of preterm birth compared with cervical length measurement and fetal fibronectin test. AB - AIM: Accurate prediction of the risk of spontaneous preterm birth is crucial for the clinical management of patients with preterm labor. The aim of the study was to investigate whether cervical sonoelastography improves prediction of spontaneous preterm birth compared with cervical length measurement and a fetal fibronectin (fFN) test. METHODS: A prospective cohort study was conducted including 64 patients with preterm labor at 23-34 weeks of gestation. Patients had an fFN test and transvaginal cervical length measurement, followed by real time cervical sonoelastography. The ratio of nondeformable tissue to the total area of a designed region of interest was analyzed and related to the gestational week of delivery. RESULTS: Cervical sonoelastography and fFN test show a significant correlation with spontaneous preterm delivery (P=0.007, P=0.001), resulting in 72.7%/36% sensitivity and 73%/95% specificity. The positive predictive value (PPV) was 61.5%/81.8% and the negative predictive value was 81.8%/70%. The cervical length was not different in cases with and without term delivery (P=0.165). CONCLUSIONS: Cervical sonoelastography is a promising technique that can complement routine diagnostic procedures to improve prediction of preterm birth. The PPV is improved by an fFN test. PMID- 25720039 TI - First trimester severe ductus venosus flow abnormalities in isolation or combination with other markers of aneuploidy and fetal anomalies. AB - BACKGROUND: Altered flow in ductus venosus (DV) may be caused by the changes in preload or afterload. Its association with aneuploidy and congenital heart defects (CHDs) was widely described. OBJECTIVES: The aim of this study was to examine the incidence of a reversed a-wave in DV flow (revDV) and the absence of DV (noDV), their coincidences with other markers of aneuploidy or fetal abnormalities in a mixed-risk population. METHODS: The study group covered women who underwent an ultrasound scan between 11+0 and 13+6 weeks' gestation. Applied inclusion criteria: Singleton pregnancies with known pregnancy outcome and a crown-rump length of 45-84 mm. RESULTS: A total of 5811 cases, including 137 aneuploidies, met the inclusion criteria: 35 subjects of noDV, 189 of revDV and 5587 of normal DV flow. The incidence of noDV in euploidy was 0.47%, and in aneuploidy 5.8%. The incidence of revDV in euploidy was 2.46%, and in aneuploidy 35.7%. Among aneuploidy, the highest prevalence of noDV was found in monosomy 45X. revDV showed the highest prevalence in trisomy 18. Isolated noDV was only found in euploidy. Isolated revDV subjects were only observed in euploidy and trisomy 21. Any combination of revDV with additional markers showed high incidence in major trisomies. Extracardiac anatomy and abnormal cardiac findings showed a higher prevalence in noDV and revDV cases. CONCLUSIONS: The presence of noDV might be useful in suspicion of monosomy X among cases with increased nuchal translucency, as well as in differentiating them from other aneuploidies. The combinations of aneuploidy markers with revDV are strong indicators of aneuploidy. revDV alone is a poor screening tool for aneuploidy and euploidy with CHD. PMID- 25720040 TI - Dental aesthetics perception and eating behavior in adolescence. AB - BACKGROUND: This correlational study explored the psychosocial aspects related to eating behavior in different age samples of adolescents in treatment from 0 to 60 months at the Clinic of Orthodontics and Dentistry of Messina, Messina, Italy. The aim of the study was to investigate the relationship between psychosocial impact, levels of self-esteem, and the possible connection with eating habits of adolescents under orthodontic treatment. METHODS: Sixty-one adolescents, aged between 12 and 22 years (mean=15.6 +/- 2.8) participated to the study. Each adolescents was interviewed with the Eating Attitudes Test, the Rosenberg Self Esteem Scale, and the Psychosocial Impact of Dental Aesthetics Questionnaire. RESULTS: Data did not show a direct connection between eating disorder and dental aesthetics, nevertheless, adolescents under orthodontic treatment, especially in the earliest phase of wearing braces, showed peculiar eating habits and underwent a higher psychological impact of dental aesthetics. Eating behaviors are strictly linked to global self-esteem. The processing of the results was made through the Student's t-test and using Pearson's correlation analysis. CONCLUSION: Increased knowledge of the psychological aspects involved in orthodontic treatment compliance may have positive effects in the relationship between adolescent patients and orthodontists. More attention should be paid to aspects that are often underestimated in clinical practice, thus, influencing the outcome of treatment and patient satisfaction, not only in terms of dental health, but also of mental health. PMID- 25720041 TI - Predictors of violence and depression: the case of adolescents in Turkey. AB - Violence is a leading problem that has a negative impact on daily living. Today, it continues to be an important topic owing to its widespread occurrence, especially among the youth. The main objective of this study is to specify the predictors that influence violence and depression observed among youth aged 15-18 years. While some of these factors are individual (age, gender, flirting, sports. etc.), the subjects' background, such as the family's education level, sibling number, etc., were investigated as social and environmental factors. In the survey, data were obtained from 109 high school students receiving education in a private teaching institution using a structured questionnaire technique. With regards the reliability of the survey, equal numbers of boys and girls were chosen from each year in high school lasting for 4 years. After asking questions that aim to obtain students' sociodemographic features, their depression level was surveyed using the Beck Depression Scale; meanwhile, the Violence Tendency Scale was used to survey their tendency to be violent. Findings revealed that some individual and domestic features of adolescents have significant impacts on their tendencies towards violence and depression. PMID- 25720042 TI - Exercise, bodyweight perception and related weight loss behavior among adolescents in Trinidad and Tobago. AB - AIM: This study attempted to evaluate the real and perceived body weight, exercise habits and weight-altering dietary supplement use by adolescents attending schools in Trinidad and Tobago. METHODS: A de novo questionnaire was administered prospectively to 15-19-year-old to determine their exercise habits, their perceived body weights, and their use of any weight gain or weight loss supplements. A subset of students had their actual height and weights recorded and BMI calculated. RESULTS: Five hundred and eighty-three students did the questionnaire (88% response rate), and 363 students had BMI calculated. Some 14.9% (54/363) of the students were overweight, and 15.4% (56/363) were obese, and more than 75% of the obese students had attempted weight loss in the past. These measures included exercise in the majority of the students and use of dietary supplements in the minority. Only 6% of the obese students exercised five or more times per week. About 28% of the students misclassified their body weights, and perception of body weight influenced weight loss behaviors more than actual body weights. CONCLUSION: Almost one third of the students were overweight or obese. Overweight students were motivated to lose weight, and these students need to have some structured health promotion program, which educates them on correct exercise habits, safe measures to lose weight, and which informs them of their actual body weight. PMID- 25720043 TI - Comprehensive obesity evaluation and treatment of three adolescents: a case series. AB - BACKGROUND: Adolescent obesity is a chronic disease that is impacted from each patient's biopsychosocial milieu. Successfully treating pediatric obesity requires long-term, innovative, systematic involvement to facilitate patient and family engagement and change. METHODS: Extensive chart review was done for three obese adolescents who underwent comprehensive weight management in an adolescent clinic seen within the past 5 years. The charts were reviewed starting from the time of initial contact through the last visit in the clinic. The patients are no longer receiving care within the clinic. RESULTS: The patients presented with BMI>99th percentile, family history of obesity, severe psychosocial stressors, and multiple obesity-related comorbidities. Their treatment involved comprehensive multidisciplinary intervention in an adolescent weight management clinic within a tertiary care center. In addition to rigorous support through frequent office visits, these patients all eventually required temporary, alternative living arrangements to successfully implement recommendations. One patient resided with another family member; two went to inpatient weight management program care for 2-3 months. All subjects successfully lost weight when away from their primary residence, and they demonstrated improvement or resolution of comorbidities. CONCLUSIONS: This case series of three adolescents who underwent comprehensive obesity evaluation and treatment demonstrates multidisciplinary care across interconnected treatment programs and active engagement of family. Those who maintained successful weight loss reduced sedentary time, demonstrated family support (e.g., key members attending follow up visits), and altered their living environment and were committed to their own health goals. PMID- 25720044 TI - Prevalence and determinants of cigarette smoking among adolescents in secondary schools in Port Harcourt, Southern Nigeria. AB - BACKGROUND: Cigarette smoking remains a major preventable public health problem associated with premature deaths worldwide. Adolescence is a unique developmental stage between childhood and adulthood. Smoking is a lifestyle habit acquired during adolescence and into adulthood, with its associated morbidity and mortality. It is therefore important to determine the factors associated with cigarette smoking in these adolescents in order to institute preventive measures and health policies to protect these adolescents early. OBJECTIVE: This study aims to determine the prevalence of smoking, factors associated with smoking, and knowledge of the harmful effects of smoking in these adolescents. METHODS: A cross-sectional study of 1120 adolescents aged 10-19 years selected from 10 secondary schools in Port Harcourt was conducted using a multistage sampling technique. The Global Youth Tobacco Survey (GYTS) core questionnaire was used to collect data from the subjects. A smoker was defined as one who had ever smoked a cigarette or who had one or two puffs, while a current smoker was defined as one who had taken a puff or smoked cigarettes in the last 30 days preceding the day of the questionnaire's completion. RESULTS: Eighty subjects (7.1%) were smokers. This was significantly (p=<0.001) higher in males (9.7%) than in females (4%). Thirty seven (3.3%) subjects were current smokers. The mean age at which smoking was initiated was 12.47+/-3.0 years. Twenty six (32.5%) of the smokers reported that they were initiated into cigarette smoking by their friends, 36 (45%) just wanted to experiment, 7 (8.8%) were influenced by media advertisements while 5 (6.3%) were due to parental exposure. Parental history of smoking and poor knowledge of cancer of the lungs as a harmful effect of smoking, was significantly (p=<0.05) associated with cigarette smoking. CONCLUSION: The prevalence of smoking in adolescents in Port Harcourt is high and is associated with parental smoking and poor knowledge of cancer of the lungs as a harmful effect. We recommend that adolescent health education with an emphasis on the harmful effects of smoking be included in the curriculum of all secondary schools. PMID- 25720045 TI - Needs and expectations of adolescent in-patients: the experience of Gaslini Children's Hospital. AB - BACKGROUND: Adolescents affected by a severe disease who undergo high-risk treatment may experience stress, pain, extreme frustration, depression, and anger. In this large spectrum of emotions, several situations must be considered carefully. To improve coping and quality of services offered to adolescents in paediatric hospitals, we elaborated a semi-structured interview and a short questionnaire (Quality of life-adolescent-Istituto Giannina Gaslini, QoL-adol-IGG scale) to investigate the quality of life, the needs and expectations of adolescent in-patients. METHODS: The study sample includes 117 in-patients aged between 10 and 20 years coming from several Italian regions who were admitted to the G. Gaslini Research Children's Hospital for a period of 10 days or more, regardless of the disease. The QoL-adol-IGG scale was administered - after obtaining informed consent from the children and their parents - in one single encounter by trained psychologist. The distribution of the answers was evaluated after stratification by patient's age, gender, area of residence, and clinical diagnosis. Continuous data were compared using the Kruskal-Wallis, while the chi2 test was used for categorical data. RESULTS: Seventy-two percent had difficulty practicing normal daily activities during their stay in the hospital, not only because of the disease (40%), but also because of the poor organization within the hospital, the lack of proposals/activities and space for spare time, and the limited access to technologies. Adolescents >=15 years were more frequently dissatisfied than youngsters concerning the access to Internet and other technologies, the possibility to make new friends and to take part in social activities. CONCLUSION: The results of this study, which evaluated the hospital's organization, but also psychological functioning in a representative sample of patients, may contribute to optimize internal procedures of clinical departments where adolescent in-patients are present, on the basis of their requests and taking into account their age. PMID- 25720046 TI - HIV testing among non-incarcerated substance-abusing juvenile offenders. AB - Juvenile offenders are a subgroup of adolescents at particular risk for HIV/STI infection. Although HIV prevalence among these youth is low (<1%) in the US, rates of other STIs, unprotected sexual activity, multiple partners, and incidents of substance use during sex are high compared with other adolescent populations. Many of these youth will enter the adult criminal justice system, which is known to have an extremely high rate of HIV infection. US constitutional mandates provide HIV/STI testing for incarcerated juveniles, but close to 80% of juvenile arrestees are never detained. Moreover, although they engage in similar HIV risk behaviors as those detained, they have limited access to available HIV/STI testing services. Thus, our study examined rates of lifetime HIV testing among a pilot sample of 60 court-involved, substance-using juveniles monitored in the community to explore rates of testing and the reasons related to lifetime testing among a high-risk, yet understudied US juvenile population. PMID- 25720047 TI - Perceptions of family styles by adolescents with eating disorders and their parents. AB - PURPOSE: The traditional view has been that there is a great deal of rigidity and enmeshment in the families of adolescents with eating disorders, with poor communication and satisfaction among family members. We used the Family Adaptability and Cohesion Evaluation Scales IV (FACES-IV) to study whether this traditional view remains true or whether family styles among those with eating disorders have changed over time to include a wider range of families. METHODS: Forty-four patients (aged 14-18 years; mean, 15.4 years; 38 females and 6 males) being treated for an eating disorder in a Division of Adolescent Medicine completed the FACES-IV questionnaire, along with the Beck Depression Inventory (BDI). Patients were diagnosed with anorexia nervosa (38.6%), eating disorders not otherwise specified (59.5%), and bulimia nervosa (2.3%) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. They had a mean BMI of 19.6 at the time of questionnaire completion, which was an average of 175 days from first visit. Parents (38 mothers and 6 fathers) completed the FACES IV and the BDI at the same visit without conferring with their children. RESULTS: A great majority of patients and parents reported their families as being connected/very connected (93% of patients and 98% of parents) and flexible/very flexible (80% and 93%), with low/very low enmeshment (89% and 89%), moderate/low/very low rigidity (77% and 95%), low/very low chaos (84% and 86%), and moderate/high/very high communication (85% and 50%). Despite these scores, all well within the normal range for families with teenagers, 70% of patients and 64% of parents reported low/very low satisfaction with their families, well below the normal range. Depression scores were moderate/severe for 44% of patients and 14% of parents. Analysis of variance and t-tests showed no differences between FACES-IV scores and age, gender, ethnicity, diagnosis, and time from first visit for patients, whereas patients and parents who were more depressed were each more likely (p<0.05) to report greater dissatisfaction with their families. CONCLUSION: A great majority of patients with eating disorders and their parents reported their family styles to be in the healthy range. However, many patients and parents, especially those with depression, expressed dissatisfaction with their families. These data demonstrate that older concepts of the families of adolescents with eating disorders need to be reconsidered. PMID- 25720048 TI - Eating disorders in adolescents: how does the DSM-5 change the diagnosis? AB - PURPOSE: This study aimed to determine the changes in diagnosis that occur in making the transition from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria in an adolescent medicine eating disorder program. METHODS: During the months of September 2011 through December 2012, a data sheet was completed at the end of each new outpatient eating disorder evaluation listing the patient's gender, age, ethnicity, weight, height, DSM-IV diagnosis, and proposed DSM-5 diagnosis. Distributions were calculated using the Mann Whitney and Wilcoxon rank sum analyses to determine differences between diagnostic groups. RESULTS: There were 309 patients evaluated during the 16-month period. DSM-IV diagnoses were as follows: anorexia nervosa, 81 patients (26.2%); bulimia nervosa, 29 patients (9.4%); binge eating disorder, 1 patient (0.3%); and eating disorder not otherwise specified (EDNOS), 198 patients (64.6%). By contrast, DSM-5 diagnoses were as follows: anorexia nervosa, 100 patients; atypical anorexia nervosa, 93 patients; avoidant/restrictive food intake disorder, 60 patients; bulimia nervosa, 29 patients; purging disorder, 18 patients; unspecified feeding or eating disorder, 4 patients; subthreshold bulimia nervosa, 2 patients; subthreshold binge eating disorder, 2 patients; and binge eating disorder, 1 patient. CONCLUSION: Almost two thirds (64.6%) of the 309 patients had a diagnosis of EDNOS based on the DSM-IV criteria. By contrast, only four patients had a diagnosis of unspecified feeding or eating disorder based on the DSM-5 criteria. These data demonstrate that the goal of providing more specific diagnoses for patients with eating disorders has been accomplished very successfully by the new DSM-5 criteria. PMID- 25720049 TI - Evaluation of fetuin-A and carotid intima-media thickness in adolescent type 1 diabetic patients. AB - OBJECTIVE: To evaluate fetuin-A level and carotid intima-media thickness (CIMT) in adolescent type 1 diabetics. PATIENTS AND METHODS: The study included 62 type 1 diabetic patients and 30 healthy volunteers of the same age and sex. Blood sample was taken for assessment of glycosylated hemoglobin (HbA1), lipid profile, and fetuin-A. Urine sample was also taken for assessment of albumin/creatinine ratio. Anthropometric measurements were taken, including weight, height, and waist and hip circumference. CIMT was assessed for all patients and controls. RESULTS: Serum fetuin-A, Rt., Lt. and both CIMT were significantly higher in diabetics. Fetuin-A had a significant positive correlation with duration of disease, waist and hip circumference, BMI, BMI SDS, waist/height ratio, Rt., Lt. and both CIMT. Stepwise multiple regression analysis revealed that the duration of disease, waist/height ratio, and HDL-c were the factors related to fetuin-A. CONCLUSION: Adolescent type 1 diabetic patients have high fetuin-A levels and increased CIMT, with the latter representing the development of early atherosclerosis. In this light, adolescents with type 1 diabetes require frequent follow up for early detection of atherosclerosis. PMID- 25720050 TI - Genetic analysis of the paired box transcription factor (PAX8) gene in a cohort of Polish patients with primary congenital hypothyroidism and dysgenetic thyroid glands. AB - BACKGROUND: The morphological and biochemical phenotype of PAX8 mutation in patients with congenital hypothyroidism (CH) is variable. The contribution of mutations in PAX8 gene in children with CH and dysgenetic thyroid glands still remains a subject of interest for researchers. PATIENTS AND METHODS: Some 48 children (37 girls and 11 boys) with CH associated with thyroid ectopy (n=22), agenesis (n=10), hypoplasia (n=6), or thyroid dysgenesis of unknown cause (n=10) were enrolled. The study participants were born in south-eastern Poland in the years 1993-2012 and were selected for neonatal mass screening for CH. DNA was extracted from peripheral blood samples using Master Pure DNA Purification Kit (Epicentre Biotechnologies, Madison, WI, USA). The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified and sequenced by the Sanger method. Capillary electrophoresis was run on ABI 3500 (Applied Biosystems, Carlsbad, CA, USA). RESULTS: Novel heterozygous transition in exon 3 (c.68G>A) was detected in a 3-year-old girl with a thyroid hypoplasia. This substitution was not identified in the patient's parents (de novo event). Additionally, a novel genetic variant in 3'UTR region of exon 12 (c.*416C>T) occurred in a 3-year old boy with ectopic thyroid tissue and concomitant congenital urogenital malformation. This heterozygous variant was also detected in other healthy family members. Thirteen well-described single nucleotide polymorphisms were revealed in the PAX8 gene. CONCLUSIONS: The study reports on the occurrence of two novel heterozygous substitutions in the PAX8 gene. Estimation of the contribution of the revealed c.68G>A variant to the etiology of CH in a girl with hypoplastic thyroid requires further functional analysis. PMID- 25720051 TI - Chondrocalcinosis related to familial hypomagnesemia with hypercalciuria and nephrocalcinosis. AB - Calcium pyrophosphate dehydrate (CPPD) crystal deposition disease (also known as chondrocalcinosis, CC) is a rare metabolic arthropathy mostly seen in elderly patients. Chondrocalcinosis may be associated with metabolic diseases such as hypomagnesemia when it occurs in young people. We report here a case with hypomagnesemia due to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) who developed CC during clinical follow-up. To our best knowledge this is the first case of a young patient with CPPD associated with FHHNC. PMID- 25720053 TI - Childhood obesity, thyroid function, and insulin resistance - is there a link? A longitudinal study. AB - BACKGROUND: Serum thyroid stimulating hormone (TSH) levels are frequently elevated in obese children and are most likely to be associated with insulin resistance. However, clinical relevance of this association remains unclear. OBJECTIVES: To assess the prevalence of hyperthyrotropinemia; to analyze the relationship between TSH and homeostasis model assessment - insulin resistance (HOMA-IR); and to verify whether TSH levels and HOMA-IR vary with weight loss in obese children. SUBJECTS AND METHODS: Retrospective longitudinal study with data from baseline and 1 year after lifestyle intervention in a pediatric obese group (344 children were recruited and 100 among them completed follow-up). For postintervention analysis, three groups were considered according to body mass index-standard deviation score (BMI-SDS) variations: <=-0.5 (significant weight loss); 0.5-0 (weight loss); and >0 (weight gain). Statistical analysis was performed using SPSS 19.0(r). RESULTS: The prevalence of increased TSH levels was 9.3%. At baseline TSH (p=0.007), fT4 (p=0.006), and HOMA-IR (p<0.001) were positively correlated to BMI-SDS (n=344). Weight reduction was verified in 67 out of 100 cases but significant loss was present in only 21 cases. Decreases in both TSH and BMI-SDS were independently associated with decreases in HOMA-IR (p=0.005 and p=0.016, respectively). There was no correlation between TSH and BMI-SDS variation. Significant decreases in the HOMA-IR (p=0.006) were only achieved in the significant weight loss group. CONCLUSIONS: The prevalence of hyperthyrotropinemia was lower than previously reported. However, cutoff values were adjusted to pubertal stage, suggesting an over report in other studies. Insulin resistance and TSH were positively correlated, independent of body status. Although weight loss was not associated with TSH variation, a decrease in TSH levels was independently associated with decreases in HOMA-IR. PMID- 25720052 TI - Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: an unusual clinical picture. AB - BACKGROUND: Inheritance of two pathogenic ABCC8 alleles typically causes severe congenital hyperinsulinism. We describe a girl and her father, both homozygous for the same ABCC8 mutation, who presented with unusual phenotypes. METHODS: Single nucleotide polymorphism microarray and Sanger sequencing were performed. Western blot, rubidium efflux, and patch clamp recordings interrogated the expression and activity of the mutant protein. RESULTS: A 16-month-old girl of consanguineous descent manifested hypoglycemia. She had dysregulation of insulin secretion, with postprandial hyperglycemia followed by hypoglycemia. Microarray revealed homozygosity for the regions encompassing KCNJ11 and ABCC8. Her father had developed diabetes at 28 years of age. Sequencing of ABCC8 identified a homozygous missense mutation, p.R1419H, in both individuals. Functional studies showed absence of working KATP channels. CONCLUSION: This is the first description of a homozygous p.R1419H mutation. Our findings highlight that homozygous loss-of-function mutations of ABCC8 do not necessarily translate into early-onset severe hyperinsulinemia. PMID- 25720054 TI - Abeta regulation-based multitarget strategy for drug discovery against Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressively neurodegenerative disease that eventually leads to the irreversible loss of neurons and intellectual abilities, including cognition and memory. AD has become the most common cause of dementia in aged people, and the ill-defined pathogenesis of AD is seriously impeding the current drug discovery against this disease. To date, there is still a lack of etiologically therapeutic drugs for AD, although some symptomatic treatments have been successfully developed. The beta-amyloid (Abeta)-induced neurodegeneration is determined as the main pathogenesis of AD, and by targeting the regulation of Abeta in production inhibition or clearance promotion, many active agents have been designed potentially for AD treatment, but no drug has yet been approved in clinical use. Actually, AD has a complex pathogenic mechanism that involves multiple aberrant signaling genes and pathways, and the idea of 'single target' for anti-AD drug research is thus full of challenges. Recently, with a deep understanding of AD pathogeneses and the development of advanced pharmacological techniques, 'multiple target'-based strategy has been widely applied for the drug discovery against this disease, and many promising results have been achieved. Here, we review the recent multitarget strategies for the drug discovery in the treatment of AD by focusing on the involvement of Abeta regulation. PMID- 25720055 TI - Sleep-related behaviors in Alzheimer's disease and dementia with Lewy bodies. AB - Abstract Prevalence studies suggest that Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common dementing illnesses in the elderly. The aim of this narrative review was to provide data on sleep-related behaviors in AD and DLB. This paper contains arguments, with a clinical approach, on both circadian rhythm changes and dissociated states of wakefulness and sleep in these two conditions. PMID- 25720056 TI - Nitric oxide synthase in hypoxic or ischemic brain injury. AB - Abstract Hypoxic or ischemic stress causes many serious brain injuries, including stroke and neonatal hypoxia ischemia encephalopathy. During brain hypoxia ischemia processes, nitric oxide (NO) may play either a neurotoxic or a neuroprotective role, depending upon factors such as the NO synthase (NOS) isoform, the cell type by which NO is produced, and the temporal stage after the onset of the hypoxic ischemic brain injury. Excessive NO production can be neurotoxic, leading to cascade reactions of excitotoxicity, inflammation, apoptosis, and deteriorating primary brain injury. In contrast, NO produced by endothelial NOS plays a neuroprotective role by maintaining cerebral blood flow and preventing neuronal injury, as well as inhibiting platelet and leukocyte adhesion. Sometimes, NO-derived inducible NOS and neuronal NOS in special areas may also play neuroprotective roles. Therefore, this review summarizes the different roles and the regulation of the three NOS isoforms in hypoxic or ischemic brain injury as revealed in research in recent years, focusing on the neurotoxic role of the three NOS isoforms involved in mechanisms of hypoxic or ischemic brain injury. PMID- 25720057 TI - Retraction Note. Reconsolidation revisited: A review and commentary on the phenomenon. PMID- 25720058 TI - A hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn ameliorates hyperalgesia and allodynia in vincristine-induced neuropathic pain in rats. AB - BACKGROUND: The hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn whole plant has demonstrated analgesic effects in acute pain models. The extract has also demonstrated anticonvulsant effects in murine models of experimental epilepsy. The present study illustrates an evaluation of the hydro-ethanolic extract of the plant for possible analgesic properties in hyperalgesia and allodynia associated with vincristine-induced neuropathy in rats. METHODS: Neuropathic pain was induced in Sprague-Dawley rats by injecting 100 MUg/kg of vincristine sulphate on alternative days for 6 days (days 0, 2, 4, 8, 10 and 12). Vincristine-induced cold allodynia, mechanical hyperalgesia and thermal hyperalgesia were measured pre-vincristine administration and on days 15, 17 and 19 post-vincristine administration. The rats were then treated with S. nodiflora extract (SNE) (100, 300 and 1000 mg/kg), pregabalin (10, 30 and 100 mg/kg) and distilled water as vehicle daily for 5 days and pain thresholds were measured on alternate days for 3 days. RESULTS: SNE and pregabalin produced analgesic properties observed as increased paw withdrawal latencies to mechanical, tactile, cold water stimuli and thermal hyperalgesic tests during the 5 days of treatment. CONCLUSIONS: The findings suggest that hydro-ethanolic extract of S. nodiflora possesses anti-hyperalgesic and anti-allodynic effects in vincristine-induced neuropathic pain in rats. PMID- 25720059 TI - Anti-inflammatory and antipyretic properties of Corchorus olitorius aqueous root extract in Wistar rats. AB - BACKGROUND: This study was designed to provide information about the antipyretic and anti-inflammatory effects of Corchorus olitorius root. METHODS: Thirty male Wistar rats were divided into six groups of five animals each; the control and reference groups were administered normal saline (10 mL/kg) and indomethacin (5 mg/kg), respectively, whereas the remaining four groups were administered aqueous extract of C. olitorius at doses of 25, 50, 100, or 200 mg/kg, respectively. Pyrexia was induced by injecting 10 mL/kg of 20% (w/v) brewer's yeast suspension into the dorsum of rats, whereas inflammation was induced through an injection of 0.1% carrageenan into the right hind paw of each rat and through a subcutaneous implantation of a 30-g sterilized cotton pellet into the groin of each rat. RESULTS: The results showed that C. olitorius root extract (p<0.05) decreased the elevated temperature after brewer's yeast injection compared with the 17 h (pre drug) temperature. In the inflammatory tests, the paw sizes and granuloma weights in the test groups were significantly (p<0.05) decreased compared with the control group. CONCLUSIONS: Corchorus olitorius root is another good source of phytomedicine that can be used effectively to treat inflammation and pyrexia that accompany some diseases. PMID- 25720060 TI - S1PR4 is required for plasmacytoid dendritic cell differentiation. AB - The sphingolipid sphingosine-1-phosphate (S1P) has various functions in immune cell biology, regulating survival, proliferation, and, most prominently, migration. S1P couples to five G protein-coupled receptors (S1PR1-5) to transduce its effects on immune cell function. Expression of S1PR4 is restricted to immune cells. However, its impact on immune cell biology is largely elusive. In the current study, we intended to answer the question of whether S1P might affect plasmacytoid dendritic cell (pDC) migration, which dominantly express S1PR4. pDC are highly specialized cells producing large amounts of type I interferon in response to TLR7/9 ligands after viral infection or during autoimmunity. Surprisingly, we noticed a reduced abundance of pDC, particularly CD4- pDC, in all organs of S1PR4-deficient vs. wildtype mice. This effect was not caused by altered migration of mature pDC, but rather a reduced potential of pDC progenitors, especially common DC progenitors, to differentiate into pDCs. In vitro studies suggested that reduced S1PR4-deficient pDC progenitor differentiation into mature pDC might be explained by both migration and differentiation of pDC progenitors in the bone marrow. As S1PR4 also affected the differentiation of CD34+ human hematopoietic stem cells into pDC, interfering with S1PR4 might be useful to reduce pDC numbers during autoimmunity. PMID- 25720061 TI - Ceramide and sphingosine in pulmonary infections. AB - Acid sphingomyelinase and ceramide have previously been shown to play a central role in infections with Neisseria gonorrhoeae, Staphylococcus aureus, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, and Mycobacterium avium. Recent studies have extended the role of sphingolipids in bacterial infections and have demonstrated that ceramide and sphingosine are central to the defense of lungs against bacterial pathogens. Ceramide accumulates in the airway epithelium of cystic fibrosis and ceramide synthase 2 (CerS2) deficient mice, which respond to the lack of very long chain (C22-C24-) ceramides with a profound compensatory increase of long chain (mainly C16-) ceramides. In contrast, sphingosine is present in healthy airways and is almost completely absent from diseased or deficient epithelial cells. Both sphingolipids are crucially involved in the high susceptibility to infection of cystic fibrosis and CerS2-deficient mice, as indicated by findings showing that the normalization of ceramide and sphingosine levels rescue these mice from acute infection with P. aeruginosa. PMID- 25720062 TI - Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application. AB - FTY720 (Fingolimod; Gilenya(r)) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates. PMID- 25720063 TI - Innate immune responses in the brain of sphingolipid lysosomal storage diseases. AB - Lysosomal storage diseases (LSDs) are mainly caused by the defective activity of lysosomal hydrolases. A sub-class of LSDs are the sphingolipidoses, in which sphingolipids accumulate intra-cellularly. We here discuss the role of innate immunity in the sphingolipidoses, and compare the pathways of activation in two classical sphingolipidoses, namely Gaucher disease and Sandhoff disease, and in Niemann-Pick C disease, in which the main storage material is cholesterol but sphingolipids also accumulate. We discuss the mechanisms leading to neuroinflammation, and the different pathways of neuroinflammation in the different diseases, and suggest that intervention in these pathways may be a useful therapeutic approach to address these devastating human diseases. PMID- 25720064 TI - Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors. AB - FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes. PMID- 25720066 TI - The effect of altered sphingolipid acyl chain length on various disease models. AB - Sphingolipids have emerged as an important lipid mediator in intracellular signalling and metabolism. Ceramide, which is central to sphingolipid metabolism, is generated either via a de novo pathway, by attaching fatty acyl CoA to a long chain base, or via a salvage pathway, by degrading pre-existing sphingolipids. As a 'sphingolipid rheostat' has been proposed, the balance between ceramide and sphingosine-1-phosphate has been the object of considerable attention. Ceramide has recently been reported to have a different function depending on its acyl chain length: six ceramide synthases (CerS) determine the specific ceramide acyl chain length in mammals. All CerS-deficient mice generated to date show that sphingolipids with defined acyl chain lengths play distinct pathophysiological roles in disease models. This review describes recent advances in understanding the associations of CerS with various diseases and includes clinical case reports. PMID- 25720067 TI - Thiol switches in mitochondria: operation and physiological relevance. AB - Mitochondria are a major source of reactive oxygen species (ROS) in the cell, particularly of superoxide and hydrogen peroxide. A number of dedicated enzymes regulate the conversion and consumption of superoxide and hydrogen peroxide in the intermembrane space and the matrix of mitochondria. Nevertheless, hydrogen peroxide can also interact with many other mitochondrial enzymes, particularly those with reactive cysteine residues, modulating their reactivity in accordance with changes in redox conditions. In this review we will describe the general redox systems in mitochondria of animals, fungi and plants and discuss potential target proteins that were proposed to contain regulatory thiol switches. PMID- 25720065 TI - Making the LINC: SUN and KASH protein interactions. AB - Cell nuclei are physically integrated with the cytoskeleton through the linker of nucleoskeleton and cytoskeleton (LINC) complex, a structure that spans the nuclear envelope to link the nucleoskeleton and cytoskeleton. Outer nuclear membrane KASH domain proteins and inner nuclear membrane SUN domain proteins interact to form the core of the LINC complex. In this review, we provide a comprehensive analysis of the reported protein-protein interactions for KASH and SUN domain proteins. This critical structure, directly connecting the genome with the rest of the cell, contributes to a myriad of cellular functions and, when perturbed, is associated with human disease. PMID- 25720068 TI - Redox imaging using genetically encoded redox indicators in zebrafish and mice. AB - Redox signals have emerged as important regulators of cellular physiology and pathology. The advent of redox imaging in vertebrate systems now provides the opportunity to dynamically visualize redox signaling during development and disease. In this review, we summarize recent advances in the generation of genetically encoded redox indicators (GERIs), introduce new redox imaging strategies, and highlight key publications in the field of vertebrate redox imaging. We also discuss the limitations and future potential of in vivo redox imaging in zebrafish and mice. PMID- 25720069 TI - Erroneous HbA1c measurements in the presence of beta-thalassemia and common Chinese hemoglobin variants. AB - BACKGROUND: HbA1c is a widely used biomarker for the management of diabetes mellitus and can be quantified from blood samples by using various methods, including ion-exchange high-performance liquid chromatography (HPLC), boronate affinity HPLC, and capillary electrophoresis (CE). Here, we evaluated the accuracy of four separation methods for determination of HbA1c values in Chinese patients with different hemoglobin disorders. METHODS: Blood samples from normal patients, patients with beta-thalassemia, patients exhibiting heterozygosity, and patients exhibiting homozygosity were analyzed using ion-exchange HPLC (Variant II Turbo, Bio-Rad and Adams A1c HA-8160, Arkray, run in diabetes mode), boronate affinity HPLC (Ultra2, Trinity Biotech), and CE (Capillarys 2 Flex Piercing, Sebia). RESULTS: Samples from patients with beta-thalassemia produced significant positive biases on the Variant II Turbo system compared to the other three systems. For heterozygous betaA/betaE patients, a good agreement was observed between Capillarys 2 Flex Piercing and Ultra2 systems, while a significant negative bias was observed between HA-8160 and Capillarys 2 Flex Piercing systems and between Variant II Turbo and Capillarys 2 Flex Piercing systems. For homozygous (betaE/betaE) patients, a clear context without HbA, all systems except the Capillarys 2 Flex Piercing system yielded random HbA1c results. Only the Capillarys 2 Flex Piercing system could detect all hemoglobin variants tested. CONCLUSIONS: beta-Thalassemia can cause errors in HbA1c determination using the Variant II Turbo system. HbE heterozygosity or HbE homozygosity also complicated HbA1c measurements. The Capillarys 2 Flex Piercing system detected all Hb variants and HbA1c in patients with beta-thalassemia and could provide measurements with high accuracy. PMID- 25720070 TI - Diagnosis of acute myocardial infarction in patients with renal insufficiency using high-sensitivity troponin T. AB - BACKGROUND: The objective of this study was to examine the diagnostic accuracy of high-sensitivity cardiac troponin T (hs-cTnT) for acute myocardial infarction (AMI) in patients with renal insufficiency, since this population has a high incidence of non-AMI elevations of hs-cTnT. METHODS: In this prospective study, we enrolled 2249 consecutive patients presenting with chest pain in the emergency department (ED), of whom 19.5% had an estimated glomerular filtration rate (eGFR)cys of <60 mL.min-1 (1.73 m2)-1. Hs-cTnT levels were measured blindly at presentation. RESULTS: Of the patients, 1108 (49.3%) were diagnosed as having AMI [321 with non-ST segment elevation myocardial infarction (NSTEMI)]. In patients whose final diagnosis was not AMI, there was a low but significant correlation between hs-cTnT and renal function [eGFRcys, r=-0.43 (-0.48, -0.38), p<0.001; eGFRcreat, r=-0.33 (-0.38, -0.27), p<0.001]. The area under the curve of the receiver operating characteristic (AUC) for hs-cTnT to diagnose AMI was 0.93 in patients with eGFRcys levels of <30 mL.min-1 (1.73 m2)-1, and AUCs did not vary significantly according to eGFR categories. On the basis of the ROC curve, the optimal threshold value for hs-cTnT was 143.6 ng.L-1 to diagnose AMI in patients with eGFRcys of <30 mL.min-1 (1.73 m2)-1, with a sensitivity of 83% and a specificity of 91%; 54.1 ng.L-1 in patients with eGFRcys between 30 and 59 mL.min 1, with a sensitivity of 90% and a specificity of 87%; 30.0 ng.L-1 in patients with eGFRcys between 60 and 89 mL.min-1, with a sensitivity of 89% and a specificity of 85%; and 20.3 ng.L-1 in patients with eGFRcys >=90 mL.min-1 (1.73 m2)-1, with a sensitivity of 92% and a specificity of 88%. The same observations were done for the diagnosis of NSTEMI. CONCLUSIONS: Using a higher hs-cTnT cut off value based on eGFR level is necessary for accurate diagnosis of AMI or NSTEMI in patients with renal insufficiency. PMID- 25720071 TI - Comparison of five automated hematology analyzers in a university hospital setting: Abbott Cell-Dyn Sapphire, Beckman Coulter DxH 800, Siemens Advia 2120i, Sysmex XE-5000, and Sysmex XN-2000. AB - BACKGROUND: Various types of automated hematology analyzers are used in clinical laboratories. Here, we performed a side-by-side comparison of five current top of the range routine hematology analyzers in the setting of a university hospital central laboratory. METHODS: Complete blood counts (CBC), differentials, reticulocyte and nucleated red blood cell (NRBC) counts of 349 patient samples, randomly taken out of routine diagnostics, were analyzed with Cell-Dyn Sapphire (Abbott), DxH 800 (Beckman Coulter), Advia 2120i (Siemens), XE-5000 and XN-2000 (Sysmex). Inter-instrument comparison of CBCs including reticulocyte and NRBC counts and investigation of flagging quality in relation to microscopy were performed with the complete set of samples. Inter-instrument comparison of five part differential was performed using samples without atypical cells in blood smear (n=292). Automated five-part differentials and NRBCs were additionally compared with microscopy. RESULTS: The five analyzers showed a good concordance for basic blood count parameters. Correlations between instruments were less well for reticulocyte counts, NRBCs, and differentials. The poorest concordance for NRBCs with microscopy was observed for Advia 2120i (Kendall's taub=0.37). The highest flagging sensitivity for blasts was observed for XN-2000 (97% compared to 65%-76% for other analyzers), whereas overall specificity was comparable between different instruments. CONCLUSIONS: To the best of our knowledge, this is the most comprehensive side-by-side comparison of five current top of the range routine hematology analyzers. Variable analyzer quality and parameter specific limitations must be considered in defining laboratory algorithms in clinical practice. PMID- 25720072 TI - Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points. AB - BACKGROUND: A novel approach to determine vitamin B12 status is to combine four blood markers: total B12 (B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B12 status is expressed as cB12=log10[(holoTC.B12)/(MMA.Hcy)]-(age factor). Here we calculate cB12 in datasets with missing biomarkers, examine the influence of folate status, and revise diagnostic cut-points. METHODS: We used a database with all four markers (n=5211) plus folate measurements (n=972). A biomarker Z (assumed missing) was plotted versus X (a combination of other markers) and Y (age). Each chart was approximated by a function Ztheor, which predicted the potentially absent value(s). Statistical distributions of cB12 were aligned with physiological indicators of deficiency and used to determine cut-offs. RESULTS: The predictive functions Ztheor allowed assessment of the "incomplete" indicators, 3cB12 (three markers known) and 2cB12 (two markers known). Predictions contained a systematic deviation associated with dispersion along two axes Z and X (and unaccounted by the least squares fit). Increase in tHcy at low serum folate was corrected (cB12+Deltafolate) based on the function of Deltafolate=log10(Hcyreal/Hcytheor) versus folate. Statistical distributions of cB12 revealed the boundaries of groups with B12 deficiency, i.e., cB12<-0.5. CONCLUSIONS: We provide equations that combine two, three or four biomarkers into one diagnostic indicator, thereby rescaling unmatched data into the same coordinate system. Adjustment of this indicator is required if serum folate is <10 nmol/L and tHcy is measured. Revised cut-points and guidelines for using this approach are provided. PMID- 25720073 TI - Reporting of hemolysis index (HI) with laboratory results should be obligatory in newborns and infants. PMID- 25720074 TI - Unmeasurably high chloride: a surrogate marker of thiocyanate poisoning identification. PMID- 25720075 TI - The clinical performance of a chemiluminescent immunoassay in detecting anti cardiolipin and anti-beta2 glycoprotein I antibodies. A comparison with a homemade ELISA method. AB - BACKGROUND: Fully automated chemiluminescence immunoassays (CLIAs) are emerging technologies for the detection of anti-cardiolipin (aCL) and anti-beta2 glycoprotein I (anti-beta2GPI) antibodies for anti-phospholipid syndrome (APS) classification, which is commonly based on an enzyme-linked immunosorbent assay (ELISA) test result. CLIA and a homemade ELISA were used in this study to detect these antibodies, and their performances were compared. METHODS: Sera were collected from 104 patients with primary APS, 88 seronegative subjects who met the clinical but not the laboratory criteria for APS, and 150 control subjects. IgG/IgM aCL and IgG/IgM anti-beta2GPI antibodies were determined in the sera using a CLIA (HemosIL AcuStar(r)) and a homemade ELISA. RESULTS: CLIA had a significantly lower comparative sensitivity for IgM aCL and IgG/IgM IgG anti beta2GPI antibodies; its comparative specificity was higher with respect to ELISA for IgM aCL and IgM anti-beta2GPI antibodies. The two techniques showed a high, significant agreement (p<0.001) and a significant titer correlation (p<0.001). CLIA also detected IgG/IgM aCL and IgG anti-beta2GPI antibodies in the seronegative patients. There was a significantly higher prevalence of IgG aCL and IgG anti-beta2GPI antibodies (p<0.001 and p=0.01, respectively) in those patients with respect to that in the control population. CONCLUSIONS: Despite a lower comparative sensitivity, CLIA showed a higher comparative specificity for some aPL and a good level of agreement and correlation with a homemade ELISA. CLIA also detected some aCL and anti-beta2GPI antibodies in the seronegative patients not usually identified by homemade ELISA. PMID- 25720076 TI - The Empower project - a new way of assessing and monitoring test comparability and stability. AB - BACKGROUND: Manufacturers and laboratories might benefit from using a modern integrated tool for quality management/assurance. The tool should not be confounded by commutability issues and focus on the intrinsic analytical quality and comparability of assays as performed in routine laboratories. In addition, it should enable monitoring of long-term stability of performance, with the possibility to quasi "real-time" remedial action. Therefore, we developed the "Empower" project. METHODS: The project comprises four pillars: (i) master comparisons with panels of frozen single-donation samples, (ii) monitoring of patient percentiles and (iii) internal quality control data, and (iv) conceptual and statistical education about analytical quality. In the pillars described here (i and ii), state-of-the-art as well as biologically derived specifications are used. RESULTS: In the 2014 master comparisons survey, 125 laboratories forming 8 peer groups participated. It showed not only good intrinsic analytical quality of assays but also assay biases/non-comparability. Although laboratory performance was mostly satisfactory, sometimes huge between-laboratory differences were observed. In patient percentile monitoring, currently, 100 laboratories participate with 182 devices. Particularly, laboratories with a high daily throughput and low patient population variation show a stable moving median in time with good between-instrument concordance. Shifts/drifts due to lot changes are sometimes revealed. There is evidence that outpatient medians mirror the calibration set-points shown in the master comparisons. CONCLUSIONS: The Empower project gives manufacturers and laboratories a realistic view on assay quality/comparability as well as stability of performance and/or the reasons for increased variation. Therefore, it is a modern tool for quality management/assurance toward improved patient care. PMID- 25720077 TI - Development of the first urinary reproductive hormone ranges referenced to independently determined ovulation day. AB - BACKGROUND: Urinary hormone level analysis provides valuable fertility status information; however, previous studies have not referenced levels to the ovulation day, or have used outdated methods. This study aimed to produce reproductive hormone ranges referenced to ovulation day determined by ultrasound. METHODS: Women aged 18-40 years (no reported infertility) collected daily urine samples for one complete menstrual cycle. Urinary luteinising hormone (LH), estrone-3-glucuronide (E3G, an estradiol metabolite), follicle stimulating hormone (FSH) and pregnanediol-3-glucuronide (P3G, a progesterone metabolite) were measured using previously validated assays. Volunteers underwent trans vaginal ultrasound every 2 days until the dominant ovarian follicle size reached 16 mm, when daily scans were performed until ovulation was observed. Data were analysed to create hormone ranges referenced to the day of objective ovulation as determined by ultrasound. RESULTS: In 40 volunteers, mean age 28.9 years, urinary LH surge always preceded ovulation with a mean of 0.81 days; thus LH is an excellent assay-independent predictor of ovulation. The timing of peak LH was assay-dependent and could be post-ovulatory; therefore should no longer be used to predict/determine ovulation. Urinary P3G rose from baseline after ovulation in all volunteers, peaking a median of 7.5 days following ovulation. Median urinary peak E3G and FSH levels occurred 0.5 days prior to ovulation. A persistent rise in urinary E3G was observed from approximately 3 days pre- until 5 days post ovulation. CONCLUSIONS: This study provides reproductive hormone ranges referenced to the actual day of ovulation as determined by ultrasound, to facilitate examination of menstrual cycle endocrinology. PMID- 25720078 TI - Comparison of four automated serum vitamin B12 assays. AB - BACKGROUND: Diagnosis of vitamin B12 deficiency is generally based on the measurement of serum vitamin B12 levels. However, in selected cases functional indices of vitamin B12, such as methylmalonic acid (MMA) and homocysteine (HCY), are needed. Here we compare the performance of four automated total vitamin B12 assays and also investigate how these assays relate to functional indices of vitamin B12 status. METHODS: Total vitamin B12, MMA and HCY were measured in 69 serum samples from routine vitamin B12 assay requests. Serum vitamin B12 analysis was performed using four different immunoassay autoanalyzers: DxI 800 Unicel (Beckman Coulter, USA), ADVIA Centaur XP (Siemens Diagnostics, Tarrytown, NY, USA), Roche Cobas E601 (Roche Diagnostics, Germany), Architect i2000sr (Abbott Laboratories, Abbott Park, IL, USA). Serum MMA levels were determined by liquid chromatography-mass spectrometry (LC-MS) and serum homocysteine levels were determined by high pressure liquid chromatography (HPLC) methods. RESULTS: Four immunoassay methods were comparable and correlated with each other. Correlation coefficients (r) ranged from 0.898 to 0.987, p<0.001. Highest correlation was observed between Roche Cobas - Architect i2000sr and poorest correlation was observed between DxI 800 Unicel - ADVIA Centaur comparison. DxI 800 Unicel assay demonstrated high mean bias [-122 pg/mL (-616-125 pg/mL)] and a concordance correlation coefficient (CCC) of 0.9161, lower than the others. MMA and HCY were correlated with the vitamin B12 results. The correlation coefficients with their 95% CI indicated that there was no statistically significant difference between the four methods according to their relationship with MMA and HCY. CONCLUSIONS: Total B12 assays correlate very well with each other. However, results of DxI 800 Unicel were lower compared to the other three autoanalyzers. All total vitamin B12 methods show similar relationships with HCY and MMA. Standardization of serum vitamin B12 assays is still not completed and further standardization studies are needed. Laboratory professionals and clinicians should be aware of this disagreement between assay methods and they should use these tests as ancillary tests. PMID- 25720079 TI - INR vs. thrombin generation assays for guiding VKA reversal: a retrospective comparison. AB - BACKGROUND: Prothrombin complex concentrate (PCC) is used to reverse vitamin K antagonist (VKA)-induced anticoagulation. Prothrombin time-derived international normalized ratio (INR) measurements are widely used in determining the required PCC dose, but this approach requires reappraisal. The aim of the present study was to determine the added value of the thrombin generation assay (TGA) compared with the INR in guidance of VKA reversal by PCC. METHODS: In an open, observational study, INR and TGA measurements were carried out on plasma samples from phenprocoumon-treated patients receiving VKA reversal. Following both analytical methods, PCC dosing correlates were calculated and compared retrospectively. Alternatively, in vitro PCC spiking experiments were performed. RESULTS: As expected, an exponential relationship between PCC dose and INR was found. For the TGA parameters peak thrombin and endogenous thrombin potential (ETP), however, this relationship was found to be linear throughout the full therapeutic range. Additional computational analysis showed a positive correlation (r2=0.7) between the initial INR and PCC dose required for a target INR of 2.1, which was completely lost at a lower target INR. In contrast, a positive correlation (r2=0.8) between initial ETP as well as peak height and PCC dose required to obtain parameter normalization was found. These correlates appeared useful for calculating PCC dose. CONCLUSIONS: Our results support the current debate questioning the rationale for the use of the INR in the management of anticoagulation by VKA. Compared with INR, TGA-based calculations may enable a more accurate PCC dosing regimen for patients requiring VKA reversal. PMID- 25720080 TI - Evaluation of a low-cost procedure for sampling, long-term storage, and extraction of RNA from blood for qPCR analyses. AB - BACKGROUND: In large clinical trials, where RNA cannot be extracted immediately after sampling, preserving RNA in whole blood is a crucial initial step in obtaining robust qPCR data. The current golden standard for RNA preservation is costly and designed for time-consuming column-based RNA-extraction. We investigated the use of lysis buffer for long-term storage of blood samples for qPCR analysis. METHODS: Blood was collected from 13 healthy adults and diluted in MagMAX lysis/binding solution or PAXgene Blood RNA tubes and stored at -20 degrees C for 0, 1, or 4 months before RNA extraction by the matching method. RNA integrity, yield and purity were evaluated and the methods were compared by subsequent analyses of the gene expression levels of 18S, ACTB, IL1B, IL1RN, IL1R2, and PGK1 using qPCR. RESULTS: The MagMAX system extracted 2.3-2.8 times more RNA per mL blood, with better performance in terms of purity, and with comparable levels of integrity relative to the PAXgene system. Gene expression analysis using qPCR of 18S, ACTB, IL1B, IL1RN, IL1R2, and the promising blood specific reference gene, PGK1, revealed negligible differences (<1-fold) between the samples stored in MagMAX lysis/binding solution over time and between samples stored and extracted by the two systems. CONCLUSIONS: The MagMAX system can be used for storage of human blood for up to 4 months and is equivalent to the PAXgene system for RNA extraction. It furthermore, provides a means for significant cost reduction in large clinical trials. PMID- 25720081 TI - Simple high-throughput analytical method using ultra-performance liquid chromatography coupled with tandem mass spectrometry to quantify total 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine. AB - BACKGROUND: Since the urinary concentration of 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL) is a reliable biomarker of exposure to tobacco smoke, we developed a relatively simple high-throughput chromatographic method to quantify total urinary NNAL concentrations in the general population. METHODS: The high-throughput analytical method was developed using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) to identify and quantify total urinary NNAL concentrations in 10 non-smokers and 15 otherwise healthy smokers. RESULTS: Loss of nitric oxide at m/z 30 was found to be the predominant mass transitioned, and therefore was used as the SIM transition to quantify both NNAL and NNAL-methyl-d3 in urine. The analytical method did not require sample derivatization. Standard curves for total NNAL concentrations were linear between 20 and 1500 pg/mL, with coefficients of determination >0.95. Precision and accuracy ranged from 2.2% to 8.6% (CV) and from -5.6% to 10.9% (percent error), respectively. The lowest limit of quantification was 6.7 pg/mL, and 2.0 pg/mL the lowest limit of detection (LLOD). Total urinary NNAL concentrations in non-smoker subjects were =2.6 ng/mL], and placental lesions consistent with acute AF infection (acute histologic chorioamnionitis and/or acute funisitis) were examined according to the results of AF cultivation and PCR/ESI-MS as well as AF IL-6 concentrations. RESULTS: 1) Culture identified bacteria in AF from 46% (21/46) of the participants, whereas PCR/ESI-MS was positive for microorganisms in 59% (27/46) - combining these two tests, microorganisms were detected in 61% (28/46) of patients with clinical chorioamnionitis at term. Eight patients had discordant test results; one had a positive culture and negative PCR/ESI-MS result, whereas seven patients had positive PCR/ESI-MS results and negative cultures. 2) Ureaplasma urealyticum (n=8) and Gardnerella vaginalis (n=10) were the microorganisms most frequently identified by cultivation and PCR/ESI-MS, respectively. 3) When combining the results of AF culture, PCR/ESI-MS and AF IL-6 concentrations, 15% (7/46) of patients did not have intra-amniotic inflammation or infection, 6.5% (3/46) had only MIAC, 54% (25/46) had microbial-associated intra-amniotic inflammation, and 24% (11/46) had intra-amniotic inflammation without detectable microorganisms. 4) Placental lesions consistent with acute AF infection were significantly more frequent in patients with microbial-associated intra-amniotic inflammation than in those without intra-amniotic inflammation [70.8% (17/24) vs. 28.6% (2/7); P=0.04]. CONCLUSION: Microorganisms in the AF were identified in 61% of patients with clinical chorioamnionitis at term; 54% had microbial-associated intra-amniotic inflammation, whereas 24% had intra amniotic inflammation without detectable microorganisms. PMID- 25720101 TI - Inference for one-step beneficial mutations using next generation sequencing. AB - Experimental evolution is an important research method that allows for the study of evolutionary processes occurring in microorganisms. Here we present a novel approach to experimental evolution that is based on application of next generation sequencing. Under this approach population level sequencing is applied to an evolving population in which multiple first-step beneficial mutations occur concurrently. As a result, frequencies of multiple beneficial mutations are observed in each replicate of an experiment. For this new type of data we develop methods of statistical inference. In particular, we propose a method for imputing selection coefficients of first-step beneficial mutations. The imputed selection coefficient are then used for testing the distribution of first-step beneficial mutations and for estimation of mean selection coefficient. In the case when selection coefficients are uniformly distributed, collected data may also be used to estimate the total number of available first-step beneficial mutations. PMID- 25720102 TI - Regularization method for predicting an ordinal response using longitudinal high dimensional genomic data. AB - Abstract An ordinal scale is commonly used to measure health status and disease related outcomes in hospital settings as well as in translational medical research. In addition, repeated measurements are common in clinical practice for tracking and monitoring the progression of complex diseases. Classical methodology based on statistical inference, in particular, ordinal modeling has contributed to the analysis of data in which the response categories are ordered and the number of covariates (p) remains smaller than the sample size (n). With the emergence of genomic technologies being increasingly applied for more accurate diagnosis and prognosis, high-dimensional data where the number of covariates (p) is much larger than the number of samples (n), are generated. To meet the emerging needs, we introduce our proposed model which is a two-stage algorithm: Extend the generalized monotone incremental forward stagewise (GMIFS) method to the cumulative logit ordinal model; and combine the GMIFS procedure with the classical mixed-effects model for classifying disease status in disease progression along with time. We demonstrate the efficiency and accuracy of the proposed models in classification using a time-course microarray dataset collected from the Inflammation and the Host Response to Injury study. PMID- 25720103 TI - Why women who have mastectomy decide not to have breast reconstruction? AB - Breast cancer is the most common malignancy occurring in women. The treatment of breast cancer is a complex, multistep process involving surgical treatment, chemotherapy, radiotherapy, hormone therapy, targeted therapy, and very often rehabilitation. After the treatment of the underlying disease, or still in its course, there remains a problem of deformation of the chest. Although the number of women opting for breast reconstructive surgery increases every year, the number of such procedures in Poland is low. The aim of the study was to investigate the reasons why women after amputation of the breast due to cancer are not likely to undergo breast reconstructive surgery. MATERIAL AND METHODS: The study comprised 73 women, residents of the province of Silesia, aged between 37 and 79 years, who had undergone mastectomy for malignancy in the years 1987 2013. RESULTS: From all of the reasons given by women for refraining from breast reconstruction, the most frequently pointed was the fear of being subjected to further surgery (38.3%). 23 women (31.5%) admitted that they were also afraid of postoperative pain. Similarly, a common response (35.6%) was that it is not essential for their mental state, and 30% of respondents fully accepted their appearance after mastectomy. Concern about the effect of failed reconstruction was reported by 24.6% of the women, and the fear that the surgery could negatively affect the process of cancer treatment by 27.4% of respondents. Lack of information about the capabilities and knowledge of breast reconstruction methods was not an important factor in decision-making. CONCLUSIONS: Most of the surveyed women who abandon breast reconstruction surgery, make this decision on the basis of more than one reasons. Fear of undergoing a second surgical procedure and pain related to it were the most important reasons for the refusal of breast reconstruction. An important factor in the decision to desist from breast reconstruction is the age of the patients. PMID- 25720104 TI - Preliminary outcome of treatment of postoperative primarily closed sternotomy wounds treated using negative pressure wound therapy. AB - Hospital infections, and in particular infections of the surgical site are a common problem of the procedural departments. Due to continuous progress of surgical techniques and patient population getting older with multiple co morbidities, multidirectional actions need to be taken to avoid these infections or, if they do occur, achieve optimal treatment outcomes. Vacuum wound therapy is one of the directions that has been developed over the recent years. The aim of the study evaluate wound healing in patients after an off-pump coronary artery bypass grafting procedure, using the internal mammary artery, treated with negative pressure wound therapy system. MATERIAL AND METHODS: This prospective, open label study evaluated healing of postoperative sternotomy wounds after their primary closure with negative pressure wound therapy, using continuous negative pressure of -80 mmHg in 40 patients and 40 patients in a control group in whom conventional dressings were applied in the postoperative period. RESULTS: The number of patients in whom primary wound healing occurred without complications was significantly higher in the negative pressure wound therapy group versus the control group (x2 test =4.50, p=0.0339) and the number of total superficial infections was significantly smaller versus the control group (x2 test =5; p=0.0254). Antibiotic therapy was also initiated significantly less often as compared to the group treated with conventional dressings (x2 test = 4.11; p=0.0425). CONCLUSIONS: Negative pressure wound therapy after primary wound closure reduces the risk of superficial infections in the population with multiple risk factors of complications in the sternotomy wound healing. PMID- 25720105 TI - Food, mechanic and septic complications in patients enterally nutritioned in home conditions. AB - Home enteral nutrition (HEN for short) allows practically normal living for patients who cannot be fed orally but at the same time do not have to stay in hospitals, which is often found to decrease their mental condition, increase of probability of complications and costs of medical treatment. The aim of the study was to analyze the frequency of nutritional, mechanical and septic complications in patients fed enterally in home conditions. MATERIAL AND METHODS: The study performed using retrospective analysis of study results and reports from control visits for patients in the period between 2012-2013. 147 patients fed enterally using HEN method participated in the study, including 70 men and 77 women aged 19 to 99 years (average 65 years). The following type of gastrointestinal tract access was used for patients: PEG in 113 (76.5%), feeding jejunostomy - 21 (1.4%), PEG-PEJ - 5 (3.5%), in case of the remaining 8 patients the nasogastric gavage (5.5%) was used. RESULTS: The most common complication were infections (of gastric tract, skin soft tissue in the region of nutritional fistula entry, in three cases the aspiration pneumonia was diagnosed) found in 55 (49.1%) of cases. Mechanical complications were found out in 29 (25.9% of all complications), nutritional complications were present 28 times, which constituted 25% of all complications. CONCLUSIONS: In the studied group of patients with an implemented HEN procedure, septic complications were the most common problem. The longest average nutrition time with PEG-PEJ probably results from the effective protection of the patient against aspiration pneumonia. PMID- 25720106 TI - CIDE-A gene expression in patients with obesity qualified for endovascular treatment of abdominal aorta aneurysm. AB - CIDE-A gene and the genes of LRP group play a key role in the regulation of the body weight and lipid metabolism in mammals. CIDE-A is defined as a potential human obesity gene and the LRP1 gene is associated with the development of abdominal aortic aneurysm (AAA). The aim of the study was to define the role of CIDE-A gene in patients with dyslipidemia and asymptomatic AAA. MATERIAL AND METHODS: The study group consisted of 38 subjects, including 27 men and 11 women qualified for endovascular aneurysm repair (EVAR). The subjects with abdominal aortic aneurysm were enrolled in the study group, depending on the body mass index (BMI); in obese patients (BMI > 30). The control group (n = 16) included subjects without lipid disorders. One-step isolation of RNA from lymphocytes and adipose tissue cells was performed using the modified TRI method by Chomc-zynski and Sacchi, and then the gene expression was tested by real-time PCR. RESULTS: The highest mean relative of the gene expression for CIDE-A was reported in subjects with the normal body weight. The lowest mean relative of the gene expression for CIDE-A was observed in the group of obese patients with aortic aneurysm and lipid disorders. A high negative correlation (r = -0.7101) in the gene expression for CIDE-A was observed in the group of obese patients with aortic aneurysm, depending on the BMI. CONCLUSIONS: Due to the important role of the CIDE-A gene and Cide-A protein in the development of metabolic syndrome, obesity and the accompanying vascular lesions such as abdominal aortic an-eurysm, seen in this context, the tested gene and protein Cide-A represent a potential therapeutic target in these diseases. PMID- 25720107 TI - Clinical significance of Van Nuys Prognostic Index as a qualification criterion to sentinel lymph node biopsy in patients diagnosed with ductal carcinoma in situ. AB - Diagnose of ductal carcinoma in situ (DCIS) requires, at least in a part of cases, assessment of auxiliary lymph nodes. The aim of the study was to analyze clinical value of Van Nuys Prognostic Index (VNPI) as the important criterion for qualification of DCIS patients to sentinel lymph node biopsy (SLNB). MATERIAL AND METHODS: Analysis included patients diagnosed with DCIS and qualified to SLNB, operated in years 2004-2013. We performed a statistical analysis to assess correlation between VNPI value and positive pathological verification of excised sentinel lymph node (SLN). The influence of other clinical factors on presence of metastases in SLN was also determined. RESULTS: 3,6% of DCIS patients were diagnosed with metastases in SLN. Metastases were diagnosed in 6.7% patients with VNPI > 10 points vs 3.4% in patients with VNPI < 10 points. In 75% of patients with metastatic SLN the value of VNPI was at least 10 points. In premenopausal patients metastases in SLN were diagnosed in 8.1% of cases vs 1.4% in postmenopausal patients. In patients diagnosed with cancer of the other breast metastases in SLN were found in 6.3% of cases vs 3.2% in one-sided cancer. Patients with multifocal cancer were over twice as often diagnosed with metastases in SLN (5% vs 2%). There was no correlation found between VNPI value and positive pathological verification of SLN. No differences between prevalence of SLN metastases depending on selected clinical features were found. CONCLUSIONS: Recommendation of VNPI as the criterion of qualification to SLNB starting with 10 points could be more favourable in patients with DCIS. Deciding on SLNB in DCIS patients, we should also take into consideration other clinical features. PMID- 25720108 TI - Phlegmon of the foot as a camel bite complication. AB - The great popularity of foreign excursions and travel in exotic directions, as well as increasing popularity of breeding exotic animals at home, is evidence that in daily practice one may observe injuries inflicted by animals atypically occurring in Poland. The study presented and described a rare case of a patient attacked by a camel living in an agro-tourism farm in our country. Thanks to the combination of surgical and conservative treatment complete wound healing was observed, including the skin grafts, with preserved motor function of the foot. PMID- 25720109 TI - Richter type of incarcerated obturator hernia; misery still continues. AB - Obturator hernia is a rare type of hernia which accounts for only 0.07-1.4% of all intra-abdominal hernias and 0.2-5.8% of small-intestinal obstructions. It develops predominantly in elderly underweight women. It has nonspecific early symptoms, so these hernias are usually discovered only after they have become incarcerated. Incarcerated obturator hernias are usually discovered on abdominal computed tomography scan or emergency surgery due to bowel obstruction. Here we present a case of a 65-year-old female who presented with intermittent abdominal pain, distension and nausea for last 3 days. She was a known case of hypothyroidism, taking Levothyroxine in inadequate dose. Her intial abdominal Xray was showing few air-fluid level with air present in rectum. She was initially managed conservatively but later developed features of peritonitis for which she was operated. In laparotomy, Richter type of right-sided incarcerated obturator hernia was discovered with a small necrotic area and perforation of small bowel. Bowel resection was performed and obturator hernia was closed with interrupted sutures. The patient recovered without complications. Obturator hernia, due to its rarity and nonspecific early symptoms, can still be misleading even to the most experienced clinicians. Delay in diagnosis of obturator hernia can lead to bowel necrosis and perforation with significant postoperative morbidity and mortality. PMID- 25720110 TI - A case of traumatic rupture of the pancreas. Combined surgical and endoscopic management. AB - Traumatic rupture of the pancreas is a rare and difficult diagnostic and therapeutic problem. The authors present a case of traumatic rupture of the pancreas (grade IV on AAST scale) where concurrent endoscopic and surgical management was used. PMID- 25720111 TI - Lymph node harvest (LNH) in colorectal cancer; a critical appraisal. PMID- 25720112 TI - Successful endoscopic treatment of a postoperative tracheomediastinal fistula caused by anastomotic insufficiency after esophageal resection with fibrin glue. AB - Fistula development after esophageal resection is considered as one of the most serious postoperative complications. The authors reported a case on clinical experiences in the postoperative diagnostic and successful therapeutic management of a tracheomediastinal fistula after esophageal resection, using endoscopic application of fibrin glue. The early approach of an anastomotic insufficiency after esophageal resection because of a squamous cell carcinoma (pT3pN0M0G2) below the tracheal bifurcation including transposition of a re-modelled gastric tube and end-to-side anastomosis 24 hours postoperatively in a 55-year old patient combined i) surgical re-intervention from the periesophageal site (reanastomosis, gastroplication, lavage, local and mediastinal drainage) and, later on, ii) extensive rinsing with consecutive endoscopic fibrin glue application into the tracheal mouth of the subsequently developed tracheomediastinal fistula as a consequence of the inflammatory changes within the surrounding tissue. In conclusion, this approach was successful and beneficial for the patient's further postoperative course, which was associated with other complications such as pneumonia and acute myocardial infarction. The fistula closed sufficiently and permanently with no further surgical intervention at the tracheal as well as mediastinal site and allowed patient's later discharge with no further complaints or problems. PMID- 25720113 TI - Primary duodenal carcinoma--case report. AB - Duodenal carcinoma is a rare tumor of the gastrointestinal tract of an insidious and secretive course, often diagnosed during the advanced stage of the disease. The study presented a case of a female patient diagnosed with duodenal carcinoma, subjected to two-staged surgery. The initial surgical intervention consisted in the implementation of a gastrointestinal anastomosis, followed by radical surgery by means of Whipple's method performed after three years. PMID- 25720114 TI - Practical approach to inguinal hernia treatment--guidelines of the Association of Polish Surgeons. PMID- 25720115 TI - Problematic internet use and social networking site use among Dutch adolescents. AB - Problematic Internet use (PIU), defined as Internet use that is risky, excessive, or impulsive in nature and leads to adverse life consequences, is an emerging health concern among adolescents worldwide. Social networking site (SNS) use is among the most popular and common Internet use activities for youth; however, risks of SNS use for PIU remain unexplored. The purpose of this study was to determine the prevalence of adolescents at risk for PIU within a national school based sample of Dutch adolescents and to explore associations between SNS use and PIU. Adolescents were recruited from six public schools in the Netherlands to complete a survey, which included SNS use questions and the Problematic and Risky Internet Use Screening Scale (PRIUSS). Logistic regression models were used to test associations between risk for PIU and demographic or SNS use variables. A total of 474 adolescents participated (98% response rate), and 11% (n=51) of adolescents were at risk for PIU. Risk for PIU was significantly associated with gender (p=0.015), increased age (p=0.034), and posting on SNS more than four times a day (p=0.003). Risk for PIU was not associated with number of SNS profiles, SNS preference or the number of online friends. Findings illustrate high risk groups for PIU includes males and older teens. Findings also illuminate that risk for PIU related to SNS was not associated with a specific SNS or number of SNSs used but was related to one's personal investment in SNSs by posting four or more times a day. PMID- 25720116 TI - Caenorhabditis elegans as a model to study sphingolipid signaling. AB - Sphingolipid signaling in Caenorhabditis elegans is vital for sensing environmental change and effecting appropriate cellular response. Many molecular components in sphingolipid intermediary metabolism are conserved throughout evolution. Here we review use of C. elegans as a model system for conducting sphingolipid-based scientific investigation, which has helped us better understand vital roles these remarkable lipids play in human metabolism and disease. PMID- 25720117 TI - Transcriptional and translational mechanisms contribute to regulate the expression of Discs Large 1 protein during different biological processes. AB - Human discs large (DLG1) has been demonstrated to be involved in cell polarity and maintenance of tissue architecture. However, the mechanisms controlling DLG1 expression are not fully understood. This is relevant as DLG1 is lost during the later stages of malignant progression. We initiated a series of studies to analyse the mechanisms regulating DLG1 expression. We have previously reported the identification of an alternative splicing event in the 5' untranslated region (5'-UTR) of DLG1 mRNA that generates transcripts with two different 5'-UTR (short and large 5'-UTR variants). In this study, we further examined the impact of the DLG1 transcription and the role of the differential expression of the alternative 5'-UTRs on DLG1 protein levels. We analysed these mechanisms during cell processes like differentiation, cell cycle progression and cell-cell contact formation, where the importance of DLG1 activities was previously established. The data presented in this report suggest that the transcriptional regulation of DLG1 strongly contributes to DLG1 abundance and that differential expression of alternative 5'-UTRs with different translational properties, also cooperates, depending on the cell type and cell situation. This study provides new evidence for understanding the transcriptional regulation of DLG1 and the changes in DLG1 expression during different biological processes. PMID- 25720118 TI - Purification and characterisation of recombinant His-tagged RgpB gingipain from Porphymonas gingivalis. AB - Gingipain proteases are important virulence factors from the periodontal pathogen Porphyromonas gingivalis and are the target of many in vitro studies. Due to their close biochemical properties, purification of individual gingipains is difficult and requires multiple chromatographic steps. In this study, we demonstrate that insertion of a hexahistidine affinity tag upstream of a C terminal outer membrane translocation signal in RgpB gingipain leads to the secretion of a soluble, mature form of RgpB bearing the affinity tag that can easily be purified by nickel-chelating affinity chromatography. The final product obtained high yielding high purity is biochemically indistinguishable from the native RgpB enzyme. PMID- 25720119 TI - Evolutionary divergence of Threonine Aspartase1 leads to species-specific substrate recognition. AB - Proteases are key regulators of life. Human Threonine Aspartase1 processes substrates, such as the mixed-lineage leukemia (MLL) protein, containing two cleavage sites, CS1 and CS2. Likewise, MLL's Drosophila ortholog trithorax is cleaved by Drosophila Threonine Aspartase1 (dTasp), suggesting a mechanistic coevolution. However, a detailed analysis of dTasp's function was missing so far. Here, active and inactive dTasp mutants allowed to compare substrate recognition and cleavage site selectivity of human and Drosophila enzymes. In contrast to the human protease, our cell-based assay revealed a preferential processing of CS2 like (QLD?Gx[xD/Dx]) targets for dTasp, whereas cleavage of CS1-like targets (QVD?Gx[xD/Dx]) was significantly impaired. Systematic mutagenesis of the CS2 sequence defined the motif x[FILMW]D?Gx[xD/Dx] as the consensus cleavage sequence for dTasp. Substrate species selectivity of the enzymes was uncovered by demonstrating that dTasp cleaves Drosophila TFIIA, but not the human ortholog, suggesting evolutionary divergence of TFIIA downstream networks. Also, Drosophila USF2 was neither predicted nor cleaved by dTasp. Moreover, we found that dTasp cleavage site selectivity is independent of heterocomplex formation, as dTasp exists predominantly as an alphabeta-monomer. Collectively, we provide novel insights into evolutionary similarities and divergence concerning Threonine Aspartase1 function in different species, which may aid to dissect and better target human Threonine Aspartase1 in malignancies. PMID- 25720120 TI - When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding. AB - DEAD-box helicases catalyze RNA duplex unwinding in an ATP-dependent reaction. Members of the DEAD-box helicase family consist of a common helicase core formed by two RecA-like domains. According to the current mechanistic model for DEAD-box mediated RNA unwinding, binding of RNA and ATP triggers a conformational change of the helicase core, and leads to formation of a compact, closed state. In the closed conformation, the two parts of the active site for ATP hydrolysis and of the RNA binding site, residing on the two RecA domains, become aligned. Closing of the helicase core is coupled to a deformation of the RNA backbone and destabilization of the RNA duplex, allowing for dissociation of one of the strands. The second strand remains bound to the helicase core until ATP hydrolysis and product release lead to re-opening of the core. The concomitant disruption of the RNA binding site causes dissociation of the second strand. The activity of the helicase core can be modulated by interaction partners, and by flanking N- and C-terminal domains. A number of C-terminal flanking regions have been implicated in RNA binding: RNA recognition motifs (RRM) typically mediate sequence-specific RNA binding, whereas positively charged, unstructured regions provide binding sites for structured RNA, without sequence-specificity. Interaction partners modulate RNA binding to the core, or bind to RNA regions emanating from the core. The functional interplay of the helicase core and ancillary domains or interaction partners in RNA binding and unwinding is not entirely understood. This review summarizes our current knowledge on RNA binding to the DEAD-box helicase core and the roles of ancillary domains and interaction partners in RNA binding and unwinding by DEAD-box proteins. PMID- 25720122 TI - Biological variation of plasma osmolality obtained with capillary versus venous blood. AB - BACKGROUND: Plasma osmolality (POsm) is a gold standard to assess hydration status but requires venipuncture. POsm obtained by lancing a digit, a source of capillary puncture blood (CAP), has not been validated. This study compared POsm from CAP versus venous blood (VEN) and validated its sensitivity to detect dehydration. METHODS: Healthy young adults (Study A: n=20 men, 22 women; Study B: n=23 men, 23 women) participated. In Study A, CAP and VEN were compared under controlled euhydration meeting dietary reference intakes for water (3.7 L men, 2.7 L women). In Study B, CAP was assessed for sensitivity to detect dehydration with receiver operating characteristic analysis over two 24 h periods: euhydration for 24 h followed by water restriction over 24 h. POsm was measured using freezing point depression. RESULTS: For all subjects, CAP POsm (283.0+/-3.9 mOsm/kg) was not significantly different (p=0.07) from VEN (284.2+/-3.5) during euhydration and met analytical goals for individuality and heterogeneity. When outliers (n=3) were eliminated, mean difference was -1.6 (+/-3.2) lower (p<0.01) with CAP. Fluid restriction increased (p<0.001) CAP POsm (284.0+/-4.4 to 292.8+/ 5.2 mOsm/kg), achieving excellent accuracy (0.92) and sensitivity (89.1%) to predict mild dehydration (2% body mass loss). CONCLUSIONS: POsm via CAP exhibited similar coefficients of variation and analytical goals compared to VEN combined with excellent accuracy and sensitivity to detect dehydration. Although CAP values were approximately 2 mOsm/kg lower than VEN, CAP appears an adequate substitute for tracking changes in non-clinical settings. PMID- 25720121 TI - Thiol-based redox switches in prokaryotes. AB - Bacteria encounter reactive oxygen species (ROS) as a consequence of the aerobic life or as an oxidative burst of activated neutrophils during infections. In addition, bacteria are exposed to other redox-active compounds, including hypochloric acid (HOCl) and reactive electrophilic species (RES) such as quinones and aldehydes. These reactive species often target the thiol groups of cysteines in proteins and lead to thiol-disulfide switches in redox-sensing regulators to activate specific detoxification pathways and to restore the redox balance. Here, we review bacterial thiol-based redox sensors that specifically sense ROS, RES and HOCl via thiol-based mechanisms and regulate gene transcription in Gram positive model bacteria and in human pathogens, such as Staphylococcus aureus and Mycobacterium tuberculosis. We also pay particular attention to emerging widely conserved HOCl-specific redox regulators that have been recently characterized in Escherichia coli. Different mechanisms are used to sense and respond to ROS, RES and HOCl by 1-Cys-type and 2-Cys-type thiol-based redox sensors that include versatile thiol-disulfide switches (OxyR, OhrR, HypR, YodB, NemR, RclR, Spx, RsrA/RshA) or alternative Cys phosphorylations (SarZ, MgrA, SarA), thiol-S alkylation (QsrR), His-oxidation (PerR) and methionine oxidation (HypT). In pathogenic bacteria, these redox-sensing regulators are often important virulence regulators and required for adapation to the host immune defense. PMID- 25720123 TI - FTL gene mutation and persistent hyperferritinemia without iron deficiency anemia after phlebotomy. PMID- 25720124 TI - Neurofilament medium polypeptide (NFM) protein concentration is increased in CSF and serum samples from patients with brain injury. AB - BACKGROUND: Brain injury is a medical emergency that needs to be diagnosed and treated promptly. Several proteins have been studied as biomarkers of this medical condition. The aims of this study were to: 1) evaluate the selectivity and precision of a commercial ELISA kit for neurofilament medium polypeptide (NFM) protein; and 2) evaluate the concentration in cerebrospinal fluid (CSF) and serum of healthy individuals and patients with brain damage. METHODS: An ELISA from Elabscience was used. The selectivity was evaluated using size-exclusion chromatography and mass spectrometry. Intra- and inter-batch coefficients of variation (CV) were also studied. Fifty-one CSF samples from 36 age-matched patients with hemorrhagic stroke (HS) (n=30), ischemic stroke (IS) (n=11) and healthy individuals (n=10) were assayed. In addition, serum samples from healthy volunteers (n=47), 68 serum samples from seven patients with HS, 106 serum samples from 12 patients with traumatic brain injury (TBI) and 68 serum samples from 68 patients with mild traumatic brain injury (mTBI) were also analyzed. RESULTS: NFM was identified in the chromatographic fraction with highest immunoreactivity. The intra- and inter-batch CVs were <=10% and <=13%, respectively. The CSF-NFM concentration in HS was significantly higher (p<0.0001) than in IS and controls. Serum NFM concentration ranged from 0.26 to 8.57 ng/mL in healthy individuals (median=2.29), from 0.97 to 42.4 ng/mL in HS (median=10.8) and from 3.48 to 45.4 ng/mL in TBI (median=14.7). Finally, 44% of patients with mTBI had increased NFM concentration, with significantly higher levels (p=0.01) in patients with polytrauma. CONCLUSIONS: To our knowledge this is the first study describing increased NFM levels in CSF and serum from patients with brain damage. PMID- 25720125 TI - The 1999 Stockholm Consensus Conference on quality specifications in laboratory medicine. AB - The setting of analytical quality specifications in laboratory medicine has been a topic of discussion and debate for over 50 years: 15 years ago, as the subject matured and a profusion of recommendations appeared, many of them from expert groups, it was realised by a number of leading professionals that there was a need for a global consensus on the setting of such specifications. The Stockholm Conference held in 1999 on "Strategies to set global analytical quality specifications in laboratory medicine" achieved this and advocated the ubiquitous application of a hierarchical structure of approaches. The hierarchy has five levels, namely: 1) evaluation of the effect of analytical performance on clinical outcomes in specific clinical settings; 2) evaluation of the effect of analytical performance on clinical decisions in general using a) data based on components of biological variation, or b) analysis of clinicians' opinions; 3) published professional recommendations from a) national and international expert bodies, or b) expert local groups or individuals; 4) performance goals set by a) regulatory bodies, or b) organisers of external quality assessment (EQA) schemes; and 5) goals based on the current state of the art as a) demonstrated by data from EQA or proficiency testing scheme, or b) found in current publications on methodology. This approach has been much used since its wide promulgation, but there have been ongoing criticisms and new developments. The time seems right for an objective reappraisal of recommended strategies to set analytical performance goals. PMID- 25720126 TI - Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants. AB - BACKGROUND: Reliable reference intervals for two novel urinary biomarkers of renal injury, neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) are lacking for infants. Therefore, the aim of our study was to establish reference intervals for urinary NGAL and KIM-1 absolute concentrations as well as normalized to urinary creatinine in young infants categorized in small age intervals. METHODS: From June 2010 to March 2014, serum and urine samples of 106 basically healthy infants (born between 37 and 42 weeks of gestation) aged 1 day to 1 year were collected. Blood samples were assayed for serum creatinine levels to confirm a healthy renal status. Urine samples were assayed for creatinine, uNGAL (ng/mL) and uKIM-1 (ng/mL). RESULTS: Two thirds of the study cohort were boys. uNGAL concentrations declined with increasing age (likelihood ratio test, p=0.001). Also, uNGAL concentrations were higher in girls (50th centile uNGAL was 27.1 ng/mL) than boys (50th centile uNGAL was 14.3 ng/mL) (two tailed Wald test, p<0.001) NGAL concentrations were not related to ethnicity. uKIM-1 concentrations were extremely low in almost all 106 subjects [median uKIM-1 was 0.08 (IQR 0.08-0.08) ng/mL] and not related with age, gender or ethnicity (all p>0.05). CONCLUSIONS: Our data uniquely provide uNGAL and uKIM 1 reference intervals for the first year of life. Notably, only uNGAL levels decreased with increasing age and were higher in girls. These reference intervals enable future studies to evaluate the performance of both biomarkers in detecting early kidney tubular injury, particularly in the setting of critical care. PMID- 25720127 TI - The highs and lows of tumor biomarkers: lost illusions. PMID- 25720128 TI - Robust bayesian sensitivity analysis for case-control studies with uncertain exposure misclassification probabilities. AB - Exposure misclassification in case-control studies leads to bias in odds ratio estimates. There has been considerable interest recently to account for misclassification in estimation so as to adjust for bias as well as more accurately quantify uncertainty. These methods require users to elicit suitable values or prior distributions for the misclassification probabilities. In the event where exposure misclassification is highly uncertain, these methods are of limited use, because the resulting posterior uncertainty intervals tend to be too wide to be informative. Posterior inference also becomes very dependent on the subjectively elicited prior distribution. In this paper, we propose an alternative "robust Bayesian" approach, where instead of eliciting prior distributions for the misclassification probabilities, a feasible region is given. The extrema of posterior inference within the region are sought using an inequality constrained optimization algorithm. This method enables sensitivity analyses to be conducted in a useful way as we do not need to restrict all of our unknown parameters to fixed values, but can instead consider ranges of values at a time. PMID- 25720129 TI - GenePEN: analysis of network activity alterations in complex diseases via the pairwise elastic net. AB - Complex diseases are often characterized by coordinated expression alterations of genes and proteins which are grouped together in a molecular network. Identifying such interconnected and jointly altered gene/protein groups from functional omics data and a given molecular interaction network is a key challenge in bioinformatics. We describe GenePEN, a penalized logistic regression approach for sample classification via convex optimization, using a newly designed Pairwise Elastic Net penalty that favors the selection of discriminative genes/proteins according to their connectedness in a molecular interaction graph. An efficient implementation of the method finds provably optimal solutions on high-dimensional omics data in a few seconds and is freely available at http://lcsb portal.uni.lu/bioinformatics. PMID- 25720130 TI - Integrating traditional medical practice with primary healthcare system in Eritrea. AB - BACKGROUND: The purpose of this paper was to assess the perceptions and attitudes of modern medical practitioners (MMPs) and traditional medical practitioners (TMPs) about traditional medical practice and to analyze the utilization of traditional medicine in Eritrea. METHODS: The data for this study were collected in a 10-month period from January to October 2004. A cross-sectional study was conducted in three sub-zones of Eritrea: Dekemhare, Ghinda, and Maekel. A total of 500 (250 each) MMPs and TMPs, and 1657 households were included in the study. Data were collected both by questionnaire and an interview (with key informants). RESULTS: Our study reveals that there is a significant difference in perception and attitude between MMPs and TMPs about traditional medical practice in Eritrea. Their differences lie not only in their way of thinking but also in their perceptions of man and health. Our study further shows that in most rural communities in Eritrea, the use of traditional medicine and self-care is extensive. This is the case even in the presence of the supposedly free/subsidized health care available in government health centers. CONCLUSIONS: Higher confidence in traditional medicine for the treatment of serious illnesses, irrespective of availability of western medical service in many parts of Eritrea, indicates the need for selective integration of traditional medical practice with the primary healthcare system of the country. PMID- 25720132 TI - SCOT Data. Organ transplantation in Saudi Arabia--2013. PMID- 25720133 TI - [Overlapping genes and antisense transcription in eukaryotes]. AB - Numerous studies showed that overlapping genes are fairly common elements of genome organization, not only in viruses and prokaryotes but also in eukaryotes. At the same time, the regulatory mechanisms of overlapping gene expression, as well as the functional relevance of antisense transcription, are still relatively unknown. This review describes the history of the discovery of regulatory antisense RNAs, the types of gene overlap, and the putative mechanisms of their functioning. In conclusion, the critical views of different authors on the problem of detecting overlapping genes and an evaluation of the level of antisense transcription are presented. PMID- 25720134 TI - [Phylogenetic diversity of microorganisms associated with the deep-water sponge Baikalospongia intermedia]. AB - The diversity of bacteria associated with deep-water sponge Baikalospongia intermedia was evaluated by sequence analysis of 16S rRNA genes from two sponge samples collected in Lake Baikal from depths of 550 and 1204 m. A total of 64 operational taxonomic units, belonging to nine bacterial phyla, Proteobacteria (classes Alphaproteobacteria,. Betaproteobacteria, Gammaproteobacteria, and Deltaproteobacteria), Actinobacteria, Planctomycetes, Cloroflexi, Verrucomicrobia, Acidobacteria, Chlorobi, and Nitrospirae, including candidate phylum WS5, were identified. Phylogenetic analysis showed that the examined communities contained phylotypes exhibiting homology to uncultured bacteria from different lake ecosystems, freshwater sediments, soil and geological formations. Moreover, a number of phylotypes were relative to psychrophilic, methane oxidizing, sulfate-reducing bacteria, and to microorganisms resistant to the influence of heavy metals. It seems likely that the unusual habitation conditions of deep-water sponges contribute to the taxonomic diversity of associated bacteria and have an influence on the presence of functionally important microorganisms in bacterial communities. PMID- 25720135 TI - [Influence of salt stress on the genetically polymorphic system of Sinorhizobium meliloti-Medicago truncatula]. AB - The impacts of salt stress (75 mM NaC1) on the ecological efficiency of the genetically polymorphic Sinorhizobium meliloti-Medicago truncatula system were studied. Its impact on a symbiotic system results in an increase of the partners' variability for symbiotic traits and of the symbiosis integrity as indicated by: a) the specificity of the partners' interactions--the nonadditive inputs of their genotypes into the variation of symbiotic parameters; and b) the correlative links between these parameters. The structure of the nodDI locus and the content correlates to the efficiency of the symbiosis between S. meliloti and M. truncatula genotypes under stress conditions more sufficiently than in the absence of stress. Correlations between the symbiotic efficiency of rhizobia strains and their growth rate outside symbiosis are expressed under stress conditions, not in the absence of stress. Under salt stress symbiotic effectiveness was decreased for M. truncatula line F83005.5, which was salt sensitive for mineral nutrition. The inhibition of symbiotic activity for this line is linked with decreased nodule formation, whereas for Jemalong 6 and DZA315.16 lines it is associated with repressed N2-fixation. It was demonstrated for the first time that salt stress impairs the M. truncatula habitus (the mass : height ratio increased 2- to 6-fold), which in the salt-resistant cultivar Jemalong 6 is normalized as the result of rhizobia inoculation. PMID- 25720136 TI - [Polymorphism of the IPK1 gene among members of the genus Glycine]. AB - The structural polymorphism of the IPK1 gene involved in the biosynthesis of phytic acid was studied in 30 samples from three species of the genus Glycine (G. max, G. soja, and G. gracilis). Single nucleotide polymorphisms in the sequences of the first and the second introns of the IPK1 gene were found, differences in the length ofmicrosatellite loci located in intron 2 were demonstrated, and a total of six polymorphic variants were identified. Dataon the distribution of the identified alleles among the samples from the working set and the analysis and discussion of these data are given. PMID- 25720137 TI - [Analysis of meiotic genome stabilization in the rye-wheat amphidiploid secalotriticum (*Secalotriticum, s/RRAABB, 2n = 42)]. AB - The results of cytogenetic studies of genome stabilization in secalotriticum are presented. Comparative analysis of microsporogenesis in hexaploid secalotriticum, triticale, and reciprocal hybrids of them (S/RRAABB, T/AABBRR, 2n = 6x = 42) was carried out. The cytogenetic properties and genotypic factors of genome stabilization in heteroplasmic triticale were found. The inheritance by the secalotriticum of the genotypically caused first meiotic division, the so-called reduction division, ofunivalents from original combinations of rye-triticale hybrids was demonstrated for the first time. PMID- 25720138 TI - [Detection of genetic determinants that define the difference of near-isogenic Triticum aestivum L. Lines in photoperiodic sensitivity]. AB - Identification of genetic determinants that define different degrees of line sensitivity to the photoperiod was conducted on material of near-isogenic lines of the soft hexaploid wheat Triticum aestivum L. using SSR markers and markers specific to the Vrn and Ppd genes. It was established that the Ppd-s line contains a dominant Ppd-Dla allele located on chromosome 2D. This allele is characterized by a vast deletion in the gene promoter region. For two other lines (Ppd-m and Ppd-w), introgression of the Ppd-B1 gene on chromosome 2B was shown from the parental Sonora variety, which is slightly sensitive to the length of the day; however, the previously described Ppd-Bla. 1 allele was not found. Another polymorphism that can cause weak photoperiodic sensitivity, an increased amount of the Ppd-B1 gene copies, was detected for these lines. PMID- 25720139 TI - [Polymorphism among RFL-PPR homologs in sunflower (Helianthus annuus L.) lines with varying ability for the suppression of the cytoplasmic male sterility phenotype]. AB - A complex comparative genetic approach was used for the investigation of the structural and functional diversity of genes for the restoration of sunflower pollen fertility. It includes (i) hybridological analysis; (ii) analysis of polymorphism among EST fragments.homologous to the known Rf genes that contain repeated motives of 35 amino acids (RFL-PPR); (iii) the development of molecular markers. Monogenic segregation in three interline cross combinations and the results of molecular marker analysis confirmed the allelic differences of parental lines in the Mendelian locus for CMS PET1 pollen fertility restoration. Introns were found in two RFL-PPR fragments. Two allelic variants of the QHL12D20 fragment were detected among the sixty lines of the sunflower genetic collection. An intron of QHL12D20 fragment was homologous to an intron of the AHBP-1B gene; the product of this gene-has a similarity with the transcription factor of the bZIP-family of Arabidopsis. A relationship between the QHL12D20 polymorphism and the functional state of the Rfl locus was revealed. PMID- 25720140 TI - [Characteristics of alpha-amylase isozymes in cytologenetically different wheat cultivars]. AB - The isoenzyme composition of alpha-amylase is studied by polyacrylamide gel electrophoresis in Tris-glycine (pH 8.3) system in wheat cultivars with different genome composition. We show that durum wheat (Triticum durum, 2n=4x=28, BBAA) lacks the isoenzymes encoded by 6D and 7D chromosomes that are present in common wheat zymograms (Triticum aestivum, 2n=6x=42, BBAADD). A similar pattern is observed in a synthetic allohexaploid carrying the BBAA genomes of wheat and the HchHch genome of barley (Hordeum chilense). Our method of electrophoresis fails to reveal additional variants of alpha-amylase encoded by the barley genome, although C-banding analysis confirms the genomic structure BBAAHChHCh of this allopolyploid. The electrophoretic spectrum of the spring common wheat cultivar Dobrynya with the wheat-Agropyron translocation 7DL-7AiL contains all of the alpha-amylase isoenzymes typical for common wheat (2n=6x=42, BBAADD) except for the zymotype encoded by the long arm of chromosome 7D. This observation confirms the results of cytogenetic analysis that identified a 7DL-7AiL translocation in this cultivar. No additional alpha-amylase isoenzymes encoded by Agropyron chromosome have been observed. Our data indicate that analysis of wheat-alien hybrids or introgressive forms should be carried out using a complex of different methods. PMID- 25720141 TI - [The influence of combinations of alien translocations on in vitro androgenesis in near-isogenic lines of spring bread wheat]. AB - The features of in vitro androgenesis were studied in Cultured anthers of spring bread wheats L503 and Dobrynya, having 7DS-7DL-7Ae#1 L translocation with genes Lrl9/Sr25 (Lrl9 translocation) from Agropyron elongatum (Host.) P.B. and their near-isogenic lines carrying combinations of Lrl9 translocation with translocations: 1BL-IR#1S with genes Pm8/Sr31/Lr26/Yr9 (Lr26translocation) from Secale cereal L., 4BS-4BL-2R#1L with genes Lr25/Pm7 (Lr25 translocation) from Secale cereal, 3DS-3DL-3Ae#1L with genes Lr24/Sr24 (Lr24 translocation) from Agropyron elongatum and 6BS-6BL-6U#1L with gene Lr9 (Lr9 translocation) from Aegilops umbellulata Zhuk. In comparison with those varieties having received the Lrl9 translocation, the following was established: (1) the combination of translocations Lr19+26 increased embryo frequency and green plant regeneration; (2) the combination of translocations Lr19+9 decreased embryo frequency but increased green plant regeneration; (3) the combination of translocations Lr19+24 decreased embryo frequency but increased green and albino plant regeneration; (4) the combination of translocations Lr19+25 increased embryo frequency and green plant regeneration but decreased albino plant regeneration. Thus, on near isogenic lines of spring bread wheat, the influences of genotypes of four alien translocation combinations on in vitro androgenesis were determined. PMID- 25720142 TI - [Intra- and interpopulation variability of southwestern Kamchatka sockeye salmon Oncorhynchus nerka inferred from the data on single nucleotide polymorphism]. AB - The variability of 45 single nucleotide polymorphism (SNP) loci was studied in nine samples of the sockeye salmon Oncorhynchus nerka from the rivers of southwestern Kamchatka. The Wahlund effect, gametic disequilibrium at some loci, and a decrease in interpopulation genetic diversity estimates observed in samples from the Bolshaya River outlet are explained in terms of the samples' heterogeneity. Partitioning of mixed samples using some biological characteristics of the individuals led to a noticeable decrease in the frequency of these phenomena. It was demonstrated that the allelic diversity between the populations within the river Plotnikovs accounted for the larger part of genetic variation, as compared to the differentiation between the basins. The SNP loci responsible for intra- and interpopulation differentiation of sockeye salmon from the rivers of southwestern Kamchatka were identified. Some recommendations for field population genetic studies of Asian sockeye salmon were formulated. PMID- 25720143 TI - [Genetic study of pike perch Sander lucioperca (Linnaeus, 1758) and bersh Sander volgensis (Gmelin, 1789) from the fishery water-bodies of Kazakhstan]. AB - The genetic polymorphism of the pike perch Sander lucioperca, sampled on the territory of the Republic of Kazakhstan (Lake Balkhash, Urals River, Syrdarya River and Shardara water reservoir, North Aral Sea) and in the Volga River, and the bersh Sandler volgensis (Lake Balkhash, Volga River) populations was examined at six microsatellite loci and the mitochondrial DNA cytochirome b gene. All examined loci were successfully amplified in both species and produced quite different allele profiles, whichallows them to be used for accurate species identification of pike perch and bersh. At the same time, neither nuclear nor mitochondrial markers revealed statistically significant differentiation betweenthe examined pike perch samples, excluding some isolation of the population from Volga River. PMID- 25720144 TI - [Identification of European (Capreolus capreolus L.) and Siberian (C. pygargus Pall.) roe deer hybrids by microsatellite marker analysis]. AB - An analysis of 130 tissue specimens of the European (Capreolus capreolus) and the Siberian (C. pygargus) roe deer from nine regions of Russia and Ukraine using microsatellite loci analysis was conducted, aimed at the identification of hybrid animals. An optimized complex of 21 microsatellite loci was selected for the determination of species specificity and the search for interspecies hybrids. Hybrid animals were revealed in the Moscow and Volgograd regions. Their ratio in the total sample obtained in the European part of Russia was 11.9%. PMID- 25720145 TI - [Modeling the dynamics of the effective population size of the Okhotsk Sea pollock in the Holocene era on the basis of genetic variability in the Nd2 and Cytb mtDNA loci]. AB - We used Bayesian statistics to investigate the demographic history of the walleye pollock in the sea of Okhotks based on polymorphisms of sequences of the Nd2 and Cytb mitochondrial genes. We determined the average age for the Most Recent Common Ancestor (MRCA) as 44.1 +/- 2 and 52.6 1.3 thousand years, respectively, for Nd2 and Cytb. These findings suggest that demographic expansion of the Okhotsk Sea pollock began 10-12 thousand years ago, which coincides with the period of global changes in the sea level during the Late Pleistocene-Early Holocene eras. PMID- 25720146 TI - [Acceptability of using Karachay surnames as a quasigenetic marker in population and genetic studies]. AB - Based on a comparison of the data on the frequencies of 1206 surnames registered in the Malokarachayevsky District of Karachay-Cherkessia with a number of other parameters and historical data, it was concluded that Karachay surnames are acceptable for use as a quasigenetic marker in a study of a population-genetic description of the area. PMID- 25720147 TI - [P-M hybrid dysgenesis affects juvenile hormone metabolism in Drosophila melanogaster females]. AB - This paper studies the metabolism of the juvenile hormone, which affects gonads functioning in Drosophila melanogasterfemales under P-M hybrid dysgenesis. It is shown that dysgenic females grown at 29 degrees C have increased levels of the juvenile hormone (its degradation and stress reactivity are reduced), which apparently is a compensatory response to ovarian hypoplasia. PMID- 25720148 TI - [Progress in microbial synthesis and application of polymalic acid]. AB - Polymalic acid, known as a bioactive material, is completely biodegradable, and has far reaching application potential in medical field. Combined with our own findings, we summarized advances in polymalic acid metabolism, microbial fermentation synthesis, and application research in the medical field. Finally, prospect for further research was addressed. PMID- 25720149 TI - [Application of proteomics in deubiquitinases research]. AB - As the major pathway mediating specific protein degradation in eukaryotes, ubiquitin-proteasome system (UPS) is involved in various physiological and pathological processes such as cell cycle regulation, immune response, signal transduction and DNA-repair. Deubiquitinases (DUB) maintain the balance of UPS and related physiological processes via reversibly removing ubiquitin from the covalently modified protein substrates, which have been implicated in various disease processes in case of their imbalance expression. Because DUB plays critical regulating roles in the UPS pathway, they may be also the ideal drug targets for severe and intractable human diseases, such as cancer and neurodegenerative disease. With the rapid development of proteomic technology, systematical investigation of specific substrates and interacting proteins of varied DUB via mass spectrometry approach may shed light on these DUB's biological function and regulating roles in the physiological and pathogenic states. In this review, we briefly introduce the characteristics of DUB and summarize the recent application and progresses of proteomics in DUB research. PMID- 25720150 TI - [Progress in nanobody and its application in diagnosis]. AB - Nanobodies are derived from the variable domain of the heavy-chain antibodies (HCAbs) that occur naturally in the serum of Camelidae. They are the smallest antibody fragments capable to bind antigens. With the characteristics of their increased solubility, increased domain stabilities, nanomolar affinities, easy crossing the blood-brain barrier, easy generation, engineering, optimization and tailoring, easy humanization, nanobodies have extensive application prospects in diagnosis and detection. Although nanobody has demonstrated tremendous success, a number of practical challenges limit its broader applications in disease diagnosis and detection, including construction of a phage library and selection of nanobody fragments with high affinity and immunogold labeling technique. Here, we review several recent findings on the use of nanobodies in molecular diagnostics and suggest some practical strategies in resolving the current challenges in this attractive research area, particularly to optimize the affinity, solubility, humanization of nanobodies. PMID- 25720151 TI - [Progresses in predicting the crystallizability of proteins]. AB - Determination of protein 3-dimensional structure offers very important information in biology researches, especially for understanding protein functions and redundant drug design. The X-ray crystallography is still the main technique for protein structure determination. Obtaining protein crystals is an essential procedure after protein purification in this technique. However, there is only 42% of soluble purified proteins yield crystals by statistics. Experimental verification of protein crystallizability is relatively expensive and time consuming. Thus it is desired to predict the protein crystallizability by a computational method before starting the experiment. In this paper, combined with our own efforts, some successful in silico methods to predict the protein crystallizability are reviewed. PMID- 25720152 TI - [Comparison of expression and antibacterial activities of recombinant porcine lactoferrin expressed in four Lactobacillus species]. AB - The coding sequence for the mature peptide of porcine lactoferrin (Plf) was synthesized according to the codon usage of lactobacillus, to establish optimized porcine lactoferrin Lactobacillus expression system. The gene was ligated into the Xho I/BamH I site of Lactobacillus expression vector pPG612.1 and the recombinant plasmid pPG612.1-plf was transformed individually into Lactobacillus casei ATCC393, Lactobacillus pentosus KLDS1.0413, Lactobacillus plantarum KLDS1.0344 or Lactobacillus paracasei KLDS1.0652 by electroporation. After induction with xylose, expression of the recombinant proteins was detected by Western blotting and confocal laser scanning microscopy. Secretion of recombinant Plf proteins from four recombinant species was determined quantitatively by ELISA. The antibacterial activities of recombinant proteins were measured by agar diffusion method. The result shows that Plf was correctly expressed in four species of recombinant lactobacillus, with molecular weight of about 73 kDa. The expression levels in recombinant Lactobacillus casei, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus paracasei were 9.6 MUg/mL, 10.8 MUg/mL, 12.5 MUg/mL and 9.9 MUg/mL, respectively. Antimicrobial activity experiment shows that the recombinant proteins were active against E. coli, Staphylococcus aureus, Salmonella typhimurium, Listeria, Pasteurella. The recombinant Plf expressed by recombinant Lactobacillus plantarum showed the best antibacterial activity among all recombinant lactobacillus species. These data represent a basis for the development and application of porcine lactoferrin from recombinant lactobacillus. PMID- 25720153 TI - [Effects of overexpression of NADH kinase gene on ethanol fermentation by Saccharomyces cerevisiae]. AB - Glycerol is the main byproduct in ethanol production by Saccharomyces cerevisiae. In order to improve ethanol yield and the substrate conversion, a cassette about 4.5 kb for gene homologous recombination, gpd2Delta::PGK1(PT)-POS5-HyBR, was constructed and transformed into the haploid strain S. cerevisiae S1 (MATa) to replace the GPD2 gene by POS5 gene. The NADH kinase gene POS5 was successfully over expressed in the recombinant strain S. cerevisiae S3. Comparing with the parent strain, the recombinant strain S. cerevisiae S3 exhibited an 8% increase in ethanol production and a 33.64% decrease in glycerol production in the conical flask fermentation with an initiatory glucose concentration of 150 g/L. Overexpression of NADH kinase gene seems effective in reducing glycerol production and increasing ethanol yield. PMID- 25720154 TI - [Expression of 4"-O-isovaleryltransferase gene from Streptomyces thermotolerans in Streptomyces lividans TK24]. AB - 4"-O-isovaleryltransferase gene (ist) was regulated by positive regulatory genes of midecamycin 4"-O-propionyltransferase gene (mpt) in Streptomyces lividans TK24. A BamH I ~8.0 kb fragment from Streptomyces mycarofaciens 1748 was proved that it contained mpt gene and linked with two positive regulatory genes, orf27 and orf28. Orf of mpt was replaced by orf of ist and linked with two regulatory genes or orf27 single, and individually cloned into the vectors pKC1139 or pWHM3 (high copy number), and then transformed into S. lividans TK24. The levels of mpt and ist expression were evaluated by the bio-tramsformation efficacy of spiramycin into 4"-O-acylspiramycins in these transformants. The results showed that 4"-O-isovalerylspiramycins could be detected only in the transformants containing the plasmids constructed with pWHM3. The efficacy of bio transformation of the transformants containing two regulatory genes was higher than that of orf27 single. So, the positive regulatory genes system of mpt gene could enhance ist gene expression. PMID- 25720155 TI - [Display cellulolytic enzymes on Saccharomyces cerevisiae cell surface by using Flo1p as an anchor protein for cellulosic ethanol production]. AB - In this study, we constructed a yeast consortium surface-display expression system by using Flo1 as an anchor protein. Endoglucanase II (EGII) and cellobiohydrolase II (CBHII) from Trichoderma reesei, and beta3-glucosidase 1 (BGLI) from Aspergillus aculeatus were immobilized on Saccharomyces cerevisiae Y5. We constructed the cellulose-displaying expression yeast consortium (Y5/fEGII:Y5/fCBHII:Y5/fBGLI = 1:1:1) and investigated the enzymatic ability and ethanol fermentation. The displayed cellulolytic enzymes was stabile during the 96-h fermentation. The yeast consortium produced 0.77 g/L ethanol from 10 g/L phosphoric acid swollen cellulose (PASC) within 96 h. The yield (in grams of ethanol produced per gram of carbohydrate consumed) was 0.35 g/g, which correspond to 68.6% of the theoretical yield. PMID- 25720156 TI - [Expression, purification and characterization of a novel fatty acid synthase from Rhodosporidium toruloides]. AB - Fatty acid synthase (FAS) catalyses the reaction between acetyl-CoA and malonyl CoA to produce fatty acids. It is one of the most important enzyme in lipid biosynthesis. FAS of the oleaginous yeast Rhodosporidium toruloides has two acyl carrier protein (ACP) domains and a distinct subunit composition compared with FASs of other species. As ACP is a protein cofactor crucial for fatty acid chain elongation, more ACPs in the FAS may facilitate the reaction. To study the biochemical and structural properties of this novel FAS from R. toruloides, plasmids were constructed and transformed into Escherichia coli BL21 (DE3). The strain ZWE06 harboring plasmids pET22b-FAS1 and pET24b-FAS2 could co-overexpress the two subunits. The recombinant FAS was purified by sequentially using ammonium sulphate precipitation, sucrose density gradient centrifugation and anion exchange chromatography. The specific activity of the recombinant FAS was 548 mU/mg. The purified complex would be used to study enzyme kinetics and protein structure of FAS, and heterogeneous expression and purification will facilitate revealing the mechanism of this novel FAS with double ACPs. PMID- 25720157 TI - [Codon usage bias in the straw mushroom Volvariella volvacea]. AB - We analyzed the whole genome coding sequence of Volvariella volvacea to study the pattern utilization of codons by Codon W 1.4.2. As results, 24 optimal codons were identified. Moreover, the frequency of codons usage was calculated by CUSP program. We compared the frequency of codons usage of V. volvacea with other organisms including 6 modal value species (Homo sapiens, Saccharomys cerevisiae, Arabidopsis thalian, Mus musculus, Danio rerio and Drosophila melanogaster) and 4 edible fungi (Coprinopsis cinerea, Agaricus bisporus, Lentinula edodes and Pleurotus ostreatus). We found that there were less differences in 3 edible fungi (excluding Pleurotus ostreatus) than 6 modal value species, comparing with the frequency of codons usage of V. volvacea. With software SPSS16.0, cluster analysis which showed differences in the size of codon bias, reflects the evolutionary relationships between species, which can be used as a reference of evolutionary relationships of species. This was the first time for analysis the codon preference among the whole coding sequences of edible fungi, serving as theoretical basis to apply genetic engineering of V. volvacea. PMID- 25720158 TI - [Expression, purification and phosphoinositide binding specifity of recombinant human SNX7 expressed in Escherichia coli]. AB - Sorting nexins (SNXs) are a large group of proteins that contain Phox (PX) domain and involve in regulating endocytosis and endosome sorting. SNX7, a member of SNXs family, contains a PX domain and a BAR domain. In zebrafish, SNX7 is a liver enriched anti-apoptotic protein and indispensible for the liver development. A fragment of SNX7 cDNA ((px-bar)snx7), encoding the PX domain and the BAR domain, was inserted into the expressing vector p28a, transformed into E. coli Rosseta 2 (DE3), and then induced by isopropyl beta-D-1-Thiogalactopyranoside (IPTG). After affinity, ion exchange and gel filtration purification, the purity of (PX BAR)SNX7 reached over 95%. Dynamic light scattering (DLS) experiment indicated that (PX-BAR)SNX7 was homogeneous in solution. Lipid overlay assay showed that (PX-BAR)SNX7 can bind to PtdIns(5)P, PtdIns(4,5)P2 and PtdIns(3,4,5)P3. PMID- 25720159 TI - [Short gel method for pretreatment of protein samples with high concentration of detergent]. AB - In proteomic research, to improve protein solubility of membrane proteins and nuclear proteins, buffers containing high concentration of detergent, such as 4% SDS, were widely used. However, high concentration of detergent might severely interfere with the downstream proteomic analysis, including protein quantitation and trypsin digestion. To improve the proteomic compatibility of buffers with high concentration of detergent, we used short gel method to pretreat buffers containing detergent. Protein samples were first separated by a short (2-2.5 mm) SDS-PAGE electrophoresis, and proteins were quantitated by comparing with bovine serum albumin standards via optical density analysis. The gel was then cut and peptides were recovered using in-gel digestion. The quantitative linearity range of this method was 1 to 8 MUg. The quantitation was accurate and reproducible. After short gel analysis, recovered peptides generated high mass spectrometry signals. In conclusion, short gel method eliminated the interference of high concentration detergent in the proteomics analysis, and it was suitable for protein samples' pretreatment, and was worth to apply in proteomic research. PMID- 25720160 TI - [Interactions between proteins and cation exchange adsorbents analyzed by NMR and hydrogen/deuterium exchange technique]. AB - In silico acquirement of the accurate residue details of protein on chromatographic media is a bottleneck in protein chromatography separation and purification. Here we developed a novel approach by coupling with H/D exchange and nuclear magnetic resonance to observe hen egg white lysozyme (HEWL) unfolding behavior adsorbed on cation exchange media (SP Sepharose FF). Analysis of 1D 1H NMR shows that protein unfolding accelerated H/D exchange rate, leading to more loss of signal of amide hydrogen owing to exposure of residues and the more unfolding of protein. Analysis of two-dimensional hydrogen-hydrogen total correlation spectroscopy shows that lysozyme lost more signals and experienced great unfolding during its adsorption on media surface. However, for several distinct fragments, the protection degrees varied, the adsorbed lysozyme lost more signal intensity and was less protected at disorder structures (coil, bend, and turn), but was comparatively more protected against exchange at secondary structure domains (alpha-helix, beta-sheet). Finally, the binding site was determined by electrostatic calculations using computer simulation methods in conjunction with hydrogen deuterium labeled protein and NMR. This study would help deeply understand the microscopic mechanism of protein chromatography and guide the purposely design of chromatographic process and media. Moreover, it also provide an effective tool to study the protein and biomaterials interaction in other applications. PMID- 25720161 TI - [Overexpression of four fatty acid synthase genes elevated the efficiency of long chain polyunsaturated fatty acids biosynthesis in mammalian cells]. AB - Three long-chain polyunsaturated fatty acids, docosahexaenoic acid (DHA, 22:6n 3), eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (ARA, 20:4n-6), are the most biologically active polyunsaturated fatty acids in the body. They are important in developing and maintaining the brain function, and in preventing and treating many diseases such as cardiovascular disease, inflammation and cancer. Although mammals can biosynthesize these long-chain polyunsaturated fatty acids, the efficiency is very low and dietary intake is needed to meet the requirement. In this study, a multiple-genes expression vector carrying mammalian A6/A5 fatty acid desaturases and multiple-genes expression vector carrying mammalian Delta6/Delta5 fatty acid desaturases and Delta6/Delta5 fatty acid elongases coding genes was used to transfect HEK293T cells, then the overexpression of the target genes was detected. GC-MS analysis shows that the biosynthesis efficiency and level of DHA, EPA and ARA were significantly increased in cells transfected with the multiple-genes expression vector. Particularly, DHA level in these cells was 2.5 times higher than in the control cells. This study indicates mammal possess a certain mechanism for suppression of high level of biosynthesis of long chain polyunsaturated fatty acids, and the overexpression of Delta6/Delta5 fatty acid desaturases and Delta6/Delta5 fatty acid elongases broke this suppression mechanism so that the level of DHA, EPA and ARA was significantly increased. This study also provides a basis for potential applications of this gene construct in transgenic animal to produce high level of these long-chain polyunsaturated fatty acid. PMID- 25720162 TI - [N terminal sequencing for practical detection of monoclonal antibody]. AB - Here we discuss whether N terminal sequencing is appropriate as one of the conventional control methods for monoclonal antibody products. We determined the N terminal sequences of two monoclonal antibody products targeting two antigens separately with both Edman degradation and mass peptide spectrometry. We also identified the characteristic peptide fragments with mass spectrometry. Furthermore, we analyzed their heterogeneity with ion exchange chromatography, capillary zone electrophoresis and Imaged Capillary Isoelectric Focusing. Edman degradation method showed that the N terminal 15 amino acids of heavy and light chains of the two monoclonal antibodies were identical. Peptide mass spectrometry demonstrated that T1 peptide fragments of heavy and light chains of the two antibodies were also the same. But in contrast, peptide mapping and the three analytical methods for heterogeneity analysis could effectively identify and differentiate the two antibodies. The N terminal sequences of two monoclonal antibodies are identical because the number of framework sequences of humanized or human monoclonal antibodies is relatively limited, so whether N terminal sequencing analysis could be regulated as one of the practical control methods should be carefully discussed. Our work also proves that the above analytical methods could combinatorially applied to the identification of monoclonal antibody products, and are more objective compared to N terminal sequencing. PMID- 25720163 TI - [16beta-hydroxylation of 4-androstene-3,17-dione by Aspergillus niger]. AB - In order to discover the steroid biotransformation ability of filamentous fungus Aspergillus niger TCCC41650, we studied the fermentation of 4-androstene-3,17 dione with A. niger TCCC41650. The transformation product was purified, crystallized and determined as 16beta-hydroxy-androst-4-ene-3,17-dione by X-ray single crystal diffraction method. The best fermentation condition was found to be pH 6.0, ethanol amount 2% with a substrate concentration of 1 per thousand, the transformation rate is 85.81% after 72 h. Based on the best of our knowledge, 16beta-hydroxylation rarely occurs in microbial transformations of steroid. This study laid the foundation for the research of 16beta-hydroxylation steroids PMID- 25720164 TI - [Optimization of the fermentation conditions for 5-keto-D-gluconic acid production]. AB - Gluconobacter oxydans converts glucose to gluconic acid and subsequently to 5 keto-D-gluconic acid (5-KGA), a precursor of industrially important L(+)-tartaric acid. To increase the yield of 5-KGA, fermentation conditions of 5-KGA production was optimized. Under the optimum medium and culture conditions in the shake flask, the highest 5-KGA production reached 19.7 g/L, increased by 43.8% after optimization. In a 5-L bioreactor, the pH was controlled at 5.5 and dissolved oxygen (DO) at 15%, 5-KGA production reached 46.0 g/L, raised at least 1.3 times than in the shake flask. Glucose feeding fermentation process was further developed, and the highest 5-KGA production of 75.5 g/L with 70% of yield was obtained, 32.0% higher than the highest reported value. Therefore, this newly developed fermentation process provided a practical and effective alternative for the commercial production of 5-KGA, and further of L(+)-tartaric acid. PMID- 25720165 TI - [Enduring legacy of a unique botanical Costa Rica - Jorge Gomez Laurito (1947 2014)]. AB - The life and professional work of the Costa Rican botanist Jorge Gomez Laurito (1947-2014) are here depicted. His 91 scientific publications and 50 new plant taxa (including a family, a genus, and 48 species) represent a long-lasting legacy. The description and publication of Ticodendraceae was his most notable professional achievement. PMID- 25720166 TI - History, applications, methodological issues and perspectives for the use of environmental DNA (eDNA) in marine and freshwater environments. AB - Genetic material (short DNA fragments) left behind by species in nonliving components of the environment (e.g. soil, sediment, or water) is defined as environmental DNA (eDNA). This DNA has been previously described as particulate DNA and has been used to detect and describe microbial communities in marine sediments since the mid-1980's and phytoplankton communities in the water column since the early-1990's. More recently, eDNA has been used to monitor invasive or endangered vertebrate and invertebrate species. While there is a steady increase in the applicability of eDNA as a monitoring tool, a variety of eDNA applications are emerging in fields such as forensics, population and community ecology, and taxonomy. This review provides scientist with an understanding of the methods underlying eDNA detection as well as applications, key methodological considerations, and emerging areas of interest for its use in ecology and conservation of freshwater and marine environments. PMID- 25720167 TI - A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype. AB - The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers' sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive. PMID- 25720168 TI - Epiphytic and endophytic bacteria that promote growth of ethnomedicinal plants in the subtropical forests of Meghalaya, India. AB - The present study was aimed to investigate the endophytic and epiphytic bacteria associated with selected ethnomedicinal plants from the pristine subtropical forests of Meghalaya and analyse them for plant growth promotion and antagonistic ability. This study is an attempt to explore plant associated bacteria which are beneficial to host plants, and thus aid in the conservation of ethnomedicinal plants of the studied subtropical forests, which are dwindling due to exploitation. The plant growth promotion parameters like indole acetic acid (IAA) production, mineral phosphate solubilisation, acid phosphatase activity, presence of 1-aminocyclopropane-1-carboxylic acid deaminase (ACC) gene, nitrogen fixation, cellulose digestion, chitin and pectin degrada- tion were screened among the isolates. The study revealed significant differences in bacterial population not only between the epiphytic and endophytic microhabitats, but also amongst the host plants. Out of the 70 isolated plant associated bacteria, Bacillus sp., Serratia sp., Pseudomonas sp., Pantoea sp., and Lysinibacillus sp. showed potent plant growth promotion properties. Bacillus siamensis C53 and B. subtilis cenB showed significant antagonistic activity against the tested pathogens. This study indicated the isolates inhabiting the plants prevalent in the subtropical sacred forests could be explored for use as plant growth promoters while practising the cultiva- tion and conservation of ethnomedicinal plants. PMID- 25720169 TI - [Spatial-temporal variation of the macroinvertebrate epibiont community on red mangrove prop roots Rhizophora mangle (Rhizophoraceae) at La Mancha coastal lagoon, Veracruz, Mexico]. AB - La Mancha lagoon is connected to the Gulf of Mexico through an estuarine ephemeral inlet, a sand bar, which opens during the rainy season and closes during the late fall and the winter storm season. As the lagoon fills up with the permanent stream flow into its Southern part, the water level increases and the sand bar opens up, releasing huge volumes of water into the ocean and leaving the previously flooded intertidal zone exposed to drying. In this study, we described the spatial and temporal variations of structure and composition of the community living on the surface of red mangrove prop roots, related to the hydrodynamic of the estuarine inlet. Four red mangrove prop roots were collected every three months, over an annual period, at ten sampling stations. Water temperature, salinity, dissolved oxygen, water depth and transparency were also measured at each sampling event. To describe the identity, abundance, biomass, and specific richness of epibiont coverage on the prop roots, measurements were taken at 10 cm intervals (herein called "horizons"). A total of 59,632 specimens and a total biomass of 172 g/cm2 were registered, and a maximum of eleven horizons presented at least one" species of epibionts. Two species of polychaetes, 12 of mollusks and 14 of crustaceans were identified, with Mytilopsis leucophaeata as the most abundant, Ficopomatus miamiensis as the most common and Crassostrea rhizophorae with the highest contribution in biomass. Sampling effort was assessed using species accumulation curves, resulting that the efficiency was, in general, greater than 90% of the richness predicted by asymptotic models. The hydrodynamics of the estuarine inlet had a great influence on the environmental conditions of the lagoon and on the spatial and temporal variation of the epibiont community: (a) when the inlet is open, there is a North-South gradient in environmental parameters (b) when the inlet is closed and the water level increases, the epibionts especially the pioneer species F. miamiensis, occupied the highest horizons of prop roots, and (c) the abundance, biomass and richness of epibionts increased towards the deeper and less saline Southern part of the lagoon, as well as on permanently submerged horizons, and during the seasonal closure of the inlet. Variations in depth are determined by the hydrodynamic behavior of the estuarine-inlet, suggesting that these factors are major biodiversity drivers of the epibiont community at La Mancha. PMID- 25720170 TI - The effect of astaxanthin on resistance of juvenile prawns Macrobrachium nipponense (Decapoda: Palaemonidae) to physical and chemical stress. AB - In recent years, the use of new scientific techniques has effectively improved aquaculture production processes. Astaxanthin has various properties in aquaculture and its antioxidant benefits have been closely related to stress resistance; besides, it is an essential factor for growth in many crustaceans and fish. The objective of this study was to evaluate the resistance of prawn (Macrobrachium nipponense) fed diets containing different amounts of astaxanthin (AX) to the shock and stress of different physicochemical environments. A 70-day trial was conducted to evaluate the effect of supplementation of a source of astaxanthin (Carophyll Pink, 10% astaxanthin, w/w, Hoffman-La Roche, Switzerland) at various levels in the diet of M. nipponense juveniles. Four dry diets were prepared: AX0 without astaxanthin, AX50 with 50 mg/kg, AX100 with 100 mg/kg, and AX150 with 150 mg/kg astaxanthin. The feeding trial was conducted in a recirculation water system consisting of 12 fiberglass tanks (1000L) used for holding prawns. Three replicate aquaria were initially stocked with 36 org/m2 per tank. During the trial, prawns were maintained on a 12:12-h light:dark photoperiod with an ordinary incandescent lamp, and the water quality parameters were maintained as follows: water temperature, 25-26 degrees C; salinity, 1 g/L; pH, 8.5-8.8; dissolved oxygen, 6.0-6.5 mg/L; and ammonia-nitrogen, 0.05 mg/L. Incorporation of AX, production output, and physiological condition were recorded after 10 weeks of feeding. At the end of the growing period, the prawns were exposed to thermal shock (0 degrees C), ammonia (0.75 mg/L), and reduced oxygen (0.5 mg/L). The time to lethargy and the time to complete death of the prawns were recorded. The results showed that control prawns had the shortest time to lethargy and death compared with prawns subjected to the other treatments. The results of this study have shown that the amount of muscle tissue and gill carotenoids in prawn fed with an AX150 diet showed greater reduction than those exposed to other treatments. It is possible that higher levels of astaxanthin in the body under oxygen reduction stress can be beneficial for prawns. These results suggest that male prawns showed lethargy earlier than females, and the percentage of carotenoid reduction in muscle and gill tissues was higher in males. PMID- 25720171 TI - Impact of minimum catch size on the population viability of Strombus gigas (Mesogastropoda: Strombidae) in Quintana Roo, Mexico. AB - The queen conch Strombus gigas represents one of the most important fishery resources of the Caribbean but heavy fishing pressure has led to the depletion of stocks throughout the region, causing the inclusion of this species into CITES Appendix II and IUCN's Red-List. In Mexico, the queen conch is managed through a minimum fishing size of 200 mm shell length and a fishing quota which usually represents 50% of the adult biomass. The objectives of this study were to determine the intrinsic population growth rate of the queen conch population of Xel-Ha, Quintana Roo, Mexico, and to assess the effects of a regulated fishing impact, simulating the extraction of 50% adult biomass on the population density. We used three different minimum size criteria to demonstrate the effects of minimum catch size on the population density and discuss biological implications. Demographic data was obtained through capture-mark-recapture sampling, collecting all animals encountered during three hours, by three divers, at four different sampling sites of the Xel-Ha inlet. The conch population was sampled each month between 2005 and 2006, and bimonthly between 2006 and 2011, tagging a total of 8,292 animals. Shell length and lip thickness were determined for each individual. The average shell length for conch with formed lip in Xel-Ha was 209.39 +/- 14.18 mm and the median 210 mm. Half of the sampled conch with lip ranged between 200 mm and 219 mm shell length. Assuming that the presence of the lip is an indicator for sexual maturity, it can be concluded that many animals may form their lip at greater shell lengths than 200 mm and ought to be considered immature. Estimation of relative adult abundance and densities varied greatly depending on the criteria employed for adult classification. When using a minimum fishing size of 200 mm shell length, between 26.2% and up to 54.8% of the population qualified as adults, which represented a simulated fishing impact of almost one third of the population. When conch extraction was simulated using a classification criteria based on lip thickness, it had a much smaller impact on the population density. We concluded that the best management strategy for S. gigas is a minimum fishing size based on a lip thickness, since it has lower impact on the population density, and given that selective fishing pressure based on size may lead to the appearance of small adult individuals with reduced fecundity. Furthermore, based on the reproductive biology and the results of the simulated fishing, we suggest a minimum lip thickness of >= 15 mm, which ensures the protection of reproductive stages, reduces the risk of overfishing, leading to non-viable density reduction. PMID- 25720172 TI - [Morphological changes in gametes of tiger barb Puntius tetrazona (Cypriniformes: Cyprinidae) and the implementation of in vitro fertilization]. AB - The production of ornamental fishes represents an economic activity of a growing number of Mexican families. Nevertheless, the reproduction of fish in captivity is one of the complications faced by farmers. This study was set up to: (i) evaluate the morphological and functional changes induced by hydration in the gametes of fish tiger barb (Puntius tetrazona; 240 samples) at tree times after hydration (10, 20 and 30s) with classic spermograms (volume, sperm concentration, viability, motility, and normal morphology); and (ii) evaluate the implementation of in vitro fertilization based on the ovulation rate, the percentage of fertilization and hatching; and the larval numbers obtained after 72 hours. The average volume of milt was 3.0 +/- 0.7 MUL, and the minimum, maximum and average concentration of sperm was 44.4 x 10(6) spz/mL, 52.3 x 10(6) spz/mL, and 48.1 +/- 5.9 x 10(6) spz/mL, respectively. The viability and motility of the sperm was 84.6 +/- 3.2% and 81.5 +/- 2.2%, respectively. The diameter of the sperm with/without water contact was 2.10 +/- 6 MUm and 3.8 +/- 1.0 MUm (p < 0.05); the largest diameter was recorded 30 seconds after the contact with water. For oocytes, the smaller and larger diameters were recorded at 10 and 30s, respectively (both with/without water contact); the oocytes diameters after 10 and 30 seconds of contact with water were 1.11 and 1.55 mm, respectively. A higher ovulation rate was recorded using the in vitro fertilization: 250 +/- 50 oocytes versus 28 +/- 09 oocytes (during natural fertilization; p < 0.05). Nevertheless, fertilization and hatching rates were higher for the natural fertilization (80 and 60%, respectively). Considering the number of larvae obtained after 72 hours, our results showed a higher value for the in vitro fertilization (75 +/- 18 compared to 13.4 +/- 12 of the natural fertilization; p < 0.05). We propose this fish as a model for other ornamental fishes of commercial interest. Our results demonstrate that the in vitro fertilization is a very high viable option to optimize and maximize resources; besides, the reproduction management optimization under controlled conditions may enhance wild fish stocks preservation. PMID- 25720173 TI - Karyotype of the invasive species Pterois volitans (Scorpaeniformes: Scorpaenidae) from Margarita Island, Venezuela. AB - The genus Pterois includes nine valid species, native to the Red Sea and Indian Ocean throughout the Western Pacific. P. volitans and P. miles are native to the Indo-Pacific, and were introduced into Florida waters as a result of aquarium releases, and have been recently recognized as invaders of the Western Atlantic and Caribbean Sea (Costa Rica to Venezuela). Thus far, cytogenetic studies of the genus Pterois only cover basic aspects of three species, including P. volitans from Indo-Pacific Ocean. Considering the lack of more detailed information about cytogenetic characteristics of this invasive species, the objective of the present study was to investigate the basic and molecular cytogenetic characteristics of P. volitans in Venezuela, and compare the results with those from the original distribution area. For this, the karyotypic characteristics of four lionfish caught in Margarita Island, Venezuela, were investigated by examining metaphase chromosomes by Giemsa staining, C-banding, Ag-NOR, and two colour-Fluorescent in situ hybridization (FISH) for mapping of 18S and 5S ribosomal genes. Comparing the sequences of the 16S gene of the specimens analyzed, with sequences already included in the Genbank, we corroborated that our specimens identified as P. volitans are in fact this species, and hence exclude the possibility of a misidentification of P. miles. The diploid number was 2n = 48 (2m + 10sm + 36a) with FN = 60. Chromosomes uniformly decreased in size, making it difficult to clearly identify the homologues except for the only metacentric pair, and the pairs number two, the largest of the submetacentric series. C-banding revealed only three pairs of chromosomes negative for C-band, whereas all remaining chromosomes presented telomeric and some interstitial C positive blocks. Only two chromosomes were C-banding positive at the pericentromeric regions. Sequential staining revealed Ag-NOR on the tips of the short arms of chromosome pair number two and the FISH assay revealed that 18S rDNA and 5S rDNA genes are co-located on this chromosome pair. The co localization of 5S rDNA and 45S rDNA is discussed. Both constitutive heterochromatin and NOR location detected in samples examined in this study, differ from those reported for P. volitans in previous analysis of specimens collected in Indian Ocean (Java), suggesting the occurrence of chromosome microrearrangements involving heterochromatin during the spread of P. volitans. PMID- 25720174 TI - New leafhopper species of Jikradia from Mesoamerica with new records, revised key to species, distribution, origin, and checklist (Hemiptera: Cicadellidae: Coelidiinae: Teruliini). AB - The following four new species of leafhoppers are described and illustrated: Jikradia dentata n. sp. and J. trispinata n. sp. from Guatemala, J. variabilis n. sp. from Belize, and J. exilis n. sp. from Costa Rica. Jikradia basipendula Nielson and J. krameri Nielson are new records for Guatemala. Belize is a new record for the genus. A record of the first introduction of the genus in the Old World is reviewed. A revised key to the known species is provided with a review of its possible origin. A checklist of all known species is also given. PMID- 25720175 TI - [Key to chironomid pupal exuviae (Diptera: Chironomidae) of tropical high Andean streams]. AB - The Chironomidae is a cosmopolitan family of Nematoceran flies with more than 20,000 species described. However the diversity of genera and species of the family in the Andean region beyond the 2,000 m.a.s.l are scarcely known. We conducted faunal surveys and biomonitoring research in different streams of Colombia, Ecuador and Peru from May 2005 to October 2011. Based on specimens collections, a taxonomic key was developed to identify pupae and pupal exuviae of 46 genera of midges (Diptera, Chironomidae) collected from streams at high altitude areas on the Andean tropical mountains. We included illustrations and brief taxonomic descriptions for all genera, of which several ones have not yet been formally described; in this latter case we used the nomenclature of Roback & Coffman (1983). For two genera, Cricotopus and Genus 1, keys to the most com- mon morphospecies were provided. Results showed that in this area the chironomid assemblages are dominated by the members of the subfamily Orthocladiinae (22 genera) followed by the Chironominae (13). Six genera of Tanypodinae were identified, while only three and two genera were present from subfamilies Podonominae and Diamesinae. This key may be very useful for both studies about drift in streams, and for biomonitoring purposes. PMID- 25720176 TI - [Relative abundance, population structure, habitat preferences and activity patterns of Tapirus bairdii (Perissodactyla: Tapiridae), in Chimalapas forest, Oaxaca, Mexico]. AB - Baird's tapir (Tapirus bairdii) is endangered primarily because of habitat loss and fragmentation, and overhunting throughout its distribution range. One of the priority land areas for the conservation of this species is the Northern part of its range in the Chimalapas forest, Oaxaca. The aim of this research was to determine the relative abundance, population struc- ture, habitat preferences and activity patterns of Baird's tapir (Tapirus bairdii) in the Chimalapas forest, Oaxaca, Mexico, through the non-invasive technique of camera-trap sampling. A total of five sampling sessions were undertaken among 2009-2013, and used a total of 30 camera-traps in each period. The determinant factor of the sampling design was the hunting between two study areas. A total sampling effort of 9000 trap days allowed to estimate an index of relative abundance (IRA) of 6.77 tapir photographs/1,000 trap-days (n = 61). IRA varied significantly between sampling stations (Mann-Whitney, p < 0.01). The frequency of Baird's tapir photos was higher in the dry season in tropical rain forest without hunting (chi2, p < 0.5). In the rainy season, the tropical rain forest and secondary vegetation habitats showed higher photo frequency than expected from random (chi2, p < 0.5). Considering population structure, a 95.08% of adult animals was obtained in photographic records (n = 58). Three types of activity pattern were observed, with more nocturnal records (88.33%; Kruskal-Wallis, p < 0.05). The Chimalapas forest appears to be the second most important terrestrial priority ecoregion, just after the Mayan Forest (Campeche, Chiapas, Quintana Roo), for the conservation of tapir populations, not only for Mexico but also for Central America. PMID- 25720177 TI - Density, distribution, and activity of the ocelot Leopardus pardalis (Carnivora: Felidae) in Southeast Mexican rainforests. AB - The ocelot Leopardus pardalis is of particular significance in terrestrial communities due to its ecological role within the group of small-sized felids and as a mesopredator. However, despite the reduction of ocelot habitat in Southeast Mexico, there are still very few ecological studies. This research aimed to contribute with some ecological aspects of the species in this region. For this, 29 camera trap stations were established in a rain forest in Los Chimalapas (an area of 22 km2) during a two years period (March 2011-June, 2013), in Oaxaca state, Southeast Mexico. Data allowed the estimation of the population density, activity pattern, sex ratio, residence time, and spatial distribution. Population density was calculated using Capture-Recapture Models for demographically open populations; besides, circular techniques were used to determine if nocturnal and diurnal activity varied significantly over the seasons, and Multiple Discriminant Analysis was used to determine which of the selected environmental variables best explained ocelot abundance in the region. A total of 103 ocelot records were obtained, with a total sampling effort of 8,529 trap-days. Density of 22-38 individuals/100 km2 was estimated. Ocelot population had a high proportion of transient individuals in the zone (55%), and the sex ratio was statistically equal to 1:1. Ocelot activity was more frequent at night (1:00-6:00h), but it also exhibited diurnal activity throughout the study period. Ocelot spatial distribution was positively affected by the proximity to the village as well as by the amount of prey. The ocelot population here appears to be stable, with a density similar to other regions in Central and South America, which could be attributed to the diversity of prey species and a low degree of disturbance in Los Chimalapas. PMID- 25720178 TI - [Diversity, relative abundance and activity patterns of medium and large mammals in a tropical deciduous forest in the Isthmus of Tehuantepec, Oaxaca, Mexico]. AB - The use of camera traps and mammal track search are complementary methods to monitoring species of which is not well documented their natural history, as in the case of medium and large mammals. To ensure its conservation and good management, it is necessary to generate information about the structure of the community and their populations. The objective of the present study was to estimate the diversity, relative abundance and activity patterns of medium and large mammals in a tropical deciduous forest located in the Isthmus of Tehuantepec, Oaxaca, Mexico. Samplings were conducted in three month intervals, from September 2011 to May 2013. We used photographic-sampling and track search, two complementary sampling methods. For photographic-sampling, 12 camera traps were placed covering an area of 60 km2, while for the tracks search a monthly tour of four line-transect surveys of three kilometers length each was undertaken. We obtained a total of 344 pictures with 5292 trap-days total sampling effort; in addition, 187 track records in a total of 144 km. With both methods we registered 21 species of mammals, in 13 families and seven orders, and five species resulted in new records to the area. The diversity index of Shannon Wiener obtained with the method of tracks was H' = 2.41, while the most abundant species were Urocyon cinereoargen- teus (IAR = 0.23) and Pecari tajacu (IAR = 0.20). By the method of trap the most abundant species were P. tajacu (IAR = 2.62) and Nasua narica (IAR = 1.28). In terms of patterns of activity P. tajacu, N. narica and Odocoileus virginianus were primarily diurnal species; Canis latrans and Leopardus pardalis did not show preference for any schedule in particular, and Didelphis virginiana and Dasypus novemcinctus preferred to have nocturnal activity. This information can be of help to the creation of programs of management and conservation of mam- mals of medium and large in the Isthmus of Tehuantepec, Oaxaca, Mexico. PMID- 25720179 TI - Habitat features influencing jaguar Panthera onca (Carnivora: Felidae) occupancy in Tortuguero National Park, Costa Rica. AB - Habitat characteristics and human activities are known to play a major role in the occupancy of jaguars Panthera onca across their range, however the key variables influencing jaguar distribution in Tortuguero National Park, Costa Rica, have yet to be identified. This study evaluated jaguar occupancy in Tortuguero National Park and the surrounding area. Jaguar detection/non-detection data was collected using digital camera traps distributed within the boundaries of the protected area. Local community members were also interviewed to determine jaguar occurrence in the Park's buffer zone. Occupancy models were then applied to identify the habitat characteristics that may better explain jaguar distribution across the study area. From June 2012 to June 2013, a total of 4,339 camera trap days were used to identify 18 individual jaguars inside the protected area; 17 of these jaguars were exclusively detected within the coastal habitat, whilst the remaining individual was detected solely within the interior of the Park. Interviewees reported 61 occasions of jaguar presence inside the buffer zone, between 1995 and 2013, with 80% of these described by the communities of Lomas de Sierpe, Barra de Parismina and La Aurora. These communities also reported the highest levels of livestock predation by jaguars (85% of attacks). In the study area, jaguar occurrence was positively correlated with the seasonal presence of nesting green turtles Chelonia mydas, and negatively correlated with distance to the Park boundary. Our findings suggested that the current occupancy of the jaguar in the study area may be a response to: 1) the vast availability of prey (marine turtles) on Tortuguero beach, 2) the decline of its primary prey species as a result of illegal hunting inside the Park, and 3) the increase in anthropogenic pressures in the Park boundaries. PMID- 25720180 TI - Do attacks by jaguars Panthera onca and pumas Puma concolor (Carnivora: Felidae) on livestock correlate with species richness and relative abundance of wild prey? AB - Abstract: Attacks by big cats on livestock are one of the major causes of human felid conflicts and, therefore, an important factor in the conservation of these species. It has been argued that a reduction in natural prey abundance promotes attacks on domestic species, but few studies have tested this statement, and some have delivered contradictory results. We investigated whether the occurrence of attacks to livestock by jaguar and puma relates to the abundance and richness of their natural prey. In the rainy season 2009, we tracked potential prey species counting signs of presence along linear transects in 14 non-attacked cattle farms (control) and in 14 attacked cattle farms in NW Costa Rica. There was a negative relationship between the occurrence of attacks and both species richness (p = 0.0014) and abundance (p = 0.0012) of natural prey. Our results support the establishment of actions to promote support and recovery of natural prey, in order to diminish attacks on livestock, while maintaining jaguar and puma populations. PMID- 25720181 TI - [Application of the elliptic fourier functions to the description of avian egg shape]. AB - Egg shape is difficult to quantify due to the lack of an exact formula to describe its geometry. Here I described a simple algorithm to characterize and compare egg shapes using Fourier functions. These functions can delineate any closed contour and had been previously applied to describe several biological objects. I described, step by step, the process of data acquisition, processing and the use of the SHAPE software to extract function coefficients in a study case. I compared egg shapes in three birds' species representing different reproductive strategies: Cuban Parakeet (Aratinga euops), Royal Tern (Thalasseus maximus) and Cuban Blackbird (Dives atroviolaceus). Using 73 digital pictures of eggs kept in Cuban scientific collections, I calculated Fourier descriptors with 4, 6, 8, 16 and 20 harmonics. Descriptors were reduced by a Principal Component Analysis and the scores of the eigen-values that account for 90% of variance were used in a Lineal Discriminant Function to analyze the possibility to differentiate eggs according to its shapes. Using four harmonics, the first five component accounted for 97% of shape variances; more harmonics diluted the variance increasing to eight the number of components needed to explain most of the variation. Convex polygons in the discriminant space showed a clear separation between species, allowing trustful discrimination (classification errors between 7-15%). Misclassifications were related to specific egg shape variability between species. In the study case, A. euops eggs were perfectly classified, but for the other species, errors ranged from 5 to 29% of misclassifications, in relation to the numbers or harmonics and components used. The proposed algorithm, despite its apparent mathematical complexity, showed many advantages to describe eggs shape allowing a deeper understanding of factors related to this variable. PMID- 25720182 TI - Causes and consequences of change rates in the habitat of the threatened tropical porcupine, Sphiggurus mexicanus (Rodentia: Erethizontidae) in Oaxaca, Mexico: implications for its conservation. AB - Land use changes by human activities have been the main causes of habitats and wildlife population degradation. In the Tehuantepec Isthmus in Oaxaca, the tropical habitat of the porcupine Sphiggurus mexicanus has been subject to vegetation and land use changes, causing its reduction and fragmentation. In this study, we estimated vegetation cover and land use (deltan) change rates and assessed habitat availability and potential cor- ridors for possible porcupine movements to avoid its isolation. In the study area, the type of vegetation with the most change rate value was the savanna (deltan = -2.9), transformed into induced grasslands. Additionally, we have observed the porcupine (since 2011) in semi-deciduous (deltan = -0.87) and tropical dry (deltan = -0.89) forests that have been transformed in temporal agriculture and mesquite and induced grasslands. The vegetation inhabited by the porcupine resulted in recording a total of 64 plant species (44 trees, nine vines, seven herbs, four shrubs), of which the vine Bunchosia lanceolata showed the highest importance value (41.85) followed by the trees Guazuma ulmifolia (22.71), Dalbergia glabra (18.05), and Enterolobium cyclocarpum (17.02). The habitat evaluation and potential corridor analysis showed that only 1 501.93ha could be considered as suitable habitats with optimum structural conditions (coverage, surface, and distances to transformed areas) to maintain viable populations of S. mexicanus, and 293.6 ha as corridors. An increasing destruction of the porcupines' habitat has been observed in the study area due to excessive logging, and actions for this species and its habitat conserva- tion and management have to be taken urgently. PMID- 25720183 TI - [Wildlife damage mitigation in agricultural crops in a Bolivian montane forest]. AB - Wildlife is often blamed for causing damage to human activities, including agricultural practices and the result may be a conflict between human interests and species conservation. A formal assessment of the magnitude of damage is necessary to adequately conduct management practices and an assessment of the efficiency of different management practices is necessary to enable managers to mitigate the conflict with rural people. This study was carried out to evaluate the effectiveness of agricultural management practices and controlled hunting in reducing damage to subsistence annual crops at the Cotapata National Park and Natural Area of Integrated Management. The design included seven fields with modified agricultural practices, four fields subjected to control hunting, and five fields held as controls. We registered cultivar type, density, frequency of visiting species to the field, crops lost to wildlife, species responsible for damage, and crop biomass. Most frequent species in the fields were Dasyprocta punctata and Dasypus novemcinctus. Hunted plots were visited 1.6 times more frequently than agriculturally managed plots. Crop lost to wildlife averaged 7.28% at agriculturally managed plots, 4.59% in plots subjected to hunting, and 27.61% in control plots. Species mainly responsible for damage were Pecari tajacu, D. punctata, and Sapajus apella. We concluded that both management strategies were effective to reduce damage by >50% as compared to unmanaged crop plots. PMID- 25720184 TI - [[Characterization of the potential geographical distribution area of parrot species in Yucatan Peninsula, Mexico]. AB - Psittacidae family is one of the most endangered groups in Mexico, since many of their habitats are disappearing. In this research, we characterized the land cover of the potential geographical distribu- tion area of eight extant parrot species within the Yucatan Peninsula. We used the Maximum Entropy algorithm (MaxEnt) and species historical records. To externally validate the models, we used presence and absence records from field observations (2010-2012). To characterize the distribution area, we used the vegetation and land use maps of INEGI Series IV (2007-2010). The models showed a good performance, according to the values of the area under the curve (AUC), which ranged between 0.88-0.95 with the training data and between 0.82-0.91 with test data. We located most of the species in sites where the models predicted their presence. In the Peninsula, over 76% of the parrots' potential geographical distribution area is forested, except for Amazona oratrix. The subhumid tropical forest is the best represented, and the livestock for land use. The most affected species within the Peninsula are: Amazona farinosa and A. oratrix. The Calakmul Biosphere Reserve is the most important area for parrots' protection in the Peninsula. Knowing the characteristics of distribution areas is an essential part in the establishment of parrots' conservation strategies. PMID- 25720185 TI - Effect of temporal lakes on avifaunal composition at the Southeast of Isthmus of Tehuantepec, Oaxaca, Mexico. AB - Oaxaca hosts one of the greatest biodiversity in Mexico, occupying first place in avian diversity compared to other regions of the country. However, the area is undergoing serious problems such as high defor- estation rates, soil erosion and over exploitation and extinction of species. These factors have all contributed to the current loss of biodiversity. Also, biological inventories are still incomplete. One of the least explored sites is the semiarid zone of Tehuantepec isthmus, around the locality of Santa Maria del Mar, Oaxaca, Mexico. The area includes floodable grasslands, mangrove areas and dry forest, providing a range of potential habitats for different species. Our objective was to evaluate the effect of temporal lakes on spatial and temporal composition of the avifauna in Santa Maria del Mar, in order to generate information regarding this group within the region and the state, and to understand the importance of flood areas for resident and transitory birds. We conducted 12 avifauna surveys between July 2006 and June 2008, and established two transects of 2km length in each of four habitat types (beach, grassland, dry forest, and mangrove). We found a total of 75 species, corresponding to 16 orders and 30 families. Within an area of 26 km2, we significantly found 10.1% of the total number of bird species recorded for the entire state, and 6.6% of the total reported in Mexico. The families most repre- sented were: Ardeidae, Laridae and Scolopacidae. Over the entire study period, dry forest was the most diverse habitat; followed by mangrove, grassland and the beach. Of all the species recorded, 38.6% were found at the edge or in the temporal lakes. We found a significant difference in species composition between seasons in the grassland, but no difference in the other habitats. Our results showed a significant effect of temporary lakes on avian diversity during the wet season; it also demonstrated the importance of grassland conservation given its relevance for presence of waterbirds. We suggested a continued and more intense monitoring; and proposed the designation of the area as an Important Conservation Bird Area (AICA). PMID- 25720186 TI - Morphological and physiological responses of seagrasses (Alismatales) to grazers (Testudines: Cheloniidae) and the role of these responses as grazing patch abandonment cues. AB - Green sea turtles, Chelonia mydas, are grazers influencing the distribution of seagrass within shallow coastal ecosystems, yet the drivers behind C. mydas patch use within seagrass beds are largely unknown. Current theories center on food quality (nutrient content) as the plant responds to grazing disturbances; however, no study has monitored these parameters in a natural setting without grazer manipulation. To determine the morphological and physiological responses potentially influencing seagrass recovery from grazing disturbances, seagrasses were monitored for one year under three different grazing scenarios (turtle grazed, fish grazed and ungrazed) in a tropical ecosystem in Akumal Bay, Quintana Roo, Mexico. Significantly less soluble carbohydrates and increased nitrogen and phosphorus content in Thalassia testudinum were indicative of the stresses placed on seagrasses during herbivory. To determine if these physiological responses were the drivers of the heterogeneous grazing behavior by C. mydas recorded in Akumal Bay, patches were mapped and monitored over a six-month interval. The abandoned patches had the lowest standing crop rather than leaf nutrient or rhi- zome soluble carbohydrate content. This suggests a modified Giving Up Density (GUD) behavior: the critical threshold where cost of continued grazing does not provide minimum nutrients, therefore, new patches must be utilized, explains resource abandonment and mechanism behind C. mydas grazing. This study is the first to apply GUD theory, often applied in terrestrial literature, to explain marine herbivore grazing behavior. PMID- 25720187 TI - [Woody species composition in invaded communities from mountains of central Argentina: their relations with local environmental factors]. AB - Invasions by exotic woody species are threatening ecosystem functions worldwide. The spread and subsequent replacement of native forest by exotic dominated stands is particularly evident nearby urban centers were exotic propagule pressure is highest. Yet, there is a lack of information on the environmental factors that underlie these replacements. In this study we addressed the following questions: (1) is there a local spatial segregation between the dominant native and exotic woody species? and (2) if this local segregation does exist, is it driven by environmental features? For this, in 2010 we established 31 plots distributed along 16 sampling sites where we surveyed the composition and abundance of all woody species with a basal diameter >= 5 cm. To characterize the environment of each plot, we measured the topographic position (slope, exposure) and different properties such as soil physics (bulk density, soil impedance), structure (soil deep, texture) and chemical characteristics (pH, nutrient and water content). Through a cluster analysis we were able to identify five different woody communities in coexistence: (1) Woodlands dominated by the exotic Ligustrum lucidum; (2) Mixed woodlands dominated by the native Lithraea molleoides and the exotic Celtis australis; (3) Scrublands dominated by the native Condalia buxifolia; (4) Scrublands dominated by the exotic Cotoneaster glaucophyllus, and (5) Scrubby grasslands with the exotic Pyracantha angustifolia. These communities were all associated with different local topographic and edaphic features. The environmental segregation among the identified communities suggests that woody invaders have the potential to colonize almost all the environments of the study site (though varying in the identity of the dominant exotic species). The observed patterns, even being restricted to a single well invaded area of mountain Chaco, may posit the spread of woody invaders towards native communities in the region. PMID- 25720188 TI - [Spatio-temporal dynamics of fishing effort in a multi-species artisanal diving fishery and its effects on catch variability: insights for sustainable management]. AB - Artisanal diving fisheries are a source of income, employment and food security of coastal areas in many countries. Understanding the dynamics of these fisheries, including the spatial and temporal dynamics of fishing effort, gears and species can help to address the challenges involved in fisheries management. We aimed to analyze the differences in fishing strategies undertaken by fishers that use two different diving methods (hookah and free diving), the conditions and their potential impacts on catches when adjustments to those strategies are applied over time. For this, detailed information of fishing operations from artisanal boats in the North Pacific coast of Costa Rica was analyzed in two fishing seasons (2007-2008 and 2011-2012). Data were collected by onboard observers (fishing site, fishing time, species composition, depth and visibility). Additionally, interviews with divers were applied to obtain information of price per species, species volume and fishing operations. From the total number of trips during both seasons, hookah diving was represented by a sample size of 69.3%, while free diving, with a sample of 41.9%. More than 15 species were identified in each fishing season. Nevertheless, three categories had substantial contributions in both seasons with differences in the proportions for each case: green lobster (Panulirus gracilis), octopus (Octopus sp.) and parrotfish (Scarus perrico and S. ghobban). It is worth noting that an important proportion of catch was retained by fishers for personal consumption purposes, including species of high commercial value. Additional night diving activity, increased the number of dives from one season to another. Besides, cooperation processes in free diving fishing operations, and changes in fishing effort between seasons, defined important changes in fishing strategies. Potential causes of changes in fishing strategies and the implications for management to ensure the sustainability of these fisheries in the long term are discussed. PMID- 25720189 TI - The community structure of macroscopic basidiomycetes (Fungi) in Brazilian mangroves influenced by temporal and spatial variations. AB - Mangroves are transitional ecosystems between terrestrial and marine environments, and are dis- tinguished by a high abundance of animals, plants, and fungi. Although macrofungi occur in different types of habitat, including mangroves, little is known about their community structure and dynamic. Therefore the aim of this study was to analyze the diversity of macrofungi in a number of Brazilian mangroves, and the relation- ship between such diversity, precipitation and area of collection. A total of 32 field trips were undertaken from 2009 to 2010, and macrofungi were studied in four 250 x 40 m transects: Timbo and Santa Cruz Channel on the Northern coast, and Maracaipe and Ariquinda on the Southern coast. All basidiomata found along the transects were placed in paper bags, air dried and identified using existing literature. It was found that Northern areas predominantly featured Avicennia schaueriana mangroves, while Rhizophora mangle dominated in Southern transects. A total of 275 specimens were collected, and 33 species, 28 genera, 14 families and six orders were represented. Overall abundance and species richness did not vary significantly among areas, but varied according to time, being higher during the rainy season. Subtle differences in composition were observed over time and between areas, probably due to variations in plant species occurrence. Further studies with collections during months of greater precipitation in transects dominated by different mangrove species of the same ecosystem are suggested to assess the overall diversity of mycobiota in these ecosystems. PMID- 25720190 TI - Morphological and micromorphological characteristics of Desmodium fruits (Leguminosae: Papilionoideae). AB - The genus Desmodium is represented in Santa Catarina State, Brazil, by 13 species, all with lomen- taceous fruits. Shape, size and isthmus margin of loments vary, while the surface is glabrous, or covered by trichomes of different types. Morphological diversity of trichomes becomes particularly relevant to taxonomic description. The trichome types present on the surface of Desmodium fruits provide data for the identification and classification of species in the State. To assess this, three fruits of each species were collected and deposited at two herbaria, HBR and FLOR, in Santa Catarina, Brazil. Some rehydrated samples were examined using light microscopy (LM); and some sections were exposed to the following histochemical reagents: Sudan III for oils and Thionine for mucilage. The structural aspects of trichomes can be classified into uni- or multicellular and may still be simple, i.e., nonglandular or glandular. Using scanning electron microscopy (SEM), five types of trichomes were identified and analyzed among the Desmodium species studied: uncinate, uniseriate, globose multicellular, globose unicellular and subulate. Characteristics, such as loment margin and article form, glabrescent or pillous indument, trichome type, with or without papillous epidermal cells and epicuticular striations, showed relevant diagnostic value. An identification key was developed for Desmodium species from Santa Catarina State, Brazil, based on macro and micromorphological characters of the fruit. PMID- 25720191 TI - [Colonization and structure of arbuscular mycorrhizal fungi community in Alsophila firma (Cyatheales: Cyatheaceae) from a tropical montane cloud forest in Veracruz, Mexico]. AB - Alsophila firma is a tree fern that is distributed mainly in tropical montane cloud forest (TMCF) and is considered as a threatened species. Arbuscular mycorrrhizal fungi (AMF) have been proposed as an alternative in rescue programs of endangered species. However, our knowledge about diversity of AMF and mycorrhizal status of the species of TMCF is limited. In Mexico TMCF shows different degrees of conservation because of fragmentation and land use change. In this study, we evaluated the level of colonization, richness and abundances of spores of AMF in three fragments with different conservation status: conserved (100 years), secondary vegetation (17 years) and disturbed. For this, soil samples and roots were collected from five individuals of A. firma per site, with at least 100 m away from each other; a total of 100 cm of roots were analysed per site. Root samples showed AMF and occasionally dark septate fungi (DSF) colonizations. For the overall study, 19 species of AMF were recorded: Gigaspora (7), Acaulospora (4), Glomus (4), Funneliformis (2), Sclerocystis (1) and Scutellospora (1). The dominant species in the three sites were Funneliformis geosporum and Acaulospora scrobiculata. The highest diversity (H') and evenness (J') (p < 0.05) were found in the conserved site (H' = 1.7, J' = 0.66), when compared to the secondary vegetation (H' = 1.5, J' = 0.61), and the disturbed site (H' = 0.74, J' = 0.41). Statistical analysis showed that the AMF degree of colonization was significantly higher (p < 0.05) in the conserved site; although, the disturbed site showed low richness and abundances of AMF, the degree of root colonization did not differ statistically (p < 0.05) with the secondary vegetation site. Chao2 (Richness estimation model) showed that the number of analysed samples were sufficient to represent the structure of the AME communities with values > 90%. The present study confirmed that A. firma is a mycorrhizal species that exhibits high levels of colonization even in disturbed sites. We suggest that F. geosporum and A. scrobiculata may have the potential to inoculate the gametophyte and young sporophyte of A. firma, to support restoration programs, because of their abundances and high tolerance to disturbed sites. PMID- 25720192 TI - [Anatomy of the vegetative organs of two species of Atriplex (Chenopodiaceae) from Venezuela]. AB - In Venezuela, Atriplex is represented by A. cristata and A. oestophora, the latter being endemic; they inhabit coastal areas with high temperatures, high solar radiation and sandy soils with high salt content. This work aimed to provide information to facilitate and clarify these species taxonomic delimitation, throughout the study of the anatomy of their vegetative organs; this may also clarify our understanding of their adaptability to soil and climatic conditions prevailing in areas they inhabit. The plant material was collected from at least three individuals of each species in Punta Taima Taima and Capatarida, Falcon. Segments of roots, located near the neck and towards the apex, apical, middle and basal internodes of stems, were taken; and of leaves, located in the middle portion of plants. This material was fixed in FAA (formaldehyde, acetic acid, 70% ethanol) until processing. Semipermanent and permanent microscope slides were prepared with transverse or longitudinal sections, made using a razor (free-hand) or a rotation microtome, in this latter case, after paraffin embedding; besides, additional plates were mounted with portions of leaf epidermis, obtained by the maceration technique. The sections were stained with aqueous toluidine blue (1%) or safranin-fast-green, and mounted in water-glycerin or in Canada balsam. In order to calculate the vulnerability index, the vessel diameter in the vascular rings of roots, as well as their density, were quantified. Our results revealed structural features in the different organs, that resulted of taxonomic value and allowed the distinction of the species: in the leaf, the presence of aquifer tissue, the number of vascular bundles and their organization in the midrib, and the collenchyma differentiation in this part of the leaf; in the roots, the xylem and phloem arrangement in the growth rings, the nature of conjunctive tissue, and the presence of included phloem in one species. In addition, the species showed typical anatomical features of halophytes and xerophytes, such as: high density of trichomes on leaves and young stems which act as salt secreting glands, abundant sclerenchyma in stems and roots, water storage tissue and Kranz anatomy in leaves, narrow cortical region in young roots, presence of cambial variants in stems and roots, as well as short and narrow xylem vessels. Vulnerability index calculations indicated that both species tend to assure conduction but not the efficiency of the system. Atriplex species have anatomical characters which facilitate their adaptation to the special conditions prevailing in their habitats and that may be used for taxonomic delimitation. PMID- 25720193 TI - Identification of gene fragments related to nitrogen deficiency in Eichhornia crassipes (Pontederiaceae). AB - Eichhornia crassipes is an aquatic plant native to the Amazon River Basin. It has become a serious weed in freshwater habitats in rivers, lakes and reservoirs both in tropical and warm temperate areas worldwide. Some research has stated that it can be used for water phytoremediation, due to its strong assimilation of nitrogen and phosphorus, and the accumulation of heavy metals, and its growth and spread may play an important role in environmental ecology. In order to explore the molecular mechanism of E. crassipes to responses to nitrogen deficiency, we constructed forward and reversed subtracted cDNA libraries for E. crassipes roots under nitrogen deficient condition using a suppressive subtractive hybridization (SSH) method. The forward subtraction included 2,100 clones, and the reversed included 2,650 clones. One thousand clones were randomly selected from each library for sequencing. About 737 (527 unigenes) clones from the forward library and 757 (483 unigenes) clones from the reversed library were informative. Sequence BlastX analysis showed that there were more transporters and adenosylhomocysteinase-like proteins in E. crassipes cultured in nitrogen deficient medium; while, those cultured in nitrogen replete medium had more proteins such as UBR4-like e3 ubiquitin-protein ligase and fasciclin-like arabinogalactan protein 8-like, as well as more cytoskeletal proteins, including actin and tubulin. Cluster of Orthologous Group (COG) analysis also demonstrated that in the forward library, the most ESTs were involved in coenzyme transportation and metabolism. In the reversed library, cytoskeletal ESTs were the most abundant. Gene Ontology (GO) analysis categories demonstrated that unigenes involved in binding, cellular process and electron carrier were the most differentially expressed unigenes between the forward and reversed libraries. All these results suggest that E. crassipes can respond to different nitrogen status by efficiently regulating and controlling some transporter gene expressions, certain metabolism processes, specific signal transduction pathways and cytoskeletal construction. PMID- 25720194 TI - Development of RAPD-SCAR markers for Lonicera japonica (Caprifolicaceae) variety authentication by improved RAPD and DNA cloning. AB - Genetic diversity within a species is a common feature, which plays a vital role in its survival and adaptability, and is important for the identification and authentication of a species. Lonicera japonica is a traditionally used medicinal plant, which have been recently genetically characterized by an improved ran- dom amplified polymorphic DNA (RAPD) analysis. In this study, the molecular markers on the basis of these RAPD fragments have been developed to identify specific L. japonica variety. The DNAs were extracted from fresh young leaves of different samples of L. japonica collected from Shenzhen, Yichang, Leshan, Emei and Loudi, China. The DNA materials were amplified using improved RAPD PCR. Different RAPD bands were excised, cloned and developed for stable sequence-characterized amplified region (SCAR) markers with differ- ent species. Two SCAR markers, JYH3 3 and JYH4-3, have been successfully cloned from improved.RAPD fragments. The SCAR marker JYH3-3 was found specific for all of the L. japonica samples collected from the different regions, and another marker JYH 4-3 was strictly specific to the Shenzhen sample from Guangdong province, which is geographically distant from Hubei, Sichuan and Hunan Provinces (source of other L. japonica samples). The marker JYH3-3 was found as specific molecular marker for the identification of L. japonica, while JYH4-3 was found as molecular marker strictly specific for the Shenzhen sample. The developed SCAR markers might serve as more specific molecular markers for L. japonica variety authentication. The combination of improved RAPD analysis and SCAR marker development have resulted useful tools to study the genetic variety of any organism, which we have successfully applied here in L. japonica. PMID- 25720195 TI - Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans. AB - CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with Ibero-American populations published data. Finally, we also aimed to describe allele frequencies among different Costa Rican ethnic groups. This research has been undertaken within the framework of the RIBEF CEIBA Consortium studies on Latin American populations. A total of 385 individuals were included in the study: 139 mestizos, 197 Amerindians, and 49 Afro-Caribbeans. CYP2D6 genotypes were determined by XL-PCR and Real-Time PCR. The CYP2D6 variant alleles *2, *3, *4, *5, *6, *10, "17, *29, *35 and *41 were also determined. For the entire Costa Rican population, the frequency of PMs and UMs was 6% and 6.5%, respectively. The percentage of UMs in the mestizo population was higher than in the Amerindian population. CYP2D6 UMs vary from 3.6% to 10.1% and PMs from 1.4% to 10.2% among three Costa Rican groups. The highest frequencies of UMs (10.1%) and PMs (10.2%) were found in the mestizo and Amerindian populations, respectively. In conclusion, the frequencies of UMs and PMs for CYP2D6 varied widely across the mestizo, Amerindian and Afro-Caribbean Costa Rican populations. Future research in this population should be oriented to identify new CYP2D6 variants through sequencing methods, as well as to determine CYP2D6 phenotype, in order to establish the phenotype-genotype relation. Finally, further studies involving genetic markers of ancestry are needed in the Costa Rican population. PMID- 25720197 TI - In this dynamic world of ours. PMID- 25720196 TI - [Specific bacterial diversity in bats of different food guilds in Southern sierra Oaxaca, Mexico]. AB - Specific bacterial diversity in bats of different food guilds in Southern sierra Oaxaca, Mexico. Bats have different ecologic roles in variable ecosystems that have been already described. They have been linked to several zoonoses, however little is known about the relationship between bat microbiota and their diet, and studies on the bacterial ecology of the microbiota in bats are limited. To contribute with the description of this important interaction between microbiota and host, the aim of this work was to characterize the composition and bacterial diversity in the oral and anal regions of 10 species of bats, in relation to food guild. For this monthly samplings were conducted using four mist nets (19:00 24:00h) from February to October 2012; nets were reviewed every 45 minutes. Each captured organism was sampled in the oral and anal cavities with sterile swabs; these were placed in pre-enrichment media and stored at 4 degrees C. Bacterial samples were studied which through selective media, chromogenic and biochemical tests. We obtained samples from 502 frugivorous, 29 hematophagous and 11 nectivorous bats. We found a total of 26 bacterial species, with the predominant phylum Proteobacteria and the family Enterobacteriaceae. Statistically significant differences were observed between oral and anal microhabitats: frugivorous (t = -3.516, g.1 = 14.761, p = 0.003), hematophagous (t = -3.320, g.l = 19.262, p = 0.003), and nectivorous (t = -2.497, g.l = 11.933, p = 0.026), and in some guilds [frugivorous and nectivorous in the anal region (t = 2.274, g.l = 29.660, p = 0.030), hematophagous and nectivorous anal region (t = 2.077, g.l = 29.904, p = 0.049)]. It was also shown that there is bacteria specificity in some guilds such as nectivorous and frugivorous with Bacillus cereus, B. sp. X. sp., as well as, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, S. epidermis, Aeromonas hydrophyla in hematophagous. Bacterial presence can be explained by the type of diet and/or by transfer of bacteria from their preys. These bacteria may be indigenous to these bats and play the role of mutual benefit, providing the host with stable growth conditions and supplemental nutrients, while the microbiota contributes to host nutrition, development of the immune system, stabilization of the microbial population and to avoid pathogens colonization. By understanding the importance of the relation- ship between host and its bacterial populations, the conservation efforts being made to protect species such as bats may be improved. PMID- 25720198 TI - Child abuse alert. New hospital it system goes live. PMID- 25720199 TI - Tax credits 'more effective' at reducing health inequalities. PMID- 25720200 TI - Newborn screening programme expanded. PMID- 25720202 TI - Community services face patient scrutiny. PMID- 25720201 TI - Parents advised to swap sugary snacks. PMID- 25720203 TI - Drowning is a 'serious and neglected' public health threat. PMID- 25720204 TI - Health visitors urged to discuss sleep patterns. PMID- 25720205 TI - NICE updates guidance on co-sleeping. PMID- 25720206 TI - Child hospital admissions for self-harm at five-year high. PMID- 25720207 TI - Determining gender: a social, construct? PMID- 25720208 TI - Championing children. PMID- 25720209 TI - School nurse 121 campaign. PMID- 25720210 TI - Health visitors' accounts of the impacts of 'Hall 4' on their practice and profession: a qualitative study. AB - The publication of the fourth edition of Health for all children (Hall 4) in 2003 marked a shift in health visiting towards a more targeted service. This paper aims to explore, through the accounts of health visitors, the impacts of this changed policy context for health visiting practice and for the health visiting profession. The study, upon which this paper is based, was a qualitative exploration carried out in one NHS locality with broad socioeconomic diversity. Semi-structured interviews were undertaken with 16 health visitors. The data was analysed using thematic and narrative techniques. In the study health visitors expressed concerns about the impacts of Hall 4 on health visiting practice, particularly in relation to health visiting expertise and the increase focus on child protection work shaping health visiting practice. In conjunction, health visitors'accounts suggest low morale as a profession.The paper concludes that the impacts of future policy change on health visiting practice must be fully considered; and, measures taken to prepare and support health visitors through periods of policy change. PMID- 25720211 TI - Using social networking sites (namely Facebook) in health visiting practice--an account of five years experience. AB - With new developments in electronic and social networking communication methods the way health visitors communicate with clients is rapidly changing. With good governance these technologies can be utilised to enhance the health visiting service and can be an effective way of accessing hard-to-reach families, saving time and resources. This paper presents five years' experience in the use of Facebook between the health visiting team and clients and explains the benefits and potential it offers to health visitors and other community practitioners. PMID- 25720212 TI - The unmet concerns of twins with special needs: diagnostic challenges and service recommendations. AB - The quality of services provided to families of twins with special needs [SPNs] was examined in a US-based study. Participants included 30 parents with monozygotic (n=8) or dizygotic (n=22) twin pairs. Parents completed questionnaires containing quantitative and qualitative components addressing the circumstances and challenges surrounding their twins' diagnoses. Areas of unmet concerns included contact withother parents, respite care and grief counseling. Beneficial services included early interventions (e.g., occupational and physical therapy). Several resources were identified as not providing sufficient benefit (e.g., inadequate state resources). These findings underline the need to improve methods by which knowledge and support are disseminated to parents regarding diagnostic information and service availability. Practitioner and service recommendations are provided. PMID- 25720213 TI - Embrace your autonomy. Be proud to be a nurse prescriber! PMID- 25720214 TI - Student health visiting: a project to foster leadership. PMID- 25720215 TI - Assessment and management of feeding difficulties in infants. PMID- 25720216 TI - [Small gifts]. PMID- 25720217 TI - [Remedies without risks and side effects]. PMID- 25720218 TI - [Humor in palliative care. Clinical competence and/or humor?]. PMID- 25720219 TI - [More gaiety in the nursing home]. PMID- 25720220 TI - [Taking the lead together]. PMID- 25720221 TI - ["Do with" instead of "do for"]. PMID- 25720222 TI - [Quality assurance in in freelance nursing care]. PMID- 25720223 TI - ["Customers have the right to professional care"]. PMID- 25720224 TI - [Motivations, goals and wishes of PhD students. From master's degree to doctor's degree]. PMID- 25720225 TI - ["Nursing provides much innovation potential"]. PMID- 25720226 TI - ["It is the diversity that I like"]. PMID- 25720227 TI - [Project evaluation in Kenya. Ultrasound examination by non-physician personnel]. PMID- 25720228 TI - [Best practice in prevention of female circumcision. Knowledge will legitimize effective action]. PMID- 25720230 TI - [A charming weapon]. PMID- 25720229 TI - [Madeleine Ducommun and Vreni Brumm. "We want to know how wraps work"]. PMID- 25720231 TI - [Humility and empathy in the foreground]. PMID- 25720232 TI - ["Students want to be involved in their future"]. PMID- 25720233 TI - [Zoom prior to recovery]. PMID- 25720234 TI - [A life marked by turmoil]. PMID- 25720235 TI - [When I meet you]. PMID- 25720236 TI - [The happy pill]. PMID- 25720237 TI - [Nursing science and practice in first place]. PMID- 25720238 TI - Critical illness associated neuromuscular disorders -- keep them in mind. AB - Neuromuscular disorders complicating sepsis and critical illness are not new and scarce phenomena yet they receive little attention in daily clinical practice. Critical illness polyneuropathy and myopathy affect nearly half of the patients with sepsis. The difficult weaning from the ventilator, the prolonged intensive care unit and hospital stay, the larger complication and mortality rate these disorders predispose to, put a large burden on the patient and the health care system. The aim of this review is to give an insight into the pathophysiological background, diagnostic possibilities and potential preventive and therapeutic measures in connection with these disorders to draw attention to their significance and underline the importance of preventive approach. PMID- 25720239 TI - [The interactive neuroanatomical simulation and practical application of frontotemporal transsylvian exposure in neurosurgery]. AB - BACKGROUND AND PURPOSE: There is an increased need for new digital education tools in neurosurgical training. Illustrated textbooks offer anatomic and technical reference but do not substitute hands-on experience provided by surgery or cadaver dissection. Due to limited availability of cadaver dissections the need for development of simulation tools has been augmented. We explored simulation technology for producing virtual reality-like reconstructions of simulated surgical approaches on cadaver. Practical application of the simulation tool has been presented through frontotemporal transsylvian exposure. METHODS: The dissections were performed on two cadaveric heads. Arteries and veins were prepared and injected with colorful silicon rubber. The heads were rigidly fixed in Mayfield headholder. A robotic microscope with two digital cameras in inverted cone method of image acquisition was used to capture images around a pivot point in several phases of dissections. Multilayered, high-resolution images have been built into interactive 4D environment by custom developed software. RESULTS: We have developed the simulation module of the frontotemporal transsylvian approach. The virtual specimens can be rotated or tilted to any selected angles and examined from different surgical perspectives at any stage of dissections. Important surgical issues such as appropriate head positioning or surgical maneuvers to expose deep situated neuroanatomic structures can be simulated and studied by using the module. CONCLUSION: The simulation module of the frontotemporal transsylvian exposure helps to examine effect of head positioning on the visibility of deep situated neuroanatomic structures and study surgical maneuvers required to achieve optimal exposure of deep situated anatomic structures. The simulation program is a powerful tool to study issues of preoperative planning and well suited for neurosurgical training. PMID- 25720240 TI - [Experience with levodopa/carbidopa intestinal gel in the treatment of advanced Parkinson's disease in Hungary]. AB - In the advanced Parkison's disease (PD) the late complications of levodopa therapy have to be considered: motor and/or non-motor fluctuations with or without disturbing dyskinesias. The non-motor fluctuations often influence the quality of life (QoL) in a much more negative way compared with the motor symptoms. In the treatment of advanced PD there are several device-aided methods deep brain stimulation, apomorphine pump, levodopa/carbidopa intestinal gel (LCIG) - to improve the symptoms, the QoL, sometimes even in an individual, tailored custom form. The LCIG therapy was introduced in Hungary in 2011. Here we summarize the data of our patients: we have tested almost 60 patients and in 43 cases we have started this treatment. We analyze the duration of illness, levodopa therapy, motor and non-motor fluctuation of patients and present our experiences with the test phase and the chronic LCIG therapy via PEG/PEJ implantation. We paid attention to the surgery and device - depending side effects. Our experiences are similar to the international data. In patients selection ,,the right treatment, to the right patient, in the right time" is of importance. PMID- 25720241 TI - [Tailored cranioplasty using CAD-CAM technology]. AB - OBJECTIVE: The majority of cranial defects are results of surgical intervention. The defect must be covered within resonable period of time usually after 4-6 week given the fact that the replacement of bone improve the brain circulation. Number of surgical techniques and materials are available to perform cranioplasty. Due to favorable properties we chosed ultra high molecular weight polyethylene as material. In this paper the authors show a procedure which allows tailored artificial bone replacement using state of art medical and engineering techniques. METHODS: between 2004 and 2012, 19 patients were operated on cranial bone defect and a total of 22 3D custom-designed implants were implanted. The average age of patients was 35.4 years. In 12 patients we performed primary cranioplasty, while seven patients had the replacement at least once. Later the implants had to be removed due to infection or other causes (bone necrosis, fracture). All patients had native and bone-windowed 1 mm resolution CT. The 3D design was made using the original CT images and with design program. Computer controlled lathe was used to prepare a precise-fitting model. During surgery, the defect was exposed and the implant was fixed to normal bone using mini titanium plates and screws. All of our patients had control CT at 3, 6 and 12 months after surgery and at the same time neurological examination. RESULTS: Twenty-one polyethylene and one titanium implants were inserted. The average follow-up of the patients was 21.5 months, ranged from two to 96 months. We follow 12 patients (63.15%) more than one year. No intraoperative implant modifications had to be made. Each of the 22 implant exactly matched the bone defect proved by CT scan. No one of our patients reported aesthetic problems and we did not notice any kind of aesthetic complication. We had short term complication in three cases due to cranioplasty, subdural, epidural haemorrhage and skin defect. CONCLUSION: Polyethylene is in all respects suitable for primary and secondary cranioplasty. Combined with 3D CAD- CAM method excellent aesthetic and functional result was achieved. In our study no case of infection occured. Proper preoperative preparation is important. PMID- 25720242 TI - [From life events to symptoms of anxiety and depression: the role of dysfunctional attitudes and coping]. AB - The aim of the present study was a systematic path-analytical investigation between the effects of life events, dysfunctional attitudes and coping strategies in relation with the exhibited depressive and anxiety symptoms in patients with mental disorders. METHODS: Self-report data of 234 patients from our outpatient psychotherapy unit were analyzed. Life events, dysfunctional attitudes, coping strategies as well as symptoms of anxiety and depression were assessed by self administerd questionnaires. Statistical methods included structural equation modelling, which enables the estimation of the magnitude and strength of individual variables within an overarching casual model, thus yielding a complex view on the possible processes underlying the development of the clinical symptoms of anxiety and depression. RESULTS: Our findings indicate that both the number of negative life events and their subjectively experienced intensity contributed to the increase of dysfunctional attitudes. The presence of dysfunctional attitudes decreased the use of problem-focused coping strategies and increased the use of emotion-focused coping strategies. The use of problem focused coping decreased symptom occurrence and emotion-focused coping strategies increased the frequency of symptoms of anxiety and depression. Our findings suggest that dysfunctional need for achievement and perfectionism directly increase the probability of depressive symptom manifestation. The attitude of external locus of control showed a significant relationship with anxiety symptoms through emotion-focused coping strategies and directly as well. CONCLUSION: Restructuring dysfunctional attitudes and developing problem-focused coping strategies are an important part of psychotherapeutic interventions aiming to decrease anxiety and depressive symptoms. PMID- 25720243 TI - [Neurocognitive impairments of HIV infected individuals -- preliminary results of a national prevalence study in Hungary]. AB - BACKGROUND and PURPOSE: The outcome of HIV infection has dramatically improved due to the widespread use of combined antiretroviral therapy (cART). Opportunistic infections faded and internal and hemato-oncological diseases along with neurological conditions came to the forth. Present study is to evaluate neurocognitive performance of the Hungarian HIV infected individuals, at first in this setting. PATIENTS and METHODS: We performed this cross-sectional pilot study within the frames of a national, single-center; prospective study on group of HIV infected patients, analyzing medical data and neurocognitive performance. Based on international recommendations visual memory, visuomotor coordination, non verbal learning ability, executive functions and reaction time were tested by six domains of a computerized neuropsychological test battery (Vienna Test System). RESULTS: Data of 59 enrolled HIV individuals were analysed; nine of whom were women (15%), median age 42.6 (IQR: 32.4-48.1) years. In 32.2% (n=19) of patients neurocognitive impairment was detected. Duration of infection and cART treatment time tended to be longer in impaired group (not significant). Lower CD4 cell count at the time of examination (p=0.047), psychiatric diseases other than depression (p=0.005) were found significantly associated with impairment; tertiary education qualification were more common (p=0.033) among non-affected patients. By correlation analysis age, infected time and duration of cART were significantly associated with motor deficit. CONCLUSION: HAND was detected in almost one third part of examined patients, which largely corresponds that in developed countries were observed. Duration of infection and of cART therapy associated motor deficit was found to be the most common impairment. This finding might be interpreted by direct effect of HIV, neurotoxicity of antiretro virals and also by accelerated ageing of this population. PMID- 25720244 TI - Symptomatic subependymomas of the ventricles. Review of twenty consecutive cases. AB - BACKGROUND AND PURPOSE: Intraventricular subependymomas are rare benign tumors, which are often misdiagnosed as ependymomas. To review the clinicopathological features of subependymomas. PATIENT SELECTION AND METHODS: Retrospective clinical analysis of intraventricular subependymomas and systematic review of histological slides operated on at our center between 1985 and 2005. RESULTS: Twenty subependymomas presented at the median age of 50 years (range 19-77). Two (10%) were found in the third, three (15%) in the forth, and 15 in the lateral ventricles. There was male preponderance (12 vs. 8). Ataxia (n=13) and papilledema (n=7) were the most common clinical presentations. Fifteen patients underwent gross total resection, and five had subtotal resection. None of the cases showed mitotic figures, vascular endothelial proliferation or necrosis. Cell proliferation marker MIB-1 activity (percentage of positive staining tumor cells) ranged from 0 to 1.4% (mean 0.3). Two cases were treated with preoperative radiation therapy (50 Gy) before the CT era, three other patients received postoperative radiation therapy for tumors originally diagnosed histologically as low grade ependymomas. Three patients (15%) died of surgical complication between one and three months postoperatively, and three patients died of unrelated causes in eight, 26 and 110 months. Fifteen patients were alive without evidence of tumor recurrence at a median follow-up time of 10 years. CONCLUSION: Subependymomas are low-grade lesions and patients do well without adjuvant radiotherapy. Small samples from more cellular areas may be confused with low grade ependymomas, and unnecessary radiotherapy may follow. Recurrences, rapid growth rates should warrant histological review, as hypocellular areas of ependymomas may also be a source of confusion. PMID- 25720245 TI - The modifying effect a PMP22 deletion in a family with Charcot-Marie-Tooth type 1 neuropathy due to an EGR2 mutation. AB - BACKGROUND: Mutations of both the PMP22 and EGR2 genes cause Charcot-Marie-Tooth (CMT) disease type 1. Deletion of the PMP22 gene, results in hereditary neuropathy with liability to pressure palsies. More publications exist about the interaction of PMP22 duplication and other CMT-causing gene mutations. In these cases the intrafamiliar discordant phenotypes draw the attention to the possible role of modifying genes. The gene-gene interactions between the PMP22 and EGR2 genes are not well understood. CASE REPORT: We report two brothers with late onset CMT1 due to a c. 1142 G>A (Arg381His) heterozygous substitution in the EGR2 gene. Additionally, the older brother with the less severe symptoms harbored the PMP22 gene deletion also. CONCLUSION: The coexistence of the two genetic alterations did not aggravate the clinical symptoms. Moreover, the PMP22 deletion appeared to have a beneficial modifying effect, thus implying potential gene-gene interaction of PMP22 and EGR2. PMP22 deletion may increase Schwann cells proliferation and compensate the dominant-negative effect of the Arg381 His substitution in the EGR2 gene. PMID- 25720246 TI - A rare paroxysmal movement disorder: mixed type of paroxysmal dyskinesia. AB - Paroxysmal dyskinesias are rare, heterogeneous group of disorders characterised by recurrent attacks of involuntary movements. The four classic categories of paroxysmal dyskinesias are kinesigenic, nonkinesigenic, exercise-induced and hypnogenic. There are some patients that do not fit in these four groups of paroxysmal dyskinesia and are termed as "mixed type". We describe a 13-year-old girl who had features of both paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia that was misdiagnosed as refractory epilepsy. She improved substantially with a combination of carbamazepine and clonazepame. It is important to recognize the clinical presentation of paroxysmal dyskinesias and distinguish these movement disorders from other disorders, such as psychogenic disorders and epilepsia, for deciding the treatment and prognosis of the patients. This case highlights the importance of the recognition of a rare paroxysmal movement disorders. PMID- 25720247 TI - [Cloning and analysis of a new aliphatic amidase gene from Rhodococcus erythropolis TA37]. AB - A new aliphatic amidase gene (ami), having a level of similarity with the nearest homologs of no more than 77%, was identified in the Rhodococcus erythropolis TA37 strain, which is able to hydrolyze a wide range of amides. The amidase gene was cloned within a 3.7 kb chromosomal locus, which also contains putative acetyl-CoA ligase and ABC-type transportergenes. The structure of this locus in the R. erythropolis TA37 strain differs from the structure of loci in other Rhodococcus strains. The amidase gene is expressed in Escherichia coli cells. It was demonstrated that amidase (generated in the recombinant strain) efficiently hydrolyzes acetamide (aliphatic anmide) and does not use 4'-nitroacetanilide (N substituted amide) as a substrate. Insertional inactivation of the amidase gene in the R. erythropolis TA37 strain results in a considerable decrease (by at least 6-7 times) in basal amidase activity, indicating functional amidase activity in the R. erythropolis TA37 strain. PMID- 25720248 TI - [Nuclear-cytoplasmic compatibility and the state of mitochondrial and chloroplast DNA regions in alloplasmic recombinant and introgressive lines (H. vulgare)-T. aestivum]. AB - Alloplasmic lines combining alien nuclear and cytoplasmic genomes are convenient models for studying the mechanisms of nuclear-cytoplasmic compatibility/incompatibility. In the.present study, we have investigated the correlation between the characters and state of mitochondrial (mt) and chloroplast (cp) DNA regions in alloplasmic recombinant common wheat lines with barley cytoplasm characterized by partial or total fertility. Fertility restoration in the studied lines (Hordeum vulgare)-Triticum aestivum is determined by different ratios of the genetic material of common wheat variety Pyrotrix 28, which is a fertility restorer in the cytoplasm of barley, and varietySaratovskaya 29, which is a fixer of sterility. In partially fertile lines with nuclear genomes dominated by the genetic material of Saratovskaya 29, plant growth and development are suppressed. In these lines we have identified the barley homoplasmy of cpDNA regions infA and rpoB and the heteroplasmy of the 18S/5S mt repeat and the cpDNA ycf5 region. Nuclear-cytoplasmic compatibility in lines with reduced fertility (the genetic material of Pyrotrix 28 predominates in their nuclear genomes) is associated with restoration of normal plant growth and development and the changes in thestate of the studied cpDNA and mtDNA regions towards the wheat type. Thus, in fertile lines, the cpDNA regions (infA, rpoB) and the 18S/5S mt repeat were identified in the homoplasmic wheat state; though the cpDNAycf5 region was in the heteroplasmic state, it was dominated by the wheat type of the copies. The nuclearicytoplasmic compatibility is not broken as a result of introgression of the alien genetic material into the nuclear genome of one of the fertile lines; the plants of introgressive lines are fertile and normally developed, and the states of the cpDNA and mtDNA regions correspond to their states in fertile recombinant lines. PMID- 25720249 TI - [Comparative analysis of ISSR markers polymorphism in populations of yak (Bos mutus) and in F1 hybrids between yak and cattle in the Sayan-Altai region]. AB - The genetic variability in seven yak populations from the Sayan-Altai region and in F1 hybrids between yak and cattle (khainags) was investigated with the help of a technique that involves the use of inter simple sequence repeat (ISSR) markers generated with PCR primers (AG)9C and (GA)9C. Samples for the analysis were collected in Mongolia, Tuva, and Altai from 2008 through 2012. The examined yak populations differed in in the presence/absence of ISSR fragments, as well as in their frequency. In total, 46 ISSR fragments were identified using two marker systems; the proportion of polymorphic loci constituted 76% and 90% for the AG ISSR and GA-ISSR markers, respectively. For the total sample of yaks, total genetic diversity (Ht), within-population diversity (Hs), and interpopulation diversity (Gst) constituted 0.081, 0.044, and 0.459 for the AG-ISSR and 0.137, 0.057, and 0.582 for the GA-ISSR markers, respectively. Based on ISSR finger printing, species- and breed-specific DNA patterns were described for the three groups of animals (yaks, cattle, khainags). For the domestic yak, the species specific profile was represented by eight ISSR fragments. Genetic relationships between the yak populations, cattle breeds, and khainags were examined with the help of four different approaches used in the analysis of population structure: estimation of phylogenetic similarity, multidimensional scaling, principal component analysis, and cluster analysis. Clear evidence on the differentiation of the populations examined at the interspecific, as well as at intraspecific, level were obtained. Similar (relative); as well as remote (isolated), yak populations were identified. Khainags occupy an intermediate position between yak and cattle. However, the data on the ISSR-PCR marker polymorphism (genome polymorphism, population structure).indicate that part of the analyzed khainag genome was more similar to the yak genome than to the cattle genome. PMID- 25720250 TI - [Inheritance of the background shell color in the snails Littorina obtusata (Gastropoda, Littorinidae)]. AB - We investigated in a gastropod mollusk Littorina obtusata (L. obtusata) the inheritance of background shell coloration of the shell, which arises on the basis of three pigments: purple, orange, and yellow. We found that the hypothesis on polyallelic inheritance, as in the genus Cepaea, cannot explain the inheritance of shell color in periwinkles. We demonstrated that a separate genetic system is responsible for incorporation of each pigment into the shell. The composition of these genetic systems includes at least tw genes each in the case of the yellow and purple pigments. Our analysis shows that caution should be applied when extending the results obtained in the studies of the Cepaea genus to the other species of gastropods. PMID- 25720251 TI - Genetic variation of 5 SNPs of MC1R gene in Chinese indigenous sheep breeds. AB - The purpose of this study was to assess genetic diversity, genetic differentiation.relationship and population structure among 10 Chinese sheep populations using 5 single nucleotide polymorphisms (SNPs). in MC1R gene. The genetic diversity indices suggested that the intra-population variation levels of Chinese Merino and Large-tailed Han,breeds were lowest than Kazakh Fat-Rumped. Chinese sheep breeds have maintained a high intra-population variation levels (95.23%). The genetic differentiation patterns and genetic relationships among Chinese sheep breeds displayed a high consistency with the traditional classification. The cluster trees were constructed by UPMGA method. The results showed that Chinese indigenous sheep populations have distinct genetic differentiation. The inter-population variation levels in Chinese sheep populations indicated three geographically independent domestication events have occurred. The Bayesian cluster analyses also showed a reliable clustering pattern, which revealed three major clusters in.Chinese indigenous sheep populations (Mongolian group, Kazakh group and Tibetan group), except for Duolang and Minxian Black-fur. There were probably caused by different breeding history, geography isolation and different levels of inbreeding. The findings supported the related records in literature, ten sheep populations originated on different time stage from the primogenitor population and communicated genetically with each other in the process of natural and artificial selection, and in different ecological environment. It is concluded that Chinese indigenous sheep have higher genetic variation and diversity, genetic differentiation exist between Chinese sheep populations. The majority breeds are consistent with the geographical distribution and breed characteristic. PMID- 25720252 TI - [Differentiation of tortoises of the genera Testudo and Agrionemys (Testudinidae) based on the polymorphism of nuclear and mitochondrial markers]. AB - Based on polymorphism of the 12S rRNA gene and RAPD markers, differentiation of 122 tortoise individuals belonging to the three species of genus Testudo (T. kleinmanni, T. marginata, and T. graeca), six subspecies of T. graeca (T. g. nikolskii, T. g. pallasi, T. g. armeniaca, T. g. zarudnyi, T. g. terrestris, T. g. ibera), and two subspecies of the Central Asian tortoise Agrionenemys horsfieldii (A. h. horsfieldii, A. h. kazakhstanica) was performed. For comparison, 32 known sequences of 12S rRNA gene (392 bp) from tortoises of the two genera inhabiting the territories of Europe, Asia, and Africa were used. In the populations of A. horsfieldii, a total of six haplotypes; including three newly described variants, were identified. In the examined tortoises of the genus Testudo, eleven 12S rRNA haplotypes were identified. One new haplotype was detected in T. kleinmanni. Among the eight subspecies of T. graeca, eight haplotypes were identified, with four newly described ones. The reported RAPD markers generally supported the reconstructions obtained with the use of the mitochondrial marker. Similarly to the 12S rRNA-based reconstructions, two independent clusters included representatives of the two genera, Agrionemys and Testudio. Among the latter, representatives of T. marginata and T. kleinmanni, as well as T. graeca, with high statistical support values, formed two reciprocally monophyletic groups. Compared to the mitochondrial markers, RAPDs more statisticallysignificantly discriminated the sample of T. g. terrestris and the four subspecies, T. g. ibera, T. g. armeniaca, T. g. pallasi, and T. g. nikolskii. In almost all cases except the representatives of T. g. ibera, the representatives of each of four subspecies formed individual subclusters. The geographical haplotype distribution patterns and possible evolutionary scenario of the origin and dispersal of tortoises of the two genera are discussed. PMID- 25720253 TI - [Nucleotide variation in the mitochondrial DNA cytochrome oxidase 1 gene in the Siberian sucker (Catostomus catostomus rostratus) from Kolyma River]. AB - This study presents the data of the first molecular genetic analysis of the Siberian sucker from Kolyma River. Polymorphism of the mtDNA cytochrome oxidase 1 gene was established. Comparative sequence analysis of the gene examined and the GenBank variants characterizing suckers from the rivers of Canada enabled the suggestion that the sucker penetrated to Asia from North America approximately at the end of Early and the beginning of the Middle Pleistocene. It was demonstrated that intrapopulation genetic variation in the Siberian sucker accounted for 11.63% of total variation, while the proportion of the intergroup, component (Fst) constituted 88.37%. It seems likely that a considerable proportion of intergroup variation was caused by the long period of isolation of the Siberian sucker in Kolyma River. The prevalence of one common haplotype, CH-COI 1, in the sample examined indicates that the founder effect played an importaht role in the history of the formation of the Kolyma population. PMID- 25720254 TI - [Genetically predetermined limitation in the use of HaCaT cells that affects their ability to serve as an experimental model of psoriasis]. AB - Proinflammatory cytokines TNF, IFNG and ILl7 play an important role in eruption of psoriasis. The activation of epidermal keratinocytes with the named cytokines alters their terminal differentiation program and causes their hyperproliferation in the diseased skin. HaCaT cells, which are immortalized human keratinocytes, are often used as a cellular model of psoriasis. The aim of this study was to evaluate changes in gene expression and the proliferation rates in cultured HaCaT cells treated with TNF, IFNG and IL17. We found that HaCaT cells decrease their proliferation rate in response to either IL17 or a combination TNF and IF-NG. The analysis of microarray data discovered a group of 12 genes, which were downregulated in HaCaT after treatments with the named cytokines and upregulated in psoriatic lesional skin. Eight genes were important for DNA replication and they also contributed to two larger networks that regulated cell progression through the cell cycle. We conclude that HaCaT cells have a sufficient limitation as a cellular model of psoriasis due to their treatment with proinflammatory cytokines, namely TNF, IFNG and IL17 does not increase their proliferation rate. Thus, the studies of psoriasis based on HaCaT cells as an experimental model shall take in account this important phenomenon. PMID- 25720255 TI - [Coordinated aberranit expression of miRNAs in colon cancer]. AB - Applying the method of multiple parallel sequencing on the MiSeq platform (Illumina, United States), a comparative analysis of miRNA expression in tumor and normal colon tissuie cells was performed. Forty miRNAs aberrantly expressed in cancer were detected. Among them, 15 and 25 miRNAs showed increased arid decreased expression, respectively, for all or most of the cases. Sixteen miRNA clusters were identified, which showed a coordinated or incompletely coordinated aberrant expression in colorectal cancer cells. In two (miR-183/182 and miR 106b/25) and four (miR-143/145, miR-497/195, miR-30e/30c-1, and miR-30a/30c-2) miRNA clusters, respectively, a statistically significant coordinated increase or decrease in expression was iegistered for all miRNAs withini the corresponding cluster. Three aberrantly expressed well-known miRNAs (miR-100-5p, mil-30d-5p, and miR-204-5p) were identified, which, however, had never 'before been associated with coloreictal cancer. The obtained results demonstrate the potential and promising application of 6 miRNA clusters with' coordinated aberrant expression as markers for colorectal cancer. PMID- 25720256 TI - [Genetics of anthocyaninless rye]. AB - Six nonallelic genes have been discovered in rye, the recessive mutations of which lead to a lack of anthocyanin. Crosses with these mutants showed that 13 new anthocyaninless lines carry mutations in the gene vi1, whereas vi2/6 mutations were identified only in single cases. Inheritance of the vi1/6 mutations in the progeny of hybrids with the wild type (Line 7, L7) corresponds to a monohybrid segregation. Segregation for three of these mutations (vi2, vi4, and vi5) in hybrids with line 2 is characterized by anthocyaninless deficiency in plants. We discuss the reasons for such deviations and the previously published data for the identification of the six anthocyanin pigmentation genes in the rye using trisomic analysis. PMID- 25720257 TI - [Spiral cores of synaptonemal complex lateral elements at the diplotene stage in rye include the ASY1 protein]. AB - After completing their functioning, synaptonemal complexes (SCs) degrade during the diplotene stage. In the pollen mother cells of rye Secale cereal L., this occurs through the formation of gaps in lateral elements of the SCs and the shortening of fragments of SCs until their complete disappearance. However, when contrasting SCs with silver nitrate solution at a pH of 3.5-4.5, these gaps appear to be filled with threads associated with SC lateral elements. As the diplotene stage proceeds and gradual degradation of SC fragments continues, these threads turn into submicroscopic spirals. In this study, we found that the threads and spirals associated with degrading synaptonemal complexes are stained by antibodies to the ASY1 protein ofArabidopsis thaliana lateral elements and thus are degradation products of the lateral elements of SCs. PMID- 25720258 TI - [Association of the genenetic polymorphism of cytokines and their receptors with climate and geographic factors in human populations]. AB - The variability of eight polymorphic variants of the IL4, IL4R, IL10, IL13, IL12A, and IL12RB2 genes encoding key cytokinesand their receptors in 57 world populations has been assessed. A correlation between the allele frequency distribution of the examined genes and climatic and geographic factors was observed. PMID- 25720259 TI - EST-SSR markers from Heterodera glycines Ichinohe. AB - The soybean cyst nematode Heterodera glycines Ichinohe is a severe agricultural pest for which genetic resources are limited. In this study, 295 simple sequence repeats (SSRs) were identified from 259 expressed sequenced tags (ESTs), Which were selected from 9,443 unigenes. The successful primer pairs were designed against six regions. In total, 30 alleles were identified from 30 individuals using the six markers, with an average of five alleles per locus (range, 4-7). The observed and expected heterozygosities were 0.074-0.900 and 0.266-0.775, respectively. Significant departure from Hardy-Weinberg equilibrium was found at three of the six loci. The EST-based SSR markers developed in this study may contribute to better understanding of the genetic structure of H. glycines populations. PMID- 25720260 TI - [5.8S rDNA variability in Allium species belonging to the third evolutionary group]. AB - Sequence analysis of 5.8S rDNA in 67 accessions of the subgenus Allium and six other subgenera belonging to the third evolutionary group of Allium genus (Friesen et al., 2006) was performed. Nucleotide substitutions in 5.8S rDNA sequences ofAllium accessions were identified and, studied for the first time. The probable secondary structure of 5.8S rRNA was constructed. It was shown that mutations in 5.8S rDNA do not involve conserved motifs, and they did not significantly affect the Secondary structure of the RNA molecule in Allium accessions. PMID- 25720261 TI - [On the classification of the cleavage patterns in amphibian embryos]. AB - This paper presents a brief survey and preliminary classification of embryonic cleavage patterns in the class Amphibia. We use published data on 41 anuran and 22 urodele species concerning the character of the third cleavage furrow (latitudinal or longitudinal) and the stage of transition from synchronous to asynchronous blastomere divisions in the animal hemisphere (4-8-celled stage, 8 16-celled stage or later). Based on this, four patterns of amphibian embryonic cleavage are recognized, and an attempt to elucidate the evolutionary relationships among these patterns is undertaken. The so-called "standard" cleavage pattern (the extensive series of synchronous blastomere divisions including latitudinal furrows of the third cleavage) with the typical model species Ambystoma mexicanum and Xenopus laevis seems to be derived and probably originated independently in the orders Anura and Caudata. The ancestral amphibian cleavage pattern seems to be represented by species with longitudinal furrows of the third cleavage and the loss ofsynchrony as early as the 8-celled stage (such as in primitive urodele species from the family Cryptobranchidae). PMID- 25720262 TI - [Hormonal regulation during plant fruit development]. AB - The modern concept of the hormonal regulation of fruit set, growth, maturation, and ripening is considered. Pollination and fertilization induce ovule activation by surmounting the blocking action of ethylene and ABA to be manifested in auxin accumulation. Active fruit growth by pericarp cell division and elongation is due to the syntheses ofauxin in the developing seed and ofgibberellins in the pericarp. In climacteric fleshy fruits, the maturation is controlled by ethylene via so-called System 1 combining the possibilities of autoinhibition and autocatalysis by ethylene of its own biosynthesis. Transition of tomato fruits from maturation to ripening is characterized by highly active synthesis of ethylene and its receptors due to the functioning of regulatory System 2 resulting in the up-regulation of much greater number of ethylene-inducible genes. In peach fruits, the hormonal regulation of ripening includes also an active auxin involvement in the ethylene biosynthesis, which is combined with the ethylene-induced expression of genes encoding both auxin biosynthesis and the response to auxin. Ethylene induces the expression of genes responsible for the fruit softening, its taste, color, and flavor. Nonclimacteric fleshy fruits produce very small amounts ofethylene; its evolution increases only by the very end of ripening and can be described by a reduced System 1. The ripening of nonclimacteric fruits only weakly depends on ethylene but is stimulated by abscisic acid. PMID- 25720263 TI - [Abnormal floral meristem development in transgenic tomato plants do not depend on the expression of genes encoding defense-related PR-proteins and antimicrobial peptides]. AB - In this study, the morphological and cytoembryological analyses of the tomato plants transformed with the genes encoding chitin-binding proteins (ac and RS intron-Shir) from Amaranthus caudatus L. andA. retroflexus L., respectively, as well as the gene amp2 encoding hevein-like antimicrobial peptides from Stellaria media L., have been performed. The transgenic lines were adapted to soil and grown the greenhouse. The analysis of putative transgenic tomato plants revealed several lines that did not differ phenotypically from the wild type plants and three lines with disruption in differentiation of the inflorescence shoot and the flower, as well as the fruit formation (modified plants of each line were transformed with a single gene as noted before). Abnormalities in the development of the generative organs were maintained for at least six vegetative generations. These transgenic plants were shown to be defective in the mail gametophyte formation, fertilization, and, consequently, led to parthenocarpic fruits. The detailed analysis of growing ovules in the abnormal transgenic plants showed that the replacement tissue was formed and proliferated instead of unfertilized embryo sac. The structure of the replacement tissue differed from both embryonic and endosperm tissue of the normal ovule. The formation of the replacement tissue occurred due to continuing proliferation of the endothelial cells that lost their ability for differentiation. The final step in the development of the replacement tissue was its death, which resulted in the cell lysis. The expression of the genes used was confirmed by RT-PCR in all three lines with abnormal phenotype, as well as in several lines that did not phenotypically differ from the untransformed control. This suggests that abnormalities in the organs of the generative sphere in the transgenic plants do not depend on the expression of the foreign genes that were introduced in the tomato genome. Here, we argue that agrobacterial transformation affects, directly or indirectly, expression of genes encoding for transcription factors that can activate a gene cascade responsible for the normal plant development. PMID- 25720264 TI - [Inductive role of mossy fibers of hippocampus in the development of dendritic spines in aberrant synaptogenesis at neurotransplantation]. AB - The dentate fascia of the hippocampal formation isolated from 20-day-old Wistar rat fetuses was subjected to heterotopic transplantation into the somatosensory area of the neocortex of adult rats of the same strain. Five months after surgery, neurotransplantates, together with neighboring area of the neocortex, were studied using light and electron microscopy. We carried out a detailed study of the ultrastructure of the ectopic synaptic endings formed by the axons of granular neurons of the dentate fascia (mossy fibers) with neurons of the neocortex unusual for them in a normal state. Ultrastructural analysis revealed that most ectopic synaptic endings produce its determinant morphological features: giant sizes ofpresynaptic knobs, active zones with branched dendritic spines, and adherens junctions with the surface of dendrites. The data indicate that the mossy fibers growing from neurotransplantates induce structural and chemical reorganization of dendrites of the neocortex using transmembrane adherens junctions, such as puncta adherentia junctions. This results in the differentiation of active zones and development of dendritic spines typical for giant synaptic endings that are invaginated into presynaptic endings. Thus, the ability of neurons of the dentate fascia to form aberrant synaptic connections at transplantation results from the inductive synaptogenic properties of mossy fibers. PMID- 25720265 TI - [Effect of D,L-buthionine-S,R-sulfoximine on the ratio of glutathione forms and the growth of tatar buckwheat calli]. AB - We studied the intracellular content of reduced (GSH) and oxidized (GSSG) glutathione, glutathione reductase activity, glutathione-S-transferase, and ascorbate peroxidase in morphogenic and nonmorphogenic Tatar buckwheat calli during the culture cycle as well as under the treatment with D,L-buthionine-S,R sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthase, the first enzyme of glutathione biosynthesis. We found that, during passaging, cultures only slightly differed in total glutathione content; however, the content of GSH was higher in the morphogenic culture, whereas the content of GSSG was higher in the nonmorphogenic culture. In the morphogenic callus, the glutathione-S transferase activity was 10-20 times higher and the glutathione reductase activity, was 2-2.5 times lower than in the nonmorphogenic callus. Under the treatment with BSO, the decrease in the GSH content in the morphogenic callus was temporary (on day 6-8 of passage), whereas that in the nonmorphogenic callus decreased within a day and remained lower than in the control throughout the entire passage. In the morphogenic callus, BSO did not affect the content of GSSG, whereas it caused GSSG accumulation in the nonmorphogenic callus. These differences are probably due to the fact that, in the BSO-containing medium, glutathione reductase is activated in the morphogenic callus and, conversely, inhibited in the nonmorphogenic callus. Although BSO caused a decrease in the total glutathione content only in the nonmorphogenic culture, the cytostatic effect of BSO was more pronounced in the morphogenic callus. In addition, BSO also had a negative effect on the differentiation ofproembryonic cell complexes in the morphogenic callus. The role of the glutathione redox status in maintaining the embryogenic activity of cultured plant cells is discussed. PMID- 25720266 TI - [Traditional and modern approaches to culture of preimplantation mammalian embryos in vitro]. AB - This review covers the basic principles and methods of in vitro culture of preimplantation mammalian embryos. The features of in vitro development of embryos of various species of animals with allowance for the composition of nutrient media are described, with special attention paid to those species that have traditionally been consideredas laboratory (i.e., mice, rats, and hamsters). The effects of suboptimal culturing conditions of preimplantation embryos on the formation of the phenotype of individuals developed from these embryos are discussed. New approaches to optimize the conditions of the development of preimplantation mammalian embryos in vitro are analyzed. PMID- 25720267 TI - [Aorta, pulmonary artery, and blood flows on them in chickens in the second half of embryogenesis and after hatching]. AB - The aim of the study was to determine changes in the blood flow in arterial trunks (coming out of the heart of chickens) by changes of the lumen of these arteries during embryogenesis (on the 10th, 15th, and 19th days) and 6 days after the hatching. For this purpose, posthumous morphometry of aorta, pulmonary arteries, and arterial (Botallo's) ducts (AD) from their exit from the heart until final extraorgan branching was conducted. It was demonstrated that, in this period, (1) initial lumens of aorta and pulmonary arteries are equal to each other and are equally increased (with temporary stop in last quarter of embryogenesis) with an increase of the body weight (BW); (2) the portion of the right ventricle in a total blood circulation minute volume (BCMV) is somewhat smaller than the portion of the left ventricle, but it approaches equality to it by the end of embryogenesis; (3) with the growth of embryos, the portion of total BCMV flowing through the anterior (before the inflow of AD into the aorta) part of the body decreases; that in the average part increases (from 17 to 31%); that in the posterior part (after bifurcation of aorta), where chorioallantoic membrane (CAM) is located, remains almost unchanged; (4) after the hatching (and disappearance of CAM), BCMV of the left ventricle multiply increases due to the junction of two blood flows from the heart (through the ascending aorta and AD) into a single flow, which flows sequentially by lesser and greater circulations, resulting in multiple increase in the organ blood flow. PMID- 25720268 TI - [Nonhormonal stimulation in vitro of oocyte maturation in sturgeons]. AB - Incubation of sturgeon full-grown ovarian follicles in amphibian Ringer solution with increased sodium bicarbonate concentration results in "spontaneous" oocyte maturation. Addition of sodium bicarbonate to diluted Leibovitz medium also induces maturation of follicle-enclosed oocytes. Effective threshold concentration of sodium bicarbonate depends on the composition of culture medium and, especially, on the physiological state of follicle-enclosed oocytes. As evidenced by experiments with actinomycin D, oocyte maturation induced by bicarbonate ions does not depend on RNA synthesis. An attempt was made to elucidate the involvement of steroidogenesis in bicarbonate ion-induced oocyte maturation. Surprisingly, the inhibitors used, such as aminogluthetimide, diltiazem, andestradiol-17beta, not only did not inhibit but also enhanced oocyte maturation. Manual removal of follicle envelopes demonstrated that denuded oocytes retained the ability to mature in a culture medium with increased sodium bicarbonate concentration. However, the range of effective bicarbonate ion concentrations for denuded oocytes is more restricted than for the follicle enclosed oocytes. A hypothesis of competition of different processes occurring in the ovarian follicle for energy resources is proposed to explain the revealed paradoxical effect of substances affecting steroidogenesis. PMID- 25720269 TI - [Embryo initiation from Pinus sibirica megagametophytes in in vitro culture]. AB - Megagametophytes of Siberian pine were cultured on an in vitro culture medium 1/2 LV supplemented with growth regulators 2,4-dichlorophenoxyacetic acid (2,4-D) and benzylaminopurine (6-BAP) to form embryos. The competency of somatic cell of explants to embryogenesis manifested itself in an organized growth and polarity. A coenocyte consisting of long vacuolated cells was formed in the megagametophyte culture. Then, the migration of the nuclei to one of the poles of the cell, their division, and formation of embryoids was observed. The megagametophyte culture of the Siberian pine differed from the zygotic embryo culture by the absence of asymmetric division in the vacuolated cell. PMID- 25720270 TI - [Prof. Olga Mikhailovna Ivanova-Kazas. The 100th anniversary of the birth]. PMID- 25720271 TI - [On a contribution of Boris Balinsky to the comparative and ecological embryology of amphibians]. AB - The outstanding embryologist Boris Ivanovich Balinsky (1905-1997) worked in the Soviet Union up to 1941 and in South Africa since 1949. His experimental studies fulfilled during the Soviet period of his scientific career mainly on the embryos of the caudate amphibians are widely known. After moving to Africa (Johannesburg), he continued the research of amphibian development, with using those possibilities, which were offered by the diverse fauna of local Anura. Other embryologists started complex studies of tropical frog ontogenies (mainly from South and Central America) 30-40 years later than Balinsky. Unfortunately, his pioneering works on numerous African species are poorly known (with the exceptions of the description of the development of endodermal derivatives in Xenopus laevis and the analysis of limb induction in the toad genus Amietophrynus). In this paper, the works of Balinsky are analyzed (with the emphasis on comparative and ecological aspects) and his priority in using of "nonmodel" tropical and subtropical anurans in embryological studies has been shown. PMID- 25720272 TI - [Homeostatic mechanisms of biological systems: formulation of the problem]. PMID- 25720273 TI - [Homeostatic mechanisms of biological systems: development homeostasis]. AB - Homeostasis as an ability to maintain structural-functional parameters of the system at the required level is a basic characteristic for providing the stability of any biological system (from biosphere and separate ecosystems to communities, populations, and individuals). The study of homeostatic-mechanisms that provide the stability ofbiological systems is the main task for solving many theoretical and practical questions. The search for criteria of homeostasis estimation and study of homeostatic mechanism ratio at different levels are principally important in this direction. Estimation of the role of homeostatic mechanisms of the organism and population for providing the stability of biological systems of different levels when using the approach based on estimation of the population state from ontogenetic positions (population developmental biology) seems promising. PMID- 25720274 TI - [Developmental instability of the organism as a result of pessimization of environment under anthropogenic transformation of natural landscapes]. AB - The value of fluctuating asymmetry is considered to be an indicator of the developmental instability of the organism. The consequences of activities of the mining industry plants, which are characterized by alienation and transformation of large areas of natural landscapes, are analyzed as an anthropogenic factor. The objects of study were small mammals (northern red-backed (Clethrionomys rutilus) and gray red-backed (Clethrionomys rufocanus) voles, tundra vole (Microtus oeconomus), Laxmann's (Sorex caecutiens) and tundra (S. tundrensis) shrews) and trees (Japanese white birch (Betula platyphylla), Betula divaricate, Betula exilis, Duschekiafruticosa, and common osier (Salix viminalis)). In total, 3500 skulls and approximately 30000 leaves collected in the taiga zone of Yakutia were studied. The index offluctuating asymmetry, as well as population parameters and composition of small mammal communities, were analyzed. The data on the value of the fluctuating asymmetry in the studied species in natural habitats are given. It is shown that, in natural conditions, this parameter can rise with deterioration in living conditions, particularly at the ecological periphery of the range. Anthropogenic transformation of natural landscapes creates an "anthropogenic periphery" and causes changes similar to the adaptive responses at the northern limit of the distribution of species. It was found that, through pollution and disruption of ecosystems, the mining industry affects all levels of organization of the living matter, but the population and cenotic parameters give an unambiguous response only at macroanthropogenic transformations. Increase in the level of fluctuating asymmetry is the most sensitive indicator of anthropogenic impact and it should also be taken into account that disruptions in the developmental stability of an organism reflect the destructive processes occurring in the population and community. PMID- 25720275 TI - [Homeostatic responses of plants to modern climate change: spatial and phenological aspects]. AB - A series of dates of unfolding of the first leaves and duration of the season of vegetation in the silver birch (Betulapendula Roth. (B. verrucosa Ehrh.)), as well as the duration of flowering of the bird cherry (Padus avium), mountain ash (Sorbus aucuparia), and small-leaved lime (Tilia cordata Mill.) for the period 1970-2010 in the central part of European Russia were studied in order to assess the trends. Differences in phenological responses to homogeneous climate changes in the trees of the same species from the northern and southern parts of the range were revealed. If spring events occur 3-7 days earlier in the northern part, no such effect is observed in the south. This fact can be interpreted as a manifestation of the different mechanisms of homeostasis in different populations determined by their biological characteristics (in particular, by the need to pass successfully the periods of organic rest and vegetation). PMID- 25720276 TI - [Evaluation of genetic homeostasis in animals at different stages of ontogenesis in the environment]. AB - Modern methods of genetic homeostasis assessment in animals are described in the present article. The single gel-electrophoresis test (Comet Assay), micronuclei test, chromosome aberration frequency, and sister chromatid exchanges are reviewed in detail. The questions of test-sensitivity of given methods and principles or their application for genetic homeostasis assessment in wild populations of animals are considered. PMID- 25720277 TI - [Analysis of cytogenetic stability in natural populations of terrestrial mollusks (based on DNA comet assay)]. AB - Abstract-Alkaline gel electrophoresis of isolated cells (comet assay) was used to assess degree of nuclear DNA damage in populations of terrestrial mollusks Bradybaenafruticum Mull., Chondrula tridens Mull., Cepaea vindobonensis Fer., and Stenomphalia ravergieri Fer. living in the forest-steppe landscape of the southern part of the Mid-Russian Upland. Evidence of differences in the parameters studied was found. The age dynamics of the degree of damage of the genetic apparatus was observed. Possible causes of the identified differences are discussed. PMID- 25720278 TI - [Morphological diversity in the postnatal skull development in representatives of two families of rodents (Spalacidae, Castoridae, Rodentia)]. AB - This is the first study to describe the results of measurement of three information parameters of morphological diversity (entropy, the measure of organization, and the Kullback-Leibler divergence) in the course of postnatal development of the skull in the populations of two rodent species (greater mole rat (Spalax microphthalmus Guld.) and Eurasian beaver (Castor fiber (L.)). The terms "morphosystem" and "morphological space" and its structure are introduced. Within the framework of the developed approach, "morphological diversity" is considered as a variable associated with the morphological space structure. Testing the hypothesis of the dominance of self-organization processes and an increase in the organization of the morphological diversity of the skull in the course ofontogeny showed its inconsistency. The morphosystem of the skull of the studied species undergoes transitions between more organized and less organized states, periodically approaching and departing from the "steady state." Such dynamics characterizes the morphosystem of the skull as a dynamic and nonlinear system. PMID- 25720279 TI - [Trait variability in ontogenesis of epiphytic lichen Hypogymnia physodes (L.) Nyl]. AB - Ontogenesis of the foliose lichen Hypogymniaphysodes has been described on the basis of the material obtained from natural populations. Ontogenetic dynamics (diameter of thallus and the number of lobes) and the features of reproductive structures (the number and diameter of labelloid and galeated sorales) were studied in ecologically different pine forests. We reasonably rejected the use of the variance analysis and nonparametric criteria for the result processing. It was shown that the median dynamics and trait variance may be either similar or different throughout the ontogenesis. The trait variances in ecologically different ecotopes were shown to be different. PMID- 25720280 TI - [Scale invariance of biosystems: from embryo to community]. AB - Abstract-Phenomena having the property of a scale invariance (that is, maintaining invariable structure in certain range of scales) are typical for biosystems of different levels. In this review, main manifestations of the scale invariant phenomena at different levels of biological organization (including ontogenetic aspects) are stated, and the reasons of such wide distribution of fractal structures in biology are discussed. Almost all biological systems can be described in terms of synergetics as open nonequilibrium systems that exist due to substance and energy flow passing through them. The phenomenon of self organization is typical for such dissipative systems; maintenance of energy flow requires the existence of complex structures that emerge spontaneously in the presence of the appropriate gradient. Critical systems, which form as a results of their activity scale-invariant structures (that are a kind of distribution channels), are optimal relative to the efficiency of substance and energy distribution. Thus, scale invariance of biological phenomena is a natural consequence of their dissipative nature. PMID- 25720281 TI - [Plasticity of neuroendocrine and immune systems in early development]. AB - This article provides an analysis of our own and published data on the reciprocal morphogenetic influence of the neiuroendocriie and imnimune systems on their formation and function in mammals. It is substantiated that, in early ontogeny, neurohormones regulate the growth and differentiation of various tissues in the body, including the lymphoid tissue. Thymicpeptides, in turn, affect the development of the hypothalamic-pitiitary-adrenal and gonadal-systems. Various adverse factors and changes in the physiological concentrations of hormones in the critical periods of development of these systems change their functions, and the plasticity of physiological systems in early ontogeny allows the body to adapt to new conditions. Disturbances in the interaction of the neuroendocrineand immune systems in the perinatal period induce apredisposition to various diseases in progeny. PMID- 25720282 TI - [Expression and activity of proteases in metastasis of ovarian cancer]. AB - The total chymotrypsin-like activity of proteasornes, the activity of 20S- and 26S-proteasome pools and calpains, and the expression of metalloproteinase PAPP-A in primary tumors and metastasized tissues were studied in 13 patients with epithelial ovarian cancer. It was shown that initiation of the process of tumor dissemination occurs against the background of active proteolytic processes; A decrease in activity of 26S-proteasomes and total calpain activity and increased expression ofmetalloproteinase PAPP-A in the primary tu mors were found in patients with ascites as compared with patients without ascites. The disease progression after treatment and achieved stabilization were found in patients with decreased activity of intracellular proteases and a high content of PAPP-A in the primary tumors. PMID- 25720283 TI - [Change in the concentration of intracellular ATP during adhesion of Rhodococcus ruber gt1 and pseudomonas fluorescens C2 cells on carbon supports]. AB - The effect of immobilization of nitrile-utilizing bacteria Rhodococcus ruber gt1 and Pseudomonasfluorescens C2 by adhesion on carbon supports on the content of the intracellular ATP immediately after adsorption and after 2 h and 24-48 h after transfer of the adhered cells into a fresh nutrient medium was studied. Adhesion was shown to lead to a decreased concentration ofATP in a cell by one order of magnitude or more in the first hours in a fresh nutrient medium that'can be attributed to energetic consumption upon the initiation of biofilm formation. A gradual rise in the quantity of ATP, which was calculated per 1 mg of adsorbed cells, was reported to take place in daily and two-daily biofilms, which confirms the cells remain viable. PMID- 25720284 TI - [Ophiostomatoid micromycetes as inidicators of the state of forest plantations in middle Siberia]. AB - The occurrence of ophiostomatoid fungi, associates of xylophagous insects, was established to be an indicator of the state of coniferous plantations under different anthropogenic influences and adverse ecological conditions at the coenotic level. The sizes of necroses developed on a tree inoculated with blue stain fungus isolates were recorded to be indicators of the state of the tree at the physiological level. PMID- 25720285 TI - [Sex structure and seed productivity of Mentha canadensis L. from natural flora of primorye of Russia]. AB - The sex structure and seed productivity of Mentha canadensis L. from different climatic regioins of Primorye of Russia was studied. We established that M. canadensis is characterized by a homogeneous population structure due to the formation of vegetative clones. The ratio of female and androgynous individuals was 1:5, and it is possible that this is a species-specific trait. Both sexual forms produced fruits under conditions of isolation from cross-pollination. We discuss the possibility of apomixis and the influence of climatic conditions on seed productivity and morphometric characteristics of plants. PMID- 25720286 TI - [The resistance of plants Setaria veridis (L.) Beauv. to the influence of cadmium]. AB - It was shown that cadmium causes a slowdown of green foxtail Setaria veridis (L.) Beauv. shoots; however it had no effect on root growth or accumulation of underground and above-ground biomass. In the analysis of the effect of cadmium on the water regime and photosynthesis of plants, it was found that it had a negative effect on the stomatal-apparatus, which led to a decrease in the transpiration rate and stomatal conductance. It was noted that the water content of tissues, as well as the rate of photosynthesis in the presence of cadmium, reinained at the level of those in'control planrits. A high resistance of green foxtail to the effects of cadmium was established, which is provided with different adaptive mechanisms and anatomical and physiologicdal characteristics associated with its affiliation to the group of C4-plants. PMID- 25720287 TI - [Pearl mussels of the genus Dahurinaia (Bivalvia, Margaritiferidae): differently sized groups of Margaritifera dahurica Middendorff, 1850]. AB - Molecularand genetic studies have revealed that all five species of pearl mussels of the Dahurinaia genus (Bivalvia, Margaritiferidae) inhabiting the upper basin of the Amur River on the territory of Transbaikalia belong to one species Margaritifera dahurica Middendorff, 1850. Based on the statistical analysis, it has been shown that morphometric shell ratios form continuous variation series without differentiation on discrete groups. It has been found that changes in these ratios are caused by the shell growth of pearl mussels and their morphological variations reflects the high level of polymorphism, Comparator species of the genus Dahurinaia are differently sized groups of one polymorphic biological species M. dahurica. PMID- 25720288 TI - [Morphological features of cellular responses to different rates of trematode: Quinqueserialis quinqueserialis (Trematoda: Notocotilidae) invasion in muskrat (Ondatra zibethicus)]. AB - The results of investigation of leukocyte morphology and leukocyte contents of blood and caecum depending on the trematode Quinqueserialis quinqueserialis invasion rate in muskrats from natural population are given. At low trematode invasion rates, there was observed systemic activation of lymphopoiesis and neutrophil granulocytopoiesis with a decrease in the monocyte-miacrophage response in caecum (trematodelocalization organ). At the same time, under high invasion rates, there was detected induction of T cell suppressor activity and the absence of a granulocyte response in the tissues under study. Intensification of B lymphocyte blast transformation in caecum tissues as well as the appearance of blast cells in the blood of infected muskrats was observed. PMID- 25720289 TI - [The Effects of Inhibitors of Rho- and tyrosine c-Src-kinases on serotonin induced constrictions of the aorta and mesenteric artery in rats]. AB - We found that the inhibitor of Rho-kinase fasudil selectively inhibited constriction of isolated rings of the aorta and mesenteric artery in rats in response to application of the agonists of 5HT2A-(DOI and TBC-2) and 5HT1A receptors (8-OH-DPAT) and did not influence vasoconstriction induced by serotonin. We demonstrate for the first time that application of the agonists of 5HT2C-receptors (MK 212 and SCH 23390) did not influence the tone of "intact" vessels. The marked vasoconstrictory effect of the agonists of 5HT2C-receptors was observed in the vessels preconstricted due to angiotensin II or vasopressin. We found that the inhibitor of Rho-kinase did not influence negatively on MK 212 or SCH 23390-induced constriction of isolated rings of the aorta and mesenteric artery in rats. We suppose.that, in the presence of fasudil, serotonin induces constriction of vessels through the interaction with 5HT2C-receptors and signal transduction from these receptors does not involve Rho-kinase activity. We found that fasudil attenuated vasoconstriction induced by norepinephrine and vasopressin by 40%. We.demonstrated that tyrosine c-Src-kinase plays the most important role in signal transduction from 5HT-receptors because its effects are specific with relation to these receptors. PMID- 25720290 TI - [Cytogenetic studies on submerged plants from the Yenisei river area in the zone of radioactive contamination]. AB - Cytogenetic studies on three species of submerged plants from different parts of the Yenisei river area subjected to radioactive impact of the Krasnoyarsk Mining and-Chemical Plant and the Electrochemical Factory have been conducted. A high level of irregularities in anatelophase and metaphase of mitoses has been revealed in test samples compared to the control: agglutination and fragmentation of chromosomes, lagging chromosomes, bridges, fragments, misdivisions, and others. The natuie of the disorders indicates that they are related in part to the direct damage to the chromosome structure and in part to damage to the spindle. PMID- 25720291 TI - [Variation trends in the parasite communities of the Chinese sleeper Perccottus glenii (Actinopterygii: Odontobutidae) in its native habitat]. AB - The diversity of parasite communities in the Chinese sleeper Perccottus glenii, at the level of single specimens and populations, is manifested through three components: the number of species, the evenness of their abundance, and the taxonomic diversity. Variations in the diversity depend on the local characteristics of water bodies, as well as the sexual and dimensional factors of the host. This study was performed in four water bodies of the Russian Far East (Primorskii krai and Sakhalin Island). PMID- 25720292 TI - [Breeding dynamic of corvids in urbanized landscapes of the European east]. AB - On the basis of counting and mapping of nests of the rook, hooded crow, and magpie in Kirov in 1975-2012, it was found that, under the conditions of an industrial city, rook colonies are highly unstable. The elimination of the private sector and neglected tree and scrub thickets leads to a reduction in the number of magpies nesting in the city. The nesting abundance of crows is limited by the quarter layout and placement of containers for household waste. PMID- 25720293 TI - [50 years of the Foundation of the Laboratory of Molecular Genetics of Somatic Cells]. PMID- 25720294 TI - A prospective study examining the incidence of asymptomatic and symptomatic lymphoceles following lymphadenectomy in patients with gynecological cancer. AB - OBJECTIVE: To identify the incidence of asymptomatic and symptomatic (i.e., causing pain, hydronephrosis, venous thrombosis, acute lymphedema of the lower or urinary urgency) lymphoceles, as well as risk factors for their development, through a prospective study of patients undergoing sole pelvic or combined pelvic and paraaortic lymphadenectomy for gynecological cancer. METHODS: Patients with endometrial, ovarian or cervical cancer scheduled for sole pelvic or combined pelvic and paraaortic lymphadenectomy as a primary surgical treatment or salvage surgery for recurrence were enrolled at single institution from February 2006 to November 2010 and prospectively followed up with ultrasound. RESULTS: Of 800 patients who underwent sole pelvic or combined pelvic and paraaortic lymphadenectomy for gynecological cancer, the overall incidence of lymphoceles was 20.2%, with symptomatic lymphoceles occurring in 5.8% of all patients. Lymphoceles are predominantly located on the left pelvic side wall. Lymphadenectomy in ovarian cancer, a higher number of lymph nodes obtained (>27), and radical hysterectomy in cervical cancer were found to be independent risk factors for the development of symptomatic lymphoceles. CONCLUSIONS: The overall incidence of lymphocele development after lymphadenectomy for gynecological cancer remains high. However, the majority of lymphoceles are only incidental finding without clinical impact. A symptomatic lymphocele is an uncommon event, occurring in only 5.8% of patients. Symptomatic lymphoceles tend to develop earlier than asymptomatic. Although such risk factors are hard to avoid, patients known to be at an increased risk of developing symptomatic lymphoceles can be counseled appropriately and followed up for specific symptoms relating to lymphocele development. PMID- 25720295 TI - The performance of mHealth in cancer supportive care: a research agenda. AB - BACKGROUND: Since the advent of smartphones, mHealth has risen to the attention of the health care system as something that could radically change the way health care has been viewed, managed, and delivered to date. This is particularly relevant for cancer, as one of the leading causes of death worldwide, and for cancer supportive care, since patients and caregivers have key roles in managing side effects. Given adequate knowledge, they are able to expect appropriate assessments and interventions. In this scenario, mHealth has great potential for linking patients, caregivers, and health care professionals; for enabling early detection and intervention; for lowering costs; and achieving better quality of life. Given its great potential, it is important to evaluate the performance of mHealth. This can be considered from several perspectives, of which organizational performance is particularly relevant, since mHealth may increase the productivity of health care providers and as a result even the productivity of health care systems. OBJECTIVE: This paper aims to review studies on the evaluation of the performance of mHealth, with particular focus on cancer care and cancer supportive care processes, concentrating on its contribution to organizational performance, as well as identifying some indications for a further research agenda. METHODS: We carried out a review of literature, aimed at identifying studies related to the performance of mHealth in general or focusing on cancer care and cancer supportive care. RESULTS: Our analysis revealed that studies are almost always based on a single dimension of performance. Any evaluations of the performance of mHealth are based on very different methods and measures, with a prevailing focus on issues linked to efficiency. This fails to consider the real contribution that mHealth can offer for improving the performance of health care providers, health care systems, and the quality of life in general. CONCLUSIONS: Further research should start by stating and explaining what is meant by the evaluation of mHealth's performance and then conduct more in-depth analysis in order to create shared frameworks to specifically identify the different dimensions of mHealth's performance. PMID- 25720296 TI - Major differences in the levels of redox status and antioxidant defence markers in the erythrocytes of pre- and full-term neonates with intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) is a pleiotropic complication of pregnancy. Prematurity and growth abnormalities are common risk factors for perinatal morbidity and mortality. Free radical damage has been recognized as a common pathogenic mechanism of many neonatal diseases. The aim of the present study was to characterize the possible links between the level of maturity, the birthweight and the antioxidant status of neonates born with IUGR. Our data suggest that the stress markers measured on the cord blood of neonates with IUGR and mature, healthy neonates do not necessarily reflect the extent of oxidative stress. However, significant correlations were found between the maturity of the neonates with IUGR and the oxidative damage. The mature IUGRs exhibited ONOO(-) accumulation and increased lipid peroxidation more frequently as compared with the pre-term group. The results suggest that the oxidative injury in IUGR may depend on the level of maturity and the birthweight. PMID- 25720297 TI - Mycotoxin zearalenone induces apoptosis in mouse Leydig cells via an endoplasmic reticulum stress-dependent signalling pathway. AB - Zearalenone (ZEN) is a Fusarium mycotoxin that causes several reproductive disorders and genotoxic effects. This study demonstrated the involvement of endoplasmic reticulum (ER) stress in ZEN-induced mouse Leydig cell death. Our study showed that ZEN reduced cell proliferation in a murine Leydig tumour cell line in a dose-dependent manner. The involvement of apoptosis as a major cause of ZEN-induced cell death was further confirmed by the results of a caspase-3 activity assay, which showed a ZEN dose-dependent increase in cell death. Treatment of MLTC-1 and primary mouse Leydig cells with ZEN upregulated the expression of the ER stress-typical markers GRP78, CHOP and caspase-12 protein. Further, pre-treating the cells with 4-phenylbutyrate or knocking down GRP78 using lentivirus-encoded shRNA significantly diminished ZEN-induced apoptosis and inhibited the expression of CHOP and caspase-12. In summary, these results suggest that the activation of an ER stress pathway plays a key role in ZEN induced apoptosis in the mouse Leydig cells. PMID- 25720298 TI - Retrieval of residual alginate impression material from a small oral-nasal communication defect in a maxillectomy patient. PMID- 25720299 TI - Characterization of Brown spider (Loxosceles intermedia) hemolymph: cellular and biochemical analyses. AB - This is the first study on the hemolymph from a spider of the Loxosceles genus. These animals are responsible for a great number of envenomation cases worldwide. Several studies on Loxosceles venoms have been published, and the knowledge about the venom and its toxins is considerable, not only regarding the biological and biochemical characterization, but also regarding structural, genetic and phylogenetic approaches. However, the literature on Loxosceles hemolymph is nonexistent. The main goal of the present study was to characterize biochemically the hemolymph content, and especially, to identify its different hemocytes. Moreover, many papers have already shown molecules whose source is the hemolymph and their very interesting activities and biomedical applications, for example, antifungal and antibacterial activities. A 2D-SDS-PAGE of brown spider hemolymph showed approximately 111 spots for pH 3-10 and 150 spots for pH 4-7. A lectin blotting assay showed that hemolymph carbohydrate residues were similar to those found in venom. Several types of TAG and DAG phospholipids were found in the hemolymph and characterized by HPTLC and mass spectrometry. Four different hemocytes were characterized in Loxosceles intermedia hemolymph: prohemocyte, plasmatocyte, granulocyte and adipohemocyte. This paper opens new possibilities on toxinology, studying an unknown biological material, and it characterizes a source of molecules with putative biotechnological applications. PMID- 25720300 TI - Effect of G-CSF on the osteoinductive property of a BCP/blood clot composite. AB - We previously reported that blood clot combined with biphasic calcium phosphate microparticles constitute a biomaterial (BRB) that can repair a bone critical defect in rat and induces subcutaneous bone formation in mice. The granulocyte colony-stimulating factor (G-CSF) is the agent most commonly used in human to enrich blood with hematopoietic stem and progenitor cells (HSPCs) as well as granulocytes (GCs). Moreover, recent data also suggest that it can mobilize mesenchymal stem cells (MSCs). Here, we asked whether the osteoinductive properties of the BRB could be further enhanced by G-CSF, either by replacing normal blood by G-CSF-mobilized blood (BRBe) or by treating the recipient animals with G-CSF. The experiments performed in C57BL/6 mice showed that G-CSF induces a marked increase of circulating HPCs and GCs, but not of MSCs. BRBe prepared with G-CSF-enriched blood induced a slight but significant decrease of subcutaneous bone formation compared to BRB prepared with normal blood. Additional injection of G-CSF to the recipient mice had no significant effect on the bone formation induced by BRB or BRBe. Altogether these results indicate that, in this model of ectopic implantation, cell mobilization induced by G-CSF has a negative effect on the osteoinductive property of this blood/BCP composite. PMID- 25720301 TI - [Prevalence of hearing impairment in northwestern Germany. Results of an epidemiological study on hearing status (HORSTAT)]. AB - BACKGROUND: A pure-tone average of 0.5, 1, 2, and 4 kHz in the better ear (PTA-4) is the international standard criterion set by the World Health Organization (WHO) to describe hearing loss. Presently, there are no epidemiological data on hearing loss in Germany based on this criterion. METHODS: A representative sample of adults from Oldenburg and Emden were invited for a hearing assessment. This article analyzes the association between hearing loss and age, sex, noise, occupation, and educational level. Age- and sex-specific prevalence rates following the WHO classification are compared with international findings. RESULTS: According to the WHO classification, the prevalence of hearing impairment in the study cohort (n=1,866) is approx. 16%. In men, who more commonly work in noisy jobs, a higher prevalence rate is observed than in women of the same age. Nevertheless, sex differences in the present study are smaller than those reported in most international studies. PTA-4 is approximately the same for men and women when effects of occupational noise are controlled, but differences in prevalence between occupational areas are still significant. CONCLUSION: Compared with international findings, age-specific prevalence rates in HORSTAT are low. In the synopsis of epidemiological studies of the past 25 years, a trend toward decreasing prevalence in middle and higher age groups can be observed. PMID- 25720302 TI - [Treatment of nasal valve stenosis]. AB - Nasal valve dysfunction is one of the most common causes of obstructed nasal ventilation. In most cases the cause is congenital, but iatrogenic occurrence after functional-aesthetic rhinoplasty is not infrequent. To diagnose nasal valve dysfunction, a thorough anamnesis, inspection, endoscopy, and palpation is required. If conservative therapy using rhinologic substances, as well as outer and inner stenting do not achieve the desired outcome, and the dysfunctional site can be localized, surgical procedures are indicated to improve nasal valve function. Numerous procedures and techniques are available, amongst which the most important ones shall be elucidated and discussed in the present article. These include septoplasty, septorhinoplasty, and enlargement of pyriform aperture stenosis, as well as corrections of the upper and lower lateral cartilages. PMID- 25720303 TI - Ultrasound-guided rectus sheath block for single-incision laparoscopic cholecystectomy. AB - INTRODUCTION: Single-incision laparoscopic cholecystectomy (SILC) is increasingly applied for cholecystectomy and has been reported as safe and feasible, with short-term operative outcomes equivalent to four-port cholecystectomy. Although many investigators in randomized studies have noted the cosmetic advantages of SILC, the benefit of decreased pain in SILC remains controversial. Therefore, this study aimed to assess the efficacy of the rectus sheath block in SILC with respect to subjective pain. METHODS: From April 2010 to March 2012, 75 patients with symptomatic gallstone or gallbladder polyps were assigned to one of three groups: (i) four-port laparoscopic cholecystectomy (n = 29); (ii) SILC (n = 15); and (iii) rectus sheath block in SILC (n = 30). We evaluated the operative details, length of hospital stay, and the need and usage of analgesia. Postoperative pain was recorded at 2, 6, 12, and 24 h after surgery based on a visual analog scale. RESULTS: There was no difference with regard to age, ASA score, BMI, duration of operation, or length of hospital stay among the three groups. A significantly lower pain score was observed in the rectus sheath block in SILC group than in the SILC group at 2 and 6 h after operation. The pain score and need for analgesia were similar between the SILC group and the four-port cholecystectomy group. CONCLUSION: SILC using an ultrasound-guided rectus sheath block significantly reduces postoperative pain. PMID- 25720305 TI - Differences between individual ZSM-5 crystals in forming hollow single crystals and mesopores during base leaching. AB - After base treatment of ZSM-5 crystals below 100 nm in size, TEM shows hollow single crystals with a 10 nm shell. SEM images confirm that the shell is well- preserved even after prolonged treatment. Determination of the Si/Al ratios with AAS and XPS in combination with argon sputtering reveals aluminum zoning of the parent zeolite, and the total pore volume increases in the first two hours of base treatment. In corresponding TEM images, the amount of hollow crystals are observed to increase during the first two hours of base treatment, and intact crystals are visible even after 10 h of leaching; these observations indicate different dissolution rates between individual crystals. TEM of large, commercially available ZSM-5 crystals shows inhomogeneous distribution of mesopores among different crystals, which points to the existence of structural differences between individual crystals. Only tetrahedrally coordinated aluminum is detected with (27) Al MAS NMR after the base leaching of nano-sized ZSM-5. PMID- 25720304 TI - Antecedent Disease is Less Prevalent in Amyotrophic Lateral Sclerosis. AB - BACKGROUND/AIMS: Recent studies suggest that antecedent disease could impact the pathophysiology of the motoneuron disease Amyotrophic Lateral Sclerosis (ALS). We performed a case-control study to examine the prevalence of 11 antecedent diseases in ALS. METHODS: Prevalence of antecedent disease in a 1,288 patient ALS population (Emory University ALS Clinic, Atlanta, Ga., USA) is compared to an age, gender, and geography-matched 7,561 subject control population using a statistical odds ratio (OR) with 95% confidence interval. RESULTS: Association of ALS with odds of arthritis (OR = 0.14); non-ALS neurological disease (OR = 0.14); liver disease (OR = 0.19); chronic obstructive pulmonary disorder or COPD (OR = 0.23); kidney disease (OR = 0.32); adult asthma (OR = 0.39); diabetes (OR = 0.47); hypertension (OR = 0.56); obesity (OR = 0.6); hyperlipidemia or hypercholesterolemia (OR = 0.62); and thyroid disease (OR = 0.78). CONCLUSIONS: The prevalence of antecedent disease was overall less in the ALS population. We present two potential lines of inquiry to explain these results: (1) 'Other disease as ALS protection'--antecedent diseases infer biochemical neuroprotection to ALS; (2) 'ALS as other disease protection'--the underpinnings of ALS could infer protection to other diseases, possibly via the mechanism hypervigilant regulation or 'too-high' regulatory feedback gains. PMID- 25720307 TI - SplicingTypesAnno: annotating and quantifying alternative splicing events for RNA Seq data. AB - Alternative splicing plays a key role in the regulation of the central dogma. Four major types of alternative splicing have been classified as intron retention, exon skipping, alternative 5 splice sites or alternative donor sites, and alternative 3 splice sites or alternative acceptor sites. A few algorithms have been developed to detect splice junctions from RNA-Seq reads. However, there are few tools targeting at the major alternative splicing types at the exon/intron level. This type of analysis may reveal subtle, yet important events of alternative splicing, and thus help gain deeper understanding of the mechanism of alternative splicing. This paper describes a user-friendly R package, extracting, annotating and analyzing alternative splicing types for sequence alignment files from RNA-Seq. SplicingTypesAnno can: (1) provide annotation for major alternative splicing at exon/intron level. By comparing the annotation from GTF/GFF file, it identifies the novel alternative splicing sites; (2) offer a convenient two-level analysis: genome-scale annotation for users with high performance computing environment, and gene-scale annotation for users with personal computers; (3) generate a user-friendly web report and additional BED files for IGV visualization. SplicingTypesAnno is a user-friendly R package for extracting, annotating and analyzing alternative splicing types at exon/intron level for sequence alignment files from RNA-Seq. It is publically available at https://sourceforge.net/projects/splicingtypes/files/ or http://genome.sdau.edu.cn/research/software/SplicingTypesAnno.html. PMID- 25720308 TI - Fine tuning of copper(II)-chlorophyll interactions in organic media. Metalation versus oxidation of the macrocycle. AB - The nature of chlorophyll interactions with copper(II) ions varies considerably in organic solvents, depending on the dominant coordinative form. Besides formation of the metallo tetrapyrrolic complex, Cu(II) ions can cause oxidation of the pigment, reversible or irreversible, which can lead to the destruction of the macrocyclic structure. All these reaction types can be distinguished within a quite narrow range of reaction conditions. The ability to form new metallo derivatives in either metalation or transmetalation reactions is obviously limited by the concentration of the potential oxidant, but can be secured below this level via suitable composition of the reaction system. The decisive factor in the selection of a specific reaction pathway is the presence of a potential ligand that can affect the reactivity of Cu(II) for example by shifting its redox potential. Spectroscopic and electrochemical studies were performed in order to determine the predominant species of Cu(II) in methanol, nitromethane and acetonitrile in the presence of chloride and acetate ions, as well as to assign their appropriate oxidizing ability. This allowed us to estimate the boundary conditions for the electron transfer processes in chlorophyll-Cu(II) systems. Chlorophyll and its free base can undergo both types of electron transfer processes, however, they reveal different susceptibilities that make this class of ligands quite versatile markers in tuning the reactivity of metal ions in solutions. PMID- 25720306 TI - Prevalence of Patent Foramen Ovale in Ischaemic Stroke in Italy: Results of SISIFO Study. AB - BACKGROUND: Although several authors have studied the association between patent foramen ovale (PFO) and ischaemic stroke, the matter is still controversial; few have suggested an association between cryptogenetic stroke and PFO, while others have denied this association. The aim of this study was to evaluate PFO prevalence in the whole ischaemic stroke population, independently from age and stroke subtypes and to identify the characteristics associated with the presence of PFO. METHODS: SISIFO study was a multicenter, prospective, single-wave, cross sectional survey conducted on consecutive patients with acute ischemic stroke admitted to selected clinical centres. Data regarding vascular risk factors were registered for each patient; all patients underwent computed tomography scan and/or magnetic resonance imaging of the brain; an electrocardiogram and standard laboratory blood tests were performed. A Doppler ultrasound study of extra cranial arteries was performed too. The cases were classified according to TOAST and OCSP criteria. Each patient underwent transcranial Doppler or transcranial color-coded duplex sonography with bubble test as diagnostic tool for right-to left-shunt. Where right-to-left shunt was detected, PFO presence was confirmed by echocardiography. FINDINGS: 1,130 consecutive patients were included. We found a PFO in 247 (21.9%; 95% CI, 19.5-24.3%) patients; PFO was present in 23.5% of patients with cryptogenic stroke and in 21.3% of patients with stroke of known causes; this difference was not statistically significant. At the univariate analysis, decreasing age, hypertension, diabetes mellitus, and atrial fibrillation, and stroke characteristics such as NIHSS, OCSP and TOAST were predictors of PFO presence. At the multivariate analysis, we found a significant interaction between age and OCSP syndrome. Being LACI the reference category, the prevalence of PFO in PACI and POCI decreased significantly along with age, whereas there was no change in TACI. CONCLUSION: If any relationship exists between stroke and PFO, this is more likely in PACI and POCI at a younger age. Our results are consistent with recent findings that underline PFO alone must not be considered a significant independent predictor for stroke; so the presence of PFO alone doesn't permit rushed causal correlations or 'therapeutic aggressiveness'. PMID- 25720309 TI - Expression of hippocampal serotonin receptors 5-HT2C and 5-HT5A in a rat model of diet-induced obesity supplemented with tryptophan. AB - Food intake regulation is a complex mechanism that involves endogenous substances and central nervous system structures like hypothalamus or even hippocampus. The neurotransmitter serotonin is distinguished as food intake mediator; within its multiples receptors, the 5-HT2C type is characterized by its inhibitory appetite action but there is no information about 5-HT5A receptors involvement in obesity disease. It is also unknown if there are any changes in the receptors expression in rats hippocampus with induced obesity during development through a high energy diet (HED) supplemented with tryptophan (W). To appreciate the receptors expression pattern in the hippocampus, obesity was induced to young Sprague Dawley rats through a HED and supplemented with W. Immunocytochemical and western blot techniques were used to study the receptor distribution and quantify the protein expression. The rats with HED diet developed obesity until week 13 of treatment. The 5-HT2C receptor expression decreased in CA1, CA2, CA3 and DG of HED group; and also in CA2, CA3 and DG for HEDW group. The 5-HT5A receptor expression only decreased in DG for HED group. Variations of the two serotonin receptors subtypes support their potential role in obesity. PMID- 25720310 TI - Prenatal exposure to a novel antipsychotic quetiapine: impact on neuro architecture, apoptotic neurodegeneration in fetal hippocampus and cognitive impairment in young rats. AB - Reports on prenatal exposure to some of the first generation antipsychotic drugs like, haloperidol, their effects on fetal neurotoxicity and functional impairments in the offspring, are well documented. But studies on in utero exposure to second generation antipsychotics, especially quetiapine, and its effects on fetal neurotoxicity, apoptotic neurodegeneration, postnatal developmental delay and neurobehavioral consequences are lacking. Therefore, the present study was undertaken to evaluate the effect of prenatal administration to equivalent therapeutic doses of quetiapine on neuro-architectural abnormalities, neurohistopathological changes, apoptotic neurodegeneration in fetal hippocampus, and postnatal development and growth as well as its long-lasting imprint on cognitive impairment in young-adult offspring. Pregnant Wistar rats (n=24) were exposed to selected doses (55 mg, 80 mg and 100mg/kg) of quetiapine, equivalent to human therapeutic doses, from gestation day 6 to 21 orally with control subjects. Half of the pregnant subjects of each group were sacrificed at gestation day 21 for histopathological, confocal and electron microscopic studies and rest of the dams were allowed to deliver naturally. Their pups were reared postnatally up to 10 weeks of age for neurobehavioral observations. In quetiapine treated groups, there was significant alterations in total and differential thickness of three typical layers of hippocampus associated with neuronal cells deficit and enhanced apoptotic neurodegeneration in the CA1 area of fetal hippocampus. Prenatally drug treated rat offspring displayed post-natal developmental delay till postnatal day 70, and these young-adult rats displayed cognitive impairment in Morris water maze and passive avoidance regimes as long lasting impact of the drug. Therefore, quetiapine should be used with cautions considering its developmental neurotoxicological and neurobehavioral potential in animal model, rat. PMID- 25720311 TI - Minimizing the use of coercive practices in mental health: the perfect storm. PMID- 25720312 TI - The Eileen Skellern Lecture 2014: physical restraint: in defence of the indefensible? AB - Aggression is reported to be prevalent in psychiatric inpatient care and its frequency towards healthcare professionals is well documented. While aggression may not be entirely avoidable, its incidence can be reduced through prevention and the minimization of restrictive practices such as physical restraint. The study aims to explore three common 'defences' to account for the use of physical restraint; to challenge each defence with regard to the evidence base; and to identify how services are responding to the challenge of reducing the use of restrictive interventions. Following a number of investigations to highlight serious problems with the use of physical restraint, it seems timely to examine its efficacy in light of the evidence base. In order to do this, three key defences for its use will be challenged using the literature. A combination of interventions to minimize the use of restraint including advance planning tools, and recognition of potential trauma is necessary at an organizational and individual level. Patients can be severely traumatized by the use of restrictive practices and there is a drive to examine, and reduce the use and impact of using these models that incorporate trauma informed care (TIC) and person centredness. PMID- 25720313 TI - Cash, choice, antipsychotic medication and the mental health nurse. PMID- 25720314 TI - Facile thermodynamic conversion of a linear metallopolymer into a self-assembled hexameric metallomacrocycle. AB - The initial metallopolymer, derived from two different organic building blocks, is a kinetic intermediate to the final stable hexanuclear (bearing 4Ru(2+) and 2Fe(2+)) metallomacrocycle obtained through a thermodynamic dis-assembly/re assembly route. The heteroleptic metallomacrocyclic architecture was characterized by NMR, UV, IR, CV, 2D-ROESY, DOSY, and ESI-MS. PMID- 25720315 TI - Diagnosing Fish Bone and Chicken Bone Impactions in the Emergency Department Setting: Measuring the System Utility of the Plain Film Screen. AB - OBJECTIVES: In the emergency department, fish and chicken bone impactions are typically evaluated with screening x-rays. We sought to determine whether this modality ultimately improves system outcomes, including length of stay (LOS), cost, and radiation dosage. METHODS: We reviewed patients >= 18 years old presenting to an urban academic emergency department over a 4-year period who received a screening soft-tissue x-ray to determine the presence of a retained fish or chicken bone. We calculated the diagnostic accuracy of x-ray and computed tomography (CT) evaluations, respectively, in addition to system outcomes. RESULTS: Twenty-seven of the 78 patients included for analysis were ultimately positive for bone impaction. Initial x-ray interpretations demonstrated a sensitivity of 24.0% (95% CI, 9.4%-45.1%) and a specificity of 90.0% (95% CI, 78.2%-96.7%). However, initial CT interpretation (ie, a preliminary read from on call residents) demonstrated a sensitivity of 75% (95% CI, 19.4%-99.4%) and a specificity of 100% (95% CI, 59.0%-100%). LOS, cost, and radiation dosage were not significantly different between patients who ultimately had true bone impactions and those who did not (P > .05). CONCLUSIONS: X-rays are poor screening tools in determining fish or chicken bone impactions with poor diagnostic and system utility. Further studies should be performed to evaluate the role of a low-radiation CT screen. PMID- 25720316 TI - Contact allergy to capryloyl salicylic acid: a mechanistic chemistry and structure-activity perspective. PMID- 25720317 TI - Chromosomal mapping of repetitive DNAs in Gobionellus oceanicus and G. stomatus (Gobiidae; Perciformes): A shared XX/XY system and an unusual distribution of 5S rDNA sites on the Y chromosome. AB - With nearly 2,000 species, Gobiidae is the most specious family of the vertebrates. This high level of speciation is accompanied by conspicuous karyotypic modifications, where the role of repetitive sequences remains largely unknown. This study analyzed the karyotype of 2 species of the genus Gobionellus and mapped 18S and 5S ribosomal RNA genes and (CA)15 microsatellite sequences onto their chromosomes. G. oceanicus (2n = 56; ? 12 metacentrics (m) + 4 submetacentrics (sm) + 1 subtelocentric (st) + 39 acrocentrics (a); ? 12m + 4sm + 2st + 38a) and G. stomatus (2n = 56; ? 20m + 14sm + 1st + 21a; ? 20m + 14sm + 2st + 20a) possess the highest diploid chromosome number among the Gobiidae and have different karyotypes. Both species share an XX/XY sex chromosome system with a large subtelocentric X and a small acrocentric Y chromosome which is rich in (CA)15 sequences and bears 5S rRNA sites. Although coding and noncoding repetitive DNA sequences may be involved in the genesis or differentiation of the sex chromosomes, the exclusive presence of 5S rDNA sites on the Y, but not on the X chromosome of both species, represents a novelty in fishes. In summary, the karyotypic differences, as well as new data on the sex chromosome systems in these 2 Gobiidae species, confirm the high chromosomal dynamism observed in this family. PMID- 25720318 TI - Computer-aided human factors analysis of the industrial vehicle driver cabin to improve occupational health. AB - Industrial vehicle operator's solace and safety have gained significant consideration because of the increment in occupational health issues and accidents. The purpose of this work was to amend the design of the excavator driver cabin through human factor analysis. Thirty operators of excavators who were serving as subjects, were interviewed and identified that their wrist, upper arm and trunk were at a higher risk level while operating. Photograph of the operators was taken and the work environment was simulated. RULA (Rapid Upper Limb Assessment) and REBA (Rapid Entire Body Assessment) scoring was made on different simulated work posture of operators using CATIA V5 and UEAT1.8 softwares. Based on overall RULA and REBA scoring, it was found nearly 46% of the operators were operating at a high hazard level and needed investigation immediately, whereas 35% of operators were at a medium risk level and only 19% of operators were operating safely. The individual RULA and REBA scoring proved prevalence of discomfort in wrist, upper arm and trunk while operating. Identifying the optimized conditions to hold the control levers will help to reduce the operator strain. From the design optimization in excavators, the optimal conditions to hold the control lever is found to be 40cm for popliteal height, 60.51 cm for distance from elbow to ground and 15.07o for reach angle from the seat reference point. PMID- 25720319 TI - Hydrogels assembled from star-shaped polypeptides with a dendrimer as the core. AB - A second or fourth generation dendrimer with primary amine as the peripheral terminal group was first synthesized via Michael addition and thiol-yne addition. A series of star-shaped polypeptides was synthesized by ring opening polymerization (ROP) of gamma-(2-(2-methoxyethoxy)ethyl) l-glutamate (l-EG2Glu) N carboxyanhydride (NCA) using the amine group terminated dendrimer as the initiator. Taking advantage of the well-defined dendrimer and ROP, the arm number and arm length can be easily controlled. These star-shaped poly(l-EG2Glu) can spontaneously form hydrogels instead of micelles in water at low concentration. The critical gelation concentration (CGC) and hydrogel strength displayed a stronger dependence on arm numbers than the arm length under similar conditions. These properties can be easily modulated by varying the poly(l-EG2Glu) arm length and arm number. The hydrogels showed shear thinning and rapid recovery properties. TEM and AFM characterization revealed that the hydrogel networks were constituted by entangled and branched fibrils. PMID- 25720321 TI - A three-tier classification system based on the depth of submucosal invasion and budding/sprouting can improve the treatment strategy for T1 colorectal cancer: a retrospective multicenter study. AB - More than 85% of patients with T1 colorectal cancer have no lymph node metastasis and can be cured by endoscopic resection. To avoid unnecessary surgery after complete endoscopic resection, accurate histologic methods for evaluating resected specimens are needed to discriminate those at high risk for lymph node metastasis. A retrospective multi-institutional, cross-sectional study of 806 T1 colorectal cancer patients was conducted. A budding/sprouting score was incorporated for predicting lymph node metastasis in addition to other parameters, including the depth of submucosal invasion, histologic grade, and lymphovascular invasion. Lymph node metastasis was detected in 97 patients. Independent predictors of lymph node metastasis by multivariate analysis were depth of submucosal invasion >=1000 MUm (odds ratio (95% confidence interval)=5.56 (2.14-19.10)) and high-grade budding/sprouting (3.14 (1.91-5.21)). Among lesions with a depth of submucosal invasion >=1000 MUm, lymph node metastasis was detected in 59 (29%) of 207 patients with high-grade budding/sprouting, and in 34 (9%) of 396 with low-grade budding/sprouting. Lymph node metastasis was detected in only 4 (2%) of 203 lesions with a depth of submucosal invasion <1000 MUm. Of these four tumors, three invaded lymphatic and/or venous vessels. Thus, the risk for lymph node metastasis can be classified into three groups: high risk with a depth of submucosal invasion >=1000 MUm and high-grade budding/sprouting, intermediate-risk with a depth of submucosal invasion >=1000 MUm and low-grade budding/sprouting, and low-risk with a depth of submucosal invasion <1000 MUm. These findings revealed that a depth of submucosal invasion >=1000 MUm and high-grade budding/sprouting are powerful predictive parameters for lymph node metastasis in T1 colorectal cancer. This three-tier risk classification system will facilitate the decision for additional major surgery for T1 colorectal cancer patients after successful endoscopic treatment. PMID- 25720320 TI - SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). AB - Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB kappa=0.7338; SDHA kappa=0.6707) or a three-tiered classification approach (SDHB kappa=0.6543; SDHA kappa=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2 mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable. PMID- 25720322 TI - Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. AB - This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence free, and overall survival were calculated using the Kaplan-Meier method and log rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53 mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment. PMID- 25720323 TI - MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors. AB - MicroRNA deregulation could be a crucial event in thyroid carcinogenesis. However, current knowledge is based on studies that have used inherently biased methods. Thus, we aimed to define in an unbiased way a list of deregulated microRNAs in well-differentiated thyroid cancer in order to identify diagnostic and prognostic markers. We performed a microRNA deep-sequencing study using the largest well-differentiated thyroid tumor collection reported to date, comprising 127 molecularly characterized tumors with follicular or papillary patterns of growth and available clinical follow-up data, and 17 normal tissue samples. Furthermore, we integrated microRNA and gene expression data for the same tumors to propose targets for the novel molecules identified. Two main microRNA expression profiles were identified: one common for follicular-pattern tumors, and a second for papillary tumors. Follicular tumors showed a notable overexpression of several members of miR-515 family, and downregulation of the novel microRNA miR-1247. Among papillary tumors, top upregulated microRNAs were miR-146b and the miR-221~222 cluster, while miR-1179 was downregulated. BRAF positive samples displayed extreme downregulation of miR-7 and -204. The identification of the predicted targets for the novel molecules gave insights into the proliferative potential of the transformed follicular cell. Finally, by integrating clinical follow-up information with microRNA expression, we propose a prediction model for disease relapse based on expression of two miRNAs (miR-192 and let-7a) and several other clinicopathological features. This comprehensive study complements the existing knowledge about deregulated microRNAs in the development of well-differentiated thyroid cancer and identifies novel markers associated with recurrence-free survival. PMID- 25720325 TI - Supplemental factors including those associated with anesthesiology for respiratory insufficiency after thymectomy in generalized myasthenia gravis. PMID- 25720324 TI - Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. AB - The abundance of tumor-infiltrating lymphocytes has been associated with a favorable prognosis in estrogen receptor-negative breast cancer. However, a high degree of spatial heterogeneity in lymphocytic infiltration is often observed and its clinical implication remains unclear. Here we combine automated histological image processing with methods of spatial statistics used in ecological data analysis to quantify spatial heterogeneity in the distribution patterns of tumor infiltrating lymphocytes. Hematoxylin and eosin-stained sections from two cohorts of estrogen receptor-negative breast cancer patients (discovery: n=120; validation: n=125) were processed with our automated cell classification algorithm to identify the location of lymphocytes and cancer cells. Subsequently, hotspot analysis (Getis-Ord Gi*) was applied to identify statistically significant hotspots of cancer and immune cells, defined as tumor regions with a significantly high number of cancer cells or immune cells, respectively. We found that the amount of co-localized cancer and immune hotspots weighted by tumor area, rather than number of cancer or immune hotspots, correlates with a better prognosis in estrogen receptor-negative breast cancer in univariate and multivariate analysis. Moreover, co-localization of cancer and immune hotspots further stratified patients with immune cell-rich tumors. Our study demonstrates the importance of quantifying not only the abundance of lymphocytes but also their spatial variation in the tumor specimen for which methods from other disciplines such as spatial statistics can be successfully applied. PMID- 25720326 TI - Application of viability PCR to discriminate the infectivity of hepatitis A virus in food samples. AB - Transmitted through the fecal-oral route, the hepatitis A virus (HAV) is acquired primarily through close personal contact and foodborne transmission. HAV detection in food is mainly carried out by quantitative RT-PCR (RT-qPCR). The discrimination of infectious and inactivated viruses remains a key obstacle when using RT-qPCR to quantify enteric viruses in food samples. Initially, viability dyes, propidium monoazide (PMA) and ethidium monoazide (EMA), were evaluated for the detection and quantification of infectious HAV in lettuce wash water. Results showed that PMA combined with 0.5% Triton X-100 (Triton) was the best pretreatment to assess HAV infectivity and completely eliminated the signal of thermally inactivated HAV in lettuce wash water. This procedure was further evaluated in artificially inoculated foods (at concentrations of ca. 6*10(4), 6*10(3) and 6*10(2)TCID50) including lettuce, parsley, spinach, cockles and coquina clams. The PMA-0.5% Triton pretreatment reduced the signal of thermally inactivated HAV between 0.5 and 2 logs, in lettuce and spinach concentrates. Moreover, this pretreatment reduced the signal of inactivated HAV by more than 1.5 logs, in parsley and ten-fold diluted shellfish samples inoculated at the lowest concentration. Overall, this pretreatment (50 MUM PMA-0.5% Triton) significantly reduced the detection of thermally inactivated HAV, depending on the initial virus concentration and the food matrix. PMID- 25720327 TI - Severe maternal morbidity and breastfeeding outcomes in the early post-natal period: a prospective cohort study from one English maternity unit. AB - Previous research has identified potential issues of establishing and maintaining breastfeeding among women who experience severe maternal morbidity associated with pregnancy and birth, but evidence in the UK maternity population was scarce. We explored the association between severe maternal morbidity and breastfeeding outcomes (uptake and prevalence of partial and exclusive breastfeeding) at 6 to 8 weeks post-partum in a UK sample. Data on breastfeeding outcomes were obtained from a large cohort study of women who gave birth in one maternity unit in England to assess the impact of women's experiences of severe maternal morbidity (defined as major obstetric haemorrhage, severe hypertensive disorder or high dependency unit/intensive care unit admission) on their post-natal health and other important outcomes including infant feeding. Results indicated that among women who responded (n = 1824, response rate = 53%), there were no statistically significant differences in breastfeeding outcomes between women who did or did not experience severe morbidity, except for women with severe hypertensive disorder who were less likely to breastfeed either partially or exclusively at 6 to 8 weeks post-partum. Rather, breastfeeding outcomes were related to multi dimensional factors including sociodemographic (age, ethnicity, living arrangement), other pregnancy outcomes (neonatal intensive care unit admission, mode of birth, women's perceived control during birth) and post-natal psychological factors (depressive symptoms). Women who experience severe maternal morbidity can be reassured that establishing successful breastfeeding can be achieved. More studies are required to understand what support is best for women who have complex health/social needs to establish breastfeeding. PMID- 25720328 TI - Family-based programmes for preventing smoking by children and adolescents. AB - BACKGROUND: There is evidence that family and friends influence children's decisions to smoke. OBJECTIVES: To assess the effectiveness of interventions to help families stop children starting smoking. SEARCH METHODS: We searched 14 electronic bibliographic databases, including the Cochrane Tobacco Addiction Group specialized register, MEDLINE, EMBASE, PsycINFO, CINAHL unpublished material, and key articles' reference lists. We performed free-text internet searches and targeted searches of appropriate websites, and hand-searched key journals not available electronically. We consulted authors and experts in the field. The most recent search was 3 April 2014. There were no date or language limitations. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions with children (aged 5-12) or adolescents (aged 13-18) and families to deter tobacco use. The primary outcome was the effect of the intervention on the smoking status of children who reported no use of tobacco at baseline. Included trials had to report outcomes measured at least six months from the start of the intervention. DATA COLLECTION AND ANALYSIS: We reviewed all potentially relevant citations and retrieved the full text to determine whether the study was an RCT and matched our inclusion criteria. Two authors independently extracted study data for each RCT and assessed them for risk of bias. We pooled risk ratios using a Mantel-Haenszel fixed effect model. MAIN RESULTS: Twenty-seven RCTs were included. The interventions were very heterogeneous in the components of the family intervention, the other risk behaviours targeted alongside tobacco, the age of children at baseline and the length of follow-up. Two interventions were tested by two RCTs, one was tested by three RCTs and the remaining 20 distinct interventions were tested only by one RCT. Twenty-three interventions were tested in the USA, two in Europe, one in Australia and one in India.The control conditions fell into two main groups: no intervention or usual care; or school-based interventions provided to all participants. These two groups of studies were considered separately.Most studies had a judgement of 'unclear' for at least one risk of bias criteria, so the quality of evidence was downgraded to moderate. Although there was heterogeneity between studies there was little evidence of statistical heterogeneity in the results. We were unable to extract data from all studies in a format that allowed inclusion in a meta-analysis.There was moderate quality evidence family-based interventions had a positive impact on preventing smoking when compared to a no intervention control. Nine studies (4810 participants) reporting smoking uptake amongst baseline non-smokers could be pooled, but eight studies with about 5000 participants could not be pooled because of insufficient data. The pooled estimate detected a significant reduction in smoking behaviour in the intervention arms (risk ratio [RR] 0.76, 95% confidence interval [CI] 0.68 to 0.84). Most of these studies used intensive interventions. Estimates for the medium and low intensity subgroups were similar but confidence intervals were wide. Two studies in which some of the 4487 participants already had smoking experience at baseline did not detect evidence of effect (RR 1.04, 95% CI 0.93 to 1.17).Eight RCTs compared a combined family plus school intervention to a school intervention only. Of the three studies with data, two RCTS with outcomes for 2301 baseline never smokers detected evidence of an effect (RR 0.85, 95% CI 0.75 to 0.96) and one study with data for 1096 participants not restricted to never users at baseline also detected a benefit (RR 0.60, 95% CI 0.38 to 0.94). The other five studies with about 18,500 participants did not report data in a format allowing meta-analysis. One RCT also compared a family intervention to a school 'good behaviour' intervention and did not detect a difference between the two types of programme (RR 1.05, 95% CI 0.80 to 1.38, n = 388).No studies identified any adverse effects of intervention. AUTHORS' CONCLUSIONS: There is moderate quality evidence to suggest that family-based interventions can have a positive effect on preventing children and adolescents from starting to smoke. There were more studies of high intensity programmes compared to a control group receiving no intervention, than there were for other compairsons. The evidence is therefore strongest for high intensity programmes used independently of school interventions. Programmes typically addressed family functioning, and were introduced when children were between 11 and 14 years old. Based on this moderate quality evidence a family intervention might reduce uptake or experimentation with smoking by between 16 and 32%. However, these findings should be interpreted cautiously because effect estimates could not include data from all studies. Our interpretation is that the common feature of the effective high intensity interventions was encouraging authoritative parenting (which is usually defined as showing strong interest in and care for the adolescent, often with rule setting). This is different from authoritarian parenting (do as I say) or neglectful or unsupervised parenting. PMID- 25720329 TI - Norepinephrine and corticosterone in the medial prefrontal cortex and hippocampus predict PTSD-like symptoms in mice. AB - This study measured changes in brain extracellular norepinephrine (NE) and free corticosterone (CORT) levels in a mouse model of post-traumatic stress disorder and related them to hyperarousal and fear memory retention. To this end, microdialysis in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of male C57BL/6NCrl mice was performed during an acoustic startle response (ASR) and following an electric foot shock (FS), as well as during an ASR and recall of contextual fear (CF) 1 day later. Changes in ASR-stimulated NE levels in the mPFC corresponded to ASR 34 days after FS. Changes in basal and ASR-stimulated extracellular NE levels in the HPC, in contrast, were related to expression of early (day 2) and late (day 34) CF after FS. The increase in extracellular NE levels correlated in a U-shape manner with arousal levels and CF, thus suggesting a non-direct relationship. Stress of different modalities/strength (ASR, FS and CF) caused a similar relative increase in free CORT levels both in the mPFC and the HPC. One day after FS, ASR-induced increases in the CORT content in the mPFC tended to correlate with the FS-potentiated ASR in a U-shape manner. Taken together, these data show that the intracerebral increase in free CORT was likely related to an immediate response to stress, whereas NE neurotransmission in the forebrain predicted arousal and CF 1 month after trauma. PMID- 25720330 TI - Challenges of coronary angiography and intervention in patients previously treated by TAVI. AB - OBJECTIVE: Since the beginning of the transcatheter aortic valve implantation (TAVI) era, many prosthetic valves have entered clinical practice. TAVI prostheses differ regarding stent design and some may potentially interfere with diagnostic or interventional catheters. The aim of our analysis was to evaluate the feasibility of coronary angiography (CA) or percutaneous coronary intervention (PCI) in patients with prior TAVI. METHODS: From 2011 to 2014, 1,000 patients were treated by TAVI at our center using eight different valve prostheses (Symetis ACURATE TA and ACURATE TF; Medtronic CoreValve and Engager; JenaValve, SJM Portico; Edwards Lifesciences SAPIEN and SAPIEN XT). In this analysis, all patients were included who underwent either CA or PCI after TAVI. CA or PCI were rated as fully feasible when coronary ostia could be fully intubated, partially feasible when coronary arteries could be displayed only unselectively or unfeasible when coronary arteries could not be displayed. RESULTS: A total of 35 patients underwent CA/PCI after TAVI at our hospital. In all patients with valves implanted in a subcoronary position (SAPIEN n = 19; JenaValve n = 1), selective intubation was feasible using standard catheters. Out of 15 patients with valve types that are placed over the coronary ostia (CoreValve n = 10, ACURATE n = 4, Portico n = 1), selective intubation of coronary arteries was not possible in 9 cases, even with the use of different diagnostic catheters. Full accessibility was possible only in 3 cases. In 2 cases, display of the right CA was only feasible using unselective aortography. In 1 case, coronary arteries could not be displayed at all immediately after a valve-in-valve procedure. CONCLUSION: CA or PCI after TAVI is usually feasible. Devices that are placed in a partially supracoronary position, however, can interfere with diagnostic or guiding catheters and impede straightforward intervention, especially when the prosthesis is not implanted in the correct position. PMID- 25720331 TI - Very late cardiac tamponade following successful transcatheter closure of an atrial septal defect with the Amplatzer septal occluder. PMID- 25720332 TI - Intraaortic balloon counterpulsation and microcirculation in cardiogenic shock complicating myocardial infarction: an IABP-SHOCK II substudy. AB - OBJECTIVES: This study sought to evaluate the influence of intraaortic balloon pump (IABP) counterpulsation on the microcirculation in patients with cardiogenic shock (CS) complicating acute myocardial infarction. BACKGROUND: In patients with shock profound alterations of the microcirculation have been observed and their clinical relevance has been described. Different treatment strategies exist to improve microvascular perfusion in patients with CS; however, the role of IABP treatment is not clearly defined. METHODS: A predefined substudy of the randomized Intraaortic Balloon Pump in Cardiogenic Shock II trial (IABP-SHOCK II) investigated the sublingual microcirculation using a sidestream darkfield intravital microscope on days 1, 2 and 4 after the onset of shock. Perfused capillary (<20 um, PCD) and vessel densities (<100 um, PVD), total capillary (TCD) and vessel (TVD) densities were determined. In addition, the proportion of perfused vessels was assessed. RESULTS: Forty-one patients were included in this substudy (n = 24 with IABP support vs. n = 17 without IABP support). No significant differences between treatment with or without IABP regarding PCD, PVD, TCD, TVD and the proportion of perfused vessels were evident on all three timepoints (p = n.s. for all). Microvascular perfusion showed inverse correlation with subsequent serum lactate levels (-0.366; p = 0.02) without being significantly correlated with lactate levels at the timepoint of the microcirculatory investigation. In Kaplan-Meier analysis microcirculatory parameters showed significant discrimination of prediction for time to death (p < 0.05 for all). CONCLUSIONS: In patients with CS, there is no effect of IABP treatment on microvascular perfusion. Parameters of the microcirculation might be helpful to identify high risk patients. PMID- 25720333 TI - Efficacy of SMS Text Message Interventions for Smoking Cessation: A Meta Analysis. AB - BACKGROUND: Mobile technology provides new opportunities for health promotion communication. The purpose of this study was to conduct a current and extensive meta-analytic review of SMS (short message service) text message-based interventions for individual smoking cessation. METHODS: Academic Search Complete, PsycINFO, PubMed, and Scopus were reviewed for articles meeting selection criteria: 1) randomized controlled trials, 2) measured smoking cessation, and 3) intervention primarily delivered through SMS text messaging. Three and 6month follow-up of 7-day point prevalence or continuous abstinence was considered from studies meeting criteria. All analyses were conducted with intention-to-treat. Both fixed and random effects models were used to calculate the global outcome measure and confidence intervals. RESULTS: Thirteen studies were identified that met inclusion criteria. The studies were found to be homogeneous [Q12=12.47, p=0.14]. Odds ratios based on the random effects models suggested that interventions generally increased quit rates compared to controls, 1.36 [95% CI=1.23, 1.51]. Intervention efficacy was higher in studies with a 3month follow-up compared to 6month follow-up. Text plus programs (e.g., text messaging plus Web or in-person intervention modalities) performed only slightly better than text only programs. Pooled results also indicate message frequency schedule can affect quit rates, in which fixed schedules performed better than decreasing or variable schedules. The use of quit status assessment messages was not related to intervention efficacy. CONCLUSION: Smoking quit rates for the text messaging intervention group were 36% higher compared to the control group quit rates. Results suggest that SMS text messaging may be a promising way to improve smoking cessation outcomes. This is significant given the relatively wide reach and low cost of text message interventions. Identifying the components that make interventions efficacious will help to increase the effectiveness of such interventions. PMID- 25720334 TI - All-in-one assembly based on 3D-intertangled and cross-jointed architectures of Si/Cu 1D-nanowires for lithium ion batteries. AB - All-in-one assemblies of separator, electrode and current collector (SECA) for lithium ion batteries are presented by using 1D nanowires of Si and Cu (nwSi and nwCu). Even without binders, integrity of SECA is secured via structural joints based on ductility of Cu as well as entanglement of nwSi and nwCu. By controlling the ratio of the nanowires, the number of contact points and voids accommodating volume expansion of Si active material are tunable. Zero volume expansion and high energy density are simultaneously achievable by the architecture. PMID- 25720335 TI - Modeling Atom Probe Tomography: A review. AB - Improving both the precision and the accuracy of Atom Probe Tomography reconstruction requires a correct understanding of the imaging process. In this aim, numerical modeling approaches have been developed for 15 years. The injected ingredients of these modeling tools are related to the basic physic of the field evaporation mechanism. The interplay between the sample nature and structure of the analyzed sample and the reconstructed image artefacts have pushed to gradually improve and make the model more and more sophisticated. This paper reviews the evolution of the modeling approach in Atom Probe Tomography and presents some future potential directions in order to improve the method. PMID- 25720336 TI - Tetraphenolate niobium and tantalum complexes for the ring opening polymerization of epsilon-caprolactone. AB - Reaction of the pro-ligand alpha,alpha,alpha',alpha'-tetra(3,5-di-tert-butyl-2 hydroxyphenyl-p-)xylene-para-tetraphenol (p-L(1)H4) with two equivalents of [NbCl5] in refluxing toluene afforded, after work-up, the complex {[NbCl3(NCMe)]2(MU-p-L(1))}.6MeCN (1.6MeCN). When the reaction was conducted in the presence of excess ethanol, the orange complex {[NbCl2(OEt)(NCMe)]2(MU-p L(1))}.31/2MeCN.0.614toluene (2.31/2MeCN.0.614toluene) was formed. A similar reaction using [TaCl5] afforded the yellow complex {[TaCl2(OEt)(NCMe)]2(MU-p L(1))}.5MeCN (3.5MeCN). In the case of the meta pro-ligand, namely alpha,alpha,alpha',alpha'tetra(3,5-di-tert-butyl-2-hydroxyphenyl-m-)xylene-meta tetraphenol (m-L(2)H4) only the use of [Nb(O)Cl3(NCMe)2] led to the isolation of crystalline material, namely the orange bis-chelate complex {[Nb(NCMe)Cl(m L(2)H2)2]}.31/2MeCN (4.31/2MeCN) or {[Nb(NCMe)Cl(m-L(2)H2)2]}.5MeCN (4.5MeCN). The molecular structures of 1-4 and the tetraphenols L(1)H4 and m-L(2)H4.2MeCN have been determined. Complexes 1-4 have been screened as pre-catalysts for the ring opening polymerization of epsilon-caprolactone, both with and without benzyl alcohol or solvent present, and at various temperatures; conversion rates were mostly excellent (>96%) with good control either at >100 degrees C over 20 h (in toluene) or 1 h (neat). PMID- 25720337 TI - Adaptation of the hepatitis B virus core protein to CD8(+) T-cell selection pressure. AB - Activation of hepatitis B virus (HBV)-specific CD8 T cells by therapeutic vaccination may promote sustained control of viral replication by clearance of covalently closed circular DNA from infected hepatocytes. However, little is known about the exact targets of the CD8 T-cell response and whether HBV reproducibly evades CD8 T-cell immune pressure by mutation. The aim of this study was to address if HBV reproducibly selects substitutions in CD8 T-cell epitopes that functionally act as immune escape mutations. The HBV core gene was amplified and sequenced from 148 patients with chronic HBV infection, and the human leukocyte antigen (HLA) class I genotype (A and B loci) was determined. Residues under selection pressure in the presence of particular HLA class I alleles were identified by a statistical approach utilizing the novel analysis package SeqFeatR. With this approach we identified nine residues in HBV core under selection pressure in the presence of 10 different HLA class I alleles. Additional immunological experiments confirmed that seven of the residues were located inside epitopes targeted by patients with chronic HBV infection carrying the relevant HLA class I allele. Consistent with viral escape, the selected substitutions reproducibly impaired recognition by HBV-specific CD8 T cells. CONCLUSION: Viral sequence analysis allows identification of HLA class I restricted epitopes under reproducible selection pressure in HBV core; the possibility of viral escape from CD8 T-cell immune pressure needs attention in the context of therapeutic vaccination against HBV. PMID- 25720340 TI - Erratum to: Starting Insulin in Type 2 Diabetes: Real-World Outcomes After the First 12 Months of Insulin Therapy in a New Zealand Cohort. PMID- 25720338 TI - Neuroinflammation after neonatal hypoxia-ischemia is associated with alterations in the purinergic system: adenosine deaminase 1 isoenzyme is the most predominant after insult. AB - Hypoxic-ischemic (HI) injury perinatal brain is a major contributor to morbidity and mortality to infants and children. Adenosine may play a role in the pathophysiology of HI, since it modulates the inflammatory process and the release of several neurotransmitters. Thus, the aim of this study was to identify the isoforms of adenosine deaminase (ADA) responsible for the enzymatic activity as well as the adenosine kinase (ADK) and A1 adenosine receptor (A1R) expression in the cerebral cortex eight days after HI. Myeloperoxidase (MPO) and N-acetyl glucosaminidase (NAG) were assessed as inflammation markers. ADA activity was analyzed, in the presence or absence of a specific ADA1 inhibitor, erythro-9-(2 hydroxy-3-nonyl) adenine. The ADA1 activity (92.6%) was significantly higher than ADA2 (7.4%) activity in the cerebral cortex eight days after HI. A1Rs and ADK protein expression showed decreased 8 days after insult. Interestingly, the ADA1, MPO, and NAG activities were correlated positively. In view of this, we conclude that the inhibitor of ADA1, in in vitro conditions, was effective in decreasing the ADA activity, and that mainly ADA1 isoform is responsible for the increase in the ADA activity 8 days after HI insult. Therefore, HI neonatal was able to alter the ADK and A1R expression. Thus, due to the importance of adenosine signaling in the regulation of inflammatory and immune process and the crucial role of ADA in the postischemic homeostase of adenosine as well as during inflammatory process, we suggest that ADA1 inhibitors may play an important role in the regulation of events that follow the HI insult, favoring the increase in the adenosine in the sites of tissue injury. Together, these results highlight a role of the purinergic signaling cascade in the pathophysiology of HI neonatal. PMID- 25720339 TI - Effect of the M1 Muscarinic Acetylcholine Receptor on Retinal Neuron Number Studied with Gene-Targeted Mice. AB - Pharmacological activation of the M1 muscarinic receptor subtype was suggested to promote the survival of retinal neurons. We examined the hypothesis that the M1 receptor is crucial for retinal neuron survival in vivo by using mice devoid of the M1 receptor gene. Muscarinic receptor gene expression was determined in the retina using real-time PCR. The amount of neurons in the retinal ganglion cell layer and of axons in the optic nerve was determined in retinal wholemounts stained with cresyl blue and in optic nerve cross-sections stained with toluidine blue, respectively. mRNA of all five muscarinic receptor subtypes (M1-M5) was detected in the retina from wild-type mice. Remarkably, M2 and M3 receptor mRNA were most abundant. In retinas from M1 receptor-deficient mice, M4 receptor mRNA expression was increased compared to that of wild-type mice, while no marked changes in the mRNA expression levels of the other muscarinic receptor subtypes were observed. The amount of cells in the retinal ganglion cell layer and the amount of axons in the optic nerve did not differ between M1 receptor-deficient and wild-type mice. The present findings suggest that the M1 receptor is not essential for the survival of retinal neurons in vivo. PMID- 25720341 TI - Dipeptidyl peptidase-4 inhibition in diabetic rats leads to activation of the transcription factor CREB in beta-cells. AB - Incretin therapies are effective in controlling blood glucose levels in type 2 diabetic patients by improving the survival and function of beta-cells. They include dipeptidyl peptidase-4 (DPP-4) inhibitors and long-acting glucagon-like peptide-1 (GLP-1) analogs. We have previously reported that GLP-1 enhances the survival of cultured human islets by activation of the transcription factor CREB. To test the in vivo relevance of these findings, we examined the effects of alogliptin, a DPP-4 inhibitor, in Zucker Diabetic rats, a model for type 2 diabetes. The plasma levels of GLP-1 increased in alogliptin-treated diabetic rats leading to normoglycemia. Pancreatic islets of untreated diabetic rats were characterized by decreased immunostaining for insulin and PDX-1. Elevation of GLP 1 in treated diabetic rats resulted in the improved survival of beta-cells. Dual immunofluorescent staining showed phosphorylation/activation of CREB in insulin positive beta-cells of islets. This led to increases in the levels of CREB targets including Bcl-2, an antiapoptotic mitochondrial protein, BIRC3, a caspase inhibitor and IRS-2, an adapter protein needed for insulin signaling. Findings from this study suggest potential activation of cytoprotective CREB by GLP-1 in pancreatic beta-cells of diabetic patients undergoing incretin-based therapies. PMID- 25720342 TI - Hydroxysafflor yellow A inhibits angiogenesis of hepatocellular carcinoma via blocking ERK/MAPK and NF-kappaB signaling pathway in H22 tumor-bearing mice. AB - Hydroxysafflor yellow A (HSYA), a flavonoid derived and isolated from traditional Chinese medicine Carthamus tinctorius L., possesses anti-tumor activity. However, its effects on hepatocellular carcinoma (HCC) have not been investigated. The proliferation and metastasis of HCC are dependent on angiogenesis, which also strongly links with several signal transduction pathways associated with cell proliferation and apoptosis. This study aimed to explore the effect of HSYA on vasculogenesis and to determine its molecular mechanism by investigating the expression of ERK/MAPK (p-c-Raf, c-Raf, p-ERK1/2, ERK1/2) and NF-kappaB (p65, IkappaB and p-IkappaB) signaling pathway in H22 tumor-bearing mice. The results showed that HSYA could considerably suppress tumor growth by inhibiting secretion of angiogenesis factors (vascular endothelial growth factor A, basic fibroblast growth factor) and vascular endothelial growth factor receptor1. At the moleculcould block ERK1/2 phosphorylation and then restrain the activation of NF kappaB and its nuclear translocation by down-regulating the expression of p65 in the nucleus, up-regulating p65 level in the cytoplasm, inhibiting IkappaB phosphorylation and cytoplasmic degradation of IkappaB-alpha. Finally, we demonstrate that HSYA could suppress mRNA expression levels of cell proliferation related genes (cyclinD1, c-myc, c-Fos) compared with negative control group. And best of all, HSYA could improve spleen/thymus indexes, which was evaluated as the marker of protective effect on the immune system. Our findings support HSYA as a promising candidate for the prevention and treatment of HCC. PMID- 25720343 TI - Evaluation of testicular tissue of adult rats treated with cisplatin incorporated into the liposome. AB - Cisplatin (CPL) is one of the most widely used and effective chemotherapeutic agents for the treatment of several human malignancies. However, it causes serious side effects, especially on reproduction. In order to reduce the undesirable effects caused by many drugs, liposomes have been used as a good system for drug delivery. The aim of this study was to investigate, for the first time, the effects of CPL incorporated into the dipalmitoyl phosphatidylcholine liposome (DPPC) on the testicular tissue of adult Wistar rats. The animals (n = 20) were distributed into four experimental groups: (a) control (distillated water); (b) liposome (DPPC, 1 mL), (c) cisplatin incorporated into liposome (CPL/DPPC), and (d) CPL (8 mg/kg body weight). The animals received a single intraperitoneal injection and were killed 10 days after each treatment for histopathological analysis of testes. The results showed that the testicular histomorphometric parameters in rats of DPPC and CPL/DPPC groups were similar to those of the control group. Meanwhile, rats of the CPL-treated group showed a variety of morphological alterations, including atrophy of seminiferous tubules and presence of multinucleated cells in the germinal epithelium. The incorporation of CPL into the liposome had no influence on the testicular weight or any other stereological parameters, but it was beneficial in maintaining the body weight of the animals. In conclusion, the liposome suppressed the cytotoxic effects caused by cisplatin in the testes of rats, suggesting a possible use in chemotherapy against cancer to reduce the side effects seen on reproduction. PMID- 25720344 TI - A Critical Review of Models of Perinatal Infection. AB - One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation. PMID- 25720345 TI - Role of polymer-drug conjugates in organ-specific delivery systems. AB - Polymers have been utilized to deliver the drug to targeted site in controlled manner, achieving the high-therapeutic efficacy. Polymeric drug conjugates having variable ligands as attachments have been proved to be biodegradable, stimuli sensitive and targeted systems. Numerous polymeric drug conjugates having linkers degraded by acidity or intracellular enzymes or sensitive to over expressed groups of diseased organ/tissue have been synthesized during last decade to develop targeted delivery systems. Most of these organs have number of receptors attached with different cells such as Kupffer cells of liver have mannose-binding receptors while hepatocytes have asialoglycoprotein receptors on their surface which mainly bind with the galactose derivatives. Such ligands can be used for achieving high targeting and intracellular delivery of the drug. This review presents detailed aspects of receptors found in different cells of specific organ and ligands with binding efficiency to these specific receptors. This review highlights the need of further studies on organ-specific polymer-drug conjugates by providing detailed account of polymeric conjugates synthesized till date having organ-specific targeting. PMID- 25720346 TI - Surgery in extensive vertebral hemangioma: case report, literature review and a new algorithm proposal. AB - Hemangiomas are benign dysplasias or vascular tumors consisting of vascular spaces lined with endothelium. Nowadays, radiotherapy for vertebral hemangiomas (VHs) is widely accepted as primary treatment for painful lesions. Nevertheless, the role of surgery is still unclear. The purpose of this study is to propose a novel algorithm of treatment about VHs. This is a case report of an extensive VH and a review of the literature. A case of vertebral fracture during radiotherapy at a total dose of 30 Gy given in 10 fractions (treatment time 2 weeks) using a linear accelerator at 15 MV high-energy photons for extensive VH is reported. Using PubMed database, a review of the literature is done. The authors have no study funding sources. The authors have no conflicting financial interests. In the literature, good results in terms of pain and neurological deficits are reported. No cases of vertebral fractures are described. However, there is no consensus regarding the treatment for VHs. Radiotherapy is widely utilized in VHs determining pain. Surgery for VHs determining neurological deficit is also widely accepted. Perhaps, regarding the width of the lesion, no indications are given. We consider it important to make an evaluation before initiating the treatment for the risk of pathologic vertebral fracture, since in radiotherapy, there is no convention regarding structural changes determined in VHs. We propose a new algorithm of treatment. We recommend radiotherapy only for small lesions in which vertebral stability is not concerned. Kyphoplasty can be proposed for asymptomatic patients in which VHs are small and in patients affected by VHs determining pain without spinal canal invasion in which the VH is small. In patients affected by pain without spinal canal invasion but in which the VH is wide or presented with spinal canal invasion and in patients affected by neurological deficits, we propose surgery. PMID- 25720347 TI - Do altered energy metabolism or spontaneous locomotion 'mediate' decelerated senescence? AB - That one or multiple measures of metabolic rate may be robustly associated with, or possibly even causative of, the progression of aging-resultant phenotypes such as lifespan is a long-standing, well-known mechanistic hypothesis. To broach this hypothesis, we assessed metabolic function and spontaneous locomotion in two genetic and one dietary mouse models for retarded aging, and subjected the data to mediation analyses to determine whether any metabolic or locomotor trait could be identified as a mediator of the effect of any of the interventions on senescence. We do not test the hypothesis of causality (which would require some experiments), but instead test whether the correlation structure of certain variables is consistent with one possible pathway model in which a proposed mediating variable has a causal role. Results for metabolic measures, including oxygen consumption and respiratory quotient, failed to support this hypothesis; similar negative results were obtained for three behavioral motion metrics. Therefore, our mediation analyses did not find support that any of these correlates of decelerated senescence was a substantial mediator of the effect of either of these genetic alterations (with or without caloric restriction) on longevity. Further studies are needed to relate the examined phenotypic characteristics to mechanisms of aging and control of longevity. PMID- 25720348 TI - Associations between HbA1c and depressive symptoms in young adults with early onset type 1 diabetes. AB - OBJECTIVE: This study sought to evaluate the associations between metabolic control and each DSM-5 (Diagnostic and Statistical Manual, fifth edition) symptom of depression among young women and men with early-onset long-duration type 1 diabetes. METHODS: The data of 202 18-21-year-old patients with type 1 diabetes from a population-based, nationwide survey (40.1% male) with a mean age of 19.4 (standard deviation 0.9) years, a mean HbA1c level of 8.3% (1.6%) (i.e., 67 [17.5]mmol/mol), and a mean diabetes duration of 15.7 (1.0) years were included. The German version of the Patient Health Questionnaire (PHQ-9) was used to assess depression symptoms. For each PHQ-9 depressive symptom, the mean HbA1c values of screening-positive and screening-negative patients were compared via t-test. The associations between HbA1c levels and depressive symptoms were analyzed using multiple linear regression analyses and stepwise adjustments for individual, socioeconomic and health-related covariates. RESULTS: Exactly 43.0% and 33.3% of female and male participants reported at least one depressive symptom, and 5.0% and 2.5% met the DSM-5 criteria for major depressive syndrome. HbA1c levels increased with psychomotor agitation/retardation (women), overeating/poor appetite (men/women), lethargy (men), and sleep difficulty (men). Overeating/poor appetite, lethargy, and total PHQ-9 score (per score increase by one) were associated with increased HbA1c levels of 1.10, 0.96 and 0.09 units (%), respectively. CONCLUSIONS: The associations between depressive symptoms and HbA1c levels vary by symptom and sex. Differentiating the symptoms of depression and targeted interventions might help to improve metabolic outcomes in young adults with early-onset type 1 diabetes and depression. PMID- 25720349 TI - Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain. AB - The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex atypical brain development in GD, we quantified regional neural gray matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male to-females had less volume in the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain. PMID- 25720350 TI - Re: The medico-legal aspects of prescribing vitamin D. PMID- 25720352 TI - A simple model for Lutz and Bujard's controllable promoters and its application for analyzing a simple genetic oscillator. AB - We develop an exact and flexible mathematical model for Lutz and Bujard's controllable promoters. It can be used as a building block for modeling genetic systems based on them. Special attention is paid to deduce all the model parameters from reported (in vitro) experimental data. We validate our model by comparing the regulatory ranges measured in vivo by Lutz and Bujard against the ranges predicted by the model, and which are calculated as the reporter activity obtained under inducing conditions divided by the activity measured under maximal repression. In particular, we verify Bond et al. assertion that the cooperativity between two lac operators can be assumed to be negligible when their central base pairs are separated by 22 or 32 bp [Gene repression by minimal lac loops in vivo, Nucleic Acids Res, 38 (2010) 8072-8082]. Moreover, we also find that the probability that two repressors LacI bind to these operators at the same time can be assumed to be negligible as well. We finally use the model for the promoter P(LlacO-1) to analyze a synthetic genetic oscillator recently build by Stricker et al. [A fast, robust and tunable synthetic gene oscillator, Nature, 456 (2008) 516-519]. PMID- 25720351 TI - Meta-Analysis of Gene Expression in Autism Spectrum Disorder. AB - Autism spectrum disorders (ASD) are clinically heterogeneous and biologically complex. In general it remains unclear, what biological factors lead to changes in the brains of autistic individuals. A considerable number of transcriptome analyses have been performed in attempts to address this question, but their findings lack a clear consensus. As a result, each of these individual studies has not led to any significant advance in understanding the autistic phenotype as a whole. Here, we report a meta-analysis of more than 1000 microarrays across twelve independent studies on expression changes in ASD compared to unaffected individuals, in both blood and brain tissues. We identified a number of known and novel genes that are consistently differentially expressed across three studies of the brain (71 samples in total). A subset of the highly ranked genes is suggestive of effects on mitochondrial function. In blood, consistent changes were more difficult to identify, despite individual studies tending to exhibit larger effects than the brain studies. Our results are the strongest evidence to date of a common transcriptome signature in the brains of individuals with ASD. PMID- 25720353 TI - How to mend a broken heart: adult and induced pluripotent stem cell therapy for heart repair and regeneration. AB - The recently developed ability to differentiate primary adult stem cells and induced pluripotent stem cells (iPSCs) into cardiomyocytes is providing unprecedented opportunities to produce an unlimited supply of cardiomyocytes for use in patients with heart disease. Here, we examine the evidence for the preclinical use of such cells for successful heart regeneration. We also describe advances in the identification of new cardiac molecular and cellular targets to induce proliferation of cardiomyocytes for heart regeneration. Such new advances are paving the way for a new innovative drug development process for the treatment of heart disease. PMID- 25720355 TI - Horror Vacui: Emptiness Might Distinguish between Major Suicide Repeaters and Nonmajor Suicide Repeaters: A Pilot Study. PMID- 25720356 TI - Striatum morphometry is associated with cognitive control deficits and symptom severity in internet gaming disorder. AB - Internet gaming disorder (IGD), identified in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Section III as a condition warranting more clinical research, may be associated with impaired cognitive control. Previous IGD-related studies had revealed structural abnormalities in the prefrontal cortex, an important part of prefrontal-striatal circuits, which play critical roles in cognitive control. However, little is known about the relationship between the striatal nuclei (caudate, putamen, and nucleus accumbens) volumes and cognitive control deficit in individuals with IGD. Twenty seven adolescents with IGD and 30 age-, gender- and education-matched healthy controls participated in this study. The volume differences of the striatum were assessed by measuring subcortical volume in FreeSurfer. Meanwhile, the Stroop task was used to detect cognitive control deficits. Correlation analysis was used to investigate the relationship between striatal volumes and performance in the Stroop task as well as severity in IGD. Relative to controls, the IGD committed more incongruent condition response errors during the Stroop task and showed increased volumes of dorsal striatum (caudate) and ventral striatum (nucleus accumbens). In addition, caudate volume was correlated with Stroop task performance and nucleus accumbens (NAc) volume was associated with the internet addiction test (IAT) score in the IGD group. The increased volumes of the right caudate and NAc and their association with behavioral characteristics (i.e., cognitive control and severity) in IGD were detected in the present study. Our findings suggest that the striatum may be implicated in the underlying pathophysiology of IGD. PMID- 25720354 TI - The ins and outs of MHC class II-mediated antigen processing and presentation. AB - Antigenic peptide-loaded MHC class II molecules (peptide-MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4(+) T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide-MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide-MHC class II complexes, the intracellular trafficking of peptide-MHC class II complexes to the APC plasma membrane and their ultimate degradation. PMID- 25720358 TI - Bone transplantation and tissue engineering, part III: allografts, bone grafting and bone banking in the twentieth century. AB - During the 20th century, allograft implantation waned in popularity as a clinical activity. Reports appeared in the literature describing several small series of patients in whom bone was obtained from amputation specimens or recently deceased individuals. The concept of bone banking became a reality during and after World War II when the National Naval Tissue Bank was established in Bethesda and a number of small banks sprang up in hospitals throughout the world. Small fragments, either of cortical or medullary bone, from these banks were used heterotopically to augment spinal fusions, to implant into cyst cavities, or to serve as a scaffolding for repair of non- or delayed union of fractures of the long bones. PMID- 25720357 TI - Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. AB - BACKGROUND: To examine cross-national patterns and correlates of lifetime and 12 month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD). METHOD: Nationally or regionally representative epidemiological interviews were administered to 74 045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI). RESULTS: 45.7% of respondents with lifetime MDD (32.0-46.5% inter-quartile range (IQR) across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8-54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9-47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset (AOO) of their first anxiety disorder than their MDD, while 13.5% reported an earlier AOO of MDD and the remaining 18.5% reported the same AOO of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4 v. 46.0%; chi 2 1 = 187.0, p < 0.001) and suicide ideation (19.5 v. 8.9%; chi 2 1 = 71.6, p < 0.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high-income countries (68.8 v. 45.4%; chi 2 1 = 108.8, p < 0.001) than low/middle-income countries (30.3 v. 20.6%; chi 2 1 = 11.7, p < 0.001). CONCLUSIONS: Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6-74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers v. causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence. PMID- 25720359 TI - Response to Jie et al.: How to explain the evaluation of the accuracy of patient specific cutting blocks for total knee arthroplasty? PMID- 25720360 TI - WHAT causes dislocation of a total hip arthroplasty; a simple mnemonic for the orthopaedic resident. PMID- 25720361 TI - Follow-up guidance for metal-on-metal hip replacement patients should be updated. PMID- 25720362 TI - The importance of echocardiography and an individual approach to patent ductus arteriosus treatment in extremely preterm infants. PMID- 25720363 TI - Herpes Simplex Virus DNAemia Preceding Neonatal Disease. AB - Polymerase chain reaction testing of blood for herpes simplex virus (HSV) is recommended for newborns delivered to mothers with active genital HSV lesions at delivery. We report an infant who had a positive blood HSV polymerase chain reaction test before the onset of clinical signs of HSV disease. PMID- 25720364 TI - Streptococcal intertrigo. PMID- 25720365 TI - Meconium Stained Newborns: Ethics for Evidence in Resuscitation. PMID- 25720366 TI - Missed opportunities for tuberculosis screening in primary care. AB - OBJECTIVE: To assess how frequently pediatric practitioners perform latent tuberculosis infection (LTBI) screening according to guidelines. We hypothesized that screening occurs less frequently among children whose parents do not speak English as the primary language. STUDY DESIGN: We conducted a retrospective cohort study of patients attending well-child visits in an urban academic pediatric primary care clinic between April 1, 2012, and March 31, 2013. We assessed documentation of 3 LTBI screening components and tested the association between parent primary language and tuberculin skin test (TST) placement and documentation of results. RESULTS: During the study period, 387 of 9143 children (4%) had no documentation of screening question responses. Among the other 8756 children, 831 (10%) were identified as at high risk for LTBI. Of these, 514 (62%) did not have documented TST placement in the appropriate time frame. Thirty-nine of 213 children (18%) who had a TST placed did not have documented results. Multivariable regression showed that parent language was not associated with TST placement or documentation of results, but non-Hispanic Black children were more likely to not have a documented test result (aOR, 2.12; 95% CI, 1.07-4.19; P=.03) when adjusting for age, sex, parent primary language, insurance status, day of the week, and study year of TST placement. CONCLUSION: Parent primary language was not associated with LTBI testing. However, we found substantial gaps in TST placement and documentation of TST results among high-risk children, the latter of which was associated with race/ethnicity. Targeted quality improvement efforts should focus on developing processes to ensure complete screening in high-risk children. PMID- 25720367 TI - Vascular Anomalies Associated with Esophageal Atresia and Tracheoesophageal Fistula. AB - OBJECTIVE: To report the incidence of congenital vascular anomalies in a cohort of patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) while describing the clinical presentation, diagnosis, and consequences, and to evaluate the diagnostic value of esophagram in diagnosing an aberrant right subclavian artery (ARSA). METHODS: All patients born with EA/TEF between 2005 and 2013 were studied. Preoperative echocardiography reports, surgical descriptions of primary esophageal repair, and esophagrams were reviewed retrospectively. RESULTS: Of the 76 children born with EA/TEF included in this study, 14 (18%) had a vascular malformation. The incidence of a right aortic arch (RAA) was 6% (5 of 76), and that of an aberrant right subclavian artery (ARSA) was 12% (9 of 76). RAA was diagnosed in the neonatal period by echocardiography (4 of 5) or surgery (1 of 5), and ARSA was diagnosed by echocardiography (7 of 9) or later on the esophagram (2 of 9). Respiratory and/or digestive symptoms occurred in 9 of the 14 patients with vascular malformation. Both long-gap EA and severe cardiac malformations necessitating surgery were significantly associated with vascular anomalies (P<.05). The sensitivity of the esophagram for diagnosing ARSA was 66%, the specificity was 98%, the negative predictive value was 95%, and the positive predictive value was 85%. CONCLUSION: ARSA and RAA have an incidence of 12% and 6% respectively, in patients with EA/TEF. A computed tomography angioscan is recommended to rule out such malformations when stenting of the esophagus is indicated, before esophageal replacement surgery, and when prolonged (>2 weeks) use of a nasogastric tube is considered. PMID- 25720368 TI - Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats. AB - Cisplatin is one of the most potent and effective chemotherapeutic agents. However, its antineoplastic use is limited due to its cumulative nephrotoxic side effects. Therefore, the present study was undertaken to examine the nephroprotective potential of dietary bee honey and royal jelly against subchronic cisplatin toxicity in rats. Male Wistar rats were randomly divided into controls, cisplatin-treated, bee honey-pretreated cisplatin-treated and royal jelly-pretreated cisplatin-treated groups. Bee honey and royal jelly were given orally at doses of 20 and 100 mg/kg, respectively. Subchronic toxicity was induced by cisplatin (1 mg/kg bw, ip), twice weekly for 10 weeks. Cisplatin treated animals revealed a significant increase in serum level of renal injury products (urea, creatinine and uric acid). Histopathologically, cisplatin produced pronounced tubulointerstitial injuries, upregulated the fibrogenic factors, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor beta1(TGF-beta1), and downregulated the cell proliferation marker, bromodeoxyuridine (Brdu). Dietary bee honey and royal jelly normalized the elevated serum renal injury product biomarkers, improved the histopathologic changes, reduced the expression of alpha-SMA and TGF-beta1 and increased the expression of Brdu. Therefore, it could be concluded that bee honey, and royal jelly could be used as dietary preventive natural products against subchronic cisplatin-induced renal injury. PMID- 25720369 TI - Acquiring Ground State Pluripotency: Switching Mouse Embryonic Stem Cells from Serum/LIF Medium to 2i/LIF Medium. AB - Mouse embryonic stem cells (ESCs) derive from the inner cell mass (ICM) of a blastocyst. These cells are pluripotent and thus able to generate both somatic and germinal lineages. It is possible to maintain ESCs in different pluripotent states depending on the in vitro culture conditions. Classically, ESCs are cultured in the presence of serum and LIF, which sustain the naive state of pluripotency but in this metastable state cells exhibit a large degree of heterogeneity. In the last few years, it has been discovered that when ESCs are cultured in a chemically defined medium (without serum), in the presence of LIF and with the addition of two small molecules (in particular the inhibitors of MAPK and Gsk-3 pathways), they reach a ground state of pluripotency where cells are more homogeneous and more "ICM-like." In this protocol, we describe how we culture mouse ESCs and the way we switch them from naive to ground state. PMID- 25720370 TI - From Naive to Primed Pluripotency: In Vitro Conversion of Mouse Embryonic Stem Cells in Epiblast Stem Cells. AB - Mouse embryonic stem cells (ESCs) derive from the inner cell mass (ICM) of a blastocyst at E3.5 while mouse epiblast stem cells (EpiSCs) derive from the late epiblast of a post-implantation embryo at E5.5-E7.5. Both cells are able to differentiate into derivatives of the three germs layers but only ESCs are able to produce chimeras when they are introduced into a blastocyst. To support the naive state of pluripotency, ESC culture requires Leukemia inhibitory factor (Lif) and either serum or inhibitors of Erk and Gsk3 pathways (2i) while the primed pluripotency of EpiSCs is maintained using Activin A and Fibroblast Growth Factor 2 (FGF2). It is possible to obtain EpiSCs in vitro starting from ESCs but also to induce ESCs starting from EpiSCs even if this second process is very difficult and inefficient. In this protocol we describe how we perform the process of conversion from ESCs to EpiSCs. PMID- 25720371 TI - TESTIN was commonly hypermethylated and involved in the epithelial-mesenchymal transition of endometrial cancer. AB - We previously reported frequent loss of TESTIN in human endometrial carcinoma, which significantly suppressed tumor proliferation and invasion. Herein, we further explored the mechanisms underlying TESTIN loss and its roles in the epithelial-mesenchymal transition (EMT, a key step for tumor spreading). Methylation-specific PCR was performed to investigate the promoter status of TESTIN in a panel of endometrial cancer and normal endometrium tissues. The expression of TESTIN mRNA was determined by real-time PCR. Up- and down regulation of TESTIN were achieved by transient transfection with pcDNA3.1-TESTIN and shRNA-TESTIN plasmids, respectively. The EMT alterations were observed under the optical microscope and EMT-related markers were detected by real-time PCR and western blot. Compared to the control (3.6%), TESTIN was hypermethylated in 43.7% endometrial cancer tissues (p < 0.001). Moreover, TESTIN hypermethylation was significantly correlated with advanced tumor stage, deep myometrial invasion and lymphatic node metastasis. In vitro, the demethylating agent dramatically restored the expression of TESTIN. In addition, up-regulation of TESTIN significantly suppressed the EMT procedure; whereas down-regulation of TESTIN enhanced EMT. In conclusion, we demonstrated that loss of TESTIN was mainly caused by hypermethylation, which might be a potent prognostic marker. Furthermore, we proved that TESTIN significantly suppressed the EMT procedure, proposing restoration of TESTIN to be a novel therapeutic strategy for endometrial carcinoma. PMID- 25720372 TI - Characterization of a novel begomovirus associated with yellow mosaic disease of three ornamental species of Jatropha grown in India. AB - Severe yellow mosaic disease was observed in three ornamental species of Jatropha: J. integerrima, J. podagrica and J. multifida grown in gardens at Lucknow, India, during a survey in 2013. The causal pathogen was successfully transmitted from diseased to healthy plants of these species by whitefly (Bemisia tabaci). The infection of begomovirus was initially detected in naturally infected plant samples by PCR using begomovirus universal primers. The begomovirus was characterized having a monopartite genome based on sequence analyses of the cloned ~2.9kb DNA-A genome amplified by rolling circle amplification using Phi-29 DNA polymerase. The genome contained 2844 nucleotides that could be translated into seven potential open reading frames. The nucleotide sequences of DNA-A genome of the begomovirus isolates: JI (KC513823), JP (KF652078) and JM (KF652077) shared 94-95% identities together and 93-95% identities with an uncharacterized begomovirus isolated from J. curcas (the only sequences available in GenBank database as GU451249 and EU798996 under the name jatropha leaf curl virus). These shared highest identity of 61% and highly distant phylogenetic relationships with other begomoviruses reported worldwide. Based on 61% sequence identities (much less than 89%, the species demarcation criteria for a new begomovirus) the isolates under study were identified as members of a new Begomovirus species for which the name was proposed as "Jatropha mosaic Lucknow virus (JMLV)". The recombination analysis also suggested that JMLV was not a recombinant species, hence considered as unidentified Begomovirus species. Koch's postulates were also established by agroinfiltration assay of agroinfectious clone of JMLV. Characterization of JMLV associated with yellow mosaic disease of J. integerrima, J. podagrica and J. multifida is being reported for the first time. PMID- 25720373 TI - Light sensitization of DNA nanostructures via incorporation of photo-cleavable spacers. AB - Using light irradiation as a trigger, large-scale structural reconfiguration of DNA nanostructures is demonstrated. We incorporated photo-cleavable spacers at strategic locations within the short oligonucleotide strands connecting adjacent helices within a DNA origami sphere, and then used light to transform the sphere into two tethered hemispheres. PMID- 25720374 TI - Antihyperlipidemic and biochemical activities of Mcy protein in streptozotocin induced diabetic rats. AB - BACKGROUND: This study was aimed to evaluate the protective effects of a novel anti-hyperglycemic "Mcy protein" isolated from the fruits of Momordica cymbalaria in streptozotocin induced- diabetes rat model. MATERIALS AND METHODS: Wild type and Streptozotocin induced diabetic male wistar albino rats were either treated with single intraperitoneal injection of 2.5 mg Mcy protein/kg body weight or acetate buffer daily for 30 days. Fasting blood glucose and, serum and tissue lipid levels were measured along with biochemical analysis for hepatic and renal function tests. RESULTS: Mcy protein significantly reduced the fasting blood glucose and, serum as well as tissue lipid levels (p<0.05), besides normalizing the levels of liver and kidney function markers in the treated diabetic rats when compared to the diabetic controls. Our studies also showed the pancreatic islet regeneration in Mcy treated rats. CONCLUSION: Mcy protein can alleviate hyperlipidemia and help manage diabetes by stimulating insulin secretion without evident toxic effects on liver and kidney. PMID- 25720375 TI - Activation of B1a cells in peritoneal cavity by T cell-independent antigen expressed on polymeric micelle. AB - A polymeric micelle (Lactosome) composed of amphiphilic polydepsipeptide, poly(sarcosine)-block-poly(L-lactic acid), was reported as a T cell-independent antigen. We show here that Lactosome-responsive B cells are predominantly found in the peritoneal cavity (PerC). After immunization of mice with Lactosome, antibody-secreting cells (ASCs) are found only in spleen and bone marrow (BM), but not in PerC. The enzyme-linked immunospot assay shows that the dominant ASCs are plasmablasts in spleen. 5-Bromo-2'-deoxyuridine (BrdU) assay reveals that Lactosome-responsive peritoneal B1a cells proliferate by the stimulation of Lactosome and the majority of them stay there. These data indicate that the primary site for Lactosome to interact with B cells is in PerC, and some of activated B cells migrate into spleen or BM and differentiate into plasmablast there. As expected, when the B1a cells in PerC are collected from the Lactosome immunized mice and are transplanted into recombination activating gene 2 (RAG2)( /-) mice, the anti-Lactosome immunoglobulin M (IgM) production is observed in the recipient mice. It is therefore considered that the peritoneal B1a cells stimulated by Lactosome are the source of the sustained plasmablasts in spleen. PMID- 25720376 TI - Beneficence and Nonmaleficence in Treating Neonatal Hypoxic-Ischemic Brain Injury. AB - The successful clinical translation of therapeutic hypothermia offers the tantalizing possibility that further improvements in outcomes may be possible by combining cooling with other neuroprotective drugs. The challenge now is to select from a daunting range of potential treatments. The patient's best interest must be central to ethical decision making at all times. However, the beneficence or nonmaleficence of potential therapies is seldom clear for any individual patient at the time of testing new therapies. Clinical randomized controlled trials are generally acknowledged by the scientific community as the 'gold standard' for evaluating interventions in health care. Therefore, ethical trial design is of the utmost importance. This paper explores contrasting ethical perspectives on how to select new interventions to treat neonatal encephalopathy after perinatal hypoxia-ischemia. PMID- 25720377 TI - The contribution of online peer-to-peer communication among patients with adrenal disease to patient-centered care. AB - BACKGROUND: Addison's disease and Cushing's syndrome are rare. The Dutch Adrenal Society offers an online forum for Dutch adrenal patients to meet and communicate. However, little is known about the added value such a forum has for the delivery of patient-centered care. OBJECTIVE: Our aim was to analyze the purposes of online patient-to-patient forum conversations, within the context of patient-centered care. METHODS: For this study a consecutive sample of 300 questions ("threads") from the past 3.5 years was selected from the forum. The content of these patient-driven questions was analyzed based on the dimensions of patient-centeredness of the Picker Institute. This analysis was performed using ATLAS.ti. RESULTS: From the 390 questions analyzed, 80.8% (N=315) were intended to gain more information about the disease, the treatment, and to verify if other patients had similar complaints. To a much lesser extent (38/390, 9.7%), questions expressed a call for emotional support. Patients answered primarily by giving practical tips to fellow patients and to share their own experiences. CONCLUSIONS: On an online patient forum for Cushing's syndrome and Addison's disease, patients appear to primarily gain knowledge and, to a lesser extent, emotional support from their peers. This experience-based knowledge has become a very important information source. As such, patients can make a substantial contribution to the creation of patient-centered care if this knowledge is integrated into the care provided by health care professionals. PMID- 25720378 TI - Association between TLR4 A299G polymorphism and pneumonia risk: a meta-analysis. AB - BACKGROUND: Several genetic studies have evaluated the association between Toll like receptor 4 (TLR4) A299G polymorphism and the risk of pneumonia. However, the results were not consistent. We thus did this meta-analysis. MATERIAL AND METHODS: Relevant studies were systematically searched by using the NCBI, Medline, Web of Science, and Embase databases. Data were extracted independently by 2 investigators. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated. RESULTS: Eight case-control studies with 658 patients and 1862 controls were included in this meta-analysis. TLR4 A299G polymorphism was significantly associated with pneumonia risk (OR=1.74; 95% CI 1.19-2.53; P=0.004). The result was significant in adults. In addition, TLR4 A299G polymorphism was also associated with community-acquired pneumonia (CAP) risk. Results from cumulative meta-analysis and sensitivity analysis suggested that the results are reliable and robust. CONCLUSIONS: The results of this meta-analysis suggest that susceptibility to pneumonia was associated with TLR4 A299G polymorphism. PMID- 25720379 TI - Neuron-type-specific signaling by the p75NTR death receptor is regulated by differential proteolytic cleavage. AB - Signaling by the p75 neurotrophin receptor (p75(NTR), also known as NGFR) is often referred to as cell-context dependent, but neuron-type-specific signaling by p75(NTR) has not been systematically investigated. Here, we report that p75(NTR) signals very differently in hippocampal neurons (HCNs) and cerebellar granule neurons (CGNs), and we present evidence indicating that this is partly controlled by differential proteolytic cleavage. Nerve growth factor (NGF) induced caspase-3 activity and cell death in HCNs but not in CGNs, whereas it stimulated NFkappaB activity in CGNs but not in HCNs. HCNs and CGNs displayed different patterns of p75(NTR) proteolytic cleavage. Whereas the p75(NTR) carboxy terminal fragment (CTF) was more abundant than the intracellular domain (ICD) in HCNs, CGNs exhibited fully processed ICD with very little CTF. Pharmacological or genetic blockade of p75(NTR) cleavage by gamma-secretase abolished NGF-induced upregulation of NFkappaB activity and enabled induction of CGN death, phenocopying the functional profile of HCNs. Thus, the activities of multifunctional receptors, such as p75(NTR), can be tuned into narrower activity profiles by cell-type-specific differences in intracellular processes, such as proteolytic cleavage, leading to very different biological outcomes. PMID- 25720381 TI - Generating conditionally immortalised podocyte cell lines from wild-type mice. AB - BACKGROUND: Understanding podocyte biology is key to deciphering the pathogenesis of numerous glomerular diseases. However, cultivation of primary podocytes results in dedifferentiation with loss of specialised architecture. Human conditionally immortalised podocytes partly overcome this problem, utilising a temperature-sensitive transgene. Conditionally immortalised murine podocytes exist, but are derived from the Immortomouse. METHODS: Using retroviral temperature-sensitive SV40 transfection, we created a conditionally immortalised podocyte cell line from wild-type mice. RESULTS: These cells develop characteristic mature podocyte morphology and robustly express slit diaphragm proteins. Functionally, these cells demonstrate comparable responses in motility and glucose uptake to human conditionally immortalised podocytes. CONCLUSION: Podocyte-specific transgenic mice are extensively used to study glomerular disease and this technique could be used to make podocyte cell lines from any mouse, allowing study at the cellular level. This will help characterise these disease models and add to the laboratory resources used to study podocytopathies and glomerular disease. PMID- 25720380 TI - Endocytic deficiency induced by ITSN-1s knockdown alters the Smad2/3-Erk1/2 signaling balance downstream of Alk5. AB - Recently, we demonstrated in cultured endothelial cells and in vivo that deficiency of an isoform of intersectin-1, ITSN-1s, impairs caveolae and clathrin mediated endocytosis and functionally upregulates compensatory pathways and their morphological carriers (i.e. enlarged endocytic structures, membranous rings or tubules) that are normally underrepresented. We now show that these endocytic structures internalize the broadly expressed transforming growth factor beta receptor I (TGFbeta-RI or TGFBR1), also known as Alk5, leading to its ubiquitylation and degradation. Moreover, the apoptotic or activated vascular cells of the ITSN-1s-knockdown mice release Alk5-bearing microparticles to the systemic circulation. These interact with and transfer Alk5 to endocytosis deficient endothelial cells, resulting in lung endothelial cell survival and phenotypic alteration towards proliferation through activation of Erk1 and Erk2 (also known as MAPK3 and MAPK1, respectively). We also show that non-productive assembly of the Alk5-Smad-SARA (Smad anchor for receptor activation, also known as ZFYVE9) signaling complex and preferential formation of the Alk5-mSos-Grb2 complex account for Erk1/2 activation downstream of Alk5 and proliferation of pulmonary endothelial cells. Taken together, our studies demonstrate a functional relationship between the intercellular transfer of Alk5 by microparticles and endothelial cell survival and proliferation, and define a novel molecular mechanism for TGFbeta and Alk5-dependent Erk1/2(MAPK) signaling that is significant for proliferative signaling and abnormal growth. PMID- 25720382 TI - Resting Energy Expenditure in Patients with Stroke during the Subacute Phases - Relationships with Stroke Types, Location, Severity of Paresis, and Activities of Daily Living. AB - BACKGROUND: The energy demands in patients with stroke during the subacute phases are unclear. However, this information is essential for appropriate clinical and nutritional management. The aims of this study were to determine the resting energy expenditure (REE) during the subacute phases, examine its relationships with stroke types, location, severity of hemiparesis, and activities of daily living (ADL), and evaluate whether estimation of REE from the Harris-Benedict equation (HB) requires the addition of a 'stress factor' to capture possible additional REE imposed by stroke. METHODS: We measured REE in 95 patients with subacute stroke (53.5 +/- 16.6 days post-stroke) with indirect calorimetry, and compared it with predicted values of energy expenditure estimated from the HB (expressed as percentage). Patients were admitted for rehabilitation of their first ischemic or nonsurgical hemorrhagic stroke. The severity of hemiparesis was assessed with the motor items of the Stroke Impairment Assessment Set (SIAS). The ADL was assessed with the Functional Independence Measure (FIM). We compared REE and %HB of the two groups divided by hemiparesis severity and ADL limitation using the Student's t-test, and those of the five groups divided by stroke location. The correlations between REE and the motor items of the SIAS and the FIM score were assessed with the Spearman rank correlation test. A multiple regression analysis for REE was conducted. RESULTS: The average body weight (BW) was 57.1 +/- 11.3 kg. The average body mass index (BMI) was 22.5 +/- 4.0. The mean REE (%HB) was 1,271 +/- 284 kcal/day (106.0 +/- 17.3%). REE and %HB of the low ADL group was less than that of the high ADL group (p < 0.05). The REE had a positive correlation with the FIM score (rs = 0.51, p < 0.01). The motor items of the SIAS were not significantly correlated with REE. BW, FIM, and stroke location were independent predictors of REE. CONCLUSIONS: Analysis of energy expenditure suggests that stroke patients are not hypermetabolic during the subacute phase. The 'stress factor' in stroke patients during the subacute phase was 1.0-1.1. This finding provides important information for improving nutritional management during the subacute phase in patients with stroke. PMID- 25720383 TI - Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin. AB - Human papillomaviruses (HPVs) have evoked numerous mechanisms to subvert host innate immunity and establish a local immunosuppressive environment to facilitate persistent virus infection. Topical application of 2,4-dinitrochlorobenzene (DNCB) was speculated to overcome this immunosuppressive environment and was employed in the immunotherapy of HPV-associated lesions. We have previously shown that DNCB treatment of skin expressing HPV16.E7 protein, the major oncogenic protein expressed in HPV-associated premalignant cervical epithelium, results in a hyperinflammatory response, with an associated induction of Th2 cytokines and infiltration of myeloid cells producing arginase-1, which also contributes to the hyperinflammation. However, the molecular mechanisms underlying arginase-1 induction and arginase-mediated hyperinflammation in K14.E7 skin have not been elucidated. Here, we show that HPV16.E7 protein expression as a transgene in skin is associated with enhanced IL-17A production by macrophages exposed to DNCB. Interestingly, induction of arginase-1 by DNCB is not seen in K14.E7 animals unable to express IL-17A. Further, blockade of either IL-17A or arginase activity alleviates DNCB-induced hyperinflammation through reduced recruitment of neutrophils, as a consequence of decreased CXCL1 and CXCL5 chemokine production. Thus, our findings suggest that increased IL-17A expression by macrophages in E7 expressing skin exposed to DNCB promotes arginase-1 induction and contributes directly to the observed hyperinflammation. PMID- 25720384 TI - Polyvinylidene Fluoride as a Suture Material: Evaluation of Comet Tail-Like Infiltrate and Foreign Body Granuloma. AB - BACKGROUND: Biocompatibility and tissue integration of a surgical suture are decisive factors for wound healing and therefore for the success of sutures. The optimal suture material is still under discussion. Polyvinylidene fluoride (PVDF) is described to have superior properties of biocompatibility and is therefore frequently used as a mesh component. Only little information is available about its use as a suture material. The aim of this study was to evaluate the biocompatibility of PVDF as a suture material in comparison to 5 different established sutures in a rat model. METHODS: In 30 male rats, a monofilamental PVDF suture (Resopren(r)) and 5 established control suture materials [polyester (Miralene(r)), polytetrafluoroethylene (Gore(r)), poliglecaprone (Monocryl(r)), polydioxanone (Monoplus(r)), polyglactin 910 (Vicryl(r)), USP size 3-0] were placed in the subcutaneous layer of the abdominal wall without knot or tension. After 3, 7 or 21 days, the abdominal walls were explanted for histopathological and immunohistochemical investigation with special regard to the size and quality of foreign body granuloma and the length of the comet tail-like infiltrate (CTI). RESULTS: The PVDF sutures showed the smallest size of foreign body granuloma (60 +/- 14 um) and the smallest CTI length (343 +/- 60 um) of all polymers after 21 days. Only PVDF (Resopren) and polydioxanone (Monoplus) showed a significant collagen I/III ratio increase between days 3 and 21 (p = 0.009 and p = 0.016). The quality of foreign body reaction regarding inflammation, proliferation and fibrotic remodeling was similar between all suture materials. CONCLUSIONS: Our data indicate that monofilamental PVDF sutures show a favorable foreign body reaction with small granuloma sizes and CTI length in comparison to established sutures. Its use as a suture material in general surgery could therefore be extended in the future. To reinforce these findings, further clinical studies need to be conducted. PMID- 25720385 TI - Morphometric analysis of lumbar pedicles in patients with spinal dysraphism. AB - BACKGROUND: In patients with open neural tube defects, the incidence of scoliosis and requirement for spinal fusions are increased. Historically, there has been no standardized measurement of vertebral morphometry in these patients. However, anecdotally, patients with open neural tube defects have a more medially oriented lumbar pedicle trajectory than the average population. METHODS: A single institution retrospective review of patients with open neural tube defects was conducted. The demographic parameters and functional and anatomical levels of the defects were noted. CT and MRI scans of the lumbar spine were analyzed; the pedicles from L 1 to S 1 were measured for width (W), length (L) and midline angle (alpha). The measurements were compared bilaterally, at each level, and with data from previously published reports. RESULTS: 16 scans of pediatric patients (mean = 3.0 ?} 4.3; age range = 7 days to 14.4 years; 7 males, 9 females) with a diagnosis of either myelomeningocele or lipomyelomeningocele were assessed. Most defects occurred in the lumbar region, with L 2 and L 5 accounting for 37.5% each. All angles demonstrated a quadratic increase from L 1 to S 1 (means: L 1 = 28.3 ?} 5.24 degrees ; L 2 = 29.1 ?} 6.2 degrees ; L 3 = 33.2 ?} 6.0 degrees ; L 4 = 36.8 ?} 5.6 degrees ; L 5 = 43.8 ?} 5.9 degrees ; S 1 = 52.0 ?} 3.6 degrees ) and were more medially angulated than those reported previously; no significant difference existed between right and left measurements (W = 0.65 <= p <= 0.94; L = 0.91 <= p <= 1; alpha = 0.24 <=p <=0.86). CONCLUSIONS: Patients with open neural tube defects had more medially angled pedicle trajectories in the lumbar spine when compared to previously reported values. PMID- 25720386 TI - Dietary Intake, FTO Genetic Variants, and Adiposity: A Combined Analysis of Over 16,000 Children and Adolescents. AB - The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1-18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 * 10(-4)), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 * 10(-4)): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 * 10(-10)) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents. PMID- 25720387 TI - Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus. AB - Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression. Genome-wide mRNA expression analysis was conducted on ECFCs from control and GDM pregnancies. Candidate genes were validated by quantitative RT PCR and Western blotting. Bisulfite sequencing evaluated DNA methylation of placenta-specific 8 (PLAC8). Proliferation and senescence assays of ECFCs transfected with siRNA to knockdown PLAC8 were performed to determine functional impact. Thirty-eight genes were differentially expressed between control and GDM exposed ECFCs. PLAC8 was highly expressed in GDM-exposed ECFCs, and PLAC8 expression correlated with maternal hyperglycemia. Methylation status of 17 CpG sites in PLAC8 negatively correlated with mRNA expression. Knockdown of PLAC8 in GDM-exposed ECFCs improved proliferation and senescence defects. This study provides strong evidence in neonatal endothelial progenitor cells that GDM exposure in utero leads to altered gene expression and DNA methylation, suggesting the possibility of altered epigenetic regulation. PMID- 25720388 TI - Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans. AB - GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist-mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation. PMID- 25720389 TI - Cellular Stress, Excessive Apoptosis, and the Effect of Metformin in a Mouse Model of Type 2 Diabetic Embryopathy. AB - Increasing prevalence of type 2 diabetes in women of childbearing age has led to a higher incidence of diabetes-associated birth defects. We established a model of type 2 diabetic embryopathy by feeding 4-week-old female mice a high-fat diet (HFD) (60% fat). After 15 weeks on HFD, the mice showed characteristics of type 2 diabetes mellitus (DM) and were mated with lean male mice. During pregnancy, control dams fed a normal diet (10% fat) were maintained on either normal diet or HFD, serving as a control group with elevated circulating free fatty acids. DM dams produced offspring at a rate of 11.3% for neural tube defect (NTD) formation, whereas no embryos in the control groups developed NTDs. Elevated markers of oxidative stress, endoplasmic reticulum stress, caspase activation, and neuroepithelial cell apoptosis (causal events in type 1 diabetic embryopathy) were observed in embryos of DM dams. DM dams treated with 200 mg/kg metformin in drinking water ameliorated fasting hyperglycemia, glucose intolerance, and insulin resistance with consequent reduction of cellular stress, apoptosis, and NTDs in their embryos. We conclude that cellular stress and apoptosis occur and that metformin effectively reduces type 2 diabetic embryopathy in a useful rodent model. PMID- 25720390 TI - Hypoxia induces an undifferentiated phenotype of oral keratinocytes in vitro. AB - The aim of this study was to determine the effects of hypoxia on the proliferating potential and phenotype of primary human oral keratinocytes cultured at ambient oxygen tension (20%) or at different levels of hypoxia (2 and 0.5% O2). The effects of oxygen tensions on cellular metabolic activity, cell proliferation, clonogenicity and proliferation heterogeneity were measured. Cell cycle profiles were analyzed by a fluorescent-activated cell sorter, and p21(WAF1/CIP1) expression in the G0/G1 phase was also concomitantly quantitated. The expression levels of cell cycle regulatory proteins were examined by immunoblotting, and the cellular senescence was assessed by senescence-associated beta-galactosidase staining. Basal and suprabasal keratinocyte phenotypes were determined by the expression levels of 14-3-3sigma, p75(NTR) and alpha6 integrin. Despite having a lower metabolism, the proliferation rate and clonogenic potential were remarkably enhanced in hypoxic cells. The significantly higher percentage of cells in the G0/G1 phase under hypoxia and the expression patterns of cell cycle regulatory proteins in hypoxic cells were indicative of a state of cell cycle arrest in hypoxia. Furthermore, a decrease in the expression of p21(WAF1/CIP1) and p16(INK4A) and fewer beta-galactosidase-positive cells suggested a quiescent phenotype rather than a senescent one in hypoxic cells. Compared with normoxic cells, the differential expression patterns of keratinocyte phenotypic markers suggest that hypoxic cells that generate minimal reactive oxygen species, suppress the mammalian target of rapamycin activity and express hypoxia-inducible factor-1alpha favor a basal cell phenotype. Thus, regardless of the predisposition to the state of cell cycle arrest, hypoxic conditions can maintain oral keratinocytes in vitro in an undifferentiated and quiescent state. PMID- 25720392 TI - The Role of Posttraumatic Stress in Acute Postconcussive Symptoms following Blast Injury in Combat. PMID- 25720391 TI - G-protein coupled receptor solubilization and purification for biophysical analysis and functional studies, in the total absence of detergent. AB - G-protein coupled receptors (GPCRs) constitute the largest class of membrane proteins and are a major drug target. A serious obstacle to studying GPCR structure/function characteristics is the requirement to extract the receptors from their native environment in the plasma membrane, coupled with the inherent instability of GPCRs in the detergents required for their solubilization. In the present study, we report the first solubilization and purification of a functional GPCR [human adenosine A2A receptor (A2AR)], in the total absence of detergent at any stage, by exploiting spontaneous encapsulation by styrene maleic acid (SMA) co-polymer direct from the membrane into a nanoscale SMA lipid particle (SMALP). Furthermore, the A2AR-SMALP, generated from yeast (Pichia pastoris) or mammalian cells, exhibited increased thermostability (~5 degrees C) compared with detergent [DDM (n-dodecyl-beta-D-maltopyranoside)]-solubilized A2AR controls. The A2AR-SMALP was also stable when stored for prolonged periods at 4 degrees C and was resistant to multiple freeze-thaw cycles, in marked contrast with the detergent-solubilized receptor. These properties establish the potential for using GPCR-SMALP in receptor-based drug discovery assays. Moreover, in contrast with nanodiscs stabilized by scaffold proteins, the non-proteinaceous nature of the SMA polymer allowed unobscured biophysical characterization of the embedded receptor. Consequently, CD spectroscopy was used to relate changes in secondary structure to loss of ligand binding ([(3)H]ZM241385) capability. SMALP solubilization of GPCRs, retaining the annular lipid environment, will enable a wide range of therapeutic targets to be prepared in native-like state to aid drug discovery and understanding of GPCR molecular mechanisms. PMID- 25720393 TI - Correction to: Andrographolide-loaded PLGA-PEG-PLGA micelles to improve its bioavailability and anticancer efficacy. PMID- 25720395 TI - Postmortem Alzheimer's Disease Hippocampi Show Oxidative Phosphorylation Gene Expression Opposite that of Isolated Pyramidal Neurons. AB - Causes of initiation and progression of sporadic Alzheimer's disease (sAD) are likely multiple and include impairment of mitochondrial bioenergetics. We analyzed RNA expression levels of multiple mitochondrial oxidative phosphorylation (OXPHOS) and biogenesis (mitobiogenesis) genes in unfixed hippocampal (WH) frozen sections (10 sAD; 9 CTL) and laser-captured hippocampal pyramidal neurons (PyNs, ~1000 neurons from each case) from 8 sAD and 7 CTL cases. Nuclear-encoded OXPHOS genes in WH were significantly increased in sAD, whereas in isolated sAD PyNs, these same genes were significantly decreased. Mitochondrial DNA-encoded genes were increased in sAD PyNs but showed a non significant downward trend in sAD WH. Relationships among WH and PyN gene expression levels in sAD distributed in a different population compared to CTL. Principal component analysis (PCA) revealed clustering of CTL but widespread heterogeneity of sAD samples. In sAD, mitochondrial bioenergetics at the gene expression level are depressed in vulnerable PyNs. PCA revealed that CTL samples clustered together, whereas sAD samples varied widely. From the perspective of OXPHOS bioenergetics, sAD is a heterogeneous syndrome and not likely due to a single abnormality. Increased stimulation of nuclear-encoded OXPHOS gene expression in PyNs is a rational therapeutic approach for most but not all cases of sAD. PMID- 25720396 TI - "Knowing What You Don't Know": Language Insight in Semantic Dementia. AB - BACKGROUND: Reduced insight commonly occurs in dementia and can be specific to one area of functioning. Despite recent models identifying a role for semantic memory, little investigation of insight has been conducted in semantic dementia (SD), with patients often described as being aware of their language problems. OBJECTIVE: This study aims to investigate language insight in SD. METHOD: Twenty two SD (n = 11 severe, n = 11 mild-moderate) and 9 nonfluent primary progressive aphasic patients completed three experimental language tasks to assess knowledge and awareness of certain words. Skills in evaluating language were tested by comparing performance ratings on the Cookie Theft task with objective scoring. Awareness regarding the existence and previous use of certain words was tested using two additional tasks. RESULTS: While SD patients were as accurate as nonfluent patients in rating their own performance on the Cookie Theft immediately following the task, they were significantly poorer at evaluating the same content re-recorded, or other examples of poor language. Compared to nonfluent patients, severe SD patients also made more errors identifying previously known low frequency words. Lastly, when tested on labels for specific aspects of an object, only SD patients made errors regarding the existence, or their past knowledge, of certain words. CONCLUSION: SD patients show a general awareness of their language impairments, but have difficulty evaluating language content. These difficulties adversely affect the ability to reflect upon current and past language skills producing an under-awareness of language deficits. This mild, secondary form of anosognosia appears to increase with greater levels of semantic impairment. PMID- 25720397 TI - An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Abeta1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients. AB - Alzheimer's disease (AD) is the most common form of dementia, with no disease modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181, and with the two ratios t-tau/Abeta1-42 and p-tau181/Abeta1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF biomarker p-tau181/Abeta1-42 ratio with consideration of APOE epsilon4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181/Abeta1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients. PMID- 25720398 TI - NK Cells are Activated in Amnestic Mild Cognitive Impairment but not in Mild Alzheimer's Disease Patients. AB - Alzheimers disease (AD) is a progressive irreversible neurological brain disorder characterized by accumulation of amyloid-beta, amyloid plaques, and neurofibrillary tangles. Inflammation and immune alterations have been linked to AD, suggesting that the peripheral immune system plays a role during the asymptomatic period of AD. NK cells participate in innate immune surveillance against intracellular pathogens and malignancy but their role in AD remains controversial. We have investigated changes in peripheral NK cell phenotypes and functions in amnestic mild cognitive impairment (aMCI, n = 10), patients with mild AD (mAD, n = 11), and healthy elderly controls (n = 10). Patients selected according to NINCDS-ADRDA criteria were classified using neuropsychological assessment tests. Phenotype analysis revealed differences in expression of CD16 (increased in mAD), NKG2A (decreased in aMCI), and TLR2 and TLR9 (both decreased in mAD). Functional assays revealed that NK cell killing activity and degranulation (CD107 expression) were unchanged in the three groups. In contrast, expression of the CD95 receptor was increased in aMCI and mAD. Granzyme B expression and cytokine production (TNFalpha, IFNgamma) were increased in aMCI but not in mAD. CCL19- but not CCL21-dependent chemotaxis was decreased in aMCI and mAD, despite the fact that CCR7 expression was increased in aMCI. Our data suggest that the number of alterations observed in peripheral NK cells in aMCI represent an activation state compared to mAD patients and that may reflect an active immune response against a still to be defined aggression. PMID- 25720399 TI - Common Pesticide, Dichlorodiphenyltrichloroethane (DDT), Increases Amyloid-beta Levels by Impairing the Function of ABCA1 and IDE: Implication for Alzheimer's Disease. AB - While early-onset familial Alzheimer's disease (AD) is caused by a genetic mutation, the vast majority of late-onset AD is likely caused by the combination of genetic and environmental factors. Unlike genetic studies, potential environmental factors affecting AD pathogenesis have not yet been thoroughly investigated. Among environmental factors, pesticides seem to be one of critical environmental contributors to late-onset AD. Recent studies reported that the serum and brains of AD patients have dramatically higher levels of a metabolite of dichlorodiphenyltrichloroethane (DDT). While these epidemiological studies provided initial clues to the environmental risks potentially contributing to disease pathogenesis, a functional approach is required to determine whether they actually have a causal role in disease development. In our study, we addressed this critical knowledge gap by investigating possible mechanisms by which DDT affects amyloid-beta (Abeta) levels. We treated H4-AbetaPPswe or H4 cells with DDT to analyze its effect on Abeta metabolism using Abeta production, clearance, and degradation assays. We found that DDT significantly increased the levels of amyloid-beta protein precursor (AbetaPP) and beta-site AbetaPP-cleaving enzyme1 (BACE1), affecting Abeta synthesis pathway in H4-AbetaPPswe cells. Additionally, DDT impaired the clearance and extracellular degradation of Abeta peptides. Most importantly, we identified for the first time that ATP-binding cassette transporter A1 (ABCA1) and insulin-degrading enzyme (IDE) are the downstream target genes adversely affected by DDT. Our findings provide insight into the molecular mechanisms by which DDT exposure may increase the risk of AD, and it further supports that ABCA1 and IDE may be potential therapeutic targets. PMID- 25720400 TI - Association between Sleep-Disordered Breathing and Neuropsychological Performance in Older Adults with Mild Cognitive Impairment. AB - Sleep-disordered breathing in middle-age and older adults has been shown to be linked to a range of neuropsychological deficits, but the extent to which these relationships are evident in older people 'at risk' of developing dementia in unknown. In this study, we aimed to determine whether changes in sleep-disordered breathing and sleep fragmentation during nocturnal sleep were related to neuropsychological dysfunction in patients with mild cognitive impairment. Forty six patients with MCI (mean age = 66.1 y, sd = 8.4) and 40 age-matched healthy controls (mean age = 63.5 y, sd = 8.9) underwent psychiatric, medical, and neuropsychological assessment, in addition to overnight polysomnography and self report questionnaires. Measures of hypoxemia, sleep fragmentation, and sleep quality were derived including the apnoea-hypopnea index, oxygen desaturation index, percentage of total sleep time spent below 90% oxygen saturation, arousal index, sleep efficiency, and wake after sleep onset. Patients with MCI did not differ from healthy aging on any measure of sleep-disordered breathing or sleep fragmentation. In MCI, processing speed was negatively correlated with greater sleep time spent below 90% oxygen saturation and a higher apnoea-hypopnea index. In contrast, in the healthy aging, processing speed was negatively correlated with an increased oxygen desaturation index and the arousal index. Sleep disordered breathing is evident in both healthy aging and MCI with associated decrements in processing speed. Future research is needed to determine the unique and synergistic effects of these differential associations, their potential to inform disease trajectory, and possible therapeutic interventions. PMID- 25720401 TI - A Simple Tool to Reach Populations at Risk for Developing Dementia and Alzheimer's Disease. AB - Identification of individuals at high risk for developing dementia and Alzheimer's disease is a major challenge. A "memory fair" is an enjoyable and affordable tool designed to reach local population at risk, mainly those with subjective cognitive impairment (SCI) or mild cognitive impairment. The fair included a free cognitive assessment and presentation on the importance of sleep, physical activity, cognitive training, and risk-factors and provided personalized recommendations. 160 individuals completed the evaluation (69.97 +/- 9.01 y, 83% women). Average Montreal Cognitive Assessment Score (MoCA) was 24.73 +/- 3.71. Six percent reported SCI and an upper estimate of mild cognitive impairment prevalence was 30.7% . SCI was found to be a sensitive predictor for MoCA <26. PMID- 25720402 TI - Fully Automated Atlas-Based Hippocampus Volumetry for Clinical Routine: Validation in Subjects with Mild Cognitive Impairment from the ADNI Cohort. AB - Hippocampus volumetry based on magnetic resonance imaging (MRI) has not yet been translated into everyday clinical diagnostic patient care, at least in part due to limited availability of appropriate software tools. In the present study, we evaluate a fully-automated and computationally efficient processing pipeline for atlas based hippocampal volumetry using freely available Statistical Parametric Mapping (SPM) software in 198 amnestic mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). Subjects were grouped into MCI stable and MCI to probable Alzheimer's disease (AD) converters according to follow-up diagnoses at 12, 24, and 36 months. Hippocampal grey matter volume (HGMV) was obtained from baseline T1-weighted MRI and then corrected for total intracranial volume and age. Average processing time per subject was less than 4 minutes on a standard PC. The area under the receiver operator characteristic curve of the corrected HGMV for identification of MCI to probable AD converters within 12, 24, and 36 months was 0.78, 0.72, and 0.71, respectively. Thus, hippocampal volume computed with the fully-automated processing pipeline provides similar power for prediction of MCI to probable AD conversion as computationally more expensive methods. The whole processing pipeline has been made freely available as an SPM8 toolbox. It is easily set up and integrated into everyday clinical patient care. PMID- 25720403 TI - PKA-CREB Signaling Suppresses Tau Transcription. AB - Accumulated and abnormally hyperphosphorylated tau aggregates into neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). cAMP response binding protein (CREB), a constitutively expressed nuclear transcription factor, is a critical component of the neuroprotective transcriptional network. Numerous studies have shown that cAMP-dependent protein kinase (PKA)-CREB signaling is down-regulated in AD brain. In the present study, we studied the regulation of tau expression by PKA-CREB signaling. We found that the promoter of human tau gene contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2, and CRE3. Overexpression of CREB or activation of PKA significantly suppressed the expression of tau at mRNA and protein levels. ChIP (Chromatin immunoprecipitation) and EMSA (electrophoretic mobility shift assay) revealed that CREB interacted with these three CRE cis-element and that CRE1, among the three elements, plays the most important role in the suppression of tau expression. Furthermore, upregulation of PKA-CREB signaling suppressed expression of endogenous tau. Collectively, these results suggest that PKA-CREB signaling down-regulates tau expression by reducing tau transcription, which may provide a novel insight into the regulation of tau expression and a molecular mechanism involved in tau pathogenesis in AD. PMID- 25720404 TI - Nasal Application of the Galantamine Pro-drug Memogain Slows Down Plaque Deposition and Ameliorates Behavior in 5X Familial Alzheimer's Disease Mice. AB - The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimer's Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid-beta (Abeta) plaque deposition in the brain. Chronic intranasal dosage of 6 mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine. PMID- 25720405 TI - MTRNR2L12: A Candidate Blood Marker of Early Alzheimer's Disease-Like Dementia in Adults with Down Syndrome. AB - Morphological abnormalities observed typically in the brains of adults with Down syndrome are identical with those present in patients with Alzheimer's disease. However, only some adults with Down syndrome suffer from early dementia, whereas others remain unaffected. We aimed to identify the genomic background responsible for this observation. We performed cognitive assessment and genome expression analysis of blood mononuclear cells in seniors with Down syndrome. Unaffected elderly patients and younger patients with severe cognitive disability or cognitive deterioration differed significantly with regard to the MTRNR2L12 gene. Our findings suggest the potential value of this gene as a blood marker of early dementia in individuals with Down syndrome. PMID- 25720406 TI - Amyloid-beta and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus. AB - BACKGROUND: Amyloid-beta (Abeta1 - 42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Abeta decreases with increasing age and advanced Abeta pathology as seen similarly in CSF. OBJECTIVE: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). METHODS: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. RESULTS: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Abeta1 - 42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Abeta1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Abeta1 - 42 levels than those six without amyloid pathology. CONCLUSIONS: This is the first study to report ISF Abeta and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease. PMID- 25720407 TI - Higher Levels of Oxidized Low Density Lipoproteins in Alzheimer's Disease Patients: Roles for Platelet Activating Factor Acetyl Hydrolase and Paraoxonase 1. AB - Alzheimer's disease (AD) is associated with oxidative damage of low density lipoproteins (ox-LDL). In order to investigate whether higher levels of ox-LDL are related to alterations of the activity of enzymes involved in lipid metabolism, we studied the activity of paraoxonase-1 (PON1) and platelet activating factor acetylhydrolase (PAF-AH) in AD patients and the relationship between biochemical markers and severity of the disease. Levels of ox-LDL, PON1 (paraoxonase, arylesterase, and lactonase activities), and PAF-AH activity were evaluated in plasma from 49 patients affected by AD and from 34 control subjects matched for gender and age. Our results demonstrated alterations in the activities of PON1 and PAF-AH in AD patients compared to controls and showed, for the first time, a relationship between the activities of these enzymes, ox-LDL levels, and severity of the disease. A significant negative correlation was observed between the ratio PON1/PAF-AH and ox-LDL. Whatever the causes that contribute to a systemic oxidative stress in AD, our results have shown that AD patients exhibit higher PAF-AH activity than control subjects and higher ox-LDL. This phenomenon, in combination with diminished PON1 in these patients and, consequently, the relatively lower ratio PON1/PAF-AH activity, could contribute to inflammation and oxidative stress of plasma lipoproteins. PMID- 25720409 TI - The 5XFAD Mouse Model of Alzheimer's Disease Exhibits an Age-Dependent Increase in Anti-Ceramide IgG and Exogenous Administration of Ceramide Further Increases Anti-Ceramide Titers and Amyloid Plaque Burden. AB - We present evidence that 5XFAD Alzheimer's disease model mice develop an age dependent increase in antibodies against ceramide, suggesting involvement of autoimmunity against ceramide in Alzheimer's disease pathology. To test this, we increased serum anti-ceramide IgG (2-fold) by ceramide administration and analyzed amyloid plaque formation in 5XFAD mice. There were no differences in soluble or total amyloid-beta levels. However, females receiving ceramide had increased plaque burden (number, area, and size) compared to controls. Ceramide treated mice showed an increase of serum exosomes (up to 3-fold using Alix as marker), suggesting that systemic anti-ceramide IgG and exosome levels are correlated with enhanced plaque formation. PMID- 25720408 TI - Turning on the Light Within: Subcortical Nuclei of the Isodentritic Core and their Role in Alzheimer's Disease Pathogenesis. AB - Pharmacological interventions in Alzheimer's disease (AD) are likely to be more efficacious if administered early in the course of the disease, foregoing the spread of irreversible changes in the brain. Research findings underline an early vulnerability of the isodendritic core (IC) network to AD neurofibrillary lesions. The IC constitutes a phylogenetically conserved subcortical system including the locus coeruleus in pons, dorsal raphe nucleus, and substantia nigra in the midbrain, and nucleus basalis of Meynert in basal forebrain. Through their ascending projections to the cortex, the IC neurons regulate homeostasis and behavior by synthesizing aminergic and cholinergic neurotransmitters. Here we reviewed the evidence demonstrating that neurons of the IC system show neurofibrillary tangles in the earliest stages of AD, prior to cortical pathology, and how this involvement may explain pre-amnestic symptoms, including depression, agitation, and sleep disturbances in AD patients. In fact, clinical and animal studies show a significant reduction of AD cognitive and behavioral symptoms following replenishment of neurotransmitters associated with the IC network. Therefore, the IC network represents a unique candidate for viable therapeutic intervention and should become a high priority for research in AD. PMID- 25720410 TI - Impaired Cerebral Hemodynamics and Cognitive Performance in Patients with Atherothrombotic Disease. AB - BACKGROUND AND OBJECTIVE: Patients with pre-existing atherothrombotic disease are prone to cognitive impairment. We tested whether impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular hemodynamic dysfunction, is associated with poorer cognitive scores among patients with and without carotid large-vessel disease. METHODS: A subgroup of non-demented patients with chronic coronary heart disease followed-up for 15 +/- 3 years was assessed for cognitive function (Neurotrax Computerized Cognitive Battery; scaled to an IQ style scale with a mean of 100 and SD of 15) and for CVR using the breath-holding index (BHI) with transcranial Doppler and for carotid plaques using ultrasound. We assessed cognitive scores in specific domains in patients with and without impaired CVR (BHI <0.47; bottom quartile). RESULTS: Among 415 patients (mean age 71.7 +/- 6.2 y) median BHI was 0.73 (25% 0.47, 75% 1.04). Impaired CVR was associated with diabetes and peripheral artery disease. Adjusting for potential confounders, impaired CVR was associated with lower executive function (p = 0.02) and global cognitive scores (p = 0.04). There was an interaction with carotid large-vessel disease for executive function (p < 0.001), memory (p = 0.03), and global cognitive scores (p = 0.02). In the carotid large-vessel disease group there were pronounced differences by CVR status in executive function (p < 0.001), memory (p = 0.02), attention (p < 0.001), and global cognitive scores (p = 0.001). CONCLUSION: Impaired CVR, a marker of cerebral microvascular dysfunction, is associated with poorer cognitive functions and in particular executive dysfunction among non-demented patients with concomitant carotid large-vessel disease. These findings emphasize the importance of cerebral hemodynamics in cognitive performance. PMID- 25720411 TI - Loss of TDP-43 Inhibits Amyotrophic Lateral Sclerosis-Linked Mutant SOD1 Aggresome Formation in an HDAC6-Dependent Manner. AB - Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, and progressive neurodegenerative disorder with no cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS; and aggresome formation of misfolded SOD1 is closely associated with ALS pathogenesis. HDAC6, one of the histone deacetylase family members, has already been demonstrated to play an important role in regulating aggresome formation of misfolded proteins and protecting cells against the toxicity induced by misfolded proteins. In this study, we found that in a cellular model with impaired proteasome activity, the TAR DNA-binding protein 43, which is closely linked with ALS and associated with various neurodegenerative disorders such as frontotemporal lobar degeneration, Alzheimer's disease, and Parkinson's disease, can regulate mutant SOD1 aggresome formation through an HDAC6-dependent manner. TDP-43 deficiency did not affect poly-ubiquitination of mutant SOD1, whereas it greatly decreased the expression level of HDAC6, which is required for aggresome formation of ALS-linked mutant SOD1. Moreover, overexpression of siRNA-resistant HDAC6 restored mutant SOD1 aggresome formation in TDP-43-knockdown cells. Thus, our data provide evidence that TDP-43 plays an important role in mutant SOD1 aggresome formation through its regulation of HDAC6. PMID- 25720413 TI - From Neurodegeneration to Brain Health: An Integrated Approach. AB - The term "brain health" integrates general health and well-being with cognitive fitness, in the context of an environment that includes the spectrum of positive and negative factors affecting the individual. Brain health incorporates the effects of neurodegeneration in an ecological sense and the effects of environment and health practices on brain function. It also provides a framework for understanding and maximizing cognitive function across the lifespan. Despite decades of research into the pathogenesis of neurodegenerative disorders, our understanding of how to treat them is relatively rudimentary. Unidimensional approaches, such as medication monotherapies, have generally produced negative results in treatment trials. New integrative paradigms that cut across the molecular and cellular level to the individual and societal level may provide new approaches to understand and treat these disorders. This report on proceedings of a multi-disciplinary conference held in Cleveland, Ohio, in October 2013 summarizes research progress in understanding neurodegenerative disorders in a brain health context. A new "brain health" paradigm is essential to finally understand neurodegenerative disorders such as Alzheimer's disease and overcome the relative stand-still in therapeutics research that has characterized the last decade. The authors summarize progress in these emerging areas with the aim of producing new integrated scientific models for understanding brain health, potentially modifying disease course and advancing care for individuals and families affected by neurodegenerative conditions. PMID- 25720412 TI - Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer's Disease. AB - The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 +/- 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p < 0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5*10 -8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person's increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease. PMID- 25720415 TI - Perfusion Index in Preterm Infants during the First 3 Days of Life: Reference Values and Relation with Clinical Variables. AB - BACKGROUND: The perfusion index (PI) derived from pulse oximetry readings represents the ratio of pulsatile (arterial blood) and nonpulsatile contributors to infrared light absorption. PI has been shown to correlate with cardiac performance. In theory, PI is readily available on every pulse oximeter; therefore, no additional sensors or infant handling are required. Currently, reference values are lacking in (preterm) neonates and the association with common clinical conditions is unclear. OBJECTIVES: To establish reference values for the PI in premature infants and at the same time determine the influence of common clinical conditions. METHODS: PI was prospectively monitored on the lower limb for 72 h in 311 neonates born with a gestational age <32 weeks between January 2011 and December 2013. Longitudinal mixed-effects modeling was used. Linear, quadratic, and cubic models were explored. Main effects and interactions were investigated. RESULTS: A squared model (0-24 h) followed by a linear model (24-72 h) provided the best fit of the data. PI was lowest around 12-18 h after birth and showed a steady increase thereafter. PI was positively related with female gender, gestational age, and pulse pressure. Negative associations were found with SIMV/HFOV ventilation, dopamine administration, mean arterial blood pressure, and arterial oxygen saturation. Although more complex, the general association with a patent ductus arteriosus was positive. CONCLUSION: PI varied according to several clinical conditions. The association with common clinical factors suggests that PI might be used for monitoring neonatal hemodynamics and possibly as an additional guidance for interventions. PMID- 25720416 TI - Glycyrrhizin ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice and inhibits TNF-alpha-induced ICAM-1 expression via NF-kappaB/MAPK in HaCaT cells. AB - BACKGROUND/AIM: Glycyrrhizin (GL) is an important derivative of certain herbal medicines used in Asian countries. Currently, GL is used to treat hepatitis and allergic disease worldwide because of its anti-viral and anti-allergy effects. In addition to these prominent functions, GL likely regulates cellular functions such as tumor cell growth and cellular immunity. However, how GL affects the keratinocyte inflammation response remains poorly understood. The current paper investigates the effect of GL on psoriasis and explores the mechanisms involved. METHODS: We used an in vitro cell model of tumor necrosis factor (TNF)-alpha induced keratinocyte inflammation and the topical application of imiquimod (IMQ) using an animal model (mouse skin) of IMQ-induced psoriasis-like inflammation (IPI) to investigate the effect of GL on skin inflammation. Cell viability was analyzed using the Cell Counting Kit-8 (CCK8). Carboxyfluorescein succinimidyl ester (CFSE) labeling was used to trace monocyte adherence to keratinocytes. A Western blot analysis was used to detect the expression of intercellular adhesion molecule 1 (ICAM-1) and the activation of the nuclear factor (NF)-kappaB/mitogen activated protein kinase (MAPK) signaling pathway. A modified version of the Psoriasis Area Severity Index (PASI) was used to monitor disease severity. Hematoxylin and eosin (H&E) staining was used to observe pathological changes. An immunohistochemistry (IHC) analysis was used to detect ICAM-1 expression in mouse skin. RESULTS: GL treatment significantly reduced the levels of ICAM-1 in TNF alpha-stimulated HaCaT cells, inhibited subsequent monocyte adhesion to keratinocytes, and suppressed the nuclear translation and phosphorylation of p65 following the degradation of inhibitor kappaB (IkappaB). GL treatment blocked the phosphorylation of extracellular signal-regulated kinase (ERK)/p38 MAPK. GL effectively delayed the onset of IPI in mice and ameliorated ongoing IPI, thereby reducing ICAM-1 expression in epidermal tissues. CONCLUSIONS: These results demonstrate that GL treatment ameliorates skin inflammation by inhibiting ICAM-1 expression via interference with the ERK/p38 MAPK and NF-kappaB signaling pathways in keratinocytes. Therefore, GL can be used as an anti-psoriasis drug. PMID- 25720417 TI - Moderating effects of voluntariness on the actual use of electronic health records for allied health professionals. AB - BACKGROUND: Mandatory versus voluntary requirement has moderating effect on a person's intention to use a new information technology. Studies have shown that the use of technology in health care settings is predicted by perceived ease of use, perceived usefulness, social influence, facilitating conditions, and attitude towards computer. These factors have different effects on mandatory versus voluntary environment of use. However, the degree and direction of moderating effect of voluntariness on these factors remain inconclusive. OBJECTIVE: This study aimed to examine the moderating effect of voluntariness on the actual use of an electronic health record (EHR) designed for use by allied health professionals in Hong Kong. Specifically, this study explored and compared the moderating effects of voluntariness on factors organized into technology, implementation, and individual contexts. METHODS: Physiotherapists who had taken part in the implementation of a new EHR were invited to complete a survey. The survey included questions that measured the levels of voluntariness, technology acceptance and use, and attitude towards technology. Multiple logistic regressions were conducted to identify factors associated with actual use of a compulsory module and a noncompulsory module of the EHR. RESULTS: In total, there were 93 participants in the study. All of them had access to the noncompulsory module, the e-Progress Note, to record progress notes of their patients. Out of the 93 participants, 57 (62%) were required to use a compulsory module, the e Registration, to register patient attendance. In the low voluntariness environment, Actual Use was associated with Effort Expectancy (mean score of users 3.51, SD 0.43; mean score of non-users 3.21, SD 0.31; P=.03). Effort Expectancy measured the perceived ease of use and was a variable in the technology context. The variables in the implementation and individual contexts did not show a difference between the two groups. In the high voluntariness environment, the mean score of Actual Use was associated with Performance Expectancy (P=.03), Organization Facilitating Condition (P=.02), and Interest in Internet and Computer (P=.052) in univariate analyses. The only variable left in the logistic regression model was Organization Facilitating Conditions (mean score of users 3.82, SD 0.35; mean score of non-users 3.40, SD 0.48; P=.03), a variable in the implementation context. The factors affecting actual use were different in mandatory and voluntary environments, indicating a moderating effect of voluntariness. CONCLUSIONS: The results of this study have provided preliminary supports of moderating effects of voluntariness on the use of EHR by allied health professionals. Different factors were identified to be associated with actual use: (1) Ease of Use in mandatory environment, and (2) Organization Facilitating Conditions in voluntary environment. More studies are needed to examine the direction of moderating effects. The findings of this study have potential practical implications. In sum, voluntariness can be a highly relevant and important moderating factor not to be ignored in the design and evaluation of EHR. PMID- 25720418 TI - Outcomes and Postoperative Complications of Robot-Assisted Laparoscopic Hysterosacropexy: Initial Experience. AB - BACKGROUND: Pelvic organ prolapse is a common condition, affecting about 50% of women with children. The aim of our study was to evaluate results and complication rates in a consecutive series of female patients undergoing robot assisted laparoscopic hysterosacropexy (RALHSP). MATERIALS AND METHODS: We performed a medical record review of female patients with uterine prolapse who had consecutively undergone RALHSP from February 2010 to 2013 at our department. RESULTS: Fifteen patients were included in the analysis. All patients had uterine prolapse stage >= II and urodynamic stress urinary incontinence. The mean age was 58.26 years. According to the Clavien-Dindo system, 4 out of 15 patients (26.6%) had grade 1 early complications and 1 patient had a grade 2 complication. At a median follow-up of 36 months, there was a significant prolapse relapse rate of 20% (3/15). CONCLUSION: In our hands RALHSP is easy to perform, with satisfying mid-term outcomes and a low complication rate. PMID- 25720414 TI - Is Vasomotion in Cerebral Arteries Impaired in Alzheimer's Disease? AB - A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer's disease (AD). Cerebral hypoperfusion and blood brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-beta (Abeta) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter damage. Vasomotion- the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds including the brain- is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of Abeta clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of Abeta clearance. In spite of potential clinical interest, studies addressing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. Abeta and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further Abeta and oxidative stress accumulation. PMID- 25720419 TI - First-rank symptoms and premorbid adjustment in young individuals at increased risk of developing psychosis. AB - BACKGROUND: Individuals at clinical high risk (CHR) for psychosis represent a heterogeneous group with a high rate of comorbid psychiatric disorders. There is little information on whether certain qualitative aspects of psychotic symptoms among CHR individuals may be predictive of future psychosis. This study focused on describing the prevalence of first-rank symptoms (FRS) among a sample of CHR individuals and its association with future transition to psychosis and, from a neurodevelopmental perspective, the level of adjustment of individuals at CHR during their childhood was also analysed. SAMPLING AND METHODS: Participants comprised 60 individuals at CHR (according to the Comprehensive Assessment of At Risk Mental States, CAARMS) at the time of their referral to an early intervention service and 60 healthy volunteers (HVs). All subjects were assessed by senior research clinicians using the Mini International Neuropsychiatric Interview (MINI), and the Positive and Negative Syndrome Scale (PANSS). FRS were defined according to Kurt Schneider's original classification, and information was collected from PANSS, CAARMS and clinical reports. Early premorbid functioning was measured using the Premorbid Adjustment Scale (PAS). We grouped individuals by number and type of FRS and analysed transitions to full-blown psychosis over a 2-year follow-up period. We also correlated the general social and functional adjustment of these individuals during their childhood (6-11 years of age) with the future development of mental states at CHR and FRS. RESULTS: Over 69% of CHR individuals had more than one DSM-IV psychiatric diagnosis, mainly within the affective and anxiety diagnostic spectra. At least one FRS was present in 43.3% of CHR individuals, and 21.6% of these had more than one. Auditory hallucinations and passivity experiences were the most commonly reported. Only 10% of individuals at CHR made a transition to first-episode psychosis (FEP) over 2 years and, except for passivity experiences, the presence of one or more FRS was not significantly associated with the transition to FEP. CHR individuals, especially those with FRS, had poorer premorbid functioning and adjustment as children across educational, social and peer relationship domains than HVs. However, this was not associated with FEP 2 years later. CONCLUSIONS: FRS might not be indicators of psychosis alone but of different psychiatric disorders. In line with the neurodevelopmental model of psychosis, individuals at CHR might be exhibiting several vulnerability traits and manifestations of abnormal developmental processes that might predict a future psychiatric disorder and/or long-term impairment. PMID- 25720420 TI - Self-assembly and biophysical properties of gemini 3-alkyloxypyridinium amphiphiles with a hydroxyl-substituted spacer. AB - New gemini pyridinium amphiphiles having alkyl chain lengths of C10, C12, C14 , and C16 and appended with hydroxyl-substituted spacers have been synthesized, characterized, and investigated for their self-assembly as well as adsorption behavior by state-of-the-art techniques such as conductometry, tensiometry, isothermal titration calorimetry (ITC), and spectrofluorometry. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) have provided excellent acumen with respect to the micellar size distribution of investigated dicationics in aqueous media. Furthermore, the interaction of these dicationics with plasmid DNA, at different charge ratios (N/P), has been studied by DLS, agarose gel electrophoresis, and ethidium bromide exclusion measurements. The cytotoxicity of these geminis has been evaluated by using an MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on BV2 (microglial) and C6 glioma cell lines. It was found that the varying alkyl chain length, fashioned by ether linkage close to the headgroup, and the presence of a polar linker significantly altered the physicochemical properties of these new dicationics as compared to the properties of nonfunctionalized gemini surfactants. PMID- 25720421 TI - Determinants of platelet-leukocyte aggregation and platelet activation in stroke. AB - BACKGROUND: Platelet-leukocyte aggregation (PLA) and platelet activation are found to be on the higher side in ischemic stroke patients. The correlation of PLA with clinical features has not been intensively investigated and the influence of genetic factors on PLA is still unexplored. The interaction of platelets with leukocytes is mainly determined by the proteins encoded by six genes: P-Selectin (SELP encodes CD62P) on the thrombocyte binding to P-Selectin Glycoprotein-Ligand-1 (PSGL1) on the leukocyte, intracellular-adhesion-molecule 2 (ICAM2) interacting with Integrin alpha M (ITGAM) and Glycoprotein 1b-alpha (GP1BA) binding to Integrin alpha L (ITGAL). METHODS: Seventy-nine patients with acute ischemic stroke and 151 controls without vascular disease from a single German center were enrolled. A neurologist and a neuroradiologist ascertained clinical and radiological features. PLA and platelet activation were analyzed using flow cytometry with various antibodies. Coding as well as tagging SNPs in six genes determining PLA were genotyped. Three groups of parameters were correlated with each other: (i) clinical and radiological parameters, (ii) laboratory parameters, (iii) genetic parameters. For the comparisons, robust nonparametric statistical tests were applicable. RESULTS: PLA and platelet activation were higher in ischemic stroke patients compared to controls. Both, anticoagulant and antiplatelet treatment in the patient group affected platelet activation but not PLA. PLA correlated weakly with measures of stroke severity but not with thrombus length or stroke etiology. The association of SNP rs2228315 in the P-Selectin Glycoprotein Ligand-1-gene (PSGL1) with ischemic stroke and platelet activation was significant before correction for multiple testing while a trend was observed for the association with PLA. Regression analysis revealed that (i) platelet activation was an independent determinant of stroke, (ii) that PLA correlated with stroke, sex, age and platelet activation and (iii) that platelet activation correlated only with stroke. None of the SNPs survived in the regression analysis for stroke, PLA or platelet activation as dependent variables. CONCLUSIONS: The most important result of our study is that PLA and platelet activation are independent of other vascular risk factors correlated with stroke in our sample. In addition, we identified the missense SNP rs2228315 in the PSGL1-gene as a candidate polymorphism for ischemic stroke-related PLA. Association between this SNP and stroke as well as coronary artery disease has also been shown by two other studies. PMID- 25720422 TI - Management of Gastrointestinal Stromal Tumour: Current Practices and Visions for the Future. AB - Gastrointestinal stromal tumour (GIST), while relatively rare, is the most common mesenchymal tumour of the gastrointestinal tract. These tumours are largely resistant to cytotoxic chemotherapy and, in the past, were typically managed surgically. However, as a result of the identification of activating mutations in the proto-oncogene KIT and the development of compounds that inhibit the KIT receptor tyrosine kinase, GISTs have, in the last 14 years, become the archetype of a targeted agent-responsive tumour. Due to the almost continual emergence of new data from clinical trials and other studies on GIST diagnosis and treatment, the management of this disease requires regular review. The 2013 ArcheoloGIST summit was convened in Prague, Czech Republic. Interaction between attending physicians and the expert faculty was a core component of the summit. The current article is based on discussions held during two interactive sessions at ArcheoloGIST 2013 in which the authors aimed to: (1) reach a consensus on the current management of GIST and (2) provide a vision for the future diagnosis and treatment of this disease. PMID- 25720423 TI - Should we use the serum vaspin level for the diagnosis and/or prognosis of subarachnoid hemorrhage? AB - BACKGROUND: We aimed to investigate whether vaspin, a member of the serine protease family, could be used as a marker for the severity and prognosis of subarachnoid hemorrhage (SAH). METHODS: Fifty-two consecutive patients (mean age, 51.46+/-3.2 years; 61.5% male) admitted to the emergency service of our hospital and hospitalized at our clinic with the diagnosis of aneurysmal SAH between 2012 and 2014 were included in the study and followed up for six months for outcome. The control group consisted of 52 healthy individuals of similar age and gender. RESULTS: During the 6-month follow-up, 8 of 52 patients died, and 18 (34.6%) patients had poor the Glasgow Outcome Score (GOS) scores. In 20 (38.46%) patients, acute hydrocephalus developed, and external ventricular drainage was performed. In the study group, the mean vaspin level was significantly higher than control group (157.88+/-33.6 pg/mL and 109.59+/-45.68 pg/mL, respectively; P<0.01). The mean vaspin level was 215.18+/-12.36 pg/mL in the non-survival group and 147.47+/-24.43 pg/mL in the survival group. Furthermore, it was 195.99+/ 21.10 pg/mL in patients with poor outcome in terms of GOS, and 137.71+/-17.61 pg/mL in those with good outcome. The vaspin levels significantly increased with worsening of GOS, the World Federation of Neurological Surgeons (WFNS) grading system, and Fisher scores and increasing plasma C-reactive protein levels (P<0.01 for all). CONCLUSIONS: In conclusion, vaspin can play a role as a new marker in the diagnosis, severity assessment, and prognosis of SAH. PMID- 25720424 TI - Narrative discourse impairments in Persian-speaking persons with traumatic brain injury: a pilot study. AB - OBJECTIVE: Studies have shown the presence of narrative discourse difficulties in persons with traumatic brain injury (TBI), even in those who do not suffer from aphasia. Yet, there still exist inconsistencies between the results of different studies, in particular at the microlinguistic level. Moreover, a limited number of languages have been studied in this regard. Therefore, this study aimed at examining these skills in Persian-speaking individuals with TBI. The purpose of this pilot study was to analyse the microlinguistic and macrolinguistic skills of these individuals to determine impaired linguistic measures at different levels of narrative discourse. PARTICIPANTS AND METHODS: Fourteen non-aphasic Persian speaking persons with TBI (9 with severe TBI and 5 with moderate TBI), aged 19-40 years (mean = 25.84, SD = 5.69), and 61 age-matched healthy adults completed a narrative task. Measures of language productivity, clause density, verbal error ratio, and cohesion ratio were calculated. Also, test-retest and inter-rater reliability coefficients were analysed. RESULTS: The TBI group was impaired in some microlinguistic and all macrolinguistic measures compared to their control peers. CONCLUSION: The results of this study suggest that multi-level narrative discourse analyses of Persian-speaking individuals with TBI may be useful for speech/language pathologists wishing to evaluate communication disorders in persons with TBI. PMID- 25720425 TI - Is Micropercutaneous Nephrolithotomy Technique Really Efficacicous for the Treatment of Moderate Size Renal Calculi? Yes. AB - OBJECTIVE: To present our clinical experiences with micropercutaneous nephrolithotomy in the treatment of moderate-sized renal calculi from a single center. METHODS: We retrospectively evaluated the patients with moderate-sized renal calculi who underwent micro-percutaneous nephrolithotomy between December 2012 and Septermber 2013. RESULTS: A total of 68 patients and 70 renal units underwent microperc procedure. Mean age of patients was 41.4 +/- 18.8. The mean stone size was 122 +/- 83 mm(2). The operations were performed under spinal anesthesia in 89.7% of the patients. Stone-free rate was 95.7 % (67/70). Clinically significant residual fragments were observed in three patients. The average duration of operation and mean fluoroscopy time was 40 +/- 23 min and 108 +/- 72 s, respectively. The mean postoperative drop in hemoglobin was 0.95 +/- 0.7 while no patient required blood transfusion. Patients were discharged after an average hospitalization time of 27.5 +/- 12.4 h. A total of 4 complications (5.7%), including urinary tract infection (Clavien I) in one patient and renal colics requiring stent insertion (Clavien IIIa) in three patients, were observed postoperatively. CONCLUSION: Microperc technique is safe, feasible, and efficacious. We suggest that micro-percutaneous nephrolithotomy should be considered for the treatment of moderate-sized renal stones as an alternative to SWL and RIRS failures and also may be considered even primarily. PMID- 25720426 TI - Intrauterine Growth Restriction: Effects on Neural Precursor Cell Proliferation and Angiogenesis in the Foetal Subventricular Zone. AB - Exposure to adverse prenatal factors can result in abnormal brain development, contributing to the aetiology of several neurological disorders. Intrauterine insults could occur during neurogenesis and gliogenesis, disrupting these events. Here we investigate the effects of chronic placental insufficiency (CPI) on cell proliferation and the microenvironment in the subventricular zone (SVZ). At 30 days of gestation (DG; term ~67 DG), CPI was induced in pregnant guinea pigs via unilateral uterine artery ligation to produce growth-restricted (GR) foetuses (n = 7); controls (n = 6) were from the unoperated horn. At 60 DG, foetal brains were stained immunohistochemically to identify proliferating cells (Ki67), immature neurons (polysialylated neuronal cell adhesion molecule), astrocytes (glial fibrillary acidic protein), microglia (ionised calcium-binding adaptor molecule-1, Iba-1) and the microvasculature (von Willebrand factor) in the SVZ. There was no overall difference (p > 0.05) in the total number of Ki67 immunoreactive (IR) cells, the percentage of SVZ occupied by blood vessels or the density of Iba-1-IR microglia in control versus GR foetuses. However, regression analysis across both groups revealed that both the number of Ki67-IR cells and the percentage of SVZ occupied by blood vessels in the ventral SVZ were negatively correlated (p < 0.05) with brain weight. Furthermore, in the SVZ (dorsal and ventral) the density of blood vessels positively correlated (p < 0.05) with the number of Ki67-IR cells. Double-labelling immunofluorescence suggested that the majority of proliferating cells were likely to be neural precursor cells. Thus, we have demonstrated an association between angiogenesis and neurogenesis in the foetal neurogenic niche and have identified a window of opportunity for the administration of trophic support to enhance a neuroregenerative response. PMID- 25720427 TI - Moral Injury in Traumatized Refugees. PMID- 25720428 TI - Increased endothelial progenitor cell circulation and VEGF production in a rat model of noise-induced hearing loss. AB - CONCLUSIONS: The vascular endothelial growth factor (VEGF)-mediated mechanism of endothelial progenitor cell (EPC) mobilization, migration, and differentiation may occur in response to noise-induced acoustic trauma of the cochlea, leading to the protection of cochlear function. OBJECTIVE: The purpose of this study was to analyze changes in the cochlear vessel under an intensive noise environment. METHODS: Sixty male Sprague-Dawley rats were randomly divided into six groups. Acoustic trauma was induced by 120 dB SPL white noise for 4 h. Auditory function was evaluated by the auditory brainstem response threshold. Morphological changes of the cochleae, the expression of VEGF, and the circulation of EPCs in the peripheral blood were studied by immunohistochemistry, Western blotting analysis, scanning electron microscopy, and flow cytometry. RESULTS: Vascular recovery of the cochlea began after noise exposure. The change in the number of EPCs was consistent with the expression of VEGF at different time points after noise exposure. We propose that VEGF evokes specific permeable and chemotactic effects on the vascular endothelial cells. These effects can mobilize EPCs into the peripheral blood, leading the EPCs to target damaged sites and to exert a neoangiogenic effect. PMID- 25720434 TI - Lenvatinib approved for certain thyroid cancers. AB - The FDA approved lenvatinib to treat progressive, differentiated thyroid cancer, potentially offering the most effective treatment to date for a subset of thyroid cancer patients who do not respond to standard therapy. PMID- 25720435 TI - Shikonin causes cell-cycle arrest and induces apoptosis by regulating the EGFR-NF kappaB signalling pathway in human epidermoid carcinoma A431 cells. AB - Shikonin, a naphthoquinone pigment isolated from the Chinese herbal Zicao, has been shown to exhibit antioxidant and anticancer effects. In the present study, we investigated the antiproliferative and pro-apoptotic effects of shikonin on A431 cells and explored the underlying molecular mechanisms. In the present study, our results showed that shikonin significantly inhibited the growth of A431 cells in a concentration- and time-dependent manner, and caused cell cycle arrest by upregulation of p21 and p27, and downregulation of cyclins and cyclin dependent kinases. In addition, shikonin evidently induced apoptosis due to decreasing Bcl-2 expression, increasing Bax expression, activating caspase and inactivating NF-kappaB, while pretreatment with a pan-caspase inhibitor Z-Asp-CH2 DCB abrogated shikonin-induced apoptosis. Moreover, EGF could significantly increase the NF-kappaB DNA-binding activity and reversed the shikonin-induced inactivation of NF-kappaB. As anticipated AG1478 (EGFR inhibitor) and Bay11-7082 (NF-kappaB inhibitor) blocked EGF-reversed the inactivation of NF-kappaB induced by shikonin. Our data also showed that EGF could evidently reverse the shikonin induced decreases in cell viability and increases in apoptosis. Then, the NF kappaB inhibitors such as Bay11-7082, SN50, Helenalin and the EGFR inhibitor AG1478 and its downstream inhibitor such as PI3K inhibitor LY294002 and STAT3 inhibitor Stattic dramatically blocked EGF-reversed decreases in cell viability and increases in apoptosis induced by shikonin. Collectively, our findings indicated that shikonin inhibited cell growth and caused cell cycle arrest of the A431 cells through the regulation of apoptosis. Moreover, these effects were mediated at least partially by suppressing the activation of the EGFR-NF-kappaB signaling pathways. PMID- 25720436 TI - Advanced mass spectrometry workflows for analyzing disulfide bonds in biologics. AB - Proteins are an important class of biologics. Their higher-order structures and therefore their functions are fundamentally determined by the correct formation of disulfide bonds (DSBs), making DSB analysis a central part of their development and production. Mass spectrometry-based bottom-up approaches are most widely used and are further classified according to different methods applied for DSB cleavage. Despite the importance of DSB analysis and the wide range of available methodologies, it is often a challenging and time consuming task. However, due to the current increase in biosimilar development in which animal and clinical trials can be reduced by extensive analytical comparability studies, increased efforts are being made to simplify DSB analysis. As an example of these developments, a matrix-assisted laser desorption/ionization time-of-flight (TOF)/TOF workflow for the automated profiling and identification of DSBs is presented. Furthermore, mass spectrometry based methodologies, which do not identify DSBs directly but measure their influence on the higher-order structure, are also considered. PMID- 25720437 TI - The role of lipid rafts in the early stage of Enterovirus 71 infection. AB - BACKGROUND/AIMS: Although it has been widely accepted that Enterovirus 71 (EV71) enters permissive cells via receptor-mediated endocytosis, the details of entry mechanism for EV71 still need more exploration. This study aimed to investigate the role of lipid rafts in the early stage of EV71 Infection. METHODS: The effect of cholesterol depletion or addition of exogenous cholesterol was detected by immunofluorescence assays and quantitative real-time PCR. Effects of cholesterol depletion on the association of EV71 with lipid rafts were determined by flow cytometry and co-immunoprecipitation assays. Localization and internalization of EV71 and its receptor were assayed by confocal microscpoy and sucrose gradient analysis. The impact of cholesterol on the activation of phosphoinositide 3' kinase/Akt signaling pathway during initial virus infection was analyzed by Western-blotting. RESULTS: Disruption of membrane cholesterol by a pharmacological agent resulted in a significant reduction in the infectivity of EV71. The inhibitory effect could be reversed by the addition of exogenous cholesterol. Cholesterol depletion post-infection did not affect EV71 infection. While virus bound equally to cholesterol-depleted cells, EV71 particles failed to be internalized by cholesterol-depleted cells. EV71 capsid protein co-localized with cholera toxin B, a lipid-raft-dependent internalization marker. CONCLUSION: Lipid rafts play a critical role in virus endocytosis and in the activation of PI3K/Akt signaling pathway in the early stage of EV71 infection. PMID- 25720439 TI - A two-photon fluorescent turn-on probe for nitroxyl (HNO) and its bioimaging application in living tissues. AB - The first two-photon fluorescent probe for specific detection of nitroxyl is designed and synthesized, and we have further demonstrated that the new two photon fluorescent probe could be employed to image nitroxyl in living cells and tissues. PMID- 25720440 TI - Novel Transparent Urinary Tract Simulator Improves Teaching of Urological Operation Skills at a Single Institution. AB - OBJECTIVE: This randomized controlled study compared a novel transparent urinary tract simulator with the traditional opaque urinary tract simulator as an aid for efficiently teaching urological surgical procedures. METHODS: Senior medical students were tested on their understanding of urological theory before and after lectures concerning urinary system disease. The students received operative training using the transparent urinary tract simulator (experimental group, n = 80) or the J3311 opaque plastic urinary tract simulator (control, n = 80), specifically in catheterization and retrograde double-J stent implantation. The operative training was followed by a skills test and student satisfaction survey. RESULTS: The test scores for theory were similar between the two groups, before and after training. Students in the experimental group performed significantly better than those in the control group on the procedural skills test, and also had significantly better self-directed learning skills, analytical skills, and greater motivation to learn. CONCLUSION: During the initial step of training, the novel transparent urinary tract simulator significantly improved the efficiency of teaching urological procedural skills compared with the traditional opaque device. PMID- 25720441 TI - Extracts of three Laserpitium L. species and their principal components laserpitine and sesquiterpene lactones inhibit microbial growth and biofilm formation by oral Candida isolates. AB - Antimicrobial properties of extracts of underground parts of three Laserpitium L. (Apiaceae) species, namely Laserpitium latifolium L., Laserpitium zernyi Hayek and Laserpitium ochridanum Micevski, were investigated. The investigated species are widely used as functional foods, as spices and for preparations in traditional medicine for treating complaints connected with infection and inflammation. Furthermore, antimicrobial and antibiofilm effects of laserpitine, the most abundant compound in the chloroform extract of L. latifolium, and guaianolide sesquiterpene lactones, such as, isomontanolide, montanolide and tarolide, principal components of the extracts of L. zernyi and L. ochridanum were assessed. The antimicrobial activity was tested using the microdilution method against five pathogenic bacteria and five fungi, as well as in the microplate biofilm assay on two Candida clinical isolates (C. albicans and C. krusei). Among the extracts, L. latifolium showed the most prominent activity. Isolated metabolites exerted higher effects against fungal than against bacterial strains, isomontanolide being the most active. Interestingly, all constituents showed higher potential on inhibition of biofilm formation than fluconazole, a reference compound. Tested metabolites may be good novel agents with high antifungal and antibacterial potential that might find practical applications in food industry as food preservatives in order to retard the growth of food spoiling microbes, but only after detailed safety assessments. PMID- 25720442 TI - Expression of microRNA-155 correlates positively with the expression of Toll-like receptor 7 and modulates hepatitis B virus via C/EBP-beta in hepatocytes. AB - Effective recognition of viral infection and successive activation of antiviral innate immune responses are vital for host antiviral defence, which largely depends on multiple regulators, including Toll-like receptors (TLRs) and microRNAs. Several early reports suggest that specific TLR-mediated immune responses can control hepatitis B virus (HBV) replication and express differentially with disease outcome. Considering the versatile function of miR 155 in the TLR-mediated innate immune response, we aimed to study the association between miR-155 and TLRs and their subsequent impact on HBV replication using both a HBV-replicating stable cell line (HepG2.2.15) and HBV-infected liver biopsy and serum samples. Our results showed that miR-155 was suppressed during HBV infection and a subsequent positive correlation of miR-155 with TLR7 activation was noted. Further, ectopic expression of miR-155 in vitro reduced HBV load as evidenced from reduced viral DNA, mRNA and subsequently reduced level of secreted viral antigens (HBsAg and HBeAg). Our results further suggested that CCAAT/enhancer-binding protein-beta (C/EBP-beta), a positive regulator of HBV transcription, was inhibited by miR-155. Taken together, our study established a correlation between miR-155 and TLR7 during HBV infection and also demonstrated in vitro that increased miR-155 level could help to reduce HBV viral load by targeting C/EBP-beta. PMID- 25720438 TI - How sex and age affect immune responses, susceptibility to infections, and response to vaccination. AB - Do men die young and sick, or do women live long and healthy? By trying to explain the sexual dimorphism in life expectancy, both biological and environmental aspects are presently being addressed. Besides age-related changes, both the immune and the endocrine system exhibit significant sex-specific differences. This review deals with the aging immune system and its interplay with sex steroid hormones. Together, they impact on the etiopathology of many infectious diseases, which are still the major causes of morbidity and mortality in people at old age. Among men, susceptibilities toward many infectious diseases and the corresponding mortality rates are higher. Responses to various types of vaccination are often higher among women thereby also mounting stronger humoral responses. Women appear immune-privileged. The major sex steroid hormones exhibit opposing effects on cells of both the adaptive and the innate immune system: estradiol being mainly enhancing, testosterone by and large suppressive. However, levels of sex hormones change with age. At menopause transition, dropping estradiol potentially enhances immunosenescence effects posing postmenopausal women at additional, yet specific risks. Conclusively during aging, interventions, which distinctively consider the changing level of individual hormones, shall provide potent options in maintaining optimal immune functions. PMID- 25720443 TI - Dental shape variability in cercopithecoid primates: a model for the taxonomic attribution of macaques from Roman archaeological contexts. AB - Morphometric variation of biological structures has been widely used to determine taxonomic affinities among taxa, and teeth are especially informative for both deep phylogenetic relationships and specific ecological signals. We report 2 dimensional geometric morphometrics (GM) analyses of occlusal crown surfaces of lower molars (M1, n = 141; M2, n = 158) of cercopithecoid primate species. A 12 landmark configuration, including cusp tips and 8 points of the molar crown contour, were used to evaluate patterns of variation in lower molar shape among cercopithecoid primates and to predict the taxonomic attribution of 2 archaeological macaques from Roman time periods. The results showed that the lower molar shape of cercopithecoid primates reflects taxonomic affinities, mostly at a subfamily level and close to a tribe level. Thus, the cusp positions and crown contour were important elements of the pattern related to interspecific variation. Additionally, the archaeological specimens, attributed to Macaca sylvanus based on osteological information, were classified using the GM molar shape variability of the cercopithecoid primates studied. The results suggest that their molar shape resembled both M. sylvanus and M. nemestrina, and species attribution varied depending on the comparative sample used. PMID- 25720444 TI - Abnormal Bodily Experiences Mediate the Relationship between Impulsivity and Binge Eating in Overweight Subjects Seeking Bariatric Surgery. PMID- 25720445 TI - Rising to the Challenges of Clinical Trial Improvement in Parkinson's Disease. AB - BACKGROUND: Despite an urgent need for new medications, clinical trials in Parkinson's have a relatively low rate of success. Although many reasons have been proposed for this, the opinions of patients and scientists, the two principal stakeholders, have not been widely canvassed. OBJECTIVE: The objective of the present study was to establish the main barriers to clinical trials success in Parkinson's, as perceived by people with Parkinson's and those engaged in conducting clinical trials in Parkinson's. METHOD: Three hundred and three people (303) with a connection to Parkinson's completed an online four-item questionnaire, directed towards discovering the barriers that interfere with the establishment of effective clinical trials. RESULTS: 87% of respondents were patients and their care partners and 11% were medical professionals involved with clinical research. In the survey, those involved in conducting research cited insufficient financial and administrative support as the biggest obstacles to carrying out effective clinical trials. For responders with Parkinson's, the principal barrier to their participation in medical research was fear of potential adverse consequences and misconceptions regarding the clinical trial system as a whole, issues rooted in a perceived lack of communication of relevant information between the research and patient communities. CONCLUSIONS: Areas for future improvement as highlighted by this survey and debated at the Rallying to the Challenge meeting of people with Parkinson's (PwP) at the Van Andel Research Institute that followed included recommendations in the areas of communication, education, funding, recruitment and compliance. PMID- 25720446 TI - The Profile of Long-term Parkinson's Disease Survivors with 20 Years of Disease Duration and Beyond. AB - BACKGROUND: Parkinson's disease (PD) patients with 20 years or more survival (PD 20) are not well characterized. OBJECTIVE: To evaluate PD-20 patient characteristics and identify areas for improvement of their health care. METHODS: The international, multicenter National Parkinson's Foundation Quality Improvement Initiative (NPF-QII) study database was queried to identify PD-20 subjects. Demographic and clinical data were analyzed. RESULTS: We identified 187 PD-20 subjects (55% men) representing 4% (187/4,619) of all NPF-QII participants. Subjects were mean age 69.5 years; mean age at PD onset was 44.0 years. The majority (75% ) had 20-25 years of PD duration, the longest duration being 49 years. They were median Hoehn and Yahr stage 3, and 75% had motor fluctuations. Half (54% ) reported exercising. The majority (89% ) were living at home and required a caregiver (88% ). They were mildly cognitively impaired for age (Montreal Cognitive Assessment estimate 22.6+/-3.7), with most deficits in verbal fluency and delayed recall. Quality of life (Parkinson's Disease Quality of Life Questionnaire index 36+/-15% ) was mild to moderately impaired, with most impairment in mobility and activities of daily living. Caregiver strain measured by the Multidimensional Caregiver Strain Index (27+/-16% ), recorded highest subscores in social constraint. PD-20 subjects aged <70 years versus >=70 only differed significantly by worse cognition (P < 0.0001). CONCLUSIONS: PD-20 subjects reflect an elite group of PD survivors with early-onset disease and relatively mild cognitive disability despite long disease duration. Interventions for caregivers, mobility, and activities of daily living are areas that could improve caregiver burden and patient quality of life. PMID- 25720448 TI - P wave analysis and left ventricular systolic function in chronic heart failure. Possible insights form the P wave - PP interval spectral coherence. AB - BACKGROUND: Chronic increase in left ventricular filling pressure represents one of the most important mechanism underlying the structural, as well as the electrical, atrial chamber remodeling leading to atrial fibrillation. The present pilot pathophysiological study sought to investigate possible relationship between short-period cross-spectral coherence of P-Q, R-R and P-P intervals and echocardiographic indices of left ventricular and atrial function. METHODS: Electrocardiographic single lead short-term cross-spectral analysis on P-Q and P P intervals was performed in 31 patients with chronic heart failure (CHF). Twenty age and therapy matched hypertensive patients acted as control group. The interval between the beginning of P wave and its peak (Ppeak) was also analyzed. RESULTS: Patients with CHF showed a significant lower PQ -> PP and Ppeak -> PP coherence (P<0.001) than the counterpart. At multivariate analysis only Ppeak -> PP was independently associated to LVEF (r2:0.312; b:60; beta:0.559; P<0.0001) and atrial volume (r2:-0.160; b:-0.15; beta:-0.400, P<0.05). CONCLUSIONS: Ppeak > PP coherence might be a simple marker of left ventricular and atrial function. Whether this index could be a useful noninvasive marker of increased left ventricular filling pressure and, possibly, of atrial fibrillation risk or not, it needs to be tested in larger prospective studies. PMID- 25720447 TI - Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson's Disease. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN DBS) ameliorates the motor symptoms of Parkinson's disease (PD). However, some aspects of executive control are impaired with STN DBS. OBJECTIVE: We tested the prediction that (i) STN DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN DBS-induced cognitive control changes are load-dependent. METHODS: Fifteen PD patients with bilateral STN DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. RESULTS: The fastest rate was associated with an increased CS1 score with STN DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. CONCLUSIONS: We provide evidence for a load-dependent effect of STN DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing. PMID- 25720450 TI - Copper(I) diselenocarbamate clusters: synthesis, structures and single-source precursors for Cu and Se composite materials. AB - Neutral tetrahedral [Cu4(Se2CNnPr2)4] (1), monocationic hydride-centered tetracapped tetrahedral [Cu8(H){Se2CNR2}6]+ (R = nPr, 2H; Et, 3H) and neutral hydride-centered tricapped tetrahedral [Cu7(H){Se2CNR2}6] (R = nPr, 4H; Et, 5H) clusters were formed. They are the first Cu(I) complexes supported by dialkyl diselenocarbamates. The as-synthesized complexes 2H and 3H, formed from a reaction mixture of Cu(I) salts, diselenocarbamates, and [BH4]- in an 8:6:1 ratio, can be further reduced to 4H and 5H, respectively, in the presence of one equiv. of [BH4]-. Replacement of [BH4]- with [BD4]- afforded the deuteride analogues [Cu8(D){Se2CNR2}6]+ (R = nPr, 2D; Et, 3D) and [Cu7(D){Se2CNR2}6] (R = nPr, 4D; Et, 5D), which confirm the presence of hydride in the corresponding (2H, 3H, 4H and 5H) compounds. These complexes were fully characterized by elemental analysis, ESI-MS, and 1H, 2H and 77Se NMR spectroscopy, and their molecular structures were unequivocally established by single crystal X-ray crystallographic analyses (1, 2H-5H). The hydride-encapsulated copper frameworks of (2H, 3H) and (4H, 5H) reveal a tetracapped tetrahedral cage of Cu8 and a tricapped tetrahedral cage of Cu7, respectively, which are enclosed within a Se12 icosahedron constituted by six dialkyl diselenocarbamate ligands. Compounds 2H and 3H display orange emission in both the solid and solution state under UV irradiation at 77 K. In addition, the thermolysis behaviors of 2H were studied to demonstrate the potential of these compounds as single-source precursors for copper selenide nanocomposites, which were analyzed by XRD, EDX, and SEM techniques. PMID- 25720449 TI - Phase changing material: an alternative method for cooling babies with hypoxic ischaemic encephalopathy. AB - BACKGROUND: Therapeutic hypothermia for hypoxic ischaemic encephalopathy (HIE) has been proved effective. Standard equipment is expensive, while ice packs used in low resource settings are labour intensive and associated with wider temperature fluctuations. OBJECTIVES: To assess the feasibility of using phase changing material (PCM) as an alternative method for providing therapeutic hypothermia. METHODS: We retrospectively analysed 41 babies with HIE who had been cooled with PCM (OM 32 or HS 29) to a target rectal temperature of 33-34 degrees C. Rectal temperature was continuously monitored and recorded every hour. If the rectal temperature was >33.8 degrees C, cool gel packs were applied, and if the temperature was <33.2 degrees C, the baby was covered with sheets and the warmer output turned on till the temperature stabilized at 33.5 degrees C. The unit's standard protocol for cooling was followed for monitoring and treatment. The outcome measures were stability and fluctuation of the rectal temperature and the need for interventions to maintain the target temperature. RESULTS: The mean (+/ SD) temperature during the cooling phase was 33.45 +/- 0.26 degrees C. Throughout the cooling phase, the target temperature range was maintained in 96.2% of the time. There was no temperature reading <32 degrees C. With HS 29, ice packs were not used in any baby, and the warmer was used for a median of 7 h (interquartile range 1.5-14). CONCLUSIONS: PCM provides a low cost and effective method to maintain therapeutic hypothermia. However, careful monitoring is required during induction and the rewarming phase to avoid hypothermia outside the therapeutic range. PMID- 25720451 TI - The role of maternal education in the 15-year trajectory of malnutrition in children under 5 years of age in Bangladesh. AB - Malnutrition in children under 5 years of age (U5s) is a serious public health problem in low- and middle-income countries including Bangladesh. Improved maternal education can contribute effectively to reduce child malnutrition. We examined the long-term impact of maternal education on the risk of malnutrition in U5s and quantified the level of education required for the mothers to reduce the risk. We used pooled data from five nationwide demographic and health surveys conducted in 1996-1997, 1999-2000, 2004, 2007 and 2011 in Bangladesh involving 28 941 U5s. A log-binomial regression model was used to examine the association between maternal education (no education, primary, secondary or more) and malnutrition in children, measured by stunting, underweight and wasting controlling for survey time, maternal age, maternal body mass index, maternal working status, parity, paternal education and wealth quintile. An overall improvement in maternal educational attainment was observed between 1996 and 2011. The prevalence of malnutrition although decreasing was consistently high among children of mothers with lower education compared with those of mothers with higher education. In adjusted models incorporating time effects, children of mothers with secondary or higher education were at lower risk of childhood stunting [risk ratio (RR): 0.86, 95% confidence interval (CI): 0.81, 0.89], underweight (RR: 0.83, 95% CI: 0.78, 0.88) and wasting (RR: 0.82, 95% CI: 0.74, 0.91) compared with children of mothers with no education. We demonstrated the importance of promoting women's education at least up to the secondary level as a means to tackle malnutrition in Bangladesh. PMID- 25720452 TI - Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies. PMID- 25720454 TI - A concept analysis of patient-centred nursing in the intensive care unit. AB - AIM: To report an analysis of the concept of patient-centred nursing in the context of intensive care. BACKGROUND: Clarification of patient-centred nursing in the intensive care unit is important because consensus definition of this concept is lacking. The severely compromised physiological state of these people and the sequelae of this differentiate patient-centred nursing in intensive care from that occurring in other hospital settings. While the broad concept has been analysed, it has not been examined in the context of intensive care. DESIGN: Concept analysis. DATA SOURCES: CINAHL, PsycINFO, Medline and PubMed databases (2000-2014) were searched. Peer-reviewed papers were identified and reference lists of relevant articles searched. METHODS: Walker and Avant's eight-stage approach was used. RESULTS: Patient-centred nursing in the intensive care unit incorporates antecedents of a physiologically compromised patient requiring biomedical intervention, a professional and competent nurse and organizational support. The concept's defining attributes entail maintenance of patient identity by a compassionate and professional nurse exercising biomedical expertise. Consequences include patient satisfaction, positive patient experience, nurse job satisfaction and better nurse workforce retention. CONCLUSION: Patient-centred nursing in intensive care is differentiated from other healthcare areas by the particular characteristics of critically ill patients, the critical care environment and the challenging bio-psycho-social demands made on intensive care nurses. Effective patient-centred nursing in this environment promotes beneficial outcomes for patients, nurses and healthcare service. Decision-makers and policymakers should support critical care nurses in this challenging role, to maintain delivery of patient-centred nursing and grow an effective nursing workforce. PMID- 25720453 TI - Effects of intraoperatively applied glucocorticoid hydrogels on residual hearing and foreign body reaction in a guinea pig model of cochlear implantation. AB - CONCLUSION: The intraoperative application of glucocorticoid-loaded hydrogels seems to cause a reduction in neutrophil infiltration. No beneficial effect on hearing thresholds was detected. OBJECTIVES: To evaluate the application of dexamethasone- and triamcinolone acetonide-loaded hydrogels for effects on hearing preservation and foreign body reaction in a guinea pig model for cochlear implantation (CI). METHODS: A total of 48 guinea pigs (n = 12 per group) were implanted with a single channel electrode and intraoperatively treated with 50 MUl of a 20% w/v poloxamer 407 hydrogel loaded with 6% dexamethasone or 30% triamcinolone acetonide, a control hydrogel, or physiological saline. Click- and tone burst-evoked compound action potential thresholds were determined preoperatively and directly postoperatively as well as on days 3, 7, 14, 21, and 28. At the end of the experiment, temporal bones were prepared for histological evaluation by a grinding/polishing technique with the electrode in situ. Three ears per treatment group were serially sectioned and evaluated for histological alterations. RESULTS: The intratympanic application of glucocorticoid-loaded hydrogels did not improve the preservation of residual hearing in this cochlear implant model. The foreign body reaction to the electrode appeared reduced in the glucocorticoid-treated animals. No correlation was found between the histologically described trauma to the inner ear and the resulting hearing threshold shifts. PMID- 25720455 TI - Finite element evaluation of the effect of fingertip geometry on contact pressure during flat contact. AB - Several studies investigated the mechanical loads developing in the hands during the use of various products in order to enhance user's performance, increase satisfaction and lower the risk of acute and cumulative trauma disorders. Values of pressure discomfort (PDT) and pressure-pain threshold (PPT) were, hence, provided. PDT and PPT may differ significantly for each subject and area of the hand because of psychological and physiological factors. A finite element study of the effect of fingertip anthropometry and anatomy geometry on mechanical loads developed during grasping is carried out in this research in order to assess physiological aspects behind variations of PDT and PPT existing between different subjects. It is found that the underlying anatomical structure and geometry (especially of the bone) significantly affect contact pressure distributions and pressure peak values. The largest difference in peak contact pressure between two different fingertips was in fact 27% for the same applied force. Furthermore, contact pressure distributions varied significantly between different subjects. The findings of this research provide novel insight into the phenomena of human grasping and the variation of contact pressure from subject to subject. PMID- 25720456 TI - Automated synthesis of arabinoxylan-oligosaccharides enables characterization of antibodies that recognize plant cell wall glycans. AB - Monoclonal antibodies that recognize plant cell wall glycans are used for high resolution imaging, providing important information about the structure and function of cell wall polysaccharides. To characterize the binding epitopes of these powerful molecular probes a library of eleven plant arabinoxylan oligosaccharides was produced by automated solid-phase synthesis. Modular assembly of oligoarabinoxylans from few building blocks was enabled by adding (2 naphthyl)methyl (Nap) to the toolbox of orthogonal protecting groups for solid phase synthesis. Conjugation-ready oligosaccharides were obtained and the binding specificities of xylan-directed antibodies were determined on microarrays. PMID- 25720457 TI - Analyzing the mobile "digital divide": changing determinants of household phone ownership over time in rural bangladesh. AB - BACKGROUND: We had a unique opportunity to examine demographic determinants of household mobile phone ownership in rural Bangladesh using socioeconomic data collected as part of a multiyear longitudinal cohort study of married women of reproductive age. OBJECTIVES: This paper explores how the demographics of household mobile phone owners have changed over time in a representative population of rural Bangladesh. METHODS: We present data collected between 2008 and 2011 on household mobile phone ownership and related characteristics including age, literacy, education, employment, electricity access, and household wealth among 35,306 individuals. Respondents were enrolled when found to be newly pregnant and contributed socioeconomic information once over the course of the time period serving as a "sample" of families within the population at that time. Univariate and multiple logistic regressions analyses were performed to identify the socioeconomic determinants of household phone ownership. RESULTS: Across 3 fiscal years, we found that reported household ownership of at least 1 working mobile phone grew from 29.85% in the first fiscal year to 56.07% in the third fiscal year. Illiteracy, unavailability of electricity, and low quartiles of wealth were identified as overall demographic constraints to mobile phone ownership. However, over time, these barriers became less evident and equity gaps among demographic status began to dissipate as access to mobile technology became more democratized. We saw a high growth rate in ownership among households in lower economic standing (illiterate, without electricity, low and lowest wealth index), likely a result of competitive pricing and innovative service packages that improve access to mobile phones as the mobile phone market matures. In contrast, as market saturation is rapidly attained in the most privileged demographics (literate, secondary schooling, electricity, high wealth index), members of the lower wealth quartiles seem to be following suit, with more of an exponential growth. CONCLUSIONS: Upward trends in household mobile phone ownership in vulnerable populations over time underline the potential to leverage this increasingly ubiquitous infrastructure to extend health and finance services across social and economic strata. PMID- 25720458 TI - Intrachromosomal 3p insertion as a cause of reciprocal pure interstitial deletion and duplication in two siblings: further delineation of the emerging proximal 3p deletion syndrome. AB - Very few cases of constitutional interstitial deletions of the proximal short arm of chromosome 3 have been reported; however, the proximal 3p deletion is emerging as a clinically recognizable syndrome. We present an intrachromosomal insertion of 3p12.3p14.1 in a phenotypic normal man (46,XY,ins(3)(p25p12.3p14.1)) which is responsible for the unbalanced karyotype in 2 affected offspring, one with a 3p12.3p14.1 interstitial deletion and the other with a reciprocal duplication. The exceptionality of these 2 reciprocal recombinants contributes to a better definition of the proximal 3p deletion syndrome and its duplication counterpart. PMID- 25720459 TI - Lumbosacral discitis following laparoscopic ventral mesh rectopexy: a rare but potentially serious complication. PMID- 25720460 TI - Review of the Bethesda System for Reporting Thyroid Cytopathology: a local study in Bohol Island, Philippines. AB - OBJECTIVES: The aim of this study was to evaluate the adaptability and reproducibility of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) in a local setting and to determine the risk of malignancy for each category. MATERIALS AND METHODS: A retrospective cross-sectional study of 80 thyroid fine-needle aspiration cytology cases using the BSRTC with corresponding histopathology was done between September 2009 and December 2012. Agreement scores were calculated using kappa statistics. RESULTS: Consensus among two readers was attained for 73 cases (91.25%). No disagreement was noted for the malignant cases. The strength of agreement was very good, with a kappa statistic of 0.90. The risk of malignancy observed histologically was as follows: benign 3%, atypia of undetermined significance (AUS) 50%, suspicious for follicular/Hurthle cell neoplasm 50%, suspicious for malignancy 78%, and malignant 100%. CONCLUSION: In this study, there is an outstanding reproducibility for the classification scheme. The application of the BSRTC as the standardized reporting is readily adaptable and therefore its application in larger medical centers is highly recommended. Our findings of a higher risk of malignancy seen in AUS (50%) and malignant (100%) categories in those who underwent surgical resection corroborated other published studies. Conveying this risk to clinical colleagues is important and will facilitate optimal patient care. PMID- 25720461 TI - [In-patient nuclear medicine therapy in Germany from 2010 to 2012. Analysis of structured quality reports]. AB - The aim of this analysis was to collect and analyse Germany-wide data on the status and development of in-patient Nuclear Medicine therapy. The official hospital quality reports were to be used as the data source. METHODS: The reference reports from all hospitals in Germany with Nuclear Medicine therapy units, compiled by Gemeinsamer Bundesausschuss (G-BA) from the machine-usable XML data of the quality reports, were analysed for the years 2010 and 2012. Results from our own preceding investigations of structured quality reports for the years 2004, 2006 and 2008 were used to assess the longer-term development. To determine the Germany-wide incidence of thyroid surgery and radio-iodine therapy, public databases of Institut fur das Entgeltsystem im Krankenhaus (InEK) were assessed for the years from 2004 to 2012. RESULTS: The total number of in-patient Nuclear Medicine treatment cases decreased from 50 363 to 47 314 patients in the period from 2010 to 2012. There was a marked decline of 17.5% in case incidence over the longer period from 2004 to 2012. The decrease is primarily due to a decrease in cases with hyperthyroidism (ICD code E05). The number of thyroid surgeries has been declining since 2009. There was a moderate 23.7% increase in the number of cases with the diagnosis of thyroid carcinoma (ICD code C73) from 2004 to 2012. CONCLUSIONS: Presumably, the improved iodine supply in Germany has led to a decline in inpatients with hyperthyroidism in nuclear medicine and consequently to a decrease in both the number of radio-iodine therapies and thyroid operations in surgery. In contrast, the number of patients in nuclear medicine therapy units diagnosed with thyroid cancer has increased moderately which correlates with the worldwide increasing incidence of this disease. PMID- 25720462 TI - Evaluation of Acid Tolerance of Drugs Using Rats and Dogs Controlled for Gastric Acid Secretion. AB - We attempted to establish animal models to evaluate the effects of drug degradation in the stomach on oral bioavailability. In addition, we assessed the utilization of animal studies in determining the need for enteric-coated formulations. In order to control the gastric pH in rats and dogs, appropriate dosing conditions were investigated using pentagastrin and rabeprazole, which stimulate and inhibit gastric acid secretion. Using animals controlled for gastric acid secretion, the area under curve (AUC) ratios (AUC with rabeprazole/AUC with pentagastrin) of all compounds unstable under acidic conditions were evaluated. The AUC ratios of omeprazole and erythromycin, which are administered orally to humans, as enteric-coated tablets, were greater than 1.9 in the rats and dogs controlled for gastric acid secretion. On the contrary, the AUC ratios of clarithromycin, azithromycin, and etoposide (commercially available as a standard immediate-release form) were less than 1.3 each. In conclusion, in vivo models using rats and dogs were optimized to evaluate the effects of gastric acid on the oral bioavailability of drugs, and demonstrated that in vivo models can lead to a better understanding of the oral bioavailability, with respect to the formulation development. PMID- 25720463 TI - Underdiagnosis of Obstructive Sleep Apnoea in Peripheral Arterial Disease. AB - Background: Obstructive sleep apnoea (OSA) has interdependently been related to the onset and progression of a large portion of atherosclerotic cardiovascular disorders. In due consideration of OSA-mediated endothelial dysfunction, its impact on peripheral artery disease is conceivable, but undefined. Objectives: The aim of this study was to identify the prevalence of OSA in a lower extremity artery disease (LEAD) study population. Methods: A total of 91 patients receiving in- and outpatient treatment for LEAD were included in this prospectively conducted trial. In addition to an angiological examination, all patients underwent nocturnal screening for sleep-disordered breathing by use of SOMNOcheck micro(r) (SC micro) and - depending on the results obtained - polysomnography. Results: Patients were principally late middle-aged (69.3 +/- 10.8 years), male (71.4%) and slightly overweight (BMI 26.8 +/- 3.9). Overnight screening determined a sleep apnoea prevalence of 78.0%, of which 90.1% exhibited a predominantly obstructive genesis. The mean apnoea-hypopnoea index (AHI; events/h) and oxygen desaturation index (events/h) averaged 11.8 +/- 13.4 and 8.9 +/- 14.2, respectively. The individual AHI categories of non-pathological (<5), mild (5 to <15), moderate (15 to <30) and severe sleep apnoea (>=30) accounted for 22.0, 59.3, 13.2 and 5.5%, respectively. A distributive examination of AHI within LEAD severity groups evinced a significant association (p = 0.047). In cases of at least moderate sleep apnoea (AHI >=15) polysomnography was performed (n = 17, 18.7% of the whole collective). Correlative analysis revealed a significant correlation between values obtained by SC micro recording and polysomnography, establishing the diagnostic accuracy of the screening results. Conclusions: OSA exhibits an important prevalence of 70.3% in LEAD patients with prior undiagnosed sleep-disordered breathing, indicating major OSA unawareness in this cardiovascular cohort. However, the impact of OSA treatment on LEAD propagation remains to be determined. (c) 2015 S. Karger AG, Basel. PMID- 25720464 TI - In vitro Anticancer Activity of Myricanone in Human Lung Adenocarcinoma A549 Cells. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Despite the new chemotherapy regimens and cytotoxic combinations investigated in multiple clinical trials in recent years, no significant improvement in the prognosis of patients with lung cancer has been achieved. Recently, scientists have focused on the potential role of extracts of traditional Chinese medicinal herbs as alternative and complementary medications for cancer treatment. Myricanone, a typical large ring of cyclic diarylheptanoids, is abundant in the bark of Myrica. Our studies have found that myricanone exerts potent anticancer activity. This study aimed to investigate the underlying mechanism of the effect of myricanone on A549 cells in vitro. METHODS: A549 cells were treated with different concentrations of myricanone for the following assays. Tritiated thymidine incorporation was used to measure growth inhibition. Flow cytometry was used to detect apoptosis and cell cycle progression, and colony formation was performed to observe the effect of myricanone on the A549 proliferation rate. RESULTS: Myricanone induced significant dose-dependent growth inhibitory effects on A549 cells with an IC50 of 3.22 ug/ml. A significant decrease in colony formation was observed. This decrease induced cell apoptosis, G1 phase arrest and the emergence of the sub-G0 peak in A549 cells. CONCLUSIONS: These results suggest that myricanone exhibits anticancer activity and may be applicable in the clinical prevention and treatment of lung cancer in the future. PMID- 25720465 TI - Genetic abnormalities and prognosis in patients with congenital and infantile nephrotic syndrome. AB - BACKGROUND: Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are caused primarily by mutations in genes that encode structural and regulatory proteins of the glomerular filtration barrier. The aim of this study was to determine genotype-phenotype correlations and prognosis in patients with CNS and INS. METHODS: NPHS1, NPHS2, LAMB2 and the eighth and ninth exons of WT1 were sequenced in 80 and 22 patients with CNS and INS, respectively. Genotype phenotype correlations and survival were evaluated. RESULTS: Causative mutations were identified in 64.7 % of patients, of which NPHS1 mutations were the most common (37.4 %). The mutation detection rate was twofold higher in CNS patients than in INS patients (72.5 vs. 36.2 %). The most commonly mutated gene in CNS patients was NPHS1 (46.3 %) versus NPHS2 (13.6 %) and WT1 (13.6 %) in INS patients. NPHS2 mutations, female patients with NPHS1 mutations, and NPHS1 mutations affecting the transmembrane or intracellular domains of nephrin were associated with longer survival. CONCLUSIONS: Based on our present findings, the likelihood of identification of a genetic cause decreases with increasing age at diagnosis. The underlying genetic abnormality should be identified as early as possible, as this knowledge will facilitate clinicians in their prognostic prediction and enable patients to receive appropriate genetic counseling. PMID- 25720467 TI - Identification of a novel coronavirus from guinea fowl using metagenomics. AB - While classical virology techniques such as virus culture, electron microscopy, or classical PCR had been unsuccessful in identifying the causative agent responsible for the fulminating disease of guinea fowl, we identified a novel avian gammacoronavirus associated with the disease using metagenomics. Next generation sequencing is an unbiased approach that allows the sequencing of virtually all the genetic material present in a given sample. PMID- 25720468 TI - Serological diagnosis of feline coronavirus infection by immunochromatographic test. AB - The immunochromatographic assay (ICA) is a simple antibody-antigen detection method, the results of which can be rapidly obtained at a low cost. We designed an ICA to detect anti-feline coronavirus (FCoV) antibodies. A colloidal gold labeled recombinant FCoV nucleocapsid protein (rNP) is used as a conjugate. The Protein A and affinity-purified cat anti-FCoV IgG are blotted on the test line and the control line, respectively, of the nitrocellulose membrane. The specific detection of anti-FCoV antibodies was possible in all heparin-anticoagulated plasma, serum, whole blood, and ascitic fluid samples from anti-FCoV antibody positive cats, and nonspecific reaction was not noted in samples from anti-FCoV antibody negative cats. PMID- 25720469 TI - Estimation of evolutionary dynamics and selection pressure in coronaviruses. AB - Evolution of coronaviruses is facilitated by the strong selection, large population size, and great genetic diversity within the susceptible hosts. This predisposition is primarily due to high error rate, and limited proofreading capability of the viral polymerase and by recombination. These characteristics make coronaviruses an interesting model system to study the mechanisms involved in viral evolution and the ways viruses adapt to switch host or to gain novel functions. Here we describe the protocol to estimate selection pressures for the spike gene and evolutionary dynamics of bovine coronaviruses. PMID- 25720470 TI - The preparation of chicken tracheal organ cultures for virus isolation, propagation, and titration. AB - Chicken tracheal organ cultures (TOCs), comprising transverse sections of chick embryo trachea with beating cilia, have proved useful in the isolation of several respiratory viruses and as a viral assay system, using ciliostasis as the criterion for infection. A simple technique for the preparation of chicken tracheal organ cultures in glass test tubes, in which virus growth and ciliostasis can be readily observed, is described. PMID- 25720466 TI - Coronaviruses: an overview of their replication and pathogenesis. AB - Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy. Coronaviruses cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs and upper respiratory disease in chickens to potentially lethal human respiratory infections. Here we provide a brief introduction to coronaviruses discussing their replication and pathogenicity, and current prevention and treatment strategies. We also discuss the outbreaks of the highly pathogenic Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently identified Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV). PMID- 25720471 TI - The preparation of chicken kidney cell cultures for virus propagation. AB - Chicken kidney (CK) cell cultures have historically proved useful for the assay of a number of viruses including coronaviruses. A technique for the preparation of such cell cultures, using a combination of manual and trypsin disaggregation of kidneys dissected from 2- to 3-week-old birds is described. This technique routinely gives high cell yield together with high viability and the resultant adherent primary cultures can be used for virus growth and plaque formation. PMID- 25720472 TI - Isolation and propagation of coronaviruses in embryonated eggs. AB - The embryonated egg is a complex structure comprised of an embryo and its supporting membranes (chorioallantoic, amniotic, yolk). The developing embryo and its membranes provide the diversity of cell types that are needed for successful replication of a wide variety of different viruses. Within the family Coronaviridae the embryonated egg has been used as a host system primarily for two avian coronaviruses within the genus Gammacoronavirus, infectious bronchitis virus (IBV) and turkey coronavirus (TCoV). The embryonated egg also has been shown to be suitable for isolation and propagation of pheasant coronavirus, a proposed member of the Gammacoronavirus genus. IBV and pheasant coronavirus replicate well in the embryonated chicken egg, regardless of inoculation route; however, the allantoic route is favored as these viruses replicate well in epithelium lining the chorioallantoic membrane, with high virus titers found in these membranes and associated allantoic fluids. TCoV replicates only in epithelium lining the embryo intestines and bursa of Fabricius, thus amniotic inoculation is required for isolation and propagation of this virus. Embryonated eggs also provide a potential host system for detection and characterization of other, novel coronaviruses. PMID- 25720473 TI - Characterization of human coronaviruses on well-differentiated human airway epithelial cell cultures. AB - The human airway serves as the entry point of human respiratory viruses, including human coronaviruses. In this chapter we outline the methods by which we establish fully differentiated airway epithelium and its use for human coronavirus propagation. Additionally, we outline methods for immunofluorescence staining of these cultures for virus detection, characterization of cell tropism, and how to perform antiviral assays and quantify viral replication. PMID- 25720474 TI - Quantification of infectious bronchitis coronavirus by titration in vitro and in ovo. AB - Quantification of the number of infectious viruses in a sample is a basic virological technique. In this chapter we provide a detailed description of three techniques to estimate the number of viable infectious avian coronaviruses in a sample. All three techniques are serial dilution assays, better known as titrations. PMID- 25720475 TI - Purification of coronavirus virions for Cryo-EM and proteomic analysis. AB - Purification of intact enveloped virus particles can be useful as a first step in understanding the structure and function of both viral and host proteins that are incorporated into the virion. Purified preparations of virions can be used to address these questions using techniques such as mass spectrometry proteomics. Recent studies on the proteome of coronavirus virions have shown that in addition to the structural proteins, accessory and non-structural virus proteins and a wide variety of host cell proteins associate with virus particles. To further study the presence of virion proteins, high-quality sample preparation is crucial to ensure reproducible analysis by the wide variety of methods available for proteomic analysis. PMID- 25720476 TI - Partial purification of IBV and subsequent isolation of viral RNA for next generation sequencing. AB - RNA viruses are known for a high mutation rate and rapid genomic evolution. As such an RNA virus population does not consist of a single genotype but is rather a collection of individual viruses with closely related genotypes-a quasispecies, which can be analyzed by next-generation sequencing (NGS). This diversity of genotypes provides a mechanism in which a virus population can evolve and adapt to a changing environment. Sample preparation is vital for successful sequencing. The following protocol describes the process of generating a high-quality RNA preparation from IBV grown in embryonated eggs and then partially purified and concentrated through a 30% sucrose cushion for NGS. PMID- 25720477 TI - Transient dominant selection for the modification and generation of recombinant infectious bronchitis coronaviruses. AB - We have developed a reverse genetics system for the avian coronavirus infectious bronchitis virus (IBV) in which a full-length cDNA corresponding to the IBV genome is inserted into the vaccinia virus genome under the control of a T7 promoter sequence. Vaccinia virus as a vector for the full-length IBV cDNA has the advantage that modifications can be introduced into the IBV cDNA using homologous recombination, a method frequently used to insert and delete sequences from the vaccinia virus genome. Here, we describe the use of transient dominant selection as a method for introducing modifications into the IBV cDNA; this has been successfully used for the substitution of specific nucleotides, deletion of genomic regions, and the exchange of complete genes. Infectious recombinant IBVs are generated in situ following the transfection of vaccinia virus DNA, containing the modified IBV cDNA, into cells infected with a recombinant fowlpox virus expressing T7 DNA-dependent RNA polymerase. PMID- 25720478 TI - Engineering infectious cDNAs of coronavirus as bacterial artificial chromosomes. AB - The large size of the coronavirus (CoV) genome (around 30 kb) and the instability in bacteria of plasmids carrying CoV replicase sequences represent serious restrictions for the development of CoV infectious clones using reverse genetic systems similar to those used for smaller positive sense RNA viruses. To overcome these problems, several approaches have been established in the last 13 years. Here we describe the engineering of CoV full-length cDNA clones as bacterial artificial chromosomes (BACs), using the Middle East respiratory syndrome CoV (MERS-CoV) as a model. PMID- 25720479 TI - Protein histochemistry using coronaviral spike proteins: studying binding profiles and sialic acid requirements for attachment to tissues. AB - Protein histochemistry is a tissue-based technique that enables the analysis of viral attachment patterns as well as the identification of specific viral and host determinants involved in the first step in the infection of a host cell by a virus. Applying recombinantly expressed spike proteins of infectious bronchitis virus onto formalin-fixed tissues allows us to profile the binding characteristics of these viral attachment proteins to tissues of various avian species. In particular, sialic acid-mediated tissue binding of spike proteins can be analyzed by pretreating tissues with various neuraminidases or by blocking the binding of the viral proteins with specific lectins. Our assay is particularly convenient to elucidate critical virus-host interactions for viruses for which infection models are limited. PMID- 25720480 TI - Identification of protein receptors for coronaviruses by mass spectrometry. AB - As obligate intracellular parasites, viruses need to cross the plasma membrane and deliver their genome inside the cell. This step is initiated by the recognition of receptors present on the host cell surface. Receptors can be major determinants of tropism, host range, and pathogenesis. Identifying virus receptors can give clues to these aspects and can lead to the design of intervention strategies. Interfering with receptor recognition is an attractive antiviral therapy, since it occurs before the viral genome has reached the relative safe haven within the cell. This chapter describes the use of an immunoprecipitation approach with Fc-tagged viral spike proteins followed by mass spectrometry to identify and characterize the receptor for the Middle East respiratory syndrome coronavirus. This technique can be adapted to identify other viral receptors. PMID- 25720481 TI - Single particle tracking assay to study coronavirus membrane fusion. AB - Single particle tracking (SPT) of individual virion fusion with host cell membranes using total internal reflection microscopy (TIRFM) is a powerful technique for quantitatively characterizing virus-host interactions. One significant limitation of this assay to its wider use across many types of enveloped viruses, such as coronavirus, has been incorporating non-lipid receptors (proteins) into the supported lipid bilayers (SLBs) used to monitor membrane fusion. Here, we describe a method for incorporating a proteinaceous viral receptor, feline aminopeptidase N (fAPN), into SLBs using cell blebbing of mammalian cells expressing fAPN in the plasma membrane. This receptor binds feline coronavirus (FECV 1683). We describe how to carry out single particle tracking of FECV fusion in this SLB platform to obtain fusion kinetics. PMID- 25720482 TI - Studying coronavirus-host protein interactions. AB - To understand the molecular mechanisms of viral replication and pathogenesis, it is necessary to establish the virus-host protein interaction networks. The yeast two-hybrid system is a powerful proteomic approach to study protein-protein interactions. After the identification of specific cellular factors interacting with the target viral protein using the yeast two-hybrid screening system, co immunoprecipitation and confocal microscopy analyses are often used to verify the virus-host protein interactions in cells. Identification of the cellular factors required for viral survival or eliminating virus infected cells could help scientists develop more effective antiviral drugs. Here we summarize a standard protocol used in our lab to study the coronavirus-host protein interactions, including yeast two-hybrid screening, co-immunoprecipitation, and immunofluorescence microscopy analyses. PMID- 25720483 TI - A field-proven yeast two-hybrid protocol used to identify coronavirus-host protein-protein interactions. AB - Over the last 2 decades, yeast two-hybrid became an invaluable technique to decipher protein-protein interaction networks. In the field of virology, it has proven instrumental to identify virus-host interactions that are involved in viral embezzlement of cellular functions and inhibition of immune mechanisms. Here, we present a yeast two-hybrid protocol that has been used in our laboratory since 2006 to search for cellular partners of more than 300 viral proteins. Our aim was to develop a robust and straightforward pipeline, which minimizes false positive interactions with a decent coverage of target cDNA libraries, and only requires a minimum of equipment. We also discuss reasons that motivated our technical choices and compromises that had to be made. This protocol has been used to screen most non-structural proteins of murine hepatitis virus (MHV), a member of betacoronavirus genus, against a mouse brain cDNA library. Typical results were obtained and are presented in this report. PMID- 25720484 TI - Investigation of the functional roles of host cell proteins involved in coronavirus infection using highly specific and scalable RNA interference (RNAi) approach. AB - Since its identification in the 1990s, the RNA interference (RNAi) pathway has proven extremely useful in elucidating the function of proteins in the context of cells and even whole organisms. In particular, this sequence-specific and powerful loss-of-function approach has greatly simplified the study of the role of host cell factors implicated in the life cycle of viruses. Here, we detail the RNAi method we have developed and used to specifically knock down the expression of ezrin, an actin binding protein that was identified by yeast two-hybrid screening to interact with the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) spike (S) protein. This method was used to study the role of ezrin, specifically during the entry stage of SARS-CoV infection. PMID- 25720485 TI - Transcriptome analysis of feline infectious peritonitis virus infection. AB - Feline infectious peritonitis (FIP) is a lethal systemic disease caused by FIP virus (FIPV). There are no effective vaccines or treatment available, and the virus virulence determinants and pathogenesis are not fully understood. Here, we describe the sequencing of RNA extracted from Crandell Rees Feline Kidney (CRFK) cells infected with FIPV using the Illumina next-generation sequencing approach. Bioinformatics analysis, based on Felis catus 2X annotated shotgun reference genome, using CLC bio Genome Workbench is used to map both control and infected cells. Kal's Z test statistical analysis is used to analyze the differentially expressed genes from the infected CRFK cells. In addition, RT-qPCR analysis is used for further transcriptional profiling of selected genes in infected CRFK cells and Peripheral Blood Mononuclear Cells (PBMCs) from healthy and FIP diagnosed cats. PMID- 25720486 TI - Quantification of interferon signaling in avian cells. AB - Activation of the type I interferon (IFN) response is an essential defense mechanism against invading pathogens such as viruses. This chapter describes two protocols to quantify activation of the chicken IFN response through analysis of gene expression by real-time quantitative PCR and by quantification of bioactive IFN protein using a bioassay. PMID- 25720487 TI - Studying the dynamics of coronavirus replicative structures. AB - Coronaviruses (CoVs) generate specialized membrane compartments, which consist of double membrane vesicles connected to convoluted membranes, the so-called replicative structures, where viral RNA synthesis takes place. These sites harbor the CoV replication-transcription complexes (RTCs): multi-protein complexes consisting of 16 nonstructural proteins (nsps), the CoV nucleocapsid protein (N) and presumably host proteins. To successfully establish functional membrane-bound RTCs all of the viral and host constituents need to be correctly spatiotemporally organized during viral infection. Few studies, however, have investigated the dynamic processes involved in the formation and functioning of the (subunits of) CoV RTCs and the replicative structures in living cells. In this chapter we describe several protocols to perform time-lapse imaging of CoV-infected cells and to study the kinetics of (subunits of) the CoV replicative structures. The approaches described are not limited to CoV-infected cells; they can also be applied to other virus-infected or non-infected cells. PMID- 25720488 TI - Preparation of cultured cells using high-pressure freezing and freeze substitution for subsequent 2D or 3D visualization in the transmission electron microscope. AB - Transmission electron microscopy (TEM) is an invaluable technique used for imaging the ultrastructure of samples and it is particularly useful when determining virus-host interactions at a cellular level. The environment inside a TEM is not favorable for biological material (high vacuum and high energy electrons). Also biological samples have little or no intrinsic electron contrast, and rarely do they naturally exist in very thin sheets, as is required for optimum resolution in the TEM. To prepare these samples for imaging in the TEM therefore requires extensive processing which can alter the ultrastructure of the material. Here we describe a method which aims to minimize preparation artifacts by freezing the samples at high pressure to instantaneously preserve ultrastructural detail, then rapidly substituting the ice and infiltrating with resin to provide a firm matrix which can be cut into thin sections for imaging. Thicker sections of this material can also be imaged and reconstructed into 3D volumes using electron tomography. PMID- 25720489 TI - Discrete and structurally unique proteins (tapirins) mediate attachment of extremely thermophilic Caldicellulosiruptor species to cellulose. AB - A variety of catalytic and noncatalytic protein domains are deployed by select microorganisms to deconstruct lignocellulose. These extracellular proteins are used to attach to, modify, and hydrolyze the complex polysaccharides present in plant cell walls. Cellulolytic enzymes, often containing carbohydrate-binding modules, are key to this process; however, these enzymes are not solely responsible for attachment. Few mechanisms of attachment have been discovered among bacteria that do not form large polypeptide structures, called cellulosomes, to deconstruct biomass. In this study, bioinformatics and proteomics analyses identified unique, discrete, hypothetical proteins ("tapirins," origin from Maori: to join), not directly associated with cellulases, that mediate attachment to cellulose by species in the noncellulosomal, extremely thermophilic bacterial genus Caldicellulosiruptor. Two tapirin genes are located directly downstream of a type IV pilus operon in strongly cellulolytic members of the genus, whereas homologs are absent from the weakly cellulolytic Caldicellulosiruptor species. Based on their amino acid sequence, tapirins are specific to these extreme thermophiles. Tapirins are also unusual in that they share no detectable protein domain signatures with known polysaccharide-binding proteins. Adsorption isotherm and trans vivo analyses demonstrated the carbohydrate-binding module-like affinity of the tapirins for cellulose. Crystallization of a cellulose-binding truncation from one tapirin indicated that these proteins form a long beta-helix core with a shielded hydrophobic face. Furthermore, they are structurally unique and define a new class of polysaccharide adhesins. Strongly cellulolytic Caldicellulosiruptor species employ tapirins to complement substrate-binding proteins from the ATP binding cassette transporters and multidomain extracellular and S-layer associated glycoside hydrolases to process the carbohydrate content of lignocellulose. PMID- 25720490 TI - Drosophila melanogaster mini spindles TOG3 utilizes unique structural elements to promote domain stability and maintain a TOG1- and TOG2-like tubulin-binding surface. AB - Microtubule-associated proteins regulate microtubule (MT) dynamics spatially and temporally, which is essential for proper formation of the bipolar mitotic spindle. The XMAP215 family is comprised of conserved microtubule-associated proteins that use an array of tubulin-binding tumor overexpressed gene (TOG) domains, consisting of six (A-F) Huntingtin, elongation factor 3, protein phosphatase 2A, target of rapamycin (HEAT) repeats, to robustly increase MT plus end polymerization rates. Recent work showed that TOG domains have differentially conserved architectures across the array, with implications for position dependent TOG domain tubulin binding activities and function within the XMAP215 MT polymerization mechanism. Although TOG domains 1, 2, and 4 are well described, structural and mechanistic information characterizing TOG domains 3 and 5 is outstanding. Here, we present the structure and characterization of Drosophila melanogaster Mini spindles (Msps) TOG3. Msps TOG3 has two unique features as follows: the first is a C-terminal tail that stabilizes the ultimate four HEAT repeats (HRs), and the second is a unique architecture in HR B. Structural alignments of TOG3 with other TOG domain structures show that the architecture of TOG3 is most similar to TOG domains 1 and 2 and diverges from TOG4. Docking TOG3 onto recently solved Stu2 TOG1. and TOG2.tubulin complex structures suggests that TOG3 uses similarly conserved tubulin-binding intra-HEAT loop residues to engage alpha- and beta-tubulin. This indicates that TOG3 has maintained a TOG1- and TOG2 like TOG-tubulin binding mode despite structural divergence. The similarity of TOG domains 1-3 and the divergence of TOG4 suggest that a TOG domain array with polarized structural diversity may play a key mechanistic role in XMAP215 dependent MT polymerization activity. PMID- 25720491 TI - Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes multidrug resistance by a novel mechanism involving the hijacking of lysosomal P glycoprotein (Pgp). AB - Multidrug resistance (MDR) is a major obstacle in cancer treatment. More than half of human cancers express multidrug-resistant P-glycoprotein (Pgp), which correlates with a poor prognosis. Intriguingly, through an unknown mechanism, some drugs have greater activity in drug-resistant tumor cells than their drug sensitive counterparts. Herein, we investigate how the novel anti-tumor agent di 2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes MDR. Four different cell types were utilized to evaluate the effect of Pgp-potentiated lysosomal targeting of drugs to overcome MDR. To assess the mechanism of how Dp44mT overcomes drug resistance, cellular studies utilized Pgp inhibitors, Pgp silencing, lysosomotropic agents, proliferation assays, immunoblotting, a Pgp ATPase activity assay, radiolabeled drug uptake/efflux, a rhodamine 123 retention assay, lysosomal membrane permeability assessment, and DCF (2',7' dichlorofluorescin) redox studies. Anti-tumor activity and selectivity of Dp44mT in Pgp-expressing, MDR cells versus drug-sensitive cells were studied using a BALB/c nu/nu xenograft mouse model. We demonstrate that Dp44mT is transported by the lysosomal Pgp drug pump, causing lysosomal targeting of Dp44mT and resulting in enhanced cytotoxicity in MDR cells. Lysosomal Pgp and pH were shown to be crucial for increasing Dp44mT-mediated lysosomal damage and subsequent cytotoxicity in drug-resistant cells, with Dp44mT being demonstrated to be a Pgp substrate. Indeed, Pgp-dependent lysosomal damage and cytotoxicity of Dp44mT were abrogated by Pgp inhibitors, Pgp silencing, or increasing lysosomal pH using lysosomotropic bases. In vivo, Dp44mT potently targeted chemotherapy-resistant human Pgp-expressing xenografted tumors relative to non-Pgp-expressing tumors in mice. This study highlights a novel Pgp hijacking strategy of the unique dipyridylthiosemicarbazone series of thiosemicarbazones that overcome MDR via utilization of lysosomal Pgp transport activity. PMID- 25720492 TI - Selective insulin resistance in adipocytes. AB - Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID- 25720493 TI - Activated alpha2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses. AB - Ligation of cell surface GRP78 by activated alpha2-macroglobulin (alpha2M*) promotes cell proliferation and suppresses apoptosis. alpha2M*-treated human prostate cancer cells exhibit a 2-3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both alpha2M* and insulin treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with alpha2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these alpha2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. alpha2M* induces a 2-3-fold increase in lipogenesis as determined by 6 [(14)C]glucose or 1-[(14)C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [(14)CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that alpha2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy. PMID- 25720494 TI - ATP6AP2/(pro)renin receptor contributes to glucose metabolism via stabilizing the pyruvate dehydrogenase E1 beta subunit. AB - Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Here, we revealed an unsuspected role for (pro)renin receptor, also known as ATP6AP2, in energy metabolism. Immunoprecipitation and mass spectrometry analyses identified the pyruvate dehydrogenase (PDH) complex as Atp6ap2-interacting proteins in the mouse retina. Yeast two-hybrid assays demonstrated direct molecular binding between ATP6AP2 and the PDH E1 beta subunit (PDHB). Pdhb immunoreactivity co-localized with Atp6ap2 in multiple retinal layers including the retinal pigment epithelium (RPE). ATP6AP2 knockdown in RPE cells reduced PDH activity, showing a predilection to anaerobic glycolysis. ATP6AP2 protected PDHB from phosphorylation, thus controlling its protein stability. Down-regulated PDH activity due to ATP6AP2 knockdown inhibited glucose-stimulated oxidative stress in RPE cells. Our present data unraveled the novel function of ATP6AP2/(P)RR as a PDHB stabilizer, contributing to aerobic glucose metabolism together with oxidative stress. PMID- 25720495 TI - Structural basis of the stereospecificity of bacterial B12-dependent 2 hydroxyisobutyryl-CoA mutase. AB - Bacterial coenzyme B12-dependent 2-hydroxyisobutyryl-CoA mutase (HCM) is a radical enzyme catalyzing the stereospecific interconversion of (S)-3 hydroxybutyryl- and 2-hydroxyisobutyryl-CoA. It consists of two subunits, HcmA and HcmB. To characterize the determinants of substrate specificity, we have analyzed the crystal structure of HCM from Aquincola tertiaricarbonis in complex with coenzyme B12 and the substrates (S)-3-hydroxybutyryl- and 2 hydroxyisobutyryl-CoA in alternative binding. When compared with the well studied structure of bacterial and mitochondrial B12-dependent methylmalonyl-CoA mutase (MCM), HCM has a highly conserved domain architecture. However, inspection of the substrate binding site identified amino acid residues not present in MCM, namely HcmA Ile(A90) and Asp(A117). Asp(A117) determines the orientation of the hydroxyl group of the acyl-CoA esters by H-bond formation, thus determining stereospecificity of catalysis. Accordingly, HcmA D117A and D117V mutations resulted in significantly increased activity toward (R)-3-hydroxybutyryl-CoA. Besides interconversion of hydroxylated acyl-CoA esters, wild-type HCM as well as HcmA I90V and I90A mutant enzymes could also isomerize pivalyl- and isovaleryl CoA, albeit at >10 times lower rates than the favorite substrate (S)-3 hydroxybutyryl-CoA. The nonconservative mutation HcmA D117V, however, resulted in an enzyme showing high activity toward pivalyl-CoA. Structural requirements for binding and isomerization of highly branched acyl-CoA substrates such as 2 hydroxyisobutyryl- and pivalyl-CoA, possessing tertiary and quaternary carbon atoms, respectively, are discussed. PMID- 25720496 TI - Mdm2 promotes myogenesis through the ubiquitination and degradation of CCAAT/enhancer-binding protein beta. AB - Myogenesis is a tightly regulated differentiation process during which precursor cells express in a coordinated fashion the myogenic regulatory factors, while down-regulating the satellite cell marker Pax7. CCAAT/Enhancer-binding protein beta (C/EBPbeta) is also expressed in satellite cells and acts to maintain the undifferentiated state by stimulating Pax7 expression and by triggering a decrease in MyoD protein expression. Herein, we show that C/EBPbeta protein is rapidly down-regulated upon induction of myogenesis and this is not due to changes in Cebpb mRNA expression. Rather, loss of C/EBPbeta protein is accompanied by an increase in Mdm2 expression, an E3 ubiquitin ligase. We demonstrate that Mdm2 interacts with, ubiquitinates and targets C/EBPbeta for degradation by the 26 S proteasome, leading to increased MyoD expression. Knockdown of Mdm2 expression in myoblasts using a shRNA resulted in high C/EBPbeta levels and a blockade of myogenesis, indicating that Mdm2 is necessary for myogenic differentiation. Primary myoblasts expressing the shMdm2 construct were unable to contribute to muscle regeneration when grafted into cardiotoxin injured muscle. The differentiation defect imposed by loss of Mdm2 could be partially rescued by loss of C/EBPbeta, suggesting that the regulation of C/EBPbeta turnover is a major role for Mdm2 in myoblasts. Taken together, we provide evidence that Mdm2 regulates entry into myogenesis by targeting C/EBPbeta for degradation by the 26 S proteasome. PMID- 25720498 TI - Evaluation of multi-outcome longitudinal studies. AB - Evaluation of intervention effects on multiple outcomes is a common scenario in clinical studies. In longitudinal studies, such evaluation is a challenge if one wishes to adequately capture simultaneous data behavior. In this situation, a common approach is to analyze each outcome separately. As a result, multiple statistical statements describing the intervention effect need to be reported and an adjustment for multiple testing is necessary. This is typically done by means of the Bonferroni procedure, which does not take into account the correlation between outcomes, thus resulting in overly conservative conclusions. We propose an alternative approach for multiplicity adjustment that incorporates dependence between outcomes, resulting in an appreciably less conservative evaluation. The ability of the proposed method to control the familywise error rate is evaluated in a simulation study, and the applicability of the method is demonstrated in two examples from the literature. PMID- 25720497 TI - The induction of apoptosis and autophagy by Wasabia japonica extract in colon cancer. AB - PURPOSE: Wasabia japonica (wasabi) has been shown to exhibit properties of detoxification, anti-inflammation and the induction of apoptosis in cancer cells. This study aimed to investigate the molecular mechanism of the cytotoxicity of wasabi extract (WE) in colon cancer cells to evaluate the potential of wasabi as a functional food for chemoprevention. METHODS: Colo 205 cells were treated with different doses of WE, and the cytotoxicity was analyzed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Apoptosis and autophagy were detected by 4',6-diamidino-2-phenylindole, 5,5',6,6'-tetrachloro-1,1',3,3' tetraethyl-imidacarbo-yanine iodide and staining for acidic vascular organelles (AVOs), along with Western blotting. RESULTS: The results demonstrated that WE induced the extrinsic pathway and mitochondrial death machinery through the activation of TNF-alpha, Fas-L, caspases, truncated Bid and cytochrome C. WE also induced autophagy by decreasing the phosphorylation of Akt and mTOR and promoting the expression of microtubule-associated protein 1 light chain 3-II and AVO formation. An in vivo xenograft model verified that tumor growth was delayed by WE treatment. CONCLUSION: Our studies revealed that WE exhibits anti-colon cancer properties through the induction of apoptosis and autophagy. These results provide support for the application of WE as a chemopreventive functional food and as a prospective treatment of colon cancer. PMID- 25720499 TI - Sensing of enantiomeric excess in chiral carboxylic acids. AB - Cinchona alkaloids (quinine, quinidine, cinchonine, cinchonidine) alkylated at N(1) with chloromethyl anthracene can serve as fluorescent sensors for chiral carboxylic acids. These cinchona ammonium salts are shown to bind chiral carboxylic acids while displaying an increase in fluorescence intensity that can be utilized in determination of enantiomeric excess (ee). Sensor arrays composed of four cinchona ammonium salts are used for quantitative analysis of ee in several non-steroidal anti-inflammatory drugs (NSAIDs), such as enantiomers of ibuprofen, ketoprofen, and naproxen. PMID- 25720500 TI - Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans. AB - Advanced glycation end products (AGEs) are formed when glucose reacts nonenzymatically with proteins; these modifications are implicated in aging and pathogenesis of many age-related diseases including type II diabetes, atherosclerosis, and neurodegenerative disorders. Thus, pharmaceutical interventions that can reduce AGEs may delay age-onset diseases and extend lifespan. Using LC-MS(E), we show that rifampicin (RIF) reduces glycation of important cellular proteins in vivo and consequently increases lifespan in Caenorhabditis elegans by up to 60%. RIF analog rifamycin SV (RSV) possesses similar properties, while rifaximin (RMN) lacks antiglycation activity and therefore fails to affect lifespan positively. The efficacy of RIF and RSV as potent antiglycating agents may be attributed to the presence of a p-dihydroxyl moiety that can potentially undergo spontaneous oxidation to yield highly reactive p-quinone structures, a feature absent in RMN. We also show that supplementing rifampicin late in adulthood is sufficient to increase lifespan. For its effect on longevity, rifampicin requires DAF-18 (nematode PTEN) as well as JNK-1 and activates DAF-16, the FOXO homolog. Interestingly, the drug treatment modulates transcription of a different subset of DAF-16 target genes, those not controlled by the conserved Insulin-IGF-1-like signaling pathway. RIF failed to increase the lifespan of daf-16 null mutant despite reducing glycation, showing thereby that DAF-16 may not directly affect AGE formation. Together, our data suggest that the dual ability to reduce glycation in vivo and activate prolongevity processes through DAF-16 makes RIF and RSV effective lifespan extending interventions. PMID- 25720502 TI - Molecular dynamics study of alkylsilane monolayers on realistic amorphous silica surfaces. AB - Interfacial properties of n-alkylsilane monolayers on silica have been investigated with molecular dynamics simulations using both reactive and classical (i.e., nonreactive) force fields. A synthesis mimetic simulation (SMS) procedure using the reactive force field ReaxFF has been developed to mimic the experimental processing of silicon wafers involved in the preparation of alkylsilane monolayers; in the SMS procedure, amorphous silica surfaces are generated and exposed to hydrogen peroxide (H2O2) to create a hydroxide surface layer. Alkylsilane monolayers are then assembled on these surfaces, and their behavior is studied. To investigate the impact of the SMS procedure on monolayer properties, simulations have also been performed using more idealized monolayers assembled on crystalline surfaces and non-H2O2-processed amorphous surfaces. The simulations reported here demonstrate that processing-induced silica surface roughness plays a key role in the structure and frictional performance of monolayers. Furthermore, ignoring these effects results in a significant underestimation of the coefficient of friction and an overestimation of the orientational ordering of the monolayers. PMID- 25720501 TI - Aphthous ulcers (recurrent). AB - INTRODUCTION: Most people with recurrent aphthous ulcers develop a few ulcers less than 10 mm in diameter that heal after 7 to 10 days without scarring. The causes are unknown but local physical trauma may trigger ulcers in susceptible people. In 10% of sufferers, lesions are more than 10 mm in diameter and can cause scarring. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of selected topical treatments for recurrent idiopathic aphthous ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics (local), corticosteroids (topical), tetracycline antibiotic mouthwash, and topical antiseptic agents (chlorhexidine and similar agents). PMID- 25720503 TI - Defining optimized properties of modified mRNA to enhance virus- and DNA- independent protein expression in adult stem cells and fibroblasts. AB - BACKGROUND: By far, most strategies for cell reprogramming and gene therapy are based on the introduction of DNA after viral delivery. To avoid the high risks accompanying these goals, non-viral and DNA-free delivery methods for various cell types are required. METHODS: Relying on an initially established PCR-based protocol for convenient template DNA production, we synthesized five differently modified EGFP mRNA (mmRNA) species, incorporating various degrees of 5 methylcytidine-5'-triphosphate (5mC) and pseudouridine-5'-triphosphate (Psi). We then investigated their effect on i) protein expression efficiencies and ii) cell viability for human mesenchymal stem cells (hMSCs) and fibroblasts from different origins. RESULTS: Our protocol allows highly efficient mmRNA production in vitro, enabling rapid and stable protein expression after cell transfection. However, our results also demonstrate that the terminally optimal modification needs to be defined in pilot experiments for each particular cell type. Transferring our approach to the conversion of fibroblasts into skeletal myoblasts using mmRNA encoding MyoD, we confirm the huge potential of mmRNA based protein expression for virus- and DNA-free reprogramming strategies. CONCLUSION: The achieved high protein expression levels combined with good cell viability not only in fibroblasts but also in hMSCs provides a promising option for mmRNA based modification of various cell types including slowly proliferating adult stem cells. Therefore, we are confident that our findings will substantially contribute to the improvement of efficient cell reprogramming and gene therapy approaches. PMID- 25720504 TI - TAPBPR: a new player in the MHC class I presentation pathway. AB - In order to provide specificity for T cell responses against pathogens and tumours, major histocompatibility complex (MHC) class I molecules present high affinity peptides at the cell surface to T cells. A key player for peptide loading is the MHC class I-dedicated chaperone tapasin. Recently we discovered a second MHC class I-dedicated chaperone, the tapasin-related protein TAPBPR. Here, we review the major steps in the MHC class I pathway and the TAPBPR data. We discuss the potential function of TAPBPR in the MHC class I pathway and the involvement of this previously uncharacterised protein in human health and disease. PMID- 25720506 TI - Autoimmune risk loci of IL12RB2, IKZF1, XKR6, TMEM39A and CSK in Chinese patients with systemic lupus erythematosus. AB - Recent genome-wide or follow-up studies conducted in European or Caucasian populations have identified single nucleotide polymorphisms (SNPs) conferring increased risk to autoimmune diseases. It is unclear whether these observations can apply to systemic lupus erythematosus (SLE) in China. An association study was performed on 395 SLE patients and 378 healthy controls recruited from the Chinese population, in which the IL12RB2 rs3790567, IKZF1 rs2366293, XKR6 rs4240671, TMEM39A rs1132200 and CSK rs34933034 polymorphisms were examined by Matrix Assisted Laser Desorption Time of Flight Mass Spectrometry. The frequency of the A allele of IL12RB2 rs3790567 was lower in the cases compared with the controls (24.8% vs 30.2%, P = 0.018) and significant difference among the AA, AG and GG genotypes of rs3790567 was detected between the SLE patients and healthy controls (P = 0.020). We also found a statistically significant difference in the dominant model (GG+AG vs AA, P = 0.008). There was no correlation between the genotypes and specific sub-phenotypes in the current cohort. Associations with IKZF1 rs2366293, XKR6 rs4240671, TMEM39A rs1132200 and CSK rs34933034 were also lacking (P > 0.05). The results supported the theory that IL12RB2 is associated with SLE in the Chinese population. PMID- 25720507 TI - A toll-like receptor 3 single nucleotide polymorphism in Japanese patients with sarcoidosis. AB - Toll-like receptor 3 (TLR3) may be associated with T helper 1 immune response. This study aimed to investigate the role of a functional TLR3 single nucleotide polymorphism (SNP) in sarcoidosis. We genotyped 220 Japanese patients with sarcoidosis and 140 controls for TLR3 SNP rs3775291 to analyze its association with susceptibility to sarcoidosis and assessed its relationship to clinical features in 172 patients over 2 years. The TLR3 rs3775291 genotype was not significantly associated with disease susceptibility. However, patients with cardiac sarcoidosis (CS) significantly more frequently had the TT genotype (p < 0.01) or the T allele (p < 0.05) than those patients without CS. We conclude that TLR3 SNP rs3775291 may affect cardiac involvement in Japanese patients with sarcoidosis. PMID- 25720508 TI - Identification a novel HLA-B*27:105 allele in a Chinese bone marrow donor by polymerase chain reaction sequence-based typing. AB - HLA-B*27:105 has one nucleotide change from HLA-B*27:04:01 at nucleotide position 404 from G to A. PMID- 25720509 TI - Identification of a novel HLA-DRB1 allele, HLA-DRB1*12:51, in a Chinese Cord Blood Donor. AB - HLA-DRB1*12:51 has a single nucleotide difference to DRB1*12:02:01 at position 208, G > T. PMID- 25720510 TI - Nomenclature for factors of the HLA system, update October 2014. PMID- 25720511 TI - Nomenclature for factors of the HLA system, update November 2014. PMID- 25720512 TI - Nomenclature for factors of the HLA system, update December 2014. PMID- 25720513 TI - The hundred most cited articles in bariatric surgery. AB - BACKGROUND: Many studies quantitatively analyzing scientific papers have appeared in the last 2 years. Citation analysis is a commonly used bibliometric method. In spite of some limitations, it remains a good measure of the impact an article has on a specific field, specialty, or a journal. The aim of this study was to analyze the qualities and characteristics of the 100 most cited articles in the field of bariatric surgery. METHODS: The Thomson Reuters Web of Knowledge was used to list all bariatric surgery-related articles (BSRA) published from 1945 to 2014. The top 100 most cited BSRA in 354 surgical and high impact general journals were selected for further analysis. RESULTS: Most of the articles were published in the 2000s (60%). The top 100 most cited were published in 17 of the 354 journals. Leading countries were USA followed by Canada and Australia. Most of the articles published (76%) were clinical experience articles. The most common level of evidence was IV (42%). CONCLUSIONS: Many of the milestone papers in bariatric surgery have been included in this bibliometric study. A huge increase in research activity during the last decade is clearly visible in the field. It is apparent that the number of citations of an article is not related to its level of evidence; a fact that is increasingly being emphasized in surgical research. PMID- 25720514 TI - Outcomes of revisional treatment modalities in non-complicated Roux-en-Y gastric bypass patients with weight regain. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (RYGB) is an effective treatment modality for severe obesity. Failure of weight loss and/or weight regain due to lack of restriction has been reported in long-term follow-up studies. The aim of this study is to determine the safety and effectiveness of reestablishing the restrictive component of the operation by trimming the pouch and/or anastomosis for pouch and/or anastomotic enlargement using a laparoscopic approach. METHODS: We retrospectively reviewed our prospectively collected database for all patients that underwent revisional surgery of RYGB for weight regain or failure of weight loss. Percent excess weight loss (%EWL) and BMI loss (BMIL) were characterized into the following three time periods: (1) primary operation to pre-revision, (2) pre-revision to post-revision, and (3) primary operation to post-revision. Post-operative follow-up was at 6, 12, 18, 24, 36, and 48 months. RESULTS: Between 2005 and 2011, a total of 121 patients in the database underwent revision of RYGB. Forty-four patients were identified that fulfilled the aforementioned parameters. In this group, 30 patients underwent trimming of the pouch and/or redo anastomosis (TPA), 8 TPA and conversion from retrocolic to antecolic Roux limb, and 6 TPA with remnant gastrectomy. Mean follow-up period was 26.1 +/- 22.7 months. The post-revision mean %EWL was 38%, and the BMI loss was 7 kg/m(2). In the pre-revision to 48 months post-revision time period, mean %EWL and BMIL were 28.6% and 4.9 kg/m(2) in the TPA-only group, 52% and 8.8 kg/m(2) in the TPA with conversion to antecolic, antegastric group, and 33.4% and 5.9 kg/m(2) in the TPA with gastrectomy group, respectively (%EWL, p = 0.096; BMIL, p = 0.227). One patient (2.3%) developed a left upper quadrant hematoma. There was no mortality in this series. CONCLUSIONS: Trimming of the pouch and/or anastomosis appears to be a safe and effective revisional modality for patients with insufficient weight loss or weight regain after gastric bypass in the hands of experienced surgeons. PMID- 25720515 TI - Prognostic Significance of Depressive Symptoms on Weight Loss and Psychosocial Outcomes Following Gastric Bypass Surgery: A Prospective 24-Month Follow-Up Study. AB - BACKGROUND: This study examined the prognostic significance of depressive symptoms in bariatric surgery patients over 24 months of follow-ups. METHODS: Three hundred fifty-seven patients completed a battery of assessments before and at 6, 12, and 24 months following gastric bypass surgery. In addition to weight loss and depressive symptoms, the assessments targeted eating disorder psychopathology and quality of life. RESULTS: Clinically significant depressive symptoms, defined as a score of 15 or greater on the Beck Depression Inventory, characterized 45% of patients prior to surgery, and 12% at 6-month follow-up, 13% at 12-month follow-up, and 18% at 24-month follow-up. Preoperative depressive symptoms did not predict postoperative weight outcomes. In contrast, postsurgery depressive symptoms were predictive of weight loss outcomes. Higher postsurgery depressive symptoms at each time point predicted a greater degree of concurrent and subsequent eating disorder psychopathology and lower quality of life. CONCLUSIONS: The frequency of elevated depressive symptoms decreases substantially following gastric bypass surgery but increases gradually over 24 months. Postoperative depressive symptoms are significantly associated with poorer weight outcomes at 6 and 12 months following surgery but do not predict longer-term weight outcomes at 24 months. Postoperative depressive symptoms prospectively predict greater eating disorder psychopathology and poorer quality of life through 24 months. Elevated depressive symptoms, readily assessed by self report, may signal a need for clinical attention after surgery. PMID- 25720516 TI - Outcomes of Robot-Assisted Roux-en-Y Gastric Bypass as a Reoperative Bariatric Procedure. AB - BACKGROUND: We evaluate the outcomes of robot-assisted Roux-en-Y gastric bypass (RRYGB) as a reoperative bariatric procedure (RBP). METHODS: A retrospective analysis was done from 2007 to 2014, and all the patients who underwent RRYGB as a RBP at a teaching university hospital were included. RESULTS: A total of 32 patients underwent RRYGB as a reoperation from adjustable gastric band (AGB n = 16) or sleeve gastrectomy (SG n = 11) or previous gastric bypass (n = 5). Twenty patients underwent conversion to RRYGB due to weight loss failure, either after AGB (n = 13) or SG (n = 7). Twelve patients underwent reoperation because of complications of index procedure. Mean preoperative weight was 109.7 +/- 29.5 kg, and BMI was 40 +/- 10.6 kg/m(2). The mean operative time for RRYGB was 226 +/- 45.3 min with a blood loss of 20 +/- 15.9 ml. Average length of stay was 3 days. In two cases, pin point leaks were detected intraoperatively during check gastroscopy, and they were repaired with sutures. There were no postoperative anastomotic leaks or hemorrhage or gastrojejunostomy strictures. None of the patients required a blood transfusion or reoperation within perioperative period. In the patients who underwent RRYGB for weight loss failure (n = 20), the mean excess weight loss (EWL) was 39.2% at 6 months (n = 11), 53.8% at 1 year (n = 13), and 60.7% at 2 years (n = 6). CONCLUSIONS: RRYGB is safe and effective to be used as a revisional bariatric procedure. The weight loss outcomes and complication rates compare favorably with the published results of laparoscopic technique, although the small sample size may not be enough to reach definite conclusions. PMID- 25720517 TI - Bariatric Surgery Patients' Response to a Chronic Pain Rehabilitation Program. AB - BACKGROUND: Chronic pain (CP) is a prevalent and disabling diagnosis in obese individuals, but how bariatric surgery patients respond to chronic pain rehabilitation treatment programs has not previously been described. OBJECTIVES: The aim of this study was to compare treatment outcomes of a chronic pain rehabilitation program (psychological and pain variables, medication use, treatment completion rates) for post-bariatric surgery patients to those of a non bariatric surgery control group. SETTING: Three week outpatient multidisciplinary chronic pain program in an academic medical center. METHODS: This was a retrospective case-control study. Medical records of patients admitted to the Pain Rehabilitation Center at Mayo Clinic from 2008 to 2012 were reviewed. One hundred six patients with a history of bariatric surgery (cases) were identified and matched to 106 patients without a history of bariatric surgery (controls) on age, gender, and smoking status (n = 202). Matched t tests and McNemar's tests were used for analyses. RESULTS: Mean age was 46 years; 91% were female and 58% were non-smokers. The majority of cases (71%) had undergone Roux-en-Y gastric bypass. Bariatric patients had higher rates of benzodiazepine use at discharge (33 vs. 19%, p = 0.0433) and were less likely to complete treatment (87 vs. 97%, p = 0.007) compared to controls. Morphine equivalent use for cases was 127.3 mg +/- 135.4 (n = 62) compared to 88.3 mg +/- 95.3 (n = 62), p = 0.12, for controls at admission. CONCLUSIONS: These results suggest that bariatric patients may be at risk for treatment non-adherence and have difficulty reducing medication use in the treatment of chronic pain. PMID- 25720518 TI - Two novel CAII mutations causing carbonic anhydrase II deficiency syndrome in two unrelated Chinese families. AB - The carbonic anhydrase II (CAII) deficiency syndrome is a rare autosomal recessive osteopetrosis with renal tubular acidosis (RTA) and cerebral calcifications (MIM259730). CAII deficiency syndrome is caused by mutations in the gene CAII, which encodes the enzyme carbonic anhydrase II. CAII mutations are rarely reported in the Asian population. Here, we described two unrelated CAII deficiency families of Chinese Han origin with clinical and genetic analysis. Altogether, 106 subjects, including 2 probands, 4 unaffected family members from two non-consanguineous Chinese families, and 100 healthy controls were recruited. All seven exons and the exon-intron boundaries of the CAII gene were amplified and directly sequenced. Reverse transcription PCR (RT-PCR) was used to study the effect of splice site mutation. All clinical and biochemical parameters of the probands were collected. Two novel mutations of CAII gene were identified by mutational analysis: A nonsense mutation in exon 4 (c.T381C p.Y127X) in both families; a splice mutation at the splice donor site of intron 3 (c.350+2T>C, IVS3+2T>C) in one family. The splice-site mutation causes exon 3 skipping in patient's mRNA resulting in an in-frame deletion and a novel premature stop codon. These mutations were predicted to result in a loss of function of CAII. This is the first report of CAII deficiency syndrome in Chinese population. Our findings extent the spectrum of CAII mutations observed in patients with CAII deficiency syndrome. PMID- 25720519 TI - Administration of umbilical cord blood cells transiently decreased hypoxic ischemic brain injury in neonatal rats. AB - This study aimed to investigate whether the administration of mononuclear cells derived from human umbilical cord blood cells (UCBCs) could ameliorate hypoxic ischemic brain injury in a neonatal rat model. The left carotid arteries of 7-day old rats were ligated, and the rats were then exposed to 8% oxygen for 60 min. Mononuclear cells derived from UCBCs using the Ficoll-Hypaque technique were injected intraperitoneally 6 h after the insult (1.0 * 10(7) cells). Twenty-four hours after the insult, the number of cells positive for the oxidative stress markers 4-hydroxy-2-nonenal and nitrotyrosine, in the dentate gyrus of the hippocampus in the UCBC-treated group, decreased by 36 and 42%, respectively, compared with those in the control group. In addition, the number of cells positive for the apoptosis markers active caspase-3 and apoptosis-inducing factor decreased by 53 and 58%, respectively. The number of activated microglia (ED1 positive cells) was 51% lower in the UCBC group compared with the control group. In a gait analysis performed 2 weeks after the insult, there were no significant differences among the sham-operated, control and UCBC groups. An active avoidance test using a shuttle box the following week also revealed no significant differences among the groups. Neither the volumes of the hippocampi, corpus callosum and cortices nor the numbers of neurons in the hippocampus were different between the UCBC and control groups. In summary, a single intraperitoneal injection of UCBC-derived mononuclear cells 6 h after an ischemic insult was associated with a transient reduction in numbers of apoptosis and oxidative stress marker-positive cells, but it did not induce long-term morphological or functional protection. Repeated administration or a combination treatment may be required to achieve sustained protection. PMID- 25720520 TI - 'Underclassism' and access to healthcare in urban centres. AB - In this article, we draw on findings from an ethnographic study that explored experiences of healthcare access from the perspectives of Indigenous and non Indigenous patients seeking services at the non-urgent division of an urban emergency department (ED) in Canada. Our aim is to critically examine the notion of 'underclassism' within the context of healthcare in urban centres. Specifically, we discuss some of the processes by which patients experiencing poverty and racialisation are constructed as 'underclass' patients, and how assumptions of those patients as social and economic Other (including being seen as 'drug users' and 'welfare dependents') subject them to marginalisation, discrimination, and inequitable treatment within the healthcare system. We contend that healthcare is not only a clinical space; it is also a social space in which unequal power relations along the intersecting axes of 'race' and class are negotiated. Given the largely invisible roles that healthcare plays in controlling access to resources and power for people who are marginalised, we argue that there is an urgent need to improve healthcare inequities by challenging the taken-for-granted assumption that healthcare is equally accessible for all Canadians irrespective of differences in social and economic positioning. PMID- 25720521 TI - From theory to clinical practice: a phenomenologically inspired intervention for patients with schizophrenia. AB - BACKGROUND: Phenomenological conceptualizations of schizophrenia regard the fundamental transformation of self-experience as the central feature of the schizophrenic state of mind. Recently, self-disorders as subtle, trait-like, merely subjective alterations of self-experience have received vast empirical attention. However, the question of how to address self-disorders psychotherapeutically has remained neglected. METHODS: From phenomenologically inspired analyses of self-disorders we derive a therapeutic intervention that focuses on the following: (1) verbalizing diffuse changes in self-experiences and (2) conceptualizing these self-experiences in terms of aggravating and relieving factors in order to stimulate coping and derive targeted therapeutic interventions. RESULTS: The clinical implementation is illustrated by two case studies. The feasibility of our approach is preliminarily supported by an exploratory study. CONCLUSIONS: This intervention seems promising in assisting patients to develop an embodied and enacted understanding of self-disorders. PMID- 25720522 TI - Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas. AB - Alterations in global DNA methylation and specific regulatory gene methylation are frequently found in cancer, but the significance of these epigenetic changes in EBV-associated gastric carcinoma (EBVaGC) remains unclear. We evaluated global DNA methylation status in 49 EBVaGC and 45 EBV-negative gastric carcinoma (EBVnGC) tissue samples and cell lines by 5-methylcytosine immunohistochemical staining and methylation quantification. We determined promoter methylation status and protein expression for the p16, FHIT, CRBP1, WWOX, and DLC-1 genes in tissues and studied the correlation between CpG island methylator phenotype (CIMP) class and clinicopathological characteristics. Changes in gene methylation and mRNA expression in EBVaGC cell line SNU-719 and in EBVnGC cell lines SGC 7901, BGC-823, and AGS were assessed after treatment with 5-aza-2'-deoxycytidine (5-aza-dC), trichostatin A (TSA), or a combination of both, by methylation specific PCR and quantitative real-time RT-PCR. Global genomic DNA hypomethylation was more pronounced in EBVnGC than in EBVaGC. Promoter methylation of all five genes was more frequent in EBVaGC than in EBVnGC (p < 0.05). p16 and FHIT methylation was reversely correlated with protein expression in EBVaGC. Most (41/49) EBVaGC exhibited CIMP-high (CIMP-H), and the prognosis of CIMP-H patients was significantly worse than that of CIMP-low (p = 0.027) and CIMP-none (p = 0.003) patients. Treatment with 5-aza-dC and/or TSA induced upregulation of RNA expression of all five genes in SNU-719; meanwhile, individual gene expression increased in EBVnGC cell lines. In summary, EBV induced hypermethylation of p16, FHIT, CRBP1, WWOX, and DLC-1 may contribute to EBVaGC development. Demethylation therapy may represent a novel therapeutic strategy for EBVaGC. PMID- 25720523 TI - Systemic treatment with capecitabine as maintenance therapy in patients with recurring or metastatic breast cancer: experience in the Oncology Hospital, National Medical Center Siglo XXI, Mexican Social Security Institute. AB - Metastatic breast cancer as initial onset represents between 20 and 30 % of cases and is considered an incurable disease. The goal of its treatment is palliative, looking for increasing the survival while reducing the symptoms. Maintenance chemotherapy studies for metastatic breast cancer have demonstrated to prolong the progression-free survival, with unclear results in terms of overall survival. The main objectives of our study were the progression-free survival and overall survival in patients with recurring or metastatic breast cancer treated with capecitabine in the maintenance chemotherapy setting compared with patients not receiving maintenance chemotherapy. As secondary objectives, the frequency of dose-limiting toxicities and response rate were determined. A non-probabilistic sampling was used, through expert selection of patients from the recurring/metastatic breast cancer survey cared within the period from January 1, 2007, to December 21, 2012. A total of 77 patients were included. Clinical data of advanced/recurrent breast cancer patients that were treated with capecitabine were recorded. The study achieved its primary objective, since the progression free survival was prolonged for the maintenance therapy group: 6.6 versus 18.1 months, p < 0.001. The absolute benefit was 11.5 months. Likewise, there was a benefit in the overall survival of 21.03 versus 29 months, p = 0.015, with an absolute benefit of 7.97 months. The toxicity profile was favorable in the maintenance group. The maintenance chemotherapy with capecitabine in patients treated at the National Medical Center Siglo XXI Oncology Hospital extends the overall survival and progression-free survival with a good toxicity profile. PMID- 25720524 TI - PPARgamma suppressed Wnt/beta-catenin signaling pathway and its downstream effector SOX9 expression in gastric cancer cells. AB - Wnt signaling pathway activation plays a critical role in biological processes of tumor progression. SOX9 belongs to the sry-related high-mobility group box (SOX) family and is a key transcription factor in the development and differentiation of multiple cell lineages. The purpose of this study was to investigate whether suppression of Wnt signaling pathway by PPARgamma gene affects target SOX9 gene expression. The pEGFP-N1-PPARgamma overexpression recombinant plasmid was structured by molecular biology technology. The overexpression plasmid and empty vector pEGFP-N1 were transfected into three types of human gastric cancer cell lines, with different levels of differentiation, MKN-28, SGC-7901 and BGC-823. The PPARgamma, beta-catenin and SOX9 mRNA levels and proteins were examined by real-time PCR and Western blot analysis. The pEGFP-N1-PPARgamma recombinant plasmid was constructed and transfected into MKN-28, SGC-7901 and BGC-823 successfully. High expression of PPARgamma (p < 0.05) for transfection recombinant plasmid group induced obviously decreased expression of beta-catenin (p < 0.05), whereas SOX9 expression decreased significantly (p < 0.05) compared with the transfection empty vector group and normal comparison group. PPARgamma can suppress beta-catenin expression in Wnt signaling pathway and its downstream effector SOX9 expression in gastric cancer cells. PMID- 25720525 TI - Pomegranate juice does not affect the disposition of simvastatin in healthy subjects. AB - Previous in vitro and in vivo investigations reported controversial results for the inhibitory potential of pomegranate on Cytochrome P450 (CYP) 3A activity. This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic parameters of simvastatin and simvastatin acid were compared among the study periods. In the period of grapefruit juice, the mean C max and AUCinf of simvastatin [the geometric mean ratio (90 % CI) 15.6 (11.6-21.0) and 9.1 (6.0-13.7)] were increased significantly when compared with the control period, whereas they were not significantly different in the period of pomegranate juice [C max and AUCinf 1.20 (0.89-1.62) and 1.29 (0.85-1.94)]. The mean C max and AUCinf of simvastatin acid were increased significantly after intake of grapefruit juice, but not pomegranate juice. These results suggest that pomegranate juice affects little on the disposition of simvastatin in humans. Pomegranate juice does not seem to have a clinically relevant inhibitory potential on CYP3A4 activity. PMID- 25720526 TI - Transition of new dental graduates into practice: a qualitative study. AB - AIMS: The aims of this study were to explore the transition of new dental graduates to gain a deeper understanding of the merits and challenges of a mentored year for new graduates in general dental practice settings. METHODS: The study was conducted in the south-west region of England. Qualitative methods were used to engage a range of stakeholders in dental education including dental students, academics, general dental practitioners, new graduates, specialists and representatives of the postgraduate dental deanery. Purposive sampling was employed, and after ethical approval, participants were contacted through professional channels. All interview transcripts were transcribed verbatim. The data were imported into NVivo 10 (QSR International Pty Ltd) and analysed thematically. RESULTS: Sixteen participants representing a variety of stakeholder groups were interviewed. The participants shared their perceptions and experiences regarding the transition new dental graduates into dental practice. The challenges and benefits are discussed along with strategies to facilitate a smooth transition. CONCLUSIONS: This study provides an insight into experience of a mentored year for new dental graduates in general practice settings. Foundation training provides a structured introduction into general practice and serves as a safety net before new graduates gain further independence in clinical practice. PMID- 25720527 TI - Virtual taphonomy: A new method integrating excavation and postprocessing in an archaeological context. AB - The objective of this paper was to integrate excavation and post-processing of archaeological and osteological contexts and material to enhance the interpretation of these with specific focus on the taphonomical aspects. A method was designed, Virtual Taphonomy, based on the use and integration of image-based 3D modeling techniques into a 3D GIS platform, and tested on a case study. Merging the 3D models and a database directly in the same virtual environment allowed the authors to fully integrate excavation and post-processing in a complex spatial analysis reconnecting contexts excavated on different occasions in the field process. The case study further demonstrated that the method enabled a deeper understanding of the taphonomic agents at work and allowed the construction of a more detailed interpretation of the skeletal remains than possible with more traditional methods. The method also proved to add transparency to the entire research process from field to post-processing and interpretation. Other benefits were the timesaving aspects in documentation, not only in the excavation process but also in post-processing without creating additional costs in material, as the equipment used is available in most archaeological excavations. The authors conclude that this methodology could be employed on a variety of investigations from archaeological to forensic contexts and add significant value in many different respects (for example, detail, objectivity, complexity, time-efficiency) compared to methods currently used. PMID- 25720528 TI - Allergenicity of pasteurized whole raw Hen's egg compared with fresh whole raw Hen's egg. AB - BACKGROUND: Oral food challenges for diagnosis and management of egg allergy using fresh egg are common; however, to limit the risk of foodborne infection, many allergy units use pasteurized raw egg. Pasteurization and drying processes have the potential to affect the structure of egg proteins in egg powder and thus the allergenicity when compared to fresh egg. Our aim was to compare the binding of serum IgE from egg-allergic children to in vitro digested and undigested pasteurized whole raw egg powder with unpasteurized fresh whole raw egg. METHODS: Egg proteins from in vitro digested or undigested pasteurized whole raw egg powder, fresh whole egg, egg white and egg yolk were separated by SDS-PAGE, transferred onto nitrocellulose membrane and incubated overnight with pooled sera from egg-allergic children. RESULTS: In both the raw egg samples and the pasteurized whole egg powder, protein bands corresponding to known molecular weights of the major egg allergens were present. Pasteurized whole raw egg powder was bound by serum IgE in a similar manner to unpasteurized whole raw egg and was unaffected by in vitro digestion. Serum IgE also bound egg yolk, indicating sensitization to both egg yolk and egg white proteins. CONCLUSIONS: The main egg allergens are present in pasteurized whole raw egg powder, and serum IgE of egg allergic children binds to them in a similar pattern to those in fresh whole raw egg. Pasteurized whole raw egg powder is a suitable substitute for raw egg in clinical practice for oral food challenges. PMID- 25720529 TI - Multi-centre variability of ISCEV standard ERGs in two normal adults. AB - BACKGROUND: The reproducibility of an individual's full-field ERG between centres has not previously been investigated. METHODS: ERGs were recorded using both silver thread and skin electrodes from the same two normal adult subjects at 15 UK centres using routine, local protocols and a highly standardised, 'ISCEV specified' protocol matching the values specified in the ISCEV standard; where the ISCEV standard allows options, a single value was chosen. RESULTS: Inter ocular differences were small, and amplitudes were smaller for skin than silver thread electrodes. No centre produced outlying data points, and ERGs across all 15 centres were remarkably similar. Amplitude variability was less for local protocols (using LED flashes) than for the ISCEV-specified protocol using xenon flashes (22 vs. 24 %, p = 0.01), but peak time variability was less for the ISCEV specified protocol (6.1 vs. 7.4 %, p = 0.001). Only the DA 0.01 ERG correlated with photometric variability. The bifidity of the DA 3 a-wave doubled its peak time variability compared with the DA 10 a-wave. CONCLUSIONS: Inter-centre amplitude variability was typically within clinically significant thresholds, suggesting that inter-centre variability with suitable standardisation may not add more to total variability than inter-subject variability. Variability improvements gained by the tighter specifications of the ISCEV-specified protocol were possibly more than lost due to imprecisions of xenon flashtubes. Peak time variability was far lower than amplitude variability, corresponding with acceptable variability of biochemical assays. These results represent a vindication of the existence of an ERG standard and suggest that further standardisation would lend itself to greater reproducibility of ERGs worldwide. PMID- 25720530 TI - [Immunotherapies for multiple sclerosis : review and update]. AB - Multiple sclerosis (MS) is an inflammatory, presumably autoimmune disease affecting the central nervous system. Early stages of the disease are characterized by conspicuous inflammation of the white and grey matter. During later stages, presumably secondary neurodegeneration leads to physical disability progression. Over the last decade increasingly effective therapeutic options have been approved. Currently 11 immunomodulatory or immunosuppressive therapies targeting relapse rate, disease progression and paraclinical disease activity are available, mostly for relapsing forms of MS. However, the ideal of "precision medicine" is still in the distant future since biomarkers for individualized treatment are lacking. For implementation of risk-management plans to minimize the risk of severe side effects, interdisciplinary collaboration between neurologists and internists is essential. In this review article we summarize practical aspects of the implemented risk-management plans, and discuss possible side effects and special caveats of the three new immunotherapies teriflunomide, dimethyl fumarate, and alemtuzumab. This article is based on, among others, the recently updated guidelines of the German Society of Neurology. Particular attention is given to the risks of new therapies, monitoring, and on special aspects needing attention when changing treatments. Teriflunomide, dimethyl fumarate, and alemtuzumab expand treatment options for relapsing-remitting MS. Treatment selection should take into consideration the safety profile of the substance, previous and concomitant diseases, and other individual factors. This requires in-depth consultation and individual assessment of current disease activity, the potential efficacy of the therapy, and the possible risks and side effects. PMID- 25720532 TI - The lateral diffusion and fibrinogen induced clustering of platelet integrin alphaIIbbeta3 reconstituted into physiologically mimetic GUVs. AB - Platelet integrin alphaIIbbeta3 is a key mediator of platelet activation and thrombosis. Upon activation alphaIIbbeta3 undergoes significant conformational rearrangement, inducing complex bidirectional signalling and protein recruitment leading to platelet activation. Reconstituted lipid models of the integrin can enhance our understanding of the structural and mechanistic details of alphaIIbbeta3 behaviour away from the complexity of the platelet machinery. Here, a novel method of alphaIIbbeta3 insertion into Giant Unilamellar Vesicles (GUVs) is described that allows for effective integrin reconstitution unrestricted by lipid composition. alphaIIbbeta3 was inserted into two GUV lipid compositions that seek to better mimic the platelet membrane. First, "nature's own", comprising 32% DOPC, 25% DOPE, 20% CH, 15% SM and 8% DOPS, intended to mimic the platelet cell membrane. Fluorescence Lifetime Correlation Spectroscopy (FLCS) reveals that exposure of the integrin to the activators Mn(2+) or DTT does not influence the diffusion coefficient of alphaIIbbeta3. Similarly, exposure to alphaIIbbeta3's primary ligand fibrinogen (Fg) alone does not affect alphaIIbbeta3's diffusion coefficient. However, addition of Fg with either activator reduces the integrin diffusion coefficient from 2.52 +/- 0.29 to MUm(2) s(-1) to 1.56 +/- 0.26 (Mn(2+)) or 1.49 +/- 0.41 MUm(2) s(-1) (DTT) which is consistent with aggregation of activated alphaIIbbeta3 induced by fibrinogen binding. The Multichannel Scaler (MCS) trace shows that the integrin-Fg complex diffuses through the confocal volume in clusters. Using the Saffman-Delbruck model as a first approximation, the diffusion coefficient of the complex suggests at least a 20-fold increase in the radius of membrane bound protein, consistent with integrin clustering. Second, alphaIIbbeta3 was also reconstituted into a "raft forming" GUV with well defined liquid disordered (Ld) and liquid ordered (Lo) phases. Using confocal microscopy and lipid partitioning dyes, alphaIIbbeta3 showed an affinity for the DOPC rich Ld phase of the raft forming GUVs, and was effectively excluded from the cholesterol and sphingomyelin rich Lo phase. Activation and Fg binding of the integrin did not alter the distribution of alphaIIbbeta3 between the lipid phases. This observation suggests partitioning of the activated fibrinogen bound alphaIIbbeta3 into cholesterol rich domains is not responsible for the integrin clustering observed. PMID- 25720531 TI - AUF-1 and YB-1 independently regulate beta-globin mRNA in developing erythroid cells through interactions with poly(A)-binding protein. AB - The normal expression of beta-globin protein in mature erythrocytes is critically dependent on post-transcriptional events in erythroid progenitors that ensure the high stability of beta-globin mRNA. Previous work has revealed that these regulatory processes require AUF-1 and YB-1, two RNA-binding proteins that assemble an mRNP beta-complex on the beta-globin 3'UTR. Here, we demonstrate that the beta-complex organizes during the erythropoietic interval when both beta globin mRNA and protein accumulate rapidly, implicating the importance of this regulatory mRNP to normal erythroid differentiation. Subsequent functional analyses link beta-complex assembly to the half-life of beta-globin mRNA in vivo, providing a mechanistic basis for this regulatory activity. AUF-1 and YB-1 appear to serve a redundant post-transcriptional function, as both beta-complex assembly and beta-globin mRNA levels are reduced by coordinate depletion of the two factors, and can be restored by independent rescue with either factor alone. Additional studies demonstrate that the beta-complex assembles more efficiently on polyadenylated transcripts, implicating a model in which the beta-complex enhances the binding of PABPC1 to the poly(A) tail, inhibiting mRNA deadenylation and consequently effecting the high half-life of beta-globin transcripts in erythroid progenitors. These data specify a post-transcriptional mechanism through which AUF1 and YB1 contribute to the normal development of erythropoietic cells, as well as to non-hematopoietic tissues in which AUF1- and YB1-based regulatory mRNPs have been observed to assemble on heterologous mRNAs. PMID- 25720533 TI - Aging and the visual perception of exocentric distance. AB - The ability of 18 younger and older adults to visually perceive exocentric distances was evaluated. The observers judged the extent of fronto-parallel and in-depth spatial intervals at a variety of viewing distances from 50cm to 164.3cm. Most of the observers perceived in-depth intervals to be significantly smaller than fronto-parallel intervals, a finding that is consistent with previous studies. While none of the individual observers' judgments of exocentric distance were accurate, the judgments of the older observers were significantly more accurate than those of the younger observers. The precision of the observers' judgments across repeated trials, however, was not affected by age. The results demonstrate that increases in age can produce significant improvements in the visual ability to perceive the magnitude of exocentric distances. PMID- 25720534 TI - Lifestyle and dental attendance as predictors of oral health-related quality of life. AB - OBJECTIVES: To evaluate the impact of health-related behaviors and dental attendance on oral health-related quality of life (OHRQoL). METHODS: One hundred and ninety-two individuals presenting for dental treatment were included in a cross-sectional survey using a self-administered questionnaire that assessed demographics, smoking and alcohol consumption, physical activity habits, dental attendance, and dental pain utilizing a numeric rating scale (NRS). Results of the Oral Health Impact Profile (OHIP)-14 questionnaire were considered as the dependent variable. A conceptual hierarchical data analysis model from distal to proximal determinants of the median OHIP-14 total score was adopted. RESULTS: Analysis of the OHIP-14 domains and total score revealed several significant protector characteristics: younger age, academic education, no alcohol consumption, regular physical activity, fewer smoking pack years, routine dental attendance, and lower NRS scores. Routine dental attendance was related to lower NRS scores (P < 0.001) which in turn were associated with lower OHIP-14 scores (P = 0.018). Better health-related behaviors (P = 0.039) and routine dental attendance (P = 0.029) also correlated directly with lower OHIP-14 scores. CONCLUSIONS: Better health-related behaviors and routine dental attendance have a protective effect on OHRQoL. Clinicians should assess these behaviors during routine diagnostic workups. Global health authorities need to integrate oral and general health care and improve both OHrQoL and HrQoL. PMID- 25720535 TI - Child Sexual Abuse and Its Relationship With Health Risk Behaviors Among Adolescents and Young Adults in Taipei. AB - This study explores the association of child sexual abuse (CSA) with subsequent health risk behaviors among a cross-section of 4354 adolescents and young adults surveyed in urban and rural Taipei. Descriptive analysis and logistic regressions were employed. The overall proportion of CSA was 5.15%, with more females (6.14%) than males (4.16%) likely to experience CSA. CSA was differently associated with multiple adverse health outcomes, after adjusting other factors, such as age, residence, economic status, education, employment status, and household instability. Both males and females with CSA experience were more likely to report drinking, gambling, and suicidal ideation compared with those who had no history of CSA. However, the significant association between CSA and smoking, fighting, and suicidal attempt was not observed among females. Effective interventions are needed to reduce CSA and its adverse effects on adolescent well being. PMID- 25720536 TI - Increased rate of deleterious variants in long runs of homozygosity of an inbred population from Qatar. AB - OBJECTIVE: The aim of this study is to evaluate the fraction of putatively deleterious variants within genomic runs of homozygosity (ROH) regions in an inbred and selected cohort of Qatari individuals. METHODS: High-density SNP array analysis was performed in 36 individuals, and for 14 of them whole-exome sequencing (WES) was also carried out. RESULTS: In all individuals, regions characterized by a high (hotspot) or low (coldspot) degree of homozygosity in all the analysed individuals were mapped, and the most frequent hotspot regions were selected. WES data were exploited to identify the single nucleotide variations (SNVs) harboured by genes located within both regions in each individual. Evolutionary conservation-based algorithms were employed to predict the potential deleteriousness of SNVs. The amount of in silico predicted deleterious SNVs was significantly different (p < 0.05) between homozygosity hotspot and coldspot regions. CONCLUSION: Genes located within ROH hotspot regions contain a significant burden of predicted putatively deleterious variants compared to genes located outside these regions, suggesting inbreeding as a possible mechanism allowing an enrichment of putatively deleterious variants at the homozygous state. PMID- 25720537 TI - Role of Pgrmc1 in estrogen maintenance of meiotic arrest in zebrafish oocytes through Gper/Egfr. AB - The regulation of receptor trafficking to the cell surface and its effect on responses of target cells to growth factors and hormones remain poorly understood. Initial evidence has been recently obtained using cancer cells that surface expression of the epidermal growth factor receptor (EGFR) is dependent on its association with progesterone receptor membrane component 1 (PGRMC1). Estrogen inhibition of oocyte maturation (OM) in zebrafish is mediated through G protein-coupled estrogen membrane receptor 1 (Gper1) and involves activation of Egfr. Therefore, in this study, the potential roles of Pgrmc1 in the cell surface expression and functions of Egfr in normal cells were investigated in this in vitro OM model of Egfr action using an inhibitor of PGMRC1 signaling, AG205. A single ~60 kDa protein band, which corresponds to the size of the Pgrmc1 dimer, was detected on plasma membranes of fully grown oocytes by western blotting. Co treatment with the PGRMC1 inhibitor AG205 (20 MUM) blocked the inhibitory effects of 100 nM estradiol-17beta and the GPER agonist, G-1, on spontaneous maturation of denuded zebrafish oocytes. Moreover, reversal of these estrogen effects on OM by the EGFR inhibitors AG1478 and AG825 (50 MUM) was prevented by co-incubation with the PGRMC1 inhibitor. Inhibition of Pgrmc1 signaling with AG205 also caused a decrease in Egfr-dependent signaling and Egfr expression on oocyte cell membranes. These results indicate that maintenance of Pgrmc1 signaling is required for Egfr expression on zebrafish oocyte cell membranes and for conserving the functions of Egfr in maintaining meiotic arrest through estrogen activation of Gper. PMID- 25720538 TI - Physical activity is the best buy in medicine, but perhaps for less obvious reasons. AB - This commentary's premise addresses why physical activity may be considered the 'best buy' in medicine, with a focus on the identification of a novel mechanism. PMID- 25720539 TI - Lithogenic factors in postmenopausal women with osteoporotic fracture. AB - BACKGROUND: The aim of this study was to show the presence of phosphorus and calcium metabolism disorders and the presence of urine lithogenic factors in women with osteoporotic fracture without previous urinary lithiasis. METHODS: We conducted a cross-sectional study including 55 women with osteoporotic fracture surgically treated in the Trauma Department. We included women with osteoporotic fracture demonstrated by the fracture area, fracture mechanism and the presence of osteoporosis by bone densitometry. We analyzed phospho-calcium metabolism as well as the calciuria, oxaluria, citraturia and uricosuria levels with fasting and 24-hour urine study. The presence of abnormal calcium and phosphorus metabolism was compared between women with hypercalciuria and normocalciuria. RESULTS: The 55 women had a mean age of 70.1+/-13.8 years and a mean body mass index of 27.9+/-3.8 kg/m2. Forty-percent of the patients showed hypercalciuria, 36.4% hyperoxaluria, 36.4% hypocitraturia, and 5.3% hyperuricosuria. When comparing patients with hypercalciuria and normocalciuria, the only statistically significant difference was fasting urinary calcium/creatinine levels (0.16 versus 0.08, respectively; P<0.0001). CONCLUSIONS: Women with osteoporotic fracture showed several lithogenic factors in the urine studies, mainly fasting hypercalciuria. Although in this study hypercalciuria did not involve the presence of lithiasis, it can favor the appearance of lithiasis with other predisposing conditions. Therefore, an accurate assessment of urine calcium levels with other lithogenic factors, such as citrate and oxalate levels, may facilitate individualized management and treatment of osteoporosis without increasing the risk of nephrolithiasis. PMID- 25720540 TI - Diagnosis and management of childhood epilepsy. AB - Epilepsy is a relatively common neurologic disorder in children that has important implications for development, parents, and society. Making the correct diagnosis starts with an accurate and complete history that consequently leads to a directed diagnostic workup. This article outlines a diagnostic and management approach to pediatric seizures and epilepsy syndromes. Making the correct diagnosis of epilepsy or nonepileptic imitators allows the practitioner to prescribe appropriate therapy. Initial management for typical epileptic syndromes and seizures and potential adverse effects are discussed. Alternative treatment options for pharmacologically resistant patients such as ketogenic diet, vagal nerve stimulation, and surgery are also discussed. While most children favorably respond to antiepileptic medications, early identification of medication failure is important to ensure optimal neurodevelopment. PMID- 25720541 TI - The motor learning induces plastic changes in dendritic spines of Purkinje cells from the neocerebellar cortex of the rat. AB - PURPOSE: The presynaptic stimulatory activity of parallel fibers on the dendritic spines of cerebellar Purkinje cells (PC) has a strong influence on the organization of motor learning. Motor learning has been shown to modify the synapses established on PC dendritic spines but the plastic changes of the different spine types, possibly underlying motor learning, have not been studied. METHODS: Adult male Sprague-Dawley rats were trained daily for 26 days using an acrobatic paradigm (AC), at the end of which dendritic spine density and the proportion of the different types of spines was assessed. RESULTS: The learning curves of AC rats reflected a robust decrease in the latency for resolution and in the errors committed during the first week of training, which subsequently stabilized until the end of training. Dendritic spine density was greater in these AC rats, reflected in a larger proportion of thin, mushroom and stubby spines. CONCLUSIONS: Since thin spines are associated with acquiring novel information whilst mushroom spines are associated with long-term information storage, there appears to be a strong relationship between AC motor learning and consolidation. The increase in stubby spines could be related to the regulation of excitatory stimulation underlying motor overactivity. PMID- 25720542 TI - Theory of mind impairment after severe traumatic brain injury and its relationship with caregivers' quality of life. AB - PURPOSE: Theory of mind (ToM) deficits are common consequences of severe Traumatic Brain Injury (sTBI), but little is known about their impact on patients' and their caregivers' quality of life. This study aimed (i) to examine the presence of ToM difficulties in individuals with sTBI and adequate levels of self-awareness (SA); (ii) to investigate their relationship with perceived Health Related Quality of Life (HRQoL) in patients and their caregivers. METHODS: Twenty individuals with sTBI and adequate levels of SA, and 20 healthy controls (HCs) were recruited. ToM was examined by the Faux-pas Recognition paradigm. The QOLIBRI questionnaire was administered to patients and their caregivers to assess their HRQoL. Cognitive functioning and psychopathology were evaluated. RESULTS: Individuals with sTBI were less accurate than HCs on the Faux-pas Recognition paradigm. Patients' satisfaction of HRQoL was related to their performance on the Wisconsin Card Sorting Test. Caregivers' satisfaction was significantly predicted by patients' score on the Faux-pas paradigm. CONCLUSIONS: ToM is impaired in individuals with sTBI and adequate levels of SA. Moreover, their ToM performance predicted HRQoL in the caregivers. From a clinical perspective, these results provide understanding of the potential impact of ToM impairment in subjects with sTBI and their social system. PMID- 25720543 TI - Comparing the Meggitt-Wagner and the University of Texas wound classification systems for diabetic foot ulcers: inter-observer analyses. AB - Accurate classification of diabetic foot ulcers is essential for inter-clinician communication, assessment of healing tendency and determination of treatment options. The aim of this study was to assess the inter-observer agreement (IOA) of the most commonly used classification systems for diabetic foot ulcers; the Meggitt-Wagner (MW) and the University of Texas (UT) systems. In this study, 95 clinicians judged digital photographs of diabetic foot ulcers in various stages of healing. Wound depth was classified along the grades of the MW and the UT systems. IOA of the MW and UT systems was only moderate among the clinicians. This moderate agreement demonstrates that the MW and the UT systems appear not to be useful as single instrument and should always be used in combination with additional clinical information to avoid erroneous interpretations. PMID- 25720544 TI - Poor adherence to medication as assessed by the Morisky Medication Adherence Scale-8 and low satisfaction with treatment in 237 psoriasis patients. AB - Previously we assessed the medication adherence for oral and topical remedies by a translated Japanese version of the Morisky Medication Adherence Scale-8 (MMAS 8) together with socioeconomic backgrounds in 3096 Japanese dermatological patients, and found the medication adherence, especially to topical drugs, was poor in these patients. In order to elucidate the disease-specific sociomedical factors, we further sub-analyzed the medication adherence in 237 psoriasis patients and compared it with that in other dermatological diseases such as atopic dermatitis, urticaria or tinea. This study was conducted among patients registered in monitoring system and 3096 eligible patients were enrolled. Our web based questionnaire included the following items such as age, sex, annual income, main health-care institution, experience of effectiveness by oral or topical medication, overall satisfaction with treatment, and MMAS-8 for oral or topical medication. Mean adherence score by MMAS-8 was 5.2 for oral and 4.3 for topical medication. More patients with psoriasis used a university hospital and fewer used a private clinic compared with those with the other skin disease patients. Experience of drug effectiveness by oral medication and overall satisfaction with treatment was lower in psoriasis patients than in other patients. In oral medication, significantly better adherence was observed in those of higher age and with higher annual income. The adherence to medication, especially to topical drugs, was poor in 237 psoriasis patients. We speculated that some severe psoriasis patients were not sufficiently treated systemically and were resistant to topical therapy, leading to poor adherence. PMID- 25720545 TI - Enhanced performance of nano-Bi2WO6-graphene as pseudocapacitor electrodes by charge transfer channel. AB - The nano-Bi2WO6/reduced graphene oxide composite obtained by a simple hydrothermal reaction demonstrates a larger specific capacitance of 922 F/g at a charge and discharge currents of 3 A/g with longer cycle life. The As comparison, pristine Bi2WO6 nanoparticles have poor specific capacitance of 574 F/g at a charge and discharge currents of 2 A/g with weak cycle life. Though analyzing the Cyclic voltammetry curves, it is found that there are two oxidation reaction occurring in the materials: oxidation of Bi (III) to Bi (IV) and Bi (III) to Bi (V). The oxidation of Bi (III) to Bi (IV) is reversible while Bi (III) to Bi (V) will cause nonreversible destroy on structure. In this nano-Bi2WO6/reduced graphene oxide composite, graphene with well conductivity will enhance the electrically conducting as charge transfer channel, so that electrons will be transfer much faster in oxidation and most Bi (III) is oxidized to be Bi (IV) which ensure larger specific capacitance and long cycle life. This nano Bi2WO6/reduced graphene oxide composite has application prospect in high performance pseudo-capacitors. PMID- 25720546 TI - Miconazole nitrate vaginal suppository 1,200 mg versus oral fluconazole 150 mg in treating severe vulvovaginal candidiasis. AB - AIMS: Miconazole is a synthetic imidazole antifungal that has a broad spectrum of activity against Candida albicans and non-albicans Candida species. The aim of this study was to evaluate the efficacy and safety of miconazole nitrate vaginal suppository and oral fluconazole in treating severe vulvovaginal candidiasis (SVVC). METHODS: In this prospective, randomized case control study, 577 cases of consecutive patients with SVVC were studied at the Gynecological Clinic of Peking University Shenzhen Hospital from January 1, 2009 through December 31, 2010. Patients with SVVC were treated with two doses of miconazole nitrate vaginal suppository 1,200 mg or two doses of fluconazole 150 mg. The patients were followed up for 7-14 and 30-35 days following the second dose of therapy. RESULTS: The mycological cure rates of the patients on days 7-14 of follow-up were 75.9% (220/290) and 84.0% (241/287) in the miconazole and fluconazole groups, respectively (p < 0.05). The mycological cure rates of the patients at the second follow-up were 64.8% (188/290) and 69.7% (200/287), respectively, in the two groups (p > 0.05). CONCLUSION: The study demonstrated that two doses of miconazole nitrate vaginal suppository 1,200 mg were as effective as two doses of an oral fluconazole 150 mg regimen in the treatment of patients with SVVC. PMID- 25720547 TI - In school-age children who were born very preterm sleep efficiency is associated with cognitive function. AB - AIMS: This study examined whether the association between sleep duration, as well as sleep continuity, and cognitive function differs between normally developing preterm children compared to full-term children during middle childhood. METHODS: A total of 58 early preterm (<32 weeks' gestation) and 55 full-term children, aged 6-10 years and enrolled in elementary school, were assessed on sleep duration, sleep continuity and cognitive function. We used in-home polysomnographic recordings of total sleep time, sleep efficiency and nocturnal awakenings. Cognitive tests included intelligence, arithmetic, selective attention, verbal memory, and visuospatial memory. RESULTS: Preterm children showed poorer performance in intelligence, arithmetic, selective attention, and visuospatial memory (d = 0.38-0.79, p < 0.05) and more objectively assessed nocturnal awakenings (d = 0.40, p = 0.03) than full-term children. Associations of sleep efficiency and cognitive functions (intelligence, arithmetic, selective attention, visuospatial memory) were positive and stronger for preterm children (beta = 0.17-0.31, p < 0.05), while they were nonsignificant for full-term children. CONCLUSION: Results confirm lower cognitive test scores and more nocturnal awakenings in normally developing early preterm children compared to full-term children. Furthermore, poor sleep efficiency may aggravate cognitive deficits, particularly in children who are more vulnerable due to premature birth. PMID- 25720548 TI - [Correlation between antibodies against porcine reproductive and respiratory syndrome virus and pathological-anatomical organ findings in slaughter pigs at farm level]. AB - OBJECTIVE: The porcine reproductive and respiratory syndrome (PRRS) worldwide causes important economic losses in pig production. Its causative agent, the PRRS virus (PRRSV), is one of the most frequently detected infectious agents in relation to respiratory diseases in pigs in Austria. We investigated the correlation between the PRRSV status of pig farms, determined by detection of PRRSV antibodies in the serum of slaughter pigs, and the prevalence of pathological-anatomical lung lesions in slaughter pigs of the respective farms. MATERIAL AND METHODS: Between December 1, 2011 and April 16, 2012, a total of 1056 serum samples of slaughter pigs from 66 pig farms were collected at an Austrian abattoir. The presence of PRRSV antibodies was tested by enzyme-linked immunosorbent assay in each sample and the PRRSV status of the respective farms was determined. No PRRSV vaccination was performed on any of the farms. In addition, the pathological-anatomical lung lesions of all slaughter pigs of the 66 farms that were slaughtered between September 1, 2011 and December 11, 2012 were recorded by authorized veterinarians at the abattoir. The prevalence of lung lesions and pleuritis in PRRSV-positive and unsuspected farms was compared and statistically interpreted. RESULTS: Slaughter pigs of PRRSV positive farms had a significantly higher prevalence of severe lung lesions and pleuritis visceralis and parietalis than slaughter pigs of PRRSV unsuspected farms. Pigs of combined farms (nursery and fattening unit at the same location) displayed a tendency for more moderate and severe lung lesions than pigs of exclusive fattening farms. CONCLUSIONS AND CLINICAL RELEVANCE: In the present study, the PRRSV status of pig farms displayed a significant influence on the prevalence of lung lesions in the slaughter pigs. Findings untypical for PRRS, including pleuritis, were also found significantly more often on those farms. This leads to the conclusion that other primary and/or secondary infections are involved, which can be exacerbated by the immunosuppressive effect of the PRRSV. There was a tendency for combined farms to be more severely affected than fattening farms. PMID- 25720549 TI - The presynaptic active zone: A dynamic scaffold that regulates synaptic efficacy. AB - Before fusing with the presynaptic plasma membrane to release neurotransmitter into the synaptic cleft synaptic vesicles have to be recruited to and docked at a specialized area of the presynaptic nerve terminal, the active zone. Exocytosis of synaptic vesicles is restricted to the presynaptic active zone, which is characterized by a unique and highly interconnected set of proteins. The protein network at the active zone is integrally involved in this process and also mediates changes in release properties, for example in response to alterations in the level of neuronal network activity. In recent years the development of novel techniques has greatly advanced our understanding of the molecular identity of respective active zone components as well as of the ultrastructure of this membranous subcompartment and of the SV release machinery. Furthermore, active zones are now viewed as dynamic structures whose composition and size are correlated with synaptic efficacy. Therefore, the dynamic remodeling of the protein network at the active zone has emerged as one potential mechanism underlying acute and long-term synaptic plasticity. Here, we will discuss this recent progress and its implications for our view of the role of the AZ in synaptic function. PMID- 25720550 TI - Solution structure and DNA binding of the catalytic domain of the large serine resolvase TnpX. AB - The transfer of antibiotic resistance between bacteria is mediated by mobile genetic elements such as plasmids and transposons. TnpX is a member of the large serine recombinase subgroup of site-specific recombinases and is responsible for the excision and insertion of mobile genetic elements that encode chloramphenicol resistance in the pathogens Clostridium perfringens and Clostridium difficile. TnpX consists of three structural domains: domain I contains the catalytic site, whereas domains II and III contain DNA-binding motifs. We have solved the solution structure of residues 1-120 of the catalytic domain I of TnpX. The TnpX catalytic domain shares the same overall fold as other serine recombinases; however, differences are evident in the identity of the proposed hydrogen donor and in the size, amino acid composition, conformation, and dynamics of the TnpX active site loops. To obtain the interaction surface of TnpX1-120 , we titrated a DNA oligonucleotide containing the circular intermediate joint attCI recombination site into (15) N-labeled TnpX1-120 and observed progressive nuclear magnetic resonance chemical shift perturbations using (15) N HSQC spectra. Perturbations were largely confined to a region surrounding the catalytic serine and encompassed residues of the active site loops. Utilizing the perturbation map and the data-driven docking program, HADDOCK, we have generated a model of the DNA interaction complex for the TnpX catalytic domain. PMID- 25720551 TI - The role of adenovirus 36 as a risk factor in obesity: the first clinical study made in the fatty tissues of adults in Turkey. AB - Obesity which developes due to multifactorial reasons, was associated recently with human Adenovirus-36 (Ad-36). The aim of this study was to investigate the prevalence of Ad-36 antibodies in obese adults and also to investigate the DNA of Ad-36 in their adipose tissue. In this cross-sectional and case-control based study, 49 obese adults, with BMI >= 30 kg/m(2), and 49 non-obese adults, with BMI <= 25 kg/m(2), applied for esthetic purposes and were included in this study as patient and control groups, respectively. Adipose tissue samples, obtained by the lipoaspiration method, were studied by single-step PCR and nested-PCR methods. Simultaneously, the presence of Ad-36 antibodies and serum leptin and adiponectin levels were assessed by serum neutralization assay (SNA) and ELISA, respectively. Serum samples which didn't cause a cytopathic effect at >= 1:8 were accepted as positive. Ad-36 antibody was detected in 6 (12.2%) of 49 patients by SNA and was statistically significant (p < 0.05). Ad-36 DNA was not detected in any of the adipose tissue samples of the patient or control groups. Mean BMI and leptin levels were higher in the Ad-36-positive group, while adiponectin levels were found to be lower in the Ad-36-positive group. Although no statistically significant difference was found in cholesterol and triglyceride levels between the two groups (p > 0.05), lower mean serum cholesterol and triglyceride levels were found in the Ad-36-positive patients. In conclusion, we couldn't detect Ad 36 DNA in adipose tissue; however, we detected significantly higher Ad-36 antibody levels in the obese group compared to the non-obese group, according to the both univariant and multivariant analyses, suggesting that Ad-36 may play a role in obesity. There is a need for new and extended serial, particularly cohort and human-based, studies in order to have a clear understanding of the Ad-36 obesity relationship. PMID- 25720552 TI - Environmental tolerance of free-living stages of the poultry roundworm Ascaridia galli. AB - The poultry roundworm Ascaridia galli is re-emerging in laying hens in many European countries due to the increase in non-caged housing. A series of in vitro experiments was carried out to study the in ovo larval development (embryonation) under different environmental conditions. Between 83% and 96% of the eggs developed to L3 within 7-21 days of incubation in water between 20 and 30 degrees C. Twenty-six percent completed development at 33 degrees C and 4% at 35 degrees C after 31 days. At 15 degrees C parasite egg development was low with 8% L3 after 56 days. In another trial larval development occurred, when parasite eggs were exposed to freeze-thaw cycle (30' to 12h) followed by incubation for 2 weeks at 25 degrees C. Alkaline and acidic conditions in the range of pH 2.5-12.5 had no adverse effect on development. Oxygen and relative humidity above 70% were necessary for development to occur. Thus, some A. galli eggs may complete development at conditions prevailing in poultry barns in temperate climate zones throughout the year. Although exposure to a 1% or 2% dilution of the broad spectrum disinfectant chlorocresol for 4h or longer was ovicidal, further work is required to improve the method of application in the field. PMID- 25720553 TI - Circulating Biomarker Panels in Alzheimer's Disease. AB - The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-beta levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles. PMID- 25720554 TI - Toxicity of chlorophyllin in different wavelengths of visible light against Fasciola gigantica larvae. AB - Toxicity of chlorophyllin against redia and cercaria larvae of Fasciola gigantica was studied under irradiation of visible light. Highest and lowest toxicity of chlorophyllin against both larvae was noted under red (redia - 8 h LC50 7.88 mg/10 mL and cercaria - 11.99 mg/10 mL) and green (redia - 8 h LC50 32.12 mg/10 mL and cercaria - 8 h LC50 43.80 mg/10 mL) light irradiation respectively. The highest toxicity of chlorophyllin under red light irradiation against redia (8h LC50 7.88 mg/10 mL)/cercaria (8h LC50 11.99 mg/10 mL) was followed by white (8 h LC50 redia - 20.48 mg/10 mL, 8 h LC50 cercaria - 18.0 3mg/10 mL), blue (8 h LC50 redia - 33.10 mg/10 mL/ 8 h LC50 cercaria - 19.98 mg/10 mL) and yellow (8 h LC50 redia - 23.87 mg/10 mL/ 8 h LC50 cercaria - 23.48 mg/10 mL). Chlorophyllin treatment in darkness (control I) and without treatment of chlorophyllin, while all other conditions were same as treatment group (control II) caused no mortality of redia/cercaria larva. Chlorophyllin might be a promising new safe strategy to replace synthetic larvicide in fasciolosis control programme. PMID- 25720555 TI - Photobiomodulation in oral medicine: a review. AB - Photobiomodulation (PBM) or low-level laser therapy (LLLT) in dentistry is an evolving science, with an increasing number of controlled clinical studies exploring its potential as a treatment modality. The present study provides an outline of the biologic mechanism of PBM and summarizes the findings of clinical studies of PBM for specific applications in oral medicine. Controversies and drawbacks associated with PBM, which require further research, are also identified. Current literature reports the potential of PBM in various applications in oral medicine. Furthermore, well-documented research confirms its efficacy in certain conditions, such as oral mucositis, recurrent herpes simplex infection, and burning mouth syndrome. The absence of any reported adverse effects is an advantage over conventional therapeutic modalities. While PBM has proved to be effective for some specific applications, it is not a panacea. The paucity in standardized studies, coupled with ambiguity over the laser parameters, has limited its credibility as a therapeutic modality. PMID- 25720556 TI - Engineering of a lipid-polymer nanoarchitectural platform for highly effective combination therapy of doxorubicin and irinotecan. AB - We developed a highly stable lipid-polymer nanoarchitectural platform for effective combination therapy of doxorubicin and irinotecan in the polyelectrolyte complex nanoparticle core, followed by incorporation of the whole assembly into a lecithin bilayer. It shows great potential for the treatment of a broad range of cancers. PMID- 25720557 TI - Timing of neck dissection in patients undergoing transoral robotic surgery for head and neck cancer. AB - BACKGROUND: Oncologic transoral robotic surgery (TORS) requires in most cases the concurrent or staged surgical treatment of the regional lymph nodes in the neck as well. The purpose of this study was to determine whether the timing of the regional lymphadenectomy (neck dissection) has an impact on the surgical outcomes and on the complication rates. METHODS: Single-institution, prospective case series with internal control group. Twenty-one patients underwent TORS and appropriate neck dissection concurrently (control group), while 20 patients underwent neck dissection in a timely staged fashion, 8.4 days (median; range, 3 28 days) following their TORS procedure (experimental group). Outcome measures included nodal yield, intraoperative pharyngocervical fistula formation, postoperative fistula formation, postoperative bleeding from the primary and from the neck dissection site, haematoma, seroma, and infection. RESULTS: Nodal yield values, as the oncologic quality indicator of a neck dissection, were comparable in the experimental and in the control group. Complication rates did not differ between the groups: intraoperative and postoperative fistula formation, postoperative bleeding, haematoma and seroma rates were similarly low in the two groups. There was no infection in either group. CONCLUSIONS: In the present cohort of 41 TORS-patients, the timing of neck dissection did not make a significant difference in the outcomes. We suggest therefore that aspiring and established TORS-teams do not restrict their appropriate indications due to robotic slot and theatre time constraints, but perform each indicated TORS-case as soon as possible within their given systems, even if the neck dissections cannot be done on the same day. PMID- 25720558 TI - Bringing Feedback in From the Outback via a Generic and Preference-Sensitive Instrument for Course Quality Assessment. AB - BACKGROUND: Much effort and many resources have been put into developing ways of eliciting valid and informative student feedback on courses in medical, nursing, and other health professional schools. Whatever their motivation, items, and setting, the response rates have usually been disappointingly low, and there seems to be an acceptance that the results are potentially biased. OBJECTIVE: The objective of the study was to look at an innovative approach to course assessment by students in the health professions. This approach was designed to make it an integral part of their educational experience, rather than a marginal, terminal, and optional add-on as "feedback". It becomes a weighted, but ungraded, part of the course assignment requirements. METHODS: A ten-item, two-part Internet instrument, MyCourseQuality (MCQ-10D), was developed following a purposive review of previous instruments. Shorthand labels for the criteria are: Content, Organization, Perspective, Presentations, Materials, Relevance, Workload, Support, Interactivity, and Assessment. The assessment is unique in being dually personalized. In part 1, at the beginning of the course, the student enters their importance weights for the ten criteria. In part 2, at its completion, they rate the course on the same criteria. Their ratings and weightings are combined in a simple expected-value calculation to produce their dually personalized and decomposable MCQ score. Satisfactory (technical) completion of both parts contributes 10% of the marks available in the course. Providers are required to make the relevant characteristics of the course fully transparent at enrollment, and the course is to be rated as offered. A separate item appended to the survey allows students to suggest changes to what is offered. Students also complete (anonymously) the standard feedback form in the setting concerned. RESULTS: Piloting in a medical school and health professional school will establish the organizational feasibility and acceptability of the approach (a version of which has been employed in one medical school previously), as well as its impact on provider behavior and intentions, and on student engagement and responsiveness. The priorities for future improvements in terms of the specified criteria are identified at both individual and group level. The group results from MCQ will be compared with those from the standard feedback questionnaire, which will also be completed anonymously by the same students (or some percentage of them). CONCLUSIONS: We present a protocol for the piloting of a student-centered, dually personalized course quality instrument that forms part of the assignment requirements and is therefore an integral part of the course. If, and how, such an essentially formative Student-Reported Outcome or Experience Measure can be used summatively, at unit or program level, remains to be determined, and is not our concern here. PMID- 25720559 TI - Successful Treatment of Severe Persistent Depressive Disorder with a Sequential Approach: Electroconvulsive Therapy Followed by Cognitive Behavioural Analysis System of Psychotherapy. PMID- 25720560 TI - Influence of the ligand frameworks on the coordination environment and properties of new phenylmercury(II) beta-oxodithioester complexes. AB - New phenylmercury(II) complexes of the form [PhHg(L1), PhHg(L2) and PhHg(L3)] (L1 = methyl-3-hydroxy-3-(p-methoxyphenyl)-2-propenedithioate (1), L2 = methyl-3 hydroxy-3-(p-bromophenyl)-2-propenedithioate (2) and L3 = methyl-3-hydroxy-(3 pyridyl)-2-propenedithioate (3)) have been synthesized and characterized by elemental analysis, IR, UV-Vis, 1H and 13C NMR. The crystal structures of 1-3 reveal a linear geometry about the mercury atom via ipso-C and S11 atoms. 1 and 2 exhibited O,S-coordination whereas 3 preferred S,S-coordination. Intramolecular Hg???O bonding interactions are also observed in 1 and 2 at distances of 2.638(14), 2.644(10) A respectively. However in 3, incorporation of the 3-pyridyl substituent on the ligand enhanced the proximity of S13 and N14, giving rise to significant intramolecular Hg???S and intermolecular Hg???N interactions at 3.141(5) A and 2.77(2) A respectively generating a 1-D polymeric chain motif. The O,S- or S,S-coordination preference and Hg???N interactions have been assessed by DFT calculations. All the complexes show metal perturbed ligand-centred luminescence characteristics in solution and in the solid phase. The band gap values 2.54, 2.66 and 2.61 eV for 1, 2 and 3, respectively, evaluated from the diffuse reflectance spectroscopy show the semiconducting nature of the complexes. PMID- 25720563 TI - Suicide acceptability as a mechanism of suicide clustering in a nationally representative sample of adolescents. AB - PURPOSE: The goal of the present study was to examine suicide acceptability as a mechanism of suicide clustering in adolescents. METHODS: Data were drawn from The National Annenberg Survey of Youth, a sample of 3302 adolescents aged 14-22 collected between 2002 and 2004. RESULTS: Results indicated that beliefs of the acceptability of suicide partially mediated the effect of exposure to suicide (defined as knowing someone who attempted or completed suicide) on 1) serious suicidal ideation and 2) suicide planning behaviors. CONCLUSIONS: The present study demonstrated that suicide acceptability is in small part a possible reason why suicides tend to cluster in adolescents. It contributes not only to the knowledge of how the phenomenon of suicide clustering might occur, but more broadly highlights the importance of examining mediators of suicide clustering. PMID- 25720562 TI - Clinical and microbiological investigation of fungemia from four hospitals in China. AB - In this study, fungemia cases from four tertiary hospitals located in Shanghai and Anhui province in China from March 2012 to December 2013 were enrolled to investigate clinical features, species distribution, antifungal susceptibility and strain relatedness. During the study period, 137 non-duplicate cases and their corresponding isolates were collected. Six different genera of fungi were identified, of which Candida spp. were the most common (126/137, 91.97 %), with C. albicans predominating (48/137, 35.03 %). The non-Candida fungi rate reached 8.03 % (11/137), and Pichia spp. was the most common (5/137, 3.65 %). Compared with C. albicans, non-C. albicans fungi-associated fungemia was more likely in younger (p = 0.004) and male patients (chi (2) = 6.2618, p = 0.0123) and patients from ICUs (chi (2) = 6.3783, p = 0.0116). Overall, the susceptible/WT rates of common Candida spp. to fluconazole, itraconazole, voriconazole, flucytosine, amphotericin B and caspofungin were 74.63, 92.31, 93.16, 96.58, 100 and 95.69 %, respectively. C. tropicalis and C. guilliermondii had a low susceptibility to fluconazole: 79.95 and 77.78 %, respectively. No isolates were resistant/WT to caspofungin, but C. parapsilosis and C. guilliermondii had high MIC90 values; 1 and 2 mg/L, respectively. In terms of genotyping, MLST was taken for C. glabrata and C. tropicalis, while microsatellite marker analysis was used for C. albicans and C. parapsilosis. C. glabrata was predominantly clone ST7, accounting for 75 %, while the other isolates showed genetic diversity. Considering the increased proportion of non-C. albicans fungi and the presence of endemic clones of C. glabrata, it is essential to undertake additional surveillance of fungemia. PMID- 25720564 TI - Regulatory link between steryl ester formation and hydrolysis in the yeast Saccharomyces cerevisiae. AB - Steryl esters and triacylglycerols are the major storage lipids of the yeast Saccharomyces cerevisiae. Steryl esters are formed in the endoplasmic reticulum by the two acyl-CoA:sterol acyltransferases Are1p and Are2p, whereas steryl ester hydrolysis is catalyzed by the three steryl ester hydrolases Yeh1p, Yeh2p and Tgl1p. To shed light on the regulatory link between steryl ester formation and hydrolysis in the maintenance of cellular sterol and free fatty acid levels we employed yeast mutants which lacked the enzymes catalyzing the degradation of steryl esters. These studies revealed feedback regulation of steryl ester formation by steryl ester hydrolysis although in a Deltatgl1Deltayeh1Deltayeh2 triple mutant the gene expression levels of ARE1 and ARE2 as well as protein levels and stability of Are1p and Are2p were not altered. Nevertheless, the capacity of the triple mutant to synthesize steryl esters was significantly reduced as shown by in vitro and in vivo labeling of lipids with [(14)C]oleic acid and [(14)C]acetate. Enzymatic analysis revealed that inhibition of steryl ester formation occurred at the enzyme level. As the amounts and the formation of sterols and fatty acids were also decreased in the triple mutant we concluded that defects in steryl ester hydrolysis also caused feedback inhibition on the formation of sterols and fatty acids which serve as precursors for steryl ester formation. In summary, this study demonstrates a regulatory link within the steryl ester metabolic network which contributes to non-polar lipid homeostasis in yeast cells. PMID- 25720565 TI - Successful Pregnancy in a Woman with Maple Syrup Urine Disease: Case Report. AB - We present the positive outcome of a pregnancy in a woman with severe classic maple syrup urine disease (MSUD). Maintaining the maternal plasma levels of leucine between 200 and 300 MUmol/L allowed normal development of the foetus. Tolerance of protein and leucine increased continuously from the 16th gestational week until delivery. The patient was able to increase protein and leucine intake from 5 g to nearly 30 g and 300-3,000 mg/day, respectively. Weekly measurement of branched-chain amino acid (BCAA) concentrations and the assessment of dietary intake were used to adjust protein intake. After 41 weeks of pregnancy, she gave birth to a healthy baby girl and was able to breastfeed her daughter for 6 months during which time, the protein and leucine intake were lower than during pregnancy, but higher than with her usual pre-pregnancy diet. The development of the girl is normal at the age of 3 years. PMID- 25720566 TI - Depression and the risk of mortality: in search of calipers. PMID- 25720567 TI - A Case of Hepatic Portal Venous Gas in a Patient Treated with Pemetrexed and Carboplatin for Lung Cancer. AB - Hepatic portal venous gas (HPVG) has rarely been reported in patients undergoing chemotherapy. We encountered a case of a 64-year-old man with stage IIIA lung adenocarcinoma who received adjuvant chemotherapy with pemetrexed and carboplatin and developed HPVG 1 day after the second chemotherapy. An emergency operation was performed, but the patient died 2 days after the operation because of multiple organ failure caused by sepsis. Since the patient had complained of alternating abdominal bloating and diarrhea during chemotherapy, we considered that the cause of HPVG was intestinal mucosal disruption and increased intraluminal pressure due to the chemotherapy. PMID- 25720568 TI - Hepatic estrogen receptor alpha improves hepatosteatosis through upregulation of small heterodimer partner. AB - BACKGROUND & AIMS: Estrogen participates in the control of energy homeostasis and lipid metabolism. However the role of hepatic estrogen receptor alpha (ERalpha) in triglyceride (TG) homeostasis remains poorly understood. This study aims to investigate the roles of estrogen and ERalpha in the regulation of hepatic TG metabolism. METHODS: Liver TG metabolism was analyzed in female mice with ovariectomy or tamoxifen treatment, and in hepatic ERalpha knockdown or overexpression. Phenotypes and expression of genes were compared in male and female mice with farnesoid X receptor deficiency. The mechanism of ERalpha in the regulation of small heterodimer partner (SHP) expression was further investigated. RESULTS: Female mice receiving ovariectomy or tamoxifen treatment exhibited hepatic TG accumulation. Ablation of ERalpha using adenoviral shRNA markedly increased hepatic TG accumulation, while overexpression of ERalpha ameliorated hepatosteatosis in obese mice. At the molecular level, estrogen upregulated hepatic SHP expression through binding to its proximal promoter. In addition, the roles of estrogen were largely blunted in mice with SHP deficiency. CONCLUSION: These findings reveal a novel role of estrogen in improving hepatosteatosis through upregulation of SHP expression. PMID- 25720569 TI - Trepanation or complete removal of the outer table of the calvarium for granulation induction: the Erbium:YAG laser as an alternative to the rose head burr. AB - BACKGROUND: Large scalp defects devoid of periosteum following tumor excisions are a surgical challenge. In this case, drilling the outer table of the calvarium with a rose head burr is a standard method to induce granulation tissue. OBJECTIVES: We describe an alternative for trepanation or complete removal of the outer table of the calvarium. METHODS: We demonstrate the use of an erbium:yttrium-aluminum-garnet (erbium:YAG) laser for the induction of granulation tissue, compare this technique with the standard procedure and evaluate the benefits and limitations. RESULTS: The erbium:YAG laser is an excellent method for trepanation or complete removal of the outer table of the calvarium and induction of granulation tissue. Conclusion: The use of the laser for trepanation of the calvarium gives results comparable to those of the rose head burr for inducing granulation tissue but has its benefits. Therefore, this method should become a standard alternative to the known procedure. PMID- 25720570 TI - Influence of cataract surgery on macular thickness: a 6-month follow-up. AB - PURPOSE: To determine long-term changes in macular thickness after cataract surgery. METHODS: Research work included 27 patients (27 eyes) who underwent uneventful cataract surgery with phacoemulsification and IOL implantation on one eye. Optical coherence tomography was used to obtain data of macular thickness before surgery and for patients who attended scheduled control measurement 1 month (22 patients), 3 months (23 patients), and 6 months (20 patients) after the surgery. RESULTS: The greatest increase in average macular thickness was seen 1 month after cataract surgery, statistically significant in all areas except in fovea and superior quarter of macula. Statistically significant decrease in macular thickness was noticed 3 and 6 months after the surgery. Comparison of macular thickness 6 months after cataract surgery and values before surgery showed no statistically significant difference. CONCLUSION: Findings confirmed the reversibility of macular thickness changes 6 months after cataract surgery and its return to preoperative values. PMID- 25720571 TI - Is it possible to use transaminases for deciding on surgical or non-operative treatment for blunt liver trauma? AB - BACKGROUND: We aimed to research the relation of transaminase levels in blunt liver trauma (BLT) with the intensity of the trauma and the use of transaminase levels for deciding on surgical or non-operative treatment. METHODS: In all, 44 patients with BLT diagnosed by computerized tomography (CT) were involved in this retrospective study. By testing the correlation of the transaminase levels and the grade of liver injury with receiver operator characteristics (ROC), area under the curve (AUC) was calculated; besides, the sensitivity, specificity, and cut-off values of transaminases were calculated separately for the grades. Moreover, same method was repeated for the surgically and non-operatively treated patients. Cut-off value was assessed for surgical and non-operative treatments. The efficiency of transaminases in deciding non-operative treatment was compared with that of other methods using ROC test applied on focused abdominal sonography in trauma (FAST), hemodynamic instability, blood replacement rate, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). RESULTS: It was observed that the AUC, sensitivity, and specificity increased correspondingly with the grade rise of transaminase levels in BLT. In the selection of non operative treatment/surgery, following values have been confirmed: AUC for AST: 0.851 (sensitivity: 86%, specificity: 73%, cut-off value: 498 U/L), AUC for ALT: 0.880 (sensitivity: 86%, specificity: 81%, cut-off value: 498 U/L), AUC for replacement: 0.948 (sensitivity: 86%, specificity: 94%), AUC for hemodynamic instability: 0.902 (sensitivity: 86%, specificity: 94%), and AUC for FAST: 0.642 (sensitivity: 57%, specificity: 75%). CONCLUSIONS: It was found that in BLT, transaminases can predict the injury rating with higher accuracy as the grade rises, and they outrival FAST in terms of determining the need for laparotomy. PMID- 25720572 TI - Limb salvage and functional outcomes among patients with traumatic popliteal artery injury: a review of 64 cases. AB - BACKGROUND: Traumatic popliteal arterial injury carries the greatest risk of limb loss among all peripheral vascular injuries and is associated with high levels of morbidity and worse functional outcomes. The purpose of this study is to analyse the functional outcome among patients with popliteal artery injury (PAI) due to blunt and penetrating trauma and identify influencing factors. METHODS: We critically reviewed 64 cases of PAI due to blunt and penetrating trauma treated at our institution over a 20-year period. We evaluated the influence of parameters, such as patient demographics, injury mechanism, initial ISS and performed interventions, on limb amputation rates and functional outcomes. Functional outcome was examined within the 12-months follow-up using the Functional Independence Measure (FIM) score for feeding, expression and locomotion. FIM scores for each category ranged from 1 (full assistance required) to 4 (fully independent), with a maximum total FIM score of 12 representing full independence. RESULTS: The mechanism of injury was blunt in 55 % and penetrating in 45 % of the patients. The overall amputation rate in our series was 28 %. Out of these, 83.3 % of all performed amputations in our series were due to blunt trauma and 88.6 % of all blunt trauma patients were severely injured (ISS > 9) or polytraumatized (ISS > 15). Blunt mechanism of injury has also shown a negative effect on the functional outcome. Analysis of the 1-year clinical follow-up showed that 30 patients (65.3 %) returned to their normal activity level within 1 year after trauma. A total of 16 patients (34.7 %) were recorded to have limited activity levels, 76.5 % of them sustained a blunt trauma. Using the FIM score to quantify the level of disability, we detected significantly worse results in both FIM total (8.8 vs. 10.4) and FIM locomotion score (3.1 vs. 2.7) following blunt trauma. CONCLUSION: The main findings of the present study were that PAI due to blunt trauma is associated with a high percentage of severely injured or even polytraumatized patients. Amputation rates following blunt trauma were significantly higher compared to penetrating trauma. Functional independence measurement, assessed 12 months after injury, also showed significantly worse results in both FIM total and FIM locomotion score after blunt trauma. Other factors that seem to have a negative influence on the outcome in terms of amputation rates after PAI are patient's age, presence of associated injuries and prolonged lower extremity ischemia. PMID- 25720573 TI - Prognostic role of pretreatment platelet/lymphocyte ratio in patients with non small cell lung cancer. AB - BACKGROUND: It was reported that hematological markers of systemic inflammatory response might be prognostic in various cancer types. We aimed to evaluate the platelet/lymphocyte ratio (PLR) as a prognostic factor and its effect on overall survival in non-small cell lung cancer (NSCLC). METHODS: Clinicopathological characteristics and basal (pretreatment) PLR of 145 patients with NSCLC were evaluated retrospectively. The preoperative or pretreatment blood count data were obtained from the recorded computerized database. PLR was defined as the absolute platelet count divided by the absolute lymphocyte count. RESULTS: A total of 145 patients were enrolled. Median age was 57 years(range 26-83). Receiver operating characteristic curves for overall survival prediction were plotted to verify the optimum cut-off point for PLR. The recommended cut-off values for PLR was 198.2 with a sensitivity of 65.0 % and a specificity of 71.4 %. Median overall survival was 34.0 (95 % confidence interval (CI) 14.7-53.3) months in the group with low PLR (< 198.2), while it was 11.0 (95 % CI 5.6-16.3) months in the group with high PLR (>= 198.2). The difference between the groups was statistically significant (p < 0.0001). CONCLUSIONS: Our study supports the view that a high basal PLR is a poor prognostic factor in NSCLC. However, the validity of the cut-off values for PLR identified in our study needs further prospective trials. PMID- 25720574 TI - Long-lived Snell dwarf mice display increased proteostatic mechanisms that are not dependent on decreased mTORC1 activity. AB - Maintaining proteostasis is thought to be a key factor in slowed aging. In several growth-restricted models of long-life, we have shown evidence of increased proteostatic mechanisms, suggesting that proteostasis may be a shared characteristic of slowed aging. The Snell dwarf mouse is generated through the mutation of the Pit-1 locus causing reductions in multiple hormonal growth factors and mTORC1 signaling. Snell dwarfs are one of the longest lived rodent models of slowed aging. We hypothesized that proteostatic mechanisms would be increased in Snell compared to control (Con) as in other models of slowed aging. Using D2O, we simultaneously assessed protein synthesis in multiple subcellular fractions along with DNA synthesis in skeletal muscle, heart, and liver over 2 weeks in both sexes. We also assessed mTORC1-substrate phosphorylation. Skeletal muscle protein synthesis was decreased in all protein fractions of Snell compared to Con, varied by fraction in heart, and was not different between groups in liver. DNA synthesis was lower in Snell skeletal muscle and heart but not in liver when compared to Con. The new protein to new DNA synthesis ratio was increased threefold in Snell skeletal muscle and heart compared to Con. Snell mTORC1-substrate phosphorylation was decreased only in heart and liver. No effect of sex was seen in this study. Together with our previous investigations in long lived models, we provide evidence further supporting proteostasis as a shared characteristic of slowed aging and show that increased proteostatic mechanisms may not necessarily require a decrease in mTORC1. PMID- 25720575 TI - The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study. AB - T regulator lymphocytes (Tregs) play a key role in the maintenance of immune tolerance and in the development of autoimmune diseases. Expression of Foxp3 is specific for Tregs, and can be used for the identification of these cells. This study investigated the variations of Tregs Foxp3+ in the kidney biopsies inflammatory infiltrate of different lupus nephritis classes compared to that of ANCA glomerulonephritis, acute tubulointerstitial nephritis and nephroangiosclerosis. Sections of paraffin-embedded tissue have been stained by immunohistochemistry with anti-CD3 and anti-FoxP3 antibodies. We find that the ratio of FoxP3+/CD3+ cells is significantly lower in patients with lupus nephritis class IV and in patients with vasculitides than in the course of nephroangiosclerosis, tubulointerstitial nephritis and lupus nephritis class V. The data presented herein demonstrate a decrease of FoxP3+ Treg cells in the inflammatory infiltrate of lupus nephritis, particularly during the most active phases of lupus nephritis, as observed in the course of a IV class nephritis. PMID- 25720576 TI - Giant left atrium calcification. PMID- 25720577 TI - Symbiodinium thermophilum sp. nov., a thermotolerant symbiotic alga prevalent in corals of the world's hottest sea, the Persian/Arabian Gulf. AB - Coral reefs are in rapid decline on a global scale due to human activities and a changing climate. Shallow water reefs depend on the obligatory symbiosis between the habitat forming coral host and its algal symbiont from the genus Symbiodinium (zooxanthellae). This association is highly sensitive to thermal perturbations and temperatures as little as 1 degrees C above the average summer maxima can cause the breakdown of this symbiosis, termed coral bleaching. Predicting the capacity of corals to survive the expected increase in seawater temperatures depends strongly on our understanding of the thermal tolerance of the symbiotic algae. Here we use molecular phylogenetic analysis of four genetic markers to describe Symbiodinium thermophilum, sp. nov. from the Persian/Arabian Gulf, a thermally tolerant coral symbiont. Phylogenetic inference using the non-coding region of the chloroplast psbA gene resolves S. thermophilum as a monophyletic lineage with large genetic distances from any other ITS2 C3 type found outside the Gulf. Through the characterisation of Symbiodinium associations of 6 species (5 genera) of Gulf corals, we demonstrate that S. thermophilum is the prevalent symbiont all year round in the world's hottest sea, the southern Persian/Arabian Gulf. PMID- 25720578 TI - DAR boosted anti-D HDFN in a Caucasian family. PMID- 25720579 TI - Papillary thyroid carcinoma with exclusive involvement of a functioning recurrent laryngeal nerve may be treated using a shaving technique: reply. PMID- 25720580 TI - Critical estradiol dose optimization for oocyte in vitro maturation in the common marmoset. AB - The aim of the present study was to critically evaluate the effect of different concentrations of estradiol (E2) during IVM of common marmoset (Callithrix jacchus) oocytes from antral follicles. The doses tested were 0, 0.1, 1, or 10 MUg/mL E2 (referred to as 0 E2, 0.1 E2, 1 E2, and 10 E2 groups). After a preincubation, the concentration of E2 in IVM drops under oil was approximately 20% of the amount added (0.02; 0.2 and 1.9 MUg/mL, respectively) because of absorption into the oil. Oocyte progression to metaphase II was significantly higher in the 0.1 E2 group than that in the absence of E2. With progressively higher doses, the maturation rate tended to decrease suggesting an overdose effect. Furthermore, the total first cleavage rate was significantly higher in the 0.1 E2 group than that in the 0 E2 group and decreased progressively with further increases in E2 concentration, with the 10 E2 group showing the same low rate as without E2. The oocytes which failed to cleave, after maturation in 10 E2, showed obvious signs of overdose with the highest rates of degeneration and abnormal spindle form, and an absence of embryo progression. In contrast to these obvious negative effects on the oocyte, 10 E2 was the only group in which a significant increase in radial cumulus expansion was observed. The concentration 0.1 E2, which is 10 times lower than the most commonly used E2 dose, produced the best results in all oocyte factors evaluated. These results represent the first study for a primate species showing a strong positive effect of E2 on oocyte maturation and embryo development, but only at the optimal concentration, and emphasize the critical limits of the optimal concentration range. PMID- 25720582 TI - Bone conductive implants in single-sided deafness. AB - CONCLUSION: Bone conduction implants (BCIs) have been shown to partially restore some of the functions lost when binaural hearing is missing, such as in subjects with single-sided deafness (SSD). The use of a single BCI needs to be recommended by a clinician based on thorough counselling with the SSD subject. OBJECTIVES: To perform an overview of the present capabilities of BCIs for SSD and to evaluate the reliability of the audiological evaluation for assessing speech recognition in noise and sound localization cues, which are major problems related to the loss of binaural hearing. METHODS: Nine subjects with SSD who received BCI implants underwent a preoperative audiological evaluation that included sound field speech audiometry, word recognition score (WRS) testing and sound localization testing in quiet and in noise. They were also tested for the accuracy of their directional word recognition in noise and their subjective perceptions of their hearing difficulties using the APHAB questionnaire. RESULTS: The mean maximum accuracy of word discrimination was 65.5% in the unaided condition and 78.9% in the BCI-aided condition. Sound localization in noise was better with the BCI than in the unaided condition, especially when the stimulus and noise were presented on the same side as the implanted ear. The accuracy of directional word recognition showed an improvement with the BCI with respect to the unaided condition on the BCI side, with either the stimulus in the implanted ear and the noise in the contralateral ear or with both the stimulus and noise presented to the implanted ear. PMID- 25720581 TI - Cyclosporine A reduces microvascular obstruction and preserves left ventricular function deterioration following myocardial ischemia and reperfusion. AB - Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10-15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 +/- 3.1%, P = 0.016) and postconditioning pigs (47.6 +/- 3.9%, P = 0.008) versus controls (53.8 +/- 4.1%). Late MVO was significantly reduced by cyclosporine (13.9 +/- 9.6%, P = 0.047) but not postconditioning (23.6 +/- 11.7%, P = 0.66) when compared with controls (32.0 +/- 16.9%). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 +/- 0.06 vs 0.21 +/- 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R(2) = 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (-7.9 +/- 2.4%, P = 0.008) but not postconditioning (-12.0 +/- 5.5%, P = 0.22) when compared with controls (-16.4 +/- 5.5%). In the three groups, infarct size (beta = -0.69, P < 0.001) and late MVO (beta = -0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R(2) = 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls. PMID- 25720583 TI - Programmed erythrocyte death following in vitro Treosulfan treatment. AB - BACKGROUND/AIMS: The cytotoxic drug Treosulfan is clinically used for the treatment of malignancy. A common side effect of Treosulfan treatment is anemia. Treosulfan is at least partially effective by triggering apoptosis of tumor cells. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane. Triggers of eryptosis include oxidative stress, Ca(2+)-entry and increase of cytosolic Ca(2+)-activity ([Ca(2+)]i). The present study explored whether Treosulfan stimulates eryptosis, which may contribute to development of anemia. METHODS: Erythrocyte volume was estimated from forward scatter, phosphatidylserine abundance at the erythrocyte surface from Fluorescein isothiocyanate (FITC)-annexin-V-binding, [Ca(2+)]i from Fluo3 fluorescence and reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA)-fluorescence. RESULTS: A 48 hours exposure of human erythrocytes to Treosulfan (800 ug/ml) significantly decreased erythrocyte forward scatter, increased the percentage of annexin-V-binding cells, increased [Ca(2+)]i, and increased ROS. The effect of Treosulfan on annexin-V-binding was virtually abrogated by removal of extracellular Ca(2+). CONCLUSION: Treosulfan stimulates suicidal erythrocyte death or eryptosis at least in part by inducing oxidative stress and stimulating Ca(2+) entry. PMID- 25720584 TI - Combined B12 and folate deficiency presenting as an aggressive hematologic malignancy. PMID- 25720585 TI - Predisposing factors for early infection in patients with open fractures and proposal for a risk score. AB - BACKGROUND: The primary goals of orthopedic treatment of open fractures are to prevent infection, stabilize bone injury and restore limb function. The objective of the current study was to identify risk factors associated with infection in patients suffering from open fractures, using the strength of association of these factors to propose a score that enables risk stratification in initial care. MATERIALS AND METHODS: A retrospective analysis was performed on 122 patients who underwent open fracture treatment. Clinical and demographic data were collected and the results were divided into two groups: those without infection and those with infection. Both groups were evaluated searching for associated factors that could lead to infection. RESULTS: Thirty-one patients out of 122 were infected (25.4 %). Infection was significantly associated with exposure time up to 24 h (mean 30.3 h; p = 0.007). Fractures classified as Gustilo III had a greater chance of infection (74.2 %; p = 0.042), especially type IIIB (41.9 %). Fractures classified as Tscherne II and III had a greater chance of infection (48.4 and 25.8 %, respectively; p = 0.001). CONCLUSIONS: It was possible to show that the exposure time and the types of fracture classified as Gustilo III and Tscherne II and III are associated with the outcome of infection. It was also possible to create a risk score (IRS) for predicting infection in these types of fractures, which can be used in the initial care of the patient, with a sensitivity of 0.840, specificity of 0.544, cut-off of 6.5 and area under the curve of 0.709 (p = 0.002). LEVEL OF EVIDENCE: Level III. PMID- 25720586 TI - Human Amnion Epithelial Cells Modulate Ventilation-Induced White Matter Pathology in Preterm Lambs. AB - BACKGROUND: Preterm infants can be inadvertently exposed to high tidal volumes (VT) during resuscitation in the delivery room due to limitations of available equipment. High VT ventilation of preterm lambs produces cerebral white matter (WM) pathology similar to that observed in preterm infants who develop cerebral palsy. We hypothesized that human amnion epithelial cells (hAECs), which have anti-inflammatory and regenerative properties, would reduce ventilation-induced WM pathology in neonatal late preterm lamb brains. METHODS: Two groups of lambs (0.85 gestation) were used, as follows: (1) ventilated lambs (Vent; n = 8) were ventilated using a protocol that induces injury (VT targeting 15 ml/kg for 15 min, with no positive end-expiratory pressure) and were then maintained for another 105 min, and (2) ventilated + hAECs lambs (Vent+hAECs; n = 7) were similarly ventilated but received intravenous and intratracheal administration of 9 * 10(7) hAECs (18 * 10(7) hAECs total) at birth. Oxygenation and ventilation parameters were monitored in real time; cerebral oxygenation was measured using near-infrared spectroscopy. qPCR (quantitative real-time PCR) and immunohistochemistry were used to assess inflammation, vascular leakage and astrogliosis in both the periventricular and subcortical WM of the frontal and parietal lobes. An unventilated control group (UVC; n = 5) was also used for qPCR analysis of gene expression. Two-way repeated measures ANOVA was used to compare physiological data. Student's t test and one-way ANOVA were used for immunohistological and qPCR data comparisons, respectively. RESULTS: Respiratory parameters were not different between groups. Interleukin (IL)-6 mRNA levels in subcortical WM were lower in the Vent+hAECs group than the Vent group (p = 0.028). IL-1beta and IL-6 mRNA levels in periventricular WM were higher in the Vent+hAECs group than the Vent group (p = 0.007 and p = 0.001, respectively). The density of Iba-1-positive microglia was lower in the subcortical WM of the parietal lobes (p = 0.010) in the Vent+hAECs group but not in the periventricular WM. The number of vessels in the WM of the parietal lobe exhibiting protein extravasation was lower (p = 0.046) in the Vent+hAECs group. Claudin-1 mRNA levels were higher in the periventricular WM (p = 0.005). The density of GFAP positive astrocytes was not different between groups. CONCLUSIONS: Administration of hAECs at the time of birth alters the effects of injurious ventilation on the preterm neonatal brain. Further studies are required to understand the regional differences in the effects of hAECs on ventilation-induced WM pathology and their net effect on the developing brain. PMID- 25720587 TI - Inter- and intramolecular annulation strategies to a cyclopentanone building block containing an all-carbon quaternary stereogenic center. AB - Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter- and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center. PMID- 25720589 TI - Complex reaction networks in high temperature hydrocarbon chemistry. AB - Complex chemical reaction mechanisms of high temperature hydrocarbon decomposition are represented as networks and their underlying graph topologies are analyzed as a dynamic system. As model reactants, 1,3-butadiene, acetylene, benzene, ethane, ethylene, methane, methyl isobutyl ketone (MIBK) and toluene are chosen in view of their importance for the global environment, energy technologies as well as their quantum chemical properties. Accurate kinetic mechanisms are computationally simulated and converted to bipartite graphs for the incremental conversion steps of the main reactant. Topological analysis of the resulting temporal networks reveals novel features unknown to classical chemical kinetics theory. The time-dependent percolation behavior of the chemical reaction networks shows infinite order phase transition and a unique correlation between the percolation thresholds and electron distribution of the reactants. These observations are expected to yield important applications in the development of a new theoretical perspective to chemical reactions and technological processes e.g. inhibition of greenhouse gases, efficient utilization of fossil fuels, and large scale carbon nanomaterial production. PMID- 25720590 TI - Carving versus Stitching: The Concept of Psychic Function and the Continuity/Discontinuity Debate. AB - BACKGROUND: The current debate on the continuity or discontinuity of psychotic symptoms and common psychic experiences has mainly dealt with methodological, epidemiological and clinical issues, but it has neglected epistemological research on the main concepts of the field. METHODS: The implicit epistemic structure of continuity models of psychotic symptoms and its effect on research are addressed. RESULTS: We explain how the seemingly commonsense, unproblematic concept of psychic function may explain the contradictions and paradoxes of research. CONCLUSIONS: A new model of symptom individuation and symptom eliciting is proposed - based on the concepts of 'schemas', 'embodied affordances' and 'thick/thin descriptions'. PMID- 25720588 TI - Dietary inflammatory index and anthropometric measures of obesity in a population sample at high cardiovascular risk from the PREDIMED (PREvencion con DIeta MEDiterranea) trial. AB - The dietary inflammatory index (DII) is a new tool to assess the inflammatory potential of the diet. In the present study, we aimed to determine the association between the DII and BMI, waist circumference and waist:height ratio (WHtR). We conducted a cross-sectional study of 7236 participants recruited into the PREvencion con DIeta MEDiterranea trial. Information from a validated 137 item FFQ was used to calculate energy, food and nutrient intakes. A fourteen-item dietary screener was used to assess adherence to the Mediterranean diet (MeDiet). Sex-specific multivariable linear regression models were fitted to estimate differences (and 95 % CI) in BMI, waist circumference and WHtR across the quintiles of the DII. All nutrient intakes, healthy foods and adherence to the MeDiet were higher in the quintile with the lowest DII score (more anti inflammatory values) except for intakes of animal protein, saturated fat and monounsaturated fat. Although an inverse association between the DII and total energy was apparent, the DII was associated with higher average BMI, waist circumference and WHtR after adjusting for known risk factors. The adjusted difference in the WHtR for women and men between the highest and lowest quintiles of the DII was 1.60 % (95 % CI 0.87, 2.33) and 1.04 % (95 % CI 0.35, 1.74), respectively. Pro-inflammatory scores remained associated with obesity after controlling for the effect that adherence to a MeDiet had on inflammation. In conclusion, the present study shows a direct association between the DII and indices of obesity, and supports the hypothesis that diet may have a role in the development of obesity through inflammatory modulation mechanisms. PMID- 25720591 TI - 'The problem here is that they want to solve everything with pills': medication use and identity among Mainland Puerto Ricans. AB - Taking medications are complex symbolic acts, infused with diverse meanings regarding body and identity. This article focuses on the meanings of medications for older Puerto Ricans living on the United States mainland, a population experiencing stark health disparities. We aim to gain an understanding of the way multiple cultural and personal meanings of medications are related to and integrated in identity, and to understand how they are situated within Puerto Rican culture, history and circumstance on the US mainland. Data is drawn from thirty qualitative interviews, transcribed and translated, with older Puerto Ricans living on mainland United States. Thematic Analysis indicated four prevalent themes: embodiment of medication use; medications redefining self through the fabric of daily life; healthcare experience defined through medication; and medicine dividing the island and the mainland. While identity is impacted by experience of chronic illness, the experience of medication prescription and consumption is further related to the construction of the sense of self in distinct ways. For these individuals, medication use captures the dilemma of immigration. While cultural belonging and well-being remains on the island of Puerto Rico, the mainland hosts both easier access to and excess reliance on medication. PMID- 25720592 TI - Establishing health-promoting workplaces in Aboriginal community organisations: healthy eating policies. AB - Aboriginal community controlled health organisations (ACCHOs) and cooperatives function at the centre of community life for local Aboriginal people across Victoria. Local Aboriginal people govern them, work within them as managers and service providers, access health and community services from them and form the constituents who determine their directions. Victorian ACCHOs reflect the unique characteristics of the local Aboriginal community. Thus, potentially, Victorian ACCHOs are key strategic sites for health promotion activities that seek to establish and nurture healthy community, family and peer norms. The Victorian Aboriginal Community Controlled Health Organisation (VACCHO) partnered five metropolitan, regional and rural ACCHOs in a pilot project towards the establishment of healthy food policies and practices in their organisations. Project activities combined both 'top-down' policy-oriented and 'bottom-up' practice-oriented strategies. This paper, drawing upon both baseline and follow up quantitative and qualitative data, describes initiatives leading to increases in healthy catering choices and related challenges for Aboriginal workplace health promotion practice. PMID- 25720593 TI - Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy. AB - Mycobacterium avium subspecies paratuberculosis (MAP) asymptomatic infection is speculated to play a role in type 1 diabetes (T1D) among Sardinian subjects. Data obtained analyzing a pediatric population from mainland Italy lends support to the hypothesis, which envisions MAP as an environmental factor at play in T1D pathogenesis. Aiming to investigate the likelihood of cross-recognition between linear determinants shared by self (proinsulin) and non-self (MAP) proteins, 59 children with new onset T1D and 60 healthy controls (HCs) from continental Italy were enrolled in the study. Serum samples were subjected to indirect enzyme linked immunosorbent assay (ELISA) for the presence of antibodies (Abs) toward four homologues MAP/proinsulin epitopes. The rate of MAP infection (42.4% in T1D children and 5% in HCs; p < 0.0001) was estimated searching for Abs against MAP specific protein MptD. The homologous MAP2404c70-85 and proinsulin (PI)46-61 peptides were recognized by 42.4 and 39% of new-onset T1D children and only in 5% of HCs (AUC = 0.76, AUC = 0.7, p < 0.0001); whereas the prevalence of Abs against MAP 1,4-alpha-gbp157-173 and PI64-80 peptides was 45.7 and 49.1% in new-onset T1D children, respectively, compared with 3.3% of HCs (AUC = 0.74 and p < 0.0001 in both). Pre-incubation of MAP Ab-positive sera with proinsulin peptides was able to block the binding to the correspondent MAP epitopes, thus showing that Abs against these homologous peptides are cross-reactive. MAP/Proinsulin Ab mediated cross-recognition, most likely via molecular mimicry, maybe a factor in accelerating and/or initiating T1D in MAP-infected children. Indeed, it is known that anti-proinsulin and anti-Insulin autoantibodies are the earliest to appear. PMID- 25720594 TI - Personalized cancer medicine: next steps in the genomic era. PMID- 25720595 TI - Evaluating protein incorporation and release in electrospun composite scaffolds for bone tissue engineering applications. AB - Electrospun polymer/ceramic composites have gained interest for use as scaffolds for bone tissue engineering applications. In this study, we investigated methods to incorporate Platelet Derived Growth Factor-BB (PDGF-BB) in electrospun polycaprolactone (PCL) or PCL prepared with polyethylene oxide (PEO), where both contained varying levels (up to 30 wt %) of ceramic composed of biphasic calcium phosphates, hydroxyapatite (HA)/beta-tricalcium phosphate (TCP). Using a model protein, lysozyme, we compared two methods of protein incorporation, adsorption and emulsion electrospinning. Adsorption of lysozyme on scaffolds with ceramic resulted in minimal release of lysozyme over time. Using emulsion electrospinning, lysozyme released from scaffolds containing a high concentration of ceramic where the majority of the release occurred at later time points. We investigated the effect of reducing the electrostatic interaction between the protein and the ceramic on protein release with the addition of the cationic surfactant, cetyl trimethylammonium bromide (CTAB). In vitro release studies demonstrated that electrospun scaffolds prepared with CTAB released more lysozyme or PDGF-BB compared with scaffolds without the cationic surfactant. Human mesenchymal stem cells (MSCs) on composite scaffolds containing PDGF-BB incorporated through emulsion electrospinning expressed higher levels of osteogenic markers compared to scaffolds without PDGF-BB, indicating that the bioactivity of the growth factor was maintained. This study revealed methods for incorporating growth factors in polymer/ceramic scaffolds to promote osteoinduction and thereby facilitate bone regeneration. PMID- 25720596 TI - The use of the MeDALL-chip to assess IgE sensitization: a new diagnostic tool for allergic disease? AB - BACKGROUND: Allergic sensitization is frequently present in asthma and rhinitis, but the role of specific immunoglobulin E (s-IgE) is not always clear. Multiple s IgE analyses may provide insight into this relationship, thus a microarray chip was developed within the EU-funded MeDALL project. The main objective was to evaluate the performance of the MeDALL-chip compared to ImmunoCAP and skin prick test (SPT) in detecting allergic sensitization in children and secondarily to investigate the association to asthma and allergic rhinitis. METHODS: From the 'Environment and Childhood Asthma Study', 265 children were investigated at 10 and 16 yr of age with clinical examination, interview, SPT, ImmunoCAP, and the MeDALL-chip including 152 allergen components in the analysis. RESULTS: Allergic sensitization at 10 yr was more frequently detected using the MeDALL-chip (38.1%) compared to the ImmunoCAP (32.8%) (p = 0.034) and SPT (25.5%) (p < 0.001), but no significant difference was seen at 16 yr (MeDALL-chip 49.8%, ImmunoCAP 48.6%, SPT 45.8%). The MeDALL-chip did not differ significantly from the ImmunoCAP or SPT in terms of detecting allergic sensitization in subjects with rhinitis or asthma at 10 or 16 yr. CONCLUSION: The prevalence of allergic sensitization increased by all three diagnostic tests from 10 to 16 yr was similar by SPT and ImmunoCAP and significantly higher with the MeDALL-chip at 10 yr. All three tests were comparable for identification of allergic sensitization among children with current rhinitis or asthma. PMID- 25720597 TI - Methods of Endotoxin Detection. AB - Endotoxin, present in the outer membrane of all gram-negative bacteria, can pose serious risks to human health, from irreversible shock to death. Therefore, it is essential to develop sensitive, accurate, and rapid methods for its detection. The rabbit pyrogen test is the first standard technique for endotoxin detection and, nowadays, has been replaced by the Limulus Amoebocyte Lysate test, which is the most popular detection technique for endotoxin. With in-depth understanding of endotoxin, biosensors based on endotoxin-sensing components are promising alternatives to pursue in developing low-cost, easy-operation, and fast-response endotoxin detection techniques. This article summarizes the recent advances of endotoxin detection methods with a particular emphasis on optical and electrochemical biosensors based on various sensing elements ranging from nature biomolecules to artificial materials. As the research and technological revolution continues, the highly integrated and miniaturized commercial devices for sensitively and reliably detecting endotoxin will provide a wide range of applications in people's daily life. PMID- 25720598 TI - Process for Assembly and Transformation into Saccharomyces cerevisiae of a Synthetic Yeast Artificial Chromosome Containing a Multigene Cassette to Express Enzymes That Enhance Xylose Utilization Designed for an Automated Platform. AB - A yeast artificial chromosome (YAC) containing a multigene cassette for expression of enzymes that enhance xylose utilization (xylose isomerase [XI] and xylulokinase [XKS]) was constructed and transformed into Saccharomyces cerevisiae to demonstrate feasibility as a stable protein expression system in yeast and to design an assembly process suitable for an automated platform. Expression of XI and XKS from the YAC was confirmed by Western blot and PCR analyses. The recombinant and wild-type strains showed similar growth on plates containing hexose sugars, but only recombinant grew on D-xylose and L-arabinose plates. In glucose fermentation, doubling time (4.6 h) and ethanol yield (0.44 g ethanol/g glucose) of recombinant were comparable to wild type (4.9 h and 0.44 g/g). In whole-corn hydrolysate, ethanol yield (0.55 g ethanol/g [glucose + xylose]) and xylose utilization (38%) for recombinant were higher than for wild type (0.47 g/g and 12%). In hydrolysate from spent coffee grounds, yield was 0.46 g ethanol/g (glucose + xylose), and xylose utilization was 93% for recombinant. These results indicate introducing a YAC expressing XI and XKS enhanced xylose utilization without affecting integrity of the host strain, and the process provides a potential platform for automated synthesis of a YAC for expression of multiple optimized genes to improve yeast strains. PMID- 25720599 TI - Toward Microbioreactor Arrays: A Slow-Responding Oxygen Sensor for Monitoring of Microbial Cultures in Standard 96-Well Plates. AB - In this study, a slow-responding chemo-optical sensor for dissolved oxygen (DO) integrated into a 96-well plate was developed. The slow response time ensures that the measured oxygen value does not change much during plate transport to the microplate reader. The sensor therefore permits at-line DO measurement of microbial cultures. Moreover, it eliminates the necessity of individual optical measurement systems for each culture plate, as many plates can be measured successively. Combined with the 96-well format, this increases the experimental throughput enormously. The novel sensor plate (Slow OxoPlate) consists of fluorophores suspended in a polymer matrix that were placed into u-bottom 96-well plates. Response time was measured using sodium sulfite, and a t90 value of 9.7 min was recorded. For application, DO values were then measured in Escherichia coli and Saccharomyces cerevisiae cultures grown under fed-batch-like conditions. Depending on the DO sensor's response time, different information on the oxygenation state of the culture plate was obtained: a fast sensor variant detects disturbance through sampling, whereas the slow sensor indicates oxygen limitation during incubation. A combination of the commercially available OxoPlate and the Slow OxoPlate enables operators of screening facilities to validate their cultivation procedures with regard to oxygen availability. PMID- 25720600 TI - The Effect of DPT-1 Intravenous Insulin Infusion and Daily Subcutaneous Insulin on Endogenous Insulin Secretion and Postprandial Glucose Tolerance. AB - OBJECTIVE: To investigate the effect of parenteral insulin therapy on endogenous insulin secretion in the Diabetes Prevention Trial-Type 1 (DPT-1). RESEARCH DESIGN AND METHODS: In the parenteral insulin arm of DPT-1, subjects without diabetes at high risk of future type 1 diabetes randomized to active treatment received a yearly 4-day intravenous insulin infusion (IV-I) and daily subcutaneous insulin (SC-I). To examine the effects of these insulin therapies on endogenous insulin secretion, C-peptide and glucose levels were compared during oral glucose tolerance tests (OGTTs) performed on and off IV-I and SC-I. Forty six paired OGTTs were performed in 30 subjects from DPT-1 to determine the effect of IV-I. Twenty paired OGTTs were performed in 15 subjects from DPT-1 to determine the effect of SC-I. RESULTS: IV-I suppressed fasting and OGTT stimulated C-peptide (62% and 40%, respectively), and it significantly lowered fasting glucose (67.4 +/- 4.5 mg/dL during IV-I vs. 90.9 +/- 1.8 mg/dL off insulin; P < 0.05). By contrast, post-OGTT glucose levels were significantly higher during IV-I: Glucose during IV-I versus off insulin at 120 min was 203.9 +/- 15.1 vs. 151.6 +/- 10.2 mg/dL, respectively (P < 0.05); 49% of OGTTs became transiently diabetic (>200 mg/dL at 120 min) when receiving IV-I. Fasting glucose was significantly lower when receiving SC-I versus when off insulin (85 +/- 3 vs. 94 +/- 2 mg/dL, respectively; P < 0.05), but SC-I did not significantly alter fasting or OGTT-stimulated C-peptide compared with being off insulin. CONCLUSIONS: These data demonstrate that the IV-I used in the DPT-1 markedly suppressed endogenous insulin secretion, which was frequently associated with postprandial glucose intolerance. SC-I, however, did not. PMID- 25720603 TI - In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats. AB - AIMS/HYPOTHESIS: ANGPTL8 is a circulatory hormone secreted from liver and adipose tissue that promotes pancreatic beta cell proliferation and interferes with triacylglycerol metabolism in mice. The clinical significance of its effects on inducing beta cell proliferation is limited because it causes severe hypertriacylglycerolaemia. METHODS: We employed ultrasound-targeted microbubble destruction (UTMD) to deliver human ANGPTL8 gene plasmids to the pancreas, liver and skeletal muscle of normal adult rats. RESULTS: Human ANGPTL8 was consistently detected in the circulation 1 month after UTMD. ANGPTL8 gene delivery promoted the proliferation of adult and aged beta cells, expanded the beta cell mass, improved glucose tolerance and increased the fasting blood insulin level after UTMD treatment without causing severe hypertriacylglycerolaemia. ANGPTL8 gene therapy significantly alleviated but did not totally reverse STZ-induced diabetes in a rat model. CONCLUSIONS/INTERPRETATION: ANGPTL8 induced adult and aged beta cell regeneration in a rat model. PMID- 25720602 TI - The role of supplementary eye field in goal-directed behavior. AB - The medial frontal cortex has been suggested to play a role in the control, monitoring, and selection of behavior. The supplementary eye field (SEF) is a cortical area within medial frontal cortex that is involved in the regulation of eye movements. Neurophysiological studies in the SEF of macaque monkeys have systematically investigated the role of SEF in various behavioral control and monitoring functions. Inhibitory control studies indicate that SEF neurons do not directly participate in the initiation of eye movements. Instead, recent value based decision making studies suggest that the SEF participates in the control of eye movements by representing the context-dependent action values of all currently possible oculomotor behaviors. These action value signals in SEF would be useful in directing the activity distribution in more primary oculomotor areas, to guide decisions towards behaviorally optimal choices. SEF also does not participate in the fast, inhibitory control of eye movements in response to sudden changes in the task requirements. Instead, it participates in the long term regulation of oculomotor excitability to adjust the speed-accuracy tradeoff. The context-dependent control signals found in SEF (including the action value signals) have to be learned and continuously adjusted in response to changes in the environment. This is likely the function of the large number of different response monitoring and evaluation signals in SEF. In conclusion, the overall function of SEF in goal-directed behavior seems to be the learning of context dependent rules that allow predicting the likely consequences of different eye movements. This map of action value signals could be used so that eye movements are selected that best fulfill the current long-term goal of the agent. PMID- 25720604 TI - Selection of LNA-containing DNA aptamers against recombinant human CD73. AB - LNA-containing DNA aptamers against CD73 (human ecto-5'-nucleotidase), a protein frequently overexpressed in solid tumours, were isolated by SELEX. A pre-defined stem-loop library, containing LNA in the forward primer region, was enriched with CD73 binding sequences through six rounds of SELEX with recombinant his-tagged CD73 immobilised on anti-his plates. Enriched pools isolated from rounds one, three and six were subjected to next-generation sequencing and analysed for enrichment using custom bioinformatics software. The software identified aptamer sequences via the primers and then performed several steps including sequence unification, clustering and alignment to identify enriched sequences. Three enriched sequences were synthesised for further analysis, two of which showed sequence similarities. These sequences exhibited binding to the recombinant CD73 with KD values of 10 nM and 3.5 nM when tested by surface plasmon resonance. Truncated variants of these aptamers and variants where the LNA nucleotides were substituted for the DNA equivalent also exhibited affinity for the recombinant CD73 in the low nanomolar range. In enzyme inhibition assays with recombinant CD73 the aptamer sequences were able to decrease the activity of the protein. However, the aptamers exhibited no binding to cellular CD73 by flow cytometry analysis likely since the epitope recognised by the aptamer was not available for binding on the cellular protein. PMID- 25720601 TI - Urinary adiponectin is an independent predictor of progression to end-stage renal disease in patients with type 1 diabetes and diabetic nephropathy. AB - OBJECTIVE: We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabetic nephropathy (DN) as well as for the principal determinants of uADP concentrations. RESEARCH DESIGN AND METHODS: uADP was measured in 2,090 patients with type 1 diabetes followed for a median of 5.8 (4.4 6.9) years and in 111 subjects without diabetes. Progression was defined as a change in albuminuria (albumin excretion rate [AER]) to a higher stage or development of end-stage renal disease (ESRD). Various Cox regression and competing risk models were used to evaluate the predictive value of uADP for DN progression. The added predictive benefit to AER or estimated glomerular filtration rate (eGFR) was estimated by the area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and other statistical indexes. The determinants of uADP were investigated by multiple regression analyses. RESULTS: uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P < 0.001) and was an even better predictor than AER (P = 0.04) or as good as eGFR (P = 0.79). Furthermore, uADP added a significant benefit when used together with AER (NRI 0.794, P = 0.03; IDI 0.115, P < 0.0001) or eGFR (NRI 0.637, P < 0.001; IDI 0.087, P < 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. CONCLUSIONS: uADP is a strong independent predictor of DN progression from macroalbuminuria to ESRD and adds a significant predictive benefit to current biomarkers in patients with type 1 diabetes. PMID- 25720606 TI - [Hypertension in the course of primary aldosteronism during pregnancy]. AB - Hypertension is one of the most common cardiovascular diseases during pregnancy. Primary hyperaldosteronism (PHA) is the most frequent endocrinological, secondary cause of hypertension, rarely diagnosed in pregnant women. In the available literature about 50 cases of PHA in pregnant women have been described. PHA is often a cause of resistant hypertension. PHA can cause life-threatening complications both for the pregnant woman and the fetus. Diagnosis of PHA in pregnancy is difficult due to the antagonistic effect of progesterone on aldosterone, physiological increase of aldosterone release during gestation and frequent normokalaemic clinical course. Typical pharmacological treatment of PHA is limited due to the anti-androgenic effect of spironolactone, lack of data concerning the safety of eplerenone and limited access to amiloride in Poland. Surgical treatment is a therapeutic option only in early pregnancy. This paper presents the current state of knowledge on diagnostic methods and treatment of PHA in pregnant women and a systematic review of cases described in the literature. PMID- 25720607 TI - [Immune system and influenza virus]. AB - Influenza viruses are a significant cause of respiratory infections, causing 3-5 million clinical infections and 250-500 thousand deaths per year. Infections caused by the influenza virus induce a host immune response at the non-specific and specific level (defined as natural and acquired), which leads to limitation of virus replication. Moreover the elements of immunological memory are induced so that they can protect against subsequent infection by the influenza virus. However, there is still no effective way for the total elimination of this virus, and the only effective method to combat this pathogen appears to be vaccination, which through immune system activation greatly limits its spread. The present paper presents the immune reaction at different levels in response to the influenza virus after entering the body and the mechanisms of the influenza virus for avoiding reactions of the immune system, which correspond to its high variability at the molecular level. Moreover, in this paper we describe various methods of stimulating the organism's immune systems with different generations of vaccines and their effectiveness in the fight against this pathogen. PMID- 25720605 TI - 3,4',5-trans-Trimethoxystilbene; a natural analogue of resveratrol with enhanced anticancer potency. AB - Resveratrol is a phytoalexin produced by many plant species as a defence mechanism. Over the last decade, this polyphenol has been reported to be active against multiple targets associated with chronic disorders. However, its poor pharmacokinetic profile, as well as multiple discrepancies related to its in vitro and in vivo profile, has resulted not only on the study of suitable delivery systems, but the use of resveratrol derivatives. In this regard, the 3,4',5-trans-trimethoxystilbene (TMS), a natural analogue of resveratrol, has emerged as a strong candidate. TMS has an enhanced anticancer profile compared to resveratrol, exhibiting higher potency than resveratrol, as shown by multiple reports describing an improved cancer cell proliferation inhibition, induction of cell cycle arrest, decreased metastasis, reduced angiogenesis, and increased apoptosis. In this review, we provide a concise summary of results reported in the literature, related to the similarities and differences between resveratrol and TMS, and we submit to the scientific community that TMS is a promising and (still) understudied natural agent candidate, with potential applications in cancer research. Nevertheless, based on the available evidence, we also submit to the scientific community that TMS may also find a niche in any other research area in which resveratrol has been used. PMID- 25720608 TI - [SWE elastography in assessment of liver fibrosis]. AB - Liver fibrosis is a relatively common consequence of chronic liver diseases, especially chronic viral hepatitis B and C. Biopsy still remains the gold standard in the assessment of liver fibrosis. However, due to its invasiveness and possible complications, less or even non-invasive methods are being developed, e.g. using biochemical parameters (Fibrotest) or elastography. Elastography is a new diagnostic tool that aims to evaluate stiffness of the tissues. Elastography techniques that are used in the assessment of liver fibrosis are transient elastography (TE), acoustic radiation force impulse (ARFI) and shear-wave elastography (SWE). SWE is a novel real-time two-dimensional elastography technique, which allows one to estimate stiffness quantitatively in kilopascals (kPa). Moreover, lapping elastography over regular B-mode allows precise choice of the region of interest. Therefore SWE creates the opportunity for accurate assessment of liver fibrosis. In this paper we describe processes leading to liver fibrosis as well as methods of liver fibrosis assessment, e.g. liver biopsy, biochemical tests or elastography. The main goal of this paper is to present the SWE technique, its role in liver fibrosis assessment and a short review of the most important clinical studies on SWE. We also present several examples of SWE examinations performed on patients with different stages of liver fibrosis - F0 to F4 on the METAVIR scale. PMID- 25720609 TI - The presence of some cytokines and Chlamydia pneumoniae in the atherosclerotic carotid plaque in patients with carotid artery stenosis. AB - BACKGROUND: Over the last few years the role of microorganisms in the pathogenesis of atherosclerosis has been widely discussed. Chlamydia pneumoniae activates immune cells to produce cytokines that are responsible for the formation of atheromatous carotid lesions. MATERIAL AND METHODS: The study was carried out at the Department of Vascular, General and Transplantation Surgery, Wroclaw Medical University, in 2002-2003, on 100 consecutive symptomatic patients with internal carotid stenosis, who underwent an endarterectomy procedure. Each patient had their carotid artery sampled in order to find C. pneumoniae DNA using the nested PCR method and some cytokines (TGF-beta, VEGF, FGF, TNF-alpha) using immunohistochemical examination. The control group consisted of 20 young organ donors who had been diagnosed with brain death and who had their healthy carotid artery harvested. Analogous genetic and immunohistochemical tests were performed. RESULTS: We did not confirm the presence of either cytokines or C. pneumoniae in the healthy carotid arteries. The presence of FGF was probably due to intima fibroblast activity, which is responsible for elastin and collagen synthesis for the extracellular matrix. C. pneumoniae was discovered in 68% of patients with carotid plaques. Three cytokines (TGF-beta, FGF, TNF-alpha) were detected in atherosclerotic internal carotid arteries as well. CONCLUSION: Chronic infection by C. pneumoniae may exacerbate carotid plaque development and may lead to its destabilization. PMID- 25720610 TI - [Irisin--a new mediator of energy homeostasis]. AB - Skeletal muscles as an active hormonal compartment in the response of physical activity secrete substances named myokines capable of modulating metabolic processes. Myokines take part in communication between muscles and other tissues. Irisin (Ir) - a newly discovered adipomyokine - is cleaved and secreted to the circulation from a fibronectin type III domain containing protein 5 (FNDC5). The mechanism of Ir action has not been described precisely, and receptors for the molecule are not defined yet, but it has been proposed to promote browning of white adipose tissue into beige fat cells. To date we have distinguished two types of adipose tissue in mammals - white, which not only functions as a store of energy but also can play a pro-inflammatory role (secreting adipokines), and brown adipose tissue. Brown adipose tissue has a high mitochondrial content and can dissipate chemical energy in the form of heat (nonshivering termogenesis). It plays a natural antiobesity role and protects against obesity-related diseases. The development of beige adipose tissue, which in its structure and function is similar to brown adipose tissue, and the possibility to modify its amount through some external factors, are nowadays among the most important targets of research on fat cell biology. PMID- 25720611 TI - [Effects of lycopene on the skeletal system]. AB - Antioxidant substances of plant origin, such as lycopene, may favorably affect the skeletal system. Lycopene is a carotenoid pigment, responsible for characteristic red color of tomatoes. It is believed that lycopene may play a role in the prevention of various diseases; despite theoretical premises and results of experimental studies, the effectiveness of lycopene has not yet been clearly demonstrated in studies carried out in humans. The aim of the study was to present the current state of knowledge on the effects of lycopene on the osseous tissue in in vitro and in vivo experimental models and on the skeletal system in humans. Results of the studies indicate that lycopene may inhibit bone resorption. Favorable effects of high doses of lycopene on the rat skeletal system in experimental conditions, including the model of osteoporosis induced by estrogen deficiency, have been demonstrated. The few epidemiological and clinical studies, although not fully conclusive, suggest a possible beneficial effect of lycopene present in the diet on the skeletal system. PMID- 25720612 TI - [HCMV infections after hematopoietic stem cell transplantation--diagnostic methods and importance of viral DNA level monitoring]. AB - HCMV infection is very common. The virus infects 30-90% of population. In immunocompromised patients effective elimination of the virus by immune system is limited by immunosuppressive therapy. Active hCMV infection after HSCT can lead to severe posttransplant complications, graft failure or even death. In addition to direct effects of hCMV infection the virus can cause indirect effects in transplant recipients such as increased immunosuppression or GvHD development/progression. Laboratory diagnostic of hCMV infections after HSCT is now routinely used. Fast and sensitive molecular methods that detect hCMV genetic material are found particularly useful. Quantitative methods, such as R-T PCR, enable identification of patients at high risk of developing hCMV disease and fast employment of appropriate prophylaxis or treatment. Moreover it allows precise monitoring of treatment efficiency and facilitates therapy - related decisions. In last years pre-emptive therapy, which depends on viral load molecular monitoring, significantly reduced morbidity and mortality of active hCMV infections in HSCT recipients. Selective prophylaxis approach enables reduction of patients treated with toxic antiviral therapy which is associated with delayed restoration of virus - specific immune response. Occurrence of symptomatic hCMV disease is still associated with high mortality among HSCT recipients. HCMV infection diagnosis requires further development. Quantitative methods should be unified and optimized. PMID- 25720613 TI - [Experimental models of acute pancreatitis]. AB - Acute pancreatitis is a severe disease with high mortality. Clinical studies can bring some data about etiology, pathogenesis and the course of acute pancreatitis. However, studies concerning early events of this disease and the new concepts of treatment cannot be performed on humans, due to ethical reasons. Animal models of acute pancreatitis have been developed to solve this problem. This review presents currently used experimental models of acute pancreatitis, their properties and clinical relevance. Experimental models of acute pancreatitis can be divided into in vivo (non-invasive and invasive) and ex vivo models. The onset, development, severity and extent of acute pancreatitis, as well as the mortality, vary considerably between these different models. Animal models reproducibly produce mild, moderate or severe acute pancreatitis. One of the most commonly used models of acute pancreatitis is created by administration of supramaximal doses of cerulein, an analog of cholecystokinin. This model produces acute mild edematous pancreatitis in rats, whereas administration of cerulein in mice leads to the development of acute necrotizing pancreatitis. Acute pancreatitis evoked by retrograde administration of sodium taurocholate into the pancreatic duct is the most often used model of acute severe necrotizing pancreatitis in rats. Ex vivo models allow to eliminate the influence of hormonal and nervous factors on the development of acute pancreatitis. PMID- 25720615 TI - Modulation of the host response by probiotic Lactobacillus brevis CD2 in experimental gingivitis. AB - OBJECTIVE: Probiotic Lactobacillus brevisCD2 (CD2) exerts anti-inflammatory properties by preventing nitric oxide synthesis. It is hypothesized that oral application of CD2 can inhibit naturally occurring gingival inflammation. MATERIALS AND METHODS: Thirty-four healthy adults were randomized to receive L. brevisCD2 lozenges or placebo, three times daily for 14 days. The subjects refrained from oral hygiene, the extent of which was determined at various time points. RESULTS: In both groups, bleeding on probing scores increased continuously throughout the study except on day 3. In the placebo group, scores increased significantly from 9.50 at baseline to 14.75 and 14.81 on days 10 and 14, respectively (P < 0.05). No significant change from baseline was observed in the CD2 group. However, scores were consistently higher with placebo, and significant intergroup differences were observed on day 10. Plaque and gingival indices increased from baseline in both treatment groups, but no intergroup differences were observed. Measurements of immune markers in gingival crevicular fluid revealed increased production of nitric oxide in the placebo group (P < 0.05). Prostaglandin E2 production decreased over time in both groups. CONCLUSION: Lactobacillus brevisCD2 may delay gingivitis development in this model by downregulating an inflammatory cascade. PMID- 25720616 TI - An intervention study of individual, apoE genotype-based dietary and physical activity advice: impact on health behavior. AB - AIM: To assess the behavioral effects of receiving personal genetic information, using apoE genotypes as a tool for promoting lifestyle changes. apoE was chosen because it has a significant impact on lipid metabolism and cholesterol absorption, both factors in cardiovascular disease. METHODS: This study was a 1 year intervention study of healthy adults aged 20-67 years (n = 107). Their behavioral changes were measured by diet (e.g., fat quality, as well as consumption of vegetables, berries, fruits, and fatty and sugary foods), alcohol consumption, and exercise. Health and taste attitudes were assessed with the Health and Taste Attitude Scales (HTAS). The measurements were performed 4 times: at baseline (T0), as well as 10 weeks (T1), 6 months (T2), and 12 months after baseline (T3). These behavioral effects were assessed for three groups: a high risk (E4+; n = 16), a low-risk (E4-; n = 35), and a control group (n = 56). RESULTS: Personal genetic information affected health behavior. Dietary fat quality improved more in the E4+ group than in the E4- and control groups after personal, genotype-based health advice. This change differed significantly between the E4+ and the control group (p < 0.05), but only for a short time. CONCLUSION: Personal genetic information, based on apoE, may affect dietary fat quality. More research is required to determine how to utilize genotype-based health information and how to efficiently achieve long-term changes in the prevention of lifestyle-related diseases. PMID- 25720614 TI - Development, growth and maintenance of beta-cell mass: models are also part of the story. AB - Pancreatic beta-cells in the islets of Langerhans play a crucial role in regulating glucose homeostasis in the circulation. Loss of beta-cell mass or function due to environmental, genetic and immunological factors leads to the manifestation of diabetes mellitus. The mechanisms regulating the dynamics of pancreatic beta-cell mass during normal development and diabetes progression are complex. To fully unravel such complexity, experimental and clinical approaches need to be combined with mathematical and computational models. In the natural sciences, mathematical and computational models have aided the identification of key mechanisms underlying the behavior of systems comprising multiple interacting components. A number of mathematical and computational models have been proposed to explain the development, growth and death of pancreatic beta-cells. In this review, we discuss some of these models and how their predictions provide novel insight into the mechanisms controlling beta-cell mass during normal development and diabetes progression. Lastly, we discuss a handful of the major open questions in the field. PMID- 25720617 TI - Individual Differences in Accurately Judging Personality From Text. AB - This research examines correlates of accuracy in judging Big Five traits from first-person text excerpts. Participants in six studies were recruited from psychology courses or online. In each study, participants performed a task of judging personality from text and performed other ability tasks and/or filled out questionnaires. Participants who were more accurate in judging personality from text were more likely to be female; had personalities that were more agreeable, conscientious, and feminine, and less neurotic and dominant (all controlling for participant gender); scored higher on empathic concern; self-reported more interest in, and attentiveness to, people's personalities in their daily lives; and reported reading more for pleasure, especially fiction. Accuracy was not associated with SAT scores but had a significant relation to vocabulary knowledge. Accuracy did not correlate with tests of judging personality and emotion based on audiovisual cues. This research is the first to address individual differences in accurate judgment of personality from text, thus adding to the literature on correlates of the good judge of personality. PMID- 25720618 TI - Individualizing HT considering metabolic risk factors and breast cancer. AB - Despite the time and evidence from observational studies, the balance between risk and benefit of using hormone therapy (HT) in postmenopausal women without comorbidities remains uncertain. HT for menopausal symptoms remains in use mainly to relieve vasomotor symptoms, but still leaves questions about its effect in preventing chronic diseases. The Women Health Initiative researched how to focus on defining and identifying the risks and benefits of HT with estrogen only and estrogen plus progestin on the risk of chronic diseases and other diseases such as coronary heart disease, breast and colorectal cancer and fractures in postmenopausal women, determining its safety and effectiveness. However, there is great concern about the increased risk found in breast cancer and cardiovascular disease using estrogen and progestin combined therapies versus estrogen only therapies, so an added risk to the use of progestin is awarded. For this reason there are new options to new treatment alternatives. PMID- 25720619 TI - Temporal changes in appropriateness of cardiac imaging. AB - BACKGROUND: Appropriate use criteria (AUC) for cardiac imaging have been available for almost 10 years. The extent to which there has been a reported improvement in appropriate use is undefined. OBJECTIVES: This study systematically reviewed published evidence to identify whether the promulgation of AUC has led to an improvement in the proportion of appropriate cardiac imaging requests. METHODS: Electronic databases were systematically searched for English language papers related to AUC and cardiovascular imaging. We found 59 reports involving 103,567 tests that were published from 2000 to 2012. The rate of appropriate testing over time was analyzed in a meta-regression. RESULTS: New AUC were associated with apparent improvements in appropriateness for transthoracic echocardiography (TTE) (80% [95% confidence interval (CI): 0.75 to 0.84] vs. 85% [95% CI: 0.81 to 0.89]), transesophageal echocardiography (TEE) (89% [95% CI: 0.81 to 0.94] vs. 95% [95% CI: 0.93 to 0.96]) and computed tomography angiography (CTA) (37% [95% CI: 0.21 to 0.55] vs. 55% [95% CI: 0.44 to 0.65]) but not stress echocardiography (53% [95% CI: 0.45 to 0.61] vs. 52% [95% CI: 0.42 to 0.61]) or single-photon emission computed tomography (72% [95% CI: 0.66 to 0.77] vs. 68% [95% CI: 0.60 to 0.74]). Although there were no correlations between the proportion of appropriate TTEs and published year (p = 0.36) for 2007 AUC, there was a positive correlation between proportion of appropriateness and the year of publication (p = 0.01) for 2011 AUC. There was a significant decrease in the proportion of appropriateness over time using the 2007 TEE AUC (p = 0.03) and 2006 CT AUC (p = 0.02). There were no meaningful associations between appropriateness and publication year for stress echocardiography, CTA, or single photon emission computed tomography. CONCLUSIONS: Rates of reported appropriate use in imaging show improvements for TTE and CTA but not for stress imaging and TEE. The observed reductions in imaging studies are not matched by reported rates of appropriate use. PMID- 25720620 TI - The first decade of appropriate use criteria: is the glass half empty or half full? PMID- 25720621 TI - Dual Antiplatelet Therapy Duration Following Coronary Stenting. [Corrected]. PMID- 25720622 TI - Comparison of everolimus- and biolimus-eluting coronary stents with everolimus eluting bioresorbable vascular scaffolds. AB - BACKGROUND: The first CE-approved bioresorbable vascular scaffold (BVS) is effective at treating simple lesions and stable coronary artery disease, but it has yet to be assessed versus the best-in-class drug-eluting stents (DES). OBJECTIVES: This study sought to compare the performance of a BVS with that of everolimus-eluting stents (EES) and biolimus-eluting stents (BES) in all-comer patients. METHODS: The EVERBIO II (Comparison of Everolimus- and Biolimus-Eluting Stents With Everolimus-Eluting Bioresorbable Vascular Scaffold Stents II) trial was a single-center, assessor-blinded study of 240 patients randomly assigned in a 1:1:1 ratio to EES, BES, or BVS. The only exclusion criterion was a reference vessel diameter >4.0 mm, which precluded treatment with BVS. The primary endpoint was angiographic late lumen loss (LLL) at 9 months. Secondary endpoints included patient-oriented major acute coronary events (MACE) (death, myocardial infarction [MI], and any revascularization), device-oriented MACE (cardiac death, MI, and target lesion revascularization), and stent thrombosis at the 9-month clinical follow-up. RESULTS: Follow-up angiography was performed in 216 patients (90.7%) at 9 months. In-stent LLL was similar between patients treated with BVS (0.28 +/- 0.39 mm) and those treated with EES/BES (0.25 +/- 0.36 mm; p = 0.30). Clinical outcomes were similar at 9 months: the patient-oriented MACE rate was 27% in BVS and 26% in the EES/BES group (p = 0.83) and the device-oriented MACE rate was 12% in BVS and 9% in the EES/BES group (p = 0.6). CONCLUSIONS: New-generation metallic DES (EES/BES) were not superior to BVS in terms of angiographic LLL and clinical outcomes. (Comparison of Everolimus- and Biolimus-Eluting Stents With Everolimus-Eluting Bioresorbable Vascular Scaffold Stents [EVERBIO II]; NCT01711931). PMID- 25720623 TI - Bioresorbable vascular scaffolds in daily clinical practice: is the essential really invisible to the eyes? PMID- 25720625 TI - Stent selection and antiplatelet therapy duration: one size does not fit all. PMID- 25720624 TI - Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates. AB - BACKGROUND: The use of drug-eluting stents (DES) in patients at high risk of bleeding or thrombosis has not been prospectively studied; limited data are available in patients who have a low restenosis risk. OBJECTIVES: This study sought to compare a hydrophilic polymer-based, second-generation zotarolimus eluting stent (ZES) with a unique drug fast-release profile versus bare-metal stents (BMS) under similar durations of dual-antiplatelet therapy (DAPT). METHODS: We randomly assigned 1,606 patients with stable or unstable symptoms, and who on the basis of thrombotic bleeding or restenosis risk criteria, qualified as uncertain candidates for DES, to receive ZES or BMS. DAPT duration was on the basis of patient characteristics, rather than stent characteristics, and allowed for a personalized 1-month dual antiplatelet regimen. The primary endpoint was the risk of 1-year major adverse cardiovascular events (MACE), which included death, myocardial infarction (MI), or target vessel revascularization (TVR). RESULTS: Median DAPT duration was 32 days (interquartile range [IQR]: 30 to 180 days) and did not differ between the groups. In the ZES group, 140 patients (17.5%) reached the primary endpoint, compared with 178 patients (22.1%) in the BMS group (hazard ratio: 0.76; 95% confidence interval: 0.61 to 0.95; p = 0.011) as a result of lower MI (2.9% vs. 8.1%; p < 0.001) and TVR rates (5.9% vs.10.7%; p = 0.001) in the ZES group. Definite or probable stent thrombosis was also significantly reduced in ZES recipients (2.0% vs. 4.1%; p = 0.019). CONCLUSIONS: Compared with BMS, DES implantation using a stent with a biocompatible polymer and fast drug-eluting characteristics, combined with an abbreviated, tailored DAPT regimen, resulted in a lower risk of 1-year MACE in uncertain candidates for DES implantation. (Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS] Study; NCT01385319). PMID- 25720626 TI - Occupational health hazards of working in the interventional laboratory: a multisite case control study of physicians and allied staff. AB - BACKGROUND: The occupational hazards of working in the interventional laboratory have been inadequately studied for physicians and remain unaddressed for nonphysician personnel. OBJECTIVES: This study sought to determine whether the prevalence of work-related musculoskeletal pain, cancer, and other medical conditions is higher among physicians and allied staff who work in interventional laboratories compared with employees who do not. METHODS: Mayo Clinic employees who work in affiliated hospitals with interventional cardiology or interventional radiology laboratories took an electronic survey. Results were stratified on the basis of self-reported occupational exposure to procedures that involve radiation. RESULTS: There were 1,543 employees (mean age 43 +/- 11.3 years, 33% male) who responded to the survey (response rate of 57%), and 1,042 (67.5%) reported being involved with procedures utilizing radiation. These employees reported experiencing work-related pain more often than the control group before (54.7% vs. 44.7%; p < 0.001) and after adjustment for age, sex, body mass index, pre-existing musculoskeletal conditions, years in profession, and job description (odds ratio: 1.67; 95% confidence interval: 1.32 to 2.11; p < 0.001). Musculoskeletal pain varied significantly by job description, with the highest incidence reported by technicians (62%) and nurses (60%) followed by attending physicians (44%) and trainees (19%; p < 0.001). There was no difference in cancer prevalence between groups (9% vs. 9%; p = 0.96). CONCLUSIONS: Musculoskeletal pain is more common among healthcare workers who participate in interventional procedures and is highest in nonphysician employees. The diagnosis of cancer in employees who participate in procedures that utilize radiation was not elevated when compared to controls within the same departments, although any conclusion regarding causality is limited by the cross-sectional nature of the study, as well as the low overall prevalence of malignancy in our study group. PMID- 25720627 TI - Orthopedic afflictions in the interventional laboratory: tales from the working wounded. PMID- 25720629 TI - Training in cardiovascular genetics. PMID- 25720630 TI - Breast arterial calcifications and their association with incident cardiovascular disease and diabetes: the Prospect-EPIC cohort. PMID- 25720628 TI - Genome-wide significant loci: how important are they? Systems genetics to understand heritability of coronary artery disease and other common complex disorders. AB - Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key "drivers" of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities. PMID- 25720631 TI - Under-recognition of aortic and aortic valve disease and the risk for sudden death in competitive athletes. PMID- 25720632 TI - High-risk plaque detected on coronary CT angiography predicts acute coronary syndrome. PMID- 25720633 TI - Reply: High-risk plaque detected on coronary CT angiography predicts acute coronary syndrome. PMID- 25720634 TI - Seek and you will find. PMID- 25720635 TI - Reply: Seek and you will find. PMID- 25720636 TI - SOCS3 promotes inflammation and apoptosis via inhibiting JAK2/STAT3 signaling pathway in 3T3-L1 adipocyte. AB - The suppressor of cytokine signaling 3 (SOCS3) is an established negative feedback regulation transcription factor associated with leptin, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and growth hormone (GH). However, the regulatory mechanism of SOCS3 on inflammation and apoptosis of adipocyte is still not clear. In this study, we found an increased expression of adipocyte inflammatory cytokines TNF-alpha and IL-6 due to leptin treatment. Meanwhile Caspase3, a key executioner of apoptosis, was also elevated in this process. In addition, we observed that SOCS3 could promote inflammation whereas SOCS3 interference reversed this effect in LPS-induced adipocytes inflammatory model. Moreover, the expression of apoptosis-associated genes Bax, cleaved Caspase9 and cleaved-Caspase3 were elevated along with decreased Bcl-2 expression as detected with Western blot and ELISA assay. The phosphorylation level of JAK2/STAT3 signal was inhibited by SOCS3 along with the elevated expression of IL 6, TNF-alpha and Caspase3. We also demonstrated that stable knockdown of SOCS3 along with SD1008, a specific inhibitor of JAK2/STAT3 signaling pathway, could significantly inhibit inflammation and apoptosis of adipocyte. Altogether, these results inferred that SOCS3 promotes adipocyte apoptosis by both aggravating inflammation and inhibiting the activity of JAK2/STAT3 signaling pathway. PMID- 25720637 TI - Comparative Analysis of Penicillin-Susceptible and Non-Susceptible Isolates of Group B Streptococci by Multilocus Sequence Typing. AB - Since Group B Streptococcus (GBS, Streptococcus agalactiae) clinical isolates are believed to be uniformly susceptible to beta-lactams, penicillin G has been used as the first-line agent for the prevention and treatment of GBS infections. However, the existence and characteristics of GBS isolates with reduced penicillin susceptibility (PRGBS) have recently been reported in Japan. Moreover, the sequence type (ST) 458 is predominant among the PRGBS in Japan. Although the majority of the PRGBS isolates in Japan have been recovered from respiratory specimens of adults, no information on the genotype of these isolates is available. Therefore, whether ST458 predominates among GBS isolates obtained from such specimens is not known. In this study, we characterized the STs of 38 penicillin-susceptible GBS isolates (PSGBS) recovered from respiratory specimens and compared them to the reported PRGBS STs. ST458, the predominant ST among the PRGBS isolates studied (10/19, 53%), was not found in the PSGBS isolates. Thirty six PSGBS isolates belonged to the ST1/19/10 group (includes 6 different STs), and the remaining 2 isolates belonged to that of ST23. Further, the PRGBS isolates were divided into the ST1 (3 STs), and ST23 (2 STs) groups. ST458 was not predominant among the PSGBS isolates recovered from respiratory specimens in Japan and may therefore be specific to the PRGBS. Thus, the ST distribution of the PRGBS isolates does not reflect that of the PSGBS. PMID- 25720638 TI - Rapid Human Immunodeficiency Virus Screening in an Emergency Department in a Region with Low HIV Seroprevalence. AB - Human immunodeficiency virus (HIV) tests are commonly performed in emergency departments (EDs) in the United States (US), but the experience and effectiveness of conducting rapid HIV tests in EDs in regions with low HIV seroprevalence outside the US have seldom been reported. An observational cross-sectional opt-in rapid HIV test and counseling program was conducted at an ED in a teaching hospital in Taiwan, a country with low seroprevalence, to determine the acceptance of rapid HIV tests as well as risky behaviors and illness presentations of people who agreed to undergo the tests. Among 7,645 ED patients between 20 and 55 years of age, 2,138 (28%) agreed to undergo rapid HIV tests, and only 2 (0.09%) tested positive. Patients diagnosed with urinary tract infections, respiratory tract infections, infectious diarrhea, and pelvic inflammatory disease were more likely to be willing to undergo rapid HIV tests in the ED. Stratified analysis revealed that sexually active patients were more likely to consent to HIV testing. Therefore, non-targeted opt-in HIV testing and counseling in the ED was feasible but was not effective in a region with low HIV seroprevalence. PMID- 25720639 TI - Diagnostic Value of Percutaneous Liver Biopsy in Fever of Unkown Origin in Patients with Human Immunodeficiency Virus Infection. AB - Fever of unknown origin (FUO) poses a major diagnostic challenge in patients infected with human immunodeficiency virus (HIV). In this retrospective study, we sought to assess the clinical utility of percutaneous liver biopsy as a diagnostic aid for FUO in HIV-infected patients and identify the factors associated with a greater likelihood of a positive diagnostic yield form this procedure. A total of 101 HIV-infected patients with FUO, who had undergone percutaneous liver biopsy in an HIV care hospital, served as the study population. The results obtained from percutaneous liver biopsy were categorized into three groups: (i) diagnostic, (ii) helpful, and (iii) not helpful. Diagnostic and helpful results were classified as useful. The mean (SD) age of patients was 37.6 (6.9) years, and the median (interquartile range [IQR]) CD4 count was 18 (3-62) cells/mm(3). The median (IQR) duration of fever was 20 (8-30) days. Percutaneous liver biopsy was diagnostic in 51 patients (50.5%), helpful in 12 (11.9%) and not helpful in 38 (37.6%) patients. On multivariate analyses, elevation of serum alkaline phosphatase level (OR 1.27 per one time elevation from the upper normal range; 95% CI, 1.03-1.57; P = 0.023), and fever duration of less than 3 weeks (OR 3.82; 95% CI, 1.03-14.18; P = 0.046) was significantly associated with the likelihood of the biopsy findings being classified as useful. Our study supports the case for percutaneous liver biopsy as a useful diagnostic aid in HIV-infected patients with FUO. PMID- 25720640 TI - Factors Associated with Immunological Discordance in HIV-Infected Patients Receiving Antiretroviral Therapy with Complete Viral Suppression in a Resource Limited Setting. AB - "Immunological discordance," i.e., immunological failure despite complete viral suppression in human immunodeficiency virus (HIV)-infected patients receiving antiretroviral therapy (ART), is associated with increased risk of AIDS or death. To evaluate risk factors for immunological discordance in a resource-limited setting in which patients usually present late with low CD4 cell counts, we conducted a case-control study among HIV-infected patients receiving ART and having undetectable HIV RNA. The study included patients with immunological discordance (cases), which was defined as CD4 cell count < 30% above baseline and absolute CD4 cell count < 200 cells/mm(3) at the first 12 months of undetectable HIV RNA (<50 copies/mL). Patients without immunological discordance were included as controls. Of 142 patients (44 cases; 98 controls), the mean age was 38.6 +/- 9.4 years and 67.6% were men; 65.5% had history of opportunistic infections. In multivariate analysis, only baseline CD4 cell count < 100 cells/mm(3) (odd ratio [OR], 2.53; 95% confidence interval [CI], 1.04-6.14; P = 0.040) and history of lost to follow-up (OR, 11.04; 95% CI, 2.87-42.46; P < 0.001) were significantly associated with immunological discordance. Early initiation of ART and intervention to improve regular clinic visit compliance and adherence to ART are crucial to prevent immunological discordance among HIV-infected patients. PMID- 25720641 TI - Incidence and Risk Factors for Colistin-Associated Nephrotoxicity. AB - Polymyxins have recently reemerged as a treatment option in response to the increasing number of resistant bacterial infections seen in recent years. Therefore, the current study aimed to determine the rate of and risk factors related to colistin-associated nephrotoxicity. All adult patients who had received colistimethate sodium (CMS) between 2010 and 2012 and met the inclusion criteria were included in the study. RIFLE (Risk, Injury, Failure, Loss of renal function and End stage of renal disease) criteria were used to evaluate nephrotoxicity. Age, sex, underlying diseases presences, daily and total CMS doses, daily blood urea and creatinine levels, as well as concurrent drug use were recorded for each patient. Nephrotoxicity occurred in 48% of patients. There was a significant difference in the baseline serum urea levels of patients who experienced nephrotoxicity and those who did not (P value (P) = 0.015). Furthermore, the multivariate analysis showed that advanced age and concomitant aminoglycoside-class antibiotic use were significantly associated with nephrotoxicity. In conclusion, colistin should be used carefully, and all patients should be monitored closely for renal nephrotoxicity. PMID- 25720642 TI - Thymic Function during 12 Months of Highly Active Antiretroviral Therapy in Thai HIV-Infected Patients with Normal and Slow Immune Recovery. AB - The aim of this study was to determine and compare thymic output during 12 months of highly active antiretroviral therapy (HAART) in HIV-infected patients with different types of immune recovery. In total, 18 Thai HIV-infected patients with normal immune recovery (NR) and 13 Thai HIV-infected patients with slow immune recovery (SR) were enrolled. T-cell receptor rearrangement excision circle (TREC) levels in peripheral blood mononuclear cells (PBMCs) and CD4(+) T cells were quantified at baseline, and after 6 and 12 months of HAART. CD4(+) T-cell counts in NR patients were significantly higher than those in SR patients after 6 and 12 months of HAART. However, the median TREC levels in PBMCs and CD4(+) T cells in both groups were comparable. Moreover, TREC levels showed similar trends in PBMCs and CD4(+) T cells in both groups during 12 months of HAART. Only patients with SR had significant increases in median TREC levels in PBMCs and CD4(+) T-cells during the first 6 months of HAART. No correlations were found between CD4(+) T cell count and TREC levels in PBMCs and CD4(+) T cells. These results imply that the increase in CD4(+) T-cell count in SR patients after 12 months of HAART is likely attributable to thymic output and other sources. PMID- 25720643 TI - Characteristics of Meningitis Due to Methylobacterium mesophilicum: A Rare Case. AB - Methylobacterium mesophilicum is a gram-negative bacillus most often isolated in medical establishments. In humans, M. mesophilicum is considered a conditionally pathogenic flora. Infections in humans generally occur in immunodeficient individuals. This article describes a rare case of M. mesophilicum infection that developed into acute meningitis in a 26-year-old patient. Decreased neutrophil bactericidal activity was also detected. To our knowledge, there have been no previous reports of meningitis due to M. mesophilicum. PMID- 25720644 TI - Seroprevalence, Seroconversion, and Risk Factors for Toxoplasmosis among Pregnant Women in Taipei, Taiwan. AB - Herein, we determined the seroprevalence, seroconversion, and risk factors associated with Toxoplasma gondii (T. gondii) infection among pregnant women in Taipei, Taiwan. Pregnant women attending antenatal consultation in a Taipei medical center were invited, and 104 women completed a self-administered structured questionnaire. Venous blood samples were collected during the first and third trimester after consent was obtained. Serum IgG and IgM antibodies (Abs) as well as IgG avidity were analyzed using an enzyme-linked fluorescent assay. Of the samples collected in the first trimester, seven were seropositive for IgG Abs and one was seropositive for IgG + IgM Abs with a borderline avidity index, resulting in an overall seroprevalence of 7.7%. No statistically significant association was found between toxoplasmosis and age, pregnancy history, or any risk factors. Seroconversion was not detected from paired sera between the first and third trimesters. Pregnant women with senior high school education level or those who claimed to knowing Toxoplasma exhibited a significantly higher seroprevalence than those with bachelor degree (P = 0.05) or those who claimed not to have this knowledge (P = 0.05). Therefore, failure to understand the importance of T. gondii infection and the prevention measures resulted in the development of toxoplasmosis among these women. PMID- 25720645 TI - Impact of Artemisinin-Based Combination Therapy on Falciparum Malaria in Urban Kolkata: A Clinic-Based Report. AB - In India, artemisinin-based combination therapy (ACT; specifically artesunate + sulfadoxine-pyrimethamine) has been implemented for uncomplicated falciparum malaria since 2010. But for vivax malaria drug policy remained unchanged i.e., chloroqine and primaquine. We observed the impact of this intervention in urban Kolkata by analyzing data from the Malaria Clinic from 2001 to 2013. In Kolkata, we observed that Plasmodium vivax was perennial, whereas P. falciparum infection was seasonal. Before ACT implementation, the proportion of P. falciparum was as high as 50% and it steadily decreased during 4 successive years post intervention. No change was observed in the number of P. vivax cases. ACT may be an effective measure in reducing falciparum malaria cases. Artemisinin-derivative combination therapies should be explored in vivax malaria to reduce the overall burden of malaria. PMID- 25720646 TI - A Pediatric Case of Bacteremia and Possible Cholecystitis Due to Moraxella osloensis. AB - We encountered a pediatric case of bacteremia and possible cholecystitis due to Moraxella osloensis that was treated successfully. We confirmed the diagnosis with the presence of a high serum titer of the antibody to the organism. Furthermore, 16S rRNA sequencing was performed to identify the bacteria. PMID- 25720647 TI - Low acuity and general practice-type presentations to emergency departments: a rural perspective. AB - OBJECTIVE: To estimate the number of general practice (GP)-type patients attending a rural ED and provide a comparative rural estimate to a metropolitan study. METHODS: Analysis of presentations to the two EDs in Northwest Tasmania from 1 January 2009 to 31 December 2013 using the Diagnosis, Sprivulis, Australian College of Emergency Medicine (ACEM) and the Australian Institute of Health and Welfare (AIHW) methods to estimate the number of GP-type presentations. RESULTS: There were 255,365 ED presentations in Northwest Tasmania during the study period. There were 86,973 GP-type presentations using the ACEM method, 142,006 using the AIHW method, 174,748 using the Diagnosis method and 28,922 low acuity patients identified using the Sprivulis method. CONCLUSIONS: The proportion of GP-type presentations identified using the four methods ranged from 15% to 69%. The results suggest that triage status and self-referral are not reliable indicators of low acuity in this rural area. In rural areas with a shortage of GPs, it is likely that many people appropriately self-refer to ED because they cannot access a GP. The results indicate that the ACEM method might be most useful for identifying GP-type patients in rural ED. However, this requires validation in other regions of Australia. PMID- 25720648 TI - Meta-analysis for models. PMID- 25720649 TI - Perceived stress and cytokine production. PMID- 25720650 TI - The 20th birthday of Journal of Peptide Science. PMID- 25720652 TI - Preoperative Neutrophil-to-Lymphocyte Ratio Has a Better Predictive Capacity in Diagnosing Tubo-Ovarian Abscess. AB - BACKGROUND: The aim of this study is to identify the inflammatory markers which predict a tubo-ovarian abscess (TOA) in the most accurate way. METHODS: This study involves 312 women. Preoperative inflammatory markers in the study group were compared with those in the healthy control group to identify the most efficient predictor of TOA with a high sensitivity and specificity. The recommended cutoff values of the neutrophil-to-lymphocyte ratio (NLR), platelet to-lymphocyte ratio (PLR), white blood cell count, and red cell distribution width were determined using receiver operating characteristic curve (ROC) analyses. RESULTS: The area under the curve (AUC = 0.99) in the ROC analysis was found to be statistically significant for NLR (p < 0.001) with a cutoff value of >=4.15 (95% CI 0.97-1.00, sensitivity 95.2%, specificity 99.4%). The positive predictive value of NLR was 99.2%, and the negative predictive value was 96.7% (p < 0.001). The recommended threshold for PLR was found to be 164.37 (AUC = 0.95, 95% CI 0.93-0.98, sensitivity 86.7%, specificity 92%), and the cutoff point of the white blood cell count in the ROC analysis was 9.55 * 103/MUl (AUC = 0.90, 95% CI 0.87-0.95, sensitivity 78.68%, specificity 96.68%). CONCLUSION: Preoperative NLR and PLR improve the predictive value of serum markers for the presence of TOA. PMID- 25720654 TI - Histogenesis of pure and combined Merkel cell carcinomas: An immunohistochemical study of 14 cases. AB - The histogenesis of Merkel cell carcinoma (MCC) has remained unresolved. Moreover, one of the questions is whether pure MCC and combined MCC represent the same histogenesis and entity. The existence of combined MCC suggests that MCC likely arise from pluripotent stem cells. Merkel cells (MC) localize within the bulge area, which is populated by hair follicle stem cells. We used hair follicle stem cell markers to investigate whether MCC share certain characteristics of these stem cells. Fourteen MCC specimens were examined histologically and immunohistochemically. There were six pure MCC and eight combined MCC. In six combined MCC, both MCC components and squamous components at least focally shared the expression of one or more of cytokeratin (CK)15, CK19 and CD200, which are hair follicle stem cell markers. On the other hand, four cases of pure MCC showed partially distinct CK19 expression, but did not show CK15 and/or CD200 expression. There was a distinct difference between pure MCC and combined MCC on the expression of hair follicle stem cell markers. The normal skin expressed CK15, CK19 and CD200 in the bulge area, whereas CK15 and CD200 were absent in the MC-rich glabrous skin and touch domes. The results led us to hypothesize that combined MCC originate from the hair follicle stem cells. We postulate that combined MCC undergo multidirectional differentiation into squamous, glandular, mesenchymal and Merkel cells. Further investigation is warranted to confirm the histogenesis of pure MCC and combined MCC. PMID- 25720653 TI - Proteomic identification of early salicylate- and flg22-responsive redox sensitive proteins in Arabidopsis. AB - Accumulation of reactive oxygen species (ROS) is one of the early defense responses against pathogen infection in plants. The mechanism about the initial and direct regulation of the defense signaling pathway by ROS remains elusive. Perturbation of cellular redox homeostasis by ROS is believed to alter functions of redox-sensitive proteins through their oxidative modifications. Here we report an OxiTRAQ-based proteomic study in identifying proteins whose cysteines underwent oxidative modifications in Arabidopsis cells during the early response to salicylate or flg22, two defense pathway elicitors that are known to disturb cellular redox homeostasis. Among the salicylate- and/or flg22-responsive redox sensitive proteins are those involved in transcriptional regulation, chromatin remodeling, RNA processing, post-translational modifications, and nucleocytoplasmic shuttling. The identification of the salicylate-/flg22 responsive redox-sensitive proteins provides a foundation from which further study can be conducted toward understanding biological significance of their oxidative modifications during the plant defense response. PMID- 25720655 TI - The trochanter tertius in a dog. AB - The tuberositas glutaea is a rudimentary structure in the dog's os femoris. It gives attachment to the superficial gluteal muscle, and is known by veterinary anatomists and orthopedic surgeons as trochanter tertius. We report an atypical eminence exposed through a surgical approach on a Cane Corso Dog. Anatomic and radiographic investigations led us to recognize this eminence as an abnormally grown tuberositas glutaea. PMID- 25720656 TI - Diminished nap effects on memory consolidation are seen under oral contraceptive use. AB - Many young females take exogenous hormones as oral contraceptive (OC), a condition rarely controlled for in studies on sleep and memory consolidation even though sex hormones influence consolidation. This study investigated the effects of OCs on sleep-related consolidation of a motor and declarative task, utilizing a daytime nap protocol. Fifteen healthy, young females taking OCs came to the sleep lab for three different conditions: nap with previous learning, wake with previous learning and nap without learning. They underwent each condition twice, once during the "pill-active" weeks and once during the "pill-free" week, resulting in 6 visits. In all conditions, participants showed a significant off line consolidation effect, independent of pill week or nap/wake condition. There were no significant differences in sleep stage duration, spindle activity or spectral EEG frequency bands between naps with or without the learning condition. The present data showed a significant off-line enhancement in memory irrespective of potential beneficial effects of a nap. In comparison to previous studies, this may suggest that the use of OCs may enhance off-line memory consolidation in motor and verbal tasks per se. These results stress the importance to control for the use of OCs in studies focusing on memory performance. PMID- 25720658 TI - The use of split-thickness versus full-thickness skin graft to resurface volar aspect of pediatric burned hands: A systematic review. AB - OBJECTIVE: The aim of this systematic review was to discuss the comparison of split-thickness skin graft (STSG) and full-thickness skin graft (FTSG) use as the treatment for volar digital and palmar burns in children. METHODS: We conducted PubMed and Cochrane Library searches using keywords "hand injuries", "contracture" and "skin transplantation". The search was limited to studies published from 1st January 1980 until 31st December 2013 and used English language. We selected the studies based on specific inclusion and exclusion criteria. We assessed the quality of the studies by using Newcastle-Ottawa Scale (NOS) for cohort studies. RESULTS: We included eight articles in our systematic review. One of those studies is a prospective cohort study and the others are retrospective cohort studies. Based on combined range of motion (ROM) evaluation in three studies, STSG group yielded poorer functional outcomes than FTSG group. However, there is no study which can fairly show that FTSG was significantly superior to STSG to achieve good functional outcomes. CONCLUSION: Currently, there is no strong, high-quality evidence to prove that FTSG is superior to STSG to cover pediatric palmar burns. Either FTSG or STSG can be utilized with consideration of several influential factors especially splinting and physiotherapy. PMID- 25720657 TI - Thermally labile components of aqueous humor potently induce osteogenic potential in adipose-derived mesenchymal stem cells. AB - Adipose-derived mesenchymal stem cells (ASCs) hold promise for use in cell-based therapies. Their intrinsic anti-inflammatory properties are potentially useful for treatments of inflammatory conditions such as uveitis, while their ability to differentiate along multiple cell lineages suggests use in regenerating damaged or degenerated tissue. However, how ASCs will respond to the intraocular environment is poorly studied. We have recently reported that aqueous humor (AH), the fluid that nourishes the anterior segment of the eye, potently increases alkaline phosphatase (ALP) activity of ASCs, indicating osteogenic differentiation. Here, we expand on our previous findings to better define the nature of this response. To this end, we cultured ASCs in the presence of 0, 5, 10, and 20% AH and assayed them for ALP activity. We found ALP activity correlates with increasing AH concentrations from 5 to 20%, and that longer treatments result in increased ALP activity. By using serum free media and pretreating AH with dextran-coated charcoal, we found that serum and charcoal adsorbable AH components augment but are not required for this response. Further, by heat-treating the AH, we established that thermally labile components are required for the osteogenic response. Finally, we showed myocilin, a protein present in AH, could induce ALP activity in ASCs. However, this was to a lesser extent than untreated 5% AH, and myocilin could only partially rescue the effect after heat treatment, documenting there were additional thermally labile constituents of AH involved in the osteogenic response. Our work adds to the understanding of the induction of ALP in ASCs following exposure to AH, providing important insight in how ASCs will be influenced by the ocular environment. In conclusion, increased osteogenic potential upon exposure to AH represents a potential challenge to developing ASC cell-based therapies directed at the eye. PMID- 25720660 TI - Chronic intermittent hypoxia orchestrates cardiorespiratory cacophony--adapting melody to malady. PMID- 25720659 TI - A prospective clinical trial comparing Biobrane((r)) Dressilk((r)) and PolyMem((r)) dressings on partial-thickness skin graft donor sites. AB - INTRODUCTION: In a single-center, prospective, randomized clinical trial three different configured wound dressings Biobrane((r)), Dressilk((r)) and PolyMem((r)) were compared with each other regarding objective and subjective healing parameters and cost efficiency. METHODS: 28 burn patients received surgical treatment with split-thickness skin grafting, while utilizing Biobrane((r)), Dressilk((r)) and PolyMem((r)) as a single bound donor site wound dressing in all patients. Following a standardized case report form, we monitored several parameters such as pain, transparency of the dressing, active bleeding, exudation and inflammation by using the Verbal Rating Scale 1-10 through out. RESULTS: With regard to re-epithelialization, pain and acute bleeding all three dressings were equivalent. Dressilk((r)) and Biobrane((r)) presented clearly superior to PolyMem((r)) in both wound assessment and in the reduction of mild inflammation and exudation. High subjective satisfaction rates were reported with Dressilk((r)) and Biobrane((r)) dressings in regard to comfort and mobility. During the continuous monitoring period Biobrane((r)) outperformed Dressilk((r)) by providing higher wound transparency rates and offering a better level of wound control during the entire study period. Regarding their cost efficiency, PolyMem((r)) and Dressilk((r)) are clearly superior to Biobrane((r)). CONCLUSION: The "ideal" wound dressing maximizes patients' comfort while reducing pain and the risk of pulling off migrating epidermal cells from the wound surface. In addition reliable wound status evaluation (minimizing complications), an increase of treatment cost value efficacy, and reduced hospitalization rates should be provided. Dressilk((r)) and Biobrane((r)) were favored by patients and surgeons for providing an effective and safe healing environment, with overall low complication rates with respect to infection and exudation. Regarding cost effectiveness PolyMem((r)) and Dressilk((r)) presented superior to Biobrane((r)). PMID- 25720661 TI - Interluekin-10 for hyperoxia-induced acute lung injury: a new direction? PMID- 25720662 TI - The many facets of electrical stimulation of vagus nerves. PMID- 25720663 TI - Vagus nerve stimulation reverses ventricular electrophysiological changes induced by hypersympathetic nerve activity. AB - NEW FINDINGS: What is the central question of this study? Previous studies have shown that hypersympathetic nerve activity results in ventricular electrophysiological changes and facilitates the occurrence of ventricular arrhythmias. Vagus nerve stimulation has shown therapeutic potential for myocardial infarction-induced ventricular arrhythmias. However, the actions of vagus nerve stimulation on hypersympathetic nerve activity-induced ventricular electrophysiological changes are still unknown. What is the main finding and its importance? We show that vagus nerve stimulation is able to reverse hypersympathetic nerve activity-induced ventricular electrophysiological changes and suppress the occurrence of ventricular fibrillation. These findings further suggest that vagus nerve stimulation may be an effective treatment option for ventricular arrhythmias, especially in patients with myocardial infarction or heart failure. Vagus nerve stimulation (VNS) has shown therapeutic potential for myocardial infarction-induced ventricular arrhythmias. This study aimed to investigate the effects of VNS on ventricular electrophysiological changes induced by hypersympathetic nerve activity. Seventeen open-chest dogs were subjected to left stellate ganglion stimulation (LSGS) for 4 h to simulate hypersympathetic tone. All animals were randomly assigned to the VNS group (n = 9) or the control group (n = 8). In the VNS group, VNS was performed at the voltage causing a 10% decrease in heart rate for hours 3-4 during 4 h of LSGS. During the first 2 h of LSGS, the ventricular effective refractory period (ERP) and action potential duration (APD) were both progressively and significantly decreased; the spatial dispersion of ERP, maximal slope of the restitution curve and pacing cycle length of APD alternans were all increased. With LSGS + VNS during the next 2 h, there was a significant return of all the altered electrophysiological parameters towards baseline levels. In the eight control dogs that received 4 h of LSGS without VNS, all the parameters changed progressively, but without any reversals. The ventricular fibrillation threshold was higher in the VNS group than in the control group (17.3 +/- 3.4 versus 11.3 +/- 3.8 V, P < 0.05). The present study demonstrated that VNS was able to reverse LSGS-induced ventricular electrophysiological changes and suppress the occurrence of ventricular fibrillation. PMID- 25720664 TI - Oxygen dissociation curves in altitude and sea-level residents. PMID- 25720665 TI - Reply: To PMID 25172885. PMID- 25720666 TI - Reply: To PMID 23313855. PMID- 25720668 TI - Delivery of vegetable oil suspensions in a shear thinning fluid for enhanced bioremediation. AB - In situ anaerobic biological processes are widely applied for dechlorination of chlorinated solvents in groundwater. A wide range of organic substrates have been tested and applied to support the dechlorination processes. Vegetable oils are a promising type of substrate and have been shown to induce effective dechlorination, have limited geochemical impacts, and maintain good longevity. Because they are non-aqueous phase liquids, distribution of vegetable oils in the subsurface has typically been approached by creating emulsified oil solutions for injection into the aquifer. In this study, inexpensive waste vegetable oils were suspended in a shear-thinning xanthan gum solution as an alternative approach for delivery of vegetable oil to the subsurface. The stability, oil droplet size distribution, and rheological behavior of the oil suspensions that are created in the xanthan solutions were studied in batch experiments. The injectability of the suspensions and the oil distribution in a porous medium were evaluated in column tests. Numerical modeling of oil droplet transport and distribution in porous media was conducted to help interpret the column-test data. Batch studies showed that simple mixing of vegetable oil with xanthan solution produced stable suspensions of the oil as micron-size droplets. The mixture rheology retains shear-thinning properties that facilitate improved uniformity of substrate distribution in heterogeneous aquifers. Column tests demonstrated successful injection of the vegetable oil suspension into a porous medium. This study provides evidence that vegetable oil suspensions in xanthan gum solutions have favorable injection properties and are a potential substrate for in situ anaerobic bioremediation. PMID- 25720669 TI - Degradation of tyrosol by a novel electro-Fenton process using pyrite as heterogeneous source of iron catalyst. AB - Tyrosol (TY) is one of the most abundant phenolic components of olive oil mill wastewaters. Here, the degradation of synthetic aqueous solutions of 0.30 mM TY was studied by a novel heterogeneous electro-Fenton (EF) process, so-called EF pyrite, in which pyrite powder was the source of Fe(2+) catalyst instead of a soluble iron salt used in classical EF. Experiments were performed with a cell equipped with a boron-doped diamond anode and a carbon-felt cathode, where TY and its products were destroyed by hydroxyl radicals formed at the anode surface from water oxidation and in the bulk from Fenton's reaction between Fe(2+) and H2O2 generated at the cathode. Addition of 1.0 g L(-1) pyrite provided an easily adjustable pH to 3.0 and an appropriate 0.20 mM Fe(2+) to optimize the EF-pyrite treatment. The effect of current on mineralization rate, mineralization current efficiency and specific energy consumption was examined under comparable EF and EF-pyrite conditions. The performance of EF-pyrite was 8.6% superior at 50 mA due to self-regulation of soluble Fe(2+) by pyrite. The TY decay in this process followed a pseudo-first-order kinetics. The absolute rate constant for TY hydroxylation was 3.57 * 10(9) M(-1) s(-1), as determined by the competition kinetics method. Aromatic products like 3,4-dihydroxyphenylethanol, 4 hydroxyphenylacetic acid, 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and catechol, as well as o-benzoquinone, were identified by GC-MS and reversed-phase HPLC. Short-chain aliphatic carboxylic acids like maleic, glycolic, acetic, oxalic and formic were quantified by ion-exclusion HPLC. Oxalic acid was the major and most persistent product found. Based on detected intermediates, a plausible mineralization pathway for TY by EF-pyrite was proposed. PMID- 25720670 TI - The effect of seasonal temperature on pathogen removal efficacy of vermifilter for wastewater treatment. AB - The present study explored the effects of seasonal temperature on the treatment efficiency and pathogen removal efficacy from synthetic domestic wastewater, earthworm population characteristics and microbial population in the filter media of a lab-scale vermifilter (VF). The experimental phase lasted for one year and daily mean room temperature showed a difference of 2-16 degrees C between winter (Dec-Feb), spring (Mar-May), summer (Jun-Aug) and autumn (Sep-Nov) periods. The results showed that variation in ambient temperature had a significant effect on chemical oxygen demand (COD) and biochemical oxygen demand (BOD) reduction, indicator organisms and pathogen removal, earthworm population, bacterial and actinomycetes number, but had no effect on total suspended solids (TSS) removal and fungi number. The study showed that higher BOD and COD removal was accomplished during the spring and autumn period when the mean temperature was 25 27 degrees C. This temperature range is optimum for the earthworm species Eisenia fetida for its activity, growth and reproduction and any variation in temperature from the optimum range led to decrease in treatment efficiency and earthworm population. However, during summer, when the maximum temperature reached 38-40 degrees C, the indicator bacteria removal was maximum by 99.9%, Salmonella reduction by 96.9% and Escherichia coli by 99.3%. The pathogen removal efficacy of VF increases with the increase in temperature, as shown by linear regression analysis, which implied that temperature had a significant contribution to the pathogen removal efficiency of VF. Pearson coefficient of correlation (r) derived an important relationship between the seasonal temperature and treatment efficiency, pathogen removal efficacy and microbial numbers during vermifiltration. PMID- 25720671 TI - In situ, high-resolution imaging of labile phosphorus in sediments of a large eutrophic lake. AB - Understanding the labile status of phosphorus (P) in sediments is crucial for managing a eutrophic lake, but it is hindered by lacking in situ data particularly on a catchment scale. In this study, we for the first time characterized in situ labile P in sediments with the Zr-oxide diffusive gradients in thin films (Zr-oxide DGT) technique at a two-dimensional (2D), submillimeter resolution in a large eutrophic lake (Lake Taihu, China, with an area of 2338 km(2)). The concentration of DGT-labile P in the sediment profiles showed strong variation mostly ranging from 0.01 to 0.35 mg L(-1) with a considerable number of hotspots. The horizontal heterogeneity index of labile P varied from 0.04 to 4.5. High values appeared at the depths of 0-30 mm, likely reflecting an active layer of labile P under the sediment-water interface (SWI). Concentration gradients of labile P were observed from the high-resolution 1D DGT profiles in both the sediment and overlying water layers close to the SWI. The apparent diffusion flux of P across the SWI was calculated between -21 and 65 ng cm(-2) d(-1), which showed that the sediments tended to be a source and sink of overlying water P in the algal- and macrophyte-dominated regions, respectively. The DGT-labile P in the 0-30 mm active layer showed a better correlation with overlying water P than the labile P measured by ex situ chemical extraction methods. It implies that in situ, high-resolution profiling of labile P with DGT is a more reliable approach and will significantly extend our ability in in situ monitoring of the labile status of P in sediments in the field. PMID- 25720672 TI - Prospective evaluation of the effect of short-term oral vitamin d supplementation on peripheral neuropathy in type 2 diabetes mellitus. AB - OBJECTIVE: We aimed to assess the efficacy of short-term oral vitamin D supplementation on peripheral neuropathy in patients with type 2 diabetes. MATERIALS AND METHODS: This prospective, placebo-controlled trial included 112 type 2 diabetic patients with diabetic peripheral neuropathy (DPN) and vitamin D [25(OH)D] deficiency. Patients were sequentially assigned to a treatment group (n = 57) and a placebo group (n = 55). DPN was assessed using a neuropathy symptom score (NSS), a neuropathy disability score (NDS) and a nerve conduction study (NCS). Vitamin D status was determined by measuring the serum total 25(OH)D concentration. Patients received either oral vitamin D3 capsules or starch capsules once weekly for 8 weeks. The primary outcome was changes in NSS and NDS from baseline. The secondary outcome was changes in the NCS result. RESULTS: Serum 25(OH)D concentrations significantly improved after oral vitamin D supplementation in the treatment group when compared to the placebo group (32.8 +/- 23.7 vs. 1.1 +/- 3.6, p < 0.0001). Similarly, the improvement in NSS values was significantly greater in the treatment group than in the placebo group (-1.49 +/- 1.37 vs. -0.20 +/- 0.59, p < 0.001). No improvement was observed for NDS and NCS between the 2 groups after treatment. CONCLUSION: Short-term oral vitamin D3 supplementation improved vitamin D status and the symptoms of neuropathy in patients with type 2 diabetes. PMID- 25720674 TI - Synthesis, molecular and electronic structure, and reactions of a Zn-Hg-Zn bonded complex. AB - Reaction of ((Ar')NacNac)ZnI with potassium/mercury amalgam gave the trimetallic compound {((Ar')NacNac)Zn}2Hg (1) containing a Zn-Hg-Zn unit and the first example of a bond between two different Group 12 metals; DFT and QTAIM analyses suggest that 1 is best described as two formally Zn(I) atoms with a Hg(0) atom positioned between them; reactions of 1 with stoichiometric I2, FpI or Fp2 gave addition products of the type ((Ar')NacNac)ZnX (X = I, Fp) and Hg. (Ar')NacNac = HC{C(Me)N(2,6-C6H3(i)Pr2)}2; Fp = CpFe(CO)2. PMID- 25720673 TI - HER2 as a target in invasive urothelial carcinoma. AB - We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of >= 2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2 positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC. PMID- 25720675 TI - A Pilot Randomized Trial of Text-Messaging for Symptom Awareness and Diabetes Knowledge in Adolescents With Type 1 Diabetes. AB - Adolescents with type 1 diabetes typically receive clinical care every 3 months. Between visits, diabetes-related issues may not be frequently reflected, learned, and documented by the patients, limiting their self-awareness and knowledge about their condition. We designed a text-messaging system to help resolve this problem. In a pilot, randomized controlled trial with 30 adolescents, we examined the effect of text messages about symptom awareness and diabetes knowledge on glucose control and quality of life. The intervention group that received more text messages between visits had significant improvements in quality of life. PMID- 25720676 TI - The effect of online chronic disease personas on activation: within-subjects and between-groups analyses. AB - BACKGROUND: Although self-management of chronic disease is important, engaging patients and increasing activation for self-care using online tools has proven difficult. Designing more tailored interventions through the application of condition-specific personas may be a way to increase engagement and patient activation. Personas are developed from extensive interviews with patients about their shared values and assumptions about their health. The resulting personas tailor the knowledge and skills necessary for self-care and guide selection of the self-management tools for a particular audience. OBJECTIVE: Pre-post changes in self-reported levels of activation for self-management were analyzed for 11 chronic health personas developed for 4 prevalent chronic diseases. METHODS: Personas were created from 20 to 25 hour-long nondirected interviews with consumers with a common, chronic disease (eg, diabetes). The interviews were transcribed and coded for behaviors, feelings, and beliefs using the principles of grounded theory. A second group of 398 adults with self-reported chronic disease were recruited for online testing of the personas and their impact on activation. The activation variables, based on an integrated theory of health behavior, were knowledge of a given health issue, perceived self-management skills, confidence in improving health, and intention to take action in managing health. Pre-post changes in activation were analyzed with a mixed design with 1 within-subjects factor (pre-post) and 1 between-group factor (persona) using a general linear model with repeated measures. RESULTS: Sixteen pre-post changes for 4 measures of activation were analyzed. All but 2 of the within-subjects effects were statistically significant and all changes were in the direction of increased activation scores at posttest. Five significant differences between personas were observed, showing which personas performed better. Of low activation participants, 50% or more shifted to high activation across the 4 measures with minimal changes (<=5%) in the reverse direction. CONCLUSIONS: The majority of participants using a persona-tailored learning path reported high levels of satisfaction with their online user experience and increased levels of activation about their own health. In the body of work on patient activation, the current study adds to understanding of both short-term impact and the content of a brief, online intervention for engagement of specific groups in self management. PMID- 25720677 TI - Draft Genome Sequence of Talaromyces cellulolyticus Strain Y-94, a Source of Lignocellulosic Biomass-Degrading Enzymes. AB - Talaromyces cellulolyticus (formerly Acremonium cellulolyticus) is a promising fungus for cellulase production. Here, we present the draft genome sequence of T. cellulolyticus strain Y-94. The genome is 36.4 Mbp long and contains genes for several enzymes involved in the degradation of lignocellulosic biomass, including cellulases, hemicellulases, pectinases, and amylases. PMID- 25720678 TI - Draft Genome Sequence of the Cellulolytic Fungus Chaetomium globosum. AB - Chaetomium globosum is a filamentous fungus typically isolated from cellulosic substrates. This species also causes superficial infections of humans and, more rarely, can cause cerebral infections. Here, we report the genome sequence of C. globosum isolate CBS 148.51, which will facilitate the study and comparative analysis of this fungus. PMID- 25720679 TI - Complete Genome Sequence of an Aldoxime Degrader, Bacillus sp. OxB-1. AB - Bacillus sp. OxB-1 has been characterized as a strain that produces a new enzyme, aldoxime dehydratase, which catalyzes the dehydration of aldoxime to form nitrile. Here, its complete genome sequence (3,594,618 bp, with a GC content of 47.85%), comprising a circular chromosome, is announced. PMID- 25720680 TI - Draft Genome Sequence of Acinetobacter calcoaceticus Strain P23, a Plant Growth Promoting Bacterium of Duckweed. AB - Acinetobacter calcoaceticus strain P23 is a plant growth-promoting bacterium, which was isolated from the surface of duckweed. We report here the draft genome sequence of strain P23. The genome data will serve as a valuable reference for understanding the molecular mechanism of plant growth promotion in aquatic plants. PMID- 25720681 TI - Complete Sequences of Six IncA/C Plasmids of Multidrug-Resistant Salmonella enterica subsp. enterica Serotype Newport. AB - Multidrug-resistant (MDR) Salmonella enterica subsp. enterica serotype Newport has been a long-standing public health concern in the United States. We present the complete sequences of six IncA/C plasmids from animal-derived MDR S. Newport ranging from 80.1 to 158.5 kb. They shared a genetic backbone with S. Newport IncA/C plasmids pSN254 and pAM04528. PMID- 25720682 TI - Complete Genome Sequence of Enterotoxigenic Escherichia coli Siphophage Seurat. AB - Enterotoxigenic Escherichia coli (ETEC) is one of the leading causes of diarrhea in developing countries. Bacteriophage therapy has the potential to aid in the prevention and treatment of ETEC-related illness. To that end, we present here the complete genome of ETEC siphophage Seurat and describe its major features. PMID- 25720683 TI - Whole-Genome Sequences of 12 Clinical Strains of Listeria monocytogenes. AB - Listeria monocytogenes is a foodborne pathogen of global concern due to the high mortality rate among immunocompromised patients. Whole-genome sequences of 12 strains of L. monocytogenes from humans were reported. The availability of these genomes should provide useful information on the evolutionary history and genetic diversity of L. monocytogenes. PMID- 25720684 TI - Genome Sequence of Salmonella Phage chi. AB - Salmonella bacteriophage chi is a member of the Siphoviridae family that gains entry into its host cells by adsorbing to their flagella. We report the complete 59,578-bp sequence of the genome of phage chi, which together with its relatives, exemplifies a largely unexplored type of tailed bacteriophage. PMID- 25720685 TI - Complete Genome Sequence of Salmonella enterica Serovar Typhimurium Siphophage Shivani. AB - Here, we describe the complete genome sequence of siphophage Shivani, a T5-like constituent phage in the therapeutic phage cocktail IntestiPhage developed for bacterial gastroenteritis. Shivani was isolated against a foodborne pathogen, Salmonella enterica, which is one of the leading causes of gastroenteritis. PMID- 25720686 TI - Analysis of the Complete Mycoplasma hominis LBD-4 Genome Sequence Reveals Strain Variable Prophage Insertion and Distinctive Repeat-Containing Surface Protein Arrangements. AB - The complete genome sequence of Mycoplasma hominis LBD-4 has been determined and the gene content ascribed. The 715,165-bp chromosome contains 620 genes, including 14 carried by a strain-variable prophage genome related to Mycoplasma fermentans MFV-1 and Mycoplasma arthritidis MAV-1. Comparative analysis with the genome of M. hominis PG21(T) reveals distinctive arrangements of repeat containing surface proteins. PMID- 25720687 TI - Draft Genome Sequence of Pantoea sp. Strain MBLJ3, Isolated in a Laboratory Environmental Control Study. AB - This report describes the draft genome sequence of a newly isolated strain, Pantoea sp. MBLJ3. The genome is 4.8 Mb in size, with a G+C content of 54.27%, and it contains 4,522 protein-coding sequences, 69 tRNA genes, and 5 rRNA genes. PMID- 25720688 TI - Whole-Genome Sequences of the Archetypal K1 Escherichia coli Neonatal Isolate RS218 and Contemporary Neonatal Bacteremia Clinical Isolates SCB11, SCB12, and SCB15. AB - Neonatal bacteremia Escherichia coli strains commonly belong to the K1 capsular type. Their ability to cause invasive neonatal disease appears to be determined by other virulence factors that have yet to be identified. We report here the genome sequences of four E. coli neonatal bacteremia isolates, including that of the archetypal strain RS218. PMID- 25720689 TI - Jean Siegfried (1931-2014). PMID- 25720690 TI - Coupling of platinated triguanides with platinum-activated nitriles as a novel strategy for generation of dimetallic systems. AB - One of two Pt(IV)-activated propanenitriles in trans-[PtCl4(EtCN)2] is involved in platinum(IV)-mediated nitrile-imine coupling with the platinum(II)-based metallacycles [PtCl2{NH=C(NR2)N(Ph)C(=NH)N(Ph)C(NR2)=NH}] [R2 = Me2 (1a), C5H10 (1b)] yielding diplatinum products, whose structures depend on molar ratios between the reactants. At a 1 : 1 ratio, the mixed-valence platinum(II)/platinum(IV) species [PtCl4{NH=C(NR2)N(Ph)C{=[(N(Et)C=NH)PtCl2(EtCN)]}N(Ph)C(NR2)=NH}] [R2 = Me2 (2a), (CH2)5 (2b)] were generated, whereas at a 1 : 2 ratio the dinuclear platinum(II)/platinum(II) complexes [PtCl2{NH=C(NR2)N(Ph)C{=[(N(Et)C=NH)PtCl2(EtCN)]}N(Ph)C(NR2)=NH}] [R2 = Me2 (3a), (CH2)5 (3b)] were obtained. In contrast to the nitrile-imine coupling observed for the platinum(IV) dinitrile complex, the reaction between the platinum(II) congener trans-[PtCl2(EtCN)2] and any one of 1a,b gives exclusively the substituted dimetallic platinum(II)/platinum(II) products [PtCl2{NH=C(NR2)N(Ph)C{=[(NH)PtCl2(EtCN)]}N(Ph)C(NR2)=NH}] [R2 = Me2 (6a), (CH2)5 (6b)] featuring platinum-containing guanidine 1 as one of the ligands. Complexes 2a,b, 3a,b, and 6a,b were characterized by elemental analyses (C, H, N), HRESI MS, IR, (1)H NMR spectroscopy, and DTA/TG. The molecular and crystal structure of 2a.2CDCl3 was additionally studied by single-crystal X-ray diffraction. Complexes 2a,b undergo further redox transformation in solutions, and single crystals of [PtCl2{NH=C(NMe2)N(Ph)C{=[(N(Et)C=NH)PtCl2(MeCN)]}N(Ph)C(NMe2)=NH}].2CH2Cl2 (3'a.2CH2Cl2) were obtained from 2a in a CH2Cl2-MeCN-C2H4Cl2 mixture and studied by X-ray crystallography. The driving forces for the generation of diplatinum products 2 and 3 were elucidated based on a quantum-chemical study. PMID- 25720691 TI - Molecular therapy: at the cutting edge of methodology and clinical development. PMID- 25720694 TI - MiR-212-3p inhibits glioblastoma cell proliferation by targeting SGK3. AB - Glioblastoma multiforme (GBM) is the most malignant brain tumor in humans. Previous studies have demonstrated that microRNA plays important roles in the development and proliferation of GBM cells. Here we defined the mechanism by which miR-212-3p regulated the proliferation of GBM. In this study, we showed that miR-212-3p expression was significantly down-regulated and negatively correlated with serum and glucocorticoid-inducible kinase 3 (SGK3) in GBM. Either over-expression of miR-212-3p or silence of SGK3 decreased viability of GBM cells. Moreover, miR-212-3p directly bound to 3'UTR of SGK3 and inhibited its mRNA and protein expression. And over-expression of SGK3 rescued the decreased proliferation of GBM cells induced by miR-212-3p. Importantly, miR-212-3p also suppressed tumor growth in vivo. Collectively, our results demonstrated that miR 212-3p inhibited proliferation of GBM cells by directly targeting SGK3, and could potentially serve as a new therapeutic target for GBM. PMID- 25720696 TI - A little knowledge is a dangerous thing. So is a lot. PMID- 25720695 TI - Clinical characteristics and surgical outcomes of primary spinal paragangliomas. AB - Spinal paragangliomas are extremely rare tumors, most frequently involving the cauda equina and the filum terminale. We aimed to investigate the clinical manifestations, radiological features, management, and follow-up data of primary spinal paraganglioma. We present the clinical data and long-term outcomes from a consecutive surgical series of 19 patients with pathologically diagnosed spinal paragangliomas. All of the patients had undergone surgical resection. Pre- and postoperative magnetic resonance imaging was performed and follow-up data and neurological functional assessment are presented and discussed. The mean age at diagnosis was 47.7 years, with a significant male predominance. The primary clinical symptoms were low back pain and sciatica. Magnetic resonance images (MRI) showed characteristic signs that help differentiate paragangliomas from other spinal tumors, including a "salt & pepper" sign, serpiginous flow void, and a peripheral hypointense rim. Also, a well-encapsulated appearance can be found intraoperatively. During a mean follow-up period of 62.1 months, remnant tumor progression was noted on MRI in three patients with incomplete resection. Pain symptoms were relieved immediately after surgical intervention, while motor and sphincter dysfunction were much slower to improve. Differential diagnosis of paraganglioma based on MR images alone is challenging, but the presence of specific characteristic features provides suggestive clues; however, accurate diagnosis depends on pathological criteria. Despite the benign course, gross total resection is ideal, given an increased risk of recurrence in situ. Timely recognition and surgical treatment should be emphasized to avoid progressive neurological deficits. PMID- 25720697 TI - Prognostic Factors for the Selection of Patients Eligible for Second-Line Chemotherapy in Advanced Biliary Tract Cancer. AB - BACKGROUND: The efficacy of second-line chemotherapy (CT2) after the failure of first-line chemotherapy (CT1) for advanced biliary tract cancer (BTC) has not been established. We investigated the favorable prognostic factors for CT2 to determine which patients could be expected to benefit from CT2. METHODS: From a total of 168 patients who were treated with chemotherapy at our institution between January 2003 and December 2012, we retrospectively reviewed 50 patients who received CT2. Patients were treated with various chemotherapeutic combinations as CT1 and CT2. RESULts: The median overall survival (OS) of patients who received and CT2 was 10.2 and 5.5 months, respectively. Good performance status (PS), a serum albumin level >3.5 g/dl and metastasis to only 1 organ were independent prognostic factors that affected the OS of the patients who received CT2. Patients who had only 1 metastastic organ, a good PS and a serum albumin level >3.5 g/dl at the beginning of CT2 demonstrated prolonged survival compared to patients who did not exhibit these 3 factors (9.5 vs. 4.3 months, p < 0.005). CONCLUSIONS: CT2 should be considered for patients with advanced BTC, especially for those who have only 1 metastatic organ and remain in generally good medical condition after the failure of CT1. PMID- 25720698 TI - Can we trust RDW for differentiation of febrile seizure types? PMID- 25720699 TI - Factors affecting the levels of red cell distribution width. PMID- 25720700 TI - Aortic stiffness in hypertrophic cardiomyopathy. PMID- 25720701 TI - Reply to: Aortic stiffness in hypertrophic cardiomyopathy. PMID- 25720702 TI - Modified round block mastopexy versus traditional round block mastopexy. AB - OBJECTIVE: Breast ptosis may be caused by several factors, including significant weight loss, pregnancy, long breastfeeding periods, and involution of the postmenopausal breast tissue. The authors performed a prospective study to evaluate patient satisfaction and the rate of complications after modified round block mastopexy versus traditional round block mastopexy. PATIENTS AND METHODS: Forty-four patients fulfilled the inclusion criteria for undergoing round block mastopexy in a prospective randomized controlled study performed from 2007 to 2008. All the patients received polyurethane silicone implants. Group A included patients who underwent the traditional round block technique described by Benelli. Group B included patients who underwent the traditional round block and 4 cardinal glando-glandular permanent sutures. The overall satisfaction with body appearance after breast mastopexy was rated on a scale of 1 (poor), 2 (fair), 3 (good), 4 (very good), and 5 (excellent). RESULTS: Group A patient ages ranged from 28 to 52 years and in Group B ranged from 29 to 49 years. The mean implant volume was 215 cc in both Groups. The complication and satisfaction rates for both Groups are reported. CONCLUSIONS: The combination of the cardinal glandulo glandular sutures along with the traditional round block appears to be key to preventing the areolar enlargement and persistent breast ptosis. The satisfaction rates in patients who underwent the modified round mastopexy appear superior when compared to the traditional round block mastopexy. Furhter long-term follow-up need to be performed in order to confirm the favorable results seen in this series of cases. PMID- 25720703 TI - Anterior cruciate ligament reconstruction and determination of tunnel size and graft obliquity. AB - OBJECTIVE: Increase in ACL (anterior cruciate ligament) reconstructions has led to a higher prevalence of patients with postoperative symptoms which require investigation. We aimed to investigate the utility of magnetic resonance imaging (MRI) and computer tomography (CT) in determining tunnel size and graft obliquity after single bundle ACL reconstruction. PATIENTS AND METHODS: A retrospective comparison was made on 29 symptomatic knees after anatomic single bundle (trans AM) and transtibial ACL reconstructions which had both MRI and CT scans at an average of 1.3 years postoperatively (2 months-5.7 years). We compared CT and MRI (T2 sequence) tunnel size and graft obliquity estimates using Pearson correlation and t-test. We also compared MRI's of ACL reconstructed knees with hamstrings or patellar autografts, which were confirmed by operative protocol as either antero medial (AM) technique (n=21) or trans-tibial (TT) technique (n=19). The surgeries were performed for an average of 6.29 (4-10) years for the TT group and 1.3 (0-3) years for the AM group, respectively. The graft inclination was measured relative to the tibial plateau using DICOM software. Statistical analysis used the mean value for each case and the data were processed using the non-parametric Kruskal Wallis test to determine the difference in graft obliquity and tunnel placement. RESULTS: Tunnel size estimates correlate well between CT and MRI on axial scans: R2=0.795 and 0.630 for femur and tibia respectively. The position of the tunnels and graft obliquity were found to differ on MRI images in both coronal and sagittal planes. Coronal graft obliquity averaged 72.38 degrees (ranging from 69 degrees to 76 degrees ) using the AM technique and 75.47 degrees (ranging from 72 degrees to 78 degrees ) with TT technique. Sagittal graft inclination angle was 54.5 (51-58.5) and 63.68 (59-69.5) respectively. MRI proves to be the most useful imaging method in determining outcome after ACL reconstruction. However, for a better revision of the ACL reconstructions, CT can offer a clearer image of tunnels and bone stock. A more anatomical graft positioning increases obliquity in coronal and sagittal planes and, thus, becomes difficult to assess both tunnels in a single slice. CONCLUSIONS: The anatomic single bundle reconstruction technique has been found to more accurately reproduce the femoral footprint and the orientation of the graft compared to the TT technique where the appropriate tibial tunnel placement resulted in a more vertical graft. PMID- 25720704 TI - Diagnostic accuracy of sonohysterography vs hysteroscopy in benign uterine endocavitary findings. AB - OBJECTIVE: To compare diagnostic accuracy of sonohysterography vs hysteroscopy in patients with benign uterine endocavitary findings. PATIENTS AND METHODS: This retrospective study evaluated 202 patients submitted to sonohysterography after transvaginal ultrasound examination suspicious for uterine endocavitary findings. Cytological sample was taken and analyzed from the fluid used to distend the uterine cavity. Of 202 patients enrolled for this study, 86 patients underwent gynaecological surgery, of whom 77 were treated with operative hysteroscopy and 9 with other gynaecological surgical techniques. Statistical analysis was performed to evaluate diagnostic agreement between sonohysterography vs hysteroscopy and cytology vs histology. RESULTS: Diagnostic concordance between sonohysterography and hysteroscopy was significant (k value 0.87). The correlation between cytological and histological findings had a moderate level of concordance (k value 0.49). CONCLUSIONS: Sonohysterography provides a diagnostic accuracy as well as hysteroscopy, therefore, it could be considered an alternative procedure in the diagnosis of benign uterine endocavitary findings. PMID- 25720705 TI - Effectiveness of embolization of the internal iliac or uterine arteries in the treatment of massive obstetrical and gynecological hemorrhages. AB - OBJECTIVE: This study evaluated the effectiveness of embolization of internal iliac artery or uterine artery in the treatment of massive obstetrical and gynecological hemorrhages, including postpartum hemorrhages. PATIENTS AND METHODS: A total of 21 patients with massive obstetrical and/or gynecological hemorrhages underwent the modified Seldinger procedure. The catheter was inserted into the femoral artery on one side. Then, internal iliac artery angiography was performed to identify lesions in the areas supplied by internal iliac artery, and the bleeding site. Gelatin sponge particles were injected to embolize the bleeding artery. A second angiography was performed to determine whether embolization was successful. RESULTS: Clinical success was achieved in 20 patients after a single embolization procedure. Hysterectomy was performed in one woman with pernicious placenta previa due to persistent massive bleeding 24 hours after the removal of uterine packing. In the remaining 20 patients, the uterus was preserved. All 21 patients were cured and discharged. CONCLUSIONS: Embolization of internal iliac artery or uterine artery is an effective method to treat massive obstetrical and gynecological hemorrhages, including postpartum hemorrhages, and provides a new option to preserve the uterus. PMID- 25720706 TI - Systemic granulomatosis after surgical injection of silicone oil for retinal detachment in a child affected by Fisher-Evans syndrome. AB - Silicone oil is used for complicated retinal detachment, but it can be associated with relevant side effects. We report a 6-year-old South American female admitted to our hospital with steroid-resistant Fisher-Evans syndrome. She also had developed a retinal detachment, managed with intravitreal oil injection. During treatment for Fisher-Evans syndrome, she progressively developed recurrent and refractory bronchospasm, peaks of hypereosinophilia and orbital soft-tissue swelling. Despite the persistent negativity of all microbiologic tests, she was treated empirically with antibiotics. Failure of the treatment led to the execution of a biopsy of the periocular tissue that revealed an intense polymorphous infiltrate constituted by numerous monoclonal population (FR2 monoclonality) of plasma-cells. A diagnosis of lymphoma with plasmacytoid differentiation was suspected and cytotoxic treatment was started without response. For the appearance of swelling in left parotid and laterocervical region, an excisional biopsy was performed and a diagnosis of granulomatous reaction to ocular implant of silicone oil was made. In consideration of the clinical evolution, enucleation was considered, but parents did not consent to the procedure until the child developed cerebral lesions suspected to be silicone localizations. After enucleation, eosinophilic count normalized and the child no longer presented any new episode of fever or swelling. CONCLUSIONS: In this patient a granulomatous reaction is present at distance from the site of oil injection. This case suggests caution in using this substance even in ocular diseases, especially in immunocompromised patients. PMID- 25720707 TI - Enhanced presence of NGF and mast cells number in nasal cavity after autologous stimulation: relation with sensorineural hearing deficit. AB - OBJECTIVE: Nerve growth factor (NGF) is a neurotrophin which promote and regulate the survival of neurons in the peripheral nervous system. We aimed to evaluate the nasal NGF expressions of mast cells in healthy patients after stimulation with sterilized isotonic solution delivered at high pressure. PATIENTS AND METHODS: The first part of the study was made with 21 voluntary individuals. The middle third of the inferior turbinate epithelial cells on the right nostril was scraped using a sterile curette and indicated as (pre), than a spray of sterilized isotonic solution at high pressure on the left nostril was delivered and 25 minutes later a similar stimulation was delivered on the same nostril. The stimulation was made with a specific spray. The middle third of the inferior turbinate epithelial cells on the left nostril was scraped using a sterile curette and indicated as (post). RESULTS: Forced nasal stress induced by local delivery of high pressure physiological solution causes an increase in the number of mast cells and enhances level of NGF in the nasal fluid compared to the control subjects. So based on the first part of our study, since NGF is universally known as effective in protection and repairing of neural cells damage, we started the second part and gave a treatment on the same patients, to increase NGF levels with a six months daily therapy and observed the variations in Sensorineural Hearing Loss (SNHL) and tinnitus intensity from the beginning to the end of the therapy. All patients received sterilized isotonic solution at high pressure (pression emission level: PEL): 7 g/sec for 0.5 sec (emission time: ET) in both nostrils. 25 minutes later a similar stimulation was delivered twice a day. The control group (21 pts) received normal therapy with betahistine dihydrochloride 16 mg twice a day. CONCLUSIONS: Upon acuphenometry, there was a lower intensity of tinnitus and the improvement was signaled by the patients. Patients with SNHL treated with conventional therapy had a slight worsening, while the patients treated with our new therapy which increased NGF levels, showed improvement of hearing. This new therapy represents a new therapy of SNHL, tinnitus and hearing disorders. PMID- 25720708 TI - Sustained improvement of psoriatic lesions in the course of sublingual immunotherapy for airborne allergens: clinical evidence of cross-tolerance. AB - BACKGROUND: A patient with psoriasis is presented who was treated with sublingual immunotherapy for airborne allergens for allergic rhinitis. Allergic rhinitis and psoriasis have entirely different cytokine profiles and result from different aberrations of the immune response. Furthermore, T-cell activation in the two diseases uses different presentation systems, psoriasis being a CD8 cytotoxic cell response requiring presentation through the Major Histocompatibility Complex I, while allergic rhinitis and its treatment with sublingual immunotherapy depend on CD4 T-helper cells and presentation by the Major Histocompatibility Complex II. The rapid and impressive improvement of the psoriatic lesions in the presented patient may, along with evidence of subsiding Th1 activity, give rise to the hypothesis that tolerogenic-to-allergen changes induced by sublingual immunotherapy may induce cross-tolerance and the selective emergence of cytotoxic T cell clones with lessened psoriasis-producing activity. PMID- 25720709 TI - F-18 FDG PET/CT imaging in the diagnostic work-up of thyroid cancer patients with high serum thyroglobulin, negative I-131 whole body scan and suppressed thyrotropin: 8-year experience. AB - OBJECTIVE: Fluorodeoxyglucose positron emission tomography/computed tomography imaging in the follow-up of patients with differentiated thyroid carcinoma who have high serum thyroglobulin, negative iodine-131 whole body scan and suppressed thyrotropin. PATIENTS AND METHODS: A total of 90 patients (31 male and 59 female) with differentiated thyroid carcinoma who have high serum thyroglobulin and negative iodine-131 whole body scan were included in the study between July 2006 and March 2014. All patients had undergone surgery (total thyroidectomy +/- lymph node dissection) followed by iodine-131 ablation. Of the patients, 82 had papillary thyroid carcinoma and 8 follicular thyroid carcinoma. Serum thyrotropin was suppressed (< 2 MU IU/ml) during the Fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging procedure. RESULTS: The overall sensitivity of fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging in the detection of metastasis of differentiated thyroid cancer was 84.8%, the specificity 79.1%, respectively. The sensitivity and specificity of fluor-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging in classic type of papillary cancer was 83.3% and 54.5%, respectively. The corresponding figures for the tall cell variant was 85.7% and 87.5%, respectively. The difference between the two histological subtypes was statistically significant (p < 0.05). CONCLUSIONS: Our results suggest that fluor 18 fluorodeoxyglucose positron emission tomography/computed tomography imaging could be a valuable test for the routine follow-up of patients with differentiated thyroid carcinoma. PMID- 25720710 TI - Clinical evaluation of the efficacy of the combination of aneurysm embolization and cerebrospinal fluid replacement in the treatment of aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To explore the clinical efficacy of aneurysm embolization and cerebrospinal fluid (CSF) replacement in the treatment of aneurysmal subarachnoid hemorrhage (SAH). PATIENTS AND METHODS: Seventy-nine patients with grade III-IV aneurysmal subarachnoid hemorrhage, who were treated in the hospital from Jan. 2012 to Jan. 2014, were included in this study. These patients were treated with different methods based on the cause of disease and the treatment chosen by their families. In the treatment group, 42 patients received aneurysm embolization and cerebrospinal fluid replacement, while 37 patients in the control group received simple aneurysm embolization. The treatment efficacy and the occurrence of complications in both groups were compared. RESULTS: The occurrence of cerebral vasospasm and hydrocephalus in the treatment group was significantly lower than the control group, and the difference was statistically significant. However, the mortality rate was decreased in both groups. CONCLUSIONS: Both methods had the advantage of minimal invasiveness and rapid post-operative recovery. But using combination of these two methods is clinically rational and could decrease the rate of disability and mortality. PMID- 25720711 TI - Color Doppler ultrasound-guided botulinum toxin type A injection combined with an ankle foot brace for treating lower limb spasticity after a stroke. AB - OBJECTIVE: To explore the effectiveness of the color Doppler ultrasound-guided botulinum toxin type A (BTX-A) injection combined with an ankle foot brace (AFO) for treating lower limb spasticity after a stroke. PATIENTS AND METHODS: A total of 103 post-stroke patients with lower limb spasticity were divided into three groups: the control group treated with conventional therapy and rehabilitation training, the observation group treated with conventional therapy, rehabilitation training and botulinum toxin type A injection, the treatment group treated with AFO plus the same treatment received by the observation group. The muscle spasms were evaluated using the Clinic Spasticity Influx (CSI), movement with the Fugl Meyer Assessment (FMA), dynamic and static balance with the Berg Balance Scale (BBS), and daily life activities with the Functional Independence Measure (FIM), respectively. RESULTS: Compared the first month after treatment with the prior treatment, there were significant differences in CSI, FMA and FIM scores in both control group and the observation group (p < 0.05). However, no differences were noticed in the control group (p > 0.05). Compared the third and sixth month after treatment with prior treatment, there were significant differences in these three groups (p < 0.05). In terms of treatment time, the BBS scores were always higher in all three groups after one month, three months and six months treatment than prior treatment (p < 0.05), and there were significant differences in third month and sixth month after treatment compared with the first month treatment (p < 0.05). Compared the third month after treatment with the sixth month, there were significant differences in all three groups (p < 0.05). CONCLUSIONS: The color Doppler ultrasound-guided BTX-A injection combined with AFO can effectively promote patients with post-stroke lower limb spasticity in lower limb muscle spasm, movement, balance and daily life activities. PMID- 25720712 TI - Blood pressure control in ultra-early basal ganglia intracerebral hemorrhage. AB - OBJECTIVE: We performed this study to investigate the effect of blood pressure control in ultra-early basal ganglia intracerebral hemorrhage. PATIENTS AND METHODS: 120 patients with ultra-early basal ganglia intracerebral hemorrhage were randomly divided into experimental group (strengthened antihypertensive) and control (normal antihypertensive). Each group consists of 60 patients, whose contractive pressure were controlled by intravenous antihypertensive drugs among 130-140 mmHg and 160-180 mmHg respectively for 24 h, after 1 h of beginning treatment. They were all evaluated by NIH Stroke Scale (NIHSS) before and after the treatment. Cranial CT, hematoma volume, hematoma enlargement, edema volume, serum matrix metalloproteinase-9 level were performed and compared between groups. RESULTS: After 24 h, hematoma volume and hematoma enlargement in the experimental group was significantly lower than control (p < 0.05). After 14 days, NIHSS score in the experimental group was significantly lower than control (p < 0.05). Cerebral edema amount and serum MMP-9 level in the experimental group were significantly lower than control after 5 days and 14 days. CONCLUSIONS: Ultra-early basal ganglia intracerebral hemorrhage can remarkably reduce hematoma enlargement, cerebral edema, serum MMP-9 level, and improve the neurological function. PMID- 25720713 TI - Combination of thrombolytic therapy and neuroprotective therapy in acute ischemic stroke: is it important? AB - Tissue plasminogen activator (tPA) is the only treatment approved by the USA FDA for acute ischemic stroke. There are many obstacles, however, when it is widely used in clinical setting, such as narrow therapeutic window, cytotoxicity and neurotoxicity. In recent years, many neuroprotective agents aiming to different molecular targets in ischemic cascade have been rapidly developed. Although these agents showed remarkable effects in experimental stroke, they failed to be translated to clinical use for many reasons. As the concept of "neurovascular unit" (NVU) is mentioned, combination of thrombolytic agents such as tPA with neuroprotectants gets more and more attention. Evidences supporting the combination therapy have been obtained from a variety of studies in many kinds of animal models, even though clinical evidences are inadequate. Combination of thrombolysis and neuroprotection has been considered as a promising approach for treatment of acute ischemic stroke. There are many advantages for the combination therapy. In this context, we review the sound rationales and researching achievements to support the therapy. PMID- 25720714 TI - Association between HLA rs3129882 polymorphism and Parkinson's disease: a meta analysis. AB - OBJECTIVE: As one of potential candidate genes for the risk of Parkinson's disease (PD), the HLA-DRA/PARK18 (rs3129882, A > G) gene has been studied extensively. However, direct evidence for the genetic association studies between PD and rs3129882 remains inconclusive. The aim of our meta-analysis was to determine a more reliable association between the rs3129882 and PD. MATERIALS AND METHODS: Comprehensive search strategy was used for electronic searches through PubMed, Elsevier, Springer Link, CNKI (Chinese National Knowledge Infrastructure) and WanFang (Chinese) databases to evaluate the association between rs3129882 and PD risk. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Finally, we performed a meta-analysis of 13 appropriate papers by using a total of 11951 patients and 11902 controls. RESULTS: The meta-analysis showed no significant association between rs3129882 and PD risk in all four models (the allele model, dominant model, homozygote model and the recessive model). In allele model, the result was OR = 1.043 (95% CI = 0.978, 1.113). Moreover, this association remained no significant in the subgroup analysis stratified by ethnicity. CONCLUSIONS: In current meta-analysis, no significant association was found for rs3129882 and PD risk. And more well designed primary researches will be needed to further evaluate the interaction of rs3129882 polymorphism and the susceptibility of PD. PMID- 25720715 TI - The role of neutrophil to lymphocyte ratio as a predictor of diastolic dysfunction in hypertensive patients. AB - OBJECTIVE: Neutrophil to lymphocyte ratio (NLR) is a novel parameter for cardiovascular research area. The higher values of NLR have been found to be associated with worse clinical outcomes in atherosclerotic heart disease, heart failure, heart valve disease and other various cardiovascular disorders. Although the relationship between NLR and almost all cardiovascular disorders have been investigated, the association between NLR and diastolic dysfunction remains unclear. We herein evaluated the association between NLR and diastolic dysfunction. PATIENTS AND METHODS: The study population consisted of 41 hypertensive patients with any grade of diastolic dysfunction and 41 hypertensive patients without diastolic dysfunction determined by echocardiographic evaluation constituted the control group. RESULTS: Mean NLR value was found to be 2.07 +/- 0.82 in the diastolic dysfunction group while the control group had a mean value of 1.69 +/- 0.60 (p = 0.020). The patients with diastolic dysfunction had significantly higher values of NLR. When grades of diastolic dysfunction were evaluated, NLR was 1.80 +/- 0.82, 2.32 +/- 0.73 and 2.75 +/- 0.45 in patients with grade 1, grade 2 and grade 3 diastolic dysfunction, respectively. The patients with higher grade of diastolic dysfunction had higher values of NLR (p = 0.001). None of the other hematologic parameters differed significantly in patients with diastolic dysfunction when compared to controls. CONCLUSIONS: Patients with diastolic dysfunction had higher values of NLR compared to subjects without diastolic dysfunction. Furthermore higher grades of diastolic dysfunction were associated with higher levels of NLR. Further studies are needed to search the possible use of NLR as a marker for prognostic stratification in diastolic dysfunction which is associated with worse cardiovascular outcomes. PMID- 25720716 TI - Omega-3 fatty acids and cardiovascular disease. AB - Cardioceuticals are nutritional supplements that contain all the essential nutrients including vitamins, minerals, omega-3-fatty acids and other antioxidants like a-lipoic acid and coenzyme Q10 in the right proportion that provide all round protection to the heart by reducing the most common risks associated with the cardiovascular disease including high low-density lipoprotein cholesterol and triglyceride levels and factors that contribute to coagulation of blood. Omega-3 fatty acids have been shown to significantly reduce the risk for sudden death caused by cardiac arrhythmias and all-cause mortality in patients with known coronary heart disease. Omega-3 fatty acids are also used to treat hyperlipidemia and hypertension. There are no significant drug interactions with omega-3 fatty acids. The American Heart Association recommends consumption of two servings of fish per week for persons with no history of coronary heart disease and at least one serving of fish daily for those with known coronary heart disease. Approximately 1 g/day of eicosapentaenoic acid plus docosahexaenoic acid is recommended for cardio protection. Higher dosages of omega-3 fatty acids are required to reduce elevated triglyceride levels (2-4 g/day). Modest decreases in blood pressure occur with significantly higher dosages of omega-3 fatty acids. PMID- 25720717 TI - Blocking the mitochondrial permeability transition pore with cyclosporine-A can restore cardioprotection of ischemic postconditioning in hypercholesterolemic rat heart. AB - OBJECTIVE: Ischemic postconditioning (IPO) reduces lethal reperfusion injury under normal conditions, but its effectiveness is blocked by hypercholesterolemia (HC). This study aims to determine whether blocking the mitochondrial permeability transition pore (mPTP) with cyclosporine-A (CsA) can restore cardioprotection of IPO in hypercholesterolemic rat heart. MATERIALS AND METHODS: Isolated rat hearts underwent 30 min global ischemia and 120 min reperfusion. Postconditioning protocol was induced by six cycles of 10s ischemia and 10s reperfusion at the onset of the reperfusion. CsA (0.5 uM or 5 uM) was administered 15 minutes before ischemia. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining. Cardiomyocyte apoptosis was assessed by TUNEL staining and creatine kinase-MB (CK-MB) was analyzed from coronary effluent. RESULTS: In normocholesterolemia (NC) groups, infarct size, cardiomyocyte apoptosis rate and release of CK-MB were significantly reduced after IPO. These reductions were completely abolished by HC, as evidenced by a similar infarct size, cardiomyocyte apoptosis rate and release of CK-MB observed between IPO-HC group and control-NC group, but were restored by IPO combinated with CsA treatment. However, CsA treatment alone could not restore cardioprotection in a state of HC. CONCLUSIONS: Ischemic postconditioning, blocked by hypercholesterolemia may due to the excessive opening of the mPTP. Inhibiting of the mPTP with CsA is able to reverse this loss of cardioprotection. PMID- 25720718 TI - Betulin inhibits pro-inflammatory cytokines expression through activation STAT3 signaling pathway in human cardiac cells. AB - OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is an important regulator of cardiac survival pathways. Decreased expression or activity of STAT3 in patients with end-stage heart failure demonstrated a clinical relevance of STAT3 in cardiac diseases. Betulin, a pentacyclic triterpene, has drawn extensive attention towards its beneficial effects. However, little is known about its roles in cardiac cells. MATERIALS AND METHODS: We investigated the effects of betulin on the pro-inflammatory processes in human cardiac AC16 cells. Genes expression of pro-inflammatory cytokines and activation of NF-kappaB signaling were analyzed. Besides, levels of phosphorylated STAT3 and its down-stream target genes were measured to evaluate the activation of STAT3. Finally, STAT3 inhibitor and small interfering RNA (siRNA) oligos were used to determine the roles of STAT3 in AC16 cells treated with betulin. RESULTS: Our results revealed that betulin inhibited pro-inflammatory cytokines expression and NF-kappaB signaling activation through STAT3 signaling. Besides, betulin treatment also induced the expression of Bcl-xL, an anti-apoptotic downstream effector of STAT3. CONCLUSIONS: Our results, for the first time, uncovered the cardioprotective roles of betulin, which may be useful to reduce the occurrence of adverse cardiovascular events. PMID- 25720719 TI - First report on the seroprevalence of the Crimean-Congo haemorrhagic fever virus, a tick-borne virus, in Malaysia's Orang Asli population. AB - OBJECTIVE: The Crimean-Congo haemorrhagic fever virus (CCHFV), which is transmitted by the ticks of Hyalomma spp. in general and H. marginatumin particular, can cause severe disease in humans, with mortality rates of 3-30%. Other than from the bites of infected ticks, CCHFV can also be transmitted through contact with patients with the acute phase of infection or contact with blood or tissues from viraemic livestock. Outbreaks of human cases of haemorrhagic manifestations have been documented since 1945 and described in parts of Africa, Asia, Eastern Europe and the Middle East and most recently India in 2011. In addition, serological evidence of the disease has been reported in some countries where no human cases were reported. As regional neighbours China and India have been affected by this virus, this study was conducted to determine the seroprevalence of CCHFV among Orang Asli population of Malaysia as the most at risk people who residing in the deep forests. PATIENTS AND METHODS: A total of 682 serum samples were collected from the Orang Asli population residing in eight states in peninsular Malaysia and analysed for the presence of anti-CCHFV immunoglobulin G (IgG) using a commercial enzyme-linked immunosorbent assay kit. RESULTS: The study subjects comprised 277 (40.6%) men and 405 (59.4%) women. However, anti-CCHFV IgG was detected in only one female serum sample (0.1%). The presence of anti-CCHFV IgG could not be correlated to age or sex from these findings. CONCLUSIONS: The results of this screening survey showed that the seroprevalence of the anti-CCHFV IgG among Malaysia's Orang Asli population is too low for detection or totally negative compared with that in neighbouring countries, such as India and China. PMID- 25720720 TI - Association of ulcerative colitis with TNF-related apoptosis inducing ligand (TRAIL) gene polymorphisms and plasma soluble TRAIL levels in Chinese Han population. AB - OBJECTIVE: The precise etiology of inflammatory bowel diseases (IBDs) is still unknown although dysregulation of apoptosis likely plays an important role in this pathogenesis. However, the significance of mucosal T-cell apoptosis in ulcerative colitis (UC) is unclear. In the present work we investigated the role of TNF-related apoptosis-inducing ligand (TRAIL), which is implicated in various human disorders. PATIENTS AND METHODS: Results from a total of 393 UC patients and 1292 healthy individuals were analyzed in this study. We determined the three single nucleotide polymorphisms of TRAIL in 3' untranslated regions (UTR), and examined the plasma soluble TRAIL (sTRAIL) levels by enzyme-linked immunosorbent assay. RESULTS: We found that the mutant genotypes of TRAIL (G1525A/G1588A/C1595T and G1525A and G1588A) were much lower in UC patients compared to the controls. Furthermore, mutant allele and genotype of TRAIL C1595T were more prevalent in severe UC patients than in other patients (p < 0.001; p = 0.005, respectively). The three polymorphic sites in 3'UTR were in a perfect linkage disequilibrium in our study. In contrast to controls, the GAT haplotype was increased (p < 0.001), while the AAT haplotype was decreased in UC patients (p < 0.001). Besides, the plasma levels of sTRAIL were significantly higher in UC patients than in controls (p < 0.001). CONCLUSIONS: Our findings suggested that increased occurrence of the genetic mutations of TRAIL in 3'UTR and possibly decreased plasma levels of sTRAIL might lead to a lower risk of UC attack in Chinese patients. PMID- 25720721 TI - Protein-loosing enteropathy in sclerosing mesenteritis. AB - Sclerosing mesenteritis (SM) is a rare, idiopathic disorder of unknown aetiology that involves the adipose tissue of the mesentery, being characterized by chronic and non-specific fibrous inflammation. Patients usually present with non-specific clinical manifestations, such as abdominal pain and diarrhoea. The diagnosis of SM is difficult and it can be definitely established only by means of surgical or imaging-guided biopsy. Different therapeutic strategies have been used in case series with different rate of success. The disease is generally self-limiting, and the long-term prognosis is good, even if some cases of severe SM are reported in literature. Here, we report a fatal case of sclerosing mesenteritis associated to protein-losing enteropathy. PMID- 25720722 TI - Research Ethics Committees and clinical research in Italy: where are we going? AB - Italian Ethics Committees (ECs) have entered a new phase because of the recent Law no. 189 of November 8 2012 and the Ministry of Health Decree of February 8 2013. The new norms have introduced important changes. In fact, ECs are now established not to serve a single hospital or research institution but to serve even Regions. Moreover, they are established on the basis of the number of inhabitants, research sites and expected amount of clinical trials. The implementation of the news norms into practice have produced a drastic reduction in the number of ECs. This fact could raise some issues but it could obtain some benefits. The paper explains the main steps of ECs and clinical research development in Italy. Special attention will be paid to recent trends. Moreover, the new norms will be illustrated, showing possible issues and benefits connected to their implementation. PMID- 25720723 TI - Beneficial effects of Flavonoids after ambulatory therapy with Combined Hemorrhoidal Radiocoagulation (CHR). AB - BACKGROUND: Phlebotropic activity, protective effect on the capillaries and anti inflammatory properties of the Flavonoids have been reported in literature. Recently, we evaluated the effect of these drugs in controlling postoperative symptoms of proctologic surgery. In this randomized study we compared the results obtained in two groups of patients, with grade II haemorrhoids, submitted to radiofrequency coagulation of the hemorrhoidal nodule with radiofrequency scalpel (CHR), to verify the effects of Flavonoids to reduce further symptoms after treatment. PATIENTS AND METHODS: Out of 70 patients initially randomized, a total of 59 patients regularly returned to outpatient visit at least for 1 month of follow-up. Consequently, two groups of patients were considered: Group A, represented by 28 individuals treated with Flavonoids, and Group B, consisting of 31 patients as a control group. Our purpose was to determine: grade of pain after procedure and at first evacuation (score from 1 to 10), bleeding, incidence of failures and complications, patient's satisfaction after 30 days from the treatment (score from 1 to 10). RESULTS: We observed that the results obtained regarding the pain reported at the end of procedures (2.51 +/- 1.4 for group A and 2.54 +/- 1.15 for group B) and at the first evacuation (2.6 +/-.1.52 for group A and 2.7 +/- 1.18 for group B) are similar in both study groups. Instead, the mean score on overall satisfaction at 30 days from the treatment showed a statistical significance (8.32 +/- 1.72 for group A and 6.64 +/- 1.78 for group B; p < 0.05). There were no reported other important issues. CONCLUSIONS: Our results confirm the usefulness of Flavonoids to make more comfortable the post treatment period. PMID- 25720724 TI - Effect of mannitol injection by intravenous catheter on ear vein endothelial cell apoptosis and venous thrombus in rabbits. AB - OBJECTIVE: To evaluate the effect of mannitol injection into the rabbit ear vein by intravenous catheter on endothelial cells apoptosis, thrombus formation, the expression of plasma tissue factor (TF) and von Willebrand factor (vWF). MATERIALS AND METHODS: Sixty-four Zealand rabbits were randomly divided into experiment and control group and received 20% mannitol or normal saline via ear margin veins, respectively. Both groups were injected daily. On days 1, 3, 5, and 7 after catheterization, rabbits were subjected to intraperitoneal anesthesia and their ear veins were isolated and then subjected to hematoxylin and eosin staining. Cell apoptosis was evaluated using TUNEL (terminal deoxynucleotide transferase mediated d-UTP nick end labeling) staining, and the levels of TF and vWF were analyzed by enzyme-linked immunosorbent assay. RESULTS: Compared with the control group, the experiment group showed significantly increased thrombus formation (p < 0.05), and a significant higher rate of apoptosis in endothelial cells (p < 0.05) on days 3, 5, and 7. In addition, the experiment group showed significant elevation of plasma TF and vWF on days 3, 5, and 7 (p < 0.05). CONCLUSIONS: Continuous mannitol injection by intravenous catheterization induces more serious venous thrombus formation and endothelial cells apoptosis and higher TF and vWF levels than normal saline injection. These data suggest that clinical use of hyperosmotic mannitol by intravenous catheter may exert direct deleterious effects on vascular endothelium. PMID- 25720725 TI - Influence of treatment with gum acacia on renal vascular responses in a rat model of chronic kidney disease. AB - OBJECTIVE: This study was conducted in order to investigate the effects of adenine-induced chronic kidney disease (CKD) on renal blood flow and biochemical changes in rats, and to assess the effect of treatment with gum acacia (GA) thereon. MATERIALS AND METHODS: CKD was induced by feeding rats with adenine (0.25% w/w, five weeks). Concomitantly, some of these rats were also given gum acacia (GA) (15% w/v in the drinking water). Before animals were sacrificed, changes in renal blood flow (RBF) were monitored in anaesthetized rat preparations. Several biochemical and histological renal function tests were also conducted. RESULTS: Adenine-induced CKD significantly impaired the vasopressor actions of acetylcholine, sodium nitroprusside and phenylephrine and concomitant treatment with GA abated these responses. Additionally, plasma concentrations of urea, creatinine, uric acid, indoxyl sulfate, nitrite and nitrate and urinary excretion of protein were all significantly increased by adenine. GA significantly mitigated the severity of adenine-induced changes. CONCLUSIONS: Adenine-induced CKD in rats significantly impaired renal vascular responses to acetylcholine, sodium nitroprusside and phenylephrine and this was mitigated by treatment with GA. This provides another experimental evidence for the usefulness of GA in the amelioration of CKD. PMID- 25720726 TI - A look inside the association codeine-paracetamol: clinical pharmacology supports analgesic efficacy. AB - Acute and chronic pain often requires a multimodal approach. Combination therapy reduces the number of individual daily administrations and improves patient's compliance with the prescribed analgesic treatment. Despite the association codeine/paracetamol is one of the most widely used central analgesic, the exact mechanism of action, particularly of paracetamol, is still object of pharmacological research. Recent findings showed that paracetamol may act through cerebral cyclo-oxygenase, descending opioidergic inhibitory pathways, serotonin pathway, and the endocannabinoid system; while codeine activity seems to related not only to its conversion to morphine, as previously known, but also by itself and through its metabolites, such as norcodeine (NORC) and codeine-6-glucuronide (C-6-G). The addition of codeine to paracetamol significantly improves the analgesic action and reduces the number needed to treat (NNT) from 5 to 2.3-3.1. Recent warnings about the risk of its metabolism related to CYP450 and its genetic variability in general population should be mainly considered when the association is used in paediatric patients undergoing tonsillectomy and/or adenoidectomy procedures for obstructive sleep apnoea syndrome (OSAS). In adults, the association codeine/paracetamol has been shown to be effective and safe in different settings: acute pain, trauma patients, and chronic nociceptive pain. PMID- 25720727 TI - Limb deformity in a newborn. Is rifampicin just an innocent bystander? AB - OBJECTIVE: The first-line antituberculous agents for use during pregnancy have minimal teratogenic effects. The possibility of limb deformity during rifampin use, however, was reported by some researchers. CASE REPORT: A male newborn was born with a hypoplastic right forearm to a mother with tuberculosis who used isoniazid and rifampicin in the first two months of her pregnancy. CONCLUSIONS: The limb anomaly in our case might be attributed to rifampicin usage during the first 2 months of pregnancy. Caution should be given with regard to possible congenital malformations which could be associated with the treatment of pregnant women with antituberculous drugs. PMID- 25720728 TI - Prevalence of ponticuli posticus among patients referred for dental examinations by cone-beam CT. AB - BACKGROUND CONTEXT: Ponticulus posticus (PP) is the bony bridge that can completely or partially embrace the vertebral artery and the suboccipital nerve root at the atlas posterior arch. The PP can be a possible cause of vertigo, vertebrobasilar insufficiency, neck pain, shoulder pain, and cervicogenic headache. Moreover, the vertebral artery injury may happen during atlas lateral mass screw insertion in the presence of PP. PURPOSE: The purpose of this study was to determine the prevalence of PP in a population of patients undergoing dental cone-beam computed tomography (CBCT) and the association between PP and atlas superior articular facet (SAF). STUDY DESIGN: This is a retrospective study. PATIENT SAMPLE: Five hundred consecutive patients who had undergone dental CBCT scans were included. OUTCOME MEASURES: Outcome measures were age, sex, and radiologic measures. METHODS: The maximum anteroposterior and transverse dimensions of atlas SAF were measured on the axial image, and then the area was calculated by using the formula for an elliptical area. The left-right differential ratios of the SAF in patients with unilateral PP were compared with those in age- and gender-matched patients without PP. The relationships among imaging findings, age, and sex were assessed with the two-tailed paired t test, chi(2) test, and logistic regression model, as appropriate. RESULTS: The overall prevalence of PP was 7% (35 of 500 patients). There were no significant differences in the prevalence of PP with gender and age. The anteroposterior dimension, transverse dimension, and area of atlas SAF on the PP side were significantly larger than those on the non-PP side in the 18 unilateral complete PP patients (p<.001, p<.001, and p<.001, respectively) and in the 11 unilateral partial PP patients (p=.001, p=.007, and p<.001, respectively). The SAF area differential ratios in patients with unilateral PP were greater than those in the patients without PP (29.8% vs. 2.9%, p=.002 for 18 complete lesions, and 23.5% vs. 1.8%, p<.001 for 11 partial lesions). CONCLUSIONS: The prevalence of PP and the measurement of SAF can be assessed by CBCT. The imaging findings show the larger SAF on the PP side and greater left-right difference of SAF area in the patients with unilateral PP. PMID- 25720729 TI - Reoperation rates after anterior cervical discectomy and fusion versus posterior cervical foraminotomy: a propensity-matched analysis. AB - BACKGROUND CONTEXT: Anterior cervical discectomy and fusion (ACDF) and posterior cervical foraminotomy (PCF) are both used to surgically treat patients with cervical radiculopathy and have been shown to have similar outcomes. Nonetheless, ACDF has become increasingly more commonplace compared with PCF, in part because of a pervasive belief that PCF has a higher incidence of required reoperations. PURPOSE: To determine the reoperation rate at the index level of ACDF versus PCF 2 years postoperatively. STUDY DESIGN: A retrospective case-control. PATIENT SAMPLE: All patients that underwent ACDF and PCF for radiculopathy (excluding myelopathy indications) between January 2005 and December 2011. OUTCOME MEASURES: Revision surgery within 2 years, at the index level, was recorded. METHODS: Propensity score analysis between the ACDF and PCF groups was done, matching for age, gender, race, body mass index, tobacco use, median income and insurance status, primary surgeon, level of surgery, surgery duration, and length of hospital stay. RESULTS: Seven hundred ninety patients met the inclusion/exclusion criteria, including 627 ACDF and 163 PCF. Before propensity matching, the PCF group was found to be significantly older and more likely to be male. After matching, there were no significant differences between groups for any baseline characteristics. Reoperation rate at the index level was 4.8% for the ACDF group and 6.4% for the PCF group (p=.7) within 2 years of the initial surgery. Using equivalence testing, based on an a priori null hypothesis that a clinically meaningful difference between the two groups would be >=5%, we found that the absolute difference of 1.6% was significantly (p=.01) less than our hypothesized difference. CONCLUSIONS: This study demonstrates that even after accounting for patient demographics, operative characteristics, and primary surgeon, there are no significant differences in 2-year reoperation rates at the index level between ACDF and PCF. The reoperation rates are statistically equivalent. Thus, spine surgeons can operate via the posterior approach without putting patients at increased risk for revision surgery at the index level. PMID- 25720730 TI - Spinal tuberculosis of the lumbar spine after percutaneous vertebral augmentation (vertebroplasty or kyphoplasty). AB - BACKGROUND CONTEXT: Spinal tuberculosis occurring after percutaneous vertebral augmentation has rarely been described. To date, only two such cases have been documented in the literature. Vertebral augmentation may reactivate a quiescent tuberculous lesion and promote the infective process in elderly patients with or without immunosuppression, thereby resulting in poor outcomes. PURPOSE: The purposes of this study were to present two cases in which spinal tuberculosis occurred after vertebroplasty or kyphoplasty, to highlight the clinical features and need for early diagnosis of this pathology, and to postulate probable reasons for this association. STUDY DESIGN: This study is based on a clinical case series and literature review. METHODS: In this report, we review the clinical histories of two old women undergoing vertebral augmentation with subsequent spinal tuberculosis. RESULTS: The first patient responded favorably to conservative treatment with multidrug antitubercular therapy and spinal braces. The second patient underwent surgical debridement through a posterior approach alone, without instrumentation, combined with adjuvant chemotherapy. By 1 year after treatment, both patients had experienced almost complete recovery and continued to be seen for follow-up visits. CONCLUSIONS: Suspicion should be high, and magnetic resonance imaging is warranted in cases with deteriorating clinical symptoms and signs of acute infection after vertebral augmentation. We propose obtaining exhaustive microbiologic and histologic evidence via needle biopsy or open surgery in a timely fashion to establish an accurate diagnosis because tubercular spondylitis occurring in such a situation may progress rapidly. PMID- 25720731 TI - Lumbar osteolytic and paraspinal lesions in a young male. PMID- 25720732 TI - Evaluating the validity and applicable domain of the toxic load model: impact of concentration vs. time profile on inhalation lethality of hydrogen cyanide. AB - The ten Berge model (or "toxic load" model) is often used to estimate the acute toxicity for varying combinations of inhaled concentration and duration. Expressed as C(n) * t = toxic load (TL), TLs are assumed constant for various combinations of concentration (C) and time (t). Experimental data in a recent acute inhalation study of rats exposed to time-varying concentrations of hydrogen cyanide (HCN) supported the validity of the toxic load model except under very brief, discontinuous, high concentration exposures. In the present investigation, experiments were conducted to extend the evaluation of the applicable domain of the model for acute lethality of HCN in the rat (cumulative exposure range of 2900-11,000 ppm min). The lethality of HCN over very short (< 5 min) durations of high concentrations did not conform to the toxic load model. A value of n=1.57 was determined for uninterrupted exposures ? 5 min. For 30-min exposures, the presence or absence of a gap between two exposure pulses of different concentrations, the relative duration, relative height, and the ordering of the pulses (low then high, vs. high then low) did not appear to have a meaningful impact on the toxic load required for median lethality. PMID- 25720733 TI - Effects of melatonin on prenatal dexamethasone-induced epigenetic alterations in hippocampal morphology and reelin and glutamic acid decarboxylase 67 levels. AB - Prenatal glucocorticoid exposure causes brain damage in adult offspring; however, the underlying mechanisms remain unclear. Melatonin has been shown to have beneficial effects in compromised pregnancies. Pregnant Sprague-Dawley rats were administered vehicle (VEH) or dexamethasone between gestation days 14 and 21. The programming effects of prenatal dexamethasone exposure on the brain were assessed at postnatal days (PND) 7, 42, and ~120. Melatonin was administered from PND21 to the rats exposed to dexamethasone, and the outcome was assessed at ~PND120. In total, there were four groups: VEH, vehicle plus melatonin (VEHM), prenatal dexamethasone-exposure (DEX), and prenatal dexamethasone exposure plus melatonin (DEXM). Spatial memory, gross hippocampal morphology, and hippocampal biochemistry were examined. Spatial memory assessed by the Morris water maze showed no significant differences among the four groups. Brain magnetic resonance imaging showed that all rats with prenatal dexamethasone exposure (DEX + DEXM) exhibited increased T2-weighted signals in the hippocampus. There were no significant differences in the levels of mRNA expression of hippocampal reln, which encodes reelin, and GAD1, which encodes glutamic acid decarboxylase 67, at PND7. At both PND42 and ~PND120, reln and GAD1 mRNA expression levels were decreased. At ~PND120, melatonin restored the reduced levels of hippocampal reln and GAD1 mRNA expression in the DEXM group. In addition, melatonin restored the reln mRNA expression levels by (1) reducing DNA methyltransferase 1 (DNMT1) mRNA expression and (2) reducing the binding of DNMT1 and the methyl-CpG binding protein 2 (MeCP2) to the reln promoter. The present study showed that prenatal dexamethasone exposure induced gross alterations in hippocampal morphology and reduced the levels of hippocampal mRNA expression of reln and GAD1. Spatial memory was unimpaired. Thus, melatonin had a beneficial effect in restoring hippocampal reln mRNA expression by reducing DNMT1 and MeCP2 binding to the reln promoter. PMID- 25720735 TI - Growth and photosynthetic responses of ectomycorrhizal pine seedlings exposed to elevated Cu in soils. AB - It is still controversial whether ectomycorrhizal (ECM) mycelia filter out toxic metals in nutrient absorption of host trees. In this study, pine (Pinus densiflora) seedlings colonized by Cu-sensitive and Cu-tolerant ECM species were exposed to a wide spectrum of soil Cu concentrations to investigate functions of ECM fungi under Cu stress. The photosynthetic rates of intact needles were monitored in situ periodically. The biomass and elements of plants were also measured after harvest. The ameliorating effect of ECM infection on host plants exposed to toxic stress was metal concentration specific. Under lower-level Cu stress, ECM fungi increased seedling performance, while ECM seedlings accumulated more Cu than nonmycorrhizal (NM) seedlings. Under higher-level Cu stress, photosynthesis decreased well before visible symptoms of Cu toxicity appeared. The reduced photosynthesis and biomass in ECM seedlings compared to NM seedlings under higher Cu conditions were also accompanied by lower phosphorus in needles. There was no marked difference between the two fungal species. Our results indicate that the two ECM fungi studied in our system may not have an ability to selectively eliminate Cu in nutrient absorption and may not act as effective barriers that decrease toxic metal uptake into host plants. PMID- 25720736 TI - Differential effects of ephemeral colonization by arbuscular mycorrhizal fungi in two Cuscuta species with different ecology. AB - Seedlings of parasitic Cuscuta species are autotrophic but can survive only a short period of time, during which they must locate and attach to a suitable host. They have an ephemeral root-like organ considered not a "true" root by most studies. In the present study, two species with contrasting ecology were examined: Cuscuta gronovii, a North American riparian species, and Cuscuta campestris, an invasive dodder that thrives in disturbed habitats. The morphology, structure, and absorptive capability of their root-like organ were compared, their potential for colonization by two species of arbuscular mycorrhizal fungi (AMF) was assessed, and the effect of the AMF on seedling growth and survival was determined. The root of both species absorbed water and interacted with AMF, but the two species exhibited dissimilar growth and survival patterns depending on the colonization level of their seedlings. The extensively colonized seedlings of C. gronovii grew more and survived longer than non colonized seedlings. In contrast, the scarce colonization of C. campestris seedlings did not increase their growth or longevity. The differential growth responses of the AMF-colonized and non-colonized Cuscuta species suggest a mycorrhizal relationship and reflect their ecology. While C. gronovii roots have retained a higher ability to interact with AMF and are likely to take advantage of fungal communities in riparian habitats, the invasive C. campestris has largely lost this ability possibly as an adaptation to disturbed ecosystems. These results indicate that dodders have a true root, even if much reduced and ephemeral, that can interact with AMF. PMID- 25720734 TI - Molecular turnover, the H3.3 dilemma and organismal aging (hypothesis). AB - The H3.3 histone variant has been a subject of increasing interest in the field of chromatin studies due to its two distinguishing features. First, its incorporation into chromatin is replication independent unlike the replication coupled deposition of its canonical counterparts H3.1/2. Second, H3.3 has been consistently associated with an active state of chromatin. In accordance, this histone variant should be expected to be causally involved in the regulation of gene expression, or more generally, its incorporation should have downstream consequences for the structure and function of chromatin. This, however, leads to an apparent paradox: In cells that slowly replicate in the organism, H3.3 will accumulate with time, opening the way to aberrant effects on heterochromatin. Here, we review the indications that H3.3 is expected both to be incorporated in the heterochromatin of slowly replicating cells and to retain its functional downstream effects. Implications for organismal aging are discussed. PMID- 25720737 TI - The importance of arbuscular mycorrhiza for Cyclamen purpurascens subsp. immaculatum endemic in Slovakia. AB - At present, there is no relevant information on arbuscular mycorrhiza and the effect of the symbiosis on the growth of wild populations of cyclamens. To fill this gap, two populations of Cyclamen purpurascens subsp. immaculatum, endemic in Nizke Tatry (NT) mountains and Velka Fatra (VF) mountains, Slovakia, were studied in situ as well as in a greenhouse pot experiment. For both populations, mycorrhizal root colonization of native plants was assessed, and mycorrhizal inoculation potential (MIP) of the soils at the two sites was determined in 3 consecutive years. In the greenhouse experiment, the growth response of cyclamens to cross-inoculation with arbuscular mycorrhizal fungi (AMF) was tested: plants from both sites were grown in their native soils and inoculated with a Septoglomus constrictum isolate originating either from the same or from the other plant locality. Although the MIP of soil at the NT site was significantly higher than at the VF site, the level of AMF root colonization of C. purpurascens subsp. immaculatum plants in the field did not significantly differ between the two localities. In the greenhouse experiment, inoculation with AMF generally accelerated cyclamen growth and significantly increased all growth parameters (shoot dry weight, leaf number and area, number of flowers, tuber, and root dry weight) and P uptake. The two populations of C. purpurascens subsp. immaculatum grown in their native soils, however, differed in their response to inoculation. The mycorrhizal growth response of NT plants was one-order higher compared to VF plants, and all their measured growth parameters were stimulated regardless of the fungal isolates' origin. In the VF plants, only the non-native (NT originating) isolate showed a significant positive effect on several growth traits. It can be concluded that mycorrhiza significantly increased fitness of C. purpurascens subsp. immaculatum, despite the differences between plant populations, implying that AMF symbionts should be taken into account in conservation programs of this endemic plant. PMID- 25720739 TI - The role of physical activity in the relationship between self-perceptions of ageing and self-rated health in older adults. AB - OBJECTIVE: Positive self-perceptions of ageing are associated with better health; however, little is known about the potentially underlying mechanisms. The present longitudinal study examines whether the relationship between self-perceptions of ageing and self-rated health is mediated by physical activity in older adults with multiple chronic conditions. DESIGN: A sample of 309 German community dwelling older adults aged 65-85 years with two or more chronic conditions was assessed at three measurement occasions over 2.5 years. Participants provided information on self-perceptions of ageing, physical activity, self-rated health, number of chronic conditions and demographics (T1). Physical activity was reassessed six months later (T2) and self-rated health after 2.5 years (T3). Data were analysed using multiple regression and path analyses. MAIN OUTCOME MEASURES: Self-rated health and physical activity. RESULTS: More positive self-perceptions of ageing were related to better self-rated health over a 2.5-year period controlling for confounding variables. Physical activity six months after T1 partially mediated this relationship. CONCLUSION: Having more positive self perceptions of ageing is associated with higher levels of physical activity, which in turn predict better self-rated health over time. This supports the hypothesis of a behavioural pathway in the self-perceptions of ageing--health link. PMID- 25720738 TI - Conjugated linoleic acid (CLA) stimulates mitochondrial biogenesis signaling by the upregulation of PPARgamma coactivator 1alpha (PGC-1alpha) in C2C12 cells. AB - Along with its effect on body fat reduction, dietary conjugated linoleic acid (CLA) has been reported to improve physical activity and endurance capacity in mice. It has been suggested these effects may in part be due to physiological changes in skeletal muscle, however, the mode of action is not completely understood. Thus, the purpose of this study was to determine the relevant mechanisms of CLA isomers for mitochondrial biogenesis, one of the most important adaptive responses in skeletal muscle. Both cis-9,trans-11 (c9,t11) and trans 10,cis-12 (t10,c12) CLA isomers increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), however, only the t10,c12 isomer, but not c9,t11, increased phosphorylation of AMP activated protein kinase (AMPK) compared to the control. Among downstream biomarkers of PGC-1alpha, the CLA mixed isomer enhanced the expression of peroxisome proliferator-activated receptor-delta (PPARdelta). Both c9,t11 and t10,c12 CLA isomers increased expression of nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam), while the c9,t11 increased expression of cytochrome c (Cyt C) and t10,c12 CLA increased expression of voltage-dependent anion channel (VDAC), respectively. Both CLA isomers significantly increased mitochondrial DNA copy number compared to that of control. These findings suggest that the individual CLA isomers potentiate mitochondrial biogenesis via PGC-1alpha-NRF-1-Tfam signaling cascade, although downstream regulation may be isomer dependent. PMID- 25720740 TI - Self-similarity of human protein interaction networks: a novel strategy of distinguishing proteins. AB - The successful determination of reliable protein interaction networks (PINs) in several species in the post-genomic era has hitherto facilitated the quest to understanding systems and structural properties of such networks. It is envisaged that a clearer understanding of their intrinsic topological properties would elucidate evolutionary and biological topography of organisms. This, in turn, may inform the understanding of diseases' aetiology. By analysing sub-networks that are induced in various layers identified by zones defined as distance from central proteins, we show that zones of human PINs display self-similarity patterns. What is observed at a global level is repeated at lower levels of inducement. Furthermore, it is observed that these levels of strength point to refinement and specialisations in these layers. This may point to the fact that various levels of representations in the self-similarity phenomenon offer a way of measuring and distinguishing the importance of proteins in the network. To consolidate our findings, we have also considered a gene co-expression network and a class of gene regulatory networks in the same framework. In all cases, the phenomenon is significantly evident. In particular, the truly unbiased regulatory networks show finer level of articulation of self-similarity. PMID- 25720741 TI - Cone-Beam Computed Tomography (CBCT) Hepatic Arteriography in Chemoembolization for Hepatocellular Carcinoma: Performance Depicting Tumors and Tumor Feeders. AB - PURPOSE: This study was designed to analyze retrospectively the performance of cone-beam computed tomography (CBCT) hepatic arteriography in depicting tumors and their feeders and to investigate the related determining factors in chemoembolization for hepatocellular carcinoma (HCC). METHODS: Eighty-six patients with 142 tumors satisfying the imaging diagnosis criteria of HCC were included in this study. The performance of CBCT hepatic arteriography for chemoembolization per tumor and per patient was evaluated using maximum intensity projection images alone (MIP analysis) or MIP combined with multiplanar reformation images (MIP + MPR analysis) regarding the following three aspects: tumor depiction, confidence of tumor feeder detection, and trackability of tumor feeders. Tumor size, tumor enhancement, tumor location, number of feeders, diaphragmatic motion, portal vein enhancement, and hepatic artery to parenchyma enhancement ratio were regarded as potential determining factors. RESULTS: Tumors were depicted in 125 (88.0 %) and 142 tumors (100 %) on MIP and MIP + MPR analysis, respectively. Imaging performances on MIP and MIP + MPR analysis were good enough to perform subsegmental chemoembolization without additional angiographic investigation in 88 (62.0 %) and 128 tumors (90.1 %) on per-tumor basis and in 43 (50 %) and 73 (84.9 %) on per-patient basis, respectively. Significant determining factors for performance in MIP + MPR analysis on per tumor basis were tumor size (p = 0.030), tumor enhancement (0.005), tumor location (p = 0.001), and diaphragmatic motion (p < 0.001). CONCLUSIONS: CBCT hepatic arteriography provided sufficient information for subsegmental chemoembolization by depicting tumors and their feeders in the vast majority of patients. Combined analysis of MIP and MPR images was essential to enhance the performance of CBCT hepatic arteriography. PMID- 25720742 TI - NAT yield for human immunodeficiency and hepatitis C viruses in Brazilian blood donors: preliminary results. PMID- 25720743 TI - Menopause is a determinant of breast adipose inflammation. AB - Chronic inflammation is recognized as a risk factor for the development of several malignancies. Local white adipose tissue (WAT) inflammation, defined by the presence of dead or dying adipocytes encircled by macrophages that form crown like structures (CLS), occurs in the breasts (CLS-B) of most overweight and obese women. Previously, we showed that the presence of CLS-B is associated with elevated tissue levels of proinflammatory mediators and aromatase, the rate limiting enzyme for estrogen biosynthesis. The associated increased levels of aromatase in the breast provide a plausible mechanistic link between WAT inflammation and estrogen-dependent breast cancers. Thus, breast WAT inflammation could be relevant for explaining the high incidence of estrogen-dependent tumors with aging despite diminished circulating estrogen levels after menopause. To explore this possibility, we determined whether menopause in addition to body mass index (BMI) is associated with breast WAT inflammation among 237 prospectively enrolled women. The presence of CLS-B and its severity (CLS B/cm(2)) as indicators of WAT inflammation correlated with menopausal status (P = 0.008 and P < 0.001) and BMI (P < 0.001 for both). In multivariable analyses adjusted for BMI, the postmenopausal state was independently associated with the presence (P = 0.03) and severity of breast WAT inflammation (P = 0.01). Mean adipocyte size increased in association with CLS-B (P < 0.001). Our findings demonstrate that breast WAT inflammation, which is associated with elevated aromatase levels, is increased in association with the postmenopausal state independent of BMI. Breast WAT inflammation, a process that can potentially be targeted, may help to explain the high incidence of estrogen-dependent tumors in postmenopausal women. PMID- 25720745 TI - High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). PMID- 25720746 TI - Cognition and Social Cognition in non-psychotic siblings of patients with schizophrenia. AB - INTRODUCTION: Deficits in Social Cognition are common in people with schizophrenia. However, it is not clear if these deficits are a vulnerability marker and whether they are independent to cognitive difficulties. This study investigates these two issues in individuals with a genetic liability to psychosis. METHODS: Twenty-one healthy siblings of patients with schizophrenia were compared with 21 healthy individuals on a range of cognitive and social cognitive measures. Significant differences in cognitive domains were controlled for when comparing the two groups on measures of social cognition. RESULTS: Siblings of people with schizophrenia performed significantly worst on tests of theory of mind and social perception but not on affect recognition. Scores on tests of executive function, processing speed and general IQ were also lower in the sibling group. When controlled for differences in cognitive tests, the two groups still retained significant differences in theory of mind and social perception. However, executive function significantly contributed to theory of mind and processing speed to social perception differences. CONCLUSIONS: These results further suggest that difficulties in some domains of social cognition are associated with a genetic vulnerability for schizophrenia. In these areas, cognitive difficulties account only partially for social cognition problems suggesting that these two domains may represent relatively independent liability factors. PMID- 25720747 TI - Exercise-induced cardioprotection: more to k'NO'w. PMID- 25720744 TI - Liquid biopsies in patients with diffuse glioma. AB - Diffuse gliomas are the most common malignant primary tumors of the central nervous system. Like other neoplasms, these gliomas release molecular information into the circulation. Tumor-derived biomarkers include proteins, nucleic acids, and tumor-derived extracellular vesicles that accumulate in plasma, serum, blood platelets, urine and/or cerebrospinal fluid. Recently, also circulating tumor cells have been identified in the blood of glioma patients. Circulating molecules, vesicles, platelets, and cells may be useful as easily accessible diagnostic, prognostic and/or predictive biomarkers to guide patient management. Thereby, this approach may help to circumvent problems related to tumor heterogeneity and sampling error at the time of diagnosis. Also, liquid biopsies may allow for serial monitoring of treatment responses and of changes in the molecular characteristics of gliomas over time. In this review, we summarize the literature on blood-based biomarkers and their potential value for improving the management of patients with a diffuse glioma. Incorporation of the study of circulating molecular biomarkers in clinical trials is essential for further assessment of the potential of liquid biopsies in this context. PMID- 25720748 TI - Patterns of Psychological Adaptation to Spousal Bereavement in Old Age. AB - BACKGROUND: While the negative effects of spousal bereavement on well-being are well documented in empirical research, the large individual differences in psychological adaptation are still not well understood. OBJECTIVE: This contribution aims to identify patterns of psychological adaptation to spousal loss in old age and to shed light on the role of intra- and interpersonal resources and contextual factors as discriminant variables among these patterns. METHODS: The data stem from a cross-sectional questionnaire study of 402 widowed individuals (228 women, 174 men) aged between 60 and 89 years (mean age 74.41 years), who lost their partner within the last 5 years, and 618 married individuals, who served as controls (312 women, 306 men; mean age 73.82 years). RESULTS: The exploratory latent profile analysis of the well-being outcomes of depressive symptoms, hopelessness, loneliness, life satisfaction and subjective health revealed three different groups in the widowed sample: 'resilients' (54% of the sample), 'copers' (39%) and 'vulnerables' (7%). The most important variables for group allocation were intrapersonal resources - psychological resilience and the Big Five personality traits - but also the quality of the former relationship and how the loss was experienced. CONCLUSION: Successful adaptation to spousal loss is primarily associated with high scores in psychological resilience and extraversion and low scores in neuroticism. Our results shed light on the variability in psychological adaptation and underline the important role of intrapersonal resources in facing spousal loss in old age. PMID- 25720749 TI - Breast Density Analysis Using an Automatic Density Segmentation Algorithm. AB - Breast density is a strong risk factor for breast cancer. In this paper, we present an automated approach for breast density segmentation in mammographic images based on a supervised pixel-based classification and using textural and morphological features. The objective of the paper is not only to show the feasibility of an automatic algorithm for breast density segmentation but also to prove its potential application to the study of breast density evolution in longitudinal studies. The database used here contains three complete screening examinations, acquired 2 years apart, of 130 different patients. The approach was validated by comparing manual expert annotations with automatically obtained estimations. Transversal analysis of the breast density analysis of craniocaudal (CC) and mediolateral oblique (MLO) views of both breasts acquired in the same study showed a correlation coefficient of rho = 0.96 between the mammographic density percentage for left and right breasts, whereas a comparison of both mammographic views showed a correlation of rho = 0.95. A longitudinal study of breast density confirmed the trend that dense tissue percentage decreases over time, although we noticed that the decrease in the ratio depends on the initial amount of breast density. PMID- 25720750 TI - The prognostic value of positron emission tomography performed after two courses (INTERIM-PET) of standard therapy on treatment outcome in early stage Hodgkin lymphoma: A multicentric study by the fondazione italiana linfomi (FIL). AB - This retrospective study included 246 patients with a new diagnosis of Hodgkin Lymphoma (HL) with a localized-stage (IA-IIA), consecutively admitted from January 2002 to December 2008, by twelve Italian hematological centers on behalf of Fondazione Italiana Linfomi (FIL). Patients were staged at baseline and after two cycles of chemotherapy with PET. All patients were treated with four cycles of ABVD followed by involved-field radiotherapy. No treatment change, based on PET-2 results was allowed. Endpoint of the study was the predictive role of PET-2 on 2-y failure-free survival (FFS). PET-2 was positive in 36 patients (15%) and negative in 210. After a mean follow-up of 46 (3-105) months 19/36 PET-2 positive patients progressed or relapsed and 17 achieved and maintained a CCR. The positive and negative predictive value of a PET2 was 53% and 95%, respectively. The sensibility, specificity and accuracy of PET2 were 65.5%, 92% and 89%, respectively. PET-2 positive scans were centrally reviewed according to the recently defined Deauville Criteria. Upon review the PPV and NPV was 73% and 96% overall. Factors with prognostic significance for progression in univariate analysis were a positive PET-2 (P = 0.000) and the presence of bulky disease (P < 0.01). In a multivariate analysis the only factor that affected negatively FFS was a positive PET-2 (P = 0.000). This study confirms that interim-PET could be considered a prognostic test also in early stage HL, but is unlikely to be a factor that will justify the change of therapeutical approach. PMID- 25720751 TI - Effect of the Si/TiO2/BiVO4 heterojunction on the onset potential of photocurrents for solar water oxidation. AB - BiVO4 has been formed into heterojunctions with other metal oxide semiconductors to increase the efficiency for solar water oxidation. Here, we suggest that heterojunction photoanodes of Si and BiVO4 can also increase the efficiency of charge separation and reduce the onset potential of the photocurrent by utilizing the high conduction band edge potential of Si in a dual-absorber system. We found that a thin TiO2 interlayer is required in this structure to realize the suggested photocurrent density enhancement and shifts in onset potential. Si/TiO2/BiVO4 photoanodes showed 1.0 mA/cm(2) at 1.23 V versus the reversible hydrogen electrode (RHE) with 0.11 V (vs RHE) of onset potential, which were a 3.3-fold photocurrent density enhancement and a negative shift in onset potential of 300 mV compared to the performance of FTO/BiVO4 photoanodes. PMID- 25720752 TI - Increased circulating heat shock protein 70 (HSPA1A) levels in gestational diabetes mellitus: a pilot study. AB - Recent data indicate that serum Hsp70 (HSPA1A) levels are increased in type 1 and 2 diabetes mellitus. However, there is no report in the literature on circulating Hsp70 levels in gestational diabetes mellitus. In this pilot study, we measured serum Hsp70 levels in 11 pregnant women with pregestational diabetes, 38 women with gestational diabetes, and 40 healthy pregnant women with ELISA. Plasma glucose levels, serum insulin concentrations, HbA1c values, and the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index were also determined. According to our results, serum Hsp70 concentrations were significantly higher in women with pregestational and gestational diabetes mellitus than in healthy pregnant women. In addition, pregestational diabetic women had significantly higher Hsp70 levels than those with gestational diabetes. Furthermore, in the group of women with gestational diabetes mellitus, serum Hsp70 levels showed a significant positive correlation with HbA1c values. However, there was no other relationship between clinical features and metabolic parameters of the study subjects and their serum Hsp70 levels in either study group. In conclusion, we demonstrated for the first time in the literature that serum Hsp70 levels are increased and correlate with HbA1c values in women with gestational diabetes mellitus. Nevertheless, further studies are needed to determine whether circulating Hsp70 plays a causative role in the pathogenesis of gestational diabetes or elevated serum Hsp70 levels are only consequences of the disease. PMID- 25720753 TI - The Journal of Physiology annual report 2014-15: a year of change and celebration. PMID- 25720754 TI - Is nitric oxide mediated sympatholysis improved with exercise? Yes or nNO? PMID- 25720755 TI - New advances in the neural control of breathing. PMID- 25720757 TI - Preparation and evaluation of novel octylmethoxycinnamate-loaded solid lipid nanoparticles. AB - OBJECTIVE: Octylmethoxycinnamate (OMC)-loaded solid lipid nanoparticles (SLNs) were prepared by ultrasonic emulsification method. Effects of process variables and formulation composition were investigated on particle size and polydispersity index (PI), and the UV absorbance. Effect of OMC concentration on entrapment efficiency (EE) was also studied. METHODS: The optimal formulation was characterized and evaluated by environment emission scanning electron microscopy (ESEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). In addition, the degradations of OMC from SLNs and OMC conventional emulsion were compared. RESULTS: The composition of optimal formulation was determined as 5% (w/w) of solid lipid, 7% (w/w) of emulsifier and 9% of loaded OMC, resulting in a particle size of 392.8 nm, and EE of 88.73%, LD of 38.05% under the preparation condition of 6 min of sonication, 400 W of sonication power. ESEM study showed spherical particles with smooth surface. DSC studies indicated OMC encapsulation within the nanoparticle matrix. The characteristic peaks for OMC-SLNs stood at 1710, 1604, 1513, 1465 and 830.3 cm( 1) . The degradation rate of OMC was decreased when using SLNs formulations compared to conventional emulsion. CONCLUSION: Hence, the developed SLNs can be used as sunscreen carrier for improve the stability. PMID- 25720758 TI - Stimulus familiarity improves consolidation of visual working memory representations. AB - Short-term consolidation is a process that stabilizes visual working memory (VWM) representations so that they are less susceptible to interference. The current study examined this process, specifically if training on specific shapes facilitated the consolidation of visual representations in working memory. Three experiments using two different training tasks compared performance between trained and novel stimuli using the backward masking paradigm. Experiment 1 used a four alternative forced choice task and found an overall advantage for trained shapes as well as evidence for faster consolidation for trained shapes and this cannot be explained by verbal labeling of the trained items (Experiment 3). Experiment 2 used a change-detection training task and showed no overall benefit of training but did show evidence of transfer of training to novel shapes. Taken together, these results show that long-term visual representations can facilitate VWM processing, but the type of training task used impacts the degree to which the long-term representations will affect VWM. PMID- 25720756 TI - Fyn in Neurodevelopment and Ischemic Brain Injury. AB - The Src family kinases (SFKs) are nonreceptor protein tyrosine kinases that are implicated in many normal and pathological processes in the nervous system. The SFKs Fyn, Src, Yes, Lyn, and Lck are expressed in the brain. This review will focus on Fyn, as Fyn mutant mice have striking phenotypes in the brain and Fyn has been shown to be involved in ischemic brain injury in adult rodents and, with our work, in neonatal animals. An understanding of Fyn's role in neurodevelopment and disease will allow researchers to target pathological pathways while preserving protective ones. PMID- 25720759 TI - Learning of monocular information facilitates breakthrough to awareness during interocular suppression. AB - Continuous flash suppression (CFS) is a potent method of inducing binocular rivalry, wherein a rapid succession of high-contrast images presented to one eye effectively blocks from awareness a low-contrast image presented to the other eye. Here we addressed whether the contents of the suppressed image can break through to awareness with extended CFS exposure. On 2/3 of the trials, we presented a faint bar (the target) to the nondominant eye while a high-contrast flickering Mondrian (the mask) was displayed to the dominant eye. Participants were first asked to report whether the target had broken through the CFS mask. Furthermore, on target-present trials, the participants were then asked to guess whether the target had appeared above or below the fixation point. In Experiment 1, the target was presented with a fixed orientation for four blocks of trials, whereas in the fifth block, the target could also have the orthogonal orientation. In Experiment 2, the target was always presented with a fixed orientation, but in the fifth block, unbeknownst to participants, the target and the mask were swapped across the eyes. We found that awareness of the target rapidly improved with training in both experiments. However, whereas Experiment 1 revealed that the improvement largely generalized across stimulus orientations, Experiment 2 showed that the effect of practice was eye-specific. The results suggest that increased breakthrough with training was due to a monocular form of learning. Finally, a control experiment was conducted to exclude the possibility that the monocular learning we reported could have been due to sensory adaptation caused by the masks. PMID- 25720760 TI - Adaptation and visual search in mammographic images. AB - Radiologists face the visually challenging task of detecting suspicious features within the complex and noisy backgrounds characteristic of medical images. We used a search task to examine whether the salience of target features in x-ray mammograms could be enhanced by prior adaptation to the spatial structure of the images. The observers were not radiologists, and thus had no diagnostic training with the images. The stimuli were randomly selected sections from normal mammograms previously classified with BIRADS Density scores of "fatty" versus "dense," corresponding to differences in the relative quantities of fat versus fibroglandular tissue. These categories reflect conspicuous differences in visual texture, with dense tissue being more likely to obscure lesion detection. The targets were simulated masses corresponding to bright Gaussian spots, superimposed by adding the luminance to the background. A single target was randomly added to each image, with contrast varied over five levels so that they varied from difficult to easy to detect. Reaction times were measured for detecting the target location, before or after adapting to a gray field or to random sequences of a different set of dense or fatty images. Observers were faster at detecting the targets in either dense or fatty images after adapting to the specific background type (dense or fatty) that they were searching within. Thus, the adaptation led to a facilitation of search performance that was selective for the background texture. Our results are consistent with the hypothesis that adaptation allows observers to more effectively suppress the specific structure of the background, thereby heightening visual salience and search efficiency. PMID- 25720762 TI - Effects of long-term dietary supplementation with conjugated linoleic acid on bovine oocyte lipid profile. AB - Nutritional and environmental conditions around conception and during early embryonic development may have significant effects on health and well-being in adult life. Here, a bovine heifer model was used to investigate the effects of rumen-protected fat supplementation on oocyte quality and embryo development. Holstein-Friesian heifers (n=84) received a dietary supplement consisting of rumen-protected conjugated linoleic acid (CLA) or stearic acid (SA), each on top of an isocaloric basic diet. Oocytes were collected via ultrasound-guided follicular aspiration and subjected to in vitro maturation followed by either desorption electrospray ionisation mass spectrometry (DESI-MS) for lipid profiling of individual oocytes or in vitro fertilisation and embryo culture. The type of supplement significantly affected lipid profiles of in vitro-matured oocytes. Palmitic acid and plasmalogen species were more abundant in the mass spectra of in vitro-matured oocytes after rumen-protected SA supplementation when compared with those collected from animals supplemented with CLA. Lipid concentrations in blood and follicular fluid were significantly affected by both supplements. Results show that rumen-protected fatty-acid supplementation affects oocyte lipid content and may pave the way for the establishment of a large-animal model for studies towards a better understanding of reproductive disorders associated with nutritional impairments. PMID- 25720761 TI - Effect of n-3 PUFA supplementation at different EPA:DHA ratios on the spontaneously hypertensive obese rat model of the metabolic syndrome. AB - The increasing incidence of the metabolic syndrome (MetS), a combination of risk factors before the onset of CVD and type 2 diabetes, encourages studies on the role of functional food components such as long-chain n-3 PUFA as preventive agents. In the present study, we explore the effect of EPA and DHA supplementation in different proportions on spontaneously hypertensive obese (SHROB) rats, a model for the MetS in a prediabetic state with mild oxidative stress. SHROB rats were randomised into four groups (n 7), each supplemented with EPA/DHA at ratios of 1:1, 2:1 and 1:2, or soyabean oil as the control for 13 weeks. The results showed that in all the proportions tested, EPA/DHA supplementation significantly lowered total and LDL-cholesterol concentrations, compared with those of the control group. EPA/DHA supplementation at the ratios of 1:1 and 2:1 significantly decreased inflammation (C-reactive protein levels) and lowered oxidative stress (decreased excretion of urinary isoprostanes), mainly at the ratio of 1:2. The activity of antioxidant enzymes increased in erythrocytes, abdominal fat and kidneys, with magnitudes depending on the EPA:DHA ratio. PUFA mixtures from fish affected different MetS markers of CVD risk factors in SHROB rats, depending on the ratios of EPA/DHA supplementation. The activation of endogenous defence systems may be related to the reduction of inflammation and oxidative stress. PMID- 25720764 TI - Fabrication of a platform to isolate the influences of surface nanotopography from chemistry on bacterial attachment and growth. AB - Billions of dollars are spent annually worldwide to combat the adverse effects of bacterial attachment and biofilm formation in industries as varied as maritime, food, and health. While advances in the fabrication of antifouling surfaces have been reported recently, a number of the essential aspects responsible for the formation of biofilms remain unresolved, including the important initial stages of bacterial attachment to a substrate surface. The reduction of bacterial attachment to surfaces is a key concept in the prevention or minimization of biofilm formation. The chemical and physical characteristics of both the substrate and bacteria are important in understanding the attachment process, but substrate modification is likely the most practical route to enable the extent of bacterial attachment taking place to be effectively controlled. The microtopography and chemistry of the surface are known to influence bacterial attachment. The role of surface chemistry versus nanotopography and their interplay, however, remain unclear. Most methods used for imparting nanotopographical patterns onto a surface also induce changes in the surface chemistry and vice versa. In this study, the authors combine colloidal lithography and plasma polymerization to fabricate homogeneous, reproducible, and periodic nanotopographies with a controllable surface chemistry. The attachment of Escherichia coli bacteria onto carboxyl (plasma polymerized acrylic acid, ppAAc) and hydrocarbon (plasma polymerized octadiene, ppOct) rich plasma polymer films on either flat or colloidal array surfaces revealed that the surface chemistry plays a critical role in bacterial attachment, whereas the effect of surface nanotopography on the bacterial attachment appears to be more difficult to define. This platform represents a promising approach to allow a greater understanding of the role that surface chemistry and nanotopography play on bacterial attachment and the subsequent biofouling of the surface. PMID- 25720763 TI - Changes in beta cell function during the proximate post-diagnosis period in persons with type 1 diabetes. AB - OBJECTIVE: Prior studies examining beta-cell preservation in type 1 diabetes have predominantly assessed stimulated C-peptide concentrations approximately 10 wk after diagnosis. We examined whether earlier assessments might aid in prediction of beta cell function over time. METHODS: Using data from a multi-center randomized trial assessing the effect of intensive diabetes management initiated within 1 wk of diagnosis, we assessed which clinical factors predicted 90-min mixed-meal tolerance test (MMTT) stimulated C-peptide values obtained 2 and 6 wk after diagnosis. We also studied associations of these factors with C-peptide values at 1- and 2-year post-diagnosis. Data from intervention and control groups were pooled. RESULTS: Among 67 study participants (mean age 13.3 +/- 5.7 yr, range 7.8-45.7 yr) in multivariable analyses, C-peptide increased from baseline to 2 wks and then 6 wk. C-peptide levels at these times were significantly correlated with 1- and 2-yr C-peptide concentrations (all p < 0.001), with the strongest observed associations between 6-wk C-peptide and the 1- and 2-yr values (r = 0.66 and r = 0.61, respectively). In multivariable analyses, greater baseline and 6-wk C-peptide, and older age independently predicted greater 1- and 2-yr C-peptide concentrations. CONCLUSIONS: C-peptide assessments close to diagnosis were predictive of subsequent C-peptide production. Our data demonstrate a clear increase in C-peptide over the initial 6 wk after diabetes diagnosis followed by a plateau. Our data do not suggest that MMTT assessments performed closer to diagnosis than 6 wk would improve prediction of subsequent residual beta cell function. PMID- 25720765 TI - Restoration of chondrocytic phenotype on a two-dimensional micropatterned surface. AB - Chondrocytes within mature cartilage reside in a 3D matrix and adopt a distinctive round morphology. A vast 2D-culture surface is well-known to induce chondrocyte dedifferentiation characterized by the loss of spherical morphology and ceased expression of chondrogenic markers. Methods to restore chondrogenesis so far only occur on a certain level producing varied cell subpopulations and inferior cartilage matrix; the critical parameters, especially for the pericellular microenvironment, are still to be precisely determined. In this study, arrays of 2D circular micropatterns were designed to hold single subcultured chondrocytes with stable adhesion. The chondrocytes rounded up forming a 3D architecture; they remodeled their cytoskeleton to resemble in-situ chondrocytes and expressed collagen II instead of collagen I or fibronectin. This technique suggested that pure physical constraints can induce chondrocytic phenotype restoration on a 2D surface; it also provides a new design pathway to precisely control the microenvironment surrounding every chondrocyte therefore to unify the redifferentiation level of individual cell. PMID- 25720767 TI - Prevalence and disability of headache among Norwegian adolescents: A cross sectional school-based study. AB - BACKGROUND: Headache is common in adolescents and affects schoolwork and relations with friends and family. In most previous epidemiological surveys, only the most bothersome headache has been documented. The aim was to determine headache prevalence not only taking into account the most bothersome headache, but also to compare characteristics of the most bothersome and less bothersome headaches, and to investigate headache-related disability. METHODS: A cross sectional school-based study was conducted in which 493 representative adolescents aged 12-18 years were recruited by stratified cluster sampling and interviewed. Headache diagnosis was made according to the new classification system of the International Headache Society (ICHD-3 beta), and the Pediatric Migraine Disability Assessment (PedMIDAS) was used to evaluate disability. RESULTS: The one-year prevalence of any headache type, definite migraine, probable migraine and tension-type headache was 88%, 23%, 13% and 58%, respectively. The point prevalence of any headache was 38%. Nine percent of participants fulfilled criteria for more than one headache diagnosis. The most bothersome headache had a significantly longer duration (p < 0.001) and higher intensity (p < 0.001) than the less bothersome headache, but similar frequency (p = 0.86). Adolescents with headaches lost up to nine days of activity each year, implicating headache as a major health issue. CONCLUSIONS: Headaches are very common and disabling among adolescents. The full extent of this health problem is better appreciated if inquiry is not limited to the most bothersome subtypes. PMID- 25720766 TI - A small molecule with anticancer and antimetastatic activities induces rapid mitochondrial-associated necrosis in breast cancer. AB - Therapy for treatment-resistant breast cancer provides limited options and the response rates are low. Therefore, the development of therapies with alternative chemotherapeutic strategies is necessary. AG311 (5-[(4-methylphenyl)thio]-9H pyrimido[4,5-b]indole-2,4-diamine), a small molecule, is being investigated in preclinical and mechanistic studies for treatment of resistant breast cancer through necrosis, an alternative cell death mechanism. In vitro, AG311 induces rapid necrosis in numerous cancer cell lines as evidenced by loss of membrane integrity, ATP depletion, HMGB1 (high-mobility group protein B1) translocation, nuclear swelling, and stable membrane blebbing in breast cancer cells. Within minutes, exposure to AG311 also results in mitochondrial depolarization, superoxide production, and increased intracellular calcium levels. Additionally, upregulation of mitochondrial oxidative phosphorylation results in sensitization to AG311. This AG311-induced cell death can be partially prevented by treatment with the mitochondrial calcium uniporter inhibitor, Ru360 [(MU)[(HCO2)(NH3)4Ru]2OCl3], or an antioxidant, lipoic acid. Additionally, AG311 does not increase apoptotic markers such as cleavage of poly (ADP-ribose) polymerase (PARP) or caspase-3 and -7 activity. Importantly, in vivo studies in two orthotopic breast cancer mouse models (xenograft and allograft) demonstrate that AG311 retards tumor growth and reduces lung metastases better than clinically used agents and has no gross or histopathological toxicity. Together, these data suggest that AG311 is a first-in-class antitumor and antimetastatic agent inducing necrosis in breast cancer tumors, likely through the mitochondria. PMID- 25720768 TI - Treatment of hemicrania continua with radiofrequency ablation and long-term follow-up. AB - OBJECTIVE: The objective of this research is to describe novel procedural treatments for hemicrania continua that allow patients to remain off indomethacin. METHODS: Case reports are presented. RESULTS: We describe four distinct patients with indomethacin-responsive hemicrania continua who were unable to discontinue the use of indomethacin without headache recurrence. No other medications were effective for their syndrome. Secondary causes of headache were ruled out in each case. Each patient underwent diagnostic blockade of either the atlanto-axial joint, C2 dorsal root ganglion or sphenopalantine ganglion depending on their clinical examination and presence of cranial autonomic symptoms. A positive response led to a radiofrequency ablation of the C2 ventral ramus, C2 dorsal root ganglion or sphenopalantine ganglion, which provided headache relief in all case patients as complete as indomethacin. Long-term follow-up of these patients has shown that all have remained essentially headache free without the need for indomethacin. One patient has needed repeat radiofrequency procedures with consistent response. CONCLUSION: Hemicrania continua is defined by its sensitivity to indomethacin but very few patients are able to discontinue the medication without headache recurrence. As the risks of chronic indomethacin use are substantial, alternative treatments are necessary to protect patient health. We are now able to suggest several radiofrequency ablation procedures as effective as indomethacin with long-term follow-up. PMID- 25720769 TI - ALK positive large B-cell lymphoma with a massive neutrophilic infiltrate: report of a case mimicking epithelioid inflammatory myofibroblastic tumour. PMID- 25720770 TI - Leigh disease due to SCO2 mutations revealed at extended autopsy. PMID- 25720773 TI - The progressive myoclonic epilepsies. AB - Progressive myoclonic epilepsies are a group of disorders characterised by a relentlessly progressive disease course until death; treatment-resistant epilepsy is just a part of the phenotype. This umbrella term encompasses many diverse conditions, ranging from Lafora body disease to Gaucher's disease. These diseases as a group are important because of a generally poor response to antiepileptic medication, an overall poor prognosis and inheritance risks to siblings or offspring (where there is a proven genetic cause). A correct diagnosis also helps patients and their families to accept and understand the nature of their disease, even if incurable. Here, we discuss the phenotypes of these disorders and summarise the relevant specific investigations to identify the underlying cause. PMID- 25720771 TI - A comparative planning study of step-and-shoot IMRT versus helical tomotherapy for whole-pelvis irradiation in cervical cancer. AB - The aim of this study was to compare the dosimetric parameters of whole-pelvis radiotherapy (WPRT) for cervical cancer between step-and-shoot IMRT (SaS-IMRT) and Helical TomotherapyTM (HT). Retrospective analysis was performed on 20 cervical cancer patients who received WPRT in our center between January 2011 and January 2014. SaS-IMRT and HT treatment plans were generated for each patient. The dosimetric values for target coverage and organ-at-risk (OAR) sparing were compared according to the criteria of the International Commission on Radiation Units and Measurements 83 (ICRU 83) guidelines. Differences in beam-on time (BOT) were also compared. All the PTV dosimetric parameters (D5%, D50% and D95%) for the HT plan were (statistically significantly) of better quality than those for the SaS-IMRT plan (P-value < 0.001 in all respects). HT was also significantly more accurate than SaS-IMRT with respect to the D98% and Dmean of the CTV (P values of 0.008 and <0.001, respectively). The median Conformity Index (CI) did not differ between the two plans (P-value = 0.057). However, the Uniformity Index for HT was significantly better than that for SaS-IMRT (P-value < 0.001). The median of D50% for the bladder, rectum and small bowel were significantly lower in HT planning than SaS-IMRT (P-value < 0.001). For D2%, we found that HT provided better sparing to the rectum and bladder (P-value < 0.001). However, the median of D2% for the small bowel was comparable for both plans. The median of Dmax of the head of the left femur was significantly lower in the HT plan, but this did not apply for the head of the right femur. BOT for HT was significantly shorter than for SaS-IMRT (P-value < 0.001). HT provided highly accurate plans, with more homogeneous PTV coverage and superior sparing of OARs than SaS-IMRT. In addition, HT enabled a shorter delivery time than SaS-IMRT. PMID- 25720774 TI - Emergency stenting for acute symptomatic carotid stenosis: dissecting the evidence. PMID- 25720772 TI - Quantitative phosphoproteomics reveals pathways for coordination of cell growth and division by the conserved fission yeast kinase pom1. AB - Complex phosphorylation-dependent signaling networks underlie the coordination of cellular growth and division. In the fission yeast Schizosaccharomyces pombe, the Dual specificity tyrosine-(Y)-phosphorylation regulated kinase (DYRK) family protein kinase Pom1 regulates cell cycle progression through the mitotic inducer Cdr2 and controls cell polarity through unknown targets. Here, we sought to determine the phosphorylation targets of Pom1 kinase activity by SILAC-based phosphoproteomics. We defined a set of high-confidence Pom1 targets that were enriched for cytoskeletal and cell growth functions. Cdr2 was the only cell cycle target of Pom1 kinase activity that we identified in cells. Mutation of Pom1 dependent phosphorylation sites in the C terminus of Cdr2 inhibited mitotic entry but did not impair Cdr2 localization. In addition, we found that Pom1 phosphorylated multiple substrates that function in polarized cell growth, including Tea4, Mod5, Pal1, the Rho GAP Rga7, and the Arf GEF Syt22. Purified Pom1 phosphorylated these cell polarity targets in vitro, confirming that they are direct substrates of Pom1 kinase activity and likely contribute to regulation of polarized growth by Pom1. Our study demonstrates that Pom1 acts in a linear pathway to control cell cycle progression while regulating a complex network of cell growth targets. PMID- 25720776 TI - Celebrating the 75th anniversary of the American Journal of Psychoanalysis. PMID- 25720775 TI - ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors. AB - The classical DNA recognition sequence of the glucocorticoid receptor (GR) appears to be present at only a fraction of bound genomic regions. To identify sequences responsible for recruitment of this transcription factor (TF) to individual loci, we turned to the high-resolution ChIP-exo approach. We exploited this signal by determining footprint profiles of TF binding at single-base-pair resolution using ExoProfiler, a computational pipeline based on DNA binding motifs. When applied to our GR and the few available public ChIP-exo data sets, we find that ChIP-exo footprints are protein- and recognition sequence-specific signatures of genomic TF association. Furthermore, we show that ChIP-exo captures information about TFs other than the one directly targeted by the antibody in the ChIP procedure. Consequently, the shape of the ChIP-exo footprint can be used to discriminate between direct and indirect (tethering to other DNA-bound proteins) DNA association of GR. Together, our findings indicate that the absence of classical recognition sequences can be explained by direct GR binding to a broader spectrum of sequences than previously known, either as a homodimer or as a heterodimer binding together with a member of the ETS or TEAD families of TFs, or alternatively by indirect recruitment via FOX or STAT proteins. ChIP-exo footprints also bring structural insights and locate DNA:protein cross-link points that are compatible with crystal structures of the studied TFs. Overall, our generically applicable footprint-based approach uncovers new structural and functional insights into the diverse ways of genomic cooperation and association of TFs. PMID- 25720777 TI - In these pages.... PMID- 25720778 TI - Decoding Ferenczi's clinical diary: biographical notes. AB - In the Clinical Diary of Sandor Ferenczi, certain codes and abbreviations are used to refer to the eight patients Ferenczi was treating in 1932. The identities of two patients are known to us. Notably, Dm. (Clara Thompson), and R.N. (Elizabeth Severn), but the others have remained a mystery. This paper uncovers the identities of the other patients in the Diary, and, for the first time, reveals their identities and life stories. Biographical notes on these patients are provided to expand and contextualize our understanding of their lives-Who were they? What kind of families did they come from? And what happened to them after their analyses? The process of uncovering their identities and the ethics of writing about historical patients will also be addressed. PMID- 25720779 TI - Thwarting the psychoanalytic detectives: defending the Severn legacy. AB - In 1993, The Legacy of Sandor Ferenczi (Aron & Harris) was published. This groundbreaking volume contained the chapter, The Case of "RN": Sandor Ferenczi's Radical Experiment in Psychoanalysis (Fortune, 1993), which told the story of "RN"-Ferenczi's code-name in his Clinical Diary for his critically important patient, Elizabeth Severn. The chapter presented biographical details and original research supporting the rich clinical material revealed in Ferenczi's Clinical Diary. Now, two decades later, RN has continued to affirm her place as one of the most important patients in the history of psychoanalysis. On this twentieth anniversary, just past, of the recognition of her story, I would like to reflect back and recount the beginnings of my "detective" work on the Case of RN, particularly my encounter with Severn's daughter, Margaret. PMID- 25720780 TI - On "polygamous analysis". AB - The close relationships among Ferenczi's analysands at the time the Clinical Diary was written are explored, and their potential influences on their analyses are discussed. It is suggested that the fact that "a virtual group" emerged in this context may have sabotaged to some extent Ferenczi's clinical work, because this setting did not allow the open joint exploration possible in an actual analytic group, and at the same time stood in the way of achieving "a background of safety" fostered by the privacy and confidentiality of a fully individual analysis. Several examples are given of situations that may have made analysands feel betrayed or abandoned by the divided loyalties of their analyst, and may have created painful splits in Ferenczi's own countertransferences. PMID- 25720781 TI - Becoming a peter pan: omnipotence, dependency and the Ferenczian child. AB - The aim of this paper is to provide a short history of the changes in Ferenczi's concept of early childhood, during the two decade period, 1913-1932. Initially, Ferenczi mainly emphasized children's feelings of omnipotence, which enable them to perceive themselves as strong, independent and capable human beings. By the mid-1920s, however, he felt that his earlier work did not give a good account of what comes after the stage of omnipotence, and that it did not adequately describe the difficulties in the transition from pleasure to reality principles. However, in his Clinical Diary, Ferenczi became fully aware of how fragile and insecure children are, and therefore how dangerous-yet necessary-it is for them to abandon the "stage of omnipotence" and to gain a "sense of reality". For Ferenczi, traumatized children are children who had not been loved in their early childhood, and therefore could not develop the capacity to make the journey from pleasure principle to that of reality. It will be suggested that a paradigmatic example for this kind of child is Peter Pan. PMID- 25720782 TI - The child as a traumatic self-component in Ferenczi's later psychoanalysis. AB - In the Ferenczi renaissance of the last few decades it has become more and more important to elaborate and reconstruct the general shape, the "Weltanschauung", of his psychoanalysis. The construct of his "psychoanalytic anthropology" is based on the relational nature of individual existence. Relationality pervades the life narrative through the concept and role of the trauma and is crucial to the understanding of Ferenczi's self-concept. He understood the human individual as essentially fragmented in a "preprimal" way, in which the split self contains the child, as an active, always present infantile component. Through powerful allegories like the "Orpha" or the "wise baby," Ferenczi suggested an essentially post-modern idea of self that can be connected and differentiated from Winnicott's True and False Self. PMID- 25720783 TI - "Freedom to grow". AB - Writing is a dangerous activity, especially as it is seemingly harmless: we rarely know what we are getting into at the start. Continuing her work on the writings of J.M. Barrie, especially on the question of the "lost child" who never grows up, the author invites the reader to listen to Sandor Ferenczi's "lost childhood" between the lines of his Clinical Diary. He begins the Diary on January 7, 1932 and the last entry is October 2 of the same year; Ferenczi died on May 22, 1933. The exceptional text of the diary is the fruit of his incisive clinical insights, his disappointment and anger with Freud and his ruthless self analysis. The author pinpoints her reading of Ferenczi, the "wise baby-lost child". PMID- 25720784 TI - Free to move, free to be. AB - The Hungarian Pikler-Loczy Institute for Infants' Well-being and Healthy Development could not have been created without the fundamental contribution of the Budapest School's approach to Object Relations. For historical reasons, very little is known in psychoanalytical circles about this extraordinary experience and work. Pikler created an original model with a space for partnership, reciprocity, and the baby's "true" autonomy, which focuses on the baby's self initiated motor development: "freedom to move". The atmosphere of this world around babies can be related to the "reveries" of Ferenczi about the necessity for an early, caring environment provided through adult tenderness as it appears in his Clinical Diary. PMID- 25720785 TI - Klein, Ferenczi and the clinical diary. AB - The aim of this article is to revisit Ferenczi's Clinical Diary (1932) to investigate the influence he had on Melanie Klein's work. It starts from the position that insufficient recognition has been given to Ferenczi's contribution to Klein's body of work and her professional development. Her analysis with Ferenczi lasted 5 years, a relatively long analysis for the period. It explores his influence in three specific areas: the importance of raw and early emotion in the maternal bond, the importance of freedom and authenticity in the analytic relationship, and finally the use of transference and countertransference feelings. Ferenczi's ill-fated experiment with mutual analysis will be discussed as it opened up a route to explore the analytic relationship, with important consequences for the future development of psychoanalysis. PMID- 25720786 TI - Lacan and Ferenczi: paradoxical kinship? AB - The kinship between Ferenczi and Lacan can be compared with the phases of an eclipse. Throughout the first period of his teaching, Lacan presents Ferenczi as the most relevant analyst among the first pioneers. It is clear that he hopes to develop Ferenczi's subversive reflections about clinical practice. Surprisingly, in the second period references to Ferenczi seem to disappear, even when he takes on the question of trauma in light of what he calls the register of the Real; he does not cite Ferenczi at all. In a third period, after Lacan's death, certain Lacanians are very critical about Ferenczi, often excessively. Today, analysts open to Lacan's teaching are discovering Ferenczi and the richness of his work, in which Lacan found numerous springheads for his own work. PMID- 25720787 TI - The Jung-Ferenczi dossier. AB - The acquaintance between Sandor Ferenczi and C G Jung pre-dates their first encounter with Sigmund Freud. Later, a triangular relationship developed when the three men crossed the Atlantic together and spent an extended period in one another's company. Ferenczi's friendship with Jung could not survive the latter's break with Freud, but its development between 1907 and 1913 is evidenced by unpublished letters from Jung to Ferenczi, found in the Ferenczi Archive, now at the Freud Museum. PMID- 25720791 TI - Influenza vaccination perception and coverage among patients with malignant disease. AB - BACKGROUND: Patients with malignancies are at increased risk of serious influenza related complications with higher rates of hospitalization and mortality than healthy cohorts. Although annual vaccination against influenza infection is recommended, vaccination rates among cancer patients are apparently low. The reasons for the low compliance to influenza vaccine and the influenza vaccination rate among Austrian cancer patients have not been studied in detail yet. PATIENTS AND METHODS: From July 1, 2013 to October 31, 2013, 444 patients treated in the outpatient departments of the Clinical Division of Oncology and the Clinical Division of Haematology and Haemostaseology of the General Hospital Vienna participated in a survey on different aspects of influenza vaccination. RESULTS: In total, only 80 out of 444 patients (18%) had received influenza vaccination in the previous year. The influenza vaccination rate was higher amongst patients with haematological malignancies (22%) compared to patients with solid tumours (13%). Higher age was significantly associated with a higher probability for being vaccinated. Collecting information about influenza vaccination primarily from media or the internet was not significantly associated with influenza vaccination status. Information through a medical consultation or a recommendation by the attending physician resulted in significant higher influenza vaccination coverage rates. Only 199 out of the 444 patients (44.8%) were informed by a physician about influenza vaccination and only 18 out of 337 patients (5.3%) with a diagnosis of a malignant disease were informed by their treating oncologist. The main reasons for influenza vaccination denial were concerns about interaction with the malignant disease and potential side-effects. CONCLUSION: Information about influenza vaccination during a medical consultation and a clear recommendation by the attending physician are highly predictive for acceptance of influenza vaccination. Increased awareness among physicians, especially oncologists is of utmost importance to effectively improve IVR in patients with malignant disease. PMID- 25720792 TI - Organization and quality of HPV vaccination programs in Europe. AB - BACKGROUND: HPV vaccination is underway in most European countries, but there are limited efforts toward optimization and standardization of organization, monitoring and evaluation. Our Europe-wide survey sought to identify how programs are currently organized, the costs associated with the organizing and ensuring quality of the program and how quality and effectiveness measurements are carried out. METHODS: A comprehensive questionnaire was developed through systematic literature review and the European guidelines for quality assurance in cervical screening. The survey was piloted in a sub-set of countries and then sent to program organizers, Ministries of Health, and key experts in 34 EU and EFTA countries (including countries within the UK). Detailed information on program organization and target population, monitoring and evaluation (including indicators used for evaluating the impact of vaccination), and associated costs were collected. In addition, documentation of program guidelines, protocols, and publications were requested. RESULTS: Of the 34 countries contacted, 27 responded. The majority of countries had some level of vaccination activity, with approximately half of the countries reporting an organized vaccination program. Centralized vaccine registries were in place in the majority of countries with an organized program, allowing for monitoring of key indicators at the national level. Costs of organization and monitoring were difficult to estimate and varied significantly, as some countries were able to use existing infrastructures while others had to create new systems, incurring greater costs. CONCLUSIONS: The organization and quality of HPV vaccination programs differ across countries and, in some instances, even across regions within the same country. The monitoring being performed varies across programs with regard to level of detail but engagement in the survey from the participating countries demonstrates that there is strong interest in reflecting on and improving program performance. This survey could serve as a basis for strengthening surveillance of HPV vaccination programs. PMID- 25720793 TI - Increasing hepatitis A immunity in men who have sex with men in Sydney, 1996 2012. AB - We examined the hepatitis A virus status of all MSM seen at a large sexual health clinic in inner Sydney between 1996 and 2012. Overall, the proportion of MSM susceptible to hepatitis A decreased from 68.1% in 1996 to 36.2% in 2012; most of this reduction was attributable to vaccination. PMID- 25720794 TI - Long-term outcomes after vestibuloplasty with a porcine collagen matrix (Mucograft(r) ) versus the free gingival graft: a comparative prospective clinical trial. AB - OBJECTIVES: Porcine collagen matrices are proclaimed being a sufficient alternative to autologous free gingival grafts (FGG) in terms of augmenting the keratinized mucosa. The collagen matrix Mucograft(r) (CM) already showed a comparable clinical performance in the early healing phase, similar histological appearance, and even a more natural appearance of augmented regions. Predictability for long-term stability does not yet exist due to missing studies reporting of a follow-up >6 months. MATERIAL AND METHODS: The study included 48 patients with atrophic edentulous or partially edentulous lower jaw situations that had undergone an implant treatment. In the context of implant exposure, a vestibuloplasty was either performed with two FGGs from the palate (n = 21 patients) or with the CM (n = 27 patients). Surgery time was recorded from the first incision to the last suture. Follow-up examinations were performed at the following time points: 10, 30, 90, and 180 days and 1, 2, 3, 4, and 5 years after surgery. The width of keratinized mucosa was measured at the buccal aspect of each implant, and augmented sites were evaluated in terms of their clinical appearances (texture and color). RESULTS: The groups showed similar healing with increased peri-implant keratinized mucosa after surgery (FGG: 13.06 mm +/- 2.26 mm and CM: 12.96 mm +/- 2.86 mm). The maximum follow-up was 5 years (5 patients per group). After 180 days, the width of keratinized mucosa had decreased to 67.08 +/- 13.85% in the FGG group and 58.88 +/- 14.62% in the CM group with no statistically significant difference. The total loss of the width of keratinized mucosa after 5 years was significant between the FGG (40.65%) and the CM group (52.89%). The CM group had significantly shorter operation times than the FGG group. Augmented soft tissues had a comparable clinical appearance to adjacent native gingiva in the CM group. FGGs could still be defined after 5 years. CONCLUSIONS: The FGG and the CM are both suitable for the regeneration of the peri-implant keratinized mucosa with a sufficient long-term stability. With the CM, tissue harvesting procedures are invalid, surgery time can be reduced, and regenerated tissues have a more esthetic appearance. PMID- 25720795 TI - Integrative analysis of lung development-cancer expression associations reveals the roles of signatures with inverse expression patterns. AB - Recent studies have focused on exploring the associations between organ development and malignant tumors; however, the clinical relevance of the development signatures was inadequately addressed in lung cancer. In this study, we explored the associations between lung development and lung cancer progression by analyzing a total of two development and seven cancer datasets. We identified representative expression patterns (continuously up- and down-regulated) from development and cancer profiles, and inverse pattern associations were observed at both the gene and functional levels. Furthermore, we dissected the biological processes dominating the associations, and found that proliferation and immunity were respectively involved in the two inverse development-cancer expression patterns. Through sub-pathway analysis of the signatures with inverse expression patterns, we finally identified a 13-gene risk signature from the cell cycle sub pathway, and evaluated its predictive performance for lung cancer patient clinical outcome using independent cohorts. Our findings indicated that the integrative analysis of development and cancer expression patterns provided a framework for identifying effective molecular signatures for clinical utility. PMID- 25720796 TI - Distinct regulation of Maf1 for lifespan extension by Protein kinase A and Sch9. AB - The Protein kinase A (PKA) and Sch9 regulates cell growth as well as lifespan in Saccharomyces cerevisiae. Maf1 is a RNA polymerase III (PolIII) inhibitor that tailors 5S rRNA and tRNA production in response to various environmental cues. Both PKA and Sch9 have been shown to phosphorylate Maf1 in vitro at similar amino acids, suggesting a redundancy in Maf1 regulation. However, here we find that activating PKA by bcy1 deletion cannot replace Sch9 for Maf1 phosphorylation and cytoplasmic retention; instead, such modulation lowers Maf1 protein levels. Consistently, loss of MAF1 or constitutive PKA activity reverses the stress resistance and the extended lifespan of sch9Delta cells. Overexpression of MAF1 partially rescues the extended lifespan of sch9Delta in bcy1Deltasch9Delta mutant, suggesting that PKA suppresses sch9Delta longevity at least partly through Maf1 abundance. Constitutive PKA activity also reverses the reduced tRNA synthesis and slow growth of sch9Delta, which, however, is not attributed to Maf1 protein abundance. Therefore, regulation of lifespan and growth can be decoupled. Together, we reveal that lifespan regulation by PKA and Sch9 are mediated by Maf1 through distinct mechanisms. PMID- 25720797 TI - 'One mission accomplished, more important ones remain': commentary on Every Palmer, S., Howick, J. (2014) How evidence-based medicine is failing due to biased trials and selective publication. Journal of Evaluation in Clinical Practice, 20 (6), 908-914. AB - Every-Palmer and Howick suggest that evidence-based medicine (EBM) is failing in its mission because of contamination of research by manufacturer and researcher motivated bias and self-interest. They fail to define that mission and to distinguish between the EBM movement and the research enterprise it was developed to critique. An educational movement, EBM accomplished its mission to simplify and package clinical epidemiological concepts in a form accessible to clinical learners. Its wide adoption within educational circles fostered critical literacy among several generations of practitioners. Illumination of bias, subterfuge and incomplete reporting of research has been a strength of EBM. Increased uptake and use of clinical research within the health care system properly defines the failing mission that eludes Every-Palmer and Howick. Responsibility for failure to make progress towards its achievement is shared by virtually all relevant streams within the system, including policy, clinical guideline development, educational movements and the development of approaches to evidence synthesis. Discordance between the epistemological premises pervading today's research and health care community and the complex social processes that ultimately determine research use constitutes an important factor that must be addressed as part of a remedy. Enhanced emphasis on and demonstration of alternative approaches to research such as realism and realist synthesis and the momentum towards development of a learning health care system hold promise as guideposts for the rapidly evolving health care environment. PMID- 25720798 TI - Increased L-ornithine production in Corynebacterium glutamicum by overexpression of a gene encoding a putative aminotransferase. AB - Overexpression of the NCgl0462 open reading frame, encoding a class II aminotransferase, was studied in conjunction with other enzymes in L-ornithine biosynthesis in an L-ornithine-producing strain. Expression of the wild-type NCgl0462 open reading frame, which displayed aminotransferase activity, was amplified by placing it under the control of the glyceraldehyde 3-phosphate dehydrogenase gene promoter in the pEK0 plasmid and in the genome. L-Ornithine production in Corynebacterium glutamicum SJC8260 harboring plasmid and the genomic NCgl0462 open reading frame was increased by 8.8 and 21.6%, respectively. In addition, the combined overexpression of the NCgl0462 open reading frame within the genome along with the mutated L-ornithine biosynthesis genes (argCJBD) placed in the pEK0 plasmid in C. glutamicum SJC8260 resulted in significant improvement in L-ornithine production (12.48 g/l for combined overexpression compared with 8.42 g/l for the control). These results suggest that overexpression of the aminotransferase-encoding NCgl0462 open reading frame plays an unequivocal role in the L-ornithine biosynthetic pathway, with overlapping substrate specificity in C. glutamicum. PMID- 25720799 TI - High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity. AB - Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage-associated molecular patterns (DAMP), such as high-mobility group box 1 (HMGB1), and dysregulated miRNAs involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in overexpression of miR-21. These changes were found to be dependent on the IL6/STAT3 signaling axis. Invasion and migration of HCC cells in vitro were inhibited by both STAT3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a posttranscriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR 21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1 mediated HCC progression through the IL6/Stat3-miR-21 axis. PMID- 25720800 TI - IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells. AB - Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1(high) (PD-1(high)) tumor antigen (TA)-specific CD8(+) T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R(+) TA-specific CD8(+) T cells to limit their proliferation and survival. PD-1 blockade augments expression of IL10R by TA-specific CD8(+) T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL10. Conversely, IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8(+) T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients. PMID- 25720802 TI - Microbiological bioassay using Bacillus pumilus to detect tetracycline in milk. AB - The tetracyclines (TCs) are widely used in the treatment of several diseases of cattle and their residues may be present in milk. To control these residues it is necessary to have available inexpensive screening methods, user-friendly and capable of analysing a high number of samples. The purpose of this study was to design a bioassay of microbiological inhibition in microtiter plates with spores of Bacillus pumilus to detect TCs at concentrations corresponding to the Maximum Residue Limits (MRLs). Several complementary experiments were performed to design the bioassay. In the first study, we determined the concentration of spores that produce a change in the bioassay's relative absorbance in a short time period. Subsequently, we assessed the concentration of chloramphenicol required to decrease the detection limit (DL) of TCs at MRLs levels. Thereafter, specificity, DL and cross-specificity of the bioassay were estimated. The most appropriate microbiological inhibition assay had a B. pumilus concentration of 1.6 * 10(9) spores/ml, fortified with 2500 MUg chloramphenicol/l (CAP) in Mueller Hinton culture medium using brilliant black and toluidine blue as redox indicator. This bioassay detected 117 MUg chlortetracycline/l, 142 MUg oxytetracycline/l and 105 MUg tetracycline/l by means of a change in the indicator's colour in a period of 5 h. The method showed good specificity (97.9%) which decreased slightly (93.3%) in milk samples with high somatic cell counts (>250,000 cells/ml). Furthermore, other antimicrobials studied (except neomycin) must be present in milk at high concentrations (from >5 to >100 MRLs) to produce positive results in this assay, indicating a low cross specificity. PMID- 25720801 TI - HIV Care Continuum for HIV-Infected Emergency Department Patients in an Inner City Academic Emergency Department. AB - STUDY OBJECTIVE: The recently released HIV Care Continuum Initiative is a cornerstone of the National AIDS Strategy and a model for improving care for those living with HIV. To our knowledge, there are no studies exploring the entirety of the HIV Care Continuum for patients in the emergency department (ED). We determine gaps in the HIV Care Continuum to identify potential opportunities for improved care for HIV-infected ED patients. METHODS: A mixed-methods approach was used in 1 inner-city ED in 2007. Data elements were derived from an identity unlinked HIV seroprevalence study, an ongoing nontargeted HIV screening program, and a structured survey of known HIV-positive ED patients. RESULTS: Identity unlinked testing of 3,417 unique ED patients found that 265 (7.8%) were HIV positive. Of patients testing HIV positive, 73% had received a previous diagnosis (based on self-report, chart review, or presence of antiretrovirals in serum), but only 61% were recognized by the clinician as being HIV infected (based on self-report or chart review). Of patients testing positive, 43% were linked to care, 39% were retained in care, 27% were receiving antiretrovirals, 26% were aware of their receiving antiretroviral treatment, 22% were virally suppressed, and only 9% were self-aware of their viral suppression. CONCLUSION: To our knowledge, this study is the first to quantify gaps in HIV care for an ED patient population, with the HIV Care Continuum as a framework. Our findings identified distinct phases (ie, testing, provider awareness of HIV diagnosis, and linkage to care) in which the greatest opportunities for intervention exist, if appropriate resources were allocated. This schema could serve as a model for other indolent treatable diseases frequently observed in EDs, where continuity of care is critical. PMID- 25720803 TI - Overexpression and activities of 1-Cys peroxiredoxin from Pseudomonas fluorescens GcM5-1A carried by pine wood nematode. AB - Peroxiredoxins (Prxs) are enzymatic antioxidants widely distributed in biological kingdoms, which constitute a family of heme-free peroxidases that reduce alkyl hydroperoxides and hydrogen peroxide. In this paper, an open reading frame (ORF) of 639 bp, which encoded a protein of 213 amino acid residues, was cloned from Pseudomonas fluorescens GcM5-1A carried by pine wood nematode. Amino acid sequence alignment showed that the encoded protein shared 99, 97, and 97 % identity with the thiol-specific antioxidant protein LsfA of P. fluorescens Q2 87, the peroxiredoxin of Pseudomonas sp. GM17 and 1-Cys peroxiredoxin of P. fluorescens Pf 0-1, respectively. The ORF was cloned into expressing vector pET 15b and introduced into Escherichia coli BL21 (DE3). Overexpression of a 27-kDa protein was achieved by IPTG induction. The recombinant protein was purified by affinity chromatography on a Ni(2+) matrix column. Non-reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicated that part of the recombinant appeared in dimer form. Bioassay results showed that purified recombinant protein had both peroxidase and thioredoxin activity. Furthermore, E. coli expressing the ORF showed tolerance to hydrogen peroxide stress, which indicated that the gene might help P. fluorescens GcM5-1A resist hydrogen peroxide generated by host pines after pine wood nematode associated with this bacterium infected pine trees. PMID- 25720804 TI - Effects of the angiotensin II Ala-scan analogs in erythrocytic cycle of Plasmodium falciparum (in vitro) and Plasmodium gallinaceum (ex vivo). AB - The anti-plasmodium activity of angiotensin II and its analogs have been described in different plasmodium species. Here we synthesized angiotensin II Ala scan analogs to verify peptide-parasite invasion preservation with residue replacements. The analogs were synthesized by 9-fluorenylmethoxycarbonyl (Fmoc) and tert-butyloxycarbonyl (t-Boc) solid phase methods, purified by liquid chromatography and characterized by mass spectrometry. The results obtained in Plasmodium falciparum assays indicated that all analogs presented some influence in parasite invasion, except [Ala(4)]-Ang II (18% of anti-plasmodium activity) that was not statistically different from control. Although [Ala(8)]-Ang II presented a lower biological activity (20%), it was statistically different from control. The most relevant finding was that [Ala(5)]-Ang II preserved activity (45%) relative to Ang II (47%). In the results of Plasmodium gallinaceum assays all analogs were not statistically different from control, except [Ala(6)]-Ang II, which was able to reduce the parasitemia about 49%. This approach provides insight for understanding the importance of each amino acid on the native Ang II sequence and provides a new direction for the design of potential chemotherapeutic agents without pressor activity. PMID- 25720805 TI - Assessment of cardiac angle in fetuses with congenital heart disease at risk of 22q11.2 deletion. AB - OBJECTIVES: To evaluate fetal cardiac angle as a screening tool for 22q11.2 deletion among cases with cardiac anomalies known to be associated with this genetic condition, to examine the correlation of fetal cardiac angle with thymic thoracic (TT)-ratio, and to assess the performance of TT ratio as a covariate in screening for 22q11.2 deletion. METHODS: This was a retrospective cohort study that reviewed the records of 74 cases with cardiac anomalies known to be associated with 22q11.2 deletion (tetralogy of Fallot, common arterial trunk, interrupted aortic arch and right aortic arch) that were diagnosed between 2007 and 2013. The karyotype was known in all cases. The fetal cardiac angle and TT ratio were measured using stored three-dimensional spatiotemporal image correlation volume datasets and compared in those with del.22q11.2 and those without. RESULTS: Of the 74 cases reviewed, 16 had 22q11.2 deletion. The mean cardiac angle was larger in the cases with 22q11.2 deletion than in those without (68.6 degrees vs 58.7 degrees , respectively; P = 0.02). Multivariate regression analysis showed an association between cardiac angle and TT-ratio in fetuses with 22q11.2 deletion (r(2) = 0.33; P = 0.02) but not in those with a normal karyotype (P = 0.4). Logistic regression analysis demonstrated that fetal cardiac angle, but not TT-ratio, is an independent predictor of 22q11.2 deletion among fetuses with 22q11.2 deletion-associated cardiac anomalies (P = 0.02; area under the receiver-operating characteristics curve = 0.69). CONCLUSIONS: An enlarged fetal cardiac angle is an independent predictor of 22q11.2 deletion among fetuses with 22q11.2 deletion-associated cardiac anomalies. However, its performance as a single variable in a screening model is not sufficient to guide management decisions regarding invasive testing. PMID- 25720806 TI - Wrapping in pancreatic surgery: a systematic review. AB - BACKGROUND: Wrapping in pancreatic surgery involves the use of the omentum or falciform ligament (FL) to wrap the local retroperitoneal vessels, the pancreatojejunal anastomosis or the pancreatic section of distal pancreatectomy. However, there is no clear evidence that wrapping in fact provides benefits. We have performed a systematic review of the literature about this topic. METHODS: We conducted a literature search in the PubMed/MEDLINE database (1966-2012) for any language using various combinations of the following terms: wrapping, omental, omentum, pancreas, pancreatoduodenectomy and falciform ligament. RESULTS: We selected 12 articles. Among five series that included a control group, only one obtained a statistically significant reduction in pancreatic fistula (PF) in the wrapping group and other series showed a lower percentage of post-operative haemorrhage in the wrapping group. In the seven series without control groups, a slight decrease in the rate of post-operative bleeding and PF was observed. CONCLUSIONS: On the basis of the literature available at present, we cannot recommend the use of wrapping with omentum and/or FL in pancreatic surgery. Prospective randomized studies applying a systematic wrapping technique are needed in order to establish whether its use should be generalized. PMID- 25720807 TI - Antimicrobial resistance of Escherichia coli isolates from canine urinary tract infections. AB - This study determined the antimicrobial resistance profiles of Escherichia coli isolates from dogs with a presumptive diagnosis of urinary tract infection (UTI). Urine samples from 201 dogs with UTI diagnosed through clinical examination and urinalysis were processed for isolation of Escherichia coli. Colonies from pure cultures were identified by biochemical reactions (n=114) and were tested for susceptibility to 18 antimicrobials. The two most frequent antimicrobials showing resistance in Urinary E. coli isolates were oxytetracycline and ampicillin. Among the resistant isolates, 17 resistance patterns were observed, with 12 patterns involving multidrug resistance (MDR). Of the 69 tetracycline-resistant E. coli isolates, tet(B) was the predominant resistance determinant and was detected in 50.9% of the isolates, whereas the remaining 25.5% isolates carried the tet(A) determinant. Most ampicillin and/or amoxicillin-resistant E. coli isolates carried blaTEM-1 genes. Class 1 integrons were prevalent (28.9%) and contained previously described gene cassettes that are implicated primarily in resistance to aminoglycosides and trimethoprim (dfrA1, dfrA17-aadA5). Of the 44 quinolone resistant E. coli isolates, 38 were resistant to nalidixic acid, and 6 were resistant to nalidixic acid, ciprofloxacin and enrofloxacin. Chromosomal point mutations were found in the GyrA (Ser83Leu) and ParC (Ser80Ile) genes. Furthermore, the aminoglycoside resistance gene aacC2, the chloramphenicol resistant gene cmlA and the florfenicol resistant gene floR were also identified. This study revealed an alarming rate of antimicrobial resistance among E. coli isolates from dogs with UTIs. PMID- 25720808 TI - Effects of pre-shipping marbofloxacin administration on fever and blood properties in healthy Thoroughbreds transported a long distance. AB - The present study evaluated the effects of single-dose marbofloxacin in protecting horses against fever associated with transportation using 48 healthy Thoroughbreds. All horses were premedicated with interferon-alpha (0.5 U/kg, sublingually, every 24 hr) for 2 days before transportation and on the day of transportation. Horses were randomly assigned to receive marbofloxacin (2 mg/kg, IV, once; MRFX group), enrofloxacin (5 mg/kg, IV, once; ERFX group) or saline (0.9% NaCl) solution (10 ml, IV, once; control group) <=1 hr before being transportation. Each group contained 16 horses (8 males, 8 females). Horses were transported 1,210 km using commercial vans over the course of approximately 26 hr. Clinical examinations and hematologic analyses were performed on all horses both before and after transportation. Post-transportation neutrophil to lymphocyte ratios were significantly lower in horses in the MRFX group compared with the control horses. The serum amyloid A levels were significantly lower in horses in the MRFX group and ERFX group compared with the control horses. Regarding the post-transportation rectal temperatures, fever was detected in 0 horses and 1 horse in the MRFX and ERFX groups, respectively, whereas fevers exceeding 39.1 degrees C were detected in 2 horses in the control group. Additionally, the number of essential post-transportation treatments provided by veterinarians was reduced 3-fold in the MRFX and ERFX groups compared with the saline group. MRFX provided ERFX-like protection against fever associated with long-distance transportation, yielding significantly better protection than saline. Administration of MRFX just before transportation deserves a further study for efficacy in preventing horse fever associated with transportation. PMID- 25720810 TI - Effect of arbuscular mycorrhizal inoculation on water status and photosynthesis of Populus cathayana males and females under water stress. AB - Drought is one of the most serious environmental limitations for poplar growth. Although the ways in which plants deal with water stress and the effects of arbuscular mycorrhizal (AM) formation have been well documented, little is known about how the male and female plants of Populus cathayana respond to drought and AM formation. We also aimed to investigate the potential role of AM fungi in maintaining gender balance. We tested the impact of drought and AM formation on water status and photosynthesis. The results suggested that both sexes showed similar responses to water stress: drought decreased the growth of stem length (GSL), growth of ground diameter (GGD), relative water content (RWC), increased the relative electrolyte leakage (REL), and limited the photosynthesis and chlorophyll fluorescence indexes. However, the responses of the two sexes to drought and AM formation differed to some extent. AM formation had positive effects on RWC, photosynthesis and the intrinsic water use efficiency (WUEi) but negative effects on the REL of males and females, especially under drought. AM formation enhanced the maximum quantum yield of photosystem II (PSII) (Fv/Fm), the actual quantum yield of PSII (PhiPSII), non-photochemical quenching (qN) and photochemical quenching (qP) under drought conditions, and had no significant effects under well-watered conditions except on the qP of males. Principal component analysis showed that males were significantly more drought tolerant than females, and AM formation enhanced drought tolerance, particularly among males, which suggested that AM fungi are beneficial for ecological stability and for P. cathayana survival under drought conditions. PMID- 25720809 TI - Informal coercion in psychiatry: a focus group study of attitudes and experiences of mental health professionals in ten countries. AB - PURPOSE: Whilst formal coercion in psychiatry is regulated by legislation, other interventions that are often referred to as informal coercion are less regulated. It remains unclear to what extent these interventions are, and how they are used, in mental healthcare. This paper aims to identify the attitudes and experiences of mental health professionals towards the use of informal coercion across countries with differing sociocultural contexts. METHOD: Focus groups with mental health professionals were conducted in ten countries with different sociocultural contexts (Canada, Chile, Croatia, Germany, Italy, Mexico, Norway, Spain, Sweden, United Kingdom). RESULTS: Five common themes were identified: (a) a belief that informal coercion is effective; (b) an often uncomfortable feeling using it; (c) an explicit as well as (d) implicit dissonance between attitudes and practice with wider use of informal coercion than is thought right in theory; (e) a link to principles of paternalism and responsibility versus respect for the patient's autonomy. CONCLUSIONS: A disapproval of informal coercion in theory is often overridden in practice. This dissonance occurs across different sociocultural contexts, tends to make professionals feel uneasy, and requires more debate and guidance. PMID- 25720811 TI - Influence of Maxillary Sinus Width on Transcrestal Sinus Augmentation Outcomes: Radiographic Evaluation Based on Cone Beam CT. AB - BACKGROUND: Maxillary sinus elevation is a predictable procedure to vertically enhance bone volume in the posterior maxilla for successful implant placement. It is speculated that graft bone resorption and remodeling which require angiogenesis may be affected by the dimensions of maxillary sinus cavity. PURPOSE: The aim of this study is to investigate the effect of sinus width (SW) on the outcomes of transcrestal sinus lift with simultaneous implant placement based on cone beam CT (CBCT). MATERIALS AND METHODS: A total of 57 elevated sites in 33 patients were included in this study. All the patients were treated with transcrestal sinus lift procedure associated with simultaneous implant placement using a composite graft material of autogenous bone and Bio-Oss. For each patient, CBCT scans were performed preoperatively, immediately after surgery and 6 months after surgery. Measurements of the linear parameters were conducted on the preoperative and postoperative CBCT images. The correlation of SW with graft resorption (GR) was analyzed using Pearson's correlation test with or without the classification of residual bone height. RESULTS: The average width of maxillary sinus was 13.68 +/- 2.66 mm. The mean height of apical graft bone decreased from 2.85 mm immediately after surgery to 1.38 mm after 6 months. A positive association between SW and GR (r = 0.323, p = .014) was found in general. CONCLUSION: The findings show that graft bone resorption in elevated sinus has a positive correlation with the SW. PMID- 25720812 TI - 3',4',7-Trihydroxyflavone prevents apoptotic cell death in neuronal cells from hydrogen peroxide-induced oxidative stress. AB - In this study, we investigated the mechanisms of 3',4',7-trihydroxyflavone (THF) protection of neuronal cells from neuronal cell death induced by the oxidative stress-related neurotoxin hydrogen peroxide (H2O2). Pretreatment with THF significantly elevated cell viability, reduced H2O2-induced lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production, glutathione (GSH) content, superoxide dismutase (SOD) activity, catalase (CAT) activity, and mitochondria membrane potential (MMP) loss. Western blot data demonstrated that THF inhibited the H2O2-induced up- or down-regulation of cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (PARP), Bax, Bcl-2, and Bcl xL, and attenuated the H2O2-induced release of cytochrome c from the mitochondria to the cytosol. In addition, pretreatment with THF attenuated H2O2-induced rapid and significant phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (MAPK), and phosphatidylinositol 3-kinases (PI3K)/Akt. THF also inhibited nuclear factor-kappaB (NF-kappaB) translocation to the nucleus induced by H2O2, down-stream of H2O2-induced phosphorylation of MAPKs and PI3K/Akt. These data provide the first evidence that THF protects neuronal cells against H2O2-induced oxidative stress, possibly through ROS reduction, mitochondria protection, and NF-kappaB modulation via MAPKs and PI3K/Akt pathways. The neuroprotective effects of THF make it a promising candidate as a therapeutic agent for neurodegenerative diseases. PMID- 25720813 TI - Effect of melamine toxicity on Tetrahymena thermophila proliferation and metallothionein expression. AB - Melamine is a raw material in the chemical industry. Because of its high nitrogen content, melamine has been utilized by unscrupulous businessmen as a food additive to enhance the indices of protein content in food and feed testing. Tetrahymena has long been used as an excellent model organism in toxicological studies. The purpose of the present study was to determine the effect of melamine on Tetrahymena. In the present study, the effects of melamine on the proliferation and mating rate of Tetrahymena were examined by microscopic counting of the cell numbers. The comet assay and DAPI nuclear staining were performed to analyze the changes in the Tetrahymena genome. Flow cytometric analysis was conducted to detect apoptosis. Furthermore, RT-PCR was performed to determine the changes in the expression of the metallothionein gene in Tetrahymena that underwent stress treatment with varying concentrations of melamine. The results indicated that melamine affected the proliferation and sexual reproduction of Tetrahymena. High melamine concentrations damaged the Tetrahymena genome to a certain extent and induced apoptosis in the organism. Expression of the metallothionein gene was upregulated in Tetrahymena exposed to melamine stress to ameliorate melamine-induced damage. These results indicated that melamine displayed significant toxicity to Tetrahymena cells. PMID- 25720814 TI - The temporal dynamics of cognitive reactivity and their association with the depression risk: an exploratory study. AB - BACKGROUND: Cognitive reactivity is the change in depressive thinking in response to negative mood. Previous research indicates that cognitive reactivity is an important variable in the etiology and course of depression. The present study tested which time interval after a negative mood induction is critical for the prediction of the depression risk. METHODS: Participants suffering from a major depressive disorder were recruited when entering inpatient treatment. At the end of inpatient treatment they completed an experimental procedure to assess their depressive thinking once before and twice after a negative mood induction. Subsequently, patients were followed up for 26 weeks. RESULTS: The immediate change in depressive thinking in response to the negative mood induction was negatively associated with future depression. The delayed change did not predict the depression risk. CONCLUSION: The negative association between the immediate change in depressive thinking and the depression risk is not in line with results from previous studies on cognitive reactivity. Previous research on emotion context insensitivity and the avoidance of negative thoughts offers hypotheses which could account for this result. Further research is needed to shed light on the processes underlying cognitive reactivity. PMID- 25720815 TI - A biocompatible porous Mg-gallate metal-organic framework as an antioxidant carrier. AB - A microporous magnesium gallate MOF was prepared from highly biocompatible reagents under environmentally friendly conditions. Its slow degradation in physiological fluids leads to the release of gallic acid and hence a high antioxidant activity, which was illustrated in the HL-60 cell line. PMID- 25720816 TI - Cross-reactivity of immunoglobulin A secreted on the nasal mucosa in mice nasally inoculated with inactivated H1N1 influenza A viruses in the presence of D octaarginine-linked polymers. AB - We evaluated cross-reactivity of immunoglobulin A (IgA) secreted on the nasal mucosa in mice that were nasally inoculated 4 times with a mixture of inactivated H1N1 influenza A viruses and poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing d-octaarginine at 7-day intervals. Three viral strains (A/Puerto Rico/8/34, A/New Caledonia/20/99 IVR116, and A/Solomon Islands/03/2006) and D octaarginine-linked polymers with different molecular weights were used as antigens and their carriers, respectively. Secretion of intranasal IgA was barely observed when the inactivated virus alone was administered. The polymer induced the production of intranasal IgA specific to the inoculated viruses, irrespective of the viral strain and molecular weight of the polymer. The respective antibodies cross-reacted to recombinant hemagglutinin proteins of not only the viral strain used for immunization but also other H1N1 strains, including A/Puerto Rico/8/34 strain whose hemagglutinin proteins are diverse from those of other strains. Mice with high reactivity of IgA to the inoculated viruses tended to acquire clear cross-reactivity to other viral strains. Notably, IgA induced by inactivated H1N1 A/New Caledonia/20/99 IVR116 strain with the strongest immunogenicity between 3 antigens in the presence of the polymer cross-reacted to recombinant hemagglutinin proteins of the A/Brisbane/10/2007 and A/Viet Nam/1194/2004 strains, which are categorized into H3N2 and H5N1, respectively. Our polymer is a potential candidate for an efficient antigen carrier that induces mucosal IgA having cross-reactivity to antigenically drifted variants, irrespective of the subtype of viral strains. PMID- 25720817 TI - Investigation of solubilising effects of bile salts on an active pharmaceutical ingredient with unusual pH dependent solubility by NMR spectroscopy. AB - The interaction between an ampholytic and amphiphilic Active Pharmaceutical Ingredient (API) showing unusual pH dependent solubility and Fasted State Simulated Intestinal Fluid (FaSSIF) was studied by NMR spectroscopy. Solubility in FaSSIF was drastically increased, about 30 fold, compared to simulated gastrointestinal fluid without bile salts. Our studies aimed at understanding the mechanisms that lead to this drastic enhancement. All species present in solution at various concentrations of API were characterised by Diffusion Ordered Spectroscopy (DOSY) NMR measurements. These indicated the presence of mixed taurocholate-lecithin and pure taurocholate micelles in pure FaSSIF, and formation of mixed taurocholate-API micelles after addition of API. The formation of taurocholate-API micelles was also supported by Nuclear Overhauser Effect/Enhancement (NOE) contacts between taurocholate and the API. Formation of mixed taurocholate-API micelles took place at the expense of pure taurocholate micelles, whereas mixed taurocholate-lecithin micelles remained uninfluenced by the presence of API. Our results showed that the increase in solubility was due to similar amphiphilic properties of the API and taurocholate which enabled formation of mixed taurocholate-API micelles. From results of determination of solubility as well as NMR experiments a phase diagram comprising several micellar species was derived. PMID- 25720818 TI - Loading amorphous Asarone in mesoporous silica SBA-15 through supercritical carbon dioxide technology to enhance dissolution and bioavailability. AB - The aim of this study was to load amorphous hydrophobic drug into ordered mesoporous silica (SBA-15) by supercritical carbon dioxide technology in order to improve the dissolution and bioavailability of the drug. Asarone was selected as a model drug due to its lipophilic character and poor bioavailability. In vitro dissolution and in vivo bioavailability of the obtained Asarone-SBA-15 were significantly improved as compared to the micronized crystalline drug. This study offers an effective, safe, and environmentally benign means of solving the problems relating to the solubility and bioavailability of hydrophobic molecules. PMID- 25720819 TI - The Nucleus Accumbens: A Comprehensive Review. AB - There is increasing interest among functional neurosurgeons in the potential for novel therapies to impact upon diseases beyond movement disorders and pain. A target of increasing interest is the nucleus accumbens (NAc), which has long been studied as a key brain region mediating a variety of behaviors, including reward and satisfaction. As such, focal modulation of the biology of the NAc with deep brain stimulation or novel biological therapies such as gene therapy or cell transplantation could have a major impact upon disorders such as depression and drug addiction. In order to both develop appropriate therapies and then deliver them in an effective fashion, a thorough understanding of the biology, physiology, and anatomy of the NAc is critical. Here, we review the existing literature regarding several areas critical to the development of new therapies, including the known pharmacology, physiology, and connectivity of the NAc, as well as evidence supporting the potential for various NAc surgical therapies in animal models. We then review the relevant anatomy of the NAc, with particular attention to the surgical anatomy, imaging, and targeting necessary to facilitate a proper localization and delivery of new agents to this region. The NAc is a fascinating and potentially rich target for stereotactic neurosurgical intervention, and analysis of existing information regarding all aspects of this structure should help potentiate therapeutic advances and reduce complications from future studies of neurosurgical intervention in this region for a variety of disorders. (c) 2015 S. Karger AG, Basel. PMID- 25720820 TI - Last drinks: A study of rural emergency department data collection to identify and target community alcohol-related violence. AB - OBJECTIVE: The present study summarises the methodology and findings of a pilot project designed to measure the sources and locations of alcohol-related harm by implementing anonymised 'last drinks' questions in the ED of a rural community. METHODS: 'Last drinks' questions were added to computerised triage systems at South West Healthcare ED in rural Warrnambool, Victoria, from 1 November 2013 to 3 July 2014. For all injury presentations aged 15 years or older, attendees were asked whether alcohol was consumed in the 12 h prior to injury, how many standard drinks were consumed, where they purchased most of the alcohol and where they consumed the last alcoholic drink. RESULTS: From 3692 injury attendances, 10.8% (n = 399) reported consuming alcohol in the 12 h prior to injury. 'Last drinks' data collection was 100% complete for participants who reported alcohol use prior to injury. Approximately two-thirds (60.2%) of all alcohol-related presentations had purchased their alcohol at packaged liquor outlets. During high-alcohol hours, alcohol-related injuries accounted for 36.1% (n = 101) of all ED injury presentations, and in total 41.7% of alcohol-related attendances during these hours reported consuming last drinks at identifiable hotels, bars, nightclubs or restaurants, or identifiable public areas/events. CONCLUSIONS: This pilot demonstrates the feasibility and reliability of implementing sustainable 'last drinks' data collection methods in the ED, and the ability to effectively map the source of alcohol-related ED attendances in a rural community. PMID- 25720821 TI - N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration. AB - Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291>128) is easily separable from DETC-NAC (MIM: 263>100) on C18 RP media with a methanol gradient. The method's linear range is 0.5-500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250 mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95 105) is discussed. PMID- 25720822 TI - Ultra-trace analysis of 12 beta2-agonists in pork, beef, mutton and chicken by ultrahigh-performance liquid-chromatography-quadrupole-orbitrap tandem mass spectrometry. AB - This paper presents an application of ultrahigh-performance liquid-chromatography - quadrupole - orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) for the ultra-trace analysis of 12 beta2-agonists in pork, beef, mutton and chicken meat. The mass spectrometer was operated in Full MS/dd-MS(2) (data dependent MS(2)) mode, under which a Full MS scan was followed by a dd-MS(2) scan with a fragmentation energy. The quantification was achieved using matrix-matched standard calibration curves with salbutamol-d3 and clenbuterol-d9 as the internal standards. The method validation included assessment of selectivity, sensitivity, calibration curve, accuracy, precision, recovery, matrix effect and stability. The results show an exceptional linear relationship with the concentrations of the analytes over wide concentration ranges (e.g., 0.01-50 MUg/kg for clenbuterol) as all the fitting coefficients of determination r(2) are >0.9986. The detection limits (LODs) were in the range of 0.0033-0.01 MUg/kg, which was much lower than the current reported methods. The recoveries were able to reach 73.0-88.7%, while the matrix effects ranged from 83.7% to 92.8%. Analysis of 400 pork, beef, mutton and chicken samples reveal that only 4.25% samples were positive for beta2-agonists. The detected beta2-agonists involved salbutamol, clenbuterol, ractopamine and clorprenaline. Overall, the novel Q-Orbitrap technique was demonstrated to have great performance for the screening, identification and quantification of ultra-trace beta2-agonists used in food animal muscles, which helps to ensure food safety and public health. PMID- 25720823 TI - Nitric oxide synthase inhibition abolishes exercise-mediated protection against isoproterenol-induced cardiac hypertrophy in female mice. AB - OBJECTIVE: Exercise training (ET) provides a cardioprotective effect against pathological cardiac hypertrophy. Nitric oxide (NO) plays an important role in modulating cardiac hypertrophy. However, few studies explore the relationship between NO signaling and the inhibitory effect of ET on pathological cardiac remodeling. METHODS: In this study, we evaluated ET effects on isoproterenol (ISO)-induced cardiac hypertrophy in female mice. Moreover, L-NAME (Nomega-nitro L-arginine methyl ester), a nonselective NO synthase (NOS) inhibitor, was used to assess the involvement of NO signaling in cardiac hypertrophy. Morphological and echocardiographic variables were assessed. Cardiac hypertrophy-related gene expression was detected by real-time PCR and the protein levels of NOS signaling molecules were determined by Western blot. RESULTS: L-NAME treatment prevented the beneficial effects of ET against the increase in heart weight (HW)/body weight (BW), HW/tibia length and lung weight/BW and echocardiographic variables following ISO injection. Also, L-NAME co-administration reversed ET-induced inhibition of myocardial fibrosis and fetal gene reactivation in ISO-treated mice. Furthermore, L-NAME treatment prevented ET-mediated up-regulation of phosphorylated endothelial NOS and plasma NO in ISO-treated mice. CONCLUSIONS: Our findings demonstrate that L-NAME treatment could abolish ET-induced cardioprotection against pathological cardiac hypertrophy and that NOS modulation may be involved in the antihypertrophic effects induced by ET. PMID- 25720824 TI - Application of HPLC mixed-mode chromatography in determining radiochemical purity of [(14) C] labeled metformin hydrochloride. AB - Metformin is currently prescribed worldwide to treat type 2 diabetes, and therefore, radiolabeled [(14) C] metformin is often prepared for clinical comparisons of new drug candidates. Prior to using the radiolabeled metformin, the purity needs to be determined to ensure the quality of the material. While typical reversed-phase LC methods are often the first choice for purity analysis, they are not suitable for this determination because the compound is poorly retained under these conditions. Mixed-mode chromatography has been demonstrated to overcome these retention issues, and therefore, this methodology was utilized for the purity determination of radiolabeled metformin. PMID- 25720825 TI - The European journal of epidemiology and the European epidemiology Federation. PMID- 25720826 TI - Intravitreal combination of dexamethasone sodium phosphate and bevacizumab in the treatment of exudative AMD. AB - The purpose of this study is to investigate the efficacy and safety of intravitreal dexamethasone sodium phosphate (DSP) combined with bevacizumab for the treatment of neovascular age-related macular degeneration (AMD). In this non comparative case study, 30 eyes of 27 patients with CNV due to AMD received intravitreal DSP (0.2 mg) and bevacizumab (1.25 mg) during a 6-month PRN (pro re nata) dosing regimen. Visual acuity, macular thickness and intraocular pressure (IOP) were monitored and recorded. After 6 months, mean retinal thickness decreased from 423.5 +/- 75.3 to 228.2 +/- 34.5 and mean visual acuity improved from 0.9 +/- 0.39 logMAR to 0.53 +/- 0.34 (p = 0.001) logMAR. During the trial period, 81 intravitreal injections were performed in 30 eyes, thus the mean number of injections per eye was 2.7 +/- 1.1. 86.7% of the eyes required 3 or less injections while only 13.3% needed 4 or more injections. None of the patients, phakic or pseudophakic, manifested an elevation of IOP during the treatment, ranging between 12 and 22 mmHg. Combined DSP and bevacizumab offers encouraging results in the challenge of AMD treatment, providing immediate response of macular edema, reduced number of intravitreal injections and stabilization or improvement of visual acuity. PMID- 25720827 TI - Association of anti-RNA polymerase III antibody and malignancy in Japanese patients with systemic sclerosis. AB - Patients with systemic sclerosis (SSc) have an increased risk of malignancy compared with the general population. Recently, SSc patients with anti-RNA polymerase III antibody have been reported to have an increased risk of malignancy as compared with those with other disease-specific autoantibodies in US, European and Australian populations. Therefore, we studied the relationship between disease-specific autoantibodies and malignancy in 261 Japanese SSc patients. The prevalence of malignancy was significantly higher in patients with anti-RNA polymerase III antibody (7/22, 31.8%) than in those with anti topoisomerase I antibody (2/82, 2.4%) and in those with anticentromere antibody (8/137, 5.8%). Importantly, among seven patients with anti-RNA polymerase III antibody and malignancy, three patients (42.9%) developed malignancy from 6 months before to 12 months after SSc onset. Thus, malignancy complication in Japanese SSc patients with anti-RNA polymerase III antibody is as high as that in other races, suggesting that SSc patients with anti-RNA polymerase III antibody share the same pathological process among different ethnic groups. PMID- 25720828 TI - Microimaging of transient concentration profiles of reactant and product molecules during catalytic conversion in nanoporous materials. AB - Microimaging by IR microscopy is applied to the recording of the evolution of the concentration profiles of reactant and product molecules during catalytic reaction, notably during the hydrogenation of benzene to cyclohexane by nickel dispersed within a nanoporous glass. Being defined as the ratio between the reaction rate in the presence of and without diffusion limitation, the effectiveness factors of catalytic reactions were previously determined by deliberately varying the extent of transport limitation by changing a suitably chosen system parameter, such as the particle size and by comparison of the respective reaction rates. With the novel options of microimaging, effectiveness factors become accessible in a single measurement by simply monitoring the distribution of the reactant molecules over the catalyst particles. PMID- 25720830 TI - Exploration of DNA binding mode, chemical nuclease, cytotoxic and apoptotic potentials of diketone based oxovanadium(IV) complexes. AB - Two diketone based oxovanadium complexes, viz., bis(4,4,4-trifluoro-1 phenylbutane-1,3-dionato)oxovanadium(IV) (1) and bis(1,1,1-trifluoropentane-2,4 dionato)oxovanadium(IV) (2), have been synthesized and characterized by spectroscopic and analytical techniques. The DNA binding and the cleaving ability of the complexes is assessed by UV-vis spectroscopy, fluorescence spectroscopy, viscometry and gel electrophoretic studies. The DNA binding constant values (Kb) are found to be 1.95 +/- 0.16 * 10(3)M(-1) for complex 1 and 1.064 +/- 0.17 * 10(3)M(-1) for complex 2, respectively. Based on the results of the spectral and viscosity studies, it is observed that the complexes, interestingly, have preferred minor groove binding with DNA. Further, the concentration-dependent oxidative cleavage pattern of pBR322 in the presence of the activating reagent, hydrogen peroxide, has also been discussed. In addition, the complexes have shown moderate cytotoxic activity by inducing apoptosis against the cervical cancer cell line, HeLa. The results of in silico analysis and logP predictions are found to be in good agreement with the experimental observations. Thus, synthesized oxovanadium complexes have displayed promising DNA binding behavior and DNA cleavage activity with moderately cytotoxic nature. PMID- 25720829 TI - C3 Polymorphism Influences Circulating Levels of C3, ASP and Lipids in Schizophrenic Patients. AB - Excessive activation of complement is associated with many diseases including schizophrenia. Investigation of C3 polymorphisms, circulating C3, cleavage product ASP/C3adesArg, and lipid metabolism. Cross-sectional analysis. C3 genotyping (CC vs GG for R102L) was performed on 434 Tunisian people consisting of 272 schizophrenic (SZ) patients and 162 control subjects. In a age- and gender matched subgroups of the three genotypes (131 SZ and 112 NOR), plasma triglycerides, total cholesterol (C), LDL-C, HDL-C, ASP, and complement C3 were measured. C3 gene polymorphism influences BMI and plasma C3, ASP, triglyceride, total cholesterol, LDL-C and HDL-C among SZ patients (p < 0.05-0.0001), with increasing values demonstrated from CC (common form) to CG (heterozygote form) to GG (rare homozygote) forms. Significant correlations between plasma C3 and BMI, triglyceride, HDL-C and ASP (p < 0.05-0.0001) were observed, while ASP correlated with BMI and LDL-C (p = 0.005, p = 0.001, respectively) in SZ patients. Further, proportional conversion of C3 to ASP (%ASP/C3) also increased (p < 0.0001, GG>CG>CC). C3 polymorphisms and plasma C3, ASP and %ASP/C3 correlated with lipid parameters in this SZ population, suggesting that factors predisposing patients to schizophrenia are permissive for complement pathway activation and dyslipidemic influences. PMID- 25720831 TI - Interaction of alphaA-crystallin F71L mutant with wild type alphaA- and alphaB crystallins by mammalian two hybrid assay. AB - Incidence of age related cataract (ARC) increases by a variety of factors including metabolic and environmental factors. Nonetheless, genetic mutations are responsible for the altered structural stability of the proteins, especially; the F71L mutation in alphaA-crystallin has been shown to be responsible for the incidence of cataracts. However, structural characteristics and chaperone function of this mutant and its interaction with wild type (WT) crystallins may aid to decipher its role in cataractogenesis. The aim of the present study is to show the interaction of F71L mutant protein with the WT alpha-crystallins. The F71L mutant used in this study was created by site-directed mutagenesis, overexpressed and purified. Biophysical characteristics determined by size exclusion HPLC, DLS, CD spectrometry, tryptophan fluorescence and surface hydrophobicity did not show significant structural changes in the mutant protein compared to WT counterpart. Interestingly, the F71L mutant displayed a significant loss in homogenous interaction with WT alphaA-crystallin and F71L mutant as well as heterogeneous interaction with alphaB-crystallin as evaluated by mammalian two hybrid system. Our findings suggest that F71L loses the ability to form homo and hetero-oligomers seems to result in the loss in chaperone like activity (CLA) and refractive index resulting in the development of cataracts. PMID- 25720832 TI - Alginate beads of Captopril using galactomannan containing Senna tora gum, guar gum and locust bean gum. AB - Gastro-retentive Captopril loaded alginate beads were prepared by an ionotropic gelation method using sodium alginate in combination with natural gums containing galactomannans (Senna tora seed gum, guar gum and locust bean gum) in the presence of calcium chloride. The process variables such as concentration of sodium alginate/natural polymer, concentration of calcium chloride, curing time, stirring speed and drying condition were optimized. Prepared beads were evaluated for various parameters such as flow property, drug content and entrapment efficiency, size and shape, and swelling index. Surface morphology of the beads was studied using scanning electron microscopy. In vitro mucoadhesion and in vitro drug release studies were carried out on the prepared beads. From the entrapment efficiency and dissolution study, it was concluded that galactomannans in combination with sodium alginate show sustained release property. The bead formulation F4 prepared using combination of sodium alginate and guar gums in the ratio 2:1 showed satisfactory sustained release for 12h. The release of Captopril from the prepared beads was found to be controlled by the swelling of the polymer followed by drug diffusion through the swelled polymer and slow erosion of the beads. PMID- 25720833 TI - Identification and characterization of an ABA-activated MAP kinase cascade in Arabidopsis thaliana. AB - Abscisic acid (ABA) is a major phytohormone involved in important stress-related and developmental plant processes. Recent phosphoproteomic analyses revealed a large set of ABA-triggered phosphoproteins as putative mitogen-activated protein kinase (MAPK) targets, although the evidence for MAPKs involved in ABA signalling is still scarce. Here, we identified and reconstituted in vivo a complete ABA activated MAPK cascade, composed of the MAP3Ks MAP3K17/18, the MAP2K MKK3 and the four C group MAPKs MPK1/2/7/14. In planta, we show that ABA activation of MPK7 is blocked in mkk3-1 and map3k17mapk3k18 plants. Coherently, both mutants exhibit hypersensitivity to ABA and altered expression of a set of ABA-dependent genes. A genetic analysis further reveals that this MAPK cascade is activated by the PYR/PYL/RCAR-SnRK2-PP2C ABA core signalling module through protein synthesis of the MAP3Ks, unveiling an atypical mechanism for MAPK activation in eukaryotes. Our work provides evidence for a role of an ABA-induced MAPK pathway in plant stress signalling. PMID- 25720834 TI - Unroofing hepatectomy: a facilitating approach for resection of deep-seated hepatocellular carcinoma adjacent to major intrahepatic vessels in cirrhotic patients. AB - BACKGROUND AND OBJECTIVES: Unroofing hepatectomy, an alternative approach to remove a deep-seated hepatocellular carcinoma (HCC) adjacent to major intrahepatic vessels by peel-off technique after sacrificing the overlying noncancerous liver, may result in tumor exposure without resection margin. The aim of the study was to examine the value of this approach in cirrhotic patients. METHODS: Between 1998 and 2012, 51 cirrhotic patients underwent unroofing hepatectomy for deep-seated newly-diagnosed HCC adjacent to major intrahepatic vessels (group A). Another 274 cirrhotic patients with similar tumor size and without gross major vessel involvement in the same period were selected as the control cohort (group B). The patients' clinicopathological characteristics, the early and long-term outcomes of the two groups were compared. RESULTS: The HCCs in group A had a significantly higher rate of tumor encapsulation, smaller number of associated satellite nodules, and smaller amount of resected liver weight. Postoperative complication and 90-day mortality rates were similar, but group A patients had a significant better 5-year disease-free (56% vs. 32%, P = 0.011) and overall survival rates (82% vs. 53%, P = 0.008). CONCLUSIONS: In selected cirrhotic patients, unroofing hepatectomy facilitates resection of deep-seated HCC adjacent to major intrahepatic vessels with acceptable early and long-term results. PMID- 25720835 TI - Synthesis of nickel-iron hydrogenase in Cupriavidus metallidurans is controlled by metal-dependent silencing and un-silencing of genomic islands. AB - Cupriavidus metallidurans CH34 is able to grow autotrophically as a hydrogen oxidizing bacterium and produces nickel-dependent hydrogenases, even under heterotrophic conditions. Loss of its two native plasmids resulted in inability of the resulting strain AE104 to synthesize the hydrogenases and to grow autotrophically in phosphate-poor, Tris-buffered mineral salts medium (TMM). Three of eleven previously identified catabolic genomic islands (CMGIs; Van Houdt et al., 2009), two of which harbor the genes for the membrane-bound (CMGI-2) and the soluble hydrogenase (CMGI-3), were silenced in strain AE104 when cultivated in phosphate-poor TMM, explaining its inability to produce hydrogenases. Production of the soluble hydrogenase from the aut region 1 of CMGI-3, and concomitant autotrophic growth, was recovered when the gene for the zinc importer ZupT was deleted in strain AE104. The transcriptome of the DeltazupT mutant exhibited two up-regulated gene regions compared to its parent strain AE104. Expression of the genes in the aut region 1 increased independently of the presence of added zinc. A second gene region was expressed only under metal starvation conditions. This region encoded a TonB-dependent outer membrane protein, a putative metal chaperone plus paralogs of essential zinc-dependent proteins, indicating the presence of a zinc allocation pathway in C. metallidurans. Thus, expression of the genes for the soluble hydrogenase and the Calvin cycle enzymes on aut region 1 of CMGI-3 of C. metallidurans is under global control and needs efficient ZupT-dependent zinc allocation for a regulatory role, which might be discrimination of nickel. PMID- 25720836 TI - Distinct conditions support a novel classification for bradykinin-mediated angio oedema. AB - BACKGROUND: Angio-oedema (AO) can be attributable to bradykinin (BK) accumulation, as is the case for prototypical hereditary AO (HAO) due to C1 inhibitor (C1-INH) deficiency. However, our clinical experience in a reference centre has shown that some patients display a clinical history suggestive of HAO, but exhibit normal C1-INH function, have no mutation in the causative genes associated with HAO (SERPING1, F12), and report no intake of drugs known to promote AO. OBJECTIVE: We sought to determine the frequency and distribution of different AO subtypes suspected to be BK-mediated AO (BK-AO) and defined by clinical, history and biological criteria (enzyme activities implicated in BK formation and catabolism). METHODS: The files of all patients referred to our centre for suspected BK-AO were retrospectively analysed. RESULTS: The distribution of patients (n = 162) was 16 and 4% with a hereditary deficiency of C1-INH or a gain of factor XII function, respectively, 29% with iatrogenic BK-AO, 21% with non-iatrogenic defective kininase activity and 30% with idiopathic increased kinin formation. CONCLUSION: BK-AO may be caused by multiple inherited or acquired factors triggering BK accumulation. Therefore, we propose a novel typology for BK-AO based on the imbalance of production/catabolism of BK. PMID- 25720837 TI - Treponema pallidum haemagglutination assay serum titres as a predictor of cerebrospinal fluid abnormalities in patients with syphilis. PMID- 25720838 TI - Glaucoma morphologic damage estimated from functional tests. AB - PURPOSE: To compare direct morphologic measurements with the ones deduced from functional tests. METHODS: A total of 111 normal eyes (examined twice) and 112 consecutive eyes with suspected or confirmed glaucoma were analyzed using Spark strategy (Oculus Easyfield Perimeter) and Cirrus optical coherence tomography (OCT). The threshold values were used to deduce the thickness of the retinal nerve fiber layer (RNFL) in 25 sectors. They were also used to derive a normalized value of the neuroretinal rim area, correcting the influence of the optic disc area size, and expressing the result as a percentage of their normal average relation. RESULTS: The correlation between the deduced and the measured RNFL thicknesses were r = 0.77 (p<0.001, standard error [SE] = 15.4 um in normal and 15.1 um in glaucomatous eyes) in the sector to sector comparison, and r = 0.80 (p<0.000001, SE = 10.0 um in normal and 10.4 um in glaucomatous eyes) for the average thickness. In normal subjects, the SE of deducing a second OCT result from the previous one was 13.2 um in the sector by sector analysis and 4.6 um for average thickness. The correlation between the deduced and measured rim area was r = 0.87 (p<0.000001, SE = 6.7% in normal and 15.9% in glaucomatous eyes). Receiver operating characteristic analysis yielded the following areas, sensitivities, and specificities: measured thickness: 0.89, 75.5%, 91.5%; deduced thickness: 0.91, 86.5%, 93.4%; measured rim area: 0.96, 89.2%, 95.3%; deduced rim area: 0.94, 82.9%, 96.2%. Additionally, the results in a new series of 71 normal and 68 glaucomatous eyes are verified. CONCLUSIONS: Spark perimetry allowed deducing glaucomatous morphologic alterations with significant accuracy. PMID- 25720839 TI - Malignant glaucoma-like syndrome after EX-PRESS filtration surgery. AB - PURPOSE: To report a case of postsurgical shallow anterior chamber and elevated intraocular pressure (IOP) simulating malignant glaucoma. METHODS: A 20-year-old woman underwent EX-PRESS(r) device implant for treatment of primary open-angle glaucoma. RESULTS: Postoperative examination showed a shallow anterior chamber, the EX-PRESS(r) device embedded in the iris, an IOP of 28 mm Hg, and an annular detachment of the choroid ciliary body, suggesting hyperfiltration followed by EX PRESS(r) blockage. The anterior chamber was restored using an ophthalmic viscoelastic and an additional suture was applied ensuring the scleral flap. The IOP progressively decreased in the following days and the anterior chamber remained deep and stable. New ocular ultrasonography showed complete resolution of the ciliary body detachment 15 days after surgery. CONCLUSIONS: After glaucoma surgery, not every patient with shallow anterior chamber and normal or high IOP necessarily has a ciliary block glaucoma. In our case, hyperfiltration led to choroidal expansion, shallow anterior chamber, obstruction of the EX-PRESS(r), and secondary blockage of outflow. The differential diagnosis is important in order to avoid further invasive procedures (i.e., lensectomy or vitrectomy). PMID- 25720840 TI - Pilot study of the influence of eyeliner cosmetics on the molecular structure of human meibum. AB - BACKGROUND/AIMS: It has been suggested that eye makeup could interact with human meibum causing a decrease in the stability of the tear film. The aim of this pilot study was to measure makeup-human meibum interactions in vitro. METHODS: Human meibum-makeup interactions were quantified by measuring order-to-disorder lipid phase transitions using infrared spectroscopy. RESULTS: Makeup products exhibited lipid phase transition temperatures that were much higher than those for meibum. One product increased the lipid phase transition temperature by 4.2 degrees C when combined with human meibum causing a large increase (from 30 to 49%) in the order of the meibum-lipid hydrocarbon chains and significantly decreased the minimum frequency, enthalpy and entropy of the phase transition of human meibum. Another eyeliner caused no significant (p < 0.05) change in the phase transition parameters of human meibum. CONCLUSION: Infrared spectroscopy may be used to measure interactions between human meibum and makeup. One makeup product increased the lipid order (viscosity) which could have adverse effects on tear film stability. Modern cosmetics are highly regulated and relatively safe to use; however, it could be beneficial to design makeup products that do not interact with meibum, especially since women have a higher prevalence of dry eye symptoms. PMID- 25720841 TI - Utilizing social media data for pharmacovigilance: A review. AB - OBJECTIVE: Automatic monitoring of Adverse Drug Reactions (ADRs), defined as adverse patient outcomes caused by medications, is a challenging research problem that is currently receiving significant attention from the medical informatics community. In recent years, user-posted data on social media, primarily due to its sheer volume, has become a useful resource for ADR monitoring. Research using social media data has progressed using various data sources and techniques, making it difficult to compare distinct systems and their performances. In this paper, we perform a methodical review to characterize the different approaches to ADR detection/extraction from social media, and their applicability to pharmacovigilance. In addition, we present a potential systematic pathway to ADR monitoring from social media. METHODS: We identified studies describing approaches for ADR detection from social media from the Medline, Embase, Scopus and Web of Science databases, and the Google Scholar search engine. Studies that met our inclusion criteria were those that attempted to extract ADR information posted by users on any publicly available social media platform. We categorized the studies according to different characteristics such as primary ADR detection approach, size of corpus, data source(s), availability, and evaluation criteria. RESULTS: Twenty-two studies met our inclusion criteria, with fifteen (68%) published within the last two years. However, publicly available annotated data is still scarce, and we found only six studies that made the annotations used publicly available, making system performance comparisons difficult. In terms of algorithms, supervised classification techniques to detect posts containing ADR mentions, and lexicon-based approaches for extraction of ADR mentions from texts have been the most popular. CONCLUSION: Our review suggests that interest in the utilization of the vast amounts of available social media data for ADR monitoring is increasing. In terms of sources, both health-related and general social media data have been used for ADR detection-while health-related sources tend to contain higher proportions of relevant data, the volume of data from general social media websites is significantly higher. There is still very limited amount of annotated data publicly available , and, as indicated by the promising results obtained by recent supervised learning approaches, there is a strong need to make such data available to the research community. PMID- 25720843 TI - Effects of Microtubule and Actin Inhibitors on Cryptococcus neoformans Examined by Scanning and Transmission Electron Microscopy. AB - BACKGROUND: Cryptococcus neoformans is one of the most important human fungal pathogens. Its cells contain rich microtubules required for nuclear division and rich F-actin cytoskeletons for cell division. Disruption of microtubules by a microtubule inhibitor should block nuclear division, and disruption of F-actin by an actin inhibitor should block cell division. We investigated the effects of microtubule and actin inhibitors to find out whether the cytoskeletons of C. neoformans can become a new anti-fungal target for the inhibition of cell division, when examined at the ultrastructural level. METHODS: Cells treated with the microtubule inhibitors vincristine (VIN) and methyl benzimidazole-2 ylcarbamate (BCM) and the actin inhibitor latrunculin A (LA), in yeast extract peptone dextrose medium, were examined by scanning (SEM) and transmission electron microscopy (TEM), and the cell number was counted using a Burker chamber. RESULTS: After 2 days of inhibition with VIN, BCM or LA, the cells did not divide, but later, resistant, proliferating cells appeared in all samples. With combined microtubule and actin inhibitors (VIN + LA or BCM + LA), cells did not divide during 6 or even 14 days, and no resistant cells originated. TEM showed that the inhibited cells were without cytoplasm and were dead; only empty cell walls persisted with reduced capsules, shown on SEM. CONCLUSION: Combined microtubule and actin inhibitors (VIN + LA or BCM + LA), have lethal effects on C. neoformans cells and no resistant cells originate. PMID- 25720842 TI - Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma. AB - The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients. PMID- 25720845 TI - Compatible interface design of CoO-based Li-O2 battery cathodes with long-cycling stability. AB - Lithium-oxygen batteries with high theoretical energy densities have great potential. Recent studies have focused on different cathode architecture design to address poor cycling performance, while the impact of interface stability on cathode side has been barely reported. In this study, we introduce CoO mesoporous spheres into cathode, where the growth of crystalline discharge products (Li2O2) is directly observed on the CoO surface from aberration-corrected STEM. This CoO based cathode demonstrates more than 300 discharge/charge cycles with excessive lithium anode. Under deep discharge/charge, CoO cathode exhibited superior cycle performance than that of Co3O4 with similar nanostructure. This improved cycle performance can be ascribed to a more favorable adsorption configuration of Li2O2 intermediates (LiO2) on CoO surface, which is demonstrated through DFT calculation. The favorable adsorption of LiO2 plays an important role in the enhanced cycle performance, which reduced the contact of LiO2 to carbon materials and further alleviated the side reactions during charge process. This compatible interface design may provide an effective approach in protecting carbon-based cathodes in metal-oxygen batteries. PMID- 25720844 TI - Differential gene expression in Staphylococcus aureus exposed to Orange II and Sudan III azo dyes. AB - We previously demonstrated the effects of azo dyes and their reduction metabolites on bacterial cell growth and cell viability. In this report, the effects of Orange II and Sudan III on gene expression profiling in Staphylococcus aureus ATCC BAA 1556 were analyzed using microarray and quantitative RT-PCR technology. Upon exposure to 6 MUg/ml Orange II for 18 h, 21 genes were found to be differently expressed. Among them, 8 and 13 genes were up- and down-regulated, respectively. Most proteins encoded by these differentially expressed genes involve stress response caused by drug metabolism, oxidation, and alkaline shock indicating that S. aureus could adapt to Orange II exposure through a balance between up and down regulated gene expression. Whereas, after exposure to 6 MUg/ml Sudan III for 18 h, 57 genes were differentially expressed. In which, 51 genes were up-regulated and 6 were down-regulated. Most proteins encoded by these differentially expressed genes involve in cell wall/membrane biogenesis and biosynthesis, nutrient uptake, transport and metabolite, and stress response, suggesting that Sudan III damages the bacterial cell wall or/and membrane due to binding of the dye. Further analysis indicated that all differentially expressed genes encoded membrane proteins were up-regulated and most of them serve as transporters. The result suggested that these genes might contribute to survival, persistence and growth in the presence of Sudan III. Only one gene msrA, which plays an important role in oxidative stress resistance, was found to be down regulated after exposure to both Orange II and Sudan III. The present results suggested that both these two azo dyes can cause stress in S. aureus and the response of the bacterium to the stress is mainly related to characteristics of the azo dyes. PMID- 25720846 TI - Simultaneous suppression of PCDD/F and NO(x) during municipal solid waste incineration. AB - Thiourea was tested as a dioxins inhibitor in a full-scale municipal solid waste incinerator with high capacity (34 t h(-1)). The suppressant, featuring a high S- and N-content, was converted into liquor and then injected (35 kg h(-1)) into the furnace (850 degrees C) through the inlets already used for Selective Non Catalytic Reduction (SNCR) of flue gas NOx. The first results show that thiourea reduces the dioxins in flue gas by 55.8 wt.%, those in fly ash by 90.3 wt.% and the total dioxins emission factor by 91.0 wt.%. The concentration of PCDD/Fs was 0.08 ng TEQ Nm(-3), below the national standard of 0.1 ng TEQ Nm(-3). The weight average chlorination degree of dioxins decreases slightly after adding the inhibitor, indicating that it suppresses both the formation and the chlorination of dioxins. Analysis of fly ash by scanning electron microscope (SEM) suggests that the particle size becomes larger after adding the inhibitor. Further analysis using an energy dispersive spectrometer (EDS) reveals that the sulphur content in fly ash rises, but the chlorine content declines when adding thiourea. These results suggest that poisoning the metal catalyst and blocking the chlorination are probably responsible for suppression. NOx reduction attains 42.6 wt.%. These tests are paving the way for further industrial application and assist in controlling the future emissions of dioxins and NOx from MSWI. PMID- 25720847 TI - Electromyographic analysis: shoulder muscle activity revisited. AB - INTRODUCTION: Restoring optimal strength and biomechanics of a pathologic shoulder knowledge of activity patterns of healthy glenohumeral muscles is mandatory. Yet, data on normal shoulder muscle activity are not always conclusive. The study was undertaken (a) to evaluate muscle activity patterns in the healthy shoulder using surface and fine-wire electromyography (EMG), and (b) to assess method's suitability in the clinical setting especially regarding painfulness and practicability. MATERIALS AND METHODS: Surface and fine-wire EMG was performed on 11 healthy subjects (2f/9 m, O age 28 years) to assess 14 muscles including rotator cuff muscles during 8 planar standardised shoulder movements (abduction, forward flexion, internal and external rotation in neutral, 45 degrees and 90 degrees abduction). Pain was assessed using the visual analogue scale before testing, after inserting the fine-wire electrodes, after maximal voluntary contraction, before and after exercises, and after electrode removal. RESULTS: The most important finding regarding EMG activity patterns in the healthy shoulder was that the subscapularis activity was found to play a major role in abduction and forward flexion. Furthermore, this study was able to show that EMG measurements, especially fine-wire EMG, is prone to high failure rates (up to 32%); however, pain was not a limiting factor. CONCLUSION: The present study (1) revealed a new insight, especially finding the subscapularis activity playing a major role in abduction and forward flexion of the healthy shoulder; and (2) motion analysis system and the use of fine-wire electrodes were prone to failure; however, pain was not a limiting factor. LEVEL OF EVIDENCE: Basic Science, Electrodiagnostic Study. PMID- 25720848 TI - The beneficial effect of Batroxobin on blood loss reduction in spinal fusion surgery: a prospective, randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: Our objective was to evaluate the efficacy and safety of Batroxobin on blood loss during spinal operations. METHODS: After obtaining approval from the ethics committee at the hospital along with informed written consent, we performed a double-blind, randomized, placebo-controlled study with 100 patients who were randomized equally into 2 groups (Batroxobin and placebo). Patients received either 2 ku IV 15 min before surgery and followed 1 ku IM of Batroxobin following surgery, or an equivalent volume of placebo (normal saline). Cost of Batroxobin treatment is amounted to 84.75 euros. The primary outcomes were intraoperative, 24 h postoperative, and total perioperative blood loss. Secondary outcomes were hemoglobin (Hb), red blood cell count (RBC), the volume of blood/fluid transfusion intraoperatively, and 24 h postoperatively. Safety evaluation parameters were the incidence of venous thrombosis in the lower extremities, active partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen. The data were analyzed using the Statistical Package for the Social Science Version 12.0. The results were presented as mean +/- SEM. The Mann Whitney test and Independent Student t test, when appropriate, were used to compare the 2 groups, and differences were considered significant if the P value was <0.05. RESULTS: 88 patients were included in the analysis while 12 patients were withdrawn from the study due to extended surgical duration, change of surgical procedure, or after the patients' request. The total perioperative blood loss was approximately 31% lower in patients given Batroxobin versus placebo (700.5 +/- 45.81 vs 485.7 +/- 30.01 mL, P = 0.001). The Batroxobin group had significantly less intraoperative blood loss (326.1 +/- 24.16) compared to the placebo group (556.0 +/- 43.58), but there was no difference in the amount of blood/fluid transfused, postoperatively Hb, or RBC between the two groups. After the operation, coagulation parameters were not significantly different between the 2 groups at the days 1 or 3 postoperatively. No adverse events related to the use of Batroxobin were recorded. There were no cases of superficial wound infection. None of the subjects died during the study. CONCLUSIONS: In this study, prophylactic use of Batroxobin provided an effective and cheap method for reducing blood loss without coagulopathy during or after operations. The use of Batroxobin for patients undergoing one-level PLIF surgery safely and effectively reduced the total amount of perioperative blood loss. PMID- 25720849 TI - Vitamin K antagonists predispose to calciphylaxis in patients with end-stage renal disease. AB - BACKGROUND/AIMS: Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis. METHODS: We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis. RESULTS: We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up. CONCLUSION: Treatment with VKA predisposes to the development of calciphylaxis. PMID- 25720850 TI - A Highly Sensitive and Reliable Strain Sensor Using a Hierarchical 3D and Ordered Network of Carbon Nanotubes. AB - A 3D network of single-walled carbon nanotubes embedded in poly (dimethylsiloxane) is presented as a promising route to the fabrication of a flexible film with ordered and interconnected single-walled carbon nanotubes. This is possible using a simple transfer method of as-grown hierarchical single walled carbon nanotubes on a Si pillar substrate. This film is used as a highly sensitive strain gauge sensor. This type of network embedded in a polymer film should be applicable to many fields involving mechanically stable and reliable strain sensors. PMID- 25720851 TI - In situ sensor technology for simultaneous spectrophotometric measurements of seawater total dissolved inorganic carbon and pH. AB - A new, in situ sensing system, Channelized Optical System (CHANOS), was recently developed to make high-resolution, simultaneous measurements of total dissolved inorganic carbon (DIC) and pH in seawater. Measurements made by this single, compact sensor can fully characterize the marine carbonate system. The system has a modular design to accommodate two independent, but similar measurement channels for DIC and pH. Both are based on spectrophotometric detection of hydrogen ion concentrations. The pH channel uses a flow-through, sample-indicator mixing design to achieve near instantaneous measurements. The DIC channel adapts a recently developed spectrophotometric method to achieve flow-through CO2 equilibration between an acidified sample and an indicator solution with a response time of only ~ 90 s. During laboratory and in situ testing, CHANOS achieved a precision of +/-0.0010 and +/- 2.5 MUmol kg(-1) for pH and DIC, respectively. In situ comparison tests indicated that the accuracies of the pH and DIC channels over a three-week time-series deployment were +/- 0.0024 and +/- 4.1 MUmol kg(-1), respectively. This study demonstrates that CHANOS can make in situ, climatology-quality measurements by measuring two desirable CO2 parameters, and is capable of resolving the CO2 system in dynamic marine environments. PMID- 25720852 TI - Dangerous liaisons? Gastroesophageal reflux disease and organizing pneumonia. PMID- 25720853 TI - Letter to the Editor on "Releasing of Tourniquet Before Wound Closure or Not in Total Knee Arthroplasty: A Meta-Analysis of Randomized Controlled Trials". PMID- 25720854 TI - Clinical Performance of the ASR and ReCap Resurfacing Implants-7 Years Follow-Up. AB - We perform a non-randomized, consecutive pilot study on the ASR and ReCap resurfacing hip implants and have completed 7 years follow-up. Forty-six non osteoporotic patients with hip osteoarthritis and anatomical conditions suitable for resurfacing were divided into 2 equal groups and operated sequentially, starting with the ASR implants. Sixteen patients operated with ASR and 19 patients with ReCap have been followed-up. There were no significant differences between the two groups preoperatively as to physical function, pain, or femoral BMD. The serum concentrations of cobalt and chromium were higher in the ASR group from 1/2 to 7 years postoperatively. Five of 16 ASR implants have been revised, and none of the ReCap implants. BMD below the femoral component increased in both groups. PMID- 25720855 TI - Early Outcomes of Titanium-Based Highly-Porous Acetabular Components in Revision Total Hip Arthroplasty. AB - Titanium-based highly-porous metal cups have been introduced as a relatively new alternative for enhanced acetabular fixation during revision THA; limited number of studies have evaluated its outcomes. We aimed to assess the clinical, functional, and patient-reported outcomes following the use of new generation highly-porous titanium acetabular implants in the revision setting. Seventy-one revisions were (1:1) matched to a conventional porous-coated cohort and were followed-up clinically and radiographically for at least 2-years. Non-significant differences in overall aseptic-survivorship were found across all types of acetabular defects comparing both cohorts (P=0.3). The overall HHS, UCLA, and SF 36 scores were similar between both cohorts. It remains to be seen if the great potential for enhanced osseointegration translates into improved long-term survivorship compared to conventional-porous devices. PMID- 25720856 TI - Discrete response patterns in the upper range of hypnotic suggestibility: A latent profile analysis. AB - High hypnotic suggestibility is a heterogeneous condition and there is accumulating evidence that highly suggestible individuals may be comprised of discrete subtypes with dissimilar cognitive and phenomenological profiles. This study applied latent profile analysis to response patterns on a diverse battery of difficult hypnotic suggestions in a sample of individuals in the upper range of hypnotic suggestibility. Comparisons among models indicated that a four-class model was optimal. One class was comprised of very highly suggestible (virtuoso) participants, two classes included highly suggestible participants who were alternately more responsive to inhibitory cognitive suggestions or posthypnotic amnesia suggestions, and the fourth class consisted primarily of medium suggestible participants. These results indicate that there are discrete response profiles in high hypnotic suggestibility. They further provide a number of insights regarding the optimization of hypnotic suggestibility measurement and have implications for the instrumental use of hypnosis for the modeling of different psychological conditions. PMID- 25720857 TI - Lower dorsal striatum activation in association with neuroticism during the acceptance of unfair offers. AB - Unfair treatment may evoke more negative emotions in individuals scoring higher on neuroticism, thereby possibly impacting their decision-making in these situations. To investigate the neural basis of social decision-making in these individuals, we examined interpersonal reactions to unfairness in the Ultimatum Game (UG). We measured brain activation with fMRI in 120 participants selected based on their neuroticism score, while they made decisions to accept or reject proposals that were either fair or unfair. The anterior insula and anterior cingulate cortex were more activated during the processing of unfair offers, consistent with prior UG studies. Furthermore, we found more activation in parietal and temporal regions for the two most common decisions (fair accept and unfair reject), involving areas related to perceptual decision-making. Conversely, during the decision to accept unfair offers, individuals recruited more frontal regions previously associated with decision-making and the implementation of reappraisal in the UG. High compared to low neurotic individuals did not show differential activation patterns during the proposal of unfair offers; however, they did show lower activation in the right dorsal striatum (putamen) during the acceptance of unfair offers. This brain region has been involved in the formation of stimulus-action-reward associations and motivation/arousal. In conclusion, the findings suggest that both high and low neurotic individuals recruit brain regions signaling social norm violations in response to unfair offers. However, when it comes to decision-making, it seems that neural circuitry related to reward and motivation is altered in individuals scoring higher on neuroticism, when accepting an unfair offer. PMID- 25720858 TI - An acute bout of exercise modulate the inflammatory response in peripheral blood mononuclear cells in healthy young men. AB - CONTEXT: Exercise increases the levels of circulating inflammatory mediators. OBJECTIVE: Does an acute bout of exercise affect the mRNA gene expression level of inflammatory markers in peripheral blood mononuclear cells (PBMCs) and contribute to the circulating levels of inflammatory mediators? MATERIALS AND METHODS: Ten healthy, non-smoking men (22-28 years old) performed 1-hour cycling at 70% of VO2 max. RESULTS: The gene transcripts of CXCL16, IL-1beta, IL-8, COX 2, TXB21 and GATA3 were significantly up-regulated in PBMCs. Serum levels of CXCL16, IL-6, TNFalpha and IL-10 were also significantly increased after exercise. DISCUSSION AND CONCLUSION: Increased mRNA transcription of inflammatory genes in PBMCs may contribute to increased level of inflammatory markers after an acute bout of exercise. The increased mRNA levels of GATA-3 and TXB21 may indicate that T cell lymphocytes are activated and secrete cytokines into the circulation. It needs to be further investigated if exercise changes the Th1/Th2 balance. PMID- 25720859 TI - The effects of two different exercise programmes on adipose tissue hormones in sedentary middle-aged women. AB - Adipokines play an important role in obesity and related inflammatory disorders. We aimed to determine the effects of exercise training on serum adipokines. Forty sedentary women were randomly assigned to two groups as aerobic (AE) and core exercise (CE). The exercise programmes were performed 4 days a week for 16 weeks. Blood samples were taken before and after the 8 and 16 weeks training period. Percent changes of each parameter were calculated. Sixteen weeks of exercise caused significant decrease in body weight and fat mass (p < 0.001), significant increase in adiponectin (16.1% in AE, 15.8% in CE group, p < 0.05) and resistin levels (21.1% in AE and 26.6% in CE group, p < 0.05) but had no effect on leptin and ghrelin levels. Eight weeks of exercise had no effect on adipokines except leptin. These data suggest that both exercise programmes have improving effects on body composition, adiponectin and resistin levels. PMID- 25720860 TI - Ethanol up-regulates phenol sulfotransferase (SULT1A1) and hydroxysteroid sulfotransferase (SULT2A1) in rat liver and intestine. AB - Ethanol-consumption impairs physiological-efficiency/endurance, expedites senescence. Impaired-regulations of steroids/biomolecules link these processes. Steroids are catabolized by cytosolic-sulfotransferases (SULTs). Ethanol induction of eukaryotic-SULTs-expression is scanty. Plant (Brassica-napus) steroid-sulfotransferase; BNST3/BNST4 (gene/BNST) is highly ethanol-inducible (protein/mRNA). Resembling mammalian-SULTs catalytic-mechanism BNSTs show broad substrate-specificities (mammalian-steroids; estradiol/dehydroepiandrosterone/pregnanolone). Recently, ethanol-regulation of SULTs-expression is verified in rat liver/intestine/cultured human hepatocarcinoma (Hep-G2) cells at enzyme-activity/protein-expression (Western blot) level. Here, two week's ethanol ingestion by male rat significantly increased SULT2A1 in their liver/intestine (p < 0.05-p < 0.001) and phenol sulfotransferase (SULT1A1) in intestine (p < 0.001) at enzyme-activity/protein levels. In human cells, ethanol significantly (2-fold) increased hSULT1A1/hSULT1E (2-3 fold) protein expressions paralleling their enzymatic-activities (p < 0.05-p < 0.01). The earlier finding of alcohol-association to the physiological impairment may be corroborated by our present findings. Inductions of SULT expressions by ethanol have significant physiological/pharmacological consequences. PMID- 25720861 TI - 'Suicide tourism': creating misleading 'scientific' news. PMID- 25720862 TI - Oxidative Stress Is a Central Target for Physical Exercise Neuroprotection Against Pathological Brain Aging. AB - Physical exercise is suggested for preventing or delaying senescence and Alzheimer's disease (AD). We have examined its therapeutic value in the advanced stage of AD-like pathology in 3xTg-AD female mice through voluntary wheel running from 12 to 15 months of age. Mice submitted to exercise showed improved body fitness, immunorejuvenation, improvement of behavior and cognition, and reduced amyloid and tau pathology. Brain tissue analysis of aged 3xTg-AD mice showed high levels of oxidative damage. However, this damage was decreased by physical exercise through regulation of redox homeostasis. Network analyses showed that oxidative stress was a central event, which correlated with AD-like pathology and the AD-related behaviors of anxiety, apathy, and cognitive loss. This study corroborates the importance of redox mechanisms in the neuroprotective effect of physical exercise, and supports the theory of the crucial role of oxidative stress in the switch from normal brain aging to pathological aging and AD. PMID- 25720863 TI - Update on ultraviolet A and B radiation generated by the sun and artificial lamps and their effects on skin. AB - Solar radiation, especially ultraviolet A (UVA) and ultraviolet B (UVB), can cause damage to the human body, and exposure to the radiation may vary according to the geographical location, time of year and other factors. The effects of UVA and UVB radiation on organisms range from erythema formation, through tanning and reduced synthesis of macromolecules such as collagen and elastin, to carcinogenic DNA mutations. Some studies suggest that, in addition to the radiation emitted by the sun, artificial sources of radiation, such as commercial lamps, can also generate small amounts of UVA and UVB radiation. Depending on the source intensity and on the distance from the source, this radiation can be harmful to photosensitive individuals. In healthy subjects, the evidence on the danger of this radiation is still far from conclusive. PMID- 25720865 TI - Analysis of the conformational profiles of fenamates shows route towards novel, higher accuracy, force-fields for pharmaceuticals. AB - In traditional molecular mechanics force fields, intramolecular non-bonded interactions are modelled as intermolecular interactions, and the form of the torsion potential is based on the conformational profiles of small organic molecules. We investigate how a separate model for the intramolecular forces in pharmaceuticals could be more realistic by analysing the low barrier to rotation of the phenyl ring in the fenamates (substituted N-phenyl-aminobenzoic acids), that results in a wide range of observed angles in the numerous fenamate crystal structures. Although the conformational energy changes by significantly less than 10 kJ mol(-1) for a complete rotation of the phenyl ring for fenamic acid, the barrier is only small because of small correlated changes in the other bond and torsion angles. The maxima for conformations where the two aromatic rings approach coplanarity arise from steric repulsion, but the maxima when the two rings are approximately perpendicular arise from a combination of an electronic effect and intramolecular dispersion. Representing the ab initio conformational energy profiles as a cosine series alone is ineffective; however, combining a cos 2xi term to represent the electronic barrier with an intramolecular atom-atom exp 6 term for all atom pairs separated by three or more bonds (1-4 interactions) provides a very effective representation. Thus we propose a new, physically motivated, generic analytical model of conformational energy, which could be combined with an intermolecular model to form more accurate force-fields for modelling the condensed phases of pharmaceutical-like organic molecules. PMID- 25720866 TI - Research excellence in UK dentistry. PMID- 25720864 TI - Visceral, vascular, and wound complications following over 13,000 lateral interbody fusions: a survey study and literature review. AB - PURPOSE: Minimally invasive lateral interbody fusion (MIS-LIF) has become a popular less invasive treatment option for degenerative spinal disease, deformity, and trauma. While MIS-LIF offers several advantages over traditional anterior and posterior approaches, the procedure is not without risk. The purpose of this study was to evaluate the incidence of visceral, vascular, and wound complications following MIS-LIF performed by experienced surgeons. METHODS: A survey was conducted by experienced (more than 100 case experience) MIS-LIF surgeons active in the society of lateral access surgery (SOLAS) to collect data on wound infections and visceral and vascular injuries. Of 77 spine surgeons surveyed, 40 (52 %) responded, including 25 (63 %) orthopedic surgeons and 15 (38 %) neurosurgeons, with 20 % practicing at an academic institution and 80 % in community practice. RESULTS: Between 2003 and 2013, 13,004 patients were treated with MIS-LIF by the 40 surgeons who responded to the survey. Of those patients, 0.08 % experienced a visceral complication (bowel injury), 0.10 % experienced a vascular injury, 0.27 % experienced a superficial wound infection, and 0.14 % experienced a deep wound infection. CONCLUSION: The incidence of surgical site infections and vascular and visceral complications following MIS-LIF in this large series was low and compared favorably with rates for alternative interbody fusion approaches. Although technically demanding, MIS-LIF is a reproducible approach for interbody fusion with a low risk of vascular and visceral complications and infections. PMID- 25720867 TI - Need, demand and time. PMID- 25720868 TI - Dentist leadership: CDO: Vital Professional Adviser. PMID- 25720869 TI - Overproducing dentists. PMID- 25720870 TI - Dental education: oblivion risk. PMID- 25720871 TI - Body art: intraoral tattoos. PMID- 25720872 TI - Get off our backs. PMID- 25720873 TI - The dental police force. PMID- 25720874 TI - ARF hike: you cannot be serious. PMID- 25720875 TI - Pharmaceuticals: tetracyclines and periodontal disease. PMID- 25720876 TI - Residual neck lump. PMID- 25720877 TI - Vulcanite denture donated to museum. PMID- 25720878 TI - Which? Survey: should dentists clean up dental costs? PMID- 25720879 TI - New index aims to ensure consistent orthognathic care across the country. PMID- 25720880 TI - Sugar consumption must be reduced throughout life. PMID- 25720881 TI - Careers: a call to action for young dentists. PMID- 25720884 TI - Exploring the use of strategic frameworks in dental practice. AB - This paper explores the use of strategic frameworks in NHS and private dental practice. It reviews the policy context of dentistry and suggests the challenges in this context will require dental practices to prioritise understanding and engagement with a strategic approach. A strategic approach will be required in order to enhance and improve performance. Two specific strategic frameworks will be explored in terms of their relevance to NHS and private dental practice. PMID- 25720885 TI - Finding your first job as an associate in general dental practice. AB - The landscape of dentistry is changing at a rapid rate and nowhere is this more apparent than in the job market. Finding work as an associate GDP is more competitive and seems increasingly driven by large corporate practices and faceless recruitment agencies. There is a massive emphasis in vocational training (VT) and dental school on clinical training, and rightly so, however, practical advice on how to obtain an associate position and what to avoid when looking for work was a little thin on the ground as I finished my degree in 2011. In this article I have attempted to give some basic tips on how to find an associate general dental practice job, what to look for in a practice and basic pitfalls to avoid. I should know--within three years of graduating I had already worked in a variety of NHS and private settings in five different practices. PMID- 25720886 TI - The implications of substance misuse for intravenous conscious sedation practice. AB - Substance misuse is a major health concern in the United Kingdom, as the consequences for individuals are significant and may include multisystem organ damage. It is important for the dentist to know which patients are misusing substances as some pharmacological agents routinely used in dental practice may be contraindicated. The dentist should be aware of the range of clinical presentations that may arise from substance misuse and when suspected, a thorough drug history must be obtained. Patients may require special consideration and further investigations when planning elective procedures, particularly under intravenous conscious sedation. Therefore, management within a specialist centre and liaison with other health professionals may be indicated to ensure treatment is provided safely. PMID- 25720887 TI - Corrigendum. Practice article (BDJ 2014; 217: 679-684). Guidelines for management of sodium hypochlorite extrusion injuries. PMID- 25720892 TI - Summary of: Supporting dental registrants in difficulty. PMID- 25720893 TI - Summary of: Inter-rater agreement between children's self-reported and parents' proxy-reported dental anxiety. PMID- 25720894 TI - The healthcare system and the provision of oral healthcare in European Union member states. Part 1: Germany. AB - Germany is the largest member state of the EU, both in terms of population and number of dentists and dental team members, with 80.5 million inhabitants and 69,236 active dentists, 182,000 dental nurses and 54,000 dental technicians in 2012. General dental practitioners in private practice provide almost all oral healthcare under a health insurance scheme. The tradition of compulsory health insurance goes back to the nineteenth century when it was introduced by Bismarck. Today, the majority of the German population (86%) are members of a statutory sick fund which reimburses a legally prescribed standard oral healthcare package provided by dentists in contract with the health insurance system. A smaller number are privately insured. Access to oral healthcare is excellent and 80% of adults visited a dentist in 2013. Healthcare expenditure in Germany has long been considered high. This has led to several reforms in recent years. This paper outlines the system for the provision of oral healthcare in Germany and explains and discusses the latest changes. PMID- 25720909 TI - Learn to love complaints. AB - Good and ongoing communication promotes patient engagement and reduces serious complaints. This article and the associated session at the 2015 British Dental Conference &Exhibition will review how complaints arise and how they can be used to improve the services provided to patients. The article and session will also provide tips and techniques for responding to complaints and concerns in ways that minimise escalation. PMID- 25720910 TI - Henry Levison. PMID- 25720911 TI - John Davis. PMID- 25720912 TI - Supporting dental registrants in difficulty. AB - Over the past few years there has been a significant increase in the number of dentists and dental care professionals (registrants) having conditions placed on their practice either by the General Dental Council or NHS area teams. There are a number of reasons for this including the fact that patients complain more often, colleagues are now expected to alert the authorities if poor practice is detected and the demographics of the dental profession in the UK are changing. Steps have already been taken to prevent dentists getting into difficulty, such as the development of requirements for continued professional development by the GDC and past initiatives at a local level set up to assist dentist in difficulty. The regional offices of Health Education England and equivalent organisations in Wales and Scotland assist registrants in difficulty in meeting these conditions. Little published research has been carried out into this important service which has had to develop rapidly over the past few years. There is a need to investigate the current service, the views of those dental professionals being assisted and those providing the support to inform the further development of the service. This paper provides an introduction to a planned series of research papers reporting on our investigation into the service provided by HEE teams. PMID- 25720913 TI - Inter-rater agreement between children's self-reported and parents' proxy reported dental anxiety. AB - BACKGROUND: Healthcare professionals often rely on parents to provide accurate dental anxiety assessment for their children. To date no studies have reported on inter-rater agreement between children's self-reported and their parents'/guardians' proxy-reported dental anxiety in the UK. AIMS: To assess the frequency of self-reported dental anxiety in 7-16-year-old children and the inter rater agreement between children's self-reported and parent/guardian proxy reported dental anxiety for their children. METHODS: Data were collected prospectively from 7-16-year-old children and their parents/guardians attending two community dental clinics in Fife, Scotland (July 2012-January 2013). Dental anxiety was assessed using faces version of Modified Child Dental Anxiety Scale. Questionnaires were separately and independently completed by children and their accompanying parent or guardian. RESULTS: One hundred and thirty-two child parent/guardian pairs participated in this study. Children's self-reported dental anxiety was 18% (n=24, 95% CI 12-25). Inter-rater agreement between children and their parent/guardian was poor for dental filling (linear weighted kappa coefficient 0.17) and tooth extraction (0.20), whereas other questions had fair inter-rater agreement (0.21-0.34). Parents' proxy-reported assessments significantly failed to recognise dental anxiety in 46% (n=11) dentally anxious children (p=0.0004). CONCLUSION: Parent/guardian proxy-reported dental anxiety differs from children's self-reported dental anxiety suggesting children should be encouraged to self-report their dental anxiety. PMID- 25720914 TI - The contents of dental implant patient information leaflets available within the UK. AB - PURPOSE: Patient information leaflets are designed to provide easy to follow information summaries and first point of contact information about treatment options. This survey reviewed the content of dental implant patient information leaflets, produced by implant companies and available within the UK in 2011. METHODS: Dental implant companies in the UK were asked to provide samples of their patient information leaflets. The information within the leaflets was then summarised, including the quantity and the types of images used and whether the source of the information was given. Quantitative data was obtained on the amount of information provided, size of images and number of references. RESULTS: A response rate of 71% was obtained and 23 leaflets were studied. Great variation was found between the leaflets, with the word counts ranging from 88 to 5,434, and 44 different topics were identified. The majority of the images used were decorative, and none of the leaflets gave any reference to the sources of their information. Implant treatment was generally described in a positive way, with an emphasis on describing the treatment and the advantages. Much less information was given about the potential disadvantages and risks of complications or failure, including the relevance of periodontal disease or smoking. CONCLUSION: Implant patient information leaflets provided by dental implant companies should not be solely relied upon to provide patients with all the information they need to give informed consent to treatment. PMID- 25720915 TI - Impact of haematologic deficiencies on recurrent aphthous ulceration: a meta analysis. AB - BACKGROUND: Recurrent aphthous ulceration (RAU) is one of the most common oral mucosal diseases, some of which may be secondary to haematologic deficiencies. This meta-analysis aims to evaluate the association between haematologic deficiencies and RAU. MATERIALS AND METHODS: Case control studies were identified using a predefined search strategy that compared the difference in haematologic deficiencies between a RAU group and a control group. A meta-analysis was performed to estimate the combined odds ratios (ORs) and 95% confidence intervals (95% CIs) in a fixed-effects model and a random-effects model, as appropriate. RESULTS: In this meta-analysis, nine case control studies, including total 710 cases in RAU groups and 602 cases in control groups, were considered eligible for inclusion. Overall, the combined results based on all studies showed that the rate of haematinic deficiencies was significantly high in the RAU group (vitamin B12: OR=3.75, 95% CI: 2.38-5.94; folic acid: OR=7.55, 95% CI: 3.91-14.60; ferritin: OR=2.62, 95% CI: 1.69-4.06; and haemoglobin: OR=1.77, 95% CI: 1.12 2.80). CONCLUSION: This meta-analysis suggests that haematologic deficiencies could be a significant risk factor for RAU. Thus, screening and treating any haematologic deficiencies may play an important role in preventing the occurrence of RAU. PMID- 25720916 TI - Association between vitamin C intake and glioma risk: evidence from a meta analysis. AB - BACKGROUND: The field of quantifying the association between the intake of vitamin C and risk of glioma still has conflicts. Thus, we performed a comprehensive meta-analysis to test the hypothesis that a high intake of vitamin C may be a protective effect on glioma risk. METHODS: Pertinent studies were identified by a search in PubMed and Web of Knowledge up to June 2014. The random effect model was used to combine study-specific results. Publication bias was estimated using Begg' funnel plot and Egger's regression asymmetry test. RESULTS: Thirteen articles with 15 studies (2 cohort study and 13 case-control studies) involving 3,409 glioma cases about vitamin C intake and glioma risk were used in this meta-analysis. The combined relative risks (RRs) of glioma associated with vitamin C intake was 0.86 (95% CIs = 0.75-0.99). Overall, significant protective associations were also found in the American population (RRs = 0.85, 95% CIs = 0.73-0.98) and case-control studies (RRs = 0.80, 95% CIs = 0.69-0.93). No publication bias was found. CONCLUSIONS: Our analysis indicated that vitamin C intake might decrease the risk of glioma, especially among the Americans. PMID- 25720917 TI - Validation of a six second cycle test for the determination of peak power output. AB - The present study examined the agreement between peak power output during a standard Wingate anaerobic test (WAnT) and a six second 'all-out' test on a Wattbike Pro. Nine males (40.7 +/- 19.4 yrs, 1.76 +/- 0.03 cm, 82.11 +/- 8.9 kg) underwent three testing protocols on separate days. The protocols consisted 30 second WAnT (WAnT30), a modified WAnT over 6 seconds (WAnT6) and a 6 second peak power test (PPT6). PPT6 was correlated with WAnT30 (r = 0.9; p < 0.001) with a mean bias of 105 W. PPT6 correlated with WAnT6 (r = 0.95; p < 0.001) with a mean bias of 74 W. WAnT6 correlated with WAnT30 (r = 0.99; p < 0.001) with a mean bias of 31 W. There was no difference in time to peak power between any trial. PPT6 resulted in significantly greater power outputs than in WAnT30 and WAnT6 (p < 0.001). We conclude that PPT6 and WAnT6 are valid measures of peak power output compared with WAnT30. This identifies that PPT6 and WAnT6 as short duration 'all out' tests that have practical applications for researchers and coaches who wish to assess peak power output without the fatiguing effects associated with a standard WAnT. PMID- 25720918 TI - Acute neonatal respiratory distress caused by a lingual thyroid: the role of nasendoscopy and medical treatment. AB - BACKGROUND: A lingual thyroid is a known cause of oropharyngeal obstruction in the neonate. It can be asymptomatic, or present as stridor, dysphonia, dysphagia or dyspnoea with faltering growth. The therapeutic options include surgical resection. CASE REPORT: A 6-day-old female neonate, born at 36 weeks gestation, presented with stridulous breathing and poor feeding. Although the cause was initially thought to be laryngomalacia, nasendoscopy revealed a lingual thyroid. The baby had deranged thyroid function, as detected on neonatal screening, but this result was not available until a later date. Despite being symptomatic, the patient was managed medically; thyroxine therapy was associated with resolution of the respiratory symptoms. CONCLUSION: Nasendoscopy provides valuable information about an ectopic thyroid gland. Thyroid replacement therapy may help to suppress the size of the ectopic gland and ultimately prevent an unnecessary surgical procedure. PMID- 25720919 TI - A case report of two different skull base pathologies causing hearing loss in the same ear: vestibular schwannoma and superior semicircular canal dehiscence. AB - Vestibular schwannoma and superior semicircular canal dehiscence are both uncommon entities, especially when present in the same ear. Here we illustrate how both of these pathologies can be repaired through the same surgical exposure, of the middle cranial fossa, with complete preservation of the cochlear nerve function and relief of symptoms caused by canal dehiscence. PMID- 25720920 TI - Bilateral hearing impairment as the initial symptom of sympathetic ophthalmia. AB - IMPORTANCE: Sympathetic ophthalmia (SO), a rare bilateral panuveitis following penetrating ocular trauma or ocular surgery to one eye, shares a strikingly similar ocular pathology to that of Vogt-Koyanagi-Harada disease (VKH). Audiovestibular dysfunction is a major extraocular manifestation of VKH; however, to date, only a few cases of sympathetic ophthalmia associated with hearing loss have been reported from ophthalmologists, but not otolaryngologists. Accordingly, little is known about the audiovestibular findings in patients with SO. We herein present two cases of SO with preceding bilateral hearing loss. OBSERVATIONS: The patient in Case 1, an 80-year-old female, experienced acute bilateral hearing loss. Five days after the onset of hearing loss, she presented with sudden bilateral blurred vision. In Case 2, a 32-year-old female noticed acute bilateral hearing loss and also experienced acute bilateral blurred vision the subsequent day. Patient 1 had a history of a penetrating injury to the right eye 25 days before the onset of hearing loss, while patient 2 had previously undergone right vitreous surgery twice for the treatment of a myopic macular hole and retinal detachment 36 and 43 days prior to the current symptom onset. Both cases were diagnosed as SO based on ocular findings of bilateral panuveitis and the history of ocular insult. Patient 1 carried HLA-DR4, HLA-DR15, HLA-A33, HLA-A24, HLA-B44 and HLA-B52, and patient 2 carried HLA-DR4. Audiograms showed bilateral mild to moderate sensorineural hearing loss in both cases, with normal auditory brainstem responses and deteriorated distortion product otoacoustic emission amplitudes. In addition, the significant recruitment phenomenon observed in case 1 suggested a cochlear origin of the hearing loss. Both patients received corticosteroid therapy, and the cochlear signs and symptoms recovered within one month. CONCLUSIONS AND RELEVANCE: This is the first report to describe the comprehensive audiovestibular findings in patients with SO. In the present study, acute bilateral hearing loss developed a couple of days prior to the onset of bilateral visual loss and auditory examinations suggested a cochlear etiology in both cases. PMID- 25720921 TI - Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages. AB - The obligate intracellular protozoan parasite Toxoplasma gondii interferes with major histocompatibility complex class II antigen presentation to dampen host CD4(+) T cell responses. While it is known that T. gondii inhibits major histocompatibility complex class II gene transcription and expression in infected host cells, the mechanism of this host manipulation is unknown. Here, we show that soluble parasite proteins inhibit IFNgamma-induced expression of major histocompatibility complex class II on the surface of the infected cell in a dose dependent response that was abolished by protease treatment. Subcellular fractionation of T. gondii tachyzoites revealed that the major histocompatibility complex class II inhibitory activity co-partitioned with rhoptries and/or dense granules. However, parasite mutants deleted for single rhoptries or dense granules genes (ROP1, 4/7, 14, 16 and 18 or GRA 2-9 and 12 knock-out strains) retained the ability to inhibit expression of major histocompatibility complex class II. In addition, excreted/secreted antigens released by extracellular tachyzoites displayed immunomodulatory activity characterized by an inhibition of major histocompatibility complex class II expression, and reduced expression and release of TNFalpha by macrophages. Tandem MS analysis of parasite excreted/secreted antigens generated a list of T. gondii secreted proteins that may participate in major histocompatibility complex class II inhibition and the modulation of host immune functions. PMID- 25720922 TI - Assessment of Cesarean hysterotomy scar in non-pregnant women: reliability of transvaginal sonography with and without contrast enhancement. AB - OBJECTIVES: To determine intra- and interobserver reliability of evaluating the appearance and measurement of Cesarean hysterotomy scars using transvaginal ultrasound (TVS), with and without saline contrast sonohysterography (SCSH), in non-pregnant women. METHODS: Fifty-six women with one previous Cesarean delivery were examined by TVS, with and without contrast enhancement, 6-9 months after the Cesarean delivery. Two observers, blinded to their own and each other's measurements, evaluated the appearance of the hysterotomy scar and measured the myometrial thickness adjacent to the scar or scar defect (MTS). If a scar defect was noted, the remaining myometrial thickness over the defect (RMT) was measured. A scar defect was defined as large if RMT was <= 2.2 mm on conventional TVS and <= 2.5 mm when SCSH was performed. Intra- and interobserver reliability of conventional TVS and SCSH were assessed. RESULTS: Intraobserver reliability was good, with intraclass correlation coefficients (ICCs) of >= 0.97 for measurements of MTS and RMT on conventional TVS and SCSH. Interobserver ICCs for measurements obtained on SCSH were 0.85 (95% CI, 0.76-0.91) for MTS and 0.96 (95% CI, 0.93 0.98) for RMT, compared with 0.82 (95% CI, 0.72-0.89) for MTS and 0.87 (95% CI, 0.68-0.95) for RMT measured on conventional TVS. The kappa coefficient for measurements obtained on SCSH was 0.92, compared with 0.85 for conventional TVS. Intermethod ICC was 0.86 (95% CI, 0.78-0.92) for measurement of MTS and 0.89 (95% CI, 0.78-0.95) for measurement of RMT, with a kappa coefficient of 0.57. CONCLUSIONS: Measurement of RMT using SCSH is a reliable method for assessing Cesarean hysterotomy scars in non-pregnant women and can be used in clinical practice. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 25720923 TI - Results of a prospective multicenter trial of CTAG thoracic endograft. AB - OBJECTIVE: As thoracic aortic aneurysms (TAAs) are more frequently being treated with endografts, the anatomic challenges of the thoracic aorta have led to design modifications of endografts. The Conformable GORE TAG (CTAG) device (W. L. Gore & Associates, Flagstaff, Ariz) was specifically designed to be more conformable in tortuous anatomy, more resistant to compression, and more accommodating to various aortic diameters compared with the original GORE TAG device. This prospective, multicenter study evaluated the safety and effectiveness of the CTAG endograft in the repair of descending TAA. METHODS: This was a prospective, multicenter regulatory study with a primary end point of freedom from major device event through 1 month after treatment. Two-year outcomes included aneurysm related morbidity (endoleaks and morphology changes), aneurysm-related mortality, and all-cause mortality. RESULTS: Fifty-one patients were enrolled between October 2009 and October 2010, with at least one endograft implanted in 50 patients. After the regulatory study successfully completed its primary end point and expanded to a continued-access phase, 15 additional patients were enrolled in the continued-access arm of the study from February 2011 until September 2011, for a total treatment group of 66 patients for the early results and 65 patients for the long-term clinical results with imaging evaluation. There was one 30-day death (1.5%), two patients (3%) with spinal cord ischemia, and two central strokes (3%) <=30 days. Five patients (7.6%) died <=1 year; 1 of ascending aortic aneurysm rupture, 2 of cardiac disease, and 2 of respiratory failure. The core laboratory adjudicated 1-month imaging in 60 patients (92.3%), where nine endoleaks (15.0%) were identified (1 type Ia, 4 type II, and 4 indeterminate). Forty-five patients (69.2%) had 2-year imaging with five endoleaks (11.1%; two type II and three indeterminate), and one patient had a distal aortic dilatation that required a secondary intervention. At 2 years, 20 of 38 imaged patients (52.6%) had aneurysm shrinkage >=5 mm, 15 (39.5%) had no change in diameter, and three patients (7.9%) had an increase in aneurysm diameter of >=5 mm. There were no conversions, fractures, compressions, or aneurysm ruptures of the treated segment through 2 years. CONCLUSIONS: This next-generation thoracic endograft has a low rate of major device events through 2 years, with no graft compressions or device failures. The data for this new endograft demonstrate favorable outcomes and confirm low risks for treatment for patients with TAA. Follow-up will be continued for 5 years. PMID- 25720924 TI - Postoperative renal failure in thoracoabdominal aortic aneurysm repair with simple cross-clamp technique and 4 degrees C renal perfusion. AB - OBJECTIVE: Acute renal failure (ARF) is reported in up to 12% of patients after thoracoabdominal aortic aneurysm (TAAA) repair with assisted circulation. ARF increases mortality, reduces quality of life, and increases length of hospital stay. This study analyzes ARF after TAAA repair done without assisted circulation. METHODS: A retrospective analysis of all patients treated for TAAA from 2000 to 2013 was performed using a concurrently maintained, institutionally approved database. All surgeries used simple cross-clamp technique, with moderate systemic hypothermia (32 degrees -33 degrees C) and renal artery perfusion with 4 degrees C solution. Serum creatinine concentration was measured preoperatively and 1 day, 3 days, 7 days, and 30 days after surgery, and Cockcroft-Gault estimated glomerular filtration rate (eGFR) was calculated. Kidney injury was classified by RIFLE (Risk, Injury, Failure, Loss of kidney function, End-stage renal disease) eGFR criteria. Changes in eGFR, kidney injury, ARF, dialysis, length of stay, mortality, and risk factors for ARF were analyzed with SAS-JMP software (SAS Institute, Cary, NC) for univariate analysis and multivariate modeling. RESULTS: From 2000 to 2013, 455 patients had TAAA surgery; 116 (25.5%) were acute. Mean preoperative eGFR was 62.3 mL/min. Mean renal ischemia time was 58.9 minutes. Eighteen patients (4%) had ARF; nine (2%) required temporary dialysis, and three (0.66%) required permanent dialysis. In univariate analysis, age, renal ischemia time, acuity, baseline eGFR, previous aortic surgery, surgical blood loss, and return to operating room for bleeding complications were significant for ARF (P < .05). Sex, aneurysm extent by Crawford type, cardiac index and mean arterial pressure after reperfusion, and use of loop diuretics were not significant for ARF. In a stepwise deletion model, acute (P = .0377), previous aortic surgery (P = .0167), return to operating room (P = .0213), and age (P = .0478) were significant for ARF. Surgical blood loss (P = .0056) and return to operating room (P = .0024) were significant for postoperative dialysis in multivariate analysis. Only surgical blood loss was significant for permanent dialysis in a multivariate model (P = .0331). CONCLUSIONS: Very low ARF after TAAA repair can be achieved by simple cross-clamp technique with moderate systemic hypothermia and profound renal cooling. Age, preoperative eGFR, previous aortic surgery, return to operating room, and surgical blood loss were significant for ARF. Return to operating room for bleeding and surgical blood loss were significant for dialysis. Baseline eGFR <30 mL/min and postoperative dialysis were significant for mortality. Most patients with ARF, even those with temporary dialysis after TAAA repair, recover renal function to near preoperative levels. PMID- 25720925 TI - Discussion. PMID- 25720926 TI - Shifting abdominal aortic aneurysm mortality trends in The Netherlands. AB - OBJECTIVE: Mortality from abdominal aortic aneurysm (AAA) in developed countries has decreased since the late 1990s. Our objective was to get an insight of mortality trends in The Netherlands for AAA disease. METHODS: Data of all AAA deaths (1980 to 2010) were collected from the Dutch cause of death register. Cause of death was divided in two groups: with the mention of rupture and without the mention of rupture. Data were standardized and divided into three age groups (55-69, 70-84, and >=85 years). Mortality rates per 100,000 were analyzed for both sexes and for each age group. Significant points of change were identified using joinpoint regression analysis. RESULTS: Total standardized AAA mortality increased from 1980 (1062 deaths) until 1995 (1728 deaths), followed by a decline until 2010 (930 deaths). This decline was most prominent in men. Deaths without mention of rupture showed an increase from 1980 until 2010. The age of AAA death was higher in women (79.2 in 1980 and 82.1 in 2010) than in men. This difference declined as the age of death from AAA increased from 72.1 in 1980 to 77.9 years in 2010 in men. Decline in AAA mortality was first seen in the young age group (55-69 years) and then seen consecutively older age groups. CONCLUSIONS: Mortality from AAA is declining due to a reduction in deaths from ruptured AAAs. This was first observed in the young age groups. Men died more often and at a lower age. PMID- 25720927 TI - Revascularization of asymptomatic carotid stenosis is not appropriate in patients on dialysis. AB - OBJECTIVE: Outcomes of carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAS) for asymptomatic disease in patients on dialysis are not well characterized, with questionable stroke prevention and survival. This study reports outcomes of carotid revascularization in asymptomatic dialysis patients in the United States. METHODS: Using United States Renal Data System (USRDS) databases, we identified all dialysis patients who underwent CEA or CAS for asymptomatic disease from 2005 to 2008. CEA and CAS were identified by Current Procedural Terminology (American Medical Association, Chicago, Ill) codes, and symptom status and comorbidities by International Classification of Diseases-9th Revision, Clinical Modification codes. Primary outcomes were stroke, cardiac complications, and death at 30 days and at 1 and 3 years. Predictors of death were identified using multivariate regression models. RESULTS: Of 738,561 dialysis patients, 2131 asymptomatic patients underwent carotid revascularization (1805 CEA, 326 CAS). The mortality rate was 4.7% at 30 days (4.6% CEA, 4.9% CAS; P = .807). Kaplan-Meier estimates of survival were 75.1% at 1 year (75.9% CEA, 70.7% CAS) and 43.4% at 3 years (43.7% CEA, 41.6% CAS). The stroke rate was 6.5% at 30 days (6.4% CEA, 6.9% CAS; P = .774) and 13.6% at 1 year (13.3% CEA, 15.0% CAS; P = .490). Cardiac complications occurred in 22.0% of patients (3.3% myocardial infarction) at 30 days (22.2% CEA, 20.6% CAS; P = .525). The combined stroke or death rate was 10.2% at 30 days (10.1% CEA, 10.9% CAS; P = .490) and 33.5% at 1 year (32.2% CEA, 39.6% CAS; P = .025). Age >70 years at the time of surgery and increased time on dialysis were predictive of death, whereas a history of renal transplant was a protective factor. CONCLUSIONS: Patients on dialysis have high perioperative and long-term stroke or death rates after CEA or CAS for asymptomatic stenosis, with a median survival that is less than recommended by current guidelines. As a result, carotid intervention in these patients appears to be inappropriate. PMID- 25720928 TI - Total laparoscopic bypass is safe and effective for aortoiliac occlusive disease. AB - OBJECTIVE: We reviewed our experience of total laparoscopic aortic bypass surgery performed for aortoiliac occlusive disease (AIOD), focusing on early 30-day mortality and morbidity and short-term and midterm outcomes. METHODS: A monocentric retrospective study was conducted between October 2002 and October 2011; we performed 173 total laparoscopic aortic surgeries to treat AIOD. RESULTS: Patients included 135 men and 38 women. The mean age was 57.2 years (range, 34-77 years). The median operative time was 205 minutes (range, 120-420 minutes), the median aortic clamping time was 50 minutes (range, 20-120 minutes), and the mean blood loss was 263 mL (range, 0-3200 mL). Conversion to open surgery was necessary in 12.1% of patients. The 30-day postoperative mortality rate was 2.3% (four of 173 patients). Major morbidity occurred in 6.9% of patients. Wound complications occurred in 8%. Four patients had a groin infection (2.3%), treated by surgical trimming in three patients and replacement of the prosthesis by venous bypass in one patient. Early graft thrombosis (within 30 days) occurred in one patient (0.6%), requiring reintervention. With a mean follow-up of 42 months (standard deviation, 37 months), 96% of bypasses were patent. Patency rates at 3 and 5 years were 97% and 85% respectively. CONCLUSIONS: In selected patients, laparoscopic aortic bypass surgery for AIOD is a safe procedure with an acceptable morbidity rate, short intensive care unit and hospital stay, fast recovery, and early return to general diet. It is a good indication after failure of endovascular surgery. PMID- 25720930 TI - A randomized clinical trial of endovenous laser ablation versus conventional surgery for small saphenous varicose veins. AB - BACKGROUND: This randomized clinical trial compared endovenous laser ablation (EVLA) and surgical ligation with attempted stripping in the treatment of small saphenous vein (SSV) insufficiency. The early results demonstrated that EVLA was more likely to eradicate axial reflux and was also associated with a faster recovery, lower periprocedural pain, and fewer sensory complications. The aim of this 2-year follow-up was to establish whether these benefits remained stable over time and whether these improved technical outcomes were associated with less clinical recurrence. METHODS: Patients with primary saphenopopliteal junction and SSV reflux were randomized to EVLA or saphenopopliteal junction ligation and attempted stripping/excision. Outcomes assessed at 2 years included the presence of residual or recurrent reflux, clinical recurrence, sensory complications, the need for secondary intervention, and patient-reported quality of life on the Aberdeen Varicose Veins Questionnaire, SF-36, and EuroQol. RESULTS: Of 106 patients who were equally randomized and successfully treated according to the protocol, 88 (83%) were successfully assessed at 2 years. The groups were comparable at baseline. At 2 years, EVLA remained superior to surgery in eradicating axial reflux in 36 patients (81.2%) compared with 29 (65.9%) in the surgery group (P = .002). There was no significant difference in clinical recurrence (EVLA: seven of 44 [16%] vs surgery: 10 of 44 [23%]; P = .736), sensory disturbance (EVLA: one [2.4%] vs surgery vs three [6.8%]; P = 1.000) or any quality of life domain. CONCLUSIONS: The results of treatment of SSV insufficiency with EVLA appear durable up until 2 years. The study does not appear to suggest that the improved abolition of reflux after EVLA compared with surgery is associated with superior outcomes than those seen after surgery by this time point, because equal effect was shown in both groups. The sensory disturbance associated with surgery appears to settle over this time frame. EVLA is therefore superior in the short-term and not inferior by 2 years. PMID- 25720929 TI - Randomized controlled trial comparing the safety and efficacy between the FUSION BIOLINE heparin-coated vascular graft and the standard expanded polytetrafluoroethylene graft for femoropopliteal bypass. AB - OBJECTIVE: Despite improvements in endovascular therapy for lower extremity arterial disease, open surgical revascularization is still required when the disease is extensive. Although autogenous vein is the conduit of choice for open femoropopliteal bypass, prosthetic grafts can be an acceptable alternative when adequate vein is not available. The FUSION BIOLINE heparin-coated vascular graft (Maquet Endovascular, Wayne, NJ) was developed to improve the patency rate associated with standard prosthetic grafts. The current study, the FINEST Trial (Comparison of Safety and Primary Patency Between the FUSION BIOLINE Heparin Coated Vascular Graft and EXXCEL Soft ePTFE), was designed to assess the clinical outcome of heparin-coated and standard vascular grafts in a prospective, randomized, controlled, multicenter trial. METHODS: During a 25-month period ending in June 2012, 209 eligible patients scheduled to undergo elective prosthetic femoral to above-knee or below-knee popliteal bypass were randomized to receive a standard expanded polytetrafluoroethylene (ePTFE) graft or the heparin-coated FUSION BIOLINE vascular graft. Among 203 patients in the efficacy analysis, claudication was the presenting symptom in 147 (72.4%), and the site of the distal anastomosis was at the above-knee level in 174 (85.7%). Grafts were assessed by duplex ultrasound imaging and ankle-brachial indices performed postoperatively at discharge and at 30 days, 6 months, and 12 months. The primary efficacy end point was primary patency of the study graft. The primary safety end point was the composite of major adverse events and periprocedural death. Secondary end points included the time to hemostasis of bleeding at the anastomotic suture hole and primary assisted and secondary patency. RESULTS: The primary patency rates at 6 months were 86.4% for the FUSION BIOLINE heparin coated vascular graft group compared with 70.0% for the standard ePTFE group, a difference of 16.4% (95% confidence interval, 2.7%-29.9%; P = .006), and the respective rates at 12 months were 76.5% and 67.0% (95% confidence interval, 4.8% to 23.0%; P = .05). The mean time to hemostasis of bleeding at the suture hole was 3.5 minutes in the FUSION BIOLINE group and 11.0 minutes in the standard ePTFE group (P < .0001). Major adverse events were significantly lower in the FUSION BIOLINE group, occurring in 17.1%, compared with 30.7% in the standard ePTFE group (P = .033), principally a result of a lower rate of major graft reinterventions through 12 months in the FUSION BIOLINE group (16.2% vs 30.7%). CONCLUSIONS: Data from this randomized multicenter study demonstrated improved midterm patency, less bleeding at the suture hole, and lower major adverse events with the FUSION BIOLINE heparin-coated vascular graft compared with standard ePTFE grafts. Although the ultimate long-term benefit of the graft cannot be ascertained with the data currently available, the utility of the FUSION BIOLINE vascular graft appears promising. PMID- 25720931 TI - Combined endovascular and surgical (hybrid) repair of type B aortic dissection with aneurysmal degeneration involving Kommerell's diverticulum and aberrant right subclavian artery. PMID- 25720932 TI - Chronic popliteal entrapment with calcified lesions results in an acute occlusion after blunt knee trauma in a 17-year-old soccer player. PMID- 25720933 TI - The outcome of the proximal radial artery arteriovenous fistula. AB - BACKGROUND: Guidelines recommend placing native arteriovenous fistulas (AVFs) as far distally in the upper extremity as possible. If there are adequate veins and adequate arteries, a wrist fistula, which offers notably lower risks than grafts and catheters, would be the first choice for long-term hemodialysis. With increasing failure and difficulty to create wrist fistulas, we reviewed outcomes of the proximal radial AVF (PRAAVF) and demonstrate that it is an effective technique. METHODS: A systemic literature research was conducted in PubMed and related bibliographies. The focus of data extraction was primary failure, primary patency rates, and secondary patency rates after 1 and 2 years. Estimates were pooled with the random effects model, and meta-regression and sensitivity analysis were performed to explore heterogeneity. RESULTS: According to selection criteria formulated a priori, 10 articles (n = 1310) were included and finally analyzed after screening 1687 articles. The pooled primary failure was 12.3% (95% confidence interval [CI], 7.6%-17.0%; chi(2) = 70.8, I(2) = 87.3%), the primary patency, including primary failure, was 73.6% (95% CI, 52.4%-94.9%; chi(2) = 71.3, I(2) = 97.2%) at 1 year and 70.5% (95% CI, 50.6%-90.5%; chi(2) = 58.8, I(2) = 96.6%) at 2 years. Secondary patency was 80.0% (95% CI, 72.8%-87.2%; chi(2) = 24.42, I(2) = 75.4%) at 1 year and 73.7% (95% CI, 65.2%-82.2%; chi(2) = 28.51, I(2) = 79.0%) at 2 years. Individual variate meta-regression analysis found the definition of primary failure was a significant source of heterogeneity (P = .009). Steal syndromes developed in four of 832 (0.5%) of the PRAAVFs, and venous hypertension developed in four of 284 (1.4%). CONCLUSIONS: The PRAAVF presented low to moderate primary failure and high primary and secondary patency rates with acceptable complications. Consideration of the specific fistula is required when creating a vascular access, especially when a wrist fistula has failed or is predicted to be unsuccessful. PMID- 25720934 TI - Similar failure and patency rates when comparing one- and two-stage basilic vein transposition. AB - OBJECTIVE: Basilic vein transposition is recommended in patients who are not candidates for a radial or brachial artery to cephalic vein fistula for dialysis access. Both one-stage and two-stage procedures have their advantages and disadvantages. Which procedure results in improved outcomes remains unclear. METHODS: A systematic review was conducted of the MEDLINE and EMBASE databases for studies that compared one-stage and two-stage brachial-basilic vein transpositions. Abstracts and full-text studies were screened independently by two reviewers with data abstraction done in duplicate. Random-effects meta analysis was used to identify differences in primary failure rates and 1-year primary and secondary patency rates. Study quality was assessed by a previously described tool designed for observational studies reporting on dialysis access outcomes. RESULTS: Of 1662 abstracts screened, 97 were selected for full-text review. Of these, eight studies (one randomized trial, seven observational studies) involving 882 patients met the inclusion criteria. The pooled odds ratio estimate for primary failure was 1.21 (95% confidence interval [CI], 0.73-1.98; P = .46), suggesting no difference in failure rate between one-stage and two-stage transpositions. Similarly, the estimated odds ratio for 1-year primary patency rate of 1.39 (95% CI, 0.71-2.72; P = .33) and 1-year secondary patency rate of 1.02 (95% CI, 0.36-2.87; P = .98) indicated no difference between the two groups. Study quality was limited by unclear outcome definitions, minimal control for confounding, and variable selection criteria. The decision to pursue a one-stage vs a two-stage procedure was often based on size of the basilic vein, with a two stage procedure reserved for patients with smaller veins. CONCLUSIONS: Meta analysis of the existing literature comparing one-stage and two-stage basilic vein transposition suggests no difference in failure and patency rates, despite the two-stage procedure's being used in patients with smaller basilic veins. These findings are limited by the small size, observational design, and inconsistent quality of included studies. Reserving a two-stage procedure for patients with smaller basilic veins appears justified, although the strength of the evidence is limited. PMID- 25720935 TI - Invited commentary. PMID- 25720936 TI - Alexis Carrel's historic leap of faith. PMID- 25720937 TI - A randomized clinical trial of endovenous laser ablation versus conventional surgery for small saphenous varicose veins. PMID- 25720938 TI - Regarding "Remodeling of aortic aneurysm and aortic neck on follow-up after endovascular repair with suprarenal fixation". PMID- 25720939 TI - Reply: To PMID 25153490. PMID- 25720940 TI - Circulating irisin concentrations in rat models of thyroid dysfunction -- effect of exercise. AB - OBJECTIVES: The speculation that the myokine irisin could regulate whole body energy expenditure led to the anticipation that irisin may have therapeutic potential in metabolic diseases. Regulation of irisin under conditions of metabolic derangements in altered thyroid status, and the changes in irisin response to exercise remain to be investigated. METHODS: Serum irisin concentration was measured in sixty male Wistar rats subjected to either sedentary life or 8-week chronic swimming exercise after induction of hyper- or hypothyroidism (10 rats/group). The effect of acute exercise on serum irisin was assessed in 10 additional rats subjected once to forced swimming against a load (5% of body weight) and compared to sedentary rats. RESULTS: Serum irisin was significantly higher in both sedentary hyper- and hypothyroid rats (by 45%, p<0.001, and 30%, p<0.001, respectively) versus euthyroid controls. Serum irisin also increased after acute exercise (p<0.001 versus sedentary control). Chronic training episodes failed to significantly alter serum irisin in all thyroid hormone profiles. Serum irisin correlated positively with serum creatine kinase (r=0.45, p<0.001) and with muscle and liver concentrations of malondialdehyde (r=0.50 and r=0.47 respectively, p<0.001 for both), and negatively with muscle and liver content of reduced glutathione (r=-0.34, p=0.003 and r=-0.28, p=0.018 respectively) in pooled groups. However, significance of these associations was waived when analyzing each group separately. Serum irisin was not associated with skeletal muscle mass, insulin resistance, blood glucose, lipids or TSH. CONCLUSIONS: Both hyper- and hypothyroidism are associated with up-regulation of serum irisin in male rats, possibly as a response to oxidative damage and/or myopathy observed in both conditions. Acute exercise, which is also associated with oxidative stress, increases serum irisin. No obvious association was detected linking serum irisin to metabolic abnormalities in thyroid dysfunction. PMID- 25720941 TI - pH dependency of sclerotial development and pathogenicity revealed by using genetically defined oxalate-minus mutants of Sclerotinia sclerotiorum. AB - The devastating plant pathogen Sclerotinia sclerotiorum produces copious (up to 50 mM) amounts of oxalic acid, which, for over a quarter century, has been claimed as the pathogenicity determinant based on UV-induced mutants that concomitantly lost oxalate production and pathogenicity. Such a claim was made without fulfilling the molecular Koch's postulates because the UV mutants are genetically undefined and harbour a developmental defect in sclerotial production. Here, we generated oxalate-minus mutants of S. sclerotiorum using two independent mutagenesis techniques, and tested the resulting mutants for growth at different pHs and for pathogenicity on four host plants. The oxalate-minus mutants accumulated fumaric acid, produced functional sclerotia and have reduced ability to acidify the environment. The oxalate-minus mutants retained pathogenicity on plants, but their virulence varied depending on the pH and buffering capacity of host tissue. Acidifying the host tissue enhanced virulence of the oxalate-minus mutants, whereas supplementing with oxalate did not. These results suggest that it is low pH, not oxalic acid itself, that establishes the optimum conditions for growth, reproduction, pathogenicity and virulence expression of S. sclerotiorum. Exonerating oxalic acid as the primary pathogenicity determinant will stimulate research into identifying additional candidates as pathogenicity factors towards better understanding and managing Sclerotinia diseases. PMID- 25720942 TI - High or low incidence of the lateral thoracic artery's origin from the thoracoacromial artery? PMID- 25720944 TI - Association between zolpidem use and glaucoma risk: a Taiwanese population-based case-control study. AB - BACKGROUND: To date, the relationship between zolpidem use and subsequent risk of glaucoma in a Taiwanese population has not been assessed. METHODS: We used data from the National Health Insurance system to investigate whether zolpidem use was related to glaucoma risk. A 1:4 matched case-control study was conducted. The cases were patients newly diagnosed with glaucoma from 2001 to 2010. The controls were randomly selected non-glaucoma subjects matched by sex and age (+/- 5 years). Zolpidem exposure and/or the average dosage of zolpidem used (mg/year) were evaluated. Medical comorbidities were considered as confounding factors. Multiple logistic regression models were used to evaluate the potential risk of zolpidem exposure on glaucoma with/without adjustment for the effects of confounding variables. RESULTS: The exposure rate of zolpidem use in the glaucoma group was significantly higher than that of the control group (2.8% vs. 2.0%, P < 0.0001). The adjusted odds ratio (OR) of the risk of glaucoma for those with zolpidem use vs. those without was 1.19 (95% confidence interval [CI], 1.02 1.38). Compared to non-zolpidem users, zolpidem users with an average dose of more than 200 mg/year had significantly increased risk of glaucoma (OR 1.31, 95% CI 1.03-1.68). CONCLUSIONS: This study suggests that the use of zolpidem might increase the risk of subsequent glaucoma. Further confirmatory studies are recommended to clarify this important issue. PMID- 25720945 TI - Accumulation of oxidized peroxiredoxin 2 in red blood cells and its prevention. AB - BACKGROUND: The thiol protein peroxiredoxin 2 (Prx2) is a major red blood cell (RBC) antioxidant that breaks down hydroperoxides and in the process is converted to an oxidized disulfide. Our objective was to determine whether Prx2 becomes oxidized during storage of RBCs, to understand the underlying mechanism, and to find ways of preventing the accumulation of the oxidized form. STUDY DESIGN AND METHODS: RBCs were stored for up to 6 weeks under simulated blood banking conditions and Prx2 oxidation was monitored by nonreducing gel electrophoresis. The ability of the cells to reverse Prx2 oxidation after storage and to respond to added hydrogen peroxide was also evaluated. RESULTS: Prx2 remained predominantly reduced during the first 3 weeks of storage, and then the oxidized form accumulated progressively. In contrast to fresh cells, oxidation was not reversed by incubation with glucose. Storage of RBCs in a high-pH, low-chloride, and high-phosphate/bicarbonate buffer (EAS-76v6) largely prevented accumulation of oxidized Prx for at least 6 weeks, and dihydrolipoic acid (DHLA), but not Rejuvesol, N-acetylcysteine, or alpha-lipoic acid, was able to reverse or protect against Prx2 oxidation. Additional, Prx2 oxidation occurred when hydrogen peroxide was added. However, this was reversible, suggesting that the reductive capacity was compromised in some but not in all cells. CONCLUSION: Prx2 remains mostly reduced in a high-pH storage solution with buffering capacity. Addition of DHLA to stored RBCs might be advantageous. Prx2 redox status could be used as a biomarker for the quality of stored RBCs. PMID- 25720946 TI - Circulating leptin and pain perception among tobacco-dependent individuals. AB - Recent preclinical evidence suggests that leptin may modulate the stress response and may increase nociception. In this study, we examined for the first time the extent to which cigarette smoking is associated with leptin levels during an extended rest period and in response to noxious stimuli. Repeated blood samples were collected during a laboratory session from smokers and nonsmokers and assayed for leptin. Pain experiences, as well as neuroendocrine and cardiovascular measures, were collected across cold pressor and thermal heat pain tests. Both analysis of variance and correlations confirmed that smokers demonstrated dysregulations in leptin responsivity and association with pain relative to nonsmokers. The flat pattern of leptin release and the weak associations of this hormone with pain in smokers suggest a long-term effect of tobacco dependence on this regulatory hormone. In light of leptin's influence on reward pathways, further investigation of leptin's involvement in nicotine dependence is warranted. PMID- 25720949 TI - In situ production of visible light absorbing Ti-based nanoparticles in solution and in a photopolymerizable cationic matrix. AB - A novel straightforward approach has been proposed to generate in situ, under light activation and in aerated media, visible-light absorbing and well-defined titanium-based nanoparticles (NPs) in solution and in an epoxide matrix using titanium derivative complexes/iodonium salt photoinitiating systems. The nature of the solvent and oxygen plays a decisive role, and two mechanisms involved in these syntheses are operative, i.e. a photofragmentation/addition process (in toluene and isopropanol) and a photoinduced sol-gel reaction (in isopropanol). PMID- 25720948 TI - Expectations and satisfaction of academic investigators in nonclinical collaboration with the pharmaceutical industry. AB - In light of a growing role of research collaborations between academia and the pharmaceutical industry, we have explored expectations and experience of academic investigators with preclinical collaborations. Researchers from Western Europe, North America, and Japan with preclinical publications in the obstructed airways or diabetes fields were invited to anonymously participate in a web-based survey. A total of 134 investigators (28 % of invitees) participated in the two sequentially performed surveys with similar responses in both therapeutic areas. A secondary but prespecified subgroup analysis was based on region of residence, gender, and career level of the investigator. Across all groups, responders considered freedom to publish, obtaining funding and obtaining compounds to be the most important objectives of nonclinical collaborations with the pharmaceutical industry, whereas cultivating professional relationships, getting external scientific input, direct relationship to disease treatment, and involvement with drug development were less important. Among eight attributes of the primary contact person in the company, trustworthiness ranked highest, followed by a collaborative spirit and transparent information sharing; supportiveness, scientific qualification, accessibility, and timeliness of responses ranked lower, and friendliness, lowest. Related to their most recent collaboration, investigators also expressed the highest level of satisfaction with the trustworthiness attribute. On the other hand, the process of reaching a contract was often considered too long and difficult, for which both university and company legal departments were reported as culprits. We conclude that academic researchers are generally satisfied with their preclinical collaboration with the pharmaceutical industry but look for improved contracting procedures. PMID- 25720947 TI - The effects of sighing on the cardiovascular system. AB - Elicitation of high-amplitude oscillations in the cardiovascular system may serve to dampen psychophysiological reactivity to emotional and cognitive loading. Prior work has used paced breathing to impose clinically valuable high-amplitude ~ 0.1 Hz oscillations. In this study, we investigated whether rhythmical sighing could likewise produce high-amplitude cardiovascular oscillations in the very low frequency range (0.003-0.05 Hz). ECG, respiration, skin conductance, and beat-to beat blood pressure were collected in 24 healthy participants during baseline, 0.1 Hz paced breathing, and 0.02 Hz paced sighing (1 sigh every 50s, with normal breathing interspersed). Results showed that each sigh elicited a strong, well defined reaction in the cardiovascular system. This reaction did not habituate when participants repeatedly sighed for 8.5 min. The result was a high-amplitude 0.02 Hz oscillation in multiple cardiovascular parameters. Thus, paced sighing is a reliable method for imposing very low frequency oscillations in the cardiovascular system, which has research and clinical implications that warrant further study. PMID- 25720951 TI - Targeting molecular hydrogen to mitochondria: barriers and gateways. AB - Although the administration of molecular hydrogen (H2, dihydrogen) has been recognized as an effective innovative therapeutic procedure in biomedicine, H2 cellular kinetics and utilization seems to be less understood. In particular, mitochondrial barriers might impact on H2 use in mitochondria-related diseases and conditions. Double-membrane organization of mitochondria and large membrane potential are important elements of mitochondrial stability that control the transport of the molecule into and out of the organelle. In this perspective paper, we advanced possible obstacles and advantages for H2 delivery to mitochondria. PMID- 25720950 TI - Vascular function, cerebral cortical thickness, and cognitive performance in middle-aged Hispanic and non-Hispanic Caucasian adults. AB - Hispanics are at increased risk for acquiring cardiovascular risk factors that contribute to cognitive dysfunction. To compare indices of vascular health with measures of cerebral gray matter integrity, 60 middle-aged Hispanic and non Hispanic Caucasian participants were matched across age, sex, years of education, and mental status. Arterial stiffness was characterized by beta-stiffness index and carotid-femoral pulse wave velocity, and magnetic resonance imaging estimated cortical thickness in a priori regions of interest known to be susceptible to vascular risk factors. Measures of arterial stiffness were significantly higher in Hispanics than in non-Hispanic Caucasians. Hispanics exhibited thinner left inferior frontal gyrus (LIFG) cortical thickness (P=.04) with concurrently lower language (P=.02), memory (P=.03), and attention-executive functioning (P=.02). These results suggest that compromised vascular health may occur simultaneously with cortical thinning of the LIFG as an early neuropathological alteration in Hispanics. PMID- 25720952 TI - Pediatric glioblastoma multiforme in association with Turner's syndrome: a case report. AB - The Ullrich-Turner syndrome (complete or partial X-chromosome monosomy) has been found to be associated with an increased rate of some extragonadal neoplasms. Sporadic reports of the Turner syndrome with various brain tumors, including few cases of glioblastoma multiforme, have been found in the literature. However, published data are insufficient to establish a definite relationship between these tumors and the Turner syndrome. Herein, a rare case of primary pediatric glioblastoma multiforme in a 7-year-old girl with Turner's syndrome is reported, and various aspects regarding clinical and pathophysiological issues have been discussed. Although Turner's syndrome is not one of the congenital chromosomal abnormalities which demand routine CNS screening, neurological assessment may be of value in those with relevant clinical findings. PMID- 25720953 TI - Predicting early post-partum depressive symptoms among older primiparous Japanese mothers. AB - AIM: The number of older primiparas is increasing in Japan. These women have been shown to be more vulnerable to post-partum depression. This study aimed to identify factors for predicting post-partum depressive symptoms during hospitalization after childbirth in Japanese primiparas aged 35 years and over. METHODS: The present authors used the data of 479 primiparas aged 35 years and over from a prospective cohort study. Data were collected using self-report questionnaires on the day before hospital discharge. The questionnaire consisted of: demographics and background information; depressive symptoms; fatigue; maternal confidence and maternal satisfaction; child-care values; physical symptoms; perceptions of daily life during hospitalization; concerns about child care and daily life; and infant feeding. Additionally, vital records data were obtained from the hospitals. A stepwise logistic regression analysis was performed on the binary outcome variable of depressive symptoms, measured by the Japanese version of the Edinburgh Postnatal Depression Scale. Women who scored 9 or more were considered to be at high risk for post-partum depression. The authors obtained informed consent from all participants and institutional ethics approvals before initiating the study. RESULTS: The following six variables reliably predicted the risk of post-partum depression: emergency cesarean section, lower satisfaction with birth experience, higher physical burden in daily life, long-term complications with the newborn, more concerns about newborn caretaking after discharge, and more concerns about one's own life after discharge. CONCLUSION: Recognition of women with these factors will help nurses to identify those at risk for developing post-partum depression and to provide appropriate care during hospitalization after childbirth. PMID- 25720954 TI - Using the Accelerometers Integrated in Smartphones to Evaluate Essential Tremor. AB - Background/Aims: Evaluation of tremor constitutes a crucial step from the diagnosis to the initial treatment and follow-up of patients with essential tremor. The severity of tremor can be evaluated using clinical rating scales, accelerometry, or electrophysiology. Clinical scores are subjectively given, may be affected by intra- and interevaluator variations due to different experience, delays between consultations, and subtle changes in tremor severity. Existing medical devices are not routinely used: they are expensive, time-consuming, not easily accessible. We aimed at showing that a smartphone application using the accelerometers embedded in smartphones is effective for quantifying the tremor of patients presenting with essential tremor. Methods: We developed a free iPhone/iPod application, Itremor, and evaluated different parameters on 8 patients receiving deep brain stimulation of the ventral intermediate nucleus of the thalamus: average and maximum accelerations, time above 1 g of acceleration, peak frequency, typical magnitude of tremor, for postural and action tremors, on and off stimulation. Results: We demonstrated good correlations between the parameters measured with Itremor and clinical score in all conditions. Itremor evaluation enabled higher discriminatory power and degree of reproducibility than clinical scores. Conclusion: Itremor can be used for routine objective evaluation of essential tremor, and may facilitate adjustment of the treatment. (c) 2015 S. Karger AG, Basel. PMID- 25720955 TI - Microwave-assisted radiosynthesis of [(18) F]ASEM, a radiolabeled alpha7 nicotinic acetylcholine receptor antagonist. AB - An improvement of the original radiochemical synthesis of [(18) F]ASEM, an alpha7 nicotinic acetylcholinergic receptor radioligand, is reported. The new procedure utilizes microwave-assisted radiofluorination. In addition, a new preparative HPLC method was developed to eliminate a chemical impurity in the final product. Quality control procedures were also enhanced to improve detection of product with enhanced resolution of potential impurities. [(18) F]ASEM was produced in 20.1 +/- 8.9% non-decay corrected (NDC) yield with an average synthesis time of 57 min and an average specific radioactivity of 856 +/- 332 GBq/umol (23 +/- 9 Ci/umol). PMID- 25720956 TI - The multi-targeted tyrosine kinase inhibitor vandetanib plays a bifunctional role in non-small cell lung cancer cells. AB - Vandetanib, a multikinase inhibitor, is a target of drug treatments for non-small cell lung cancer (NSCLC). However, phase II and III clinical trials have not conclusively demonstrated the curative effects of vandetanib for NSCLC, and the reasons for this are unknown. In the present study, we use the NSCLC cell line Calu-6 as a model to determine the cellular and biological effects of vandetanib. Our results demonstrate that vandetanib impairs Calu-6 cell migration and invasion. We find that vandetanib can directly inhibit RET activity, which influences the Rho-JNK pathway. Overexpression of a constitutively active Rho GTPase antagonizes the inhibitory effects of vandetanib on Calu-6 cells invasion and JNK pathway activation. In addition, vandetanib induces autophagy by increasing the level of reactive oxygen species (ROS) in Calu-6 cells, and blockade of autophagy or ROS effectively enhances the cell death effect of vandetanib. In this study, we find vandetanib is of a double effect in some NSCLC cells, presenting new possibilities for the pharmacological treatment of NSCLC and introducing a novel role for vandetanib in treatment options. PMID- 25720959 TI - Tipping the metabolic scales towards increased longevity in mammals. AB - A hallmark of ageing is dysfunction in nutrient signalling pathways that regulate glucose homeostasis, negatively affecting whole-body energy metabolism and ultimately increasing the organism's susceptibility to disease. Maintenance of insulin sensitivity depends on functional mitochondrial networks, but is compromised by alterations in mitochondrial energy metabolism during ageing. Here we discuss metabolic paradigms that influence mammalian longevity, and highlight recent advances in identifying fundamental signalling pathways that influence metabolic health and ageing through mitochondrial perturbations. PMID- 25720960 TI - In vivo reprogramming for tissue repair. AB - Vital organs such as the pancreas and the brain lack the capacity for effective regeneration. To overcome this limitation, an emerging strategy consists of converting resident tissue-specific cells into the cell types that are lost due to disease by a process called in vivo lineage reprogramming. Here we discuss recent breakthroughs in regenerating pancreatic beta-cells and neurons from various cell types, and highlight fundamental challenges that need to be overcome for the translation of in vivo lineage reprogramming into therapy. PMID- 25720961 TI - Merlin's wizardry guides cohesive migration. AB - Cells often migrate in tightly connected groups with coordinated movement and polarity. The collective migration of epithelial cell sheets is now shown to be mediated by a signalling axis that involves the merlin tumour-suppressor protein, the tight-junction-associated angiomotin-Rich1 complex and the Rac1 small GTPase. PMID- 25720962 TI - Huntingtin facilitates selective autophagy. AB - Selective autophagy is essential for maintaining cellular homeostasis under different growth conditions. Huntingtin, mutated versions of which have been implicated in Huntington disease, is now shown to act as a scaffold protein that couples the induction of autophagy and the selective recruitment of cargo into autophagosomes. PMID- 25720963 TI - Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. AB - The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca2+ signalling mechanism controls the activities of the phosphatase calcineurin and of its substrate TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ release through mucolipin 1 (MCOLN1) activates calcineurin, which binds and dephosphorylates TFEB, thus promoting its nuclear translocation. Genetic and pharmacological inhibition of calcineurin suppressed TFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect. Induction of autophagy and lysosomal biogenesis through TFEB required MCOLN1-mediated calcineurin activation. These data link lysosomal calcium signalling to both calcineurin regulation and autophagy induction and identify the lysosome as a hub for the signalling pathways that regulate cellular homeostasis. PMID- 25720965 TI - A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly. PMID- 25720966 TI - Palladium-catalyzed vicinal amino alcohols synthesis from allyl amines by in situ tether formation and carboetherification. AB - Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium catalyzed oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic amines. High regio- and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form. The obtained compounds are important building blocks, which can be orthogonally deprotected to give either free alcohols, amines, or terminal alkynes. PMID- 25720967 TI - Disseminated superficial actinic porokeratosis in a psoriasis patient with a long term sun-bathing habit. PMID- 25720964 TI - FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification. AB - Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7alpha interacts with HSF1 through a conserved motif phosphorylated by GSK3beta and ERK1. FBXW7alpha ubiquitylates HSF1 and loss of FBXW7alpha results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7alpha is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7alpha deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer. PMID- 25720968 TI - Spatial distribution patterns of molybdenum (Mo) concentrations in potable groundwater in Northern Jordan. AB - Two hundred and three groundwater samples were collected during March 2011 to June 2012 from the B2/A7 aquifer water supply wells of northern part of Jordan. The physicochemical properties were analyzed in situ for the major cations, anions, while certain heavy metals were analyzed in the laboratory. Some oilshale rock samples were geochemically analyzed. The Upper Cretaceous aquifer (B2/A7) is used as water supply for most of the communities in the study area. It consists of limestone, marly limestone, bedded chert, and minor phosphorite. Hydrochemical results from the B2/A7 aquifer indicate two main water types: alkaline-earth water (CaHCO3) and alkaline-earth water with high alkaline component (NaHCO3 (-), Na2SO4). Standard column leaching experiments on oilshale rock samples and the R mode factor analysis suggest that the sources for elevated Mo concentrations in the groundwater of certain parts of northern Jordan are attributed to water oilshale interaction, mobility of Mo down to the groundwater and the extensive use of fertilizers within these areas. Molybdenum (Mo) concentrations in the groundwater water range from 0.07 to 1.44 mg/L with an average value of 98 MUg/L. They are found to exceed the JISM and WHO guidelines in two areas in northern part of Jordan. Spatial distribution of Mo, using ordinary kriging techniques and the resulting map, shows high Mo concentration in the northwestern part near Wadi Al Arab area reaching concentrations of 650 MUg/L and in the southeastern corner of the investigated area, south of Al Ukaydir village, with an average concentration of 468 MUg/L. Both areas are characterized by extensive oilshale exposures with average concentration of 11.7 mg/kg Mo and intensive agricultural activities. These two areas represent approximately 33 % of the groundwater in the northern part of Jordan. Mobility of Mo to the groundwater in northern part of Jordan is attributed to two mechanisms. First, there is reductive dissolution of Fe-oxide, which releases substantial adsorbed Mo concentrations. Secondly, there is oxidation of Mo into dissolved forms in sulfide organic-rich system. PMID- 25720969 TI - Improving soil microbiology under rice-wheat crop rotation in Indo-Gangetic Plains by optimized resource management. AB - The resource-intensive agriculture involving use of chemical fertilizers, irrigation, and tillage practices is a major cause of soil, water, and air pollution. This study was conducted to determine whether integrated use of nutrient, water, and tillage (reduced) can be manipulated to improve the population of plant growth promoting rhizobacteria (Azotobacter, Bacillus, and Pseudomonas) to enhance soil fertility and yield. The study was conducted in the Indo-Gangetic plain (IGP) region of India, where resource-intensive agriculture is practiced. Various combinations of chemical (urea) and organic fertilizers (farmyard manure (FYM), biofertilizer, and green manure) were used on replicated field plots for all the experiments. The effect of integrated resource management (IRM) on activities of Azotobacter, Bacillus, and Pseudomonas and its relation to the yields of rice and wheat crops in subtropical soils of IGP region were also observed. The increased population of all the three microbes, namely, Azotobacter (5.01-7.74 %), Bacillus (3.37-6.79 %), and Pseudomonas (5.21-7.09 %), was observed due to improved structure and increased organic matter in the soil. Similarly, kernel number and 1000 kernel weight were found increased with sole organic N source, three irrigations, and conservation tillage. Thus, it was found that the IRM practices affect the environment positively by increasing the population of beneficial soil microbes and crop yield as compared to high-input agriculture (conventional practices). PMID- 25720970 TI - Application of multivariate optimization procedures for preconcentration and determination of Au(III) and Pt(IV) in aqueous samples with graphene oxide by X ray fluorescence spectrometry. AB - A simple method was developed for the determination of Au(III) and Pt(IV) contents in aqueous samples after preconcentration. The method was based on the sorption of analytes as 2-amino-5-mercapto-1,3,4-thiadiazol complexes onto graphene oxide and subsequent direct determination by wavelength dispersive X-ray fluorescence (WDXRF). The optimization step was carried out using two-level full factorial and Box-Behnken designs. The effects of four variables (pH, ligand mass, sonication time, and temperature) were studied by a full-factorial design to find significant variables and their interactions. Results of two-level full factorial design for Au extraction showed that the factors: pH, ligand mass, temperature of sonication beside the interaction of pH-ligand mass, and interaction sonication temperature-ligand mass were significant. For Pt, the results revealed pH, ligand mass, sonication time, and interaction of pH-ligand mass were statistically significant. Box-Behnken matrix design was applied to determine the optimum level of significant parameters for extraction of two analytes simultaneously. The optimum values of the factors were pH 2.5, 0.9 mL ligand solution, 56 min sonication time and 15 degrees C temperature. The limits of detection (LOD) were found to be 8 ng mL(-1) for Au and 6 ng mL(-1) for Pt. The adsorption capacity for Au and Pt were 115 and 169 MUg mg(-1), respectively. The relative standard deviation (RSD) was lower than 1.4 % (n = 5), and the extraction percentage was more than 95 % for both elements. The method was validated by determination of Au and Pt in spiked water samples and certified reference standard materials. PMID- 25720971 TI - Organic compounds in circumstellar and interstellar environments. AB - Recent research has discovered that complex organic matter is prevalent throughout the Universe. In the Solar System, it is found in meteorites, comets, interplanetary dust particles, and planetary satellites. Spectroscopic signatures of organics with aromatic/aliphatic structures are also found in stellar ejecta, diffuse interstellar medium, and external galaxies. From space infrared spectroscopic observations, we have found that complex organics can be synthesized in the late stages of stellar evolution. Shortly after the nuclear synthesis of the element carbon, organic gas-phase molecules are formed in the stellar winds, which later condense into solid organic particles. This organic synthesis occurs over very short time scales of about a thousand years. In order to determine the chemical structures of these stellar organics, comparisons are made with particles produced in the laboratory. Using the technique of chemical vapor deposition, artificial organic particles have been created by injecting energy into gas-phase hydrocarbon molecules. These comparisons led us to believe that the stellar organics are best described as amorphous carbonaceous nanoparticles with mixed aromatic and aliphatic components. The chemical structures of the stellar organics show strong similarity to the insoluble organic matter found in meteorites. Isotopic analysis of meteorites and interplanetary dust collected in the upper atmospheres have revealed the presence of pre-solar grains similar to those formed in old stars. This provides a direct link between star dust and the Solar System and raises the possibility that the early Solar System was chemically enriched by stellar ejecta with the potential of influencing the origin of life on Earth. PMID- 25720972 TI - Absorbable sternal pins improve sternal closure stability within a small deviation. AB - OBJECTIVE: Sternum external fixation with a sternal wire is widely used. However, it was inadequate fixation in the anterior-posterior and cranial-caudal directions. Using sternal pins can improve the stability. The utility of a small deviation was important with respect to sternal pain. Here, we evaluated the efficacy of a sternal pin in a small deviation in three directions. METHODS: Polyurethane foam was used. In the wire group, models were closed using two stainless steel wires. In the wire and sternal pin group, a hydroxyapatite/poly-L lactide acid (HA/PLLA) sternal pin was used for internal fixation in addition to wire fixation. A sternal pin was inserted inside. Both sides were fixed with the testing machine and the shear stress was directed to one side. In each group, six models were tested for three directions. The relationship between the load and displacement of the model was measured at 1-mm displacement. RESULTS: In the anterior-posterior direction, the load value was 138.8 +/- 8.3 (N) in the wire and sternal pin group and 51.6 +/- 9.5 (N) in the wire group (p = 0.0003). In the cranial-caudal direction, the values were 148.0 +/- 12.0 (N) and 83.1 +/- 26.6 (N), respectively (p < 0.0001). In the lateral direction, these values were 273.2 +/- 49.3 (N) and 266.9 +/- 50.6 (N), respectively (p = 0.8323). CONCLUSIONS: Additional internal fixation using an HA/PLLA sternal pin significantly improved the stability of sternotomy closure in the anterior-posterior and cranial-caudal directions within a small deviation. PMID- 25720973 TI - Diospyros perigrena bark extract induced apoptosis in filarial parasite Setaria cervi through generation of reactive oxygen species. AB - CONTEXT: Lymphatic filariasis is a major neglected tropical disease. Diospyros perigrena Gurke (Ebenaceae) was selected for antifilarial chemotherapy because of unavailability of proper medicine. In India, different parts of this plant were used for the treatment of diabetes, diarrhea, dysentery, cholera, mouth ulcers, and wounds. OBJECTIVE: The present study was undertaken to access antifilarial potential and mechanism of action of n-butanol extract (NBE) of D. perigrena stem bark on Setaria cervi Rudolphi (Onchocercidae). MATERIALS AND METHODS: In vitro efficacy and apoptotic mechanism were evaluated by Hoechst, TUNEL, DNA fragmentation assay, pro- and anti-apoptotic gene expression in NBE (250, 125, 62.5, 31.25, and 15.6 ug/ml)-treated S. cervi after 24 h of incubation. Reactive oxygen species (ROS) up-regulation was also determined by GSH, GST, SOD assays, and super oxide anion level. RESULTS: Significant in vitro antifilarial activity of NBE was found 50% inhibitory concentration (IC50): adult = 57.6 MUg/ml, microfilariae (mf) = 56.1 MUg/ml, and lethal dose (LD100) in mf is 187.17 MUg/ml) after 24 h of treatment. NBF-induced apoptosis was proved by Hoechst, TUNEL, RT PCR, and Western blot method. NBF (250 ug/ml) decreased the level of GSH (17.8%) and GST (65.4%), increased SOD activity (1.42-fold) and super oxide anion production (1.32-fold) in the treated parasite which culminated into ROS up regulation. DISCUSSION AND CONCLUSION: NBE induced apoptosis in different life cycle stages of S. cervi. In future, a detailed study of NBF will give us a novel antifilarial compound which will be used for antifilarial chemotherapy. PMID- 25720974 TI - Study of cytotoxic activity, podophyllotoxin, and deoxypodophyllotoxin content in selected Juniperus species cultivated in Poland. AB - CONTEXT: The demand for podophyllotoxin and deoxypodophyllotoxin is still increasing and commercially exploitable sources are few and one of them, Podophyllum hexandrum Royle (Berberidaceae), is a "critically endangered" species. OBJECTIVE: The first aim was to quantify the amount of podophyllotoxin and deoxypodophyllotoxin in 61 Juniperus (Cupressaceae) samples. Cytotoxic activity of podophyllotoxin and ethanolic leaf extracts of Juniperus scopulorum Sarg. "Blue Pacific" and Juniperus communis L. "Depressa Aurea" was examined against different leukemia cell lines. MATERIALS AND METHODS: Ultra-performance liquid chromatography (UPLC) analysis was performed with the use of a Waters ACQUITY UPLC(TM) system (Waters Corp., Milford, MA). The peaks of podophyllotoxin and deoxypodophyllotoxin were assigned on the basis of their retention data and mass-to-charge ratio (m/z). Trypan blue assay was performed to obtain IC50 cytotoxicity values against selected leukemia cell lines. RESULTS: Juniperus scopulorum was characterized with the highest level of podophyllotoxin (486.7 mg/100 g DW) while Juniperus davurica Pall. contained the highest amount of deoxypodophyllotoxin (726.8 mg/100 g DW). Podophyllotoxin IC50 cytotoxicity values against J45.01 and CEM/C1 leukemia cell lines were 0.0040 and 0.0286 ug/mL, respectively. Juniperus scopulorum extract examined against J45.01 and HL 60/MX2 leukemia cell lines gave the respective IC50 values: 0.369-9.225 ug/mL. Juniperus communis extract was characterized with the following IC50 cytotoxity values against J45.01 and U-266B1 cell lines: 3.310-24.825 ug/mL. CONCLUSIONS: Juniperus sp. can be considered as an alternative source of podophyllotoxin and deoxypodophyllotoxin. Cytotoxic activity of podophyllotoxin and selected leaf extracts of Juniperus sp. against a set of leukemia cell lines was demonstrated. PMID- 25720975 TI - Antioxidant and anticholinesterase activities of five wild mushroom species with total bioactive contents. AB - CONTEXT: Recently, mushrooms are interesting natural products to be investigated due to exhibiting various bioactivities. OBJECTIVE: This study determines the antioxidant and anticholinesterase activities of various extracts of five wild mushroom species. In addition, the total bioactive contents, namely, ascorbic acid, beta-carotene, and lycopene along with phenolic and flavonoid contents were also determined spectrophotometrically. MATERIALS AND METHODS: Antioxidant activity was tested by using five complementary tests; namely, beta-carotene linoleic acid, DPPH(*) scavenging, ABTS(*+) scavenging, cupric-reducing antioxidant capacity (CUPRAC), and metal chelating assays. The in vitro anticholinesterase activity was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes using the Ellman method. The spectrophotometric methods were used to determine the total phenolic, flavonoid, ascorbic acid, beta-carotene, and lycopene contents. RESULTS: The current study has shown that ethyl acetate extracts of Ganoderma lucidum (Curtis) P. Karst (IC50: 1.55 +/- 0.05 ug/mL) and Funalia trogii (Berk.) Bondartsev & Singer (IC50: 4.31 +/- 0.18 ug/mL) exhibited good lipid peroxidation inhibitory activity. The DPPH, ABTS, and CUPRAC assays supported this activity. The ethyl acetate and methanol extracts of Funalia trogii and Ganoderma lucidum indicated good anticholinesterase activity. Ganoderma lucidum had rich phenolic and flavonoid contents, indicating 98.67 +/- 0.32 mg PEs/g extract and 160.38 +/- 1.25 mg QEs/g extract, respectively. DISCUSSION AND CONCLUSION: The results demonstrate that some of the mushroom species tested herein could be used in food and pharmaceutical industries as natural antioxidants. PMID- 25720977 TI - Characterization of an inhibitor of apoptosis protein in Crassostrea gigas clarifies its role in apoptosis and immune defense. AB - The inhibitor of apoptosis (IAP) proteins maintain a balance between cell proliferation and cell death by inhibiting caspase activity and facilitating immune responses. In this study, phylogenetic analysis revealed lineage-specific expansion and tandem duplication of IAPs in the Pacific oyster Crassostrea gigas. We then investigated a representative oyster-specific XIAP-like gene (CgIAP2) to understand how it regulates initiator caspase. Cloning of full-length CgIAP2 from oyster cDNA uncovered a deduced protein containing two BIR domains and a RING domain. Homolog comparison demonstrated that CgIAP2 clustered into the invertebrate branch. We found that CgIAP2 was likely involved in apoptosis inhibition and immune defense, based on high mRNA expression in the gills and labial palps, as well as increased mRNA expression after bacterial challenge. A yeast two-hybrid assay revealed that the BIR2 domain was necessary and sufficient to mediate interaction between CgIAP2 and Cgcaspase-2, providing direct evidence that CgIAP2 participates in apoptosis inhibition. PMID- 25720978 TI - Overlapping and unique signatures in the proteomic and transcriptomic responses of the nematode Caenorhabditis elegans toward pathogenic Bacillus thuringiensis. AB - Pathogen infection can activate multiple signaling cascades that ultimately alter the abundance of molecules in cells. This change can be measured both at the transcript and protein level. Studies analyzing the immune response at both levels are, however, rare. Here, we compare transcriptome and proteome data generated after infection of the nematode and model organism Caenorhabditis elegans with the Gram-positive pathogen Bacillus thuringiensis. Our analysis revealed a high overlap between abundance changes of corresponding transcripts and gene products, especially for genes encoding C-type lectin domain-containing proteins, indicating their particular role in worm immunity. We additionally identified a unique signature at the proteome level, suggesting that the C. elegans response to infection is shaped by changes beyond transcription. Such effects appear to be influenced by AMP-activated protein kinases (AMPKs), which may thus represent previously unknown regulators of C. elegans immune defense. PMID- 25720979 TI - Laminin receptor protein is implicated in hemocyte homeostasis for the whiteleg shrimp Penaeus (Litopenaeus) vannamei. AB - Here we show that knockdown of laminin receptor (Lamr) with PvLamr dsRNA in the whiteleg shrimp Penaeus (Litopenaeus) vannamei (Pv) caused a dramatic reduction specifically in hyaline hemocytes prior to death. Since apoptosis was not detected in hemocytes or hematopoietic cells, other possible causes of hemocyte loss were investigated. Reports that suppression of crustacean hematopoietic factor (CHF)-like protein or hemocyte homeostasis-associated protein (HHAP) also reduced shrimp hemocyte counts led us to carry out yeast two-hybrid (Y2H) and co immunoprecipitation (co-IP) assays to test for interactions between Lamr and Pv homologues to these proteins (PvCHF-like and PvHHAP). The assays revealed that Lamr bound to both these homologues, but that the homologues did not bind to each other. Subsequent RT-PCR assays confirmed that PvLamr dsRNA injection significantly reduced expression levels for both PvCHF-like and PvHHAP genes. Further work is needed to determine how interaction among these three proteins can regulate shrimp hemocyte homeostasis. PMID- 25720980 TI - Serpin-15 from Bombyx mori inhibits prophenoloxidase activation and expression of antimicrobial peptides. AB - Serine protease inhibitors (SPIs) play a key role in physiological responses by controlling protease activities. In this study, we studied the biochemical functions of serpin-15, an SPI, from Bombyx mori (Bmserpin-15). Recombinant Bmserpin-15 was expressed in Escherichia coli cells and used to raise rabbit anti Bmserpin-15 polyclonal antibodies. Bmserpin-15 mRNA and protein expression was detected in all tested tissues, particularly in the fat body and silk gland. After challenge with four different microorganisms (Escherichia coli, Beauveria bassiana, Micrococcus luteus and B. mori nuclear polyhedrosis virus), the expressions of Bmserpin-15 mRNA and protein were induced significantly, particularly by B. bassiana and M. luteus. Recombinant Bmserpin-15 inhibited prophenoloxidase activation, but did not affect phenoloxidase activity, in B. mori hemolymph. Injection of recombinant Bmserpin-15 into B. mori larvae reduced significantly the transcript levels of antimicrobial peptides in fat body. Our results suggested that Bmserpin-15 plays an important role in the innate immunity of B. mori. PMID- 25720981 TI - Clinical value of maternal bile Acid quantification in intrahepatic cholestasis of pregnancy as an adverse perinatal outcome predictor. AB - AIMS: To evaluate the correlation between perinatal outcome and bile acid levels in intrahepatic cholestasis of pregnancy (ICP), and to evaluate variations in the mean bile acid level when stratifying by maternal and perinatal factors. A comparison between mild and severe ICP was made. METHODS: A prospective observational study was performed in pregnant patients who underwent blood tests for bile acids due to persistent pruritus. Based on bile acid levels, maternal and neonatal data were obtained and were compared between patients presenting with ICP and gestational pruritus (normal bile acid level). RESULTS: A total of 145 patients were included, 47 of whom were diagnosed as ICP (52 newborns) and 98 as gestational pruritus (102 newborns). The ICP group had a higher rate of NICU admission (14/42 vs. 6/98, p < 0.001) and global neonatal morbidity (13/42 vs. 9/98, p = 0.002), but these differences were no longer seen after adjusting for gestational age, singleton pregnancies and induction of labour. Patients presenting with severe ICP (maximum bile acids levels above 40 umol/l) showed a higher rate of meconium-stained amniotic fluid (0/28 vs. 4/14, p = 0.009), NICU admission (9/34 vs. 11/17, p = 0.01) and neonatal global morbidity (5/32 vs. 8/17, p = 0.02). CONCLUSIONS: ICP patients have higher rates of adverse neonatal outcomes when compared to those with gestational pruritus. Some of this neonatal morbidity may be secondary to late spontaneous preterm deliveries, multiple gestation and a policy of elective induction of labour after 37 weeks of gestation. A comparison of outcomes among patients with mild and severe ICP shows that the severely affected group has higher rates of meconium-stained amniotic fluid and neonatal morbidity. PMID- 25720982 TI - Repair of Bone Defects Filled with New Calcium Aluminate Cement (EndoBinder). AB - INTRODUCTION: The aim of this study was to evaluate and compare the repair of bone defects filled with calcium aluminate cement (EndoBinder), mineral trioxide aggregate (MTA), and calcium hydroxide. METHODS: After mixing, the cements were inserted into bone defects (3.3 mm) mechanically created in the right and left tibias of 30 rats (Rattus norvegicus, Wistar). In the control group, the bone defects were filled with blood clot of the animal itself. After time intervals of 7, 30, and 90 days had elapsed, bone tissue biopsies (n = 5) were surgically obtained and submitted to laboratory processing. The response of bone tissue in contact with the materials was microscopically analyzed. The percentage of neoformed bone tissue in the defect was determined by means of planimetry counting points superimposed on the histologic image. RESULTS: Significant increase in the percentage of neoformed bone tissue was observed throughout the experimental periods in all groups (P < .05). For the cements EndoBinder and MTA (30 and 90 days), these percentage values were statistically higher than those of the control group (P < .05); however, they were similar to those of calcium hydroxide (P > .05). CONCLUSIONS: EndoBinder and MTA allowed complete repair of bone defects created in rat tibias. PMID- 25720983 TI - Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Are Required for Lipopolysaccharide mediated Mineralization in Murine Odontoblast-like Cells. AB - INTRODUCTION: Odontoblasts play an important role in post-developmental control of mineralization in response to external stimuli in the tooth. The present study investigated whether lipopolysaccharide (LPS), a major bacterial cell wall component, influenced mineralization in a murine odontoblast-like cell (OLC) line and the related intracellular signaling pathways involved. METHODS: Alizarin red S staining was used to assess mineralized nodule formation in OLCs in response to LPS. The effects of LPS on gene expression of odontoblastic markers were investigated by using quantitative real-time reverse-transcriptase polymerase chain reaction. The potential involvement of toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-kappaB), mitogen-activated protein kinase (MAPK), or phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in the mineralized nodule formation, and mRNA expression of several odontoblastic markers of OLCs induced by LPS was assessed by using alizarin red S staining and quantitative real-time reverse-transcriptase polymerase chain reaction. Moreover, LPS stimulation resulted in phosphorylation of protein that was determined by Western blot analysis. RESULTS: OLCs showed reduced mineralized nodule formation and several odontoblastic markers expression in response to LPS exposure. Furthermore, inhibition of TLR4, extracellular signal-regulated kinase (ERK), and PI3K/Akt signaling noticeably antagonized LPS-mediated mineralization in OLCs. However, p38 MAPK, c-Jun N-terminal kinase, and NF-kappaB signaling inhibitors did not affect LPS-mediated mineralization in OLCs. Notably, LPS treatment resulted in a time-dependent phosphorylation of ERK and PI3K/Akt in OLCs, which was abrogated by their specific inhibitors. CONCLUSIONS: LPS decreased mineralization in OLCs via TLR4, ERK MAPK, and PI3K/Akt signaling pathways, but not p38, c-Jun N-terminal kinase, or NF-kappaB signaling. PMID- 25720984 TI - Comparison of the effect of root canal preparation by using WaveOne and ProTaper on postoperative pain: a randomized clinical trial. AB - INTRODUCTION: WaveOne is a single-file reciprocating instrumentation system with the benefits of M-Wire alloy that has increased flexibility and improved resistance to cyclic fatigue over the conventional alloy. Root canal preparation techniques may cause postoperative pain. The goal of the present study was to compare the intensity and duration of postoperative pain when using WaveOne or ProTaper Universal systems for instrumentation of root canals. METHODS: Forty-two patients who fulfilled specific inclusion criteria were assigned to 2 groups according to the root canal instrumentation technique used, WaveOne or ProTaper Universal. Root canal treatment was carried out in 2 appointments, and the severity of postoperative pain was assessed by numerical rating scale (NRS) score after each session until complete pain relief was achieved. Analgesic consumption, duration of pain, and root canal preparation time were also recorded. RESULTS: The mean NRS score and duration of pain after both appointments were significantly higher in the WaveOne group (P < .05); however, the mean analgesic consumption was only significantly higher in the WaveOne group after the first appointment (P < .05). In all groups the highest mean NRS score was seen 6 hours after each therapeutic appointment. Canal preparation time was significantly shorter in the WaveOne group (P < .001). CONCLUSIONS: Postoperative pain was significantly lower in patients undergoing canal instrumentation with ProTaper Universal rotary instruments compared with the WaveOne reciprocating single-file technique. PMID- 25720985 TI - Strawberry homologue of terminal flower1 integrates photoperiod and temperature signals to inhibit flowering. AB - Photoperiod and temperature are major environmental signals affecting flowering in plants. Although molecular pathways mediating these signals have been well characterized in the annual model plant Arabidopsis, much less information is known in perennials. Many perennials including the woodland strawberry (Fragaria vesca L.) are induced to flower in response to decreasing photoperiod and temperature in autumn and they flower following spring. We showed earlier that, in contrast with Arabidopsis, the photoperiodic induction of flowering in strawberry occurs in short days (SD) when the decrease in FvFT1 (flowering locus T) and FvSOC1 (suppressor of the overexpression of constans1) expression leads to lower mRNA levels of the floral repressor, FvTFL1 (terminal flower1). By using transgenic lines and gene expression analyses, we show evidence that the temperature-mediated changes in the FvTFL1 mRNA expression set critical temperature limits for the photoperiodic flowering in strawberry. At temperatures below 13 degrees C, low expression level of FvTFL1 in both SD and long days (LD) allows flower induction to occur independently of the photoperiod. Rising temperature gradually increases FvTFL1 mRNA levels under LD, and at temperatures above 13 degrees C, SD is required for the flower induction that depends on the deactivation of FvSOC1 and FvTFL1. However, an unknown transcriptional activator, which functions independently of FvSOC1, enhances the expression of FvTFL1 at 23 degrees C preventing photoperiodic flowering. We suggest that the observed effect of the photoperiod * temperature interaction on FvTFL1 mRNA expression may allow strawberry to induce flowers in correct time in different climates. PMID- 25720986 TI - Prospective randomized controlled clinical study comparing two dental implant types: volumetric soft tissue changes at 1 year of loading. AB - OBJECTIVE: To evaluate the volumetric changes occurring from prosthesis insertion to the 1-year follow-up (FU) using one- and two-piece dental implants. METHODS: Sixty patients were randomly assigned to receive one-piece or two-piece implants. Casts were obtained at baseline (insertion of final reconstruction) and at 1 year of loading. Finally, 33 pairs of casts (BRA = 18, STM = 15) were deemed appropriate for volumetric analysis of the peri-implant tissues. If the patients had more than one implant, one was randomly selected for analysis. Casts were scanned to obtain stereolithography (STL) files. Baseline and 1-year FU digital models were superimposed with an image analysis program. Linear and volumetric measurements were performed including (i) crown height changes (CHCs), (ii) volumetric changes, and (iii) changes in tissue thickness at three levels below the mucosal margin on the buccal side of the implants (at 1,3, and 5 mm). The Mann-Whitney U-test and the paired t-test were used to analyze the data between the two groups using the patient as the unit of analysis. RESULTS: No significant baseline differences were observed between the one- and two-piece groups for the linear measurements. The mean CHCs in the two-piece group amounted to 0.02 mm (SD +/- 0.32), whereas the one-piece group exhibited a change of -0.17 mm (+/-0.57). The mean volume changes (VCs) were -0.12 mm (+/-0.27) (two-piece group) and -0.03 mm (+/-0.29) (one-piece group). With regard to the changes in tissue thickness, the two-piece group presented a change of -0.15 mm (+/-0.20) at 1 mm, -0.06 mm (+/-0.20) at 3 mm, and -0.2 mm (+/-0.51) at 5 mm. The respective values for the one-piece group were -0.03 mm (+/-0.35), 0.01 mm (+/-0.28), and -0.01 mm (+/ 0.51) at the three levels. None of the differences in linear measurements between baseline and the 1-year FU reached significance. Positive correlations were seen for tissue thickness changes at 1 and 3 mm for both groups (P < 0.05). Significant positive correlations were found for VCs and tissue thickness at 1 mm for the two-piece group and for VCs and tissue thickness at 1,3, and 5 mm for the one-piece group (P < 0.05). CONCLUSION: Within the first year of loading, minimal changes occur with regard to tissue thickness, crown height, and facial volume for both implant types. PMID- 25720987 TI - Bioactive quinone derivatives from the marine brown alga Sargassum thunbergii induce anti-adipogenic and pro-osteoblastogenic activities. AB - BACKGROUND: Health problems related to the lack of bone formation are a major problem for ageing populations in the modern world. As a part of the ongoing trend to develop natural substances that attenuate bone loss in osteoporosis, the effects of the edible brown alga Sargassum thunbergii and its active contents on adipogenic differentiation in 3T3-L1 fibroblasts and osteoblast differentiation in MC3T3-E1 pre-osteoblasts were evaluated. RESULTS: Treatment with S. thunbergii significantly reduced lipid accumulation and expression of adipogenic differentiation markers such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha and sterol regulatory element binding protein 1c. In addition, S. thunbergii successfully enhanced osteoblast differentiation as indicated by increased alkaline phosphatase activity along raised levels of osteoblastogenesis indicators, namely bone morphogenetic protein 2, osteocalcin and collagen type I. Two compounds, sargaquinoic and sargahydroquinoic acid, were isolated from active extract and shown to be active by means of osteogenesis inducement. CONCLUSION: S. thunbergii could be a source for functional food ingredients for improved treatment of osteoporosis and obesity. PMID- 25720988 TI - Conformation-dependent binding and tumor-targeted delivery of siRNA by a designed TRBP2: Affibody fusion protein. AB - Efficiency of systemically delivered siRNA in gene silencing is compromised due to lack of target-specific delivery and rapid clearance of siRNA by in vivo elimination pathways. We designed a fusion protein consisting of a dsRNA binding domain of transactivation response RNA binding protein (TRBP2) fused to ErbB2 binding affibody (AF) for target specific delivery of siRNA. Designated as TRAF, the fusion protein is stable and binds efficiently and specifically to siRNA, forming homogenous non-aggregated and nuclease-resistant particles that efficiently and selectively transport siRNA into HER-2 overexpressing cancer cells and tissues. Administration of siRNA by TRAF into cells resulted in significant silencing of chosen genes involved in cell proliferation viz. AURKB and ErbB2. Noticeably, intravenous administration of TRAF:siRNA against these genes resulted in remarkable tumor suppression in the SK-OV-3 xenograft mouse model. Our results establish the potential of engineered proteins for specific and systemic delivery of siRNA for cancer therapy. FROM THE CLINICAL EDITOR: The use of siRNA in one of many novel treatments in cancer therapy. However, a major challenge for using siRNA is the lack of specificity and rapid RNA clearance. In this article, the authors designed a tumor targeting fusion protein, which can deliver siRNA specifically. In the experimental xenograft model, it was shown that intravenous administration of this resulted in significant tumor suppression. The results seem to hold promise in future clinical studies. PMID- 25720989 TI - Smart polyhydroxyalkanoate nanobeads by protein based functionalization. AB - The development of innovative medicines and personalized biomedical approaches calls for new generation easily tunable biomaterials that can be manufactured applying straightforward and low-priced technologies. Production of functionalized bacterial polyhydroxyalkanoate (PHA) nanobeads by harnessing their natural carbon-storage granule production system is a thrilling recent development. This branch of nanobiotechnology employs proteins intrinsically binding the PHA granules as tags to immobilize recombinant proteins of interest and design functional nanocarriers for wide range of applications. Additionally, the implementation of new methodological platforms regarding production of endotoxin free PHA nanobeads using Gram-positive bacteria opened new avenues for biomedical applications. This prompts serious considerations of possible exploitation of bacterial cell factories as alternatives to traditional chemical synthesis and sources of novel bioproducts that could dramatically expand possible applications of biopolymers. FROM THE CLINICAL EDITOR: In the 21st century, we are coming into the age of personalized medicine. There is a growing use of biomaterials in the clinical setting. In this review article, the authors describe the use of natural polyhydroxyalkanoate (PHA) nanoparticulates, which are formed within bacterial cells and can be easily functionalized. The potential uses would include high-affinity bioseparation, enzyme immobilization, protein delivery, diagnostics etc. The challenges of this approach remain the possible toxicity from endotoxin and the high cost of production. PMID- 25720990 TI - The RANKL-RANK Story. AB - Receptor activator of nuclear factor x03BA;B (RANK) and its ligand (RANKL) have originally been described for their key roles in bone metabolism and the immune system. Subsequently, it has been shown that the RANKL-RANK system is critical in the formation of mammary epithelia in lactating females and the thermoregulation of the central nervous system. RANKL and RANK are under the tight control of the female sex hormones estradiol and progesterone. A reduction of the circulating female sex hormones leading to an increase in RANKL-RANK signaling is the leading cause of osteoporosis in postmenopausal women. Denosumab, a human monoclonal anti RANKL antibody, has been approved for the treatment of postmenopausal osteoporosis, where it is showing great promise. In addition, RANKL-RANK signaling also plays a critical role in other bone pathologies, bone metastasis or hormone-driven breast cancer. This review will highlight some of the functions of RANKL-RANK in bone turnover, the immune system and brain with a focus on the regulatory role of the female sex hormones. PMID- 25720991 TI - The effect of disease-modifying antirheumatic drugs on retinal function in the electrophysiological ex vivo model of the isolated perfused vertebrate retina. AB - BACKGROUND: Disease-modifying antirheumatic drugs (DMARDs) have been suggested in the treatment of inflammatory ophthalmological diseases. The aim of the present study was to investigate the effects of these DMARDs on bovine retinal function. METHODS: Bovine retina preparations were perfused with a standard solution. After recording stable electroretinograms the nutrient solution was substituted by a DMARD medium with varying concentrations of different drugs (etanercept and infliximab) for 30 min. Afterwards b-wave recovery was observed. RESULTS: Significant decreases in the b-wave amplitude (p < 0.05) were found for etanercept 0.5 mg/ml (p = 0.0022). Infliximab 2 mg/ml (p = 0.1276) did not result in any statistically significant b-wave reduction. CONCLUSION: The presented data suggest that infliximab might have the better safety profile than etanercept. PMID- 25720992 TI - Congenital and disseminated pyogenic granuloma-like vascular lesions. PMID- 25720993 TI - Therapeutic potential in 'metaphysical care'. PMID- 25720994 TI - Posttraumatic stress disorder according to DSM-5 and DSM-IV diagnostic criteria: a comparison in a sample of Congolese ex-combatants. AB - BACKGROUND: Compared to DSM-IV, the criteria for diagnosing posttraumatic stress disorder (PTSD) have been modified in DSM-5. OBJECTIVE: The first aim of this study was to examine how these modifications impact rates of PTSD in a sample of Congolese ex-combatants. The second goal of this study was to investigate whether PTSD symptoms were associated with perpetrator-related acts or victim-related traumatic events. METHOD: Ninety-five male ex-combatants in the eastern Democratic Republic of Congo were interviewed. Both the DSM-IV and the DSM-5 PTSD symptom criteria were assessed. RESULTS: The DSM-5 symptom criteria yielded a PTSD rate of 50% (n=47), whereas the DSM-IV symptom criteria were met by 44% (n=42). If the DSM-5 would be set as the current "gold standard," then DSM-IV would have produced more false negatives (8%) than false positives (3%). A minority of participants (19%, n=18) indicated an event during which they were involved as a perpetrator as their most stressful event. RESULTS of a regression analysis (R (2)=0.40) showed that, after accounting for the number of types of traumatic events, perpetrated violent acts were not associated with the symptom severity of PTSD. CONCLUSIONS: The findings demonstrate that more diagnostic cases were produced with the DSM-5 diagnostic rules than were dropped resulting in an increase in PTSD rates compared to the DSM-IV system. The missing association between PTSD symptoms and perpetrated violent acts might be explained by a potential fascinating and excited perception of these acts. PMID- 25720995 TI - Esophageal cancer and head and neck cancer: the earlier, the better. PMID- 25720996 TI - Lessons from interval gastric cancer: read between the lines. PMID- 25720997 TI - Expanding indications of endoscopic submucosal dissection for early gastric cancer: hope or hype? PMID- 25720998 TI - Is microscopic colitis really microscopic? PMID- 25720999 TI - Prognostic significance of CpG island methylator phenotype in colorectal cancer. PMID- 25721000 TI - Endoscopic nasogallbladder drainage in patients with acute cholecystitis: what's predictive factor for technical success? PMID- 25721002 TI - Perspective on peroral endoscopic myotomy for achalasia: Zhongshan experience. AB - Worldwide, peroral endoscopic myotomy (POEM) has achieved remarkable initial outcomes in the treatment of achalasia. In China, POEM has developed very quickly since the first case was performed in our center in August 2010. With ex perience, we have successfully performed POEM for special cases (such as pediatric patients, patients with sigmoid-type esophagus, and patients with recurrent symptoms after previous surgery) and have altered our technique to achieve long-term symptom remission and simplify the POEM proce-dure. These changes include posterior wall incision, full-thick-ness myotomy, a "push-and pull" technique for myotomy, and water-jet assisted POEM. In this article, our experiences in POEM are summarized, including changes in technique, ap-plications of the procedure, and the management of possible complications. (Gut Liver, 2015;9:152-158). PMID- 25721001 TI - Colorectal cancer screening and surveillance in the elderly: updates and controversies. AB - Colorectal cancer is common worldwide, and the elderly are disproportionately affected. Increasing age is a risk factor for the development of precancerous adenomas and colorectal cancer, thus raising the issue of screening and surveillance in older patients. Elderly patients are a diverse and heteroge-neous group, and special considerations such as comorbid medical conditions, functional status and cognitive ability play a role in deciding on the utility of screening and sur-veillance. Colorectal cancer screening can be beneficial to patients, but at certain ages and under some circumstances the harm of screening outweighs the benefits. Increasing ad-verse events, poorer bowel preparation and more incomplete examinations are observed in older patients undergoing colo-noscopy for diagnostic, screening and surveillance purposes. Decisions regarding screening, surveillance and treatment for colorectal cancer require a multidisciplinary approach that accounts not only for the patient's age but also for their overall health, preferences and functional status. This review provides an update and examines the challenges surround-ing colorectal cancer diagnosis, screening, and treatment in the elderly. PMID- 25721003 TI - A case of toxic megacolon caused by clostridium difficile infection and treated with fecal microbiota transplantation. AB - Clostridium difficile infection. The mortality rate of fulminant C. difficile infection is reported to be as high as 50%. Fecal microbiota transplantation is a highly effective treatment in patients with recurrent or refractory C. difficile infection. However, there are few published articles on the use of such transplantation for fulminant C. difficile infection. Here, we report on a patient with toxic megacolon complicated by C. difficile infection who was treated successfully with fecal mi-crobiota transplantation. (Gut Liver, 2015;9:247-250). PMID- 25721004 TI - A unique use of a double-pigtail plastic stent: correction of kinking of the common bile duct due to a metal stent. AB - A 72-year-old man with jaundice by ampullary adenocarci-noma was treated at our hospital. For biliary decompression, a transpapillary, fully covered, self expandable metal stent (FCSEMS) was deployed. Four days later, the patient devel oped acute cholangitis. Endoscopic carbon dioxide cholan-giography revealed kinking of the common bile duct above the proximal end of the FCSEMS. A 7-F double-pigtail plastic stent was therefore placed through the FCSEMS to correct the kink, straightening the common bile duct (CBD) and im-proving cholangitis. This is the first report of a unique use of a double-pigtail plastic stent to correct CBD kinking. The place-ment of a double-pigtail plastic stent can correct CBD kink-ing, without requiring replacement or addition of a FCSEMS, and can lead to cost savings. PMID- 25721005 TI - The cumulative colectomy rate in patients with cytomegalovirus-positive ulcerative colitis. PMID- 25721006 TI - Reply: careful assessment is needed in patients with ulcerative colitis with evidence of cytomegalovirus reactivation. PMID- 25721007 TI - A parent-based intervention to promote healthy eating and active behaviours in pre-school children: evaluation of the MEND 2-4 randomized controlled trial. AB - BACKGROUND: There is a paucity of studies evaluating targeted obesity prevention interventions in pre-school children. OBJECTIVES: We conducted a randomized controlled trial to evaluate the efficacy of a parent-based obesity prevention intervention for pre-schoolers - MEND (Mind, Exercise, Nutrition ... Do It!) 2-4 on child diet, eating habits, physical activity/sedentary behaviours, and body mass index (BMI). METHODS: Parent-child dyads attended 10 weekly 90-min workshops relating to nutrition, physical activity and behaviours, including guided active play and healthy snack time. Assessments were conducted at baseline, immediately post-intervention, and 6 and 12 months post-intervention; child intake of vegetables, fruit, beverages, processed snack foods, fussiness, satiety responsiveness, physical activity, sedentary behaviour and neophobia were assessed via parent proxy report. Parent and child height and weight were measured. RESULTS: Two hundred one parent-child dyads were randomized to intervention (n = 104) and control (n = 97). Baseline mean child age was 2.7 (standard deviation [SD] 0.6) years, and child BMI-for-age z-score (World Health Organization) was 0.66 (SD 0.88). We found significant positive group effects for vegetable (P = 0.01) and snack food (P = 0.03) intake, and satiety responsiveness (P = 0.047) immediately post-intervention. At 12 months follow-up, intervention children exhibited less neophobia (P = 0.03) than controls. CONCLUSION: Future research should focus on additional strategies to support parents to continue positive behaviour change. ACTRN12610000200088. PMID- 25721008 TI - The Optimal Treatment Modality in Patients with T4N2M0 Non-Small Cell Lung Cancer: The Best Choice May Be Definitive Chemoradiotherapy Followed by Consolidation Chemotherapy. AB - BACKGROUND: Stage IIIB non-small cell lung cancer (NSCLC) consists of T4N2M0 and TXN3M0 NSCLC. In the present study, we aimed to evaluate the efficacy of different treatment strategies on the survival of patients with radiologically confirmed T4N2M0 NSCLC. METHODS: A total of 145 patients were evaluated in three groups according to the treatment protocol: induction chemotherapy followed by chemoradiotherapy (induction group); chemoradiotherapy (CRT group), and chemoradiotherapy followed by consolidation chemotherapy (consolidation group). The groups were compared regarding survival. RESULTS: The median progression-free survival (PFS) was 10.9, 10.8 and 17.1 months for the induction, CRT and consolidation groups, respectively (p = 0.021). The median overall survival (OS) was 17.6, 13.8 and 25.2 months for the induction, CRT and consolidation groups, respectively (p = 0.001). CONCLUSIONS: The patients with T4N2M0 NSCLC who were treated with chemoradiotherapy followed by consolidation chemotherapy had the best outcome in terms of PFS and OS. PMID- 25721009 TI - Pestle-pounding and nut-cracking by wild chimpanzees at Kpala, Liberia. AB - Bossou in Guinea is one of the longitudinal study sites of wild chimpanzees, and is located only a few kilometers away from the national border between Guinea and Liberia. The forests in the area spread over the national border of Guinea, and the Bossou chimpanzees have been found to use the neighboring Liberian forest. Local assistants and I started surveying these forests in Liberia, and found that additional groups of chimpanzees lived in Nimba County, Liberia. The present study reports tool use behaviors by chimpanzees living in forests of the Kpala area in Nimba County. We directly observed pestle-pounding behavior, which had been confirmed only in the Bossou group of wild chimpanzees. Moreover, we heard sounds of nut-cracking, and successfully filmed chimpanzees cracking open oil palm nuts with stones. The uniqueness of stone-tool use behaviors has been emphasized with the group of chimpanzees that have been longitudinally studied at Bossou, but the behaviors probably have a wide distribution in this area. Emigrant chimpanzees are thought to contribute to the propagation of the cultural tool-use behaviors. It is also thought that, if the distantly located groups share similar cultural behaviors, there might be genetic exchange between them. Conservation efforts should be needed not only at Bossou, but also in a wider area including nonprotected forests beyond the national border. PMID- 25721010 TI - Size control by rate control in colloidal PbSe quantum dot synthesis. AB - A recently demonstrated approach to control the size of colloidal nanoparticles, "size control by rate control", which was validated on the examples of colloidal CdSe- and CdS-quantum dot (CQD) synthesis, appears to be a general strategy for designing technically applicable CQD-syntheses. The "size control by rate control" concept allows full-yield syntheses of ensembles of CQDs with different sizes by tuning the solute formation rate. In this work, we extended this strategy to dialkylphosphine enhanced hot-injection synthesis of PbSe-CQDs. Furthermore, we provide new insight into the reaction mechanism of dialkylphosphine enhancement in TOPSe based CQD-syntheses. PMID- 25721011 TI - Talking circles: an approach to discipline in schools. PMID- 25721012 TI - Measurement of perihematomal edema in intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Perihematomal edema (PHE) is a marker of secondary injury in intracerebral hemorrhage (ICH). PHE measurement on computed tomography (CT) is challenging, and the principles used to detect PHE have not been described fully. We developed a systematic approach for CT-based measurement of PHE. METHODS: Two independent raters measured PHE volumes on baseline and 24-hour post-ICH CT scans of 20 primary supratentorial ICH subjects. Boundaries were outlined with an edge detection tool and adjusted after inspection of the 3 orthogonal planes. PHE was delineated with the additional principle that it should be (a) more hypodense than the corresponding area in the contralateral hemisphere and (b) most hypodense immediately surrounding the hemorrhage. We examined intra- and interrater reliability using intraclass correlation coefficients and Bland-Altman plots for interrater consistency. CT-based PHE was also compared using magnetic resonance imaging-based PHE detection for 18 subjects. RESULTS: Median PHE volumes were 22.7 cc at baseline and 20.4 cc at 24 hours post-ICH. There were no statistically significant differences in PHE measurements between raters. Interrater and intrarater reliability for PHE were excellent. At baseline and 24 hours, interrater intraclass correlation coefficients were 0.98 (0.96-1.00) and 0.98 (0.97-1.00); intrarater intraclass correlation coefficients were 0.99 (0.99 1.00) and 0.99 (0.98-1.00). Bland-Altman analysis showed the bias for PHE measurements at baseline and 24 hours, -0.5 cc (SD, 5.4) and -3.2 cc (SD, 5.0), was acceptably small. PHE volumes determined by CT and magnetic resonance imaging were similar (23.9+/-16.9 cc versus 23.9+/-16.0 cc, R(2) = 0.98, P<0.0001). CONCLUSIONS: Our method measures PHE with excellent reliability at baseline and 24 hours post-ICH. PMID- 25721013 TI - Enhanced interhemispheric functional connectivity compensates for anatomical connection damages in subcortical stroke. AB - BACKGROUND AND PURPOSE: Motor recovery after stroke has been shown to be correlated with both the fractional anisotropy (FA) of the affected corticospinal tract (CST) and the interhemispheric resting-state functional connectivity (rsFC) of the primary motor cortex (M1). However, the role of the restoration or enhancement of the M1-M1 rsFC in motor recovery remains largely unknown. We aimed to clarify this issue by investigating the correlations between the M1-M1 rsFC and the integrity of the M1-M1 anatomic connection and the affected CST in chronic subcortical stroke patients with good motor outcomes. METHODS: Twenty patients and 16 healthy controls underwent multimodal magnetic resonance imaging examinations. Diffusion tensor imaging was used to reconstruct the M1-M1 anatomic connection and bilateral CSTs. White matter integrity of these tracts was assessed using FA. Resting-state functional magnetic resonance imaging was used to calculate M1-M1 rsFC. Group differences in these measures were compared. Correlations between M1-M1 rsFC and FA of the M1-M1 anatomic connection and the affected CST were analyzed in patients with stroke. RESULTS: Compared with healthy controls, patients with stroke exhibited significantly reduced FA in the affected CST and the M1-M1 anatomic connection and a significantly increased M1 M1 rsFC. The FA values of the affected CST were positively correlated with the M1 M1 anatomic connection, and these FA values were negatively correlated with the M1-M1 rsFC in these patients. CONCLUSIONS: Our findings suggest that the M1-M1 anatomic connection impairment is secondary to CST damage, and the M1-M1 rsFC enhancement may reflect compensatory or reactive neural plasticity in stroke patients with CST impairment. PMID- 25721014 TI - Significant period between presentation and diagnosis in basilar artery occlusion: five cases and the lessons learned. AB - Basilar artery occlusion remains a challenging pathological process. Time delay between presentation and diagnosis and treatment can be associated with poor outcome, but the low frequency and variable presentation in BAO makes rapid diagnosis difficult. Clinicians should maintain an index of suspicion for basilar artery occlusion in patients of any age who present with focal neurological symptoms that could be referable to the basilar artery. Timely vessel imaging is critical for the diagnosis and initiation of treatment in these patients. PMID- 25721015 TI - Letter by Zuo and Xu regarding article, "Norrin protected blood-brain barrier via frizzled-4/beta-catenin pathway after subarachnoid hemorrhage in rats". PMID- 25721016 TI - Response to letter regarding article, "Norrin protected blood-brain barrier via frizzled-4/beta-catenin pathway after subarachnoid hemorrhage in rats". PMID- 25721017 TI - Defining the ischemic penumbra using magnetic resonance oxygen metabolic index. AB - BACKGROUND AND PURPOSE: Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography-derived cerebral metabolic rate of oxygen utilization (CMRO2), to derive a pair of ischemic thresholds: (1) an irreversible injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. METHODS: Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: <4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured cerebral blood flow, and an asymmetrical spin echo sequence measured oxygen extraction fraction, to derive OMI (OMI=cerebral blood flow*oxygen extraction fraction). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in 3 tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. RESULTS: The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. CONCLUSIONS: OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample. PMID- 25721018 TI - Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. AB - BACKGROUND AND PURPOSE: Lacunar stroke accounts for ~25% of ischemic stroke, but optimal antiplatelet regimen to prevent stroke recurrence remains unclear. We aimed to evaluate the efficacy of antiplatelet agents in secondary stroke prevention after a lacunar stroke. METHODS: We searched MEDLINE, Embase, and the Cochrane library for randomized controlled trials that reported risk of recurrent stroke or death with antiplatelet therapy in patients with lacunar stroke. We used random effects meta-analysis and evaluated heterogeneity with I(2). RESULTS: We included 17 trials with 42,234 participants (mean age 64.4 years, 65% male) and follow up ranging from 4 weeks to 3.5 years. Compared with placebo, any single antiplatelet agent was associated with a significant reduction in recurrence of any stroke (risk ratio [RR] 0.77, 0.62-0.97, 2 studies) and ischemic stroke (RR 0.48, 0.30-0.78, 2 studies), but not for the composite outcome of any stroke, myocardial infarction, or death (RR 0.89, 0.75-1.05, 2 studies). When other antiplatelet agents (ticlodipine, cilostazol, and dipyridamole) were compared with aspirin, there was no consistent reduction in stroke recurrence (RR 0.91, 0.75-1.10, 3 studies). Dual antiplatelet therapy did not confer clear benefit over monotherapy (any stroke RR 0.83, 0.68-1.00, 3 studies; ischemic stroke RR 0.80, 0.62-1.02, 3 studies; composite outcome RR 0.90, 0.80-1.02, 3 studies). CONCLUSIONS: Our results suggest that any of the single antiplatelet agents compared with placebo in the included trials is adequate for secondary stroke prevention after lacunar stroke. Dual antiplatelet therapy should not be used for long-term stroke prevention in this stroke subtype. PMID- 25721019 TI - An efficient process for wastewater treatment to mitigate free nitrous acid generation and its inhibition on biological phosphorus removal. AB - Free nitrous acid (FNA), which is the protonated form of nitrite and inevitably produced during biological nitrogen removal, has been demonstrated to strongly inhibit the activity of polyphosphate accumulating organisms (PAOs). Herein we reported an efficient process for wastewater treatment, i.e., the oxic/anoxic/oxic/extended-idle process to mitigate the generation of FNA and its inhibition on PAOs. The results showed that this new process enriched more PAOs which thereby achieved higher phosphorus removal efficiency than the conventional four-step (i.e., anaerobic/oxic/anoxic/oxic) biological nutrient removal process (41 +/- 7% versus 30 +/- 5% in abundance of PAOs and 97 +/- 0.73% versus 82 +/- 1.2% in efficiency of phosphorus removal). It was found that this new process increased pH value but decreased nitrite accumulation, resulting in the decreased FNA generation. Further experiments showed that the new process could alleviate the inhibition of FNA on the metabolisms of PAOs even under the same FNA concentration. PMID- 25721020 TI - Developing intuitions about free will between ages four and six. AB - Our folk psychology includes intuitions about free will; we believe that our intentional acts are choices and that, when such actions are not constrained, we are free to act otherwise. In a series of five experiments, we ask children about their own and others' freedom of choice and about the physical and mental circumstances that place limitations on that freedom. We begin with three experiments establishing a basis for this understanding at age four. We find that 4-year-olds endorse their own and others' ability to "do otherwise" only when they or others are free to choose a course of action, but not when others' actions are physically impossible (Experiment 1), their own actions are physically constrained (Experiment 2), and their own actions are epistemically constrained (Experiment 3). We then examine developmental changes in children's understanding of actions and alternatives that lead to more adult-like free will intuitions. Across two experiments, 6-year-olds, but not 4-year-olds, endorse another person's (Experiment 4) or their own (Experiment 5) freedom to act against stated desires. These age-related changes suggest relationships between a belief in free will and other cognitive and conceptual developments in theory of mind, self-control and self-awareness that take place in early childhood. PMID- 25721021 TI - Children's mappings between number words and the approximate number system. AB - Humans can represent number either exactly--using their knowledge of exact numbers as supported by language, or approximately--using their approximate number system (ANS). Adults can map between these two systems--they can both translate from an approximate sense of the number of items in a brief visual display to a discrete number word estimate (i.e., ANS-to-Word), and can generate an approximation, for example by rapidly tapping, when provided with an exact verbal number (i.e., Word-to-ANS). Here we ask how these mappings are initially formed and whether one mapping direction may become functional before the other during development. In two experiments, we gave 2-5 year old children both an ANS to-Word task, where they had to give a verbal number response to an approximate presentation (i.e., after seeing rapidly flashed dots, or watching rapid hand taps), and a Word-to-ANS task, where they had to generate an approximate response to a verbal number request (i.e., rapidly tapping after hearing a number word). Replicating previous results, children did not successfully generate numerically appropriate verbal responses in the ANS-to-Word task until after 4 years of age- well after they had acquired the Cardinality Principle of verbal counting. In contrast, children successfully generated numerically appropriate tapping sequences in the Word-to-ANS task before 4 years of age--well before many understood the Cardinality Principle. We further found that the accuracy of the mapping between the ANS and number words, as captured by error rates, continues to develop after this initial formation of the interface. These results suggest that the mapping between the ANS and verbal number representations is not functionally bidirectional in early development, and that the mapping direction from number representations to the ANS is established before the reverse. PMID- 25721023 TI - Pre-eclampsia during pregnancy and cardiovascular disease later in life: the case for a risk group. AB - INTRODUCTION: Women with pre-eclampsia (PE) have an increased risk of cardiovascular disease (CVD) later in life. This association might reflect an effect of pre-eclampsia on mechanisms inducing a higher risk of CVD or the presence of a group at risk. MATERIALS AND METHODS: The possibility that women with a magnesium deficiency might constitute a risk group was examined using published evidence form investigations on PE and CVD. RESULTS: Available data strongly suggest that a magnesium deficiency is a major risk factor for both PE and for CVD disease later in life. CONCLUSIONS: Magnesium homeostasis studies in women with PE should be undertaken for validation purposes. The results suggest that women with PE should be given dietary counselling to decrease future risks of CVD. PMID- 25721022 TI - Environmental effects of modified clay flocculation on Alexandrium tamarense and paralytic shellfish poisoning toxins (PSTs). AB - Among various mitigation strategies for harmful algal blooms (HABs), the flocculation of algal cells by using modified clay (MC) has been widely applied in the field, particularly in Japan, Korea and China. However, to examine the long-term effects and the environmental safety of this method, we investigated alterations in macronutrients and paralytic shellfish poisoning toxins (PSTs) induced by the application of MC treatment to a toxic bloom, Alexandrium tamarense. The control, algal cells grew in nature condition (A1), was compared to the only MC flocculation (A2) and the MC-sediment co-matrix systems of A. tamarense (A3). The low-dosage of 0.25 g L(-1) MC could efficiently remove >90% of the A. tamarense cells within 3.5h. The mechanisms underlying the effects elicited by MC flocculation on nutrient cycling, PSTs and Chl-a degradation were also discussed. This study demonstrated that MC treatment was able to significantly remove the macronutrients (43-60% TP removal and 17-30% TN removal) and scavenge most of the PSTs from seawater, thereby speeding up the nutrient settling and the transformation and degradation of PSTs (83% decreasing in A2). Simultaneously, the study firstly demonstrated the potential detoxification of PSTs by using MC treatment, from the high toxicity of gonyautoxin 1 and 4 (GTX1 and GTX4) to the lower toxicity decarbamoyl gonyautoxins (dcGTX3) and gonyautoxin 2 (GTX2), particularly within the water-sediment environment during the two month incubation. PMID- 25721024 TI - In silico studies, synthesis and binding evaluation of substituted 2 pyrrolidinones as peptidomimetics of RGD tripeptide sequence. AB - In silico optimisation, synthesis and binding evaluation of alphavbeta3 integrin's affinity for precursors of a new RGD peptidomimetics family are presented. The 2-pyrrolidinone building block was obtained by condensation of l lysine with dimethoxydihydrofuran followed by reduction. The ring was functionalized with a carboxylic acid and a guanidinium appendage. On the pyrrolidinone heterocycle, the effects on affinity of position, length and relative geometry of the two acid or basic functionalized side chains introduced on the pyrrolidinone ring have been previously evaluated by docking studies. Peptidomimetics have finally been evaluated by competition binding assays for alphavbeta3 integrin's affinity using radio-ligands. PMID- 25721025 TI - Antiplasmodial activity: the first proof of inhibition of heme crystallization by marine isonitriles. AB - Over a decade ago Wright et al., proposed a putative antiplasmodial mechanism of action for marine isonitriles (1, and 3-6) and isothiocyanate (2) that involved interference in heme detoxification by Plasmodium falciparum thus inhibiting the growth of the parasite. In the current paper we describe the successful down scaling of Egan's beta-hematin inhibition assay for analyses of small quantities of marine natural products as potential beta-hematin inhibitors. The modified assay revealed for the first time that the most active antiplasmodial marine isonitrile 4 (IC50 13 nM) totally inhibited beta-hematin crystallization while 5 (IC50 31 nM) and 6 (IC50 81 nM) showed inhibition at lower levels. A cursory ab initio molecular dynamics investigation into the relative stabilities of bonded complexes between isocyanate, isothiocyanate and isonitrile groups with the iron center of heme supported our findings that these marine metabolites do indeed interfere with biocrystallization of heme. PMID- 25721026 TI - Polyoxometalate-Based Organic-Inorganic Hybrids as Antitumor Drugs. AB - Polyoxometalates (POMs) have shown encouraging antitumor activity. However, their cytotoxicity in normal cells and unspecific interactions with biomolecules are two major obstacles that impede the practical applications of POMs in clinical cancer treatment. Derivatization of POMs with more biocompatible organic ligands is expected to cause a synergetic effect and achieve improved bioactivity and biospecificity. Herein, the synthesis of an amphiphilic organic-inorganic hybrid is reported by grafting a long-chain organoalkoxysilane lipid onto a POM. The amphiphilic POM hybrid could spontaneously assemble into the vesicles and exhibits enhanced antitumor activity for human colorectal cancer cell lines (HT29) compared to that of parent POMs. This detailed study reveals that the amphiphilic nature of POM hybrids enables the as-formed vesicles to easily bind to the cell membranes and then be uptaken by the cells, thus leading to a substantial increase in antitumor activity. Such prominent antitumor action is mostly accomplished via cell apoptosis, which ultimately results in cell death. Our finding demonstrates that novel POM hybrids-based drugs with increased bioactivity could be obtained by decorating POMs with selective organic ligands. PMID- 25721027 TI - TLR2 Involved in Naive CD4+ T Cells Rescues Stress-Induced Immune Suppression by Regulating Th1/Th2 and Th17. AB - Stress, either physical or psychological, can have a dramatic impact on our immune system. There has been little progress, however, in understanding chronic stress-induced immunosuppression. Naive CD4+ T cells could modulate immune responses via differentiation to T helper (Th) cells. In this study, we showed that stress promotes the release of the Th1 cytokines interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, the Th2 cytokines interleukin (IL)-4 and IL-10 and the Th17 cytokine IL-17 of splenic naive CD4+ T cells. This suggests that stress promotes the differentiation of naive CD4+ T cells to Th1, Th2 and Th17 cells. Knockout strategies verified that TLR2 might modulate the differentiation of Th1/Th2 cells by inhibiting p38 mitogen-activated protein kinase (MAPK). Taken together, our data suggest that chronic stress induces immune suppression by targeting TLR2 and p38 MAPK in naive CD4+ T cells. PMID- 25721028 TI - Influence of the N-N Coligand: C-C coupling instead of formation of imidazol-2-yl complexes at {Mo(eta(3)-allyl)(CO)2} fragments. Theoretical and experimental studies. AB - New N-methylimidazole (N-MeIm) complexes of the {Mo(eta(3)-allyl)(CO)2(N-N)} fragment have been prepared, in which the N,N-bidentate chelate ligand is a 2 pyridylimine. The addition of a strong base to the new compounds deprotonates the central CH group of the imidazole ligand and subsequently forms the C-C coupling product that results from the nucleophilic attack to the imine C atom. This reactivity contrasts with that previously found for the analogous 2,2'-bipyridine compounds [Mo(eta(3)-allyl)(CO)2(bipy)(N-RIm)]OTf [N-RIm = N-MeIm, N mesitylimidazole (N-MesIm, Mes= 2,4,6-trimethylphenyl); OTf = trifluoromethanesulfonate) which afforded imidazol-2-yl complexes upon deprotonation. Density Functional Theory (DFT) computations uncover that the reactivity of the imine C atom along with its ability to delocalize electron density are responsible for the new reactivity pattern found for the kind of molybdenum complexes reported herein. PMID- 25721029 TI - Prenatal diagnosis and treatment of spina bifida. Preface. PMID- 25721031 TI - Soluble urokinase-type plasminogen activator levels are related to plasma cytokine levels but have low predictive value for mortality in trauma patients. AB - INTRODUCTION: Soluble urokinase-type plasminogen activator (suPAR) represents a marker for immune activation and has predictive value in critically ill patients. The kinetics of suPAR and its correlation with the immune response and outcome in trauma patients are unknown. METHODS: Plasma concentrations of inflammatory cytokines and suPAR were determined in adult trauma patient (n = 69) samples obtained by the Helicopter Emergency Medical Services at arrival at the emergency department (ED) and at days 1, 3, 5, 7, 10, and 14. RESULTS: Initial suPAR levels were unrelated to injury severity score and higher in nonsurvivors compared with survivors, although no difference was observed between early and late mortality. The area under the receiver operating characteristic curve to predict mortality was 0.6 (95% confidence interval, 0.48-0.72). Soluble urokinase-type plasminogen activator levels increased over time in 94% of patients, although suPAR increase did not precede death. Tumor necrosis factor alpha at the ED correlated with suPAR at that time point, whereas concentrations of other proinflammatory cytokines at the ED correlated with suPAR levels at days 1 and 5. CONCLUSIONS: After trauma, initial suPAR plasma concentrations are higher in nonsurvivors compared with survivors, but its predictive value is low. Soluble urokinase-type plasminogen activator levels increase over time after trauma, and concentrations at later time points are related to cytokine levels at the ED. PMID- 25721030 TI - Increased incidence of diuretic use in critically ill obese patients. AB - OBJECTIVE: Sodium retention occurs commonly in cardiac and liver disease, requiring the administration of diuretics to restore fluid balance. Whether obesity is associated with sodium retention has not been fully evaluated. METHODS: In a large single-center cohort of critically ill patients, we evaluated whether admission body mass index was associated with the administration of either oral or intravenous diuretics during the intensive care unit (ICU) stay. MAIN RESULTS: Of 7724 critically ill patients, 3946 (51.1%) were prescribed diuretics during the ICU stay. Overweight, class I obesity, and class II/III obesity were associated with a 1.35 (95% confidence interval [CI], 1.20-1.53; P < .001), 1.56 (95% CI, 1.35-1.80; P < .001), and 1.91 (95% CI, 1.61-2.26; P < .001) adjusted risk of receiving diuretics within the ICU, respectively. In adjusted analysis, a 5-kg/m(2) increment of body mass index was associated with a 1.19 (95% CI, 1.14-1.23; P < .001) increased adjusted risk of within-ICU diuretics. Among those patients receiving loop diuretics, obese patients received significantly larger daily diuretic doses. CONCLUSION: Critically ill obese patients are more likely to receive diuretics during their stay in the ICU and to receive higher dosages of diuretics. Our data suggest that obesity is an independent risk factor for sodium retention. PMID- 25721032 TI - Cancer risk in dermatomyositis: a meta-analysis of cohort studies. AB - BACKGROUND: An association between dermatomyositis (DM) and cancer has been reported since 1916; however, estimates of the associated risk vary widely. For cost-effectiveness reasons it might be important to elucidate the degree of overall cancer risk in DM. OBJECTIVE: The aim of this systematic review was to investigate the association of cancer in DM by performing a meta-analysis of cohort studies. DATA SOURCES: A systematic literature search of PubMed, Ovid MEDLINE, EMBASE, Web of Science, Scopus, and the Cochrane Collaboration was conducted without language restriction, to 1 May 2014. STUDY SELECTION: Inclusion criteria included cohort studies assessing overall cancer risk in DM. Two reviewers independently performed the study selection. Inter-rater reliability for inclusion decisions was quantified using Cohen's kappa statistic. Disagreements were resolved by discussion. DATA EXTRACTION AND SYNTHESIS: Desired variables were extracted from eligible studies independently by two investigators and disagreements were resolved by discussion. Quality of the selected studies was assessed using a modification of a recently employed system designed with reference to Meta-analysis Of Observational Studies in Epidemiology (MOOSE), Quality Assessment Tool for Systematic Reviews of Observational Studies (QATSO), and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). Summary estimates were derived using a random-effects model. MAIN OUTCOME(S) AND MEASURE(S): Main outcome was the calculated relative risk of developing cancer after diagnosis of DM compared with the general population, estimated as the age- and sex-adjusted standardized incidence ratio (SIR). We hypothesized a priori that the relative risk would be higher in patients diagnosed with DM. RESULTS: A total of 1,272 articles were initially identified but only ten studies met the inclusion criteria. Selected studies included seven population-based and three hospital-based DM cohorts that ranged from 49 to 1,012 patients and had mean follow-up times from 3.7 to 10.4 years. The pooled SIR for the incidence of overall cancer in DM patients was 4.79 (95% confidence interval 3.71-5.87) with significant heterogeneity (I(2) = 85.8%). However, the heterogeneity had no substantial influence on the pooled SIR for overall cancer in DM according to the sensitivity analysis. CONCLUSIONS: Compared with the general population, DM patients are at a significantly increased risk for developing cancer. Understanding the magnitude of this risk is highly relevant toward assisting healthcare providers in clinical decision making, such as screening DM patients for cancer. PMID- 25721033 TI - 15-year longitudinal study of mortality in a general neurosurgical practice. AB - This paper analyses patient mortality rates in a prospectively acquired database of all admissions under one consultant neurosurgeon over a 15-year period from April 1999 to March 2014. Out of 6006 admissions, there were 163 deaths (2.7%). Surgical mortality was 3.0% (129/4255 cases). In 105 of the surgical patients, the aim of surgery was recorded preoperatively as being 'to save life' (81%). 14 patients had surgery for pathology that was not life threatening (11%) - four had burr hole surgery for a chronic subdural haematoma and one died after surgical treatment for subarachnoid haemorrhage. Seven died from complications of tumour surgery and two died following epilepsy surgery. A further ten died after endovascular treatment of an aneurysm (9%). The average annual mortality was 10.8 cases (standard deviation +/- 3.06). 147 patients were admitted as an emergency (90%). Only five patients were admitted from a waiting list to be classified as elective retrospectively. The paper helps to define that vital element of neurosurgery practice, which involves the management of patients with life threatening pathology. Elective mortality rates may be a truer representation of individual surgical competence but these do not reflect overall neurosurgical practice. PMID- 25721034 TI - David Price--Pioneer of digital ICP monitoring, neurosurgeon and teacher. AB - In early 1970s first personal desk-top computers started to be available in hospitals. Mr Price was one of the pioneers introducing his own software to identify Marmarou's model of CSF space during infusion studies to diagnose patients suffering from hydrocephalus. His closed-loop control system for infusion of mannitol to manage patients at risk of intracranial hypertension was designed in 1977. The system worked successfully for 10 years in Pinderfields Hospital in Wakefield, UK. In the middle 1980's he initiated international cooperation with Children's Health Centre in Poland in long-term computer assisted monitoring and analysis of ICP. Software designed in a course of this cooperation paved the way for contemporary package of ICM+ (Intensive Care Monitor, University of Cambridge, UK). Our scientific portfolio from these years (1985-1995) contains hundreds of head injured patients with waveform ICP analysis, introduction of compensatory reserve index RAP, few highly cited papers. Now, we understand ICP much better thanks to David's personal passion and extremely friendly support. PMID- 25721035 TI - Sinking skin flap syndrome (or Syndrome of the trephined): A review. AB - BACKGROUND: Bone defects of the skull are observed in various pathological conditions, including head trauma and conditions requiring surgery of the skull. Independent of the consequences of the original aetiology that necessitated the craniectomy, the bone defect alone may be the cause of the symptoms, called 'trephined syndrome' or 'sinking skin flap syndrome'. Despite the early recognition of neurological symptoms directly linked to craniectomy, the description of this syndrome has often relied on a small series or single clinical case reports. OBJECTIVES: To list the previously reported symptoms of SSFS. DATA SOURCES: We selected the references for this review by searching PubMed, focusing on articles published prior to June 2013 and using references from relevant articles. STUDY ELIGIBILITY CRITERIA: We used the following search terms: 'trephined syndrome', 'syndrome of the trephined', 'Sinking skin flap', and 'sinking skin flap syndrome'. There were no language restrictions. The final reference list was generated on the basis of its relevance to the topics covered in this review. CONCLUSIONS: Clinicians need to be aware of sinking skin flap syndrome and to look for abnormal neurological developments in patients with craniectomy in order to avoid unnecessary testing and to prevent its occurrence. Accordingly, cranioplasty can be undertaken as soon as necessary. PMID- 25721036 TI - One of few or one of many: Social identification and psychological well-being among minority youth. AB - Feeling belongingness with small social groups such as the family or a group of friends predicts psychological well-being. Acculturation research has argued for similar effects of belongingness with large social groups. In particular, a strong ethnic identity is assumed to improve psychological well-being among members of minority groups, but this conclusion has been drawn based on cross sectional data. This study uses three-wave longitudinal data collected among adolescents from ethnic minority groups (N = 705), comparing identification with small groups (the family and the school class) with identification with large groups (the ethnic in-group and the nation) as predictors of psychological well being (self-esteem, mental health problems, and life satisfaction). Analyses suggest that identification with small groups, in particular with the family, can predict developments in psychological well-being (self-esteem and mental health). In contrast, the data gave no support for causal effects from ethnic identity or national identity, in spite of substantial bivariate correlations with all three dimensions in psychological well-being. The findings have implications for acculturation research. In particular, research on ethnic or national identity as predictors of psychological well-being will benefit from adding small-group identities as covariates and using longitudinal data. PMID- 25721037 TI - Charcot osteoarthropathy and coronary artery disease in diabetes: the twilight of innocence? PMID- 25721038 TI - Anisotropic shock sensitivity in a single crystal delta-cyclotetramethylene tetranitramine: a reactive molecular dynamics study. AB - The anisotropic shock sensitivity in a single crystal delta-cyclotetramethylene tetranitramine (delta-HMX) was investigated using the compress-shear reactive dynamics (CS-RD) computational protocol. Significant anisotropies in the thermo mechanical and chemical responses were found by measuring the shear stress, energy, temperature, and chemical reactions during the dynamical process for the shock directions perpendicular to the (100), (010), (001), (110), (101), (011), and (111) planes. We predict that delta-HMX is sensitive for the shocks perpendicular to the (111), (011), (110), and (101) planes, which is intermediate to the (100) and (010) plane and is insensitive to the (001) plane. The internal energy accumulated within the duration of the surmounting shear stress barrier is a useful criterion to distinguish the sensitive directions from the less sensitive ones. The molecular origin of the anisotropic sensitivity is suggested to be the intermolecular steric arrangements across a slip plane induced by shock compression. The shear deformation induced by the shock along the sensitive direction encounters strong intermolecular contacts and has small intermolecular free space for geometry relaxation when the molecules collide, leading to high shear stress barriers and energy accumulation, which benefits the temperature increase and initial chemical bond breaking that trigger further reactions. PMID- 25721039 TI - What came first: MDS or AML? AB - In this issue of Blood, Lindsley et al have identified a set of 8 genes that, when mutated, appear to be highly specific for secondary acute myeloid leukemia (AML) vs de novo AML. PMID- 25721040 TI - CD30: seeing is not always believing. AB - Although most investigators are well aware of the incredible success of brentuximab vedotin in the treatment of patients with Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma (ALCL), the study by Jacobsen and colleagues in this issue of Blood demonstrates surprising activity of this agent in patients with B-cell non-Hodgkin lymphoma (NHL). PMID- 25721041 TI - Treatment of primary CNS lymphoma. AB - In this issue of Blood, Omuro et al report the results of a phase 2 study for patients with newly diagnosed primary central nervous system lymphoma (PCNSL) using induction immunochemotherapy (rituximab, high-dose methotrexate [MTX], vincristine, procarbazine) followed by a novel consolidation high-dose chemotherapy (thiotepa, busulfan, cyclophosphamide) and autologous stem cell transplantation (HDC-ASCT). PMID- 25721042 TI - Malignant TOXication of T cells. AB - In this issue of Blood, Huang et al show that aberrant expression of TOX plays a central role in malignant survival, proliferation, and tumor formation in cutaneous T-cell lymphoma (CTCL). PMID- 25721043 TI - Targeting BCR-ABL and JAK2 in Ph+ ALL. AB - In this issue of Blood, Appelmann et al provide evidence for prolonged survival and prevention of resistance in a mouse model of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) by combined targeting of the BCR-ABL kinase and Janus kinase 2 (JAK2) with dasatinib and ruxolitinib, respectively. PMID- 25721044 TI - A bit of sweetness for GVHD prevention. AB - In this issue of Blood, Parmar et al report on preclinical data suggesting that use of ex vivo fucosylated third-party human regulatory T cells (Tregs) could be an effective strategy for prevention of graft-versus-host disease (GVHD). PMID- 25721045 TI - The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells. AB - Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs. PMID- 25721046 TI - Reversible induction of translational isoforms of p53 in glucose deprivation. AB - Tumor suppressor protein p53 is a master transcription regulator, indispensable for controlling several cellular pathways. Earlier work in our laboratory led to the identification of dual internal ribosome entry site (IRES) structure of p53 mRNA that regulates translation of full-length p53 and Delta40p53. IRES-mediated translation of both isoforms is enhanced under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum stress, oncogene induced senescence and cancer. In this study, we addressed nutrient-mediated translational regulation of p53 mRNA using glucose depletion. In cell lines, this nutrient-depletion stress relatively induced p53 IRES activities from bicistronic reporter constructs with concomitant increase in levels of p53 isoforms. Surprisingly, we found scaffold/matrix attachment region-binding protein 1 (SMAR1), a predominantly nuclear protein is abundant in the cytoplasm under glucose deprivation. Importantly under these conditions polypyrimidine-tract binding protein, an established p53 ITAF did not show nuclear-cytoplasmic relocalization highlighting the novelty of SMAR1-mediated control in stress. In vivo studies in mice revealed starvation-induced increase in SMAR1, p53 and Delta40p53 levels that was reversible on dietary replenishment. SMAR1 associated with p53 IRES sequences ex vivo, with an increase in interaction on glucose starvation. RNAi-mediated-transient SMAR1 knockdown decreased p53 IRES activities in normal conditions and under glucose deprivation, this being reflected in changes in mRNAs in the p53 and Delta40p53 target genes involved in cell-cycle arrest, metabolism and apoptosis such as p21, TIGAR and Bax. This study provides a new physiological insight into the regulation of this critical tumor suppressor in nutrient starvation, also suggesting important functions of the p53 isoforms in these conditions as evident from the downstream transcriptional target activation. PMID- 25721047 TI - Utility of the hand-drawn spiral as a tool in clinical-epidemiological research on essential tremor: data from four essential tremor cohorts. AB - BACKGROUND: In descriptive epidemiological studies, investigators must screen large numbers of individuals. How one best screens populations for essential tremor (ET); however, remains an open question. The collection of a standardized writing sample (e.g., a hand-drawn spiral) is a method with many practical advantages, yet there are virtually no data on the validity of this particular method. METHODS: Four hand-drawn spirals (2 right, 2 left) were collected from 831 ET cases across four distinct study settings (population-based study, family study, environmental epidemiological study, brain repository) and, in two of these studies, from 697 controls. Spirals were rated (range 0-3) by a senior movement disorder neurologist. These 1,528 participants also underwent a detailed neurological examination, and total tremor scores (range 0-36) and ET diagnoses were assigned by the neurologist. RESULTS: The proportion of cases with hand drawn spiral ratings >=1.5 in either arm ranged from 78.8-97.0%; only 4.7% of controls had spirals with tremor of that severity. The hand-drawn spiral rating was highly correlated with the total tremor score (r = 0.65-0.73, p < 0.001). CONCLUSIONS: The hand-drawn spiral is a sensitive and specific method of screening for ET. Furthermore, it serves as a valid measure of overall tremor severity. PMID- 25721049 TI - Role of Chinese herbal medicinal ingredients in secretion of cytokines by PCV2 induced endothelial cells. AB - While T-lymphocytes are the major cell type responsible for host responses to a virus (including induction of inflammatory responses to aid in ultimate removal of virus), other cells, including macrophages, epithelial and dendritic cells also have key roles. Endothelial cells also play important roles in physiologic/pathologic processes, like inflammation, during viral infections. As endothelial cells can be activated to release various endogenous compounds, including some cytokines, ex vivo measures of cytokine formation by the cells can be used to indirectly assess any potential endothelial dysfunction in situ. The research presented here sought to investigate potential immunolomodulatory effects of five saponins on endothelial cells: Saikosaponins A (SSA) and D (SSD), Panax Notoginseng Saponin (PNS) and Notoginsenoside R1 (SR1) and Anemoside B4 (AB4). For this, cells (porcine iliac artery endothelial line) were challenged with a virus isolate PCV2-AH for 24 h and then treated with the test saponin (at 1, 5 or 10 MUg/ml) for an additional 24 h at 37 degrees C. The culture supernatants were then collected and analyzed for interleukin (IL)-2, -4 and -10, as well as interferon (IFN)-gamma by ELISA. The results revealed that PNS and SR1 inhibited the production of IL-4; PNS, SR1 and AB4 inhibited the secretion of IL 10; SSA, SSD and PNS up-regulated IL-2 expression; SSA and SSD increased the level of IFNgamma. All these changes were significant. Taken together, the data suggested these saponins might potentially have a capacity to regulate immune responses in vivo via changes in production of these select cytokines by infected endothelial cells. Nevertheless, the impact of these agents on other key cell types involved in anti-viral responses, including T-lymphocytes, remains to be determined. PMID- 25721050 TI - Exposure to DDT metabolite p,p'-DDE increases autoimmune type 1 diabetes incidence in NOD mouse model. AB - The incidence of autoimmune Type 1 diabetes (T1D) has been steadily rising in developed countries. Although the exact cause of T1D remains elusive, it is known that both genetics and environmental factors play a role in its immunopathogenesis. Whereas a positive association between p,p'-DDE, a DDT metabolite, and Type 2 diabetes (T2D) has been well established, its role in T1D development in an experimental animal model has never been elucidated. This study seeks to investigate the effects of DDE exposure on the development of T1D in a NOD mouse model. As T1D is a T-cell-mediated disease, the underlying mechanism of DDE action on T-cells was studied in vitro and, in the context of acute and chronic DDE exposure, in vivo by investigating lymphocytes' viability, proliferation, their subsets and cytokine profiles. Chronic high-dose DDE treatment, initiated in pre-diabetic 8-week-old NOD females administered twice weekly intraperitoneally with 50 mg/kg DDE, significantly increased diabetes incidence and augmented disease severity in treated animals. Whereas T-cell proliferation and cell viability in the spleens of treated mice were not affected, diabetogenic action of chronic DDE exposure was associated with a decrease in regulatory T-cells and a suppression of secretion of protective cytokines, such as IL-4 and IL-10. Interestingly, an acute high-dose in vivo treatment of 8-week-old NOD males with 100 mg DDE/kg, administered intraperitoneally every other day over a period of 10 days, increased T-cell proliferation and potentiated pro-inflammatory and TH1-type cytokine secretion, without affecting the splenocytes viability and the T-cell sub-populations. These results confirm that high-dose DDE treatments affect the immune system, in particularly T-cell function. In conclusion, this study shows for the first time that high-dose chronic DDE exposure exhibits a diabetogenic potential, with an underlying immunomodulatory mechanism of action, in the development of T1D in an experimental mouse NOD model. PMID- 25721048 TI - Genetic variants in TNFalpha, TGFB1, PTGS1 and PTGS2 genes are associated with diisocyanate-induced asthma. AB - Diisocyanates are the most common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants in inflammatory response genes (TNFalpha, IL1alpha, IL1beta, IL1RN, IL10, TGFB1, ADAM33, ALOX-5, PTGS1, PTGS2 and NAG-1/GDF15) are associated with increased susceptibility to diisocyanate asthma (DA). These genes were selected based on their role in asthmatic inflammatory processes and previously reported associations with asthma phenotypes. The main study population consisted of 237 Caucasian French Canadians from among a larger sample of 280 diisocyanate exposed workers in two groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95) and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5' nuclease PCR assay. After adjusting for potentially confounding variables of age, smoking status and duration of exposure, the PTGS1 rs5788 and TGFB1 rs1800469 single nucleotide polymorphisms (SNP) showed a protective effect under a dominant model (OR = 0.38; 95% CI = 0.17, 0.89 and OR = 0.38; 95% CI = 0.18, 0.74, respectively) while the TNFalpha rs1800629 SNP was associated with an increased risk of DA (OR = 2.08; 95% CI = 1.03, 4.17). Additionally, the PTGS2 rs20417 variant showed an association with increased risk of DA in a recessive genetic model (OR = 6.40; 95% CI = 1.06, 38.75). These results suggest that genetic variations in TNFalpha, TGFB1, PTGS1 and PTGS2 genes contribute to DA susceptibility. PMID- 25721051 TI - A multilocus variable number tandem repeat analysis assay provides high discrimination for genotyping Leptospira santarosai strains. AB - Considering the prevalence of Leptospira santarosai infections in the Americas and the scarce information about the species, we aimed to apply a multilocus variable number tandem repeat (VNTR) analysis (MLVA) for the molecular typing of L. santarosai isolates from various sources. Amplification of three VNTR loci selected from L. santarosai genome sequences resulted in a wide range of sizes for the amplified products amongst the 21 L. santarosai strains analysed. This suggested a variation in tandem repeat copy numbers in the VNTR loci. secY sequencing also showed a high nucleotide diversity, confirming the MLVA data. In conclusion, this novel MLVA provided a high level of discrimination between L. santarosai isolates, and this new typing tool could be used to investigate leptospirosis in regions where L. santarosai predominates. PMID- 25721052 TI - Potential anti-obesogenic properties of non-digestible carbohydrates: specific focus on resistant dextrin. AB - Alterations in the composition and metabolic activity of the gut microbiota appear to contribute to the development of obesity and associated metabolic diseases. However, the extent of this relationship remains unknown. Modulating the gut microbiota with non-digestible carbohydrates (NDC) may exert anti obesogenic effects through various metabolic pathways including changes to appetite regulation, glucose and lipid metabolism and inflammation. The NDC vary in physicochemical structure and this may govern their physical properties and fermentation by specific gut bacterial populations. Much research in this area has focused on established prebiotics, especially fructans (i.e. inulin and fructo-oligosaccharides); however, there is increasing interest in the metabolic effects of other NDC, such as resistant dextrin. Data presented in this review provide evidence from mechanistic and intervention studies that certain fermentable NDC, including resistant dextrin, are able to modulate the gut microbiota and may alter metabolic process associated with obesity, including appetite regulation, energy and lipid metabolism and inflammation. To confirm these effects and elucidate the responsible mechanisms, further well-controlled human intervention studies are required to investigate the impact of NDC on the composition and function of the gut microbiota and at the same time determine concomitant effects on host metabolism and physiology. PMID- 25721053 TI - The Baltimore Experience Corps Trial: Enhancing Generativity via Intergenerational Activity Engagement in Later Life. AB - OBJECTIVES: Being and feeling generative, defined as exhibiting concern and behavior to benefit others, is an important developmental goal of midlife and beyond. Although a growing body of evidence suggests mental and physical health benefits of feeling generative in later life, little information exists as to the modifiability of generativity perceptions. The present study examines whether participation in the intergenerational civic engagement program, Experience Corps (EC), benefits older adults' self-perceptions of generativity. METHOD: Levels of generativity were compared in older adults randomized to serve as EC volunteers or controls (usual volunteer opportunities) in the Baltimore Experience Corps Trial at 4-, 12-, and 24-month evaluation points over the 2-year trial. Analyses utilized intention-to-treat and complier average causal effects (CACE) analyses which incorporate degree of intervention exposure in analytic models. RESULTS: Participants randomized to the EC group had significantly higher levels of generative desire and perceptions of generative achievement than controls at each follow-up point; CACE analyses indicate a dose-response effect with a greater magnitude of intervention effect with greater exposure to the EC program. DISCUSSION: Results provide the first-ever, large-scale experimental demonstration that participation in an intergenerational civic engagement program can positively alter self-perceptions of generativity in older adulthood. PMID- 25721054 TI - Detection of insemination status in live Aedes aegypti females. AB - Using the technique described in this report, the presence or absence of sperm in spermathecae of female Aedes aegypti is detectable without dissection. Spermathecae of a lightly anesthetized female can be visualized by phase contrast microscopy through the distended abdomen, after the intersegmental membranes are stretched by ventral placement of a glass cover slip. Most females recovered after the procedure were capable of subsequent reproductive activities. Albeit tedious, this technique preserves the female alive for subsequent experiments or observations. Its extension to other mosquito species, or other Diptera and insects, will depend on spermathecal and sperm visibility through the distended abdomen. PMID- 25721055 TI - A whole genome screening and RNA interference identify a juvenile hormone esterase-like gene of the diamondback moth, Plutella xylostella. AB - Juvenile hormone (JH) plays a crucial role in preventing precocious metamorphosis and stimulating reproduction. Thus, its hemolymph titer should be under a tight control. As a negative controller, juvenile hormone esterase (JHE) performs a rapid breakdown of residual JH in the hemolymph during last instar to induce a larval-to-pupal metamorphosis. A whole genome of the diamondback moth (DBM), Plutella xylostella, has been annotated and proposed 11 JHE candidates. Sequence analysis using conserved motifs commonly found in other JHEs proposed a putative JHE (Px004817). Px004817 (64.61 kDa, pI=5.28) exhibited a characteristic JHE expression pattern by showing high peak at the early last instar, at which JHE enzyme activity was also at a maximal level. RNA interference of Px004817 reduced JHE activity and interrupted pupal development with a significant increase of larval period. This study identifies Px004817 as a JHE-like gene of P. xylostella. PMID- 25721056 TI - Methyl farnesoate synthesis is necessary for the environmental sex determination in the water flea Daphnia pulex. AB - Sex-determination systems can be divided into two groups: genotypic sex determination (GSD) and environmental sex determination (ESD). ESD is an adaptive life-history strategy that allows control of sex in response to environmental cues in order to optimize fitness. However, the molecular basis of ESD remains largely unknown. The micro crustacean Daphnia pulex exhibits ESD in response to various external stimuli. Although methyl farnesoate (MF: putative juvenile hormone, JH, in daphnids) has been reported to induce male production in daphnids, the role of MF as a sex-determining factor remains elusive due to the lack of a suitable model system for its study. Here, we establish such a system for ESD studies in D. pulex. The WTN6 strain switches from producing females to producing males in response to the shortened day condition, while the MFP strain only produces females, irrespective of day-length. To clarify whether MF has a novel physiological role as a sex-determining factor in D. pulex, we demonstrate that a MF/JH biosynthesis inhibitor suppressed male production in WTN6 strain reared under the male-inducible condition, shortened day-length. Moreover, we show that juvenile hormone acid O-methyltransferase (JHAMT), a critical enzyme of MF/JH biosynthesis, displays MF-generating activity by catalyzing farnesoic acid. Expression of the JHAMT gene increased significantly just before the MF-sensitive period for male production in the WTN6 strain, but not in the MFP strain, when maintained under male-inducible conditions. These results suggest that MF synthesis regulated by JHAMT is necessary for male offspring production in D. pulex. Our findings provide novel insights into the genetic underpinnings of ESD and they begin to shed light on the physiological function of MF as a male-fate determiner in D. pulex. PMID- 25721057 TI - Hemodynamic effects of intravenous nicardipine in severely pre-eclamptic women with a hypertensive crisis. AB - OBJECTIVE: Nicardipine permits rapid control of blood pressure in women with severe pre-eclampsia (PE) and hypertensive crisis. Our objective was to investigate its maternal and fetal hemodynamic effects. METHODS: Ten severely pre eclamptic pregnant women who required intravenous nicardipine for severe hypertension were included in this prospective observational trial. Maternal macrocirculation was assessed by transthoracic echocardiography. Maternal microcirculatory perfusion was examined sublingually with the sidestream dark field imaging technique. Fetal hemodynamics were assessed by Doppler examinations of the uteroplacental and fetal circulations. Maternal cardiac output, total vascular resistance, mitral E/A ratio and capillary heterogeneity index, uterine artery pulsatility index and fetal cerebroplacental ratio were considered primary outcomes. Paired measurements, obtained before administration of nicardipine infusion and after stabilization of blood pressure, were compared. RESULTS: Administration of nicardipine significantly reduced the mean arterial blood pressure (median difference, 26 mmHg; P = 0.002) and total vascular resistance (median difference, 791 dynes * s/cm(5) ; P = 0.002) in all included women. This induced a reflex tachycardia with consequent increase in cardiac output of 1.55 L/min (P = 0.004). There were no significant changes in the other determinants of maternal or fetal hemodynamic parameters. CONCLUSIONS: Nicardipine effectively reduces blood pressure through selective afterload reduction that triggers an increase in cardiac output, without affecting maternal diastolic function, or microcirculatory, uteroplacental or fetal perfusion. This hemodynamic response is uniform and predictable. Fetomaternal cardiovascular profiling can be achieved by combining transthoracic echocardiography with obstetric Doppler. PMID- 25721058 TI - Effects of isolation on patients and staff. AB - A matched case-control study and a qualitative investigation were used to identify adverse events in diverse dimensions associated with isolation. Overall satisfaction with care was similar among patients in isolation, but staff was found to be less responsive. Isolation was also associated with depression, but not with increased anxiety. PMID- 25721059 TI - Patients' perceptions of hospital-acquired infections in northern Queensland, Australia: a pilot study. PMID- 25721060 TI - Necrotizing fasciitis in patients with head and neck cancer. AB - Necrotizing fasciitis is a severe polybacterial infection characterized by necrosis of the fascia and adjacent soft tissues with rapid expansion of the infection along the fascial planes. It is a rare and potentially fatal entity in the head and neck region. We present 2 patients with head and neck cancers who developed necrotizing fasciitis during the postoperative period. PMID- 25721061 TI - Advancing the competency of infection preventionists. AB - The Association of Professionals in Infection Control and Epidemiology (APIC) has identified advancing infection prevention competency as a core goal in their Strategic Plan 2020. To achieve this goal, APIC has published a self-assessment tool to help infection preventionists identify where they are on a predefined scale. This project trialed APIC's self-assessment tool along with an internally developed objective assessment. The objective was to determine if the tools help identify areas for improvement to advance overall group competency at BJC HealthCare, a large Midwestern health care system with nearly 30 infection preventionists. PMID- 25721062 TI - Handling Europe's first Ebola case: internal hospital communication experience. AB - Europe's first Ebola virus disease (EVD) case was diagnosed in our hospital. There was an unjustified panic in the population because of an imbalance of credibility assigned to the media as opposed to scientific information. A reinforcement of hospital internal communication was needed to keep health care workers informed with up-to-date scientific EVD information. The proactive management of information flow to both internal and external actors is required to reduce unjustified fear within the public. PMID- 25721063 TI - Use of an ultraviolet light at point-of-dispense faucet to eliminate Pseudomonas aeruginosa. AB - Tap water is believed to be a significant source of Pseudomonas aeruginosa in health care environments. This study evaluated an ultraviolet (UV) light point-of dispense water treatment system for control of P aeruginosa. No P aeruginosa was detected in 30 different water dispensers in which the UV light device had been operating for 1-34 months. In comparison, P aeruginosa was found in other taps that did not feature this UV light system. PMID- 25721064 TI - Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody(r) targeting the DR5 receptor. AB - PURPOSE: TAS266 is a novel agonistic tetravalent Nanobody((r)) targeting the DR5 receptor. In preclinical studies, TAS266 was more potent than a cross-linked DR5 antibody or TRAIL. This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of TAS266. METHODS: Adult patients with advanced solid tumors were to receive assigned doses of TAS266 (3, 10, 15, or 20 mg/kg) intravenously on days 1, 8, 15, and 22 of a 28-day treatment cycle. RESULTS: Grade >=3 elevations in aspartate aminotransferase and/or alanine aminotransferase levels, occurring during cycle 1 in three of four patients at the 3 mg/kg dose level, were attributed to TAS266 and led to early study termination. Liver enzyme levels quickly returned to grade <=1 following TAS266 discontinuation. Evidence of preexisting antibodies able to bind to TAS266 was found in the three patients who experienced these dose-limiting toxicities. Immunogenic responses remained elevated and strengthened at end-of-treatment (EOT). In the one patient who did not develop hepatotoxicity, no evidence of immunogenicity was observed at baseline or following administration of 4 TAS266 doses; however, incipient positive immunogenicity was observed at the EOT visit. CONCLUSION: TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, factors including the molecule's high potency, immunogenicity to TAS266, and possibly increased DR5 expression on hepatocytes further enhancing the activity of the Nanobody((r)) may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis. PMID- 25721065 TI - Society for Vascular Surgery Practice guidelines for atherosclerotic occlusive disease of the lower extremities management of asymptomatic disease and claudication. Introduction. PMID- 25721066 TI - A systematic review for the screening for peripheral arterial disease in asymptomatic patients. AB - BACKGROUND: Peripheral arterial disease (PAD) is common and associated with significant morbidity and mortality. PAD can be detected through a noninvasive measurement of the ankle-brachial index (ABI). METHODS: We conducted a systematic review of several electronic bibliographic databases for studies that evaluated ABI as a screening test for PAD in asymptomatic individuals. We conducted random effects meta-analysis, reporting pooled hazard ratios (HRs) when appropriate. RESULTS: We included 40 individual studies, 2 systematic reviews, and 1 individual-patient data meta-analysis. We found no studies comparing ABI screening with no screening in terms of patient-important outcomes (mortality, amputations). The yield of PAD screening averaged 17% (range, 1%-42%) and was 1% to 4% in lower risk populations. Patients with PAD had higher adjusted risk of all-cause mortality (HR, 2.99; 95% confidence interval, 2.16-4.12) and of cardiovascular mortality (HR, 2.35; 95% confidence interval, 1.91-2.89). Data on benefits, harms, and cost-effectiveness of screening were limited; however, ABI screening was associated with additional prognostic information and risk stratification for heart disease. The overall quality of evidence supporting screening was low. CONCLUSIONS: The current available evidence demonstrates that PAD is common in patients with multiple cardiovascular risk factors and is associated with significant morbidity and mortality, but it does not support the benefit of routine ABI screening. PMID- 25721067 TI - A systematic review of treatment of intermittent claudication in the lower extremities. AB - BACKGROUND: Peripheral arterial disease is common and is associated with significant morbidity and mortality. METHODS: We conducted a systematic review to identify randomized trials and systematic reviews of patients with intermittent claudication to evaluate surgery, endovascular therapy, and exercise therapy. Outcomes of interest were death, amputation, walking distance, quality of life, measures of blood flow, and cost. RESULTS: We included eight systematic reviews and 12 trials enrolling 1548 patients. Data on mortality and amputation and on cost-effectiveness were sparse. Compared with medical management, each of the three treatments (surgery, endovascular therapy, and exercise therapy) was associated with improved walking distance, claudication symptoms, and quality of life (high-quality evidence). Evidence supporting superiority of one of the three approaches was limited. However, blood flow parameters improved faster and better with both forms of revascularization compared with exercise or medical management (low- to moderate-quality evidence). Compared with endovascular therapy, open surgery may be associated with longer length of hospital stay and higher complication rate but resulted in more durable patency (moderate-quality evidence). CONCLUSIONS: In patients with claudication, open surgery, endovascular therapy, and exercise therapy were superior to medical management in terms of walking distance and claudication. Choice of therapy should rely on patients' values and preferences, clinical context, and availability of operative expertise. PMID- 25721068 TI - Commentary: Factors associated with non-participation in cohort studies emphasize the need to generalize the results with care. PMID- 25721069 TI - Registration on the renal transplantation waiting list and mortality on dialysis: an analysis of the French REIN registry using a multi-state model. AB - BACKGROUND: Access to the renal transplantation (RT) waiting list depends on factors related to lower mortality rates and often occurs after dialysis initiation. The aim of the study was to use a flexible regression model to determine if registration on the RT waiting list is associated with mortality on dialysis, independent of the comorbidities associated with such registration. METHODS: Data from the French REIN registry on 7138 incident hemodialysis (HD) patients were analyzed. A multi-state model including four states ('HD, not wait listed', 'HD, wait-listed', 'death', and 'RT') was used to estimate the effect of being wait-listed on the probability of death. RESULTS: During the study, 1392 (19.5%) patients were wait-listed. Of the 2954 deaths observed in the entire cohort during follow-up, 2921 (98.9%) were observed in the not wait-listed group compared with only 33 (1.1%) in the wait-listed group. In the multivariable analysis, the adjusted hazard ratio for death associated with non-registration on the waiting list was 3.52 (95% CI, 1.70-7.30). The risk factors for death identified for not wait-listed patients were not found to be significant risk factors for wait-listed patients, with the exception of age. CONCLUSIONS: The use of a multi-state model allowed a flexible analysis of mortality on dialysis. Patients who were not wait-listed had a much higher risk of death, regardless of co-morbidities associated with being wait-listed, and did not share the same risk factors of death as wait-listed patients. Registration on the waiting list should therefore be taken into account in survival analysis of patients on dialysis. PMID- 25721070 TI - Association between nocturnal breastfeeding and snacking habits and the risk of early childhood caries in 18- to 23-month-old Japanese children. AB - BACKGROUND: Early childhood caries (ECC) is one of the most prevalent chronic diseases among children. The aim of this cross-sectional study was to investigate the association between nocturnal breastfeeding, snacking habits, or other risk factors and ECC in 18- to 23-month-old Japanese children. METHODS: Study subjects were 1675 children aged 18 to 23 months. A self-administered questionnaire was completed by parents or guardians of the children. The survey contents included such things as number of decayed, missing, and filled teeth per child, smokers in the home, nocturnal breastfeeding habit, snack times, kinds of snacks consumed >= 4 days a week, kinds of drinks consumed >= 4 days a week, parents brushing their child's teeth daily, and the use of fluoride toothpaste. Logistic regression analysis was performed to estimate the odds of ECC. RESULTS: The average number of decayed, missing and filled teeth was 0.10. The prevalence of dental caries was 3.3%. Nocturnal breastfeeding habits were reported in 357 subjects (21.3%). After excluding items of multicollinearity, significant associations were observed between ECC and nocturnal breastfeeding, drinking or eating sweets after dinner every day, and the intake of candy, soda and/or isotonic drinks >= 4 days a week. CONCLUSIONS: This study suggests that nocturnal breastfeeding and snacking habits are correlated with ECC. PMID- 25721072 TI - The relationship between disability-adjusted life years of cataracts and ambient erythemal ultraviolet radiation in China [J Epidemiol 2015;25(1):57-65]. PMID- 25721071 TI - Aspirin use associated with amyotrophic lateral sclerosis: a total population based case-control study. AB - BACKGROUND: The association of aspirin use and nonsteroid anti-inflammatory drug (NSAID) use with amyotrophic lateral sclerosis (ALS) risk is unclear. This study determined whether use of any individual compound is associated with ALS risk by conducting a total population-based case-control study in Taiwan. METHODS: A total of 729 patients with newly diagnosed ALS who had a severely disabling disease certificate between January 1, 2002, and December 1, 2008, comprised the case group. These cases were compared with 7290 sex-, age-, residence-, and insurance premium-matched controls. Drug use by each Anatomical Therapeutic Chemical code was analyzed using conditional logistic regression models. False discovery rate (FDR)-adjusted P values were reported in order to avoid inflating false positives. RESULTS: Of the 1336 compounds, only the 266 with use cases exceeding 30 in our database were included in the screening analysis. Without controlling for steroid use, the analysis failed to reveal any compound that was inversely associated with ALS risk according to FDR criteria. After controlling for steroid use, we found use of the following compounds to be associated with ALS risk: aspirin, diphenhydramine (one of the antihistamines), and mefenamic acid (one of the NSAIDs). A multivariate analysis revealed that aspirin was independently inversely associated with ALS risk after controlling for diphenhydramine, mefenamic acid, and steroid use. The inverse association between aspirin and ALS was present predominately in patients older than 55 years. CONCLUSIONS: The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people. PMID- 25721073 TI - Metagenomic profiling of the viromes of plasma collected from blood donors with elevated serum alanine aminotransferase levels. AB - BACKGROUND: In Japanese Red Cross (JRC) blood centers, blood collected from donors with serum alanine aminotransferase (ALT) levels of more than 60 U/L are disqualified even if serologically negative for transfusion-transmitted infections (TTIs). To assess potential risks of TTIs in plasma with elevated serum ALT levels in the current donor screening program of the JRC, we conducted a metagenomic analysis (MGA) of virome profiles in the plasma of blood donors with or without elevated serum ALT levels. STUDY DESIGN AND METHODS: Based on serum ALT levels, donors were classified into three groups: "high," more than 79 U/L; "middle," 61 to 79 U/L; and "low," less than 61 U/L. We individually analyzed 100 plasma samples from each group by MGA, employing shotgun sequencing. Viral sequences detected using MGA were partly confirmed using real-time polymerase chain reaction (PCR). RESULTS: Donors with high and middle ALT levels were significantly younger than those with low ALT levels, and more than 90% were males. Herpesviridae, Anelloviridae, Picornaviridae, and Flaviviridae sequences were identified in plasma samples, and their distribution and frequency were not significantly different among the three groups. CONCLUSION: The serum ALT test may be unsuitable for monitoring for additional risks of TTIs in blood donors who were negative for typical TTIs using serologic and nucleic acid tests. Although MGA is less sensitive than PCR, it remains the best technology to detect known viruses in these donors. PMID- 25721074 TI - Double dissociation of working memory and attentional processes in smokers and non-smokers with and without nicotine. AB - Nicotine has been shown to affect cortical excitability measured using transcranial magnetic stimulation in smoking and non-smoking subjects in different ways. In tobacco-deprived smokers, administration of nicotine restores compromised cortical facilitation while in non-smokers, it enhances cortical inhibition. As cortical excitability and activity are closely linked to cognitive processes, we aimed to explore whether nicotine-induced physiological alterations in non-smokers and smokers are associated with cognitive changes. Specifically, we assessed the impact of nicotine on working memory performance (n-back letter task) and on attentional processes (Stroop interference test) in healthy smokers and non-smokers. Both tasks have been shown to rely on prefrontal areas, and nicotinic receptors are relevantly involved in prefrontal function. Sixteen smoking and 16 non-smoking subjects participated in the 3-back letter task and 21 smoking and 21 non-smoking subjects in the Stroop test after the respective application of placebo or nicotine patches. The results show that working memory and attentional processes are compromised in nicotine-deprived smokers compared to non-smoking individuals. After administration of nicotine, working memory performance in smokers improved, while non-smoking subjects displayed decreased accuracy with increased number of errors. The effects have been shown to be more apparent for working memory performance than attentional processes. In summary, cognitive functions can be restored by nicotine in deprived smokers, whereas non smokers do not gain additional benefit. The respective changes are in accordance with related effects of nicotine on cortical excitability in both groups. PMID- 25721075 TI - Multimodal CT provides improved performance for lacunar infarct detection. AB - BACKGROUND AND PURPOSE: Lacunar infarcts account for approximately 25% of acute ischemic strokes. Compared with NCCT alone, the addition of CTP improves sensitivity for detection of infarcts overall. Our aim was to systematically evaluate the diagnostic benefit and interobserver reliability of an incremental CT protocol in lacunar infarction. MATERIALS AND METHODS: Institutional review board approval and patient consent were obtained. One hundred sixty-three patients presenting with a lacunar syndrome <=4.5 hours from symptom onset were enrolled. Images were reviewed incrementally by 2 blinded readers in 3 separate sessions (NCCT only, NCCT/CTA, and NCCT/CTA/CTP). Diagnostic confidence was recorded on a 6-point scale with DWI/ADC as a reference. Logistic regression analysis calculated differences between actual and observed diagnoses, adjusted for confidence. Predictive effects of observed diagnostic accuracy and confidence score were quantified with the entropy r(2) value. Sensitivity, specificity, and confidence intervals were calculated accounting for multiple readers. Receiver operating characteristic analyses were compared among diagnostic strategies. Interobserver agreement was established with Cohen kappa statistic. RESULTS: The final study cohort comprised 88 patients (50% male). DWI/ADC-confirmed lacunar infarction occurred in 59/88 (67%) with 36/59 (61%) demonstrating a concordant abnormal finding on CTP. Sensitivity for definite or probable presence of lacunar infarct increased significantly from 9.3% to 42.4% with incremental protocol use, though specificity was unchanged (range, 91.9%-95.3%). The observed diagnosis was significantly related to the actual diagnosis after adjusting for CTP confidence level (P = .04) and was 5.1 and 2.4 times more likely to confirm lacunar infarct than NCCT or CTA source images. CTP area under the curve (0.77) was significantly higher than that of CTA source images (0.68, P = .006) or NCCT (0.55, P < .001). CONCLUSIONS: CTP offers an improved diagnostic benefit over NCCT and CTA for the diagnosis of lacunar infarction. PMID- 25721076 TI - Evaluation of 4D vascular flow and tissue perfusion in cerebral arteriovenous malformations: influence of Spetzler-Martin grade, clinical presentation, and AVM risk factors. AB - BACKGROUND AND PURPOSE: The role of intracranial hemodynamics in the pathophysiology and risk stratification of brain AVMs remains poorly understood. The purpose of this study was to assess the influence of Spetzler-Martin grade, clinical history, and risk factors on vascular flow and tissue perfusion in cerebral AVMs. MATERIALS AND METHODS: 4D flow and perfusion MR imaging was performed in 17 patients with AVMs. Peak velocity and blood flow were quantified in AVM feeding and contralateral arteries, draining veins, and the straight sinus. Regional perfusion ratios (CBF, CBV, and MTT) were calculated between affected and nonaffected hemispheres. RESULTS: Regarding flow parameters, high grade AVMs (Spetzler-Martin grade of >2) demonstrated significantly increased peak velocity and blood flow in the major feeding arteries (P < .001 and P = .004) and straight sinus (P = .003 and P = .012) and increased venous draining flow (P = .001). The Spetzler-Martin grade significantly correlated with cumulative feeding artery flow (r = 0.85, P < .001) and draining vein flow (r = 0.80, P < .001). Regarding perfusion parameters, perinidal CBF and CBV ratios were significantly lower (P < .001) compared with the remote ratios and correlated negatively with cumulative feeding artery flow (r = -0.60, P = .014 and r = -0.55, P = .026) and draining vein flow (r = -0.60, P = .013 and r = 0.56, P = .025). Multiple regression analysis revealed no significant association of AVM flow or perfusion parameters with clinical presentation (rupture and seizure history) and AVM risk factors. CONCLUSIONS: Macrovascular flow was significantly associated with increasing Spetzler-Martin grade and correlated with perinidal microvascular perfusion in cerebral AVMs. Future longitudinal studies are needed to evaluate the potential of comprehensive cerebral flow and perfusion MR imaging for AVM risk stratification. PMID- 25721077 TI - Changes of time-attenuation curve blood flow parameters in patients with and without carotid stenosis. AB - BACKGROUND AND PURPOSE: From the time-attenuation curves of DSA flow parameters, maximal intensity, maximal slope, and full width at half maximum of selected vascular points are defined. The study explores the reliability of defining the flow parameters by the time-attenuation curves of DSA. MATERIALS AND METHODS: Seventy patients with unilateral carotid artery stenosis (group A) and 56 healthy controls (group B) were retrospectively enrolled. Fixed contrast injection protocols and DSA acquisition parameters were used with all patients. The M1, sigmoid sinus, and internal jugular vein on anteroposterior view DSA and the M2, parietal vein, and superior sagittal sinus on lateral view DSA were chosen as ROI targets for measuring flow parameters. The difference of time of maximal intensity between 2 target points was defined as the circulation time between the target points. RESULTS: The maximal intensity difference of 2 selected points from the ICA to the M1, sigmoid sinus, internal jugular vein, M2, parietal vein, and superior sagittal sinus was significantly longer in group A than in group B. The maximum slope of M1, M2, and the superior sagittal sinus was significantly lower in group A than in group B. The full width at half maximum of M1 and M2 was significantly larger in group A than in group B. The maximal slope of M1 demonstrated the best diagnostic performance. CONCLUSIONS: The maximal intensity difference of 2 selected points derived from DSA can be used as a definitive alternative flow parameter for intracranial circulation time measurement. Maximal slope and full width at half maximum complement the maximal intensity difference of 2 selected points in defining flow characteristics of healthy subjects and patients with carotid stenosis. PMID- 25721078 TI - Quantitative diffusion-weighted MRI parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: Patients with human papillomavirus-positive oropharyngeal squamous cell carcinomas have a better survival rate than those with human papillomavirus-negative oropharyngeal squamous cell carcinomas. DWI characterizes biologically relevant tumor features, and the generated ADC may also provide prognostic information. We explored whether human papillomavirus status and ADC values are independent tumor characteristics. MATERIALS AND METHODS: Forty-four patients with oropharyngeal squamous cell carcinomas underwent pretreatment DWI. ADC values for the primary tumors were determined by using 3 b-values in an ROI containing the largest area of solid tumor on a single section of an axial DWI image. Human papillomavirus status was determined with p16 immunostaining, followed by high-risk human papillomavirus DNA detection on the p16-positive cases. RESULTS: Twenty-two patients were human papillomavirus-positive (50.0%). ADC values were not significantly different between human papillomavirus-negative (ADC(mean) = 1.56 [1.18-2.18] * 10(3) mm(2)/s) and human papillomavirus-positive tumors (ADC(mean) = 1.46 [1.07-2.16] * 10(3) mm(2)/s). CONCLUSIONS: No significant association between ADC and human papillomavirus status was found in oropharyngeal squamous cell carcinomas. In our study population, differences in genetic and histologic features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas did not translate into different ADC values. Long-term follow-up studies are needed to establish whether ADC has prognostic value and whether this is independent of the human papillomavirus status. PMID- 25721079 TI - The FRED flow-diverter stent for intracranial aneurysms: clinical study to assess safety and efficacy. AB - BACKGROUND AND PURPOSE: Flow-diverter stents are emerging for the endovascular treatment of difficult-to-treat or otherwise untreatable cerebral aneurysms (wide neck, fusiform, dissecting, blisterlike, or giant). We assessed the clinical safety and efficacy of the Flow-Redirection Endoluminal Device. MATERIALS AND METHODS: This was an institutional review board-approved single-center observational clinical study in 29 patients with 34 aneurysms elected to be treated by endovascular intervention. After providing informed consent, patients were included according to the following criteria: aneurysm fundus-to-neck ratio <2 or neck diameter >4 mm, fusiform, dissecting, or giant aneurysms. The primary end point for clinical safety was the absence of death, absence of major or minor stroke, and absence of transient ischemic attack. The primary end point for treatment efficacy was complete angiographic occlusion according to the O'Kelly Marotta grading scale immediately after the procedure and at follow-up after 3 and 6 months (O'Kelly Marotta D: complete occlusion). RESULTS: The Flow Redirection Intraluminal Device deployment was technically successful in all cases. In 26/29 (89%) of patients, the primary end point of safety was reached; in the 3 remaining patients, 1 disabling ischemic stroke and 2 minor strokes with complete recovery at follow-up were observed. Angiographic (DSA and MRA) and clinical follow-up were available after 3 months in 29/29 (100%) and after 6 months in 25/29 (86%) patients (after 6 months, only MRA follow-up was performed according to our study protocol and institutional standard). At 3-month follow up, complete occlusion was reached in 19/34 aneurysms (O'Kelly Marotta D: 19/34; 56%). At 6-month follow-up, aneurysm occlusion was complete in 22/30 aneurysms (O'Kelly Marotta D: 22/30; 73%). CONCLUSIONS: Deployment of the Flow-Redirection Intraluminal Device flow-diverter stent is safe and effective in the treatment of difficult-to-treat or otherwise untreatable intracranial aneurysms. PMID- 25721080 TI - Panhypopituitarism with ectopic posterior pituitary lobe, heterotopia, polymicrogyria, corpus callosum dysgenesis, and optic chiasm/nerve hypoplasia: is that an undefined neuronal migration syndrome? PMID- 25721081 TI - The role of heat shock proteins in cancer. AB - Heat shock proteins (HSPs) are an evolutionary family of proteins that act as molecular chaperones. According to their size they have been classified into the following families; HSP90, HSP70, HSP60, HSP40 and HSP27. They prevent the formation of nonspecific protein aggregates and they assist proteins in the acquisition of their normal architecture. Moreover, HSPs are likely to have anti apoptotic properties and are actively involved in various processes as tumor cell proliferation, invasion, metastases and death. Notably, these proteins have been reported to be significantly elevated in a plethora of human cancers. Their over expression has been robustly associated with therapeutic resistance and poor survival. In this way, HSPs may have important therapeutic implications and they can be targeted by specific drugs. In this review, we discuss the influence of HSP27, HSP40, HSP60, HSP70 and HSP90 on human cancers. In addition, we report the existing scientific data on this issue with an effort to highlight the possible future implication of HSPs as tumor biomarkers or drug targets for improving prognosis and treatment of cancer patients around the world. PMID- 25721082 TI - Sensitizing tumor cells to radiation by targeting the heat shock response. AB - Elevated levels of heat shock proteins (HSPs) contribute to tumor cell survival and mediate protection against radiation-induced cell death. Hsp90 inhibitors are promising radiosensitizers but also activate heat shock factor 1 (HSF1) and thereby induce the synthesis of cytoprotective Hsp70. In this study the heat shock response inhibitor NZ28 either alone or in combination with the Hsp90 inhibitor NVP-AUY922 was investigated for radiosensitizing effects, alterations in cell cycle distribution and effects on migratory/invasive capacity of radioresistant tumor cells. NZ28 reduced the constitutive and NVP-AUY922-induced Hsp70 expression by inhibition of the HSF1 activity and inhibited migration and invasion in human lung and breast tumor cells. Treatment of tumor cells with NZ28 significantly increased their radiation response. One possible mechanism might be a decrease of the radioresistant S-phase. When combined with the Hsp90 inhibitor NVP-AUY922 the concentration of NZ28 could be significantly reduced (1/10th 1/20th) to achieve the same radiosensitization. Our results demonstrate that a dual targeting of Hsp70 and Hsp90 with NZ28 and NVP-AUY922 potentiates the radiation response of tumor cells that are otherwise resistant to ionizing radiation. PMID- 25721083 TI - Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors. AB - Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC. Using MTT and soft-agar colony formation assays, we selected NSCLC cell lines that exhibited intrinsic resistance to vorinostat. Treatment with vorinostat activated IGF-1R signaling in vorinostat-resistant but not vorinostat sensitive NSCLC cells. Other HDAC inhibitors, including trichostatin A, sodium butyrate, and depsipeptide, also activated IGF-1R signaling in vorinostat resistant NSCLC cells. Blockade of IGF-1R signaling via IGF-1R monoclonal antibodies (mAbs) or through knockdown of IGF-1R via RNA interference sensitized vorinostat-resistant cells to HDAC inhibition. Finally, IGF-1R mAbs sensitized xenograft tumors of vorinostat-resistant cells to vorinostat treatment in vivo. These findings suggest that IGF-1R activation is generally involved in resistance to HDAC inhibitors and that targeting IGF-1R is an effective strategy for overcoming resistance to HDAC inhibitors in NSCLC. PMID- 25721084 TI - The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. However, the treatments for HCC are limited, and most of them are only available to the early stage. In the later stages, traditional chemotherapy has only marginal effects and may include toxicity. Thus, the identification of new predictive markers is urgently needed. New targets for non-conventional treatments will help to accelerate research on the molecular pathogenesis of HCC. A new class of transcripts, long non-coding RNAs (lncRNAs), has recently been found to be pervasively transcribed in the human genome. Aberrant expression of several lncRNAs was found to be involved in the tumorigenesis of HCC. In this review, we describe the possible molecular mechanisms that underlie lncRNA expression changes in HCC, as well as potential future applications of lncRNA research in the diagnosis and treatment of HCC. PMID- 25721085 TI - Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth. AB - Identifying chemotherapy candidates with high selectivity against cancer cells is a major challenge in cancer treatment. Tumor microenvironments cause chronic endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) as an adaptive response. Here, one novel small-molecule compound, 17#, was discovered as a potent pan-UPR inhibitor. It exhibited good selection for growth inhibition when cancer cells were cultured in 2-deoxy-D-glucose (2DG), mimicking an in vitro glucose-deprived status. Additionally, 17# alone could mildly suppress the growth of HeLa tumor xenografts, and a synergistic anti-cancer effect was observed when 17# was combined with 2DG. A mechanistic study showed that 17#-induced selective anti-cancer effects were highly dependent on UPR inhibition, and overexpressing GRP78 or XBP1s reversed the 17#-induced growth inhibition and cell cycle arrest, partially by delaying the downregulation of the cell cycle regulator cyclin B1. Furthermore, 17# improved the sensitivity of anti cancer drugs such as doxorubicin or etoposide. Our study presents evidence that disrupting the UPR has selective therapeutic potential and may enhance drug sensitivity. PMID- 25721086 TI - Upregulation of B-cell translocation gene 2 by epigallocatechin-3-gallate via p38 and ERK signaling blocks cell proliferation in human oral squamous cell carcinoma cells. AB - Oral squamous cell carcinoma (OSCC) is a well-known malignancy that accounts for the majority of oral cancers. B-cell translocation gene 2 (BTG2) is an important regulator of cell cycle dynamics in cancer cells. However, the role of BTG2 in OSCC cells and the influences of epigallocatechin-3-gallate (EGCG) on BTG2 gene expressions have not been well evaluated. The objectives of this study were to examine the effect of EGCG-induced BTG2 expression and the potential signal pathways involved. The (3)H-thymidine incorporation and Western-blot assays revealed cell proliferation was attenuated by EGCG via upregulation of BTG2 expression causing cell cycle G1 phase arrest in OSCC cells. BTG2 overexpression decreased tumor cell growth, while BTG2 knockdown illuminated the opposite effect in xenograft animal studies. Overexpressed BTG2 arrested the cell cycle at the G1 phase and downregulated protein expressions of cyclin A, cyclin D, and cyclin E. Western-blot assays indicated that EGCG induced phosphorylation of p38, JNK, and ERK. However, pretreatments with selective mitogen-activated protein kinase (MAPK) inhibitors, SB203580 (p38 inhibitor) and PD0325901 (ERK1/2 inhibitor), significantly suppressed the activation of EGCG on BTG2 expression. Our results indicate that EGCG attenuates cell proliferation of OSCC cells by upregulating BTG2 expression via p38 and ERK pathways. PMID- 25721087 TI - WITHDRAWN: Effective suppression of Rituximab-resistant B-cell lymphoma by a comb like anti-CD20 mAb nanocluster. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25721088 TI - Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. AB - Human hepatocellular carcinoma (HCC) has a high rate of tumor recurrence and metastasis, resulting in shortened survival times. The efficacy of current systemic therapies for HCC is limited. In this study, we used xenograft tumor models to investigate the use of antibodies that block CD47 and inhibit HCC tumor growth. Immunostaining of tumor tissue and HCC cell lines demonstrated CD47 over expression in HCC as compared to normal hepatocytes. Macrophage phagocytosis of HCC cells was increased after treatment with CD47 antibodies (CD47mAbs) that block CD47 binding to SIRPalpha. Further, CD47 blockade inhibited tumor growth in both heterotopic and orthotopic models of HCC, and promoted the migration of macrophages into the tumor mass. Our results demonstrate that targeting CD47 by specific antibodies has potential immunotherapeutic efficacy in human HCC. PMID- 25721090 TI - Synthesis and characterization of pi-conjugated copolymers with thieno-imidazole units in the main chain: application for bulk heterojunction polymer solar cells. AB - In this paper the three new narrow bandgap D-A conjugated copolymers P1, P2 and P3 based on different weak donor fused thiophene-imidazole containing derivatives and the same benzothiadiazole acceptor unit were synthesized by Stille cross coupling polymerization and characterized by 1H NMR, elemental analysis, GPC, TGA, DSC. These copolymers exhibit intensive absorbance in the range 350-900 nm and the optical bandgap lies in the range of 1.50-1.61 eV, which corresponds to the maximum photon flux of the solar spectrum. The electrochemical bandgap derived from cyclic voltammetry varies within the limits 1.47-1.65 eV and is approximately very close to the optical bandgap. The highest occupied molecular orbital (HOMO) energy level of all copolymers is deep lying (-5.24 eV and -5.37 eV and -5.25 eV for P1, P2 and P2, respectively) which shows that copolymers have good stability in the air and assured a higher open circuit voltage (Voc) for polymer BHJ solar cells. These copolymers were used as donors along with PC71BM and the BHJ polymer solar cells based on P1:PC71BM, P2:PC71BM and P3:PC71BM processed from chloroform (CF) solvent with 3 v% DIO as an additive showed an overall PCE of 4.55%, 6.76% and 5.16%, respectively. PMID- 25721089 TI - Nasopharyngeal carcinoma progression is mediated by EBER-triggered inflammation via the RIG-I pathway. AB - EBERs (EBER1 and EBER2) are suggested to be involved in cellular transformation and tumor growth. Cytoplasmic pattern recognition receptor-RIG-I, which is characterized by the recognition of viral dsRNAs, could efficiently trigger the downstream pathways of innate immunity. Although some previous reports have shown that EBERs and RIG-I associate with hematological malignancies, the role of EBERs RIG-I signaling in solid tumors remains to be clarified. Here we demonstrate that EBER mediation of the inflammatory response via RIG-I contributes to NPC development in vitro and in vivo. We first verified that the expression level of RIG-I was associated with EBER transcription in a dose-dependent manner in NPC cells and specimens from NPC patients. Furthermore, pro-inflammatory cytokine transcription and release were sharply reduced after RIG-I knockdown compared with the control shRNA group in the presence of EBERs, accompanied by an attenuation of the NF-kappaB and MAPK signaling pathways. Consequently, the tumor burden was greatly alleviated in the RIG-I knockdown group in a xenograft model. In addition, macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP-1), which promote the maturation and attraction of tumor-associated macrophages, were stimulated upon the introduction of EBERs, and this upregulation conceivably led to the tumor-promoting subset transition of the macrophages. Taken together, our results reveal that EBERs could promote NPC progression through RIG-I-mediated cancer-related inflammation. PMID- 25721091 TI - Additional survival benefit of involved-lesion radiation therapy after R-CHOP chemotherapy in limited stage diffuse large B-cell lymphoma. AB - PURPOSE: The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. METHODS AND MATERIALS: We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (>= 7 cm); and 75.3% underwent >= 6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). RESULTS: After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed >= 6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012). CONCLUSIONS: Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level. PMID- 25721092 TI - Comprehensive proteome analysis of fresh frozen and optimal cutting temperature (OCT) embedded primary non-small cell lung carcinoma by LC-MS/MS. AB - Clinical tissue samples provide valuable information for understanding human diseases. One major type of clinical tissue sample that is amenable to various kinds of analysis is fresh frozen and optimal cutting temperature (OCT)-embedded primary patient tissue. Recent advances in mass spectrometry (MS) technologies have been widely applied to study human proteomes by using clinical specimens. However, polymeric compounds such as OCT can interfere with MS analyses. Here we present methods that enable the preparation and analysis of fresh frozen and OCT embedded primary tissue samples by LC-MS/MS. A scraping method was first introduced to reduce the heterogeneity of OCT-embedded non-small cell lung carcinoma tumor sections. OCT compound was reproducibly removed by a series of washing steps involving ethanol and water prior to trypsin digestion. In data dependent acquisition mode, optimized dynamic exclusion duration settings were established to maximize peptide identifications. These sample preparation conditions and MS parameter settings should be utilized or carefully adjusted in order to achieve optimal comprehensive proteome characterization starting from fresh frozen and OCT embedded clinical tissue specimens. PMID- 25721093 TI - Regulation of primary metabolic pathways in oyster mushroom mycelia induced by blue light stimulation: accumulation of shikimic acid. AB - Shikimic acid is a key intermediate in the aromatic amino acid pathway as well as an important starting material for the synthesis of Tamiflu, a potent and selective inhibitor of the neuraminidase enzyme of influenza viruses A and B. Here we report that in oyster mushroom (Pleurotus ostreatus) mycelia cultivated in the dark, stimulation with blue light-emitting diodes induces the accumulation of shikimic acid. An integrated analysis of primary metabolites, gene expression and protein expression suggests that the accumulation of shikimic acid caused by blue light stimulation is due to an increase in 3-deoxy-D-arabinoheptulosonate 7 phosphate synthase (DAHPS, EC2.5.1.54), the rate-determining enzyme in the shikimic acid pathway, as well as phosphofructokinase (PFK, EC2.7.1.11) and glucose-6-phosphate dehydrogenase (G6PD, EC1.1.1.49), the rate-determining enzymes in the glycolysis and pentose phosphate pathways, respectively. This stimulation results in increased levels of phosphoenolpyruvic acid (PEP) and erythrose-4-phosphate (E4P), the starting materials of shikimic acid biosynthesis. PMID- 25721095 TI - Effectiveness of propranolol in the treatment of infantile hemangioma beyond the proliferation phase. AB - During the last 5 years, many studies have shown the efficacy of propranolol as first-line treatment for infantile hemangiomas (IHs), but not much has been written about the role of propranolol beyond the proliferation phase of IH (>1 year). Our aim was to assess propranolol efficacy and safety in the treatment of patients older than 1 year. A retrospective study of patients older than 1 year diagnosed with IH and treated in our vascular anomalies clinic between 2009 and 2013 was performed. Eighteen patients older than 1 year with a diagnosis of IH (15 girls, 3 boys) were identified. The mean age at the time of initiation of treatment was 25.7 months (range 13-72 mos). Single lesions were observed in 13 patients and multiple lesions in 5. Fifteen patients had focal lesions and three had segmental. The median duration of treatment with oral propranolol was 11.8 months (range 2-33 mos). Complete response was observed in 72.2% of the patients and partial response in 27.8%. Recurrence was observed in three patients 4.7 months after completion of therapy (range 0.3-8 mos). These patients required further therapy with propranolol for 6 more months. Bradycardia was documented in two patients and night terrors in one patient, which led to discontinuation of treatment. In our experience, propranolol may be useful in the treatment of IHs beyond the proliferation phase (>1 year old), but more studies are needed to support this observation. PMID- 25721094 TI - Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. AB - Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine. PMID- 25721096 TI - Cobalt phosphide nanowires: efficient nanostructures for fluorescence sensing of biomolecules and photocatalytic evolution of dihydrogen from water under visible light. AB - The detection of specific DNA sequences plays an important role in the identification of disease-causing pathogens and genetic diseases, and photochemical water splitting offers a promising avenue to sustainable, environmentally friendly hydrogen production. Cobalt-phosphorus nanowires (CoP NWs) show a high fluorescence quenching ability and different affinity toward single- versus double-stranded DNA. Based on this result, the utilization of CoP NWs as fluorescent DNA nanosensors with a detection limit of 100 pM and a selectivity down to single-base mismatch was demonstrated. The use of a thrombin specific DNA aptamer also enabled the selective detection of thrombin. The photoinduced electron transfer from the excited dye that labels the oligonucleotide probe to the CoP semiconductor led to efficient fluorescence quenching, and largely enhanced the photocatalytic evolution of hydrogen from water under visible light. PMID- 25721097 TI - The Relation between Catheter Occlusion and Backflow during Intraparenchymal Cerebral Infusions. AB - Background/Aims: The distribution of infusate into the brain by convection enhanced delivery can be affected by backflow along the catheter shaft. This work assesses the following: (1) whether tissue coring and occlusion of the catheter lumen occurs when an open end-port catheter is inserted, (2) whether there is a relationship between intracatheter pressure and backflow, and (3) whether catheter occlusion increases backflow. Methods: Freshly excised monkey brains were used to assess tissue coring and its correlation with the behavior of the line pressure. In vivo infusions of gadolinium solution into monkey putamen at 1 MUl/min were conducted with and without a stylet during insertion. The effect of flow during insertion was evaluated in vivo in the pig thalamus. MRI and line pressure were continuously monitored during in vivo infusions. Results: Ex vivo testing showed that open end-port insertions always cored tissue (which temporarily plugs the catheter tip) and increased pressure followed by a rapid fall after its expulsion. Catheter insertion with a stylet in place prevented coring but not flow insertion; neither affected backflow. Conclusion: Open end port catheters occlude during insertion, which can be prevented by temporarily closing the port with a stylet but not by infusing while inserting. Backflow was not completely prevented by any insertion method. (c) 2015 S. Karger AG, Basel. PMID- 25721099 TI - Urinary Retention Due to Severe Pseudocystic Mucoid Degeneration of the Prostatic Matrix: A Rare Urologic Manifestation of Cystic Fibrosis. AB - Cystic fibrosis (CF) is an autosomal recessive genetic disease, which is characterized by the production of thick mucus in exocrine glands. The main cause for morbidity and mortality in CF patients is respiratory failure. The gastrointestinal system is also commonly affected. Urologic manifestations of CF include infertility and azoospermia, nephrolithiasis, and stress urinary incontinence. In this report, we describe a 33-year-old male, who presented with recurrent urinary retention due to prostatic enlargement despite his young age. After transurethral resection, the voiding problems resolved. Histopathological examination, however, revealed a severe pseudocystic mucoid degeneration of the prostatic matrix as a cause of his subvesical obstruction. Although these structural changes are most probably due to his underlying disease, detailed histologic features have not been described in the literature. PMID- 25721098 TI - Another functional frame-shift polymorphism of DEFB126 (rs11467497) associated with male infertility. AB - DEFB126 rs140685149 mutation was shown to cause sperm dysfunction and subfertility. Indel rs11467497 is another 4-nucleotide frame-shift mutation (151bp upstream of rs140685149) that leads to the premature termination of translation and the expression of peptide truncated at the carboxyl terminus. In the present study, we performed a comprehensive association study to check the contribution of rs140685149 and rs11467497 to male infertility. Our results confirmed the previous findings that there was no association between rs140685149 and sperm motility. In contrast, we found a significant association of another indel rs11467497 with male infertility. Moreover, rs11467497 was shown to be associated with higher number of round cells in the infertile males with low sperm motility. Surprisingly, the two mutations commonly existed in the sperm donors (n = 672), suggesting a potential application of the two indels in the screening for eligible sperm donors. Western blotting assays showed the sperms with rs140685149 2-nt deletion tended to have unstable DEFB126 protein in contrast of no DEFB126 protein expressed in the sperms with rs11467497 4-nt deletion, suggesting a more severe consequence caused by rs11467497 mutation. In conclusion, our study presented a significant contribution of another functional frame-shift polymorphism of DEFB126 (rs11467497) to male infertility. PMID- 25721100 TI - Establishment and characterization of fin cell lines from diploid, triploid, and tetraploid oriental weatherfish (Misgurnus anguillicaudatus). AB - Continuous fin cell lines from diploid, triploid, and tetraploid oriental weatherfish, Misgurnus anguillicaudatus, were established and characterized. The cell lines, designated DIMF, TRMF, and TEMF, respectively, were subcultured more than 80 times since initiation in October 2012 and were preserved at the China Center for Type Culture Collection as sample numbers C2013109, C2013110, C2013111, respectively. The cell lines consist predominantly of fibroblast-like cells. At the 50th passage, the population doubling times were 48.43 h (DIMF), 36.01 h (TRMF), and 41.45 h (TEMF). Cell survival rate of these three kinds of cells was 80.88 +/- 1.38, 84.48 +/- 1.13, and 81.57 +/- 1.28 %, respectively, when recovered after storage in liquid nitrogen for 60 days at the 40th passage. The chromosome numbers measured from 100 metaphase plates at the 50th passage were 2n = 50 (68 %), 3n = 75 (59 %), and 4n = 100 (54 %) for DIMF, TRMF, and TEMF cells, respectively. At the 60th passage, the chromosome numbers for DIMF and TRMF cells were still 50 (52 %) and 75 (70 %), but the chromosome number for TEMF cells ranged from 88 to 100; a chromosome number of 96 accounted for 26 % of the cells, and the karyotype analysis showed 4n = 96, 16 m + 8sm + 72t, NF = 120; thus, compared with cells at the 50th passage, a group of metacentric chromosomes was missing. Microsatellite marker analysis was conducted using DIMF, TRMF, and TEMF cells and muscle tissue of oriental weatherfish, which confirmed that the three cell lines established in this study were from oriental weatherfish. The cell lines were exposed to two fish viruses to determine their susceptibility to infection; they were susceptible to spring viremia of carp virus but not to piscine nodavirus. Establishment of fin cell lines from different ploidy oriental weatherfish increases the existing number of fish cell lines available for research, and it provides a model for investigating the mechanisms of growth and genetics in polyploid fish. PMID- 25721101 TI - Longitudinal trajectory patterns of social support: correlates and associated mental health in an Australian national cohort of young women. AB - PURPOSE: Although social support is a significant contributor to health and well being, little is known about patterns of perceived social support over time in young adulthood. It is also unclear which personal characteristics are associated with different patterns, and whether there is an association between social support and mental health over time. We explore these issues in a large national cohort of young women. METHODS: We used six waves of longitudinal data spanning 16 years, from 10,369 women from the Australian Longitudinal Study on Women's Health, initially aged 18-23. We used group-based trajectory modelling to identify patterns of social support across Surveys 2-6; multinomial logistic regression to identify socio-demographic and health-behaviour predictors at Survey 1 and correlates at Survey 6 for each trajectory group; and generalised linear mixed modelling to estimate mean levels of mental health over the trajectory period for each group, adjusted for confounders. RESULTS: Four distinct trajectory groups of social support were identified: 'High' (58.5 %), 'Decreasing' (20.6 %), 'Low' (9.3 %), and 'Increasing' (11.6 %). Poor health and living outside metropolitan areas at both Surveys 1 and 6 were characteristics of women in all trajectory groups other than the 'High' group, as were early motherhood and being un-partnered at age 34-39. Other characteristics were specific to one or two trajectory groups. Patterns of mental health over time were consistent with patterns of social support. CONCLUSION: Longitudinal trajectory patterns of social support are associated with mental health, health behaviours, and demographic factors even in early adulthood. PMID- 25721103 TI - The Apple of the mind's eye: Everyday attention, metamemory, and reconstructive memory for the Apple logo. AB - People are regularly bombarded with logos in an attempt to improve brand recognition, and logos are often designed with the central purpose of memorability. The ubiquitous Apple logo is a simple design and is often referred to as one of the most recognizable logos in the world. The present study examined recall and recognition for this simple and pervasive logo and to what degree metamemory (confidence judgements) match memory performance. Participants showed surprisingly poor memory for the details of the logo as measured through recall (drawings) and forced-choice recognition. Only 1 participant out of 85 correctly recalled the Apple logo, and fewer than half of all participants correctly identified the logo. Importantly, participants indicated higher levels of confidence for both recall and recognition, and this overconfidence was reduced if participants made the judgements after, rather than before, drawing the logo. The general findings did not differ between Apple and PC users. The results provide novel support for theories of attentional saturation, inattentional amnesia, and reconstructive memory; additionally they show how an availability heuristic can lead to overconfidence in memory for logos. PMID- 25721102 TI - Atherosclerotic vascular disease in the autoimmune rheumatologic patient. AB - Autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have a strong association with an increased risk of atherosclerotic cardiovascular diseases (ASCVD), particularly ischemic heart disease (IHD). A majority of the autoimmune conditions occur predominantly in women, and as women continue to experience a higher cardiovascular mortality compared to men, this potential added risk factor must be recognized. Inflammation and immune mechanisms have been shown to be an underlying mechanism for the development of atherosclerosis, thus sharing a common mechanism with rheumatologic conditions. There is an under recognition, in both patient and physician, of the increased cardiovascular (CV) risk within the autoimmune population, with present CV risk profile algorithms performing poorly in these patients. Traditional risk factors play a role in the development of IHD in the autoimmune patient, but their overall significance is unclear and does not fully explain the elevated CV risk. The role of inflammation and risk factors in autoimmune conditions, and their link to the elevated CV risk will be explored within this article. PMID- 25721104 TI - Sex reassignment of transsexual people from a gynecologist's and urologist's perspective. AB - Cross-sex hormone treatment of transgender persons is usually uneventful, but hormone-sensitive malignancies of the (reproductive) organs of the natal and new sex (breasts, neovagina) may arise. Sex reassignment surgery impacts on the urodynamics of the reassigned sex. Pathology originating from organ systems of the natal sex may be overlooked in the new sex. In male-to-female transgender individuals, malignant tumors of the breasts and prostate may occur. Neovaginas are constructed with skin or sigmoid. Shortening of the male urethra to female dimensions is usually uneventful. In female-to-male transgender individuals breast cancer may develop, sometimes in residual mammary tissue after reductive mammoplasty. Malignancies of the vagina and ovaries are rare. Testosterone may be aromatized to estrogens, with effects on the endometrium. Lengthening of the female urethra to male dimensions may cause urethral fistulae, urethral strictures, and meatal stenoses. A degree of post-voiding incontinence may occur. PMID- 25721105 TI - On the functions, mechanisms, and malfunctions of intracortical contextual modulation. AB - A broad neuron-centric conception of contextual modulation is reviewed and re assessed in the light of recent neurobiological studies of amplification, suppression, and synchronization. Behavioural and computational studies of perceptual and higher cognitive functions that depend on these processes are outlined, and evidence that those functions and their neuronal mechanisms are impaired in schizophrenia is summarized. Finally, we compare and assess the long term biological functions of contextual modulation at the level of computational theory as formalized by the theories of coherent infomax and free energy reduction. We conclude that those theories, together with the many empirical findings reviewed, show how contextual modulation at the neuronal level enables the cortex to flexibly adapt the use of its knowledge to current circumstances by amplifying and grouping relevant activities and by suppressing irrelevant activities. PMID- 25721107 TI - Exploring initial inappropriate use of urinary catheters among hospitalised older patients in Taiwan. AB - AIMS AND OBJECTIVES: To explore the incidence, associated factors and adverse outcomes for initial inappropriate use of urinary catheters in hospitalised older patients. BACKGROUND: Urinary catheters can lead to substantial complications. The related factors and adverse outcomes associated with initial inappropriate urinary catheter use among hospitalised older patients have not been studied. DESIGN: Prospective cohort study. METHODS: A total of 321 older patients admitted to the hospital in southern Taiwan having urinary catheters placed within 24 hours of admission were recruited. Demographic factors, voiding function history, health conditions and care conditions of catheter placement were collected through a review of medical records, interviewing participants or their primary caregivers. Catheter-associated urinary tract infection during hospitalisation, transfer to a nursing home, length of hospital stay and change in activities of daily living determined as outcomes. Criteria for urinary catheter placement were developed to identify inappropriate use. RESULTS: The incidence of initial inappropriate use of urinary catheters among hospitalised Taiwanese older patients was 38.3%. The rationale most often reported for initial inappropriate use was 'convenience of care' (49.6%). Factors associated with initial inappropriate use were, chronic constipation, urinary tract infection history, medical treatment diagnosis, cognitive impairment, depressive symptoms and independence in activities of daily living and, insertion of catheter during evening and night shifts and lack of nursing documentation of the rationale for catheterisation. Patients with initial inappropriate use showed greater decline in activities of daily living function between admission and discharge. CONCLUSION: Older patients with greater care needs may become the victims of initial inappropriate use of urinary catheters. Inappropriate use may devastate the activities of daily living in older patients. Nurses' awareness of indications for urinary catheters may prevent inappropriate use. RELEVANCE TO CLINICAL PRACTICE: A policy to strengthen nurses' awareness of the use of urinary catheters is needed in Taiwan. PMID- 25721106 TI - The Anti-Inflammatory Effects of the Small Molecule Pifithrin-u on BV2 Microglia. AB - Neonatal encephalopathy (NE) is a leading cause of childhood death and disability in term infants. Treatment options for perinatal brain injury are limited and developing therapies that target multiple pathways within the pathophysiology of NE are of great interest. Pifithrin-u (PFT-u) is a drug with striking neuroprotective abilities in a preclinical model of hypoxia-ischemia (HI)-induced NE wherein cell death is a substantial cause of injury. Work from neurons and tumor cells reports that PFT-u is able to inhibit p53 binding to the mitochondria, heat shock protein (HSP)-70 substrate binding and activation of the NF-kB pathway. The purpose of this study is to understand whether the neuroprotective effects of PFT-u also include direct effects on microglia. We utilized the microglial cell line, BV2, and we studied the dose-dependent effect of PFT-u on M1-like and M2-like phenotype using qRT-PCR and Western blotting, including the requirement for the presence of p53 or HSP-70 in these effects. We also assessed phagocytosis and the effects of PFT-u on genes within metabolic pathways related to phenotype. We noted that PFT-u robustly reduced the M1-like (lipopolysaccharide, LPS-induced) BV2 response, spared the LPS-induced phagocytic ability of BV2 and had no effect on the genes related to metabolism and that effects on phenotype were partially dependent on the presence of HSP-70 but not p53. This study demonstrates that the neuroprotective effects of PFT-u in HI induced NE may include an anti-inflammatory effect on microglia and adds to the evidence that this drug might be of clinical interest for the treatment of NE. PMID- 25721108 TI - Surgeons' performance data: challenge and opportunity. PMID- 25721109 TI - High-risk surgery: the courage to fail. PMID- 25721112 TI - Global health and security in the age of counterterrorism. PMID- 25721113 TI - Virtue ethics - an old answer to a new dilemma? Part 1. Problems with contemporary medical ethics. AB - The commonest practical model used in contemporary medical ethics is Principlism. Yet, while Principlism is a widely accepted consensus statement for ethics, the moral theory that underpins it faces serious challenges in its attempt to provide a coherent and accepted system of moral analysis. This inevitably challenges the stability of such a consensus statement and makes it vulnerable to attack by competitors such as preference consequentialism. This two-part paper proposes an inclusive version of virtue theory as a more grounded system of moral analysis. PMID- 25721114 TI - Appraising the quality of sub-Saharan African cancer registration systems that contributed to GLOBOCAN 2008: a review of the literature and critical appraisal. AB - OBJECTIVE: To critically appraise the quality of sub-Saharan African cancer registration systems that submitted data to GLOBOCAN 2008 with respect to population coverage using publicly available information and to show the use of GLOBOCAN statistics in determining global health priorities. DESIGN: Sources of cancer registration data for twenty-six sub-Saharan African cancer registries were identified from GLOBOCAN 2008 factsheets. Additional information was extracted from International Agency for Research on Cancer publications. A literature search was conducted to identify studies that reported additional information on data collection methods and provided 27 studies. The websites of the 10 largest funders of development assistance for health were searched for GLOBOCAN citations. SETTING AND PARTICIPANTS: Twenty-six sub-Saharan African cancer registration systems submitting data to GLOBOCAN 2008 in relation to 21 countries. MAIN OUTCOME MEASURES: Information on 15 quality variables were extracted and compared with the international gold standard for cancer registration systems. RESULTS: Population coverage of the cancer registries ranged from from 2.3% of the population in Kenya to 100% in The Gambia, with a heavy urban bias in all countries. However, 20 countries (300 million people) had no cancer registration systems. Nineteen of the 26 registries failed to meet more than five of the 15 quality criteria and only one country met more than 10. Seven of the 10 largest funders of development assistance for health cite GLOBOCAN statistics in support of policy priorities. CONCLUSIONS: GLOBOCAN 2008 estimates are based on data drawn from poor quality cancer registration systems, with limited or no population registry coverage. It is essential the GLOBOCAN 2012 estimates should provide information on the quality of the data collection and explain the limitations of the estimates. Development organisations and the World Health Organization need to take a more cautious approach when using these data to determine priorities and allocating resources. PMID- 25721115 TI - Alexander Lesassier Hamilton's 1816 report of a controlled trial of bloodletting. PMID- 25721116 TI - The intensive care of the coronary crisis. PMID- 25721120 TI - Fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. AB - BACKGROUND: The U.S. Food and Drug Administration-approved method for detecting EML4-ALK rearrangement is fluorescence in situ hybridization (FISH); however, data supporting the use of immunohistochemistry (IHC) for that purpose are accumulating. Previous studies that compared FISH and IHC considered FISH the gold standard, but none compared data with the results of next-generation sequencing (NGS) analysis. MATERIALS AND METHODS: We studied FISH and IHC (D5F3 antibody) systematically for EML4-ALK rearrangement in 51 lung adenocarcinoma patients, followed by NGS in case of discordance. RESULTS: Of 51 patients, 4 were positive with FISH (7.8%), and 8 were positive with IHC (15.7%). Three were positive with both. NGS confirmed that four of the five patients who were positive with IHC and negative with FISH were positive for ALK. Two were treated by crizotinib, with progression-free survival of 18 and 6 months. Considering NGS as the most accurate test, the sensitivity and specificity were 42.9% and 97.7%, respectively, for FISH and 100% and 97.7%, respectively, for IHC. CONCLUSION: The FISH-based method of detecting EML4-ALK rearrangement in lung cancer may miss a significant number of patients who could benefit from targeted ALK therapy. Screening for EML4-ALK rearrangement by IHC should be strongly considered, and NGS is recommended in borderline cases. Two patients who were negative with FISH and positive with IHC were treated with crizotinib and responded to therapy. PMID- 25721121 TI - Development and Evaluation of Self-Management and Task-Oriented Approach to Rehabilitation Training (START) in the Home: Case Report. AB - BACKGROUND: The incidence of stroke and subsequent level of disability will increase, as age is the greatest risk factor for stroke and the world's population is aging. Hospital admissions are too brief for patients to regain necessary function. Research to examine therapy delivered within the home environment has the potential to expedite relearning of function and reduce health care expenditures. PURPOSE: This case report describes the use of the knowledge-to-action cycle (KTA) to develop and evaluate an evidence-based approach for rehabilitation in the home that incorporates self-management and task-oriented functional training (TOFT) for people with stroke. CASE DESCRIPTION: The KTA cycle was used to guide adaptation of evidence from self management and TOFT into an approach titled START (Self-Management and Task Oriented Approach to Rehabilitation Training). Three stakeholder symposiums identified barriers and supports to implementation. Clinical practice leaders were engaged as partners in the development of the intervention. An online learning management system housed the resources to support therapist training. Therapist focus groups were conducted and stroke outcomes were used to assess patient response. OUTCOMES: Eight therapists completed 4 workshops and applied the home intervention in 12 people with stroke. A mentoring process for therapists included feedback from peers and experts after viewing treatment videos. Therapist response was determined from the focus groups; patient response was measured by standardized assessments. The therapists noted that the intervention was easier to implement with patients who were motivated and had minimal cognitive impairment. DISCUSSION: The KTA cycle provided a structure for the development of this evidence-based rehabilitation intervention, which was feasible to implement in the home. Further evaluation needs to be undertaken to assess the effectiveness of START. PMID- 25721122 TI - Effect of Trunk Support on Upper Extremity Function in People With Chronic Stroke and People Who Are Healthy. AB - BACKGROUND: Trunk control is thought to contribute to upper extremity (UE) function. However, this common assumption in neurorehabilitation has not been validated in clinical trials. OBJECTIVE: The study objectives were to investigate the effect of providing external trunk support on trunk control and UE function and to examine the relationship between trunk control and UE function in people with chronic stroke and people who were healthy. DESIGN: A cross-sectional study was conducted. METHODS: Twenty-five people with chronic stroke and 34 people who were healthy and matched for age and sex were recruited. Trunk control was assessed with the Trunk Impairment Scale (TIS), and UE impairment and UE function were assessed with the UE subsection of the Fugl-Meyer Assessment (FMA-UE) and the Streamlined Wolf Motor Function Test (SWMFT), respectively. The TIS and SWMFT were evaluated, with and without external trunk support; the FMA-UE was evaluated without trunk support. RESULTS: With trunk support, people with stroke showed improvement from 18 to 20 points on the TIS, a reduction in SWMFT performance times from 37.20 seconds to 35.37 seconds for the affected UE, and improvement from 3.3 points to 3.4 points on the SWMFT Functional Ability Scale for the function of the affected UE. With trunk support, the SWMFT performance time for people who were healthy was reduced from 1.61 seconds to 1.48 seconds for the dominant UE and from 1.71 seconds to 1.59 seconds for the nondominant UE. A significant moderate correlation was found between the TIS and the FMA-UE (r=.53) for people with stroke. LIMITATIONS: The limitations included a nonmasked assessor and a standardized height of the external trunk support. CONCLUSIONS: External trunk support improved trunk control in people with chronic stroke and had a statistically significant effect on UE function in both people with chronic stroke and people who were healthy. The findings suggest an association between trunk control and the UE when external trunk support was provided and support the hypothesis that lower trunk and lumbar stabilization provided by external support enables an improvement in the ability to use the UE for functional activities. PMID- 25721124 TI - Lupus nephritis: through the looking-glass. PMID- 25721123 TI - Shoulder Strength and Physical Activity Predictors of Shoulder Pain in People With Paraplegia From Spinal Injury: Prospective Cohort Study. AB - BACKGROUND: Shoulder joint pain is a frequent secondary complaint for people following spinal cord injury (SCI). OBJECTIVE: The purpose of this study was to determine predictors of shoulder joint pain in people with paraplegia. METHODS/DESIGN: A 3-year longitudinal study was conducted. Participants were people with paraplegia who used a manual wheelchair for at least 50% of their mobility and were asymptomatic for shoulder pain at study entry. Participants were classified as having developed shoulder pain if they experienced an increase of >=10 points on the Wheelchair User's Shoulder Pain Index in the 3-year follow up period. Measurements of maximal isometric shoulder torques were collected at study entry (baseline), 18 months, and 3 years. Daily activity was measured using a wheelchair odometer, and self-reported daily transfer and raise frequency data were collected by telephone every 6 weeks. RESULTS: Two hundred twenty-three participants were enrolled in the study; 39.8% developed shoulder pain over the 3 year follow-up period. Demographic variables and higher activity levels were not associated with shoulder pain onset. Baseline maximal isometric torque (normalized by body weight) in all shoulder muscle groups was 10% to 15% lower in participants who developed shoulder pain compared with those who remained pain free. Lower shoulder adduction torque was a significant predictor of shoulder pain development (log-likelihood test=11.38), but the model explained only 7.5% of shoulder pain onset and consequently is of limited clinical utility. LIMITATIONS: Time since SCI varied widely among participants, and transfer and raise activity was measured by participant recall. CONCLUSIONS: Participants who developed shoulder pain had decreased muscle strength, particularly in the shoulder adductors, and lower levels of physical activity prior to the onset of shoulder pain. Neither factor was a strong predictor of shoulder pain onset. PMID- 25721126 TI - Retraction. The migrant worker: visible, yet invisible. PMID- 25721125 TI - Aberrant TCRdelta rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency. AB - Ataxia telangiectasia mutated (ATM) is a protein kinase and a master regulator of DNA-damage responses. Germline ATM inactivation causes ataxia-telangiectasia (A T) syndrome with severe lymphocytopenia and greatly increased risk for T-cell lymphomas/leukemia. Both A-T and T-cell prolymphoblastic leukemia patients with somatic mutations of ATM frequently carry inv(14;14) between the T-cell receptor alpha/delta (TCRalpha/delta) and immunoglobulin H loci, but the molecular origin of this translocation remains elusive. ATM(-/-) mice recapitulate lymphocytopenia of A-T patients and routinely succumb to thymic lymphomas with t(12;14) translocation, syntenic to inv(14;14) in humans. Here we report that deletion of the TCRdelta enhancer (Edelta), which initiates TCRdelta rearrangement, significantly improves alphabeta T cell output and effectively prevents t(12;14) translocations in ATM(-/-) mice. These findings identify the genomic instability associated with V(D)J recombination at the TCRdelta locus as the molecular origin of both lymphocytopenia and the signature t(12;14) translocations associated with ATM deficiency. PMID- 25721127 TI - A Multipurpose, High-Throughput Single-Nucleotide Polymorphism Chip for the Dengue and Yellow Fever Mosquito, Aedes aegypti. AB - The dengue and yellow fever mosquito, Aedes aegypti, contributes significantly to global disease burden. Genetic study of Aedes aegypti is essential to understanding its evolutionary history, competence as a disease vector, and the effects and efficacy of vector control methods. The prevalence of repeats and transposable elements in the Aedes aegypti genome complicates marker development and makes genome-wide genetic study challenging. To overcome these challenges, we developed a high-throughput genotyping chip, Axiom_aegypti1. This chip screens for 50,000 single-nucleotide polymorphisms present in Aedes aegypti populations from around the world. The array currently used genotypes 96 samples simultaneously. To ensure that these markers satisfy assumptions commonly made in many genetic analyses, we tested for Mendelian inheritance and linkage disequilibrium in laboratory crosses and a wild population, respectively. We have validated more than 25,000 of these markers to date, and expect this number to increase with more sampling. We also present evidence of the chip's efficacy in distinguishing populations throughout the world. The markers on this chip are ideal for applications ranging from population genetics to genome-wide association studies. This tool makes rapid, cost-effective, and comparable genotype data attainable to diverse sets of Aedes aegypti researchers, from those interested in potential range shifts due to climate change to those characterizing the genetic underpinnings of its competence to transmit disease. PMID- 25721129 TI - Personality and overweight in 6-12-year-old children. AB - BACKGROUND: Personality may be an important yet understudied influence on childhood obesity. OBJECTIVE: We investigated the association between children's personality traits and weight status in a sample of 1533 6-12 year olds. METHODS: Mothers rated their child's personality using the Norwegian Hierarchical Personality Inventory for Children, and reported on their child's height and weight. RESULTS: Relative to their normal weight peers, overweight children were rated lower on energy, optimism, compliance, concentration, perseverance, and self-confidence, and higher on egocentricity, irritability, and anxiety. CONCLUSIONS: These findings suggest possible mechanisms to investigate in future research relating personality to childhood obesity. PMID- 25721130 TI - Gamma Knife Stereotactic Radiosurgery for Trigeminal Neuralgia Caused by a Developmental Venous Anomaly. AB - Background: Trigeminal neuralgia (TN) is mostly caused by vascular compression of the nerve's root entry zone due to an ectatic artery. Rarer causes include compression from tumors, vascular malformations or multiple sclerosis plaques. Developmental venous anomalies (DVAs) are benign, aberrantly appearing venous structures that drain normal cerebral tissue. DVAs are a rare etiology of TN. The management of TN caused by a DVA is controversial as disruption of the DVA can be catastrophic. Methods: We report a case of a young man with severe medically refractory TN related to a brachium pontis DVA who was successfully treated by gamma knife stereotactic radiosurgery (GKSR) to the trigeminal nerve. Results: Within 2 weeks of GKSR, the patient reported experiencing 60% pain relief; 5 years postoperatively, he remains completely pain free with some mild sensory loss in the V2 and V3 areas. Conclusions: GKSR has an established role in the management of TN. This is the first reported case of using GKSR to treat TN caused by a DVA. In the setting of a DVA, GKSR should be an initial consideration for TN therapy after medical failure because of the high surgical risk related to disrupting the DVA. (c) 2015 S. Karger AG, Basel. PMID- 25721128 TI - Leveraging DNA damage response signaling to identify yeast genes controlling genome stability. AB - Oncogenesis frequently is accompanied by rampant genome instability, which fuels genetic heterogeneity and resistance to targeted cancer therapy. We have developed an approach that allows precise, quantitative measurement of genome instability in high-throughput format in the Saccharomyces cerevisiae model system. Our approach takes advantage of the strongly DNA damage-inducible gene RNR3, in conjunction with the reporter synthetic genetic array methodology, to infer mutants exhibiting genome instability by assaying for increased Rnr3 abundance. We screen for genome instability across a set of ~1000 essential and ~4200 nonessential mutant yeast alleles in untreated conditions and in the presence of the DNA-damaging agent methylmethane sulfonate. Our results provide broad insights into the cellular processes and pathways required for genome maintenance. Through comparison with existing genome instability screens, we isolated 130 genes that had not previously been linked to genome maintenance, 51% of which have human homologs. Several of these homologs are associated with a genome instability phenotype in human cells or are causally mutated in cancer. A comprehensive understanding of the processes required to prevent genome instability will facilitate a better understanding of its sources in oncogenesis. PMID- 25721131 TI - Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer. AB - Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target specificity of the formed polyplexes. Implementation of endosomal escape promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor. PMID- 25721132 TI - Sensor-Based Interactive Balance Training with Visual Joint Movement Feedback for Improving Postural Stability in Diabetics with Peripheral Neuropathy: A Randomized Controlled Trial. AB - BACKGROUND: Individuals with diabetic peripheral neuropathy (DPN) have deficits in sensory and motor skills leading to inadequate proprioceptive feedback, impaired postural balance and higher fall risk. OBJECTIVE: This study investigated the effect of sensor-based interactive balance training on postural stability and daily physical activity in older adults with diabetes. METHODS: Thirty-nine older adults with DPN were enrolled (age 63.7 +/- 8.2 years, BMI 30.6 +/- 6, 54% females) and randomized to either an intervention (IG) or a control (CG) group. The IG received sensor-based interactive exercise training tailored for people with diabetes (twice a week for 4 weeks). The exercises focused on shifting weight and crossing virtual obstacles. Body-worn sensors were implemented to acquire kinematic data and provide real-time joint visual feedback during the training. Outcome measurements included changes in center of mass (CoM) sway, ankle and hip joint sway measured during a balance test while the eyes were open and closed at baseline and after the intervention. Daily physical activities were also measured during a 48-hour period at baseline and at follow up. Analysis of covariance was performed for the post-training outcome comparison. RESULTS: Compared with the CG, the patients in the IG showed a significantly reduced CoM sway (58.31%; p = 0.009), ankle sway (62.7%; p = 0.008) and hip joint sway (72.4%; p = 0.017) during the balance test with open eyes. The ankle sway was also significantly reduced in the IG group (58.8%; p = 0.037) during measurements while the eyes were closed. The number of steps walked showed a substantial but nonsignificant increase (+27.68%; p = 0.064) in the IG following training. CONCLUSION: The results of this randomized controlled trial demonstrate that people with DPN can significantly improve their postural balance with diabetes-specific, tailored, sensor-based exercise training. The results promote the use of wearable technology in exercise training; however, future studies comparing this technology with commercially available systems are required to evaluate the benefit of interactive visual joint movement feedback. PMID- 25721134 TI - ADHD is a risk factor for premature death, Danish study shows. PMID- 25721133 TI - Dependence of internal friction on folding mechanism. AB - An outstanding challenge in protein folding is understanding the origin of "internal friction" in folding dynamics, experimentally identified from the dependence of folding rates on solvent viscosity. A possible origin suggested by simulation is the crossing of local torsion barriers. However, it was unclear why internal friction varied from protein to protein or for different folding barriers of the same protein. Using all-atom simulations with variable solvent viscosity, in conjunction with transition-path sampling to obtain reaction rates and analysis via Markov state models, we are able to determine the internal friction in the folding of several peptides and miniproteins. In agreement with experiment, we find that the folding events with greatest internal friction are those that mainly involve helix formation, while hairpin formation exhibits little or no evidence of friction. Via a careful analysis of folding transition paths, we show that internal friction arises when torsion angle changes are an important part of the folding mechanism near the folding free energy barrier. These results suggest an explanation for the variation of internal friction effects from protein to protein and across the energy landscape of the same protein. PMID- 25721135 TI - Observing magnetic anisotropy in electronic transport through individual single molecule magnets. AB - We review different electron transport methods to probe the magnetic properties, such as the magnetic anisotropy, of an individual Fe4 SMM. The different approaches comprise first and higher order transport through the molecule. Gate spectroscopy, focusing on the charge degeneracy-point, is presented as a robust technique to quantify the longitudinal magnetic anisotropy of the SMM in different redox states. We provide statistics showing the robustness and reproducibility of the different methods. In addition, conductance measurements typically show high-energy excited states well beyond the ground spin multiplet of SMM. Some of these excitations have their origin in excited spin multiplets, others in vibrational modes of the molecule. The interplay between vibrations, charge and spin may yield a new approach for spin control. PMID- 25721136 TI - Combination of Matrine and Sorafenib Decreases the Aggressive Phenotypes of Hepatocellular Carcinoma Cells. AB - BACKGROUND: The aim of this study was to determine the effects of matrine (a natural alkaloid) on sorafenib-induced cytotoxicity against hepatocellular carcinoma (HCC) cells, and to explore the molecular mechanisms involved. METHODS: HepG2 and Hep3B cells were treated with matrine alone or in combination with sorafenib, and cell viability and apoptosis were assessed. The involvement of micro (mi)RNA-21 in the action of matrine was examined. RESULTS: Matrine significantly augmented the antiproliferative activity of sorafenib in a dose dependent manner. Matrine significantly increased apoptosis, coupled with enhanced cleavage of caspase-3 and poly (ADP-ribose) polymerase. miRNA-21 overexpressing HCC cells showed a marked decrease in matrine-induced growth suppression and the expression of phosphatase and tensin homolog (PTEN). The suppressive effect of combining matrine and sorafenib was significantly reduced by miRNA-21 overexpression or PTEN inhibition. CONCLUSION: Matrine in combination with sorafenib leads to increased cytotoxic effects against HCC cells, at least partially, via the suppression of miRNA-21 and the subsequent induction of PTEN. PMID- 25721137 TI - Isolation and identification of chemical constituents from Origanum majorana and investigation of antiproliferative and antioxidant activities. AB - BACKGROUND: Origanum majorana L., belonging to the Lamiaceae family, has great potential and has been used as a folk medicine against asthma, indigestion, headache and rheumatism; in addition, the essential oils of this plant have been used widely in the food industry. Plant materials have been harvested from the Medicinal and Aromatic Plant Field of Gaziosmanpasa University. Air-dried plant materials were boiled in water, filtered, and the solvent part subsequently extracted with hexane and ethyl acetate. The chromatographic method was applied to the ethyl acetate extract to isolate bioactive secondary metabolites, the structures of which were elucidated by spectroscopic techniques: basically one dimensional and two-dimensional nuclear magnetic resonance and quadrupole time-of flight liquid chromatography. Antiproliferative and antioxidant activities of isolated secondary metabolites were determined. RESULTS: 5,6,3'-Trihydroxy-7,8,4' trimethoxyflavone, hesperetin, hydroquinone, arbutin and rosmarinic acid were isolated from the water-soluble ethyl acetate extract of aerial parts of O. majorana. Antioxidant activities of isolated compounds and water-soluble ethyl acetate extract were investigated using assays of DPPH(*), ABTS(*+), reducing power and total phenolic content. Antiproliferative activities of the isolated compounds and plant extracts were investigated against C6 and HeLa cell lines using BrdU cell proliferation enzyme-linked immunosorbent assay and xCELLigence assay, respectively. Both hesperetin and hydroquinone were determined to have stronger antiproliferative activities against C6 and HeLa cells than the other isolated compounds and 5-fluorouracil. CONCLUSION: The results showed that the extract and isolated compounds exhibited significant antioxidant activities. Hence this plant has the potential to be a natural antioxidant in the food industry and an anticancer drug. PMID- 25721138 TI - Improvement of bisphenol A quantitation from urine by LCMS. AB - Bisphenol A (BPA) is a synthetic chemical extensively used in many consumer products. It mimics estrogen activities and is related to developmental disorders and metabolic diseases. The current challenge of BPA detection is their low circulating levels at 0.1~10 ng/mL which is close to the detection limit of most of current analytical methods. In this report, we developed a simple, sensitive, and accurate liquid chromatography mass spectrometry (LCMS) method after 1 methylimidazole-2-sulfonyl chloride derivatization. The method significantly improves sensitivity 5~9-fold over dansyl derivatization and approximately 100 fold without derivatization. PMID- 25721139 TI - Surgical outcomes and complications of prophylactic salpingectomy at the time of benign hysterectomy in premenopausal women. AB - STUDY OBJECTIVE: To compare the surgical outcome and short-term postoperative complications in premenopausal women who had undergone hysterectomies for benign indication with or without prophylactic bilateral salpingectomy. DESIGN: A cohort of consecutive women who had undergone hysterectomy plus bilateral salpingectomy between May 2012 and July 2014 (group A) were compared with the same number of consecutive premenopausal patients who had undergone simple hysterectomy operated on before May 2012 (group B). Inclusion criteria included premenopausal women and benign indication for surgery (Canadian Task Force classification III). SETTING: tertiary care hospital. INTERVENTION: Salpingectomy versus no salpingectomy at the time of benign hysterectomy. MEASUREMENTS AND MAIN RESULTS: A total of 97 and 71 patients were included in groups A and B, respectively. No differences between the 2 groups were observed regarding patient characteristics. The average operative time, estimated blood loss, uterine size, and intraoperative complications were similar between groups. The mean (standard deviation) length of hospitalization time was 43.7 (22.4) hours in group A and 53.9 (83.5) hours in group B (p = .008). There were no significant differences in terms of the incidence of postoperative complications, emergency visits after readmission, and hospital readmission between both groups of patients. CONCLUSION: Prophylactic salpingectomy at the time of benign hysterectomy in premenopausal women is safe and feasible and does not worsen surgical outcomes or the incidence of intraoperative and postoperative complications. PMID- 25721140 TI - Studying surgical innovations: challenges of the randomized controlled trial. AB - The randomized controlled trial (RCT) is designed to measure the efficacy of an intervention and is considered to be the most rigorous form of research, allowing for causal inferences to be made between treatments and outcomes. When designing an RCT, one must consider its essential methodological components including randomization, allocation, blinding, choice of outcome measures, sample size, loss to follow-up, and crossover. In contrast to RCTs of medical therapy, surgical trials face unique challenges that can affect study design, implementation, and interpretation of results. However, there are strategies that researchers can use to try to mitigate many of these challenges to improve the validity of the study. In addition, there are unique ethical considerations that must be examined when designing surgical trials, and steps must be taken to acknowledge them while maintaining the integrity of the study design. RCTs remain the best design to evaluate the efficacy of novel surgical treatments; however, researchers should be aware of and address the unique challenges inherent to surgical trials. PMID- 25721141 TI - Minilaparoscopic aortic lymphadenectomy. AB - STUDY OBJECTIVE: To show the feasibility of performing aortic lymphadenectomy with 3-mm instruments in gynecologic malignancies. PATIENT: A 43-year-old, multiparous patient with serous ovarian cancer grading 2, Federation Internationale de Gynecologie et d'Obstetrique stage IC (intraoperative spillage). INTERVENTION: The patient was accidentally diagnosed with ovarian cancer after a right adnexectomy performed for an ovarian cyst. Once referred to our center, a delayed surgical staging was planned including total hysterectomy, left adnexectomy, aortic and pelvic lymphadenectomy, peritoneal biopsies, and total omentectomy. Minilaparoscopy was believed to be feasible to achieve it. MEASUREMENTS AND MAIN RESULTS: The operation was performed successfully with no intraoperative or postoperative complication. Operative time was 150 minutes overall, and blood loss was 50 mL. Twenty-three aortic lymph nodes were removed. The pathology report came back clean. The patient was discharged on day 1 and 10 days later started adjuvant chemotherapy. After 16 months, no recurrence was detected. CONCLUSION: Minilaparoscopy aortic lymphadenectomy is technically feasible when performed by trained surgeons. PMID- 25721142 TI - Theoretical perspectives on the mechanism and kinetics of the OH radical initiated gas-phase oxidation of PCB126 in the atmosphere. AB - Polychlorinated biphenyls (PCBs) primarily exist in the gas phase in air and may undergo atmospheric oxidation degradations, particularly the oxidation reaction initiated by OH radicals. In this work, the mechanism of the OH radical-initiated atmospheric oxidation of the most toxic PCB congener 3,3',4,4',5 pentachlorobiphenyl (PCB126) was investigated by using quantum chemistry methods. The rate constants of the crucial elementary reactions were estimated by the Rice Ramsperger-Kassel-Marcus (RRKM) theory. The oxidation products of the reaction of PCB126 with OH radicals include 3,3',4,4',5-pentachlorobiphenyl-ols, chlorophenols, 2,3,4,7,8-pentachlorodibenzofuran, 2,3,4,6,7 pentachlorodibenzofuran, dialdehydes, 3,3',4,4',5-pentachloro-5'-nitro-biphenyl, and 4,5-dichloro-2-nitrophenol. Particularly, the formation of polychlorinated dibenzofurans (PCDFs) from the atmospheric oxidation of PCBs is revealed for the first time. The overall rate constant of the OH addition reaction is 2.52*10( 13)cm(3)molecule(-1)s(-1) at 298K and 1atm. The atmospheric lifetime of PCB126 determined by OH radicals is about 47.08days which indicates that PCB126 can be transported long distances from local to global scales. PMID- 25721143 TI - Spatial distribution and partitioning behavior of selected poly- and perfluoroalkyl substances in freshwater ecosystems: a French nationwide survey. AB - The spatial distribution and partitioning of 22 poly- and perfluoroalkyl substances (PFASs) in 133 selected rivers and lakes were investigated at a nationwide scale in mainland France. SigmaPFASs was in the range99% of SigmaPFASs in the sediment, likely as a consequence of industrial point source discharge). Several treatments for data below detection limits (non-detects) were used to compute descriptive statistics, differences among groups, and correlations between congeners, as well as log Kd and log Koc partition coefficients; in that respect, the Regression on Order Statistics (robust ROS) method was preferred for descriptive statistics computation while the Akritas-Theil-Sen estimator was used for regression and correlation analyses. Multiple regression results suggest that PFAS levels in the dissolved phase and sediment characteristics (organic carbon fraction and grain size) may be significant controlling factors of PFAS levels in the sediment. PMID- 25721144 TI - Effects of water flow regulation on ecosystem functioning in a Mediterranean river network assessed by wood decomposition. AB - Mediterranean rivers are extensively modified by flow regulation practises along their courses. An important part of the river impoundment in this area is related to the presence of small dams constructed mainly for water abstraction purposes. These projects drastically modified the ecosystem morphology, transforming lotic into lentic reaches and increasing their alternation along the river. Hydro morphologial differences between these reaches indicate that flow regulation can trigger important changes in the ecosystem functioning. Decomposition of organic matter is an integrative process and this complexity makes it a good indicator of changes in the ecosystem. The aim of this study was to assess the effect caused by flow regulation on ecosystem functioning at the river network scale, using wood decomposition as a functional indicator. We studied the mass loss from wood sticks during three months in different lotic and lentic reaches located along a Mediterranean river basin, in both winter and summer. Additionally, we identified the environmental factors affecting decomposition rates along the river orders. The results revealed differences in decomposition rates between sites in both seasons that were principally related to the differences between stream orders. The rates were mainly related to temperature, nutrient concentrations (NO2(-), NO3(2-)) and water residence time. High-order streams with higher temperature and nutrient concentrations exhibited higher decomposition rates compared with low order streams. The effect of the flow regulation on the decomposition rates only appeared to be significant in high orders, especially in winter, when the hydrological characteristics of lotic and lentic habitats widely varied. Lotic reaches with lower water residence time exhibited greater decomposition rates compared with lentic reaches probably due to more physical abrasion and differences in the microbial assemblages. Overall, our study revealed that in high orders the reduction of flow caused by flow regulation affects the wood decomposition indicating changes in ecosystem functioning. PMID- 25721145 TI - Subungual angiokeratoma presenting as a longitudinal pigmented band in the nail. PMID- 25721146 TI - Comparison of Assertive Community Treatment Fidelity Assessment Methods: Reliability and Validity. AB - Assertive community treatment is known for improving consumer outcomes, but is difficult to implement. On-site fidelity measurement can help ensure model adherence, but is costly in large systems. This study compared reliability and validity of three methods of fidelity assessment (on-site, phone-administered, and expert-scored self-report) using a stratified random sample of 32 mental health intensive case management teams from the Department of Veterans Affairs. Overall, phone, and to a lesser extent, expert-scored self-report fidelity assessments compared favorably to on-site methods in inter-rater reliability and concurrent validity. If used appropriately, these alternative protocols hold promise in monitoring large-scale program fidelity with limited resources. PMID- 25721147 TI - Response. PMID- 25721150 TI - Novel Oral Anticoagulants for DC Cardioversion Procedures: Utilization and Clinical Outcomes Compared with Warfarin. AB - BACKGROUND: Novel oral anticoagulant (NOAC) agents dabigatran, rivaroxaban, and apixaban are increasingly utilized as thromboembolic prevention for patients with atrial fibrillation undergoing direct current cardioversion (DCCV) with post hoc analyses of clinical trials suggesting satisfactory safety and efficacy. This study characterizes utilization, effectiveness, and complications of NOAC agents for stroke prophylaxis in the setting of DCCV. METHODS: Comparison of warfarin and NOAC agents as periprocedural anticoagulation for DCCV procedures performed at Cleveland Clinic from January 2009 through December 2013. Variables of interest include utilization rates for each NOAC agent stratified by clinical parameters including CHADS2 score, and associated clinical outcomes including cerebrovascular accident (CVA), transient ischemic attack (TIA), peripheral arterial embolism (PAE), and bleeding events during 8 weeks of postprocedure follow-up. RESULTS: Among 5,320 DCCV procedures, 673 (12.6%) cases were excluded due to inadequate follow-up. Warfarin was utilized in 3,721 (80.1%), dabigatran in 719 (15.5%), rivaroxaban in 159 (3.4%), and apixaban in 48 (1.0%) with a steady increase in NOAC utilization from 2011 to 2013. There were low rates of CVA/TIA (warfarin: 0.97% vs NOAC 1.62%, P = 0.162) and bleeding (warfarin: 1.02% vs NOAC: 0.5%, P = 0.247) and no significant differences detected between agents. Higher CHADS2 /CHA2 DS2 -VASC scores were associated with thromboembolic and bleeding risk. Increasing age, chronic kidney disease, diabetes, coronary disease, and deep vein thrombosis/pulmonary embolism were associated with increased bleeding risk. CONCLUSION: In a high-volume, single-center experience, NOAC utilization has grown to account for over a third of cardioversion procedures, and these agents appear safe and effective compared to warfarin with low rates of thromboembolic and bleeding complications. PMID- 25721149 TI - A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo. AB - The role of the obesity cytokine leptin in breast cancer progression has raised interest in interfering with leptin's actions as a valuable therapeutic strategy. Leptin interacts with its receptor through three different binding sites: I-III. Site I is crucial for the formation of an active leptin-leptin receptor complex and in its subsequent activation. Amino acids 39-42 (Leu-Asp-Phe-Ile- LDFI) were shown to contribute to leptin binding site I and their mutations in alanine resulted in muteins acting as typical antagonists. We synthesized a small peptide based on the wild-type sequence of leptin binding site I (LDFI) and evaluated its efficacy in antagonizing leptin actions in breast cancer using in vitro and in vivo experimental models. The peptide LDFI abolished the leptin-induced anchorage dependent and -independent growth as well as the migration of ERalpha-positive (MCF-7) and -negative (SKBR3) breast cancer cells. These results were well correlated with a reduction in the phosphorylation levels of leptin downstream effectors, as JAK2/STAT3/AKT/MAPK. Importantly, the peptide LDFI reversed the leptin-mediated up-regulation of its gene expression, as an additional mechanism able to enhance the peptide antagonistic activity. The described effects were specific for leptin signalling, since the developed peptide was not able to antagonize the other growth factors' actions on signalling activation, proliferation and migration. Finally, we showed that the LDFI pegylated peptide markedly reduced breast tumour growth in xenograft models. The unmodified peptide LDFI acting as a full leptin antagonist could become an attractive option for breast cancer treatment, especially in obese women. PMID- 25721151 TI - A sustainable freeze-drying route to porous polysaccharides with tailored hierarchical meso- and macroporosity. AB - Bio-derived polysaccharide aerogels are of interest for a broad range of applications. To date, these aerogels have been obtained through the time- and solvent-intensive procedure of hydrogel fomation, solvent exchange, and scCO2 drying, which offers little control over meso/macropore distribution. A simpler and more versatile route is developed, using freeze drying to produce highly mesoporous polysaccharide aerogels with various degrees of macroporosity. The hierarchical pore distribution is controlled by addition of different quantities of t-butanol (TBA) to hydrogels before drying. Through a systematic study an interesting relationship between the mesoporosity and t-butanol/water phase diagram is found, linking mesoporosity maxima with eutectic points for all polysaccharides studied (pectin, starch, and alginic acid). Moreover, direct gelation of polysaccharides in aqueous TBA offers additional time savings and the potential for solvent reuse. This finding is a doorway to more accessible polysaccharide aerogels for research and industrial scale production, due to the widespread accessibility of the freeze drying technology and the simplicity of the method. PMID- 25721152 TI - Olfactory screening: validation of Sniffin' Sticks in Denmark. AB - OBJECTIVES: The Sniffin' Sticks 12-identification test (SIT-12) is the most commonly applied Danish olfaction screening tool; however, it has never been validated in a Danish population. The screening score depends on familiarity with descriptors, which is strongly influenced by linguistic and cultural factors, why validation is mandatory. This study aimed to validate the SIT-12 in a Danish population. DESIGN: Prospective controlled study. SETTING: Otorhinolaryngology department. PARTICIPANTS: The SIT-12 was applied to 100 normosmic, healthy adult Danish participants. MAIN OUTCOME MEASURES: Choice of descriptors was registered, along with nasal endoscopic examination, screening for cognitive impairment, depression and sinonasal symptoms. Descriptors of the original version of SIT-12 were evaluated in 50 participants, and misleading descriptors were identified. Modifications to these descriptors were subsequently validated in a comparable group of 50 participants. RESULTS: Mean odorant identification score in the evaluation group was 11.0 of a possible 12, and 11.6 in the validation group (P < 0.0001). Among all odorant identification errors in the evaluation group, 60% were due to two incorrect descriptors having close resemblance to the correct descriptors, lemon and cinnamon. Two additional descriptors were unfamiliar to more than half the participants. There was a significant difference in the distribution of wrong identification answers between odorants in the evaluation group (P < 0.001), but not in the validation group. CONCLUSIONS: The identified systematically wrong descriptors have been modified and validated in the Danish SIT-12. PMID- 25721153 TI - Immediate postoperative inflammation is an important prognostic factor in breast cancer. AB - OBJECTIVE: Inflammation is associated with worse outcomes in cancer. Operations induce an acute inflammatory response and could impact the clinical outcomes in breast cancer. The neutrophil-lymphocyte ratio (NLR) is a well-known indicator of inflammation. We investigated the prognostic significance of perioperative inflammation with the NLR in breast cancer. METHODS: We reviewed the clinical and pathological records of women diagnosed with invasive breast carcinoma at the Samsung Medical Center between 2000 and 2010. The NLR levels in the immediate preoperative period and the postoperative periods (1 week and 1 month) were assessed. RESULTS: The NLRs of a total of 3,116 breast cancer patients were examined. In the univariate analysis, the NLR in postoperative week 1, total mastectomy, the presence of lymphovascular invasion, a higher nuclear grade and pathologic TNM stage, and negative hormone receptor and subtypes were factors associated with poor disease-specific survival. The NLR in postoperative week 1 remained a significant prognostic factor in the multivariate analysis. A cutoff level of 5.2, determined by the minimum p value approach, was found to be a significant level for discriminating the impact on breast cancer-specific mortality (p = 0.0116 adjusted by the Bonferroni correction). CONCLUSIONS: Immediate postoperative inflammation is an important prognostic marker in breast cancer patients. PMID- 25721155 TI - Toxicology at the speed of light: an interview with Dr. Craig Venter. PMID- 25721154 TI - MIF and TNFalpha serum levels in rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs: a cross-sectional study. AB - Macrophage migration inhibitory factor (MIF) and tumor necrosis factor alpha (TNFalpha) play a pivotal role in rheumatoid arthritis (RA). MIF is considered a relevant cytokine because it appears before TNFalpha in the inflammatory cascade thus stimulating TNFalpha production and MIF's relationship with traditional synthetic disease modifying antirheumatic drugs (sDMARDs) is unknown. In this cross-sectional study, we investigated the association of MIF and TNFalpha serum levels with methotrexate (MTX) and in combination with chloroquine (CLQ) and sulfasalazine (SSZ) in RA patients classified according to the ACR/EULAR 2010 criteria. Patients were divided into three groups: MTX-monotherapy group (n = 40), MTX combination therapy groups: MTX + CLQ (n = 41), and MTX + CLQ + SSZ (n = 42). MIF and TNFalpha serum levels were determined by ELISA. We found high levels of ESR, CRP, RF, and anti-CCP in all therapy groups. Furthermore, we subclassified 97 patients with established RA (>=2 years of disease duration) and found that TNFalpha serum levels were lower in the combination therapy group (MTX + CLQ + SSZ) in comparison with the monotherapy MTX group (16.7 pg/mL versus 13.6 pg/mL, p = 0.02). However, we did not find differences between sDMARD therapies in MIF serum levels. We did find a significant reduction in MIF serum levels in patients treated with oral steroids compared with patients without oral steroids (1.7 ng/mL versus 4.3 ng/mL, p < 0.001). In conclusion, this study supports the role of sDMARDs in modifying TNFalpha serum levels and oral steroids MIF serum levels. Nevertheless, we found that MIF serum levels are not modified by sDMARD treatment. PMID- 25721156 TI - Society of Toxicology Board of Publications Best Paper Award for 2015. PMID- 25721157 TI - Declines in highly active antiretroviral therapy initiation at CD4 cell counts <= 200 cells/MUL and the contribution of diagnosis of HIV at CD4 cell counts <= 200 cells/MUL in British Columbia, Canada. AB - OBJECTIVES: The aim of the study was to examine trends in initiating highly active antiretroviral therapy (HAART) with a CD4 count <= 200 cells/MUL and the contribution of having a CD4 count <= 200 cells/MUL at the time of diagnosis to these trends, in British Columbia (BC), Canada. METHODS: We included in the analysis treatment-naive BC residents aged >= 19 years who initiated HAART from 2003 to 2012. Participants were classified as follows: Group 1: diagnosed and initiated HAART with a CD4 count > 200 cells/MUL; Group 2: diagnosed with a CD4 count > 200 cells/MUL and initiated HAART with a CD4 count <= 200 cells/MUL; and Group 3: diagnosed and initiated HAART with a CD4 count <= 200 cells/MUL. We measured trends in initiating HAART with a CD4 count <= 200 cells/MUL and used logistic regression models to measure factors associated with initiating HAART with a CD4 count <= 200 cells/MUL, stratified by having a CD4 count <= 200 cells/MUL or > 200 cells/MUL at the time of diagnosis. RESULTS: Between 2003 and 2012, 3506 BC residents initiated HAART. Of these, 44% (1558 of 3506) initiated HAART with a CD4 count <= 200 cells/MUL. This proportion declined from 69% (198 of 287) in 2003 to 21% (81 of 330) in 2012 (P < 0.001). The proportion of those in Group 3 increased from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2012 (P < 0.001). Overall, 56% (1948), 22% (776) and 22% (782) made up Groups 1, 2, and 3, respectively. In adjusted analyses, seeing a specialist was significantly associated with being in Group 3. Using injection drugs and seeing a specialist were associated with being in Group 2. CONCLUSIONS: In recent years, among individuals who ever initiated HAART in BC, being diagnosed with low CD4 cell counts has become a greater contributor to initiating HAART with low CD4 cell counts. PMID- 25721158 TI - Decitabine plus thalidomide yields more sustained survival rates than decitabine monotherapy for risk-tailored elderly patients with myelodysplastic syndrome. AB - OBJECTIVE: The open-label, prospective, observational study aimed to evaluate whether decitabine (DAC) plus thalidomide versus DAC monotherapy improved progression-free (PFS), overall survival (OS) and acute myeloid leukemia-free survival (AML-FS) for risk-tailored elderly patients with myelodysplastic syndromes (MDS). METHOD: Enrolled 107 patients (age: 65-82 years) received DAC (52/107) or DAC plus thalidomide (55/107) therapy for MDS. RESULTS: 35/52 patients (67.3%) with DAC therapy reached overall response (OR), compared with 36/55 patients (65.5%) in DAC+thalidomide regimen (P>0.05). DAC+thalidomide administered did not gain more profits of PFS and OS than DAC monotherapy. Risk tailored analysis showed that DAC+thalidomide therapy did not enhance PFS (48.9% versus 42.8%, P>0.05) and OS (78.6% versus 71.2%, P>0.05) when compared with simple DAC regimen. Nevertheless, DAC+thalidomide markedly improved OS over DAC monotherapy (50.6% versus 40.2%, P<0.05) in high risk profile. Meanwhile, low risk group was superior to high risk group in AML-FS (57.2% versus 21.3%, P<0.01), but DAC+thalidomide still did not prolong 2-year AML-FS when compared with DAC (32.4% versus 27.8%, P<0.05). Moreover, thalidomide had a favorable toxicity profile as a single agent. In comparison with DAC monotherapy, the DAC+thalidomide regimen was relatively well tolerated. There was no severe non hematological toxicity appearing in elderly patients with MDS. CONCLUSIONS: The study demonstrated that DAC+thalidomide improved 2-year OS for high risk patients. Thalidomide's proven activity and low toxicity profile made it an alternative treatment option for risk-tailored elderly patients with MDS. PMID- 25721159 TI - A graphene-based resistive pressure sensor with record-high sensitivity in a wide pressure range. AB - Pressure sensors are a key component in electronic skin (e-skin) sensing systems. Most reported resistive pressure sensors have a high sensitivity at low pressures (<5 kPa) to enable ultra-sensitive detection. However, the sensitivity drops significantly at high pressures (>5 kPa), which is inadequate for practical applications. For example, actions like a gentle touch and object manipulation have pressures below 10 kPa, and 10-100 kPa, respectively. Maintaining a high sensitivity in a wide pressure range is in great demand. Here, a flexible, wide range and ultra-sensitive resistive pressure sensor with a foam-like structure based on laser-scribed graphene (LSG) is demonstrated. Benefitting from the large spacing between graphene layers and the unique v-shaped microstructure of the LSG, the sensitivity of the pressure sensor is as high as 0.96 kPa(-1) in a wide pressure range (0 ~ 50 kPa). Considering both sensitivity and pressure sensing range, the pressure sensor developed in this work is the best among all reported pressure sensors to date. A model of the LSG pressure sensor is also established, which agrees well with the experimental results. This work indicates that laser scribed flexible graphene pressure sensors could be widely used for artificial e skin, medical-sensing, bio-sensing and many other areas. PMID- 25721160 TI - Neurobehavioral effects of exposure to organophosphates and pyrethroid pesticides among Thai children. AB - The use of pesticides for crop production has grown rapidly in Thailand during the last decade, resulting in significantly greater potential for exposure among children living on farms. Although some previous studies assessed exposures to pesticides in this population, no studies have been conducted to evaluate corresponding health effects. Twenty-four children from a rice farming community (exposed) and 29 from an aquaculture (shrimp) community (control) completed the study. Participants completed a neurobehavioral test battery three times at 6 month intervals: Session I: preliminary orientation; Session II: high pesticide use season; Session III: low pesticide-use season. Only sessions II and III were used in the analyses. High and low pesticide use seasons were determined by pesticide use on rice farms. Urinary metabolites of organophosphates (OPs) and pyrethroids (PYR) were analyzed from first morning void samples collected the day of neurobehavioral testing. Rice farm participants had significantly higher concentrations of dialkylphosphates (DAPs) (common metabolites of OPs) and TCPy (a specific metabolite of chlorpyrifos) than aquaculture farm children during both seasons. But, TCPy was significantly higher during the low rather than the high pesticide use season for both participant groups. Rice farm children had significantly higher DCCA, a metabolite of PYR, than aquaculture participants only during the high exposure season. Otherwise, no significant differences in PYR metabolites were noted between the participant groups or seasons. No significant adverse neurobehavioral effects were observed between participant groups during either the high or low pesticide use season. After controlling for differences in age and the Home Observation for Measurement of the Environment (HOME) scores, DAPs, TCPy, and PYR were not significant predictors of adverse neurobehavioral performance during either season. Increasing DAP and PYR metabolites predicted some relatively small improvement in latency of response. However, due to the small sample size and inability to characterize chronic exposure, any significant differences observed should be regarded with caution. Moreover although not statistically significant, confidence intervals suggest that small to moderate adverse effects of pesticide exposure cannot be ruled out for some indicators of neurobehavioral performance. PMID- 25721161 TI - Comments on the 2014 ESC guidelines on the diagnosis and treatment of aortic diseases. PMID- 25721163 TI - Aortic regurgitation directed toward right ventricle. PMID- 25721166 TI - 2014 annual summary and new projects in Revista Espanola de Cardiologia. PMID- 25721167 TI - Plerixafor on demand in ten healthy family donors as a rescue strategy to achieve an adequate graft for stem cell transplantation. AB - BACKGROUND: In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate number of HSCs while maintaining a high level of safety for healthy donors is fundamental. Inadequate HSC mobilization can be seen with the standard use of granulocyte-colony-stimulating (G-CSF). Plerixafor (PL) is a chemokine receptor CXC Type 4-stromal-derived factor 1 inhibitor; its HSC mobilizing properties are synergistic with G-CSF in poor mobilizing patients. The use of PL as adjuvant or alternative to G-CSF in healthy donors has shown a good safety profile but is so far off-label. STUDY DESIGN AND METHODS: We report 10 healthy HSC donors treated with PL because of insufficient response to G-CSF alone or contraindication to G-CSF. Eight donors did not mobilize enough CD34+ cells with G-CSF alone because poor mobilizers or because insufficient HSCs were harvested according to the clinical need of the patient; in two cases G-CSF administration and marrow harvest were unfeasible or contraindicated in the donor. RESULTS: The use of PL for mobilization increased the number of circulating CD34+ cells by 2.8-fold and the CD34+/kg collection by 3.0-fold. Only mild adverse events were reported (bone pain or discomfort) and not univocally attributable to PL. Rate of engraftment and graft-versus-host disease were similar to those seen in recipients of grafts from G-CSF only-mobilized donors. CONCLUSION: We exposed 10 allogeneic donors to mobilization with PL. PL was well tolerated in all cases and ensured procurement of an adequate graft for transplantation resulting in a normal hematopoietic engraftment. PMID- 25721168 TI - S-777469, a novel cannabinoid type 2 receptor agonist, suppresses itch-associated scratching behavior in rodents through inhibition of itch signal transmission. AB - We have previously reported that S-777469 [1-([6-ethyl-1-(4-fluorobenzyl)-5 methyl-2-oxo-1,2-dihydropyridine-3-carbonyl]amino)-cyclohexanecarboxylic acid], a novel cannabinoid type 2 receptor (CB2) agonist, significantly suppressed compound 48/80-induced scratching behavior in mice in a dose-dependent manner when it was administered orally. Here, we demonstrated that the inhibitory effects of S-777469 on compound 48/80-induced scratching behavior are reversed by pretreatment with SR144528, a CB2-selective antagonist. In addition, we investigated the effects of S-777469 on itch-associated scratching behavior induced by several pruritogenic agents in mice and rats. S-777469 significantly suppressed scratching behavior induced by histamine or substance P in mice or by serotonin in rats. In contrast, the H1-antihistamine fexofenadine clearly inhibited histamine-induced scratching behavior but did not affect scratching behavior induced by substance P or serotonin. Moreover, S-777469 significantly inhibited histamine-induced peripheral nerve firing in mice. In conclusion, these results suggest that S-777469 produces its antipruritic effects by inhibiting itch signal transmission through CB2 agonism. PMID- 25721169 TI - Are European lobsters (Homarus gammarus) susceptible to infection by a temperate Hematodinium sp.? AB - Hematodinium spp. infect over 40 species of crustaceans worldwide, but have not been reported to infect the European lobster, Homarus gammarus. In this study, Hematodinium parasites (a mixture of uni- and multinucleate trophont-like stages) were taken from donor crabs (Cancer pagurus) and injected into juvenile H. gammarus. Juvenile C. pagurus were also injected with the same inoculum. Haemolymph was taken at regular intervals and examined for the presence of Hematodinium using light microscopy and PCR, in two separate experiments of duration 4 and 8months. All lobsters were negative for Hematodinium whilst the C. pagurus challenged became infected. It is concluded that European lobsters are not susceptible to infection with a clade of Hematodinium that infects C. pagurus. PMID- 25721170 TI - Enhancement of Bacillus thuringiensis insecticidal activity by combining Cry1Ac and bi-functional toxin HWTX-XI from spider. AB - In order to assess the potency of bi-functional HWTX-XI toxin from spider Ornithoctonus huwena in improving the insecticidal activity of Bacillus thuringiensis, a fusion gene of cry1Ac and hwtx-XI was constructed and expressed in an acrystalliferous B. thuringiensis strain Cry(-)B. Western blot analysis and microscopic observation revealed that the recombinant strain could express 140 kDa Cry1Ac-HWTX-XI fusion protein and produce parasporal inclusions during sporulation. Bioassay using the larvae of Helicoverpa armigera and Spodoptera exigua showed that the Cry1Ac-HWTX-XI fusion was more toxic than the control Cry1Ac protoxin, as revealed by 95% lethal concentration. Our study indicated that the HWTX-XI from spider might be a candidate for enhancing the toxicity of B. thuringiensis products. PMID- 25721171 TI - The impact of individualized interaction on the quality of life of elderly dependent on care as a result of dementia: a study with a pre-post design. AB - BACKGROUND: The aim was to assess the impact of a one-to-one 30-min individualized interaction per day on the behavior and quality of life of care dependent residents with dementia. METHODS: In a pre-/post-test study, 15 care dependent residents with dementia (mean age 88.8 years, 86.7% women) were included. Resident behavior was measured using video observation and quality of life using Qualidem. Health care professionals (n = 13) and direct relatives (n = 4) were interviewed about the effect of the intervention. The effect of the intervention was analyzed using the Friedman analysis of variance. RESULTS: The video observation showed that maintaining eye contact, touching, responding to speaking, tracking observable stimuli and asking questions about the activity significantly increased during the intervention. These findings were supported by interviews with nurses who described experiences of making human-to-human contact with the residents. No significant overall changes were found in quality of life. These findings were partially supported by interviews with health care professionals and relatives as some perceived effects beyond the 30-min intervention. CONCLUSIONS: Interaction offered on a one-to-one basis tailored to individual preferences significantly improved positive interactive behavior of care-dependent residents with dementia during the intervention. Surveys revealed no significant overall effect of the intervention. The interviews indicated there might be effects beyond the intervention for some residents. PMID- 25721172 TI - Parastomal hernia repair with the Sugarbaker technique using e-PTFE mesh. AB - PURPOSES: Although surgery is commonly used to treat parastomal hernia, it is very difficult and has shown poor results. Recently, repair with prosthetic materials has been thought to be a more promising method. METHODS: The Sugarbaker technique with e-PTFE mesh (Dualmesh(r)) performed via open surgery was adopted for seven patients with parastomal hernia. Two of them were recurrent cases. Three of the patients experienced incarceration of the intestine and recovered conservatively before surgery. The median age of the patients at the parastomal hernia repair was 77.6 years old (range 37.7-84.7). RESULTS: The median operative time was 211 min (range 147-256). The median hernia size was 28 cm2 (range 7.5-60 cm2). The median amount of blood loss during the operation was 158 g (range 0-370 g). Surgical site infection was not observed. The postoperative median hospital stay was 17 days (range 13-40) and the median follow-up was 2.4 years (range 1.0 3.7). During the follow-up period, we did not observe recurrence or readmission. CONCLUSIONS: The surgical results were satisfactory with minimal morbidity and no recurrences. The Sugarbaker technique for parastomal repair using e-PTFE mesh may be suitable as a standard method for treating parastomal hernia. PMID- 25721173 TI - Recent trend of acute appendicitis during pregnancy. AB - PURPOSE: We report the clinical presentation, management and outcomes of 33 patients who underwent surgery for acute appendicitis during pregnancy between April 1997 and March 2011. METHODS: Several variables were compared between these 33 patients (pregnant group, n = 33) and non-pregnant females aged 20-40 years who underwent an acute appendectomy during the same period (control group, n = 124). RESULTS: No significant differences were found between the two groups in terms of the type of anesthesia, operative method, duration of surgery, pathology, duration of antibiotic use, and incidence of surgical site infection, except for a higher frequency of pararectal incision performed and higher leukocyte counts in the pregnant group (P < 0.01). Tocolytic agents were administered to 17 patients (52%). Preterm labor occurred in 10 patients (30%), one of whom experienced preterm delivery. CONCLUSIONS: These results suggest that acute appendicitis during pregnancy can be managed successfully without fetal loss. PMID- 25721174 TI - Liver transplantation for advanced hepatocellular carcinoma in patients with Child-Pugh A and B. AB - PURPOSE: To investigate the outcomes of living donor liver transplantation for advanced hepatocellular carcinoma in Child-Pugh A/B patients and the usefulness of our expanded selection criteria, the Kyoto criteria. METHODS: A total of 82 recipients with a Child-Pugh class A (n = 27) or B (n = 55) status having either multiple hepatic nodules or solitary tumors >=5 cm in size treated between February 1999 and August 2012 were enrolled in this study. RESULTS: The overall recurrence rate was significantly less for the Child-Pugh B patients than for the Child-Pugh A patients (P = 0.042), while the survival rates did not differ. In the Child-Pugh A and B patients, the survival rate was significantly greater, while the recurrence rate was lower among the patients meeting the Kyoto criteria than those exceeding these criteria (P = 0.006, P = 0.001, P = 0.032 and P < 0.001, respectively). In the Child-Pugh B patients, the overall survival and recurrence rates did not differ between the patients treated with and without pretreatment for hepatocellular carcinoma. In the Child-Pugh B patients treated with pretreatment, the overall survival rate was significantly greater, while the recurrence rate was lower among the patients meeting the Kyoto criteria than those exceeding these criteria (P < 0.001, P < 0.001, respectively). CONCLUSIONS: Living donor liver transplantation performed within the Kyoto criteria achieves excellent overall survival and recurrence rates, especially for Child-Pugh B patients, even those with advanced hepatocellular carcinoma. PMID- 25721175 TI - Osler on migraine. AB - William Osler's 1892 textbook The Principles and Practice of Medicine became the dominant medical text in the English-speaking world. Osler was labeled a therapeutic nihilist by some. The topic of migraine, including treatment, was succinctly covered in his text. The objectives of this study were to review Osler's thoughts on migraine, and outline his therapeutic recommendations. Preventively Osler mentioned bromides, iron, arsenic, nitroglycerin, and cannabis. Acutely he recommended coffee, chloroform, cannabis, antipyrin, antifebrin, phenacetin, caffeine citrate, nux vomica, or ergot. He thought cannabis was the most satisfactory remedy. Osler was not a therapeutic nihilist when it came to migraine, and his treatment recommendations were similar to other writers of his time. Osler did not draw upon his personal experience to contribute new knowledge about migraine. Regardless, given the popularity and clarity of his text, Osler's well-summarized migraine chapter had a great influence on practicing physicians. PMID- 25721176 TI - Ultra-small rhenium clusters supported on graphene. AB - The adsorption of very small rhenium clusters (2-13 atoms) supported on graphene was studied by high-angle annular dark field-scanning transmission electron microscopy (HAADF-STEM). The atomic structure of the clusters was fully resolved with the aid of density functional theory calculations and STEM simulations. It was found that octahedral and tetrahedral structures work as seeds to obtain more complex morphologies. Finally, a detailed analysis of the electronic structure suggested that a higher catalytic effect can be expected in Re clusters when adsorbed on graphene than in isolated ones. PMID- 25721177 TI - Multifunctional gold nanorods for selective plasmonic photothermal therapy in pancreatic cancer cells using ultra-short pulse near-infrared laser irradiation. AB - Gold nanorods (AuNRs) have attracted considerable attention in plasmonic photothermal therapy for cancer treatment by exploiting their selective and localized heating effect due to their unique photophysical properties. Here we describe a strategy to design a novel multifunctional platform based on AuNRs to: (i) specifically target the adenocarcinoma MUC-1 marker through the use of the EPPT-1 peptide, (ii) enhance cellular uptake through a myristoylated polyarginine peptide (MPAP) and (iii) selectively induce cell death by ultra-short near infrared laser pulses. We used a biotin-avidin based approach to conjugate EPPT-1 and MPAP to AuNRs. Dual-peptide (EPPT-1+MPAP) labelled AuNRs showed a significantly higher uptake by pancreatic ductal adenocarcinoma cells when compared to their single peptide or avidin conjugated counterparts. In addition, we selectively induced cell death by ultra-short near infrared laser pulses in small target volumes (~1 MUm3), through the creation of plasmonic nanobubbles that lead to the destruction of a local cell environment. Our approach opens new avenues for conjugation of multiple ligands on AuNRs targeting cancer cells and tumors and it is relevant for plasmonic photothermal therapy. PMID- 25721178 TI - Here and there: the art (and science) of psychotherapy. PMID- 25721179 TI - My use of humor in therapy: a performance-in-practice self-study. PMID- 25721180 TI - Child/Adolescent Anxiety Multimodal Study safety. PMID- 25721181 TI - Cognitive training for attention-deficit/hyperactivity disorder: meta-analysis of clinical and neuropsychological outcomes from randomized controlled trials. AB - OBJECTIVE: The authors performed meta-analyses of randomized controlled trials to examine the effects of cognitive training on attention-deficit/hyperactivity disorder (ADHD) symptoms, neuropsychological deficits, and academic skills in children/adolescents with ADHD. METHOD: The authors searched Pubmed, Ovid, Web of Science, ERIC, and CINAHAL databases through May 18, 2014. Data were aggregated using random-effects models. Studies were evaluated with the Cochrane risk of bias tool. RESULTS: Sixteen of 695 nonduplicate records were analyzed (759 children with ADHD). When all types of training were considered together, there were significant effects on total ADHD (standardized mean difference [SMD] = 0.37, 95% CI = 0.09-0.66) and inattentive symptoms (SMD = 0.47, 95% CI = 0.14 0.80) for reports by raters most proximal to the treatment setting (i.e., typically unblinded). These figures decreased substantially when the outcomes were provided by probably blinded raters (ADHD total: SMD = 0.20, 95% CI = 0.01 0.40; inattention: SMD = 0.32, 95% CI = -0.01 to 0.66). Effects on hyperactivity/impulsivity symptoms were not significant. There were significant effects on laboratory tests of working memory (verbal: SMD = 0.52, 95% CI = 0.24 0.80; visual: SMD = 0.47, 95% CI = 0.23-0.70) and parent ratings of executive function (SMD = 0.35, 95% CI = 0.08-0.61). Effects on academic performance were not statistically significant. There were no effects of working memory training, specifically on ADHD symptoms. Interventions targeting multiple neuropsychological deficits had large effects on ADHD symptoms rated by most proximal assessors (SMD = 0.79, 95% CI = 0.46-1.12). CONCLUSION: Despite improving working memory performance, cognitive training had limited effects on ADHD symptoms according to assessments based on blinded measures. Approaches targeting multiple neuropsychological processes may optimize the transfer of effects from cognitive deficits to clinical symptoms. PMID- 25721182 TI - Cognitive-behavioral therapy for child anxiety confers long-term protection from suicidality. AB - OBJECTIVE: Evidence for an independent relationship between anxiety and suicidality has been mixed. Few studies have examined this relationship in youth seeking treatment for anxiety. The present study examined the relationship between response to treatment for an anxiety disorder in childhood and suicidal ideation, plans, and attempts at a follow-up interval of 7 to 19 years. We hypothesized that successful treatment for an anxiety disorder in childhood would be protective against later suicidality. METHOD: The present study was a 7- to 19 year (mean = 16.24 years; SD = 3.56 years) follow-up study. Adults (N = 66) completed cognitive-behavioral treatment (CBT) for anxiety as children. Information regarding suicidality at follow-up was obtained via the World Mental Health Survey Initiative version of the World Health Organization Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II). RESULTS: Results indicate that participants who responded favorably to CBT during childhood were less likely to endorse lifetime, past-month, and past-2 week suicidal ideation than treatment nonresponders. This was consistent across self-report and interview-report of suicidal ideation. Treatment response was not significantly associated with suicide plans or attempts, although the infrequent occurrence of both limited the ability to detect findings. CONCLUSION: Results suggest more chronic and enduring patterns of suicidal ideation among individuals with anxiety in childhood that is not successfully treated. This study adds to the literature that suggests that successful CBT for childhood anxiety confers long-term benefits and underscores the importance of the identification and evidence-based treatment of youth anxiety. PMID- 25721183 TI - Child/Adolescent anxiety multimodal study: evaluating safety. AB - OBJECTIVE: To evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents. METHOD: Participants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC). RESULTS: There were no differences between the double blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p < .01) and COMB (p < .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (<=12 years) across all arms (31.7% versus 23.1%, p < .05). Total PSC scores decreased over time, with no significant differences between treatment groups. CONCLUSION: The results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (<=12 years). Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov; NCT00052078. PMID- 25721184 TI - Family-based interpersonal psychotherapy for depressed preadolescents: examining efficacy and potential treatment mechanisms. AB - OBJECTIVE: To conduct a randomized controlled trial to evaluate the preliminary efficacy of family-based interpersonal psychotherapy (FB-IPT) for treating depression in preadolescents (aged 7-12 years) as compared to child-centered therapy (CCT), a supportive and nondirective treatment that closely approximates the standard of care for pediatric depression in community mental health. METHOD: Preadolescents with depression (N = 42) were randomly assigned FB-IPT or CCT. Pre and posttreatment assessments included clinician-administered measures of depression, parent- and child-reported depression and anxiety symptoms, and parent-child conflict and interpersonal impairment with peers. RESULTS: Preadolescents receiving FB-IPT had higher rates of remission (66.0% versus 31%), a greater decrease in depressive symptoms from pre- to posttreatment, and lower depressive symptoms at posttreatment (R(2) = 0.35, DeltaR(2) = 0.22; B = -8.15, SE = 2.61, t[37] = -3.13, p = .002, F(2) = 0.28) than did preadolescents with depression receiving CCT. Furthermore, preadolescents in the FB-IPT condition reported significant reductions in anxiety and interpersonal impairment compared with preadolescents in the CCT condition. Changes in social and peer impairment from pre- to posttreatment were associated with preadolescents' posttreatment depressive symptoms. There was a significant indirect effect for decreased social impairment accounting for the association between the FB-IPT and preadolescents' posttreatment depressive symptoms. CONCLUSION: Findings indicate FB-IPT is an effective treatment for preadolescent depression and support further investigation of interpersonal mechanisms by which FB-IPT may reduce preadolescent depression. Clinical trial registration information-Phase II Study of Family Based Interpersonal Psychotherapy (FB-IPT) for Depressed Preadolescents; http://clinicaltrials.gov; NCT02054312. PMID- 25721185 TI - Predictors associated with improved cognitive-behavioral therapy outcome in pediatric obsessive-compulsive disorder. AB - OBJECTIVE: To identify predictors of treatment response in a large sample of pediatric participants with obsessive-compulsive disorder (OCD). The Nordic Long term Obsessive compulsive disorder (OCD) Treatment Study (NordLOTS) included 269 children and adolescents, 7 to 17 years of age, with a DSM-IV diagnosis of OCD. Outcomes were evaluated after 14 weekly sessions of exposure-based cognitive behavioral therapy (CBT). METHOD: The association of 20 potential predictors, identified by literature review, along with their outcomes, was evaluated using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) posttreatment. A CY-BOCS total score of <=15 was the primary outcome measure. RESULTS: The univariate analyses showed that children and adolescents who were older had more severe OCD, greater functional impairment, higher rates of internalizing and externalizing symptoms, and higher levels of anxiety and depression symptoms before treatment had significantly poorer outcomes after 14 weeks of treatment. However, only age was a significant predictor in the multivariate model. CONCLUSION: In the multivariate analysis, only age predicted better treatment outcome. Using univariate analysis, a variety of predictors of poorer treatment outcome after CBT was identified. The high impact of comorbid symptoms on outcome in pediatric OCD suggests that treatment should address comorbidity issues. The lack of a family predictor may be related to high family involvement in this study. Future research strategies should focus on optimizing intervention in the presence of these characteristics to achieve greater benefits for patients with OCD. Clinical trial registration information-Nordic Long-term Obsessive compulsive disorder (OCD) Treatment Study; www.controlled-trials.com; ISRCTN66385119. PMID- 25721186 TI - Randomized comparative trial of a social cognitive skills group for children with autism spectrum disorder. AB - OBJECTIVE: This study evaluated the efficacy of a targeted social skills training group in school-aged children with autism spectrum disorder (ASD). The intervention, Seaver-NETT (Nonverbal communication, Emotion recognition, and Theory of mind Training), is a 12-session cognitive-behavioral intervention (CBI) for verbal, school-aged children targeting ASD-specific social behavioral impairments. METHOD: Sixty-nine children with ASD, 8 to 11 years of age, with verbal IQs greater than 70, participated in a randomized comparative trial to examine the efficacy of NETT relative to a facilitated play group. Treatment outcomes included caregiver reports of social behavior and neuropsychological assessments of social cognition conducted by blinded raters. Outcomes were collected at baseline, endpoint, and 3 months posttreatment. RESULTS: Significant improvements were found on social behavior outcomes such as nonverbal communication, empathic responding, and social relations in the NETT condition relative to the active control at endpoint. Verbal IQ moderated the interaction effect on social behavior, with higher verbal IQ associated with improvements in the CBI condition. No significant improvements were found on social cognitive outcomes. No significant group differences were found at 3-month follow-up conducted with approximately half the sample (n = 34). CONCLUSION: These data indicate that targeted CBI social skills groups such as NETT improve social communication deficits in verbal, school-aged children with ASD. The moderating effects of high verbal IQ suggest a need to consider participant and treatment characteristics associated with outcomes in future studies. Clinical trial registration information-Neural and Behavioral Outcomes of Social Skills Groups in Children With Autism Spectrum Disorder; https://clinicaltrials.gov; NCT01190917. PMID- 25721187 TI - Olanzapine/Fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To assess the efficacy and safety of olanzapine/fluoxetine combination (OFC) for the acute treatment of bipolar depression in children and adolescents. METHOD: Patients 10 to 17 years of age with bipolar I disorder (BP-I), depressed episode, baseline Children's Depression Rating Scale-Revised (CDRS-R) total score >=40, Young Mania Rating Scale (YMRS) total score <=15, and YMRS-item 1 <=2 were randomized to OFC (6/25-12/50 mg/day olanzapine/fluoxetine; n = 170) or placebo (n = 85) for up to 8 weeks of double-blind treatment. The primary efficacy measure was mean change in CDRS-R using mixed-model repeated-measures methodology. RESULTS: Baseline-to-week-8 least-squares mean change in CDRS-R total score was greater for OFC-treated patients than for placebo-treated patients (-28.4 versus -23.4, p = .003; effect size = .46), with between-group differences statistically significant at week 1 (p = .02) and all subsequent visits (all p < .01). Rates of and times to response and remission were statistically significantly greater for OFC- than for placebo-treated patients. The most frequent treatment-emergent adverse events in the OFC group were weight gain, increased appetite, and somnolence. Mean weight gain at patient's endpoint was significantly greater for OFC- than for placebo-treated patients (4.4 kg versus 0.5 kg, p < .001). Treatment-emergent hyperlipidemia was very common among OFC-treated patients. Abnormal increases in hepatic analytes, prolactin, and corrected QT interval (QTc) were also common or very common but generally not clinically significant. CONCLUSION: In this study, OFC was superior to placebo, and has been approved by the US Food and Drug Administration (FDA) for the acute treatment of bipolar I depression in patients 10 to 17 years of age. Benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia. Clinical trial registration information-A Study for Assessing Treatment of Patients Ages 10-17 with Bipolar Depression; http://clinicaltrials.gov; NCT00844857. PMID- 25721188 TI - Social isolation and mental health at primary and secondary school entry: a longitudinal cohort study. AB - OBJECTIVE: We tested whether children who are socially isolated early in their schooling develop mental health problems in early adolescence, taking into account their mental health and family risk at school entry. METHOD: We used data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a birth cohort of 2,232 children born in England and Wales in 1994 and 1995. We measured social isolation using mothers' and teachers' reports at ages 5 and 12 years. We assessed mental health symptoms via mothers' and teachers' ratings at age 5 and self-report measures at age 12. We collected mother-reported information about the family environment when children were 5 years old. We conducted regression analyses to test concurrent and longitudinal associations between early family factors, social isolation, and mental health difficulties. RESULTS: At both primary and secondary school, children who were socially isolated experienced greater mental health difficulties. Children with behavioral problems or attention-deficit/hyperactivity disorder (ADHD) symptoms at age 5 years had an elevated risk of becoming more socially isolated at age 12. However, children who were isolated at age 5 did not have greater mental health symptoms at age 12, over and above pre-existing difficulties. CONCLUSION: Although social isolation and mental health problems co-occur in childhood, early isolation does not predict worse mental health problems later on. However, children who exhibit problematic behaviors may struggle to cope with the social challenges that accompany their progression through the early school years. PMID- 25721189 TI - Treatment of delirium in the context of anti-N-methyl-D-aspartate receptor antibody encephalitis. PMID- 25721192 TI - Thermodynamics of nanoalloys. AB - This article reviews recent advances in our understanding of how temperature affects the structure and the phase of multimetallic nanoparticles. Focusing on bimetallic systems, we discuss the interplay of size, shape and chemical order on the stable configurations at thermal equilibrium. Besides some considerations about experimental evidence for thermally-induced transformations, most insight is generally gained from theory and computation. The perspectives offered by mesoscopic approaches (i.e. corrected from the bulk) and atomistic simulations complement each other and often provide detailed information about the respective roles of coordination, composition and more generally surface effects to be evaluated. Order-disorder transitions and the melting phase change are strongly altered in nanoscale systems, and we describe how they possibly impact entire phase diagrams. PMID- 25721191 TI - Follicle-stimulating hormone receptor polymorphism affects the outcome of ovulation induction in normogonadotropic (World Health Organization class 2) anovulatory subfertility. AB - OBJECTIVE: To assess whether an FSH receptor polymorphism (Asn680Ser, rs6166) can affect the outcome of ovulation induction in normogonadotropic (World Health Organization class 2 [WHO2]) anovulatory subfertile women. DESIGN: Prospective, longitudinal, cohort study. SETTING: University-based fertility unit. PATIENT(S): A total of 240 consecutive women diagnosed with WHO2 anovulatory subfertility who underwent ovulation induction therapy. Results were replicated in a retrospective cohort of 185 patients with polycystic ovary syndrome (PCOS) (Rotterdam criteria). INTERVENTION(S): Ovulation induction using clomiphene citrate (CC) as first-line and exogenous gonadotropins (exFSH) as second-line therapy. MAIN OUTCOME MEASURE(S): Clomiphene-resistant anovulation (CRA), clomiphene failure (CCF), and ongoing pregnancy rate. RESULT(S): Genotyped patients (n = 159) were similar to nongenotyped women (n = 81) regarding clinical characteristics and outcomes of ovulation induction. The 680(Ser) allele was associated with CRA. A pooled analysis of both cohorts showed an 89% higher chance of CRA after CC treatment (odds ratio 1.9 [95% confidence interval 1.1-3.3]) in homozygous carriers of the FSH receptor variant (680(Ser/Ser)). A lower chance of ongoing pregnancy (hazard ratio 0.51 [95% confidence interval 0.27-0.98]) was observed among these patients during CC treatment in the prospective cohort. CONCLUSION(S): An FSH receptor polymorphism is associated with CRA during treatment with clomiphene citrate. These data may be used to design a treatment algorithm that is more efficacious and better tailored to the individual patient. PMID- 25721193 TI - Caffeine intake from coffee or tea and cognitive disorders: a meta-analysis of observational studies. AB - BACKGROUND: Observational epidemiological studies such as cross-sectional, case control, and cohort studies have reported inconsistent findings regarding the association between caffeine intake from coffee or tea and the risk of cognitive disorders such as dementia, Alzheimer's disease, cognitive impairment, and cognitive decline. METHODS: We searched PubMed and EMBASE in September 2014. Three evaluators independently extracted and reviewed articles, based on predetermined selection criteria. RESULTS: Out of 293 articles identified through the search and bibliographies of relevant articles, 20 epidemiological studies from 19 articles, which involved 31,479 participants (8,398 in six cross sectional studies, 4,601 in five case-control studies, and 19,918 in nine cohort studies), were included in the final analysis. The pooled odds ratio (OR) or relative risk (RR) of caffeine intake from coffee or tea for cognitive disorders (dementia, Alzheimer's disease, cognitive impairment, and cognitive decline) was 0.82 (95% confidence interval [CI], 0.67-1.01, I2 = 63.2%) in a random-effects meta-analysis. In the subgroup meta-analysis by caffeine sources, the summary OR or RR of coffee intake was 0.83 (95% CI, 0.70-0.98; I2 = 44.8%). However, in the subgroup meta-analysis by study design, the summary estimates (RR or OR) of coffee intake for cognitive disorders were 0.70 (95% CI, 0.50-0.98; I2 = 42.0%) for cross-sectional studies, 0.82 (95% CI, 0.55-1.24; I2 = 33.4%) for case control studies, and 0.90 (95% CI, 0.59-1.36; I2 = 60.0%) for cohort studies. CONCLUSIONS: This meta-analysis found that caffeine intake from coffee or tea was not associated with the risk of cognitive disorders. PMID- 25721194 TI - Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F AB-PINACA. AB - Whereas non-fluoropentylindole/indazole synthetic cannabinoids appear to be metabolized preferably at the pentyl chain though without clear preference for one specific position, their 5-fluoro analogs' major metabolites usually are 5 hydroxypentyl and pentanoic acid metabolites. We determined metabolic stability and metabolites of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3 carboxamide (AB-PINACA) and 5-fluoro-AB-PINACA (5F-AB-PINACA), two new synthetic cannabinoids, and investigated if results were similar. In silico prediction was performed with MetaSite (Molecular Discovery). For metabolic stability, 1 MUmol/L of each compound was incubated with human liver microsomes for up to 1 h, and for metabolite profiling, 10 MUmol/L was incubated with pooled human hepatocytes for up to 3 h. Also, authentic urine specimens from AB-PINACA cases were hydrolyzed and extracted. All samples were analyzed by liquid chromatography high-resolution mass spectrometry on a TripleTOF 5600+ (AB SCIEX) with gradient elution (0.1% formic acid in water and acetonitrile). High-resolution full-scan mass spectrometry (MS) and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot (AB SCIEX) using different data processing algorithms. Both drugs had intermediate clearance. We identified 23 AB-PINACA metabolites, generated by carboxamide hydrolysis, hydroxylation, ketone formation, carboxylation, epoxide formation with subsequent hydrolysis, or reaction combinations. We identified 18 5F-AB-PINACA metabolites, generated by the same biotransformations and oxidative defluorination producing 5-hydroxypentyl and pentanoic acid metabolites shared with AB-PINACA. Authentic urine specimens documented presence of these metabolites. AB-PINACA and 5F-AB-PINACA produced suggested metabolite patterns. AB-PINACA was predominantly hydrolyzed to AB PINACA carboxylic acid, carbonyl-AB-PINACA, and hydroxypentyl AB-PINACA, likely in 4-position. The most intense 5F-AB-PINACA metabolites were AB-PINACA pentanoic acid and 5-hydroxypentyl-AB-PINACA. PMID- 25721195 TI - The transnasal VideoPanendoscopy (ViP): diagnostics of the upper aerodigestive tract using an anatomically correct model from the model to the patient. AB - Endoscopy of the upper aerodigestive tract (UADT) develops rapidly. New endoscopes in combination with special imaging techniques allow complete examinations of the UADT in an ambulatory setting. Therefore, it is necessary to educate and train young physicians in a standardized protocol. A special anatomical training model has been designed to allow a stepwise endoscopy training course. It can be used by specialists who would like to take advantage of transnasal VideoPanendoscopy for examination of suitable candidate patients. This method offers advantages for ENT doctors, gastroenterologists as well as endoscopic surgeons. PMID- 25721196 TI - The presence of Helicobacter pylori in laryngeal squamous cell carcinoma. AB - A definitive relationship between Helicobacter pylori (HP) and upper respiratory tract disorders has not been established. In this case-control study, we investigated the relationship between HP and laryngeal carcinoma by real-time PCR method in Turkey. 74 subjects were enrolled from patients who were admitted to the Otolaryngology Department. Formalin-fixed-paraffin-embedded tissue samples with laryngeal cancer were used and all samples were evaluated by real-time PCR method. Our study population included 72 males and 2 females with a mean age range of 62.7 years. Helicobacter Pylori was detected in only one case. The positive case was also investigated with histopathologic evaluation and HP immunohistochemistry. However, we could not detect HP in this case with both methods. This study revealed that HP might not contribute to the pathogenesis of laryngeal carcinoma. A definitive relationship between HP and upper respiratory tract disorders has not been established. PMID- 25721197 TI - Influenza-like infection and laryngeal cancer. PMID- 25721198 TI - A novel muscle for electroneurography in peripheral facial palsy: occipitalis. AB - Electroneurography (ENoG) is one of the most objective tests in grading the damage and prediction of prognosis in peripheral facial palsy (PFP). We aimed to determine temporal changes of ENoG recorded over occipitalis muscle in acute idiopathic PFP. Consecutive 21 patients with unilateral acute idiopathic PFP and age- and sex-matched 15 healthy volunteers were included in the study. Nasal and occipital ENoG values were recorded once in the control group and the same procedure was repeated daily between the second and eight days of the disorder in the PFP group. Occipital ENoG value began to increase on the third day while nasal ENoG value was still within the normal range (27.04 vs 7.69 %, p = 0.0001). In the fourth, fifth and sixth days, occipital ENoG value was significantly high compared to nasal ENoG value (p = 0.0001 for each day) whereas nasal and occipital ENoG values were very similar in the seventh and eighth days (p = 0.181 and p = 0.584, respectively). Our study presents further support for technical possibility of occipital ENoG which may reflect the degree of fiber degeneration earlier than the nasalis muscle in PFP. PMID- 25721199 TI - The role of ultrasonic instruments in pharyngolaryngeal endoscopic surgery. AB - The purpose of this study was to assess the applicability and efficacy of ultrasonic instruments in laryngeal and pharyngeal endoscopic surgery. This article describes three cases of supraglottic laryngopharyngeal carcinoma transorally treated with the Harmonic forceps, which are indicative of our preliminary experience in this field. Based on our preliminary experience, we believe that the use of the ACE Harmonic forceps opens up very encouraging prospects in transoral endoscopic surgery of pharyngolaryngeal tumors and can potentially become a key instrument in this area. Given their different characteristics, we believe that ultrasonic instruments should be used not so much as an alternative to, but rather in addition to those traditionally used in pharyngolaryngeal endoscopic surgery and laser in particular. Finally, we hope that a more widespread use of these instruments in this surgical field may encourage manufacturers to solve the current technical limitations of miniaturization, thus designing and developing more precise and accurate instruments for this type of surgery. PMID- 25721200 TI - Comprehensive selection of reference genes for quantitative gene expression analysis during seed development in Brassica napus. AB - KEY MESSAGE: MicroRNAs have higher expression stability than protein-coding genes in B. napus seeds and are therefore good reference genes for miRNA and mRNA RT qPCR analysis. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) has become the "gold standard" to gain insight into function of genes. However, the accuracy of the technique depends on appropriate reference genes for quantification analysis in different experimental conditions. Accumulation of microRNAs (miRNAs) has also been studied by RT-qPCR, but there are no reference genes currently validated for normalization of Brassica napus miRNA expression data. In this study, we selected 43 B. napus miRNAs and 18 previously validated mRNA reference genes. The expression stability of the candidate reference genes was evaluated in different tissue samples (stages of seed development, flowers, and leaves) using geNorm, NormFinder, and RefFinder analysis. The best-ranked reference genes for expression studies during seed development (miR167-1_2, miR11-1, miR159-1 and miR168-1) were used to asses the expression of miR03-1. Since candidate miRNAs showed higher expression stability than protein-coding genes in most of the tested conditions, the expression profile of DGAT1 gene was compared when normalized by the four most stable miRNAs reference genes and by the four most stable mRNA reference genes. The expected expression pattern of DGAT1 during seed development was achieved with the use of miRNA as reference genes. In conclusion, the most stable miRNA reference genes can be employed in the normalization of RT-qPCR quantification of miRNAs and protein-coding genes. This work is the first to perform a comprehensive survey of the stability of miRNA reference genes in B. napus and provides guidelines to obtain more accurate RT-qPCR results in B. napus seeds studies. PMID- 25721201 TI - Cloning and functional validation of molybdenum cofactor sulfurase gene from Ammopiptanthus nanus. AB - KEY MESSAGE: The molybdenum cofactor sulfurase gene ( AnMCSU ) was cloned from xerophytic desert plant Ammopiptanthus nanus and validated for its function of tolerance toward abiotic stresses by heterologous expression in Arabidopsis thaliana. Molybdenum cofactor sulfurase participates in catalyzing biosynthesis of abscisic acid, which plays a crucial role in the response of plants to abiotic stresses. In this study, we cloned molybdenum cofactor sulfurase gene (AnMCSU) from a super-xerophytic desert plant, Ammopiptanthus nanus, by using rapid amplification of cDNA ends method. This gene has a total length of 2544 bp, with a 5'- and a 3'-untranslated region of 167 and 88 bp, and an open reading frame of 2289 bp, which encodes an 84.85 kDa protein of 762 amino acids. The putative amino acid sequence shares high homology and conserved amino acid residues crucial for the function of molybdenum cofactor sulfurases with other leguminous species. The encoded protein of the AnMCSU gene was located in the cytoplasm by transient expression in Nicotiana benthamiana. The result of real-time quantitative PCR showed that the expression of the AnMCSU gene was induced by heat, dehydration, high salt stresses, and ABA induction, and inhibited by cold stress. The heterologous expression of the AnMCSU gene significantly enhanced the tolerance of Arabidopsis thaliana to high salt, cold, osmotic stresses, and abscisic acid induction. All these results suggest that the AnMCSU gene might play a crucial role in the adaptation of A. nanus to abiotic stress and has potential to be applied to transgenic improvement of commercial crops. PMID- 25721202 TI - Molecular characterization of the basic helix-loop-helix (bHLH) genes that are differentially expressed and induced by iron deficiency in Populus. AB - KEY MESSAGE: Two Populus bHLH genes ( PtFIT and PtIRO ) were cloned and characterized. The iron deficiency tolerance may be regulated by the PtFIT dependent response pathway in Populus. Five orthologs of eight Arabidopsis basic helix-loop-helix (bHLH) genes responding to iron deficiency in Populus were analyzed. Open reading frame (ORF) regions of two bHLH genes (PtFIT and PtIRO) were isolated from the iron deficiency tolerant (PtG) and susceptible (PtY) genotypes of Populus tremula 'Erecta'. Gene sequence analyses showed that each of the two genes was identical in PtG and PtY. Phylogenetic analysis revealed that PtFIT was clustered with the bHLH genes regulating iron deficiency responses, while PtIRO was clustered with another group of the bHLH genes regulating iron deficiency responses in a FIT-independent pathway. Tissue-specific expression analysis indicated that PtFIT was only detected in the root among all tested tissues, while PtIRO was rarely detected in all tested tissues. Real-time PCR showed that PtFIT was up-regulated in roots under the iron-deficient condition. A higher level of PtFIT transcripts was detected in PtG than in PtY. Pearson Correlation Coefficient calculations indicated a strong positive correlation (r = 0.94) between PtFIT and PtIRT1 in PtG. It suggests that the iron deficiency tolerance of PtG may be regulated by the PtFIT-dependent response pathway. The PtFIT-transgenic poplar plants had an increased expression level of PtFIT and PtIRT1 responding to iron deficiency. One PtFIT-transgenic line (TL2) showed enhanced iron deficiency tolerance with higher chlorophyll content and Chl a/b ratio under iron deficiency than the control plants, indicating that PtFIT is involved in iron deficiency response in Populus. The results would provide useful information to understand iron deficiency response mechanisms in woody species. PMID- 25721203 TI - Gate-controlled generation of optical pulse trains using individual carbon nanotubes. AB - In single-walled carbon nanotubes, electron-hole pairs form tightly bound excitons because of limited screening. These excitons display a variety of interactions and processes that could be exploited for applications in nanoscale photonics and optoelectronics. Here we report on optical pulse-train generation from individual air-suspended carbon nanotubes under an application of square wave gate voltages. Electrostatically induced carrier accumulation quenches photoluminescence, while a voltage sign reversal purges those carriers, resetting the nanotubes to become luminescent temporarily. Frequency-domain measurements reveal photoluminescence recovery with characteristic frequencies that increase with excitation laser power, showing that photoexcited carriers provide a self limiting mechanism for pulsed emission. Time-resolved measurements directly confirm the presence of an optical pulse train synchronized to the gate voltage signal, and flexible control over pulse timing and duration is also demonstrated. These results identify an unconventional route for optical pulse generation and electrical-to-optical signal conversion, opening up new prospects for controlling light at the nanoscale. PMID- 25721204 TI - Oncolytic viruses: focusing on the tumor microenvironment. PMID- 25721205 TI - Gene therapy for radioprotection. AB - Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy. PMID- 25721206 TI - Novel lentiviral-inducible transgene expression systems and versatile single plasmid reporters for in vitro and in vivo cancer biology studies. AB - Many of the cancer cell lines derived from solid tumors are difficult to transfect using commonly established transfection approaches. This hurdle for some DNA transfection systems has hindered cancer biology studies. Moreover, there are limited tools for studying pathway activities. Therefore, highly efficient improved gene transfer and versatile genetic tools are required. In this study, we established and developed a comprehensive set of new lentiviral tools to study gene functions and pathway activities. Using the optimized conditions, cancer cell lines achieved >90% transduction efficiency. Novel lentiviral doxycycline-regulated pTet-IRES-EGFP (pTIE) systems for transgene expression and TRE reporters used for pathway activity determination were developed and tested. The pTIE Tet-Off system showed in vitro doxycycline sensitive responses with low or undetectable leakage of protein expression and in vivo tumor suppression as illustrated using candidate tumor suppressors, Fibulin 2 and THY1. In contrast, the Tet-On system showed dose-dependent responses. The pTRE-EGFP (pTE) and pTRE-FLuc-EF1alpha-RLuc (pT-FER) reporters with the NFkappaB p65 subunit consensus sequence showed GFP and firefly luciferase responses, which were directly correlated with TNFalpha stimulation, respectively. Taken together, these newly developed lentiviral systems provide versatile in vitro and in vivo platforms to strengthen our capabilities for cancer biology studies. PMID- 25721209 TI - MALAT2-activated long noncoding RNA indicates a biomarker of poor prognosis in gastric cancer. AB - The purpose of this study is to investigate the role of the long noncoding RNA metastasis associated lung adenocarcinoma transcript 2 (MALAT2) in the prognosis of stage II/III gastric cancer (GC) patients. The expression of MALAT2 was evaluated in cancer tissues from 146 stage II/III GC patients undergoing radical resection and 60 paired normal samples using quantitative real-time reverse transcriptase PCR. Differences in the expression of MALAT2 between 23 GC and paired normal colonic mucosa samples were analysed with the Wilcoxon test. Relationships between the expression level of MALAT2, patient clinico pathological parameters and disease-free survival and overall survival were analysed using the uni-variate Kaplan-Meier method and the multivariate COX regression model. The quantitative polymerase chain reaction results showed that MALAT2 was frequently over-expressed in cancer tissues and this over-expression was found to significantly correlate with lymph node metastasis and tumor stage. The ectopic expression of MALAT2 contributed to the migration of human GC SGC 7901 cells, whereas knockdown of MALAT2 inhibited the migration of the SGC-7901 cells in vitro. Further investigation into the underlying mechanisms responsible for the migratory effects revealed that MALAT2 induced the epithelial-mesenchymal transition (EMT) through an MEK/extracellular signal-regulated kinase-dependent mechanism as treatment with the MEK inhibitor, U0126, decreased migration and reversed the EMT in the MALAT2 over-expressed SGC-7901 cells. The expression of MALAT2 is upregulated in GC tissues, and a higher expression level of MALAT2 might serve as a negative prognostic marker in stage II/III GC patients which implies the potential application of MALAT2 in the therapeutic treatment of GC.Cancer Gene Therapy advance online publication, 27 February 2015; doi:10.1038/cgt.2015.6. PMID- 25721208 TI - Identification of crucial genes in intracranial aneurysm based on weighted gene coexpression network analysis. AB - The rupture of intracranial aneurysm (IA) is the leading cause for devastating subarachnoid hemorrhage. This study aimed to investigate genes related to IA and potential diagnosis targets. Two data sets (GSE15629 and GSE54083) were downloaded from Gene Expression Omnibus database. GSE15629 contained eight RI (ruptured IA), six UI (unruptured IA) and five control IA samples. GSE54083 included 8 RI, 5 UI and 10 superficial temporal artery samples. In total, 452 differentially expressed genes (DEGs) between RI and control, and 570 DEGs between UI and control, were identified. Protein-protein interaction networks for two kinds of DEGs related to RI and UI were constructed, respectively. Module networks were searched for DEGs related to RI or UI based on WGCNA (weighted gene coexpression network analysis). In the significant modules, FOS, CCL2, COL4A2 and CXCL5 were screened as crucial nodes with high degrees. Among them, FOS and CCL2 were enriched in immune response and COL4A2 was involved in the ECM (extracellular matrix) pathway, whereas CXCL5 was related to cytokine-cytokine receptor pathway. Taken together, FOS, CCL2, COL4A2 and CXCL5 might participate in the pathogenesis of RI or UI, and could serve as potential diagnosis targets. PMID- 25721207 TI - Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies. AB - Adoptive transfer of tumor-infiltrating lymphocytes (TILs) and genetically engineered T lymphocytes expressing chimeric antigen receptors (CARs) or conventional alpha/beta T-cell receptors (TCRs), collectively termed adoptive cell therapy (ACT), is an emerging novel strategy to treat cancer patients. Application of ACT has been constrained by the ability to isolate and expand functional tumor-reactive T cells. The transition of ACT from a promising experimental regimen to an established standard of care treatment relies largely on the establishment of safe, efficient, robust and cost-effective cell manufacturing protocols. The manufacture of cellular products under current good manufacturing practices (cGMPs) has a critical role in the process. Herein, we review current manufacturing methods for the large-scale production of clinical grade TILs, virus-specific and genetically modified CAR or TCR transduced T cells in the context of phase I/II clinical trials as well as the regulatory pathway to get these complex personalized cellular products to the clinic. PMID- 25721210 TI - Infiltration of dendritic cells and T lymphocytes predicts favorable outcome in epithelial ovarian cancer. AB - We aimed to analyze the association between the distribution of dendritic cells (DC) with expression of tumor-infiltrating T lymphocytes and clinicopathologic parameters with prognosis in epithelial ovarian cancer (EOC). Thirty-three EOC patient samples were surgically resected, and pathology was examined for clinicopathological variables. Expression of S-100, CD1a, CD45RA and CD45RO was detected using the avidin-biotin complex immunohistochemical technique. The correlation of protein expression with surgical and pathological stage, histological grade, pathological type and prognosis was analyzed. There was significant difference in the CD45RA positive rate in early- and advanced-stage EOC with 50 and 10.5%, respectively (P<0.05). Univariate analysis showed that CD45RO, histological grade and surgical-pathological staging were all factors that influenced the prognosis of patients with EOC. Higher survival rates were found in patients with harboring populations of CD1a(+) DC and CD45RO(+) T lymphocytes or populations of S-100(+) DC and CD45RO(+) T lymphocytes (P<0.05). In addition, histological grade is related to cumulative survival rate. The higher degree of cell differentiation presented better outcome. In conclusion, EOC patients with populations of DC and CD45RO(+) T lymphocytes had a higher survival rate. Histological grade and surgical-pathological stage were independent factors affecting prognosis. PMID- 25721211 TI - miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells. AB - MicroRNAs (miRNAs) have been identified as important posttranscriptional regulators involved in various biological and pathological processes of cells, but their association with tumor chemoresistance has not been fully understood. We detected miR-15b expression in two lung adenocarcinoma cell lines, A549 and A549/CDDP, and then investigated the effects of miR-15b on the metastasis and the chemosensitivity of cancer cells, using both gain- and loss-of-function studies. The correlation between miR-15b level and chemoresistance was further investigated in clinical lung adenocarcinoma specimens. miR-15b was significantly upregulated in cisplatin-resistant lung adenocarcinoma A549/CDDP cells compared with parental A549 cells. miR-15b regulates epithelial-mesenchymal transition (EMT) and cisplatin resistance in vitro and modulates response of lung adenocarcinoma cells to cisplatin in vivo. Further studies identified phosphatidylethanolamine-binding protein 4 (PEBP4) as a direct and functional target of miR-15b. Small-interfering RNA-mediated PEBP4 knockdown revealed similar effects as that of ectopic miR-15b expression, whereas overexpression of PEBP4 attenuated the function of miR-15b in lung adenocarcinoma cells. Increased miR-15b expression was also detected in tumor tissues sampled from lung adenocarcinoma patients treated with cisplatin-based chemotherapy and was proved to be correlated with low expression of PEBP4, decreased sensitivity to cisplatin and poor prognosis. Our results suggest that upregulation of miR-15b could suppress PEBP4 expression and in turn contribute to chemoresistance of lung adenocarcinoma cells to cisplatin. PMID- 25721212 TI - Implementing robotic surgery to gynecologic oncology: the first 300 operations performed at a tertiary hospital. AB - OBJECTIVE: To investigate the initial experience with robotic-assisted laparoscopic surgery in gynecologic oncology. DESIGN: A retrospective survey. SETTING: Tertiary referral center. POPULATION: The first 300 patients operated on using robotic assistance at the Department of Obstetrics and Gynecology of Tampere University Hospital, from March 2009 through January 2013. METHODS: Retrospective patient chart review. MAIN OUTCOME MEASURES: The primary outcome measure was the learning curve events, and the complication and conversion rates were secondary outcome measures. RESULTS: The commonest type of operation was hysterectomy, bilateral salpingoophorectomy and pelvic lymphadenectomy (LH + BSO + PLND, n = 89), followed by the same procedure amended by para-aortic lymphadenectomy (PALND, n = 74), type II radical hysterectomy (n = 24), and PLND + PALND +/- omentectomy (n = 15). A learning curve was most evident for LH + BSO + PLND: whereas the median operative time of all 89 operations was 167 min (range 403-104), it was 260 (range 403-135) and 153 (range 247-104) min in the case of the first and last 20 operations, respectively. The learning curve was short, or 10 procedures. A learning curve was also seen for the preoperative time in the operation room and for the number of lymph nodes harvested. The median blood loss during all 300 operations was 100 mL (range 5-3200). The median postoperative hospital stay was 1 day. The conversion rate was 4.0%, and the complication rate 19.3% (major in 9%). CONCLUSION: The learning curve of robotic-assisted laparoscopic surgery appears to be short, or 10 operations. Robotic-assisted procedures seem to offer a safe and useful alternative to traditional techniques. PMID- 25721213 TI - Semicircular lipoatrophy: an electrostatic hypothesis. AB - BACKGROUND: Semicircular lipoatrophy (SL) is a benign pathology characterized by subcutaneous adipose tissue atrophy. OBJECTIVE: To determine causes of SL. METHODS: We performed research on 42 cases of SL who had developed symptoms of lipoatrophy with a technical study of the building and clinical study of the affected patients. RESULTS: Electromagnetic field and electrostatic charge measurements were performed. No signals different from typical radio, TV and other wireless communication devices were recorded. Electrostatic charges were recorded in floors, environments and on different furniture; they were positive, and all charges disappeared on contact with the worker's skin. Data about the workplace were collected, and clinical examinations were performed, including blood and biochemistry tests and 18 ultrasound skin tests. CONCLUSIONS: As no abnormal electromagnetic measurements were found and electrostatic changes and occupational behaviors showed some relevant data and as after changes in order to control the electrostatic environment all of them improved, we can conclude that electrostatic charges but not electromagnetic ones are the main cause of SL. PMID- 25721214 TI - Mindfulness-based psychoeducation for parents of children with attention deficit/hyperactivity disorder: an applied clinical project. AB - TOPIC: Attention-deficit/hyperactivity disorder (ADHD) affects more than 5 million American children; the likelihood of their parents experiencing stress is high, which may lead to negative outcomes. Mindful parenting is a parent training modality that teaches compassion, listening, and creative engagement with one's child, and has been shown to be effective in decreasing levels of parental stress. PURPOSE: An 8-week evidence-based applied clinical project (N = 7) was designed to answer the question: In parents of children with the diagnosis of ADHD, or exhibiting ADHD traits, what is the effect of providing mindful parenting psychoeducation in addition to standard of care treatment on levels of parental stress post intervention? SOURCES USED: An exhaustive literature search was performed using the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, Psyc-INFO, and PubMed. CONCLUSIONS: Outcomes were measured using the Parenting Stress Index, Fourth Edition Short Form (PSI-4-SF). Scores on the Total Stress scale decreased significantly after 8 weeks (p = .018); a significant decrease also occurred across two of the three PSI-4-SF subscales (Parental Distress and Parent-Child Dysfunctional Interaction). Recommendations for practice change, suggestions for future clinical inquiry, and project limitations are discussed. PMID- 25721215 TI - Nav1.5 channels can reach the plasma membrane through distinct N-glycosylation states. AB - BACKGROUND: Like many voltage-gated sodium channels, the cardiac isoform Nav1.5 is well known as a glycoprotein which necessarily undergoes N-glycosylation processing during its transit to the plasma membrane. In some cardiac disorders, especially the Brugada syndrome (BrS), mutations in Nav1.5 encoding gene lead to intracellular retention and consequently trafficking defect of these proteins. We used two BrS mutants as tools to clarify both Nav1.5 glycosylation states and associated secretory behaviors. METHODS: Patch-clamp recordings and surface biotinylation assays of HEK293T cells expressing wild-type (WT) and/or mutant Nav1.5 proteins were performed to assess the impact of mutant co-expression on the membrane activity and localization of WT channels. Enzymatic deglycosylation assays and brefeldin A (BFA) treatments were also employed to further characterize recombinant and native Nav1.5 maturation. RESULTS: The present data demonstrate that Nav1.5 channels mainly exist as two differentially glycosylated forms. We reveal that dominant negative effects induced by BrS mutants upon WT channel current result from the abnormal surface expression of the fully glycosylated forms exclusively. Furthermore, we show that core-glycosylated channels can be found at the surface membrane of BFA-treated or untreated cells, but obviously without generating any sodium current. CONCLUSIONS: Our findings provide evidence that native and recombinant Nav1.5 subunits are expressed as two distinct matured forms. Fully-glycosylated state of Nav1.5 seems to determine its functionality whereas core-glycosylated forms might be transported to the plasma membrane through an unconventional Golgi-independent secretory route. GENERAL SIGNIFICANCE: This work highlights that N-linked glycosylation processing would be critical for Nav1.5 membrane trafficking and function. PMID- 25721216 TI - The effect of different doses of isotretinoin on pituitary hormones. AB - BACKGROUND: There are a limited number of studies investigating the side effects and effectiveness of various doses of isotretinoin (ISO). We have previously shown that high-dose ISO affects pituitary hormones. OBJECTIVES: To our knowledge, there is no study in the literature looking into the effects of various doses of ISO on pituitary hormones. We searched pituitary hormones in three groups of different doses in acne patients. METHODS: We included 105 acne vulgaris patients from two different centers. We divided the patients into three groups; the first group received 0.5-1 mg/kg/day, the second 0.2-0.5 mg/kg/day and the third intermittent 0.5-1 mg/kg/day (only 1 week in 1 month) ISO treatment. Blood samples were collected for biochemistry and hormone analysis, before the treatment and after 3 months. RESULTS: After 3 months of treatment with ISO, luteinizing hormone (LH) (p < 0.001), prolactin (p < 0.001), total testosterone (p < 0.001), adrenocorticotropic hormone (ACTH) (p < 0.001), cortisol (p < 0.001), insulin-like growth factor-binding protein 3 (p < 0.001), insulin-like growth factor 1 (IGF-1) (p = 0.002), growth hormone (GH) (p = 0.002) and free T3 (fT3) (p < 0.001) levels had decreased significantly. Furthermore, we split data into three different groups. Among the patients receiving intermittent dose ISO, LH, ACTH, IGF-1, GH and fT3 measurements lost significance. Most of the significant measurements observed in the whole group were also significant among the patients receiving high-dose ISO. Additionally, dehydroepiandrosterone sulfate (p = 0.003) levels increased, and free T4 levels decreased significantly. CONCLUSIONS: ISO affects pituitary hormones at all of these three doses. The differences in pituitary hormones are more pronounced in high-dose treatment. The weakest effect was observed in the intermittent-dose group. Choosing lower doses of ISO may decrease side effects, however the effectiveness of the treatment may also be diminished. ISO, by affecting the PPARgamma/RXR system, may affecting hormone systems. These changes in various hormone systems may be related to the effectiveness of ISO. PMID- 25721217 TI - Number of sons contributes to ageing-associated inflammation. AB - The rate of inflammation increases in elderly individuals, a phenomenon called inflammaging, and is associated with degenerative diseases. However, the causes of inflammaging and the origin of the associated inflammatory mediators have remained enigmatic. We show herein that there is a positive correlation between the number of sons born and C-reactive protein concentrations in 90-year-old women. This association is influenced by HLA genetics known to regulate the immune response against HY antigens. PMID- 25721219 TI - The insertion domain 1 of class IIA dimeric glycyl-tRNA synthetase is a rubredoxin-like zinc ribbon. AB - The insertion domain 1 (ID1) of class IIA dimeric glycyl-tRNA synthetase (alpha2GRS) is an appended domain in the core catalytic region of the enzyme. ID1 has been shown to play a role in tRNA aminoacylation, mediating interaction with the acceptor arm of tRNA and diadenosine tetraphosphate (Ap4A) synthesis. Mutations in alpha2GRS, including those in the ID1 region, have been implicated in distal hereditary motor neuropathy-V (dHMN-V) and Charcot-Marie-Tooth (CMT) disease. Through sequence and structure based evolutionary analysis, we show that ID1 of alpha2GRS is a rubredoxin-like zinc ribbon domain. The zinc-chelating cysteines of ID1 are well conserved in all archaeal versions of the enzyme and also in several eukaryotes, which most likely have acquired them via horizontal gene transfer from bacteria; but in all other eukaryotes, the zinc-chelating residues are not preserved. ID1 from bacteria display a selective preservation of zinc-binding residues, ranging from complete conservation to complete loss. The ID1 from different organisms harbor variable-sized non-conserved insertions between the two zinc-binding half-sites of the zinc ribbon. Three of the previously identified CMT-associated mutations in alpha2GRS, viz., human D146N, mouse C157R and human S211F, are located in the zinc ribbon region of ID1. Interestingly, human Asp146 which is implicated in the synthesis of Ap4A, a molecule known to act during neuronal transmission, has also been reported to be mutated in dHMN-V, suggesting a possible link between hereditary motor neuropathy and Ap4A synthesis. PMID- 25721218 TI - Predicting the risk of recurrent venous thromboembolism (VTE). AB - To optimize patient outcomes with anticoagulation for venous thromboembolism (VTE), it is essential to assess patients for their recurrence risk. In this article, I will review the impact of clinical and laboratory risk factors for recurrent VTE. The presence or absence of VTE risk factors at the time of the index thrombotic event provides important information regarding recurrence risk. Patients with potent situational risk factors for thrombosis (e.g., surgery) are at low risk for recurrence while patients suffering unprovoked events are at high risk for recurrence. The presence of non-surgical clinical risk factors place patients at intermediate recurrence risk. Other clinical risk factors of variable recurrence potential include age, sex, cancer, pregnancy/puerperium, hormonal therapy and obesity. Laboratory risk factors for recurrence include thrombophilia, D dimer and other global coagulation assays as well as residual venous obstruction. Several multivariate VTE risk assessment models have been developed that combine clinical and laboratory risk factors of recurrence. If validated, these risk scores may allow for personalized anticoagulation therapy tailored to patients' individual recurrence risk. PMID- 25721220 TI - Reference Equations for Static Lung Volumes and TLCO from a Population Sample in Northern Greece. AB - Background: The most commonly used reference equations for the measurement of static lung volumes/capacities and transfer factor of the lung for CO (TLCO) are based on studies around 30-40 years old with significant limitations. Objectives: Our aim was to (1) develop reference equations for static lung volumes and TLCO using the current American Thoracic Society/European Respiratory Society guidelines, and (2) compare the equations derived with those most commonly used. Methods: Healthy Caucasian subjects (234 males and 233 females) aged 18-91 years were recruited. All of them were healthy never smokers with a normal chest X-ray. Static lung volumes and TLCO were measured with a single-breath technique according to the latest guidelines. Results: Curvilinear regression prediction equations derived from the present study were compared with those that are most commonly used. Our reference equations in accordance with the latest studies show lower values for all static lung volume parameters and TLCO as well as a different way of deviation of those parameters (i.e. declining with age total lung capacity, TLCO age decline in both sex and functional residual capacity age rise in males). Conclusions: We suggest that old reference values of static lung volumes and TLCO should be updated, and our perception of deviation of some spirometric parameters should be revised. Our new reference curvilinear equations derived according to the latest guidelines could contribute to the updating by respiratory societies of old existing reference values and result in a better estimation of the lung function of contemporary populations with similar Caucasian characteristics. (c) 2015 S. Karger AG, Basel. PMID- 25721221 TI - Orange-brown chromonychia and Kawasaki disease: a possible novel association? AB - A 4-year-old girl with clinical and laboratory signs of Kawasaki disease (KD) was hospitalized and given intravenous immunoglobulin plus aspirin therapy, with rapid defervescence and clinical improvement, and was discharged 48 hours after admission. At the time of her follow-up echocardiography on day 14, orange-brown pigmentation of the nail beds was noticed and confirmed with dermoscopy. No clear association between KD and orange-brown chromonychia has been demonstrated, although reports and case series suggest a possible link between these two entities. We suggest that this particular finding might be encompassed in late (subacute) changes of extremities as part of KD diagnostic criteria. PMID- 25721222 TI - Comment on: "Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus". PMID- 25721224 TI - Intense Upconversion Luminescence of CaSc2 O4 :Ho(3+) /Yb(3+) from Large Absorption Cross Section and Energy-Transfer Rate of Yb(3.). AB - Concentration-optimized CaSc2 O4 :0.2 % Ho(3+) /10 % Yb(3+) shows stronger upconversion luminescence (UCL) than a typical concentration-optimized upconverting phosphor Y2 O3 :0.2 % Ho(3+) /10 % b(3+) upon excitation with a 980 nm laser diode pump. The (5) F4 +(5) S2 ->(5) I8 green UCL around 545 nm and (5) F5 ->(5) I8 red UCL around 660 nm of Ho(3+) are enhanced by factors of 2.6 and 1.6, respectively. On analyzing the emission spectra and decay curves of Yb(3+) : (2) F5/2 ->(2) F7/2 and Ho(3+) : (5) I6 ->(5) I8 , respectively, in the two hosts, we reveal that Yb(3+) in CaSc2 O4 exhibits a larger absorption cross section at 980 nm and subsequent larger Yb(3+) : (2) F5/2 ->Ho(3+) : (5) I6 energy-transfer coefficient (8.55*10(-17) cm(3) s(-1) ) compared to that (4.63*10(-17) cm(3) s(-1) ) in Y2 O3 , indicating that CaSc2 O4 :Ho(3+) /Yb(3+) is an excellent oxide upconverting material for achieving intense UCL. PMID- 25721223 TI - Author's reply to De Ponti et al.: "Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus". PMID- 25721225 TI - Corrigendum. PMID- 25721226 TI - Treatment of Primary Fetal Hydrothorax with OK-432 (Picibanil): Outcome in 14 Fetuses and a Review of the Literature. AB - BACKGROUND: Primary fetal hydrothorax (PFHT) is an uncommon condition with an estimated prevalence of 1 in 10,000/15,000 pregnancies. Therapeutic interventions include thoracocentesis, thoraco-amniotic shunting (TAS), and pleurodesis using OK-432. METHODS: A review of the literature was performed to identify all cases of PFHT treated with TAS and OK-432. All cases of PFHT referred to the Fetal Maternal Unit at Royal Prince Alfred Hospital between 2002 and 2012 were retrospectively reviewed. In the cohort of fetuses treated with OK-432, the main perinatal outcomes evaluated were termination of pregnancy, live birth, neonatal death, and fetal death in utero. Secondary outcomes included gestational age (GA) at diagnosis, GA at treatment, GA at resolution, birth weight, and GA at birth. The development of the children was screened using the Ages and Stages Questionnaires, Version 3 (ASQ-3, 2009). RESULTS: Primary hydrothorax was diagnosed in 31 fetuses, of which 14 had treatment with OK-432. One pregnancy terminated after treatment with OK-432. Survival was 85% (11/13): 100% in fetuses treated with OK-432 without hydrops, and 78% in those treated with hydrops. This compares well to the cases of TAS in the literature with an average survival of 63%: 85% in fetuses without hydrops and 55% with hydrops. The mean GA at birth was 36(+4) weeks and mean birth weight 3,007 g. Eight of the 9 children screened with ASQ-3 scored well within the normal range. CONCLUSION: OK-432 appears to be a valid treatment option in fetuses with PFHT, particularly in those diagnosed at early GAs. PMID- 25721227 TI - Fitness trade-offs explain low levels of persister cells in the opportunistic pathogen Pseudomonas aeruginosa. AB - Microbial populations often contain a fraction of slow-growing persister cells that withstand antibiotics and other stress factors. Current theoretical models predict that persistence levels should reflect a stable state in which the survival advantage of persisters under adverse conditions is balanced with the direct growth cost impaired under favourable growth conditions, caused by the nonreplication of persister cells. Based on this direct growth cost alone, however, it remains challenging to explain the observed low levels of persistence (<<1%) seen in the populations of many species. Here, we present data from the opportunistic human pathogen Pseudomonas aeruginosa that can explain this discrepancy by revealing various previously unknown costs of persistence. In particular, we show that in the absence of antibiotic stress, increased persistence is traded off against a lengthened lag phase as well as a reduced survival ability during stationary phase. We argue that these pleiotropic costs contribute to the very low proportions of persister cells observed among natural P. aeruginosa isolates (3 * 10(-8) -3 * 10(-4)) and that they can explain why strains with higher proportions of persister cells lose out very quickly in competition assays under favourable growth conditions, despite a negligible difference in maximal growth rate. We discuss how incorporating these trade-offs could lead to models that can better explain the evolution of persistence in nature and facilitate the rational design of alternative therapeutic strategies for treating infectious diseases. PMID- 25721228 TI - Constant Current versus Constant Voltage Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease. AB - Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established therapy for advanced Parkinson's disease (PD). Motor efficacy and safety have been established for constant voltage (CV) devices and more recently for constant current (CC) devices. CC devices adjust output voltage to provide CC stimulation irrespective of impedance fluctuation, while the current applied by CV stimulation depends on the impedance that may change over time. No study has directly compared the clinical effects of these two stimulation modalities. Objective: To compare the safety and clinical impact of CC STN DBS to CV STN DBS in patients with advanced PD 2 years after surgery. Methods: Patients were eligible for inclusion if they had undergone STN DBS surgery for idiopathic PD, had been implanted with a Medtronic Activa PC and if their stimulation program and medication had been stable for at least 1 year. This single-center trial was designed as a double-blind, randomized, prospective study with crossover after 2 weeks. Motor equivalence of the 2 modalities was confirmed utilizing part III of the Unified Parkinson's Disease Rating Scale (UPDRS). PD diaries and multiple subjective and objective evaluations of quality of life, depression, cognition and emotional processing were evaluated on both CV and on CC stimulation. Analysis using the paired t test with Bonferroni correction for multiple comparisons was performed to identify any significant difference between the stimulation modalities. Results: 8 patients were recruited (6 men, 2 women); 1 patient did not complete the study. The average age at surgery was 56.7 years (range 47-63). Disease duration at the time of surgery was 7.5 years (range 3 12). Patients were recruited 23.8 months (range 22.5-24) after surgery. At the postoperative study baseline, this patient group showed an average motor improvement of 69% (range 51-97) as measured by the change in UPDRS part III with stimulation alone. Levodopa equivalent medication was reduced on average by 67% (range 15-88). Patients were poorly compliant with PD diaries, and these did not yield useful information. The minor deterioration in quality-of-life scores (Parkinson's Disease Questionnaire-39, Quality of Life Enjoyment and Satisfaction Questionnaire) with CC stimulation were not statistically significant. Two measures of depression (Hamilton Rating Scale D17, Quick Inventory of Depressive Symptomatology - Self-Report) showed a nonsignificant lower score (less depression) with CC stimulation, but a third (Beck Depression Inventory) showed equivalence. Cognitive testing (Mini Mental State Examination) and emotional processing (Montreal Affective Voices) were equivalent for CC and CV. Conclusion: CC STN DBS is safe. For equivalent motor efficacy, no significant difference could be identified between CC and CV stimulation for nonmotor evaluations in PD patients 2 years after surgery. (c) 2015 S. Karger AG, Basel. PMID- 25721229 TI - Processing of affective prosody in boys suffering from attention deficit hyperactivity disorder: A near-infrared spectroscopy study. AB - Neurobiological studies on facial affect recognition have demonstrated reduced response amplitudes to anger cues in patients suffering from attention deficit hyperactivity disorder (ADHD). It is still unclear whether a similar deficit exists in the auditory domain. Therefore, this near-infrared spectroscopy study focused on neuronal correlates of affective prosody processing. Fourteen boys suffering from ADHD and fourteen healthy boys were exposed to emotionally intoned, standardized sentences of the categories anger, sadness, happiness, and to affectively neutral sentences. Relative to controls, the patients displayed a diminished activation of the right superior temporal gyrus (STG) when processing anger prosody, which was correlated with aggressive behavior. There were no group differences for the other emotions. Additionally, the ADHD group showed increased supramarginal gyrus (SMG) activation in the anger condition. This might mirror compensatory attention allocation. In summary, we identified a selectively lowered STG activation to auditory anger cues in ADHD patients. Consequently, STG recruitment during anger exposure might be used for evaluation of psychotherapy effects. PMID- 25721230 TI - Specific features in linear and spatial organizations of pericentromeric heterochromatin regions in polytene chromosomes of the closely related species Drosophila virilis and D. kanekoi (Diptera: Drosophilidae). AB - Heterochromatin plays an important role in the spatial arrangement and evolution of the eukaryotic genetic apparatus. The closely related species Drosophila virilis (phyla virilis) and D. kanekoi (phyla montana) differ in the amount of heterochromatin along the chromosomes as well as by the presence of the metacentric chromosome 2, which emerged as a result of a pericentric inversion during speciation, in the D. kanekoi karyotype. The purpose of this study was to establish if chromosome rearrangements have any influence on the linear redistribution of centromeric heterochromatin in polytene chromosomes and the spatial organization of chromosomes in the nuclei of nurse cell. We have microdissected the chromocenter of D. virilis salivary gland polytene chromosomes; obtained a DNA library of this region (DvirIII); and hybridized (FISH) DvirIII to the salivary gland and nurse cell polytene chromosomes of D. virilis and D. kanekoi. We demonstrated that DvirIII localizes to the pericentromeric heterochromatin regions of all chromosomes and peritelomeric region of chromosome 5 in both species. Unlike D. virilis, the DvirIII signal in D. kanekoi chromosomes is detectable in the telomeric region of chromosome 2. We have also conducted a 3D FISH of DvirIII probe to the D. virilis and D. kanekoi nurse cell chromosomes. In particular, the DvirIII signal in D. virilis was observed in the local chromocenter at one pole of the nucleus, while the signal belonging to the telomeric region of chromosome 5 was detectable at the other pole. In contrast, in D. kanekoi there exist two separate DvirIII-positive regions. One of these regions belongs to the pericentromeric region of chromosome 2 and the other, to pericentromeric regions of the remaining chromosomes. These results suggest that chromosome rearrangements play an important role in the redistribution of heterochromatin DNA sequences in the genome, representing a speciation mechanism, which, in general, could also affect the chromosome orientation in the 3D nuclear space. PMID- 25721231 TI - Additively Manufactured Device for Dynamic Culture of Large Arrays of 3D Tissue Engineered Constructs. AB - The ability to test large arrays of cell and biomaterial combinations in 3D environments is still rather limited in the context of tissue engineering and regenerative medicine. This limitation can be generally addressed by employing highly automated and reproducible methodologies. This study reports on the development of a highly versatile and upscalable method based on additive manufacturing for the fabrication of arrays of scaffolds, which are enclosed into individualized perfusion chambers. Devices containing eight scaffolds and their corresponding bioreactor chambers are simultaneously fabricated utilizing a dual extrusion additive manufacturing system. To demonstrate the versatility of the concept, the scaffolds, while enclosed into the device, are subsequently surface coated with a biomimetic calcium phosphate layer by perfusion with simulated body fluid solution. 96 scaffolds are simultaneously seeded and cultured with human osteoblasts under highly controlled bidirectional perfusion dynamic conditions over 4 weeks. Both coated and noncoated resulting scaffolds show homogeneous cell distribution and high cell viability throughout the 4 weeks culture period and CaP-coated scaffolds result in a significantly increased cell number. The methodology developed in this work exemplifies the applicability of additive manufacturing as a tool for further automation of studies in the field of tissue engineering and regenerative medicine. PMID- 25721232 TI - Three-year outcomes of adults with anxiety and related disorders following cognitive-behavioral therapy in a non-research clinical setting. AB - Anxiety and related disorders are highly prevalent and costly to society. Fortunately, a large number of randomized controlled trials have demonstrated the efficacy of cognitive behavioral therapy (CBT) in the treatment of anxiety and related disorders. A smaller number of effectiveness studies have also demonstrated that similar outcomes to randomized controlled trials can be obtained in "real-world" settings. There is minimal research, however, into long term outcomes in effectiveness research. This study describes the outcomes of 98 individuals with anxiety and related disorders treated in an outpatient, fee-for service setting using a case formulation CBT approach. Participants were followed up each year after their discharge, for a period of 3 years. The results indicate that patients maintained their treatment gains, with large effect sizes obtained from pre-treatment to each follow-up time point (d=1.11-1.60). The results provide preliminary evidence to suggest that individuals treated with CBT in "real-world" settings maintain their treatment gains in the long-term. PMID- 25721233 TI - Feasibility of Focused Stepping Practice During Inpatient Rehabilitation Poststroke and Potential Contributions to Mobility Outcomes. AB - BACKGROUND: Optimal physical therapy strategies to maximize locomotor function in patients early poststroke are not well established. Emerging data indicate that substantial amounts of task-specific stepping practice may improve locomotor function, although stepping practice provided during inpatient rehabilitation is limited (<300 steps/session). OBJECTIVE: The purpose of this investigation was to determine the feasibility of providing focused stepping training to patients early poststroke and its potential association with walking and other mobility outcomes. METHODS: Daily stepping was recorded on 201 patients <6 months poststroke (80% < 1 month) during inpatient rehabilitation following implementation of a focused training program to maximize stepping practice during clinical physical therapy sessions. Primary outcomes included distance and physical assistance required during a 6-minute walk test (6MWT) and balance using the Berg Balance Scale (BBS). Retrospective data analysis included multiple regression techniques to evaluate the contributions of demographics, training activities, and baseline motor function to primary outcomes at discharge. RESULTS: Median stepping activity recorded from patients was 1516 steps/d, which is 5 to 6 times greater than that typically observed. The number of steps per day was positively correlated with both discharge 6MWT and BBS and improvements from baseline (changes; r = 0.40-0.87), independently contributing 10% to 31% of the total variance. Stepping activity also predicted level of assistance at discharge and discharge location (home vs other facility). CONCLUSION: Providing focused, repeated stepping training was feasible early poststroke during inpatient rehabilitation and was related to mobility outcomes. Further research is required to evaluate the effectiveness of these training strategies on short- or long-term mobility outcomes as compared with conventional interventions. PMID- 25721234 TI - Five-year mortality for patients with end-stage renal disease who undergo upper extremity amputation. AB - PURPOSE: To compare the 5-year survival rate of patients on dialysis requiring an upper extremity amputation with those who did not require such surgery and to analyze whether such an amputation was prognostic for mortality. METHODS: The medical records of 20 consecutive patients with end-stage renal disease who received upper extremity amputations were reviewed. Control patients (n = 40) were matched based on age, sex, and duration of dialysis treatment. A Kaplan Meier survival analysis was performed. RESULTS: The mean survival time after the index surgery for the surgical group was 4.95 years +/- 0.90 years, and the mean survival for the control group was 8.40 years +/- 0.61 years. The probability of death (the event) was statistically greater in the surgical group. The overall 5 year survival rates for the surgical and the nonsurgical groups were 35% (7 of 20) and 70% (28 of 40), respectively. Patients with diabetes in the surgical group had a significantly lower 5-year survival rate, a greater number of amputations, and a greater number of wound-healing failures. CONCLUSIONS: The 5 year survival rate from the index surgery of the surgical group was half that of the nonsurgical group. Increased mortality may be partially attributed to the poor vascular health of the patient. This analysis may help the hand surgeon to more effectively counsel patients with end-stage renal disease about the prognosis associated with an upper extremity amputation and, more importantly, supports the goal of timely intervention by the multidisciplinary team to optimize care planning and to improve surgical outcomes and quality of life. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 25721235 TI - Complications associated with hinged external fixation for chronic elbow dislocations. AB - PURPOSE: To evaluate the outcomes of patients who underwent application of hinged external fixators for chronic elbow fracture-dislocations. We hypothesized that patients treated for this injury pattern can achieve satisfactory outcomes but encounter many complications and require numerous additional procedures. METHODS: We performed a retrospective review of 7 patients who were surgically treated with application of a hinged external fixator for chronic ulnohumeral elbow fracture-dislocation. Patients were included only if they had complete ulnohumeral dislocation of greater than 1 month's duration. Demographics, injury pattern, and range of motion were documented. Preoperative and postoperative range of motion was recorded and any treatment complications or additional surgeries were noted. RESULTS: The interval between the initial injury and index procedure averaged 8 months. All patients underwent initial treatment with open reduction internal fixation. Average arc of ulnohumeral motion improved from 26 degrees (range, 0 degrees to 60 degrees ) to 120 degrees (range, 100 degrees to 145 degrees ). Overall, 4 of 7 patients developed at least one complication during treatment. Three patients required additional procedures aside from removal of the hinged external fixator. These 3 patients underwent a total of 13 additional procedures. CONCLUSIONS: Although patients can achieve good outcomes, realistic expectations should be set. Patients should be aware that surgery can be associated with a high risk of complications, potential treatment failure, and a need for additional surgical procedures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25721236 TI - Soft tissue complications of dorsal versus volar plating for ulnar shortening osteotomy. AB - PURPOSE: To compare the results and complications of fixed-angle dorsal locking plate fixation for ulnar shortening osteotomy (USO) with the conventional technique of volar plating. METHODS: We performed a retrospective review of 32 patients undergoing USO on 34 wrists and compared the outcomes of 16 consecutive cases with dorsal 2.4/2.7-mm fixed-angle plating and 18 consecutive cases with volar 3.5-mm plating. A minimum of 12 months' follow-up was used to assess outcomes. Primary outcomes were painful hardware and removal of symptomatic implants. Secondary outcomes were pain, Patient-Rated Wrist Evaluation, range of motion, time to union, grip strength, and complications. RESULTS: There were no significant differences in Patient-Rated Wrist Evaluation, pain score, range of motion, or time to union. Relative grip strength compared with the contralateral upper extremity in the dorsal group was higher than the volar group. After adjusting for hand dominance, dorsal plating was significantly associated with higher relative grip strength. There were 2 complications in the dorsal group, including one case with painful hardware. This was significantly lower than in the volar group, which had 10 complications including 2 nonunions and 6 cases of hardware-related soft tissue irritation. CONCLUSIONS: Both volar and dorsal plating techniques for USO yielded good functional outcomes. There was a higher incidence of painful hardware requiring removal of implants in the volar group. Based on these findings, we advocate dorsal plate position using a smaller fixed angle plate for USO in ulnar impaction syndrome. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 25721237 TI - Flexor digitorum superficialis repair outside the A2 pulley after zone II laceration: gliding and bowstringing. AB - PURPOSE: To evaluate the changes in maximum flexion angle, gliding coefficient, and bowstringing after a combined repair of both flexor tendons with the flexor digitorum superficialis (FDS) rerouted outside the A2 pulley in cadaveric hands. METHODS: We performed 4 different repairs on cadaveric hands, with each repair tested on 9 unique digits. In total, 12 cadaveric hands and 36 digits were used. The thumb and little finger were removed from each hand and excluded from testing. Group 1 was sham surgery. Group 2 combined flexor digitorum profundus (FDP) and FDS laceration and repair with both slips of the FDS repaired inside the A2 pulley. Group 3 was FDP repair with one slip of the FDS repaired inside A2 and the other slip left unrepaired. Group 4 was FDP repair with both slips of the FDS rerouted and repaired outside the A2 pulley. Maximum flexion angle, gliding coefficient, and bowstringing were measured in simulated active digital motion for each group. RESULTS: Rerouting and repairing the FDS outside the A2 pulley (group 4) significantly lowered gliding coefficient compared with repairs with both slips inside A2, with values similar to sham surgery. We observed no significant differences in maximum flexion angle among the 4 groups. Increased bowstringing was observed with both slips of the FDS repaired and rerouted outside the A2 pulley. CONCLUSIONS: In this cadaveric model, repair of both slips of the FDS outside the A2 pulley improved the gliding coefficient relative to repair within the A2 pulley, which suggests decreased resistance to finger flexion. Repair of the FDS outside the A2 pulley led to a slight increase in bowstringing of the FDS tendon. CLINICAL RELEVANCE: We describe a technique for managing combined laceration of the FDP and FDS tendons that improves gliding function and merits consideration. PMID- 25721238 TI - Intraoperative periprosthetic fractures associated with metacarpophalangeal joint arthroplasty. AB - PURPOSE: To assess the incidence of and identify risk factors for intraoperative periprosthetic fractures during primary and revision metacarpophalangeal (MCP) joint arthroplasty. METHODS: Through our institutional Joint Registry Database, we identified 818 MCP joint arthroplasties performed in 285 patients from 1998 to 2012, including 690 primary arthroplasties and 128 revision arthroplasties. Primary diagnoses included inflammatory arthritis (667), osteoarthritis (75), and posttraumatic arthritis (76). Periprosthetic fractures were identified through review of medical records. RESULTS: Intraoperative periprosthetic fractures occurred in 23 (3%) fingers (21 patients), including 19 primary and 4 revision arthroplasties. Twelve fractures required stabilization, 4 required only bone grafting, and 1 required both. The fractures occurred during broaching (12), implantation (10), or prior implant removal (1). Diabetes mellitus (DM), younger age, pyrocarbon implant insertion, and cementless fixation increased risk for intraoperative fracture. In particular, DM and the use of pyrocarbon implants significantly increased fracture risk. At 4 years (range, 1.3-10.2 y) average follow-up, no patient with intraoperative fracture had developed a subsequent fracture compared with 3 postoperative fractures in patients without intraoperative fractures. All fractures had healed by the time of the last follow up. The 2- and 5-year implant survival rates were 96% and 80% in those with intraoperative fractures, respectively, which was not significantly different from those without an intraoperative fracture. When comparing patients with an intraoperative fracture with those without, there was an increased risk of postoperative MCP joint instability defined as implant dislocation. Patients with intraoperative fractures still had noteworthy improvements in their postoperative pain levels and pinch strengths. CONCLUSIONS: Intraoperative fractures occurred in 3% of MCP joint arthroplasties, including 3% of primary and 3% of revision arthroplasties. Increased risk for fracture was associated with the use of pyrocarbon implants, cementless fixation, and DM. Although these fractures did not appear to adversely affect implant survival, they were associated with increased risk of postoperative instability. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 25721239 TI - The hand surgery fellowship application process: expectations, logistics, and costs. AB - PURPOSE: To investigate expectations, logistics, and costs relevant to the hand surgery fellowship application process. We sought to discover (1) what both applicants and program directors are seeking, (2) what both parties have to offer, (3) how both parties collect information about each other, and (4) the costs incurred in arranging each match. METHODS: We conducted on-line surveys of hand surgery fellowship applicants for appointment in 2015 and of current fellowship program directors. RESULTS: Sixty-two applicants and 41 program directors completed the survey. Results revealed applicants' demographic characteristics, qualifications, method of ranking hand fellowship programs, costs incurred (both monetary and opportunity) during the application process, ultimate match status, and suggestions for change. Results also revealed program directors' program demographics, rationale for offering interviews and favorably ranking applicants, application-related logistical details, costs incurred (both monetary and opportunity) during the application process, and suggestions for change. CONCLUSIONS: Applicants for hand surgery fellowship training are primarily interested in a potential program's academic reputation, emphasis on orthopedic surgery, and location. The typical, successfully matched applicant was a 30-year-old male orthopedic resident with 3 publications to his credit. Applicants rely on peers and Web sites for information about fellowships. Fellowship directors are primarily seeking applicants recommended by other experienced surgeons and with positive personality traits. The typical fellowship director offers a single year of orthopedic-based fellowship training to 2 fellows per year and relies on a common application and in-person interviews to collect information about applicants. Applicants appear to be more concerned than directors about the current state of the match process. Applicants and directors alike incur heavy costs, in both dollars and opportunity, to arrange each match. A nuanced understanding of the match process suggests specific changes and may help reduce these costs. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analysis V. PMID- 25721240 TI - Distal radius fractures in the elderly. PMID- 25721241 TI - Efficient screening of 2D molecular polymorphs at the solution-solid interface. AB - Formation of multiple polymorphs during two-dimensional (2D) crystallization of organic molecules is more of a routine occurrence than rarity. Although such diverse crystalline structures provide exciting possibilities for studying crystal engineering in 2D, predicting the occurrence of polymorphs for a given building block is often non-trivial. Moreover, there is scarcity of methods that can experimentally verify the presence of such crystalline polymorphs in a straightforward fashion. Here we demonstrate a relatively simple experimental approach for screening of 2D polymorphs formed at the solution-solid interface. The strategy involves use of solution flow produced by contacting a piece of tissue paper to the sample to generate a lateral density gradient along the substrate surface. In situ generation of such gradient allows rapid discovery and nanoscale separation of multiple 2D polymorphs in a single experiment. The concept is demonstrated using three structurally different building blocks that differ in terms of intermolecular interactions responsible for 2D crystal formation. The method described here represents a powerful tool for efficient screening of 2D polymorphs formed at the solution-solid interface. PMID- 25721242 TI - Association of hypothyroidism with low-level arsenic exposure in rural West Texas. AB - It has been reported recently that a higher airborne arsenic level was correlated with higher urinary arsenic concentration and lower serum thyroxin level among urban policemen and rural highway workmen in Italy. The current study was to determine whether exposure to low-level arsenic groundwater (2-22ug/L) is associated with hypothyroidism among 723 participants (118 male and 267 female Hispanics; 108 male and 230 female non-Hispanic whites, NHW) living in rural West Texas counties. Arsenic and iodine levels in their groundwater used for drinking and or cooking were estimated by the inverse distance weighted (IDW) interpolation technique. Groundwater arsenic was >=8ug/L in 36% of the subjects' wells while iodine concentration was <1ug/L in 91% of their wells. Logistic regression analysis showed that arsenic in groundwater >=8ug/L and cumulative arsenic exposure (groundwater arsenic concentration multiplied by the number of years living in the current address) but not groundwater iodine concentration were significant predictors for hypothyroidism among Hispanics (p<0.05) but not NHW after adjusting for covariates such as age, gender, annual household income and health insurance coverage. The ethnic difference may be due to a marginally higher percentage of Hispanics (p=0.0622) who lived in areas with groundwater arsenic >=8ug/L compared with NHW. The prevalence of hypothyroidism was significantly higher in Hispanics or NHW of this rural cohort than the national prevalence. Measures should be taken to reduce arsenic in drinking water in order to prevent hypothyroidism in rural areas. PMID- 25721243 TI - Predicting concentrations of cytostatic drugs in sewage effluents and surface waters of Catalonia (NE Spain). AB - Cytostatic drugs, used in chemotherapy, are excreted unchanged by urine and feces or modified as metabolites. Elimination of these drugs in wastewater treatment plants (WWTPs) is often incomplete and residues reach surface water. Their presence in the natural environment depends on consumption patterns, excretion fraction and the effectiveness of the wastewater treatment. This study compiled the total consumption of cytostatic drugs in Catalonia (NE Spain) and provides data on the occurrence and risk of anticancer drugs in the aquatic environment by calculating predicted environmental concentrations (PECs). PECs were estimated using publicly available consumption data in the period of 2010-2012, published or calculated excretion values and wastewater elimination rates for a suite of 132 compounds. This allows predicting the range of concentrations in effluent wastewaters and receiving waters. Out of the 132 cytostatics, mycophenolic acid and hydroxycarbamide had a PEC value higher than 10ngL(-1). PECs were compared with MECs (measured environmental concentrations) to evaluate the reliability of the estimation. A risk assessment was conducted to determine the potential adverse effects of cytostatics in the environment. All the risk quotients calculated using EC50 in Daphnia magna were below 1, showing no significant risk. PMID- 25721245 TI - Formulation of intumescent flame retardant coatings containing natural-based tea saponin. AB - Natural product tea saponin (TS), extracted from the nutshell of camellia (Camellia oleifera Abel, Theaceae), was introduced into intumescent flame retardant formulations as blowing agent and carbon source. The formulations of the flame retardant system were optimized to get the optimum proportion of TS, and intumescent flame retardant coatings containing tea saponin (TS-IFRCs) were then prepared. It was found that TS can significantly affect the combustion behavior and the thermal stability of TS-IFRCs evaluated by cone calorimetry and simultaneous thermal analyzer, respectively. It was shown that TS, degraded to water vapor and carbon at high temperatures, can combine with other components to form a well-developed char layer. The char layer was supposed to inhibit erosion upon exposure to heat and oxygen and enhance the flame retardancy of TS-IFRCs. In addition, the smoke release of TS-IFRCs was also studied, which provided a low amount of smoke production. PMID- 25721244 TI - The influence of obesity on blood mercury levels for U.S. non-pregnant adults and children: NHANES 2007-2010. AB - BACKGROUND: In animal studies obesity is associated with higher blood and tissue mercury concentrations; however human studies are lacking. Although the mechanism underlying this association is uncertain, obesity may alter the metabolism and distribution of methylmercury. OBJECTIVES: We determined whether obesity influenced blood mercury levels, the majority of which was methylmercury, for U.S. non-pregnant adults (>=20 years) and children (2-19 years) after controlling for methylmercury intake through fish and shellfish consumption, and other confounders. METHODS: We completed secondary data analysis of the National Health and Nutrition Examination Survey (NHANES) (2007-2010) for participants who consumed fish/shellfish within 24h of blood collection for mercury analysis. Weighted least squares regression models related blood mercury levels (the dependent variable) to methylmercury exposure (MUg) from fish consumed in the previous 24h, body mass index (BMI) (for adults), BMI z-scores (for children), and other confounders. RESULTS: In adjusted models, blood mercury levels were inversely correlated with BMI for adults [beta, 95% confidence interval (CI)= 0.54 (-0.90, -0.18)]. For children, blood mercury levels were inversely correlated with BMI z-scores but the trend was not significant [beta (95% CI)= 0.016 (-0.066, 0.035)]. When obese adults or children were compared with those who were overweight/normal weight, blood mercury averaged 22% lower for obese adults (95% CI: -33%, -8.2%), while blood mercury did not differ significantly for obese children [beta (95% CI)=-1.7% (-31%, +39%)]. CONCLUSIONS: After adjusting for the main, if not exclusive, exogenous source of methylmercury exposure (through fish/shellfish intake) and other confounders, our results support potential changes in the metabolism, distribution or excretion of methylmercury with increasing BMI (for adults). PMID- 25721246 TI - The Relationship of Sleep Duration with Obesity and Sarcopenia in Community Dwelling Older Adults. AB - BACKGROUND: Numerous studies have reported the relationship between sleep duration and obesity in elderly adults; however, little is known about the relationship of sleep duration and sarcopenia. OBJECTIVE: We examined the relationship of sleep duration with obesity and sarcopenia in community-dwelling older adults. METHODS: A total of 488 community-dwelling adults (224 men and 264 women) aged >=65 years were included in the analysis. Self-reported sleep duration and anthropometric data were collected. Skeletal muscle mass was estimated using the predicted equation from a bioelectrical impedance analysis measurement. Obesity and sarcopenia were defined according to the body mass index and the skeletal muscle mass index, respectively. RESULTS: The association between sleep duration and sarcopenia exhibited a U shape in older adults. Compared to adults with 6-8 h of sleep, adults with <6 h of sleep had a nearly 3 fold increased likelihood of sarcopenia (odds ratio, OR: 2.76, 95% confidence interval, CI: 1.28-5.96), while adults with >=8 h of sleep had a nearly 2-fold increased risk of sarcopenia (OR: 1.89, 95% CI: 1.01-3.54). Older adults with a sleep duration <6 h were more prone to obesity (OR: 2.15, 95% CI: 1.08-4.30). After gender stratification, the association between obesity and short sleep duration was more robust in women. CONCLUSION: There were significant associations of sleep duration with either obesity or sarcopenia in community dwelling older adults. Gender differences in these associations were also observed. PMID- 25721247 TI - Management of the hospitalized transplant patient. AB - Significant hyperglycemia is commonly observed immediately after solid organ and bone marrow transplant as well as with subsequent hospitalizations. Surgery and procedures are well known to cause pain and stress leading to secretion of cytokines and other hormones known to aggravate insulin action. Immunosuppression required for transplant and preexisting risk are also major factors. Glucose control improves outcomes for all hospitalized patients, including transplant patients, but is often more challenging to achieve because of frequent and sometimes unpredictable changes in immunosuppression doses, renal function, and nutrition. As a result, risk of hypoglycemia can be greater in this patient group when trying to achieve glucose control goals for hospitalized patients. Key to successful management of hyperglycemia is regular communication between the members of the care team as well as anticipating and rapidly implementing a new treatment paradigm in response to changes in immunosuppression, nutrition, renal function, or evidence of changing insulin resistance. PMID- 25721248 TI - The impact of health systems on diabetes care in low and lower middle income countries. AB - This review will highlight the current challenges and barriers to diabetes management in low and lower middle income countries using the World Health Organization's 6 Building Blocks for Health Systems (service delivery; healthcare workforce; information; medical products, vaccines and technologies; financing; and leadership and governance). Low and lower middle income countries are characterized by low levels of income and insufficient health expenditure. These countries face a shift in disease burden from communicable to non-communicable diseases including diabetes. Many argue that health systems in these countries do not have the capacity to meet the needs of people with chronic conditions such as diabetes. A variety of barriers exist in terms of organization of health systems and care, human resources, sufficient information for decision-making, availability and affordability of medicines, policies, and alleviating the financial burden of care. These health system barriers need to be addressed, taking into account the need to have diabetes included in the global development agenda and also tailoring the response to local contexts including the needs of people with diabetes. PMID- 25721249 TI - Suppressive Effect of Matrine on Tumor Invasion in N-Butyl-N-(4 Hydroxybutyl)Nitrosamine-Induced Urinary Bladder Carcinogenesis. AB - AIMS: This study was designed to investigate the mechanisms and suppressive effects of matrine on the development of urinary bladder cancers induced by N butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. METHODS: Male Sprague-Dawley rats were given BBN (200 mg/rat) twice a week for a period of 8 weeks. Oral administration of matrine (50 and 100 mg/kg) was started 1 week before BBN exposure for 35 weeks. Half of each bladder was histopathologically analyzed and the remainder was extracted for protein analysis by Western blot. RESULTS: The bladders of BBN-treated rats demonstrated progression from epithelial hyperplasia to papillary urothelial neoplasia and even poorly differentiated invasive cancer. Matrine (50 and 100 mg/kg) treatment decreased the formation of large bladder tumors by 31.6 and 21.1%, respectively. An incidence of cancer cells was detected in rats given BBN [70% (14/20)] and matrine [50 mg/kg: 68.4% (13/19) and 100 mg/kg: 57.9% (11/19), respectively]. The frequency of invasive tumors in the matrine treatment groups [50 mg/kg: 15.4% (2/13), 100 mg/kg: 9.1% (1/11)] was significantly lower than in the BBN-alone group [57% (8/14)]. Furthermore, oral administration of matrine (50 and 100 mg/kg) markedly attenuated the BBN-induced upregulation of bladder cyclooxygenase-2 (COX-2) expression and the elevation of bladder cytosolic phospholipase A2 (cPLA2) levels. Although the contents of 15 prostaglandin dehydrogenase (PGDH), which degrades PGE2, were dramatically reduced by BBN, matrine exerted no effects on reduced PGDH contents. CONCLUSION: Our results suggest that matrine suppressed bladder tumor invasion in a rat model, and this might be primarily mediated through regulation of the protein contents, COX-2 and cPLA2 in the bladder. PMID- 25721250 TI - Recommended drug use after acute myocardial infarction by migration status and education level. AB - PURPOSE: The purpose of this study is to investigate the association between migration status and education level and the use of recommended drugs after first acute myocardial infarction (MI). METHODS: A nationwide cohort study performed in Sweden from January 1, 2006 to August 1, 2008. The cohort consisted of 49,037 incident cases of first acute MI. In total, 37,570 individuals survived 180 days after MI, of whom 4782 (12.7%) were foreign-born. We used logistic regression to estimate the odds ratio (OR) with 95% confidence interval (CI) of the association between migration status and education level and prescribed drugs after MI. RESULTS: One third of the patients who were not on any recommended cardiovascular drugs before MI continued to be without recommended cardiovascular drugs after MI. Among those with no cardiovascular drugs before MI, we found no difference in recommended drug use after MI by migration status (OR 1.00, 95% CI 0.89-1.12). Among those with some but not all recommended cardiovascular drugs before MI, foreign-born cases had a slightly non-significant lower use of recommended drugs (OR 0.92, 95% CI 0.83-1.03). Foreign-born patients with low education had a slightly lower use of recommended drug compared to Sweden-born. Women with low education had a lower use of drugs after MI (Sweden born, OR 0.85; 95% CI 0.74 0.96 and foreign born OR 0.51; 95% CI 0.34-0.77). CONCLUSION: There is no apparent difference between foreign-born and Sweden-born in recommended drug use after MI. However, our study reveals an inequity in secondary prevention therapy after myocardial infarction by education level. PMID- 25721251 TI - Prediction of drug clearance in children. AB - The pediatric population is often exposed to drugs without sufficient knowledge about pharmacokinetics. The prediction of accurate clearance values in children, especially in neonates and infants, will improve the rational in dosing decisions. Drug clearances from birth to adulthood were compiled after a systematic review of pharmacokinetic reports. The analysis was performed using NONMEM. Clearance predictions were then evaluated by external validation. Prediction errors were also compared with those obtained from weight-based allometric scaling and physiologically based clearance (PBCL) models. For the analysis, 17 and 15 drugs were used for model building and external validation, respectively. A model based on the adult drug clearance value and taking into account both weight and age was retained. Age-related maturation of clearance reached 90% of the adult value within 1.5 years of life. For children less than 2 years old, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction in the 6 months-2 years age group (prediction error < 25%). Predictions obtained from the PBCL approach were close to our results. This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months. PMID- 25721252 TI - Investigation of the immediate pre-operative physical capacity of patients scheduled for elective abdominal surgery using the 6-minute walk test. AB - OBJECTIVES: To evaluate the effects of repetition of the 6-minute walk test in patients scheduled to undergo abdominal surgery within the next 48 hours, and to verify the physical capacity of these subjects before surgery. DESIGN: Cross sectional study. SETTING: University teaching hospital. PARTICIPANTS: Forty-two patients scheduled for elective abdominal surgery within the next 48 hours. OUTCOME MEASURES: Distance walked in the 6-minute walk test, heart rate, peripheral oxygen saturation, dyspnoea and leg fatigue. RESULTS: Thirty-one patients (74%) were able to walk for a longer distance when the test was repeated. In these subjects, the mean increase in distance walked was 35.4 [standard deviation (SD) 19.9]m. Heart rate, dyspnoea and leg fatigue increased significantly over time on both tests (P<0.05). The mean heart rate at the end of the sixth minute was significantly higher on the second test (P=0.022). Peripheral oxygen saturation remained above 90% in both tests. The furthest distance walked was, on average, 461.3 (SD 89.7)m. This value was significantly lower than that predicted for the sample (P<0.001). CONCLUSION: Patients scheduled to undergo abdominal surgery were able to walk further when they performed a second 6-minute walk test. Moreover, they showed reduced physical ability before surgery. These findings suggest that repetition of the 6-minute walk test may increase the accuracy of the distance walked, which is useful for studies assessing the physical capacity of patients undergoing abdominal surgery. PMID- 25721253 TI - Anisotropic conductivity in magnetic topological insulators. AB - We study the surface conductivity of a three dimensional topological insulator doped with magnetic impurities. The spin-momentum locking of surface electrons makes their scattering from magnetic impurities anisotropic and the standard relaxation time approximation is not applicable. Using the semiclassical Boltzmann approach together with a generalized relaxation time scheme, we obtain closed forms for the relaxation times and analytic expressions for the surface conductivities of the system as functions of the bulk magnetization and the orientation of the aligned surface magnetic impurities. We show that the surface conductivity is anisotropic, and strongly depends both on the direction of the spins of magnetic impurities and on the magnitude of the bulk magnetization. In particular, we find that the surface conductivity has its minimum value when the spin of surface impurities are aligned perpendicular to the surface of TI, and therefore the backscattering probability is enhanced due to the magnetic torque exerted by impurities on the surface electrons. PMID- 25721254 TI - Decisional stage distribution for colorectal cancer screening among diverse, low income study participants. AB - Colorectal cancer (CRC) screening uptake among minorities and those with lower incomes is suboptimal. Behavioral interventions specifically tailored to these populations can increase screening rates and save lives. The Precaution Adoption Process Model (PAPM) allows assignment of a decisional stage for adoption of a behavior such as CRC screening. Here, we characterize the PAPM decisional stage distribution among 470 low income, racially and ethnically diverse study participants at intake into a behavioral intervention study designed to increase CRC screening uptake. We staged participants for stool blood test (SBT) and colonoscopy separately and used the highest stage for the two tests as the 'overall' stage for CRC screening. For SBT, sex, language (English versus Spanish) and doctor recommendation were significantly related to PAPM stage for CRC screening. For colonoscopy, language, education level, doctor recommendation and self-efficacy were related to stage. For overall CRC screening stage, all the variables associated with either SBT or colonoscopy, with the exception of language were significant. This study suggests attending to these key variables in designing interventions to promote CRC screening, particularly with respect to medically underserved populations. PMID- 25721255 TI - Detection and quantification of Anaplasma phagocytophilum and Babesia spp. in Ixodes ricinus ticks from urban and rural environment, northern Poland, by real time polymerase chain reaction. AB - Anaplasma phagocytophilum and Babesia spp. are emerging tick-borne pathogens which can threaten human health. A duplex real-time PCR and qPCRs with primers and probes targeting 97 and 116 bp fragments of 16S rRNA and 18S rRNA genes, respectively, were used for qualitative and quantitative detection of both pathogens in Ixodes ricinus ticks. Altogether 1875 ticks (1084 adults and 791 nymphs) were collected from rural and urban habitats in northern Poland. Of them, at least 0.9% were found to be infected with A. phagocytophilum while 2.5% with Babesia spp. A comparison of the infection rates by the tick stage, the type of area, the collection site, habitats of different tick density and by the month of collection was done. The prevalence of pathogens was significantly lower in nymphs than in adult ticks (p = 0.02) and in rural areas than in urban areas (p = 0.007). Four different 16S rRNA gene variants of A. phagocytophilum were determine, however none of them showed 100% identity with compared sequences isolated from human patients. The dominant Babesia species was B. venatorum. Results of qPCRs with circular and linearized forms of plasmids used as the standards showed significant difference in the pathogen loads (p = 0.001). The copy numbers of A. phagocytophilum and Babesia spp. estimated from the linear plasmids were 28.7 and 5.1 times lower, respectively, when compared with their circular forms, and were accepted as more reliable. The average number of copies of 16S rRNA gene of A. phagocytophilum in the positive I. ricinus samples were 3.39 * 10(5) +/- 6.09 * 10(5). The mean copy number of 18S rRNA gene of Babesia spp. was ~2.55 * 10(5) +/- 1.04 * 10(6). We confirmed the presence of A. phagocytophilum and Babesia spp. in I. ricinus in both rural and urban environments. The determined low infection rates suggests, however, that the risk for local population and tourists to acquire infection is also low. Moreover, we confirmed recent findings that serious overestimation by circular plasmid DNA makes it less suitable as a standard and that the linear standards should be recommended for qPCR. PMID- 25721256 TI - An update on the ecological distribution of the Ixodidae ticks in Zimbabwe. AB - In total 7657 ticks were collected from 121 dip tanks in 12 districts representative of Zimbabwe's five ecological regions between September 2013 and May 2014. Based on morphological traits four genera and 13 species of ticks were identified. Amblyomma hebraeum (60.3 %), Rhipicephalus microplus (58.7 %), Rhipicephalus decoloratus (47.1 %), Rhipicephalus appendiculatus (56.2 %), Rhipicephalus evertsi evertsi (67.8 %), Rhipicephalus (near) punctatus (13.2 %), Hyalomma truncatum (38 %) and Hyalomma rufipes (46.3 %) were found in all the ecological regions of the country. Amblyomma variegatum and Rhipicephalus compositus (0.8 %) were only found in the north central part of the country while Rhipicephalus simus (5 %) had a sparse distribution. The Haemaphysalis leachi group (1.7 %) and Rhipicephalus sanguineus (1.7 %) were found whenever dogs were sampled suggesting these could be widespread throughout the country. The study confirmed the continued limited distribution of A. variegatum (3.3 %) in the north central parts of the country, whereas A. hebraeum was found to have a wide distribution also encroaching areas of high rainfall and lower temperatures where it was not previously recorded. A parapatric relationship existed between these two Amblyomma species. Rhipicephalus appendiculatus was also widely distributed although its presence was dominant in the cooler and wetter parts of the country. The traditionally held view that Hyalomma species and R. evertsi evertsi can survive well under diverse conditions is upheld in this study. Rhipicephalus microplus was also present in dry regions but its adaptability to these regions requires further investigation. PMID- 25721257 TI - Cell type-restricted expression of erythrocyte tropomodulin Isoform41 in exon 1 knockout/LacZ knock-in heterozygous mice. AB - Full-length erythrocyte tropomodulin (E-Tmod or Tmod1) isoform of 41 kDa is an actin nucleation protein and caps the pointed end of tropomyosin-coated actin filaments. It participates in the length control of short actin protofilaments in the erythrocyte membrane skeletal network as well as the organization of microfilaments in non-erythroid cells. Recently we discovered and characterized a truncated isoform of 29 kDa, which lacks the N-terminal sequence encoded by exons 1 and 2 required for nucleation and capping. Thus, it is important to study the expression pattern of solely the E-Tmod41 isoform in tissues. We utilized our exon 1 knockout (KO) mouse model with a knock-in lacZ reporter gene which reports the expression of E-Tmod41, but not E-Tmod29. Because this homozygous isoform specific KO is an embryonic lethal mutation, we used heterozygous mice. X-gal staining localized specific signals at the single cell level and revealed a timed expression during embryonic development and restricted expression in adult mice. Our results showed that E-Tmod41 expressing cells include developing and young erythroid cells, developing somites, young fiber cells in the lens, certain subtype(s) of tubular cells in the kidney, smooth muscle cells in various tissues, and horizontal cells in the retina. A comparison with previous studies revealed that most if not all tissues known to express E-Tmod contained lacZ expressing cells. Interestingly, some tubular cells were lacZ-positive while others in the same renal tubule were not, indicating heterogeneity within the tubular cells. Combined with double immunocytochemistry, we further localized E Tmod41 to dendritic spines of horizontal cells. These timed and cell-type restricted expressions of E-Tmod41 suggest a role of actin nucleation and/or short actin protofilaments in these cell types and sub-cellular structures. PMID- 25721258 TI - The effect of physical activity on depression in adolescence and emerging adulthood: a growth-curve analysis. AB - This study examined the influence of physical activity on the trajectory of depression from adolescence through emerging adulthood (EA). Using data from the National Longitudinal Study of Adolescent Health (Waves I to IV), latent growth curve modeling was performed to assess how physical activity and gender influenced depression across adolescence and EA. Higher levels of physical activity in mid-adolescence were associated with lower levels of depression during mid-adolescence and slower inclines and declines in depression over time. Boys had lower levels of depression in mid-adolescence and slower inclines and declines in depression over time compared to girls. Findings provide evidence that current theories on understanding depression and mental health prevention programs may be enhanced by the inclusion of physical activity. PMID- 25721259 TI - Description of the Anatomy, Surgical Technique, and Outcome of Hemipelvectomy in 4 Dogs and 5 Cats. AB - OBJECTIVE: To provide (1) a comprehensive description of hemipelvectomy; and (2) report clinical application and outcome of hemipelvectomy in dogs and cats. STUDY DESIGN: Descriptive report and retrospective case series. ANIMALS: Dogs (n = 4) and 5 cats. METHODS: Cadaveric dissection was performed for imaging purposes using 4 mixed breed dogs euthanatized for reasons unrelated to this study. Medical records (2005-2012) were reviewed for dogs and cats that had hemipelvectomy. Data collected included signalment, body weight, body condition score, clinical presentation, diagnostic imaging findings, location and extent of tumor, definitive diagnosis, use of adjuvant therapy, ability to ambulate postoperatively, complications, and survival. RESULTS: The most common indication for hemipelvectomy in cats was injection site sarcoma (ISS) and in dogs, osteosarcoma or peripheral nerve sheath tumor (PNST). Complete tumor excision was achieved in 6 (67%) cases. Incomplete excision occurred in 2 dogs with lumbosacral PNST and 1 cat having a 2nd surgery for ISS. Complications included intraoperative hemorrhage (n = 2), postoperative soft tissue infection (2), and discharge from the incision site (1). All but 1 animal were ambulatory at the time of discharge. Hospitalization ranged from 1-10 days (median, 4 days). Survival after surgery was individually assessed. CONCLUSION: With in-depth anatomic familiarity, hemipelvectomy can be successful for excision of neoplastic lesions of the proximal aspect of the pelvic limb, with only minor complications. PMID- 25721260 TI - Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis. AB - The bone marrow stroma constitutes the marrow-blood barrier, which sustains immunochemical homoeostasis and protection of the haematopoietic tissue in sequelae of systemic bacterial infections. Under these conditions, the bone marrow stromal cells affected by circulating bacterial pathogens shall elicit the adaptive stress-response mechanisms to maintain integrity of the barrier. The objective of this communication was to demonstrate (i) that in vitro challenge of mesenchymal stromal cells, i.e. colony-forming unit fibroblasts (CFU-F), with Staphylococcus epidermidis can activate the autophagy pathway to execute antibacterial defence response, and (ii) that homoeostatic shift because of the bacteria-induced stress includes the mitochondrial remodelling and sequestration of compromised organelles via mitophagy. Implication of Drp1 and PINK1-PARK2 dependent mechanisms in the mitophagy turnover of the aberrant mitochondria in mesenchymal stromal cells is investigated and discussed. PMID- 25721261 TI - Biotechnological uses of RNAi in plants: risk assessment considerations. AB - RNAi offers opportunities to generate new traits in genetically modified (GM) plants. Instead of expressing novel proteins, RNAi-based GM plants reduce target gene expression. Silencing of off-target genes may trigger unintended effects, and identifying these genes would facilitate risk assessment. However, using bioinformatics alone is not reliable, due to the lack of genomic data and insufficient knowledge of mechanisms governing mRNA-small (s)RNA interactions. PMID- 25721262 TI - Interferon-gamma Inhibits Melanogenesis and Induces Apoptosis in Melanocytes: A Pivotal Role of CD8+ Cytotoxic T Lymphocytes in Vitiligo. AB - Increased expression of the cytokine interferon (IFN)-gamma plays a pivotal role in vitiligo-induced depigmentation. However, the major source of IFN-gamma in vitiligo patients and the mechanisms underlying melanocyte destruction are unknown. In this study, a large number of skin infiltrating IFN-gamma+ cells and CD8+ T cells were detected in progressive vitiligo. Among the peripheral blood mononuclear cells (PBMCs) of vitiligo patients, CD8+ cytotoxic T lymphocytes (CTLs) that express IFN-gamma exhibited significant expansion, which suggests that activated CTLs are the main source of increased IFN-gamma in progressive vitiligo. An in vitro analysis demonstrated that IFN-gamma inhibits melanogenesis in primary cultured human melanocytes by altering melanogenic enzyme mRNA expression and, more importantly, that IFN-gamma directly induces melanocyte apoptosis. Our data indicate that vitiligo pathophysiology may be linked to globally activated CD8+ CTL subpopulations, which produce increased IFN-gamma and induce melanocyte dysfunction and apoptosis. PMID- 25721263 TI - Comonomer-induced stereo-selectivity enhancement in a c2 -symmetric metallocene catalyzed propylene polymerization. AB - Propylene polymerization is carried out with a C 2 -symmetric metallocene catalyst of rac-Et(Ind)2 ZrCl2 /MAO at 40 degrees C in the presence of a cyclo triene of trans,trans,cis-1,5,9-cyclododecatriene ((E,E,Z)-CDT). Comonomer incorporations are rather low (<0.10 mol%). However, it is shown for the first time that the comonomer causes a noticeable increase in poly-propylene isotacticity (>7% in [mmmm]). (E,E,Z)-CDT is speculated to coordinate to the metal center forming comonomer-complexed active sites in charge of the entire polymerization reaction with decreased activity however increased propylene enantiomorphic selectivity. PMID- 25721264 TI - Postoperative Systolic Blood Pressure as a risk factor for haematoma following thyroid surgery. AB - OBJECTIVES: To examine potential factors that may predict development of postoperative haematoma following thyroid surgery, with particular attention to postoperative systolic blood pressure. DESIGN: Retrospective, observational case control study of patients undergoing thyroid surgery. SETTING: Secondary General Hospital. PARTICIPANTS: Patients attending Counties Manukau District Health Board (CMDHB) between 2002 and 2012. MAIN OUTCOME MEASURES: Post-operative Haematoma formation that required re-exploration of the wound. RESULTS: The overall rate of postoperative haematoma was 2.57% (16/621). Three patients bled immediately (i.e. after wound closure but while still on the operating table); 10 patients (1.6%) bled in the early postoperative period; and three others bled 24 h or more after surgery. The principal independent risk factor for postoperative haemorrhage that remained after multivariable regression was postoperative systolic blood pressure level. There was a 39% increase in risk of bleeding for every 10 points rise of highest blood pressure recordings in our patient population (OR 1.39; 95% CI = 1.09-1.8). CONCLUSIONS: This study identifies postoperative hypertension as significantly related to development of early postoperative haematoma. Cause for late post-thyroidectomy bleeding remains speculative. PMID- 25721265 TI - NICE endorses TURis system for prostate surgery. PMID- 25721266 TI - Additive Neuroprotection of a 20-HETE Inhibitor with Delayed Therapeutic Hypothermia after Hypoxia-Ischemia in Neonatal Piglets. AB - The severity of perinatal hypoxia-ischemia and the delay in initiating therapeutic hypothermia limit the efficacy of hypothermia. After hypoxia-ischemia in neonatal piglets, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been found to contribute to oxidative stress at 3 h of reoxygenation and to eventual neurodegeneration. We tested whether early administration of a 20-HETE synthesis inhibitor after reoxygenation augments neuroprotection with 3-hour delayed hypothermia. In two hypothermic groups, whole body cooling from 38.5 to 34 degrees C was initiated 3 h after hypoxia-ischemia. Rewarming occurred from 20 to 24 h; then anesthesia was discontinued. One hypothermic group received a 20-HETE inhibitor at 5 min after reoxygenation. A sham-operated group and another hypoxia-ischemia group remained normothermic. At 10 days of recovery, resuscitated piglets with delayed hypothermia alone had significantly greater viable neuronal density in the putamen, caudate nucleus, sensorimotor cortex, CA3 hippocampus, and thalamus than did piglets with normothermic recovery, but the values remained less than those in the sham operated group. In piglets administered the 20-HETE inhibitor before hypothermia, the density of viable neurons in the putamen, cortex and thalamus was significantly greater than in the group with hypothermia alone. Cytochrome P450 4A, which can synthesize 20-HETE, was expressed in piglet neurons in these regions. We conclude that early treatment with a 20-HETE inhibitor enhances the therapeutic benefit of delayed hypothermia in protecting neurons in brain regions known to be particularly vulnerable to hypoxia-ischemia in term newborns. PMID- 25721268 TI - Interleukin-23 promotes the epithelial-mesenchymal transition of oesophageal carcinoma cells via the Wnt/beta-catenin pathway. AB - As the eighth most common malignant tumour worldwide, oesophageal cancer (OC) is often diagnosed during the metastasis of its advanced stage. Interleukin (IL)-23 is an immunomodulatory cytokine that has recently been identified as a cancer associated factor. However, the role of IL-23 in the evolution of OC remains unclear. In the present study, we found that IL-23 was significantly expressed in the tumours of OC patients suffering metastasis and demonstrated that IL-23 contributed to epithelial-mesenchymal transition (EMT) through the Wnt/beta catenin pathway, promoting the migration and invasion of OC cells. In conclusion, IL-23 plays a pivotal role in the development of OC via EMT. PMID- 25721269 TI - Comparison of BCG artifact removal methods for evoked responses in simultaneous EEG-fMRI. AB - Simultaneous recording of electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) has gained attention due to the complimentary properties of the two imaging modalities. Their combined recording enables the study of brain function while taking advantage of the high temporal resolution of EEG and high spatial resolution of fMRI. However EEG data recorded inside the MR scanner is significantly contaminated by two main sources of artifacts: MR gradient artifacts and ballistocardiogram (BCG) artifacts. Most existing removal approaches for these artifacts fall into two main categories: average artifact subtraction (AAS) and optimal basis selection (OBS). While these techniques can improve the data quality significantly, highly effective removal of artifacts - particularly the BCG artifact - from the data is still lacking. Here, we compared two of the most commonly used algorithms for BCG artifact removal (OBS and AAS) based on the estimated signal-to-noise ratio (SNR) of auditory and visual evoked responses recorded during fMRI acquisition. We also further compared optimization of OBS for groups, and at the individual subject and run level. The results suggest that performance of the OBS algorithm can be significantly improved by choosing the optimum number of principal components. Furthermore, optimizing the number of principal components at the individual participant and run level results in significant improvements in the SNR of evoked responses compared to group optimization. PMID- 25721270 TI - Causal inference in neuronal time-series using adaptive decomposition. AB - BACKGROUND: The assessment of directed functional connectivity from neuronal data is increasingly common in neuroscience by applying measures based in the Granger causality (GC) framework. Although initially these consisted in simple analyses based on directionality strengths, current methods aim to discriminate causal effects both in time and frequency domain. NEW METHOD: We study the effect of adaptive data analysis on the GC framework by combining empirical mode decomposition (EMD) and causal analysis of neuronal signals. EMD decomposes data into simple amplitude and phase modulated oscillatory modes, the intrinsic mode functions (IMFs), from which it is possible to compute their instantaneous frequencies (IFs). Hence, we propose a method where causality is estimated between IMFs with comparable IFs, in a static or time-varying procedure, and then attributed to the frequencies corresponding to the IF of the driving IMF for improved frequency localization. RESULTS: We apply a thorough simulation framework involving all possible combinations of EMD algorithms with causality metrics and realistically simulated datasets. Results show that synchrosqueezing wavelet transform and noise-assisted multivariate EMD, paired with generalized partial directed coherence or with Geweke's GC, provide the highest sensitivity and specificity results. COMPARISON WITH EXISTING METHODS: Compared to standard causal analysis, the output of selected representative instances of this methodology result in the fulfillment of performance criteria in a well-known benchmark with real animal epicranial recordings and improved frequency resolution for simulated neural data. CONCLUSIONS: This study presents empirical evidence that adaptive data analysis is a fruitful addition to the existing causal framework. PMID- 25721267 TI - Benefits of task-shifting HIV care to nurses in terms of health-related quality of life in patients initiating antiretroviral therapy in rural district hospitals in Cameroon [Stratall Agence Nationale de Recherche sur le SIDA (ANRS) 12110/Ensemble pour une Solidarite Therapeutique Hospitaliere en Reseau (ESTHER) substudy]. AB - OBJECTIVES: The World Health Organization (WHO) recommends task-shifting HIV care to nurses in low-resource settings with limited numbers of physicians. However, the effect of such task-shifting on the health-related quality of life (HRQL) of people living with HIV (PLHIV) has seldom been evaluated. We aimed to investigate the effect of task-shifting HIV care to nurses on HRQL outcomes in PLHIV initiating antiretroviral therapy (ART) in rural district hospitals in Cameroon. METHODS: Outcomes in PLHIV were longitudinally collected in the 2006-2010 Stratall trial. PLHIV were followed up for 24 months by nurses and/or physicians. Six HRQL dimensions were assessed during face-to-face interviews using the WHO Quality of Life (WHOQOL)-HIV BREF scale: physical health; psychological health; independence level; social relationships; environment; and spirituality/religion/personal beliefs. The degree of task-shifting was estimated using a consultant ratio (i.e. the ratio of nurse-led to physician-led visits). The effect of task-shifting and other potential correlates on HRQL dimensions was explored using a Heckman two-stage approach based on linear mixed models to adjust for the potential bias caused by missing data in the outcomes. RESULTS: Of 1424 visits in 440 PLHIV (70.5% female; median age 36 years; median CD4 count 188 cells/MUL at enrolment), 423 (29.7%) were task-shifted to nurses. After multiple adjustment, task-shifting was associated with higher HRQL level for four dimensions: physical health [coefficient 0.7; 95% confidence interval (CI) 0.1 1.2; P = 0.01], psychological health (coefficient 0.5; 95% CI 0.0-1.0; P = 0.05), independence level (coefficient 0.6; 95% CI 0.1-1.1; P = 0.01) and environment (coefficient 0.6; 95% CI 0.1-1.0; P = 0.02). CONCLUSIONS: Task-shifting HIV care to nurses benefits the HRQL of PLHIV. Together with the previously demonstrated comparable clinical effectiveness of physician-based and nurse-based models of HIV care, our results support the WHO recommendation for task-shifting. PMID- 25721271 TI - Fungal genome sequencing: basic biology to biotechnology. AB - The genome sequences provide a first glimpse into the genomic basis of the biological diversity of filamentous fungi and yeast. The genome sequence of the budding yeast, Saccharomyces cerevisiae, with a small genome size, unicellular growth, and rich history of genetic and molecular analyses was a milestone of early genomics in the 1990s. The subsequent completion of fission yeast, Schizosaccharomyces pombe and genetic model, Neurospora crassa initiated a revolution in the genomics of the fungal kingdom. In due course of time, a substantial number of fungal genomes have been sequenced and publicly released, representing the widest sampling of genomes from any eukaryotic kingdom. An ambitious genome-sequencing program provides a wealth of data on metabolic diversity within the fungal kingdom, thereby enhancing research into medical science, agriculture science, ecology, bioremediation, bioenergy, and the biotechnology industry. Fungal genomics have higher potential to positively affect human health, environmental health, and the planet's stored energy. With a significant increase in sequenced fungal genomes, the known diversity of genes encoding organic acids, antibiotics, enzymes, and their pathways has increased exponentially. Currently, over a hundred fungal genome sequences are publicly available; however, no inclusive review has been published. This review is an initiative to address the significance of the fungal genome-sequencing program and provides the road map for basic and applied research. PMID- 25721272 TI - Dental implants--from experimental dreams to mainstream practice. PMID- 25721273 TI - Genetic factors affecting dental caries risk. AB - This article reviews the literature on genetic aspects of dental caries and provides a framework for the rapidly changing disease model of caries. The scope is genetic aspects of various dental factors affecting dental caries. The PubMed database was searched for articles with keywords 'caries', 'genetics', 'taste', 'diet' and 'twins'. This was followed by extensive handsearching using reference lists from relevant articles. The post-genomic era will present many opportunities for improvement in oral health care but will also present a multitude of challenges. We can conclude from the literature that genes have a role to play in dental caries; however, both environmental and genetic factors have been implicated in the aetiology of caries. Additional studies will have to be conducted to replicate the findings in a different population. Identification of genetic risk factors will help screen and identify susceptible patients to better understand the contribution of genes in caries aetiopathogenesis. Information derived from these diverse studies will provide new tools to target individuals and/or populations for a more efficient and effective implementation of newer preventive measures and diagnostic and novel therapeutic approaches in the management of this disease. PMID- 25721274 TI - Nanoscratch testing for the assessment of enamel demineralization under conditions simulating wine erosion. AB - BACKGROUND: Erosive tooth wear and dentinal hypersensitivity are common problems affecting professional wine tasters. By using nanoscratch testing, the aim of this in vitro study was to assess enamel softening under conditions simulating 10 one-minute episodes of wine erosion. METHODS: Ten enamel specimens were bathed in artificial saliva for 2 hours before being eroded for 10 episodes, with each episode comprising one minute of wine erosion followed by one minute of remineralization in artificial saliva. Nanoscratches were placed with a spherical tip (20 MUm radius) in a nanoindenter under a load of 100 mN at baseline (stage 1), after a one-erosion episode (stage 2) and after 10-erosion episodes (stage 3). RESULTS: There were significant effects of erosion stages on both scratch depth (p<0.001) and surface roughness (p<0.001). Post hoc tests showed significant differences in both scratch depths and surface roughness between stages 1 and 3 (p<0.001), and between stages 2 and 3 (p<0.01). CONCLUSIONS: Enamel softening occurs at an early stage of wine tasting, emphasizing the need to implement early preventive strategies in professional wine tasters. Further research elucidating the fundamental mechanisms involved in early stages of erosion has the potential to lead to development of more effective preventive strategies. PMID- 25721275 TI - Clinical features of gingival lesions in patients with dystrophic epidermolysis bullosa: a cross-sectional study. AB - BACKGROUND: Gingival lesions in patients with dystrophic epidermolysis bullosa (DEB) are a common manifestation. However, their clinical features, frequency and severity are currently unknown. METHODS: Forty-five DEB patients were assessed by an oral medicine specialist, who analysed the presence/absence of four clinical signs (erythema, erosion/ulcer, atrophy, blister) on free and attached gingiva, using the Epidermolysis Bullosa Oropharyngeal Severity score. RESULTS: Twenty eight (62.2%) out of 45 DEB patients showed different types of gingival lesions, whose presence/absence and total frequency/distribution were not significantly different between males and females (p=0.087 and p=0.091, respectively). Erythema was the most prevalent lesion (66.2%) and the recessive DEB severe generalized (RDEB-sev gen) reached the highest median disease activity score. A significant correlation was observed between the DEB subtypes and the disease activity median score (p<0.001), but not between age and total disease activity score in each group of DEB (p>0.05). Lastly, logistic regression showed that only gender (p=0.031) and RDEB-sev gen (p=0.001) were risks factors for the presence of gingival lesions. CONCLUSIONS: Gingival lesions in DEB patients are a relatively common entity and may have multiple clinical aspects, emphasizing the need for thorough attention and awareness among dentists. PMID- 25721276 TI - The influence of varnish and high fluoride on erosion and abrasion in a laboratory investigation. AB - BACKGROUND: The aim of this study was to investigate the potential of concentrated fluoride varnishes to reduce enamel loss from repeated cycles of citric acid erosion and toothbrush abrasion in vitro. METHODS: Polished human enamel samples were exposed to fluoride varnishes: Bifluorid10(r) (NaF&CaF2- 45,200 ppmF), Duraphat(r) (NaF 22,600 ppmF), Fluor-Protector(r) (difluorsilane 1000 ppmF) and a control coating of copal ether varnish (0 ppmF) group and a deionized water group. For each group of 16 samples, nine cycles of erosion and nine cycles of erosion-abrasion [1 cycle=erosion (0.3% citric acid, pH 3.2, 5 min)+artificial saliva (1 h, pH 7.0)+abrasion (120 linear strokes in artificial saliva from Oral B medium soft brushes 300 g loading]. The change in the enamel surface was evaluated using optical profilometry. RESULTS: Duraphat(r) and Bifluorid10(r) applications had a median (IQR) step height of 4.21 um (1.59) and 5.01 um (1.02). This was statistically significantly less than Fluor-Protector(r) 6.83 um (1.25), copal ether 7.22 um (1.97) and water 7.39 um (1.96) (p<0.001). For erosion-abrasion, both Duraphat(r) and Bifluorid(r) had statistically lower step heights than the other products (p<0.01). CONCLUSIONS: The action of fluoride in a range of single-application topical varnishes was effective in reducing enamel wear from erosion and erosion-abrasion in this laboratory study. PMID- 25721277 TI - Survey of Australian oral health practitioners and their smoking cessation practices. AB - BACKGROUND: Smoking is a significant health and economic burden in Australia. Studies of smoking cessation practices in dental settings have primarily concentrated on dentists rather than other oral health practitioner (OHP) groups (dental hygienists, dental therapists and oral health therapists). The aim of this study was to measure Australian OHPs' attitudes, behaviours, interest and barriers to delivering smoking cessation interventions. METHODS: Members of the two peak professional bodies representing Australian OHPs were invited to participate in an anonymous online questionnaire. RESULTS: There were discrepancies between practitioner attitudes and current smoking cessation practices. While the majority of practitioners (90.1%) frequently screened for smoking behaviour, fewer (51.1%) assisted patients to quit smoking. The principal form of assistance was referral to Quitline (45.7%) or to a general medical practitioner (44.4%). The most prevalent barriers identified were lack of knowledge of pharmacological treatments (45.8%) and lack of access to smoking cessation resources (44.2%). Contrary to international studies, time and financial incentive were not commonly cited barriers to delivering smoking cessation interventions. CONCLUSIONS: This survey identifies a need for continuing education in smoking cessation practice. Dissemination of policies, guidelines and resources may assist OHPs to become more engaged and confident in delivering smoking cessation interventions as part of their routine practice. PMID- 25721278 TI - Screening and referral of oral mucosal pathology: a check-up of Australian dentists. AB - BACKGROUND: Oral squamous cell carcinomas and potentially malignant oral disorders can be detected early by visually inspecting the oral soft tissues. This study aimed to determine Australian dentists' opinions and practices regarding oral mucosal screening, referral and oral cancer prevention. METHODS: Nine hundred and ninety-nine randomly selected general dentists were mailed a questionnaire. The questionnaire queried practitioners' opinions and perceptions of oral mucosal screening, their referral practices and their beliefs regarding detection and prevention of oral cancer. RESULTS: A total of n=640 individuals responded, yielding a response rate of 70.2%. Most Australian dentists reported to routinely perform oral mucosal screening. Lack of training, confidence, time and financial incentives were seen as barriers to performing mucosal screening to at least some degree by participants in this study. Most dentists manage referrals for oral mucosal pathology appropriately; however, only about half believe in following up with referred patients. Only half of dentists surveyed believed that they could influence a patient to quit smoking. CONCLUSIONS: Australian dentists place importance on oral mucosal screening. Some changes to dental education and training could be made to further improve confidence and ability of dentists in detecting and referring oral mucosal pathology. PMID- 25721279 TI - Mouth self-examination in a population at risk of oral cancer. AB - BACKGOUND: Cancer of the oral cavity is a public health problem and many cases are not diagnosed until the disease has reached an advanced stage. The aim of this study was to initiate an educational programme in self-examination for patients at risk from oral cancer. METHODS: This quasi-experimental study set out to initiate an educational programme in self-examination for patients at risk from oral cancer, assessing the outcomes after three months. In individual 15 minute face-to-face sessions, patients were given information and training in oral cancer risk factors and then verbal instructions as how to carry out oral self-examination. Three months later, patients were interviewed by telephone and asked if they had carried out self-examination independently at home. The programme was evaluated by means of a health belief model questionnaire on perceived susceptibility (3 items), severity (8 items), benefits (4 items), barriers (8 items) and efficacy (6 items). RESULTS: Eighty-six patients (37 females [43.1%] and 49 males [56.9%]) with a mean age of 58.60+/-10.7 completed the oral self-examination programme. Logistic regression analysis indicated that patients who felt themselves subject to susceptibility (OR: 0.03 95% CI: 0.0 0.86; p<0.04), severity (OR 0.23 95% 0.08-0.68; p<0.008) and benefits (OR 0.11 95% 0.02-0.63; p<0.013) were more likely to perform self-examination. CONCLUSIONS: Training programmes in oral self-examination are needed to decrease morbidity and mortality from oral cancer. PMID- 25721280 TI - Comparative evaluation of the effectiveness of desensitizing agents in dentine tubule occlusion using scanning electron microscopy. AB - BACKGROUND: Dentine hypersensitivity (DH) occurs on exposed dentine and is dependent on the patency of dentinal tubules. This study compared the effectiveness of red propolis extract (RPE), calcium sodium phosphosilicate (Novamin) and arginine-calcium carbonate (ACC) in occluding dentine tubules. METHODS: Eighty dentine discs from extracted human molars were randomly divided into four groups (n=20): Group 1--RPE; Group 2--Novamin; Group 3--ACC; Group 4- saline. The discs were etched with 37.5% phosphoric acid and treated with the test agents. Ten treated discs from each group were then exposed to 6% citric acid challenge. The extent of tubule occlusion was assessed using scanning electron microscopy (SEM). Three blinded assessors scored each SEM image on the degree of tubule occlusion. Differences in occlusion were tested using ANOVA and Tukey adjustment. RESULTS: Discs treated with ACC demonstrated more tubule occlusion, followed by RPE and Novamin, and were greater in statistical significance when compared to discs treated with saline. Following acid challenge, RPE treated discs maintained more occlusion, followed by ACC and Novamin. CONCLUSIONS: All three agents demonstrated tubule occlusion. Although ACC showed more occlusion following treatment, RPE demonstrated a higher degree of occlusion following acid challenge. PMID- 25721281 TI - Caries burden and efficacy of a referral pathway in a cohort of preschool refugee children. AB - BACKGROUND: This study aimed to assess the early caries experience and the efficacy of a community based dental referral pathway in preschool refugees in Western Australia. METHODS: Preschool refugee children referred to the Western Australian paediatric hospital Refugee Health Clinic were prospectively screened for caries by a paediatric dentist before being referred to community dental clinics. Dental forms and medical records were audited to assess decayed, missing and filled teeth (dmft), medical data and dental services engagement. Poisson regression analysis determined the contribution of count variables to the final model. RESULTS: Among the 105 screened children (54% male, median age 3.2 years, 41% Burmese), community dental clinic engagement was low (46%, n=48). Of the 62% with caries (n=65/105, mean dmft 5.2, SD 4.1), 45% were recommended for specialist dental services and 48% were treated. After adjustment for age, gender and total number of teeth, caries incidence was significantly associated with BMI for-age Z score (p=0.02). CONCLUSIONS: Preschool refugee caries burden was high. The community dental referral pathway was ineffective compared to co-located intersectorial dental screening. Specialist dental service needs are high in this cohort and require a targeted approach. PMID- 25721282 TI - Effect of silver diamine fluoride and potassium iodide on residual bacteria in dentinal tubules. AB - BACKGROUND: This study evaluated the antimicrobial effect of a silver diamine fluoride (SDF)/potassium iodide (KI) product (Riva Star) on the viability of intratubular bacteria. METHODS: Forty-five dentine discs prepared from caries free maxillary premolars were randomly divided into nine groups. Group 1 (negative control) contained non-infected sound dentine discs. The remaining discs were infected with Streptococcus mutans suspension and received dentine treatments as follows: Group 2 (positive control), discs were left untreated; Group 3 SDF/KI (Riva Star); Group 4 chlorhexidine (CHX); Group 5 CHX+SDF/KI; Group 6 Carisolv; Group 7 Carisolv+SDF/KI; Group 8 Papacarie, and Group 9 Papacarie+SDF/KI. The discs were then fractured into two halves, stained with fluorescent LIVE/DEAD stain and observed using confocal laser scanning microscopy. RESULTS: SDF/KI exhibited a potent antibacterial effect, as represented by a significantly higher percentage of dead bacteria, in comparison with Carisolv and Papacarie (p<0.05). The application of SDF/KI following Carisolv and Papacarie chemomechanical caries removel gels significantly reduced the viability of intra-tubular bacteria in these groups. CONCLUSIONS: The use of the silver diamine fluoride/potassium iodide product is effective in reducing the numbers of S. mutans in dentinal tubules infected with this organism. PMID- 25721283 TI - Reporting dental trauma and its inclusion in an injury surveillance system in Victoria, Australia. AB - BACKGROUND: This study investigated the frequency, patterns and causes of dental trauma in patients seeking emergency treatment at a dental hospital, and evaluated the impact of an electronic structured injury history form to collect key information. METHODS: A retrospective audit was undertaken of all emergency presentations at the Royal Dental Hospital of Melbourne from 2009 to 2012. Dental trauma and injury surveillance data were collected and evaluated with reference to the criteria of the Victorian Emergency Minimum Dataset. Statistical analysis included chi-squared and Fisher's exact tests. RESULTS: A total of 88,610 new emergency courses of care were created, with 3642 (4.1%) identified as new dental trauma cases in 3574 patients. A total of 6001 teeth were injured with a mean of 1.7 teeth per patient (range: 1-8 teeth). The improvement of injury surveillance information collected using the electronic form compared with the paper form was statistically significant (p<0.001). CONCLUSIONS: The dental trauma findings of this study are consistent with other studies regarding age, gender, location, cause and injury type. This study also confirmed the benefits of electronic collection of dental injury surveillance data that can assist policy planners and health service providers in designing and delivering effective dental injury prevention and management services. PMID- 25721284 TI - Arginine promotes fluoride uptake into artificial carious lesions in vitro. AB - BACKGROUND: This study focused on the interaction of arginine and fluoride on the remineralization of artificial enamel carious lesions in vitro. METHODS: Human enamel blocks with artificial carious lesions were prepared and randomly divided into six treatment groups (n=30 for each group): deionized water, arginine solution, NaF solution, arginine/NaF solution, arginine-free fluoride toothpaste slurry and arginine-containing fluoride toothpaste slurry. After a pH-cycling regimen for 10 days, subsets of specimens from each group were subjected to independent analysis, including surface microhardness (n=8/30), cross-sectional microhardness (n=8/30), enamel fluoride uptake (n=8/30) and polarized light microscopy (n=6/30). The samples tested for surface microhardness were further subjected to simulated plaque acid challenge before surface microhardness was remeasured. RESULTS: Arginine solution promoted remineralization compared with deionized water control (p<0.05). When used in combination with fluoride, arginine significantly increased fluoride uptake compared with fluoride alone (p<0.05). In addition, lesions treated with arginine-containing toothpaste also showed superior fluoride uptake compared with those treated with conventional fluoride toothpaste (p<0.05). CONCLUSIONS: Arginine promoted enamel fluoride uptake when used in combination with fluoride, thereby contributing to resistance of enamel to carious demineralization. PMID- 25721285 TI - Oral ulcer: an uncommon site in primary tuberculosis. AB - Tuberculosis is a chronic infectious disease and a major cause of morbidity and mortality worldwide. It can affect any part of the body, including the oral cavity. Oral lesions of tuberculosis, though uncommon, have been observed in both primary and secondary stages of the disease. This article presents a case of primary tuberculosis manifested as a non-healing, tender ulcer on the lingual mucosa of the edentulous right mandibular arch molar zone, an uncommon site. The diagnosis was confirmed after histopathology examination, polymerase chain reaction and purified protein derivative tests and chest radiograph. A recommended treatment plan of six months with four anti-tuberculotic antibiotics was commenced. Clinically, the oral ulcer disappeared three months after the commencement of treatment. The resurgence of tuberculosis should compel clinicians to include the disease in the differential diagnosis of various types of non-healing oral ulcers. PMID- 25721286 TI - Oral manifestations as an early clinical sign of acute myeloid leukaemia: a case report. AB - Leukaemia is the most common malignancy in children and one of the most common malignancies in young adults. Acute myeloid leukaemia is often associated with early oral manifestations. The purpose of this study is to report the case of a 49-year-old male with spontaneous gingival bleeding for over two years with undiagnosed leukaemia. Haematological investigation was instigated and on referral to the Haematology Department at Dunedin Public Hospital, the diagnosis of an acute myeloid leukaemia was confirmed. Since oral lesions can be one of the early events of acute myeloid leukaemia, they may be considered as an important diagnostic indicator for oral health practitioners, and their roles in diagnosing and treating such patients. PMID- 25721289 TI - Per-Ingvar Branemark: 3 May 1929--20 December 2014. PMID- 25721290 TI - The plight of Australian dental schools. PMID- 25721291 TI - Rhinosinusitis in oral medicine and dentistry. PMID- 25721292 TI - A comparative analysis of Media Lengua and Quichua vowel production. AB - This study presents a comparative analysis of F1 and F2 vowel frequencies from Pijal Media Lengua (PML) and Imbabura Quichua. Mixed-effects models are used to test Spanish-derived high and low vowels against their Quichua-derived counterparts for statistical significance. Spanish-derived and Quichua-derived high vowels are also tested against Spanish-derived mid vowels. This analysis suggests that PML may be manipulating as many as eight vowels where Spanishderived high and low vowels coexist as near-mergers with their Quichua derived counterparts, while high and mid vowels coexist with partial overlap. Quichua, traditionally viewed as a three-vowel system, shows similar results and may be manipulating as many as six vowels. PMID- 25721293 TI - Sulforaphane induces ROS mediated induction of NKG2D ligands in human cancer cell lines and enhances susceptibility to NK cell mediated lysis. AB - AIMS: The goal of this study is to investigate the tumor cytotoxic effects of sulforaphane (SFN) and ionizing radiation (IR) as well as their ability to up regulate natural killer group 2, member D (NKG2D) ligands and modulate the susceptibility of tumor cells to natural killer (NK) cell-mediated killing. MAIN METHODS: Expression of MHC class I-related chain molecules A and B (MICA/MICB) and total reactive oxygen species (ROS) were assessed by flow cytometry following labeling with appropriate dyes or antibodies. NK cell cytotoxicity was determined by calcein release of target cells. KEY FINDINGS: The expression of NKG2D ligands MICA/MICB was found to vary in all the four tumor cell lines tested (MCF7 < A549 < MDA-MB-231 < U937). Exposure of these cells to IR and SFN resulted in a differential induction of these ligands. IR induced an increase in expression of MICA/MICB in MCF7 cells and SFN induced MICA/MICB expression in A549 and MDA-MB 231 cells. This SFN induced increase in receptor expression resulted in increased susceptibility to NK cell mediated killing of tumor cells which was abrogated by blocking with anti-MICA/MICB antibody. SFN induced increase in MICA/MICB expression as well as increased susceptibility to NK cell mediated killing was abrogated by N-acetyl cysteine in A549 and MDA-MB-231 cells suggesting a ROS mediated mechanism. SIGNIFICANCE: Our results indicate that SFN has an immunotherapeutic potential to be used in cancer therapy. PMID- 25721294 TI - Sitagliptin attenuates transient cerebral ischemia/reperfusion injury in diabetic rats: implication of the oxidative-inflammatory-apoptotic pathway. AB - AIMS: Ischemic stroke is a major macrovascular complication of diabetes mellitus. Sitagliptin, a dipeptidyl peptidase-IV inhibitor, was recently shown to improve cognitive functions in diabetic rats; hence the present study was conducted to evaluate its protective effect against transient ischemia-reperfusion (I/R) in diabetic animals. MAIN METHODS: Diabetes was induced by streptozotocin (40 mg/kg). Six weeks later, cerebral I/R was induced by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Sitagliptin (250 mg/kg; p.o.) was administered daily during the last 2 weeks before I/R. KEY FINDINGS: The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NF-kappa)B, and consequently the downstream inflammatory cytokines tumor necrosis factor-alpha and interleukin-6. In parallel, the anti-inflammatory cytokine interleukin-10 was elevated. Antioxidant potential of sitagliptin was depicted, where it reduced neutrophil infiltration, lipid peroxides and nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NF-kappaB signaling pathway as well as improved oxidant status. Sitagliptin exerted an anti-apoptotic effect as reflected by the reduction of the mitochondrial matrix component cytochrome -C and the key downstream executioner caspase-3. Histopathological examination corroborated the biochemical data. SIGNIFICANCE: These findings suggest that sitagliptin is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms and hence may provide a novel agent for the management of ischemic stroke in diabetics. PMID- 25721295 TI - Disease duration did not influence the rates of loss of efficacy of the anti-TNF therapy in Latin American Crohn's disease patients. AB - BACKGROUND/AIMS: The efficacy of both Infliximab (IFX) and Adalimumab (ADA) can be reduced over time. The aim of this study was to analyze the incidence of loss of efficacy (LOE) of both IFX and ADA, and outline the influence of disease duration on its occurrence. METHODS: Retrospective, multicenter, observational cohort study, with CD patients treated with anti-TNF therapy. LOE was defined as the need for steroids, occurrence of major abdominal surgery during treatment, dose increase, interval shortening or switching of the anti- TNF agent. Patients were allocated in three subgroups based on disease duration (DD): <24 months, between 24 and 60 months and >60 months. RESULTS: 175 patients were included in the study (117 under IFX and 58 under ADA therapy). LOE occurred in 32% of patients with DD <24 months, in 33.3% with DD between 24 and 60 months and in 31.3% of subjects with DD over 60 months (p = 0.975). CONCLUSIONS: Disease duration (DD) did not influence LOE rates. These results suggest that in real world observational practice, patients with early CD might have the same rates of LOE than patients with a disease prolonging for a longer duration. PMID- 25721297 TI - A tortoise-infecting picornavirus expands the host range of the family Picornaviridae. AB - While picornaviruses can cause diseases in many mammals, little is known of their host range for replication in non-mammalian vertebrates. Here, a picornavirus in liver and kidney tissues from diseased Sulawesi tortoises (Indotestudo forsteni) was genetically characterized. Tortoise rafivirus A (ToRaV-A, KJ415177) represents a potential new genus in the family Picornaviridae, for which we propose the name "Rafivirus". Our finding confirms the susceptibility of reptiles to picornaviruses. PMID- 25721296 TI - Patient-specific biomechanical model as whole-body CT image registration tool. AB - Whole-body computed tomography (CT) image registration is important for cancer diagnosis, therapy planning and treatment. Such registration requires accounting for large differences between source and target images caused by deformations of soft organs/tissues and articulated motion of skeletal structures. The registration algorithms relying solely on image processing methods exhibit deficiencies in accounting for such deformations and motion. We propose to predict the deformations and movements of body organs/tissues and skeletal structures for whole-body CT image registration using patient-specific non-linear biomechanical modelling. Unlike the conventional biomechanical modelling, our approach for building the biomechanical models does not require time-consuming segmentation of CT scans to divide the whole body into non-overlapping constituents with different material properties. Instead, a Fuzzy C-Means (FCM) algorithm is used for tissue classification to assign the constitutive properties automatically at integration points of the computation grid. We use only very simple segmentation of the spine when determining vertebrae displacements to define loading for biomechanical models. We demonstrate the feasibility and accuracy of our approach on CT images of seven patients suffering from cancer and aortic disease. The results confirm that accurate whole-body CT image registration can be achieved using a patient-specific non-linear biomechanical model constructed without time-consuming segmentation of the whole-body images. PMID- 25721298 TI - Detection and characterization of the first North American mastrevirus in switchgrass. AB - Virus infections have the potential to reduce biomass yields in energy crops, including Panicum virgatum (switchgrass). As a first step towards managing virus induced biomass reduction, deep sequencing was used to identify viruses associated with mosaic symptoms in switchgrass. Two sequences with homology to mastreviruses were identified. Total DNA extracted from switchgrass varieties 'Dewey Blue' and 'Cloud Nine' was used as template to amplify mastrevirus DNA by the rolling-circle method. Complete mastrevirus genome sequences were obtained from cloned amplicons. The two nucleotide sequences were 88 % identical to each other but only 56-57 % identical to the closest relatives in the genus Mastrevirus. Predicted amino acid sequences of the coat protein, replication associated protein A, replication-associated protein, and putative movement protein encoded by the two mastrevirus-like sequences were 95 %, 79 %, 79 %, and 87 % identical to each other, respectively, and 46-48 %, 31 %, 31 %, and 42-48 % identical to those of the closest mastrevirus relatives. Based on a genome-wide identity threshold of 75 % set by the International Committee on Taxonomy of Viruses and phylogenetic analyses, the two virus sequences appear to represent a new mastrevirus species. The mastrevirus is tentatively named switchgrass mosaic associated virus 1 (SgMaV-1) and is the first mastrevirus reported from North America. PMID- 25721299 TI - Merkel cell polyomavirus and human papillomavirus infections in cervical disease in Iranian women. AB - Human papillomavirus (HPV) infection is a necessary cause of cervical neoplasia. Concomitant infection with other infectious agents has been demonstrated to be a cofactor for HPV-related cervical carcinogenesis. The present investigation aimed to determine the prevalence of HPV and Merkel cell polyomavirus (MCPyV) infections and to evaluate the role of MCPyV as a co-factor for HPV-related cervical carcinogenesis in Iranian women. From 2011 to 2013, a total of 112 cervical samples were examined. Forty-five samples (40.2 %) were positive for HPV. MCPyV was found in 37 samples (33 %). Both HPV and MCPyV were present in 14 samples (12.5 %). MCPyV was seen in 30 % of squamous cell carcinomas, 37.5 % of adenocarcinomas, and 16.7 % of undifferentiated carcinomas. The MCPyV large T antigen (LT-Ag) DNA load was determined as the viral copy number per cell. The median MCPyV LT-Ag copy number in positive women was 0.049 * 10(-3) per cell (range 0.0006 * 10(-3)-4.558 * 10(-3) copies per cell). In comparison with other types of cervical cancer, the MCPyV LT-Ag load was higher in adenocarcinomas (0.1024 * 10(-3) copies per cell). A logistic regression model adjusted to HPV positivity and age revealed no statistically significant association between MCPyV infection and cervical cancer (OR, 1.12; 95 % CI, 0.07-16.83). More studies should be conducted to clarify the role of MCPyV in cervical carcinogenesis. PMID- 25721300 TI - Erratum to: Complete genome sequence of a filamentous bacteriophage, RS611, that infects the phytopathogen Ralstonia solanacearum. PMID- 25721301 TI - Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine. AB - Intestinal epithelial cell renewal relies on the right balance of epithelial cell migration, proliferation, differentiation, and apoptosis. Intestinal epithelial cells consist of absorptive and secretory lineage. The latter is comprised of goblet, Paneth, and enteroendocrine cells. Fibroblast growth factor 10 (FGF10) plays a central role in epithelial cell proliferation, survival, and differentiation in several organs. The expression pattern of FGF10 and its receptors in both human and mouse intestine and their role in small intestine have yet to be investigated. First, we analyzed the expression of FGF10, FGFR1, and FGFR2, in the human ileum and throughout the adult mouse small intestine. We found that FGF10, FGFR1b, and FGFR2b are expressed in the human ileum as well as in the mouse small intestine. We then used transgenic mouse models to overexpress Fgf10 and a soluble form of Fgfr2b, to study the impact of gain or loss of Fgf signaling in the adult small intestine. We demonstrated that overexpression of Fgf10 in vivo and in vitro induces goblet cell differentiation while decreasing Paneth cells. Moreover, FGF10 decreases stem cell markers such as Lgr5, Lrig1, Hopx, Ascl2, and Sox9. FGF10 inhibited Hes1 expression in vitro, suggesting that FGF10 induces goblet cell differentiation likely through the inhibition of Notch signaling. Interestingly, Fgf10 overexpression for 3 days in vivo and in vitro increased the number of Mmp7/Muc2 double-positive cells, suggesting that goblet cells replace Paneth cells. Further studies are needed to determine the mechanism by which Fgf10 alters cell differentiation in the small intestine. PMID- 25721302 TI - CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice. AB - The role of stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptor CXC chemokine receptor-4 (CXCR4) in ischemic liver injury and recovery has not been studied. Some reports suggest that this chemokine may aid in liver regeneration, but others suggest that it may be profibrotic through its activation of hepatic stellate cells. In this study we sought to elucidate the role of SDF-1 and its receptor CXCR4 during liver injury, recovery, and regeneration after ischemia reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. CXCR4 was expressed constitutively in the liver, and hepatic levels of SDF-1 peaked 8 h after reperfusion but remained significantly increased for 96 h. Treatment of mice with the CXCR4 antagonist AMD3100 or agonist SDF-1 had no effect on acute liver injury assessed 8 h after I/R. However, treatment with AMD3100 increased hepatocyte proliferation after 72 and 96 h of reperfusion and reduced the amount of liver necrosis. In contrast, treatment with SDF-1 significantly decreased hepatocyte proliferation. These effects appeared to be dependent on the presence of liver injury, as AMD3100 and SDF-1 had no effect on hepatocyte proliferation or liver mass in mice undergoing 70% partial hepatectomy. The data suggest that signaling through CXCR4 is detrimental to liver recovery and regeneration after I/R and that clinical therapy with a CXCR4 antagonist may improve hepatic recovery following acute liver injury. PMID- 25721303 TI - Optical reconstruction of murine colorectal mucosa at cellular resolution. AB - The mucosal layer of the colon is a unique and dynamic site where host cells interface with one another and the microbiome, with major implications for physiology and disease. However, the cellular mechanisms mediating colonic regeneration, inflammation, dysplasia, and dysbiosis remain undercharacterized, partly because the use of thin tissue sections in many studies removes important volumetric context. To address these challenges in visualization, we have developed the deep mucosal imaging (DMI) method to reconstruct continuous extended volumes of mouse colorectal mucosa at cellular resolution. Use of ScaleA2 and SeeDB clearing agents enabled full visualization of the colonic crypt, the fundamental unit of adult colon. Confocal imaging of large colorectal expanses revealed epithelial structures involved in repair, inflammation, tumorigenesis, and stem cell function, in fluorescent protein-labeled, immunostained, paraffin-embedded, or human biopsy samples. We provide freely available software to reconstruct and explore on computers with standard memory allocations the large DMI datasets containing in toto representations of distal colonic mucosal volume. Extended-volume imaging of colonic mucosa through the novel, extensible, and readily adopted DMI approach will expedite mechanistic investigations of intestinal physiology and pathophysiology at intracrypt to multicrypt length scales. PMID- 25721305 TI - The effects of music therapy in endotracheal suctioning of mechanically ventilated patients. AB - BACKGROUND: Endotracheal suctioning has been identified as a painful procedure for critically ill patients. AIM: To determine the effect of music therapy on pain intensity, sedation level and physiological parameters during endotracheal suctioning of mechanically ventilated patients in cardiovascular surgery intensive care unit (ICU). DESIGN: Experimental survey. METHODS: The study was conducted between May 2010 and June 2013 in Ordu Medical Park Hospital Cardiovascular Surgery Intensive Care Unit. The study sample consisted of 66 patients (33 experimental and 33 control) who complied with the criteria of inclusion for the study. Data was collected using the 'Patient Information Form', 'Critical-Care Pain Observation Tool', 'Ramsay Sedation Scale' and 'Form of Physiological Parameters'. RESULTS: The mean scores of the Ramsay Sedation Scale during endotracheal aspiration were respectively 1.88 and 1.55 in the experimental and control group and the difference between the groups was statistically significant (p = 0.003). The mean score of Critical-Care Pain Observation Tool during endotracheal suctioning in the experimental group was found to be lower statistically than those of the control group (p < 0.001). There were no significant differences before, during and 20 min after suctioning between the two groups with regard to systolic blood pressure, diastolic blood pressure, heart rate and oxygen saturation (p > 0.05). CONCLUSIONS: The results of this study implies that music therapy can be effective practice for nurses attempting to reduce patients' pain and control sedation level in patients on mechanical ventilators during endotracheal suctioning. RELEVANCE TO CLINICAL PRACTICE: It is recommended that music therapy should be added to the routine nursing care for mechanically ventilated patients. PMID- 25721304 TI - Suppression of contractile activity in the small intestine by indomethacin and omeprazole. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat a number of conditions, and proton pump inhibitors (PPIs) are often used to prevent NSAID induced gastric mucosal damage; however, the effects of NSAIDs on intestinal motility are poorly understood. The purpose of the present study is to determine the effects of a prototypical NSAID, indomethacin, either alone or in conjunction with the PPI omeprazole, on intestinal motility. Rats were randomly divided into four groups treated with vehicle, omeprazole, indomethacin, or a combination of indomethacin and omeprazole. Intestinal motility and transit were measured along with inflammatory mediators in the intestinal smooth muscle, markers of mucosal damage, and bacterial counts in the intestinal wall. Indomethacin, but not omeprazole, caused mucosal injury indicated by lower gut bleeding; however, both omeprazole and indomethacin suppressed contractile activity and frequency in the distal part of the small intestine. Cotreatment with omeprazole did not reduce indomethacin-induced intestinal bleeding. Furthermore, although indomethacin caused increased inflammation as indicated by increased edema development and inflammatory mediators, cotreatment with omeprazole did not reduce inflammation in the intestinal smooth muscle or prevent the increased bacterial count in the intestinal wall induced by indomethacin. We conclude that both NSAID and PPI treatment suppressed contractile activity in the distal regions of the small intestine. The suppression of intestinal contractility was associated with increased inflammation in both cases; however, indomethacin and omeprazole appear to affect intestinal motility by different mechanisms. PMID- 25721306 TI - Strict infection control leads to low incidence of methicillin-resistant Staphylococcus aureus bloodstream infection over 20 years. AB - OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is a worldwide issue associated with significant morbidity and mortality. Multiple infection control (IC) approaches have been tested to control its spread; however, the success of the majority of trials has been short-lived and many efforts have failed. We report the long-term success of MRSA control from a prospective observational study over 20 years. SETTING: University Hospital Basel is a large tertiary care center with a median bed capacity of 855 and 5 intensive care units (ICUs); currently, the facility has >32,000 admissions per year. METHODS: The IC program at the University Hospital Basel was created in 1993, after 2 MRSA outbreaks. The program has included strict contact precautions with single rooms for MRSA-colonized or -infected patients, targeted admission screening of high risk patients and healthcare workers at risk for carriage, molecular typing of all MRSA strains and routine decolonization of MRSA carriers including healthcare workers. We used the incidence of MRSA bloodstream infections (BSIs) to assess the effectiveness of this program. All MRSA cases were prospectively classified using a standardized case report form in nosocomial and nonnosocomial cases, based on CDC definitions. RESULTS: Between 1993 and 2012, 540,669 blood samples were cultured. The number of blood cultures increased from 865 per 10,000 patient days in 1993 to 1,568 per 10,000 patient days in 2012 (P<.001). We identified 1,268 episodes of S. aureus BSI from 1,204 patients. MRSA accounted for 34 episodes (2.7%) and 24 of these (1.9%) were nosocomial. MRSA BSI incidence varied between 0 and 0.27 per 10,000 patient days and remained stable with no significant variation throughout the study period (P=.882). CONCLUSIONS: Long term control of MRSA is feasible when a bundle of IC precautions is strictly enforced over time. PMID- 25721307 TI - A phase II trial of AZD1152 in relapsed/refractory diffuse large B-cell lymphoma. PMID- 25721308 TI - Thermal relaxation of lithium dendrites. AB - The average lengths lambda of lithium dendrites produced by charging symmetric Li(0) batteries at various temperatures are matched by Monte Carlo computations dealing both with Li(+) transport in the electrolyte and thermal relaxation of Li(0) electrodeposits. We found that experimental lambda(T) variations cannot be solely accounted by the temperature dependence of Li(+) mobility in the solvent but require the involvement of competitive Li-atom transport from metastable dendrite tips to smoother domains over DeltaE(++)(R) ~ 20 kJ mol(-1) barriers. A transition state theory analysis of Li-atom diffusion in solids yields a negative entropy of activation for the relaxation process: DeltaS(++)(R) ~ -46 J mol(-1) K(-1) that is consistent with the transformation of amorphous into crystalline Li(0) electrodeposits. Significantly, our DeltaE(++)(R) ~ 20 kJ mol(-1) value compares favorably with the activation barriers recently derived from DFT calculations for self-diffusion on Li(0)(001) and (111) crystal surfaces. Our findings suggest a key role for the mobility of interfacial Li-atoms in determining the morphology of dendrites at temperatures above the onset of surface reconstruction: TSR ~ 0.65 TMB (TMB = 453 K: the melting point of bulk Li(0)). PMID- 25721309 TI - Ultraviolet photodetectors with high photosensitivity based on type-II ZnS/SnO2 core/shell heterostructured ribbons. AB - Semiconducting heterostructures with type-II band structure have attracted much attention due to their novel physical properties and wide applications in optoelectronics. Herein, we report, for the first time, a controlled synthesis of type-II ZnS/SnO2 heterostructured ribbon composed of SnO2 nanoparticles that uniformly cover the surface of ZnS ribbon via a simple and versatile thermal evaporation approach. Structural analysis indicated that the majority of SnO2 nanoparticles have an equivalent zone axis, i.e., <-313> of rutile SnO2, which is perpendicular to +/-(2-1-10) facets (top/down surfaces) of ZnS ribbon. For those SnO2 nanoparticles decorated on +/-(01-10) facets (side surfaces) of ZnS ribbon, an epitaxial relationship of (01-10)ZnO//(020)SnO2 and [2-1-10]ZnO//[001]SnO2 was identified. To explore their electronic and optoelectronic properties, we constructed field-effect transistors from as-prepared new heterostructures, which exhibited an n-type characteristic with an on/off ratio of ~10(3) and a fast carrier mobility of ~33.2 cm2 V(-1) s(-1). Owing to the spatial separation of photogenerated electron-hole pairs from type-II band alignment together with the good contacts between electrodes and ribbon, the resultant photodetector showed excellent photoresponse properties, including large photocurrent, high sensitivity (external quantum efficiency as high as ~2.4*10(7)%), good stability and reproducibility, and relatively fast response speed. Our results suggest great potential of ZnS/SnO2 heterostructures for efficient UV light sensing, and, more importantly, signify the advantages of type-II semiconducting heterostructures for construction of high-performance nano-photodetectors. PMID- 25721310 TI - Senses or Schizophrenia. PMID- 25721312 TI - [Geriatric post-graduate training: Current recommendations and opinion of the trainees]. AB - OBJECTIVE: To evaluate the level of compliance with the official curriculum residence programme by geriatrics trainees, and to analyse their level of satisfaction. MATERIAL AND METHODS: A questionnaire was developed including these sections: trainee filiation, and questions related to their clinical training, academic formation, research training, satisfaction, and other comments. The survey was performed in Survey Monkey and sent to a geriatric trainee per hospital in March 2014. The results were collected between March and April of 2014. RESULTS: Responses were received from 41% of the trainees of 23 Geriatric Teaching Units. Rates of over 95% were observed as regards clinical rotations in the basic period, while in the specific period these percentages varied between 34% and 69%, probably because some of the trainees had not yet arrived at the period in which these rotations are programmed. An external rotation could be performed by 83% of the trainees, and 90% do the recommended number of shifts. The mean number of instruction sessions per week was 2.3, and the number of meetings with the tutor was 2.5 times per year. The median number of presentations in congresses was 3.7 per trainee, with 0.2 publications during training. Each trainee attended 1.2 national meetings, 0.3 European meetings, and 0.1 American. Most of the trainees (85%) were satisfied or very satisfied with their training. CONCLUSIONS: Geriatrics curricula for trainees are followed in the basic aspects, but not so much in the specific ones. The average level satisfaction of the trainees is very high. The recommended training activities within the specific department (sessions, etc.) are not always fulfilled. The research activity, evaluated by publications and presentations at meetings, is low. Following these data, reflection and the establishment of improvements are required in Geriatrics training at post-graduate level. PMID- 25721311 TI - The facts about sexual (Dys)function in schizophrenia: an overview of clinically relevant findings. AB - A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and alpha1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce. PMID- 25721314 TI - Electronic state dependence of heterogeneous electron transfer: injection from the S1 and S2 state of phlorin into TiO2. AB - Ultrafast time-resolved measurements were performed on a novel pentafluorophenyl substituted 5,5-dimethyl phlorin derivative in solution and when attached to TiO2 colloidal films. The complex excited state dynamics of this porphyrinoid after S1 and S2 excitation was compared at different wavelengths and can be assigned to several subsequent relaxation mechanisms. The difference between excited state dynamics in the free molecule and when attached to an electron accepting electrode was measured. For both cases the dynamics was compared after excitation to the S1 and the S2 state. For the free molecule in solution an intermediate relaxation step was identified and assigned to a buckling motion of the tetrapyrrole ring. On the electrode, heterogeneous electron transfer (HET) times from both states were very similar and around 50 fs. Surprisingly, the large difference in the density of acceptor states that are resonant with the respective donor level of the molecule does not significantly influence HET dynamics. This result indicates that HET proceeds into intermediate transition states that are different from steady state surface states obtained from experiments or computations. The density of states (DOS) of these transient acceptor states appears not to be directly related to the corresponding surface or bulk DOS. PMID- 25721315 TI - Relationship between neurological disorders and heart disease: a national population health survey. PMID- 25721313 TI - [Epidemiology of accidents in a cohort of adults over 64 years old in the Autonomous Community of the Basque Country]. AB - INTRODUCTION: Accidents represent a significant health problem for elderly people. The objective of this study was to assess the incidence of accidents in over-64-year-olds in the Basque Country population, and to describe the clinical epidemiological features leading to them. MATERIAL AND METHODS: This was a prospective cohort study of 15,192 non-institutionalised individuals over 64 years of age, conducted under the auspices of the Basque Sentinel Practice Network (Red Vigia) over one year. A questionnaire was completed for each accident. The rates and risks of accidents were calculated by sex and age group of the individuals who had the accidents. RESULTS: The rates of accidents were 46.52 and 81.87 per 1000 men and women, respectively. The most common type of accident was a fall (92%), and the most severe injuries were fractures (17%), with the risk of an accident being significantly higher in women and in the over 75-year-olds. CONCLUSIONS: These data reflect the scale of accidents in over-64 year-olds in the Basque Country. The most frequent accident was the fall, which represents a dramatic event among the elderly, being one of the main causes of injury, disability and institutionalisation among this population group. PMID- 25721316 TI - A novel PET tracer for targeted imaging of atherosclerosis. PMID- 25721317 TI - Inhibition of MAPK/ERK signaling blocks hippocampal neurogenesis and impairs cognitive performance in prenatally infected neonatal rats. AB - Hippocampus endogenous neurogenesis has been postulated to play a favorable role in brain restoration after injury. However, the underlying molecular mechanisms have been insufficiently deciphered. Here we investigated the potential regulatory capacity of MAPK/ERK signaling on neurogenesis and the associated cognitive performance in prenatally infected neonatal rats. From our data, intrauterine infection could induce hippocampal neuronal apoptosis and promote endogenous repair by evoking neural stem cell proliferation and survival. We also found intrauterine infection could induce increased levels of p-ERK, p-CREB and BDNF, which might be responsible for the potential endogenous rescue system. Furthermore, inhibition of MAPK/ERK signaling could aggravate hippocampal neuronal apoptosis, decrease neurogenesis, and impair the offspring's cognitive performances and could also down-regulate the levels of p-ERK, p-CREB and BDNF. Our data strongly suggest that the activation of MAPK/ERK signaling may play a significant role in promoting survival of newly generated neural stem cells via an anti-apoptotic mechanism, which may be particularly important in endogenous neuroprotection associated with cognitive performance development in prenatally infected rats. PMID- 25721318 TI - Modulating tibiofemoral contact force in the sheep hind limb via treadmill walking: Predictions from an opensim musculoskeletal model. AB - Sheep are a predominant animal model used to study a variety of orthopedic conditions. Understanding and controlling the in-vivo loading environment in the sheep hind limb is often necessary for investigations relating to bone and joint mechanics. The purpose of this study was to develop a musculoskeletal model of an adult sheep hind limb and investigate the effects of treadmill walking speed on muscle and joint contact forces. We constructed the skeletal geometry of the model from computed topography images. Dual-energy x-ray absorptiometry was utilized to establish the inertial properties of each model segment. Detailed dissection and tendon excursion experiments established the requisite muscle lines of actions. We used OpenSim and experimentally-collected marker trajectories and ground reaction forces to quantify muscle and joint contact forces during treadmill walking at 0.25 m* s(-1) and 0.75 m* s(-1) . Peak compressive and anterior-posterior tibiofemoral contact forces were 20% (0.38 BW, p = 0.008) and 37% (0.17 BW, p = 0.040) larger, respectively, at the moderate gait speed relative to the slower speed. Medial-lateral tibiofemoral contact forces were not significantly different. Adjusting treadmill speed appears to be a viable method to modulate compressive and anterior-posterior tibiofemoral contact forces in the sheep hind limb. The musculoskeletal model is freely available at www.SimTK.org. PMID- 25721319 TI - Photoacoustic breast tomography prototypes with reported human applications. AB - OBJECTIVES: Photoacoustic breast tomography could provide optical molecular imaging with near-infrared light at sonographic image resolution by utilizing the photoacoustic effect. This review summarizes reports about current prototypes that were applied in vivo in humans. METHODS: Four databases were searched for reports about prototypes of photoacoustic breast tomography that were tested in vivo in humans. Data extracted from the reports comprised details about system design, phantom studies, and clinical studies. RESULTS: Five prototypes were included. System designs comprised planar, hemicylindrical and hemispherical geometries. In total, 52 of 61 breast cancers (85 %) were detected by three of the prototypes, showing image details such as ring-pattern of the haemoglobin rich tumour vasculature. A refined prototype provided submillimetre resolution at a good contrast-to-noise ratio up to a depth of about 5 cm in a cup-shaped breast configuration. Another novel prototype demonstrated that in the mammographic imaging geometry, the total imaging depth approximately duplicates with bilateral laser illumination. Most prototypes focused on detecting elevated haemoglobin content related to tumours, but proof-of-principle was also given for multispectral optoacoustic tomography by additional imaging of tissue oxygenation. CONCLUSIONS: Photoacoustic breast tomography can detect breast cancer. This radiation-free molecular imaging technology should be further refined and studied for clinical applications. KEY POINTS: * Photoacoustics combines optical imaging with sonographic signal detection. * Photoacoustic tomography could provide molecular imaging at high image resolution. * Prototypes have been designed for human breast cancer imaging. * Preliminary evaluation studies show that photoacoustic tomography detects breast cancer. * This radiation-free method should be further improved and studied for clinical applications. PMID- 25721321 TI - Emotional self-efficacy and alcohol and tobacco use in adolescents. AB - This study examined relationships between emotional self-efficacy (ESE) and alcohol and tobacco use in a statewide sample of public high school adolescents (n = 2,566). The Center for Disease Control Youth Risk Behavior Survey and an adolescent ESE scale were utilized. Logistic regression analyses indicated the presence of any significant race by gender associations between lower ESE and alcohol and tobacco use. Results suggest that alcohol and cigarette use was significantly associated (p <= .05) with lower levels of ESE for certain race/gender groups. Results have implications for school- and community-based mental health services and substance use prevention/education programs for adolescents. Measures of ESE as a component of comprehensive assessments of adolescent mental health in fieldwork, research, and substance abuse prevention/education program evaluation efforts should be considered. PMID- 25721320 TI - Nomogram including pretherapeutic parameters for prediction of survival after SIRT of hepatic metastases from colorectal cancer. AB - OBJECTIVES: Pre-therapeutic prediction of outcome is important for clinicians and patients in determining whether selective internal radiation therapy (SIRT) is indicated for hepatic metastases of colorectal cancer (CRC). METHODS: Pre therapeutic characteristics of 100 patients with colorectal liver metastases (CRLM) treated by radioembolization were analyzed to develop a nomogram for predicting survival. Prognostic factors were selected by univariate Cox regression analysis and subsequent tested by multivariate analysis for predicting patient survival. The nomogram was validated with reference to an external patient cohort (n = 25) from the Bonn University Department of Nuclear Medicine. RESULTS: Of the 13 parameters tested, four were independently associated with reduced patient survival in multivariate analysis. These parameters included no liver surgery before SIRT (HR:1.81, p = 0.014), CEA serum level >= 150 ng/ml (HR:2.08, p = 0.001), transaminase toxicity level >=2.5* upper limit of normal (HR:2.82, p = 0.001), and summed computed tomography (CT) size of the largest two liver lesions >=10 cm (HR:2.31, p < 0.001). The area under the receiver-operating characteristic curve for our prediction model was 0.83 for the external patient cohort, indicating superior performance of our multivariate model compared to a model ignoring covariates. CONCLUSIONS: The nomogram developed in our study entailing four pre-therapeutic parameters gives good prediction of patient survival post SIRT. KEY POINTS: * Four individual parameters predicted reduced survival following SIRT in CRC. * These parameters were combined into a nomogram of pre-therapeutic risk stratification. * The model provided good prediction of survival in two independent patient cohorts. PMID- 25721322 TI - Immediate Effects of Project EX in Spain: A Classroom-Based Smoking Prevention and Cessation Intervention Program. AB - Tobacco use is of high prevalence among Spanish adolescents. Programming to counteract tobacco use has been needed. There is a lack of knowledge on the efficacy of teen tobacco use cessation programming. The current study provides an immediate outcome evaluation of the Project EX tobacco use prevention and cessation program among Spanish adolescents. An eight-session, classroom-based curriculum was translated from English to Spanish and adapted to the Spanish culture. Next, it was tested using a randomized controlled trial with 1,546 Spanish students, involving three program and three control high schools. Participants at the program group provided moderately favorable process ratings of the program. Compared to the standard care control condition, the program condition revealed a greater reduction in smoking intentions and CO ppm levels. PMID- 25721323 TI - Narrowband light detection via internal quantum efficiency manipulation of organic photodiodes. AB - Spectrally selective light detection is vital for full-colour and near-infrared (NIR) imaging and machine vision. This is not possible with traditional broadband absorbing inorganic semiconductors without input filtering, and is yet to be achieved for narrowband absorbing organic semiconductors. We demonstrate the first sub-100 nm full-width-at-half-maximum visible-blind red and NIR photodetectors with state-of-the-art performance across critical response metrics. These devices are based on organic photodiodes with optically thick junctions. Paradoxically, we use broadband-absorbing organic semiconductors and utilize the electro-optical properties of the junction to create the narrowest NIR-band photoresponses yet demonstrated. In this context, these photodiodes outperform the encumbent technology (input filtered inorganic semiconductor diodes) and emerging technologies such as narrow absorber organic semiconductors or quantum nanocrystals. The design concept allows for response tuning and is generic for other spectral windows. Furthermore, it is material-agnostic and applicable to other disordered and polycrystalline semiconductors. PMID- 25721324 TI - Detection of dietary plant-based small RNAs in animals. PMID- 25721325 TI - A novel chemopreventive strategy based on therapeutic microRNAs produced in plants. PMID- 25721326 TI - A comparison of the McGrath(r) Series 5 videolaryngoscope and Macintosh laryngoscope for double-lumen tracheal tube placement in patients with a good glottic view at direct laryngoscopy. AB - We compared the McGrath(r) Series 5 videolaryngoscope with the Macintosh laryngoscope for double-lumen tracheal tube placement in patients with a predicted good glottic view on assessment of the airway. An initial laryngoscopy was performed using the Macintosh laryngoscope; 96 patients with Cormack and Lehane grade-1 or -2a views were randomly assigned to undergo intubation using either the McGrath or Macintosh device. Compared with the Macintosh laryngoscope, the McGrath videolaryngoscope provided more Cormack and Lehane grade-1 views (47 (97.9%) vs 29 (60.4%), p < 0.05), a longer mean (SD) intubation time (39.6 (10.0) s vs 24.4 (7.3) s, p < 0.05) and a higher incidence of double-lumen tube malposition (6 (12.5%) vs 0, p < 0.05). However, in 18 non-randomised patients with Cormack and Lehane grade >= 2b on initial laryngoscopy using the Macintosh, the glottic view was improved on intubation with the McGrath videolaryngoscope, with a total success rate of double-lumen tube placement of 94.4% and mean (SD) intubation time of 50.0 (18.6) s. We recommend that in patients with a low airway risk index score requiring intubation with a double-lumen tracheal tube, the Macintosh laryngoscope is used as the first device and the McGrath videolaryngoscope is used only if this provides a poor glottic view. PMID- 25721327 TI - Increased posterior hippocampal volumes in children with lower increase in body mass index: a 3-year longitudinal MRI study. AB - People are generally lean during childhood and show more variability in body sizes and shapes later in life. Cortical development generally correlates with body growth. However, in children cortical growth may be impaired with oversized body growth. Inverse correlations between body mass index (BMI) and brain volumes suggest that lean bodies may be associated with increased cortical volume. To clarify the positive effects of a lean body on a child's cortical development, we used MRI to measure brain structures longitudinally in 107 children and adolescents aged 5-16 years. The relationships between changes in BMI and cortical volumes during 3 years of development were investigated, while controlling for age, gender and intracranial volume changes. Voxel-based morphometry analyses revealed that an increase in the volume of the right posterior medial temporal lobe - including the hippocampus and parahippocampal gyrus - was associated with lower BMI increases. No correlations were observed between higher BMI increases and cortical volumes. Our results suggest that keeping a lean body - or not getting fat - during childhood can induce an increase in regional cortical volume rather than impair growth. This is the first longitudinal study showing positive effects of a lean body on cortical development in children. PMID- 25721328 TI - Transcription factors and chromatin proteins as therapeutic targets in cancer. AB - Targeting the factors that regulate gene transcription is a compelling strategy in cancer therapeutics. Traditionally, these have been considered intractable targets, but recent work has revealed novel strategies for the regulation of transcription factor activity in cancer. This review will highlight some of the emerging concepts and provide examples where agents that target transcription factors are being exploited clinically for cancer therapies. PMID- 25721329 TI - Untranslatable tospoviral NSs fragment coupled with L conserved region enhances transgenic resistance against the homologous virus and a serologically unrelated tospovirus. AB - Tospoviruses cause severe damages to important crops worldwide. In this study, Nicotiana benthamiana transgenic lines carrying individual untranslatable constructs comprised of the conserved region of the L gene (denoted as L), the 5' half of NSs coding sequence (NSs) or the antisense fragment of whole N coding sequence (N) of Watermelon silver mottle virus (WSMoV), individually or in combination, were generated. A total of 15-17 transgenic N. benthamiana lines carrying individual transgenes were evaluated against WSMoV and the serologically unrelated Tomato spotted wilt virus (TSWV). Among lines carrying single or chimeric transgenes, the level of resistance ranged from susceptible to completely resistant against WSMoV. From the lines carrying individual transgenes and highly resistant to WSMoV (56-63% of lines assayed), 30% of the L lines (3/10 lines assayed) and 11% of NSs lines (1/9 lines assayed) were highly resistant against TSWV. The chimeric transgenes provided higher degrees of resistance against WSMoV (80-88%), and the NSs fragment showed an additive effect to enhance the resistance to TSWV. Particularly, the chimeric transgenes with the triple combination of fragments, namely L/NSs/N or HpL/NSs/N (a hairpin construct), provided a higher degree of resistance (both 50%, with 7/14 lines assayed) against TSWV. Our results indicate that the untranslatable NSs fragment is able to enhance the transgenic resistance conferred by the L conserved region. The better performance of L/NSs/N and HpL/NSs/N in transgenic N. benthamiana lines suggests their potential usefulness in generating high levels of enhanced transgenic resistance against serologically unrelated tospoviruses in agronomic crops. PMID- 25721331 TI - No Overlap among Serum GAD65, NMDAR and AQP4 Antibodies in Patients with Neuromyelitis Optica Spectrum Disorders. AB - OBJECTIVE: To evaluate whether serum glutamic acid decarboxylase (GAD), N-methyl D-aspartate-receptor (NMDAR), and aquaporin-4 (AQP4) autoantibodies coexist in patients with neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD). METHODS: Serum samples were collected from 98 patients with NMO/NMOSD. Serum GAD65, NMDAR and AQP4 antibodies were measured using a cell-based assay. RESULTS: A total of 63 patients (64.3%) had myelitis and optic neuritis and satisfied the revised diagnostic criteria for NMO. Longitudinally extensive transverse myelitis was seen on spinal cord magnetic resonance imaging, showing continuous T2-weighted signal abnormalities in at least three vertebral segments in 26 patients (26.5%); 5 patients (5.1%) had recurrent optic neuritis, and 4 patients (4.1%) had brain syndromes with optic neuritis and myelitis. None of the 98 patients had diabetes, stiff-man syndrome, or epilepsy. All 98 patients tested positive for AQP4 antibody. No patients tested positive for GAD65 and NMDAR antibodies. CONCLUSIONS: In the present study, we found no simultaneous presence of serum GAD65, NMDAR and AQP4 antibodies in patients with NMO/NMOSD. PMID- 25721332 TI - Effect of dietary arginine on the immune response and gene expression in head kidney and spleen following infection of Jian carp with Aeromonas hydrophila. AB - This study was conducted to test the hypothesis that elevated dietary arginine enhances immunity of juvenile Jian carp (Cyprinus carpio var. Jian). Fish were fed graded levels of dietary arginine for 9 weeks. Subsequently, a challenge test was conducted by injection of Aeromonas hydrophila. Head kidney and spleen weights, as well as erythrocyte and leukocyte counts were significantly influenced by dietary arginine levels. A similar trend was also observed for hemagglutination titre, serum lysozyme activity, IgM concentration, C3 and C4 content. The highest survival rates following A. hydrophila infection were obtained in fish fed the diets containing arginine at 16.1-21.9 g/kg diet. Phagocytic activity of leukocytes was significantly enhanced by dietary arginine supplementation. In contrast, acid phosphatase activity significantly decreased with dietary arginine levels. Dietary arginine levels did not have a significant effect on the total iron-binding capacity. Gene expression of TNF-alpha and TGF beta in head kidney significantly increased with dietary arginine levels up to 21.9 g/kg diet, and decreased thereafter. Fish fed the basal diet exhibited the highest IL-10 mRNA expression level. Gene expression of IL-1beta and TOR increased with dietary arginine addition, reaching a plateau at 18.5 and 21.9 g arginine/kg diet, respectively. In spleen, higher IL-1beta and TNF-alpha gene expressions were obtained in fish fed the diets containing 24.5 g arginine/kg diet than in fish fed the other dietary treatments. TGF-beta mRNA expression levels were significantly lower in fish fed the diets containing <=21.9 g arginine/kg diet. IL-10 and TOR mRNA expression levels were lower in fish fed 16.1 g arginine/kg diet, while 4E-BP mRNA expression levels increased with dietary arginine levels up to 12.7 g/kg diet and decreased thereafter. Our results indicate that arginine has beneficial effects on regulating mRNA expression of inflammatory cytokines, as well as TOR and 4E-BP and improving humoral and cellular immunity, therefore enhancing disease resistance of fish. PMID- 25721333 TI - Going beyond horizontal equity: an analysis of health expenditure allocation across geographic areas in Mozambique. AB - In contexts where health services are mostly publicly provided and access is still limited, health financing systems require some mechanism for distributing financial resources across geographic areas according to population need. Equity in public health expenditure has been evaluated either by comparing allocations across spending units to equitable shares established using resource allocation formulae, or by using benefit incidence analysis to look at the distribution of expenditure across individual service users. In the latter case, the distribution across individuals has typically not been linked to the mechanisms that determine the allocation across geographic areas, and to the utilization of specific services by individuals. In this paper, we apply benefit incidence analysis in an innovative way to assess horizontal and vertical equity in the geographic allocation of recurrent expenditure for outpatient health care across districts in Mozambique. We compare the actual distribution of expenditure with horizontal and vertical equity benchmarks, set according to measures of economic status and need for health care. We quantify the observed inequities and the relative contributions of service use and resource allocation. We analyse government and donor expenditure separately and combined, for the years 2008-2011 to compare changes over time and funding source. We use data from a number of national routine sources. Results show improvements in both horizontal and vertical equity, along with the gradual alignment of government and donor resources over time, which resulted in almost horizontally and vertically equitable resource allocation in 2011. However, inequities in the distribution of expenditure across beneficiaries persisted and were driven by inequities in service use. The discrepancy between economic and need indicators highlighted initial differences in government and donor expenditure targets, raising questions about the purpose of public health expenditure and confirming the importance of clearly defining equity objectives to inform and evaluate resource allocation policies. PMID- 25721334 TI - The role of boundary maintenance and blurring in a UK collaborative research project: how researchers and health service managers made sense of new ways of working. AB - The paper investigates whether, how and in what circumstances boundary blurring or boundary maintenance is productive or destructive of sense in collaborative research based on a case study involving researchers from two universities and two principal organisational stakeholders in a local healthcare system in England between 2009 and 2012. Adopting a narrative method, using meeting observation, document analysis and interviews, we describe two key sets of activities in the evolution of collaboration, which allows us to tackle the question at two levels. Studying the production of documents and their use as boundary objects in project management meetings, we show how these were used to enable cooperation by establishing a truce between worldviews, giving participants a better feel for the game and a clearer perception of its stakes. Studying how the partnership expanded to take in other organisations besides the two formal partners, we show how the project accommodated pre-existing organisational interests but thereby sacrificed its experimental ethos. In showing how actors needed to subvert their experimental script to enact collaborative partnership, we argue for understanding and evaluating the latter as the co-produced outcome of disputes and co-orientations towards a practical ideal, not as an organisational format for knowledge co-production. PMID- 25721335 TI - Professor Heinrich W. Herzog (1920-2014). PMID- 25721337 TI - Conformational structures of a decapeptide validated by first principles calculations and cold ion spectroscopy. AB - Calculated structures of the two most stable conformers of a protonated decapeptide gramicidin S in the gas phase have been validated by comparing the vibrational spectra, calculated from first- principles and measured in a wide spectral range using infrared (IR)-UV double resonance cold ion spectroscopy. All the 522 vibrational modes of each conformer were calculated quantum mechanically and compared with the experiment without any recourse to an empirical scaling. The study demonstrates that first-principles calculations, when accounting for vibrational anharmonicity, can reproduce high-resolution experimental spectra well enough for validating structures of molecules as large as of 200 atoms. The validated accurate structures of the peptide may serve as templates for in silico drug design and absolute calibration of ion mobility measurements. PMID- 25721336 TI - Targeting the Serotonin 5-HT7 Receptor in the Search for Treatments for CNS Disorders: Rationale and Progress to Date. AB - The 5-HT7 (5-hydroxytryptamine 7, serotonin 7) receptor is one of the most recently identified members of the serotonin receptor family. Pharmacological tools, including selective antagonists and, more recently, agonists, along with 5 HT7 receptor (5-HT7R) knock-out mice have revealed the involvement of this receptor in central nervous system processes. Its well-established role in controlling body temperature and regulating sleep and circadian rhythms has implicated this receptor in mood disorders. Thus, the 5-HT7R has gained much attention as a possible target for the treatment of depression. Although preclinical data support the antidepressant-like actions of 5-HT7R antagonists, their clinical efficacy has not been yet established. Other evidence has implicated the 5-HT7R in learning and memory. Preclinical findings suggest that blockade of this receptor may be beneficial against schizophrenia-like cognitive deficits. Other possible indications include nociception, epilepsy, migraine, autism spectrum disorders, and Rett Syndrome. However, the question is whether the beneficial effects may be achieved by activation or blockade of 5-HT7Rs. Hence, this review briefly summarises the recent findings on the role of 5-HT7Rs and their ligands in CNS disorders. PMID- 25721338 TI - Expression of DJ-1 and mTOR in eutopic and ectopic endometria of patients with endometriosis and adenomyosis. AB - OBJECTIVE: Endometrial cells may aberrantly express molecules involved in invasion and migration, leading to endometriosis. The aim of this study was to investigate the expression of DJ-1 and phosphorylated mammalian target of rapamycin (p-mTOR) in ectopic and eutopic endometria of endometriosis and adenomyosis. METHODS: Endometrial specimens were obtained from healthy non menopausal women (n = 17) or patients with ovarian endometriotic cysts (n = 48) or adenomyosis (n = 30) during January 2011 to June 2012. The expressions of DJ-1 and p-mTOR were evaluated by immunohistochemistry and western blotting methods. RESULTS: The expressions of DJ-1 and p-mTOR were significantly higher in the ectopic endometria than those in the eutopic endometria of endometriosis and adenomyosis patients or normal endometria (FDR < 0.05). DJ-1 expression was positively correlated with the p-mTOR expression no matter at endometriosis (r = 0.736, FDR < 0.001) or adenomyosis (r = 0.809, FDR < 0.001). CONCLUSION: DJ-1 protein may be involved in endometrial cells proliferation, migration and angiogenesis by modulating the PI3K/Akt/p-mTOR signaling pathway, which provides an underlying theoretical target for endometriosis and adenomyosis. PMID- 25721339 TI - Cancer screening behaviours among South Asian immigrants in the UK, US and Canada: a scoping study. AB - South Asian (SA) immigrants settled in the United Kingdom (UK) and North America [United States (US) and Canada] have low screening rates for breast, cervical and colorectal cancers. Incidence rates of these cancers increase among SA immigrants after migration, becoming similar to rates in non-Asian native populations. However, there are disparities in cancer screening, with low cancer screening uptake in this population. We conducted a scoping study using Arksey & O'Malley's framework to examine cancer screening literature on SA immigrants residing in the UK, US and Canada. Eight electronic databases, key journals and reference lists were searched for English language studies and reports. Of 1465 identified references, 70 studies from 1994 to November 2014 were included: 63% on breast or cervical cancer screening or both; 10% examined colorectal cancer screening only; 16% explored health promotion/service provision; 8% studied breast, cervical and colorectal cancer screening; and 3% examined breast and colorectal cancer screening. A thematic analysis uncovered four dominant themes: (i) beliefs and attitudes towards cancer and screening included centrality of family, holistic healthcare, fatalism, screening as unnecessary and emotion-laden perceptions; (ii) lack of knowledge of cancer and screening related to not having heard about cancer and its causes, or lack of awareness of screening, its rationale and/or how to access services; (iii) barriers to access including individual and structural barriers; and (iv) gender differences in screening uptake and their associated factors. Findings offer insights that can be used to develop culturally sensitive interventions to minimise barriers and increase cancer screening uptake in these communities, while recognising the diversity within the SA culture. Further research is required to address the gap in colorectal cancer screening literature to more fully understand SA immigrants' perspectives, as well as research to better understand gender-specific factors that influence screening uptake. PMID- 25721340 TI - The Influence of Positioning and Muscle Activity on Motor Threshold during Motor Cortex Stimulation Programming. AB - Background: Stimulation parameters are crucial for the efficacy and safety of motor cortex stimulation (MCS). Motor threshold (MT) can be defined as the lowest voltage that produces motor contraction. The final stimulation parameters are always a smaller percentage of MT in order to avoid seizures. We determined how patient position and activity affect MT. Methods: Prospective MT measurements were made while patients were either lying down or sitting up, and in a resting state or while actively contracting the target muscle. Paired 1-tailed t tests were performed to assess for statistically significant differences between MT measurements made under the 4 different combinations of position and activity. Results: The MT was lower when the target muscle was being actively contracted compared to resting in both supine and upright positions (both p < 0.001). The MT was also lower when upright compared to supine in both resting and active states of muscle contraction (both p < 0.001). The mean difference between supine resting and upright active states is 0.79 V. Conclusion: When selecting final stimulation parameters for MCS, clinicians should be aware that the lowest MT is elicited while patients are seated upright and actively contracting the target muscle. Using this method of determining the MT when calculating the final stimulation parameters could reduce the chance of MCS-induced seizures. (c) 2015 S. Karger AG, Basel. PMID- 25721342 TI - Human Value, Dignity, and the Presence of Others. AB - In the health care professions, the meaning of--and implications for--'dignity' and 'value' are progressively more important, as scholars and practitioners increasingly have to make value judgments when making care decisions. This paper looks at the various arguments for competing sources of human value that medical professionals can consider--human rights, autonomy, and a higher-order moral value--and settles upon a foundational model that is related to (though distinct from) the Kantian model that is popular within the medical community: human value is foundational; human dignity, autonomy, and rights derive from the relational quality of human dignity. Moral dignity is expressed though the relationships we cultivate, the communal ends we pursue, and the rights we enjoy. Correlatively, human dignity is inseparable from its ground (i.e., morality), and the relationship between these two is best represented for Kant in the humanities formulation. The foundational model of dignity ensures that human value is non circularly derived, but is ultimately tied to expressions of individual human dignity that comes from the dignity of morality. Linking Kant's dignity of humanity to the dignity of morality affords a unique and efficacious response to the discussion of human value. In one sense, dignity is amplificatory, since its worth is inextricable with that of autonomy and the rights afforded to the autonomous. But that isn't to say that the worth of dignity is merely amplificatory. Rather, human dignity indicates the absolute inner value (MM 6:435) found in each individual in virtue of being human (MM 6:435, 462). That inner worth engenders certain universal rights--derivable from the dignity and fundamental rational appeal of morality--just as it provides for the possibility for a community of beings to seek to live the moral life. PMID- 25721341 TI - Review of the fundamental theories behind small angle X-ray scattering, molecular dynamics simulations, and relevant integrated application. AB - In this paper, the fundamental concepts and equations necessary for performing small angle X-ray scattering (SAXS) experiments, molecular dynamics (MD) simulations, and MD-SAXS analyses were reviewed. Furthermore, several key biological and non-biological applications for SAXS, MD, and MD-SAXS are presented in this review; however, this article does not cover all possible applications. SAXS is an experimental technique used for the analysis of a wide variety of biological and non-biological structures. SAXS utilizes spherical averaging to produce one- or two-dimensional intensity profiles, from which structural data may be extracted. MD simulation is a computer simulation technique that is used to model complex biological and non-biological systems at the atomic level. MD simulations apply classical Newtonian mechanics' equations of motion to perform force calculations and to predict the theoretical physical properties of the system. This review presents several applications that highlight the ability of both SAXS and MD to study protein folding and function in addition to non-biological applications, such as the study of mechanical, electrical, and structural properties of non-biological nanoparticles. Lastly, the potential benefits of combining SAXS and MD simulations for the study of both biological and non-biological systems are demonstrated through the presentation of several examples that combine the two techniques. PMID- 25721343 TI - Mild hyperthermia enhances transport of liposomal gemcitabine and improves in vivo therapeutic response. AB - Obstructive biological barriers limit the transport and efficacy of cancer nanotherapeutics. Creative manipulation of tumor microenvironment provides promising avenues towards improving chemotherapeutic response. Such strategies include the use of mechanical stimuli to overcome barriers, and increase drug delivery and therapeutic efficacy. The rational use of gold nanorod-mediated mild hyperthermia treatment (MHT) alters tumor transport properties, increases liposomal gemcitabine (Gem Lip) delivery, and antitumor efficacy in pancreatic cancer CAPAN-1 tumor model. MHT treatment leads to a threefold increase in accumulation of 80-nm liposomes and enhances spatial interstitial distribution. I.v. injection of Gem Lip and MHT treatment lead to a threefold increase in intratumor gemcitabine concentration compared to chemotherapeutic infusion alone. Furthermore, combination of MHT treatment with infusion of 12 mg kg(-1) Gem Lip leads to a twofold increase in therapeutic efficacy and inhibition of CAPAN-1 tumor growth when compared to equimolar chemotherapeutic treatment alone. Enhanced therapeutic effect is confirmed by reduction in tumor size and increase in apoptotic index where MHT treatment combined with 12 mg kg(-1) Gem Lip achieves similar therapeutic efficacy as the use of 60 mg kg(-1) free gemcitabine. In conclusion, improvements in vivo efficacy are demonstrated resulting from MHT treatment that overcome transport barriers, promote delivery, improve efficacy of nanomedicines. PMID- 25721344 TI - Quiet eye training facilitates visuomotor coordination in children with developmental coordination disorder. AB - INTRODUCTION: Quiet eye training (QET) has been shown to be more effective than traditional training (TT) methods for teaching a throw and catch task to typically developing 8-10 yr old children. The current study aimed to apply the technique to children with developmental coordination disorder (DCD). METHOD: 30 children with DCD were randomly allocated into TT or QET intervention groups. The TT group were taught how to control their arm movements during the throw and catch phases, while the QET group were also taught to fixate a target location on the wall prior to the throw (quiet eye1; QE1), followed by tracking the ball prior to the catch (quiet eye2; QE2). Performance, gaze and motion analysis data were collected at pre/post-training and 6-week retention. RESULTS: The QET group significantly increased QE durations from pre-training to delayed retention (QE1 = +247 ms, QE2 = +19%) whereas the TT group experienced a reduction (QE1 = -74 ms, QE2 = -4%). QET participants showed significant improvement in the quality of their catch attempts and increased elbow flexion at catch compared to the TT group (QET = -28 degrees , TT = -1 degrees ). CONCLUSION: QET changed DCD children's ability to focus on a target on the wall prior to the throw, followed by better anticipation and pursuit tracking on the ball, which in turn led to improved catching technique. QET may be an effective adjunct to traditional instructions, for therapists teaching visuomotor skills to children with DCD. PMID- 25721345 TI - Dynamic control of the location of nanoparticles in hybrid co-assemblies. AB - We herein demonstrated an approach to control the spatial distribution of components in hybrid microspheres. Hybrid core-shell structured microspheres (CSMs) prepared through co-assembly were used as starting materials, which are comprised of anthracene-ended hyperbranched poly(ether amine) (AN-hPEA) in the shell and crystallized anthracene containing polyhedral oligomer silsesquioxane (AN-POSS). Upon thermal annealing at a temperature higher than the melting point of AN-POSS, the diffusion of AN-POSS from the core to the shell of CSM leads to a transition of morphology from the core-shell structure to core-transition-shell to the more stable homogeneous morphology, which has been revealed by experimental results of TEM and DSC. The mechanism for the morphology transition of CSM induced by the diffusion of AN-POSS was disclosed by a dissipative particle dynamics (DPD) simulation. A mathematical model for the diffusion of POSS in the hybrid microsphere is established according to Fick's law of diffusion and can be used to quantify its distribution in CSM. Thus, the spatial distribution of POSS in the microsphere can be controlled dynamically by tuning the temperature and time of thermal annealing. PMID- 25721346 TI - [Breast cancer treated by antibiotherapy? Granulomatous mastitis with Corynebacterium]. AB - Granulomatous mastitis is a rare disease, often associated with Corynebacterium infection. It raises the problem of diagnosis of breast tumor with a fast evolution and inflammatory character. We report two cases of granulomatous mastitis with Corynebacterium. It concerns the clinical and radiological description, followed by the therapeutic alternatives and future of the patients. The clinical presentation is variable. The treatment consists in a surgical procedure of resection. The medical treatment based of corticosteroids also proves efficient. The association between Corynebacterium presence and this pathology seems frequent and needs a specific bacteriological search. PMID- 25721347 TI - [Analysis from the French DRG-based information system (PMSI) of conservative surgical treatment for abnormal uterine bleeding in 2008-2010]. AB - OBJECTIVE: To evaluate the conservative surgical treatment for abnormal uterine bleeding from the Medicalized Information System Program (PMSI). MATERIALS AND METHODS: The diagnosis codes were selected from 10th version of the international classification disease. A transversal and longitudinal descriptive analysis was performed from hospital stays, patient's characteristics, medical procedures between 2008-2010. RESULTS: Nineteen thousand six hundred and seventy-nine patients were admitted in hospital (public or private) for treatment of abnormal uterine bleeding. Endometrial ablation increased by 16,7%, 10.2% for first generation technique (G1) and 63.5% for second generation techniques (G2). G2 were used in 15% of indications. The median age was respectively 45.2+/-6.4 years old versus 45.8+/-4.9 years old for G2. The median length of hospital stay was 1.6 +/-1with 69% of patients in ambulatory care. The likelihood to have a hysterectomy in the 3 years follow-up was higher after G1 than G2 treatments (P=0.0034) for the patients above 40 years old. In longitudinal study, defined only by endometrial hyperplasia, 11,532 patients were included and only 8.2% had been treated by G2. CONCLUSION: In spite of the international guidelines since 2008, 85% of patients treated with first generation surgical technique. The failure rate defined by a re-ablation or a hysterectomy is higher after G1. This result must be discussed in relationship with cost effective aspects. PMID- 25721348 TI - [Paraplegia and pregnancy]. AB - OBJECTIVES: To describe the characteristics of the management of pregnancy and child birth in women with spinal cord injury. MATERIALS AND METHODS: Retrospective cohort study including paraplegics patients with motor deficit (whatever the etiology) who gave birth at the University Hospital of Toulouse between March 2003 and March 2014 (11 years). Monitoring and outcome of pregnancy were studied. RESULTS: Seventeen deliveries (15 patients) were performed on a total of 46,888 in the studied period (prevalence=0.40/00). All patients had urinary tract infections: lower urinary tract (100%), recurrent cystitis (75%), pyelonephritis (31.3%). One patient (6.3%) presented dysautonomia during pregnancy. The cesarean rate was 47% (the indication was in any case an obstetrical reason). Among vaginal deliveries, four (44%) required an instrumental extraction. Epidural analgesia was the method of choice in the absence of contraindication. CONCLUSION: Pregnancy associated with spinal cord injury requires a multidisciplinary approach. Autonomic hyperreflexia syndrome must be known and can be avoided by epidural analgesia in early labor. Vaginal delivery should be the rule. PMID- 25721349 TI - [Benefits of multidisciplinary care for excised women]. AB - AIM: To present the results of multidisciplinary care model for excised women. PATIENTS AND METHODS: Qualitative retrospective study on multidisciplinary care between 2007 and 2012 within Excised Women Care Unit. Patients are seen by three specialists: a gynecologist obstetrician, a psychotrauma therapist and anthropologist, a psycho-sexologist. The Unit welcomes any excised woman, whatever are her demands. Women wishing for a clitoridian surgery meet systematically the three specialists. The study covers a population of 270 women, most of them aged between 18 and 40years. RESULTS: The presented results are related to women having asked for clitoridian surgery. Two outstanding results come out from multidisciplinary care: few women finally go for surgery, and a high rate of patients wishing for surgery present a sexual trauma other than female genital mutilation/cutting. CONCLUSION: The importance of the psychotraumatic and interpersonal dimension (marital - familial) in the problems presented by the patients indicates that the "repair" of excision cannot be reached by the sole surgery and requires a medical, psychological and sexological management. PMID- 25721350 TI - To what extent do English language RCT meta-analysis justify induction of low risk pregnancy for postdates? AB - Induction for postdates in low-risk pregnancy was adopted with the intent to prevent post-term antepartum stillbirth, the most common cause of perinatal death, based on evidence derived in English language RCT meta-analysis. Systematic English language meta-analysis of RCT studies of induction for postdates in low-risk pregnancy report perinatal mortality rates (PMRs) for low risk pregnancy ranging from 2.6 to 7.6/1000, based on 2-5 stillbirths among 13-16 perinatal deaths, including diabetic pregnancies as well as other high-risk pregnancies irrelevant to the study question. Baseline PMR>=41 weeks in large international databases for high and low risk pregnancies before routine induction 1998-2003 range from 0.9 to 2.4/1000 or about 300% lower than the reported PMR rates for postdate pregnancies in the expectant management arm in English language RCT meta-analysis. Deaths in the first week far exceed stillbirths in the RCT meta-analysis, the opposite of what is expected. These 2 implausible results bring into question the evidence used to justify induction for postdates>=41 weeks. PMID- 25721351 TI - [Twin pregnancy with complete mole and coexisting fetus: Reach fetal viability is possible]. AB - Twin pregnancies combining complete hydatidiform mole and coexistent fetus are a rare situation (incidence in 1/20,000 in 1/100,000 pregnancies) and a challenge for diagnosis. Their complications can be important - bleeding, preeclampsia, miscarriage - and their management remains complex and controversial. In case of continuing the pregnancy, nearly 40% of women have lives babies. Three quarters of fetal loss occur before 24weeks gestation. We report here three new cases; only one of these cases had a favorable outcome. PMID- 25721352 TI - Chronic bacterial seminal vesiculitis as a potential disease entity in men with chronic prostatitis. AB - OBJECTIVES: To investigate bacterial infection in the seminal vesicles by bacteriological examination and radionuclide imaging in men with chronic prostatitis. METHODS: The study included 50 patients with chronic prostatitis who showed hot uptake in seminal vesicles on Tc-99m ciprofloxacin imaging and eight patients who did not show hot uptake. The evaluation included the National Institutes of Health Chronic Prostatitis Symptom Index and four-glass test. In all participants, transperineal aspiration of seminal vesicle fluid under the guidance of transrectal ultrasonography and bacteriological examination was carried out. RESULTS: Of the 50 patients who showed hot uptake in the seminal vesicles on the isotope study, microorganisms were isolated from the seminal vesicle fluid in 17 patients (positive predictive value, 34%). The most common causative organisms were Escherichia coli in 13 patients (26%), followed by coagulase-negative Staphylococcus species in two patients (4%), Enterococcus faecalis in one patient (2%) and Chlamydia trachomatis in one patient (2%). No microorganisms were isolated in the eight patients who did not show hot uptake in the seminal vesicles (negative predictive value, 100%). However, there were no significant differences in National Institutes of Health Chronic Prostatitis Symptom Index total scores and subscores between the study groups. CONCLUSIONS: Chronic bacterial seminal vesiculitis might simultaneously affect a considerable portion of patients with chronic prostatitis, although the clinical implication of the disease remains to be further investigated. PMID- 25721353 TI - Decreased number of circulating endothelial progenitor cells in hidradenitis suppurativa patients. AB - BACKGROUND: Hidradenitis suppurativa (HS) is nowadays regarded as a systemic disease associated with metabolic syndrome. Some recent studies have also demonstrated an increased cardiovascular risk in patients with HS. Circulating endothelial progenitor cells (EPCs) play an integral role in the regulation and protection of the endothelium and in the maintenance of vascular homeostasis. OBJECTIVE: This study was undertaken to determine the possible alterations in the number of EPCs in patients with HS compared to controls. METHODS: The number of EPCs, identified as CD133+/KDR+ cells, was determined with flow cytometry in the peripheral blood of 25 HS patients and 31 controls. RESULTS: The number of EPCs was significantly reduced in HS sufferers compared with controls (p < 0.0001). The mean number of EPCs was assessed as 191.3 +/- 118.5/ml and 672.4 +/- 343.0/ml for patients and controls, respectively. CONCLUSION: A decreased number of EPCs among HS sufferers may contribute to endothelial malfunction resulting in increased cardiovascular risk in this group of patients. PMID- 25721354 TI - Cellular immunity and cardiac remodeling after myocardial infarction: role of neutrophils, monocytes, and macrophages. AB - Today, innate immunity is recognized as an important pathophysiologic factor and therapeutic target for cardiac remodeling after myocardial infarction (MI). The innate immune system exerts its function via soluble and cellular components. Recently, function and kinetics of immune cells after MI have been clarified using new innovative technology. Therefore, herein, we will discuss the function of neutrophils, monocytes, and macrophages in the pathophysiology of cardiac remodeling after MI in basic as well as clinical science. PMID- 25721355 TI - Is there a role for invasive hemodynamic monitoring in acute heart failure management? AB - The place of invasive hemodynamic monitoring in patients with acute heart failure is still debated, even though frequently used. Invasive techniques, which include the pulmonary artery catheter and transpulmonary thermodilution, provide important information on cardiac output and intravascular pressures or volume. These techniques should be used in combination with echocardiography and allow nurse-driven semicontinuous hemodynamic monitoring. These techniques are useful not only in the diagnosis of circulatory or respiratory failure but also for the evaluation of the effects of therapies. Admittedly, large-scale randomized trials failed to demonstrate a survival benefit with the pulmonary artery catheter (and were even not yet performed with transpulmonary thermodilution). However, these trials may be subjected to selection bias, as patients from recruiting centers not included in the trial but receiving the pulmonary artery catheter were more severe and had higher mortality rates than patient included in the trial. Hence, invasive techniques may still have a place in selected patients with acute circulatory failure and especially in the most severe cases. PMID- 25721356 TI - A Randomised Phase II Trial Comparing Docetaxel Plus Prednisone with Docetaxel Plus Prednisone Plus Low-Dose Cyclophosphamide in Castration-Resistant Prostate Cancer. AB - BACKGROUND: Docetaxel plus prednisone is a standard treatment for castration resistant prostate cancer. Cyclophosphamide may be an effective combination partner. METHODS: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. RESULTS: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered to be cancer related. CONCLUSIONS: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results. PMID- 25721357 TI - The accuracy of prenatal ultrasound in determining the type of orofacial cleft. AB - OBJECTIVE: The aim of this study was to assess the accuracy of prenatal transabdominal ultrasound in determining the oral cleft type. METHODS: A retrospective cohort study was performed on all consecutive cases of orofacial cleft diagnosed by prenatal ultrasound examination in the Wilhelmina Children's Hospital, a tertiary referral hospital, between January 2002 and December 2012. Prenatal findings were compared with postnatal diagnoses. RESULTS: A total of 134 patients were included. The mean gestational age at ultrasound examination was 24 weeks + 5 days. Prenatal diagnosis was in accordance with postnatal findings in 76.9% of the cases (103/134) with regard to the cleft type. Underestimation of the cleft occurred in 19.4% (26/134), whereas in 3.7% (5/134), the extent was overestimated. In distinguishing bilateral from unilateral clefts, no errors were made. CONCLUSION: Prenatal ultrasound is accurate in assessing the types of orofacial clefts in a large majority of the cases and is completely accurate in distinguishing between unilateral and bilateral clefts. This study indicates that it is a reliable technique to assess the cleft type, which is important for counseling future parents. Although, the clinician should be aware of the fact that a cleft palate is easily missed, and subsequently, underestimation of cleft extend is frequent. PMID- 25721358 TI - A high pressure neutron study of colossal magnetoresistant NdMnAsO(0.95)F(0.05). AB - A high pressure neutron diffraction study of the oxypnictide NdMnAsO0.95F0.05 has been performed at temperatures of 290-383 K and pressures up to 8.59 GPa. The results demonstrate that the antiferromagnetic order of the Mn spins is robust to pressures of up to 8.59 GPa. TN is enhanced from 360 to 383 K upon applying an external pressure of 4.97 GPa, a rate of 4.63 K GPa(-1). NdMnAsO0.95F0.05 is shown to violate Bloch's rule which would suggest that NdMnAsO0.95F0.05 is on the verge of a localized to itinerant transition. There is no evidence of a structural transition but applied pressure tends to result in more regular As-Mn As and Nd-O-Nd tetrahedra. The unit cell is significantly more compressible along the c-axis than the a-axis, as the interlayer coupling is weaker than the intrinsic bonds contained within NdO and MnAs slabs. PMID- 25721360 TI - Advance Care Planning in palliative care: a qualitative investigation into the perspective of Paediatric Intensive Care Unit staff. AB - BACKGROUND: The majority of children and young people who die in the United Kingdom have pre-existing life-limiting illness. Currently, most such deaths occur in hospital, most frequently within the intensive care environment. AIM: To explore the experiences of senior medical and nursing staff regarding the challenges associated with Advance Care Planning in relation to children and young people with life-limiting illnesses in the Paediatric Intensive Care Unit environment and opportunities for improvement. DESIGN: Qualitative one-to-one, semi-structured interviews were conducted with Paediatric Intensive Care Unit consultants and senior nurses, to gain rich, contextual data. Thematic content analysis was carried out. SETTING/PARTICIPANTS: UK tertiary referral centre Paediatric Intensive Care Unit. Eight Paediatric Intensive Care Unit consultants and six senior nurses participated. FINDINGS: Four main themes emerged: recognition of an illness as 'life-limiting'; Advance Care Planning as a multi disciplinary, structured process; the value of Advance Care Planning and adverse consequences of inadequate Advance Care Planning. Potential benefits of Advance Care Planning include providing the opportunity to make decisions regarding end of-life care in a timely fashion and in partnership with patients, where possible, and their families. Barriers to the process include the recognition of the life-limiting nature of an illness and gaining consensus of medical opinion. Organisational improvements towards earlier recognition of life-limiting illness and subsequent Advance Care Planning were recommended, including education and training, as well as the need for wider societal debate. CONCLUSIONS: Advance Care Planning for children and young people with life-limiting conditions has the potential to improve care for patients and their families, providing the opportunity to make decisions based on clear information at an appropriate time, and avoid potentially harmful intensive clinical interventions at the end of life. PMID- 25721361 TI - The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis. AB - Hypoxia is one of severe cellular stress and it is well known to be associated with a worse outcome since a lack of oxygen accelerates the induction of apoptosis. Autophagy, an important and evolutionarily conserved mechanism for maintaining cellular homeostasis, is closely related to the apoptosis caused by hypoxia. Generally autophagy blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase which could reduce cellular injury. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis, which could aggravate cell damage under hypoxia condition. In addition, the activation of apoptosis-related proteins-caspase can also degrade autophagy-related proteins, such as Atg3, Atg4, Beclin1 protein, inhibiting autophagy. Although the relationship between autophagy and apoptosis has been known for rather complex for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This short review discusses and summarizes the dual role of autophagy and the interaction and molecular regulatory mechanisms between autophagy and apoptosis under hypoxia. PMID- 25721362 TI - Adenosine monophosphate activated protein kinase (AMPK), a mediator of estradiol induced apoptosis in long-term estrogen deprived breast cancer cells. AB - Estrogens stimulate growth of hormone-dependent breast cancer but paradoxically induce tumor regress under certain circumstances. We have shown that long-term estrogen deprivation (LTED) enhances the sensitivity of hormone dependent breast cancer cells to estradiol (E2) so that physiological concentrations of estradiol induce apoptosis in these cells. E2-induced apoptosis involve both intrinsic and extrinsic pathways but precise mechanisms remain unclear. We found that exposure of LTED MCF-7 cells to E2 activated AMP activated protein kinase (AMPK). In contrast, E2 inhibited AMPK activation in wild type MCF-7 cells where E2 prevents apoptosis. As a result of AMPK activation, the transcriptional activity of FoxO3, a downstream factor of AMPK, was up-regulated in E2 treatment of LTED. Increased activity of FoxO3 was demonstrated by up-regulation of three FoxO3 target genes, Bim, Fas ligand (FasL), and Gadd45alpha. Among them, Bim and FasL mediate intrinsic and extrinsic apoptosis respectively and Gadd45alpha causes cell cycle arrest at the G2/M phase. To further confirm the role of AMPK in apoptosis, we used AMPK activator AICAR in wild type MCF-7 cells and examined apoptosis, proliferation and expression of Bim, FasL, and Gadd45alpha. The effects of AICAR on these parameters recapitulated those observed in E2-treated LTED cells. Activation of AMPK by AICAR also increased expression of Bax in MCF-7 cells and its localization to mitochondria, which is a required process for apoptosis. These results reveal that AMPK is an important factor mediating E2-induced apoptosis in LTED cells, which is implicative of therapeutic potential for relapsing breast cancer after hormone therapy. PMID- 25721363 TI - Molecular genetic analysis of Plasmodium vivax isolates from Eastern and Central Sudan using pvcsp and pvmsp-3alpha genes as molecular markers. AB - In Sudan, Plasmodium vivax accounts for approximately 5-10% of malaria cases. This study was carried out to determine the genetic diversity of P. vivax population from Sudan by analyzing the polymorphism of P. vivax csp (pvcsp) and pvmsp-3alpha genes. Blood samples (n=76) were taken from suspected malaria cases from 2012-2013 in three health centers of Eastern and Central Sudan. Parasite detection was performed by microscopy and molecular techniques, and genotyping of both genes was performed by PCR-RFLP followed by DNA sequence for only pvcsp gene (n=30). Based on microscopy analysis, 76 (%100) patients were infected with P. vivax, whereas nested-PCR results showed that 86.8% (n=66), 3.9% (n=3), and 3.9% (n=3) of tested samples had P. vivax as well as Plasmodium falciparum mono- and mixed infections, respectively. Four out of 76 samples had no results in molecular diagnosis. All sequenced samples were found to be of VK210 (100%) genotype with six distinct amino acid haplotypes, and 210A (66.7%) was the most prevalent haplotype. The Sudanese isolates displayed variations in the peptide repeat motifs (PRMs) ranging from 17 to 19 with GDRADGQPA (PRM1), GDRAAGQPA (PRM2) and DDRAAGQPA (PRM3). Also, 54 polymorphic sites with 56 mutations were found in repeat and post-repeat regions of the pvcsp and the overall nucleotide diversity (pi) was 0.02149+/-0.00539. A negative value of dN-dS (-0.0344) was found that suggested a significant purifying selection of Sudanese pvcsp, (Z test, P<0.05). Regarding pvmsp-3alpha, three types were detected: types A (94.6%, 52/55), type C (3.6%, 2/55), and type B (1.8%, 1/55). No multiclonal infections were detected, and RFLP analysis identified 13 (Hha I, A1-A11, B1, and C1) and 16 (Alu I, A1-A14, B1, and C1) distinct allelic forms. In conclusion, genetic investigation among Sudanese P. vivax isolates indicated that this antigen showed limited antigenic diversity. PMID- 25721364 TI - Annotation and genetic diversity of the chicken collagenous lectins. AB - Collectins and ficolins are multimeric proteins present in various tissues and are actively involved in innate immune responses. In chickens, six different collagenous lectins have been characterized so far: mannose-binding lectin (MBL), surfactant protein A (SP-A), collectin 10 (COLEC10), collectin 11 (COLEC11), collectin 12 (COLEC12), lung lectin (LL) and one ficolin (FCN). However, the structural and functional features of the chicken collectins and ficolin are still not fully understood. Therefore, the aims of this study were: (i) to make an overview of the genetic structure and function of chicken collectins and the ficolin, (ii) to investigate the variation in the chicken collectins and the ficolin gene in different chicken populations, and (iii) to assess the presence of MBL gene variants in different chicken populations. We performed comparative genomic analysis using publically available data. The obtained results showed that collectins and ficolins have conserved protein sequences and gene structure across all vertebrate groups and this is especially notable for COLEC10, COLEC11 and COLEC12. For the purpose of studying the genetic variation, 179 animals from 14 populations were genotyped using 31 SNPs covering five genomic regions. The obtained results revealed low level of heterozygosity in the collagenous lectins except for the COLEC12 gene and the LL-SPA-MBL region compared to heterozygosity at neutral microsatellite markers. In addition, the MBL gene variants were assessed in different chicken populations based on the polymorphisms in the promoter region. We observed 10 previously identified MBL variants with A2/A8 and A4 as the most frequent alleles. PMID- 25721365 TI - Report of the 2014 joint workshop of the international research coordination network for biodiversity of ciliates and the british society for protist biology. PMID- 25721367 TI - To grow or defend? Pine seedlings grow less but induce more defences when a key resource is limited. PMID- 25721366 TI - Identification of estrone-degrading Betaproteobacteria in activated sludge by microautoradiography fluorescent in situ hybridization. AB - Natural oestrogens, which are degraded but not completely removed in wastewater treatment plants, are suspected of causing the endocrine disruption of aquatic organisms in the receiving water body. While several bacterial isolates were reported to be oestrogen-degrading bacteria, our previous study implied that only the unidentified rod-shaped Betaproteobacteria in chains were responsible for estrone (E1) degradation by activated sludge especially at the sub-milligram per litre level. The Betaproteobacteria were suspected to be related to genera Sphaerotilus and Leptothrix according to morphological observations. Probe Spha823 was newly developed to target 16S rRNA gene clones obtained from activated sludge and closely related to the above genera. [(3) H]E1-incubated sludge samples showed that most of the (3) H-labelled cells hybridized with probe Spha823 by microautoradiography (MAR) fluorescent in situ hybridization. Spha823 defined cells were present in all three activated sludge samples tested, where they accounted for up to 3% of the total microbial biomass. Spha823-defined cells comprised 59.5-80.1% of the total MAR-positive cells, which suggested that the Sphaerotilus-Leptothrix-related bacteria were the most abundant micro-organisms involved in E1 degradation (at 200 MUg l(-1) ) in the activated sludge samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Estrone (E1) is one of the natural estrogens, which can be degraded but is not always completely removed in wastewater treatment plants. E1 is suspected of causing the endocrine disruption of aquatic organisms in the receiving water body. We identified dominant E1 incorporating bacteria, which should include E1-degrading bacteria, in activated sludge treating domestic wastewater. Sphaerotilus-Leptothrix-related bacteria, which had never been reported in the previous attempts based on culture-dependent approach, occupied 60-80% of the E1-incorporating bacteria. This study demonstrates the identification of functionally active bacteria to degrade micro pollutants at sub-milligram per litre level. PMID- 25721368 TI - Invasive insect effects on nitrogen cycling and host physiology are not tightly linked. AB - Invasive insects may dramatically alter resource cycling and productivity in forest ecosystems. Yet, although responses of individual trees should both reflect and affect ecosystem-scale responses, relationships between physiological and ecosystem-scale responses to invasive insects have not been extensively studied. To address this issue, we examined changes in soil nitrogen (N) cycling, N uptake and allocation, and needle biochemistry and physiology in eastern hemlock (Tsuga canadensis (L) Carr) saplings, associated with infestation by the hemlock woolly adelgid (HWA) (Adelges tsugae Annand), an invasive insect causing widespread decline of eastern hemlock in the eastern USA. Compared with uninfested saplings, infested saplings had soils that exhibited faster nitrification rates, and more needle (15)N uptake, N and total protein concentrations. However, these variables did not clearly covary. Further, within infested saplings, needle N concentration did not vary with HWA density. Light saturated net photosynthetic rates (Asat) declined by 42% as HWA density increased from 0 to 3 adelgids per needle, but did not vary with needle N concentration. Rather, Asat varied with stomatal conductance, which was highest at the lowest HWA density and accounted for 79% of the variation in Asat. Photosynthetic light response did not differ among HWA densities. Our results suggest that the effects of HWA infestation on soil N pools and fluxes, (15)N uptake, needle N and protein concentrations, and needle physiology may not be tightly coupled under at least some conditions. This pattern may reflect direct effects of the HWA on N uptake by host trees, as well as effects of other scale dependent factors, such as tree hydrology, affected by HWA activity. PMID- 25721369 TI - The influence of masting phenomenon on growth-climate relationships in trees: explaining the influence of previous summers' climate on ring width. AB - Tree growth is frequently linked to weather conditions prior to the growing season but our understanding of these lagged climate signatures is still poorly developed. We investigated the influence of masting behaviour on the relationship between growth and climate in European Beech (Fagus sylvatica L.) using a rare long-term dataset of seed production and a new regional tree ring chronology. Fagus sylvatica is a masting species with synchronous variations in seed production which are strongly linked to the temperature in the previous two summers. We noted that the weather conditions associated with years of heavy seed production (mast years) were the same as commonly reported correlations between growth and climate for this species. We tested the hypothesis that a trade-off between growth and reproduction in mast years could be responsible for the observed lagged correlations between growth and previous summers' temperatures. We developed statistical models of growth based on monthly climate variables, and show that summer drought (negative correlation), temperature of the previous summer (negative) and temperature of the summer 2 years previous (positive) are significant predictors of growth. Replacing previous summers' temperature in the model with annual seed production resulted in a model with the same predictive power, explaining the same variance in growth. Masting is a common behaviour in many tree species and these findings therefore have important implications for the interpretation of general climate-growth relationships. Lagged correlations can be the result of processes occurring in the year of growth (that are determined by conditions in previous years), obviating or reducing the need for 'carry-over' processes such as carbohydrate depletion to be invoked to explain this climate signature in tree rings. Masting occurs in many tree species and these findings therefore have important implications for the interpretation of general climate-growth relationships. PMID- 25721370 TI - Greater efficiency of water use in poplar clones having a delayed response of mesophyll conductance to drought. AB - Improvement of water use efficiency is a key objective to improve the sustainability of cultivated plants, especially fast growing species with high water consumption like poplar. It is well known that water use efficiency (WUE) varies considerably among poplar genotypes, and it was recently suggested that the use of the mesophyll-to-stomatal conductance ratio (gm/gs) would be an appropriate trait to improve WUE. The responses of 7-week-old cuttings of four hybrid poplar clones and one native Balsam poplar (Populus balsamifera L.) to a water stress-recovery cycle were examined to evaluate the relation between the gm/gs ratio and transpiration efficiency (TE), a leaf-level component of WUE. A contrasting gs response to water stress was observed among the five clones, from stomatal closure early on during soil drying up to limited closure in Balsam poplar. However in the hybrids, the decline in gm was consistently delayed by a few days compared with gs. Moreover, in the most water use-efficient hybrids, the recovery following rehydration occurred faster for gm than for gs. Thus, the delay in the response of gm to drought and its faster recovery upon rewatering increased the gm/gs of the hybrids and this ratio scaled positively with TE. Our results support the use of the gm/gs ratio to select genotypes with improved WUE, and the notion that breeding strategies focusing mainly on stomatal responses to soil drying should also look for a strong curvilinearity between net carbon assimilation rate and gs, the indication of a significant increase in gm/gs in the earlier stages of stomatal closure. PMID- 25721371 TI - Mast cells for cell-mediated therapy. PMID- 25721372 TI - Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation. AB - There is a range of methotrexate dosing regimens for psoriasis. This review summarizes the evidence for test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and use of folic acid. A literature search for randomized controlled trials and guidelines was performed. Twenty-three randomized controlled trials (29 treatment groups) and 10 guidelines were included. Two treatment groups used a test-dose, 5 guidelines recommend it. The methotrexate start-dose in randomized controlled trials varied from 5 to 25 mg/week, most commonly being either 7.5 mg or 15 mg. Guidelines vary from 5 to 15 mg/week. Methotrexate was administered as a single dose or in a Weinstein schedule in 15 and 11 treatment-groups, respectively; both recommended equally in guidelines. A fixed dose (n = 18), predefined dose (n = 3), or dose adjusted on clinical improvement (n = 8) was used, the last also being recommended in guidelines. Ten treatment groups used folic acid; in 2 it was allowed, in 14 not mentioned, and in 3 no folic acid was used. Most guidelines recommend the use of folic acid. Authors' suggestions for methotrexate dosing are given. PMID- 25721373 TI - Traumatic head injuries in patients with maxillofacial fractures: a retrospective case-control study. AB - OBJECTIVES: To analyse and evaluate the correlation between traumatic head injuries (THIs) and maxillofacial fractures (MF). Age, gender and trauma mechanism correlated with THI were also investigated. PATIENTS AND METHODS: We conducted a hospital-based retrospective case-control study at Stomatology College and Hospital, Wuhan University. From January 2000 to December 2009, a total of 1131 patients with MF were enrolled in the statistical study to evaluate the association of THI and other risk factors with MF. Among these patients, 86 presented with THI. We utilized binary logistic regression and risk analysis to investigate the associations among MF and other risk factors with HI. RESULTS: Head injuries (103 injuries) were sustained by 86 patients (7.6%), with male-to female ratio of 4.1:1.0. Most of the patients (52 patients, 50.5%) also exhibited cranial bone fractures. The age group with most patients was the 30-39 years age group (26 patients, 30.2%), followed by the 19-29 years age group (22 patients, 25.6%). Motor vehicle accident (MVA) was the most common mechanism of injury (49 patients, 74.1%). Patients older than 50 years showed the highest risk for head injury (OR, 2.0; 95% confidence interval, 1.1-3.7; P = 0.025). MVA had a sixfold risk of head injury (OR, 6.2; 95% confidence interval, 1.5-26.1; P = 0.013). Head injuries were more prone to occur in patients who had combined fracture of the mid-face and mandible (OR = 4.6, P < 0.001), and only a 0.3-fold risk of multimandible fractures (P < 0.001), 0.5-fold risk of single mandibular fracture (P = 0.017) and 0.3-fold risk of patients who sustained only single mandibular condylar fracture (P = 0.019). CONCLUSIONS: The occurrence of head injuries is significantly related to age, aetiology and the pattern and position of maxillofacial fractures. PMID- 25721374 TI - Redox and anti-oxidant state within cattle oocytes following in vitro maturation with bone morphogenetic protein 15 and follicle stimulating hormone. AB - The developmental competence of cumulus oocyte complexes (COCs) can be increased during in vitro oocyte maturation with the addition of exogenous oocyte-secreted factors, such as bone morphogenetic protein 15 (BMP15), in combination with hormones. FSH and BMP15, for example, induce different metabolic profiles within COCs-namely, FSH increases glycolysis while BMP15 stimulates FAD and NAD(P)H accumulation within oocytes, without changing the redox ratio. The aim of this study was to investigate if this BMP15-induced NAD(P)H increase was due to de novo NADPH production. Cattle COCs were cultured with FSH and/or recombinant human BMP15, resulting in a significant decrease in glucose-6-phosphate dehydrogenase activity (P < 0.05). Inhibition of isocitrate dehydrogenase (IDH) during this process decreased NAD(P)H intensity threefold in BMP15-treated oocytes, suggesting that BMP15 stimulates IDH and NADPH production via the tricarboxylic acid cycle. As NADPH is a reducing agent, reduced glutathione (GSH), H2O2, and mitochondrial activity were also measured to assess the general redox status of the oocyte. FSH alone decreased GSH levels whereas the combination of BMP15 and FSH sustained higher levels. Expression of genes encoding glutathione-reducing enzymes were also lower in oocytes cultured in the presence of FSH alone. BMP15 supplementation further promoted mitochondrial localization patterns that are consistent with enhanced developmental competence. Metabolomics revealed significant consumption of glutamine and production of alanine by COCs matured with both FSH and BMP15 compared to the control (P < 0.05). Hence, BMP15 supplementation differentially modulates reductive metabolism and mitochondrial localization within the oocyte. In comparison, FSH-stimulation alone decreases the oocytes' ability to regulate cellular stress, and therefore utilizes other mechanisms to improve developmental competence. PMID- 25721375 TI - Theory of nodal s +/- -wave pairing symmetry in the Pu-based 115 superconductor family. AB - The spin-fluctuation mechanism of superconductivity usually results in the presence of gapless or nodal quasiparticle states in the excitation spectrum. Nodal quasiparticle states are well established in copper-oxide, and heavy fermion superconductors, but not in iron-based superconductors. Here, we study the pairing symmetry and mechanism of a new class of plutonium-based high-Tc superconductors and predict the presence of a nodal s(+/-) wave pairing symmetry in this family. Starting from a density-functional theory (DFT) based electronic structure calculation we predict several three-dimensional (3D) Fermi surfaces in this 115 superconductor family. We identify the dominant Fermi surface "hot spots" in the inter-band scattering channel, which are aligned along the wavevector Q = (pi, pi, pi), where degeneracy could induce sign-reversal of the pairing symmetry. Our calculation demonstrates that the s(+/-) wave pairing strength is stronger than the previously thought d-wave pairing; and more importantly, this pairing state allows for the existence of nodal quasiparticles. Finally, we predict the shape of the momentum- and energy-dependent magnetic resonance spectrum for the identification of this pairing symmetry. PMID- 25721376 TI - Burnout in early course psychosis caregivers: the role of illness beliefs and coping styles. AB - AIMS: In occupational settings, burnout is a common response to chronic exposure stressors and has been frequently documented in formal caregivers (i.e. paid psychiatric staff). However, the literature is limited on reports of burnout among informal caregivers and particularly within early psychosis groups. The current study sought to investigate reports of burnout in carers of young adults treated within a specialist early psychosis service and links with key appraisals reported about the illness and coping. METHODS: Seventy-two carers completed the Maslach Burnout Inventory along with self-report measures of coping styles and illness beliefs. RESULTS: Seventy-eight per cent of carers reported high burnout in at least one of the three key burnout markers (i.e. emotional exhaustion, depersonalization or low personal accomplishment). Seven per cent of carers met full criteria for high burnout across all the three domains. A carer's belief about the negative consequences of the illness for themselves was a significant predictor of emotional exhaustion and depersonalization. Low personal accomplishment was linked to a carer's less optimistic beliefs about the illness timeline and fewer reports of adaptive coping. CONCLUSIONS: The results provide preliminary support for the importance of asking carers in the early illness phase about their experiences of caregiving. Targeted assessment may serve as a helpful tool to identify and intervene with carers in need of additional support with stress management, use of adaptive coping strategies, and balanced recovery focused information about psychosis. PMID- 25721378 TI - Expression of aquaporin-1, aquaporin-3, and aquaporin-5 correlates with nodal metastasis in colon cancer. AB - OBJECTIVES: The clinical significance of aquaporin-1 (AQP1), aquaporin-3 (AQP3), and aquaporin-5 (AQP5) expression was analyzed in a large number of patients with colon cancer. METHODS: AQP1, AQP3, and AQP5 expression was investigated based on the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery. Scores were given to the staining intensity and percentage of positive cells, and the staining score was defined as the sum of these scores then used to categorize the AQP expression as negative, weakly AQP-positive, or strongly AQP-positive. RESULTS: A total of 298 (61.3%) patients were identified as strongly AQP1-positive (staining score >= 6), while 38 (7.8%) were strongly AQP3-positive and 145 (29.8%) were strongly AQP5 positive. The overexpression of AQP1, AQP3, and AQP5 was significantly correlated with lymph node metastasis in a multivariate logistic analysis (AQP1, p = 0.026; AQP3, p = 0.023; AQP5, p = 0.003). While the multivariate survival analysis, which included age, histology, TNM stage, and CEA level showed that the expression of AQP1, AQP3, and AQP5 had no effect on the overall survival and disease-free survival. CONCLUSIONS: The current study found a significant correlation between AQP1, AQP3, and AQP5 expression and lymph node metastasis in patients with surgically resected colon cancer. PMID- 25721379 TI - Hyperferritinemia and markers of inflammation and oxidative stress in the cord blood of HIV-exposed, uninfected (HEU) infants. AB - OBJECTIVES: The purpose of this study was to evaluate markers of iron status and inflammation/oxidative stress in maternal and cord blood (CB) of HIV-infected and HIV-uninfected women as potential mechanisms for poor outcomes among HIV-exposed, uninfected (HEU) infants. METHODS: Maternal venous blood and CB specimens were obtained from 87 pregnant women (45 HIV-infected and 42 HIV-uninfected) enrolled at Kalafong Hospital, Pretoria, South Africa. Iron status [serum iron, ferritin and transferrin concentrations, transferrin saturation, soluble transferrin receptor (sTfR) concentration and the sTfR/log ferritin (sTfR/F) index], antenatal exposure to inflammation (CB C-reactive protein and interleukin-6 concentrations and haptoglobin switch-on status) and oxidative stress [total radical trapping ability of CB plasma (TRAP) and chronic oxidative stress (soluble receptor of advanced glycation end-products (sRAGE) concentration] were assessed in laboratory studies. RESULTS: There were no differences between the HIV-infected and HIV-uninfected groups in maternal haematological and iron indices, except that HIV-infected mothers had decreased white blood cell counts (P = 0.048) and increased serum ferritin concentrations (P = 0.032). Ferritin levels were significantly higher in CB than in maternal blood (P < 0.001) in both groups and further elevated in the CB of HEU infants (P = 0.044). There was also an inverse relationship between CB sTfR/F index and sRAGE (r = -0.43; P = 0.003) in the HIV-infected but not in the HIV-uninfected group. CONCLUSIONS: Our study showed for the first time that ferritin was significantly elevated in CB of HEU infants. The inverse relationship between sTfR/F index and sRAGE in CB suggests that chronic oxidative stress or RAGE axis activation in HIV-infected mothers may play a role in modulating ferritin levels. PMID- 25721380 TI - Cost-effectiveness of routine varicella vaccination using the measles, mumps, rubella and varicella vaccine in France: an economic analysis based on a dynamic transmission model for varicella and herpes zoster. AB - PURPOSE: Each year in France, varicella and zoster affect large numbers of children and adults, resulting in medical visits, hospitalizations for varicella- and zoster-related complications, and societal costs. Disease prevention by varicella vaccination is feasible, wherein a plausible option involves replacing the combined measles, mumps, and rubella (MMR) vaccine with the combined MMR and varicella (MMRV) vaccine. This study aimed to: (1) assess the cost-effectiveness of adding routine varicella vaccination through MMRV, using different vaccination strategies in France; and (2) address key uncertainties, such as the economic consequences of breakthrough varicella cases, the waning of vaccine-conferred protection, vaccination coverage, and indirect costs. METHODS: Based on the outputs of a dynamic transmission model that used data on epidemiology and costs from France, a cost-effectiveness model was built. A conservative approach was taken regarding the impact of varicella vaccination on zoster incidence by assuming the validity of the hypothesis of an age-specific boosting of immunity against varicella. FINDINGS: The model determined that routine MMRV vaccination is expected to be a cost-effective option, considering a cost-effectiveness threshold of ?20,000 per quality-adjusted life-year saved; routine vaccination was cost-saving from the societal perspective. Results were driven by a large decrease in varicella incidence despite a temporary initial increase in the number of zoster cases due to the assumption of exogenous boosting. In the scenario analyses, despite moderate changes in assumptions about incidence and costs, varicella vaccination remained a cost-effective option for France. IMPLICATIONS: Routine vaccination with MMRV was associated with high gains in quality-adjusted life-years, substantial reduction in the occurrences of varicella- and zoster-related complications, and few deaths due to varicella. Routine MMRV vaccination is also expected to provide reductions in costs related to hospitalizations, medication use, and general-practitioner visits, as well as indirect costs, and it is expected to be a cost-effective intervention in France (GSK study identifier: HO-12-6924). PMID- 25721381 TI - Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B. AB - Immunogenic cell death (ICD) is a new concept appeared in recent years. Despite growing interests of research on ICD, the circumstances that trigger immune responses against dying tumor cells remain largely unknown. It was demonstrated that recombinant Clostridium difficile toxin B (rTcdB) can induce ICD in intoxicated cells, but its mechanism remains unclear. This work aims at exploring whether reactive oxygen species (ROS) involved in rTcdB induced ICD using the chemical agent N-acetyl cysteine (NAC), diphenylene iodonium (DPI) and Antimycin A (Anti.A). The results suggested that ROS involved in rTcdB induced apoptosis and autophagy. DPI and Anti.A successfully inhibited the antitumor immune effect induced by rTcdB. As ICD is determined by a variety of factors, rTcdB is a potential tool for further exploring the circumstances that trigger ICD, which may offer us a good choice for designing the new chemotherapeutic drugs with immunogenic properties. PMID- 25721382 TI - Multifunctional biocompatible and biodegradable folic acid conjugated poly(epsilon-caprolactone)-polypeptide copolymer vesicles with excellent antibacterial activities. AB - Cancer patients after chemotherapy may also suffer bacterial attack due to badly decreased immunity. Although with high bacterial efficacy, conventional antibiotics are prone to inducement of drug resistance and may be not suitable for some cancer patients. In contrast, antibacterial peptides are highly effective in inhibiting bacteria without inducing resistance in pathogens. Presented in this article is a novel kind of highly effective antibacterial peptide-based biocompatible and biodegradable block copolymer vesicle. The copolymer is poly(epsilon-caprolactone)-block-poly[phenylalanine-stat-lysine-stat (lysine-folic acid)] [PCL19-b-poly[Phe12-stat-Lys9-stat-(Lys-FA)6]], which can self-assemble into vesicles in aqueous solution. The biocompatible and biodegradable PCL forms the vesicle membrane, whereas the poly[Phe12-stat-Lys9 stat-(Lys-FA)6] block constitutes the vesicle coronas. Compared to the individual polymer chains, the vesicles showed enhanced antibacterial activities against both Gram-positive and Gram-negative bacteria (16 MUg mL(-1)) due to the locally concentrated antibacterial poly[Phe12-stat-Lys9-stat-(Lys-FA)6] coronas, which may avoid the inducement of antibiotic-resistant bacteria and side effects of multidrug interactions. Furthermore, folic acid is introduced into the vesicle coronas for potential further applications such as cancer-targeted drug delivery. Moreover, the amino groups can be further functionalized when necessary. This low cytotoxic, biocompatible, biodegradable, and antibacterial vesicle (without antibiotic resistance) may benefit patients after tumor surgery because it is highly anti-inflammatory, and it is possible to deliver the anticancer drug to tumor cells simultaneously. PMID- 25721383 TI - Impacts of the Three Gorges Dam on microbial structure and potential function. AB - The Three Gorges Dam has significantly altered ecological and environmental conditions within the reservoir region, but how these changes affect bacterioplankton structure and function is unknown. Here, three widely accepted metagenomic tools were employed to study the impact of damming on the bacterioplankton community in the Xiangxi River. Our results indicated that bacterioplankton communities were both taxonomically and functionally different between backwater and riverine sites, which represent communities with and without direct dam effects, respectively. There were many more nitrogen cycling Betaproteobacteria (e.g., Limnohabitans), and a higher abundance of functional genes and KEGG orthology (KO) groups involved in nitrogen cycling in the riverine sites, suggesting a higher level of bacterial activity involved in generating more nitrogenous nutrients for the growth of phytoplankton. Additionally, the KO categories involved in carbon and sulfur metabolism, as well as most of the detected functional genes also showed clear backwater and riverine patterns. As expected, these diversity patterns all significantly correlated with environmental characteristics, confirming that the bacterioplankton communities in the Xiangxi River were really affected by environmental changes from the Three Gorges Dam. This study provides a first comparative metagenomic insight for evaluating the impacts of the large dam on microbial function. PMID- 25721384 TI - Analysis of the complete genomic sequences of two virus subpopulations of the Australian infectious bronchitis virus vaccine VicS. AB - Although sequencing of the 3' end of the genome of Australian infectious bronchitis viruses (IBVs) has shown that their structural genes are distinct from those of IBVs found in other countries, their replicase genes have not been analysed. To examine this, the complete genomic sequences of the two subpopulations of the VicS vaccine, VicS-v and VicS-del, were determined. Compared with VicS-v, the more attenuated VicS-del strain had two non-synonymous changes in the non-structural protein 6 (nsp6), a transmembrane (TM) domain that may participate in autocatalytic release of the 3-chymotrypsin-like protease, a polymorphic difference at the end of the S2 gene, which coincided with the body transcription-regulating sequence (B-TRS) of mRNA 3 and a truncated open reading frame for a peptide encoded by gene 4 (4b). These genetic differences could be responsible for the differences between these variants in pathogenicity in vivo, and replication in vitro. Phylogenetic analysis of the whole genome showed that VicS-v and VicS-del did not cluster with strains from other countries, supporting the hypothesis that Australian IBV strains have been evolving independently for some time, and analyses of individual polymerase peptide and S glycoprotein genes suggested a distant common ancestor with no recent recombination. This study suggests the potential role of the TM domain in nsp6, the integrity of the S2 protein and the B-TRS 3, and the putative accessory protein 4b, as well as the 3' untranslated region, in the virulence and replication of IBV and has provided a better understanding of relationships between the Australian vaccine strain of IBV and those used elsewhere. PMID- 25721385 TI - Preceptors enrich practice, profession. PMID- 25721386 TI - Let's Move! Celebrates 5 Years. PMID- 25721387 TI - Global food practices, cultural competency, and dietetics. PMID- 25721388 TI - Ethical decisions for withholding/withdrawing medically assisted nutrition and hydration. PMID- 25721389 TI - Position of the academy of nutrition and dietetics: promoting and supporting breastfeeding. AB - It is the position of the Academy of Nutrition and Dietetics that exclusive breastfeeding provides optimal nutrition and health protection for the first 6 months of life, and that breastfeeding with complementary foods from 6 months until at least 12 months of age is the ideal feeding pattern for infants. Breastfeeding is an important public health strategy for improving infant and child morbidity and mortality, improving maternal morbidity, and helping to control health care costs. Research continues to support the positive effects of human milk on infant and maternal health, as it is a living biological fluid with many qualities not replicable by human milk substitutes. Recent research advancements include a greater understanding of the human gut microbiome, the protective effect of human milk for premature infants and those born to women experiencing gestational diabetes mellitus, the relationship of breastfeeding with human immunodeficiency virus, and the increased ability to characterize cellular components of human milk. Registered dietitian nutritionists and nutrition and dietetics technicians, registered, should continue efforts to shift the norm of infant feeding away from use of human milk substitutes and toward human milk feeds. The role of registered dietitian nutritionists and nutrition and dietetics technicians, registered, in breastfeeding promotion and support, in the context of the professional code of ethics and the World Health Organization's International Code of Marketing of Breast-Milk Substitutes, are discussed in the "Practice Paper of the Academy of Nutrition and Dietetics: Promoting and Supporting Breastfeeding," published on the Academy website at: www.eatright.org/positions. PMID- 25721390 TI - Academy of Nutrition and Dietetics: revised 2015 standards of practice and standards of professional performance for registered dietitian nutritionists (competent, proficient, and expert) in pediatric nutrition. AB - All of the health care professions recognize that care of infants and children is best managed as a specialty area of practice. Nutrition plays a key role in normal growth and development. Appropriate nutrition care is vital adjuvant therapy for infants and children with acute or chronic illness. Provision of nutrition services in pediatric practice requires that registered dietitian nutritionists (RDNs) have advanced knowledge in the focus area of pediatric nutrition. Therefore, the Pediatric Nutrition Dietetic Practice Group, with guidance from the Academy of Nutrition and Dietetics Quality Management Committee, has developed this revision of the Standards of Practice and Standards of Professional Performance for RDNs in Pediatric Nutrition as a resource for RDNs working in pediatric nutrition to assess skill level and to identify needs for professional development to advance practice in pediatric nutrition. This revision reflects recent advances in pediatric nutrition and replaces the previous Standards published in 2009. The Standards of Practice represent the four steps of the Nutrition Care Process as applied to the care of patients/clients. The Standards of Professional Performance represent six domains of professionalism: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. The Standards of Practice and Standards of Professional Performance are complementary resources for RDNs working in pediatric nutrition and dietetics practice. PMID- 25721391 TI - Dietitian, dietician, or nutritionist? PMID- 25721392 TI - The first wave of B lymphopoiesis develops independently of stem cells in the murine embryo. AB - In the developing mouse embryo, there are several waves of hematopoiesis. Primitive and definitive erythromyeloid lineages appear prior to hematopoietic stem cell (HSC) emergence, and these waves are considered to be transient and support embryonic homeostasis until HSC-derived hematopoiesis is established. However, recent evidence strongly suggests that HSC-independent immune cells, such as tissue macrophages and some innate lymphoid cells, develop in the mouse embryo and persist into postnatal life. Innate type B-1 cells have also been reported to emerge from hemogenic endothelial cells in the extraembryonic yolk sac and para-aortic splanchnopleura, and continue to develop in the fetal liver, even in HSC-deficient mouse embryos. Here, this review discusses B-1 cell development in the context of the layered immune system hypothesis of B lymphopoiesis and the emergence of B-1 cells independent of HSCs. PMID- 25721393 TI - Individual differences in learning talker categories: the role of working memory. AB - The current study explores the question of how an auditory category is learned by having school-age listeners learn to categorize speech not in terms of linguistic categories, but instead in terms of talker categories (i.e., who is talking). Findings from visual-category learning indicate that working memory skills affect learning, but the literature is equivocal: sometimes better working memory is advantageous, and sometimes not. The current study examined the role of different components of working memory to test which component skills benefit, and which hinder, learning talker categories. Results revealed that the short-term storage component positively predicted learning, but that the Central Executive and Episodic Buffer negatively predicted learning. As with visual categories, better working memory is not always an advantage. PMID- 25721394 TI - Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1. AB - Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) known to modulate dopaminergic system through several mechanisms. Mice lacking this receptor show a higher sensitivity to dopaminergic stimuli, such as amphetamine; however, it is not clear whether D1 or D2 dopamine receptors and which associated intracellular signaling events are involved in this modulation. In the striatum of TAAR1 knock out (TAAR1-KO mice) we found that D2, but not D1, dopamine receptors were over-expressed, both in terms of mRNA and protein levels. Moreover, the D2 dopamine receptor-related G protein-independent AKT/GSK3 signaling pathway was selectively activated, as indicated by the decrease of phosphorylation of AKT and GSK3beta. The decrease in phospho-AKT levels, suggesting an increase in D2 dopamine receptor activity in basal conditions, was associated with an increase of AKT/PP2A complex, as revealed by co immunoprecipitation experiments. Finally, we found that the locomotor activation induced by the D2 dopamine receptor agonist quinpirole, but not by the full D1 dopamine receptor agonist SKF-82958, was increased in TAAR1-KO mice. These data demonstrate pronounced supersensitivity of postsynaptic D2 dopamine receptors in the striatum of TAAR1-KO mice and indicate that a close interaction of TAAR1 and D2 dopamine receptors at the level of postsynaptic structures has important functional consequences. PMID- 25721395 TI - Peripheral MU-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals. AB - While MU-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+) activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective MU-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects. PMID- 25721397 TI - Factors influencing survival after pancreatoduodenectomy for ductal adenocarcinoma depend on patients' age. AB - BACKGROUND: It is supposed that a prolonged lifetime will be associated with increased incidence of PDAC among the elderly. Some studies show a tendency toward decreased survival in the elderly patients following pancreatoduodenectomy for PDAC. The aim of this study was to evaluate factors, influencing survival following pancreatoduodenectomy for PDAC in different age groups. METHODS: Data of 251 patients after pancreatoduodenectomy for PDAC between 1999 and 2012 were analyzed. The Kaplan-Meier method and log-rank test were used to calculate survival and to compare differences between groups. The Cox proportional hazard model was applied to indentify independent prognosticators. RESULTS: The overall median survival was 14.9 months. Postoperative morbidity was 25.5% with a 5.1% mortality rate. No significant differences in the overall morbidity (22.4 vs. 29.6%) or mortality (2.8 vs. 8.3%) rates were observed between different patients' age groups (<70 years and >70 years). Multivariate analysis revealed R1 resection (HR 1.76) and poor tumor differentiation (G3-G4) (HR 1.48) were independent negative factors for survival in patients <70 years. Lymph-node metastases (N1) - HR 4.89 and perineural invasion - HR 2.73 were independent prognosticators in the elderly. CONCLUSIONS: Our study highlighted different factors influencing long-term survival after pancreatoduodenectomy: R1 resection and poor tumor differentiation (G3-G4) were independent negative factors for survival in patients <70 years, while perineural invasion and lymph-node metastases result in worse survival among the elderly. PMID- 25721398 TI - Targeting carbonic anhydrase IX with small organic ligands. AB - Carbonic anhydrase IX (CAIX) is expressed in many solid tumors in response to hypoxia and plays an important role in tumor acid-base homeostasis under these conditions. It is also constitutively expressed in the majority of renal cell carcinoma. Its functional inhibition with small molecules has recently been shown to retard tumor growth in murine models of cancer, reduce metastasis and tumor stem cell expansion. Additionally, CAIX is a promising antigen for targeted drug delivery approaches. Initially validated with anti-CAIX antibodies, the tumor homing capacity of high-affinity small-molecule ligands of CAIX has recently been demonstrated. Indeed, conjugates formed of CAIX ligands and potent cytotoxic drugs could eradicate CAIX-expressing solid tumors in mice. These results suggest that CAIX is a promising target for the development of novel therapies for the treatment of solid tumors. PMID- 25721396 TI - Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity. AB - The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC and hippocampus. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2B containing receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders such as autism. PMID- 25721399 TI - Manchester authority is set to take control of L6bn worth of health and social care spending. PMID- 25721400 TI - Chronic activation of mTOR complex 1 by branched chain amino acids and organ hypertrophy. AB - The mitochondrial branched chain aminotransferase-deficient mouse model (BCATm KO), which exhibits elevated plasma and tissue branched chain amino acids (BCAAs), was used to study the effect of BCAAs on mammalian target of rapamycin complex 1 (mTORC1) regulation of organ size. BCATm is the first enzyme in the BCAA catabolic pathway. BCATm KO mouse exhibited hypertrophy of heart, kidneys, and spleen. On the other hand, the mass of the gastrocnemius was reduced relative to body mass. Feeding the mice with a diet supplemented with rapamycin prevented the enlargement of the heart and spleen, suggesting that mTORC1 is the mediator of these effects. Consistently, enlargement of these organs was accompanied by the activation of mTORC1 complex as evidenced by enhanced levels of S6 and 4E-BP1 phosphorylation. HSP20, HSP27 and GAPDH were also increased in the heart but not gastrocnemius, consistent with mTORC1 activation. Liver, however, displayed no weight difference between the KO and the wild-type mice despite the highest activation level of mTORC1 complex. These observations suggest that the anabolic effect of mTORC1 activation at the organ level by BCAAs and inhibition by rapamycin are complex phenomenon and tissue-specific. In addition, it suggests that rapamycin can be used to counter hypertrophy of the organs when activation of mTORC1 is the underlying cause. PMID- 25721402 TI - A robust type I interferon gene signature from blood RNA defines quantitative but not qualitative differences between three major IFNbeta drugs in the treatment of multiple sclerosis. AB - We analysed gene expression microarray data from whole blood samples from 228 multiple sclerosis (MS) patients either untreated or treated with one of three alternative commonly used interferon beta (IFNbeta) disease modifying drugs: Avonex (*1 weekly), Betaseron (every second day) or Rebif (*3 weekly). Patient injections were not timed to coordinate sample collections, thus providing a global transcriptomic profile for each population of patients studied. Three hundred and fifty one genes were significantly differentially expressed by at least one of the IFNbeta drugs. Despite the different drug sources with distinct injection and dosage protocols, a striking similarity was found in the identity and functional classes of the differentially expressed genes induced. Using the 25 most-upregulated genes, we defined a robust IFNbeta gene expression signature that quantifies the IFN activation state per blood sample collected irrespective of the type of IFNbeta therapy. This 25-gene signature also defined basal IFN activation states among untreated MS patients, which differed among individuals but remained relatively constant per patient with time. The maximum drug-induced IFN-activation state was similar for all three drugs despite a 1.7-2.0-fold diminished average effect for Avonex. This and a more erratic effect of Avonex per patient across longitudinal measurements is likely a result of its reduced injection frequency. In summary, we have defined a robust blood-derived type I IFN gene signature from MS patients. This signature could potentially serve to generically quantify the systemic Type I IFN activation status for any other clinical manifestation, inclusive of other autoimmune diseases. PMID- 25721401 TI - Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. AB - Acyl-CoA dehydrogenase 9 (ACAD9) is an assembly factor for mitochondrial respiratory chain Complex I (CI), and ACAD9 mutations are recognized as a frequent cause of CI deficiency. ACAD9 also retains enzyme ACAD activity for long chain fatty acids in vitro, but the biological relevance of this function remains controversial partly because of the tissue specificity of ACAD9 expression: high in liver and neurons and minimal in skin fibroblasts. In this study, we hypothesized that this enzymatic ACAD activity is required for full fatty acid oxidation capacity in cells expressing high levels of ACAD9 and that loss of this function is important in determining phenotype in ACAD9-deficient patients. First, we confirmed that HEK293 cells express ACAD9 abundantly. Then, we showed that ACAD9 knockout in HEK293 cells affected long-chain fatty acid oxidation along with Cl, both of which were rescued by wild type ACAD9. Further, we evaluated whether the loss of ACAD9 enzymatic fatty acid oxidation affects clinical severity in patients with ACAD9 mutations. The effects on ACAD activity of 16 ACAD9 mutations identified in 24 patients were evaluated using a prokaryotic expression system. We showed that there was a significant inverse correlation between residual enzyme ACAD activity and phenotypic severity of ACAD9-deficient patients. These results provide evidence that in cells where it is strongly expressed, ACAD9 plays a physiological role in fatty acid oxidation, which contributes to the severity of the phenotype in ACAD9-deficient patients. Accordingly, treatment of ACAD9 patients should aim at counteracting both CI and fatty acid oxidation dysfunctions. PMID- 25721403 TI - Role of contextual factors in the rehabilitation of adolescent survivors of traumatic brain injury: emerging concepts identified through modified narrative review. AB - BACKGROUND: Recently research in traumatic brain injury (TBI) intervention has identified the benefits of contextualized, embedded, functionally based approaches to maximize treatment outcomes. An essential component of contextualized intervention is the direct and purposeful consideration of the broader context, in which the person with TBI functions. However, systematic consideration of contextual factors remains limited both in research and clinical practice. AIMS: The purposes of this modified narrative review were (1) to provide a succinct review of the available literature regarding the contextual factors that are specific to adolescent survivors of TBI, one of highest incidence groups for brain injury; (2) to connect these contextual factors to the direct long-term management of TBI and to identify their potential impact on outcome; and (3) to highlight areas that are open to research and clinical advances that could enhance positive outcomes for adolescent survivors of TBI. The framework of the World Health Organization's (WHO) International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY; 2007) was used as a foundation for this review. METHODS & PROCEDURES: A systematic literature search was conducted using databases and hand searches. A total of 102 articles were originally identified. Twenty-five original research articles, eight review papers and four expert opinion papers met inclusion and exclusion criteria and were included in the final review. MAIN CONTRIBUTION: The body of research specifically focused on contextual factors is an emerging area. Early findings indicate that a focus on the direct modification of contextual factors is promising for the facilitation of positive outcomes long into the chronic phase of management for adolescences who have survived a TBI. The contextual factors included in this review were the overall ability of the school to support a student post-TBI, family psychosocial risk (sibling/sibling relationships/stress/burden/support), coping style (TBI survivor and their caregivers), and socioeconomic status of the family. Given the promise of these findings, research and clinical application efforts should be focused on identifying well-prescribed rehabilitation paradigms that capitalize on the modification of contextual factors throughout the recovery process. CONCLUSIONS & IMPLICATIONS: The results of this modified narrative review provide an initial summary of the available evidence for addressing contextual factors in the rehabilitation process for adolescents with TBI. This is an area that is wide open for both systematic research and clinical application and holds potential to improve long-term outcome for survivors of adolescent TBI. PMID- 25721404 TI - Carrots and sticks: achieving high healthcare personnel influenza vaccination rates without a mandate. AB - OBJECTIVE: Achieving high healthcare personnel (HCP) influenza vaccination rates has typically required mandating vaccination, which is often challenging to implement. Our objective was to achieve >90% employee influenza vaccination without a mandate. DESIGN: Prospective quality improvement initiative SETTING AND PARTICIPANTS: All employees of a 2-hospital, 1,100-bed, community-based academic healthcare system. METHODS: The multimodal HCP vaccination campaign consisted of a mandatory declination policy, mask-wearing for non-vaccinated HCP, highly visible "I'm vaccinated" hanging badges, improved vaccination tracking, weekly compliance reports to managers and vice presidents, disciplinary measures for noncompliant HCP, vaccination stations at facility entrances, and inclusion of a target employee vaccination rate (>75%) metric in the annual employee bonus program. The campaign was implemented in the 2011-2012 influenza season and continued throughout the 2012-2013 through 2014-2015 influenza seasons. Employee compliance, vaccination, exemption and declination rates were calculated and compared with those of the seasons prior to the intervention. RESULTS: Compared with vaccination rates of 57%-72% in the 3 years preceding the intervention, employee influenza vaccination increased to 92% in year 1 and 93% in years 2-4 (P<.001). The proportion of employees declaring medical/religious exemptions or declining vaccination decreased during the 4 years of the program (respectively, 1.2% to 0.5%, P<.001; 4.4% to 3.8%, P=.001). CONCLUSIONS: An integrated multimodal approach incorporating peer pressure, accountability, and financial incentives was associated with increased employee vaccination rate from <=72% to >=92%, which has been sustained for 4 influenza seasons. Such programs may provide a model for behavioral change within healthcare organizations. PMID- 25721405 TI - The lived experiences of individuals with Tourette syndrome or tic disorders: a meta-synthesis of qualitative studies. AB - There is a growing body of qualitative literature describing the lived experiences of people with tic disorders (TDs). The aim of this paper was to conduct a systematic review of this literature, synthesizing the perspectives of individuals on their experiences. Meta-synthesis methodology was utilized to review and draw together findings from 10 articles, from which key concepts were extracted, and over-arching themes generated. Six themes were identified to encompass the experience of TDs, including (1) cultural, semantic issues of the condition; (2) negative experiences in organizations and treatment; (3) the value and negative impact on interpersonal relationships; (4) personal identity in the constant presence of TDs; (5) concerns for the future; and (6) strategies to control and manage the observable presence of tics. Adaptive coping strategies were found to encompass continuous social adaptation, strategies to manage tics and social perceptions, self-acceptance, advocacy, and support from others. The results highlighted the significant role of social and cultural issues related to understanding and stigma, which underpinned many of the lived experiences. Implications for clinical practice in supporting individuals with TDs were also highlighted. PMID- 25721406 TI - The ratio and topology effects of benzodithiophene donor-benzooxadiazole acceptor fragments on the optoelectronic properties of donor molecules toward solar cell materials. AB - A series of conjugated donor molecules (DmAnSq where m = 1-4, n = 1-7 while D = benzodithiophene, A = benzooxadiazole and S denotes ethyne spacers between D and A or D and D fragments) with various ratios of D/A fragments and topologies have been designed and investigated for OPV applications. An increase in the ratio of the acceptor fragment with respect to the donor fragment decreases the LUMO energy level and narrows the Eg for the designed molecule. More vertically (C4 and C8 substituted phenyl ring positions) bonded acceptor fragments than linearly (C2 and C6 substituted thiophene ring positions) bonded fragments result in a significant red shift in the maximum absorption wavelength. While, linearly bonded fragments lead to stronger absorption bands. Molecules with D-A-D topology exhibit more significant optical and electronic characteristics than those with D D topology. All donor molecules (m = 2-4) of the D-A-D type show lower lambdah values than those of 1 donor containing (DAn) molecules. D-D type molecules show only lower lambdae values than DAn molecules because of the presence of a second donor fragment. The charge transfer phenomenon is shape dependent. The branched or anisotropic X, H, pi, n, and square shaped molecules display higher charge transfer rates than the corresponding linear isomers due to better dimensionality. On the basis of these results, we suggest that designed donor and corresponding matched acceptor molecules have potential to act as promising candidates in solar cell devices. PMID- 25721407 TI - Dual-protection of a graphene-sulfur composite by a compact graphene skin and an atomic layer deposited oxide coating for a lithium-sulfur battery. AB - A reduced graphene oxide (rGO)-sulfur composite aerogel with a compact self assembled rGO skin was further modified by an atomic layer deposition (ALD) of ZnO or MgO layer, and used as a free-standing electrode material of a lithium sulfur (Li-S) battery. The rGO skin and ALD-oxide coating worked as natural and artificial barriers to constrain the polysulfides within the cathode region. As a result, the Li-S battery based on this electrode material exhibited superior cycling stability, good rate capability and high coulombic efficiency. Furthermore, ALD-ZnO coating was tested for performance improvement and found to be more effective than ALD-MgO coating. The ZnO modified G-S electrode with 55 wt% sulfur loading delivered a maximum discharge capacity of 998 mA h g(-1) at a current density of 0.2 C. A high capacity of 846 mA h g(-1) was achieved after charging/discharging for 100 cycles with a coulombic efficiency of over 92%. In the case of using LiNO3 as a shuttle inhibitor, this electrode showed an initial discharge capacity of 796 mA h g(-1) and a capacity retention of 81% after 250 cycles at a current density of 1 C with an average coulombic efficiency higher than 99.7%. PMID- 25721408 TI - Pinning synchronization of fractional-order complex networks with Lipschitz-type nonlinear dynamics. AB - This paper deals with pinning synchronization problem of fractional-order complex networks with Lipschitz-type nonlinear nodes and directed communication topology. We first reformulate the problem as a global asymptotic stability problem by describing network evolution in terms of error dynamics. Then, a novel frequency domain approach is developed by using Laplace transform, algebraic graph theory and generalized Gronwall inequality. We show that pinning synchronization can be ensured if the extended network topology contains a spanning tree and the coupling strength is large enough. Furthermore, we provide an easily testable criterion for global pinning synchronization depending on fractional-order, network topology, oscillator dynamics and state feedback. Numerical simulations are provided to illustrate the effectiveness of the theoretical analysis. PMID- 25721409 TI - A novel label-free upconversion fluorescence resonance energy transfer-nanosensor for ultrasensitive detection of protamine and heparin. AB - A novel label-free fluorescence nanosensor was developed for ultrasensitive detection of protamine and heparin based on fluorescence resonance energy transfer (FRET) between NaYF4:Yb,Er upconversion nanoparticles (UCNPs) and gold nanoparticles (AuNPs). The FRET system was formed by the electrostatic adsorption of AuNPs on UCNPs, and the fluorescence of UCNPs was significantly quenched. When protamine was added to the mixture of UCNPs-AuNPs, the AuNPs interacted with protamine and then desorbed from the surface of UCNPs and aggregated, resulting in the recovery of the fluorescence of UCNPs. On the addition of both protamine and heparin, the FRET system formed owing to the stronger interaction between heparin and protamine than that with AuNPs, leading to a marked fluorescence quenching of UCNPs. The concentrations of protamine and heparin were proportional to the changes of the fluorescence of UCNPs. The linear response range was obtained over the concentration ranges of 0.02 to 1.2MUg/ml and 0.002 to 2.0MUg/ml with low detection limits of 6.7 and 0.7ng/ml for protamine and heparin, respectively. Simultaneous measurement of protamine and heparin in human serum can be achieved, suggesting that the nanosensor can be used in a complex biological sample matrix. PMID- 25721410 TI - A robust social and professional connection between master educator and Doctor of Nursing Practice (DNP) student instructor: Virtual mentoring and preceptorship via distance education. PMID- 25721411 TI - Specific features of electronic structures and optical susceptibilities of g-BC3 and t-BC3 phases. AB - Details of comparison for some specific features of electronic structures and optical susceptibilities of g-BC3 and t-BC3 phases are provided. Calculations show that the g-BC3 phase is a narrow band gap semiconductor constructed from the ABAB stacking sequence. Whereas t-BC3 is a metallic phase constructed by a sandwich-like metal-insulator lattice from an alternately stacking sequence of metallic CBC and insulating CCC blocks. The two phases possess only two types of bonds (B-C and C-C). The density of states at the Fermi level N(EF) of the t-BC3 phase is determined by the overlapping of B-2p and C-2p empty orbitals of the CBC block with C-2p empty orbitals of the CCC block, and the shape of the Fermi surface originated from these empty orbitals. The B atoms cause a small perturbation on the C-ring's structure and hence to the charge density distribution. The linear optical properties of the two phases confirm the existence of the lossless regions and the considerable anisotropy. The second harmonic generation of the t-BC3 phase shows that chi(omega) is the dominant component of about 3.9 pm V(-1) at the static limit and 5.8 pm V(-1) at lambda = 1064 nm, which suggests that the t-BC3 phase could be considered as a promising nonlinear optical material in comparison with the well known KTiOPO4 nonlinear optical single crystal. PMID- 25721412 TI - Treatment issues in multiple sclerosis in Latin America. PMID- 25721413 TI - Interpersonal Sensitivity and Sexual Functioning in Young Men with Testicular Cancer: the Moderating Role of Coping. AB - BACKGROUND: Interpersonal sensitivity is characterized by the predisposition to perceive and elicit criticism, rejection, and negative social evaluation. It may be linked to poorer physical or functional health outcomes, particularly in the interpersonal context (cancer-related sexual dysfunction). PURPOSE: This study tested the association of interpersonal sensitivity with sexual functioning following testicular cancer in young men and whether this association is moderated by coping processes. METHOD: Men ages 18 to 29 (N = 171; M age = 25.2, SD = 3.32) with a history of testicular cancer were recruited via the California State Cancer Registry and completed questionnaire measures including assessments of interpersonal sensitivity, sexual functioning, and approach and avoidance coping. RESULTS: Regression analysis controlling for education, age, partner status, ethnic status, and time since diagnosis revealed that higher interpersonal sensitivity was significantly related to lower sexual functioning (beta = -0.18, p < 0.05). Cancer-related approach-oriented coping was associated with better sexual functioning (beta = 0.19, p < 0.05). No significant association was observed for avoidance coping (beta = -0.08, ns). Approach oriented coping, but not avoidance, moderated the relationship with sexual functioning (beta = 0.19, p < 0.05), such that higher interpersonal sensitivity was more strongly associated with lower functioning among men with relatively low use of approach coping. CONCLUSION: Interpersonal sensitivity may be an important individual difference in vulnerability to sexual dysfunction after testicular cancer. Enhancement of coping skills may be a useful direction for intervention development for interpersonally sensitive young men with cancer. PMID- 25721414 TI - Accuracy of MRI skeletal age estimation for subjects 12-19. Potential use for subjects of unknown age. AB - INTRODUCTION: In forensic practice, there is a growing need for accurate methods of age estimation, especially in the cases of young individuals of unknown age. Age can be estimated through somatic features that are universally considered associated with chronological age. Unfortunately, these features do not always coincide with the real chronological age: for these reasons that age determination is often very difficult. Our aim is to evaluate accuracy of skeletal age estimation using Tomei's MRI method in subjects between 12 and 19 years old for forensic purposes. MATERIAL AND METHODS: Two investigators analyzed MRI images of the left hand and wrist of 77 male and 74 female caucasian subjects, without chronic diseases or developmental disorders, whose age ranged from 12 to 19 years. Skeletal maturation was determined by two operators, who analyzed all MRI images separately, in blinded fashion to the chronological age. Inter-rater agreement was measured with Pearson (R (2)) coefficient. One of the examiners repeated the evaluation after 6 months, and intraobserver variation was analyzed. Bland-Altman plots were used to determine mean differences between skeletal and chronological age. RESULTS: Inter-rater agreement Pearson coefficient showed a good linear correlation, respectively, 0.98 and 0.97 in males and females. Bland-Altman analysis demonstrated that the differences between chronological and skeletal age are not significant. Spearman's correlation coefficient showed good correlation between skeletal and chronological age both in females (R (2) = 0.96) and in males (R (2) = 0.94). CONCLUSIONS: Our results show that MRI skeletal age is a reproducible method and has good correlation with chronological age. PMID- 25721415 TI - Hepatitis B prevalence and incidence in Greenland: a population-based cohort study. AB - Greenland remains a highly endemic area for hepatitis B virus (HBV) infection. This is in sharp contrast to other modern societies, such as Denmark. To address this discrepancy, we investigated the natural history of HBV infection in Greenland by estimating the age-specific incidence of HBV infection, the proportion of chronic carriers, and the rates of hepatitis B surface antigen seroclearance. In total, 8,879 Greenlanders (16% of the population) from population-based surveys conducted in 1987 and 1998 were followed through March 2010. Data on HBV status were supplemented by HBV test results from all available HBV registries in Greenland to determine changes in HBV status over time. Incidence rates of HBV infection and hepatitis B surface antigen seroclearance were estimated after taking into account interval censoring. The incidence of HBV infection in 5-14-year-old subjects was less than 1 per 100 person-years and peaked at 5 per 100 person-years in persons 15-24 years of age. Overall, 17.5% of persons infected in adulthood were estimated to become chronic carriers. HBV is primarily transmitted in adolescence and adulthood in Greenland. In contrast to what is observed in most other populations, HBV-infected adults in Greenland have a high risk of progressing to chronic HBV carriage. This phenomenon might explain how the high rate of infection is maintained in Greenland. PMID- 25721417 TI - Abnormal tibial position is correlated to early degenerative changes one year following ACL reconstruction. AB - Altered knee kinematics following ACL reconstruction may predispose patients to the development of early onset post-traumatic osteoarthritis. The goal of our study was to examine the longitudinal interrelationship between altered tibial position relative to the femur and cartilage health measured by quantitative T1rho MRI. Twenty-five patients with isolated unilateral ACL injury underwent kinematic and cartilage T1rho MRI at baseline prior to ACL reconstruction and then at 1-year post-reconstruction. Tibial position relative to the femur in the anterior-posterior plane was calculated as well as cartilage T1rho relaxation values in the injured and uninjured knee. At baseline prior to ACL reconstruction, the tibia was in a significantly more anterior position relative to the femur in the ACL deficient knee compared to the healthy contralateral knee. This difference was no longer present at 1-year follow-up. Additionally, the side-side difference in tibial position correlated to increased cartilage T1rho relaxation values in the medial compartment of the knee 1-year post reconstruction. Altered tibial position following ACL reconstruction is correlated with detectable cartilage degeneration as soon as 1 year following ACL reconstruction. PMID- 25721416 TI - Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome. AB - Mice with a null mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene show intestinal structure alterations and bacterial overgrowth. To determine whether these changes are model-dependent and whether the intestinal microbiome is altered in cystic fibrosis (CF) mouse models, we characterized the ileal tissue and intestinal microbiome of mice with the clinically common DeltaF508 Cftr mutation (FVB/N Cftr(tm1Eur)) and with Cftr null mutations (BALB/c Cftr(tm1UNC) and C57BL/6 Cftr(tm1UNC)). Intestinal disease in 12-week-old CF mice, relative to wild-type strain controls, was measured histologically. The microbiome was characterized by pyrosequencing of the V4-V6 region of the 16S rRNA gene and intestinal load was measured by RT-PCR of the 16S rRNA gene. The CF-associated increases in ileal crypt to villus axis distention, goblet cell hyperplasia, and muscularis externa thickness were more severe in the BALB/c and C57BL/6 Cftr(tm1UNC) mice than in the FVB/N Cftr(tm1Eur) mice. Intestinal bacterial load was significantly increased in all CF models, compared to levels in controls, and positively correlated with circular muscle thickness in CF, but not wild-type, mice. Microbiome profiling identified Bifidobacterium and groups of Lactobacillus to be of altered abundance in the CF mice but overall bacterial frequencies were not common to the three CF strains and were not correlative of major histological changes. In conclusion, intestinal structure alterations, bacterial overgrowth, and dysbiosis were each more severe in BALB/c and C57BL/6 Cftr(tm1UNC) mice than in the FVB/N Cftr(tm1Eur) mice. The intestinal microbiome differed among the three CF mouse models. PMID- 25721418 TI - Checkpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements. AB - Replication fork inactivation can be overcome by homologous recombination, but this can cause gross chromosomal rearrangements that subsequently missegregate at mitosis, driving further chromosome instability. It is unclear when the chromosome rearrangements are generated and whether individual replication problems or the resulting recombination intermediates delay the cell cycle. Here we have investigated checkpoint activation during HR-dependent replication restart using a site-specific replication fork-arrest system. Analysis during a single cell cycle shows that HR-dependent replication intermediates arise in S phase, shortly after replication arrest, and are resolved into acentric and dicentric chromosomes in G2. Despite this, cells progress into mitosis without delay. Neither the DNA damage nor the intra-S phase checkpoints are activated in the first cell cycle, demonstrating that these checkpoints are blind to replication and recombination intermediates as well as to rearranged chromosomes. The dicentrics form anaphase bridges that subsequently break, inducing checkpoint activation in the second cell cycle. PMID- 25721419 TI - beta-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells. AB - An F-box protein, beta-TrCP recognizes substrate proteins and destabilizes them through ubiquitin-dependent proteolysis. It regulates the stability of diverse proteins and functions as either a tumor suppressor or an oncogene. Although the regulation by beta-TrCP has been widely studied, the regulation of beta-TrCP itself is not well understood yet. In this study, we found that the level of beta TrCP1 is downregulated by various protein kinase inhibitors in triple-negative breast cancer (TNBC) cells. A PI3K/mTOR inhibitor PI-103 reduced the level of beta-TrCP1 in a wide range of TNBC cells in a proteasome-dependent manner. Concomitantly, the levels of c-Myc and cyclin E were also downregulated by PI 103. PI-103 reduced the phosphorylation of beta-TrCP1 prior to its degradation. In addition, knockdown of beta-TrCP1 inhibited the proliferation of TNBC cells. We further identified that pharmacological inhibition of mTORC2 was sufficient to reduce the beta-TrCP1 and c-Myc levels. These results suggest that mTORC2 regulates the stability of beta-TrCP1 in TNBC cells and targeting beta-TrCP1 is a potential approach to treat human TNBC. PMID- 25721420 TI - Conservation of the ethanol-induced locomotor stimulant response among arthropods. AB - Ethanol-induced locomotor stimulation has been variously described as reflective of the disinhibitory, euphoric, or reinforcing effects of ethanol and is commonly used as an index of acute ethanol sensitivity in rodents. The fruit fly Drosophila melanogaster also shows a locomotor stimulant response to ethanol that is believed to occur via conserved, ethanol-sensitive neurobiological mechanisms, but it is currently unknown whether this response is conserved among arthropod species or is idiosyncratic to D. melanogaster. The current experiments surveyed locomotor responses to ethanol in a phylogenetically diverse panel of insects and other arthropod species. A clear ethanol-induced locomotor stimulant response was seen in 9 of 13 Drosophilidae species tested, in 8 of 10 other species of insects, and in an arachnid (wolf spider) and a myriapod (millipede) species. Given the diverse phylogenies of the species that showed the response, these experiments support the hypothesis that locomotor stimulation is a conserved behavioral response to ethanol among arthropod species. Further comparative studies are needed to determine whether the specific neurobiological mechanisms known to underlie the stimulant response in D. melanogaster are conserved among arthropod and vertebrate species. PMID- 25721421 TI - Comparison of a pectinolytic extract of Kluyveromyces marxianus and a commercial enzyme preparation in the production of Ives (Vitis labrusca) grape juice. AB - This study analyses the effect of the crude enzymatic extract produced by Kluyveromyces marxianus (EEB) in the maceration and clarification of juice produced from Ives (Vitis labrusca) grapes compared to the commercial enzyme preparation Pectinex((r))Ultra Color (PEC). Treatments were conducted with a total pectinolytic activity of 1 U/mL of fruit juice, at 40 degrees C, for 60 min. After the enzymatic treatment, the juices were evaluated with respect to yield, viscosity, and degree of clarification, as well as the effect of the enzymes on polyphenol concentration, anthocyanins, and juice color. The results showed that both EEB and PEC increase yield, reduce viscosity and contribute to the clarification of grape juice. After enzyme treatment with the EEB preparation, the extraction yield increased 28.02 % and decreased 50.70 % in viscosity during the maceration of the pulp. During the juice production process clarification increased 11.91 %. With PEC, higher values for these parameters: 42.36, 63.20, and 26.81 % respectively, were achieved. The addition of EEB resulted in grape juice with better color intensity and extraction of phenolic compounds and anthocyanins. Considering all comparison criteria, the enzymatic extract of K. marxianus NRRL-Y-7571 can potentially be used in the production of juice. PMID- 25721422 TI - Five new secoiridoid glycosides and one unusual lactonic enol ketone with anti HBV activity from Swertia cincta. AB - Five new secoiridoid glycosides, swericinctosides A and B (1-2), 9-epi swertiamarin (3), 2'-O-m-hydroxybenzoyl swertiamarin (4), 4"-O-acetyl swertianoside E (5), and one unusual lactonic enol ketone, 3-(hydroxymethyl ene) dihydro-2H-pyran-2, 4(3H)-dione (6), together with three known compounds, swertiaside (7), swertianoside C (8) and decentapicrin B (9) were isolated from Swertia cincta. The structures of the new compounds were determined by extensive spectroscopic analyses including 1D and 2D NMR, HRESIMS, UV, IR and [alpha]D spectra. Anti-HBV assay on HepG 2.2.15 cell line in vitro demonstrated that compounds 1-9 possessed inhibitory activity on HBV DNA replication with IC50 values from 0.05 to 1.83mM, and compounds 1, 3, 5, 7 and 8 could inhibit the secretion of HBsAg with IC50 values from 0.24 to 1.06mM. PMID- 25721423 TI - Anti-cancer agents derived from solid-state fermented Antrodia camphorata mycelium. AB - Three new ubiquinone derivatives, antrocamol LT1, antrocamol LT2, and antrocamol LT3, along with two known compounds, were isolated from Antrodia camphorata (Polyporaceae) mycelium. The structures of these compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analyses. These ubiquinones exhibited selective cytotoxicities against five human cancer cell lines (CT26, A549, HepG2, PC3 and DU-145) with IC50 values ranging from 0.01 to 1.79MUMU. PMID- 25721424 TI - Value of the Gastroesophageal Reflux Disease Questionnaire (GerdQ) in predicting the proton pump inhibitor response in coronary artery disease patients with gastroesophageal reflux-related chest pain. AB - Chest pain experienced by patients with coronary artery disease can be partly due to gastroesophageal reflux-induced chest pain (GERP). Empirical proton pump inhibitor (PPI) therapy has been recommended as an initial clinical approach for treating GERP. However, PPI use may lead to some health problems. The Gastroesophageal Reflux Disease Questionnaire (GerdQ) may represent a noninvasive and cost-effective approach for avoiding PPI misuse and for identifying the appropriate patients for the PPI trial test. The aim of this pilot study was to prospectively evaluate the association between GerdQ scores and PPI response in patients with coronary artery disease (CAD) and GERP to determine whether the GerdQ predicts the PPI response in patients with CAD and GERP and to further validate the clinical application value of the GerdQ. A total of 154 consecutive patients with potential GERP were recruited to complete a GerdQ with subsequent PPI therapy. Based on the PPI trial result, patients were divided into a PPI positive response group and a PPI-negative response group. The difference in the GerdQ scores between the two groups was assessed. The receiver operating characteristic (ROC) curve of GerdQ score was drawn according to the PPI response as the gold standard. The ability of GerdQ to predict the PPI response was assessed. A total of 96 patients completed the entire study; 62 patients (64.6%) were assigned to the PPI-positive response group, and 34 patients (35.4%) to the PPI-negative response group. The GerdQ score of the PPI-positive response group (8.11 +/- 3.315) was significantly higher than that of the PPI-negative response group (4.41 +/- 2.743), and the difference was statistically significant (t = 5.863, P = 0.000). The ROC curve was drawn according to a PPI response assessment result with a score above 2 as the gold standard. The area under curve was 0.806. When the critical value of GerdQ score was 7.5, Youden index was up to 0.514, the diagnostic sensitivity was 0.661, and the diagnostic specificity was 0.853. A GerdQ score greater than 7.5 better predicts the response to the PPI trial therapy. There is a strong association between the GerdQ score and the response to PPI therapy. Higher GerdQ scores were predictive of a positive PPI response in CAD patients with GERP. The GerdQ may be a reasonable screening tool for GERP in patients with CAD who are prepared to accept PPI therapy. PMID- 25721425 TI - Pre-Operative Twin Anemia/Polycythemia in the Setting of Twin-Twin Transfusion Syndrome (TTTS). AB - INTRODUCTION: Twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS) are classified as distinct clinical disorders associated with unbalanced blood flow through placental vascular communications. Typically, TAPS placentas demonstrate few <1 mm arteriovenous (AV) communications, and at fetoscopy the twins are visibly pale and plethoric. MATERIALS AND METHODS: In a cohort of TTTS patients who underwent laser surgery, those with preoperative findings suggestive of anemia/polycythemia (AP) were compared to those with TTTS alone. AP was defined as middle cerebral artery peak systolic velocity in one twin >1.5 multiples of the median (MoM), and <1.0 MoM in the other. RESULTS: Of 369 TTTS patients, 9 (2.4%) met criteria for preoperative AP. The mean number (+/ SD) of AV communications in the TTTS + AP group was 5.6 +/- 5.7, compared with 8.8 +/- 4.8 in the TTTS-alone group (p = 0.013). Five TTTS + AP patients (56%) had a few thin AV communications (mean 2.8 +/- 1.6); all 5 had visibly pale and plethoric twins. The remaining 4 (44%) had large or numerous anastomoses (mean 10.5 +/- 6.8); none had fetal skin color discordance. DISCUSSION: Preoperative AP affected 2% of TTTS patients. Of these, approximately half had placental and skin color findings typically reported with isolated TAPS. PMID- 25721426 TI - Phase and amplitude correlations in resting-state activity in human stereotactical EEG recordings. AB - Inter-areal interactions of neuronal oscillations may be a key mechanism in the coordination of anatomically distributed neuronal processing. In humans, invasive stereo-electroencephalography (SEEG) is emerging as a reference method for electrophysiological recordings because of its excellent spatial and temporal resolution. It could thus be also considered an optimal method for mapping neuronal inter-areal interactions. However, the common bipolar (BP) referencing of SEEG data may both confuse signals from distinct sources and suppress true neuronal interactions whereas the alternative monopolar (MP) reference yields data contaminated by volume conduction. We advance here a novel referencing scheme for SEEG data where electrodes in grey matter are referenced to closest white-matter (CW) electrodes. Using a 22 subject cohort and these three referencing schemes, we observed that both inter-areal phase and amplitude correlations decayed as function of distance and frequency but remained significant and stable across distances up to 10cm. Furthermore, we found that deep and superficial cortical laminae exhibit distinct spectral profiles of oscillation power as well as distinct patterns of inter-areal phase and amplitude interactions. These effects were qualitatively similar in MP and CW but distorted with BP referencing. Importantly CW was not influenced by the apparent large scale volume conduction inherent to MP. We thus demonstrate here that with CW referencing, the superior anatomical accuracy of SEEG can be leveraged to yield accurate quantification and qualitatively novel insight into phase and amplitude interactions in human brain activity. PMID- 25721427 TI - Cortical excitability and the shape of the haemodynamic response. AB - Individual differences in the temporal dynamics of the haemodynamic response can reflect cortical excitation and can reveal underlying cortical physiology. Here, we show differences in the shape of the haemodynamic response that are dependent on stimulus parameters. Two sets of visual stimuli were used varying in parameters that are known to manipulate the haemodynamic response in the visual cortex. We measured the oxyhaemoglobin response using near infrared spectroscopy. The first set of stimuli comprised chromatic square-wave gratings that varied with respect to the separation in the CIE UCS chromaticities of the alternating bars. The gratings with large separations in chromaticity evoked an oxyhaemoglobin response with greater amplitude, consistent with greater activation of the visual cortex. The second set of stimuli comprised horizontal achromatic gratings that (1) were static, (2) drifted at a constant velocity towards fixation, or (3) reversed direction every half spatial cycle to create a vertical vibrating motion. Although the three types of grating had a similar effect on the amplitude of the oxyhaemoglobin response, the moving gratings (2 and 3) evoked a steeper decrease in oxyhaemoglobin concentration after stimulus offset. The steeper slope appears to reflect the post-stimulus undershoot and the slope may provide a correlate of cortical excitability when the amplitude of the haemodynamic response has saturated. PMID- 25721428 TI - Dynamic p53 protein expression and phosphorylation in the kidneys of rats that experienced intrauterine growth restriction. AB - AIM: This study investigated the mechanisms involved in intrauterine growth restriction (IUGR). METHODS: The IUGR model was established by feeding pregnant SD rats a low-protein diet. Protein expression and phosphorylation were detected using Western blot and/or immunohistochemistry. Cell apoptosis was detected by TUNEL staining. The MDM2 mRNA expression was measured by real-time PCR. RESULTS: Pups from the IUGR group had significantly lower body (7th day, 2 months) and kidney weights (1st day, 7th day, 2 months) compared to pups from the control group (p < 0.01). The glomeruli number in IUGR pups was significantly less than that in the control pups at 2 and 3 months after birth (p < 0.01). p53 protein level and p53 phosphorylation at Ser(15) were time-dependently decreased in the kidney at 1st day, 7th day, 21st day, 2 months and 3 months, but their levels in the kidney of the IUGR pups was significantly higher than that in control pups at each time point (p < 0.05, p < 0.01, or p < 0.001). Significantly more positive p21 staining was observed in IUGR pups than in control pups at each time point. Real-time PCR of MDM2 mRNA expression showed no significant difference between IUGR and control pups (p > 0.05). Significant apoptosis was observed in the kidneys of IUGR pups compared to control pups. CONCLUSION: Malnutrition-induced IUGR may be associated with the activation of p53-p21 signaling in the kidney. PMID- 25721429 TI - Tip variant of focal segmental glomerulosclerosis: is it truly a benign variant? AB - BACKGROUND: Even though frequently described as a benign entity, the outcomes of the tip variant of focal segmental glomerulosclerosis (FSGS) have proven to be unclear. METHODS: This retrospective study includes a cohort of tip variant cases who presented to us from 2009 to 2012 and the analysis of their presenting clinical, histopathological features and treatment outcomes in comparison to the not otherwise specified (NOS) variants from our center in East India. RESULTS: Of the 224 biopsies of primary FSGS, 30 cases were the tip variant (13.39%). The mean age of presentation was around 29 years, with 57% being males. A nephrotic presentation was seen in 87% of cases, with 20% showing a presentation at <18 years of age for the first time. Global sclerosis, interstitial fibrosis, tubular atrophy and arteriolar hyalinosis were seen more commonly in the NOS variant. Twenty five patients of tip variant received steroid therapy and eight received alternative immunosuppression. Around 87% of the tip variant cases achieved some form of remission in proteinuria and 13.3% had a doubling of creatinine at a median follow-up of 2 years in comparison to NOS group in which 80% achieved some form of remission and 20% had a doubling of creatinine. CONCLUSION: Though the histopathological features and treatment responsiveness of the tip variant appear to be better than the NOS variety, the prognostic outcome does not seem to be as favorable as implicated previously with an important percentage of patients showing progressive worsening of renal function within a relatively short time span (2 years) in our cohort. PMID- 25721430 TI - What hemodynamic (fNIRS), electrophysiological (EEG) and autonomic integrated measures can tell us about emotional processing. AB - Due to its fast temporal evolution and its representation and integration among complex and widespread neural networks, the emotion perception process should preferably be examined by means of multimethodological approach. Indeed the indubitable vantage of acquiring both the autonomic (arousal-related) and the central (cortical-related) activities stands in the possibility to better elucidate the reciprocal interplay of the two compartments. In the present study EEG (frequency band analysis), systemic SCR and heart rate (HR) were all recorded simultaneously with hemodynamic (NIRS, Near-Infrared Spectroscopy) measurements as potential biological markers of emotions, related to both central and peripheral systems. These multiple measures were then related to the self-report correlates, that is the subjective appraisal in term of valence (positive vs. negative) and arousal (high vs. low) by using SAM rating. Twenty subjects were submitted to emotional cues processing (IAPS) when fNIRS, frequency bands (alpha, beta, delta, theta), SCR and HR were recorded. As shown by O2Hb increasing within the right hemisphere, the contribution of prefrontal cortex was elucidated, by pointing out a relevant lateralization effect (more right-PFC activity) induced by the specific valence (negative) of the emotional patterns. Secondly, EEG activity (mainly low-frequency theta and delta bands) was intrinsically associated with the cortical hemodynamic responsiveness to the negative emotional patterns, within the right side. Finally SCR increased mainly in response to negative patterns, and the autonomic behavior was related to explicit (SAM) and cortical (NIRS; EEG) activity. The intrinsic relationships between these three different levels are discussed. PMID- 25721431 TI - Metabolic pathways visualization skills development by undergraduate students. AB - We have developed a metabolic pathways visualization skill test (MPVST) to gain greater insight into our students' abilities to comprehend the visual information presented in metabolic pathways diagrams. The test is able to discriminate students' visualization ability with respect to six specific visualization skills that we identified as key to the understanding of metabolic map diagrams. Application of the MPVST to B. S. Biochemistry students showed that their visualization skills develop informally and progressively during their college years. Furthermore, the complex nature of biochemical pathways, together with students' lack of familiarity with metabolic maps, suggests that it is important for instructors to spend more time than usual explaining visual representations to their students. PMID- 25721432 TI - Effects of Physical Exercise Interventions on Gait-Related Dual-Task Interference in Older Adults: A Systematic Review and Meta-Analysis. AB - Dual-task interference during walking can substantially limit mobility and increase the risk of falls among community-dwelling older adults. Previous systematic reviews examining intervention effects on dual-task gait and mobility have not assessed relative dual-task costs (DTC) or investigated whether there are differences in treatment-related changes based on the type of dual task or the type of control group. The purpose of this systematic review was to examine the effects of physical exercise interventions on dual-task performance during walking in older adults. A meta-analysis of randomized controlled trials (RCTs) compared treatment effects between physical exercise intervention and control groups on single- and dual-task gait speed and relative DTC on gait speed. A systematic search of the literature was conducted using the electronic databases PubMed, CINAHL, EMBASE, Web of Science, and PsycINFO searched up to September 19, 2014. Randomized, nonrandomized, and uncontrolled studies published in English and involving older adults were selected. Studies had to include a physical exercise intervention protocol and measure gait parameters during continuous, unobstructed walking in single- and dual-task conditions before and after the intervention. Of 614 abstracts, 21 studies met the inclusion criteria and were included in the systematic review. Fourteen RCTs were included in the meta analysis. The mean difference between the intervention and control groups significantly favored the intervention for single-task gait speed (mean difference: 0.06 m/s, 95% CI: 0.03, 0.10, p < 0.001), dual-task gait speed (mean difference: 0.11 m/s, 95% CI 0.07, 0.15, p < 0.001), and DTC on gait speed (mean difference: 5.23%, 95% CI 1.40, 9.05, p = 0.007). Evidence from subgroup comparisons showed no difference in treatment-related changes between cognitive motor and motor-motor dual tasks, or when interventions were compared to active or inactive controls. In summary, physical exercise interventions can improve dual-task walking in older adults primarily by increasing the speed at which individuals walk in dual-task conditions. Currently, evidence concerning whether physical exercise interventions reduce DTC or alter the self-selected dual-task strategy during unobstructed walking is greatly lacking, mainly due to the failure of studies to measure and report reciprocal dual-task effects on the non gait task. PMID- 25721434 TI - In memoriam Professor Heinrich Herzog. PMID- 25721433 TI - Daclatasvir: a review of its use in adult patients with chronic hepatitis C virus infection. AB - Daclatasvir (Daklinza(r)) is an inhibitor of hepatitis C virus (HCV) NS5A protein. It is a new, oral, direct-acting antiviral with potent pangenotypic activity. This article provides a narrative review of the efficacy and tolerability of daclatasvir in combination with other agents in the treatment of patients with chronic HCV infection and summarizes its pharmacological properties. Since daclatasvir has a different mechanism of action to other current direct-acting antivirals, it provides additive or synergistic antiviral activity when used in combination. It produces high sustained virological response rates when used in combination with peginterferon-alpha plus ribavirin in patients chronically infected with HCV genotypes 1-4, and provides even higher response rates when used in an interferon-free, all-oral combination with sofosbuvir, with or without ribavirin. Daclatasvir has a moderately high genetic barrier to resistance, is effective during short-term treatment over 12 weeks and has a tolerability profile similar to that of placebo. In conclusion, daclatasvir is a highly effective and well tolerated, oral, once-daily, direct-acting antiviral for use in combination therapy in adult patients chronically infected with HCV. PMID- 25721435 TI - Urolithiasis--an interdisciplinary diagnostic, therapeutic and secondary preventive challenge. AB - BACKGROUND: The prevalence of urolithiasis in Germany is 4.7%; its incidence has trebled in the last three decades. The risk of recurrence is 50-80%, depending on the type of stone, unless secondary prevention is instituted. Risk-adapted secondary prevention lowers this risk to 10-15%. METHODS: This review is based on publications retrieved by a selective search in PubMed using the key words "urolithiasis," "urinary stones," "epidemiology," "lithogenesis," "biominerals," "risk factors," and "diagnosis, therapy, metaphylaxis." These publications were evaluated with the aid of the urolithiasis guideline of the European Association of Urology. RESULTS: Acute renal colic can usually be diagnosed without sophisticated equipment. Stones can be dealt with by a variety of techniques depending on their size and location, including extracorporeal shock-wave lithotripsy, ureterorenoscopy, percutaneous nephrolitholapaxy, and open surgery. Most ureteric stones of diameter up to 5 mm pass spontaneously. 75% of patients have no complications. The basic evaluation needed for secondary prevention can be carried out by any physician on an ambulatory basis. In the 25% of patients who have complications, a more extensive interdisciplinary evaluation of metabolic parameters should be performed in a clinical center for urinary stones. CONCLUSION: Urolithiasis has many causes and can be treated in many different ways. An extensive metabolic work-up is often necessary for secondary prevention. The various treatment options must be considered for their suitability in each individual patient. Robust data are now available on surgical and interventional methods, but there are as yet no high-quality trials of secondary prevention. Further research should concentrate on the etiology and pathogenesis of urolithiasis. PMID- 25721437 TI - Comparative investigation on clinical outcomes of robot-assisted radical prostatectomy between experienced open prostatic surgeons and novice open surgeons in a laparoscopically naive center with a limited caseload. AB - OBJECTIVES: To compare perioperative, oncological and functional outcomes of robot-assisted radical prostatectomy between experienced and novice open radical prostatectomy surgeons in a laparoscopically naive center with a limited caseload. METHODS: Six surgeons carried out robot-assisted radical prostatectomy in 154 patients, which were divided into the following three groups: group 1 (n = 90), including patients operated on by a surgeon with experience in both open radical prostatectomy and robot-assisted radical prostatectomy; group 2 (n = 36), including patients operated on by two surgeons with experience in open radical prostatectomy only; and group 3 (n = 28), including patients operated on by three surgeons with limited experience in both open radical prostatectomy or robot assisted radical prostatectomy. RESULTS: Groups 2 and 3 did not differ significantly in their median values of external blood loss (P = 0.165) or console time (P = 0.103). Positive surgical margin rates for pT2 patients were also similar in these two groups: 21.2% (7/33) in group 2 and 22.7% (5/22) in group 3 (P = 0.894). Kaplan-Meier analysis showed that 12 months after robot assisted radical prostatectomy the prostate-specific antigen-free rate for pT2 patients was 96.0% in group 2 and 100% in group 3, but the pad-free continence rate was just 91.0% in group 1, 88.0% in group 2 and 75.5% in group 3 (group 1 vs group 3, P = 0.037; group 2 vs group 3, P = 0.239). The major complication rate after robot-assisted radical prostatectomy was 3.3% (3/90) in group 1, 11.1% (4/36) in group 2 and 17.9% (5/28) in group 3 (group 1 vs group 3, P = 0.008; group 2 vs group 3; P = 0.441). CONCLUSIONS: Robot-assisted radical prostatectomy offers satisfactory postoperative outcomes even when carried out by surgeons with limited experience in open radical prostatectomy. PMID- 25721436 TI - Uveitis in juvenile idiopathic arthritis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common systemic disease causing uveitis in childhood, with a prevalence of 10 per 100 000 persons. JIA often takes a severe inflammatory course, and its complications often endanger vision. METHODS: This review is based on pertinent articles retrieved by a selective literature search up to 18 August 2014 and on the current interdisciplinary S2k guideline on the diagnostic evaluation and anti inflammatory treatment of juvenile idiopathic uveitis. RESULTS: Uveitis arises in roughly 1 in 10 patients with JIA. Regular eye check-ups should be performed starting as soon as JIA is diagnosed. 75-80% of patients are girls; antinuclear antibodies are found in 70-90%. The risk to vision is higher if JIA begins in the preschool years. As for treatment, only a single, small-scale randomized controlled trial (RCT) and a small number of prospective trials have been published to date. Topical corticosteroids should be given as the initial treatment. Systemic immunosuppression is needed if irritation persists despite topical corticosteroids, if new complications arise, or if the topical steroids have to be given in excessively high doses or have unacceptable side effects. If the therapeutic effect remains inadequate, conventional and biological immune modulators can be given as add-on (escalation) therapy. Treatment lowers the risk of uveitis and its complications and thereby improves the prognosis for good visual function. CONCLUSION: Severely affected patients should be treated in competence centers to optimize their long-term outcome. Multidisciplinary, individualized treatment is needed because of the chronic course of active inflammation and the ensuing high risk of complications that can endanger vision. Future improvements in therapy will be aided by prospective, population-based registries and by basic research on biomarkers for the prediction of disease onset, prognosis, tissue damage, and therapeutic response. PMID- 25721438 TI - A lysinated thiophene-based semiconductor as a multifunctional neural bioorganic interface. AB - Lysinated molecular organic semiconductors are introduced as valuable multifunctional platforms for neural cells growth and interfacing. Cast films of quaterthiophene (T4) semiconductor covalently modified with lysine-end moieties (T4Lys) are fabricated and their stability, morphology, optical/electrical, and biocompatibility properties are characterized. T4Lys films exhibit fluorescence and electronic transport as generally observed for unsubstituted oligothiophenes combined to humidity-activated ionic conduction promoted by the charged lysine end moieties. The Lys insertion in T4 enables adhesion of primary culture of rat dorsal root ganglion (DRG), which is not achievable by plating cells on T4. Notably, on T4Lys, the number on adhering neurons/area is higher and displays a twofold longer neurite length than neurons plated on glass coated with poly-l lysine. Finally, by whole-cell patch-clamp, it is shown that the biofunctionality of neurons cultured on T4Lys is preserved. The present study introduces an innovative concept for organic material neural interface that combines optical and iono-electronic functionalities with improved biocompatibility and neuron affinity promoted by Lys linkage and the softness of organic semiconductors. Lysinated organic semiconductors could set the scene for the fabrication of simplified bioorganic devices geometry for cells bidirectional communication or optoelectronic control of neural cells biofunctionality. PMID- 25721439 TI - Reactions of State-Selected Atomic Oxygen Ions O(+)((4)S, (2)D, (2)P) with Methane. AB - An experimental study has been carried out on the reactions of state selected O(+)((4)S, (2)D, (2)P) ions with methane with the aims of characterizing the effects of both the parent ion internal energy and collision energy on the reaction dynamics and determining the fate of oxygen species in complex media, in particular the Titan ionosphere. Absolute cross sections and product velocity distributions have been determined for the reactions of (16)O(+) or (18)O(+) ions with CH4 or CD4 from thermal to 5 eV collision energies by using the guided ion beam (GIB) technique. Dissociative photoionization of O2 with vacuum ultraviolet (VUV) synchrotron radiation delivered by the DESIRS beamline at the SOLEIL storage ring and the threshold photoion photoelectron coincidence (TPEPICO) technique are used for the preparation of purely state-selected O(+)((4)S, (2)D, (2)P) ions. A complete inversion of the product branching ratio between CH4(+) and CH3(+) ions in favor of the latter is observed for excitation of O(+) ions from the (4)S ground state to either the (2)D or the (2)P metastable state. CH4(+) and CH3(+) ions, which are by far the major products for the reaction of ground state and excited states, are strongly backward scattered in the center of mass frame relative to O(+) parent ions. For the reaction of O(+)((4)S), CH3(+) production also rises with increasing collision energy but with much less efficiency than with O(+) excitation. We found that a mechanism of dissociative charge transfer, mediated by an initial charge transfer step, can account very well for all the observations, indicating that CH3(+) production is associated with the formation of H and O atoms (CH3(+) + H + O) rather than with OH formation by an hydride transfer process (CH3(+) + OH). Therefore, as the CH4(+) production by charge transfer is also associated with O atoms, the fate of oxygen species in these reactions is essentially the O production, except for the reaction of O(+)((4)S), which also produces appreciable amounts of H2O(+) ions but only at very low collision energy. The production of O atoms and the nature of the states in which they are formed are discussed for the reactions of O(+) ions with CH4 and N2. PMID- 25721440 TI - From pillar to post: homeless women's experiences of social care. AB - This paper reports findings from a longitudinal study of homeless women. Thirty eight women were recruited with a retention rate of 58% over three rounds of interviews. Interviews explored specific events in women's lives, their current living arrangements and how their experiences and needs, including for social care, changed over time. Data were analysed thematically using a priori codes. Women reported a range of complex issues, consistent with experiences of deep social exclusion and received support from both statutory and voluntary agencies. Although women appreciated the support they received, many reported that services were fragmented and rarely personalised to their needs. PMID- 25721441 TI - Si/Ag composite with bimodal micro-nano porous structure as a high-performance anode for Li-ion batteries. AB - A one-step dealloying method is employed to conveniently fabricate a bimodal porous (BP) Si/Ag composite in high throughput under mild conditions. Upon dealloying the carefully designed SiAgAl ternary alloy in HCl solution at room temperature, the obtained Si/Ag composite has a uniform bicontinuous porous structure in three dimensions with micro-nano bimodal pore size distribution. Compared with the traditional preparation methods for porous Si and Si-based composites, this dealloying route is easily operated and environmentally benign. More importantly, it is convenient to realize the controllable components and uniform distribution of Si and Ag in the product. Owing to the rich porosity of the unique BP structure and the incorporation of highly conductive Ag, the as made Si/Ag composite possesses the improved conductivity and alleviated volume changes of the Si network during repeated charging and discharging. As expected, the BP Si/Ag anode exhibits high capacity, excellent cycling reversibility, long cycling life and good rate capability for lithium storage. When the current rate is up to 1 A g(-1), BP Si/Ag can deliver a stable reversible capacity above 1000 mA h g(-1), and exhibits a capacity retention of up to 89.2% against the highest capacity after 200 cycles. With the advantages of unique performance and easy preparation, the BP Si/Ag composite holds great application potential as an advanced anode material for Li-ion batteries. PMID- 25721442 TI - Eruptive disseminated pyogenic granulomas following lightning injury. AB - BACKGROUND: Pyogenic granuloma (PG) is a common benign acquired vascular tumor. It classically presents as a solitary friable nodule on the face or distal extremities. Disseminated eruption is rare and can occur spontaneously or secondary to various triggers, including burn injury. To date, the literature reports only 13 cases of eruptive PGs following burn injury, most from exposure to boiling milk or water. We report the first case of disseminated eruptive PGs following a lightning injury. CASE: A 17-year-old previously healthy boy developed second- and third-degree burns following lightning injury. Two weeks later, he developed widespread dark-purple polypoid exophytic tumors ranging from 1 to 10 cm in diameter extending beyond the limits of the initial burn injury. The lesions were friable and often formed erosions and crusts. The patient was otherwise well and laboratory and microbiological investigations were normal. Excisional biopsy of a lesion was diagnostic of PG and the patient was treated with surgical excision of the lesions, without recurrence. CONCLUSION: The exact pathogenesis of multiple PGs remains unknown. Several pathogenic mechanisms have been suggested, including production of angiogenic factors that stimulate endothelial proliferation and formation of minute arteriovenous fistulas by trauma. PMID- 25721443 TI - Experiments: Why and How? AB - An experiment, in the standard scientific sense of the term, is a procedure in which some object of study is subjected to interventions (manipulations) that aim at obtaining a predictable outcome or at least predictable aspects of the outcome. The distinction between an experiment and a non-experimental observation is important since they are tailored to different epistemic needs. Experimentation has its origin in pre-scientific technological experiments that were undertaken in order to find the best technological means to achieve chosen ends. Important parts of the methodological arsenal of modern experimental science can be traced back to this pre-scientific, technological tradition. It is claimed that experimentation involves a unique combination of acting and observing, a combination whose unique epistemological properties have not yet been fully clarified. PMID- 25721444 TI - Scientists' Ethical Obligations and Social Responsibility for Nanotechnology Research. AB - Scientists' sense of social responsibility is particularly relevant for emerging technologies. Since a regulatory vacuum can sometimes occur in the early stages of these technologies, individual scientists' social responsibility might be one of the most significant checks on the risks and negative consequences of this scientific research. In this article, we analyze data from a 2011 mail survey of leading U.S. nanoscientists to explore their perceptions the regarding social and ethical responsibilities for their nanotechnology research. Our analyses show that leading U.S. nanoscientists express a moderate level of social responsibility about their research. Yet, they have a strong sense of ethical obligation to protect laboratory workers (in both universities and industry) from unhealthy exposure to nanomaterials. We also find that there are significant differences in scientists' sense of social and ethical responsibility depending on their demographic characteristics, job affiliation, attention to media content, risk perceptions and benefit perceptions. We conclude with some implications for future research. PMID- 25721446 TI - A case of esophageal "double jeopardy". PMID- 25721447 TI - Rare case of a giant cystic pararectal mass. PMID- 25721448 TI - Splenic lesions in a patient with Crohn's disease. PMID- 25721449 TI - A rare esophageal complication after autologous stem cell transplantation. PMID- 25721450 TI - Correlation among disorder, electronic and magnetic phases of SrRuO3. AB - Electric and magnetic properties of Sr1-xBaxRu1-xTixO3 (0 ? x ? 0.8) have been investigated to find the interrelationship between metallicity and ferromagnetism in SrRuO3 (SRO). The simultaneous doping of Sr and Ru with Ba and Ti results in single phase SRO at x = 0.1 and mixed phase of SRO and hexagonal BaTiO3 (h-BTO) at x ? 0.2. Co-doping at Sr and Ru sites gives rise to oxygen vacancy and mixed valency of Ru (Ru(3+) and Ru(4+)). Room temperature resistivity increases due to modification of p(O)-d(Ru) hybridization and phase segregation. Temperature dependent resistivity reveals metal-insulator transition around 232 K at x = 0.1 and insulator down to 2 K at x ? 0.2. The insulating state (x = 0.1) at low temperature is well described by weak localization and electron-electron interaction. Temperature dependence of resistivity (x ? 0.2) follows Mott's three dimensional variable range hopping model. Localization length and average hopping distance decrease with the increase of x, indicating the presence of more disorder. Ferromagnetic transition temperature decreases to 149 K at x = 0.1 and remains constant up to x = 0.5. The Curie-Wiess (CW) temperature (ThetaCW) decreases monotonically and becomes negative at x = 0.5. The effective magnetic moment estimated from CW law is smaller than that of pure SRO due to the formation of Ru(3+) ions. The saturation magnetization diminishes, suggesting the demagnetization factor owing to diamagnetic h-BTO. The coercivity increases from 6700 Oe (x = 0) to 12 500 Oe (x = 0.4) and then decreases to 3700 Oe (x = 0.5). Ferromagnetic cluster comprising of doped SRO gives rise to the formation of a Griffith-like phase. The co-occurrence of high jump in resistivity ratio and disappearance of ferromagnetism suggests an interplay between transport process and magnetism at low temperature. PMID- 25721445 TI - Phosphatidylinositol-3,4,5-triphosphate and cellular signaling: implications for obesity and diabetes. AB - Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) is one of the most important phosphoinositides and is capable of activating a wide range of proteins through its interaction with their specific binding domains. Localization and activation of these effector proteins regulate a number of cellular functions, including cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism. Phosphoinositides have been investigated as an important agonist-dependent second messenger in the regulation of diverse physiological events depending upon the phosphorylation status of their inositol group. Dysregulation in formation as well as metabolism of phosphoinositides is associated with various pathophysiological disorders such as inflammation, allergy, cardiovascular diseases, cancer, and metabolic diseases. Recent studies have demonstrated that the impaired metabolism of PtdIns(3,4,5)P3 is a prime mediator of insulin resistance associated with various metabolic diseases including obesity and diabetes. This review examines the current status of the role of PtdIns(3,4,5)P3 signaling in the regulation of various cellular functions and the implications of dysregulated PtdIns(3,4,5)P3 signaling in obesity, diabetes, and their associated complications. PMID- 25721451 TI - Phenotypic and genetic characterization of rhizobia isolated from Hedysarum flexuosum in Northwest region of Morocco. AB - Seventy bacterial strains were isolated from root nodules of the legume Hedysarum flexuosum grown wild in soils from Northwest Morocco. Repetitive extragenic palindromic (REP)-polymerase chain reaction (PCR) clustered the strains into 30 REP-PCR groups. The nearly complete sequence of the 16S rRNA gene from a representative strain of each REP-PCR pattern showed that 17 strains were closely related to members of the genus Rhizobium of the family Rhizobiaceae of the Alphaproteobacteria. Pairwise alignments between globally aligned sequences of the 16S rRNA gene indicated that the strains from H. flexuosum had 99.75-100% identity with Rhizobium sullae type strain IS123(T). The phenotypic characteristics analyzed allowed description of a wide physiological diversity among the isolates, where the carbohydrate assimilation test was the most discriminating. Analysis of the 16S rRNA gene of a representative strains from the remaining 13 REP-PCR groups showed they belong to a wide variety of phylogenetic groups being closely related to species of genera Stenotrophomonas, Serratia, Massilia, Acinetobacter, Achromobacter, and Pseudomonas from the Beta- and Gammaproteobacteria. The R. sullae strains identified in this study produced effective symbiosis with their original host plant. None of the other bacterial strains could form nodules on H. flexuosum. PMID- 25721452 TI - Force-Sensing Enhanced Simulation Environment (ForSense) for laparoscopic surgery training and assessment. AB - BACKGROUND: Excessive or inappropriate tissue interaction force during laparoscopic surgery is a recognized contributor to surgical error, especially for robotic surgery. Measurement of force at the tool-tissue interface is, therefore, a clinically relevant skill assessment variable that may improve effectiveness of surgical simulation. Popular box trainer simulators lack the necessary technology to measure force. The aim of this study was to develop a force sensing unit that may be integrated easily with existing box trainer simulators and to (1) validate multiple force variables as objective measurements of laparoscopic skill, and (2) determine concurrent validity of a revised scoring metric. METHODS: A base plate unit sensitized to a force transducer was retrofitted to a box trainer. Participants of 3 different levels of operative experience performed 5 repetitions of a peg transfer and suture task. Multiple outcome variables of force were assessed as well as a revised scoring metric that incorporated a penalty for force error. RESULTS: Mean, maximum, and overall magnitudes of force were significantly different among the 3 levels of experience, as well as force error. Experts were found to exert the least force and fastest task completion times, and vice versa for novices. Overall magnitude of force was the variable most correlated with experience level and task completion time. The revised scoring metric had similar predictive strength for experience level compared with the standard scoring metric. CONCLUSION: Current box trainer simulators can be adapted for enhanced objective measurements of skill involving force sensing. These outcomes are significantly influenced by level of expertise and are relevant to operative safety in laparoscopic surgery. Conventional proficiency standards that focus predominantly on task completion time may be integrated with force-based outcomes to be more accurately reflective of skill quality. PMID- 25721453 TI - Behavioral reactivity to acute stress among Black and White women with type 2 diabetes: The roles of income and racial discrimination. AB - This study investigated relationships of income and self-reported racial discrimination to diabetes health behaviors following an acute stressor. A total of 77 diabetic women (51% Black, 49% White) completed a laboratory public speaking stressor. That evening, participants reported same-day eating, alcohol consumption, and medication adherence; physical activity was measured with actigraphy, and the next morning participants reported sleep quality. Measures were repeated on a counterbalanced control day. There was no mean level difference in health behaviors between stressor and control days. On stressor day, lower income predicted lower physical activity, sleep quality, and medication adherence, and higher racial discrimination predicted more eating and alcohol consumed, even after accounting confounders including race and control day behaviors. PMID- 25721454 TI - A qualitative analysis of male couples' coping with HIV: Disentangling the "we". AB - Research suggests that optimal couple functioning depends on adopting a "we" orientation to health. Using qualitative data from 20 male couples in which at least one partner was HIV-positive, we examined how couples viewed their health involvement and its relation to social support. One group described their health as highly interconnected; in a second group, at least one partner viewed health as a personal responsibility. Results revealed that there was not a uniform "we" approach toward health; rather, sero-concordance, sero-discordance, and coping with other chronic illnesses strongly contributed to orientations toward health. Orientations toward health were not found to determine social support. PMID- 25721455 TI - Follow-up of psychological outcomes of interventions in patients diagnosed with disorders of sexual development: A systematic review. AB - The objective of this study was to perform a systematic review of articles that followed up the psychological outcomes of interventions in patients with disorders of sexual development. The analysis focused on the methodological quality of the studies and the assumptions on the evaluation of the intervention outcomes. The review signaled the need for better consideration about the complexity of intersexuality and for a shift from the anatomical/functional/aesthetic to the subjective outcomes related to patient's quality of life. Furthermore, it is suggested that the interventions should be better investigated, given the lack of evidence for the necessity of early procedures. PMID- 25721456 TI - The clinical efficacy of extracorporeal shock wave lithotripsy in pediatric urolithiasis: a systematic review and meta-analysis. AB - The aim was to investigate the clinical efficacy and safety of extracorporeal shock wave lithotripsy (ESWL) in pediatric urolithiasis. A comprehensive systematic review and meta-analysis were performed. PubMed, Embase, and the Cochrane central register of controlled trials (CENTRAL) were searched, and the stone-free rates (SFRs) of various stone sizes and stone positions were extracted from the eligible articles. The quality of the original articles was assessed according to the McHarm Scale. The risk ratios (RRs) and 95% confidential intervals (CIs) were pooled, and the sensitive analysis was performed to evaluate the heterogeneity among all eligible studies. In total, 14 studies with 1842 patients were identified. The pooled RR for the SFR of stones less than 10 mm and greater than 10 mm was 1.14 (95% CI: 1.07, 1.21, P < 0.001); the RR for the SFR of stones in the renal pole calix (PC) and the renal pelvis was 0.95 (95% CI: 0.893, 1.009, P < 0.01); the RR for the SFR of stones in the upper/middle PC and the lower PC was 1.07 (95% CI: 0.997, 1.156, P < 0.061); and the RR for the SFR of stones in the proximal ureter and middle/distal ureter was 1.077 (95% CI: 1.005, 1.154, P = 0.036). Heterogeneity was low in all the analyses. Major complications in ESWL of pediatric urolithiasis were steinstrasse and abdominal colic, the incidences of which were 6.00 and 6.29 %, respectively. The SFR of stones <10 mm was significantly higher than stones >10 mm, and the SFR of stones located in proximal ureter was statistically greater than stones in middle or distal ureter in pediatric urolithiasis, leaving no significant between stones in renal PC and renal pelvis, or between upper/middle PC and lower PC. The use of ESWL in children is highly efficient, with negligible complications; ESWL therapy could be considered the first-line treatment for pediatric urolithiasis. PMID- 25721457 TI - Peripheral circulation evaluation with near-infrared spectroscopy in skeletal muscle during cardiopulmonary bypass. AB - BACKGROUND: We designed a non-invasive, observational, real-time study, using near-infrared spectroscopy (NIRS) to assess the in vivo effects of cardiopulmonary bypass (CPB) on patients' skeletal muscle as well as the effects of hemodilution and hypothermia on tissue oxygen delivery during CPB. METHODS: The study included 20 consecutive adult patients undergoing open-heart surgery with CPB. Evaluation parameters for peripheral circulation were measured using the NIRO-200NX and recorded every 30 seconds. To assess how hemodilution influences peripheral circulation parameters, we compared data between a group of patients with hematocrit (Hct) values >22% (high Hct group) and those with Hct values ?22% (low Hct group). RESULTS: Changes in the concentration of oxygenated hemoglobin (DeltaO2Hb, MUmol/L), which flows into the skeletal muscle, was an important factor for deciding the tissue oxygenation index (TOI%), showing the tissue oxygen saturation. The low Hct group showed a significant increase in the normalized tissue hemoglobin index (nTHI), showing the percentage change in the amount of initial hemoglobin and TOI compared to the high Hct group. Changes in the concentration of oxygenated hemoglobin (DeltaO2Hb, MUmol/L) and deoxygenated hemoglobin (DeltaHHb, MUmol/L) were significantly less in the low Hct group than in the high Hct group, thus, showing good peripheral circulation despite the low hematocrit levels. CONCLUSION: Our study indicated the presence of a compensatory mechanism in which increased blood flow of the microcirculation is in compensation for the lack of oxyhemoglobin delivery caused by hemodilution. PMID- 25721458 TI - Antitumor effect of conditioned media derived from murine MSCs and 5 aminolevulinic acid (5-ALA) mediated photodynamic therapy in breast cancer in vitro. AB - BACKGROUND: Mesenchymal stem cells are multi-potent progenitor cells that inhibit tumor growth by some ligands and releasing factors including TRAIL, DKK-1 and DKK 3. On other hands, photodynamic therapy is commonly used for treatment of different types of cancer. The aims of this study are to investigate of MSCs conditioned media and ALA mediated photodynamic therapy in breast cancer. MATERIAL AND METHODS: Condition media was derived after documentation of mouse adipose derived MSCs. For photodynamic therapy (PDT), ALA was used at the final concentrations of 1mM for 4-h followed by exposure to red light with a peak wave length of 632-nm, delivered from diode laser located at 2 cm to achieve a total light dose of 5 Joules (J)/cm(2). Apoptosis and growth of 4T1 cancer cells were analyzed in different groups including MSCs derived condition media, PDT and MSCs derived condition media plus PDT by flow cytometry. Growth of cancer cells were assessed using MTT test. RESULTS: Our findings showed expression of TRAIL on mouse adipose-derived MSCs surfaces. Furthermore, treatment of 4T1 cancer cells with MSCs conditioned media cause to inhibit the cancer cells growth. Also, MSCs conditioned media with PDT have significantly synergic effects to induce apoptosis in breast cancer cells (P < 0.05). Growth of cancer cells remarkably decreased after treatment with MSCs conditioned media and PDT in time-dependent manner (P < 0.01). CONCLUSION: Results revealed that MSCs conditioned media induced the apoptosis in 4T1 breast cancer cells and apoptotic effects of MSCs conditioned media were intensified following photodynamic therapy. This study showed that MSCs conditioned media combined with PDT may be useful as a novel treatment modality into the development of therapeutic strategies for treatment of breast cancer. PMID- 25721459 TI - The Cobb Collection: current status and future research directions. PMID- 25721460 TI - Proceedings of the Human Biology Association 39th Annual Meeting, April 9-10, 2014, Hyatt Regency Calgary, Calgary, Canada. PMID- 25721464 TI - Evaluating an individualized lifestyle and life skills intervention to prevent antipsychotic-induced weight gain in first-episode psychosis. AB - AIM: Initiating antipsychotic medication frequently induces rapid, clinically significant weight gain. We aimed to evaluate the effectiveness of a lifestyle and life skills intervention, delivered within 4 weeks of antipsychotic medication initiation, in attenuating weight gain in youth aged 14-25 years with first-episode psychosis (FEP). METHODS: We undertook a prospective, controlled study in two early psychosis community services. Intervention participants (n = 16) received a 12-week individualized intervention delivered by specialist clinical staff (nurse, dietician and exercise physiologist) and youth peer wellness coaches, in addition to standard care. A comparison group was recruited from a similar service and received standard care (n = 12). RESULTS: The intervention group experienced significantly less weight gain at 12 weeks compared to standard care (1.8 kg, 95% CI -0.4 to 2.8 vs. 7.8 kg, 4.8-10.7, P < 0.001). Thirteen per cent (2/16) of the intervention group experienced clinically significant weight gain (greater than 7% of baseline weight), while 75% (9/12) of the standard care group experienced this level of weight gain. Similar positive effects of the intervention were observed for waist circumference. CONCLUSIONS: A lifestyle and life skills intervention delivered as part of standard care attenuated antipsychotic-induced weight gain in young people with FEP. The intervention was acceptable to the young people referred to the service. Such interventions may prevent the seeding of future disease risk and in the long-term help reduce the life expectancy gap for people living with serious mental illness. PMID- 25721465 TI - Comparative genome analysis reveals the molecular basis of nicotine degradation and survival capacities of Arthrobacter. AB - Arthrobacter is one of the most prevalent genera of nicotine-degrading bacteria; however, studies of nicotine degradation in Arthrobacter species remain at the plasmid level (plasmid pAO1). Here, we report the bioinformatic analysis of a nicotine-degrading Arthrobacter aurescens M2012083, and show that the moeB and mogA genes that are essential for nicotine degradation in Arthrobacter are absent from plasmid pAO1. Homologues of all the nicotine degradation-related genes of plasmid pAO1 were found to be located on a 68,622-bp DNA segment (nic segment-1) in the M2012083 genome, showing 98.1% nucleotide acid sequence identity to the 69,252-bp nic segment of plasmid pAO1. However, the rest sequence of plasmid pAO1 other than the nic segment shows no significant similarity to the genome sequence of strain M2012083. Taken together, our data suggest that the nicotine degradation-related genes of strain M2012083 are located on the chromosome or a plasmid other than pAO1. Based on the genomic sequence comparison of strain M2012083 and six other Arthrobacter strains, we have identified 17 sigma(70) transcription factors reported to be involved in stress responses and 109 genes involved in environmental adaptability of strain M2012083. These results reveal the molecular basis of nicotine degradation and survival capacities of Arthrobacter species. PMID- 25721466 TI - TceSR two-component regulatory system of Brucella melitensis 16M is involved in invasion, intracellular survival and regulated cytotoxicity for macrophages. AB - The mechanisms of invasion and intracellular survival of Brucella are still poorly understood. Previous studies showed that the two-component regulatory systems (TCSs) play an important role in the intracellular survival of Brucella. To investigate if TCSs involve in the virulence and cytotoxicity of Brucella melitensis, we introduced a mutation into one of the TCSs in chromosome II in Br. melitensis 16M strain, and generated 16MDeltaTceSR, a mutant of Br. melitensis 16M strain. In vitro infection experiments using murine macrophage cell line (RAW 264.7) showed that the survival of 16MDeltaTceSR mutant in macrophages decreased 0.91-log compared with that of wild type Br. melitensis 16M strain at 2 h postinfection, replication of 16MDeltaTceSR mutant in macrophages was 5.65-log, which was much lower than that wild type strain. Results of lactate dehydrogenase cytotoxicity assays in macrophages demonstrated high dose infection with wide type strain produced high level cytotoxicity to macrophages, but 16MDeltaTceSR mutant had very low level cytotoxicity, indicating mutation of TCSs impaired the cytotoxicity of Br. melitensis to macrophages. Animal experiments showed that the spleen colonization of 16MDeltaTceSR was significantly reduced compared with its wild type strains. The lower levels of survival of 16MDeltaTceSR in various stress conditions suggested that the mutation of the TCSs of Br. melitensis was the causative factor of its reduced resistance to stress conditions. Taken together, our results demonstrated TCS TceSR involves in the intracellular survival, virulence and cytotoxicity of Br. melitensis during its infection. Significance and impact of the study: Two-component systems (TCSs) are predominant bacterial signal transduction mechanisms. The pathogenicity of Brucella is due to its ability to adapt to the intracellular environment including low levels of acidic pH, high-salt and heat shock. TCSs are designed to sense diverse stimuli, transfer signals and enact an appropriate adaptive physiological response. Here, we show that Br. meilitensis TCS TceSR is not only involved in regulation of Br. meilitensis virulence and adaptation of environmental stresses, but also can regulate cytotoxicity in macrophages. PMID- 25721467 TI - Social anxiety disorder and agoraphobia in dermatology patients; two cases and a review of the literature. PMID- 25721468 TI - Development of an avidity assay for detection of recent HIV infections. AB - HIV avidity can measure the incidence of recent infections within the population. The aim of this study was to evaluate an HIV avidity assay, initially from a clinically defined group of patients and then apply the assay to a prospective study to determine the false recency rate and mean duration of recency for the assay. The assay is a commercial ELISA modified with 7 M urea. The validation of the assay used plasma from patients split into Group 1 (recently infected N=25) and group 2 (established infection N=301). The prospective study tested 178 newly diagnosed HIV patients for avidity. A total of 326 retrospective samples of known HIV status were collected and tested. The initial evaluation gave a sensitivity 100% (CI 86.16-100%) and specificity of 98.65% (95% CI 97.05-99.78%). The prospective study incorporating 178 newly diagnosed patients found 22 patients with low avidity. Follow-up samples obtained from low avidity patients determined the estimated mean duration of recency to be between 3 and 4 months with a false recency rate of 0.89% (CI: 0.24-2.3%). The assay described here compares well in sensitivity, specificity and false recency rate with that of other published avidity assays. PMID- 25721469 TI - Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex. AB - Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase-activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP-knockdown (KD) mouse model created by retroviral insertion of a LacZ-encoding gene-trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunohistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. Bromodeoxyuridine birth dating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II-IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP-KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition from multipolar to bipolar morphology in migrating postmitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of the cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP-KD brains. We found that Dab2IP-KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a subpopulation of later born (layers II-IV) neurons, likely through the regulation of Rap1 and integrin signaling. PMID- 25721470 TI - Effect of periodontal dressing on non-surgical periodontal treatment outcomes: a systematic review. AB - BACKGROUND: Periodontal dressing has been advocated and showed some positive outcomes for placing over the surgical site after periodontal surgery. However, little is known about its effect on non-surgical therapy. PURPOSE: The aim of this review was to assess the clinical effect of periodontal dressing when used after non-surgical therapy. MATERIAL AND METHODS: Two examiners performed an electronic search in several databases for relevant articles published in English up to November 2013. Selected studies were randomized human clinical trials (prospective or retrospective trials) with the clear aim of investigating the effect of periodontal dressing placement upon periodontal non-surgical mechanical therapy. Data were extracted from the included articles for analysis. RESULTS: Three randomized clinical trials fulfilled the inclusion criteria and thus were included in the data analysis. Statistical analysis could not be carried out due to the lack of clear data of the included studies. However, descriptive analysis showed its effectiveness in improving clinical parameters such as gain of clinical attachment level and reduction of probing pocket depth. CONCLUSION: Placement of periodontal dressing right after non-surgical mechanical therapy can be beneficial in improving overall short-term clinical outcomes, although more controlled studies are still needed to validate this finding. PMID- 25721471 TI - Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1 associated neurocognitive impairment during antiretroviral treatment switch. AB - OBJECTIVES: The aim of the study was to evaluate HIV-1 viral load (VL) and inflammatory markers in cerebrospinal fluid (CSF) and neurocognitive performance in patients with neurocognitive impairment (NCI) while they were receiving tenofovir (TDF)/ emtricitabine (FTC)/efavirenz (EFV) and after switching to a regimen with enhanced central nervous system (CNS) penetrability. METHODS: This was a prospective, single-arm pilot study. HIV-1-infected patients with plasma viral suppression and HIV-associated NCI on a regimen including TDF/FTC/EFV were switched to abacavir (ABC)/lamivudine (3TC)/maraviroc (MVC). The Global Deficit Score (GDS) was used to score cognitive function at baseline and 48 weeks after treatment switch. Both CSF and blood samples were taken at baseline and between weeks 24 and 36 after switching. HIV-1 RNA in plasma and CSF was determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Inflammatory biomarkers in CSF were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 71 patients receiving TDF/FTC/EFV were screened. Twelve of them (17%) had documented NCI, lacked the human leucocyte antigen (HLA) B*57:01 haplotype and harboured Chemokine Receptor Type-5 (CCR5)-tropic virus. Eight patients had detectable HIV-1 RNA (between 2.7 and 41.6 HIV-1 RNA copies/mL) in CSF at baseline. All participants had elevated levels of neopterin and Monocyte Chemoattractant Protein 1 (MCP-1) in CSF at baseline. Eight out of 12 patients completed their follow-up assessment after treatment switch. The GDS decreased from 0.55 to 0.4 (P = 0.085). Median HIV-1 RNA in CSF decreased from 3.49 to 2.20 (P = 0.23). Among the inflammation markers in CSF, tumour necrosis factor (TNF)-alpha decreased significantly from median 0.51 to 0.35 pg/mL (P = 0.027), showing a correlation with the changes in neopterin, interferon (IFN) gamma and interleukin (IL)-6. CONCLUSIONS: Most patients with NCI receiving TDF/FTC/EFV had low-level viraemia and/or increased inflammatory markers in CSF. Treatment switching to an MVC-containing regimen with better CNS penetration resulted in a trend towards improvement in neurocognitive status and reduced TNF alpha concentrations in CSF. PMID- 25721472 TI - Plasmid-borne cadmium resistant determinants are associated with the susceptibility of Listeria monocytogenes to bacteriophage. AB - Listeria monocytogenes is an intracellular pathogen causing gastroenteritis, central nervous system infections and abortions. Chromosomal virulence determinants have been extensively investigated. However, the function of genes encoded by plasmids in L. monocytogenes has not been fully understood. In this study, we determined the prevalence and molecular profile of plasmids in food isolates of L. monocytogenes and examined the contribution of four plasmid-borne cadmium-resistant genes to the susceptibility of L. monocytogenes to bacteriophage infection. The results showed that plasmids were isolated from 55% (11/20) of the isolates and the plasmids exhibited 10 molecular types as determined by restriction enzyme digestion. Furthermore, 65% and 15% of the isolates were tolerant to cadmium and benzalkonium chloride (BC), respectively. All the BC-resistant isolates were resistant to cadmium. The prevalence of predicted cadmium resistance determinants (cadA1, cadA2, cadA3 and cadC) was determined and the results showed that cadA1 (35%) in isolates of serotypes 1/2a and 1/2b was much more prevalent than cadC (15%). As expected, both cadA and cadC mutants had reduced resistance to cadmium, while the resistance to BC was not significantly affected. Interestingly, both cadA and cadC mutants showed significantly higher susceptibility against L. monocytogenes phage LipG2-5 and FWLLm3 compared with the wide-type strain. Based on these results, we concluded that plasmids from L. monocytogenes encoded important functional determinants that are not only associated with cadmium resistance, but also phage susceptibility. PMID- 25721473 TI - Paenibacillus yonginensis DCY84(T) induces changes in Arabidopsis thaliana gene expression against aluminum, drought, and salt stress. AB - Current agricultural production methods, for example the improper use of chemical fertilizers and pesticides, create many health and environmental problems. Use of plant growth-promoting bacteria (PGPB) for agricultural benefits is increasing worldwide and also appears to be a trend for the future. There is possibility to develop microbial inoculants for use in agricultural biotechnology, based on these beneficial plant-microbe interactions. For this study, ten bacterial strains were isolated from Yongin forest soil for which in vitro plant-growth promoting trait screenings, such as indole acetic acid (IAA) production, a phosphate solubilization test, and a siderophore production test were used to select two PGPB candidates. Arabidopsis thaliana plants were inoculated with Paenibacillus yonginensis DCY84(T) and Micrococcus yunnanensis PGPB7. Salt stress, drought stress and heavy metal (aluminum) stress challenges indicated that P. yonginensis DCY84(T)-inoculated plants were more resistant than control plants. AtRSA1, AtVQ9 and AtWRKY8 were used as the salinity responsive genes. The AtERD15, AtRAB18, and AtLT178 were selected to check A. thaliana responses to drought stress. Aluminum stress response was checked using AtAIP, AtALS3 and AtALMT1. The qRT-PCR results indicated that P. yonginensis DCY84(T) can promote plant tolerance against salt, drought, and aluminum stress. P. yonginensis DCY84(T) also showed positive results during in vitro compatibility testing and virulence assay against X. oryzae pv. oryzae Philippine race 6 (PXO99). Better germination rates and growth parameters were also recorded for the P. yonginensis DCY84(T) Chuchung cultivar rice seed which was grown on coastal soil collected from Suncheon. Based on these results, P. yonginensis DCY84(T) can be used as a promising PGPB isolate for crop improvement. PMID- 25721474 TI - Silver nanoparticles mediated altered gene expression of melanin biosynthesis genes in Bipolaris sorokiniana. AB - Melanin production in many fungal phytopathogens has been investigated to play direct or indirect role in pathogenesis. However, in Bipolaris sorokiniana, the spot blotch pathogen of wheat, much less is known about the role melanin play in pathogenesis. As an extension of our previous report, the present study aims to investigate the plausible association between melanin production and virulence factor in B. sorokiniana. In the previous study, we carried out analysis on the antifungal efficacy of biosynthesized silver nanoparticles (AgNPs) against B. sorokiniana. The present investigation revealed the gene expression analysis of melanin biosynthesis genes viz. polyketide synthase (PKS1) and scytalone dehydratase (SCD1) under the influence of AgNPs. The 0.05mg/ml concentration of AgNPs yielded noticeable inhibition of B. sorokiniana growth, while 0.1mg/ml concentration of AgNPs accounted for complete inhibition of pathogen growth. In addition, the semiquantitative RT-PCR analysis exhibited reduced expression of PKS1 and SCD1 under the influence of AgNPs treatment. Furthermore, the qRT-PCR demonstrated 6.47 and 1.808 fold significant decrease in the expression pattern of PKS1 and SCD1, respectively, in B. sorokiniana treated with AgNPs. The present study provides probable understanding of molecular events underlying the antifungal role of AgNPs against B. sorokiniana. PMID- 25721475 TI - Composition, function, and regulation of T6SS in Pseudomonas aeruginosa. AB - Bacterial cells can communicate with their surrounding environment through secretion systems. Type VI secretion system (T6SS) is one of the most recently discovered secretion systems, which is distributed widely in Gram-negative bacteria such as Pseudomonas aeruginosa (P. aeruginosa), an important opportunistic pathogen. This protein secretion system shares similarity with the puncturing device of bacteriophages in structure. P. aeruginosa is an important opportunistic pathogen and distributes widely in diverse environment. T6SS is beneficial to survival advantage of P. aeruginosa by delivering toxins to its neighboring pathogens and translocating protein effectors into the host cells. T6SS is also the virulence factor and takes part in biofilm formation of P. aeruginosa. The functions of T6SS in P. aeruginosa are regulated at transcriptional, posttranscriptional and posttranslational levels by diverse mechanisms. This article reviews the latest progress in the structure, effector proteins, biological function, and regulation mechanisms of P. aeruginosa T6SS. PMID- 25721476 TI - Bacterial growth rates are influenced by cellular characteristics of individual species when immersed in electromagnetic fields. AB - Previous studies have shown that exposure to extremely low-frequency electromagnetic fields (ELF-EMFs) have negative effects on the rate of growth of bacteria. In the present study, two Gram-positive and two Gram-negative species were exposed to six magnetic field conditions in broth cultures. Three variations of the 'Thomas' pulsed frequency-modulated pattern; a strong-static "puck" magnet upwards of 5000G in intensity; a pair of these magnets rotating opposite one another at ~30rpm; and finally a strong dynamic magnetic field generator termed the 'Resonator' with an average intensity of 250MUT were used. Growth rate was discerned by optical density (OD) measurements every hour at 600nm. ELF-EMF conditions significantly affected the rates of growth of the bacterial cultures, while the two static magnetic field conditions were not statistically significant. Most interestingly, the 'Resonator' dynamic magnetic field increased the rates of growth of three species (Staphylococcus epidermidis, Staphylococcus aureus, and Escherichia coli), while slowing the growth of one (Serratia marcescens). We suggest that these effects are due to individual biophysical characteristics of the bacterial species. PMID- 25721477 TI - [Contribution of reflectance confocal microscopy in the diagnosis of eyelid dermal nevus]. PMID- 25721478 TI - [Massive and diffuse cutaneous calcinosis complicating adulthood dermatomyositis]. PMID- 25721479 TI - Why Sn doping significantly enhances the dielectric properties of Ba(Ti 1-x Snx)O3. AB - Through appropriate doping, the properties of BaTiO3-based ferroelectrics can be significantly enhanced. To determine the physical process induced by the doping of Sn atoms in Ba(Ti0.8Sn0.2)O3, we performed high-resolution scanning transmission electron microscopy experiments and observed that the regions with low Sn content formed polar nano regions (PNRs) embedded in the matrix in Ba(Ti0.8Sn0.2)O3. The interactions among Sn, Ti, Ba and O atoms were determined using first principles calculations. Based on the characteristics of the electronic structure and crystal lattice strain fields, the effects of doping with Sn were investigated. The Sn doping not only changed the electronic structure of the crystal but also increased the dielectric properties of the PNRs. Moreover, the Sn doping was also responsible for the diffuse phase transition of the Ba(Ti 1-x Snx)O3 material. The effects mentioned in this paper are universal in lead-free ferroelectrics, and similar elements such as Sb, Mg, and Zr may have the same functions in other systems. Thus, these results provide guidance for the design of the doping process and new systems of ferroelectric or relaxor materials. PMID- 25721481 TI - Effects of Cerebellothalamic Tractotomy on Cognitive and Emotional Functioning in Essential Tremor: A Preliminary Study in 5 Essential Tremor Patients. AB - Background: Subthalamic stereotactic interventions have recently caught renewed interest as a treatment for essential tremor (ET). However, it is not clear whether these interventions are associated with neurocognitive, mood or personality changes. Objective: To investigate neurocognition, neuropsychiatric functions and personality variables in patients with ET and to explore the neurocognitive and neuropsychiatric effects of cerebellothalamic tractotomy (CTT), a form of subthalamotomy. Methods: In our study, we investigated cognitive functions, frontal functions, mood and personality variables in 5 patients with intractable ET. Patients were tested before and 3 months after surgery using neuropsychological tests, clinical scales for depression, anxiety, anger regulation and a personality test. Results: Before surgery, ET patients showed normal neurocognitive function, a slightly elevated frontal lobe score in the dimensions mental control and memory, without being indicative of a frontal lesion, and no elevated depression or anxiety scores compared to norm values. After surgery, there was no change in neurocognitive function and no increase in depression or anxiety scores. Conclusion: In this exploratory study on 5 ET patients, CTT was not associated with alterations of mood or neurocognitive functions. (c) 2015 S. Karger AG, Basel. PMID- 25721480 TI - Saccadic palsy following cardiac surgery: a review and new hypothesis. AB - The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBN) and omnipause neurons (OPN) within the brainstem, both types of cells are highly active. Experimental lesions of EBN and OPN cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBN and OPN. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBN and OPN are ensheathed by perineuronal nets (PN), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PN, rather than to the neurons they support, could lead to neuronal dysfunction-such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PN. PMID- 25721482 TI - Early improvement of functional mitral regurgitation in patients with idiopathic dilated cardiomyopathy. AB - The aim of the study was to assess the clinical and prognostic impact of early functional mitral regurgitation (FMR) improvement on the outcome of patients with idiopathic dilated cardiomyopathy (IDC). The prevalence and prognostic role of FMR improvement, particularly at early follow-up, in patients with IDC are still unclear. From 1988 to 2009, we enrolled 470 patients with IDC with available FMR data at baseline and after 6 +/- 2 months. According to the evolution of FMR, patients were classified into 3 groups: stable absent-mild FMR, early FMR improvement (downgrading from moderate-severe to absent-mild), and persistence/early development of moderate-severe FMR. At baseline, 177 of 470 patients (38%) had moderate-severe FMR. Patients with early FMR improvement had significantly better survival rate-free from heart transplant with respect to those with persistence/early development of moderate-severe FMR (93%, 81%, and 66% vs 91%, 64%, and 52% at 1, 6, and 12 years, respectively; p = 0.044). At 6 month follow-up multivariate analysis, FMR improvement was associated with better prognosis (hazard ratio 0.78, 95% confidence interval [CI] 0.64 to 0.96, p = 0.02); the other independent predictors were male gender, heart failure duration, and early re-evaluation of the New York Heart Association class and left ventricle systolic function. This model provided more accurate risk stratification compared with the baseline model (Net Reclassification Index 80% at 12 months and 41% at 72 months). In conclusion, in a large cohort of patients with IDC receiving optimal medical treatment, early improvement of FMR was frequent (53%) and emerged as a favorable independent prognostic factor with an incremental short- and long-term power compared with the baseline evaluation. PMID- 25721483 TI - Coronary artery disease performance measures and statin use in patients with recent percutaneous coronary intervention or recent coronary artery bypass grafting (from the NCDR PINNACLE registry). AB - The association between coronary revascularization strategy (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) and compliance with coronary artery disease (CAD) performance measures is not well studied. Our analysis studied patients enrolled in the Practice Innovation and Clinical Excellence registry, who underwent coronary revascularization using PCI or CABG in the 12 months before their most recent outpatient visit in 2011. We compared the attainment of CAD performance measures and statin use in eligible patients with PCI and CABG using hierarchical logistic regression models. Our study cohort consisted of 112,969 patients (80,753 with PCI and 32,216 with CABG). After adjustment for site and patient characteristics, performance measure compliance for tobacco use query (odds ratio [OR] 0.80; 95% confidence interval [CI] 0.76 to 0.86), antiplatelet therapy (OR 0.9; 95% CI 0.86 to 0.94) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy (OR 0.89; 95% CI 0.84 to 0.94) was lower in CABG compared with patients with PCI. Patients who underwent recent CABG had higher rates of beta-blocker (OR 1.25; 95% CI 1.16 to 1.33) and statin treatment (OR 1.37; 95% CI 1.31 to 1.43) compared with patients with PCI. Of the 79 practice sites, 15 (19%) had >=75% of their patients with CAD (CABG or PCI) meeting 75% to 100% of all eligible CAD performance measures. In conclusion, gaps persist in compliance with specific CAD performance measures in patients with recent PCI or CABG, and 1 in 5 practices had >=75% compliance of eligible CAD performance measures in the most of their patients. PMID- 25721484 TI - Gallbladder ejection fraction declines with age in patients undergoing cholecystectomy for acalculous biliary symptoms but has low accuracy in the prediction of gallbladder pathology. AB - BACKGROUND/AIMS: Hepatobiliary Iminodiacetic Acid (HIDA) scan provides a technique to quantify gallbladder ejection fraction (EF) in patients suffering acalculous biliary colic (ACBC). We wished to evaluate the accuracy of EF in the prediction of gallbladder pathology in patients undergoing cholecystectomy. METHODS: Data were retrieved from a database of patients referred for HIDA scan for ACBC, including EF and the pathological outcome of those undergoing cholecystectomy, and compared to normal values obtained from a review of related studies. Significant associations were demonstrated by chi-square, Mann-Whitney test, and linear regression. The predictive accuracy of different cut-offs of EF was demonstrated by the ROC curve analysis. RESULTS: Of 83 patients referred for HIDA scan for ACBC, 41 underwent cholecystectomy. The median EF of this group (33%) was significantly lower than the composite normal median value from previous studies (56%). Thirty-two patients revealed evidence of gallbladder pathology. The EF declined with age (coefficient = -0.51, 95% CI = -0.99 to 0.33), but the median value did not differ between those with gallbladder pathology (34%) and those with normal gallbladders (29%). CONCLUSION/DISCUSSION: Although an EF cut-off of 35% had the greatest accuracy in the prediction of pathology of those tested (0.56), the poor negative predictive value (23.5%) was a major contributor to its low accuracy. Although patients with ACBC have reduced gallbladder EF compared to the normal population, its quantitative assessment is of limited value in the prediction of gallbladder pathology. PMID- 25721485 TI - Epothilone B induces human ovarian cancer OV-90 cell apoptosis via external pathway. AB - We evaluated molecular events associated with apoptosis induced by Epothilone B (EpoB, Patupilone) and paclitaxel (PTX) in human ovarian papillary serous adenocarcinoma cell line (OV-90). Epothilones are compounds of natural origin with mechanisms of action similar to taxanes, but with more potent antiproliferative activity. Apoptosis was one of the major forms of cell death induced by EpoB. The mode of cell death was assessed colorimetrically, fluorimetrically, cytometry, and by immunoblot analyses through measuring DNA fragmentation, the level of TRAIL, the cleavage of poly(ADP-ribose) polymerase (PARP) and the activation of caspase-9, -8 and -3. We measured also additional markers of apoptosis, like phosphatidylserine externalization and morphological changes. Moreover, we estimated glycoprotein P (P-gp) activity in OV-90 ovarian cancer cell line. The studies indicated that the extrinsic pathway of apoptosis, which is triggered by certain TNF family members and engages their respective receptors on the surface of the target cell, was predominant. We were the first to have demonstrated (using immunoassay) the release of TNF-related apoptosis inducing ligand (TRAIL) after treatment with EpoB. EpoB and PTX mediate activation of both initiator caspases-8 and -9, leading to the appearance of caspase-3. In EpoB treated cells, DNA fragmentation was also detected. EpoB leads to the reduction in DNA repair capacity. In summary, we report that Epothilone B induces apoptosis in OV-90 cells via a TRAIL and caspase 8-dependent pathway. PTX leads to smaller apoptotic events in comparison to EpoB. PMID- 25721486 TI - Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats. AB - Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (gammaGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days. PMID- 25721487 TI - Thalidomide improves clinical remission in children with Crohn's disease. PMID- 25721488 TI - Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013-2014. AB - Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 10,641 viruses collected by WHO-recognized National Influenza Centres between May 2013 and May 2014 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. In addition, neuraminidase (NA) sequence data, available from the WHO CCs and from sequence databases (n=3206), were screened for amino acid substitutions associated with reduced NAI susceptibility. Ninety-five per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 2% (n=172) showed highly reduced inhibition (HRI) against at least one of the four NAIs, commonly oseltamivir, while 0.3% (n=32) showed reduced inhibition (RI). Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=169), A(H3N2) with NA E119V (n=1), B/Victoria-lineage with NA E117G (n=1) and B/Yamagata-lineage with NA H273Y (n=1); amino acid position numbering is A subtype and B type specific. Although approximately 98% of circulating viruses tested during the 2013-2014 period were sensitive to all four NAIs, a large community cluster of A(H1N1)pdm09 viruses with the NA H275Y substitution from patients with no previous exposure to antivirals was detected in Hokkaido, Japan. Significant numbers of A(H1N1)pdm09 NA H275Y viruses were also detected in China and the United States: phylogenetic analyses showed that the Chinese viruses were similar to those from Japan, while the United States viruses clustered separately from those of the Hokkaido outbreak, indicative of multiple resistance-emergence events. Consequently, global surveillance of influenza antiviral susceptibility should be continued from a public health perspective. PMID- 25721489 TI - Determining the general utilization and characteristics of orthopedic complementary and alternative medicine using a self-administered online questionnaire in Japan. AB - BACKGROUND: Acupuncture and moxibustion, massage, bone-setting, manual therapy, and chiropractic treatments are representative components of orthopedic complementary and alternative medicine (OCAM) in Japan. However, the state of their utilization and characteristics are unclear, and have yet to be thoroughly surveyed. The objective of this study was to survey the utilization and characteristics of OCAM in the general public. MATERIALS AND METHODS: In January 2011, we conducted a self-administered online questionnaire survey with 10,400 members of the general public, who were registered as consumer reviewers at the internet survey company. Survey topics were the use of OCAM within one month prior to the survey, the objective of using OCAM, and the presence or absence of consultation with and recommendation or referral by a physician. The subjects were divided into those who used and did not use OCAM as user and non-user groups, respectively, and the age, sex, and prevalence of past treatment for orthopedic diseases at medical institutions were compared between the groups. Data of 3,211 subjects (1,611 males and 1,600 females, mean age: 44.7 years old) were analyzed. RESULTS: Four hundred and thirty-eight subjects (13.6%) used OCAM within one month prior to the survey. The subjects in their forties used OCAM most frequently, followed by those in their twenties. The most frequent objective of OCAM usage was treatment, accounting for 63% (275 subjects) of the subjects. Fifty-three subjects (12.1%) consulted a physician, and 48 (11%) were recommended or referred by a physician. Upon logistic regression analysis, significant differences were detected in age, sex, and prevalence of treatment at a medical institution in the user group. A decreasing trend in the odds ratio correlated with subjects having received previous treatment at a medical institution, female subjects, and subjects of a younger age (p = 0.01; odds ratio = 4.33, 1.43, and 1.01, respectively), and these factors were independent. CONCLUSION: It was determined that 13.6% of the subjects had used OCAM, and many relatively young females (especially those in their forties or twenties) with a past medical history used it based on their own judgment. PMID- 25721490 TI - Changes in health-related quality of life and activities of daily living after hip fracture because of a fall in elderly patients: a prospective cohort study. AB - BACKGROUND: The impact of hip fracture because of a fall on health-related quality of life (HRQoL) and activities of daily living (ADL) have not been well established. AIM: To evaluate changes in HRQoL and the ability to conduct ADL among patients with hip fracture because of a fall and to compare these changes with patients who did not fall and break a hip, adjusting by gender and age. METHODS: Adults aged 65 or more who attended the emergency departments of seven public hospitals were recruited in a prospective double-cohort study (fracture cohort, n = 776; non-fracture cohort, n = 115). ADL and HRQoL were assessed at baseline (during the postfall hospitalisation or by telephone afterwards) and 6 months later using the Barthel Index and the Lawton Brody Index for ADL, and the Short Form Health Survey (SF-12) and Western Ontario and McMaster Universities Osteoarthritis Index short form (WOMAC-SF) for HRQoL. RESULTS: Adjusting by gender, age and baseline status, a hip fracture was a strong predictor of decline in all outcomes measured except for mental quality of life among men (measured by SF-12). Hip fracture patients younger than 74 years reported significantly more pain (measured by WOMAC-SF) than the comparison group (p = 0.02), but this difference was not observed among older patients (p = 0.19 for 75-84 years; p = 0.39 for >= 85 years). DISCUSSION: Hip fractures have profound effects on HRQoL and ADL in both men and women, regardless of age. This indicates the need for special follow-up care of elderly hip fracture patients in the immediate and late postfracture periods. PMID- 25721492 TI - Case-fatality of hand, foot and mouth disease associated with EV71: a systematic review and meta-analysis. AB - Hand, foot and mouth disease (HFMD) associated with enterovirus 71 (EV71) is a growing public health concern. This study aimed to estimate the case-fatality of HFMD associated with EV71 on the basis of a meta-analysis. We searched PubMed, Cochrane, Web of Science, Elsevier, CNKI, Wanfang, and VIP databases. Two authors independently selected relevant studies. The pooled estimate of case-fatality was calculated using a random-effects model. Potential sources of heterogeneity were explored using subgroup analysis, sensitivity analysis and meta-regression. We identified 14 eligible studies with a total population of 112 546. The random effects pooled case-fatality was 1.7% (95% confidence interval 1.2-2.4). The funnel plot was asymmetrical. The estimate of case-fatality was highest in mainland China (1.8%). Removal of eight local Chinese studies decreased the original estimate. The pooled case-fatality in the period of 1998-2007 (1.5%) was lower than that in the period 2008-2012 (1.8%). Control measures for HFMD associated with EV71 are essential because of the increased case-fatality over time, especially in East Asia. PMID- 25721493 TI - Metal-free ferromagnetic metal and intrinsic spin semiconductor: two different kinds of SWCNT functionalized BN nanoribbons. AB - Two different kinds of SWCNT functionalized zigzag edge BN nanoribbons with n chains (n-ZBNNRs), namely, (a) B-edge functionalized by (m,m)SWCNT and N-edge modified with H (nZBNNR-B-(m,m)SWCNTs); and (b) the B-edge modified with H and the N-edge functionalized by (m,m)SWCNT (nZBNNR-N-(m,m)SWCNTs), have been predicted. Amazingly, we find that unlike the semiconducting and nonmagnetic H modified n-ZBNNRs, the nZBNNR-B-(m,m)SWCNTs are intrinsic ferromagnetic metals, regardless of ribbon widths n and tube diameters (m,m). At a given (m,m), their local magnetic moments, at first, exhibit oscillation with increasing n, whereas when n is larger than 5, they are independent of n. In contrast, unlike the metallic and nonmagnetic (m,m)SWCNTs, the nZBNNR-N-(m,m)SWCNTs are ferromagnetic intrinsic spin-semiconductors with direct band gaps, regardless of n and (m,m). Their local magnetic moments and band gaps are independent of n and (m,m). The DFT calculations reveal that the process of SWCNT functionalization of the n ZBNNRs does not need any activation energy. Moreover, the formation energies of the SWCNT functionalized n-ZBNNRs are always less than zero. Therefore, the SWCNT functionalized n-ZBNNRs are not only stable, but can also be spontaneously formed. Furthermore, compared with n-ZBNNRs, the SWCNT functionalized n-ZBNNRs show significant improvements in their thermal and mechanical stabilities. Thus, (m,m)SWCNT functionalization of n-ZBNNRs may open new routes toward practical nanoelectronic and optoelectronic as well as spintronic devices based on BNC based materials. PMID- 25721491 TI - Clonotypically similar hybrid alphabeta T cell receptors can exhibit markedly different surface expression, antigen specificity and cross-reactivity. AB - Emerging data indicate that particular major histocompatibility complex (MHC) bound antigenic peptides can be recognized by identical or near-identical alphabeta T cell receptors (TCRs) in different individuals. To establish the functional relevance of this phenomenon, we artificially paired alpha and beta chains from closely related TCRs specific for the human leucocyte antigen (HLA) B*35:01-restricted HIV-1 negative regulatory factor (Nef)-derived epitope VY8 (VPLRPMTY, residues 74-81). Several hybrid TCRs generated in this manner failed to express at the cell surface, despite near homology with naturally isolated alphabeta chain combinations. Moreover, a substantial proportion of those alphabeta TCRs that did express lost specificity for the index VY8 peptide sequence. One such hybrid alphabeta pair gained neo-variant specificity in the context of the VY8 backbone. Collectively, these data show that clonotypically similar TCRs can display profound differences in surface expression, antigen specificity and cross-reactivity with potential relevance for the control of mutable viruses. PMID- 25721494 TI - Fabrication of a white electroluminescent device based on bilayered yellow and blue quantum dots. AB - Until now most work on colloidal quantum dot-light-emitting diodes (QLEDs) has been focused on the improvement of the electroluminescent (EL) performance of monochromatic devices, and multi-colored white QLEDs comprising more than one type of QD emitter have been rarely investigated. To demonstrate a white EL as a result of color mixing between blue and yellow, herein a unique combination of two dissimilar QDs of blue- CdZnS/ZnS plus a yellow-emitting Cu-In-S (CIS)/ZnS is used for the formation of the emitting layer (EML) of a multilayered QLED. First, the QLED consisting of a single EML randomly mixed with two QDs is fabricated, however, its EL is dominated by blue emission with the contribution of yellow emission substantially weaker. Thus, another EML configuration is devised in the form of a QD bilayer with two stacking sequences of CdZnS/ZnS//CIS/ZnS QD and vice versa. The QLED with the former stacking sequence shows an overwhelming contribution of blue EL, similar to the mixed QD EML-based device. Upon applying the oppositely stacked QD bilayer of CIS/ZnS//CdZnS/ZnS, however, a bicolored white EL can be successfully achieved by means of the effective extension of the radiative excitonic recombination zone throughout both QD EML regions. Such QD EML configuration-dependent EL results, which are discussed primarily using the proposed device energy level diagram, strongly suggest that the positional design of individual QD emitters is a critical factor for the realization of multicolored, white emissive devices. PMID- 25721495 TI - Chelerythrine inhibits the sarco/endoplasmic reticulum Ca(2+)-ATPase and results in cell Ca(2+) imbalance. AB - The isoquinoline alkaloid chelerythrine is described as an inhibitor of SERCA. The ATPase inhibition presented two non-competitive components, Ki1=1, 2 MUM and Ki2=26 MUM. Conversely, chelerythrine presented a dual effect on the p nitrophenylphosphatase (pNPPase) of SERCA. Ca(2+)-dependent pNPPase was activated up to ~5 MUM chelerythrine with inhibition thereafter. Ca(2+)-independent pNPPase was solely inhibited. The phosphorylation of SERCA with ATP reached half inhibition with 10 MUM chelerythrine and did not parallel the decrease of ATPase activity. In contrast, chelerythrine up to 50 MUM increased the phosphorylation by Pi. Cross-linking of SERCA with glutaraldehyde was counteracted by high concentrations of chelerythrine. The controlled tryptic digestion of SERCA shows that the low-affinity binding of chelerythrine evoked an E2-like pattern. Our data indicate a non-competitive inhibition of ATP hydrolysis that favors buildup of the E2-conformers of the enzyme. Chelerythrine as low as 0.5-1.5 MUM resulted in an increase of intracellular Ca(2+) on cultured PBMC cells. The inhibition of SERCA and the loss of cell Ca(2+) homeostasis could in part be responsible for some described cytotoxic effects of the alkaloid. Thus, the choice of chelerythrine as a PKC-inhibitor should consider its potential cytotoxicity due to the alkaloid's effects on SERCA. PMID- 25721496 TI - Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast. AB - Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in the human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on l-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assay in recombinant cell lines derived from four different species, although significant species differences in relative potency were observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. M. furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner. PMID- 25721497 TI - Carotenoids and their conversion products in the control of adipocyte function, adiposity and obesity. AB - A novel perspective of the function of carotenoids and carotenoid-derived products - including, but not restricted to, the retinoids - is emerging in recent years which connects these compounds to the control of adipocyte biology and body fat accumulation, with implications for the management of obesity, diabetes and cardiovascular disease. Cell and animal studies indicate that carotenoids and carotenoids derivatives can reduce adiposity and impact key aspects of adipose tissue biology including adipocyte differentiation, hypertrophy, capacity for fatty acid oxidation and thermogenesis (including browning of white adipose tissue) and secretory function. Epidemiological studies in humans associate higher dietary intakes and serum levels of carotenoids with decreased adiposity. Specifically designed human intervention studies, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. The objective of this review is to summarize recent findings in this area, place them in physiological contexts, and provide likely regulatory schemes whenever possible. The focus will be on the effects of carotenoids as nutritional regulators of adipose tissue biology and both animal and human studies, which support a role of carotenoids and retinoids in the prevention of abdominal adiposity. PMID- 25721498 TI - GAP-43 slows down cell cycle progression via sequences in its 3'UTR. AB - Growth-associated protein 43 (GAP-43) is a neuronal phosphoprotein associated with initial axonal outgrowth and synaptic remodeling and recent work also suggests its involvement in cell cycle control. The complex expression of GAP-43 features transcriptional and posttranscriptional components. However, in some conditions, GAP-43 gene expression is controlled primarily by the interaction of stabilizing or destabilizing RNA-binding proteins (RBPs) with adenine and uridine (AU)-rich instability elements (AREs) in its 3'UTR. Like GAP-43, many proteins involved in cell proliferation are encoded by ARE-containing mRNAs, some of which codify cell-cycle-regulating proteins including cyclin D1. Considering that GAP 43 and cyclin D1 mRNA stabilization may depend on similar RBPs, this study evaluated the participation of GAP-43 in cell cycle control and its underlying mechanisms, particularly the possible role of its 3'UTR, using GAP-43-transfected NIH-3T3 fibroblasts. Our results show an arrest in cell cycle progression in the G0/G1 phase. This arrest may be mediated by the competition of GAP-43 3'UTR with cyclin D1 3'UTR for the binding of Hu proteins such as HuR, which may lead to a decrease in cyclin D1 expression. These results might lead to therapeutic applications involving the use of sequences in the B region of GAP-43 3'UTR to slow down cell cycle progression. PMID- 25721499 TI - A national population-based study of the incidence of adnexal torsion in the Republic of Korea. PMID- 25721500 TI - Real-space grids and the Octopus code as tools for the development of new simulation approaches for electronic systems. AB - Real-space grids are a powerful alternative for the simulation of electronic systems. One of the main advantages of the approach is the flexibility and simplicity of working directly in real space where the different fields are discretized on a grid, combined with competitive numerical performance and great potential for parallelization. These properties constitute a great advantage at the time of implementing and testing new physical models. Based on our experience with the Octopus code, in this article we discuss how the real-space approach has allowed for the recent development of new ideas for the simulation of electronic systems. Among these applications are approaches to calculate response properties, modeling of photoemission, optimal control of quantum systems, simulation of plasmonic systems, and the exact solution of the Schrodinger equation for low-dimensionality systems. PMID- 25721501 TI - Meconium aspiration syndrome: possible pathophysiological mechanisms and future potential therapies. AB - Does meconium cause meconium aspiration syndrome (MAS) or is meconium discharge only a marker of fetal hypoxia? This dispute has lasted for centuries, but since the 1960s, detrimental effects of meconium itself on the lungs have been demonstrated in animal experiments. In clinical MAS, persistent pulmonary hypertension of the newborn is the leading cause of death in MAS. Regarding the complex chemical composition of meconium, it is difficult to identify a single agent responsible for the pathophysiology. However, considering that meconium is stored in the intestines, partly unexposed to the immune system, aspirated meconium could be recognized as 'danger', representing damaged self. The common denominator in the pathophysiology could therefore be activation of innate immunity. Thus, a bulk of evidence implies that meconium is a potent activator of inflammatory mediators, including cytokines, complement, prostaglandins and reactive oxygen species. We hypothesize that the two main recognition systems of innate immunity, the Toll-like receptors and the complement system, recognize meconium as 'danger', which leads not only to lung dysfunction but also to a systemic inflammatory response. This might have therapeutic implications in the future. PMID- 25721502 TI - No influence of lower leg heating on central arterial pulse pressure in young men. AB - Central arterial pulse pressure (PP), a strong predictor of cardiovascular disease, mainly consists of an incident wave generated by left ventricular ejection and a late-arriving reflected wave emanating from the lower body. We have tested the hypothesis that a reduction in leg vascular tone by heat treatment of the lower leg attenuates the central arterial PP. Pressure and wave properties of the peripheral and central arteries were measured in eight young men before and after heat treatment of the lower leg (temperature approx. 43 degrees C) for 30 and 60 min, respectively. Following the lower leg heat trial, leg (femoral-ankle) pulse wave velocity (PWV) was significantly decreased, but aortic (carotid-femoral) PWV and parameters of wave reflection and carotid arterial PP did not change significantly. No significant changes were observed in these parameters in the control trial. These results suggest that the reduction in leg vascular tone induced by heat treatment of the lower leg may not affect wave reflection and central arterial PP in young men. PMID- 25721503 TI - Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. AB - Evolutionary expansion of the human neocortex reflects increased amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis. In this work, we analyze the transcriptomes of distinct progenitor subpopulations isolated by a cell polarity-based approach from developing mouse and human neocortex. We identify 56 genes preferentially expressed in human apical and basal radial glia that lack mouse orthologs. Among these, ARHGAP11B has the highest degree of radial glia-specific expression. ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. Hence, ARHGAP11B may have contributed to evolutionary expansion of human neocortex. PMID- 25721504 TI - Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. AB - Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol (DNP) has beneficial effects on NAFLD, insulin resistance, and obesity in preclinical models but is too toxic for clinical use. We developed a controlled-release oral formulation of DNP, called CRMP (controlled-release mitochondrial protonophore), that produces mild hepatic mitochondrial uncoupling. In rat models, CRMP reduced hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. It also normalized plasma transaminase concentrations, ameliorated liver fibrosis, and improved hepatic protein synthetic function in a methionine/choline-deficient rat model of NASH. Chronic treatment with CRMP was not associated with any systemic toxicity. These data offer proof of concept that mild hepatic mitochondrial uncoupling may be a safe and effective therapy for the related epidemics of metabolic syndrome, T2D, and NASH. PMID- 25721505 TI - Statistics. What is the question? PMID- 25721506 TI - Bee declines driven by combined stress from parasites, pesticides, and lack of flowers. AB - Bees are subject to numerous pressures in the modern world. The abundance and diversity of flowers has declined; bees are chronically exposed to cocktails of agrochemicals, and they are simultaneously exposed to novel parasites accidentally spread by humans. Climate change is likely to exacerbate these problems in the future. Stressors do not act in isolation; for example, pesticide exposure can impair both detoxification mechanisms and immune responses, rendering bees more susceptible to parasites. It seems certain that chronic exposure to multiple interacting stressors is driving honey bee colony losses and declines of wild pollinators, but such interactions are not addressed by current regulatory procedures, and studying these interactions experimentally poses a major challenge. In the meantime, taking steps to reduce stress on bees would seem prudent; incorporating flower-rich habitat into farmland, reducing pesticide use through adopting more sustainable farming methods, and enforcing effective quarantine measures on bee movements are all practical measures that should be adopted. Effective monitoring of wild pollinator populations is urgently needed to inform management strategies into the future. PMID- 25721507 TI - Crystal growth. Aqueous formation and manipulation of the iron-oxo Keggin ion. AB - There is emerging evidence that growth of synthetic and natural phases occurs by the aggregation of prenucleation clusters, rather than classical atom-by-atom growth. Ferrihydrite, an iron oxyhydroxide mineral, is the common form of Fe(3+) in soils and is also in the ferritin protein. We isolated a 10 angstrom discrete iron-oxo cluster (known as the Keggin ion, Fe13) that has the same structural features as ferrihydrite. The stabilization and manipulation of this highly reactive polyanion in water is controlled exclusively by its counterions. Upon dissolution of Fe13 in water with precipitation of its protecting Bi(3+) counterions, it rapidly aggregates to ~22 angstrom spherical ferrihydrite nanoparticles. Fe13 may therefore also be a prenucleation cluster for ferrihydrite formation in natural systems, including by microbial and cellular processes. PMID- 25721508 TI - Multidrug resistant tuberculosis. PMID- 25721509 TI - Enteral administration of monosodium phosphate, monopotassium phosphate and monocalcium phosphate for the treatment of hypophosphataemia in lactating dairy cattle. AB - Hypohosphataemia is a frequent finding in early lactating and anorectic dairy cows. Sodium phosphate is commonly used for oral phosphorus (P) supplementation, although other phosphate salts may present useful treatment alternatives. Objectives of this study were to compare the efficacy of monopotassium phosphate (KH2PO4) and monocalcium phosphate (Ca(H2PO4)2) to monosodium phosphate (NaH2PO4) in P-depleted cows. Furthermore, the effect of concentrated NaH2PO4 on the reticular groove reflex was studied. Six healthy but P-depleted dairy cows underwent four treatments in randomised order. Treatments consisted of intraruminal administration of NaH2PO4, KH2PO4 and Ca(H2PO4)2 providing the equivalent of 60 g P. A fourth treatment consisting of concentrated NaH2PO4 combined with acetaminophen as a marker substance was administered orally to determine whether the reticular groove reflex could be induced. Intraruminal administration of NaH2PO4 and KH2PO4 resulted in similar increases in plasma Pi concentrations ([Pi]) while intraruminal Ca(H2PO4)2 resulted in lower increases in plasma [Pi]. Oral and intraruminal administration of NaH2PO4 resulted in similar times to peak plasma [Pi] and acetaminophen concentration, indicating that concentrated NaH2PO4 administered orally did not trigger the reticular groove reflex. These results suggest that oral administration of KH2PO4 is equally effective as NaH2PO4. Oral administration of Ca(H2PO4)2 in contrast has a less pronounced effect on the plasma [Pi]. PMID- 25721510 TI - Prevalence of ovine pulmonary adenocarcinoma (Jaagsiekte) in a UK slaughterhouse sheep study. PMID- 25721511 TI - A new tissue-engineered biodegradable surgical patch for high-pressure systems ?. AB - OBJECTIVES: Ideal alternatives for replacing native arteries, which have biocompatibility such as growth potential, anti-thrombogenesis and durability, have yet to be discovered. We previously demonstrated the utility of tissue engineered vascular autografts; however, the use of these autografts is limited to low-pressure conditions. The aim of this study was to create the tissue engineered arterial patch (TEAP) that could be used in high-pressure systems, and to evaluate the maturation in this regenerative tissue. METHODS: We developed a new biodegradable polymer scaffold, which is composed of a co-polymer of epsilon caprolactone and lactide acid [P(CL/LA)] and a poly-L-lactide acid (PLLA). To obtain mechanical strength, we modified PLLA that is degraded by hydrolysis for 1 2 years in contrast to polyglycolic acid in our low-pressure study previously. We implanted an oval-shaped patch (30 * 15 mm) of this polymer without cell seeding into the descending aorta of 12 dogs, and followed the animals for 1, 3 and 6 months (n = 4 in each group). The cell proliferation in the patch was evaluated with histological and immunohistochemical methods. Additionally, the expression of vascular endothelial growth factor (VEGF) and smooth muscle myosin heavy chain (smMHC) mRNA in the patches was determined with reverse transcriptase-polymerase chain reaction. RESULTS: Macroscopically, there was no incidence of rupture or aneurysmal formation on the patch. The luminal surface of the TEAP was covered with a single layer of endothelial cells stained with vWF immunohistochemically at 1 month after implantation. alphaSMA-positive cells that indicated smooth muscle cells and collagen fibres were observed in the patch and they increased over time. The VEGF mRNA expression in the patch at 1 month was significantly higher than that of native arterial tissue (1 month; 0.124 +/- 0.017 ng/ul, native; 0.009 +/- 0.003 ng/ul, P < 0.05). The smMHC mRNA expression gradually increased, and reached ~ 60% of that of the native artery at 6 months (6 months: 0.351 +/- 0.028 ng/ul, native: 0.540 +/- 0.027 ng/ul). CONCLUSIONS: We demonstrated the maturation of endothelial and smooth muscle cells in TEAP, suggesting that this biodegradable polymer scaffold could be used as an alternative vascular material even in high-pressure systems. PMID- 25721512 TI - Erratum to: Heart rate variability in male shift workers in automobile manufacturing factories in South Korea. PMID- 25721513 TI - Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise. AB - The role of inflammation in tendon injury is uncertain and a topic of current interest. In vitro studies of tendon accelerated overload damage can serve as a valuable source of information on the early stages of tendinopathy. Viable fascicle bundles from bovine flexor tendons were subjected to cyclic uniaxial loading from 1-10% strain. Immuno-staining for inflammatory markers and matrix degradation markers was performed on the samples after mechanical testing. Loaded samples exhibited visible extracellular matrix damage, with disrupted collagen fibers and fiber kinks, and notable damage to the interfascicular matrix. Inflammatory markers COX-2 and IL-6 were only expressed in the cyclically loaded samples. Collagen degradation markers MMP-1 and C1,2C were colocalized in many areas, with staining occurring in the interfascicular matrix or the fascicular tenocytes. These markers were present in control samples, but staining became increasingly intense with loading. Little MMP-3 or MMP-13 was evident in control sections. In loaded samples, some sections showed intense staining of these markers, again localized to interfascicular regions. This study suggests that inflammatory markers may be expressed rapidly after tendon overload exercise. Interestingly, both inflammation and damage-induced matrix remodeling seem to be concentrated in, or in the vicinity of, the highly cellular interfascicular matrix. PMID- 25721514 TI - Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis. AB - The spatial orientation of cell divisions is fundamental for tissue architecture and homeostasis. Here we analysed neuroepithelial progenitors in the developing mouse spinal cord to determine whether extracellular signals orient the mitotic spindle. We report that Semaphorin3B (Sema3B) released from the floor plate and the nascent choroid plexus in the cerebrospinal fluid (CSF) controls progenitor division orientation. Delivery of exogenous Sema3B to neural progenitors after neural tube opening in living embryos promotes planar orientation of their division. Preventing progenitor access to cues present in the CSF by genetically engineered canal obstruction affects the proportion of planar and oblique divisions. Sema3B knockout phenocopies the loss of progenitor access to the CSF. Sema3B binds to the apical surface of mitotic progenitors and exerts its effect via Neuropilin receptors, GSK3 activation and subsequent inhibition of the microtubule stabilizer CRMP2. Thus, extrinsic control mediated by the Semaphorin signalling orients progenitor divisions in neurogenic zones. PMID- 25721515 TI - Reply to 'Lack of positive effect of intravitreal bevacizumab in central serous chorioretinopathy: meta-analysis and review'. PMID- 25721516 TI - Methodological remarks concerning the recent meta-analysis on the effect of intravitral bevacizumab in central serous chorioretinopathy. PMID- 25721517 TI - Mini-incision cataract surgery and toric lens implantation for the reduction of high myopic astigmatism in patients with pellucid marginal degeneration. AB - PURPOSE: To evaluate the clinical outcomes, safety, and efficacy of cataract surgery with the implantation of a toric intraocular lens (IOL) in eyes with stable pellucid marginal degeneration (PMD). METHODS: Eleven eyes (eight patients) diagnosed as stable PMD and cataract underwent mini-incision 2.2 mm cataract surgery followed by the implantation of hydrophobic toric aspheric IOL (AcrySof IQ Toric IOL, Alcon, Fort Worth, TX, USA). Perioperative variables of interest included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, manifest refraction, and corneal topography. Paired samples t-tests were used to analyze preoperative and postoperative visual acuity, astigmatism, and spherical equivalent (SE) parameters. Follow-up was 6 months. RESULTS: The mean CDVA was 0.62+/-0.26 logMAR preoperatively and 0.07+/-0.07 logMAR postoperatively. The mean preoperative sphere and cylinder was -3.14+/-3.58D and 4.84+/-2.02D, respectively. The mean postoperative manifest refractive sphere and cylinder was -0.30+/-0.51D and -0.81+/-1.51D, respectively. There was a significant reduction in refractive astigmatism after toric IOL implantation (P<0.002). The toric IOL axis rotation was <5 degrees in all cases at the final follow-up. CONCLUSIONS: Implantation of hydrophobic toric IOL was a safe and effective surgical procedure to correct mild to moderate stable PMD. PMID- 25721518 TI - Comparison of visual field progression between temporally tilted disc and nontilted disc, in patients with normal tension glaucoma. AB - PURPOSE: To investigate the long-term visual field (VF) progression of temporally tilted disc and nontilted disc in normal tension glaucoma (NTG). METHODS: Retrospective, observational case series. Forty-seven patients with temporally tilted disc (47 eyes), 44 patients with nontilted disc in NTG (44 eyes) patients, who were examined by at least 5 VF tests, and were followed-up over a 5-year period, at the Department of Ophthalmology of the Samsung Medical Center, from May 1998 to 2013. VF progression was defined by modified Anderson-Hodapp criteria, and Glaucoma Progression Analysis (GPA). Multivariate analysis was used to identify the risk factors for VF progression in the temporally tilted disc. RESULTS: According to the Anderson-Hodapp criteria, progression rates of the temporally tilted disc and nontilted disc at 60 months were 19% and 72%, respectively (P<0.0001). According to GPA, they were 25% and 53%, respectively (P<0.0001). Twenty of 47 patients in the temporally tilted disc did not show progression. Among them, the more tilted disc showed the more VF defects. The hazard ratio of retinal nerve fiber layer (RNFL) defect type was 3.08 (95% CI, 1.17-8.14; P=0.02). The simultaneous superior and inferior RNFL defect type was the most common in progressors in the temporally tilted disc (P=0.04). CONCLUSION: Through long-term follow-up, the cumulative survival rate of temporally tilted disc was higher than that of nontilted disc. Caution is required in the treatment of the temporally tilted disc. New treatment policy for the temporally tilted disc may follow. PMID- 25721519 TI - Opaque intraocular lens implantation. PMID- 25721520 TI - Blood flow velocity measured using the Retinal Function Imager predicts successful ranibizumab treatment in neovascular age-related macular degeneration: early prospective cohort study. AB - PURPOSE: Anti-VEGF treatment has a potent vasoconstrictive effect. Early changes of retinal blood flow velocity (RBFV) measured using the Retinal Function Imager (RFI) combined with indicators of vascular status may help in predicting the visual outcome 1 month post injection in patients with neovascular age-related macular degeneration (nvAMD) under ranibizumab treatment. To develop a simple prediction model based on the change in RBFV 3 days post injection and indicators of a patient's vascular status to assess the probability of a successful visual outcome 1 month post injection. METHODS: RBFV measured using RFI were prospectively collected pre-injection and 3 days post injection in 18 eyes of 15 patients. Indicators of vascular status (history of hypertension, diabetes mellitus without retinal affection, and smoking) were assessed by medical history. By univariate analyses, parameters associated with visual outcome were weighted (-1 to 6 points). A multivariate logistic regression model with the categorized visual outcome parameter (>=0 letters gained after 1 month) as the dependent variate and the sum score as the independent variate (continuous scale) was used to estimate the score value-specific probabilities of letters gained >=0 1 month post injection. RESULTS: The indicators of vascular status negatively influenced the likelihood of a letter gain >=0 whereas an increase in the arterial RBFV strongly increased it. The area under the receiver operating characteristics curve for these parameters investigated was 0.71 (95% CI: 0.43 1.00). CONCLUSION: Changes in the arterial RBFV following 3 days after ranibizumab injection combined with three indicators of the vascular status identified nvAMD patients with favorable visual outcome accurately. PMID- 25721521 TI - Response to 'Opaque intraocular lens implantation'. PMID- 25721522 TI - In vivo reflectance confocal microscopy characterization of field-directed 5 fluorouracil 0.5%/salicylic acid 10% in actinic keratosis. AB - Actinic keratosis (AK), a frequently diagnosed cutaneous neoplasm in individuals with chronic sun exposure or fair skin, is a risk factor for squamous cell carcinoma. AK presents as clinically visible lesions and/or as subclinical lesions where an entire field of area (field cancerization) contains lesions of various grades. The diagnosis and surveillance of subclinical AK is challenging. We report a new AK management approach, including subclinical AK, with noninvasive in vivo reflectance confocal microscopy (RCM) monitoring of field directed topical 5-fluorouracil 0.5%/salicylic acid 10.0% (5-FU/SA; currently approved for single lesions). In this case series, eight patients with primarily recurrent, multiple AKs received <= 6 weeks of field-directed 5-FU/SA; complete clearance of clinical/subclinical AKs on various body areas was shown in most patients using RCM. RCM facilitated the detection/characterization of subclinical AKs in the setting of field cancerization. Topical field-directed 5-FU/SA monitored with RCM is a promising management approach for subclinical AKs. PMID- 25721523 TI - Determination of physiological, taxonomic, and molecular characteristics of a cultivable arsenic-resistant bacterial community. AB - A collection of 219 bacterial arsenic-resistant isolates was constituted from neutral arsenic mine drainage sediments. Isolates were grown aerobically or anaerobically during 21 days on solid DR2A medium using agar or gelan gum as gelling agent, with 7 mM As(III) or 20 mM As(V) as selective pressure. Interestingly, the sum of the different incubation conditions used (arsenic form, gelling agent, oxygen pressure) results in an overall increase of the isolate diversity. Isolated strains mainly belonged to Proteobacteria (63%), Actinobacteria (25%), and Bacteroidetes (10%). The most representative genera were Pseudomonas (20%), Acinetobacter (8%), and Serratia (15%) among the Proteobacteria; Rhodococcus (13%) and Microbacterium (5%) among Actinobacteria; and Flavobacterium (13%) among the Bacteroidetes. Isolates were screened for the presence of arsenic-related genes (arsB, ACR3(1), ACR3(2), aioA, arsM, and arrA). In this way, 106 ACR3(1)-, 74 arsB-, 22 aioA-, 14 ACR3(2)-, and one arsM-positive PCR products were obtained and sequenced. Analysis of isolate sensitivity toward metalloids (arsenite, arsenate, and antimonite) revealed correlations between taxonomy, sensitivity, and genotype. Antimonite sensitivity correlated with the presence of ACR3(1) mainly present in Bacteroidetes and Actinobacteria, and arsenite or antimonite resistance correlated with arsB gene presence. The presence of either aioA gene or several different arsenite carrier genes did not ensure a high level of arsenic resistance in the tested conditions. PMID- 25721524 TI - Oxidative stress and brain mitochondria swelling induced by endosulfan and protective role of quercetin in rat. AB - The neurological damages resulted by endosulfan poisoning is not completely elucidated, especially in cellular organelles such as mitochondria. In the present study, the pro-oxidant effect of endosulfan on brain mitochondria was first investigated. Gavages of endosulfan into rats at the dose of 2 mg/kg induced oxidative stress in this organelle since it provokes a significant reduction of catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) level. In addition, a significant increase in mitochondria swelling and malondialdehyde (MDA) levels were observed in neuronal mitochondria, indicating clearly an intense peroxidation within mitochondria. Second, the protective effect of quercetin (QE) (10 mg/kg) against endosulfan-induced oxidative stress in mitochondria was also assessed. Indeed, the pretreatment of rats with QE protects brain mitochondria from oxidative stress, lipid peroxidation, and mitochondria swelling induced by endosulfan. The activities of antioxidant enzymes and the mitochondrial content of GSH and MDA were returned to control values. Thus, although endosulfan can have neurotoxic effects in brain rats, this toxicity can be prevented by quercetin. PMID- 25721525 TI - The effect of aging on sequestration and bioaccessibility of oxytetracycline in soils. AB - Veterinary antibiotics introduced into soil environment may change the composition and functioning of soil microbial communities and promote the spreading of antibiotic resistance. Actual risks depend on the antibiotic's bioaccessibility and sequestration in soils, which may vary with contact time and soil properties. We elucidated changes in the horsebean plant's bioaccessible oxytetracycline with increasing contact time in three different soils (cinnamon, red, and brown soil) and observed discrepancy in oxytetracycline dissipation using sequential extractions with H2O-, 0.01 M CaCl2-, and Mcllvaine- in the same three soils. The results showed lower quantities of oxytetracycline with increasing contact time over 20 days than the level in freshly contaminated soils but hugely discrepant quantities among the three tested soils. In addition, aging largely reduced dissipation of H2O-, 0.01 M CaCl2-, and Mcllvaine- extracted oxytetracycline in soils before planting. However, bioturbation helped increase the H2O-, CaCl2-, and Mcllvaine- extracted oxytetracyline from cinnamon and brown soils with aging. Lastly, correlation analysis indicated that bioaccessibility of oxytetracycline significantly correlates with the total of H2O-, CaCl2-, and Mcllvaine- extracted oxytetracycline (0.676**, p < 0.01) in soils, especially the H2O- (0.789**, p < 0.01) and Mcllvaine- (0.686**, p < 0.01) extracted oxytetracycline with aging. Overall, this study provides some basic understanding of the aging effect on sequestration and bioaccessibility of veterinary antibiotics in soils. PMID- 25721526 TI - Biodegradation of free cyanide and subsequent utilisation of biodegradation by products by Bacillus consortia: optimisation using response surface methodology. AB - A mesophilic alkali-tolerant bacterial consortium belonging to the Bacillus genus was evaluated for its ability to biodegrade high free cyanide (CN(-)) concentration (up to 500 mg CN(-)/L), subsequent to the oxidation of the formed ammonium and nitrates in a continuous bioreactor system solely supplemented with whey waste. Furthermore, an optimisation study for successful cyanide biodegradation by this consortium was evaluated in batch bioreactors (BBs) using response surface methodology (RSM). The input variables, that is, pH, temperature and whey-waste concentration, were optimised using a numerical optimisation technique where the optimum conditions were found to be as follows: pH 9.88, temperature 33.60 degrees C and whey-waste concentration of 14.27 g/L, under which 206.53 mg CN(-)/L in 96 h can be biodegraded by the microbial species from an initial cyanide concentration of 500 mg CN(-)/L. Furthermore, using the optimised data, cyanide biodegradation in a continuous mode was evaluated in a dual-stage packed-bed bioreactor (PBB) connected in series to a pneumatic bioreactor system (PBS) used for simultaneous nitrification, including aerobic denitrification. The whey-supported Bacillus sp. culture was not inhibited by the free cyanide concentration of up to 500 mg CN(-)/L, with an overall degradation efficiency of >= 99 % with subsequent nitrification and aerobic denitrification of the formed ammonium and nitrates over a period of 80 days. This is the first study to report free cyanide biodegradation at concentrations of up to 500 mg CN( )/L in a continuous system using whey waste as a microbial feedstock. The results showed that the process has the potential for the bioremediation of cyanide containing wastewaters. PMID- 25721527 TI - Industrial sources of primary and secondary organic aerosols in two urban environments in Spain. AB - In urban areas, primary and secondary organic aerosols are typically considered to originate from vehicular traffic emissions. However, industrial emissions within or in the vicinity of urban areas may also be significant contributors to carbonaceous aerosol concentrations. This hypothesis was tested and validated in two urban areas in Spain. The observed unusual dominance of organic carbon (OC) over elemental carbon (EC), the analysis of the variability of OC, EC and OC/EC and their correlation with transport patterns suggested the presence of OC sources associated with industrial activities. A methodology based on chemical speciation of particulate matter (PM) followed by the application of receptor modelling techniques allowed for the identification of the specific industrial sources of OC, which were linked to primary OC emissions from a grain drying plant (cereal) and to secondary OC formation from paper production activities (paper mills), as well as from urban sources and biogenic emissions. This work presents an integrated approach to identifying and characterizing of industrial sources of carbonaceous aerosols in urban areas, aiming to improve the scarce body of literature currently available on this topic. PMID- 25721528 TI - Effects of time, soil organic matter, and iron oxides on the relative retention and redistribution of lead, cadmium, and copper on soils. AB - In order to predict the bioavailability of toxic metals in soils undergoing degradation of organic matter (OM) and iron oxides (IOs), it is vital to understand the roles of these soil components in relation to metal retention and redistribution with time. In this present work, batch competitive sorptions of Pb(II), Cu(II), and Cd(II) were investigated between 1 and 90 days. Results showed that competition affected Cd(II) sorption more than Cu(II) and Pb(II). The sorption followed the trend Pb(II) > > Cu(II) > Cd(II), irrespective of aging, and this high preference for Pb(II) ions in soils reduced with time. Removal of OM led to reduction in distribution coefficient (K d) values of ~33% for all cations within the first day. However, K d increased nearly 100% after 7 days and over 1000% after 90-day period. The enhanced K d values indicated that sorptions occurred on the long run on surfaces which were masked by OM. Removal of IO caused selective increases in the K d values, but this was dependent on the dominant soil constituent(s) in the absence of IO. The K d values of the IO degraded samples nearly remained constant irrespective of aging indicating that sorptions on soil components other than the IO are nearly instantaneous while iron oxides played greater role than other constituents with time. Hence, in the soils studied, organic matter content determines the immediate relative metal retention while iron oxides determine the redistribution of metals with time. PMID- 25721529 TI - Ag@helical chiral TiO2 nanofibers for visible light photocatalytic degradation of 17alpha-ethinylestradiol. AB - Ag-modified helical chiral TiO2 NFs (Ag@chiral TiO2 NFs) were fabricated and characterized by ultraviolet-visible absorption spectroscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. This novel material exhibited efficient photocatalytic activity for the degradation of 17alpha-ethinylestradiol (EE2) in water under visible light irradiation with an optimum size of deposited silver nanoparticles (Ag NPs) in the range of 12 ~ 14 nm. The pseudo-first-order rate constant (k obs) for EE2 photodegradation by Ag@chiral TiO2 NFs increased by up to a factor of 20.1 when compared with that of pure chiral TiO2 NFs. The high photocatalytic activity can be attributed to the interactions between helical chiral TiO2 NFs and surface plasmon resonance effect of Ag NPs. The new catalyst retains its photocatalytic activity at least up to five consecutive cycles. The results clearly demonstrate the feasibility of using Ag@chiral TiO2 NFs for the photocatalytic removal of EE2 and other endocrine-disrupting chemicals from water. PMID- 25721530 TI - Stable isotope probing reveals the importance of Comamonas and Pseudomonadaceae in RDX degradation in samples from a Navy detonation site. AB - This study investigated the microorganisms involved in hexahydro-1,3,5-trinitro 1,3,5-triazine (RDX) degradation from a detonation area at a Navy base. Using Illumina sequencing, microbial communities were compared between the initial sample, samples following RDX degradation, and controls not amended with RDX to determine which phylotypes increased in abundance following RDX degradation. The effect of glucose on these communities was also examined. In addition, stable isotope probing (SIP) using labeled ((13)C3, (15)N3-ring) RDX was performed. Illumina sequencing revealed that several phylotypes were more abundant following RDX degradation compared to the initial soil and the no-RDX controls. For the glucose-amended samples, this trend was strong for an unclassified Pseudomonadaceae phylotype and for Comamonas. Without glucose, Acinetobacter exhibited the greatest increase following RDX degradation compared to the initial soil and no-RDX controls. Rhodococcus, a known RDX degrader, also increased in abundance following RDX degradation. For the SIP study, unclassified Pseudomonadaceae was the most abundant phylotype in the heavy fractions in both the presence and absence of glucose. In the glucose-amended heavy fractions, the 16S ribosomal RNA (rRNA) genes of Comamonas and Anaeromxyobacter were also present. Without glucose, the heavy fractions also contained the 16S rRNA genes of Azohydromonas and Rhodococcus. However, all four phylotypes were present at a much lower level compared to unclassified Pseudomonadaceae. Overall, these data indicate that unclassified Pseudomonadaceae was primarily responsible for label uptake in both treatments. This study indicates, for the first time, the importance of Comamonas for RDX removal. PMID- 25721531 TI - Intervention to reduce PCBs: learnings from a controlled study of Anniston residents. AB - Nonabsorbable dietary lipid reduces the absorption of dietary PCBs and increases the excretion of previously absorbed stored PCBs. Absorption of all PCB congeners will presumably be interrupted by nonabsorbable lipid; however excretion will be enhanced only for PCBs that have not been metabolized and also for their lipophilic metabolites. Our study with the nonabsorbable lipid, olestra, in a controlled trial in Anniston residents with elevated PCB levels demonstrated that it is possible to enhance removal of PCBs from the body in the clinically meaningful time frame of 1 year. The rate of disappearance of PCBs in participants who ate 15 g/day of olestra was significantly faster than the rate determined during the 5 years prior to intervention. The rate of disappearance was not changed from the pretrial rate in participants who ingested vegetable oil. Consideration of the role of body weight and fat is an important factor in the design of intervention trials of this kind, and the results of this trial suggest that the level of body fat in individuals will influence the rate of removal from the body. Previously reported data from animals and from a case report indicate that weight loss combined with nonabsorbable dietary lipid will maximize removal of PCBs and presumably other stored organochlorine compounds. The design of future intervention trials should include a focus on body fat levels and changes. Future trials should also include the testing of dietary compounds other than olestra that have affinity for PCBs, such as plant-derived polyphenols. PMID- 25721532 TI - Stimulus control in a go/no-go procedure with compound stimuli with pigeons. AB - Our previous study using a go/no-go procedure with compound stimuli taught pigeons to peck at two-component compounds A1B1, A2B2, B1C1, B2C2 and refrain from pecking at A1B2, A2B1, B1C2, B2C1. Subjects showed training-consistent responding in tests presenting compounds rotated 180 degrees (BA and CB relations) but not recombined (AC and CA relations). It is unclear whether the responses to BA and CB stimuli were controlled by the relation between the components (conditional discrimination) or by the compounds functioning as a unitary stimulus (simple discrimination). The present study assessed whether the four pigeons from our previous study would show maintained discrimination when the positions of the components of each compound were changed relative to the training stimuli. Training components were rotated 90 degrees to the right and left (Tests 1 and 2, respectively), presented with a 1cm separation (Test 3), and presented with a 1cm separation and rotated 180 degrees (Test 4). Subject P11 maintained discriminations in all tests. Maintained discriminations were only observed in Tests 1 and 2 for P21, 1-3 for P10, and 1, 2, and 4 for P9. Results indicate that pigeons may not maintain discrimination when stimulus elements are presented further apart and/or rotated 180 degrees relative to training. PMID- 25721533 TI - Investigating intertemporal choice through experimental evolutionary robotics. AB - In intertemporal choices, subjects face a trade-off between value and delay: achieving the most valuable outcome requires a longer time, whereas the immediately available option is objectively poorer. Intertemporal choices are ubiquitous, and comparative studies reveal commonalities and differences across species: all species devalue future rewards as a function of delay (delay aversion), yet there is a lot of inter-specific variance in how rapidly such devaluation occurs. These differences are often interpreted in terms of ecological rationality, as depending on environmental factors (e.g., feeding ecology) and the physiological and morphological constraints of different species (e.g., metabolic rate). Evolutionary hypotheses, however, are hard to verify in vivo, since it is difficult to observe precisely enough real environments, not to mention ancestral ones. In this paper, we discuss the viability of an approach based on evolutionary robotics: in Study 1, we evolve robots without a metabolism in five different ecologies; in Study 2, we evolve metabolic robots (i.e., robots that consume energy over time) in three different ecologies. The intertemporal choices of the robots are analyzed both in their ecology and under laboratory conditions. Results confirm the generality of delay aversion and the usefulness of studying intertemporal choice through experimental evolutionary robotics. PMID- 25721534 TI - Normal values of 24-hour ambulatory esophageal impedance-pH monitoring in a rural South African cohort of healthy participants. AB - There are no data on 24-hour multichannel intraluminal impedance and pH monitoring in African populations. The purpose of this study was to provide the normal values of esophageal impedance and pH monitoring in a rural African populations. South African healthy rural participants were recruited and underwent 24 hours of esophageal impedance and pH monitoring. The median and the 95th percentiles of the total reflux episodes were 49 and 97, respectively, of which the corresponding number of acidic, weakly acidic, and weakly alkaline reflux were 15 and 55, 17 and 51, and 8 and 36, respectively. The compositions of the total reflux were 5 and 21 for liquid, 27 and 72 for mixed, and 10 and 39 for gas reflux, respectively. The median bolus clearance was 18 seconds and the median bolus exposure was 14 minutes/24 hours. The proximal extent was 6%. The 95th percent time of esophageal exposure to acid was 8.6 in 24 hours. Female and overweight participants were associated with an increased number of reflux events. There were more reflux episodes, and of which, more were weakly alkaline compared with previous similar studies. The findings provide reference values of gastroesophageal reflux for a South African rural population. PMID- 25721535 TI - Height, weight, and age predict quadriceps tendon length and thickness in skeletally immature patients. AB - BACKGROUND: Quadriceps tendon autografts have been used with success in adults and are becoming a popular graft option in pediatric patients because of size, decreased donor site morbidity, ease of harvest, and favorable biomechanical characteristics. However, little is known about the length and thickness of the quadriceps tendon in pediatric patients. PURPOSE: This study aimed to determine whether quadriceps tendon length and thickness follow a predictable pattern of development based on height, weight, age, and body mass index in skeletally immature patients. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The height, weight, age, and sex of 151 children between 4 and 16 years old were recorded. Ultrasound measurements of the length and thickness of bilateral quadriceps tendons were performed by a single technician and recorded for statistical analysis. RESULTS: The average quadriceps tendon length and thickness were 6.87 +/- 1.49 cm and 0.37 +/- 0.12 cm, respectively. Tendon length averaged 3.89 cm at age 4 years and 7.98 cm at 16 years, whereas thickness averaged 0.24 cm at 4 years and 0.40 cm at 16 years of age. There was no significant difference in tendon length or thickness between males and females (P = .97). Tendon length and thickness increased significantly with age, weight, and height (P < .01 for all). CONCLUSION: The quadriceps tendon is of sufficient length and thickness to be used as an autograft for pediatric patients. The size of the graft is predictable using the age, height, and weight of the patient. Graft length and thickness can be easily confirmed using ultrasound. PMID- 25721536 TI - Towards detecting open spina bifida in the first trimester: the examination of the posterior brain. AB - INTRODUCTION: Our aim was to examine the value of indirect signs of open spina bifida in the mid-sagittal view of the posterior brain at the 11-13 weeks' ultrasound examination and to summarize the current evidence for the first trimester diagnosis of spina bifida. METHODS: This was a prospective study in routine obstetric population. The presence of four almost parallel lines (four line view) in the posterior brain was recorded. Biparietal diameter (BPD), intracranial translucency (IT) and cisterna magna (CM) were measured. The ratio of IT to CM (R ratio) was calculated. RESULTS: 2,491 pregnancies were examined prospectively. Updated reference ranges for IT and CM were constructed. There were 3 cases with open spina bifida, and the four-line view was abnormal in 2 of them. The abnormal fetuses had smaller BPD as well as pronounced reduction in the CM and increase in the R ratio. DISCUSSION: Examination of the posterior brain was feasible in all fetuses in the setting of the routine 11-13 weeks' ultrasound examination. Indirect signs of spina bifida are visible in the mid-sagittal view of the posterior brain, and the assessment of these structures can be a reliable tool in the early identification of this abnormality. PMID- 25721537 TI - Molecular phylogeny of Arcoidea with emphasis on Arcidae species (Bivalvia: Pteriomorphia) along the coast of China: challenges to current classification of arcoids. AB - The current classifications of arcoids are based on phenetic similarity, which display considerable convergence in several shell and anatomical characters, challenging phylogenetic analysis. Independent molecular analysis of DNA sequences is often necessary for accurate taxonomic assignments of arcoids, especially when morphological characters are equivocal. Here we present molecular evidence of the phylogenetic relationships among arcoid species based on Bayesian inference and Maximum Likelihood analyses of three nuclear genes (18SrRNA, 28SrRNA, and histone H3) and two mitochondrial genes (COI and 12S). Tree topologies are discussed by considering traditional arrangements of taxonomic units and previous molecular studies. The results confirm the monophyly of the order Arcoida, the family Noetiidae, and the subfamilies Anadarinae and Striarcinae, with support for the inclusion of the Glycymerididae in the Arcoidea. The subfamily Arcinae and the genera Arca, Barbatia, Scapharca, Anadara, and Glycymeris are non-monophyletic, suggesting that taxonomic issues still remain. The families Noetiidae, Cucullaeidae, and Glycymerididae appear as subgroups within, rather than sister groups to, the Arcidae. This study strongly suggests the need to carry out a taxonomic revision of the Arcoidea, especially the Arcidae, through combined analysis of morphological, paleontological, and molecular data. PMID- 25721538 TI - MitoPhAST, a new automated mitogenomic phylogeny tool in the post-genomic era with a case study of 89 decapod mitogenomes including eight new freshwater crayfish mitogenomes. AB - The increased rate at which complete mitogenomes are being sequenced and their increasing use for phylogenetic studies have resulted in a bioinformatic bottleneck in preparing and utilising such data for phylogenetic analysis. Hence, we present MitoPhAST, an automated tool that (1) identifies annotated protein coding gene features and generates a standardised, concatenated and partitioned amino acid alignment directly from complete/partial GenBank/EMBL-format mitogenome flat files, (2) generates a maximum likelihood phylogenetic tree using optimised protein models and (3) reports various mitochondrial genes and sequence information in a table format. To demonstrate the capacity of MitoPhAST in handling a large dataset, we used 81 publicly available decapod mitogenomes, together with eight new complete mitogenomes of Australian freshwater crayfishes, including the first for the genus Gramastacus, to undertake an updated test of the monophyly of the major groups of the order Decapoda and their phylogenetic relationships. The recovered phylogenetic trees using both Bayesian and ML methods support the results of studies using fragments of mtDNA and nuclear markers and other smaller-scale studies using whole mitogenomes. In comparison to the fragment-based phylogenies, nodal support values are generally higher despite reduced taxon sampling suggesting there is value in utilising more fully mitogenomic data. Additionally, the simple table output from MitoPhAST provides an efficient summary and statistical overview of the mitogenomes under study at the gene level, allowing the identification of missing or duplicated genes and gene rearrangements. The finding of new mtDNA gene rearrangements in several genera of Australian freshwater crayfishes indicates that this group has undergone an unusually high rate of evolutionary change for this organelle compared to other major families of decapod crustaceans. As a result, freshwater crayfishes are likely to be a useful model for studies designed to understand the evolution of mtDNA rearrangements. We anticipate that our bioinformatics pipeline will substantially help mitogenome-based studies increase the speed, accuracy and efficiency of phylogenetic studies utilising mitogenome information. MitoPhAST is available for download at https://github.com/mht85/MitoPhAST. PMID- 25721539 TI - Mitogenomics reveals phylogeny and repeated motifs in control regions of the deep sea family Siboglinidae (Annelida). AB - Deep-sea tubeworms in the annelid family Siboglinidae have drawn considerable interest regarding their ecology and evolutionary biology. As adults, they lack a digestive tract and rely on endosymbionts for nutrition. Moreover, they are important members of chemosynthetic environments including hydrothermal vents, cold seeps, muddy sediments, and whale bones. Evolution and diversification of siboglinids has been associated with host-symbiont relationships and reducing habitats. Despite their importance, the taxonomy and phylogenetics of this clade are debated due to conflicting results. In this study, 10 complete and 2 partial mitochondrial genomes and one transcriptome were sequenced and analyzed to address siboglinid evolution. Notably, repeated nucleotide motifs were found in control regions of these mt genomes, which may explain previous challenges of sequencing siboglinid mt genomes. Phylogenetic analyses of amino acid and nucleotide datasets were conducted in order to infer evolutionary history. Both analyses generally had strong nodal support and suggest Osedax is most closely related to the Vestimentifera+Sclerolinum clade, rather than Frenulata, as recently reported. These results imply Osedax, the only siboglinid lineage with heterotrophic endosymbionts, evolved from a lineage utilizing chemoautotrophic symbionts. PMID- 25721540 TI - History of chronic stress modifies acute stress-evoked fear memory and acoustic startle in male rats. AB - Chronicity of trauma exposure plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD). Thus, exposure to multiple traumas on a chronic scale leads to worse outcomes than acute events. The rationale for the current study was to investigate the effects of a single adverse event versus the same event on a background of chronic stress. We hypothesized that a history of chronic stress would lead to worse behavioral outcomes than a single event alone. Male rats (n = 14/group) were exposed to either a single traumatic event in the form of electric foot shocks (acute shock, AS), or to footshocks on a background of chronic stress (chronic variable stress-shock, CVS-S). PTSD-relevant behaviors (fear memory and acoustic startle responses) were measured following 7 d recovery. In line with our hypothesis, CVS-S elicited significant increases in fear acquisition and conditioning versus the AS group. Unexpectedly, CVS-S elicited reduced startle reactivity to an acoustic stimulus in comparison with the AS group. Significant increase in FosB/DeltaFosB-like immunostaining was observed in the dentate gyrus, basolateral amygdala and medial prefrontal cortex of CVS-S rats. Assessments of neuropeptide Y (NPY), a stress-regulatory transmitter associated with chronic PTSD, revealed selective reduction in the hippocampus of CVS-S rats. Collectively, our data show that cumulative stress potentiates delayed fear memory and impacts defensive responding. Altered neuronal activation in forebrain limbic regions and reduced NPY may contribute to these phenomena. Our preclinical studies support clinical findings reporting worse PTSD outcomes stemming from cumulative traumatization in contrast to acute trauma. PMID- 25721541 TI - Early adversity, immunity and infectious disease. AB - Complex interactions between biological, behavioral and environmental factors are involved in mediating individual differences in health and disease. In this review, we present evidence suggesting that increased vulnerability to infectious disease may be at least, in part, due to long-lasting effects of early life psychosocial adversities. Studies have shown that maternal psychosocial stress during pregnancy is associated with long lasting changes in immune function and disease resistance in the offspring. Studies further indicated that harsh environmental conditions during the neonatal period may also cause lasting changes in host response to infectious disease. Although the mechanisms involved in these effects have not been fully examined, several potential mediators have been described, including changes in the development of the offspring hypothalamic-pituitary-adrenal axis, alterations in epigenetic pathways, stress related maternal health risk behavior and infection during pregnancy. Although there are ample literature indicating that perinatal psychosocial stress increases vulnerability to disease, other reports suggest that mild predictable stressors may benefit the organism and allow better coping with future stressors. Thus, understanding the possible consequences of perinatal adversities and the mechanisms that are involved in immune regulation is important for increasing awareness to the potential outcomes of early negative life events and providing insight into potential therapies to combat infection in vulnerable individuals. PMID- 25721543 TI - Long-term independent brain-computer interface home use improves quality of life of a patient in the locked-in state: a case study. AB - OBJECTIVE: Despite intense brain-computer interface (BCI) research for >2 decades, BCIs have hardly been established at patients' homes. The current study aimed at demonstrating expert independent BCI home use by a patient in the locked in state and the effect it has on quality of life. DESIGN: In this case study, the P300 BCI-controlled application Brain Painting was facilitated and installed at the patient's home. Family and caregivers were trained in setting up the BCI system. After every BCI session, the end user indicated subjective level of control, loss of control, level of exhaustion, satisfaction, frustration, and enjoyment. To monitor BCI home use, evaluation data of every session were automatically sent and stored on a remote server. Satisfaction with the BCI as an assistive device and subjective workload was indicated by the patient. In accordance with the user-centered design, usability of the BCI was evaluated in terms of its effectiveness, efficiency, and satisfaction. The influence of the BCI on quality of life of the end user was assessed. SETTING: At the patient's home. PARTICIPANT: A 73-year-old patient with amyotrophic lateral sclerosis in the locked-in state. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The BCI has been used by the patient independent of experts for >14 months. The patient painted in about 200 BCI sessions (1-3 times per week) with a mean painting duration of 81.86 minutes (SD=52.15, maximum: 230.41). BCI improved quality of life of the patient. RESULTS: In most of the BCI sessions the end user's satisfaction was high (mean=7.4, SD=3.24; range, 0-10). Dissatisfaction occurred mostly because of technical problems at the beginning of the study or varying BCI control. The subjective workload was moderate (mean=40.61; range, 0-100). The end user was highy satisfied with all components of the BCI (mean 4.42-5.0; range, 1 5). A perfect match between the user and the BCI technology was achieved (mean: 4.8; range, 1-5). Brain Painting had a positive impact on the patient's life on all three dimensions: competence (1.5), adaptability (2.17) and self-esteem (1.5); (range: -3 = maximum negative impact; 3 maximum positive impact). The patient had her first public art exhibition in July 2013; future exhibitions are in preparation. CONCLUSIONS: Independent BCI home use is possible with high satisfaction for the end user. The BCI indeed positively influenced quality of life of the patient and supports social inclusion. Results demonstrate that visual P300 BCIs can be valuable for patients in the locked-in state even if other means of communication are still available (eye tracker). PMID- 25721542 TI - Brain-computer interface: current and emerging rehabilitation applications. AB - A formal definition of brain-computer interface (BCI) is as follows: a system that acquires brain signal activity and translates it into an output that can replace, restore, enhance, supplement, or improve the existing brain signal, which can, in turn, modify or change ongoing interactions between the brain and its internal or external environment. More simply, a BCI can be defined as a system that translates "brain signals into new kinds of outputs." After brain signal acquisition, the BCI evaluates the brain signal and extracts signal features that have proven useful for task performance. There are 2 broad categories of BCIs: implantable and noninvasive, distinguished by invasively and noninvasively acquired brain signals, respectively. For this supplement, we will focus on BCIs that use noninvasively acquired brain signals. PMID- 25721544 TI - Toward independent home use of brain-computer interfaces: a decision algorithm for selection of potential end-users. AB - Noninvasive brain-computer interfaces (BCIs) use scalp-recorded electrical activity from the brain to control an application. Over the past 20 years, research demonstrating that BCIs can provide communication and control to individuals with severe motor impairment has increased almost exponentially. Although considerable effort has been dedicated to offline analysis for improving signal detection and translation, far less effort has been made to conduct online studies with target populations. Thus, there remains a great need for both long term and translational BCI studies that include individuals with disabilities in their own homes. Completing these studies is the only sure means to answer questions about BCI utility and reliability. Here we suggest an algorithm for candidate selection for electroencephalographic (EEG)-based BCI home studies. This algorithm takes into account BCI end-users and their environment and should assist in study design and substantially improve subject retention rates, thereby improving the overall efficacy of BCI home studies. It is the result of a workshop at the Fifth International BCI Meeting that allowed us to leverage the expertise of multiple research laboratories and people from multiple backgrounds in BCI research. PMID- 25721545 TI - Brain-computer interface users speak up: the Virtual Users' Forum at the 2013 International Brain-Computer Interface Meeting. AB - More than 300 researchers gathered at the 2013 International Brain-Computer Interface (BCI) Meeting to discuss current practice and future goals for BCI research and development. The authors organized the Virtual Users' Forum at the meeting to provide the BCI community with feedback from users. We report on the Virtual Users' Forum, including initial results from ongoing research being conducted by 2 BCI groups. Online surveys and in-person interviews were used to solicit feedback from people with disabilities who are expert and novice BCI users. For the Virtual Users' Forum, their responses were organized into 4 major themes: current (non-BCI) communication methods, experiences with BCI research, challenges of current BCIs, and future BCI developments. Two authors with severe disabilities gave presentations during the Virtual Users' Forum, and their comments are integrated with the other results. While participants' hopes for BCIs of the future remain high, their comments about available systems mirror those made by consumers about conventional assistive technology. They reflect concerns about reliability (eg, typing accuracy/speed), utility (eg, applications and the desire for real-time interactions), ease of use (eg, portability and system setup), and support (eg, technical support and caregiver training). People with disabilities, as target users of BCI systems, can provide valuable feedback and input on the development of BCI as an assistive technology. To this end, participatory action research should be considered as a valuable methodology for future BCI research. PMID- 25721546 TI - What would brain-computer interface users want: opinions and priorities of potential users with spinal cord injury. AB - OBJECTIVES: To identify perceptions among people with spinal cord injury (SCI) of the priorities for brain-computer interface (BCI) applications and design features along with the time investment and risk acceptable to obtain a BCI. DESIGN: Survey. SETTING: Research registry participants surveyed via telephone and BCI usage study participants surveyed in person before BCI use. PARTICIPANTS: Convenience sample of people with SCI (N=40), consisting of persons from the registry (n=30) and from the BCI study (n=10). Participants were classified as those with low function (n=24) and those with high function (n=16). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Descriptive statistics of functional independence, living situations and support structures, ratings of importance of different task and design features, and acceptable levels of performance, risk, and time investment. RESULTS: BCIs were of interest to 96% of the low-function group. Emergency communication was the top priority task (ranked in the top 2 by 43%). The most important design features were "functions the BCI provides" and "simplicity of BCI setup." Desired performance was 90% accuracy, with standby mode errors no more than once every 4 hours and speeds of more than 20 letters per minute. Dry electrodes were preferred over gel or implanted electrodes (P<.05). Median acceptable setup time was 10 to 20 minutes, satisfying 65% of participants. CONCLUSIONS: People with low functional independence resulting from SCI have a strong interest in BCIs. Advances in speed and setup time will be required for BCIs to meet the desired performance. Creating BCI functions appropriate to the needs of those with SCI will be of ultimate importance for BCI acceptance with this population. PMID- 25721547 TI - Assistive device with conventional, alternative, and brain-computer interface inputs to enhance interaction with the environment for people with amyotrophic lateral sclerosis: a feasibility and usability study. AB - OBJECTIVE: To evaluate the feasibility and usability of an assistive technology (AT) prototype designed to be operated with conventional/alternative input channels and a P300-based brain-computer interface (BCI) in order to provide users who have different degrees of muscular impairment resulting from amyotrophic lateral sclerosis (ALS) with communication and environmental control applications. DESIGN: Proof-of-principle study with a convenience sample. SETTING: An apartment-like space designed to be fully accessible by people with motor disabilities for occupational therapy, placed in a neurologic rehabilitation hospital. PARTICIPANTS: End-users with ALS (N=8; 5 men, 3 women; mean age +/- SD, 60 +/- 12 y) recruited by a clinical team from an ALS center. INTERVENTIONS: Three experimental conditions based on (1) a widely validated P300 based BCI alone; (2) the AT prototype operated by a conventional/alternative input device tailored to the specific end-user's residual motor abilities; and (3) the AT prototype accessed by a P300-based BCI. These 3 conditions were presented to all participants in 3 different sessions. MAIN OUTCOME MEASURES: System usability was evaluated in terms of effectiveness (accuracy), efficiency (written symbol rate, time for correct selection, workload), and end-user satisfaction (overall satisfaction) domains. A comparison of the data collected in the 3 conditions was performed. RESULTS: Effectiveness and end-user satisfaction did not significantly differ among the 3 experimental conditions. Condition III was less efficient than condition II as expressed by the longer time for correct selection. CONCLUSIONS: A BCI can be used as an input channel to access an AT by persons with ALS, with no significant reduction of usability. PMID- 25721548 TI - Hybrid P300-based brain-computer interface to improve usability for people with severe motor disability: electromyographic signals for error correction during a spelling task. AB - OBJECTIVE: To evaluate the impact of a hybrid control on usability of a P300 based brain-computer interface (BCI) system that was designed to control an assistive technology software and was integrated with an electromyographic channel for error correction. DESIGN: Proof-of-principle study with a convenience sample. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Participants (N=11) in this pilot study included healthy (n=8) and severely motor impaired (n=3) persons. The 3 people with severe motor disability were identified as potential candidates to benefit from the proposed hybrid BCI system for communication and environmental interaction. INTERVENTIONS: To eventually investigate the improvement in usability, we compared 2 modalities of BCI system control: a P300-based and a hybrid P300 electromyographic-based mode of control. MAIN OUTCOME MEASURES: System usability was evaluated according to the following outcome measures within 3 domains: (1) effectiveness (overall system accuracy and P300-based BCI accuracy); (2) efficiency (throughput time and users' workload); and (3) satisfaction (users' satisfaction). We also considered the information transfer rate and time for selection. RESULTS: Findings obtained in healthy participants were in favor of a higher usability of the hybrid control as compared with the nonhybrid. A similar trend was indicated by the observational results gathered from each of the 3 potential end-users. CONCLUSIONS: The proposed hybrid BCI control modality could provide end-users with severe motor disability with an option to exploit some residual muscular activity, which could not be fully reliable for properly controlling an assistive technology device. The findings reported in this pilot study encourage the implementation of a clinical trial involving a large cohort of end-users. PMID- 25721549 TI - Sensorimotor modulation assessment and brain-computer interface training in disorders of consciousness. AB - OBJECTIVES: To assess awareness in subjects who are in a minimally conscious state by using an electroencephalogram-based brain-computer interface (BCI), and to determine whether these patients may learn to modulate sensorimotor rhythms with visual feedback, stereo auditory feedback, or both. DESIGN: Initial assessment included imagined hand movement or toe wiggling to activate sensorimotor areas and modulate brain rhythms in 90 trials (4 subjects). Within subject and within-group analyses were performed to evaluate significant activations. A within-subject analysis was performed involving multiple BCI technology training sessions to improve the capacity of the user to modulate sensorimotor rhythms through visual and auditory feedback. SETTING: Hospital, homes of subjects, and a primary care facility. PARTICIPANTS: Subjects (N=4; 3 men, 1 woman) who were in a minimally conscious state (age range, 27-53 y; 1-12 y after brain injury). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Awareness detection was determined from sensorimotor patterns that differed for each motor imagery task. BCI performance was determined from the mean classification accuracy of brain patterns by using a BCI signal processing framework and assessment of performance in multiple sessions. RESULTS: All subjects demonstrated significant and appropriate brain activation during the initial assessment, and real-time feedback was provided to improve arousal. Consistent activation was observed in multiple sessions. CONCLUSIONS: The electroencephalogram-based assessment showed that patients in a minimally conscious state may have the capacity to operate a simple BCI-based communication system, even without any detectable volitional control of movement. PMID- 25721550 TI - Proof of principle of a brain-computer interface approach to support poststroke arm rehabilitation in hospitalized patients: design, acceptability, and usability. AB - OBJECTIVE: To evaluate the feasibility of brain-computer interface (BCI)-assisted motor imagery training to support hand/arm motor rehabilitation after stroke during hospitalization. DESIGN: Proof-of-principle study. SETTING: Neurorehabilitation hospital. PARTICIPANTS: Convenience sample of patients (N=8) with new-onset arm plegia or paresis caused by unilateral stroke. INTERVENTIONS: The BCI-based intervention was administered as an "add-on" to usual care and lasted 4 weeks. Under the supervision of a therapist, patients were asked to practice motor imagery of their affected hand and received as a discrete feedback the movements of a "virtual" hand superimposed on their own. Such a BCI-based device was installed in a rehabilitation hospital ward. MAIN OUTCOME MEASURES: Following a user-centered design, we assessed system usability in terms of motivation, satisfaction (by means of visual analog scales), and workload (National Aeronautics and Space Administration-Task Load Index). The usability of the BCI-based system was also evaluated by 15 therapists who participated in a focus group. RESULTS: All patients successfully accomplished the BCI training. Significant positive correlations were found between satisfaction and motivation (P=.001, r=.393). BCI performance correlated with interest (P=.027, r=.257) and motivation (P=.012, r=.289). During the focus group, professionals positively acknowledged the opportunity offered by BCI-assisted training to measure patients' adherence to rehabilitation. CONCLUSIONS: An ecological BCI-based device to assist motor imagery practice was found to be feasible as an add-on intervention and tolerable by patients who were exposed to the system in the rehabilitation environment. PMID- 25721551 TI - Facilitating effects of transcranial direct current stimulation on motor imagery brain-computer interface with robotic feedback for stroke rehabilitation. AB - OBJECTIVE: To investigate the efficacy and effects of transcranial direct current stimulation (tDCS) on motor imagery brain-computer interface (MI-BCI) with robotic feedback for stroke rehabilitation. DESIGN: A sham-controlled, randomized controlled trial. SETTING: Patients recruited through a hospital stroke rehabilitation program. PARTICIPANTS: Subjects (N=19) who incurred a stroke 0.8 to 4.3 years prior, with moderate to severe upper extremity functional impairment, and passed BCI screening. INTERVENTIONS: Ten sessions of 20 minutes of tDCS or sham before 1 hour of MI-BCI with robotic feedback upper limb stroke rehabilitation for 2 weeks. Each rehabilitation session comprised 8 minutes of evaluation and 1 hour of therapy. MAIN OUTCOME MEASURES: Upper extremity Fugl Meyer Motor Assessment (FMMA) scores measured end-intervention at week 2 and follow-up at week 4, online BCI accuracies from the evaluation part, and laterality coefficients of the electroencephalogram (EEG) from the therapy part of the 10 rehabilitation sessions. RESULTS: FMMA score improved in both groups at week 4, but no intergroup differences were found at any time points. Online accuracies of the evaluation part from the tDCS group were significantly higher than those from the sham group. The EEG laterality coefficients from the therapy part of the tDCS group were significantly higher than those of the sham group. CONCLUSIONS: The results suggest a role for tDCS in facilitating motor imagery in stroke. PMID- 25721552 TI - Critical issues using brain-computer interfaces for augmentative and alternative communication. AB - Brain-computer interfaces (BCIs) may potentially be of significant practical value to patients in advanced stages of amyotrophic lateral sclerosis and locked in syndrome for whom conventional augmentative and alternative communication (AAC) systems, which require some measure of consistent voluntary muscle control, are not satisfactory options. However, BCIs have primarily been used for communication in laboratory research settings. This article discusses 4 critical issues that should be addressed as BCIs are translated out of laboratory settings to become fully functional BCI/AAC systems that may be implemented clinically. These issues include (1) identification of primary, secondary, and tertiary system features; (2) integrating BCI/AAC systems in the World Health Organization's International Classification of Functioning, Disability and Health framework; (3) implementing language-based assessment and intervention; and (4) performance measurement. A clinical demonstration project is presented as an example of research beginning to address these critical issues. PMID- 25721553 TI - Fipronil induced oxidative stress involves alterations in SOD1 and catalase gene expression in male mice liver: Protection by vitamins E and C. AB - In the present investigation, hepatic oxidative stress induced by fipronil was evaluated in male mice. We also investigated whether pretreatment with antioxidant vitamins E and C could protect mice against these effects. Several studies conducted in cell lines have shown fipronil as a potent oxidant; however, no information is available regarding its oxidative stress inducing potential in an animal model. Out of 8 mice groups, fipronil was administered to three groups at low, medium, and high dose based on its oral LD50 (2.5, 5, and 10 mg/kg). All three doses of fipronil caused a significant increase in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level with concomitant increase in the absolute and relative weight of liver. High dose of fipronil caused significant down-regulation in the hepatic mRNA expression of superoxide dismutase 1 (SOD1) and catalase (0.412 +/- 0.01 and 0.376 +/- 0.05-fold, respectively) as well as an increase in the lipid peroxidation (LPO). Also, decrease in the activity of antioxidant enzymes; SOD, catalase, and glutathione-S transferase (GST) and the content of nonantioxidant enzymes; glutathione and total thiol were recorded. Histopathological examination of liver revealed dose dependant changes such as severe fatty degeneration and vacuolation leading to hepatocellular necrosis. Prior administration of vitamin E or vitamin C against fipronil high dose caused decrease in lipid peroxidation and increased activity of antioxidant enzymes. Severe reduction observed in functional activities of antioxidant enzymes was aptly substantiated by down-regulation seen in their relative mRNA expression. Thus results of the present study imply that liver is an important target organ for fipronil and similar to in vitro reports, it induces oxidative stress in the mice liver, which in turn could be responsible for its hepatotoxic nature. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1147-1158, 2016. PMID- 25721554 TI - Biocompatible enzymatic roller pens for direct writing of biocatalytic materials: "do-it-yourself" electrochemical biosensors. AB - The development of enzymatic-ink-based roller pens for direct drawing of biocatalytic sensors, in general, and for realizing renewable glucose sensor strips, in particular, is described. The resulting enzymatic-ink pen allows facile fabrication of high-quality inexpensive electrochemical biosensors of any design by the user on a wide variety of surfaces having complex textures with minimal user training. Unlike prefabricated sensors, this approach empowers the end user with the ability of "on-demand" and "on-site" designing and fabricating of biocatalytic sensors to suit their specific requirement. The resulting devices are thus referred to as "do-it-yourself" sensors. The bio-active pens produce highly reproducible biocatalytic traces with minimal edge roughness. The composition of the new enzymatic inks has been optimized for ensuring good biocatalytic activity, electrical conductivity, biocompati-bility, reproducible writing, and surface adherence. The resulting inks are characterized using spectroscopic, viscometric, electrochemical, thermal and microscopic techniques. Applicability to renewable blood glucose testing, epidermal glucose monitoring, and on-leaf phenol detection are demonstrated in connection to glucose oxidase and tyrosinase-based carbon inks. The "do-it-yourself" renewable glucose sensor strips offer a "fresh," reproducible, low-cost biocatalytic sensor surface for each blood test. The ability to directly draw biocatalytic conducting traces even on unconventional surfaces opens up new avenues in various sensing applications in low-resource settings and holds great promise for diverse healthcare, environmental, and defense domains. PMID- 25721555 TI - Apoptosis-related gene expression profile in chronic myeloid leukemia patients after imatinib mesylate and dasatinib therapy. AB - BACKGROUND/AIMS: We investigated the effects of tyrosine kinase inhibitors (TKIs) on the expression of apoptosis-related genes (BCL-2 and death receptor family members) in chronic myeloid leukemia (CML) patients. METHODS: Peripheral blood mononuclear cells from 32 healthy subjects and 26 CML patients were evaluated before and after treatment with imatinib mesylate (IM) and dasatinib (DAS) by quantitative PCR. RESULTS: Anti-apoptotic genes (c-FLIP and MCL-1) were overexpressed and the pro-apoptotic BIK was reduced in CML patients. Expression of BMF, A1, c-FLIP, MCL-1, CIAP-2 and CIAP-1 was modulated by DAS. In IM resistant patients, expression of A1, c-FLIP, CIAP-1 and MCL-1 was upregulated, and BCL-2, CIAP-2, BAK, BAX, BIK and FASL expression was downregulated. CONCLUSION: Taken together, our results point out that, in CML, DAS interferes with the apoptotic machinery regulation. In addition, the data suggest that apoptosis-related gene expression profiles are associated with primary resistance to IM. PMID- 25721556 TI - Editorial Comment to Chronic bacterial seminal vesiculitis as a potential disease entity in men with chronic prostatitis. PMID- 25721557 TI - Effectiveness and safety of therapy with vitamin K antagonists in Italian patients aged 80 years or older: a multicentre retrospective study comparing the Zeus algorithm with the PARMA algorithm or manual therapy. AB - BACKGROUND: The use of oral anticoagulant therapy (OAT) has constantly increased in the prevention of thromboembolism, particularly in patients 80 years of age or older. OBJECTIVE: The aim of this multicentre study was to evaluate the efficacy and safety of vitamin K antagonists (VKAs) in elderly patients managed with a computer dosing algorithm compared with a dosage decided by expert physicians. MATERIALS AND METHODS: Nine Italian thrombosis centres utilising the Zeus dosing algorithm were involved. The before-after study enrolled patients managed firstly by medical staff (manual system) or with the PARMA algorithm for 12 months from July 2008 to June 2009 and then with the Zeus algorithm during the analogous period from 2010 to 2011. Of 7605 patients in the OAT maintenance phase, 2281 were older than 80 years (mean age 84.2 years). Data for these 2281 patients managed with both modalities were analysed. RESULTS: Of the 2281 patients 80 years of age or older, 1776 underwent OAT for atrial fibrillation (AF). Use of a dosing algorithm increased the OAT quality: time in therapeutic range (TTR) was significantly (p < 0.001) higher during the Zeus period than during the manual period (71.6 vs. 68.8 %). The TTR achieved with Zeus was similar to that obtained with the PARMA algorithm. In addition, patients managed with Zeus took a weekly drug dosage significantly (p < 0.01) lower than that both suggested by PARMA and prescribed by expert physicians, with a reduced number of adverse events. CONCLUSIONS: This study confirms that the effectiveness and safety of VKA therapy in patients 80 years of age or older increases with computer dosing algorithms. PMID- 25721558 TI - Robust L1-norm two-dimensional linear discriminant analysis. AB - In this paper, we propose an L1-norm two-dimensional linear discriminant analysis (L1-2DLDA) with robust performance. Different from the conventional two dimensional linear discriminant analysis with L2-norm (L2-2DLDA), where the optimization problem is transferred to a generalized eigenvalue problem, the optimization problem in our L1-2DLDA is solved by a simple justifiable iterative technique, and its convergence is guaranteed. Compared with L2-2DLDA, our L1 2DLDA is more robust to outliers and noises since the L1-norm is used. This is supported by our preliminary experiments on toy example and face datasets, which show the improvement of our L1-2DLDA over L2-2DLDA. PMID- 25721559 TI - White Adipose Tissue Depot-Specific Activity of Lipogenic Enzymes in Response to Fasting and Refeeding in Young and Old Rats. AB - BACKGROUND: Although the heterogeneity of white adipose tissue (WAT) in different anatomical sites is a well-known phenomenon, there are scarce data on aging associated metabolic alterations in various WAT depots. OBJECTIVE: We used the model of fasting and refeeding to analyze the effect of aging on the activity of key lipogenic enzymes in retroperitoneal (rWAT), epididymal (eWAT), and subcutaneous (sWAT) adipose tissue depots. METHODS: 5- and 24-month-old male Wistar rats were fasted for 48 h or were fasted for 2 days and subsequently refed for 2 or 4 days. Control animals had ad libitum access to chow. Samples obtained from three WAT deposits were analyzed for the enzymatic activities of ATP citrate lyase (ACL), fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PD). Concentrations of lipids and proteins were measured in the blood serum. RESULTS: Fasting for 2 days decreased the concentration of free fatty acids only in the young rats. The basal activities of ACL and FAS were lower in eWAT than in rWAT and sWAT of the young rats. In the young rats, fasting did not change ACL and FAS activities in any of the studied depots. Refeeding increased these activities more quickly in rWAT than in eWAT, while in sWAT no induction was observed. ACL and FAS activities were manifold lower in all WAT depots of the old than in those of the young rats. In the old animals fasting had no effect on ACL activity in any depot and decreased FAS activity only in sWAT. After 4 days of refeeding, FAS activity increased in rWAT and sWAT, but no change in ACL activity occurred. G6PD activity in the young rats was lower by 40% in eWAT than in rWAT. The induction of the enzyme by refeeding occurred faster in rWAT than in eWAT, while in sWAT no change in G6PD activity was observed. G6PD activity did not change with aging. Fasting of the old rats decreased G6PD activity in rWAT and sWAT. Refeeding failed to induce the enzyme in these depots, whereas in eWAT G6PD activity increased by 76% after 4 days of refeeding. CONCLUSION: Fasting and refeeding revealed WAT depot-specific, age-related changes of the activities of lipogenic enzymes. PMID- 25721560 TI - Polymorphism and DNA methylation in the promoter modulate KISS1 gene expression and are associated with litter size in goats. AB - Polymorphisms in the promoter region are likely to impact KISS1 gene transcription and reproductive traits. In this study, Guanzhong (GZ, n=350) and Boer (BE, n=196) goats were used to detect polymorphism in the promoter of the goat KISS1 gene by DNA sequencing. In the GZ goats, the g.1384G>A mutation was identified in the promoter of the goat KISS1 gene. Guanzhong goats were in Hardy Weinberg disequilibrium at g.1384G>A locus (P<0.05). The 1384A allele was predicted to eliminate methylation, AHR-arnt heterodimers and AHR-related factors (AHRR) and myoblast determining factors (MYOD) transcription factor-binding sites. Statistical results indicated that the g.1384G>A SNP was associated with litter size in the GZ goats (P<0.05). Luciferase assay analysis suggested that the 1384A allele increased luciferase activity when compared to the 1384G allele. The RT-qPCR assay also demonstrated that the 1384A allele had greater amounts of KISS1 mRNA than the 1384G allele in homozygous individuals. Functional analysis suggested that this g.1384G>A SNP may be an important genetic regulator of KISS1 gene expression with effects on downstream processes that are modulated by KISS1 gene because of the changes of methylation and transcription factor-binding sites. Therefore, the current study provides evidence in goats for genetic markers that might be used in breeding programs. PMID- 25721561 TI - Relationships between milk fatty acids composition in early lactation and subsequent reproductive performance in Czech Fleckvieh cows. AB - Increase of milk yield after calving causes changes in milk fatty acids (FA) composition and simultaneously corresponds with reproduction performance decrease. The objective of this study was to evaluate the relationships between milk FA group composition (SFA, saturated fatty acids; MUFA, monounsaturated fatty acids; and PUFA, polyunsaturated fatty acids) during the first 5 lactation weeks and subsequent reproductive results (INT, calving to first service interval; NUM, number of services per conception, and DO, days open) in Czech Fleckvieh cows. A total of 1231 individual milk samples from 382 cows were collected and subsequently analyzed. Simultaneously, body condition score (BCS) was weekly evaluated as well. Software SAS 9.1 was used for statistical analysis. Daily milk yields increased whereas BCS, milk fat and protein contents decreased during period observed. The reduction of basic milk components (% of fat, % of protein) was associated with increased SFA and decreased MUFA, respectively PUFA contents. Significant (P<0.01-0.05 days) increase in NUM (+0.15 to +0.29 AI dose) and DO (+8.16 to 15.44 days) were detected in cows with the lowest SFA content. On the contrary, cows with the highest content of MUFA presented significantly (P<0.01-0.05) higher values of NUM (+0.13 to +0.30) and DO (+7.26 to +15.35 days). Milk FA groups composition in early lactation potentially used as NEB indicators, especially SFA and MUFA proportion, affected subsequent reproductive results of Czech Fleckvieh cows. Therefore, its post-partum values could serve as predictors of potential fertility of dairy cows. PMID- 25721562 TI - Endometrial echotexture variables in postpartum cows with subclinical endometritis. AB - The aim of this study was to evaluate endometrial echotexture changes on ultrasonographic digital images during subclinical endometritis using a computer assisted image analysis program. Endometrial samples were collected from 140 Brown Swiss cows (days in milk = 35 +/- 3) using a cytobrush method and classified as having a non-inflamed uterus (n = 66) and uterus with acute (n = 42), subacute (n = 21), and chronic (n = 11) inflammations. The mean cellular infiltration density was 0%, 31 +/- 5%, 37 +/- 6%, and 16 +/- 8% for cows with non-inflamed uterus and cows with acute, subacute, and chronic uterine inflammations (P < 0.0001). As the cell infiltration density increased, both cervical diameter and mean gray level did not change. There were a liner decrease in homogeneity and a linear increase in contrast in response to increased cellular infiltration density. The sensitivity and specificity were 79.73% and 46.97% for the homogeneity value and 59.46% and 69.70% for the contrast value, respectively. In conclusion, monitoring endometrial echotexture alterations, especially homogeneity and contrast, changed depending on the cellular density and inflammation status and may be potential diagnostic markers for subclinical endometritis in cows. PMID- 25721563 TI - Descriptive analysis of sperm head morphometry in Iberian ibex (Capra pyrenaica): optimum sampling procedure and staining methods using Sperm-Class Analyzer (r). AB - Sperm morphology has been identified as one characteristic which can be useful in prediction of fertility in a species. The development of computer automated sperm morphometry analysis allows for objective analysis of sperm head dimensions. The aim of the current study was to develop an optimum sampling procedure to characterize the Iberian ibex (Capra pyrenaica) sperm head morphometrically. Fresh semen from 11 males was collected using transrectal ultrasonic-guided massage of accessory sex glands and electroejaculation and prepared on slides for morphometric analysis to evaluate technical variation and standardize automated sperm morphometry analysis procedures by Sperm-Class Analyzer((r)). Three staining methods (Diff-Quik((r)), Hemacolor((r)), Spermblue((r))), number of sperm cells necessary to sample and repeatability of the staining technique were assessed. There were significant differences in size of sperm head depending on stain used. Hemacolor((r)) was stain most suitable for sperm head morphometry evaluation (length=8.42 MUm; width=4.21 MUm; area=29.37 MUm(2); perimeter=21.93 MUm; elongation=0.33; elipticity=2.01; regularity=0.95; rugosity=0.77). Morphometric values obtained from samples of 50, 100, 150, 175 and 200 sperm heads were compared. The most efficient method of analyzing sperm morphometry was to evaluate 100 sperm cells at 60* objective magnification. Thus, this study has allowed for description of optimal sample processing to determine morphometric parameters of sperm heads (size and shape) in Iberian ibex by Sperm-Class Analyzer((r)) and provides a basis for future studies on the relationship with freezability and fertility in this species. PMID- 25721565 TI - New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal. PMID- 25721564 TI - Optic nerve head characteristics in eyes with papillomacular bundle defects in glaucoma. AB - To evaluate the pattern of retinal nerve fibre layer defects (RNFLD) with regard to involvement of papillomacular bundle (PMB) in glaucoma. This observational study included patients attending glaucoma imaging services at our centre from 2011 to 2012. All images were exported to Image J software for analysis and rescaled to a unified scale for measurement of degree of RNFLD defined by its angular width, pattern of involvement with regard to involvement or sparing of PMB in particular and horizontal and vertical distance of central vessel trunk (CVT) from the disc margin. Association of clinical data with pattern of defects with regard to PMB involvement was analysed. Sixty-two fundus photographs with discernible nerve fibre layer defects on red free images were selected, including 48 normal tension glaucoma, two primary angle closure glaucoma (PACG) and 12 primary open angle glaucoma (POAG) eyes. Discernible PMB involvement was seen in 35 eyes which included 31 defects in inferior quadrant while CVT exit was placed in the quadrant opposite to the quadrant of RNFLD in that eye. The mean vertical distance from the nearest disc margin was greater in eyes without PMB involvement, 0.4 +/- 0.02 mm, than eyes with PMB defects, 0.3 +/- 0.01 mm, p < 0.001. On multivariate logistic regression, PMB involvement was significantly associated with decreased linear horizontal of the CVT from the disc margin, p = 0.003. Selective involvement of superior and inferior PMB suggests different retinotopic representation within the optic disc. Exit of the CVT towards the disc margin may be a predisposing factor for RNFLD and involvement of the PMB. PMID- 25721566 TI - Functional connectivity patterns reflect individual differences in conflict adaptation. AB - Individuals differ in the ability to utilize previous conflict information to optimize current conflict resolution, which is termed the conflict adaptation effect. Previous studies have linked individual differences in conflict adaptation to distinct brain regions. However, the network-based neural mechanisms subserving the individual differences of the conflict adaptation effect have not been studied. The present study employed a psychophysiological interaction (PPI) analysis with a color-naming Stroop task to examine this issue. The main results were as follows: (1) the anterior cingulate cortex (ACC)-seeded PPI revealed the involvement of the salience network (SN) in conflict adaptation, while the posterior parietal cortex (PPC)-seeded PPI revealed the engagement of the central executive network (CEN). (2) Participants with high conflict adaptation effect showed higher intra-CEN connectivity and lower intra-SN connectivity; while those with low conflict adaptation effect showed higher intra SN connectivity and lower intra-CEN connectivity. (3) The PPC-centered intra-CEN connectivity positively predicted the conflict adaptation effect; while the ACC centered intra-SN connectivity had a negative correlation with this effect. In conclusion, our data demonstrated that conflict adaptation is likely supported by the CEN and the SN, providing a new perspective on studying individual differences in conflict adaptation on the basis of large-scale networks. PMID- 25721567 TI - Modulation of attention functions by anodal tDCS on right PPC. AB - Attention is a complex construct that comprises at least three major subcomponents: alerting, spatial (re-)orienting, and executive functions, all of which have specific neural correlates along frontoparietal networks. Attention deficits are a common consequence of brain damage. Transcranial direct current stimulation (tDCS) has been shown to modulate spatial attention. We investigated whether tDCS of different stimulation targets differentially modulates alerting, spatial (re-)orienting, and executive functions. Twenty-four healthy participants were included in this randomized, double-blinded study, which employed a within subject design. On four different days, the effects of 1.5 mA anodal tDCS (real and sham) on the left dorsolateral (EEG 10-20 point F3), left parietal (P3) and right parietal cortex (P4) were assessed using a modified attention network test. tDCS of the right parietal cortex enhanced spatial re-orienting, while tDCS of the other cortical targets did not modulate the assessed attention functions. With regard to visual field asymmetries in attentional processing, right parietal tDCS selectively enhanced mean network efficiency for targets presented in the contralateral left visual field. The observed visual field specific tDCS effects on reorienting suggest that systematic investigations into novel approaches for the treatment of patients suffering from spatial neglect patients are warranted. PMID- 25721568 TI - Prediction of the pKa's of aqueous metal ion +2 complexes. AB - Aqueous metal ions play an important role in many areas of chemistry. The acidities of [Be(H2O)4](2+), [M(H2O)6](2+), M = Mg(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Hg(2+), and [M(H2O)n](2+), M = Ca(2+) and Sr(2+), n = 7 and 8, complexes have been predicted using density functional theory, second-order Moller-Plesset perturbation theory (MP2), and coupled cluster CCSD(T) theory in the gas phase. pKa's in aqueous solution were predicted by using self-consistent reaction field (SCRF) calculations with different solvation models. The most common binding motif of the majority of the metal +2 complexes is coordination number (CN) 6, with each hexaaquo cluster having reasonably high symmetry for the best arrangement of the water molecules in the first solvation shell. Be(2+) is tetracoordinated, but a second solvation shell of 8 waters is needed to predict the pKa. The Ca(2+) and Sr(2+) aquo clusters have a coordination number of 7 or 8 as found in terms of the energy of the reaction M(H2O)7(2+) + H2O -> M(H2O)8(2+) and the pKa values. The calculated geometries are in reasonable agreement with experiment. The SCRF calculations with the conductor-like screening model (COSMO), and the conductor polarized continuum model (CPCM) using COSMO-RS radii, consistently agree best with experiment at the MP2/aug-cc-pVDZ and CCSD(T)/aug-cc-pVDZ levels of theory. The CCSD(T) level provides the most accurate pKa's, and the MP2 level also provides reliable predictions. Our predictions were used to elucidate the properties of metal +2 ion complexes. The pKa predictions provide confirmation of the size of the first solvation shell sizes. The calculations show that it is still difficult to predict pKa's using this cluster/implicit solvent approach to better than 1 pKa unit. PMID- 25721569 TI - Development of two measures of client engagement for use in home aged care. AB - The aim of the study was to develop and validate measures of client engagement in aged homecare. The Homecare Measure of Engagement-Staff questionnaire (HoME-S) is a self-complete measure of six dimensions of client engagement: client acceptance, attention, attitude, appropriateness, engagement duration and passivity. The Homecare Measure of Engagement-Client/Family report (HoME-CF) is a researcher-rated interview which obtains client and/or family perspectives regarding frequency and valence of conversational and recreational engagement during care worker visits. Care workers (n = 84) completed the HoME-S and a measure of relationship bond with client. Researchers interviewed clients (n = 164) and/or their family (n = 117) and completed the HoME-CF, and measures of agitation, dysphoria, apathy and cognitive functioning. The HoME-S and HoME-CF demonstrated good test-retest and inter-rater reliability, and showed significant negative correlations with apathy, agitation and non-English-speaking background. Controlling for client and care service characteristics, a stronger care worker client relationship bond and English-speaking background were independently associated with higher HoME-S scores, and apathy was independently associated with higher HoME-CF scores. In conclusion, the HoME-S and HoME-CF are psychometrically sound engagement measures for use in homecare. Clients who are apathetic or from non-English-speaking backgrounds may be less responsive to traditional care worker engagement strategies. Engagement may be augmented in clients who have stronger relationships with their care workers. PMID- 25721570 TI - Grading the strength of a body of evidence when assessing health care interventions: an EPC update. AB - OBJECTIVES: To revise 2010 guidance on grading the strength of evidence (SOE) of the effectiveness of drugs, devices, and other preventive and therapeutic interventions in systematic reviews produced by the Evidence-based Practice Center (EPC) program, established by the US Agency for Healthcare Research and Quality (AHRQ). STUDY DESIGN AND SETTING: A cross-EPC working group reviewed authoritative systems for grading SOE [primarily the approach from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group] and conducted extensive discussions with GRADE and other experts. RESULTS: Updated guidance continues to be conceptually similar to GRADE. Reviewers are to evaluate SOE separately for each major treatment comparison for each major outcome. We added reporting bias as a required domain and retained study limitations (risk of bias), consistency, directness, and precision (and three optional domains). Additional guidance covers scoring consistency, precision, and reporting bias, grading bodies of evidence with randomized controlled trials and observational studies, evaluating single study bodies of evidence, using studies with high risk of bias, and presenting findings with greater clarity and transparency. SOE is graded high, moderate, low, or insufficient, reflecting reviewers' confidence in the findings for a specific treatment comparison and outcome. CONCLUSION: No single approach for grading SOE suits all reviews, but a more consistent and transparent approach to reporting summary information will make reviews more useful to the broad range of audiences that AHRQ's work aims to reach. EPC working groups will consider ongoing challenges and modify guidance as needed, on issues such as combining trials and observational studies in bodies of evidence, weighting domains, and combining qualitative and quantitative syntheses. PMID- 25721571 TI - Real-world outcome analysis of continuously and intermittently treated patients with moderate to severe psoriasis after switching to a biologic agent. AB - BACKGROUND: Clinical studies of continuous versus intermittent biologic therapy for moderate to severe psoriasis demonstrate improved efficacy with continuous treatment. OBJECTIVE: To analyse Swedish real-world data of continuously and intermittently treated biologic-naive patients after switching to a biologic agent. METHODS: This is an observational study based on PsoReg, the Swedish registry for systemic psoriasis treatment. Outcome effects in biologic-naive patients who switched to a biologic agent (n = 351) were analysed in groups of continuous, intermittent and terminated treatment. RESULTS: Intermittently treated patients (n = 50) reported higher Psoriasis Area and Severity Index and Dermatology Life Quality Index values after switching than patients with continuous (n = 260) or terminated treatment (n = 41). STUDY LIMITATIONS: The reason for intermittent treatment was not recorded. The intermittently treated patients may be a heterogeneous group and a limitation is that it cannot be determined whether less than continuous use was offered to handle negative aspects. CONCLUSION: Patients with continuous biologic treatment tend to achieve better outcomes compared to intermittently treated patients. PMID- 25721572 TI - Photoresponse of polyaniline-functionalized graphene quantum dots. AB - Polyaniline-functionalized graphene quantum dots (PANI-GQD) and pristine graphene quantum dots (GQDs) were utilized for optoelectronic devices. The PANI-GQD based photodetector exhibited higher responsivity which is about an order of magnitude at 405 nm and 7 folds at 532 nm as compared to GQD-based photodetectors. The improved photoresponse is attributed to the enhanced interconnection of GQD by island-like polymer matrices, which facilitate carrier transport within the polymer matrices. The optically tunable current-voltage (I-V) hysteresis of PANI GQD was also demonstrated. The hysteresis magnifies progressively with light intensity at a scan range of +/-1 V. Both GQD and PANI-GQD devices change from positive to negative photocurrent when the bias reaches 4 V. Photogenerated carriers are excited to the trapping states in GQDs with increased bias. The trapped charges interact with charges injected from the electrodes which results in a net decrease of free charge carriers and a negative photocurrent. The photocurrent switching phenomenon in GQD and PANI-GQD devices may open up novel applications in optoelectronics. PMID- 25721573 TI - Early secreted antigen ESAT-6 of Mycobacterium Tuberculosis promotes apoptosis of macrophages via targeting the microRNA155-SOCS1 interaction. AB - BACKGROUND: The early secreted antigenic target 6-kDa protein (ESAT-6) of Mycobacterium tuberculosis (Mtb) not only acts as a key player for virulence but also exhibits a strong immunotherapeutic potential against Mtb. However, little is known about the molecular basis for its potential in immunotherapy. The present study was designed to unravel the role of miRNA-155 in ESAT-6-mediated enhancement of host immunity and apoptosis in macrophages. METHODS: Lentivirus mediated miR-155 sponge and miR-155 and SOCS1 overexpression vectors were developed in macrophages. TLR2- or p65-specific siRNA knockdown was employed to silence TLR2 or p65. Quantitative polymerase chain reaction and western blotting analyses were performed to determine mRNA and protein expression levels, respectively. Macrophage apoptosis was analyzed by flow cytometry. RESULTS: ESAT 6 significantly increased miR-155 expression, which was dependent on TLR2/NF kappaB activation in macrophages. Induced expression of miRNA-155 was required for the ESAT-6-mediated protective immune response and macrophage apoptosis. ESAT 6 promoted macrophage apoptosis by targeting the miR-155-SOCS1 pathway. The differential expression levels of TLR2, BIC, and SOCS1 were involved in regulating the immune response in human peripheral blood mononuclear cells of patients with active tuberculosis (TB) and latent TB (LTB). CONCLUSION: ESAT-6 promotes apoptosis of macrophages via targeting the miRNA155-SOCS1 interaction. PMID- 25721574 TI - CORR Insights((r)): Modified Dunn Procedure is Superior to In Situ Pinning for Short-term Clinical and Radiographic Improvement in Severe Stable SCFE. PMID- 25721575 TI - Time-driven Activity-based Costing More Accurately Reflects Costs in Arthroplasty Surgery. AB - BACKGROUND: Cost estimates derived from traditional hospital cost accounting systems have inherent limitations that restrict their usefulness for measuring process and quality improvement. Newer approaches such as time-driven activity based costing (TDABC) may offer more precise estimates of true cost, but to our knowledge, the differences between this TDABC and more traditional approaches have not been explored systematically in arthroplasty surgery. QUESTIONS/PURPOSES: The purposes of this study were to compare the costs associated with (1) primary total hip arthroplasty (THA); (2) primary total knee arthroplasty (TKA); and (3) three surgeons performing these total joint arthroplasties (TJAs) as measured using TDABC versus traditional hospital accounting (TA). METHODS: Process maps were developed for each phase of care (preoperative, intraoperative, and postoperative) for patients undergoing primary TJA performed by one of three surgeons at a tertiary care medical center. Personnel costs for each phase of care were measured using TDABC based on fully loaded labor rates, including physician compensation. Costs associated with consumables (including implants) were calculated based on direct purchase price. Total costs for 677 primary TJAs were aggregated over 17 months (January 2012 to May 2013) and organized into cost categories (room and board, implant, operating room services, drugs, supplies, other services). Costs derived using TDABC, based on actual time and intensity of resources used, were compared with costs derived using TA techniques based on activity-based costing and indirect costs calculated as a percentage of direct costs from the hospital decision support system. RESULTS: Substantial differences between cost estimates using TDABC and TA were found for primary THA (USD 12,982 TDABC versus USD 23,915 TA), primary TKA (USD 13,661 TDABC versus USD 24,796 TA), and individually across all three surgeons for both (THA: TDABC = 49%-55% of TA total cost; TKA: TDABC = 53%-55% of TA total cost). Cost categories with the most variability between TA and TDABC estimates were operating room services and room and board. CONCLUSIONS: Traditional hospital cost accounting systems overestimate the costs associated with many surgical procedures, including primary TJA. TDABC provides a more accurate measure of true resource use associated with TJAs and can be used to identify high-cost/high-variability processes that can be targeted for process/quality improvement. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25721576 TI - What Is the Rerevision Rate After Revising a Hip Resurfacing Arthroplasty? Analysis From the AOANJRR. AB - BACKGROUND: More than 15,000 primary hip resurfacing arthroplasties have been recorded by the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) with 884 primary procedures requiring revision for reasons other than infection, a cumulative percent revision rate at 12 years of 11%. However, few studies have reported the survivorship of these revision procedures. QUESTIONS/PURPOSES: (1) What is the cumulative percent rerevision rate for revision procedures for failed hip resurfacings? (2) Is there a difference in rerevision rate among different types of revision or bearing surfaces? METHODS: The AOANJRR collects data on all primary and revision hip joint arthroplasties performed in Australia and after verification against health department data, checking of unmatched procedures, and subsequent retrieval of unreported procedures is able to obtain an almost complete data set relating to hip arthroplasty in Australia. Revision procedures are linked to the known primary hip arthroplasty. There were 15,360 primary resurfacing hip arthroplasties recorded of which 884 had undergone revision and this was the cohort available to study. The types of revisions were acetabular only, femoral only, or revision of both acetabular and femoral components. With the exception of the acetabular-only revisions, all revisions converted hip resurfacing arthroplasties to conventional (stemmed) total hip arthroplasties (THAs). All initial revisions for infection were excluded. The survivorship of the different types of revisions and that of the different bearing surfaces used were estimated using the Kaplan-Meier method and compared using Cox proportional hazard models. Cumulative percent revision was calculated by determining the complement of the Kaplan-Meier survivorship function at that time multiplied by 100. RESULTS: Of the 884 revisions recorded, 102 underwent further revision, a cumulative percent rerevision at 10 years of 26% (95% confidence interval, 19.6-33.5). There was no difference in the rate of rerevision between acetabular revision and combined femoral and acetabular revision (hazard ratio [HR], 1.06 [0.47-2], p = 0.888), femoral revision and combined femoral and acetabular revision (HR, 1.00 [0.65-2], p = 0.987), and acetabular revision and femoral revision (HR, 1.06 [0.47-2], p = 0.893). There was no difference in the rate of rerevision when comparing different bearing surfaces (metal-on-metal versus ceramic-on-ceramic HR, 0.46 [0.16-1.29], p = 0.141; metal-on-metal versus ceramic-on-crosslinked polyethylene HR, 0.51 [0.15 1.76], p = 0.285; metal-on-metal versus metal-on-crosslinked polyethylene HR, 0.62 [0.20-1.89], p = 0.399; and metal-on-metal versus oxinium-on-crosslinked polyethylene HR, 0.53 [0.14-2.05], p = 0.356). CONCLUSIONS: Revision of a primary hip resurfacing arthroplasty is associated with a high risk of rerevision. This study may help surgeons guide their patients about the outcomes in the longer term after the first revision of hip resurfacing arthroplasty. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25721577 TI - Bicruciate-retaining Total Knee Replacement Provides Satisfactory Function and Implant Survivorship at 23 Years. AB - BACKGROUND: One of the goals of a TKA is to approximate the function of a normal knee. Preserving the natural ligaments might provide a method of restoring close to normal function. Sacrifice of the ACL is common and practical during a TKA. However, this ligament is functional in more than 60% of patients undergoing a TKA and kinematic studies support the concept of bicruciate-retaining (that is, ACL-preserving) TKA; however, relatively few studies have evaluated patients treated with bicruciate-retaining TKA implants. QUESTIONS/PURPOSES: I asked: (1) what is the long-term (minimum 20-year) survivorship, (2) what are the functional results, and (3) what are the reasons for revision of bicruciate-retaining knee arthroplasty prostheses? METHODS: From January 1989 to September 1992, I performed 639 total knee replacements in 537 patients. Of these, 489 were performed in 390 patients using a bicruciate-retaining, minimally constrained device. During the period in question, this knee prosthesis was used for all patients observed intraoperatively to have an intact, functional ACL with between 15 degrees varus and 15 degrees valgus joint deformity. There were 234 women and 156 men with a mean age at surgery of 65 years (range, 42-84 years) and a primary diagnosis of osteoarthritis in 89%. The patella was resurfaced in all knees. The mean followup was 23 years (range, 20-24 years). At the time of this review, 199 (51%) patients had died and 31 (8%) patients were lost to followup, leaving 160 (41%) patients (214 knees) available for review. Component survivorship was determined by competing-risks analysis and Kaplan Meier survivorship analysis with revision for any reason as the primary endpoint. Patients were evaluated every 2 years to assess ROM, joint laxity, knee stability, and to determine American Knee Society scores. RESULTS: The Kaplan Meier survivorship was 89% (95% CI, 82%-93%) at 23 years with revision for any reason as the endpoint. Competing-risks survivorship was 94% (95% CI, 91%%-96 %) at 23 years. At followup, the mean age of the patients was 84 years (range, 63 101 years), the mean flexion was 117 degrees (range, 90 degrees -130 degrees ), the mean American Knee Society score improved from a preoperative mean of 42 (range, 26-49) to 91 (range, 61-100; p < .001). Twenty-two knees in 21 patients (5.6%) were revised, most commonly because of polyethylene wear. CONCLUSIONS: ACL sacrifice may be an unnecessary concession during TKA. This study found satisfactory survivorship and function after more than 20 years of use for patients receiving a bicruciate-retaining TKA implant. A TKA that preserves cruciate ligaments provides a stable, well-functioning knee with a low likelihood of revision at long-term followup. Retaining both cruciate ligaments during knee arthroplasty is an attractive concept that is worth considering. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25721578 TI - Intrinsic interfacial phenomena in manganite heterostructures. AB - We review recent advances in our understanding of interfacial phenomena that emerge when dissimilar materials are brought together at atomically sharp and coherent interfaces. In particular, we focus on phenomena that are intrinsic to the interface and review recent work carried out on perovskite manganites interfaces, a class of complex oxides whose rich electronic properties have proven to be a useful playground for the discovery and prediction of novel phenomena. PMID- 25721580 TI - Errata. PMID- 25721579 TI - Emerging roles for RNA degradation in viral replication and antiviral defense. AB - Viral replication significantly alters the gene expression landscape of infected cells. Many of these changes are driven by viral manipulation of host transcription or translation machinery. Several mammalian viruses encode factors that broadly dampen gene expression by directly targeting messenger RNA (mRNA). Here, we highlight how these factors promote mRNA degradation to globally regulate both host and viral gene expression. Although these viral factors are not homologous and use distinct mechanisms to target mRNA, many of them display striking parallels in their strategies for executing RNA degradation and invoke key features of cellular RNA quality control pathways. In some cases, there is a lack of selectivity for degradation of host versus viral mRNA, indicating that the purposes of virus-induced mRNA degradation extend beyond redirecting cellular resources towards viral gene expression. In addition, several antiviral pathways use RNA degradation as a viral restriction mechanism, and we will summarize new findings related to how these host-encoded ribonucleases target and destroy viral RNA. PMID- 25721581 TI - [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography after limb salvage surgery: post-surgical appearance, attenuation correction and local complications. AB - BACKGROUND: Metal endoprostheses and internal fixation devices cause significant artifacts on CT after limb salvage surgery; positron emission tomography (PET) images should be evaluated for artifacts. OBJECTIVE: (1) To describe [F-18]2 fluoro-2-deoxyglucose (FDG) PET uptake patterns after limb salvage surgery. (2) To determine whether metal endoprostheses and fixation hardware cause significant artifacts on CT attenuation-corrected PET that interfere with diagnostic use of PET/CT after limb salvage surgery. MATERIALS AND METHODS: We reviewed 92 studies from 18 patients ages 5-21 years. Diagnoses were osteogenic sarcoma in 14, Ewing sarcoma in 3, and malignant peripheral nerve sheath tumor originating in bone in 1. Nine patients had distal femur/knee endoprostheses, five had lower-extremity bone allografts secured by large metal plates and four had upper-extremity limb salvage procedures. Maximum standardized uptake value was calculated at lower extremity soft-tissue-endoprosthesis interfaces. In 15 patients with PET/CT imaging, the first PET/CT scan after limb salvage surgery was reviewed for metal artifacts on CT images and for artifacts at locations on PET corresponding to the CT metal artifacts. RESULTS: Increased FDG uptake was consistently present at soft-tissue interfaces with endoprostheses, allografts and internal fixation devices, with little or no FDG uptake at cemented endoprosthesis-bone interfaces. Maximum standardized uptake value at margins of femur/knee endoprostheses ranged from 1.4 to 5.7. In four patients with distal femur/knee endoprostheses, minimal artifact was noted on attenuation-corrected PET images, but image interpretation was not affected. In the other 11 patients who had CT attenuation correction, we detected no artifacts caused by the attenuation correction. CONCLUSION: CT attenuation correction did not cause artifacts that affected interpretation of attenuation-corrected PET images. PMID- 25721582 TI - Phosphaturic mesenchymal tumor of the tibia with oncogenic osteomalacia in a teenager. AB - Phosphaturic mesenchymal tumor is an uncommon cause of a paraneoplastic syndrome that can be associated with osteogenic osteomalacia. This tumor most commonly occurs in middle-aged men and women. We report a rare case of a phosphaturic mesenchymal tumor in a 16-year-old girl with multiple fractures as a result of severe osteoporosis. CT and MRI showed a mass arising from the tibia. PMID- 25721583 TI - Dr. Edward B. Singleton (1920-2015). PMID- 25721584 TI - FDG PET/CT imaging of desmoplastic small round cell tumor: findings at staging, during treatment and at follow-up. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a very uncommon soft tissue tumor of children and young adults. It has an aggressive course with generally poor survival. In general the assessment of tumor burden and response has relied upon CT or MRI. However these tumors are often metabolically active and can be evaluated using FDG PET/CT imaging. OBJECTIVE: The purpose of this study was to determine the metabolic activity of desmoplastic small round cell tumors using FDG PET/CT imaging and the potential utility of FDG PET/CT in this disease. MATERIALS AND METHODS: Eight patients (seven male, one female; ages 2-20 years, median 11 years) with confirmed DSRCT underwent 82 positron emission tomography/computed tomography (PET/CT) scans. PET/CT was used for initial staging (seven patients, eight scans), monitoring response to therapy (eight patients, 37 scans) and for surveillance of DSRCT recurrence (six patients, 37 scans). RESULTS: Each scan performed at diagnosis showed abnormally elevated uptake in the primary tumor. Five patients had abdominal pelvic involvement, and two of those also had thoracic disease. Six patients whose scans showed no abnormal sites of uptake at the end of therapy have had progression-free survivals of 2-10 years. One patient whose scan continued to show uptake during treatment died of disease 1.3 years from diagnosis. Another patient with persistent uptake remained in treatment 3 years after initial diagnosis. One surveillance scan identified recurrent disease. CONCLUSION: FDG PET/CT identified elevated metabolic activity in each patient studied. Despite our small sample size, FDG PET/CT scans appear useful for the management of patients with DSCRT. Patients whose studies become negative during or following treatment may have a prolonged remission. PMID- 25721585 TI - Different effects of sodium chloride preincubation on cadmium tolerance of Pichia kudriavzevii and Saccharomyces cerevisiae. AB - Application of growing microorganisms for cadmium removal is restricted by high cadmium toxicity. The effects of sodium chloride (NaCl) preincubation on the cadmium tolerance and removal ability of Pichia kudriavzevii and Saccharomyces cerevisiae were investigated in this study. NaCl preincubation improved the biomass of P. kudriavzevii under cadmium stress, while no obvious effect was observed in S. cerevisiae. The improved activities of peroxidase (POD) and catalase (CAT) after NaCl preincubation might be an important reason for the decrease of the reactive oxygen species (ROS) accumulation, cell death, and oxidative damage of proteins and lipids induced by cadmium, contributing to the improvement of the yeast growth. The cadmium bioaccumulation capacity of P. kudriavzevii decreased significantly after NaCl preincubation, which played an important role in mitigating the cadmium toxicity to the yeast. The cadmium removal rate of P. kudriavzevii was obviously higher than S. cerevisiae and was significantly enhanced after NaCl preincubation. The results suggested that NaCl preincubation improved the cadmium tolerance and removal ability of P. kudriavzevii. PMID- 25721587 TI - Nutrition-based evolution of intracellular pathogens. PMID- 25721588 TI - The usefulness of evolutionary principles: predicting the unexpected. PMID- 25721589 TI - Acinetobacter baumanni - understanding and fighting a new emerging pathogen. PMID- 25721590 TI - Technological challenges to understanding the microbial ecology of deep subsurface ecosystems. PMID- 25721591 TI - The universe under a microscope. PMID- 25721592 TI - Causes and interventions: need of a multiparametric analysis of microbial ecobiology. PMID- 25721593 TI - From environmental microbiology to ecogenomics: spotting the emerging field of fungal-bacterial interactions. PMID- 25721594 TI - It's the metabolism, stupid! PMID- 25721595 TI - Predicting ecosystem emergent properties at multiple scales. PMID- 25721596 TI - Fortunate those that are starting now. PMID- 25721597 TI - Microbes don't play solitaire: how cooperation trumps isolation in the microbial world. PMID- 25721598 TI - Out of sight, out of mind. PMID- 25721599 TI - Microbial life at the thermodynamic limit: how much energy is required to sustain life? PMID- 25721600 TI - Ex-phot: a new take on primitive utilization of solar energy. PMID- 25721601 TI - Re-defining microbial diversity from its single-celled building blocks. PMID- 25721602 TI - 'Metagenomics 2.0'. PMID- 25721603 TI - Culturable endophytic microbial communities in the circumpolar grass, Deschampsia flexuosa in a sub-Arctic inland primary succession are habitat and growth stage specific. AB - Little is known about endophytic microbes in cold climate plants and how their communities are formed.We compared culturable putative endophytic bacteria and fungi in the ecologically important circumpolargrass, Deschampsia flexuosa growing in two successional stages of subarctic sand dune (68 degrees 29'N).Sequence analyses of partial 16S rRNA and internal transcribed spacer (ITS) sequences of culturable endophytes showed that diverse bacteria and fungi inhabit different tissues of D. flexuosa. A total of 178 bacterial isolates representing seven taxonomic divisions, Alpha, Beta and Gammaproteobacteria, Actinobacteria, Bacteroidetes, Firmicutes and Acidobacteria, and 30 fungal isolates representing the phylum Ascomycota were identified. Several endophytes were affiliated with specific plant tissues or successional stages. This first report of bacterial endophytes in D. flexuosa revealed that the genus Pseudomonas is tightly associated with D. flexuosa, and encompassed 39% of the bacterial isolates, and 58% of seed isolates. Based on 16S rRNA and ITS sequence data, most of the D. flexuosa endophytes were closely related to microbes from other cold environments. The majority of seed endophytic bacterial isolates were able to solubilize organic form of phosphate suggesting that these endophytes could play a role in resource mobilization in germinating seeds in nutrient-poor habitat. PMID- 25721604 TI - Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer: results from the WSG-AGO EC-Doc trial. AB - Taxane-anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 >= 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38-0.986), age <50 years old (HR = 1.682; 95 %CI 1.025-2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809-11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209-4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203-0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis. PMID- 25721605 TI - Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP 1. AB - The objective of this study is to investigate interactions between adipocytes and breast cancer cells, and identify the responsible factors for the observed effects. In 27 breast cancer patients undergoing mastectomy, mammary adipose tissue was obtained from the breast quadrant bearing the tumor and corresponding non-tumoral quadrant. Isolated normal breast adipocytes (NBAs) and cancer associated adipocytes (CAAs) were cultured in collagen gels to mimic the in vivo environment. Immunohistochemistry, qRT-PCR, and cell proliferation assays were performed to analyze adipocyte phenotypes. MCF7 and MDA-MB-231 breast cancer cell lines were co-cultured with adipocytes to detect phenotypic changes. Migration of MCF7 and MDA-MB-231 cells was assessed in NBA- and CAA-conditioned media. Cytokine levels in conditioned media were measured by cytokine array. Migration assays were repeated using conditioned media containing neutralizing antibodies. NBAs and CAAs lost their morphological phenotype in culture, acquiring a spindle like shape, and CAAs showed higher cell proliferation, suggesting reversion to an immature phenotype. In co-cultures with MCF7 or MDA-MB-231 cells, NBAs exhibited increased cell proliferation, indicating acquisition of the immature phenotype of CAAs. MCF7 and MDA-MB-231 showed higher migration in a CAA-conditioned medium than in an NBA-conditioned medium. Cytokine array analysis of conditioned media revealed higher levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in the CAA-conditioned medium. Neutralization experiments using antibodies against IL-6 or MCP-1 showed abrogation of migration-enhancing effects of the CAA-conditioned medium. Adipocytes revert to an immature and proliferative phenotype in the presence of breast cancer cells, and promote cancer cell migration via adipokines including IL-6 and MCP-1. PMID- 25721606 TI - Inhibition of BET proteins impairs estrogen-mediated growth and transcription in breast cancers by pausing RNA polymerase advancement. AB - Estrogen (E2)-induced transcription requires coordinated recruitment of estrogen receptor alpha (ER) and multiple factors at the promoter of activated genes. However, the precise mechanism by which this complex stimulates the RNA polymerase II activity required to execute transcription is largely unresolved. We investigated the role of bromodomain (BRD) containing bromodomain and extra terminal (BET) proteins, in E2-induced growth and gene activation. JQ1, a specific BET protein inhibitor, was used to block BET protein function in two different ER-positive breast cancer cell lines (MCF7 and T47D). Real-time PCR and ChIP assays were used to measure RNA expression and to detect recruitment of various factors on the genes, respectively. Protein levels were measured by Western blotting. JQ1 suppressed E2-induced growth and transcription in both MCF7 and T47D cells. The combination of E2 and JQ1 down-regulated the levels of ER protein in MCF7 cells but the loss of ER was not responsible for JQ1-mediated inhibition of E2 signaling. JQ1 did not disrupt E2-induced recruitment of ER and co-activator (SRC3) at the E2-responsive DNA elements. The E2-induced increase in histone acetylation was also not altered by JQ1. However, JQ1 blocked the E2 induced transition of RNA polymerase II from initiation to elongation by stalling it at the promoter region of the responsive genes upstream of the transcription start site. This study establishes BET proteins as the key mediators of E2 induced transcriptional activation. This adds another layer of complexity to the regulation of estrogen-induced gene activation that can potentially be targeted for therapeutic intervention. PMID- 25721607 TI - Web resources for mass spectrometry-based proteomics. AB - With the development of high-resolution and high-throughput mass spectrometry (MS) technology, a large quantum of proteomic data is continually being generated. Collecting and sharing these data are a challenge that requires immense and sustained human effort. In this report, we provide a classification of important web resources for MS-based proteomics and present rating of these web resources, based on whether raw data are stored, whether data submission is supported, and whether data analysis pipelines are provided. These web resources are important for biologists involved in proteomics research. PMID- 25721608 TI - A brief review of software tools for pangenomics. AB - Since the proposal for pangenomic study, there have been a dozen software tools actively in use for pangenomic analysis. By the end of 2014, Panseq and the pan genomes analysis pipeline (PGAP) ranked as the top two most popular packages according to cumulative citations of peer-reviewed scientific publications. The functions of the software packages and tools, albeit variable among them, include categorizing orthologous genes, calculating pangenomic profiles, integrating gene annotations, and constructing phylogenies. As epigenomic elements are being gradually revealed in prokaryotes, it is expected that pangenomic databases and toolkits have to be extended to handle information of detailed functional annotations for genes and non-protein-coding sequences including non-coding RNAs, insertion elements, and conserved structural elements. To develop better bioinformatic tools, user feedback and integration of novel features are both of essence. PMID- 25721609 TI - Web resources for microbial data. AB - There are multitudes of web resources that are quite useful for the microbial scientific research community. Here, we provide a brief introduction on some of the most notable microbial web resources and an evaluation of them based upon our own user experience. PMID- 25721610 TI - Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients. AB - Thymidylate synthase (TYMS) is an important enzyme for 5-fluorouracil (5-FU) metabolism in metastatic colorectal cancer (mCRC) patients. The search for this enzyme in circulating tumor cells (CTCs) can be a powerful tool to follow-up cancer patients. mCRC patients were enrolled before the beginning of 5-FU-based chemotherapy. The blood was filtered on Isolation by Size of Epithelial Tumor Cells (ISET), and the analysis of TYMS expression in CTCs was made by immunocytochemistry. Additionally, we verified TYMS staining in primary tumors and metastases from the same patients. There were included 54 mCRC patients and 47 of them received 5-FU-based chemotherapy. The median CTCs number was 2 per mL. We were not able to analyze immunocytochemistry in 13 samples (9 patients with absence of CTCs and 4 samples due to technical reasons). Therefore, TYMS expression on CTCs was analyzed in 34 samples and was found positive in 9 (26.5%). Six of these patients had tumor progression after treatment with 5-FU. We found an association between CTC TYMS staining and disease progression (DP), although without statistical significance (P = 0.07). TYMS staining in primary tumors and metastases tissues did not have any correlation with disease progression (P = 0.67 and P = 0.42 respectively). Patients who had CTC count above the median (2 CTCs/mL) showed more TYMS expression (P = 0.02) correlating with worse prognosis. Our results searching for TYMS staining in CTCs, primary tumors and metastases suggest that the analysis of TYMS can be useful tool as a 5 FU resistance predictor biomarker if analyzed in CTCs from mCRC patients. PMID- 25721611 TI - Extending a structural model of somatization to South Koreans: Cultural values, somatization tendency, and the presentation of depressive symptoms. AB - BACKGROUND: Somatization refers to the tendency to emphasize somatic symptoms when experiencing a psychiatric disturbance. This tendency has been widely reported in patients from East Asian cultural contexts suffering from depression. Recent research in two Chinese samples have demonstrated that the local cultural script for depression, involving two aspects-the experience and expression of distress (EED) and conceptualization and communication of distress (CCD)-can be evoked to help explain somatization. Given the beliefs and practices broadly shared across Chinese and South Korean cultural contexts, the current study seeks to replicate this explanatory model in South Koreans. METHODS: Our sample included 209 psychiatric outpatients from Seoul and Wonju, South Korea. Self report questionnaires were used to assess somatization tendency, adherence to traditional values, and psychological and somatic symptoms of depression. RESULTS: Results from SEM showed that the EED and CCD factors of somatization tendency were differently associated with cultural values and somatic symptoms, replicating our previous findings in Chinese outpatients. LIMITATIONS: The reliance on a brief self-report measure of somatization tendency, not originally designed to assess separate EED and CCD factors, highlights the need for measurement tools for the assessment of cultural scripts in cross-cultural depression research. CONCLUSIONS: The replication of the Chinese structural model of somatization in South Korea lends empirical support to the view that somatization can be understood as the consequence of specific cultural scripts. These scripts involve the experience and expression of distress as well as culturally meaningful ways in which this distress is conceptualized and communicated to others. PMID- 25721612 TI - Lower PHQ-9 cutpoint accurately diagnosed depression in people with long-term conditions attending the Accident and Emergency Department. AB - BACKGROUND: Major Depressive Disorder (MDD) is frequent in the Accident and Emergency Department (AED) but is often unrecognized. We aimed to assess the prevalence of MDD and determine the psychometric properties of the PHQ-9 in diagnosing MDD in patients with long-term medical conditions attending an AED. METHODS: The PHQ-9 was administered to 349 patients with diabetes, COPD and chronic inflammatory rheumatic diseases, mainly rheumatoid arthritis and spondyloarthropathies, visiting an AED. The MINI interview was used as the criterion standard for MDD. Receiver operator characteristic (ROC) curve analysis was performed to determine the optimal PHQ-9 cutpoint for MDD. Construct validators included psychological distress (SCL-90-R), illness perceptions (B IPQ) and Health-Related Quality of Life (WHOQOL-BREF). RESULTS: The prevalence of MDD was 27.2%. At an optimal cutpoint of 8, PHQ-9 had a sensitivity of 90.5% and specificity of 89.4%. The area under the curve (0.96) was excellent. Convergent validity was established by the strong associations between PHQ-9 scores and functional status, SCL-90-R depression, illness perceptions and AED visits during the previous year. LIMITATIONS: The sample consisted of multiple rather a single disease group, preventing us from accounting for illness severity using specific disease severity indices. CONCLUSION: MDD is frequent in patients with long-term medical conditions attending the AED and the PHQ-9, at a cutpoint of 8, is an accurate, reliable and valid measure for MDD screening in this patient population. PMID- 25721613 TI - Chinese label for people at risk for psychosis. AB - AIM: With the movement of early detection and intervention for people at risk for psychosis, there is a growing need for a uniform terminology to describe the condition. A diagnostic label that can adapt into local culture and value may have positive effect in minimizing stigma. This study explored the preference of Chinese label for people at risk of psychosis and its associated stigma in Hong Kong. METHODS: A total of 149 individuals from the general public and 51 health care professionals were recruited between March 2013 and May 2014. The condition of at risk for psychosis was described in a vignette. Participants' preference of label and perceived stigma of the condition and their basic demographics were collected by self-administered questionnaires. RESULTS: The most preferred Chinese label was 'yun-niang-qi' (developing period, 45%), followed by 'qian-qu qi' (precursor period, 19%), 'feng-xian-qi' (risky period, 18%), 'zao-xian-qi' (early sign period, 16%) and 'gao-wei-qi' (high risk period, 4%). Gender, age, occupation and previous contact with mental health were not associated with preference of any Chinese label. CONCLUSIONS: The process in searching for this potential and locally accepted label for people at risk for psychosis has raised the awareness among the professionals. A proper label may help promote future clinical research and mental health services in Hong Kong. PMID- 25721614 TI - In North America, some ovarian cancers express the oncogenes of preventable human papillomavirus HPV-18. AB - Some researchers in other regions have recommended human papillomavirus (HPV) vaccination to reduce risk of ovarian cancer, but not in North America, where evidence has previously suggested no role for HPV in ovarian cancer. Here we use a large sample of ovarian cancer transcriptomes (RNA-Seq) from The Cancer Genome Atlas (TCGA) database to address whether HPV is involved with ovarian cancer in North America. We estimate that a known high-risk type of HPV (type 18) is present and active in 1.5% of cases of ovarian epithelial cancers in the US and Canada. Our detection methods were verified by negative and positive controls, and our sequence matches indicated high validity, leading to strong confidence in our conclusions. Our results indicate that previous reports of zero prevalence of HPV in North American cases of ovarian cancer should not be considered conclusive. This is important because currently used vaccines protect against the HPV-18 that is active in ovarian tumors and, therefore, may reduce risk in North America of cancers of the ovaries as well as of the cervix and several other organ sites. PMID- 25721615 TI - Osteomalacia and Fanconi's syndrome caused by long-term low-dose adefovir dipivoxil. AB - WHAT IS KNOWN AND OBJECTIVE: Adefovir dipivoxil (ADV) is recommended for patients infected with lamivudine-refractory hepatitis B virus (HBV). We report a case of low-dose ADV-induced hypophosphatemic osteomalacia that initially presented as diffuse musculoskeletal pain. CASE SUMMARY: A 59-year-old Chinese man reported an 18-month history of severe chest wall pain and multiple bone pain during the previous 4 months with no antecedent trauma. There was no clinical evidence of an infectious, inflammatory or malignant process. Medical history showed that the patient had a history of chronic hepatitis B infection, and receiving lamivudine at a daily dose of 100 mg for 70 months. Lamivudine was changed to adefovir (10 mg/day) for the past 42 months. His serum inorganic phosphorus concentration was significantly low (0.4 mmol/l; 0.81-1.5 mmol/L), and the result of a urine routine test was abnormal. Combined with unbearable bone pain, spontaneous fractures, changes in laboratory markers and the result of ECT and other radiographic findings, the diagnosis of Fanconi's syndrome with osteomalacia was established. Dramatic clinical, laboratory and imaging improvement was observed after ADV discontinuation. WHATS IS NEW AND CONCLUSION: This case indicates that Fanconi's syndrome with osteomalacia can be acquired by a chronic hepatitis B patient taking ADV at a conventional dosage of 10 mg/day. Therefore, patients with HBV treated with long-term ADV should be regularly monitored for renal function, serum calcium and serum phosphate. Urine testing for ion concentration should also be undertaken. PMID- 25721617 TI - Diazepam Inhibits Proliferation of Lymph Node Cells Isolated from Rats with Experimental Autoimmune Encephalomyelitis. AB - OBJECTIVE: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to human multiple sclerosis involving peripheral activation of autoreactive T cells which infiltrate the central nervous system and react to self antigens leading to damage. In previous studies, we have demonstrated that treatment with diazepam decreases the incidence and histological signs associated with the disease and diminishes immunological responses. The aim of the present work was to evaluate direct effects of diazepam on isolated T cells involved in immune responses during the development of EAE. METHODS: Animals were sensitized with whole myelin to induce EAE and sacrificed during the acute phase of the disease. In mononuclear cells isolated from popliteal lymph nodes, cell viability, apoptosis induction, proliferation and cytokine production were evaluated. RESULTS: Diazepam did not have a toxic or proapoptotic effect on the cells, at least up to the concentration of 25 MUM, but proliferation, CD8+ T-cell activation and proinflammatory cytokine production were dose-dependently decreased. CONCLUSIONS: Diazepam has a direct inhibitory effect on the proliferation and activation of T lymphocytes isolated from the main lymphoid organ involved in disease onset and this could be one of the mechanisms that contribute to the beneficial effect previously observed with diazepam in vivo during EAE development. PMID- 25721618 TI - Patient management. AB - Hospital-associated infections, including those caused by zoonotic agents, represent an increasing concern in veterinary practice. Veterinarians and hospital staff are obligated and expected to provide education about and protection from transmission of pathogens among animal patients and between animal patients and human beings (eg, veterinary staff, volunteers, owners) who come into contact with infected animals. Patient management involves assessing risks of pathogen transmission, identification of animals either suspected of or proved to be infected with a transmissible infectious disease agent, and the implementation of measures that minimize the likelihood of transmission of the infectious agent. PMID- 25721616 TI - ACE2 and Ang-(1-7) protect endothelial cell function and prevent early atherosclerosis by inhibiting inflammatory response. AB - BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a counter-regulator against ACE by converting angiotensin II (Ang-II) to Ang-(1-7), but the effect of ACE2 and Ang-(1-7) on endothelial cell function and atherosclerotic evolution is unknown. We hypothesized that ACE2 overexpression and Ang-(1-7) may protect endothelial cell function by counterregulation of angiotensin II signaling and inhibition of inflammatory response. METHODS: We used a recombinant adenovirus vector to locally overexpress ACE2 gene (Ad-ACE2) in human endothelial cells in vitro and in apoE-deficient mice in vivo. The Ang II-induced MCP-1, VCAM-1 and E selectin expression, endothelial cell migration and adhesion of human monocytic cells (U-937) to HUVECs by ACE2 gene transfer were evaluated in vitro. Accelerated atherosclerosis was studied in vivo, and atherosclerosis was induced in apoE-deficient mice which were divided randomly into four groups that received respectively a ACE2 gene transfer, Ad-ACE2, Ad-EGFP, Ad-ACE2 + A779, an Ang-(1-7) receptor antagonist, control group. After a gene transfer for 4 weeks, atherosclerotic pathology was evaluated. RESULTS: ACE2 gene transfer not only promoted HUVECs migration, inhibited adhesion of monocyte to HUVECs and decreased Ang II-induced MCP-1, VCAM-1 and E-selectin protein production in vitro, but also decreased the level of MCP-1, VCAM-1 and interleukin 6 and inhibit atherosclerotic plaque evolution in vivo. Further, administration of A779 increased the level of MCP-1, VCAM-1 and interleukin 6 in vivo and led to further advancements in atherosclerotic extent. CONCLUSIONS: ACE2 and Ang-(1-7) significantly inhibit early atherosclerotic lesion formation via protection of endothelial function and inhibition of inflammatory response. PMID- 25721619 TI - Antimicrobial stewardship in small animal veterinary practice: from theory to practice. AB - Despite the increasing recognition of the critical role for antimicrobial stewardship in preventing the spread of multidrug-resistant bacteria, examples of effective antimicrobial stewardship programs are rare in small animal veterinary practice. This article highlights the basic requirements for establishing stewardship programs at the clinic level. The authors provide suggestions and approaches to overcome constraints and to move from theoretic concepts toward implementation of effective antimicrobial stewardship programs in small animal clinics. PMID- 25721620 TI - Colony Stimulating Factors 1, 2, 3 and early pregnancy steps: from bench to bedside. AB - Reproductive immunology applies general immunology principles to specialised targets, reproduction and development. The involvement of colony-stimulating factors (CSFs) in reproduction illustrates this. The CSF family includes CSF-1 or macrophage CSF (M-CSF), CSF-2 or granulocyte macrophage CSF (GM-CSF), and CSF-3 or granulocyte CSF (G-CSF). Each member has a specific localisation and timed expression in the reproductive tract with specific functions involving them in ovulation, embryo implantation, placentation and further embryonic development. They are used in reproductive medicine, either as biomarkers of oocyte quality and competence (follicular G-CSF), or to supplement embryo culture media with human recombinant GM-CSF, or they are used as an innovative therapy by using human recombinant G-CSF for infertile patients. Given fundamental considerations on CSFs and their strong implication in reproduction, this review aimed to detail the current knowledge for each member of the family to improve our understanding of their implication in the maternal-foetal cytokinic dialogue and in possibly preventing reproductive disorders. PMID- 25721621 TI - Influence of a loop electrosurgical excision procedure (LEEP) on levels of cytokines in cervical secretions. AB - Over the past decade, there has been heightened interest in determining if there is an increased risk of adverse reproductive outcomes among women who had a loop electrosurgical excision procedure (LEEP) to remove cervical intraepithelial neoplasia (CIN). The objective of this exploratory study was to determine if the treatment of CIN with a LEEP is associated with changes in cervical soluble immune markers. Cervical cytokine concentrations were measured in women treated with LEEP and a control group of women who had colposcopy only and did not undergo LEEP. Cytokines were examined in cervical secretions collected in Merocel((r)) sponges at study entry and at 6-month follow-up. Cytokines were measured using a Luminex 18-plex cytokine bead assay. The mean cytokine levels were not significantly changed from baseline to follow-up in either group, with the exception of TNF-alpha, which decreased among women who underwent a LEEP. When the mean levels of cytokines of the treated and untreated groups at baseline or follow-up were compared, cytokine levels tended to be lower in the treated group (particularly IFN-gamma, IL-6, IL-8, and MCP-1). Findings from adjusted repeated measures analyses revealed no differences between the two groups with regard to changes in cytokine levels over time. Overall, women undergoing a LEEP showed few changes in the cervical microenvironment relative to untreated women. Future studies with additional cervical environment markers and larger sample sizes are needed to determine if a LEEP is associated with dysregulation of the cervical microenvironment. PMID- 25721623 TI - Response surface optimization of culture medium for enhanced docosahexaenoic acid production by a Malaysian thraustochytrid. AB - Docosahexaenoic acid (DHA, C22:6n-3) plays a vital role in the enhancement of human health, particularly for cognitive, neurological, and visual functions. Marine microalgae, such as members of the genus Aurantiochytrium, are rich in DHA and represent a promising source of omega-3 fatty acids. In this study, levels of glucose, yeast extract, sodium glutamate and sea salt were optimized for enhanced lipid and DHA production by a Malaysian isolate of thraustochytrid, Aurantiochytrium sp. SW1, using response surface methodology (RSM). The optimized medium contained 60 g/L glucose, 2 g/L yeast extract, 24 g/L sodium glutamate and 6 g/L sea salt. This combination produced 17.8 g/L biomass containing 53.9% lipid (9.6 g/L) which contained 44.07% DHA (4.23 g/L). The optimized medium was used in a scale-up run, where a 5 L bench-top bioreactor was employed to verify the applicability of the medium at larger scale. This produced 24.46 g/L biomass containing 38.43% lipid (9.4 g/L), of which 47.87% was DHA (4.5 g/L). The total amount of DHA produced was 25% higher than that produced in the original medium prior to optimization. This result suggests that Aurantiochytrium sp. SW1 could be developed for industrial application as a commercial DHA-producing microorganism. PMID- 25721624 TI - [Erysipelas is not the same as erysipelas and leishmaniasis is not the same as Leishmaniasis]. PMID- 25721626 TI - Leishmaniasis. AB - Infections with Leishmania spp. rank among the top three most common travel associated dermatoses. Depending on the country where the infection was acquired and the patient's immune status, different disease manifestations may be observed. Ninety percent of cases present as cutaneous leishmaniasis, but the infection may also affect internal organs (visceral leishmaniasis). Without treatment, the latter is often fatal. Intermediate types include recurrent, diffuse, or mucocutaneous forms. Nodular lesions on exposed skin with a tendency to ulcerate over time in combination with a travel history should therefore prompt workup for leishmaniasis. The diagnosis is made through histology, parasite culture, and PCR using biopsy material. Therapeutic options range from local therapies in cases with singular lesions to systemic therapy in patients with more severe forms. The present review discusses the most important clinical features, details about diagnostic measures, and current therapeutic approaches. PMID- 25721627 TI - Indications and practical implementation of microbiologic diagnostics in patients with chronic wounds. AB - Microbiology diagnostics are frequently performed in patients with chronic wounds. However, there is currently a lack of uniformity with respect to indications as well as the practical implementation of such workup. The fact that diagnostic results may be significantly affected by the sampling technique used as well as the preceding (wound) preparation underscores the need for uniform standards, which have been missing so far. In Germany, bacteriologic wound swabs are routinely performed, particularly with the intent to screen for multiresistant pathogens. For this indication, prior wound cleansing should be avoided, and sampling using the Essen Rotary technique provides a quick and easy to-use option. If there is clinical suspicion of an infection, wound cleansing with sterile saline solution (0.9 %) and/or sterile cotton gauze should be carried out prior to obtaining bacteriologic swabs. While routine diagnostic biopsies are generally not required in chronic wound patients, they may be useful in case of clinically suspected wound infections, particularly in patients with deep ulcerations, diabetic foot syndrome, severe soft tissue infection, or fistula tissue. Moreover, biopsies are indispensable in the microbiology workup of specific pathogens such as mycobacteria, Leishmania, actinomycetes, Nocardia ssp. or molds. PMID- 25721629 TI - Histologic features of granulomatous skin diseases. Part 1: Non-infectious granulomatous disorders. AB - Granulomatous disorders affecting the skin belong to a heterogeneous group of diseases. With the exception of granulomas induced by infectious agents or foreign bodies, the etiopathogenesis of granulomatous disorders is still poorly understood. The knowledge of histopathologic changes is of great importance for understanding clinical presentation and disease course. PMID- 25721632 TI - Beliefs, perceptions and psychosocial impact of acne amongst Singaporean students in tertiary institutions. AB - BACKGROUND: Acne vulgaris is a common skin condition which can have a negative impact on a patient's quality of life. PATIENTS AND METHODS: A survey was distributed among students at tertiary institutions. Data was collected on participants' own rating of acne grade and how acne affected their social life. A clinician on-site graded the participants' acne. RESULTS: Of the 429 students who participated in the survey, 59.8 % felt embarrassed or self-conscious because of their acne. There was a low but statistically significant correlation (Spearman's Correlation Coefficient = 0.471, p < 0.001) between participants' and clinicians' grading of acne. CONCLUSIONS: Acne vulgaris causes a considerable amount of psychosocial stress. There are unfounded beliefs surrounding acne and unawareness of treatment options available. PMID- 25721634 TI - Deep abdominal wall ulceration in a patient with Behcet's disease. PMID- 25721637 TI - Pilomatricomas in Rubinstein-Taybi syndrome. PMID- 25721640 TI - Multiple factitious hemifacial lesions in Wallenberg syndrome. PMID- 25721645 TI - [Austrian and European initiatives in the field of rare diseases perspectives for a "marginal group" of many millions of patients]. PMID- 25721646 TI - [Report on the 22nd Annual Meeting of the Working Group on Dermatological Histology (ADH) from 04 to 06 April 2014 in Marburg]. PMID- 25721649 TI - Dyssynergic defecation may aggravate constipation: results of mostly pediatric cases with congenital anorectal malformation. AB - BACKGROUND: Most patients with congenital anorectal malformation suffer from mild chronic constipation. To date, it is unclear why a subgroup of patients develops a persistent form of constipation. Because dyssynergic defecation is a common cause of constipation in the general population, we hypothesized that the severe form of constipation may be caused by dyssynergic defecation. METHODS: Retrospectively, we reviewed the medical records of 29 patients with anorectal malformations who had undergone anorectal function tests because of severe constipation. The study was conducted at the University Medical Center Groningen, The Netherlands. RESULTS: All patients had increased maximum rectal pressure and increased anal sphincter pressure during balloon expulsion and therefore suffered from dyssynergic defecation. CONCLUSIONS: Patients with congenital anorectal malformations may also suffer from dyssynergic defecation. It is important, therefore, to check whether these patients have severe constipation due to dyssynergic defecation because perhaps it may be treated effectively with pelvic physiotherapy. PMID- 25721650 TI - Minimally invasive esophagectomy with right bronchial occlusion under artificial pneumothorax. AB - AIMS: To assess the safety and feasibility of minimally invasive esophagectomy and selected three-field lymphadenectomy with the right bronchial occlusion in left semi-prone position under artificial pneumothorax. METHODS: Thoracoscopic laparoscopic subtotal esophagectomy and selected three-field lymphadenectomy were performed in 166 patients with esophageal carcinoma by the right bronchial occlusion in left semi-prone position under artificial pneumothorax. RESULTS: 109 patients received two-field lymphadenectomy and 57 received three-field lymphadenectomy. The average operative time was 202.5 +/- 21.3 min; the average thoracoscopic operative time was 98.4 +/- 15.5 min. The average blood loss was 39.6 +/- 4.2 ml, and no blood transfusion was needed during the surgery. The mean lymph node harvest was 28.4 +/- 5.2 nodes. Hospital stay ranged from 7 to 95 days and the average was 11.3 days. The postoperative complication rate was 29.5%, and the mortality rate was 1.2%. CONCLUSIONS: It is feasible and safe to perform thoracoscopic-laparoscopic subtotal esophagectomy and selected three-field lymphadenectomy with the right bronchial occlusion in left semi-prone position under artificial pneumothorax for esophageal carcinoma. The procedure shows advantages in improved visibility and accessibility of the surgical field, and better subsequent surgical outcomes. PMID- 25721651 TI - LRAT overexpression diminishes intracellular levels of biologically active retinoids and reduces retinoid antitumor efficacy in the murine melanoma B16F10 cell line. AB - BACKGROUND/AIM: Vitamin A (all- trans -retinol, ATRol) serves as a precursor for all- trans -retinoic acid (ATRA), a ligand for the retinoic acid receptor (RAR), representing a potent regulator for many physiological processes. While murine melanoma cells are highly sensitive to retinoid treatment, human melanoma cells have developed still unidentified mechanisms that mediate cellular retinoid resistance. One of the key retinoid metabolizing enzymes is lecithin retinol acyltransferase (LRAT), which catalyzes the transformation of ATRol into inactive retinyl esters. LRAT is highly expressed in human melanoma cells. The aim of this study was to identify the mechanisms in retinol metabolism that are responsible for cellular retinoid sensitivity in the murine melanoma cell line B16F10. METHODS: mRNA expression analysis, cell viability assessment and determination of intracellular retinoid levels using HPLC analysis of a generated LRAT overexpressing B16F10 cell line compared to the control B16F10 cell line. RESULTS: We found that the murine retinoid-sensitive B16F10 cell line does not express the enzyme LRAT. LRAT overexpression decreased the antiproliferative effects of retinoid treatment in these melanoma cells. The RAR-regulated enzyme Cyp26a1 showed a significantly lower expression in LRAT-overexpressing B16F10 cells. Cyp26a1 expression was restored after ATRA incubation. HPLC analysis revealed that the level of inactive retinyl ester increased after ATRol treatment, and levels of the substrate ATRol and biologically active ATRA significantly decreased in LRAT-overexpressing murine melanoma. Consistently with this, levels of 4-oxoretinoic acid, an ATRA metabolite and Cyp26a1 product, were also decreased in LRAT-overexpressing cells. CONCLUSION: Our results revealed a direct link between LRAT expression and regulation of ATRA levels indicating that the absence of LRAT-catalyzed retinol esterification is important for mediating retinoid sensitivity in murine melanoma cells. Thus, our data suggest that LRAT overexpression represents a novel mechanism by which tumor cells can escape high supplementary ATRA levels that mediate tumor-suppressive RAR signaling. PMID- 25721652 TI - Synthesis, crystal structure, spectroscopic and density functional theory (DFT) study of N-[3-anthracen-9-yl-1-(4-bromo-phenyl)-allylidene]-N benzenesulfonohydrazine. AB - N-[3-anthracen-9-yl-1-(4-bromo-phenyl)-allylidene]-N-benzenesulfonohydrazine has been synthesized and characterized by various spectroscopic techniques including FT-IR, UV-vis, (1)H-NMR, (13)C-NMR spectroscopy, and the structure was unequivocally confirmed by single crystal X-ray diffraction studies. The compound crystallized in monoclinic system with P21/n space group, and adopted cis geometry around the azomethine CN double bond. The X-ray crystal structure revealed that the intermolecular packing was stabilized by C-H?O type hydrogen bonding interaction, whereas NH was not involved in hydrogen bonding due to steric hindrance. Absorption wavelength was studied by scanning UV-vis. absorption spectrum in different solvents to explore excited state stability of the molecule in polar solvent. Density functional theory calculations were performed at B3LYP/6-31G (d, p) level in order to compare the experimental results with the theoretical results. The simulated molecular electrostatic potential (MEP), Mulliken charges and NPA (natural population analysis) also confirmed the presence of specific intermolecular hydrogen bonding (C-H?O). In addition natural bond orbital (NBO) analysis (intra and inter molecular bonding and interaction among bonds), frontier molecular orbital analysis (electronic properties) and first hyperpolarizability analysis (nonlinear optical response) were simulated at B3LYP/6-31G (d, p) level of theory. PMID- 25721653 TI - Copper(II) complexes as catalyst for the aerobic oxidation of o-phenylenediamine to 2,3-diaminophenazine. AB - Two new mononuclear copper(II) complexes [Cu (L) (NO3)2] (1) and [Cu (L) Br2] (2) where (L=bis(1-(pyridin-2-ylmethyl)-benzimidazol-2-ylmethyl)ether) are synthesized and characterized by single-crystal X-ray diffraction analysis, elemental analysis, UV-Visible, IR spectroscopy, EPR and cyclic voltammetry. The complexes exhibit different coordination structures; the E1/2 value of the complex (1) is found to be relatively more cathodic than that of complex (2). X band EPR spectra at low temperature in DMF supports a tetragonally distorted complex (1) while complex (2) shows three different g values suggesting a rhombic geometry. These complexes were utilized as a catalyst for the aerobic oxidation of o-phenylenediamine to 2,3-diaminophenazine assisted by molecular oxygen. The initial rate of reaction is dependent on the concentration of Cu(II) complex as well as substrate, and was found to be higher for the nitrate bound complex, while presence of acetate anion acts as a mild inhibitor of the reaction, as it is likely to pick up protons generated during the course of reaction. The inhibition suggests that the generated protons are further required in another important catalytic step. PMID- 25721654 TI - The conformational stability, solvation and the assignments of the experimental infrared, Raman, (1)H and (13)C NMR spectra of the local anesthetic drug lidocaine. AB - The structure, vibrational and (1)H and (13)C NMR spectra of the local anesthetic drug lidocaine were investigated by the B3LYP/6-311G(**) calculations. The molecule was predicted to have the non-planar cis (NCCN~0 degrees ) structures being about 2-6kcal/mol lower in energy than the corresponding trans (NCCN~180 degrees ) forms. The calculated NCCN (9.6 degrees ) and CNCC (-132.2 degrees ) torsional angles were in a good qualitative agreement with the reported X-ray angles (3.1 and 13.0 degrees , -102.67 and -77.9 degrees , respectively, for H bonded dimers). The Gibbs energy of solution of lidocaine in formamide, water, dimethylsulfoxide, acetonitrile, methanol, ethanol and chloroform solutions was estimated at the B3LYP level. The predicted affinity of lidocaine toward the alcohols, acetonitrile and chloroform solutions was in excellent agreement with the reported experimental solubility of the drug in organic solvents. The analysis of the observed vibrational spectra is consistent with the presence of lidocaine in only one conformation at room temperature. The (1)H and (13)C NMR spectra of lidocaine were interpreted by experimental and DFT calculated chemical shifts of the drug. The RMSD between experimental and theoretical (1)H and (13)C chemical shifts for lidocaine is 0.47 and 8.26ppm, respectively. PMID- 25721655 TI - Structural prediction of a novel laminarinase from the psychrophilic Glaciozyma antarctica PI12 and its temperature adaptation analysis. AB - Here, we present a novel psychrophilic beta-glucanase from Glaciozyma antarctica PI12 yeast that has been structurally modeled and analyzed in detail. To our knowledge, this is the first attempt to model a psychrophilic laminarinase from yeast. Because of the low sequence identity (<40%), a threading method was applied to predict a 3D structure of the enzyme using the MODELLER9v12 program. The results of a comparative study using other mesophilic, thermophilic, and hyperthermophilic laminarinases indicated several amino acid substitutions on the surface of psychrophilic laminarinase that totally increased the flexibility of its structure for efficient catalytic reactions at low temperatures. Whereas several structural factors in the overall structure can explain the weak thermal stability, this research suggests that the psychrophilic adaptation and catalytic activity at low temperatures were achieved through existence of longer loops and shorter or broken helices and strands, an increase in the number of aromatic and hydrophobic residues, a reduction in the number of hydrogen bonds and salt bridges, a higher total solvent accessible surface area, and an increase in the exposure of the hydrophobic side chains to the solvent. The results of comparative molecular dynamics simulation and principal component analysis confirmed the above strategies adopted by psychrophilic laminarinase to increase its catalytic efficiency and structural flexibility to be active at cold temperature. PMID- 25721657 TI - Safety of intravenous thrombolysis for acute ischaemic stroke including concomitant neoplastic disease sufferers - experience from Poland. AB - BACKGROUND: Ischaemic stroke (IS), brain haemorrhage and cerebral venous thrombosis can occur as an early and late complication of cancer in the clinical course. Cancer patients are at increased risk for stroke from direct and indirect effects of their malignancy. AIMS: The aim of our study was to evaluate the relationship between neoplastic disease and the long-term outcome, mortality and the presence of haemorrhagic complications in patients with acute IS treated with i.v. thrombolysis. METHODS: We retrospectively evaluated the demographic and clinical data of 495 Caucasian patients with acute IS and 40 patients with IS and concomitant neoplastic disease who were consecutively treated from 2006 to 2013 in two experienced stroke centres. RESULTS: In analysed group, there were 7.8% of patients with cancer [50.0% male, mean age 72.3 +/- 9.3; National Institutes of Health Stroke Scale - 13 (range 9.5-17)]. Cancer was diagnosed before i.v. thrombolysis in 28 (70.0%) patients. After 3 months of follow up, 60% of patients were independent (mRS 0-2) compared with the group of patients without cancer - 55% (p = 0.54), 17.5% died (18.4%; p = 0.89), 12.4% suffered haemorrhagic transformation (HT) (17.6%; p = 0.41) and 2.5% experienced SICH (4.4%; p = 0.56, respectively). Other clinical complications were not found. A multivariate analysis showed no impact of neoplastic disease on unfavourable outcomes [modified Rankin scale 3-6)] after 3 months (p = 0.15). CONCLUSION: Intravenous thrombolysis performed in Caucasian stroke patients with past or current neoplastic diseases, but not in the course of chemo- and radiotherapy, can be a safe and effective method of treatment. In making decision on the thrombolytic treatment, the risk of bleeding complications and the life expectancy should be assessed. PMID- 25721658 TI - Norovirus genotype diversity associated with gastroenteritis outbreaks in aged care facilities. AB - Noroviruses are a major cause of gastroenteritis. Vaccine strategies against norovirus are currently under consideration but depend on a detailed knowledge of the capsid genotypes. This study examined the incidence of norovirus outbreaks in residential aged-care facilities in Victoria, Australia over one year (2013) and documented the (capsid) norovirus genotypes associated with these outbreaks. It was found that 65.0% of 206 outbreaks tested were associated with norovirus infection, thereby showing norovirus to be the major cause of viral gastroenteritis in residential aged-care facilities. Fifteen capsid (open reading frame 2) genotypes were identified as follows: GI.2 (0.9%), GI.3 (1.8%), GI.4 (3.7%), GI.6 (0.9%), GI.7 (0.9%), GI.8 (0.9%), GII.1 (0.9%), GII.2 (0.9%), GII.3 (1.8%), GII.4 (2009-like) (0.9%), GII.4 (2012) (48.6%), GII.4 (2012-like) (16.5%), GII.4 (unknown) (9.2%), GII.5 (2.8%), GII.6 (0.9%), GII.7 (0.9%), GII.13 (6.4%) and an as yet unclassified GII genotype (0.9%). Although GII.4 was the most common norovirus capsid genotype detected, the great diversity of norovirus genotypes in the elderly indicates vaccination strategies for this demographic are not straightforward. PMID- 25721659 TI - Tailored interface and enhanced elastic modulus in epoxy-based composites in presence of branched poly(ethyleneimine) grafted multiwall carbon nanotubes. AB - In this study, branched poly(ethyleneimine), BPEI, was synthesized from carboxylic acid terminated multi-walled carbon nanotubes (c-MWNTs) and characterized using FTIR, TEM and TGA. The BPEI was then chemically grafted onto MWNTs to enhance the interfacial adhesion with the epoxy matrix. The epoxy composites with c-MWNTs and the BPEI-g-MWNTs were prepared using a sonication and mechanical stirring method, followed by curing at 100 degrees C and post-curing at 120 degrees C. The dynamic mechanical thermal analysis showed an impressive 49% increment in the storage elastic modulus in the composites. In addition, the nanoindentation on the composites exhibited significant improvement in the hardness and decrease in the plasticity index in the presence of the BPEI-g MWNTs. Thus, epoxy composites with BPEI-g-MWNTs can be further explored as self healing materials. PMID- 25721660 TI - Polycation-functionalized gold nanoparticles with different morphologies for superior gene transfection. AB - Favorable physical and chemical properties endow Au nanoparticles (Au NPs) with various biomedical applications. After appropriate surface functionalization, Au NPs could construct promising drug/gene carriers with multiple functions. There is now ample evidence that physicochemical properties, such as size, shape, and surface chemistry, can dramatically influence the behaviors of Au NPs in biological systems. Investigation of these parameters could be fundamentally important for the application of Au NPs as drug/gene carriers. In this work, we designed a series of novel gene carriers employing polycation-functionalized Au NPs with five different morphologies (including Au nanospheres, Au nano octahedra, arrow-headed Au nanorods, and Au nanorods with different aspect ratios). The effects of the particle size and shape of these different carriers on gene transfection were investigated in detail. The morphology of Au NPs is demonstrated to play an important role in gene transfection. The most efficient gene carriers are those fabricated with arrow-headed Au nanorods. Au nanosphere based carriers exhibit the poorest performance in gene transfection. In addition, Au nanorods with smaller aspect ratios perform better than longer ones. These results may provide new avenues to develop promising gene carriers and gain useful information on the interaction of Au NPs with biological systems. PMID- 25721661 TI - Simultaneous neuron- and astrocyte-specific fluorescent marking. AB - Systematic and simultaneous analysis of multiple cell types in the brain is becoming important, but such tools have not yet been adequately developed. Here, we aimed to generate a method for the specific fluorescent labeling of neurons and astrocytes, two major cell types in the brain, and we have developed lentiviral vectors to express the red fluorescent protein tdTomato in neurons and the enhanced green fluorescent protein (EGFP) in astrocytes. Importantly, both fluorescent proteins are fused to histone 2B protein (H2B) to confer nuclear localization to distinguish between single cells. We also constructed several expression constructs, including a tandem alignment of the neuron- and astrocyte expression cassettes for simultaneous labeling. Introducing these vectors and constructs in vitro and in vivo resulted in cell type-specific and nuclear localized fluorescence signals enabling easy detection and distinguishability of neurons and astrocytes. This tool is expected to be utilized for the simultaneous analysis of changes in neurons and astrocytes in healthy and diseased brains. PMID- 25721662 TI - Heat shock transcription factor delta32 is targeted for degradation via an ubiquitin-like protein ThiS in Escherichia coli. AB - The posttranslational modification of proteins with ubiquitin and ubiquitin-like proteins (UBLs) plays an important role in eukaryote biology, through which substrate proteins are targeted for degradation by the proteasome. Prokaryotes have been thought to degrade proteins by an ubiquitin independent pathway. Here, we show that ThiS, an ubiquitin-like protein, is covalently attached to delta(32) and at least 27 other proteins, leading to their subsequent degradation by proteases, in a similar manner to the ubiquitin-proteasome system (UPS) in eukaryotes. Molecular biology and biochemical studies confirm that specific lysine sites in delta(32) can be modified by ThiS. The results presented here establish a new model for delta(32) degradation and show that Escherichia coli uses a small-protein modifier to control protein stability. PMID- 25721663 TI - Characterization of C-terminal adaptors, UFD-2 and UFD-3, of CDC-48 on the polyglutamine aggregation in C. elegans. AB - CDC-48 (also called VCP or p97 in mammals and Cdc48p in yeast) is a AAA (ATPases associated with diverse cellular activities) chaperone and participates in a wide range of cellular activities including modulation of protein complexes and protein aggregates. UFD-2 and UFD-3, C-terminal adaptors for CDC-48, reportedly bind to CDC-48 in a mutually exclusive manner and they may modulate the fate of substrates for CDC-48. However, their cellular functions have not yet been elucidated. In this study, we found that CDC-48 preferentially interacts with UFD 3 in Caenorhabditis elegans. We also found that the number of polyglutamine (polyQ) aggregates was reduced in the ufd-3 deletion mutant but not in the ufd-2 deletion mutant. Furthermore, the lifespan and motility of the ufd-3 deletion mutant, where polyQ40::GFP was expressed, were greatly decreased. Taken together, we propose that UFD-3 may promote the formation of polyQ aggregates to reduce the polyQ toxicity in C. elegans. PMID- 25721664 TI - F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. AB - It has been demonstrated previously that F-box protein Fbxl15 targets HECT-type E3 Smurf1 and forms a functionally active SCF complex for ubiquitination and proteasomal degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly ubiquitination and proteasomal degradation. Different from Fbxl15, Fbxo3 targets all the Nedd4 family members for their degradation, indicating that Fbxo3 plays an important role in controlling the stability of Nedd4. Taken together, we show that Smurf1 is an endogenous substrate of Fbxo3. Our study gains further insight into the novel role of Fbxo3 in BMP signaling. PMID- 25721665 TI - Characterization of a novel domain 'GATE' in the ABC protein DrrA and its role in drug efflux by the DrrAB complex. AB - A novel domain, GATE (Glycine-loop And Transducer Element), is identified in the ABC protein DrrA. This domain shows sequence and structural conservation among close homologs of DrrA as well as distantly-related ABC proteins. Among the highly conserved residues in this domain are three glycines, G215, G221 and G231, of which G215 was found to be critical for stable expression of the DrrAB complex. Other conserved residues, including E201, G221, K227 and G231, were found to be critical for the catalytic and transport functions of the DrrAB transporter. Structural analysis of both the previously published crystal structure of the DrrA homolog MalK and the modeled structure of DrrA showed that G215 makes close contacts with residues in and around the Walker A motif, suggesting that these interactions may be critical for maintaining the integrity of the ATP binding pocket as well as the complex. It is also shown that G215A or K227R mutation diminishes some of the atomic interactions essential for ATP catalysis and overall transport function. Therefore, based on both the biochemical and structural analyses, it is proposed that the GATE domain, located outside of the previously identified ATP binding and hydrolysis motifs, is an additional element involved in ATP catalysis. PMID- 25721666 TI - Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. AB - In diabetes mellitus (DM), high glucose (HG) and advanced glycation end products (AGEs) are involved in bone quality deterioration. Osteocytes produce sclerostin and receptor activator of nuclear factor-kB ligand (RANKL) and regulate osteoblast and osteoclast function. However, whether HG or AGEs directly affect osteocytes and regulate sclerostin and RANKL production is unknown. Here, we examined the effects of HG, AGE2, and AGE3 on the expression of sclerostin and RANKL and on apoptosis in osteocyte-like MLO-Y4-A2 cells. Treatment of the cells with 22 mM glucose, 100 MUg/mL either AGE2 or AGE3 significantly increased the expression of sclerostin protein and mRNA; however, both AGEs, but not glucose, significantly decreased the expression of RANKL protein and mRNA. Moreover, treatment of the cells with HG, AGE2, or AGE3 for 72 h induced significant apoptosis. These detrimental effects of HG, AGE2, and AGE3 on sclerostin and RANKL expressions and on apoptosis were antagonized by pretreatment of the cells with 10(-8) M human parathyroid hormone (PTH)-(1-34). Thus, HG and AGEs likely suppress bone formation by increasing sclerostin expression in osteocytes, whereas AGEs suppress bone resorption by decreasing RANKL expression. Together, these processes may cause low bone turnover in DM. In addition, HG and AGEs may cause cortical bone deterioration by inducing osteocyte apoptosis. PTH may effectively treat these pathological processes and improve osteocyte function. PMID- 25721667 TI - Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation. AB - Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24 hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. PMID- 25721668 TI - Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR). AB - The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC-1alpha) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1alpha in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. PMID- 25721669 TI - G7731A mutation in mouse mitochondrial tRNALys regulates late-onset disorders in transmitochondrial mice. AB - We previously generated mito-mice-tRNA(Lys7731) as a model for primary prevention of mitochondrial diseases. These mice harbour a G7731A mtDNA mutation in the tRNA(Lys) gene, but express only muscle weakness and short body length by four months. Here, we examined the effects of their aging on metabolic and histologic features. Unlike young mito-mice-tRNA(Lys7731), aged mito-mice-tRNA(Lys7731) developed muscle atrophy, renal failures, and various metabolic abnormalities, such as lactic acidosis and anemia, characteristic of patients with mitochondrial diseases. These observations provide convincing evidence that the respiration defects induced by high G7731A mtDNA levels cause these late-onset disorders that are relevant to mitochondrial diseases. PMID- 25721670 TI - Phosphorylation of voltage-dependent anion channel by c-Jun N-terminal Kinase-3 leads to closure of the channel. AB - Stress activated c-Jun N-terminal Kinase-3 (JNK3) has been reported to act on mitochondrion to promote neuronal cell death. Phosphorylation of mitochondrial Voltage-Dependent Anion Channel (VDAC) plays an important role in mitochondria mediated cell death. Keeping these in view phosphorylation of rat brain VDAC by JNK3 has been studied in vitro. Pro Q Diamond phospho-protein staining experiment demonstrates VDAC is phosphorylated by JNK3. Bilayer electrophysiological experiments show that single-channel conductance of VDAC phosphorylated by JNK3 is significantly lower than that of the native VDAC at a membrane potential. The opening probability of VDAC undergoes massive reduction due to phosphorylation by JNK3. These indicate closure of VDAC due to phosphorylation by JNK3. Treatment of phosphorylated VDAC with alkaline phosphatase reversed the VDAC functional activity as shown by single-channel current and opening probability. The physiological consequence of closure of VDAC as a result of phosphorylation has been attributed to JNK3 dependent mitochondria-mediated apoptosis. PMID- 25721671 TI - 1alpha,25 dihydroxi-vitamin D3 modulates CDK4 and CDK6 expression and localization. AB - We recently reported that the vitamin D receptor (VDR) and p38 MAPK participate in pro-differentiation events triggered by 1alpha,25(OH)2-vitamin D3 [1,25D] in skeletal muscle cells. Specifically, our studies demonstrated that 1,25D promotes G0/G1 arrest of cells inducing cyclin D3 and cyclin dependent kinases inhibitors (CKIs) p21(Waf1/Cip1) and p27(Kip1) expression in a VDR and p38 MAPK dependent manner. In this work we present data indicating that cyclin-dependent kinases (CDKs) 4 and 6 also play a role in the mechanism by which 1,25D stimulates myogenesis. To investigate VDR involvement in hormone regulation of CDKs 4 and 6, we significantly reduced its expression by the use of a shRNA against mouse VDR, generating the skeletal muscle cell line C2C12-VDR. Investigation of changes in cellular cycle regulating proteins by immunoblotting showed that the VDR is involved in the 1,25D -induced CDKs 4 and 6 protein levels at 6 h of hormone treatment. CDK4 levels remains high during S phase peak and G0/G1 arrest while CDK6 expression decreases at 12 h and increases again al 24 h. The up-regulation of CDKs 4 and 6 by 1,25D (6 h) was abolished in C2C12 cells pre-treated with the ERK1/2 inhibitor, UO126. Moreover, CDKs 4 and 6 expression induced by the hormone nor was detected when alpha and beta isoforms of p38 MAPK were inhibited by compound SB203580. Confocal images show that there is not co-localization between VDR and CDKs at 6 h of hormone treatment, however CDK4 and VDR co-localizates in nucleus after 12 h of 1,25D exposure. Of relevance, at this time 1,25D promotes CDK6 localization in a peri-nuclear ring. Our data demonstrate that the VDR, ERK1/2 and p38 MAPK are involved in the control of CDKs 4 and 6 by 1,25D in skeletal muscle cells sustaining the operation of a VDR and MAPKs -dependent mechanism in hormone modulation of myogenesis. PMID- 25721672 TI - Identification of putative bone anabolic peptides targeting adherent plasma membrane. AB - Bone matrix provides unknown essential cues for osteoblast lineage cells to develop, grow, repair and remodel bones via adherent plasma membrane. Because of its tight sealing with bone matrix in vivo and culture surface in vitro as well, the adherent plasma membrane has been unveiled target of investigation to date. Herein, we report a new approach to explore the adherence plasma membrane of osteoblasts with biofunctional peptide candidates in a bacterial peptide library. To accomplish this, human osteoblast like hFOB 1.19 cells were cultured on porous filter with 8 MUm pore through which bacterial peptides were allowed to meet the membrane for affinity selection. The affinity-selected peptides were coated on culture plate to further evaluate their influence on osteoblastic cell adhesion, as well as expressions of osteoblast differentiation markers, alkaline phosphatase and osteocalcin. Finally, the serial screenings identified two prominent active peptides that enhanced the differentiation markers nearly to the same level as a control peptide of bone morphogenetic protein-2. Osteogenic activity is expected for the peptides when immobilized on bone implant surface. PMID- 25721673 TI - Unfolding and refolding of a protein by cholesterol and cyclodextrin: a single molecule study. AB - Unfolding/refolding of a plasma protein, human serum albumin (HSA), is studied using fluorescence correlation spectroscopy (FCS) and single molecule fluorescence resonance energy transfer (sm-FRET). Addition of cholesterol causes unfolding of HSA resulting in an increase in the hydrodynamic diameter (dH = 2rH) from 76 A in the native state to 120 A upon addition of 1 mM cholesterol. Addition of beta-cyclodextrin to HSA (unfolded by cholesterol) restores the hydrodynamic diameter back to 78 A. The cholesterol induced unfolding and beta cyclodextrin induced refolding are also monitored by measuring the distance between a FRET donor (CPM dye, D) and a FRET acceptor (Alexa 488, A) covalently attached to the protein (HSA). It is observed that the average D-A distance increases from 45 +/- 1 A at 0 mM cholesterol to 51 +/- 1 A at 1 mM cholesterol. Upon addition of beta-cyclodextrin, the D-A distance is restored to 45 +/- 1 A. The binding study indicates that nearly 94% of HSA molecules remain bound to cholesterol in the absence of beta-cyclodextrin and only 5% binds to cholesterol in the presence of beta-cyclodextrin. As much as 57% of the HSA and 99% of the cholesterol molecules bind to beta-cyclodextrin. Thus beta-cyclodextrin removes cholesterol from HSA by hydrophobic binding to cholesterol ("strip off") and also, itself binds to HSA. The conformational dynamics results suggest that addition of beta-cyclodextrin restores native like binding free energy and folding dynamics. PMID- 25721674 TI - Effect of bronchodilators on forced expiratory volume in 1 s in preterm-born participants aged 5 and over: a systematic review. AB - BACKGROUND AND OBJECTIVES: Preterm-born participants are at risk of long-term deficits in percentage predicted forced expiratory volume in 1 s (%FEV1). Since it is unclear if these deficits respond to bronchodilators, we systematically reviewed the evidence for reversibility of deficits in %FEV1 by bronchodilators in preterm-born participants. DESIGN: Studies reporting a change in %FEV1 in response to bronchodilator treatment in preterm-born participants at >=5 years of age, with or without a term-born control group, were identified. The quality of studies was assessed by adapted tools. Due to considerable heterogeneity between studies, formal meta-analysis was not possible. RESULTS: From 8,839 titles, 22 studies were identified after an updated search in May 2013. Twenty-one studies assessed the response to a single inhaled dose of a bronchodilator, and 1 study assessed longer-term effects. Most studies observed decreased %FEV1 in preterm born participants compared with controls. Most studies observed improved %FEV1 after a single dose of bronchodilator, with the largest improvements noted in those with bronchopulmonary dysplasia, who had greater deficits of %FEV1 when compared with preterm and term controls. One long-term study investigated a 2 week terbutaline administration, but the initial FEV1 after a single dose did not show a change in %FEV1 of >=15%, but 5/29 (17%) children had an increased %FEV1 of >=10%. CONCLUSIONS: In this systematic review, disparate studies were identified. Although single doses of bronchodilators appear to improve the FEV1 in the short term, further studies are required to assess their longer-term benefits not only on airway obstruction, but also their effect on respiratory symptoms. PMID- 25721675 TI - Use of Probiotic Bacillus spp. in Rotifer (Brachionus plicatilis) and Artemia (Artemia urmiana) Enrichment: Effects on Growth and Survival of Pacific White Shrimp, Litopenaeus vannamei, Larvae. AB - This study was to evaluate the effect of a preparation of Bacillus probiotic (Bacillus licheniformis and B. subtilis, 1:1) on growth and survival rate of Pacific white shrimp, Litopenaeus vannamei larvae. The larvae were fed on Artemia urmiana nauplii and Brachionus plicatilis enriched with the probiotic preparation at 1 * 10(6) CFU mL(-1) rate. The experimental setup was completely randomized design comprised of six treatments, namely solo Artemia nauplii (A) or rotifer (R), Artemia nauplii and rotifer without any enrichment (A + R), Artemia nauplii enrichment with probiotic bacilli (Bacillus licheniformis and B. subtilis) (A + B), rotifer enrichment with probiotic bacilli (R + B) and enriched Artemia nauplii and rotifer (A + R + B). All treatments were performed in triplicate. Chemical parameters of rearing water viz. pH, salinity and temperature were 7.5 8, 30-31 ppt and 31-32 degrees C, respectively. Photoperiod was 16L:8D. Shrimp larvae were fed Artemia nauplii and rotifers at 5-20 and 10-40 individuals per shrimp larvae four times a day, respectively. Growth and survival rate of larvae were determined at MII, MIII, PL1, PL4, PL7 and PL10 stages. Larvae in A + R + B treatment showed the highest total length (10.89 +/- 0.51 mm), weight (674 +/- 73 MUg) and survival rate (65% +/- 3.5). Lowest total length, weight and survival rate (7.96 +/- 0.63 mm, 493 +/- 52 MUg and 24.5 +/- 2.4%, respectively) were recorded in treatment B larvae. We concluded that Bacillus probiotic can improve growth and survival rate of Pacific white shrimp larvae without conceivably undesirable effects. PMID- 25721676 TI - Static postural differences between neutral and flat feet in children with and without symptoms. AB - BACKGROUND: Flatfoot is a common variant of foot posture. Whilst usually benign, in some children flatfoot is accompanied by pain and functional complaints. Comparisons between the posture of asymptomatic and symptomatic flat feet are few. If a difference does exist, it may help understand symptoms and guide management. METHODS: This paper investigated differences in lower limb posture between neutral and flat feet with and without symptoms during standing using the multi-segment Oxford Foot Model. 97 children between five and 18years old were assessed by a physiotherapist; each foot was classified into one of four categories: asymptomatic neutral (n=88), asymptomatic mild flatfoot (n=47), asymptomatic flatfoot (n=29), or symptomatic flatfoot (n=30). For each child, Oxford Foot Model markers were applied, and mean values of 11-Euler angles at the foot, ankle, and knee joints during standing were calculated. Analysis of variance and post-hoc tests were used to identify differences between groups. FINDINGS: Hindfoot eversion was significantly increased (P<0.001) in children with asymptomatic and, to a greater extent, symptomatic flatfoot. The forefoot was significantly more abducted (P<0.001) in the symptomatic than asymptomatic groups, and in the flat than neutral group. The forefoot was more supinated relative to the hindfoot in the flatfoot groups (P=0.023), although post-hoc analysis did not identify specific group differences. INTERPRETATION: Hindfoot eversion and forefoot abduction were much greater in the symptomatic population. The differences in foot alignment may relate to the presence of symptoms. PMID- 25721677 TI - [Special hematological diagnostics and therapy options for ocular lymphoma taking CNS involvement into account]. AB - BACKGROUND: Intraocular lymphomas are very rare and occur as either vitreoretinal or uveal tumors. Management in the clinical routine is highly variable and controversial. OBJECTIVES: To present the most important aspects of the diagnostics and therapy from the perspective of hematological oncologists and formulate management recommendations. METHODS: The English language literature was reviewed and the most important data were analyzed for presentation. RESULTS: In patients with vitreoretinal lymphoma evaluation for central nervous system (CNS) involvement should be performed due to its strong association with primary CNS lymphoma (PCNSL). The prognosis is relatively poor, particularly when the CNS is involved. Optimal therapy has not yet been established. For isolated vitreoretinal manifestations local therapy, such as intraocular methotrexate (MTX) or rituximab or radiation is recommended; however, there is a very high frequency of CNS relapse. Systemic high-dose MTX-based chemotherapy analogous to PCNSL treatment is an alternative option and is the treatment of choice in patients with simultaneous CNS and vitreoretinal lymphoma. Primary uveal lymphoma is usually an indolent lymphoma and treated by local therapy, whereas secondary uveal lymphoma predominantly occurs in aggressive systemic (non-CNS) lymphoma and is treated by systemic chemotherapy. DISCUSSION: Data on intraocular lymphoma are derived from small, usually retrospective and very heterogeneous studies with a relatively short follow-up. To gain more knowledge on this rare disease, inclusion of patients in the prospective registry, currently in progress in Germany, is desirable. PMID- 25721678 TI - Stereotactic body radiation therapy salvage reirradiation of radiorecurrent prostatic carcinoma relapsed in the prostatic bed. AB - A 67-year-old man presented with a slow increase of prostate-specific antigen value after radical prostatectomy and postoperative radiotherapy for prostate cancer. The patient had received 3D conformal radiotherapy to a total dose of 66 Gy in 33 fractions of 2 Gy each on the prostatic bed. Three years later, a macroscopic local failure was diagnosed at the apical region. The patient could not receive androgenic deprivation therapy or other types of treatment owing to comorbid conditions. Thus, stereotactic body radiation therapy with helical image guided tomotherapy was administered. The total dose was 30 Gy in 5 consecutive fractions of 6 Gy each to the site of the local failure. The treatment was preceded by a transperineal-guided injection of a self-absorbable hydrogel into the prostatic bed, between rectum and bladder, in order to preserve the rectal wall, which already had received significant doses from the first radiation course. Radiation therapy was well-tolerated. After a follow-up period of 6 months, the patient remains healthy, and there has been no further evidence of metastatic spread or recurrence. PMID- 25721679 TI - Hypersensitivity and tumor lysis syndrome associated with cetuximab treatment: should we be afraid? AB - The majority of the chemotherapy agents in use today cause various infusion reactions, from mild flushing to life-threatening events. The frequency of the reported hypersensitivity reactions induced by cetuximab varies between 3% and 22%. It is recommended in the literature to stop the infusion and replace cetuximab with panitumumab in case of hypersensitivity reactions observed during the treatment of colon cancer. Tumor lysis syndrome (TLS) may occur in colorectal cancers with heavy tumor load. Tumor lysis syndrome may be life-threatening. In our patient with widespread bone and liver metastases, treatment continued with cetuximab as a combination therapy with irinotecan in spite of the hypersensitivity and TLS led to a complete treatment response. The complete response observed after 3 months through continued therapy in our patient may present an example supporting treatment with cetuximab in spite of severe reactions. PMID- 25721680 TI - Laparoscopic adrenalectomy--10-year experience at a teaching hospital. AB - BACKGROUND: Minimally invasive adrenalectomy has been adopted as the treatment of choice for benign adrenal tumors. This study aimed to investigate the outcome of laparoscopic adrenalectomies performed over a 10-year period at a teaching hospital. METHODS: All laparoscopic adrenalectomies carried out between 1 April 2000 and 31 March 2010 were evaluated with respect to perioperative management, complications, conversion rate, learning curve, tumor size, and surgically relevant characteristics of different adrenal pathologies. RESULTS: Over a period of 10 years, 215 laparoscopic lateral transabdominal adrenalectomies were carried out for Conn's syndrome (n = 90), Cushing's syndrome (n = 72), pheochromocytoma (n = 30), metastatic disease (n = 8), incidentalomas (n = 10), and other rare adrenal pathologies (n = 5). Morbidity, mortality, and conversion rate were 7.0, 0.9, and 4.2 %, respectively. Patients with Cushing's disease and bilateral adrenalectomy showed a higher complication rate. In retrospect, the indication for a laparoscopic approach was at least questionable in five cases. During these 10 years, four surgeons unfamiliar with the technique received intensive training to a defined plan. CONCLUSIONS: Laparoscopic adrenalectomy represents a safe operating technique associated with few complications and a low conversion rate. Patients with severe Cushing's disease are prone to complications and require intensive monitoring postoperatively. Laparoscopic adrenalectomy is associated with a learning curve, and particular emphasis should be given to surgical training. PMID- 25721681 TI - Actin cytoskeleton contributes to the elastic modulus of embryonic tendon during early development. AB - Tendon injuries are common and heal poorly. Strategies to regenerate or replace injured tendons are challenged by an incomplete understanding of normal tendon development. Our previous study showed that embryonic tendon elastic modulus increases as a function of developmental stage. Inhibition of enzymatic collagen crosslink formation abrogated increases in tendon elastic modulus at late developmental stages, but did not affect increases in elastic modulus of early stage embryonic tendons. Here, we aimed to identify potential contributors to the mechanical properties of these early stage embryonic tendons. We characterized tendon progenitor cells in early stage embryonic tendons, and the influence of actin cytoskeleton disruption on tissue elastic modulus. Cells were closely packed in embryonic tendons, and did not change in density during early development. We observed an organized network of actin filaments that seemed contiguous between adjacent cells. The actin filaments exhibited a crimp pattern with a period and amplitude that matched the crimp of collagen fibers at each developmental stage. Chemical disruption of the actin cytoskeleton decreased tendon tissue elastic modulus, measured by atomic force microscopy. Our results demonstrate that early developmental stage embryonic tendons possess a well organized actin cytoskeleton network that contributes significantly to tendon tissue mechanical properties. PMID- 25721683 TI - Intracranial aneurysms in the youngest patients: characteristics and treatment challenges. AB - BACKGROUND: Characteristics and treatment challenges of aneurysms in young children differ from those in older pediatric patients. METHODS: Records of children undergoing cerebral or spinal angiography by the senior neurointerventionalist (D.B.O.) from October 2006 to January 2014 were reviewed to identify patients with digital subtraction angiography-confirmed intracranial aneurysms. Demographics, presentation, subtype of aneurysm, treatment strategy, and outcome were evaluated. RESULTS: Of 763 pediatric cases, 33 were of children harboring cerebral aneurysms. Overall, 48% were male, 24% presented with hemorrhage and 67% harbored fusiform/dissecting aneurysms. Patients aged 0-10 years were significantly more likely to harbor nonsaccular, dissecting/fusiform aneurysms (84 vs. 43%, p = 0.02). A total of 13/22 pediatric patients harboring dissecting/fusiform aneurysms were male (59%) compared to 3/11 with saccular aneurysms (27%, p = 0.14). Overall, 15 patients underwent endovascular treatment (45%) and 8 underwent microsurgical treatment (24%). There was no significant difference in treatment approach based on patient age or aneurysm morphology. Overall, 19/23 aneurysms were occluded after initial treatment (83%); there were 2 procedure-related complications with neurological sequelae (9%). CONCLUSION: We demonstrate that the youngest patients (10 years and under) have aneurysms even more distinct and less similar to adult aneurysms than those in the larger pediatric cohort. PMID- 25721684 TI - Medical Council of India orders doctors' suspension for drug industry junket. PMID- 25721682 TI - Diverse uncultivated ultra-small bacterial cells in groundwater. AB - Bacteria from phyla lacking cultivated representatives are widespread in natural systems and some have very small genomes. Here we test the hypothesis that these cells are small and thus might be enriched by filtration for coupled genomic and ultrastructural characterization. Metagenomic analysis of groundwater that passed through a ~0.2-MUm filter reveals a wide diversity of bacteria from the WWE3, OP11 and OD1 candidate phyla. Cryogenic transmission electron microscopy demonstrates that, despite morphological variation, cells consistently have small cell size (0.009+/-0.002 MUm(3)). Ultrastructural features potentially related to cell and genome size minimization include tightly packed spirals inferred to be DNA, few densely packed ribosomes and a variety of pili-like structures that might enable inter-organism interactions that compensate for biosynthetic capacities inferred to be missing from genomic data. The results suggest that extremely small cell size is associated with these relatively common, yet little known organisms. PMID- 25721685 TI - Gastrointestinal release behaviour of modified-release drug products: dynamic dissolution testing of mesalazine formulations. AB - The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC), a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol((r)) 800, Octasa((r)), Mezavant((r)) XL, Salofalk((r)), Pentasa((r))), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant((r)) XL (Lialda((r))) (lag time 290 min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa((r)) showed a similar lag time to Mezavant((r)) XL. Drug release from Asacol((r)) 800 (Asacol((r)) HD) showed a wide standard deviation, reflecting the great variability in vivo. Salofalk((r)) displayed both delayed release and extended release characteristics. Pentasa((r)) released more than 50% of its drug load in the stomach compartment of the model, which is attributed to the absence of a gastro-resistant coating in this product. The new dissolution method provided a realistic and discriminative in vitro assessment of mesalazine release from different formulations. These results demonstrate that this strategy can be used to predict intestinal release behaviour, and potentially aid the rational design of products developed to target different sites of the gut. PMID- 25721686 TI - Thorough characterization of a Self-Emulsifying Drug Delivery System with Raman hyperspectral imaging: a case study. AB - Newly developed drugs often have poor bioavailability due to their poor water solubility (BCS class 2 drugs). It is therefore necessary to develop new strategies to enhance their solubility and their activity, among which, Self Emulsifying Drug Delivery System (SEDDS). The efficacy of the drugs contained in these preparations is mainly affected by the solid state and the particle size of the active pharmaceutical ingredient (API). However, it is quite complex, long and expensive to characterize these parameters with classical techniques such as X-ray powder diffraction, differential scanning calorimetry or hot stage microscopy. The present article presents, through a case study, the advantages of the Raman hyperspectral imaging in the characterization of such formulations. Indeed, Raman chemical imaging may fully characterize SEDDS with single equipment and operator in a non-destructive way allowing the follow-up of the formulation during stability studies. Raman imaging is therefore a tool of choice in the PAT framework since it increases the knowledge of the formulation and the process. A quantitative multivariate method using Raman hyperspectral imaging to assay the API in the lipid based formulation has been developed and fully validated following the "total error" approach. PMID- 25721687 TI - Skin aging modulates percutaneous drug absorption: the impact of ultraviolet irradiation and ovariectomy. AB - Ultraviolet (UV) exposure and menopause are known as the inducers of damage to the skin structure. The combination of these two factors accelerates the skin aging process. In this study, we aimed to evaluate the influence of UV and ovariectomy (OVX) on the permeation of drugs through the skin. The role of tight junctions (TJs) and adherens junctions (AJs) in the cutaneous absorption of extremely lipophilic permeants and macromolecules was explored. The OVX nude mouse underwent bilateral ovary removal. Both UVA and UVB were employed to irradiate the skin. The physiological and biochemical changes of the skin structure were examined with focus on transepidermal water loss (TEWL), skin color, immunohistochemistry, and mRNA levels of proteins. UVB and OVX increased TEWL, resulting in stratum corneum (SC) integrity disruption and dehydration. A hyperproliferative epidermis was produced by UVB. UVA caused a pale skin color tone due to keratinocyte apoptosis in the epidermis. E-cadherin and beta-catenin showed a significant loss by both UVA and UVB. OVX downregulated the expression of filaggrin and involucrin. A further reduction was observed when UV and OVX were combined. The in vitro cutaneous absorption demonstrated that UV increased the skin permeation of tretinoin by about twofold. However, skin accumulation and flux of estradiol were not modified by photoaging. OVX basically revealed a negligible effect on altering the permeation of small permeants. OVX increased tretinoin uptake by the appendages from 1.36 to 3.52 MUg/cm(2). A synergistic effect on tretinoin follicular uptake enhancement was observed for combined UV and OVX. However, the intervention of OVX to photoaged skin resulted in less macromolecule (dextran, molecular weight = 4 kDa) accumulation in the skin reservoir because of retarded partitioning into dry skin. The in vivo percutaneous absorption of lipophilic dye examined by confocal microscopy had indicated that the SC was still important to controlling topical delivery, although the role of epidermal junctions could not be simply ignored. PMID- 25721688 TI - Patients with eating disorders showed no signs of coeliac disease before and after nutritional intervention. AB - AIM: This study assessed the presence of specific antibodies for coeliac disease in outpatients suffering from eating disorders before and after nutritional intervention. We also evaluated whether those patients should undergo regular screening for coeliac disease. METHODS: The sample consisted of 154 patients with a mean age of 16.7 years - ranging from one to 19 years of age - suffering from eating disorders. Serology screening for coeliac disease and total immunoglobulin A (IgA) levels was evaluated in the 154 children before the nutritional intervention and in 104 patients after the intervention. The patients consumed an adequate amount of gluten in both phases. RESULTS: Postintervention evaluation revealed that 92 patients (88.5%) achieved a normal body weight, while the remaining 12 (11.5%) became obese. Postprandial abdominal discomfort and pain were resolved. The serology tests were negative in all patients, before and after intervention. None displayed IgA deficiency. CONCLUSION: To the best of our knowledge, this was the first prospective study where patients underwent a screening serology for coeliac disease before and after nutritional intervention. No indication of the coexistence of eating disorders and coeliac disease was documented, and the patients in our study were unlikely to require regular screening for coeliac disease. PMID- 25721689 TI - Early enteral nutrition compared with parenteral nutrition for esophageal cancer patients after esophagectomy: a meta-analysis. AB - Early postoperative enteral nutrition (EN) after esophagectomy in esophageal cancer patient has been reported to be correlated with a better rehabilitation than parenteral nutrition (PN). However, a robust conclusion has not been achieved. Therefore, we performed a meta-analysis to compare the postoperative EN and PN in patients with esophageal cancer undergoing esophagectomy. Three electronic databases were searched for eligible studies to be included in the meta-analysis. The summary relative risk/weighted mean difference (RR/WMD) estimates and corresponding 95% confidence interval (CI) were calculated using fixed- and random-effects models. Ten studies met the inclusion criteria. The analysis demonstrated that the early postoperative EN could significantly decrease the pulmonary complications (RR = 0.37, 95% CI = 0.22-0.62, P = 0.00, test for heterogeneity: I(2) = 0.0%, P = 0.89) and anastomotic leakage (RR = 0.46, 95% CI = 0.22-0.96, P = 0.04, test for heterogeneity: I(2) = 0.0%, P = 0.66) compared with PN. On the eighth postoperative day, the EN group had a higher levels of albumin (WMD = 1.84, 95% CI = 0.47-3.21, P = 0.01, test for heterogeneity: I(2) = 84.5%, P = 0.00) and prealbumin (WMD = 12.96, 95% CI = 3.63 22.29, P = 0.01, test for heterogeneity: I(2) = 0.0%, P = 0.63) compared with the PN group. However, there was no difference in digestive complications between these two approaches (RR = 1.30, 95% CI = 0.79-2.13, P = 0.30, test for heterogeneity: I(2) = 0.0%, P = 0.97). For patients with esophageal cancer following esophagectomy, the early postoperative EN support could decrease the morbidity of severe complications, such as pulmonary complications and anastomotic leakage, and maintain patients at a better nutritional status than parenteral nutrion support. PMID- 25721690 TI - The BS/BSOB Ratio in Aneuploidy Fetuses at 11-13 Weeks Gestation. AB - OBJECTIVE: The posterior fossa of normal fetuses was evaluated and compared with those having chromosomal abnormalities at 11-13+6 weeks' gestation in Chinese population. METHODS: In 518 normal fetuses referred to first trimester screening, fetal brain stem (BS) and brain stem to occipital bone distance (BSOB) were measured prospectively. The BS and BSOB were also measured on stored images in fetuses with confirmed trisomy 21 (n = 38), Trisomy 18 (n = 26), Trisomy 13 (n = 8), and monosomy X (n = 8). RESULTS: The BS diameter and BSOB distance correlated linearly with fetal crown-rump length (CRL) by regression analysis. The BS to BSOB ratio was below the 5th percentile in 2 (5.26%), 11 (44%), 4 (50%) and 4 (50%) fetuses with trisomy 21, trisomy 18, trisomy 13 and monosomy X, respectively. Thus, both BS and BS/BSOB ratio were significantly lower in trisomy 18, trisomy 13 and monosomy X fetuses when compared to the reference range but not in fetuses with Trisomy 21. CONCLUSION: In ultrasound scans performed at the 11-13(+6) gestation weeks, fetuses with trisomy 18, 13, and monosomy X had lower BS/BSOB ratios. But trisomy 21 fetuses did not show significant differences in posterior fossa compared to the normal population. PMID- 25721691 TI - A computational study on how theta modulated inhibition can account for the long temporal windows in the entorhinal-hippocampal loop. AB - A recent experimental study (Mizuseki, Sirota, Pastalkova, & Buzsaki, 2009) has shown that the temporal delays between population activities in successive entorhinal and hippocampal anatomical stages are longer (about 70-80ms) than expected from axon conduction velocities and passive synaptic integration of feed forward excitatory inputs. We investigate via computer simulations the mechanisms that give rise to such long temporal delays in the hippocampus structures. A model of the dentate gyrus (DG), CA3 and CA1 microcircuits is presented that uses biophysical representations of the major cell types including granule cells, CA3 and CA1 pyramidal cells (PCs) and six types of interneurons: basket cells (BCs), axo-axonic cells (AACs), bistratified cells (BSCs), oriens lacunosum-moleculare cells (OLMs), mossy cells (MCs) and hilar perforant path associated cells (HC). Inputs to the network came from the entorhinal cortex (EC) (layers 2 and 3) and the medial septum (MS). The model simulates accurately the timing of firing of different hippocampal cells with respect to the theta rhythm. The model shows that the experimentally reported long temporal delays in the DG, CA3 and CA1 hippocampal regions are due to theta modulated somatic and axonic inhibition. The model further predicts that the phase at which the CA1 PCs fire with respect to the theta rhythm is determined primarily by their increased dendritic excitability caused by the decrease of the axial resistance and the A-type K(+) conductance along their dendritic trunk. The model predicted latencies by which the DG, CA3 and CA1 principal cells fire are inline with the experimental evidence. Finally, the model proposes functional roles for the different inhibitory interneurons in the retrieval of the memory pattern by the DG, CA3 and CA1 networks. The model makes a number of predictions, which can be tested experimentally, thus leading to a better understanding of the biophysical computations in the hippocampus. PMID- 25721692 TI - Reactivity of sorbose dehydrogenase from Sinorhizobium sp. 97507 for 1,5-anhydro D-glucitol. AB - Purified recombinant sorbose dehydrogenase from Sinorhizobium sp. 97507 exhibited high reactivity for 1,5-anhydro-D-glucitol (1,5-AG) and L-sorbose, but little activity for the other sugars or sugar alcohols tested. Kinetic analysis revealed that its catalytic efficiency (k(cat)/Km) for L-sorbose and 1,5-AG is 1.8 * 10(2) and 1.5 * 10(2) s(-1).M(-1), respectively. PMID- 25721693 TI - Suppression of the TNF-alpha level is mediated by Gan-Lu-Yin (traditional Chinese medicine) in human oral cancer cells through the NF-kappa B, AKT, and ERK dependent pathways. AB - Oral cancer is one of the major causes of deaths in the male population of Taiwan. Gan-Lu-Yin (GLY) is used for an adjuvant treatment of Traditional Chinese Medicine in clinical patients. In this study, we investigated the molecular mechanisms in oral cancer cell lines after exposure to GLY. The cytometric bead based array (CBA) method was used for the examining and analyzing of tumor necrosis factor-alpha (TNF-alpha) secretion level. TNF-alpha mRNA expression was determined by real-time PCR analysis. Nuclear factor kappa B (NF-kappaB) activity and other relative proteins were determined by NF-kappaB promoter assay, Western blotting, electrophoretic mobility shift assay (EMSA), and immuno-staining analyses. GLY decreased the secretion of TNF-alpha from the oral cancer CAL 27 cells. Furthermore, 2000 MUg/mL of GLY significantly suppressed TNF-alpha mRNA expression of CAL 27 cells in a time-dependent manner. GLY reduced the levels of proteins, including nuclear NF-kappaB (p65 and p50), p-IKK (ser176), p-IkappaB, p AKT, p-ERK, and nuclear Egr-1 in a time and dose-dependent manner. GLY also suppressed the NF-kappaB activity and translocation in CAL 27 cells. We suggest that GLY might promote the cure of oral cancer through decreasing the level of TNF-alpha cytokine, and these actions were mediated partially through the NF kappaB, AKT, and ERK-dependent pathways in vitro. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1196-1205, 2016. PMID- 25721694 TI - Advances in skin regeneration: application of electrospun scaffolds. AB - The paucity of cellular and molecular signals essential for normal wound healing makes severe dermatological ulcers stubborn to heal. The novel strategies of skin regenerative treatments are focused on the development of biologically responsive scaffolds accompanied by cells and multiple biomolecules resembling structural and biochemical cues of the natural extracellular matrix (ECM). Electrospun nanofibrous scaffolds provide similar architecture to the ECM leading to enhancement of cell adhesion, proliferation, migration and neo tissue formation. This Review surveys the application of biocompatible natural, synthetic and composite polymers to fabricate electrospun scaffolds as skin substitutes and wound dressings. Furthermore, the application of biomolecules and therapeutic agents in the nanofibrous scaffolds viz growth factors, genes, antibiotics, silver nanoparticles, and natural medicines with the aim of ameliorating cellular behavior, wound healing, and skin regeneration are discussed. PMID- 25721695 TI - Rare case of temporally spontaneous regression of retroperitoneal paraganglioma. PMID- 25721696 TI - The cost effectiveness of erythropoietin-stimulating agents for treating anemia in patients on dialysis: a systematic review. AB - BACKGROUND: Anemia is a common complication associated with kidney failure and is marked by poor health and increased risk of morbidity and mortality. There are ongoing concerns with the use of Erythropoietin Stimulating Agents (ESAs) to treat anemia in patients with kidney failure on dialysis. Questions as to their benefits, harms and overall effect on quality of life are still relevant today. Our objective was to systematically review studies evaluating the cost effectiveness of ESAs in patients with kidney failure on dialysis. METHODS: We performed a systematic review of studies determining the cost-effectiveness of ESAs in adult patients on dialysis. Databases, including PubMed, EMBASE, and Cochrane Database of Systematic Reviews, were searched from their establishment until June 2013. Studies that reported an incremental cost-effectiveness ratio of hemoglobin correction strategies based on ESA treatments in comparison to red blood cell transfusions, lower hemoglobin targets, or no ESA treatment were included. RESULTS: Seven studies met inclusion criteria. Reported cost/quality adjusted life-year (QALY) ratios ranged from USD 931-677,749/QALY across five studies comparing ESAs to red blood cell transfusions. There was heterogeneity in results when considering higher hemoglobin targets, with studies finding higher targets to be both dominant and dominated. Mortality, hospitalization, and utility estimates were major drivers. CONCLUSIONS: There is substantial variability in the estimates of the cost-effectiveness of using ESAs in the dialysis population. New models incorporating recent meta-analyses for estimates of utility, mortality, and hospitalization changes would allow for a more comprehensive answer to this question. PMID- 25721697 TI - The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review. AB - BACKGROUND: Recombinant human growth hormone (rhGH) is being used to promote linear growth in short children with Noonan syndrome. However, its efficacy is still controversial. AIMS: To systematically determine the impact of rhGH therapy on adult height in children with Noonan syndrome. METHODS: We searched the Cochrane Central Register of Controlled Trials, ISI Web of Science, MEDLINE, and the bibliographic references from all retrieved articles published until April 2014. Studies reporting adult/near-adult height in children with Noonan syndrome treated with rhGH or reporting at least a 3-year follow-up were analysed. Quality and strength of recommendation were assessed according to the Endocrine Society criteria. RESULTS: No controlled trials reporting adult height were available. Five studies were identified reporting adult height or near adult height. Data comparison showed inter-individual variability in the response to rhGH, mean height gain standard deviation score ranging between 0.6 and 1.4 according to national standards, and between 0.6 and 2 according to Noonan standards. Significant biases affected all the studies. CONCLUSIONS: High-quality controlled trials on the impact of rhGH therapy on adult height are lacking, and the robustness of available data is not sufficient to recommend such therapy in children with Noonan syndrome. PMID- 25721698 TI - Estimation of the optimum dose of vitamin D for disease prevention in older people: rationale, design and baseline characteristics of the BEST-D trial. AB - BACKGROUND: Previous large trials of vitamin D for prevention of fractures and other disease outcomes have reported conflicting results, possibly because the doses tested were insufficient to maintain optimum blood levels of vitamin D (25[OH]D) predicted by the observational studies. This report describes the design and baseline characteristics of the BEST-D (Biochemical Efficacy and Safety Trial of vitamin D) trial which aims to establish the best dose of vitamin D to assess in a future large outcome trial. METHODS: The BEST-D trial will compare the biochemical and other effects of daily dietary supplementation with 100 MUg or 50 MUg vitamin D3 or placebo, when administered for 12 months, in 305 ambulant community-dwelling older people living in Oxfordshire, England. The primary analyses will compare 12-month mean plasma concentrations of 25(OH)D as well as the proportion of participants with a 12-month concentration >90 nmol/L between participants allocated 100 MUg and participants allocated 50 MUg daily. Secondary analyses will compare the two active doses (both separately and when combined) with placebo. Additional end-points include biochemical assessments of safety, blood pressure, arterial stiffness, falls, fractures, heel and wrist bone density, grip strength and physical performance and echocardiographic assessments of cardiac function in a random sample of participants. RESULTS: About one-third of eligible participants agreed to participate in the trial. The mean age was 72 (SD 6) years with equal numbers of men and women. About one third reported a prior history of fracture or hypertension, one-fifth reported a prior cardiovascular event, and one tenth reported diabetes or a fall in the previous 6 months. CONCLUSIONS: The results of this trial will help determine the optimum dose of vitamin D to test in a larger trial investigating whether vitamin D supplementation can reduce the risk of fractures, cardiovascular disease or cancer. PMID- 25721699 TI - The serum estradiol concentration is the main determinant of the estradiol concentration in normal breast tissue. AB - BACKGROUND: The estrogen concentration has been determined in breast tissue, focusing largely on samples obtained from breast cancers. In this study, estradiol concentration was determined in normal breast tissue obtained from women undergoing esthetic, and oncoplastic surgery. METHODS: Normal breast tissue was obtained during 68 operations for esthetic or reconstructive indications in women with and without a history of breast cancer. Our study included six different groups of women. The first three groups were normal cycling women, women taking oral contraceptives, and normal postmenopausal women, all undergoing a bilateral esthetic breast reduction. The second three groups were premenopausal and postmenopausal women, with a history of breast cancer and currently taking tamoxifen treatment, or postmenopausal women currently taking an aromatase inhibitor, needing contra-lateral corrective esthetic surgery. FINDINGS: In the group of women without history of breast cancer, normal cycling women (n=24) presented a strong correlation (r=0.853; P<0.0001) between 17beta-estradiol concentration in serum (median: 29.7 pg/mL; IQR: 10.8-82.3 pg/mL) and in breast tissue (30.6 pg/g; IQR: 18.6-183.8 pg/g). Postmenopausal women had low 17beta estradiol concentrations both in serum and breast tissue (r=0.813; P<0.0001, n=16). Women taking oral contraceptives (n=12) had low serum and breast tissue levels of estradiol (r=0.376; P=n.s.). Premenopausal women (n=6, mean age: 44.2 years) with a history of breast cancer and currently taking tamoxifen, had very high concentrations of 17beta-estradiol both in serum (277.9 pg/mL; IQR: 96.2 544.7 pg/mL) and in epithelial cells (251.9 pg/g; IQR: 115.0-426.5 pg/g) (r=0.803; P<0.001). Postmenopausal women taking tamoxifen (n=4, mean age: 48.3) had low concentrations of 17beta-estradiol in serum (7.0 pg/mL; IQR: 5.7-16.3 pg/mL) and in epithelial cells (14.6 pg/g IQR: 13.3-16.3 pg/g) (r=0.10; P=n.s.). The estradiol concentration in the breast of premenopausal women taking tamoxifen was 8.2 times higher that observed in the breast of normal cycling women, and 17.3 times higher that observed in postmenopausal women taking tamoxifen. Women taking adjuvant aromatase inhibitors had extremely low concentrations of 17beta estradiol both in serum and in breast tissue. INTERPRETATION: This study shows that serum estradiol levels largely determine estrogen levels in normal breast tissue. PMID- 25721701 TI - Early childhood hospitalisation with infection and subclinical atherosclerosis in adulthood: the Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: Most infections occur in pre-school children but the severity of the inflammatory response to common pathogens varies considerably. We examined the relationship between early childhood infections of sufficient severity to warrant hospitalisation, and markers of subclinical atherosclerosis in adulthood. METHODS: We investigated whether infection-related hospitalisation (IRH) in early childhood (0-5 years) was associated with adverse non-invasive phenotypes of atherosclerosis (carotid artery distensibility and intima-media thickness (IMT), and brachial artery flow-mediated dilation (FMD)) in adulthood in participants from the Cardiovascular Risk in Young Finns study. Analyses were adjusted for age, sex, and socioeconomic status and cardiovascular risk factors in childhood and adulthood. 1043 participants had lifetime IRH data with a mean age at adult follow-up of 33 years. RESULTS: Brachial FMD levels were significantly lower among individuals with early child IRH (mean +/- SEM 8.15 +/- 0.37 vs. 9.10 +/- 0.16%, p = 0.03). These individuals had a 1.84% (95% CI 0.64-3.04, p = 0.002) greater decrease in FMD over a 6-year interval between two adult follow-ups at mean ages 27 and 33 years. Childhood IRH was associated with increased asymmetrical dimethylarginine (ADMA) in adulthood (0.62 +/- 0.01 vs. 0.59 +/- 0.01 MUmol/l, p = 0.04), adjusted for age, sex, adult body mass index, and serum creatinine. Early childhood IRH was associated with lower carotid distensibility levels (1.95 +/- 0.06 vs. 2.09 +/- 0.02%/10 mmHg, p = 0.02), but not with carotid intima-media thickness (0.601 +/- 0.006 vs. 0.596 +/- 0.003 mm). All findings remained unchanged after adjustments for age, sex and conventional cardiovascular risk factors in childhood or adulthood. CONCLUSION: Infection-related hospitalisation in the pre-school period was associated with adverse adult atherosclerotic phenotypes and increased ADMA. Infection may contribute to causal pathways leading to the development of endothelial dysfunction and early atherosclerosis. PMID- 25721700 TI - Infectious and immunologic phenotype of MECP2 duplication syndrome. AB - MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected - in 4/21 patients accompanied by IgA deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG. PMID- 25721702 TI - Exercise training protects the LDL I subfraction from oxidation susceptibility in an aged human population. AB - BACKGROUND: Exercise training is considered an effective strategy to improve metabolic disease. Despite this, less is known regarding exercise training in the prevention and susceptibility of LDL subfraction oxidation, particularly in an aged population. METHODS: Eleven aged (55 +/- 4 yrs) and twelve young (21 +/- 2 yrs) participants were randomly separated into an experimental or control group as follows: young exercise (n = 6); young control (n = 6); aged exercise (n = 6) and aged control (n = 5). The participants assigned to the exercise groups performed 12 weeks of moderate intensity (55-65% VO2max) exercise training. Venous blood was extracted at baseline, and 48 h following 12 weeks of exercise and assayed for a range of metabolites associated with lipid composition and lipoprotein susceptibility to oxidation. RESULTS: Although there was no difference in the oxidation potential (time 1/2 max) of LDL I, II or III between groups at baseline (p > 0.05), there was an increase in time 1/2 max for LDL I following exercise within the aged exercise group (p < 0.05). Moreover, alpha tocopherol concentration was selectively lower in the aged exercise group, compared to the young exercise at baseline. The lipid composition of LDL I, LDL II, LDL III, VLDL, HDL2, HDL3 and serum lipid hydroperoxides remained unchanged as a function of exercise training and ageing (p > 0.05). CONCLUSION: The primary finding of this study demonstrates that adaptations in LDL resistance to oxidation occur following 12 weeks of exercise training in the aged, and this may be of clinical significance, as oxidation of LDL has been implicated in atherosclerosis. PMID- 25721703 TI - Feasibility and precision of transcutaneous very-high resolution ultrasound for quantification of arterial structures in human neonates - comparison with conventional high resolution vascular ultrasound imaging. AB - BACKGROUND: Non-invasive transcutaneous very-high resolution ultrasound (VHRU, 25 55 MHz) has recently been developed to quantify superficial vascular structures in humans. The performance of the method has yet not been evaluated in vivo in neonates. The aim of the study was to compare VHRU with conventional high resolution ultrasound (HRU, 7-12 MHz), and to assess the feasibility and precision of VHRU in this population. METHODS: 150 images from central elastic (common carotid, CCA) and peripheral muscular (brachial, BA; femoral, FA) arteries were obtained in 25 neonates of different gestational ages (range 33 + 0 to 41 + 5 gestational weeks) and weights (range 1570-4950 g) with VHRU, and the use of HRU for comparison assessed in five. RESULTS: Images were captured from CCAs with 35 MHz, FAs using 35 and 55 MHz, and BAs using 55 MHz. 12 MHz was unable to assess FAs and BAs, and the CCA IMT was grossly overestimated compared with 35-55 MHz. IMTs of the smallest BAs and FAs were beyond the axial resolution of VHRU (<0.05 mm), thus immeasurable. For VHRU, the intra-, inter- and test retest coefficients of variation (CV) were for LDs (range 1.44-2.62 mm, CVs between 1.6 and 4.8%), IMATs (range 0.141-0.161 mm, CVs between 8.8 and 19.9%), and IMTs (range 0.062-0.165 mm, CVs between 12.8 and 24.8%) for the different arteries. CONCLUSION: VHRU is feasible, accurate and precise in the assessment of superficial proximal conduit arteries but unable to assess the abdominal aorta in human neonates HRU-derived neonatal conduit arterial wall layer thicknesses are below the ultrasound axial resolution. PMID- 25721705 TI - Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review. AB - Background: Selective serotonin reuptake inhibitors (SSRI) are widely used in medical practice. They have been associated with a broad range of symptoms, whose clinical meaning has not been fully appreciated. Methods: The PRISMA guidelines were followed to conduct a systematic review of the literature. Titles, abstracts, and topics were searched using the following terms: 'withdrawal symptoms' OR 'withdrawal syndrome' OR 'discontinuation syndrome' OR 'discontinuation symptoms', AND 'SSRI' OR 'serotonin' OR 'antidepressant' OR 'paroxetine' OR 'fluoxetine' OR 'sertraline' OR 'fluvoxamine' OR 'citalopram' OR 'escitalopram'. The electronic research literature databases included CINAHL, the Cochrane Library, PubMed and Web-of-Science from inception of each database to July 2014. Results: There were 15 randomized controlled studies, 4 open trials, 4 retrospective investigations, and 38 case reports. The prevalence of the syndrome was variable, and its estimation was hindered by a lack of case identification in many studies. Symptoms typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering. However, many variations are possible, including late onset and/or longer persistence of disturbances. Symptoms may be easily misidentified as signs of impending relapse. Conclusions: Clinicians need to add SSRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs. The term 'discontinuation syndrome' that is currently used minimizes the potential vulnerabilities induced by SSRI and should be replaced by 'withdrawal syndrome'. (c) 2015 S. Karger AG, Basel. PMID- 25721704 TI - Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: the Athero-Express Genomics Study. AB - BACKGROUND: The eicosanoid genes ALOX5, ALOX5AP and LTA4H have been implicated in atherosclerosis. We assessed the impact of common variants in these genes on gene expression, circulating protein levels, and atherosclerotic plaque phenotypes. METHODS: We included patients from the Stockholm Atherosclerosis Gene Expression study (STAGE, N = 109), and the Athero-Express Biobank Study (AE, N = 1443). We tested 1453 single-nucleotide variants (SNVs) in ALOX5, ALOX5AP and LTA4H for association with gene expression in STAGE. We also tested these SNVs for association with seven histologically defined plaque phenotypes in the AE (which included calcification, collagen, cellular content, atheroma size, and intraplaque vessel density and hemorrhage). RESULTS: We replicate a known cis eQTL (rs6538697, p = 1.96 * 10(-6)) for LTA4H expression in whole blood of patients from STAGE. We found no significant association for any of the SNVs tested with serum levels of ALOX5 or ALOX5AP (p > 5.79 * 10(-4)). For atherosclerotic plaque phenotypes the strongest associations were found for intraplaque vessel density and smooth muscle cells in the ALOX5AP locus (p > 1.67 * 10(-4)). CONCLUSIONS: We replicate a known eQTL for LTA4H expression in whole blood using STAGE data. We found no associations of variants in and around ALOX5, ALOX5AP and LTA4H with serum ALOX5 or ALOX5AP levels, or plaque phenotypes. On the supposition that these genes play a causal role in atherosclerosis, these results suggest that common variants in these loci play a limited role (if any) in influencing advanced atherosclerotic plaque morphology to the extent that it impacts atherosclerotic disease. PMID- 25721706 TI - Advances in SPECT and PET Hardware. AB - There have been significant recent advances in single photon emission computed tomography (SPECT) and positron emission tomography (PET) hardware. Novel collimator designs, such as multi-pinhole and locally focusing collimators arranged in geometries that are optimized for cardiac imaging have been implemented to reduce imaging time and radiation dose. These new collimators have been coupled with solid state photon detectors to further improve image quality and reduce scanner size. The new SPECT scanners demonstrate up to a 7-fold increase in photon sensitivity and up to 2 times improvement in image resolution. Although PET scanners are used primarily for oncological imaging, cardiac imaging can benefit from the improved PET sensitivity of 3D systems without inter-plane septa and implementation of the time-of-flight reconstruction. Additionally, resolution recovery techniques are now implemented by all major PET vendors. These new methods improve image contrast, image resolution, and reduce image noise. Simultaneous PET/magnetic resonance (MR) hybrid systems have been developed. Solid state detectors with avalanche photodiodes or digital silicon photomultipliers have also been utilized in PET. These new detectors allow improved image resolution, higher count rate, as well as a reduced sensitivity to electromagnetic MR fields. PMID- 25721707 TI - Glycerol monooleate reverse micelles in nonpolar solvents: computer simulations and small-angle neutron scattering. AB - The formation of glycerol monooleate reverse micelles in n-heptane and toluene at room temperature is studied using molecular-dynamics simulations and small-angle neutron scattering. The glycerol monooleate concentrations under consideration are in the range of 5-20 wt %. Under these conditions, spontaneous reverse micelle formation is observed on the simulation timescale (up to 30 ns). From simulations, the typical dimensions (semiaxes) of the equivalent ellipsoids with the same masses and moments of inertia are in the range of 15-23 A, with instantaneous shapes that are slightly nonspherical. By analyzing the scattering form factors from simulation and experiment, the radii of gyration of the reverse micelles are determined to be approximately 15 A. The number of glycerol monooleate molecules in a reverse micelle is smaller in toluene (~20) than in n heptane (~30), but the overall dimensions are similar due to greater penetration of the toluene in to the reverse micelle. The effects of low concentrations (1 wt %) of water, acetic acid, and ethanol on the reverse-micelle dimensions are determined. The overall structural effects are small, but the distributions of the molecules within the reverse micelles are shown to be sensitive to the molecular polarity. PMID- 25721708 TI - Does administrative support negate the consequences of nurse abuse? AB - AIM: To assess the relationship between disruptive/abusive situations and the 'intention to leave' nursing. BACKGROUND: While every nurse deserves to feel safe in his or her working environment, nurse abuse remains a common occurrence worldwide. Only when hospitals are safe, is retention enhanced and patient care improved. METHOD: A cross-sectional survey was conducted with 1053 nurses. RESULTS: Almost 70% of nurses experienced stressful disruptive/abusive situations that were mainly caused by patients/families. The majority felt skilled in dealing with these situations, yet around 40% considered leaving nursing because of disruption/abuse. Stress from disruption/abuse, the skill in dealing with abuse and the administrations' support were the best predictors for the 'intention to leave'. CONCLUSIONS: It may not be the amount of abuse per se that affects the nurses' intention to leave, but rather how the abuse is perceived, the skill in dealing with it and the support received from administration. IMPLICATIONS FOR NURSING MANAGEMENT: The support received from nursing administration may negate the effect of stress and the 'intention to leave' because of disruptive/abusive situations. This should behove nurse managers and administrators to have a system in place to provide support for nurses, which in turn could improve job satisfaction and retention. PMID- 25721709 TI - Imaging characteristics of androgen insensitivity syndrome. AB - Androgen insensitivity syndrome (AIS), also known as testicular feminization, is a genetic disorder which leads to lack of response to androgens caused by a defect in the androgen receptor. It is relatively uncommon and is usually diagnosed through clinical symptoms, laboratory findings, physical exam, radiological imaging, and genetic analysis. Our case is a middle-aged woman with complete AIS and demonstrates the importance of the various imaging modalities that are implemented in initially diagnosing and assisting in surgical management. PMID- 25721710 TI - Dual-phase F-18 FDG PET-CT in staging and lymphoscintigraphy for detection of sentinel lymph nodes in oral cavity cancers. AB - AIM: Our objective was to evaluate the diagnostic role of dual-phase fluor-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography-computed tomography (PET-CT) and planar lymphoscintigraphy in patients with oral cavity cancer (OCC). We also investigated the combined impact of F-18 FDG PET-CT and sentinel lymph node biopsy (SLNB) in decision making for patients with OCC. METHODS: Sixteen patients (4 female, 12 male; age range, 29-81 years) were included in this prospective study. F-18 FDG PET-CT [1 (early) and 2 h (delayed) after injection] and planar lymphoscintigraphy (2h before the surgery) were performed for all the patients before surgery. The sensitivity, specificity, and negative and positive predictive values in F-18 FDG PET-CT for the early and the delayed scans and tumor/liver uptake (T/L) in the lymph nodes were calculated. Receiver operating characteristic curves were obtained for standardized uptake value (SUV)max and T/L. RESULTS: Histopathological evaluations revealed that 5 patients had metastatic lymph nodes (pN+) whereas 11 patients had benign lymph nodes (pN-). Out of 43 lymph nodes visualized as cN(+) in F-18 FDG PET-CT, 14 were pathologically positive for malignancy, whereas 29 were pathologically benign. There was no statistical difference between the N(+) and N(-) patients in terms of age, depth of primary tumor, and the number of mitoses. However, there was a significant difference between the N(+) and N(-) patients (P=.011) in terms of early and delayed F-18 FDG uptake of primary tumors. There was a statistically significant difference in the value of SUVmax between the early and the delayed scans for the malignant lymph nodes (P=.00). CONCLUSION: This study indicates that F-18 FDG PET-CT is a reliable method for the correct evaluation of primary tumor and N staging in OCCs. Delayed phase of F-18 FDG imaging may increase primary lesion detectability due to higher FDG uptake in primary tumors compared to the early phase of imaging. F-18 FDG PET-CT might demonstrate skip metastasis in lymph nodes which can be missed with SLNB. Although SUV values increased in the delayed phase of F-18 PET-CT imaging in detecting lymph node metastases, the specificity and positive predictive value did not increase. PMID- 25721711 TI - Osteoid osteoma of the scaphoid: magnetic resonance imaging vessel sign. AB - Osteoid osteomas can be a challenging diagnosis, especially in smaller bones and, particularly, in the carpus. Clinical and imaging diagnosis may both be delayed due to other, more common, post-traumatic or inflammatory pathology in the same area. We present a case of a pathologically proven scaphoid osteoid osteoma with a feeding vessel sign on magnetic resonance imaging, previously described in long bones with computed tomography, as a helpful sign for accurate diagnosis in the scaphoid. PMID- 25721712 TI - Establishing a supportive care register improves end-of-life care for patients with advanced chronic kidney disease. AB - BACKGROUND: End-of-life care for patients with advanced chronic kidney disease (CKD) is recognised as an important area for improvement. These patients have a significant mortality and, although some is unpredictable, there is a role for the nephrology multi-disciplinary team (MDT) and palliative care physicians to engage in advance care planning and support patients to discuss their preferences. METHODS: Retrospective and prospective data were obtained to conduct a comparison observational study to assess the impact of introducing a supportive care register on the end-of-life care for patients with advanced CKD. An electronic supportive care register was implemented. This required a programme of multi-disciplinary staff education, collaborative working with Palliative Care to establish renal-specific protocols and dissemination activities. The impact of the intervention was assessed by analysing all deaths in two six-month periods where all those with an eGFR <15 ml/min/1.73 m(2) at the time of their death were included. RESULTS: A total of 91 patients were included. Post-intervention, there was a 25.4% (95% CI: 6.5-44.3%, p = 0.008) improvement in patients having a documented discussion about end-of-life planning. There was also a 19.7% (95% CI: 4.0-35.5%, p = 0.01) improvement in establishing the place of death. All patients who expressed a preferred place of death died there. The intervention increased engagement with the wider MDT and led to significant improvements in access to specialist palliative care services. CONCLUSIONS: These results show that the interventions implemented to introduce a supportive care register resulted in meaningful improvements to the end-of-life care for patients in our region with advanced CKD. (c) 2015 S. Karger AG, Basel. PMID- 25721713 TI - Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells. AB - Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy. PMID- 25721714 TI - Wnt1 positively regulates CD36 expression via TCF4 and PPAR-gamma in macrophages. AB - BACKGROUND: Scavenger receptors including CD36 control the phagocytosis of oxidized low-density lipoprotein and play an important role in macrophage physiology, but the underlying molecular mechanism by which CD36 is regulated in macrophages or during macrophage differentiation from monocytes remains to be determined. METHODS: Here, we investigated the relationship between Wnt1 and CD36 during macrophage differentiation. CD36 was suppressed following knockdown of Wnt1 by siRNA, while it was increased by ectopic overexpression of Wnt1 in macrophages. Using a beta-catenin inhibitor, peroxisome proliferator-activated receptor gamma (PPAR-gamma) siRNA, and transcription factor 4 (TCF4) siRNA, we demonstrated that Wnt1 regulates the expression of CD36 through TCF4 and PPAR gamma. Co-immunoprecipitation, chromatin immunoprecipitation, and immunofluorescence experiments showed that beta-catenin interacted with PPAR gamma and that PPAR-gamma and TCF4 colocalized in the nucleus. Furthermore, Pax3 regulated Wnt1 via binding to the first binding site in the Wnt1 promoter. RESULTS: Our study demonstrated that during macrophage differentiation from monocytes, Wnt1 promotes CD36 expression via activation of PPAR-gamma and TCF4. CONCLUSIONS: Our findings suggest that Wnt1 plays an important role in macrophage physiology via activation of the canonical Wnt pathway. PMID- 25721715 TI - Hegemonic Masculinity, HIV/AIDS Risk Perception, and Sexual Behavior Change Among Young People in Ghana. AB - Among the youth in some parts of sub-Saharan Africa, a paradoxical mix of adequate knowledge of HIV/AIDS and high-risk behavior characterizes their daily lives. Based on original qualitative research in Ghana, I explore in this article the ways in which the social construction of masculinity influences youth's responses to behavior change HIV/AIDS prevention interventions. Findings show that although awareness of the HIV/AIDS epidemic and the risks of infection is very high among the youth, a combination of hegemonic masculinity and perceptions of personal invulnerability acts to undermine the processes of young people's HIV/AIDS risk construction and appropriate behavioral change. I argue that if HIV/AIDS prevention is to be effective and sustained, school- and community-based initiatives should be developed to provide supportive social spaces in which the construction of masculinity, the identity of young men and women as gendered persons, and perceptions of their vulnerability to HIV/AIDS infection are challenged. PMID- 25721716 TI - Birthing and Parenting a Premature Infant in a Cultural Context. AB - The purpose of this longitudinal qualitative descriptive study was to explore American Indian mothers' perceptions of parenting their premature infants over their first year of life in the context of their culture, including the birth and hospitalization experience. A convenience sample of 17 American Indian mothers and their premature infants were recruited from either a neonatal intensive care unit (NICU) or pediatric clinic in the southeast. Semistructured interviews were conducted at two time points. Through content analytic methods, three broad categories were revealed: descriptions of having a premature infant in the NICU, descriptions of parenting a premature infant, and the influence of Lumbee culture on parenting a premature infant. Certain aspects of American Indian culture appear to be important in having a premature infant in the NICU and in parenting a premature infant. We recommend that health care providers deliver culturally appropriate care that fully supports American Indian mothers and their premature infants. PMID- 25721718 TI - What is so new about mixed methods? AB - In this article, I dispute claims that mixed methods research emerged only recently in the social sciences. I argue that some anthropologists and sociologists (and others) have used mixed methods in fieldwork for at least 80 years, and there are studies from early in the 20th century that clearly fall within the definition of "mixed methods." I explore some of the history of the mixing of qualitative and quantitative data in earlier ethnographic works and show that in some sectors of social science research, the "emergence" and proliferation of mixed methods were particularly notable around the middle of the 20th century. Furthermore, concerning issues about "paradigms of research" in the social sciences, I identify some of the types of research in which the mixing of QUAL and QUAN approaches was more likely to occur. I suggest that some of the literature about research paradigms has involved a certain amount of "myth making" in connection with descriptions of qualitative and quantitative research assumptions and styles. PMID- 25721717 TI - Nursing Home Stakeholder Views of Resident Involvement in Medical Care Decisions. AB - Demand by nursing home residents for involvement in their medical care, or, patient-centered care, is expected to increase as baby boomers begin seeking long term care for their chronic illnesses. To explore the needs in meeting this proposed demand, we used a qualitative descriptive method with content analysis to obtain the joint perspective of key stakeholders on the current state of person-centered medical care in the nursing home. We interviewed 31 nursing home stakeholders: 5 residents, 7 family members, 8 advanced practice registered nurses, 5 physicians, and 6 administrators. Our findings revealed constraints placed by the long-term care system limited medical involvement opportunities and created conflicting goals for patient-centered medical care. Resident participation in medical care was perceived as low, but important. The creation of supportive educational programs for all stakeholders to facilitate a common goal for nursing home admission and to provide assistance through the long-term care system was encouraged. PMID- 25721719 TI - The Nature of Fatigue in Chronic Fatigue Syndrome. AB - In this article, we report the findings of our study on the nature of fatigue in patients diagnosed with chronic fatigue syndrome. Using ethnoscience as a design, we conducted a series of unstructured interviews and card sorts to learn more about how people with chronic fatigue syndrome describe fatigue. Participants (N = 14) described three distinct domains: tiredness, fatigue, and exhaustion. Most participants experienced tiredness prior to diagnosis, fatigue during daily life, and exhaustion after overexertion. We also discuss participants' ability to adapt to a variety of stressors and prevent shifts to exhaustion, and relate our findings to stress theory and other current research. Primary strategies that promoted adaptation to stressors included pacing and extended rest periods. These findings can aid health care professionals in detecting impending shifts between tiredness, fatigue, and exhaustion and in improving adaptive strategies, thereby improving quality of life. PMID- 25721720 TI - Study on Biological Effects of La(3+) on Rat Liver Mitochondria by Microcalorimetric and Spectroscopic Methods. AB - The effects of lanthanum on heat production of mitochondria isolated from Wistar rat liver were investigated with microcalorimetry; simultaneously, the effects on mitochondrial swelling and membrane potential (Deltapsi) were determined by spectroscopic methods. La(3+) showed only inhibitory action on mitochondrial energy turnover with IC50 being 55.8 MUmol L(-1). In the spectroscopic experiments, La(3+), like Ca(2+), induced rat liver mitochondrial swelling and decreased membrane potential (Deltapsi), which was inhibited by the specific permeability transition inhibitor, cyclosporine A (CsA). The induction ability of La(3+) was stronger than that of Ca(2+). These results demonstrated that La(3+) had some biotoxicity effect on mitochondria; the effects of La(3+) and Ca(2+) on rat liver mitochondrial membrane permeability transition (MPT) are different, and La represents toxic action rather than Ca analogy. PMID- 25721721 TI - Selenium as a feed supplement for heat-stressed poultry: a review. AB - Heat stress is associated with compromised performance and productivity in poultry due to declines in feed intake, nutrient utilization, growth rate, egg production and quality, and feed efficiency. Emerging evidences have shown that acute heat exposure results in increased production of free radicals and causes oxidative damage to lipids, proteins, and DNA. Additionally, heat stress can influence immune response by changing the expression of cytokines and by making the immune cells more susceptible to oxidative stress. Selenium, as a part of specific selenoproteins, can help to maintain antioxidant defenses, thereby preventing damages to tissues. An optimum response with supplementation of selenium in diet has been found to improve feed intake, body weight gain, feed efficiency, egg production and quality, and antioxidant status in heat-stressed poultry. Selenium compounds are also known to improve immune responses by altering the production of certain cytokines secreted by cells of the immune system and by enhancing the resistance of the immune cells to oxidative stress. It was reported that selenium supplementation had inhibitory effects on tumor necrosis factor alpha levels in heat-stressed broiler chicks, but the details are not completely elucidated. In the present review, the effect of selenium on production performance, nutrient utilization, antioxidative status, and immune responses of heat-stressed poultry is summarized. PMID- 25721722 TI - Halomicroarcula salina sp. nov., isolated from a marine solar saltern. AB - Halophilic archaeal strain YGHS18(T) was isolated from the Yinggehai marine solar saltern near Shanya city of Hainan Province, China. Cells from the strain were observed to be pleomorphic rods, stained Gram-negative, and formed red-pigmented colonies on solid media. Strain YGHS18(T) was found to be able to grow at 20-50 degrees C (optimum 37 degrees C), with 0.9-4.8 M NaCl (optimum 2.1 M) and at pH 5.5-9.0 (optimum pH 7.0). The cells lysed in distilled water and the minimum NaCl concentration to prevent cell lysis was found to be 0.9 M. The major polar lipids of the strain were identified as phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate, glucosyl mannosyl glucosyl diether and a diglycosyl diether (DGD-2). Strain YGHS18(T) possessed two heterogeneous 16S rRNA genes (rrnA and rrnB) and both were related to those of members of the genera Haloarcula (93.1-96.9% sequence similarity) and Halomicroarcula (92.7-96.1% similarity). The rrnA gene (orthologous gene) of strain YGHS18(T) clustered phylogenetically with members of the genus Halomicroarcula while the rrnB gene formed a paraphyly with members of the genera Halomicroarcula and Haloarcula . The rpoB' gene of strain YGHS18(T) was related phylogenetically to species of the genera Halomicroarcula (91.6-92.7% sequence similarity) and Haloarcula (91.5-92.4% similarity). EF-2 gene analysis revealed that strain YGHS18(T) was related phylogenetically to species of the genus Halomicroarcula (92.2-92.9% sequence similarity) rather than to those of the genus Haloarcula (90.9-91.7% similarity). The DNA G+C content of strain YGHS18(T) was determined to be 64.5 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain YGHS18(T) ( =CGMCC 1.12128(T) =JCM 18369(T)) represents a novel species of the genus Halomicroarcula , for which the name Halomicroarcula salina sp. nov. is proposed. PMID- 25721723 TI - Halococcus agarilyticus sp. nov., an agar-degrading haloarchaeon isolated from commercial salt. AB - Two agar-degrading halophilic archaeal strains, 62 E(T) and 197 A, were isolated from commercial salt samples. Cells were non-motile cocci, approximately 1.2-2.0 um in diameter and stained Gram-negative. Colonies were pink-pigmented. Strain 62 E(T) was able to grow with 24-30% (w/v) NaCl (optimum, 27%), at pH 6.5-8.5 (optimum, pH 7.5) and at 22-47 degrees C (optimum, 42 degrees C). The 16S rRNA gene sequences of strains 62 E(T) and 197 A were identical, and the level of DNA DNA relatedness between them was 90 and 90% (reciprocally). The closest relative was Halococcus saccharolyticus JCM 8878(T) with 99.7% similarity in 16S rRNA orthologous gene sequences, followed by Halococcus salifodinae JCM 9578(T) (99.6%), while similarities with other species of the genus Halococcus were equal to or lower than 95.1%. The rpoB' gene tree strongly supported that the two strains were members of the genus Halococcus . Mean DNA-DNA relatedness between strain 62 E(T) and H. saccharolyticus JCM 8878(T) and H. salifodinae JCM 9578(T) was 46 and 44%, respectively. The major polar lipids were archaeol derivatives of phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, derived from both C20C20 and C20C25 archaeol, and sulfated diglycosyl archaeol-1. Several unidentified glycolipids were present. Based on the phenotypic and phylogenetic analyses, the isolates are considered to represent a novel species of the genus Halococcus , for which the name Halococcus agarilyticus sp. nov. is proposed. The type strain is 62 E(T) ( = JCM 19592(T) =KCTC 4143(T)). PMID- 25721724 TI - Halocalculus aciditolerans gen. nov., sp. nov., an acid-tolerant haloarchaeon isolated from commercial salt. AB - Three halophilic archaeal strains, MH2-243-1(T), MH2-93-1 and MH2-91-1 were isolated from commercial salt samples from Japan, Australia, and Bolivia. Strain MH2-243-1(T) was able to grow in the presence of 12-30% (w/v) NaCl (optimum, 18% NaCl), at pH 4.5-7.0 (optimum, pH 6.0) and at 20-60 degrees C (optimum, 40 degrees C). Strains MH2-91-1 and MH2-93-1 grew in slightly different ranges. The orthologous 16S rRNA gene sequences of the three strains were almost identical (99.8-99.9% similarities), and the closest relative was Salarchaeum japonicum JCM 16327(T) with 94.2-94.3% 16S rRNA gene sequence similarities, followed by strains of members of the closely related genera Halobacterium and Halarchaeum . The RNA polymerase subunit B' gene (rpoB') sequence also showed the highest similarity (86.6%) to that of Salarchaeum japonicum JCM 16327(T). The DNA G+C contents of strains MH2-243-1(T), MH2-93-1 and MH2-91-1 were 68.5, 68.8 and 68.3 mol%, respectively. DNA-DNA relatedness values amongst the three strains were 97-99%. The polar lipids of the three strains were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, and at least seven unidentified glycolipids. The polar lipid composition differed from those of Salarchaeum japonicum and species of the genera Halobacterium and Halarchaeum . Based on the phenotypic and phylogenetic analyses, it is proposed that the isolates represent a novel species of a new genus, for which the name Halocalculus aciditolerans gen. nov., sp. nov. is proposed. The type strain of the type species is MH2-243 1(T) ( = JCM 19596(T) =KCTC 4149(T)) isolated from solar salt produced in Japan. MH2-93-1 ( = JCM 19595) and MH2-91-1 ( = JCM 19594) are additional strains of the type species. PMID- 25721725 TI - Erratum to: Viable but not Culturable Forms of Legionella pneumophila Generated After Heat Shock Treatment are Infectious for Macrophage-like and Alveolar Epithelial cells after Resuscitation on Acanthamoeba polyphaga. PMID- 25721726 TI - Marine Oxygen-Deficient Zones Harbor Depauperate Denitrifying Communities Compared to Novel Genetic Diversity in Coastal Sediments. AB - Denitrification is a critically important biogeochemical pathway that removes fixed nitrogen from ecosystems and thus ultimately controls the rate of primary production in nitrogen-limited systems. We examined the community structure of bacteria containing the nirS gene, a signature gene in the denitrification pathway, from estuarine and salt marsh sediments and from the water column of two of the world's largest marine oxygen-deficient zones (ODZs). We generated over 125,000 nirS gene sequences, revealing a large degree of genetic diversity including 1,815 unique taxa, the vast majority of which formed clades that contain no cultured representatives. These results underscore how little we know about the genetic diversity of metabolisms underlying this critical biogeochemical pathway. Marine sediments yielded 1,776 unique taxa when clustered at 95 % sequence identity, and there was no single nirS denitrifier that was a competitive dominant; different samples had different highly abundant taxa. By contrast, there were only 39 unique taxa identified in samples from the two ODZs, and 99 % of the sequences belonged to 5 or fewer taxa. The ODZ samples were often dominated by nirS sequences that shared a 92 % sequence identity to a nirS found in the anaerobic ammonium-oxidizing (anammox) genus Scalindua. This sequence was abundant in both ODZs, accounting for 38 and 59 % of all sequences, but it was virtually absent in marine sediments. Our data indicate that ODZs are remarkably depauperate in nirS genes compared to the remarkable genetic richness found in coastal sediments. PMID- 25721727 TI - Subtraction coronary CT angiography using second-generation 320-detector row CT. AB - The purpose of this study was to explore the feasibility of subtraction coronary computed tomography angiography (CCTA) by second-generation 320-detector row CT in patients with severe coronary artery calcification using invasive coronary angiography (ICA) as the gold standard. This study was approved by the institutional board, and all subjects provided written consent. Twenty patients with calcium scores of >400 underwent conventional CCTA and subtraction CCTA followed by ICA. A total of 82 segments were evaluated for image quality using a 4-point scale and the presence of significant (>50 %) luminal stenosis by two independent readers. The average image quality was 2.3 +/- 0.8 with conventional CCTA and 3.2 +/- 0.6 with subtraction CCTA (P < 0.001). The percentage of segments with non-diagnostic image quality was 43.9 % on conventional CCTA versus 8.5 % on subtraction CCTA (P = 0.004). The segment-based diagnostic accuracy for detecting significant stenosis according to ICA revealed an area under the receiver operating characteristics curve of 0.824 (95 % confidence interval [CI], 0.750-0.899) for conventional CCTA and 0.936 (95 % CI 0.889-0.936) for subtraction CCTA (P = 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value for conventional CCTA were 88.2, 62.5, 62.5, and 88.2 %, respectively, and for subtraction CCTA they were 94.1, 85.4, 82.1, and 95.3 %, respectively. As compared to conventional, subtraction CCTA using a second-generation 320-detector row CT showed improvement in diagnostic accuracy at segment base analysis in patients with severe calcifications. PMID- 25721728 TI - Long-term safety and feasibility of three-vessel multimodality intravascular imaging in patients with ST-elevation myocardial infarction: the IBIS-4 (integrated biomarker and imaging study) substudy. AB - We assessed the feasibility and the procedural and long-term safety of intracoronary (i.c) imaging for documentary purposes with optical coherence tomography (OCT) and intravascular ultrasound (IVUS) in patients with acute ST elevation myocardial infarction (STEMI) undergoing primary PCI in the setting of IBIS-4 study. IBIS4 (NCT00962416) is a prospective cohort study conducted at five European centers including 103 STEMI patients who underwent serial three-vessel coronary imaging during primary PCI and at 13 months. The feasibility parameter was successful imaging, defined as the number of pullbacks suitable for analysis. Safety parameters included the frequency of peri-procedural complications, and major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI) and any clinically-indicated revascularization at 2 years. Clinical outcomes were compared with the results from a cohort of 485 STEMI patients undergoing primary PCI without additional imaging. Imaging of the infarct-related artery at baseline (and follow-up) was successful in 92.2% (96.6%) of patients using OCT and in 93.2% (95.5%) using IVUS. Imaging of the non infarct-related vessels was successful in 88.7% (95.6%) using OCT and in 90.5% (93.3%) using IVUS. Periprocedural complications occurred <2.0% of OCT and none during IVUS. There were no differences throughout 2 years between the imaging and control group in terms of MACE (16.7 vs. 13.3%, adjusted HR1.40, 95% CI 0.77 2.52, p = 0.27). Multi-modality three-vessel i.c. imaging in STEMI patients undergoing primary PCI is consistent a high degree of success and can be performed safely without impact on cardiovascular events at long-term follow-up. PMID- 25721729 TI - Evidence of novel plant-species specific ammonia oxidizing bacterial clades in acidic South African fynbos soils. AB - Ammonia-oxidizing bacteria (AOB) are essential in the biogeochemical cycling of nitrogen as they catalyze the rate-limiting oxidation of ammonia into nitrite. Since their first isolation in the late 19th century, chemolithoautotrophic AOBs have been identified in a wide range of natural (e.g., soils, sediments, estuarine, and freshwaters) and man created or impacted habitats (e.g., wastewater treatment plants and agricultural soils). However, little is known on the plant-species association of AOBs, particularly in the nutrient-starved fynbos terrestrial biome. In this study, we evaluated the diversity of AOBs in the plant canopy of three South African fynbos-specific plant species, namely Leucadendron xanthoconus, Leucospermum truncatulum and Leucadendron microcephalum, through the construction of amoA-gene clone libraries. Our results clearly demonstrate that plant-species specific and monophyletic AOB clades are present in fynbos canopy soils. PMID- 25721730 TI - The CNT1 Domain of Arabidopsis CRY1 Alone Is Sufficient to Mediate Blue Light Inhibition of Hypocotyl Elongation. PMID- 25721732 TI - Cigarette Taxes and Older Adult Smoking: Evidence from the Health and Retirement Study. AB - In this study, we use the Health and Retirement Study to test whether older adult smokers, defined as those 50 years and older, respond to cigarette tax increases. Our preferred specifications show that older adult smokers respond modestly to tax increases: a $1.00 (131.6%) tax increase leads to a 3.8-5.2% reduction in cigarettes smoked per day (implied tax elasticity = -0.03 to -0.04). We identify heterogeneity in tax elasticity across demographic groups as defined by sex, race/ethnicity, education, and marital status and by smoking intensity and level of addictive stock. These findings have implications for public health policy implementation in an aging population. PMID- 25721731 TI - Association of PSCA rs2294008 gene variants with poor prognosis and increased susceptibility to gastric cancer and decreased risk of duodenal ulcer disease. AB - Two recent genome-wide association studies in Asians have reported the association between the PSCA (prostate stem cell antigen) rs2294008C>T gene polymorphism and two Helicobacter pylori infection-related diseases such as gastric cancer (GC) and duodenal ulcer (DU). Since rs2294008 allele frequencies differ notably among ethnicities, we aimed to assess the role of rs2294008 on the susceptibility to GC and DU in a Caucasian population in Spain. Moreover, the relevance of rs2294008 on GC prognosis was evaluated. Genomic DNA from 603 Spanish patients with primary GC, 139 with DU and 675 healthy controls was typed for the PSCA rs2294008C>T polymorphism by PCR-TaqMan assays. H. pylori infection [odds ratio (OR): 8.27; 95% confidence interval (CI): 3.45-15.33] and nonsteroidal anti-inflammatory drugs (OR: 6.54; 95% CI: 3.19-12.43) were identified as independent risk factors for DU whereas the rs2294008T allele was associated with reduced risk of developing the disease (OR: 0.52; 95% CI: 0.33 0.82). Infection with CagA strains (OR: 2.10; 95% CI: 1.63-2.34), smoking (OR: 1.93; 95% CI: 1.54-2.61), family history of GC (OR: 2.83; 95% CI: 2.01-3.83), and the rs2294008T allele (OR: 1.46; 95% CI: 1.07-1.99) were associated with increased risk of GC. Interestingly, the association with the rs2294008T allele was restricted to noncardia GC (OR: 1.43; 95% CI: 1.12-1.82), particularly of the diffuse histotype (OR: 1.59; 95% CI: 1.16-1.92). Finally, Cox regression analysis identified the rs2294008T variant as a prognosis factor associated with worse overall survival in patients with diffuse-type GC (hazard ratio: 1.85; 95% CI: 1.12-3.06). From these results we conclude that the PSCA rs2294008 polymorphism is involved in the susceptibility to GC and DU, as well as in the prognosis of the diffuse-type of GC in Caucasians. PMID- 25721733 TI - Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms. AB - The Warburg effect is a well-known feature of cancer cells. However, its' functional significance hasn't been elucidated yet. Pyruvate kinase muscle (PKM), which is a rate-limiting glycolytic enzyme, has 2 isoforms, PKM1 and PKM2. It has been reported that PKM2 is a tumor-specific isoform and promotes the Warburg effect. Also, it has been thought that tumor cells switch their PKM isoform from PKM1 to PKM2 during tumor development. Here, we showed that this switching machinery was induced only in limited cases, based on PKM expression in normal tissues, and that brain-specific microRNA (miR)-124 and muscle-specific miR-133b regulated this machinery by controlling PKM expression through targeting polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of the PKM gene. Also, we confirmed that the PKM2/PKM1 ratio was further elevated in other PKM2-dominant organs such as colon through the down-regulation of these PTB1 associated microRNAs during tumor development. PMID- 25721734 TI - IL-33 Receptor (ST2) Signalling is Important for Regulation of Th2-Mediated Airway Inflammation in a Murine Model of Acute Respiratory Syncytial Virus Infection. AB - T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is the ligand-binding component of the receptor for the cytokine IL-33, a newly identified cytokine known to amplify the Th2 cell-dominant immune responses. The function of IL-33/ST2 signalling during respiratory syncytial virus (RSV) infection is not fully known. In this study, following intranasal infection with RSV, BALB/c mice showed a marked increase in the production of IL 33, with an elevated expression of ST2 mRNA as well as a massive infiltration of CD45(+) ST2(+) cells in the lungs, suggesting that during the early phase of RSV infection, IL-33 target cells which express ST2 on cell surface, may play a critical role for the development of RSV-induced airway inflammation. Indeed, blocking ST2 signalling using anti-ST2 monoclonal antibody diminished not only RSV-induced eosinophil recruitment, but also the amounts of Th2-associated cytokines, particularly IL-13, and Th17-type cytokine IL-17A in the lungs of infected mice. However, anti-ST2 antibody treatment did not affect the production of Th1-type cytokine IFN-gamma as well as pulmonary viral growth and clearance. These results indicate that IL-33/ST2 signalling is involved in RSV-induced, Th2 associated airway inflammation but not protective immunity. PMID- 25721737 TI - Chronic high fat feeding increases anxiety-like behaviour and reduces transcript abundance of glucocorticoid signalling genes in the hippocampus of female rats. AB - The consumption of diets high in saturated fats and obesity have been associated with impaired physical and mental health. Previous studies indicate that chronic high fat diet consumption leads to systemic inflammation in humans and non-human animal models. Studies in non-human animals suggest that altered physiological responses to stress are also a consequence of high fat diet consumption. Glucocorticoid signalling mechanisms may link immune and stress-related pathways in the brain, and were shown to be significantly altered in the brains of female rat offspring of mothers exposed to chronic high fat diet during pregnancy and lactation. For adult females, the consequence of chronic high fat diet consumption on these signalling pathways and their relationship to stress-related behaviour is not known. In this study, we examined the effects of chronic consumption of a high fat diet compared to a low fat control diet among adult female Long Evans rats. We found significant differences in weight gain, caloric intake, anxiety-related behaviours, and glucocorticoid-related gene expression over a 10-week exposure period. As expected, rats in the high fat diet group gained the most weight and consumed the greatest number of calories. Rats in the high fat diet group showed significantly greater levels of anxiety-related behaviour in the Light Dark and Open Field tasks compared to rats in the low fat diet group. Rats consuming high fat diet also exhibited reduced transcript abundance in the hippocampus of stress-related mineralocorticoid receptor and glucocorticoid receptor genes, as well as nuclear factor kappa beta gene expression, implicated in inflammatory processes. Together, these data indicate that chronic high fat diet consumption may increase anxiety-like behaviour at least in part via alterations in glucocorticoid signalling mechanisms in limbic brain regions. PMID- 25721735 TI - Regulation and function of the NFE2 transcription factor in hematopoietic and non hematopoietic cells. AB - The NFE2 transcription factor was identified over 25 years ago. The NFE2 protein forms heterodimers with small MAF proteins, and the resulting complex binds to regulatory elements in a large number of target genes. In contrast to other CNC transcription family members including NFE2L1 (NRF1), NFE2L2 (NRF2) and NFE2L3 (NRF3), which are widely expressed, earlier studies had suggested that the major sites of NFE2 expression are hematopoietic cells. Based on cell culture studies it was proposed that this protein acts as a critical regulator of globin gene expression. However, the knockout mouse model displayed only mild erythroid abnormalities, while the major phenotype was a defect in megakaryocyte biogenesis. Indeed, absence of NFE2 led to severely impaired platelet production. A series of recent data, also summarized here, shed new light on the various functional roles of NFE2 and the regulation of its activity. NFE2 is part of a complex regulatory network, including transcription factors such as GATA1 and RUNX1, controlling megakaryocytic and/or erythroid cell function. Surprisingly, it was recently found that NFE2 also has a role in non-hematopoietic tissues, such as the trophoblast, in which it is also expressed, as well as the bone, opening the door to new research areas for this transcription factor. Additional data showed that NFE2 function is controlled by a series of posttranslational modifications. Important strides have been made with respect to the clinical significance of NFE2, linking this transcription factor to hematological disorders such as polycythemias. PMID- 25721736 TI - Dopamine in the nucleus accumbens modulates the memory of social defeat in Syrian hamsters (Mesocricetus auratus). AB - Conditioned defeat (CD) is a behavioral response that occurs in Syrian hamsters after they experience social defeat. Subsequently, defeated hamsters no longer produce territorial aggression but instead exhibit heightened levels of avoidance and submission, even when confronted with a smaller, non-aggressive intruder. Dopamine in the nucleus accumbens is hypothesized to act as a signal of salience for both rewarding and aversive stimuli to promote memory formation and appropriate behavioral responses to significant events. The purpose of the present study was to test the hypothesis that dopamine in the nucleus accumbens modulates the acquisition and expression of behavioral responses to social defeat. In Experiment 1, bilateral infusion of the non-specific D1/D2 receptor antagonist cis(z)flupenthixol (3.75 MUg/150 nl saline) into the nucleus accumbens 5 min prior to defeat training significantly reduced submissive and defensive behavior expressed 24h later in response to a non-aggressive intruder. In Experiment 2, infusion of 3.75 MUg cis-(Z)-flupenthixol 5 min before conditioned defeat testing with a non-aggressive intruder significantly increased aggressive behavior in drug-infused subjects. In Experiment 3, we found that the effect of cis-(Z)-flupenthixol on aggression was specific to defeated animals as infusion of drug into the nucleus accumbens of non-defeated animals did not significantly alter their behavior in response to a non-aggressive intruder. These data demonstrate that dopamine in the nucleus accumbens modulates both acquisition and expression of social stress-induced behavioral changes and suggest that the nucleus accumbens plays an important role in the suppression of aggression that is observed after social defeat. PMID- 25721738 TI - Adenosine signaling in reserpine-induced depression in rats. AB - A single, 6 mg/kg intraperitoneal injection of reserpine increased floating time during forced swim testing 24h after administration in rats in five experiments. Although such behavioral depression traditionally is attributed to drug-induced depletion of brain monoamines, we examined the potential contribution of adenosine signaling, which is plausibly activated by reserpine treatment and contributes to behavioral depression in other paradigms. Whereas peripheral administration of the highly selective A1 receptor antagonist 8-cyclopentyl-1,3 dipropylxanthine (0.5, 1.0, or 5.0mg/kg i.p.) 15 min before swim testing failed to improve performance in reserpine-treated rats, swim deficits were completely reversed by 7 mg/kg of the nonselective receptor antagonist caffeine. Performance deficits were also reversed by the nonselective A2 antagonist 3,7 dimethylxanthine (0, 0.5, 1.0mg/kg i.p.), and the highly selective A2A receptor antagonist (CSC: 8-(3 chlorostyral)caffeine) (0.01, 0.1, or 1.0mg/kg i.p.) in a dose-dependent manner. The highly selective A2B antagonist alloxazine had no beneficial effect on swim performance at any dose under study (0.1, 1.0, and 5.0mg/kg i.p.). PMID- 25721739 TI - Mice deficient in carbonic anhydrase type 8 exhibit motor dysfunctions and abnormal calcium dynamics in the somatic region of cerebellar granule cells. AB - The waddles (wdl) mouse is characterized by a namesake "side-to-side" waddling gait due to a homozygous mutation of the Car8 gene. This mutation results in non functional copies of the protein carbonic anhydrase type 8. Rota-rod testing was conducted to characterize the wdl mutations' effect on motor output. Results indicated that younger homozygotes outperformed their older cohorts, an effect not seen in previous studies. Heterozygotes, which were thought to be free of motor impairment, displayed motor learning deficiencies when compared with wild type performance. Acute cerebellar slices were then utilized for fluorescent calcium imaging experiments, which revealed significant alterations in cerebellar granule cell somatic calcium signaling when exposed to glutamate. The contribution of GABAergic signaling to these alterations was also verified using bath application of bicuculline. Changes in somatic calcium signals were found to be applicable to an in vivo scenario by comparing group responses to electrical stimulation of afferent mossy fiber projections. Finally, intracellular calcium store function was also found to be altered by the wdl mutation when slices were treated with thapsigargin. These findings, taken together with previous work on the wdl mouse, indicate a widespread disruption in cerebellar circuitry hampering proper neuronal communication. PMID- 25721740 TI - Modulating activity in the prefrontal cortex changes decision-making for risky gains and losses: a transcranial direct current stimulation study. AB - When making choices under uncertainty, people usually consider both the risks and benefits of each option. Previous studies have found that weighing of risks and benefits during decision-making involves a complex neural network that includes the dorsolateral prefrontal cortex (DLPFC), but the causal effect of this network on risk decision-making has remained unclear. This experiment was based on a risk measurement table designed to provide a direct measure of risk preference, with a weighted value of the choices (denoted as weighted risk aversion, WRA) as an index of the participant's degree of risk aversion. We studied whether bifrontal transcranial direct current stimulation (tDCS) applied over the right and left prefrontal cortex can change the balance of risky vs. safe responses under both gain frame and loss frame. A total of 60 volunteers performed risk tasks while receiving either anodal over the right with cathodal over the left DLPFC, anodal over the left with cathodal over the right DLPFC, or sham stimulation. The participants tended to choose more risky options in the gain frame and more safe options in the loss frame after the right anodal/left cathodal tDCS. We also found that right anodal/left cathodal tDCS significantly decreased the WRA values compared with those associated with sham stimulation. These findings extend the notion that DLPFC activity is critical for risk decision-making, indicating an asymmetric role of the right DLPFC in the gain frame vs. the loss frame of risk decision-making. PMID- 25721741 TI - Sex differences in the single prolonged stress model. AB - Post traumatic stress disorder (PTSD) is a debilitating anxiety disorder resulting from traumatic stress exposure. Females are more likely to develop PTSD than males, but neurobiological mechanisms underlying female susceptibility are lacking. This can be addressed by using nonhuman animal models. Single prolonged stress (SPS), a nonhuman animal model of PTSD, results in cued fear extinction retention deficits and hippocampal glucocorticoid receptor (GR) upregulation in male rats. These effects appear linked in the SPS model, as well as in PTSD. However, the effects of SPS on cued fear extinction retention and hippocampal GRs in female rats remain unknown. Thus, we examined sex differences in SPS-induced cued fear extinction retention deficits and hippocampal GR upregulation. SPS induced cued fear extinction retention deficits in male rats but not female rats. SPS enhanced GR levels in the dorsal hippocampus of female rats, but not male rats. SPS had no effects on ventral hippocampal GR levels, but ventral hippocampal GR levels were attenuated in female rats relative to males. These results suggest that female rats are more resilient to the effects of SPS. The results also suggest that GR upregulation and cued fear extinction retention deficits can be dissociated in the SPS model. PMID- 25721743 TI - Evaluation of gait impairment in mice subjected to craniotomy and traumatic brain injury. AB - Traumatic brain injury (TBI) represents a significant global health burden and causes long-lasting neuromotor deficits, particularly in individuals who sustain severe TBI. A better understanding of gait impairment after experimental TBI will provide valuable information for the recovery and rehabilitation of TBI survivors. Here we utilised the DigiGait system to perform kinematic gait analysis in mice subjected to brain injury induced by the controlled cortical impact (CCI) TBI model. Naive mice, non-craniotomised and craniotomised mice were included as controls. The temporal and spatial profile of gait was mapped from 3h to 1-week post-TBI. Remarkably, there was a noticeable alteration in some aspects of gait in craniotomised sham mice from their pre-surgery baseline at various time-points over the testing period. This was not observed in naive mice or non craniotomised sham controls over the same time period. This finding indicates that the craniotomy procedure alone effects gait. When craniotomised mice were subjected to TBI, additional deleterious effects on gait function were observed, including forelimb stance and swing duration as well as left hindlimb swing and stride duration and frequency. Hence, mice subjected to CCI-induced TBI develop clear alterations in gait but part of this is attributable to the effect of craniotomy alone. This study also highlights the need to include both non craniotomised and craniotomised sham mice as controls when undertaking the CCI induced model of TBI, particularly when early time points are being evaluated. PMID- 25721742 TI - Cardioacceleration in alloparents in response to stimuli from prairie vole pups: the significance of thermoregulation. AB - Autonomic responses, including changes in heart rate and respiratory sinus arrhythmia (RSA) can provide indications of emotional reactivity to social stimuli in mammals. We have previously reported that male prairie voles (Microtus ochrogaster) spontaneously care for unfamiliar infants, showing a robust and sustained increase in heart rate in the presence of a pup, thus providing an opportunity to examine the physiology of care-giving in reproductively naive animals. However, the purpose of such heart rate increases has not been explained by previous efforts. In the present study, we first compared male and female prairie vole cardiac responses in the presence of a pup and found no evidence of sex differences in heart rate or RSA. Using male prairie voles, we then examined the characteristics of pups that were capable of eliciting physiological responses, including age of the pup and pup odors. As prairie vole pups increased in age they vocalized less and there was an associated decline in alloparental cardioacceleration. Exposure to pup-related odors induced cardioacceleration in adult males, and this effect also diminished with increasing pup age. Finally, we were able to block the cardioacceleratory effect when the testing environment was warmed to a temperature of 36 degrees C [vs ambient room temperature (approximately 22 degrees C)]. These findings suggest that pup-induced cardioacceleration is a robust phenomenon across alloparental prairie voles of both sexes, and depends on multi-modal processing of different stimuli from the pups. Young pups require care-giving behavior, which appears to drive cardioacceleration in the alloparents. This study also supports the usefulness of autonomic measures in the evaluation of social experiences. PMID- 25721744 TI - Inactivation of BRD7 results in impaired cognitive behavior and reduced synaptic plasticity of the medial prefrontal cortex. AB - BRD7 is a bromodomain-containing protein (BCP), and recent evidence implicates the role of BCPs in the initiation and development of neurodevelopmental disorders. However, few studies have investigated the biological functions of BRD7 in the central nervous system. In our study, BRD7 was found to be widely expressed in various regions of the mouse brain, including the medial prefrontal cortex (mPFC), caudate putamen (CPu), hippocampus (Hip), midbrain (Mb), cerebellum (Cb), and mainly co-localized with neuron but not with glia. Using a BRD7 knockout mouse model and a battery of behavioral tests, we report that disruption of BRD7 results in impaired cognitive behavior leaving the emotional behavior unaffected. Moreover, a series of proteins involved in synaptic plasticity were decreased in the medial prefrontal cortex and there was a concomitant decrease in neuronal spine density and dendritic branching in the medial prefrontal cortex. However, no significant difference was found in the hippocampus compared to the wild-type mice. Thus, BRD7 might play a critical role in the regulation of synaptic plasticity and affect cognitive behavior. PMID- 25721745 TI - Risk factors for renal function decline in adults with normal kidney function: a 7-year cohort study. AB - BACKGROUND: We aimed to examine the risk factors for renal function decline (RFD) in a community-based cohort of a rural Chinese population with normal kidney function (estimated glomerular filtration rate, eGFR >=60 mL/min/1.73 m(2)), both for the population as a whole and stratified by sex. METHODS: 2518 participants were included in the current analysis. RFD was defined as follows: a drop in the eGFR category accompanied by a 25% or greater drop in eGFR from baseline; or a sustained decline in eGFR of more than 5 mL/min/1.73 m(2)/year. RESULTS: The incidence rate of RFD was 8.7% (women 7.4% and men 9.8%). In the multivariable logistic regression model, the ORs (95% CI) of developing RFD was 1.60 (1.01 to 2.54) for men versus women, and 1.51 (1.09 to 2.08) for participants with obesity or abdominal obesity versus none (1.35 (0.85 to 2.14) for men, and 1.65 (1.04 to 2.64) for women). However, prehypertension (OR=1.64; 95% CI 1.02 to 2.63) or hypertension (2.05; 1.21 to 3.47), higher mean blood pressure (>=90 vs <80 mm Hg, 2.63; 1.11 to 6.20), higher pulse pressure (>=50 vs <40 mm Hg, 2.00; 1.26 to 3.18), lower high-density lipoprotein cholesterol (<0.9 vs >=0.9 mmol/L, 2.65; 1.08 to 6.50) and low physical activity levels (vs high, 3.11; 1.59 to 6.10) were major risk factors for RFD in men. Current smoking (3.22; 1.22 to 2.64) and worse self-reported health (vs better, 2.57; 1.20 to 5.50) were major risk factors for RFD in women. CONCLUSIONS: Our findings suggested that sex-specific risk factors should be considered in prevention of RFD in the Chinese rural population with normal kidney function. PMID- 25721746 TI - Preliminary Evidence for a Compromised T-Cell Compartment in Maltreated Children with Depression and Posttraumatic Stress Disorder. AB - OBJECTIVE: Adverse childhood experiences, such as maltreatment, and affective disorders are associated with a proinflammatory state and/or variably compromised counts in lymphocyte subsets in adults. Animal models of social stress indicate that recent thymic emigrant cells (RTE), which maintain the T-cell compartment, are affected. METHODS: In this study, we examined the association between lymphocyte subsets, and depression and posttraumatic stress disorder (PTSD) among 16 maltreated children (aged 6-17 years) 1-3 years after the intervention by the Child Protection Team and among 14 healthy age-matched controls. The participants completed psychological assessment and had blood drawn for fluorescent-activated cell sorting analysis. RESULTS: Among maltreated children and adolescents, depression was associated with lower counts of RTEs and T-helper cells after controlling for age. We found additional trends and large effect sizes with regard to the percentages of these cells, as well as for related lymphocyte subsets. Similar effects were found for PTSD, i.e. lower counts of naive T cells, which was also supported by a trend for their percentage. Compared to controls, maltreated participants with a clinical level of depression had decreased percentages of RTEs, with a similar trend for PTSD. CONCLUSION: Limited by the nature of a pilot study and the small sample size, these preliminary findings of a compromised T-cell compartment related to psychiatric symptoms in maltreated children and adolescents need to be further studied; particularly the role of RTEs needs further evaluation. PMID- 25721747 TI - A history of the population attributable fraction and related measures. AB - PURPOSE: Since Doll published the first PAF in 1951, it has been a mainstay. Confusion in terminology abounds with regard to these measures. The ability to estimate all of them in case-control studies as well as in cohort studies is not widely appreciated. METHODS: This article reviews and comments on the historical development of the population attributable fraction (PAF), the exposed attributable fraction (EAF), the rate difference (ID), the population rate (or incidence) difference (PID), and the caseload difference (CD). RESULTS: The desire for PAFs to sum to no more than 100% and the interpretation of the complement of a PAF as the proportion of a rate that can be attributed to other causes are shown to stem from the same problem: a failure to recognize the pervasiveness of shared etiologic responsibility among causes. A lack of appreciation that "expected" numbers of cases and deaths are not actually the numbers to be expected when an exposure or intervention appreciably affects person-time denominators for rates, as in the case of smoking and nonnormal body mass, makes many CD estimates inflated. A movement may be gaining momentum to shift away from assuming, often unrealistically, the complete elimination of harmful exposures and toward estimating the effects of realistic interventions. This movement could culminate in a merger of the academic concept of transportability with the applied discipline of risk assessment. CONCLUSIONS: A suggestion is offered to pay more attention to absolute measures such as the rate difference, the population rate difference, and the CD, when the latter can be validly estimated and less attention to proportional measures such as the EAF and PAF. PMID- 25721749 TI - Hyperprolactinaemia: psychological aspects and menstrual attitudes of women with schizophrenia. PMID- 25721748 TI - Colorectal cancer deaths attributable to nonuse of screening in the United States. AB - PURPOSE: Screening is a major contributor to colorectal cancer (CRC) mortality reductions in the United States but is underused. We estimated the fraction of CRC deaths attributable to nonuse of screening to demonstrate the potential benefits from targeted interventions. METHODS: The established microsimulation screening analysis colon model was used to estimate the population attributable fraction (PAF) in people aged >=50 years. The model incorporates long-term patterns and effects of screening by age and type of screening test. PAF for 2010 was estimated using currently available data on screening uptake. PAF was also projected assuming constant future screening rates to incorporate lagged effects from past increases in screening uptake. We also computed PAF using Levin's formula to gauge how this simpler approach differs from the model-based approach. RESULTS: There were an estimated 51,500 CRC deaths in 2010, about 63% (N ~ 32,200) of which were attributable to nonscreening. The PAF decreases slightly to 58% in 2020. Levin's approach yielded a considerably more conservative PAF of 46% (N ~ 23,600) for 2010. CONCLUSIONS: Most of the current United States CRC deaths are attributable to nonscreening. This underscores the potential benefits of increasing screening uptake in the population. Traditional methods of estimating PAF underestimated screening effects compared with model-based approaches. PMID- 25721750 TI - An open-label, single-arm, phase 1 study to assess biomarker effects, efficacy and safety of ofatumumab in patients with refractory chronic lymphocytic leukemia. AB - This open-label, phase 1 study evaluated the effects of ofatumumab on QTc intervals, safety, efficacy, B-cell and neutrophil counts, complement levels, and cytokine and chemokine concentrations. Fourteen patients with fludarabine refractory chronic lymphocytic leukemia received 12 ofatumumab infusions. A higher maximum infusion rate of 400 mL/h was tested at the first two doses and was well tolerated. The 43% overall response rate was similar to previous data (42-51%). B-cell depletion was observed along with complement consumption; median C2 and CH50 levels appeared lower during monthly dosing in patients who responded. Responding patients appeared to have higher median levels of certain pro-inflammatory cytokines and lower median levels of certain immunotolerant cytokines than patients who did not respond. Ofatumumab-induced complement dependent cytotoxicity activity can be detected clinically by measuring complement and may be associated with clinical activity. The potential relationship between changes in complement or cytokines and clinical response to ofatumumab warrants further study. PMID- 25721751 TI - Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal. AB - No optimum treatment of iatrogenic immunodeficiency-associated lymphoproliferative disorders due to methotrexate in patients with rheumatoid arthritis (MTX-LPD) has yet been established, although MTX withdrawal is known to have a substantial effect on tumor regression. Here, we retrospectively analyzed 20 cases of MTX-LPD. Tumor shrinkage occurred in 18 of 20 cases, but only following MTX withdrawal. This tumor regression ratio was considerably better than in previous reports, and appeared due to longer "watchful waiting." Lymphocyte recovery at 2 weeks after MTX withdrawal was significantly higher in cases with tumor regression in 1 month than in those without tumor regression (p = 0.001). Median time to maximal efficacy after MTX cessation in cases without chemotherapy was 12 weeks (range 2-76). In conclusion, watchful waiting for a longer period after MTX cessation with observation of early lymphocyte recovery and uninterrupted continuation of other anti-rheumatoid drugs may be an acceptable management plan for MTX-LPD. PMID- 25721752 TI - Role of topotecan, vinorelbine, thiotepa and gemcitabine chemotherapy in relapsed/refractory adult acute leukemia. PMID- 25721753 TI - Radiotherapy with rituximab as first-line treatment for early-stage follicular lymphoma. PMID- 25721754 TI - Co-infusion of mesenchymal stromal cells has no effect on relapse and infection in patients with leukemia undergoing haploidentical hematopoietic stem cell transplant. PMID- 25721755 TI - Is 70 the new 60? New international prognostic index with an older age cut-off for diffuse large B-cell lymphoma. PMID- 25721756 TI - DNMT3A R882 mutation is associated with elevated expression of MAFB and M4/M5 immunophenotype of acute myeloid leukemia blasts. AB - Researchers have recognized that aberrant methylation is an important initiating event in the pathogenesis of hematological malignancies. DNMT3A is a DNA methyltransferase that plays a vital role in de novo methylation of DNA. Somatic mutation of DNMT3A, especially at the Arg882 (R882) site of the DNMT3A coding sequence, has been identified in pre-leukemic stem cell clones as one of the driver mutations of acute myeloid leukemia (AML). Statistical analysis has indicated that patients with AML with DNMT3A mutation tend to have the M4/M5 subtype of AML according to the French-American-British classification. In this study we aimed to investigate the association between the typical immunophenotype of leukemic blasts and mutation of DNMT3A R882. In addition, we further determined the relationship between DNMT3A R882 mutation and the expression of monocytic differentiation genes, and its clinical significance. PMID- 25721757 TI - Allo-transplant for older patients with acute lymphoblastic leukemia: does it work? PMID- 25721758 TI - Multiple mechanisms sustain a plant-animal facilitation on a coastal ecotone. AB - Theory suggests that species distributions are expanded by positive species interactions, but the importance of facilitation in expanding species distributions at physiological range limits has not been widely recognized. We investigated the effects of the nurse shrub Tamarix chinensis on the crab Helice tientsinensis on the terrestrial borders of salt marshes, a typical coastal ecotone, where Tamarix and Helice were on their lower and upper elevational distribution edges, respectively. Crab burrows were abundant under Tamarix, but were absent in open areas between Tamarix. Removing Tamarix decreased associated crab burrows with time, while simulating Tamarix in open areas by shading, excluding predators, and adding Tamarix branches as crab food, increased crab burrows. Measurements of soil and microclimate factors showed that removing Tamarix increased abiotic stress, while simulating Tamarix by shading decreased abiotic stress. Survival of tethered crabs was high only when protected from desiccation and predation. Thus, by alleviating abiotic and biotic stresses, as well as by food provision, Tamarix expanded the upper intertidal distribution of Helice. Our study provides clear evidence for the importance of facilitation in expanding species distributions at their range limits, and suggests that facilitation is a crucial biological force maintaining the ecotones between ecosystems. PMID- 25721759 TI - Maternal and infant factors associated with reasons for introducing solid foods. AB - The current UK Department of Health advice is to introduce solid foods to infants at around 6 months of age, when the infant is showing signs of developmental readiness for solid foods. However, many mothers introduce solid foods before this time, and for a wide variety of reasons, some of which may not promote healthy outcomes. The aim of the current study was to examine infant and maternal characteristics associated with different reasons for introducing solid foods. Seven hundred fifty-six mothers with an infant aged 6-12 months old completed a questionnaire describing their main reason for introducing solid foods alongside demographic questions, infant weight, gender, breast/formula feeding and timing of introduction to solid foods. The majority of mothers introduced solid foods for reasons explicitly stated in the Department of Health advice as not signs of readiness for solid foods. These reasons centred on perceived infant lack of sleep, hunger or unsettled behaviour. Maternal age, education and parity, infant weight and gender and breast/formula feeding choices were all associated with reasons for introduction. A particular association was found between breastfeeding and perceiving the infant to be hungrier or needing more than milk could offer. Male infants were perceived as hungry and needing more energy than female infants. Notably, signs of readiness may be misinterpreted with some stating this reason for infants weaned prior to 16 weeks. The findings are important for those working to support and educate new parents with the introduction of solid foods in understanding the factors that might influence them. PMID- 25721760 TI - What does the head impulse test versus caloric dissociation reveal about vestibular dysfunction in Meniere's disease? AB - In patients with Meniere's disease (MD), caloric testing can show, depending on the stage and activity of the disease, a variety of results. Between attacks, many, or perhaps even most, patients with unilateral early or mild MD have normal caloric tests; late MD can show abnormalities ranging from mild to severe unilateral canal paresis with or without directional preponderance. The explanation of canal paresis in MD is not clear. The most obvious explanation, severe loss of lateral canal hair cells, is not likely to be correct because hair cell loss will not explain the fluctuating canal paresis to caloric stimulation. In contrast, the published evidence is that rotational testing of semicircular canal function in MD patients typically shows little reduction in function and even enhancement of vestibulo-ocular reflex gain, at least in the early stages of the disease. Here, we offer a novel explanation for this dissociation. We propose that hydropic expansion of the lateral canal membranous labyrinth permits convective recirculation within the duct that allows dissipation of the hydrostatic force that would normally cause cupular displacement and nystagmus in the caloric test. PMID- 25721761 TI - In the strategies to prevent asthma exacerbations, allergic asthma needs specific treatment. AB - No generally accepted definition of asthma exacerbation is thus far available, though in 2012 an expert committee endorsed by the National Institute of Health proposed such definition as "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome". Graham and Eid reviewed the impact of asthma exacerbations, and noted that, analysing the outcomes with existing treatments, many patients with asthma remain symptomatic and experience exacerbations. This requires the introduction of new strategies to more effectively reduce the exacerbation risk, based on correct diagnosis, stopping smoking, correct inhaler technique, consistent adherence, weight management, and gaining control with the addition of medication". Indeed, as allergic asthma is the most common form, a specific approach by allergen immunotherapy should receive more attention. Actually, the efficacy of immunotherapy in allergic asthma, by the subcutaneous or the sublingual route, is supported by robust meta analyses. The most important allergen source causing asthma is the house dust mite, but an increasing role for molds is apparent due to the ongoing climate change. PMID- 25721762 TI - Late transition metal-catalyzed hydroamination and hydroamidation. PMID- 25721763 TI - [In vitro study of the flow duration of antibiotics solutions prepared in elastomeric infusion devices: effect of cold storage for 3 to 7days]. AB - INTRODUCTION: Within the cystic fibrosis patients' home care, EMERAA network ("Together against Cystic fibrosis in Rhone-Alpes and Auvergne") organizes parenteral antibiotics cures at home prepared in elastomeric infusion devices by hospital pharmacies. However, patients and nurses found that the durations of infusion with these devices were often longer than the nominal duration of infusion indicated by their manufacturer. This study aimed to identify the potential different causes in relation to these discordances. MATERIAL AND METHODS: Three hundred and ninety devices of two different manufacturers are tested in different experimental conditions: three antibiotics each at two different doses, duration of cold storage (three days or seven days) or immediate tests without cold storage, preparation and storage of the solution in the device (protocol Device) or transfer in the device just before measurement (protocol Pocket). RESULTS: All tests highlighted a longer flow duration for devices prepared according to the protocol Device versus the protocol Pocket (P=0.004). Flow duration is increased in the case of high doses of antibiotics with high viscosity such as piperacilline/tazobactam. DISCUSSION: The results of this in vitro study showed the impact of: (1) the time between the filling of the device and the flow of the solution; (2) cold storage of elastomeric infusion devices; (3) concentration of antibiotics and therefore the viscosity of the solution to infuse. CONCLUSION: It is therefore essential that health care teams are aware of factors, which may lead to longer infusion durations with these infusion devices. When the additional time for infusion remain acceptable, it should be necessary to inform the patient and to relativize these lengthening compared to many benefits that these devices provide for home care. PMID- 25721764 TI - The indications for hepatectomy for multinodular hepatocellular carcinoma: experience from a single institution. AB - AIMS: This study was conducted in order to investigate the indications for hepatecomy for multinodular hepatocellular carcinoma (MNHCC) in single institution. METHODS: We retrospectively analyzed the medical records from 55 MNHCC patients, mainly with Child-Pugh A liver function, who underwent hepatectomy from January 2006 to December 2008. Both short- and long-term outcomes were analyzed. In addition, the prognostic significance of clinicopathological factors on overall survival (OS) was investigated by univariate analysis using the log-rank test. A Cox proportional hazards model was used in a subsequent multivariate analysis. RESULTS: The perioperative morbidity rate (grade II or higher) was 18.2% (n = 10), and the in-hospital mortality rate was 3.6%. The median OS was 23.9 months (range, 2.5-84 months), whereas the median disease-free survival was 8.75 months (range, 1-65 months). Independent prognostic risk factors of 5-year OS included the number of tumors >2 (p = 0.032) and gross morphology indicating multiple tumor nodules scattered throughout the liver (p = 0.009). CONCLUSIONS: The postoperative morbidity and mortality rates were acceptable. The number of tumors >2 and gross morphology indicating multiple tumor nodules scattered throughout the liver were independent prognostic risk factors for patients with MNHCC after hepatectomy. Patients with both of these features had a very poor prognosis and were not considered suitable for surgery. PMID- 25721765 TI - Selenoprotein W controls epidermal growth factor receptor surface expression, activation and degradation via receptor ubiquitination. AB - Epidermal growth factor (EGF) receptor (EGFR) is the founding member of the ErbB family of growth factor receptors that modulate a complex network of intracellular signaling pathways controlling growth, proliferation, differentiation, and motility. Selenoprotein W (SEPW1) is a highly conserved, diet-regulated 9kDa thioredoxin-like protein required for normal cell cycle progression. We report here that SEPW1 is required for EGF-induced EGFR activation and that it functions by suppressing EGFR ubiquitination and receptor degradation. SEPW1 depletion inhibited EGF-dependent cell cycle entry in breast and prostate epithelial cells. In prostate cells, SEPW1 depletion decreased EGFR auto-phosphorylation, while SEPW1 overexpression increased EGFR auto phosphorylation. SEPW1 depletion increased the rate of EGFR degradation, which decreased total and surface EGFR and suppressed EGF-dependent EGFR endocytosis, EGFR dimer formation, and activation of EGF-dependent pathways. EGFR ubiquitination was increased in SEPW1-depleted cells--in agreement with the increased rate of EGFR degradation, and suggests that SEPW1 suppresses EGFR ubiquitination. Ubiquitination-directed lysozomal degradation controls post translational EGFR expression and is dysregulated in many cancers. Thus, suppression of EGFR ubiquitination by SEPW1 may be related to the putative increase in cancer risk associated with high selenium intakes. Knowledge of the mechanisms underlying SEPW1's regulation of EGFR ubiquitination may reveal new opportunities for nutritional cancer prevention or cancer drug development. PMID- 25721766 TI - Effect of a hospital policy of not accepting free infant formula on in-hospital formula supplementation rates and breast-feeding duration. AB - OBJECTIVE: To investigate the effect of public hospitals in Hong Kong not accepting free infant formula from manufacturers on in-hospital formula supplementation rates and breast-feeding duration. DESIGN: Prospective cohort study. SETTING: In-patient postnatal units of four public hospitals in Hong Kong. SUBJECTS: Two cohorts of breast-feeding mother-infant pairs (n 2560). Cohort 1 (n 1320) was recruited before implementation of the policy to stop accepting free infant formula and cohort 2 (n 1240) was recruited after policy implementation. Participants were followed prospectively for 12 months or until they stopped breast-feeding. RESULTS: The mean number of formula supplements given to infants in the first 24 h was 2.70 (sd 3.11) in cohort 1 and 1.17 (sd 1.94) in cohort 2 (P<0.001). The proportion of infants who were exclusively breast-fed during the hospital stay increased from 17.7 % in cohort 1 to 41.3 % in cohort 2 (P<0.001) and the risk of breast-feeding cessation was significantly lower in cohort 2 (hazard ratio=0.81; 95 % CI 0.73, 0.90). Participants who non-exclusively breast fed during the hospital stay had a significantly higher risk of stopping any or exclusive breast-feeding. Higher levels of formula supplementation also increased the risk of breast-feeding cessation in a dose-response pattern. CONCLUSIONS: After implementation of a hospital policy to pay market price for infant formula, rates of in-hospital formula supplementation were reduced and the rates of in hospital exclusive breast-feeding and breast-feeding duration increased. PMID- 25721767 TI - A fully three-dimensional model of the interaction of driven elastic filaments in a Stokes flow with applications to sperm motility. AB - In many animals, sperm flagella exhibit primarily planar waveforms. An isolated sperm with a planar flagellar beat in a three-dimensional unbounded fluid domain would remain in a plane. However, because sperm must navigate through complex, three-dimensional confined spaces along with other sperm, forces that bend or move the flagellum out of its current beat plane develop. Here we present an extension of previous models of an elastic sperm flagellar filament whose shape change is driven by the pursuit of a preferred curvature wave. In particular, we extend the energy of the generalized elastica to include a term that penalizes out-of-plane motion. We are now able to study the interaction of free-swimmers in a 3D Stokes flow that do not start out beating in the same plane. We demonstrate the three-dimensional nature of swimming behavior as neighboring sperm swim close to each other and affect each others' trajectories via fluid-structure coupling. PMID- 25721768 TI - A novel analytical approach for determining the frictional moments and torques acting on modular femoral components in total hip replacements. AB - A three dimensional analytical approach was developed to determine the frictional moment vector generated by the relative sliding of the head-cup bearing couple of a total hip replacement. The frictional moment projection onto the femoral neck was also determined over the loading cycle. Predicted frictional moments for nine combinations of bearing materials and diameters were in close agreement with existing in vitro data. The analytical method was then applied to simplified gait (lubrication conditions of dry and serum), ISO standard gait and physiological level gait loading cycles. ISO standard gait had a total contact force of about two fold of physiological level gait and there was a corresponding increase in the maximum frictional torque on neck from 0.66*BW%m to 0.88*BW%m. For the ISO standard gait, the maximum frictional torque occurred at the same instance of maximum frictional moment and the maximum contact force. In contrast, for the physiological level gait, the frictional torque did not occur at the same instance as the peak load. This suggests that the neck frictional torque is a function of other parameters, such as angle between neck axis and frictional moment vector, as well as the magnitude of the contact force and frictional moment. The developed methodology was able to predict the maximum magnitude and change of directions of moments and the variation of torque at the head neck interface. The data will be useful for experimental studies assessing the fretting behaviour of the head neck junction, by providing appropriate loading data. PMID- 25721769 TI - Trabecular orientation in the human femur and tibia and the relationship with lower-limb alignment for patients with osteoarthritis of the knee. AB - Wolff's Law suggests that the orientation of trabeculae in human bone changes in response to altered loading patterns. The aim of this study was to investigate trabecular orientation in both the femur and tibia and to compare this with the mechanical axis of the leg. The study involved analysis of radiographs from patients with osteoarthritis of the knee (n=91). For each patient, the trabecular orientation in both the distal femur and proximal tibia was measured from a standard anteroposterior radiograph of the knee and the mechanical axis of the leg was calculated from a long leg view taken while weight bearing. There was a significant correlation between the mechanical axis and the trabecular orientation in each of the regions considered in the femur (r=-0.41, -0.30, 0.52, and 0.23) and tibia (r=-0.27 and 0.31). Multiple regression analysis, with mechanical axis as the dependent variable, produced an R(2) of 0.62. Greater trabecular anisotropy (i.e. greater alignment) was observed in the medial femur and tibia compared to the lateral side (p<0.01). The results give an insight into the trabecular changes that may take place during development of osteoarthritis and following surgery. In particular, we propose that the orientation of the trabeculae in both the distal femur and proximal tibia will reflect the angle of mechanical loading through the knee. PMID- 25721770 TI - Ciprofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: A randomized trial. AB - BACKGROUND AND STUDY AIMS: Helicobacter pylori eradication rates with standard triple therapy have declined to unacceptable levels. This randomized trial aimed at evaluating the efficacy of a ciprofloxacin containing sequential regimen in the eradication of H. pylori-infected patients vs. a clarithromycin containing sequential therapy. METHODS: A total of 212 patients were randomized into 14-day therapeutic schemes (106 patients per group): (1) clarithromycin-containing sequential therapy rabeprazole plus amoxicillin for 7 days, followed by rabeprazole plus clarithromycin plus metronidazole for 7 days, and (2) ciprofloxacin-containing sequential therapy using ciprofloxacin instead of clarithromycin. Eradication was confirmed by stool H. pylori antigen. Adverse effects and compliance were assessed by a questionnaire. RESULTS: Per protocol cure rates were as follows: 87.6 % in the ciprofloxacin-containing sequential therapy and 76 % in the clarithromycin group. Intention-to-treat cure rates were as follows: 73.5 % for the ciprofloxacin group and 66 % for the clarithromycin group. No differences in compliance or adverse effects were demonstrated among treatments. CONCLUSION: Ciprofloxacin-containing sequential therapy is more effective and equally safe compared to a clarithromycin-containing sequential therapy. PMID- 25721771 TI - The effect of light intensity on prey detection behavior in two Lake Malawi cichlids, Aulonocara stuartgranti and Tramitichromis sp. AB - Two sand-dwelling cichlids from Lake Malawi (Aulonocara stuartgranti, Tramitichromis sp.) that feed on benthic invertebrates, but have different lateral line phenotypes, use lateral line and/or visual cues to detect prey under light versus dark conditions. The current study examined how ecologically relevant variation in light intensity [0-800 lux (lx)] influences detection of prey (mobile, immobile) in each species by analyzing six behavioral parameters. Both species fed at light intensities >=1 lx and trends in behavior among light intensities were informative. However, prey type and/or time of day (but not light intensity) predicted all four parameters analyzed with generalized linear mixed models in A. stuartgranti, whereas the interaction of light intensity and time of day predicted three of these parameters in Tramitichromis sp. Data suggest that the critical light intensity is 1-12 lx for both species, that the integration of visual and lateral line input explains differences in detection of mobile and immobile prey and behavioral changes at the transition from 1 to 0 lx in A. stuartgranti, and that Tramitichromis sp. likely uses binocular vision to locate prey. Differences in the sensory biology of species that exploit similar prey will have important implications for the trophic ecology of African cichlid fishes. PMID- 25721772 TI - The effect of parathyroid hormones on hair follicle physiology: implications for treatment of chemotherapy-induced alopecia. AB - Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) influence hair follicles through paracrine and intracrine routes. There is significant evidence that PTH and PTHrP influence the proliferation and differentiation of hair follicle cells. The PTH/PTHrP receptor signalling plays an important role in the hair follicle cycle and may induce premature catagen telogen transition. Transgenic mice with an overexpression or blockade (PTH/PTHrP receptor knockout mice) of PTHrP activity revealed impaired or increased hair growth, respectively. Some findings also suggest that PTHrP may additionally influence the hair cycle by inhibiting angiogenesis. Antagonists of the PTH/PTHrP receptor have been shown to stimulate proliferation of hair follicle cells and hair growth. A hair-stimulating effect of a PTH/PTHrP receptor antagonist applied topically to the skin has been observed in hairless mice, as well as in mice treated with cyclophosphamide. These data indicate that the PTH/PTHrP receptor may serve as a potential target for new (topical) hair growth-stimulating drugs, especially for chemotherapy-induced alopecia. PMID- 25721773 TI - Computational approaches to homogeneous gold catalysis. AB - Homogenous gold catalysis has been exploding for the last decade at an outstanding pace. The best described reactivity of Au(I) and Au(III) species is based on gold's properties as a soft Lewis acid, but new reactivity patterns have recently emerged which further expand the range of transformations achievable using gold catalysis, with examples of dual gold activation, hydrogenation reactions, or Au(I)/Au(III) catalytic cycles.In this scenario, to develop fully all these new possibilities, the use of computational tools to understand at an atomistic level of detail the complete role of gold as a catalyst is unavoidable. In this work we aim to provide a comprehensive review of the available benchmark works on methodological options to study homogenous gold catalysis in the hope that this effort can help guide the choice of method in future mechanistic studies involving gold complexes. This is relevant because a representative number of current mechanistic studies still use methods which have been reported as inappropriate and dangerously inaccurate for this chemistry.Together with this, we describe a number of recent mechanistic studies where computational chemistry has provided relevant insights into non-conventional reaction paths, unexpected selectivities or novel reactivity, which illustrate the complexity behind gold-mediated organic chemistry. PMID- 25721774 TI - Gold pi-Complexes as Model Intermediates in Gold Catalysis. AB - Homogeneous gold catalysis has emerged as a powerful method for activating hydrocarbon double and triple bonds. Methodology development and computational studies have blossomed in the past 20 years. In contrast, experimental exploration of mechanisms and structure-reactivity relationships has gained traction only in the past 5 years. Recent developments in the synthesis of organometallic intermediates have revealed exciting new details about the mechanisms of gold catalysis. Central to these studies are the structure and reactivity of gold pi-complexes. Following successes in structurally characterizing these key structures, advancements are gradually being made in placing them in the context of an overall catalytic cycle. As a result, a research field has emerged which is rich with potential for continued discovery and catalyst improvement. PMID- 25721775 TI - Microwave spectroscopy of biomolecular building blocks. AB - Microwave spectroscopy, considered as the most definitive gas phase structural probe, is able to distinguish between different conformational structures of a molecule, because they have unique spectroscopic constants and give rise to distinct individual rotational spectra.Previously, application of this technique was limited to molecular specimens possessing appreciable vapor pressures, thus discarding the possibility of studying many other molecules of biological importance, in particular those with high melting points, which had a tendency to undergo thermal reactions, and ultimately degradation, upon heating.Nowadays, the combination of laser ablation with Fourier transform microwave spectroscopy techniques, in supersonic jets, has enabled the gas-phase study of such systems. In this chapter, these techniques, including broadband spectroscopy, as well as results of their application into the study of the conformational panorama and structure of biomolecular building blocks, such as amino acids, nucleic bases, and monosaccharides, are briefly discussed, and with them, the tools for conformational assignation - rotational constants, nuclear quadrupole coupling interaction, and dipole moment. PMID- 25721776 TI - Silicosis: Some Necessary Clarifications. PMID- 25721777 TI - Selective fluorescence sensing of Cu(II) and Zn(II) using a simple Schiff base ligand: naked eye detection and elucidation of photoinduced electron transfer (PET) mechanism. AB - A simple Schiff base compound 2-((cyclohexylmethylimino)-methyl)-naphthalen-1-ol (2CMIMN1O) has been synthesized and characterized by (1)H NMR, (13)C NMR and FT IR spectroscopic techniques. A significantly low emission yield of the compound has been rationalized in anticipation with photo-induced electron transfer (PET) from the imine receptor moiety to the naphthalene fluorophore unit. Consequently, an evaluation of the transition metal ion-induced modification of the fluorophore receptor communication reveals the promising prospect of the title compound to function as a chemosensor for Cu(2+) and Zn(2+) ions selectively, through remarkable fluorescence enhancement as well as visual changes. While perturbation of the PET process has been argued to be the plausible mechanism behind the fluorescence enhancement, the selectivity for these two metal ions has been interpreted on the grounds of an appreciably strong binding interaction. Particularly notable aspects regarding the chemosensory activity of the compound is its ability to detect the aforesaid transition metal ions down to the level of micromolar concentration (detection limit being 2.74 and 2.27ppm respectively), along with a simple and efficient synthetic procedure. PMID- 25721778 TI - Synthesis of novel Schiff's bases of highly potential biological activities and their structure investigation. AB - Novel bisaldehyde-hydrazide Schiff's bases AS1 (2,2'-(ethane-1,2 diylbis(oxy))dibenzaldehyde terephthalohydrazide) and AS2 (N',N'"-(((ethane-1,2 diylbis(oxy))bis(2,1-phenylene))bis(methanylylidene))di(benzohydrazide)) were prepared as new macrocyclic compounds via condensation reactions. AS1 had been prepared by condensation between (2,2'-(ethane-1,2-diylbis(oxy))dibenzaldehyde) bisaldehyde and terephthalohydrazide in a ratio1:1. AS2 had been obtained by condensation between (2,2'-(ethane-1,2-diylbis(oxy))dibenzaldehyde) bisaldehyde and benzohydrazide in ratio 1:2. The structures of AS1 and AS2 were characterized by elemental analysis (EA), mass (MS), FT-IR and (1)H-NMR spectra, and thermal analyses (TG, DTG). The activation thermodynamic parameters such as DeltaE(*), DeltaH(*), DeltaS(*) and DeltaG(*) were calculated from the TG curves using Coats Redfern method. It is important to investigate their molecular structures to know the active groups and weak bonds responsible for their biological activities. Consequently in the present work, the obtained thermal (TA) and mass (MS) practical results are confirmed by semi-empirical MO-calculations (MOCS) using PM3 procedure. Their biological activities had been tested in vitro against Escherichia coli, Proteus vulgaris, Bacillus subtilis and Staphylococcus aurous bacteria in order to assess their anti-microbial potential. PMID- 25721779 TI - Synthesis, spectral analysis, structural elucidation and quantum chemical studies of (E)-methyl-4-[(2-phenylhydrazono)methyl]benzoate. AB - The title compound, (E)-methyl-4-[(2-phenylhydrazono)methyl]benzoate, (I), (C15H14N2O2), has been synthesized by condensation reaction of methyl-4 formylbenzoate and phenylhydrazine. The compound has been characterized by elemental analysis, IR, (1)H NMR, (13)C NMR, UV-Vis spectroscopies and single crystal X-ray diffraction techniques. Optimized molecular structure, harmonic vibrational frequencies, (1)H and (13)C NMR chemical shifts have been investigated by B3LYP/6-31G(d,p) method using density functional theory (DFT). Global chemical reactivity descriptors, natural population analysis (NPA), thermodynamic and non-linear optical (NLO) properties have also been studied. The energetic behavior of the compound has been examined in solvent media using the integral equation formalism polarizable continuum model (IEF-PCM). PMID- 25721780 TI - Electron-transfer reactions of cobalt(III) complexes. 1. The kinetic investigation of the reduction of various surfactant cobalt(III) complexes by iron(II) in surface active ionic liquids. AB - The kinetics of outer sphere electron transfer reaction of surfactant cobalt(III) complex ions, cis-[Co(en)2(C12H25NH2)2](3+) (1), cis-[Co(dp)2(C12H25NH2)2](3+) (2), cis-[Co(trien)(C12H25NH2)2](3+) (3), cis-[Co(bpy)2(C12H25NH2)2](3+) (4) and cis-[Co(phen)2(C12H25NH2)2](3+) (5) (en: ethylenediamine, dp: diaminopropane, trien : triethylenetetramine, bpy: 2,2'-bipyridyl, phen: 1,10-phenanthroline and C12H25NH2 : dodecylamine) have been interrogated by Fe(2+) ion in ionic liquid (1 butyl-3-methylimidazoliumbromide) medium at different temperatures (298, 303, 308, 313, 318 and 323K) by the spectrophotometry method under pseudo first order conditions using an excess of the reductant. Experimentally the reactions were found to be of second order and the electron transfer as outer sphere. The second order rate constant for the electron transfer reaction in ionic liquids was found to increase with increase in the concentration of all these surfactant cobalt(III) complexes. Among these complexes (from en to phen ligand), complex containing the phenanthroline ligand rate is higher compared to other complexes. By assuming the outer sphere mechanism, the results have been explained based on the presence of aggregated structures containing cobalt(III) complexes at the surface of ionic liquids formed by the surfactant cobalt(III) complexes in the reaction medium. The activation parameters (enthalpy of activation DeltaH(?) and entropy of activation DeltaS(?)) of the reaction have been calculated which substantiate the kinetics of the reaction. PMID- 25721781 TI - Spectroscopic [FT-IR and FT-Raman] and theoretical [UV-Visible and NMR] analysis on alpha-Methylstyrene by DFT calculations. AB - In the present research work, the FT-IR, FT-Raman and (13)C and (1)H NMR spectra of the alpha-Methylstyrene were recorded. The observed fundamental frequencies in finger print as well as functional group regions were assigned according to their uniqueness region. The Gaussian computational calculations are carried out by HF and DFT (B3LYP and B3PW91) methods with 6-31++G(d,p) and 6-311++G(d,p) basis sets and the corresponding results were tabulated. The impact of the presence of vinyl group in phenyl structure of the compound is investigated. The modified vibrational pattern of the molecule associated vinyl group was analyzed. Moreover, (13)C NMR and (1)H NMR were calculated by using the gauge independent atomic orbital (GIAO) method with B3LYP methods and the 6-311++G(d,p) basis set and their spectra were simulated and the chemical shifts linked to TMS were compared. A study on the electronic and optical properties; absorption wavelengths, excitation energy, dipole moment and frontier molecular orbital energies were carried out. The kubo gap of the present compound was calculated related to HOMO and LUMO energies which confirm the occurring of charge transformation between the base and ligand. Besides frontier molecular orbitals (FMO), molecular electrostatic potential (MEP) was performed. The NLO properties related to Polarizability and hyperpolarizability based on the finite-field approach were also discussed. PMID- 25721782 TI - Women's toileting behaviours: an online survey of female advanced practice providers. AB - AIMS: An online survey of female advanced practice providers (APPs) in a large urban healthcare system was conducted to describe behaviours they use to manage their personal bladder emptying. METHODS: The questionnaire contained items on demographics, presence of urinary incontinence (UI), and behaviours used to void in work, public and home settings. RESULTS: One hundred thirteen female APPs responded to the survey and 109 responded to items on UI. Over half (53%) reported experiencing UI at least once a week. In general, the APPs reported being worried about the cleanliness of public toilets and delaying voiding when busy. Incontinent APPs were older and had histories of more pregnancies than continent women. Incontinent APPs also used public toilets more frequently and when there was no or little need to void, and delayed or put off voiding while at work and when busy. CONCLUSION: Although APPs have specialised knowledge about lower urinary tract anatomy and physiology, many engage in behaviours that may be detrimental to bladder health. More research is needed to explore behaviours women use to manage voiding and the effect of these behaviours on bladder health. PMID- 25721783 TI - Organogenesis and morphogenesis. Preface. PMID- 25721784 TI - Au-ZnO hybrid nanoparticles exhibiting strong charge-transfer-induced SERS for recyclable SERS-active substrates. AB - Flower-shaped Au-ZnO hybrid nanoparticles have been prepared via seeding growth and subsequent wet-chemical etching of Au-ZnO core-shell nanoparticles. The etched Au-ZnO hybrid nanoparticles have shown a stronger surface-enhanced Raman scattering (SERS) signal of the nontotally symmetric (b2) vibrational modes of PATP molecules than Au nanoparticles alone, which is attributed to the chemical enhancement effect of the ZnO layer which is greatly excited by the localized surface plasmon resonance (LSPR) of Au cores. Further, the mechanism of the LSPR enhanced charge transfer (CT) effect has been proved by the SERS spectra of PATP molecules excited using different laser sources from 325 to 785 nm. Moreover, the photocatalytic experimental results indicated that Au-ZnO hybrid nanoparticles are promising as biologically compatible and recyclable SERS-active platforms for different molecular species. PMID- 25721785 TI - Valproic acid ameliorates ischemic brain injury in hyperglycemic rats with permanent middle cerebral occlusion. AB - Valproic acid (VPA) is widely used for the clinical treatment of epilepsy. Previous studies have demonstrated that VPA ameliorates brain injury following experimental stroke. However, the effect of VPA in stroke models featuring comorbid conditions has not been fully explored. In this study, we investigate the effects of VPA on permanent ischemic stroke with hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) injection 3 days before. Test animals received a single injection of VPA immediately after induction of ischemia. Control animals received occlusion and physiological saline injection, or STZ, occlusion, and saline. Magnetic resonance imaging of cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) was performed 60 min after ischemia. Infarct volume, neurological deficits, rotarod test performance, and immunohistological markers were assessed 3 days after ischemia. Hyperglycemia significantly expanded the area of decreased of CBF and ADC, and increased the number of myeloperoxidase-positive cells, ionized calcium binding adapter molecule 1-positive cells, inducible nitric oxide synthase-positive cells, von Willebrand factor-positive cells, and Fluoro-Jade C-positive cells in the ischemic boundary zone, which was accompanied by increased infarct volume and deteriorated neurological deficit and rotarod test compared with normoglycemia (P < 0.05). VPA significantly alleviated the aggravation of functional outcome accompanied by suppressing these inflammation, endothelial injury, and neuronal degeneration compared with saline-treated group (P < 0.05). A single injection of VPA following permanent ischemia in STZ-induced hyperglycemic rats ameliorates neurological deficits and reduces neuronal degeneration by inhibiting inflammation and endovascular injury. VPA may be promising as a candidate therapy for human stroke. PMID- 25721786 TI - Effect of low frequency repetitive transcranial magnetic stimulation on kindling induced changes in electrophysiological properties of rat CA1 pyramidal neurons. AB - In this study, the effect of repetitive transcranial magnetic stimulation (rTMS) on the kindling induced changes in electrophysiological firing properties of hippocampal CA1 pyramidal neurons was investigated. Male Wistar rats were kindled by daily electrical stimulation of the basolateral amygdala in a semi-rapid manner (12 stimulations/day) until they achieved stage-5 seizure. One group (kindled+rTMS (KrTMS)) of animals received rTMS (240 pulses at 1 Hz) at 5 min after termination of daily kindling stimulations. Twenty-four hours following the last kindling stimulation electrophysiological properties of hippocampal CA1 pyramidal neurons were investigated using a whole-cell patch clamp technique, under current clamp condition. Amygdala kindling significantly decreased the adaptation index, post-afterhyperpolarization, rheobase current, utilization time, and delay to the first rebound spike. It also caused an increase in the voltage sag, number of rebound spikes and number of evoked action potential. Results of the present study revealed that application of rTMS following kindling stimulations had antiepileptogenic effects. In addition, application of rTMS prevented hyperexcitability of CA1 pyramidal neurons induced by kindling and conserved the normal neuronal firing. PMID- 25721788 TI - Not so different after all: The same oscillatory processes support different types of attention. AB - Scientific research from the last two decades has provided a vast amount of evidence that brain oscillations reflect physiological activity enabling diverse cognitive processes. The goal of this review is to give a broad empirical and conceptual overview of how ongoing oscillatory activity may support attention processes. Keeping in mind that definitions of cognitive constructs like attention are prone to being blurry and ambiguous, the present review focuses mainly on the neural correlates of 'top-down' attention deployment. In particular, we will discuss modulations of (ongoing) oscillatory activity during spatial, temporal, selective, and internal attention. Across these seemingly distinct attentional domains, we will summarize studies showing the involvement of two oscillatory processes observed during attention deployment: power modulations mainly in the alpha band, and phase modulations in lower frequency bands. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25721787 TI - Effects of chronic and acute stimulants on brain functional connectivity hubs. AB - The spatial distribution and strength of information processing 'hubs' are essential features of the brain's network topology, and may thus be particularly susceptible to neuropsychiatric disease. Despite growing evidence that drug addiction alters functioning and connectivity of discrete brain regions, little is known about whether chronic drug use is associated with abnormalities in this network-level organization, and if such abnormalities could be targeted for intervention. We used functional connectivity density (FCD) mapping to evaluate how chronic and acute stimulants affect brain hubs (i.e., regions with many short range or long-range functional connections). Nineteen individuals with cocaine use disorders (CUD) and 15 healthy controls completed resting-state fMRI scans following a randomly assigned dose of methylphenidate (MPH; 20mg) or placebo. Short-range and long-range FCD maps were computed for each participant and medication condition. CUD participants had increased short-range and long-range FCD in the ventromedial prefrontal cortex, posterior cingulate/precuneus, and putamen/amygdala, which in areas of the default mode network correlated with years of use. Across participants, MPH decreased short-range FCD in the thalamus/putamen, and decreased long-range FCD in the supplementary motor area and postcentral gyrus. Increased density of short-range and long-range functional connections to default mode hubs in CUD suggests an overrepresentation of these resource-expensive hubs. While the effects of MPH on FCD were only partly overlapping with those of CUD, MPH-induced reduction in the density of short range connections to the putamen/thalamus, a network of core relevance to habit formation and addiction, suggests that some FCD abnormalities could be targeted for intervention. PMID- 25721790 TI - Biostimulation and nursing modify mating-induced c-FOS immunoreactivity in the female rabbit forebrain. AB - Mating in rabbits lasts only 3-5s but profoundly changes the female's physiology and behavior (e.g., inhibition of scent-marking and ambulation, changes in EEG, and release of GnRH). The behavioral responsiveness to copulation is reduced in lactating rabbits, relative to estrous does, but is enhanced after suppressing a single nursing bout ("biostimulation"). Little is known about the mechanisms mediating the differential responsiveness to mating among estrous, lactating, and biostimulated rabbits. To begin addressing this issue we quantified the number of c-FOS-immunoreactive (IR) cells in the preoptic area (POA), dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH), infundibular nucleus (INF), paraventricular nucleus (PVN), supraoptic nucleus (SON), and lateral septum (LS) in mated and unmated does from the above three reproductive conditions. Mating increased c-FOS-IR cells in the POA and PVN relative to unmated estrous does. Biostimulation increased c-FOS-IR cells in the PVN, relative to lactating does, regardless of mating. Lactation reduced the responsiveness of the LS and INF to copulation but increased it in the DMH. No differences were found in the VMH. CONCLUSIONS: a) copulation activates forebrain nuclei that regulate scent-marking (POA), ovulation (INF), and post-coital oxytocin release (PVN); b) lactation and suppression of one nursing bout modulate the magnitude of such changes. PMID- 25721789 TI - Allosteric modulation of the glycine receptor activated by agonists differing in efficacy. AB - The glycine receptor (GlyR) is the predominant inhibitory neurotransmitter receptor in the brainstem and spinal cord but is also found in higher brain regions. GlyR function is affected by a variety of allosteric modulators including drugs of abuse, such as ethanol and inhalants and the ubiquitous divalent cation zinc. Two-electrode voltage-clamp experiments were conducted on Xenopus laevis oocytes expressing wild-type alpha1 homomeric glycine receptors to compare the degree of enhancement produced by zinc on GlyR activated by two agonists (glycine vs. taurine) that vary markedly in their efficacies. Zinc potentiation of both glycine- and taurine-evoked currents was the same at the concentrations of agonists that produced the same currents, corresponding to 6% of the maximal effect of glycine compared to 23% of the maximal effect of taurine. Similar results were seen with 50 and 200 mM ethanol. A direct comparison of agonist concentration-response curves showed that zinc enhancement was greater, overall, for taurine-activated than glycine-activated receptors. In addition, zinc only enhanced taurine- but not glycine-activated GlyR when agonists were applied at saturating concentrations. These data suggest that zinc affects taurine affinity, as well as the probability of channel opening at sub maximal taurine concentrations, and that the magnitude of allosteric modulation at the GlyR depends on the efficacy of the agonist tested. This has implications for mutagenesis studies in which changes in the degree of allosteric modulation observed may result from mutation-induced changes in agonist efficacy. PMID- 25721791 TI - Electrophysiological manifestations of mirror visual feedback during manual movement. AB - OBJECTIVE: To investigate the neurophysiological manifestations of the mechanism underlying the effects of Mirror Visual Feedback (MVF) during manual movement. METHOD: Thirteen healthy right handed individuals were assessed while performing repeated unilateral wrist extension movements with and without MVF. The effect of MVF on EEG oscillations was studied in 3 distinct frequency ranges (low mu, high mu, low beta). RESULTS: Analysis of the low beta range showed that MVF reduces the magnitude of event-related de-synchronization (ERD) in the hemisphere contra lateral to the moving hand. This effect reached significance when the moving hand was the dominant hand. In the analysis of the low mu range, bi-hemispheric amplification of ERD by the mirror pointed to an added effect of neural recruitment. This effect reached significance when the moving hand was the non dominant hand. CONCLUSIONS: MVF applied during unilateral manual movement (a) attenuates hemispheric activation asymmetry, and (b) is likely to involve recruitment of the mirror neuron system. SIGNIFICANCE: As each of the above two effects reached significance only in one hand (dominant and non-dominant, respectively), clinical application of MVF might show a different level of efficacy in the treatment of right and left hemiparesis. PMID- 25721792 TI - Three-dimensional culture conditions differentially affect astrocyte modulation of brain endothelial barrier function in response to transforming growth factor beta1. AB - Blood-brain barrier (BBB) function is regulated by dynamic interactions among cell types within the neurovascular unit, including astrocytes and endothelial cells. Co-culture models of the BBB typically involve astrocytes seeded on two dimensional (2D) surfaces, which recent studies indicate cause astrocytes to express a phenotype similar to that of reactive astrocytes in situ. We hypothesized that the culture conditions of astrocytes would differentially affect their ability to modulate BBB function in vitro. Brain endothelial cells were grown alone or in co-culture with astrocytes. Astrocytes were grown either as conventional (2D) monolayers, or in a collagen-based gel which allows them to grow in a three-dimensional (3D) construct. Astrocytes were viable in 3D conditions, and displayed a marked reduction in their expression of glial fibrillary acidic protein (GFAP), suggesting reduced activation. Stimulation of astrocytes with transforming growth factor (TGF)beta1 decreased transendothelial electrical resistance (TEER) and reduced expression of claudin-5 in co-cultures, whereas treatment of endothelial cells in the absence of astrocytes was without effect. The effect of TGFbeta1 on TEER was significantly more pronounced in endothelial cells cultured with 3D astrocytes compared to 2D astrocytes. These results demonstrate that astrocyte culture conditions differentially affect their ability to modulate brain endothelial barrier function, and suggest a direct relationship between reactive gliosis and BBB permeability. Moreover, these studies demonstrate the potential importance of physiologically relevant culture conditions to in vitro modeling of disease processes that affect the neurovascular unit. PMID- 25721793 TI - Endophilin-1 regulates blood-brain barrier permeability via EGFR-JNK signaling pathway. AB - Endophilin-1 (Endo1), a multifunctional protein, is essential for synaptic vesicle endocytosis. However, the role and mechanism of endophilin-1 in blood brain barrier (BBB) function are still unclear. This study was performed to determine whether endophilin-1 regulated BBB permeability via the EGFR-JNK signaling pathway. In the present study, we found that endophilin-1 over expression in human cerebral microvascular endothelial cell (hCMEC/D3) increased BBB permeability and meanwhile reduced the expression levels of epidermal growth factor receptor (EGFR), phosphorylated c-Jun N-terminal kinase (p-JNK). While endophilin-1 knockdown led to the contrary results. After JNK inhibitor SP600125 was administered to the endophilin-1 silenced hCMEC/D3 cells, the transendothelial electrical resistance (TEER) value was decreased and the permeability coefficient values to 4kDa and 40kDa FITC-dextran were increased. Results observed by Transmission electron microscopy (TEM) showed that tight junctions (TJs) were opened. Moreover, immunofluorescence and Western blot assays revealed the discontinuous distribution of TJ-associated proteins ZO-1, occludin on cell-cell boundaries and a significant decrease in protein expressing levels. Therefore, these results indicated that endophilin-1 positively regulated BBB permeability via the EGFR-JNK signaling pathway in hCMEC/D3 cells, which would provide an experimental basis for further research on endophilin-1 mediated the opening of BBB. PMID- 25721794 TI - Cyanidin-3-glucoside inhibits glutamate-induced Zn2+ signaling and neuronal cell death in cultured rat hippocampal neurons by inhibiting Ca2+-induced mitochondrial depolarization and formation of reactive oxygen species. AB - Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is a potent natural antioxidant. However, effects of C3G on glutamate-induced [Zn(2+)]i increase and neuronal cell death remain unknown. We studied the effects of C3G on glutamate-induced [Zn(2+)]i increase and cell death in cultured rat hippocampal neurons from embryonic day 17 maternal Sprague-Dawley rats using digital imaging methods for Zn(2+), Ca(2+), reactive oxygen species (ROS), mitochondrial membrane potential and a MTT assay for cell survival. Treatment with glutamate (100 uM) for 7 min induces reproducible [Zn(2+)]i increase at 35 min interval in cultured rat hippocampal neurons. The intracellular Zn(2+)-chelator TPEN markedly blocked glutamate-induced [Zn(2+)]i increase, but the extracellular Zn(2+) chelator CaEDTA did not affect glutamate-induced [Zn(2+)]i increase. C3G inhibited the glutamate-induced [Zn(2+)]i response in a concentration-dependent manner (IC50 of 14.1 +/- 1.1 ug/ml). C3G also significantly inhibited glutamate-induced [Ca(2+)]i increase. Two antioxidants such as Trolox and DTT significantly inhibited the glutamate-induced [Zn(2+)]i response, but they did not affect the [Ca(2+)]i responses. C3G blocked glutamate-induced formation of ROS. Trolox and DTT also inhibited the formation of ROS. C3G significantly inhibited glutamate-induced mitochondrial depolarization. However, TPEN, Trolox and DTT did not affect the mitochondrial depolarization. C3G, Trolox and DTT attenuated glutamate-induced neuronal cell death in cultured rat hippocampal neurons, respectively. Taken together, all these results suggest that cyanidin-3-glucoside inhibits glutamate induced [Zn(2+)]i increase through a release of Zn(2+) from intracellular sources in cultured rat hippocampal neurons by inhibiting Ca(2+)-induced mitochondrial depolarization and formation of ROS, which is involved in neuroprotection against glutamate-induced cell death. PMID- 25721795 TI - Auditory feedback in error-based learning of motor regularity. AB - Music and speech are skills that require high temporal precision of motor output. A key question is how humans achieve this timing precision given the poor temporal resolution of somatosensory feedback, which is classically considered to drive motor learning. We hypothesise that auditory feedback critically contributes to learn timing, and that, similarly to visuo-spatial learning models, learning proceeds by correcting a proportion of perceived timing errors. Thirty-six participants learned to tap a sequence regularly in time. For participants in the synchronous-sound group, a tone was presented simultaneously with every keystroke. For the jittered-sound group, the tone was presented after a random delay of 10-190 ms following the keystroke, thus degrading the temporal information that the sound provided about the movement. For the mute group, no keystroke-triggered sound was presented. In line with the model predictions, participants in the synchronous-sound group were able to improve tapping regularity, whereas the jittered-sound and mute group were not. The improved tapping regularity of the synchronous-sound group also transferred to a novel sequence and was maintained when sound was subsequently removed. The present findings provide evidence that humans engage in auditory feedback error-based learning to improve movement quality (here reduce variability in sequence tapping). We thus elucidate the mechanism by which high temporal precision of movement can be achieved through sound in a way that may not be possible with less temporally precise somatosensory modalities. Furthermore, the finding that sound-supported learning generalises to novel sequences suggests potential rehabilitation applications. PMID- 25721796 TI - Hyperacusis following unilateral damage to the insular cortex: a three-case report. AB - The insula is a multisensory area involved in various brain functions, including central auditory processing. However, its specific role in auditory function remains unclear. Here we report three cases of persistent hypersensitivity to auditory stimuli following damage to the insular cortex, using behavioral and neurophysiological measures. Two patients who complained of auditory disturbance since they suffered an isolated unilateral insular stroke, and one epileptic patient who underwent right insular resection for control of drug-resistant seizures, were involved in this study. These patients, all young adult women, were tested for auditory function more than one year after brain injury, and were compared to 10 healthy control participants matched for age, sex, and education. The assessment included pure-tone detection and speech detection in quiet, loudness discomfort levels, random gap detection, recognition of frequency and duration patterns, binaural separation, dichotic listening, as well as late latency auditory event-related potentials (ERPs). Each patient showed mild or moderate hyperacusis, as revealed by decreased loudness discomfort levels, which was more important on the side of lesion in two cases. Tests of temporal processing also revealed impairments, in concordance with previous findings. ERPs of two patients were characterised by increased amplitude of the P3b component elicited during a two-tone auditory oddball detection task. This study is the first to report cases of persistent hyperacusis following damage to the insular cortex, and suggests that the insula is involved in modulating the perceived intensity of the incoming auditory stimuli during late-stage processing. PMID- 25721798 TI - Improving the efficiency of inverted polymer solar cells by introducing inorganic dopants. AB - Cadmium selenide (CdSe) quantum dots (QDs) utilized as additives have been incorporated intopolymer solar cells (PSCs) composed of poly[N-9''-hepta-decanyl 2,7-carbazolealt-5,5-(4',7'-di-2-thienyl-2',1',3'-ben-zothiadiazole)] (PCDTBT) and fullerene derivative [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM). The maximum power conversion efficiency (PCE) of 6.94% has been achieved, corresponding to 33% enhancement compared with the control devices. The introduction of CdSe QDs allows not only the improvement of charge transport properties but also tuning of the energy levels, which leads to a higher short circuit current (Jsc), fill factor (FF), and open-circuit voltage (Voc). PMID- 25721797 TI - Controlled cortical impact before or after fear conditioning does not affect fear extinction in mice. AB - Post-traumatic stress disorder (PTSD) is characterized in part by impaired extinction of conditioned fear. Traumatic brain injury (TBI) is thought to be a risk factor for development of PTSD. We tested the hypothesis that controlled cortical impact (CCI) would impair extinction of fear learned by Pavlovian conditioning, in mice. To mimic the scenarios in which TBI occurs prior to or after exposure to an aversive event, severe CCI was delivered to the left parietal cortex at one of two time points: (1) Prior to fear conditioning, or (2) after conditioning. Delay auditory conditioning was achieved by pairing a tone with a foot shock in "context A". Extinction training involved the presentation of tones in a different context (context B) in the absence of foot shock. Test for extinction memory was achieved by presentation of additional tones alone in context B over the following two days. In pre- or post-injury paradigms, CCI did not influence fear learning and extinction. Furthermore, CCI did not affect locomotor activity or elevated plus maze testing. Our results demonstrate that, within the time frame studied, CCI does not impair the acquisition and expression of conditioned fear or extinction memory. PMID- 25721799 TI - Ketamine Attenuates the ACTH Response to Hypoxia in Late-Gestation Ovine Fetus. AB - BACKGROUND: Ketamine, a noncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist, is a commonly used dissociative anesthetic in neonatology. We have proposed that ketamine reduces fetal stress responsiveness to stimuli that involve reduced oxygen supply to the fetal brain. Previously, we have shown that ketamine inhibits plasma ACTH levels in late-gestation fetal sheep subjected to brachiocephalic artery occlusion (BCO), an ischemic hypoxia model that might activate some of the same direct and reflex responses as hypoxia. OBJECTIVES: We performed the current study to test the hypothesis that ketamine pretreatment will reduce fetal ACTH responses to hypoxic hypoxia (HH). METHODS: Fetal sheep were chronically catheterized at least 5 days prior to study. Ketamine (3 mg/kg) was administered intravenously to the fetus 10 min prior to normoxia or a period of hypoxia induced by administration of nitrogen gas to the maternal trachea for 30 min. RESULTS: Hypoxia significantly increased both fetal ACTH and cortisol levels in both the control and ketamine groups (p < 0.0005, interaction effect of time.stimulus in two-way ANOVA), and the ACTH response was blunted by ketamine (p < 0.005). CONCLUSIONS: Ketamine reduced fetal ACTH responses to HH, possibly due to antagonism of the NMDA receptors in the fetal brain. Interestingly, in contrast to the responses to BCO, ACTH responses to HH were only partially inhibited, suggesting that multiple neurotransmitter pathways mediate the ACTH response to HH. PMID- 25721801 TI - Dynamic locking plates provide symmetric axial dynamization to stimulate fracture healing. AB - Axial dynamization of an osteosynthesis construct can promote fracture healing. This biomechanical study evaluated a novel dynamic locking plate that derives symmetric axial dynamization by elastic suspension of locking holes within the plate. Standard locked and dynamic plating constructs were tested in a diaphyseal bridge-plating model of the femoral diaphysis to determine the amount and symmetry of interfragmentary motion under axial loading, and to assess construct stiffness under axial loading, torsion, and bending. Subsequently, constructs were loaded until failure to determine construct strength and failure modes. Finally, strength tests were repeated in osteoporotic bone surrogates. One body weight axial loading of standard locked constructs produced asymmetric interfragmentary motion that was over three times smaller at the near cortex (0.1 +/- 0.01 mm) than at the far cortex (0.32 +/- 0.02 mm). Compared to standard locked constructs, dynamic plating constructs enhanced motion by 0.32 mm at the near cortex and by 0.33 mm at the far cortex and yielded a 77% lower axial stiffness (p < 0.001). Dynamic plating constructs were at least as strong as standard locked constructs under all test conditions. In conclusion, dynamic locking plates symmetrically enhance interfragmentary motion, deliver controlled axial dynamization, and are at least comparable in strength to standard locked constructs. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1218-1225, 2015. PMID- 25721800 TI - Frontotemporal correlates of impulsivity and machine learning in retired professional athletes with a history of multiple concussions. AB - The frontotemporal cortical network is associated with behaviours such as impulsivity and aggression. The health of the uncinate fasciculus (UF) that connects the orbitofrontal cortex (OFC) with the anterior temporal lobe (ATL) may be a crucial determinant of behavioural regulation. Behavioural changes can emerge after repeated concussion and thus we used MRI to examine the UF and connected gray matter as it relates to impulsivity and aggression in retired professional football players who had sustained multiple concussions. Behaviourally, athletes had faster reaction times and an increased error rate on a go/no-go task, and increased aggression and mania compared to controls. MRI revealed that the athletes had (1) cortical thinning of the ATL, (2) negative correlations of OFC thickness with aggression and task errors, indicative of impulsivity, (3) negative correlations of UF axial diffusivity with error rates and aggression, and (4) elevated resting-state functional connectivity between the ATL and OFC. Using machine learning, we found that UF diffusion imaging differentiates athletes from healthy controls with significant classifiers based on UF mean and radial diffusivity showing 79-84 % sensitivity and specificity, and 0.8 areas under the ROC curves. The spatial pattern of classifier weights revealed hot spots at the orbitofrontal and temporal ends of the UF. These data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour. Furthermore, a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion. PMID- 25721803 TI - High Expression of Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma Is Associated with Improved Prognosis. AB - INTRODUCTION: In this study we analyzed major histocompatibility complex class I (MHCI) expression as a potential prognostic immune marker for patients with clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: 34 patients with localized ccRCC (pT1-pT3) who had undergone nephrectomy and had at least 4 years of clinical follow-up data were included in the study. Immunohistochemical staining for MHCI was performed on tumor sections. An automated image analysis algorithm was applied to representative tumor areas to quantitate the proportion of stained pixels (positivity score = positive pixels/total pixels) on scanned digital slides. RESULTS: At the end of the study, the patients who were alive had increased MHCI expression (mean positivity score 0.80) compared to those who died of the disease (mean positivity score 0.53; p < 0.0001, t test). Patients who were alive with recurrence had increased MHCI expression (positivity score 0.81) compared to those who succumbed to their disease recurrence (positivity score 0.53; p < 0.0001, t test). Survival was higher among patients with high MHCI expression compared to patients with low MHCI expression (p < 0.0001, Mantel Cox). CONCLUSIONS: With an automated high-throughput image analysis technique, this study shows that higher tumor cell MHCI expression promotes increased survival and reduced incidence of recurrence compared to patients with lower tumor cell MHCI expression. PMID- 25721802 TI - Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells. AB - The goal of most vaccines is the induction of long-lived memory T and B cells capable of protecting the host from infection by cytotoxic mechanisms, cytokines and high-affinity antibodies. However, efforts to develop vaccines against major human pathogens such as HIV and HCV have not been successful, thereby highlighting the need for novel approaches to circumvent immunoregulatory mechanisms that limit the induction of protective immunity. Here, we show that mouse natural killer (NK) cells inhibit generation of long-lived virus-specific memory T- and B cells as well as virus-specific antibody production after acute infection. Mechanistically, NK cells suppressed CD4 T cells and follicular helper T cells (T(FH)) in a perforin-dependent manner during the first few days of infection, resulting in a weaker germinal centre (GC) response and diminished immune memory. We anticipate that innovative strategies to relieve NK cell mediated suppression of immunity should facilitate development of efficacious new vaccines targeting difficult-to-prevent infections. PMID- 25721804 TI - Antiplasmodial activity of medicinal plants from Chhotanagpur plateau, Jharkhand, India. AB - BACKGROUND: The alarmingly increasing problem of drug resistance in treatment of malaria has led to an urgent need for identifying new anti-malarial drugs for both prophylaxis and chemotherapy. AIM OF THE STUDY: The present study presents a systematic exploration of the ex vivo blood stage antiplasmodial potential of medicinal plants to corroborate their traditional usage against malaria in Jharkhand, India. METHODS: An ethnobotanical survey in and around Ranchi was done to grasp the traditional knowledge of medicinal plants used by local healers for malaria, other fevers and for other medicinal purposes like, antiamoebic, antihelmenthic, antidote to poisons, etc. Following the survey, the selected 22 plant samples were extracted in ethanol for studying ex vivo SYBR Green I fluorescence assay based anti-plasmodial activity against both chloroquine sensitive Pf3D7 and chloroquine resistant PfINDO strains of Plasmodium falciparum grown in human red blood cell cultures. Cytotoxicity was determined against HeLa and L929 cells using MTT assay. Further the most potent extract was chromatographed on reverse phase HPLC towards antiplasmodial activity guided purification of metabolites. RESULTS: Of the 22 plant species assayed, the highest antiplasmodial activity (Pf3D7IC50 <= 5 ug/ml) was seen in leaf ethanol extracts of Corymbia citriodora (Hook.) K.D.Hill & L.A.S.Johnson, Calotropis procera (Aiton) Dryand. and Annona squamosa L. and bark ethanol extract of Holarrhena pubescens Wall. ex G.Don. Leaf ethanol extract of H. pubescens, bark ethanol extract of Pongamia pinnata (L.) Pierre and whole plant ethanol extract of Partheniumhysterophorus L. showed promising activity (IC50 6-10 ug/ml). Good antiplasmodial activity (IC50: 11-20 ug/ml) was observed in leaf ethanol extract of Bryophyllum pinnatum (Lam.) Oken and whole plant ethanol extract of Catharanthus roseus (L.) G.Don. The extracts of plants showing highest to good antiplasmodial activity exhibited HeLa/Pf3D7 selectivity indices of the order of 20-45. Bioassay guided fractionation of P. hysterophorus led to fivefold enrichment of antiplasmodial activities (IC50 ~450 ng/ml) in some fractions. CONCLUSION: These results provide confirmation to the traditional usage of some medicinal plants against malaria in areas around Ranchi, Jharkhand. PMID- 25721805 TI - Gamisasangja-tang suppresses pruritus and atopic skin inflammation in the NC/Nga murine model of atopic dermatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gamisasangja-tang (GST) is a traditional herbal formula prescribed for patients with intractable pruritus in association with various inflammatory skin diseases. To evaluate the effects of GST on pruritic skin inflammation and investigate its cellular and molecular mechanisms. MATERIALS AND METHODS: We orally administered GST to NC/Nga (NC) mice, an animal model of atopic dermatitis. Scratching frequency and the dermatitis index were evaluated, and histological examination was performed using hematoxylin and eosin and toluidine blue staining. The levels of interleukin (IL)-31 and T-helper cell type 2 (TH2) cytokines were determined in both the dorsal skin and cultured splenocytes by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum levels of chemokines and immunoglobulin E (IgE) were determined by ELISA. Changes in the inflammatory cell population were analyzed by a hemocytometer. RESULTS: GST significantly lowered scratching frequency and inhibited increases in dermatitis index, thickness of epidermis/dermis and infiltration of chemokine (C-C motif) receptor 3 (CCR3)(+) and cluster of differentiation (CD)117(+)/FcepsilonRIalpha (Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide)(+) cells in atopic skin. Both IL-31 mRNA expression and production were significantly reduced by GST, which was accomrease in the levels of IL-4, IL-5, and IL-13. Further, GST treatment suppressed the secretion of eotaxin, TARC (thymus and activation-regulated chemokine), IgE, and increases in the number of basophils and eosinophils in the blood. CONCLUSION: GST may have potential as an effective treatment for pruritic skin disease such as atopic dermatitis. PMID- 25721806 TI - From traditional use to clinical trials and meta-analyses. PMID- 25721807 TI - Incidence, treatment and survival of paediatric patients with bone sarcomas in Finland from 1991 to 2005. AB - AIM: Our aims were to establish the 10-year overall and event-free survival rates among children and adolescents with bone sarcomas in Finland, estimate their respective incidences, evaluate the treatment given and describe the key prognostic factors. METHODS: We included 88 patients of <18 years of age diagnosed with a bone sarcoma during 1991-2005 in this retrospective, nationwide and population-based study. Median follow-up time was 12.2 years (range 5.8-20.3 years) for surviving patients. RESULTS: The overall incidence among children and adolescents was 5.1 per million: 3.6 for osteosarcoma, 1.2 for Ewing's sarcoma and 0.3 for chondrosarcoma. The 10-year event-free and overall survival of those with a localised disease at diagnosis was 69% and 82%, respectively. The overall 10-year survival of those with a metastatic disease at diagnosis was 47%. Prognostic factors for localised disease included an axial versus peripheral primary tumour site in Ewing's sarcoma (p = 0.022) and age at diagnosis in osteosarcoma (p = 0.027). CONCLUSION: The 10-year overall survival of children and adolescents diagnosed with a bone sarcoma in Finland during 1991 to 2005 was very good, at 82% if the disease was localised at diagnosis and 47% if it was metastatic at diagnosis. PMID- 25721808 TI - Brightening the future: supporting youth to reach their potential. AB - Mental illnesses are the chronic diseases of young people. By bridging research, practice, and advocacy for early intervention, particularly for first episode psychosis, we can reduce the debilitating outcomes all too common for these illnesses. Our vision for the future is one in which every young person has coverage for the care they need, early in the course of their illness, at a treatment organization that provides a comprehensive array of evidence-based services and supports to help that person navigate the journey into recovery. PMID- 25721809 TI - Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression. AB - Epithelial-mesenchymal transition (EMT) is a highly conserved process defined by the loss of epithelial characteristics, and acquisition of the mesenchymal phenotype. In addition to its central role in development, EMT has been implicated as a cellular process during tumourigenesis which facilitates tumour cell invasion and metastasis. The EMT process has been largely defined by signal transduction networks and transcriptional factors that activate mesenchymal associated gene expression. Knowledge of secretome components that influence EMT including secreted proteins/peptides and membrane-derived extracellular vesicles (EVs) (i.e., exosomes) has emerged. Here we review EV cargo associated with inducing the hallmarks of EMT and cancer progression, modulators of cell transformation, invasion/migration, angiogenesis, and components involved in establishing the metastatic niche. PMID- 25721810 TI - Extracellular vesicles in the biology of brain tumour stem cells--Implications for inter-cellular communication, therapy and biomarker development. AB - Extracellular vesicles (EVs) act as carriers of molecular and oncogenic signatures present in subsets of tumour cells and tumour-associated stroma, and as mediators of intercellular communication. These processes likely involve cancer stem cells (CSCs). EVs represent a unique pathway of cellular export and cell-to-cell transfer of insoluble molecular regulators such as membrane receptors, signalling proteins and metabolites, thereby influencing the functional integration of cancer cell populations. While mechanisms that control biogenesis, cargo and uptake of different classes of EVs (exosomes, microvesicles, ectosomes, large oncosomes) are poorly understood, they likely remain under the influence of stress-responses, microenvironment and oncogenic processes that define the biology and heterogeneity of human cancers. In glioblastoma (GBM), recent molecular profiling approaches distinguished several disease subtypes driven by distinct molecular, epigenetic and mutational mechanisms, leading to formation of proneural, neural, classical and mesenchymal tumours. Moreover, molecularly distinct clonal cellular lineages co-exist within individual GBM lesions, where they differentiate according to distinct stem cell hierarchies resulting in several facets of tumour heterogeneity and the related potential for intercellular interactions. Glioma stem cells (GSCs) may carry signatures of either proneural or mesenchymal GBM subtypes and differ in several biological characteristics that are, at least in part, represented by the output and repertoire of EV production (vesiculome). We report that vesiculomes differ between known GBM subtypes. EVs may also reflect and influence the equilibrium of the stem cell hierarchy, contain oncogenic drivers and modulate the microenvironment (vascular niche). The GBM/GSC subtype-specific differentials in EV cargo of proteins, transcripts, microRNA and DNA may enable detection of the dynamics of the stem cell compartment and result in biological effects that remain to be fully characterized. PMID- 25721811 TI - Oxidative and other posttranslational modifications in extracellular vesicle biology. AB - Extracellular vesicles including exosomes, microvesicles and apoptotic vesicles, are phospholipid bilayer surrounded structures secreted by cells universally, in an evolutionarily conserved fashion. Posttranslational modifications such as oxidation, citrullination, phosphorylation and glycosylation play diverse roles in extracellular vesicle biology. Posttranslational modifications orchestrate the biogenesis of extracellular vesicles. The signals extracellular vesicles transmit between cells also often function via modulating posttranslational modifications of target molecules, given that extracellular vesicles are carriers of several active enzymes catalysing posttranslational modifications. Posttranslational modifications of extracellular vesicles can also contribute to disease pathology by e.g. amplifying inflammation, generating neoepitopes or carrying neoepitopes themselves. PMID- 25721814 TI - Influence of sampling site on uterine artery Doppler indices at 11-13+6 weeks gestation. AB - INTRODUCTION: Uterine artery pulsatility index (PI) is a key variable in the first trimester screening for pre-eclampsia. The aims of the study were to examine the effect of sampling the uterine arteries at a site distal to the level of the internal os, and to determine a lower limit of peak systolic velocity (PSV) to establish an auditable standard. MATERIAL AND METHODS: PI and PSV measurements were performed at 11-13(+6) weeks' gestation at two sites: at the level of the internal os and 3 cm distal to the internal os. Comparative analyses utilised the Student's paired t-test. A 90% reference interval of transformed PSV measurements at the internal os was generated by polynomial regression. RESULTS: There was a significant reduction in both the PI (14.9%) and the PSV (17.4%) when measured at the distal site compared to the level of the internal os (both p < 0.001). The best estimated 5th centile for uterine artery PSV at 11-13(+6) weeks was 60.9 cm/s. CONCLUSION: PI measurements performed distal to the internal os are significantly lower and will result in inaccurate pre-eclampsia risk assessment. PSV measurements below 60 cm/s are likely to indicate an incorrect sampling site. Development of auditable measurement standards is important to ensure accuracy of prospective pre-eclampsia screening. PMID- 25721813 TI - Prospective, comparative effectiveness trial of cow's milk elimination and swallowed fluticasone for pediatric eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease in which food antigens play a key role. Current therapeutic options are limited to long term steroid medication and dietary elimination of multiple foods, each of which is challenging. Our objective was to compare single food elimination of cow's milk to swallowed fluticasone in pediatric EoE patients. This is a prospective, comparative effectiveness trial of newly diagnosed EoE patients (ages 2-18 years) treated with swallowed fluticasone (n = 24) or elimination of cow's milk (n = 20). The dual outcome measures of repeat esophageal biopsy (6-8 weeks) and change in Pediatric Quality of Life Inventor (PedsQL) EoE Module and Symptoms Scales were used to assess response to treatment. After 6-8 weeks of treatment, peak esophageal eosinophil counts decreased to below the threshold of 15 eosinophils/high-power field in 64% of patients treated with cow's milk elimination and 80% of patients treated with swallowed fluticasone (P = 0.4). Mean PedsQL EoE Module total scores (69 vs. 82; P < 0.005) and Total Symptoms scores (58 vs. 75; P = 0.001) showed significant improvement with cow's milk elimination. Among children treated with swallowed fluticasone, mean PedsQL EoE Module total scores (64 vs. 75; P < 0.05) and Total Symptoms scores (58 vs. 69; P < 0.01) were also significantly improved after 6-8 weeks of therapy. Removal of cow's milk from the diet is an effective single food elimination treatment for pediatric patients with EoE as assessed by statistically significant histologic and symptomatic improvement. Cow's milk elimination may be more desirable for EoE patients who do not want to take chronic, long-term steroid medications. PMID- 25721815 TI - Effects of phytochemicals on in vitro anti-inflammatory activity of Bifidobacterium adolescentis. AB - Probiotics have been shown to improve the condition of not only the human gastrointestinal tract but also the entire body. We found that quercetin enhances the anti-inflammatory activity of Bifidobacterium adolescentis, which is abundant in human intestines. Here, we assessed whether certain phytochemicals could enhance the anti-inflammatory activity of B. adolescentis. Bifidobacteria were anaerobically cultured with phytochemicals for 3 h, and the anti-inflammatory activity of the supernatants was estimated by testing their ability to inhibit nitric oxide (NO) production by lipopolysaccharide-stimulated RAW264 macrophages. Of the 55 phytochemicals tested, phloretin, (+)-taxifolin, and (-) epigallocatechin gallate as well as quercetin-3-O-glucoside and quercetin-4'-O glucoside were similar to quercetin in promoting NO suppression by B. adolescentis. In addition, the phytochemicals excluding quercetin increased the concentrations of lactic and acetic acids in the co-culture supernatants. These results suggest that some phytochemicals may activate the anti-inflammatory function of B. adolescentis. PMID- 25721812 TI - Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. AB - Since their first description, extracellular vesicles (EVs) have been the topic of avid study in a variety of physiologic contexts and are now thought to play an important role in cancer. The state of knowledge on biogenesis, molecular content and horizontal communication of diverse types of cancer EVs has expanded considerably in recent years. As a consequence, a plethora of information about EV composition and molecular function has emerged, along with the notion that cancer cells rely on these particles to invade tissues and propagate oncogenic signals at distance. The number of in vivo studies, designed to achieve a deeper understanding of the extent to which EV biology can be applied to clinically relevant settings, is rapidly growing. This review summarizes recent studies on cancer-derived EV functions, with an overview about biogenesis and molecular cargo of exosomes, microvesicles and large oncosomes. We also discuss current challenges and emerging technologies that might improve EV detection in various biological systems. Further studies on the functional role of EVs in specific steps of cancer formation and progression will expand our understanding of the diversity of paracrine signaling mechanisms in malignant growth. PMID- 25721816 TI - High resistance of transgenic cabbage plants with a synthetic cry1Ia8 gene from Bacillus thuringiensis against two lepidopteran species under field conditions. AB - BACKGROUND: Plutella xylostella (Linnaeus) has become the most destructive pest in cabbage throughout the world. Cry1Ia8 cabbage has been developed to reduce pest attacks. To gain a better understanding of the efficacy of Cry1Ia8 cabbage, a homozygous Cry1Ia8 cabbage line A14-5 was produced, and its resistance to P. xylostella, Pieris rapae (Linnaeus) and other lepidopteran pests was evaluated in the field in 2011, 2012 and 2013. RESULTS: Under natural infestation conditions, the homozygous transgenic line was highly resistant against P. xylostella and P. rapae as compared with the untransformed control and susceptible to Mamestra brassicae (Linnaeus) and Spodoptera exigua (Hubner). The homozygous transgenic plants showed slight symptoms of damaged leaves by lepidopteran species, while the untransformed plants exhibited serious damage symptoms throughout the cabbage growing season. CONCLUSION: Compared with the control, the homozygous transgenic cabbage line showed great potential for protecting cabbage from attack by P. xylostella and P. rapae in the field. PMID- 25721817 TI - Patients who do not reach a distance of 500 m during the 6-min walk test have an increased risk of postoperative complications and prolonged hospital stay after lobectomy. AB - OBJECTIVES: Exercise testing is an additional tool to standard pulmonary assessment before radical pulmonary resection in lung cancer patients. Evidence is lacking, supporting the significance of routine implementation of these simple physiological tests in preoperative evaluation. METHODS: Between April 2009 and October 2011, 253 lung cancer patients, who underwent lobectomy in a single institution, were entered into this study. All of the patients were accepted for resection based on a standard evaluation protocol. Additionally on the day before the surgery, patients performed a 6-min walk test (6MWT). Patients were categorized, depending on the result of 6MWT, in order to stratify their risk of postoperative complications. Threshold values of 6MWT were assessed on the basis of maximum area under ROC curves. RESULTS: There were 148 men and 105 women with a mean age of 63 years. All patients underwent lobectomies due to primary lung cancer. A distance of 500 m and 100% of the predicted 6MWT were taken as threshold values differentiating risk of postoperative complications. The cut-off value of 500 m separates individuals with an increased risk of postoperative complications [60.6 vs 36.9%, odds ratio (OR): 2631; 95% confidence interval (CI): 1.423-4.880] and prolonged hospitalization (7 vs 6 days). By applying a cut off value of 500 m, the higher incidence of atrial fibrillation (21.2 vs 11.7%; OR: 2019; 95% CI: 0.904-4.484) and higher requirement for blood transfusion (18.1 vs 9.0%; OR: 2222; 95% CI: 0.928-5.289) fairly reached the level of significance. There were no early postoperative deaths in the analysed groups. CONCLUSIONS: Patients who walk <500 m during the 6MWT before lobectomy have an increased risk of postoperative complications and prolonged hospital stay. PMID- 25721818 TI - Italian multicentre study on type A acute aortic dissection: a 33-year follow up?. AB - OBJECTIVES: Despite substantial progress in surgical techniques and perioperative management, the treatment and long-term follow-up of type A acute aortic dissection (AAD) still remain a major challenge. The objective of this retrospective, multicentre study was to assess in a large series of patients the early and long-term results after surgery for type A AAD. METHODS: We analysed the preoperative, intraoperative and postoperative conditions of 1.148 consecutive patients surgically treated in seven large referral centres from 1981 to 2013. We applied to each patient three different multi-parameter risk profiles (preadmission risk, admission risk and post-surgery risk) in order to compare risk factors and outcome. Long-term Kaplan-Meier survival was evaluated. RESULTS: The median age was 64 years and the male population was predominant (66%). Identified diagnosis of collagen disease was present in 9%, and Marfan syndrome in 5%. Bicuspid aortic valve was present in 69 patients (6%). Previous cardiac surgery was identified in 10% of the patients. During surgery, the native aortic valve was preserved in 72% of the cases, including leaflet resuspension in 23% and David operation in 1.2%. Considering aortic valve replacement (AVR: 28%), bioprosthesis implantation was performed in 14.7% of the subjects. Neurological impairment at discharge was shown in 23% of the cases among which 21% of patients had new neurological impairment versus preoperative conditions. The overall 30 day mortality rate was 25.7%. All risk profiles remained independently associated with in-hospital mortality. During the available follow-up of hospital survivors (median: 70 months, interquartile range: 34-113, maximum: 396), cardiac-related death occurred in 7.9% of the subjects. The cumulative survival rate for cardiac death was 95.3% at 5 years, 92.8% at 10 years and 52.8% at 20 years. Severe aortic regurgitation (AR) (grade 3-4) at the time of surgery showed to be a significant risk factor for reintervention during the follow-up (P < 0.001). Among risk profiles, only the preadmission risk was independently associated with late mortality after multivariate analysis. Unexpectedly, there was no difference in freedom from cardiac death between patients with and without AVR. CONCLUSIONS: Although surgery for type A has remained challenging over more than three decades, there is a positive trend in terms of hospital mortality and long-term follow-up. About 90% of patients were free from reoperation in the long term, although late AR remains a critical issue, suggesting that a thorough debate on surgical options, assessment and results of a conservative approach should be considered. PMID- 25721819 TI - Catheter ablation of symptomatic postoperative atrial arrhythmias after epicardial surgical disconnection of the pulmonary veins and left atrial appendage ligation in patients with atrial fibrillation. AB - OBJECTIVES: Minimally invasive thoracoscopic epicardial pulmonary vein isolation (MIPI) has an important role in the surgical treatment of atrial fibrillation (AF). However, the management of recurrent atrial arrhythmias after MIPI and long term success rate of catheter ablation have not been well studied. METHODS: Electrophysiological study was performed in 23 patients, 378 +/- 282 days after MIPI surgery, because of recurrent symptomatic atrial arrhythmias. RESULTS: A total of 20 patients presented with paroxysmal and persistent AF, 2 patients had a combination of AF and atrial tachycardia (AT) and 1 patient had a combination of AF and atrial flutter. All patients showed pulmonary vein (PV) reconnection. ATs were micro-re-entry PV-related ATs and atrial flutter was cavotricuspid isthmus dependent. Eighteen of 23 patients (78.3%) were free of atrial arrhythmias after one catheter ablation procedure at a mean follow-up of 50 +/- 16 months. Three patients underwent a second ablation procedure for recurrent AF and macro-re-entry left atrial flutter. Eventually 20 of 23 patients (87%) remained free of atrial arrhythmias after a mean of 1.1 +/- 0.3 ablation procedures. CONCLUSIONS: Catheter ablation of recurrent atrial arrhythmias following MIPI for paroxysmal and persistent AF is a feasible and effective treatment with a good long-term success rate. Reconnection of PVs accounts for most recurrences. PMID- 25721820 TI - Inhibition of intimal hyperplasia of the vein graft with degradable poly lactic co-glycolic acid vascular external sheaths carrying slow-release bosentan. AB - OBJECTIVES: Intimal hyperplasia is a major reason for the restenosis of vein grafts. A vascular external sheath was designed to inhibit intimal hyperplasia of vein grafts. METHODS: Using the biodegradable material poly(lactic-co-glycolic acid) and fibrin, a high porosity external sheath carrying bosentan with a stratified internal spiral structure was made by grouping mould extraction and low-temperature deposition techniques. Bosentan, a dual endothelin A and B receptor antagonist, was carried in the new designed external sheath, and could be slowly released. Rabbits underwent carotid bypass with ipsilateral jugular vein without external sheath (control, Group C), with external sheath (Group S) or with external sheath carrying bosentan (Group S + B). RESULTS: Eight weeks after interposition, ultrasonography indicated that the change rate of the diameter of vein grafts of Group C (42.3 +/- 5.8%) was much higher than that of Group S (18.5 +/- 8.6%) or S + B (1.1 +/- 13.2%) (P < 0.01, respectively). The change rate of peak velocity of Group S + B (-0.5 +/- 9.8%) was lower than that of Group S (5.7 +/- 7.4%) or C (25.6 +/- 13.1%) (P < 0.01 vs Group C; P < 0.05 vs Group S). The sheaths degraded completely 9 weeks after interposition and the histological examination showed that the ratio of long/short diameter of vein grafts was much higher in Group C (P < 0.01, respectively). The ratio of the area of intima-media to the area of lumen and the ratio of thickness of intima to the thickness of media of Group S + B were significantly lower (P < 0.01 vs Group C; P < 0.05 vs Group S, respectively). Masson and Alcian Blue staining indicated that the remodelling of collagen and the distribution of proteoglycan in vein grafts of Group S + B were more similar to those of the artery. CONCLUSIONS: The degradable vascular external sheath with slow-release bosentan can inhibit hyperplasia of intima, and improve the shape of experimental vein grafts. PMID- 25721821 TI - Pathology-specific late outcome after endovascular repair of thoracic aorta: a single-centre experience. AB - OBJECTIVES: Endovascular treatment of thoracic aortic lesions appears to be advantageous. However, long-term outcomes remain poorly reported. This retrospective study reported 6-year outcomes of thoracic endovascular aortic repair. METHODS: A total of 74 patients underwent endovascular thoracic aorta treatments between 1999 and 2007; 13 had thoracic aortic dissections, 19 had traumatic aortic injuries, 35 had aneurysms, 6 had pseudoaneurysms and 1 had a penetrating ulcer. The mean follow-up was 66 months after 30 perioperative days. Yearly follow-ups included computed tomography angiography or magnetic resonance angiography. Patient demographics, mortality, complications and reinterventions were analysed. RESULTS: The early 30-day mortality and the overall late mortality were 9.5 (7/74) and 37.8% (28/74), respectively. Late mortality was higher in patients with aneurysms than in the other groups (20/35; 57% vs 8/39; 20.5%; P = 0.002). Aortic-related mortality occurred in 5/35 (14%) patients with aneurysms, but not in other groups (P = 0.02). No relationships among late complications were found for traumatic aortic injuries. The most common complication was an endoleak (21/74, 28.4%), which occurred more frequently with aneurysms than other disorders (18/35, 51.4% vs 3/39, 7.7%; P < 0.001). Endoleaks also occurred most frequently in aortic-related deaths (16/69 vs 5/5; P = 0.001). Type 1 endoleaks occurred significantly more often with aneurysms (13/35) than with other disorders (P = 0.004). Reintervention was required in 9 patients (12%); 8 with atherosclerotic aneurysms (8/35; 23%). A false lumen was thrombosed in 54% of dissections (7/13), and shrank in 39% (5/13). CONCLUSIONS: Long-term outcomes depended on aortic pathology. Aortic aneurysms were the most complicated and caused the highest mortality, probably due to atherosclerotic disease evolution. Patients with traumatic aortic injuries appeared to have the best long-term outcomes. PMID- 25721822 TI - The evolution of bronchoplasty and broncho-angioplasty as treatments for lung cancer: evaluation of 30 years of data from a single institution. AB - OBJECTIVES: The purpose of this study was to evaluate the factors contributing to the outcomes of bronchoplasty for lung cancer by analysing a single institution's data for a 30-year period. METHODS: A retrospective review of 213 patients who underwent bronchoplasty for lung cancer between 1980 and 2010 was undertaken. The patients were divided into two groups by the date of surgery: the first period was 1980-95, and the second period was 1996-2010. RESULTS: Bronchoplasty and broncho-angioplasty were performed in 100 (75.8%) and 32 (24.2%) patients, respectively, in the first period and 61 (75.3%) and 20 (24.7%) patients, respectively, in the second period. Overall 90-day operative morbidity and mortality rates were 25.8 and 9.8%, respectively, in the first period and 45.7 and 2.5%, respectively, in the second period. Thirty-day mortality rates were 6.8% in the first period and 0% in the second period. Five-year survival was 41.1% (n = 132) in the first period and 61.5% (n = 81) in the second period (P = 0.0003). Comparing bronchoplasty and broncho-angioplasty, the 5-year survival was 45.6 and 26.5%, respectively, in the first period (P = 0.0048) and 60.9 and 62.1%, respectively, in the second period (P = 0. 8131). Using multivariate analysis to identify potential prognostic factors, the type of operation (broncho angioplasty), postoperative complications and histology (non-squamous cell carcinoma) were significant factors affecting survival in the first period, but none of the factors significantly affected survival in the second period. When the rates of pN2 or N3 histological type disease were compared in each period, the rate of pN2 or N3 disease in non-squamous cell carcinoma was 51.4% in the first period and 45.5% in the second period; both were significantly higher than in squamous cell carcinoma (31.6 and 16.9%, respectively; P = 0. 0365 and 0.0073). CONCLUSIONS: The present study suggests that progress in the preoperative staging system and perioperative medical management, as well as surgery, has contributed to current improvements in patients undergoing bronchoplasty and broncho-angioplasty. However, since nodal status in non squamous cell carcinoma is not precisely evaluated before the operation, the indication for bronchoplasty should be considered carefully. PMID- 25721823 TI - The role of annular dimension and annuloplasty in tricuspid aortic valve repair. AB - OBJECTIVES: Valve sparing reimplantation can improve the durability of bicuspid aortic valve repair compared with subcommissural annuloplasty, especially in patients with a large basal ring. This study analyses the effect of basal ring size and annuloplasty on valve repair in the setting of a tricuspid aortic valve. METHODS: From 1995 to 2013, 382 patients underwent elective tricuspid aortic valve repair. We included only those undergoing subcommissural annuloplasty, valve sparing reimplantation or no annuloplasty and in whom intraoperative transoesophageal echocardiography images were available for retrospective pre- and post-repair basal ring measurements (n = 323, subcommissural annuloplasty: 146, valve sparing reimplantation: 154, no annuloplasty: 23). In a subgroup of patients with available echocardiographic images, basal ring was retrospectively measured at the latest follow-up or prior to reoperation. subcommissural annuloplasty and valve sparing reimplantation were compared after matching for degree of aortic regurgitation and root size. RESULTS: All three groups differed significantly for most of preoperative characteristics. Hospital mortality was 0.9%. The median follow-up was 4.7 years. At 8 years, overall survival was 80 +/- 5%. Freedom from reoperation and freedom from aortic regurgitation >1+ were 92 +/ 5% and 71 +/- 8%, respectively. In multivariate analysis, predictors of aortic regurgitation >1+ were left ventricular end-diastolic diameter (P = 0.003), cusp repair (P = 0.006), body surface area (P = 0.01) and subcommissural annuloplasty (P = 0.05). In subcommissural annuloplasty, freedom from aortic regurgitation >1+ was lower for patients with basal ring >=28 mm compared with patients with basal ring <28 mm (P = 0.0001). In valve sparing reimplantation, freedom from aortic regurgitation >1+ was independent of basal ring size (P = 0.38). In matched comparison between subcommissural annuloplasty and valve sparing reimplantation, freedom from aortic regurgitation >1+ was not significantly different (P = 0.06), but in patients with basal ring >=28 mm, valve sparing reimplantation was superior to subcommissural annuloplasty (P = 0.04). Despite similar intraoperative reduction in basal ring size in subcommissural annuloplasty and valve sparing reimplantation, patients with subcommissural annuloplasty exhibited greater increase in basal ring size during the follow-up compared with the valve sparing reimplantation group (P < 0.001). CONCLUSIONS: As with a bicuspid aortic valve, a large basal ring predicts recurrence of aortic regurgitation in patients with tricuspid aortic valve undergoing repair with the subcommissural annuloplasty technique. This recurrence is caused by basal ring dilatation over time after subcommissural annuloplasty. With the valve sparing reimplantation technique, large basal ring did not predict aortic regurgitation recurrence, as prosthetic-based circumferential annuloplasty displayed better stability over time. Stable circumferential annuloplasty is recommended in tricuspid aortic valve repair whenever the basal ring size is >=28 mm. PMID- 25721824 TI - Caring for the bereaved parent: Guidelines for practice. AB - PURPOSE: The purpose of this research review was to create practical guidelines for the primary care practitioner in comforting, counseling, and educating bereaved parents and their significant supporters. DATA SOURCES: The authors used an extensive review of the literature for original research reports of bereaved parents' self-identified needs for comfort from their friends, family, and healthcare practitioners. Insight gained from the authors' clinical work with bereaved parents added further understanding. CONCLUSIONS: Parents express strong preferences and needs regarding support from both social relationships and healthcare personnel. Specific guidelines were created for use by both friends/family members and health professionals. IMPLICATIONS FOR PRACTICE: Nurse practitioners have an important role in supporting bereaved parents, and educating their friends and family on the most helpful behaviors during this painful time. PMID- 25721825 TI - Myoepithelial carcinoma of the parotid: a rare tumour that may provide diagnostic difficulty. AB - This report presents the case of a 57-year-old man with a 6-week history of a slowly enlarging lump in the right parotid gland. Initial ultrasound investigation confirmed a 3 cm solid mass located within the superficial lobe of the right parotid gland. Sonographically, the mass demonstrated possible malignant features with internal heterogeneity of architecture and some loss of marginal clarity. Ultrasound-guided core biopsy (USCB) of the mass reported a mixed neoplasm with epithelial and myoepithelial appearances consistent with likely benign adenoma or myoepithelioma. A right superficial parotidectomy was subsequently performed. Histological and immunohistochemical analysis of the excised specimen showed a myoepithelial carcinoma. Postoperative CT and MR staging scans did not show evidence of metastases and no further treatment was given following discussion of the case at the regional speciality multidisciplinary meeting. This case illustrates the clinical and pathological features of this rare salivary gland tumour, but also discusses the diagnostic difficulties that may be encountered preoperatively. PMID- 25721826 TI - Thompson and Hamilton type IV Freiberg's disease with involvement of multiple epiphyses of both feet. AB - A 17-year-old boy reported left second and third toe pain after axial loading injury to his left foot. Radiographs showed collapse of the second metatarsal heads and epiphysial irregularities of the fifth metatarsal heads and the condyle of the proximal phalanx of the hallux of both feet. The patient was diagnosed to have Thompson and Hamilton type IV Freiberg's disease. He was screened for epiphysial dysplasia of the other sites. He had on and off bilateral hip and knee pain. Radiographs showed bilateral symmetrical epiphysial abnormalities with morphological change as focal concavity in bilateral femoral heads and fragmentation of the patellar articular surface with preservation of the patellofemoral joint space. PMID- 25721827 TI - Lumbar blood patching for proximal CSF leaks: where does the blood go? AB - Epidural blood patching (EBP) is an important therapeutic approach in managing spontaneous cerebrospinal fluid leaks. The mechanism of action of blood patching is likely to be twofold; fluid replacement having an immediate tamponade effect and the proximal flow of blood products having a 'plug' effect. The negative pressure gradient within the epidural space may be important to the rostral flow of injected blood and is possibly increased in intracranial hypotension. PMID- 25721828 TI - Flat trachea syndrome: a rare condition with symptoms similar to obstructive airway disease. AB - Flat trachea syndrome, commonly known as 'tracheobronchomalacia', is a central airway disease characterised by excessive expiratory collapse of the tracheobronchial posterior membrane due to weakness in the airway walls. Patients present with symptoms such as chronic cough, dyspnoea and recurrent respiratory tract infections, which are often attributed to more common conditions such as asthma and chronic obstructive pulmonary disease (COPD). The term 'Flat Trachea Syndrome' was first proposed by Niranjan and Marzouk in 2010 following a retrospective study of 28 patients with the condition who underwent surgery for it. The authors advocated the term due to the primary abnormality being collapse of the posterior membranous wall of the central airways as opposed to softening of the tracheal cartilage (tracheobronchomalacia), which they proposed is a misnomer. We present a rare case of a patient with flat trachea syndrome on a history of COPD who initially presented with recurrent respiratory tract infections. PMID- 25721829 TI - Spontaneous iliopsoas haematoma: a complication of hypertensive urgency. AB - Iliopsoas haematoma is a rare clinical entity which can be life threatening in extreme cases. We are reporting a case of iliopsoas haematoma as a complication of hypertensive urgency. A 67-year old woman presented to emergency room with hypertensive urgency and hip pain. During hospitalisation, her haemoglobin was decreasing and on further evaluation, she did not have any signs of external bleeding and laboratory results were not suggestive of haemolysis. CT scan of abdomen and pelvis revealed a spontaneous iliopsoas haematoma. A likely explanation for this presentation in the absence of coagulopathy and trauma is very high blood pressure. Patient was on low-dose aspirin at home which could have further aggravated her bleeding due to platelet dysfunction. She was managed conservatively with blood transfusions and blood pressure was reduced to target after which she recovered. PMID- 25721830 TI - Colitis possibly induced by quetiapine. AB - A 39-year-old man with bipolar disorder was hospitalised for depression. He was started on quetiapine (titrated up to 300 mg), lactulose (a laxative) and tropatepine (an anticholinergic). Valpromide (a mood stabiliser) and prazepam were later added and rapidly withdrawn. Seven days after quetiapine initiation, the patient reported abdominal pain and constipation; 2 days later, CT revealed an important distention of the colon including the caecum and a pre-perforation. A subtotal colectomy was performed and histology confirmed necrotising ischaemic colitis. The patient survived. This is the first case reported so far of ischaemic colitis related to quetiapine, in the absence of other antipsychotics simultaneously prescribed. Tropatepine likely acted as a cofactor to determine colitis. Clinicians need to be aware of the potential danger of the co prescription of quetiapine with tropatepine (and possibly other anticholinergics). PMID- 25721831 TI - Spontaneous flexor tendon rupture in the palm. AB - Spontaneous flexor intratendinous ruptures are rare and incompletely understood. They occur within the substance of the tendon, and in the absence of underlying pathological processes or direct trauma. We present an unusual case of spontaneous flexor digitorum profundus tendon rupture in the palm. PMID- 25721832 TI - New diagnosis myasthenia gravis and preeclampsia in late pregnancy. AB - Myasthenia gravis is a chronic autoimmune disease of neuromuscular transmission resulting in fatigable skeletal muscle weakness. Preeclampsia is a multisystem disease of pregnancy which is characterised by hypertension and involvement of one or more organ systems. Both diseases are responsible for considerable morbidity and mortality for mother and fetus. The occurrence of both preeclampsia and myasthenia gravis in pregnancy is very rare, and conflicts arise when considering the optimal management of each disease.We present a case of a parturient who was newly diagnosed with both myasthenia gravis and preeclampsia in late pregnancy. Myasthenia treatment was started with prednisolone and pyridostigmine, and delivery was by caesarean section at 37 weeks gestation under spinal anaesthesia. Postnatally, the patient developed worsening of myasthenia and preeclampsia symptoms. We consider the anaesthetic implications for both diseases and describe our approach for the management of this case. PMID- 25721833 TI - Pneumatosis intestinalis presenting as pneumoperitoneum in a teenage girl with pyloric stenosis. AB - A 16-year-old girl presented with free gas under the diaphragm after endoscopic balloon dilation for pyloric stenosis. There was no perforation site identified on laparotomy. However, there was massive pneumatosis intestinalis involving the entire small bowel. PMID- 25721834 TI - Sideroblastic anaemia and primary adrenal insufficiency due to a mitochondrial respiratory chain disorder in the absence of mtDNA deletion. AB - A fatigued 8-year-old boy was found to have sideroblastic anaemia (haemoglobin 7.8 g/dL) which over time became transfusion dependent. Subtle neurological dysfunction, initially manifesting as mild spastic diplegia, was slowly progressive and ultimately led to wheelchair dependence. Elevated plasma lactate and urinary 3-methylglutaconate led to a muscle biopsy which confirmed partial complex IV deficiency. PCR in leucocytes and muscle was negative for mitochondrial DNA (mtDNA) deletions. Faltering growth prompted an insulin tolerance test which confirmed growth hormone sufficiency and adrenal insufficiency. Plasma renin was elevated and adrenal androgens were low, suggesting primary adrenal insufficiency. Glucocorticoid and mineralocorticoid replacement therapy was initiated. A renal tubular Fanconi syndrome and diabetes mellitus developed subsequently. Sideroblastic anaemia and primary adrenal insufficiency, both individually and collectively, are associated with mtDNA deletion; however, absence of the same does not exclude the possibility that sideroblastic anaemia and primary adrenal insufficiency are of mitochondrial origin. PMID- 25721835 TI - Iliopsoas tendon rupture: a new differential for atraumatic groin pain post-total hip arthroplasty. AB - Groin pain post-total hip arthroplasty (THA) is of concern for the patient and the surgeon, especially when there is no history of any traumatic event. Obvious concern centres on complications from the prosthesis. The use of multiple imaging modalities allow for accurate diagnosis of groin pain. Atraumatic iliopsoas rupture is rare and has only been reported once before in the setting of THA. We present the case of 53-year old female with atraumatic rupture of the iliopsoas tendon that presented with severe groin pain and limited flexion. We discuss the clinical presentation, radiological features and follow-up of the patient. We also discuss the relevant published literature on the topic. This is a rare phenomenon but should be consider in patients with groin pain post-THA, especially after prosthesis complications have been ruled out. PMID- 25721836 TI - Late onset adrenal insufficiency and achalasia in Allgrove syndrome. PMID- 25721837 TI - A case of craniofacial fibrous dysplasia associated with McCune-Albright syndrome lost to follow-up. AB - McCune-Albright syndrome is a rare fibro-osseous syndrome characterised by a classic triad of fibrous dysplasia (FD), cafe-au-lait macules and various underlying endocrinopathies. This case report describes how a patient was rediagnosed by a general dental practitioner following attendance for a routine dental examination. The patient had been previously diagnosed with the condition 28 years earlier but no follow-up or monitoring of her condition had taken place. As a result, she was found to have several undiagnosed and untreated complications of the disease including FD of the mandible, optic neuropathy and potential thyroid involvement. PMID- 25721838 TI - Extracorporeal laparoscopically assisted resection of a perforated Meckel's diverticulum due to a chicken bone. AB - Meckel's diverticulum is the commonest congenital anomaly of the small intestine. It can, however, present acutely relating to a number of complications that may require emergency surgery and possible bowel resection. Perforation is a rare complication and there are only seven cases reported of an inflamed Meckel's diverticulum due to a chicken bone. Laparoscopic repair of Meckel's diverticulum associated complications has gained popularity over the recent years. We present a case of chicken bone perforation that was treated with laparoscopic-assisted extracorporeal resection of the affected small bowel segment. PMID- 25721839 TI - Lipoma of the corpus callosum. PMID- 25721840 TI - Extensive spontaneous spinal epidural haematoma: when 'treatment turned to tragedy'. PMID- 25721841 TI - Superior mesenteric artery syndrome as a cause for recurrent abdominal pain and vomiting in a 9-year-old girl. AB - A 9-year-old girl was admitted under our general surgical team with 2 days of diffuse abdominal pain and vomiting. This was one of multiple admissions for similar symptoms over the past 5 years. She was feverish on admission but haemodynamically stable. On examination, she had a diffusely tender and hypersensitive abdomen, with no guarding or peritonism, and no palpable masses. Of note, the patient was very thin, with almost no body fat. Blood tests were otherwise normal, with a normal abdominal X-ray and abdominal ultrasound. She had undergone three previous abdominal ultrasounds over the past 5 years for similar symptoms, all of which were normal. Following this, CT revealed a diagnosis of superior mesenteric artery syndrome. The patient was transferred to our regional children's hospital for analgaesia, nasogastric decompression and nutritional supplementation. She made a swift improvement with plans for ongoing follow-up by the paediatric team. PMID- 25721842 TI - Haemodialysis catheter-related giant right atrial and superior cava thrombi. PMID- 25721843 TI - Dental manifestations of congenital rubella syndrome. PMID- 25721844 TI - Diagnosis and management of symptomatic residual ureteral stump after nephrectomy. PMID- 25721845 TI - Discrete ('acral nonpapular') localised lichen myxedematosus. PMID- 25721846 TI - The Relationship between Serum Osteocalcin Concentration and Glucose and Lipid Metabolism in Patients with Type 2 Diabetes Mellitus - The Role of Osteocalcin in Energy Metabolism. AB - BACKGROUND: Recent animal studies have found that the osteocalcin secreted by osteoblasts could participate in glucose and lipid metabolism. Our study aimed to investigate the relationship between serum osteocalcin concentration and glucose and lipid metabolism in patients with type 2 diabetes mellitus. METHODS: 985 patients with type 2 diabetes were divided into the male group (n = 495) and the postmenopausal female group (n = 490). The average ages were 54.42 +/- 10.535 and 64.93 +/- 9.277, respectively. We collected the parameters of age, duration, fasting plasma glucose, HbA1c, fasting insulin, fasting C peptide, blood lipid, 25 (OH) VD3, parathyroid hormone (PTH), Alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), beta-C-terminal telopeptide of type I collagen (beta-CTx), osteocalcin, HOMA-IR, HOMA-beta, body mass index (BMI), and waist-to-hip ratio (WHR). The relationship of osteocalcin and these parameters were analyzed by Pearson/Spearman correlation analysis and stepwise multiple regression analysis. RESULTS: Osteocalcin was negatively correlated with HbA1c (p < 0.05) and it was also an independent relevant factor affecting HbA1c in both groups. Osteocalcin was positively correlated with HOMA-beta and it was an independent relevant factor affecting HOMA-beta in male group (p < 0.01). CONCLUSIONS: These findings indicate the association between serum osteocalcin and glucose metabolism and beta cell function. No relationship was found between osteocalcin and insulin resistance and lipid metabolism in type 2 diabetes. PMID- 25721847 TI - Editorial Comment from Dr Shiroki to Comparative investigation on clinical outcomes of robot-assisted radical prostatectomy between experienced open prostatic surgeons and novice open surgeons in a laparoscopically naive center with a limited caseload. PMID- 25721849 TI - Hunt rejects criminal record checks on all NHS volunteers in wake of Savile scandal. PMID- 25721848 TI - CA-SSR1 Polymorphism in Intron 1 of the EGFR Gene in Patients with Malignant Tumors Who Develop Acneiform Rash Associated with the Use of Cetuximab. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibitors are not equally effective in all cancer patients. One potential clinical factor that could help in selecting patients who may benefit from treatment with cetuximab is acneiform rash, which correlates with the clinical response to EGFR inhibitors. Some previous studies have suggested that the tendency to develop rash may depend on polymorphisms in the EGFR gene. In this investigation, the association of degree of CA dinucleotide polymorphism with skin rash and cetuximab therapy outcome was examined. METHODS: The study included 60 patients treated with cetuximab. For each patient, the severity of acneiform rash was assessed, and the type of polymorphism was determined by genotyping. Associations between genotypes, the acneiform rash, and response to treatment were determined by using the chi-square test and Spearman's rank correlation. The cutoffs S<=17(CA), L>17(CA), n(CA)<=35, and n(CA)>35 were tested, as well as the sum of the two allele repetitions. RESULTS: A correlation was found between body surface area covered by rash and the sum of the two allele repetitions (p=0.030). No statistically significant relationship between genotype and response to treatment was observed. However, in patients who have had partial remission, we noticed a higher incidence of polymorphism, with less CA dinucleotide repetitions and early onset of rash. CONCLUSION: A correlation between genotype and severity of rash was observed. That is, the severity of rash decreased with an increased number of CA repetitions. PMID- 25721850 TI - Inflammation and proliferation - a causal event of host response to Helicobacter pylori infection. AB - Helicobacter pylori is a major aetiological agent in the development of various gastroduodenal diseases. Its persistence in gastric mucosa is determined by the interaction between various host, microbial and environmental factors. The bacterium colonizes the gastric epithelium and induces activation of various chemokine mediators, including NFkappaB, the master regulator of inflammation. H. pylori infection is also associated with an increase in expression of cell cycle regulators, thereby leading to mucosal cell hyper-proliferation. Thus, H. pylori associated infections manifest activation of key host response events, which inadvertently could lead to the establishment of chronic infection and neoplastic progression. This article reviews and elaborates the current knowledge in H. pylori-induced activation of various host signalling pathways that could promote cancer development. Special focus is placed on the inflammatory and proliferative responses that could serve as suitable biomarkers of infection, since a sustained cell proliferation in an environment rich in inflammatory cells is characteristic in H. pylori-associated gastric malignancies. Here, the role of ERK and WNT signalling in H. pylori-induced activation of inflammatory and proliferative responses respectively is discussed in detail. An in depth analysis of the underlying signalling pathways and interacting partners causing alterations in these crucial host responses could contribute to the development of successful therapeutic strategies for the prevention, management and treatment of H. pylori infection. PMID- 25721851 TI - PilB localization correlates with the direction of twitching motility in the cyanobacterium Synechocystis sp. PCC 6803. AB - Twitching motility depends on the adhesion of type IV pili (T4P) to a substrate, with cell movement driven by extension and retraction of the pili. The mechanism of twitching motility, and the events that lead to a reversal of direction, are best understood in rod-shaped bacteria such as Myxococcus xanthus. In M. xanthus, the direction of movement depends on the unipolar localization of the pilus extension and retraction motors PilB and PilT to opposite cell poles. Reversal of direction results from relocalization of PilB and PilT. Some cyanobacteria utilize twitching motility for phototaxis. Here, we examine twitching motility in the cyanobacterium Synechocystis sp. PCC 6803, which has a spherical cell shape without obvious polarity. We use a motile Synechocystis sp. PCC 6803 strain expressing a functional GFP-tagged PilB1 protein to show that PilB1 tends to localize in 'crescents' adjacent to a specific region of the cytoplasmic membrane. Crescents are more prevalent under the low-light conditions that favour phototactic motility, and the direction of motility strongly correlates with the orientation of the crescent. We conclude that the direction of twitching motility in Synechocystis sp. PCC 6803 is controlled by the localization of the T4P apparatus, as it is in M. xanthus. The PilB1 crescents in the spherical cells of Synechocystis can be regarded as being equivalent to the leading pole in the rod shaped cells. PMID- 25721852 TI - Cervical spine MRI findings in patients with Mucopolysaccharidosis type II. AB - Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2 sulfatase (EC 3.1.6.13). The purpose of this report is to describe cervical spine magnetic resonance (MRI) findings in MPS II patients and to correlate them with clinical phenotype. Seven cervical spine MRI examinations from Polish MPS II patients (mean age 11.4 years, median age 8 years, range 5-30) were evaluated. Six patients were classified as neurological (85.7%) and 1 as attenuated (14.3%). Five patients were treated with idursulfase (range 110-260 weeks, mean 195, median 200), while 2 patients never received the treatment. The following features were assessed: periodontoid thickening, spinal stenosis, dens hypoplasia, myelopathy, and vertebral and intervertebral disc abnormalities. Mean age at evaluation was 11 years (range 5-30, median 8). Cervical spine MRI was abnormal in all the patients and the most frequent abnormalities found were dens hypoplasia (100%), periodontoid thickening (100%), disc abnormalities (100%) and spinal stenosis (43%). There was no clear correlation between MRI findings and patients' phenotypes. PMID- 25721853 TI - Continuous cardiac output measurement by un-calibrated pulse wave analysis and pulmonary artery catheter in patients with septic shock. AB - Septic shock is a serious medical condition. With increased concerns about invasive techniques, a number of non-invasive and semi-invasive devices measuring cardiac output (CO) have become commercially available. The aim of the present study was to determine the accuracy, precision and trending abilities of the FloTrac and the continuous pulmonary artery catheter thermodilution technique determining CO in septic shock patients. Consecutive septic shock patients were included in two centres and CO was measured every 4 h up to 48 h by FloTrac (APCO) and by pulmonary artery catheter (PAC) using the continuous (CCO) and intermittent (ICO) technique. Forty-seven septic shock patients with 326 matched sets of APCO, CCO and ICO data were available for analysis. Bland and Altman analysis revealed a mean bias +/-2 SD of 0.0 +/- 2.14 L min(-1) for APCO-ICO (%error = 34.5 %) and 0.23 +/- 2.55 L min(-1) for CCO-ICO (%error = 40.4 %). Trend analysis showed a concordance of 85 and 81 % for APCO and CCO, respectively. In contrast to CCO, APCO was influenced by systemic vascular resistance and by mean arterial pressure. In septic shock patients, APCO measurements assessed by FloTrac but also the established CCO measurements using the PAC did not meet the currently accepted statistical criteria indicating acceptable clinical performance. PMID- 25721854 TI - Docetaxel, cisplatin, and fluorouracil for patients with inoperable recurrent or metastatic head and neck squamous cell carcinoma. AB - OBJECTIVE: The first-line treatment for inoperable recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has long been the combination of cisplatin and fluorouracil (PF). Recently, cetuximab has been shown to provide an additional survival benefit to PF. It remains unknown whether docetaxel adds additional benefits to PF. Therefore, we sought to evaluate the efficacy and toxicity of docetaxel, cisplatin, and fluorouracil (TPF) for inoperable recurrent or metastatic HNSCC. METHODS: A retrospective chart review from January 2005 to March 2013 identified patients who were treated with docetaxel 60 mg/m(2) on day 1, followed by cisplatin 60 mg/m(2) on day 1, and fluorouracil 600 mg/m(2)/day on days 1-5 (modified TPF) every 4 weeks for inoperable recurrent or metastatic HNSCC. RESULTS: Twenty-four patients were identified; seven and five patients had locoregional disease only and distant metastasis only, respectively, while 12 patients had locoregional disease and distant metastasis simultaneously. Of the 17 patients with distant metastasis, multiple organs were affected in 9 patients, with the most frequently affected organ being the lung (n=11). Three patients had no prior treatment, whereas 21 patients underwent intensive prior treatment. In 17 of 21 patients who had received prior treatment, the treatment included chemoradiotherapy and/or chemotherapy. The median number of cycles of modified TPF was two (range, 1-5). One patient showed complete response, four patients showed partial response, two patients had stable disease, and 17 patients had progressive disease. Overall, the rate of objective response was 21%, with a 95% confidence interval (CI) of 9-40%. Median overall survival was 8.0 months (95%CI, 4.4-10.6 months). The treatment efficacy differed significantly according to extent of disease. Objective response in patients with distant metastasis alone was better than in patients with locoregional disease with or without distant metastasis (60% vs. 11%, respectively; P=0.02). Median overall survival in the former patients was longer than in the latter patients (not reached vs. 7.0 months, respectively; P=0.02). Fifteen patients (63%) had Grades 3-4 neutropenia, and seven patients (29%) developed Grade 3 febrile neutropenia. There were no toxic deaths. CONCLUSION: The efficacy of modified TPF in the setting of first line treatment for recurrent or metastatic HNSCC is not very high, while the toxicity is acceptable with extensive care. The development of more efficacious chemotherapeutic regimen is required. PMID- 25721855 TI - Powder wettability at a static air-water interface. AB - The reconstitution of a beverage from a dehydrated powder involves several physical mechanisms that determine the practical difficulty to obtain a homogeneous drink in a convenient way and within an acceptable time for the preparation of a beverage. When pouring powder onto static water, the first hurdle to overcome is the air-water interface. We propose a model to predict the percentage of powder crossing the interface in 45 s, namely the duration relevant for this application. We highlight theoretically the determinant role of the contact angle and of the particle size distribution. We validate experimentally the model for single spheres and use it to predict the wettability performance of commercial food powders for different contact angles and particles sizes. A good agreement is obtained when comparing the predictions and the wettability of the tested powders. PMID- 25721856 TI - Preparation of core-shell mesoporous silica nanoparticles with bimodal pore structures by regrowth method. AB - Core-shell structured mesoporous silica nanoparticles (MSNs) with different pore characteristics in the cores and shells have been prepared by the regrowth method. Adding a silica source to a dispersion of presynthesized silica surfactant composite nanoparticles with two-dimensional hexagonal mesostructures results in regrowth in preference to generation of new particles. Core-shell MSNs with bimodal porosities are easily obtained by adding a pore-expanding agent, 1,3,5-trimethylbenzene, in either the core or shell formation step. Detailed characterization of the core-shell MSNs reveals that the shells consist of disordered arrangements of relatively large or small pores and that the pore sizes in the cores change when the shells formed. Core-shell MSNs will be useful for controlling the release rates of the encapsulated guest molecules and for protecting internal pores from being plugged by other species. PMID- 25721857 TI - Abatement of aqueous anionic contaminants by thermo-responsive nanocomposites: (poly(N-isopropylacrylamide))-co-silylanized magnesium/aluminun layered double hydroxides. AB - A series of novel thermo-responsive composite sorbents, were prepared by free radical co-polymerization of N-isopropylacrylamide (NIPAm) and the silylanized Mg/Al layered double hydroxides (SiLDHs), named as PNIPAm-co-SiLDHs. For keeping the high affinity of Mg/Al layered double hydroxides towards anions, the layered structure of LDHs was assumed to be reserved in PNIPAm-co-SiLDHs by the silanization of the wet LDH plates as evidenced by the X-ray powder diffraction. The sorption capacity of PNIPAm-co-SiLDH (13.5 mg/g) for Orange-II from water was found to be seven times higher than that of PNIPAm (2.0mg/g), and the sorption capacities of arsenate onto PNIPAm-co-SiLDH are also greater than that onto PNIPAm, for both As(III) and As(V). These sorption results suggest that reserved LDH structure played a significant role in enhancing the sorption capacities. NO3(-) intercalated LDHs composite showed the stronger sorption capacity for Orange-II than that of CO3(2-). After sorption, the PNIPAm-co-SiLDH may be removed from water because of its gel-like nature, and may be easily regenerated contributing to the accelerated desorption of anionic contaminants from PNIPAm-co SiLDHs by the unique phase-transfer feature through slightly heating (to 40 degrees C). These recyclable and regeneratable properties of thermo-responsive nanocomposites facilitate its potential application in the in-situ remediation of organic and inorganic anions from contaminated water. PMID- 25721858 TI - Effect of charge balance and dosage of polyelectrolyte complexes on the shear resistance of mineral floc strength and reversibility. AB - We evaluated the effect of polyelectrolyte complexes (PEC) with varying balance of charges on the flocculation of precipitated calcium carbonate (PCC) particles. PECs composed of polyacrylamides carrying opposite charges (A-PAM and C-PAM) were investigated in terms of PCC floc shear resistance and re-flocculation effects. Light transmission was used in real time to monitor the dynamics of flocculation under shear fields. Compared to the single polyelectrolytes, PECs greatly enhanced particle re-flocculation while minor differences in shear resistance were observed. Shear resistance and re-flocculation depended strongly on the molecular weight and charge ratio of the PEC components. In order to achieve floc stability and re-flocculation conditions a minimum concentration of charge asymmetric PEC should be applied. PMID- 25721859 TI - Highly efficient, long life, reusable and robust photosynthetic hybrid core-shell beads for the sustainable production of high value compounds. AB - An efficient one-step process to synthesize highly porous (Ca-alginate-SiO2 polycation) shell: (Na-alginate-SiO2) core hybrid beads for cell encapsulation, yielding a reusable long-life photosynthetically active material for a sustainable manufacture of high-value metabolites is presented. Bead formation is based on crosslinking of an alginate biopolymer and mineralisation of silicic acid in combination with a coacervation process between a polycation and the silica sol, forming a semi-permeable external membrane. The excellent mechanical strength and durability of the monodispersed beads and the control of their porosity and textural properties is achieved by tailoring the silica and alginate loading, polycation concentration and incubation time during coacervation. This process has led to the formation of a remarkably robust hybrid material that confers exceptional protection to live cells against sheer stresses and contamination in a diverse range of applications. Dunaliella tertiolecta encapsulated within this hybrid core-shell system display high photosynthetic activity over a long duration (>1 year). This sustainable biotechnology could find use in high value chemical harvests and biofuel cells to photosynthetic solar cells (energy transformation, electricity production, water splitting technologies). Furthermore the material can be engineered into various forms from spheres to variable thickness films, broadening its potential applications. PMID- 25721860 TI - Green synthesis of Pd/CuO nanoparticles by Theobroma cacao L. seeds extract and their catalytic performance for the reduction of 4-nitrophenol and phosphine-free Heck coupling reaction under aerobic conditions. AB - We report the green synthesis of palladium/CuO nanoparticles (Pd/CuO NPs) using Theobroma cacao L. seeds extract and their catalytic activity for the reduction of 4-nitrophenol and Heck coupling reaction under aerobic conditions. The catalyst was characterized using the powder XRD, TEM, EDS, UV-vis and FT-IR. This method has the advantages of high yields, elimination of surfactant, ligand and homogeneous catalysts, simple methodology and easy work up. The catalyst can be recovered from the reaction mixture and reused several times without any significant loss of catalytic activity. PMID- 25721861 TI - A Telephone- and Text Message-Based Telemedicine Concept for Patients with Mental Health Disorders: Results of a Randomized Controlled Trial. AB - Background: A telemedicine care concept based on telephone contacts and individualized text messages was developed for patients with mental disorders to continue treatment after therapy in a psychiatric day hospital. The primary objective of this study was to evaluate the effectiveness of the telemedicine interventions. Methods: The study had a 3-armed, randomized design with 2 intervention arms (intervention 1: telephone contacts; intervention 2: telephone contacts and short text messages; both took place over a period of 6 months and in addition to usual care), and a control group with usual care. Primary outcomes were 18-item Brief Symptom Inventory (BSI-18) scores for anxiety, depression and somatization. All participants were recruited from psychiatric day hospitals. The study was registered in the German Clinical Trials Register (DRKS00000662). Results: 113 participants were analyzed 6 months after starting the intervention. The average BSI-18 anxiety score after 6 months was -2.04 points lower in intervention group 2 than in the control group (p value: 0.042). The difference in BSI depression score between these two groups was marginally significant (p value: 0.1), with an average treatment effect of -1.73. In an exploratory sensitivity analysis restricted to the 75% of patients with the highest symptom scores at baseline, intervention group 1 yielded a significant effect for anxiety and depression compared to the control group (p = 0.036 and 0.046, respectively). Conclusions: Telemedicine provides a novel option in psychiatric ambulatory care with statistically significant effects on anxiety. A positive tendency was observed for depression, especially in cases with higher symptom load at baseline. (c) 2015 S. Karger AG, Basel. PMID- 25721862 TI - Synthesis of phenstatin/isocombretastatin-chalcone conjugates as potent tubulin polymerization inhibitors and mitochondrial apoptotic inducers. AB - A series of phenstatin/isocombretastatin-chalcones were synthesized and screened for their cytotoxic activity against various human cancer cell lines. Some representative compounds exhibited significant antiproliferative activity against a panel of sixty human cancer cell lines of the NCI, with GI50 values in the range of 0.11 to 19.0 MUM. Three compounds (3b, 3c and 3e) showed a broad spectrum of antiproliferative efficacy on most of the cell lines in the sub micromolar range. In addition, all the synthesized compounds (3a-l and 4a-l) displayed moderate to excellent cytotoxicity against breast cancer cells such as MCF-7 and MDA-MB-231 with IC50 values in the range of 0.5 to 19.9 MUM. Moreover, the tubulin polymerization assay and immunofluorescence analysis results suggest that some of these compounds like 3c and 3e exhibited significant inhibitory effect on the tubulin assembly with an IC50 value of 0.8 MUM and 0.6 MUM respectively. A competitive binding assay suggested that these compounds bind at the colchicine-binding site of tubulin. A cell cycle assay revealed that these compounds arrest at the G2/M phase and lead to apoptotic cell death. Furthermore, this was confirmed by Hoechst 33258 staining, activation of caspase 9, DNA fragmentation, Annexin V-FITC and mitochondrial membrane depolarization. Molecular docking studies indicated that compounds like 3e occupy the colchicine binding site of tubulin. PMID- 25721863 TI - Effectiveness of type formula on clinical and nutritional statues in ICU trauma patients in an Iranian population. PMID- 25721864 TI - The relationship between immediate preoperative serum 25-hydroxy-vitamin D3 levels and cardiac function, dysglycemia, length of stay, and 30-d readmissions in cardiac surgery patients. AB - OBJECTIVES: Vitamin D has pleiotropic effects on cardiac, renal, and endocrine diseases like diabetes mellitus and deficiency has been correlated with increased Intensive Care Unit (ICU) morbidity and mortality. We studied the relationship between preoperative Vitamin D levels and several short-term endpoints including cardiovascular events, glucose levels, ICU, and hospital length of stay. METHODS: Standard demographic data were obtained. Blood samples were drawn for 25-hydroxy vitamin D3 (Vit D) levels at baseline (just before induction of anesthesia) and on postoperative day (POD #1). The number of inotropes used on POD # 0, 1, and 2 was recorded as well as the Cardiac Index (CI). Baseline glucose, Blood Urea Nitrogen and Creatinine (Cr) levels were obtained and repeated on POD # 1 & 2. Other variables studied are number of days of ICU and hospital stay. RESULTS: Of the 64 patients included in the cohort, 3 were excluded because of inadequate data. 69% had Vit D levels <20 ng/mL and 31% had levels >=20 ng/mL. More than 90% of the cohort had a significant decrease in POD # 1 Vit D levels (P < 0.001). Age, sex, race, and body mass index did not predict the preoperative Vit D levels; however, the timing of surgery was associated with preoperative Vit D levels, lowest in subjects who had surgery performed during winter. Preoperative Vit D levels had no effect on postoperative glycemic control, cardiac index, or composite outcome-arrhythmias, respiratory failure, or prolonged inotropic support. On regression analysis, preoperative Vit D levels did show a significant effect on ICU and hospital length of stay in this cohort. CONCLUSIONS: The low levels in this study truly represent the Vit D status as they were obtained before any intervention, including surgery or fluid administration. Vit D levels decreased rapidly after surgery and hence future studies on Vit D may need to focus on premorbid levels obtained at the time of initial presentation and not those obtained after resuscitation or ICU admission. In contrast to epidemiologic reports, we found no association between low Vit D levels and postoperative cardiovascular events. However, low Vit D levels did affect the ICU and hospital length of stay in patients who were undergoing cardiac surgery. This is an important finding especially when many institutions and regulatory agencies are investigating novel therapies and processes to reduce the length of hospitalization. More studies are required to investigate the effect on hospital length of stay of early preadmission or preoperative Vit D supplementation before elective surgery. PMID- 25721865 TI - Invasion rather than nuclear features correlates with outcome in encapsulated follicular tumors: further evidence for the reclassification of the encapsulated papillary thyroid carcinoma follicular variant. AB - The prognosis of the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) and its relationship to encapsulated follicular carcinoma (EFC) and follicular adenoma (FA) is subject to controversy. All EFVPTCs, EFCs, and FAs identified at a single institution between 1981 and 2003 were analyzed microscopically. A cohort of FAs from a different hospital was also examined. EFVPTCs were subdivided into noninvasive EFVPTC (NIEFVPTC) and invasive EFVPTC (IEFVPTC) displaying capsular/vascular invasion. There were 83 EFVPTCs (57 noninvasive, 26 invasive), 14 EFCs, and 52 FAs. Similar to FA, over a median follow-up of 9.5 years, none of the NIEFVPTCs manifested lymph node metastasis (LNM) or recurred. Furthermore, with a median follow-up of 10.5 years, none of 39 NIEFVPTCs without radioactive iodine therapy recurred. Four (15%) of 26 IEFVPTCs and none of 14 EFCs harbored distant metastasis (P = .29). There was no difference in LNM rate and degree of vascular or capsular invasion between IEFVPTC and EFC (P > .1). All 4 IEFVPTCs with adverse behavior presented with distant metastasis and no LNM. Sixteen percent of IEFVPTCs had poor outcome, whereas there was none in the NIEFVPTCs (P = .007). In conclusion, NIEFVPTC seems to behave similarly to FA, whereas IEFVPTC can metastasize and spread like EFC. Thus, invasion rather than nuclear features drives outcome in encapsulated follicular tumors. Non-IEFVPTC could be treated in a conservative manner sparing patients unnecessary total thyroidectomy and radioactive iodine therapy. The position of the EFVPTC in the classification of thyroid neoplasia should be reconsidered. PMID- 25721866 TI - A Randomized, Double-Blind, Parallel-Group, Multicenter Clinical Study of Escherichia coli-Lyophilized Lysate for the Prophylaxis of Recurrent Uncomplicated Urinary Tract Infections. AB - BACKGROUND: One strategy for managing recurrent uncomplicated urinary tract infections (UTIs) is prevention. This study tested OM-89S, a lyophilized lysate of 18 Escherichia coli strains manufactured using a modified lytic process. METHODS: This was a randomized, double-blind trial in 451 female subjects with recurrent uncomplicated UTIs. Period 1 of the study tested 6 mg of OM-89S versus placebo (3 months), plus a 3-month observation. Period 2 of the study was a 3 month treatment period (each monthly cycle consisted of 6 mg of OM-89S daily for 10 days and placebo for 20 days, vs. 50 mg nitrofurantoin daily for 30 days), plus a 3-month observation. RESULTS: There was no difference in the mean rate of UTI episodes between the OM-89S (0.66 +/- 0.93) and placebo groups (0.63 +/- 0.86; p = 0.95) in period 1. Similar findings were obtained for period 2. OM-89S was well-tolerated. CONCLUSIONS: Our results did not demonstrate a preventive effect of OM-89S compared to placebo. This may be due to the low number of UTIs that occurred during the study, the high number of protocol violations, and/or the modified manufacturing process used for OM-89S. PMID- 25721867 TI - Nanocluster of superparamagnetic iron oxide nanoparticles coated with poly (dopamine) for magnetic field-targeting, highly sensitive MRI and photothermal cancer therapy. AB - In this paper, a core-shell nanocomposite of clusters of superparamagnetic iron oxide nanoparticles coated with poly(dopamine) (SPION clusters@PDA) is fabricated as a magnetic field-directed theranostic agent that combines the capabilities of highly sensitive magnetic resonance imaging (MRI) and photothermal cancer therapy. The highly concentrated SPION cluster core is suitable for sensitive MRI due to its superparamagnetic properties, and the poly(dopamine) coating layer can induce cancer cell death under near-infrared (NIR) laser irradiation because of the photothermal conversion ability of PDA. MRI scanning reveals that the nanocomposite has relatively high r2 and r2(*) relaxivities, and the r2(*) values are nearly threefold higher than the r2 values because of the clustering of the SPIONs in the nanocomposite core. Due to the rapid response to magnetic field gradients, enhanced cellular uptake of our nanocomposite mediated by an external magnetic field can be achieved, thus producing significantly enhanced local photothermal killing efficiency against cancer cells under NIR irritation. PMID- 25721868 TI - Impact of autophagy inhibition at different stages on cytotoxic effect of autophagy inducer in glioblastoma cells. AB - BACKGROUND/AIMS: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a poor prognosis. Combination treatment of autophagy inducer and autophagy inhibitor may be a feasible solution to improve the therapeutic effects. However, the correlation between them is unclear. The purpose of this study was to investigate the effect of autophagy inhibition at different stages on cytotoxicity of autophagy inducers in glioblastoma cells. METHODS: Autophagy inhibition at early stage was achieved by 3-methyladenine (3-MA) or Beclin 1 shRNA. Autophagy inhibition at late stage was achieved by chloroquine (CQ) or Rab7 shRNA. Cell viability was assessed by MTT assay. Autophagy was measured using transmission electron microscopy and western blot. Apoptosis was measured using western blot and flow-cytometry. RESULTS: Inhibition of early steps of autophagy by 3-MA or Beclin 1 knockdown decreased the toxic effect of arsenic trioxide (ATO) in GBM cell lines. In contrast, blockade of autophagy flux at late stage by CQ or Rab7 knockdown enhanced the cytotoxicity of ATO, and caused accumulation of degradative autophagic vacuoles and robust apoptosis. Moreover, depletion of Beclin 1 abolished the synergistic effect of ATO and CQ by reducing autophagy and apoptosis. Combination of CQ with other autophagy inducers also induced synergistic apoptotic cell death. CONCLUSION: These results suggest that inhibition of late process of autophagy, not initial step, increases the cytotoxic effect of autophagy inducers via autophagy and apoptosis, which may contribute to GBM chemotherapy. PMID- 25721869 TI - Resveratrol Inhibits Proliferation and Induces Apoptosis of Pathological Scar Fibroblasts Through the Mechanism Involving TGF-beta1/Smads Signaling Pathway. AB - The objective of this study was to determine the effect of resveratrol (Res) treatment on pathological scar fibroblasts and the changes in TGF-beta1/Smads signaling pathway. For this purpose, cultured pathological scar fibroblasts were treated with various concentrations of Res (10, 50, and, 100 umol/l), and the morphological changes in target cells were studied using scanning electron microscopy (SEM). The cellular proliferation was assessed by MTT assay; the mRNA and protein expressions of TGF-beta1 and Smad-2,3,4,7 were determined by reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence assay, respectively. We found that Res-treated fibroblasts exhibited the typical apoptotic morphological changes. As shown by MTT assay, the OD values of Res treated fibroblasts, as a measure of cell growth, were significantly lower than those of controls (P < 0.05). In addition, as compared to controls, TGF-beta1 and Smad-2,3,4 mRNA/protein expression decreased but those of Smad7 increased in a dose-dependent manner (P < 0.05). It was, therefore, concluded that Res treatment inhibited the pathological scar fibroblast proliferation and induced cell apoptosis through the mechanism involving downregulation of TGF-beta1, Smad 2,3,4, and upregulation of Smad7. PMID- 25721870 TI - Arsenic Trioxide and Icariin Show Synergistic Anti-leukemic Activity. AB - Although As2O3 (ATO) has been recommended as the front-line agent for treatment of acute promyelocytic leukemia (APL), particularly for relapsed or refractory APL, it has been associated with profound toxicity. Icariin is a natural compound with activity against a variety of cancers. This study was designed to investigate the effect of Icariin on APL cells and to determine whether Icariin can potentiate the antitumor activity of ATO in APL cells. Cell proliferation and apoptosis were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis and proliferation-related molecules was detected by Western blotting. Reactive oxygen species (ROS) and mitochondrial membrane potential were determined with florescence staining. Icariin inhibited proliferation in a dose-dependent manner and induced apoptosis in both of the tested APL cell lines. Icariin enhanced the in vitro antitumor activity of ATO against APL. The antitumor activity of Icariin and its enhancement of the antitumor activity of ATO correlated with the increase in accumulation of intracellular ROS. Our results showed that Icariin, by increasing intracellular ROS, exhibited antitumor activity and potentiated the antitumor activity of ATO against APL. Therefore, combination treatment with Icariin and ATO might offer a novel therapeutic option for patients with APL, although further studies are needed. PMID- 25721871 TI - Dimethyl fumarate suppresses Theiler's murine encephalomyelitis virus-induced demyelinating disease by modifying the Nrf2-Keap1 pathway. AB - Dimethyl fumarate (DMF) is a modifier of the nuclear factor (erythroid-derived 2) 2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) pathway. DMF treatment in the effector phase significantly suppressed the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) both clinically and histologically. DMF treatment leads to an enhanced Nrf2 antioxidant response in TMEV-IDD mice. DMF treatment in the effector phase significantly suppressed the level of IL-17A mRNA. DMF is known to inhibit differentiation of T helper 17 (Th17) cells via suppressing NF-kappaB. Taken together, our data suggest that DMF treatment in the effector phase may suppress TMEV-IDD not only via enhancing the antioxidant response but also via suppressing IL-17A. PMID- 25721872 TI - Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young. AB - Mutations in the insulin (INS) gene rarely occur in patients with Maturity-Onset Diabetes of the Young (MODY). We aimed to describe in detail two MODY families with INS mutations. The INS gene was screened by direct sequencing. The probands and their affected relatives underwent a mixed-meal test. Mutation predictions were modeled using I-TASSER and were visualized by Swiss-PdbViewer. A novel heterozygous frameshift mutation p.Gln78fs in the INS gene was found in three generations of patients with clinically distinct diabetes. The single nucleotide deletion (c.233delA) is predicted to change and prolong amino acid sequence, resulting in aberrant proinsulin without native structures of C-peptide and A chain. In the second family, the heterozygous mutation c.188-31G>A within the terminal intron was detected. The mother and her daughter were misdiagnosed as having type 1 diabetes since the ages of 6 and 2 years, respectively. This result is in contrast to the previously described carrier of the same mutation who was diagnosed with permanent neonatal diabetes. We identified a novel coding frameshift mutation and an intronic mutation in the INS gene leading to childhood onset diabetes. INS mutations may result in various phenotypes, suggesting that additional mechanisms may be involved in the pathogenesis and clinical manifestation of diabetes. PMID- 25721873 TI - Novel nonsense mutation in the PTRF gene underlies congenital generalized lipodystrophy in a consanguineous Saudi family. AB - Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare, monogenic disorders characterized by loss of sub-cutaneous fat, muscular hypertrophy, acanthosis nigricans, hepatomegaly, cardiac arrhythmias, impaired metabolism and mental retardation. Four different but overlapping phenotypes (CGL1-4) have been identified, which are caused by mutations in AGPAT2 at 9q34.3, BSCL2 at 11q13, CAV1 at 7q31.1, and PTRF at 17q21.2. In this study, we performed genome-wide homozygosity mapping of two affected and one unaffected subject in a Saudi family using a 300K HumanCytoSNPs12v12.1 array with the Illumina iScan system. A common homozygous region at chromosome 17q22.1, from 34.4 to 45.3 Mb, was identified in both the affected individuals. The region is flanked by SNPs rs139433362 and rs185263326, which encompass the PTRF gene. Bidirectional DNA sequencing of the PTRF gene covering all of the coding exons and exon-intron boundaries was performed in all family members. Sequencing analysis identified a novel homozygous nonsense mutation in the PTRF gene (c.550G>T; p.Glu184*), leading to a premature stop codon. To the best of our knowledge, we present a novel mutation of PTRF from Saudi Arabia and our findings broaden the mutation spectrum of PTRF in the familial CGL4 phenotype. Homozygosity mapping coupled with candidate gene sequencing is an effective tool for identifying the causative pathogenic variants in familial cases. PMID- 25721874 TI - A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family. AB - In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (>= 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44. IN CONCLUSION: the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable. PMID- 25721875 TI - Identification and characterization of enolase as a collagen-binding protein in Lactobacillus plantarum. AB - Collagen is a target of pathogens for adhesion, colonization, and invasion of host tissue. Probiotic bacteria can mimic the same mechanism as used by the pathogens in the colonization process, expressing cell surface proteins that specifically interact with extracellular matrix component proteins. The capability to bind collagen is expressed by several Lactobacillus isolates, including some Lactobacillus plantarum strains. In this study we report the involvement of the L. plantarum EnoA1 alfa-enolase in type I collagen (CnI) binding. By adhesion assays, we show that the mutant strain LM3-CC1, carrying a null mutation in the enoA1 gene, binds to immobilized collagen less efficiently than wild type strain. CnI overlay assay and Elisa tests, performed on the purified EnoA1, show that this protein can bind collagen both under denaturing and native conditions. By using truncated recombinant enolase proteins, we also show that the region spanning from 73rd to the 140th amino acid residues is involved in CnI binding. PMID- 25721876 TI - APOBEC3H polymorphisms associated with the susceptibility to HIV-1 infection and AIDS progression in Japanese. AB - Human APOBEC3H (A3H) is a member of APOBEC3 cytidine deaminase family that potently restricts HIV-1 replication. Because A3H is genetically divergent with different intracellular stability and anti-HIV-1 activity in vitro, we investigated a possible association of A3H with susceptibility to HIV-1 infection and disease progression in Japanese populations. A total of 191 HIV-1-infected individuals (HIV group), 93 long-term non-progressors to AIDS (LTNP group) and 421 healthy controls were genotyped for two functional APOBEC3H polymorphisms, rs139292 and rs139297. As compared with the controls, minor allele frequency (MAF) for rs139292 was high in the HIV group (MAF in cases vs. controls; 0.322 vs. 0.263, odds ratio (OR) = 1.33, 95% confidence interval (95% CI) = 1.02-1.74, p = 0.035) and low in the LTNP group (0.161 vs. 0.263, OR = 0.54, 95% CI = 0.36 0.82, p = 0.004, pc = 0.007), whereas the MAF for rs139297 was high in the HIV group (0.367 vs. 0.298, OR = 1.36, 95% CI = 1.07-1.76, p = 0.017, pc = 0.035). In addition, haplotype analyses revealed that the frequencies of A3H-hapC and -hapA were high (0.322 vs. 0.262, OR = 1.33, 95% CI = 1.02-1.74, p = 0.003) and low (0.634 vs. 0.697, OR = 0.75, 95 % CI = 0.58-0.97, p = 0.002), respectively, in the HIV group, whereas the frequencies of A3H-hapC and -hapB were low (0.161 vs. 0.262, OR = 0.54, 95% CI = 0.36-0.82, p = 0.00003) and high (0.097 vs. 0.040, OR = 2.55, 95% CI = 1.40-4.62, p = 0.000008), respectively, in the LTNP group, as compared with those in the controls. These observations suggest that the A3H with low anti-HIV-1 activity, A3H-hapC, is associated with the susceptibility to HIV-1 infection, whereas the A3H producing a stable protein, A3H-hapB, may confer a low risk of disease progression to AIDS. PMID- 25721877 TI - V genes in primates from whole genome sequencing data. AB - The adaptive immune system uses V genes for antigen recognition. However, the evolutionary diversification and selection processes within and across species and orders remain poorly understood. Here, we studied the amino acid (AA) sequences obtained from the translated in-frame V exons of immunoglobulins (IG) and T cell receptors (TR) from 16 primate species whose genomes have been sequenced. Multi-species comparative analysis supports the hypothesis that V genes in the IG loci undergo birth/death processes, thereby permitting rapid adaptability over evolutionary time. We also show that multiple cladistic groupings exist in the TRA (35 clades) and TRB (25 clades) V gene loci and that each primate species typically contributes at least one V gene to each of these clades. The results demonstrate that IG V genes and TR V genes have quite different evolutionary pathways; multiple duplications can explain the IG loci results, while coevolutionary pressures can explain the phylogenetic results of the TR V gene loci. Our results suggest that there exist evolutionary relationships between V gene clades in the TRA and TRB loci. Due to the long standing preservation of these clades, such genes may have specific and necessary roles for the viability of a species. PMID- 25721878 TI - Personality dimensions and emotional problems: the mediating role of irrational beliefs in Pakistani adult non-clinical sample. AB - This study presents the first examination of the relation between the Big Five personality traits, irrational beliefs and emotional problems in Pakistan, which is an understudied country in the psychological distress literature. A total of 195 participants (aged 25-60 years), employees at COMSATS University, completed a demographic information sheet, the Big Five Personality Questionnaire, the Irrational Belief Inventory and two subscales of the Brief Symptom Inventory including depression and anxiety. Direct effects of neuroticism, openness and conscientiousness were also observed for depression and anxiety. Structural Equation Modelling demonstrated that irrational beliefs played a significant mediating role in the relationship between neuroticism and anxiety and neuroticism and depression. The results highlight the importance of cognitive beliefs in functionally linking personality traits and emotional problems. PMID- 25721879 TI - The beneficial effect of Tai Chi on self-concept in adolescents. AB - Previous research has documented the beneficial effect of Tai Chi, but most of the studies focused on elders and patients with specific health conditions. The aim of the study was to test whether Tai Chi can help to improve self-concept in adolescents with a longitudinal study. The sample comprised 160 students from a Chinese middle school; half of students formed the experimental group and the rest formed the control group. A 1-year Tai Chi intervention was delivered in 60 minute sessions, five times a week. Both groups were instructed to complete the measure of self-concept at the beginning and end of the intervention. Statistical analysis shows the significant reduction of good behaviour, intellectual and school status, popularity and anxiety in the experimental group compared with the control group. The results suggest that the Tai Chi intervention could improve self-concept in adolescents. PMID- 25721880 TI - Testing crossover effects in an actor-partner interdependence model among Chinese dual-earner couples. AB - The purpose of the present study is to examine the crossover effects from one partner's work-family interface (work-family conflict [WFC] and work-family enrichment [WFE]) to the other partner's four outcomes (psychological strain, life satisfaction, marital satisfaction and job satisfaction) in a sample of Chinese dual-earner couples. Married couples (N = 361) completed a battery of questionnaires, including the work-family interface scale, the psychological strain scale, the life, marital, as well as job satisfaction scale. Results from the actor-partner interdependence model (APIM) analyses showed that wives' WFE was negatively associated with husbands' psychological strain, and positively associated with husbands' life, marital and job satisfaction. Furthermore, husbands' WFC was negatively related to wives' marital satisfaction, whereas husbands' WFE was positively related to wives' marital satisfaction. Theoretical and practical implications were discussed, and future research directions were provided. PMID- 25721881 TI - Self-esteem mediates the relationship between spirituality and subjective well being in Iran. AB - Self-esteem appears to play a central role in the spiritual life and ethical behaviour of the typical Iranian. For example, for many Iranians, humankind is believed to be the crown of creation, and each person is believed to be individually valued by God. Previous empirical studies also indicate that in Iran spirituality is positively associated with self-esteem. On this basis, it was hypothesised that self-esteem would be one of the mechanisms through which spirituality leads to increased mental well-being. Mediation analysis showed that self-esteem was a partial mediator of the spirituality-well-being relationship. Moreover, results of moderated mediation analysis revealed that this mediation was not significantly moderated by gender, and that the indirect path through self-esteem was significant in both genders. Implications of the results and their relevance to other western and eastern religions (e.g. Christianity and Buddhism) are discussed. PMID- 25721882 TI - Corrigendum: A stable binary BeB2 phase. PMID- 25721883 TI - Autoimmune Response to IGF2 mRNA-Binding Protein 2 (IMP2/p62) in Breast Cancer. AB - The purpose of this study was to understand the autoimmune response and immunogenicity of a tumour-associated antigen IMP2/p62 in breast cancer. Autoantibody responses to IMP2/p62 were evaluated by enzyme-linked immunosorbent assay (ELISA), Western blotting and indirect immunofluorescence assay in sera from patients with breast cancer, benign breast tumour and normal human individuals. Immunohistochemistry (IHC) study with breast cancer tissues was also performed to analyse protein expression of IMP2/p62. The results have demonstrated that IMP2/p62 can induce a relatively higher frequency of autoantibody response in breast cancer (14.3%, 7/49) compared to patients with benign breast tumour (5.6%, 2/36) and normal individuals (2.2%, 1/44). The frequency of IMP2/p62 expression in breast cancer tissues was significantly higher than that in normal tissues (P < 0.01). The data suggest that autoantibody against IMP2/p62 may be a useful serum biomarker for early-stage breast cancer screening and diagnosis. PMID- 25721885 TI - Perceived Expectations for Active Aging, Formal Productive Roles, and Psychological Adjustment Among the Young-Old. AB - We investigated how older adults' perceptions of societal expectations for active aging, or activation demands (e.g., to stay fit and to contribute to the public good), relate to their involvement in paid work and formal volunteering and psychological adjustment. We used two waves of survey data on young-old Germans (aged 56-75, N(T1) = 1,508, N(T2) = 602). With the exception of several items on perceived activation demands, paid work and volunteering were not significant longitudinal predictors of such demands. In females, perceived activation demands increased the likelihood to work for pay a year later. Finally, among nonworking individuals, perceived activation demands predicted a better physical self concept and a higher positive affect, whereas among nonvolunteers, such demands predicted fewer depressive symptoms a year later. We conclude that the policy debate on active aging may benefit some older German adults but is of little consequence for most of them. PMID- 25721886 TI - Abstracts of the SIR 2015 Annual Scientific Meeting, February 28-March 5, 2015, Atlanta, GA. PMID- 25721887 TI - Iron bioavailability in 8-24-month-old Thai children from a micronutrient fortified quick-cooking rice containing ferric ammonium citrate or a mixture of ferrous sulphate and ferric sodium ethylenediaminetetraacetic acid. AB - A quick-cooking rice, produced from broken rice, is a convenient ingredient for complementary foods in Thailand. The rice is fortified with micronutrients including iron during the processing procedure, which can cause unacceptable sensory changes. A quick-cooking rice fortified with ferric ammonium citrate (FAC) or a mixture of ferrous sulphate (FeSO4 ) and ferric sodium ethylenediaminetetraacetic acid (NaFeEDTA), with a 2:1 molar ratio of iron from FeSO4 : iron from NaFeEDTA (FeSO4 + NaFeEDTA), gave a product that was organoleptically acceptable. The study compared iron absorption by infants and young children fed with micronutrient-fortified quick-cooking rice containing the test iron compounds or FeSO4 . Micronutrient-fortified quick-cooking rice prepared as a traditional Thai dessert was fed to two groups of 15 8-24-month healthy Thai children. The iron fortificants were isotopically labelled with (57) Fe for the reference FeSO4 or (58) Fe for the tested fortificants, and iron absorption was quantified based on erythrocyte incorporation of the iron isotopes 14 days after feeding. The relative bioavailability of FAC and of the FeSO4 + NaFeEDTA was obtained by comparing their iron absorption with that of FeSO4 . Mean fractional iron absorption was 5.8% [+/-standard error (SE) 1.9] from FAC and 10.3% (+/-SE 1.9) from FeSO4 + NaFeEDTA. The relative bioavailability of FAC was 83% (P = 0.02). The relative bioavailability of FeSO4 + NaFeEDTA was 145% (P = 0.001). Iron absorption from the rice containing FAC or FeSO4 + NaFeEDTA was sufficiently high to be used in its formulation, although iron absorption from FeSO4 + NaFeEDTA was significantly higher (P < 0.00001). PMID- 25721888 TI - Nuclear envelope proteins Nesprin2 and LaminA regulate proliferation and apoptosis of vascular endothelial cells in response to shear stress. AB - The dysfunction of vascular endothelial cells (ECs) influenced by flow shear stress is crucial for vascular remodeling. However, the roles of nuclear envelope (NE) proteins in shear stress-induced EC dysfunction are still unknown. Our results indicated that, compared with normal shear stress (NSS), low shear stress (LowSS) suppressed the expression of two types of NE proteins, Nesprin2 and LaminA, and increased the proliferation and apoptosis of ECs. Targeted small interfering RNA (siRNA) and gene overexpression plasmid transfection revealed that Nesprin2 and LaminA participate in the regulation of EC proliferation and apoptosis. A protein/DNA array was further used to detect the activation of transcription factors in ECs following transfection with target siRNAs and overexpression plasmids. The regulation of AP-2 and TFIID mediated by Nesprin2 and the activation of Stat-1, Stat-3, Stat-5 and Stat-6 by LaminA were verified under shear stress. Furthermore, using Ingenuity Pathway Analysis software and real-time RT-PCR, the effects of Nesprin2 or LaminA on the downstream target genes of AP-2, TFIID, and Stat-1, Stat-3, Stat-5 and Stat-6, respectively, were investigated under LowSS. Our study has revealed that NE proteins are novel mechano-sensitive molecules in ECs. LowSS suppresses the expression of Nesprin2 and LaminA, which may subsequently modulate the activation of important transcription factors and eventually lead to EC dysfunction. PMID- 25721889 TI - Management of reflux esophagitis: does the choice of proton pump inhibitor matter? AB - BACKGROUND: Proton pump inhibitors (PPIs) are the treatment of choice for reflux esophagitis (RE). The effectiveness of PPIs throughout RE management, from healing to maintenance, has not been fully studied. AIM: To compare esomeprazole with lansoprazole or pantoprazole for RE management using a management model. METHODS: Data from six studies comparing esomeprazole with lansoprazole or pantoprazole for healing (4-8 weeks) or maintenance of healing (6 months) of RE were incorporated into hypothetical management models to determine the proportion of patients in endoscopic remission after sequential healing and maintenance therapy, assuming that patients received the same PPI throughout. The number needed to treat (NNT) to achieve one more patient in remission with esomeprazole vs. other PPIs was estimated. The hypothetical model was validated using results from the EXPO study, which compared esomeprazole with pantoprazole for RE healing and maintenance. RESULTS: Overall, esomeprazole 40 mg produced higher rates of healing (life-table estimates) than lansoprazole 30 mg (82.4-92.6% vs. 77.5 88.8%; p < 0.01) or pantoprazole 40 mg (95.5% vs. 92.0%; p < 0.001) and higher rates of endoscopic and symptomatic remission at 6 months than lansoprazole (83.0 84.8% vs. 74.0-75.9%; p < 0.001; life-table estimates) or pantoprazole (70.9% vs. 59.6%; p < 0.0001; observed rates). In the hypothetical management model, the NNT for esomeprazole was 9 vs. lansoprazole and 8 vs. pantoprazole. The actual NNT for esomeprazole vs. pantoprazole in the EXPO study was 9 (95% confidence interval: 6; 16). CONCLUSIONS: In this management model, esomeprazole was more effective than either lansoprazole or pantoprazole for maintaining remission after sequential healing and 6 months' maintenance therapy for RE. PMID- 25721891 TI - Universal ocular screening of 1021 term infants using wide-field digital imaging in a single public hospital in India - a pilot study. AB - PURPOSE: Universal eye screening of neonates is currently not standard of care. Early detection of abnormalities could offer prompt management and a reduction in visual morbidity. We report a pilot study using wide-field digital imaging to screen all infants at birth to explore its feasibility as a tool for universal screening. METHODS: Consecutively enrolled 1021 term infants in a public hospital were imaged within 72 hr of birth using the Retcam shuttle (Clarity MSI, USA). Anterior and dilated posterior segment images were obtained. Infants with abnormal images were examined clinically, and medical or surgical treatment was given when needed, at no cost to the family. RESULTS: Of the 1021 healthy full term newborns, 48 babies had abnormal findings (4.7%). Retinal haemorrhages were the most common (52.1%) abnormality of which 24% were macular. A 'ridge' resembling retinopathy of prematurity in both eyes constituted 18.8% of all abnormalities. Nine infants (18.8% of abnormalities and 0.9% overall) had conditions meriting medical or surgical intervention and would have been missed otherwise. Seven of these nine babies (0.7%) needed medical attention with a systemic work-up for conditions such as posterior uveitis with linear perivasculitis, salt and pepper retinopathy or posterior synechia. Two of nine babies (0.2%) required surgical intervention for unilateral cataract and retinoblastoma. CONCLUSION: Universal eye screening of all neonates using wide field digital imaging is possible and safe. Extrapolating our results to the national scenario, we estimate that 226 950 infants requiring treatment would go undiagnosed annually. Universal infant eye imaging strategies must receive serious national consideration. PMID- 25721890 TI - Neurophysiological models for new treatment development in schizophrenia: early sensory approaches. AB - Schizophrenia is a major mental disorder associated with core neurocognitive impairments. The ability to recreate these deficits in animal models is limited, hampering ongoing translational drug development efforts. This paper reviews the use of electroencephalography (EEG)-based neurophysiological measures, such as event-related potentials (ERPs) or event-related spectral perturbations (ERSPs), as novel translational biomarkers for both etiological and treatment development research in neuropsychiatry. In schizophrenia, cognitive impairments manifest as deficits not only in high-level processes, such as working memory or executive processing, but also as deficits in neurophysiological responses to simple auditory and visual stimuli. Moreover, neurophysiological responses can be assessed even in untrained animals and are therefore particularly amenable to translational, cross-species investigation. To date, several sensory-level ERP measures, including auditory mismatch negativity and N1, and visual P1 and steady state responses, have been validated in both human clinical investigations and animal models. Deficits have been tied to impaired neurotransmission at N-methyl d-aspartate-type glutamate receptors (NMDARs). Time-frequency analysis of ERSP permits further extension of these findings from physiological to circuit/cellular levels of analysis. PMID- 25721892 TI - Apoptotic effects of dillapiole on maturation of mouse oocytes, fertilization and fetal development. AB - Previously, we reported that dillapiole, a phenylpropanoid with antileishmanial, anti-inflammatory, antifungal and acaricidal activities, is a risk factor for normal embryonic development that triggers apoptotic processes in the inner cell mass of mouse blastocysts, leading to impaired embryonic development and cell viability. In the current study, we investigated the deleterious effects of dillapiole on mouse oocyte maturation, in vitro fertilization (IVF) and subsequent pre- and post-implantation development, both in vitro and in vivo. Notably, dillapiole induced significant impairment of mouse oocyte maturation, decrease in the IVF rate and inhibition of subsequent embryonic development in vitro. Pre-incubation of oocytes with dillapiole during in vitro maturation led to an increase in post-implantation embryo resorption and decrease in mouse fetal weight. In an in vivo animal model, 2.5, 5 or 10 MUM dillapiole provided in drinking water caused a decrease in oocyte maturation and IVF, and led to deleterious effects on early embryonic development. Importantly, pre-incubation of oocytes with a caspase-3-specific inhibitor effectively blocked dillapiole triggered deleterious effects, clearly implying that embryonic injury induced by dillapiole is mediated via a caspase-dependent apoptotic mechanism. To the best of our knowledge, this is the first study to establish the impact of dillapiole on maturation of mouse oocytes, fertilization and sequential embryonic development. PMID- 25721893 TI - Characterization of Atypical Preeclampsia. AB - OBJECTIVE: To characterize patients with atypical preeclampsia (PE), in relation to socio-demographic characteristics, clinical presentation, maternal complications and perinatal outcome. MATERIALS AND METHODS: Between July 1, 2011 and November 30, 2013, a cohort was created of women attended at a Obstetric High dependency Unit who met criteria for atypical PE: gestational hypertension with severe hypertension or symptoms or laboratory signs suggestive of microangiopathy/hemolysis; normotensive proteinuria with the presence of symptoms or laboratory signs suggestive of microangiopathy/hemolysis; presence of PE or eclampsia or HELLP syndrome appearing after 48 h postpartum, and, PE or eclampsia appearing before 20 weeks of pregnancy. RESULTS: A total of 200 women fulfilling criteria for atypical PE, were included: 61.5% corresponded to non-proteinuric gestational hypertension, 35.5% to normotensive proteinuria and 3% to PE/eclampsia in late postpartum. Criteria for severe maternal morbidity were present in 12% of the cases and there were no maternal deaths. There were 6 perinatal deaths. CONCLUSION: Atypical preeclampsia is a type of preeclampsia not fully recognized that is associated with maternal and neonatal morbidity, mainly related to smallness-for-gestational-age and low birth weight. Vasospasm symptoms are a key element to detect this condition. PMID- 25721894 TI - Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate. AB - Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2 (-/-)) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2 (-/-) mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation. PMID- 25721895 TI - Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM). AB - A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS. PMID- 25721896 TI - CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. AB - Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML. PMID- 25721897 TI - Phase I/II trial of lenalidomide and high-dose melphalan with autologous stem cell transplantation for relapsed myeloma. PMID- 25721899 TI - 3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes. AB - Genomically distal mutations can contribute to the deregulation of cancer genes by engaging in chromatin interactions. To study this, we overlay viral cancer causing insertions obtained in a murine retroviral insertional mutagenesis screen with genome-wide chromatin conformation capture data. Here we find that insertions tend to cluster in 3D hotspots within the nucleus. The identified hotspots are significantly enriched for known cancer genes, and bear the expected characteristics of bona fide regulatory interactions, such as enrichment for transcription factor-binding sites. In addition, we observe a striking pattern of mutual exclusive integration. This is an indication that insertions in these loci target the same gene, either in their linear genomic vicinity or in their 3D spatial vicinity. Our findings shed new light on the repertoire of targets obtained from insertional mutagenesis screening and underline the importance of considering the genome as a 3D structure when studying effects of genomic perturbations. PMID- 25721898 TI - A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase mutant chronic myeloid leukemia. AB - Targeted therapy of chronic myeloid leukemia (CML) is currently based on small molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CC(mut3), which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CC(mut3) exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CC(mut3) inhibits colony formation by primary CML CD34(+) cells ex vivo, including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies. PMID- 25721900 TI - Effects of Food-Derived Collagen Peptides on the Expression of Keratin and Keratin-Associated Protein Genes in the Mouse Skin. AB - Oral ingestion of collagen peptides (CP) has long been suggested to exert beneficial effects on the skin, but the molecular events induced by CP on the skin remain unclear. Here, we investigated the effects of oral CP administration on gene expression in hairless mouse skin and of prolyl-hydroxyproline (Pro-Hyp), a collagen-derived dipeptide, on gene expression in a coculture of mouse skin keratinocytes and fibroblasts. Using microarray analysis, we found that oral administration of CP to hairless mice for 6 weeks induced increased expression of Krtap and Krt genes in the skin. Annotation analysis using DAVID revealed that a group of the up-regulated genes, Gprc5d, Sprr2a1, Krt27 and Krtap16-7, is associated with the development of the epidermis and the hair cycle. In addition, the presence of Pro-Hyp (200 MUM) induced an increase in the expression of Krtap16-7, Krtap15, Krtap14 and Krtap8-2 in keratinocytes in coculture, partially resembling the in vivo result. The Pro-Hyp-induced up-regulation of these genes was not observed when keratinocytes were cultured without fibroblasts, suggesting that the presence of fibroblasts is essential for the effects of Pro-Hyp. Our study presents new insights into the effects of CP on the skin, which might link to the hair cycle. PMID- 25721901 TI - Low-dose steroid after thymectomy in myasthenia gravis: is it a complete solution for postoperative respiratory insufficiency? PMID- 25721903 TI - Persistent major molecular response to nilotinib therapy in a patient with chronic myeloid leukemia harboring ABL gene T315I mutation. PMID- 25721904 TI - High resolution single nucleotide polymorphism array reveals cryptic indicating information about myelodysplastic syndrome-related myeloid malignancies. PMID- 25721902 TI - Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. AB - Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL (#) . With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n = 109) and FC (n = 118), respectively (p < 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p = 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p = 0.002, p < 0.001), Rai stage (p = 0.006, p = 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p < 0.0001, p = 0.005, respectively), trisomy 12 with mutated Notch1 (p = 0.003, p = 0.03, respectively) and unmutated IGHV (p = 0.009, p = 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL. PMID- 25721905 TI - Seismological evidence for a non-monotonic velocity gradient in the topmost outer core. AB - The Earth's core is mostly an Fe-Ni alloy with a fraction of light elements (~10 wt%, mainly O, S and Si). Accumulation of these light elements under the core mantle boundary (CMB) may lead to chemical stratification. Seismic observations have been presented both for and against the stratification in the topmost region of the outer core. Here we investigate the structure under the CMB using differential travel times between SKKS and S3KS waves. We obtain 606 high-quality S3KS-SKKS differential travel times with global path coverage. Result from a Bayesian inversion of these differential times indicates that the seismic velocity in the top 800 km of the outer core is ~0.07% on average lower than that in model PREM. The depth-dependent velocity profile, in particular a low-velocity zone of up to ~0.25% lower than PREM at ~80 km below the CMB, strongly favors the existence of stratification at the top of the outer core. PMID- 25721906 TI - Time-lapse systems for embryo incubation and assessment in assisted reproduction. AB - BACKGROUND: Embryo incubation and assessment is a vital step in assisted reproductive technology (ART). Traditionally, embryo assessment has been achieved by removing embryos from a conventional incubator daily for assessment of quality by an embryologist, under a light microscope. Over recent years time-lapse systems (TLSs) have been developed which can take digital images of embryos at frequent time intervals. This allows embryologists, with or without the assistance of computer algorithms, to assess the quality of the embryos without physically removing them from the incubator.The potential advantages of a TLS include the ability to maintain a stable culture environment, therefore limiting the exposure of embryos to changes in gas composition, temperature and movement. Additionally a TLS has the potential advantage of improving embryo selection for ART treatment by utilising additional information gained through monitoring embryo development. OBJECTIVES: To determine the effect of a TLS compared to conventional embryo incubation and assessment on clinical outcomes in couples undergoing ART. SEARCH METHODS: A comprehensive search of all the major electronic databases, including grey literature, was undertaken in co-ordination with the Trials Search Co-ordinator of the Cochrane Menstrual Disorders and Subfertility Group in July 2014 and repeated in November 2014 to confirm that the review is up to date. SELECTION CRITERIA: Two authors (SA and NA) independently scanned the titles and abstracts of the articles retrieved by the search. Full texts of potentially eligible randomised controlled trials (RCTs) were obtained and examined independently by the authors for their suitability according to the review inclusion criteria. In the case of doubt between the two authors, a third author (LC) was consulted to gain consensus. The selection process is documented with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart. DATA COLLECTION AND ANALYSIS: Data were obtained and extracted by two authors. Disagreement was resolved by consensus. Trial authors were contacted by e-mail to obtain further study information and data. All extracted data were dichotomous outcomes and odds ratios (OR) were calculated on an intention-to-treat basis. Where enough data were available, meta-analysis was undertaken. MAIN RESULTS: Three studies involving 994 women were found for inclusion. Data from all three studies were used to address comparison one, TLS with or without cell-tracking algorithms versus conventional incubation. No studies were found to address comparison two, TLS utilising cell-tracking algorithms versus TLS not utilising cell-tracking algorithms.There was only one study which reported live birth (n = 76). The results demonstrated no conclusive evidence of a difference in live birth rate per couple randomly assigned to the TLS and conventional incubation arms of the study (OR 1.1, 95% CI 0.45 to 2.73, 1 RCT, n = 76, moderate quality evidence).All three studies reported miscarriage (n = 994). There was no conclusive evidence of a difference in miscarriage rates per couple randomly assigned to the TLS and conventional incubation arms (OR 0.70, 95% CI 0.47 to 1.04, 3 RCTs, n = 994, I(2) = 0%, low quality evidence).Only one study reported stillbirth rates (n = 76). There were equal numbers of stillbirths in both the TLS and conventional incubation arms of the study. Therefore, there was no evidence of a difference in the stillbirth rate per couple randomly assigned to TLS and conventional incubation (OR 1.0, 95% CI 0.13 to 7.49, 1 RCT, moderate quality evidence).All three studies reported clinical pregnancy rates (n = 994). There was no conclusive evidence of a difference in clinical pregnancy rate per couple randomly assigned to the TLS and conventional incubation arms (OR 1.23, 95% CI 0.96 to 1.59, 3 RCTs, n = 994, I(2) = 0%, low quality evidence). None of the included studies reported cumulative clinical pregnancy rates. AUTHORS' CONCLUSIONS: There is insufficient evidence of differences in live birth, miscarriage, stillbirth or clinical pregnancy to choose between TLS and conventional incubation. Further data explicitly comparing the incubation environment, the algorithm for embryo selection, or both, are required before recommendations for a change of routine practice can be justified. PMID- 25721907 TI - Ebola crisis has alerted politicians to global health threats, debate hears. PMID- 25721908 TI - Parallel confocal microscopy using high-order axially symmetric polarized beams. AB - A novel scheme of parallel confocal microscopy using high-order axially symmetric polarized beams (ASPBs) is proposed. The basic concept of ASPBs is introduced first, then the principle of the scheme is presented, finally some numerical results are shown to verify the feasibility of the scheme. Seen from the results, multiple imaging spots are obtained and the size of spots is about 70% of the spot size in the single lens microscopy, and a kind of high temporal and spatial resolution parallel confocal microscopy is achieved, which may find wide applications in the fields of 3D profile measurement and biomedical imaging. PMID- 25721909 TI - New method for the determination of bile acids in human plasma by liquid-phase microextraction using liquid chromatography-ion-trap-time-of-flight mass spectrometry. AB - Bile acids (BAs) are derived from cholesterol and produced in the liver. The most abundant bile acids in humans are usually conjugated with glycine and taurine and are divided into primary BAs such as cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BAs like deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA). The differences amongst individual bile acids (BAs) are significant in order to distinguish different pathological processes and exposure to chemical compounds. Hollow fiber based liquid-phase microextraction (HF-LPME) is a technique that combines sample cleansing, extraction and the concentration of analytes, where a hydrophobic porous capillary membrane is impregnated with an organic extraction solvent and the lumen is filled with microliters of a phase acceptor both organic by nature. The aim of this study was to develop a new method to extract bile acids from plasma through HF-LPME of two phases (octanol as the acceptor phase) using LCMS-IT-TOF. The optimized two phased LPME procedure for the extraction of bile acids showed limits of detection 1.0 MUg L(-1) and limits of quantification of 5.0 MUg L(-1). The intra-assay precision ranged from 2.1 to 11.9%. The method developed was linear over the range of 5.0-200.0 MUg L(-1) for all analytes. The hollow-fiber liquid-phase microextraction method was applied to human plasma from workers exposed to organic and halogenated solvents and also to unexposed volunteers. The method is simple, low cost and it does not require large amounts of organic solvents, therefore it is quite suitable for the analysis of bile acids exposed to hepatotoxic compounds. PMID- 25721910 TI - Hemoglobinopathy in India. AB - OBJECTIVES: Variations in hemoglobin structure as well as number of globin chains give rise to a wide spectrum of heritable disorders. As such, their detection is significant from epidemiological perspective, especially in India in which there is a large multi-cultural population with distinct geographic distribution. Although a few variants present severe clinical symptoms in homozygotes, co existence of heterozygous mutants can lead to deleterious conditions. The aim of the present study is to provide an overview on the prevalence of different hemoglobinopathies among Asian Indians. DESIGN AND METHODS: A large cohort of samples from all regions of India was analyzed by high performance liquid chromatography (HPLC) (n=25,297) and capillary electrophoresis (CE) (n=21,219). RESULTS: Using HPLC, 8029 hemoglobin variants were detected. HbS trait was detected at the highest frequency (33.03%), principally from the Chattisgarh region. Using CE, 6524 variants were detected. HbS trait, again, represented the most common mutation (25.67%). A total of 40 variants including compound heterozygous cases were detected by HPLC and CE. CONCLUSIONS: Our report is one of the few to analyze a large cohort and report on the spectrum of hemoglobin variants in India. PMID- 25721911 TI - Evaluation of entomopathogenic nematodes and the supernatants of the in vitro culture medium of their mutualistic bacteria for the control of the root-knot nematodes Meloidogyne incognita and M. arenaria. AB - BACKGROUND: The suppressive effects of various formulations of four entomopathogenic nematode (EPN) species and the supernatants of their mutualistic bacteria on the root-knot nematodes (RKNs) Meloidogyne incognita and M. arenaria in tomato roots were evaluated. The EPNs Steinernema carpocapsae, S. feltiae, S. glaseri and Heterorhabditis bacteriophora were applied as either live infective juveniles (IJs) or infected insect cadavers. Spent medium from culturing the bacterial symbionts Xenorhabdus bovienii and Photorhabdus luminescens kayaii with the cells removed was also applied without their nematode partners. RESULTS: The aqueous suspensions of IJs, infected cadaver applications of EPNs and especially treatments of X. bovienii supernatant suppressed the negative impact of RKNs on tomatoes. Specific responses to treatment were reduced RKN egg masses, increased plant height and increased fresh and dry weights compared with the control where only RKNs were applied. CONCLUSION: Among the treatments tested, the plant dipping method of X. bovienii into bacterial culture fluid may be the most practical and effective method for M. incognita and M. arenaria control. PMID- 25721912 TI - Continuous-flow system and monitoring tools for the dielectrophoretic integration of nanowires in light sensor arrays. AB - Although nanowires (NWs) may improve the performance of many optoelectronic devices such as light emitters and photodetectors, the mass commercialization of these devices is limited by the difficult task of finding reliable and reproducible methods to integrate the NWs on foreign substrates. This work shows the fabrication of zinc oxide NWs photodetectors on conventional glass using transparent conductive electrodes to effectively integrate the NWs at specific locations by dielectrophoresis (DEP). The paper describes the careful preparation of NW dispersions by sedimentation and the dielectrophoretic alignment of NWs in a home-made system. This system includes an impedance technique for the assessment of the alignment quality in real time. Following this procedure, ultraviolet photodetectors based on the electrical contacts formed by the DEP process on the transparent electrodes are fabricated. This cost-effective mean of contacting NWs enables front-and back-illumination operation modes, the latter eliminating shadowing effects caused by the deposition of metals. The electro optical characterization of the devices shows uniform responsivities in the order of 106 A W(-1) below 390 nm under both modes, as well as, time responses of a few seconds. PMID- 25721913 TI - Deep Invasive Endometriosis Lesions of the Rectosigmoid May Be Related to Alterations in Cell Kinetics. AB - OBJECTIVES: The aim of this study was to analyze cell kinetics through expression and apoptosis of topoisomerase 2-alpha (TOP2A), p53, and c-erb2 in rectosigmoid endometriotic lesions and in healthy endometrial tissue and to establish correlations between such findings and clinical data in patients with rectosigmoid endometriosis. METHODS: Sixty patients with rectosigmoid endometriosis and 20 control women without endometriosis were included. Immunohistochemical assays were used to measure expression of TOP2A, p53, and c erB-2. Apoptosis was quantified by directly counting the apoptotic bodies. FINDINGS: The number of lesions was positively correlated with expression of TOP2A in the lesion. There was also significant correlation between the lesions' size and number and cell turnover index. Apoptosis index (AI) was the same for endometriosis lesions and eutopic endometrium. Expression of TOP2A was significantly lower in the endometriosis group compared to the controls. CONCLUSIONS: Changes in cell proliferation but not in the AI in rectosigmoid endometriosis are indicative of an imbalance in cell kinetics that may lead to the development of the disease. PMID- 25721914 TI - Correlation of urine and plasma cytokine levels among reproductive-aged women. AB - BACKGROUND: Inflammation is implicated in many adverse health conditions, and recent interest has focused on the effects of chronic low-grade inflammation in generally healthy populations. Cytokines measured in plasma or serum are commonly used as biomarkers of systemic levels of inflammation. Measurement of cytokines in urine may offer a simpler and less invasive alternative, although the degree to which levels of cytokines correlate in plasma and urine among healthy individuals is unknown. MATERIALS AND METHODS: We assessed the correlation of blood and urine levels of 13 cytokines, including interleukin (IL)-1b, IL-2, IL 4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70) and IL-13, granulocyte macrophage colony-stimulating factor, interferon gamma and tumour necrosis factor alpha in 61 healthy women aged 18-30. Cytokine concentrations were considered with and without correction for creatinine. RESULTS: Plasma and urine levels of the 13 cytokines were not significantly correlated using measured urinary cytokine concentrations and after adjustment for creatinine. Correlation coefficients for log-transformed cytokine concentrations in paired plasma and urine specimens ranged from -0.28 to 0.087. CONCLUSIONS: These results suggest that urine has limited utility as a proxy for plasma for the measurement of inflammatory factors in a healthy population with low levels of inflammation. PMID- 25721915 TI - The Three-Month Effect of Mobile Internet-Based Cognitive Therapy on the Course of Depressive Symptoms in Remitted Recurrently Depressed Patients: Results of a Randomized Controlled Trial. AB - Background: Internet-based cognitive therapy with monitoring via text messages (mobile CT), in addition to treatment as usual (TAU), might offer a cost effective way to treat recurrent depression. Method: Remitted patients with at least 2 previous episodes of depression were randomized to mobile CT in addition to TAU (n = 126) or TAU only (n = 113). A linear mixed model was used to examine the effect of the treatment condition on a 3-month course of depressive symptoms after remission. Both an intention-to-treat analysis (n = 239) and a completer analysis (n = 193) were used. Depressive symptoms were assessed using the Inventory of Depressive Symptomatology (IDS-SR30) at baseline and 1.5 and 3 months after randomization. Results: Residual depressive symptoms showed a small but statistically significant decrease in the intention-to-treat group over 3 months in the mobile CT group relative to the TAU group (difference: -1.60 points on the IDS-SR30 per month, 95% CI = -2.64 to -0.56, p = 0.003). The effect of the treatment condition on the depressive symptomatology at the 3-month follow-up was small to moderate (Cohen's d = 0.44). All analyses among completers (>=5 modules) showed more pronounced treatment effects. Adjustment for unequally distributed variables did not markedly affect the results. Conclusions: Residual depressive symptoms after remission showed a more favorable course over 3 months in the mobile CT group compared to the TAU group. These results are a first indication that mobile CT in addition to TAU is effective in treating recurrently depressed patients in remission. However, demonstration of its long-term effectiveness and replication remains necessary. (c) 2015 S. Karger AG, Basel. PMID- 25721916 TI - Newborn infants detect cues of concurrent sound segregation. AB - Separating concurrent sounds is fundamental for a veridical perception of one's auditory surroundings. Sound components that are harmonically related and start at the same time are usually grouped into a common perceptual object, whereas components that are not in harmonic relation or have different onset times are more likely to be perceived in terms of separate objects. Here we tested whether neonates are able to pick up the cues supporting this sound organization principle. We presented newborn infants with a series of complex tones with their harmonics in tune (creating the percept of a unitary sound object) and with manipulated variants, which gave the impression of two concurrently active sound sources. The manipulated variant had either one mistuned partial (single-cue condition) or the onset of this mistuned partial was also delayed (double-cue condition). Tuned and manipulated sounds were presented in random order with equal probabilities. Recording the neonates' electroencephalographic responses allowed us to evaluate their processing of the sounds. Results show that, in both conditions, mistuned sounds elicited a negative displacement of the event-related potential (ERP) relative to tuned sounds from 360 to 400 ms after sound onset. The mistuning-related ERP component resembles the object-related negativity (ORN) component in adults, which is associated with concurrent sound segregation. Delayed onset additionally led to a negative displacement from 160 to 200 ms, which was probably more related to the physical parameters of the sounds than to their perceptual segregation. The elicitation of an ORN-like response in newborn infants suggests that neonates possess the basic capabilities of segregating concurrent sounds by detecting inharmonic relations between the co-occurring sounds. PMID- 25721917 TI - Interleukin-6 is a better metabolic biomarker than interleukin-18 in young healthy adults. PMID- 25721918 TI - Adequate timely treatment of patent ductus arteriosus in extremely low birth weight infants: an ongoing challenge. PMID- 25721919 TI - Evaluation of fibrin sealant as a wound closure agent in mandibular third molar surgery--a prospective, randomized controlled clinical trial. AB - The aim of this randomized controlled trial was to assess the effectiveness of fibrin sealants in achieving haemostasis and wound closure following mandibular third molar extraction, in comparison with conventional suturing. Thirty patients with bilateral mandibular third molar impactions were recruited for the study. Using a split-mouth study design, wound closure following extraction was done using fibrin sealant on the study side and suturing on the control side. Sample allocation was done by simple randomization. The primary outcome measures were (1) the time taken to achieve wound closure and haemostasis and (2) postoperative mouth opening, pain, and swelling. Data analysis involved descriptive statistics and paired t-tests (P<0.05). IBM SPSS software (v.20.0) was used for the data analysis. The study group demonstrated a statistically significant reduction in duration to achieve haemostasis (1.2 vs. 251.9s; P<0.001) and wound closure (152.8 vs. 328.8s; P<0.001) in comparison with the control group. The study group also exhibited significantly reduced pain scores (2.0 vs. 3.5; P<0.001) and increased post-surgical mouth opening (P<0.001). No adverse effects of fibrin sealant were observed. In conclusion, fibrin sealant is a superior intraoral wound closure and haemostatic agent and a worthy alternative to suturing. PMID- 25721920 TI - The rotational genioplasty: a modified technique for patients with obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is a serious condition that can be the cause of a number of systemic symptoms and conditions. The diagnosis of OSA is made by clinical and radiological examination, with polysomnography as the gold standard for recording the severity of the disorder. Among the many therapies offered for OSA, maxillomandibular advancement is recognized as a powerful technique for relieving upper airway obstruction. The upper airway may be further opened by an advancement genioplasty, but this may compromise facial aesthetics by over projecting the chin prominence. To overcome this difficulty, a modified genioplasty is presented. This is designed to enable a rotational repositioning that allows for advancement of the genioglossus attachments but also avoids an excessive projection of pogonion, which would otherwise result in an unfavourable profile. PMID- 25721921 TI - Outbreak of swine flu in India is no worse than seasonal flu, say specialists. PMID- 25721922 TI - Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort. AB - Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. PMID- 25721923 TI - Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. AB - Hyperimmunoglobulinemia D syndrome (HIDS) is an autoinflammatory disorder that is caused by mevalonate kinase deficiency (MKD). Recent advances in the pathogenesis of MKD, including the proposed mechanisms of inflammasome activation, provide the basis for the development of new treatment modalities. So far, feedback on the treatment of HIDS with biological medicines has come from case reports with limited numbers of patients. In this review, we summarize the data that is currently available on the treatment of HIDS in children, with the emphasis on new therapies, and present three Finnish pediatric cases treated with anakinra. Case reports have been published on 33 pediatric HIDS patients who have been treated with biological medicines, and in some cases, they were treated with more than one drug. Of these patients, 21 were treated with anakinra and 16 with etanercept, resulting in complete or partial responses in 90 and 50% of cases, respectively. A further five patients were treated with canakinumab, with complete or partial responses. CONCLUSION: The accumulating evidence on the efficacy and safety of biological drugs in pediatric HIDS suggests that the anti interleukin-1 agent anakinra is the drug of choice for HIDS in children. WHAT IS KNOWN: * Various biologic drugs have been tried for the treatment of HIDS. What is New: * Based on the 90% response rate, anakinra seems to be the drug of choice for HIDS in children. PMID- 25721924 TI - Relationship between epicardial adipose tissue thickness and early impairment of left ventricular systolic function in patients with preserved ejection fraction. AB - Epicardial adipose tissue (EAT) is metabolically bioactive fat. The present study aimed to clarify the relationship between EAT amount and early impairment of left ventricular (LV) systolic function in patients with preserved ejection fraction (EF), all evaluated echocardiographically. Participants comprised 62 elderly women (mean age +/- standard deviation, 68 +/- 11 years) with lifestyle-related diseases and EF >= 60 %. EAT amount was evaluated as thickness. Parameters suggesting early impairment of systolic function such as decreases in systolic mitral annular velocity (S') and tissue mitral annular displacement percentage (TMAD %) were evaluated along with EF. Correlations between EAT thickness and these LV systolic functions were assessed. Influences of various factors on the resultant significant relationships were also assessed. EAT thickness correlated inversely with S' and TMAD % (r = -0.402, p = 0.001 and r = -0.585, p < 0.001, respectively), but did not correlate with EF (r = 0.054, not significant). These significant relationships were maintained after considering factors such as body mass index, age, presence of lifestyle-related diseases and blood test results. A significant relationship existed between EAT amount and early impairment of LV systolic function in patients with preserved EF. Accumulation of EAT might contribute to the initial development of LV systolic dysfunction. PMID- 25721925 TI - Herd factors associated with dairy cow mortality. AB - Summary studies of dairy cow removal indicate increasing levels of mortality over the past several decades. This poses a serious problem for the US dairy industry. The objective of this project was to evaluate associations between facilities, herd management practices, disease occurrence and death rates on US dairy operations through an analysis of the National Animal Health Monitoring System's Dairy 2007 survey. The survey included farms in 17 states that represented 79.5% of US dairy operations and 82.5% of the US dairy cow population. During the first phase of the study operations were randomly selected from a sampling list maintained by the National Agricultural Statistics Service. Only farms that participated in phase I and had 30 or more dairy cows were eligible to participate in phase II. In total, 459 farms had complete data for all selected variables and were included in this analysis. Univariable associations between dairy cow mortality and 162 a priori identified operation-level management practices or characteristics were evaluated. Sixty of the 162 management factors explored in the univariate analysis met initial screening criteria and were further evaluated in a multivariable model exploring more complex relationships. The final weighted, negative binomial regression model included six variables. Based on the incidence rate ratio, this model predicted 32.0% less mortality for operations that vaccinated heifers for at least one of the following: bovine viral diarrhea, infectious bovine rhinotracheitis, parainfluenza 3, bovine respiratory syncytial virus, Haemophilus somnus, leptospirosis, Salmonella, Escherichia coli or clostridia. The final multivariable model also predicted a 27.0% increase in mortality for operations from which a bulk tank milk sample tested ELISA positive for bovine leukosis virus. Additionally, an 18.0% higher mortality was predicted for operations that used necropsies to determine the cause of death for some proportion of dead dairy cows. The final model also predicted that increased proportions of dairy cows with clinical mastitis and infertility problems were associated with increased mortality. Finally, an increase in mortality was predicted to be associated with an increase in the proportion of lame or injured permanently removed dairy cows. In general terms, this model identified that mortality was associated with reproductive problems, non-infectious postpartum disease, infectious disease and infectious disease prevention, and information derived from postmortem evaluations. Ultimately, addressing excessive mortality levels requires a concerted effort that recognizes and appropriately manages the numerous and diverse underlying risks. PMID- 25721926 TI - A resected case of combined small cell lung carcinoma with carcinosarcoma. PMID- 25721929 TI - Bi- to tetravalent glycoclusters presenting GlcNAc/GalNAc as inhibitors: from plant agglutinins to human macrophage galactose-type lectin (CD301) and galectins. AB - Emerging insights into the functional spectrum of tissue lectins leads to identification of new targets for the custom-made design of potent inhibitors, providing a challenge for synthetic chemistry. The affinity and selectivity of a carbohydrate ligand for a lectin may immensely be increased by a number of approaches, which includes varying geometrical or topological features. This perspective leads to the design and synthesis of glycoclusters and their testing using assays of physiological relevance. Herein, hydroquinone, resorcinol, benzene-1,3,5-triol and tetra(4-hydroxyphenyl)ethene have been employed as scaffolds and propargyl derivatives obtained. The triazole-containing linker to the alpha/beta-O/S-glycosides of GlcNAc/GalNAc presented on these scaffolds was generated by copper-catalysed azide-alkyne cycloaddition. This strategy was used to give a panel of nine glycoclusters with bi-, tri- and tetravalency. Maintained activity for lectin binding after conjugation was ascertained for both sugars in solid-phase assays with the plant agglutinins WGA (GlcNAc) and DBA (GalNAc). Absence of cross-reactivity excluded any carbohydrate-independent reactivity of the bivalent compounds, allowing us to proceed to further testing with a biomedically relevant lectin specific for GalNAc. Macrophage galactose(-binding C)-type lectin, involved in immune defence by dendritic cells and in virus uptake, was produced as a soluble protein without/with its alpha-helical coiled coil stalk region. Binding to ligands presented on a matrix and on cell surfaces was highly susceptible to the presence of the tetravalent inhibitor derived from the tetraphenylethene-containing scaffold, and presentation of GalNAc with an alpha-thioglycosidic linkage proved favorable. Cross-reactivity of this glycocluster to human galectins-3 and -4, which interact with Tn-antigen presenting mucins, was rather small. Evidently, the valency and spatial display of alpha-GalNAc residues is a key factor to design potent and selective inhibitors for this lectin. PMID- 25721930 TI - Impact of renin-angiotensin system-targeting antihypertensive drugs on treatment of Alzheimer's disease: a meta-analysis. AB - OBJECTIVE: The impacts of renin-angiotensin system (RAS)-targeting antihypertensive drugs on Alzheimer's disease (AD) remain controversial. We performed this meta-analysis to evaluate the precise value of RAS-targeting antihypertensive drugs in terms of attenuating incidence of AD and slowing down cognitive decline in patients with AD. METHODS: A systematic literature search was conducted using PubMed, Embase, ScienceDirect and CBM (China Biology Medicine Disc) before September 2014. Studies analysing incidence of AD and cognitive changes in AD patients with RAS-targeting antihypertensive drugs were identified. The principal outcome measures were hazard ratios (HRs) for incidence of AD and standardised mean difference (SMD) for cognitive changes in AD patients. Pooled data were calculated using fixed or random effects models according to the heterogeneity. RESULTS: In total, 12 studies involving 896,410 participants met our inclusion criteria. RAS-targeting antihypertensive drugs were significantly associated with a reduced incidence rate of AD (HR 0.81, 95% CI 0.72-0.92, p = 0.001). In subgroup analysis, both angiotensin renin blockers and angiotensin converting enzyme inhibitors were shown to effectively decrease the incidence rate of AD. In the analysis of cognitive changes, a slower rate of cognitive decline was observed in AD patients with RAS-targeting antihypertensive drug (SMD 0.30, 95% CI 0.09-0.50, p = 0.004), when randomised trials and observational trials were combined. However, analysis of randomised trials alone did not show the same result (SMD 0.20, 95% CI -0.10 to 0.50, p = 0.182). CONCLUSIONS: Renin angiotensin system-targeting antihypertensive drugs may be a potential treatment for reducing the incidence and progression of AD. Further studies on RAS targeting antihypertensive drugs, especially large randomised clinical trials, should be conducted in the future. PMID- 25721931 TI - A comparison of 120 W laser photoselective vaporization versus transurethral resection of the prostate for bladder outlet obstruction by prostate cancer. AB - OBJECTIVE: To compare the mid-term outcomes of photoselective vaporization of prostate (PVP) with GreenLight HPS 120 W laser and transurethral resection of the prostate (TURP) for obstructive lower urinary tract symptoms (LUTS) in men with prostate cancer (CaP). PATIENTS AND METHODS: Seventy four patients with locally advanced (T3/T4) CaP with severe LUTS or acute urinary retention (AUR) were allocated to TURP (n = 36) or PVP (n = 38). International Prostate Symptom Scores (IPSS), maximum flow rates (Qmax) and post-void residual volumes (Vres), PSA levels, prostate volumes, complications, catheter removal and hospitalization periods were recorded. Patients were reassessed at 3, 6, and 12 months. RESULTS: The catheter removal time was significantly longer in the TURP group (3.8 +/- 1.1 vs. 1.2 +/- 0.7 days, p = 0.02), whereas failure of initial voiding trial was higher in PVP (2.7 vs. 13.1%, p = 0.01). No significant difference in IPSS, Qmax and Vres values was observed within the follow-up period between two groups. A significant difference in urethral stricture rate (8.3 vs. 0%), catheter removal time (3.8 +/- 11 vs. 1.2 +/- 0.7 days) and hospital stay (2.9 +/- 0.6 vs. 1.1 +/- 0.5 days) was observed in favor of PVP. CONCLUSIONS: Palliative PVP is very safe and effective by means of symptomatic relief in patients with locally advanced CaP. PMID- 25721932 TI - Towards efficient photoinduced charge separation in carbon nanodots and TiO2 composites in the visible region. AB - In this work, photoinduced charge separation behaviors in non-long-chain-molecule functionalized carbon nanodots (CDs) with visible intrinsic absorption (CDs-V) and TiO2 composites were investigated. Efficient photoinduced electron injection from CDs-V to TiO2 with a rate of 8.8 * 10(8) s(-1) and efficiency of 91% was achieved in the CDs-V/TiO2 composites. The CDs-V/TiO2 composites exhibited excellent photocatalytic activity under visible light irradiation, superior to pure TiO2 and the CDs with the main absorption band in the ultraviolet region and TiO2 composites, which indicated that visible photoinduced electrons and holes in such CDs-V/TiO2 composites could be effectively separated. The incident photon-to current conversion efficiency (IPCE) results for the CD-sensitized TiO2 solar cells also agreed with efficient photoinduced charge separation between CDs-V and the TiO2 electrode in the visible range. These results demonstrate that non-long chain-molecule-functionlized CDs with a visible intrinsic absorption band could be appropriate candidates for photosensitizers and offer a new possibility for the development of a well performing CD-based photovoltaic system. PMID- 25721933 TI - Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence. AB - Reproductive competence in mammals depends on the projection of gonadotropin releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic-pituitary-gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle. PMID- 25721934 TI - Palmitoyl Serine: An Endogenous Neuroprotective Endocannabinoid-Like Entity After Traumatic Brain Injury. AB - The endocannabinoid (eCB) system helps recovery following traumatic brain injury (TBI). Treatment with 2-arachidonoylglycerol (2-AG), a cerebral eCB ligand, was found to ameliorate the secondary damage. Interestingly, the fatty acid amino acid amide (FAAA) N-arachidonoyl-L-serine (AraS) exerts similar eCB dependent neuroprotective. The present study aimed to investigate the effects of the FAAA palmitoyl-serine (PalmS) following TBI. We utilized the TBI model in mice to examine the therapeutic potential of PalmS, injected 1 h following closed head injury (CHI). We followed the functional recovery of the injured mice for 28 days post-CHI, and evaluated cognitive and motor function, lesion volume, cytokines levels, molecular signaling, and infarct volume at different time points after CHI. PalmS treatment led to a significant improvement of the neurobehavioral outcome of the treated mice, compared with vehicle. This effect was attenuated in the presence of eCBR antagonists and in CB2-/- mice, compared to controls. Unexpectedly, treatment with PalmS did not affect edema and lesion volume, TNFalpha and IL1beta levels, anti-apoptotic mechanisms, nor did it exert improvement in cognitive and motor function. Finally, co-administration of PalmS, AraS and 2-AG, did not enhance the effect of the individual drugs. We suggest that the neuroprotective action of PalmS is mediated by indirect activation of the eCB receptors following TBI. One such mechanism may involve receptor palmitoylation which has been reported to result in structural stabilization of the receptors and to an increase in their activity. Further research is required in order to establish this assumption. PMID- 25721935 TI - Long-term treatment with low-molecular-weight heparin prolonged the survival time for acute pulmonary embolism patients concurrent with malignancy: an observational analysis from a long-term follow-up study. AB - BACKGROUND: As a special group in pulmonary embolism (PE), the baseline characteristics, better therapeutic strategy and prognosis of patients with concurrent malignancy need to be investigated. Long-term low-molecular-weight heparin (LMWH) is recommended for these patients, however, whether therapeutic strategy affects long-term prognosis remains unclear. METHODS: In this prospective study, acute symptomatic PE patients confirmed by imaging examinations, with/without malignancy, were enrolled and followed. Qanadli score was used to assess the embolic burden. The clinical endpoints included symptomatic recurrent venous thromboembolism (VTE), all-cause death and clinic relevant bleeding. RESULTS: In the 627 patients enrolled, 92 patients had malignancy at baseline. The median follow-up period was 36 months. The Qanadli score at baseline was lower in malignancy group than non-malignancy group (P=0.003). 48.9% of patients with malignancy died, while 11.4% of non-malignancy group died (P <0.001). Malignancy was a risk factor of death (HR 5.659, 95%CI 3.090-10.366, P <0.001). In malignancy group, 56 patients used long-term LMWH and 36 patients received oral vitamin K antagonist (VKA). The median survival time was 30 months in LMWH group, significantly longer than 12.5 months in VKA group (P=0.041). The mortality in the first 6 months was lower in LMWH group than VKA group (19.6% vs. 41.7%, P=0.022). CONCLUSIONS: PE patients with malignancy had much higher incidence of all-cause death in spite of less embolic burden compared with patients without malignancy. Anticoagulation using long-term LMWH could prolong the survival time of PE patients with malignancy, and it was more effective than VKA. PMID- 25721937 TI - On the cross-cultural trail, searching for (non)-replication. AB - In this response to the manuscript by Pilati, attribution theory as applied to motivation is first reviewed. Then shortcomings of Pilati's method and analysis are pointed out. In addition, issues concerning the significance of lack of cross cultural replication are discussed. PMID- 25721936 TI - Enhanced Pharmacokinetics of Factor VIIa as a Monomeric Fc Fusion. AB - Recombinant Factor VIIa (rFVIIa) is utilized for on-demand treatment of bleeding episodes in hemophilia patients with neutralizing antibodies (inhibitors) against Factor VIII or Factor IX, but a short half-life in the circulation (~2.5hrs) limits its use in a prophylactic setting. Recombinant FVIIa variants with improved pharmacokinetic properties may enable improved treatment and prevention of bleeding episodes in the inhibitor population. In this study we describe recombinant FVIIaFc (rFVIIaFc), a recombinant Fc-fusion protein generated to utilize the neonatal Fc receptor (FcRn)-mediated recycling pathway that protects immunoglobulin G from catabolism. On the basis of activity, rFVIIaFc exhibited a 5.5-fold extension in terminal half-life in hemophilia A mice compared to rFVIIa. The potency of rFVIIaFc was comparable to that of rFVIIa in thrombin generation assay and ROTEM. In agreement with these data, rFVIIaFc and rFVIIa showed similar acute efficacy at comparable molar doses in the tail clip bleeding model in hemophilia A mice. Taken together, these studies demonstrate enhanced pharmacokinetics and similar hemostatic properties for rFVIIaFc compared to rFVIIa. PMID- 25721938 TI - The application of the Johns Hopkins Hospital Template on urine cytology. AB - BACKGROUND: To evaluate the utility of the Johns Hopkins Hospital (JHH) template in detection of high-grade urothelial carcinoma (HGUC). METHODS: A computerized search of our laboratory information system was performed for all urine cytology cases from 2009 to 2011 processed by the SurePathTM. We included only cases with correlating surgical pathology within 6 months after the urinary samples were obtained. The original cytologic diagnoses were reclassified according to the JHH template, and these cytolog ic diagnoses were then correlated with the follow-up surgical pathology diagnoses. RESULTS: A total of 273 urine samples with histopathologic follow-up were identified. The reclassified cytologic diagnoses included negative for urothelial atypia or malignancy (NUAM) 110; atypical urothelial cells of undetermined significance (AUC-US) 83; atypical urothelial cells, cannot exclude high-grade urothelial carcinoma (AUC-H) 49; HGUC 29; and low-grade urothelial carcinoma (LGUC) 2. More than one-half of patients (58%) who had biopsy-confirmed high-grade urothelial lesions had a preceding cytologic diagnosis of AUC-H or HGUC. AUC-H and HGUC are associated with high-grade urothelial lesions in 80% and 90% of the cases and show statistical significance when compared with AUC-US or NUAM (P < 0.05). CONCLUSION: The JHH template is useful and effective in identifying patients with high-grade urothelial lesions who need to undergo cystoscopy. PMID- 25721939 TI - National trends, complications, and hospital charges in pediatric patients with Chiari malformation type I treated with posterior fossa decompression with and without duraplasty. AB - BACKGROUND: The treatment of type 1 Chiari malformation (CM-1) with posterior fossa decompression without (PFD) or with duraplasty (PFDD) is controversial. The authors analyze both options in a national sample of pediatric patients. METHODS: Utilizing the Kids' Inpatient Database, CM-1 patients undergoing PFD or PFDD from 2000 through 2009 were analyzed. RESULTS: 1,593 patients with PFD and 1,056 with PFDD were evaluated. The average age was 10.3 years, slightly younger in PFD (9.8 vs. 10.9 years, p = 0.001). PFDD patients were more likely White (81.2 vs 75.6%, p = 0.04) and less likely admitted emergently (8.4 vs. 13.8%, p = 0.007). They also underwent more reoperations (2.1 vs. 0.7%, p = 0.01), had more procedure related complications (2.3 vs. 0.8%, p = 0.003), a longer length of stay (4.4 vs. 3.8 days, p = 0.001) and higher charges (USD 35,321 vs. 31,483, p = 0.01). CONCLUSIONS: This large national study indicates that PFDD is performed more often in Caucasians, less so emergently, and associated with significantly more complications and immediate reoperations, while PFD is more frequent in those with syringomyelia and more economical, requiring fewer hospital resources. Overall, PFD is more favorable for CM-1, though it would be prudent to conduct a prospective trial, as this analysis is limited by data on preoperative presentations and long-term outcomes. PMID- 25721940 TI - Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model. AB - Augmented microfracture techniques use growth factors, cells, and/or scaffolds to enhance the healing of microfracture-treated cartilage defects. This study investigates the effect of delivering recombinant human fibroblastic growth factor 18 (rhFHF18, Sprifermin) via a collagen membrane on the healing of a chondral defect treated with microfracture in an ovine model. Eight millimeter diameter chondral defects were created in the medial femoral condyle of 40 sheep (n = 5/treatment group). Defects were treated with microfracture alone, microfracture + intra-articular rhFGF-18 or microfracture + rhFGF-18 delivered on a membrane. Outcome measures included mechanical testing, weight bearing, International Cartilage Repair Society repair score, modified O'Driscoll score, qualitative histology, and immunohistochemistry for types I and II collagen. In animals treated with 32 MUg rhFGF-18 + membrane and intra-articularly, there was a statistically significant improvement in weight bearing at 2 and 4 weeks post surgery and in the modified O'Driscoll score compared to controls. In addition, repair tissue stained was more strongly stained for type II collagen than for type I collagen. rhFGF-18 delivered via a collagen membrane at the point of surgery potentiates the healing of a microfracture treated cartilage defect. PMID- 25721942 TI - Empirical or unconscious reduction of the secondary immunosuppressive drug concomitantly with intended calcineurin inhibitor reduced exposure to improve kidney graft function can be followed by antibody mediated rejections. PMID- 25721941 TI - Neurostimulation in Alzheimer's disease: from basic research to clinical applications. AB - The development of different methods of brain stimulation provides a promising therapeutic tool with potentially beneficial effects on subjects with impaired cognitive functions. We performed a systematic review of the studies published in the field of neurostimulation in Alzheimer's disease (AD), from basic research to clinical applications. The main methods of non-invasive brain stimulation are repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Preliminary findings have suggested that both techniques can enhance performances on several cognitive functions impaired in AD. Another non-invasive emerging neuromodulatory approach, the transcranial electromagnetic treatment, was found to reverse cognitive impairment in AD transgenic mice and even improves cognitive performance in normal mice. Experimental studies suggest that high frequency electromagnetic fields may be critically important in AD prevention and treatment through their action at mitochondrial level. Finally, the application of a widely known invasive technique, the deep brain stimulation (DBS), has increasingly been considered as a therapeutic option also for patients with AD; it has been demonstrated that DBS of fornix/hypothalamus and nucleus basalis of Meynert might improve or at least stabilize cognitive functioning in AD. Initial encouraging results provide support for continuing to investigate non-invasive and invasive brain stimulation approaches as an adjuvant treatment for AD patients. PMID- 25721943 TI - Returning to emotional eating: the emotional eating scale psychometric properties and associations with body image flexibility and binge eating. AB - PURPOSE: This study tests the Emotional Eating Scale (EES) psychometric properties and correlates, and the moderator effect of body image flexibility on the association between emotional eating and binge eating. METHODS: The EES factorial structure was examined in female college students and women from the general population, through a principal component analysis and a confirmatory factor analysis. EES psychometric properties and moderation analyses were further conducted. RESULTS: The EES presented a three-factor structure-Depression, Anxiety and Anger-a good model fit, internal consistency, construct validity and temporal stability. EES was positively associated with general and eating psychopathology, binge eating, and negatively associated with mindfulness and body image flexibility. Body image flexibility moderated the association between emotional eating and binge eating. CONCLUSIONS: Findings showed that EES is a valid measure of emotional eating, and clarified the association between emotional eating and binge eating moderated by body image flexibility. PMID- 25721944 TI - We need drones, robots, and autonomous ambulances. PMID- 25721945 TI - Detection of Symptomatic Carotid Plaque Using Source Data from MR and CT Angiography: A Correlative Study. AB - BACKGROUND: Carotid plaque MRI has been a useful method to characterize vulnerable atherosclerotic plaque elements. Recent investigations have suggested that source images from CT angiography (CTA) and MR angiography (MRA) can identify the simple high-risk features of symptom-producing carotid artery plaque. We studied the correlation and relative diagnostic accuracies of CTA and MRA source images in detecting symptomatic carotid artery plaque. METHODS: Subjects were eligible if they had carotid stenosis between 50 and 99% and had MRA and CTA exams performed within 10 days of one another. We measured the soft (non-calcified) plaque and hard (calcified) plaque thickness on CTA axial source images and intraplaque high-intensity signal (IHIS) on 3D-time-of-flight MRA source images in subjects. We assessed whether a correlation existed between increasing CTA soft plaque thicknesses and the presence of MRA IHIS using the Student's t-test. We calculated the differences in sensitivity and specificity measures of CTA and MRA source-imaging data with the occurrence of recent ipsilateral stroke or transient ischemic attack (TIA) as the reference standard. We also performed logistic regression analyses to evaluate the predictive strength of plaque showing both IHIS and increased CTA soft plaque thickness in predicting symptomatic disease status. RESULTS: Of 1994 screened patients, 48 arteries met the final inclusion criteria with MRA and CTA performed within 10 days of one another. The mean and median time between CTA and MRA exams were 2.0 days and 1 day, respectively. A total of 34 of 48 stenotic vessels (70.8%) were responsible for giving rise to ipsilateral stroke or TIA. CTA mean soft plaque thickness was significantly greater (4.47 vs. 2.30 mm, p < 0.0001) in patients with MRA-defined IHIS, while CTA hard plaque thickness was significantly greater (2.09 vs. 1.16 mm, p = 0.0134) in patients without MRA evidence of IHIS. CTA soft plaque thickness measurements were more sensitive than MRA IHIS (91.2 vs. 67.6%, p = 0.011) in detecting symptomatic plaque, while differences in specificity were not significantly different (p = 0.1573). In the subset of patients with both IHIS on MRA and plaque thickness >2.4 mm on CTA, the odds ratio of detecting symptomatic plaque, corrected for stenosis severity, was 45.3 (p < 0.0005). CONCLUSIONS: Unprocessed source images from CTA and MRA, which are routinely evaluated for clinical studies demonstrate the highly correlated presence of IHIS and increasing soft plaque thickness. In particular, plaque that shows high-risk features on both MRA and CTA are very strongly associated with symptom-producing carotid plaque. With further validation, such techniques are promising practical methods of extracting risk information from routine neck angiographic imaging. PMID- 25721946 TI - Transmyocardial laser revascularization versus medical therapy for refractory angina. AB - BACKGROUND: This is an update of a review previously published in 2009. Chronic angina and advanced forms of coronary disease are increasingly more frequent. In spite of the improvement in the efficacy of available revascularization treatments, a subgroup of patients continue suffering from refractory angina. Transmyocardial laser revascularization (TMLR) has been proposed to improve the clinical situation of these patients. OBJECTIVES: To assess the effects (both benefits and harms) of TMLR versus optimal medical treatment in people with refractory angina who are not candidates for percutaneous coronary angioplasty or coronary artery bypass graft, in alleviating angina severity, reducing mortality and improving ejection fraction. SEARCH METHODS: We searched the following resources up to June 2014: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the metaRegister of Controlled Trials database, ClinicalTrials.gov, and the WHO International Clinical Trials Registry. We applied no languages restrictions. We also checked reference lists of relevant papers. SELECTION CRITERIA: We selected studies if they fulfilled the following criteria: randomized controlled trials (RCTs) of TMLR, by thoracotomy, in patients with Canadian Cardiovascular Society or New York Heart Association angina grade III-IV who were excluded from other revascularization procedures. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data for each trial about the population and interventions compared and assessed the risk of bias of the studies, evaluating randomisation sequence generation, allocation concealment, blinding (of participants, personnel and outcome assessors), incomplete outcome data, selective outcome reporting, and other potential sources of bias. MAIN RESULTS: From a total of 502 references, we retrieved 47 papers for more detailed evaluation. We selected 20 papers, reporting data from seven studies, which included 1137 participants, of which 559 were randomized to TMLR. Participants and professionals were not blinded, which suggests high risk of performance bias. Overall, 43.8% of participants in the treatment group decreased two angina classes, as compared with 14.8% in the control group: odds ratio (OR) 4.63, 95% confidence interval (CI) 3.43 to 6.25), and heterogeneity was present. Mortality by intention-to-treat analysis was similar in both groups at 30 days (4.0% in the TMLR group and 3.5% in the control group), and one year (12.2% in the TMLR group and 11.9% in the control group). However, the 30-day mortality as treated was 6.8% in the TMLR group and 0.8% in the control group (pooled OR was 3.76, 95% CI 1.63 to 8.66), mainly due to a higher mortality in participants crossing from standard treatment to TMLR. The assessment of subjective outcomes, such as improvement in angina, was affected by a high risk of bias and this may explain the differences found. Other adverse events such as myocardial infarction, arrhythmias or heart failure, were not considered in this review, as they were not predefined outcomes in trials design and they show a high inconsistency across studies. No new trials on transmyocardial laser revascularization have been published in the last ten years and it is very unlikely that new research will be undertaken in this field. AUTHORS' CONCLUSIONS: This review shows that risks associated with TMLR outweigh the potential clinical benefits. Subjective outcomes are subject to high risk of bias and no differences were found in survival, but a significant increase in postoperative mortality and other safety outcomes suggests that the procedure may pose unacceptable risks. PMID- 25721947 TI - Nemaline myopathy with KLHL40 mutation presenting as congenital totally locked-in state. AB - We report a case of nemaline myopathy with KLHL40 mutation, presenting as congenital totally locked-in state. At birth, a male patient developed hydrops fetalis, which was diagnosed based on the generalized edema and pleural effusion and could perform no significant spontaneous movements. His eyes were open, without blinking, and the eyeballs were locked in the midposition. He could not express his intentions by vocalization or moving his trunk, extremities, facial muscles, mouth, eyelids, or eyeballs in response to ambient events or personal interactions. Electrophysiological tests and neuroimaging revealed no evidence of visual or auditory impairment that might indicate a lack of sensory perception, and no evidence of impaired consciousness or intellectual disorder(s) that might prevent him from recognizing ambient events or expressing his intentions. He subsequently died at 4 years of age. Our case highlights the fact that severe congenital neuromuscular disorders can present as congenital totally locked-in state, and that special attention should be provided to these patients. PMID- 25721948 TI - Pulmonary artery diastolic pressure gradient as an indicator of severity of illness in patients with pulmonary hypertension related to left-sided heart disease. AB - INTRODUCTION: Pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is most commonly due to passive backward transmission of elevated left sided heart pressures. A subgroup of these patients develop pulmonary artery remodeling, resulting in systolic and mean pulmonary artery pressures that are 'reactive' or 'out of proportion' to the elevated left-sided heart pressures. These patients have historically been identified by a transpulmonary gradient (TPG) > 12 mmHg. However, since diastolic pulmonary artery pressures are less susceptible to changes in pulmonary blood flow, a diastolic pulmonary gradient (DPG) ? 7 mmHg may be a superior indicator of worse clinical function and prognosis. METHODS: Based on measurements from a right-heart catheterization (RHC) database (Baylor College of Medicine, Houston, TX, USA), comparisons of several clinical parameters were made among three Group 2 PH patients: normal TPG and DPG (Group 2A), elevated TPG and normal DPG (Group 2B), and elevated TPG and DPG (Group 2C). RESULTS: Among 173 RHCs, 39 were found to have Group 2 PH. Among these 39 cases, 10 (32%), 13 (32%), and 16 (36%) cases were categorized into Groups 2A, 2B, and 2C, respectively. Group 2C patients had significantly worse 6 min walk distance (308 +/- 69 m) than Group 2A (425 +/- 81 m) and Group 2B (350 +/- 103 m) (p = 0.038). There was no significant difference in cardiac output, cardiac index, and right atrial pressure among the three subgroups. DISCUSSION: Among patients with Group 2 PH, elevated DPG proved to be a more specific indicator of worse functional status than the historically used TPG. International guidelines and protocols for performing RHC for the assessment and diagnosis of PH should include the measurement of DPG. PMID- 25721949 TI - Validation of a patient-specific simulator for laparoscopic renal surgery. AB - OBJECTIVES: To describe and to validate a novel patient-specific virtual-reality based simulator for laparoscopic surgery. METHODS: Three surgeons carried out 13 preoperative simulations at Yokohama City University Hospital, Yokohama, Kanagawa, Japan, from 2011 to 2012. The procedures included seven nephrectomies, four partial nephrectomies and two pyeloplasties. We evaluated whether the anatomies reproduced by the simulator matched those encountered during the actual operations. Furthermore, the surgeons were asked to use visual analog scales (from 1 to 5; higher scores are better) to evaluate the anatomical integrity and utility of the simulations, and their intraoperative confidence during the subsequent surgical procedures. RESULTS: The simulator reproduced the patients' anatomies almost perfectly. Only a few minor mistakes were identified. Regarding the surgeons' evaluations of the system, the mean scores for the anatomical integrity and utility of the simulations, and the surgeons' intraoperative confidence were 3.4, 4.2 and 4.1, respectively. In all 13 cases, the surgeons were able to carry out preoperative training with ease, and they stated that the simulator was useful for producing preoperative images. CONCLUSIONS: A patient specific simulator for laparoscopic renal surgery has been successfully developed. This system correctly reproduces anatomical structures, and it seems to be a useful preoperative training tool. PMID- 25721951 TI - Prevalence of birth defects among American-Indian births in California, 1983 2010. AB - BACKGROUND: Approximately 6.3 million live births and fetal deaths occurred during the ascertainment period in the California Birth Defects Monitoring Program registry. American-Indian and non-Hispanic white women delivered 40,268 and 2,044,118 births, respectively. While much information has been published about non-Hispanic white infants, little is known regarding the risks of birth defects among infants born to American-Indian women. METHODS: This study used data from the California Birth Defects Monitoring Program to explore risks of selected birth defects in offspring of American-Indian relative to non-Hispanic white women in California. The study population included all live births and fetal deaths 20 weeks or greater from 1983 to 2010. Prevalence ratios and corresponding 95% confidence intervals (CI) were computed using Poisson regression for 51 groupings of birth defects. RESULTS: Prevalence ratios were estimated for 51 groupings of birth defects. Of the 51, nine had statistically precise results ranging from 0.78 to 1.85. The eight groups with elevated risks for American-Indian births were reduction deformities of brain, anomalies of anterior segments, specified anomalies of ear, ostium secundum type atrial septal defect, specified anomalies of heart, anomalies of the aorta, anomalies of great veins, and cleft lip with cleft palate. CONCLUSION: Our results suggest that American-Indian women having babies in California may be at higher risk for eight birth defect phenotypes compared with non-Hispanic whites. Further research is needed to determine whether these risks are observed among other populations of American-Indian women or when adjusted for potential covariates. PMID- 25721950 TI - Metastatic breast cancer: the potential of miRNA for diagnosis and treatment monitoring. AB - Breast cancer affects approximately 12 % women worldwide and results in 14 % of all cancer-related fatalities. Breast cancer is commonly categorized into one of four main subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) positive and basal), indicating molecular characteristics and informing treatment regimes. The most severe form of breast cancer is metastasis, when the tumour spreads from the breast tissue to other parts of the body. Significantly, the primary tumour subtype affects rates and sites of metastasis. Currently, up to 5 % of patients present with incurable metastasis, with an additional 10-15 % of patients going on to develop metastasis within 3 years of diagnosis. MicroRNAs (miRNAs) are short 21-25 long nucleotides that have been shown to significantly affect gene expression. Currently, >2000 miRNAs have been identified and significantly, specific miRNAs have been found associated with diseases states. Importantly, miRNAs are found circulating in the blood, presenting an opportunity to use these circulating disease-related miRNAs as biomarkers. Clearly, the identification of circulating miRNA specific to metastatic breast cancer presents a unique opportunity for early disease identification and for monitoring disease burden. Currently however, few groups have identified miRNA associated with metastatic breast cancer. Here, we review the literature surrounding the identification of metastatic miRNA in breast cancer patients, highlighting key areas where miRNA biomarker discovery could be beneficial, identifying key concepts, recognizing critical areas requiring further research and discussing potential problems. PMID- 25721952 TI - Factors associated with high hospital resource use in a population-based study of children with orofacial clefts. AB - BACKGROUND: Little is known about population-based maternal, child, and system characteristics associated with high hospital resource use for children with orofacial clefts (OFC) in the US. METHODS: This was a statewide, population based, retrospective observational study of children with OFC born between 1998 and 2006, identified by the Florida Birth Defects Registry whose records were linked with longitudinal hospital discharge records. We stratified the descriptive results by cleft type [cleft lip with cleft palate, cleft lip, and cleft palate] and by isolated versus nonisolated OFC (accompanied by other coded major birth defects). We used Poisson regression to analyze associations between selected characteristics and high hospital resource use (>=90th percentile of estimated hospitalized days and inpatient costs) for birth, postbirth, and total hospitalizations initiated before age 2 years. RESULTS: Our analysis included 2,129 children with OFC. Infants who were born low birth weight (<2500 grams) were significantly more likely to have high birth hospitalization costs for CLP (adjusted prevalence ratio: 1.6 [95% confidence interval: 1.0-2.7]), CL (adjusted prevalence ratio: 3.0 [95% confidence interval: 1.1-8.1]), and CP (adjusted prevalence ratio: 2.3 [95% confidence interval: 1.3-4.0]). Presence of multiple birth defects was significantly associated with a three- to eleven-fold and a three- to nine-fold increase in the prevalence of high costs and number of hospitalized days, respectively; at birth, postbirth before age 2 years and overall hospitalizations. CONCLUSION: Children with cleft palate had the greatest hospital resources use. Additionally, the presence of multiple birth defects contributed to greater inpatient days and costs for children with OFC. PMID- 25721953 TI - The association between maternal parity and birth defects. AB - BACKGROUND: Previous studies observed that first birth is associated with an increased risk of some categories of birth defects. However, multiple statistical tests were conducted and it was unclear which of these associations would be replicated in a larger study. We used a large database to assess the association between maternal parity and 65 birth defects including birth defects that have not been previously studied. METHODS: Using data from the Texas Birth Defects Registry for years 1999-2009, the risk of a birth defect occurring in a first, third, or fourth or higher birth was compared to the risk of a birth defect occurring in a second birth. RESULTS: Women having their first birth had significantly increased odds of having an infant with 24 of 65 categories of birth defects when compared to women having their second birth. We also observed associations between first birth and an increased risk of five birth defects not previously reported (small penis, preaxial polydactyly, anomalies of the thoracic vertebrae, anomalies of the lumbar vertebrae, and sacroccygeal anomalies). Women having their third or fourth or higher birth had significantly increased odds of giving birth to infants with five of 65 birth defects when compared to second births. CONCLUSIONS: Our observations regarding the categories of birth defects that were associated with first births were highly consistent with observations from two previous studies. Research into biological, behavioral, and environmental factors that may increase the risk of specific birth defects among first births is needed to further explore these associations. PMID- 25721955 TI - The high health burden from alcohol in New Zealand and the need for an appropriate government response. PMID- 25721956 TI - Euthanasia and physician-assisted dying: editorial comment and reply to the Waikato GP survey findings by Dr Havill. PMID- 25721957 TI - Motor neurone disease: bringing New Zealand patients onto the world stage. PMID- 25721958 TI - The burden of disease and injury attributable to alcohol in New Zealanders under 80 years of age: marked disparities by ethnicity and sex. AB - AIM: To update and improve estimates of morbidity and mortality due to alcohol consumption in New Zealand. METHOD: We applied the comparative risk assessment methods of the Global Burden of Disease Study at country level, and separately for Maori and non-Maori where possible. Analysis was restricted to 0-79 year olds. RESULTS: We estimated 5.4% of all deaths under 80 years old were attributable to alcohol in 2007 (802 deaths) and these represented 13,769 years of life lost (YLLs). Injuries accounted for 43%, cancer for 30% and other diseases for 27% of deaths. We also calculated 351 deaths were averted by alcohol use, but only 3095 YLLs, resulting in a net annual loss of more than 10,000 years of life. Sex and ethnic disparities were marked, with twice as many deaths in men as women for both Maori and non- Maori, and the age-standardised death rate for Maori two and a half times the rate for non-Maori. Injury was the biggest cause of alcohol-related deaths and YLLs in the young and overall, but the leading cause of alcohol-related death in both Maori and non-Maori women was breast cancer. We estimated 6.5% of all healthy life lost among 0-79 year olds in 2004 was attributable to alcohol (28,403 DALYs lost), and 6538 DALYs were prevented. The sex disparity in DALYs lost mirrored the mortality analysis, but no disaggregation by ethnicity was possible. CONCLUSION: Alcohol consumption results in substantial loss of good health across the life course in New Zealand. It makes an important contribution to Maori/non-Maori and male/female health disparities. High average consumption and heavy drinking occasions confer the greatest risk of harm to the drinker and others. At a population level there are no documented health benefits of drinking before middle-age and benefits in later life are increasingly uncertain. PMID- 25721959 TI - Motor neurone disease in the greater Wellington region: an observational study. AB - AIMS: This study investigated the demographic and disease characteristics of motor neurone disease (MND), as well as specific aspects of healthcare provision for MND patients in the greater Wellington region. METHODS: Data was collected from clinical records of all known patients with a diagnosis of Motor Neurone Disease MND in the Capital and Coast and Hutt Valley district health board catchment zones over a 12-month period. Survival data was collected at 2-year follow-up. RESULTS: The study population consisted of 40 patients. The mean age at diagnosis was 66.2 years (SD of 13.2). Thirty patients (75%) were New Zealand European. Predominantly limb signs were present in 12 (30%), and 11 (27.5%) had bulbar signs, while 14 (35%) had a mixed pattern and a further 3 (7.5%) had respiratory muscle weakness. At 2-year follow-up, the median survival time following symptom onset in the 32 deceased patients was 29 months (range 6-126 months). CONCLUSIONS: The demographics and disease characteristics of MND in this cohort of patients from the Wellington region is similar to those found in overseas studies. The majority of patients received care in accordance with established guidelines, although certain aspects of healthcare delivery could be further improved. PMID- 25721960 TI - Does Pukawakawa (the regional-rural programme at the University of Auckland) influence workforce choice? AB - AIMS: Relative shortages of rural doctors persist. In 2008 the University of Auckland medical programme introduced a Year 5 regional and rural immersion programme, Pukawakawa, based in Northland, New Zealand (NZ). This study evaluates the early workforce outcomes of graduates of this programme. METHODS: During 2013 we surveyed Auckland medical graduates who were in the 2008-2011 Pukawakawa cohorts. Questions were asked regarding recent and current place of work, future intentions for place of work, and career preference with reasons why. Qualitative analysis was undertaken to analyse free text responses about experiences of Pukawakawa on this choice. RESULTS: Of the 72 Pukawakawa participants, 45 completed the survey, for a response rate of 63%. In 2013, 62% were working in rural or regional areas, with 31% in the Northland DHB. The great majority intend to work rurally or regionally, with 35.6% intending to return to Northland DHB. Of the respondents, 68% listed general practice in their top three future career intentions. CONCLUSIONS: In the early postgraduate years, medical graduates who participated in Pukawakawa are very likely to be working in rural and regional areas. These graduates also show an intention to work in general practice and rural medicine. PMID- 25721961 TI - Prevalence predictions for age-related macular degeneration in New Zealand have implications for provision of healthcare services. AB - AIM: To predict the prevalence of age-related macular degeneration (AMD) in New Zealand from 2014 through to 2026. METHOD: Prevalence estimates for AMD in New Zealand for 2014 through to 2026 were generated by applying ethnic prevalence rate estimates for any, early and late AMD to New Zealand population projections for European, Maori, Pacific and Asian peoples. RESULTS: The prevalence of any AMD in New Zealand for the 45-85 year age group is estimated to be 184,400 in 2014 (10.3% of this age group) and increase 12.9% to 208,200 (9.9% of this age group) in 2026. For 2014 and 2026 respectively, early disease is estimated to be 167,500 and increase to 189,200 and late disease is estimated to be 7,600 and increase to 8,600. CONCLUSION: The prevalence of AMD is expected to markedly increase from 2014 through 2026. New Zealand has the lowest funding of treatment for AMD in the OECD and a relatively low ophthalmic workforce. As such, there is a need to plan for an increasing demand for intervention strategies and associated ophthalmic services. PMID- 25721962 TI - The dissolution of the Alcohol Advisory Council: a blow for public health. AB - In June 2012 the Alcohol Advisory Council (ALAC) ceased to be after more than three decades of providing advice on alcohol policy, undertaking health promotion activities, and funding research on the prevalence and causes of unhealthy alcohol use and strategies to address alcohol-related harm. Perversely, its dissolution followed soon after the Law Commission's "once in a generation" review recommending law reform to address New Zealand's substantial alcohol related health burden. ALAC's functions were ostensibly taken over by the Health Promotion Agency (HPA) but this new entity was given less autonomy than ALAC and a remit including areas as disparate as rheumatic fever and sun safety. In addition, HPA was compromised from the start by the appointment of a food, alcohol and tobacco industry representative to its Board. ALAC sometimes fell short of community and scientists' expectations that it provide independent and fearless advice on politically contested matters, such as controls on alcohol marketing. However, it seems that the way the HPA has been set up makes effective action to address health and social problems caused by alcohol consumption in New Zealand unlikely. PMID- 25721963 TI - Rare presentation of a treatable disorder: glutaric aciduria type 1. AB - A 32-year-old female patient presented with migraine and a bipolar disorder with frontal lobe dysfunction and bilateral pyramidal tract signs on examination. MRI brain revealed confluent bilateral symmetric white matter signal abnormality on T2 and FLAIR images with mild cerebral atrophy. Classic widening of Sylvian fissures and CSF space anterior to temporal lobes was seen. In view of the clinical and radiologic findings suggestive of a leukodystrophy, she was investigated for the same. Her investigations revealed an high level of urinary glutaric acid 857 mmol/mol creatinine (normal <4mmol/mol creatinine) and 3 hydroxyglutaric acid 44 mmol/mol creatinine (normal <1 mmol/mol creatinine) and plasma glutaryl carnitine 1.2 micromol/L; (normal <0.34 micromol/L). This was diagnostic of glutaric aciduria type 1. She was started on L-carnitine with which she showed clinical improvement. Testing for urinary organic acids is important when looking for treatable metabolic disorders (such as glutaric aciduria type I) in patients with leukodystrophy. PMID- 25721964 TI - Medical image. An unusual cause of right lower quadrant pain. Perforating foreign body. PMID- 25721965 TI - Medical image. Neuromyelitis optica masquerading as sepsis. PMID- 25721966 TI - Physician-assisted dying--a survey of Waikato general practitioners. PMID- 25721967 TI - Pacific women's experiences and views of participating in a novel dietary intervention for weight loss. PMID- 25721968 TI - Hypertension in young adults. PMID- 25721969 TI - Total ambulatory management of patients undergoing coronary angiography and intervention: a pilot study. PMID- 25721970 TI - Biotechnological conversion of spent coffee grounds into polyhydroxyalkanoates and carotenoids. AB - Coffee is one of the world's most popular beverages and has been growing steadily in commercial importance. Nowadays, coffee is the second largest traded commodity in the world, after petroleum. Hence, coffee industry is responsible for the generation of large amounts of waste, especially spent coffee grounds (SCG). Various attempts to valorize this waste stream of coffee industry were made. This article summarizes our research and publications aiming at the conversion of SCG into valuable products - polyhydroxyalkanoates (PHAs) and carotenoids. At first, oil extracted from SCG (approx. 15 wt% oil in SCG) can be efficiently (YP/S=0.82 g/g) converted into PHA employing Cupriavidus necator H16. Further, the solid residues after oil extraction can be hydrolyzed (by the combination of chemical and enzymatic hydrolysis) yielding fermentable sugars, which can be further used as a substrate for the production of PHAs employing Bacillus megaterium (YP/S=0.04 g/g) or Burkholderia cepacia (YP/S=0.24 g/g). Alternatively, SCG hydrolysate can be used as a substrate for biotechnological production of carotenoids by carotenogenic yeast Sporobolomyces roseus. Solid residues after either oil extraction or hydrolysis can be used as fuel in industrial boilers to generate heat and energy. Therefore, entire biomass of SCG can be used for sustainable production of PHAs and/or carotenoids employing bio-refinery approach. PMID- 25721971 TI - Quenching resonance energy transfer (QRET): a single-label technique for inhibitor screening and interaction studies. AB - The increased number of therapeutic targets has led to a growing need for screening methods enabling possible inhibitor compound selection. Information for new therapeutic targets has been found mostly from sequencing of the human genome but this knowledge cannot be directly converted into clinically relevant drug molecules. After target identification, the multistep drug development process takes many years and hundreds of millions of dollars are spent without certainty of the outcome. The first and the most critical step in the drug development process is hit selection. The optimal high throughput screening method should provide the highest possible number of true positive hits for further studies and lead discovery. The result should be achieved with low material consumption in a rapid and automated process. Radioactive label based methods are sensitive, but due to the problems arising from the radioactivity, luminescence-based methods have become increasingly popular in screening. In this review, the time-resolved luminescence based quenching resonance energy transfer (QRET) technique is discussed for primary screening. PMID- 25721973 TI - Crispene E, a cis-clerodane diterpene inhibits STAT3 dimerization in breast cancer cells. AB - Crispene E, a new clerodane-type diterpene, inhibited STAT3 dimerization in a cell-free fluorescent polarisation assay and was found to have significant toxicity against STAT3-dependent MDA-MB 231 breast cancer cell line and selectively inhibited the expression of STAT3 and STAT3 target genes cyclin D1, Fascin and bcl-2. Molecular docking studies suggest the molecule inhibits STAT3 by interacting with its SH2 domain. The compound has been isolated from Tinospora crispa and characterized using standard spectroscopic techniques. PMID- 25721972 TI - Genistein stimulates jejunum chloride secretion via an Akt-mediated pathway in intact female mice. AB - BACKGROUND/AIMS: We have previously shown that daily subcutaneous injections with the naturally occurring phytoestrogen genistein (600 mg genistein/kg body weight/day, 600G) results in a significantly increased basal intestinal chloride, Cl(-), secretion (Isc, a measure of transepithelial secretion) in intact C57BL/6J female mice after 1-week of treatment, compared to controls (DMSO vehicle injected). Removal of endogenous estrogen via ovariectomy (OVX) had no effect on the 600G-mediated increase in basal Isc. METHODS: Given the estrogen-like characteristics of genistein, we compared the effects of daily estradiol (E2) injections (10 mg E2/kg body weight/day, 10E2) on basal Isc in intact and OVX mice. In intact mice, 10E2 was without effect on basal Isc, however, in OVX mice, 10E2 significantly increased basal Isc (mimicked 600G). The goal of the current study was to characterize the intracellular signaling pathways responsible for mediating 600G- or 10E2-stimulated increases in basal Isc in intact female or OVX mice. RESULTS: We measured total protein expression in isolated segments of jejunum using western blot from the following six groups of mice; intact or OVX with; 600G, 10E2 or control. The proteins of interest were: Akt, p-Akt, p-PDK1, p PTEN, p-c-Raf, p-GSK-3beta, rap-1 and ERK1/2. All blots were normalized to GAPDH levels (n = 6-18/group). CONCLUSION: These data suggest that the presence of the endogenous sex steroid, estrogen, modifies the intracellular signaling pathway required to mediate Cl(-) secretion when the intestine is exposed to exogenous 600G or E2. These studies may have relevance for designing pharmacological tools for women with intestinal chloride secretory dysfunctions. PMID- 25721974 TI - Characterization of a novel strain phylogenetically related to Kocuria rhizophila and its chemical modification to improve performance of microbial fuel cells. AB - It is certainly an important research area to discovery new exoelectrogens for microbial fuel cells (MFCs), and how to effectively manipulate its cell property to improve power performance is still a great challenge. In this study, a new electrochemically active bacterium phylogenetically related to Kocuria rhizophila was first isolated and found electrogenic in MFCs, which was identified through the combination methods of molecular biology, physiological, biochemical and morphological characteristics. The MFCs inoculated with this strain generated power from a wide variety of substrates, reached a maximum power density of 75mW/m(2) in the substrate of 1g/L glucose. And the electron transfer mechanism was confirmed to be dominantly direct biofilm mechanism. Chemical treatment with five reagents was verified to be a feasible strategy to improve the power density of MFCs, increasing approximately 1.75 fold at most after treated with lysozyme. This enhancement was contributed to the significant enhancement on cell permeability, cell membrane fluidity and Coenzyme Q10 (the electron carrier). Thus this work offered a novel Gram-positive electrogenic bacterium and proved chemical treatment was a feasible strategy to improve electron transfer for application in MFCs. PMID- 25721975 TI - Trapping cells in paper for white blood cell count. AB - White blood cell count is an important indicator of each individual's health condition. An abnormal white blood cell count usually results from an infection, cancer, or other conditions that trigger systemic inflammation responses. White blood cell count also provides predictive information on the incidence of cardiovascular diseases and Type 2 diabetes. Therefore, monitoring white blood cell count on a regular basis can potentially help individuals to take preventive measures and improve healthcare outcomes. Currently, white blood cell count is primarily conducted in centralized laboratories, and it requires specialized equipment and dedicated personnel to perform the test and interpret the results. So far there has been no rapid test that allows white blood cell count in low resource settings. In this study, we have demonstrated a vertical flow platform that quantifies white blood cells by trapping them in the paper. White blood cells were tagged with gold nanoparticles, and flowed through the paper via a small orifice. The white blood cell count was determined by measuring the colorimetric intensity of gold nanoparticles on the surface of white blood cells that were trapped in the paper mesh. Using this platform, we were able to quantify white blood cells in 15 MUL of blood, and visually differentiate the abnormal count of white blood cells from the normal count. The proposed platform enabled rapid white blood cell count in low resource settings with a small sample volume requirement. Its low-cost, instrument-free operations would be attractive for point-of-care applications. PMID- 25721976 TI - Silver nanoprism etching-based plasmonic ELISA for the high sensitive detection of prostate-specific antigen. AB - Ultrasensitive and quantitative detection using simple and low-cost assays is critical in clinical diagnostics. In this report, we developed a triangular silver nanoprism (AgNPRs) etching-based plasmonic biosensor for the detection of cancer biomarkers. The triangular AgNPRs-based plasmonic biosensor is an enzyme linked immunosorbent assay combined with the enzyme-mediated surface plasmon resonance (SPR) of triangular AgNPRs. Triangular AgNPRs uses the immune response of prostate-specific antigen (PSA) to trigger the glucose oxidase (GOx)-catalysed oxidation of glucose (Glu), producing hydrogen peroxide. Hydrogen peroxide acts as an oxidant to etch the triangular AgNPRs into smaller spherical silver nanoparticles, which is accompanied by a substantial blueshift of the SPR peak and a colourimetric blue-to-purple change that can be observed by the naked eye. The SPR peak shift enables the quantitative assessment of PSA due to the remarkable colour change. The triangular AgNPRs-based plasmonic ELISA approach exhibited a quasilinear response to logarithmic PSA concentrations in the range of 10fg/mL to 100pg/mL with a limit of detection (LOD) of 4.1fg/mL. In addition, the LOD of PSA in this approach exceeds that of the conventional HRP-based ELISA (1.25ng/mL) approach by more than 5 orders of magnitude. Patient serum samples from 16 donors were assayed with triangular AgNPRs-based plasmonic ELISA. The results from the triangular AgNPRs-based immunoassay and the time-resolved fluorescence immunoassay showed excellent correlation, and there were no significant differences in the quantified amounts of PSA. The triangular AgNPRs based plasmonic ELISA approach has advantages (ultrasensitive, cost-effective, ease of operation) that are expected to be of great interest in diagnostics and to be suitable for a point-of-care test. PMID- 25721977 TI - Role of livestock effluent suspended particulate in sealing effluent ponds. AB - Intensive livestock feed-lots have become more prevalent in recent years to help in meeting the predicted food production targets based on expected population growth. Effluent from these is stored in ponds, representing a potential concern for seepage and contamination of groundwater. Whilst previous literature suggests that effluent particulate can limit seepage adequately in combination with a clay liner, this research addresses potential concerns for sealing of ponds with low concentration fine and then evaluates this against proposed filter-cake based methodologies to describe and predict hydraulic reduction. Short soil cores were compacted to 98% of the maximum dry density and subject to ponded head percolation with unfiltered-sediment-reduced effluent, effluent filtered to <3 MUm, and chemically synthesized effluent. Reduction in hydraulic conductivity was observed to be primarily due to the colloidal fraction of the effluent, with larger particulate fractions providing minimal further reduction. Pond sealing was shown to follow mathematical models of filter-cake formation, but without the formation of a physical seal on top of the soil surface. Management considerations based on the results are presented. PMID- 25721978 TI - Effects of handling parameters on hydrogen sulfide emission from stored dairy manure. AB - Hydrogen sulfide (H2S) emission from liquid manure in the process preceding field application is an important issue in fertigation systems. Given that H2S poses a significant health risk, it is important to determine the effects of different handling parameters on H2S emissions to prevent health risks to farmers. In this study, the effects of total solids (TS; 3, 5, 7, 9, and 11%) and mixing speed (100, 200, 300, and 400 rpm), duration (5, 15, 30, and 60 min), and frequency (one, two, three, and four times a day) on H2S emissions from two different dairy manures were investigated. The results indicate that the quantity of sulfur containing substrate intake determines the potential of dairy manure to emit H2S because manure from cows fed with concentrate-based feed generates higher amounts of H2S than manure from cows fed with forage-based feed. The H2S concentration increased with TS concentration and reached a maximum of 1133 ppm at a TS of 9%; thereafter, it decreased with further increases in TS concentration. H2S emission increased with mixing speed with a peak concentration of 3996 ppm at 400 rpm. A similar trend was observed for mixing duration. However, there were no significant differences between the amounts H2S emitted at different frequencies of mixing (P > 0.05). The results indicate that mixing speed, duration, and TS are the major determinants of the quantity of H2S emitted from dairy manure. Therefore, to prevent health risks associated with H2S emission from dairy manure, it is recommended that the mixing speed and duration should be kept as low as possible, while a TS concentration of above 9% should be applied during the fertigation of dairy manure. PMID- 25721979 TI - Optimization of electrocoagulation (EC) process for the purification of a real industrial wastewater from toxic metals. AB - In the present work, the efficiency evaluation of electrocoagulation (EC) in removing toxic metals from a real industrial wastewater, collected from Aspropyrgos, Athens, Greece was investigated. Manganese (Mn), copper (Cu) and zinc (Zn) at respective concentrations of 5 mg/L, 5 mg/L and 10 mg/L were present in the wastewater (pH=6), originated from the wastes produced by EBO-PYRKAL munitions industry and Hellenic Petroleum Elefsis Refineries. The effect of operational parameters such as electrode combination and distance, applied current, initial pH and initial metal concentration, was studied. The results indicated that Cu and Zn were totally removed in all experiments, while Mn exhibited equally high removal percentages (approximately 90%). Decreasing the initial pH and increasing the distance between electrodes, resulted in a negative effect on the efficiency and energy consumption of the process. On the other hand, increasing the applied current, favored metal removal but resulted in a power consumption increase. Different initial concentrations did not affect metal removal efficiency. The optimal results, regarding both cost and EC efficiency, were obtained with a combination of iron electrodes, at 2 cm distance, at initial current of 0.1 A and pH=6. After 90 min of treatment, maximum removal percentages obtained were 89% for Mn, 100% for Cu and 100% for Zn, at an energy consumption of 2.55 kWh/m(3). PMID- 25721980 TI - The effect of organic load and feed strategy on biohydrogen production in an AnSBBR treating glycerin-based wastewater. AB - An anaerobic sequencing batch biofilm reactor (AnSBBR) with recirculation of the liquid phase (at 30 degrees C with 3.5 L of working volume and treating 1.5 L per cycle) treating pure glycerin-based wastewater was applied to biohydrogen production. The applied volumetric organic load (AVOL) ranged from 7.7 to 17.1 kgCOD m(-3) d(-1), combining different influent concentrations (3000, 4000 and 5000 mgCOD L(-1)) and cycle lengths (4 and 3 h). The feed strategy used was to maintain the feeding time equal to half of the cycle time. The increase in the influent concentration and the decrease in cycle length improved the molar yield and molar productivity of hydrogen. The highest productivity (100.8 molH2 m(-3) d(-1)) and highest yield of hydrogen per load removed (20.0 molH2 kgCOD(-1)) were reached when the reactor operated with an AVOL of 17.1 kgCOD m(-3) d(-1), with 68% of H2 and only 3% of CH4 in its biogas. It was also found that pretreatment of the sludge/inoculum does not influence the productivity/yield of the process and the use of crude industrial glycerin-based wastewater in relation to the pure glycerol-based wastewater substantially decreased the production and composition of the hydrogen produced. PMID- 25721981 TI - Adsorption of 2,4-dichlorophenoxyacetic acid by mesoporous activated carbon prepared from H3PO4-activated langsat empty fruit bunch. AB - The removal of toxic herbicide from wastewater is challenging due to the availability of suitable adsorbents. The Langsat empty fruit bunch is an agricultural waste and was used in this study as a cheap precursor to produce activated carbon for the adsorption of herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) at different initial concentrations ranging from 50 to 400 mg/L. The produced Langsat empty fruit bunch activated carbon (LEFBAC) was mesoporous and had high surface area of 1065.65 m(2)/g with different active functional groups. The effect of shaking time, temperature and pH on 2,4-D removal were investigated using the batch technique. The adsorption capacity of 2,4-D by LEFBAC was decreased with increase in pH of solution whereas adsorption capacity increased with temperature. The adsorption data was well described by Langmuir isotherm followed by removal capacity of 261.2 mg/g at 30 degrees C. The results from this work showed that LEFBAC can be used as outstanding material for anionic herbicide uptake from wastewater. PMID- 25721982 TI - Prevalence of fecal incontinence (FI) and associated factors in institutionalized older adults. AB - The objective of this work is to determine the prevalence of FI and associated factors in institutionalized elderly. A cross-sectional study is presented herein, conducted between October and December 2013, in 10 nursing homes (NHs) of the city of Natal (Northeast Brazil). Individuals over the age of 60 were included in the study, while those hospitalized or in terminal phase were excluded. Data collection included sociodemographic information, FI characterization, as well as variables related to the institution itself and to health conditions (comorbidities, medication, pelvic floor surgery, Barthel Index for functional capacity and Pfeiffer test for cognitive status). FI was verified through the Minimum Data Set (MDS) 3.0, which was also used to assess toileting programs. The Chi-square test and the linear Chi-square test were performed for bivariate analysis, as well as logistic regression for multivariate analysis. The final sample consisted of 321 elderly, mostly females, with mean age of 81.5 years. The prevalence of FI was 42.68% (CI 95%, 37.39-48.15). Most residents presenting FI were always incontinent (83.9%) and the most frequent incontinence type was total FI (solid and liquid stools). Incontinence control measures were applied only to 9.7% of the residents. The final model revealed a statistically significant association between FI and functional and cognitive impairments. It is concluded that FI is a health issue that affects almost half of the institutionalized elderly, and is associated with functional and cognitive disability. PMID- 25721983 TI - MRT letter: A unified accelerated maximum likelihood technique for widefield, confocal, and super-resolution 4Pi microscopy. AB - We propose an algorithmic technique for accelerating maximum likelihood (ML) algorithm for image reconstruction in fluorescence microscopy. This is made possible by integrating Biggs-Andrews (BA) method with ML approach. The results on widefield, confocal, and super-resolution 4Pi microscopy reveal substantial improvement in the speed of 3D image reconstruction (the number of iterations has reduced by approximately one-half). Moreover, the quality of reconstruction obtained using accelerated ML closely resembles with nonaccelerated ML method. The proposed technique is a step closer to realize real-time reconstruction in 3D fluorescence microscopy. PMID- 25721984 TI - Enhancement of docetaxel solubility using binary and ternary solid dispersion systems. AB - CONTEXT: Poor biopharmaceutical properties and toxicities associated with the intravenous formulation of docetaxel (DTX) necessitate the exploration of an alternate oral route of delivery. OBJECTIVE: This study aims at enhancing the solubility of poorly soluble drug, DTX with the help of solid dispersion (SD) technique. METHOD: DTX SDs were formulated with selected solubilizers, including Kollidon 12PF, Lutrol F68, Soluplus and Hydroxypropyl-beta-cyclodextrin in different weight ratios. Freeze-drying method was used to prepare the binary and ternary SDs. Kinetic solubility of the SDs was evaluated in order to select best DTX-solubilizer combination. Best performing combination was then characterized using differential scanning calorimeter (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). RESULTS AND DISCUSSION: Among all SDs tested, Soluplus outperformed all the excipients at equivalent weight ratio. Binary SD of DTX and Soluplus (1:10) resulted in the highest improvement in solubility (362.93 +/- 11.01 ug/mL). This is approximately a 93-fold increment as compared to the solubility of crystalline DTX (3.9 +/- 0.2 ug/mL). This exceptional performance can be attributed to solid state transformation as well as micellization. CONCLUSION: Among all the excipients tested, Soluplus dispersion is the most promising candidate for oral formulation development. PMID- 25721985 TI - Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery. AB - The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that beta cyclodextrin could improve the solubility of valsartan and showed AL type solubility curve. A 1:1 stoichiometric ratio of valsartan to beta cyclodextrin was revealed from phase solubility studies and Job's plot. The prepared complex showed significantly better dissolution efficiency (p < 0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan beta cyclodextrin complex was significantly higher (p < 0.05) compared to pure drug, in second part press-coated tablets of valsartan beta cyclodextrin complex were subsequently prepared and application of the Plackett-Burman screening design revealed that HPMC K4M and EC showed significant effect on lag time. A 3(2) full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6 h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180 mg of coating and revealed a close agreement between observed and predicted value (R(2 )= 0.9694). PMID- 25721986 TI - The Effects of Ozurdex(r) (Dexamethasone Intravitreal Implant) on Experimental Proliferative Vitreoretinopathy. AB - PURPOSE: To investigate a new sustained-release formulation of dexamethasone (Ozurdex(r)) for inhibiting proliferative vitreoretinopathy (PVR) and its effect on the expression of retinal glial reaction and inflammation in experimental PVR eyes. METHODS: We used 30 pigmented rabbits for this study. One week after gas compression, the eyes were injected with 5 * 10(4) retinal pigment epithelial cells into the vitreous cavity to induce PVR. Concurrently, one eye also received an intravitreal injection of Ozurdex; the other eye was used as a control. PVR was graded by indirect ophthalmoscopy on days 1, 3, 7, 14, 21, and 28. The expression of the retinal glial reaction and inflammation in experimental PVR eyes were evaluated by Western blot analysis. RESULTS: PVR severity increased gradually and peaked after 14 days, and no differences in PVR severity between the study and control groups were observed at any time point. The expression of glial fibrillary acid protein (GFAP) increased on days 7 and 14 in both the PVR control and study groups. While the use of Ozurdex in the study group showed less GFAP expression, this difference was not significant. The expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 significantly increased on days 7 and 14 in PVR control eyes. There was a significant difference in TNF alpha between PVR control eyes and Ozurdex-treated eyes on days 7 (p < 0.001) and 14 (p = 0.019). Ozurdex in the study group showed lower IL-6 expression; however, this difference was not significant on days 7 (p = 0.063) and 14 (p = 0.052). CONCLUSIONS: The intravitreal injection of Ozurdex suppressed the expression of inflammatory markers; however, it did not mitigate the severity of experimental PVR in this animal model. (c) 2015 S. Karger AG, Basel. PMID- 25721987 TI - Analysis of the effects of evaporative cooling on the evaporation of liquid droplets using a combined field approach. AB - During liquid evaporation, the equations for the vapor concentration in the atmosphere and for the temperature in the liquid are coupled and must be solved in an iterative manner. In the present paper, a combined field approach which unifies the coupled fields into one single hybrid field and thus makes the iteration unnecessary is proposed. By using this approach, the influences of the evaporative cooling on the evaporation of pinned sessile droplets are investigated, and its predictions are found in good agreement with the previous theoretical and experimental results. A dimensionless number Ec which can evaluate the strength of the evaporative cooling is then introduced, and the results show that both the evaporation flux along the droplet surface and the total evaporation rate of the droplet decrease as the evaporative cooling number Ec increases. For drying droplets, there exists a critical value EcCrit below which the evaporative cooling effect can be neglected and above which the significance of the effect increases dramatically. The present work may also have more general applications to coupled field problems in which all the fields have the same governing equation. PMID- 25721988 TI - Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. AB - Phylogenetic analysis of 11 genetic loci and results from many genotyping studies revealed significant genetic diversity with the pathogenic Cryptococcus gattii/Cryptococcus neoformans species complex. Genealogical concordance, coalescence-based, and species tree approaches supported the presence of distinct and concordant lineages within the complex. Consequently, we propose to recognize the current C. neoformans var. grubii and C. neoformans var. neoformans as separate species, and five species within C. gattii. The type strain of C. neoformans CBS132 represents a serotype AD hybrid and is replaced. The newly delimited species differ in aspects of pathogenicity, prevalence for patient groups, as well as biochemical and physiological aspects, such as susceptibility to antifungals. MALDI-TOF mass spectrometry readily distinguishes the newly recognized species. PMID- 25721989 TI - L-DOPA decarboxylase mRNA levels provide high diagnostic accuracy and discrimination between clear cell and non-clear cell subtypes in renal cell carcinoma. AB - OBJECTIVES: Renal cell carcinoma (RCC) is the most frequent type of kidney cancer. RCC patients frequently present with arterial hypertension due to various causes, including intrarenal dopamine deficiency. L-DOPA decarboxylase (DDC) is the gene encoding the enzyme that catalyzes the biosynthesis of dopamine in humans. Several studies have shown that the expression levels of DDC are significantly deregulated in cancer. Thus, we herein sought to analyze the mRNA levels of DDC and evaluate their clinical significance in RCC. DESIGN AND METHODS: DDC levels were analyzed in 58 surgically resected RCC tumors and 44 adjacent non-cancerous renal tissue specimens via real-time PCR. Relative levels of DDC were estimated by applying the 2(-DeltaDeltaC)T method, while their diagnostic accuracy and correlation with the clinicopathological features of RCC tumors were assessed by comprehensive statistical analysis. RESULTS: DDC mRNA levels were found to be dramatically downregulated (p<0.001) in RCC tumors, exhibiting remarkable diagnostic accuracy as assessed by ROC curve analysis (AUC: 0.910; p<0.001) and logistic regression (OR: 0.678; p=0.001). Likewise, DDC was found to be differentially expressed between clear cell RCC and the group of non clear cell subtypes (p=0.001) consisted of papillary and chromophobe RCC specimens. Furthermore, a statistically significant inverse correlation was also observed when the mRNA levels of DDC were analyzed in relation to tumor grade (p=0.049). CONCLUSIONS: Our data showed that DDC constitutes a highly promising molecular marker for RCC, exhibiting remarkable diagnostic accuracy and potential to discriminate between clear cell and non-clear cell histological subtypes of RCC. PMID- 25721990 TI - Differential ferritin interpretation methods that adjust for inflammation yield discrepant iron deficiency prevalence. AB - We reassessed the iron deficiency (ID) prevalence in a South African trial that formed part of the International Research on Infant Supplementation study by comparing four methods that account for the high prevalence of acute (28.6%) and chronic (41.8%) inflammation observed in the study. Serum ferritin (SF) was measured as marker of iron status in 192 apparently healthy, 4-13-month-old infants. Alpha-1 glycoprotein and C-reactive protein concentrations were determined to indicate chronic and acute inflammation, respectively. The ID prevalence was obtained by four methods that adjust for inflammation: (1) excluding infants with inflammation; (2) using a higher cut-off (SF < 30 MUg L( 1) ); (3) using different cut-offs for infants with vs. without inflammation (SF < 30 MUg L(-1) vs. SF < 12 MUg L(-1) ); and (4) adjusting SF concentrations with correction factors (CFs) were compared with a reference method (SF < 12 MUg L(-1) ) not accounting for inflammation. Using the higher SF cut-off method resulted in the highest ID prevalence (52.1%), followed by using two different cut-offs (31.8%), using CFs (21.9%) and excluding subjects with inflammation (17.6%). The CF method showed the best agreement with the reference method. Disregarding inflammation resulted in a significantly lower ID prevalence (17.2%). ID anaemia (IDA) prevalence ranged from 13.2% to 24.5%, with the lowest prevalence (12.0%) for the reference method. Our analysis highlights the challenge of assessing ID and IDA using only SF as marker of iron status in the presence of inflammation. We demonstrate the importance of measuring inflammation markers to account for their elevating effect on SF. PMID- 25721991 TI - Increased frequency of late-senescent T cells lacking CD127 in chronic hepatitis C disease. AB - BACKGROUND: Hepatitis C virus (HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. MATERIALS AND METHODS: We characterized the distinct T-cell phenotypes based on the expression of costimulatory molecules CD28 and CD27, senescence markers PD-1 and CD57, chronic immune activation markers CD38 and HLA-DR, and survival marker CD127 (IL 7R) by flow cytometry following activation of T cells using HCV peptides and phytohemagglutinin. RESULTS: HCV-specific CD4+ and CD8+ T cells from chronic HCV (CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4+ T cells of CHC-infected subjects displayed relatively increased expression of HLA-DR and CD38 relative to HCV-specific CD8+ T cells. The CD4+ and CD8+ T cells from HCV-infected individuals showed significant increase of late differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated with the levels of CD57 and PD-1 expressed on T cells. CONCLUSIONS: Chronic HCV infection results in increased turnover of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection. PMID- 25721992 TI - Bi-8-carboxamidoquinoline derivatives for the fluorescent recognition of Zn2+. AB - Three fluorescent sensors which were composed of a phendiol (o-, m-, p-isomers) and two carboxamidoquinolines have been synthesized and characterized. Research on the Zn(2+)-sensing properties of the three sensors was carried out, and the results showed a significant difference in the recognition performance for Zn(2+). The fluorescence intensity (I(510 nm)) of ortho isomeric sensor binding to Zn(2+) was enhanced 23-fold, the meta 15-fold, the para 8-fold. As the distance between two carboxamidoquinolines became longer, the fluorescence enhancement decreased. In addition, the selectivity of sensors got poor and the detection limit became higher with rising the distance between two receptors. PMID- 25721993 TI - Investigation of the binding between pepsin and nucleoside analogs by spectroscopy and molecular simulation. AB - In this paper, the interactions of pepsin with CYD (cytidine) or nucleoside analogs, including FNC (2'-deoxy-2'-beta-fluoro-4'-azidocytidine) and CMP (cytidine monophosphate), were investigated by fluorescence, UV-visible absorption and synchronous fluorescence spectroscopy under mimic physiological conditions. The results indicated that FNC (CYD/CMP) caused the fluorescence quenching by the formation of complex. The binding constants and thermo-dynamic parameters at three different temperatures were obtained. The hydrophobic and electrostatic interactions were the predominant intermolecular forces to stabilize the complex. The F atom in FNC might weaken the binding of nucleoside analog to pepsin. Results showed that CYD was the strongest quencher and bound to pepsin with higher affinity. PMID- 25721994 TI - Defining early mycosis fungoides: validation of a diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas. AB - BACKGROUND: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma and is often difficult to diagnose. Early-stage disease is particularly challenging and requires clinical and histopathologic correlation to make an accurate diagnosis. In order to facilitate the diagnosis of early MF, an algorithm has been proposed by the International Society for Cutaneous Lymphomas (ISCL) whereby clinical and histopathologic characteristics as well as immunohistochemistry and T-cell receptor gene rearrangement studies may be applied to suspected cases of MF. The diagnostic utility of this algorithm has not yet been validated. We sought to determine the validity of the proposed algorithm via an investigator-blinded, retrospective, case-control study. METHODS: A total of 34 cases were randomly selected from the database of a clinic for cutaneous T-cell lymphomas and included patients with MF and patients with clinicopathologic mimics. The proposed diagnostic algorithm was systematically applied to the entire cohort. Each case was assigned a composite score based on the parameters in the proposed algorithm. RESULTS: Among the 24 cases of MF, 21 cases achieved four or more points through application of the algorithm. Among the 10 cases of MF mimics, only four achieved four or more points. This difference was significant (Fisher's exact test, p = 0.009). The sensitivity of the 4-point threshold for a diagnosis of MF was 87.5% and the specificity was 60%. CONCLUSIONS: The diagnostic algorithm proposed by the ISCL is a statistically valid method for defining cases of early MF and distinguishing these cases from other benign dermatoses. However, the clinical utility of the algorithm may be limited by its low specificity. Further refinement of the algorithm may improve its accuracy. PMID- 25721995 TI - In vivo 3T and ex vivo 7T diffusion tensor imaging of prostate cancer: Correlation with histology. AB - The purpose of this work was to test whether fractional anisotropy (FA) can contribute to the diagnosis and grading of prostate cancer. Turbo spin echo T2 weighted (T2W) and single shot echo planar imaging diffusion tensor imaging (EPI DTI) data were collected from 13 subjects with biopsy proven prostate cancer prior to surgical removal of the gland. Rapid acquisition with relaxation enhancement (RARE) T2W and spin-echo DTI data were acquired ex-vivo from the fixed prostatectomy specimens. Digitized whole mount histology sections, examined and annotated by a pathologist, were registered to the in-vivo and ex-vivo DTI data, and the average values of apparent diffusion coefficient (ADC) and FA were calculated from ROIs encompassing normal and cancerous peripheral zone (PZ). In addition, Monte Carlo simulations were carried out to assess the dependence of the apparent FA on the ADC values for different signal to noise ratios (SNRs). ADC values were significantly lower in tumors than in normal PZ both in-vivo and ex-vivo, while the difference in FA values between tumors and normal PZ was significant only in-vivo. Paired t-test showed significant difference between in vivo and ex-vivo FA values in tumors, but not in the normal PZ. The simulations showed that lower SNR results in an increasing overestimation of the FA values with decreasing ADC. These results suggest that the in-vivo increase in FA values in tumors is due to low SNR, rather than the presence of cancer. The results of this study suggest that FA does not contribute significantly to the diagnostic capabilities of DTI in prostate cancer. PMID- 25721996 TI - Reduced field-of-view imaging for single-shot MRI with an amplitude-modulated chirp pulse excitation and Fourier transform reconstruction. AB - PURPOSE: We employ an amplitude-modulated chirp pulse to selectively excite spins in one or more regions of interest (ROIs) to realize reduced field-of-view (rFOV) imaging based on single-shot spatiotemporally encoded (SPEN) sequence and Fourier transform reconstruction. MATERIALS AND METHODS: The proposed rFOV imaging method was theoretically analyzed and illustrated with numerical simulation and tested with phantom experiments and in vivo rat experiments. In addition, point spread function was applied to demonstrate the feasibility of the proposed method. To evaluate the proposed method, the rFOV results were compared with those obtained using the EPI method with orthogonal RF excitation. RESULTS: The simulation and experimental results show that the proposed method can image one or two separated ROIs along the SPEN dimension in a single shot with higher spatial resolution, less sensitive to field inhomogeneity, and practically no aliasing artifacts. In addition, the proposed method may produce rFOV images with comparable signal-to noise ratio to the rFOV EPI images. CONCLUSION: The proposed method is promising for the applications under severe susceptibility heterogeneities and for imaging separate ROIs simultaneously. PMID- 25721997 TI - Quantifying brain iron deposition in patients with Parkinson's disease using quantitative susceptibility mapping, R2 and R2. AB - PURPOSE: To evaluate the sensitivity and specificity of quantitative magnetic resonance (MR) iron mapping including R2, R2* and magnetic susceptibility to differentiate patients with Parkinson's disease (PD) from healthy controls. MATERIALS AND METHODS: Thirty (30) healthy controls (HC) (64+/-7years old) and 20 patients with idiopathic PD (66+/-8years old) were studied using a 3T MR imaging scanner. R2 maps were generated from GRASE sequence while R2*, and quantitative susceptibility mapping (QSM) were obtained from a conventional multi-echo gradient-echo sequence. R2, R2* and relative susceptibility (Deltachi) values of structures in the basal ganglia were measured for each patient and control. An analysis of sensitivity and specificity and unpaired t-test was applied to the two groups. RESULTS: A significant difference (p<0.05) was found for R2 and ?chi values in the substantia nigra as a whole and in the pars compacta for PD patients. The R2* values were different significantly (p<0.05) only on the substantia nigra pars compacta. QSM presented the highest sensitivity and specificity to differentiate the two populations. CONCLUSION: The QSM map was the most sensitive quantitative technique for detecting a significant increase of iron for PD. The highest significant difference between controls and patients was found in the substantia nigra pars compacta using QSM. PMID- 25721998 TI - Extended 3D approach for quantification of abnormal ascending aortic flow. AB - BACKGROUND: Flow displacement quantifies eccentric flow, a potential risk factor for aneurysms in the ascending aorta, but only at a single anatomic location. The aim of this study is to extend flow displacement analysis to 3D in patients with aortic and aortic valve pathologies. METHODS: 43 individuals were studied with 4DFlow MRI in 6 groups: healthy, tricuspid aortic valve (TAV) with aortic stenosis (AS) but no dilatation, TAV with dilatation but no AS, and TAV with both AS and dilatation, BAV without AS or dilatation, BAV without AS but with dilation. The protocol was approved by our institutional review board, and informed consent was obtained. Flow displacement was calculated for multiple planes along the ascending aorta, and 2D and 3D analyses were compared. RESULTS: Good correlation was found between 2D flow displacement and both maximum and average 3D values (r>0.8). Healthy controls had significantly lower flow displacement values with all approaches (p<0.05). The highest flow displacement was seen with stenotic TAV and aortic dilation (0.24+/-0.02 with maximum flow displacement). The 2D approach underestimated the maximum flow displacement by more than 20% in 13 out of 36 patients (36%). CONCLUSIONS: The extended 3D flow displacement analysis offers a more comprehensive quantitative evaluation of abnormal systolic flow in the ascending aorta than 2D analysis. Differences between patient subgroups are better demonstrated, and maximum flow displacement is more reliably assessed. PMID- 25721999 TI - Cluster analysis of Dairy Herd Improvement data to discover trends in performance characteristics in large Upper Midwest dairy herds. AB - Principal component analysis (PCA) is a variable reduction method used on over parameterized data sets with a vast number of variables and a limited number of observations, such as Dairy Herd Improvement (DHI) data, to select subsets of variables that describe the largest amount of variance. Cluster analysis (CA) segregates objects, in this case dairy herds, into groups based upon similarity in multiple characteristics simultaneously. This project aimed to apply PCA to discover the subset of most meaningful DHI variables and to discover groupings of dairy herds with similar performance characteristics. Year 2011 DHI data was obtained for 557 Upper Midwest herds with test-day mean >=200 cows (assumed mostly freestall housed), that remained on test for the entire year. The PCA reduced an initial list of 22 variables to 16. The average distance method of CA grouped farms based on best goodness of fit determined by the minimum cophenetic distance. Six groupings provided the optimal fitting number of clusters. Descriptive statistics for the 16 variables were computed per group. On observations of means, groups 1, 2, and 6 demonstrated the best performances in most variables, including energy-corrected milk, linear somatic cell score (log of somatic cell count), dry period intramammary infection cure rate, new intramammary infection risk, risk of subclinical intramammary infection at first test, age at first calving, days in milk, and Transition Cow Index. Groups 3, 4, and 5 demonstrated the worst mean performances in most the PCA-selected variables, including DIM, age at first calving, risk of subclinical intramammary infection at first test, and dry period intramammary infection cure rate. Groups 4 and 5 also had the worst mean herd performances in energy-corrected milk, Transition Cow Index, linear somatic cell score, and new intramammary infection risk. Further investigation will be conducted to reveal patterns of management associated with herd categorization. The PCA and CA should be used when describing the multivariate performance of dairy herds and whenever working with over-parameterized data sets, such as DHI databases. PMID- 25722000 TI - The perceived value of dairy product traceability in modern society: An exploratory study. AB - The current study assessed the perceived value of food traceability in modern society by young consumers. After experiencing numerous recalls and food safety related incidences, consumers are increasingly aware of the tools available to mitigate risks. Food traceability has been associated with food safety procedures for many years, but recent high-profile cases of food fraud around the world have given traceability a different strategic purpose. Focusing solely on dairy products, our survey results offer a glimpse of consumer perceptions of traceability as a means to preserve food integrity and authenticity. This study explored the various influences that market-oriented traceability has had on dairy consumers. For example, results show that if the dairy sector could guarantee that their product is in fact organic, 53.8% of respondents who often purchase organic milk would consider always purchasing traceable organic milk. This research produced a quantitative set of information related to the perceived value of food traceability, which could be useful for the creation and development of improved guidelines and better education for consumers. We discuss limitations and suggest areas for new research. PMID- 25722001 TI - Reciprocal osmotic challenges reveal mechanisms of divergence in phenotypic plasticity in the killifish Fundulus heteroclitus. AB - The killifish Fundulus heteroclitus is an estuarine species with broad physiological plasticity, enabling acclimation to diverse stressors. Previous work suggests that freshwater populations expanded their physiology to accommodate low salinity environments; however, it is unknown whether this compromises their tolerance to high salinity. We used a comparative approach to investigate the mechanisms of a derived freshwater phenotype and the fate of an ancestral euryhaline phenotype after invasion of a freshwater environment. We compared physiological and transcriptomic responses to high- and low-salinity stress in fresh and brackish water populations and found an enhanced plasticity to low salinity in the freshwater population coupled with a reduced ability to acclimate to high salinity. Transcriptomic data identified genes with a conserved common response, a conserved salinity-dependent response and responses associated with population divergence. Conserved common acclimation responses revealed stress responses and alterations in cell-cycle regulation as important mechanisms in the general osmotic response. Salinity-specific responses included the regulation of genes involved in ion transport, intracellular calcium, energetic processes and cellular remodeling. Genes diverged between populations were primarily those showing salinity-specific expression and included those regulating polyamine homeostasis and the cell cycle. Additionally, when populations were matched with their native salinity, expression patterns were consistent with the concept of 'transcriptomic resilience', suggesting local adaptation. These findings provide insight into the fate of a plastic phenotype after a shift in environmental salinity and help to reveal mechanisms allowing for euryhalinity. PMID- 25722002 TI - Distinct physiological strategies are used to cope with constant hypoxia and intermittent hypoxia in killifish (Fundulus heteroclitus). AB - Many fish encounter hypoxia on a daily cycle, but the physiological effects of intermittent hypoxia are poorly understood. We investigated whether acclimation to constant (sustained) hypoxia or to intermittent diel cycles of nocturnal hypoxia (12 h normoxia:12 h hypoxia) had distinct effects on hypoxia tolerance or on several determinants of O2 transport and O2 utilization in estuarine killifish. Adult killifish were acclimated to normoxia, constant hypoxia, or intermittent hypoxia for 7 or 28 days in brackish water (4 ppt). Acclimation to both hypoxia patterns led to comparable reductions in critical O2 tension and resting O2 consumption rate, but only constant hypoxia reduced the O2 tension at loss of equilibrium. Constant (but not intermittent) hypoxia decreased filament length and the proportion of seawater-type mitochondrion-rich cells in the gills (which may reduce ion loss and the associated costs of active ion uptake), increased blood haemoglobin content, and reduced the abundance of oxidative fibres in the swimming muscle. In contrast, only intermittent hypoxia augmented the oxidative and gluconeogenic enzyme activities in the liver and increased the capillarity of glycolytic muscle, each of which should facilitate recovery between hypoxia bouts. Neither exposure pattern affected muscle myoglobin content or the activities of metabolic enzymes in the brain or heart, but intermittent hypoxia increased brain mass. We conclude that the pattern of hypoxia exposure has an important influence on the mechanisms of acclimation, and that the optimal strategies used to cope with intermittent hypoxia may be distinct from those for coping with constant hypoxia. PMID- 25722003 TI - Sound pressure enhances the hearing sensitivity of Chaetodon butterflyfishes on noisy coral reefs. AB - Butterflyfishes are conspicuous members of coral reefs that communicate with acoustic signals during social interactions with mates and other conspecifics. Members of the genus Chaetodon have a laterophysic connection (LC) - a unique association of anterior swim bladder horns and the cranial lateral line - but the action of the LC system on auditory sensitivity is unexplored. Here, we show in baseline auditory evoked potential threshold experiments that Forcipiger flavissimus (which lacks swim bladder horns and LC) is sensitive to sound tones from 100 Hz up to 1000 Hz, and that thresholds for three species of Chaetodon are 10-15 dB lower, with extended hearing ranges up to 1700-2000 Hz. The relatively high thresholds to sound pressure and low pass response near 500 Hz for all four species are consistent with a primary sensitivity to hydrodynamic particle acceleration rather than sound pressure. Deflation of the swim bladder in F. flavissimus had no measurable effect on auditory sensitivity. In contrast, displacement of gas from the swim bladder horns in Chaetodon multicinctus and Chaetodon auriga increased thresholds (decreased sensitivity) by 5-20 dB, with the greatest effect at 600 Hz. The evolution of swim bladder horns associated with the LC system in Chaetodon species has increased hearing sensitivity through sound pressure transduction in the frequency bands used for social acoustic communication. The close affiliative behaviors that are common in Chaetodon species and other butterflyfish facilitate sound perception and acoustic communication at close distances relative to the high background noise levels found in their natural reef environment. PMID- 25722004 TI - Trophic dynamics of scleractinian corals: stable isotope evidence. AB - Reef-building corals form symbioses with dinoflagellates from the diverse genus Symbiodinium. This symbiotic association has developed adaptations to acquire and share nutrients, which are essential for its survival and growth in nutrient-poor tropical waters. The host is thus able to prey on a wide range of organic food sources (heterotrophic nutrition) whereas the symbionts acquire most of the inorganic nutrients (autotrophic nutrition). However, nutrient fluxes between the two partners remain unclear, especially concerning heterotrophically acquired carbon and nitrogen. We combined physiological measurements and pulse-chase isotopic labeling of heterotrophic carbon and nitrogen, as well as autotrophic carbon to track nutrient fluxes in two coral species, Stylophora pistillata and Turbinaria reniformis, in symbiosis with Symbiodinium clades A, and C,D respectively. We showed a rapid acquisition, exchange and a long-term retention of heterotrophic nutrients within the symbiosis, whereas autotrophic nutrients were rapidly used to meet immediate metabolic needs. In addition, there was a higher retention of heterotrophic nitrogen compared with carbon, in agreement with the idea that tropical corals are nitrogen-limited. Finally, a coupling between auto- and heterotrophy was observed in the species S. pistillata, with a higher acquisition and retention of heterotrophic nutrients under low irradiance to compensate for a 50% reduction in autotrophic nutrient acquisition and translocation. Conversely, T. reniformis conserved an equivalent heterotrophic nutrient acquisition at both light levels because this coral species did not significantly reduce its rates of gross photosynthesis and autotrophic carbon acquisition between the two irradiances. These experiments advance the current understanding of the nutrient exchanges between the two partners of a symbiotic association, providing evidence of the complexity of the host-symbiont relationship. PMID- 25722005 TI - The role of acid-sensing ion channels in epithelial Na+ uptake in adult zebrafish (Danio rerio). AB - Acid-sensing ion channels (ASICs) are epithelial Na(+) channels gated by external H(+). Recently, it has been demonstrated that ASICs play a role in Na(+) uptake in freshwater rainbow trout. Here, we investigate the potential involvement of ASICs in Na(+) transport in another freshwater fish species, the zebrafish (Danio rerio). Using molecular and histological techniques we found that asic genes and the ASIC4.2 protein are expressed in the gill of adult zebrafish. Immunohistochemistry revealed that mitochondrion-rich cells positive for ASIC4.2 do not co-localize with Na(+)/K(+)-ATPase-rich cells, but co-localize with cells expressing vacuolar-type H(+)-ATPase. Furthermore, pharmacological inhibitors of ASIC and Na(+)/H(+)-exchanger significantly reduced uptake of Na(+) in adult zebrafish exposed to low-Na(+) media, but did not cause the same response in individuals exposed to ultra-low-Na(+) water. Our results suggest that in adult zebrafish ASICs play a role in branchial Na(+) uptake in media with low Na(+) concentrations and that mechanisms used for Na(+) uptake by zebrafish may depend on the Na(+) concentration in the acclimation medium. PMID- 25722006 TI - Slime moulds use heuristics based on within-patch experience to decide when to leave. AB - Animals foraging in patchy, non-renewing or slowly renewing environments must make decisions about how long to remain within a patch. Organisms can use heuristics ('rules of thumb') based on available information to decide when to leave the patch. Here, we investigated proximate patch-departure heuristics in two species of giant, brainless amoeba: the slime moulds Didymium bahiense and Physarum polycephalum. We explicitly tested the importance of information obtained through experience by eliminating chemosensory cues of patch quality. In P. polycephalum, patch departure was influenced by the consumption of high, and to a much lesser extent low, quality food items such that engulfing a food item increased patch-residency time. Physarum polycephalum also tended to forage for longer in darkened, 'safe' patches. In D. bahiense, engulfment of any food item increased patch residency irrespective of that food item's quality. Exposure to light had no effect on the patch-residency time of D. bahiense. Given that these organisms lack a brain, our results illustrate how the use of simple heuristics can give the impression that individuals make sophisticated foraging decisions. PMID- 25722007 TI - Natural selection constrains personality and brain gene expression differences in Atlantic salmon (Salmo salar). AB - In stream-spawning salmonid fishes there is a considerable variation in the timing of when fry leave the spawning nests and establish a feeding territory. The timing of emergence from spawning nests appears to be related to behavioural and physiological traits, e.g. early emerging fish are bolder and more aggressive. In the present study, emerging Atlantic salmon (Salmo salar L.) alevins were sorted into three fractions: early, intermediate and late emerging. At the parr stage, behaviour, stress responses, hindbrain monoaminergic activity and forebrain gene expression were explored in fish from the early and late emerging fractions (first and last 25%). The results show that when subjected to confinement stress, fish from the late emerging fraction respond with a larger activation of the brain serotonergic system than fish from the early fraction. Similarly, in late emerging fish, stress resulted in elevated expression of mRNA coding for serotonin 1A receptors (5-HT1A), GABA-A receptor-associated protein and ependymin, effects not observed in fish from the early emerging fraction. Moreover, fish from the early emerging fraction displayed bolder behaviour than their late emerging littermates. Taken together, these results suggest that time of emergence, boldness and aggression are linked to each other, forming a behavioural syndrome in juvenile salmon. Differences in brain gene expression between early and late emerging salmon add further support to a relationship between stress coping style and timing of emergence. However, early and late emerging salmon do not appear to differ in hypothalamus-pituitary-interrenal (HPI) axis reactivity, another characteristic of divergent stress coping styles. PMID- 25722008 TI - Sex pheromones in mate assessment: analysis of nutrient cost of sex pheromone production by females of the moth Heliothis virescens. AB - It has been postulated that sex pheromones, in addition to their role in mate recognition and/or finding, may also serve a role in assessment of mate quality. For this, a sex pheromone must give honest information about a signaler's quality, with honesty ensured by a direct metabolic or indirect fitness cost to the signaler. Using a stable isotope tracer-tracee method, we characterized the nutrient pools that fuel sex pheromone production in females of the moth Heliothis virescens, as well as the relative importance of larval- and adult acquired nutrients to this process. Females used three pools for de novo biosynthesis of sex pheromone, hemolymph trehalose, glycogen (via trehalose) and fat, and produced ca. 25% of pheromone directly from stored (previously synthesized) precursor fatty acids. Pheromone was produced roughly equally from carbohydrate and fat. Adult feeding was very important for pheromone biosynthesis, with a maximum of 65% of de novo biosynthesized pheromone produced from a single adult feed (carbohydrate). Although these nutrient pools are shared with other reproductive physiologies, notably oocyte production, it is unlikely that pheromone production imposes a significant metabolic cost on females, because (i) the amount of nutrients used for pheromone production is negligible compared with that available, (ii) the hemolymph trehalose pool is readily replaceable throughout the adult life, and (iii) in mated females, carbohydrate shortages result in reduced allocation to pheromone. PMID- 25722009 TI - Effect of topical prostaglandin analogues on corneal hysteresis. AB - PURPOSE: To evaluate possible changes in corneal hysteresis (CH) after topical treatment with a prostaglandin analogue in medication-naive eyes. METHODS: This was a prospective, observational cohort study. Sixty-eight eyes of 68 patients were prospectively included who were newly diagnosed with primary open-angle glaucoma or ocular hypertension in our institution. All patients were treatment naive. Patients were evaluated at baseline and after 6 months of treatment with latanoprost in the eye with the lower intraocular pressure (IOP) measured by Goldmann applanation tonometry (GAT). The ocular response analyzer was used to measure CH. RESULTS: CH increased significantly (p = 0.0001) from 8.96 +/- 2.3 mmHg to 9.79 +/- 1.97 mmHg, and this increase was correlated significantly (p = 0.0001, r = 0.64, r(2) = 0.41) with the basal CH. We identified a weak but significant (r(2) = 0.06, p = 0.01) relationship between the basal CH and the drug-induced reduction of the GAT IOP. Nevertheless, the increase in the drug induced CH was not correlated with the decrease in the GAT IOP. CONCLUSION: Treatment with latanoprost increases CH. The CH increase was not correlated with the drug-induced decrease in the GAT IOP, which suggested a direct effect of latanoprost on the viscoelastic corneal properties. PMID- 25722010 TI - Reply: To PMID 25164003. PMID- 25722012 TI - There is level 1 evidence for intensive glycemic control for reducing the progression of diabetic retinopathy in persons with type 2 diabetes. PMID- 25722011 TI - Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism. AB - Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [(3)H2] dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism. PMID- 25722014 TI - Human chorionic gonadotropin improves endometriosis through downregulation of leptin expression in rats. AB - OBJECTIVE: To investigate whether and how human chorionic gonadotropin (HCG) treatment ameliorates endometriosis in an endometriotic rat model. METHODS: Twenty-four endometriosis rats were established and were randomly divided into four groups, and then the rats were treated with 19.4, 25.8, and 51.6 IU/100 g weight/day of HCG, respectively. The control group was treated with 0.9% NaCl. After 15 days (3 estrous cycles), the ectopic lesion volume and the expression of leptin protein in eutopic and ectopic endometrium were investigated. RESULTS: After HCG treatment, the volumes of endometriotic lesions were significantly smaller than those before treatment. During endometriosis development, the expression of leptin protein in eutopic and ectopic endometrium was remarkably increased. HCG administration reversed leptin upregulation in endometriotic tissues. CONCLUSION: HCG therapy appears to be an effective treatment for endometriosis in rats through down-regulation of leptin expression in eutopic and ectopic endometrium. PMID- 25722013 TI - Epigenetic alterations in human parathyroid tumors. AB - Epigenetics alterations are involved in tumorigenesis and have been identified in endocrine neoplasia. In particular, DNA methylation, microRNAs deregulations and histone methylation impairment are detected in tumors of the parathyroid glands. Parathyroid tumors are the second most common endocrine neoplasia following thyroid cancer in women, and it is associated with primary hyperparathyroidism, a disease sustained by PTH hypersecretion. Despite the hallmark of global promoter hypomethylations was not detectable in parathyroid tumors, increase of hypermethylation in specific CpG islands was detected in the progression from benign to malignant parathyroid tumors. Furthermore, deregulation of a panel of embryonic-related microRNAs (miRNAs) was documented in parathyroid tumors compared with normal glands. Impaired expression of the histone methyltransferases EZH2, BMI1, and RIZ1 have been described in parathyroid tumors. Moreover, histone methyltransferases have been shown to be modulated by the oncosuppressors HIC1, MEN1, and HRPT2/CDC73 gene products that characterize tumorigenesis of parathyroid adenomas and carcinomas, respectively. The epigenetic scenario in parathyroid tumors have just began to be decoded but emerging data highlight the involvement of an embryonic gene signature in parathyroid tumor development. PMID- 25722015 TI - Acrophobia impairs visual exploration and balance during standing and walking. AB - This review shows that persons with visual height intolerance or acrophobia exhibit typical restrictions of visual exploration and imbalance during stance and locomotion when exposed to heights. Eye and head movements are reduced, and gaze freezes to the horizon. Eye movements tend to be horizontal saccades during stance and vertical saccades during locomotion. Body posture is characterized by a stiffening of the musculoskeletal system with increased open-loop diffusion activity of body sway, a lowered sensory feedback threshold for closed-loop balance control, and increased co-contraction of antigravity leg and neck muscles. Walking is slow and cautious, broad-based, consisting of small, flat footed steps with less dynamic vertical oscillation of the body and head. Anxiety appears to be the critical symptom that causes the typical but not specific eye and body motor behavior, which can be described as tonic immobility. Guidelines for preventing acrophobia, which could be an add-on to behavioral therapy, are provided. PMID- 25722016 TI - Newborn meconium and urinary metabolome response to maternal gestational diabetes mellitus: a preliminary case-control study. AB - Recently, the number of women suffering from gestational diabetes mellitus (GDM) has risen dramatically. GDM attracts increasing attention due to its potential harm to the heath of both the fetus and the mother. We designed this case-control study to investigate the metabolome response of newborn meconium and urine to maternal GDM. GDM mothers (n = 142) and healthy controls (n = 197) were recruited during June-July 2012 in Xiamen, China. The newborns' metabolic profiles were acquired using liquid chromatography coupled to mass spectrometry. The data showed that meconium and urine metabolome patterns clearly discriminated GDM cases from controls. Fourteen meconium metabolic biomarkers and three urinary metabolic biomarkers were tentatively identified for GDM. Altered levels of various endogenous biomarkers revealed that GDM may induce disruptions in lipid metabolism, amino acid metabolism, and purine metabolism. An unbalanced lipid pattern is suspected to be a GDM-specific feature. Furthermore, the relationships between the potential biomarkers and GDM risk were evaluated by binary logistic regression and receiver operating characteristic analysis. A combined model of nine meconium biomarkers showed a great potential in diagnosing GDM-induced disorders. PMID- 25722017 TI - Prenatal diagnosis of a female fetus with ring chromosome 9, 46,XX,r(9)(p24q34), and a de novo interstitial 9p deletion. AB - Ring chromosomes are circular structures formed as a result of breaks in the chromosome arms and the fusion of the proximal broken ends with a loss of distal material, or by fusion of dysfunctional telomeres without any loss. The mechanism underlying this process has not yet been sufficiently explained. Commonly, rings occur as acquired genetic abnormalities; however, sometimes they are found as constitutional aberrations with a prevalence of around 1:50,000 live births. Here, we present a new case of r(9) in a female fetus with intrauterine growth retardation and slight craniofacial dysmorphisms. Both parents had a normal phenotype. Amniotic fluid karyotype showed r(9)(p24q34). An array CGH revealed 3 deletion segments: a ring chromosome with a 2.57-Mb deletion at 9pterp24.2 (chr9:163,131-2,729,722), a 2.60-Mb deletion at 9q34.3qter (chr9:138,523,302 141,122,055), and also a 0.15-Mb interstitial deletion at 9p24.1 (chr9:5,090,443 5,235,765). These deletions overlap with proposed regions for the 9p24.3 deletion and Kleefstra syndrome. Segregation analysis revealed a maternal origin of the rearranged chromosome. We conclude that both the ring chromosome and the interstitial deletion occurred de novo. This last deletion has not been reported before. Prenatal array CGH, combined with fine mapping of breakpoints contributes to the assessment of genotype-phenotype correlations. PMID- 25722018 TI - Genetic diversity of Cryptosporidium spp. including novel identification of the Cryptosporidium muris and Cryptosporidium tyzzeri in horses in the Czech Republic and Poland. AB - Faecal samples were collected from 352 horses on 23 farms operating under six different management systems in the Czech Republic and Poland during 2011 and 2012. Farms were selected without previous knowledge of parasitological status. All faecal samples were screened for Cryptosporidium spp. presence using microscopy, following aniline-carbol-methyl violet staining and PCR analysis of the small-subunit (SSU) rRNA and the 60-kDa glycoprotein (gp60) genes. Cryptosporidium muris-positive samples were additionally genotyped at four minisatellite markers: MS1 (encoding a hypothetical protein), MS2 (encoding a 90 kDa heat shock protein), MS3 (encoding a hypothetical protein) and MS16 (encoding a leucine-rich repeat family protein). Cryptosporidium spp. was detected by PCR in 12/352 (3.4%) samples from 4 out of 13 farms. None of the samples tested by microscopy was positive. There was no relationship between Cryptosporidium prevalence and age, sex, diarrhoea or management system; however, Cryptosporidium was found only on farms where horses were kept on pasture during the day and in a stable overnight. Sequence analyses of SSU and gp60 genes revealed the presence of C. muris RN66 (n = 9), Cryptosporidium parvum IIaA15G2R1 (n = 1), Cryptosporidium tyzzeri IXbA22R9 (n = 1), and Cryptosporidium horse genotype VIaA15G4 (n = 1). The C. muris subtypes were identified as MS1-M1, MS2-M4, novel MS2-M7 and MS16-M1 by multilocus sequence of three minisatellite loci. The MS3 locus was not amplified from any isolate. This is the first report of C. tyzzeri and C. muris subtypes from horses. PMID- 25722019 TI - Relation between stroke severity, patient characteristics and CT-perfusion derived blood-brain barrier permeability measurements in acute ischemic stroke. AB - PURPOSE: Increased blood-brain barrier permeability (BBBP) can result from ischemia. In this study the relation between stroke severity, patient characteristics and admission BBBP values measured with CT-perfusion (CTP) was investigated in acute ischemic stroke patients. METHODS: From prospective data of the Dutch Acute Stroke Study 149 patients with a middle cerebral artery stroke and extended CTP were selected. BBBP values were measured in the penumbra and infarct core as defined by CTP thresholds, and in the contra-lateral hemisphere. The relation between stroke (severity) variables and patient characteristics, including early CT signs, dense vessel sign (DVS), time to scan and National Institute of Health Stroke Score (NIHSS), and BBBP parameters in penumbra and infarct core was quantified with regression analysis. RESULTS: Early CT signs were related to higher BBBP values in the infarct core (B = 0.710), higher ipsi- to contra-lateral BBBP ratios (B = 0.326) and higher extraction ratios in the infarct core (B = 16.938). Females were found to have lower BBBP values in penumbra and infarct core (B = - 0.446 and - 0.776 respectively) and lower extraction ratios in the infarct core (B = - 10.463). If a DVS was present the ipsi- to contra-lateral BBBP ratios were lower (B = - 0.304). There was no relation between NIHSS or time to scan and BBBP values. CONCLUSION: Early CT signs are related to higher BBBP values in the infarct core, suggesting that only severe ischemic damage alters BBBP within the first hours after symptom onset. PMID- 25722020 TI - Intracranial Migration of Intravitreal Silicone Oil: A Case Report. PMID- 25722021 TI - Quo vadis? The challenges of recombinant protein folding and secretion in Pichia pastoris. AB - The development of Pichia pastoris as a production platform for recombinant proteins has been a remarkable success story over the last three decades. Stable cheap production processes and the good protein secretion abilities were pacemakers of this development. However, limitations of protein folding, glycosylation or secretion have been identified quite early on. With the availability of genome sequences and the development of systems biology characterization in the last 5 years, remarkable success in strain improvement was achieved. Here, we focus on recent developments of characterization and improvement of P. pastoris production strains regarding protein folding, intracellular trafficking, glycosylation and proteolytic degradation. PMID- 25722022 TI - Bacterial biodegradation and bioconversion of industrial lignocellulosic streams. AB - Lignocellulose is a term for plant materials that are composed of matrices of cellulose, hemicellulose, and lignin. Lignocellulose is a renewable feedstock for many industries. Lignocellulosic materials are used for the production of paper, fuels, and chemicals. Typically, industry focuses on transforming the polysaccharides present in lignocellulose into products resulting in the incomplete use of this resource. The materials that are not completely used make up the underutilized streams of materials that contain cellulose, hemicellulose, and lignin. These underutilized streams have potential for conversion into valuable products. Treatment of these lignocellulosic streams with bacteria, which specifically degrade lignocellulose through the action of enzymes, offers a low-energy and low-cost method for biodegradation and bioconversion. This review describes lignocellulosic streams and summarizes different aspects of biological treatments including the bacteria isolated from lignocellulose-containing environments and enzymes which may be used for bioconversion. The chemicals produced during bioconversion can be used for a variety of products including adhesives, plastics, resins, food additives, and petrochemical replacements. PMID- 25722023 TI - Characterisation of a novel thermostable endoglucanase from Alicyclobacillus vulcanalis of potential application in bioethanol production. AB - A novel endoglucanase encoding gene was cloned from Alicyclobacillus vulcanalis and expressed in E. coli. The deduced amino acid sequence showed highest identity with alpha-L-arabinofuranosidase-like proteins from glycoside hydrolase family 51. The recombinant enzyme was purified by affinity chromatography and characterised in terms of its potential suitability for lignocellulose hydrolysis at high temperature in the production of bioethanol. The purified enzyme displayed maximum activity at 80 degrees C and pH 3.6-4.5. Tween 20 was found to have a beneficial effect on enzyme activity and thermal stability. When incubated in the presence of 0.1% Tween 20, the enzyme retained full activity after 72 h at 70 degrees C and 78% of original activity after 72 h at 75 degrees C. Maximum activity was observed on carboxymethyl cellulose, and the purified enzyme also hydrolysed lichenan, barley beta-glucan and xylan. The purified enzyme decreased the viscosity of carboxymethyl cellulose when assessed at 70-85 degrees C and was capable of releasing reducing sugars from acid-pretreated straw at 70 and 75 degrees C. The results indicate the potential suitability of the enzyme for industrial application in the production of cellulosic bioethanol. PMID- 25722024 TI - Information on new drugs at market entry: retrospective analysis of health technology assessment reports versus regulatory reports, journal publications, and registry reports. AB - BACKGROUND: When a new drug becomes available, patients and doctors require information on its benefits and harms. In 2011, Germany introduced the early benefit assessment of new drugs through the act on the reform of the market for medicinal products (AMNOG). At market entry, the pharmaceutical company responsible must submit a standardised dossier containing all available evidence of the drug's added benefit over an appropriate comparator treatment. The added benefit is mainly determined using patient relevant outcomes. The "dossier assessment" is generally performed by the Institute for Quality and Efficiency in Health Care (IQWiG) and then published online. It contains all relevant study information, including data from unpublished clinical study reports contained in the dossiers. The dossier assessment refers to the patient population for which the new drug is approved according to the summary of product characteristics. This patient population may comprise either the total populations investigated in the studies submitted to regulatory authorities in the drug approval process, or the specific subpopulations defined in the summary of product characteristics ("approved subpopulations"). OBJECTIVE: To determine the information gain from AMNOG documents compared with non-AMNOG documents for methods and results of studies available at market entry of new drugs. AMNOG documents comprise dossier assessments done by IQWiG and publicly available modules of company dossiers; non AMNOG documents comprise conventional, publicly available sources-that is, European public assessment reports, journal publications, and registry reports. The analysis focused on the approved patient populations. DESIGN: Retrospective analysis. DATA SOURCES: All dossier assessments conducted by IQWiG between 1 January 2011 and 28 February 2013 in which the dossiers contained suitable studies allowing for a full early benefit assessment. We also considered all European public assessment reports, journal publications, and registry reports referring to these studies and included in the dossiers. DATA ANALYSIS: We assessed reporting quality for each study and each available document for eight methods and 11 results items (three baseline characteristics and eight patient relevant outcomes), and dichotomised them as "completely reported" or "incompletely reported (including items not reported at all)." For each document type we calculated the proportion of items with complete reporting for methods and results, for each item and overall, and compared the findings.Results 15 out of 27 dossiers were eligible for inclusion and contained 22 studies. The 15 dossier assessments contained 28 individual assessments of 15 total study populations and 13 approved subpopulations. European public assessment reports were available for all drugs. Journal publications were available for 14 out of 15 drugs and 21 out of 22 studies. A registry report in ClinicalTrials.gov was available for all drugs and studies; however, only 11 contained results. In the analysis of total study populations, the AMNOG documents reached the highest grade of completeness, with about 90% of methods and results items completely reported. In non-AMNOG documents, the rate was 75% for methods and 52% for results items; journal publications achieved the best rates, followed by European public assessment reports and registry reports. The analysis of approved subpopulations showed poorer complete reporting of results items, particularly in non-AMNOG documents (non-AMNOG versus AMNOG: 11% v 71% for overall results items and 5% v 70% for patient relevant outcomes). The main limitation of our analysis is the small sample size. CONCLUSION: Conventional, publicly available sources provide insufficient information on new drugs, especially on patient relevant outcomes in approved subpopulations. This type of information is largely available in AMNOG documents, albeit only partly in English. The AMNOG approach could be used internationally to develop a comprehensive publication model for clinical studies and thus represents a key open access measure. PMID- 25722025 TI - Detecting the temporal structure of sound sequences in newborn infants. AB - Most high-level auditory functions require one to detect the onset and offset of sound sequences as well as registering the rate at which sounds are presented within the sound trains. By recording event-related brain potentials to onsets and offsets of tone trains as well as to changes in the presentation rate, we tested whether these fundamental auditory capabilities are functional at birth. Each of these events elicited significant event-related potential components in sleeping healthy neonates. The data thus demonstrate that the newborn brain is sensitive to these acoustic features suggesting that infants are geared towards the temporal aspects of segregating sound sources, speech and music perception already at birth. PMID- 25722026 TI - Design and solid phase synthesis of new DOTA conjugated (+)-biotin dimers planned to develop molecular weight-tuned avidin oligomers. AB - Chemical modifications of the biotin carrier in pretargeted avidin-biotin radionuclide therapy may be of paramount importance for tuning the amount of the radioactivity delivered to cancer cells by labelled biotins. We report here the synthesis of a collection of new synthetic DOTA-constructs bearing two (+)-biotin molecules (bis-biotins), designed for the creation of multimeric Av units (tetramers) bonded to the antibody. All the syntheses were carried out following the solid phase strategy and growing the molecules on a Rink Amide resin. The biotin heads are connected through spacers containing PEG or non-PEG residues. Molecular modelling calculations suggested that the Av cross-linking ability of the bis-biotins depends mainly on the spacers length, with the best results being expected for arms affording distances in the range of 10-25 A between the biotin carboxylate atoms, in the fully extended conformation. SEC-HPLC MALLS analysis of the products of our Av/bis-biotin reaction mixtures have confirmed this hypothesis. The bis-biotin 16, where the non-PEG linker ensured a distance of 26.7 A between the biotin moieties, gave about 50% of Av oligomers while the shorter analogue 18 (19.5 A) afforded 100% of an Av polymer containing about 21 protein units. Remarkably, the solubility of both the bis-biotins, i.e.16 and 18, in aqueous solutions was good and they showed excellent stability against the action of peptidases. PMID- 25722027 TI - Effects of low-intensity ultrasound on oxidative damage in retinal pigment epithelial cells in vitro. AB - Oxidative stress in retinal pigment epithelium (RPE) is one of the key causative factors of RPE injury in age-related macular degeneration (AMD). Low-intensity ultrasound (LIUS) less than 1 W/cm(2) in intensity has been found to have cytoprotective and anti-inflammatory effects in many cell types and diseases. In this study, we investigated for the first time the feasibility of using LIUS to protect RPE cells from oxidative damage. ARPE-19 cells were treated with H2O2 (an exogenous source of reactive oxygen species) or L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthase inhibitor, and exposed immediately to LIUS at intensities of 50, 100 and 200 mW/cm(2) and a frequency of 1 MHz for 20 min. Both H2O2 and BSO increased the percentage of cells positive for mitochondrial reactive oxygen species at 1 h, but not at 24 h. Co-treatment with LIUS clearly repressed these cells similarly at all intensities by approximately 34%-43% for H2O2 and 24%-25% for BSO (p < 0.05). The percentage of cells with mitochondrial membrane depolarization also increased with H2O2 and BSO treatment, particularly at 1 h, and decreased by approximately 60% with LIUS at 100 mW/cm(2) (p < 0.05). The amount of intracellular calcium ion ([Ca(2+)]i) was elevated only by BSO at 24 h and was also significantly diminished, by approximately 45%, by LIUS at 100 mW/cm(2) (p < 0.05). Both H2O2 and BSO significantly hampered cell viability at 24 h, but LIUS at 100 mW/cm(2) restored only BSO-induced cell viability by approximately 2.7-fold (p < 0.05). This study illustrated that LIUS has a protective effect on RPE cells against oxidative damage caused by BSO, an endogenous mitochondrial reactive oxygen species generator. We speculate that LIUS has the potential to treat oxidative damage and related pathologic changes in RPE. PMID- 25722028 TI - Comparison of carotid artery blood velocity measurements by vector and standard Doppler approaches. AB - Although severely affected by the angle dependency, carotid artery peak systolic velocity measurements are widely used for assessment of stenosis. In this study, blood peak systolic velocities in the common and internal carotid arteries of both healthy volunteers and patients with internal carotid artery stenosis were measured by two vector Doppler (VD) methods and compared with measurements obtained with the conventional spectral Doppler approach. Although the two VD techniques were completely different (using the transmission of focused beams and plane waves, respectively), the measurement results indicate that these techniques are nearly equivalent. The peak systolic velocities measured in 22 healthy common carotid arteries by the two VD techniques were very close (according to Bland-Altman analysis, the average difference was 3.2%, with limits of agreement of +/- 8.6%). Application of Bland-Altman analysis to comparison of either VD technique with the spectral Doppler method provided a 21%-25% average difference with +/- 13%-15% limits of agreement. Analysis of the results obtained from 15 internal carotid arteries led to similar conclusions, indicating significant overestimation of peak systolic velocity with the spectral Doppler method. Inter- and intra-operator repeatability measurements performed in a group of 8 healthy volunteers provided equivalent results for all of the methods (coefficients of variability in the range 2.7%-6.9%), even though the sonographers were not familiar with the VD methods. The results of this study suggest that the introduction of vector Doppler methods in commercial machines may finally be considered mature and capable of overcoming the angle-dependent overestimation typical of the standard spectral Doppler approach. PMID- 25722029 TI - What do we know about shear wave dispersion in normal and steatotic livers? AB - A number of new approaches to measure the viscoelastic properties of the liver are now available to clinicians, many involving shear waves. However, we are at an early stage in understanding the physical processes that govern shear wave propagation in normal liver, with more unknowns added when pathologies such as steatosis are present. This technical note focuses on what is known about the characterization of normal and steatotic (or fatty) livers, with a particular focus on dispersion. Some studies in phantoms and mouse livers support the hypothesis that, starting with a normal liver, increasing accumulations of micro- and macrosteatosis will increase the lossy viscoelastic properties of shear waves in a medium. This results in an increased dispersion (or slope) of shear wave speed and attenuation in the steatotic livers. Theoretical and empirical findings across a number of studies are summarized. PMID- 25722030 TI - Making mental health an integral part of sustainable development: the contribution of a social determinants framework. AB - There have been repeated calls to include mental health in the sustainable development goals (SDGs), arguing that progress in development will not be made without improvements in mental health. Although these calls are starting to gain political traction, currently only a tiny fraction of international development work includes mental health. A social determinants framework may be useful in incorporating mental health into sustainable development because it promotes a multi-sectorial and multi-disciplinary approach which is the corner stone of good development practice. Two approaches are suggested to make mental health a part of sustainable development: (1) integrate mental health into existing development programmes to promote social and economic environments that prevent mental health problems developing; (2) ensure that mental health programmes are better at promoting sustainable development by preventing the negative social and economic consequences of mental illness. Real-world examples of these approaches are provided. To achieve this, the mental health impact of wider development programmes, and the social and economic consequences of mental health interventions, must be evaluated. Development agencies should ensure that they have equity for mental health in all their policies, and investment must be increased for those mental health prevention, promotion and treatment programmes which have the greatest impact on sustainable development. The SDGs bring the promise of a more holistic approach to development. It is now the task of global mental health to demonstrate not just that mental health is an integral part of sustainable development, but that affordable and effective solutions exist which can improve mental health and development more broadly. PMID- 25722032 TI - Unusual osseous metastases from rectal adenocarcinoma: a case report and review of the literature. AB - INTRODUCTION: Rectal adenocarcinoma typically metastasizes to the liver. When osseous spread occurs, it is most commonly detected in the vertebrae and pelvis. Distal osseous spread is unusual and may be the first presentation of the carcinoma. We present a review of the current literature on unusual osseous rectal adenocarcinoma metastases and highlight a case of a scapular lesion as the first presentation of rectal carcinoma from our institution. MATERIALS AND METHODS: A Pubmed search using keywords 'rectal carcinoma metastases,' 'colorectal cancer metastases' and 'skeletal metastases' was performed. RESULTS: Twenty-four cases were identified (54 % male, mean age at diagnosis 61 +/- 16 years). The most common site was the mandible, followed by the foot. In four cases, the metastasis was the first presentation of the carcinoma. Mean time from resection of the primary tumour to osseous metastases diagnosis of skeletal metastases was 26 +/- 17 (SD) months. Mean time from diagnosis of skeletal metastases to death was 3.2 (+/-2.8) months. CONCLUSION: Rectal adenocarcinoma osseous metastases located distal to the pelvis and/or vertebrae are rare and associated with a poor prognosis. Unusual bony lesions should raise an index of suspicion for distal carcinoma, including rectal carcinoma. PMID- 25722033 TI - Langerhans cell precursors acquire RANK/CD265 in prenatal human skin. AB - The skin is the first barrier against foreign pathogens and the prenatal formation of a strong network of various innate and adaptive cells is required to protect the newborn from perinatal infections. While many studies about the immune system in healthy and diseased adult human skin exist, our knowledge about the cutaneous prenatal/developing immune system and especially about the phenotype and function of antigen-presenting cells such as epidermal Langerhans cells (LCs) in human skin is still scarce. It has been shown previously that LCs in healthy adult human skin express receptor activator of NF-kappaB (RANK), an important molecule prolonging their survival. In this study, we investigated at which developmental stage LCs acquire this important molecule. Immunofluorescence double-labeling of cryostat sections revealed that LC precursors in prenatal human skin either do not yet [10-11 weeks of estimated gestational age (EGA)] or only faintly (13-15 weeks EGA) express RANK. LCs express RANK at levels comparable to adult LCs by the end of the second trimester. Comparable with adult skin, dermal antigen-presenting cells at no gestational age express this marker. These findings indicate that epidermal leukocytes gradually acquire RANK during gestation - a phenomenon previously observed also for other markers on LCs in prenatal human skin. PMID- 25722034 TI - Co-expression of TTF-1 and neuroendocrine markers in the human fetal lung and pulmonary neuroendocrine tumors. AB - The expression pattern of thyroid transcription factor 1 (TTF-1) and neuroendocrine markers, neuron cell adhesion molecule (NCAM; CD56), chromogranin A (CgA) and synaptophysin (Syp), of different lung cell lineages was histologically analyzed in 15 normal human fetal lungs and 12 neuroendocrine tumors (NETs) using immunohistochemical methods. During pseudoglandular phase strong nuclear TTF-1 staining was detected in the columnar nonciliated epithelial cells, while NCAM, CgA and Syp had a moderate expression in the proximal airways and mild expression in the distal airways. Neuroendocrine cells (NECs) in proximal lung airway were co-localizing TTF-1 and other neuroendocrine markers while neuroendocrine bodies (NEBs) exhibit only staining with NCAM and Syp. In the canalicular phase TTF-1 nuclear staining was expressed only in several epithelial cells in proximal airways, while budding airways epithelium showed strong TTF-1 expression. Expression of NCAM, CgA and Syp in this phase equals the one in pseudoglandular phase. NEBs cells were co-localizing TTF-1 and NCAM in proximal airways and few NECs in distal airway were co-localizing TTF-1 and Syp. TTF-1 staining in the saccular phase was limited to subsets of epithelial cells in the proximal airways with stronger positivity in the distal airways. NCAM expression is moderate only in proximal airways, while Syp and CgA show mild expression in proximal and distal airways. NECs were co-localizing TTF-1 and NCAM in proximal lung airway. With regard to NECs, all small cell lung cancer (SCLC) cells had strong TTF-1, NCAM, Syp and CgA positivity and TTF-1 co-localized with other neuroendocrine markers. All pulmonary typical carcinoids were TTF-1 negative, while pulmonary atypical carcinoids were focal positive for TTF-1 and some neoplastic cells co-localized TTF-1 with neuroendocrine markers. Our results indicate that TTF-1 expression in NECs suggests a possible role in their normal development and differentiation. Our results also indicate that possible cell of origin for poorly differentiated SCLC and some atypical carcinoid could be a progenitor cell in neuroendocrine lineage while in typical carcinoids possible cell of origin is localized in terminally differentiated NECs. PMID- 25722035 TI - Proliferation, apoptosis and expression of matrix metalloproteinase-9 in human fetal lung. AB - Expression pattern of the Ki-67, caspase-3 and matrix metalloproteinases-9 (MMP 9) factors were immunohistochemically analyzed in 48 human fetal lungs from 12 to 40 weeks of gestation. The number of Ki-67 positive cells in the epithelium of canaliculare (88cells/mm(2)) and sacculare stage (93cells/mm(2)) were significantly higher than in the epithelium of pseudoglandular stage (12cells/mm(2)) (p=0.0008 vs. p=0.003). The number of Ki-67 positive cells in the mesenchyme of canaliculare stage (132cells/mm(2)) was significantly higher than in the mesenchyme of pseudoglandular stage (37cells/mm(2)) (p=0.001). The proliferation of mesenchymal cells was higher than the epithelial cells in all developmental stages, especially in the canaliculare stage (p=0.007). Similarly, the number of caspase-3 positive cells in the epithelium of canalicular stage (13cells/mm(2)) was significantly higher than in the epithelium of pseudoglandular stage (6cells/mm(2)) (p=0.002) with peaks in the conductive epithelium of canalicular stage. The number of caspase-3 positive cells in the mesenchyme of canaliculare stage (3cells/mm(2)) was significantly higher than in the mesenchyme of saccular stage (0cells/mm(2)) (p=0.05). There were no caspase-3 positive cells in the mesenchyme of pseudoglandular stage. However, unlike the Ki 67 expression, mesenchymal cells in comparison to epithelial cells express substantially less caspase-3 in all developmental stages. Up to the saccular stage, the expression of MMP-9 in mesenchymal cells showed a linear increase with most pronounced expression in that stage. The number of MMP-9 positive cells in the mesenchyme of canaliculare (20cells/mm(2)) and sacculare (39cells/mm(2)) stage were significantly higher than in the mesenchyme of pseudoglandular stage (12cells/mm(2)) (p=0.04 vs. p=0.004). The first epithelial cells that express MMP 9 were present only at the alveolar stage. Increased proliferation and apoptosis of the mesenchymal cells of canalicular stage is important for formation of definite structures within the stroma of the lung parenchyma. Although apoptosis in the epithelium is not pronounced as proliferation, it is important for thinning of the epithelium and consequent spread of respiratory tract. However in the saccular stage when mesenchyme disappears, MMP-9 expression is more important for primitive alveoli differentiation. PMID- 25722036 TI - The complete mitochondrial genome of the ice pigeon (Columba livia breed ice). AB - The ice pigeon is a breed of fancy pigeon developed over many years of selective breeding. In the present work, we report the complete mitochondrial genome sequence of ice pigeon for the first time. The total length of the mitogenome was 17,236 bp with the base composition of 30.2% for A, 24.0% for T, 31.9% for C, and 13.9% for G and an A-T (54.2 %)-rich feature was detected. It harbored 13 protein coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The arrangement of all genes was identical to the typical mitochondrial genomes of pigeon. The complete mitochondrial genome sequence of ice pigeon would serve as an important data set of the germplasm resources for further study. PMID- 25722037 TI - The complete mitochondrial genome of Ambastaia sidthimunki (Cypriniformes: Cobitidae). AB - Ambastaia sidthimunki is a beautiful small-sized fish and it was categorized as Endangered B2ab (iii,v) in the IUCN Red List. In this study, we reported the complete mitochondrial genome of the A. sidthimunki. The mitochondrial genome sequence was a circular molecule with 16,574 bp in length, and it contained 2 ribosomal RNA genes, 22 transfer RNA genes, 13 protein-coding genes, an L-strand replication origin (OL) and a control region (D-loop). The nucleotide acid composition of the entire mitogenome was 26.94% for C, 15.55% for G, 31.84% for A and 25.67% for T, with an AT content of 57.51%. This research contributes new molecular data for the conservation of this Endangered species. PMID- 25722038 TI - Fine-needle aspiration of superficial myxoid neurofibroma in the region of the breast. AB - Myxoid neurofibromas are benign spindle cell tumors of perineural cell origin with a broad pathologic differential diagnosis, which includes myxoma, myxoid liposarcoma, myxoid dermatofibrosarcoma protuberans, and low-grade fibromyxoid sarcoma. We present an unusual case of superficial myxoid neurofibroma in the region of the breast that underwent pre-operative fine-needle aspiration (FNA). The differential diagnosis for a myxoid subcutaneous lesion should include myxoid neurofibroma when myxoid material is encountered in an otherwise hypocellular FNA. PMID- 25722039 TI - Late Stenotrophomonas maltophilia pacemaker infective endocarditis. PMID- 25722041 TI - The glassy behaviour of poorly crystalline Fe2O3 nanorods obtained by thermal decomposition of ferrous oxalate. AB - Nanorod ferrous oxalate dihydrate (FeC2O4 * 2H2O) which had been synthesized by the microemulsion method, was used as a precursor in the thermal decomposition process performed in air atmosphere. The formation of nanocrystalline hematite as the final product was preceded by the appearence of an intermediate product. Comprehensive study comprising several complementary techniques (x-ray diffraction, transmission electron microscopy, selected area electron diffraction, thermogravimetric/differential thermal analyses and SQUID magnetometry) confirmed that the intermediate product corresponds to the poorly crystalline Fe2O3. Due to the specific nanorod shape and poorly crystalline structure, the investigated Fe2O3 showed high coercive field value of ~0.5 T at 5 K. Special attention in this study was devoted to the peculiar magnetic properties of poorly crystalline Fe2O3, which were thoroughly investigated by employing sophisticated experimental procedures such as relaxation of thermoremanent magnetization for different cooling fields, zero field and field cooled memory effects as well as aging experiments for different waiting times. At low temperatures and weak applied magnetic fields, the investigated system behaves similarly to spin glasses, manifesting slow, collective relaxation dynamics of magnetic moments through memory, rejuvenation and aging effects. PMID- 25722040 TI - Legionnaires' disease in France. AB - The aim of this review was to describe the current knowledge of Legionnaires' disease (LD) illustrated by the epidemiological situation in France in 2013. LD is a severe pneumonia commonly caused by Legionella pneumophila serogroup 1. The diagnosis is usually based on the urinary antigen test. This rapid method reduces the delay between clinical suspicion and initiation of an appropriate treatment. However, the availability of a clinical strain is important to improve knowledge of circulating bacteria, to document case clusters, and to identify the sources of contamination. The source of contamination is unknown in most cases. The main contamination sources generating aerosols are water network systems and cooling towers. Thanks to the strengthening of clinical and environmental monitoring and to several guidelines, no epidemic has been reported in France since 2006. Despite these efforts, the number of LD cases has not decreased in recent years. It is essential that applied research continue to better understand the spatial and temporal dynamics of the disease and its characteristics (impact of environmental factors, sources of exposure, strains, host, etc.). Fundamental knowledge has been greatly improved (pathogenesis, immune mechanisms, etc.). The results of this research should help define new strategies for the diagnosis, prevention, and control to decrease the number of LD cases diagnosed every year. PMID- 25722042 TI - Treating Treatment-Resistant Patients with Panic Disorder and Agoraphobia Using Psychotherapy: A Randomized Controlled Switching Trial. AB - Background: Nonresponsiveness to therapy is generally acknowledged, but only a few studies have tested switching to psychotherapy. This study is one of the first to examine the malleability of treatment-resistant patients using acceptance and commitment therapy (ACT). Methods: This was a randomized controlled trial that included 43 patients diagnosed with primary panic disorder and/or agoraphobia (PD/A) with prior unsuccessful state-of-the-art treatment (mean number of previous sessions = 42.2). Patients were treated with an ACT manual administered by novice therapists and followed up for 6 months. They were randomized to immediate treatment (n = 33) or a 4-week waiting list (n = 10) with delayed treatment (n = 8). Treatment consisted of eight sessions, implemented twice weekly over 4 weeks. Primary outcomes were measured with the Panic and Agoraphobia Scale (PAS), the Clinical Global Impression (CGI), and the Mobility Inventory (MI). Results: At post-treatment, patients who received ACT reported significantly more improvements on the PAS and CGI (d = 0.72 and 0.89, respectively) than those who were on the waiting list, while improvement on the MI (d = 0.50) was nearly significant. Secondary outcomes were consistent with ACT theory. Follow-up assessments indicated a stable and continued improvement after treatment. The dropout rate was low (9%). Conclusions: Despite a clinically challenging sample and brief treatment administered by novice therapists, patients who received ACT reported significantly greater changes in functioning and symptomatology than those on the waiting list, with medium-to-large effect sizes that were maintained for at least 6 months. These proof-of-principle data suggest that ACT is a viable treatment option for treatment-resistant PD/A patients. Further work on switching to psychotherapy for nonresponders is clearly needed. (c) 2015 S. Karger AG, Basel. PMID- 25722043 TI - An anionic phosphenium complex as an ambident nucleophile. AB - A unique anionic phosphenium complex was prepared from reaction of an N heterocyclic chlorophosphine with Collman's reagent or K[HFe(CO)4]/NaH and characterized by spectral and XRD data. The complex behaves as an ambident nucleophile. Reactions with acetic acid, ClSnPh3, and a further equivalent of an N-heterocyclic chlorophosphine proceed via electrophilic functionalization at the metal site to yield appropriate mono- or bis-phosphenium complexes. Reaction with MeI at -70 degrees C produces a P-alkylation product as the first spectroscopically detectable intermediate, which decays at a higher temperature to give a mixture of free P-methylated N-heterocyclic phosphine and its Fe(CO)4 complex. The different reaction products were characterized by spectral and XRD data. Computational studies indicate that the NHP units in all complexes display pi-acceptor behaviour but show no disposition to adopt phosphide-like character or formally oxidize the metal centre. PMID- 25722044 TI - Evolution of pigment-dispersing factor neuropeptides in Panarthropoda: Insights from Onychophora (velvet worms) and Tardigrada (water bears). AB - Pigment-dispersing factor (PDF) denotes a conserved family of homologous neuropeptides present in several invertebrate groups, including mollusks, nematodes, insects, and crustaceans (referred to here as pigment-dispersing hormone [PDH]). With regard to their encoding genes (pdf, pdh), insects possess only one, nematodes two, and decapod crustaceans up to three, but their phylogenetic relationship is unknown. To shed light on the origin and diversification of pdf/pdh homologs in Panarthropoda (Onychophora + Tardigrada + Arthropoda) and other molting animals (Ecdysozoa), we analyzed the transcriptomes of five distantly related onychophorans and a representative tardigrade and searched for putative pdf homologs in publically available genomes of other protostomes. This revealed only one pdf homolog in several mollusk and annelid species; two in Onychophora, Priapulida, and Nematoda; and three in Tardigrada. Phylogenetic analyses suggest that the last common ancestor of Panarthropoda possessed two pdf homologs, one of which was lost in the arthropod or arthropod/tardigrade lineage, followed by subsequent duplications of the remaining homolog in some taxa. Immunolocalization of PDF-like peptides in six onychophoran species, by using a broadly reactive antibody that recognizes PDF/PDH peptides in numerous species, revealed an elaborate system of neurons and fibers in their central and peripheral nervous systems. Large varicose projections in the heart suggest that the PDF neuropeptides functioned as both circulating hormones and locally released transmitters in the last common ancestor of Onychophora and Arthropoda. The lack of PDF-like-immunoreactive somata associated with the onychophoran optic ganglion conforms to the hypothesis that onychophoran eyes are homologous to the arthropod median ocelli. PMID- 25722045 TI - Multidisciplinary management of heart failure just beginning in Japan. AB - The mortality associated with end-stage heart failure (HF) is high despite the development of new and increasingly effective drugs and non-pharmacological therapies. Repetitive hospitalizations predict fatal outcomes and each hospitalization should prompt individual conversations with the patient, the family, and the caregivers. A multidisciplinary disease management program promotes the education of patients and their families and modifies their behavior, with a view to ultimately improve the prognosis and quality of life. From the early to the late stages of HF, a multidisciplinary disease management program should be implemented. In Western societies this multidisciplinary management has long been debated and endorsed, in contrast to Japan, where it has just begun. In 2012, the Japanese Nursing Association launched a certification in chronic HF nursing. A Japanese version of HF disease management should soon be developed in its own social environment. PMID- 25722046 TI - Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction. AB - BACKGROUND: Human atrial natriuretic peptide (hANP) and spontaneous nitric oxide (NO) donor share cyclic guanosine monophosphate (cGMP) as a second messenger, but their effect on myocardium may differ. We compared the effect of hANP and sodium nitroprusside (SNP) on left ventricular (LV) mechano-energetics in heart failure (HF). METHODS: Ten patients with HF due to previous myocardial infarction (LV ejection fraction: 45+/-3%) were instrumented with conductance and coronary sinus thermodilution catheters. LV contractility (Ees: slope of end-systolic pressure volume relation) and the ratio of LV stroke work (SW) to myocardial oxygen consumption (SW/MVO2=mechanical efficiency) were measured in response to intravenous infusion of ANP (0.05 MUg/kg/min) or SNP (0.3 MUg/kg/min) to lower blood pressure by at least 10 mmHg, and changes in plasma cGMP. RESULTS: SNP had no effect on Ees, SW, or MVO2, thus SW/MVO2 remained unchanged (40.54+/-5.84% to 36.59+/-5.72%, p=0.25). ANP increased Ees, and decreased MVO2 with preserved SW, resulting in improved SW/MVO2 (40.49+/-6.35% to 50.30+/-7.96%, p=0.0073). Infusion of ANP (10.42-34.95 pmol/ml, p=0.0003) increased cGMP levels, whereas infusion of SNP had no effect (10.42-12.23 pmol/ml, p=0.75). CONCLUSIONS: Compared to SNP, the ANP-dependent increase in cGMP may ameliorate myocardial inotropy and energetics in HF. PMID- 25722047 TI - Review of low-grade gliomas in children--evolving molecular era and therapeutic insights. AB - Low-grade gliomas are the commonest brain tumor in children comprising heterogeneous pathological entities. Though the overall prognosis is good, unresectable, and recurrent or progressive tumors in eloquent areas of the brain remain major therapeutic challenge even with advances in chemotherapeutic strategies. With the evolving surge of molecular data, improved understanding of the biology of these tumors is now perceivable that could provide insights into novel therapies. We hope the new era will enable us to profile comprehensive histopathological/molecular classification and prognostic molecular markers in these tumors and guide us to tailor optimal targeted therapy. PMID- 25722048 TI - The Gentle Giant: Kenneth Daniel Blackfan and his contributions to pediatric neurosurgery. PMID- 25722049 TI - "STA-MCA bypass with encephalo-duro-myo-synangiosis combined with bifrontal encephalo-duro-periosteal-synangiosis" as a one-staged revascularization strategy for pediatric moyamoya vasculopathy. AB - PURPOSE: Moyamoya vasculopathy progressively compromises cerebral blood flow resulting in chronic hypoperfusion. The middle cerebral artery (MCA) territory and the bifrontal areas are the regions most frequently affected. Although most techniques aim to only revascularize the MCA territory, augmentation of blood flow of the bifrontal areas is of importance in the pediatric moyamoya population since these regions play an important role in cognition, intellectual development, and in lower extremity and sphincter function. We recently described a one-staged surgical procedure combining revascularization of three regions, the MCA territory unilaterally and the frontal areas bilaterally. The purpose of this article is to report our surgical experience in eight children and to emphasize the rational for bifrontal revascularization. METHODS: We report a case series consisting of eight children where the following surgical strategy was applied: (1) a direct superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass with encephalo-duro-myo-synangiosis (EDMS) for unilateral MCA revascularization; in combination with (2) a bifrontal encephalo-duro-periosteal synangiosis (EDPS) for bifrontal revascularization. Patients' characteristics and 30-day follow-up data are reported. RESULTS: The patient group consisted of six girls and two boys (mean age 10.0, range 4.2-17.5 years): six children presented with moyamoya disease, two with moyamoya syndrome. We performed a one-staged revascularization of one MCA territory and both frontal areas in all patients. No significant complications occurred. Two patients experienced postoperative focal seizures, successfully treated with anti-epileptic medication. CONCLUSIONS: The single-staged STA-MCA bypass with EDMS combined with bifrontal EDPS allowed revascularization of three regions (the MCA territory unilaterally and the frontal areas bilaterally) and may serve as an alternative and safe treatment option for pediatric moyamoya patients. PMID- 25722050 TI - Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study. AB - Immune aberrations are often noted in children with autism spectrum disorder (ASD), but whether asthma and allergy are related to ASD is not well defined. This study examined asthma and allergies in association with ASD and phenotypic subsets. Participants were 560 children with confirmed ASD and 391 typically developing children from the CHildhood Autism Risks from Genetics and the Environment study. Maternally reported child asthma and allergy was compared between cases and controls, and in association with cognitive and behavioral test scores. Prevalence of asthma and overall allergies did not differ between cases and controls, but overall allergy in children with ASD was associated with higher stereotypy scores as measured by the Aberrant Behavior Checklist. In addition, reported food allergies were significantly associated with ASD (adjusted odds ratio = 2.23, 95% confidence interval 1.28, 3.89). Our results suggest food allergies and sensitivities may be more common in children with ASD, and that these issues may correlate with other behaviors. PMID- 25722051 TI - Mass spectrometry-based proteomic approaches to study pathogenic bacteria-host interactions. AB - Elucidation of molecular mechanisms underlying host-pathogen interactions is important for control and treatment of infectious diseases worldwide. Within the last decade, mass spectrometry (MS)-based proteomics has become a powerful and effective approach to better understand complex and dynamic host-pathogen interactions at the protein level. Herein we will review the recent progress in proteomic analyses towards bacterial infection of their mammalian host with a particular focus on enteric pathogens. Large-scale studies of dynamic proteomic alterations during infection will be discussed from the perspective of both pathogenic bacteria and host cells. PMID- 25722052 TI - CRISPR/Cas9 and TALE: beyond cut and paste. AB - Nuclease-based genome editing has proven to be a powerful and promising tool for disease modeling and gene therapy. Recent advances in CRISPR/Cas and TALE indicate that they could also be used as a targeted regulator of gene expression, as well as being utilized for illuminating specific chromosomal structures or genomic regions. PMID- 25722053 TI - Identification and expression analysis of 26 oncogenes of the receptor tyrosine kinase family in channel catfish after bacterial infection and hypoxic stress. AB - Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones. RTKs are not only key regulators of normal cellular processes, but are also involved in the progression of many types of tumors, and responses to various biotic and abiotic stresses. Catfish is a primary aquaculture species in the United States, while its industry is drastically hindered by several major diseases including enteric septicemia of catfish (ESC) that is caused by Edwardsiella ictaluri. Disease outbreaks are often accompanied by hypoxic stress, which affects the performance and survival of fish by reducing disease resistance. In this study, we identified 26 RTK oncogenes in the channel catfish genome, and determined their expression profiles after ESC infection and hypoxic stress. The 26 RTK genes were divided into four subfamilies according to phylogenetic analysis, including TIE (2 genes), ErbB (6 genes), EPH (14 genes), and INSR (4 genes). All identified RTKs possess a similar molecular architecture including ligand-binding domains, a single transmembrane helix and a cytoplasmic region, which suggests that these genes could play conserved biological roles. The expression analysis revealed that eight RTKs were significantly regulated after bacterial infection, with dramatic induction of insulin receptor genes including INSRb, IGF1Ra, and IGF1Rb. Upon hypoxic stress, EPHB3a, EGFR, ErbB4b, and IGF1Rb were expressed at higher levels in the tolerant catfish, while EPHA2a, EPHA2, TIE1 and INSRa were expressed at higher levels in the intolerant catfish. These results suggested the involvement of RTKs in immune responses and hypoxic tolerance. PMID- 25722054 TI - Coxiella burnetii seroprevalence. PMID- 25722055 TI - One Health surveillance - More than a buzz word? AB - One Health surveillance describes the systematic collection, validation, analysis, interpretation of data and dissemination of information collected on humans, animals and the environment to inform decisions for more effective, evidence- and system-based health interventions. During the second International Conference on Animal Health Surveillance (ICAHS) in Havana, Cuba, a panel discussion was organised to discuss the relevance of One Health in the context of surveillance. A number of success stories were presented which generally focused on the obvious interfaces between human and veterinary medicine such as zoonoses and food safety. Activities aimed at strengthening inter-sectoral networking through technical collaboration, conferences, workshops and consultations have resulted in recommendations to advance the One Health concept. There are also several One Health educational programmes offered as Masters programmes. Continuing challenges to One Health surveillance were identified at both technical as well as organisational level. It was acknowledged that the public health sector and the environmental sector could be engaged more in One Health activities. Legal issues, hurdles to data sharing, unclear responsibilities and structural barriers between ministries prevent integrated action. Policy makers in the health sector often perceive One Health as a veterinary-driven initiative that is not particularly relevant to their priority problems. Whilst some funding schemes allow for the employment of scientists and technicians for research projects, the development of a sustainable One Health workforce has yet to be broadly demonstrated. Funding opportunities do not explicitly promote the development of One Health surveillance systems. In addition, organisational, legal and administrative barriers may prevent operational implementation. Strategies and communication across sectors need to be aligned. Whilst at the technical or local level the formal separation can be bridged, separate funding sources and budgets can jeopardise the overall strategy, especially if funding cuts are later required. To overcome such challenges, a strong business case for One Health surveillance is needed. This should include the costs and benefits of One Health activities or projects including consequences of different strategies as well as risks. Integrated training should also be further promoted. Future ICAHS conferences should continue to provide a platform for discussing surveillance in the One Health context and to provide a forum for surveillance professionals from all relevant sectors to interact. PMID- 25722056 TI - Preclinical Models of Encephalopathy of Prematurity. AB - Encephalopathy of prematurity (EoP) encompasses the central nervous system (CNS) abnormalities associated with injury from preterm birth. Although rapid progress is being made, limited understanding exists of how cellular and molecular CNS injury from early birth manifests as the myriad of neurological deficits in children who are born preterm. More importantly, this lack of direct insight into the pathogenesis of these deficits hinders both our ability to diagnose those infants who are at risk in real time and could potentially benefit from treatment and our ability to develop more effective interventions. Current barriers to clarifying the pathophysiology, developmental trajectory, injury timing, and evolution include preclinical animal models that only partially recapitulate the molecular, cellular, histological, and functional abnormalities observed in the mature CNS following EoP. Inflammation from hypoxic-ischemic and/or infectious injury induced in utero in lower mammals, or actual prenatal delivery of more phylogenetically advanced mammals, are likely to be the most clinically relevant EOP models, facilitating translation to benefit infants. Injury timing, type, severity, and pathophysiology need to be optimized to address the specific hypothesis being tested. Functional assays of the mature animal following perinatal injury to mimic EoP should ideally test for the array of neurological deficits commonly observed in preterm infants, including gait, seizure threshold and cognitive and behavioral abnormalities. Here, we review the merits of various preclinical models, identify gaps in knowledge that warrant further study and consider challenges that animal researchers may face in embarking on these studies. While no one model system is perfect, insights relevant to the clinical problem can be gained with interpretation of experimental results within the context of inherent limitations of the chosen model system. Collectively, optimal use of multiple models will address a major challenge facing the field today - to identify the type and severity of CNS injury these vulnerable infants suffer in a safe and timely manner, such that emerging neurointerventions can be tailored to specifically address individual reparative needs. PMID- 25722057 TI - Arabidopsis MSH1 mutation alters the epigenome and produces heritable changes in plant growth. AB - Plant phenotypes respond to environmental change, an adaptive capacity that is at least partly transgenerational. However, epigenetic components of this interplay are difficult to measure. Depletion of the nuclear-encoded protein MSH1 causes dramatic and heritable changes in plant development, and here we show that crossing these altered plants with isogenic wild type produces epi-lines with heritable, enhanced growth vigour. Pericentromeric DNA hypermethylation occurs in a subset of msh1 mutants, indicative of heightened transposon repression, while enhanced growth epi-lines show large chromosomal segments of differential CG methylation, reflecting genome-wide reprogramming. When seedlings are treated with 5-azacytidine, root growth of epi-lines is restored to wild-type levels, implicating hypermethylation in enhanced growth. Grafts of wild-type floral stems to mutant rosettes produce progeny with enhanced growth and altered CG methylation strikingly similar to epi-lines, indicating a mobile signal when MSH1 is downregulated, and confirming the programmed nature of methylome and phenotype changes. PMID- 25722058 TI - Bees explain floral variation in a recent radiation of Linaria. AB - The role of pollinators in floral divergence has long attracted the attention of evolutionary biologists. Although abundant studies have reported the effect of pollinators on flower-shape variation and plant speciation, the influence of pollinators on plant species differentiation during rapid radiations and the specific consequences of shifts among similar pollinators are not well understood. Here, we evaluate the association between pollinators and floral morphology in a closely related and recently diversifying clade of Linaria species (sect. Supinae subsect. Supinae). Our approach combined pollinator observations, functional floral morphometric measures and phylogenetic comparative analyses. The fauna visiting Linaria species was determined by extensive surveys and categorized by a modularity algorithm, and the size and shape of flowers were analysed by means of standard and geometric morphometric measures. Standard measures failed to find relationships between the sizes of representative pollinators and flowers. However, discriminant function analyses of geometric morphometric data revealed that pollination niches are finer predictors of flower morphologies in Linaria if compared with phylogenetic relationships. Species with the most restrictive flowers displayed the most slender spurs and were pollinated by bees with larger proboscides. These restrictive flower shapes likely appeared more than once during the evolutionary history of the study group. We show that floral variation can be driven by shifts between pollinators that have been traditionally included in a single functional group, and discuss the consequences of such transitions for plant species differentiation during rapid radiations. PMID- 25722059 TI - Effects of Fe oxide on N transformations in subtropical acid soils. AB - Subtropical ecosystems are often characterized by high N cycling rates, but net nitrification rates are often low in subtropical acid soils. NO3(-)-N immobilization into organic N may be a contributing factor to understand the observed low net nitrification rates in these acid soils. The effects of Fe oxide and organic matter on soil N transformations were evaluated using a (15)N tracing study. Soil net nitrification was low for highly acidic yellow soil (Ferralsols), but gross ammonia oxidation was 7 times higher than net nitrification. In weakly acidic purple soil (Cambisols), net nitrification was 8 times higher than in Ferralsols. The addition of 5% Fe oxide to Cambisols, reduced the net nitrification rate to a negative rate, while NO3(-)-N immobilization rate increased 8 fold. NO3(-)-N immobilization was also observed in Ferralsols which contained high Fe oxides levels. A possible mechanism for these reactions could be stimulation of NO3(-)-N immobilization by Fe oxide which promoted the abiotic formation of nitrogenous polymers, suggesting that the absence of net nitrification in some highly acid soils may be due to high rates of NO3(-)-N immobilization caused by high Fe oxide content rather than a low pH. PMID- 25722060 TI - Is There Any Relationship between Plasma Pentraxin 3 Levels and Gestational Diabetes Mellitus? AB - BACKGROUND: Pentraxin 3 (PTX3) is a novel vascular inflammatory marker which increases in vascular events such as diabetes mellitus. The aim of this study was to investigate the relationship between serum PTX3 levels and gestational diabetes mellitus (GDM). METHODS: This prospective observational study was comprised of 88 pregnant women with singleton pregnancies. The subjects were classified into 3 groups according to their response to a 50-gram glucose challenge test (GCT) and a 100-gram oral glucose tolerance test: control group (n = 28), impaired glucose tolerance group (n = 30), and GDM group (n = 30). Serum PTX3 levels were measured to examine the relationship between GDM and GCT values. RESULTS: Significant differences in PTX3 levels were observed among the 3 groups in the sample (F = 7.598; p = 0.001). The mean PTX3 value was found to be significantly higher in the GDM group (3.17 +/- 1.16 ng/ml) than in the control group (2.20 +/- 0.83 ng/ml; p = 0.001). A significant positive correlation between PTX3 and GCT values was detected (r = 0.289; p = 0.008). CONCLUSION: Maternal serum PTX3 levels were found to be significantly related to high blood glucose levels. This may be an indicator of vascular pathology in GDM around the time of an oral glucose tolerance test. PMID- 25722061 TI - Effect of reproductive history, lactation, first pregnancy age and dietary habits on bone mineral density in natural postmenopausal women. AB - AIM: The aim of this study was to investigate the possible risk factors related with osteoporosis in women with spontaneous menopause. METHODS: Five hundred and one postmenopausal women were divided into three groups as normal, osteopenic and osteoporotic according to their bone mineral density (BMD). By face-to-face interview, parity, age at menarche, age at menopause, duration of fertility, duration of menopause, first pregnancy age, total lactation period, exercise, smoking were assessed. Women with menopause age before 40 years, surgical menopause, who had any anti-osteoporosis treatment, hormone replacement therapy at the time of BMD measurement and corticosteroid use longer than 6 months were excluded from the study. RESULTS: Among 501 postmenopausal women, 107 women were classified as normal, 170 as osteopenic and 224 as osteoporotic. Among demographic features of patients, there was statistically significant difference between the groups in age, BMI and parity (p < 0.001, p < 0.0001 and p = 0.002, respectively). There were statistically significant differences between the groups in case of age at menopause, duration of fertility and duration of menopause (p = 0.013, p = 0.013 and p < 0.0001, respectively). In the multivariate logistic regression analysis, BMI over 32 and fertility duration over 33 years had a statistically significant protective effect against osteoporosis (OR 0.42, CI 95 % 0.27-0.66; OR 0.36, CI 95 % 0.24-0.56, respectively), but age was positively correlated with osteoporosis (OR 1.13, CI 95 % 1.01-1.17) CONCLUSIONS: Duration of fertility (years of menstruation) longer than 33 years and body mass index higher than 32 seem to protect against postmenopausal osteoporosis. Age is also an independent risk factor for postmenopausal osteoporosis. PMID- 25722062 TI - Promoting physical activity in rheumatoid arthritis: a narrative review of behaviour change theories. AB - PURPOSE: Despite physical activity having significant health benefits for people with rheumatoid arthritis (RA), current levels of physical activity in this population are suboptimal. Changing behaviour is challenging and interventions aimed at increasing physical activity in this context have had varying levels of success. This review provides an overview of common behaviour change theories used in interventions to promote physical activity and their application for promoting physical activity in people with RA. METHOD: A scoping, narrative review was conducted of English language literature, using the search terms "physical activity/exercise" and keywords, which are associated with behaviour change interventions. The theoretical basis of such interventions in people with RA was assessed using the "theory coding scheme". RESULTS: Six theories which have been used in physical activity research are discussed. Further, four studies which aimed to increase physical activity levels in people with RA are explored in detail. CONCLUSIONS: To date, behaviour change interventions conducted in RA populations to increase physical activity levels have not had a strong theoretical underpinning. It is proposed that an intervention utilising the theory of planned behaviour is developed with the aim of increasing physical activity in people with RA. Implications for Rehabilitation Interventions to promote physical activity in the rheumatoid arthritis (RA) population have failed to change participants' behaviour. A small number of studies have used behaviour change theories in the development and delivery of interventions. The theory of planned behaviour is recommended as the theoretical basis for an intervention to promote physical activity in the RA population. PMID- 25722063 TI - Long-standing poliomyelitis and psychological health. AB - OBJECTIVE: To compare the psychological health of the individuals with long standing poliomyelitis, with or without post-polio syndrome (PPS), to the general population and to identify the role of work as well as other variables with regard to their psychological health. DESIGN: A cross-sectional study. SUBJECTS: One hundred and ninety-five polio patients attending postpolio clinic in Jerusalem. METHODS: Emotional distress (ED) was measured using the general health questionnaire (GHQ-12). Demographic, medical, social and functional data were recorded using a specific structured questionnaire. Each polio patient was compared to four age- and sex-matched controls. RESULTS: ED was higher in the polio population as compared to the general population. Within the polio population ED was inversely correlated with work status. No correlation was found between ED and the functional level of polio participants and no difference was found in GHQ score between polio participants with or without post-polio. In addition, ED was less affected by subjective perception of physical health among polio patients as compared to the general population. CONCLUSIONS: Long-standing poliomyelitis is associated with decreased psychological health as compared to the general population. Yet, the resilience of polio survivors is manifested by their ability to block further decline of their psychological health in spite of deterioration in their physical health. Work appears as a significant source of resilience in the polio population. Implications for Rehabilitation Individuals with long-standing poliomyelitis often suffer from high emotional distress and may benefit from psychotherapy aimed at reducing distress. As active employment status is associated with increased mental health among polio survivors, encouraging participation at work needs to be a significant component of psychotherapeutic programs. Polio survivors, although physically disabled, may be relatively resilient, as their mental health is less affected by their negative health perception. This and other expressions of resilience may serve as a platform for increasing personal growth among them by implementing hope-oriented psychotherapy. PMID- 25722064 TI - Emotional support for diabetes management: an international cross-cultural study. AB - PURPOSE: The purpose of this study was to explore how emotional support emerged in interactions between peer supporters (PSs) and adults living with type 2 diabetes. METHODS: Qualitative data were analyzed from 22 semistructured interviews with PSs in 3 settings: low-income Latinos in Chicago, middle-class Caucasians in the United Kingdom, and low-income African American women in North Carolina. Emotional support was defined as expressions of empathy, trust, and caring. RESULTS: Across all sites, emotional support gradually emerged over time, was often combined with informational support, and was conveyed both implicitly (through nonverbal actions connoting emotional acceptance; eg, a walk together without discussion of problems) and explicitly (eg, by reassurance or discussion of stressors). Cross-site differences did appear regarding the strategies to address barriers to diabetes management (eg, PSs in North Carolina and Chicago reported providing support for social stressors) and the role of PSs (eg, PSs in Chicago reported providing directive support). CONCLUSIONS: Across different settings and populations, emotional support for diabetes management evolved over time, was often integrated with informational support, and emerged through both implicit and explicit strategies that addressed varied context-specific stressors. PMID- 25722065 TI - Biochemical bone turnover markers in diabetes mellitus - A systematic review. AB - BACKGROUND: Diabetes mellitus is associated with an increased risk of fractures, which is not explained by bone mineral density. Other markers as bone turnover markers (BTMs) may be useful. AIM: To assess the relationship between BTMs, diabetes, and fractures. METHODS: A systematic literature search was conducted in August 2014. The databases searched were Medline at Pubmed and Embase. Medline at Pubmed was searched by "Diabetes Mellitus" (MESH) and "bone turnover markers" and Embase was searched using the Emtree by "Diabetes Mellitus" and "bone turnover", resulting in 611 studies. The eligibility criteria for the studies were to assess BTM in either type 1 diabetes (T1D) or type 2 diabetes (T2D) patients. RESULTS: Of the 611 eligible studies, removal of duplicates and screening by title and abstract lead to 114 potential studies for full-text review. All these studies were full-text screened for eligibility and 45 studies were included. Two additional studies were added from other sources. Among the 47 studies included there were 1 meta-analysis, 29 cross-sectional studies, 13 randomized controlled trials, and 4 longitudinal studies. Both T1D and T2D were studied. Most studies reported fasting BTM and excluded renal disease. CONCLUSION: Markers of bone resorption and formation seem to be lower in diabetes patients. Bone specific alkaline phosphatase is normal or increased, which suggests that the matrix becomes hypermineralized in diabetes patients. The BTMs: C-terminal cross-link of collagen, insulin-like growth factor-1, and sclerostin may potentially predict fractures, but longitudinal trials are needed. This article is part of a Special Issue entitled Bone and diabetes. PMID- 25722066 TI - Influence of laser photobiomodulation (GaAlAs) on salivary flow rate and histomorphometry of the submandibular glands of hypothyroid rats. AB - The aim of this study was to analyze the influence of laser photobiomodulation in salivary flow, weight, and histomorphometry of the submandibular glands of hypothyroid rats. Fifty-six male Wistar albino rats were divided in euthyroid group and hypothyroid group, treated with propylthiouracil (PTU) to induce hypothyroidism. Each group was divided into control (without laser) and laser groups (GaAlAs): lambda660 nm (40 mW), lambda780 nm (40 mW), and lambda780 nm (70 mW). The laser application on the submandibular gland occurred after 2 weeks of PTU treatment and repeatedly during 2 weeks every 48 h. The rats were anesthetized, tracheostomized, and the evaluation of the salivary flow rate (MUL/min/100 g body weight) was made by the weight of the saliva collected for 15 min from the first drop. After the animals' death, the glands were dissected and processed for histological analysis. There was an evident reduction of the salivary flow of hypothyroid rats in all groups in comparison to euthyroid group (Mann-Whitney test, p < 0.05). No significant difference was found in the salivary flow of rats that received laser photobiomodulation compared with their control groups. Histological analysis revealed a decrease in the parenchyma of the salivary glands of hypothyroid rats, but the laser was not able to reverse this process. Hypothyroid rats irradiated or not with laser showed acini and acinar cells with significantly smaller areas than euthyroid groups. The laser photobiomodulation protocol used was not able to change salivary flow or reverse the acinar atrophy process in the submandibular glands of hypothyroid rats. PMID- 25722067 TI - Light-emitting diode therapy (LEDT) before matches prevents increase in creatine kinase with a light dose response in volleyball players. AB - Low-level laser (light) therapy (LLLT) has been applied over skeletal muscles before intense exercise (muscular pre-conditioning) in order to reduce fatigue and muscle damage (measured by creatine kinase, CK) in clinical trials. However, previous exercise protocols do not exactly simulate the real muscle demand required in sports. For this reason, the aim of this randomized and double-blind placebo-controlled trial was to investigate whether light-emitting diode therapy (LEDT) applied over the quadriceps femoris muscles, hamstrings, and triceps surae of volleyball players before official matches could prevent muscle damage (CK) with a dose response, establishing a therapeutic window. A professional male volleyball team (12 athletes) was enrolled in this study, and LEDT was applied before 4 matches during a national championship. LEDT used an array of 200 light emitting diodes (LEDs) arranged in 25 clusters of 4 infrared LEDs (850 +/- 20 nm; 130 mW) and 25 clusters of 4 red LEDs (630 +/- 10 nm; 80 mW). Athletes were randomized to receive one of four different total doses over each muscle group in a double-blind protocol: 105 J (20 s), 210 J (40 s), 315 J (60 s), and placebo (no light for 30 s). CK in blood was assessed 1 h before and 24 h after each match. LEDT at 210 J avoided significant increases in CK (+10 %; P = 0.993) as well as 315 J (+31 %, P = 0.407). Placebo (0 J) allowed a significant increase in CK (+53 %; P = 0.012) as well as LEDT at 105 J (+59 %; P = 0.001). LEDT prevented significant increases of CK in blood in athletes when applied before official matches with a light dose response of 210-315 J, suggesting athletes might consider applying LEDT before competition. PMID- 25722068 TI - Lymphatic endothelial cancerization in papillary thyroid carcinoma: hidden evidence of lymphatic invasion. AB - We hypothesize that cystic structures in metastatic papillary thyroid carcinoma (PTC) develop along the framework of lymphatic channels. To investigate this phenomenon, different categories of PTC were immunostained for D2-40 and TTF1. In this study, reactivity for D2-40 was considered as positive when there is membranous staining as often seen in lymphatic endothelial cells. Thirty cases of PTC with lymph node metastasis or with potential for lymphatic invasion and 20 cases metastatic PTC in lymph nodes were reviewed and found to show double/mosaic immunoreactivity for TTF1/D2-40 in 40-100% of cases. PTC metastasis in lymph nodes with cysts and some branching lymphatic-like channels lined by follicular cells with or without nuclear features of PTC were diffusely reactive to TTF1, and focally to D2-40. For primary and metastatic PTC, focal membranous D2-40 reactivity was also demonstrated in cysts or cleft linings. For25 thyroid neoplasms with no known potential for lymphatic invasion, there was no such immunoreactivity. The mosaic or double immunoreactivity for TTF1/D2-40 suggests lymphatic cancerization and possible endothelial mimicry of follicular cells. Mosaic/double immunoreactivity is helpful to detect the hidden pattern of lymphatic invasion masquerading as 'benign-appearing' follicles and supports our hypothesis of malignant cells developing along the lymphatic framework. PMID- 25722069 TI - Transition-metal-free decarboxylation of dimethyl malonate: an efficient construction of alpha-amino acid esters using TBAI/TBHP. AB - A transition-metal-free decarboxylation coupling process for the preparation of alpha-amino acid esters, which succeeded in merging hydrolysis/decarboxylation/nucleophilic substitution, is well described. This strategy uses commercially available inexpensive starting materials, catalysts and oxidants and has a wide substrate scope and operational simplicity. PMID- 25722070 TI - Brain natriuretic peptide modulates calcium homeostasis and epidermal growth factor receptor gene signalling in asthmatic airways smooth muscle cells. AB - The airway epithelium acts as a barrier and provides a critical interface between the body and the external environment. Brain natriuretic peptide (BNP) plays an important role in several bronchial functions, including relaxation. BNP relaxes airways by binding and activating natriuretic peptide receptor-A expressed from the airway epithelium. Although relaxation effect has been extensively investigated, less is known about BNP-regulated intracellular biomolecular pathways leading to bronchial relaxation. To this aim, we investigated BNP effects on gene signalling of airway smooth muscle cells (ASM) obtained from donors with asthma by using a RT(2) profilerTM PCR array. When compared with control, treatment for 2 h with supernatant from BNP-treated (1 MUM) bronchial epithelial cells (BEAS-2B) induced in asthmatic ASM cells a rapid reduction of transcription of EGFR and genes involving in actin and calcium homeostasis, as those of Protein kinase C (PKC) and RhoA-ROCK gene pathways. Immunofluorescence and western blotting did not shown any difference comparing control and ASM cells treated with conditioned medium from BNP-treated BEAS-2B. This study provides evidence that the effect of BNP on relaxing bronchial in ASM cells is mediated from epithelium and associates to rapid changes of EGFR and calcium homeostasis associated gene levels. PMID- 25722071 TI - Budesonide increases TLR4 and TLR2 expression in Treg lymphocytes of allergic asthmatics. AB - BACKGROUND: Reduced innate immunity responses as well as reduced T regulatory activities characterise bronchial asthma. OBJECTIVES: In this study the effect of budesonide on the expression of TLR4 and TLR2 in T regulatory lymphocyte sub population was assessed. METHODS: TLR4 and TLR2 expression in total peripheral blood mononuclear cells (PBMC), in CD4+/CD25+ and in CD4+/CD25- was evaluated, by flow cytometric analysis, in mild intermittent asthmatics (n = 14) and in controls (n = 11). The in vitro effects of budesonide in modulating: TLR4 and TLR2 expression in controls and in asthmatics; IL-10 expression and cytokine release (IL-6 and TNF-alpha selected by a multiplex assay) in asthmatics were also explored. RESULTS: TLR4 and TLR2 were reduced in total PBMC from asthmatics in comparison to PBMC from controls. CD4+CD25+ cells expressed at higher extent TLR2 and TLR4 in comparison to CD4+CD25- cells. Budesonide was able to increase the expression of TLR4, TLR2 and IL-10 in CD4+/CD25 highly+ cells from asthmatics. TLR4 ligand, LPS induced Foxp3 expression. Budesonide was also able to reduce the release of IL-6 and TNF-alpha by PBMC of asthmatics. CONCLUSIONS: Budesonide potentiates the activity of Treg by increasing TLR4, TLR2 and IL-10 expression. This event is associated to the decreased release of IL-6 and TNF alpha in PBMC treated with budesonide. These findings shed light on new mechanisms by which corticosteroids, drugs widely used for the clinical management of bronchial asthma, control T lymphocyte activation. PMID- 25722072 TI - Parent Training in Autism Spectrum Disorder: What's in a Name? AB - Parent training (PT) is well understood as an evidence-based treatment for typically developing children with disruptive behavior. Within the field of autism spectrum disorder (ASD), the term parent training has been used to describe a wide range of interventions including care coordination, psychoeducation, treatments for language or social development, as well as programs designed to address maladaptive behaviors. As a result, the meaning of "parent training" in ASD is profoundly uncertain. This paper describes the need to delineate the variants of PT in ASD and offers a coherent taxonomy. Uniform characterization of PT programs can facilitate communication with families, professionals, administrators, and third-party payers. Moreover, it may also serve as a framework for comparing and contrasting PT programs. In support of the taxonomy, a purposive sampling of the literature is presented to illustrate the range of parent training interventions in ASD. PMID- 25722073 TI - Catalytic effect of light illumination on bioleaching of chalcopyrite. AB - The influence of visible light exposure on chalcopyrite bioleaching was investigated using Acidithiobacillus ferrooxidans. The results indicated, in both shake-flasks and aerated reactors with 8500-lux light, the dissolved Cu was 91.80% and 23.71% higher, respectively, than that in the controls without light. The catalytic effect was found to increase bioleaching to a certain limit, then plateaued as the initial chalcopyrite concentration increased from 2% to 4.5%. Thus a balanced mineral concentration is highly amenable to bioleaching via offering increased available active sites for light adsorption while eschewing mineral aggregation and screening effects. Using semiconducting chalcopyrite, the light facilitated the reduction of Fe(3+) to Fe(2+) as metabolic substrates for A.ferrooxidans, leading to better biomass, lower pH and redox potential, which are conducive to chalcopyrite leaching. The light exposure on iron redox cycling was further confirmed by chemical leaching tests using Fe(3+), which exhibited higher Fe(2+) levels in the light-induced system. PMID- 25722074 TI - Differences in contraceptive use between family planning providers and the U.S. population: results of a nationwide survey. AB - OBJECTIVES: To describe contraceptive use among U.S. female family planning providers and to compare their contraceptive choices to the general population. STUDY DESIGN: We surveyed a convenience sample of female family planning providers ages 25-44 years, including physicians and advanced practice clinicians, via an internet-based survey from April to May 2013. Family planning providers were compared to female respondents ages 25-44 years from the 2011-2013 National Survey of Family Growth. RESULTS: A total of 488 responses were eligible for analysis; 331 respondents (67.8%) were using a contraceptive method. Providers' contraceptive use differed markedly from that of the general population, with providers significantly more likely to use intrauterine contraception, an implant, and the vaginal ring. Providers were significantly less likely to use female sterilization and condoms. There were no significant differences between providers and the general population in use of partner vasectomy or the pill. Long-acting reversible contraception (LARC) use was significantly higher among providers than in the general population (41.7% vs. 12.1%, p<.001). These results were consistent when stratifying by variables including self-identified race/ethnicity and educational level. CONCLUSIONS: The contraceptive choices of this sample of female family planning providers differed significantly from the general population. These findings have implications for clinical practice, patient education, and health policy. IMPLICATIONS: Family planning providers report higher use of LARC than the general population. This may reflect differences in preferences and access. Providers might consider sharing these findings with patients, while maintaining patient choice and autonomy. PMID- 25722075 TI - Lifetime of Prevalence and Risk Factors of Problem and Pathologic Gambling in North Cyprus. AB - In this article, the results of the national survey of adult gambling behavior in North Cyprus (NC) in 2012 are presented. The aim of this study is to investigate the characteristics of adults' participation in gambling, and to determine the prevalence of 'problem and pathological gambling' in NC. The population of this study was formed from all the people living permanently in NC, speaking Turkish, and within the age group 18-65. Household interviews were conducted with 966 people. To obtain data, a 30 item questionnaire prepared by the researchers and a Turkish version of the Revised South Oaks Gambling Screen were used. Prevalence rates are compared with the results of the study conducted in 2007 using the same methodology and survey form. The lifetime prevalence of participating at least once in any of the 17 gambling activities investigated in the survey was 66.4 %. 3.5 % of the respondents scored as lifetime probable pathological gamblers and 9.2 % as probable problem gamblers. Risk factors for becoming probable problem and pathological gamblers include being male, being in the 19-28 age group, having a high education level, having a job and being born in Cyprus. This study shows that the prevalence of problem gambling is high in NC and increasing gradually. NC has socio-cultural features such as a history of colonization, socioeconomic problems and high unemployment, similar to other high prevalence gambling regions, which is suggestive of the importance of socio-cultural factors on gambling behavior. PMID- 25722076 TI - A Case of Mistaken Identity? A Comparison of Professional and Amateur Problem Gamblers. AB - Professional gamblers are more likely than amateur gamblers to meet criteria for problem gambling but minimal research has examined their gambling behavior and its consequences. This study compared gambling behavior, problem gambling symptoms, related harms, recognition, and help-seeking among problem semi/professional gamblers (PPGs/PSPGs) and problem amateur gamblers (PAGs). Surveys completed by 57 self-identified professional gamblers, 311 semi professional gamblers and 4226 amateur gamblers were analysed. PPGs/PSPGs were significantly more likely than PAGs to be male, younger, never married, speak a language other than English at home, and have higher psychological distress, compared to PAGs. PPGs/PSPGs were more likely to gamble more frequently on many skills-based forms, but most also participated in several chance-based forms. PPGs'/PSPGs' most common problematic gambling form was electronic gaming machines and they were more likely to have problems with sports betting than PAGs. Most PPGs/PSPGs reported coming out behind on all gambling forms over the previous year. PPGs/PSPGs were more likely than PAGs to report chasing losses and numerous detrimental financial gambling consequences. This group's self-identification as PPGs/PSPGs is clearly inaccurate and perhaps a means to avoid stigma, elevate status and support problem denial. PPGs/PSPGs may represent an extreme example of gamblers with erroneous cognitions and beliefs who lack the required discipline and skill to be successful professional gamblers. The findings identify a group of problem gamblers who may benefit from interventions to dispel their mistaken self-identity, and emphasize the need for more rigorous confirmation of professional gambler status in future research. PMID- 25722077 TI - Religious Background and Gambling Among Young Adults in the United States. AB - Despite the rapid growth of the gambling industry over the last 40 years, there have been few large-scale, nationally representative longitudinal studies of gambling among young adults. We use data from the National Longitudinal Study of Adolescent to Adult Health to investigate whether and how the gambling behavior of young adults is associated with their religious beliefs and practices during adolescence. We find that young adults who grew up as conservative Protestants, mainline Protestants, Mormons, and Jehovah's Witnesses; those were raised in a community with a higher percentage of conservative Protestants; and those who attended religious services weekly are less likely to have ever gambled. Among gamblers, young adults who attended religious services up to three times per month as adolescents are more likely to experience gambling problems than those who never attend. Notably, accounting for a young adult's propensity for risk taking behavior does not explain the associations between religion and gambling. PMID- 25722078 TI - Hours in non-parental child care are related to language development in a longitudinal cohort study. AB - BACKGROUND: The effects of child care services on several domains of child development have been extensively investigated, but evidence regarding the effects of child care on language development remains inconclusive. METHODS: Within a large-scale population-based study, we examined the longitudinal associations between non-parental child care and language development from 1 to 6 years (n = 5375). RESULTS: Results showed that more hours in non-parental child care were associated with better language abilities. However, more hours in care in the first year of life were associated with less language proficiency at ages 1 to 1.5. At later ages, this effect disappeared and language proficiency increased. Furthermore, children who spent more hours in centre-based care had better language scores than children in home-based care. Ethnicity, socio economic status, gender or parity did not change these results. CONCLUSIONS: This large, multi-ethnic study demonstrates beneficial effects of non-parental child care, particularly centre-based care, on language proficiency later in childhood. PMID- 25722079 TI - Wolff-Parkinson-White syndrome (WPW) and athletes: Darwin at play? PMID- 25722080 TI - Simulation-based certification for cataract surgery. AB - PURPOSE: To evaluate the EyeSi(TM) simulator in regard to assessing competence in cataract surgery. The primary objective was to explore all simulator metrics to establish a proficiency-based test with solid evidence. The secondary objective was to evaluate whether the skill assessment was specific to cataract surgery. METHODS: We included 26 ophthalmic trainees (no cataract surgery experience), 11 experienced cataract surgeons (>4000 cataract procedures) and five vitreoretinal surgeons. All subjects completed 13 different modules twice. Simulator metrics were used for the assessments. RESULTS: Total module score on seven of 13 modules showed significant discriminative ability between the novices and experienced cataract surgeons. The intermodule reliability coefficient was 0.76 (p < 0.001). A pass/fail level was defined from the total score on these seven modules using the contrasting-groups method. The test had an overall ability to discriminate between novices and experienced cataract surgeons, as 21 of 26 novices (81%) versus one of 11 experienced surgeons (9%) did not pass the test. The vitreoretinal surgeons scored significantly higher than the novices (p = 0.006), but not significantly lower than the experienced cataract surgeons (p = 0.32). CONCLUSION: We have established a performance test, consisting of seven modules on the EyeSi(TM) simulator, which possess evidence of validity. The test is a useful and reliable tool for assessment of both cataract surgical and general microsurgical skills in vitro. PMID- 25722081 TI - Residual soil DNA extraction increases the discriminatory power between samples. AB - Forensic soil analysis relies on capturing an accurate and reproducible representation of the diversity from limited quantities of soil; however, inefficient DNA extraction can markedly alter the taxonomic abundance. The performance of a standard commercial DNA extraction kit (MOBIO PowerSoil DNA Isolation kit) and three modified protocols of this kit: soil pellet re extraction (RE); an additional 24-h lysis incubation step at room temperature (RT); and 24-h lysis incubation step at 55 degrees C (55) were compared using high-throughput sequencing of the internal transcribed spacer I ribosomal DNA. DNA yield was not correlated with fungal diversity and the four DNA extraction methods displayed distinct fungal community profiles for individual samples, with some phyla detected exclusively using the modified methods. Application of a 24 h lysis step will provide a more complete inventory of fungal biodiversity, and re extraction of the residual soil pellet offers a novel tool for increasing discriminatory power between forensic soil samples. PMID- 25722082 TI - Liver disease in China: A long way to go. PMID- 25722083 TI - DNA and RNA editing of retrotransposons accelerate mammalian genome evolution. AB - Genome evolution is commonly viewed as a gradual process that is driven by random mutations that accumulate over time. However, DNA- and RNA-editing enzymes have been identified that can accelerate evolution by actively modifying the genomically encoded information. The apolipoprotein B mRNA editing enzymes, catalytic polypeptide-like (APOBECs) are potent restriction factors that can inhibit retroelements by cytosine-to-uridine editing of retroelement DNA after reverse transcription. In some cases, a retroelement may successfully integrate into the genome despite being hypermutated. Such events introduce unique sequences into the genome and are thus a source of genomic innovation. adenosine deaminases that act on RNA (ADARs) catalyze adenosine-to-inosine editing in double-stranded RNA, commonly formed by oppositely oriented retroelements. The RNA editing confers plasticity to the transcriptome by generating many transcript variants from a single genomic locus. If the editing produces a beneficial variant, the genome may maintain the locus that produces the RNA-edited transcript for its novel function. Here, we discuss how these two powerful editing mechanisms, which both target inserted retroelements, facilitate expedited genome evolution. PMID- 25722084 TI - Potato aphid salivary proteome: enhanced salivation using resorcinol and identification of aphid phosphoproteins. AB - Aphids deliver saliva into plants and acquire plant sap for their nourishment using a specialized mouthpart or stylets. Aphid saliva is of great importance because it contains effectors that are involved in modulating host defense and metabolism. Although profiling aphid salivary glands and identifying secreted proteins have been successfully used, success in direct profiling of aphid saliva have been limited due to scarcity of saliva collected in artificial diets. Here we present the use of a neurostimulant, resorcinol, for inducing aphid salivation. Saliva of potato aphids (Macrosiphum euphorbiae), maintained on tomato, was collected in resorcinol diet. Salivary proteins were identified using mass spectrometry and compared with the existing M. euphorbiae salivary proteome collected in water. Comparative analysis was also performed with existing salivary proteomes from additional aphid species. Most of the proteins identified in the resorcinol diet were also present in the water diet and represented proteins with a plethora of functions in addition to a large number of unknowns. About half of the salivary proteins were not predicted for secretion or had canonical secretion signal peptides. We also analyzed the phosphorylation states of M. euphorbiae salivary proteins and identified three known aphid effectors, Me_WB01635/Mp1, Me10/Mp58, and Me23 that carry phosphorylation marks. In addition to insect proteins, tomato host proteins were also identified in aphid saliva. Our results indicate that aphid saliva is complex and provides a rich resource for functional characterization of effectors. PMID- 25722085 TI - Diffraction-unlimited imaging: from pretty pictures to hard numbers. AB - Diffraction-unlimited fluorescence imaging allows the visualization of intact, strongly heterogeneous systems at unprecedented levels of detail. Beyond the acquisition of detailed pictures, increasing efforts are now being focused on deriving quantitative insights from these techniques. In this work, we review the recent developments on sub-diffraction quantization that have arisen for the various techniques currently in use. We pay particular attention to the information that can be obtained but also the practical problems that can be faced, and provide suggestions for solutions or workarounds. We also show that these quantitative metrics not only provide a way to turn raw data into hard statistics but also help to understand the features and pitfalls associated with sub-diffraction imaging. Ultimately, these developments will lead to a highly standardized and easily applicable toolbox of techniques, which will find widespread application in the scientific community. PMID- 25722086 TI - High-glucose-increased expression and activation of NADPH oxidase in human vascular smooth muscle cells is mediated by 4-hydroxynonenal-activated PPARalpha and PPARbeta/delta. AB - High glucose induces vascular smooth muscle cell (SMC) dysfunction by generating oxidative stress attributable, in part, to the up-regulated NADPH oxidases (Nox). We have attempted to elucidate the high-glucose-generated molecular signals that mediate this effect and hypothesize that products of high-glucose-induced lipid peroxidation regulate Nox by activating peroxisome proliferator-activated receptors (PPARs). Human aortic SMCs were exposed to glucose (5.5-25 mM) or 4 hydroxynonenal (1-25 MUM, 4-HNE). Lucigenin assay, real-time polymerase chain reaction, western blot, and promoter analyses were employed to investigate Nox. We found that high glucose generated an increase in Nox activity and expression. It also promoted oxidative stress that consequently induced lipid peroxidation, which resulted in the production of 4-HNE. Pharmacological inhibition of Nox activity significantly reduced the formation of high-glucose-induced 4-HNE. Exposure of SMCs to non-cytotoxic concentrations (1-10 MUM) of 4-HNE alone mimicked the effect of high glucose incubation, whereas scavenging of 4-HNE by N acetyl L-cysteine completely abolished both the effects of high glucose and 4 HNE. The latter exerted its effect by activating PPARalpha and PPARbeta/delta, but not PPARgamma, as assessed pharmacologically by the inhibitory effect of selective antagonists and following the silencing of the expression of these receptors. These new data indicate that 4-HNE, generated following Nox activation, functions as an endogenous activator of PPARalpha and PPARbeta/delta. The newly discovered "lipid peroxidation products-PPARs-Nox axis" represents a novel mechanism of Nox regulation and an additional therapeutic target for oxidative stress in diabetes. PMID- 25722088 TI - The antibody-mediated targeted delivery of interleukin-13 to syngeneic murine tumors mediates a potent anticancer activity. AB - We describe the expression and in vivo characterization of an antibody-cytokine fusion protein, based on murine Interleukin-13 (IL13) and the monoclonal antibody F8, specific to the alternatively spliced extra domain A of fibronectin, a marker of neo-angiogenesis. The IL13 moiety was fused at the C-terminal extremity of the F8 antibody in diabody format. The resulting F8-IL13 immunocytokine retained the full binding properties of the parental antibody and cytokine bioactivity. The fusion protein could be expressed in mammalian cells, purified to homogeneity and showed a preferential accumulation at the tumor site. When used as single agent at doses of 200 MUg, F8-IL13 exhibited a strong inhibition of tumor growth rate in two models of cancer (F9 teratocarcinoma and Wehi-164), promoting an infiltration of various types of leukocytes into the neoplastic mass. This anticancer activity could be potentiated by combination with an immunocytokine based on the F8 antibody and murine IL12, leading to complete and long-lasting tumor eradications. Mice cured from Wehi-164 sarcomas acquired a durable protective antitumor immunity, and selective depletion of immune cells revealed that the antitumor activity was mainly mediated by cluster of differentiation 4 positive T cells. This study indicates that IL13 can be efficiently delivered to the tumor neo-vasculature and that it mediates a potent anticancer activity in the two models of cancer investigated in this study. The observed mechanism of action for F8-IL13 was surprising, since immunocytokines based on other payloads (e.g., IL2, IL4, IL12 and TNF) eradicate cancer by the combined contribution of natural killer cells and cluster of differentiation 8-positive T cells. PMID- 25722087 TI - Prolonged high fat diet ingestion, obesity, and type 2 diabetes symptoms correlate with phenotypic plasticity in myenteric neurons and nerve damage in the mouse duodenum. AB - Symptoms of diabetic gastrointestinal dysmotility indicate neuropathy of the enteric nervous system. Long-standing diabetic enteric neuropathy has not been fully characterized, however. We used prolonged high fat diet ingestion (20 weeks) in a mouse model to mimic human obese and type 2 diabetic conditions, and analyzed changes seen in neurons of the duodenal myenteric plexus. Ganglionic and neuronal size, number of neurons per ganglionic area, density indices of neuronal phenotypes (immunoreactive nerve cell bodies and varicosities per ganglion or tissue area) and nerve injury were measured. Findings were compared with results previously seen in mice fed the same diet for 8 weeks. Compared to mice fed standard chow, those on a prolonged high fat diet had smaller ganglionic and cell soma areas. Myenteric VIP- and ChAT-immunoreactive density indices were also reduced. Myenteric nerve fibers were markedly swollen and cytoskeletal protein networks were disrupted. The number of nNOS nerve cell bodies per ganglia was increased, contrary to the reduction previously seen after 8 weeks, but the density index of nNOS varicosities was reduced. Mice fed high fat and standard chow diets experienced an age-related reduction in total neurons, with bias towards neurons of sensory phenotype. Meanwhile, ageing was associated with an increase in excitatory neuronal markers. Collectively, these results support a notion that nerve damage underlies diabetic symptoms of dysmotility, and reveals adaptive ENS responses to the prolonged ingestion of a high fat diet. This highlights a need to mechanistically study long-term diet-induced nerve damage and age-related impacts on the ENS. PMID- 25722089 TI - [Relevance of preoperative risk factors on morbidity after esophagectomy]. PMID- 25722090 TI - Immunohistochemical study on the neuronal diversity and three-dimensional organization of the mouse entopeduncular nucleus. AB - The entopeduncular nucleus (EPN) is one of the major output nuclei of the basal ganglia in rodents. Previous studies have divided it into rostral and caudal halves, with the former containing somatostatin (SOM)-immunoreactive neurons and the latter dominated by parvalbumin (PV)-containing neurons, respectively. However, it is unclear whether this simple rostrocaudal segmentation is appropriate, and the possibility of the existence of other neuronal populations remains to be investigated. In this study the cytoarchitecture of the mouse EPN was analyzed immunohistochemically. Substance P (SP)-immunoreactivity determined the extent of the EPN, which was 800 MUm-long along the rostrocaudal axis. PV positive neurons were concentrated in the caudal two-thirds of this range. PV negative neurons were abundant in the rostral half but were further located caudally around the PV neuron-rich core. PV(+)/SOM(-) and PV(-)/SOM(+) neurons constituted 28.6% and 45.7% of EPN neurons, respectively, whereas the remaining population (25.7%) exhibited neither immunoreactivity. Eleven percent of EPN neurons lacked immunoreactivity for glutamic acid decarboxylase, indicating their non-GABAergic nature. Three-dimensional reconstruction revealed that PV-rich/SP poor core was surrounded by PV-poor/SP-rich shell region. Therefore, presumptive thalamus-targeting PV neurons are outnumbered by other populations, and the regional heterogeneity shown here might be related to functionally distinct pathways through the basal ganglia. PMID- 25722091 TI - Photoinduced intercomponent excited-state decays in a molecular dyad made of a dinuclear rhenium(I) chromophore and a fullerene electron acceptor unit. AB - A novel molecular dyad, 1, made of a dinuclear {[Re2(MU-X)2(CO)6(MU-pyridazine)]} component covalently-linked to a fullerene unit by a carbocyclic molecular bridge has been prepared and its redox, spectroscopic, and photophysical properties - including pump-probe transient absorption spectroscopy in the visible and near infrared region - have been investigated, along with those of its model species. Photoinduced, intercomponent electron transfer occurs in 1 from the thermally equilibrated, triplet metal/ligand-to-ligand charge-transfer ((3)MLLCT) state of the dinuclear rhenium(I) subunit to the fullerene acceptor, with a time constant of about 100 ps. The so-formed triplet charge-separated state recombines in a few nanoseconds by a spin-selective process yielding, rather than the ground state, the locally-excited, triplet fullerene state, which finally decays to the ground state by intersystem crossing in about 290 ns. PMID- 25722092 TI - Capsule Commentary on Berkowitz et al., Building Equity Improvement into Quality Improvement: Reducing Socioeconomic Disparities in Colorectal Cancer Screening as Part of Population Health Management. PMID- 25722093 TI - Using patient race, ethnicity, and language data to achieve health equity. PMID- 25722094 TI - An Unusual Cause of Facial Rash. PMID- 25722095 TI - Wellens' Syndrome in an Elderly Patient with Dementia. PMID- 25722096 TI - Screening for ACTH-dependent hypercortisolism in patients affected with pituitary incidentaloma. AB - CONTEXT: Pituitary incidentalomas (PIs) are commonly encountered in clinical practice. The management of these asymptomatic pituitary lesions is still controversial. Systematic screening for subclinical or mild ACTH-dependent hypercortisolism (AH) is not presently recommended, due to the limited data available thus far on the epidemiological and clinical relevance of this condition in patients with PIs. As subclinical hypercortisolism (SH) was considered to be associated with chronic complications of overt cortisol excess, such as hypertension, diabetes, and osteoporosis, this disorder should be diagnosed at the early stage. OBJECTIVE: The objective of this study was to evaluate the prevalence of hypercortisolism in a population of subjects with PIs. DESIGN, SUBJECTS, AND METHODS: A total of 68 consecutive patients (48 females and 20 males, aged 18-82 years) without clinically overt hypercortisolism, who were referred for evaluation of PIs between January 2010 and March 2013, were prospectively investigated for AH. Pituitary hypercortisolism was diagnosed in the presence of cortisol >50 nmol/l after 1 mg dexamethasone suppression test, non-suppressed ACTH, and the additional finding of one of the following: urinary free cortisol (UFC) >193 nmol/24 h, and midnight serum and salivary cortisol levels >207 and 2.8 nmol/l respectively. RESULTS: Among patients with PIs, we found a 7.3% rate of pituitary hypercortisolism diagnosed with biochemical criteria and a 4.4% rate of histologically confirmed AH. CONCLUSIONS: Subclinical or mild hypercortisolism may be more common than generally perceived in patients with PIs. PMID- 25722097 TI - Management of endocrine disease: Mortality remains increased in Cushing's disease despite biochemical remission: a systematic review and meta-analysis. AB - The aim of this systematic review and meta-analysis was to investigate whether mortality is increased in patients biochemically cured after initial treatment for Cushing's disease. This is a systematic review and meta-analysis of follow-up studies in patients cured from Cushing's disease after initial treatment was performed. Eight electronic databases were searched from 1975 to March 2014 to identify potentially relevant articles. Original articles reporting the standardized mortality ratio (SMR) for patients cured of Cushing's disease were eligible for inclusion. SMRs were pooled in a random effects model. I(2) statistics was used for quantification of heterogeneity. Eight cohort studies with a total of 766 patients were included. Out of eight studies, seven showed an SMR above 1.0 for cured patients. The pooled SMR was 2.5 (95% CI 1.4-4.2). The I(2) statistics showed evidence for statistical heterogeneity (78%, Q-statistics P<0.001), which was largely explained by two outliers. This meta-analysis reveals that mortality remains increased in patients with Cushing's disease even after initial biochemical cure remission, suggesting that cure does not directly reverse the metabolic consequences of long-term overexposure to cortisol. Other conditions such as hypopituitarism, including persistent adrenocortical insufficiency after surgery, may also contribute to the increased mortality risk. PMID- 25722098 TI - Treatment allocation in trials: stratified randomisation. PMID- 25722099 TI - Comparative cost-effectiveness of fine needle aspiration biopsy versus image guided biopsy, and open surgical biopsy in the evaluation of breast cancer in the era of Affordable Care Act: a changing landscape. AB - BACKGROUND: Proven as a time challenged and cost-effective sampling procedure, the use of FNAB has still remained controversial among the scientific community. Currently, other minimally invasive sampling procedures such as ultrasound guided fine needle aspiration biopsy (US-FNAB) and image guided core needle biopsy (IG CNB) have become the preferred sampling procedures for evaluation of breast lesions. However, changes in the medical economy and the current growing emphasis on cost containment in the era of the Affordable Care Act make it necessary to stimulate a renewed interest in the use of FNAB as the initial diagnostic sampling procedure. This study was designed to define the changing trend in the practice of tissue sampling during the last several years, and to assess the comparative effectiveness and appropriateness of the procedure of choice for breast cancer diagnosis. METHODS: After Institutional Review Board (IRB) approval, the computer database of the Pathology Department, University of Florida, College of Medicine-Jacksonville at UF Health was retrospectively searched to identify all breast biopsy pathology reports issued during the period of January 2004 to December 2011. The inclusion criteria were all women that underwent any of the following biopsy types: FNAB, US-FNAB, IG-CNB, and surgical biopsy (SB). Diagnostic procedures were identified using current procedural terminology (CPT) codes recorded on claims from the UF Health Jacksonville patient accounting application files. The data obtained was used to determine which technique has the best cost-effectiveness in the diagnosis of breast cancer. The outcome variable for this project was a positive breast cancer diagnosis resulting from these methodologies. The predictor variable was the biopsy type used for sampling. The rate of cancer detection for each procedure was also determined. RESULTS: Among the four groups of procedures compared, the lower cost was attributed to FNAB, followed by US-FNAB, and SB. IG-CNB was the most costly procedure, even more expensive than SB. The more costs associated with IG-CNB compared to SB is related to the expense involved in the use of localizing devices and also attempts to sample a lesion more than once. More importantly, cancer yield by FNAB was the highest among all the procedures under study. CONCLUSION: This study confirms the comparative effectiveness of FNAB in the evaluation of patients with breast cancer and justifies serious endorsement of this procedure as the initial diagnostic sampling modality for its unique potential in rapid reporting and cost-saving. PMID- 25722100 TI - An ionic liquid process for mercury removal from natural gas. AB - Efficient scrubbing of mercury vapour from natural gas streams has been demonstrated both in the laboratory and on an industrial scale, using chlorocuprate(II) ionic liquids impregnated on high surface area porous solid supports, resulting in the effective removal of mercury vapour from natural gas streams. This material has been commercialised for use within the petroleum gas production industry, and has currently been running continuously for three years on a natural gas plant in Malaysia. Here we report on the chemistry underlying this process, and demonstrate the transfer of this technology from gram to ton scale. PMID- 25722101 TI - Paradoxical response to tuberculosis treatment producing bowel obstruction. PMID- 25722102 TI - Water-enema multidetector computed tomography for planning surgery. AB - PURPOSE: Water-enema multidetector computed tomography (WE-MDCT) is a technique for the localization and preoperative T- and N-stage assessments of colon cancer. It may be a useful tool for planning surgery. The primary aim of this study was to evaluate the diagnostic accuracy of WE-MDCT for T-staging and its ability to locate tumors for laparoscopy planning. The secondary aim was to assess reading reproducibility and diagnostic accuracy for the preoperative determination of N stage. METHODS: We performed a study to evaluate preoperative WE-MDCT for surgical planning in patients with symptomatic colon adenocarcinomas who underwent surgery between June 2010 and January 2014. A radiologist and a surgeon read the WE-MDCTs separately. Results were compared with colonoscopy and the surgical specimen. RESULTS: Seventy-one patients (42 men (59.1%); mean age 73.1 years (range 45 to 95)) were included. Seventy-six tumors were assessed. The intraclass correlation coefficient (ICC) for location as determined by surgery and that determined by WE-MDCT was 1, and the ICC for location between colonoscopy and WE-MDCT was 0.85 (95% CI 0.75-0.91). For T-stage determination, sensitivity was 96 and 94% and specificity 83 and 88% for readers 1 and 2, respectively. The T-stage assessment allowed for the programing of surgical access and showed good sensitivity and specificity for the assessment of invasion in adjacent organs. CONCLUSION: WE-MDCT is relatively easy to perform, and its results can be read effectively by radiologists and surgeons. WE-MDCT indicated the location of tumors perfectly and permitted a good determination of their T stage. The technique is thus pertinent for the planning of laparoscopic surgery for colon cancer. PMID- 25722103 TI - Methods of milk expression for lactating women. AB - BACKGROUND: This is an update of a 2008 Cochrane review. Breastfeeding is important. However, not all infants can feed at the breast and methods of expressing milk need evaluation. OBJECTIVES: To assess acceptability, effectiveness, safety, effect on milk composition, contamination and cost implications of methods of milk expression. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2014), CINAHL (1982 to March 2014), conference proceedings, secondary references and contacted researchers. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing methods at any time after birth. DATA COLLECTION AND ANALYSIS: Three authors independently assessed trials, extracted data and assessed risk of bias. MAIN RESULTS: This updated review includes 34 studies involving 1998 participants, with 17 trials involving 961 participants providing data for analysis. Eight studies compared one or more types of pump versus hand expression and 14 studies compared one type of pump versus another type of pump, with three of these studies comparing both hand expression and multiple pump types. Fifteen studies compared a specific protocol or adjunct behaviour including sequential versus simultaneous pumping protocols (five studies), pumping > 4 times per day versus < 3 times per day (one study), provision of a milk expression education and support intervention to mothers of preterm infants versus no provision (one study), provision of audio/visual relaxation to mothers of preterm infants versus no specific relaxation (two studies), commencing pumping within one hour of delivery versus between one to six hours (one study), breast massage before or during pumping versus no massage (two studies, of which one also tested a second behaviour), therapeutic touch versus none (one study), warming breasts before pumping versus not warming breasts (one study), combining hand expression with pumping versus pumping alone (one study) and a breast cleansing protocol versus no protocol (one study).There were insufficient comparable data on outcomes to undertake meta-analysis and data reported relates to evidence from single studies.Only one of the 17 studies examining maternal satisfaction/acceptability provided data in a way that could be analysed, reporting that mothers assigned to the pumping group had more agreement with the statement 'I don't want anyone to see me pumping' than mothers in the hand expression group and the statement 'I don't want anyone to see me hand expressing' (n = 68, mean difference (MD) -0.70, 95% confidence interval (CI) -1.25 to -0.15, P = 0.01), and that mothers found instructions for hand expression were clearer than for pumping (n = 68, MD 0.40, 95% CI 0.05 to 0.75, P = 0.02). No evidence of a difference was found between methods related to adverse effects of milk contamination (one study, n = 28, risk ratio (RR) 0.89, 95% CI 0.62 to 1.27, P = 0.51), (one study, n = 142 milk samples, MD 0.20, 95% CI -0.18 to 0.58, P = 0.30), (one study, n = 123 milk samples, MD 0.10, 95% CI -0.29 to 0.49, P = 0.61), (one study, n = 141 milk samples, MD -0.10, 95% CI -0.46 to 0.26, P = 0.59 ); or level of maternal breast or nipple pain or damage (one study, n = 68, MD 0.02, 95% CI -0.67 to 0.71, P = 0.96).For the secondary outcomes, greater volume was obtained when mothers with infants in a neonatal unit were provided with a relaxation tape or music listening interventions to use while pumping, when the breasts was warmed before pumping or massaged while pumping.Initiation of milk pumping within 60 minutes of birth of a very low birthweight infant obtained higher mean milk quantity in the first week than the group who initiated pumping later. No evidence of difference in volume was found with simultaneous or sequential pumping or between pumps studied. Differences between methods was found for sodium, potassium, protein and fat constituents; no evidence of difference was found for energy content.No consistent effect was found related to prolactin change or effect on oxytocin release with pump type or method. Economic aspects were not reported.Most studies were classified as unclear or low risk of bias. Most studies did not provide any information regarding blinding of outcome assessment. Fifteen of the 25 studies that evaluated pumps or products had support from the manufacturers. AUTHORS' CONCLUSIONS: The most suitable method for milk expression may depend on the time since birth, purpose of expression and the individual mother and infant. Low-cost interventions including early initiation when not feeding at the breast, listening to relaxation music, massage and warming of the breasts, hand expression and lower cost pumps may be as effective, or more effective, than large electric pumps for some outcomes. Small sample sizes, large standard deviations, and the diversity of the interventions argue caution in applying these results beyond the specific method tested in the specific settings. PMID- 25722104 TI - Synthesis, structural studies and ligand influence on the stability of aryl-NHC stabilised trimethylaluminium complexes. AB - Treatment of a series of aromatic NHCs (IMes, SIMes, IPr and SIPr) with trimethylaluminium produced their corresponding Lewis acid-base adducts: IMes.AlMe3 (1), SIMes.AlMe3 (2), IPr.AlMe3 (3), and SIPr.AlMe3 (4). These complexes expand the few known examples of saturated NHC stabilised Group 13 complexes. Furthermore, compounds 1-4 show differential stability depending on the nature of the NHC ligand. Analyses of topographic steric maps and NHC %V(Bur) were used to explain these differences. All the compounds have been fully characterised by multinuclear NMR spectroscopy, IR and single crystal X-ray analysis together with computational studies. PMID- 25722106 TI - Second-Generation Antipsychotic Drugs in Anorexia Nervosa: A Meta-Analysis of Randomized Controlled Trials. AB - Background: Second-generation antipsychotic drugs (SGAs) are increasingly administered to achieve weight gain in anorexia nervosa. In this meta-analysis, we aimed to determine if any evidence for this treatment option can be derived from randomized controlled trials (RCTs). Methods: Based on the 'World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Eating Disorders', a systematic update literature search was applied to identify all RCTs investigating the efficacy, acceptability, and tolerability of SGAs in anorexia nervosa in comparison to placebo/no treatment. The primary outcome was weight gain measured by mean change in body mass index (BMI). Secondary outcomes were mean changes in Yale-Brown-Cornell Eating Disorders Scale (YBC-EDS) total score and Eating Disorders Inventory (EDI) total score and premature discontinuation of treatment. Employing a random-effects model standardized mean differences based on Hedges's g and Mantel-Haenszel risk ratios were calculated. Results: Seven RCTs (n = 201) investigating olanzapine (N = 4), quetiapine (N = 2), and risperidone (N = 1) were included. We found no statistically significant between-group differences for mean BMI change when pooling the SGAs (N = 7, n = 161; Hedges's g = 0.13, 95% CI: -0.17 to 0.43; p = 0.4) and when examining the individual drugs. Furthermore, the SGAs failed to differentiate statistically significantly from placebo/no treatment for all secondary outcomes. Conclusions: Based on the current evidence, pharmacological treatment of anorexia nervosa with SGAs cannot be generally recommended although some individuals or subgroups of patients might benefit from an antipsychotic medication. Further research is required to identify which patients will likely benefit from such a treatment option. (c) 2015 S. Karger AG, Basel. PMID- 25722105 TI - Measurement of the photoreceptor pointing in the living chick eye. AB - The chick eye is used in the study of ocular growth and emmetropization; however optical aberrations in the lens and cornea limit the ability to visualize fine retinal structure in living eyes. These aberrations can be corrected using adaptive optics (AO) allowing for cellular level imaging in vivo. Here, this capability is extended to measure the angular tuning properties of individual photoreceptors. The left eyes from two White Leghorn chicks (Gallus gallus domesticus) labeled chick A and chick B, were imaged using an AO flood illuminated fundus camera. By translating the entrance pupil position, the same retinal location was illuminated with light of varying angles allowing for the measurement of individual photoreceptor pointing. At 30 degrees nasal from the pecten tip, the pointing direction for both chicks was towards the pupil center with a narrow distribution. These particular chicks were found to have a temporal (T) and inferior (I) bias in the alignment with peak positions of (0.81 T, 0.23 I) and (0.57 T, 0.18 I) mm from the pupil center for chicks A and B respectively. The rho, rho, values for the major, rhoL, and minor, rhos, axes were 0.14 and 0.17mm(-2) for chick A and 0.09 and 0.20mm(-2) for chick B. The small disarray in the alignment of the chick photoreceptors implies that the photoreceptors are aligned to optimize the light entering the eye through the central portion of the pupil aperture. The ability to measure pointing properties of individual photoreceptors will have application in the study of eye growth and various retinal disorders. PMID- 25722107 TI - Effect of the presence of pyrite traces on silver behavior in natural porous media. AB - In order to better understand the fate of the toxic element Ag(I), sorption of Ag(I) was studied from batch experiments, at different pHs (2-8) and at 298 K. A pure quartz sand (99.999% SiO2) and "natural" quartz sand (99% SiO2, and traces of Fe, Al, Mn (hydr)oxides, of clays and of pyrite) were used as sorbents. The Ag(I) sorption behavior depends strongly on pH with isotherm shapes characteristic of Langmuir-type relationship for initial Ag concentration [Ag(I)], range between 5.0*10(-7) and 1.0*10(-3) M. Even if the Ag (I) sorption capacity on pure quartz sand is very low compared to the natural quartz sands, its affinity is rather high. From speciation calculations, several sites were proposed: at pHi 4, 6 and 8, the first surface site is assumed to be due to iron (hydr)oxides while the second surface site is attributed to silanols. At pHi 2, sorption of Ag(I) was assumed to be on two surface sites of iron (hydr)oxides and a third surface site on silanol groups. Even if the sand is mainly composed of silica, the trace minerals play an important role in sorption capacity compared to silica. The conditional surface complexation constants of Ag(I) depend on pH. On the other hand, it is shown that the Ag speciation depends strongly on the history of "natural" quartz sand due to initial applied treatment, little rinsing or longer washing. In the presence of low amount of pyrite, strong complexes between Ag(I) and sulfur compounds such as thiosulfates due to oxidative dissolution of pyrite are formed what decreases Ag sorption capability. SEM-EDS analyses highlighted the surface complexation-precipitation of Ag2S and Ag(0) colloids which confirmed the important role of pyrite on Ag(I) speciation. PMID- 25722108 TI - Paediatric nodal marginal zone B-cell lymphadenopathy of the neck: a Haemophilus influenzae-driven immune disorder? AB - Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified six children and one adolescent with cervical lymphadenopathy showing prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and four adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED-2-IG PCR analysis. Haemophilus influenzae was identified in all six cases of pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in three pNMZLs and 28 non-specific reactive cervical lymph nodes of age matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 years). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules, the expanded germinal centres and variably sized marginal zones were colonized by activated B-cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In four cases tested, this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD+ marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL. PMID- 25722109 TI - Giant retroperitoneal liposarcoma: Case report and review of the literature. AB - AIM: Retroperitoneal soft-tissue sarcomas are relatively uncommon diseases, the most frequent histotype, ranging from 20% to 45% of all cases, is represented by liposarcoma, which is a hard-to treat condition for its local aggressiveness and clinical aspecificity. PRESENTATION OF CASE: We report a case of a 64-years-old woman who underwent surgical resection for a giant pleomorphic retroperitoneal liposarcoma. DISCUSSION: Currently chemotherapy for retroperitoneal soft-tissue sarcomas is no effective, and radiotherapy has limited efficacy due to the toxicity affecting adjacent intra-abdominal structures, showed validity only in case of high-grade malignancy by reducing local recurrence, but with no advantage in overall survival. Nowadays only, the complete surgical resection remains the most important predictor of local recurrence and overall survival. CONCLUSION: The removal of a retroperitoneal sarcoma of remarkable size is a challenge for the surgeon owing to the anatomical site, to the absence of an anatomically evident vascular-lymphatic peduncle and to the adhesions contracted with the contiguous organs and with the great vessels. Therefore, we believe that, particularly for large-size diseases associated to high-grade malignancy, a complete surgical resection with removal of the contiguous intra and retroperitoneal organs when infiltrated represents the only therapeutic option to obtain a negative margin and therefore an oncological radicality. PMID- 25722110 TI - Identifying microRNA-mRNA regulatory network in gemcitabine-resistant cells derived from human pancreatic cancer cells. AB - Pancreatic cancer is unresectable in over 80 % of patients owing to difficulty in early diagnosis. Chemotherapy is the most frequently adopted therapy for advanced pancreatic cancer. The development of drug resistance to gemcitabine (GEM), which is always used in standard chemotherapy, often results in therapeutic failure. However, the molecular mechanisms underlying the gemcitabine resistance remain unclear. Therefore, we sought to explore the microRNA-mRNA network that is associated with the development of gemcitabine resistance and to identify molecular targets for overcoming the gemcitabine resistance. By exposing SW1990 pancreatic cancer cells to long-term gemcitabine with increasing concentrations, we established a gemcitabine-resistant cell line (SW1990/GEM) with a high IC50 (the concentration needed for 50 % growth inhibition, 847.23 MUM). The mRNA and microRNA expression profiles of SW1990 cells and SW1990/GEM cells were determined using RNA-seq analysis. By comparing the results in control SW1990 cells, 507 upregulated genes and 550 downregulated genes in SW1990/GEM cells were identified as differentially expressed genes correlated with gemcitabine sensitivity. Gene ontology (GO) analysis showed that the differentially expressed genes were related to diverse biological processes. The upregulated genes were mainly associated with drug response and apoptosis, and the downregulated genes were correlated with cell cycle progression and RNA splicing. Concurrently, the differentially expressed microRNAs, which are the important player in drug resistance development, were also examined in SW1990/GEM cells, and 56 differential microRNAs were identified. Additionally, the expression profiles of selected genes and microRNAs were confirmed by using Q-PCR assays. Furthermore, combining the differentially expressed microRNAs and mRNAs as well as the predicted targets for these microRNAs, a core microRNA-mRNA regulatory network was constructed, which included hub microRNAs, such as hsa-miR-643, hsa-miR-4644, hsa-miR-4650-5p, hsa-miR-4455, hsa-miR-1261, and hsa-miR-3676. The predicted targets of these hub microRNAs in the microRNA-mRNA network were also observed in the identified differential genes. As a result, a differential gene and microRNA expression pattern was constructed in gemcitabine-resistant pancreatic cancer cells. Therefore, these data may be useful for the detection and treatment of drug resistance in pancreatic cancer patients, and the microRNA-mRNA network based analysis is expected to be more effective and provides deep insights into the molecular mechanism of drug resistance. PMID- 25722111 TI - Prognostic value of purinergic P2X7 receptor expression in patients with hepatocellular carcinoma after curative resection. AB - The family of type 2 purinergic (P2) receptors, especially P2X7, is responsible for the direct tumor-killing functions of extracellular adenosine triphosphate (ATP), but the precise role of P2X7 in the progression of hepatocellular carcinoma (HCC) remains elusive. This study aims to evaluate prognostic value of P2X7 expression in HCC patients after surgical resection. Expression of P2X7 was assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissues from 273 patients with HCC who had undergone hepatectomy between 2006 and 2007. Prognostic value of P2X7 expression and clinical outcomes were evaluated. Peritumoral P2X7 expression was significantly higher than intratumoral P2X7 expression. No significant prognostic difference was observed for overall survival for intratumoral P2X7 density, whereas peritumoral P2X7 density indicates unfavorable overall survival in training set and BCLC stage 0-A subset. Besides, peritumoral P2X7 density, which correlated with tumor size, venous invasion, and BCLC stage, was identified as an independent poor prognosticator for overall survival and recurrence-free survival. The association was further validated in validation set. Peritumoral P2X7 is a potential unfavorable prognosticator for overall survival and recurrence free survival in HCC patients after surgical resection. Further external validation and functional analysis should be pursued to evaluate its potential prognostic value and therapeutic significance for HCC patients. PMID- 25722112 TI - Serum microRNA-145 as a novel biomarker in human ovarian cancer. AB - Ovarian cancer is one of the most threatening diseases among women in the world. Current detection methods are expensive and lack accuracy. Thus, a fast, non invasive biomarker for detecting ovarian cancer is urgently needed. Compelling evidences have been demonstrated that microRNAs, a large family of single stranded and non-protein-coding RNA molecules, can serve as useful biomarkers in cancer detection. In this study, the relative expressions of microRNA-145 (miR 145) in the serum of patients with ovarian cancer and healthy controls were investigated in an independent study. Subsequently, the diagnosis and prognosis value of miR-145 as a biomarker for ovarian cancer were examined. Furthermore, we performed a meta-analysis to summarize all the results from published studies and this study. Relative expressions of miR-145 were investigated in three independent groups (malignant ovarian cancer, benign ovarian tumor, and healthy controls), comprising a total of 270 participants. Receiver operating characteristic (ROC) curves and overall survival (OS) curves were conducted to compare miR-145 level and clinical characteristics among the three groups. The results showed that relative expressions of the serum miR-145 were significantly down-regulated in patients with malignant ovarian cancer and benign ovarian cancer, compared to healthy controls (P < 0.01). Serum miR-145 levels could discriminate patients with malignant ovarian cancer from healthy controls, with a power area under the curve (AUC) of 0.82 (95 % confidence interval (CI) = 0.77 0.88). Furthermore, patients with low serum levels of miR-145 had a significantly shorter median overall survival rate (hazard ratio (HR) = 1.81, 95 % CI = 1.03 3.17, P = 0.039). The meta-analysis yields good diagnostic performances of miR 145 in various cancers, with an AUC of 0.82 (95 % CI, 0.78-0.85). In conclusion, the present study suggested that miR-145 can potentially serve as an outstanding biomarker for ovarian and other human cancers detection. PMID- 25722113 TI - Dormancy activation mechanism of oral cavity cancer stem cells. AB - Radiotherapy and chemotherapy are targeted primarily at rapidly proliferating cancer cells and are unable to eliminate cancer stem cells in the G0 phase. Thus, these treatments cannot prevent the recurrence and metastasis of cancer. Understanding the mechanisms by which cancer stem cells are maintained in the dormant G0 phase, and how they become active is key to developing new cancer therapies. The current study found that the anti-cancer drug 5-fluorouracil, acting on the oral squamous cell carcinoma KB cell line, selectively killed proliferating cells while sparing cells in the G0 phase. Bisulfite sequencing PCR showed that demethylation of the Sox2 promoter led to the expression of Sox2. This then resulted in the transformation of cancer stem cells from the G0 phase to the division stage and suggested that the transformation of cancer stem cells from the G0 phase to the division stage is closely related to an epigenetic modification of the cell. PMID- 25722114 TI - 3B, a novel of photosensitizer, exhibited anti-tumor effects via mitochondrial apoptosis pathway in MCF-7 human breast carcinoma cells. AB - Photodynamic therapy (PDT) has been recognized as an innovated therapeutic modality for the treatment of various cancers. In this study, we evaluated the anticancer effect of a new photosensitizer 3B in breast cancer, which was considered one of the most common cancers in women worldwide. Here, we determined the effect of 3B not only on the cell growth, apoptosis, and Bcl-2 signal pathway in vitro but also on the anti-cancer effect in nude mice in vivo. Our results showed that 3B was primarily accumulated in mitochondria, increased the level of ROS, induced apoptotic cells death via Bcl-2 family, and its activity could be blocked by the caspase inhibitor (Z-VAD-FMK). In vivo study, 3B made a significant opening inhibition of tumor growth and showed drug toxicity hardly. TUNEL assay indicated that PDT group showed more positive cells (green) than other groups. These data supported that 3B might develop as potential therapeutic drug for the treatment of breast cancer. PMID- 25722115 TI - Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia. AB - Depression is highly prevalent in patients with schizophrenia and is associated with significant clinical consequences, but there is no known biomarker for depression in schizophrenia. One of the putative neurochemical biomarkers for depression in major depressive disorder (MDD) is reduced cerebral concentration of myo-Inositol. We examined whether myo-Inositol levels provide a potential marker for depressive symptoms in schizophrenia similar to that in MDD and are informative regarding causal biological pathways underlying both depression and schizophrenia. We used proton magnetic resonance spectroscopy to examine myo Inositol levels in the anterior cingulate cortex (ACC) in 59 schizophrenia spectrum disorder (SSD) patients and 69 matched community comparison participants. Participants completed the Maryland Trait and State Depression (MTSD) scale to measure symptoms of depression experienced around time of assessment ('State' subscale) and longitudinally ('Trait' subscale). Myo-Inositol in the ACC was negatively correlated with MTSD-Trait scores in both patients (rho=-0.336, p=0.009) and community comparison samples (rho=-0.328, p=0.006). Furthermore, patients with a diagnosis of schizoaffective disorder or a history of at least one major depressive episode had lower levels of myo-Inositol compared with schizophrenia patients without a current or past affective diagnosis (p=0.012). Since reduced brain myo-Inositol is associated with MDD, myo Inositol may be a biochemical marker of depressive mood symptoms across diagnostic boundaries. If confirmed, this finding may aid investigation of the pathophysiology and therapeutics of depression common between depression, schizophrenia and other psychiatric diagnoses. PMID- 25722118 TI - A motion- and sound-activated, 3D-printed, chalcogenide-based triboelectric nanogenerator. AB - A multilayered triboelectric nanogenerator (MULTENG) that can be actuated by acoustic waves, vibration of a moving car, and tapping motion is built using a 3D printing technique. The MULTENG can generate an open-circuit voltage of up to 396 V and a short-circuit current of up to 1.62 mA, and can power 38 LEDs. The layers of the triboelectric generator are made of polyetherimide nanopillars and chalcogenide core-shell nanofibers. PMID- 25722116 TI - Overexpression of Protein Kinase Mzeta in the Prelimbic Cortex Enhances the Formation of Long-Term Fear Memory. AB - Neuroplasticity in the prefrontal cortex (PFC) after fear conditioning has been suggested to regulate the formation and expression of fear memory. Protein kinase Mzeta (PKMzeta), an isoform of protein kinase C with persistent activity, is involved in the formation and maintenance of memory. However, less is known about the role of PKMzeta in the PFC in the formation of fear memory. We investigated whether the overexpression of PKMzeta enhances the formation of auditory fear memory in rats. We found that microinfusion of lentiviral vector-expressing PKMzeta into the prelimbic cortex (PrL) selectively enhanced the expression of PKMzeta without influencing the expression of other isoforms of PKC. The overexpression of PKMzeta in the PrL enhanced the formation of long-term fear memory without affecting short-term fear memory, whereas the overexpression of PKMzeta in the infralimbic cortex had no effect on either short-term or long-term fear memory. The overexpression of PKMzeta in the PrL had no effect on anxiety like behavior or locomotor activity. We also found that PKMzeta overexpression potentiated the fear conditioning-induced increase in the membrane levels of glutamate subunit 2 of AMPA receptors in the PrL. These results demonstrate that the overexpression of PKMzeta in the PrL but not infralimbic cortex selectively enhanced the formation of long-term fear memory, and PKMzeta in the PrL may be involved in the formation of fear memory. PMID- 25722117 TI - Tonsil-derived mesenchymal stem cells ameliorate CCl4-induced liver fibrosis in mice via autophagy activation. AB - Liver transplantation is the treatment of choice for chronic liver failure, although it is complicated by donor shortage, surgery-related complications, and immunological rejection. Cell transplantation is an alternative, minimally invasive treatment option with potentially fewer complications. We used human palatine tonsil as a novel source of mesenchymal stem cells (T-MSCs) and examined their ability to differentiate into hepatocyte-like cells in vivo and in vitro. Carbon tetrachloride (CCl4) mouse model was used to investigate the ability of T MSCs to home to the site of liver injury. T-MSCs were only detected in the damaged liver, suggesting that they are disease-responsive. Differentiation of T MSCs into hepatocyte-like cells was confirmed in vitro as determined by expression of hepatocyte markers. Next, we showed resolution of liver fibrosis by T-MSCs via reduction of TGF-beta expression and collagen deposition in the liver. We hypothesized that autophagy activation was a possible mechanism for T-MSC mediated liver recovery. In this report, we demonstrate for the first time that T MSCs can differentiate into hepatocyte-like cells and ameliorate liver fibrosis via autophagy activation and down-regulation of TGF-beta. These findings suggest that T-MSCs could be used as a novel source for stem cell therapy targeting liver diseases. PMID- 25722119 TI - Weight-loss strategies used by baby boomer men: a mixed methods approach. AB - BACKGROUND: Baby Boomer men (those born in 1946-1964) are becoming obese at an earlier age compared to previous generations. The present study aimed to identify weight-loss strategies used by Baby Boomer men, to determine whether those strategies varied by weight status and to explore their dieting experiences. METHODS: The study used a cross-sectional survey of 211 men and 20 in-depth interviews. RESULTS: Men had a mean (SD) body mass index (BMI) of 29.35 (5.07) kg m(-2), with 82% being overweight or obese. Fifty-six percent were currently trying to lose weight. Healthy weight-loss strategies included reducing portions, increasing physical activity, cutting back on fried foods, cutting back on sweets, cutting back on alcohol, using meal replacement drinks/bars and joining a weight-loss programme. Unhealthy strategies included skipping meals and using over-the-counter 'diet pills'. Men who reduced portions, skipped meals, cut back on sweets, joined a weight-loss programme and used diet pills had significantly higher BMIs than men who said they did not (P < 0.05 for all). Interviews revealed that older men struggle to lose weight, 'I've been struggling for the last 2-3 years'. 'The last time I really tried to lose weight I stayed on the diet for just a day or two'. Wives were considered essential to their weight management success. CONCLUSIONS: Men used a do-it-yourself weight-loss approach using both healthy and unhealthy strategies. Obese men were more likely to use unhealthy practices than overweight men. PMID- 25722120 TI - Transforaminal endoscopic solution to disk reherniation post-mini-TLIF: case report. PMID- 25722121 TI - 21st century training in psychosis. PMID- 25722122 TI - Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part I. Biotherapeutics. AB - Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment. PMID- 25722123 TI - Policy brief. PMID- 25722124 TI - Behavioral functioning among Mexican-origin children: does parental legal status matter? AB - Using data on 2,535 children included in the Los Angeles Family and Neighborhood Survey, we investigate how the legal status of immigrant parents shapes their children's behavioral functioning. Variation in internalizing and externalizing problems among Mexican youth with undocumented mothers, documented or naturalized citizen mothers, and U.S.-born mothers is analyzed using a comparative framework that contrasts their experience with that of other ethnoracial groups. Our findings reinforce the importance of differentiating children of immigrants by parental legal status in studying health and well-being. Children of undocumented Mexican migrants have significantly higher risks of internalizing and externalizing behavior problems than their counterparts with documented or naturalized citizen mothers. Regression results are inconsistent with simple explanations that emphasize group differences in socioeconomic status, maternal mental health, or family routines. PMID- 25722125 TI - In sickness and in health? Physical illness as a risk factor for marital dissolution in later life. AB - The health consequences of marital dissolution are well known, but little work has examined the impact of health on the risk of marital dissolution. In this study we use a sample of 2,701 marriages from the Health and Retirement Study (1992-2010) to examine the role of serious physical illness onset (i.e., cancer, heart problems, lung disease, and/or stroke) in subsequent marital dissolution due to either divorce or widowhood. We use a series of discrete-time event history models with competing risks to estimate the impact of husband's and wife's physical illness onset on risk of divorce and widowhood. We find that only wife's illness onset is associated with elevated risk of divorce, while either husband's or wife's illness onset is associated with elevated risk of widowhood. These findings suggest the importance of health as a determinant of marital dissolution in later life via both biological and gendered social pathways. PMID- 25722126 TI - Healthy time use in the encore years: do work, resources, relations, and gender matter? AB - Social engagement is theorized to promote health, with ages 55 to 75-what some call "encore" adulthood-potentially being a time for ongoing engagement or social isolation. We use the American Time Use Survey (N = 11,952) and a life course perspective to examine associations between paid work, resources, relations, and healthy time use for men and women in the first (55-64) and second (65-74) halves of the encore years. Work limits sufficient sleep (full-time working men) and television watching (all workers) but also time spent in physical activity (full time workers). College-educated and healthy encore adults-across age and gender divides-are more likely to exercise and watch less television. Marriage and caregiving encourage socializing and limit television watching, despite differential effects on physical activity and sleep. These findings fit well with a gendered life course perspective suggesting socially patterned (by work, resources, relationships, gender, age) health behaviors. PMID- 25722127 TI - Different contexts, different effects? Work time and mental health in the United States and Germany. AB - This paper takes a comparative approach to the topic of work time and health, asking whether weekly work hours matter for mental health. We hypothesize that these relationships differ within the United States and Germany, given the more regulated work time environments within Germany and the greater incentives to work long hours in the United States. We further hypothesize that German women will experience greatest penalties to long hours. We use data from the German Socioeconomic Panel and the National Longitudinal Survey of Youth to examine hours effects on mental health score at midlife. The results support our initial hypothesis. In Germany, longer work time is associated with worse mental health, while in the United States, as seen in previous research, the associations are more complex. Our results do not show greater mental health penalties for German women and suggest instead a selection effect into work hours operating by gender. PMID- 25722128 TI - Gendered contexts: variation in suicidal ideation by female and male youth across U.S. states. AB - We use data from the National Longitudinal Study of Adolescent Health (13,186 respondents in 30 states) to develop a unique state-level measure of the gendered context in order to examine the influence of gender normative attitudes and behaviors on state rates of suicidal ideation and individual-level suicidal ideation for female and male youth (ages 13 to 22). The findings demonstrate the negative consequences for youth, especially females who report feminine-typical traits, who live in contexts defined by restrictive gender norms at both the ecological and individual levels. This study points to the importance of fatalistic suicide for female youth and suggests possible mechanisms to explain this association. PMID- 25722129 TI - Suicidal disclosures among friends: using social network data to understand suicide contagion. AB - A robust literature suggests that suicide is socially contagious; however, we know little about how and why suicide spreads. Using network data from the National Longitudinal Study of Adolescent to Adult Health, we examine the effects of alter's (1) disclosed and (2) undisclosed suicide attempts, (3) suicide ideation, and (4) emotional distress on ego's mental health one year later to gain insights into the emotional and cultural mechanisms that underlie suicide contagion. We find that when egos know about alter's suicide attempt, they report significantly higher levels of emotional distress and are more likely to report suicidality, net of extensive controls; however, alter's undisclosed suicide attempts and ideation have no significant effect on ego's mental health. Finally, we find evidence that emotional distress is contagious in adolescence, though it does not seem to promote suicidality. We discuss the implications of our findings for suicide contagion specifically and sociology more generally. PMID- 25722130 TI - KPC-producing Enterobacter aerogenes infection. AB - BACKGROUND: Enterobacter is a common nosocomial microorganism and its carbapenem's resistance has increased. The management of these cases is unclear. OBJECTIVE: We evaluated 16 patients with KPC-producing Enterobacter aerogenes infections, detailing the site of infection, therapy, clinical and epidemiological data. METHODS: A retrospective and descriptive study. Clinical data were revised and KPC-2 detection was by molecular methods. Risk factors associated with mortality were compared using appropriate tests according to variable type with a significance level of 0.05. RESULTS: The 30-day mortality rate was 37.5% with no association with inadequate treatment. Age (p=0.004) and Charlson score of comorbidities (p=0.048) were independent risk factors associated with death in the multivariate analysis. The odds ratio for age >43 years was 3.00 (95% CI: 1.02-9.32) and for Charlson score >3 was 2.00 (95% CI: 1.08-3.71). Five strains were pan-resistant based on automated susceptibility tests. All patients were treated with monotherapy. CONCLUSION: The clinician should be alert to carbapenem-resistant Enterobacteriaceae infection in older patients with comorbidities. The mortality is high and we believe that prompt and adequate therapy must be employed. PMID- 25722131 TI - ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms. AB - Reactive oxygen species (ROS) and antioxidant ingredients are a series of crucial signaling molecules in oxidative stress response. Under some pathological conditions such as traumatic brain injury, ischemia/reperfusion, and hypoxia in tumor, the relative excessive accumulation of ROS could break cellular homeostasis, resulting in oxidative stress and mitochondrial dysfunction. Meanwhile, autophagy is also induced. In this process, oxidative stress could promote the formation of autophagy. Autophagy, in turn, may contribute to reduce oxidative damages by engulfing and degradating oxidized substance. This short review summarizes these interactions between ROS and autophagy in related pathological conditions referred to as above with a focus on discussing internal regulatory mechanisms. The tight interactions between ROS and autophagy reflected in two aspects: the induction of autophagy by oxidative stress and the reduction of ROS by autophagy. The internal regulatory mechanisms of autophagy by ROS can be summarized as transcriptional and post-transcriptional regulation, which includes various molecular signal pathways such as ROS-FOXO3-LC3/BNIP3-autophagy, ROS-NRF2-P62-autophagy, ROS-HIF1-BNIP3/NIX-autophagy, and ROS-TIGAR-autophagy. Autophagy also may regulate ROS levels through several pathways such as chaperone mediated autophagy pathway, mitophagy pathway, and P62 delivery pathway, which might provide a further theoretical basis for the pathogenesis of the related diseases and still need further research. PMID- 25722132 TI - Detoxification of mycotoxin patulin by the yeast Rhodosporidium paludigenum. AB - Patulin is a mycotoxin produced by Penicillium species which often contaminates fruit and fruit-derived products. In this work the degradation of patulin by the yeast Rhodosporidium paludigenum was studied and the toxicity of the degradation product was determined. Patulin-degrading activity of R. paludigenum was inducible by patulin; it was located within yeast cells and the enzyme did not require a dissociable cofactor. Chromatographic behavior and molecular mass of the degradation product indicated that R. paludigenum transformed patulin into desoxypatulinic acid. The degradation product was significantly less toxic to Arabidopsis thaliana and human liver cells than patulin; it was not toxic to Escherichia coli at the highest concentration tested. The detoxification activity of R. paludigenum toward patulin is a promising tool for the control of patulin contamination in food and feed. PMID- 25722133 TI - Edible flowers of Viola tricolor L. as a new functional food: antioxidant activity, individual phenolics and effects of gamma and electron-beam irradiation. AB - Edible flowers are used in food preparations, being also recognized for their beneficial effects on human health. Nevertheless, these species are highly perishable, and irradiation treatment might be applied to ensure food quality and increase their shelf life. Viola tricolor L. is a typical edible flower, with multiple applications and biological properties, mainly provided by the flavonoid content. In the present work, the phenolic compounds were analyzed by HPLC-DAD ESI/MS, and the antioxidant activity was evaluated using biochemical assays. Linear discriminant analyses (LDA) were performed in order to compare the results obtained with flowers submitted to different irradiation doses and technologies (cobalt-60 and electron-beam). In general, irradiated samples (mostly with 1 kGy) showed the highest phenolic content and antioxidant activity. Furthermore, the significant differences observed in the LDA allow determination of which dose and/or technology is suitable to obtain flowers with higher antioxidant potential. PMID- 25722134 TI - An economical and efficient technology for the extraction of resveratrol from peanut (Arachis hypogaea) sprouts by multi-stage countercurrent extraction. AB - In this paper, an economical and efficient technology for the extraction of resveratrol from peanut sprouts by multi-stage countercurrent extraction (MSCE) was investigated based on the alkaline extraction and acid precipitation method (AEAP). Firstly, the MSCE equipment and operation procedures were designed. Then, the optimal parameters of MSCE were obtained by using single-factor experiments and Box-Behnken design (BBD) as follows: extraction temperature of 46.6 degrees C, CaO to raw material ratio of 6:100, water to raw material ratio of 8.8:1 and extraction time of 51.7 min. Finally, the performance of MSCE was compared against the single pot extraction (SPE) under optimal conditions. The results demonstrated that MSCE was a time-saving, energy-saving, and cost-saving extraction technology for manufacturing resveratrol from peanut sprouts. PMID- 25722135 TI - Optimization and preparation of nanocapsules for food applications using two methodologies. AB - This study investigated preparation of nanocapsules (NCs) containing food-grade ingredients using two experimental designs: a one-factor-at-a-time method (OFATM) and an optimization method (OM). Response surface methodology (RSM) was used to optimize the process. The variables explored were concentration and type of polymer wall, using polycaprolactone (PCL) and polyethylene glycol-polybutylene adipate-polyethylene glycol (PEG-PBA-PEG) (1.0-4.0 mg) polyester triblock copolymer; food oil, using olive and avocado oil (0.5-2.0 mg); solvent, using acetone and ethyl acetate (6-12 ml); and surfactant concentration, using Tween 80 and Tween 60 (1-5 mg). The optimum conditions to obtain NCs were found to be 2.0 mg of PCL and 1.65 mg of PEG-PBA-PEG, olive oil (0.5 and 0.88 mg), acetone (6 and 10.25 ml), and Tween 60 (3.0 and 4.25 mg), with 90.9 and 71.9 nm for OFATM and OM, respectively. This research was conducted to investigate the use of NCs in the manufacture of fruits. PMID- 25722136 TI - Evaluation of extra virgin olive oil stability by artificial neural network. AB - The stability of extra virgin olive oil in polyethylene terephthalate bottles and tinplate cans stored for 6 months under dark and light conditions was evaluated. The following analyses were carried out: free fatty acids, peroxide value, specific extinction at 232 and 270 nm, chlorophyll, L(*)C(*)h color, total phenolic compounds, tocopherols and squalene. The physicochemical changes were evaluated by artificial neural network (ANN) modeling with respect to light exposure conditions and packaging material. The optimized ANN structure consists of 11 input neurons, 18 hidden neurons and 5 output neurons using hyperbolic tangent and softmax activation functions in hidden and output layers, respectively. The five output neurons correspond to five possible classifications according to packaging material (PET amber, PET transparent and tinplate can) and light exposure (dark and light storage). The predicted physicochemical changes agreed very well with the experimental data showing high classification accuracy for test (>90%) and training set (>85). Sensitivity analysis showed that free fatty acid content, peroxide value, L(*)Cab(*)hab(*) color parameters, tocopherol and chlorophyll contents were the physicochemical attributes with the most discriminative power. PMID- 25722137 TI - Immobilization and controlled release of beta-galactosidase from chitosan-grafted hydrogels. AB - Chitosan-grafted hydrogels were employed for immobilization and controlled released of beta-galactosidase. These hydrogels containing immobilized enzymes were employed to simulate the production of lactose-free food and controlled release of beta-galactosidase into lactose-intolerant individuals. The degree of swelling, efficiency of immobilization (i.e., fractional uptake of enzyme), and controlled release were studied as a function of pH and temperature. The degrees of swelling decreased in acidic media: 49.4 g absorbed water per g hydrogel at pH 7.0, and 8.4 g absorbed water per g hydrogel at pH 3.5. The immobilization efficiency was 19%, indicating that chitosan-grafted hydrogels are promising matrices for enzyme adsorption and immobilization. Cyclic experiments reveal that chitosan-grafted hydrogels containing immobilized enzymes can be reused several times without introducing additional enzyme prior to each cycle. There is no significant decrease in the activity of the immobilized enzyme during reutilization studies. All results were conducted in triplicate by considering t tests at a 95% significance level. Analysis of beta-galactosidase activity and controlled release reveals that chitosan-grafted hydrogels containing immobilized enzymes are useful for the production of lactose-free food and controlled enzyme release with high performance. PMID- 25722138 TI - Bioaccessibility of curcuminoids in buttermilk in simulated gastrointestinal digestion models. AB - In vitro gastrointestinal digestion models were used to investigate bioaccessibility of curcuminoids delivered with buttermilk. The percentage of solubilised curcuminoids that partitioned into the micelle in aqueous phase was determined. In fasted states (0-2.5 mg bile extract/mL sample), the bioaccessibility of curcuminoids (2% v/v ethanol) ranged from 16.3% to 26.7% in buttermilk, and from 11.4% to 18.7% with neat curcuminoids. In fed states (10-40 mg bile extract/mL sample), the bioaccessibility of curcuminoids in buttermilk was 21.3% (no ethanol) and ranged from 37.1% to 69.2% (2% v/v ethanol), while for neat curcuminoids bioaccessibility was 14.1% (no ethanol), ranging from 45.6% to 79.6% (2% v/v ethanol). The in vitro bioaccessibility of curcuminoids was influenced by the presence of the carrier (buttermilk) and ethanol, and increased significantly with increasing amount of bile extract. Curcuminoids did not markedly influence the digestibility of protein or lipids. These findings demonstrated that buttermilk could be used as a carrier for curcuminoids especially if delivered with food. PMID- 25722139 TI - The influence of chitosan on the structural properties of whey protein and wheat starch composite systems. AB - The structural properties of medium molecular weight chitosan (CHT), whey protein isolate (WPI) and native wheat starch (WS) from low- to intermediate-solid single systems and composite matrices were investigated. Analysis involved monitoring the thermal behavior of these biopolymers during controlled heating from 25 up to 95 degrees C and subsequent cooling to 5 degrees C under small deformation dynamic oscillation in-shear and micro differential scanning calorimetry experiments. Further information regarding the molecular interactions of components and overall network morphology of the systems was revealed through subjecting thermally developed gels to large deformation compression testing, scanning electron microscopy and infrared spectroscopy. Our study found a significant change in the structure of WPI networks upon incorporation of CHT in preparations due to electrostatic forces developing between the two polymeric constituents. In the tertiary system, the presence of low levels of starch contributed to a reduction in the firmness of the gel matrix. However, at higher additions of the polysaccharide, a recovery in the stored energy of composite materials was apparent, as recorded in the thermomechanical protocol. PMID- 25722140 TI - Assessment of the action spectrum for photooxidation in full fat bovine milk. AB - The action spectrum for photooxidation in full fat bovine milk was measured. Samples of milk with air or argon in headspace were exposed to narrow wavelength bands of light in the range 400-700 nm. Photooxidation in terms of off-flavors was measured by a sensory panel, volatile compounds by headspace solid phase micro extraction (SPME-GC-MS), and photobleaching of photosensitizers in milk (riboflavin, protoporphyrin IX and a chlorophyllic compound) by front face fluorescence spectroscopy. The action spectrum deviated significantly from the absorption spectrum of milk. Significant oxidation was induced by wavelengths around 400 nm and 500-650 nm in milk with air in headspace. Argon in headspace gave significant oxidation also at 700 nm. It is suggested that protoporphyrin IX and chlorophyll are responsible for oxidation induced by wavelengths >500 nm, and that also riboflavin is contributing from 400 to 500 nm. PMID- 25722141 TI - High performance liquid chromatography coupled to mass spectrometry for profiling and quantitative analysis of folate monoglutamates in tomato. AB - Folates are essential micronutrients for animals as they play a major role in one carbon metabolism. Animals are unable to synthesize folates and obtain them from plant derived food. In the present study, a high performance liquid chromatography coupled to mass spectrometric (HPLC-MS/MS) method was developed for the high throughput screening and quantitative analysis of folate monoglutamates in tomato fruits. For folate extraction, several parameters were optimized including extraction conditions, pH range, amount of tri-enzyme and boiling time. After processing the extract was purified using ultra-filtration with 10 kDa membrane filter. The ultra-filtered extract was chromatographed on a RP Luna C18 column using gradient elution program. The method was validated by determining linearity, sensitivity and recovery. This method was successfully applied to folate estimation in spinach, capsicum, and garden pea and demonstrated that this method offers a versatile approach for accurate and fast determination of different folate monoglutamates in vegetables. PMID- 25722142 TI - Quality assessment of noodles made from blends of rice flour and canna starch. AB - Canna starch and its derivatives (retrograded, retrograded debranched, and cross linked) were evaluated for their suitability to be used as prebiotic sources in a rice noodle product. Twenty percent of the rice flour was replaced with these tested starches, and the noodles obtained were analyzed for morphology, cooking qualities, textural properties, and capability of producing short-chain fatty acids (SCFAs). Cross-linked canna starch could increase tensile strength and elongation of rice noodles. Total dietary fiber (TDF) content of noodles made from rice flour was 3.0% and increased to 5.1% and 7.3% when rice flour was replaced with retrograded and retrograded debranched starches, respectively. Cooking qualities and textural properties of noodles containing 20% retrograded debranched starch were mostly comparable, while the capability of producing SCFAs and butyric acid was superior to the control rice noodles; the cooked noodle strips also showed fewer tendencies to stick together. PMID- 25722143 TI - An integrated fingerprinting and kinetic approach to accelerated shelf-life testing of chemical changes in thermally treated carrot puree. AB - To have a better understanding of chemical reactions during shelf-life, an integrated analytical and engineering toolbox: "fingerprinting-kinetics" was used. As a case study, a thermally sterilised carrot puree was selected. Sterilised purees were stored at four storage temperatures as a function of time. Fingerprinting enabled selection of volatiles clearly changing during shelf-life. Only these volatiles were identified and studied further. Next, kinetic modelling was performed to investigate the suitability of these volatiles as quality indices (markers) for accelerated shelf-life testing (ASLT). Fingerprinting enabled selection of terpenoids, phenylpropanoids, fatty acid derivatives, Strecker aldehydes and sulphur compounds as volatiles clearly changing during shelf-life. The amount of Strecker aldehydes increased during storage, whereas the rest of the volatiles decreased. Out of the volatiles, based on the applied kinetic modelling, myristicin, alpha-terpinolene, beta-pinene, alpha-terpineol and octanal were identified as potential markers for ASLT. PMID- 25722144 TI - Fat and fatty acid composition of cooked meat from UK retail chickens labelled as from organic and non-organic production systems. AB - This study compared fat and fatty acids in cooked retail chicken meat from conventional and organic systems. Fat contents were 1.7, 5.2, 7.1 and 12.9 g/100 g cooked weight in skinless breast, breast with skin, skinless leg and leg with skin respectively, with organic meat containing less fat overall (P<0.01). Meat was rich in cis-monounsaturated fatty acids, although organic meat contained less than did conventional meat (1850 vs. 2538 mg/100 g; P<0.001). Organic meat was also lower (P<0.001) in 18:3 n-3 (115 vs. 180 mg/100 g) and, whilst it contained more (P<0.001) docosahexaenoic acid (30.9 vs. 13.7 mg/100 g), this was due to the large effect of one supermarket. This system by supermarket interaction suggests that poultry meat labelled as organic is not a guarantee of higher long chain n-3 fatty acids. Overall there were few major differences in fatty acid contents/profiles between organic and conventional meat that were consistent across all supermarkets. PMID- 25722145 TI - Non-protein amino acids in Australian acacia seed: implications for food security and recommended processing methods to reduce djenkolic acid. AB - Seed of Australian acacia species, Acacia colei, Acacia elecantha, Acacia torulosa, Acacia turmida and Acacia saligna, were analysed for the presence of toxic non-protein amino acids and the levels of essential amino acids. Amines were derivatised with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate before analysis using liquid chromatography electrospray ionisation triple quadrupole mass spectrometry (LC-ESI-QQQ-MS). Multiple reaction monitoring (MRM) with optimised transitions and collision energies for each analyte were employed. The known nephrotoxic compound djenkolic acid was found to be present at elevated levels in all species tested. The lowest levels were in A. colei (0.49% w/w) and the highest in A. saligna (1.85% w/w). Observed levels of djenkolic acid are comparable to measured and reported levels found in the djenkol bean. Subsequent testing of seed processing methods showed djenkolic acid levels can be significantly reduced by over 90% by dry roasting at 180 degrees C rendering the seed safe for human consumption. PMID- 25722146 TI - Effect of different aging techniques on the polysaccharide and phenolic composition and sensory characteristics of Syrah red wines fermented using different yeast strains. AB - The effect of high levels of the polysaccharide Saccharomyces cerevisiae yeast strain (HPS) and another conventional yeast strain (FERM) on the polysaccharide and phenolic composition of Syrah red wines during alcoholic fermentation and subsequent aging on lees, with or without oak wood chips, and on inactive dry yeast was investigated. The HPS yeast released higher amounts of polysaccharides during alcoholic fermentation than FERM yeast (485 g L(-1) and 403 g L(-1), respectively) and after the aging period (516 g L(-1) and 500 g L(-1), respectively). The different aging techniques increased the polysaccharide concentration; the concentration was dependent on the aging technique applied. The interaction of the polysaccharides with the phenolic compounds depended on the yeast strain, aging technique, aging period and compound analysed. The HPS wines exhibited better sensory characteristics than the FERM wines after alcoholic fermentation; however, during the aging period, it was difficult to determine which technique produced the best wine due to the interactions of aging technique, aging period and sensory attribute evaluated. PMID- 25722147 TI - Quality and chemical profiles of monovarietal north Moroccan olive oils from "Picholine Marocaine" cultivar: registration database development and geographical discrimination. AB - Current knowledge of the quality and composition of Moroccan olive oil is still incomplete and no consistent database compiling its properties is available. This study was carried out to achieve a comprehensive characterisation of north Moroccan olive oils. Thus, 279 olive samples of "Picholine Marocaine" cultivar grown in 7 Moroccan regions were collected, and oils extracted over two consecutive crop seasons (2011 and 2012) and analysed (considering physicochemical quality parameters and purity criteria). Results indicated that all the studied samples showed values fulfilling the established limits set by the International Olive Council (IOC) standards, with the exception of 32 samples that had a linolenic acid content higher than 1%, which is the maximum value fixed by the IOC regulation. Furthermore, the usefulness of the evaluated parameters for tracing the geographical origin of the studied samples was tested by using canonical discriminant analysis. A good rate of correct classification and prediction was achieved. PMID- 25722148 TI - Amazon acai: chemistry and biological activities: a review. AB - Acai (acai or assai) is one of the Amazon's most popular functional foods and widely used in the world. There are many benefits to its alleged use in the growing market for nutraceuticals. The acai extracts have a range of polyphenolic components with antioxidant properties, some of those present in greater quantity are orientin, isoorientin and vanillic acid, as well as anthocyanins cyanidin-3 glucoside and cyanidin-3-rutinoside. The presence of these substances is linked mainly to the antioxidant, anti- inflammatory, anti-proliferative and cardioprotective activities. Importantly, there are two main species of the Euterpe genus which produce acai. There are several differences between them but they are still quite unknown, from literature to producers and consumers. In this review are highlighted the chemical composition, botanical aspects, pharmacological, marketing and nutrition of these species based on studies published in the last five years in order to unify the current knowledge and dissimilarities between them. PMID- 25722149 TI - Stability of dicyclohexylamine and fumagillin in honey. AB - Fumagillin is extensively used to control nosema disease in apiculture. In the commercial formulation, fumagillin is present as a salt in an equimolar quantity with dicyclohexylamine (DCH). In this study DCH was observed to be significantly more resistant to degradation in honey than fumagillin using LC-MS/MS analysis. Observed half-lives for DCH ranged from a minimum of 368 days when kept at 34 degrees C in darkness, to a maximum of 852 days when stored at 21 degrees C in darkness. A maximum half-life of 246 days was observed for fumagillin in samples kept in darkness at a temperature of 21 degrees C. The observed half-life of fumagillin was estimated to be 3 days when exposed to light at 21 degrees C, and complete decomposition was observed after 30 days under the same conditions. The stability of DCH, combined with its genotoxicity and tumorigenic properties make it an important potential contaminant in honey destined for human consumption. PMID- 25722150 TI - Phytochemical profile of commercially available food plant powders: their potential role in healthier food reformulations. AB - Reformulation of existing processed food or formulation of new foods using natural products (plant-based) will inherently confer to new products with less calories, fat, salt, phosphates and other synthetic components, and higher amounts of fibre, antioxidants, vitamins and other beneficial components. Plant ingredients, such as food plant powders, are currently being used in food manufacturing, predominantly for flavouring and colouring purposes. To expand their use as a food ingredient, freeze-dried powders representing major vegetable groups were characterised by targeted LC-MS/MS analysis of their phytochemicals. All the plant powders were found to be rich in flavonoids, phenolic acids and derivatives; total content in these compounds varied from around 130 mg kg(-1) (green pea) to around 930 mg kg(-1) (spinach). The food plant powders' phytochemical content represents valuable information for the food industry in the development of healthier novel foods and for the reformulation of existing food products in relation to antioxidants, food preservatives and alternatives to nitrite use. PMID- 25722151 TI - Identification of potential protein markers of noble rot infected grapes. AB - The evaluation of Botrytis cinerea as noble rot on withered grapes is of great importance to predict the wine sensory/organoleptic properties and to manage the winemaking process of Amarone, a passito dry red wine. This report describes the first proteomic analysis of grapes infected by noble rot under withering conditions to identify possible markers of fungal infection. 2-D gel electrophoresis revealed that protein profiles of infected and not infected grape samples are significantly different in terms of number of spots and relative abundance. Protein identification by MS analysis allowed to identify only in infected berries proteins of B. cinerea that represent potential markers of the presence of the fungus in the withered grapes. PMID- 25722152 TI - Non-destructive prediction of thiobarbituricacid reactive substances (TBARS) value for freshness evaluation of chicken meat using hyperspectral imaging. AB - This study examined the potential of hyperspectral imaging (HSI) for rapid prediction of 2-thiobarbituric acid reactive substances (TBARS) content in chicken meat during refrigerated storage. Using the spectral data and the reference values of TBARS, a partial least square regression (PLSR) model was established and yielded acceptable results with regression coefficients in prediction (Rp) of 0.944 and root mean squared errors estimated by prediction (RMSEP) of 0.081. To simplify the calibration model, ten optimal wavelengths were selected by successive projections algorithm (SPA). Then, a new SPA-PLSR model based on the selected wavelengths was built and showed good results with Rp of 0.801 and RMSEP of 0.157. Finally, an image algorithm was developed to achieve image visualization of TBARS values in some representative samples. The encouraging results of this study demonstrated that HSI is suitable for determination of TBARS values for freshness evaluation in chicken meat. PMID- 25722153 TI - Usefulness of (1)H NMR in assessing the extent of lipid digestion. AB - Proton Nuclear Magnetic Resonance ((1)H NMR) is proved to be, for the first time, a very useful technique in monitoring the extent of lipid hydrolysis in digestion processes. Sunflower oil and minced fish flesh, as model foods, were subjected to different in vitro digestion experiments and the lipolysis levels reached were evaluated using (1)H NMR spectral data. Simple observation of the spectra gives very valuable information about the extent of the lipolysis and enables a rapid discrimination among samples having different hydrolysis degree. Equations were developed to quantify all the lipolytic products, and either referred to acyl groups plus fatty acids, or to glyceryl structures. The main hydrolysis products were 1,2-diglycerides, 2-monoglycerides, glycerol and fatty acids, although small proportions of 1,3-diglycerides and of 1-monoglycerides were also found. With this methodology, determination of the extent of lipid digestion in its different definitions can be made. It has been shown that these definitions are not equivalent, which is evidence for the need for a consensus in this regard. PMID- 25722154 TI - Identification of polyphenolic compounds in the flesh of Argan (Morocco) fruits. AB - High performance liquid chromatography coupled with negative electrospray ionization (HPLC-ESI) along with fragmentation patterns generated by nano electrospray ionization (nano-ESI-MS-MS) and NMR techniques were utilized for the identification of phenolic compounds in Argan fruits. A total of 15.4 g/kg was determined represented by catechins (39%), flavonoids (28%), procyanidins (26%), free phenolic acids (6%) and phenolic acid glycosides (1%). Twenty-one phenolic compounds were identified for the first time in Argan fruits namely III. epicatechin-(4beta->8)-catechin dimer (procyanidin B1), IV. p-coumaric acid glycoside, VI. epicatechin-(4beta->8)-epicatechin dimer (procyanidin B2), VIII. caffeic acid glycoside, XIX. epicatechin-(4beta->8)-epicatechin-(4beta->8) epicatechin trimer (procyanidin C1), X. p-hydroxybenzaldehyde XI. ferulic acid glycoside, XII. vanillic acid, XIII. sinapic acid glycoside, XVI. p-coumaric acid, XVII. ferulic acid, XVIII. sinapic acid, XIX. rutin pentoside, XX. quercetin glycopentoside, XXI. 4,4'-dihydroxy-3,3'-imino-di-benzoic acid, XXV. quercetin-3-O-rhamnogalactoside, XXVII. quercetin glycohydroxybenzoate, XXVIII. quercetin glycocaffeate, XXIX. quercetin glycosinapate, XXX. quercetin glycoferulate and XXXI. quercetin glycocoumarate. PMID- 25722155 TI - Altered concentrate to forage ratio in cows ration enhanced bioproduction of specific size subpopulation of milk fat globules. AB - The mechanism underlying the shift in milk-fat-globule (MFG) mean diameter upon changing the concentrate-to-forage ratio in dairy cow rations was investigated. Cows were fed high-concentrate low-forage (HCLF) or high-forage low-concentrate (LCHF) rations for 4 weeks. Mean diameter of MFG, determined in raw whole milk, was 0.4 MUm larger in the LCHF-fed vs. HCLF-fed group. The main compositional differences between treatments were found in a specific MFG subgroup with the diameter of 3.3 MUm (F1), with higher capric, lauric, myristic and lower oleic acid concentrations in HCLF vs. LCHF milk. Similarly, lipid concentration differences between treatments were only found in F1, with higher triglyceride and phosphatidylethanolamine, and lower sphingomyelin concentrations in LCHF vs. HCLF milk. The higher MFG mean diameter in whole raw LCHF milk might therefore be attributed to increased secretion of F1-group MFG, while fat content and composition in the other MFG size groups remains unchanged. PMID- 25722156 TI - Hydrophilic gallic acid-imprinted polymers over magnetic mesoporous silica microspheres with excellent molecular recognition ability in aqueous fruit juices. AB - Hydrophilic molecularly imprinted polymers (MIPs) for gallic acid (GA) were prepared with excellent recognition ability in an aqueous solution. The proposed MIPs were designed by self-polymerization of dopamine (DA) on magnetic mesoporous silica (Fe3O4@SiO2@mSiO2, MMS) using GA as template. Resulting Fe3O4@SiO2@mSiO2@MIPs (MMS-MIPs) were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), thermo gravimetric analysis (TGA), Brunauer-Emmett-Teller (BET), vibrating sample magnetometer (VSM), and evaluated by adsorption isotherms/kinetics and competitive adsorption. The adsorption behavior between GA and MMS-MIPs followed Langmuir and Sips adsorption isotherms with a maximum adsorption capacity at 88.7 mg/g and pseudo-second-order reaction kinetics with fast binding (equilibrium time at 100 min). In addition, MMS-MIPs showed rapid magnetic separation (10 s) and stability (retained 95.2% after six cycles). Subsequently, MMS-MIPs were applied for the selective extraction and determination of GA from grape, apple, peach and orange juices (4.02, 3.91, 5.97, and 0.67 MUg/g, respectively). Generally, the described method may pave the way towards rationally designing more advanced hydrophilic MIPs. PMID- 25722157 TI - beta-Carotene and astaxanthin with human and bovine serum albumins. AB - beta-Carotene and astaxanthin are two carotenoids with powerful antioxidant properties. In this study, the interaction of these two carotenoids with human serum albumin (HSA) and bovine serum albumin (BSA) under physiological conditions was investigated using several spectroscopic techniques. The experimental results indicate the quenching mechanism of HSA/BSA, by the two carotenoids, is a static process. The binding constants and number of binding sites were evaluated at different temperatures. Thermodynamic investigations revealed the interaction between the two carotenoids and HSA/BSA is synergistically driven by enthalpy and entropy, and hydrophobic forces and electrostatic attraction have a significant role in the reactions. Binding site I was found to be the primary binding site for beta-carotene and astaxanthin. In addition, as shown by synchronous fluorescence spectroscopy and FT-IR, the two carotenoids may induce conformational and micro-environmental changes in HSA/BSA. PMID- 25722158 TI - The effect of curdlan on the rheological properties of restructured ribbonfish (Trichiurus spp.) meat gel. AB - The influence of curdlan at different levels, as well as the method of addition, on the viscoelastic characteristics of ribbonfish meat gel was investigated. From a small amplitude oscillatory shear analysis (SAOA), a variety of viscoelastic parameters were established and identified to measure the intensity of the interactions between curdlan and protein in the fish meat gel network structure. The results of water holding capacity, texture, sensory property and microstructure analyses were strongly in agreement with the rheology data, suggesting that SAOA might be an appropriate method for the industrial assessment of the quality of fish meat gel. Additionally, the recombination mechanism of the complex system formed by the fish protein and curdlan was also clarified. Compared with the irreversible curdlan gel samples, the addition of reversible curdlan gel to the fish meat gel formed a much denser cross-linked interpenetrating structure, which led to a more stable and ordered three dimensional gel complex. PMID- 25722159 TI - Effects of waterlogging after pollination on the physicochemical properties of starch from waxy maize. AB - Waterlogging frequently occurs in Southern China in summer and significantly affects waxy maize growth. This study investigated the physicochemical properties of starch from six waxy maize varieties exposed to waterlogging for 1-7 days after pollination. Waterlogging decreased the starch granule size. Starch maximum absorption wavelength, iodine-binding capacity, crystallinity, and peak intensities in response to waterlogging depended on varieties. Swelling power and solubility in response to waterlogging increased in Wannuo5 and decreased in the other five varieties. Gelatinization and pasting temperatures were only slightly affected by waterlogging. Gelatinization enthalpy was unaffected in Nongkeyu301, increased in Guangbainuo5, and decreased in the other four varieties. Peak and breakdown viscosities decreased and retrogradation percentage increased when plants were subjected to waterlogging after pollination. In conclusion, waterlogging decreased starch granule size, crystallinity, swelling power, and solubility, resulting in deteriorated starch quality (i.e., low swelling, less sticky and easy to retrograde). PMID- 25722160 TI - Development and validation of a method for the determination of low-ppb levels of macrocyclic lactones in butter, using HPLC-fluorescence. AB - An analytical method was developed and validated for the simultaneous determination of four macrocyclic lactones (ML) (abamectin, doramectin, ivermectin and moxidectin) in butter, using liquid chromatography with fluorescence detection. The method employed heated liquid-liquid extraction and a mixture of acetonitrile, ethyl acetate and water, with preconcentration and derivatization, to produce stable fluorescent derivatives. The chromatographic run time was <12.5 min, with excellent separation. The method validation followed international guidelines and employed fortified butter samples. The figures of merit obtained, e.g. recovery (72.4-106.5%), repeatability (8.8%), within laboratory reproducibility (15.7%) and limits of quantification (0.09-0.16 MUg kg(-1)) were satisfactory for the desired application. The application of the method to real samples showed that ML residues were present in six of the ten samples evaluated. The method proved to be simple, easy and appropriate for simultaneous determination of ML residues in butter. To our knowledge, this is the first method described for the evaluation of ML in butter. PMID- 25722161 TI - Influence of succinylation on the conformation of yak casein micelles. AB - Succinylation modifies the physicochemical characteristics and improves the functional properties of proteins. This study assessed the effects of succinylation on the conformation of yak casein micelles with seven degree of modification. The results revealed that succinylation contributed to the dissociation of casein micelles. With the increase of succinylated degree, soluble nitrogen and minerals content increased, while casein micelle size and polydispersity index of micelles decreased. Succinylation affected the spatial conformation of yak casein micelles: turn decreased, beta-sheet and alpha-helix increased, and irregular structure were non-significantly affected. The intrinsic and ANS fluorescence intensity decreased and the maximum emission wavelength shifted red with increasing succinylation. Based on the results, the structure of yak casein micelles was characteristic of the sub-micelle model. PMID- 25722162 TI - Rapid determination of total aflatoxins and ochratoxins A in meat products by immuno-affinity fluorimetry. AB - Total aflatoxins (AFT) and ochratoxin A (OTA) levels were estimated using the VICAM AflaTest and OchraTest immunoaffinity fluorometric method in a total of 50 meat products (25 each of beef luncheon and beef burger) purchased from different supermarkets in Mansoura city, Egypt. All the meat samples analyzed were contaminated with both AFT and OTA with mean values of 1.1 MUg/kg and 5.23 MUg/kg, respectively, for beef luncheon and mean values of 3.22 MUg/kg and 4.55 MUg/kg, respectively, for beef burger. None of the beef luncheon and burger samples analyzed exceeded the permissible limits set by FDA for AFT, but 40% of beef burgers exceeded the FAO AFT permissible limit. Similarly, 52% and 36% of beef luncheon and beef burger samples exceeded the FAO OTA permissible limit. Application of the immunoaffinity fluorometric method is an accurate, safe and rapid method for mycotoxins determination in meat products to ensure their safety for human consumption. PMID- 25722163 TI - Characteristics of remixed fermentation dough and its influence on the quality of steamed bread. AB - In this study, the effects of the amount of remixed flour on the properties of remixed fermentation dough and the quality of Chinese steamed breads were investigated. The hardness, chewiness and whiteness of steamed bread increased when the amount of remixed flour was higher than 10 g/100 g, whereas the specific volume of steamed bread significantly decreased. SEM analysis demonstrated that the gas cells of the steamed bread remained as a discrete spherical or oval-like entity only at 10 g/100 g level of remixed flour. Time-domain NMR showed that water migrated from T22 population to T21 population with increasing the amount of remixed flour. The XRD results indicated that starch in the steamed bread with remixed flour was gelatinized. A significant decrease of both the rate and extent of starch hydrolysis of the steamed bread was observed when flour was remixed. PMID- 25722164 TI - AOT/isooctane reverse micelles with a microaqueous core act as protective shells for enhancing the thermal stability of Chromobacterium viscosum lipase. AB - According to the different environmental systems for lipase reactions, changes in thermal stability were investigated by employing the Chromobacterium viscosum lipase and a two-step series-type deactivation model. The half-life (6.81 h) of the lipase entrapped in reverse micelles at 70 degrees C was 9.87- and 14.80 fold longer than that in glycerol pool or in aqueous buffer. The deactivation constants for the first and second step (k1 and k2) at all temperatures drastically decreased when the lipase was entrapped in reverse micelles. In particular, k1 (3.84 h(-1)) at 70 degrees C in reverse micelles was 1.57-fold lower than that in aqueous buffer (6.03 h(-1)). Based on the fluorescence spectrometry, the amount of excited forms of tryptophan and tyrosine increased markedly during the thermal-treatment in aqueous buffer, whereas no significant fluctuation was noted in the reversed micellar system. These results indicated that the encapsulation in reverse micelles could be favorable for preventing the enzyme from heat-induced denaturation. PMID- 25722165 TI - Optimization of extraction efficiency by shear emulsifying assisted enzymatic hydrolysis and functional properties of dietary fiber from deoiled cumin (Cuminum cyminum L.). AB - This study evaluated the optimal conditions for extracting dietary fiber (DF) from deoiled cumin by shear emulsifying assisted enzymatic hydrolysis (SEAEH) using the response surface methodology. Fat adsorption capacity (FAC), glucose adsorption capacity (GAC), and bile acid retardation index (BRI) were measured to evaluate the functional properties of the extracted DF. The results revealed that the optimal extraction conditions included an enzyme to substrate ratio of 4.5%, a reaction temperature of 57 degrees C, a pH value of 7.7, and a reaction time of 155 min. Under these conditions, DF extraction efficiency and total dietary fiber content were 95.12% and 84.18%, respectively. The major components of deoiled cumin DF were hemicellulose (37.25%) and cellulose (33.40%). FAC and GAC increased with decreasing DF particle size (51-100 MUm), but decreased with DF particle sizes <26 MUm; BRI increased with decreasing DF particle size. The results revealed that SEAEH is an effective method for extracting DF. DF with particle size 26-51 MUm had improved functional properties. PMID- 25722166 TI - Isolation of dimeric, trimeric, tetrameric and pentameric procyanidins from unroasted cocoa beans (Theobroma cacao L.) using countercurrent chromatography. AB - The main procyanidins, including dimeric B2 and B5, trimeric C1, tetrameric and pentameric procyanidins, were isolated from unroasted cocoa beans (Theobroma cacao L.) using various techniques of countercurrent chromatography, such as high speed countercurrent chromatography (HSCCC), low-speed rotary countercurrent chromatography (LSRCCC) and spiral-coil LSRCCC. Furthermore, dimeric procyanidins B1 and B7, which are not present naturally in the analysed cocoa beans, were obtained after semisynthesis of cocoa bean polymers with (+)-catechin as nucleophile and separated by countercurrent chromatography. In this way, the isolation of dimeric procyanidin B1 in considerable amounts (500mg, purity>97%) was possible in a single run. This is the first report concerning the isolation and semisynthesis of dimeric to pentameric procyanidins from T. cacao by countercurrent chromatography. Additionally, the chemical structures of tetrameric (cinnamtannin A2) and pentameric procyanidins (cinnamtannin A3) were elucidated on the basis of (1)H NMR spectroscopy. Interflavanoid linkage was determined by NOE-correlations, for the first time. PMID- 25722167 TI - Isolation, identification and synthesis of four novel antioxidant peptides from rice residue protein hydrolyzed by multiple proteases. AB - Multiple proteases were optimized to hydrolyze the rice residue protein (RRP) to produce novel antioxidant peptides. An antioxidant peptide fraction (RRPB3) with IC50 of 0.25 mg/ml was purified from the RRP hydrolysate using membrane ultrafiltration followed by size exclusion chromatography and reversed-phase FPLC. RRPB3 was found to include four peptides (RRPB3 I-IV) and their amino acid sequences were RPNYTDA (835.9 Da), TSQLLSDQ (891.0 Da), TRTGDPFF (940.0 Da) and NFHPQ (641.7 Da), respectively. Furthermore, four peptides were chemically synthesized and their antioxidant activities were assessed by DPPH radical scavenging, ABTS radical scavenging assay and FRAP-Fe(3+) reducing assay, respectively. Both RRPB3 I and III showed synergistic antioxidant activity compared to each of them used alone. All four synthetic peptides showed excellent stability against simulated gastrointestinal proteases. Therefore, the peptides isolated from RRP may be used as potential antioxidants in the food and drug industries. PMID- 25722168 TI - Study of hydration properties of wheat bran as a function of particle size. AB - New insights in the hydration properties of wheat bran as function of particle size were gained based on a novel water retention capacity test. Upon milling coarse bran with an average particle size of 1687 MUm down to 77 MUm, the specific surface increases by twofold, structural integrity was lost and water extractable arabinoxylan and damaged starch content were practically unaffected. A standard centrifugation-based water retention capacity, swelling capacity and Enslin-Neff absorption test showed up to threefold higher water absorption for large particles. During these hydration tests, bran is not (continuously) subjected to external forces which allows larger particles to hold more water in between bran particles and probably in micropores. In contrast, the water retention capacity as determined by a novel drainage centrifugation method, and Farinograph absorption were not affected by particle size. In these methods, continuous exposure of bran to external forces causes bran to retain only strongly bound water which is most likely bound in cell wall nanopores and through hydrogen bonding. These insights reconcile contradicting observations in literature with regard to this matter. PMID- 25722169 TI - Role of quercetin as an alternative for obesity treatment: you are what you eat! AB - Obesity is one of the most serious global health problems, which increases the risk of other different chronic diseases. The crucial role of oxidative stress in the initiation and progression of obesity leads to the hypothesis that antioxidants can be used as therapeutic agents for obesity treatment. Among antioxidants, much attention has been paid to polyphenols due to their negligible adverse effects. Among them, quercetin is one of the most common dietary antioxidants widely distributed in different plant materials, such as fruits, vegetables and cereals. Quercetin shows a wide range of biological and health promoting effects, such as anticancer, hepatoprotective, antidiabetic, anti inflammatory and antibacterial activities. Furthermore, quercetin has anti obesity activity through mitogen-activated protein kinase and adenine monophosphate-activated protein kinase signaling pathways. In this study, we reviewed the available scientific reports concerning the beneficial role of quercetin against obesity with emphasis on its mechanisms of action. PMID- 25722170 TI - Oligosaccharides of Cabernet Sauvignon, Syrah and Monastrell red wines. AB - Wine oligosaccharides were recently characterized and their concentrations, their composition and their roles on different wines remain to be determined. The concentration and composition of oligosaccharides in Cabernet Sauvignon, Syrah and Monastrell wines was studied. Oligosaccharide fractions were isolated by high resolution size-exclusion chromatography. The neutral and acidic sugar composition was determined by gas chromatography. The MS spectra of the oligosaccharides were performed on an AccuTOF mass spectrometer. Molar-mass distributions were determined by coupling size exclusion chromatography with a multi-angle light scattering device (MALLS) and a differential refractive index detector. Results showed significant differences in the oligosaccharidic fraction from Cabernet Sauvignon, Syrah and Monastrell wines. This study shows the influence that the grape variety seems have on the quantity, composition and structure of oligosaccharides in the finished wine. To our knowledge, this is the first report to research the oligosaccharides composition of Cabernet Sauvignon, Syrah and Monastrell wines. PMID- 25722171 TI - Sensitive determination of Amaranth in drinks by highly dispersed CNT in graphene oxide "water" with the aid of small amounts of ionic liquid. AB - Graphene oxide (GO) is a pH-dependent amphiphile. In this paper, it was found that carbon nanotubes (CNTs) can be highly dispersed in graphene oxide "water" with the aid of prototype ionic liquid of 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]). The introduction of [BMIM][PF6] not only can minimize the defects of poor electrical conductivity of GO, but also can improve the dispersibility of CNT in water. Hence, a new composite of CNT/GO-[BMIM][PF6] with high dispersibility and strong conductivity was presented for the first time and employed in the sensitive determination of Amaranth in soft drinks. The detection limit achieved (0.1 nM) is much lower than the guideline values in soft drinks. The ease of preparation, low background current, high sensitivity and stability can create novel avenues and applications for fabricating robust sensors for determination of other azo dyes in foods. PMID- 25722172 TI - Nitrite detection in meat products samples by square-wave voltammetry at a new single walled carbon naonotubes--myoglobin modified electrode. AB - A new modified electrode was realized in a simple way, consisting by the immobilization of a myoglobin (My) - single walled carbon nanotubes (SWCNT) mixture on the surface of a graphite electrode with a Nafion film. The cyclic voltammetry investigations realized with the obtained electrode (G/My SWCNT/Nafion) showed a voltammetric signal due to a one-step redox reaction of the surface-confined myoglobin, in a deaerated 0.1 M phosphate buffer, pH 7. Also, the G/My-SWCNT/Nafion modified electrode demonstrated a great potential for the analytical determination of nitrite ions by square-wave voltammetry and an alternative for the already existing methods. The use of the sensor for the detection of nitrite ions in samples of meat products leads to comparable results with those obtained with the standard Griess spectrophotometric assay (ISO 2918/1975), proving the suitability of using immobilized myoglobin as electrocatalyst in the nitrite reduction process. PMID- 25722173 TI - Human exposure to mercury, lead and cadmium through consumption of canned mackerel, tuna, pilchard and sardine. AB - Total mercury (Hg), cadmium (Cd) and lead (Pb) concentrations were determined in canned fish on the Ghanaian market. Total mercury was determined using an automatic mercury analyzer while cadmium and lead levels were determined by flame atomic absorption spectrophotometry. The metal contents in the samples, expressed in MUg g(-1) (wet weight), varied from <0.01 to 0.20 with an average value of 0.03 for mercury, from <0.01 to 0.45 with an average value of 0.34 for cadmium, and from <0.01 to 1.44 with an average value of 0.72 for lead. The results indicate that canned fish from the Ghanaian market have concentrations well below the permissible FAO/WHO for these toxic metals. Thus considering the Provisional Tolerable Weekly Intake (PTWI) of Hg, Pb and Cd the levels obtained in this study are unlikely to constitute a significant exposure to the public through consumption of moderate amounts. PMID- 25722174 TI - Polyphenols content, phenolics profile and antioxidant activity of organic red wines produced without sulfur dioxide/sulfites addition in comparison to conventional red wines. AB - Wine exerts beneficial effects on human health when it is drunk with moderation. Nevertheless, wine may also contain components negatively affecting human health. Among these, sulfites may induce adverse effects after ingestion. We examined total polyphenols and flavonoids content, phenolics profile and antioxidant activity of eight organic red wines produced without sulfur dioxide/sulfites addition in comparison to those of eight conventional red wines. Polyphenols and flavonoids content were slightly higher in organic wines in respect to conventional wines, however differences did not reach statistical significance. The phenolic acids profile was quite similar in both groups of wines. Antioxidant activity was higher in organic wines compared to conventional wines, although differences were not statistically significant. Our results indicate that organic red wines produced without sulfur dioxide/sulfites addition are comparable to conventional red wines with regard to the total polyphenols and flavonoids content, the phenolics profile and the antioxidant activity. PMID- 25722175 TI - Volatile and sensory profiling of cocktail bitters. AB - Aromatic cocktail bitters are derived from the alcoholic extraction of a variety of plant materials and are used as additives in mixed drinks to enhance aroma and flavor. In this study sixteen commercial bitters were analyzed using volatile (GC MS) and sensory profiling and multivariate statistics including Principal Component Analysis (PCA) and Partial Least Squares Regression (PLS). The samples differed significantly in their citrus, celery, and spice characteristics. 148 volatile compounds were tentatively identified and the composition varied significantly with the type of bitters sample evaluated. PLS analysis showed that the volatile data correlated well overall to the sensory data, explaining 60% of the overall variability in the dataset. Primary aldehydes and phenylpropanoids were most closely related to green and spice-related sensory descriptors. However, the sensory impact of terpenoid compounds was difficult to predict in many cases. This may be due to the wide range of aroma qualities associated with terpenes as well as to concentration, synergistic or masking effects. PMID- 25722178 TI - [From hand eczema to skin cancer: news from the occupational dermatology]. PMID- 25722176 TI - Molecular analysis of Iranian colorectal cancer patients at risk for Lynch syndrome: a new molecular, clinicopathological feature. AB - PURPOSE: Microsatellite instability (MSI) and mismatch repair (MMR) gene expression present a hallmark mutational signature of Lynch syndrome as a common hereditary cancer predisposing condition. Since there is not enough data of molecular and clinicopathological aspects of the disease in Iranian populations, this article is a new description in Central Iran. METHODS: It is a descriptive analytical study in which we screened 1659 colorectal cancer (CRC) patients based on early-onset disease and Amsterdam II criteria during 14 years (2000-2013). MSI testing was applied through a commercial kit evaluating five mononucleotide markers (BAT-25, BAT-26, MON0-27, NR-21, and NR-24) using a fluorescent multiplex PCR method. Immunohistochemistry (IHC) staining was set up to detect expression of four mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2. SPSS 16 software was used to analyze the data. RESULTS: Overall, 31 of 45 screened at risk families were eventually included to MSI testing of which 9/31 patients (~29 %) showed MSI in their tumor tissues including 6 (19.4 %) MSI-H (high). BAT-26 was the most instable marker with instability in 7/31 MSI tumors (22.6 %). IHC MMR staining was absent in 7/31 probands (22.6 %) of which in 4 cases, both MSH2/MSH6 (57.1 %) and, in 2 cases, both MLH1/PMS2 showed deficiency (28.6 %), and just in one case, MSH6 was defective (14.3 %). IHC-MMR was absent in all 6 MSI-H tumors while none of 3 MSI-L tumors were MMR-deficient. Just single MSH6 defective tumor showed MSS state. The frequency of CRC among MMR-deficient and MMR-proficient families was 67.5 and 27.9 %, respectively. The most common extracolonic cancer among both MMR-deficient and MMR-proficient groups was stomach, respectively, with 26.7 and 16.5 %. CONCLUSIONS: A different molecular and clinicopathological phenotype of tumors in CRC Iranian patients at risk for Lynch syndrome could suggest some new molecular mechanisms about which more evaluations are necessary. PMID- 25722177 TI - A brief peripheral motion contrast threshold test predicts older drivers' hazardous behaviors in simulated driving. AB - Our research group has previously demonstrated that the peripheral motion contrast threshold (PMCT) test predicts older drivers' self-report accident risk, as well as simulated driving performance. However, the PMCT is too lengthy to be a part of a battery of tests to assess fitness to drive. Therefore, we have developed a new version of this test, which takes under two minutes to administer. We assessed the motion contrast thresholds of 24 younger drivers (19 32) and 25 older drivers (65-83) with both the PMCT-10min and the PMCT-2min test and investigated if thresholds were associated with measures of simulated driving performance. Younger participants had significantly lower motion contrast thresholds than older participants and there were no significant correlations between younger participants' thresholds and any measures of driving performance. The PMCT-10min and the PMCT-2min thresholds of older drivers' predicted simulated crash risk, as well as the minimum distance of approach to all hazards. This suggests that our tests of motion processing can help predict the risk of collision or near collision in older drivers. Thresholds were also correlated with the total lane deviation time, suggesting a deficiency in processing of peripheral flow and delayed detection of adjacent cars. The PMCT-2min is an improved version of a previously validated test, and it has the potential to help assess older drivers' fitness to drive. PMID- 25722179 TI - [Costello syndrome. A rare RASopathy with cutaneous symptoms]. AB - An 18-year-old female with palmoplantar keratoderma, hyperhidrosis, facial verruciform papillomatosis, coarse face, growth retardation and developmental delay presented to our outpatient clinic. A diagnosis of Costello syndrome was made, and genetic counseling and a molecular genetic analysis were initiated. By this means, a heterozygous missense mutation in exon 2 of the HRAS gene, designated c.34G > A (p.Gly12Ser), was detected, confirming the clinical diagnosis. Costello syndrome belongs to the group of clinically and genetically heterogeneous RASopathies with cutaneous symptoms. Collectively, the RASopathies are caused by mutations in different genes, which lead to dysregulation of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. This signaling route regulates the delicate balance between cell proliferation and differentiation, and plays an important role in embryogenesis and carcinogenesis. In the RASopathies with cutaneous symptoms, overlapping clinical findings may hamper making an accurate diagnosis. Therefore, a molecular genetic analysis may be useful, as in the patient described here. PMID- 25722181 TI - Tyrosine fluorescence probing of the surfactant-induced conformational changes of albumin. AB - Tyrosine fluorescence in native proteins is known to be effectively quenched, whereas its emission increases upon proteins' unfolding. This suggests that tyrosine fluorescence could be exploited for probing structural rearrangements of proteins in addition to the extensively used tryptophan emission. We studied the possibility of using tyrosine fluorescence as an indicator of surfactant-induced conformational changes in albumins. It was shown that fluorescence of tyrosine residues, which are uniformly distributed all over the protein molecules, allows the detection of subtle structural rearrangements of proteins upon surfactant binding, which do not influence the properties of a single tryptophan residue buried in the inner hydrophobic region of human serum albumin. Tyrosine fluorescence properties, including its fluorescence lifetime, revealed the multistage character of surfactant binding to albumin, consistent with the data provided by other methods. The obtained results demonstrate the possibility of probing conformational changes in proteins using tyrosine photophysical parameters as indicators. PMID- 25722180 TI - Factors affecting range of motion after total knee arthroplasty in patients with more than 120 degrees of preoperative flexion angle. AB - PURPOSE: The postoperative flexion angle reportedly shows a positive correlation with the preoperative flexion angle, but in some cases, the postoperative flexion angle decreases in patients with a large preoperative flexion angle. The purpose of this study was to investigate factors affecting the range of motion after total knee arthroplasty (TKA) in patients with a large preoperative flexion angle. METHODS: The study evaluated 120 knees with more than 120 degrees of preoperative flexion angle that underwent NexGen LPS-Flex mobile bearing. The groups with and without a reduction in the postoperative flexion angle were compared. Also, a logistic regression analysis was performed, where the presence or absence of a reduction in the postoperative flexion angle was the dependent variable and age, sex, body mass index (BMI), preoperative femorotibial angle (FTA), gamma angle, delta angle, pre/postoperative change amount in posterior condylar offset (PCO), pre/postoperative change amount in joint line, and pre/postoperative change amount in patellar thickness were independent variables. RESULTS: Those with preoperative FTA of 186 degrees or larger did not have a reduction in the postoperative flexion angle, compared with the angle of 185 degrees or smaller. Those with delta angle of 83 degrees or smaller also did not have a reduction in the postoperative flexion angle, compared with the angle of 84 degrees or larger. CONCLUSIONS: Our results showed that preoperative FTA and delta angle had an impact on a reduction in the postoperative flexion angle. The installation angle of the tibial component in the sagittal plane is important. PMID- 25722182 TI - Enhancing the hydrolysis and methane production potential of mixed food waste by an effective enzymatic pretreatment. AB - In this study, a fungal mash rich in hydrolytic enzymes was produced by solid state fermentation (SSF) of waste cake in a simple and efficient manner and was further applied for high-efficiency hydrolysis of mixed food wastes (FW). The enzymatic pretreatment of FW with this fungal mash resulted in 89.1 g/L glucose, 2.4 g/L free amino nitrogen, 165 g/L soluble chemical oxygen demand (SCOD) and 64% reduction in volatile solids within 24h. The biomethane yield and production rate from FW pretreated with the fungal mash were found to be respectively about 2.3 and 3.5-times higher than without pretreatment. After anaerobic digestion of pretreated FW, a volatile solids removal of 80.4+/-3.5% was achieved. The pretreatment of mixed FW with the fungal mash produced in this study is a promising option for enhancing anaerobic digestion of FW in terms of energy recovery and volume reduction. PMID- 25722183 TI - Delayed access to treatments for rare diseases: who's to blame? AB - The development and commercialization of drugs for rare diseases, termed 'orphan drugs', has historically been economically unattractive. However, because of the introduction of legislation that provides financial and regulatory incentives for the development of orphan drugs, new developments are making their way through the regulatory approval processes. Unfortunately, delays in availability of new drugs for treating rare disease continue to persist. This paper reviews the approach of several regulatory jurisdictions to orphan drugs in an effort to determine their relative effectiveness in providing patient access. Generally speaking, regulatory authorities across jurisdictions have recognized the need to enhance timely access to safe, effective treatment for patients with rare diseases and have been able to shift the approval timelines for access to new care. The greater impediment to orphan drug access appears to be funding, particularly in publicly sponsored health-care systems. Redundancies in federal and provincial reviews of orphan drugs can result in significant delays in access to new drugs. Clearly, more must be done to accelerate access to the treatments so desperately needed by patients. Public payers must be held accountable for their process and decisions--especially for rare disease therapies. PMID- 25722184 TI - Actively using clopidogrel correlates with an increased risk of acute pancreatitis in Taiwan. AB - The aim of this study is to assess whether there is an association between clopidogrel use and risk of acute pancreatitis in Taiwan. We conducted a case control study using the database of the Taiwan National Health Insurance Program from 2000 to 2011. There were 5644 subjects aged 20-84 years with a first-time attack of acute pancreatitis as the case group and 22,576 randomly selected sex matched and age-matched subjects without acute pancreatitis as the control group. We defined clopidogrel use as "actively using" if the final clopidogrel prescription was filled between 0 and 7 days before the date of diagnosing acute pancreatitis, or "not actively using" if the final clopidogrel prescription was filled ? 8 days before the date of diagnosing acute pancreatitis. Subjects who never used clopidogrel were defined as never used. The multivariable logistic regression model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) of acute pancreatitis associated with clopidogrel use. Comparing the subjects actively using clopidogrel to those who never used clopidogrel, the adjusted OR of acute pancreatitis was 8.46 (95%CI 5.25, 13.7). The adjusted OR decreased to 1.16 among subjects not actively using clopidogrel (95%CI 0.95, 1.43). Persons actively using clopidogrel are at an increased risk of acute pancreatitis. Further studies are necessary to prove the causal relationship. PMID- 25722185 TI - Researcher fails in legal bid to halt expression of concern by journal Diabetes. PMID- 25722186 TI - O-glycan repertoires on a mucin-type reporter protein expressed in CHO cell pools transiently transfected with O-glycan core enzyme cDNAs. AB - Glyco-engineering of host cells is used to increase efficacy, decrease immunogenicity and increase circulatory half-lives of protein biopharmaceuticals. The effect of transiently expressed O-glycan core chain glycosyltransferases on O glycan biosynthesis pathways in CHO cells is reported. Liquid chromatography-mass spectrometry and Western blotting were used to map the O-glycome of a mucin-type fusion protein transiently co-transfected with beta1,3-N acetylglucosaminyltransferase 3 (extended C1 beta3GnT3), core 2 beta1,6-N acetylglucosaminyltransferase I (C2 beta3GnT1) or core 3 beta1,3-N acetylglucosaminyltransferase 6 (C3 beta3GnT6) in CHO cells. Extended core 1 (GlcNAcbeta1,3Galbeta1,3GalNAc) and core 3 (GlcNAcbeta1,3GalNAc), and increased expression of core 2 [Galbeta1,3(GlcNAcbeta1,6)GalNAc], O-glycans were generated on P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL1/mIgG2b). Endogenous poly-N acetyllactosamine (poly-LacNAc) synthase elongated extended core 1 and core 3 generating O-glycans with up to five LacNAc repeats. Low amounts of core 3 O glycans appeared upon extended C1 beta3GnT3 expression. The alpha2,6-sialylated type 2 chain was detected upon co-transfection with the beta-galactoside alpha2,6 sialyltransferase I. N-acetylglucosamine-6-O-sulfotransferase 2 transferred sulfate to carbon 6 of GlcNAc in poly-LacNAc sequences. CHO cells with its known O-glycan repertoire can be used to express recombinant mucin-type proteins together with selected glycosyltransferases in order to recreate carbohydrate determinants on defined O-glycan chains. They will become important tools for assessing the core chain-dependent binding activity of carbohydrate-binding proteins. PMID- 25722187 TI - Enhanced Ga2O3-photocatalyzed and photochemical degradation of the Fipronil insecticide by UVC irradiation in mixed aqueous/organic media under an inert atmosphere. AB - Agrochemicals such as the insecticide Fipronil that bear fluoro groups are generally fat-soluble and nearly insoluble in water, so that their photodegradation in a heterogeneous aqueous gallium oxide dispersion presents some challenges. This article examined the photodegradation of this insecticide by solubilizing it through the addition of organic solvents (EtOH, MeOH, THF, 1,4 dioxane and ethylene glycol) to an aqueous medium and then subjecting the insecticide to 254 nm UVC radiation under photocatalytically inert (Ga2O3/N2) and air-equilibrated (Ga2O3/O2) conditions, as well as photochemically in the absence of Ga2O3 but also under inert and air-equilibrated conditions. Defluorination, dechlorination, desulfonation and denitridation of Fipronil were examined in mixed aqueous/organic media (10, 25 and 50 vol% in organic solvent). After 3 h of UVC irradiation (50 vol% mixed media) defluorination with Ga2O3/N2 was ~65% greater than in aqueous media, and ca. 80% greater than the direct photolysis of Fipronil under inert (N2) conditions; under air-equilibrated conditions both Ga2O3-photocatalyzed and photochemical defluorination were significantly lower than in aqueous media. Dechlorination of Fipronil was ~160% (Ga2O3/N2) and 140% (photochemically, N2) greater than in aqueous media; under air-equilibrated conditions, both photocatalyzed and photochemical formation of Cl(-) ions in mixed media fell rather short relative to aqueous media. The photocatalyzed (Ga2O3/N2) and photochemical (N2) conversion of the sulfur group in Fipronil to SO4(2(-)) ions was ca. 20% and 30% greater, respectively, in mixed media, while under air-equilibrated conditions photocatalyzed desulfonation was nearly twofold less than in the aqueous phase; direct photolysis showed little variations in mixed media. Denitridation of the nitrogens in Fipronil occurred mostly through the formation of ammonia (as NH4(+)) under all conditions with negligible quantities of NO3(-); again mixed media offered enhanced denitridation, particularly under inert N2 conditions. Time-of-flight electrospray (TOF-MS/ESI( )) mass spectrometry revealed a fairly large number of intermediates formed in the degradation of Fipronil, particularly under photocatalytic conditions. Only a couple of intermediates were identified in the photodegradation and the presence of Ga2O3 enhanced the complexity of an already cumbersome problem owing to the involvement of organic solvents. PMID- 25722188 TI - BMP signaling mediated by constitutively active Activin type 1 receptor (ACVR1) results in ectopic bone formation localized to distal extremity joints. AB - BMP signaling mediated by ACVR1 plays a critical role for development of multiple structures including the cardiovascular and skeletal systems. While deficient ACVR1 signaling impairs normal embryonic development, hyperactive ACVR1 function (R206H in humans and Q207D mutation in mice, ca-ACVR1) results in formation of heterotopic ossification (HO). We developed a mouse line, which conditionally expresses ca-ACVR1 with Nfatc1-Cre(+) transgene. Mutant mice developed ectopic cartilage and bone at the distal joints of the extremities including the interphalangeal joints and hind limb ankles as early as P4 in the absence of trauma or exogenous bone morphogenetic protein (BMP) administration. Micro-CT showed that even at later time points (up to P40), cartilage and bone development persisted at the affected joints most prominently in the ankle. Interestingly, this phenotype was not present in areas of bone outside of the joints - tibia are normal in mutants and littermate controls away from the ankle. These findings demonstrate that this model may allow for further studies of heterotopic ossification, which does not require the use of stem cells, direct trauma or activation with exogenous Cre gene administration. PMID- 25722189 TI - IFT46 plays an essential role in cilia development. AB - Cilia are microtubule-based structures that project into the extracellular space. Ciliary defects are associated with several human diseases, including polycystic kidney disease, primary ciliary dyskinesia, left-right axis patterning, hydrocephalus and retinal degeneration. However, the genetic and cellular biological control of ciliogenesis remains poorly understood. The IFT46 is one of the highly conserved intraflagellar transport complex B proteins. In zebrafish, ift46 is expressed in various ciliated tissues such as Kupffer's vesicle, pronephric ducts, ears and spinal cord. We show that ift46 is localized to the basal body. Knockdown of ift46 gene results in multiple phenotypes associated with various ciliopathies including kidney cysts, pericardial edema and ventral axis curvature. In ift46 morphants, cilia in kidney and spinal canal are shortened and abnormal. Similar ciliary defects are observed in otic vesicles, lateral line hair cells, olfactory pits, but not in Kupffer's vesicle. To explore the functions of Ift46 during mouse development, we have generated Ift46 knock out mice. The Ift46 mutants have developmental defects in brain, neural tube and heart. In particular Ift46(-/-) homozygotes displays randomization of the embryo heart looping, which is a hallmark of defective left-right (L/R) axis patterning. Taken together, our results demonstrated that IFT46 has an essential role in vertebrate ciliary development. PMID- 25722191 TI - Erratum to: Does social status within a dominance hierarchy mediate individual growth, residency and relocation? PMID- 25722190 TI - Integration of comprehensive 3D microCT and signaling analysis reveals differential regulatory mechanisms of craniofacial bone development. AB - Growth factor signaling regulates tissue-tissue interactions to control organogenesis and tissue homeostasis. Specifically, transforming growth factor beta (TGFbeta) signaling plays a crucial role in the development of cranial neural crest (CNC) cell-derived bone, and loss of Tgfbr2 in CNC cells results in craniofacial skeletal malformations. Our recent studies indicate that non canonical TGFbeta signaling is activated whereas canonical TGFbeta signaling is compromised in the absence of Tgfbr2 (in Tgfbr2(fl/fl);Wnt1-Cre mice). A haploinsufficiency of Tgfbr1 (aka Alk5) (Tgfbr2(fl/fl);Wnt1-Cre;Alk5(fl/+)) largely rescues craniofacial deformities in Tgfbr2 mutant mice by reducing ectopic non-canonical TGFbeta signaling. However, the relative involvement of canonical and non-canonical TGFbeta signaling in regulating specific craniofacial bone formation remains unclear. We compared the size and volume of CNC-derived craniofacial bones (frontal bone, premaxilla, maxilla, palatine bone, and mandible) from E18.5 control, Tgfbr2(fl/fl);Wnt1-Cre, and Tgfbr2(fl/fl);Wnt1 Cre;Alk5(fl/+)mice. By analyzing three dimensional (3D) micro-computed tomography (microCT) images, we found that different craniofacial bones were restored to different degrees in Tgfbr2(fl/fl);Wnt1-Cre;Alk5(fl/+) mice. Our study provides comprehensive information on anatomical landmarks and the size and volume of each craniofacial bone, as well as insights into the extent that canonical and non canonical TGFbeta signaling cascades contribute to the formation of each CNC derived bone. Our data will serve as an important resource for developmental biologists who are interested in craniofacial morphogenesis. PMID- 25722192 TI - Isocline analysis of competition predicts stable coexistence of two amphibians. AB - We investigated the interaction between larvae of two anuran amphibian species (Rana temporaria and Bufo bufo) to test models of two-species competition. The study had a response surface experimental design with four replicates, each consisting of 24 density combinations. Larval performance-and, by assumption, change in population size-was defined by a linear combination of survival, growth, and development. We fit six competition models from the literature and discovered that density dependence was strongly non-linear, with the highest support for the Hassel-Comins model. Rana temporaria was competitively superior to B. bufo; the impacts of both species on growth and development were about five to tenfold greater than those on survival. Isocline analysis predicted a stable configuration, which agrees with the observation that these two species are syntopic in nature. The results of this study confirm competition theory by identifying a model structure that agrees with data and making predictions that are broadly supportive of the observations. PMID- 25722193 TI - National Heart, Lung, and Blood Institute (NHLBI) strategic visioning: setting an agenda together for the NHLBI of 2025. PMID- 25722194 TI - Differential effects of dietary copper deficiency and excess on lipid metabolism in yellow catfish Pelteobagrus fulvidraco. AB - The present study was conducted to investigate the effects and mechanism of dietary Cu deficiency and excess on lipid metabolism in the liver, muscle and VAT of juvenile Pelteobagrus fulvidraco. To this end, yellow catfish were fed 0.76 (Cu deficiency), 4.18 (adequate Cu) and 92.45 (Cu excess) mg Cu kg(-1) diet, respectively, for 8 weeks. WG and SGR in the adequate Cu group were significantly higher than those in Cu deficiency and excess groups. In liver, Cu deficiency showed no significant effect on Cu and lipid contents, the activities of 6PGD, G6PD and FAS, and the mRNA levels of many tested genes, including 6PGD, G6PD, FAS, ACCalpha, PPARgamma, LXR, HSL, PPARalpha and ATGL. Cu excess induced Cu accumulation, reduced the lipid content, FAS activity as well as the mRNA levels of 6PGD, G6PD, FAS, ACCalpha, PPARgamma, HSL and ATGL. In muscle, dietary Cu levels showed no significant effects on lipid content, the activities of lipogenic enzymes and the mRNA levels of the most tested genes, including of 6PGD, G6PD, FAS, SREBP-1, PPARgamma, HSL and LPL. In VAT, Cu and lipid contents, FAS activity, and the mRNA levels of 6PGD, G6PD, FAS, SREBP-1, LXR, PPARalpha and LPL were not significantly influenced by dietary Cu levels. Thus, the change of lipid contents among tissues could be related to the enzymatic activities and gene expression related to lipid metabolism. Different response patterns of enzymatic activities and gene expression in various tissues following dietary Cu levels indicated the tissue-specific regulatory effect by Cu. PMID- 25722195 TI - The association of antibiotic treatment regimen and hospital mortality in patients hospitalized with Legionella pneumonia. AB - BACKGROUND: Guidelines recommend azithromycin or a quinolone antibiotic for treatment of Legionella pneumonia. No clinical study has compared these strategies. METHODS: We performed a retrospective cohort analysis of adults hospitalized in the United States with a diagnosis of Legionella pneumonia in the Premier Perspectives database (1 July 2008-30 June 2013). Our primary outcome was hospital mortality; we additionally evaluated hospital length of stay, development of Clostridium difficile colitis, and total hospital cost. We used propensity-based matching to compare patients treated with azithromycin vs a quinolone. All analyses were repeated on a subgroup of more severely ill patients, defined as requiring intensive care unit admission or mechanical ventilation or having a predicted probability of hospital mortality in the top quartile for all patients. RESULTS: Legionella pneumonia was diagnosed in 3152 adults across 437 hospitals. Quinolones alone were used in 28.8%, azithromycin alone was used in 34.0%, and 1.8% received both. Crude hospital mortality was similar: 6.6% (95% confidence interval [CI], 5.0%-8.2%) for quinolones vs 6.4% (95% CI, 5.0%-7.9%) for azithromycin (P = .87); after propensity matching (n = 813 in each group), mortality remained similar (6.3% [95% CI, 4.6%-7.9%] vs 6.5% [95% CI, 4.8%-8.2%], P = .84 for the whole cohort, and 14.9% [95% CI, 10.0% 19.8%] vs 18.3% [95% CI, 13.0%-23.6%], P = .36 for the more severely ill). There was no difference in hospital length of stay, development of C. difficile, or total hospital cost. CONCLUSIONS: Use of azithromycin alone or a quinolone alone for treatment of Legionella pneumonia was associated with similar hospital mortality. Few patients receive combination therapy. PMID- 25722196 TI - Tuberculosis prophylaxis with levofloxacin in liver transplant patients is associated with a high incidence of tenosynovitis: safety analysis of a multicenter randomized trial. AB - BACKGROUND: It is necessary to develop a safe alternative to isoniazid for tuberculosis prophylaxis in liver transplant recipients. This study was designed to investigate the efficacy and safety of levofloxacin. METHODS: An open-label, prospective, multicenter, randomized study was conducted to compare the efficacy and safety of levofloxacin (500 mg q24h for 9 months) initiated in patients awaiting liver transplantation and isoniazid (300 mg q24h for 9 months) initiated post-transplant when liver function was stabilized. Efficacy was measured by tuberculosis incidence at 18 months after transplantation. All adverse events related to the medication were recorded. RESULTS: CONSORT guidelines were followed in order to present the results. The safety committee suspended the study through a safety analysis when 64 patients had been included (31 in the isoniazid arm and 33 in the levofloxacin arm). The reason for suspension was an unexpected incidence of severe tenosynovitis in the levofloxacin arm (18.2%). Although the clinical course was favorable in all cases, tenosynovitis persisted for 7 weeks in some patients. No patients treated with isoniazid, developed tenosynovitis. Only 32.2% of patients randomized to isoniazid (10/31) and 54.5% of patients randomized to levofloxacin (18/33, P = .094) completed prophylaxis. No patient developed tuberculosis during the study follow-up (median 270 days). CONCLUSIONS: Levofloxacin prophylaxis of tuberculosis in liver transplant candidates is associated with a high incidence of tenosynovitis that limits its potential utility. PMID- 25722197 TI - Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study. AB - In STRIDE, slow metabolizer CYP2B6 and NAT2 genotypes were each associated with increased plasma efavirenz concentrations during antituberculosis therapy. Concentrations were greater on therapy than off therapy in 58% with CYP2B6 and 93% with NAT2 slow metabolizer genotypes. Individuals with slow metabolizer genotypes in both genes had markedly elevated concentrations. PMID- 25722198 TI - Use of influenza antiviral medications among outpatients at high risk for influenza-associated complications during the 2013-2014 influenza season. AB - During the 2013-2014 influenza season, we analyzed data from 6004 outpatients aged >=6 months with acute respiratory illness (ARI). Among the 2786 ARI patients at higher risk for influenza complications, 835 (30%) presented to care <=2 days from symptom onset; among those, 126 (15%) were prescribed an antiviral medication. PMID- 25722199 TI - A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa. AB - BACKGROUND: HTLV-1 infection is endemic to Central African populations. The risk factors for HTLV-1 acquisition in humans via the interspecies transmission of STLV-1 (its simian counterpart) remain largely unknown. METHODS: We studied 269 individuals (254 men, 15 women) bitten by a nonhuman primate (NHP), mostly during hunting activities. These, Pygmies and Bantus, living in the southern Cameroonian rainforest, were matched for sex, age, and ethnicity with individuals from the same settlements reporting no NHP bites. HTLV-1 serology was performed by Western blot on plasma samples. PCR was carried out for HTLV-1 provirus on buffy-coat DNAs. The amplified products were sequenced and analyzed by phylogenetic analyses. RESULTS: HTLV-1 prevalence was 8.6% (23/269) in individuals with bites, vs 1.5% (4/269) in matched controls (P < .001). Moreover, HTLV-1 infection was linked to bite severity. The 23 HTLV-1-positive bitten individuals reported being bitten by a gorilla (17), chimpanzee (3), or small monkey (3). Thirteen (56%) were coinfected with a simian foamy virus known to be acquired through severe bites. Mother-to-child infection was excluded in 6 HTLV-1-infected bitten individuals. All the HTLV-1-positive hunters bitten by a gorilla or chimpanzee were infected with a subtype B strain similar to that present in apes from the same area. Two hunters bitten by small monkeys (C. agilis in one case) were infected with a HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. CONCLUSIONS: These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities. PMID- 25722200 TI - High resolution computed tomography angiography improves the radiographic diagnosis of invasive mold disease in patients with hematological malignancies. AB - BACKGROUND: Computed tomography pulmonary angiography (CTPA) may improve the diagnostic capabilities of CT imaging for invasive mold disease, but its performance relative to other signs (ie, halo sign, hypodense sign, pleural effusion, reversed halo sign) is unknown. METHODS: We prospectively compared the diagnostic performance of CTPA vs other CT imaging findings in 100 patients with hematological malignancies and possible invasive mold disease defined by EORTC/MSG criteria. After undergoing extensive diagnostic work-up, patients were upgraded to probable or proven mold disease based on galactomannan antigen, culture or histology; or remained as possible mold disease if an alternative diagnosis could not be established. RESULTS: In total, 46 /100 patients who underwent CTPA were upgraded to probable or proven mold disease. Excluding 8 CTPA cases that were nonevaluable by the radiologist, a positive occlusion sign identified by CTPA was 100% sensitive for the diagnosis of probable or proven mold disease (41/41). Among patients who could not be upgraded from the possible mold disease category (n = 51), 25 (49%) had evidence of vessel occlusion by CTPA with only one positive patient eventually reaching an alternative diagnosis (Staphylococcus aureus septic thrombosis). Intravenous and/or oral antifungal therapy was stopped earlier in patients with a negative vs positive CTPA results (P <= .001). CONCLUSIONS: Vessel occlusion detected by CTPA is a more sensitive and possibly more specific radiographic sign vs other common CT findings of invasive mold disease in patients with hematological malignancies. PMID- 25722201 TI - The importance of clinical surveillance in detecting legionnaires' disease outbreaks: a large outbreak in a hospital with a Legionella disinfection system Pennsylvania, 2011-2012. AB - BACKGROUND: Healthcare-associated Legionnaires' disease (LD) is a preventable pneumonia with a 30% case fatality rate. The Centers for Disease Control and Prevention guidelines recommend a high index of suspicion for the diagnosis of healthcare-associated LD. We characterized an outbreak and evaluated contributing factors in a hospital using copper-silver ionization for prevention of Legionella growth in water. METHODS: Through medical records review at a large, urban tertiary care hospital in November 2012, we identified patients diagnosed with LD during 2011-2012. Laboratory-confirmed cases were categorized as definite, probable, and not healthcare associated based on time spent in the hospital during the incubation period. We performed an environmental assessment of the hospital, including collection of samples for Legionella culture. Clinical and environmental isolates were compared by genotyping. Copper and silver ion concentrations were measured in 11 water samples. RESULTS: We identified 5 definite and 17 probable healthcare-associated LD cases; 6 case patients died. Of 25 locations (mostly potable water) where environmental samples were obtained for Legionella-specific culture, all but 2 showed Legionella growth; 11 isolates were identical to 3 clinical isolates by sequence-based typing. Mean copper and silver concentrations were at or above the manufacturer's recommended target for Legionella control. Despite this, all samples where copper and silver concentrations were tested showed Legionella growth. CONCLUSIONS: This outbreak was linked to the hospital's potable water system and highlights the importance of maintaining a high index of suspicion for healthcare-associated LD, even in the setting of a long-term disinfection program. PMID- 25722202 TI - Non-invasive health status detection system using Gabor filters based on facial block texture features. AB - Blood tests allow doctors to check for certain diseases and conditions. However, using a syringe to extract the blood can be deemed invasive, slightly painful, and its analysis time consuming. In this paper, we propose a new non-invasive system to detect the health status (Healthy or Diseased) of an individual based on facial block texture features extracted using the Gabor filter. Our system first uses a non-invasive capture device to collect facial images. Next, four facial blocks are located on these images to represent them. Afterwards, each facial block is convolved with a Gabor filter bank to calculate its texture value. Classification is finally performed using K-Nearest Neighbor and Support Vector Machines via a Library for Support Vector Machines (with four kernel functions). The system was tested on a dataset consisting of 100 Healthy and 100 Diseased (with 13 forms of illnesses) samples. Experimental results show that the proposed system can detect the health status with an accuracy of 93 %, a sensitivity of 94 %, a specificity of 92 %, using a combination of the Gabor filters and facial blocks. PMID- 25722203 TI - Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant. AB - Treatment with an all-oral interferon-free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3-F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV-based regimens) received treatment and were followed for a median of 30 weeks (range 12 53 weeks). The median time from LT to treatment was 32 months (range 2-317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84% 96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3-F4 (71%) compared to those with F0-F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug-induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. CONCLUSION: An all oral interferon-free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. PMID- 25722205 TI - Mediastinal mass: a mystery of two rounded chambers. PMID- 25722204 TI - Simultaneous morphological and biochemical endogenous optical imaging of atherosclerosis. AB - AIMS: The aim of this study was to validate novel imaging technology for simultaneous morphological and biochemical endogenous optical imaging of coronary atherosclerotic plaque. METHODS AND RESULTS: Optical coherence tomography (OCT) generates high-resolution 3D images of plaque morphology and endogenous fluorescence lifetime imaging microscopy (FLIM) characterizes biochemical composition. Both imaging modalities rely on plaque's intrinsic optical characteristics, making contrast agents unnecessary. A multimodal OCT/FLIM system was utilized to generate luminal biochemical maps superimposed on high-resolution (7 um axial and 13 um lateral) structural volumetric images. Forty-seven fresh postmortem human coronary segments were imaged: pathological intimal thickening (PIT, n = 26), fibroatheroma (FA, n = 12), thin-cap FA (TCFA, n = 2), and fibrocalcific plaque (CA, n = 7), determined by histopathology. Multimodal images were evaluated, and each plaque identified as PIT, FA, TCFA, or CA based on expert OCT readers, and as having high-lipid (HL), high-collagen (HC), or low collagen/low-lipid (LCL) luminal composition based on linear discriminant analysis of FLIM. Of 47 plaques, 89.4% (42/47) of the plaques were correctly identified based on OCT/FLIM evaluation using tissue histopathology and immunohistochemistry as the gold standard. Four of the misclassifications corresponded to confusing PIT with HL luminal composition for FA with HL cap. The other corresponded to confusing FA with a HC cap for FA with an LCL cap. CONCLUSION: We have demonstrated the feasibility of accurate simultaneous OCT/FLIM morphological and biochemical characterization of coronary plaques at spatial resolutions and acquisition speeds compatible with catheter-based intravascular imaging. The success of this pilot study sets up future development of a multimodal intravascular imaging system that will enable studies that could help improve our understanding of plaque pathogenesis. PMID- 25722206 TI - Toward a systems-level view of mitotic checkpoints. AB - Reproduction and natural selection are the key elements of life. In order to reproduce, the genetic material must be doubled, separated and placed into two new daughter cells, each containing a complete set of chromosomes and organelles. In mitosis, transition from one process to the next is guided by intricate surveillance mechanisms, known as the mitotic checkpoints. Dis-regulation of cell division through checkpoint malfunction can lead to developmental defects and contribute to the development or progression of tumors. This review approaches two important mitotic checkpoints, the spindle assembly checkpoint (SAC) and the spindle position checkpoint (SPOC). The highly conserved spindle assembly checkpoint (SAC) controls the onset of anaphase by preventing premature segregation of the sister chromatids of the duplicated genome, to the spindle poles. In contrast, the spindle position checkpoint (SPOC), in the budding yeast Saccharomyces cerevisiae, ensures that during asymmetric cell division mitotic exit does not occur until the spindle is properly aligned with the cell polarity axis. Although there are no known homologs, there is indication that functionally similar checkpoints exist also in animal cells. This review can be regarded as an "executable model", which could be easily translated into various quantitative concrete models like Petri nets, ODEs, PDEs, or stochastic particle simulations. It can also function as a base for developing quantitative models explaining the interplay of the various components and proteins controlling mitosis. PMID- 25722207 TI - Human Conjunctival Stem Cells are Predominantly Located in the Medial Canthal and Inferior Forniceal Areas. AB - PURPOSE: The conjunctiva plays a key role in ocular surface defence and maintenance of the tear film. Ex vivo expansion of conjunctival epithelial cells offers potential to reconstruct the ocular surface in cases of severe cicatrising disease, but requires initial biopsies rich in stem cells to ensure long-term success. The distribution of human conjunctival stem cells, however, has not been clearly elucidated. METHODS: Whole human cadaveric conjunctiva was retrieved and divided into specific areas for comparison. From each donor, all areas from one specimen were cultured for colony-forming efficiency assays and immunocytochemical studies; all areas from the other specimen were fixed and paraffin embedded for immunohistochemical studies. Expression of CK19, p63, and stem cell markers ABCG2, DeltaNp63, and Hsp70 were analyzed. Results were correlated to donor age and postmortem retrieval time. RESULTS: Conjunctiva was retrieved from 13 donors (26 specimens). Colony-forming efficiency and expression of stem cell markers ABCG2, DeltaNp63, and Hsp70 in cultures and ABCG2 in fixed tissue were all consistently demonstrated throughout the tissue but with highest levels in the medial canthal and inferior forniceal areas (P < 0.01 for each). Both increasing donor age and longer postmortem retrieval times were associated with significantly lower colony-forming efficiency, stem cell marker expression in cell cultures and ABCG2 expression in fixed tissue. CONCLUSIONS: Biopsies from the medial canthus and inferior forniceal areas, from younger donors, and with short postmortem retrieval times offer the greatest potential to developing conjunctival stem cell-rich epithelial constructs for transplantation. PMID- 25722208 TI - BDNF Rescues RGCs But Not Intrinsically Photosensitive RGCs in Ocular Hypertensive Albino Rat Retinas. AB - PURPOSE: To study the responses of the general population of retinal ganglion cells (Brn3a(+)RGCs) versus the intrinsically photosensitive RGCs (melanopsin expressing RGCs [m(+)RGCs]) to ocular hypertension (OHT), the effects of brain derived neurotrophic factor (BDNF) on the survival of axonally intact and axonally nonintact RGCs, and the correlation of vascular integrity with sectorial RGC loss. METHODS: In Sprague-Dawley rats, 5 MUg BDNF or vehicle was intravitreally injected into the left eye followed by laser photocoagulation of the limbal tissues. To identify RGCs with an active retrograde axonal transport, Fluorogold was applied to both superior colliculi 1 week before euthanasia (FG(+)RGCs). Retinas were dissected 12 or 15 days after lasering and immunoreacted against Brn3a (to identify all RGCs except m(+)RGCs), melanopsin, or RECA1 (inner retinal vasculature). RESULTS: Ocular hypertension resulted at 12 to 15 days in sectorial loss of FG(+)RGCs (78%-84%, respectively) while Brn3a(+)RGCs were significantly greater, indicating that a substantial proportion (approximately 21%-26%) of RGCs with their retrograde axonal transport impaired survive in the retina. Brain-derived neurotrophic factor increased the survival of Brn3a(+)RGCs to 81% to 67% at 12 to 15 days, respectively. The inner retinal vasculature showed no abnormalities that could account for the sectorial loss of RGCs. At 12 to 15 days, m(+)RGCs decreased to approximately 50% to 51%, but this loss was diffuse across the retina and was not prevented by BDNF. CONCLUSIONS: The responses of m(+)RGCs against OHT-induced retinal degeneration and neuroprotection differ from those of Brn3a(+)RGCs; while OHT induces similar loss of Brn3a(+)RGCs and m(+)RGCs, Brn3a(+)RGCs are lost in sectors and can be rescued with BDNF, but m(+)RGCs do not respond to BDNF and their loss is diffuse. PMID- 25722209 TI - TCF4 Triplet Repeat Expansion and Nuclear RNA Foci in Fuchs' Endothelial Corneal Dystrophy. AB - PURPOSE: Expansion of the intronic CTG18.1 triplet repeat locus within TCF4 contributes significant risk to the development of Fuchs' endothelial corneal dystrophy (FECD) in Eurasian populations, but the mechanisms by which the expanded repeats result in degeneration of the endothelium have been hitherto unknown. The purpose of this study was to examine FECD endothelial samples for the presence of RNA nuclear foci, the hallmark of toxic RNA, as well as evidence of haploinsufficiency of TCF4. METHODS: Using fluorescence in situ hybridization, we examined for the presence of nuclear RNA foci containing expanded CUG transcripts in corneal endothelial samples from FECD subjects with CTG18.1 expansion. We also examined for any changes in expression levels of TCF4 by quantitative real-time PCR. RESULTS: Numerous discrete nuclear RNA foci were identified in endothelial samples of FECD subjects (n = 8) harboring the CTG18.1 expansion, but not in controls lacking the expansion (n = 5) (P = 7.8 * 10(-4)). Percentage of cells with foci in expansion-positive endothelial samples ranged from 33% to 88%. RNA foci were absent in endothelial samples from an FECD subject without CTG18.1 expansion and a subject with endothelial dysfunction without FECD. Expression of the constitutive TCF4 exon encoding the basic helix-loop helix domain was unaltered with CTG18.1 expansion. CONCLUSIONS: Our findings suggest that the RNA nuclear foci are pathognomonic for CTG18.1 expansion mediated endothelial disease. The RNA nuclear foci have been previously found only in rare neurodegenerative disorders caused by repeat expansions. Our detection of abundant ribonuclear foci in FECD implicates a role for toxic RNA in this common disease. PMID- 25722211 TI - A Murine Model for Metastatic Conjunctival Melanoma. AB - PURPOSE: Conjunctival melanoma (CM) is an ocular malignancy with a high rate of local recurrences after treatment, and can give rise to deadly metastases. The establishment of a murine model will further our understanding of this disease and allow in vivo testing of new therapies. We therefore analyzed the ability of three CM cell lines to grow orthotopically and spread to distant sites. Furthermore, we determined the characteristics of the xenografts and their metastases. METHODS: Orthotopic xenografts of human CM were established by subconjunctival injection of three different CM cell lines into NOD/SCID IL2 rgammanull mice. Single-cell suspensions were generated from the primary tumors and placed subconjunctivally in another set of mice, which were then screened for metastases. The presence of melanoma markers was determined on the cell lines and during tumor development. RESULTS: Subconjunctival injection of cultured CM cells into immunodeficient mice led to excellent subconjunctival tumor growth in all inoculated mice (n = 101) within 2 weeks; however, no metastases were found at the time of autopsy. Serial in vivo passage of primary tumor cells resulted in metastatic tumors in the draining lymph nodes (n = 21). The CM cell lines, as well as the tumor xenografts and their metastases, were positive for the melanoma markers HMB-45, S100B, and MART-1. Two cell lines and their corresponding xenografts carried a BRAF mutation, the third showed an NRAS mutation. CONCLUSIONS: We established a murine model for CM that shows excellent formation of metastases in a pattern that accurately resembles metastatic human CM following in vivo passaging. PMID- 25722210 TI - Progressive degeneration of retinal and superior collicular functions in mice with sustained ocular hypertension. AB - PURPOSE: We investigated the progressive degeneration of retinal and superior collicular functions in a mouse model of sustained ocular hypertension. METHODS: Focal laser illumination and injection of polystyrene microbeads were used to induce chronic ocular hypertension. Retinal ganglion cell (RGC) loss was characterized by in vivo optical coherence tomography (OCT) and immunohistochemistry. Retinal dysfunction was also monitored by the full-field ERG. Retinal ganglion cell light responses were recorded using a 256-channel multielectrode array (MEA), and RGC subtypes were characterized by noncentered spike-triggered covariance (STC-NC) analysis. Single-unit extracellular recordings from superficial layers of the superior colliculus (SC) were performed to examine the receptive field (RF) properties of SC neurons. RESULTS: The elevation of intraocular pressure (IOP) lasted 4 months in mice treated with a combination of laser photocoagulation and microbead injection. Progressive RGC loss and functional degeneration were confirmed in ocular hypertensive (OHT) mice. These mice had fewer visually responsive RGCs than controls. Using the STC NC analysis, we classified RGCs into ON, OFF, and ON-OFF functional subtypes. We showed that ON and OFF RGCs were more susceptible to the IOP elevation than ON OFF RGCs. Furthermore, SC neurons of OHT mice had weakened responses to visual stimulation and exhibited mismatched ON and OFF subfields and irregular RF structure. CONCLUSIONS: We demonstrated that the functional degeneration of RGCs is subtype-dependent and that the ON and OFF pathways from the retina to the SC were disrupted. Our study provides a foundation to investigate the mechanisms underlying the progressive vision loss in experimental glaucoma. PMID- 25722212 TI - Lamina cribrosa depth in different stages of glaucoma. AB - PURPOSE: To compare lamina cribrosa (LC) depth between normal eyes and eyes with different stages of treated glaucoma. METHODS: Serial enhanced depth imaging (EDI) optical coherence tomography (OCT) B-scans of the optic nerve head were obtained. To generate the mean LC depth for each eye, LC depths were measured in 11 equally spaced horizontal B-scans and averaged. The mean LC depth was compared among normal, preperimetric, mild-to-moderate, and severe glaucoma groups. Among patients with visual field (VF) loss, correlation analysis was performed (1) between mean LC depth and VF mean deviation (MD), and (2) between mean LC depth and retinal nerve fiber layer (RNFL) thickness. RESULTS: Eighty-six normal eyes (age, 56 +/- 14 years), 47 preperimetric glaucoma eyes (age, 60 +/- 16 years), 55 mild-to-moderate glaucoma eyes (age, 59 +/- 16 years; VF MD, -6.0 +/- 3.2 dB), and 60 severe glaucoma eyes (age, 59 +/- 17 years; VF MD, -19.7 +/- 6.1 dB) were included. Mean LC depth was significantly greater in preperimetric glaucoma than in normal eyes (390 vs. 344 MUm, P = 0.004) and in mild-to-moderate than in preperimetric glaucoma eyes (448 vs. 390 MUm, P = 0.001). However, no significant difference was observed between mild-to-moderate and severe glaucoma eyes (448 vs. 437 MUm, P = 0.52). No correlation was observed between LC depth and VF MD (P = 0.56) or RNFL thickness (P = 0.90) in glaucomatous eyes with VF loss. CONCLUSIONS: In treated glaucoma, posterior LC displacement occurs mostly in the preperimetric and mild-to-moderate glaucoma stages. This warrants further investigation of LC depth as a parameter to monitor glaucoma progression in the early stages. PMID- 25722213 TI - The Relationship Between Aldose Reductase C106T Polymorphism and Diabetic Retinopathy: An Updated Meta-Analysis. AB - PURPOSE: Studies investigating the associations between aldose reductase (ALR) genetic polymorphisms and diabetic retinopathy (DR) have reported controversial results. Therefore, to shed light on these inconclusive findings, we performed this meta-analysis to clarify the effects of ALR C(-106)T polymorphism on DR risk. METHODS: Relevant studies were selected through an extensive search of PubMed, EMBASE, the Web of Science databases and Chinese National Knowledge Infrastructure, VIP, and Wan Fang databases in Chinese. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated by using random-effects model. RESULTS: The present meta-analysis included 3512 diabetes mellitus (DM) patients with DR and 4319 DM patients without DR. Overall, the pooled ORs showed a nonsignificant association between ALR C(-106)T polymorphism and DR susceptibility in all genetic models (C allele versus T allele: OR = 1.08, 95% CI = 0.90-1.29; CT/TT versus CC: OR = 0.90, 95% CI = 0.72-1.13; TT versus CT/CC: OR = 0.87, 95% CI = 0.69-1.10; TT versus CC: OR = 0.87, 95% CI = 0.64-1.18; CT versus CC: OR = 0.93, 95% CI = 0.73-1.19). No significant association was detected between ALR C(-106)T polymorphism and nonproliferative diabetic retinopathy or proliferative diabetic retinopathy. An additional analysis showed that the association of C(-106)T polymorphism with DR was significant in type 1 DM (C allele versus T allele: OR = 1.78, 95% CI = 1.39-2.28; CT/TT versus CC: OR = 0.49, 95% CI = 0.36-0.68; TT versus CT/CC: OR = 0.48, 95% CI = 0.28-0.84; TT versus CC: OR = 0.33, 95% CI = 0.17-0.67; CT versus CC: OR = 0.52, 95% CI = 0.37 0.74) but not in type 2 DM. CONCLUSIONS: The results of this meta-analysis showed that ALR C(-106)T polymorphism was not associated with an increased risk of DR. However, subgroup analysis showed a genetic association between ALR C(-106)T polymorphism and the risk of DR of type 1 DM but not DR of type 2 DM. PMID- 25722214 TI - Differential Expression of IL-6/gp130 Cytokines, Jak-STAT Signaling and Neuroprotection After Muller Cell Ablation in a Transgenic Mouse Model. AB - PURPOSE: It is anticipated that the interleukin-6/glycoprotein 130 (IL-6/gp130) family of cytokines and Jak-STAT signaling may be amenable to therapeutic manipulation for retinal diseases. Muller cells, which exhibit morphologic and functional changes in prevalent retinal diseases, are implicated in their induction and action. METHODS: We characterized expression of endogenous IL 6/gp130 cytokines and Jak-STAT signaling after inducible Muller cell ablation in the neural retinas of adult mice. This resulted in photoreceptor apoptosis and reactive activation of surviving Muller cells. Analysis was performed by using a combination of quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. Recombinant leukemia inhibitory factor (rLIF) was intravitreally injected in an attempt to inhibit photoreceptor degeneration following selective Muller cell ablation. RESULTS: Significant differential expression (both increases and decreases) of multiple IL-6/gp130 cytokines, such as LIF, oncostatin-M, and ciliary neurotrophic factor, occurred after Muller cell ablation, with concomitant increase in signal transducers and activators of transcription and extracellular kinases 1 and 2, particularly in surviving, activated Muller cells. Basic fibroblast growth factor was robustly increased in photoreceptors after selective Muller cell ablation. Multiple injections of rLIF failed to prevent photoreceptor degeneration. CONCLUSIONS: These results further characterize expression of IL-6/gp130 cytokines and Jak-STAT signaling in outer retinal disease, suggesting Muller cells are critical for their induction and action. Lack of rLIF-mediated neuroprotection contrasts with other retinal degenerations where Muller cell integrity remains intact or photoreceptor apoptosis occurs in a more rapid, synchronous manner. The presence of Muller cells may be critical for the functional benefits of rLIF and potentially other IL-6/gp130 cytokines. PMID- 25722215 TI - Large gene deletion and changes in corneal endothelial cells in a family with choroideremia. AB - PURPOSE: We provided the first report of an association between changes in corneal endothelial cells, retina, and choriocapillaris in a choroideremia family. METHODS: Four members of an Asian choroideremia family, comprising two affected patients and two carriers, were evaluated. All participants underwent complete eye examinations, including visual acuity (VA), slit-lamp examination, ophthalmoscopy, perimetry, and electrophysiology tests. In addition, images of corneal endothelium were captured with a noncontact specular microscope. Genomic DNA amplification and whole-genome cytogenic array analysis were used to confirm the diagnosis of choroideremia and determine the molecular basis of the phenotype. RESULTS: In the affected patients, funduscopy revealed characteristic features of RPE and chorioretinal atrophy. The slit-lamp biomicroscopy disclosed unexpected pigmented punctate lesions in the corneal endothelium in one of them. Surprisingly, specular microscopy detected decreased endothelial cell density (ECD) with features of pleomorphism and polymegethism. Genomic DNA analysis revealed large deletion (~4.5 mega base pairs) of the entire CHM gene and encompassed region. In carriers, funduscopy revealed stippling pigmentary change despite normal electrophysiological results. Specular microscopy also disclosed reduced ECD with features of pleomorphism and polymegethism. CONCLUSIONS: To our knowledge, this is the first description of corneal changes in choroideremia patients. The loss of corneal ECD is conspicuous and is accompanied by pleomorphism and polymegethism in this family. The observed changes in corneal endothelium may be associated with larger encompassed regions of the CHM gene defect or dysfunction in the blood-aqueous barrier. It warrants further investigation and clarification of the pathophysiology and associations between retinal and corneal changes in choroideremia. PMID- 25722216 TI - Choroidal vascular hyperpermeability and punctate hyperfluorescent spot in choroidal neovascularization. AB - PURPOSE: To evaluate the prevalence of choroidal vascular hyperpermeability and punctate hyperfluorescent spots in eyes with choroidal neovascularization (CNV). METHODS: This retrospective, observational study included 382 eyes with typical exudative AMD (97 eyes), polypoidal choroidal vasculopathy (PCV, 163 eyes), retinal angiomatous proliferation (RAP, 37 eyes), or myopic CNV (86 eyes). The prevalence of choroidal vascular hyperpermeability and punctate hyperfluorescent spots was estimated based on available indocyanine green angiography (ICGA) images. RESULTS: Choroidal vascular hyperpermeability was noted in 12.4% (12 eyes) and 26.9% (42 eyes) of eyes with typical exudative AMD and PCV, respectively. Choroidal vascular hyperpermeability was not noted in any eye with RAP or myopic CNV. Punctate hyperfluorescent spots were noted in 43.3% (42 eyes), 72.4% (118 eyes), 10.8% (4 eyes), and 4.7% (4 eyes) of eyes with typical exudative AMD, PCV, RAP, and myopic CNV, respectively. Of the 56 eyes with choroidal vascular hyperpermeability, punctate hyperfluorescent spots were noted in 55 eyes (98.2%). CONCLUSIONS: Choroidal vascular hyperpermeability and punctate hyperfluorescent spots may have a common pathophysiology. Although choroidal vascular hyperpermeability and punctate hyperfluorescent spots have been thought to be associated with pathologic conditions, the markedly low prevalence of these findings in eyes with RAP and myopic CNV may not be a normal finding. It is possible that compromised choroidal perfusion, with or without associated with choroidal thinning, may lead the low prevalence of these abnormalities in eyes with these two disorders. PMID- 25722217 TI - Evaluation of transforming growth factor-beta1 suppress Pokemon/epithelial mesenchymal transition expression in human bladder cancer cells. AB - Transforming growth factor-beta1 (TGF-beta1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-beta1 in bladder cancer cells and the relationship with POK erythroid myeloid ontogenic factor (Pokemon). TGF-beta1 and its receptors mediate several tumorigenic cascades that regulate cell proliferation, migration, and survival of bladder cancer cells. Bladder cancer cells T24 were treated with different levels of TGF-beta1. Levels of Pokemon, E-cadherin, Snail, MMP2, MMP9, Twist, VEGF, and beta-catenin messenger RNA (mRNA) and protein were examined by real-time quantitative fluorescent PCR and Western blot analysis, respectively. The effects of TGF-beta1 on epithelial mesenchymal transition of T24 cells were evaluated with wound-healing assay, proliferation of T24 was evaluated with reference to growth curves with MTT assay, and cell invasive ability was investigated by Transwell assay. Data show that Pokemon was inhibited by TGF-beta1 treatment; the gene and protein of E cadherin and beta-catenin expression level showed decreased markedly after TGF beta1 treatment (P < 0.05). While the bladder cancer cell after TGF-beta1 treatment showed a significantly reduced wound-closing efficiency at 6, 12, and 24 h, mechanistic analyses demonstrated that different levels of TGF-beta1 promotes tumor cell growth, migration, and invasion in bladder cancer cells (P < 0.01, P < 0.05, respectively). In summary, our findings suggest that TGF-beta1 may inhibit the expression of Pokemon, beta-catenin, and E-cadherin. The high expression of TGF-beta1 leads to an increase in the phenotype and apical-base polarity of epithelial cells. These changes of cells may result in the recurrence and progression of bladder cancer at last. Related mechanism is worthy of further investigation. PMID- 25722219 TI - Laguna Negra Virus Infection Causes Hantavirus Pulmonary Syndrome in Turkish Hamsters (Mesocricetus brandti). AB - Laguna Negra virus (LNV) is a New World hantavirus associated with severe and often fatal cardiopulmonary disease in humans, known as hantavirus pulmonary syndrome (HPS). Five hamster species were evaluated for clinical and serologic responses following inoculation with 4 hantaviruses. Of the 5 hamster species, only Turkish hamsters infected with LNV demonstrated signs consistent with HPS and a fatality rate of 43%. Clinical manifestations in infected animals that succumbed to disease included severe and rapid onset of dyspnea, weight loss, leukopenia, and reduced thrombocyte numbers as compared to uninfected controls. Histopathologic examination revealed lung lesions that resemble the hallmarks of HPS in humans, including interstitial pneumonia and pulmonary edema, as well as generalized infection of endothelial cells and macrophages in major organ tissues. Histologic lesions corresponded to the presence of viral antigen in affected tissues. To date, there have been no small animal models available to study LNV infection and pathogenesis. The Turkish hamster model of LNV infection may be important in the study of LNV-induced HPS pathogenesis and development of disease treatment and prevention strategies. PMID- 25722218 TI - Higher circulating levels of chemokine CCL22 in patients with breast cancer: evaluation of the influences of tumor stage and chemokine gene polymorphism. AB - The receptor for CCL22 is named CCR4 that preferentially is expressed on the regulatory T cells (Treg), and accordingly, CCL22 acts as a chemoattractant for the intratumoral Treg migration. The aim of this study was to evaluate the serum CCL22 levels and a single nucleotide polymorphism (SNP) in chemokine gene, [2030 G/C (rs223818)], in patients with breast cancer. Blood samples were collected from 100 women with breast cancer before receiving chemotherapy, radiotherapy, or immunotherapy and 100 age-matched healthy women as a control group. The serum CCL22 levels were measured by ELISA. The DNA extracted and the SNP rs223818 determined by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. The mean serum CCL22 levels in patients with breast cancer (2398.5 +/- 123 Pg/mL) was significantly higher in comparison to healthy control group (974.2 +/- 39.9 Pg/mL; P < 0.001). According to the tumor stages, the mean serum levels of CCL22 were 999.8 +/- 85.0 Pg/mL in stage I, 1718.8 +/- 82.3 Pg/mL in stage II, 2846.8 +/- 118.0 Pg/mL in stage III, and 3954.5 +/- 245.2 Pg/mL in stage IV. There was significant difference between tumor stages regarding the serum CCL22 levels (P < 0.001). In patients with breast cancer, the frequencies of CC genotype (63%) and C allele (79%) at rs223818 were significantly higher as compared to healthy controls (31 and 52%, respectively; P < 0.001). In both patients and control groups, the mean serum levels of CCL22 in subjects with CC genotype or C allele at rs223818 were also significantly higher as compared to subjects with GG genotype or G allele (P < 0.001). Higher serum CCL22 levels were observed in patients with breast cancer that is increased with advanced stages. These findings represent that the CCL22 may contribute in tumor development. The CC genotype and C allele at rs223818 were more frequent in breast cancer patients. The serum CCL22 levels were affected by genetic variations at SNP rs223818. Accordingly, SNP rs223818 may play a role in the susceptibility to breast cancer. PMID- 25722220 TI - Antimetastatic effects of Celastrus orbiculatus on human gastric adenocarcinoma by inhibiting epithelial-mesenchymal transition and NF-kappaB/snail signaling pathway. AB - AIM OF THE STUDY: Celastrus orbiculatus has been used as a folk medicine in China for the treatment of many diseases. In the laboratory, the ethyl acetate extract of Celastrus orbiculatus (COE) displays a wide range of anticancer functions. However, the inhibition of the metastasis mechanism of COE in gastric cancer cells has not been investigated so far. The present study was undertaken to determine if the antimetastatic effects of COE were involved in inhibition of the epithelial-mesenchymal transition (EMT) of human gastric adenocarcinoma SGC-7901 cells. METHODS: The adhesion, invasion, and migration of SGC-7901 cells were determined by COE treatment in vitro, using Matrigel-coated plate, transwell membrane chamber, and wound healing models, respectively. In vivo, the growth inhibiting and antimetastatic effects of COE on the nude mice model of gastric cancer were tested and the mechanisms were explored. The expression of EMT markers and nuclear factor kappaB (NF-kappaB)/Snail signaling pathway were evaluated by using western blotting and immunohistochemistry. RESULTS: Treatment with COE dose-dependently inhibited the proliferation, adhesion, invasion, and migration of SGC-7901 cells in vitro, which was realized by enhancing the expression of E-cadherin and reducing N-cadherin and vimentin expression. Moreover, COE suppressed the activation of NF-kappaB/Snail signaling pathway induced by tumor necrosis factor-alpha. In addition, COE effectively suppressed tumor growth and metastasis in the nude mice model due to reduced expression of N cadherin, vimentin, NF-kappaB p65, and Snail and increased expression of E cadherin in the tumor tissues. CONCLUSION: Our findings provided new evidence that COE is an effective inhibitor of metastatic potential of SGC-7901 cells through suppression of EMT and NF-kappaB/Snail signal pathway. Based on these findings, COE may be considered a novel anticancer agent for the treatment of metastasis in gastric cancer. PMID- 25722221 TI - Inadequacy of initiating rosuvastatin then metformin on biochemical profile of polycystic ovarian syndrome patients. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) afflicts at least 5% of women. Both metformin and statin have been used as methods to ameliorate symptoms and improve prognosis. AIM: To test the efficacy of concomitant usage of metformin and statins in PCOS patients. MATERIALS AND METHODS: This is a prospective, randomized, double-blinded, placebo controlled study. 37 patients received rosuvastatin (10 mg/day) for a period of 3 months, then the patients were randomly allocated to one of two groups: the first group (or intervention group) received rosuvastatin (10 mg/day) plus metformin (850 mg twice daily after meals), and the second group (referred to as control group hereafter) received rosuvastatin (10 mg/day) plus placebo for a period of 3 months. Biochemical and clinical data were collected at each time point. RESULTS: There were no significant differences between the intervention and control groups for baseline lipid profile (LDL, HDL, triglycerides, total cholesterol), CRP, homocysteine, DHEAS, testosterone and insulin (p > 0.05 for all variables). There were no significant differences in lipid profile, CRP, homocysteine, DHEAS, testosterone and insulin between the intervention and placebo groups at 3 and 6 months after treatment (p > 0.05 for all). Significant differences in the outcome variables of LDL, total cholesterol and FBS emerged within the intervention group, with significantly higher levels at 6 months compared to 3 months. We also did not find any significant group differences in unit change of the outcome variables between baseline and 3 months. CONCLUSIONS: We found that the combination of statin and metformin has no advantage in PCOS management. In fact, the increase of LDL, total cholesterol and FBS within the intervention group warrants reassessment of current regimens to avoid any patient harm. PMID- 25722222 TI - Hypoglycemia affects the changes in endothelial progenitor cell levels during insulin therapy in type 2 diabetic patients. AB - PURPOSE: Hypoglycemia is a barrier to the achievement of glycemic targets and limits the beneficial effects of improved glucose control on cardiovascular outcomes in type 2 diabetes (T2D). Circulating endothelial progenitor cells (EPCs) participate in cardiovascular homeostasis and predict future cardiovascular events. Therefore, we herein analyzed the association between occurrence of hypoglycemia and EPC changes in T2D patients after optimization of glucose control with basal insulin therapy. METHODS: In the NCT00699686 trial, 42 T2D insulin-naive patients received a 3 + 3-month cross-over therapy with glargine and detemir. There were 43 minor and 2 severe hypoglycemic episodes in 19 patients (45.2 %, 0.54 episodes/patient/year). Changes in EPCs were analyzed in relation to the occurrence of hypoglycemia during the trial. RESULTS: Patients with hypoglycemia had a higher final HbA1c at 6 months than patients without, although absolute HbA1c changes were not significantly different. Though PCs increased at study end, in patients experiencing at least 1 hypoglycemic episode, the changes in CD34(+), CD133(+) progenitor cells and CD34(+)KDR(+) EPCs were significantly lower than the respective changes in patients without incident hypoglycemia, even after correcting for confounders. During treatment with detemir, which induced >twofold less hypoglycemia than glargine, CD34(+)KDR(+) EPCs increased significantly more than during treatment with glargine. CONCLUSIONS: In naive T2D patients initiating basal insulin, hypoglycemia prevents the increase in vasculoprotective PCs. Clinically, these data strengthen the importance of avoiding hypoglycemia to improve cardiovascular outcomes during the treatment of T2D. PMID- 25722223 TI - Relationships between thyroid function and autoimmunity with metabolic derangement at the onset of type 1 diabetes: a cross-sectional and longitudinal study. AB - BACKGROUND: Type 1 diabetes (T1DM) is an autoimmune disease often associated with thyroid abnormalities. PURPOSE: We investigated the correlation between thyroid function and metabolic derangement at onset and the influence of autoimmunity on thyroid function at onset and subsequently. METHODS: We evaluated 152 patients diagnosed with T1DM between 2000 and 2012 at onset and during a mean follow-up of 5.45 +/- 2.8 years. Thyroid function at onset was correlated with metabolic derangement (degree of acidosis, metabolic control and adrenal function) and compared with that of 78 healthy children. Follow-up consisted of regular evaluation of thyroid function and autoimmunity. RESULTS: Thyroid hormonal pattern was not influenced at onset by thyroid autoimmunity, but only by metabolic derangement: pH and base excess in fact were significantly lower in patients with impaired thyroid function (p < 0.0001). Patients presenting normal thyroid function at onset showed a reduced conversion from FT4 to FT3 compared to nondiabetic children (FT3/FT4 0.3 +/- 0.4 in the control group, 0.24 +/- 0.4 in diabetic patients, p < 0.0001). Multiple regression analysis showed the highest correlation (negative) between FT3 levels at onset and base excess (p < 0.005). Thyroid abnormalities related to metabolic derangement disappeared during follow up. Patients with thyroid antibodies at T1DM onset were at higher risk to require levothyroxine treatment during follow-up (p < 0.05). CONCLUSIONS: Thyroid function at T1DM onset is mainly influenced by metabolic derangement, irrespective of thyroid autoimmunity. Antithyroid antibodies evaluation at T1DM onset may be helpful to define which patients are at higher risk of developing hypothyroidism. PMID- 25722224 TI - Surgical menopause versus natural menopause and cardio-metabolic disturbances: A 12-year population-based cohort study. AB - PURPOSE: Menopausal status exposes women to increased risk of cardiovascular disease. This study was performed to compare the effect of menopausal types, including surgical and natural, on metabolic syndrome and other metabolic disorders 3 years before and after menopause. METHODS: Of 437 postmenopausal women, who participated in the Tehran Lipid and Glucose Study, 13 women with surgical menopause and 39 age-matched controls with natural menopause were selected. During the follow-up period, changes in metabolic and biochemical profiles were compared between surgical and natural menopause women. RESULTS: Odds of incidence of metabolic syndrome in surgical menopause women, compared to natural menopause women, was 9.7 (95 % CI 1.8-51.8). CONCLUSIONS: Metabolic disturbances after menopause are highly influenced by type of menopause and are more prevalent in those undergoing surgical menopause. PMID- 25722225 TI - IL-4 and IL-6 levels and adipose tissue distribution in HIV-1 patients under antiretroviral therapy. AB - PURPOSE: Combined antiretroviral therapy (cART) for the treatment of HIV-1 infection has been associated with complications, including lipodystrophy. Several interleukins have been implicated in the pathology and physiology of lipodystrophy. The present study aimed to compare the levels of IL-4 and IL-6 in HIV-1 patients under cART with and without, clinically and fat mass ratio defined, lipodystrophy and in four different groups of fat distribution: (1) no lipodystrophy; (2) isolated central fat accumulation; (3) isolated lipoatrophy and (4) mixed forms of lipodystrophy. METHODS: In the present cross-sectional study we evaluated IL-4 and IL-6 levels, insulin resistance and insulin sensitivity indexes in 86 HIV-infected adults under cART. RESULTS: No significant differences in IL-4 and IL-6 levels between the four groups of body composition were observed. Patients with HOMA-IR >4 presented higher levels of IL-6 and lower levels of IL-4, although without statistical significance. No correlation between IL-6, or IL-4, HOMA-IR and quantitative body fat mass distribution was found. CONCLUSION: Although there was a tendency for patients with isolated lipoatrophy and isolated fat accumulation to present higher IL-6 levels, these differences were not statistically significant. No differences were found relating IL-4 levels. PMID- 25722226 TI - Effects of treatment modalities for Graves' hyperthyroidism on Graves' orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. PMID- 25722227 TI - Preclinical target validation using patient-derived cells. AB - The Structural Genomics Consortium (SGC) and its clinical, industry and disease foundation partners are launching open-source preclinical translational medicine studies. PMID- 25722228 TI - Fragile X disappointments upset autism ambitions. PMID- 25722232 TI - Regulatory watch: Efficiency indicators for new drugs approved by the FDA from 2003 to 2013. PMID- 25722233 TI - Patent watch: US Supreme Court revises patent claim construction standards. PMID- 25722234 TI - What does it take to produce a breakthrough drug? PMID- 25722235 TI - Fibrotic disease: Fixing a feedback loop in fibrosis. PMID- 25722236 TI - Anticancer agents: An alternative route to targeting telomere elongation. PMID- 25722237 TI - Cardiovascular disease: MYDGF promotes heart repair after myocardial infarction. PMID- 25722238 TI - Cancer stem cells: Targeting the root of cancer relapse. PMID- 25722242 TI - Stroke: Meddling with the mind. PMID- 25722245 TI - Modulation in the mirror neuron system when action prediction is not satisfied. AB - The ability to understand competitive games is closely connected to the mirror neuron system (MNS). This network is activated not only when an action is performed, but also when it is observed. Apart from allowing the understanding of actions performed by others, the MNS has been implicated in predicting subsequent actions. However, the results concerning the modulation of this network by the final outcome of these predictions are contradictory. These contradictions may be related to the use of complex experimental conditions. The aim of this research is to identify changes in the activity of the MNS when the predictions are or are not satisfied in a simple intransitive action-based game. An event-related functional magnetic resonance imaging study was conducted. It consisted of the observation of videos with two actors playing the well-known rock-paper-scissors game. The participants were asked to predict the response of the second actor when the first actor performed one of the three possible actions. In some videos (congruents) the prediction was satisfied, but in the rest of the videos (incongruents) the prediction was not satisfied. When the result was shown, higher activity in the MNS was observed in the congruent videos than in the incongruent ones. Therefore, the observation of a simple manual game leads to a significant activation of the MNS, and this activity seems to be modulated by the final outcome of a prediction, and when predictions are satisfied the activity is higher. PMID- 25722246 TI - MPs call for regular scrutiny of Better Care Fund after numerous concerns. PMID- 25722244 TI - Advances in the development of influenza virus vaccines. AB - Influenza virus infections are a major public health concern and cause significant morbidity and mortality worldwide. Current influenza virus vaccines are an effective countermeasure against infection but need to be reformulated almost every year owing to antigenic drift. Furthermore, these vaccines do not protect against novel pandemic strains, and the timely production of pandemic vaccines remains problematic because of the limitations of current technology. Several improvements have been made recently to enhance immune protection induced by seasonal and pandemic vaccines, and to speed up production in case of a pandemic. Importantly, vaccine constructs that induce broad or even universal influenza virus protection are currently in preclinical and clinical development. PMID- 25722248 TI - Increased aortic blood pressure augmentation in patients with congenital heart defects - A cross-sectional study in 1125 patients and 322 controls. AB - OBJECTIVE: Multiple studies have demonstrated the predictive value of arterial stiffness parameters like augmentation index (AIx) for cardiovascular events, the onset of hypertension, and the progression of heart failure. There is evidence that arterial stiffness is increased in some diagnostic subgroups of patients with congenital heart defects (CHD). This study aims to investigate AIx in a large cross-sectional cohort of patients with CHD. PATIENTS AND METHODS: We prospectively examined 1125 consecutive patients with various congenital heart defects (27.3 +/- 12.1 years, 464 female) referred for routine cardiopulmonary exercise testing (CPET) in our institution, and 322 healthy volunteers (29.4 +/- 18.4 years, 165 female). AIx was estimated in supine position using the oscillometric Vicorder device (SMT medical, Wurzburg, Germany). Afterward patients performed a CPET. RESULTS: In multivariable regression, presence of a CHD emerged as independent risk factor for higher AIx (p<.001). AIx was also higher in older (p<.001), smaller (p<.001) and heavier (p<.001) patients and in females (p=.008). Patients with aortic stenosis (p<.001), Tetralogy of Fallot (p<.001), transposition of the great arteries after atrial switch (p<.001) or Rastelli procedure (p=.013) and after Fontan procedure (p=.002) had higher AIx. Higher peak oxygen uptake (p<.001) and an ACE-inhibitor (p=.088) were associated with a lower AIx. CONCLUSIONS: AIx is increased in patients with CHD. Several diagnostic subgroups are at risk. A better understanding of pathophysiologic mechanisms, genetic predisposition, the role of surgical aortic scars or implanted conduits/patches and medication is needed to define the value of AIx for further cardiovascular risk assessment in this cohort. PMID- 25722247 TI - Insights from 20 years of bacterial genome sequencing. AB - Since the first two complete bacterial genome sequences were published in 1995, the science of bacteria has dramatically changed. Using third-generation DNA sequencing, it is possible to completely sequence a bacterial genome in a few hours and identify some types of methylation sites along the genome as well. Sequencing of bacterial genome sequences is now a standard procedure, and the information from tens of thousands of bacterial genomes has had a major impact on our views of the bacterial world. In this review, we explore a series of questions to highlight some insights that comparative genomics has produced. To date, there are genome sequences available from 50 different bacterial phyla and 11 different archaeal phyla. However, the distribution is quite skewed towards a few phyla that contain model organisms. But the breadth is continuing to improve, with projects dedicated to filling in less characterized taxonomic groups. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system provides bacteria with immunity against viruses, which outnumber bacteria by tenfold. How fast can we go? Second-generation sequencing has produced a large number of draft genomes (close to 90 % of bacterial genomes in GenBank are currently not complete); third-generation sequencing can potentially produce a finished genome in a few hours, and at the same time provide methlylation sites along the entire chromosome. The diversity of bacterial communities is extensive as is evident from the genome sequences available from 50 different bacterial phyla and 11 different archaeal phyla. Genome sequencing can help in classifying an organism, and in the case where multiple genomes of the same species are available, it is possible to calculate the pan- and core genomes; comparison of more than 2000 Escherichia coli genomes finds an E. coli core genome of about 3100 gene families and a total of about 89,000 different gene families. Why do we care about bacterial genome sequencing? There are many practical applications, such as genome-scale metabolic modeling, biosurveillance, bioforensics, and infectious disease epidemiology. In the near future, high-throughput sequencing of patient metagenomic samples could revolutionize medicine in terms of speed and accuracy of finding pathogens and knowing how to treat them. PMID- 25722249 TI - Structurally governed cell mechanotransduction through multiscale modeling. AB - Mechanotransduction has been divided into mechanotransmission, mechanosensing, and mechanoresponse, although how a cell performs all three functions using the same set of structural components is still highly debated. Here, we bridge the gap between emerging molecular and systems-level understandings of mechanotransduction through a multiscale model linking these three phases. Our model incorporates a discrete network of actin filaments and associated proteins that responds to stretching through geometric relaxation. We assess three potential activating mechanisms at mechanosensitive crosslinks as inputs to a mixture model of molecular release and benchmark each using experimental data of mechanically-induced Rho GTPase FilGAP release from actin-filamin crosslinks. Our results suggest that filamin-FilGAP mechanotransduction response is best explained by a bandpass mechanism favoring release when crosslinking angles fall outside of a specific range. Our model further investigates the difference between ordered versus disordered networks and finds that a more disordered actin network may allow a cell to more finely tune control of molecular release enabling a more robust response. PMID- 25722250 TI - An immunosuppressed man with an aortic rupture secondary to Salmonella aortitis successfully treated with endovascular aortic repair. AB - A 75-year-old immunosuppressed man presented with fever and central abdominal pain 3 weeks after having positive blood cultures for Salmonella enteritidis. A computed tomography scan demonstrated a contained perforation of a nonaneurysmal abdominal aorta. Salmonella aortitis was suspected, and given his recent history of coronary artery stent insertion, endovascular aortic repair was performed, with lifelong antibiotic therapy. At 6 months, there were no remaining clinical or radiological concerns for aortitis or aneurysmal development. This case highlights the high index of suspicion required for aortitis in immunosuppressed patients and verifies endovascular aortic repair, an appropriate alternative in patients with severe comorbidities. PMID- 25722251 TI - Endovascular aortic repair combined with chimney technique in the treatment of stanford type B aortic dissection involving aortic arch. AB - BACKGROUND: In this study, we sought to explore the efficacy of endovascular aortic repair combined with the chimney technique in the treatment of Stanford type B aortic dissection involving the aortic arch. METHODS: Between June 2009 and June 2012, 41 consecutive patients were treated with chimney technique at our institute for aortic arch dissection with the primary entry tear adjacent to the orifices of the supra-aortic arteries. The chimney technique was used to reconstruct the left subclavian artery (n = 5) and the left common carotid artery (n = 34). Additionally, in 2 cases, the double chimney technique was used to simultaneously reconstruct the innominate artery and the left common carotid artery. RESULTS: Eight of the 41 patients had undergone emergent surgery. All the patients survived the surgery, and the mean follow-up period was 17.3 +/- 6.1 months. None of the patients had type I endoleak. Four patients had type II endoleak, and 3 of them underwent implantation of the patent ductus arteriosus occluder in the left subclavian artery. Among these 3 patients, one patient who was pregnant with Marfan syndrome and pregnancy-induced hypertension required additional medication for recovery. None of the patients had any severe neurological complications, left ischemia of the subclavian artery, migration of the stent graft, or occlusion of the stent grafts. CONCLUSIONS: Thus, endovascular aortic repair combined with the chimney technique appears to be a feasible, safe, and effective treatment option for the management of Stanford type B aortic dissection involving the aortic arch. PMID- 25722253 TI - Visible School Security Measures and Student Academic Performance, Attendance, and Postsecondary Aspirations. AB - Many U.S. schools use visible security measures (security cameras, metal detectors, security personnel) in an effort to keep schools safe and promote adolescents' academic success. This study examined how different patterns of visible security utilization were associated with U.S. middle and high school students' academic performance, attendance, and postsecondary educational aspirations. The data for this study came from two large national surveys--the School Crime Supplement to the National Crime Victimization Survey (N = 38,707 students; 51% male, 77% White, MAge = 14.72) and the School Survey on Crime and Safety (N = 10,340 schools; average student composition of 50% male, 57% White). The results provided no evidence that visible security measures had consistent beneficial effects on adolescents' academic outcomes; some security utilization patterns had modest detrimental effects on adolescents' academic outcomes, particularly the heavy surveillance patterns observed in a small subset of high schools serving predominantly low socioeconomic students. The findings of this study provide no evidence that visible security measures have any sizeable effects on academic performance, attendance, or postsecondary aspirations among U.S. middle and high school students. PMID- 25722252 TI - Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2. AB - BACKGROUND: Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca(2+) release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias. METHODS AND RESULTS: Optical maps of action potentials and Ca(2+) transients from Langendorff rabbit hearts were measured at low (150*150 MUm(2)/pixel) and high (1.5*1.5 MUm(2)/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca(2+) elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca(2+-)waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca(2+-)elevations were synchronous within individual myocytes, appeared 188+/-30 ms after the action potential-upstroke, occurred during high cytosolic Ca(2+) (40%-60% of peak-Ca(2+)-transients), appeared first in small islands (0.5*0.5 mm(2)) that enlarged and spread throughout the epicardium. Synchronous systolic Ca(2+-)elevations preceded voltage-depolarizations (9.2+/-5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca(2+)-transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca(2+)-dynamics (multiple chaotic Ca(2+) waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca(2+)-elevations and arrhythmias. CONCLUSIONS: The results indicate that systolic and diastolic Ca(2+)-elevations emanate from sarcoplasmic reticulum Ca(2+)-release and systolic Ca(2+)-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca(2+), which overcomes source-sink mismatch to trigger arrhythmias in intact hearts. PMID- 25722261 TI - Social media in pediatrics: a call for guidelines. PMID- 25722262 TI - Post-licensure monitoring to evaluate vaccine safety. PMID- 25722263 TI - Preventing pediatric readmissions: which ones and how? PMID- 25722264 TI - 50 years ago in The Journal of Pediatrics: intestinal glycosidase activities in congenital malabsorption of disaccharides. PMID- 25722265 TI - 50 years ago in The Journal of Pediatrics: congenital pyloric stenosis: a controlled evaluation of medical treatment utilizing methyl-scopolamine-nitrate. PMID- 25722266 TI - 50 years ago in The Journal of Pediatrics: malabsorption defect induced by ingestion of beta lactoglobulin. PMID- 25722267 TI - Sleep disordered breathing in young boys with Duchenne muscular dystrophy. AB - OBJECTIVES: To describe sleep-disordered breathing (SDB) in young boys with Duchenne muscular dystrophy (DMD) and its relationship with pulmonary function tests (PFTs). STUDY DESIGN: This retrospective study examined diagnostic polysomnogram and PFT data of boys younger than 18 years with DMD and treated with steroids. Spirometry, respiratory muscle strength, body mass index (BMI), sleep architecture variables, and indices of SDB were analyzed. We examined the effect of PFT measures on the risk of each type of respiratory event using logistic regression and have reported results as OR (95% CI). RESULTS: Subjects included 110 boys with DMD, mean age 11.5 (5.6-17.9) years. Mean (+/-SD) percent forced vital capacity predicted was 79.5% +/- 29.1%. Mean BMI for all subjects was 21.9 +/- 7.0 kg/m(2), and mean BMI z-score was 0.65 +/- 1.93. Seventy (63.6%) subjects had obstructive sleep apnea; 37 (33.6%) subjects had central sleep apnea; 18 (17%) subjects had hypoventilation. Median (IQR) Apnea Hypopnea Index was 2.9 (1.6-6.9) and median Obstructive Index was 1.5 (0.5-3.8). Obstructive Index during rapid eye movement sleep positively correlated with BMI (r = 0.33, P = .002), BMI z-score (r = 0.22, P = .04), and age (r = 0.31, P = .004). Lower forced vital capacity was associated with increased risk of hypoventilation (OR 0.8, P = .001). CONCLUSION: SDB is common in young boys with DMD treated with steroids. It is manifest with rapid eye movement-obstructive sleep apnea, often severe, and strongly influenced by BMI. PMID- 25722268 TI - The effect of obstructive sleep apnea syndrome on growth and development in nonobese children: a parallel study of twins. AB - OBJECTIVE: To explore the effects of obstructive sleep apnea syndrome (OSAS) on children's growth by the study of identical twins. STUDY DESIGN: Seventeen cases of nonobese children with OSAS were included in this study. The control group was their identical twin sibling, who had no signs of OSAS. Data including height, weight, and serum insulin-like growth factor 1 levels were analyzed before tonsillectomy and adenoidectomy (T&A) and at 3, 6, and 12 months after surgery. RESULTS: The mean apnea hyponea index was 3.9 times/hour in patients with OSAS and became normal after surgery. Minimum oxygen saturation gradually increased after T&A. The height and weight of the OSAS group before T&A was lower than the control group. During the follow-up period, height and weight increased but were lower than the control group. Serum insulin-like growth factor 1 levels in the OSAS group before T&A were lower than the control group. The level was significantly increased 3 months after T&A. CONCLUSION: OSAS impairs growth and development. Significant growth recovery occurs after T&A, and early surgical intervention is an important factor for improvement in growth. PMID- 25722269 TI - 50 years ago in The Journal of Pediatrics: a note on the influence of thermal factors upon oxygen consumption of the newborn human. PMID- 25722270 TI - Growth and endothelial function in the first 2 years of life. AB - OBJECTIVE: To test the hypothesis that the inverse association between infant growth and endothelial function at 6 months would persist to 24 months and that accelerated growth would lead to an increased percent body fat, which would, in turn, impact negatively on endothelial function. STUDY DESIGN: In a prospective observational study, 104 healthy term newborns underwent anthropometry and measurements of vascular vasodilation at 0, 6, 12, and 24 months. We recorded maximum vasodilation in response to acetylcholine (endothelium-dependent) and nitroprusside (endothelium-independent) by use of laser-Doppler vascular perfusion monitoring of the forearm skin vasculature. Additional anthropometry at 1 and 3 months was collected from child welfare centers. The data were analyzed by multilevel linear regression. RESULTS: Weight gain from 0-1 month was associated inversely with maximum perfusion in response to acetylcholine at the age of 2 years (b = -8.28 perfusion units [PU] per Delta z-score, P = .03). Weight gain from 0-1 month was related positively to maximum perfusion in response to nitroprusside (b = 10.12 PU per Delta z-score, P = .04), as was birth weight (b = 8.02 PU per z-score, P = .02). Body fat percentage did not have a significant effect in any of the perfusion models and was not related to maximum perfusion at 2 years. CONCLUSION: Infant weight gain from 0-1 month is inversely related to endothelial function in healthy term infants, at least to the age of 2 years. This relationship was not explained by an increased percentage body fat. PMID- 25722271 TI - Prediction by clinicians of quality of life for children and adolescents with cardiac disease. AB - OBJECTIVE: To determine whether clinicians could reliably predict health-related quality of life (HRQOL) for children with cardiac disease, the level of agreement in predicted HRQOL scores between clinician sub-types, and agreement between clinician-predicted HRQOL scores and patient and parent-proxy reported HRQOL scores. STUDY DESIGN: In this multicenter, cross-sectional study, a random sample of clinical summaries of children with cardiac disease and related patient and parent-proxy reported HRQOL scores were extracted from the Pediatric Cardiac Quality of Life Inventory data registry. We asked clinicians to review each clinical summary and predict HRQOL. RESULTS: Experienced pediatric cardiac clinicians (n = 140), including intensive care physicians, outpatient cardiologists, and intensive care, outpatient, and advanced practice nurses, each predicted HRQOL for the same 21 pediatric cardiac patients. Reliability within clinician subspecialty groups for predicting HRQOL was poor (intraclass correlation coefficients, 0.34-0.38). Agreement between clinician groups was low (Pearson correlation coefficients, 0.10-0.29). When comparing the average clinician predicted HRQOL scores to those reported by patients and parent-proxies by Bland Altman plots, little systematic bias was present, but substantial variability existed. Proportional bias was found, in that clinicians tended to overestimate HRQOL for those patients and parent-proxies who reported lower HRQOL, and underestimate HRQOL for those reporting higher HRQOL. CONCLUSIONS: Clinicians perform poorly when asked to predict HRQOL for children with cardiac disease. Clinicians should be cognizant of these data when providing counseling. Incorporating reported HRQOL into clinical assessment may help guide individualized treatment decision-making. PMID- 25722272 TI - Serum anti-tissue transglutaminase antibodies detected during febrile illness may not be produced by the intestinal mucosa. AB - Anti-transglutaminase antibodies are the diagnostic marker of celiac disease, and are considered to be synthesized only by intestinal B-lymphocytes. During an infectious disease, these antibodies are transiently detected in serum. We show that these infection-triggered antibodies may not originate in the intestinal mucosa and are not an indication of celiac disease. PMID- 25722273 TI - Retroclival hematoma. PMID- 25722274 TI - Early intervention cognitive effects not sustained past preschool. PMID- 25722275 TI - Porphylactic emollient use beginning at birth prevents atopic dermatitis. PMID- 25722276 TI - Antibiotic prophylaxis prevents urinary tract infection recurrence. PMID- 25722277 TI - Unclear effect of fish oil supplementation on adolescent hypertriglyceridemia. PMID- 25722278 TI - Pulse oximetry based decisions increase hospitalization in bronchiolitis. PMID- 25722279 TI - Is Africa the origin of major Haitian Staphylococcus aureus lineages? PMID- 25722280 TI - Controlling Ebola: what we can learn from China's 1911 battle against the pneumonic plague in Manchuria. AB - The pneumonic plague, which spread across Northeast China during the winter of 1910 and spring of 1911, caused numerous deaths and brought about severe social turmoil. After compulsory quarantine and other epidemic prevention measures were enforced by Dr Wu Lien-teh, the epidemic was brought to an end within 4 months. This article reviews the ways in which the plague was dealt with from a historical perspective, based on factors such as clinical manifestations, duration of illness, case fatality rate, degree of transmissibility, poverty, inadequate healthcare infrastructure, and the region's recent strife-filled history. Similarities were sought between the pneumonic plague in Northeast China in the twentieth century and the Ebola virus outbreak that is currently ravaging Africa, and an effort made to summarize the ways in which specific measures were applied successfully to fight the earlier epidemic. Our efforts highlight valuable experiences that are of potential benefit in helping to fight the current rampant Ebola epidemic in West Africa. PMID- 25722281 TI - Human subcutaneous/ocular dirofilariasis in the Russian Federation and Belarus, 1997-2013. AB - OBJECTIVES: This study was performed to determine the yearly frequency, trends in spread, and clinical-epidemiological characteristics of human subcutaneous/ocular dirofilariasis (HSOD) in the Russian Federation and Belarus. METHODS: The surveillance data of HSOD cases occurring between January 1997 and June 2013, obtained from the regional health administrations of the Russian Federation and Belarus, were analyzed. The spatial distribution of cases was assessed using a GIS map, and the clinical-epidemiological characteristics were defined using 719 cases for which information on anatomical location, age, sex, and area of residence was available. The statistical analysis was performed using the Chi square test. RESULTS: One thousand two hundred and seventy-two clinical cases of HSOD were identified, the majority of them reported in the south-western regions of the Russian Federation. The disease has spread into northern areas, changing its limit from latitude 45 degrees N in 1997 to latitude 61 degrees N in 2013. The statistical analysis of the data showed that the disease is more frequent in the ocular location, in women, in patients aged between 41 and 60 years, and in patients living in urban areas. CONCLUSIONS: Alternative sources to the scientific literature could be necessary to assess the epidemiological situation regarding HSOD in some areas where it has become an emerging condition. There is an urgent need for uniform criteria for reporting and retrieving human cases of dirofilariasis. PMID- 25722282 TI - Measuring hand hygiene compliance rates in different special care settings: a comparative study of methodologies. AB - OBJECTIVES: The purpose of this study was to compare methods for assessing compliance with hand hygiene in an intensive care unit (ICU), a step-down unit (SDU), and a hematology-oncology unit. METHODS: Over a 20-week period, we compared hand hygiene compliance measurements by three different methods: direct observation, electronic handwash counter for alcohol gel, and measuring the volume of product used (alcohol gel) in an ICU, an SDU, and a hematology-oncology unit of a tertiary care, private hospital. RESULTS: By direct observation we evaluated 1078 opportunities in the ICU, 1075 in the SDU, and 517 in the hematology-oncology unit, with compliance rates of 70.7%, 75.4%, and 73.3%, respectively. A total of 342,299, 235,914, and 248,698 hand hygiene episodes were recorded by the electronic devices in the ICU, SDU, and hematology-oncology unit, respectively. There were also 127.2 ml, 85.3 ml, and 67.6 ml of alcohol gel used per patient-day in these units. We could find no correlation between the three methods. CONCLUSIONS: Hand hygiene compliance was reasonably high in these units, as measured by direct observation. However, a lack of correlation with results obtained by other methodologies brings into question the validity of direct observation results, and suggests that periodic audits using other methods may be needed. PMID- 25722283 TI - The first human infection with severe fever with thrombocytopenia syndrome virus in Shaanxi Province, China. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. In July 2013, the first human infection with SFTS virus (SFTSV) was detected in Shaanxi Province, Western China. METHODS: A seroprevalence study among humans was carried out in an SFTS endemic village; specifically, serum samples were collected from 363 farmers in an SFTS endemic village in Shaanxi Province. The presence of SFTSV antibodies in serum was determined using an ELISA. RESULTS: SFTSV antibodies were found in a total of 20 people (5.51%), with no significant difference between males and females (6.93% and 4.42%, respectively; Chi-square=1.29, p=0.25). Moreover, the SFTSV antibody positive rate was not significantly different across different age groups (Chi-square=2.23, p=0.69). CONCLUSIONS: SFTSV readily infects humans with outdoor exposure. The results of the serological study indicate that the virus circulates widely in Shaanxi Province. SFTSV represents a public health threat in China. PMID- 25722284 TI - Public-private mix for tuberculosis care and control: a systematic review. AB - BACKGROUND: Public-private mix (PPM), recommended by the World Health Organization (WHO), was introduced to cope with the tuberculosis (TB) epidemic worldwide. In many developing countries, PPM has played a powerful role in TB control, while in others it has failed to meet expectations. Thus we performed a systematic review to determine the mechanisms used by global PPM programs implemented in different countries and to evaluate their performance. METHODS: A comprehensive search of the current literature for original studies published up to May 2014 was done using electronic databases and online resources; these publications were then screened using rigorous criteria. Descriptive information and evaluative outcomes data were extracted from eligible studies for synthesis and analysis. RESULTS: A total of 78 eligible studies were included in the final review. These assessed 48 PPM TB programs worldwide, subsequently categorized into three mechanisms based on collaborative characteristics: support, contract, and multi-partner group. Furthermore, we assessed the effectiveness of PPM programs against six health system themes, including utilization of the directly observed treatment strategy (DOTS), case detection, treatment outcomes, case management, costs, and access and equity, under the different collaborative mechanisms. Analysis of the comparative studies suggested that PPM could improve overall outcomes of a TB service, and multiple collaborative mechanisms may significantly promote case detection, treatment, referral, and service accessibility, especially in resource-limited areas. However, the less positive outcomes of several programs indicated limited funding and poor governance to be the predominant reasons. CONCLUSIONS: PPM is a promising strategy to strengthen global TB care and control, but is affected by contextual characteristics in different areas. The scaling-up of PPM should contain essential commonalities, particularly substantial financial support and continuous material input. Additionally, it is important to improve program governance and training for the health providers involved, through integrated collaborative mechanisms. PMID- 25722285 TI - A woman with cough: gastrobronchial fistula as a delayed complication of bariatric surgery. Case report and literature review. PMID- 25722286 TI - Acute first diagonal artery occlusion: a characteristic pattern of ST elevation in noncontiguous leads. PMID- 25722287 TI - Use of extracorporeal membrane oxygenation in severe traumatic lung injury with respiratory failure. AB - OBJECTIVES: The use of extracorporeal membrane oxygenation (ECMO) in managing acute respiratory distress syndrome had been accepted. Severe lung injury with respiratory failure is often encountered in trauma patients. We report our experience with the use of ECMO in severe traumatic lung injury. METHODS: Patients with severe traumatic lung injury that met the following criteria were candidates for ECMO: (1) severe hypoxemia, Pao2/fraction of inspired oxygen (1.0) less than 60, and positive end-expiratory pressure greater than 10 cm H2O in spite of vigorous ventilation strategy; (2) irreversible CO2 retention with unstable hemodynamics; and (3) an initial arterial Pao2/fraction of inspired oxygen (1.0) less than 60, where the pulmonary condition and hemodynamics rapidly deteriorated despite vigorous mechanical ventilation strategy. RESULTS: Over 60 months, a total of 19 patients with severe traumatic lung injury who received ECMO management were retrospectively reviewed. The median age was 38 years (25-58 years), the median injury severity score was 29 (25-34), the median admission Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 25 (21 36), and the median blood transfusion volume was 5500 mL (3500-13 000). There were 9 venovenous and 10 venoarterial types. The survival rate was 68.4% (13/19). The survivors were younger (30 vs 53 years; 21-39 vs 48-63). There were 6 mortalities (3 pneumonia, 2 coagulopathy, and 1 cardiac rupture with cardiac tamponade). There were 5 of 19 patients with pre-ECMO traumatic brain hemorrhage (3 survived and 2 mortalities). A total of 16 patients received heparinization with 5 mortalities. CONCLUSIONS: The use of ECMO may offer an additional treatment modality in severe traumatic lung injury with respiratory failure that is unresponsive to optimal conventional ventilator support. Timely ECMO intervention is of value. PMID- 25722288 TI - PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. AB - Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum. PMID- 25722289 TI - SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites. AB - SUMOylation plays important roles in the DNA damage response. However, whether it is important for interstrand crosslink repair remains unknown. We report that the SLX4 nuclease scaffold protein is regulated by SUMOylation. We have identified three SUMO interaction motifs (SIMs) in SLX4, mutating all of which abrogated the binding of SLX4 to SUMO-2 and covalent SLX4 SUMOylation. An SLX4 mutant lacking functional SIMs is not recruited to PML nuclear bodies nor stabilized at laser induced DNA damage sites. Additionally, we elucidated a novel role for PARylation in the recruitment of SLX4 to sites of DNA damage. Combined, our results uncover how SLX4 is regulated by post-translational modifications. PMID- 25722291 TI - Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial. AB - BACKGROUND: Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. METHODS: A CC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, "CC-H5N1") was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 ug or 3.75 ug of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 ug of plain HA), embryonated-egg-derived vaccines (3.75 ug of HA with AS03 or 15 ug of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. RESULTS: AS03 adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 ug of HA and AS03 appeared to be similar to those for the licensed egg derived AS03-adjuvanted control vaccine. CONCLUSIONS: The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CC-H5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. CLINICAL TRIALS REGISTRATION: NCT01236040. PMID- 25722292 TI - Increased Rates of Respiratory and Diarrheal Illnesses in HIV-Negative Persons Living With HIV-Infected Individuals in a Densely Populated Urban Slum in Kenya. AB - BACKGROUND: Prolonged pathogen shedding and increased duration of illness associated with infections in immunosuppressed individuals put close human immunodeficiency virus (HIV)-negative contacts of HIV-infected persons at increased risk of exposure to infectious pathogens. METHODS: We calculated incidence and longitudinal prevalence (number of days per year) of influenzalike illness (ILI), diarrhea, and nonspecific febrile illness during 2008 from a population-based surveillance program in the urban slum of Kibera (Kenya) that included 1830 HIV-negative household contacts of HIV-infected individuals and 13 677 individuals living in exclusively HIV-negative households. RESULTS: For individuals >=5 years old, incidence was significantly increased for ILI (risk ratio [RR], 1.47; P < .05) and diarrhea (RR, 1.41; P < .05) in HIV-negative household contacts of HIV-infected individuals compared with exclusively HIV negative households. The risk of illness among HIV-negative persons was directly proportional to the number of HIV-infected persons living in the home for ILI (RR, 1.39; P < .05) and diarrhea (RR, 1.36; P < .01). We found no increased rates of illness in children <5 years old who lived with HIV-infected individuals. CONCLUSIONS: Living with HIV-infected individuals is associated with modestly increased rates of respiratory and diarrheal infections in HIV-negative individuals >5 years old. Targeted interventions are needed, including ensuring that HIV-infected persons are receiving appropriate care and treatment. PMID- 25722290 TI - The biology of IQGAP proteins: beyond the cytoskeleton. AB - IQGAP scaffold proteins are evolutionarily conserved in eukaryotes and facilitate the formation of complexes that regulate cytoskeletal dynamics, intracellular signaling, and intercellular interactions. Fungal and mammalian IQGAPs are implicated in cytokinesis. IQGAP1, IQGAP2, and IQGAP3 have diverse roles in vertebrate physiology, operating in the kidney, nervous system, cardio-vascular system, pancreas, and lung. The functions of IQGAPs can be corrupted during oncogenesis and are usurped by microbial pathogens. Therefore, IQGAPs represent intriguing candidates for novel therapeutic agents. While modulation of the cytoskeletal architecture was initially thought to be the primary function of IQGAPs, it is now clear that they have roles beyond the cytoskeleton. This review describes contributions of IQGAPs to physiology at the organism level. PMID- 25722293 TI - The Role of HIV in the Household Introduction and Transmission of Influenza in an Urban Slum, Nairobi, Kenya, 2008-2011. AB - BACKGROUND: Little is known about how human immunodeficiency virus (HIV) infection affects influenza transmission within homes in sub-Saharan Africa. METHODS: We used respiratory illness surveillance and HIV testing data gathered in Kibera, an urban slum in Nairobi, Kenya, to examine the impact of HIV status on (1) introducing influenza to the home and (2) transmitting influenza to household contacts. RESULTS: While HIV status did not affect the likelihood of being an influenza index case, household contacts of HIV-infected influenza index cases had twice the risk of developing secondary influenza-like illness than contacts of HIV-negative index cases. CONCLUSIONS: HIV-infected influenza index cases may facilitate transmission of influenza within the home. PMID- 25722294 TI - Immunogenicity of the Bivalent Oral Cholera Vaccine Shanchol in Haitian Adults With HIV Infection. AB - We evaluated immune responses following bivalent oral cholera vaccination (Shanchol [Shantha Biotechnics]; BivWC) in a cohort of 25 human immunodeficiency virus (HIV)-infected adults in Haiti. Compared with adults without HIV infection, vaccination in HIV-infected individuals resulted in lower vibriocidal responses against Vibrio cholerae O1, and there was a positive relationship between the CD4(+) T-cell count and vibriocidal responses following vaccination. Nevertheless, seroconversion occurred at a rate of 65% against the Ogawa serotype and 74% against the Inaba serotype in adults with HIV infection. These results suggest that the vaccine retains substantial immunogenicity in adults with HIV infection and may benefit this population by protecting against cholera. PMID- 25722295 TI - Role of the 2B4 Receptor in CD8+ T-Cell-Dependent Immune Control of Epstein-Barr Virus Infection in Mice With Reconstituted Human Immune System Components. AB - Patients with X-linked lymphoproliferative (XLP) disease due to deficiency in the adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) are highly susceptible to one specific viral pathogen, the Epstein-Barr virus (EBV). This susceptibility might result from impaired CD8(+) T-cell and natural killer cell responses to EBV infection in these patients. We demonstrate that antibody blocking of the SAP-dependent 2B4 receptor is sufficient to induce XLP-like aggravation of EBV disease in mice with reconstituted human immune system components. CD8(+) T cells require 2B4 for EBV-specific immune control, because 2B4 blockade after CD8(+) T-cell depletion did not further aggravate symptoms of EBV infection. PMID- 25722296 TI - Factors Associated With Plasma IL-6 Levels During HIV Infection. AB - BACKGROUND: Elevated interleukin 6 (IL-6) levels have been linked to cardiovascular disease, cancer and death. Persons with human immunodeficiency virus (HIV) infection receiving treatment have higher IL-6 levels, but few data are available on factors associated with circulating IL-6. METHODS: Participants in 3 trials with IL-6 measured at baseline were included (N = 9864). Factors associated with IL-6 were identified by linear regression. Demographic and HIV variables (nadir/entry CD4(+) cell count, HIV RNA level, antiretroviral therapy regimen) were investigated in all 3 trials. In the SMART (Strategies for Management of Anti-Retroviral Therapy) trial, CD4/CD8 ratio, smoking, comorbid conditions, serum lipids, renal function (estimated glomerular filtration rate [eGFR]), and educational level were assessed. RESULTS: Demographics associated with higher IL-6 levels were older age and lower education, whereas black race was associated with lower IL-6. Higher HIV RNA levels were associated with higher IL-6 levels, and higher nadir CD4(+) cell counts with lower IL-6 levels. Compared with efavirenz, protease inhibitors were associated with higher and nevirapine with lower IL-6 levels. Smoking and all comorbid conditions were related to higher IL-6. IL-6 levels increased with decreasing eGFR and decreasing serum lipids. CONCLUSIONS: Higher levels of IL-6 were associated with older age, nonblack race, higher body mass index, lower serum lipid levels, HIV replication, low nadir CD4(+) cell count, protease inhibitor use, comorbid conditions, and decreased eGFR. Multiple factors affect inflammation in HIV and should be considered in studies of IL-6 as a biomarker of clinical outcomes. PMID- 25722297 TI - Effect of Q211 and K222 PRNP Polymorphic Variants in the Susceptibility of Goats to Oral Infection With Goat Bovine Spongiform Encephalopathy. AB - BACKGROUND: The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear. METHODS: Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrP(Sc)) and prion infectivity by mouse bioassay. RESULTS: R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrP(Sc) were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrP(Sc) accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44-45 months). CONCLUSIONS: These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE. PMID- 25722298 TI - Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever. AB - BACKGROUND: Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever. METHODS: Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, alphavbeta3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes. RESULTS: Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 ( 938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure. CONCLUSIONS: Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (-938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever. PMID- 25722299 TI - Staphylococcus aureus Inhibits Neutrophil-derived IL-8 to Promote Cell Death. AB - While Staphylococcus aureus accelerates human neutrophil cell death, the underlying host- and pathogen-derived mechanisms remain incompletely defined. Previous studies demonstrated that the S. aureus SaeR/S sensory system is essential for pathogen survival following neutrophil phagocytosis. Herein, we demonstrate that the SaeR/S system promoted accelerated cell death, suppressed phosphorylation of nuclear factor-kappaB, and reduced interleukin-8 (IL-8) production in human neutrophils. Treatment of neutrophils with recombinant IL-8 significantly reduced bacterial burden and apoptosis. Our findings demonstrate a mechanism by which S. aureus suppresses the early neutrophil-derived IL-8 response to disrupt cell fate and promote disease. PMID- 25722300 TI - Evaluation of intermittent preventive treatment of malaria against group B Streptococcus colonization in pregnant women: a nested analysis of a randomized controlled clinical trial of sulfadoxine/pyrimethamine versus mefloquine. AB - OBJECTIVES: Streptococcus agalactiae constitutes an important cause of neonatal infections in sub-Saharan Africa. Sulfadoxine/pyrimethamine-the current intermittent preventive treatment of malaria in pregnancy (IPTp)-has proven in vitro activity against group B Streptococcus (GBS). Because of specific drug resistance to sulfadoxine/pyrimethamine, mefloquine-an antimalarial without in vitro activity against GBS-was evaluated as a potential alternative. This study assessed the potential of sulfadoxine/pyrimethamine-IPTp to reduce the prevalence of GBS colonization in pregnant women in Gabon when compared with the inactive control mefloquine-IPTp. METHODS: Pregnant women participating in a randomized controlled clinical trial evaluating mefloquine-IPTp versus sulfadoxine/pyrimethamine-IPTp were invited to participate and recto-vaginal swabs were collected at delivery for detection of GBS colonization. Prevalence of recto-vaginal GBS colonization was compared between IPTp regimens and risk factor and birth outcome analyses were computed. RESULTS: Among 549 participants, 106 were positive for GBS colonization at delivery (19%; 95% CI = 16%-23%). Prevalence of maternal GBS colonization showed no significant difference between the two IPTp regimens (mefloquine-IPTp: 67 of 366 women = 18%; 95% CI = 14%-22%; sulfadoxine/pyrimethamine-IPTp: 39 of 183 women = 21%; 95% CI = 15%-27%). Risk factor analysis for GBS colonization demonstrated a significant association with illiteracy (adjusted OR = 2.03; 95% CI = 1.25-3.30). GBS colonization had no impact on birth outcome, anaemia at delivery, gestational age and birth weight. CONCLUSIONS: Sulfadoxine/pyrimethamine did not reduce colonization rates when used as the IPTp drug during pregnancy. Illiteracy was associated with GBS colonization. PMID- 25722301 TI - MRSA carrying mecC in captive mara. AB - OBJECTIVES: To characterize the staphylococcal cassette chromosome mec (SCCmec), virulence and antimicrobial susceptibility of Staphylococcus aureus ST130 isolated from mara (Dolichotis patagonum), a large rodent species native to South America and kept in captivity at Copenhagen Zoo. METHODS: The presence of mecC was confirmed by PCR in 15 S. aureus ST130 isolated from mara during a previous study. WGS was performed on two randomly selected isolates to characterize their genomes with respect to SCCmec, virulence and resistance gene content. Antimicrobial susceptibility was tested using commercial broth microdilution tests. RESULTS: All the isolates belonged to spa type t528 ST130 and carried mecC. Based on WGS, mecC was 100% identical to the prototype sequence of S. aureus strain LGA251. The sequence of SCCmec type XI in the mara isolates had 23 SNPs compared with the one described in LGA251. The two sequenced strains harboured a set of virulence factors and other genomic features previously observed in ST130. Both strains carried norA as the only putative antimicrobial resistance gene in addition to mecC. CONCLUSIONS: Our findings support the notion that a genetically conserved mecC-carrying MRSA ST130 clone is widespread in a variety of unrelated hosts in Denmark. Since the mara at Copenhagen Zoo have limited contact with humans and other animal species, it remains unclear whether mara are natural hosts of ST130 or acquired this lineage from unknown sources. The broad host range of MRSA ST130 supports its designation as a generalist lineage. PMID- 25722302 TI - Introduction of an antifungal stewardship programme targeting high-cost antifungals at a tertiary hospital in Cambridge, England. AB - BACKGROUND: Antifungal stewardship aims to promote the optimal use of antifungals through the careful selection of agents based on patient profile, target organism, toxicity, costs and the likelihood of emergence and spread of resistance. METHODS: We report on an observational prospective 12 month study conducted by an antifungal stewardship team targeting the use of echinocandins (caspofungin and micafungin), voriconazole and liposomal amphotericin B in a tertiary referral hospital in the UK. RESULTS: One-hundred-and-seventy-three patients were reviewed on 294 occasions. Clinical advice was given and implemented during review of 45 (88.2%) of micafungin prescriptions, 70 (78.7%) of those receiving voriconazole, 78 (62.4%) of those receiving liposomal amphotericin B and 3 (27.3%) of those receiving caspofungin. Except for voriconazole, nearly half of all treatments reviewed were stopped or changed. This study found that a crude cost saving of ~L180 000 in antifungal drugs was generated compared with the previous year. CONCLUSIONS: Using a multidisciplinary team, antifungal stewardship can achieve significant improvements in patient management and it may reduce costs. PMID- 25722303 TI - Targeting MPS1 Enhances Radiosensitization of Human Glioblastoma by Modulating DNA Repair Proteins. AB - To ensure faithful chromosome segregation, cells use the spindle assembly checkpoint (SAC), which can be activated in aneuploid cancer cells. Targeting the components of SAC machinery required for the growth of aneuploid cells may offer a cancer cell-specific therapeutic approach. In this study, the effects of inhibiting Monopolar spindle 1, MPS1 (TTK), an essential SAC kinase, on the radiosensitization of glioblastoma (GBM) cells were analyzed. Clonogenic survival was used to determine the effects of the MPS1 inhibitor NMS-P715 on radiosensitivity in multiple model systems, including GBM cell lines, a normal astrocyte, and a normal fibroblast cell line. DNA double-strand breaks (DSB) were evaluated using gammaH2AX foci, and cell death was measured by mitotic catastrophe evaluation. Transcriptome analysis was performed via unbiased microarray expression profiling. Tumor xenografts grown from GBM cells were used in tumor growth delay studies. Inhibition of MPS1 activity resulted in reduced GBM cell proliferation. Furthermore, NMS-P715 enhanced the radiosensitivity of GBM cells by decreased repair of DSBs and induction of postradiation mitotic catastrophe. NMS-P715 in combination with fractionated doses of radiation significantly enhanced the tumor growth delay. Molecular profiling of MPS1 silenced GBM cells showed an altered expression of transcripts associated with DNA damage, repair, and replication, including the DNA-dependent protein kinase (PRKDC/DNAPK). Next, inhibition of MPS1 blocked two important DNA repair pathways. In conclusion, these results not only highlight a role for MPS1 kinase in DNA repair and as prognostic marker but also indicate it as a viable option in glioblastoma therapy. IMPLICATIONS: Inhibition of MPS1 kinase in combination with radiation represents a promising new approach for glioblastoma and for other cancer therapies. PMID- 25722305 TI - [In Process Citation]. PMID- 25722304 TI - Breast Cancer-Specific miR Signature Unique to Extracellular Vesicles Includes "microRNA-like" tRNA Fragments. AB - Extracellular vesicles (EV), including exosomes and shed vesicles, have been implicated in intercellular communication; however, their biomarker potential is less clear. Therefore, EVs derived from MCF7 and MCF10A cells were analyzed to identify unique miRNA (miR) profiles that distinguish their origin. One characteristic common to the miR profiles of MCF7 EVs and their parent cells is the high abundance of miR-21, let-7a, miR-100, and miR-125b, and low levels of miR-205. A second characteristic is the high abundance of "miRNA-like" tRNA fragments, which is unique to the MCF7 EVs, and is not found in comparing the cellular profiles. In addition, correlations were examined in the MCF7 cellular expression levels of these five miRs and two tRNA-derived miRNAs, miR-720 and miR 1274b, and compared with the correlations in MCF7 EV levels. Interestingly, correlations in the cellular expression of miR-125b, miR-100, and let-7a are mirrored in the EVs. In contrast, correlations in tRNA-derived miRNA levels are found only in the EVs. The findings suggest that EV miR clusters can be defined based on functional miR interactions related to correlated cellular expression levels or physical miR interactions, for example, aggregation due to comparable binding affinities to common targets. IMPLICATIONS: These results point to using high levels of tRNA-derived small RNA fragments in combination with known miR signatures of tumors to distinguish tumor-derived EVs in circulation from EVs derived from other cell sources. Such biomarkers would be unique to the EVs where high abundances of tRNA fragments are amplified with respect to their cellular levels. PMID- 25722306 TI - [In Process Citation]. AB - Postinfectious glomerulonephritis is an immune-mediated disease occurring as a result of the host response to an extrarenal infection. The classical form of poststreptococcal disease is decreasing worldwide but remains a significant health care problem in developing countries, especially in children. In industrialised countries postinfectious glomerulonephritis is now primarily due to non-streptococcal disease. In elderly patients with risk factors such as diabetes mellitus, alcohol-dependency or neoplasia and in intravenous drug users postinfectious glomerulonephritis is most often associated with staphylococcal infections of various locations. Compared to the good outcome of classical poststreptococcal glomerulonephritis the severity of the nephritic syndrom is increased and the prognosis is worse, especially if pre-existing renal disease such as diabetic or vascular nephropathy is present. The recognition and adequate therapy, often including surgical measures, of the primary focus of infection is of utmost importance to improve the outcome of this condition. Especially in patients with diabetic foot syndrome and in intravenous drug users with signs of infection and renal insufficiency or abnormal urinalysis, there should be a high index of suspicion for postinfectious glomerulonephritis. PMID- 25722307 TI - [In Process Citation]. AB - Diabetic nephropathy is the most common cause of end-stage renal disease and is associated with a high morbidity and mortality. Early diagnosis is important as tight control of albuminuria and hypertension improves the renal prognosis. Similarly, good control of hyperglycemia is critical, but emphasis should be given on individualization of treatment goals. Once the estimated GFR is < 60 ml/min/1.73 m2 the antidiabetic medication needs to be reviewed and a dose reduction of many drugs is necessary. The risk for hypoglycemia is particularly high for the sulfonylureas glibenclamide and glimepiride and they are contraindicated once the GFR is < 60 ml/min/1.73 m2. Because of the increased risk of lactic acidosis, metformin requires a dose adjustment if the GFR is < 60 ml/min/1.73 m2 and the drug should be stopped once the GFR falls < 45 ml/min/1.73 m2. In addition, metformin needs to be paused if acute renal failure is imminent. Inhibitors of the DPP-4 enzyme can be employed with impaired renal function, but their use usually requires dose adjustments. Prescription of GLP-1 receptor agonists is possible with a moderately impaired renal function but they should be discontinued if the GFR falls < 30/min/1.73 m2. From the new class of SGLT2 inhibitors canagliflozin and empagliflozin can be used in an adjusted dose as long as the GFR is > 45 ml/min/1.73 m2. PMID- 25722308 TI - [In Process Citation]. AB - IgA nephropathy is the most common glomerulonephritis in Europe. The disease has been discovered in 1968 in Paris by Jean Berger at the Necker-Children's Hospital. Diagnosis is made by kidney biopsy and requires the presence of mesangial deposits of IgA. This form of glomerulonephritis can be seen in children and adults. In childhood, it most frequently presents within the context of Schoenlein-Henoch purpura. In adulthood, the most common form is limited to the kidney. Schoenlein-Henoch purpura can be seen in adults and manifests as a very aggressive vasculitis, usually in the context of a specific drug intake. The underlying pathophysiological concept today is an insufficient glycosylation of the IgA1 hinge region triggering the formation of autoantibodies against this site. Therapeutic options for the disease are limited. Important is optimal blood pressure control. Selected patients will profit from steroid therapy. PMID- 25722309 TI - [In Process Citation]. AB - Pauci-immune glomerulonephritis and ANCA associated vasculitides (AAV) are chronic autoimmune diseases with necrotizing inflammation of the small vessels, affecting several organ systems with a variety of symptoms, in rarer cases isolated renal manifestation without extrarenal vasculitis. The term "pauci immune" defines the characteristic absence of immune complexes in the tissues. Circulating antineutrophil cytoplasmic antibodies (ANCA) are of pathogenic and diagnostic relevance. The typical renal manifestation is rapidly progressive glomerulonephritis, progressing to dialysis within weeks without treatment. To prevent diagnostic delay practitioners should measure ANCA promptly in case of acute kidney injury with hematuria. Current immunosuppressive regimens have impressively improved patient and kidney survival, but are far away from being optimal due to a high rate of adverse events and relapses. PMID- 25722310 TI - [In Process Citation]. AB - Lupus nephritis represents the most common visceral organ manifestation of systemic lupus erythematosus and has a major impact on lupus related morbidity and quality of life. Histologically, renal lupus involvement exhibits a broad range of patterns, which cause diverse clinical manifestations, ranging from mild asymptomatic urinary test abnormalities to severe nephrotic syndrome or rapidly progressive renal failure. Therapeutic options have considerably improved over the last decades, but despite intensive research efforts continue to be based on relatively unspecific immunosuppression. Given their considerable side effects, immunosuppressive treatments must be well tailored to the severity of lupus nephritis. For such a rational treatment planning, the exact histological diagnosis based on kidney biopsy plays a central role. This review article summarizes the basis of pathogenesis, histological manifestations, clinical pictures, diagnosis and treatment approaches of lupus nephritis. PMID- 25722311 TI - [In Process Citation]. AB - Membranous nephropathy is one of the most common glomerular diseases and leading causes of nephrotic syndrome in Caucasian adults. Known as a clinico-pathologic entity for over 50 years, it is defined by thickening of the glomerular capillary membrane with subepithelial immuncomplexes. Secondary forms (e. g. hepatitis B, autoimmune disease or medication-induced) are distinguished from idiopathic forms. Despite spontaneous remissions in about 30 % of cases, one third of idiopathic forms progress to end-stage renal disease after 10 years. Seminal research progress of the last decade has allowed the identification of autoantibodies directed against podocytary elements leading to secondary damage to the filtration barrier. The so-called idiopathic membranous nephropathy has thus become a prototype of autoimmune disease. The autoantibodies detectable in 70 - 80 % of cases of idiopathic membranous nephropathy are directed against the M-type phospholipase A2-receptor on the podocyte membrane and correlate with disease activity. These epochal findings influence on diagnostic and therapeutic strategies establishing a rationale for the use of B cell-directed therapy on top of optimal supportive therapy. PMID- 25722312 TI - [In Process Citation]. AB - Focal segmental glomerulosclerosis (FSGS) is a common histological diagnosis in adults with nephrotic proteinuria and one of the most frequent causes of end stage renal disease (ESRD) among the primary glomerulopathies. Renal histology reveals the "endpoint" of most glomerulopathies, whereby nephron loss results in functional overload and further damage of the remaining ones. FSGS is thus the clinico-pathological manifestation of genetical and acquired damages to the podocytes. Secundary FSGS is much more frequent than the primary ones. While secondary FSGS is characterized by slow progression of proteinuria and decline of kidney function, idiopathic FSGS presents already at first manifestation with renal insufficiency and nephrotic proteinuria with fast progression to ESRD. An etiological definition of FSGS is crucial for its management, since treatment of secundary forms is only symptomatic and if possibly causal, while immunosuppression is indicated in the cases of idiopathic FSGS. Primary FSGS presents a high risk of relapse after kidney transplantation. PMID- 25722313 TI - [In Process Citation]. AB - The nephrotic syndrome is characterized by a combination of pathological lab values and clinical symptoms, i. e. pronounced proteinuria (usually more than 3 - 3,5 g protein/24 h), hypoalbuminemia, edema and hyperlipidemia. The causes of the nephrotic syndrome are manifold and can be inherited or acquired, chronically persistent or reversible. The frequency of the causes of the nephrotic syndrome is different among children and adults. While in adults acquired forms are common, genetic forms are more abundant among children. All diseases related to nephrotic proteinuria have in common that the causal defect affects the glomerular podocyte in a primary or secondary manner. This review article discusses the question when nowadays genetic diagnostics should be considered. PMID- 25722314 TI - [In Process Citation]. AB - Recurrence of glomerulonephritis after kidney transplantation is especially in the long term an important cause of renal allograft failure. The exact frequency depends on the one hand how the diagnosis of recurrence was established, either on clinical grounds or histologically via a kidney transplant biopsy, and on the other hand on the type of the underlying or primary glomerular disease. The consequences of a relapse on allograft function and survival vary, depending on the primary disease. For example, recurrences after IgA nephropathy occur depending on the length of the observation period in over 50 % of the allografts with often relatively slow progression. However, focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis recurrence generally have a much more rapid progression and poorer prognosi. The recent findings on the pathogenesis of certain glomerulopathies have led to new therapies, which have shown quite positive results in studies of smaller patient groups. New therapeutical approaches have been reported in particular for the following diseases: focal segmental glomerulosclerosis, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis type 2 (dense deposit disease), IgA nephropathy and atypical hemolytic uremic syndrome (aHUS). In particular, rituximab or eculizumab represent interesting therapeutic options in some of these entities. Recurrence of glomerulonephritis - after allograft rejection and death with a functioning organ - is the third most common cause of kidney transplant failure. Overall, patients transplanted because of glomerular diseases have a longterm allograft survival comparable to patients suffering from other primary renal disorders. Nevertheless, a recent investigation showed a slightly worse long-term renal transplant survival in patients with a glomerulonephritis as the primary kidney disease. It is important to state that glomerulonephritis as the primary renal disorder does not represent a contraindication for kidney transplantation, including living kidney donation. PMID- 25722315 TI - Challenges in the differential diagnosis of interdigitating dendritic cell sarcoma of intraparotid lymph node vs. metastatic malignant melanoma with unknown primary site. AB - Interdigitating dendritic cell sarcoma (IDCS) is an uncommon form of malignant histiocytosis affecting dendritic cells. The parotid gland more frequently than other salivary glands has metastasis from extraparotid tumours, which in 80% of cases are melanomas and squamous cell carcinomas. Herein we report our case, a 64 year-old woman who presented with a short history of fluctuating in size swelling below her right ear. Ultrasound scan showed a loculated cystic lesion extending in the parotid parenchyma. Fine needle aspiration (FNA) revealed appearances that were highly suspicious of malignancy, therefore MRI scan was arranged, and parotidectomy planned. The histology of tumour was a malignant spindle cell neoplasm, with immunohistochemical features highly suggestive of metastatic malignant melanoma with divergent differentiation. The challenges in the differential diagnosis of IDCS of intraparotid lymph node vs. metastatic malignant melanoma with unknown primary tumour are described here. The rarity of this neoplasm figures highlights the importance of describing all new cases putting special emphasis on the steps to be taken in order to shorten the diagnosis, management and treatment process. PMID- 25722316 TI - Late hepatic metastasis from a duodenal gastrointestinal stromal tumor (29 years after surgery): report of a case and review of the literature. AB - Gastrointestinal stromal tumor (GIST) metastases are found most commonly in the liver, on average 16 to 38 months after resection of the primary tumor, even if some delayed hepatic metastases from GISTs have been described. We report a case of a man with a giant liver mass at computed tomography scan. In September 1984, the patient had undergone resection of a duodenal tumor, diagnosed as schwannoma. A liver biopsy revealed a neoplasm composed of epithelioid and spindled cells, immunohistochemically positive to c-kit and Dog-1. Reexamining the duodenal tumor resected in 1984, it was reclassified as GIST. Sequencing revealed the same mutation of the c-kit gene in both duodenal and hepatic lesions. To the best of our knowledge, this case represents the longest disease-free interval between a primary GIST and its metastasis. A brief review of the literature and an analysis of the potential prognostic role of particular c-kit mutations are also provided. PMID- 25722317 TI - Anal melanoma with neuroendocrine differentiation: report of a case. AB - Melanoma of the anal cavity is an uncommon malignant tumor with an aggressive clinical behavior. The presence of nonmelanocytic cell or tissue components, designated as divergent differentiation, is an unusual but well-documented phenomenon in melanoma. We experienced a rare case of amelanotic melanoma with neuroendocrine differentiation of the anal canal, occurring in a 68-year old woman. This tumor was characterized by a clear-cut radial growth phase and an invasive component composed of a diffuse small cells population positive for neuroendocrine markers with a focal but convincing co-expression of S100 protein. To the best of our knowledge, this represents the first case of neuroendocrine differentiation in a primary melanoma of the anal cavity. Although anal melanoma with neuroendocrine differentiation is exceptional, clinical practitioners should be aware of its possibility at this site. PMID- 25722319 TI - Defective circulating CD4+LAP+ regulatory T cells in patients with dilated cardiomyopathy. AB - There has been increasing evidence that chronic immune activation plays critical roles in the pathogenesis of DCM. CD4(+) LAP(+) Tregs are a newly identified T cell subset with suppressive function on the immune response. This study was designed to investigate whether the circulating frequency and function of CD4(+)LAP(+) Tregs would be impaired in patients with DCM. The results demonstrated that DCM patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs compared with control donors. CD4(+)LAP(+) Tregs from DCM patients showed compromised function to suppress proliferation of CD4(+) LAP( )CD25(int/low) T cells and proliferation and IgG production of B cells. Moreover, B cell proliferation and IgG subset production could be directly suppressed by CD4(+) LAP(+) Tregs. TGF-beta and contact-dependent mechanisms were involved in CD4(+)LAP(+) Treg-mediated suppression. Correlation analysis suggested that CD4(+)LAP(+) Treg frequency was positively correlated with LVEF and negatively correlated with serum IgG3 and NT-proBNP concentration in patients with DCM. Our results are the first to demonstrate that the frequencies of CD4(+)LAP(+) Tregs in patients with DCM are reduced and that their suppressive function is compromised. Defective CD4(+) LAP(+) Tregs may be an underlying mechanism of immune activation in DCM patients. PMID- 25722320 TI - PLCzeta or PAWP: revisiting the putative mammalian sperm factor that triggers egg activation and embryogenesis. AB - In mammals, egg activation is initiated by multiple cytosolic Ca(2+) transients (Ca(2+) oscillations) that are triggered following delivery of a putative sperm factor from the fertilizing sperm. The identity of this 'sperm factor' thus holds much significance, not only as a vital component in creating a new life, but also for its potential therapeutic and diagnostic value in human infertility. Recent data have emerged suggesting the sperm factor may be a post-acrosomal sheath WW domain-binding protein (PAWP). However, a significant body of research points to a testis-specific phospholipase C zeta (PLCzeta) as the sperm factor. Herein, we examine the evidence presented in favour of PAWP in relation to PLCzeta and the requisite physiological properties of the mammalian sperm factor. PMID- 25722318 TI - Targeting the androgen receptor in prostate and breast cancer: several new agents in development. AB - Prostate cancer (PCa) and breast cancer (BCa) share similarities as hormone sensitive cancers with a wide heterogeneity of both phenotype and biology. The androgen receptor (AR) is a hormone receptor involved in both benign and malignant processes. Targeting androgen synthesis and the AR pathway has been and remains central to PCa therapy. Recently, there has been increased interest in the role of the AR in BCa development and growth, with results indicating AR co expression with estrogen, progesterone, and human epidermal growth factor receptors, across all intrinsic subtypes of BCa. Targeting the AR axis is an evolving field with novel therapies in development which may ultimately be applicable to both tumor types. In this review, we offer an overview of available agents which target the AR axis in both PCa and BCa and provide insights into the novel drugs in development for targeting this signaling pathway. PMID- 25722322 TI - BVA presents its strategic plan for the next three years. PMID- 25722321 TI - Integrated approach to early detection of cardiovascular toxicity induced by a ghrelin receptor agonist. AB - Cardiovascular (CV) safety concerns are among the leading causes of compound attrition in drug development. This work describes a strategy of applying novel end points to a 7-day rodent study to increase the opportunity to detect and characterize CV injury observed in a longer term (ie, 28 days) study. Using a ghrelin receptor agonist (GSK894281), a compound that produces myocardial degeneration/necrosis in rats after 28 days at doses of 0.3, 1, 10, or 60 mg/kg/d, we dosed rats across a range of similar doses (0, 0.3, 60, or 150 mg/kg/d) for 7 days to determine whether CV toxicity could be detected in a shorter study. End points included light and electron microscopies of the heart; heart weight; serum concentrations of fatty acid-binding protein 3 (FABP3), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and N-terminal proatrial natriuretic peptide (NT-proANP); and a targeted transcriptional assessment of heart tissue. Histologic evaluation revealed a minimal increase in the incidence and/or severity of cardiac necrosis in animals administered 150 mg/kg/d. Ultrastructurally, mitochondrial membrane whorls and mitochondrial degeneration were observed in rats given 60 or 150 mg/kg/d. The FABP3 was elevated in rats given 150 mg/kg/d. Cardiac transcriptomics revealed evidence of mitochondrial dysfunction coincident with histologic lesions in the heart, and along with the ultrastructural results support a mechanism of mitochondrial injury. There were no changes in cTnI, cTnT, NT-proANP, or heart weight. In summary, enhancing a study design with novel end points provides a more integrated evaluation in short term repeat dose studies, potentially leading to earlier nonclinical detection of structural CV toxicity. PMID- 25722323 TI - RCVS commits L1 million to mental health and wellbeing initiative. PMID- 25722324 TI - Welsh Government to consult further on compulsory microchipping of dogs. PMID- 25722325 TI - All veterinary nurses now regulated as RCVS Royal Charter comes into effect. PMID- 25722327 TI - Encouraging researchers at an early stage of their careers. PMID- 25722328 TI - Next phase of distance learning project begins. PMID- 25722329 TI - Mapping antibiotic resistance around the UK. PMID- 25722330 TI - Budding equine vets hone their skills and knowledge. AB - One hundred and fifty 'equine enthusiast' veterinary students gathered at Bristol veterinary school's Langford campus earlier this month for a national student equine veterinary symposium. A wide-ranging programme of lectures, practicals and seminars gave participants an opportunity to learn from some of the most experienced equine clinicians in the UK. Lorna Sowerbutts, vice-president of the Bristol Equine Veterinary Society, reports. PMID- 25722331 TI - Application for restoration to the RCVS Register refused. PMID- 25722332 TI - Views sought on plans to change the way TB statistics are reported. PMID- 25722333 TI - Fresh LEGS for emergencies. PMID- 25722334 TI - Endemic zoonoses in the tropics: a public health problem hiding in plain sight. AB - Zoonotic diseases are a significant burden on animal and human health, particularly in developing countries. Despite recognition of this fact, endemic zoonoses often remain undiagnosed in people, instead being mistaken for febrile diseases such as malaria. Here, as part of Veterinary Record's ongoing series of articles on One Health, a multidisciplinary team of researchers from Scotland, Tanzania and New Zealand argues that a One Health approach is needed to effectively combat these diseases. PMID- 25722335 TI - Benzalkonium chloride intoxication in cats. PMID- 25722336 TI - Postcards during World War I. PMID- 25722337 TI - One swallow makes a runner. PMID- 25722338 TI - Increase in canine leptospirosis cases. PMID- 25722339 TI - RCVS funding for health support programme. PMID- 25722340 TI - Role of vets in abattoirs. PMID- 25722341 TI - Managing customer service. AB - Zoe Paget is the customer services manager at YourVets. Her role includes managing the company's call centre, social media marketing, working with the marketing department to develop customer care initiatives and reporting service levels to the company's directors. PMID- 25722342 TI - Diary of a parliamentary intern. AB - Hannah Jordan, parliamentary intern to Lord Trees, is in thoughtful mood as she reflects on February's events, both personal and professional. PMID- 25722344 TI - Just-in-Time Compound Pooling Increases Primary Screening Capacity without Compromising Screening Quality. AB - Compound pooling, or multiplexing more than one compound per well during primary high-throughput screening (HTS), is a controversial approach with a long history of limited success. Many issues with this approach likely arise from long-term storage of library plates containing complex mixtures of compounds at high concentrations. Due to the historical difficulties with using multiplexed library plates, primary HTS often uses a one-compound-one-well approach. However, as compound collections grow, innovative strategies are required to increase the capacity of primary screening campaigns. Toward this goal, we have developed a novel compound pooling method that increases screening capacity without compromising data quality. This method circumvents issues related to the long term storage of complex compound mixtures by using acoustic dispensing to enable "just-in-time" compound pooling directly in the assay well immediately prior to assay. Using this method, we can pool two compounds per well, effectively doubling the capacity of a primary screen. Here, we present data from pilot studies using just-in-time pooling, as well as data from a large >2-million compound screen using this approach. These data suggest that, for many targets, this method can be used to vastly increase screening capacity without significant reduction in the ability to detect screening hits. PMID- 25722345 TI - Reconfiguring phosphorylation signaling by genetic polymorphisms affects cancer susceptibility. AB - Large-scale sequencing has characterized an enormous number of genetic variations (GVs), and the functional analysis of GVs is fundamental to understanding differences in disease susceptibility and therapeutic response among and within populations. Using a combination of a sequence-based predictor with known phosphorylation and protein-protein interaction information, we computationally detected 9606 potential phosSNPs (phosphorylation-related single nucleotide polymorphisms), including 720 known, disease-associated SNPs that dramatically modify the human phosSNP-associated kinase-substrate network. Further analyses demonstrated that the proteins in the network are heavily associated in various signaling and cancer pathways, while cancer genes and drug targets are significantly enriched. We re-constructed four population-specific kinase substrate networks and found that several inherited disease or cancer genes, such as IRS1, RAF1, and EGFR, were differentially regulated by phosSNPs. Thus, phosSNPs may influence disease susceptibility and be involved in cancer development by reconfiguring phosphorylation networks in different populations. Moreover, by systematically characterizing potential phosphorylation-related cancer mutations (phosCMs) in 12 types of cancers, we observed that both types of GVs preferentially occur in the known cancer genes, while a considerable number of phosphorylated proteins, especially those over-representing cancer genes, contain both phosSNPs and phosCMs. Furthermore, it was observed that phosSNPs were significantly enriched in amplification genes identified from breast cancers and tyrosine kinase circuits of lung cancers. Taken together, these results should prove helpful for further elucidation of the functional impacts of disease associated SNPs. PMID- 25722343 TI - Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice. AB - Lipin proteins (lipin 1, 2, and 3) regulate glycerolipid homeostasis by acting as phosphatidic acid phosphohydrolase (PAP) enzymes in the TG synthesis pathway and by regulating DNA-bound transcription factors to control gene transcription. Hepatic PAP activity could contribute to hepatic fat accumulation in response to physiological and pathophysiological stimuli. To examine the role of lipin 1 in regulating hepatic lipid metabolism, we generated mice that are deficient in lipin-1-encoded PAP activity in a liver-specific manner (Alb-Lpin1(-/-) mice). This allele of lipin 1 was still able to transcriptionally regulate the expression of its target genes encoding fatty acid oxidation enzymes, and the expression of these genes was not affected in Alb-Lpin1(-/-) mouse liver. Hepatic PAP activity was significantly reduced in mice with liver-specific lipin 1 deficiency. However, hepatocytes from Alb-Lpin1(-/-) mice had normal rates of TG synthesis, and steady-state hepatic TG levels were unaffected under fed and fasted conditions. Furthermore, Alb-Lpin1(-/-) mice were not protected from intrahepatic accumulation of diacylglycerol and TG after chronic feeding of a diet rich in fat and fructose. Collectively, these data demonstrate that marked deficits in hepatic PAP activity do not impair TG synthesis and accumulation under acute or chronic conditions of lipid overload. PMID- 25722346 TI - Gammaherpesviruses and canine lymphoma: no evidence for direct involvement in commonly occurring lymphomas. AB - Lymphoma is the most common haematopoietic malignancy in dogs, but little is known about the aetiology of this heterogeneous group of cancers. In humans, the Epstein-Barr virus (EBV) is associated with several lymphoma subtypes. Recently, it was suggested that EBV or an EBV-like virus is circulating in dogs. We therefore investigated whether EBV, or a novel herpesvirus, is associated with canine lymphoma using both serological and molecular techniques. In an assay designed to detect antibodies to EBV viral capsid antigens, 41 % of dogs were positive. Dogs with cancers, including lymphoma, were more frequently positive than controls, but no particular association with B-cell lymphoma was noted. EBV specific RNA and DNA sequences were not detected in lymphoma tissue by in situ hybridization or PCR, and herpesvirus genomes were not detected using multiple degenerate PCR assays with the ability to detect novel herpesviruses. We therefore found no evidence that herpesviruses are directly involved in common types of canine lymphoma although cannot exclude the presence of an EBV-like virus in the canine population. PMID- 25722347 TI - Cis- and cell-type-dependent trans-requirements for Lassa virus-like particle production. AB - Lassa virus (LASV) small zinc-finger protein (Z), which contains two L-domain motifs, plays a central role in virus budding. Here, we report that co-expression of glycoprotein (GPC) altered the requirements for cholesterol but not the L domains and host factor, Tsg101, for Z-induced virus-like particle (VLP) production. In particular, the cholesterol requirement for VLP production was cell-type-dependent. In addition, GPC was found to be important for co localization of Z with CD63, a late endosomal marker. We also found that the N terminal region (aa 3-10) of Z was critical for its myristoylation and VLP production. These findings will contribute to our understanding of LASV assembly and budding. PMID- 25722348 TI - Can clinical signs, clinicopathological findings and abdominal ultrasonography predict the site of histopathological abnormalities of the alimentary tract in cats? AB - OBJECTIVES: Many cats with gastrointestinal signs have coexisting abnormalities in the intestine, liver and pancreas. Investigations typically involve clinicopathological tests, diagnostic imaging and biopsy, either at coeliotomy or by non-invasive means. While exploratory coeliotomy enables all organs to be sampled simultaneously, it is invasive and might not be necessary. The aim of the current study was to assess the performance of preliminary clinical information in predicting the histopathological presence of abnormalities in alimentary tract organs in cats. METHODS: The records of 38 cats with alimentary tract signs, which had ultimately undergone exploratory coeliotomy and surgical biopsy, were reviewed. The clinical signs, clinicopathological findings, diagnostic imaging findings and histopathology results were reviewed. RESULTS: On histopathological analysis, lesions were detected in 29/37 (78%) liver biopsies, in 29/35 (83%) gastrointestinal biopsies and in 17/37 (46%) pancreatic samples, the majority of which were inflammatory in nature. Clinical signs were generally poor markers of the presence of lesions in the alimentary tract. Further, while liver enzyme activity was relatively specific (88-100%) for detecting histopathological abnormalities in the liver, sensitivity was poor (11-50%). Pancreatic histopathological abnormalities were present in 1/3 of the cats with a positive pancreas-specific lipase result, and in 6/8 cats with a negative result. While relatively specific (57-100%) for both intestinal (57-100%) and hepatic (71-80%) histopathological abnormalities, abdominal ultrasonography lacked sensitivity for both organs (intestine 50-80%; liver 20-25%). In contrast, ultrasonography was relatively sensitive (50-80%), but not specific (17-22%) for detecting pancreatic lesions. CONCLUSIONS AND RELEVANCE: Clinical signs, and clinicopathological and ultrasonographic abnormalities lack precision for hepatic and pancreatic histopathological lesions in cats with alimentary tract signs, and cannot reliably predict from which organs biopsies should be collected. Arguably, therefore, exploratory coeliotomy is necessary to determine the site of histopathological abnormalities in feline alimentary tract disorders. PMID- 25722349 TI - The Modified Telephone Interview for Cognitive Status is More Predictive of Memory Abilities Than the Mini-Mental State Examination. AB - Although not as popular as the Mini-Mental State Examination (MMSE), the modified Telephone Interview for Cognitive Status (mTICS) has some distinct advantages when screening cognitive functioning in older adults. The current study compared these 2 cognitive screening measures in their ability to predict performance on a memory composite (ie, delayed recall of verbal and visual information) in a cohort of 121 community-dwelling older adults, both at baseline and after 1 year. Both the MMSE and the mTICS significantly correlated with the memory composite at baseline (r's of .41 and .62, respectively) and at 1 year (r's of .36 and .50, respectively). At baseline, stepwise linear regression indicated that the mTICS and gender best predicted the memory composite score (R (2) = .45, P < .001), and the MMSE and other demographic variables did not significantly improve the prediction. At 1 year, the results were very similar. Despite its lesser popularity, the mTICS may be a more attractive option when screening for cognitive abilities in this age range. PMID- 25722351 TI - Happy (belated) anniversary, Helsinki. PMID- 25722350 TI - Statin use and risk of primary liver cancer in the Clinical Practice Research Datalink. AB - BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely prescribed to reduce cholesterol levels. Studies have suggested that statins are associated with reduced risk of liver cancer, but much of the evidence is from regions of the world with high liver cancer incidence rates. The current study examined the statins-liver cancer relationship in a low-rate region and examined the effects of preexisting liver disease and diabetes on that association. METHODS: A nested case-control study was conducted within the United Kingdom's Clinical Practice Research Datalink (CPRD). Persons diagnosed with primary liver cancer between 1988 and 2011 were matched to controls at a four-to one ratio. Matches stratified on liver disease and on diabetes were also completed. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations of statins with liver cancer were estimated using conditional logistic regression. RESULTS: In total, 1195 persons with primary liver cancer were matched to 4640 control patients. Statin use was associated with a statistically significantly reduced risk of liver cancer (ORadj = 0.55, 95% CI = 0.45 to 0.69), especially among current users (ORadj = 0.53, 95% CI = 0.42 to 0.66). The reduced risk was statistically significant in the presence (ORadj = 0.32, 95% CI = 0.17 to 0.57) and absence of liver disease (ORadj = 0.65, 95% CI = 0.52 to 0.81) and in the presence (ORadj = 0.30, 95% CI = 0.21 to 0.42) and absence of diabetes (ORadj = 0.66, 95% CI = 0.51 to 0.85). CONCLUSIONS: In the current study in a low rate area, statin use was associated with a statistically significantly reduced risk of liver cancer overall. Risk was particularly reduced among persons with liver disease and persons with diabetes, suggesting that statin use may be especially beneficial in persons at elevated risk of liver cancer. PMID- 25722352 TI - Activity tolerance after periacetabular osteotomy: letter to the editor. PMID- 25722353 TI - "Hidden lesions" of the extra-articular biceps after subpectoral biceps tenodesis: letter to the editor. PMID- 25722354 TI - "Hidden lesions" of the extra-articular biceps after subpectoral biceps tenodesis: response. PMID- 25722355 TI - Twenty-five years of breast cancer risk models and their applications. PMID- 25722356 TI - Survey of Italian human milk banks. AB - BACKGROUND: At present, the Italian Association of Donor Human Milk Banks (Associazione Italiana Banche del Latte Umano Donato, AIBLUD) consists of 31 milk banks, whose management is based on Italian Guidelines. In 2013, AIBLUD performed a systematic survey to collect data on the activities of banks operating in Italy in the years previous to this date. OBJECTIVE: The purpose of this survey was to evaluate the operational procedures of Italian Human Milk Banks in order to identify both areas of strength and room for improvement. METHODS: A questionnaire was utilized to obtain national data from the 28 banks active in the year 2012 in order to evaluate the number of donors, volume of human milk collected, and other information relating to the period 2007 to 2012. RESULTS: In all, 89% of the banks (25/28) responded to the survey. Data received primarily concerned the number of donors, volume of milk collected, and average amount of milk from each donor in the period 2007 to 2012. It was evident that in 2012 human milk banks collected a higher volume of milk than in 2007. Further, the average amount of milk from each donor was higher. Most of the milk banks were following the Italian Guidelines for traceability, control of donors, bacteriological checks, method of pasteurization, storage, thawing, type of containers, and utilization of the Hazard Analysis and Critical Control Points system. CONCLUSION: This survey identified both areas of strength and room for improvement in the Italian human milk banks. PMID- 25722357 TI - Evidence-based medicine and osteopathic medicine: no paradox. PMID- 25722358 TI - Professionalism score and academic performance: with objective measures of professionalism, do we measure what we want to measure? PMID- 25722359 TI - Osteopathic manipulative treatment use in the emergency department: a retrospective medical record review. AB - CONTEXT: Although the use of osteopathic manipulative treatment (OMT) appears to be declining, data on the use of OMT in the emergency department (ED) are not available. OBJECTIVE: To determine the quantity and characteristics of OMT performed in a single, community academic ED that houses an osteopathic emergency medicine residency. DESIGN: Retrospective medical record review. SETTING: A single large community academic ED with an osteopathic emergency medicine residency from July 14, 2005, to March 4, 2013. PARTICIPANTS: Patients in the ED who received OMT (N=2076). MAIN OUTCOME MEASURES: Medical record data were analyzed to determine patient demographics; treatment characteristics including number of procedures and patients per physician, OMT techniques used, night vs day procedure variation, and financial implication of future billing for OMT; chief complaints; primary discharge diagnoses; and length of stay in the ED. RESULTS: Patients were aged 0 to 95 years (mean, 39 years) and were predominately female (1260 [60.69%]) and white (1300 [62.62%]). A mean of 0.74 patients received OMT per day, and a mean of 29.65 procedures were performed per physician. When data for residents were looked at separately, the mean was higher at 40.32 procedures per physician. The top 3 discharge diagnoses were low back pain (189 patients [9.10%]), muscle spasm (106 patients [5.11%]), and spasm: muscle, back (93 patients [4.48%]). Eleven different OMT techniques were recorded, with myofascial release being used most frequently (1150 of 2868 procedures [40.09%]), followed by muscle energy (672 [23.43%]). The average length of stay in the ED was 206 minutes. A total of 1663 OMT procedures (80%) were performed during the day, whereas 413 (20%) were performed at night. Potential procedural billing for all OMT performed during the study period was $33.09 per day. CONCLUSION: In contrast to perceptions that OMT use is declining, the authors found that OMT is being performed on a near daily basis in the ED. Additional research is needed to fully understand the impact of OMT in the ED. PMID- 25722360 TI - Effectiveness of osteopathic manipulative treatment for carpal tunnel syndrome: a pilot project. AB - CONTEXT: Osteopathic manipulative treatment (OMT) has been recognized as a management option for carpal tunnel syndrome (CTS), although limited research exists to substantiate its effectiveness. OBJECTIVE: To evaluate the effectiveness of OMT in the management of CTS. METHODS: This single-blinded quasi controlled trial was conducted at an academic institution. Participants with CTS underwent weekly OMT sessions for 6 consecutive weeks. The main outcome measures were the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ), a sensory symptom diagram (SSD), patient estimate of overall change, electrophysiologic testing of the median nerve (trans-carpal tunnel motor and sensory nerve conduction velocity and amplitude ratio), and carpal tunnel ultrasound imaging of the cross-sectional area of the median nerve and transverse carpal ligament length and bowing. All outcome measures were administered to participants before the first OMT session. Immediately after the first session, electrophysiologic testing of the median nerve and ultrasound imaging of the carpal tunnel were repeated. After 6 weeks of OMT, all outcome measures were readministered. RESULTS: Results of the BCTQ revealed statistically significant improvements in symptoms and function after 6 weeks of OMT (F=11.0; P=.004), and the improvements tended to be more pronounced on the treated side. The drop in SSD scores after 6 weeks of treatment was statistically significant (F=4.19; P=.0002). Patient estimate of overall improvement of symptoms was statistically significant for the treated side. No statistically significant changes in electrophysiologic function of the median nerve, cross-sectional area of the median nerve, or transverse carpal ligament bowing were observed. After treatment, the increase in transverse carpal ligament length was statistically significant, but no side-to-side difference was detected. CONCLUSION: Osteopathic manipulative treatment resulted in patient perceived improvement in symptoms and function associated with CTS. However, median nerve function and morphology at the carpal tunnel did not change, possibly indicating a different mechanism by which OMT acted, such as central nervous system processes. PMID- 25722361 TI - Adult-acquired hidden penis in obese patients: a critical survey of the literature. AB - CONTEXT: Hidden penis is anatomically defined by a lack of firm attachments of the skin and dartos fascia to the underlying Buck fascia. OBJECTIVE: To critically appraise the research evidence that could support the most effective surgical techniques for adult-acquired hidden penis in obese patients. METHODS: Studies investigating patients with a diagnosis of hidden penis were identified. Of these studies, only those with adult patients classified as overweight or obese (body mass index >25) were included in the review. Three reviewers examined the abstracts of the studies identified in the initial Medline search, and abstracts considered potentially relevant underwent full-text review. Studies that included patients with congenital, iatrogenic (eg, circumcision issues or aesthetic genital surgery), or traumatic causes of hidden penis were excluded. Studies that did not define the diagnostic criteria for hidden penis were excluded to minimize the risk of definition bias. The quality of evidence for each study was determined after considering the following sources of bias: method of allocation to study groups, data analysis, presence of baseline differences between groups, objectivity of outcome, and completeness of follow-up. Using these criteria, studies were then graded as high, moderate, or low in quality. RESULTS: Seven studies with a total of 119 patients met the inclusion criteria. All but 1 of the studies were nonrandomized. One study provided a clear presentation of results and appropriate statistical analysis. Six studies accounted for individual-based differences, and 1 study failed to account for baseline differences altogether. Four studies addressed follow-up. One study was of high quality, 2 were of moderate quality, and 4 were of low quality. CONCLUSION: Building a clinical practice guideline for the surgical management of hidden penis has proven difficult because of a lack of high-quality, statistically significant data in the research synthesis. The authors elucidate the challenges and epitomize the collective wisdom of surgeons who have investigated this problem and emphasize the need for rigorous evaluative studies. PMID- 25722362 TI - Osteopathic medical students' understanding of the Patient Protection and Affordable Care Act: a first step toward a policy-informed curriculum. AB - CONTEXT: Current osteopathic medical students will play an important role in implementing, modifying, and advocating for or against the Patient Protection and Affordable Care Act (ACA) of 2010. Accordingly, medical educators will need to address curricular gaps specific to the ACA and medical practice. Research that gauges osteopathic medical students' level of understanding of the ACA is needed to inform an evidence-based curriculum. OBJECTIVE: To assess first- and second year osteopathic medical students' beliefs about the ACA. METHODS: In this descriptive cross-sectional survey-based study, first- and second-year students were recruited because their responses would be indicative of what, if any, information about the ACA was being covered in the preclinical curriculum. A 30 item survey was distributed in November 2013, after the health insurance exchanges launched on October 1, 2013. RESULTS: A total of 239 first- and second year osteopathic medical students completed the survey. One hundred ten students (46%) disagreed and 103 (43.1%) agreed that the ACA would provide health insurance coverage for all US citizens. The ACA was predicted to lead to lower wages and fewer jobs (73 students [30.5%]), as well as small business bankruptcy because of employees' health insurance costs (96 [40.2%]). Regarding Medicare recipients, 113 students (47.3%) did not know whether these individuals would be required to buy insurance through the health insurance exchanges. The majority of students knew that the ACA would require US citizens to pay a penalty if they did not have health insurance (198 [82.8%]) and understood that not everyone would be required to purchase health insurance through health insurance exchanges (137 [57.3%]). Although students took note of certain clinical benefits for patients offered by the ACA, they remained concerned about the ACA's impact on their professional prospects, particularly in the area of primary care. CONCLUSION: These findings build on the existing literature that emphasize the need for incorporating into the osteopathic medical curriculum knowledge of the dynamics of health care policy and reform and for creating opportunities for students to follow health policy developments as they evolve in real time. PMID- 25722363 TI - Postoperative singultus: an osteopathic approach. AB - Singultus, or hiccups, is a common medical condition. Despite exponential leaps in medicine, the pathophysiologic cause remains poorly defined. Persistent singultus has been associated with conditions such as pulmonary embolism and myocardial infarction. Singultus is also a well-known postoperative complication. The criterion standard of care for patients with singultus involves ruling out lethal pathologic causes, attempting physical stimulation with Valsava maneuvers or drinking water, and, if no relief has been achieved, administering drugs to ease the symptoms. The authors report a case of a man whose postoperative singultus was successfully managed with osteopathic manipulative treatment. This approach addresses many of the possible underlying neuromechanical causes of the aberrant reflex with minimal potential for adverse effects. Physicians should consider osteopathic manipulative treatment in the care of patients with singultus. PMID- 25722364 TI - Disseminated herpes zoster. PMID- 25722365 TI - Urinary Angiotensinogen Level Predicts AKI in Acute Decompensated Heart Failure: A Prospective, Two-Stage Study. AB - A major challenge in prevention and early treatment of acute cardiorenal syndrome (CRS) is the lack of high-performance predictors. To test the hypothesis that urinary angiotensinogen (uAGT) is an early predictor for acute CRS and 1-year prognosis in patients with acute decompensated heart failure (ADHF), we performed a prospective, two-stage, multicenter cohort study in patients with ADHF. In stage I (test set), 317 patients were recruited from four centers. In stage II (validation set), 119 patients were enrolled from two other centers. Daily uAGT levels were analyzed consecutively. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. In stage I, 104 (32.8%) patients developed AKI during hospitalization. Daily uAGT peaked on the first hospital day in patients who subsequently developed AKI. After multivariable adjustment, the highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared with the lowest quartile. For predicting AKI, uAGT (area under the receiver-operating characteristic curve [AUC]=0.84) outperformed urinary neutrophil gelatinase associated lipocalin (AUC=0.78), the urinary albumin/creatinine ratio (AUC=0.71), and the clinical model (AUC=0.77). Survivors in stage I were followed prospectively for 1 year after hospital discharge. The uAGT level independently predicted the risk of 1-year mortality (adjusted odds ratio, 4.5; 95% confidence interval, 2.1 to 9.5) and rehospitalization (adjusted odds ratio, 3.6; 95% confidence interval, 1.6 to 5.7). The ability of uAGT in predicting AKI was validated in stage II (AUC=0.79). In conclusion, uAGT is a strong predictor for acute CRS and 1-year prognosis in ADHF. PMID- 25722366 TI - Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis. AB - BACKGROUND: Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVES: To investigate the frequency of CV risks in patients with MS and their association with MRI outcomes. METHODS: In a prospective study, 326 patients with relapsing remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status. RESULTS: Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed >= 2 CV risks (p = 0.003), while the frequency of >= 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS. CONCLUSIONS: Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy. PMID- 25722367 TI - Dissecting the role of the phi29 terminal protein DNA binding residues in viral DNA replication. AB - Phage phi29 DNA replication takes place by a protein-priming mechanism in which the viral DNA polymerase catalyses the covalent linkage of the initiating nucleotide to a specific serine residue of the terminal protein (TP). The N terminal domain of the phi29 TP has been shown to bind to the host DNA in a sequence-independent manner and this binding is essential for the TP nucleoid localisation and for an efficient viral DNA replication in vivo. In the present work we have studied the involvement of the TP N-terminal domain residues responsible for DNA binding in the different stages of viral DNA replication by assaying the in vitro activity of purified TP N-terminal mutant proteins. The results show that mutation of TP residues involved in DNA binding affects the catalytic activity of the DNA polymerase in initiation, as the Km for the initiating nucleotide is increased when these mutant proteins are used as primers. Importantly, this initiation defect was relieved by using the phi29 double-stranded DNA binding protein p6 in the reaction, which decreased the Km of the DNA polymerase for dATP about 130-190 fold. Furthermore, the TP N-terminal domain was shown to be required both for a proper interaction with the DNA polymerase and for an efficient viral DNA amplification. PMID- 25722368 TI - SC3-seq: a method for highly parallel and quantitative measurement of single-cell gene expression. AB - Single-cell mRNA sequencing (RNA-seq) methods have undergone rapid development in recent years, and transcriptome analysis of relevant cell populations at single cell resolution has become a key research area of biomedical sciences. We here present single-cell mRNA 3-prime end sequencing (SC3-seq), a practical methodology based on PCR amplification followed by 3-prime-end enrichment for highly quantitative, parallel and cost-effective measurement of gene expression in single cells. The SC3-seq allows excellent quantitative measurement of mRNAs ranging from the 10,000-cell to 1-cell level, and accordingly, allows an accurate estimate of the transcript levels by a regression of the read counts of spike-in RNAs with defined copy numbers. The SC3-seq has clear advantages over other typical single-cell RNA-seq methodologies for the quantitative measurement of transcript levels and at a sequence depth required for the saturation of transcript detection. The SC3-seq distinguishes four distinct cell types in the peri-implantation mouse blastocysts. Furthermore, the SC3-seq reveals the heterogeneity in human-induced pluripotent stem cells (hiPSCs) cultured under on feeder as well as feeder-free conditions, demonstrating a more homogeneous property of the feeder-free hiPSCs. We propose that SC3-seq might be used as a powerful strategy for single-cell transcriptome analysis in a broad range of investigations in biomedical sciences. PMID- 25722369 TI - RNAe: an effective method for targeted protein translation enhancement by artificial non-coding RNA with SINEB2 repeat. AB - In this study, a universal protein expression enhancement RNA tool, termed RNAe, was developed by modifying a recently discovered natural long non-coding RNA. At the moment, RNAe is the only technology for gene expression enhancement, as opposed to silencing, at the post-transcriptional level. With this technology, an expression enhancement of 50-1000% is achievable, with more than 200% enhancement achieved in most cases. This work identified the sufficient and necessary element for RNAe function, which was found to be merely 300 nucleotides long and was named minRNAe. It contains a 72-nt 5' pairing sequence which determines the specificity, a 167-nt short non-pairing interspersed nuclear element (SINE) B2 sequence which enhances ribosome recruitment to the target mRNA, and a poly(A) tail, provided together on a plasmid bearing the appropriate sequences. Cellular delivery of RNAe was achieved using routine transfection. The RNAe platform was validated in several widely-used mammalian cell lines. It was proven to be efficient and flexible in specifically enhancing the expression of various endogenous and exogenous proteins of diverse functions in a dose-dependent manner. Compared to the expression-inhibitory tool RNAi, the RNAe tool has a comparable effect size, with an enhancing as opposed to inhibitory effect. One may predict that this brand new technology for enhancing the production of proteins will find wide applications in both research and biopharmaceutical production. PMID- 25722370 TI - The RNA helicase DDX6 regulates cell-fate specification in neural stem cells via miRNAs. AB - In neural stem cells (NSCs), the balance between stem cell maintenance and neuronal differentiation depends on cell-fate determinants such as TRIM32. Previously, we have shown that TRIM32 associates with the RNA-induced silencing complex and increases the activity of microRNAs such as Let-7a. However, the exact mechanism of microRNA regulation by TRIM32 during neuronal differentiation has yet to be elucidated. Here, we used a mass spectrometry approach to identify novel protein-protein interaction partners of TRIM32 during neuronal differentiation. We found that TRIM32 associates with proteins involved in neurogenesis and RNA-related processes, such as the RNA helicase DDX6, which has been implicated in microRNA regulation. We demonstrate, that DDX6 colocalizes with TRIM32 in NSCs and neurons and that it increases the activity of Let-7a. Furthermore, we provide evidence that DDX6 is necessary and sufficient for neuronal differentiation and that it functions in cooperation with TRIM32. PMID- 25722371 TI - DNA repair and recovery of RNA synthesis following exposure to ultraviolet light are delayed in long genes. AB - The kinetics of DNA repair and RNA synthesis recovery in human cells following UV irradiation were assessed using nascent RNA Bru-seq and quantitative long PCR. It was found that UV light inhibited transcription elongation and that recovery of RNA synthesis occurred as a wave in the 5'-3' direction with slow recovery and TC NER at the 3' end of long genes. RNA synthesis resumed fully at the 3'-end of genes after a 24 h recovery in wild-type fibroblasts, but not in cells deficient in transcription-coupled nucleotide excision repair (TC-NER) or global genomic NER (GG-NER). Different transcription recovery profiles were found for individual genes but these differences did not fully correlate to differences in DNA repair of these genes. Our study gives the first genome-wide view of how UV-induced lesions affect transcription and how the recovery of RNA synthesis of large genes are particularly delayed by the apparent lack of resumption of transcription by arrested polymerases. PMID- 25722372 TI - multiSNV: a probabilistic approach for improving detection of somatic point mutations from multiple related tumour samples. AB - Somatic variant analysis of a tumour sample and its matched normal has been widely used in cancer research to distinguish germline polymorphisms from somatic mutations. However, due to the extensive intratumour heterogeneity of cancer, sequencing data from a single tumour sample may greatly underestimate the overall mutational landscape. In recent studies, multiple spatially or temporally separated tumour samples from the same patient were sequenced to identify the regional distribution of somatic mutations and study intratumour heterogeneity. There are a number of tools to perform somatic variant calling from matched tumour-normal next-generation sequencing (NGS) data; however none of these allow joint analysis of multiple same-patient samples. We discuss the benefits and challenges of multisample somatic variant calling and present multiSNV, a software package for calling single nucleotide variants (SNVs) using NGS data from multiple same-patient samples. Instead of performing multiple pairwise analyses of a single tumour sample and a matched normal, multiSNV jointly considers all available samples under a Bayesian framework to increase sensitivity of calling shared SNVs. By leveraging information from all available samples, multiSNV is able to detect rare mutations with variant allele frequencies down to 3% from whole-exome sequencing experiments. PMID- 25722373 TI - Unraveling the mechanistic features of RNA polymerase II termination by the 5'-3' exoribonuclease Rat1. AB - Within a complex with Rai1, the 5'-3' exoribonuclease Rat1 promotes termination of RNA polymerase II (RNAPII) on protein-coding genes, but its underlying molecular mechanism is still poorly understood. Using in vitro transcription termination assays, we have found that RNAPII is prone to more effective termination by Rat1/Rai1 when its catalytic site is disrupted due to NTP misincorporation, implying that paused RNAPII, which is often found in vivo near termination sites, could adopt a similar configuration to Rat1/Rai1 and trigger termination. Intriguingly, yeast Rat1/Rai1 does not terminate Escherichia coli RNAP, implying that a specific interaction between Rat1/Rai1 and RNAPII may be required for termination. Furthermore, the efficiency of termination increases as the RNA transcript undergoing degradation by Rat1 gets longer, which suggests that Rat1 may generate a driving force for dissociating RNAPII from the template while degrading the nascent transcripts to catch up to the polymerase. These results indicate that multiple mechanistic features contribute to Rat1-mediated termination of RNAPII. PMID- 25722374 TI - Dynamic Escherichia coli SeqA complexes organize the newly replicated DNA at a considerable distance from the replisome. AB - The Escherichia coli SeqA protein binds to newly replicated, hemimethylated DNA behind replication forks and forms structures consisting of several hundred SeqA molecules bound to about 100 kb of DNA. It has been suggested that SeqA structures either direct the new sister DNA molecules away from each other or constitute a spacer that keeps the sisters together. We have developed an image analysis script that automatically measures the distance between neighboring foci in cells. Using this tool as well as direct stochastic optical reconstruction microscopy (dSTORM) we find that in cells with fluorescently tagged SeqA and replisome the sister SeqA structures were situated close together (less than about 30 nm apart) and relatively far from the replisome (on average 200-300 nm). The results support the idea that newly replicated sister molecules are kept together behind the fork and suggest the existence of a stretch of DNA between the replisome and SeqA which enjoys added stabilization. This could be important in facilitating DNA transactions such as recombination, mismatch repair and topoisomerase activity. In slowly growing cells without ongoing replication forks the SeqA protein was found to reside at the fully methylated origins prior to initiation of replication. PMID- 25722375 TI - Structural basis for recognition of G-1-containing tRNA by histidyl-tRNA synthetase. AB - Aminoacyl-tRNA synthetases (aaRSs) play a crucial role in protein translation by linking tRNAs with cognate amino acids. Among all the tRNAs, only tRNA(His) bears a guanine base at position -1 (G-1), and it serves as a major recognition element for histidyl-tRNA synthetase (HisRS). Despite strong interests in the histidylation mechanism, the tRNA recognition and aminoacylation details are not fully understood. We herein present the 2.55 A crystal structure of HisRS complexed with tRNA(His), which reveals that G-1 recognition is principally nonspecific interactions on this base and is made possible by an enlarged binding pocket consisting of conserved glycines. The anticodon triplet makes additional specific contacts with the enzyme but the rest of the loop is flexible. Based on the crystallographic and biochemical studies, we inferred that the uniqueness of histidylation system originates from the enlarged binding pocket (for the extra base G-1) on HisRS absent in other aaRSs, and this structural complementarity between the 5' extremity of tRNA and enzyme is probably a result of coevolution of both. PMID- 25722376 TI - Base-resolution methylation patterns accurately predict transcription factor bindings in vivo. AB - Detecting in vivo transcription factor (TF) binding is important for understanding gene regulatory circuitries. ChIP-seq is a powerful technique to empirically define TF binding in vivo. However, the multitude of distinct TFs makes genome-wide profiling for them all labor-intensive and costly. Algorithms for in silico prediction of TF binding have been developed, based mostly on histone modification or DNase I hypersensitivity data in conjunction with DNA motif and other genomic features. However, technical limitations of these methods prevent them from being applied broadly, especially in clinical settings. We conducted a comprehensive survey involving multiple cell lines, TFs, and methylation types and found that there are intimate relationships between TF binding and methylation level changes around the binding sites. Exploiting the connection between DNA methylation and TF binding, we proposed a novel supervised learning approach to predict TF-DNA interaction using data from base-resolution whole-genome methylation sequencing experiments. We devised beta-binomial models to characterize methylation data around TF binding sites and the background. Along with other static genomic features, we adopted a random forest framework to predict TF-DNA interaction. After conducting comprehensive tests, we saw that the proposed method accurately predicts TF binding and performs favorably versus competing methods. PMID- 25722377 TI - Downhill running and exercise in hot environments increase leukocyte Hsp72 (HSPA1A) and Hsp90alpha (HSPC1) gene transcripts. AB - Stressors within humans and other species activate Hsp72 and Hsp90alpha mRNA transcription, although it is unclear which environmental temperature or treadmill gradient induces the largest increase. To determine the optimal stressor for priming the Hsp system, physically active but not heat-acclimated participants (19.8 +/- 1.9 and 20.9 +/- 3.6 yr) exercised at lactate threshold in either temperate (20 degrees C, 50% relative humidity; RH) or hot (30 degrees C, 50% RH) environmental conditions. Within each condition, participants completed a flat running (temperate flat or hot flat) and a downhill running (temperate downhill or hot downhill) experimental trial in a randomized counterbalanced order separated by at least 7 days. Venous blood samples were taken immediately before (basal), immediately after exercise, and 3 and 24 h postexercise. RNA was extracted from leukocytes and RT-quantitative PCR conducted to determine Hsp72 and Hsp90alpha mRNA relative expression. Leukocyte Hsp72 mRNA was increased immediately after exercise following downhill running (1.9 +/- 0.9-fold) compared with flat running (1.3 +/- 0.4-fold; P = 0.001) and in hot (1.9 +/- 0.6-fold) compared with temperate conditions (1.1 +/- 0.5-fold; P = 0.003). Leukocyte Hsp90alpha mRNA increased immediately after exercise following downhill running (1.4 +/- 0.8-fold) compared with flat running (0.9 +/- 0.6-fold; P = 0.002) and in hot (1.6 +/- 1.0-fold) compared with temperate conditions (0.9 +/- 0.6-fold; P = 0.003). Downhill running and exercise in hot conditions induced the largest stimuli for leukocyte Hsp72 and Hsp90alpha mRNA increases. PMID- 25722378 TI - Change in weight and body composition in obese subjects following a hypocaloric diet plus different training programs or physical activity recommendations. AB - The aim of the present study was to compare the effects of different physical activity programs, in combination with a hypocaloric diet, on anthropometric variables and body composition in obese subjects. Ninety-six obese (men: n = 48; women: n = 48; age range: 18-50 yr) participated in a supervised 22-wk program. They were randomized into four groups: strength training (S; n = 24), endurance training (E; n = 26), combined strength + endurance training (SE; n = 24), and physical activity recommendations (C; n = 22). In addition, all groups followed the same hypocaloric diet. At baseline and at the end of the intervention, dietetic and physical activity variables were assessed using validated questionnaires. Anthropometric variables were recorded along with body composition variables measured using dual-energy X-ray absorptiometry techniques. At the end of the intervention, significant improvements were seen within groups in terms of body weight (S: -9.21 +/- 0.83 kg; E: -10.55 +/- 0.80 kg; SE: -9.88 +/- 0.85 kg; C: -8.69 +/- 0.89 kg), and total fat mass (S: -5.24 +/- 0.55%; E: 5.35 +/- 0.55%; SE: -4.85 +/- 0.56%; C: -4.89 +/- 0.59%). No differences were seen between groups at this time in terms of any other anthropometric or body composition variables examined. All groups increased their total physical activity in metabolic equivalents (MET) per week during the intervention, but with no difference between groups (S: 976 +/- 367 MET-min/wk; E: 954 +/- 355 MET min/wk; SE: 1 329 +/- 345 MET-min/wk; C: 763 +/- 410 MET-min/wk). This study shows that, when combined with a hypocaloric diet, exercise training and adherence to physical activity recommendations are equally effective at reducing body weight and modifying body composition in the treatment of obesity (Clinical Trials Gov. number: NCT01116856). PMID- 25722379 TI - Agent-based computational model investigates muscle-specific responses to disuse induced atrophy. AB - Skeletal muscle is highly responsive to use. In particular, muscle atrophy attributable to decreased activity is a common problem among the elderly and injured/immobile. However, each muscle does not respond the same way. We developed an agent-based model that generates a tissue-level skeletal muscle response to disuse/immobilization. The model incorporates tissue-specific muscle fiber architecture parameters and simulates changes in muscle fiber size as a result of disuse-induced atrophy that are consistent with published experiments. We created simulations of 49 forelimb and hindlimb muscles of the rat by incorporating eight fiber-type and size parameters to explore how these parameters, which vary widely across muscles, influence sensitivity to disuse induced atrophy. Of the 49 muscles modeled, the soleus exhibited the greatest atrophy after 14 days of simulated immobilization (51% decrease in fiber size), whereas the extensor digitorum communis atrophied the least (32%). Analysis of these simulations revealed that both fiber-type distribution and fiber-size distribution influence the sensitivity to disuse atrophy even though no single tissue architecture parameter correlated with atrophy rate. Additionally, software agents representing fibroblasts were incorporated into the model to investigate cellular interactions during atrophy. Sensitivity analyses revealed that fibroblast agents have the potential to affect disuse-induced atrophy, albeit with a lesser effect than fiber type and size. In particular, muscle atrophy elevated slightly with increased initial fibroblast population and increased production of TNF-alpha. Overall, the agent-based model provides a novel framework for investigating both tissue adaptations and cellular interactions in skeletal muscle during atrophy. PMID- 25722380 TI - Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study. AB - BACKGROUND: We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer. PATIENTS AND METHODS: A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone. RESULTS: Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt). CONCLUSIONS: In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients. PMID- 25722381 TI - A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)?. AB - BACKGROUND: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS: Eligible patients with histologically confirmed KRAS mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52 1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in >=20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01362296. PMID- 25722382 TI - Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. AB - BACKGROUND: Tecemotide is a MUC1-antigen-specific cancer immunotherapy. The phase III START study did not meet its primary end point but reported notable survival benefit with tecemotide versus placebo in an exploratory analysis of the predefined patient subgroup treated with concurrent chemoradiotherapy. Here, we attempted to gain further insight into the effects of tecemotide in START. PATIENTS AND METHODS: START recruited patients who did not progress following frontline chemoradiotherapy for unresectable stage III non-small-cell lung cancer. We present updated overall survival (OS) data and exploratory analyses of OS for baseline biomarkers: soluble MUC1 (sMUC1), antinuclear antibodies (ANA), neutrophil/lymphocyte ratio (NLR), lymphocyte count, and HLA type. RESULTS: Updated OS data are consistent with the primary analysis: median 25.8 months (tecemotide) versus 22.4 months (placebo) (HR 0.89, 95% CI 0.77-1.03, P = 0.111), with ~20 months additional median follow-up time compared with the primary analysis. Exploratory analysis of the predefined subgroup treated with concurrent chemoradiotherapy revealed clinically relevant prolonged OS with tecemotide versus placebo (29.4 versus 20.8 months; HR 0.81, 95% CI 0.68-0.98, P = 0.026). No improvement was seen with sequential chemoradiotherapy. High sMUC1 and ANA correlated with a possible survival benefit with tecemotide (interaction P = 0.0085 and 0.0022) and might have future value as biomarkers. Interactions between lymphocyte count, NLR, or prespecified HLA alleles and treatment effect were not observed. CONCLUSION: Updated OS data support potential treatment benefit with tecemotide in patients treated with concurrent chemoradiotherapy. Exploratory biomarker analyses suggest that elevated sMUC1 or ANA levels correlate with tecemotide benefit. CLINICALTRIALSGOV NUMBER: NCT00409188. PMID- 25722383 TI - Searching for targets for the systemic therapy of mesothelioma. AB - Malignant mesothelioma is an incurable disease associated with asbestos exposure arising in the pleural cavity and less frequently in the peritoneal cavity. Platinum-based combination chemotherapy with pemetrexed is the established standard of care. Multimodality approaches including surgery and radiotherapy are being investigated. Increasing knowledge about the molecular characteristics of mesothelioma had led to the identification of novel potential targets for systemic therapy. Current evidence suggests pathways activated in response to merlin deficiency, including Pi3K/mTOR and the focal adhesion kinase, as well as immunotherapeutic approaches to be most promising. This review elaborates on the rationale behind targeted approaches that have been and are undergoing exploration in mesothelioma and summarizes available clinical results and ongoing efforts to improve the systemic therapy of mesothelioma. PMID- 25722385 TI - Wider attention for GOF science. PMID- 25722384 TI - Structural and functional assessment of the brain in European Americans with mild to-moderate kidney disease: Diabetes Heart Study-MIND. AB - BACKGROUND: Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs). METHODS: A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2) and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education. RESULTS: Participants were 55.2% female, 78.2% had T2D; mean +/- SD age 67.6 +/- 9.0 years, T2D duration 16.4 +/- 6.5 years, eGFR 92.0 +/- 22.3 mL/min/1.73 m(2) and UACR 23.8 +/- 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (beta): -72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (beta: -1.0, P = 0.03) and UACR and normalized TWMLV (beta: -0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing. CONCLUSIONS: In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in EAs. PMID- 25722387 TI - Planetary science. Plumes on Europa tease NASA mission planners. PMID- 25722388 TI - Seismic risk. New jitters over megaquakes in Himalayas. PMID- 25722390 TI - Plant biology. Research at Kew overhauled for leaner times. PMID- 25722389 TI - Biosecurity. As new botulism threat implodes, more questions. PMID- 25722391 TI - Higher education. Japan looks to instill global mindset in grads. PMID- 25722392 TI - Line of attack. PMID- 25722393 TI - What's in a name? PMID- 25722394 TI - Plasma physics. Understanding particle acceleration in astrophysical plasmas. PMID- 25722395 TI - Anthropology. How wheat came to Britain. PMID- 25722396 TI - Virology. Delineating Ebola entry. PMID- 25722397 TI - Evolution. An unexpected cost of sex. PMID- 25722398 TI - Actuating materials. Shape-shifting liquid crystals. PMID- 25722399 TI - Plant science. Insecticidal RNA, the long and short of it. PMID- 25722400 TI - Climate change. Why the Pacific is cool. PMID- 25722401 TI - Sustainability. Prediction, precaution, and policy under global change. PMID- 25722402 TI - Reindeer Ewenki's fading culture. PMID- 25722403 TI - Genetic privacy: trust is not enough. PMID- 25722404 TI - Navigating Massive Open Online Courses. PMID- 25722405 TI - Water splitting. Metal-free efficient photocatalyst for stable visible water splitting via a two-electron pathway. AB - The use of solar energy to produce molecular hydrogen and oxygen (H2 and O2) from overall water splitting is a promising means of renewable energy storage. In the past 40 years, various inorganic and organic systems have been developed as photocatalysts for water splitting driven by visible light. These photocatalysts, however, still suffer from low quantum efficiency and/or poor stability. We report the design and fabrication of a metal-free carbon nanodot-carbon nitride (C3N4) nanocomposite and demonstrate its impressive performance for photocatalytic solar water splitting. We measured quantum efficiencies of 16% for wavelength lambda = 420 +/- 20 nanometers, 6.29% for lambda = 580 +/- 15 nanometers, and 4.42% for lambda = 600 +/- 10 nanometers, and determined an overall solar energy conversion efficiency of 2.0%. The catalyst comprises low cost, Earth-abundant, environmentally friendly materials and shows excellent stability. PMID- 25722406 TI - Plasma physics. Stochastic electron acceleration during spontaneous turbulent reconnection in a strong shock wave. AB - Explosive phenomena such as supernova remnant shocks and solar flares have demonstrated evidence for the production of relativistic particles. Interest has therefore been renewed in collisionless shock waves and magnetic reconnection as a means to achieve such energies. Although ions can be energized during such phenomena, the relativistic energy of the electrons remains a puzzle for theory. We present supercomputer simulations showing that efficient electron energization can occur during turbulent magnetic reconnection arising from a strong collisionless shock. Upstream electrons undergo first-order Fermi acceleration by colliding with reconnection jets and magnetic islands, giving rise to a nonthermal relativistic population downstream. These results shed new light on magnetic reconnection as an agent of energy dissipation and particle acceleration in strong shock waves. PMID- 25722407 TI - Surface chemistry. Probing the transition state region in catalytic CO oxidation on Ru. AB - Femtosecond x-ray laser pulses are used to probe the carbon monoxide (CO) oxidation reaction on ruthenium (Ru) initiated by an optical laser pulse. On a time scale of a few hundred femtoseconds, the optical laser pulse excites motions of CO and oxygen (O) on the surface, allowing the reactants to collide, and, with a transient close to a picosecond (ps), new electronic states appear in the O K edge x-ray absorption spectrum. Density functional theory calculations indicate that these result from changes in the adsorption site and bond formation between CO and O with a distribution of OC-O bond lengths close to the transition state (TS). After 1 ps, 10% of the CO populate the TS region, which is consistent with predictions based on a quantum oscillator model. PMID- 25722408 TI - Actuating materials. Voxelated liquid crystal elastomers. AB - Dynamic control of shape can bring multifunctionality to devices. Soft materials capable of programmable shape change require localized control of the magnitude and directionality of a mechanical response. We report the preparation of soft, ordered materials referred to as liquid crystal elastomers. The direction of molecular order, known as the director, is written within local volume elements (voxels) as small as 0.0005 cubic millimeters. Locally, the director controls the inherent mechanical response (55% strain) within the material. In monoliths with spatially patterned director, thermal or chemical stimuli transform flat sheets into three-dimensional objects through controlled bending and stretching. The programmable mechanical response of these materials could yield monolithic multifunctional devices or serve as reconfigurable substrates for flexible devices in aerospace, medicine, or consumer goods. PMID- 25722409 TI - Mosquito biology. Evolution of sexual traits influencing vectorial capacity in anopheline mosquitoes. AB - The availability of genome sequences from 16 anopheline species provides unprecedented opportunities to study the evolution of reproductive traits relevant for malaria transmission. In Anopheles gambiae, a likely candidate for sexual selection is male 20-hydroxyecdysone (20E). Sexual transfer of this steroid hormone as part of a mating plug dramatically changes female physiological processes intimately tied to vectorial capacity. By combining phenotypic studies with ancestral state reconstructions and phylogenetic analyses, we show that mating plug transfer and male 20E synthesis are both derived characters that have coevolved in anophelines, driving the adaptation of a female 20E-interacting protein that promotes oogenesis via mechanisms also favoring Plasmodium survival. Our data reveal coevolutionary dynamics of reproductive traits between the sexes likely to have shaped the ability of anophelines to transmit malaria. PMID- 25722410 TI - Climate change. Atlantic and Pacific multidecadal oscillations and Northern Hemisphere temperatures. AB - The recent slowdown in global warming has brought into question the reliability of climate model projections of future temperature change and has led to a vigorous debate over whether this slowdown is the result of naturally occurring, internal variability or forcing external to Earth's climate system. To address these issues, we applied a semi-empirical approach that combines climate observations and model simulations to estimate Atlantic- and Pacific-based internal multidecadal variability (termed "AMO" and "PMO," respectively). Using this method, the AMO and PMO are found to explain a large proportion of internal variability in Northern Hemisphere mean temperatures. Competition between a modest positive peak in the AMO and a substantially negative-trending PMO are seen to produce a slowdown or "false pause" in warming of the past decade. PMID- 25722411 TI - Pest control. Full crop protection from an insect pest by expression of long double-stranded RNAs in plastids. AB - Double-stranded RNAs (dsRNAs) targeted against essential genes can trigger a lethal RNA interference (RNAi) response in insect pests. The application of this concept in plant protection is hampered by the presence of an endogenous plant RNAi pathway that processes dsRNAs into short interfering RNAs. We found that long dsRNAs can be stably produced in chloroplasts, a cellular compartment that appears to lack an RNAi machinery. When expressed from the chloroplast genome, dsRNAs accumulated to as much as 0.4% of the total cellular RNA. Transplastomic potato plants producing dsRNAs targeted against the beta-actin gene of the Colorado potato beetle, a notorious agricultural pest, were protected from herbivory and were lethal to its larvae. Thus, chloroplast expression of long dsRNAs can provide crop protection without chemical pesticides. PMID- 25722412 TI - Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. AB - Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy. PMID- 25722413 TI - Archaeology. Sedimentary DNA from a submerged site reveals wheat in the British Isles 8000 years ago. AB - The Mesolithic-to-Neolithic transition marked the time when a hunter-gatherer economy gave way to agriculture, coinciding with rising sea levels. Bouldnor Cliff, is a submarine archaeological site off the Isle of Wight in the United Kingdom that has a well-preserved Mesolithic paleosol dated to 8000 years before the present. We analyzed a core obtained from sealed sediments, combining evidence from microgeomorphology and microfossils with sedimentary ancient DNA (sedaDNA) analyses to reconstruct floral and faunal changes during the occupation of this site, before it was submerged. In agreement with palynological analyses, the sedaDNA sequences suggest a mixed habitat of oak forest and herbaceous plants. However, they also provide evidence of wheat 2000 years earlier than mainland Britain and 400 years earlier than proximate European sites. These results suggest that sophisticated social networks linked the Neolithic front in southern Europe to the Mesolithic peoples of northern Europe. PMID- 25722414 TI - Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. AB - Reactivation of telomerase, the chromosome end-replicating enzyme, drives human cell immortality and cancer. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter occur at high frequency in multiple cancers, including urothelial cancer (UC), but their effect on telomerase function has been unclear. In a study of 23 human UC cell lines, we show that these promoter mutations correlate with higher levels of TERT messenger RNA (mRNA), TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and UC patient outcome, we find that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in two independent UC patient cohorts (n = 35; n = 87). These results suggest that high telomerase activity may be a better marker of aggressive UC tumors than TERT promoter mutations alone. PMID- 25722415 TI - Evolution. Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system. AB - A central process in evolution is the recruitment of genes to regulatory networks. We engineered immotile strains of the bacterium Pseudomonas fluorescens that lack flagella due to deletion of the regulatory gene fleQ. Under strong selection for motility, these bacteria consistently regained flagella within 96 hours via a two-step evolutionary pathway. Step 1 mutations increase intracellular levels of phosphorylated NtrC, a distant homolog of FleQ, which begins to commandeer control of the fleQ regulon at the cost of disrupting nitrogen uptake and assimilation. Step 2 is a switch-of-function mutation that redirects NtrC away from nitrogen uptake and toward its novel function as a flagellar regulator. Our results demonstrate that natural selection can rapidly rewire regulatory networks in very few, repeatable mutational steps. PMID- 25722417 TI - Follow your star. PMID- 25722416 TI - CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. AB - Polycomb and Trithorax group proteins encode the epigenetic memory of cellular positional identity by establishing inheritable domains of repressive and active chromatin within the Hox clusters. Here we demonstrate that the CCCTC-binding factor (CTCF) functions to insulate these adjacent yet antagonistic chromatin domains during embryonic stem cell differentiation into cervical motor neurons. Deletion of CTCF binding sites within the Hox clusters results in the expansion of active chromatin into the repressive domain. CTCF functions as an insulator by organizing Hox clusters into spatially disjoint domains. Ablation of CTCF binding disrupts topological boundaries such that caudal Hox genes leave the repressed domain and become subject to transcriptional activation. Hence, CTCF is required to insulate facultative heterochromatin from impinging euchromatin to produce discrete positional identities. PMID- 25722418 TI - Sustainability. Systems integration for global sustainability. AB - Global sustainability challenges, from maintaining biodiversity to providing clean air and water, are closely interconnected yet often separately studied and managed. Systems integration-holistic approaches to integrating various components of coupled human and natural systems-is critical to understand socioeconomic and environmental interconnections and to create sustainability solutions. Recent advances include the development and quantification of integrated frameworks that incorporate ecosystem services, environmental footprints, planetary boundaries, human-nature nexuses, and telecoupling. Although systems integration has led to fundamental discoveries and practical applications, further efforts are needed to incorporate more human and natural components simultaneously, quantify spillover systems and feedbacks, integrate multiple spatial and temporal scales, develop new tools, and translate findings into policy and practice. Such efforts can help address important knowledge gaps, link seemingly unconnected challenges, and inform policy and management decisions. PMID- 25722419 TI - A new look. PMID- 25722420 TI - The Society for Vascular Medicine: the first quarter century. AB - The Society for Vascular Medicine was founded in 1989. During the subsequent 25 years, the Society has grown to approximately 500 members and has achieved international recognition while making important contributions to vascular disease education, clinical vascular medicine and biology research, and patient care. In celebration of the Society's 25th anniversary, its past and current presidents reflect on the Society's history, challenges, and achievements, and emphasize the vital role of the SVM in the discipline of vascular medicine. PMID- 25722421 TI - Varicose veins. PMID- 25722422 TI - Corrigendum to Pseudoaneurysm of the dorsalis pedis artery following ankle arthroscopy. AB - The publishers would like to apologize for the following error which appeared in Pseudoaneurysm of the dorsalis pedis artery following ankle arthroscopy by Jung Nam Kwon, Seok Youn Lee and Yu Mi Kim, DOI : 10.1177/1358863X14557153, which was published in Vascular Medicine 2014, Vol. 19(6) 510-511. The year for the funding information was incorrect; it reads 2013 when it should be the following: FUNDING: This paper was supported by Wonkwang University in 2012. PMID- 25722425 TI - Interpretation of meta-analysis evaluating progression-free survival as a surrogate endpoint for overall survival in glioblastoma. PMID- 25722426 TI - Concise review: making and using clinically compliant pluripotent stem cell lines. AB - The field of pluripotent stem cells (PSCs) is in a state of dynamic flux driven by significant advances in the derivation of specific phenotypes from embryonic stem cells, breakthroughs in somatic cell nuclear transfer, and dramatic improvements in generating induced PSCs using zero footprint methods. Spurred by these technological advances, companies have begun to plan clinical studies using human PSC derivatives manufactured in current Good Manufacturing Practice compliant conditions. In the present review, we discuss the challenges in making these biological products, starting from tissue sourcing to the processes involved in manufacture, storage, and distribution. Additional challenges exist to meeting the regulatory requirements and keeping costs affordable. A model is described that has been proposed by the U.S. National Institutes of Health for reducing the costs and permitting flexibility and innovation by individual investigators. This model, combined with small adjustments in the regulatory processes tailored to address the unique properties of PSCs, has the potential of significantly accelerating the implementation of PSC-based cell therapy. PMID- 25722428 TI - Systemically delivered adipose stromal vascular fraction cells disseminate to peripheral artery walls and reduce vasomotor tone through a CD11b+ cell-dependent mechanism. AB - Vasoactivity, an important aspect of tissue healing, is often compromised in disease and tissue injury. Dysfunction in the smaller vasoactive arteries is most impactful, given the role of these vessels in controlling downstream tissue perfusion. The adipose stromal vascular fraction (SVF) is a mix of homeostatic cells shown to promote tissue healing. Our objective was to test the hypothesis that autologous SVF cells therapeutically modulate peripheral artery vasoactivity in syngeneic mouse models of small artery function. Analysis of vasoactivity of saphenous arteries isolated from normal mice 1 week after intravenous injection of freshly isolated SVF cells revealed that pressure-dependent artery vasomotor tone was decreased by the SVF cell isolate, but not one depleted of CD11b(+) cells. Scavenging hydrogen peroxide in the vessel wall abrogated the artery relaxation promoted by the SVF cell isolate. Consistent with a CD11b(+) cell being the relevant cell type, SVF-derived F4/80-positive macrophages were present within the adventitia of the artery wall coincident with vasorelaxation. In a model of artery inflammation mimicking a common disease condition inducing vasoactive dysfunction, the SVF cells potentiated relaxation of saphenous arteries without structurally remodeling the artery via a CD11b(+) cell-dependent manner. Our findings demonstrate that freshly isolated, adipose SVF cells promote vasomotor relaxation in vasoactive arteries via a hydrogen peroxide-dependent mechanism that required CD11b(+) cells (most likely macrophages). Given the significant impact of small artery dysfunction in disease, we predict that the intravenous delivery of this therapeutic cell preparation would significantly improve tissue perfusion, particularly in diseases with diffuse vascular involvement. PMID- 25722429 TI - Spatiotemporal expression dynamics of selectins govern the sequential extravasation of neutrophils and monocytes in the acute inflammatory response. AB - OBJECTIVE: Leukocyte recruitment to the site of inflammation is a key event in a variety of cardiovascular pathologies. Infiltrating neutrophils constitute the first line of defense that precedes a second wave of emigrating monocytes reinforcing the inflammatory reaction. The mechanisms initiating this sequential process remained largely obscure. APPROACH AND RESULTS: Using advanced in vivo microscopy and in vitro/ex vivo techniques, we identified individual spatiotemporal expression patterns of selectins and their principal interaction partners on neutrophils, resident/inflammatory monocytes, and endothelial cells. Coordinating the intraluminal trafficking of neutrophils and inflammatory monocytes to common sites of extravasation, selectins assign different sites to these immune cells for their initial interactions with the microvascular endothelium. Whereas constitutively expressed leukocyte L-selectin/CD62L and endothelial P-selectin/CD62P together with CD44 and P-selectin glycoprotein ligand-1/CD162 initiate the emigration of neutrophils, de novo synthesis of endothelial E-selectin/CD62E launches the delayed secondary recruitment of inflammatory monocytes. In this context, P-selectin/CD62P and L-selectin/CD62L together with P-selectin glycoprotein ligand-1/CD162 and CD44 were found to regulate the flux of rolling neutrophils and inflammatory monocytes, whereas E selectin/CD62E selectively adjusts the rolling velocity of inflammatory monocytes. Moreover, selectins and their interaction partners P-selectin glycoprotein ligand-1/CD162 and CD44 differentially control the intraluminal crawling behavior of neutrophils and inflammatory monocytes collectively enabling the sequential extravasation of these immune cells to inflamed tissue. CONCLUSIONS: Our findings provide novel insights into the mechanisms initiating the sequential infiltration of the perivascular tissue by neutrophils and monocytes in the acute inflammatory response and might thereby contribute to the development of targeted therapeutic strategies for prevention and treatment of cardiovascular diseases. PMID- 25722430 TI - Atheroma progression in hyporesponders to statin therapy. AB - OBJECTIVE: Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. APPROACH AND RESULTS: Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5 +/- 6.1 versus 30.3 +/- 5.9 kg/m(2); P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127 +/- 15 versus 132 +/- 17 mm Hg; P=0.01) and LDL-C (2.5 +/- 0.6 versus 3.4 +/- 0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9 +/- 9.8% versus 38.3 +/- 9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19 +/- 0.48% versus 0.09 +/- 0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83 +/- 0.58% versus -0.21 +/- 0.52%; P=0.006). CONCLUSIONS: A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy. PMID- 25722427 TI - Concise review: workshop review: understanding and assessing the risks of stem cell-based therapies. AB - The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new products. PMID- 25722431 TI - Vascular smooth muscle cells are responsible for a prothrombotic phenotype of spontaneously hypertensive rat arteries. AB - OBJECTIVE: The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. APPROACH AND RESULTS: We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12- but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl3-induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibalpha-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. CONCLUSIONS: The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibalpha-von Willebrand factor inhibitors. PMID- 25722432 TI - COX2 inhibition reduces aortic valve calcification in vivo. AB - OBJECTIVE: Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality, which affects ~1% of the US population and is characterized by calcific nodule formation and stenosis of the valve. Klotho deficient mice were used to study the molecular mechanisms of CAVD as they develop robust aortic valve (AoV) calcification. Through microarray analysis of AoV tissues from klotho-deficient and wild-type mice, increased expression of the gene encoding cyclooxygenase 2 (COX2; Ptgs2) was found. COX2 activity contributes to bone differentiation and homeostasis, thus the contribution of COX2 activity to AoV calcification was assessed. APPROACH AND RESULTS: In klotho-deficient mice, COX2 expression is increased throughout regions of valve calcification and is induced in the valvular interstitial cells before calcification formation. Similarly, COX2 expression is increased in human diseased AoVs. Treatment of cultured porcine aortic valvular interstitial cells with osteogenic media induces bone marker gene expression and calcification in vitro, which is blocked by inhibition of COX2 activity. In vivo, genetic loss of function of COX2 cyclooxygenase activity partially rescues AoV calcification in klotho-deficient mice. Moreover, pharmacological inhibition of COX2 activity in klotho-deficient mice via celecoxib-containing diet reduces AoV calcification and blocks osteogenic gene expression. CONCLUSIONS: COX2 expression is upregulated in CAVD, and its activity contributes to osteogenic gene induction and valve calcification in vitro and in vivo. PMID- 25722433 TI - Etv2 and fli1b function together as key regulators of vasculogenesis and angiogenesis. AB - OBJECTIVE: The E26 transformation-specific domain transcription factor Etv2/Etsrp/ER71 is a master regulator of vascular endothelial differentiation during vasculogenesis, although its later role in sprouting angiogenesis remains unknown. Here, we investigated in the zebrafish model a role for Etv2 and related E26 transformation-specific factors, Fli1a and Fli1b in developmental angiogenesis. APPROACH AND RESULTS: Zebrafish fli1a and fli1b mutants were obtained using transposon-mediated gene trap approach. Individual fli1a and fli1b homozygous mutant embryos display normal vascular patterning, yet the angiogenic recovery observed in older etv2 mutant embryos does not occur in embryos lacking both etv2 and fli1b. Etv2 and fli1b double-deficient embryos fail to form any angiogenic sprouts and show greatly increased apoptosis throughout the axial vasculature. In contrast, fli1a mutation did not affect the recovery of etv2 mutant phenotype. Overexpression analyses indicate that both etv2 and fli1b, but not fli1a, induce the expression of multiple vascular markers and of each other. Temporal inhibition of Etv2 function using photoactivatable morpholinos indicates that the function of Etv2 and Fli1b during angiogenesis is independent from the early requirement of Etv2 during vasculogenesis. RNA-Seq analysis and chromatin immunoprecipitation suggest that Etv2 and Fli1b share the same transcriptional targets and bind to the same E26 transformation-specific sites. CONCLUSIONS: Our data argue that there are 2 phases of early vascular development with distinct requirements of E26 transformation-specific transcription factors. Etv2 alone is required for early vasculogenesis, whereas Etv2 and Fli1b function redundantly during late vasculogenesis and early embryonic angiogenesis. PMID- 25722434 TI - MicroRNA-22 regulates smooth muscle cell differentiation from stem cells by targeting methyl CpG-binding protein 2. AB - OBJECTIVE: In this study, we attempted to uncover the functional impact of microRNA-22 (miR-22) and its target gene in smooth muscle cell (SMC) differentiation and delineate the molecular mechanism involved. APPROACH AND RESULTS: miR-22 was found to be significantly upregulated during SMC differentiation from embryonic stem cells and adventitia stem/progenitor cells. Enforced expression of miR-22 by its mimic, while knockdown of miR-22 by its antagomiR, promotes or inhibits SMC differentiation from embryonic stem cells and adventitia stem/progenitor cells, respectively. Expectedly, miR-22 overexpression in stem cells promoted SMC differentiation in vivo. Methyl CpG-binding protein 2 (MECP2) was predicted as one of the top targets of miR-22. Interestingly, the gene expression levels of MECP2 were significantly decreased during SMC differentiation, and MECP2 was dramatically decreased in miR-22 overexpressing cells but significantly increased when miR-22 was knockdown in the differentiating stem cells. Importantly, luciferase assay showed that miR-22 substantially inhibited wild-type, but not mutant MECP2-3' untranslated region luciferase activity. In addition, modulation of MECP2 expression levels affects multiple SMC-specific gene expression in differentiated embryonic stem cells. Mechanistically, our data showed that MECP2 could transcriptionally repress SMC gene expression through modulating various SMC transcription factors, as well as several proven SMC differentiation regulators. Evidence also revealed that enrichment of H3K9 trimethylation around the promoter regions of the SMC differentiation regulators genes were significantly increased by MECP2 overexpression. Finally, miR-22 was upregulated by platelet-derived growth factor BB and transforming growth factor-beta through a transcriptional mechanism during SMC differentiation. CONCLUSIONS: miR-22 plays an important role in SMC differentiation, and epigenetic regulation through MECP2 is required for miR-22 mediated SMC differentiation. PMID- 25722435 TI - SORTILIN: many headed hydra. PMID- 25722436 TI - The transcriptional landscape of regenerating newborn mouse hearts. PMID- 25722437 TI - Can the DNA damage response be harnessed to modulate atherosclerotic plaque phenotype? PMID- 25722438 TI - wRAPping up early monocyte and neutrophil recruitment in atherogenesis via Annexin A1/FPR2 signaling. PMID- 25722439 TI - Mechanisms of cardiac alternans in atrial cells: intracellular Ca2+ disturbances lead the way. PMID- 25722440 TI - Myocardial infarction and inflammation: lost in the biomarker labyrinth. PMID- 25722441 TI - Citation impact of NHLBI R01 grants funded through the American Recovery and Reinvestment Act as compared to R01 grants funded through a standard payline. AB - RATIONALE: The American Recovery and Reinvestment Act (ARRA) allowed National Heart, Lung, and Blood Institute to fund R01 grants that fared less well on peer review than those funded by meeting a payline threshold. It is not clear whether the sudden availability of additional funding enabled research of similar or lesser citation impact than already funded work. OBJECTIVE: To compare the citation impact of ARRA-funded de novo National Heart, Lung, and Blood Institute R01 grants with concurrent de novo National Heart, Lung, and Blood Institute R01 grants funded by standard payline mechanisms. METHODS AND RESULTS: We identified de novo (type 1) R01 grants funded by National Heart, Lung, and Blood Institute in fiscal year 2009: these included 458 funded by meeting Institute's published payline and 165 funded only because of ARRA funding. Compared with payline grants, ARRA grants received fewer total funds (median values, $1.03 versus $1.87 million; P<0.001) for a shorter duration (median values including no-cost extensions, 3.0 versus 4.9 years; P<0.001). Through May 2014, the payline R01 grants generated 3895 publications, whereas the ARRA R01 grants generated 996. Using the InCites database from Thomson-Reuters, we calculated a normalized citation impact for each grant by weighting each article for the number of citations it received normalizing for subject, article type, and year of publication. The ARRA R01 grants had a similar normalized citation impact per $1 million spent as the payline grants (median values [interquartile range], 2.15 [0.73-4.68] versus 2.03 [0.75-4.10]; P=0.61). The similar impact of the ARRA grants persisted even after accounting for potential confounders. CONCLUSIONS: Despite shorter durations and lower budgets, ARRA R01 grants had comparable citation outcomes per $million spent to that of contemporaneously funded payline R01 grants. PMID- 25722443 TI - Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. AB - Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis. PMID- 25722442 TI - Lifestyle effects on hematopoiesis and atherosclerosis. AB - Diet, exercise, stress, and sleep are receiving attention as environmental modifiers of chronic inflammatory diseases, including atherosclerosis, the culprit condition of myocardial infarction and stroke. Accumulating data indicate that psychosocial stress and a high-fat, high-cholesterol diet aggravate cardiovascular disease, whereas regular physical activity and healthy sleeping habits help prevent it. Here, we raise the possibility that inflammation associated leukocyte production plays a causal role in lifestyle effects on atherosclerosis progression. Specifically, we explore whether and how potent real life disease modifiers influence hematopoiesis' molecular and cellular machinery. Lifestyle, we hypothesize, may rearrange hematopoietic topography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. These changes may involve progenitor-extrinsic and intrinsic communication nodes that connect organ systems along neuroimmune and immunometabolic axes, ultimately leading to an altered number and phenotype of lesional macrophages. We propose that, in conjunction with improved public health policy, future therapeutics could aim to modulate the quantitative and qualitative output, as well as the location, of the hematopoietic tree to decrease the risk of atherosclerosis complications. PMID- 25722444 TI - Are there genetic paths common to obesity, cardiovascular disease outcomes, and cardiovascular risk factors? AB - Clustering of obesity, coronary artery disease, and cardiovascular disease risk factors is observed in epidemiological studies and clinical settings. Twin and family studies have provided some supporting evidence for the clustering hypothesis. Loci nearest a lead single nucleotide polymorphism (SNP) showing genome-wide significant associations with coronary artery disease, body mass index, C-reactive protein, blood pressure, lipids, and type 2 diabetes mellitus were selected for pathway and network analyses. Eighty-seven autosomal regions (181 SNPs), mapping to 56 genes, were found to be pleiotropic. Most pleiotropic regions contained genes associated with coronary artery disease and plasma lipids, whereas some exhibited coaggregation between obesity and cardiovascular disease risk factors. We observed enrichment for liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor/RXR nuclear receptor signaling among pleiotropic genes and for signatures of coronary artery disease and hepatic steatosis. In the search for functionally interacting networks, we found that 43 pleiotropic genes were interacting in a network with an additional 24 linker genes. ENCODE (Encyclopedia of DNA Elements) data were queried for distribution of pleiotropic SNPs among regulatory elements and coding sequence variations. Of the 181 SNPs, 136 were annotated to >= 1 regulatory feature. An enrichment analysis found over-representation of enhancers and DNAse hypersensitive regions when compared against all SNPs of the 1000 Genomes pilot project. In summary, there are genomic regions exerting pleiotropic effects on cardiovascular disease risk factors, although only a few included obesity. Further studies are needed to resolve the clustering in terms of DNA variants, genes, pathways, and actionable targets. PMID- 25722445 TI - PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma. AB - We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). METHODS: Seventy-three patients underwent (18)F-FDG PET/CT before and after 2-4 cycles of neoadjuvant chemotherapy with RHT for STS. Progression-free survival (PFS) and time to local and distant progression were among other factors correlated with response according to PET Response Criteria in Solid Tumors (PERCIST 1.0) and Response Evaluation Criteria in Solid Tumors (RECIST 1.1). RESULTS: Metabolic response by PERCIST (n = 44/73) was an independent predictor for PFS (P = 0.002; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.18-0.68) and time to local or distant progression. Other independent predictors for PFS by multivariate analysis were adjuvant radiotherapy (P = 0.010; HR, 0.39; 95% CI, 0.20-0.80) and a baseline tumor size less than 5.7 cm (P = 0.012; HR, 0.43; 95% CI, 0.22-0.83). Response by RECIST 1.1 was seen in a small group of patients (n = 22/73) and allowed prediction of PFS for patients with sarcoma outside the abdomen (P = 0.048; HR, 0.13; 95% CI, 0.02 0.98). CONCLUSION: Metabolic response by (18)F-FDG PET predicts PFS and time to local and distant progression after 2-4 cycles of neoadjuvant chemotherapy plus RHT for STS. PMID- 25722446 TI - Feasibility of in situ, high-resolution correlation of tracer uptake with histopathology by quantitative autoradiography of biopsy specimens obtained under 18F-FDG PET/CT guidance. AB - Core biopsies obtained using PET/CT guidance contain bound radiotracer and therefore provide information about tracer uptake in situ. Our goal was to develop a method for quantitative autoradiography of biopsy specimens (QABS), to use this method to correlate (18)F-FDG tracer uptake in situ with histopathology findings, and to briefly discuss its potential application. METHODS: Twenty-seven patients referred for a PET/CT-guided biopsy of (18)F-FDG-avid primary or metastatic lesions in different locations consented to participate in this institutional review board-approved study, which complied with the Health Insurance Portability and Accountability Act. Autoradiography of biopsy specimens obtained using 5 types of needles was performed immediately after extraction. The response of autoradiography imaging plates was calibrated using dummy specimens with known activity obtained using 2 core-biopsy needle sizes. The calibration curves were used to quantify the activity along biopsy specimens obtained with these 2 needles and to calculate the standardized uptake value, SUVARG. Autoradiography images were correlated with histopathologic findings and fused with PET/CT images demonstrating the position of the biopsy needle within the lesion. Logistic regression analysis was performed to search for an SUVARG threshold distinguishing benign from malignant tissue in liver biopsy specimens. Pearson correlation between SUVARG of the whole biopsy specimen and average SUVPET over the voxels intersected by the needle in the fused PET/CT image was calculated. RESULTS: Activity concentrations were obtained using autoradiography for 20 specimens extracted with 18- and 20-gauge needles. The probability of finding malignancy in a specimen is greater than 50% (95% confidence) if SUVARG is greater than 7.3. For core specimens with preserved shape and orientation and in the absence of motion, one can achieve autoradiography, CT, and PET image registration with spatial accuracy better than 2 mm. The correlation coefficient between the mean specimen SUVARG and SUVPET was 0.66. CONCLUSION: Performing QABS on core-biopsy specimens obtained using PET/CT guidance enables in situ correlation of (18)F-FDG tracer uptake and histopathology on a millimeter scale. QABS promises to provide useful information for guiding interventional radiology procedures and localized therapies and for in situ high-spatial-resolution validation of radiopharmaceutical uptake. PMID- 25722447 TI - The reverse Warburg effect and 18F-FDG uptake in non-small cell lung cancer A549 in mice: a pilot study. AB - The purpose of this study was to observe the effect of fasting and feeding on (18)F-FDG uptake in a mouse model of human non-small cell lung cancer. METHODS: In in vivo studies, (18)F-FDG small-animal PET scans were acquired in 5 mice bearing non-small cell lung cancer A549 xenografts on each flank with continuous feeding and after overnight fasting to observe the changes in intratumoral distribution of (18)F-FDG and tumor (18)F-FDG standardized uptake value (SUV). In ex vivo studies, intratumoral spatial (18)F-FDG distribution assessed by autoradiography was compared with the tumor microenvironment (including hypoxia by pimonidazole and stroma by hematoxylin and eosin stain). Five overnight-fasted mice and 5 fed mice with A549 tumors were observed. RESULTS: Small-animal PET scans were obtained in fed animals on day 1 and in the same animals after overnight fasting; the lapse was approximately 14 h. Blood glucose concentration after overnight fasting was not different from fed mice (P = 0.42), but body weight loss was significant after overnight fasting (P = 0.001). Intratumoral distribution of (18)F-FDG was highly heterogeneous in all tumors examined, and change in spatial intratumoral distribution of (18)F-FDG between 2 sets of PET images from the same mouse was remarkably different in all mice. Tumor (18)F-FDG mean SUV and maximum SUV were not significantly different between fed and fasted animals (all P > 0.05, n = 10). Only tumor mean SUV weakly correlated with blood glucose concentration (R(2) = 0.17, P = 0.03). In ex vivo studies, in fasted mice, there was spatial colocalization between high levels of (18)F-FDG uptake and pimonidazole-binding hypoxic cancer cells; in contrast, pimonidazole-negative normoxic cancer cells and noncancerous stroma were associated with low (18)F-FDG uptake. However, high (18)F-FDG uptake was frequently observed in noncancerous stroma of tumors but rarely in viable cancer cells of the tumors in fed animals. CONCLUSION: Host dietary status may play a key role in intratumoral distribution of (18)F-FDG. In the fed animals, (18)F-FDG accumulated predominantly in noncancerous stroma in the tumors, that is, reverse Warburg effect. In contrast, in fasted status, (18)F-FDG uptake was found in hypoxic cancer cells component (Pasteur effect). Our findings may provide a better understanding of competing cancer glucose metabolism hypotheses: the Warburg effect, reverse Warburg effect, and Pasteur effect. PMID- 25722449 TI - Imaging in clinical oncology. PMID- 25722448 TI - Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates. AB - (86)Y (half-life = 14.74 h, 33% beta(+)) is within an emerging class of positron emitting isotopes with relatively long physical half-lives that enables extended imaging of biologic processes. We report the synthesis and evaluation of 3 low molecular-weight compounds labeled with (86)Y for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding (90)Y-labeled radiotherapeutics. METHODS: Multistep syntheses were used in preparing (86)Y- 4: 6: PSMA inhibition constants were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for (86)Y- 4: - 6: and by biodistribution studies of (86)Y- 4: and (86)Y- 6: out to 24 h after injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using (86)Y- 6 RESULTS: Compounds (86)Y- 4: - 6: were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/MUmol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that (86)Y- 4-6: had high site-specific uptake in PSMA-positive PC-3 PIP tumor starting at 20 min after injection and remained high at 24 h. Compound (86)Y- 6: demonstrated the highest tumor uptake and retention, with 32.17 +/- 7.99 and 15.79 +/- 6.44 percentage injected dose per gram (%ID/g) at 5 and 24 h, respectively. Low activity concentrations were associated with blood and normal organs, except for the kidneys, a PSMA-expressing tissue. PET imaging in baboons reveals that all organs have a 2-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in the kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq of (86)Y- 6: CONCLUSION: Compound (86)Y- 6: is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future (90)Y or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6. PMID- 25722450 TI - The 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology study. AB - The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by PET using the selective radiotracer (11)C (R)PK11195. We investigated (11)C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma-associated microglia/macrophages (GAMs) within the tumors. METHODS: Twenty-two glioma patients underwent dynamic (11)C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of (11)C-(R)PK11195 binding potential (BPND) were generated. Coregistered MR/PET images were used to guide tumor biopsy. The tumor tissue was quantitatively assessed for TSPO expression and infiltration of GAMs using immunohistochemistry and double immunofluorescence. The imaging and histopathologic parameters were compared among different histotypes and grades and correlated with each other. RESULTS: BPND of (11)C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated positively with BPND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BPND. CONCLUSION: PET with (11)C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment. PMID- 25722451 TI - PET assessment of vascular inflammation and atherosclerotic plaques: SUV or TBR? PMID- 25722452 TI - Variability and uncertainty of 18F-FDG PET imaging protocols for assessing inflammation in atherosclerosis: suggestions for improvement. AB - PET with (18)F-FDG shows promise for the evaluation of metabolic activities in atherosclerotic plaques. Although recommendations regarding the acquisition and measurement protocols to be used for (18)F-FDG PET imaging of atherosclerosis inflammation have been published, there is no consensus regarding the most appropriate protocols, and the image reconstruction approach has been especially overlooked. Given the small size of the targeted lesions, the reconstruction and measurement methods might strongly affect the results. We determined the differences in results due to the protocol variability and identified means of increasing the measurement reliability. METHODS: An extensive literature search was performed to characterize the variability in atherosclerosis imaging and quantification protocols. Highly realistic simulations of atherosclerotic carotid lesions based on real patient data were designed to determine how the acquisition and processing protocol parameters affected the measured values. RESULTS: In 49 articles, we identified 53 different acquisition protocols, 51 reconstruction protocols, and 46 quantification methods to characterize atherosclerotic lesions from (18)F-FDG PET images. The most important parameters affecting the measurement accuracy were the number of iterations used for reconstruction and the postfiltering applied to the reconstructed images, which could together make the measured standardized uptake values (SUVs) vary by a factor greater than 3. Image sampling, acquisition duration, and metrics used for the measurements also affected the results to a lesser extent (SUV varying by a factor of 1.3 at most). For an acceptable SUV variability, the lowest bias in SUV was observed using an 8 min acquisition per bed position; ordered-subset expectation maximization reconstruction with at least 120 maximum likelihood expectation maximization equivalent iterations, including a point spread function model using a 1 mm(3) voxel size; and no postfiltering. Because of the partial-volume effect, measurement bias remained greater than 60%. The use and limitations of the target to-blood activity ratio metrics are also presented and discussed. CONCLUSION: (18)F-FDG PET protocol harmonization is needed in atherosclerosis imaging. Optimized protocols can significantly reduce the measurement errors in wall activity estimates, but PET systems with higher spatial resolution and advanced partial-volume corrections will be required to accurately assess plaque inflammation from (18)F-FDG PET. PMID- 25722453 TI - Analysis of 177Lu-DOTA-octreotate therapy-induced DNA damage in peripheral blood lymphocytes of patients with neuroendocrine tumors. AB - Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (gamma-H2AX) is a reliable and sensitive technique to monitor external-beam ionizing radiation-induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether gamma-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with (177)Lu-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. METHODS: We analyzed the kinetics of gamma-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of gamma-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. RESULTS: The decrease in (177)Lu activity in blood with time followed a biexponential kinetic pattern, with approximately 90% of circulating activity in blood cleared within 2 h. Absorbed dose to blood, but not to spleen or bone marrow, correlated with the administered (177)Lu activity. PRRT increased gamma-H2AX foci in lymphocytes in all patients, relative to pretherapy values. The response varied significantly between patients, but the average number of foci indicated a general trend toward an increase at 0.5-4 h with a subsequent decrease by 24-72 h after treatment. The peak number of foci correlated with the absorbed dose to tumor and bone marrow and the extent of PBL reduction. CONCLUSION: gamma-H2AX can be exploited in the LuTate PRRT as a biomarker of PBL cytotoxicity. Long-term follow-up studies investigating whether elevated residual gamma-H2AX values are associated with acute myelotoxicity and secondary blood malignancy may be worthwhile. PMID- 25722454 TI - gamma-H2AX foci in peripheral blood lymphocytes to quantify radiation-induced DNA damage after 177Lu-DOTA-octreotate peptide receptor radionuclide therapy. PMID- 25722456 TI - Contrast induced acute kidney injury in acute coronary syndrome patients: A single centre experience. AB - BACKGROUND: The aim of the study was to investigate predictors of contrast induced acute kidney injury, in-hospital and long-term mortality in patients with acute coronary syndrome treated by percutaneous coronary intervention. METHODS: We investigated 536 consecutive patients with acute coronary syndrome who underwent percutaneous coronary intervention. Contrast induced acute kidney injury was classified according to risk, injury, failure, loss of kidney function and end-stage kidney disease/acute kidney injury network (RIFLE/AKIN) criteria into those with normal kidney function, risk, RIFLE stage I and those with stage ? II. We investigated in-hospital, all-cause mortality during index hospitalization and long-term all-cause mortality during the follow-up period of 94 months (interquartile 81.6-108.9 months) in adjustment with parameters of the Global Risk of Acute Coronary Events score. RESULTS: Patients with contrast induced acute kidney injury had worse baseline clinical characteristics and displayed more co-morbidities than patients with normal kidney function. In multivariate logistic regression analysis intra-aortic balloon pump use, congestive heart failure, age >75 years and admission serum creatinine >1.5mg/dl were independent predictors of contrast induced acute kidney injury development. contrast induced acute kidney injury RIFLE stage ? II was an independent predictor of in-hospital mortality (odds ratio 33.16, confidence interval 1.426 770.79, p=0.029) and long-term mortality (hazard ratio 4.713, confidence interval 1.53-14.51, p=0.007) even after adjustment for confounders (variables of Global Risk of Acute Coronary Events score). CONCLUSION: Contrast induced acute kidney injury is a common complication of acute coronary syndrome patients treated by percutaneous coronary intervention. Advanced deterioration in renal function after percutaneous coronary intervention is an independent predictor for in hospital and long-term mortality. PMID- 25722455 TI - The mitochondrial permeability transition pore regulates endothelial bioenergetics and angiogenesis. AB - RATIONALE: The mitochondrial permeability transition pore is a well-known initiator of cell death that is increasingly recognized as a physiological modulator of cellular metabolism. OBJECTIVE: We sought to identify how the genetic deletion of a key regulatory subunit of the mitochondrial permeability transition pore, cyclophilin D (CypD), influenced endothelial metabolism and intracellular signaling. METHODS AND RESULTS: In cultured primary human endothelial cells, genetic targeting of CypD using siRNA or shRNA resulted in a constitutive increase in mitochondrial matrix Ca(2+) and reduced nicotinamide adenine dinucleotide (NADH). Elevated matrix NADH, in turn, diminished the cytosolic NAD(+)/NADH ratio and triggered a subsequent downregulation of the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1). Downstream of SIRT1, CypD deficient endothelial cells exhibited reduced phosphatase and tensin homolog expression and a constitutive rise in the phosphorylation of angiogenic Akt. Similar changes in SIRT1, phosphatase and tensin homolog, and Akt were also noted in the aorta and lungs of CypD knockout mice. Functionally, CypD-deficient endothelial cells and aortic tissue from CypD knockout mice exhibited a dramatic increase in angiogenesis at baseline and when exposed to vascular endothelial growth factor. The NAD(+) precursor nicotinamide mononucleotide restored the cellular NAD(+)/NADH ratio and normalized the CypD-deficient phenotype. CypD knockout mice also presented accelerated wound healing and increased neovascularization on tissue injury as monitored by optical microangiography. CONCLUSIONS: Our study reveals the importance of the mitochondrial permeability transition pore in the regulation of endothelial mitochondrial metabolism and vascular function. The mitochondrial regulation of SIRT1 has broad implications in the epigenetic regulation of endothelial phenotype. PMID- 25722457 TI - Adiponectin and ischemia-reperfusion injury in ST segment elevation myocardial infarction. AB - BACKGROUND: Models of experimental ischemia-reperfusion (IR) in adiponectin knockout animals have shown that adiponectin mediates protection against the development of IR injury. However, the role of adiponectin in IR injury in humans is largely unknown. METHODS: In a total of 234 ST segment elevation myocardial infarction (STEMI) patients, baseline circulating total adiponectin concentration was correlated with IR injury after primary percutaneous coronary intervention (pPCI) and with major adverse cardiac events (MACE, death and cardiac hospitalization) during one year of follow up. IR injury was defined by serial electrocardiography (ECG) as >30% persistent ST segment elevation despite successful restoration of vessel patency and by angiography as thrombolysis in myocardial infarction (TIMI) blush grade<2. RESULTS: IR injury was present in 31% of patients according to ECG criteria and in 28% of patients according to angiographic criteria. The median adiponectin level was 6.8 ug/ml in patients with ECG signs of IR injury and 6.5 ug/ml in patients without ECG signs of IR (p=0.26). When the angiographic criteria of IR were used, the median adiponectin level was 6.9 ug/ml for patients with IR versus 6.3 ug/ml for patients without IR (p=0.06). MACE occurred in 27% of the patients. Median adiponectin levels were similar in patients with MACE and in those without MACE: 6.3 vs. 6.4 ug/ml (p=0.24). In a multivariate model, no significant relation between circulating adiponectin levels and IR injury or MACE was evident. CONCLUSION: In the current era of pPCI, IR injury still occurs in almost one third of STEMI patients. Our findings do not support a major protective role of adiponectin in the prevention or attenuation of IR injury in these patients. PMID- 25722458 TI - Embryo genome profiling by single-cell sequencing for preimplantation genetic diagnosis in a beta-thalassemia family. AB - BACKGROUND: The embryonic genome, including genotypes and haplotypes, contains all the information for preimplantation genetic diagnosis, representing great potential for mendelian disorder carriers to conceive healthy babies. METHODS: We developed a strategy to obtain the full embryonic genome for a beta-thalassemia carrier couple to have a healthy second baby. We carried out sequencing for single blastomere cells and the family trio and further developed the analysis pipeline, including recovery of the missing alleles, removal of the majority of errors, and phasing of the embryonic genome. RESULTS: The final accuracy for homozygous and heterozygous single-nucleotide polymorphisms reached 99.62% and 98.39%, respectively. The aneuploidies of embryos were detected as well. Based on the comprehensive embryonic genome, we effectively performed whole-genome mendelian disorder diagnosis and human leukocyte antigen matching tests. CONCLUSIONS: This retrospective study in a beta-thalassemia family demonstrates a method for embryo genome recovery through single-cell sequencing, which permits detection of genetic variations in preimplantation genetic diagnosis. It shows the potential of single-cell sequencing technology in preimplantation genetic diagnosis clinical practices. PMID- 25722459 TI - Proteomics of Colorectal Cancer in a Genomic Context: First Large-scale Mass Spectrometry-Based Analysis from the Cancer Genome Atlas. PMID- 25722460 TI - Is there a role for conventional MRI and MR diffusion-weighted imaging for distinction of skull base chordoma and chondrosarcoma? AB - BACKGROUND: Chordoma and chondrosarcoma are locally invasive skull base tumors with similar clinical symptoms and anatomic imaging features as reported in the literature. PURPOSE: To determine differentiation of chordoma and chondrosarcoma of the skull base with conventional magnetic resonance imaging (cMRI) and diffusion-weighted MR imaging (DWI) in comparison to histopathological diagnosis. MATERIAL AND METHODS: This retrospective study comprised 96 (chordoma, n = 64; chondrosarcoma, n = 32) patients with skull base tumors referred to the Paul Scherrer Institute (PSI) for proton therapy. cMRI signal intensities of all tumors were investigated. In addition, median apparent diffusion coefficient (ADC) values were measured in a subgroup of 19 patients (chordoma, n = 11; chondrosarcoma, n = 8). RESULTS: The majority 81.2% (26/32) of chondrosarcomas displayed an off-midline growth pattern, 18.8% (6/32) showed clival invasion, 18.8% (6/32) were located more centrally. Only 4.7% (3/64) of chordomas revealed a lateral clival origin. Using cMRI no significant differences in MR signal intensities were observed in contrast to significantly different ADC values (subgroup of 19/96 patients examined by DWI), with the highest mean value of 2017.2 * 10(-6 )mm(2)/s (SD, 139.9( )mm(2)/s) for chondrosarcoma and significantly lower value of 1263.5 * 10(-6 )mm(2)/s (SD, 100.2 * 10(-6 )mm(2)/s) for chordoma (P = 0.001/median test). CONCLUSION: An off-midline growth pattern can differentiate chondrosarcoma from chordoma on cMRI in a majority of patients. Additional DWI is a promising tool for the differentiation of these skull base tumors. PMID- 25722461 TI - Exophytic renal angiomyolipoma and perirenal liposarcoma: revisiting the role of CT for differential diagnosis. AB - BACKGROUND: Exophytic renal angiomyolipoma and liposarcoma are two representative tumors in the retroperitoneum with fatty components that have potential to be misdiagnosed with each other. PURPOSE: To compare the computed tomography (CT) findings of exophytic renal angiomyolipoma and perirenal liposarcoma. MATERIAL AND METHODS: Fourteen and 16 cases with histologically-proven exophytic renal angiomyolipoma and perirenal liposarcoma, respectively, with preoperative CT from January 2000 to December 2013 were reviewed by two radiologists blinded to the clinical and pathological findings for an array of CT findings. These findings were compared between exophytic renal angiomyolipoma and perirenal liposarcoma using the Student t-test and Fisher's exact test. RESULTS: Patients with exophytic renal angiomyolipoma were younger (P = 0.001) without differences in sex (P = 1.000). Exophytic renal angiomyolipomas were smaller (P = 0.004) and more commonly showed the following findings: renal parenchymal defect (P < 0.001), multiple linear vessels (P = 0.026), aneurysmal dilatation of intratumoral vessels (P = 0.024), renal parenchymal vascular pedicle (P < 0.001), hemorrhage (P = 0.037), encapsulated margin (P = 0.001), and other intrarenal fatty lesions (P = 0.037). No significant difference was seen in laterality, renal hilar vascular pedicle, non-fatty soft tissue nodule, calcification, or kidney displacement (P = 0.236-1.000). CONCLUSION: Several CT findings were significantly different between exophytic renal angiomyolipoma and perirenal liposarcoma and may be helpful for differentiating between the two entities when confronting a fatty mass in the perirenal space. PMID- 25722462 TI - Increased serum fibroblast growth factor 21 levels in patients with schizophrenia. PMID- 25722463 TI - The prevalence and correlates of childhood trauma in patients with early psychosis. AB - OBJECTIVE: To describe the prevalence and demographic, clinical and functional correlates of childhood trauma in patients attending early psychosis clinics. METHOD: Participants were recruited from outpatients attending four early psychosis services. Exposure to childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Psychopathology was measured using the Positive and Negative Syndrome Scale and the Depression, Anxiety and Stress Scale. Social and vocational functioning and substance use were also assessed. RESULTS: Over three quarters of the 100 patients reported exposure to any childhood trauma. Emotional, physical and sexual abuse were reported by 54%, 23% and 28% of patients, respectively, while 49% and 42% of patients reported emotional and physical neglect, respectively. Female participants were significantly more likely to be exposed to emotional and sexual abuse. Exposure to childhood trauma was correlated with positive psychotic symptoms and higher levels of depressive, anxiety and stress symptoms; however, it had no impact on social or vocational functioning or recent substance use. CONCLUSION: Exposure to childhood trauma was common in patients with early psychosis, and associated with increased symptomatology. Existing recommendations that standard clinical assessment of patients with early psychosis should include inquiry into exposure to childhood trauma are supported. PMID- 25722464 TI - Nonassociative learning in invertebrates. AB - The simplicity and tractability of the neural circuits mediating behaviors in invertebrates have facilitated the cellular/molecular dissection of neural mechanisms underlying learning. The review has a particular focus on the general principles that have emerged from analyses of an example of nonassociative learning, sensitization in the marine mollusk Aplysia. Learning and memory rely on multiple mechanisms of plasticity at multiple sites of the neuronal circuits, with the relative contribution to memory of the different sites varying as a function of the extent of training and time after training. The same intracellular signaling cascades that induce short-term modifications in synaptic transmission can also be used to induce long-term changes. Although short-term memory relies on covalent modifications of preexisting proteins, long-term memory also requires regulated gene transcription and translation. Maintenance of long term cellular memory involves both intracellular and extracellular feedback loops, which sustain the regulation of gene expression and the modification of targeted molecules. PMID- 25722465 TI - Drosophila Central Nervous System Glia. AB - Molecular genetic approaches in small model organisms like Drosophila have helped to elucidate fundamental principles of neuronal cell biology. Much less is understood about glial cells, although interest in using invertebrate preparations to define their in vivo functions has increased significantly in recent years. This review focuses on our current understanding of the three major neuron-associated glial cell types found in the Drosophila central nervous system (CNS)-astrocytes, cortex glia, and ensheathing glia. Together, these cells act like mammalian astrocytes: they surround neuronal cell bodies and proximal neurites, are coupled to the vasculature, and associate closely with synapses. Exciting recent work has shown essential roles for these CNS glial cells in neural circuit formation, function, plasticity, and pathology. As we gain a more firm molecular and cellular understanding of how Drosophila CNS glial cells interact with neurons, it is becoming clear they share significant molecular and functional attributes with mammalian astrocytes. PMID- 25722467 TI - Duplex sonography for detection of deep vein thrombosis of upper extremities: a 13-year experience. AB - OBJECTIVES: To determine the prevalence and characteristics of sonographically evident upper-extremity deep vein thrombosis in symptomatic Chinese patients and identify its associated risk factors. SETTING: Regional hospital, Hong Kong. PATIENTS: Data on patients undergoing upper-extremity venous sonography examinations during a 13-year period from November 1999 to October 2012 were retrieved. Variables including age, sex, history of smoking, history of lower extremity deep vein thrombosis, major surgery within 30 days, immobilisation within 30 days, cancer (history of malignancy), associated central venous or indwelling catheter, hypertension, diabetes mellitus, sepsis within 30 days, and stroke within 30 days were tested using binary logistic regression to understand the risk factors for upper-extremity deep vein thrombosis. MAIN OUTCOME MEASURES: The presence of upper-extremity deep vein thrombosis identified. RESULTS: Overall, 213 patients with upper-extremity sonography were identified. Of these patients, 29 (13.6%) had upper-extremity deep vein thrombosis. The proportion of upper-extremity deep vein thrombosis using initial ultrasound was 0.26% of all deep vein thrombosis ultrasound requests. Upper limb swelling was the most common presentation seen in a total of 206 (96.7%) patients. Smoking (37.9%), history of cancer (65.5%), and hypertension (27.6%) were the more prevalent conditions among patients in the upper-extremity deep vein thrombosis-positive group. No statistically significant predictor of upper-extremity deep vein thrombosis was noted if all variables were included. After backward stepwise logistic regression, the final model was left with only age (P=0.119), female gender (P=0.114), and history of malignancy (P=0.024) as independent variables. History of malignancy remained predictive of upper-extremity deep vein thrombosis. CONCLUSIONS: Upper-extremity deep vein thrombosis is uncommon among symptomatic Chinese population. The most common sign is swelling and the major risk factor for upper-extremity deep vein thrombosis identified in this study is malignancy. PMID- 25722466 TI - Chromosome Dynamics during Mitosis. AB - The primary goal of mitosis is to partition duplicated chromosomes into daughter cells. Eukaryotic chromosomes are equipped with two distinct classes of intrinsic machineries, cohesin and condensins, that ensure their faithful segregation during mitosis. Cohesin holds sister chromatids together immediately after their synthesis during S phase until the establishment of bipolar attachments to the mitotic spindle in metaphase. Condensins, on the other hand, attempt to "resolve" sister chromatids by counteracting cohesin. The products of the balancing acts of cohesin and condensins are metaphase chromosomes, in which two rod-shaped chromatids are connected primarily at the centromere. In anaphase, this connection is released by the action of separase that proteolytically cleaves the remaining population of cohesin. Recent studies uncover how this series of events might be mechanistically coupled with each other and intricately regulated by a number of regulatory factors. PMID- 25722468 TI - Falls prevention in the elderly: translating evidence into practice. AB - Falls are a common problem in the elderly. A common error in their management is that injury from the fall is treated, without finding its cause. Thus a proactive approach is important to screen for the likelihood of fall in the elderly. Fall assessment usually includes a focused history and a targeted examination. Timed up-and-go test can be performed quickly and is able to predict the likelihood of fall. Evidence-based fall prevention interventions include multi-component group or home-based exercises, participation in Tai Chi, environmental modifications, medication review, management of foot and footwear problems, vitamin D supplementation, and management of cardiovascular problems. If possible, these are best implemented in the form of multifactorial intervention. Bone health enhancement for residential care home residents and appropriate community patients, and prescription of hip protectors for residential care home residents are also recommended. Multifactorial intervention may also be useful in a hospital and residential care home setting. Use of physical restraints is not recommended for fall prevention. PMID- 25722469 TI - Halt hereditary tragedy by bridging the gap between knowledge and application of technology. PMID- 25722470 TI - Doping through supplement use: a review of the available empirical data. AB - The potential for supplement use to result in doping infringements is likely to be of concern for anyone involved in sports nutrition. The available data indicates that between 40-70% of athletes use supplements, and that between 10 15% of supplements may contain prohibited substances. Such data indicates that there is a considerable risk of accidental or inadvertent doping through using supplements. Accordingly, this paper sets out to provide an overview of the currently available empirical evidence of accidental doping by supplement use. In carrying out this task, the authors refer to press releases and proxy measures associated with nutritional supplement use, as well as statistical data on supplement contamination rates and doping infractions. A number of different indications as to the percentage of doping cases that might be attributed to supplement use are presented, ranging from 6.4% to 8.8%. Such percentages are not comparable; instead they are provided as indications as to how difficult it is to ascertain or estimate the scale of this problem. Although some forms of estimation can be made, it is suggested that it is currently not possible to quantify the scale of the problem. By way of conclusion, it is argued that antidoping regulators may wish to review current data gathering and information provision systems so that the problem of inadvertent doping can be more directly assessed as a factor in sports doping overall. PMID- 25722472 TI - Tuberculosis and HIV Coinfection. AB - Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) constitute the main burden of infectious disease in resource limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact on the immune response to HIV, accelerating the progression from HIV infection to AIDS. The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS). PMID- 25722473 TI - The human placental methylome. AB - This review provides an overview of the unique features of DNA methylation in the human placenta. We discuss the importance of understanding placental development, structure, and function in the interpretation of DNA methylation data. Examples are given of how DNA methylation is important in regulating placental-specific gene expression, including monoallelic expression and X-chromosome inactivation in the placenta. We also discuss studies of global DNA methylation changes in the context of placental pathology and environmental exposures. PMID- 25722475 TI - Intersubjectivity effects of the high-quality communication intervention in people with deafblindness. PMID- 25722476 TI - National Institute for Health and Care Excellence 2014 guidance on cardiac implantable electronic devices: health economics reloaded. PMID- 25722474 TI - RNA-Seq: Improving Our Understanding of Retinal Biology and Disease. AB - Over the past several years, rapid technological advances have allowed for a dramatic increase in our knowledge and understanding of the transcriptional landscape, because of the ability to study gene expression in greater depth and with more detail than previously possible. To this end, RNA-Seq has quickly become one of the most widely used methods for studying transcriptomes of tissues and individual cells. Unlike previously favored analysis methods, RNA-Seq is extremely high-throughput, and is not dependent on an annotated transcriptome, laying the foundation for novel genetic discovery. Additionally, RNA-Seq derived transcriptomes provide a basis for widening the scope of research to identify potential targets in the treatment of retinal disease. PMID- 25722477 TI - Proarrhythmic effect of 'Reverse Mode Switch' in a patient with dilated cardiomyopathy and drug-induced long QTc interval. PMID- 25722478 TI - How are patients with atrial fibrillation approached and informed about their risk profile and available therapies in Europe? Results of the European Heart Rhythm Association Survey. AB - This European Heart Rhythm (EHRA) Scientific Initiatives Committee EP Wire Survey aimed at exploring the common practices in approaching patients with atrial fibrillation (AF) and informing them about their risk profiles and available therapies in Europe. In the majority of 53 responding centres, patients were seen by cardiologists (86.8%) or arrhythmologists (64.2%). First- and follow-up visits most commonly lasted 21-30 and 11-20 min (41.5 and 69.8% of centres, respectively). In most centres (80.2%) stroke and bleeding risk had the highest priority for discussion with AF patients; 50.9% of centres had a structured patient education programme for stroke prevention. Individual patient stroke risk was assessed at every visit in 69.2% of the centres; 46.1% of centres had a hospital-based anticoagulation clinic. Information about non-vitamin K oral anticoagulants (NOACs) was communicated to all AF patients eligible for oral anticoagulation (38.5% of centres) or to warfarin-naive/unstable patients (42.3%). Only two centres (3.8%) had a structured NOAC adherence follow-up programme; in eight centres (15.4%) patients were requested to sign the statement they have been informed about the risks of non-adherence to NOAC therapy, and three centres (5.8%) had a patient education programme. Patient preferences were of the highest relevance regarding oral anticoagulation and AF ablation (64.7 and 49.0% of centres, respectively). This EP Wire Survey shows that in Europe considerable amount of time and resources are used in daily clinical practice to inform AF patients about their risk profile and available therapies. However, a diversity of strategies used across the European hospitals was noted, and further research is needed to better define optimal strategies for informing AF patients about their risk profile and treatment options. PMID- 25722479 TI - New electrocardiographic criteria to differentiate the type-2 Brugada pattern from electrocardiogram of healthy athletes with r'-wave in leads V1/V2. PMID- 25722480 TI - A potential explanation for lower minor complication rate for lead extraction in high-volume centres Response to the letter by Tolga Aksu, Kazim Serham Ozcan, Tumer Erdem Guler. PMID- 25722481 TI - Base of the triangle to determine a Brugada electrocardiogram pattern. PMID- 25722482 TI - Unassisted detection of depression by GPs: who is most likely to be misclassified? AB - BACKGROUND: Meta-analyses indicate 50% of cases of depression are not detected by GPs. It is important to examine patient and GP characteristics associated with misclassification so that systems can be improved to increase accurate detection and optimal management for groups at risk of depression. OBJECTIVE: To examine patient and GP characteristics associated with GP misclassification of depression for patients classified by the Patient Health Questionnaire-9 as depressed. METHODS: A cross-sectional study within general practices in two states of Australia. GPs completed a one-page paper and pencil survey indicating whether they thought each patient was clinically depressed. Patients completed a computer tablet survey while waiting for their appointment to provide demographic information and indicate depression status. Chi-square analyses were used to determine whether patient and GP characteristics were associated with a false negative and false-positive result. The probability of misclassification was modelled using Generalized Estimating Equations to account for clustering of patients. RESULTS: Fifty GPs from 12 practices participated. GPs completed surveys for 1880 patients. Younger patients aged 25-44, and those with a health care card were less likely to have a false-negative assessment. Patients with 0-3 GP visits in the past 12 months, and those with private health insurance were less likely to have a false-positive assessment. GPs who worked five sessions or fewer per week were more likely to make false-positive assessments. PMID- 25722483 TI - Anti-tick-borne encephalitis (TBE) virus neutralizing antibodies dynamics in natural infections versus vaccination. AB - Tick-borne encephalitis (TBE) virus infection elicits a life-long lasting protection. However, little is known about the neutralizing antibodies titres following natural infection. In this study, subjects with past TBE disease (n = 62) were analysed for the presence and titre of anti-TBE neutralizing antibodies, and compared with a vaccinated cohort (n = 101). Neutralizing antibody titres were higher in individuals with past TBE and did not show an age-dependent decrease when compared with vaccinees. PMID- 25722484 TI - DNA methylation differentially regulates cytokine secretion in gingival epithelia in response to bacterial challenges. AB - Epigenetic modifications are changes in gene expression without altering DNA sequence. We previously reported that bacteria-specific innate immune responses are regulated by epigenetic modifications. Our hypothesis is that DNA methylation affects gingival cytokine secretion in response to bacterial stimulation. Gingival epithelial cells (GECs) were treated with DNMT-1 inhibitors prior to Porphyromonas gingivalis (Pg) or Fusobacterium nucleatum (Fn) exposure. Protein secretion was assessed using ELISA. Gene expression was quantified using qRT-PCR. The ability of bacteria to invade inhibitor pretreated GECs was assessed utilizing flow cytometry. Changes were compared to unstimulated GECs. GEC upregulation of IL-6 and CXCL1 by Pg or Fn stimulation was significantly diminished by inhibitor pretreatment. Pg stimulated IL-1alpha secretion and inhibitor pretreatment significantly enhanced this upregulation, while Fn alone or with inhibitor pretreatment had no effect on IL-1alpha expression. GEC upregulation of human beta-definsin-2 in response to Pg and Fn exposure was enhanced following the inhibitor pretreatment. GEC susceptibility to bacterial invasion was unaltered. These results suggest that DNA methylation differentially affects gingival cytokine secretion in response to Pg or Fn. Our data provide basis for better understanding of how epigenetic modifications, brought on by exposure to oral bacteria, will subsequently affect host susceptibility to oral diseases. PMID- 25722485 TI - Imbalance of circulating lymphoid cells in Q fever endocarditis. AB - Q fever endocarditis is characterized by a defective cell-mediated immune response, which may be associated with the dysregulation of circulating subsets of immune cells. In this study, we found that naive CD8(+) T lymphocytes and CD56dim natural killer cells were decreased patients whereas central memory CD8(+) T lymphocytes were increased. It is likely that these different subsets of immune cells play a role in the immunosuppression accompanying Q fever endocarditis. PMID- 25722486 TI - An effective DNA priming-protein boosting approach for the cervical cancer vaccination. AB - Considerable advances have been made in developing human papillomaviruses (HPV) prophylactic vaccines based on L1 virus-like particles (VLPs). However, there are limitations in the availability of these vaccines in developing countries, where most cases of cervical cancer occur. In the current study, the prime-boost immunization strategies were studied using a DNA vaccine carrying HPV-16 L1 gene (pcDNA/L1) and insect cell baculovirus-derived HPV-16 L1 VLP. The humoral immunity was evaluated by measuring the specific IgG levels, and the T-cell immune response was assessed by measuring different cytokines such as IFN-gamma, TNF-alpha and IL-10. Results showed that although immunization with pcDNA/L1 alone could induce strong cellular immune responses, higher immunogenicity especially antibody response was achieved in pcDNA/L1 priming-VLP boosting regimen. Therefore, we suggest that prime-boost regimen can be considered as an efficient prophylactic and therapeutic vaccine. PMID- 25722487 TI - Molecular identification and genotyping of Pseudomonas aeruginosa isolated from cystic fibrosis and non-cystic fibrosis patients with bronchiectasis. AB - There is no standard methodology for the molecular identification and genotyping of Pseudomonas aeruginosa which are frequently isolated in bronchiectasis patients. Hence, the main goal of this work was to propose a methodology capable to simultaneously identify and genotype, in less than 6 h, clinical P. aeruginosa collected from cystic fibrosis (CF) and non-CF patients with bronchiectasis. Molecular analyses were conducted in clinical isolates by testing the newly colony-PCR strategy and SNaPaer assay. A total of 207 isolates of P. aeruginosa were collected from clinical samples. To assess the assay specificity, other Gram negative non-aeruginosa bacteria, namely Pseudomonas and Burkholderia, were tested. The complete group of 23 markers included in the SNaPaer panel was observed exclusively in P. aeruginosa; more than 18 markers failed in other bacteria. A total of 43 SnaP profiles were obtained for clinical P. aeruginosa, being the profiles highly patient-specific. Six CF patients were colonized with P. aeruginosa isolates with very distinct SnaP profiles, particularly following adjustments on antibiotic therapy, thus suggesting changes on the dynamics and dominance of these bacteria. SnaPaer proved to be a good and reliable tool for identification and genotyping of clinical P. aeruginosa in a single-tube multiplex PCR. Combined with the proposed colony-PCR strategy, SnaPaer assay facilitates the molecular analysis of P. aeruginosa. PMID- 25722488 TI - Molecular profile of the T cell receptor beta variable in peripheral blood lymphocytes from chronic asymptomatic HBV carriers. AB - T cell receptor beta variable (TCRBV) repertoire could imply the composition and function status of T cells in subjects with HBV infection. The gene melting spectral pattern (GMSP) can be used to determine the profile of TCRBV gene family. The molecular profile of TCRBV in peripheral lymphocytes from asymptomatic HBV carriers (AsC) remains ill-defined. Peripheral blood mononuclear cells (PBMCs) were separated and sorted, and the profiles of TCRBV complementarity-determining region 3 (CDR3) in CD4(+), CD8(+) T subsets and PBMCs were assayed using GMSP. The number of skewed TCRBV in the PBMCs was significantly lower than that in the CD4(+) or CD8(+) T subsets, and the number of monoclonal TCRBV families in the CD8(+) T subset was significantly higher than that in CD4(+) T subset. Compared to healthy donors, TCRBV11, BV13.1, BV20 and BV24 were used more frequently than other TCRBV members in PBMCs from AsC subjects. Furthermore, the relatively conserved CDR3 motifs were detected in these TCRBVs. The results indicate that the T cell response in AsC subjects involves several TCRBVs, and that the CD8(+) T subset maybe more relevant to pathogenesis of AsC. Moreover, the four relative conserved TCRBVs maybe a target for personalized treatments for persistent HBV infection. PMID- 25722489 TI - Influence of quorum sensing in multiple phenotypes of the bacterial pathogen Chromobacterium violaceum. AB - Chromobacterium violaceum is a bacterial pathogen that communicates through quorum sensing (QS), via the C6-homoserine lactone signal (C6-HSL). It is well known that the production of the pigment violacein is controlled by QS in this microorganism, in fact QS-dependent violacein production is widely used as a marker to evaluate the efficiency of potential anti-QS molecules, such as those extracted from plants. In addition to violacein, the production of chitinase is also known to be controlled by QS, but besides those two phenotypes there is a lack of experimental studies aimed to discover additional process controlled by QS in this organism; therefore, in this work the production of exoprotease, aggregation, biofilm formation, swarming motility, H2O2 resistance as well as carbon and nitrogen utilization was determined in the wild-type strain and the QS negative mutant CVO26. Our results indicate that alkaline exoprotease activity is QS controlled in this organism, that QS increases aggregation, biofilm formation, swarming, that may increase H2O2 stress tolerance, and that it may influence the utilization of several carbon and nitrogen sources. PMID- 25722490 TI - Ophthalmic statistics note 6: effect sizes matter. PMID- 25722491 TI - Visual impairment and depressive symptoms in an older Australian cohort: longitudinal findings from the Blue Mountains Eye Study. AB - AIMS: To assess the association between visual impairment (VI) and subsequent presence of depressive symptoms among older persons. METHODS: Of the 3654 baseline participants (aged over 49 years) of the Blue Mountains Eye Study, 2334, 1952 and 1149 were re-examined after 5, 10 and 15 years, respectively. VI was defined as best-corrected visual acuity <6/12 in either or both eyes. Presence of depressive symptoms was defined if mental health index (MHI) scores <59 or incident use of antidepressant medications. Persons with VI detected at the 5 year or 10-year follow-up visits were assessed for depressive symptoms in 5 years. Persons with VI detected at baseline or the 5-year follow-up were assessed for depressive symptoms over 10 years. Controls were persons without VI over the corresponding period. Discrete logistic regression models with time-dependent study and outcome variables were used, adjusting for potential confounders. RESULTS: Of 1568 participants who had the MHI assessed at two consecutive visits, 226 had bilateral or unilateral VI detected 5 years earlier and 120 had VI detected over 10 years earlier. Depressive symptoms were reported in 27% and 31.6% of cases with VI detected 5 and over 10 years earlier, respectively, compared with 10.8%-11.5% of controls. There was a significantly greater odds of presenting depressive symptoms among VI cases detected 5 years earlier (OR, 3.06, 95% CI 1.72 to 5.44), but this was non-significant for cases detected over 10 years earlier (OR 1.29, 95% CI 0.84 to 1.98). CONCLUSIONS: VI was associated with subsequently presenting depressive symptoms over 5 years among older persons. PMID- 25722492 TI - Effects of posterior vitreous detachment on aqueous humour levels of VEGF and inflammatory cytokines. AB - PURPOSE: To investigate the association of posterior vitreous detachment (PVD) with aqueous levels of vascular endothelial growth factor (VEGF) and other inflammatory cytokines. METHODS: These are prospective comparative studies. Subjects comprised 98 eyes for VEGF concentration and 80 eyes for other cytokines, which are normal except for cataract. PVD was examined by B-mode ultrasonography, and the subjects were divided into complete PVD group (PVD group) or the other group (without PVD group). At the beginning of cataract surgery, aqueous humour was collected and the concentrations of VEGF and other inflammatory cytokines were determined using ELISA and a multiplex cytokine assay, respectively. The concentrations of these cytokines were compared between the two groups. RESULTS: Complete PVD was observed in 56 (57%) eyes for VEGF concentration analysis, and 51 (64%) eyes for the other cytokines analysis. The concentrations of VEGF, adjusted for the average age, axial length and gender distribution, was 47 pg/mL in the PVD group and 72 pg/mL in the without PVD group. The concentrations of IP-10, MCP-1, CXCL13 and CCL11 were 53, 450, 3.8 and 6.0 pg/mL in the PVD group, and 100, 560, 7.0 and 8.4 pg/mL in the without PVD group, respectively. Multiple regression analysis revealed that the logarithmic concentration of VEGF, IP-10, MCP-1, CXCL13 and CCL11 were significantly lower in the eyes with PVD than in those without PVD independently of age, sex and axial length (p=0.01, p=0.002, p=0.009, 0.006 and 0.03, respectively). CONCLUSIONS: PVD is related to the change in the multiple intraocular inflammatory cytokines. PMID- 25722493 TI - En face swept-source optical coherence tomography in neovascular age-related macular degeneration. AB - PURPOSE: To describe en face swept-source optical coherence tomography (SS-OCT) findings in the retinal pigment epithelium (RPE) and choroid and to correlate them with fluorescein angiography (FA) and/or indocyanine green angiography (ICGA) in neovascular age-related macular degeneration (AMD). METHODS: Thirty eight eyes with the recent diagnosis of neovascular AMD were imaged using an SS OCT system. En face images were obtained at RPE, choriocapillaris, Sattler's layer and Haller's layer level. Analysis of the images and correlation with colour fundus photographs, FA, ICGA in selected cases, were made. RESULTS: En face images at RPE level revealed changes in all eyes. The neovascular complex appeared hyper-reflective in 9 of 38 eyes (23.7%), and in 29 of 38 eyes (76.3%), it was hyporeflective. The choriocapillaris en face image showed pathological changes in all eyes as well, and in 20 out of 38 eyes (52.6%), the alterations were hyper-reflective, while 18 of 38 eyes (47.4%) showed hyporeflective changes. Twenty (52.6%) eyes and 19 (50.0%) had a hyper-reflective lesion in Sattler's layer and Haller's layer, respectively, and 15 (39.4%) cases showed a hyporeflective lesion in both layers. No differences were found between the neovascular complex area, horizontal and vertical diameters, measured in the en face image and FA (p=0.171, p=0.061, p=0.133, respectively). Hyporeflective changes were predominant at RPE level and hyper-reflective at choriocapillaris, Sattler's and Haller's layers. CONCLUSIONS: En face SS-OCT is a rapid, non invasive, high-resolution, promising technology, which allows a complementary study to angiography of neovascular AMD. There is a correlation between angiography and en face SS-OCT images in neovascular AMD. PMID- 25722494 TI - Prevalence of canaliculitis after smartplug insertion during long-term follow-up. AB - PURPOSE: To evaluate the long-term prevalence of canaliculitis associated with the use of SmartPlugs. METHODS: This retrospective study included 42 eyes of 25 dry eye patients at our institution who received a SmartPlug insertion between 2004 and 2008. Irrigation of the lacrimal system was performed in all patients prior to SmartPlug insertion to ensure the patency of the system. The median follow-up time was 7.9 (5.6-10.5) years after plug insertion. RESULTS: Six patients (seven eyes) of 25 patients (42 eyes) developed canaliculitis. The prevalence of canaliculitis per patient was 24%, and the prevalence of canaliculitis per SmartPlug was 16.6%. The median time from SmartPlug insertion to the onset of canaliculitis was 4.7 (1.4-6.0) years. The median age of the affected patients was 61.5 (36-74) years. Five of these patients were women and one was man. The pathogens were identified as Actinomyces in four eyes and as Staphylococcus aureus in three eyes. In five patients (six eyes), the canaliculitis was resolved by the application of topical antibiotics and repeated lacrimal irrigations with antibiotics and povidone-iodine. In one patient, a canaliculotomy was necessary to cure the condition. CONCLUSIONS: The late onset of complications after SmartPlug insertion requires long-term observation to identify the majority of complications associated with SmartPlugs. In our patients with a follow-up of up to 10.5 years, the use of SmartPlugs was associated with the highest prevalence of canaliculitis published thus far. PMID- 25722495 TI - Personality influences responses to inequity and contrast in chimpanzees. AB - Several species besides humans respond negatively to inequity (i.e. receiving a less preferred outcome as compared to a social partner). Among primates, the taxon for which inequity responses have been most comprehensively studied, there are large individual differences in responses that have, thus far, not been well explained by demographic features such as sex, rank and age. Recent evidence shows that individuals' personalities are important in explaining differences in behavioural outcomes in other contexts. Thus, in the current study, we explored whether personality was associated with chimpanzees' responses to both inequity and contrast (i.e. receiving less than anticipated). Chimpanzees were paired with multiple members of their social groups. These pairs alternated trading a token to receive food rewards that either differed from what their partner received (inequity condition) or from what was initially offered (contrast condition) and we compared their responses to a control in which both subjects were offered and received the same reward for trading the token. We predicted that both personality and the quality and length of the pairs' relationship would influence subjects' reactions to unequal outcomes, as measured by their refusal to exchange tokens. The quality of subjects' relationships, based on a weighted average of grooming, contact and proximity, did not correlate with refusals to exchange, whereas pairs that had lived together longer were less likely to refuse in the contrast condition than were pairs that had lived together for less time. Considering personality, some of the dimensions influenced responses to both inequity and contrast similarly, but the more 'social' personality dimensions ('extraversion' and 'agreeableness') were more strongly correlated with sensitivity to inequity. These results highlight the importance of considering individual differences, including personality, when evaluating responses in cognitive and behavioural tests. PMID- 25722496 TI - Beyond Black and White: Color and Mortality in Post Reconstruction Era North Carolina. AB - A growing empirical literature in economics and sociology documents the existence of differences in social and economic outcomes between mixed-race blacks and other blacks . However, few researchers have considered whether the advantages associated with mixed-race status may have also translated into differences in mortality outcomes between subgroups of blacks and how both groups compared to whites. We employ previously untapped 1880 North Carolina Mortality census records in conjunction with data from the 1880 North Carolina Population Census to examine whether mulatto, or mixed-race blacks may have experienced mortality advantages over to their colored, or non-mixed race counterparts. For men between the ages of 20-44, estimates demonstrate that all black males are more likely than whites to die. Although our results indicate that there are no statistically significant differences in mortality between mulatto and colored blacks, there are some indications that mulatto males may have enjoyed a slight mortality advantage compared to their colored counterparts. However, we find a substantial mortality advantage associated with mixed-race status among women. These findings indicate that mixed-race women, rather than men, may have accrued any mortality advantages associated with color and white ancestry. PMID- 25722497 TI - FPGA Electronics for OPET: A Dual-Modality Optical and Positron Emission Tomograph. AB - The development of a prototype dual-modality optical and PET (OPET) small animal imaging tomograph is underway in the Crump Institute for Molecular Imaging at the University of California Los Angeles. OPET consists of a single ring of six detector modules with a diameter of 3.5 cm. Each detector has an 8 * 8 array of optically isolated BGO scintillators which are coupled to multichannel photomultiplier tubes and open on the front end. The system operates in either PET or optical mode and reconstructs the data sets as 3D tomograms. The detectors are capable of detecting both annihilation events (511 keV) from PET tracers as well as Single Photon Events (SPEs) (2-3 eV) from bioluminescence. Detector channels are readout using a custom multiplex readout scheme and then filtered in analog circuitry using either a gamma-ray or SPE specific filter. Shaped pulses are sent to a Digital Signal Processing (DSP) unit for event processing. The DSP unit has 100 MHz Analog-to-Digital Converters on the front-end which send digitized samples to Field Programmable Gate Arrays which are programmed via user configurable algorithms to process PET coincidence events or bioluminescence SPEs. Information determined using DSP includes: event timing, energy determination-discrimination, position determination-lookup, and coincidence processing. Coincidence or SPE events are recorded to an external disk and minimal post processing is required prior to image reconstruction. Initial imaging results from a phantom filled with 18FDG solution and an optical pattern placed on the front end of a detector module in the vicinity of a SPE source are shown. PMID- 25722498 TI - Knowledge, Attitudes, and Commitment Concerning Evidence-Based Prevention Programs: Differences between Family and Consumer Sciences and 4-H Youth Development Educators. AB - In this article, we describe the results of a study designed to assess knowledge, perceptions, and attitudes towards evidence-based and other prevention programs among county Extension educators. We examined differences across educators from the Family and Consumer Sciences (FCS) and 4-H Youth Development program areas. Analyses based on a multi-state sample of educators revealed significant differences across program areas such that, compared to their 4-H counterparts, FCS educators were more knowledgeable of evidence-based programs and had more favorable perceptions and attitudes towards evidence-based and other pre-packaged prevention programs. These findings suggest that Cooperative Extension administrators should work to encourage the use of evidence-based and other prevention programs, particularly within the 4-H program area. PMID- 25722499 TI - Design, Synthesis and Application of Fluorine-Labeled Taxoids as 19F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems. AB - Novel tumor-targeting drug conjugates, BLT-F2 (1) and BLT-S-F6 (2), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as 19F NMR probes. Fluorine atoms and CF3 groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with 19F NMR. Time-resolved 19F NMR study on probe 1 disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods. Probe 2 was designed to bear two CF3 groups in the taxoid moiety as "3 FAB" reporters for enhanced sensitivity and a polyethylene glycol oligomer insert to improve solubility. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma or cell culture media by HPLC and 1H NMR is troublesome, due to the overlap of key signals/peaks with background arising from highly complex ingredients in biological systems. Accordingly, the use of 19F NMR would provide a practical solution to this problem. In fact, our "3-FAB" probe 2 was proven to be highly useful to investigate the stability and reactivity of the self-immolative disulfide linker system in human blood plasma by 19F NMR. It has also been revealed that the use of polysorbate 80 as excipient for the formulation of probe 2 dramatically increases the stability of the disulfide linker system. This finding further indicates that the tumor-targeting drug conjugates with polysorbate 80/EtOH/saline formulation for in vivo studies would have high stability in blood plasma, while the drug release in cancer cells proceeds smoothly. PMID- 25722500 TI - Phosphorus uptake by Zea mays L. is quantitatively predicted by infinite sink extraction of soil P. AB - BACKGROUND AND AIMS: Sink extraction of phosphorus from soils has been utilised to study soil P desorption kinetics and as index of plant availability, but not for quantitative prediction of P uptake by plants. Here we investigate the potential of a modified sink extraction method for determining P desorption kinetics and for quantifying plant available soil P. METHODS: Modified diffusive gradients in thin films samplers were immersed in shaken soil suspensions for long-term extraction of soil P. Results were evaluated in terms of P desorption kinetics and compared to the P uptake of Zea mays L. and standard soil extracts. RESULTS: In contrast to literature reports, four of the six studied soils only showed a rapid, but not a slowly desorbing P fraction. The quantity of P desorbed by long-term sink extraction not only showed the highest correlation to plant P uptake, but also matched plant P uptake quantitatively. CONCLUSIONS: Our data indicates that soils with only a fast desorbing P fraction might exist. Sink extraction methods have the potential to quantitatively predict plant P uptake. Furthermore, they could become valuable research tools for understanding P acquisition and might serve as a benchmark for calibrating soil P tests. PMID- 25722501 TI - Social Evaluations of Stereotypic Images in Video Games: Unfair, Legitimate, or "Just Entertainment"? AB - The aim of this study was to assess adolescents' evaluations of, and reasoning about, gender stereotypes in video games. Female (N = 46) and male (N = 41), predominantly European-American, mean age = 19 years, were interviewed about their knowledge of game usage, awareness and evaluation of stereotypes, beliefs about the influences of games on the players, and authority jurisdiction over 3 different types of games: games with negative male stereotypes, and games with negative female stereotypes, and gender-neutral games. Gender differences were found for how participants evaluated these games. Males were more likely than females to find stereotypes acceptable. Results are discussed in terms of social reasoning, video game playing, and gender differences. PMID- 25722502 TI - Negative and Positive Factors Associated With the Well-Being of Lesbian, Gay, Bisexual, Transgender, Queer, and Questioning (LGBTQ) Youth. AB - Factors associated with the well-being of lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth were qualitatively examined to better understand how these factors are experienced from the youths' perspectives. Largely recruited from LGBTQ youth groups, 68 youth participated in focus groups (n = 63) or individual interviews (n = 5). The sample included 50% male, 47% female, and 3% transgender participants. Researchers used a consensual methods approach to identify negative and positive factors across 8 domains. Negative factors were associated with families, schools, religious institutions, and community or neighborhood; positive factors were associated with the youth's own identity development, peer networks, and involvement in the LGBTQ community. These findings suggest a pervasiveness of negative experiences in multiple contexts, and the importance of fostering a positive LGBTQ identity and supportive peer/community networks. Efforts should work towards reducing and eliminating the prejudicial sentiments often present in the institutions and situations that LGBTQ youth encounter. PMID- 25722503 TI - Bipolar and Depressive Disorders in Diagnostic and Statistical Manual of Mental Disorders-5: Clinical Implications of Revisions from Diagnostic and Statistical Manual of Mental Disorders-IV. PMID- 25722504 TI - Insight in schizophrenia: relationship to positive, negative and neurocognitive dimensions. AB - Impairment of insight is considered as the hallmark of schizophrenia. Substantial proportion of patients with schizophrenia has either poor or absent insight. Insight is a multidimensional and dynamic construct which appears to have intricate links with other symptom dimensions of the psychotic illness. A better appreciation of the association that insight shares with other symptom clusters in psychosis could help us in gaining knowledge about aetiology, prognosis and treatment-related facets of the disorder. This is likely to have critical implications in the understanding and therapeutics of schizophrenia. PMID- 25722505 TI - Intentional Self-harm in Children and Adolescents: A Study from Psychiatry Consultation Liaison Services of a Tertiary Care Hospital. AB - OBJECTIVE: The objective of this study was to evaluate the socio-demographic and the clinical profile of children and adolescents presenting with Intentional self harm. MATERIALS AND METHODS: Records of all children and adolescents (<=19 years) seen by the consultation liaison (CL) services during the period of 2000-2012 were screened. Patients with a diagnosis of intentional self-harm (at the time of assessment) were taken up for this study. Data was extracted from the records, to study the socio-demographic and clinical profile. RESULTS: During the study period, 101 patients aged <=19 years and diagnosed with intentional self-harm at the time of admission were evaluated by the psychiatry CL services in various emergency and medical surgical wards. In the study population, females (N = 61; 60.4%) outnumbered males. The age of the patients ranged from 12 to 19 with a median and mean of 17.0 years (standard deviation-1.6 years; interquartile range 16-18 years). Children and adolescent with self harm were more commonly females, from nuclear families, middle socio-economic status and Hindu by religion. The common method of self-harm in adolescents is by ingestion of insecticides (65%) and the self-harm behavior was often precipitated by interpersonal problems in the family context. About one-fifth of the patients have psychiatric morbidity. CONCLUSION: Findings suggest that the most common method of intentional self-harm in children and adolescents is consumption of insecticides and precipitated by interpersonal problems in the family context. PMID- 25722506 TI - On somatic symptoms measurement: the scale for assessment of somatic symptoms revisited. AB - BACKGROUND: Scale for assessment of somatic symptoms (SASS) has been widely used for assessing somatic complaints since many years. With impending changes in the classificatory system on somatoform disorders, we re- assessed the test-retest reliability and inter-rater reliability of SASS. MATERIALS AND METHODS: SASS was administered twice with a gap of 24 h on 20 subjects for test retest reliability. Two clinicians assessed inter-rater reliability on 20 subjects. Kendall tau B and Cronbach's alpha were calculated from the data. RESULTS: All of the items except burning sensation, weakness of mind and trembling had strong correlation with values >+/-0.40 on both test retest and inter-rater reliability; burning sensation and trembling were not reported by any subject. On inter-rater reliability the items constipation, diarrhea, lack of libido weren't scored by any subjects. Cronbach's alpha for test retest was 0.982 and 0.840 indicating good internal consistency. CONCLUSION: Majority of the symptoms in SASS had high correlation in both test retest reliability as well as inter-rater reliability, however few items needs revision. PMID- 25722507 TI - Brief cognitive behavior therapy in patients with social anxiety disorder: a preliminary investigation. AB - CONTEXT: Cognitive behavior therapy (CBT) is the treatment of choice in anxiety disorders. However, there is little evidence for the effectiveness brief CBT in social anxiety. AIMS: We examined the effectiveness of a brief CBT of six sessions in patients with social anxiety disorder. SETTINGS AND DESIGN: A single case design study baseline; post and 1 month follow-up was adopted. MATERIALS AND METHODS: Seven patients with a DSM IV diagnosis of social anxiety underwent 6 weekly sessions of brief CBT. Their diagnosis was confirmed using structured diagnostic interviews. They were assessed at baseline, post and 1-month follow-up on CGI- Severity, Leibowitz Social Anxiety Scale (LSAS), Social Phobia Rating Scale, Brief Fear of Negative Evaluation, and Beck's Depression Inventory. STATISTICAL ANALYSIS: Data were analyzed using the method of clinical significance. RESULTS: Results indicated that brief CBT was effective in reducing social anxiety in all patients. Brief CBT was also effective in reducing social avoidance and self consciousness. However, brief CBT was not effective in reducing fear of negative evaluation in all patients, suggesting the need for longer duration for cognitive changes in some dysfunctional beliefs. CONCLUSIONS: This preliminary case series indicates that brief CBT may be a promising and a cost and time effective approach to managing for social anxiety. PMID- 25722508 TI - Vitamin B12 deficiency: an important reversible co-morbidity in neuropsychiatric manifestations. AB - BACKGROUND: Vitamin B12 deficiency is a common condition causing neurologic, cognitive, psychiatric, and mood symptoms. With varied religious, ethnic, and socioeconomic heterogeneity among the people in India greatly influencing their dietary habits and with the high prevalence of Helicobacter pylori infection, Vitamin B12 deficiency is not uncommon, but is often under recognized due to the lack of classical symptomatic presentation. MATERIALS AND METHODS: Retrospective study on Vitamin B12 deficiency with neuropsychiatric symptoms in patients who attended neurology, psychiatry, and geriatric OPDs for a period of 1 year in a specialized neuropsychiatric institute in South India. RESULTS: Out of 259 patients who had Vitamin B12 deficiency (<220 pmol/L), 60 had neuropsychiatric symptoms. Among them the Vitamin B12 levels were <150 (severe), 150-200 (moderate), and 201-220 pmol/L (mild) in 19, 24, 17 patients, respectively. Twenty one were diagnosed with Posterior dementias, 20 with frontotemporal dementia, 7 with Schizophrenia, 4 each with Parkinson's disease and alcohol dependent syndromes (ADS), 3 with bipolar affective disorder, and 1 with Creutzfeldt-Jakob disease. Eight patients also had hypothyroidism. First symptom of presentation was behavioral disturbances in 30 (50%), memory loss in 20 (33.9%), and sensorimotor and movement disorders in 9 (15.3%), and 56.7% were vegetarians while 43.3% were nonvegetarians. In our study, Vitamin B12 deficiency was more prevalent in elderly males (56.67%) and was associated with increased severity of behavioral disturbances (P = 0.043) which was the most common presentation. Memory loss was present in 16 (84.2%) patients of severe Vitamin B12 deficiency. Hindi mental status examination (HMSE) score was graded as <20, 20-24, 24-31 in 37 (61.7%), 10 (16.7%), and 13 (21.7%) patients, respectively. Cognitive decline in Vitamin B12 deficiency was significantly associated with increased serum cholesterol (P = 0.019) and was significantly prevalent in neurological disorders when compared with primary psychiatric illnesses (P = 0.001). Mean folate and mean homocysteine in our study was 11.7 +/- 6.44 ng/ml and 17.77 +/- 5.45 MUmol/L, respectively. Eighty percent of the population had normal folate levels whereas mean homocysteine values were much higher than that of the western population (10-12 MUmol/L). CONCLUSION: Vitamin B12 deficiency though common in India is often overlooked. It increases the load of cognitive decline and accentuates vascular risk factors in neuropsychiatric illnesses. Vitamin B12 deficiency also increases homocysteine levels contributing to the vascular comorbidity in cerebro and cardiovascular illnesses. So prevention, early detection, and management of this reversible Vitamin B12 deficiency state is of profound importance. PMID- 25722509 TI - Risk factors for suicidal attempts among lower socioeconomic rural population of telangana region. AB - BACKGROUND: Suicide is an act of intentionally causing one's own death. Number of suicidal incidences is proportional to attempted suicide cases hence if attempt cases are reduced, number of suicidal death can also be decreased and for that purpose risk factors should be identified and reduced. Therefore, this study is planned to identify risk factors among lower socioeconomic rural population of surrounding areas of Hyderabad in India. MATERIALS AND METHODS: This was a prospective study in which all the suicide attempt cases reported at Bhaskar Medical College and General Hospital were included. The study period was from January 2013 to July 2013. They were undergone a detailed psychiatric interview, including their demographic details, and complete suicide risk assessment was done using Beck's suicide intent scale. RESULTS: It was found that females in the age group of 20-30 years, uneducated, married and daily laborers by occupation had higher incidence of suicidal attempts. Depressive disorder is the most common associated psychiatric disorder in both the genders, followed by alcohol use related problems. Family disputes are the other major risk factors. Most common mode for attempt was organophosphorous poisoning followed by ingestion of calotropis. CONCLUSION: Risk of suicide attempt is almost equal in terms of medium and high category of suicide assessment scale in both genders. We suggest that all individuals with alcohol related disorders must be screened for suicidal ideation so that appropriate methods can be adopted to reduce the risk. PMID- 25722510 TI - Early Life Stress as a Risk Factor for Substance use Disorders: Clinical and Neurobiological Substrates. AB - BACKGROUND: Early Life Stress (ELS) can profoundly influence an individual's genotype and phenotype. Effects of ELS can manifest in the short-term, late life and even in subsequent generations. ELS activate corticotrophin releasing factor (CRF); CRF influences drug seeking and addiction. The aim of this study was to examine the effects of endogenous elevated levels of CRF on addiction. MATERIALS AND METHODS: Inducible forebrain over-expression of CRF mice (tetop-CRH x CaMKII tTA) was used for this study. Morphine (10 mg/kg) was administered every other day for 10 days or with increasing doses of morphine: 20, 40, 60, 80, 100, and 100 mg/kg. The behavioral trials including morphine sensitization, Somatic Opiate Withdrawal Symptoms (SOWS) were conducted in a single, open field, activity. After behavioral trial, animals were perfused for immunohistochemistry analysis. RESULTS: CRF-over expressed (CRF-OE) mice showed increase in morphine sensitization and withdrawal symptoms after morphine administration compared to wild type (WT) mice. The two-way ANOVA in the morphine sensitization study showed a significant effect of treatment (P<0.05) and genotype for distance traveled (P<0.01). In the SOWS study, opiate withdrawal symptoms such as rearings, circling behavior, grooming, and jump in CRF-OE were amplified in parallel to WT mice. In the immunohistochemistry study, pro-dynorphine (PDYN) expression was increased after morphine administration in both amygdala and nucleus accumbens (NAcc). CONCLUSIONS: CRF-OE in the forebrain increases the sensitization and withdrawal symptoms in morphine treated mice. On exposure to morphine, in CRF-OE mice the PDYN protein expression was increased as compared to WT mice in the amygdala and NAcc. PMID- 25722512 TI - IQ in Autism: Is there an Alternative Global Cognitive Index? AB - BACKGROUND: Intelligence quotient (IQ) but not the core symptoms have been known to predict outcomes in autism. Besides resource issues in India, assessing IQ in presence of autistic symptoms is challenging in general. MATERIALS AND METHODS: In a pilot study, we explored different global indices of development in 30 children with confirmed autism. These included Wechsler intelligence scale for children or Wechsler preprimary scale of intelligence-revised (n = 10), Raven's progressive matrices (RPM) (n = 10), Vineland adaptive behavior scales II, parent report version (VABS) (n = 30) and teacher's estimate of mental age (TIQ) (n = 30). Three subgroups (Group A) with Wechsler's scales derived IQ (WISIQ), (Group B) with RPM derived IQ and (Group C) those without a formal IQ measure were compared. RESULTS: All groups were comparable on age and their scores on Childhood Autism Rating Scale and Indian Scale for Assessment of Autism Adaptive behavior composite scores (Ad Bh composite) derived from VABS and WISIQ showed significant correlations with each other in Group A; TIQ significantly correlated with Ad Bh composite scores, but not with the WISIQ, although the latter two scores themselves did not significantly differ from each other. RPM consistently overestimated children's performance compared to Ad Bh composite or TIQ in Group B, but the Ad Bh composite and TIQ were themselves significantly correlated. In Group C, there were poor correlations between Ad Bh composite and TIQ. The Ad Bh composite score in this group was significantly different from the other two groups. CONCLUSION: There is a need to fine tune the assessment for global cognitive measures in autism and explore their real world importance. PMID- 25722511 TI - Apraxias in neurodegenerative dementias. AB - BACKGROUND: Apraxia is a state of inability to carry out a learned motor act in the absence of motor, sensory or cerebellar defect on command processed through the Praxis circuit. Breakdown in default networking is one of the early dysfunction in cortical dementias and result in perplexity, awkwardness, omission, substitution errors, toying behavior and unrecognizable gestures in response to command with voluntary reflex dissociation where, when unobserved patient will carry out reflex movements normally. Awareness into the organicity of these phenomenas will help in early diagnosis, which will help in initiating appropriate treatment and slowing down the progression of the disease. AIMS AND OBJECTIVES: The aim was to look for the various kinds of apraxias in patients with dementia using appropriate simple tests. PATIENTS AND METHODS: Three hundred patients satisfying Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia were evaluated in detail with mandatory investigations for dementia followed by testing for ideational, ideomotor, limb kinetic, buccopharyngeal, dressing apraxia, constructional apraxia and gait apraxias in addition to recording of rare apraxias when present. RESULTS: Alzheimer's disease showed maximum association with apraxias in all the phases of the disease ideational, ideomotor, dressing and constructional apraxias early and buccopharyngeal and gait apraxia late. Frontotemporal lobe dementia showed buccopharyngeal and gait apraxias late into the disease. Cortical basal ganglionic degeneration showed limb apraxias and diffuse Lewy body disease showed more agnosias and less apraxias common apraxias seen was Ideational and Ideomotor. CONCLUSION: Recognition of the apraxias help in establishing organicity, categorization, caregiver education, early strategies for treatment, avoiding anti-psychotics and introducing disease modifying pharmacotherapeutic agents and also prognosticating. PMID- 25722513 TI - Event-related potentials study in children with borderline intellectual functioning. AB - BACKGROUND: Low general cognitive ability is a common cause for learning and academic difficulties. The present study was undertaken to objectively investigate the cognitive functioning of children having borderline intelligence using electrophysiological measures. MATERIALS AND METHODS: The study was conducted on children having borderline intelligence (IQ: 70-85). The cognitive functioning of children was assessed using event-related potentials. RESULTS: Significant prolongation of the latency of P200, N200, and P300 with no significant difference in the amplitudes was seen in the children having borderline intelligence as compared to controls. CONCLUSIONS: Brain systems that are important for stimulus discrimination and using cognitive representation to guide cognition and behavior are impaired in children with borderline intelligence. PMID- 25722514 TI - Mirror neuron dysfunction and ego-boundary disturbances in schizophrenia: a transcranial magnetic stimulation study. AB - BACKGROUND: Ego-boundary disturbance (EBD) is a unique symptom cluster characterized by passivity experiences (involving thoughts, actions, emotions and sensations) attributed by patients to some external agency. The neurobiology of these "first rank" symptoms is poorly understood. Aberrant mirror neuron activation may explain impaired self-monitoring and agency attribution underlying these symptoms. We aim to study mirror neuron activity (MNA) in schizophrenia patients with and without EBD using transcranial magnetic stimulation (TMS). MATERIALS AND METHODS: 50 right-handed schizophrenia patients (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were evaluated using the Mini-International Neuropsychiatric Interview and the Positive and Negative Syndrome Scale. They completed a TMS experiment to assess putative premotor MNA. Motor evoked potential (MEP) was recorded in the right first dorsal interosseous muscle (FDI) with (a) 120% of resting motor threshold (RMT), (b) stimulus intensity set to evoke MEP of motor threshold 1 mV amplitude (MT1), (c) two paired pulse paradigms (short- and long interval intra-cortical inhibition). These were done in three states: Actual observation of an action using the FDI, virtual-observation (video) of this action and resting state. The percent change of MEP from resting to action-observation states formed the measure of putative MNA. RESULTS: MNA measured using MT1 and 120% RMT paradigms was significantly lower in the 18 patients with EBD (thought-broadcast/withdrawal/insertion, made act/impulse/affect and somatic passivity) than the 32 patients without EBD (t = 2.431, P = 0.020; t = 2.051, P = 0.04 respectively for the two paradigms). The two groups did not differ on age, gender, education and total symptom scores. CONCLUSION: Schizophrenia patients with EBD have lower premotor MNA. This highlights the role of MNA dysfunction in the pathophysiology of this unique and intriguing symptom cluster in schizophrenia. PMID- 25722515 TI - Prevalence of psychiatric disorders in patients with a diagnosis of polycystic ovary syndrome in kashmir. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the common endocrine disorders and is associated with reproductive, metabolic, and psychological disturbances affecting one in five women of reproductive age group. OBJECTIVE: To investigate the prevalence of psychiatric disorders among women in ambulatory treatment with a diagnosis of PCOS. MATERIALS AND METHODS: One hundred and ten patients of PCOS were evaluated using Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria by means of Mini International Neuropsychiatric Interview, English version 5.0.0. Diagnosis of PCOS was confirmed according to the National Institute of Health/National Institute of Child Health and Human Development, 1990 consensus conference criteria. Forty subjects without PCOS who were matched for age and body mass index were taken as a comparison group. RESULTS: About 23% of cases had major depressive disorder as compared to 7.5% of controls, 1.8% had dysthymia, 15.45% had panic disorder compared to 5% of controls, 6.36% had obsessive compulsive disorder compared to 2.5% of controls, 8% cases had suicidality, 2.72% of cases were bipolar affective disorder, and 15.45% had generalized anxiety disorder (GAD). CONCLUSION: A high prevalence of mental disorders was observed, especially major depression, panic disorder, and GAD in patients with PCOS in our study. The results suggest that screening and appropriate management for psychiatric disorders should be part of the routine evaluation of these patients. PMID- 25722516 TI - Cost of care: a study of patients hospitalized for treatment of psychotic illness. AB - BACKGROUND: Combination of ill health and poverty poses special challenges to health care providers. Mental illness and costs are linked in terms of long-term treatment and lost productivity, and it affects social development. The purpose of the present study is to assess the economic burden of poor families when a family member needs hospitalization due to psychosis. MATERIALS AND METHODS: The information was gathered from caregivers of 100 psychotic inpatients of Medical College Hospital of Kerala during a period of 6 months. Data regarding components of expenses such as cost of medicine, laboratory investigations, food, travel, and other miscellaneous expenses during their inpatient period were collected by direct personal interview using specially designed proforma. The data were analyzed using Epi-info software. The patients below the poverty line (BPL) were compared with those above poverty line (APL). RESULTS: There was no significant difference between patients from BPL and APL in respect of amounts spent on the studied variables except for laboratory investigations during the hospital stay. CONCLUSIONS: The results showed that the studied subjects are facing financial difficulties not only due to hospitalization, but also due to the recurrent expense of their ongoing medication. The study recommends the need of financial support from the government for the treatment of psychotic patients. PMID- 25722517 TI - Pattern and predictors of alcohol use disorders in a family practice in Nigeria. AB - BACKGROUND: Primary care has been identified as a key setting for the reduction of alcohol-related harm, while general practitioners are expected to play a significant role. The study aimed at identifying pattern of, and factors that are associated with alcohol use disorders (AUDs) among patients attending Family Medicine unit of State University Teaching Hospital. MATERIALS AND METHODS: Sample was selected through a random sampling from a population of patients, aged 18-65 years, attending the general medical out-patients unit of the hospital from January to April 2013. A pretested, semi-structured questionnaire was administered, incorporating sociodemographics and the diagnoses made by the attending Physician. The participants also completed the alcohol use disorders identification test (AUDIT) questionnaire and the patient health questionnaire-9. RESULTS: The prevalence of AUDs among the population of general out-patients was 9.7%. The AUDIT scores of the participants range from 0 to 29 with a mean of 1.3 (standard deviation = 4.08). AUDs were significantly associated with gender, level of education, occupational class, and the presence of significant depressive symptoms (P < 0.05). There was no statistically significant association found for age, employment status, marital status, and religion. CONCLUSION: The prevalence of AUDs among population studied was lower compared with a similar study in similar setting, but however, significant. AUDs were predicted by gender, lower education level, occupational group, and the presence of significant depressive symptoms mostly in the mild to moderate form. Identifying the group at risk in clinical setting may go a long way in reducing the adverse effect of AUDs in our society. PMID- 25722518 TI - Can masturbatory guilt lead to severe psychopathology: a case series. AB - Masturbation is common in all societies. Despite being common, it is admonished culturally and almost all religions prohibit masturbation and consider it an act of immorality. The prohibition for masturbation leads to a lot of cultural beliefs, including certain myths, which influence sexual behavior of the person. The impact of these common cultural myths associated with masturbation, are clinically understood as Dhat syndrome and masturbatory guilt. Although there is a reasonable literature on Dhat syndrome, there is limited literature with regard to masturbatory guilt especially linking the same with axis-I psychopathology. In this case series, three cases of masturbatory guilt are presented in whom masturbatory guilt was associated with manifestation of severe psychopathology. This report suggests that masturbatory guilt must be enquired for in patients presenting with severe mental disorder. PMID- 25722519 TI - Effectiveness of solution-focused brief therapy for an adolescent girl with moderate depression. AB - Globally, the solution-focused brief therapy is practiced in persons with depression. In India, fewer studies have documented about the treatment outcome of solution-focused therapy among persons with depression. The current study was carried out with a 19-year-old girl, studying SSLC (10(th) Standard) was diagnosed with moderate depression. She had difficulty in attention, concentration, memory, irritability and sad mood, poor academic performance, guilt feelings, lethargic, anhedonia, decreased sleep, and decreased appetite. The case worker has chosen provided 6 sessions of solution focused therapy for depression. There was considerable improvement in her symptoms and in scholastic performance. The current study supports the effectiveness of solution-focused therapy in persons with depression. PMID- 25722520 TI - Munchausen syndrome by proxy: an alarming face of child abuse. AB - Munchausen syndrome by proxy (MSBP) is emerging as a serious form of child abuse. It is an intentional production of illness in another, usually children by mothers, to assume sick role by proxy. It is poorly understood and a controversial diagnosis. Treatment is very difficult. We present a case of 9-year old boy brought to Pt. B. D. Sharma, PGIMS, Rohtak, a tertiary care hospital in northern India by his father and paternal uncle with complaints of hematemesis since July 2012. He underwent many invasive procedures until the diagnosis of MSBP was finally considered. The examination of the blood sample confirmed the diagnosis. The child was placed under custody of his mother. The case was reported to social services, which incorporated whole family in the management. PMID- 25722521 TI - Dermatosis neglecta in schizophrenia: a rare case report. AB - Dermatosis neglecta is a chronic, dermatologic disorder results in ignored, neglected body parts due to chronic disability or painful conditions. There is scarcity of literature supporting the existence of dermatosis neglecta in the context of psychiatric illnesses. In this case report, we attempts to highlight, dermatosis neglecta in a homeless patient suffering from schizophrenia. PMID- 25722522 TI - Mania induced by opipramol. AB - Antidepressants have propensity to induce manic switch in patients with bipolar disorder. Opipramol is an atypical anxiolytic and antidepressant drug which predominantly acts on sigma receptors. Although structurally resembles tricyclic antidepressant imipramine it does not have inhibitory action on the reuptake of norepinephrine/serotonin and hence it is not presumed to cause manic switch in bipolar depression. Here, we describe a case of mania induced by opipramol, in a patient with bipolar affective disorder who was treated for moderate depressive episode with lithium and opipramol and we discuss neurochemical hypothesis of opipramol-induced mania. PMID- 25722523 TI - Carbamazepine induced asterixis with hyperammonemia: a case report with review of literature. AB - Asterixis with hyperammonemia is an uncommon side-effect reported with carbamazepine. We report a case of carbamazepine induced asterixis with hyperammonemia and also the review of published literature on the same. PMID- 25722524 TI - Musical obsessions: a case report and review of literature. AB - The phenomenon of musical obsessions is scantly researched and poorly established. Here we present a case with musical obsessions in addition to body dysmorphophia and severe depression and review the available literature for musical obsessions. PMID- 25722525 TI - Sleep-walking a rarest side effect of zolpidem. AB - A 46-years-old male, with past history of road traffic accident and with no current/past history of substance abuse and no family history of sleep-walking, took zolpidem 10 mg without any prescription and after few days, the patient's son noticed the patient waking up in the middle of night and walking into their room with a staring expression and some incoherent speech. The patient had no memory of this event in the morning. This sleep-walking episode was attributed to zolpidem, as no medication change was made besides new start of zolpidem and the patient had no history of such episodes in the past. Zolpidem treatment was stopped, and since then, no further complaints of sleep-walking were reported. PMID- 25722526 TI - Tramadol and sexual dysfunction. PMID- 25722527 TI - Is dhat syndrome indeed a culturally determined form of depression? PMID- 25722528 TI - Relevance of early career psychiatrist associations. PMID- 25722529 TI - Psychobiotics: the latest psychotropics. PMID- 25722530 TI - Erratum: psychiatric morbidity and quality of life in vitiligo patients: erratum. AB - [This corrects the article on p. 302 in vol. 36, PMID: 25035556.]. PMID- 25722531 TI - Prognostic utility of vitamin D in acute coronary syndrome patients in coastal Norway. AB - BACKGROUND: An inverse relationship between cardiovascular risk and levels of vitamin D and omega-3 index may exist. OBJECTIVES: To evaluate the prognostic utility of serum 25-hydroxyvitamin D [25(OH)D] in 871 patients with suspected acute coronary syndrome (ACS) and to assess the seasonal correlation between 25(OH)D and the omega-3 index in 456 ACS patients from southwestern Norway. RESULTS: In the univariate analysis the hazard ratio (HR) at 2-year follow-up for all-cause mortality in the highest as compared to the lowest quartile of 25(OH)D in the total population was 0.61 (95% confidence interval (CI), 0.37-1.00), P = 0.050. At 7-year follow-up, the corresponding HR for all-cause mortality was 0.66 (95% CI, 0.49-0.90), P = 0.008, and for females alone 0.51 (95% CI, 0.32-0.83), P = 0.006. Quartile survival did not differ in the multivariable analysis, whereas 25(OH)D < 40 nM (<16 ng/mL) was found to be independently related to mortality. Seasonal differences in 25(OH)D, but not for the omega-3 index, were noted, and the two biomarkers were positively correlated, especially during winter-spring; Pearson's correlation coefficient was 0.358, P < 0.001. CONCLUSION: Vitamin D levels are related to survival, especially in females, and correlate with the omega-3 index. PMID- 25722533 TI - In vivo and in vitro phenotypic differences between Great Lakes VHSV genotype IVb isolates with sequence types vcG001 and vcG002. AB - Viral hemorrhagic septicemia virus (VHSV) is an aquatic rhabdovirus first recognized in farmed rainbow trout in Denmark. In the past decade, a new genotype of this virus, IVb was discovered in the Laurentian Great Lakes basin and has caused several massive die-offs in some of the 28 species of susceptible North American freshwater fishes. Since its colonization of the Great Lakes, several closely related sequence types within genotype IVb have been reported, the two most common of which are vcG001 and vcG002. These sequence types have different spatial distributions in the Great Lakes. The aim of this study was to determine whether the genotypic differences between representative vcG001 (isolate MI03) and vcG002 (isolate 2010-030 #91) isolates correspond to phenotypic differences in terms of virulence using both an in vitro and in vivo approach. In vitro infection of epithelioma papulosum cyprini (EPC), bluegill fry (BF-2), and Chinook salmon embryo (CHSE) cells demonstrated some differences in onset and rate of growth in EPC and BF-2 cells, without any difference in the quantity of RNA produced. In vivo infection of round gobies (Neogobius melanostomus) via immersion exposure to different concentrations of vcG001 or vcG002 caused a significantly greater mortality in round gobies exposed to 102 plaque forming units ml-1 of vcG001. These experiments suggest that there are phenotypic differences between Great Lakes isolates of VHSV genotype IVb. PMID- 25722532 TI - Fatigue in patients with multiple sclerosis: is it related to pro- and anti inflammatory cytokines? AB - OBJECTIVE: To investigate the pathophysiological role of pro- and anti inflammatory cytokines in primary multiple sclerosis-related fatigue. METHODS: Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue <=34) and fatigued (CIS20r fatigue >=35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1beta, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFalpha, and IFN-gamma) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. RESULTS: Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. CONCLUSION: The pro-inflammatory cytokine interleukin 6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS. TRIAL REGISTRATIONS: ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628. PMID- 25722534 TI - The Media and Technology Usage and Attitudes Scale: An empirical investigation. AB - Current approaches to measuring people's everyday usage of technology-based media and other computer-related activities have proved to be problematic as they use varied outcome measures, fail to measure behavior in a broad range of technology related domains and do not take into account recently developed types of technology including smartphones. In the present study, a wide variety of items, covering a range of up-to-date technology and media usage behaviors. Sixty-six items concerning technology and media usage, along with 18 additional items assessing attitudes toward technology, were administered to two independent samples of individuals, comprising 942 participants. Factor analyses were used to create 11 usage subscales representing smartphone usage, general social media usage, Internet searching, e-mailing, media sharing, text messaging, video gaming, online friendships, Facebook friendships, phone calling, and watching television in addition to four attitude-based subscales: positive attitudes, negative attitudes, technological anxiety/dependence, and attitudes toward task switching. All subscales showed strong reliabilities and relationships between the subscales and pre-existing measures of daily media usage and Internet addiction were as predicted. Given the reliability and validity results, the new Media and Technology Usage and Attitudes Scale was suggested as a method of measuring media and technology involvement across a variety of types of research studies either as a single 60-item scale or any subset of the 15 subscales. PMID- 25722535 TI - Gaseous and Particulate Emissions from Diesel Engines at Idle and under Load: Comparison of Biodiesel Blend and Ultralow Sulfur Diesel Fuels. AB - Diesel exhaust emissions have been reported for a number of engine operating strategies, after-treatment technologies, and fuels. However, information is limited regarding emissions of many pollutants during idling and when biodiesel fuels are used. This study investigates regulated and unregulated emissions from both light-duty passenger car (1.7 L) and medium-duty (6.4 L) diesel engines at idle and load and compares a biodiesel blend (B20) to conventional ultralow sulfur diesel (ULSD) fuel. Exhaust aftertreatment devices included a diesel oxidation catalyst (DOC) and a diesel particle filter (DPF). For the 1.7 L engine under load without a DOC, B20 reduced brake-specific emissions of particulate matter (PM), elemental carbon (EC), nonmethane hydrocarbons (NMHCs), and most volatile organic compounds (VOCs) compared to ULSD; however, formaldehyde brake specific emissions increased. With a DOC and high load, B20 increased brake specific emissions of NMHC, nitrogen oxides (NOx), formaldehyde, naphthalene, and several other VOCs. For the 6.4 L engine under load, B20 reduced brake-specific emissions of PM2.5, EC, formaldehyde, and most VOCs; however, NOx brake-specific emissions increased. When idling, the effects of fuel type were different: B20 increased NMHC, PM2.5, EC, formaldehyde, benzene, and other VOC emission rates from both engines, and changes were sometimes large, e.g., PM2.5 increased by 60% for the 6.4 L/2004 calibration engine, and benzene by 40% for the 1.7 L engine with the DOC, possibly reflecting incomplete combustion and unburned fuel. Diesel exhaust emissions depended on the fuel type and engine load (idle versus loaded). The higher emissions found when using B20 are especially important given the recent attention to exposures from idling vehicles and the health significance of PM2.5. The emission profiles demonstrate the effects of fuel type, engine calibration, and emission control system, and they can be used as source profiles for apportionment, inventory, and exposure purposes. PMID- 25722536 TI - Does probability of occurrence relate to population dynamics? AB - Hutchinson defined species' realized niche as the set of environmental conditions in which populations can persist in the presence of competitors. In terms of demography, the realized niche corresponds to the environments where the intrinsic growth rate (r) of populations is positive. Observed species occurrences should reflect the realized niche when additional processes like dispersal and local extinction lags do not have overwhelming effects. Despite the foundational nature of these ideas, quantitative assessments of the relationship between range-wide demographic performance and occurrence probability have not been made. This assessment is needed both to improve our conceptual understanding of species' niches and ranges and to develop reliable mechanistic models of species geographic distributions that incorporate demography and species interactions. The objective of this study is to analyse how demographic parameters (intrinsic growth rate r and carrying capacity K) and population density (N) relate to occurrence probability (Pocc ). We hypothesized that these relationships vary with species' competitive ability. Demographic parameters, density, and occurrence probability were estimated for 108 tree species from four temperate forest inventory surveys (Quebec, Western US, France and Switzerland). We used published information of shade tolerance as indicators of light competition strategy, assuming that high tolerance denotes high competitive capacity in stable forest environments. Interestingly, relationships between demographic parameters and occurrence probability did not vary substantially across degrees of shade tolerance and regions. Although they were influenced by the uncertainty in the estimation of the demographic parameters, we found that r was generally negatively correlated with Pocc , while N, and for most regions K, was generally positively correlated with Pocc . Thus, in temperate forest trees the regions of highest occurrence probability are those with high densities but slow intrinsic population growth rates. The uncertain relationships between demography and occurrence probability suggests caution when linking species distribution and demographic models. PMID- 25722537 TI - The influence of interspecific interactions on species range expansion rates. AB - Ongoing and predicted global change makes understanding and predicting species' range shifts an urgent scientific priority. Here, we provide a synthetic perspective on the so far poorly understood effects of interspecific interactions on range expansion rates. We present theoretical foundations for how interspecific interactions may modulate range expansion rates, consider examples from empirical studies of biological invasions and natural range expansions as well as process-based simulations, and discuss how interspecific interactions can be more broadly represented in process-based, spatiotemporally explicit range forecasts. Theory tells us that interspecific interactions affect expansion rates via alteration of local population growth rates and spatial displacement rates, but also via effects on other demographic parameters. The best empirical evidence for interspecific effects on expansion rates comes from studies of biological invasions. Notably, invasion studies indicate that competitive dominance and release from specialized enemies can enhance expansion rates. Studies of natural range expansions especially point to the potential for competition from resident species to reduce expansion rates. Overall, it is clear that interspecific interactions may have important consequences for range dynamics, but also that their effects have received too little attention to robustly generalize on their importance. We then discuss how interspecific interactions effects can be more widely incorporated in dynamic modeling of range expansions. Importantly, models must describe spatiotemporal variation in both local population dynamics and dispersal. Finally, we derive the following guidelines for when it is particularly important to explicitly represent interspecific interactions in dynamic range expansion forecasts: if most interacting species show correlated spatial or temporal trends in their effects on the target species, if the number of interacting species is low, and if the abundance of one or more strongly interacting species is not closely linked to the abundance of the target species. PMID- 25722538 TI - Anticipating the spatio-temporal response of plant diversity and vegetation structure to climate and land use change in a protected area. AB - Vegetation is a key driver of ecosystem functioning (e.g. productivity and stability) and of the maintenance of biodiversity (e.g. creating habitats for other species groups). While vegetation sensitivity to climate change has been widely investgated, its spatio-temporally response to the dual efects of land management and climate change has been ignored at landscape scale. Here we use a dynamic vegetation model called FATE-HD, which describes the dominant vegetation dynamics and associated functional diversity, in order to anticipate vegetation response to climate and land-use changes in both short and long-term perspectives. Using three contrasted management scenarios for the Ecrins National Park (French Alps) developed in collaboration with the park managers, and one regional climate change scenario, we tracked the dynamics of vegetation structure (forest expansion) and functional diversity over 100 years of climate change and a further 400 additional years of stabilization. As expected, we observed a slow upward shift in forest cover distribution, which appears to be severely impacted by pasture management (i.e. maintenance or abandonment). The tme lag before observing changes in vegetation cover was the result of demographic and seed dispersal processes. However, plant diversity response to environmental changes was rapid. Afer land abandonment, local diversity increased and spatial turnover was reduced, whereas local diversity decreased following land use intensification. Interestingly, in the long term, as both climate and management scenarios interacted, the regional diversity declined. Our innovative spatio temporally explicit framework demonstrates that the vegetation may have contrasting responses to changes in the short and the long term. Moreover, climate and land-abandonment interact extensively leading to a decrease in both regional diversity and turnover in the long term. Based on our simulations we therefore suggest a continuing moderate intensity pasturing to maintain high levels of plant diversity in this system. PMID- 25722539 TI - Are different facets of plant diversity well protected against climate and land cover changes? A test study in the French Alps. AB - Climate and land cover changes are important drivers of the plant species distributions and diversity patterns in mountainous regions. Although the need for a multifaceted view of diversity based on taxonomic, functional and phylogenetic dimensions is now commonly recognized, there are no complete risk assessments concerning their expected changes. In this paper, we used a range of species distribution models in an ensemble-forecasting framework together with regional climate and land cover projections by 2080 to analyze the potential threat for more than 2,500 plant species at high resolution (2.5 km * 2.5 km) in the French Alps. We also decomposed taxonomic, functional and phylogenetic diversity facets into alpha and beta components and analyzed their expected changes by 2080. Overall, plant species threats from climate and land cover changes in the French Alps were expected to vary depending on the species' preferred altitudinal vegetation zone, rarity, and conservation status. Indeed, rare species and species of conservation concern were the ones projected to experience less severe change, and also the ones being the most efficiently preserved by the current network of protected areas. Conversely, the three facets of plant diversity were also projected to experience drastic spatial re-shuffling by 2080. In general, the mean alpha-diversity of the three facets was projected to increase to the detriment of regional beta-diversity, although the latter was projected to remain high at the montane-alpine transition zones. Our results show that, due to a high-altitude distribution, the current protection network is efficient for rare species, and species predicted to migrate upward. Although our modeling framework may not capture all possible mechanisms of species range shifts, our work illustrates that a comprehensive risk assessment on an entire floristic region combined with functional and phylogenetic information can help delimitate future scenarios of biodiversity and better design its protection. PMID- 25722541 TI - Intelligence and social competence among high-risk adolescents. AB - Interactions between intelligence and psychosocial factors were examined in terms of influences on social competence among 144 inner-city ninth-grade students. Psychosocial variables examined included ego development, locus of control, and positive and negative life events. Definitions of social competence were based on peer ratings, teacher ratings, and school grades. Results indicated that, unlike their less intelligent peers, intelligent youngsters showed higher competence levels at high versus low levels of both ego development and internal locus of control. Findings were interpreted in the context of sociocultural influences on academic achievement among disadvantaged adolescents. PMID- 25722542 TI - Resilience is not a unidimensional construct: Insights from a prospective study of inner-city adolescents. AB - The maintenance of high social competence despite stress was examined in a 6 month prospective study of 138 inner-city ninth-grade students. The purpose was to provide a replication and extension of findings derived from previous cross sectional research involving a comparable sample of children. Specifically, goals were to examine the extent to which high-stress children with superior functioning on one or more aspects of school-based social competence could evade significant difficulties in (a) other spheres of competence at school and (b) emotional adjustment. Measurements of stress were based on uncontrollable negative life events. Competence was assessed via behavioral indices including school grades, teacher ratings, and peer ratings, and emotional distress was measured via self-reports. Results indicated that high-stress children who showed impressive behavioral competence were highly vulnerable to emotional distress over time. Furthermore, almost 85% of the high-stress children who seemed resilient based on at least one domain of social competence at Time 1 had significant difficulties in one or more domains examined when assessed at both Time 1 and Time 2. Findings are discussed in terms of conceptual and empirical issues in resilience research. PMID- 25722540 TI - Toxicant exposure and bioaccumulation: a common and potentially reversible cause of cognitive dysfunction and dementia. AB - Juxtaposed alongside the ongoing rise in the incidence and prevalence of dementia, is the surge of recent research confirming widespread exposure and bioaccumulation of chemical toxicants. Evidence from sources such as the Centers for Disease Control reveals that most people have accrued varying degrees of assorted toxic pollutants including heavy metals, flame retardants, and pesticide residues within their bodies. It has been well established that many of these toxicants have neurodegenerative as well as neurodevelopmental impact as a result of various pathophysiologic mechanisms including neuronal mitochondrial toxicity and disruption of neurotransmitter regulation. Elimination of stockpiled toxicants from the body may diminish adverse toxicant impact on human biology and allow restoration of normal physiological function. Incorporating a review of medical literature on toxicant exposure and dementia with a case history of a lead-exposed individual diagnosed with dementia, this paper will discuss a much overlooked and potentially widespread cause of declining brain function and dementia. PMID- 25722543 TI - Displaced and non-displaced Colombian children's evaluations of moral transgressions, retaliation, and reconciliation. AB - In order to assess the effects of displacement and exposure to violence on children's moral reasoning, Colombian children exposed to minimal violence (non displaced or low-risk) (N = 99) and to extreme violence (displaced or high-risk) (N = 94), evenly divided by gender, at 6-, 9-, and 12 - years of age, were interviewed regarding their evaluation of peer-oriented moral transgressions (hitting and not sharing toys). The vast majority of children evaluated moral transgressions as wrong. Group and age differences were revealed, however, regarding provocation and retaliation. Children who were exposed to violence, in contrast to those with minimum exposure, judged it more legitimate to inflict harm or deny resources when provoked and judged it more okay to retaliate for reasons of retribution. Surprisingly, and somewhat hopefully, all children viewed reconciliation as feasible. The results are informative regarding theories of morality, culture, and the effects of violence on children's social development. PMID- 25722544 TI - Proximal or distal? That is the question! PMID- 25722545 TI - It's only infection prevention, but infection prevention is all we have. PMID- 25722546 TI - Gradual sucrose gastric loading test: Does it really matter? PMID- 25722547 TI - Randomized study to compare nasojejunal with nasogastric nutrition in critically ill patients without prior evidence of altered gastric emptying. AB - BACKGROUND AND AIMS: Studies comparing jejunal and gastric nutrition show inconsistent results regarding pneumonia. The aim of this study was to evaluate the incidence of pneumonia comparing gastric with jejunal nutrition. Secondarily, we evaluated 28(th) day Intensive Care Unit (ICU) mortality rate and other complications related to enteral feeding. SUBJECTS: Age >18 years; need for enteral nutrition without contraindication for placement of an enteral tube, duration of ICU stay > than 48 h. METHODS: Patients were randomly assigned to receive enteral feed via a gastric or jejunal tube. Jejunal tubes were inserted at bedside and placement was confirmed radiographically. RESULTS: A total of 115 patients were enrolled, with 61 patients into the gastric tube group and 54 patients into the jejunal group tube. Baseline characteristics were similar. There was no difference in pneumonia or ICU mortality rates, ICU length of stay and ventilator days. Complications rates were similar. CONCLUSIONS: We conclude that the enteral nutrition through a jejunal tube does not reduce the rate of pneumonia in comparison to a gastric tube. In addition, we did not observe differences in rates of gastrointestinal complications or ICU mortality. The routine placement of a jejunal tube in critically ill-patients cannot be recommended. PMID- 25722548 TI - Knowledge and attitude of doctors and nurses regarding indication for catheterization and prevention of catheter-associated urinary tract infection in a tertiary care hospital. AB - BACKGROUND AND AIMS: Catheter-associated urinary tract infection (CAUTI) is one of the most common health care acquired infection encountered in clinical practice. The present study was planned to assess the knowledge and attitude of health care providers regarding the indications for catheterization and methods of preventing CAUTI. METHODS: A prospective questionnaire-based survey was done from March 2011 to August 2011. A structured questionnaire comprising of 41 items related to demographic details of the respondents, their knowledge regarding indications for catheterization and methods of preventing CAUTI was given to 54 doctors and 105 nurses. The response was evaluated for statistical correlation using a computer software. RESULTS: The mean years of experience of the respondents in the health care setup was 6.8 years. Only 57% of the respondents could identify all the measures for prevention of CAUTI. The knowledge regarding the indication for catheterization though suboptimal was significantly better amongst the doctors as compared to nurses. CONCLUSION: The knowledge regarding indication and preventive measures was suboptimal in our study group. There is a tremendous scope of improvement in catheterization practices in our hospital and education induced intervention would be the most appropriate effort toward reducing the incidence of CAUTI. PMID- 25722549 TI - A comparative study of complications and long term outcomes of Surgical Tracheostomy and two techniques of Percutaneous Tracheostomy. AB - CONTEXT: The operative technique for surgical tracheostomy has remained unchanged, but different techniques for percutaneous tracheostomy have evolved due to interest in minimally invasive procedures for the critically ill patient. AIMS: To compare the periprocedural complications and long term outcomes of bedside surgical tracheostomy (ST) with two percutaneous tracheostomy (PCT) techniques, namely serial guide wire dilating forceps (GWDF) and PercuTwist (PT). SETTINGS AND DESIGN: This prospective observational study was carried out in ICU of a tertiary referral centre over three year period on adult intubated patients needing elective tracheostomy. MATERIALS AND METHODS: Patients with anticipated difficult neck anatomy were assigned for ST based on discretion of intensivist. Patients included for PCT were randomly assigned to the GWDT and PT technique. 90 patients underwent either bedside ST (n = 30), PCT by GWDF technique (n = 30) or PCT with PercuTwist (n = 30) and were followed up with fibreoptic bronchoscopy monthly for 06 months. STATISTICAL ANALYSIS USED: Data was analyzed by applying chi square tests for categorical variables. RESULTS: Periprocedural complications during PCT included major bleeding (>100ml) in two patients in GWDF group which required conversion to ST. Periprocedural bleeding was also the main complication in ST. Increased incidence of granulation tissue and tracheal narrowing in long term was seen in both ST and PCT groups. All of the P values analysed for the intra operative, post operative complications or long term outcomes were >0.05. CONCLUSIONS: There was no statistically significant difference in incidence of complications of ST and two techniques of PCT. Proper case selection makes PCT as safe as ST. PMID- 25722550 TI - Comparison of acute physiology and chronic health evaluation II and acute physiology and chronic health evaluation IV to predict intensive care unit mortality. AB - CONTEXT: Clinical assessment of severity of illness is an essential component of medical practice to predict the outcome of critically ill-patient. Acute Physiology and Chronic Health Evaluation (APACHE) model is one of the widely used scoring systems. AIMS: This study was designed to evaluate the Performance of APACHE II and IV scoring systems in our Intensive Care Unit (ICU). SETTINGS AND DESIGN: A prospective study in 6 bedded ICU, including 76 patients all above 15 years. SUBJECTS AND METHODS: APACHE II and APACHE IV scores were calculated based on the worst values in the first 24 h of admission. All enrolled patients were followed, and outcome was recorded as survivors or nonsurvivors. STATISTICAL ANALYSIS USED: SPSS version 17. RESULTS: The mean APACHE score was significantly higher among nonsurvivors than survivors (P < 0.005). Discrimination for APACHE II and APACHE IV was fair with area under receiver operating characteristic curve of 0.73 and 0.79 respectively. The cut-off point with best Youden index for APACHE II was 17 and for APACHE IV was 85. Above cut-off point, mortality was higher for both models (P < 0.005). Hosmer-Lemeshow Chi-square coefficient test showed better calibration for APACHE II than APACHE IV. A positive correlation was seen between the models with Spearman's correlation coefficient of 0.748 (P < 0.01). CONCLUSIONS: Discrimination was better for APACHE IV than APACHE II model however Calibration was better for APACHE II than APACHE IV model in our study. There was good correlation between the two models observed in our study. PMID- 25722551 TI - Gradual sucrose gastric loading test: A method for the prediction of nonsuccess gastric enteral feeding in critically ill surgical patients. AB - BACKGROUND AND AIMS: Intolerance of gastric enteral feeding (GEN) commonly occurs in surgical Intensive Care Unit (SICU). A liquid containing sugar could prolong gastric emptying time. This study was to propose a method for prediction of nonsuccess GEN using gastric volume after loading (GVAL) following gradual sucrose gastric loading. MATERIALS AND METHODS: Mechanical ventilator supported and hemodynamically stable patients in SICU were enrolled. About 180-240 min before the GEN starting, a sucrose solution (12.5%; 450 mosmole/kg, 800 mL) was administered via gastric feeding tube over 30 min with 45 degrees head upright position. GVAL was measured at 30, 60, 90, and 120 min after loading. GEN success status using clinical criteria was assessed at 72 h after the starting GEN protocol. The receiving operating characteristic (ROC) and c statistic were used for discrimination at each time point of GVAL. RESULTS: A total of 32 patients were enrolled and completed the protocol. 14 patients (43.7%) were nonsuccessful GEN. The nonsuccess group was found to have significantly more GVAL than the other group at all-time points during the test (P < 0.05). The most discriminating point of GVAL for the prediction of nonsuccess was 150 mL at 120 min after loading with a sensitivity of 92.3%, specificity of 88.9%, positive predictive value of 85.7%, negative predictive value of 94.1%, and ROC area 0.97 (95% confidence interval 0.91-1.00). CONCLUSION: A high GVAL following sucrose gastric loading test might be a method to predict nonsuccess GEN in critically ill surgical patients. PMID- 25722552 TI - Antimicrobial dosing in critically ill patients with sepsis-induced acute kidney injury. AB - Severe sepsis often leads to multiple organ dysfunction syndromes (MODS) with acute kidney injury (AKI). AKI affects approximately, 35% of Intensive Care Unit patients, and most of these are due to sepsis. Mortality rate of sepsis-induced AKI is high. Inappropriate use of antimicrobials may be responsible for higher therapeutic failure, mortality rates, costs and toxicity as well as the emergence of resistance. Antimicrobial treatment is particularly difficult due to altered pharmacokinetic profile, dynamic changes in patient's clinical status and, in many cases, need for renal replacement therapy. This article aims to describe the appropriate antimicrobial dosing and reviews the factors contributing to the difficulties in establishing precise guidelines for antimicrobial dosing in sepsis-induced AKI patients. SEARCH STRATEGY: Text material was collected by systematic search in PubMed, Google (1978-2013) for original articles. PMID- 25722553 TI - Aluminum phosphide poisoning: Possible role of supportive measures in the absence of specific antidote. AB - Aluminum phosphide (ALP) poisoning is one of the major causes of suicidal deaths. Toxicity by ALP is caused by the liberation of phosphine gas, which rapidly causes cell hypoxia due to inhibition of oxidative phosphorylation, leading to circulatory failure. Treatment of ALP toxicity is mainly supportive as there is no specific antidote. We recently managed 7 cases of ALP poisoning with severe hemodynamic effects. Patients were treated with supportive measures including gastric lavage with diluted potassium permanganate, coconut oil and sodium bicarbonate first person account should be avoided in a scientific paper. Intravenous magnesium sulfate, proper hemodynamic monitoring and vasopressors. Four out of 7 survived thus suggesting a role of such supportive measures in the absence of specific antidote for ALP poisoning. PMID- 25722554 TI - Stuck suction catheter in endotracheal tube. AB - Endotracheal tube (ETT) suction is essential to clear secretions so that airway patency can be maintained. Stuck suction catheter in ETT is an uncommon event, and it can be dangerous in patients with difficult airway cases. PMID- 25722555 TI - Cerebral venous air embolism during epidural injection in adult. AB - A bolus of 0.125% bupivacaine (8ml) was given for post-operative analgesia with considerable resistance. It was immediately followed by hemodynamic deterioration along with fall in sensorium. After resuscitation, CT brain revealed pneumoencephalus around the brainstem. The higher force generated during injection could have injured epidural venous plexus and air inadvertently entered the veins. The source of air could have been from the epidural catheter or injection syringe. Hence it is suggested that position and patency of the epidural catheter must be checked each time before administration of injections especially after position changes. On presence of slightest resistance, injections should be withheld till the cause is ascertained by a trained personnel. PMID- 25722556 TI - Primary aorto-esophageal fistula: Great masquerader of esophageal variceal bleeding. AB - Aorto-esophageal fistula is a rare cause of upper gastrointestinal bleeding. Thoracic aneurysm, the most common cause of this condition, will slowly increase over time and can erode the wall of the aorta creating a fistula and leading to torrential bleeding. High clinical suspicion is required for timely diagnosis as common investigations routinely done for gastrointestinal (GI) bleeding, including esophagogastroduodenoscopy, fails to detect most cases. The classical triad of midthoracic pain, herald bleeding and fatal hematemesis described in this condition is seen in only one-third of cases. Physician should be wary of this condition, especially in elderly patients with uncontrolled GI bleeding and who are also at risk of thoracic aneurysm. Computed tomography angiogram detects most cases and emergent endovascular repair with stents controls the initial bleeding. Later, both the aorta and the esophagus are repaired and reconstructed in staged procedures. PMID- 25722557 TI - An unusual cause of type 2 respiratory failure. AB - We present a female patient who was referred for management of respiratory failure. She was being evaluated and managed as worsening chronic inflammatory demyelinating polyneuropathy with type 2 respiratory failure. Initial examination showed hypertrichosis, clubbing and papilledema along with severe distal and proximal motor-predominant weakness with impending respiratory failure. She was managed with noninvasive ventilation (NIV) and plasmapheresis awaiting diagnostic investigations. Immunofixation showed an "M band" and free lambda chain levels were elevated. Radiographs showed the classic osteosclerotic lesions of POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, M-protein and Skin abnormalities) syndrome. Six weeks after commencing radiotherapy to the osteosclerotic lesions, the patient responded favorably and remains off nocturnal NIV support. PMID- 25722558 TI - Successful treatment of a case of primary amoebic meningoencephalitis: How important is history taking. PMID- 25722559 TI - Abnormal U-shape course of central venous catheter. PMID- 25722560 TI - Should ratol paste be banned? PMID- 25722561 TI - Potassium permanganate toxicity: A rare case with difficult airway management and hepatic damage. PMID- 25722562 TI - Platelet storage lesion: An update. PMID- 25722563 TI - Waldenstrom's macroglobulinemia: The role of hospital transfusion medicine laboratory in the diagnosis and management. PMID- 25722564 TI - Comparative analysis of activity of coagulation Factors V and VIII and level of fibrinogen in fresh frozen plasma and frozen plasma. AB - BACKGROUND: The aim of this study was to analyse and compare the activity of factor V, VIII and fibrinogen level in fresh frozen plasma and frozen plasma frozen after 8 hrs but within 24 hours after phlebotomy. MATERIALS AND METHODS: Fresh frozen plasma separated from whole blood within 8 hours was compared with plasma separated within 24 hours after phlebotomy in terms of coagulation factors V and VIII and level of fibrinogen by standard methods using semi automated coagulometer sysmex CA50. RESULTS: Longer storage of whole blood before processing resulted in significant decrease (18.4%) in activity of factor VIII but the fall in activity of factor V (6.52%) or level of fibrinogen (1.81%) was not significant. DISCUSSION: These data suggest that there is good retention of coagulation factors in both types of plasma. Although there is significant fall in activity of factor VIII, but it is an acute phase reactant and raised in most of the diseases so it is suggested that frozen plasma would be an acceptable product for most patients requiring fresh frozen plasma. PMID- 25722565 TI - Automated nucleic acid amplification testing in blood banks: An additional layer of blood safety. AB - CONTEXT: A total of 30 million blood components are transfused each year in India. Blood safety thus becomes a top priority, especially with a population of around 1.23 billion and a high prevalence rate of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) in general population. Nucleic acid amplification testing (NAT) in blood donor screening has been implemented in many developed countries to reduce the risk of transfusion transmitted viral infections (TTIs). NAT takes care of the dynamics of window period of viruses and offers the safest blood pack for donation. AIMS: The aim of this study is to show the value of NAT in blood screening. SETTINGS AND DESIGN: Dhanavantari Blood Bank, Rajahmundry, Andhra Pradesh, India. SUBJECTS AND METHODS: Over a period of 1 year from January 2012 to December 2012, a total number of 15,000 blood donor samples were subjected to tests for HIV, HBV, and HCV by enzyme-linked immunosorbent assay (ELISA) method and 8000 ELISA nonreactive samples were subjected for NAT using multiplex polymerase chain reaction technology. RESULTS: Of the 15,000 donors tested, 525 were seroreactive. In 8000 ELISA negative blood samples subjected to NAT, 4 donor samples were reactive for HBV. The NAT yield was 1 in 2000. CONCLUSIONS: NAT could detect HIV, HBV, and HCV cases in blood donor samples those were undetected by serological tests. NAT could interdict 2500 infectious donations among our approximate 5 million annual blood donations. PMID- 25722566 TI - A multivariate analysis to assess the effect of packed red cell transfusion and the unit age of transfused red cells on postoperative complications in patients undergoing cardiac surgeries. AB - BACKGROUND: Transfusion of blood components and age of transfused packed red cells (PRCs) are independent risk factors for morbidity and mortality in cardiac surgeries. MATERIALS AND METHODS: We retrospectively examined data of patients undergoing cardiac surgery at our institute from January 1, 2012 to September 30, 2012. Details of transfusion (autologous and allogenic), postoperative length of stay (PLOS), postoperative complications were recorded along with other relevant details. The analysis was done in two stages, in the first both transfused and nontransfused individuals and in the second only transfused individuals were considered. Age of transfused red cells as a cause of morbidity was analyzed only in the second stage. RESULTS: Of the 762 patients included in the study, 613 (80.4%) were males and 149 (19.6%) were females. Multivariate analysis revealed that factors like the number and age of transfused PRCs and age of the patient had significant bearing upon the morbidity. Morbidity was significantly higher in the patients transfused with allogenic PRCs when compared with the patients not receiving any transfusion irrespective of the age of transfused PRCs. Transfusion of PRC of over 21 days was associated with higher postoperative complications, but not with in-hospital mortality. CONCLUSION: In patients undergoing cardiac surgery, allogenic blood transfusion increases morbidity. The age of PRCs transfused has a significant bearing on morbidity, but not on in-hospital mortality. Blood transfusion services will therefore have to weigh the risks and benefits of providing blood older than 21 days in cardiac surgeries. PMID- 25722567 TI - Blood donor notification and counseling: Our experience from a tertiary care hospital in India. AB - AIMS: To evaluate the response rate of transfusion-transmissible infection (TTI) reactive donors after notification of their abnormal test results for the year 2012. MATERIALS AND METHODS: This study is an observational descriptive study performed in our department over a period of 1 year. We evaluated the response rate of TTI-reactive donors after notification of their abnormal test results over 1 year as per the existing strategy (three telephonic and two postal communications). RESULTS: During the study period, among the annual donation of 15,322 units, 464 blood donors were found to be seroreactive. Of these 464 seroreactive cases, 47 were HIV positive, 284 were reactive for Hepatitis B surface antigen (HBsAg), 49 were Hepatitis C (HCV) positive and 84 were VDRL reactive. The TTI-reactive donors (464) for various markers were contacted: 229 (49.4%) telephonically and the remaining 235 (50.6%) not contacted on phone were informed by post. Of the 229 contacted donors, the response rate was 98.2% as only 225 donors reported (221 on the first, three on second and one on the third call) for one to one counseling. The remaining four non-responders were - one HIV and three HBsAg reactive. The remaining 235 (50.6%) reactive donors did not respond to any communication. CONCLUSION: Donor notification and post-donation counseling are an essential aspect of the blood bank that entails provision of information on serological status, assess the impact of test results on the donor and finally referral for medical care. As in our data only 49.4% of the blood donors could be contacted successfully, incomplete demographic details was the major limiting factor in communicating with rest. Of the 229 contacted donors, the response rate was 98.2%. A large majority (94.75%) of the notified donors in our study contacted their health care provider when given clear instructions to do so. These results are encouraging because they indicate that a major element of the notification message is acted upon when it is worded clearly. The very high response rate of the contacted donors ensured their concern for knowing their test result status. PMID- 25722568 TI - A study of the noncompliance of blood banks on safety and quality parameters in blood donation camps in Bengaluru. AB - AIMS: The compliance of safety and quality parameters laid out by national and international guidelines in outdoor blood donation camps has not been studied in India. Our study aimed at identifying, monitoring, analyzing, and developing preventive strategies for several key parameters associated with the quality and safety of outdoor voluntary blood donation camps (VBDC). SETTINGS: The study covered a total of 424 VBDCs at various locations in Bengaluru, Karnataka (South India) from 2009 to 2013. Seven government hospitals based blood banks, three private hospitals based blood banks and two voluntary standalone blood banks participated in the VBDCs included in the study. MATERIALS AND METHODS: At the onset, the quality and safety standards to be followed were discussed and agreed upon. During the study, noncompliance (NC) to the agreed upon standards were recorded and shared. Periodic trainings were also organized to help minimize NC. RESULTS: One or more instances of NC in 73% of the VBDCs. Highest NC were observed associated with punctuality (34%), wearing gloves (16%), hemoglobin (Hb) estimation (11%) and donor screening and selection other than Hb check (8-9%). CONCLUSION: For all 16 parameters under study, significant NC was observed. As a whole private hospital based blood banks were more noncompliant. The high degree of NC to matters relating to quality and safety in VBDCs is high and warrants for urgent attention and further study. Our study also shows that regular monitoring and systematic and strategic intervention can decrease the rate of NC. PMID- 25722569 TI - Evaluation of the Procleix Ultrio Plus ID NAT assay for detection of HIV 1, HBV and HCV in blood donors. AB - INTRODUCTION: The Procleix Ultrio Plusassay is a new-generation qualitative in vitro nucleic acid amplification test used to screen for human immunodeficiency virus type 1 (HIV-1) RNA, hepatitis C virus (HCV) RNA and hepatitis B virus (HBV) DNA in blood donors. This study was performed to compare the Procleix Ultrio assay with the new-generation Procleix Ultrio Plus Nucleic Acid Test (NAT) assays. MATERIALS AND METHODS: Ten thousand three hundred and two donor samples were run in parallel for ID NAT using the Procleix Ultrio and the Procleix Ultrio Plus assay. Simultaneously, enzyme-linked immunosorbent assay testing was performed on an EVOLIS Walk away System for HIV, HCV, HBsAg and anti-HBc. Reactive samples were confirmed using polymerase chain reaction. RESULTS: In the 10,302 samples tested during the study period, we identified 15 NAT yields, and all these revealed HBV DNA in the discriminatory assays. Eight of these were exclusive yields from the Ultrio Plus assay and the remaining seven cases were determined as HBV NAT yield, both by the Procleix Ultrio as well as the Ultrio Plus assays, i.e. "Combined" yields. No HCV or HIV 1 yields were detected during the study period by either of two assays. CONCLUSION: With an overall yield rate of 1 in 687 and an exclusive yield rate of 1 in 1287, the Procleix Ultrio Plus assay proved to be highly sensitive in detecting occult HBV infections. PMID- 25722570 TI - Defining an appropriate leucoreduction strategy by serial assessment of cytokine levels in platelet concentrates prepared by different methods. AB - BACKGROUND AND OBJECTIVES: Different methods of platelet concentrate preparations leave behind certain number of residual leukocytes, accounting for most of the febrile nonhemolytic transfusion reactions, especially in multitransfused patients. Various inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 are generated during storage and have been implicated for these adverse effects. We have studied the levels of these cytokines and their correlation with leucocyte contents in platelet concentrates prepared by three different methods. STUDY DESIGN AND METHODS: Five pools of platelet rich plasma platelet concentrates (PRP-PC) and buffy-coat platelet concentrates (BC-PC) each were prepared and divided into two halves. One half of the pool was leucofiltered (LF), whereas the other half was stored as such. Ten apheresis units were also included in the study. All the platelet concentrates were assessed for leucocyte load and cytokine content (IL-1beta, IL 6, and TNF-alpha) on different days of storage (0, 3, and 5) using Nageotte chamber and commercially available immunoassays respectively. RESULTS: There was a statistically significant rise in cytokine levels (IL-1beta, IL-6, and TNF alpha) in nonleucofiltered (NLF) random donor platelet concentrates (RDPs) (PRP PC and BC-PC) during storage (day 3 and 5) whereas LF RDP concentrates (PRP-PC and BC-PC) and apheresis platelet concentrates (AP-PC) did not show any significant rise in cytokine levels (on day 3 and 5) over the baseline values at day 0. CONCLUSION: This data suggests that although AP-PCs are superior to PRP-PC (NLF) and BC-PC (NLF) in terms of in vitro quality control parameters and cytokine generation during storage, BC-PC mode of platelet preparation followed by leucofiltration is the best method to store platelets and minimise the cytokine accumulation. This strategy is best suited for transfusion in multitransfused hematooncologic patients, who cannot afford single donor apheresis platelets. PMID- 25722571 TI - A cost effective model for appropriate administration of red cell units and salvaging un-transfused red cell units by using temperature sensitive indicators for blood component transportation in a hospital setting. AB - BACKGROUND: A rule called "30-min rule" defines that red cell unit cannot be used if it has been out of blood bank refrigerator for over 30 min. This rule is useful to guide initiation of transfusion, but is inadequate for deciding whether to reuse or discard units received-back at blood transfusion services (BTS). A simple cost-effective temperature-sensitive indicator was evaluated to decide upon reuse (cold chain was uninterrupted) or discard (where cold chain was interrupted) in a simulation exercise. MATERIALS AND METHODS: Temperature sensitive indicators TH-FTM that irreversibly changed color from white to red demonstrated that heat excursion has occurred and the cumulative temperature has exceeded 10 degrees C for over 30 min, were used in outdated red cells for simulating units, which are not used and received-back. These units were also tagged with a standard temperature monitoring device, which was a re-usable credit card sized device, which would log the actual time and temperature. In few units percent hemolysis was also calculated. RESULTS: Statistically insignificant elevation in average temperature was noted in 102 simulated units at the time of return to BTS (Delta 0.04 degrees C), despite the fact that these units were in the transport box for over 4 h. The average supernatant hemoglobin in these units was 0.24%, much below the prescribed threshold. CONCLUSION: Transportation of blood in controlled conditions with temperature-sensitive indicator is a cost effective model to save blood, a precious human resource. PMID- 25722572 TI - Serial changes in morphology and biochemical markers in platelet preparations with storage. AB - BACKGROUND: This study was designed to perform serial assessment of alterations in platelet (PLT) count, morphology and biochemical markers of PLT activation during storage of platelet concentrates (PCs) and to correlate morphological changes with these activation markers. MATERIALS AND METHODS: Our study included the platelet-rich plasma (PRP)-PC and buffy coat reduced PC (BC-PC) prepared from whole blood (WB) donations and the apheresis platelets (AP-PC). Routinely evaluated in vitro PLT parameters were followed. Morphology score (MS) was performed using the light microscopy, glucose and lactate concentration and soluble P-selectin (sP-selectin) level were determined using commercial kits. RESULTS: The fall in mean pH from day 0 to the last day of storage was significant (P < 0.001) in all the groups. Glucose utilization was less in PRP-PC prepared from WB donations at Blood Donation Centre [PRP-PC (BDC)] when compared to PRP-PC prepared from WB donations at mobile blood drives [PRP-PC (M)] and BC PC. Lactate accumulation was almost similar in these groups on day 3 of storage, but it was significantly lower in the AP-PC (67.54 mg/dl) except on day 5. The deterioration in MS (out of 200) was similar for PRP-PC and BC-PC on day 3 (145/144 and 145 respectively), whereas the AP-PC had a score of 161 and 147 on days 4 and 5 respectively. sP-selectin level was significantly higher in PRP-PC (BDC) in comparison to BC-PC (P = 0.001) from day 1 to day 3 and in AP-PC it was not so high (P = 0.067) even on day 5. A negative correlation existed between the MS and sP-selectin level on all days of storage within each group of PC (r = 0.351; P < 0.001) and a positive correlation was found between the MS and pH from day 0 to day 3 (r = 0.680; P = 0.004). CONCLUSION: The AP-PCs are superior to the BC-PC and PRP-PC with respect to in vitro quality control parameters, morphological changes and biochemical markers of PLT activation. The PRP-PCs prepared from WB donations at outstation exhibiting more rapid changes should be utilized earlier for transfusion. PMID- 25722573 TI - Molecular basis of Rh blood group system in the Malaysian population. AB - BACKGROUND: Rh molecular studies have been previously mainly conducted in Caucasians and African population. There is a limited data on the molecular basis for Rh genotypes among Asians. AIMS: This study aims to characterize the Rh genes and frequency of the various RH genotypes among blood donors in National Blood Centre (NBC), Kuala Lumpur. MATERIALS AND METHODS: A total of 1014 blood samples were obtained from blood donors from four different ethnic groups (360 Malays, 434 Chinese, 164 Indians and 56 others). Serological and molecular analysis of all 1014 blood samples were performed. An automated deoxyribonucleic acid sequencing analysis was performed. RESULTS: Rh phenotypes and RH genotypes showed heterogeneity and significant association with ethnicities. Discrepancies in allele D, C/c and E/e between phenotypes and genotypes results were observed. Discrepancy results in allele D showed significant association with the ethnic groups of the blood donors in NBC. There were multiple novel mutations (23) and published mutations (5) found in this study. Significant associations between discrepancy results and mutations were found in allele D and C/c. CONCLUSION: Performing RH molecular analysis in Malaysian population provided the basic database for the distribution of Rh genotypes of donors from major ethnic groups in Malaysia. PMID- 25722574 TI - Impact of hemoglobin nitrite to nitric oxide reductase on blood transfusion for resuscitation from hemorrhagic shock. AB - BACKGROUND: Transfusion of blood remains the gold standard for fluid resuscitation from hemorrhagic shock. Hemoglobin (Hb) within the red blood cell transports oxygen and modulates nitric oxide (NO) through NO scavenging and nitrite reductase. AIMS: This study was designed to examine the effects of incorporating a novel NO modulator, RRx-001, on systemic and microvascular hemodynamic response after blood transfusion for resuscitation from hemorrhagic shock in a hamster window chamber model. In addition, to RRx-001 the role of low dose of nitrite (1 * 10(-9) moles per animal) supplementation after resuscitation was studied. MATERIALS AND METHODS: Severe hemorrhage was induced by arterial controlled bleeding of 50% of the blood volume (BV) and the hypovolemic state was maintained for 1 h. The animals received volume resuscitation by an infusion of 25% of BV using fresh blood alone or with added nitrite, or fresh blood treated with RRx-001 (140 mg/kg) or RRx-001 (140 mg/kg) with added nitrite. Systemic and microvascular hemodynamics were followed at baseline and at different time points during the entire study. Tissue apoptosis and necrosis were measured 8 h after resuscitation to correlate hemodynamic changes with tissue viability. RESULTS: Compared to resuscitation with blood alone, blood treated with RRx-001 decreased vascular resistance, increased blood flow and functional capillary density immediately after resuscitation and preserved tissue viability. Furthermore, in RRx-001 treated animals, both mean arterial pressure (MAP) and met Hb were maintained within normal levels after resuscitation (MAP >90 mmHg and metHb <2%). The addition of nitrite to RRx-001 did not significantly improve the effects of RRx-001, as it increased methemoglobinemia and lower MAP. CONCLUSION: RRx-001 alone enhanced perfusion and reduced tissue damage as compared to blood; it may serve as an adjunct therapy to the current gold standard treatment for resuscitation from hemorrhagic shock. PMID- 25722575 TI - Prevalence of risk factors for platelet transfusion refractoriness in multitransfused hemato-oncological patients at tertiary care center in North India. AB - BACKGROUND: This study was designed to determine the prevalence and assess the risk factors responsible for platelet transfusion refractoriness in hemato oncological patients. MATERIALS AND METHODS: The study included 30 patients. Twelve were clinically diagnosed as aplastic anemia and the 18 were of acute myeloid leukemia. A prospective 3 months follow-up was planned to monitor the response of platelet transfusion therapy, based on their posttransfusion corrected count increment at 1(st) and 24(th) h. Based on the observations, patients were categorized into refractory and nonrefractory groups. Common nonimmunological causes such as fever, sepsis, bleeding, disseminated intravascular coagulation, chemotherapy, splenomegaly, ABO mismatch, and antithymocyte globulin therapy were monitored. Among the immunological causes, presence of antihuman leukocyte antigen (HLA) class I antibodies and platelet glycoprotein antibodies in patient's serum were monitored. RESULTS: During the study period, 17 (56.66%) patients did not show desired platelet count increment. Transfusion requirements of refractory group for both red cell and platelet product were significantly higher (P < 0.05) in comparison to nonrefractory group. Among immunological causes, anti HLA class I antibodies (P < 0.013), antihuman platelet antigen-5b antibodies (P < 0.033) were significantly associated with refractoriness. Among nonimmunological causes, bleeding (P < 0.019, odd ratio 8.7), fever (P < 0.08, odd ratio 5.2), and infection (P < 0.07, odd ratio 5.4) were found to associated with refractoriness. CONCLUSION: Platelet refractoriness should be suspected in multitransfused patients not showing expected increment in platelet counts and thoroughly investigated to frame further guidelines in order to ensure proper management of these kind of patients. PMID- 25722576 TI - Evaluation of a new serological test for syphilis based on chemiluminescence assay in a tertiary care hospital. AB - CONTEXT: Syphilis is a transfusion transmissible infections and it is mandatory to do serological test for syphilis (STS) on all donor blood samples. STS is usually based on detection of antibodies against the cardiolipin-lecithin antigen or against the Treponema-specific antigen. STS with good sensitivity and specificity helps enhance blood safety and consolidation of STS along with other transfusion transmittable infections such as human immunodeficiency virus, hepatitis-C virus, and hepatitis-B virus helps in reducing the errors and enhances efficiency. AIMS: This study was designed to evaluate the performance of newly introduced VITROS((r)) syphilis Treponema pallidum agglutination (TPA) assay based on enhanced chemiluminescence principle for its analytical performance for use as a STS on donor blood samples at a tertiary care health center in National Capital Region, India. MATERIALS AND METHODS: A total of 108 random blood units collected from the donors (both voluntary and replacement donors) and 28 known syphilis sero-reactive samples stored at -20 degrees C, were used to evaluate the performance of VITROS((r)) syphilis TPA assay based on enhanced chemiluminescence assay on VITROS((r)) ECiQ immunodiagnostics system along with its analytical performance in terms of its sensitivity, precision, cross-reactivity and interference studies. RESULTS: VITROS((r)) syphilis TPA showed 100% sensitivity and specificity with precision (20 days study) of <10% co efficient of variation. There was no cross-reactivity with other viral and auto immune antibodies. No interference was observed from endogenous interfering substances like free hemoglobin or fats. CONCLUSIONS: Performance of the VITROS((r)) syphilis TPA assay meets the requirements for its use as STS in blood bank, thus allowing consolidation with other transfusion transmittable infections screening assay on chemiluminescence platform, which is highly valuable for optimizing workflow and efficiency. PMID- 25722577 TI - Circulating thrombopoietin levels in normal healthy blood donors and in aplastic anemia patients in relation to disease severity. AB - BACKGROUND: Thrombopoietin (TPO) is the key hematopoietic growth factor regulating the production of platelets from bone marrow megakaryocytes and maintaining platelet hemostasis. This study was done to find any relationship between the levels of thrombopoietin and the severity of disease in patients with aplastic anemia. MATERIALS AND METHODS: Serum samples were collected from 52 patients with a confirmed diagnosis of aplastic anemia and 45 normal healthy blood donors of both sexes over a period of 2 years, and TPO was estimated by using commercially available TPO-specific-enzyme-linked immunosorbent assay. RESULTS: The median TPO level of 1190 pg/ml (range 625-7651 pg/ml) in aplastic anemia patients was significantly higher than the median TPO level of 121.1 pg/ml (81.25-237.7 pg/ml) in normal healthy blood donors (P = 0.000). No significant difference was observed in TPO levels of male and female patients (P = 0.453). The median TPO concentrations observed in very severe aplastic anemia, severe aplastic anemia, and nonsevere aplastic anemia were 2765 pg/ml (range 625-6451 pg/ml), 1190 pg/ml (range 672.1-7651 pg/ml), and 1111.5 pg/ml (range 761.1-2289.2 pg/ml), respectively. TPO in patients of very severe aplastic anemia was significantly higher than patients of nonsevere aplastic anemia (P = 0.043), with no significant relation among rest of the groups. DISCUSSION: TPO levels in aplastic anemia patients were significantly higher than in healthy blood donors; however, in aplastic anemia patients TPO levels were significantly higher only in patients with very severe disease. PMID- 25722578 TI - Detection of rare blood group, Bombay (Oh) phenotype patients and management by acute normovolemic hemodilution. AB - BACKGROUND: Due to lack of correct blood grouping practices, the rare Bombay Oh phenotype may be missed, subjecting patients to the risk of severe hemolytic transfusion reaction. In the absence of blood donor registry, transfusion management of patients needing immediate surgery is a challenge. This study presents detection of rare Bombay Oh phenotype patients and their management by acute peri-operative acute normovolemic hemodilution (ANH) in a hospital from central India. MATERIALS AND METHODS: Blood grouping of patients and blood donors with a standard tube method was carried out and samples identified as rare Bombay phenotype were confirmed by saliva inhibition test. Surgical management of cases needing transfusion was done by ANH, as per the British Committee for Standards in Hematology guidelines. RESULTS: The incidence of Bombay phenotype was 0.002% or 1 in 51,924 in the study. Amongst three cases (patients) identified as Bombay phenotype, one was Bombay Oh, Rh negative. Two cases were missed in the first instance and one case actually did not require transfusion. In the absence of a blood donor registry for Bombay phenotype, the cases needing transfusion were successfully managed with ANH in the operation theatre. CONCLUSION: A simple test like blood grouping should be done with serious intention with incorporation of both forward and reverse grouping, so that no patient receives wrong blood leading to fatal hemolysis due to transfusion. ANH is a cost-effective transfusion option for suitable patients. Appropriate clinical decision making, use of strategies to decrease peri-operative blood losses and cost-effective country based planning could be more widely applied to improve clinical transfusion practice. PMID- 25722579 TI - Study of red blood cell alloimmunization in multitransfused thalassemic children of Jammu region. AB - INTRODUCTION: Thalassemia is one of the most common genetic disorder of hemoglobin synthesis in Jammu region. Although RBC transfusion is life saving for these patients, it may be associated with some complications like RBC alloimmunization. Thus, the aim of this study was to determine the frequency of alloimmunization and the most common alloantibodies involved. MATERIAL AND METHODS: This was a descriptive study involving a total of 70 thalassemic patients in the age range of 2-17 years receiving regular blood transfusions, registered at SMGS Blood Bank, Jammu. Relevant clinical and laboratory data was collected with reference to age at the start of transfusions, total number of transfusions received and splenectomy status. Antibodies screening, antibody identification, and cross matching was done on allpatient samples included in the study, during the period between November 2009 and October 2010. RESULTS: In this study, a total of six alloantibodies six patients (8.5%) and one autoantibody (1.42%) was detected. All identified alloantibodies belonged to Rh system (i.e. anti-E, in 3 patients (50%), anti D, in one patient (16.66%)) and Kell system (anti-K, in two patients (33.34%)). Higher frequency of alloimmunization was found, with increase in number of transfusions and in those who received transfusions after 1 year of age. Alloimmunization was not significantly associated with gender and splenectomy status (P-value > 0.05). CONCLUSION: Red cell alloantibodies developed in 8.5% of thalassemic patients and 1.42% had autoantibodies. The most common alloantibodies identified were anti Rh system antibodies (anti-E and anti-D) present in 50% and 16.66% of patients respectively. Alloimmunization is not an uncommon problem faced by blood banks and finding compatible units for regularly transfused thalassemic patients may become very difficult. In order to reduce alloimmunization, a policy for performing extended red cell phenotyping of these patients is essential and at least antigen E and Kell negative blood should be provided for transfusion to these patients. PMID- 25722580 TI - A case of Hepatitis E in a blood donor. AB - The threat of hepatitis E is being felt in blood banks in recent times. The disease is usually self-limiting, but may progress to a fulminant fatal form. We report a unique case of a hepatitis E virus (HEV)-positive asymptomatic blood donor who later developed jaundice and informed the blood bank. A blood donor passed all eligibility criteria tests and donated blood. After 20 days, the blood bank was informed by the donor that he had developed vomiting and jaundice 1 day postdonation. He was investigated by a local laboratory 1 day postdonation for liver profile, which was high. There had been a major outbreak in his community of similar symptoms during the same period. HEV IgM antibody by enzyme-linked immunosorbent assay was positive. Silent infections may be lurking in apparently healthy donors. Donors need to be encouraged to revert in case of any significant developments after donation and maintain open channels of communication. PMID- 25722581 TI - Therapeutic platelet reduction: Use in postsplenectomy thrombocytosis. AB - Therapeutic platelet reduction is an effective modality for the reduction of platelet count in patients with treatment of extreme thrombocytosis resulting from a variety of primary and secondary causes of thrombocytosis, which may be associated with thrombotic or hemorrhagic complications of varying degrees. These cases when symptomatic fall into the ASFA Category II indication for therapeutic platelet apheresis procedure. Here, we report a case of postsplenectomy secondary thrombocytosis presenting with extremely high platelet counts and subsequent thrombosis in the shunt and successful treatment after therapeutic platelet reduction. The case is being presented to bring forth the fact that therapeutic platelet reduction is an easy procedure that gives quick and good results and also to bring to the attention of transfusion specialists an associated but as yet unreported procedural finding. PMID- 25722582 TI - Guillain - Barre syndrome in a patient with acute myocardial infarction with ventricular septal defect repair treated with plasma exchange. AB - Guillain - Barre syndrome (GBS) is an acute, frequently severe progressive illness of peripheral nervous system that is autoimmune in nature. GBS after myocardial infarction (MI) with ventricular septal defect (VSD) is uncommon with high mortality rate if not treated promptly.[1] We report a successful outcome of GBS post MI with VSD in a 60-year-old male patient who was on a ventilator treated successfully with therapeutic plasma exchange. PMID- 25722583 TI - Report of two cases of anti-M antibody in antenatal patients. AB - Anti-M is a relatively common naturally occurring antibody reacting optimally at 4 degrees C and weakly or nonreactive at 37 degrees C. It is usually clinically insignificant but can be active at 37 degrees C because of thermal amplitude of IgM component or presence of IgG component. It can cause or delayed hemolytic transfusion reactions or hemolytic disease of newborn. At our center we have encountered two cases of anti-M antibodies- one presenting as crossmatch incompatibility and other as blood grouping discrepancy in the last 8 months. PMID- 25722584 TI - Anti-N antibody reacting at 37 degrees C: An unusual occurrence interfering with routine testing: Two interesting cases. AB - Most anti-N antibodies are naturally occurring, IgM antibodies, and not active above 25 degrees C and are not clinically significant but IgG anti- N has also been described. Immune anti-N resulting from multiple transfusions does occur & has been implicated as the cause of hemolytic transfusion reactions and mild hemolytic disease of fetus and newborn. Anti- N reacting at room temperature can be a cause for ABO blood group discrepancy. PMID- 25722585 TI - Approach to a case of multiple irregular red cell antibodies in a liver transplant recipient: Need for developing competence. AB - Liver transplant procedure acts as a challenge for transfusion services in terms of specialized blood components, serologic problems, and immunologic effects of transfusion. Red cell alloimmunization in patients awaiting a liver transplant complicate the process by undue delay or unavailability of compatible red blood cell units. Compatible blood units can be provided by well-equipped immunohematology laboratory, which has expertise in resolving these serological problems. This report illustrates resolution of a case with multiple alloantibodies using standard techniques, particularly rare antisera. Our case re emphasizes the need for universal antibody screening in all patients as part of pretransfusion testing, which helps to identify atypical antibodies and plan for appropriate transfusion support well in time. We recommend that the centers, especially the ones that perform complex procedures like solid organ transplants and hematological transplants should have the necessary immunohematological reagents including rare antisera to resolve complex cases of multiple antibodies as illustrated in this case. PMID- 25722586 TI - Maternal anti-M induced hemolytic disease of newborn followed by prolonged anemia in newborn twins. AB - Allo-anti-M often has an immunoglobulin G (IgG) component but is rarely clinically significant. We report a case of hemolytic disease of the fetus and newborn along with prolonged anemia in newborn twins that persisted for up to 70 days postbirth. The aim was to diagnose and successfully manage hemolytic disease of newborn (HDN) due to maternal alloimmunization. Direct antiglobulin test (DAT), antigen typing, irregular antibody screening and identification were done by polyspecific antihuman globulin cards and standard tube method. At presentation, the newborn twins (T1, T2) had HDN with resultant low reticulocyte count and prolonged anemia, which continued for up to 70 days of life. Blood group of the twins and the mother was O RhD positive. DAT of the both newborns at birth was negative. Anti-M was detected in mothers as well as newborns. Type of antibody in mother was IgG and IgM type whereas in twins it was IgG type only. M antigen negative blood was transfused thrice to twin-1 and twice to twin-2. Recurring reduction of the hematocrit along with low reticulocyte count and normal other cell line indicated a pure red cell aplastic state. Anti-M is capable of causing HDN as well as prolonged anemia (red cell aplasia) due to its ability to destroy the erythroid precursor cells. Newborns with anemia should be evaluated for all the possible causes to establish a diagnosis and its efficient management. Mother should be closely monitored for future pregnancies as well. PMID- 25722587 TI - In-house preparation of lectin panel and detection of Tn polyagglutination. AB - Polyagglutination is a condition in which red cells are agglutinated by ABO compatible adult human sera, but not by cord blood sera and may be acquired or inherited. Lectins are invaluable reagents in the investigation of red cells polyagglutination. We prepared in-house lectin panel and confirmed Tn polyagglutination in a pregnant lady. The lady was anemic and refused blood transfusion elsewhere due to serological discrepancy. We found ABO discrepancy and an incompatible minor cross-match in the initial investigation and suspected polyagglutination. Confirmation of polyagglutination was done using adult and cord sera. We then used the in-house lectin panels to detect the type of polyagglutination. The agglutination pattern with the various lectins was suggestive of Tn polyagglutination, which was further supported by the enzyme study. Most blood banks in India lack commercial lectin panels because of cost and procurement difficulty. Lectins play an important role in the diagnosis and differentiation of polyagglutination and immunohematological management of patient. The important and basic lectins can be prepared in-house using specific raw seeds following standardized protocol. PMID- 25722588 TI - Donor hemovigilance: Delayed vasovagal reaction with injury in a blood donor. PMID- 25722589 TI - Undetermined blood loss due to accidental injury and its management in a male patient of classical Bombay (Oh) phenotype in a hospital in the remote part of east India. PMID- 25722590 TI - Clinical efficacy and applications of therapeutic plasma exchange: A tertiary care center experience from Jammu. PMID- 25722591 TI - Further evidence for naturally occurring anti Jk(a) antibodies. PMID- 25722592 TI - Incidence of Kell blood group in blood donors: A population-based study. PMID- 25722593 TI - Rapid plasma reagin test: High false positivity or important marker of high risk behavior. PMID- 25722594 TI - Regenerative medicine in aesthetic surgery: hope or hype? PMID- 25722595 TI - Principles and Methods of Preparation of Platelet-Rich Plasma: A Review and Author's Perspective. AB - The utility of platelet-rich plasma (PRP) has spanned various fields of dermatology from chronic ulcer management to trichology and aesthetics, due to its role in wound healing. Though PRP is being used over a long time, there is still confusion over proper terminology to define, classify and describe the different variations of platelet concentrates. There is also a wide variation in the reported protocols for standardization and preparation of PRP, in addition to lack of accurate characterization of the tested products in most articles on the topic. Additionally, the high cost of commercially available PRP kits, precludes its use over a larger population. In this article, we review the principles and preparation methods of PRP based on available literature and place our perspective in standardizing a safe, simple protocol that can be followed to obtain an optimal consistent platelet yield. PMID- 25722596 TI - Glycolic Acid peels for nail rejuvenation. AB - BACKGROUND: With the increasing use of nail paints, nail art, acetone, repeated manicures, cosmetic nail procedures and detergents, the nail plate undergoes regular damage resulting in rough, lusterless and pigmented nails. Besides that onychomycosis, nail lichen planus, nail pitting and ridging due to various diseases also cause cosmetically disfiguring nails. OBJECTIVE: The study is directed toward use of 70% glycolic acid for controlled keratolysis of the nail plate, resulting that could result in shinier, smoother and brighter nails. MATERIALS AND METHODS: A prospective single-center open-label uncontrolled study of 31 patients, 22 with dry, rough, discolored nails and 9 with hyperkeratotic nails were included in the study group. After examination and ruling out any infection, petroleum jelly was applied on the cuticle margins of the nails for protection and 70% glycolic acid was applied over the nail plate for 45 minutes. In dry rough discolored nails, only a single sitting was done while in hyper keratotic nail conditions multiple weekly sittings were done. RESULTS: In 22 patients with dry rough nails, 80% showed good improvement, 10% showed average improvement, whereas 10% were non-responsive. Nine patients with thickened nail plate showed good improvement in 60% average improvement in 25% improvement and 15% were non-responsive, after multiple sessions. CONCLUSION: Controlled keratolysis of the nail plate with application of 70% glycolic acid can be a promising treatment for modality for thick, uneven, rough and pigmented nail plate conditions with cosmetically pleasing results. PMID- 25722597 TI - Role of chemical peeling in nail disorders. PMID- 25722598 TI - Intralesional immunotherapy for difficult to treat warts with Mycobacterium w vaccine. AB - BACKGROUND: Immunotherapy is an evolving therapeutic modality for the treatment of warts. We conducted a study to assess the efficacy and safety of intralesional Mycobacterium w vaccine for the treatment of warts at sites that were difficult to treat. MATERIALS AND METHODS: Thirty patients with at least one wart present on either the plantar surface of their feet, palms, volar aspect of their fingers, or periungual or subungual region, were treated with 0.1 ml of killed Mycobacterium w vaccine given intralesionally in a single wart, without any prior sensitisation dose. Thereafter, a single injection of 0.1 ml of vaccine was given at intervals of four weeks in a single wart till there was complete resolution of the warts or a maximum of 10 injections. Treatment was stopped if there was no response after three injections. The patients were followed up for at least six months. RESULTS: Out of the 30 patients, 28 (93.33%) patients had complete resolution of their warts, both at the injected and distant sites. The mean (SD) time for complete clearance of warts was 43.71(32.82) days and the mean (SD) dose of vaccine that was required for complete clearance of warts was 0.186 ml (0.101). Four patients (14.28%) had a recurrence of warts. The treatment was well tolerated and the side effects were reversible in the majority of the patients. CONCLUSION: In comparison to the earlier studies using Mycobacterium w vaccine for the treatment of warts, our study was different in the following aspects: No sensitisation dose was given, only a single wart was injected at a time and the duration between the period of injections was increased to four weeks. With all these changes we eliminated the complications due to the sensitisation dose and achieved good results. This study provides new insight into the dose and schedule of treatment of this evolving therapeutic modality. PMID- 25722599 TI - Split Face Comparative Study of Microneedling with PRP Versus Microneedling with Vitamin C in Treating Atrophic Post Acne Scars. AB - INTRODUCTION: Acne scars are largely preventable complications of acne. 95% of the scars occur over the face thus impacting the quality of life. Correction of scars is the priority for acne patients. MATERIALS AND METHODS: Thirty patients with post acne atrophic facial scars attending the OPD during the period from April to October 2013 were offered four sittings of microneedling with PRP on one side and microneedling with vitamin C on other side of the face at an interval of 1 month. RESULTS: Twenty-seven out of the total 30 patients completed the treatment schedule. Two patients were lost to follow up and one dropped out of the study due to severe PIH. Mean age of the patients was 27.5 years. Out of 30 patients, 23 achieved reduction in scarring by one or two grades. Excellent response was seen in five (18.5%) patients with platelet-rich plasma (PRP) as compared to two (7%) patients who received treatment with vitamin C according to physician's assessment. As far as up gradation by 1 score is considered, i.e., good response, it was similar in both cases. Vitamin C did not prove to be as efficacious as PRP since 10 (37%) patients had poor response in vitamin C-treated area compared to only 6 (22.2%) patients who underwent PRP therapy, but vitamin C proved to be efficacious in dealing with post inflammatory hyper-pigmentation secondary to acne. Patients were more satisfied with PRP as compared to vitamin C. The results were evaluated and statistical analysis was done using SPSS 16.0.2. CONCLUSIONS: Overall results were better with microneedling and PRP. Vitamin C combined with microneedling also showed improvement with respect to firmness and smoothness of skin; as well as post inflammatory hyper-pigmentation. Microneedling combined with PRP proved to be good in treating boxcar and rolling scars but had limited efficacy in dealing with ice pick scars. PMID- 25722600 TI - Study of platelet-rich plasma injections in the treatment of androgenetic alopecia through an one-year period. AB - BACKGROUND: Platelet-rich plasma (PRP) is defined as an autologous concentration of plasma with a greater count of platelets than that of whole blood. Its action depends on the released growth factors from platelets. It has been investigated and used in numerous fields of medicine. Recently, PRP has received growing attention as a potential therapeutic tool for hair loss. AIMS: To evaluate the efficacy and safety of PRP injections in the scalp of patients with androgenetic alopecia. SETTINGS AND DESIGN: Prospective cohort study. MATERIALS AND METHODS: 20 patients, 18 males and 2 females, with androgenetic alopecia were enrolled in the study. PRP was prepared using a single spin method (Regenlab SA). Upon activation, it was injected in the androgen-related areas of scalp. Three treatment sessions were performed with an interval of 21 days and a booster session at 6 months following the onset of therapy. STATISTICAL ANALYSIS: Statistical analysis of the data was performed using the Statistical Package for the Social Sciences (SPSS), version 19.0 (IBM, NY, USA). RESULTS: Hair loss reduced and at 3 months it reached normal levels. Hair density reached a peak at 3 months (170.70 +/- 37.81, P < 0.001). At 6 months and at 1 year, it was significantly increased, 156.25 +/- 37.75 (P < 0.001) and 153.70 +/- 39.92 (P < 0.001) respectively, comparing to baseline. Patients were satisfied with a mean result rating of 7.1 on a scale of 1-10. No remarkable adverse effects were noted. CONCLUSIONS: Our data suggest that PRP injections may have a positive therapeutic effect on male and female pattern hair loss without remarkable major side effects. Further studies are needed to confirm its efficacy. PMID- 25722601 TI - Alternative nipple suspension technique in the treatment of inverted nipple: reverse s-shaped design. AB - The primary aim in the treatment of inverted nipple is to achieve a satisfactory and permanent projection of the nipple. The drawbacks of reported techniques include sensory disturbance of the nipple, marked scarring of the nipple and areola, destruction of breast function and incomplete correction. In the present study, the authors introduced a new modification of using two opposite nipple based areolar dermal flap in the treatment of grades 2 and 3 inverted nipple cases. Nipple-based areolar flaps designed at 3 o'clock and 9 o'clock were raised by two linear incisions and the tip of each flap was sutured on the base of the nipple close to the base itself in a reverse S shape at 6 and 12 o'clock. Successful outcome was obtained due to a strongly suspending effect of the design of the flaps. The mean follow-up period was 6 months. The patients were satisfied with the result and the scars were minimal. The authors recommend the use of the technique that is a simple, reliable and with minimal scars for correcting grades 2 and 3 inverted nipples. PMID- 25722602 TI - Railroading technique of dermal grafting for linear atrophic scarring. AB - Dermal grafting is a valuable technique in the field of dermatosurgery for the treatment of atrophic scars where the source of filler material is the patient's own dermis. However, it is underused for the reasons being difficulties in placing the graft in the tunnel, keratin cysts and complications due to biofilms. Railroading technique used in urology for rupture urethra has been described for dermal grafts to overcome the technical difficulties of graft placement. PMID- 25722603 TI - Angiofibroma on cheek mucosa: a rare entity and its management with laser. AB - A rare presentation of an angiofibroma in the oral cavity is reported, which was treated with a diode laser. The benefits of laser treatment include bloodless procedure with instant precise coagulation of vessels. Although rare and unusual, it is suggested that angiofibroma should be included as one of the differential diagnoses of soft tissue swellings in the oral cavity. PMID- 25722604 TI - Treatment of a non-healing diabetic foot ulcer with platelet-rich plasma. AB - Lower extremity ulcers and amputations are an increasing problem among individuals with diabetes. Among diabetes mellitus-related complications, foot ulceration is the most common, affecting approximately 15% of diabetic patients during their lifetime. The pathogenesis of diabetic ulcer is peripheral sensory neuropathy, calluses, oedema and peripheral vascular disease. Diabetic ulcer is managed by adequate control of infections and blood sugar levels, surgical debridement with various dressings and off loading of the foot from pressure. In spite of these standard measures, some recalcitrant non-healing ulcers need additional growth factors for healing. Autologous platelet-rich plasma is easy and cost-effective method in treating diabetic ulcers as it provides necessary growth factors which enhance healing. PMID- 25722605 TI - Pseudoepitheliomatous hyperplasia: a clinical entity mistaken for squamous cell carcinoma. PMID- 25722606 TI - Excellent response to intralesional bacillus calmette-guerin vaccine in a recalcitrant periungual wart. PMID- 25722607 TI - Infiltrating oral lipoma a rare variant. PMID- 25722608 TI - An unusual case of lipoma attached to the frontalis muscle. PMID- 25722609 TI - Extensive abdominal wall and genital pyoderma gangrenosum: combination therapy in unusual presentations. PMID- 25722610 TI - Utility of gel nails in improving the appearance of cosmetically disfigured nails: experience with 25 cases. PMID- 25722611 TI - State of globe: rabies: the lethality since antiquity! PMID- 25722612 TI - Survival or Safety: Balancing act with Colistin. PMID- 25722613 TI - Evaluation of Geno Type MTBDRplus Line Probe Assay for Early Detection of Drug Resistance in Tuberculous Meningitis Patients in India. AB - BACKGROUND: Molecular methods which allow for rapid and reliable detection of drug resistance have yet not been sufficiently evaluated for timely management of patients with tuberculous meningitis. AIMS: We aimed to evaluate Geno Type MTBDRplus line probe assay for early detection of drug resistance in Mycobacterium tuberculosis isolates and CSF samples of confirmed tuberculous meningitis patients. SETTINGS AND DESIGN: This was a multicentric prospective study carried out from July 2011 to December 2013 in tertiary care hospitals of Delhi. MATERIALS AND METHODS: The assay was performed on 89 M. tuberculosis isolates and 31 direct CSF samples from microbiologically confirmed tuberculous meningitis patients. The sensitivity and specificity of this assay was calculated in comparison to drug susceptibility testing by BACTEC MGIT 960 system. RESULTS: The sensitivity, specificity for detection of resistance to Isoniazid was 93%, 97% and to Rifampicin was 80%, 98.8%, respectively by this assay in comparison with the phenotypic drug susceptibility testing. The line probe assay could detect M. tuberculosis in 55% of CSF samples from patients with microbiologically confirmed tuberculous meningitis. Only 5/89 isolates (5.6%) were resistant to both Isoniazid and Rifampicin while 9/89 (10%) isolates were additionally resistant to Isoniazid. Resistance to any of the drugs, namely Isoniazid, Rifampicin, Streptomycin or Ethambutol, was seen in 24.7% of strains. CONCLUSION: The line probe assay has a good sensitivity and specificity for detection of drug resistance to Isoniazid and Rifampicin in M. tuberculosis culture isolates. However, this assay has limited role in detection of M. tuberculosis and drug resistance from direct samples with confirmed diagnosis of tuberculous meningitis. PMID- 25722614 TI - Risk assessment for yellow Fever in Western and north-Western provinces of zambia. AB - BACKGROUND: North-Western and Western provinces of Zambia were reclassified as low-risk areas for yellow fever (YF). However, the current potential for YF transmission in these areas is unclear. AIMS: To determine the current potential risk of YF infection. SETTING AND DESIGN: A cross sectional study was conducted in North-Western and Western provinces of Zambia. MATERIALS AND METHODS: Samples were tested for both YF virus-specific IgG and IgM antibodies by the ELISA and YF virus confirmation was done using Plaque Reduction Neutralization Test. The samples were also tested for IgG and IgM antibodies against other flaviviruses. RESULTS: Out of the 3625 respondents who participated in the survey, 46.7% were males and 9.4% were aged less than 5 years. Overall, 58.1% of the participants slept under an impregnated insecticide-treated net and 20.6% reported indoor residual spraying of insecticides. A total of 616 (17.0%) samples were presumptive YF positive. The prevalence for YF was 0.3% for long-term infection and 0.2% for recent YF infection. None of the YF confirmed cases had received YF vaccine. Prevalence rates for other flaviviruses were 149 (4.1%) for Dengue, 370 (10.2%) for West Nile and 217 (6.0%) for Zika. CONCLUSION: There is evidence of past and recent infection of YF in both provinces. Hence, they are at a low risk for YF infection. Yellow fever vaccination should be included in the EPI program in the two provinces and strengthen surveillance with laboratory confirmation. PMID- 25722615 TI - Influence of pseudomonas aeruginosa on exacerbation in patients with bronchiectasis. AB - BACKGROUND: A majority of the studies done on the western population have shown that Pseudomonas aeruginosa causes many severe infections in patients with bronchiectasis as compared to other pathogens. There is scarcity of similar data from the Asian population. MATERIALS AND METHODS: A prospective study was undertaken to identify the various pathogens isolated from the respiratory samples of 117 patients with bronchiectasis from south India and to compare the clinicomicrobiological profile of infections caused by P. aeruginosa and other respiratory pathogens. RESULTS: The respiratory pathogens were isolated from 63 (53.8%) patients. P. aeruginosa was the most common isolate (46.0%) followed by Klebsiella pneumoniae (14.3%) and other pathogenic bacteria. Patients included in the P. aeruginosa group had a higher number of exacerbations (p: 0.008), greater number of hospital admissions (p: 0.007), a prolonged hospital stay (p: 0.03), and poor lung function, compared to the patients infected with the non Pseudomonas group. CONCLUSION: It is necessary to investigate the etiology of respiratory tract infections among bronchiectasis patients followed by the prompt management of cases diagnosed with P. aeruginosa infections, so as to lower the morbidity and have a better prognosis. PMID- 25722616 TI - Risk correlates of diarrhea in children under 5 years of age in slums of bankura, west bengal. AB - BACKGROUND: Diarrheal diseases are an important cause of mortality and morbidity globally in children under 5 years of age. OBJECTIVE: To find the prevalence and risk factors of diarrhea among children under 5 years. MATERIALS AND METHODS: A population-based analytical cross-sectional study was conducted in the urban slums of Bankura, West Bengal on the prevalence of diarrhea and feeding practices, nutrition, and immunization among 152 children under 5 years (69 males and 83 females). RESULTS: Overall prevalence of diarrhea was 22.36%; 21.73% males and 22.89% females were affected with diarrhea. There were 57.69% diarrhea cases in children of 7-12 months age group, followed by 25.71% in those of 13-24 months age group; with increasing age, the prevalence of diarrhea gradually decreased. Diarrhea was noted to be 20.33% in exclusively breastfed children and 31.57% in children who were breastfed for less than 6 months. In bottle-fed children, the frequency of diarrhea was 26.08%. The prevalence of diarrhea was 21.83% in completely immunized children and 30% in partially immunized children. Risk of diarrhea was 19.80% in normal participants and 27.45% in undernourished children. CONCLUSION: The present study identified a high prevalence of diarrhea in children under the age of 5 years. Findings of the study also revealed the demographic features, feeding practices, immunization practices, and nutritional status as risk factors of diarrhea, which can be tackled by effective education of the community. PMID- 25722617 TI - Epidemiological characteristics of patients attending for rabies post-exposure prophylaxis at the infectious diseases hospital of lucknow, India. AB - AIMS: The objective of the study was to assess epidemiological and anti-rabies vaccination status in animal bite patients attending the Infectious Diseases Hospital, Lucknow. MATERIALS AND METHODS: A longitudinal survey was conducted in the Infectious Diseases Hospital of Lucknow from January to December 2013. During this duration a total of 390 patients presenting with animal bites were included. RESULTS: A majority (63.3%) of patients were in the 16-59 years age group. 75% of patients had attended the IDH for rabies post-exposure prophylaxis (PEP) within 24 hours. The male to female ratio was 2.98:1. A majority (79.5%) of patients were injured by dogs. 9.0% patients were in close contact with rabies patient. On the basis of WHO classification, 4.2% of animal bite patients were placed in grade I, 88.2 in grade II and 7.6% in grade III. In 73.3% of patients wound were in lower limbs. Complete vaccination was found in 65.0% and the use of human rabies immune globulin was only in 11.1%. CONCLUSION: Outcome of an animal bite can be fatal. The only preventive/curative measure available is anti-rabies vaccination and the use of human rabies immune globulin, hence to assure 100% compliance for the same awareness campaign is required. PMID- 25722618 TI - Cysticercal encephalitis presenting with a "starry sky" appearance on neuroimaging. AB - A lady in her early forties was brought to our hospital in an unconscious state with history of generalized tonic-clonic seizures for last 6 h. She had multiple episodes of seizures in last 4 months, but did not receive any treatment. Relatives also gave a history of fever, headache, and vomiting for last 1 week. Her seizures were controlled with intravenous lorazepam and valproate. Clinical examination revealed a delirious patient with bilateral papilledema, brisk deep tendon reflexes, and extensor plantars. She had aspirated and had bilateral coarse crepitations on chest auscultation. Computed tomography (CT) of brain showed multiple small hyperdense calcific lesions extending throughout both the cerebral hemispheres leading to a "starry sky" appearance, suggestive of cysticercal encephalitis. The patient succumbed to progressive aspiration pneumonitis on the 6(th) day after hospitalization. PMID- 25722619 TI - Typing and Antibiogram of Vibrio cholerae Isolates from a Tertiary Care Hospital in Pune: A 3 Year Study. AB - A retrospective analysis was done over a period of 3 years (January 2010- December 2012) in a tertiary care hospital, Pune, to note the changes in the prevalence and distribution of biotypes, serotypes, antibiotic susceptibility pattern and phage types of Vibrio cholerae isolates from clinical samples so as to be vigilant and curtail major outbreak in future. Vibrio cholerae isolates were obtained from 4.4% of the 1126 fecal specimens processed from cases of acute watery diarrhea. Majority of the isolates were identified as V. cholerae O1 biotype El Tor serotype Ogawa (98%); Phage 27 was the predominant type (77.5%). Majority of the cases were encountered during the months June-August (68%). Antibiogram over a period of 3 years showed that isolates were consistently resistant to Ampicillin (90%) and Furazolidone (88%). Low level of resistance was seen with Norfloxacin (8%), Gentamicin (8%) and Tetracycline (6%). All isolates were susceptible to Chloramphenicol. PMID- 25722620 TI - Diabetic Foot Gangrene Patient with Multi-drug Resistant Pseudomonas Putida Infection in Karawaci District, Indonesia. AB - Pseudomonas putida is a rod-shaped, non fermenting Gram-negative organism frequently found in the environment that utilizes aerobic metabolism, previously thought to be of low pathogenicity. It had been reported as cause of skin and soft tissue infection, especially in immunocompromised patients. A female green grocer, 51 year-old came to internal medicine out-patient clinic with gangrene and osteomyelitis on her 1(st), 2(nd) and 3(rd) digit and wound on the sole of the right foot since 1 month prior. The patient had history of uncontrolled diabetes since a year ago. She was given ceftriaxone 2 grams b.i.d, metronidazole 500 mg t.i.d empirically and then amikacin 250 mg b.i.d, followed by amputation of the digits and wound debridement. The microorganism's culture from pus revealed multi drug resistant Pseudomonas putida. She recovered well after antibiotics and surgery. PMID- 25722621 TI - Fungus or parasite or both: a diagnostic challenge. AB - Protothecosis is a rare opportunistic infection caused by achlorophilic algae Prototheca wickerhamii, mainly in immunocompromised hosts. Due to their morphologic appearance in routine culture media, they can often mimic yeast-like opportunistic pathogens such as Pneumocystis jirovecii. This can delay the identification of other culprit organisms. We present a fatal case of protothecosis in a 74-year-old immunosuppressed male with concomitant Pneumocystis jirovecii pneumonia (PJP). The presence of a coinfection along with resemblance in routine culture media and microbiological and histopathological staining can prove to be a diagnostic challenge and delay appropriate care of an immunosuppressed patient. PMID- 25722622 TI - Elizabethkingia meningoseptica outbreak in intensive care unit. PMID- 25722623 TI - Elbow mycobacterium tuberculosis in america. PMID- 25722624 TI - Comments on investigating a community wide outbreak of hepatitis a in India. PMID- 25722625 TI - Antibiotic resistance profile of non-fermenting Gram-negative bacilli isolated from the blood cultures of cancer patients. PMID- 25722626 TI - Low rates of Hepatitis B and Human Immunodeficiency Virus coinfection in rural northern Tanzania. PMID- 25722627 TI - Candida endocarditis: the insidious killer. PMID- 25722628 TI - Synthesis of novel spin-labeled derivatives of 5-FU as potential antineoplastic agents. AB - Chemotherapy is a general treatment option for various cancers, including lung cancer. In order to find compounds with superior bioactivity and less toxicity against lung cancer, novel spin-labeled 5-fluorouracil (5-FU) derivatives (3a-f) were synthesized and evaluated against four human tumor cell lines (A-549, DU 145, KB, and KBvin). Two promising compounds 3d and 3f exhibited IC50 values of 2.76 and 2.38 MUM, respectively, against non-small cell lung carcinoma cell line A-549. These compounds were twofold more cytotoxic than 5-FU and less toxic against other tested cell lines. Compound 3f exhibited seven times more selective cytotoxicity against A-549 than 5-FU. Our results suggest that compounds 3d and 3f merit further investigation for development into clinical trial candidates for non-small cell lung cancer. PMID- 25722629 TI - Single-incision laparoscopic repair of Spigelian hernia. AB - INTRODUCTION: Spigelian hernias represent only 1% to 2% of all abdominal wall hernias. The treatment, however, remains controversial but depends on institutional expertise. This case series reports the first experience with single-incision laparoscopic totally extraperitoneal (SILTEP) repair of Spigelian hernias with telescopic extraperitoneal dissection in combination with inguinal hernia repair. METHODS: From February 2013 to April 2014, all patients referred with inguinal or Spigelian hernias, without histories of extraperitoneal intervention, underwent SILTEP repair with telescopic extraperitoneal dissection. A single-port device, 5.5 mm/52 cm/30 degrees angled laparoscope, and conventional straight dissecting instruments were used for all cases. Extraperitoneal dissection was performed under direct vision with preservation of preperitoneal fascia overlying retroperitoneal nerves. Inguinal herniorrhaphy was performed with lightweight mesh that covered low-lying Spigelian defects. High lying Spigelian defects were repaired with additional mesh. RESULTS: There were 131 patients with 186 (92 direct) inguinal hernias and 7 patients with 8 Spigelian hernias (6 incidental, including 1 bilateral and 2 preoperatively diagnosed), with a mean age of 51.3 years and a mean body mass index of 25.1 kg/m(2). An additional piece of mesh was used for 3 hernias. All Spigelian hernias were associated with direct inguinal hernias, and 8 combined inguinal and Spigelian hernias were successfully repaired with SILTEP repair with telescopic extraperitoneal dissection as day cases. There were no clinical recurrences during a mean follow-up period of 6 months (range, 1-15 months). CONCLUSIONS: Combined Spigelian and inguinal hernias can be successfully treated with SILTEP herniorrhaphy with telescopic extraperitoneal dissection. The high incidence of Spigelian hernias associated with direct inguinal hernias suggests a high index of suspicion for Spigelian hernias during laparoscopic inguinal herniorrhaphy. PMID- 25722630 TI - Re: JSLS. 2013;17:414-417. Effects of electrosurgery and vaginal closure technique on postoperative vaginal cuff dehiscence. PMID- 25722632 TI - Erratum. PMID- 25722631 TI - Re: JSLS. 2014;18:211-224. Robotic-assisted versus laparoscopic colectomy: cost and clinical outcomes. PMID- 25722633 TI - Retraction. PMID- 25722634 TI - Natural health product use in children: Common and important. PMID- 25722635 TI - Community health centres: Potential opportunities for community paediatrics. From interprofessional clinical care to board governance. PMID- 25722636 TI - Case 1: A 16-year-old girl with strange behaviour. PMID- 25722637 TI - Case 2: A 13-year-old boy with fever and rash. PMID- 25722638 TI - Evidence for Clinicians: Nebulized epinephrine for croup in children. PMID- 25722639 TI - What kids think about boys getting the HPV vaccine as well as girls. PMID- 25722641 TI - The Academic Half-Day redesigned: Improving generalism, promoting CanMEDS and developing self-directed learners. AB - BACKGROUND: The Montreal Children's Hospital Pediatric Residency Program redesigned its Academic Half-Day based on program concerns consistent with the published literature. These concerns included inadequate preparation for general paediatric practice, gaps in CanMEDS education and exclusive use of didactic lectures. Novel instructional methods included monthly simulation sessions to learn CanMEDS competencies, increased use of general paediatricians as instructors, implementation of a 'systems-based' curriculum and development of self-directed learning skills through activities such as 'Residents as Teachers'. METHOD: A postimplementation online survey was sent to all 18 residents who had been exposed to both curricula. The survey was designed to determine the impact of the new curriculum on their perceived ability to retain information and acquire the competencies of a general paediatrician, and to assess the effect on their self-directed learning. Responses were recorded on a five-point Likert scale ranging from 'strongly disagree' to 'strongly agree'. RESULTS: Fourteen of 18 (78%) residents completed the survey. All residents preferred the 'systems based' educational program. Seventy-nine percent of all residents agreed that the simulation sessions were an effective method of learning the CanMEDS competencies. Importantly, 64% of residents voluntarily read more about the topics presented and 71% agreed that they retained the content better. Moreover, 79% believed that changes made to the teaching curriculum better prepared them for a general paediatric practice and 64% of residents believed that it better 'supplements' learning in the clinical setting. CONCLUSION: The authors propose that the new curriculum is comprehensive, while developing the skills required for life-long learning as a general paediatrician. PMID- 25722640 TI - The use of natural health products by paediatric patients in respite care. AB - OBJECTIVES: To determine the use and potential interactions of natural health products (NHPs) with conventional medications in children with life-limiting illnesses. METHODS: The present study was a retrospective medical record review of palliative care patients <18 years of age who were admitted for respite care to a Canadian paediatric hospice between January 1, 2008 and December 31, 2013. The NHPs were identified according to Health Canada's inclusion criteria. RESULTS: A total of 106 children were included in the present study. Eighty-two (77.4%) had used one or more NHPs: 60 (56%) used vitamins and minerals; 45 (42.5%) used other products including probiotics, omega-3, organic acids and essential fatty acids; 34 (32.1%) used everyday consumer products; 12 (11.3%) used herb or plant-based remedies; and one (0.9%) used homeopathic remedies. Thirty-nine potential NHP-medication and 10 potential NHP-NHP interactions were identified. A considerable number of patients (n=54) used at least one medication and NHP, or two NHPs with potential interactions. The most common type of interaction was pharmacokinetic: decreasing blood concentrations of the medication, NHP or both (43.9% of NHP users); and enhancing the blood concentration of an NHP for NHP-NHP interactions (22% of NHP users). CONCLUSION: A high proportion of patients in respite care use NHPs. Most used NHPs and medications that have potential interactions, although there were no adverse clinical manifestations in the present study. It is important to educate health care professionals about NHPs, the evidence available and lack thereof. This could reduce the most serious interactions and improve the alliance between parents and health care providers to balance the potential risks and benefits of NHPs. PMID- 25722643 TI - Prophylactic antibiotics for children with recurrent urinary tract infections. AB - Prophylactic antibiotics for urinary tract infections are no longer routinely recommended. A large number of children must be given prophylaxis to prevent one infection and antibiotic resistance is a major concern when treating community acquired urinary tract infections. The results of three recent significant studies are examined, with focus on the efficacy of prophylaxis, and recommendations are made. PMID- 25722642 TI - Managing type 1 diabetes in school: Recommendations for policy and practice. AB - Diabetes requiring insulin is increasingly common and likely to impact students in most, if not all, schools. Diabetes and its complications have major personal, social and economic impact, and improved diabetes control reduces the risk of both short- and long-term complications. Evidence shows that more intensive management of diabetes - through frequent blood glucose monitoring, insulin administration with injections and/or insulin pumps, and careful attention to diet and exercise - leads to better control. Since children spend 30 to 35 hours per week at school, effectively managing their diabetes while there is integral to their short- and long-term health. The Canadian Paediatric Society and the Canadian Pediatric Endocrine Group recommend that minimum standards for supervision and care be established across Canada to support children and youth with type 1 diabetes in schools. These recommendations are derived from evidence based clinical practice guidelines, with input from diabetes care providers from across Canada, and are consistent with the Canadian Diabetes Association's Guidelines for the Care of Students Living with Diabetes at School. PMID- 25722644 TI - Hypoglycemia in an unmonitored full-term newborn. PMID- 25722645 TI - The Evidence-based Practice for Improving Quality method has greater impact on improvement of outcomes than dissemination of practice change guidelines and quality improvement training in neonatal intensive care units. AB - OBJECTIVES: To determine whether outcome improvements achieved by neonatal intensive care units (NICUs) in the Evidence-based Practice for Improving Quality (EPIQ) trial could be reproduced in other NICUs by providing quality improvement (QI) training and practice change guidelines developed during the EPIQ trial; and to examine whether the results of the EPIQ trial were sustained. METHODS: The present prospective before-after study included 5812 infants born at <=32 weeks' gestation and admitted to 19 level 3 NICUs in the Canadian Neonatal Network between October 1, 2005 and December 31, 2007. During a three-month baseline period, multi-disciplinary teams received general training in QI techniques at a two-day workshop, and practice change guidelines targeting nosocomial infection (NI) and bronchopulmonary dysplasia (BPD) developed during the EPIQ trial were provided to all participants. Outcome data collected during the intervention period were compared with data from the baseline period and reported quarterly. RESULTS: In NICUs that had not previously participated in the EPIQ trial (non EPIQ NICUs), there were no significant changes in the incidence trends of NI or BPD. However, within NICUs that had previously participated in the EPIQ trial (EPIQ NICUs) there was a continued reduction in the incidence trend of NI and BPD among EPIQ NICUs randomized during the trial to reduce NI and BPD, respectively. CONCLUSIONS: Providing NICUs with QI training and practice change guidelines developed during a successful QI initiative in other units is not effective. The authors speculate that successful practice change involves organizational culture and behaviour change, and should be driven by context-specific evidence. PMID- 25722646 TI - Health impact: longitudinal analysis of employment at middle and old age in Mexico. AB - We use longitudinal data from the Mexican Health and Aging Study to analyze the relationship between health and labor force participation of population aged 50 years and older in Mexico. The results confirm that health, measured through chronic diseases and difficulty to perform activities of daily living, has a powerful influence on labor force participation. We also find important differences by gender; hypertension and diabetes have effects in both, men and women; heart disease and stroke only in men. We provide concrete evidence on economic participation and highlight the importance of public policies to create adequate jobs for the population at middle and old age. PMID- 25722647 TI - Experimental Evidence of Negative Linear Compressibility in the MIL-53 Metal Organic Framework Family. AB - We report a series of powder X-ray diffraction experiments performed on the soft porous crystals MIL-53(Al) and NH2-MIL-53(Al) in a diamond anvil cell under different pressurization media. Systematic refinements of the obtained powder patterns demonstrate that these materials expand along a specific direction while undergoing total volume reduction under an increase in hydrostatic pressure. The results confirm for the first time the Negative Linear Compressibility behaviour of this family of materials recently predicted from quantum chemical calculations. PMID- 25722648 TI - Chronoamperometric study of elemental sulphur (S) nanoparticles (NPs) in NaCl water solution: new methodology for S NPs sizing and detection. AB - BACKGROUND: Elemental sulfur (S) persists in natural aquatic environment in a variety of forms with different size distributions from dissolved to particulate. Determination of S speciation mainly consists of the application of chromatographic and electrochemical techniques while its size determination is limited only to the application of microscopic and light scattering techniques. S biological and geochemical importance together with recent increases of S industrial applications requires the development of different analytical tools for S sizing and quantification. In recent years the use of electrochemical measurements as a direct, fast, and inexpensive technique for the different nanoparticles (NPs) characterization (Ag, Au, Pt) is increasing. In this work, electrochemical i.e. chronoamperometric measurements at the Hg electrode are performed for determination of the size distribution of the S NPs. RESULTS: S NPs were synthesized in aqueous medium by sodium polysulphide acidic hydrolysis. Chronoamperometric measurements reveal the polydisperse nature of the formed suspension of S NPs. The electrochemical results were compared with dynamic light scattering measurements parallel run in the same S NPs suspensions. The two methods show fairly good agreement, both suggesting a log-normal size distribution of the S NPs sizes characterized by similar parameters. CONCLUSIONS: The preliminary results highlight the amperometric measurements as a promising tool for the size determination of the S NPs in the water environment. PMID- 25722649 TI - A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether a therapeutic-only platelet transfusion policy (platelet transfusions given when patient bleeds) is as effective and safe as a prophylactic platelet transfusion policy (platelet transfusions given to prevent bleeding usually when the platelet count falls below a given trigger level) in patients with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation. PMID- 25722650 TI - Alternative agents versus prophylactic platelet transfusion for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether alternative agents (e.g. artificial platelet substitutes, platelet-poor plasma, fibrinogen, rFVIIa, thrombopoietin mimetics) are as effective and safe as the use of platelet transfusions for the prevention of bleeding (prophylactic platelet transfusion) in patients with haematological disorders who are undergoing myelosuppressive chemotherapy or stem cell transplantation. Antifibrinolytics (lysine analogues) will not be included in this review because they have been the focus of another Cochrane review (Wardrop 2013). PMID- 25722651 TI - Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether different platelet transfusion thresholds for administration of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect the efficacy and safety of prophylactic platelet transfusions in preventing bleeding in patients with haematological disorders after chemotherapy with or without stem cell transplantation. PMID- 25722652 TI - Different doses of prophylactic platelet transfusion for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether different doses of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect their efficacy and safety in preventing bleeding in patients with haematological disorders after chemotherapy with or without stem cell transplantation. PMID- 25722653 TI - Corrigendum to "unique characteristics of the pyrrolysine system in the 7th order of methanogens: implications for the evolution of a genetic code expansion cassette". AB - [This corrects the article DOI: 10.1155/2014/374146.]. PMID- 25722654 TI - Conjugated linoleic acid induces an atheroprotective macrophage MPhi2 phenotype and limits foam cell formation. AB - BACKGROUND: Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds. We have previously shown that a specific CLA blend (80:20 cis-9,trans-11:trans-10,cis-12-CLA) induces regression of pre established atherosclerosis in vivo, via modulation of monocyte/macrophage function. However, the exact mechanisms through which CLA mediates this effect remain to be elucidated. METHODS: Here, we address if CLA primes monocytes towards an anti-inflammatory MPhi2 macrophage and examine the effect of individual CLA isomers and the atheroprotective blend on monocyte-macrophage differentiation, cytokine generation, foam cell formation and cholesterol metabolism in human peripheral blood monocyte (HPBMC)-derived macrophages. RESULTS: cis-9,trans-11-CLA and the atheroprotective 80:20 CLA blend regulates expression of pro-inflammatory mediators and modulates the inflammatory cytokine profile of macrophages and foam cells. In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MPhi2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression. Furthermore, this altered macrophage phenotype impacts on foam cell formation, inhibiting ox-LDL accumulation and promoting cholesterol efflux via both PPARgamma and LXRalpha dependent pathways. CONCLUSION: The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype. PMID- 25722655 TI - Human parainfluenza virus type 3 (HPIV3) induces production of IFNgamma and RANTES in human nasal epithelial cells (HNECs). AB - BACKGROUND: Human parainfluenza virus type 3 (HPIV3), while infecting lower airway epithelial cells induces pneumonia and bronchiolitis in infants and children, and may lead to asthma exacerbations in children and adults. Respiratory viruses invading the airway epithelium activate innate immune response and induce inflammatory cytokine release contributing to the pathophysiology of upper and lower airway disorders. However, the effects of HPIV3 infection on nasal epithelial cells have not been well defined. The aim of this study was to evaluate the effect of the HPIV3 infection on cultured human nasal epithelial cells (HNECs) and the release of interferon gamma and other cytokines. METHODS: RPMI 2650, a human nasal epithelial cell line was cultured into confluence and was infected with HPIV3 (MOI of 0.1, 0.01 and 0.001). The protein release into supernatants and mRNA expression of selected cytokines were assessed 24, 48 and 72 h after infection. Cytokine concentrations in supernatants were measured by ELISA and expression of cytokine mRNA in RPMI 2650 cells confirmed by real time RT-PCR analysis. RESULTS: HNECs infection with HPIV3 did not induce cytotoxicity for at least 48 hours, but significantly increased IFN gamma protein concentration in the cell supernatants at 24 h and 48 h post infection (by 387% and 485% respectively as compared to mock infected cells). At 24 h a significant increase in expression of mRNA for IFNgamma was observed. RANTES protein concentration and mRNA expression were significantly increased at 72 h after infection (mean protein concentration: 3.5 +/- 1.4 pg/mL for 0.001 MOI, 10.8 +/- 4.6 pg/mL for 0.01 MOI and 61.5 +/- 18.4 pg/mL for 0.1 MOI as compared to 2.4 +/- 1.3 pg/mL for uninfected cells). No measurable concentrations of TNF-alpha, IL-10, TSLP, IL-8, GM-CSF or eotaxin, were detected in virus infected cells supernatants. CONCLUSIONS: HPIV3 effectively infects upper airway epithelial cells and the infection is associated with induction of IFN-gamma and generation of RANTES. PMID- 25722656 TI - Health-related quality of life after TBI: a systematic review of study design, instruments, measurement properties, and outcome. AB - Measurement of health-related quality of life (HRQL) is essential to quantify the subjective burden of traumatic brain injury (TBI) in survivors. We performed a systematic review of HRQL studies in TBI to evaluate study design, instruments used, methodological quality, and outcome. Fifty-eight studies were included, showing large variation in HRQL instruments and assessment time points used. The Short Form-36 (SF-36) was most frequently used. A high prevalence of health problems during and after the first year of TBI was a common finding of the studies included. In the long term, patients with a TBI still showed large deficits from full recovery compared to population norms. Positive results for internal consistency and interpretability of the SF-36 were reported in validity studies. The Quality of Life after Brain Injury instrument (QOLIBRI), European Brain Injury Questionnaire (EBIQ), Child Health Questionnaire (CHQ), and the World Health Organization Quality of Life short version (WHOQOL-BREF) showed positive results, but evidence was limited. Meta-analysis of SF-36 showed that TBI outcome is heterogeneous, encompassing a broad spectrum of HRQL, with most problems reported in the physical, emotional, and social functioning domain. The use of SF-36 in combination with a TBI-specific instrument, i.e., QOLIBRI, seems promising. Consensus on preferred methodologies of HRQL measurement in TBI would facilitate comparability across studies, resulting in improved insights in recovery patterns and better estimates of the burden of TBI. PMID- 25722658 TI - An assessment of the nutritional intake of soccer referees. AB - OBJECTIVE: The present study aims to analyze the eating habits and attitudes of a group of soccer referees and linesmen. METHOD: A nutritional study was undertaken of thirty-five soccer referees (aged between 18 and 50) refereeing at different levels, from the Spanish national third division down to the provincial second division. Through the use of a 3-day food diary and 24-hour recall, this study analyzed the intake and distribution of macro- and micro-nutrients and of dietary fiber consumed on different types of day (normal, training, and match days). RESULTS: There were no significant differences in calorie intake related to the three types of day (normal, training, and match days). This was true both of overall amounts (2371.1 kcal, 2479.7 kcal, and 2368.4 kcal, respectively) and amounts per unit of body weight (32.4 kcal/kg, 33.9 kcal/kg, and 32.4 kcal/kg, respectively). In respect of macro-nutrient intake, more specifically carbohydrates, the subjects consumed a diet with an insufficient amount of carbohydrates: 279 g, as against the 371 g (REC1) or 540 g (REC2) recommended according to physical activity levels. Slight increases were observed on game days, but were not statistically significant. Consideration of micro-nutrients showed that the quantities of three vitamins (B6, B12, and C) consumed were above the recommended amounts. However, this was not an issue, since the figures related to water-soluble vitamins. Finally, the amounts of minerals (Ca, Mg, and Fe) and fiber consumed were close to recommended values, regardless of the type of day being considered. CONCLUSIONS: This study found that the group of referees investigated consumed a diet that did not have sufficient calories from carbohydrates, in view of their occupation. This poor nutritional status might interfere with the development of their sporting performance and ultimately increase the risk of injury. This implies a need to design and implement a diet and to introduce educational programs on nutrition for these sportspeople. PMID- 25722659 TI - Vitamin C, A and E supplementation decreases the expression of HSPA1A and HSPB1 genes in the leukocytes of young polish figure skaters during a 10-day training camp. AB - BACKGROUND: Overexpression of HSPA1A and HSPB1 has been shown to indicate stress and the degradation of damaged proteins. Therefore, the expression of these genes is often evaluated during exercise. Vitamin supplementation in young athletes may affect the expression of these genes, and help to maintain health and improve the effects of training. METHODS: Fourteen top junior female athletes (age 14-15y +/- 0.3 SD, body mass 51 kg +/- 5 SD, and BMI of 20.15 +/- 0.9 SD, time in professional training 8.5 y +/- 0.5 SD) attended a conditioning camp that included meals planned by a team dietitian. To examine the effects of vitamin supplementation on antioxidant status we supplemented the athletes with either vitamin A (16 ug/kg/day), vitamin C (8 mg/kg/day) and vitamin E (1 mg/kg/day) or an inert placebo. Blood samples were taken before and after (12 h post) the camp to assess the relative expression of HSPA1A and HSPB1 mRNA in leukocytes via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Overall, participants trained ~135 min daily (1345 min total). No statistically significant differences in HSPA1A and HSPB1 expression were observed between the groups before the camp. In the unsupplemented group, there was a non statistically significant increase in HSPA1A expression (100% change) and a significant increase (37% change, p < 0.05) in HSPB1 expression over the study period. The supplemented group experienced a significant decrease in HSPA1A (40% change, p = 0.01) and HSPB1 (25% change p = 0.03) expression over the study period. CONCLUSION: Our results indicate that supplementation with antioxidant vitamins decreases HSPA1A and HSPB1 mRNA expression in leukocytes, and thereby may reduce exercise-induced stress in young athletes, not only during training, but also in sports competitions. PMID- 25722657 TI - Challenges and Successes in Dissemination of Evidence-Based Treatments for Posttraumatic Stress: Lessons Learned From Prolonged Exposure Therapy for PTSD. AB - Posttraumatic stress disorder (PTSD) poses monumental public health challenges because of its contribution to mental health, physical health, and both interpersonal and social problems. Recent military engagements in Iraq and Afghanistan and the multitude of resulting cases of PTSD have highlighted the public health significance of these conditions. There are now psychological treatments that can effectively treat most individuals with PTSD, including active duty military personnel, veterans, and civilians. We begin by reviewing the effectiveness of these treatments, with a focus on prolonged exposure (PE), a cognitive-behavioral therapy (CBT) for PTSD. Many studies conducted in independent research labs have demonstrated that PE is highly efficacious in treating PTSD across a wide range of trauma types, survivor characteristics, and cultures. Furthermore, therapists without prior CBT experience can readily learn and implement the treatment successfully. Despite the existence of highly effective treatments like PE, the majority of individuals with PTSD receive treatments of unknown efficacy. Thus, it is crucial to identify the barriers and challenges that must be addressed in order to promote the widespread dissemination of effective treatments for PTSD. In this review, we first discuss some of the major challenges, such as a professional culture that often is antagonistic to evidence-based treatments (EBTs), a lack of clinician training in EBTs, limited effectiveness of commonly used dissemination techniques, and the significant cost associated with effective dissemination models. Next, we review local, national, and international efforts to disseminate PE and similar treatments and illustrate the challenges and successes involved in promoting the adoption of EBTs in mental health systems. We then consider ways in which the barriers discussed earlier can be overcome, as well as the difficulties involved in effecting sustained organizational change in mental health systems. We also present examples of efforts to disseminate PE in developing countries and the attendant challenges when mental health systems are severely underdeveloped. Finally, we present future directions for the dissemination of EBTs for PTSD, including the use of newer technologies such as web-based therapy and telemedicine. We conclude by discussing the need for concerted action among multiple interacting systems in order to overcome existing barriers to dissemination and promote widespread access to effective treatment for PTSD. These systems include graduate training programs, government agencies, health insurers, professional organizations, healthcare delivery systems, clinical researchers, and public education systems like the media. Each of these entities can play a major role in reducing the personal suffering and public health burden associated with posttraumatic stress. PMID- 25722660 TI - The effects PCSO-524(r), a patented marine oil lipid and omega-3 PUFA blend derived from the New Zealand green lipped mussel (Perna canaliculus), on indirect markers of muscle damage and inflammation after muscle damaging exercise in untrained men: a randomized, placebo controlled trial. AB - BACKGROUND: The purpose of the present study was to evaluate the effects of PCSO 524(r), a marine oil lipid and n-3 LC PUFA blend, derived from New Zealand green- lipped mussel (Perna canaliculus), on markers of muscle damage and inflammation following muscle damaging exercise in untrained men. METHODS: Thirty two untrained male subjects were randomly assigned to consume 1200 mg/d of PCSO- 524(r) (a green-lipped mussel oil blend) or placebo for 26 d prior to muscle damaging exercise (downhill running), and continued for 96 h following the muscle damaging exercise bout. Blood markers of muscle damage (skeletal muscle slow troponin I, sTnI; myoglobin, Mb; creatine kinase, CK), and inflammation (tumor necrosis factor, TNF-alpha), and functional measures of muscle damage (delayed onset muscle soreness, DOMS; pressure pain threshold, PPT; knee extensor joint range of motion, ROM; isometric torque, MVC) were assessed pre- supplementation (baseline), and multiple time points post-supplementation (before and after muscle damaging exercise). At baseline and 24 h following muscle damaging exercise peripheral fatigue was assessed via changes in potentiated quadriceps twitch force (?Qtw,pot) from pre- to post-exhaustive cycling ergometer test in response to supra-maximal femoral nerve stimulation. RESULTS: Compared to placebo, supplementation with the green-lipped mussel oil blend significantly attenuated (p < 0.05) sTnI and TNF-alpha at 2, 24, 48, 72 and 96 h., Mb at 24, 48, 72, 96 h., and CK-MM at all-time points following muscle damaging exercise, significantly reduced (p < 0.05) DOMS at 72 and 96 h post-muscle damaging exercise, and resulted in significantly less strength loss (MVC) and provided a protective effect against joint ROM loss at 96 h post- muscle damaging exercise. At 24 h after muscle damaging exercise perceived pain was significantly greater (p < 0.05) compared to baseline in the placebo group only. Following muscle damaging exercise ?Qtw,pot was significantly less (p < 0.05) on the green-lipped mussel oil blend compared to placebo. CONCLUSION: Supplementation with a marine oil lipid and n-3 LC PUFA blend (PCSO-524(r)), derived from the New Zealand green lipped mussel, may represent a useful therapeutic agent for attenuating muscle damage and inflammation following muscle damaging exercise. PMID- 25722661 TI - Energy availability discriminates clinical menstrual status in exercising women. AB - BACKGROUND: Conditions of low energy availability (EA) (<30 kcal/kgLBM) have been associated with suppressed metabolic hormones and reductions in LH pulsatility in previously sedentary women during short-term manipulations of energy intake (EI) and exercise energy expenditure (EEE) in a controlled laboratory setting. The purpose of this study was to examine if EA, defined as EA = (EI-EEE)/kgLBM, is associated with disruptions in ovarian function in exercising women. METHODS: Menstrual status was confirmed with daily measures of urinary reproductive metabolites across 1-3 menstrual cycles or 28-day monitoring periods. EA was calculated for exercise days using EI from 3-day diet logs, EEE from heart-rate monitors and/or exercise logs for a 7-day period, and body composition from DXA. Resting energy expenditure (REE) was measured by indirect calorimetry. Total triiodothyronine (TT3) was measured from a fasting blood sample. RESULTS: 91 exercising women (23.1 +/- 0.5 years) were categorized clinically as either exercising amenorrheic (ExAmen, n = 30), exercising oligomenorrheic (ExOligo, n = 20) or exercising eumenorrheic (ExEumen, n = 41). The eumenorrheic group was further divided into more specific subclinical groups as either exercising ovulatory (ExOv, n = 20), exercising inconsistent (ExIncon, n = 13), or exercising anovulatory (ExAnov, n = 8). An EA threshold of 30 kcal/kgLBM did not distinguish subclinical menstrual status (chi (2) = 0.557, p = 0.46) nor did EA differ across subclinical disturbance groups (p > 0.05). EA was lower in the ExAmen vs. ExEumen (30.9 +/- 2.4 vs. 36.9 +/- 1.7 kcal/kgLBM, p = 0.04). The ratio of REE/predicted REE was lower in the ExAmen vs. ExEumen (0.85 +/- 0.02 vs. 0.92 +/- 0.01, p = 0.001) as was TT3 (79.6 +/- 4.1 vs. 95.3 +/- 2.9 ng/mL, p = 0.002). CONCLUSIONS: EA did not differ among subclinical forms of menstrual disturbances in a large sample of exercising women, but EA did discriminate clinical menstrual status, i.e., amenorrhea from eumenorrhea. PMID- 25722663 TI - Understanding self-organized regularities in healthcare services based on autonomy oriented modeling. AB - Self-organized regularities in terms of patient arrivals and wait times have been discovered in real-world healthcare services. What remains to be a challenge is how to characterize those regularities by taking into account the underlying patients' or hospitals' behaviors with respect to various impact factors. This paper presents a case study to address such a challenge. Specifically, it models and simulates the cardiac surgery services in Ontario, Canada, based on the methodology of Autonomy-Oriented Computing (AOC). The developed AOC-based cardiac surgery service model (AOC-CSS model) pays a special attention to how individuals' (e.g., patients and hospitals) behaviors and interactions with respect to some key factors (i.e., geographic accessibility to services, hospital resourcefulness, and wait times) affect the dynamics and relevant patterns of patient arrivals and wait times. By experimenting with the AOC-CSS model, we observe that certain regularities in patient arrivals and wait times emerge from the simulation, which are similar to those discovered from the real world. It reveals that patients' hospital-selection behaviors, hospitals' service adjustment behaviors, and their interactions via wait times may potentially account for the self-organized regularities of wait times in cardiac surgery services. PMID- 25722662 TI - Front line defenders of the ecological niche! Screening the structural diversity of peptaibiotics from saprotrophic and fungicolous Trichoderma/Hypocrea species. AB - Approximately 950 individual sequences of non-ribosomally biosynthesised peptides are produced by the genus Trichoderma/Hypocrea that belong to a perpetually growing class of mostly linear antibiotic oligopeptides, which are rich in the non-proteinogenic alpha-aminoisobutyric acid (Aib). Thus, they are comprehensively named peptaibiotics. Notably, peptaibiotics represent ca. 80 % of the total inventory of secondary metabolites currently known from Trichoderma/Hypocrea. Their unique membrane-modifying bioactivity results from amphipathicity and helicity, thus making them ideal candidates in assisting both colonisation and defence of the natural habitats by their fungal producers. Despite this, reports on the in vivo-detection of peptaibiotics have scarcely been published in the past. In order to evaluate the significance of peptaibiotic production for a broader range of potential producers, we screened nine specimens belonging to seven hitherto uninvestigated fungicolous or saprotrophic Trichoderma/Hypocrea species by liquid chromatography coupled to electrospray high resolution mass spectrometry. Sequences of peptaibiotics found were independently confirmed by analysing the peptaibiome of pure agar cultures obtained by single-ascospore isolation from the specimens. Of the nine species examined, five were screened positive for peptaibiotics. A total of 78 peptaibiotics were sequenced, 56 (=72 %) of which are new. Notably, dihydroxyphenylalaninol and O-prenylated tyrosinol, two C-terminal residues, which have not been reported for peptaibiotics before, were found as well as new and recurrent sequences carrying the recently described tyrosinol residue at their C-terminus. The majority of peptaibiotics sequenced are 18- or 19-residue peptaibols. Structural homologies with 'classical representatives' of subfamily 1 (SF1)-peptaibiotics argue for the formation of transmembrane ion channels, which are prone to facilitate the producer capture and defence of its substratum. PMID- 25722664 TI - Utilising a simulation platform to understand the effect of domain model assumptions. AB - Computational and mathematical modelling approaches are increasingly being adopted in attempts to further our understanding of complex biological systems. This approach can be subjected to strong criticism as substantial aspects of the biological system being captured are not currently known, meaning assumptions need to be made that could have a critical impact on simulation response. We have utilised the CoSMoS process in the development of an agent-based simulation of the formation of Peyer's patches (PP), gut-associated lymphoid organs that have a key role in the initiation of adaptive immune responses to infection. Although the use of genetic tools, imaging technologies and ex vivo culture systems has provided significant insight into the cellular components and associated pathways involved in PP development, interesting questions remain that cannot be addressed using these approaches, and as such well justified assumptions have been introduced into our model to counter this. Here we focus not on the development of the model itself, but instead demonstrate how the resultant simulation can be used to assess how these assumptions impact the simulation response. For example, we consider the impact of our assumption that the migration rate of lymphoid tissue cells into the gut remains constant throughout PP development. We demonstrate that an analysis of the assumptions made in the construction of the domain model may either increase confidence in the model as a representation of the biological system it captures, or may suggest areas where further biological experimentation is required. PMID- 25722665 TI - A Patient with a Large Gastric Tumor and Protein-Losing Gastroenteropathy Successfully Treated with Neoadjuvant TS-1 Combined with CDDP Therapy. AB - Gastric cancer with protein-losing gastroenteropathy is relatively rare worldwide. The most important problem for the treatment of these patients is their low nutritional status and protein level, which can cause severe postoperative complications. We report a 49-year-old Japanese female with a large gastric tumor and protein-losing gastroenteropathy successfully treated with neoadjuvant TS-1 combined with CDDP therapy. She had a type 5 tumor with partially cauliflower-like appearance. Her blood chemistry revealed low serum total protein (3.3 g/dl) and low albumin (1.7 g/dl). She was additionally diagnosed with protein-losing gastroenteropathy based on (99m)Tc-human serum albumin scintigraphy. Initial neoadjuvant chemotherapy decreased the size of the tumor and led to a marked improvement in her serum protein levels. She then underwent a total gastrectomy and lymph node dissection (D2) with a combined resection of the spleen and gallbladder. Therefore, neoadjuvant chemotherapy may provide a safe treatment before definitive surgery for gastric cancer with protein-losing gastroenteropathy. PMID- 25722666 TI - Thymoma with autoimmune hemolytic anemia. AB - A 38-year-old Japanese male was referred to our hospital with abnormal chest X ray results and severe Coombs-positive hemolytic anemia. He was diagnosed with a stage IV, WHO type A thymoma and was treated with oral prednisolone (1 mg/kg/day) and subsequent chemotherapy. After chemotherapy, the patient underwent surgical resection of the thymoma. Hemolysis rapidly disappeared and did not return after the discontinuation of oral corticosteroids. Corticosteroid therapy may be preferable to chemotherapy or thymoma surgical resection in the management of autoimmune hemolytic anemia with thymoma. PMID- 25722667 TI - Lung Adenocarcinoma with Pulmonary Miliary Metastases and Complex Somatic Heterozygous EGFR Mutation. AB - The pretreatment detection of an activating mutation of EGFR is now routinely performed in metastatic nonsquamous non-small cell lung cancer (NSCLC). The therapeutic impact of such a detection is major, as patients with advanced NSCLC exhibiting a mutation of exon 19 or 21 will benefit from EGFR-tyrosine kinase inhibitors (TKI). The presence of an EGFR resistance mutation, such as T790M in EGFR-TKI-naive patients, is seldom looked for and is related either to a germinal mutation or to somatically mutated subclones. It has a negative predictive impact. We present the case of a patient with a lung papillary adenocarcinoma and miliary intrapulmonary metastases whose tumor displays a somatic complex heterozygous EGFR mutation, combining L858R (exon 21) and a primary resistance mutation T790M (exon 20), both detected by direct sequencing. PMID- 25722668 TI - Herpes simplex encephalitis as a complication of whole-brain radiotherapy: a case report and review of the literature. AB - A 55-year-old male recently diagnosed with stage IV lung adenocarcinoma presented with altered mental status approximately 1 week after the completion of 14 fractions of whole-brain radiotherapy (WBRT) for brain metastases. On admission, he was somnolent but oriented and without focal neurological deficits. Brain imaging revealed marked regression of his brain metastases. Laboratory values were only significant for hyponatremia with urine hyperosmolality consistent with syndrome of inappropriate antidiuretic hormone secretion. The patient developed seizures 3 days after admission, at which time cerebrospinal fluid was significant for positive herpes simplex virus (HSV)-1 PCR but with a negative cell count, and acyclovir was started for HSV encephalitis (HSE). After 3 weeks of acyclovir 10 mg/dl i.v. 3 times per day, he had significant neurological recovery and was discharged. Although HSE is a relatively rare condition, it is the most common cause of sporadic encephalitis in Western countries. Since the pathogenesis is believed to be due to the reactivation of latent HSV, it is possible that patients who are immunosuppressed are at higher risk for HSE. In addition, patients who are immunosuppressed or immunocompromised often present atypically, which may delay time to diagnosis and treatment, thus significantly worsening prognosis. This case report intends to raise awareness of this severe condition in the context of patients who have received WBRT and immunosuppressive therapy. In addition, important considerations of diagnosis and treatment of HSE in this patient population are discussed. PMID- 25722669 TI - Granulocyte colony-stimulating factor-producing carcinoma of unknown primary site. AB - Granulocyte colony-stimulating factor (G-CSF)-producing nonhematopoietic malignancies have been reported in various organs and are associated with a poor clinical outcome. Moreover, carcinoma of unknown primary site (CUP) is an uncommon malignancy that occurs in about 2-6% of cancer patients. CUP also has a poor prognosis due to its missing profile. Since both G-CSF-producing carcinoma and CUP are rare, G-CSF-producing CUP (GCSF-CUP) is considered to have an even poorer prognosis and is seldom encountered. Herein, we report the case of a GCSF CUP patient. A 75-year-old man was admitted to our hospital complaining of cervical lymphadenopathy. Multiple bulky lymph nodes without a primary site were revealed by image analysis. His complete blood count showed leukocytosis, and his blood chemistry panel indicated highly elevated levels of G-CSF. Although the patient was treated with combination chemotherapy of carboplatin, paclitaxel, bevacizumab and erlotinib, he died of intestinal perforation due to tumor invasion 23 days after the start of the therapy. An autopsy confirmed that the tumor was positive for anti-G-CSF antibody, but the primary site was still not detected. PMID- 25722670 TI - Icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels in the hippocampus of the senescence- accelerated mouse. AB - At 8 weeks after intragastric administration of icariin to senescence-accelerated mice (P8 strain), Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increased. Immunohistochemical staining and western blot assay detected significantly increased levels of cyclic adenosine monophosphate response element binding protein. These results suggest that icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels and improves learning and memory functions in hippocampus of the senescence-accelerated mouse. PMID- 25722671 TI - Gastrodin blocks neural stem cell differentiation into glial cells mediated by kainic acid. AB - Kainic acid can simulate excitatory amino acids in vitro. Neural stem cells, isolated from newborn Wistar rats, were cultured in vitro and exposed to 100-4 000 MUM kainic acid for 7 days to induce neuronal cell differentiation, causing the number of astrocytes to be significantly increased. Treatment with a combination of 0.5 mg/L gastrodin and kainic acid also caused the number of differentiated neurons to be significantly increased compared with treatment with kainic acid alone. Experimental findings suggest that gastrodin reduces the excitability of kainic acid and induces neural stem cell differentiation into neurons. PMID- 25722672 TI - Pine pollen inhibits cell apoptosis-related protein expression in the cerebral cortex of mice with arsenic poisoning. AB - Previous studies have demonstrated that pine pollen can inhibit cerebral cortical cell apoptosis in mice with arsenic poisoning. The present study sought to detect the influence of pine pollen on apoptosis-related proteins. Immunohistochemistry, western blotting and enzyme-linked immunosorbent assays were used to measure the levels of apoptosis-related proteins in the cerebral cortex of mice with arsenic poisoning. Results indicated that pine pollen suppressed cell apoptosis in the cerebral cortex of arsenic-poisoned mice by reducing Bax, Bcl-2 protein expression and increasing p53 protein expression. PMID- 25722673 TI - Diffusion tensor imaging detects Wallerian degeneration of the corticospinal tract early after cerebral infarction. AB - To investigate the feasibility and time window of early detection of Wallerian degeneration in the corticospinal tract after middle cerebral artery infarction, 23 patients were assessed using magnetic resonance diffusion tensor imaging at 3.0T within 14 days after the infarction. The fractional anisotropy values of the affected corticospinal tract began to decrease at 3 days after onset and decreased in all cases at 7 days. The diffusion coefficient remained unchanged. Experimental findings indicate that diffusion tensor imaging can detect the changes associated with Wallerian degeneration of the corticospinal tract as early as 3 days after cerebral infarction. PMID- 25722674 TI - Magnetic resonance perfusion imaging evaluation in perfusion abnormalities of the cerebellum after supratentorial unilateral hyperacute cerebral infarction. AB - Magnetic resonance imaging (MRI) data of 10 patients with hyperacute cerebral infarction (<= 6 hours) were retrospectively analyzed. Six patients exhibited perfusion defects on negative enhancement integral maps, four patients exhibited perfusion differences in pseudo-color on mean time to enhance maps, and three patients exhibited perfusion differences in pseudo-color on time to minimum maps. Dynamic susceptibility contrast-enhanced perfusion weighted imaging revealed a significant increase in region negative enhancement integral in the affected hemisphere of patients with cerebral infarction. The results suggest that dynamic susceptibility contrast-enhanced perfusion weighted imaging can clearly detect perfusion abnormalities in the cerebellum after unilateral hyperacute cerebral infarction. PMID- 25722675 TI - Screen-imaging guidance using a modified portable video macroscope for middle cerebral artery occlusion. AB - The use of operating microscopes is limited by the focal length. Surgeons using these instruments cannot simultaneously view and access the surgical field and must choose one or the other. The longer focal length (more than 1 000 mm) of an operating telescope permits a position away from the operating field, above the surgeon and out of the field of view. This gives the telescope an advantage over an operating microscope. We developed a telescopic system using screen-imaging guidance and a modified portable video macroscope constructed from a Computar MLH 10 * macro lens, a DFK-21AU04 USB CCD Camera and a Dell laptop computer as monitor screen. This system was used to establish a middle cerebral artery occlusion model in rats. Results showed that magnification of the modified portable video macroscope was appropriate (5-20 *) even though the Computar MLH 10 * macro lens was placed 800 mm away from the operating field rather than at the specified working distance of 152.4 mm with a zoom of 1-40 *. The screen imaging telescopic technique was clear, life-like, stereoscopic and matched the actual operation. Screen-imaging guidance led to an accurate, smooth, minimally invasive and comparatively easy surgical procedure. Success rate of the model establishment evaluated by neurological function using the modified neurological score system was 74.07%. There was no significant difference in model establishment time, sensorimotor deficit and infarct volume percentage. Our findings indicate that the telescopic lens is effective in the screen surgical operation mode referred to as "long distance observation and short distance operation" and that screen-imaging guidance using an modified portable video macroscope can be utilized for the establishment of a middle cerebral artery occlusion model and micro-neurosurgery. PMID- 25722676 TI - Expression profiles of microRNAs after focal cerebral ischemia/reperfusion injury in rats. AB - Rat models of focal cerebral ischemia/reperfusion injury were established by occlusion of the middle cerebral artery. Microarray analysis showed that 24 hours after cerebral ischemia, there were nine up-regulated and 27 down-regulated microRNA genes in cortical tissue. Bioinformatic analysis showed that bcl-2 was the target gene of microRNA-384-5p and microRNA-494, and caspase-3 was the target gene of microRNA-129, microRNA-320 and microRNA-326. Real-time PCR and western blot analyses showed that 24 hours after cerebral ischemia, bcl-2 mRNA and protein levels in brain tissue were significantly decreased, while caspase-3 mRNA and protein levels were significantly increased. This suggests that following cerebral ischemia, differentially expressed microRNA-384-5p, microRNA-494, microRNA-320, microRNA-129 and microRNA-326 can regulate bcl-2 and caspase-3 expression in brain tissue. PMID- 25722677 TI - Survivin small interfering RNA suppresses glioblastoma growth by inducing cellular apoptosis. AB - A survivin small interfering RNA sequence specific for a human and mouse homogenous sequence was constructed. Survivin small interfering RNA could significantly inhibit glioma cell proliferation and induce apoptosis when it was transfected into either a human glioma cell line U251 or rat glioma C6 cells in vitro. In addition, treatment of rat orthotopic glioma models with survivin small interfering demonstrated the inhibition of glioma growth in vivo. Our experimental findings suggest that the use of RNA interference techniques to target the survivin sequence may be useful in the treatment of glioma. PMID- 25722678 TI - Gene expression by simian virus 40 large T antigen-induced medulloblastomas in mice. AB - Signaling pathways known to have components with mutations in human medulloblastoma include sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor. Microarray analysis was applied to examine the gene expression changes in medulloblastomas of pTet-on/pTRE-SV40Tag transgenic mice. Altogether, 14 112 genes were detectable, including 152 genes with significantly different expression levels. These genes were associated with immunity, the cell cycle, signal transduction, cytoskeleton and metabolism. To further confirm the microarray data, real-time polymerase chain reactions were used to examine the expression changes of genes related to sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor signal pathways. Immunohistochemistry detected insulin receptor substrate-1 in the nuclei of brain tumor tissue cells from pTet-on/pTRE SV40Tag transgenic mice, suggesting that SV40 large T antigen may activate the insulin-like growth factor signal pathway to promote tumorigenesis. PMID- 25722679 TI - A change in injured corticospinal tract originating from the premotor cortex to the primary motor cortex in a patient with intracerebral hemorrhage. AB - Many studies have attempted to elucidate the motor recovery mechanism of stroke, but the majority of these studies focus on cerebral infarct and relatively little is known about the motor recovery mechanism of intracerebral hemorrhage. In this study, we report on a patient with intracerebral hemorrhage who displayed a change in injured corticospinal tract originating from the premotor cortex to the primary motor cortex on diffusion tensor imaging. An 86-year-old woman presented with complete paralysis of the right extremities following spontaneous intracerebral hemorrhage in the left frontoparietal cortex. The patient showed motor recovery, to the extent of being able to extend affected fingers against gravity and to walk independently on even ground at 5 months after onset. Diffusion tensor imaging showed that the left corticospinal tract originated from the premotor cortex at 1 month after intracerebral hemorrhage and from the left primary motor cortex and premotor cortex at 5 months after intracerebral hemorrhage. The change of injured corticospinal tract originating from the premotor cortex to the primary motor cortex suggests motor recovery of intracerebral hemorrhage. PMID- 25722680 TI - Cortical infarction of the right parietal lobe and neurogenic heart disease: A report of three cases. AB - Three male patients were diagnosed with new cortical infarctions of the right parietal lobe on the basis of head magnetic resonance imaging; high-intensity signals indicating lesions in the right parietal lobe were noted on diffusion weighted images at admission. Two of them presented with left hand weakness, and one exhibited left upper limb weakness. Treatment for improving blood supply to the brain was administered. One patient died suddenly because of ventricular fibrillation 3 days after admission. The other two patients had increased troponin levels and abnormal electrocardiograms, and were diagnosed with acute myocardial infarction half a month after admission. When lesions exist in field 7 of the parietal cortex (resulting in paralysis of the contralateral hand), the sympathetic center of the posterior lateral nucleus of the hypothalamus demonstrates compensatory excitement, which easily causes tachyarrhythmia and sudden death. Our experimental findings indicate that close electrocardiograph monitoring and cerebral infarction treatment should be standard procedures to predict and help prevent heart disease in patients with cerebral infarction in the right parietal lobe and left upper limb weakness as the main complaint. PMID- 25722681 TI - Hypoxia inducible factor-1alpha mediates protection of DL-3-n-butylphthalide in brain microvascular endothelial cells against oxygen glucose deprivation-induced injury. AB - Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on oxygen glucose deprivation -induced hypoxia inducible factor-1alpha expression. In this study, we hypothesized that DL-3-n-butylphthalide can protect against oxygen glucose deprivation-induced injury of newborn rat brain microvascular endothelial cells by means of upregulating hypoxia inducible factor-1alpha expression. MTT assay and Hoechst staining results showed that DL-3-n-butylphthalide protected brain microvascular endothelial cells against oxygen glucose deprivation-induced injury in a dose-dependent manner. Western blot and immunofluorescent staining results further confirmed that the protective effect was related to upregulation of hypoxia inducible factor-1alpha. Real-time RT-PCR reaction results showed that DL 3-n-butylphthalide reduced apoptosis by inhibiting downregulation of pro apoptotic gene caspase-3 mRNA expression and upregulation of apoptosis-executive protease bcl-2 mRNA expression; however, DL-3-n-butylphthalide had no protective effects on brain microvascular endothelial cells after knockdown of hypoxia inducible factor-1alpha by small interfering RNA. These findings suggest that DL 3-n-butylphthalide can protect brain microvascular endothelial cells against oxygen glucose deprivation-induced injury by upregulating bcl-2 expression and downregulating caspase-3 expression though hypoxia inducible factor-1alpha pathway. PMID- 25722682 TI - 3,4-methylenedioxyamphetamine upregulates p75 neurotrophin receptor protein expression in the rat brain. AB - The p75 neurotrophin receptor, which is a member of the tumor necrosis factor receptor superfamily, facilitates apoptosis during development and following central nervous system injury. Previous studies have shown that programmed cell death is likely involved in the neurotoxic effects of 3, 4-methylenedioxy-N methylamphetamine (MDMA), because MDMA induces apoptosis of immortalized neurons through regulation of proteins belonging to the Bcl-2 family. In the present study, intraperitoneal injection of different doses of MDMA (20, 50, and 100 mg/kg) induced significant behavioral changes, such as increased excitability, increased activity, and irritability in rats. Moreover, changes exhibited dose dependent adaptation. Following MDMA injection in rat brain tissue, the number of apoptotic cells dose-dependently increased and p75 neurotrophin receptor expression significantly increased in the prefrontal cortex, cerebellum, and hippocampus. These findings confirmed that MDMA induced neuronal apoptosis, and results suggested that this effect was related by upregulated protein expression of the p75 neurotrophin receptor. PMID- 25722683 TI - Actin-binding Rho activating protein is expressed in the central nervous system of normal adult rats. AB - Previous studies show that actin-binding Rho activating protein (Abra) is expressed in cardiomyocytes and vascular smooth muscle cells. In this study, we investigated the expression profile of Abra in the central nervous system of normal adult rats by confocal immunofluorescence. Results showed that Abra immunostaining was located in neuronal nuclei, cytoplasm and processes in the central nervous system, with the strongest staining in the nuclei; in the cerebral cortex, Abra positive neuronal bodies and processes were distributed in six cortical layers including molecular layer, external granular layer, external pyramidal layer, internal granular layer, internal pyramidal layer and polymorphic layer; in the hippocampus, the cell bodies of Abra positive neurons were distributed evenly in pyramidal layer and granular layer, with positive processes in molecular layer and orien layer; in the cerebellar cortex, Abra staining showed the positive neuronal cell bodies in Purkinje cell layer and granular layer and positive processes in molecular layer; in the spinal cord, Abra-immunopositive products covered the whole gray matter and white matter; co localization studies showed that Abra was co-stained with F-actin in neuronal cytoplasm and processes, but weakly in the nuclei. In addition, in the hippocampus, Abra was co-stained with F-actin only in neuronal processes, but not in the cell body. This study for the first time presents a comprehensive overview of Abra expression in the central nervous system, providing insights for further investigating the role of Abra in the mature central nervous system. PMID- 25722684 TI - Methyl 3,4-dihydroxybenzoate promotes neurite outgrowth of cortical neurons cultured in vitro. AB - Cerebral cortical neurons from neonatal rats were cultured in the presence of methyl 3,4-dihydroxybenzoate (MDHB; 2, 4, and 8 MUM). Results showed that MDHB significantly promoted neurite outgrowth and microtubule-associated protein 2 mRNA expression, and increased neuronal survival in a dose-dependent manner. Moreover, MDHB induced brain-derived neurotrophic factor expression. These findings suggest that MDHB has a neurotrophic effect, which may be due to its ability to increase brain-derived neurotrophic factor expression. PMID- 25722685 TI - Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson's disease. AB - In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson's disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5 bromo-2'-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson's disease. Immunohistochemical staining showed that, 5-bromo-2'-deoxyuridine immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson's disease. PMID- 25722686 TI - Isolation, cultivation and identification of brain glioma stem cells by magnetic bead sorting. AB - This study describes a detailed process for obtaining brain glioma stem cells from freshly dissected human brain glioma samples using an immunomagnetic bead technique combined with serum-free media pressure screening. Furthermore, the proliferation, differentiation and self-renewal biological features of brain glioma stem cells were identified. Results showed that a small number of CD133 positive tumor cells isolated from brain glioma samples survived as a cell suspension in serum-free media and proliferated. Subcultured CD133 positive cells maintained a potent self-renewal and proliferative ability, and expressed the stem cell-specific markers CD133 and nestin. After incubation with fetal bovine serum, the number of glial fibrillary acidic protein and microtubule associated protein 2 positive cells increased significantly, indicating that the cultured brain glioma stem cells can differentiate into astrocytes and neurons. Western blot analysis showed that tumor suppressor phosphatase and tensin homolog was highly expressed in tumor spheres compared with the differentiated tumor cells. These experimental findings indicate that the immunomagnetic beads technique is a useful method to obtain brain glioma stem cells from human brain tumors. PMID- 25722687 TI - Melatonin combined with exercise cannot alleviate cerebral injury in a rat model of focal cerebral ischemia/reperfusion injury. AB - Previous studies have demonstrated that melatonin combined with exercise can alleviate secondary damage after spinal cord injury in rats. Therefore, it is hypothesized that melatonin combined with exercise can also alleviate ischemic brain damage. In this study, adult rats were subjected to right middle cerebral artery occlusion after receiving 10 mg/kg melatonin or vehicle subcutaneously twice daily for 14 days. Forced exercise using an animal treadmill was performed at 20 m/min for 30 minutes per day for 6 days prior to middle cerebral artery occlusion. After middle cerebral artery occlusion, each rat received melatonin combined with exercise, melatonin or exercise alone equally for 7 days until sacrifice. Interestingly, rats receiving melatonin combined with exercise exhibited more severe neurological deficits than those receiving melatonin or exercise alone. Hypoxia-inducible factor 1alpha mRNA in the brain tissue was upregulated in rats receiving melatonin combined with exercise. Similarly, microtubule associated protein-2 mRNA expression was significantly upregulated in rats receiving melatonin alone. Chondroitin sulfate proteoglycan 4 (NG2) mRNA expression was significantly decreased in rats receiving melatonin combined with exercise as well as in rats receiving exercise alone. Furthermore, neural cell loss in the primary motor cortex was significantly reduced in rats receiving melatonin or exercise alone, but the change was not observed in rats receiving melatonin combined with exercise. These findings suggest that excessive intervention with melatonin, exercise or their combination may lead to negative effects on ischemia/reperfusion-induced brain damage. PMID- 25722688 TI - Increased expression of receptor for advanced glycation end-products worsens focal brain ischemia in diabetic rats. AB - A rat model of diabetes mellitus was induced by a high fat diet, followed by focal brain ischemia induced using the thread method after 0.5 month. Immunohistochemistry showed that expression of receptor for advanced glycation end-products was higher in the ischemic cortex of diabetic rats compared with non diabetic rats with brain ischemia. Western blot assay revealed increased phosphorylated c-Jun N-terminal kinase expression, and unchanged phosphorylated extracellular signal-regulated protein kinase protein expression in the ischemic cortex of diabetic rats compared with non-diabetic rats with brain ischemia. Additionally, phosphorylated p38 mitogen-activated protein kinase protein was not detected in any rats in the two groups. Severity of limb hemiplegia was worse in diabetic rats with brain ischemia compared with ischemia alone rats. The results suggest that increased expression of receptor for advanced glycation end-products can further activate the c-Jun N-terminal kinase pathway in mitogen-activated protein kinase, thereby worsening brain injury associated with focal brain ischemia in diabetic rats. PMID- 25722689 TI - Paroxetine engenders analgesic effects through inhibition of p38 phosphorylation in a rat migraine model. AB - In this study, a model of migraine was established by electrical stimulation of the superior sagittal sinus in rats. These rats were then treated orally with paroxetine at doses of 2.5, 5, or 10 mg/kg per day for 14 days. Following treatment, mechanical withdrawal thresholds were significantly higher, extracellular concentrations of 5-hydroxytryptamine in the periaqueductal grey matter and nucleus reticularis gigantocellularis were higher, and the expression of phosphorylated p38 in the trigeminal nucleus caudalis was lower. Our experimental findings suggest that paroxetine has analgesic effects in a rat migraine model, which are mediated by inhibition of p38 phosphorylation. PMID- 25722690 TI - Survivin-specific small interfering RNAs enhance sensitivity of glioma U-87MG cells to paclitaxel by promoting apoptosis. AB - A survivin siRNA expression vector was transfected into glioma U-87MG cells and these cells were then treated with paclitaxel. The results showed that survivin specific siRNA combined with paclitaxel treatment synergistically inhibited glioma U-87MG cell proliferation and promoted apoptosis. This treatment also inhibited the expression of the cell cycle regulatory proteins, survivin, cyclinD1, c-Myc and CDK4 and enhanced the sensitivity of U-87MG cells to paclitaxel. PMID- 25722691 TI - Histone acetylation of the htr3a gene in the prefrontal cortex of Wistar rats regulates ethanol-seeking behavior. AB - Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5 HT3 receptor by the htr3a gene was related to ethanol-seeking behavior. However, the effects of a histone deacetylase inhibitor on ethanol-seeking behavior and epigenetic regulation of htr3a mRNA expression after chronic ethanol exposure are not fully understood. Using quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation analysis, we investigated the effects of chronic ethanol exposure and its interaction with a histone deacetylase inhibitor on histone-acetylation-mediated changes in htr3a mRNA expression in the htr3a promoter region. The conditioned place preference procedure was used to evaluate ethanol-seeking behavior. Chronic exposure to ethanol effectively elicited place conditioning. In the prefrontal cortex, the acetylation of H3K9 and htr3a mRNA expression in the htr3a promoter region were significantly higher in the ethanol group than in the saline group. The histone deacetylase inhibitor sodium butyrate potentiated the effects of ethanol on htr3a mRNA expression and enhanced ethanol-induced conditioned place preferences. These results suggest that ethanol upregulates htr3a levels through mechanisms involving H3K9 acetylation, and that histone acetylation may be a therapeutic target for treating ethanol abuse. PMID- 25722693 TI - The neural butterfly effect: The injury to peripheral nerves changes the brain. PMID- 25722692 TI - Tolerance effects of non-steroidal anti-inflammatory drugs microinjected into central amygdala, periaqueductal grey, and nucleus raphe: Possible cellular mechanism. AB - Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs (NSAIDs), or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic (intraperitoneal) administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting. PMID- 25722694 TI - Neurogenesis in the adult peripheral nervous system. AB - Most researchers believe that neurogenesis in mature mammals is restricted only to the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle in the central nervous system. In the peripheral nervous system, neurogenesis is thought to be active only during prenatal development, with the exception of the olfactory neuroepithelium. However, sensory ganglia in the adult peripheral nervous system have been reported to contain precursor cells that can proliferate in vitro and be induced to differentiate into neurons. The occurrence of insult-induced neurogenesis, which has been reported by several investigators in the brain, is limited to a few recent reports for the peripheral nervous system. These reports suggest that damage to the adult nervous system induces mechanisms similar to those that control the generation of new neurons during prenatal development. Understanding conditions under which neurogenesis can be induced in physiologically non-neurogenic regions in adults is one of the major challenges for developing therapeutic strategies to repair neurological damage. However, the induced neurogenesis in the peripheral nervous system is still largely unexplored. This review presents the history of research on adult neurogenesis in the peripheral nervous system, which dates back more than 100 years and reveals the evidence on the under estimated potential for generation of new neurons in the adult peripheral nervous system. PMID- 25722695 TI - Hippocampal plasticity after a vagus nerve injury in the rat. AB - Stimulation of the vagus nerve has been previously reported to promote neural plasticity and neurogenesis in the brain. Several studies also revealed plastic changes in the spinal cord after injuries to somatosensory nerves originating from both the brachial and lumbo-sacral plexuses. However, the neurogenic responses of the brain to the injury of the viscerosensory innervation are not as yet well understood. In the present study, we investigated whether cells in the dentate gyrus of the hippocampus respond to a chemical and physical damage to the vagus nerve in the adult rat. Intraperitoneal capsaicin administration was used to damage non-myelinated vagal afferents while subdiaphragmatic vagotomy was used to damage both the myelinated and non-myelinated vagal afferents. The 5-bromo-2 deoxyuridine (BrdU) incorporation together with cell-specific markers was used to study neural proliferation in subgranular zone, granule cell layer, molecular layer and hilus of the dentate gyrus. Microglia activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter-binding molecule 1. Results revealed that vagotomy decreased BrdU incorporation in the hilus 15 days after injury compared to the capsaicin group. Capsaicin administration decreased BrdU incorporation in the granular cell layer 60 days after the treatment. Capsaicin decreased the number of doublecortin-expressing cells in the dentate gyrus, whereas vagotomy did not alter the expression of doublecortin in the hippocampus. Both the capsaicin- and the vagotomy-induced damage to the vagus nerve decreased microglia activation in the hippocampus at 15 days after the injury. At 30 days post injury, capsaicin-treated and vagotomized rats revealed significantly more activated microglia. Our findings show that damage to the subdiaphragmatic vagus in adult rats is followed by microglia activation and long-lasting changes in the dentate gyrus, leading to alteration of neurogenesis. PMID- 25722696 TI - Exogenous reference gene normalization for real-time reverse transcription polymerase chain reaction analysis under dynamic endogenous transcription. AB - Quantitative real-time reverse transcription-polymerase chain reaction (qPCR) is widely used to investigate transcriptional changes following experimental manipulations to the nervous system. Despite the widespread utilization of qPCR, the interpretation of results is marred by the lack of a suitable reference gene due to the dynamic nature of endogenous transcription. To address this inherent deficiency, we investigated the use of an exogenous spike-in mRNA, luciferase, as an internal reference gene for the 2(-??Ct) normalization method. To induce dynamic transcription, we systemically administered capsaicin, a neurotoxin selective for C-type sensory neurons expressing the TRPV-1 receptor, to adult male Sprague-Dawley rats. We later isolated nodose ganglia for qPCR analysis with the reference being either exogenous luciferase mRNA or the commonly used endogenous reference beta-III tubulin. The exogenous luciferase mRNA reference clearly demonstrated the dynamic expression of the endogenous reference. Furthermore, variability of the endogenous reference would lead to misinterpretation of other genes of interest. In conclusion, traditional reference genes are often unstable under physiologically normal situations, and certainly unstable following the damage to the nervous system. The use of exogenous spike-in reference provides a consistent and easily implemented alternative for the analysis of qPCR data. PMID- 25722697 TI - Respiratory neuroplasticity following carotid body denervation: Central and peripheral adaptations. AB - Historically, the role of the carotid bodies in ventilatory control has been understated, but the current view suggests that the carotid bodies (1) provide a tonic, facilitory input to the respiratory network, (2) serve as the major site of peripheral O2 chemoreception and minor contributor to CO2/H(+) chemoreception, and (3) are required for ventilatory adaptation to high altitude. Each of these roles has been demonstrated in studies of ventilation in mammals after carotid body denervation. Following carotid body denervation, many of the compromised ventilatory "functions" show a time-dependent recovery plasticity that varies in the degree of recovery and time required for recovery. Respiratory plasticity following carotid body denervation is also dependent on species, with contributions from peripheral and central sites/mechanisms driving the respiratory plasticity. The purpose of this review is to provide a summary of the data pointing to peripheral and central mechanisms of plasticity following carotid body denervation. We speculate that after carotid body denervation there are altered excitatory and/or inhibitory neuromodulator mechanisms that contribute to the initial respiratory depression and the subsequent respiratory plasticity, and further suggest that the continued exploration of central effects of carotid body denervation might provide useful information regarding the capacity of the respiratory network for plasticity following neurologic injury in humans. PMID- 25722698 TI - Anti-parkinsonian effects of octacosanol in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice. AB - Our previous research showed that octacosanol exerted its protective effects in 6 hydroxydopamine-induced Parkinsonian rats. The goal of this study was to investigate whether octacosanol would attenuate neurotoxicity in 1-methyl-4 phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated C57BL/6N mice and its potential mechanism. Behavioral tests, tyrosine hydroxylase immunohistochemistry and western blot were used to investigate the effects of octacosanol in a mouse model of Parkinson's disease. Oral administration of octacosanol (100 mg/kg) significantly improved behavioral impairments in mice treated by MPTP and markedly ameliorated morphological appearances of tyrosine hydroxylase-positive neuronal cells in the substantia nigra. Furthermore, octacosanol blocked MPTP induced phosphorylation of p38MAPK and JNK, but not ERK1/2. These findings implicated that the protective effects afforded by octacosanol might be mediated by blocking the phosphorylation of p38MAPK and JNK on the signal transduction in vivo. Considering its excellent tolerability, octacosanol might be considered as a candidate agent for clinical application in treating Parkinson's disease. PMID- 25722699 TI - Inhibiting p38 mitogen-activated protein kinase attenuates cerebral ischemic injury in Swedish mutant amyloid precursor protein transgenic mice. AB - Cerebral ischemia was induced using photothrombosis 1 hour after intraperitoneal injection of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB239063 into Swedish mutant amyloid precursor protein (APP/SWE) transgenic and non transgenic mice. The number of surviving neurons in the penumbra was quantified using Nissl staining, and the activity of p38 MAPKs was measured by western blotting. The number of surviving neurons in the penumbra was significantly reduced in APP/SWE transgenic mice compared with non-transgenic controls 7 days after cerebral ischemia, but the activity of p38 MAPKs was significantly elevated compared with the non-ischemic hemisphere in the APP/SWE transgenic mice. SB239063 prevented these changes. The APP/SWE mutation exacerbated ischemic brain injury, and this could be alleviated by inhibiting p38 MAPK activity. PMID- 25722701 TI - Cell viability and dopamine secretion of 6-hydroxydopamine-treated PC12 cells co cultured with bone marrow-derived mesenchymal stem cells. AB - In the present study, PC12 cells induced by 6-hydroxydopamine as a model of Parkinson's Disease, were used to investigate the protective effects of bone marrow-derived mesenchymal stem cells bone marrow-derived mesenchymal stem cells against 6-hydroxydopamine-induced neurotoxicity and to verify whether the mechanism of action relates to abnormal alpha-synuclein accumulation in cells. Results showed that co-culture with bone marrow-derived mesenchymal stem cells enhanced PC12 cell viability and dopamine secretion in a cell dose-dependent manner. MitoLight staining was used to confirm that PC12 cells co-cultured with bone marrow-derived mesenchymal stem cells demonstrate reduced levels of cell apoptosis. Immunocytochemistry and western blot analysis found the quantity of alpha-synuclein accumulation was significantly reduced in PC12 cell and bone marrow-derived mesenchymal stem cell co-cultures. These results indicate that bone marrow-derived mesenchymal stem cells can attenuate 6-hydroxydopamine induced cytotoxicity by reducing abnormal alpha-synuclein accumulation in PC12 cells. PMID- 25722700 TI - Overexpression of estrogen receptor beta alleviates the toxic effects of beta amyloid protein on PC12 cells via non-hormonal ligands. AB - After binding to the estrogen receptor, estrogen can alleviate the toxic effects of beta-amyloid protein, and thereby exert a therapeutic effect on Alzheimer's disease patients. Estrogen can increase the incidence of breast carcinoma and endometrial cancer in post-menopausal women, so it is not suitable for clinical treatment of Alzheimer's disease. There is recent evidence that the estrogen receptor can exert its neuroprotective effects without estrogen dependence. Real time quantitative PCR and flow cytometry results showed that, compared with non transfected PC12 cells, adenovirus-mediated estrogen receptor beta gene transfected PC12 cells exhibited lower expression of tumor necrosis factor alpha and interleukin 1beta under stimulation with beta-amyloid protein and stronger protection from apoptosis. The Akt-specific inhibitor Abi-2 decreased the anti inflammatory and anti-apoptotic effects of estrogen receptor beta gene transfection. These findings suggest that overexpression of estrogen receptor beta can alleviate the toxic effect of beta-amyloid protein on PC12 cells, without estrogen dependence. The Akt pathway is one of the potential means for the anti-inflammatory and anti-apoptotic effects of the estrogen receptor. PMID- 25722702 TI - Effects of cytokines and chemokines on migration of mesenchymal stem cells following spinal cord injury. AB - We investigated the effects of cytokines and chemokines and their associated signaling pathways on mesenchymal stem cell migration after spinal cord injury, to determine their roles in the curative effects of mesenchymal stem cells. This study reviewed the effects of tumor necrosis factor-alpha, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, basic fibroblast growth factor, insulin like growth factor-1, stromal cell-derived factor and monocyte chemoattractant protein-1, 3 during mesenchymal stem cell migration to damaged sites, and analyzed the signal transduction pathways involved in their effects on mesenchymal stem cell migration. The results confirmed that phosphatidylinositol 3-kinase/serine/threonine protein kinases and nuclear factor-kappaB play crucial roles in the migration of mesenchymal stem cells induced by cytokines and chemokines. PMID- 25722703 TI - Altered serous levels of monoamine neurotransmitter metabolites in patients with refractory and non-refractory depression. AB - The study examined plasma metabolite changes of monoamine neurotransmitters in patients with treatment-resistant depression (TRD) and non-TRD before and after therapy. All 30 TRD and 30 non-TRD patients met the diagnostic criteria for a depressive episode in accordance with the International Classification of Diseases, Tenth Revision. Before treatment, and at 4, 6, and 8 weeks after treatment, the plasma metabolite products of monoamine neurotransmitters in TRD group, including 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenyl ethylene glycol and homovanillic acid, were significantly lower than those in the non-TRD group. After two types of anti-depressive therapy with 5-serotonin and norepinephrine reuptake inhibitor, combined with psychotherapy, the Hamilton Depression Rating Scale scores were significantly reduced in both groups of patients, and the serous levels of 5-hydroxyindoleacetic acid and 3-methoxy-4 hydroxyphenyl ethylene glycol were significantly increased. In contrast, the homovanillic acid level exhibited no significant change. The levels of plasma metabolite products of peripheral monoamine neurotransmitters in depressive patients may predict the degree of depression and the therapeutic effects of treatment. PMID- 25722704 TI - Serum containing Tongqiaohuoxue decoction suppresses glutamate-induced PC12 cell injury. AB - Glutamate application is an established method of inducing PC12 cell injury. PC12 cells were cultured with serum containing Tongqiaohuoxue decoction consisting of moschus, Carthamus tinctorius, Rhizoma chuanxiong, Semen pruni persicae, and Radix Paeoniae Rubra. After 24 hours of co-cultivation, glutamate (12.5 mM) was added to the culture medium. We found that serum containing Tongqiaohuoxue decoction prevented the increase in reactive oxygen species, and the decreases in superoxide dismutase and Na(+)-K(+)-ATPase activity, induced by glutamate. It also reduced the concentration of malondialdehyde, enhanced the mitochondrial transmembrane potential, inhibited the elevation of cellular calcium, and decreased phosphorylation of calmodulin-dependent protein kinase II. Thus, serum containing Tongqiaohuoxue decoction had protective effects on cell proliferation and membrane permeability in glutamate-injured PC12 cells. PMID- 25722705 TI - Wendan decoction improves learning and memory deficits in a rat model of schizophrenia. AB - An experimental model of schizophrenia was established using dizocilpine (MK 801). Rats were intragastrically administered with Wendan decoction or clozapine for 21 days prior to establishing the model. The results revealed that the latency of schizophrenia model rats to escape from the hidden platform in the Morris water maze was significantly shortened after administration of Wendan decoction or clozapine. In addition, the treated rats crossed the platform significantly more times than the untreated model rats. Moreover, the rate of successful long-term potentiation induction in the Wendan decoction group and clozapine group were also obviously increased compared with the model group, and the population spike peak latency was significantly shortened. These experimental findings suggest that Wendan decoction can improve the learning and memory ability of schizophrenic rats to the same extent as clozapine treatment. PMID- 25722706 TI - Electroacupuncture promotes the proliferation of endogenous neural stem cells and oligodendrocytes in the injured spinal cord of adult rats. AB - A contusive model of spinal cord injury at spinal segment T8-9 was established in rats. Huantiao (GB30) and Huatuojiaji (Ex-B05) were punctured with needles, and endogenous neural stem cells were labeled with 5-bromo-2'-deoxyuridine (BrdU) and NG2. Double immunofluorescence staining showed that electroacupuncture markedly increased the numbers of BrdU(+)/NG2(+) cells at spinal cord tissue 15 mm away from the injury center in the rostral and caudal directions. The results suggest that electroacupuncture promotes the proliferation of endogenous neural stem cells and oligodendrocytes in rats with spinal cord injury. PMID- 25722707 TI - Suspended moxibustion at Tianshu (ST25) inhibits prokineticin 1 and prokineticin receptor 1 expression in the spinal cord of rats with chronic visceral hypersensitivity. AB - Suspended moxibustion can decrease the expression of prokineticin 1 and its receptor in colonic tissue from rats modeling chronic visceral hyperalgesia. This study aimed to verify if rat spinal cord prokineticin 1 and its receptor contribute to the analgesic effect of suspended moxibustion in a rat model of irritable bowel syndrome where rats display chronic visceral hypersensitivity. Results showed that suspended moxibustion at Tianshu (ST25) point significantly decreased visceral sensitivity to colorectal distention in a chronic visceral hyperalgesia rat model; also protein and mRNA expression of prokineticin 1 and prokineticin receptor 1 in the spinal cord of rats was significantly decreased. Experimental findings indicate that prokineticin 1 and prokineticin receptor 1 are involved in the analgesia using suspended moxibustion in rats with chronic visceral hyperalgesia. PMID- 25722708 TI - Brain functional changes in facial expression recognition in patients with major depressive disorder before and after antidepressant treatment: A functional magnetic resonance imaging study. AB - Functional magnetic resonance imaging was used during emotion recognition to identify changes in functional brain activation in 21 first-episode, treatment naive major depressive disorder patients before and after antidepressant treatment. Following escitalopram oxalate treatment, patients exhibited decreased activation in bilateral precentral gyrus, bilateral middle frontal gyrus, left middle temporal gyrus, bilateral postcentral gyrus, left cingulate and right parahippocampal gyrus, and increased activation in right superior frontal gyrus, bilateral superior parietal lobule and left occipital gyrus during sad facial expression recognition. After antidepressant treatment, patients also exhibited decreased activation in the bilateral middle frontal gyrus, bilateral cingulate and right parahippocampal gyrus, and increased activation in the right inferior frontal gyrus, left fusiform gyrus and right precuneus during happy facial expression recognition. Our experimental findings indicate that the limbic cortical network might be a key target region for antidepressant treatment in major depressive disorder. PMID- 25722709 TI - Functional magnetic resonance imaging evaluation of brain function reorganization in cerebral stroke patients after constraint-induced movement therapy. AB - In this study, stroke patients received constraint-induced movement therapy for 3 weeks. Before and after constraint-induced movement therapy, the flexibility of their upper limbs on the affected side was assessed using the Wolf motor function test, and daily use of their affected limbs was assessed using the movement activities log, and cerebral functional reorganization was assessed by functional magnetic resonance imaging. The Wolf motor function test score and the movement activities log quantity and quality scores were significantly increased, while action performance time in the Wolf motor function test was significantly decreased after constraint-induced movement therapy. By functional magnetic resonance imaging examination, only scattered activation points were visible on the affected side before therapy. In contrast, the volume of the activated area was increased after therapy. The activation volume in the sensorimotor area was significantly different before and after therapy, and the activation area increased and appeared adjusted. In addition to the activated area around the lesions being decreased, there were also some new activated areas, including the supplementary movement area, premotor area and the ipsilateral sensorimotor area. Our findings indicate that constraint-induced movement therapy significantly improves the movement ability and daily use of the affected upper limbs in stroke patients and promotes cerebral functional reorganization. PMID- 25722710 TI - Quantitative analysis of intraspinal cerebrospinal fluid flow in normal adults. AB - The present study quantitatively analyzed intraspinal cerebrospinal fluid flow patterns in 19 normal adults using fast cine phase-contrast magnetic resonance imaging. Results showed increased downward flow velocity and volume compared with upward flow, and the average downward flow volume of intraspinal cerebrospinal fluid decreased from top to bottom at different intervertebral disc levels. Upward and downward cerebrospinal fluid flow velocity reached a peak at the thoracic intraspinal anterior region, and velocity reached a minimum at the posterior region. Overall measurements revealed that mean upward and downward flow volume positively correlated with the subarachnoid area. Upward peak flow velocity and volume positively correlated with spinal anteroposterior diameter. However, downward peak flow velocity and volume exhibited a negative correlation with spinal anteroposterior diameter. Further flow measurements showed that flow velocity in upward and downward directions was associated with subarachnoid anteroposterior diameter, respectively. The present experimental results showed that cerebrospinal fluid flow velocity and volume varied at different intraspinal regions and were affected by subarachnoid space area and anteroposterior diameter size. PMID- 25722711 TI - Electrospun silk fibroin nanofibers promote Schwann cell adhesion, growth and proliferation. AB - In this study, Schwann cells, at a density of 1 * 10(5) cells/well, were cultured on regenerated silk fibroin nanofibers (305 +/- 84 nm) prepared using the electrospinning method. Schwann cells cultured on the silk fibroin nanofibers appeared more ordered, their processes extended further, and they formed more extensive and complex interconnections. In addition, the silk fibroin nanofibers had no impact on the proliferation of Schwann cells or on the secretion of ciliary neurotrophic factor, brain-derived neurotrophic factor or nerve growth factor. These findings indicate that regenerated electrospun silk fibroin nanofibers can promote Schwann cell adhesion, growth and proliferation, and have excellent biocompatibility. PMID- 25722712 TI - Effect of chitosan/type I collagen/gelatin composites in biocompatibility and nerve repair. AB - Chitosan, collagen I and gelatin were mixed in appropriate quantities to develop a new nerve repair material, with good arrangement and structure, as well as even aperture size. The composite material was sterilized by (60)Co irradiation for 24 hours prior to implantation in the right thigh of rats following sciatic nerve damage. Results showed that the material was nontoxic to the kidneys and the liver, and did not induce an inflammatory response in the muscles. The composite material enhanced the recovery of sciatic nerve damage in rats. These experimental findings indicate that the composite material offers good biocompatibility and has a positive effect on injured nerve rehabilitation. PMID- 25722713 TI - Paravertebral fascial massage promotes brain development of neonatal rats via the insulin-like growth factor 1 pathway. AB - Massage in traditional Chinese medicine can promote body and brain development of premature and normal newborn infants. In the present study, neonatal rats (1 day old) underwent paravertebral fascial massage (15 consecutive days), followed by subcutaneous injection of insulin-like growth factor 1 receptor antagonist, JB1 (9 consecutive days). Paravertebral fascial massage significantly increased insulin-like growth factor 1 expression and cell proliferation in the subventricular zone of the lateral ventricle and dentate gyrus of the hippocampus. However, JB1 inhibited this increase. Results suggest that paravertebral fascial massage can promote brain development of neonatal rats via the insulin-like growth factor 1 pathway. PMID- 25722714 TI - Acupuncture in stroke rehabilitation: Literature retrieval based on international databases. AB - OBJECTIVE: To identify global research trends of acupuncture in stroke rehabilitation using a bibliometric analysis of the Web of Science and the Clinical Trials registry database (ClinicalTrials.gov). DATA RETRIEVAL: We performed a bibliometric analysis of data retrievals for acupuncture in stroke rehabilitation from 1992 to 2011 using the Web of Science and ClinicalTrials.gov. SELECTION CRITERIA: INCLUSION CRITERIA: (1) Web of Science: (a) Peer-reviewed articles on acupuncture in stroke rehabilitation that were published and indexed in the Web of Science. (b) Type of articles: original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material and news items. (c) Year of publication: 1992-2011. (2) ClinicalTrials.gov: All clinical trials relating to acupuncture in stroke rehabilitation were searched in this database. EXCLUSION CRITERIA: (1) Web of Science: (a) Articles that required manual searching or telephone access. (b) We excluded documents that were not published in the public domain. (c) We excluded a number of corrected papers from the total number of articles. (2) ClinicalTrials.gov: (a) We excluded clinical trials that were not in the ClinicalTrials.gov database. (b) We excluded clinical trials that dealt with magnetic stimulation other than acupuncture in stroke rehabilitation in the ClinicalTrials.gov database. MAIN OUTCOME MEASURES: (1) Type of literature; (2) annual publication output; (3) distribution according to journals; (4) distribution according to country; (5) distribution according to institution; (6) top cited articles over the last 20 years; and (7) clinical trials registered. RESULTS: (1) In all, 92 studies on acupuncture in stroke rehabilitation appeared in the Web of Science from 1992 to 2011, almost half of which derived from Chinese and American authors and institutes. The number of studies addressing acupuncture in stroke rehabilitation has gradually increased over the past 20 years. Most papers on acupuncture in stroke rehabilitation appeared in journals with a particular focus on rehabilitation research, such as Stroke, Archives of Physical Medicine, Cochrane Database of Systematic Reviews and Journal of Alternative and Complementary Medicine. (2) In the ClinicalTrials.gov, three studies can be searched on acupuncture and stroke, all of which were registered and sponsored by Chinese institutions since February 2009. CONCLUSION: From our analysis of the literature and research trends, we found that acupuncture in stroke rehabilitation may offer further benefits in regenerative medicine. PMID- 25722715 TI - Tightening up the structure, lighting up the pathway: Application of molecular constraints and light to manipulate protein folding, self-assembly and function. AB - Chemical cross-linking provides an effective avenue to reduce the conformational entropy of polypeptide chains and hence has become a popular method to induce or force structural formation in peptides and proteins. Recently, other types of molecular constraints, especially photoresponsive linkers and functional groups, have also found increased use in a wide variety of applications. Herein, we provide a concise review of using various forms of molecular strategies to constrain proteins, thereby stabilizing their native states, gaining insight into their folding mechanisms, and/or providing a handle to trigger a conformational process of interest with light. The applications discussed here cover a wide range of topics, ranging from delineating the details of the protein folding energy landscape to controlling protein assembly and function. PMID- 25722717 TI - A framework for final drive simultaneous failure diagnosis based on fuzzy entropy and sparse bayesian extreme learning machine. AB - This research proposes a novel framework of final drive simultaneous failure diagnosis containing feature extraction, training paired diagnostic models, generating decision threshold, and recognizing simultaneous failure modes. In feature extraction module, adopt wavelet package transform and fuzzy entropy to reduce noise interference and extract representative features of failure mode. Use single failure sample to construct probability classifiers based on paired sparse Bayesian extreme learning machine which is trained only by single failure modes and have high generalization and sparsity of sparse Bayesian learning approach. To generate optimal decision threshold which can convert probability output obtained from classifiers into final simultaneous failure modes, this research proposes using samples containing both single and simultaneous failure modes and Grid search method which is superior to traditional techniques in global optimization. Compared with other frequently used diagnostic approaches based on support vector machine and probability neural networks, experiment results based on F 1-measure value verify that the diagnostic accuracy and efficiency of the proposed framework which are crucial for simultaneous failure diagnosis are superior to the existing approach. PMID- 25722716 TI - Peroxisome Proliferator-Activated Receptor- gamma in Thyroid Autoimmunity. AB - Peroxisome proliferator-activated receptor- (PPAR-) gamma expression has been shown in thyroid tissue from patients with thyroiditis or Graves' disease and furthermore in the orbital tissue of patients with Graves' ophthalmopathy (GO), such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif) receptor 3 (CXCR3) and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-gamma agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-gamma agonists in the treatment of thyroid autoimmune disorders. PMID- 25722718 TI - Early or Delayed Intervention for Bile Duct Injuries following Laparoscopic Cholecystectomy? A Dilemma Looking for an Answer. AB - Background. To evaluate the effect of timing of management and intervention on outcomes of bile duct injury. Materials and Methods. We retrospectively analyzed 92 patients between 1991 and 2011. Data concerned patient's demographic characteristics, type of injury (according to Strasberg classification), time to referral, diagnostic procedures, timing of surgical management, and final outcome. The endpoint was the comparison of postoperative morbidity (stricture, recurrent cholangitis, required interventions/dilations, and redo reconstruction) and mortality between early (less than 2 weeks) and late (over 12 weeks) surgical reconstruction. Results. Three patients were treated conservatively, two patients were treated with percutaneous drainage, and 13 patients underwent PTC or ERCP. In total 74 patients were operated on in our unit. 58 of them underwent surgical reconstruction by end-to-side Roux-en-Y hepaticojejunostomy, 11 underwent primary bile duct repair, and the remaining 5 underwent more complex procedures. Of the 56 patients, 34 patients were submitted to early reconstruction, while 22 patients were submitted to late reconstruction. After a median follow-up of 93 months, there were two deaths associated with BDI after LC. Outcomes after early repairs were equal to outcomes after late repairs when performed by specialists. Conclusions. Early repair after BDI results in equal outcomes compared with late repair. BDI patients should be referred to centers of expertise and experience. PMID- 25722719 TI - Value of 18-F-FDG PET/CT and CT in the Diagnosis of Indeterminate Adrenal Masses. AB - The purpose of this paper was to study the value of 18-FDG PET/CT and reassess the value of CT for the characterization of indeterminate adrenal masses. 66 patients with 67 indeterminate adrenal masses were included in our study. CT/MRI images and 18F-FDG PET/CT data were evaluated blindly for tumor morphology, enhancement features, apparent diffusion coefficient values, maximum standardized uptake values, and adrenal-to-liver maxSUV ratio. The study population comprised pathologically confirmed 16 adenomas, 19 metastases, and 32 adrenocortical carcinomas. Macroscopic fat was observed in 62.5% of the atypical adenomas at CT but not in malignant masses. On 18F-FDG PET/CT, SUVmax and adrenal-to-liver maxSUV ratio were significantly lower in adenomas than in malignant tumors. An SUVmax value of less than 3.7 or an adrenal-to-liver maxSUV ratio of less than 1.29 is highly predictive of benignity. PMID- 25722720 TI - Subclassification of follicular neoplasms recommended by the Japan thyroid association reporting system of thyroid cytology. AB - Background. The Japan Thyroid Association recently published guidelines for clinical practice for the management of thyroid nodules, which include a diagnostic system for reporting thyroid fine needle aspiration cytology. It is characterized by the subclassification of follicular neoplasms, which is different from other internationally accepted reporting systems. Materials and Methods. This study examined observer variability in the subclassification of follicular neoplasms among 4 reviewers using Papanicolaou-stained smear samples from 20 surgically treated patients with indeterminate cytology. Results. The favor malignant subcategory had high predictive value of malignancy (risk of malignancy: 60-75%) and good agreement among the 4 reviewers (kappa = 0.7714). Conclusion. These results clearly confirmed that the risk stratification of follicular neoplasms, which was adapted from cytology practice of high-volume thyroid centers in Japan, can provide clinically helpful information to estimate the risk of malignancy and to triage patients for surgery. PMID- 25722721 TI - Corrigendum to "Cucurbitacin B Causes Increased Radiation Sensitivity of Human Breast Cancer Cells via G2/M Cell Cycle Arrest". AB - [This corrects the article DOI: 10.1155/2012/601682.]. PMID- 25722722 TI - Hematopoietic stem-cell transplantation in the developing world: experience from a center in Western India. AB - We describe our experience of first 50 consecutive hematopoietic stem-cell transplants (HSCT) done between 2007 and 2012 at the Apollo Hospital, Gandhinagar, 35 autologous HSCT and 15 allogeneic HSCT. Indications for autologous transplant were multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, and acute myeloid leukemia, and indications for allogeneic transplants were thalassemia major, aplastic anaemia, chronic myeloid leukemia, and acute lymphoblastic and myeloid leukaemia. The median age of autologous and allogeneic patient's cohort was 50 years and 21 years, respectively. Median follow-up period for all patients was 39 months. Major early complications were infections, mucositis, acute graft versus host disease, and venoocclusive disease. All of our allogeneic and autologous transplant patients survived during the first month of transplant. Transplant related mortality (TRM) was 20% (N = 3) in our allogeneic and 3% (N = 1) in autologous patients. Causes of these deaths were disease relapse, sepsis, hemorrhagic complications, and GVHD. 46% of our autologous and 47% of our allogeneic patients are in complete remission phase after a median follow-up of 39 months. 34% of our autologous patients and 13% of our allogeneic patients had disease relapse. Overall survival rate in our autologous and allogeneic patients is 65.7% and 57.1%, respectively. Our results are comparable to many national and international published reports. PMID- 25722723 TI - Analytical quality by design: a tool for regulatory flexibility and robust analytics. AB - Very recently, Food and Drug Administration (FDA) has approved a few new drug applications (NDA) with regulatory flexibility for quality by design (QbD) based analytical approach. The concept of QbD applied to analytical method development is known now as AQbD (analytical quality by design). It allows the analytical method for movement within method operable design region (MODR). Unlike current methods, analytical method developed using analytical quality by design (AQbD) approach reduces the number of out-of-trend (OOT) results and out-of specification (OOS) results due to the robustness of the method within the region. It is a current trend among pharmaceutical industry to implement analytical quality by design (AQbD) in method development process as a part of risk management, pharmaceutical development, and pharmaceutical quality system (ICH Q10). Owing to the lack explanatory reviews, this paper has been communicated to discuss different views of analytical scientists about implementation of AQbD in pharmaceutical quality system and also to correlate with product quality by design and pharmaceutical analytical technology (PAT). PMID- 25722724 TI - Reduction of Silver Ions by Cell Free Extracts of Westiellopsis sp. AB - Biosynthesis of silver nanoparticles using Westiellopsis sp. (A15), a filamentous cyanobacterium belonging to the family Fischerellaceae, has been demonstrated. Aqueous silver ions (Ag(+)) when exposed to the culture filtrate of Westiellopsis were reduced in the solution, which were characterized by biophysical measures utilizing the UV-Vis spectroscopy, scanning electron microscopy (SEM), and FTIR. The nanoparticles exhibited the maximum absorbance at 420 nm in UV-Vis spectroscopy, while the SEM micrograph revealed that the aggregated nanoparticles vary in size between 20 nm and 5 um. However, the FTIR analysis provided evidence for presence of proteins in the filtrate to be involved in the reduction of silver ions. PMID- 25722725 TI - The complications of sinusitis in a tertiary care hospital: types, patient characteristics, and outcomes. AB - Objective. To study the complications of sinusitis in a referral hospital and the outcome of the treatment according to the type of complication. Methods. A retrospective study was performed on patients with sinusitis who were admitted to a referral hospital from 2003 to 2012. The data for the sinusitis patients who had complications were reviewed. Results and Discussion. Eighty-five patients were included in the study, of whom 50 were male (58.8%). Fourteen of the cases were less than 15 years old, and 27 of the patients (31.7%) had more than one type of complication. The most common complication was of the orbital type (100% in the children, 38% in the adults). After the treatment, all of the children and 45 of the adults (63.4%) recovered, eight of the adult patients died (11.3%), and 18 of the adults were cured with morbidity (25.3%). The patients with more numerous complications had poorer outcomes. When the types of complications were compared (adjusted for age, gender, and comorbidities), the intracranial complication was the only one that was statistically significant for mortality. Conclusion. The outcomes of the treatment depended on the number and type of complications, with the poorest results achieved in cases of intracranial complications. PMID- 25722726 TI - Placental Oxidative Status throughout Normal Gestation in Women with Uncomplicated Pregnancies. AB - The effects of gestational age on placental oxidative balance throughout gestation were investigated in women with uncomplicated pregnancies. Placental tissues were obtained from normal pregnant women who delivered at term or underwent elective pregnancy termination at 6 to 23 + 6 weeks of pregnancy. Placental tissues were analyzed for total antioxidant capacity (TAC) and lipid peroxide (malondialdehyde, MDA) levels using commercially available kits. Two hundred and one placental tissues were analyzed and the mean +/- SD MDA (pmol/mg tissue) and TAC (umol Trolox equivalent/mg tissue) levels for first, second, and third trimester groups were 277.01 +/- 204.66, 202.66 +/- 185.05, and 176.97 +/- 141.61, P < 0.004 and 498.62 +/- 400.74, 454.90 +/- 374.44, and 912.19 +/- 586.21, P < 0.0001 by ANOVA, respectively. Our data reflects an increased oxidative stress in the placenta in the early phase of normal pregnancy. As pregnancy progressed, placental antioxidant protective mechanisms increased and lipid peroxidation markers decreased resulting in diminution in oxidative stress. Our findings provide a biochemical support to the concept of a hypoxic environment in early pregnancy. A decrease in placental oxidative stress in the second and third trimesters appears to be a physiological phenomenon of normal pregnancy. Deviations from this physiological phenomenon may result in placental mediated disorders. PMID- 25722727 TI - Mode of vaginal delivery: a modifiable intrapartum risk factor for obstetric anal sphincter injury. AB - The aim of this study was to analyze the comparative risks of this anal sphincter injury in relation to the type of intervention in vaginal delivery. We performed an observational, retrospective study of all vaginal deliveries attended at a tertiary university hospital between January 2006 and December 2009. We analyzed the incidence of obstetric anal sphincter injury for each mode of vaginal delivery: spontaneous delivery, vacuum, Thierry spatulas, and forceps. We determined the proportional incidence between methods taking spontaneous delivery as the reference. Ninety-seven of 4526 (2.14%) women included in the study presented obstetric anal sphincter injury. Instrumental deliveries showed a significantly higher risk of anal sphincter injury (2.7 to 4.9%) than spontaneous deliveries (1.1%). The highest incidence was for Thierry spatulas (OR 4.804), followed by forceps (OR 4.089) and vacuum extraction (OR 2.509). The type of intervention in a vaginal delivery is a modifiable intrapartum risk factor for obstetric anal sphincter injury. Tearing can occur in any type of delivery but proportions vary significantly. All healthcare professionals attending childbirth should be aware of the risk for each type of intervention and consider these together with the obstetric factors in each case. PMID- 25722728 TI - Antiphospholipid syndrome in a pregnant female presenting with severe thrombocytopenia and bleeding. AB - The antiphospholipid antibody syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism or pregnancy morbidity. Antithrombotic therapy is the mainstay of treatment given the high risk of recurrent thromboembolism that characterizes this condition. Despite the prothrombotic nature of APS, thrombocytopenia is present in a proportion of patients, which can complicate management and limit the use of antithrombotic therapy. The mechanism of APS associated thrombocytopenia is multifactorial and its relation to thrombotic risk is poorly characterized. The presence of thrombocytopenia does not appear to reduce thrombotic risk in patients with APS, who can develop thromboembolic complications necessitating antithrombotic treatment. In these cases, treatment of the thrombocytopenia may be necessary to facilitate administration of antithrombotic agents. We present such a pregnant lady with history of recurrent pregnancy losses who presented with severe thrombocytopenia and bleeding manifestations, who was subsequently diagnosed to have antiphospholipid antibody syndrome. She was initially managed with steroids and when her platelet counts improved, antithrombotic therapy was started. She delivered an uneventful and successful pregnancy outcome without any complications during follow-up. PMID- 25722729 TI - Giant congenital melanocytic nevi and neurocutaneous melanosis. AB - Introduction. The major medical concern with giant congenital melanocytic nevi CMN is high risk of developing cutaneous melanoma, leptomeningeal melanoma, and neurocutaneous melanocytosis. Case Report. A 30-year-old woman with a giant congenital melanocytic nevus covering nearly the entire right thoracodorsal region and multiple disseminated melanocytic nevi presented with neurological symptoms. Cerebral magnetic resonance imaging revealed a large expansive lesion in the left frontal region. Postsurgically pathological diagnosis revealed characteristics of melanoma. Immunohistochemical examination showed S100(+), HMB45(+), MelanA(+), and MiTF(+). She received radiotherapy with temozolomide followed by two more chemotherapy cycles with temozolomide. She followed a rapidly progressive course, reflecting widespread leptomeningeal infiltration, and she died of multiorgan failure seven months after diagnosis of cerebral melanoma. Discussion. This patient was diagnosed as having a neurocutaneous melanosis with malignant widespread leptomeningeal infiltration. Diffuse spinal involvement is unusual and is described in only another patient. PMID- 25722730 TI - Corrigendum to "population-based placental weight ratio distributions". AB - [This corrects the article DOI: 10.1155/2014/291846.]. PMID- 25722731 TI - Development of Animal Models of Human IgA Nephropathy. AB - IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. IgAN is characterized by the mesangial accumulation of immune complexes containing IgA1, usually with co-deposits of complement C3 and variable IgG and/or IgM. Although more than 40 years have passed since IgAN was first described, the mechanisms underlying the disease development are not fully understood. Small-animal experimental models of IgAN can be very helpful in studies of IgAN, but development of these models has been hindered by the fact that only humans and hominoid primates have IgA1 subclass. Thus, multiple models have been developed, that may be helpful in studies of some specific aspects of IgAN. These models include a spontaneous animal model of IgAN, the ddY mouse first reported in 1985. These mice show mild proteinuria without hematuria, and glomerular IgA deposits, with a highly variable incidence and degree of glomerular injury, due to the heterogeneous genetic background. To obtain a murine line consistently developing IgAN, we intercrossed an earlyonset group of ddY mice, in which the development of IgAN includes mesangial IgA deposits and glomerular injury. After selective intercrossing for >20 generations, we established a novel 100% early-onset grouped ddY murine model. All grouped ddY mice develop proteinuria within eight weeks of age. The grouped ddY mouse model can be a useful tool for analysis of multiple aspects of the pathogenesis of IgAN and may aid in assessment of some approaches for the treatment of IgAN. PMID- 25722732 TI - Lupus Nephritis: Animal Modeling of a Complex Disease Syndrome Pathology. AB - Nephritis as a result of autoimmunity is a common morbidity associated with Systemic Lupus Erythematosus (SLE). There is substantial clinical and industry interest in medicinal intervention in the SLE nephritic process; however, clinical trials to specifically treat lupus nephritis have not resulted in complete and sustained remission in all patients. Multiple mouse models have been used to investigate the pathologic interactions between autoimmune reactivity and SLE pathology. While several models bear a remarkable similarity to SLE-driven nephritis, there are limitations for each that can make the task of choosing the appropriate model for a particular aspect of SLE pathology challenging. This is not surprising given the variable and diverse nature of human disease. In many respects, features among murine strains mimic some (but never all) of the autoimmune and pathologic features of lupus patients. Although the diversity often limits universal conclusions relevant to pathogenesis, they provide insights into the complex process that result in phenotypic manifestations of nephritis. Thus nephritis represents a microcosm of systemic disease, with variable lesions and clinical features. In this review, we discuss some of the most commonly used models of lupus nephritis (LN) and immune-mediated glomerular damage examining their relative strengths and weaknesses, which may provide insight in the human condition. PMID- 25722733 TI - Animal models of regression/progression of kidney disease. AB - Current medical therapies may delay chronic kidney disease progression. However, increasing experimental evidence indicates remission or even regression can be achieved. In order to study mechanisms progression vs. regression by different interventions, appropriate animal models and research design must be implemented. We review key information of selected models, including etiology, pathogenesis, procedure, time course and assessment of potential regression. PMID- 25722734 TI - Far-Infrared Therapy Promotes Nerve Repair following End-to-End Neurorrhaphy in Rat Models of Sciatic Nerve Injury. AB - This study employed a rat model of sciatic nerve injury to investigate the effects of postoperative low-power far-infrared (FIR) radiation therapy on nerve repair following end-to-end neurorrhaphy. The rat models were divided into the following 3 groups: (1) nerve injury without FIR biostimulation (NI/sham group); (2) nerve injury with FIR biostimulation (NI/FIR group); and (3) noninjured controls (normal group). Walking-track analysis results showed that the NI/FIR group exhibited significantly higher sciatic functional indices at 8 weeks after surgery (P < 0.05) compared with the NI/sham group. The decreased expression of CD4 and CD8 in the NI/FIR group indicated that FIR irradiation modulated the inflammatory process during recovery. Compared with the NI/sham group, the NI/FIR group exhibited a significant reduction in muscle atrophy (P < 0.05). Furthermore, histomorphometric assessment indicated that the nerves regenerated more rapidly in the NI/FIR group than in the NI/sham group; furthermore, the NI/FIR group regenerated neural tissue over a larger area, as well as nerve fibers of greater diameter and with thicker myelin sheaths. Functional recovery, inflammatory response, muscular reinnervation, and histomorphometric assessment all indicated that FIR radiation therapy can accelerate nerve repair following end-to-end neurorrhaphy of the sciatic nerve. PMID- 25722736 TI - Sparing spiders: faeces as a non-invasive source of DNA. AB - INTRODUCTION: Spiders are important arthropod predators in many terrestrial ecosystems, and molecular tools have boosted our ability to investigate this taxon, which can be difficult to study with conventional methods. Nonetheless, it has typically been necessary to kill spiders to obtain their DNA for molecular applications, especially when studying their diet. RESULTS: We successfully tested the novel approach of employing spider faeces as a non-invasive source of DNA for species identification and diet analysis. Although the overall concentration of DNA in the samples was very low, consumer DNA, suitable for species identification, was amplified from 84% of the faecal pellets collected from lycosid spiders. Moreover, the most important prey types detected in the gut content of the lycosids were also amplified from the faecal samples. CONCLUSION: The ability to amplify DNA from spider faeces with specific and general primers suggests that this sample type can be used for diagnostic PCR and sequence-based species and prey identification such as DNA barcoding and next generation sequencing, respectively. These findings demonstrate that faeces provide a non invasive alternative to full-body DNA extracts for molecular studies on spiders when killing or injuring the animal is not an option. PMID- 25722735 TI - Exploitation of cytotoxicity of some essential oils for translation in cancer therapy. AB - Essential oils are complex mixtures of several components endowed with a wide range of biological activities, including antiseptic, anti-inflammatory, spasmolytic, sedative, analgesic, and anesthetic properties. A growing body of scientific reports has recently focused on the potential of essential oils as anticancer treatment in the attempt to overcome the development of multidrug resistance and important side effects associated with the antitumor drugs currently used. In this review we discuss the literature on the effects of essential oils in in vitro and in vivo models of cancer, focusing on the studies performed with the whole phytocomplex rather than single constituents. PMID- 25722737 TI - Computer-assisted cognitive behavior therapy for obsessive-compulsive disorder: a randomized trial on the impact of lay vs. professional coaching. AB - BACKGROUND: The purpose of the study was to examine the impact of computerized cognitive behavior therapy (CBT) self-help treatment for obsessive-compulsive disorder (OCD) (BT Steps) both alone and when supported by coaching from either a lay non-therapist coach or an experienced CBT therapist. METHODS: Eighty-seven subjects with clinically significant OCD were recruited through newspaper ads and randomly assigned to receive 12 weeks of treatment with either BT Steps alone (n = 28), BT Steps with non-therapist coaching (n = 28), or BT Steps with CBT therapist coaching (n = 31). Subjects worked on BT Steps at their own pace. Subjects receiving BT Steps alone received a welcome call from the project manager. Subjects randomized to either of the coaching arms received regularly scheduled weekly phone calls for coaching, encouragement, and support. No formal therapy was provided by the coaches; thus, both lay and CBT coaches completed the same tasks. RESULTS: All three treatment arms showed a significant reduction in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores, with mean (SD) changes of 6.5 (5.7), 7.1 (6.1), and 6.5 (6.1) for the no coaching, lay coaching, and therapist coaching arms, respectively (all p's < .001). These represent effect sizes of 1.16, 1.41, and 1.12, respectively. No significant differences were found between treatment arms on YBOCS change scores, F(2) = 0.10, p = .904, or number of exposures sessions done (F(2) = 0.033, p = .967). When asked which method of therapy (computer vs. clinician) they preferred, 48% said computer, 33% said face-to-face therapy, and 19% had no preference. CONCLUSIONS: Results support the use of online self-help for the treatment of moderate OCD. The addition of coaching by either a lay coach or a CBT therapist coach did not significantly improve outcomes. PMID- 25722738 TI - Protein docking with predicted constraints. AB - This paper presents a constraint-based method for improving protein docking results. Efficient constraint propagation cuts over 95% of the search time for finding the configurations with the largest contact surface, provided a contact is specified between two amino acid residues. This makes it possible to scan a large number of potentially correct constraints, lowering the requirements for useful contact predictions. While other approaches are very dependent on accurate contact predictions, ours requires only that at least one correct contact be retained in a set of, for example, one hundred constraints to test. It is this feature that makes it feasible to use readily available sequence data to predict specific potential contacts. Although such prediction is too inaccurate for most purposes, we demonstrate with a Naive Bayes Classifier that it is accurate enough to more than double the average number of acceptable models retained during the crucial filtering stage of protein docking when combined with our constrained docking algorithm. All software developed in this work is freely available as part of the Open Chemera Library. PMID- 25722739 TI - A practical scoring system to predict mortality in patients with perforated peptic ulcer. AB - INTRODUCTION: The mortality rate of perforated peptic ulcer is still high particularly for aged patients and all the existing scoring systems to predict mortality are complicated or based on history taking which is not always reliable for elderly patients. This study's aim was to develop an easy and applicable scoring system to predict mortality based on hospital admission data. METHODS: Total 227 patients operated for perforated peptic ulcer in two centers were included. All data that may be potential predictors with respect to hospital mortality were retrospectively analyzed. RESULTS: The mortality and morbidity rates were 10.1% and 24.2%, respectively. Multivariated analysis pointed out three parameters corresponding 1 point for each which were age >65 years, albumin <=1,5 g/dl and BUN >45 mg/dl. Its prediction rate was high with 0,931 (95% CI, 0,890 to 0,961) value of AUC. The hospital mortality rates for none, one, two and three positive results were zero, 7.1%, 34.4% and 88.9%, respectively. CONCLUSION: Because the new system consists only age and routinely measured two simple laboratory tests (albumin and BUN), its application is easy and prediction power is satisfactory. Verification of this new scoring system is required by large scale multicenter studies. PMID- 25722740 TI - Effects of chrysin (5,7-dihydroxyflavone) on vascular remodeling in hypoxia induced pulmonary hypertension in rats. AB - BACKGROUND: Chrysin (5,7-dihydroxyflavone) inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation and arterial intima hyperplasia. This study aims to investigate the effects of chrysin on rat pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (PH). METHODS: Sprague-Dawley rats were continuously exposed to 10% O2 for 4 weeks to induce PH. The effect of chrysin (50 or 100 mg/kg/d, subcutaneous) on vascular remodeling was investigated in hypoxia-induced PH model. At the end of the experiments, the indexes for pulmonary vascular remodeling and right ventricle hypertrophy were measured by vascular medial wall thickness and the ratio of right ventricle to (left ventricle plus septum). The expressions of NOX4, collagen I, and collagen III were analyzed by immunohistochemistry, real-time PCR, or western blotting. The proliferation of cultured pulmonary artery smooth muscle cells (PASMCs) was determined by BrdU incorporation and flow cytometry. The levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were also determined by thiobarbituric acid reactive substances assay and 2'7' dichlorofluorescein diacetate method. RESULTS: Chrysin treatment for 4 weeks significantly attenuated pulmonary vascular remodeling and improved collagen accumulation and down-regulated collagen I and collagen III expressions, accompanied by downregulation of NOX4 expression in the pulmonary artery (P = 0.012 for 50 mg/kg/d, P < 0.001 for 100 mg/kg/d) and lung tissue (P = 0.026, P < 0.001). In vitro, chrysin (1, 10, and 100 MUM) remarkably attenuated PASMC proliferation (P = 0.021 for 1 MUM, P < 0.001 for 10 MUM, and P < 0.001 for 100 MUM), collagen I expression (P = 0.035, P < 0.001, and P < 0.001), and collagen III expression (P = 0.027, P < 0.001, and P < 0.001) induced by hypoxia, and these inhibitory effects of chrysin were accompanied by inhibition of NOX4 expression (P = 0.019, P < 0.001, and P < 0.001), ROS production (P = 0.038, P < 0.001, and P < 0.001), and MDA generation (P = 0.024, P < 0.001, and P < 0.001). CONCLUSIONS: This study demonstrated that chrysin treatment in hypoxia-induced PH in rats reversed the hypoxia-induced (1) elevations of NOX4 expression, (2) productions of ROS and MDA, (3) proliferation of PASMC, and (4) accumulation of collagen. PMID- 25722741 TI - Biofilm formation by designed co-cultures of Caldicellulosiruptor species as a means to improve hydrogen productivity. AB - BACKGROUND: Caldicellulosiruptor species have gained a reputation as being among the best microorganisms to produce hydrogen (H2) due to possession of a combination of appropriate features. However, due to their low volumetric H2 productivities (Q H2), Caldicellulosiruptor species cannot be considered for any viable biohydrogen production process yet. In this study, we evaluate biofilm forming potential of pure and co-cultures of Caldicellulosiruptor saccharolyticus and Caldicellulosiruptor owensensis in continuously stirred tank reactors (CSTR) and up-flow anaerobic (UA) reactors. We also evaluate biofilms as a means to retain biomass in the reactor and its influence on Q H2. Moreover, we explore the factors influencing the formation of biofilm. RESULTS: Co-cultures of C. saccharolyticus and C. owensensis form substantially more biofilm than formed by C. owensensis alone. Biofilms improved substrate conversion in both of the reactor systems, but improved the Q H2 only in the UA reactor. When grown in the presence of each other's culture supernatant, both C. saccharolyticus and C. owensensis were positively influenced on their individual growth and H2 production. Unlike the CSTR, UA reactors allowed retention of C. saccharolyticus and C. owensensis when subjected to very high substrate loading rates. In the UA reactor, maximum Q H2 (approximately 20 mmol . L(-1) . h(-1)) was obtained only with granular sludge as the carrier material. In the CSTR, stirring negatively affected biofilm formation. Whereas, a clear correlation was observed between elevated (>40 MUM) intracellular levels of the secondary messenger bis-(3'-5') cyclic dimeric guanosine monophosphate (c-di-GMP) and biofilm formation. CONCLUSIONS: In co-cultures C. saccharolyticus fortified the trade of biofilm formation by C. owensensis, which was mediated by elevated levels of c-di-GMP in C. owensensis. These biofilms were effective in retaining biomass of both species in the reactor and improving Q H2 in a UA reactor using granular sludge as the carrier material. This concept forms a basis for further optimizing the Q H2 at laboratory scale and beyond. PMID- 25722742 TI - Genome-wide transcriptional analysis suggests hydrogenase- and nitrogenase mediated hydrogen production in Clostridium butyricum CWBI 1009. AB - BACKGROUND: Molecular hydrogen, given its pollution-free combustion, has great potential to replace fossil fuels in future transportation and energy production. However, current industrial hydrogen production processes, such as steam reforming of methane, contribute significantly to the greenhouse effect. Therefore alternative methods, in particular the use of fermentative microorganisms, have attracted scientific interest in recent years. However the low overall yield obtained is a major challenge in biological H2 production. Thus, a thorough and detailed understanding of the relationships between genome content, gene expression patterns, pathway utilisation and metabolite synthesis is required to optimise the yield of biohydrogen production pathways. RESULTS: In this study transcriptomic and proteomic analyses of the hydrogen-producing bacterium Clostridium butyricum CWBI 1009 were carried out to provide a biomolecular overview of the changes that occur when the metabolism shifts to H2 production. The growth, H2-production, and glucose-fermentation profiles were monitored in 20 L batch bioreactors under unregulated-pH and fixed-pH conditions (pH 7.3 and 5.2). Conspicuous differences were observed in the bioreactor performances and cellular metabolisms for all the tested metabolites, and they were pH dependent. During unregulated-pH glucose fermentation increased H2 production was associated with concurrent strong up-regulation of the nitrogenase coding genes. However, no such concurrent up-regulation of the [FeFe] hydrogenase genes was observed. During the fixed pH 5.2 fermentation, by contrast, the expression levels for the [FeFe] hydrogenase coding genes were higher than during the unregulated-pH fermentation, while the nitrogenase transcripts were less abundant. The overall results suggest, for the first time, that environmental factors may determine whether H2 production in C. butyricum CWBI 1009 is mediated by the hydrogenases and/or the nitrogenase. CONCLUSIONS: This work, contributing to the field of dark fermentative hydrogen production, provides a multidisciplinary approach for the investigation of the processes involved in the molecular H2 metabolism of clostridia. In addition, it lays the groundwork for further optimisation of biohydrogen production pathways based on genetic engineering techniques. PMID- 25722743 TI - Development of cancer genetic services in the UK: A national consultation. AB - BACKGROUND: Technological advances in DNA sequencing have made gene testing fast and affordable, but there are challenges to the translation of these improvements for patient benefit. The Mainstreaming Cancer Genetics (MCG) programme is exploiting advances in DNA sequencing to develop the infrastructure, processes and capabilities required for cancer gene testing to become routinely available to all those that can benefit. METHODS: The MCG programme held a consultation day to discuss the development of cancer genetics with senior representation from all 24 UK cancer genetic centres. The current service landscape and capacity for expansion was assessed through structured questionnaires. Workshop discussion addressed the opportunities and challenges to increasing cancer gene testing in the National Health Service (NHS). RESULTS: Services vary with respect to population served and models of service delivery, and with respect to methods and thresholds for determining risk and testing eligibility. Almost all centres want to offer more cancer gene testing (82%) and reported increasing demand for testing from non-genetic clinical colleagues (92%). Reported challenges to increasing testing include the complexity of interpreting the resulting genetic data (79%), the level of funding and complexity of commissioning (67%), the limited capacity of current processes and cross-disciplinary relationships (38%), and workforce education (29%). CONCLUSIONS: Priorities to address include the development and evaluation of models of increasing access to gene testing, the optimal process for interpretation of large-scale genetic data, implementation of appropriate commissioning and funding processes, and achieving national consistency. The UK cancer genetics community have high expertise and strong commitment to maximising scientific advances for improved patient benefit and should be pivotally involved in the implementation of increased cancer gene testing. PMID- 25722744 TI - Transcriptional profiling defines dynamics of parasite tissue sequestration during malaria infection. AB - BACKGROUND: During intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood. RESULTS: We generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion. CONCLUSIONS: This study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo. PMID- 25722745 TI - The Sweden Cancerome Analysis Network - Breast (SCAN-B) Initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine. AB - BACKGROUND: Breast cancer exhibits significant molecular, pathological, and clinical heterogeneity. Current clinicopathological evaluation is imperfect for predicting outcome, which results in overtreatment for many patients, and for others, leads to death from recurrent disease. Therefore, additional criteria are needed to better personalize care and maximize treatment effectiveness and survival. METHODS: To address these challenges, the Sweden Cancerome Analysis Network - Breast (SCAN-B) consortium was initiated in 2010 as a multicenter prospective study with longsighted aims to analyze breast cancers with next generation genomic technologies for translational research in a population-based manner and integrated with healthcare; decipher fundamental tumor biology from these analyses; utilize genomic data to develop and validate new clinically actionable biomarker assays; and establish real-time clinical implementation of molecular diagnostic, prognostic, and predictive tests. In the first phase, we focus on molecular profiling by next-generation RNA-sequencing on the Illumina platform. RESULTS: In the first 3 years from 30 August 2010 through 31 August 2013, we have consented and enrolled 3,979 patients with primary breast cancer at the seven hospital sites in South Sweden, representing approximately 85% of eligible patients in the catchment area. Preoperative blood samples have been collected for 3,942 (99%) patients and primary tumor specimens collected for 2,929 (74%) patients. Herein we describe the study infrastructure and protocols and present initial proof of concept results from prospective RNA sequencing including tumor molecular subtyping and detection of driver gene mutations. Prospective patient enrollment is ongoing. CONCLUSIONS: We demonstrate that large scale population-based collection and RNA-sequencing analysis of breast cancer is feasible. The SCAN-B Initiative should significantly reduce the time to discovery, validation, and clinical implementation of novel molecular diagnostic and predictive tests. We welcome the participation of additional comprehensive cancer treatment centers. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02306096. PMID- 25722746 TI - The effectiveness of extracorporeal shock wave therapy for the treatment of lower limb ulceration: a systematic review. AB - Extracorporeal shock wave therapy has been reported as an effective treatment for lower limb ulceration. The aim of this systematic review was to investigate the effectiveness of extracorporeal shock wave therapy for the treatment of lower limb ulceration. Five electronic databases (Ovid MEDLINE, CINAHL, Web of Knowledge, Scopus and Ovid AMED) and reference lists from relevant studies were searched in December 2013. All study designs, with the exception of case-reports, were eligible for inclusion in this review. Assessment of each study's methodological quality was performed using the Quality Index tool. The effectiveness of studies was measured by calculating effect sizes (Cohen's d) from means and standard deviations. Five studies, including; three randomised controlled trials, one quasi-experimental study and one case-series design met our inclusion criteria and were reviewed. Quality assessment scores ranged from 38 to 63% (mean 53%). Improvements in wound healing were identified in these studies following extracorporeal shock wave therapy. The majority of wounds assessed were associated with diabetes and the effectiveness of ESWT as an addition to standard care has only been assessed in one randomised controlled trial. Considering the limited evidence identified, further research is needed to support the use of extracorporeal shock wave therapy in the treatment of lower limb ulceration. PMID- 25722747 TI - The association of foot structure and footwear fit with disability in children and adolescents with Down syndrome. AB - BACKGROUND: Foot deformity, flat feet, and the use of ill-fitting footwear are common in children and adolescents with Down syndrome (DS). The aim of this study was to determine whether these observations are associated with foot-specific disability in this group. METHODS: A cross-sectional study design. Foot structure (foot posture determined using the Arch Index, presence of hallux valgus and lesser toe deformities) and footwear fit (determined by length and width percentage differences between the participant's foot and footwear) were assessed in 50 participants with DS (22 females, 28 males) aged five to 18 with a mean (SD) age of 10.6 (3.9) years. Foot-specific disability was determined using the parent-reported Oxford Ankle Foot Questionnaire for Children (OxAFQ-C). Associations between foot structure and footwear fit with the four domains (Physical, School and play, Emotional and Footwear) of the OxAFQ-C were determined using multivariate regression modelling. RESULTS: The mean (SD) Arch Index was 0.29 (0.08), and the prevalence of flat feet, hallux valgus and lesser toe deformities was 76%, 10% and 12% respectively. Few participants wore footwear that was too short (10%), but the use of footwear that was too narrow was common (58%). The presence of hallux valgus was significantly associated with increased disability for the OxAFQ-C School and play domain scores. The use of narrow fitting footwear was significantly associated with increased levels of disability for the OxAFQ-C Physical, School and play, and Emotional domains. However, these variables only explained between 10% to 14% of the variance in the OxAFQ-C domain scores. There were no significant associations between foot structure and footwear fit with the OxAFQ-C Footwear domain scores. CONCLUSIONS: Flatter feet and lesser toe deformities are not associated with foot-specific disability in children and adolescents with DS. Hallux valgus is associated with foot-specific disability during school and play activities. Ill-fitting footwear (too narrow) is common and is associated with foot-specific disability. Further research is required to identify if the relationship between narrow-fitting footwear and foot specific disability is causal, and to identify other factors associated with foot specific disability in children and adolescents with DS. PMID- 25722748 TI - Clinical and imaging features of mixed Alzheimer and vascular pathologies. AB - The co-occurrence of both Alzheimer disease (AD) pathology and vascular brain injury (VBI) is very common, especially amongst the oldest of old. In neuropathologic studies, the prevalence of AD, VBI, and mixed AD/VBI lesions ranks ahead of Lewy bodies and hippocampal sclerosis. In the modern era of structural magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) imaging, this review examines 1) the prevalence of mixed AD and VBI pathology, 2) the significance of these pathologies for cognitive impairment (AD and vascular cognitive impairment (VCI)), and 3) the diagnosis and treatment of mixed AD/VCI. Although epidemiologic studies report that vascular risk factors for arteriosclerosis increase the risk of incident AD, both autopsy and amyloid PET studies indicate that AD and VBI contribute additively, but independently, to the risk of dementia. The literature confirms the malignancy of AD and highlights the adverse effects of microinfarcts on cognitive function. For the clinical diagnosis of mixed AD/VCI, the presence of AD can be recognized by neuropsychological profile, structural imaging, cerebrospinal fluid biomarkers, and glucose PET and amyloid PET imaging. The diagnosis of VBI, however, still hinges predominantly on the structural MRI findings. Severe amnesia and atrophy of the hippocampus are characteristic of early AD, whereas the cognitive profile for VCI is highly variable and dependent on size and location of VBI. The cognitive profile of mixed AD/VBI is dominated by AD. With the notable exception of microinfarcts (which elude in vivo detection), infarcts, hemorrhages, and white matter hyperintensities on structural MRI currently represent the best markers for the presence VBI. Better markers that reflect the health and reactivity of intracerebral blood vessels are needed. For prevention and treatment, the type of underlying cerebrovascular disease (for example, arteriosclerosis or cerebral amyloid angiopathy) should be considered. It is likely that reduction of vascular risk factors for arteriosclerosis can significantly reduce vascular contributions to mixed dementia. PMID- 25722749 TI - 'Hearts and minds': association, causation and implication of cognitive impairment in heart failure. AB - The clinical syndrome of heart failure is one of the leading causes of hospitalisation and mortality in older adults. An association between cognitive impairment and heart failure is well described but our understanding of the relationship between the two conditions remains limited. In this review we provide a synthesis of available evidence, focussing on epidemiology, the potential pathogenesis, and treatment implications of cognitive decline in heart failure. Most evidence available relates to heart failure with reduced ejection fraction and the syndromes of chronic cognitive decline or dementia. These conditions are only part of a complex heart failure-cognition paradigm. Associations between cognition and heart failure with preserved ejection fraction and between acute delirium and heart failure also seem evident and where data are available we will discuss these syndromes. Many questions remain unanswered regarding heart failure and cognition. Much of the observational evidence on the association is confounded by study design, comorbidity and insensitive cognitive assessment tools. If a causal link exists, there are several potential pathophysiological explanations. Plausible underlying mechanisms relating to cerebral hypoperfusion or occult cerebrovascular disease have been described and it seems likely that these may coexist and exert synergistic effects. Despite the prevalence of the two conditions, when cognitive impairment coexists with heart failure there is no specific guidance on treatment. Institution of evidence-based heart failure therapies that reduce mortality and hospitalisations seems intuitive and there is no signal that these interventions have an adverse effect on cognition. However, cognitive impairment will present a further barrier to the often complex medication self-management that is required in contemporary heart failure treatment. PMID- 25722750 TI - Autocatalytic sets and boundaries. AB - Autopoietic systems, chemotons, and autogens are models that aim to explain (the emergence of) life as a functionally closed and self-sustaining system. An essential element in these models is the notion of a boundary containing, maintaining, and being generated by an internal reaction network. The more general concept of collectively autocatalytic sets, formalized as RAF theory, does not explicitly include this notion of a boundary. Here, we argue that (1) the notion of a boundary can also be incorporated in the formal RAF framework, (2) this provides a mechanism for the emergence of higher-level autocatalytic sets, (3) this satisfies a necessary condition for the evolvability of autocatalytic sets, and (4) this enables the RAF framework to formally represent and analyze (at least in part) the other models. We suggest that RAF theory might thus provide a basis for a unifying formal framework for the further development and study of such models. Graphical abstractThe emergence of an autocatalytic (super)set of autocatalytic (sub)sets. PMID- 25722751 TI - Role of intra-operative contrast-enhanced ultrasound (CEUS) in robotic-assisted nephron-sparing surgery. AB - This review examines studies of intra-operative contrast-enhanced ultrasound (CEUS) and its emerging role and advantages in robotic-assisted nephron-sparing surgery. Contrast-enhanced ultrasound is a technology that combines the use of second-generation contrast agents consisting of microbubbles with existent ultrasound techniques. Until now, this novel technology has aided surgeons with procedures involving the liver. However, with recent advances in the CEUS technique and the introduction of robotics in nephron-sparing surgery, CEUS has proven to be efficacious in answering several clinical questions with respect to the kidneys. In addition, the introduction of the microbubble-based contrast agents has increased the image quality and signal uptake by the ultrasound probe. This has led to better, enhanced scanning of the macro and microvasculature of the kidneys, making CEUS a powerful diagnostic modality. This imaging method is capable of further lowering the learning curve and warm ischemia time (WIT) during robotic-assisted nephron-sparing surgery, with its increased level of capillary perfusion and imaging. CEUS has the potential to increase the sensitivity and specificity of intra-operative images, and can significantly improve the outcome of robotic-assisted nephron-sparing surgery by increasing the precision and diagnostic insight of the surgeon. The purpose of this article is to review the practical and potential uses of CEUS as an intra-operative imaging technique during robotic-assisted nephron-sparing surgery. PMID- 25722753 TI - Electrocardiographic imaging of heart rhythm disorders: from bench to bedside. AB - Noninvasive electrocardiographic imaging (ECGI; also called ECG mapping) can reconstruct potentials, electrograms, activation sequences, and repolarization patterns on the epicardial surface of the heart with high resolution. ECGI can possibly be used to quantify synchrony, identify potential responders/nonresponders to cardiac resynchronization therapy, and guide electrode placement for effective resynchronization therapy. This article provides a brief description of the ECGI procedure and selected previously published examples of its application in important clinical conditions, including heart failure, cardiac resynchronization therapy, atrial arrhythmias, and ventricular tachycardia. PMID- 25722754 TI - Pediatric electrocardiographic imaging applications. AB - Noninvasive electrocardiographic imaging (ECGI) has been used in pediatric and congenital heart patients to better understand their electrophysiologic substrates. In this article we focus on the 4 subjects related to pediatric ECGI: (1) ECGI in patients with congenital heart disease and Wolff-Parkinson-White syndrome, (2) ECGI in patients with hypertrophic cardiomyopathy and preexcitation, (3) ECGI in pediatric patients with Wolff-Parkinson-White syndrome, and (4) ECGI for pediatric cardiac resynchronization therapy. PMID- 25722755 TI - FLOBOTS: ROBOTIC FLOWERS FOR BEE BEHAVIOUR EXPERIMENTS. AB - Studies of pollinator foraging behaviour often require artificial flowers that can refill themselves, allowing pollinators to forage for long periods of time under experimental conditions. Here I describe a design for inexpensive flowers that can refill themselves upon demand and that are easy enough to set up and clean that they can be used in arrays of 30 or more flowers. I also summarize of a variety of artificial flower designs developed by other researchers. PMID- 25722756 TI - 'Hygienic' lymphocytes convey increased cancer risk. AB - Risk of developing inflammation-associated cancers has increased in industrialized countries during the past 30 years. One possible explanation is societal hygiene practices with use of antibiotics and Caesarian births that provide too few early life exposures of beneficial microbes. Building upon a 'hygiene hypothesis' model whereby prior microbial exposures lead to beneficial changes in CD4+ lymphocytes, here we use an adoptive cell transfer model and find that too few prior microbe exposures alternatively result in increased inflammation-associated cancer growth in susceptible recipient mice. Specifically, purified CD4+ lymphocytes collected from 'restricted flora' donors increases multiplicity and features of malignancy in intestinal polyps of recipient ApcMin/+ mice, coincident with increased inflammatory cell infiltrates and instability of the intestinal microbiota. We conclude that while a competent immune system serves to maintain intestinal homeostasis and good health, under hygienic rearing conditions CD4+ lymphocytes instead exacerbate inflammation associated tumorigenesis, subsequently contributing to more frequent cancers in industrialized societies. PMID- 25722757 TI - Judicial Perceptions of Media Portrayals of Offenders with High Functioning Autistic Spectrum Disorders. AB - In recent years, sensational media reporting focusing on crimes committed by those diagnosed with or thought to have High Functioning Autistic Spectrum Disorders (hfASDs) has caused societal speculation that there is a link between the disorder and violent criminality. No research exists on how and if the judiciary understands and is affected by this coverage. Therefore this study aims to examine how judges perceive and are influenced by media attention surrounding hfASDs and criminality. Semi-structured interviews were conducted with 21 California Superior Court Judges, including questions on media portrayal. Judges perceived general media portrayals of hfASDs in both positive and negative ways. However, almost all judges who had experienced media coverage surrounding hfASDs and criminality identified it as misleading and harmful to public perceptions of the disorder. These findings suggest judges are not exempt from media attention surrounding violence and hfASDs, and they recognize the potential adverse effects of this negative coverage. Although judges' report their opinions are not affected, the results demonstrate that judges are worried that the public and potentially other criminal justice actors are adversely affected and will continue to be moving forward. PMID- 25722758 TI - Pattern of congenital heart diseases in Rwandan children with genetic defects. AB - INTRODUCTION: Congenital heart diseases (CHD) are commonly associated with genetic defects. Our study aimed at determining the occurrence and pattern of CHD association with genetic defects among pediatric patients in Rwanda. METHODS: A total of 125 patients with clinical features suggestive of genetic defects were recruited. Echocardiography and standard karyotype studies were performed in all patients. RESULTS: CHDs were detected in the majority of patients with genetic defects. The commonest isolated CHD was ventricular septal defect found in many cases of Down syndrome. In total, chromosomal abnormalities represented the majority of cases in our cohort and were associated with various types of CHDs. CONCLUSION: Our findings showed that CHDs are common in Rwandan pediatric patients with genetic defects. These results suggest that a routine echocardiography assessment combined with systematic genetic investigations including standard karyotype should be mandatory in patients presenting characteristic clinical features in whom CHD is suspected to be associated with genetic defect. PMID- 25722759 TI - [Management strategy for hypertension in chronic hemodialysis: a model applied to patient education (FTE)]. PMID- 25722760 TI - [Pseudo tumor pelvic actinomycosis associated with intrauterine device: report of three cases]. PMID- 25722761 TI - [Combine theory and practice in the fight against the AIDS pandemic]. PMID- 25722762 TI - [Role of radiotherapy in the treatment of ameloblastoma: report of two cases]. PMID- 25722763 TI - [Acetabular fracture-dislocations: care and long-term prognosis; retrospective study of 40 cases]. PMID- 25722764 TI - [A disease can hide another: Pott's disease revealing a schwannoma]. PMID- 25722765 TI - [Butterfly wing appearance on Xray does not always mean acute pulmonary edema: think of bronchial adenocarcinoma]. PMID- 25722766 TI - [The benefits of the accompaniment for cancer patients: characteristics in Morocco]. PMID- 25722767 TI - [Sternoclavicular location of amyloidosis]. PMID- 25722768 TI - [Hemogram profile of malaria in children 0-5 years under quinine--situation in the Democratic Republic of Congo]. PMID- 25722769 TI - Duane retraction syndrome in a Nigerian child. AB - We report a case of a four year old Nigerian girl who presented to the paediatric unit of our eye clinic with complaints of a squint on looking to the right side and reduction in the size of the right eye when looking to the left. On examination, she had right exotropia in the primary position of gaze. There was limitation of abduction and widening of the palpebral fissure of the right eye on right gaze. On left gaze there was narrowing of the palpebral fissure of the right eye with marked limitation of adduction and an upshoot, or occasionally a downshoot, of the eyeball. This report demonstrates that Duane's syndrome occurs in West Africa. Therefore, detailed examination of all patients with squints is important to ensure accurate diagnosis and appropriate management of the patient's condition. PMID- 25722770 TI - Non-technical skills of anaesthesia providers in Rwanda: an ethnography. AB - INTRODUCTION: Patient safety depends on excellent practice of anaesthetists' non technical skills (ANTS). The ANTS framework has been validated in developed countries but there is no literature on the practice of ANTS in low-income countries. This study examines ANTS in this unexplored context. METHODS: This qualitative ethnographic study used observations of Rwandan anaesthesia providers and in-depth interviews with both North American and Rwandan anaesthesia providers to understand practice of ANTS in Rwanda. RESULTS: Communication is central to the practice of ANTS. Cultural factors in Rwanda, such as lack of assertiveness and discomfort taking leadership, and the strains of working in a resource-limited environment hinder the unfettered and focused communication needed for excellent anaesthesia practice. CONCLUSION: Despite the challenges, anaesthesia providers are able to coordinate activities when good communication is actively encouraged. Future teaching interventions should address leadership and communication skills through encouraging both role definition and speaking up for patient safety. PMID- 25722771 TI - [Acute lymphoblastic leukemia revealed by an invasion of the cavernous sinus in a young man]. PMID- 25722772 TI - Adenoid cystic carcinoma of cervix in younger women: report of two new cases. AB - Adenoid cystic carcinoma is a malignant epithelial neoplasm derived from the salivary glands. Primary adenoid cystic carcinoma of the cervix is extremely rare, accounting for less than 1% of all cervical carcinomas. Its origin is debatable. It generally presents in elderly age group, however only twenty three cases have been reported in women less than age 45 years old. In this paper we report two new cases of primary adenoid cystic carcinoma in younger women and include the cytopathology and histopathology findings. A 36, 41 year-old women were admitted with signs and symptoms suggestive of a cervical cancer. Speculum examination showed a firm mass in the uterine cervix. The diagnosis of adenoid cystic carcinoma was confirmed by the histopathology examination of the biopsy specimen in the two patients, which characteristically revealed the presence of a cribriform pattern and cylindromatous structures of the tumor cells, adhered around hyaline stoma. They were managed successfully by concurrent radiotherapy. Adenoid cystic carcinoma of the cervix is a rare disease. It usually occurs in an elderly age group. We report these two cases because of its rarity in young patients, with description of illustrative pathology and discussion on the histological diagnosis. PMID- 25722773 TI - [Post traumatic cubitus varus]. PMID- 25722774 TI - [Chronic inflammatory demyelinating polyradiculoneuropathy revealing essential thrombocythemia]. PMID- 25722775 TI - [Aneurysm of the vein of Galen revealed in adulthood]. PMID- 25722776 TI - The impact of medical tourism and the code of medical ethics on advertisement in Nigeria. AB - Advances in management of clinical conditions are being made in several resource poor countries including Nigeria. Yet, the code of medical ethics which bars physician and health practices from advertising the kind of services they render deters these practices. This is worsened by the incursion of medical tourism facilitators (MTF) who continue to market healthcare services across countries over the internet and social media thereby raising ethical questions. A significant review of the advertisement ban in the code of ethics is long overdue. Limited knowledge about advances in medical practice among physicians and the populace, the growing medical tourism industry and its attendant effects, and the possibility of driving brain gain provide evidence to repeal the code. Ethical issues, resistance to change and elitist ideas are mitigating factors working in the opposite direction. The repeal of the code of medical ethics against advertising will undoubtedly favor health facilities in the country that currently cannot advertise the kind of services they render. A repeal or review of this code of medical ethics is necessary with properly laid down guidelines on how advertisements can be and cannot be done. PMID- 25722777 TI - [Deferred twin birth: report of two cases observed at the maternity of Creil Hospital Centre]. PMID- 25722778 TI - Commencing open heart surgery in resource limited countries: lessons from the LASUTH experience. AB - The challenge of commencing cardiac surgery in developing countries of Africa is onerous. We present a model from the experience of carrying out open cardiac surgical procedures at the Lagos State University Teaching Hospital (LASUTH) with three separate missions between 2004 and 2006. This paper details the challenges of starting open heart surgery in a resource limited environment. We propose that owing to the huge financial investment needed, government sponsorship as well as collaboration with overseas based and local non-governmental agencies may be required to jump start the process of open cardiac surgery. Local staff training opportunities are also provided by such missions and this can further be complemented by overseas exposure in areas of need for capacity building. In our centre, the initial investment has led to the recruitment of additional trained staff including 2 cardiothoracic surgeons. Further benefits of training of 2 perfusionists and a nurse has improved capacity in cardiac surgery service at our center. PMID- 25722780 TI - Primitive bilateral nipple necrosis: a case report. PMID- 25722779 TI - Establishing a One Health office in Kenya. AB - A One Health (OH) approach that integrates human,animal and environmental approaches to management of zoonotic diseases has gained momentum in the last decadeas part of a strategy to prevent and control emerging infectious diseases. However, there are few examples of howan OH approach can be established in a country. Kenya establishment of an OH office, referred to asthe Zoonotic Disease Unit (ZDU) in 2011. The ZDU bridges theanimal and human health sectors with a senior epidemiologist deployed from each ministry; and agoal of maintaining collaboration at the animal and human health interface towards better prevention and control of zoonoses. The country is adding an ecologist to the ZDU to ensure that environmental risks are adequately addressed in emerging disease control. PMID- 25722781 TI - [Inverse pseudo-hypopyon with congenital polycoria]. PMID- 25722782 TI - [Atypical scalp and adrenal metastasis of a urothelial carcinoma of the bladder]. PMID- 25722783 TI - [Orbital abscess: report of 7 cases]. PMID- 25722784 TI - [Cerebral radiation necrosis in patients irradiated for nasopharyngeal cancer: report of 3 cases]. PMID- 25722785 TI - [A case of congenital cerulean cataract]. PMID- 25722786 TI - Determinants of folic acid intake during preconception and in early pregnancy by mothers in Ibadan, Nigeria. AB - INTRODUCTION: In order to identify targets for primary preventive strategies, we explored possible predictors of periconceptional folic acid (pFA) intake in a Nigerian population of reproductively active women. METHODS: A cross sectional study of mothers attending immunization clinics at two hospitals was conducted between May and November 2012. Information obtained included sociodemographic and obstetric details and periconceptional usage of FA. Independent variables were analysed as predictors of pFA intake using chi-square statistical test and multinomial logistic regression. RESULTS: The study involved 602 mothers aged 17 to 42 years; 23% had a university degree and 66% were in the working class. Preconceptional usage was proven in only 15 (2.5%). Periconceptional usage was more likely among professionals (X2=41.194, p<0.001), have university degree (X2=53.089, p<0.001), be primigravid (X2=18.415, p<0.001) and early antenatal clinic attendees (X2=355.9, p<0.001). Women were less likely to know that FA could prevent birth defects if in the working class (1.7% vs. 11.1%, X2=25.593, p<0.001), less educated (0.5 vs. 10.9%, X2=38.083, p<0.001) or booked late for antenatal care (2.0 vs. 5.9%, X2=5.767, p=0.016). The determinants of late commencement of FA were low social class (OR=4.29, 95% CI: 1.59, 11.31), lack of university education (OR=4.58, 95% CI: 3.06, 6.87) and late booking (OR=104.27, 95% CI: 53.09, 204.76). CONCLUSION: In this population of reproductively active women, pFA intake and knowledge of its health benefits are poor amongst mothers- in working class, with limited education, and who present late for antenatal care. PMID- 25722787 TI - Incidence and predictors of recovery from anaemia within an HIV-infected South African Cohort, 2004-2010. AB - INTRODUCTION: Anaemia is one of the most frequent haematological complications in HIV-infected persons. Understandingfactors associated with recovery from anaemia during ART is vital in improving clinical outcomes since anaemia is a strong predictor of mortality. METHODS: Cohort study of 12,441 HIV-infected adults initiating ART between 2004-2010 in Johannesburg, South Africa. A further 2,489 patients with prevalent anaemia at ART initiation were examined to determine the incidence and predictors of recovery from anaemia. Cox proportional hazards models were fitted to investigate predictors of recovery from anaemia. RESULTS: Of the 2,489 patients with prevalent anaemia, most patients (n=2,225, 89.4%) recovered from anaemia. Median time to anaemia recoverywas 3.9 months (IQR: 3.22 6.20) and incidence rate was 180 per 100person years (95% CI: 172-187). In univariateanalysis, sex, CD4 count, BMI, WHO stage, employment status, smoking status and presence of tuberculosis at initiation ofART were significant predictors of recovery from anaemia. However in multivariateanalysis, predictors of recovery from anaemia were: male sex-HR: 1.43 (95% CI: 1.29-1.59) p<0.001, advanced WHO stage III/IV-HR: 1.17 (95% CI: 1.07-1.29) p=0.001). There was no significant association with CD4 count in multivariate analysis. CONCLUSION: A large proportion of HIV infected patients with anaemia at baseline recover early during the course of ART. Females and those with less advanced WHO stage seem to be at higher risk of poor recovery from anaemia. Understanding the predictors for poor recovery from anaemia would allow closer follow-up and more targeted interventions thus reducing excess anaemia and mortality burden. PMID- 25722788 TI - [Orbital myiasis: a historical case]. PMID- 25722789 TI - [Organizing pneumonia revealing a polymyositis]. PMID- 25722790 TI - [Vesico-sigmoid fistula complicating intestinal hydatid disease: report of a rare case]. PMID- 25722791 TI - A new approach to oxidative stress and inflammatory signaling during labour in healthy mothers and neonates. AB - The objective of the current study was to investigate for the first time and simultaneously the oxidative stress and inflammatory signaling induced during the delivery in healthy mothers and their neonates. 56 mothers with normal gestational course and spontaneous delivery were selected. Blood samples were taken from mother (before and after delivery) both from vein and artery of umbilical cord. Lower antioxidant enzymes activities were observed in neonates compared with their mothers and lower oxidative stress in umbilical cord artery with respect to vein. There was an overexpression of inflammatory cytokines in the mother, such as IL-6 and TNF-alpha, and, in addition, PGE2 was also increased. Neonates showed lower levels of IL-6 and TNF-alpha and higher values of sTNF-RII and PGE2 in comparison with their mothers. Parturition increases oxidative damage in the mother, although the indicators of oxidative damage were lower in umbilical cord artery with respect to umbilical vein. The overexpression of inflammatory cytokines reveals that fetus suffers its own inflammatory process during parturition. PMID- 25722792 TI - Cardiopulmonary bypass and oxidative stress. AB - The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state. Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes. The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress. PMID- 25722793 TI - Glutathione suppresses cerebral infarct volume and cell death after ischemic injury: involvement of FOXO3 inactivation and Bcl2 expression. AB - Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusion in vivo and the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditions in vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death. PMID- 25722794 TI - A novel antioxidant multitarget iron chelator M30 protects hepatocytes against ethanol-induced injury. AB - The multitarget iron chelator, M30, is a novel antioxidant and protective agent against oxidative stress in a spectrum of diseases. However, there is no report regarding its role in liver diseases. Since oxidative stress is one of the major pathological events during the progression of alcoholic liver diseases, the protective effects and mechanisms of M30 on ethanol-induced hepatocyte injury were investigated in this study. Rat hepatocyte line BRL-3A was pretreated with M30 prior to ethanol treatment. Cell death, apoptosis, oxidative stress, and inflammation were examined. Specific antagonists and agonists were applied to determine the involvements of hypoxia inducible factor-1 alpha (HIF-1alpha) and its upstream adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A (PKA)/HIF 1alpha/NOD-like receptor 3 (NLRP3) inflammasome pathway. We found that M30 significantly attenuated ethanol-induced cellular death, apoptosis, production of reactive oxygen species (ROS), and secretion of inflammatory cytokines and inhibited activation of the AC/cAMP/PKA/HIF-1alpha/NLRP3 inflammasome pathway. Inhibition and activation of the AC/cAMP/PKA/HIF-1alpha pathway mimicked and abolished the effects of M30, respectively. In conclusion, inhibition of the AC/cAMP/PKA/HIF-1alpha/NLRP3 inflammasome pathway by M30 partially contributes to its attenuation of hepatocyte injury caused by ethanol exposure. PMID- 25722795 TI - Cell adhesion and long-term survival of transplanted mesenchymal stem cells: a prerequisite for cell therapy. AB - The literature provides abundant evidence that mesenchymal stem cells (MSCs) are an attractive resource for therapeutics and have beneficial effects in regenerating injured tissues due to their self-renewal ability and broad differentiation potential. Although the therapeutic potential of MSCs has been proven in both preclinical and clinical studies, several questions have not yet been addressed. A major limitation to the use of MSCs in clinical applications is their poor viability at the site of injury due to the harsh microenvironment and to anoikis driven by the loss of cell adhesion. To improve the survival of the transplanted MSCs, strategies to regulate apoptotic signaling and enhance cell adhesion have been developed, such as pretreatment with cytokines, growth factors, and antiapoptotic molecules, genetic modifications, and hypoxic preconditioning. More appropriate animal models and a greater understanding of the therapeutic mechanisms of MSCs will be required for their successful clinical application. Nevertheless, the development of stem cell therapies using MSCs has the potential to treat degenerative diseases. This review discusses various approaches to improving MSC survival by inhibiting anoikis. PMID- 25722796 TI - Effects of concurrent training on oxidative stress and insulin resistance in obese individuals. AB - Obesity is associated with insulin resistance (IR) and increased oxidative stress. Thus, the present study aimed to evaluate anthropometric parameters, IR, and oxidative stress in obese individuals subjected to two types of concurrent training at the same intensity but differing in frequency. Accordingly, 25 individuals were divided into two groups: concurrent training 1 (CT1) (5 d/wk) and concurrent training 2 (CT2) (3 d/wk), both with moderate intensity. Anthropometric parameters, IR, and oxidative stress were analyzed before and after 26 sessions of training. Both groups had reduced body weight and body mass index (P < 0.05), but only CT1 showed lower body fat percentage and increased basal metabolic rate (P < 0.05). Moreover, CT1 had increased HOMA-IR and decreased protein damage (carbonyl level), and CT2 had decreased HOMA-IR and increased lipid peroxidation (TBARS level) (P < 0.05). On the other hand, both training protocols reduced the GPx activity. It can be concluded that both types of concurrent training could be an alternative for lowering body weight and BMI. Also, it was observed that concurrent training, depending on the frequency, can contribute to reducing body fat, oxidative damage (protein oxidation), and IR but can induce oxidative damage to lipids. More studies are needed to elucidate the mechanisms involved. PMID- 25722797 TI - Results of the open surgery after endoscopic basket impaction during ERCP procedure. AB - AIM: To report the results of open surgery for patients with basket impaction during endoscopic retrograde cholangiopancreatography (ERCP) procedure. METHODS: Basket impaction of either classical Dormia basket or mechanical lithotripter basket with an entrapped stone occurred in six patients. These patients were immediately operated for removal of stone(s) and impacted basket. The postoperative course, length of hospital stay, diameter of the stone, complication and the surgical procedure of the patients were reported retrospectively. RESULTS: Six patients (M/F, 0/6) were operated due to impacted basket during ERCP procedure. The mean age of the patients was 64.33 +/- 14.41 years. In all cases the surgery was performed immediately after the failed ERCP procedure by making a right subcostal incision. The baskets containing the stone were removed through longitudinal choledochotomy with the stone. The choledochotomy incisions were closed by primary closure in four patients and T tube placement in two patients. All patients were also performed cholecystectomy additionally since they had cholelithiasis. In patients with T-tube placement it was removed on the 13(th) day after a normal T-tube cholangiogram. The patients remained stable at postoperative period and discharged without any complication at median 7 d. CONCLUSION: Open surgical procedures can be applied in patients with basket impaction during ERCP procedure in selected cases. PMID- 25722798 TI - Hepatic portal venous gas after endoscopy in a patient with anastomotic obstruction. AB - A 72-year-old male underwent a laparoscopic low anterior resection for advanced rectal cancer. A diverting loop ileostomy was constructed due to an anastomotic leak five days postoperatively. Nine months later, colonoscopy performed through the stoma showed complete anastomotic obstruction. The mucosa of the proximal sigmoid colon was atrophic and whitish. Ten days after the colonoscopy, the patient presented in shock with abdominal pain. Abdominal computed tomography scan showed hepatic portal venous gas (HPVG) and a dilated left colon. HPVG induced by obstructive colitis was diagnosed and a transverse colostomy performed emergently. His subsequent hospital course was unremarkable. Rectal anastomosis with diverting ileostomy is often performed in patients with low rectal cancers. In patients with anastomotic obstruction or severe stenosis, colonoscopy through diverting stoma should be avoided. Emergent operation to decompress the obstructed proximal colon is necessary in patients with a blind intestinal loop accompanied by HPVG. PMID- 25722799 TI - The effects of working hours on nerve conduction test in computer operators. AB - BACKGROUND: Long hours of work at a computer can result in potential adverse effects such as pain, paraesthesia, and subjective weakness of upper extremities with associated decreased nerve conduction velocities of peripheral nerves (median and ulnar). OBJECTIVE: To determine whether repetitive tasks performed for long hours by computer operators can lead to peripheral neuropathy as measured by nerve conduction studies of upper extremities. MATERIAL AND METHODS: We performed nerve conduction tests on 50 computer operators in two study groups. Group I consisted of computer operators who worked a minimum of 6 hours per day at the computer while Group II worked a maximum of 2 hours per day. RESULTS: Significant differences were observed between groups for most physical signs. In addition, there were significant differences between the groups for nerve conduction velocities of the medial (motor & sensory) and ulnar (motor & sensory) nerves. CONCLUSION: We found symptoms of pain, paraesthesia and subjective weaknesses as well as decreased conduction velocities of peripheral nerves in computer operators who work long hours. Further nerve conduction studies are needed to confirm predictive value for the development of carpal tunnel syndrome. KEY WORDS: computer operator, long work hours, nerve conduction studies. PMID- 25722800 TI - A short term follow up comparison of genu varum corrective surgery using open and closed wedge high tibial osteotomy. AB - INTRODUCTION: Knee deformity associated with osteoarthritis (OA) is one of the most common complications seen in patients referred to orthopaedic surgeons. High tibial osteotomy (HTO) is an accepted method for treatment of medial knee osteoarthritis with varus deformity. The aim of this study was to compare results of osteotomy methods in patients with genu varum (GV) deformity. METHODS: In this cohort study, the sample consisted of 32 patients with genu varum deformity (42 knees) who were divided into two groups and matched according to age and gender. The patients were treated with open or closed wedge osteotomy. After surgery, they were followed-up and compared for 6 months. RESULTS: The sample consisted of 25 women (87.2%) and 7 men (21.8%). Ten patients (31.2%) presented with bilateral deformity. The incidence of complications was the same for both procedures (12.5%); this included one peroneal nerve injury following closed wedge surgery. Overall, patient satisfaction was 87.5% and 75% for the open and closed wedge methods respectively. Operative time, days to full weight bearing, and days to return to routine activities were significantly shorter for patients treated with the open wedge method (p<0.001). CONCLUSION: Open wedged HTO is associated with shorter operating time, shorter recovery time, higher patient satisfaction, and probable lower risk of neurological injury. KEY WORDS: High Tibial Osteotomy, Open Wedge Osteotomy, Closed Wedge Osteotomy. PMID- 25722801 TI - Results of posterior dislocation of elbow associated with bony and soft tissue injury. AB - Elbow trauma is challenging to manage by virtue of its complex articular structure and capsuloligamentous and musculotendinous arrangements. We included 17 patients with elbow dislocation and associated injuries in this study. The study protocol included early elbow reduction and planned fixation of the medial or lateral condyle, coronoid and radial head. The sample was 73% male and 27% female with mean duration follow-up of 8 months, and mean age of 37 years. The mean Mayo Elbow Performance Score was 96 points at conclusion of follow-up, indicating an excellent result in 14 patients. Whenever the radial head was excised, we performed a strong transosseous ligamentous repair of the medial and lateral collateral ligaments. Fixation of the coronoid is essential for elbow stability. A small avulsed fragment can be fixed using an ACL jig. We found this technique very useful. Early planned intervention, stable fixation, and repair provide sufficient stability and enhance functional outcomes. KEY WORDS: elbow dislocation, ligament instability, coronoid fracture. PMID- 25722802 TI - Augmented repair of degenerative tears of tendo achilles using peroneus brevis tendon: early results. AB - Reconstruction of degenerated ruptures of the tendoachilles is a challenge. Ruptured tendons and the remaining tendon ends are abnormal. A number of methods have been described in literature reconstruct the tendoachilles, but with variable results(1). We used peroneus brevis tendon in 20 patients to augment the repair of degenerated tendoachilles tears by creating a dynamic loop as described by Teuffer et al(2). All patients were followed up for atleast 18 months. At the last postoperative visit, 18 out of 20 patients were able to do a toe raise. Eighty-five per cent of patients had excellent or good results and 15% had fair or poor results using modified Rupp scoring. Advantages offered by this procedure are the use of a single incision and mini incision and use of a dispensable tendon such as the peroneus brevis without entirely depending on the damaged tendon for healing. KEY WORDS: Degenerative tear of tendoachilles, augmented repair, peroneus brevis tendon. PMID- 25722803 TI - The NRAMP1 polymorphism as a risk factor for tuberculous spondylitis. AB - In the present study, we analysed the association between the incidence of tuberculous spondylitis with the Natural Resistance Associated Macrophage Protein 1 (NRAMP1, also known as Solute Carrier Family 11a member1) polymorphism by studying the genetic segregation of this polymorphism and the incidence of the disease among members of the West Javanese population undergoing surgery for tuberculous spondylitis at our institution. We compared the distribution of NRAMP1 polymorphism at two specific sites, namely D543N, and 3'UTR, among subjects with pulmonary tuberculosis and tuberculous spondylitis. We found no significant differences in distribution of polymorphism between the two groups, or between pulmonary tuberculosis and tuberculous spondylitis compared to healthy subjects. However, a pattern emerged in that polymorphisms at the two sites seemed to be protective against development of tuberculous spondylitis in our study population. We concluded that in the West Javanese population, there is no association between NRAMP1 polymorphism with the propensity for development of pulmonary tuberculosis or tuberculous spondylitis. In fact, NRAMP1 may provide protection against the development of tuberculous spondylitis. KEY WORDS: tuberculous spondylitis, NRAMP1, polymorphism. PMID- 25722804 TI - Early Functional Outcome of Resection and Endoprosthesis Replacement for Primary Tumor around the Knee. AB - We evaluated functional outcomes for patients who underwent surgery for resection and endoprosthesis replacement for primary tumours around the knee. We used the Musculoskeletal Tumour Society Scoring System (MSTS) for functional evaluations to compare differences between distal femur (DF) and proximal tibia (PT) placements. The study sample included 34 cases of distal femur and 20 cases of proximal tibia endoprosthesis replacement. Primary tumours were classified as follows: 33 osteosarcoma, 20 stage III giant cell tumour (GCT) and one case of mesenchymal chondrosarcoma. The mean MSTS score for both DF and PT endoprosthesis together was 21.13 (70.43%), and The MSTS scores for DF was 21.94 (73.13%) and PT was 19.75 (65.83%) Infection developed in 7 cases and 5 of which were PT endoprosthesis cases. Three deep infections required early, two-stage revision and resulted in poor MSTS scores. We conclude that endoprosthesis replacement for primary bone tumours had early good to excellent functional outcome. There were no differences in functional outcomes when comparing distal femur endoprostheses with proximal tibia endoprostheses. KEY WORDS: functional outcome, bone tumour, knee, and endoprosthesis. PMID- 25722805 TI - Patients with blunt traumatic spine injuries with neurological deficits presenting to an urban tertiary care centre in mumbai: an epidemiological study. AB - INTRODUCTION: Traumatic spine injuries are on the rise. The literature is sparse regarding epidemiology of patients with traumatic spine injuries from this part of the world. OBJECTIVES: To analyse the following in patients with traumatic spine injuries with neurological deficits: demographic and social profile, common modes of injury, pre-hospitalisation practices, region of spine affected, severity of neurological deficit and the lay individuals' awareness about traumatic spine injuries. METHODS: The study sample comprised 52 adult patients with traumatic spine injuries with neurological deficits. We collected data on demographic and social characteristics, mode of injury, pre-hospitalisation treatment, interval between injury and presentation, spine region affected and severity of neurological deficits and patient's knowledge about such injuries. RESULTS: The average patient age was 31.32y. The male: female ratio was 2.25:1, and the most common modes of injury were fall from height, followed by traffic accident. More than half of the patients suffered cervical spine injuries, followed by dorsolumbar spine injuries. Only 9.61% of patients received pre hospitalisation treatment. All patients understood there could be complete functional recovery after treatment for traumatic spine injuries. CONCLUSION: There is a growing need to improve railway and roadway safety equipment and to make it accessible and affordable to the susceptible economically weaker population. Attempts should be made to increase awareness regarding traumatic spine injuries. KEY WORDS: Trauma; Spine; Deficit; Poor; safety; awareness. PMID- 25722806 TI - The In-Vitro Effects of Sea Cucumber (Stichopus sp1) Extract on Human Osteoblast Cell Line. AB - Despite its claimed therapeutic effects, the action of sea cucumber (known as gamat in the Malay language) on human osteoblast cells is still unknown. We performed in vitro studies utilising extract of Stichopus sp1 (gamat) to elucidate its effects on cell viability and functional activity. We found an inverse relationship between gamat concentration and its effect on osteoblast cell viability (p<0.001). Only gamat concentration at 1mg/ml significantly promoted cell viability at day 3 of incubation. There was a trend towards increased osteoblast cell function in the presence of gamat at 5mg/ml and 10mg/ml but this observation was not consistent at different incubation periods. KEY WORDS: Alkaline phosphatase, Stichopus, Sea Cucumbers, Osteoblasts, Tetrazolium Salts. PMID- 25722807 TI - Hand injuries in the oil fields of brunei darussalam. AB - Hands are essential organs and their agility and dexterity are vital to our daily lives. In the present study, we analysed 107 patients who presented at the local hospital with hand injuries sustained in the oil fields, oil industries and related employment sectors from the surrounding regions. All the patients were male and the mean age was 37.89 years (range, 21-61y). Forty-seven (43.93%) patients had simple cut injuries, 14 patients (13.08%) had tendon injuries, 13 patients (12.14%) had amputation of the digit (30.84%) had bone fractures (including 20 (66.66%) open fractures). Only 19 (17.75%) patients were admitted in hospital for further treatment. Ninety-one (85.04%) patients injured within one year of employment and 57(53.27%) patients were not satisfied with instructions and orientation before starting their job. Hand injury is one of the most common injuries in the oil industry and overtime work further increases incidence of this injury. KEY WORDS: Hand injury, trauma, oil field, digital fractures. PMID- 25722808 TI - Comparative study between coaptive film versus suture for wound closure after long bone fracture fixation. AB - BACKGROUND: Coaptive film (i.e., Steri-StripsTM) is an adhesive tape used to replace sutures in wound closure. The use of coaptive film for wound closure after long bone fracture fixation has not been well documented in the literature. METHODS: The aim of this prospective, randomized controlled trial comparing coaptive film with sutures for wound closure after long bone fracture fixation was skin closure time, incidence of wound complications and scar width at 12 week follow-up. Forty-five patients underwent femur fracture fixation (22 patients' wound closed with sutures, 23 with coaptive film). RESULTS: The mean time for skin closure using coaptive film was 171.13 seconds compared to 437.27 seconds using suture. The mean wound lengths in the coaptive film group and suture group were 187.65 mm and 196.73 mm, respectively. One patient in each group had wound complications. CONCLUSION: Coaptive film is a time-saving procedure for skin closure following long bone fracture fixation. There is no difference in the incidence of wound complications and scar width between these two methods of skin closure. PMID- 25722809 TI - Outcome of surgical treatment of pelvic osteosarcoma: hospital universiti sains malaysia experience. AB - We reviewed the surgical treatment and outcomes of 13 patients with pelvic osteosarcoma treated in our centre in the past decade. The study sample included 9 males and 4 females with a mean age of 28.1 years. Four patients had ileal lesions, five had acetabulum lesions, one had a ischiopubis lesion, and three had involvement of the whole hemipelvis. Seven patients presented with distant metastases at diagnosis. Limb salvage was performed in 6 patients and amputation in 7. In 60% of cases in the limb salvage surgery group, we attempted wide resection with positive microscopic margin compared to only 16.7% in the amputation group. Local recurrence was higher in the limb salvage group. Overall survival was 18 months for mean follow up of 14.8 months. Median survival was 19 months in the limb salvage group compared to 9 months in amputation group. The outcome of surgical treatment of pelvic osteosarcoma remains poor despite advancements in musculoskeletal oncology treatment. KEY WORDS: Pelvic osteosarcoma, limb salvage surgery, hemipelvectomy, margins, oncologic outcomes. PMID- 25722810 TI - Osteomyelitis of scapula with secondary septic arthritis of shoulder joint in a six month old child. AB - We report a case of delayed diagnosis of osteomyelitis of the scapula extending to glenoid, with secondary septic arthritis of glenohumeral joint in a 6-month old female infant. We performed urgent arthrotomy of the shoulder joint through an anterior approach with drainage of pus from the scapula through a posterior approach and prescribed intravenous antibiotics. Diagnosis was delayed as the patient initially presented with pneumonia, for which she was treated in the neonatal intensive care unit; at that time, all medical efforts were directed toward saving her life. Had the diagnosis been made earlier, septic arthritis of the shoulder might have been prevented. Diagnosis of septic shoulder arthritis is rare and difficult, requiring a high index of suspicion. KEY WORDS: septic arthritis, infection, scapular osteomyelitis. PMID- 25722811 TI - Spontaneous subtrochanteric femoral stress fracture related to alendronate : a case report. AB - Spontaneous atypical fractures of the femur have been reported in patients on long-term antiresorptive bisphosphonate therapy. Here, we report a case of subtrochanteric stress fracture in a seventy-year-old female patient on long-term alendronate therapy, and accompanying management challenges. Potential measures to prevent this complication of antiresorptive treatment for osteoporosis include the following: setting strict criteria for prescribing antiresorptive therapy, limiting the duration of continuous antiresorptive therapy, and increasing the use of bone anabolic agents. KEY WORDS: atypical femoral fractures, alendronate, osteoporosis. PMID- 25722812 TI - Isolated post-traumatic radial head dislocation, a rare and easily missed injury a case report. AB - Dislocation of the head of the radius may be either congenital, an isolated injury or more commonly part of a complex injury to the elbow such as the Monteggia fracturedislocation. Isolated traumatic radial head dislocation without associated injuries in children is a rare and easily missed condition. We report such a case in a 7-year-old boy without any associated injuries or co-morbid conditions. Initially the diagnosis was missed, and 6 weeks later open reduction was performed with annular ligament reconstruction surgery. At the one-year follow up, the patient had returned to most normal activities, showing only slight terminal restriction of pronation. We discuss the injury mechanism and management for the Monteggia fracturedislocation and review the available literature. KEY WORDS: radial head dislocation, traumatic, Monteggia fracturedislocation. PMID- 25722813 TI - Modified pectoralis major tendon transfer for reanimation of elbow flexion as a salvage procedure in complete brachial plexus injury: a case report. AB - Traumatic brachial plexus injuries rarely recover spontaneously and if the window period for neurotisation has elapsed, the only option for restoration of function lies in a salvage procedure. Many such salvage procedures have been described in the literature with variable functional results. We report the case of a 16-year old boy who presented after unsuccessful treatment for a complete brachial plexus injury; we performed a pectoralis major tendon transfer to attain elbow flexion. Postoperatively, the elbow was splinted with flexion at 100 degrees . After 4 weeks of immobilization the splint was removed and the patient could actively flex his elbow from 30 degrees to 100 degrees . KEY WORDS: brachial plexus injury, salvage procedure, pectoralis major tendon transfer. PMID- 25722814 TI - An unusual case of "locking" of the knee four years post fixation of an open supracondylar femur fracture. AB - The introduction of locking plate devices have increased the number of viable options for fracture fixation. An understanding of the indications and contraindications and technique limitations are important to minimise associated adverse events. We report the case of a patient who presented with a single broken screw head four years following fixation of a supracondylar femur fracture, resulting in symptoms of migratory knee pain and locking. He underwent implant and foreign body removal and made an unremarkable recovery postoperatively. With the increasing use of locking plate devices, we are likely to see more such complications. KEY WORDS: bone plates, bone screws, fractures. PMID- 25722815 TI - Combined avulsion fracture of the tibial tuberosity and lateral tibial plateau in an adolescent: case report. AB - Avulsion of the tibial tuberosity is uncommon. It is usually an athletic injury, accounting for less than 3% of all epiphyseal injuries. We report the case of an avulsion fracture of the tibial tuberosity with unusual articular involvement of the lateral tibial plateau treated with open reduction and internal fixation using cancellous screws. The result was excellent, with complete union of the fracture site, full range of movement at three months and return to normal athletic activity within six months with no complications. KEY WORDS: tibial tuberosity; avulsion fracture; tibial plateau; adolescent. PMID- 25722816 TI - Use of Beach Shoes for Foot Protection during the Bangkok Flood of 2011. AB - BACKGROUND: Foot injury was common as a result of the Bangkok flood of 2011. In the future, this type of injury should be prevented to lessen the burden during a disaster. OBJECTIVES: The study was performed to ascertain what type of footwear is appropriate for volunteer rescue workers during a flood. MATERIAL AND METHODS: The study was carried out during the flood in November 2011 at Siriraj Hospital. There were 15 volunteers enrolled in the study. None of the volunteers had any foot deformity or injury before the study. Participants were divided into 3 groups of 5 volunteers: group A, the barefoot group; group B, the high top shoe group; and group C, the beach shoe group. All volunteers worked in the areas close to Siriraj Hospital and were followed up after 5 days of rescue work. Prevalence of foot and ankle injuries, satisfaction regarding work conditions and willingness to use the shoes were subjectively evaluated. Wearing of beach shoes during rescue was satisfactory during the early phase of the flood. RESULTS: The age range of volunteers was 20-28. In the group A, most volunteers were barely satisfied with conducting rescue work in water with bare feet, that bare feet were good for working on a wet surface and were 'just satisfied' to not satisfied that bare feet were good for work on dry surfaces. In group B, most of the volunteers had opinions similar to group A with the exception that they felt better while they were working on dry surfaces. In group C, most volunteers were significantly more satisfied under all three conditions. Foot injury occurred in 2 volunteers from group A. CONCLUSION: Beach shoes offer adequate foot protection during flood rescue. PMID- 25722817 TI - Is closed manipulative reduction and percutaneous Kirschner wiring of supracondylar humeral fracture in children as day-care surgery a safe procedure ? AB - INTRODUCTION: Supracondylar fracture of the humerus is a common injury in children. It accounts for 60% of fractures around the elbow children. If the fracture is not treated properly it may give rise to many complications like malunion, Volkmann's ischemic contracture, nerve injury, arterial injury, skin slough, heterotopic bone formation , and stiffness of elbow. The management of displaced supracondylar fracture of the elbow is one of the most difficult of the many fractures seen in children. The purpose of the study was to evaluate the anatomical and functional results of treatment of supracondylar fractures of humerus with closed reduction and percutaneous 'K' wire fixation as a day care procedure and record associated complications, thus decreasing the cost of treating these fractures and hospitalization. METHODS: Fifty displaced closed extension type supracondylar fractures (Gartland's type III) of the humerus in children were treated by closed reduction and percutaneous fixation with Kirschner wires. All the patients selected for this study had been treated in a day care unit and were discharged in the same evening and followed up at 3 and 6 weeks and 3 months. Open fractures, fractures with neurovascular complications and children older than 15 yrs were excluded. The final results were evaluated by Flynn's criteria. RESULTS: The majority (72%), of the patients had fracture displaced posteomedially, Fourty one of the fifty patients had satisfactory results. The majority of the patients were male, and the average age was 8-9 years. CONCLUSION: Percutaneous fixation of supracondylar humerus done as a day care procedure is an acceptable modality of treatment and reduces the duration of hospital stay for the patient. KEY WORDS: Supracondylar humerus, K-wire fixation, day care procedure. PMID- 25722818 TI - Treatment of femoral neck fractures: unipolar versus bipolar hemiarthroplasty. AB - BACKGROUND AND OBJECTIVE: Intracapsular femoral neck fractures are common in the elderly population. To avoid the poor outcome of internal fixation and for early mobilization, hemiarthroplasty is performed. However, there is inadequate evidence to support the choice between unipolar or bipolar hemiarthroplasty. The aim of this study was to compare the outcome of unipolar with the bipolar prosthesis in geriatric patients. METHODS: Forty-one patients above 60 years of age and an acute displaced fracture of the femoral neck were randomly allocated to treatment by either unipolar or bipolar hemiarthroplasty, in the Department of Orthopaedics, between September 2009 and October 2012. Functional outcome was assessed and compared using Harris hip score and radiological parameters with a follow-up of one year. RESULTS: The two groups of patients with mean age of 67.3 in bipolar group and 75.6 in unipolar group did not differ in their pre-injury characteristics and perioperative parameters. The mean Harris hip score in bipolar and unipolar groups was 86.18+/-12.18 and 79.79+/-15.55, respectively (p=0.183); range of motion was 210.63+/-28.39 and 181.58+/-37(p=0.015) with bipolar and unipolar groups, respectively. Functional activities were better in the bipolar group. Complications like painful hip, posterior dislocation, periprosthetic fracture and acetabular erosion were encountered in unipolar prostheses. CONCLUSION: The use of bipolar endoprosthesis in the management of displaced femoral neck fractures in the elderly was associated with better mean Harris hip score and incidence of complications was limited. Hence, bipolar would be a better option in elderly patients with fracture neck of femur. KEY WORDS: Unipolar; Bipolar; Hemiarthroplasty. PMID- 25722819 TI - Femoral Shaft Cortical Pathology associated with longterm Alendronate Therapy: A New Classification. AB - There are reported cases of cortical reaction over the tension side of the normal femoral shafts in patients on long term treatment with alendronate, leading to subsequent femoral shaft fractures. We performed a retrospective review of patients with low-energy femoral shaft fracture on alendronate, admitted to our institution during the period 2004 to May 2009. The presence of radiological changes of cortical hypertrophy with or without Looser's zone over the tension side of the femoral bone (normal limb) was determined and correlated with clinical symptoms. Thirteen patients were identified. Average duration of alendronate use was 6.5 +/- 3.3 years (ranges, two to 10 years). These radiological changes were noted in four patients. Average duration of alendronate usage in these four patients was 6.5 +/- 2.4 years (ranges, 5 to10 years). Prodromal thigh pain was present in a patient, who had cortical hypertrophy with the presence of a Looser's zone traversing the cortex on the femoral shaft. One patient had Looser's zone limited at the lateral hypertrophied cortex without prodromal pain. The interobserver kappa coefficient was 0.96. A femoral radiograph should be performed in all patients who are on long-term alendronate therapy who present with thigh pain. We propose a new grading system based on our observation of the radiological features in these four cases. This new grading of the radiological spectrum of femoral shaft cortical pathology has the potential to stratify the risk of low energy femoral fracture for patients treated with long-term alendronate therapy. KEY WORDS: Femur, Cortical Hypertrophy, Looser Zone, Alendronate. PMID- 25722820 TI - Radiofrequency-induced intradiscal nucleoplasty chronic low back pain secondary to lumbar disc herniation. AB - We set out to assess the efficacy of radiofrequency-induced intradiscal nucleoplasty in reducing pain in symptomatic patients with MRI-defined lumbar disc herniation and their satisfaction with the procedure. We compared the patients' pain intensity and severity of disability scores before and after undergoing the procedure in a retrospective questionnaire. These patients reported statistically significant reduction of pain intensity and disability level after the procedure. We conclude that radiofrequencyinduced intradiscal nucleoplasty is an acceptable alternative minimally invasive procedure in relieving the symptoms of patients with lumbar disc herniation. KEY WORDS: Radiofrequency-induced intradiscal nucleoplasty, coblation therapy, percutaneous lumbar disc decompression, intervertebral disc herniation, low back pain. PMID- 25722821 TI - Recurrent admissions for diabetic foot complications. AB - Diabetic foot complications are a significant source of morbidity and mortality. Patients who undergo recurrent admissions for the same diabetic foot problems represent a difficult subgroup to treat. From July 2007 to June 2008, there were 38 such patients who were admitted recurrently. Eighteen patients (47%) were re admitted because of previous refusal of surgical treatment. Eighteen patients (47%) received treatment as necessary but were still readmitted for recurrent infection at the same wound site. Assessment of patients' compliance to outpatient treatment was found to be generally lacking. As a significant proportion were re-admitted because of previous refusal of surgery, a trained counselor may be suitable in counselling patients for debridement or amputation surgery. KEY WORDS: Diabetic foot, complications, ulcer, abscess, amputation. PMID- 25722822 TI - Hip pain in the paediatric age group - transient synovitis versus septic arthritis. AB - Hip pain, in the paediatric population, is a common complaint and a cause for admission. There are several diagnoses one has to keep in mind, when making the differential diagnosis, as the treatment for each can be quite different. Often, the radiographs obtained for these patients turn up normal. Hence one has to rely on clinical findings, laboratory parameters, and possibly an ultrasound investigation in order to clinch the diagnosis and initiate the appropriate treatment. KEY WORDS: Paediatric, hip, pain, normal radiographs. PMID- 25722823 TI - Improvised suction apparatus for closure of large soft tissue deficit. AB - BACKGROUND: Vacuum Assisted Closure (VAC) is an established method that can be used in order to cover for soft tissue defects. This study focuses on the use of a modified suction machine in the form of an aquarium pump as an economical substitute for the VAC dressing. The improvised suction apparatus was a regular aquarium pump, which was altered in order to draw air in instead of expelling it. The patients were followed-up for a period of three weeks in the wards. METHODS: VAC was applied over the soft tissue defects. Sterilized foam was used and attached to a French 16 suction tube. A tight seal was ensured using a sterile adhesive covering. The tube was then attached to the modified vacuum machine, which maintained the negative pressure. Case Studies : Three cases are presented in this study. The first and second cases involved pediatric patients who sustained degloving injuries of the foot. The third case involved a 23 year-old male who sustained an open patellar fracture due to a motorcycle accident. The dressing was changed every five days and the progress was documented using photographs. The patients were placed on VAC dressing for a period of two weeks. On the 14th day, good granulation was evident on the soft tissue defects hence; the patients were scheduled and subsequently underwent splitthickness skin grafting. Discussion : The modified suction pump is an effective and economical alternative to the VAC machine for the purpose of providing constant negative pressure to promote tissue granulation and healing for large tissue defects. However, in order to establish the efficacy of the proposed intervention, the modified suction pump should be tested on more cases. KEY WORDS: Vacuum-assisted Closure (VAC) System, modified VAC, aquarium pump, soft tissue defect coverage, alternative negative pressure source. PMID- 25722824 TI - Bilateral traumatic fracture of neck of femur in a child: a case report. AB - Bilateral femoral neck fractures are rare in the pediatric age group, and only a few cases have been reported following major trauma in children. A 9-year old girl presented with bilateral femoral neck fractures following a motor vehicle accident. The patient was managed with early operative fixation of the fractures with a successful outcome. This case highlights the importance of awareness of the occurrence of bilateral femoral neck fractures in the polytrauma patients. This case is presented due to its rarity. PMID- 25722825 TI - Free non-vascularized fibular graft for treatment of pediatric traumatic radial bone loss: a case report. AB - Various methods, such as vascularized bone transfers, Illizarov bone transport, allogenic bone grafts, bone graft substitutes, are available in treating traumatic bone loss. Free non-vascularised fibular graft is an autografting method that only requires minimal facilities or expertise. However, this method is not popularized due to its avascular property and there is not many reports regarding its use in treating a large traumatic bone loss. We reported a case in our center to demonstrate its possibility of successfully treating the traumatic radial bone loss in pediatric patient. Patient had good recovery with the regain of good range of movement of forearm and there is no harvest site morbidity after two years of follow up. KEY WORDS: Free non-vascularized fibular graft, pediatric radial bone loss. PMID- 25722826 TI - Ipsilateral femoral fracture non-union and delayed union treated by hybrid plate nail fixation and vascularized fibula bone grafting: a case report. AB - Non-union is a well recognized complication of femoral neck fractures. The decision whether to attempt fracture fixation or to resort to hip replacement is particularly difficult in patients in the borderline age group in whom complex attempts at gaining union may fail and later present a difficult revision. On the other hand the patient may be young enough that arthroplasty best be avoided . Besides, presence of ipsilateral femoral shaft fracture with delayed union in addition to the femoral neck non-union will pose major problems at operation. We share our experience in treating a femoral neck fracture non-union with ipsilateral femoral shaft delayed union in the shaft and in the distal femur in a fifty years old patient. The fracture was treated with an angle blade plate and supracondylar nail supplemented with a free vascularised fibular bone grafting and autologous cancellous graft. There was radiological union at fourth month. At sixth months, the patient was free of pain and able to walk without support. Thus, we would like to suggest that vascularised fibula bone grafting with supracondylar nailing is a viable option for this pattern of fracture. KEY WORDS: Vascularized fibular bone graft, neck of femur, femoral shaft fracture, non union. PMID- 25722827 TI - Bilateral lower limb amputations in a nigerian child following high-voltage electrical burns injury: a case report. AB - The human body conducts electricity very well. Direct contact with electric current can be lethal. The passage of electric current through the body is capable of producing a wide spectrum of injuries, including serious damage to the heart, brain, skin and muscles. Naked high-voltage electric cables negligently abandoned in residential, commercial and industrial areas are a recipe for disaster. This is a case report of a 5-year girl child who had bilateral lower limb gangrene following electrical burns injury. She presented with a fourday history of electrical burns injuries of both lower limbs including both gluteal regions, associated with a three-day history of fever, with full thickness burns and sepsis, ultimately leading to bilateral above knee guillotine amputations. KEY WORDS: High-voltage electric current, bilateral lower limb gangrene, bilateral above knee amputation. PMID- 25722828 TI - Pilomatrixoma of left shoulder in an elderly female: a case report. AB - We report a huge pilomatrixoma of the left shoulder in an elderly female, raising fear of malignancy. Magnetic Resonance Imaging delineated the swelling and wide surgical excision was performed. Post operative recovery was uneventful. Long term follow up is necessary in view of the possibility of recurrence and malignant transformation. KEY WORDS: Pilomatrixoma, Pilomatricoma, Calcifying Epithelioma of Malherbe, Shoulder, Upper Limb, Elderly, Female. PMID- 25722829 TI - Quantitative Analysis of TDLUs using Adaptive Morphological Shape Techniques. AB - Within the complex branching system of the breast, terminal duct lobular units (TDLUs) are the anatomical location where most cancer originates. With aging, TDLUs undergo physiological involution, reflected in a loss of structural components (acini) and a reduction in total number. Data suggest that women undergoing benign breast biopsies that do not show age appropriate involution are at increased risk of developing breast cancer. To date, TDLU assessments have generally been made by qualitative visual assessment, rather than by objective quantitative analysis. This paper introduces a technique to automatically estimate a set of quantitative measurements and use those variables to more objectively describe and classify TDLUs. To validate the accuracy of our system, we compared the computer-based morphological properties of 51 TDLUs in breast tissues donated for research by volunteers in the Susan G. Komen Tissue Bank and compared results to those of a pathologist, demonstrating 70% agreement. Secondly, in order to show that our method is applicable to a wider range of datasets, we analyzed 52 TDLUs from biopsies performed for clinical indications in the National Cancer Institute's Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project and obtained 82% correlation with visual assessment. Lastly, we demonstrate the ability to uncover novel measures when researching the structural properties of the acini by applying machine learning and clustering techniques. Through our study we found that while the number of acini per TDLU increases exponentially with the TDLU diameter, the average elongation and roundness remain constant. PMID- 25722830 TI - Evaluation of shear bond strength between dual cure resin cement and zirconia ceramic after thermocycling treatment. AB - PURPOSE: This study was performed to evaluate shear bond strength (SBS) between three dual-cured resin cements and silica coated zirconia, before and after thermocycling treatment. MATERIALS AND METHODS: Sixty specimens were cut in 15 * 2.75 mm discs using zirconia. After air blasting of 50 um alumina, samples were prepared by tribochemical silica coating with RocatecTM plus. The specimens were divided into three groups according to the dual-cure resin cement used: (1) Calibra silane+Calibra(r), (2) Monobond S+Multilink(r) N and (3) ESPN sil+RelyXTM Unicem Clicker. After the resin cement was bonded to the zirconia using a Teflon mold, photopolymerization was carried out. Only 10 specimens in each group were thermocycled 6,000 times. Depending on thermocycling treatment, each group was divided into two subgroups (n=10) and SBS was measured by applying force at the speed of 1 mm/min using a universal testing machine. To find out the differences in SBS according to the types of cements and thermocycling using the SPSS, two way ANOVA was conducted and post-hoc analysis was performed by Turkey's test. RESULTS: In non-thermal aged groups, SBS of Multilink group (M1) was higher than that of Calibra (C1) and Unicem (U1) group (P<.05). Moreover, even after thermocycling treatment, SBS of Multilink group (M2) was higher than the other groups (C2 and U2). All three cements showed lower SBS after the thermocycling than before the treatments. But Multilink and Unicem had a significant difference (P<.05). CONCLUSION: In this experiment, Multilink showed the highest SBS before and after thermocycling. Also, bond strengths of all three cements decreased after thermocycling. PMID- 25722831 TI - Assessment of swallowing and masticatory performance in obturator wearers: a clinical study. AB - PURPOSE: To assess function by identifying changes in swallowing and masticatory performance in maxillary obturator prosthesis wearers. MATERIALS AND METHODS: Sixty subjects were recruited for the study, of which 20 were obturator wearers, 20 were completely dentulous and 20 had removable partial/complete dentures with similar Eichner's Index. Swallowing ability was evaluated with and without obturator using the "Water Drinking Test"; Masticatory performance was evaluated with the Sieve test; and maximum occlusal force was recorded with the help of a digital bite sensor. The data was analyzed using the Statistical Package for Social Science version 15.0 with a confidence level at 95%. RESULTS: Profile, behavior of drinking and time taken to drink were significantly improved (P<.001) in subjects after wearing obturator. Masticatory performance was not significantly different (P=.252) in obturator wearer when compared with dentulous or removable partial/complete denture wearer, but significantly (P<.001) high inter group difference in maximum occlusal force existed. Correlation between masticatory performance and maximum occlusal force was not significant (P=.124). CONCLUSION: Swallowing ability was significantly improved after wearing obturator but masticatory performance was not significantly different from those having similar occlusal support zone in their dentition. PMID- 25722832 TI - Evaluation of the resin cement thicknesses and push-out bond strengths of circular and oval fiber posts in oval-shapes canals. AB - PURPOSE: The aim of this study was to evaluate whether the push-out bond strength varies between oval and circular fiber posts, and to examine the effect on the resin cement thicknesses around the posts. MATERIALS AND METHODS: Eighteen mandibular premolar roots were separated into two groups for oval and circular fiber posts systems. Post spaces were prepared and fiber posts were luted to the post spaces. Roots were cut horizontally to produce 1-mm-thick specimens. Resin cement thicknesses were determined with a metallographic optical microscope and push-out tests were done. RESULTS: No significant differences were observed in terms of push-out bond strength between the oval and circular fiber posts (P>.05) The resin cement thicknesses of the oval posts were greater than those of the circular posts group in the coronal, middle and apical specimens (P<.05). CONCLUSION: In the light of these results, it can be stated that resin cement thickness does not affect the push-out bond strength. PMID- 25722833 TI - Cytotoxicity of temporary cements on bovine dental pulp-derived cells (bDPCs) using realtime cell analysis. AB - PURPOSE: To evaluate the cytotoxicity of temporary luting cements on bovine dental pulp-derived cells (bDPCs). MATERIALS AND METHODS: Four different temporary cements were tested: Rely X Temp E (3M ESPE), Ultratemp (Ultradent), GC Fuji Temp (GC), and Rely X Temp NE (3M ESPE). The materials were prepared as discs and incubated in Dulbecco's modified eagle's culture medium (DMEM) for 72 hours according to ISO 10993-5. A real-time cell analyzer was used to determine cell vitality. After seeding 200 uL of the cell suspensions into the wells of a 96-well plate, the bDPCs were cured with bioactive components released by the test materials and observed every 15 minutes for 98 hours. One-way ANOVA and Tukey-Kramer tests were used to analyze the results of the proliferation experiments. RESULTS: All tested temporary cements showed significant decreases in the bDPCs index. Rely X Temp E, GC Fuji Temp, and Rely X Temp NE were severely toxic at both time points (24 and 72 hours) (P<.001). When the cells were exposed to media by Ultratemp, the cell viability was similar to that of the control at 24 hours (P>.05); however, the cell viability was significantly reduced at 72 hours (P<.001). Light and scanning electron microscopy examination confirmed these results. CONCLUSION: The cytotoxic effects of temporary cements on pulpal tissue should be evaluated when choosing cement for luting provisional restorations. PMID- 25722834 TI - In vitro study of fracture strength of provisional crown materials. AB - PURPOSE: The purpose of this report was to evaluate the effect of the fabrication method and material type on the fracture strength of provisional crowns. MATERIALS AND METHODS: A master model with one crown (maxillary left second premolar) was manufactured from Cr-Co alloy. The master model was scanned, and the data set was transferred to a CAD/CAM unit (Yenamak D50, Yenadent Ltd, Istanbul, Turkey) for the Cercon Base group. For the other groups, temporary crowns were produced by direct fabrication methods (Imident, Temdent, Structur Premium, Takilon, Systemp c&b II, and Acrytemp). The specimens were subjected to water storage at 37C for 24 hours, and then they were thermocycled (TC, 5000*, 5 55C) (n=10). The maximum force at fracture (Fmax) was measured in a universal test machine at 1 mm/min. Data was analyzed by non-parametric statistics (alpha=.05). RESULTS: Fmax values varied between 711.09-1392.1 N. In the PMMA groups, Takilon showed the lowest values (711.09 N), and Cercon Base showed the highest values (959.59 N). In the composite groups, Structur Premium showed the highest values (1392.1 N), and Acrytemp showed the lowest values (910.05 N). The composite groups showed significantly higher values than the PMMA groups (P=.01). CONCLUSION: Composite-based materials showed significantly higher fracture strengths than PMMA-based materials. The CAD-CAM technique offers more advantages than the direct technique. PMID- 25722835 TI - The influence of saliva pH value on the retention and durability of bar-clip attachments. AB - PURPOSE: The aim of this study was to compare the durability and retention of 4 types of attachments placed over computer aided design/computer aided manufacturing (CAD/CAM) titanium bars when subjected to different pH conditions. MATERIALS AND METHODS: Four commercially available attachments were investigated: Hader Yellow, Hader Red, Ackerman Gold and Ackerman Stainless Steel. These attachments and Ackerman CAD/CAM titanium bars were placed in 2 vessels containing different artificial saliva solutions (pH 7/pH 4) at 37C for one month to simulate corrosion conditions, and they were then subjected to mechanical testing (5400 cycles of insertion and removal). RESULTS: The results revealed that there were significant differences in the average values of insertion/removal force due to the pH (F (1, 24)=9.207, P<.05) and the type of attachment (F (3, 24)=11.742, P<.05). CONCLUSION: More acidic pH values were found to have a negative influence on the retention capacity of the attachments. PMID- 25722836 TI - Mechanical and interfacial characterization of laser welded Co-Cr alloy with different joint configurations. AB - PURPOSE: The mechanical and interfacial characterization of laser welded Co-Cr alloy with two different joint designs. MATERIALS AND METHODS: Dumbbell cast specimens (n=30) were divided into 3 groups (R, I, K, n=10). Group R consisted of intact specimens, group I of specimens sectioned with a straight cut, and group K of specimens with a 45 degrees bevel made at the one welding edge. The microstructure and the elemental distributions of alloy and welding regions were examined by an SEM/EDX analysis and then specimens were loaded in tension up to fracture. The tensile strength (TS) and elongation (epsilon) were determined and statistically compared among groups employing 1-way ANOVA, SNK multiple comparison test (alpha=.05) and Weibull analysis where Weibull modulus m and characteristic strength sigmaomicron were identified. Fractured surfaces were imaged by a SEM. RESULTS: SEM/EDX analysis showed that cast alloy consists of two phases with differences in mean atomic number contrast, while no mean atomic number was identified for welded regions. EDX analysis revealed an increased Cr and Mo content at the alloy-joint interface. All mechanical properties of group I (TS, epsilon, m and sigmaomicron) were found inferior to R while group K showed intermediated values without significant differences to R and I, apart from elongation with group R. The fractured surfaces of all groups showed extensive dendritic pattern although with a finer structure in the case of welded groups. CONCLUSION: The K shape joint configuration should be preferred over the I, as it demonstrates improved mechanical strength and survival probability. PMID- 25722837 TI - Effect of light-curing, pressure, oxygen inhibition, and heat on shear bond strength between bis-acryl provisional restoration and bis-acryl repair materials. AB - PURPOSE: This study aimed to discover a way to increase the bond strength between bis-acryl resins, using a comparison of the shear bond strengths attained from bis-acryl resins treated with light curing, pressure, oxygen inhibition, and heat. MATERIALS AND METHODS: Self-cured bis-acryl resin was used as both a base material and as a repair material. Seventy specimens were distributed into seven groups according to treatment methods: pressure - stored in a pressure cooker at 0.2 Mpa; oxygen inhibition- applied an oxygen inhibitor around the repaired material,; heat treatment - performed heat treatment in a dry oven at 60C, 100C, or 140C. The shear bond strength was measured with a universal testing machine, and the shear bond strength (MPa) was calculated from the peak load of failure. A comparison of the bond strength between the repaired specimens was conducted using one-way ANOVA and Tukey multiple comparison tests (alpha=.05). RESULTS: There were no statistically significant differences in the shear bond strength between the control group and the light curing, pressure, and oxygen inhibition groups. However, the heat treatment groups showed statistically higher bond strengths than the groups treated without heat, and the groups treated at a higher temperature resulted in higher bond strengths. Statistically significant differences were seen between groups after different degrees of heat treatment, except in groups heated at 100C and 140C. CONCLUSION: Strong bonding can be achieved between a bis-acryl base and bis-acryl repair material after heat treatment. PMID- 25722838 TI - A torque-measuring micromotor provides operator independent measurements marking four different density areas in maxillae. AB - PURPOSE: Bone density at implant placement site is a key factor to obtain the primary stability of the fixture, which, in turn, is a prognostic factor for osseointegration and long-term success of an implant supported rehabilitation. Recently, an implant motor with a bone density measurement probe has been introduced. The aim of the present study was to test the objectiveness of the bone densities registered by the implant motor regardless of the operator performing them. MATERIALS AND METHODS: A total of 3704 bone density measurements, performed by means of the implant motor, were registered by 39 operators at different implant sites during routine activity. Bone density measurements were grouped according to their distribution across the jaws. Specifically, four different areas were distinguished: a pre-antral (between teeth from first right maxillary premolar to first left maxillary premolar) and a sub-antral (more distally) zone in the maxilla, and an interforaminal (between and including teeth from first left mandibular premolar to first right mandibular premolar) and a retroforaminal (more distally) zone in the lower one. A statistical comparison was performed to check the inter-operators variability of the collected data. RESULTS: The device produced consistent and operator independent bone density values at each tooth position, showing a reliable bone density measurement. CONCLUSION: The implant motor demonstrated to be a helpful tool to properly plan implant placement and loading irrespective of the operator using it. PMID- 25722839 TI - Influence of shape and finishing on the corrosion of palladium-based dental alloys. AB - PURPOSE: The purpose of this study was to evaluate the effects of the surface treatment and shape of the dental alloy on the composition of the prosthetic work and its metallic ion release in a corrosive medium after casting. MATERIALS AND METHODS: Orion Argos (Pd-Ag) and Orion Vesta (Pd-Cu) were used to cast two crowns and two disks. One of each was polished while the other was not. Two as-received alloys were also studied making a total of 5 specimens per alloy type. The specimens were submersed for 7 days in a lactic acid/sodium chloride solution (ISO standard 10271) and evaluated for surface structure characterization using SEM/EDAX. The solutions were quantitatively analysed for the presence of metal ions using ICP-MS and the results were statistically analysed with one-way ANOVA and a Tukey post-hoc test. RESULTS: Palladium is released from all specimens studied (range 0.06-7.08 ug.cm(-2).week(-1)), with the Pd-Cu alloy releasing the highest amounts. For both types of alloys, ion release of both disk and crown pairs were statistically different from the as-received alloy except for the Pd Ag polished crown (P>.05). For both alloy type, disk-shaped pairs and unpolished specimens released the highest amounts of Pd ions (range 0.34-7.08 ug.cm( 2).week(-1)). Interestingly, in solutions submerged with cast alloys trace amounts of unexpected elements were measured. CONCLUSION: Shape and surface treatment influence ion release from dental alloys; polishing is a determinant factor. The release rate of cast and polished Pd alloys is between 0.06-0.69 ug.cm(-2).week(-1), which is close to or exceeding the EU Nickel Directive 94/27/EC compensated for the molecular mass of Pd (0.4 ug.cm(-2).week(-1)). The composition of the alloy does not represent the element release, therefore we recommend manufacturers to report element release after ISO standard corrosion tests beside the original composition. PMID- 25722840 TI - Effects of counter torque and transposition (transfer) of installed implants timing on their integration in dog tibia. AB - PURPOSE: The purpose of this research was to evaluate the amount of reosseointegration after counter torquing (reverse torque) and transposing the installed implants at different times. MATERIALS AND METHODS: This study was done on ten tibiae of five cross-bred dogs. At the first day one implant was installed in each tibia. After one week half of the implants were randomly counter torqued (1WCT) and the other half were explanted and reimplanted in a new juxtaposition site (transposed)(1WT). At the same time three new implants were installed in each dog, one of them was considered as one week control (1WC) and remaining two as 8 week groups (8WCT&8WT). After eight weeks the 1WCT and 1WT implants were loosened by counter torque and the quantity of needed force for liberation was measured with the digital device (BGI). At the same time one implant was installed in each dog as eight week control (8WC) and the same protocol was repeated for 8 week groups after another 8 weeks. RESULTS: All implants were osseointegrated. Mean quantities of osseointegration in case groups indicated better amounts rather than control groups. CONCLUSION: Counter torque or transposition of the installed implants one week or eight weeks after the implantation did lead to osseointegration. PMID- 25722841 TI - Comparative study of the shear bond strength of various veneering materials on grade II commercially pure titanium. AB - PURPOSE: To compare the shear bond strength of various veneering materials to grade II commercially pure titanium (CP-Ti). MATERIALS AND METHODS: Thirty specimens of CP-Ti disc with 9 mm diameter and 10 mm height were divided into three experimental groups. Each group was bonded to heat-polymerized acrylic resin (Lucitone 199), porcelain (Triceram), and indirect composite (Sinfony) with 7 mm diameter and 2 mm height. For the control group (n=10), Lucitone 199 were applied on type IV gold alloy castings. All samples were thermocycled for 5000 cycles in 5-55C water. The maximum shear bond strength (MPa) was measured with a Universal Testing Machine. After the shear bond strength test, the failure mode was assessed with an optic microscope and a scanning electron microscope. Statistical analysis was carried out with a Kruskal-Wallis Test and Mann-Whitney Test. RESULTS: The mean shear bond strength and standard deviations for experimental groups were as follows: Ti-Lucitone 199 (12.11 +/- 4.44 MPa); Ti Triceram (11.09 +/- 1.66 MPa); Ti-Sinfony (4.32 +/- 0.64 MPa). All of these experimental groups showed lower shear bond strength than the control group (16.14 +/- 1.89 MPa). However, there was no statistically significant difference between the Ti-Lucitone 199 group and the control group, and the Ti-Lucitone 199 group and the Ti-Triceram group. Most of the failure patterns in all experimental groups were adhesive failures. CONCLUSION: The shear bond strength of veneering materials such as heat-polymerized acrylic resin, porcelain, and indirect composite to CP-Ti was compatible to that of heatpolymerized acrylic resin to cast gold alloy. PMID- 25722842 TI - The path of placement of a removable partial denture: a microscope based approach to survey and design. AB - This article reviews the topic of how to identify and develop a removable partial denture (RPD) path of placement, and provides a literature review of the concept of the RPD path of placement, also known as the path of insertion. An optimal RPD path of placement, guided by mutually parallel guide planes, ensures that the RPD flanges fit intimately over edentulous ridge structures and that the framework fits intimately with guide plane surfaces, which prevents food collecting empty spaces between the intaglio surface of the framework and intraoral surfaces, and ensures that RPD clasps engage adequate numbers of tooth undercuts to ensure RPD retention. The article covers topics such as the causes of obstructions to RPD intra-oral seating, the causes of food collecting empty spaces that may exist around an RPD, and how to identify if a guide plane is parallel with the projected RPD path of placement. The article presents a method of using a surgical operating microscope, or high magnification (6-8x or greater) binocular surgical loupes telescopes, combined with co-axial illumination, to identify a preliminary path of placement for an arch. This preliminary path of placement concept may help to guide a dentist or a dental laboratory technician when surveying a master cast of the arch to develop an RPD path of placement, or in verifying that intra-oral contouring has aligned teeth surfaces optimally with the RPD path of placement. In dentistry, a well-fitting RPD reduces long-term periodontal or structural damage to abutment teeth. PMID- 25722843 TI - Immunity to poliovirus serotypes in children population of selected communities in South-west, Nigeria. AB - BACKGROUND: Poliovirus outbreaks are still reported in Nigeria despite renewed efforts to improve vaccine coverage, thus suggesting the existence of susceptible hosts. Also, there is anecdotal evidence of variation in vaccine coverage by region and specifically between urban and rural communities. Consequently, this study assessed neutralizing antibodies to poliovirus serotypes among children in selected urban and rural communities in south western Nigeria. METHODOLOGY: Two hundred and forty-four {(M=119, F=125); Urban: 142 (M=63, F=79); Rural: 102 (M=56, F=46)} children of consenting parent/guardian aged one week to 15 years were enrolled for the study. About 2-3ml of blood was collected from each child by venepuncture into a labelled sterile container free of anticoagulants. Subsequently, questionnaire was administered to the parent/guardian of each child to retrieve relevant information. Recovered sera were analysed for detectable neutralizing antibodies to poliovirus serotypes by the standard method of constant virus, varying serum dilutions. RESULTS: Overall, 64.3% (n=157) of the children had detectable neutralizing antibodies to the three poliovirus serotypes. Also, 84.8% (n=207), 91.0% (n=222) and 75.0% (n=183) of the children had detectable antibodies to poliovirus serotypes 1, 2 and 3 respectively. Eighty seven (35.7%) of the children had no detectable neutralizing antibody to at least one of the three poliovirus serotypes, while 9 (3.7%) children had no detectable neutralizing antibody to the three poliovirus serotypes. Geometric mean titre (GMT) of neutralizing antibodies to the three poliovirus serotypes varied significantly (p=0.0005). CONCLUSION: Disparity in immunity to poliovirus infection and existence of children with low or zero neutralizing antibody levels were confirmed. PMID- 25722844 TI - A controlled, crossover study of a persistent antiseptic to reduce hospital acquired infection. AB - BACKGROUND: Alcohol sanitizers have not been demonstrated to reduce hospital acquired infections over handwashing alone in controlled, well-designed clinical studies. A major reason for this may be the failure of traditional alcohol sanitizers to provide any residual, or persistent, activity. Any lapse in hand hygiene protocol then leaves patients and staff open to transmitting pathogens. The purpose of the study was to determine whether a persistent sanitizer would reduce hospital-acquired infection in a hospital setting as compared to handwashing alone. MATERIALS AND METHODS: A controlled, crossover study was conducted in three wards of a hospital over the course of three months. Two months were assigned as control periods, while the third month the test product was added. More than 6,000 patient-days were evaluated. Hospital staff were given a questionnaire to determine overall satisfaction with the product. The product used was a persistent, alcohol-based hand sanitizer (Zylast Antiseptic, 76% v/v ethyl alcohol). RESULTS: Control data showed that the hospital had a standard hospital-acquired infection rate of 23.1% across the three wards. No hospital acquired infections were reported during use of the Antiseptic. The product was well tolerated by the staff and improved skin condition. CONCLUSION: The Antiseptic was demonstrated to significantly (p < 0.0005) reduce the hospital acquired infection rate as compared to handwashing alone and is well-tolerated in a healthcare setting. The novel, persistent product has the ability to significantly reduce hospital-acquired infection and improve patient care in medical facilities. PMID- 25722845 TI - Malaria Parasitaemia among Blood Donors in Ilorin, Nigeria. AB - BACKGROUND: The prevalence of malaria parasitaemia among blood donors in Ilorin has not been documented. In this study, we determined the prevalence of malaria parasitaemia among blood donors in Ilorin, as well as, the sociodemographic and other factors associated with it. METHOD: This was a hospital-based cross sectional study involving 308 consenting blood donors. The sociodemographic characteristics of participants as well as blood donation history were obtained using structured questionnaires specifically designed for this purpose. Giemsastained thick and thin blood films to identify malaria parasites were performed using standard method. ABO blood grouping and haemoglobin electrophoresis tests were also done using standard methods. RESULTS: The prevalence of malaria parasitaemia among blood donors in Ilorin was 27.3%. The parasite species found were more of Plasmodium falciparum(85.7%) than Plasmodium malariae(14.3%) . There was no age or sex difference in malaria parasitaemia. (p value of 0.8 and 0.32 respectively). A greater proportion of blood group O individuals had malaria parasitaemia than groups A and B but this difference was not significant (p-value = 0.13). There was also no significant difference among haemoglobin genotypes. CONCLUSION: The prevalence of malaria parasites among blood donors in Ilorin is considerably high and lack of routine screening of blood puts recipients at risk. We recommend that routine screening for malaria parasites be commenced in our blood banks. Treatment of donor blood with riboflavin and UV light to inactivate malaria parasites and other infectious pathogens before they are transfused to patients may also be considered in our blood banks. PMID- 25722846 TI - HBV Infection Among HIV-Infected Cohort and HIV-Negative Hospital Attendees in South Western Nigeria. AB - BACKGROUND: Prevalence, association and probable mode of acquisition of HBV and HIV dual infections have not been fully explored. Thus, HBV intervention plan and services are sometimes exclusively targeted towards HIV-infected population. We investigated HBV infection among HIV-infected cohort in comparison with HIV negative hospital attendees to ascertain dual infectivity pattern; thereby encouraging appropriate allotment of intervention services. MATERIALS AND METHODS: A total of 349 (M=141; F=208; Mean=33.98 years; Range= 0.33-80 years) plasma specimens from two virus diagnostic laboratories in south-western Nigeria were analysed. These include 182 HIV-positive and 167 HIV-negative specimens from ART and GDV laboratories respectively. The specimens were initially screened for detectable HIV antigen/antibody, and subsequently HBsAg by ELISA technique. RESULTS: Overall, HBsAg was detected in 20.92% (95% CI: 16.65-25.19%) of the patients. Also, 24.82% (95% CI: 17.69-31.95%) and 18.27% (95% CI: 13.02-23.52%) HBsAg positivity was recorded for males and females respectively. CHI square analysis showed no association (P=0.14) between gender and prevalence of HBsAg. Similarly, comparison of prevalence of HBsAg by age groups shows no significant difference (P=0.24). Overall, no significant difference (P=0.59) was observed in the prevalence of HBsAg among the HIV-infected cohort and HIV-negative hospital attendees. CONCLUSIONS: Results of the study confirm endemicity and comparable rates of HBV infection independent of HIV-status. PMID- 25722847 TI - Ruthenium-catalysed Z-selective cross metathesis of allylic-substituted olefins. AB - The Z-selective cross metathesis of allylic-substituted olefins is explored with recently developed ruthenium-based metathesis catalysts. The reaction proceeds with excellent stereoselectivity for the Z-isomer (typically >95%) and yields of up to 88% for a variety of allylic substituents. This includes the first synthesis of Z-alpha,beta-unsaturated acetals by cross metathesis and their elaboration to Z-alpha,beta-unsaturated aldehydes. In addition, the reaction is tolerant of a variety of cross partners, varying in functionality and steric profile. PMID- 25722849 TI - Hyperbaric oxygen therapy in China. AB - Hyperbaric oxygen therapy (HBOT) is defined as a treatment in which a patient intermittently breathes 100% oxygen while the treatment chamber is pressurized to a pressure greater than sea level (1.0 atmosphere absolute, ATA). In China, for nearly 50 years, HBOT has been used as a primary or adjuvant therapy to treat a variety of diseases. This article mainly reviewed the indications and contraindications of HBOT, as well as the status of clinical and experimental HBOT research in China. At the same time, there is a brief introduction of hyperbaric oxygen preconditioning (HBO-PC) in China. PMID- 25713697 TI - Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-. AB - We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A- ( G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene. PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol ( GPI) anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been selected because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking co-trimoxazole, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode. PMID- 25722848 TI - Mechanisms of lead and manganese neurotoxicity. AB - Human exposure to neurotoxic metals is a global public health problem. Metals which cause neurological toxicity, such as lead (Pb) and manganese (Mn), are of particular concern due to the long-lasting and possibly irreversible nature of their effects. Pb exposure in childhood can result in cognitive and behavioural deficits in children. These effects are long-lasting and persist into adulthood even after Pb exposure has been reduced or eliminated. While Mn is an essential element of the human diet and serves many cellular functions in the human body, elevated Mn levels can result in a Parkinson's disease (PD)-like syndrome and developmental Mn exposure can adversely affect childhood neurological development. Due to the ubiquitous presence of both metals, reducing human exposure to toxic levels of Mn and Pb remains a world-wide public health challenge. In this review we summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity. PMID- 25722851 TI - The physiological effects of hypobaric hypoxia versus normobaric hypoxia: a systematic review of crossover trials. AB - Much hypoxia research has been carried out at high altitude in a hypobaric hypoxia (HH) environment. Many research teams seek to replicate high-altitude conditions at lower altitudes in either hypobaric hypoxic conditions or normobaric hypoxic (NH) laboratories. Implicit in this approach is the assumption that the only relevant condition that differs between these settings is the partial pressure of oxygen (PO2), which is commonly presumed to be the principal physiological stimulus to adaptation at high altitude. This systematic review is the first to present an overview of the current available literature regarding crossover studies relating to the different effects of HH and NH on human physiology. After applying our inclusion and exclusion criteria, 13 studies were deemed eligible for inclusion. Several studies reported a number of variables (e.g. minute ventilation and NO levels) that were different between the two conditions, lending support to the notion that true physiological difference is indeed present. However, the presence of confounding factors such as time spent in hypoxia, temperature, and humidity, and the limited statistical power due to small sample sizes, limit the conclusions that can be drawn from these findings. Standardisation of the study methods and reporting may aid interpretation of future studies and thereby improve the quality of data in this area. This is important to improve the quality of data that is used for improving the understanding of hypoxia tolerance, both at altitude and in the clinical setting. PMID- 25722852 TI - Second-generation PLINK: rising to the challenge of larger and richer datasets. AB - BACKGROUND: PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for faster and scalable implementations of key functions, such as logistic regression, linkage disequilibrium estimation, and genomic distance evaluation. In addition, GWAS and population-genetic data now frequently contain genotype likelihoods, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. FINDINGS: To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, [Formula: see text]-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. We have also developed an extension to the data format which adds low overhead support for genotype likelihoods, phase, multiallelic variants, and reference vs. alternate alleles, which is the basis of our planned second release (PLINK 2.0). CONCLUSIONS: The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use. PMID- 25722853 TI - Live time-lapse dataset of in vitro wound healing experiments. AB - BACKGROUND: The wound healing assay is the common method to study collective cell migration in vitro. Computational analyses of live imaging exploit the rich temporal information and significantly improve understanding of complex phenomena that emerge during this mode of collective motility. Publicly available experimental data can allow application of new analyses to promote new discoveries, and assess algorithms' capabilities to distinguish between different experimental conditions. FINDINGS: A freely-available dataset of 31 time-lapse in vitro wound healing experiments of two cell lines is presented. It consists of six different experimental conditions with 4-6 replicates each, gathered to study the effects of a growth factor on collective cell migration. The raw data is available at 'The Cell: an Image Library' repository. This Data Note provides detailed description of the data, intermediately processed data, scripts and experimental validations that have not been reported before and are currently available at GigaDB. This is the first publicly available repository of live collective cell migration data that includes independent replicates for each set of conditions. CONCLUSIONS: This dataset has the potential for extensive reuse. Some aspects in the data remain unexplored and can be exploited extensively to reveal new insight. The dataset could also be used to assess the performance of available and new quantification methods by demonstrating phenotypic discriminatory capabilities between the different experimental conditions. It may allow faster and more elaborated, reproducible and effective analyses, which will likely lead to new biological and biophysical discoveries. PMID- 25722854 TI - The signed Kolmogorov-Smirnov test: why it should not be used. AB - The two-sample Kolmogorov-Smirnov (KS) test is often used to decide whether two random samples have the same statistical distribution. A popular modification of the KS test is to use a signed version of the KS statistic to infer whether the values of one sample are statistically larger than the values of the other. The underlying hypotheses of the KS test are intrinsically incompatible with this approach and the test can produce false positives supported by extremely low p values. This potentially makes the signed KS test a tool of p-hacking, which should be discouraged by replacing it with standard tests such as the t-test and by providing confidence intervals instead of p-values. PMID- 25722855 TI - Drainage systems, an occluded source of sanitation related outbreaks. AB - BACKGROUND: Drainage systems and its role in sanitation related outbreaks are evident but still occluded once it has been installed. This current review evaluates if drainage systems can cause infections and thus be of clinical concern. METHOD: A review of the literature was analyzed. Papers, guidelines, and quality management systems have been considered. RESULTS: Adequate sanitation is fundamental and a prerequisite for safe life and productivity. In contrast, malfunctioning sanitation has been reported to cause outbreaks all over the world. In areas with no sanitation, diarrheal mortality is high and has been shown to decrease by 36% after interventions to improve sanitation. Often, infections are faeces associated and when present in wastewater and sewage sludge poses a high risk of infection upon exposure. Hence, there are working safety guidelines and in industries where infection reduction is essential strict quality assurance systems, i.e. HACCP (hazard analysis critical control points) and GMP (Good Manufacturing Practice) must be complied. Healthcare has recently taken interest in the HACCP system in their efforts to reduce healthcare associated infections as a response to increasing number of ineffective antibiotics and the threat of mortality rate like the pre-antibiotic era. The last few years have called for immediate action to contain the emergence of increasing resistant microorganisms. Resistance is obtained as a result of overuse and misuse of antibiotics in both healthcare and agriculture. Also, by the discharge of antibiotics from manufacturers, healthcare and society. One mechanism of development of novel resistant pathogens has been shown to be by effortless sharing of genetic mobile elements coding for resistance from microbes in the environment to human microbes. These pathogens have been sampled from the drainage systems. These were noticed owing to their possession of an unusual antibiotic resistance profile linking them to the outbreak. Often the cause of sanitation related outbreaks is due to inadequate sanitation and maintenance. However, in general these infections probably go unnoticed. CONCLUSION: Drainage systems and its maintenance, if neglected, could pose a threat in both community and healthcare causing infections as well as emergence of multi-resistant bacteria that could cause unpredictable clinical manifestations. PMID- 25722858 TI - Correction. AB - [This corrects the article DOI: 10.1136/openhrt-2014-000196.]. PMID- 25722857 TI - Comparative genome analysis of non-toxigenic non-O1 versus toxigenic O1 Vibrio cholerae. AB - Pathogenic strains of Vibrio cholerae are responsible for endemic and pandemic outbreaks of the disease cholera. The complete toxigenic mechanisms underlying virulence in Vibrio strains are poorly understood. The hypothesis of this work was that virulent versus non-virulent strains of V. cholerae harbor distinctive genomic elements that encode virulence. The purpose of this study was to elucidate genomic differences between the O1 serotypes and non-O1 V. cholerae PS15, a non-toxigenic strain, in order to identify novel genes potentially responsible for virulence. In this study, we compared the whole genome of the non O1 PS15 strain to the whole genomes of toxigenic serotypes at the phylogenetic level, and found that the PS15 genome was distantly related to those of toxigenic V. cholerae. Thus we focused on a detailed gene comparison between PS15 and the distantly related O1 V. cholerae N16961. Based on sequence alignment we tentatively assigned chromosome numbers 1 and 2 to elements within the genome of non-O1 V. cholerae PS15. Further, we found that PS15 and O1 V. cholerae N16961 shared 98% identity and 766 genes, but of the genes present in N16961 that were missing in the non-O1 V. cholerae PS15 genome, 56 were predicted to encode not only for virulence-related genes (colonization, antimicrobial resistance, and regulation of persister cells) but also genes involved in the metabolic biosynthesis of lipids, nucleosides and sulfur compounds. Additionally, we found 113 genes unique to PS15 that were predicted to encode other properties related to virulence, disease, defense, membrane transport, and DNA metabolism. Here, we identified distinctive and novel genomic elements between O1 and non-O1 V. cholerae genomes as potential virulence factors and, thus, targets for future therapeutics. Modulation of such novel targets may eventually enhance eradication efforts of endemic and pandemic disease cholera in afflicted nations. PMID- 25722859 TI - Implementation of NICE Clinical Guideline 95 for assessment of stable chest pain in a rapid access chest pain clinic reduces the mean number of investigations and cost per patient. AB - OBJECTIVE: In 2010, the National Institute for Health and Care Excellence (NICE) in the UK published Clinical Guideline 95 (CG95) advocating risk stratification of patients using 'CADScore' to guide appropriate cardiac investigations for chest pain of recent onset. Implementation of the guideline in the University College London Hospitals NHS Foundation Trust was evaluated to see if it led to a reduction in the average cost of the diagnostic journey per patient and fewer investigations per patient in order to confirm a diagnosis. METHODS: This was a single centre study at a Tertiary Centre in Central London. The investigative journey for each patient presenting to the Rapid Access Chest Pain Clinic (RACPC) at University College London Hospitals NHS Foundation Trust was recorded. Retrospective analysis on this data was performed. RESULTS: Data for 4968 patients presenting to the RACPC from 2004 to 2012 was analysed and a size matched cohort of 1503 patients preimplementation and postimplementation of the guidelines was compared. The mean cost of investigations postimplementation was L291.83 as compared to L319.54 preimplementation of the guidelines despite higher costs associated with some of the recommended initial investigations. The mean number of tests per patient postguidelines was 0.78 compared to 0.97 for preguidelines. An approximate twofold increase in patients not requiring tests was seen post-CG95 implementation (245 pre-CG95 vs 476 post-CG95). CONCLUSIONS: The implementation of the NICE guidelines in our trust has reduced the average cost of the investigative journey and the number of investigations required per patient. PMID- 25722860 TI - Inaugural editorial: Military Medical Research. AB - Military medicine is one of the most innovative part of human civilization. Along with the rapid development of medicine and advances in military techniques, military medicine has become the focus and intersection of new knowledge and new technologies. Innovation and development within military medicine are always ongoing, with a long and challenging path ahead. The establishment of "Military Medical Research" is expected to be a bounden responsibility in the frontline of Chinese military medicine. PMID- 25722861 TI - Military medicine in China: old topic, new concept. AB - Military medicine is important in both war and peace. In China, military medicine plays a key role in supporting and maintaining health, in preventing injuries and diseases in military staff and in enhancing the military armed forces during war. Additionally, military medicine participates in actions such as emergency public health crises, natural disasters, emerging conflicts and anti-terrorist campaigns during peacetime. In this paper, we summary the current condition and achievements in military medicine in China and provide our perspective for its future. PMID- 25722862 TI - Relationship between acute stress and sleep disorder in grass-root military personnel: mediating effect of social support. AB - BACKGROUND: Sleep disorder induced by acute stress has always been an important topic for study among the general population. However, the mediating effect of social support between acute stress and sleep disorder has rarely been reported before. METHODS: A total of 2,411 grass-root military personnel were randomly selected by cluster sampling, and administered the Chinese Military Personnel Sleep Disorder Scale, Military Acute Stress Scale and Social Support Rating Scale. RESULTS: The total score of acute stress scale was positively correlated with the total score and factor scores of sleep disorder scale (r = 0.209 ~ 0.465, P < 0.01); The total score of social support scale was positively correlated with the total score of acute stress scale and the total score and factor scores of sleep disorder scale (r = 0.356 ~ 0.537, P < 0.01). The analysis of mediating effects showed that lack of social support partially mediated between acute stress and the factors of sleep disorder. The analysis of structural equation model showed that acute stress not only had a direct effect on sleep disorder (the path coefficient was 0.29, P = 0.000), but also on lack of social support (the path coefficient was 0.39, P = 0.000); lack of social support had a direct effect on sleep disorder (the path coefficient was 0.48, P = 0.000). CONCLUSIONS: Acute stress and lack of social support are two significant factors of sleep disorder in grass-root military personnel. Well-established social support could alleviate sleep disorder induced by acute stress. Lack of social support was a partial mediator between acute stress and sleep disorder. PMID- 25722863 TI - Effect of intra-abdominal volume increment on kidneys in minipigs with intra abdominal hypertension after hemorrhagic shock and resuscitation. AB - BACKGROUND: To investigate the effect of intra-abdominal volume increment (IAVI) on intra-abdominal hypertension (IAH) in the kidneys. METHODS: Eight minipigs were successfully established as IAH models and were randomly divided into two groups: the IAVI group and the sham-operated group. The intravesicular pressure, inferior vena cava pressure and urine volume were measured before shock, 2 h after IAH, and 22 h after surgery, respectively. The following indices were measured: serum creatinine, urea nitrogen, renal cortical thickness, ratio of abdominal anteroposterior diameter/transverse diameter, renal thickness, diameter of the renal sinus and the wet/dry ratio of renal tissues. RESULTS: The intravesicular pressure (IVP) of the 8 minipig IAH models was calculated to be 21.16 +/- 4.63 mmHg. There was a significant increase in the abdominal anteroposterior diameter/transverse diameter ratio. The minipigs in the IAVI group survived during the observational period, whereas 2 minipigs died at 18 h and 20 h in the sham-operated group. Twenty-two hours after surgery, the animals in the IAVI group displayed increased urinary volume (UV) and decreased Cr and Ur and remarkable decreases of VP and IVCP. After IAH, the renal cortical thickness and the renal thickness increased significantly. The renal wet/dry ratio in the sham-operated group was higher than that in the IAVI group. CONCLUSION: IAVI helps to control renal dysfunction after IAH, which may be related to lowering the intra-abdominal pressure, thus alleviating renal edema and blood stasis. PMID- 25722864 TI - Clinical trials comparing norepinephrine with vasopressin in patients with septic shock: a meta-analysis. AB - BACKGROUND: The effect of norepinephrine in patients with septic shock remains controversial. We conducted a meta-analysis to compare the mortality rates and benefits of norepinephrine and vasopressin. METHODS: PubMed, EMBASE, and the Cochrane Library database were searched from database inception to December 2013. We selected randomized controlled trials in adults with septic shock and compared norepinephrine with vasopressin. After assessing the heterogeneity of treatment effects across trials using the I (2) statistic, we used a fixed effects model (P >= 0.1) and expressed the results as risk ratios (RRs) for dichotomous outcomes or as standardized mean differences (SMDs) for continuous data with 95% confidence intervals (CIs). Meta-analysis was conducted using Review Manager 5.1 software. RESULTS: Seven trials (n = 2323) met the inclusion criteria. Overall, the mortality rate in these seven trials was 36.2% (840/2323). There was no difference in mortality following the use of norepinephrine or vasopressin (RR 1.07; 95%CI 0.97-1.20; P = 0.19). Compared to norepinephrine, vasopressin had no significant effect on heart rate (HR) (SMD 0.21; 95%CI -0.08-0.50; P = 0.15), mean arterial pressure (MAP) (SMD 0.15; 95%CI -0.15-0.44; P = 0.33), cardiac index (CI) (SMD -0.10; 95%CI -0.64-0.44; P = 0.73), systemic vascular resistance index (SVRI) (SMD 0.15; 95%CI -0.39-0.70; P = 0.58), oxygen delivery (DO2) (SMD 0.06; 95%CI -0.62-0.49; P = 0.82), oxygen consumption (VO2) (SMD 0.03; 95%CI 0.52-0.59; P = 0.91) or lactic acid (SMD 0.07; 95%CI -0.23-0.36; P = 0.66). No significant heterogeneity was found in these comparisons (P >= 0.1). CONCLUSIONS: There is not sufficient evidence to prove conclusively that norepinephrine is superior to vasopressin in terms of mortality and hemodynamics. The effects of norepinephrine and vasopressin on patients with septic shock require further study in large randomized controlled trials. PMID- 25722865 TI - Ten-year retrospective analysis of multiple trauma complicated by pulmonary contusion. AB - BACKGROUND: This study reports a 10-year retrospective analysis of multiple trauma complicated by pulmonary contusion. The purpose of this study is to ascertain the risk factors for mortality due to trauma in patients with pulmonary contusion, the impact of various treatment options for prognosis, and the risk factors for concurrent Acute Respiratory Distress Syndrome (ARDS). METHODS: We retrospectively analyzed 252 trauma patients with lung contusion admitted to the General Hospital of Guangzhou Command from January 2000 to June 2011 by using the statistical processing system SPSS 17.0 for Windows. RESULTS: We included 252 patients in our study, including 214 males and 38 females. The average age was 37.1 +/- 14.9 years. There were 110 cases admitted to the ICU, of which 26 cases with ARDS. Nine of the 252 patients died. We compared those who survived with those who died by gender and age, the difference was not statistically significant (P = 0.199, P = 0.200). Separate univariate analysis of those who died and those who survived found that shock on admission (P = 0.000), coagulation disorders (P = 0.000), gastrointestinal bleeding (P = 0.02), the need for emergency surgery on admission (P = 0.000), pre-hospital intubation (P = 0.000), blood transfusion within 24 hours (P = 0.006), the use of mechanical ventilation (P = 0.000), and concurrent ARDS (P = 0.000) are poor prognosis risk factors. Further logistic analysis, including the admission GCS score (OR = 0.708, 95% CI 0.516-0.971, P = 0.032), ISS score (OR 1.135, 95% CI 1.006-1.280, P = 0.039), and concurrent ARDS (OR = 15.814, 95% CI 1.819-137.480, P = 0.012), identified the GCS score, ISS score and concurrent ARDS as independent risk factors of poor prognosis. Shock (OR = 9.121, 95% CI 0.857-97.060, P = 0.067) was also related to poor prognosis. Patients with injury factors such as road accident, falling injury, blunt injury and crush injury, et al.(P = 0.039), infection (P = 0.005), shock (P = 0.004), coagulation disorders (P = 0.006), emergency surgery (P = 0.01), pre-hospital intubation (P = 0.000), chest tube insertion (P = 0.004), blood transfusion (P = 0.000), usage of hormones (P = 0.002), phlegm (P = 0.000), ventilation (P = 0.000) were at a significantly increased risk for ARDS complications. CONCLUSIONS: Those patients with multiple trauma and pulmonary contusion admitted to the hospital with shock, coagulopathy, a need for emergency surgery, pre-hospital intubation, and a need for mechanical ventilation could have a significantly increased risk of mortality and ARDS incidence. A risk for poor prognosis was associated with gastrointestinal bleeding. A high ISS score, high APACHE2, and low GCS score were independent risk factors for poor prognosis. If patients developed an infection or were given drainage, hormones, and phlegm treatment, they were at higher risk of ARDS. Pre hospital intubation and drainage were independent risk factors for ARDS. In patients with ARDS, the ICU stay, total length of stay, and hospital costs might increase significantly. A GCS score < 5.5, APACHE 2 score > 16.5, and ISS score > 20.5 could be considered indicators of poor prognosis for patients with multiple trauma and lung contusion. PMID- 25722867 TI - Review on emergency medical response against terrorist attack. AB - Terrorism is a global issue and a constant international threat. As a result, anti-terrorism and emergency response strategies are tasks of critical importance that have a direct impact on the national security of every country in the world. This paper reviews new characteristics of international anti-terrorism measures and offers an in-depth reflection on emergency medical response countermeasures; additionally, this paper presents the goals of related research, which include: 1) to present a model of a highly efficient medical response command; 2) to introduce the pre-planning phases of the emergency medical response; 3) to establish a response system capable of handling various types of terror attacks; 4) to promote anti-terrorism awareness to the general public and emphasize its prevention; and 5) to continue basic investigations into emergency medical responses for various types of terrorist attacks (for example, the classifications and characteristics of new injuries, pathophysiology, prevention and treatment of the resultant stress disorders, improved high-efficiency medical response measures and equipment, etc.). PMID- 25722866 TI - Research progress on combat trauma treatment in cold regions. AB - Cold regions are a special combat environment in which low temperatures have a great impact on human metabolism and other vital functions, including the nervous, motion, cardiovascular, circulatory, respiratory, and urinary systems; consequently, low temperatures often aggravate existing trauma, leading to high mortality rates if rapid and appropriate treatment is not provided. Hypothermia is an independent risk factor of fatality following combat trauma; therefore, proactive preventative measures are needed to reduce the rate of mortality. After summarizing the basic research on battlefield environments and progress in the prevention and treatment of trauma, this article concludes that current treatment and prevention measures for combat trauma in cold regions are inadequate. Future molecular biology studies are needed to elucidate the mechanisms and relevant cell factors underlying bodily injury caused by cold environment, a research goal will also allow further exploration of corresponding treatments. PMID- 25722868 TI - Can minimally invasive puncture and drainage for hypertensive spontaneous Basal Ganglia intracerebral hemorrhage improve patient outcome: a prospective non randomized comparative study. AB - BACKGROUND: The treatment of hypertensive spontaneous intracranial hemorrhage (ICH) is still controversial. The purpose of the present study was to investigate whether minimally invasive puncture and drainage (MIPD) could improve patient outcome compared with decompressive craniectomy (DC). METHODS: Consecutive patients with ICH (?30 mL in basal ganglia within 24 hours of ictus) were non randomly assigned to receive MIPD (group A) or DC (group B) hematoma evacuation. The primary outcome was death at 30 days after onset. Functional independence was assessed at 1 year using the Glasgow Outcome Scale. RESULTS: A total of 198 patients met the per protocol analysis (84 in group A and 114 in group B). The initial Glasgow Coma Scale (GCS) score was 8.1 +/- 3.4 and the National Institutes of Health Stroke Scale (NIHSS) score was 20.8 +/- 5.3. The mean hematoma volume (HV) was 56.7 +/- 23.0 mL, and there was extended intraventricular hemorrhage (IVH) in 134 patients. There were no significant intergroup differences in the above baseline data, except group A had a higher mean age than that of group B (59.4 +/- 14.5 vs. 55.3 +/- 11.1 years, P = 0.025). The cumulative mortalities at 30 days and 1 year were 32.3% and 43.4%, respectively, and there were no significant differences between groups A and B. However, the mortality for patients ?60 years, NIHSS < 15 or HV?60 mL was significantly lower in group A than that in group B (all P < 0.05). The cumulative functional independence at 1 year was 26.8%, and the difference between group A (33/84, 39.3%) and group B (20/114, 17.5%) was significant (P = 0.001). Multivariate logistic regression analysis showed that a favorable outcome after 1 year was associated with the difference in therapies, age, GCS, HV, IVH and pulmonary infection (all P <0.05). CONCLUSIONS: For patients with hypertensive spontaneous ICH (HV?30 mL in basal ganglia), MIPD may be a more effective treatment than DC, as assessed by a higher rate of functional independence at 1 year after onset as well as reduced mortality in patients ?60 years of age, NIHSS < 15 or HV?60 mL. PMID- 25722869 TI - Development and application of a rapid rehabilitation system for reconstruction of maxillofacial soft-tissue defects related to war and traumatic injuries. AB - BACKGROUND: The application of a maxillofacial prosthesis is an alternative to surgery in functional-aesthetic facial reconstruction. Computer aided design/computer aided manufacturing has opened up a new approach to the fabrication of maxillofacial prostheses. An intelligentized rapid simulative design and manufacturing system for prostheses was developed to facilitate the prosthesis fabrication procedure. METHODS: The rapid simulation design and rapid fabrication system for maxillofacial prostheses consists of three components: digital impression, intelligentized prosthesis design, and rapid manufacturing. The patients' maxillofacial digital impressions were taken with a structured light 3D scanner; then, the 3D model of the prostheses and their negative molds could be designed with specific software; lastly, with resin molds fabricated by the rapid prototyping machine, the prostheses could be produced directly and quickly. RESULTS: Fifteen patients with maxillofacial defects received prosthesis rehabilitation provided by the established system. The total clinical time used for each patient was only 4 hours over 2 appointments on average. The contours of the prostheses coordinated properly with the appearance of the patients, and the uniform-thickness border sealed well to adjacent tissues. All of the patients were satisfied with their prostheses. CONCLUSIONS: The rapid simulative rehabilitation system of maxillofacial defects is approaching completion. It could provide an advanced technological solution for the Army in cases of maxillofacial defect rehabilitation. PMID- 25722870 TI - Development and application of triage and medical evacuation system for casualties at sea. AB - Traditional triage could not meet the needs of battlefield casualties' care in modern warfare. This paper designs of triage and medical evacuation system for casualties at sea that can quickly address mass-casualty triage, and store and transmit medical information during battlefield treatment and medical evacuation. This system consists of a high-capacity medical information card, a simulated patient generator, a triage classifier and a multifunctional airbag triage vest. PMID- 25722872 TI - China's great wall, Israel's Bar Lev Line, and passive infectious disease surveillance. AB - Emerging infectious diseases are some of modern society's greatest threats. Like some great construction efforts designed to protect mankind, current public health measures against these emerging pathogens have not always been successful. This paper highlights the importance of embracing new interdisciplinary approaches towards emerging pathogen threats. One such approach, termed One Health, is quickly being embraced by professional organizations and public health institutions across the world as a way forward. This paper briefly discusses the above problems and preliminary steps taken by Chinese academic institutions to embrace the One Health approach. PMID- 25722871 TI - Medical aspects of terrorist bombings - a focus on DCS and DCR. AB - Although terrorist bombings have tormented the world for a long time, currently they have reached unprecedented levels and become a continuous threat without borders, race or age. Almost all of them are caused by improvised explosive devices. The unpredictability of the terrorist bombings, leading to simultaneous generation of a large number of casualties and severe "multidimensional" blast trauma require a constant vigilance and preparedness of every hospital worldwide. Approximately 1-2.6% of all trauma patients and 7% of the combat casualties require a massive blood transfusion. Coagulopathy is presented in 65% of them with mortality exceeding 50%. Damage control resuscitation is a novel approach, developed in the military practice for treatment of this subgroup of trauma patients. The comparison with the conventional approach revealed mortality reduction with 40-74%, lower frequency of abdominal compartment syndrome (8% vs. 16%), sepsis (9% vs. 20%), multiorgan failure (16% vs. 37%) and a significant reduction of resuscitation volumes, both crystalloids and blood products. DCS and DCR are promising new approaches, contributing for the mortality reduction among the most severely wounded patients. Despite the lack of consensus about the optimal ratio of the blood products and the possible influence of the survival bias, we think that DCR carries survival benefit and recommend it in trauma patients with exsanguinating bleeding. PMID- 25722873 TI - Smoking is associated with the incidence of AMS: a large-sample cohort study. AB - BACKGROUND: In recent years, the number of people visiting high altitudes has increased. After rapidly ascending to a high altitude, some of these individuals, who reside on plains or other areas of low altitude, have suffered from acute mountain sickness (AMS). Smoking interferes with the body's oxygen metabolism, but research about the relationship between smoking and AMS has yielded controversial results. METHODS: We collected demographic data, conducted a smoking history and performed physical examinations on 2000 potential study participants, at sea level. Blood pressure (BP) and pulse oxygen saturation (SpO2) were measured for only some of the patients due to time and manpower limitations. We ultimately recruited 520 smokers and 450 nonsmokers according to the inclusion and exclusion criteria of our study. Following acute high-altitude exposure, we examined their Lake Louise Symptom (LLS) scores, BP, HR and SpO2; however, cerebral blood flow (CBF) was measured for only some of the subjects due to limited time, manpower and equipment. RESULTS: Both the incidence of AMS and Lake Louise Symptom (LLS) scores were lower in smokers than in nonsmokers. Comparing AMS-related symptoms between nonsmokers and smokers, the incidence and severity of headaches and the incidence of sleep difficulties were lower in smokers than in nonsmokers. The incidences of both cough and mental status change were higher in smokers than in nonsmokers; blood pressure, HR and cerebral blood flow velocity were lower in smokers than in nonsmokers. CONCLUSION: Our findings suggest that the incidence of AMS is lower in the smoking group, possibly related to a retardation of cerebral blood flow and a relief of AMS-related symptoms, such as headache. PMID- 25722874 TI - Relationship between excessive erythrocytosis and acute mountain sickness: a field study. AB - BACKGROUND: Alterations in hematology, especially erythroid changes, may be involved in acute mountain sickness (AMS) at high altitude. This study aimed to identify the relationship between excessive erythrocytosis and AMS following different durations of high-altitude exposure. METHODS: A total of 692 healthy young Chinese men were recruited for the study in June and July of 2012 and were divided into the following five groups: I) the 24-h group (24 hours after arrival at Lhasa, 3,700 m, n = 261); II) the 7-d group (exposed at Lhasa, 3,700 m for seven days, n = 99); III) the re-exposure group (re-exposed at Yang Bajing, 4,400 m for seven days after >1 year of acclimation at 3,700 m,n = 94); IV) the acclimated group (>1 year of acclimation at 3,700 m, Lhasa, n = 42); and V) the sea-level control (control group, Chengdu, n = 196). Case report forms were used to record the subjects' demographic information and AMS-related symptoms. All of the subjects underwent routine blood tests. RESULTS: The red blood cell (RBC) count fell slightly but was not significant upon acute exposure to high altitude, whereas the hemoglobin concentration ([Hb]) increased significantly. After high altitude re-exposure, both of the [Hb] and RBC count showed significant increases. The incidence of AMS was 65.1%, 26.3% and 51.1%, respectively in the 24-h, 7-d and re-exposure groups. The [Hb] (P = 0.024) and hematocrit (P = 0.017) were greater in the AMS(+) individuals than in the AMS(-) individuals in 7-d group. A correlation analysis revealed that the [Hb] and hematocrit were closely related with AMS score in 7-d and re-exposure groups, while the RBC showed a correlation with AMS score only in the re-exposure group. The AMS incidence was lowest when the [Hb] was between 140 and 160 g/L in the 24-h and 7-d groups. CONCLUSIONS: AMS is associated with both [Hb] and excessive erythrocytosis. Additionally, our findings indicate the existence of an optimal [Hb] for preventing AMS. PMID- 25722875 TI - Correlation between blood pressure changes and AMS, sleeping quality and exercise upon high-altitude exposure in young Chinese men. AB - BACKGROUND: Excessive elevation of arterial blood pressure (BP) at high altitude can be detrimental to our health due to acute mountain sickness (AMS) or some AMS symptoms. This prospective and observational study aimed to elucidate blood pressure changes induced by exposure to high-altitude hypoxia and the relationships of these changes with AMS prevalence, AMS severity, sleep quality and exercise condition in healthy young men. METHODS: A prospective observational study was performed in 931 male young adults exposed to high altitude at 3,700 m (Lhasa) from low altitude (LA, 500 m). Blood pressure measurement and AMS symptom questionnaires were performed at LA and on day 1, 3, 5, and 7 of exposure to high altitude. Lake Louise criteria were used to diagnose AMS. Likewise, the Athens Insomnia Scale (AIS) and the Epworth Sleepiness Scale (ESS) were filled out at LA and on day 1, 3, and 7 of exposure to high altitude. RESULTS: After acute exposure to 3,700 m, diastolic blood pressure (DBP) and mean arterial blood pressure (MABP) rose gradually and continually (P < 0.05). Analysis showed a relationship with AMS for only MABP (P < 0.05) but not for SBP and DBP (P > 0.05). Poor sleeping quality was generally associated with higher SBP or DBP at high altitude, although inconsistent results were obtained at different time (P < 0.05). SBP and Pulse BP increased noticeably after high-altitude exercise (P < 0.05). CONCLUSIONS: Our data demonstrate notable blood pressure changes under exposure to different high-altitude conditions: 1) BP increased over time. 2) Higher BP generally accompanied poor sleeping quality and higher incidence of AMS. 3) SBP and Pulse BP were higher after high-altitude exercise. Therefore, we should put more effort into monitoring BP after exposure to high altitude in order to guard against excessive increases in BP. PMID- 25722876 TI - Septic encephalopathy: when cytokines interact with acetylcholine in the brain. AB - Sepsis-associated encephalopathy (SAE) is a brain dysfunction that occurs secondary to infection in the body, characterized by alteration of consciousness, ranging from delirium to coma, seizure or focal neurological signs. SAE involves a number of mechanisms, including neuroinflammation, in which the interaction between cytokines and acetylcholine results in neuronal loss and alterations in cholinergic signaling. Moreover, the interaction also occurs in the periphery, accelerating a type of immunosuppressive state. Although its diagnosis is not specific in biochemistry and imaging tests, it could potentiate severe outcomes, including increased mortality, cognitive decline, progressive immunosuppression, cholinergic anti-inflammatory deficiency, and even metabolic and hydroelectrolyte imbalance. Therefore, the bilateral communication between SAE and the multiple peripheral organs and especially the immune system should be emphasized in sepsis management. PMID- 25722878 TI - Advances in the biological effects of terahertz wave radiation. AB - The terahertz (THz) band lies between microwave and infrared rays in wavelength and consists of non-ionizing radiation. Both domestic and foreign research institutions, including the army, have attached considerable importance to the research and development of THz technology because this radiation exhibits both photon-like and electron-like properties, which grant it considerable application value and potential. With the rapid development of THz technology and related applications, studies of the biological effects of THz radiation have become a major focus in the field of life sciences. Research in this field has only just begun, both at home and abroad. In this paper, research progress with respect to THz radiation, including its biological effects, mechanisms and methods of protection, will be reviewed. PMID- 25722877 TI - Emerging and re-emerging infectious diseases: challenges and opportunities for militaries. AB - The communal nature of living and training environments, alongside suboptimal hygiene and stressors in the field, place military personnel at higher risk of contracting emerging infectious diseases. Some of these diseases spread quickly within ranks resulting in large outbreaks, and personnel deployed are also often immunologically naive to otherwise uncommonly-encountered pathogens. Furthermore, the chance of weaponised biological agents being used in conventional warfare or otherwise remains a very real, albeit often veiled, threat. However, such challenges also provide opportunities for the advancement of preventive and therapeutic military medicine, some of which have been later adopted in civilian settings. Some of these include improved surveillance, new vaccines and drugs, better public health interventions and inter-agency co-operations. The legacy of successes in dealing with infectious diseases is a reminder of the importance in sustaining efforts aimed at ensuring a safer environment for both military and the community at large. PMID- 25722879 TI - The injury progression of T lymphocytes in a mouse model with subcutaneous injection of a high dose of sulfur mustard. AB - BACKGROUND: In clinical studies, the findings on sulfur mustard (SM) toxicity for CD3(+)CD4(+) and CD3(+)CD8(+) T lymphocyte subsets are contradictory. In animal experiments, the effect of SM on the T cell number and proliferation is incompatible and is even the opposite of the results in human studies. In this study, we observed the dynamic changes of T lymphocytes in the first week in a high-dose SM-induced model. METHODS: Mice were exposed to SM by subcutaneous injection (20 mg/kg) and were sacrificed 4 h, 24 h, 72 h and 168 h later. Spleen T lymphocyte proliferation was evaluated by (3)H-TdR. Flow cytometric analysis was used to observe the percentage of CD3(+)CD4(+) and CD3(+)CD8(+) T lymphocyte subsets. The IL-1beta, IL-6, IL-10 and TNF-alpha levels in plasma were assayed using the Luminex method. DNA damage in bone marrow cells was observed with the single cell gel electrophoresis technique (SCGE). RESULTS: SM continuously inhibited the proliferation of lymphocytes for 7 days, and there was a significant rebound of Con A-induced T lymphocyte proliferation only at 24 h. The percentage of CD3(+)CD4(+) and CD3(+)CD8(+) lymphocytes was upregulated, which was accompanied by increased IL-1beta and TNF-alpha and decreased IL-10. The IL-6 level was gradually decreased in the PG group at 4 h. The peak of lymphocytic apoptosis and DNA damage occurred at 24 h and 72 h, respectively. CONCLUSION: Our results show that SM significantly inhibited T lymphocyte proliferation as well as induced CD3(+)CD4(+) and CD3(+)CD8(+) upregulation. SM intoxication also significantly increased the levels of pro-inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and inhibited the level of anti-inflammatory cytokine IL-10. Our results may partly be due to the significant SM induced significant apoptosis and necrosis of lymphocytes as well as DNA damage of bone marrow cells. The results provided a favorable evaluation of SM immune toxicity in an animal model. PMID- 25722880 TI - Current knowledge and future directions of TLR and NOD signaling in sepsis. AB - The incidence of sepsis is increasing over time, along with an increased risk of dying from the condition. Sepsis care costs billions annually in the United States. Death from sepsis is understood to be a complex process, driven by a lack of normal immune homeostatic functions and excessive production of proinflammatory cytokines, which leads to multi-organ failure. The Toll-like receptor (TLR) family, one of whose members was initially discovered in Drosophila, performs an important role in the recognition of microbial pathogens. These pattern recognition receptors (PRRs), upon sensing invading microorganisms, activate intracellular signal transduction pathways. NOD signaling is also involved in the recognition of bacteria and acts synergistically with the TLR family in initiating an efficient immune response for the eradication of invading microbial pathogens. TLRs and NOD1/NOD2 respond to different pathogen-associated molecular patterns (PAMPs). Modulation of both TLR and NOD signaling is an area of research that has prompted much excitement and debate as a therapeutic strategy in the management of sepsis. Molecules targeting TLR and NOD signaling pathways exist but regrettably thus far none have proven efficacy from clinical trials. PMID- 25722881 TI - Mesenchymal stem cell therapy for acute radiation syndrome: innovative medical approaches in military medicine. AB - After a radiological or nuclear event, acute radiation syndrome (ARS) will present complex medical challenges that could involve the treatment of hundreds to thousands of patients. Current medical doctrine is based on limited clinical data and remains inadequate. Efforts to develop medical innovations that address ARS complications are unlikely to be generated by industry because of market uncertainties specific to this type of injury. A prospective strategy could be the integration of cellular therapy to meet the medical demands of ARS. The most clinically advanced cellular therapy to date is the administration of mesenchymal stem cells (MSCs). Results of currently published investigations describing MSC safety and efficacy in a variety of injury and disease models demonstrate the unique qualities of this reparative cell population in adapting to the specific requirements of the damaged tissue in which the cells integrate. This report puts forward a rationale for the further evaluation of MSC therapy to address the current unmet medical needs of ARS. We propose that the exploration of this novel therapy for the treatment of the multivariate complications of ARS could be of invaluable benefit to military medicine. PMID- 25722882 TI - First imported Plasmodium ovale malaria in Central America: case report of a Guatemalan soldier and a call to improve its accurate diagnosis. AB - The Mesoamerican Ministers of Health have set 2020 as the target for malaria elimination to be achieved in the region. Imported malaria cases are a potential threat to countries attempting elimination or working to prevent resurgence. We report the first imported Plasmodium ovale infection with molecular confirmation in Central America, which occurred in a Guatemalan soldier that had been deployed in Africa. The obstacles for its diagnosis using the standard microscopy technique and the need to improve its detection are discussed. PMID- 25722883 TI - Risk-adjusted analysis of relevant outcome drivers for patients after more than two kidney transplants. AB - Renal transplantation is the treatment of choice for patients suffering end-stage renal disease, but as the long-term renal allograft survival is limited, most transplant recipients will face graft loss and will be considered for a retransplantation. The goal of this study was to evaluate the patient and graft survival of the 61 renal transplant recipients after second or subsequent renal transplantation, transplanted in our institution between 1990 and 2010, and to identify risk factors related to inferior outcomes. Actuarial patient survival was 98.3%, 94.8%, and 88.2% after one, three, and five years, respectively. Actuarial graft survival was 86.8%, 80%, and 78.1% after one, three, and five years, respectively. Risk-adjusted analysis revealed that only age at the time of last transplantation had a significant influence on patient survival, whereas graft survival was influenced by multiple immunological and surgical factors, such as the number of HLA mismatches, the type of immunosuppression, the number of surgical complications, need of reoperation, primary graft nonfunction, and acute rejection episodes. In conclusion, third and subsequent renal transplantation constitute a valid therapeutic option, but inferior outcomes should be expected among elderly patients, hyperimmunized recipients, and recipients with multiple operations at the site of last renal transplantation. PMID- 25722884 TI - The balanced two-string technique for sulcus intraocular lens implantation in the absence of capsular support. AB - Purpose. To describe and explore an alternative approach for sulcus intraocular lens (IOL) implantation in the absence of capsular support. Methods. The commonly available one-piece poly(methyl methacrylate) (PMMA) lens is stabilized in the sulcus by two intraocular horizontal strings of 10/0 polypropylene suture passed through the lens dialing holes in opposite directions to achieve a mechanical balance. The horizontal strings of 10/0 polypropylene work as a rail track for the IOL optics, allowing some side to side lens adjustment even following wound closure. The stability of the IOL was tested in vitro. Six aphakic patients underwent in-sulcus IOL secondary implantation using the balanced two-string technique. Patients were followed up for a minimum of six months. Best spectacle corrected vision was assessed. Lens centration and lens tilt were measured by anterior segment optical coherence tomography (AS-OCT). Results. All patients had successful lens insertion. Best spectacle corrected visual acuity (BSCVA) improved in all patients. Lens decentration ranged between 0.21 mm and 0.9 mm (average 0.53 mm). Lens tilt ranged between 1.2 degrees and 2.8 degrees (average 2.17 degrees ). Conclusion. The mechanically balanced two-string technique is an alternative option for sulcus IOL implantation in absence of capsular support, allowing lens centration adjustment with no additional risks. PMID- 25722885 TI - Mucolytics for intubated asthmatic children: a national survey of United kingdom paediatric intensive care consultants. AB - Aim. The extent to which mucolytics are utilised in mechanically ventilated asthmatic children is unknown. We sought to establish current practice in the United Kingdom (UK) including choice of mucolytic, dose, and frequency of utilisation. Methods. A national electronic survey was distributed to UK consultants during April and May 2014. We were able to identify 168 PICU consultants at 25 institutions to whom we were able to electronically distribute a survey, representing an estimated 81% of UK NHS PICU consultants. Results. Replies were received from 87 consultants at 21 institutions (response rate = 52%). Recombinant human DNase (rhDNase) does get administered by 63% of clinicians, with 54% and 19% that administer hypertonic saline or N acetylcysteine, respectively. Of those that do administer rhDNase the majority (48%) dilute it with 0.9% saline and blindly administer it, whereas 35% administer rhDNase under bronchoscopic guidance and 17% judge the necessity for bronchoscopy according to clinical severity. 25 respondents described 7 different methods to calculate rhDNase dose. A majority (87%) of respondents expressed an interest to consider enrolling patients into an RCT that evaluates rhDNase. Conclusion. Significant variation exists regarding the necessity for mucolytics, choice of agent, optimal route, and dose in intubated asthmatic children. PMID- 25722886 TI - Predictors of patient satisfaction with tertiary hospitals in Korea. AB - This study examined the general and system-related predictors of outpatient satisfaction with tertiary health care institutions in Korea. A cross-sectional descriptive study design was employed. The subjects were 1,194 outpatients recruited from 29 outpatient clinics of a university medical center in Korea. Measurements included 5 outpatient service domains (i.e., doctor service, nurse service, technician service, convenience, and physical environment of facility) and patient satisfaction. Of the five domains, nurse service was the domain with the highest mean score (M = 4.21) and convenience was the domain with the lowest mean score (M = 3.77). The most significant predictor of patient satisfaction was the constructs of convenience (beta = 0.21). The results of this study suggest that the concept of patient satisfaction with health care institutions in modern hospitals reflects an integrative process that includes not only the concerned health care personnel but also improved convenience such as user-friendly reservation system and comfortable waiting areas. PMID- 25722887 TI - Effects of intense pulsed light on tissue vascularity and wound healing: a study with mouse island skin flap model. AB - Intense pulsed light (IPL) has been used extensively in aesthetic and cosmetic dermatology. To test whether IPL could change the tissue vascularity and improve wound healing, mice were separated into 4 groups. Mice in Group I were not treated with IPL, whereas, dorsal skins of mice in Groups II, III, and IV were treated with 35 J/cm(2), 25 J/cm(2), and 15 J/cm(2) IPL, respectively. After 2 weeks, dorsal island skin flaps were raised, based on the left deep circumflex iliac vessels as pedicles; then, survival rate was assessed. Flaps in Group IV (treated with lowest dose of IPL) have a survival rate significantly higher than other groups. Counting blood vessels did not demonstrate any significant differences; however, vessel dilation was found in this group. The results show that IPL at the therapeutic doses which are usually applied to humans is harmful to mouse dorsal skin and did not enhance wound healing, whereas, IPL at much lower dose could improve wound healing. The possible mechanism is the dilation of tissue vasculature thanks to the electromagnetic character of IPL. Another mechanism could be the heat-shock protein production. PMID- 25722888 TI - (99m)Technetium Sestamibi-(123)Iodine Scintigraphy Is More Accurate Than (99m)Technetium Sestamibi Alone before Surgery for Primary Hyperparathyroidism. AB - Objectives. Studies comparing outcome of single-(99m)Tc-methoxyisobutylisonitrile ((99m)Tc-sestamibi) and dual-tracer (99m)Tc-sestamibi scintigraphy in combination with (123)I before primary surgery of primary hyperparathyroidism (PHPT) are scarce. Methods. We compared (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi in a single-centre retrospective series of 269 PHPT patients. The results were related to laboratory, surgical and histological findings. Results. (99m)Tc sestamibi/(123)I and (99m)Tc-sestamibi were positive in 206 (76.6%) and 111 (41.3%) of 269 patients, respectively (P < 0.001). Accuracies for (99m)Tc sestamibi/(123)I and (99m)Tc-sestamibi were 63.4% and 34.9%, respectively (96% CI, P < 0.001). Prevalence of multiglandular disease was 15.2%. In multiglandular disease, (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi revealed 43.8 and 22.1% of pathological glands, respectively (P < 0.001). Cure rate was similar for patients with (191/206; 92.7%) and without (59 of 63; 93.7%) a positive (99m)Tc sestamibi/(123)I finding. Duration of targeted surgery (one or two quadrants) was 21 and 15 minutes shorter than bilateral neck exploration, respectively (both P < 0.001). Higher serum calcium (P = 0.014) and PTH (P = 0.055) concentrations and larger tumours (P < 0.001) characterized the 206 patients with a positive preoperative scan who were cured by removal of a single adenoma. Conclusions. (99m)Tc-sestamibi/(123)I scintigraphy is more accurate than (99m)Tc-sestamibi before surgery of PHPT. However, outcome of surgery is not determined by scintigraphy alone. PMID- 25722889 TI - Predictor's of Mortality in Patients with Aneurysmal Subarachnoid Haemorrhage and Reebleding. AB - Methods. "Ameijeiras Brother's" and "Cmdt. Manuel Fajardo" Hospitals enrolled 64 patients (multicentre retrospective cohort) with aneurysmal subarachnoid haemorrhage and rebleeding. The patients were admitted to the Stroke Unit (SU) between January 1, 2006, and December 1, 2013. Demographic, clinical, and radiological variables were examined in logistic regression to evaluate independent factors for increasing the risk of death. Results. Patients with systolic blood pressure >160 mmHg (P = 0.02), serum glucose >7 mmol/L (P = 0.02), aneurysm location in artery communicant anterior (P = 0.03), and black/mixed race (P = 0.008) were significant related to death in univariate analysis. Risk factors (HTA, smoke, alcohol consumption, and DM), complication, multiplex rebleeding and stage of WFNS, and Fisher's scale were not related to mortality. Patients with three or more complications had a higher mortality rate (P = 0.002). The results of the multivariate logistic regression analysis indicated that race (black/mixed, P = 0.00, OR 4.62, and 95% IC 1.40-16.26), systolic blood pressure (>160 mmHg, P = 0.05, OR 2.54, and 95% IC 1.01-3.13), and serum glucose (>7.0 mmol/L, P = 0.05, OR 1.82, and 95% IC 1.27-2.67) were independent risk factors for death. Conclusions. The black/mixed race, SBP, and serum glucose were independent predictors of mortality. Three or more complications were associated with increasing the probability to death. Further investigation is necessary to validate these findings. PMID- 25722890 TI - Brain Activity during Lower-Limb Movement with Manual Facilitation: An fMRI Study. AB - Brain activity knowledge of healthy subjects is an important reference in the context of motor control and reeducation. While the normal brain behavior for upper-limb motor control has been widely explored, the same is not true for lower limb control. Also the effects that different stimuli can evoke on movement and respective brain activity are important in the context of motor potentialization and reeducation. For a better understanding of these processes, a functional magnetic resonance imaging (fMRI) was used to collect data of 10 healthy subjects performing lower-limb multijoint functional movement under three stimuli: verbal stimulus, manual facilitation, and verbal + manual facilitation. Results showed that, with verbal stimulus, both lower limbs elicit bilateral cortical brain activation; with manual facilitation, only the left lower limb (LLL) elicits bilateral activation while the right lower limb (RLL) elicits contralateral activation; verbal + manual facilitation elicits bilateral activation for the LLL and contralateral activation for the RLL. Manual facilitation also elicits subcortical activation in white matter, the thalamus, pons, and cerebellum. Deactivations were also found for lower-limb movement. Manual facilitation is stimulus capable of generating brain activity in healthy subjects. Stimuli need to be specific for bilateral activation and regarding which brain areas we aim to activate. PMID- 25722891 TI - Characterization of protein complexes and subcomplexes in protein-protein interaction databases. AB - The identification and characterization of protein complexes implicated in protein-protein interaction data are crucial to the understanding of the molecular events under normal and abnormal physiological conditions. This paper provides a novel characterization of subcomplexes in protein interaction databases, stressing definition and representation issues, quantification, biological validation, network metrics, motifs, modularity, and gene ontology (GO) terms. The paper introduces the concept of "nested group" as a way to represent subcomplexes and estimates that around 15% of those nested group with the higher Jaccard index may be a result of data artifacts in protein interaction databases, while a number of them can be found in biologically important modular structures or dynamic structures. We also found that network centralities, enrichment in essential proteins, GO terms related to regulation, imperfect 5 clique motifs, and higher GO homogeneity can be used to identify proteins in nested complexes. PMID- 25722892 TI - Vascular leakage in dengue hemorrhagic Fever is associated with dengue infected monocytes, monocyte activation/exhaustion, and cytokines production. AB - The vascular leakage was shown by the increment of hematocrit (Hct), dengue viral infected monocyte, monocyte status, and cytokines production in patients infected with dengue virus. Dengue viral antigens were demonstrated in monocytes (CD14+) from peripheral blood mononuclear cells. The increased levels of Hct, interleukin (IL-) 10, and tumor necrosis factor-alpha (TNF-alpha) were detected in dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) patients as compared with other febrile illnesses (OFIs). The highest levels of Hct and IL-10 were detected in DSS patients as compared with other groups (P < 0.05) especially on one day before and after defervescence. The unstimulated and lipopolysaccharide- (LPS-) stimulated monocytes from DSS patients showed the significantly decreased of intracellular IL-1beta and TNF-alpha. In addition, the lowest level of mean fluorescence intensity (MFI) of CD11b expression on monocytes surface in DSS patients was also demonstrated. Furthermore, the negative correlations between IL-10 levels and intracellular IL-1beta and MFI of CD11b expression in unstimulated and LPS-stimulated monocytes were also detected. Nevertheless, not only were the relationships between the prominent IL-10 and the suppression of intracellular monocyte secretion, namely, IL-1beta, TNF-alpha, demonstrated but also the effect of vascular leakage was observed. PMID- 25722893 TI - Sleeve gastrectomy and Roux-en-Y gastric bypass alter the gut-brain communication. AB - This study investigated the anatomical integrity of vagal innervation of the gastrointestinal tract following vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) operations. The retrograde tracer fast blue (FB) was injected into the stomach to label vagal neurons originating from nodose ganglion (NG) and dorsal motor nucleus of the vagus (DMV). Microglia activation was determined by quantifying changes in the fluorescent staining of hindbrain sections against an ionizing calcium adapter binding molecule 1 (Iba1). Reorganization of vagal afferents in the hindbrain was studied by fluorescent staining against isolectin 4 (IB4). The density of Iba1- and IB4-immunoreactivity was analyzed using Nikon Elements software. There was no difference in the number of FB-labeled neurons located in NG and DMV between VSG and VSG-sham rats. RYGB, but not RYGB-sham rats, showed a dramatic reduction in number of FB-labeled neurons located in the NG and DMV. VSG increased, while the RYGB operation decreased, the density of vagal afferents in the nucleus tractus solitarius (NTS). The RYGB operation, but not the VSG procedure, significantly activated microglia in the NTS and DMV. Results of this study show that the RYGB, but not the VSG procedure, triggers microglia activation in vagal structures and remodels gut-brain communication. PMID- 25722894 TI - Generation of new neurons in dorsal root Ganglia in adult rats after peripheral nerve crush injury. AB - The evidence of neurons generated ex novo in sensory ganglia of adult animals is still debated. In the present study, we investigated, using high resolution light microscopy and stereological analysis, the changes in the number of neurons in dorsal root ganglia after 30 days from a crush lesion of the rat brachial plexus terminal branches. Results showed, as expected, a relevant hypertrophy of dorsal root ganglion neurons. In addition, we reported, for the first time in the literature, that neuronal hypertrophy was accompanied by massive neuronal hyperplasia leading to a 42% increase of the number of primary sensory neurons. Moreover, ultrastructural analyses on sensory neurons showed that there was not a relevant neuronal loss as a consequence of the nerve injury. The evidence of BrdU immunopositive neurons and neural progenitors labeled with Ki67, nanog, nestin, and sox-2 confirmed the stereological evidence of posttraumatic neurogenesis in dorsal root ganglia. Analysis of morphological changes following axonal damage in addition to immunofluorescence characterization of cell phenotype suggested that the neuronal precursors which give rise to the newly generated neurons could be represented by satellite glial cells that actively proliferate after the lesion and are able to differentiate toward the neuronal lineage. PMID- 25722895 TI - Natal teeth: a case report and reappraisal. AB - The presence of teeth at birth (natal teeth) or within a month after delivery (neonatal teeth) is a rare condition. Natal and neonatal teeth are conditions of significant importance to pediatric dentists and pediatricians. This report discusses a case in which a five-day-old infant required extraction of a mobile mandibular natal tooth to avoid the risk of aspiration and interference with feeding. Also, a review of the literature was conducted to discuss the etiology, clinical features, complications, and management of natal and neonatal teeth. PMID- 25722896 TI - Multiple congenital granular cell epulis: case report and immunohistochemical profile with emphasis on vascularization. AB - Congenital granular cell epulis is a rare benign soft tissue lesion arising from the alveolar ridge in neonates. A rare case of multiple congenital granular cell epulis is reported, alongside a description of its vascular immunohistochemical profile. A female newborn presented with two exophytic pedunculated red nodules located on the alveolar ridge between the future eruption sites of the incisors and canines of the mandible and maxilla. A conservative surgical excision was performed on the second day of life. Histology revealed proliferation of round granular cells containing an abundant eosinophilic cytoplasm with basophilic nuclei, ranging from round to oval in shape. Numerous blood vessels were also seen. Immunohistochemical analysis of the granular cells revealed positivity for CD68, D2-40, Ki67, VEGF, and FGF and negativity for S100, CD34, and CD105. Immunostaining for CD34, CD105, and D2-40 confirmed the presence of a large number of blood and lymphatic vessels. Although rare, an understanding of this lesion is paramount for correct diagnosis and appropriate treatment. In the present report, the immunohistochemical profile confirmed increased vascularization, proving that these lesions are composed of not only new and preexisting blood vessels, but also lymphatic vessels. PMID- 25722897 TI - Exceptional complex chromosomal rearrangements in three generations. AB - We report an exceptional complex chromosomal rearrangement (CCR) found in three individuals in a family that involves 4 chromosomes with 5 breakpoints. The CCR was ascertained in a phenotypically abnormal newborn with additional chromosomal material on the short arm of chromosome 4. Maternal karyotyping indicated that the mother carried an apparently balanced CCR involving chromosomes 4, 6, 11, and 18. Maternal transmission of the derivative chromosome 4 resulted in partial trisomy for chromosomes 6q and 18q and a partial monosomy of chromosome 4p in the proband. Further family studies found that the maternal grandmother carried the same apparently balanced CCR as the proband's mother, which was confirmed using the whole chromosome painting (WCP) FISH. High resolution whole genome microarray analysis of DNA from the proband's mother found no evidence for copy number imbalance in the vicinity of the CCR translocation breakpoints, or elsewhere in the genome, providing evidence that the mother's and grandmother's CCRs were balanced at a molecular level. This structural rearrangement can be categorized as an exceptional CCR due to its complexity and is a rare example of an exceptional CCR being transmitted in balanced and/or unbalanced form across three generations. PMID- 25722898 TI - Novel mutation in a patient with cholesterol ester storage disease. AB - Cholesterol ester storage disease (CESD) is a chronic liver disease that typically presents with hepatomegaly. It is characterized by hypercholesterolemia, hypertriglyceridemia, high-density lipoprotein deficiency, and abnormal lipid deposition within multiple organs. It is an autosomal recessive disease that is due to a deficiency in lysosomal acid lipase (LAL) activity, which is coded by the lysosomal acid lipase gene (LIPA). We describe the case of a 5-year-old south Asian female incidentally found to have hepatomegaly, and subsequent workup confirmed the diagnosis of CESD. DNA sequencing confirmed the presence of a novel hepatic mutation. It is a four nucleotide deletion c.57_60delTGAG in exon 2 of the LIPA gene. This mutation is predicted to result in a premature translation stop downstream of the deletion (p.E20fs) and, therefore, is felt to be a disease-causing mutation. PMID- 25722899 TI - A prenatally ascertained de novo terminal deletion of chromosomal bands 1q43q44 associated with multiple congenital abnormalities in a female fetus. AB - Terminal deletions in the long arm of chromosome 1 result in a postnatally recognizable disorder described as 1q43q44 deletion syndrome. The size of the deletions and the resulting phenotype varies among patients. However, some features are common among patients as the chromosomal regions included in the deletions. In the present case, ultrasonography at 22 weeks of gestation revealed choroid plexus cysts (CPCs) and a single umbilical artery (SUA) and therefore amniocentesis was performed. Chromosomal analysis revealed a possible terminal deletion in 1q and high resolution array CGH confirmed the terminal 1q43q44 deletion and estimated the size to be approximately 8 Mb. Following termination of pregnancy, performance of fetopsy allowed further clinical characterization. We report here a prenatal case with the smallest pure terminal 1q43q44 deletion, that has been molecularly and phenotypically characterized. In addition, to our knowledge this is the first prenatal case reported with 1q13q44 terminal deletion and Pierre-Robin sequence (PRS). Our findings combined with review data from the literature show the complexity of the genetic basis of the associated syndrome. PMID- 25722900 TI - Primary cutaneous cryptococcosis treated with debridement and fluconazole monotherapy in an immunosuppressed patient: a case report and review of the literature. AB - Cryptococcus neoformans is an opportunistic yeast present in the environment. Practitioners are familiar with the presentation and management of the most common manifestation of cryptococcal infection, meningoencephalitis, in patients with AIDS or other conditions of immunocompromise. There is less awareness, however, of uncommon presentations where experience rather than evidence guides therapy. We report a case of primary cutaneous cryptococcosis (PCC) in a patient who had been immunosuppressed by chronic high-dose corticosteroid for the treatment of severe asthma. This case highlights the importance of early recognition of aggressive cellulitis that fails standard empiric antibiotic treatment in an immunocompromised patient. It also demonstrates successful treatment of PCC with a multispecialty approach including local debridement and fluconazole monotherapy. PMID- 25722901 TI - Uterine myxoid leiomyosarcoma with tumor embolism extending into the right atrium. AB - Uterine myxoid leiomyosarcoma (MLMS) is an extremely rare variant of uterine leiomyosarcoma; only 56 cases were reported from 1982 to 2013. Uterine MLMS is characterized by a myxoid appearance and highly malignant behavior. We herein report a case involving a 65-year-old woman with uterine MLMS with a large tumor embolism that reached the right atrium. A total abdominal hysterectomy, bilateral salpingooophorectomy, and tumor embolism resection with the use of a heart-lung machine were performed. Epirubicin-ifosfamide chemotherapy in the adjuvant setting led to reductions in both the tumor emboli and peritoneal dissemination. The patient retained a good quality of life for 10 months after the initial surgery. She then developed progressive disease despite treatment with pazopanib. She died of her disease 14 months after the initial surgery. Although complete surgical resection of the tumor is desirable, tumor reduction surgery followed by adjuvant chemotherapy might help to retain a good quality of life. This is the first reported case of a primary uterine MLMS with tumor emboli. PMID- 25722902 TI - Metastatic, her-2 amplified lacrimal gland carcinoma with response to lapatinib treatment. AB - Carcinoma of the lacrimal gland is a rare malignancy, limiting opportunities to develop new therapeutic regimens through clinical trials. There are no standard guidelines on optimal treatment of lacrimal gland carcinoma. In addition, lacrimal gland carcinoma includes several different subtypes with distinct behavior and response to treatment, further complicating treatment. Overexpression of the Her-2/neu protein, a potential target for new therapeutic agents, has previously been described in lacrimal gland carcinoma; however, there are no published reports regarding treatment of lacrimal gland cancer with Her-2 directed medications. This case report describes treatment of a patient with metastatic lacrimal gland carcinoma with lapatinib, an oral agent with activity against Her-2/neu amplified malignancies. In this case, Her-2 overexpression was confirmed by biopsy of a metastatic site. PET imaging obtained 6 months after the initiation of lapatinib showed evidence of a partial response to treatment, although the patient later developed progressive neurologic complications related to her malignancy and ultimately died. Lapatinib and other Her-2 targeted agents may represent an effective therapeutic option for this rare malignancy, in cases of metastatic disease. PMID- 25722903 TI - A case of calcified metastatic colorectal adenocarcinoma mimicking a benign lesion: pitfalls in diagnosis. AB - The radiological finding of a calcified intracranial lesion commonly represents a slow growing benign mass. Brain metastases originating from colorectal cancers are rare, occurring in approximately 2-3% of patients. Therefore the presence of a calcified brain lesion in a patient with a positive oncological history requires a high index of suspicion for brain metastases. Presented herein is a case of a frontoparietal calcified lesion initially overlooked as a benign tumour. Subsequent imaging following a neurological episode revealed a significant increase in size of the lesion with surrounding tissue oedema, prompting further investigation for suspicion of a calcified metastatic colorectal adenocarcinoma. PMID- 25722904 TI - Catastrophic antiphospholipid syndrome presenting as bilateral central retinal artery occlusions. AB - A previously healthy 22-year-old African American woman presented with bilateral vision loss associated with headache. Her ocular examination was significant for bilateral retinal arterial "boxcarring," retinal whitening, retinal hemorrhages, and cherry red spots. She was diagnosed with bilateral central retinal artery occlusions and was hospitalized due to concomitant diagnosis of stroke and hypercoagulable state. She was also found to be in heart failure and kidney failure. Rheumatology was consulted and she was diagnosed with catastrophic antiphospholipid syndrome in association with systemic lupus erythematosus. Approximately 7 months after presentation, the patient's vision improved and remained stable at 20/200 and 20/80. PMID- 25722905 TI - Hyperbaric oxygen therapy in branch retinal artery occlusion in a 15-year-old boy with methylenetetrahydrofolate reductase mutation. AB - Purpose. To report the efficacy of hyperbaric oxygen (HBO) therapy in a case of branch retinal artery occlusion (BRAO) in a 15-year-old boy. Methods. We report a 15-year-old boy with sudden loss of vision due to BRAO. Examination included laboratory evaluation for systemic risk factors. Follow-up exams included visual acuity, fundus examination, fundus fluorescein angiography, and visual field testing. HBO therapy was employed for treatment. Results. Medical history was positive for isolated glucocorticoid deficiency. Laboratory evaluation disclosed hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) mutation. The visual acuity 0.05 at presentation improved to 0.8 after 20 days of HBO therapy. There was no change on visual fields. Conclusion. In this pediatric case, HBO therapy was useful in the treatment of BRAO. PMID- 25722906 TI - Intravitreal bevacizumab and triamcinolone for treatment of cystoid macular oedema associated with chronic myeloid leukaemia and imatinib therapy. AB - Purpose. To evaluate the efficacy of intravitreal bevacizumab and triamcinolone in the treatment of cystoid macular oedema in a case with chronic myeloid leukaemia on imatinib treatment. Methods. We treated a 78-year-old man with bilateral cystoid macular oedema with intravitreal triamcinolone and subsequent bevacizumab in one eye and intravitreal bevacizumab, alone, in the fellow eye. Results. Serial intravitreal bevacizumab with and without triamcinolone treated cystoid macular oedema in both eyes and improved the vision. Conclusion. Intravitreal bevacizumab and triamcinolone could be viable options to treat cystoid macular oedema due to chronic myeloid leukaemia and imatinib therapy. PMID- 25722907 TI - Unusual bilateral rim fracture in femoroacetabular impingement. AB - This is a report of one case of bilateral acetabular rim fracture in association with femoroacetabular impingement (FAI), which was treated with a hip arthroscopic procedure, performing a partial resection, a labral reinsertion, and a subsequential internal fixation with cannulated screws. Up to date, there are in the literature only two reports of rim fracture and "os acetabuli" in association with FAI. In the case we present, the pincer and cam resection were performed without complications; the technique used was published previously. With this technique the head of the screw lays hidden by the reattached labrum. We removed partially the fractured rim fragment and the internal fixation of the remaining portion was achieved with a screw. In the event of a complete resection of the fragment, it would have ended with a LCE angle of 18 degrees and a high probability of hip instability. We believe that this bilateral case helps establish the efficacy and reproducibility of the technique described by Larson. PMID- 25722908 TI - Diagnosis and treatment of a lateral meniscal cyst with musculoskeletal ultrasound. AB - Meniscal cysts are a relatively uncommon occurrence that may result in pain and disability in the knee. It is widely believed that meniscal cysts are secondary to fluid extrusion from a meniscus tear. Typically, diagnosis of a meniscal cyst typically requires magnetic resonance imaging (MRI) to delineate the cyst and any associated injuries. With improvements in sonographic technology, ultrasound has emerged as a sensitive modality for detection of meniscal cysts. We present a patient with a contraindication to MRI who was diagnosed with a lateral meniscal cyst by musculoskeletal ultrasound and treated with an ultrasound-guided lateral meniscal cyst aspiration and injection. PMID- 25722909 TI - Beta-human chorionic gonadotropin producing osteosarcoma of the sacrum in a 26 year-old woman: a case report and review of the literature. AB - Ectopic secretion of beta-human chorionic gonadotropin is considered a poor prognostic marker in epithelial tumors. However, very few cases have been reported in sarcomas. We present the case of a 26-year-old female who presented with a metastatic osteosarcoma. She underwent usual testing prior to starting treatment and was found to have elevated levels of beta-human chorionic gonadotropin. As the patient was not pregnant, another source of beta-human chorionic gonadotropin secretion had to be considered. The tumor cells demonstrated positive staining for beta-human chorionic gonadotropin by immunohistochemistry, and serum levels of beta-human chorionic gonadotropin were used to monitor tumor progression and response to chemotherapy. We review the literature and discuss a potential role of beta-human chorionic gonadotropin in the treatment of such patients. PMID- 25722911 TI - Ultrasound elastographic findings of mammary fibromatosis. AB - Mammary fibromatosis is an uncommon, benign tumor of the breast. It is locally aggressive and has a high rate of recurrence. Its clinical presentation and imaging results always call for suspicion of malignancy. Here we describe a case of mammary fibromatosis with clinical manifestation, radiographic and pathologic results, and imaging findings from ultrasound elastography. PMID- 25722910 TI - Hypoxia: an unusual cause with specific treatment. AB - Hypoxia is a well-recognized consequence of venous admixture resulting from right to left intracardiac shunting. Right to left shunting is usually associated with high pulmonary artery pressure or alteration in the direction of blood flow due to an anatomical abnormality of the thorax. Surgical or percutaneous closure remains controversial; however it is performed frequently for patients presenting with clinical sequela presumed to be resulting from paradoxical embolization secondary to right to left shunting. We report two patients with hypoxia and dyspnea due to right to left shunting through a patent foramen ovale (PFO) and venous admixture in the absence of elevated pulmonary artery pressures or other predisposing conditions like pneumonectomy or diaphragmatic weakness. Percutaneous closures of the PFOs with the self-centering Amplatzer device resulted in resolution of hypoxia and symptoms related to it. PMID- 25722912 TI - Epidural venous plexus engorgement: what lies beneath? AB - Epidural venous plexus engorgement may occur due to several conditions that prevent the normal venous circulation. Inferior vena cava agenesis is a very rare cause of epidural venous enlargement. We present a case with a very thin inferior vena cava and left iliac vein agenesis who presented with back pain due to epidural vein engorgement and lacked other venous problems such as deep vein thrombosis. PMID- 25722913 TI - Perforated closed-loop obstruction secondary to gallstone ileus of the transverse colon: a rare entity. AB - Introduction. Gallstone ileus (GSI) of the colon is an extremely rare entity with potentially serious complications including perforation. Case Presentation. An 88 year-old man presented to the emergency department with abdominal pain and distension. Clinical exam revealed signs of peritonism. Computed tomography (CT) revealed GSI of the transverse colon with a closed-loop large bowel obstruction (LBO) and caecal perforation. The patient underwent emergency laparotomy. A right hemicolectomy was performed, the gallstone was removed, and a primary bowel anastomosis was undertaken. A Foley catheter was sutured into the residual gallbladder bed to create a controlled biliary fistula. The patient recovered well postoperatively with no complications. He was discharged home with the Foley catheter in situ. Discussion. Gallstone ileus is a difficult diagnosis both clinically and radiologically with only 50% of cases being diagnosed preoperatively. Most commonly it is associated with impaction at the ileocaecal valve and small bowel obstruction. Gallstone ileus should also be considered as a rare but potential cause of LBO. This is the first reported case of caecal perforation secondary to gallstone ileus of the transverse colon. Successful operative management consisted of a one-stage procedure with right hemicolectomy and formation of a controlled biliary fistula. PMID- 25722914 TI - The Natural History of Depression in Parkinson's Disease within 30-Month Follow Up. AB - Depression is one of the most common and persistent nonmotor syndromes occurring in 35% of patients diagnosed with PD. However, little information is known about the longitudinal study of its natural history of depression in PD. In this study, we identified 110 patients who are diagnosed with idiopathic PD and recruited them for assessing information about their PD related motor and nonmotor symptoms and rating scales. A follow-up evaluation was performed in 103 patients 30 months later. About 66.7% depressed patients at baseline were still depressed at follow up, and 24.4% had incident depression among subjects without depression at baseline. Greater decline on MMSE (P = 0.029), higher baseline UPDRS-II (P < 0.001) score, change of UPDRS-II (P = 0.026), and female (P < 0.001) were associated with the worsening of HDRS scores. Higher baseline HDRS score (P < 0.001) and greater decline on MMSE (P = 0.001) were related to the occurrence of depression. In conclusion, cognitive decline is a disease related factor of worsening and the occurrence of depression. Activities of Daily Living (ADL) symptoms in PD and female gender may be crucial factors of increasing depressive symptoms. PMID- 25722915 TI - Effect of exercise on motor and nonmotor symptoms of Parkinson's disease. AB - Background. Novel rehabilitation strategies have demonstrated potential benefits for motor and non-motor symptoms of Parkinson's disease (PD). Objective. To compare the effects of Lee Silverman Voice Therapy BIG (LSVT BIG therapy) versus a general exercise program (combined treadmill plus seated trunk and limb exercises) on motor and non-motor symptoms of PD. Methods. Eleven patients with early-mid stage PD participated in the prospective, double-blinded, randomized clinical trial. Both groups received 16 one-hour supervised training sessions over 4 weeks. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Modified Fatigue Impact Scale (MFIS). Five patients performed general exercise and six patients performed LSVT BIG therapy. Post-intervention evaluations were conducted at weeks 4, 12 and 24. Results. The combined cohort made improvements at all follow-up evaluations with statistical significance for UPDRS total and motor, BDI, and MFIS (P < 0.05). Conclusion. This study demonstrated positive effects of general exercise and LSVT BIG therapy on motor and non-motor symptoms of patients with PD. Our results suggest that general exercise may be as effective as LSVT BIG therapy on symptoms of PD for patients not able to readily access outpatient LSVT BIG therapy. PMID- 25722916 TI - Changes of retina are not involved in the genesis of visual hallucinations in Parkinson's disease. AB - Parkinson's disease (PD) is characterized by motor and nonmotor symptoms. Nonmotor symptoms include primarily visual hallucinations (VH). The aim of our study was to establish whether patients with PD and visual hallucinations (PDH+) have structural changes of retina detected by an optical coherence tomography (OCT) in comparison with PD patients without visual hallucinations (PDH-). We examined 52 PD patients (18 with VH, 34 without VH) and 15 age and sex matched healthy controls. Retinal nerve fiber layer (RNFL) thickness and macular thickness and volume were assessed by OCT. Functional impairment of retina was assessed using 2.5% contrast sensitivity test. For OCT outcomes we analyzed 15 PDH+ and 15 PDH- subjects matched for age, gender, and PD duration. For contrast sensitivity we analyzed 8 pairs of patients matched for age, gender, and visual acuity. There was no significant difference in RNFL thickness and macular thickness and macular volume between 15 PDH+ and 15 PDH- subjects, and also between a group of 44 PD patients (both PDH+ and PDH-) and 15 age and gender matched healthy controls. No significant difference was found for 2.5% contrast sensitivity test values between PDH+ and PDH- subjects. Therefore we conclude that functional and structural changes in retina play no role in genesis of VH in PD. PMID- 25722918 TI - Alloimmunization in patients with sickle cell disease in French Guiana. AB - This study in French Guiana assessed the frequency of alloimmunization to red cell antigens in sickle cell disease patients over 1995-2011 and identified the most common antibodies. A retrospective analysis of the transfusion history and medical records of 302 patients showed that 29/178 transfused patients had developed alloantibodies (16%). The most frequent alloantibodies were anti-LE1, anti-MNS1, anti-LE2, and anti-FY1 and were developed after transfusion of standard red cell units. The frequency of the clinically significant antibodies in this population of SCD patients was 11% (19/178). The antibodies found on those patients who had delayed hemolytic transfusion reaction were anti-K1, anti FY1, and anti-MNS3. The strategies used to decrease alloimmunization in French Guiana are discussed. PMID- 25722917 TI - Medical acute complications of intracerebral hemorrhage in young adults. AB - Background. Frequency and impact of medical complications on short-term mortality in young patients with intracerebral hemorrhage (ICH) have gone unstudied. Methods. We reviewed data of all first-ever nontraumatic ICH patients between 16 and 49 years of age treated in our hospital between January 2000 and March 2010 to identify medical complications suffered. Logistic regression adjusted for known ICH prognosticators was used to identify medical complications associated with mortality. Results. Among the 325 eligible patients (59% males, median age 42 [interquartile range 34-47] years), infections were discovered in 90 (28%), venous thrombotic events in 13 (4%), cardiac complications in 4 (1%), renal failure in 59 (18%), hypoglycemia in 15 (5%), hyperglycemia in 165 (51%), hyponatremia in 146 (45%), hypernatremia in 91 (28%), hypopotassemia in 104 (32%), and hyperpotassemia in 27 (8%). Adjusted for known ICH prognosticators and diabetes, the only independent complication associated with 3-month mortality was hyperglycemia (plasma glucose >8.0 mmol/L) (odds ratio: 5.90, 95% confidence interval: 2.25-15.48, P < 0.001). Three or more separate complications suffered also associated with increased mortality (7.76, 1.42-42.49, P = 0.018). Conclusions. Hyperglycemia is a frequent complication of ICH in young adults and is independently associated with increased mortality. However, multiple separate complications increase mortality even further. PMID- 25722919 TI - Health technology in perspective. PMID- 25722920 TI - Analysis of periodontal data using mixed effects models. AB - A fundamental problem in analyzing complex multilevel-structured periodontal data is the violation of independency among the observations, which is an assumption in traditional statistical models (e.g., analysis of variance and ordinary least squares regression). In many cases, aggregation (i.e., mean or sum scores) has been employed to overcome this problem. However, the aggregation approach still exhibits certain limitations, such as a loss of power and detailed information, no cross-level relationship analysis, and the potential for creating an ecological fallacy. In order to handle multilevel-structured data appropriately, mixed effects models have been introduced and employed in dental research using periodontal data. The use of mixed effects models might account for the potential bias due to the violation of the independency assumption as well as provide accurate estimates. PMID- 25722921 TI - A three-dimensional finite element analysis of the relationship between masticatory performance and skeletal malocclusion. AB - PURPOSE: The aim of this study was to evaluate the transfer of different occlusal forces in various skeletal malocclusions using finite element analysis (FEA). METHODS: Three representative human cone-beam computed tomography (CBCT) images of three skeletal malocclusions were obtained from the Department of Orthodontics, Yonsei University Dental Hospital, Seoul, South Korea. The CBCT scans were read into the visualization software after separating bones and muscles by uploading the CBCT images into Mimics (Materialise). Two separate three-dimensional (3D) files were exported to visualize the solid morphology of skeletal outlines without considering the inner structures. Individual dental impressions were taken and stone models were scanned with a 3D scanner. These images were integrated and occlusal motions were simulated. Displacement and Von Mises stress were measured at the nodes of the FEA models. The displacement and stress distribution were analyzed. FEA was performed to obtain the 3D deformation of the mandibles under loads of 100, 150, 200, and 225 kg. RESULTS: The distortion in all three skeletal malocclusions was comparable. Greater forces resulted in observing more distortion in FEA. CONCLUSIONS: Further studies are warranted to fully evaluate the impact of skeletal malocclusion on masticatory performance using information on muscle attachment and 3D temporomandibular joint movements. PMID- 25722922 TI - Comparison of serum amyloid A protein and C-reactive protein levels as inflammatory markers in periodontitis. AB - PURPOSE: The purpose of this study was to compare serum amyloid A (SAA) protein levels with high-sensitive C-reactive protein (hs-CRP) levels as markers of systemic inflammation in patients with chronic periodontitis. The association of serum titers of antibodies to periodontal microbiota and SAA/hs-CRP levels in periodontitis patients was also studied. METHODS: A total of 110 individuals were included in this study. Patients were assessed for levels of hs-CRP and SAA. Nonfasting blood samples were collected from participants at the time of clinical examination. The diagnosis of adipose tissue disorders was made according to previously defined criteria. To determine SAA levels, a sandwich enzyme-linked immunosorbent assay was utilized. Paper points were transferred to a sterile tube to obtain a pool of samples for polymerase chain reaction processing and the identification of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia. The serum level of IgG1 and IgG2 antibodies to P. gingivalis, A. actinomycetemcomitans, and T. forsythia was also determined. RESULTS: SAA and hs-CRP levels were higher in periodontitis patients than in controls (P<0.05). In bivariate analysis, high levels of hs-CRP (>3 mg/L) and SAA (>10 mg/L) were significantly associated with chronic periodontitis (P=0.004). The Spearman correlation analysis between acute-phase proteins showed that SAA positively correlated with hs-CRP (r=0.218, P=0.02). In the adjusted model, chronic periodontitis was associated with high levels of SAA (odds ratio [OR], 5.5; 95% confidence interval [CI], 1.6-18.2; P=0.005) and elevated hs-CRP levels (OR, 6.1, 95% CI, 1.6-23.6; P=0.008). Increased levels of serum IgG2 antibodies to P. gingivalis were associated with high levels of SAA (OR, 3.6; 95% CI, 1.4-8.5; P=0.005) and high concentrations of hs-CRP (OR, 4.3; 95% CI, 1.9 9.8; P<0.001). CONCLUSIONS: SAA and hs-CRP concentrations in patients with chronic periodontitis are comparably elevated. High serum titers of antibodies to P. gingivalis and the presence of periodontal disease are independently related to high SAA and hs-CRP levels. PMID- 25722923 TI - Complication incidence of two implant systems up to six years: a comparison between internal and external connection implants. AB - PURPOSE: This study was conducted to compare the cumulative survival rates (CSRs) and the incidence of postloading complications (PLCs) between a bone-level internal connection system (ICS-BL) and an external connection system (ECS). METHODS: The medical records of patients treated with either a ICS-BL or ECS between 2007 and 2010 at Asan Medical Center were reviewed. PLCs were divided into two categories: biological and technical. Biological complications included >4 mm of probing pocket depth, thread exposure in radiographs, and soft tissue complications, whereas technical complications included chipping of the veneering material, fracture of the implant, fracture of the crown, loosening or fracture of the abutment or screw, loss of retention, and loss of access hole filling material. CSRs were determined by a life-table analysis and compared using the log-rank chi-square test. The incidence of PLC was compared with the Pearson chi squared test. RESULTS: A total of 2,651 implants in 1,074 patients (1,167 ICS-BLs in 551 patients and 1,484 ECSs in 523 patients) were analyzed. The average observation periods were 3.4 years for the ICS-BLs and 3.1 years for the ECSs. The six-year CSR of all implants was 96.1% (94.9% for the ICS-BLs and 97.1% for the ECSs, P=0.619). Soft tissue complications were more frequent with the ECSs (P=0.005) and loosening or fracture of the abutment or screw occurred more frequently with the ICS-BLs (P<0.001). CONCLUSIONS: Within the limitations of this study, the ICS-BL was more prone to technical complications while the ECS was more vulnerable to biological complications. PMID- 25722924 TI - Bone cement grafting increases implant primary stability in circumferential cortical bone defects. AB - PURPOSE: Implant beds with an insufficient amount of cortical bone or a loss of cortical bone can result in the initial instability of a dental implant. Thus, the objective of this study was to evaluate the effect of bone cement grafting on implant initial stability in areas with insufficient cortical bone. METHODS: Two different circumferential defect depths (2.5 mm and 5 mm) and a control (no defect) were prepared in six bovine rib bones. Fourteen implants of the same type and size (4 mm*10 mm) were placed in each group. The thickness of the cortical bone was measured for each defect. After the implant stability quotient (ISQ) values were measured three times in four different directions, bone cement was grafted to increase the primary stability of the otherwise unstable implant. After grafting, the ISQ values were measured again. RESULTS: As defect depth increased, the ISQ value decreased. In the controls, the ISQ value was 85.45+/ 3.36 (mean+/-standard deviation). In circumferential 2.5-mm and 5-mm defect groups, the ISQ values were 69.42+/-7.06 and 57.43+/-6.87, respectively, before grafting. These three values were significantly different (P<0.001). After grafting the bone cement, the ISQ values significantly increased to 73.72+/-8.00 and 67.88+/-10.09 in the 2.5-mm and 5.0-mm defect groups, respectively (P<0.05 and P<0.001). The ISQ value increased to more than double that before grafting in the circumferential 5-mm defect group. The ISQ values did not significantly differ when measured in any of the four directions. CONCLUSIONS: The use of bone cement remarkably increased the stability of the implant that otherwise had an insufficient level of stability at placement, which was caused by insufficient cortical bone volume. PMID- 25722925 TI - Target specificity of the CRISPR-Cas9 system. AB - The CRISPR-Cas9 system, naturally a defense mechanism in prokaryotes, has been repurposed as an RNA-guided DNA targeting platform. It has been widely used for genome editing and transcriptome modulation, and has shown great promise in correcting mutations in human genetic diseases. Off-target effects are a critical issue for all of these applications. Here we review the current status on the target specificity of the CRISPR-Cas9 system. PMID- 25722926 TI - Surgical technique for repair of complex anterior skull base defects. AB - BACKGROUND: Modern microsurgical techniques enable en bloc resection of complex skull base tumors. Anterior cranial base surgery, particularly, has been associated with a high rate of postoperative cerebrospinal fluid (CSF) leak, meningitis, intracranial abscess, and pneumocephalus. We introduce simple modifications to already existing surgical strategies designed to minimize the incidence of postoperative CSF leak and associated morbidity and mortality. METHODS: Medical records from 1995 to 2013 were reviewed in accordance with the Institutional Review Board. We identified 21 patients who underwent operations for repair of large anterior skull base defects following removal of sinonasal or intracranial pathology using standard craniofacial procedures. Patient charts were screened for CSF leak, meningitis, or intracranial abscess formation. RESULTS: A total of 15 male and 6 female patients with an age range of 26-89 years were included. All patients were managed with the same operative technique for reconstruction of the frontal dura and skull base defect. Spinal drainage was used intraoperatively in all cases but the lumbar drain was removed at the end of each case in all patients. Only one patient required re-operation for repair of persistent CSF leak. None of the patients developed meningitis or intracranial abscess. There were no perioperative mortalities. Median follow-up was 10 months. CONCLUSION: The layered reconstruction of large anterior cranial fossa defects resulted in postoperative CSF leak in only 5% of the patients and represents a simple and effective closure option for skull base surgeons. PMID- 25722927 TI - Posterior clinoid meningioma: A case report with discussion on terminology and surgical approach. AB - BACKGROUND: Posterior clinoid process (PCP) meningiomas are rare lesions. In close proximity to these lesions are the perforators from internal carotid artery and the oculomotor nerve, which need to be considered while deciding the appropriate surgical approach. CASE DESCRIPTION: We describe a basal frontotemporo-orbito-zygomatic approach with splitting of the sylvian fissure to resect an eccentrically placed PCP meningioma. CONCLUSION: A basal frontotemporo orbito-zygomatic approach with splitting of the sylvian fissure is a safe approach to resect an eccentrically placed PCP meningioma. PMID- 25722928 TI - How has the nationwide use of off-label experimental endovascular devices been allowed for two decades as first choice and sometimes the only alternative to conventional standard and advanced surgical techniques? PMID- 25722929 TI - Neuroethics are more than the bioethics of neuroscience. PMID- 25722930 TI - Factors affecting ventriculoperitoneal shunt survival in adult patients. AB - BACKGROUND: Ventriculoperitoneal (VP) shunt insertion remains the mainstay of treatment for hydrocephalus despite a high rate of complications. The predictors of shunt malfunction have been studied mostly in pediatric patients. In this study, we report our 11-year experience with VP shunts in adult patients with hydrocephalus. We also assess the various factors affecting shunt survival in a developing country setting. METHODS: A retrospective chart analysis was conducted for all adult patients who had undergone shunt placement between the years 2001 and 2011. Kaplan-Meier curves were used to determine the duration from shunt placement to first malfunction and log-rank (Cox-Mantel) tests were used to determine the factors affecting shunt survival. RESULTS: A total of 227 patients aged 18-85 years (mean: 45.8 years) were included in the study. The top four etiologies of hydrocephalus included post-cranial surgery (23.3%), brain tumor or cyst (22.9%), normal pressure hydrocephalus (15%), and intracranial hemorrhage (13.7%). The overall incidence of shunt malfunction was 15.4% with the median time to first shunt failure being 120 days. Etiology of hydrocephalus (P = 0.030) had a significant association with the development of shunt malfunction. Early shunt failure was associated with age (P < 0.001), duration of hospital stay (P < 0.001), Glasgow Coma Scale (GCS) score less than 13 (P = 0.010), excision of brain tumors (P = 0.008), and placement of extra-ventricular drains (P = 0.033). CONCLUSIONS: Patients with increased age, prolonged hospital stay, GCS score of less than 13, extra-ventricular drains in situ, or excision of brain tumors were more likely to experience early shunt malfunction. PMID- 25722931 TI - A rare case of giant cell tumor involving the clivus resected through Le Fort I Osteotomy and median maxillotomy. AB - BACKGROUND: Giant cell tumors (GCTs) are bone tumors that seldom involve the skull. Skull GCTs preferentially occur in the sphenoid and temporal bones with few reported cases involving the clivus. Due to the rarity and complex location, surgical management is not well established for clival GCTs. CASE DESCRIPTION: A 49-year-old male presented with headaches and blurred vision in the right eye for 2 weeks. Computed tomography (CT) with contrast revealed a sellar mass eroding through the sphenoid sinuses with compression of optic chiasm. Biopsy was consistent with GCT. Patient underwent tumor resection by Le Fort I Osteotomy and median maxillotomy for an extended transsphenoidal approach. Upon discharge, patient showed no neurological deficits and intact cranial nerves. CONCLUSION: This case contributes to the limited amount of skull-based GCT cases worldwide. Additionally, the extended transoral approach can be performed safely in the context of a GCT within the clivus with acceptable morbidity and cosmesis. PMID- 25722932 TI - Robotics in the neurosurgical treatment of glioma. AB - BACKGROUND: The treatment of glioma remains a significant challenge with high recurrence rates, morbidity, and mortality. Merging image guided robotic technology with microsurgery adds a new dimension as they relate to surgical ergonomics, patient safety, precision, and accuracy. METHODS: An image-guided robot, called neuroArm, has been integrated into the neurosurgical operating room, and used to augment the surgical treatment of glioma in 18 patients. A case study illustrates the specialized technical features of a teleoperated robotic system that could well enhance the performance of surgery. Furthermore, unique positional and force information of the bipolar forceps during surgery were recorded and analyzed. RESULTS: The workspace of the bipolar forceps in this robot-assisted glioma resection was found to be 25 * 50 * 50 mm. Maximum values of the force components were 1.37, 1.84, and 2.01 N along x, y, and z axes, respectively. The maximum total force was 2.45 N. The results indicate that the majority of the applied forces were less than 0.6 N. CONCLUSION: Robotic surgical systems can potentially increase safety and performance of surgical operation via novel features such as virtual fixtures, augmented force feedback, and haptic high-force warning system. The case study using neuroArm robot to resect a glioma, for the first time, showed the positional information of surgeon's hand movement and tool-tissue interaction forces. PMID- 25722933 TI - Bionanotechnology and the future of glioma. AB - Designer nanoscaled materials have the potential to revolutionize diagnosis and treatment for glioma. This review summarizes current progress in nanoparticle based therapies for glioma treatment including targeting, drug delivery, gene delivery, and direct tumor ablation. Preclinical and current human clinical trials are discussed. Although progress in the field has been significant over the past decade, many successful strategies demonstrated in the laboratory have yet to be implemented in human clinical trials. Looking forward, we provide examples of combined treatment strategies, which harness the potential for nanoparticles to interact with their biochemical environment, and simultaneously with externally applied photons or magnetic fields. We present our notion of the "ideal" nanoparticle for glioma, a concept that may soon be realized. PMID- 25722934 TI - Convection-enhanced drug delivery for gliomas. AB - In spite of aggressive multi-modality treatments, patients diagnosed with anaplastic astrocytoma and glioblastoma continue to display poor median survival. The success of our current conventional and targeted chemotherapies are largely hindered by systemic- and neurotoxicity, as well as poor central nervous system (CNS) penetration. Interstitial drug administration via convection-enhanced delivery (CED) is an alternative that potentially overcomes systemic toxicities and CNS delivery issues by directly bypassing the blood-brain barrier (BBB). This novel approach not only allows for directed administration, but also allows for newer, tumor-selective agents, which would normally be excluded from the CNS due to molecular size alone. To date, randomized trials of CED therapy have yet to definitely show survival advantage as compared with today's standard of care, however, early studies appear to have been limited by "first generation" delivery techniques. Taking into consideration lessons learned from early trials along with decades of research, newer CED technologies and therapeutic agents are emerging, which are reviewed herein. PMID- 25722935 TI - Immunotherapy for malignant glioma. AB - Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM. PMID- 25722936 TI - Interstitial chemotherapy for malignant glioma: Future prospects in the era of multimodal therapy. AB - The advent of interstitial chemotherapy has significantly increased therapeutic options for patients with malignant glioma. Interstitial chemotherapy can deliver high concentrations of chemotherapeutic agents, directly at the site of the brain tumor while bypassing systemic toxicities. Gliadel, a locally implanted polymer that releases the alkylating agent carmustine, given alone and in combination with various other antitumor and resistance modifying therapies, has significantly increased the median survival for patients with malignant glioma. Convection enhanced delivery, a technique used to directly infuse drugs into brain tissue, has shown promise for the delivery of immunotoxins, monoclonal antibodies, and chemotherapeutic agents. Preclinical studies include delivery of chemotherapeutic and immunomodulating agents by polymer and microchips. Interstitial chemotherapy was shown to maximize local efficacy and is an important strategy for the efficacy of any multimodal approach. PMID- 25722937 TI - Treatment of Gliomas: How did we get here? AB - Over the past 30 years, the treatment of gliomas has become more multi-modality with clinical trials demonstrating that adjuvant chemo-radiation following surgery improves survival of patients. Unfortunately, this advance in therapeutic intervention has had a modest impact on patient survival, with only a 3-6 month improvement in survival during this time period. In this review, we discuss the progress made in each key aspect of glioma treatment; chemotherapy, surgery and radiation therapy. We present key clinical trials that were used as basis for current management guidelines for patients with gliomas. Ultimately, it is clear that future treatments of patients with gliomas will entail specific chronologic combinations of these three modalities in personalized regimens designed for individual patient tumor sub-type. PMID- 25722938 TI - Personalized medicine for gliomas. AB - Personalized medicine for cancer entails tailoring therapy for each patient based on unique features of the patient's tumor; physiologic, molecular, genetic and epigenetic. Our ability to molecularly characterize tumor cells has increased dramatically and shown that there are significant differences between samples from patients with the same tumor type. Given this extensive variability in mutations and pathways driving tumors in patients, seeking a single bullet is an unrealistic approach for achieving a cure. In glioblastoma multiforme (GBM), the most common adult brain tumor, this inter-tumoral heterogeneity is further complicated by intra-tumoral heterogeneity within the tumor. This suggests that for personalized therapy to work for GBMs, pharmacologic agents would not only be tailored to target the differences from patient to patient but also the clonal diversity within each patient's tumor. In this review, we provide a historical perspective on clinical trials for cancer. We also discuss the current state of molecular biology and immunology based strategies for personalized therapies for glioblastoma multiforme. PMID- 25722941 TI - Virtual microscopy in the undergraduate teaching of pathology. AB - BACKGROUND: Little evidence is available concerning the impact of virtual microscopy (VM) in the undergraduate teaching of pathology. We aimed: (1) to determine the impact in student scores when moving from conventional microscopy (CM) to VM; (2) to assess the students' impressions and changes in study habits regarding the impact of this tool. METHODS: We evaluated two groups taking the discipline of pathology in the same course, one using CM and the other VM. The same set of slides used in the CM classes was digitized in a VENTANA iScan HT (Roche Diagnostics, Sant Cugat, Spain) at *20 and observed by the students using the Virtuoso viewer (Roche Diagnostics). We evaluated the skill level reached by the students with an online test. A voluntary survey was undertaken by the VM group to assess the students' impressions regarding the resource. The day and time of any accession to the viewer were registered. RESULTS: There were no differences between the two groups in their marks in the online test (mean marks for the CM and the VM groups: 9.87 +/- 0.34 and 9.86 +/- 0.53, respectively; P = 0.880). 86.6% of the students found the software friendly, easy-to-use and effective. 71.6% of the students considered navigation easier with VM than with CM. The most appreciated feature of VM was the possibility to access the images anywhere and at any time (93.3%). 57.5% of the accesses were made on holidays and 41.9% later than 6:00 pm. CONCLUSIONS: Virtual microscopy can effectively replace the traditional methods of learning pathology, providing mobility and convenience to medical students. PMID- 25722940 TI - Macro- and Micro-heterogeneity in Pituitary and Urinary Follicle-Stimulating Hormone Glycosylation. AB - FSH glycosylation macroheterogeneity in pituitary and urinary hFSH samples was evaluated by Western blotting. Microheterogeneity in two highly purified urinary and pituitary hFSH preparations was evaluated by nano-electrospray mass spectrometry of peptide-N-glycanase-released oligosaccharides. An age-related loss of hypo-glycosylated hFSH in individual female pituitaries was indicated by progressively reduced abundance of hFSH21 relative to hFSH24. Urinary hFSH was evaluated as a potentially non-invasive indicator of glycoform abundance, as the only way for pituitary FSH to reach the urine is through the blood. Both highly purified and crude postmenopausal urinary hFSH preparations possessed the same amount of hFSH21 as postmenopausal pituitary gland FSH. Considerable microheterogeneity was encountered in both pituitary and urinary hFSH glycan populations, as 84 pituitary hFSH glycan ions were observed as compared with 68 urinary hFSH glycans. The biggest quantitative differences between the two populations were reduced abundance of bisecting GlcNAc-containing and fucosylated glycans, along with sulfated glycans in the urinary hFSH glycan population. The relative abundance of sialic acid and glycan antenna did not rationalize the retarded electrophoretic mobilities of the urinary hFSHbeta21- and alpha-subunit bands relative to the corresponding pituitary hFSH bands, as the most abundant glycans in the former possessed only 2 more branches and the same sialic content as in the latter. Site-specific glycosylation information will probably be necessary. PMID- 25722942 TI - Development and validation of an app-based cell counter for use in the clinical laboratory setting. AB - INTRODUCTION: For decades cellular differentials have been generated exclusively on analog tabletop cell counters. With the advent of tablet computers, digital cell counters - in the form of mobile applications ("apps") - now represent an alternative to analog devices. However, app-based counters have not been widely adopted by clinical laboratories, perhaps owing to a presumed decrease in count accuracy related to the lack of tactile feedback inherent in a touchscreen interface. We herein provide the first systematic evidence that digital cell counters function similarly to standard tabletop units. METHODS: We developed an app-based cell counter optimized for use in the clinical laboratory setting. Paired counts of 188 peripheral blood smears and 62 bone marrow aspirate smears were performed using our app-based counter and a standard analog device. Differences between paired data sets were analyzed using the correlation coefficient, Student's t-test for paired samples and Bland-Altman plots. RESULTS: All counts showed excellent agreement across all users and touch screen devices. With the exception of peripheral blood basophils (r = 0.684), differentials generated for the measured cell categories within the paired data sets were highly correlated (all r >= 0.899). Results of paired t-tests did not reach statistical significance for any cell type (all P > 0.05), and Bland-Altman plots showed a narrow spread of the difference about the mean without evidence of significant outliers. CONCLUSIONS: Our analysis suggests that no systematic differences exist between cellular differentials obtained via app-based or tabletop counters and that agreement between these two methods is excellent. PMID- 25722939 TI - The future of high-grade glioma: Where we are and where are we going. AB - High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy. PMID- 25722943 TI - Reqscan: An open source solution for laboratory requisition scanning, archiving and retrieval. AB - Requisition storage and retrieval are an integral part of the outpatient laboratory testing process. It is frequently necessary to review an original requisition to confirm the ordering physician, patient demographics, diagnostic information, and requested tests. Manual retrieval of a paper requisition is time consuming and tedious. Although commercial solutions exist for the scanning and archiving of barcoded paper requisitions, the tools to accomplish this are freely available from the open source software community. We present a simple dedicated piece of software, Reqscan, for scanning patient laboratory requisitions, finding all barcode information, and saving the requisition as a portable document format named according the barcode(s) found. This Python application offers a simple solution to patient requisition digitization. Reqscan has been successfully tested and implemented into routine practice for storage and retrieval of outpatient requisitions at St. Paul's Hospital, Department of Pathology and Laboratory Medicine in Vancouver, British Columbia, Canada. PMID- 25722944 TI - Chronic cerebrospinal venous insufficiency: the end of "the Big Idea"? PMID- 25722945 TI - "Liberation treatment" for chronic cerebrospinal venous insufficiency in multiple sclerosis: the truth will set you free. AB - BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been introduced as a chronic state of impaired cerebral or cervical venous drainage that may be causally implicated in multiple sclerosis (MS) pathogenesis. Moreover, percutaneous transluminal angioplasty of extracranial veins termed "Liberation treatment" has been proposed (based on nonrandomized data) as an alternative therapy for MS. METHODS: A comprehensive literature search was conducted to identify available published, peer-reviewed, clinical studies evaluating (1) the association of CCSVI with MS, (2) the reproducibility of proposed ultrasound criteria for CCSVI detection (3) the safety and efficacy of "Liberation treatment" in open-label and randomized-controlled trial (RCT) settings. RESULTS: There is substantial heterogeneity between ultrasound case control studies investigating the association of CCSVI and MS. The majority of independent investigators failed to reproduce the initially reported high prevalence rates of CCSVI in MS. The prevalence of extracranial venous stenoses evaluated by other neuroimaging modalities (contrast or MR venography) is similarly low in MS patients and healthy individuals. One small RCT failed to document any benefit in MS patients with CCSVI receiving "Liberation treatment", while an exacerbation of disease activity was observed. "Liberation treatment" has been complicated by serious adverse events (SAEs) in open-label studies (e.g., stroke, internal jugular vein thrombosis, stent migration, hydrocephalus). CONCLUSION: CCSVI appears to be a poorly reproducible and clinically irrelevant sonographic construct. "Liberation treatment" has no proven efficacy, may exacerbate underlying disease activity and has been complicated with SAEs. "Liberation treatment" should stop being offered to MS patients even in the settings of RCTs. PMID- 25722946 TI - Altered reward processing in pathological computer gamers--ERP-results from a semi-natural gaming-design. AB - INTRODUCTION: Internet Gaming Disorder has been added as a research diagnosis in section III for the DSM-V. Previous findings from neuroscientific research indicate an enhanced motivational attention toward cues related to computer games, similar to findings in substance-related addictions. On the other hand in clinical observational studies tolerance effects are reported by patients with Internet Gaming disorder. In the present study we investigated whether an enhanced motivational attention or tolerance effects are present in patients with Internet Gaming Disorder. METHODS: A clinical sample from the Outpatient Clinic for Behavioral Addictions in Mainz, Germany was recruited, fulfilling the diagnostic criteria for Internet Gaming Disorder. In a semi-natural EEG design participants played a computer game during the recording of event-related potentials to assess reward processing. RESULTS: The results indicated an attenuated P300 for patients with Internet Gaming Disorder in response to rewards in comparison to healthy controls, while the latency of N100 was prolonged and the amplitude of N100 was increased. CONCLUSIONS: Our findings support the hypothesis that tolerance effects are present in patients with Internet Gaming Disorder, when actively playing computer games. In addition, the initial orienting toward the gaming reward is suggested to consume more capacity for patients with Internet Gaming Disorder, which has been similarly reported by other studies with other methodological background in disorders of substance related addictions. PMID- 25722947 TI - Membrane potential depolarization causes alterations in neuron arrangement and connectivity in cocultures. AB - BACKGROUND: The disruption of neuron arrangement is associated with several pathologies. In contrast to action potentials, the role of resting potential (Vmem) in regulating connectivity remains unknown. METHODS: Neuron assemblies were quantified when their Vmem was depolarized using ivermectin (Ivm), a drug that opens chloride channels, for 24 h in cocultures with astrocytes. Cell aggregation was analyzed using automated cluster analysis methods. Neural connectivity was quantified based on the identification of isolated somas in phase-contrast images using image processing. Vmem was measured using voltage sensitive dyes and whole-cell patch clamping. Immunocytochemistry and Western blotting were used to detect changes in the distribution and production of the proteins. RESULTS: Data show that Vmem regulates cortical tissue shape and connectivity. Automated cluster analysis methods revealed that the degree of neural aggregation was significantly increased (0.26 clustering factor vs. 0.21 in controls, P <= 0.01). The number of beta-tubulin III positive neural projections was also significantly increased in the neural aggregates in cocultures with Ivm. Hyperpolarized neuron cells formed fewer connections (33% at 24 h, P <= 0.05) compared to control cells in 1-day cultures. Glia cell densities increased (33.3%, P <= 0.05) under depolarizing conditions. CONCLUSION: Vmem can be a useful tool to probe neuronal cells, disease tissues models, and cortical tissue arrangements. PMID- 25722948 TI - Conscientiousness is modified by genetic variation in catechol-O methyltransferase to reduce symptom complaints in IBS patients. AB - BACKGROUND: Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions or genes associated with cognitive function or sympathetic tone can influence complaints. Genetic variation in catechol-O methyltransferase (COMT) is associated with anxiety, personality, pain, and response to placebo treatment. We hypothesized that the association of complaint reporting with personality might be modified by variation in the COMT val158met genotype. METHODS: We administered a standard 25-item complaint survey weekly over 3-weeks to a convenience sample of 187 irritable bowel syndrome patients enrolled in a placebo intervention trial and conducted a repeated measures analysis. RESULTS: We found that complaint severity rating, our primary outcome, was negatively associated with the personality measures of conscientiousness (beta = -0.31 SE 0.11, P = 0.003) and agreeableness (beta = -0.38 SE 0.12, P = 0.002) and was positively associated with neuroticism (beta = 0.24 SE 0.09, P = 0.005) and anxiety (beta = 0.48 SE 0.09, P < 0.0001). We also found a significant interaction effect of COMT met alleles (beta = -32.5 SE 14.1, P = 0.021). in patients genotyped for COMT val158met (N = 87) specifically COMT * conscientiousness (beta = 0.73 SE 0.26, P = 0.0042) and COMT * anxiety (beta = 0.42 SE 0.16, P = 0.0078) interaction effects. CONCLUSION: These findings potentially broaden our understanding of the factors underlying clinical complaints to include the personality dimension of conscientiousness and its modification by COMT. PMID- 25722950 TI - Polytraumatization in an adult national sample and its association with psychological distress and self-esteem. AB - OBJECTIVE: The objective of this study was to examine the prevalence of self reported experiences of potential childhood traumas and polytraumatization, and to find cut-off values for different kinds of potential traumatic events in a national representative sample of adults in Sweden. In addition, to analyse the association between polytraumatization and both psychological distress and global self-esteem. METHOD: A web-based survey - containing SCL-25 and Rosenberg Self Esteem Scale, and Linkoping Difficult Life Events Scale - Adult - was sent out to a nationally reprative sample and 5062 people chose to participate in the study. RESULTS: Results showed that almost everyone (97%) has experienced at least one potential traumatic event and that polytraumatization (the 10% of the participants with most reported traumas) was significantly (Z = 12.57, P < 0.001, r = 0.18) associated with psychological distress and global self-esteem. Gender differences were significant (Z = 8.44, P < 0.001, r = 0.12), in that men experience more noninterpersonal traumas but women report more symptoms. The effect sizes regarding the impact of potential trauma on self-esteem were largest for women with experience of polytraumatization in the age group 18-25 (r = 0.48). There was almost linear increase in psychological distress and linear decrease in self-esteem with increasing number of traumatic events experienced. CONCLUSION: Experience of polytrauma can be considered an important factor to take into account in psychiatric settings as well. PMID- 25722951 TI - The neurophysiology of biological motion perception in schizophrenia. AB - INTRODUCTION: The ability to recognize human biological motion is a fundamental aspect of social cognition that is impaired in people with schizophrenia. However, little is known about the neural substrates of impaired biological motion perception in schizophrenia. In the current study, we assessed event related potentials (ERPs) to human and nonhuman movement in schizophrenia. METHODS: Twenty-four subjects with schizophrenia and 18 healthy controls completed a biological motion task while their electroencephalography (EEG) was simultaneously recorded. Subjects watched clips of point-light animations containing 100%, 85%, or 70% biological motion, and were asked to decide whether the clip resembled human or nonhuman movement. Three ERPs were examined: P1, N1, and the late positive potential (LPP). RESULTS: Behaviorally, schizophrenia subjects identified significantly fewer stimuli as human movement compared to healthy controls in the 100% and 85% conditions. At the neural level, P1 was reduced in the schizophrenia group but did not differ among conditions in either group. There were no group differences in N1 but both groups had the largest N1 in the 70% condition. There was a condition * group interaction for the LPP: Healthy controls had a larger LPP to 100% versus 85% and 70% biological motion; there was no difference among conditions in schizophrenia subjects. CONCLUSIONS: Consistent with previous findings, schizophrenia subjects were impaired in their ability to recognize biological motion. The EEG results showed that biological motion did not influence the earliest stage of visual processing (P1). Although schizophrenia subjects showed the same pattern of N1 results relative to healthy controls, they were impaired at a later stage (LPP), reflecting a dysfunction in the identification of human form in biological versus nonbiological motion stimuli. PMID- 25722949 TI - Multimodal imaging of mild traumatic brain injury and persistent postconcussion syndrome. AB - BACKGROUND: Persistent postconcussion syndrome (PCS) occurs in around 5-10% of individuals after mild traumatic brain injury (mTBI), but research into the underlying biology of these ongoing symptoms is limited and inconsistent. One reason for this could be the heterogeneity inherent to mTBI, with individualized injury mechanisms and psychological factors. A multimodal imaging study may be able to characterize the injury better. AIM: To look at the relationship between functional (fMRI), structural (diffusion tensor imaging), and metabolic (magnetic resonance spectroscopy) data in the same participants in the long term (>1 year) after injury. It was hypothesized that only those mTBI participants with persistent PCS would show functional changes, and that these changes would be related to reduced structural integrity and altered metabolite concentrations. METHODS: Functional changes associated with persistent PCS after mTBI (>1 year postinjury) were investigated in participants with and without PCS (both n = 8) and non-head injured participants (n = 9) during performance of working memory and attention/processing speed tasks. Correlation analyses were performed to look at the relationship between the functional data and structural and metabolic alterations in the same participants. RESULTS: There were no behavioral differences between the groups, but participants with greater PCS symptoms exhibited greater activation in attention-related areas (anterior cingulate), along with reduced activation in temporal, default mode network, and working memory areas (left prefrontal) as cognitive load was increased from the easiest to the most difficult task. Functional changes in these areas correlated with reduced structural integrity in corpus callosum and anterior white matter, and reduced creatine concentration in right dorsolateral prefrontal cortex. CONCLUSION: These data suggest that the top-down attentional regulation and deactivation of task-irrelevant areas may be compensating for the reduction in working memory capacity and variation in white matter transmission caused by the structural and metabolic changes after injury. This may in turn be contributing to secondary PCS symptoms such as fatigue and headache. Further research is required using multimodal data to investigate the mechanisms of injury after mTBI, but also to aid individualized diagnosis and prognosis. PMID- 25722953 TI - Robot-Assisted Pterygium Surgery: Feasibility Study in a Nonliving Porcine Model. AB - PURPOSE: This study aims to investigate the feasibility of pterygium surgery using the DaVinci Si HD robotic surgical system, and to describe a porcine model for pterygium surgery and evaluate its usefulness. METHODS: The pterygium models were constructed using enucleated pig eyes and cold cuts. Robotically-assisted pterygium surgeries in nonliving biological pterygium models were performed using the DaVinci Si HD robotic surgical system. Twelve models were prepared, and 12 pterygium excision and conjunctival autografts were performed. RESULTS: The DaVinci system provided the necessary dexterity to perform delicate ocular surface surgery and robotic tools were safe for the tissues. The mean duration of the surgical procedures was 36 minutes. There were no intraoperative complications and no unexpected events. CONCLUSIONS: Robotic-assisted pterygium surgery is technically feasible for porcine eyes using the DaVinci Si HD robotic surgical system. The pterygium model that we describe could be of interest for surgical training. TRANSLATIONAL RELEVANCE: Little research has been done in robotic microsurgery. Animal experimentation will allow the advantages of robotic assisted microsurgery to be identified, while underlining the improvements and innovations necessary for clinical use. PMID- 25722954 TI - The Impact of Neonatal Illness on Nutritional Requirements-One Size Does Not Fit All. AB - Sick neonates are at high risk for growth failure and poorer neurodevelopment than their healthy counterparts. The etiology of postnatal growth failure in sick infants is likely multi-factorial and includes undernutrition due to the difficulty of feeding them during their illness and instability. Illness also itself induces fundamental changes in cellular metabolism that appear to significantly alter nutritional demand and nutrient handling. Inflammation and physiologic stress play a large role in inducing the catabolic state characteristic of the critically ill newborn infant. Inflammatory and stress responses are critical short-term adaptations to promote survival, but are not conducive to promoting long-term growth and development. Conditions such as sepsis, surgery, necrotizing enterocolitis, chronic lung disease and intrauterine growth restriction and their treatments are characterized by altered energy, protein and micronutrient metabolism that result in nutritional requirements that are different from those of the healthy, growing term or preterm infant. PMID- 25722955 TI - Systems Biology Approaches Applied to Regenerative Medicine. AB - Systems biology is the creation of theoretical and mathematical models for the study of biological systems, as an engine for hypothesis generation and to provide context to experimental data. It is underpinned by the collection and analysis of complex datasets from different biological systems, including global gene, RNA, protein and metabolite profiles. Regenerative medicine seeks to replace or repair tissues with compromised function (for example, through injury, deficiency or pathology), in order to improve their functionality. In this paper, we will address the application of systems biology approaches to the study of regenerative medicine, with a particular focus on approaches to study modifications to the genome, transcripts and small RNAs, proteins and metabolites. PMID- 25722956 TI - Dedifferentiation, Transdifferentiation, and Proliferation: Mechanisms Underlying Cardiac Muscle Regeneration in Zebrafish. AB - The adult mammalian heart is increasingly recognized as a regenerative organ with a measurable capacity to replenish cardiomyocytes throughout its lifetime, illuminating the possibility of stimulating endogenous regenerative capacity to treat heart diseases. Unlike mammals, certain vertebrates possess robust capacity for regenerating a damaged heart, providing a model to understand how regeneration could be augmented in injured human hearts. Facilitated by its rich history in the study of heart development, the teleost zebrafish Danio rerio has been established as a robust model to investigate the underlying mechanism of cardiac regeneration. This review discusses the current understanding of the endogenous mechanisms behind cardiac regeneration in zebrafish, with a particular focus on cardiomyocyte dedifferentiation, transdifferentiation, and proliferation. PMID- 25722957 TI - Initial evaluation of nighttime restlessness in a naturally occurring canine model of osteoarthritis pain. AB - Chronic pain due to osteoarthritis (OA) can lead to significant disruption of sleep and increased restlessness. Our objective was to assess whether naturally occurring canine OA is associated with nighttime restlessness and so has potential as a model of OA-associated sleep disturbance. The study was designed as a two-part prospective masked, placebo-controlled study using client-owned dogs (Part A n = 60; Part B n = 19). Inclusion criteria consisted of OA associated joint pain and mobility impairment. The primary outcome measure for both parts was nighttime accelerometry. In Part B, quality of sleep was assessed using a clinical metrology instrument (Sleep and Night Time Restlessness Evaluation Score, SNoRE). Part A included dogs receiving two weeks of non steroidal anti-inflammatory drug (NSAID) preceded with two weeks of no treatment. Part B was a crossover study, with NSAID/placebo administered for two weeks followed by a washout period of one week and another two weeks of NSAID/placebo. Repeated measures analysis of variance was used to assess differences between baseline and treatment. There were no significant changes in accelerometry measured nighttime activity as a result of NSAID administration. SNoRE measures indicated significant improvements in aspects of the quality of nighttime sleep that did not involve obvious movement. These results reflect the few similar studies in human OA patients. Although accelerometry does not appear to be useful, this model has potential to model the human pain-related nighttime sleep disturbance, and other outcome measures should be explored in this model. PMID- 25722958 TI - Are epidemiological approaches suitable to study risk/preventive factors for human birth defects? AB - Birth defects are a major cause of infant morbidity and mortality and contribute substantially to long-term disability. One out of every 33 babies is born with some type of birth defect. Despite decades of research on environmental, behavioral and genetic risk factors, the vast majority of birth defects still occur without known cause. It is possible that birth defects are largely stochastic (and unavoidable) events, at which efforts to investigate their causes would be futile and unjustified. In this commentary we argue for the continued research into risk/preventive factors of human birth defects, and outline why epidemiological studies are suitable for such endeavors. First we discuss what factors to target (genetic or environmental) and how to define the pertinent research questions. Then we present a short review of both epidemiological contributions in the past and approaches to advance the field in the future. After considering also their limitations, we conclude that modern epidemiologic approaches are invaluable to advance our understanding of risk factors for human birth defects, and that interdisciplinary collaborations will also be essential to further our knowledge. PMID- 25722959 TI - Is The Allergen Really Needed in Allergy Immunotherapy? AB - Immunotherapy for type I allergies is well established and is regarded to be the most efficient treatment option besides allergen avoidance. As of today, different forms of allergen preparations are used in this regard, as well as different routes of application. Virus-like particles (VLPs) represent a potent vaccine platform with proven immunogenicity and clinical efficacy. The addition of toll-like receptor ligands and/or depot-forming adjuvants further enhances activation of innate as well as adaptive immune responses. CpG motifs represent intensively investigated and potent direct stimulators of plasmacytoid dendritic cells and B cells, while T cell responses are enhanced indirectly through increased antigen presentation and cytokine release. This article will focus on the function of VLPs loaded with DNA rich in nonmethylated CG motifs (CpGs) and the clinical experience gained in the treatment of allergic rhinitis, demonstrating clinical efficacy also if administered without allergens. Several published studies have demonstrated a beneficial impact on allergic symptoms by treatment with CpG-loaded VLPs. Subcutaneous injection of VLPs loaded with CpGs was tested with or without the adjuvant alum in the presence or absence of an allergen. The results encourage further investigation of VLPs and CpG motifs in immunotherapy, either as a stand-alone product or as adjuvants for allergen specific immunotherapy. PMID- 25722960 TI - Emerging roles of frailty and inflammaging in risk assessment of age-related chronic diseases in older adults: the intersection between aging biology and personalized medicine. AB - A chronic disease in older adults usually runs a course that is less predictable than in younger individuals. Unexplained variations in disease incidence, prognosis, therapeutic responses, and toxicity are frequently observed among older adults. This heterogeneity poses huge challenges to the current one-size fits-all health care systems, and calls for more personalized managements of chronic diseases in older adults. Aging is characterized by progressive deterioration of bodily functions with increasing risk of failure over time. The entire process is hierarchically organized, and progresses from intracellular events to changes at systemic and ultimately organism levels at different rates among different individuals. Aging biology exerts great influences on the development and progression of most age-related chronic diseases. Thus, aging biology could contribute to the complexity of illnesses that increase with age, and aging biomarkers possess a great potential to enable personalized health risk assessment and health care. We review evidences supporting the roles of aging biomarkers in risk assessment of prevalent age-related diseases. Frailty phenotype is an objectively measured indicator of advanced-stage aging that is characterized by organism-level dysfunction. In contrast, altered inflammation markers level signifies an earlier stage between cellular abnormalities and systems dysfunction. Results of human observational studies and randomized controlled trials indicate that these measures, albeit simple, greatly facilitate classification of older patients with cancer, chronic kidney disease, cardiovascular diseases and type 2 diabetes mellitus into groups that vary in disease incidence, prognosis and therapeutic response/toxicity. As the detailed mechanisms underlying the complex biologic process of aging are unraveled in the future, a larger array of biomarkers that correlate with biologic aging at different stages will be discovered. Following the translational research framework described in this article, these research efforts would result in innovations in disease prevention and management that address the huge unmet health needs of aging populations. PMID- 25722962 TI - Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal-amygdala 'aversive amplification' circuit in unmedicated generalized and social anxiety disorders. AB - BACKGROUND: We have delineated, across four prior studies, the role of positive dorsal medial prefrontal/anterior cingulate cortex (dmPFC/ACC)-amygdala circuit coupling during aversive processing in healthy individuals under stress. This translational circuit, termed the 'aversive amplification circuit', is thought to drive adaptive, harm-avoidant behavior in threatening environments. Here, in a natural progression of this prior work, we confirm that this circuit also plays a role in the pathological manifestation of anxiety disorders. METHODS: Forty-five unmedicated participants (N=22 generalized and social anxiety disorder/N=23 controls) recruited from Washington DC metropolitan area completed a simple emotion identification task during functional magnetic resonance imaging at the National Institutes of Health, Bethesda, MD, USA. FINDINGS: As predicted, a diagnosis by valence interaction was seen in whole-brain amygdala connectivity within the dmPFC/ACC clusters identified in our prior study; driven by significantly greater circuit coupling during fearful versus happy face processing in anxious, but not healthy, participants. Critically, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, providing evidence of a continuous circuit-subjective symptomatology relationship. INTERPRETATION: We track the functional role of a single neural circuit from its involvement in adaptive threat-biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety related circuit across its adaptive and maladaptive stages. Clinically, this may provide a step towards a more mechanistic spectrum-based approach to anxiety disorder diagnosis and may ultimately lead to more targeted treatments. PMID- 25722963 TI - Geostatistics: a common link between medical geography, mathematical geology, and medical geology. AB - Since its development in the mining industry, geostatistics has emerged as the primary tool for spatial data analysis in various fields, ranging from earth and atmospheric sciences to agriculture, soil science, remote sensing, and more recently environmental exposure assessment. In the last few years, these tools have been tailored to the field of medical geography or spatial epidemiology, which is concerned with the study of spatial patterns of disease incidence and mortality and the identification of potential 'causes' of disease, such as environmental exposure, diet and unhealthy behaviours, economic or socio demographic factors. On the other hand, medical geology is an emerging interdisciplinary scientific field studying the relationship between natural geological factors and their effects on human and animal health. This paper provides an introduction to the field of medical geology with an overview of geostatistical methods available for the analysis of geological and health data. Key concepts are illustrated using the mapping of groundwater arsenic concentration across eleven Michigan counties and the exploration of its relationship to the incidence of prostate cancer at the township level. PMID- 25722961 TI - Neuroepigenomics: Resources, Obstacles, and Opportunities. AB - Long-lived post-mitotic cells, such as the majority of human neurons, must respond effectively to ongoing changes in neuronal stimulation or microenvironmental cues through transcriptional and epigenomic regulation of gene expression. The role of epigenomic regulation in neuronal function is of fundamental interest to the neuroscience community, as these types of studies have transformed our understanding of gene regulation in post-mitotic cells. This perspective article highlights many of the resources available to researchers interested in neuroepigenomic investigations and discusses some of the current obstacles and opportunities in neuroepigenomics. PMID- 25722964 TI - Practical approach for the prevention and management of vitamin d deficiency in adults. AB - CONTEXT: Vitamin D inadequacy is a global problem and it is one of the most common endocrine diseases world-wide. In this review article, we covered the important practical clinical issues for screening, prevention and treatment of vitamin D deficiency in adults as well as during pregnancy and lactation. PMID- 25722965 TI - Insulin resistance, impaired glucose tolerance and alpha-thalassemia carrier state. AB - BACKGROUND: This study was designed to determine relationship between the glucose metabolism disorder (the insulin resistance and the impaired glucose tolerance) and alpha-thalassemia. METHODS: In this historical cohort study, 80Alpha thalassemia carriers and 80 healthy people were enrolled. The participants had no diabetes familial history and the waist circumference and blood pressure were in normal range (waist circumference of less than 102 cm in men, 88 cm in women and blood pressure <120/80 mmHg). The serum insulin level, fasting blood glucose (after 12 hours fasting) and two-hour plasma glucose during an oral glucose tolerance test (2-h OGTT) were measured. Insulin resistance was estimated according to homeostasis model assessment method (HOMA). Chi-square test, independent sample t-test and the relative risk were used for data analysis. RESULTS: According to FBS and OGTT results, the percentage of diabetes mellitus and pre-diabetes were 1.3% and 33.8% in Alpha-thalassemia carriers, respectively. The control group showed 2.5% diabetic and 13.8% pre-diabetic cases as well. The relative risk for the glucose tolerance impairment (diabetes and pre-diabetes) was 2.78 (95% CI: 1.31-5.88, P = 0.07).Six and a half percent of the Alpha thalassemia group and 2.5% in the control group had 2.25 <= HOMAIR <= 3.59 (an intermediate state of Insulin sensitivity) p = 0.443. In the study, there was no subject with insulin resistance (HOMAIR >3.59). CONCLUSIONS: The possibility of risk enhancement of the impaired glucose tolerance (pre-diabetes and diabetes mellitus) in patients with alpha-thalassemia is almost three times greater than the normal population without relationship with insulin resistance. Diabetic and pre-diabetic Alpha-thalassemia carrier state is younger than the general population suffering of these disorders. PMID- 25722966 TI - Effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes: a systematic review of interventional studies. AB - BACKGROUND: Diabetes and vitamin D deficiency are global epidemics. Researchers have long been exploring the role of potentially modifiable factors to manage type 2 diabetes. We conducted a systematic review of prospective studies and randomized controlled trials that involved vitamin D supplementation and specifically intended to study glycemic outcomes related to type 2 diabetes. METHODS: Two authors independently searched Medline and PubMed for longitudinal studies that had assessed the effect of vitamin D supplements on glycemic control, insulin resistance and beta-cell dysfunction in patients with diabetes. RESULTS: Seventeen randomized control trials and seven longitudinal studies with a minimum follow-up of one month were included. Results of the various short-term studies (follow up <= 3 months) suggested that vitamin D supplementation had a positive impact on glycemic control and metabolic parameters such as insulin resistance and beta cell dysfunction. However, the evidence was weak due to the low methodological quality of the studies. There was no significant effect on HbA1c, beta cell function and insulin resistance in the long-term studies (follow up > 3 months). There existed heterogeneity in the methodology of the studies, inclusion criteria, mode of supplementation of vitamin D and the duration of follow up. CONCLUSIONS: Current evidence based on randomized controlled trials and longitudinal studies do not support the notion that vitamin D supplementation can improve hyperglycemia, beta cell secretion or insulin sensitivity in patients with type 2 diabetes. Large-scale trials with proper study design, optimal vitamin D supplementation and longer follow up need to be conducted. PMID- 25722967 TI - Bioabsorbable osteofixation for orthognathic surgery. AB - Orthognathic surgery requires stable fixation for uneventful healing of osteotomized bony segments and optimal remodeling. Titanium plates and screws have been accepted as the gold standard for rigid fixation in orthognathic surgery. Although titanium osteofixation is the most widely used approach, the use of bioabsorbable devices has been increasing recently. Biodegradation of bioabsorbable devices eliminates the need for a second operation to remove metal plates and screws. However, long-term stability and relapse frequency in bioabsorbable osteofixation are still insufficiently studied, especially in cases of segmental movements of great magnitude or segmental movements to a position where bony resistance exists. This paper reviews the background, techniques, and complications of bioabsorbable osteofixation and compares bioabsorbable and titanium osteofixation in orthognathic surgery in terms of skeletal stability. PMID- 25722968 TI - Analysis of the Thinopyrum elongatum Transcriptome under Water Deficit Stress. AB - The transcriptome of Thinopyrum elongatum under water deficit stress was analyzed using RNA-Seq technology. The results showed that genes involved in processes of amplification of stress signaling, reductions in oxidative damage, creation of protectants, and roots development were expressed differently, which played an important role in the response to water deficit. The Th. elongatum transcriptome research highlights the activation of a large set of water deficit-related genes in this species and provides a valuable resource for future functional analysis of candidate genes in the water deficit stress response. PMID- 25722969 TI - Helicobacter pylori: Genomic Insight into the Host-Pathogen Interaction. AB - The advent of genomic analyses has revolutionized the study of human health. Infectious disease research in particular has experienced an explosion of bacterial genomic, transcriptomic, and proteomic data complementing the phenotypic methods employed in traditional bacteriology. Together, these techniques have revealed novel virulence determinants in numerous pathogens and have provided information for potential chemotherapeutics. The bacterial pathogen, Helicobacter pylori, has been recognized as a class 1 carcinogen and contributes to chronic inflammation within the gastric niche. Genomic analyses have uncovered remarkable coevolution between the human host and H. pylori. Perturbation of this coevolution results in dysregulation of the host-pathogen interaction, leading to oncogenic effects. This review discusses the relationship of H. pylori with the human host and environment and the contribution of each of these factors to disease progression, with an emphasis on features that have been illuminated by genomic tools. PMID- 25722970 TI - Predictive contribution of neutrophil/lymphocyte ratio in diagnosis of brucellosis. AB - Here we wanted to investigate predictive value of neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in the diagnosis of brucellosis. Thirty two brucellosis patients diagnosed with positive serum agglutination test and thirty-two randomized healthy subjects were enrolled in this study retrospectively. Result with ROC analyzes the baseline NLR and hemoglobin values were found to be significantly associated with brucellosis (P = 0.01, P = 0.01, resp.). Herein we demonstrated for the first time that NLR values were significantly associated with brucellosis. This situation can help clinicians during diagnosis of brucellosis. PMID- 25722971 TI - Proinflammatory cytokines in prostate cancer development and progression promoted by high-fat diet. AB - BACKGROUND: We aimed to examine whether proinflammatory cytokines participated in prostate cancer (PCa) development and progression promoted by high-fat diet (HFD). METHODS: TRAMP (transgenic adenocarcinoma mouse prostate) mice were randomly divided into two groups: normal diet group and HFD group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24th, and 28th week, respectively. Levels of proinflammatory cytokines, including IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were tested by FlowCytomix. Prostate tissue of TRAMP mice was used for histology study. RESULTS: A total of 13 deaths of TRAMP mice were observed, among which 3 (8.33%) were from the normal diet group and 10 (27.78%) from the HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P = 0.032). Tumor formation rate at 20th week of age of HFD group was significantly higher than that of normal diet group (P = 0.045). Proinflammatory cytokines levels, including IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were significantly higher in HFD TRAMP mice. CONCLUSIONS: HFD could promote TRAMP mouse PCa development and progression with elevated proinflammatory cytokines levels. Proinflammatory cytokines could contribute to PCa development and progression promoted by HFD. PMID- 25722972 TI - Prediction of protein-protein interactions related to protein complexes based on protein interaction networks. AB - A method for predicting protein-protein interactions based on detected protein complexes is proposed to repair deficient interactions derived from high throughput biological experiments. Protein complexes are pruned and decomposed into small parts based on the adaptive k-cores method to predict protein-protein interactions associated with the complexes. The proposed method is adaptive to protein complexes with different structure, number, and size of nodes in a protein-protein interaction network. Based on different complex sets detected by various algorithms, we can obtain different prediction sets of protein-protein interactions. The reliability of the predicted interaction sets is proved by using estimations with statistical tests and direct confirmation of the biological data. In comparison with the approaches which predict the interactions based on the cliques, the overlap of the predictions is small. Similarly, the overlaps among the predicted sets of interactions derived from various complex sets are also small. Thus, every predicted set of interactions may complement and improve the quality of the original network data. Meanwhile, the predictions from the proposed method replenish protein-protein interactions associated with protein complexes using only the network topology. PMID- 25722973 TI - Muscle IGF-1-induced skeletal muscle hypertrophy evokes higher insulin sensitivity and carbohydrate use as preferential energy substrate. AB - We characterized the metabolic profile of transgenic mice exhibiting enhanced muscle mass driven by increased mIGF-1 expression (MLC/mIGF-1). As expected, 6 month-old MLC/mIGF-1 mice were heavier than age-matched wild type (WT) mice (37.4 +/- 0.3 versus 31.8 +/- 0.6 g, resp.). MLC/mIGF-1 mice had higher respiratory quotient when compared to WT (0.9 +/- 0.03 versus 0.74 +/- 0.02, resp.) suggesting a preference for carbohydrate as the major fuel source. MLC/mIGF-1 mice had a higher rate of glucose disposal when compared to WT (3.25 +/- 0.14 versus 2.39 +/- 0.03%/min, resp.). The higher disposal rate correlated to ~ 2 fold higher GLUT4 content in the extensor digitorum longus (EDL) muscle. Analysis of mRNA content for the glycolysis-related gene PFK-1 showed ~ 3-fold upregulation in MLC/mIGF-1 animals. We also found a 50% downregulation of PGC1alpha mRNA levels in MLC/mIGF-1 mouse EDL muscle, suggesting less abundant mitochondria in this tissue. We found no difference in the expression of PPARalpha and PPARbeta/delta, suggesting no modulation of key elements in oxidative metabolism. These data together suggest a shift in metabolism towards higher carbohydrate utilization, and that could explain the increased insulin sensitivity of hypertrophied skeletal muscle in MLC/mIGF-1 mice. PMID- 25722975 TI - Corrigendum to "Long-term nitric oxide exposure enhances lung cancer cell migration". PMID- 25722974 TI - The interplay between cyclic AMP, MAPK, and NF-kappaB pathways in response to proinflammatory signals in microglia. AB - Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-alpha and IL-1beta, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-alpha stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-alpha produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-kappaB in this regulation. Following TNF-alpha there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-kappaB p65, IkappaB degradation, and NF-kappaB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-kappaB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease. PMID- 25722976 TI - Oxidative stress control by apicomplexan parasites. AB - Apicomplexan parasites cause infectious diseases that are either a severe public health problem or an economic burden. In this paper we will shed light on how oxidative stress can influence the host-pathogen relationship by focusing on three major diseases: babesiosis, coccidiosis, and toxoplasmosis. PMID- 25722977 TI - Insufflation with humidified and heated carbon dioxide in short-term laparoscopy: a double-blinded randomized controlled trial. AB - BACKGROUND: We tested the hypothesis that warm-humidified carbon dioxide (CO2) insufflation would reduce postoperative pain and morphine requirement compared to cold-dry CO2 insufflation. METHODS: A double-blinded, randomized, controlled trial was conducted to compare warm, humidified CO2 and cold-dry CO2. Patients with benign uterine diseases were randomized to either treatment (n = 48) or control (n = 49) group during laparoscopically assisted vaginal hysterectomy. Primary endpoints of the study were rest pain, movement pain, shoulder-tip pain, and cough pain at 2, 4, 6, 24, and 48 hours postoperatively, measured by visual analogue scale. Secondary outcomes were morphine consumption, rejected boli, temperature change, recovery room stay, and length of hospital stay. RESULTS: There were no significant differences in all baseline characteristics. Shoulder tip pain at 6 h postoperatively was significantly reduced in the intervention group. Pain at rest, movement pain, and cough pain did not differ. Total morphine consumption and rejected boli at 24 h postoperatively were significantly higher in the control group. Temperature change, recovery room stay, and length of hospital were similar. CONCLUSIONS: Warm, humidified insufflation gas significantly reduces postoperative shoulder-tip pain as well as morphine demand. This trial is registered with Clinical Trial Registration Number DRKS00003853 (German Clinical Trials Register (DRKS)). PMID- 25722978 TI - Identification of susceptibility genes for peritoneal, ovarian, and deep infiltrating endometriosis using a pooled sample-based genome-wide association study. AB - Characterizing genetic contributions to endometriosis might help to shorten the time to diagnosis, especially in the most severe forms, but represents a challenge. Previous genome-wide association studies (GWAS) made no distinction between peritoneal endometriosis (SUP), endometrioma (OMA), and deep infiltrating endometriosis (DIE). We therefore conducted a pooled sample-based GWAS and distinguished histologically confirmed endometriosis subtypes. We performed an initial discovery step on 10-individual pools (two pools per condition). After quality control filtering, a Monte-Carlo simulation was used to rank the significant SNPs according to the ratio of allele frequencies and the coefficient of variation. Then, a replication step of individual genotyping was conducted in an independent cohort of 259 cases and 288 controls. Our approach was very stringent but probably missed a lot of information due to the Monte-Carlo simulation, which likely explained why we did not replicate results from "classic" GWAS. Four variants (rs227849, rs4703908, rs2479037, and rs966674) were significantly associated with an increased risk of OMA. Rs4703908, located close to ZNF366, provided a higher risk of OMA (OR = 2.22; 95% CI: 1.26-3.92) and DIE, especially with bowel involvement (OR = 2.09; 95% CI: 1.12-3.91). ZNF366, involved in estrogen metabolism and progression of breast cancer, is a new biologically plausible candidate for endometriosis. PMID- 25722979 TI - A randomized study on the effectiveness of prophylactic clipping during endoscopic resection of colon polyps for the prevention of delayed bleeding. AB - BACKGROUNDS: The efficacy of clipping for preventing the delayed bleeding after the removal of colon polyps is still controversial. In order to clarify this efficacy, a randomized controlled study was performed. METHODS: One hundred and fifty-six patients with colon neoplasms (288 lesions) were enrolled in the study. The patients were randomly divided into two groups: clipping or nonclipping groups using a sealed envelope method before the endoscopic resections. Eight specialists and nine residents were invited to perform this procedure. The risk factors and the rates of delayed bleeding after the endoscopic resections in each group were investigated. RESULTS: There were no significant differences in the bleeding rate between the clipping and nonclipping groups, while the length of the procedure was significantly longer and the cost was higher in the clipping group than in the nonclipping group. The rate of bleeding was significantly higher in cases with polyps 2 cm or larger and with a longer procedure time, while none of the other factors affected the bleeding rate. CONCLUSIONS: This randomized controlled study revealed no significant effect of prophylactic clipping for preventing delayed bleeding after the endoscopic resection of colon polyps. PMID- 25722980 TI - Statistical optimization of conditions for decolorization of synthetic dyes by Cordyceps militaris MTCC 3936 using RSM. AB - In the present study, the biobleaching potential of white rot fungus Cordyceps militaris MTCC3936 was investigated. For preliminary screening, decolorization properties of C. militaris were comparatively studied using whole cells in agar based and liquid culture systems. Preliminary investigation in liquid culture systems revealed 100% decolorization achieved within 3 days of incubation for reactive yellow 18, 6 days for reactive red 31, 7 days for reactive black 8, and 11 days for reactive green 19 and reactive red 74. RSM was further used to study the effect of three independent variables such as pH, incubation time, and concentration of dye on decolorization properties of cell free supernatant of C. militaris. RSM based statistical analysis revealed that dye decolorization by cell free supernatants of C. militaris is more efficient than whole cell based system. The optimized conditions for decolorization of synthetic dyes were identified as dye concentration of 300 ppm, incubation time of 48 h, and optimal pH value as 5.5, except for reactive red 31 (for which the model was nonsignificant). The maximum dye decolorizations achieved under optimized conditions for reactive yellow 18, reactive green 19, reactive red 74, and reactive black 8 were 73.07, 65.36, 55.37, and 68.59%, respectively. PMID- 25722981 TI - Using coronary artery calcification combined with pretest clinical risk assessment as a means of determining investigation and treatment in patients presenting with chest pain in a rural setting. AB - 462 patients presenting with chest pain to a rural district general hospital underwent calcium scoring and pretest clinical risk assessment in order to stratify subsequent investigations and treatment was retrospectively reviewed. The patients were followed up for two years and further investigations and outcomes recorded. Of the 206 patients with zero calcium score, 132 patients were immediately discharged from cardiac follow-up with no further investigation on the basis of their calcium score, low pretest risk of coronary artery disease, and no significant incidental findings. After further tests, 267 patients were discharged with no further cardiac therapy, 88 patients were discharged with additional medical therapy, and 19 patients underwent coronary artery by-pass grafting or percutaneous intervention. 164 patients with incidental findings on the chest CT (computed tomography) accompanying calcium scoring were reviewed, of which 88 patients underwent further tests and follow-up for noncardiac causes of chest pain. The correlations between all major risk factors and calcium scores were weak except for a combination of diabetes and hypertension in the male gender (P = 0.012), The use of calcium scoring and pretest risk appeared to reduce the number of unnecessary cardiac investigations in our patients: however, the calcium scoring test produced a high number of incidental findings on the associated CT scans. PMID- 25722982 TI - The influence of tea tree oil (Melaleuca alternifolia) on fluconazole activity against fluconazole-resistant Candida albicans strains. AB - The aim of this study was to evaluate the activity of fluconazole against 32 clinical strains of fluconazole-resistant Candida albicans, and C. albicans ATCC 10231 reference strain, after their exposure to sublethal concentrations of tea tree oil (TTO) or its main bioactive component terpinen-4-ol. For all tested fluconazole-resistant C. albicans strains TTO and terpinen-4-ol minimal inhibitory concentrations (MICs) were low, ranging from 0.06% to 0.5%. The 24 hour exposure of fluconazole-resistant C. albicans strains to fluconazole with sublethal dose of TTO enhanced fluconazole activity against these strains. Overall, 62.5% of isolates were classified as susceptible, 25.0% exhibited intermediate susceptibility, and 12.5% were resistant. For all of the tested clinical strains the fluconazole MIC decreased from an average of 244.0 MUg/mL to an average of 38.46 MUg/mL, and the fluconazole minimal fungicidal concentrations (MFC) decreased from an average of 254.67 MUg/mL to an average of 66.62 MUg/mL. Terpinen-4-ol was found to be more active than TTO, and strongly enhanced fluconazole activity against fluconazole-resistant C. albicans strains. The results of this study demonstrate that combining natural substances such as TTO and conventional drug such as fluconazole, may help treat difficult yeast infections. PMID- 25722983 TI - Diffusion weighted MR imaging of primary and recurrent middle ear cholesteatoma: an assessment by readers with different expertise. AB - INTRODUCTION AND PURPOSE: Diffusion weighted imaging (DWI) has been proven to be valuable in the diagnosis of middle ear cholesteatoma. The aims of our study were to evaluate the advantage of multi-shot turbo spin echo (MSh TSE) DWI compared to single-shot echo-planar (SSh EPI) DWI for the diagnosis of cholesteatoma. MATERIAL AND METHODS: Thirty-two patients with clinical suspicion of unilateral cholesteatoma underwent preoperative MRI (1.5T) with SSh EPI and MSh TSE. Images were separately analyzed by 4 readers with different expertise to confirm the presence of cholesteatoma. Sensitivity, specificity, diagnostic accuracy, and positive (PPV) and negative predictive values (NPV) were assessed for each observer and interrater agreement was assessed using kappa statistics. Diagnosis was obtained at surgery. RESULTS: Overall MSh TSE showed higher diagnostic accuracy and lower negative predictive value (NPV) compared to conventional SSh EPI. Interreader agreement between the observers revealed the superiority of MSh TSE compared to SSh EPI. Interrater agreement among all the four observers was higher by using MSh TSE compared to SSh EPI. CONCLUSION: Our findings suggest that MSh TSE DWI has higher sensitivity for detection of cholesteatoma and lower probability of misdiagnosis. MSh TSE DWI is useful in guiding less experienced observers to the diagnosis. PMID- 25722985 TI - Factors affecting the accumulation of curcumin in microrhizomes of Curcuma aromatica Salisb. AB - Curcuminoids, and mainly curcumin, are potential therapeutic agents for the prevention of various diseases; however, little is known about the factors that influence their accumulation in Curcuma species. In this study, the effects of factors such as sucrose concentration, different ratios of 6-benzylaminopurine (6 BA) and alpha-naphthalene acetic acid (NAA), and light quality on the accumulation of curcumin and other curcuminoids in Curcuma aromatica were investigated. Microrhizomes grown on media containing 3% sucrose produced more curcumin and other curcuminoids than those grown on higher concentrations. Moreover, when compared to other ratios of 6-BA and NAA, microrhizomes induced on 3% sucrose media supplemented with 3.0 mg/L 6-BA and 0.5 mg/L NAA produced more curcumin and other curcuminoids; however, the amount was less than in microrhizomes grown on 3% sucrose alone. We determined that a 5% sucrose medium supplemented with 3.0 mg/L of 6-BA and 0.5 mg/L of NAA enhanced the levels of curcumin and curcuminoids and that exposure to red light further increased production. PMID- 25722984 TI - Crosstalk between red blood cells and the immune system and its impact on atherosclerosis. AB - Atherosclerosis is a chronic multifactorial disease of the arterial wall characterized by inflammation, oxidative stress, and immune system activation. Evidence exists on a pathogenic role of oxidized red blood cells (RBCs) accumulated in the lesion after intraplaque hemorrhage. This review reports current knowledge on the impact of oxidative stress in RBC modifications with the surface appearance of senescent signals characterized by reduced expression of CD47 and glycophorin A and higher externalization of phosphatidylserine. The review summarizes findings indicating that oxidized, senescent, or stored RBCs, due to surface antigen modification and release of prooxidant and proinflammatory molecules, exert an impaired modulatory activity on innate and adaptive immune cells and how this activity contributes to atherosclerotic disease. In particular RBCs from patients with atherosclerosis, unlike those from healthy subjects, fail to control lipopolysaccharide-induced DC maturation and T lymphocyte apoptosis. Stored RBCs, accompanied by shedding of extracellular vesicles, stimulate peripheral blood mononuclear cells to release proinflammatory cytokines, augment mitogen-driven T cell proliferation, and polarize macrophages toward the proinflammatory M1 activation pathway. Collectively, literature data suggest that the crosstalk between RBCs with immune cells represents a novel mechanism by which oxidative stress can contribute to atherosclerotic disease progression and may be exploited for therapeutic interventions. PMID- 25722986 TI - Pathfast presepsin assay for early diagnosis of systemic inflammatory response syndrome in patients with nephrolithiasis. AB - It is relatively difficult to diagnose bacterial sepsis in nephrolithiasis patients. The aim of the study is to evaluate the diagnostic ability of presepsin in the differential diagnosis including SIRS, infection, or sepsis and to compare its diagnostic value with other markers, mainly as CRP, procalcitonin (PCT), and white blood cell (WBC) in patients of nephrolithiasis presenting with SIRS. 39 patients of nephrolithiasis who were diagnosed as SIRS were prospectively investigated. Plasma presepsin was detected by Pathfast presepsin assay system; CRP and PCT were measured as well. Additionally, 25 nephrolithiasis patients without SIRS were included. At all timing samples, patients were classified as SIRS or non-SIRS group. Median plasma presepsin levels were significantly increased in the SIRS group compared with non-SIRS group (452 pg/mL versus 178 ng/mL, P < 0.001), and presepsin was markedly elevated even in the early stage of SIRS (584 pg/mL 6 h, 660 pg/mL 24 h versus 452 pg/mL, P < 0.001). According to the receiver-operating characteristic (ROC) analysis, presepsin demonstrated a high diagnostic value compared with either PCT or CRP. In the early stage of SIRS, presepsin remained a highly sensitive (74.7%) and specific (88.4%) diagnostic marker compared with either PCT, CRP, or WBC. Moreover, the areas under the curve (AUCs) of presepsin (84.6%) were also superior to those seen in either PCT (79.6%) or CRP (71.8%). Thus plasma presepsin levels have comparable performance in SIRS for patients with nephrolithiasis. PMID- 25722987 TI - Anti-CCP antibody levels are not associated with MS: results from a case-control study. AB - Citrullinated proteins have been suggested to play a critical role in the pathogenesis of multiple sclerosis (MS). Anticyclic citrullinated peptide (anti CCP) antibody is used in the early diagnosis of rheumatoid arthritis (RA). The objective of this study was to investigate the presence of anti-CCP antibody in patients with MS compared to RA patients and healthy controls. Fifty patients with MS (38 females, 12 males; mean age 36.72 +/- 8.82 years), 52 patients with RA (40 females, 12 males; mean age 40.87 +/- 10.17 years), and 50 healthy controls (32 females, 18 males; mean age 38.22 +/- 11.59 years) were included in this study. The levels of serum anti-CCP antibody were measured using an enzyme linked immunosorbent assay (ELISA). The results of the study showed that anti-CCP antibody levels were significantly higher in RA patients versus MS or healthy controls (P < 0.001). Moreover, anti-CCP antibody was positive in 43 (83%) patients with RA, while it was negative in all MS patients as well as in all healthy controls. Also, no significant correlation was found between the anti-CCP levels and EDSS scores (r = -0.250). In conclusion, the results of this study did not support a positive association between serum anti-CCP antibody and MS. PMID- 25722988 TI - COMT-by-sex interaction effect on psychosis proneness. AB - Schizotypy phenotypes in the general population share etiopathogenic mechanisms and risk factors with schizophrenia, supporting the notion of psychosis as a continuum ranging from nonclinical to clinical deviance. Catechol-O methyltransferase (COMT) is a candidate susceptibility gene for schizophrenia that is involved in the regulation of dopamine in the prefrontal cortex. Several recent studies have reported a sex difference in the impact of COMT genotype on psychiatric and cognitive phenotypes and personality traits. The present study investigated the association of COMT Val158Met (rs4680) with psychometric positive and negative schizotypy and psychotic experiences in a sample of 808 nonclinical young adults. The main finding was that sex moderates the association of COMT genotype with the negative dimension of both schizotypy and psychotic experiences. Male subjects carrying the Val allele tended to score higher on the negative dimension of both trait and symptom-like measures. The results from the present study are consistent with recent work suggesting an association between negative schizotypy and diminished prefrontal dopamine availability. They support the idea that a biological differentiation underlies the positive and negative schizotypy dimensions. Additionally, these findings contribute to the growing literature on sex-specific effects of COMT on the predisposition to psychiatric disorders and personality traits. PMID- 25722990 TI - A general class of derivative free optimal root finding methods based on rational interpolation. AB - We construct a new general class of derivative free n-point iterative methods of optimal order of convergence 2 (n-1) using rational interpolant. The special cases of this class are obtained. These methods do not need Newton's iterate in the first step of their iterative schemes. Numerical computations are presented to show that the new methods are efficient and can be seen as better alternates. PMID- 25722989 TI - Homocysteine, cortisol, diabetes mellitus, and psychopathology. AB - OBJECTIVE: This study investigates the association of homocysteine and cortisol with psychological factors in type 2 diabetic patients. METHOD: Homocysteine, cortisol, and psychological variables were analyzed from 131 diabetic patients. Psychological factors were assessed with the Eysenck Personality Questionnaire (EPQ), Hostility and Direction of Hostility Questionnaire (HDHQ), the Symptom Checklist 90-R (SCL 90-R), the Zung Self-Rating Depression Scale (ZDRS), and the Maudsley O-C Inventory Questionnaire (MOCI). Blood samples were taken by measuring homocysteine and cortisol in both subgroups during the initial phase of the study (T0). One year later (T1), the uncontrolled diabetic patients were reevaluated with the use of the same psychometric instruments and with an identical blood analysis. RESULTS: The relation of psychoticism and homocysteine is positive among controlled diabetic patients (P value = 0.006 < 0.05) and negative among uncontrolled ones (P value = 0.137). Higher values of cortisol correspond to lower scores on extraversion subscale (r(p) = -0.223, P value = 0.010). Controlled diabetic patients showed a statistically significant negative relationship between homocysteine and the act-out hostility subscale (r(sp) = 0.247, P = 0.023). There is a statistically significant relationship between homocysteine and somatization (r(sp) = -0.220, P = 0.043). CONCLUSIONS: These findings support the notion that homocysteine and cortisol are related to trait and state psychological factors in patients with diabetes mellitus type 2. PMID- 25722992 TI - Globally Optimal Finsler Active Contours. AB - We present a continuous and convex formulation for Finsler active contours using seed regions or utilizing a regional bias term. The utilization of general Finsler metrics instead of Riemannian metrics allows the segmentation boundary to favor appropriate locations (e.g. with strong image discontinuities) and suitable directions (e.g. aligned with dark to bright image gradients). Strong edges are not required everywhere along the desired segmentation boundary due to incorporation of a regional bias. The resulting optimization procedure is simple and efficient, and leads to binary segmentation results regardless of the underlying continuous formulation. We demonstrate the proposed method in several examples. PMID- 25722991 TI - An update on current management of advanced renal cell cancer, biomarkers, and future directions. AB - In the past decade, metastatic renal cell carcinoma (mRCC) treatment underwent significant advancement that resulted in an unprecedented improvement in the prognosis of this disease. This review will provide an updated review of currently approved treatment options, namely antiangiogenic and immunotherapy, as well as treatment guideline recommended by the National Comprehensive Cancer Network (NCCN). We will summarize studies ongoing in determining prognostic and predictive biomarkers in maximizing therapeutic benefit in the treatment of this disease. Lastly, we will discuss promising agents in clinical testing. PMID- 25722993 TI - A dual-responsive pH-sensor and its potential as a universal probe for assays of pH-changing enzymes. AB - We described a dual turn-on probe sensitive to both acidity and basicity, which could be designed by connecting a fluorophore to a quencher via metal-ligand interaction. Atto488-labeled nitrilotriacetic acid and polyhistidine peptide were used as the fluorophore and the quencher, respectively, and linked to each other by coordination with a cobalt(II) ion. After preparation of the probe, the pH sensitive dual turn-on property of the probe has been successfully observed upon responding to both acidity and basicity of the solution. The probe has been employed as a signal reporter in assays of pH-changing enzymes such as penicillinase generating acidity and adenosine deaminase generating basicity. Furthermore, the practical utility of the probe was also demonstrated by utilizing the probe in the discrimination of beta-lactamase-producing bacteria. PMID- 25722994 TI - Raman microspectroscopy of noncancerous and cancerous human breast tissues. Identification and phase transitions of linoleic and oleic acids by Raman low temperature studies. AB - We present the results of Raman studies in the temperature range of 293-77 K on vibrational properties of linoleic and oleic acids and Raman microspectroscopy of human breast tissues at room temperature. Our results confirmed the significant role of unsaturated fatty acids in differentiation of noncancerous and cancerous breast tissues and the role of vibrational spectroscopy in phase transition identification. We have found that vibrational properties are very sensitive indicators to specify phases and phase transitions typical of unsaturated fatty acids at the molecular level. Using Raman spectroscopy we have identified high temperature, middle-temperature and low-temperature phases of linoleic acid. Results obtained for linoleic acid were compared with parameters characteristic of alpha and gamma phases of oleic acid - the parent compound of polyunsaturated fatty acids. PMID- 25722995 TI - Slow-equilibration approximation in studying kinetics of protein adsorption on capillary walls. AB - Adsorption of proteins on inner capillary walls affects the quality of capillary electrophoresis (CE) analyses. Coating the capillary surface with an anti adhesive layer is a method typically used to suppress protein adsorption. The successful development of methods for prevention of protein adsorption requires quantitative characterization of the surface ability to adsorb and desorb a protein. It can be done by determining kinetic rate constants of adsorption, kad, and desorption, kdes. We have recently developed a pattern-based method for determination of kad and kdes for protein interaction with a capillary wall. The protein is moved through the capillary in a CE instrument by pressure and a temporal pattern of protein propagation through the detector is recorded. The experimental pattern is fitted with a numerical solution of the protein mass transfer to find kad and kdes. The fitting procedure is not "transparent" and can be complicated. In the present work, we obtained approximate analytical solutions of the protein mass transfer equations in the case of slow-equilibration during adsorption and desorption of the protein. These analytical solutions allow us to introduce a fitting-free parameter based method for determination of kad and kdes. It uses simple explicit expressions for kad and kdes in terms of experimental characteristics easily measured in capillaries. We tested the accuracy of the method by applying it to signals simulated with numerical solutions of protein mass-transfer equations. For the slow equilibration approximation the accuracy of kad and kdes was better than 12%. PMID- 25722996 TI - Asymmetric hydroamination catalyzed by a new chiral zirconium system: reaction scope and mechanism. AB - A new class of chiral zirconium complexes supported by chiral tridentate [O(-)NO( )]-type of ligands derived from amino acids were synthesized and structurally characterized. They catalyzed asymmetric hydroamination/cyclization of primary aminoalkenes to give five- and six-membered N-heterocyclic amines with up to 94% ee. PMID- 25722997 TI - A highly porous medical metal-organic framework constructed from bioactive curcumin. AB - A highly porous bio-MOF, medi-MOF-1, constructed from Zn and the pharmaceutical ingredient curcumin has been successfully synthesized. It can display permanent porosity with a surface area as high as ca. 3002 m(2) g(-1), which exhibits great potential in bioapplications. Its ibuprofen delivery ability, biodegradation and cytotoxicity were also studied. PMID- 25722998 TI - A competitive amino-carboxylic hydrogen bond on a gold surface. AB - An amino-carboxylic motif is identified as a novel synthon in the formation of 2D hetero-organic architectures at surfaces. The well-defined interacting scheme we describe herein represents an ideal prototypical system for further investigation of the interaction at surfaces of the two functional groups. PMID- 25722999 TI - The value of 18F-FDG positron emission tomography/computed tomography on the pre operative staging and the management of patients with pancreatic carcinoma. AB - BACKGROUND/AIMS: To evaluate the value of FDG-PET/CT on the pre-operative staging of pancreatic cancer and its impact on clinical management. METHODOLOGY: From December 2006 to January 2013, data of pancreatic carcinoma patients who underwent surgical treatment at our center was collected retrospectively. MDCT and FDGPET/CT were used separately to diagnose and stage the tumor. Pre-operation staging by MDCT with chest x-ray and by FDG-PET/CT was compared according to the final pathological staging. RESULTS: A total of 79 histologically proven pancreatic cancer patients were enrolled in this study. FDG-PET/CT was more accurate in the detection of tumor (PET/CT vs. MDCT: 93.67% vs. 88.61%, p=0.402). The SE (60.00% vs. 24.00%, p=0.01) and accuracy (87.81% vs. 76.83%, p=0.015) of PET/CT to detect distant metastasis is significantly higher than those of MDCT. FDG-PET/CT also showed advantage over CT in the detection of metastatic lymph nodes (52.83% vs. 16.98%, p<0.001; accuracy: 66.67% vs. 41.33, p=0.002). The extra staging information PET/CT provided could have skipped eight patients (10.13%) of unnecessary surgical exploration. CONCLUSION: FDG-PET/CT is an important staging procedure and helps to make the clinical decision for the patients with pancreatic carcinoma. PMID- 25723000 TI - Current concepts in the biopsy of musculoskeletal tumors. AB - BACKGROUND: A musculoskeletal tumor biopsy can involve fine needle aspiration, core needle biopsy, or incisional biopsy. Controversy regarding the diagnostic yield of these biopsy techniques continues. The purpose of this article is to summarize the current concepts in the biopsy of musculoskeletal tumors. METHODS: We performed a literature review of clinical articles reporting on the biopsy of bone and soft-tissue primary tumors. Clinical articles were excluded on the basis on abstract content if they represented case reports, review or opinion articles, or technique descriptions. Eighteen of the thirty-nine articles that remained were excluded because the results did not indicate the diagnostic accuracy of the various biopsy techniques. Thus, twenty-one articles with diagnostic data on the biopsy of bone and soft-tissue tumors were included in this review. RESULTS: Core needle biopsy appeared to be more accurate than fine needle aspiration, and incisional biopsy appeared to be more accurate than both of these techniques, but the differences did not reach significance. Incisional biopsy was more expensive than the percutaneous biopsy methods. In deep musculoskeletal tumors, incorporation of ultrasonography or computed tomography for guidance is easy and safe and can be useful for increasing the accuracy of the biopsy. Advantages of a percutaneous technique compared with an incisional one are the low risk of contamination and the minimally invasive nature. Certain anatomic locations and histologic types were associated with diagnostic difficulty. Vertebral tumors had the lowest diagnostic accuracy regardless of the biopsy technique. Myxoid, infection, and round cell histologies were associated with the lowest diagnostic accuracy. CONCLUSIONS: The current literature has not clarified the optimal biopsy technique for the diagnosis of bone and soft-tissue tumors. However, core needle biopsy is usually preferable to incisional biopsy because of the low risk of contamination and the low cost. In addition, the use of imaging guidance increases the diagnostic accuracy of musculoskeletal biopsies and reduces the risk of complications. If the result of a percutaneous biopsy is nondiagnostic, a small incisional biopsy should be performed. PMID- 25723002 TI - European Society of Cardiology Gold medallists 2014. PMID- 25723001 TI - Mechanisms of plant-insect interaction. PMID- 25723003 TI - Bernard J. Gersh, Mayo Clinic, Rochester, MN, USA, provides a transatlantic perspective on the 2014 European Society of Cardiology Guidelines on Diagnosis and Management of Hypertrophic Cardiomyopathy. PMID- 25723005 TI - The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3 ((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5?' methoxyspiro[cyclopropane-1,3?'-indolin]-2?'-one (CFI-400945) as a potent, orally active antitumor agent. AB - Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3 ((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy. PMID- 25723006 TI - ["Musical Ear" before or after cochlear implantation usually well tolerated]. PMID- 25723007 TI - [Visible defect in hearing loss and vestibular symptoms]. PMID- 25723008 TI - [Rhinomanometry and acoustic rhinometry]. PMID- 25723010 TI - Ebola guidance available from ADA. PMID- 25723009 TI - Gene-environment correlation linking aggression and peer victimization: do classroom behavioral norms matter? AB - Using a genetically informed design based on 197 Monozygotic and Dizygotic twin pairs assessed in grade 4, this study examined 1) whether, in line with a gene environment correlation (rGE), a genetic disposition for physical aggression or relational aggression puts children at risk of being victimized by their classmates, and 2) whether this rGE is moderated by classroom injunctive norm salience in regard to physical or relational aggression. Physical aggression and relational aggression, as well as injunctive classroom norm salience in regard to these behaviors, were measured via peer nominations. Peer victimization was measured via self-reports. Multi-Level Mixed modeling revealed that children with a genetic disposition for either aggressive behavior are at higher risk of being victimized by their peers only when classroom norms are unfavourable toward such behaviors. However, when classroom injunctive norms favor aggressive behaviors, a genetic disposition for physical or relational aggression may actually protect children against peer victimization. These results lend further support to the notion that bullying interventions must include the larger peer context instead of a sole focus on victims and bullies. PMID- 25723011 TI - Point-of-care tests may decrease number of antibiotic prescriptions. PMID- 25723012 TI - Tobacco use, human papillomavirus linked, researchers say. PMID- 25723013 TI - [Synchronization and propagation of electrical potentials in neural networks of the brain cortex]. AB - On the basis of the published data the scheme is proposed which explains the spread and synhronization of oscillatory activity in cortex. The main property of the neocortex is the existence of vertically oriented functional columns. Within and between the neuronal columns exist a feedforward and feedback morphological and functional connections. At the certain conditions inside the single module temporal windows are created using inhibitory process, and a synchronized activity can be generated of variable frequency (oscillations). The activity in the columns is enhanced by the synchronous involvement of great amount of neurons which is expressed in the form of local field potentials of high amplitude. Further the information about arisen in a single generator activity is transmitted through direct links to the nearby generator or to the group of such generators. In the nearby generator the activity increases and is transferred to the next generator. At the same time the signal is transmitted through feedback to the primary generator, and the activity is terminated until the next cycle will be initiated and so on along the cortex. The most important notion is that in the transfer of activity from one generator to another is involved a small number of elements. The major part of recorded oscillations of different frequency or epileptiform discharges, is not transmitted via the brain, but is generated in each module according to the characteristics transferred to it. The generation of epileptiform spikes occurs in cases when balance of inhibition determined by GABA A and GABA B receptors is disturbed. PMID- 25723014 TI - [Effects of anxiety and the COMT gene on cortical evoked potentials and performance effectiveness of selective attention]. AB - We studied influence of the anxiety-related trait Harm Avoidance and the COMT gene, which is an important modulator of prefrontal functioning, on event-related potentials in oddball paradigm and performance effectiveness of selective attention. For 50 individuals accuracy and time of searching words among letters at any desired rate and then under an instruction to perform the task as quickly and accurate as possible were measured. Scores on the Harm Avoidance scale from Cloninger's Temperament and Character Inventory, N100 and P300 parameters, and COMTVa1158Met genotypes were obtained for them as well. Searching accuracy and time were mainly related to N100 amplitude. The COMT genotype and Harm Avoidance did not affect N100 amplitude; however, the N100 amplitude modulated their effects on accuracy and time dynamics. Harm Avoidance was positively correlated with P300 latency. The results suggest that anxiety and the COMT gene effects on performance effectiveness of selective attention depend on cognitive processes reflected in N100 parameters. PMID- 25723015 TI - [Functional state of adolescents with high and low stress reactivity under informational load]. AB - The analysis of a complex psycho-physiological set of changes of 13-14 year-old adolescents with high and low stress reactivity under the circumstances of informational loads of different complex levels showed that the test tasks rise their level of CNS activity, the autonomic balance shift to the predominance of the sympathetic part of ANS and system circulatory dynamics stimulation. It is stated that at the beginning the rise of psycho-physiological reactivity under a tense informational load of boys' sexual maturation levels (SML) of a particular typological groups is coming up. It shows a high physiological cost of adaptation and low functional capabilities of adolescents' organisms who are under II and III SML. It is also stated that there are some valuable differences between the adolescents with high and low stress reactivity on the considering SML which are conditioned by the specific of cortical-stem and limbic-reticulated mechanisms of functional state regulation. PMID- 25723016 TI - [Auditory evoked potentials under attentional lapses]. AB - In order to study spontaneous attentional lapses the experimental task was used that created a moderately high attentional load and involved response choice based on stimulus feature conjunction. The participant's average correct response rate was 85.1%; they made errors in 9.6% trials and response omissions in 5.4% trials. Peak N1 of the evoked potential was consistent across all behavioral outcomes, while peak P2 amplitude was significantly greater before errors and response omissions compared to correct responses. The analysis of polygraphic indexes (ECG, EMG, SGR) did not reveal any arousal level reduction before attentional lapses. The proposed interpretation of the results obtained is based on the assumption that attentional lapses are mediated by the suppression of external stimuli information processing caused by the state of mind-wandering. PMID- 25723017 TI - [Dynamics of driven rhythm in neuron in sensorimotor cerebral cortices in rabbit on electrodermal paw stimulation]. AB - The dominant centre is a zone of proof higher excitation of neurons in the cortex of the brain, resulting from long stimulation or effector (in our case of a forepaw of an animal) or direct cortical representations of this effector. Besides of higher excitation and the firmness of excitation neurones, the dominant centre has two more very important properties--ability to summation (addition) coming to a cortex and extending on cortical neural networks excitations and inertia. Last property is shown what even in some days after the termination of the stimulations which have formed a dominant, in reply to testing stimulus (earlier indifferent for an animal) the centre is activated and puts in action effector. By means of irritation of a paw of rabbits rhythmic impulses of a current of threshold force us had been formed a rhythmic defensive dominant. Interconnected (coincidence) neuronal activity of the sensorimotor cortex of rabbits, in which the rhythmic defensive dominanta has been created, was investigated. Temporal of sequences intervals between the coincidence impulses in peaks of crosscorrelation histograms (CCH) was analyzed. Frequency of occurrence of the coincidence impulses (intervals between impulses), forming CCH was defined by means of "secondary" autocorrelation histograms (ACH) in during a minute. Peaks on "secondary" ACH showed prevalent intervals between of the coincidence impulses. For the further analysis only those peaks of "secondary" ACH, which prevailed over an average level of the histogram with significance p < 0.05 was used. It has been found that in the formed locus of the defensive dominant the coincidence impulses appear not only in the rhythm of stimulation applied in experiment-- s, but also in multiple beat to it (4, 6 and 8 s). Registration and analysis of neuronal activity were done after creation of a rhythmic dominant. At the beginning of each experiment (i.e. before a presentation of testing stimulus) single 2 --econd peaks were mainly observed, but doubles peaks of coincidence im ulses appeared with latency 2, 4 or 6 s, were absent or appeared a few case. During application of testing stimulus a significant increase doubles peaks was observed. It is supposed, that application of testing stimulus strengthens already created earlier latent focus of excitation, which begin proved as a compli-ation of rhythm:. PMID- 25723018 TI - [Cognitive abilities of rats in behavior of the active avoidance in age differences]. AB - The components of cognitive operant behavior of rats was investigated after preliminary development of a unilateral conditioned reinforcement reflex of an active avoidance aversive stimulus in the problem chamber. It is established, that cognitive abilities associated with phenotypes factors, as age and a sex. In applied aspect of research comparable actions by efficiency with Pyracetamum are reveal nootrop and activating properties at the Chinese vegetative preparation. Use of neurotropic preparations has allowed reveal their positive and negative influence on primary mental components operant behavior of an active avoidance. PMID- 25723019 TI - [Visual input affects the expression of the early genes c-Fos and ZENK in auditory telencephalic centers of pied flycatcher nestlings during the acoustically-guided freezing]. AB - The present study analyzed expression of transcriptional factors c-Fos and ZENK in 9-day-old pied flycatcher nestlings' (Ficedula hypoleuca) telencephalic auditory centers (field L, caudomedial nidopallium and caudomedial mesopallium) involved in the acoustically-guided defense behavior. Species-typical alarm call was presented to the young in three groups: 1--intact group (sighted control), 2- nestlings visually deprived just before the experiment for a short time (unsighted control) 3--nestlings visually deprived right after hatching (experimental deprivation). Induction of c-Fos as well as ZENK in nestlings from the experimental deprivation group was decreased in both hemispheres as compared with intact group. In the group of unsighted control, only the decrease of c-Fos induction was observed exclusively in the right hemisphere. These findings suggest that limitation of visual input changes the population of neurons involved into the acoustically-guided behavior, the effect being dependant from the duration of deprivation. PMID- 25723020 TI - [Behavior and functional state of the dopaminergic brain system in pups of depressive WAG/Rij rats]. AB - In the present work, it has been studied for the first time behavior and functional state of the dopaminergic brain system in pups of "depressive" WAG/Rij rats. Offspring of "depressive" WAG/Rij rats at age of 6-16 days compared with offspring of "normal" (non-depressed) outbred rats of the same age exhibited reduced rate of pshychomotor development, lower body weight, attenuation in integration of coordinated reflexes and vestibular function (greater latency of righting reflex, abnormal negative geotaxis), hyper-reactivity to tactile stimulation, reduced motivation to contact with mother (reduced infant-mother attachment). Differences in a nest seeking response induced by olfactory stimuli (olfactory discrimination test) and in locomotor activity (tests "gait reflex" and "small open field") have not been revealed. Acute injection of the antagonist of D2-like dopamine receptors clebopride 20 min before testing aggravated mother oriented behavior in 15-days-old pups of both "depressive" and "non-depressive" rats. However this effect was greater in pups of "depressive" WAG/Rij rats compared with pups of "normal" rats that may indicate reduced functional activity of the dopaminergic brain system in offspring of "depressive" rats. It is proposed that reduced attachment behavior in pups of "depressive" WAG/Rij rats might be a consequence of maternal depression and associated with it reduced maternal care. Moreover, reduced attachment behavior in pups of "depressive" rats might be an early precursor (a marker) of depressive-like pathology which become apparent later in life (approximately at age of 3 months). PMID- 25723021 TI - [Chronic recording of scapular movements in quadruped animal (dog)]. AB - The simple and relatively non-traumatic method of attaching the sensor to the scapular for chronic recording the scapula movements with magnetic tracking device is presented. During experiment the sensor fixed to the skin with the nylon thread passing through the m. deltoideus in the middle part of the scapula. This method provided stable recording of the scapular movements, shown in four dogs with previously learned coordination of head and forelimb movements. PMID- 25723022 TI - [Huntington's disease: cellular and molecular basis of pathology]. AB - Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a polyQ expansion (>36 glutamine repeats) in Huntingtin (Htt) protein. It is believed that dysfunction of corticostriatal system is one of the main pathological events. Special attention is paid to synaptic dysfunction of transmission between cortical and striatal neurons. This review focuses on modern concepts of molecular and cellular mechanisms of HD pathology and especially on alterations in corticostriatal connectivity. Calcium hypothesis of HD and new pharmacological targets are described. PMID- 25723023 TI - [Sensory analysis of the words with different occurrence frequency in the norm and in patients with schizophrenia and schizophrenic spectrum disorders]. AB - The paper introduces the study of the early stages of verbal information processing in the brain during the passive reading of single words with different occurrence frequency in Russian and of pseudo-words in healthy subjects and in patients with schizophrenia and schizophrenic spectrum disorders using evoked potentials method. It is shown that the latency of P100 and N170 in healthy subjects increased during visual perception of rare words compared to frequent ones and pseudo-words that apparently reflected the necessity to involve large quantity of brain resources during sensory stages of the processing of the verbal stimulus with intricate semantic. In patients with schizophrenia and schizophrenic spectrum disorders more complicate pattern was observed during the perception of verbal stimuli of various categories. P100 latency was the largest during pseudo-words reading, and P100 amplitude--during frequent words reading in this group. N170 atency in the patients' group was maximal during frequent words reading. Abnormality of evoked potentials polarity in anterior cortical areas most evident during visual perception of meaningful verbal information was also found in these subjects. The obtained results may point to the dysfunction ofprefrontal cortex top-down influence in schizophrenia and schizophrenic spectrum disorders, which is manifested in the disturbed sensory processing ofvarious categories verbal stimuli. PMID- 25723024 TI - [Mathematical model of mental time]. AB - On the basis of Ernst Mach's ideas and developed before the mathematical theory of mental processes, mathematical definition of duration of an interval of mental time, all over again for perception (experience) of separate event, and then- generally, i.e. for perception (experience) of sequence of events is entered. Its dependence on duration of an appropriating interval of physical time is investigated. Communication of mental time with perception of time (for two cases: "greater" and "small" intervals) is investigated. Comparison of theoretical formulas with results of experimental measurements is spent. Is defined process time which can be used, in particular, as a measure of work. The effect of the inverse of the psychological time, described in works of the Mach is analyzed and modelled. PMID- 25723025 TI - [Power of gamma responses to facial expression at eight second interval between the target and trigger stimuli]. AB - Power EEG gamma-band (21-60 Hz) in the process of forming and testing the cognitive set on the face expression is seen in conditions of the model, which provides a higher load on working memory by lengthening the intervals between the target and trigger stimuli to 8 s. The results are compared with data from previous experiments with increased load in the form of additional cognitive tasks, when there was an increase of gamma responses by "success" of the job subjects. In this study, the responses to set-stimuli were observed significant lower (relative to prestimulus period) in all groups of subjects that were treated as inhibition of gamma activity. Significant differences in the levels of power gamma-band between the groups were identified by comparing the set up steps (forming and testing), and frequency-bands. The second important difference is the absence of differences in the dynamics of power patterns gamma2 (41-60 Hz) between groups of subjects depending on the "success" of the job. We present arguments to substantiate the "paradoxical" results in the conditions of use of the plant model. PMID- 25723026 TI - [The role of the top-down inhibitory control in providing flexibility of cortical processes of recognition of emotional face expression]. AB - On the ground of own and those found in literature it is argued that the neural mechanism of implicit estimation of time intervals between significant visual events should be considered in the framework of top-down cognitive control. Based on that view, putative mechanism of active inhibition are considered. Based on the set model on recognition of emotionally negative face expression it is shown that implicit estimation of time intervals between significant visual events plays an important role in providing flexibility of cognitive processes. PMID- 25723027 TI - [Neurophysiological manifestations of the monotony state in the human-operators with different alpha-activity hemispheric asymmetry]. AB - This paper presents the monotony state investigation of the human-operator while simulator driving by using a combination of psychophysiological testing, registration of an electrocardiogram and electroencephalogram (EEG). The appearance of specific EEG-pattern (power ascension of the theta-, alpha- and beta-rhythms) during operator activity due to the monotony state progression was revealed. We found out the reduction in health, decrease activity, the increase of the situational anxiety, and the reaction time after 90 minutes of the monotonous activity. The signs of drowsiness were detected at the rest with closed eyes after operator activity. Moreover, these negative manifestations of the monotony state were observed mainly in subjects with domination of the alpha activity in the left hemisphere. PMID- 25723028 TI - [Selection for catatonic reaction in rats: a study of interstrain differences by magnetic resonance imaging]. AB - Brain studies by magnetic resonance imaging, angiography, and spectroscopy have been performed with rat strains Wistar, GC (genetic and catatonia), and PM+ (pendulum movements). Both GC and PM+ rats show similar deviations from the ancestral Wistar population in having smaller areas of the right striatum (coronal slice). The anterior horns of lateral ventricles in GC rats are smaller than in the control strain. The maximum blood flow velocity in the common carotid arteries of PM+ rats is greater. The GC and PM+ strains differ in myo-inositol level in the hippocampus. The PM+ strain is characterized by a lower taurine level in the hippocampus, which may be one of the participants regulated the predisposition to audiogenic seizures. PMID- 25723029 TI - [Comparative analysis of the maternal motivation expression in WAG/Rij and Wistar rats in the place preference and open field tests]. AB - Maternal behavior in females of WAG/Rij and Wistar rats was compared in the place preference test from 2 to 8 days after delivery, as well as in the open field test from 4 to 6 days after delivery. In females of WAG/Rij rats compared with females of Wistar rats weaker expression of maternal motivation has been revealed in both tests: they spend less time in the compartment associated with pups. Moreover, in females of WAG/Rij rats, number of approaches to pups, number of pup carryings and time spent with pups (time of contacts) were less than in females of Wistar rats. Reduced maternal motivation in females of WAG/Rij rats in the place preference test persisted in repeated testing, while in the open field test it was detected only in the first testing, indicating higher reliability of the place preference test for revealing inter-strain differences in the expression of maternal motivation. It is supposed that weaker expression of maternal behavior and preference is due to hypo-function of the mesolimbic dopaminergic bran system in WAG/Rij rats as a genetic model of depression associated with absence epilepsy. PMID- 25723030 TI - [Effects of intrabasolateral amygdala infusions of GABAA-receptor agonist and antagonist on expression and extinction of conditioned fear in rats with different freezing duration]. AB - The rats were divided into two groups (little and much freezing animals) on the grounds of differences in freezing times after fear conditioning. Effects of bilateral intrabasolateral amygdale infusions of GABAA-receptors agonist (muscimol, 0.1 microg/0.5 microL in each side), antagonist (bicuculline, 0.07 microg/0.5 microL), saline (control, 0.5 microL) on expression and extinction of fear were compared in two rats groups. Muscimol infusion before retention test led to a decrease the time of freezing, it maximal biased on fear expression in little freezing rats. Bicuculline infusion increased aggressiveness of rats, decreased freezing time, induced elements of panic behavior, and evoked maximal behavioral changes in much freezing animals. Muscimol or bicuculline infusion before extinction training resulted in facilitation of extinction in much freezing rats, but not effected in little freezing animals. Received results testified to non-equivalence influences of GABA-receptors agonist and antagonist in animals with different fear levels and supposed differences in GABAergic receptors. PMID- 25723031 TI - [Molecular mechanisms of cardiovascular disease]. AB - There are the point of molecular personified medicine view the applied importance of studying the expression of a variety of genetic and epigenetic factors (miRNAs, chemokines, cytokines, adhesion molecules, proliferation and apoptosis factors of vessel endothelium) as an innovative approach to the diagnostics and treatment of atherosclerosis, coronary heart disease, myocardial infarction. The review has described the data, which is connected with development new biological active vaso- and cardioprotective substances on the peptides base. These substances can regulate the expression of signaling molecules--the molecular markers of cardiovaslular diseases. PMID- 25723032 TI - [Functional maturing of the central nervous system, elementary school, disadaptation]. AB - Data on processes of growth and maturing of children of younger school age, basic for formation of the person are generalised. The factors of school limiting concerning formation of somatic and mental properties of schoolboys are surveyed. Signs of backlog and deformation of development of the nervous system, determining a disadaptation of the child are taped. PMID- 25723033 TI - [GABAergic receptor system and its role in system activity of the brain]. AB - In the review the analysis of structural and functional features of the main types of GABA-receptors and their distribution in various regions of a brain of vertebrata is carried out. Questions of an involvement of various types of GABA receptors in various processes of brain activity are investigated. The data concerning tonic GABAergic inhibition in CNS, connected with extrasynaptic receptors, are shown. The physiological importance of mechanisms of tonic inhibition is discussed. PMID- 25723034 TI - Editorial: introduction of the last issue in 2014. PMID- 25723035 TI - Re Elliot (2014). Personal reflections on veterinary science training and the Three Rs. ATLA 42, P38-P40. PMID- 25723036 TI - 2013 Lush Training Prize winner: XCellR8. PMID- 25723038 TI - 2013 Lush Lobbying Prize winner: International Council for Animal Protection in OECD Programme (ICAPO). PMID- 25723037 TI - 2013 Lush Training Prize winner: Anna Maria Bassi's research team, Laboratory of Analysis and Research of Physiopathology (LARF), Department of Experimental Medicine, University of Genova, Italy. PMID- 25723039 TI - 2013 Lush Lobbying Prize winner: the Swedish Fund for Research without Animal Experiments. PMID- 25723040 TI - 2013 Lush Public Awareness Prize winner: PETA, Laboratory Investigations Department, USA. PMID- 25723041 TI - 2013 Lush Public Awareness Prize winner: SAFE (Save Animals From Exploitation), New Zealand. PMID- 25723042 TI - The relationship between spirituality, health and life satisfaction of undergraduate students in the UK: an online questionnaire study. AB - US students with higher spirituality scores report better health and life satisfaction.This is the first UK study to explore the relationship between spirituality, health and life satisfaction of undergraduate students. Over 500 undergraduates completed an online questionnaire. Significant differences in spirituality score were present across college,ethnicity and religious belief. There appears to be a desire for spirituality amongst many students. Universities have a role to play in supporting students' search for meaning and purpose. Additional research is warranted to further understand the role of spirituality in the health and well-being of undergraduates. PMID- 25723043 TI - Coping with stroke: a prospective comparative cross-cultural research. AB - In the present study, the coping strategies of stroke patients were examined. An intercultural comparison between patients from Germany and Pakistan was made to investigate the impact of culture on coping processes and the need to consider these in the therapy of stroke patients. Six self-completed questionnaires were given to 53 stroke patients from Germany and 44 from Pakistan. In addition to coping processes, potential determinants on coping such as religiosity, social support and locus of control were examined. Analysis suggested both samples to be characterized by similar coping processes,but the German and Pakistani patients eventually differ in the extent they use these psychosocial determinants. This study provides modern treatment strategies for coping with stroke. PMID- 25723044 TI - Author reply: To PMID 24008807. PMID- 25723045 TI - A lifelong challenge: conflict resolution. PMID- 25723046 TI - Sodium bromide induced micelle to vesicle transitions of newly synthesized anionic surface active ionic liquids based on dodecylbenzenesulfonate. AB - Dodecylbenezenesulfonate-based anionic surface active ionic liquids (DBS-ILs) paired with onium cations, n-butyltrimethylammonium ([N1114]), 1-butyl-3 methylimidazolium ([C4mim]), and N-butylpyridinium ([C4Py]) have been synthesized. DBS-ILs were found to be highly surface active having critical micelle concentration (CMC) lower than that of their conventional analogue sodium dodecylbenezenesulfonate ([Na][DBS]). The CMC values of DBS-ILs were determined from surface tension (ST) and isothermal titration calorimetry (ITC). DBS-ILs formed micelles predominantly in the aqueous medium, and unlike [Na]DBS, the micelles of DBS-ILs could be transformed into vesicles with the addition of sodium bromide (NaBr). Micelle to vesicle transitions (MVTs) were evidenced from dynamic light scattering (DLS), turbidity, proton nuclear magnetic resonance ((1)H NMR), and cryo-TEM techniques. Thermodynamics of aggregation was investigated from ITC which indicated that the aggregation process is primarily driven by the entropy factor. The formation of a vesicle upon addition of NaBr has been accounted to the increased electrostatic interactions between the less hydrated sulfonate headgroup and the more populated bigger sized counterions along with the favored cation-pi or pi-pi interactions between them as evidenced from 2D-NOESY NMR experiments. The stimuli-responsive morphological transitions in the self-assembly of the reported anionic surface active ionic liquids (SAILs) will be useful for encapsulation and delivery of active (bio)molecules in the targeted biomedical applications. PMID- 25723047 TI - Aquatic pollution may favor the success of the invasive species A. franciscana. AB - The genus Artemia consists of several bisexual and parthenogenetic sibling species. One of them, A. franciscana, originally restricted to the New World, becomes invasive when introduced into ecosystems out of its natural range of distribution. Invasiveness is anthropically favored by the use of cryptobiotic eggs in the aquaculture and pet trade. The mechanisms of out-competition of the autochthonous Artemia by the invader are still poorly understood. Ecological fitness may play a pivotal role, but other underlying biotic and abiotic factors may contribute. Since the presence of toxicants in hypersaline aquatic ecosystems has been documented, our aim here is to study the potential role of an organophosphate pesticide, chlorpyrifos, in a congeneric mechanism of competition between the bisexual A. franciscana (AF), and one of the Old World parthenogenetic siblings, A. parthenogenetica (PD). For this purpose we carried out life table experiments with both species, under different concentrations of the toxicant (0.1, 1 and 5MUg/l), and analyzed the cholinesterase inhibition at different developmental stages. The results evidence that both, AF and PD, showed an elevated tolerance to high ranges of chlorpyrifos, but AF survived better and its fecundity was less affected by the exposure to the pesticide than that of PD. The higher fecundity of AF is a selective advantage in colonization processes leading to its establishment as NIS. Besides, under the potential selective pressure of abiotic factors, such as the presence of toxicants, its higher resistance in terms of survival and biological fitness also indicates out competitive advantages. PMID- 25723048 TI - Sensitive RIA measures testosterone concentrations in prepubertal and pubertal children comparable to tandem mass spectrometry. AB - BACKGROUND: Immunoassays have been criticized for poor accuracy at low testosterone concentrations. Mass spectrometry (MS) has been proposed as the only reliable method for testosterone determination. The aim of this study was to compare a sensitive testosterone radioimmunoassay (RIA) with results from different MS. METHODS: We compared testosterone concentrations determined by a sensitive testosterone RIA, lower limit of detection 0.03 nmol/L and limit of quantitation 0.1 nmol/L, with four tandem MS that were included in an international external quality assessment program for laboratory medicine. We also compared the morning concentrations of testosterone in girls and boys at different pubertal stages, using results from the RIA, with reported values determined by LC-MS/MS, developed for androgen determination in children. RESULTS: The mean (SD), concentrations were similar between RIA and MS: 1.5 (0.3) and 1.4 (0.4) in the child/women range (0.8-2.6 nmol/L) and 16.0 (3.7) and 17.8 (4.5) nmol/L for the adult male range (10.1-30.0 nmol/L), respectively. The ratio between RIA and MS versus results from mean values of the four MS methods was 1.0 (0.18); 1.1 (0.18) for child/women concentrations and 0.9 (0.13) for male testosterone concentrations. Furthermore, compared to the pediatric reference values determined by LC-MS/MS, the sensitive testosterone RIA delivered similar testosterone values across the different pubertal stages. CONCLUSIONS: The comparison between different tandem MS methods and a sensitive testosterone RIA illustrates that there are immunoassays that deliver clinically useful information in prepubertal and pubertal children. PMID- 25723049 TI - Multi-mycotoxin screening reveals separate occurrence of aflatoxins and ochratoxin a in Asian rice. AB - The determination of important regulated mycotoxins in rice has been reported previously but not in the individual matrix of white, brown, red, and basmati rice with respect to the matrix effect, recovery, and stability. A total of 190 Asian rices were examined for regulated mycotoxin contamination by the LC-ESI MS/MS method. Significant variation (p < 0.05) in the matrix effect was observed for fumonisins. Methanol improved the limits of detection (LOD) for HT-2 from 50 MUg/kg to 2.3 MUg/kg by promoting ionization efficiency of the ammonium-adduct. LOD and limits of quantitation ranged from 0.1 to 18 MUg/kg and 0.2-31 MUg/kg, respectively. All analytes degraded by more than 50% on storage, except fumonisins. Acetic acid (1%) provided significant improvement (p < 0.05) in recovery for all analytes in selected white rice from Thailand and China. Mean recovery ranged from 70 to 120%. RSD values were lower than 15% for all analytes. Five AFB1 and single OTA positive samples were detected. No correlation between mycotoxin contamination and rice species (r = 0) exists. PMID- 25723050 TI - Biomimetic syntheses of rubialatins A, B and related congeners. AB - The first total syntheses of rubialatins A and B, two newly discovered naphthohydroquinone dimers, were achieved with high efficiency and elegancy through rationally designed biomimetic approaches. The tandem ring contraction/Michael addition/aldol reaction followed by oxidation enabled the rapid access of prerubialatin from readily available precursors, which then diverted into rubialatins A and B via epoxidation and photoinduced skeletal rearrangement, respectively. Moreover, several new rubialatin congeners were also obtained along the synthetic tour, some of which were proved to be authentic natural products. PMID- 25723051 TI - Direct epitaxial integration of the ferromagnetic semiconductor EuO with silicon for spintronic applications. AB - Following a remarkable success of metallic spintronics, tremendous efforts have been invested into the less developed semiconductor spintronics, in particular, with the aim to produce three-terminal spintronic devices, e.g., spin transistors. One of the most important prerequisites for such a technology is an effective injection of spin-polarized carriers into a nonmagnetic semiconductor, preferably one of those currently used for industrial applications such as Si-a workhorse of modern electronics. Ferromagnetic semiconductor EuO is long believed to be the best candidate for integration with Si. Although EuO proved to offer optimal conditions for effective spin injection into silicon and in spite of considerable efforts, the direct epitaxial stabilization of stoichiometric EuO thin films on Si without any buffer layer has not been demonstrated to date. Here we report a new technique for control of EuO/Si interface on submonolayer level. Using this technique we solve a long-standing problem of direct epitaxial growth on silicon of thin EuO films which exhibit structural and magnetic properties of EuO bulk material. This result opens up new possibilities in developing all semiconductor spintronic devices. PMID- 25723052 TI - Curcumin restores mitochondrial functions and decreases lipid peroxidation in liver and kidneys of diabetic db/db mice. AB - BACKGROUND: Nitrosative and oxidative stress play a key role in obesity and diabetes-related mitochondrial dysfunction. The objective was to investigate the effect of curcumin treatment on state 3 and 4 oxygen consumption, nitric oxide (NO) synthesis, ATPase activity and lipid oxidation in mitochondria isolated from liver and kidneys of diabetic db/db mice. RESULTS: Hyperglycaemia increased oxygen consumption and decreased NO synthesis in liver mitochondria isolated from diabetic mice relative to the control mice. In kidney mitochondria, hyperglycaemia increased state 3 oxygen consumption and thiobarbituric acid reactive substances (TBARS) levels in diabetic mice relative to control mice. Interestingly, treating db/db mice with curcumin improved or restored these parameters to normal levels; also curcumin increased liver mitochondrial ATPase activity in db/db mice relative to untreated db/db mice. CONCLUSIONS: These findings suggest that hyperglycaemia modifies oxygen consumption rate, NO synthesis and increases TBARS levels in mitochondria from the liver and kidneys of diabetic mice, whereas curcumin may have a protective role against these alterations. PMID- 25723053 TI - Human papillomavirus 16E6 and NFX1-123 potentiate Notch signaling and differentiation without activating cellular arrest. AB - High-risk human papillomavirus (HR HPV) oncoproteins bind host cell proteins to dysregulate and uncouple apoptosis, senescence, differentiation, and growth. These pathways are important for both the viral life cycle and cancer development. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and they collaboratively increase the growth and differentiation master regulator, Notch1. In 16E6 expressing keratinocytes (16E6 HFKs), the Notch canonical pathway genes Hes1 and Hes5 were increased with overexpression of NFX1-123, and their expression was directly linked to the activation or blockade of the Notch1 receptor. Keratinocyte differentiation genes Keratin 1 and Keratin 10 were also increased, but in contrast their upregulation was only indirectly associated with Notch1 receptor stimulation and was fully unlinked to growth arrest, increased p21(Waf1/CIP1), or decreased proliferative factor Ki67. This leads to a model of 16E6, NFX1-123, and Notch1 differently regulating canonical and differentiation pathways and entirely uncoupling cellular arrest from increased differentiation. PMID- 25723054 TI - Serum fetuin-A and arginase-1 in human obesity model: Is there any interaction between inflammatory status and arginine metabolism? AB - Obesity is a major risk factor for many chronic metabolic diseases such as inflammation, insulin resistance (IR) and fatty liver injury. It was reported that obesity causes some variations on the serum levels of fetuin-A and is associated with arginine metabolism, especially arginase-1 levels. The aim of our study was to evaluate, the interaction and possible changes of these liver over produced proteins, fetuin-A and arginase-1 levels in obesity-related inflammatory status. Study groups were composed of individuals aged between 19 and 63 (n = 62). The control group included healthy subjects with BMI < 25, obese group included obese patients with BMI > 30 and with no other chronic disease. Biochemical markers were determined by an auto-analyzer. Adiponectin, fetuin-A, arginase-1, asymmetric dimethylarginine (ADMA), arginine, Hexanoyl-lysine (HEL) and leptin levels were measured with commercial ELISA immunoassay kits. Nitrite and nitrate were determined with colorimetric assay kit in serum samples. High sensitive C-reactive protein (hsCRP) levels and liver function enzymes activities were higher in the obese group in respect to the control group. Serum fetuin-A, arginase-1 and leptin levels were increased but adiponectin levels were decreased in obese subjects. Fetuin-A levels showed significant correlations with arginase 1 and HOMA-IR. Consequently, we carried out an investigation about higher serum fetuin-A and arginase-1 levels may have an important role in obesity and obesity related liver damage. PMID- 25723056 TI - Evaluation of biodegradation-promoting additives for plastics. AB - Biodegradation-promoting additives for polymers are increasingly being used around the world with the claim that they effectively render commercial polymers biodegradable. However, there is a lot of uncertainty about their effectiveness in degrading polymers in different environments. In this study, we evaluated the effect of biodegradation-promoting additives on the biodegradation of polyethylene (PE) and polyethylene terephthalate (PET). Biodegradation was evaluated in compost, anaerobic digestion, and soil burial environments. None of the five different additives tested significantly increased biodegradation in any of these environments. Thus, no evidence was found that these additives promote and/or enhance biodegradation of PE or PET polymers. So, anaerobic and aerobic biodegradation are not recommended as feasible disposal routes for nonbiodegradable plastics containing any of the five tested biodegradation promoting additives. PMID- 25723055 TI - Early-adult correlates of maltreatment in girls with attention deficit/hyperactivity disorder: Increased risk for internalizing symptoms and suicidality. AB - We examined whether maltreatment experienced in childhood and/or adolescence prospectively predicts young adult functioning in a diverse and well characterized sample of females with childhood-diagnosed attention deficit/hyperactivity disorder (N = 140). Participants were part of a longitudinal study and carefully evaluated in childhood, adolescence, and young adulthood (M age = 9.6, 14.3, and 19.7 years, respectively), with high retention rates across time. A thorough review of multisource data reliably established maltreatment status for each participant (M kappa = 0.78). Thirty-two (22.9%) participants experienced at least one maltreatment type (physical abuse, sexual abuse, or neglect). Criterion variables included a broad array of young adult measures of functioning gleaned from multiple-source, multiple-informant instruments. With stringent statistical control of demographic, prenatal, and family status characteristics as well as baseline levels of the criterion variable in question, maltreated participants were significantly more impaired than nonmaltreated participants with respect to self-harm (suicide attempts), internalizing symptomatology (anxiety and depression), eating disorder symptomatology, and well-being (lower overall self-worth). Effect sizes were medium. Comprising the first longitudinal evidence linking maltreatment with key young adult life impairments among a carefully diagnosed and followed sample of females with attention-deficit/hyperactivity disorder, these findings underscore the clinical importance of trauma experiences within this population. PMID- 25723057 TI - Roles of TRAF3 in T cells: many surprises. AB - Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) is broadly involved in different receptor-mediated signaling pathways. Considerable progress was made recently in understanding the role of TRAF3 in T cell biology. Here we review these new findings about how TRAF3 participates in T cell development and function. The different roles of TRAF3 in distinct immune cells are also compared. That TRAF3 is required for T cell effector functions, and invariant Natural Killer T cell function and development, was unexpected. Another surprising finding is that TRAF3 normally restrains regulatory T cell development. It is now clear that TRAF3 regulates signaling to T cells not only through costimulatory members of the TNFR superfamily, but also through the T cell receptor complex, and cytokine receptors. The diverse roles it plays support the multifaceted nature of this molecule. How TRAF3 mediates integration of different signaling cascades is an important topic for future study. PMID- 25723059 TI - The impact of dose, irradiance and growth conditions on Aspergillus niger (renamed A. brasiliensis) spores low-pressure (LP) UV inactivation. AB - The use of Aspergillus niger (A. niger) fungal spores as challenge organism for UV reactor validation studies is attractive due to their high UV-resistance and non-pathogenic nature. However A. niger spores UV dose-response was dependent upon sporulation conditions and did not follow the Bunsen-Roscoe Principle of time-dose reciprocity. Exposure to 8 h of natural sunlight for 10 consecutive days increased UV resistance when compared to spores grown solely in dark conditions. Application of 250 mJ cm(-2) at high irradiance (0.11 mW cm(-2)) resulted in a 2-log inactivation; however, at low irradiance (0.022 mW cm(-2)) a 1-log inactivation was achieved. In addition, surface electron microscopy (SEM) images revealed morphological changes between the control and UV exposed spores in contrast to other well accepted UV calibrated test organisms, which show no morphological difference with UV exposure. PMID- 25723060 TI - Endocrine disruptive effects of cadmium on steroidogenesis: human adrenocortical carcinoma cell line NCI-H295R as a cellular model for reproductive toxicity testing. AB - Cadmium (Cd) is a known endocrine disruptor with the ability to affect the production of hormones involved in the regulation of reproductive processes. In this study human adrenocortical carcinoma cell line NCI-H295R was used as an in vitro biological model to study the effect of cadmium (CdCl2) on steroidogenesis. The cell cultures were exposed to different concentrations of CdCl2 (1.90, 3.90, 7.80, 15.60, 31.20 and 62.50 MUM) and compared to control (medium without CdCl2). Cell viability was measured by the metabolic activity (MTT) assay for estimation of mitochondria structural integrity. Quantification of sexual steroid production directly from aliquots of the medium was performed by enzyme linked immunosorbent assay (ELISA). Following 48 h culture of the cells in the presence of CdCl2 a concentration-dependent depletion in progesterone production was observed at the lower concentrations of CdCl2. The lowest amount of progesterone was significantly detected in groups with the higher doses (>= 31.20 MUM) of CdCl2, which elicited significant (P < 0.01) cytotoxic action, too. Cadmium decreased testosterone release in the whole applied range even at the lower concentration of CdCl2. The release of 17beta-estradiol decreased as well, but the decline was less pronounced compared to decrease of progesterone and testosterone. The cytotoxic effect was significantly (P < 0.01) detected at all concentrations of CdCl2 (1.90-62.50 MUM) used in the study. However, the cell viability remained relatively high (>75%) up to 7.80 MUM of CdCl2 and significantly (P < 0.01) decreased at 15.60 MUM and higher concentrations of CdCl2. These results suggest that cadmium has endocrine disruptive effects on sexual steroid synthesis even at very low concentrations. PMID- 25723058 TI - Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option? AB - Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial. PMID- 25723061 TI - Enzymatic cyanide degradation by cell-free extract of Rhodococcus UKMP-5M. AB - The cell-free extract of locally isolated Rhodococcus UKMP-5M strain was used as an alternative to develop greener and cost effective cyanide removal technology. The present study aims to assess the viability of the cell-free extract to detoxify high concentrations of cyanide which is measured through the monitoring of protein concentration and specific cyanide-degrading activity. When cyanide grown cells were subjected to grinding in liquid nitrogen which is relatively an inexpressive and fast cell disruption method, highest cyanide-degrading activity of 0.63 mM min(-1) mg(-1) protein was obtained in comparison to enzymatic lysis and agitation with fine glass beads. The cell-free extracts managed to degrade 80% of 20 mM KCN within 80 min and the rate of cyanide consumption increased linearly as the concentration of protein was raised. In both cases, the addition of co-factor was not required which proved to be advantageous economically. The successful formation of ammonia and formate as endproducts indicated that the degradation of cyanide by Rhodococcus UKMP-5M proceeded via the activity of cyanidase and the resulting non-toxic products are safe for disposal into the environment. Further verification with SDS-PAGE revealed that the molecular weight of the active enzyme was estimated to be 38 kDa, which is consistent with previously reported cyanidases. Thus, the utilization of cell-free extracts as an alternative to live microbial in cyanide degradation offers numerous advantageous such as the potential to tolerate and degrade higher concentration of cyanide and total reduction in the overall cost of operation since the requirement for nutrient support is irrelevant. PMID- 25723062 TI - Stimulation of 2-methylisoborneol (MIB) production by actinomycetes after cyclic chlorination in drinking water distribution systems. AB - The impact of fluctuation in chlorine residual on actinomycetes and the production of 2-methylisoborneol (MIB) were studied in cast-iron and PVC model distribution systems. Actinomycetes were spiked in each system and continued operation for a 12-day non-chlorine experiment, resulting in no changes in actinomycetes and MIB concentrations. Three cyclic chlorination events were performed and chlorine residuals were maintained as follows: 1.0 mg L(-1) for 24 h, 0 mg L(-1) for 48 h, 0.5 mg L(-1) for 48 h, 0 mg L(-1) for 48 h and 2 mg L(-1) for 24 h. After each chlorination event, 2 -3 log decrease in actinomycetes was noted in both systems. However, within 48 h at 0 mg L(-1) chlorine, the actinomycetes recovered to the pre-chlorination levels. On the contrary, MIB concentration in both systems remained un-impacted after the first cycle and increased by fourfold (< 5 to > 20 mg L(-1)) after the second cycle, which lasted through the third cycle despite the fact that actinomycetes numbers fluctuated 2 3 logs during this time period. For obtaining biofilm samples from field, water meters were collected from municipality drinking water distribution systems located in central Arizona. The actinomycetes concentration in asbestos cement pipe and cast iron pipe averaged 3.1 * 10(3) and 1.9 * 10(4) CFU cm(-2), respectively. The study shows that production of MIB is associated with changes in chlorine residual in the systems. This is the first report of cyclic chlorine shock as a stimulus for MIB production by actinomycetes in drinking water distribution system's ecology. PMID- 25723063 TI - Degradation of phenylamine by catalytic wet air oxidation using metal catalysts with modified supports. AB - The effect of acid treatments with HCl and HNO3 on the surface area and surface chemistry of three granular activated carbons was studied. These supports were characterized and the hydrochloric acid treatment leads to the best activated carbon support (AC2-C). The catalytic behavior of Pt, Ru and Fe (1 wt.%) supported on granular activated carbon treated with HCl was tested in the phenylamine continuous catalytic wet air oxidation in a three-phase, high pressure catalytic reactor over a range of reaction temperatures 130-170oC and total pressure of 1.0-3.0 MPa at LHSV = 0.4-1 h(-1), whereas the phenylamine concentration range and the catalyst loading were 5-16 mol.m(-3) and 0.5-1.5 g, respectively. Activity as well as conversion varied as a function of the metal, the catalyst preparation method and operation conditions. Higher activities were obtained with Pt incorporated on hydrochloric acid -treated activated carbon by the ion exchange method. In steady state, approximately 98% phenylamine conversion, 77% of TOC and 94% of COD removal, was recorded at 150oC, 11 mol m( 3) of phenylamine concentration and 1.5 g of catalyst, and the selectivity to non organic compounds was 78%. Several reaction intermediaries were detected. A Langmuir-Hinshelwood model gave an excellent fit of the kinetic data of phenylamine continuous catalytic wet air oxidation over the catalysts of this work. PMID- 25723064 TI - Mathematical modeling of COD removal via the combined treatment of domestic wastewater and landfill leachate based on the PACT process. AB - The experiments performed in this study consisted of 16 batch reactors fed different mixtures of landfill leachate combined with synthetic wastewater treated using the Powdered Activated Carbon Treatment (PACT) process. The objective was to measure the COD mass removal per liter each day for each reactor using two models: the first model combined the variables PAC concentration (0 g.L(-1), 2 g.L(-1), 4 g.L(-1), and 6 g.L(-1)) and leachate rate in the wastewater (0%, 2%, 5%, and 10%), and the second model combined the PAC concentration and the influent COD. The Response Surface Methodology with Central Composite Design was used to describe the response surface of both models considered in this study. Domestic wastewater was produced under controlled conditions in the laboratory where the experiments were performed. The results indicated that the PAC effect was null when the influent did not contain leachate; however, as the concentration of leachate applied to the mixture was increased, the addition of a higher PAC concentration resulted in a better COD mass removal in the reactors. The adjusted R(2) values of the two models were greater than 0.95, and the predicted R(2) values were greater than 0.93. The models may be useful for wastewater treatment companies to calculate PAC requirements in order to meet COD mass removal objectives in combined treatment. PMID- 25723065 TI - Adsorptive removal of Cu(II) and Ni(II) from single-metal, binary-metal, and industrial wastewater systems by surfactant-modified alumina. AB - Batch adsorption was carried out to investigate the possibility of utilizing surfactant-modified alumina (SMA) as an adsorbent for the removal of Cu(II) and Ni(II) from single-metal and binary-metal solutions. Scanning electron microscopic (SEM) images of SMA before and after metal removal from single-metal matrix, showed no significant changes, whereas energy dispersive X-ray (EDX) studies confirmed the incorporation of Cu(II) (~ 0.74 atomic%) and Ni(II) (~ 0.64 atomic%) on the adsorbent surface. The removal of Cu(II) and Ni(II), using SMA depends on contact time, adsorbent dose and medium pH. The sorption kinetics followed pseudo-second-order model for Cu(II). However, for Ni(II), either pseudo first-order or pseudo-second-order model is applicable. The batch experimental data were fitted to Langmuir and Freundlich isotherm, and based on the correlation coefficient value (R(2)), the adsorption could be described more precisely by the Freundlich isotherm. The maximum adsorption capacity from Langmuir isotherm of Cu(II) was 9.34 mg g(-1) and for Ni(II) 6.87 mg g(-1). In a synthetic binary mixture of Cu(II) and Ni(II), having a concentration of 10 mg L( 1) each, removal of Cu(II) was better. The treatment method was further applied to real wastewater from an electroplating industry. The batch experiment results showed that SMA was effective in the simultaneous removal of Cu(II) and Ni(II) to a significant extent, with additional improvement of water quality of the industrial effluent considered. PMID- 25723066 TI - Simultaneous removal of nutrients from milking parlor wastewater using an AO2 sequencing batch reactor (SBR) system. AB - The feasibility of using a lab-scale, anaerobic-aerobic-anoxic-aerobic sequencing batch reactor ((AO)2 SBR) to simultaneously remove biological organics, nitrogen and phosphorus from dairy milking parlor wastewater was investigated in this study. Three hydraulic retention times (HRT = 2.1, 2.7, and 3.5 days) and three mixing-to-process time ratios (TM/TP = 0.43, 0.57, and 0.68) were evaluated as two controlling factors using a 3 * 3 experimental design to determine the optimal combination. Results showed that the HRT of 2.7 days with TM/TP = 0.57 was the best to achieve simultaneous nutrients removal for the influent with initial soluble chemical oxygen demand (SCOD) of about 2000 mg L(-1) (only 0.55 mg L(-1) NH4-N, < 0.1 mg L(-1) nitrate, and 0.14 mg L(-1) soluble phosphorus in the effluent). Good correlations between pH and ORP, and ORP and DO, were also obtained with correlation coefficients all higher than or equal to 0.975. These relationships could be used to develop real-time control strategies to optimize the duration of each operating phase in the (AO)2 SBR system to save energy and enhance treatment efficiency. PMID- 25723067 TI - Reduction of pollutants and disinfection of industrial wastewater by an integrated system of copper electrocoagulation and electrochemically generated hydrogen peroxide. AB - The objective of this study was to evaluate the effect of copper electrocoagulation and hydrogen peroxide on COD, color, turbidity, and bacterial activity in a mixed industry wastewater. The integrated system of copper electrocoagulation and hydrogen peroxide is effective at reducing the organic and bacterial content of industrial wastewater. The copper electrocoagulation alone reduces COD by 56% in 30 min at pH 2.8, but the combined system reduces COD by 78%, biochemical oxygen demand (BOD5) by 81%, and color by 97% under the same conditions. Colloidal particles are flocculated effectively, as shown by the reduction of zeta potential and the 84% reduction in turbidity and 99% reduction in total solids. Additionally, the total coliforms, fecal coliforms, and bacteria are all reduced by 99%. The integrated system is effective and practical for the reduction of both organic and bacterial content in industrial wastewater. PMID- 25723068 TI - Role of iron and aluminum coagulant metal residuals and lead release from drinking water pipe materials. AB - Bench-scale experiments investigated the role of iron and aluminum residuals in lead release in a low alkalinity and high (> 0.5) chloride-to-sulfate mass ratio (CSMR) in water. Lead leaching was examined for two lead-bearing plumbing materials, including harvested lead pipe and new lead: tin solder, after exposure to water with simulated aluminum sulfate, polyaluminum chloride and ferric sulfate coagulation treatments with 1-25-MUM levels of iron or aluminum residuals in the water. The release of lead from systems with harvested lead pipe was highly correlated with levels of residual aluminum or iron present in samples (R(2) = 0.66-0.88), consistent with sorption of lead onto the aluminum and iron hydroxides during stagnation. The results indicate that aluminum and iron coagulant residuals, at levels complying with recommended guidelines, can sometimes play a significant role in lead mobilization from premise plumbing. PMID- 25723069 TI - Arsenic sorption onto titanium dioxide, granular ferric hydroxide and activated alumina: batch and dynamic studies. AB - The aim of this work was to evaluate and compare the efficiencies of three different adsorbents for arsenic (As) removal from water: titanium dioxide (TiO2), granular ferric hydroxide (GFH) and activated alumina (AA). Equilibrium experiments for dissolved arsenite and arsenate were carried out through batch tests. Freundlich and Langmuir isotherm models were adopted and their parameters were estimated by non-linear regressions. In addition, dynamic experiments were performed in mini fixed bed columns and breakthrough curves were obtained for each combination of sorbate/adsorbent. Experimental results obtained by column assays were compared with predictions of well-known breakthrough models (Bohart Adams and Clark). Results indicate that As(V) is more easily adsorbed than As(III) for AA and GFH, while TiO2 has a similar behavior for both species. The titanium-based material is the most efficient adsorbent to carry out the process, followed by the GFH. PMID- 25723070 TI - In vitro evaluation of microbial contamination of orthodontic brackets as received from the manufacturer using microbiological and molecular tests. AB - OBJECTIVE: To test the null hypothesis that orthodontic brackets as supplied by manufacturers do not have microbial contamination. MATERIALS AND METHODS: The sample comprised 140 brackets of four different commercially available brands, used directly from the manufacturer's packaging, divided into 14 groups (n = 10 brackets each). Of the 140 pieces, 60 were full cases and 80 were replacement brackets. Materials were tested to detect bacterial growth, analyze types of bacteria present (biochemical test), and identify bacteria (molecular test with polymerase chain reaction [PCR]). RESULTS: In two of 12 groups the brackets showed microbial contamination: group 1, Morelli full case brackets, and group 12, Abzil-3M Unitek replacement brackets. Staphylococcus aureus and Staphylococcus epidermidis were the bacteria identified in groups 1 and 12, respectively (suggested by the biochemical test and confirmed by PCR). CONCLUSIONS: Brackets of two brands (Morelli and Abzil-3M Unitek) were found to be contaminated by bacteria in the original packages supplied by the manufacturers, which suggests a risk for patient contamination. These data suggest that the manufacturers of these materials should improve the quality control of the packaging used, including sterilization, for the security of patient health. PMID- 25723071 TI - [Recurrent implantation failure and thrombophilia]. AB - OBJECTIVE: Bring a comprehensive overview of the available knowledge about the importance of thrombophilic mutations in patients with recurrent implantation failure and summary of therapeutic options. DESIGN: Overview study. SETTING: Department of Obstetric and Gynecology, University Hospital Olomouc. METHODS: Analysis of literary sources and databases Ovid, Medline. CONCLUSION: Failure of implantation in the context of assisted reproduction is associated with impaired endometrial receptivity. In women with normal anatomy may affect the implantation of embryos during stimulation hormonal changes, immunological factors or thrombophilic mutations. Recurrent implantation failure patients should be tested for the presence of thrombophilic mutations. Subsequently, these patients should be individually consulted and low molecular weight heparin should be used only in indicated cases. According to the available data treatment is recommended only in patients with known acquired or inherited thrombophilic disorder. PMID- 25723072 TI - [The risk factors for pelvic floor trauma following vaginal delivery]. AB - OBJECTIVE: The evaluation of the risk and protective factors for pelvic floor trauma in relation to vaginal delivery. DESIGN: Review. SETTING: Department of Obstetrics and Gynecology, University Hospital of Ostrava. METHODOLOGY AND RESULTS: The aim was to provide a comprehensive survey of studies focused on risk factors for pelvic floor trauma following vaginal delivery; and to constitute the relationship between the risk and protective factors and levator ani injury. To state the prognosis of the pelvic floor injury before a child delivery is difficult and almost impossible, but it has been assumed that an operative vaginal delivery (obstetrical forceps) represents a significant risk factor for avulsion. The change in obstetric practice can prevent the injury and thus to reduce an adverse effect. CONCLUSIONS: Pregnancy and the methods of childbirth are important factors with an impact on pelvic floor injury, potentially contributing to the development of pelvic organ prolapse, and stress and anal incontinence. The recognition of the factors, the proper training of medical staff in the management of labour, and subsequently the proper treatment of perineal tears should prevent pelvic floor injury. PMID- 25723073 TI - Eclampsia as a cause of secondary non-obstructive central sleep hypoventilation. AB - The central alveolar hypoventilation of Ondine's curse is a disorder characterized by absent or diminished ventilatory response to hypercapnia, hypoxia or both, with parallel decrease in saturation to 50%. The secondary form may begin mainly after insult that affects the brain stem. We present a case of a 24-years old primipara in the 41st gestational week with an uncomplicated course of pregnancy and with secondary non-obstructive sleeping hypoventilation which occurred after eclamptic seizure. This obstetric case provides evidence for the benefit of home BiPAP use for patients with secondary Ondine's curse. PMID- 25723074 TI - [Hyperechogenic fetal bowel as a marker of fetal cystic fibrosis]. AB - INTRODUCTION: Hyperechogenic bowel (HB) occurs in 0.1 to 1.8% of normal pregnancies. In most cases it has no consequence for the foetus, but can be associated with cystic fibrosis (CF), chromosomal defects, genetic syndromes, viral infections, gastrointestinal pathology, missed gravidity, IUGR and preterm labour. OBJECTIVES: Assessment the risk of the foetus having CF or other abnormalities when HB was detected during ultrasound screening in the second trimester of pregnancy in our centre. DESIGN: Retrospective study. SETTING: Department of Obstetrics and Gynecology, Centre of Fetal Medicine and Genetics, KNTB a.s. Zlin. METHODS: Retrospective analysis of 149 cases of HB between 17 to 22 weeks of pregnancy detected from January 2008 to April 2012. HB was evaluated according to its degree of echogenicity (Slotnik/Abuhamed classification), presence or absence of other ultrasound markers and the result of first trimester combined screening result. When stage II or III HB and/or borderline risk in first trimester screening, and presence of other ultrasound markers was detected, amniocentesis (AMC) was performed to investigate the karyotype, mutations in the CFTR gene and presence of viral infections (cytomegalovirus and parvovirus B19). If stage I or II HB and/or negative I. trimester screening and no other ultrasound markers, viral infections and mutations in the CFTR gene were investigated form maternal blood. If positive, paternal blood sampling testing for mutation in the CFTR gene was performed. If a mutation was detected in both parents, AMC was performed. Mutations of the CFTR gene was investigated with a commercial panel of 33 to 50 most common mutations. Postnatally the outcome of neonatal screening for CF(IRT) and any newborns with congenital malformations were ascertained. RESULTS: HB was seen in 149 foetuses, AMC was performed in 94 (63%), and blood sampling in 55 (37%). Two mutations in the CFTR gene associated with a severe form of CF (deltaF508/3849 KBC +10 T) were found in one foetus from the AMC group with stage III HB. The parents decided to terminate the pregnancy. The incidence of HB in our group was 0.7%. In 4 foetuses (2.7%) with stage II HB heterozygous deltaF508 mutation was found, in the rest no mutations were detected. Parents of heterozygous carriers underwent genetic consultation. Postnatal CF screening (IRT level from a heel prick sample) was negative; therefore no further molecular genetic analysis was performed. Infection was detected in three foetuses; one case was managed with intrauterine transfusion and in the other two cases parents decided for termination. Four cases (2.7%) were terminated because of severe congenital anomalies. Minor congenital abnormalities were detected in seven (4.7%) cases. Intrauterine death was detected in three (2%) pregnancies. CONCLUSION: Based on our results, HB can be considered as a significant marker for the risk of CF, especially in HB stages II and III. It also demonstrates the importance of this marker for the risk of other foetal abnormalities. PMID- 25723075 TI - [Transurethral injection of polyacrylamide hydrogel (Bulkamid(r)) for the treatment of recurrent stress urinary incontinence after failed tape surgery]. AB - OBJECTIVE: The objective of this study was to evaluate the cure effect of a transurethral injection of Bulkamid(r) for recurrent female stress and mixed urinary incontinence in women who had undergone failed tape surgery. Our hypothesis was that cure effect of Bulkamid(r) is positive in patients when previous tape anti-incontinence surgery has been unsuccessful. DESIGN: Retrospective clinical study. SETTINGS: Department of Obstetrics and Gynecology, 1st Medical Faculty, Charles University and General Faculty Hospital in Prague. MATERIALS AND METHODS: This retrospective study featured 34 patients with recurrent urinary incontinence (SUI: 28, mixed: 6 - predominant symptom was SUI) after unsuccessful tape anti-incontinence surgery. 25 of the patients had undergone anti-incontinence surgery more than once. The cure effect of a transurethral injection of Bulkamid(r) was evaluated an average of 29 months after the surgery; the minimum period after surgery was 6 months. Subjective assessment of the leakage of urine was based on the International Consultation on Incontinence Questionnaire - Short form (ICIQ-UI SF) filled in before and after surgery. An improvement in urinary incontinence was defined as a drop in the score of more than 50%. Objective assessment of leakage of urine was assessed by cough test. The cure effect was evaluated by VAS (Visual Analogue Scale) score and by using the five-point Likert score. Ethical committee approval was obtained, and all subjects gave written informed consent to participate in the study. RESULTS: The mean age of patients was 71.03 years, mean body mass index (BMI) 29.12 and mean parity 1.91. The cough test showed that 4/34 (11.8%) of patients had negative results for this test after the operation. The ICIQ-UI SF questionnaire showed that 14/34 (41.2%) of our patients were dry or improved after surgery. The mean VAS score was 62.4 after the operation. The Likert score was 4 or 5 (cured or improved) after the operation for 88.2% of patients. CONCLUSIONS: Our hypothesis that the cure effect of Bulkamid(r) operation would be positive in patients who have undergone previous unsuccessful tape anti incontinence surgery was partially confirmed. The Likert and VAS scores indicate that the effect of Bulkamid(r) surgery is good; however, an evaluation of the cure effect of this procedure based on the ICIQ-UI SF score is less positive. This kind of operation, which is minimally invasive, is less arduous for patients, and it is also suitable for patients who have refused further surgical treatment. PMID- 25723076 TI - [HPV in etiology of orofaryngeal cancer according to sexual activity]. AB - OBJECTIVE: The objective of this study is to confirm or exclude the presence of the HPV in oral cavity according to sexual activity. DESIGN: Prospective not blinded study. SETTING: Clinic of Oral and Maxillofacial Surgery, Clinic of Obsterics and Gynecology, Department of Microbiology, Medical Faculty Palacky University and University Hospital Olomouc. METHODS: The patients were examined during the screenig for cervix carcioma at the Clinic of Obsterics and Gynecology. After filling the Consent Form and the questionnaire for possible exposure to potentional risk the swabs from cervix and mouth were sampled. The samples have been processed at the Department of Microbiology by the Real Time PCR. RESULTS: The results have not confirmed the relation between sexual practices and infection of oral cavity by the HPV. CONCLUSION: Our results correspond with certain authors. There is unclear correlation between total number of sexual partners and infection of mouth with the HPV. Nevertheless the HPV related tumors have been proven - especially in the oropharynx- but the way how the infection enters the mouth remains still unclear, according to us. PMID- 25723077 TI - [Vacuum-assisted vaginal delivery does not significantly contribute to the higher incidence of levator ani avulsion]. AB - OBJECTIVE: To draw a comparison between spontaneous vaginal delivery and vacuum assisted vaginal delivery in relation to the incidence and the type of levator ani avulsion in primiparas. DESIGN: Retrospective observational study. SETTIMG: Department of Obstetrics and Gynaecology, University Hospital of Ostrava. METHODOLOGY: In the study, the primiparas who were from 6 to 12 months after spontaneous vaginal delivery (group A, n = 52) or after childbirth with vacuum extraction (group B, n = 51) underwent translabial 3D ultrasound. The obstetric data had been obtained from the hospital database. Translabial 3D ultrasound examination were performed by two sonographists. The monitored parameter was the distance between urethra and fibres of musculus levator ani - levator urethra gap [6]. The distance longer than 25 mm was considered an avulsion injury [6, 22]. Other parameters assessed in relation to the avulsion were: women's age, BMI, epidural analgesia, episiotomy performance, the length of the first and the second stages of labour, and fetal weight. RESULTS: Musculus levator ani avulsion was diagnosed in 10 women - unilateral in 8 cases and bilateral in 2 cases. In group A, women after spontaneous birth, we noticed avulsion injury in 7.7% of cases, whereas in group B, women after vacuum extraction, we recorded avulsion injury in 11.8% of cases. Thus the use of vacuum extraction is not statistically significant risk factor for avulsion musculus levator ani. Statistically significant difference in comparison group A and B was recorded in BMI, the length of the second stages of labour and episiotomy performance. CONCLUSION: We did not prove a statistically significant connection between avulsion injury and delivery with the use of vacuum extraction in comparison to avulsion injury incidence in uncomplicated vaginal delivery group (tab. 1). Vacuum extraction does not appear as a risk factor for avulsion in contrast to forceps delivery. PMID- 25723078 TI - [Basal cell carcinoma in a young patient]. AB - OBJECTIVE: The aim of this article is to highlight a possible occurrence of basal cell carcinoma in young patient. DESIGN: Case report. SETTING: Porodnicko gynekologicka klinika FN Ostrava. METHODS: We report case of a 37-year-old patient with a lesion of a vulva, which persisted for 3 years. The patient was during these free years repeatedly examined by a gynecologist and a dermatologist. She was treated by antibiotics and corticosteroids without any effect. After 3 years she was sent to an expert examination, during which was removed a biopsy. From the biopsy specimen was diagnosed basal cell carcinoma. Radical excision was indicated due tu the finding. RESULTS: Patient is now 29 months disease-free. CONCLUSION: Any persistent lesion in the vulvar region should be subjected to histological examination, even in young patients where the diagnosis of basal cell vulvar carcinoma is very unlikely. PMID- 25723079 TI - [Anterior colporrhaphy under local anesthesia]. AB - OBJECTIVE: To evaluate the advantage of the usage of local anesthesia for vaginal surgery in gerontological patients. DESIGN: Prospective study. SETTING: Charles University in Prague, 1st Medical Faculty and Hospital Bulovka, Department of Obstetrics and Gynaecology, Prague. METHODS: 43 patients over 60, 4 were younger, with diagnosed descent of anterior vaginal wall G II-III according to International Continence Society classification, were included into the study. They underwent anterior vaginal wall repair in the sole local anesthesia. For the assessment of the procedure, we used anamnestic data and quality of life questionnaires Visual analogue scale, International Consultation on Incontinence Questionnaire - Short Form, Pelvic Floor Distress Inventory - 20. RESULTS: The results of used questionnaires confirmed positive results of the local anesthesia. We demonstrated statistically significant improvement of the urinary incontinence too, as well as subjective perception of the descent. CONCLUSION: Excellent subjective assessment of usage of local anesthesia showed us new operative possibility in treatment applicable in high-risk patients. PMID- 25723080 TI - [The 2-dose schedule of HPV vaccines in young adolescents]. AB - OBJECTIVE: To summarize new knowledge about the 2-dose HPV vaccine schedule in young adolescents. DESIGN: Review article. SETTING: Department of Gynaecology and Obstetrics, First Faculty of Medicine, Charles University and Hospital Na Bulovce in Prague; Oncogynaecological Center, First Faculty of Medicine, Charles University and General University Hospital in Prague. RESULTS: The goal of immunization programs in many countries is the prevention of cervical cancer using either the bivalent or the quadrivalent HPV vaccine. The vaccines, which were designed to prevent cervical cancer outcomes in adults, need to be administered before the onset of sexual activity. Since the HPV vaccines are among the most expensive of all the widely recommended vaccines, limited financial resources restrain the HPV vaccination in some countries around the word. Higher immunogenicity of both HPV vaccines in young adolescents, as well as potential cost savings, have prompted discussions about the efficacy of the 2 dose HPV vaccine schedule. Results of the immunobridging studies showed that two doses of the bivalent and the quadrivalent HPV vaccine in young girls induced geometric mean antibody titers that were non-inferior to geometric mean antibody titers elicited in older girls and women with three doses of the same vaccine. Non-inferiority for HPV-16, -18, -31 and -45 was obtained for the 2-dose of the bivalent HPV vaccine in girls 9-14 years old in the period of 48 months and for HPV-6, -11, -16 and -18 for the 2-dose of the quadrivalent HPV vaccine in girls 9 13 years old in the period of 36 months. CONCLUSION: These results indicate that the bivalent and the quadrivalent vaccine HPV vaccine applied in 2 doses has sufficient immunogenity in young girls. PMID- 25723081 TI - [Fetal magnetocardiography: a promising way to diagnose fetal arrhytmia and to study fetal heart rate variability?]. AB - OBJECTIVE: An overwiev of the new diagnostic method of fetal wellbeing - fetal magnetocardiography (fMCG). DESIGN: A review article. SETTING: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. METHODS: An analysis of the literature using database search engines PubMed, and SCOPE in field of fMCG. RESULTS: Fetal magnetocardiography is a non-invasive technique able to monitor the spontaneous electrophysiological activity of the fetal heart. Compared to cardiotocography and fetal electrocardiography, this is a more effective method with a higher resolution. The signal obtained from the fetal heart is sufficiently precise and the quality allows an assessment of PQRST complex alterations, and to detect fetal arrhythmia. Thanks to early diagnosis of fetal arrhythmia, there is the possibility for appropriate therapeutic intervention and the reduction of unexplained fetal death in late gestation. fMCG with high temporal resolution also increases the level of clinical trials which record fetal heart rate (FHR) variability. According to the latest theories, FHR variability is a possible indicator of fetal status and enables the study of the fetal autonomic nervous system indirectly. fMCG is an experimental method that requires expensive equipment. It is yet to be shown in the future, if this method will get any application in clinical practice. PMID- 25723082 TI - [Urinary incontinence induced by the antidepressants - case report]. AB - AIM: Case study of the patient with urinary incontinence induced by the antidepressant mirtazapin and the review of the related literature. DESIGN: Case Report. SETTING: Department of Urology, University Hospital Ostrava-Poruba. CASE REPORT: A case of 55-years old patiens, who was reffered to the surgical treatment of the urinary incontinence. We found a major discrepancies during the evaluation that led us to suspect that this is not a common uncomplicated case of stress urinary incontinence. Based on the detailed history we identified the antidepressant mirtazapine as a likely causal factor. After discontinuing mirtazapin patient has achieved full control of the continence. CONCLUSION: Given that antidepressants affects adrenergic and dopaminergic regulatory mechanisms in the central nervous system, they may affect the lower urinary tract function. This work presents a case report where the disclosure of the less common cause of incontinence saved the patientoriginally proposed surgical treatment and allowed the effective restoration of the continence. We emphasize the need to consider the potential interaction of antidepressants with lower urinary tract function in daily practice. PMID- 25723083 TI - [Peripartal hemorrhage with a necessity to make a hysterectomy as a life-rescuing operation - case report]. AB - OBJECTIVE: To present a case of peripartal hemorrhage with a necessity to make a hysterectomy. DESIGN: Case Report. SETTING: Department of Obstetrics and Gynecology, Hospital Mlada Boleslav. CASE REPORT: We report a case of 34-year-old secundigravida secundipara in 40th week of pregnancy after caesarean section, when after an iterative caesarean section strong peripartal hemorrhage appeared with a necessity to make an urgent revision of an abdominal cavity. Conservative farmacological methods do not stop the bleeding, so it is necessary to make a hysterectomy as a life-rescuing operation. CONCLUSION: Presenting this case report authors want to refer to the fact, that even in these days of modern medicine it is still necessary to manage the technic of abdominal hysterectomy as a life-rescuing operation and claim necessity of interdisciplinary co-operation, especially in between obstetrician, anesthetist and haematologist. PMID- 25723084 TI - The 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency, which triggers fetal hemodynamic centralization. AB - OBJECTIVE: To describe a case report of 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency. DESIGN: Case report. SETTING: Department of Public Health, State University of Ceara (UECE), Fortaleza-CE, Brazil. CASE REPORT: Hereditary hypofibrinolysis, which is mediated by 4G/4G homozygosity for the PAI-1 gene, is an independent risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency. We report a case of a low risk pregnancy, which separately presented placental insufficiency and fetal centralization at the beginning of the third trimester, without any other clinical manifestations during pregnancy. However, immediately after childbirth, the patient had a deep vein thrombosis of a lower limb. The anatomopathological examination of the placenta showed old and recent placental infarcts. Homozygosity for the 4G allele of PAI-1 gene was subsequently diagnosed as the sole probable causal factor. PMID- 25723085 TI - [Placenta accreta - case report]. AB - OBJECTIVE: To draw attention to the issue of placenta accreta, which is nowadays one of the main indications for a postpartum hysterectomy. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, Hospital Kolin. CASE REPORT: We report a case of a patient that needed a hysterectomy after the elective cesarean section because of placenta accreta and risk of a life-threatening bleeding. CONCLUSION: Placenta accreta is a life-threatening diagnosis, which is due to the growing number of caesarea sections becoming a serious perinatal problem. For most patients, the method of choice is elective cesarean section followed by hysterectomy. For women who wish to preserve fertility, a conservative procedure may be considered. PMID- 25723086 TI - Correction to Complete Stereochemistry and Preliminary Structure-Activity Relationship of Rakicidin A, a Hypoxia-Selective Cytotoxin from Micromonospora sp. PMID- 25723087 TI - Will nanobiosensors change therapeutic drug monitoring? The case of methotrexate. PMID- 25723088 TI - Highlights from the latest articles in nanoscale drug delivery and nanodiagnostics. PMID- 25723089 TI - Nanoscale stimulation of osteoblastogenesis from mesenchymal stem cells: nanotopography and nanokicking. AB - AIM: Mesenchymal stem cells (MSCs) have large regenerative potential to replace damaged cells from several tissues along the mesodermal lineage. The potency of these cells promises to change the longer term prognosis for many degenerative conditions currently suffered by our aging population. We have endeavored to demonstrate our ability to induce osteoblatogenesis in MSCs using high-frequency (1000-5000 Hz) piezo-driven nanodisplacements (16-30 nm displacements) in a vertical direction. MATERIALS & METHODS: Osteoblastogenesis has been determined by the upregulation of osteoblasic genes such as osteonectin (ONN), RUNX2 and Osterix, assessed via quantitative real-time PCR; the increase of osteocalcin (OCN) and osteopontin (OPN) at the protein level and the deposition of calcium phosphate determined by histological staining. RESULTS: Intriguingly, we have observed a relationship between nanotopography and piezo-stimulated mechanotransduction and possibly see evidence of two differing osteogenic mechanisms at work. These data provide confidence in nanomechanotransduction for stem cell differentiation without dependence on soluble factors and complex chemistries. CONCLUSION: In the future it is envisaged that this technology may have beneficial therapeutic applications in the healthcare industry, for conditions whose overall phenotype maybe characterized by weak or damaged bones (e.g., osteoporosis and bone fractures), and which can benefit from having an increased number of osteoblastic cells in vivo. PMID- 25723090 TI - New insight of squaraine-based biocompatible surface-enhanced Raman scattering nanotag for cancer-cell imaging. AB - AIM: Development of highly sensitive diagnostic nanoprobe for cancer imaging based on surface-enhanced Raman scattering (SERS) platform. MATERIALS & METHODS: Synthesis of novel squaraine dyes as a Raman signature molecule denoted as lipoic squaraine-lipoic (LSL), propyl-squaraine-lipoic (PSL) and propyl-squaraine-propyl (PSP). The SERS-nanotag constructed with a Raman signature molecule which is attached on gold nanoparticle and further encapsulated with heterofunctionalized PEG. Antibody conjugation with best SERS-nanotag for target specific recognition. RESULTS: SERS nanotag Au-LSL-PEG showed significant signal intensity and remarkable stability. Anti-EGF receptor and Her2-conjugated Au-LSL-PEG-nanotag were successfully applied for selective recognition of cancer cells like A549, OSCC and MCF7. CONCLUSION: The newly developed SERS-nanotag Au-LSL-PEG serves as a valuable tool for diagnostic detection of cancer cells, and may find potential applications for cancer screening in real patient samples. PMID- 25723091 TI - Targeted nanodiamonds as phenotype-specific photoacoustic contrast agents for breast cancer. AB - The aim is to develop irradiated nanodiamonds (INDs) as a molecularly targeted contrast agent for high-resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. The surface of acid treated radiation damaged nanodiamonds was grafted with PEG to improve its stability and circulation time in blood, followed by conjugation to an anti-HER2 peptide with a final nanoparticle size of approximately 92 nm. Immunocompetent mice bearing orthotopic HER2-positive or negative tumors were administered INDs and PA imaged using an 820-nm near-infrared laser. PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 h. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are nontoxic. PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype-specific monitoring of cancer growth. PMID- 25723092 TI - In vivo evaluation of paclitaxel-loaded lipid nanocapsules after intravenous and oral administration on resistant tumor. AB - AIM & METHODS: The aim of the present work was to encapsulate paclitaxel (Ptx) in various lipid nanocapsules (LNCs) formulations and then to compare their pharmacokinetics and efficacy on a subcutaneous isograft model in rats. RESULTS: Three different Ptx formulations were obtained. Drug payloads ranged from 1.32 to 3.62 mg Ptx/g of formulation. After oral administration the area under concentration-time curve was higher (p < 0.05) if Ptx was encapsulated, (1,2 Distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(PEG)] (DSPE-PEG-NH2)) LNCs displaying the highest area under concentration-time curve (p < 0.05). Efficacy was better than control for standard LNCs after oral administration (p < 0.05) and for (DSPE-PEG-NH2) LNCs after intravenous administration. Despite good absorption, (DSPE-PEG-NH2) LNCs failed to remain efficient after oral route. CONCLUSION: This study highlights the importance of efficacy studies paired to pharmacokinetic studies for nanomedicines. PMID- 25723093 TI - Potentiation of antimicrobial photodynamic inactivation mediated by a cationic fullerene by added iodide: in vitro and in vivo studies. AB - BACKGROUND: Antimicrobial photodynamic inactivation with fullerenes bearing cationic charges may overcome resistant microbes. METHODS & RESULTS: We synthesized C60-fullerene (LC16) bearing decaquaternary chain and deca-tertiary amino groups that facilitates electron-transfer reactions via the photoexcited fullerene. Addition of the harmless salt, potassium iodide (10 mM) potentiated the ultraviolet A (UVA) or white light-mediated killing of Gram-negative bacteria Acinetobacter baumannii, Gram-positive methicillin-resistant Staphylococcus aureus and fungal yeast Candida albicans by 1-2+ logs. Mouse model infected with bioluminescent Acinetobacter baumannii gave increased loss of bioluminescence when iodide (10 mM) was combined with LC16 and UVA/white light. CONCLUSION: The mechanism may involve photoinduced electron reduction of (1)(C60>)* or (3)(C60>)* by iodide producing I. or I2 followed by subsequent intermolecular electron transfer events of (C60>)-. to produce reactive radicals. PMID- 25723094 TI - Graphene in neurosurgery: the beginning of a new era. AB - Nanotechnology has revolutionized the approach to different fields of industry and medicine. Among the new nanomaterial used, one of the most promising appears to be graphene. Its versatility, due to a particular chemical configuration, confers to it enormous potential of application. Graphene has recently been tested also in biomedical research with excellent results. Neurosurgery can benefit of this material for therapeutic purposes such as targeting controlled drug/gene delivery in brain tumor treatment, as well as photothermal and photodynamic cancer therapy, improving biosensing and bioimaging, and lastly as biocompatible material for intracranial and/or spinal devices. However, it still remains an experimental material whose in vitro and in vivo toxicity is tested with controversial results for the human health. Noteworthy is the fact that it is not possible so far to know its long-term toxicity. PMID- 25723096 TI - Combinatorial library strategies for synthesis of cationic lipid-like nanoparticles and their potential medical applications. AB - The past two decades have witnessed the high efficiency and efficacy of cationic lipids and liposomal formations for drug delivery. The tedious synthesis of conventional lipids and the inefficiency in studying structure-activity relationships, however, have hindered the clinical translation of lipid nanoparticle delivery systems. Combinatorial synthesis of lipid-like nanoparticles ('lipidoids') has recently emerged as an approach to accelerate the development of these delivery platforms. Utilizing a high-throughput screening strategy, the libraries of lipidoids are sorted and prime candidates for the delivery in the intended application can be identified and optimized for the next generation. In this review, we outline methods used for combinatorial lipidoid synthesis, the application of high-throughput screening, and the current medical applications of candidate lipidoids. PMID- 25723097 TI - Regulatory challenges and approaches to characterize nanomedicines and their follow-on similars. AB - Nanomedicines are highly complex products and are the result of difficult to control manufacturing processes. Nonbiological complex drugs and their biological counterparts can comprise nanoparticles and therefore show nanomedicine characteristics. They consist of not fully known nonhomomolecular structures, and can therefore not be characterized by physicochemical means only. Also, intended copies of nanomedicines (follow-on similars) may have clinically meaningful differences, creating the regulatory challenge of how to grant a high degree of assurance for patients' benefit and safety. As an example, the current regulatory approach for marketing authorization of intended copies of nonbiological complex drugs appears inappropriate; also, a valid strategy incorporating the complexity of such systems is undefined. To demonstrate sufficient similarity and comparability, a stepwise quality, nonclinical and clinical approach is necessary to obtain market authorization for follow-on products as therapeutic alternatives, substitution and/or interchangeable products. To fill the regulatory gap, harmonized and science-based standards are needed. PMID- 25723095 TI - Nanotechnology strategies for antibacterial and remineralizing composites and adhesives to tackle dental caries. AB - Dental caries is the most widespread disease and an economic burden. Nanotechnology is promising to inhibit caries by controlling biofilm acids and enhancing remineralization. Nanoparticles of silver were incorporated into composites/adhesives, along with quaternary ammonium methacrylates (QAMs), to combat biofilms. Nanoparticles of amorphous calcium phosphate (NACP) released calcium/phosphate ions, remineralized tooth-lesions and neutralized acids. By combining nanoparticles of silver/QAM/NACP, a new class of composites and adhesives with antibacterial and remineralization double benefits was developed. Various other nanoparticles including metal and oxide nanoparticles such as ZnO and TiO2, as well as polyethylenimine nanoparticles and their antibacterial capabilities in dental resins were also reviewed. These nanoparticles are promising for incorporation into dental composites/cements/sealants/bases/liners/adhesives. Therefore, nanotechnology has potential to significantly improve restorative and preventive dentistry. PMID- 25723098 TI - Involvement of the inhibition of intestinal glucuronidation in enhancing the oral bioavailability of resveratrol by labrasol containing nanoemulsions. AB - Nanoemulsions have been developed for the oral delivery of poorly bioavailable phenolic compounds that are sensitive to intestinal glucuronidation. However, little is known about the contribution of UDP-glucuronosyltransferase (UGT) inhibitory excipients in nanoemulsions toward the inhibition of intestinal glucuronidation and the consequent enhanced bioavailability. In this study, Labrasol but not poloxamer 188 (F68) was found to inhibit the glucuronidation of resveratrol (RES), a model phenolic compound, in an inhibition assay with rat microsomes. Subsequently, two nanoemulsions, Lab-N and F68-N, were prepared with similar particle size distribution, zeta potentials, and entrapment efficiency by coemulsifying with Labrasol or F68, respectively. Although Lab-N exhibited inferior or comparable profiles of in vitro release, cellular uptake in Caco-2 cells, and lymphatic transport in rats to F68-N, the in vitro absorption study with everted sacs suggested that Labrasol containing formulations significantly and dose-dependently increased the transport of RES relative to free RES or F68-N by decreasing the amount of permeated metabolite, RES-3-glucuronide (RES-G). The in vivo pharmacokinetic experiments indicated that Lab-N exhibited increments in the maximum plasma concentration and the bioavailability of RES by 1098% and 560%, respectively, and significant decreases in those of RES-G, compared to F68 N. The overall results demonstrated that the improved oral bioavailability of RES by Lab-N was mainly attributable to the inhibition of intestinal glucuronidation by the presence of UGT inhibitory excipient. PMID- 25723099 TI - Ultrasensitive room-temperature piezoresistive transduction in graphene-based nanoelectromechanical systems. AB - The low mass and high quality factors that nanomechanical resonators exhibit lead to exceptional sensitivity in the frequency domain. This is especially appealing for the design of ultrasensitive force and mass sensors. The sensitivity of a nanomechanical mass and force sensor depends on its mass and quality factor; a low resonator mass and a higher quality factor reduce both the minimum resolvable mass and force. Graphene, a single atomic layer thick membrane is an ideal candidate for nanoelectromechanical resonators due to its extremely low mass and high stiffness. Here, we show that by employing the intrinsic piezoresistivity of graphene to transduce its motion in nanoelectromechanical systems, we approach a force resolution of 16.3 +/- 0.8 aN/Hz(1/2) and a minimum detectable mass of 1.41 +/- 0.02 zeptograms (10(-21) g) at ambient temperature. Quality factors of the driven response of the order of 10(3) at pressures ~10(-6) Torr on several devices are also observed. Moreover, we demonstrate this at ambient temperature on chemical-vapor-deposition-grown graphene to allow for scale-up, thus demonstrating its potential for applications requiring exquisite force and mass resolution such as mass spectroscopy and magnetic resonance force microscopy. PMID- 25723100 TI - Stereoselective construction of 2,6-cis-disubstituted tetrahydropyrans via intramolecular amide enolate alkylation: total synthesis of (-)-centrolobine. AB - A highly stereoselective construction of 2,6-cis-disubstituted tetrahydropyrans was achieved by using an intramolecular amide enolate alkylation with KHMDS. The efficiency and practicality of this methodology was successfully demonstrated in the total synthesis of (-)-centrolobine (1). PMID- 25723101 TI - Bioinspired fabrication and characterization of a synthetic fish skin for the protection of soft materials. AB - The scaled skin of fish is a high-performance natural armor that represents a source of inspiration for novel engineering designs. In this paper, we present a biomimetic fish skin material, fabricated with a design and components that are simple, that achieves many of the advantageous attributes of natural materials, including the unique combination of flexibility and mechanical robustness. The bioinspired fish skin material is designed to replicate the structural, mechanical, and functional aspects of a natural teleost fish skin comprised of leptoid-like scales, similar to that of the striped red mullet Mullus surmuletus. The man-made fish skin material consists of a low-modulus elastic mesh or "dermis" layer that holds rigid, plastic scales. The mechanics of the synthetic material is characterized under in-plane, bending, and indentation modes of deformation and is successfully described by theoretical deformation models that have been developed. This combined experimental and modeling approach elucidates the critical mechanisms by which the composite material achieves its unique properties and provides design rules that allow for the engineering of scaled skins. Such artificial scaled skins that are flexible, lightweight, transparent, and robust under mechanical deformation may thus have potential as thin protective coatings for soft materials. PMID- 25723103 TI - Analysis of trauma care education in the South Sudan community health worker training curriculum. AB - INTRODUCTION: Trauma is a leading cause of morbidity and mortality worldwide, with the majority occurring in low- and middle-income countries (LMICs). Allied health workers are often on the front lines of caring for trauma patients; this is the case in South Sudan, where a system of community health workers (CHWs) and clinical officers (COs) form an essential part of the health care structure. However, curricula for these workers vary, and it is unclear how much these training programs include trauma education. HYPOTHESIS/METHODS: The CHW training curriculum in South Sudan was reviewed to evaluate the degree to which it incorporates trauma education, according to established guidelines from the World Health Organization (WHO). To the authors' knowledge, this is the first formal comparison of a CHW curriculum with established WHO trauma guidelines. RESULTS: The curriculum incorporated a number of essential components of the WHO guidelines; however, the concepts taught were limited in scope. The curriculum only covered about 50% of the content required for basic providers, with major deficiencies being in the management of head and spinal injuries, safety protocols for health care personnel, and in the management of pediatric patients. DISCUSSION/CONCLUSION: The CHW training curriculum lacks the requisite content to provide adequately a basic level of trauma care and requires amending to ensure that all South Sudan citizens receive appropriate treatment. It is recommended that other LMICs review their existing training curricula in order to improve their ability to provide adequate trauma care and to ensure they meet the basic WHO guidelines. PMID- 25723104 TI - Combining structural and chemical information at the nanometer scale by correlative transmission electron microscopy and atom probe tomography. AB - In many cases, the three-dimensional reconstructions from atom probe tomography (APT) are not sufficiently accurate to resolve crystallographic features such as lattice planes, shear bands, stacking faults, dislocations or grain boundaries. Hence, correlative crystallographic characterization is required in addition to APT at the exact same location of the specimen. Also, for the site-specific preparation of APT tips containing regions of interest (e.g. grain boundaries) correlative electron microscopy is often inevitable. Here we present a versatile experimental setup that enables performing correlative focused ion beam milling, transmission electron microscopy (TEM), and APT under optimized characterization conditions. The setup was designed for high throughput, robustness and practicability. We demonstrate that atom probe tips can be characterized by TEM in the same way as a standard TEM sample. In particular, the use of scanning nanobeam diffraction provides valuable complementary crystallographic information when being performed on atom probe tips. This technique enables the measurement of orientation and phase maps as known from electron backscattering diffraction with a spatial resolution down to one nanometer. PMID- 25723102 TI - Gateways to the FANTOM5 promoter level mammalian expression atlas. AB - The FANTOM5 project investigates transcription initiation activities in more than 1,000 human and mouse primary cells, cell lines and tissues using CAGE. Based on manual curation of sample information and development of an ontology for sample classification, we assemble the resulting data into a centralized data resource (http://fantom.gsc.riken.jp/5/). This resource contains web-based tools and data access points for the research community to search and extract data related to samples, genes, promoter activities, transcription factors and enhancers across the FANTOM5 atlas. PMID- 25723105 TI - Poly(E-caprolactone) (PCL)-polymeric micelle hybrid sheets for the incorporation and release of hydrophilic proteins. AB - Sheets have several advantages over conventional gel- or particle-type drug carriers. Sheets have several notable attributes: sheets' size and shape are easily adjustable, sheets are highly accessible in surgery, and sheets have a large contact area relative to drug-targeting sites. However, it is difficult to incorporate hydrophilic proteins into hydrophobic sheets and to release the proteins over the long term in a sustained manner. In the present study, we show that "poly(E-caprolactone) (PCL)-polymeric micelle hybrid sheets" can be used for the incorporation and release of hydrophilic proteins. Polymeric micelles (i.e., spaces that can incorporate hydrophilic compounds) are, in this study, uniformly dispersed in hydrophobic and biocompatible biomaterial sheet. We have clarified that the composition of block copolymer, methoxy-terminated poly(ethylene glycol) block-poly(E-caprolactone) (CH3O-PEG-b-PCL), can affect two variables: the stability of w/o emulsion and the release properties of the resulting sheets, by means of visual qualitative observations, newly developed quantitative analyses (advanced fractal analysis, advanced FD) based on deviation of the fractal dimension (FD), and release experiments. We clarified that the release behavior of BSA was affected by the composition of the block copolymers and the resulting emulsion. The results obtained in this paper show that the hydrophobic sheets in which polymeric micelles providing hydrophilic spaces were dispersed could be an effective platform for incorporating and releasing hydrophilic proteins. PMID- 25723106 TI - Measurement of the 240Pu/239Pu mass ratio using a transition-edge-sensor microcalorimeter for total decay energy spectroscopy. AB - We have developed a new category of sensor for measurement of the (240)Pu/(239)Pu mass ratio from aqueous solution samples with advantages over existing methods. Aqueous solution plutonium samples were evaporated and encapsulated inside of a gold foil absorber, and a superconducting transition-edge-sensor microcalorimeter detector was used to measure the total reaction energy (Q-value) of nuclear decays via heat generated when the energy is thermalized. Since all of the decay energy is contained in the absorber, we measure a single spectral peak for each isotope, resulting in a simple spectral analysis problem with minimal peak overlap. We found that mechanical kneading of the absorber dramatically improves spectral quality by reducing the size of radioactive inclusions within the absorber to scales below 50 nm such that decay products primarily interact with atoms of the host material. Due to the low noise performance of the microcalorimeter detector, energy resolution values of 1 keV fwhm (full width at half-maximum) at 5.5 MeV have been achieved, an order of magnitude improvement over alpha-spectroscopy with conventional silicon detectors. We measured the (240)Pu/(239)Pu mass ratio of two samples and confirmed the results by comparison to mass spectrometry values. These results have implications for future measurements of trace samples of nuclear material. PMID- 25723107 TI - Acidobacteria appear to dominate the microbiome of two sympatric Caribbean Sponges and one Zoanthid. AB - BACKGROUND: Marine invertebrate-associated microbial communities are interesting examples of complex symbiotic systems and are a potential source of biotechnological products. RESULTS: In this work, pyrosequencing-based assessment from bacterial community structures of sediments, two sponges, and one zoanthid collected in the Mexican Caribbean was performed. The results suggest that the bacterial diversity at the species level is higher in the sediments than in the animal samples. Analysis of bacterial communities' structure showed that about two thirds of the bacterial diversity in all the samples belongs to the phyla Acidobacteria and Proteobacteria. The genus Acidobacterium appears to dominate the bacterial community in all the samples, reaching almost 80% in the sponge Hyrtios. CONCLUSIONS: Our evidence suggests that the sympatric location of these benthonic species may lead to common bacterial structure features among their bacterial communities. The results may serve as a first insight to formulate hypotheses that lead to more extensive studies of sessile marine organisms' microbiomes from the Mexican Caribbean. PMID- 25723108 TI - Emerging Adjuvant Therapy for Cancer: Propolis and its Constituents. AB - Propolis is a bee-metabolized resinous substance (bee glue) from plant sap and gums. It has been in usage as a healing agent since antiquity, yet has not garnered global popularity as a health promoter. Its biological effects, which range from antimicrobial, antioxidant, anti-inflammatory, antidiabetic, dermatoprotective, anti-allergic, laxative and immunomodulatory to anticancer, have been validated. Propolis has shown efficacy against brain, head and neck, skin, breast, liver, pancreas, kidney, bladder, prostate, colon and blood cancers. The inhibition of matrix metalloproteinases, anti-angiogenesis, prevention of metastasis, cell-cycle arrest, induction of apoptosis and moderation of the chemotherapy-induced deleterious side effects have been deduced as the key mechanisms of cancer manipulation. The components conferring antitumor potentials have been identified as caffeic acid phenethyl ester, chrysin, artepillin C, nemorosone, galangin, cardanol, etc. These compounds target various genetic and biochemical pathways of cancer progression. Depending on the botanical sources and the geographical origin, biological activities of propolis vary. Despite phenomenal development in cancer research, conventional therapy falls short in complete malignancy management. The findings obtained so far build hope that propolis as a complementary medicine may address the lacunae. This review documents the recent advances and scope of amendement in cancer remediation with adequate emphasis on the mechanistic aspect of propolis. PMID- 25723110 TI - Ovarian seromucinous carcinoma: report of a series of a newly categorized and uncommon neoplasm. AB - Seromucinous neoplasms are a new category of ovarian epithelial tumor in the revised World Health Organization Classification of Tumours of the Female Reproductive Organs. Borderline variants are well described, but there have been few reports of seromucinous carcinomas. We report the clinicopathologic features in 19 cases of ovarian seromucinous carcinoma in patients aged 16 to 79 years (mean 47). In 16 cases, the neoplasm was unilateral and in 3 cases bilateral. The tumors ranged in size from 1.8 to 18 cm (mean 10.5 cm). The tumors were stage I (n=15), stage II (n=1), and stage III (n=3). The histologic features were highly variable both within and between individual tumors. The majority of neoplasms (12 cases) exhibited a predominant papillary architecture with lesser components of glandular, microglandular, and solid growth. A predominant glandular architecture was present in 6 cases, whereas 1 had a predominantly solid growth. A characteristic feature was an admixture of cell types. Most of the tumors (15 cases) were mainly composed of endocervical-like mucinous cells, whereas in 4 cases there was predominant endometrioid differentiation. Other cell types, present in varying proportions, included hobnail cells, eosinophilic cells, squamous cells, clear cells, and signet-ring cells. An infiltrate of neutrophil polymorphs was a prominent feature in most cases. Most cases also exhibited areas of microglandular architecture with cytoplasmic clearing and intraluminal polymorphs, the features closely resembling cervical microglandular hyperplasia. Areas of stromal hyalinization, adenofibromatous growth, and psammoma bodies were present in a minority of cases. Endometriosis was identified in the same ovary in 10 cases, and in 10 there was a component of seromucinous borderline tumor. Thirteen, 5, and 1 tumor were of grades 1, 2, and 3, respectively (using the FIGO grading system for endometrioid adenocarcinomas of the uterine corpus). A synchronous uterine endometrioid adenocarcinoma was present in 1 case. Immunohistochemically, there was positive staining with CK7 (17/17 cases), estrogen receptor (16/16 cases), progesterone receptor (6/7 cases), CA125 (15/15 cases), PAX8 (8/8 cases), CEA (8/13 cases), CA19.9 (8/9 cases), and WT1 (2/13 cases). CK20 and CDX2 were negative in all cases tested (16 and 14, respectively). p53 showed "wild-type" staining in 4/4 cases, and p16 was focally positive in 5/5 cases. Follow-up information was available in 8 patients. Seven were alive with no evidence of disease (follow-up 3 to 74 mo), whereas 1 patient who initially presented with a stage IIB tumor died of disease at 192 months. Given the characteristic admixture of cell types and the overlapping morphologic features with low-grade serous, mucinous, and endometrioid neoplasms, the most appropriate categorization of seromucinous carcinomas is uncertain, but we believe they are best regarded as a distinct type of ovarian epithelial malignancy and are most similar to endometrioid adenocarcinomas. We recommend grading them in an analogous manner to ovarian endometrioid adenocarcinomas. PMID- 25723109 TI - Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. AB - Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer. PMID- 25723111 TI - Glomerular endothelial vesicles in a renal allograft: an unusual pattern of immunoglobulin deposition in a patient with biclonal gammopathy of unknown significance. AB - Paraproteins have varied effects on the kidney on the basis of molecular structure, concentration, and renal function. Prototypical patterns include myeloma cast nephropathy, monoclonal immunoglobulin deposition disease, and amyloid, among others. We report a 69-year-old man with end-stage diabetic nephropathy and biclonal gammopathy of unknown significance. Serum monoclonal immunoglobulin G (IgG)-kappa and urine monoclonal free lambda light chains were identified during workup for nephrotic syndrome. A native renal biopsy demonstrated diabetic nephropathy, without indication of paraprotein-related pathology. After transplantation, a surveillance biopsy showed endothelialitis (type 2 rejection) and abundant eosinophilic droplets, nearly occluding glomerular capillary loops. Electron microscopy localized tightly packed electron dense vesicles in glomerular endothelial cells. Immunofluorescence studies revealed IgG-kappa-dominant endothelial staining, along with lambda monotypic protein resorption droplets in tubules. Two additional biopsies within the following year showed this same paraprotein distribution, with some increase in mesangial sclerosis. Two years after transplant the patient remains asymptomatic with normal creatinine levels. Literature review yields rare cases of immunoglobulin crystalline deposits in multiple glomerular cell types, rarely including endothelial cells; however, this appears to be the first report of monoclonal immunoglobulin vesicles localized solely to endothelial cells. As these vesicles were not seen in the native kidney biopsy, we hypothesize an interaction of alloimmune-mediated endothelial injury and the physiochemical properties of the IgG-kappa paraprotein. In addition, this case illustrates simultaneous different patterns of accumulation of monoclonal immunoglobulin and light chain components in this unique patient with biclonal gammopathy of unknown significance. PMID- 25723113 TI - Molecular characterization of apocrine salivary duct carcinoma. AB - Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, beta-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine." PMID- 25723112 TI - The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. AB - The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC. PMID- 25723114 TI - Prognostic Impact of Intra-alveolar Tumor Spread in Pulmonary Adenocarcinoma. AB - Tumor spread, in general, is the most important factor determining outcome in almost all malignant tumors. Lung tumors are unique with respect to potential routes for tumor dissemination, as apart from vascular, nodal, and distant spread of tumor cells, tumor spread through air spaces (STAS) might also occur. However, morphologic criteria for STAS and its prognostic impact have not been defined yet. We evaluated a series of 569 resected pulmonary adenocarcinomas (ADCs) for predefined morphologic criteria of limited and extensive STAS and correlated our findings with clinical, morphologic, molecular, and outcome data. Limited (21.6%) or extensive (29%) STAS was present in roughly half of all ADCs. The presence and type of STAS was tightly linked to specific growth patterns (P<0.001). STAS was much more prevalent in high-stage (P<0.001), nodal-positive (P<0.001) ADC with distant metastasis (P=0.010). STAS was associated with lower rates of EGFR (P=0.009) but higher rates of BRAF (P=0.016) mutations. Furthermore, STAS was associated with significantly reduced overall (P=0.020) and disease-free survival (P=0.004), which was growth pattern but not stage independent. We analyzed morphologic characteristics of a yet underestimated type of tumor spread of pulmonary ADC through air spaces. STAS is a novel morphologic prognosticator, which should be further validated and considered for implementation in routine diagnostic evaluation and reporting. PMID- 25723115 TI - MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma. AB - MYD88 L265P is a somatic mutation that has been identified in about 90% of Waldenstrom macroglobulinemia/lymphoplasmacytic lymphomas (LPLs). It has also been detected in a subset of marginal zone lymphoma (MZL) cases, but the frequency and clinical and histologic features of these mutated MZL cases has only been partially characterized. We have developed a customized TaqMan allele specific polymerase chain reaction for sensitive detection of this mutation in paraffin-embedded tissue. We analyzed samples from 19 patients with LPL, 88 patients with splenic marginal zone lymphoma (SMZL), 8 patients with nodal marginal zone lymphoma (NMZL), 21 patients with extranodal mucosa-associated lymphoid tissue (MALT), and 2 patients with B-cell lymphoma not otherwise specified. By integrating mutational, histologic, and clinical data, 5 cases were reclassified as LPL. After reclassification, MYD88 L265P was detected in 13/86 (15%) SMZL and in 19/24 LPL (79%) cases. The mutation was absent from NMZL and MALT cases. A strong correlation was found between the presence of an IgM monoclonal paraproteinemia and the MYD88 L265P mutation (P<0.0001). SMZL cases positive for MYD88 L265P were also associated with monoclonal IgM paraproteinemia (4/13 cases; P<0.0283), although with less serum paraproteinemia. They also had a higher frequency of plasmacytic differentiation (9/13) but with no correlation between the presence of mutation and of light chain-restricted plasma cells in tissue. Demonstration of the MYD88 L265 mutation is a valuable tool for the diagnosis of LPL, although some SMZL cases carrying the mutation do not fulfill the diagnostic criteria for LPL. PMID- 25723116 TI - Small cell osteosarcoma: clinicopathologic, immunohistochemical, and molecular analysis of 36 cases. AB - Small round cell osteosarcoma is a very rare type of osteosarcoma, histologically mimicking other small round cell malignancies of bone, most notably Ewing sarcoma. To distinguish small cell osteosarcoma from other primary small cell malignancies of bone, we evaluated the immunohistochemical (IHC) expression of CD99 and SATB2, a marker of osteoblastic differentiation. Second, we analyzed EWSR1 and FUS gene aberrations using fluorescence in situ hybridization and/or reverse transcription-polymerase chain reaction (RT-PCR) techniques to assess whether small cell osteosarcoma and Ewing sarcoma share the same genetic alteration analysis. Thirty-six cases of primitive small cell osteosarcoma of bone were included in this study. All the cases of small cell osteosarcoma showed strong nuclear expression of SATB2 associated with negativity for CD99 antibody or weak, cytoplasmic staining in few neoplastic cells. Reverse transcription polymerase chain reaction was negative for EWS-FLI1 type 1-2, EWS-ERG type 1, and CIC-DUX4 in the 10 available cases of small cell osteosarcoma analyzed. Fluorescence in situ hybridization analysis was feasible with a readable signal in 13 cases of small cell osteosarcoma, and none of these cases showed any EWSR1 and FUS gene rearrangements. In conclusion, it appears extremely useful to combine IHC analysis of SATB2 and CD99 with molecular analysis of Ewing sarcoma associated genetic aberrations, to differentiate small cell osteosarcoma from other small round cell malignancies of bone. The strong IHC expression of SATB2 associated with CD99 immunonegativity and the absence of EWSR1 and FUS gene rearrangements in small cell osteosarcoma argues against the existence of a morphologic/genetic continuum with Ewing sarcoma. PMID- 25723117 TI - Case report: extreme patient positioning for retinal surgery in advanced kyphosis. AB - PURPOSE: To describe the atypical intraoperative positioning of a kyphosis patient resulting in successful retinal detachment repair. METHODS: Case report. RESULTS: A 66-year-old man presented with bilateral vision loss, and pars plana lensectomy and retinal detachment repair were planned for the left eye. Innovative surgical positioning was required for the patient's severe ankylosing spondylitis-related kyphosis, a fixed 90 degrees curvature of his cervical spine. With straps, orthopedic padding and surgical tape, he was securely placed head-down on the operating table. No intraoperative complications occurred, and the retina remained attached at follow-up. CONCLUSION: To our knowledge, this is the first report of special positioning for a 90 degrees kyphosis patient requiring retinal surgery. Extreme spinal curvature can hinder suitable horizontal positioning of the eye, but resourceful solutions can make surgical repair possible. PMID- 25723118 TI - Minimally invasive percutaneous screw fixation of traumatic spondylolisthesis of the axis. AB - OBJECT Most cases of traumatic spondylolisthesis of the axis (hangman's fracture) can be treated nonoperatively with reduction and subsequent immobilization in a rigid cervical collar or halo. However, in some instances, operative management is necessary and can be accomplished by using either anterior or posterior fusion techniques. Because open posterior procedures can result in significant blood loss, pain, and limited cervical range of motion, other less invasive options for posterior fixation are needed. The authors describe a minimally invasive, navigation-guided technique for surgical treatment of Levine-Edwards (L-E) Type II hangman's fractures. METHODS For 5 patients with L-E Type II hangman's fracture requiring operative reduction and internal fixation, percutaneous screw fixation directed through the fracture site was performed. This technique was facilitated by use of intraoperative 3D fluoroscopy and neuronavigation. RESULTS Of the 5 patients, 2 were women, 3 were men, and age range was 46-67 years. No intraoperative or postoperative complications occurred. All patients wore a rigid cervical collar, and flexion-extension radiographs were obtained at 6 months. For all patients, dynamic imaging demonstrated a stable construct. CONCLUSIONS L-E type II hangman's fractures can be safely repaired by using percutaneous minimally invasive surgical techniques. This technique may be appropriate, depending on circumstances, for all L-E Type I and II hangman's fractures; however, the degree of associated ligament injury and disc disruption must be accounted for. Percutaneous fixation is not appropriate for L-E Type III fractures because of significant displacement and ligament and disc disruption. This report is meant to serve as a feasibility study and is not meant to show superiority of this procedure over other surgical options. PMID- 25723119 TI - Catastrophic neurological complications of emergent endotracheal intubation: report of 2 cases. AB - Although exceedingly rare, catastrophic neurological decline may result from endotracheal intubation of patients with preexisting cervical spine disease. The authors report on 2 cases of quadriplegia resulting from emergent endotracheal intubation in the intensive care unit. A 68-year-old man with ankylosing spondylitis became quadriplegic after emergent intubation. A new C6-7 fracturedislocation was identified, and the patient underwent emergent open reduction and C4-T2 posterior fixation and fusion. The patient remained quadriplegic and ultimately died of pneumonia 1 year later. This is the first report with radiographic documentation of a cervical fracture-dislocation resulting from intubation in a patient with ankylosing spondylitis. A 73-year-old man underwent posterior C6-T1 decompression and fixation for a C6-7 fracture. On postoperative Day 12, emergent intubation for respiratory distress resulted in C6 level quadriplegia. Imaging revealed acute spondyloptosis at C6-7, and the patient underwent emergent open reduction with revision and extension of posterior fusion from C-3 to T-2. He remained quadriplegic and ventilator dependent. Five days after the second operation, care was withdrawn. This is the first report of intubation as a cause of significant neurological decline related to disruption of a recently fixated cervical fracture. Risk factors are identified and pertinent literature is reviewed for cases of catastrophic neurological complications after emergent endotracheal intubation. Strategies for obtaining airway control in patients with cervical spine pathology are also identified. Awareness of the potential dangers of airway management in patients with cervical spine pathology is critical for all involved subspecialty team members. PMID- 25723120 TI - Patient misconceptions concerning lumbar spondylosis diagnosis and treatment. AB - OBJECT Patient outcome measures are becoming increasingly important in the evaluation of health care quality and physician performance. Of the many novel measures currently being explored, patient satisfaction and other subjective measures of patient experience are among the most heavily weighted. However, these subjective measures are strongly influenced by a number of factors, including patient demographics, level of understanding of the disorder and its treatment, and patient expectations. In the present study, patients referred to a neurosurgery clinic for degenerative spinal disorders were surveyed to determine their understanding of lumbar spondylosis diagnosis and treatment. METHODS A multiple-choice, 6-question survey was distributed to all patients referred to a general neurosurgical spine clinic at a tertiary care center over a period of 11 months as a quality improvement initiative to assist the provider with individualized patient counseling. The survey consisted of questions designed to assess patient understanding of the role of radiological imaging in the diagnosis and treatment of low-back and leg pain, and patient perception of the indications for surgical compared with conservative management. Demographic data were also collected. RESULTS A total of 121 surveys were included in the analysis. More than 50% of the patients indicated that they would undergo spine surgery based on abnormalities found on MRI, even without symptoms; more than 40% of patients indicated the same for plain radiographs. Similarly, a large proportion of patients (33%) believed that back surgery was more effective than physical therapy in the treatment of back pain without leg pain. Nearly one-fifth of the survey group (17%) also believed that back injections were riskier than back surgery. There were no significant differences in survey responses among patients with a previous history of spine surgery compared with those without previous spine surgery. CONCLUSIONS These results show that a surprisingly high percentage of patients have misconceptions regarding the diagnosis and treatment of lumbar spondylosis, and that these misconceptions persist in patients with a history of spine surgery. Specifically, patients overemphasize the value of radiological studies and have mixed perceptions of the relative risk and effectiveness of surgical intervention compared with more conservative management. These misconceptions have the potential to alter patient expectations and decrease satisfaction, which could negatively impact patient outcomes and subjective valuations of physician performance. While these results are preliminary, they highlight a need for improved communication and patient education during surgical consultation for lumbar spondylosis. PMID- 25723121 TI - Postoperative nonsteroidal antiinflammatory drugs and the prevention of heterotopic ossification after cervical arthroplasty: analysis using CT and a minimum 2-year follow-up. AB - OBJECT Heterotopic ossification (HO) after cervical arthroplasty is not uncommon and may cause immobility of the disc. To prevent HO formation, study protocols of clinical trials for cervical arthroplasty undertaken by the US FDA included perioperative use of nonsteroidal antiinflammatory drugs (NSAIDs). However, there are few data supporting the use of NSAIDs to prevent HO after cervical arthroplasty. Therefore, this study aimed to evaluate the efficacy of NSAIDs in HO formation and clinical outcomes. METHODS Consecutive patients who underwent 1- or 2-level cervical arthroplasty with a minimum follow-up of 24 months were retrospectively reviewed. All patients were grouped into 1 of 2 groups, an NSAID group (those patients who had used NSAIDs postoperatively) and a non-NSAID group (those patients who had not used NSAIDs postoperatively). The formation of HO was detected and classified using CT in every patient. The incidence of HO formation, disc mobility, and clinical outcomes, including visual analog scale (VAS) scores of neck and arm pain, neck disability index (NDI) scores, and complications were compared between the two groups. Furthermore, a subgroup analysis of the patients in the NSAID group, comparing the selective cyclooxygenase (COX)-2 to nonselective COX-2 NSAID users, was also conducted for each of the above mentioned parameters. RESULTS A total of 75 patients (mean age [+/- SD] 46.71 +/- 9.94 years) with 107 operated levels were analyzed. The mean follow-up duration was 38.71 +/- 9.55 months. There were no significant differences in age, sex, and levels of arthroplasty between the NSAID and non-NSAID groups. There was a nonsignificantly lower rate of HO formation in the NSAID group than the non-NSAID group (47.2% vs. 68.2%, respectively; p = 0.129). During follow-up, most of the arthroplasty levels remained mobile, with similar rates of immobile discs in the NSAID and non-NSAID groups (13.2% and 22.7%, respectively; p = 0.318). Furthermore, there was a nonsignificantly lower rate of HO formation in the selective COX-2 group than the nonselective COX-2 group (30.8% vs 52.5%, respectively; p = 0.213). The clinical outcomes, including VAS neck, VAS arm, and NDI scores at 24 months postoperatively, were all similar in the NSAID and non NSAID groups, as well as the selective and nonselective COX-2 groups (all p > 0.05). CONCLUSIONS In this study there was a trend toward less HO formation and fewer immobile discs in patients who used postoperative NSAIDs after cervical arthroplasty than those who did not, but this trend did not reach statistical significance. Patients who used selective COX-2 NSAIDs had nonsignificantly less HO than those who used nonselective COX-2 NSAIDs. The clinical outcomes were not affected by the use of NSAIDs or the kinds of NSAIDs used (selective vs nonselective COX-2). However, the study was limited by the number of patients included, and the efficacy of NSAIDs in the prevention of HO after cervical arthroplasty may need further investigation to confirm these results. PMID- 25723122 TI - Comparison of minimally invasive surgery with standard open surgery for vertebral thoracic metastases causing acute myelopathy in patients with short- or mid-term life expectancy: surgical technique and early clinical results. AB - OBJECT Spinal metastasis is common in patients with cancer. About 70% of symptomatic lesions are found in the thoracic region of the spine, and cord compression presents as the initial symptom in 5%-10% of patients. Minimally invasive spine surgery (MISS) has recently been advocated as a useful approach for spinal metastases, with the aim of decreasing the morbidity associated with more traditional open spine surgery; furthermore, the recovery time is reduced after MISS, such that postoperative chemotherapy and radiotherapy can begin sooner. METHODS Two series of oncological patients, who presented with acute myelopathy due to vertebral thoracic metastases, were compared in this study. Patients with complete paraplegia for more than 24 hours and with a modified Bauer score greater than 2 were excluded from the study. The first group (n = 23) comprised patients who were prospectively enrolled from May 2010 to September 2013, and who were treated with minimally invasive laminotomy/laminectomy and percutaneous stabilization. The second group (n = 19) comprised patients from whom data were retrospectively collected before May 2010, and who had been treated with laminectomy and stabilization with traditional open surgery. Patient groups were similar regarding general characteristics and neurological impairment. Results were analyzed in terms of neurological recovery (American Spinal Injury Association grade), complications, pain relief (visual analog scale), and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and EORTC QLQ-BM22 scales) at the 30-day follow-up. Operation time, postoperative duration of bed rest, duration of hospitalization, intraoperative blood loss, and the need and length of postoperative opioid administration were also evaluated. RESULTS There were no significant differences between the 2 groups in terms of neurological recovery and complications. Nevertheless, the MISS group showed a clear and significant improvement in terms of blood loss, operation time, and bed rest length, which is associated with a more rapid functional recovery and discharge from the hospital. Postoperative pain and the need for opioid administration were also significantly less pronounced in the MISS group. Results from the EORTC QLQ-C30 and QLQ-BM22 scales showed a more pronounced improvement in quality of life at follow-up in the MISS group. CONCLUSIONS In the authors' opinion, MISS techniques should be considered the first choice for the treatment for patients with spinal metastasis and myelopathy. MISS is as safe and effective for spinal cord decompression and spine fixation as traditional surgery, and it also reduces the impact of surgery in critical patients. However, further studies are needed to confirm these findings. PMID- 25723123 TI - Dissolved organic matter composition drives the marine production of brominated very short-lived substances. AB - Brominated very short-lived substances (BrVSLS), such as bromoform, are important trace gases for stratospheric ozone chemistry. These naturally derived trace gases are formed via bromoperoxidase-mediated halogenation of dissolved organic matter (DOM) in seawater. Information on DOM type in relation to the observed BrVSLS concentrations in seawater, however, is scarce. We examined the sensitivity of BrVSLS production in relation to the presence of specific DOM moieties. A total of 28 model DOM compounds in artificial seawater were treated with vanadium bromoperoxidase (V-BrPO). Our results show a clear dependence of BrVSLS production on DOM type. In general, molecules that comprise a large fraction of the bulk DOM pool did not noticeably affect BrVSLS production. Only specific cell metabolites and humic acid appeared to significantly enhance BrVSLS production. Amino acids and lignin phenols suppressed enzyme-mediated BrVSLS production and may instead have formed halogenated nonvolatile molecules. Dibromomethane production was not observed in any experiments, suggesting it is not produced by the same pathway as the other BrVSLS. Our results suggest that regional differences in DOM composition may explain the observed BrVSLS concentration variability in the global ocean. Ultimately, BrVSLS production and concentrations are likely affected by DOM composition, reactivity, and cycling in the ocean. PMID- 25723124 TI - A preorganized ditopic borane as highly efficient one- or two-electron trap. AB - Reduction of the bis(9-borafluorenyl)methane 1 with excess lithium furnishes the red dianion salt Li2[1]. The corresponding dark green monoanion radical Li[1] is accessible through the comproportionation reaction between 1 and Li2[1]. EPR spectroscopy on Li[1] reveals hyperfine coupling of the unpaired electron to two magnetically equivalent boron nuclei (a((11)B) = 5.1 +/- 0.1 G, a((10)B) = 1.7 +/ 0.2 G). Further coupling is observed to the unique B-CH-B bridgehead proton (a((1)H) = 7.2 +/- 0.2 G) and to eight aromatic protons (a((1)H) = 1.4 +/- 0.1 G). According to X-ray crystallography, the B...B distances continuously decrease along the sequence 1 -> [1](*-) -> [1](2-) with values of 2.534(2), 2.166(4), and 1.906(3) A, respectively. Protonation of Li2[1] leads to the cyclic borohydride species Li[1H] featuring a B-H-B two-electron-three-center bond. This result strongly indicates a nucleophilic character of the boron atoms; the reaction can also be viewed as rare example of the protonation of an element-element sigma bond. According to NMR spectroscopy, EPR spectroscopy, and quantum-chemical calculations, [1](2-) represents a closed-shell singlet without any spin contamination. Detailed wave function analyses of [1](*-) and [1](2-) reveal strongly localized interactions of the two boron pz-type orbitals, with small delocalized contributions of the 9-borafluorenyl pi systems. Overall, our results provide evidence for a direct B-B one-electron and two-electron bonding interaction in [1](*-) and [1](2-), respectively. PMID- 25723125 TI - Parental Experiences of Medication Administration to Children at Home and Understanding of Adverse Drug Events. AB - BACKGROUND: Medication administration errors are the most common type of error in pediatric medicine. Preventing medication errors is an important part of ensuring safe and quality patient care for pediatric patients. Few studies have described this issue from the perspective of the parents of pediatric patients. PURPOSE: This study describes parents' administration of medication to their children at home and the understanding of these parents of adverse drug events (ADEs). METHODS: A cross-sectional survey design was used to gather data from 179 parents of pediatric patients at two pediatric units at a hospital and three children's daycare centers in Korea. Data were collected from July to August 2012 using a self-reported questionnaire. RESULTS: Participants reported administering antipyretics (94.4%), decongestants (89.4%), and antibiotics (77.7%) to their children at home. The major source of medication information was instruction sheets. Parents more commonly used dosing cups (43.6%) and droppers (32.9%) when administering liquid medication to children. Furthermore, 12.3% of the children experienced ADEs. Only 48% of the participants were provided information on ADEs, 15.1% were unsure about the recommended dosage, and 11.2% were unsure of the recommended method for administering the medication. Analysis of variance and post hoc tests showed that level of parental education and monthly income each had a significant impact on participant understanding of ADEs. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study suggests that parents should be educated about ways to avoid common medication errors in children. In addition, in the case of low-income families, home visits should be carried out to understand how to reduce home medication errors and provide drug-related information to parents. Strategies are needed to reduce pediatric home medication errors and minimize ADEs and to provide medication information to parents. PMID- 25723126 TI - Metal uptake by homegrown vegetables - the relative importance in human health risk assessments at contaminated sites. AB - Risk assessments of contaminated land often involve the use of generic bioconcentration factors (BCFs), which express contaminant concentrations in edible plant parts as a function of the concentration in soil, in order to assess the risks associated with consumption of homegrown vegetables. This study aimed to quantify variability in BCFs and evaluate the implications of this variability for human exposure assessments, focusing on cadmium (Cd) and lead (Pb) in lettuce and potatoes sampled around 22 contaminated glassworks sites. In addition, risks associated with measured Cd and Pb concentrations in soil and vegetable samples were characterized and a probabilistic exposure assessment was conducted to estimate the likelihood of local residents exceeding tolerable daily intakes. The results show that concentrations in vegetables were only moderately elevated despite high concentrations in soil, and most samples complied with applicable foodstuff legislation. Still, the daily intake of Cd (but not Pb) was assessed to exceed toxicological thresholds for about a fifth of the study population. Bioconcentration factors were found to vary more than indicated by previous studies, but decreasing BCFs with increasing metal concentrations in the soil can explain why the calculated exposure is only moderately affected by the choice of BCF value when generic soil guideline values are exceeded and the risk may be unacceptable. PMID- 25723127 TI - Enhanced bioelectricity harvesting in microbial fuel cells treating food waste leachate produced from biohydrogen fermentation. AB - Microbial fuel cells (MFCs) treating the food waste leachate produced from biohydrogen fermentation were examined to enhance power generation and energy recovery. In batch mode, the maximum voltage production was 0.56 V and the power density reached 1540 mW/m(2). The maximum Coulombic efficiency (CEmax) and energy efficiency (EE) in the batch mode were calculated to be 88.8% and 18.8%, respectively. When the organic loading rate in sequencing batch mode varied from 0.75 to 6.2 g COD/L-d (under CEmax), the maximum power density reached 769.2 mW/m(2) in OLR of 3.1 g COD/L-d, whereas higher energy recovery (CE=52.6%, 0.346 Wh/g CODrem) was achieved at 1.51 g COD/L-d. The results demonstrate that readily biodegradable substrates in biohydrogen fermentation can be effectively used for the enhanced bioelectricity harvesting of MFCs and a MFC coupled with biohydrogen fermentation is of great benefit on higher electricity generation and energy efficiency. PMID- 25723128 TI - Characterization of typical household food wastes from disposers: fractionation of constituents and implications for resource recovery at wastewater treatment. AB - Food wastes with typical US food composition were analyzed to characterize different constituents in both particulate and soluble phases i.e., solids, chemical oxygen demand (COD), 5-day biochemical oxygen demand (BOD), nitrogen (N), phosphorus (P). Relationships between various pollutants were also investigated using 50 samples. One gram of dry food waste generated 1.21 g COD, 0.58 g BOD5, 0.36 g Total SS, 0.025 g Total N, and 0.013 g Total P. Distribution of constituents between particulate and aqueous phases indicated that 40% of COD and 30% of nitrogen were present in soluble form. Relative mass ratios of COD and nitrogen to solids were three to five times higher in particulates than in aqueous phase. However, COD/N ratios were higher in aqueous form than particulates at 63:1 versus 42:1. Detailed relationships between parameters showed that COD, nitrogen, and phosphorus in particulates are 200%, 3.6%, and 3.5% of the volatile suspended solids. PMID- 25723129 TI - Effects of genetic variation and growing condition of prairie cordgrass on feedstock composition and ethanol yield. AB - Prairie cordgrass (Spartina pectinata L.) has the potential to be a feedstock for bioethanol. It is native to North America, and has extensive genetic diversity. Eleven natural populations of prairie cordgrass harvested in 2011 and 2012 were studied. Compositions of the samples showed significant differences within the same year, and between the two years. Two highest, one medium and two lowest glucan concentration samples from each year were selected to evaluate ethanol yield after dilute acid pretreatment and simultaneous saccharification and co fermentation using Saccharomycescerevisiae SR8 that can ferment both glucose and xylose. Up to 88% of theoretical ethanol yields were achieved. Our research demonstrates the potential of prairie cordgrass as a dedicated energy crop with ethanol yields of 205.0-275.6 g/kg biomass and 1748-4368 L/ha, depending on feedstock composition and biomass yield. These ethanol yields are comparable with those of switchgrass, corn stover and bagasse. PMID- 25723130 TI - Application of enhanced membrane bioreactor (eMBR) to treat dye wastewater. AB - An enhanced membrane bioreactor (eMBR) consisting of two anoxic bioreactors (ARs) followed by an aerated membrane bioreactor (AMBR), UV-unit and a granular activated carbon (GAC) filter was employed to treat 50-100 mg/L of remazol blue BR dye. The COD of the feed was 2334 mg/L and COD:TN:TP in the feed was 119:1.87:1. A feed flow rate of 5 L/d was maintained when the dye concentration was 50 mg/L; 10 L/d of return activated sludge was recirculated to each AR from the AMBR. Once the biological system is acclimatised, 95% of dye, 99% of COD, 97% of nitrogen and 73% of phosphorus were removed at a retention time of 74.4 h. When the effluent from the AMBR was drawn at a flux rate of 6.5 L/m(2)h, the trans-membrane pressure reached 40 kPa in every 10 days. AMBR effluent was passed through the UV-unit and GAC filter to remove the dye completely. PMID- 25723131 TI - Construction of multiferrocenyl metallacycles and metallacages via coordination driven self-assembly: from structure to functions. AB - Recently, the construction of discrete multiferrocenyl organometallic structures via coordination-driven self-assembly has attracted considerable attention because of their interesting electrochemical properties and wide range of applications in the areas of organometallic chemistry, electrochemistry, and materials science. Coordination-driven self-assembly has proven to be a simple yet highly efficient approach for the preparation of various multiferrocenyl metallacycles and metallacages with predetermined shapes and sizes as well as the distribution and total number of ferrocenes. This review focuses on the recent progress in the construction of a variety of discrete multiferrocenyl metallacycles and metallacages via coordination-driven self-assembly. The characterization, the structure-related electrochemical properties, and the applications of these multiferrocenyl supramolecular architectures are also discussed. PMID- 25723132 TI - Dispersive liquid-liquid microextraction method based on solidification of floating organic droplet for the determination of thiamphenicol and florfenicol in environmental water samples. AB - Dispersive liquid-liquid microextraction with solidification of a floating organic droplet (DLLME-SFO) followed by high performance liquid chromatography ultraviolet (HPLC-UV) detection was applied for the determination of thiamphenicol (TAP), florfenicol (FF) in water samples. 1-Undecanol was used as the extraction solvent which has lower density than water, low toxicity, and low melting point (19 degrees C). A mixture of 800mL acetone (disperser solvent) and 80uL of 1-undecanol (extraction solvent) was injected into 20mL of aqueous solution. After 5min, 0.6g of NaCl was added and the sample vial was shaken. After 5min, the sample was centrifuged at 3500rpm for 3min, and then placed in an ice bath. When the extraction solvent floating on the aqueous solution had solidified, it was transferred into another conical vial where it was melted quickly at room temperature, and was diluted with methanol to 1mL, and analyzed by HPLC-UV detection. Parameters influencing the extraction efficiency were thoroughly examined and optimized. The extraction recoveries (ER) and the enrichment factors (EF) ranged from 67% to 72% and 223 to 241, respectively. The limits of detection (LODs) (S/N=3) were 0.33 and 0.56ugL(-1) for TAP and FF, respectively. Linear dynamic range (LDR) was in the range of 1.0-550ugL(-1) for TAP and 1.5-700ugL(-1) for FF, the relative standard deviations (RSDs) were in the range of 2.6-3.5% and the recoveries of spiked samples ranged from 94% to 106%. PMID- 25723133 TI - Biological treatment with fungi of olive mill wastewater pre-treated by photocatalytic oxidation with nanomaterials. AB - Olive mill wastewater (OMW) still is a major environmental problem due to its high chemical oxygen demand (COD) and total phenolic content (TPC), contributing for the high toxicity and recalcitrant nature. Several attempts have been made for developing more efficient treatment processes, but no chemical or biological approaches were found to be totally effective, especially in terms of toxicity reduction. In this context, the main purpose of this study was to investigate the treatability of OMW by the combination of photocatalytic oxidation, using two nanomaterials as catalysts (TiO2 and Fe2O3), with biological degradation by fungi (Pleurotus sajor caju and Phanerochaete chrysosporium). Photocatalytic oxidation was carried out using different systems, nano-TiO2/UV, nano-Fe2O3/UV, nano TiO2/H2O2/UV and nano-Fe2O3/H2O2/UV. The effectiveness of the treatment was assessed through color (465nm), aromatics (270nm), COD and TPC reductions, as well as by the decrease in toxicity using the bacterium Vibrio fischeri. The chemical treatment with the system nano-TiO2/H2O2/UV promoted 43%, 14%, 38% and 31% reductions in color, aromatics content, COD and TPC, respectively. However no toxicity reduction was observed. The combination with a biological treatment increased the reduction of COD and TPC as well as a reduction in toxicity. The treatment with P. chrysosporium promoted the highest reduction in toxicity, but P. sajor caju was responsible for the best reduction in COD and TPC. However, the biological treatment was more effective when no hydrogen peroxide was used in the pre-treatment. PMID- 25723134 TI - Pretreatment with low-dose gamma irradiation enhances tolerance to the stress of cadmium and lead in Arabidopsis thaliana seedlings. AB - Heavy metals are important environmental pollutants with negative impact on plant growth and development. To investigate the physiological and molecular mechanisms of heavy metal stress mitigated by low-dose gamma irradiation, the dry seeds of Arabidopsis thaliana were exposed to a Cobalt-60 gamma source at doses ranging from 25 to 150Gy before being subjected to 75uM CdCl2 or 500uM Pb(NO3)2. Then, the growth parameters, and physiological and molecular changes were determined in response to gamma irradiation. Our results showed that 50-Gy gamma irradiation gave maximal beneficial effects on the germination index and root length in response to cadmium/lead stress in Arabidopsis seedlings. The hydrogen peroxide and malondialdehyde contents in seedlings irradiated with 50-Gy gamma rays under stress were significantly lower than those of controls. The antioxidant enzyme activities and proline levels in the irradiated seedlings were significantly increased compared with the controls. Furthermore, a transcriptional expression analysis of selected genes revealed that some components of heavy metal detoxification were stimulated by low-dose gamma irradiation under cadmium/lead stress. Our results suggest that low-dose gamma irradiation alleviates heavy metal stress, probably by modulating the physiological responses and gene expression levels related to heavy metal resistance in Arabidopsis seedlings. PMID- 25723135 TI - Gint2D-T2 correlation NMR of porous media. AB - The internal magnetic field gradient induced in porous media by magnetic susceptibility differences at material interfaces impacts diffusion measurements in particular at high magnetic field and can be used to probe the pore structure. Insight about the relationship between pore space and internal gradient G(int) can be obtained from 2D Laplace NMR experiments. When measuring distributions of transverse relaxation times T(2) in fluid filled porous media, relaxation and diffusion in internal gradients arise simultaneously and data are often interpreted with the assumption that one or the other parameter be constant throughout the sample. To examine this assumption we measure correlations of the distributions of G(int)(2)D and T(2) by 2D Laplace NMR for three different kinds of samples, glass beads with different bead diameters saturated with water, glass beads filled with oil and water, and a wet mortar sample. For the first two samples the cases where either the internal gradient or diffusion dominates were examined separately in order to better understand the relationship between G(int) and D. These results are useful for assessing the impact of internal gradients and diffusion in unknown samples, such as the mortar sample. The experiments were performed at different magnetic field strengths corresponding to 300 MHz and 700 MHz (1)H Larmor frequency to identify the impact of the magnetic field on the internal gradient. Subsequently, spatially resolved Gint(2)D-T(2) maps were obtained to study the sample heterogeneity. PMID- 25723136 TI - Synthesis and photosensitivity of isoxazolin-5-one glycosides. AB - A novel procedure for the synthesis of isoxazolin-5-one glycosides starting from unprotected carbohydrates is described. The substrate scope of the one-pot synthetic protocol was explored using D-configured glucose, xylose, maltose, fructose, ribose and 2-deoxyribose. Naturally occurring 2-(beta-D-glucopyranosyl) 3-isoxazolin-5-one and four novel isoxazolin-5-one glycosides derived from xylose, maltose and fructose were synthesized and purified by flash chromatography. The compounds were characterized in terms of chemical structure, photophysical properties as well as pH stability. The photohydrolysis rates of the synthesized glycosides were compared with uridine as a standard to determine the quantum yields for the photoreactions in water. PMID- 25723137 TI - Rh2(esp)2-catalyzed allylic and benzylic oxidations. AB - The dirhodium(II) catalyst Rh2(esp)2 allows direct solvent-free allylic and benzylic oxidations by T-HYDRO with a remarkably low catalyst loading. This method is operationally simple and scalable at ambient temperature without the use of any additives. The high catalyst stability in these reactions may be attributed to a dirhodium(II,II) catalyst resting state, which is less prone to decomposition. PMID- 25723138 TI - Evolution of antiretroviral therapy services for HIV-infected pregnant women in Cape Town, South Africa. AB - BACKGROUND: Approaches to antiretroviral therapy (ART) in HIV-infected pregnant women have changed considerably in recent years, but there are few comparative data on the implementation of different models of service delivery. METHODS: Using routine clinic records we examined ART initiation in pregnant women attending a large antenatal care (ANC) facility between January 2010 and December 2013 in Cape Town, South Africa. Over this time six different service delivery models were implemented sequentially to provide ART in pregnancy, including the integration of ART into ANC, use of point-of-care CD4 cell count testing, and universal ART initiation for all HIV-infected pregnant women. RESULTS: During the study period 19,432 women sought ANC, levels of HIV testing were high (98%) and 30% of pregnant women tested HIV-positive. Integration of ART into ANC was associated with significant increases in the proportion of eligible women initiating treatment before delivery compared to referral to a separate ART clinic (p<0.001). When CD4 cell counts were used to determine ART eligibility, point-of-care testing was associated with decreased delays to ART initiation compared to laboratory-based testing (p<0.001). The strategy of universal ART led to the highest levels of ART initiation (with 92% of women starting before delivery) and the shortest delays, with 82% of women starting ART on the day of the first ANC visit. CONCLUSION: Developments in service delivery models, most notably service integration and universal ART for pregnant women, have improved antenatal ART initiation dramatically in this setting. Further research is needed into how strategies for antenatal ART initiation impact maternal and child health over the long-term. PMID- 25723139 TI - Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients. AB - BACKGROUND: The risk of liver enzyme elevation (LEE) after different ritonavir boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. METHODS: Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. RESULTS: A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. CONCLUSIONS: Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus. PMID- 25723141 TI - Distance measurement error in time-of-flight sensors due to shot noise. AB - Unlike other noise sources, which can be reduced or eliminated by different signal processing techniques, shot noise is an ever-present noise component in any imaging system. In this paper, we present an in-depth study of the impact of shot noise on time-of-flight sensors in terms of the error introduced in the distance estimation. The paper addresses the effect of parameters, such as the size of the photosensor, the background and signal power or the integration time, and the resulting design trade-offs. The study is demonstrated with different numerical examples, which show that, in general, the phase shift determination technique with two background measurements approach is the most suitable for pixel arrays of large resolution. PMID- 25723142 TI - Fast and flexible movable vision measurement for the surface of a large-sized object. AB - The presented movable vision measurement for the three-dimensional (3D) surface of a large-sized object has the advantages of system simplicity, low cost, and high accuracy. Aiming at addressing the problems of existing movable vision measurement methods, a more suitable method for large-sized products on industrial sites is introduced in this paper. A raster binocular vision sensor and a wide-field camera are combined to form a 3D scanning sensor. During measurement, several planar targets are placed around the object to be measured. With the planar target as an intermediary, the local 3D data measured by the scanning sensor are integrated into the global coordinate system. The effectiveness of the proposed method is verified through physical experiments. PMID- 25723143 TI - Development of a passive liquid valve (PLV) utilizing a pressure equilibrium phenomenon on the centrifugal microfluidic platform. AB - In this paper, we propose an easy-to-implement passive liquid valve (PLV) for the microfluidic compact-disc (CD). This valve can be implemented by introducing venting chambers to control the air flow of the source and destination chambers. The PLV mechanism is based on equalizing the main forces acting on the microfluidic CD (i.e., the centrifugal and capillary forces) to control the burst frequency of the source chamber liquid. For a better understanding of the physics behind the proposed PLV, an analytical model is described. Moreover, three parameters that control the effectiveness of the proposed valve, i.e., the liquid height, liquid density, and venting chamber position with respect to the CD center, are tested experimentally. To demonstrate the ability of the proposed PLV valve, microfluidic liquid switching and liquid metering are performed. In addition, a Bradford assay is performed to measure the protein concentration and evaluated in comparison to the benchtop procedure. The result shows that the proposed valve can be implemented in any microfluidic process that requires simplicity and accuracy. Moreover, the developed valve increases the flexibility of the centrifugal CD platform for passive control of the liquid flow without the need for an external force or trigger. PMID- 25723140 TI - Antiretroviral Treatment Is Associated With Iron Deficiency in HIV-Infected Malawian Women That Is Mitigated With Supplementation, but Is Not Associated With Infant Iron Deficiency During 24 Weeks of Exclusive Breastfeeding. AB - OBJECTIVE: In resource-limited settings without safe alternatives to breastfeeding, the WHO recommends exclusive breastfeeding and antiretroviral (ARV) prophylaxis. Given the high prevalence of anemia among HIV-infected women, mothers and their infants (through fetal iron accretion) may be at risk of iron deficiency. We assessed the effects of maternal micronutrient-fortified lipid based nutrient supplements (LNS) and maternal ARV treatment or infant ARV prophylaxis on maternal and infant iron status during exclusive breastfeeding from birth to 24 weeks. METHODS: The Breastfeeding, Antiretrovirals, and Nutrition study was a randomized controlled trial conducted in Lilongwe, Malawi, from 2004 to 2010. HIV-infected mothers (CD4 >200 cells/MUL) and their infants were randomly assigned to 28-week interventions: maternal LNS/maternal ARV (n = 424), maternal LNS/infant ARV (n = 426), maternal LNS (n = 334), maternal ARV (n = 425), infant ARV (n = 426), or control (n = 334). Longitudinal models tested intervention effects on hemoglobin (Hb). In a subsample (n = 537) with multiple iron indicators, intervention effects on Hb, transferrin receptors (TfR), and ferritin were tested with linear and Poisson regression. RESULTS: In longitudinal models, LNS effects on maternal and infant Hb were minimal. In subsample mothers, maternal ARVs were associated with tissue iron depletion (TfR >8.3 mg/L) (risk ratio: 3.1, P < 0.01), but not in ARV-treated mothers receiving LNS (P = 0.17). LNS without ARVs was not associated with iron deficiency or anemia (P > 0.1). In subsample infants, interventions were not associated with impaired iron status (all P > 0.1). CONCLUSIONS: Maternal ARV treatment with protease inhibitors is associated with maternal tissue iron depletion; but LNS mitigates adverse effects. ARVs do not seem to influence infant iron status; however, extended use needs to be evaluated. PMID- 25723144 TI - Symphony: a framework for accurate and holistic WSN simulation. AB - Research on wireless sensor networks has progressed rapidly over the last decade, and these technologies have been widely adopted for both industrial and domestic uses. Several operating systems have been developed, along with a multitude of network protocols for all layers of the communication stack. Industrial Wireless Sensor Network (WSN) systems must satisfy strict criteria and are typically more complex and larger in scale than domestic systems. Together with the non deterministic behavior of network hardware in real settings, this greatly complicates the debugging and testing of WSN functionality. To facilitate the testing, validation, and debugging of large-scale WSN systems, we have developed a simulation framework that accurately reproduces the processes that occur inside real equipment, including both hardware- and software-induced delays. The core of the framework consists of a virtualized operating system and an emulated hardware platform that is integrated with the general purpose network simulator ns-3. Our framework enables the user to adjust the real code base as would be done in real deployments and also to test the boundary effects of different hardware components on the performance of distributed applications and protocols. Additionally we have developed a clock emulator with several different skew models and a component that handles sensory data feeds. The new framework should substantially shorten WSN application development cycles. PMID- 25723145 TI - Distributed sensor architecture for intelligent control that supports quality of control and quality of service. AB - This paper is part of a study of intelligent architectures for distributed control and communications systems. The study focuses on optimizing control systems by evaluating the performance of middleware through quality of service (QoS) parameters and the optimization of control using Quality of Control (QoC) parameters. The main aim of this work is to study, design, develop, and evaluate a distributed control architecture based on the Data-Distribution Service for Real-Time Systems (DDS) communication standard as proposed by the Object Management Group (OMG). As a result of the study, an architecture called Frame Sensor-Adapter to Control (FSACtrl) has been developed. FSACtrl provides a model to implement an intelligent distributed Event-Based Control (EBC) system with support to measure QoS and QoC parameters. The novelty consists of using, simultaneously, the measured QoS and QoC parameters to make decisions about the control action with a new method called Event Based Quality Integral Cycle. To validate the architecture, the first five Braitenberg vehicles have been implemented using the FSACtrl architecture. The experimental outcomes, demonstrate the convenience of using jointly QoS and QoC parameters in distributed control systems. PMID- 25723147 TI - Airway involvement of relapsing polychondritis revealed by 18F-fluoride PET/CT. AB - A 48-year-old man with progressive respiratory symptoms was suspected of having relapsing polychondritis (RPC). A 99mTc-MDP bone scintigraphy showed only mild activity in the bilateral costal cartilage. In contrast, 18F-fluoride PET/CT revealed intense radioactivity accumulation in the tracheal cartilages. Biopsy results from tracheal cartilage were consistent with a diagnosis of RPC. The patient received therapy toward RPC, and his symptoms was gradually alleviated. PMID- 25723146 TI - Novel selection methods for DNA-encoded chemical libraries. AB - Driven by the need for new compounds to serve as biological probes and leads for therapeutic development and the growing accessibility of DNA technologies including high-throughput sequencing, many academic and industrial groups have begun to use DNA-encoded chemical libraries as a source of bioactive small molecules. In this review, we describe the technologies that have enabled the selection of compounds with desired activities from these libraries. These methods exploit the sensitivity of in vitro selection coupled with DNA amplification to overcome some of the limitations and costs associated with conventional screening methods. In addition, we highlight newer techniques with the potential to be applied to the high-throughput evaluation of DNA-encoded chemical libraries. PMID- 25723148 TI - Yawning in depression: worth looking into. AB - Yawning often occurs during states of increased sleep propensity. Depression is associated with sleep problems and tiredness. The aim of this paper is to review the present knowledge about possible changes of yawning during an episode of major depression (MD) and to report data on yawning from an online depression forum comprising of 450,000 postings. A literature search did not reveal any study about yawning in people with MD when compared to controls. However, there is evidence for an increased frequency of yawning under the influence of antidepressants. Analysis of the depression forum postings revealed 63 people writing about increased yawning in the context of depression. However, all but one of them were treated with antidepressants; and yawning was not reported as a symptom of depression, but in most cases (N=56) as occurring as a result of treatment with antidepressants. These findings are in agreement with a tonic hyperarousal in typical depression which is reduced by all standard antidepressants. For clinicians, it would be of interest to know whether yawning is reduced in untreated depression and whether it predicts treatment outcome. PMID- 25723149 TI - Correction: The physical properties of supramolecular peptide assemblies: from building block association to technological applications. AB - Correction for 'The physical properties of supramolecular peptide assemblies: from building block association to technological applications' by Lihi Adler Abramovich et al., Chem. Soc. Rev., 2014, DOI: . PMID- 25723150 TI - Biologically active metabolites produced by the basidiomycete Quambalaria cyanescens. AB - Four strains of the fungus Quambalaria cyanescens (Basidiomycota: Microstromatales), were used for the determination of secondary metabolites production and their antimicrobial and biological activities. A new naphthoquinone named quambalarine A, (S)-(+)-3-(5-ethyl-tetrahydrofuran-2-yliden) 5,7,8-trihydroxy-2-oxo-1,4-naphthoquinone (1), together with two known naphthoquinones, 3-hexanoyl-2,5,7,8-tetrahydroxy-1,4-naphthoquinone (named here as quambalarine B, 2) and mompain, 2,5,7,8-tetrahydroxy-1,4-naphthoquinone (3) were isolated. Their structures were determined by single-crystal X-ray diffraction crystallography, NMR and MS spectrometry. Quambalarine A (1) had a broad antifungal and antibacterial activity and is able inhibit growth of human pathogenic fungus Aspergillus fumigatus and fungi co-occurring with Q. cyanescens in bark beetle galleries including insect pathogenic species Beauveria bassiana. Quambalarine B (2) was active against several fungi and mompain mainly against bacteria. The biological activity against human-derived cell lines was selective towards mitochondria (2 and 3); after long-term incubation with 2, mitochondria were undetectable using a mitochondrial probe. A similar effect on mitochondria was observed also for environmental competitors of Q. cyanescens from the genus Geosmithia. PMID- 25723151 TI - Protein complexes in bacteria. AB - Large-scale analyses of protein complexes have recently become available for Escherichia coli and Mycoplasma pneumoniae, yielding 443 and 116 heteromultimeric soluble protein complexes, respectively. We have coupled the results of these mass spectrometry-characterized protein complexes with the 285 "gold standard" protein complexes identified by EcoCyc. A comparison with databases of gene orthology, conservation, and essentiality identified proteins conserved or lost in complexes of other species. For instance, of 285 "gold standard" protein complexes in E. coli, less than 10% are fully conserved among a set of 7 distantly-related bacterial "model" species. Complex conservation follows one of three models: well-conserved complexes, complexes with a conserved core, and complexes with partial conservation but no conserved core. Expanding the comparison to 894 distinct bacterial genomes illustrates fractional conservation and the limits of co-conservation among components of protein complexes: just 14 out of 285 model protein complexes are perfectly conserved across 95% of the genomes used, yet we predict more than 180 may be partially conserved across at least half of the genomes. No clear relationship between gene essentiality and protein complex conservation is observed, as even poorly conserved complexes contain a significant number of essential proteins. Finally, we identify 183 complexes containing well-conserved components and uncharacterized proteins which will be interesting targets for future experimental studies. PMID- 25723152 TI - A genomic data viewer for iPad. AB - The Integrative Genomics Viewer (IGV) for iPad, based on the popular IGV application for desktop and laptop computers, supports researchers who wish to take advantage of the mobility of today's tablet computers to view genomic data and present findings to colleagues. PMID- 25723153 TI - Two types of functionally distinct fiber containing structural protein complexes are produced during infection of adenovirus serotype 5. AB - Adenoviruses are common pathogens. The localization of their receptors coxsackievirus and adenovirus receptor, and desmoglein-2 in cell-cell junction complexes between polarized epithelial cells represents a major challenge for adenovirus infection from the apical surface. Structural proteins including hexon, penton base and fiber are excessively produced in serotype 5 adenovirus (Ad5)-infected cells. We have characterized the composition of structural protein complexes released from Ad5 infected cells and their capacity in remodeling cell cell junction complexes. Using T84 cells as a model for polarized epithelium, we have studied the effect of Ad5 structural protein complexes in remodeling cell cell junctions in polarized epithelium. The initial Ad5 infection in T84 cell culture was inefficient. However, progressive distortion of cell-cell junction in association with fiber release was evident during progression of Ad5 infection. Incubation of T84 cell cultures with virion-free supernatant from Ad5 infected culture resulted in distortion of cell-cell junctions and decreased infectivity of Ad5-GFP vector. We used gel filtration chromatography to fractionate fiber containing virion-free supernatant from Ad5 infected culture supernatant. Fiber containing fractions were further characterized for their capacity to inhibit the infection of Ad5-GFP vector, their composition in adenovirus structural proteins using western blot and LC-MS/MS and their capacity in remolding cell-cell junctions. Fiber molecules in complexes containing penton base and hexon, or mainly hexon were identified. Only the fiber complexes with relatively high content of penton base, but not the fiber-hexon complexes with low penton base, were able to penetrate into T84 cells and cause distortion of cell-cell junctions. Our findings suggest that these two types of fiber complexes may play different roles in adenoviral infection. PMID- 25723154 TI - How volatilities nonlocal in time affect the price dynamics in complex financial systems. AB - What is the dominating mechanism of the price dynamics in financial systems is of great interest to scientists. The problem whether and how volatilities affect the price movement draws much attention. Although many efforts have been made, it remains challenging. Physicists usually apply the concepts and methods in statistical physics, such as temporal correlation functions, to study financial dynamics. However, the usual volatility-return correlation function, which is local in time, typically fluctuates around zero. Here we construct dynamic observables nonlocal in time to explore the volatility-return correlation, based on the empirical data of hundreds of individual stocks and 25 stock market indices in different countries. Strikingly, the correlation is discovered to be non-zero, with an amplitude of a few percent and a duration of over two weeks. This result provides compelling evidence that past volatilities nonlocal in time affect future returns. Further, we introduce an agent-based model with a novel mechanism, that is, the asymmetric trading preference in volatile and stable markets, to understand the microscopic origin of the volatility-return correlation nonlocal in time. PMID- 25723156 TI - The hunger games. AB - Although AgRP and POMC neurons in the hypothalamus have long been associated with regulation of food intake, in this issue of Cell, Chen et al. use direct imaging in vivo to demonstrate rapid changes in their activity upon food presentation. The rapidity of their altered responses challenges classic notions of their functions and raises new hypotheses. PMID- 25723157 TI - For longevity, perception is everything. AB - Aging is a risk factor for chronic diseases, and identifying targets for intervention is a goal of the aging field. Burkewitz et al. now describe a mechanism that mediates the specific role for AMPK in longevity, whereby its activity in neurons modulates metabolism and mitochondrial integrity in peripheral tissues. PMID- 25723158 TI - Finding the right match fast. AB - DNA recombinases face the daunting task of locating and pairing up specific sequences among millions of base pairs in a genome, all within about an hour. Qi et al. show that recombinases solve this problem by searching in 8-nt microhomology units, reducing the search space and accelerating the homology search. PMID- 25723159 TI - ALT telomeres get together with nuclear receptors. AB - Nuclear receptors bind chromosome ends in "alternative lengthening of telomeres" (ALT) cancer cells that maintain their ends by homologous recombination instead of telomerase. Marzec et al. now demonstrate that, in ALT cells, nuclear receptors not only trigger distal chromatin associations to mediate telomere telomere recombination events, but also drive chromosome-internal targeted telomere insertions (TTI). PMID- 25723160 TI - Fertile waters for aging research. AB - The quest to slow aging has come far, and what used to be the domain of science fiction writers and snake oil salesmen may soon become science fact. Innovative new approaches, such as the use of the very short-lived African killifish (Harel et al.), are bridging the translational gap and bring the promise of healthy longevity to fruition. PMID- 25723161 TI - Homeostasis, inflammation, and disease susceptibility. AB - While modernization has dramatically increased lifespan, it has also witnessed the increasing prevalence of diseases such as obesity, hypertension, and type 2 diabetes. Such chronic, acquired diseases result when normal physiologic control goes awry and may thus be viewed as failures of homeostasis. However, while nearly every process in human physiology relies on homeostatic mechanisms for stability, only some have demonstrated vulnerability to dysregulation. Additionally, chronic inflammation is a common accomplice of the diseases of homeostasis, yet the basis for this connection is not fully understood. Here we review the design of homeostatic systems and discuss universal features of control circuits that operate at the cellular, tissue, and organismal levels. We suggest a framework for classification of homeostatic signals that is based on different classes of homeostatic variables they report on. Finally, we discuss how adaptability of homeostatic systems with adjustable set points creates vulnerability to dysregulation and disease. This framework highlights the fundamental parallels between homeostatic and inflammatory control mechanisms and provides a new perspective on the physiological origin of inflammation. PMID- 25723162 TI - Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal. AB - Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARalpha ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging. PMID- 25723163 TI - Evolvability as a function of purifying selection in TEM-1 beta-lactamase. AB - Evolvability-the capacity to generate beneficial heritable variation-is a central property of biological systems. However, its origins and modulation by environmental factors have not been examined systematically. Here, we analyze the fitness effects of all single mutations in TEM-1 beta-lactamase (4,997 variants) under selection for the wild-type function (ampicillin resistance) and for a new function (cefotaxime resistance). Tolerance to mutation in this enzyme is bimodal and dependent on the strength of purifying selection in vivo, a result that derives from a steep non-linear ampicillin-dependent relationship between biochemical activity and fitness. Interestingly, cefotaxime resistance emerges from mutations that are neutral at low levels of ampicillin but deleterious at high levels; thus the capacity to evolve new function also depends on the strength of selection. The key property controlling evolvability is an excess of enzymatic activity relative to the strength of selection, suggesting that fluctuating environments might select for high-activity enzymes. PMID- 25723164 TI - Mechanism of human antibody-mediated neutralization of Marburg virus. AB - The mechanisms by which neutralizing antibodies inhibit Marburg virus (MARV) are not known. We isolated a panel of neutralizing antibodies from a human MARV survivor that bind to MARV glycoprotein (GP) and compete for binding to a single major antigenic site. Remarkably, several of the antibodies also bind to Ebola virus (EBOV) GP. Single-particle EM structures of antibody-GP complexes reveal that all of the neutralizing antibodies bind to MARV GP at or near the predicted region of the receptor-binding site. The presence of the glycan cap or mucin-like domain blocks binding of neutralizing antibodies to EBOV GP, but not to MARV GP. The data suggest that MARV-neutralizing antibodies inhibit virus by binding to infectious virions at the exposed MARV receptor-binding site, revealing a mechanism of filovirus inhibition. PMID- 25723166 TI - Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers. AB - The breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors. PMID- 25723165 TI - Structural basis for Marburg virus neutralization by a cross-reactive human antibody. AB - The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 A crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry. PMID- 25723167 TI - Early telomerase inactivation accelerates aging independently of telomere length. AB - Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even early after telomerase inactivation (ETI), yeast mother cells show transient DNA damage response (DDR) episodes, stochastically altered cell-cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI phenotypes occurred well before the population senescence caused late after telomerase inactivation (LTI). They were morphologically distinct from LTI senescence, were genetically uncoupled from telomere length, and were rescued by elevating dNTP pools. Our combined genetic and single-cell analyses show that, well before critical telomere shortening, telomerase is continuously required to respond to transient DNA replication stress in mother cells and that a lack of telomerase accelerates otherwise normal aging. PMID- 25723168 TI - Atomic structure of T6SS reveals interlaced array essential to function. AB - Type VI secretion systems (T6SSs) are newly identified contractile nanomachines that translocate effector proteins across bacterial membranes. The Francisella pathogenicity island, required for bacterial phagosome escape, intracellular replication, and virulence, was presumed to encode a T6SS-like apparatus. Here, we experimentally confirm the identity of this T6SS and, by cryo electron microscopy (cryoEM), show the structure of its post-contraction sheath at 3.7 A resolution. We demonstrate the assembly of this T6SS by IglA/IglB and secretion of its putative effector proteins in response to environmental stimuli. The sheath has a quaternary structure with handedness opposite that of contracted sheath of T4 phage tail and is organized in an interlaced two-dimensional array by means of beta sheet augmentation. By structure-based mutagenesis, we show that this interlacing is essential to secretion, phagosomal escape, and intracellular replication. Our atomic model of the T6SS will facilitate design of drugs targeting this highly prevalent secretion apparatus. PMID- 25723169 TI - Structure of the type VI secretion system contractile sheath. AB - Bacteria use rapid contraction of a long sheath of the type VI secretion system (T6SS) to deliver effectors into a target cell. Here, we present an atomic resolution structure of a native contracted Vibrio cholerae sheath determined by cryo-electron microscopy. The sheath subunits, composed of tightly interacting proteins VipA and VipB, assemble into a six-start helix. The helix is stabilized by a core domain assembled from four beta strands donated by one VipA and two VipB molecules. The fold of inner and middle layers is conserved between T6SS and phage sheaths. However, the structure of the outer layer is distinct and suggests a mechanism of interaction of the bacterial sheath with an accessory ATPase, ClpV, that facilitates multiple rounds of effector delivery. Our results provide a mechanistic insight into assembly of contractile nanomachines that bacteria and phages use to translocate macromolecules across membranes. PMID- 25723170 TI - TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. AB - Subsets of long-lived, tumor-initiating stem cells often escape cancer therapies. However, sources and mechanisms that generate tumor heterogeneity and drug resistant cell population are still unfolding. Here, we devise a functional reporter system to lineage trace and/or genetic ablate signaling in TGF-beta activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-beta's impact on malignant progression, we demonstrate that TGF-beta concentrating near tumor-vasculature generates heterogeneity in TGF-beta signaling at tumor-stroma interface and bestows slower-cycling properties to neighboring SCC-SCs. While non responding progenies proliferate faster and accelerate tumor growth, TGF-beta responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-beta-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-beta transcriptionally activates p21, which stabilizes NRF2, thereby markedly enhancing glutathione metabolism and diminishing effectiveness of anti cancer therapeutics. Together, these findings establish a surprising non-genetic paradigm for TGF-beta signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance. PMID- 25723171 TI - Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. AB - There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo. PMID- 25723172 TI - A hardwired HIV latency program. AB - Biological circuits can be controlled by two general schemes: environmental sensing or autonomous programs. For viruses such as HIV, the prevailing hypothesis is that latent infection is controlled by cellular state (i.e., environment), with latency simply an epiphenomenon of infected cells transitioning from an activated to resting state. However, we find that HIV expression persists despite the activated-to-resting cellular transition. Mathematical modeling indicates that HIV's Tat positive-feedback circuitry enables this persistence and strongly controls latency. To overcome the inherent crosstalk between viral circuitry and cellular activation and to directly test this hypothesis, we synthetically decouple viral dependence on cellular environment from viral transcription. These circuits enable control of viral transcription without cellular activation and show that Tat feedback is sufficient to regulate latency independent of cellular activation. Overall, synthetic reconstruction demonstrates that a largely autonomous, viral-encoded program underlies HIV latency-potentially explaining why cell-targeted latency reversing agents exhibit incomplete penetrance. PMID- 25723173 TI - An evolutionary role for HIV latency in enhancing viral transmission. AB - HIV latency is the chief obstacle to eradicating HIV but is widely believed to be an evolutionary accident providing no lentiviral fitness advantage. However, findings of latency being "hardwired" into HIV's gene-regulatory circuitry appear inconsistent with latency being an evolutionary accident, given HIV's rapid mutation rate. Here, we propose that latency is an evolutionary "bet-hedging" strategy whose frequency has been optimized to maximize lentiviral transmission by reducing viral extinction during mucosal infections. The model quantitatively fits the available patient data, matches observations of high-frequency latency establishment in cell culture and primates, and generates two counterintuitive but testable predictions. The first prediction is that conventional CD8-depletion experiments in SIV-infected macaques increase latent cells more than viremia. The second prediction is that strains engineered to have higher replicative fitness via reduced latency-will exhibit lower infectivity in animal-model mucosal inoculations. Therapeutically, the theory predicts treatment approaches that may substantially enhance "activate-and-kill" HIV-cure strategies. PMID- 25723175 TI - Identification and deletion of Tft1, a predicted glycosyltransferase necessary for cell wall beta-1,3;1,4-glucan synthesis in Aspergillus fumigatus. AB - Aspergillus fumigatus is an environmental mold that causes severe, often fatal invasive infections in immunocompromised patients. The search for new antifungal drug targets is critical, and the synthesis of the cell wall represents a potential area to find such a target. Embedded within the main beta-1,3-glucan core of the A. fumigatus cell wall is a mixed linkage, beta-D-(1,3;1,4)-glucan. The role of this molecule or how it is synthesized is unknown, though it comprises 10% of the glucans within the wall. While this is not a well-studied molecule in fungi, it has been studied in plants. Using the sequences of two plant mixed linkage glucan synthases, a single ortholog was identified in A. fumigatus (Tft1). A strain lacking this enzyme (tft1Delta) was generated along with revertant strains containing the native gene under the control of either the native or a strongly expressing promoter. Immunofluorescence staining with an antibody against beta-(1,3;1,4)-glucan and biochemical quantification of this polysaccharide in the tft1Delta strain demonstrated complete loss of this molecule. Reintroduction of the gene into the knockout strain yielded reappearance in amounts that correlated with expected expression of the gene. The loss of Tft1 and mixed linkage glucan yielded no in vitro growth phenotype. However, there was a modest increase in virulence for the tft1Delta strain in a wax worm model. While the precise roles for beta-(1,3;1,4)-glucan within A. fumigatus cell wall are still uncertain, it is clear that Tft1 plays a pivotal role in the biosynthesis of this cell wall polysaccharide. PMID- 25723174 TI - The adjuvant effects of high-molecule-weight polysaccharides purified from Antrodia cinnamomea on dendritic cell function and DNA vaccines. AB - The biological activity of the edible basidiomycete Antrodia cinnamomea (AC) has been studied extensively. Many effects, such as anti-cancer, anti-inflammatory, and antioxidant activities, have been reported from either crude extracts or compounds isolated from AC. However, research addressing the function of AC in enhancing immunity is rare. The aim of the present study is to investigate the active components and the mechanism involved in the immunostimulatory effect of AC. We found that polysaccharides (PS) in the water extract of AC played a major role in dendritic cell (DC) activation, which is a critical leukocyte in initiating immune responses. We further size purified and identified that the high-molecular weight PS fraction (greater than 100 kDa) exhibited the activating effect. The AC high-molecular weight PSs (AC hmwPSs) promoted pro-inflammatory cytokine production by DCs and the maturation of DCs. In addition, DC-induced antigen-specific T cell activation and Th1 differentiation were increased by AC hmwPSs. In studying the molecular mechanism, we confirmed the activation of the MAPK and NF-kappaB pathways in DCs after AC hmwPSs treatment. Furthermore, we demonstrated that TLR2 and TLR4 are required for the stimulatory activity of AC hmwPSs on DCs. In a mouse tumor model, we demonstrated that AC hmwPSs enhanced the anti-tumor efficacy of the HER-2/neu DNA vaccine by facilitating specific Th1 responses. Thus, we conclude that hmwPSs are the major components of AC that stimulate DCs via the TLR2/TLR4 and NF-kappaB/MAPK signaling pathways. The AC hmwPSs have potential to be applied as adjuvants. PMID- 25723176 TI - Reducing uncertainty in the american community survey through data-driven regionalization. AB - The American Community Survey (ACS) is the largest survey of US households and is the principal source for neighborhood scale information about the US population and economy. The ACS is used to allocate billions in federal spending and is a critical input to social scientific research in the US. However, estimates from the ACS can be highly unreliable. For example, in over 72% of census tracts, the estimated number of children under 5 in poverty has a margin of error greater than the estimate. Uncertainty of this magnitude complicates the use of social data in policy making, research, and governance. This article presents a heuristic spatial optimization algorithm that is capable of reducing the margins of error in survey data via the creation of new composite geographies, a process called regionalization. Regionalization is a complex combinatorial problem. Here rather than focusing on the technical aspects of regionalization we demonstrate how to use a purpose built open source regionalization algorithm to process survey data in order to reduce the margins of error to a user-specified threshold. PMID- 25723177 TI - A time-critical adaptive approach for visualizing natural scenes on different devices. AB - To automatically adapt to various hardware and software environments on different devices, this paper presents a time-critical adaptive approach for visualizing natural scenes. In this method, a simplified expression of a tree model is used for different devices. The best rendering scheme is intelligently selected to generate a particular scene by estimating the rendering time of trees based on their visual importance. Therefore, this approach can ensure the reality of natural scenes while maintaining a constant frame rate for their interactive display. To verify its effectiveness and flexibility, this method is applied in different devices, such as a desktop computer, laptop, iPad and smart phone. Applications show that the method proposed in this paper can not only adapt to devices with different computing abilities and system resources very well but can also achieve rather good visual realism and a constant frame rate for natural scenes. PMID- 25723178 TI - The interaction of RNA helicase DDX3 with HIV-1 Rev-CRM1-RanGTP complex during the HIV replication cycle. AB - Molecular traffic between the nucleus and the cytoplasm is regulated by the nuclear pore complex (NPC), which acts as a highly selective channel perforating the nuclear envelope in eukaryotic cells. The human immunodeficiency virus (HIV) exploits the nucleocytoplasmic pathway to export its RNA transcripts across the NPC to the cytoplasm. Despite extensive study on the HIV life cycle and the many drugs developed to target this cycle, no current drugs have been successful in targeting the critical process of viral nuclear export, even though HIV's reliance on a single host protein, CRM1, to export its unspliced and partially spliced RNA transcripts makes it a tempting target. Due to recent findings implicating a DEAD-box helicase, DDX3, in HIV replication and a member of the export complex, it has become an appealing target for anti-HIV drug inhibition. In the present research, we have applied a hybrid computational protocol to analyze protein-protein interactions in the HIV mRNA export cycle. This method is based on molecular docking followed by molecular dynamics simulation and accompanied by approximate free energy calculation (MM/GBSA), computational alanine scanning, clustering, and evolutionary analysis. We highlight here some of the most likely binding modes and interfacial residues between DDX3 and CRM1 both in the absence and presence of RanGTP. This work shows that although DDX3 can bind to free CRM1, addition of RanGTP leads to more concentrated distribution of binding modes and stronger binding between CRM1 and RanGTP. PMID- 25723179 TI - Conformational changes in a hyperthermostable glycoside hydrolase: enzymatic activity is a consequence of the loop dynamics and protonation balance. AB - Endo-beta-1, 4-mannanase from Thermotoga petrophila (TpMan) is a modular hyperthermostable enzyme involved in the degradation of mannan-containing polysaccharides. The degradation of these polysaccharides represents a key step for several industrial applications. Here, as part of a continuing investigation of TpMan, the region corresponding to the GH5 domain (TpManGH5) was characterized as a function of pH and temperature. The results indicated that the enzymatic activity of the TpManGH5 is pH-dependent, with its optimum activity occurring at pH 6. At pH 8, the studies demonstrated that TpManGH5 is a molecule with a nearly spherical tightly packed core displaying negligible flexibility in solution, and with size and shape very similar to crystal structure. However, TpManGH5 experiences an increase in radius of gyration in acidic conditions suggesting expansion of the molecule. Furthermore, at acidic pH values, TpManGH5 showed a less globular shape, probably due to a loop region slightly more expanded and flexible in solution (residues Y88 to A105). In addition, molecular dynamics simulations indicated that conformational changes caused by pH variation did not change the core of the TpManGH5, which means that only the above mentioned loop region presents high degree of fluctuations. The results also suggested that conformational changes of the loop region may facilitate polysaccharide and enzyme interaction. Finally, at pH 6 the results indicated that TpManGH5 is slightly more flexible at 65 degrees C when compared to the same enzyme at 20 degrees C. The biophysical characterization presented here is well correlated with the enzymatic activity and provide new insight into the structural basis for the temperature and pH-dependent activity of the TpManGH5. Also, the data suggest a loop region that provides a starting point for a rational design of biotechnological desired features. PMID- 25723181 TI - Expression of desmosomal proteins in acantholytic squamous cell carcinoma of the skin. AB - Acantholytic (adenoid) squamous cell carcinoma (ASCC) is a subtype of squamous cell carcinoma (SCC) in which neoplastic tumour cells form gland-like structures. Little is known about the pathogenetic mechanisms of ASCC. We hypothesised that they may be related to the compositon of desmosomes. We analysed the immunohistochemical expression of desmosomal proteins in 5 cases of ASCC of the skin, in comparison to 5 cases of conventional SCC of the skin. The most consistent findings were loss of desmoglein 1 (DSG 1), desmoglein 3 (DSG3), desmocollin 1 (DSC1), desmocollin 2 (DSC2), desmocollin 3 (DSC 3), and plakophilin 1 (PKP 1), and decreased expression of desmoplakin 1 (DP 1) and plakoglobin (PG). In conventional well to moderately differentiated SCC, the expression of desmosomal proteins was decreased, but membranous staining was mostly preserved with patterns similar to normal epidermis. Our results suggest that loss of desmosomal cadherins and decreased expression of desmosomal plaque proteins might be responsible for the formation of gland-like structures in ASCC. It seems that desmosomal cadherins, which correspond to the transmembrane core of desmosomes, are predominantly affected in ASCC, while DP 1 and PG, which correspond to cytoplasmic plaque of desmosomes, probably play a lesser role in maintenance of tumour cell cohesion. Our results also indicate that, in addition to previously described verrucous and spindle cell carcinoma, ASCC is another subtype of SCC with a characteristic expression pattern of desmosomal proteins. PMID- 25723183 TI - Ferric chloride-induced arterial thrombosis in mice. AB - Because of its high sensitivity and reproducibility, the FeCl3 -induced arterial thrombosis mouse model is widely used to study molecular mechanisms as well as the efficacy of antithrombotic agents. The model also carries the additional advantages of being relatively easy to establish and requiring minimal instrumentation. However, the various parameters that influence the outcome must be optimized to the experimental requirements and the individual laboratory conditions. Here, we describe a standard protocol for FeCl3 -induced common carotid artery thrombosis, parameters that influence thrombus growth, ways to optimize the experiment, and interpretation of the data. PMID- 25723182 TI - Survival nomogram for curatively resected Korean gastric cancer patients: multicenter retrospective analysis with external validation. AB - BACKGROUND: A small number of nomograms have been previously developed to predict the individual survival of patients who undergo curative resection for gastric cancer. However, all were derived from single high-volume centers. The aim of this study was to develop and validate a nomogram for gastric cancer patients using a multicenter database. METHODS: We reviewed the clinicopathological and survival data of 2012 patients who underwent curative resection for gastric cancer between 2001 and 2006 at eight centers. Among these centers, six institutions were randomly assigned to the development set, and the other two centers were assigned to the validation set. Multivariate analysis using the Cox proportional hazard regression model was performed, and discrimination and calibration were evaluated by external validation. RESULTS: Multivariate analyses revealed that age, tumor size, lymphovascular invasion, depth of invasion, and metastatic lymph nodes were significant prognostic factors for overall survival. In the external validation, the concordance index was 0.831 (95% confidence interval, 0.784-0.878), and Hosmer-Lemeshow chi-square statistic was 3.92 (P = 0.917). CONCLUSIONS: We developed and validated a nomogram to predict 5-year overall survival after curative resection for gastric cancer based on a multicenter database. This nomogram can be broadly applied even in general hospitals and is useful for counseling patients, and scheduling follow-up. PMID- 25723184 TI - Inducible models of bone loss. AB - Bone is an essential organ that not only confers structural stability to the organism, but also serves as a reservoir for hematopoietic elements and is thought to affect systemic homeostasis through the release of endocrine factors as well as calcium. The loss of bone mass due to an uncoupling of bone formation and bone resorption leads to increased fragility that can result in devastating fractures. Further understanding of the effects of environmental stimuli on the development of bone disease in humans is needed, and they can be studied using animal models. Here, we present established and novel methods for the induction of bone loss in mice, including manipulation of diet and environment, administration of drugs, irradiation, and surgically induced hormone deficiency. All of these models are directly related to human cases, and thus, can be used to investigate the causes of bone loss resulting from these interventions. PMID- 25723185 TI - Histopathological analysis of the respiratory tract. AB - The basic anatomy of the mouse respiratory system is similar to that of other mammals and can be usefully examined under the light microscope in phenotyping studies, inhalation toxicity studies, and studies involving mouse models of human disease. In many studies, however, only the lungs are examined, leaving the possibility that phenotypic information from the majority of the conducting airways is lost. This unit provides standard approaches for tissue collection at necropsy and subsequent selection of a range of respiratory tissues for histological and pathological analysis. The major anatomical features to be found in each section are highlighted, and potential artifacts and methods to avoid them are discussed. PMID- 25723186 TI - Conservation of mouse models through embryo freezing. AB - The ability to interrogate the entire coding sequence of the mouse combined with the tools to manipulate the genome has firmly established the mouse as the model organism of choice for studying the causes of human disease. Consequently, a huge number of novel mouse models are generated each year to support active research programs. However, it is neither ethically justifiable, nor economically viable to maintain mouse colonies on the shelf that are not part of active research programs. This means that novel mouse lines have to be preserved in some way. If this is not done and the line is simply killed off, the genetics will be lost to future generations of scientists. This article describes the current practices used in cryopreservation laboratories to archive and recover mouse embryos frozen using controlled-rate freezing and vitrification techniques. PMID- 25723188 TI - Potential applications of induced pluripotent stem cells (iPSCs) in the modeling of gastrointestinal disorders. AB - Induced pluripotent stem cells (iPSCs) technology provides unique possibilities for human disease modeling and novel therapeutic approach in regenerative medicine. By applying this technology, it is possible to establish high-fidelity human disease models from biopsy samples of different individuals with various genetic backgrounds. This may provide a better understanding of patient-specific pathophysiological processes of a wide variety of diseases. Stem cell-derived intestinal epithelia and human intestinal organoids (HIOs) generated in vitro, for example, can faciliate drug screening and modeling of inflammation-associated gastrointestinal diseases. In this review, we highlight novel achievements of generating disease-related iPSCs and discuss their potential applications in the modeling of gastrointestinal disorders. The critical influencing factors, main limitations and possible improvements in the process of iPSCs-based disease modeling are also discussed. PMID- 25723187 TI - In-vivo assessment of femoral bone strength using Finite Element Analysis (FEA) based on routine MDCT imaging: a preliminary study on patients with vertebral fractures. AB - PURPOSE: To experimentally validate a non-linear finite element analysis (FEA) modeling approach assessing in-vitro fracture risk at the proximal femur and to transfer the method to standard in-vivo multi-detector computed tomography (MDCT) data of the hip aiming to predict additional hip fracture risk in subjects with and without osteoporosis associated vertebral fractures using bone mineral density (BMD) measurements as gold standard. METHODS: One fresh-frozen human femur specimen was mechanically tested and fractured simulating stance and clinically relevant fall loading configurations to the hip. After experimental in vitro validation, the FEA simulation protocol was transferred to standard contrast-enhanced in-vivo MDCT images to calculate individual hip fracture risk each for 4 subjects with and without a history of osteoporotic vertebral fractures matched by age and gender. In addition, FEA based risk factor calculations were compared to manual femoral BMD measurements of all subjects. RESULTS: In-vitro simulations showed good correlation with the experimentally measured strains both in stance (R2 = 0.963) and fall configuration (R2 = 0.976). The simulated maximum stress overestimated the experimental failure load (4743 N) by 14.7% (5440 N) while the simulated maximum strain overestimated by 4.7% (4968 N). The simulated failed elements coincided precisely with the experimentally determined fracture locations. BMD measurements in subjects with a history of osteoporotic vertebral fractures did not differ significantly from subjects without fragility fractures (femoral head: p = 0.989; femoral neck: p = 0.366), but showed higher FEA based risk factors for additional incident hip fractures (p = 0.028). CONCLUSION: FEA simulations were successfully validated by elastic and destructive in-vitro experiments. In the subsequent in-vivo analyses, MDCT based FEA based risk factor differences for additional hip fractures were not mirrored by according BMD measurements. Our data suggests, that MDCT derived FEA models may assess bone strength more accurately than BMD measurements alone, providing a valuable in-vivo fracture risk assessment tool. PMID- 25723189 TI - Electric double-layer structure in primitive model electrolytes: comparing molecular dynamics with local-density approximations. AB - We evaluate the accuracy of local-density approximations (LDAs) using explicit molecular dynamics simulations of binary electrolytes comprised of equisized ions in an implicit solvent. The Bikerman LDA, which considers ions to occupy a lattice, poorly captures excluded volume interactions between primitive model ions. Instead, LDAs based on the Carnahan-Starling (CS) hard-sphere equation of state capture simulated values of ideal and excess chemical potential profiles extremely well, as well as the relationship between surface charge density and electrostatic potential. Excellent agreement between the EDL capacitances predicted by CS-LDAs and computed in molecular simulations is found even in systems where ion correlations drive strong density and free charge oscillations within the EDL, despite the inability of LDAs to capture the oscillations in the detailed EDL profiles. PMID- 25723190 TI - High relaxivity Gd(III)-DNA gold nanostars: investigation of shape effects on proton relaxation. AB - Gadolinium(III) nanoconjugate contrast agents (CAs) have distinct advantages over their small-molecule counterparts in magnetic resonance imaging. In addition to increased Gd(III) payload, a significant improvement in proton relaxation efficiency, or relaxivity (r1), is often observed. In this work, we describe the synthesis and characterization of a nanoconjugate CA created by covalent attachment of Gd(III) to thiolated DNA (Gd(III)-DNA), followed by surface conjugation onto gold nanostars (DNA-Gd@stars). These conjugates exhibit remarkable r1 with values up to 98 mM(-1) s(-1). Additionally, DNA-Gd@stars show efficient Gd(III) delivery and biocompatibility in vitro and generate significant contrast enhancement when imaged at 7 T. Using nuclear magnetic relaxation dispersion analysis, we attribute the high performance of the DNA-Gd@stars to an increased contribution of second-sphere relaxivity compared to that of spherical CA equivalents (DNA-Gd@spheres). Importantly, the surface of the gold nanostar contains Gd(III)-DNA in regions of positive, negative, and neutral curvature. We hypothesize that the proton relaxation enhancement observed results from the presence of a unique hydrophilic environment produced by Gd(III)-DNA in these regions, which allows second-sphere water molecules to remain adjacent to Gd(III) ions for up to 10 times longer than diffusion. These results establish that particle shape and second-sphere relaxivity are important considerations in the design of Gd(III) nanoconjugate CAs. PMID- 25723191 TI - Geometry of quantum observables and thermodynamics of small systems. AB - We show that for classical and quantum observables, the integrability-to ergodicity transition leaves constant the sum of (a) the ensemble variance of the temporal average and (b) the ensemble average of temporal variance. The induced Frobenius (Hilbert-Schmidt) geometry of quantum observables encodes how eigenstate thermalization appears, the inverse participation ratio decreases, and the integrals of motion disappear during the transition. We use it to optimize the set of conserved quantities entering the generalized Gibbs ensemble for integrable, near-integrable, or mesoscopic systems. PMID- 25723192 TI - Classifying directional Gaussian entanglement, Einstein-Podolsky-Rosen steering, and discord. AB - Using Venn diagrams, we classify the different types of two-mode Gaussian continuous variable quantum correlation including directional entanglement and Einstein-Podolsky-Rosen (EPR) steering. We establish unified signatures for one- and two-way quantum steering, entanglement, and discord beyond entanglement in terms of an EPR-type variance. By focusing on Gaussian states, we link an optimized condition for entanglement based on an EPR variance to the Simon-Peres condition. This allows us to quantify the asymmetry of the Gaussian entanglement, and to relate the asymmetry to a directional quantum teleportation protocol where Alice and Bob possess asymmetrically noisy channels. Our analysis enables a determination of the type and direction of quantum correlation in a way that is easily measured in experiment. We also find that for symmetric states, when discord exceeds a certain threshold, the states are necessarily steerable. PMID- 25723193 TI - Quantification of Gaussian quantum steering. AB - Einstein-Podolsky-Rosen steering incarnates a useful nonclassical correlation which sits between entanglement and Bell nonlocality. While a number of qualitative steering criteria exist, very little has been achieved for what concerns quantifying steerability. We introduce a computable measure of steering for arbitrary bipartite Gaussian states of continuous variable systems. For two mode Gaussian states, the measure reduces to a form of coherent information, which is proven never to exceed entanglement, and to reduce to it on pure states. We provide an operational connection between our measure and the key rate in one sided device-independent quantum key distribution. We further prove that Peres' conjecture holds in its stronger form within the fully Gaussian regime: namely, steering bound entangled Gaussian states by Gaussian measurements is impossible. PMID- 25723194 TI - Necessary and sufficient quantum information characterization of Einstein Podolsky-Rosen steering. AB - Steering is the entanglement-based quantum effect that embodies the "spooky action at a distance" disliked by Einstein and scrutinized by Einstein, Podolsky, and Rosen. Here we provide a necessary and sufficient characterization of steering, based on a quantum information processing task: the discrimination of branches in a quantum evolution, which we dub subchannel discrimination. We prove that, for any bipartite steerable state, there are instances of the quantum subchannel discrimination problem for which this state allows a correct discrimination with strictly higher probability than in the absence of entanglement, even when measurements are restricted to local measurements aided by one-way communication. On the other hand, unsteerable states are useless in such conditions, even when entangled. We also prove that the above steering advantage can be exactly quantified in terms of the steering robustness, which is a natural measure of the steerability exhibited by the state. PMID- 25723195 TI - Determinism, independence, and objectivity are incompatible. AB - Hidden-variable models aim to reproduce the results of quantum theory and to satisfy our classical intuition. Their refutation is usually based on deriving predictions that are different from those of quantum mechanics. Here instead we study the mutual compatibility of apparently reasonable classical assumptions. We analyze a version of the delayed-choice experiment which ostensibly combines determinism, independence of hidden variables on the conducted experiments, and wave-particle objectivity (the assertion that quantum systems are, at any moment, either particles or waves, but not both). These three ideas are incompatible with any theory, not only with quantum mechanics. PMID- 25723196 TI - What can quantum optics say about computational complexity theory? AB - Considering the problem of sampling from the output photon-counting probability distribution of a linear-optical network for input Gaussian states, we obtain results that are of interest from both quantum theory and the computational complexity theory point of view. We derive a general formula for calculating the output probabilities, and by considering input thermal states, we show that the output probabilities are proportional to permanents of positive-semidefinite Hermitian matrices. It is believed that approximating permanents of complex matrices in general is a #P-hard problem. However, we show that these permanents can be approximated with an algorithm in the BPP^{NP} complexity class, as there exists an efficient classical algorithm for sampling from the output probability distribution. We further consider input squeezed-vacuum states and discuss the complexity of sampling from the probability distribution at the output. PMID- 25723197 TI - Hyperuniformity and phase separation in biased ensembles of trajectories for diffusive systems. AB - We analyze biased ensembles of trajectories for diffusive systems. In trajectories biased either by the total activity or the total current, we use fluctuating hydrodynamics to show that these systems exhibit phase transitions into "hyperuniform" states, where large-wavelength density fluctuations are strongly suppressed. We illustrate this behavior numerically for a system of hard particles in one dimension and we discuss how it appears in simple exclusion processes. We argue that these diffusive systems generically respond very strongly to any nonzero bias, so that homogeneous states with "normal" fluctuations (finite compressibility) exist only when the bias is very weak. PMID- 25723198 TI - Nonequilibrium quantum Landauer principle. AB - Using the operational framework of completely positive, trace preserving operations and thermodynamic fluctuation relations, we derive a lower bound for the heat exchange in a Landauer erasure process on a quantum system. Our bound comes from a nonphenomenological derivation of the Landauer principle which holds for generic nonequilibrium dynamics. Furthermore, the bound depends on the nonunitality of dynamics, giving it a physical significance that differs from other derivations. We apply our framework to the model of a spin-1/2 system coupled to an interacting spin chain at finite temperature. PMID- 25723199 TI - Nonequilibrium fluctuations for a single-particle analog of gas in a soft wall. AB - We investigate the motion of a colloidal particle driven out of equilibrium by a time-varying stiffness of the optical trap that produces persistent nonequilibrium work. Measurements of work production for repeated cycles composed of the compression and expansion processes for the optical potential show huge fluctuations due to thermal motion. Using a precise technique to modulate the stiffness in time, we accurately estimate the probability distributions of work produced for the compression and expansion processes. We confirm the fluctuation theorem from the ratio of the two distributions. We also show that the average values of work for the two processes comply with the Jarzynski equality. This system has an analogy with a gas in a breathing soft wall. We discuss about its applicability to a heat engine and an information engine operated by feedback control. PMID- 25723200 TI - Angular momentum transport and particle acceleration during magnetorotational instability in a kinetic accretion disk. AB - Angular momentum transport and particle acceleration during the magnetorotational instability (MRI) in a collisionless accretion disk are investigated using three dimensional particle-in-cell simulation. We show that the kinetic MRI can provide not only high-energy particle acceleration but also enhancement of angular momentum transport. We find that the plasma pressure anisotropy inside the channel flow with p(?)>p(?) induced by active magnetic reconnection suppresses the onset of subsequent reconnection, which, in turn, leads to high-magnetic field saturation and enhancement of the Maxwell stress tensor of angular momentum transport. Meanwhile, during the quiescent stage of reconnection, the plasma isotropization progresses in the channel flow and the anisotropic plasma with p(?)>p(?) due to the dynamo action of MRI outside the channel flow contribute to rapid reconnection and strong particle acceleration. This efficient particle acceleration and enhanced angular momentum transport in a collisionless accretion disk may explain the origin of high-energy particles observed around massive black holes. PMID- 25723201 TI - Bending of light in quantum gravity. AB - We consider the scattering of lightlike matter in the presence of a heavy scalar object (such as the Sun or a Schwarzschild black hole). By treating general relativity as an effective field theory we directly compute the nonanalytic components of the one-loop gravitational amplitude for the scattering of massless scalars or photons from an external massive scalar field. These results allow a semiclassical computation of the bending angle for light rays grazing the Sun, including long-range h contributions. We discuss implications of this computation, in particular, the violation of some classical formulations of the equivalence principle. PMID- 25723202 TI - Postinflationary Higgs relaxation and the origin of matter-antimatter asymmetry. AB - The recent measurement of the Higgs boson mass implies a relatively slow rise of the standard model Higgs potential at large scales, and a possible second minimum at even larger scales. Consequently, the Higgs field may develop a large vacuum expectation value during inflation. The relaxation of the Higgs field from its large postinflationary value to the minimum of the effective potential represents an important stage in the evolution of the Universe. During this epoch, the time dependent Higgs condensate can create an effective chemical potential for the lepton number, leading to a generation of the lepton asymmetry in the presence of some large right-handed Majorana neutrino masses. The electroweak sphalerons redistribute this asymmetry between leptons and baryons. This Higgs relaxation leptogenesis can explain the observed matter-antimatter asymmetry of the Universe even if the standard model is valid up to the scale of inflation, and any new physics is suppressed by that high scale. PMID- 25723203 TI - Universality far from equilibrium: from superfluid Bose gases to heavy-ion collisions. AB - Isolated quantum systems in extreme conditions can exhibit unusually large occupancies per mode. This overpopulation gives rise to new universality classes of many-body systems far from equilibrium. We present theoretical evidence that important aspects of non-Abelian plasmas in the ultrarelativistic limit admit a dual description in terms of a Bose condensed scalar field theory. PMID- 25723206 TI - Neutral naturalness from orbifold Higgs models. AB - We present a general class of natural theories in which the Higgs boson is a pseudo-Goldstone boson in an orbifolded gauge theory. The symmetry protecting the Higgs boson at low energies is an accidental global symmetry of the quadratic action, rather than a full continuous symmetry. The lightest degrees of freedom protecting the weak scale carry no standard model (SM) quantum numbers and interact with visible matter principally through the Higgs portal. This opens the door to the systematic study of "neutral naturalness": natural theories with SM neutral states that are as yet untested by the LHC. PMID- 25723205 TI - Precision determination of the Cabibbo-Kobayashi-Maskawa element V(cb). AB - We extract the magnitude of the Cabibbo-Kobayashi-Maskawa matrix element V(c)} and the most relevant parameters of the heavy quark expansion from data of inclusive semileptonic B decays. Our calculation includes the recently computed O(alpha(s)Lambda(QCD)(2)/m(b)(2)) corrections and a careful estimate of the residual theoretical uncertainty. Using a recent determination of the charm quark mass, we obtain |V(cb)|=(42.21+/-0.78)*10(-3) and m(b)(kin)(1 GeV)=(4.553+/ 0.020) GeV. PMID- 25723212 TI - Three loop cusp anomalous dimension in QCD. AB - We present the full analytic result for the three loop angle-dependent cusp anomalous dimension in QCD. With this result, infrared divergences of planar scattering processes with massive particles can be predicted to that order. Moreover, we define a closely related quantity in terms of an effective coupling defined by the lightlike cusp anomalous dimension. We find evidence that this quantity is universal for any gauge theory and use this observation to predict the nonplanar n(f)-dependent terms of the four loop cusp anomalous dimension. PMID- 25723213 TI - Parity-violating nucleon-nucleon force in the 1/N(c) expansion. AB - Several experimental investigations have observed parity violation (PV) in nuclear systems-a consequence of the weak force between quarks. We apply the 1/N(c) expansion of QCD to the P-violating T-conserving component of the nucleon nucleon (NN) potential. We show there are two leading-order operators, both of which affect p[over ->]p scattering at order N(c). We find an additional four operators at order N(c)(0)sin(2)theta(W) and six at O(1/N(c)). Pion exchange in the PV NN force is suppressed by 1/N(c) and sin(2)theta(W), providing a quantitative explanation for its nonobservation up to this time. The large-N(c) hierarchy of other PV NN force mechanisms is consistent with estimates of the couplings in phenomenological models. The PV observed in p[over ->]p scattering data is compatible with natural values for the strong and weak coupling constants: there is no evidence of fine-tuning. PMID- 25723211 TI - Measurement of the two-photon exchange contribution to the elastic e(+/-)p scattering cross sections at the VEPP-3 storage ring. AB - The ratio of the elastic e(+)p to e(-)p scattering cross sections has been measured precisely, allowing the determination of the two-photon exchange contribution to these processes. This neglected contribution is believed to be the cause of the discrepancy between the Rosenbluth and polarization transfer methods of measuring the proton electromagnetic form factors. The experiment was performed at the VEPP-3 storage ring at beam energies of 1.6 and 1.0 GeV and at lepton scattering angles between 15 degrees and 105 degrees . The data obtained show evidence of a significant two-photon exchange effect. The results are compared with several theoretical predictions. PMID- 25723215 TI - Carrier plasmon induced nonlinear band gap renormalization in two-dimensional semiconductors. AB - In reduced-dimensional semiconductors, doping-induced carrier plasmons can strongly couple with quasiparticle excitations, leading to a significant band gap renormalization. However, the physical origin of this generic effect remains obscure. We develop a new plasmon-pole theory that efficiently and accurately captures this coupling. Using monolayer MoS(2) and MoSe(2) as prototype two dimensional (2D) semiconductors, we reveal a striking band gap renormalization above 400 meV and an unusual nonlinear evolution of their band gaps with doping. This prediction significantly differs from the linear behavior that is observed in one-dimensional structures. Notably, our predicted band gap renormalization for MoSe(2) is in excellent agreement with recent experimental results. Our developed approach allows for a quantitative understanding of many-body interactions in general doped 2D semiconductors and paves the way for novel band gap engineering techniques. PMID- 25723209 TI - Towards a resolution of the proton form factor problem: new electron and positron scattering data. AB - There is a significant discrepancy between the values of the proton electric form factor, G(E)(p), extracted using unpolarized and polarized electron scattering. Calculations predict that small two-photon exchange (TPE) contributions can significantly affect the extraction of G(E)(p) from the unpolarized electron proton cross sections. We determined the TPE contribution by measuring the ratio of positron-proton to electron-proton elastic scattering cross sections using a simultaneous, tertiary electron-positron beam incident on a liquid hydrogen target and detecting the scattered particles in the Jefferson Lab CLAS detector. This novel technique allowed us to cover a wide range in virtual photon polarization (epsilon) and momentum transfer (Q(2)) simultaneously, as well as to cancel luminosity-related systematic errors. The cross section ratio increases with decreasing epsilon at Q(2)=1.45 GeV(2). This measurement is consistent with the size of the form factor discrepancy at Q(2)~1.75 GeV(2) and with hadronic calculations including nucleon and Delta intermediate states, which have been shown to resolve the discrepancy up to 2-3 GeV(2). PMID- 25723214 TI - Magnetism of an excited self-conjugate nucleus: precise measurement of the g factor of the 2(1)(+) state in (24)Mg. AB - A precise measurement of the g factor of the first-excited state in the self conjugate (N=Z) nucleus (24)Mg is performed by a new time-differential recoil-in vacuum method based on the hyperfine field of hydrogenlike ions. Theory predicts that the g factors of such states, in which protons and neutrons occupy the same orbits, should depart from 0.5 by a few percent due to configuration mixing and meson-exchange effects. The experimental result, g=0.538+/-0.013, is in excellent agreement with recent shell-model calculations and shows a departure from 0.5 by almost 3 standard deviations, thus achieving, for the first time, the precision and accuracy needed to test theory. Proof of the new method opens the way for wide applications including measurements of the magnetism of excited states of exotic nuclei produced as radioactive beams. PMID- 25723208 TI - Measurement of the charged-pion polarizability. AB - The COMPASS collaboration at CERN has investigated pion Compton scattering, pi( )gamma->pi(-)gamma, at center-of-mass energy below 3.5 pion masses. The process is embedded in the reaction pi(-)Ni->pi(-)gammaNi, which is initiated by 190 GeV pions impinging on a nickel target. The exchange of quasireal photons is selected by isolating the sharp Coulomb peak observed at smallest momentum transfers, Q(2)<0.0015 (GeV/c)(2). From a sample of 63,000 events, the pion electric polarizability is determined to be alpha(pi)=(2.0+/-0.6(stat)+/-0.7(syst))*10(-4) fm(3) under the assumption alpha(pi)=-beta(pi), which relates the electric and magnetic dipole polarizabilities. It is the most precise measurement of this fundamental low-energy parameter of strong interaction that has been addressed since long by various methods with conflicting outcomes. While this result is in tension with previous dedicated measurements, it is found in agreement with the expectation from chiral perturbation theory. An additional measurement replacing pions by muons, for which the cross-section behavior is unambiguously known, was performed for an independent estimate of the systematic uncertainty. PMID- 25723216 TI - Composite-light-pulse technique for high-precision atom interferometry. AB - We realize beam splitters and mirrors for atom waves by employing a sequence of light pulses rather than individual ones. In this way we can tailor atom interferometers with improved sensitivity and accuracy. We demonstrate our method of composite pulses by creating a symmetric matter-wave interferometer which combines the advantages of conventional Bragg- and Raman-type concepts. This feature leads to an interferometer with a high immunity to technical noise allowing us to devise a large-area Sagnac gyroscope yielding a phase shift of 6.5 rad due to the Earth's rotation. With this device we achieve a rotation rate precision of 120 nrad s(-1) Hz(-1/2) and determine the Earth's rotation rate with a relative uncertainty of 1.2%. PMID- 25723217 TI - Plasma luminescence from femtosecond filaments in air: evidence for impact excitation with circularly polarized light pulses. AB - Filaments produced in air by intense femtosecond laser pulses emit UV luminescence from excited N(2) and N(2)(+) molecules. We report on a strong dependence at high intensities (I>=1.4*10(14) W/cm(2)) of this luminescence with the polarization state of the incident laser pulses. We attribute this effect to the onset of new impact excitation channels from energetic electrons produced with circularly polarized laser pulses above a threshold laser intensity. PMID- 25723218 TI - Efficient real-time time-dependent density functional theory method and its application to a collision of an ion with a 2D material. AB - We have developed an efficient real-time time-dependent density functional theory (TDDFT) method that can increase the effective time step from <1 as in traditional methods to 0.1-0.5 fs. With this algorithm, the TDDFT simulation can have comparable speed to the Born-Oppenheimer (BO) ab initio molecular dynamics (MD). As an application, we simulated the process of an energetic Cl particle colliding onto a monolayer of MoSe(2). Our simulations show a significant energy transfer from the kinetic energy of the Cl particle to the electronic energy of MoSe(2), and the result of TDDFT is very different from that of BO-MD simulations. PMID- 25723219 TI - Revealing the mechanism of the low-energy electron yield enhancement from sensitizing nanoparticles. AB - We provide a physical explanation for the enhancement of the low-energy electron production by sensitizing nanoparticles due to irradiation by fast ions. It is demonstrated that a significant increase in the number of emitted electrons arises from the collective electron excitations in the nanoparticle. We predict a new mechanism of the yield enhancement due to the plasmon excitations and quantitatively estimate its contribution to the electron production. Revealing the nanoscale mechanism of the electron yield enhancement, we provide an efficient tool for evaluating the yield of the emitted electron from various sensitizers. It is shown that the number of low-energy electrons generated by the gold and platinum nanoparticles of a given size exceeds that produced by the equivalent volume of water and by other metallic (e.g., gadolinium) nanoparticles by an order of magnitude. This observation emphasizes the sensitization effect of the noble-metal nanoparticles and endorses their application in novel technologies of cancer therapy with ionizing radiation. PMID- 25723220 TI - Measuring the transverse spin density of light. AB - We generate tightly focused optical vector beams whose electric fields spin around an axis transverse to the beams' propagation direction. We experimentally investigate these fields by exploiting the directional near-field interference of a dipolelike plasmonic field probe placed adjacent to a dielectric interface. This directionality depends on the transverse electric spin density of the excitation field. Near- to far-field conversion mediated by the dielectric interface enables us to detect the directionality of the emitted light in the far field and, therefore, to measure the transverse electric spin density with nanoscopic resolution. Finally, we determine the longitudinal electric component of Belinfante's elusive spin momentum density, a solenoidal field quantity often referred to as "virtual." PMID- 25723221 TI - Classical-to-quantum transition with broadband four-wave mixing. AB - A key question of quantum optics is how nonclassical biphoton correlations at low power evolve into classical coherence at high power. Direct observation of the crossover from quantum to classical behavior is desirable, but difficult due to the lack of adequate experimental techniques that cover the ultrawide dynamic range in photon flux from the single photon regime to the classical level. We investigate biphoton correlations within the spectrum of light generated by broadband four-wave mixing over a large dynamic range of ~80 dB in photon flux across the classical-to-quantum transition using a two-photon interference effect that distinguishes between classical and quantum behavior. We explore the quantum classical nature of the light by observing the interference contrast dependence on internal loss and demonstrate quantum collapse and revival of the interference when the four-wave mixing gain in the fiber becomes imaginary. PMID- 25723222 TI - Laser filamentation as a new phase transition universality class. AB - We show that the onset of laser multiple filamentation can be described as a critical phenomenon that we characterize both experimentally and numerically by measuring a set of seven critical exponents. This phase transition deviates from any existing universality class and offers a unique perspective of conducting two dimensional experiments of statistical physics at a human scale. PMID- 25723223 TI - Shock wave formation in the collapse of a vapor nanobubble. AB - In this Letter, the dynamics of a collapsing vapor bubble is addressed by means of a diffuse-interface formulation. The model cleanly captures, through a unified approach, all the critical features of the process, such as phase change, transition to supercritical conditions, thermal conduction, compressibility effects, and shock wave formation and propagation. Rather unexpectedly for pure vapor bubbles, the numerical experiments show that the process consists in the oscillation of the bubble associated with the emission of shock waves in the liquid, and with the periodic disappearance and reappearance of the liquid-vapor interface due to transition to super- or subcritical conditions. The results identify the mechanism of shock wave formation as strongly related to the transition of the vapor to the supercritical state, with a progressive steepening of a focused compression wave evolving into a shock which is eventually reflected as an outward propagating wave in the liquid. PMID- 25723207 TI - Measurement of the B(s)(0) lifetime in the flavor-specific decay channel B(s)(0) >D(s)(-)MU(+)nuX. AB - We present an updated measurement of the B(s)(0) lifetime using the semileptonic decays B(s)(0)->D(s)(-)MU(+)nuX, with D(s)(-)->phipi(-) and phi->K(+)K(-) (and the charge conjugate process). This measurement uses the full Tevatron Run II sample of proton-antiproton collisions at ?[s]=1.96 TeV, comprising an integrated luminosity of 10.4 fb(-1). We find a flavor-specific lifetime tau(fs)(B(s)(0))=1.479+/-0.010(stat)+/-0.021(syst) ps. This technique is also used to determine the B(0) lifetime using the analogous B(0)->D(-)MU(+)nuX decay with D(-)->phipi(-) and phi->K(+)K(-), yielding tau(B(0))=1.534+/-0.019(stat)+/ 0.021(syst) ps. Both measurements are consistent with the current world averages, and the B(s)(0) lifetime measurement is one of the most precise to date. Taking advantage of the cancellation of systematic uncertainties, we determine the lifetime ratio tau(fs)(B(s)(0))/tau(B(0))=0.964+/-0.013(stat)+/ 0.007(syst). PMID- 25723224 TI - Excitation of flow-stabilized resistive wall mode by coupling with stable eigenmodes in tokamaks. AB - In a rotating toroidal plasma surrounded by a resistive wall, it is shown that linear MHD instabilities can be excited by couplings between the resistive wall mode (RWM) and stable ideal MHD modes. In particular, it is shown that the RWM can couple not only with stable external kink modes but also with Alfven eigenmodes that are ordinarily in the stable continuum of a toroidal plasma. The RWM growth rate is shown to peak whenever the Doppler shift caused by the plasma rotation cancels the frequency of an ideal MHD mode, so that the mode appears to have zero frequency in the laboratory frame. At these values of the rotation frequency, the RWM can overcome the stabilizing effects of plasma rotation, continuum damping, and ion Landau damping. PMID- 25723225 TI - Temporal intermittency of energy dissipation in magnetohydrodynamic turbulence. AB - Energy dissipation in magnetohydrodynamic (MHD) turbulence is known to be highly intermittent in space, being concentrated in sheetlike coherent structures. Much less is known about intermittency in time, another fundamental aspect of turbulence which has great importance for observations of solar flares and other space or astrophysical phenomena. In this Letter, we investigate the temporal intermittency of energy dissipation in numerical simulations of MHD turbulence. We consider four-dimensional spatiotemporal structures, "flare events," responsible for a large fraction of the energy dissipation. We find that although the flare events are often highly complex, they exhibit robust power-law distributions and scaling relations. We find that the probability distribution of dissipated energy has a power-law index close to alpha~1.75, similar to observations of solar flares, indicating that intense dissipative events dominate the heating of the system. We also discuss the temporal asymmetry of flare events as a signature of the turbulent cascade. PMID- 25723226 TI - Quantum mechanical rippling of a MoS2 monolayer controlled by interlayer bilayer coupling. AB - Nanoscale corrugations are of great importance in determining the physical properties of two-dimensional crystals. However, the mechanical behavior of atomically thin films under strain is not fully understood. In this Letter, we show a layer-dependent mechanical response of molybdenum disulfide (MoS(2)) subject to atomistic-precision strain induced by 2H-bilayer island epitaxy. Dimensional crossover in the mechanical properties is evidenced by the formation of star-shaped nanoripple arrays in the first monolayer, while rippling instability is completely suppressed in the bilayer. Microscopic-level quantum mechanical simulations reveal that the nanoscale rippling is realized by the twisting of neighboring Mo-S bonds without modifying the chemical bond length, and thus invalidates the classical continuum mechanics. The formation of nanoripple arrays significantly changes the electronic and nanotribological properties of monolayer MoS(2). Our results suggest that quantum mechanical behavior is not unique for sp(2) bonding but general for atomic membranes under strain. PMID- 25723227 TI - Grain-size-independent plastic flow at ultrahigh pressures and strain rates. AB - A basic tenet of material science is that the flow stress of a metal increases as its grain size decreases, an effect described by the Hall-Petch relation. This relation is used extensively in material design to optimize the hardness, durability, survivability, and ductility of structural metals. This Letter reports experimental results in a new regime of high pressures and strain rates that challenge this basic tenet of mechanical metallurgy. We report measurements of the plastic flow of the model body-centered-cubic metal tantalum made under conditions of high pressure (>100 GPa) and strain rate (~10(7) s(-1)) achieved by using the Omega laser. Under these unique plastic deformation ("flow") conditions, the effect of grain size is found to be negligible for grain sizes >0.25 MUm sizes. A multiscale model of the plastic flow suggests that pressure and strain rate hardening dominate over the grain-size effects. Theoretical estimates, based on grain compatibility and geometrically necessary dislocations, corroborate this conclusion. PMID- 25723228 TI - Nonlinear acoustics at GHz frequencies in a viscoelastic fragile glass former. AB - Using a picosecond pump-probe ultrasonic technique, we study the propagation of high-amplitude, laser-generated longitudinal coherent acoustic pulses in the viscoelastic fragile glass former DC704. We observe an increase of almost 10% in acoustic pulse propagation speed at the highest optical pump fluence which is a result of the supersonic nature of nonlinear propagation in the viscous medium. From our measurement, we deduce the nonlinear acoustic parameter of the glass former in the gigahertz frequency range across the glass transition temperature. PMID- 25723229 TI - Heat and mass transfer across interfaces in complex nanogeometries. AB - Heat and mass transfer in nanodevices depends much on the geometry due to the strong influence of curvature on interfacial properties, such as the Kapitza resistance. We present a method which combines nonequilibrium square gradient theory and nonequilibrium molecular dynamics simulations to obtain the coefficients in a curvature expansion of the interface transfer coefficients. The expansion can be used directly to describe heat and mass transfer in complex nanogeometries. As examples of complex nanogeometries, we consider an oblate spheroidal droplet, a prolate spheroidal bubble, and a toroidal bubble. Depending on the sign and magnitude of the curvature, transfer is enhanced or reduced significantly. The presented method is applicable to many types of interfaces and substances, and we expect it to contribute to the understanding and design of future nanodevices. PMID- 25723230 TI - Surface-induced optimal packing of two-dimensional molecular networks. AB - High-density packing in organic crystals is usually associated with an increase of the coordination between molecules. Such a concept is not necessarily extended to two-dimensional molecular networks self-assembled on a solid surface, for which we demonstrate the key role of the surface in inducing the optimal packing. By a combination of scanning tunneling microscopy experiments and multiscale computer simulations, we study the phase transition between two polymorphs. We find that, contrary to intuition, the structure with the lowest packing fraction corresponds to the highest molecular coordination number, due to the competition between surface and intermolecular forces. Having the lowest free energy, this structure spreads out as the most stable polymorph over a wide range of molecular concentrations. PMID- 25723231 TI - Spin Andreev-like reflection in metal-Mott insulator heterostructures. AB - Using the time-dependent density-matrix renormalization group (tDMRG), we study the time evolution of electron wave packets in one-dimensional (1D) metal superconductor heterostructures. The results show Andreev reflection at the interface, as expected. By combining these results with the well-known single spin-species electron-hole transformation in the Hubbard model, we predict an analogous spin Andreev reflection in metal-Mott insulator heterostructures. This effect is numerically confirmed using 1D tDMRG, but it is expected to also be present in higher dimensions, as well as in more general Hamiltonians. We present an intuitive picture of the spin reflection, analogous to that of Andreev reflection at metal-superconductor interfaces. This allows us to discuss a novel antiferromagnetic proximity effect. Possible experimental realizations are discussed. PMID- 25723233 TI - Magnetic fluctuations and specific heat in Na(x)CoO2 near a Lifshitz transition. AB - We analyze the temperature and doping dependence of the specific heat C(T) in Na(x)CoO(2). This material was conjectured to undergo a Lifshitz-type topological transition at x=x(c)=0.62, in which a new electron Fermi pocket emerges at the Gamma point, in addition to the existing hole pocket with large k(F). The data show that near x=x(c), the temperature dependence of C(T)/T at low T gets stronger as x approaches x(c) from below and then reverses the trend and changes sign at x>=x(c). We argue that this behavior can be quantitatively explained within the spin-fluctuation theory. We show that magnetic fluctuations are enhanced near x(c) at momenta around k(F), and their dynamics changes between x<=x(c) and x>x(c), when the new pocket forms. We demonstrate that this explains the temperature dependence of C(T)/T. We show that at larger x (x>0.65) the system enters a magnetic quantum critical regime where C(T)/T roughly scales as logT. This behavior extends to progressively lower T as x increases towards a magnetic instability at x~0.75. PMID- 25723232 TI - One-dimensional edge states with giant spin splitting in a bismuth thin film. AB - To realize a one-dimensional (1D) system with strong spin-orbit coupling is a big challenge in modern physics, since the electrons in such a system are predicted to exhibit exotic properties unexpected from the 2D or 3D counterparts, while it was difficult to realize genuine physical properties inherent to the 1D system. We demonstrate the first experimental result that directly determines the purely 1D band structure by performing spin-resolved angle-resolved photoemission spectroscopy of Bi islands on a silicon surface that contains a metallic 1D edge structure with unexpectedly large Rashba-type spin-orbit coupling suggestive of the nontopological nature. We have also found a sizable out-of-plane spin polarization of the 1D edge state, consistent with our first-principles band calculations. Our result provides a new platform to realize exotic quantum phenomena at the 1D edge of the strong spin-orbit-coupling systems. PMID- 25723234 TI - Gauge-invariant calculation of static and dynamical magnetic properties from the current density. AB - In this work we solve two problems related to the calculation of static and dynamical magnetic properties with ab initio theories. First, we show that the dependence of the dynamical magnetic dipole moment on the reference point of the multipole expansion and on the gauge origin of the vector potential have a clear physical significance. They are due to a dynamical electric dipole moment and an electric field, respectively. Both are fully determined by the experimental setup and do not pose any fundamental problem, contrary to what is commonly assumed. Second, in the static case, any dependence on the gauge origin is an artifact of the computational method. We show that the artificial dependence on the gauge origin can be removed in an elegant way by the introduction of a sum rule that puts the diamagnetic and paramagnetic contributions on equal footing. Our approach can be applied to calculate any magnetic observable that can be derived from the current density, and can be used in combination with any ab initio theory from which it can be obtained. To illustrate our method we apply it here to time-dependent current-density-functional theory for the calculation of static and dynamical magnetizabilities of molecules. PMID- 25723236 TI - Connection of a topological surface state with the bulk continuum in Sb(2)Te(3)(0001). AB - The surface state of a Z(2) topological insulator connects with the conduction and valence band continua of the bulk, thereby bridging the band gap of the volume. We investigate this connection of the surface and bulk electronic structure for Sb(2)Te(3)(0001) by photoemission experiments and calculations. Upon crossing the topmost valence band the topological surface state (TSS) maintains a coherent spectral signature, a two-dimensional character, and a linear dispersion relation. Surface-bulk coupling manifests itself in the spectra through (i) a characteristic kink in the TSS dispersion as it crosses the topmost valence band and (ii) the appearance of hybridization gaps between the TSS and bulk-derived surface resonance states at higher binding energies. The findings provide a natural explanation for the unexpectedly weak surface-bulk mixing indicated by recent transport experiments on Sb(2)Te(3). PMID- 25723235 TI - Nonsinusoidal current-phase relationship in Josephson junctions from the 3D topological insulator HgTe. AB - We use superconducting quantum interference device microscopy to characterize the current-phase relation (CPR) of Josephson junctions from the three-dimensional topological insulator HgTe (3D HgTe). We find clear skewness in the CPRs of HgTe junctions ranging in length from 200 to 600 nm. The skewness indicates that the Josephson current is predominantly carried by Andreev bound states with high transmittance, and the fact that the skewness persists in junctions that are longer than the mean free path suggests that the effect may be related to the helical nature of the Andreev bound states in the surface of HgTe. These experimental results suggest that the topological properties of the normal state can be inherited by the induced superconducting state, and that 3D HgTe is a promising material for realizing the many exciting proposals that require a topological superconductor. PMID- 25723237 TI - Van der Waals heterostructure of phosphorene and graphene: tuning the Schottky barrier and doping by electrostatic gating. AB - In this Letter, we study the structural and electronic properties of single-layer and bilayer phosphorene with graphene. We show that both the properties of graphene and phosphorene are preserved in the composed heterostructure. We also show that via the application of a perpendicular electric field, it is possible to tune the position of the band structure of phosphorene with respect to that of graphene. This leads to control of the Schottky barrier height and doping of phosphorene, which are important features in the design of new devices based on van der Waals heterostructures. PMID- 25723238 TI - Very large thermophase in ferromagnetic Josephson junctions. AB - The concept of thermophase refers to the appearance of a phase gradient inside a superconductor originating from the presence of an applied temperature bias across it. The resulting supercurrent flow may, in suitable conditions, fully counterbalance the temperature-bias-induced quasiparticle current therefore preventing the formation of any voltage drop, i.e., a thermovoltage, across the superconductor. Yet, the appearance of a thermophase is expected to occur in Josephson-coupled superconductors as well. Here, we theoretically investigate the thermoelectric response of a thermally biased Josephson junction based on a ferromagnetic insulator. In particular, we predict the occurrence of a very large thermophase that can reach pi/2 across the contact for suitable temperatures and structure parameters; i.e., the quasiparticle thermal current can reach the critical current. Such a thermophase can be several orders of magnitude larger than that predicted to occur in conventional Josephson tunnel junctions. In order to assess experimentally the predicted very large thermophase, we propose a realistic setup realizable with state-of-the-art nanofabrication techniques and well-established materials, based on a superconducting quantum interference device. This effect could be of strong relevance in several low-temperature applications, for example, for revealing tiny temperature differences generated by coupling the electromagnetic radiation to one of the superconductors forming the junction. PMID- 25723239 TI - Pressure-induced Mott transition in an organic superconductor with a finite doping level. AB - We report the pressure study of a doped organic superconductor with a Hall coefficient and conductivity measurements. We find that maximally enhanced superconductivity and a marginal-Fermi liquid appear around a certain pressure where mobile carriers increase critically, suggesting a possible quantum phase transition between strongly and weakly correlated regimes. This observation points to the presence of a criticality in Mottness for a doped Mott insulator with tunable correlation. PMID- 25723240 TI - Ultrafast dynamics of fluctuations in high-temperature superconductors far from equilibrium. AB - Despite extensive work on high-temperature superconductors, the critical behavior of an incipient condensate has so far been studied exclusively under equilibrium conditions. Here, we excite Bi(2)Sr(2)CaCu(2)O(8+delta) with a femtosecond laser pulse and monitor the subsequent nonequilibrium dynamics of the midinfrared conductivity. Our data allow us to discriminate temperature regimes where superconductivity is either coherent, fluctuating or vanishingly small. Above the transition temperature T(c), we make the striking observation that the relaxation to equilibrium exhibits power-law dynamics and scaling behavior, both for optimally and underdoped superconductors. Our findings can in part be modeled using time-dependent Ginzburg-Landau theory, and they provide strong indication of universality in systems far from equilibrium. PMID- 25723241 TI - Uniaxial-stress control of spin-driven ferroelectricity in multiferroic Ba(2)CoGe(2)O(7). AB - We have demonstrated that spin-driven ferroelectricity in a tetragonal multiferroic Ba(2)CoGe(2)O(7) is controlled by applying uniaxial stress. We found that the application of compressive stress along the [110] direction leads to a 45 degrees or 135 degrees rotation of the sublattice magnetization of the staggered antiferromagnetic order in this system. This allows the spontaneous electric polarization to appear along the c axis. The present study suggests that an application of anisotropic stress, which is the simplest way to control symmetry of matter, can induce a variety of cross-correlated phenomena in spin driven multiferroics. PMID- 25723242 TI - Optical spin-transfer-torque-driven domain-wall motion in a ferromagnetic semiconductor. AB - We demonstrate optical manipulation of the position of a domain wall in a dilute magnetic semiconductor, GaMnAsP. Two main contributions are identified. First, photocarrier spin exerts a spin-transfer torque on the magnetization via the exchange interaction. The direction of the domain-wall motion can be controlled using the helicity of the laser. Second, the domain wall is attracted to the hot spot generated by the focused laser. Unlike magnetic-field-driven domain-wall depinning, these mechanisms directly drive domain-wall motion, providing an optical tweezerlike ability to position and locally probe domain walls. PMID- 25723243 TI - Measuring the photon coalescence time window in the continuous-wave regime for resonantly driven semiconductor quantum dots. AB - We revisit Mandel's notion that the degree of coherence equals the degree of indistinguishability by performing Hong-Ou-Mandel- (HOM-)type interferometry with single photons elastically scattered by a cw resonantly driven excitonic transition of an InAs/GaAs epitaxial quantum dot. We present a comprehensive study of the temporal profile of the photon coalescence phenomenon which shows that photon indistinguishability can be tuned by the excitation laser source, in the same way as their coherence time. A new figure of merit, the coalescence time window, is introduced to quantify the delay below which two photons are indistinguishable. This criterion sheds new light on the interpretation of HOM experiments under cw excitation, particularly when photon coherence times are longer than the temporal resolution of the detectors. The photon indistinguishability is extended over unprecedented time scales beyond the detectors' response time, thus opening new perspectives to conducting quantum optics with single photons and conventional detectors. PMID- 25723244 TI - Ultrafast structural dynamics of the Fe-pnictide parent compound BaFe(2)As(2). AB - Using femtosecond time-resolved x-ray diffraction we investigate the structural dynamics of the coherently excited A(1g) phonon mode in the Fe-pnictide parent compound BaFe(2)As(2). The fluence dependent intensity oscillations of two specific Bragg reflections with distinctly different sensitivity to the pnictogen height in the compound allow us to quantify the coherent modifications of the Fe As tetrahedra, indicating a transient increase of the Fe magnetic moments. By a comparison with time-resolved photoemission data, we derive the electron-phonon deformation potential for this particular mode. The value of DeltaMU/Deltaz=-(1.0 1.5) eV/A is comparable with theoretical predictions and demonstrates the importance of this degree of freedom for the electron-phonon coupling in the Fe pnictides. PMID- 25723245 TI - Cooperativity and heterogeneity in plastic crystals studied by nonlinear dielectric spectroscopy. AB - The glassy dynamics of plastic-crystalline cyclo-octanol and ortho-carborane, where only the molecular reorientational degrees of freedom freeze without long range order, is investigated by nonlinear dielectric spectroscopy. Marked differences to canonical glass formers show up: While molecular cooperativity governs the glassy freezing, it leads to a much weaker slowing down of molecular dynamics than in supercooled liquids. Moreover, the observed nonlinear effects cannot be explained with the same heterogeneity scenario recently applied to canonical glass formers. This supports ideas that molecular relaxation in plastic crystals may be intrinsically nonexponential. Finally, no nonlinear effects were detected for the secondary processes in cyclo-octanol. PMID- 25723210 TI - Observation of two new Xi(b)(-) baryon resonances. AB - Two structures are observed close to the kinematic threshold in the Xi(b)(0)pi(-) mass spectrum in a sample of proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb(-1), recorded by the LHCb experiment. In the quark model, two baryonic resonances with quark content bds are expected in this mass region: the spin-parity J(P)=(1/2)(+) and J(P)=(3/2)(+) states, denoted Xi(b)('-) and Xi(b)(*-). Interpreting the structures as these resonances, we measure the mass differences and the width of the heavier state to be m(Xi(b)(' ))-m(Xi(b)(0))-m(pi(-))=3.653+/-0.018+/-0.006 MeV/c(2), m(Xi(b)(*-))-m(Xi(b)(0)) m(pi(-))=23.96+/-0.12+/-0.06 MeV/c(2), Gamma(Xi(b)(*-))=1.65+/-0.31+/-0.10 MeV, where the first and second uncertainties are statistical and systematic, respectively. The width of the lighter state is consistent with zero, and we place an upper limit of Gamma(Xi(b)('-))<0.08 MeV at 95% confidence level. Relative production rates of these states are also reported. PMID- 25723246 TI - From phase to microphase separation in flocking models: the essential role of nonequilibrium fluctuations. AB - We show that the flocking transition in the Vicsek model is best understood as a liquid-gas transition, rather than an order-disorder one. The full phase separation observed in flocking models with Z(2) rotational symmetry is, however, replaced by a microphase separation leading to a smectic arrangement of traveling ordered bands. Remarkably, continuous deterministic descriptions do not account for this difference, which is only recovered at the fluctuating hydrodynamics level. Scalar and vectorial order parameters indeed produce different types of number fluctuations, which we show to be essential in selecting the inhomogeneous patterns. This highlights an unexpected role of fluctuations in the selection of flock shapes. PMID- 25723247 TI - Synthesis of programmable reaction-diffusion fronts using DNA catalyzers. AB - We introduce a DNA-based reaction-diffusion (RD) system in which reaction and diffusion terms can be precisely and independently controlled. The effective diffusion coefficient of an individual reaction component, as we demonstrate on a traveling wave, can be reduced up to 2.7-fold using a self-assembled hydrodynamic drag. The intrinsic programmability of this RD system allows us to engineer, for the first time, orthogonal autocatalysts that counterpropagate with minimal interaction. Our results are in excellent quantitative agreement with predictions of the Fisher-Kolmogorov-Petrovskii-Piscunov model. These advances open the way for the rational engineering of pattern formation in pure chemical RD systems. PMID- 25723248 TI - Drift of scroll waves in thin layers caused by thickness features: asymptotic theory and numerical simulations. AB - A scroll wave in a very thin layer of excitable medium is similar to a spiral wave, but its behavior is affected by the layer geometry. We identify the effect of sharp variations of the layer thickness, which is separate from filament tension and curvature-induced drifts described earlier. We outline a two-step asymptotic theory describing this effect, including asymptotics in the layer thickness and calculation of the drift of so-perturbed spiral waves using response functions. As specific examples, we consider drift of scrolls along thickness steps, ridges, ditches, and disk-shaped thickness variations. Asymptotic predictions agree with numerical simulations. PMID- 25723249 TI - Effects of macromolecular crowding on the collapse of biopolymers. AB - Experiments show that macromolecular crowding modestly reduces the size of intrinsically disordered proteins even at a volume fraction (phi) similar to that in the cytosol, whereas DNA undergoes a coil-to-globule transition at very small phi. We show using a combination of scaling arguments and simulations that the polymer size R(g)(phi) depends on x=R(g)(0)/D, where D is the phi-dependent distance between the crowders. If x?O(1), there is only a small decrease in R(g)(phi) as phi increases. When x?O(1), a cooperative coil-to-globule transition is induced. Our theory quantitatively explains a number of experiments. PMID- 25723250 TI - Comment on "Universality of returning electron wave packet in high-order harmonic generation with midinfrared laser pulses". PMID- 25723251 TI - Comment on "Human time-frequency acuity beats the Fourier uncertainty principle". PMID- 25723252 TI - Simple time-saving method for iron determination based on fluorescence quenching of an azaflavanon-3-ol compound. AB - A simple and time-saving spectrofluorometric method developed using an azaflavanon-3-ol compound was used for the determination of iron in various food samples. Nitric acid and hydrogen peroxide were used for digestion of samples in a closed microwave system. The method was validated by analyzing two certified reference materials (CRM-SA-C Sandy Soil C and Mixed Polish Herbs INCT-MPH-2). Measurements were carried out using a modified standard addition method. The standard addition graph was linear until 21.6 mg/L in the determination of iron(III). Detection and quantification limits were 0.81 and 2.4 mg/L, respectively. Satisfactory accuracy was obtained for spinach, dill, mint, purslane, rocket, red lentils, dry beans, and two iron medicinal tablets. High recoveries were found for streamwater samples fortified at three different concentrations. The method is simple, time-saving, cost-effective, and suitable for the determination of the iron content of foods. PMID- 25723253 TI - Ultrathin, ultrasmooth gold layer on dielectrics without the use of additional metallic adhesion layers. AB - With advances in the plasmonics and metamaterials research field, it has become more and more important to fabricate thin and smooth Au metal films in a reliable way. Here, by thin films we mean that their average height is below 10 nm and their average roughness is below 5% of the total thickness. In this article, we investigated the use of amino- and mercaptosilanes to increase the adhesion of Au on Si wafers, thus obtaining a smooth and thin layer. This method does not include the use of other metals to improve the adhesion of gold, like Ti or Cr, since they would reduce the optical characteristics of the structure. Our results show that layers having 6 nm thickness and below 0.3 nm roughness can be reproducibly obtained using aminosilanes. Layers having a nominal thickness of 5 nm have a yield of 58%; thus, this thickness is the limit for the process that we investigated. PMID- 25723254 TI - Safety of therapeutic hypothermia in children on veno-arterial extracorporeal membrane oxygenation after cardiac surgery. AB - OBJECTIVE: The aim of this study was to evaluate whether the use of therapeutic hypothermia in patients receiving extracorporeal membrane oxygenation after paediatric cardiac surgery is associated with increased complication rates. METHODS: We undertook a retrospective study to compare the complication rates and clinical course of children after cardiac surgery in two groups - extracorporeal membrane oxygenation without therapeutic hypothermia (group 1) and extracorporeal membrane oxygenation with therapeutic hypothermia (group 2). Therapeutic hypothermia was performed via the extracorporeal membrane oxygenation circuit heater-cooler device. RESULTS: A total of 96 patients were included in this study (59 in group 1 and 37 in group 2). Complications were comparable between group 1 and group 2, except that more patients with therapeutic hypothermia had hypertension while on extracorporeal membrane oxygenation. Therapeutic hypothermia was not independently associated with in-hospital mortality (adjusted odds ratio 1.16, 95% CI: 0.33-4.03; p=0.82). CONCLUSION: Therapeutic hypothermia can be safely provided to children on extracorporeal membrane oxygenation after cardiac surgery without an increase in complication rates. PMID- 25723255 TI - Enantioselective 1,1-arylborylation of alkenes: merging chiral anion phase transfer with Pd catalysis. AB - A palladium-catalyzed three-component coupling of alpha-olefins, aryldiazonium salts, and bis(pinacolato)diboron affords direct access to chiral benzylic boronic esters. This process is rendered highly enantioselective using an unprecedented example of cooperative chiral anion phase transfer and transition metal catalysis. PMID- 25723256 TI - Gargantulide A, a complex 52-membered macrolactone showing antibacterial activity from Streptomyces sp. AB - Gargantulide A (1), an extremely complex 52-membered macrolactone, was isolated from Streptomyces sp. A42983 and displayed moderate activity against MRSA. The planar structure of 1 was determined using 2D NMR, and its stereochemistry was partially established on the basis of NOESY correlations, J-based configuration analysis, and Kishi's universal NMR database. PMID- 25723257 TI - Chiral bifunctional guanidine-catalyzed enantioselective Aza-Henry reaction of isatin-derived ketimines. AB - An efficient asymmetric aza-Henry reaction of isatin-derived ketimines has been achieved by using a chiral guanidine-amide organocatalyst. A series of 3 substituted 3-amino-2-oxindoles was obtained with excellent results (up to 99% yield, 94% ee). Other functionalized derivatives were also conveniently transformed. This metal-free system was convenient, practical, and insensitive to air and moisture. On the basis of the crystal structure of the catalyst and NMR spectra analysis, a bifunctional catalytic model was suggested to explain the origin of the asymmetric process. PMID- 25723258 TI - The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies. AB - The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in haematopoietic cells. By converting PI(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane, SHIP1 modifies PI3-kinase mediated signaling. We have recently demonstrated that SHIP1 is a nucleo-cytoplasmic shuttling protein and SHIP1 nuclear puncta partially colocalize with FLASH, a component of nuclear bodies. In this study, we demonstrate that endogenous SHIP1 localizes to intranucleolar regions of both normal and leukemic haematopoietic cells. In addition, we report that ectopically expressed SHIP1 accumulates in nucleolar cavities and colocalizes with the tumor suppressor protein p53 and components of PML nuclear bodies (e.g. SP100, SUMO-1 and CK2). Moreover, SHIP1 also colocalizes in nucleolar cavities with components of the ubiquitin-proteasome pathway. By using confocal microscopy data, we generated 3D-models revealing the enormous extent of the SHIP1 aggresomes in the nucleolus. Furthermore, treatment of cells with the proteasome inhibitor MG132 causes an enlargement of nucleolar SHIP1 containing structures. Unexpectedly, this accumulation can be partially prevented by treatment with the inhibitor of nuclear protein export Leptomycin B. In recent years, several proteins aggregating in nucleolar cavities were shown to be key factors of neurodegenerative diseases and cancerogenesis. Our findings support current relevance of nuclear localized SHIP1. PMID- 25723259 TI - Superlinear composition-dependent photocurrent in CVD-grown monolayer MoS2(1 x)Se2x alloy devices. AB - Transition metal dichalcogenides (TMDs) have emerged as a new class of two dimensional materials that are promising for electronics and photonics. To date, optoelectronic measurements in these materials have shown the conventional behavior expected from photoconductors such as a linear or sublinear dependence of the photocurrent on light intensity. Here, we report the observation of a new regime of operation where the photocurrent depends superlinearly on light intensity. We use spatially resolved photocurrent measurements on devices consisting of CVD-grown monolayers of TMD alloys spanning MoS2 to MoSe2 to show the photoconductive nature of the photoresponse, with the photocurrent dominated by recombination and field-induced carrier separation in the channel. Time dependent photoconductivity measurements show the presence of persistent photoconductivity for the S-rich alloys, while photocurrent measurements at fixed wavelength for devices of different alloy compositions show a systematic decrease of the responsivity with increasing Se content associated with increased linearity of the current-voltage characteristics. A model based on the presence of different types of recombination centers is presented to explain the origin of the superlinear dependence on light intensity, which emerges when the nonequilibrium occupancy of initially empty fast recombination centers becomes comparable to that of slow recombination centers. PMID- 25723260 TI - Early-warning systems: staff-related illness. PMID- 25723261 TI - Know your sepsis toolkit: help more patients survive. PMID- 25723262 TI - A qualitative study of televideo consultations for COPD patients. AB - This article presents results from a small qualitative study investigating the experiences of patients who have chronic obstructive pulmonary disease (COPD) with televideo consultations at home, as a supplement to conventional control and treatment. The research question was: what are the experiences and preferences of COPD patients in relation to discharge from hospital with televideo consultations? The study shows that the patients' assessments of the effectiveness and value of the televideo consultations in their everyday lives are based on tough cost-benefit calculation of the extent to which the intervention makes their lives easier or more difficult. In public settings, the expectations are high that digital mediation between clients' everyday lives and the healthcare system can strengthen patients' abilities regarding their self management. Nonetheless, the study shows that patients have a number of reservations concerning televideo consultations at home. The patients' assessments of the service must be understood in relation to the routines and strategies developed to handle the array of problems related to a life affected by chronic illness. PMID- 25723263 TI - Selecting compression hosiery. PMID- 25723264 TI - Assistant practitioners: essential support in a climate of austerity. AB - In Britain the last decade has witnessed the growth of the assistant practitioner (AP), a higher-level support worker role situated at band 4 of the NHS career framework, just below registered nurse. Various factors are given for the role's development but little analysis is provided as to the economic reasons for its implementation. With reference to the period since the economic crisis of 2007 08, this article proposes that the AP's implementation and function is influenced by the needs of the economy. With the UK Coalition Government refusing to increase public expenditure as it is thought detrimental to economic growth, emphasising instead the need to reduce public debt, an expansion of registered nurses is unlikely despite growing service user demand. As a result, the AP has become an important economic development in an attempt to maintain standards of nursing care in the present economic climate. PMID- 25723265 TI - Sex and the older man. AB - Sexual health is an important part of an individual's physical and emotional wellbeing. Sexuality and sexual wellbeing are often associated with young people and therefore the needs of the older person can be overlooked. Such discrimination is unjustifiable given that statistics show a rise in sexually transmitted infections (STIs) and new diagnoses of HIV in the older man. These worrying trends emphasise the legitimate need for nurses to address sexuality and sexual wellbeing as an essential component of health care. PMID- 25723266 TI - Professional culture and care: what is best for the patient? AB - In this monthly column, Aysha Mendes discusses potential causes of ethical dilemmas and what actions can be taken to ensure health professions act in the best interests of their patients. PMID- 25723267 TI - Lived experience, enhanced recovery and laparoscopic colonic resection. AB - AIM: To explore patients' lived experience of undergoing laparoscopic colonic resection on an enhanced recovery programme. METHOD: Eleven patients were interviewed at home, between 14 and 16 days following discharge. The transcribed interview texts were interpreted with a hermeneutical-phenomenological method. FINDINGS: Participants were keen to achieve their goals and participate actively in the enhanced recovery programme. They strived to return to full health as soon as possible after surgery, but all participants indicated that it was taking longer than they had expected. As they became more independent regarding their self-care needs during their hospital stay, participants noticed that the nursing presence became more distant, which could result in unmet psychological needs. Their recovery at home was perceived to be taking longer than it should and was often prolonged by symptoms. The minimally invasive approach associated with laparoscopic surgery led the participants to expect a lesser physical and psychological effect from this major surgery. CONCLUSION: Nurses need to acknowledge and attend not only to the physical but also to the emotional needs of patients on an enhanced recovery programme, right up until the point of discharge. Nurses also need to prepare patients more fully for what to expect after discharge. PMID- 25723268 TI - Exploring the experiences of young people nursed on adult wards. AB - This paper reports on a study of experiences of young people aged 14 to 18 years who were nursed on acute adult hospital wards in NHS hospitals in England. In spite of British government guidelines, young people from 14 years of age continue to be admitted to adult wards in the UK. Although much has been written about the transition of the young person to adult services, there is little research about the experiences of young people who are nursed on adult wards. Hermeneutic phenomenology was used to explore the lived experiences of eight young people who had been nursed on adult wards between 2004 and 2010. Data were collected in 2010. In-depth interviews were recorded, transcribed and analysed using Colaizzi's framework ( Colaizzi, 1978 ). Themes explored included expectations of what the experience may be like, young people's first impressions of the ward environment, the feelings of the young person while in hospital, the attitudes of people towards them including, both staff and other patients, and future admissions and how they would cope with readmissions. Better provision needs to be made for young people including appropriately trained staff, adolescent-friendly environments and areas in adult wards that are dedicated to adolescents. PMID- 25723269 TI - The professional duty of candour: implications for nursing. PMID- 25723270 TI - Can the new NMC Code improve standards of care delivery? AB - Professor Alan Glasper from the University of Southampton discusses the recently published revised NMC Code. PMID- 25723271 TI - Unlocking the NHS Constitution: recommendations for change. AB - In the final part of his two-part series, John Tingle continues his discussion of a new report from the Patients Association on patient and public awareness of the NHS Constitution. PMID- 25723272 TI - Written communication: from staff nurse to nurse consultant. PMID- 25723273 TI - Showing and measuring compassion. PMID- 25723274 TI - Intramolecular vibrations in low-frequency normal modes of amino acids: L-alanine in the neat solid state. AB - This paper presents a theoretical analysis of the low-frequency phonons of L alanine by using the solid-state density functional theory at the Gamma point. We are particularly interested in the intramolecular vibrations accessing low frequency phonons via harmonic coupling with intermolecular vibrations. A new mode-analysis method is introduced to quantify the vibrational characteristics of such intramolecular vibrations. We find that the torsional motions of COO(-) are involved in low-frequency phonons, although COO(-) is conventionally assumed to undergo localized torsion. We also find the broad distributions of intramolecular vibrations relevant to important functional groups of amino acids, e.g., the COO( ) and NH3(+) torsions, in the low-frequency phonons. The latter finding is illustrated by the concept of frequency distribution of vibrations. These findings may lead to immediate implications in other amino acid systems. PMID- 25723275 TI - Influence of copper recovery on the water quality of the acidic Berkeley Pit lake, Montana, U.S.A. AB - The Berkeley Pit lake in Butte, Montana, formed by flooding of an open-pit copper mine, is one of the world's largest accumulations of acidic, metal-rich water. Between 2003 and 2012, approximately 2 * 10(11) L of pit water, representing 1.3 lake volumes, were pumped from the bottom of the lake to a copper recovery plant, where dissolved Cu(2+) was precipitated on scrap iron, releasing Fe(2+) back to solution and thence back to the pit. Artificial mixing caused by this continuous pumping changed the lake from a meromictic to holomictic state, induced oxidation of dissolved Fe(2+), and caused subsequent precipitation of more than 2 * 10(8) kg of secondary ferric compounds, mainly schwertmannite and jarosite, which settled to the bottom of the lake. A large mass of As, P, and sulfate was also lost from solution. These unforeseen changes in chemistry resulted in a roughly 25-30% reduction in the lake's calculated and measured total acidity, which represents a significant potential savings in the cost of lime treatment, which is not expected to commence until 2023. Future monitoring is needed to verify that schwertmannite and jarosite in the pit sediment do not convert to goethite, a process which would release stored acidity back to the water column. PMID- 25723277 TI - A novel marker for undifferentiated human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are pluripotent stem cells from early embryos, and their self-renewal capacity depends on the sustained expression of hESC specific molecules and the suppressed expression of differentiation-associated genes. To discover novel molecules expressed on hESCs, we generated a panel of monoclonal antibodies against undifferentiated hESCs. The antigen recognized by MAb2 is expressed on the cell surface of undifferentiated hESCs; three diffused bands with molecular mass between 30 and 60 kDa in the lysates of hESCs were diminished during hESC differentiation into neural cells. The expression of MAb2 antigen was also observed on the plasma membrane of lung cancer cells, and MAb2 detected 55, 50, and 35 kDa protein bands in the cell lysates. Immunoprecipitation followed by proteomics analyses identified CD147/basigin as a MAb2 antigen. Finally, the positive expression of CD147/basigin protein in undifferentiated hESCs was confirmed. These results suggested that CD147/basigin could be another undifferentiated hESC marker. PMID- 25723276 TI - Anti-mouse properdin TSR 5/6 monoclonal antibodies block complement alternative pathway-dependent pathogenesis. AB - The complement alternative pathway (AP) is a major contributor to a broad and growing spectrum of diseases that includes age-related macular degeneration, atypical hemolytic uremic syndrome, and preeclampsia. As a result, there is much interest in the therapeutic disruption of AP activity. Properdin, the only positive regulator of the AP, is a particularly promising AP target. Several issues need to be clarified before the potential for properdin-directed therapy can be realized. In this report we use a portion of the mouse properdin protein, expressed in a bacterial system, to raise rabbit polyclonal and hamster monoclonal antibodies that block properdin-dependent pathogenesis. These antibodies, when employed with AP-dependent mouse disease models, can help evaluate the feasibility of properdin-directed therapy. PMID- 25723278 TI - Development of a hybridoma cell line secreting monoclonal antibody against S protein of a Chinese variant of PEDV. AB - Gene encoding 22-380 aa of spike protein of porcine epidemic diarrhea virus (PEDV) isolate in China was cloned and expressed as a recombinant protein in Escherichia coli BL21(DE3). Female BALB/c mice were immunized with the purified recombinant S protein, and a monoclonal antibody (MAb) designated as 2D1 against S protein was achieved by hybridoma technique. MAb 2D1 reacted with S protein of PEDV specifically. The monoclonal antibody 2D1 may provide a useful tool as a specific diagnostic reagent for detecting S protein of the Chinese variant of PEDV and for further investigation into the virus' pathogenic mechanism. PMID- 25723279 TI - Development and characterization of neutralizing monoclonal antibodies against the S1 subunit protein of QX-like avian infectious bronchitis virus strain Sczy3. AB - Infectious bronchitis (IB) is a highly contagious disease in chickens caused by infectious bronchitis virus (IBV). The present study was carried out with the aim to develop anti-spike 1 (S1) subunit monoclonal antibodies (MAbs) that could react with IBV strains of different genotypes. The high antigenicity region of S1 gene of an QX-like IBV strain Sczy3 was amplified and ligated into the prokaryotic expression vector pET-32a(+), and the recombinant His-S1 fusion proteins were expressed and purified. The purified whole viral antigen of Sczy3 strain was used to immunize BALB/c mice to produce hybridoma-secreting anti-IBV MAbs. Eleven anti-IBV MAbs were generated, and two MAbs 1C8 and 2C10 were positive in indirect ELISA against both His-S1 protein and the purified whole viral antigen. These two MAbs showed positive reaction with IBV in Western blot, and the isotype were both IgM. These two MAbs react specifically with IBV but not with Newcastle disease virus (NDV) or avian influenza virus (AIV) subtype H9 or H5, and could cross-react with other 10 IBV strains in five different genotypes. End-point neutralizing assay performed in chicken embro kidney (CEK) cells revealed that the neutralization titer of 1C8 and 2C10 against Sczy3 reached 1:2.82 and 1:4.70, respectively. The anti-S1 MAbs produced in the present work may be valuable in developing an antigen-capture ELISA test for antigen detection or a competitive ELISA test for antibody detection or therapeutic medicine for IB in poultry. PMID- 25723280 TI - A novel monoclonal antibody against human GRK6 antigen. AB - G protein-coupled receptor kinase 6 (GRK6) plays a universal role in receptor desensitization, by acting as a receptor-G protein interface, thereby affecting serine/threonine kinases. In this study, a 20-aa-long peptide of human GRK6 C terminus domain was synthesized and covalently coupled to keyhole limpet hemocyanin (KLH). A mouse monoclonal antibody against human GRK6 (anti-GRK6 MAb) was successfully prepared through hybridoma technique by immunizing BALB/c mice with synthesized GRK6426-446-KLH peptides. A high specificity and affinity strain of hybridoma 5D12 were established. The titer of the purified anti-GRK6 MAb was 1.28 * 10(6) measured by indirect ELISA. Western blot and immunocytochemistry experiments were also applied to characterize the antibody specificity. Antibody absorption assays showed that the anti-GRK6 MAb can be blocked by GRK6426-446 peptides. These results indicated that the antibody could bind to GRK6 antigen specifically. This MAb provides valuable support for further studies on the functional properties of GRK6. PMID- 25723281 TI - Generation of med28 specific monoclonal antibodies. AB - Med28 plays a role in transcription, signal transduction, and cell proliferation. The overexpression of med28 is associated with tumor progression in in vitro and in vivo models. Recently it has been reported that the elevated expression of med28 is associated with poor outcome in women with breast cancer. The expression level of med28 in in vitro and in vivo was examined by using anti-rabbit polyclonal antibody in previous reports. In this study, we report for the first time the generation and characterization of four monoclonal antibodies against med28 through immunoblotting, immunofluorescence microscopy, immunoprecipitation, and immunohistochemical analyses. These antibodies will be useful in detecting med28 in in vitro and in vivo. PMID- 25723282 TI - Production and characterization of a peptide-based monoclonal antibody against CD44 variant 6. AB - The gene that codes for the CD44 family members consists of 20 exons, nine of which encode the standard form of the molecule. The other exons can be inserted in various combinations into the membrane proximal region of the extracellular domain of the protein, giving rise to variant isoforms (CD44v). CD44 variants, especially the CD44v6, have been reported to regulate tumor invasion, progression, and metastasis of carcinomas. Producing a high affinity monoclonal antibody against human CD44v6 provides a powerful tool to monitor and trace CD44v6 function in different biological fluids. In this study, a synthetic peptide from CD44v6 was conjugated to keyhole limpet hemocyanin (KLH) and injected into BALB/c mice. Splenocytes from the immunized mice were fused with murine SP2/0 myeloma cells followed by selection of antibody producing hybridoma cells. After screening of hybridoma colonies by ELISA, high affinity antibodies were selected and purified by affinity chromatography. Western blot, immunocytochemistry, and flow cytometry experiments were used to characterize the antibodies. Six stable hybridoma cell lines, designated as 1H1, 1H2, 2A12, 2G11, 3H3, and 3H7, were obtained. Flow cytometry and immunocytochemistry results showed that the new monoclonal antibodies recognized CD44v6 on the cell surface. This novel panel of anti-CD44v6 antibodies has the potential for investigating the role of CD44v6 in cancer pathogenesis. PMID- 25723283 TI - Characterization of monoclonal antibody LpMab-3 recognizing sialylated glycopeptide of podoplanin. AB - Podoplanin (PDPN/Aggrus/T1alpha/gp36/OTS-8), a type I transmembrane sialoglycoprotein, is involved in platelet aggregation, cell invasion, and cancer metastasis. Podoplanin expression in cancer cells or cancer-associated fibroblasts was reported to be involved in poor prognosis of several cancers. Furthermore, podoplanin is expressed in lymphatic endothelial cells or lung type I alveolar cells. Although many anti-podoplanin monoclonal antibodies (MAbs), such as NZ-1 and D2-40, have been established, almost all anti-podoplanin MAbs are produced against a platelet aggregation-inducing (PLAG) domain. In this study, we produced and characterized a novel anti-podoplanin monoclonal antibody, LpMab-3, the epitope of which is a sialylated glycopeptide of podoplanin. We identified the minimum epitope of LpMab-3 as Thr76-Glu81 of human podoplanin, which is different from PLAG domain, using Western blot analysis and flow cytometry. Immunohistochemical analysis showed that LpMab-3 is useful for detecting lung type I alveolar cells and lymphatic endothelial cells. Because LpMab-3 detects only sialylated podoplanin, it could be useful for uncovering the physiological function of sialylated human podoplanin. PMID- 25723284 TI - Monoclonal antibody to N protein of porcine epidemic diarrhea virus. AB - The N gene of porcine epidemic diarrhea virus (PEDV) was amplified by RT-PCR using specific primers, and inserted into the expression vector pCold-I to construct a recombinant plasmid pCold-I-N. The recombinant plasmid was expressed in Escherichia coli BL21 (DE3) under IPTG induction. Then, female BALB/c mice were immunized with the purified recombinant N protein and one strain of hybridoma cells named 2B8 secreting anti-N protein monoclonal antibodies (MAb) was obtained by hybridoma technique. The MAb was specifically reacted with PEDV and identified by Western blot and indirect immunofluorescence assays. This work indicated that the MAb would be a valuable tool as a specific diagnostic reagent for PEDV epidemiological surveys and diagnosis in the future. PMID- 25723285 TI - New monoclonal antibodies specific for 1-(5-fluoropentyl)-3-(2 iodobenzoyl)indole. AB - 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole (AM694) is one of the synthetic cannabinoids and an illegal drug in Japan. It is important to generate a monoclonal antibody (MAb) against AM694 for use in the rapid and sensitive detection of the drug. Two monoclonal antibodies, named HN0124 (IgG1) and NK0504 (IgG1), were obtained, which were possibly effective for detecting AM694 and its derivatives. The cross-reactive ability of these MAbs was evaluated using a competitive enzyme-linked immunosorbent assay. In the results, both of these antibodies recognize 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole, 1-(5 fluoropentyl)-3-(3-iodobenzoyl)indole, 1-(5-fluoropentyl)-3-(4 iodobenzoyl)indole. Forty nmol/L AM694 can be detected using HN0124 MAb. Thus, MAbs produced in this study could be considered a useful tool for the detection of AM694. PMID- 25723290 TI - Comments on 'Does the type of creatinine assay affect creatinine clearance determination?'. PMID- 25723291 TI - Response to the letter from Kallner: Comments on 'Does the type of creatinine assay affect creatinine clearance determination?'. PMID- 25723292 TI - The Use of Haddon's Matrix to Plan for Injury and Illness Prevention at Outdoor Music Festivals. AB - INTRODUCTION: Mass-gathering music events, such as outdoor music festivals (OMFs), increase the risk of injuries and illnesses among attendees. This increased risk is associated with access to alcohol and other drugs by young people and an environment that places many people in close contact with each other. AIM: The purpose of this report was to demonstrate how Haddon's matrix was used to examine the factors that contributed to injuries and illnesses that occurred at 26 OMFs using data from the Ranse and Hutton's minimum data set. METHODS: To help understand the kinds of injuries and illnesses experienced, Hutton et al identified previous patterns of patient presentations at 26 OMFs in Australia. To develop effective prevention strategies, the next logical step was to examine the risk factors associated with each illness/injury event. The Haddon matrix allows event practitioners to formulate anticipatory planning for celebratory-type events. RESULTS: What was evident from this work was that the host, the agent, and the physical and social environments contributed to the development of injuries and illness at an event. The physical environment could be controlled, to a certain extent, through event design, safety guidelines, and legislation. However, balancing cultural norms, such as the importance placed on celebratory events, with the social environment is more difficult. DISCUSSION: The use of the Haddon matrix demonstrates that interventions need to be targeted at all stages of the event, particularly both pre-event and during the event. The opportunity to promote health is lost by the time of post event. The matrix provided vital information on what factors may contribute to injury at OMFs; form this information, event planners can strategize possible interventions. PMID- 25723293 TI - "....and he did what?! ": giving a second opinion in orthodontics. PMID- 25723295 TI - Secretion of RNA-Containing Extracellular Vesicles by the Porcine Whipworm, Trichuris suis. AB - Trichuris suis is a common parasitic helminth of pigs. As with many other parasites, T. suis ensures its own survival by evading host immune responses, but little is known about how this is achieved. MicroRNAs (miRNA) have been shown to be involved in various immunological processes by post-transcriptional regulation of specific genes, and the potential of using these molecules as biomarkers of disease is currently being examined. It has recently been shown that parasites may secrete extracellular structures such as exosomes and microvesicles, containing proteins and miRNA. The fusion of these structures with host cells has been demonstrated, and a role of exosome-derived miRNA in host gene regulation has been suggested. In the present study, we show that exosome- and microvesicular-like structures are secreted by T. suis L1 larvae and also demonstrate the presence of miRNA-sized RNA inside these structures. A potential role of these molecules in host-parasite interactions is suggested. In addition, an electron-dense layer covering the surface of the larvae was observed, which may play a function in host immune evasion. PMID- 25723296 TI - Capping agent-free gold nanostars show greatly increased versatility and sensitivity for biosensing. AB - We report the first assessment of the plasmonic biosensing capabilities of capping agent-free gold nanostars. Capping agent removal was carried out using aqueous solutions of sodium borohydride, which yielded a refractive index sensitivity of 474 nm/RIU for the polyvinylpyrrolidone (PVP)-free nanostars compared with 98 nm/RIU for PVP-coated gold nanostars. Following PVP removal, biotinylated thiol and streptavidin protein were added to the nanostars, which resulted in red shifts as large as 51 nm and a limit of detection as low as 0.1 pM. Refractive index-based sensing of prostate specific antigen (PSA) both in buffer and serum was then carried out and was shown to yield shifts as large as 127 nm and have a limit of detection of 100 pM in serum. Last, a sandwich assay involving PSA was developed to aggregate the nanostars together for greater sensitivity. The sandwich assay did, indeed, give shifts close to 200 nm and was capable of detecting 10(-17) M PSA in serum. The greatly increased sensitivity and amenability to functionalization of PVP-free gold nanostars should prove useful in applications ranging from catalysis to drug delivery. PMID- 25723297 TI - Analysis of neurosurgical reoperations: use of a surgical checklist and reduction of infection-related and preventable complication-related reoperations. AB - OBJECT: Use of the WHO surgical checklist has been proven to reduce surgical morbidity and mortality, but its effect on surgical complications requiring reoperation has not been previously studied. The aim of this study was to determine whether the use of the WHO surgical checklist would have an impact on the number and causes of neurosurgical complications leading to a reoperation. METHODS: The authors retrospectively gathered information on all neurosurgical reoperations using hospital discharge data as well as the operations and procedures registry, and tracked all primary neurosurgical operations (n = 175) preceding a complication-related reoperation from 2007 to 2011. There were a total of 5418 neurosurgical operations during the study period. For further analysis of electronic patient records, the primary operations were divided into 2 groups based on the time of the WHO surgical checklist implementation in the authors' unit: 103 operations before and 72 after the introduction of the checklist. Observed adverse events and reoperations were categorized as preventable or unpreventable, and the actual use of the checklist during each operation was recorded. RESULTS: The overall rate of preventable complication related neurosurgical reoperations decreased from 3.3% (95% CI 2.7%-4.0%) to 2.0% (95% CI 1.5%-2.6%) after the checklist implementation. The reoperations were mainly due to wound infections, 46% before and 39% after the checklist. All infection-related reoperations proportioned to all neurosurgical operations (2.5% before vs 1.6% after checklist implementation) showed a significant reduction (p = 0.02) after the implementation of the checklist. In particular, there was a significant decrease (p = 0.006) in the rate of preventable infections associated with reoperations, i.e., 2.2% before versus 1.2% after checklist implementation. The overall adherence to checklist use (the "time out" phase) in neurosurgical operations was 78%, and adherence was 70% in primary operations preceding a complication-related reoperation regarded as preventable. CONCLUSIONS: The implementation of the WHO surgical checklist in neurosurgery was associated with a decrease in complication-related reoperations, especially those due to preventable infection complications, the majority of which were wound infections. The adherence to checklist use in individual operations after the checklist implementation did not appear to have an impact on the results. PMID- 25723298 TI - Editorial: Does chiasmatic blood supply dictate endonasal corridors? PMID- 25723299 TI - Letter to the Editor: Timing of surgical aneurysmal exclusion in SAH. PMID- 25723300 TI - Letter to the Editor: Fusion antibody Fc-endostatin. PMID- 25723301 TI - Is there a risk of seizures in "preventive" awake surgery for incidental diffuse low-grade gliomas? AB - OBJECT: Although a large amount of data supports resection for symptomatic diffuse low-grade glioma (LGG), the therapeutic strategy regarding incidental LGG (ILGG) is still a matter of debate. Indeed, early "preventive" surgery has recently been proposed in asymptomatic patients with LGG, after showing that the extent of resection was larger than in symptomatic patients with LGG. However, the quality of life should be preserved by avoiding both neurological deficit and epilepsy. The aim of this study was to determine the risk of seizures related to such a prophylactic surgical treatment in ILGG. METHODS: The authors report a prospective series of 21 patients with ILGG who underwent awake surgery with a minimum follow-up of 20 months following resection. Data regarding clinicoradiological features, surgical procedures, and outcomes were collected and analyzed. In particular, the eventual occurrence and type of seizures in the intra- and postoperative periods were studied, as follows: early (< 3 months) and long-term (until last follow-up) periods. RESULTS: There were no intraoperative seizures in this series. During the early postoperative period, the authors observed only a single episode of partial seizures in a patient with no antiepileptic drug (AED) prophylaxis-all other patients were given antiepileptic treatment following resection. The AEDs were discontinued in all cases, with a mean delay of 8 months after surgery (range 3-24 months). No patient had permanent neurological deficits. All 21 patients returned to an active familial, social, and professional life (working full time in all cases). Total or even "supratotal" resection (the latter meaning that a margin around the tumor visible on FLAIR-weighted MRI was removed) was achieved in 14 cases (67%). In 7 patients (33%) subtotal resection was performed, with a mean residual tumor volume of 1.5 ml (range 1-7 ml). No oncological treatment was administered in the postsurgical period. The mean follow-up after surgery was 49 months (range 20-181 months). Only 2 patients had seizures during the long-term follow-up. Indeed, due to tumor progression after incomplete resection, seizures occurred in 2 cases, 39 and 78 months postsurgery, leading to administration of AEDs and adjuvant treatment. So far, all patients are still alive and enjoy a normal life. CONCLUSIONS: The risk of inducing seizures is very low in ILGG, and it does not represent an argument against early surgery. These data strongly support the proposal of a screening policy for LGG that will evolve toward a preventive treatment in a more systematic manner. PMID- 25723303 TI - Suprachiasmatic translamina terminalis corridor used in endoscopic endonasal approach for resecting third ventricular craniopharyngioma. AB - OBJECT: The translamina terminalis corridor was used in the transcranial anterior route to treat third ventricular craniopharyngioma (TVC), which presents a challenge to neurosurgeons. The endoscopic endonasal approach (EEA) has recently been used to treat craniopharyngiomas. However, there are few reports of the EEA being used to treat TVC. The authors' novel surgical approach of treating selected TVC by the endoscopic endonasal route via the suprachiasmatic translamina terminalis (STLT) corridor is described. METHODS: In this single center study, the EEA via the STLT corridor was used to resect TVC with great upper and anterior extension causing bulged lamina terminalis, and TVC with a residual upper compartment, after routine infrachiasmatic transmetastalk corridor resection. RESULTS: The STLT corridor was used in 3 patients. Gross-total resection was achieved in all cases. One patient achieved visual improvement, and the other 2 patients showed partial visual improvement. Leakage of CSF occurred in 1 patient. Postoperative hormone replacement therapy was required in all patients. CONCLUSIONS: The STLT corridor is a complementary minimally invasive corridor used in the EEA for treating selected TVC. The STLT alone or combined with infrachiasmatic transmetastalk corridors should be selected depending on the size of suprachiasmatic and infrachiasmatic space. PMID- 25723302 TI - On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model. AB - OBJECT: The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with "on-demand'" convection-enhanced intracerebral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. METHODS: A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hippocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [(14)C]-autoradiography was used to determine AED distribution. RESULTS: Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with ondemand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. CONCLUSIONS: Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter pathways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone. PMID- 25723304 TI - Suture retraction technique to prevent parent vessel obstruction following aneurysm tandem clipping. AB - With large or giant aneurysms, the use of multiple tandem clips can be essential for complete obliteration of the aneurysm. One potential disadvantage, however, is the considerable cumulative weight of these clips, which may lead to kinking of the underlying parent vessels and obstruction of flow. The authors describe a simple technique to address this problem, guided by intraoperative blood flow measurements, in a patient with a ruptured near-giant 2.2 * 1.7-cm middle cerebral artery bifurcation aneurysm that was treated with the tandem clipping technique. A total of 11 clips were applied in a vertical stacked fashion. The cumulative weight of the clips caused kinking of the temporal M2 branch of the bifurcation with reduction of flow. A 4-0 Nurolon suture tie was applied to the hub of one of the clips and was tethered to the dura of the sphenoid ridge by a small mini-clip and reinforced by application of tissue sealant. The patient underwent intraoperative indocyanine green videoangiography as well as catheter angiography, which demonstrated complete aneurysmal obliteration and preservation of vessel branches. Postoperative angiography confirmed patency of the bifurcation vessels with mild vasospasm. The patient had a full recovery with no postoperative complications and was neurologically intact at her 6-month follow up. The suture retraction technique allows a simple solution to parent vessel obstruction following aneurysm tandem clipping, in conjunction with the essential guidance provided by intraoperative flow measurements. PMID- 25723305 TI - Long-term follow-up of peptidergic and nonpeptidergic reinnervation of the epidermis following sciatic nerve reconstruction in rats. AB - OBJECT: Peripheral nerve injuries are a commonly encountered clinical problem and often result in long-term functional deficits. The current gold standard for transected nerves is an end-to-end reconstruction, which results in the intermittent appearance of neuropathic pain. METHODS: To improve our understanding of the relation between this type of reconstruction and neuropathic pain, the authors transected and immediately end-to-end reconstructed the sciatic nerve in rats. The effect of this procedure on neuropathic pain, as measured by thermal and mechanical hypersensitivity at 4 different time points (5, 10, 20, and 30 weeks), was related to the density of peptidergic and nonpeptidergic fiber innervation in the glabrous skin of rats' hind paws. RESULTS: Thermal hypersensitivity occurring 20 weeks after reconstruction was accompanied by a significant increase in peptidergic epidermal fibers. However, the lesion-induced reduction in the density of nonpeptidergic epidermal fibers remained decreased at all experimental time points. Moreover, temporal collateral sprouting by undamaged saphenous nerve was visualized using the recently revised Evans blue extravasation technique. Strikingly, as the sciatic nerve repopulated rats' hind paw, the saphenous nerve withdrew to its original territory. CONCLUSIONS: The authors conclude that the transient thermal hypersensitivity is related to increased density of epidermal peptidergic fibers, which mainly originate from regenerating fibers. Furthermore, a changed composition in the peptidergic and nonpeptidergic epidermal fibers is demonstrated following end-to-end reconstruction of the sciatic nerve. PMID- 25723306 TI - Consistent delayed unilateral neuronal death after modified transient focal cerebral ischemia in mice that mimics neuronal injury after transient global cerebral ischemia. AB - OBJECT: Numerous studies have attempted to reveal the pathophysiology of ischemic neuronal injury using a representative transient global cerebral ischemia (tGCI) model in rodents; however, most of them have used gerbil or rat models. Recent advances in transgene and gene-knockout technology have enabled the precise molecular mechanisms of ischemic brain injury to be investigated. Because the predominant species for the study of genetic mutations is the mouse, a representative mouse model of tGCI is of particular importance. However, simple mouse models of tGCI are less reproducible; therefore, a more complex process or longer duration of ischemia, which causes a high mortality rate, has been used in previous tGCI models in mice. In this study, the authors aimed to overcome these problems and attempted to produce consistent unilateral delayed hippocampal CA1 neuronal death in mice. METHODS: C57BL/6 mice were subjected to short-term unilateral cerebral ischemia using a 4-mm silicone-coated intraluminal suture to obstruct the origin of the posterior cerebral artery (PCA), and regional cerebral blood flow (rCBF) of the PCA territory was measured using laser speckle flowmetry. The mice were randomly assigned to groups of different ischemic durations and histologically evaluated at different time points after ischemia. The survival rate and neurological score of the group that experienced 15 minutes of ischemia were also evaluated. RESULTS: Consistent neuronal death was observed in the medial CA1 subregion 4 days after 15 minutes of ischemia in the group of mice with a reduction in rCBF of < 65% in the PCA territory during ischemia. Morphologically degenerated cells were mostly positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and cleaved caspase 3 staining 4 days after ischemia. The survival rates of the mice 24 hours (n = 24), 4 days (n = 15), and 7 days (n = 7) after being subjected to 15 minutes of ischemia were 95.8%, 100%, and 100%, respectively, and the mice had slight motor deficits. CONCLUSIONS: The authors established a model of delayed unilateral hippocampal neuronal death in C57BL/6 mice by inducing ischemia in the PCA territory using an intraluminal suture method and established inclusion criteria for PCAterritory rCBF monitored by laser speckle flowmetry. This model may be useful for investigating the precise molecular mechanisms of ischemic brain injury. PMID- 25723307 TI - Usefulness of the indocyanine green fluorescence endoscope in endonasal transsphenoidal surgery. AB - OBJECT: To avoid disorientation during endoscopic endonasal transsphenoidal surgery (ETSS), the confirmation of anatomical landmarks is essential. Neuronavigation systems can be pointed at exact sites, but their spatial resolution power is too low for the detection of vessels that cannot be seen on MR images. On Doppler ultrasonography the shape of concealed arteries and veins cannot be visualized. To address these problems, the authors evaluated the clinical usefulness of the indocyanine green (ICG) endoscope. METHODS: The authors included 38 patients with pituitary adenomas (n = 26), tuberculum sellae meningiomas (n = 4), craniopharyngiomas (n = 3), chordomas (n = 2), Rathke's cleft cyst (n = 1), dermoid cyst (n = 1), or fibrous dysplasia (n = 1). After opening the sphenoid sinus and placing the ICG endoscope, the authors injected 12.5 mg of ICG into a peripheral vein as a bolus and observed the internal carotid arteries (ICAs), cavernous sinus, intercavernous sinus, and pituitary. RESULTS: The ICA was clearly identified by a strong fluorescence signal through the dura mater and the covering thin bone. The intercavernous and cavernous sinuses were visualized a few seconds later. In patients with tuberculum sellae meningiomas, the abnormal tumor arteries in the dura were seen and the vague outline of the attachment was identified. At the final inspection after tumor removal, perforators to the brain, optic nerves, chiasm, and pituitary stalk were visualized. ICG fluorescence signals from the hypophyseal arteries were strong enough to see and spread to the area of perfusion with the passage of time. CONCLUSIONS: The ICA and the patent cavernous sinus were detected with the ICG endoscope in real time and at high resolution. The ICG endoscope is very useful during ETSS. The authors suggest that the real-time observation of the blood supply to the optic nerves and pituitary helps to predict the preservation of their function. PMID- 25723308 TI - Synthesis of chemically and configurationally stable monofluoro acylboronates: effect of ligand structure on their formation, properties, and reactivities. AB - The recent disclosures of two classes of acylborons, potassium acyltrifluoroborates (KATs) and N-methyliminodiacetyl (MIDA) acylboronates, demonstrated that certain acylboron species can be both remarkably stable and uniquely reactive. Here we report new classes of ligands for acylboronates that have a significant influence on the formation, properties, and reactivities of acylboronates. Our systematic investigations identified a class of neutral, monofluoroboronates that can be prepared in a one step, gram-scale fashion from readily accessible KATs. These monofluoroboronates are stable to air, moisture, and silica gel chromatography and can be easily handled without any special precautions. X-ray crystallography, NMR spectroscopy, and HPLC studies showed that they are tetravalent, configurationally stable B-chiral acylboronates. Significantly, the ligands on the boronate allow for fine-tuning of the properties and reactivity of acylboronates. In amide-forming ligation with hydroxylamines under aqueous conditions, a considerable difference in reactivity was observed as a function of ligand structure. The solid-state structures suggested that subtle steric and conformational factors modulate the reactivities of the acylboronates. PMID- 25723310 TI - Beyond 'Doing Gender': Incorporating Race, Class, Place, and Life Transitions into Feminist Drug Research. AB - This essay draws from our research with US rural women methamphetamine users in 2009 to offer strategies for "revisioning" the drug use(r) field to better understand the impact of gender on drug use and drug market participation. We highlight the insights and limitations of a popular strategy in feminist research that conceptualizes gender as performance- commonly referred to as "doing gender" using illustrations from our research. We encourage scholars to move beyond a primarily normative orientation in studying gender, and investigate gendered organizational features of social life including their intersections with other aspects of social inequality such as those of race, class, and place. In addition, we suggest that feminist scholars can integrate gender in a rigorous way into theoretical perspectives that are typically inattentive to its import, as a means of challenging, enriching, and refining research on drug use, drug users, and drug market participation. PMID- 25723309 TI - Big Events in Greece and HIV Infection Among People Who Inject Drugs. AB - Big Events are processes like macroeconomic transitions that have lowered social well-being in various settings in the past. Greece has been hit by the global crisis and experienced an HIV outbreak among people who inject drugs. Since the crisis began (2008), Greece has seen population displacement, inter-communal violence, cuts in governmental expenditures, and social movements. These may have affected normative regulation, networks, and behaviors. However, most pathways to risk remain unknown or unmeasured. We use what is known and unknown about the Greek HIV outbreak to suggest modifications in Big Events models and the need for additional research. PMID- 25723311 TI - Big Events and Risks to Global Substance Using Populations: Unique Threats and Common Challenges. AB - In this commentary, we review a set of "Big Events" from around the world that have adversely impacted substance using populations by first identifying common thematic areas between them, and then describing the unique challenges faced by the diverse and vulnerable populations impacted. The Big Events reviewed are multifaceted and complex in nature, and include the recent global financial crisis, economic and trade sanctions, political transition and its impact on ethnic minorities, colonialism and indigenous communities, and ecological disasters. All have led to immense trauma, displacement, and disruption to critical healthcare services/treatment for people who use drugs, populations who are left underserved in the midst of these crises. It is our hope that through this comparative assessment, global policymakers will proactively identify Big Events and prioritize the development of interventions and policy that meet the unique and immediate needs of substance using population in order to mitigate the significant negative short- and long-term impacts on global public health. PMID- 25723312 TI - Entangled in Big Events: Rise of Heroin Use Among Children of Ex-Gurkhas in Hong Kong. AB - Big event models have been developed to demonstrate the relationships between wars and socioeconomic political transitions, and between rise of drug use and HIV epidemic outbreaks. This ethnographic interview-based study of a Nepali, Hong Kong community, carried out between 2009 and 2011, explored increased heroin use among the children of Hong Kong's Nepali ex-Gurkhas since its political transition in 1997. Data from its 59 informants were coded and analyzed using the grounded-theory approach. Three derived themes influencing drug use among ex Gurkha children were identified: (1) reorganization of social networks, (2) redefinition of social norms, and (3) renegotiation of self-identity. Their associated processes crossed the boundaries of time and space. These findings document that big event modeling variables can and do overlap, are interconnected in many different ways, and their relationships are dialectical and are culturally shaped even as individuals may and do influence these processes and outcomes. Study's limitations are noted. PMID- 25723313 TI - Economic Sanctions Against Iran, and Drug Use in Tehran, Iran: A 2013 Pilot Study. AB - This qualitative study was conducted in 2013 among male drug user patients referred to Drop-In Centers (n = 23) and Residential Treatment Centers (n = 25) in Tehran. The results show that when the price of drugs increases, some drug users tend to use cheaper drugs, which are more harmful, use more harmful routes of administration, such as injecting drugs, sharing needles, and make money illegally. Economic sanctions have threatened Iranian people's economic status since 2006 and have become more intense in 2010 and 2011. As an important consequence of these economic sanctions, the price of drugs, as well as other goods and services, have increased in Iran in recent years. Given these "big economic events," big changes in the patterns of drug use, and an increase in drug use-related harms, can be expected to occur in the near future. PMID- 25723314 TI - The Need to Restructure the Substance Misuse Behavioral Science Research Enterprise. PMID- 25723315 TI - Rethinking Gender within Alcohol and Drug Research. PMID- 25723316 TI - Application of dual carbon-bromine isotope analysis for investigating abiotic transformations of tribromoneopentyl alcohol (TBNPA). AB - Many of polybrominated organic compounds, used as flame retardant additives, belong to the group of persistent organic pollutants. Compound-specific isotope analysis is one of the potential analytical tools for investigating their fate in the environment. However, the isotope effects associated with transformations of brominated organic compounds are still poorly explored. In the present study, we investigated carbon and bromine isotope fractionation during degradation of tribromoneopentyl alcohol (TBNPA), one of the widely used flame retardant additives, in three different chemical processes: transformation in aqueous alkaline solution (pH 8); reductive dehalogenation by zero-valent iron nanoparticles (nZVI) in anoxic conditions; oxidative degradation by H2O2 in the presence of CuO nanoparticles (nCuO). Two-dimensional carbon-bromine isotope plots (delta(13)C/Delta(81)Br) for each reaction gave different process-dependent isotope slopes (Lambda(C/Br)): 25.2 +/- 2.5 for alkaline hydrolysis (pH 8); 3.8 +/- 0.5 for debromination in the presence of nZVI in anoxic conditions; infinity in the case of catalytic oxidation by H2O2 with nCuO. The obtained isotope effects for both elements were generally in agreement with the values expected for the suggested reaction mechanisms. The results of the present study support further applications of dual carbon-bromine isotope analysis as a tool for identification of reaction pathway during transformations of brominated organic compounds in the environment. PMID- 25723317 TI - Simultaneous application of BrdU and WST-1 measurements for detection of the proliferation and viability of airway smooth muscle cells. AB - BACKGROUND: BrdU is a commonly used reagent in cell proliferation assays, and WST 1 measurement is widely used to detect cell viability. However, no previous study has formally reported the combination of the two assays, which may be used to detect the proliferation and viability simultaneously. In this study, we examined the effect of adding BrdU 2 h prior to the WST-1 assay and tried to test the possibility of the combined detection using rat airway smooth muscle cells. RESULTS: The WST-1 measurements obtained from the combined detection were consistent with those obtained from the separate detection, which suggested that the addition of BrdU 2 h prior to the WST-1 analysis did not affect the WST-1 results. The BrdU measurements obtained from the combined detection also demonstrated the same trend as that obtained from the separate detection, and dosages of 200, 400 and 800 ng/ml testing reagent significantly inhibited the proliferation of rat airway smooth muscle cells. CONCLUSIONS: Our study suggests that the BrdU and WST-1 measurements can be applied simultaneously without mutual interference, which may increase the efficacy and consistency of these measurements to a certain extent. PMID- 25723318 TI - Proteomic analysis of the regenerating liver following 2/3 partial hepatectomy in rats. AB - BACKGROUND: Liver regeneration (LR) after 2/3 partial hepatectomy (PH) is one of the most studied models of cell, organ, and tissue regeneration. Although the transcriptional profile analysis of regenerating liver has been carried out by many reserachers, the dynamic protein expression profile during LR has been rarely reported up to date. Therefore, this study aims to detect the global proteomic profile of the regenerating rat liver following 2/3 hepatectomy, thereby gaining some insights into hepatic regeneration mechanism. RESULTS: Protein samples extracted from the sham-operated and the regenerating rat livers at 6, 12, 24, 72, 120 and 168 h after PH were separated by IEF/SDS-PAGE and then analyzed by MALDI-TOF/TOF mass spectrometry. Compared to sham-operated groups, there were totally 220 differentially expressed proteins (including 156 up regulated, 62 down-regulated, and 2 up/down-regulated ones) identified in the regenerating rat livers, and most of them have not been previously related to liver regeneration. According to the expression pattern analysis combined with gene functional analysis, it showed that lipid and carbohydrate metabolism were enhanced at the early phase of LR and continue throughout the regeneration process. Ingenuity Pathway Analysis indicated that YWHAE protein (one of members of the 14-3-3 protein family) was located at the center of pathway networks at all the timepoints after 2/3 hepatectomy under our experimental conditions, maybe suggesting a central role of this protein in regulating liver regeneration. Additionally, we also revealed the role of Cdc42 (cell division cycle 42) in the termination of LR. CONCLUSIONS: For the first time, our proteomic analysis suggested an important role of YWHAE and pathway mediated by this protein in liver regeneration, which might be helpful in expanding our understanding of LR amd unraveling the mechanisms of LR. PMID- 25723319 TI - Pesticidal and pest repellency activities of a plant derived triterpenoid 2alpha,3beta,21beta,23,28-penta hydroxyl 12-oleanene against Tribolium castaneum. AB - BACKGROUND: Tribolium castaneum (Herbst) is a major pest of stored grain-based products, and cause severe damage to cereal grains throughout the world. The present investigation was aimed to determine the pesticidal and pest repellent activities of 2alpha,3beta,21beta,23,28-penta hydroxyl 12-oleanene against T. castaneum. The compound 2alpha,3beta,21beta,23,28-penta hydroxyl 12-oleanene is a triterpenoid which was isolated from the roots of Laportea crenulata Gaud. Surface film technique was used for pesticidal screening, whereas, pest repellency property of the triterpenoid was determined by filter paper disc method. RESULTS: At 24 hours of exposure duration, significant mortality records (80% and 86%) were observed at doses 0.88 and 1.77 mg/cm(2). No significant change in mortality records was observed when duration of exposure was increased up to 48 hours. The triterpenoid showed significant repellency activity at doses 0.47 and 0.94 mg/cm(2). CONCLUSION: These data suggest that the triterpenoid 2alpha,3beta,21beta,23,28-penta hydroxyl 12-oleanene possess both pesticidal and pest repellency activities against T. castaneum and can be used in controlling the pest of grain-based products. PMID- 25723320 TI - Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation. RESULTS: We identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28 5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas. CONCLUSIONS: Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis. PMID- 25723204 TI - Search for displaced supersymmetry in events with an electron and a muon with large impact parameters. AB - A search for new long-lived particles decaying to leptons is presented using proton-proton collisions produced by the LHC at ?[s]=8 TeV. Data used for the analysis were collected by the CMS detector and correspond to an integrated luminosity of 19.7 fb(-1). Events are selected with an electron and muon with opposite charges that both have transverse impact parameter values between 0.02 and 2 cm. The search has been designed to be sensitive to a wide range of models with nonprompt e-MU final states. Limits are set on the "displaced supersymmetry" model, with pair production of top squarks decaying into an e-MU final state via R-parity-violating interactions. The results are the most restrictive to date on this model, with the most stringent limit being obtained for a top squark lifetime corresponding to ctau=2 cm, excluding masses below 790 GeV at 95% confidence level. PMID- 25723322 TI - Ebulin from dwarf elder (Sambucus ebulus L.): a mini-review. AB - Sambucus ebulus L. (dwarf elder) is a medicinal plant, the usefulness of which also as food is restricted due to its toxicity. In the last few years, both the chemistry and pharmacology of Sambucus ebulus L. have been investigated. Among the structural and functional proteins present in the plant, sugar-binding proteins (lectins) with or without anti-ribosomal activity and single chain ribosome-inactivating proteins (RIPs) have been isolated. RIPs are enzymes (E.C. 3.2.2.22) that display N-glycosidase activity on the 28S rRNA subunit, leading to the inhibition of protein synthesis by arresting the step of polypeptide chain elongation. The biological role of all these proteins is as yet unknown. The evidence suggests that they could be involved in the defense of the plant against predators and viruses or/and a nitrogen store, with an impact on the nutritional characteristics and food safety. In this mini-review we describe all the isoforms of ebulin that have to date been isolated from dwarf elder, as well as their functional characteristics and potential uses, whilst highlighting concern regarding ebulin toxicity. PMID- 25723321 TI - Structures of eukaryotic ribosomal stalk proteins and its complex with trichosanthin, and their implications in recruiting ribosome-inactivating proteins to the ribosomes. AB - Ribosome-inactivating proteins (RIP) are RNA N-glycosidases that inactivate ribosomes by specifically depurinating a conserved adenine residue at the alpha sarcin/ricin loop of 28S rRNA. Recent studies have pointed to the involvement of the C-terminal domain of the eukaryotic stalk proteins in facilitating the toxic action of RIPs. This review highlights how structural studies of eukaryotic stalk proteins provide insights into the recruitment of RIPs to the ribosomes. Since the C-terminal domain of eukaryotic stalk proteins is involved in specific recognition of elongation factors and some eukaryote-specific RIPs (e.g., trichosanthin and ricin), we postulate that these RIPs may have evolved to hijack the translation-factor-recruiting function of ribosomal stalk in reaching their target site of rRNA. PMID- 25723326 TI - [Drug delivery strategies for targeted treatment of inflammatory bowel disease]. AB - Inflammatory bowel disease (IBD) is a frequently occurring disease in young people, which is characterized by chronic inflammation of the gastrointestinal tract. The therapy of IBD is dominated by the administration of anti-inflammatory and immunosuppressive agents, which suppress the intestinal inflammatory burden and improve the disease-related symptoms. Present treatment strategies are characterized by a limited therapeutical efficacy and the occurrence of adverse drug reactions. The development of novel disease-targeted drug delivery strategies is preferable for a more effective therapy and thus demonstrates the potential to address unmet medical needs. This review gives an overview about drug delivery strategies for the treatment of IBD. Therefore, established intestine-targeting strategies for a selective drug release into the diseased part of the gastrointestinal tract will be presented, including prodrugs, and dosage forms with pH-/time-dependent drug release. Furthermore future-oriented disease-targeting strategies for a selective drug release into the intestinal inflammation will be described, including micro-/nanosized synthetic and biologic drug carriers. This novel therapeutic approach may enable a more effective anti inflammatory treatment of IBD with reduced risks of adverse reactions. PMID- 25723323 TI - Biology, genetics, and management of ergot (Claviceps spp.) in rye, sorghum, and pearl millet. AB - Ergot is a disease of cereals and grasses caused by fungi in the genus Claviceps. Of particular concern are Claviceps purpurea in temperate regions, C. africana in sorghum (worldwide), and C. fusiformis in pearl millet (Africa, Asia). The fungi infect young, usually unfertilized ovaries, replacing the seeds by dark mycelial masses known as sclerotia. The percentage of sclerotia in marketable grain is strictly regulated in many countries. In winter rye, ergot has been known in Europe since the early Middle Ages. The alkaloids produced by the fungus severely affect the health of humans and warm-blooded animals. In sorghum and pearl millet, ergot became a problem when growers adopted hybrid technology, which increased host susceptibility. Plant traits reducing ergot infection include immediate pollination of receptive stigmas, closed flowering (cleistogamy), and physiological resistance. Genetic, nonpollen-mediated variation in ergot susceptibility could be demonstrated in all three affected cereals. Fungicides have limited efficacy and application is weather dependent. Sorting out the sclerotia from the harvest by photocells is expensive and time consuming. In conclusion, molecular-based hybrid rye breeding could improve pollen fertility by introgressing effective restorer genes thus bringing down the ergot infection level to that of conventional population cultivars. A further reduction might be feasible in the future by selecting more resistant germplasm. PMID- 25723327 TI - Whatever happened to adverbs? PMID- 25723325 TI - Preliminary estimation of deoxynivalenol excretion through a 24 h pilot study. AB - A duplicate diet study was designed to explore the occurrence of 15 Fusarium mycotoxins in the 24 h-diet consumed by one volunteer as well as the levels of mycotoxins in his 24 h-collected urine. The employed methodology involved solvent extraction at high ionic strength followed by dispersive solid phase extraction and gas chromatography determination coupled to mass spectrometry in tandem. Satisfactory results in method performance were achieved. The method's accuracy was in a range of 68%-108%, with intra-day relative standard deviation and inter day relative standard deviation lower than 12% and 15%, respectively. The limits of quantitation ranged from 0.1 to 8 ug/Kg. The matrix effect was evaluated and matrix-matched calibrations were used for quantitation. Only deoxynivalenol (DON) was quantified in both food and urine samples. A total DON daily intake amounted to 49.2 +/- 5.6 ug whereas DON daily excretion of 35.2 +/- 4.3 ug was determined. DON daily intake represented 68.3% of the established DON provisional maximum tolerable daily intake (PMTDI). Valuable preliminary information was obtained as regards DON excretion and needs to be confirmed in large-scale monitoring studies. PMID- 25723328 TI - What is your hospitality quotient? AB - In addition to the behind-the-scenes work involved with planning and implementing continuing nursing education activities, there are additional ways we can enhance the learner's experience. This article presents ideas on how to improve your hospitality quotient. PMID- 25723324 TI - Centipede venom: recent discoveries and current state of knowledge. AB - Centipedes are among the oldest extant venomous predators on the planet. Armed with a pair of modified, venom-bearing limbs, they are an important group of predatory arthropods and are infamous for their ability to deliver painful stings. Despite this, very little is known about centipede venom and its composition. Advances in analytical tools, however, have recently provided the first detailed insights into the composition and evolution of centipede venoms. This has revealed that centipede venom proteins are highly diverse, with 61 phylogenetically distinct venom protein and peptide families. A number of these have been convergently recruited into the venoms of other animals, providing valuable information on potential underlying causes of the occasionally serious complications arising from human centipede envenomations. However, the majority of venom protein and peptide families bear no resemblance to any characterised protein or peptide family, highlighting the novelty of centipede venoms. This review highlights recent discoveries and summarises the current state of knowledge on the fascinating venom system of centipedes. PMID- 25723329 TI - Using the gugging swallowing screen (GUSS) for dysphagia screening in acute stroke patients. AB - Aspiration pneumonia from dysphagia following stroke presents significant morbidity and mortality in that population. Dysphagia screening before oral intake has been a standard of care for years, but there is a lack of consensus on the best screening tool. The Gugging Swallowing Screen (GUSS) is presented as a potentially better alternative to other dysphagia screens due to its safer progression of oral intake, more thorough evaluation of swallowing, and ability to enable earlier nutrition. PMID- 25723330 TI - Teasing leadership development out of clinical scenarios. AB - Staff development professionals increasingly use clinical simulation, case studies, and nonsimulated, real-time clinical performance for strengthening clinical judgment and corresponding action when training clinicians. Leadership competencies can also be strengthened and reinforced during these educational opportunities. Through debriefing and peer evaluation, clinical scenarios are rich with leadership development opportunities. PMID- 25723331 TI - Culturally and linguistically responsive teaching: part II. AB - This part II of a two-part article about culturally and linguistically responsive teaching provides suggestions for evaluating learners who are culturally and linguistically diverse (CALD) and are often under-represented in nursing education settings. PMID- 25723332 TI - Preparing staff to care for veterans in a way they need and deserve. AB - More than 2.5 million military veterans have been deployed for service in Iraq and/or Afghanistan, whereas another 20 million veterans currently reside in the United States. For various reasons, increasing numbers of military and associated personnel from various wars could go to civilian population-based care facilities for their rest-of-life health care. Therefore, educational activities are important to prepare nursing staff for the culturally sensitive care that veterans, their dependents, and civilian contractor personnel need. This article (a) provides rationale for veterans' admissions, (b) summarizes some common health situations that veterans are likely to encounter, (c) stresses major educational goals, and (d) emphasizes the use of the universal assessment question: Have you ever served in the military? Several educational implications and challenges are discussed, including war zone physiology, reintegration, military culture and pride, ethical challenges, educational speakers, simulation, veteran individuality, and compassion fatigue. Available resources to accompany this content are provided. PMID- 25723333 TI - The lived experience of new graduate nurses working in an acute care setting. AB - The high attrition rate of graduate nurses will exacerbate the current nursing shortage as Baby Boomer nurses (born between 1946 and 1964) retire, negatively affecting the quality of patient care and increasing employer costs. The purpose of this phenomenological study was to explore the lived experiences of new graduate nurses employed in an acute care setting in southwest Florida. This information provides further guidance to nurse educators as they develop curricula, support graduate nurses to transition into professional practice, and create strategies to increase retention. Ten participants who were traditional students in generic baccalaureate nursing programs, selected through purposeful and snowball sampling, were interviewed via open-ended questions. Using Colaizzi's classic phenomenological method of data analysis and NVivo 10 software, three over-arching themes emerged-knowledge, skills, and environment which were interpreted in relation to graduates' lived experience. Recommendations include implementation of innovative initiatives that address new graduates' experience and increase retention. PMID- 25723334 TI - Educating nurses to provide culturally competent care during disasters. AB - Health disparities are exacerbated during times of disasters. To decrease health disparities, it is essential that health care providers understand the specific needs, culture, and norms of individuals, groups, and populations in a disaster. Survivors respond and recover from disaster events within the context of their culture and beliefs; therefore, implementing cultural competent interventions for disaster victims is central to providing services and care. This article describes the development, implementation, and evaluation of a continuing education program and academic courses for nurses and nursing students. PMID- 25723335 TI - Bridger: a new framework for de novo transcriptome assembly using RNA-seq data. AB - We present a new de novo transcriptome assembler, Bridger, which takes advantage of techniques employed in Cufflinks to overcome limitations of the existing de novo assemblers. When tested on dog, human, and mouse RNA-seq data, Bridger assembled more full-length reference transcripts while reporting considerably fewer candidate transcripts, hence greatly reducing false positive transcripts in comparison with the state-of-the-art assemblers. It runs substantially faster and requires much less memory space than most assemblers. More interestingly, Bridger reaches a comparable level of sensitivity and accuracy with Cufflinks. Bridger is available at https://sourceforge.net/projects/rnaseqassembly/files/?source=navbar. PMID- 25723336 TI - Paraoxonase-3 is depleted from the high-density lipoproteins of autoimmune disease patients with subclinical atherosclerosis. AB - Patients with autoimmune diseases have a significantly increased risk of developing cardiovascular disease. In disease, high-density lipoprotein (HDL) particles lose their anti-inflammatory and antioxidant properties and become dysfunctional. The purpose of this study was to test the hypothesis that alterations in the HDL proteomic profile are associated with subclinical atherosclerosis and HDL dysfunction in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes. Targeted proteomics was used to quantify the relative abundance of 18 proteins in HDL from SLE patients with and without atherosclerotic plaque detectable by carotid ultrasound. Changes in the proteomic profile were compared against the in vitro ability of HDL to protect against lipid oxidation. The same proteins were quantified in HDL from patients with type 1 diabetes with or without coronary artery calcification as determined by computed tomography. In each population, paraoxonase-3 (PON3), a potent antioxidant protein, was depleted from the HDL of patients with subclinical atherosclerosis. PON3 expression in HDL was positively correlated with HDL antioxidant function. These results suggest that PON3 may be an important protein in preventing atherosclerosis and highlight the importance of antioxidant proteins in the prevention of atherosclerosis in vivo. PMID- 25723337 TI - Interaction of oil drops with surfaces of different interfacial energy and topography. AB - During a marine oil spill, the oil can interact with and potentially wet a variety of surfaces such as corals, skin/shells of marine animals, and bird feathers. We present both qualitative and quantitative data for the interaction of a dodecane droplet submerged in water with surfaces varying in both surface energy and roughness. Flat, unstructured silicon surfaces with water in air contact angles of 0 degrees , 43 degrees , 66 degrees , 87 degrees , 96 degrees , and 108 degrees were tested first to obtain base readings, after which photolithography was used to introduce structured surfaces representative of marine biological systems. We find that the more hydrophilic a surface, the less prone it is to oil contamination. Also, the Cassie-Baxter approximation holds up for submerged oil in water systems and can be used to predict contact angles of oil on solid rough surfaces submerged in an aqueous environment. Furthermore, the addition of surface structure, even on strongly hydrophobic (oleophilic) surfaces, greatly reduced (~75% reduction in F(adhesion)) a surface's affinity for oil. PMID- 25723338 TI - The opportunities and challenges of multi-site evaluations: lessons from the jail diversion and trauma recovery national cross-site evaluation. AB - Multi-site evaluations, particularly of federally funded service programs, pose a special set of challenges for program evaluation. Not only are there contextual differences related to project location, there are often relatively few programmatic requirements, which results in variations in program models, target populations and services. The Jail Diversion and Trauma Recovery-Priority to Veterans (JDTR) National Cross-Site Evaluation was tasked with conducting a multi site evaluation of thirteen grantee programs that varied along multiple domains. This article describes the use of a mixed methods evaluation design to understand the jail diversion programs and client outcomes for veterans with trauma, mental health and/or substance use problems. We discuss the challenges encountered in evaluating diverse programs, the benefits of the evaluation in the face of these challenges, and offer lessons learned for other evaluators undertaking this type of evaluation. PMID- 25723339 TI - Influence of a compost layer on the attenuation of 28 selected organic micropollutants under realistic soil aquifer treatment conditions: insights from a large scale column experiment. AB - Soil aquifer treatment is widely applied to improve the quality of treated wastewater in its reuse as alternative source of water. To gain a deeper understanding of the fate of thereby introduced organic micropollutants, the attenuation of 28 compounds was investigated in column experiments using two large scale column systems in duplicate. The influence of increasing proportions of solid organic matter (0.04% vs. 0.17%) and decreasing redox potentials (denitrification vs. iron reduction) was studied by introducing a layer of compost. Secondary effluent from a wastewater treatment plant was used as water matrix for simulating soil aquifer treatment. For neutral and anionic compounds, sorption generally increases with the compound hydrophobicity and the solid organic matter in the column system. Organic cations showed the highest attenuation. Among them, breakthroughs were only registered for the cationic beta blockers atenolol and metoprolol. An enhanced degradation in the columns with organic infiltration layer was observed for the majority of the compounds, suggesting an improved degradation for higher levels of biodegradable dissolved organic carbon. Solely the degradation of sulfamethoxazole could clearly be attributed to redox effects (when reaching iron reducing conditions). The study provides valuable insights into the attenuation potential for a wide spectrum of organic micropollutants under realistic soil aquifer treatment conditions. Furthermore, the introduction of the compost layer generally showed positive effects on the removal of compounds preferentially degraded under reducing conditions and also increases the residence times in the soil aquifer treatment system via sorption. PMID- 25723340 TI - On the validity of travel-time based nonlinear bioreactive transport models in steady-state flow. AB - Travel-time based models simplify the description of reactive transport by replacing the spatial coordinates with the groundwater travel time, posing a quasi one-dimensional (1-D) problem and potentially rendering the determination of multidimensional parameter fields unnecessary. While the approach is exact for strictly advective transport in steady-state flow if the reactive properties of the porous medium are uniform, its validity is unclear when local-scale mixing affects the reactive behavior. We compare a two-dimensional (2-D), spatially explicit, bioreactive, advective-dispersive transport model, considered as "virtual truth", with three 1-D travel-time based models which differ in the conceptualization of longitudinal dispersion: (i) neglecting dispersive mixing altogether, (ii) introducing a local-scale longitudinal dispersivity constant in time and space, and (iii) using an effective longitudinal dispersivity that increases linearly with distance. The reactive system considers biodegradation of dissolved organic carbon, which is introduced into a hydraulically heterogeneous domain together with oxygen and nitrate. Aerobic and denitrifying bacteria use the energy of the microbial transformations for growth. We analyze six scenarios differing in the variance of log-hydraulic conductivity and in the inflow boundary conditions (constant versus time-varying concentration). The concentrations of the 1-D models are mapped to the 2-D domain by means of the kinematic (for case i), and mean groundwater age (for cases ii & iii), respectively. The comparison between concentrations of the "virtual truth" and the 1-D approaches indicates extremely good agreement when using an effective, linearly increasing longitudinal dispersivity in the majority of the scenarios, while the other two 1-D approaches reproduce at least the concentration tendencies well. At late times, all 1-D models give valid approximations of two dimensional transport. We conclude that the conceptualization of nonlinear bioreactive transport in complex multidimensional domains by quasi 1-D travel time models is valid for steady-state flow fields if the reactants are introduced over a wide cross-section, flow is at quasi steady state, and dispersive mixing is adequately parametrized. PMID- 25723341 TI - Dissection of respiration and photosynthesis in the cyanobacterium Synechocystis sp. PCC6803 by the analysis of chlorophyll fluorescence. AB - In cyanobacteria, photosynthesis and respiration share some components of electron transport chain. To explore the interaction between photosynthesis and respiration, we monitored the change in the yield of chlorophyll fluorescence due to state transition in ndh genes disruptants, deficient in NAD(P)H dehydrogenase (NDH-1) complexes serving for respiration or for carbon concentrating mechanism (CCM). The disruption of ndh genes essential for respiration resulted in low levels of chlorophyll fluorescence quenching in the dark (NPQDark) as well as in the low light (NPQLL). The lowered NPQDark and NPQLL in these ndh genes disruptants could be ascribed to the oxidation of the PQ pool due to the poor electron supply from NDH-1 complexes in respiratory electron transport. On the other hand, only NPQLL decreased upon disruption of the ndh genes essential for CCM. We propose that, in the disruptants of these ndh genes, the PQ pool is oxidized in the light through the increased photosystem I content, resulting in the lowered NPQLL. Apparently, the two different subsets of ndh genes affect photosynthetic electron transport although in totally different manners. It is also suggested that monitoring state transition is a simple method to evaluate the condition of photosynthesis, respiration and CCM. PMID- 25723342 TI - Characterization of green synthesized nano-formulation (ZnO-A. vera) and their antibacterial activity against pathogens. AB - The application of nanotechnology in medicine has recently been a breakthrough in therapeutic drugs formulation. This paper presents the structural and optical characterization of a new green nano-formulation (ZnO-Aloe vera) with considerable antibacterial activity against pathogenic bacteria. Its particle structure, size and morphology were characterized by XRD, TEM and SEM. And optical absorption spectra and photoluminescence were measured synchronously. Their antibacterial activity against Escherichia coli and Staphylococcus aureus was also investigated using thermokinetic profiling and agar well diffusion method. The nano-formulation is spherical shape and hexagonal with a particle size ranging from 25 to 65 nm as well as an increased crystallite size of 49 nm. For antibacterial activity, the maximum inhibition zones of ZnO and ZnO+A. vera are 18.33 and 26.45 mm for E. coli, 22.11 and 28.12 mm for S. aureus (p<0.05). Considering Pmax, Qt and k, ZnO+A. vera nano-formulation has a significant (p < 0.05) antibacterial effect against S. aureus almost at all concentration and against E. coli at 15 and 25mg/L. ZnO+A. vera nano-formulation is much more toxic against S. aureus than E. coli, with an IC50 of 13.12 mg/L and 21.31 mg/L, respectively. The overall results reveal that the ZnO-A. vera nano-formulation has good surface energy, crystallinity, transmission, and enriched antibacterial activities. Their antibacterial properties are possibly relevant to particle size, microstructural ionization, the crystal formation and the Gram property of pathogens. This ZnO-A. vera nano-formulation could be utilized effectively as a spectral and significant antibacterial agent for pathogens in future medical and environmental concerns. PMID- 25723343 TI - Colour changes in Labeo rohita (Ham.) due to pigment translocation in melanophores, on exposure to municipal wastewater of Tung Dhab drain, Amritsar, India. AB - The present study was aimed to evaluate the effect of municipal wastewater of Tung Dhab drain on morphology of scale melanophores in freshwater fish Labeo rohita (Ham.). Chronic, non-renewal toxicity tests were performed with sub lethal concentrations (17.7, 26.6 and 35.4%) of wastewater for exposure durations of 15, 30 and 60 days. Recovery experiments were also performed for duration of 60 days. The scales were removed, processed and diameters of melanophores were measured using an ocular micrometer. The results showed concentration and duration dependent changes in melanophore morphology (size and dendricity) in experimental fish as compared to control fish. The values of mean melanophore size index (MMSI) varied from 5.37 +/- 0.49 (17.7%) to 12.12 +/- 0.81 (35.5%) in comparison to control values of 4.32 +/- 0.32 and 4.55 +/- 0.29 for 15 and 60 days respectively. The recovery experiments suggested that observed dark colouration due to pigment translocation is reversible, even after chronic exposure for 60 days. PMID- 25723344 TI - Nano-anisotropic surface coating based on drug immobilized pendant polymer to suppress macrophage adhesion response. AB - Exploring drug molecules for material design, to harness concepts of nano anisotropy and ligand-receptor interactions, are rather elusive. The aim of this study is to demonstrate the bottom-up design of a single-step and bio-interactive polymeric surface coating, based on drug based pendant polymer. This can be applied on to polystyrene (PS) substrates, to suppress macrophage adhesion and spreading. The drug molecule is used in this coating for two purposes. The first one is drug as a "pendant" group, to produce nano-anisotropic properties that can enable adhesion of the coatings to the substrate. The second purpose is to use the drug as a "ligand", to produce ligand-receptor interaction, between the bound ligand and receptors of albumin, to develop a self-albumin coat over the surface, by the preferential binding of albumin in biological environment, to reduce macrophage adhesion. Our in silico studies show that, diclofenac (DIC) is an ideal drug based "ligand" for albumin. This can also act as a "pendant" group with planar aryl groups. The combination of these two factors can help to harness, both nano-anisotropic properties and biological functions to the polymeric coating. Further, the drug, diclofenac (DIC) is immobilized to the polyvinyl alcohol (PVA), to develop the pendant polymer (PVA-DIC). The interaction of bound DIC with the albumin is a ligand-receptor based interaction, as per the studies by circular dichroism, differential scanning calorimetry, and SDS-PAGE. The non-polar pi-pi* interactions are regulating; the interactions between PVA bound DIC-DIC interactions, leading to "nano-anisotropic condensation" to form distinct "nano-anisotropic segments" inside the polymeric coating. This is evident from, the thermo-responsiveness and uniform size of nanoparticles, as well as regular roughness in the surface coating, with similar properties as that of nanoparticles. In addition, the hydrophobic DIC-polystyrene (PS) interactions, between the PVA-DIC coating and PS-substrate produce improved coating stability. Subsequently, the PVA-DIC coated substrate has the maximum capacity to suppress the macrophage (RAW 264.7 cell line) adhesion and spreading, which is partly due to wavy-surface topography of hydrophilic PVA and preferential albumin binding capacity of PVA bound DIC. Our result shows that, such surfaces suppress the macrophages, even under stimulation with lipopolysaccharide (LPS). The modified tissue culture plates can be used as an in vitro tool, to study the macrophage response under low spatial cues. PMID- 25723345 TI - Synthesis and antimicrobial activity of monodisperse copper nanoparticles. AB - Metallic monodisperse copper nanoparticles at a relatively high concentration (300 ppm CuNPs) have been synthesized by the reduction of copper salt with hydrazine in the aqueous SDS solution. The average particles size and the distribution size were characterized by Dynamic Light Scattering (DLS), Nanosight Nanoparticle Tracking Analysis (NTA). The morphology and structure of nanoparticles were investigated using Scanning Electron Microscopy (SEM). The chemical composition of the copper nanoparticles was determined by X-ray Photoelectron Spectroscopy (XPS). Monodisperse copper nanoparticles with average diameter 50 nm were received. UV/vis absorption spectra confirmed the formation of the nanoparticles with the characteristic peak 550 nm. The antimicrobial studies showed that the copper nanoparticles had high activity against Gram positive bacteria, standard and clinical strains, including methicillin-resistant Staphylococcus aureus, comparable to silver nanoparticles and some antibiotics. They also exhibited antifungal activity against Candida species. PMID- 25723346 TI - Research on possible medical use of silk produced by caddisfly larvae of Hydropsyche angustipennis (Trichoptera, Insecta). AB - Silk products are used in medicine as biomaterials, and are particularly promising as scaffolds in tissue engineering. To date only silkworm and spider silk medical potential has been evaluated, whereas the possible application of the material spun by caddisflies in wet environment has not been examined. Biomedical application of every natural material requires biocompatibility testing and evaluation of unique microbiological and mechanical properties. This article focuses on silk fibers formed in caddisflies cocoons of Hydropsyche angustipennis (Insecta, Trichoptera) larvae. Preliminary biological evaluation shows that trichopteran silk is not cytotoxic to human cells. Caddisfly silk itself does not possess antiseptic properties and thus sterilization is indispensable for its application in medicine. Among tested methods of sterilization and disinfection only thermal methods (tyndallization and autoclaving) enabled complete eradication of bacteria and gave fully sterile material. Caddisfly silk appeared to be resistant to high temperature. Fully sterile fibers can be stored without a loss of breaking force and tensile strength. Our work shows that trichopteran silk has a significant potential to be used as a biomaterial. PMID- 25723347 TI - Non-linear effects in quantitative 2D NMR of polysaccharides: pitfalls and how to avoid them. AB - Quantitative 2D NMR is a powerful analytical tool which is widely used to determine the concentration of small molecules in complex samples. Due to the site-specific response of the 2D NMR signal, the determination of absolute concentrations requires the use of a calibration or standard addition approach, where the analyte acts as its own reference. Standard addition methods, where the targeted sample is gradually spiked with known amounts of the targeted analyte, are particularly well-suited for quantitative 2D NMR of small molecules. This paper explores the potential of such quantitative 2D NMR approaches for the quantitative analysis of a high molecular weight polysaccharide. The results highlight that the standard addition method leads to a strong under-estimation of the target concentration, whatever the 2D NMR pulse sequence. Diffusion measurements show that a change in the macromolecular organization of the studied polysaccharide is the most probable hypothesis to explain the non-linear evolution of the 2D NMR signal with concentration. In spite of this non-linearity -the detailed explanation of which is out of the scope of this paper--we demonstrate that accurate quantitative results can still be obtained provided that an external calibration is performed with a wide range of concentrations surrounding the target value. This study opens the way to a number of studies where 2D NMR is needed for the quantitative analysis of macromolecules. PMID- 25723348 TI - A systematic strategy for the identification and determination of pharmaceuticals in environment using advanced LC-MS tools: application to ground water samples. AB - In the present study, a novel analytical strategy was employed to study the occurrence of 40 drug residues belonging to different medicinal classes, e.g., antibiotics, beta blockers, NSAIDs, antidiabetics, proton pump inhibitors, H2 receptor antagonists, antihypertensives, antihyperlipidemics, etc. in ground water samples collected from villages adjoining to S.A.S. Nagar, Punjab, India. The drug residues were extracted from the samples using solid-phase extraction, and LC-ESI-HRMS and LC-ESI-MS/MS were used for identification and quantitation of the analytes. Initially, qualifier and quantifier MRM transitions were classified for 40 targeted drugs, followed by development of LC-MS methods for the separation of all the drugs, which were divided into three categories to curtail overlapping of peaks. Overall identification was done through matching of retention times and MRM transitions; matching of intensity ratio of qualifier to quantifier transitions; comparison of base peak MS/MS profiles; and evaluation of isotopic abundances (wherever applicable). Final confirmation was carried out through comparison of accurate masses obtained from HRMS studies for both standard and targeted analytes in the samples. The application of the strategy allowed removal of false positives and helped in identification and quantitation of diclofenac in the ground water samples of four villages, and pitavastatin in a sample of one village. PMID- 25723349 TI - Molecular modeling and identification of novel glucokinase activators through stepwise virtual screening. AB - The glucose phosphorylating enzyme glucokinase (GK) is a 50kD monomeric protein having 465 amino acids. It maintains glucose homeostasis inside cells, acts as a glucose sensor in pancreatic beta-cells and as a rate controlling enzyme for hepatic glucose clearance and glycogen synthesis. It has two binding sites, one for binding d-glucose and the other for a putative allosteric activator named glucokinase activator (GKA). The GKAs interact with the same region of the GK enzyme that is commonly affected by naturally occurring mutations in humans. However, many GKAs do not bind to GK in the absence of glucose. Recently, it has been reported that GKAs are highly effective in patients with type 2 diabetes mellitus. In this milieu a molecular modeling study has been carried out on three natural variants of GK that lie in the GKA binding site and are known to cause maturity onset diabetes of young (MODY). Additionally, a 10ns molecular dynamics simulation was done on each of the modeled variant in order to explore the flexibility of this site. Subsequently, a systematic virtual screening study was done to identify compounds which can bind with high affinity at GKA binding site of mutant GK. PMID- 25723350 TI - Human PD-1 binds differently to its human ligands: a comprehensive modeling study. AB - Programmed death-1 (PD-1) is a potent inhibitory receptor of T cells which binds to two different ligands, namely PD-L1 and PD-L2, and upon binding, it inhibits T cell activation, differentiation, and proliferation, leading to a state of immune tolerance. Blocking these interactions recently emerged as a 'game changer' approach in immunotherapy. Despite the significant therapeutic potential of targeting the PD-1 pathway, the interaction between human PD-1 and its two human ligands is not fully understood. Current crystal structures describe the interactions of mouse PD-1 with human PD-L1 or mouse PD-L2. However, recent mutational and nuclear magnetic resonance (NMR) analyses suggest that human PD-1 binds its human ligands differently compared to their mouse counterparts. No detailed model is currently available to consistently fit these data. The lack of these accurate structures constitutes a high barrier against rationally developing more effective and safer agents targeting these interactions. Here we describe for the first time two accurate models for human PD-1 bound to its two human ligands. Our methodology involved combining molecular dynamics (MD) simulations with protein-protein docking and binding energy analysis to predict the most probable binding conformations for PD1 to its ligands. Our results confirm the available experimental NMR and mutational data and reveal the most accurate atomistic details so far of how human PD-1 binds to human PD-Ls and why the two ligands bind with different affinities to the same receptor. PMID- 25723351 TI - Oxycodone for cancer-related pain. AB - BACKGROUND: Many patients with cancer experience moderate to severe pain that requires treatment with strong opioids, of which oxycodone and morphine are examples. Strong opioids are, however, not effective for pain in all patients, nor are they well-tolerated by all patients. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for patients with cancer pain. OBJECTIVES: To assess the effectiveness and tolerability of oxycodone for pain in adults with cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In-Process (Ovid), EMBASE (Ovid), Science Citation Index, Conference Proceedings Citation Index - Science (ISI Web of Science), BIOSIS (ISI), PsycINFO (Ovid) and PubMed to March 2014. We also searched Clinicaltrials.gov, metaRegister of Controlled Trials (mRCT), EU Clinical Trials Register and World Health Organization International Clinical Trials Registry Platform (ICTRP). We checked the bibliographic references of relevant identified studies and contacted the authors of the included studies to find additional trials not identified by the electronic searches. No language, date or publication status restrictions were applied to the search. SELECTION CRITERIA: We included randomised controlled trials (parallel-group or cross-over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults. DATA COLLECTION AND ANALYSIS: Two authors independently extracted study data (study design, participant details, interventions and outcomes) and independently assessed the quality of the included studies according to standard Cochrane methodology. Where possible, we meta-analysed the pain intensity data using the generic inverse variance method, otherwise these data were summarised narratively along with the adverse event and patient preference data. The overall quality of the evidence for each outcome was assessed according to the GRADE approach. MAIN RESULTS: We included 17 studies which enrolled/randomised 1390 patients with 1110 of these analysed for efficacy and 1170 for safety. The studies examined a number of different drug comparisons. Four studies compared controlled release (CR) oxycodone to immediate release (IR) oxycodone and pooled analysis of three of these studies showed that the effects of CR and IR oxycodone on pain intensity after treatment were similar (standardised mean difference (SMD) 0.1, 95% confidence interval (CI) -0.06 to 0.26; low quality evidence). This was in line with the finding that none of the included studies reported differences in pain intensity between the treatment groups. Three of the four studies also found similar results for treatment acceptability and adverse events in the IR and CR groups; but one study reported that, compared to IR oxycodone, CR oxycodone was associated with significantly fewer adverse events.Six studies compared CR oxycodone to CR morphine and pooled analysis of five of these studies indicated that pain intensity did not differ significantly between the treatments (SMD 0.14, 95% CI -0.04 to 0.32; low quality evidence). There were no marked differences in adverse event rates, treatment acceptability or quality of life ratings.The remaining seven studies either compared oxycodone in various formulations or compared oxycodone to different alternative opioids. None of them found any clear superiority or inferiority of oxycodone for cancer pain, neither as an analgesic agent nor in terms of adverse event rates and treatment acceptability.The quality of this evidence base was limited by the risk of bias of the studies and by small sample sizes for many outcomes. Random sequence generation and allocation concealment were under-reported, and the results were substantially compromised by attrition with data missing from more than 20% of the enrolled/randomised patients for efficacy and from more than 15% for safety. AUTHORS' CONCLUSIONS: Overall, the data included within this review suggest that oxycodone offers similar levels of pain relief and adverse events to other strong opioids including morphine, which is commonly considered the gold standard strong opioid. Our conclusions are consistent with other recent reviews and suggest that while the reliability of the evidence base is low, given the absence of important differences within this analysis it seems unlikely that larger head to head studies of oxycodone versus morphine will be justified. This means that for clinical purposes oxycodone or morphine can be used as first line oral opioids for relief of cancer pain. PMID- 25723352 TI - Magnetic resonance imaging study of a simian/human immunodeficiency virus infected Chinese rhesus macaque with HIV-associated dementia. PMID- 25723353 TI - Disseminated histoplasmosis with mucocutaneous immune reconstitution inflammatory syndrome in an HIV-infected patient. PMID- 25723354 TI - Thin Films Formed from Conjugated Polymers with Ionic, Water-Soluble Backbones. AB - This paper compares the morphologies of films of conjugated polymers in which the backbone (main chain) and pendant groups are varied between ionic/hydrophilic and aliphatic/hydrophobic. We observe that conjugated polymers in which the pendant groups and backbone are matched, either ionic-ionic or hydrophobic-hydrophobic, form smooth, structured, homogeneous films from water (ionic) or tetrahydrofuran (hydrophobic). Mismatched conjugated polymers, by contrast, form inhomogeneous films with rough topologies. The polymers with ionic backbone chains are conjugated polyions (conjugated polymers with closed-shell charges in the backbone), which are semiconducting materials with tunable bad-gaps, not unlike uncharged conjugated polymers. PMID- 25723355 TI - Toward bioderived intelligent nanocarriers for controlled pollutant recovery and pH-sensitive binding. AB - The pH-triggered formation of supramolecular complexes between the cationic biopolysaccharide chitosan and an environmentally friendly anionic surfactant is exploited for the formulation of selective and controlled-recovery systems. A strong advantage of this system is the very small pH range in which the binding/release process takes place. Because of this high pH responsiveness, chitosan-surfactant complexes are employed for the sequestration of various compounds by binding or releasing them from the complexes. In particular, the selective recovery of a model hydrophobic pollutant in the presence of a hydrophilic one is presented. The process is highly selective and effective, with more than 90% of the hydrophobic dye and ca. 10% of the hydrophilic dye recovered. Furthermore, the method can be extended to the selective recovery of metal ions, and in both cases, the original surfactant and chitosan mixture can be recovered, thereby rendering this an efficient and sustainable process. These showcase experiments depict quite different scenarios in which pH-responsive fully biodegradable polysaccharide-surfactant complexes can be employed and may substitute synthetic products in various fields, e.g., wastewater treatment, cosmetics, and agriculture, thereby yielding environmentally improved approaches. PMID- 25723356 TI - A randomized, double-blind, placebo-controlled trial to assess the bacterial anti adhesion effects of cranberry extract beverages. AB - In this study, we examined the ex vivo urinary anti-adhesion activity of low calorie cranberry extract beverages in both a pilot study (n = 10) and a randomized, double-blind, placebo controlled clinical trial (n = 59). In the pilot study, subjects consumed a cranberry extract beverage (CEB) or a cranberry extract and juice beverage (CEJB), compared to placebo. Both cranberry beverages utilized a standardized cranberry extract powder at a level equivalent to low calorie cranberry juice cocktail (LCJC) on a PAC content basis. Clean-catch urine samples collected at baseline and post intervention were tested for anti-adhesion activity utilizing a mannose-resistant human red blood cell hemagglutination assay specific for P-fimbriated E. coli. Results from the pilot study indicated that ex vivo anti-adhesion activity for both cranberry treatments were higher (p < 0.05) than placebo. In the clinical trial, we compared CEJB to LCJC and a placebo beverage. Post-consumption urine from both cranberry treatment groups showed significantly higher (p < 0.05) anti-adhesion activity compared to placebo. There were no differences observed in anti-adhesion activity between CJEB and LCJC, indicating similar bioactivity. Therefore, acute beverage consumption of cranberry extract and/or juice provides ex vivo anti-adhesion activity, which may help to improve urinary tract health. PMID- 25723357 TI - Correction: Black titanium dioxide (TiO2) nanomaterials. PMID- 25723358 TI - An artificial heme-enzyme with enhanced catalytic activity: evolution, functional screening and structural characterization. AB - Synthetic proteins represent useful tools for reproducing metalloprotein functions in minimal, well-defined scaffolds. Herein, we describe the rational refinement of function into heme-protein models from the Mimochrome family. Originally designed to mimic the bis-His cytochrome b, the Mimochrome structure was modified to introduce a peroxidase-like activity, by creating a distal cavity on the heme. The success with the first asymmetric system, Mimochrome VI (MC6), gave the opportunity to explore further modifications in order to improve the catalytic activity. Starting from ferric MC6, single amino acid substitutions were introduced in the peptide chains to obtain four compounds, which were screened for peroxidase activity. The detailed structural and functional analysis of the best analogue, Fe(III)-E(2)L(TD)-MC6, indicates that an arginine residue in proximity to the heme-distal site could assist with catalysis by favoring the formation of the intermediate "compound I", thus mimicking R(38) in HRP. This result highlights the potential of using small scaffolds for exploring the main factors that tune the heme-protein activity, and for programming new desired functions. PMID- 25723359 TI - Could a Transient Deficiency in Von Willebrand Factor Be a Cause of Gastrointestinal Angiodysplasia? PMID- 25723360 TI - A rare type of common arterial trunk with interrupted aortic arch, partial anomalous pulmonary venous connection, and phenylketonuria. AB - Common arterial trunk with arch obstruction is a rare conotruncal abnormality. We report, with confirmatory images, a neonate with this anomaly and additional supracardiac partial anomalous pulmonary venous connection, as well as phenylketonuria. PMID- 25723362 TI - Exoselective 1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2 acylcycloheptatrienes: stereoselectivity and mechanistic insight. AB - A highly exo-selective 1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2-acylcycloheptatrienes was realized with a Cu(I)/(S,R(p))-PPF-NHMe complex as the catalyst, leading to a diverse range of bridged piperidines with multiple functionalities in good yield with excellent stereoselectivity control. Theoretical calculations indicated a stepwise mechanism for this exo-selective [3 + 6] annulation, which accounts for the remarkable feature of this annulation: all of the larger substituent groups occupy the axial positions in the six membered chairlike conformation of the piperidine ring. PMID- 25723361 TI - Synthesis and properties of 2'-deoxy-2',4'-difluoroarabinose-modified nucleic acids. AB - We report the synthesis, thermal stability, and RNase H substrate activity of 2' deoxy-2',4'-difluoroarabino-modified nucleic acids. 2'-Deoxy-2',4' difluoroarabinouridine (2,'4'-diF-araU) was prepared in a stereoselective way in six steps from 2'-deoxy-2'-fluoroarabinouridine (2'-F-araU). NMR analysis and quantum mechanical calculations at the nucleoside level reveal that introduction of 4'-fluorine introduces a strong bias toward the North conformation, despite the presence of the 2'-betaF, which generally steers the sugar pucker toward the South/East conformation. Incorporation of the novel monomer into DNA results on a neutral to slightly stabilizing thermal effect on DNA-RNA hybrids. Insertion of 2',4'-diF-araU nucleotides in the DNA strand of a DNA-RNA hybrid decreases the rate of both human and HIV reverse transcriptase-associated RNase H-mediated cleavage of the complement RNA strand compared to that for an all-DNA strand or a DNA strand containing the corresponding 2'-F-araU nucleotide units, consistent with the notion that a 4'-fluorine in 2'-F-araU switches the preferred sugar conformation from DNA-like (South/East) to RNA-like (North). PMID- 25723363 TI - Functionalization of transition metal dichalcogenides with metallic nanoparticles: implications for doping and gas-sensing. AB - Transition metal dichalcogenides (TMDs), belonging to the class of two dimensional (2D) layered materials, have instigated a lot of interest in diverse application fields due to their unique electrical, mechanical, magnetic, and optical properties. Tuning the electrical properties of TMDs through charge transfer or doping is necessary for various optoelectronic applications. This paper presents the experimental investigation of the doping effect on TMDs, mainly focusing on molybdenum disulfide (MoS2), by metallic nanoparticles (NPs), exploring noble metals such as silver (Ag), palladium (Pd), and platinum (Pt) as well as the low workfunction metals such as scandium (Sc) and yttrium (Y) for the first time. The dependence of the doping behavior of MoS2 on the metal workfunction is demonstrated and it is shown that Pt nanoparticles can lead to as large as 137 V shift in threshold voltage of a back-gated monolayered MoS2 FET. Variation of the MoS2 FET transfer curves with the increase in the dose of NPs as well as the effect of the number of MoS2 layers on the doping characteristics are also discussed for the first time. Moreover, the doping effect on WSe2 is studied with the first demonstration of p-type doping using Pt NPs. Apart from doping, the use of metallic NP functionalized TMDs for gas sensing application is also demonstrated. PMID- 25723364 TI - Arabinogalactan biosynthesis: Implication of AtGALT29A enzyme activity regulated by phosphorylation and co-localized enzymes for nucleotide sugar metabolism in the compartments outside of the Golgi apparatus. AB - Arabinogalactan proteins are abundant cell surface proteoglycans in plants and are implicated to act as developmental markers during plant growth. We previously reported that AtGALT31A, AtGALT29A, and AtGLCAT14A-C, which are involved in the biosynthesis of arabinogalactan proteins, localize not only to the Golgi cisternae but also to smaller compartments, which may be a part of the unconventional protein secretory pathway in plants. In Poulsen et al., (1) we have demonstrated increased targeting of AtGALT29A to small compartments when Y144 is substituted with another amino acid, and we implicated a role for Y144 in the subcellular targeting of AtGALT29A. In this paper, we are presenting another aspect of Y144 substitution in AtGALT29A; namely, Y144A construct demonstrated a 2.5-fold increase while Y144E construct demonstrated a 2-fold decrease in the galactosyltransferase activity of AtGALT29A. Therefore, the electrostatic status of Y144, which is regulated by an unknown kinase/phosphatase system, may regulate AtGALT29A enzyme activity. Moreover, we have identified additional proteins, apyrase 3 (APY3; At1g14240) and UDP-glucuronate epimerases 1 and 6 (GAE1, At4g30440; GAE6, At3g23820), from Arabidopsis thaliana that co-localize with AtGALT31A in the small compartments when expressed transiently in Nicotiana benthamiana. These proteins may play roles in nucleotide sugar metabolism in the small compartments together with arabinogalactan glycosyltransferases. PMID- 25723365 TI - A Bridge to a Woman's Heart as the Cause of Recurrent Chest Pain: A Case on Myocardial Bridge. AB - Myocardial bridge is a congenital structural variant of the coronary arteries where a segment of the epicardial vessel is surrounded by the myocardium. It is an uncommon entity that may go unnoticed in patients with recurrent chest pain. We present a case on a 36-year-old woman with recurrent chest pain. Initial workup revealed normal routine laboratory test results, cardiac biomarkers, electrocardiogram, and an echocardiogram showing preserved ejection fraction with no valvulopathies. A dobutamine myocardial perfusion stress test was performed; this induced chest pain in the patient with electrocardiogram changes evident for 1-mm ST segment elevation in lead V5 and V6 consistent with myocardial ischemia. Perfusion imaging revealed a small fixed myocardial perfusion defect of the apical inferior wall. A cardiac catheterization revealed moderate-to-severe myocardial bridging involving the middle left anterior descending artery. Treatment with metoprolol and ranolazine resolved her symptoms. This case portrays the importance of recognizing myocardial bridge as the potential cause of recurrent chest pain and its ability to cause myocardial ischemia under stress. PMID- 25723366 TI - The acute oncology clinical nurse specialist. PMID- 25723367 TI - Improving the care of cancer patients: holistic needs assessment. AB - This discussion paper presents a review of holistic needs assessments (HNAs) in the care of patients with cancer. HNAs entail a structured review of patient needs as articulated by the patient. This discussion then leads to a care plan grounded in issues pertinent to that patient. Despite policy guidance advocating its use, there are barriers to overcome in order to integrate HNAs into routine care. This article discusses what role communication skills and clinician confidence may have on the use of HNAs in practice, and suggests a strategy to support HNAs becoming the norm. PMID- 25723368 TI - The role of a nurse specialist in a modern lung-cancer service. AB - The delivery of a modern cancer service is dependent on the nurse specialist occupying a central role in the overall pathway. However, there are significant variations in the access to a lung cancer clinical nurse specialist (CNS) across the UK and the USA. In the UK, the lung cancer CNS plays a pivotal role in the delivery of high-quality care and treatment to patients with (presumed) thoracic malignancy. They are in an ideal position to provide holistic care to patients with lung cancer-ensuring that all needs are addressed from the time of initial referral to commencement of definitive treatment or palliative care. In addition the role provides support and advice to people on the increasingly complex treatment options and on survivorship, and plays an essential role in end-of-life care. In the USA, the nurse navigator is a core member of the lung cancer screening programme. In this review the authors provide a transatlantic perspective on the history, current practice and potential future roles for the lung cancer CNS in the UK and nurse navigator in the US. PMID- 25723369 TI - The rise of biosimilars in cancer care. PMID- 25723370 TI - Key changes to cancer care in the UK. PMID- 25723371 TI - Legitimising fatigue after breast-cancer treatment. AB - This study aimed to explore the experience of women living with fatigue following chemotherapy for breast cancer. Six focus groups were conducted (n=40); all participants had taken part in a multi-site acupuncture trial. There were three to seven people per focus group. Additionally, two people attended one-to-one interviews and four people provided written responses to the trigger questions. The audiotapes from these sessions were transcribed and analysed using a thematic approach. Participants raised concerns about fatigue possibly being a symptom of the cancer coming back or a sign of senility. Respondents described the effects of fatigue on relationships, sexuality, social life, home life and returning to work. The Coping with Fatigue booklet ( Macmillan Cancer Support, 2011 ) was discussed in terms of legitimising the experience of cancer-related fatigue and explaining symptoms to family and work colleagues. More research work is required to evaluate non-pharmaceutical interventions and advice to support women living with fatigue after chemotherapy for breast cancer. PMID- 25723372 TI - Quantifying reactivity for electrophilic aromatic substitution reactions with Hirshfeld charge. AB - An electrophilic aromatic substitution is a process where one atom or group on an aromatic ring is replaced by an incoming electrophile. The reactivity and regioselectivity of this category of reactions is significantly impacted by the group that is already attached to the aromatic ring. Groups promoting substitution at the ortho/para and meta position are called ortho/para and meta directing groups, respectively. Earlier, we have shown that regioselectivity of the electrophilic aromatic substitution is dictated by the nucleophilicity of the substituted aromatic ring, which is proportional to the Hirshfeld charge on the regioselective site. Ortho/para directing groups have the largest negative charge values at the ortho/para positions, whereas meta directing groups often have the largest negative charge value at the meta position. The electron donation or acceptance feature of a substitution group is irrelevant to the regioselectivity. In this contribution, we extend our previous study by quantifying the reactivity for this kind of reactions. To that end, we examine the transition-state structure and activation energy of an identity reaction for a series of monosubstituted-benzene molecules reacting with hydrogen fluoride using BF3 as the catalyst in the gas phase. A total of 18 substitution groups will be considered, nine of which are ortho/para directing and the other nine groups meta directing. From this study, we found that the barrier height of these reactions strongly correlates with the Hirshfeld charge on the regioselective site for both ortho/para and meta directing groups, with the correlation coefficient R(2) both better than 0.96. We also discovered a less accurate correlation between the barrier height and HOMO energy. These results reconfirm the validity and effectiveness of employing the Hirshfeld charge as a reliable descriptor of both reactivity and regioselectivity for this vastly important category of chemical transformations. PMID- 25723373 TI - Methane as a resource: can the methanotrophs add value? AB - Methane is an abundant gas used in energy recovery systems, heating, and transport. Methanotrophs are bacteria capable of using methane as their sole carbon source. Although intensively researched, the myriad of potential biotechnological applications of methanotrophic bacteria has not been comprehensively discussed in a single review. Methanotrophs can generate single cell protein, biopolymers, components for nanotechnology applications (surface layers), soluble metabolites (methanol, formaldehyde, organic acids, and ectoine), lipids (biodiesel and health supplements), growth media, and vitamin B12 using methane as their carbon source. They may be genetically engineered to produce new compounds such as carotenoids or farnesene. Some enzymes (dehydrogenases, oxidase, and catalase) are valuable products with high conversion efficiencies and can generate methanol or sequester CO2 as formic acid ex vivo. Live cultures can be used for bioremediation, chemical transformation (propene to propylene oxide), wastewater denitrification, as components of biosensors, or possibly for directly generating electricity. This review demonstrates the potential for methanotrophs and their consortia to generate value while using methane as a carbon source. While there are notable challenges using a low solubility gas as a carbon source, the massive methane resource, and the potential cost savings while sequestering a greenhouse gas, keeps interest piqued in these unique bacteria. PMID- 25723374 TI - Paraoxonase and arylesterase activities in patients with papillary thyroid cancer. AB - OBJECTIVE: The aim of this study was to evaluate paraoxonase-1 (PON1) activities and oxidative stress status, and the changes in their levels after total thyroidectomy in patients with papillary thyroid cancer (PTC). MATERIALS AND METHODS: Twenty-five patients with PTC and 27 healthy controls were enrolled in the study. Blood samples were obtained from the PTC patients before and 3 months after the operation. Preoperative and postoperative serum samples from PTC patients and healthy controls were analyzed for paraoxonase (PON), arylesterase (ARE) activities, and lipid hydroperoxide (LOOH) and -SH (total free sulfhydryl) levels. RESULTS: The preoperative PON, ARE and -SH levels of the patients with PTC were significantly lower compared to those of the control group (p = 0.033, p < 0.001, p = 0.002, respectively), while LOOH levels were significantly higher (p < 0.001). The levels of PON and ARE decreased significantly in patients with PTC after the operation (p = 0.038, p = 0.023, respectively), while LOOH and -SH levels remained unchanged (p = 0.117, p = 0.487, respectively). PON and ARE levels showed a positive correlation with -SH (r = 0.211, p = 0.065; r = 0.471, p < 0.001, respectively) and a negative correlation with LOOH (r = - 0.391, p < 0.001, r = - 0.486, p < 0.001, respectively). CONCLUSION: Serum PON1 activity is decreased in patients with PTC, and serum PON1 is positively correlated with -SH, a well-known antioxidant, and negatively correlated with LOOH, an oxidant. PON1 activity is significantly decreased after total thyroidectomy. PMID- 25723375 TI - Michael-type cyclizations in lantibiotic biosynthesis are reversible. AB - Lanthipeptides are members of the ribosomally synthesized and post translationally modified peptides (RiPPs). They are generated in two biosynthetic steps: dehydration of Ser and Thr residues to the corresponding dehydroamino acids and subsequent conjugate addition by the thiol of Cys residues to generate the characteristic lanthionine and methyllanthionine thioether-bridged structures. Typically, a lanthipeptide contains multiple thioether cross-links. Recent studies have proposed that the final ring topology may be under thermodynamic control. If so, then the Michael-type cyclization reaction would need to be reversible, but such reversibility has never been demonstrated. We show here for the class I lanthipeptide cyclase NisC and class II lanthipeptide synthetase HalM2 that, indeed, the conjugate addition reactions are reversible and that the enzymes can open up all thioether rings in their products. We also propose that a His residue that is conserved among the lanthipeptide cyclases acts as the acid or base that protonates or generates the enolate intermediate during thioether ring formation and opening, respectively. PMID- 25723376 TI - Characterization of Hydroxymethylation Patterns in the Promoter of beta-globin Clusters in Murine Fetal Livers. AB - DNA methylation of 5-methylcytosine (5mC) is a key epigenetic regulator in mammals; the dynamic balance between methylation and demethylation affects the transcriptional activity of beta-globin. However, the dynamic cytosine methylation of beta-globin in vivo during the different stages of embryogenesis and in developing liver has not been fully established. 5-Hydroxymethylcytosine (5hmC) is a newly discovered epigenetic modification that is presumably generated by oxidation of 5mC by the ten-eleven translocation (TET) family and it has not been fully identified in beta-globin clusters. Here, we determined the 5hmC modifications in the promoter of murine beta-globin from fetal livers during normal embryonic development with the methods of bisulfite (BS) and oxidative bisulfite (oxBS)-based pyrosequencing techniques, with the combination of methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The results characterized the 5hmC modification at the CpG sites of -426, -388, and -151 of E(y) promoters and 50 and -487 CpG of beta(h1) from transcriptional start sites from E15.5 and E17.5 livers, while 5hmC modification was not observed in the adult beta-globin promoters. These observations were validated by the induction of TET transcription after being treated with a potent demethylating agent 5 azacytidine, and TET-mediated hydroxymethylation of E(y) and beta(h1) from E13.5 livers was also confirmed in our study. These results suggested the 5hmC modification in promoters of E(y) and beta(h1) and indicated that the 5hmC modification is essential for the beta-globin switching before the embryonic globin reactivation. PMID- 25723377 TI - Visfatin in obese children and adolescents and its association with insulin resistance and metabolic syndrome. AB - BACKGROUND: Visfatin, also known as nicotinamide phosphoribosyltransferase, is an adipokine that has been implicated in obesity, insulin resistance (IR) and diabetes mellitus. Since obesity profoundly affects serum lipids, insulin, and glucose metabolism, the aim of this study was to evaluate the relationships between visfatin and metabolic parameters in childhood obesity. METHODS: A total of 73 Iranian children and adolescents (31 controls; 42 obese), between the ages of 7 and 16 years, were selected and clinically evaluated. Serum visfatin, leptin, insulin and adiponectin were measured using ELISA, and insulin resistance was calculated by the Homeostasis Model of Assessment of Insulin Resistance (HOMA IR). Fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), LDL C and HDL-C were also measured. Metabolic syndrome (MetS) was determined according to IDF criteria. RESULTS: Obese subjects presented significantly higher levels of insulin, LDL-C, HOMA-IR, and leptin and lower levels of adiponectin. Serum Visfatin was higher in obese children than in the control children, and it was significantly higher in obese children with MetS or IR, compared with obese children without MetS or IR. Visfatin levels showed positive correlations with FPG, insulin, and HOMA-IR, in obese subjects and a negative correlation with adiponectin, but no correlation with leptin. Adiponectin levels were correlated with HDL-C and Insulin levels in obese subjects. Leptin levels were correlated with Body mass index (BMI) but not with metabolic parameters. CONCLUSIONS: Visfatin is increased in obese children and adolescents, and has a more prominent association with IR and MetS parameters, compared with leptin and adiponectin. PMID- 25723378 TI - Factors Associated with Failure of Non-invasive Positive Pressure Ventilation in a Critical Care Helicopter Emergency Medical Service. AB - INTRODUCTION: Non-invasive positive pressure ventilation (NIPPV) is used to treat severe acute respiratory distress. Prehospital NIPPV has been associated with a reduction in both in-hospital mortality and the need for invasive ventilation. HYPOTHESIS/PROBLEM: The authors of this study examined factors associated with NIPPV failure and evaluated the impact of NIPPV on scene times in a critical care helicopter Emergency Medical Service (HEMS). Non-invasive positive pressure ventilation failure was defined as the need for airway intervention or alternative means of ventilatory support. METHODS: A retrospective chart review of consecutive patients where NIPPV was completed in a critical care HEMS was conducted. Factors associated with NIPPV failure in univariate analyses and from published literature were included in a multivariable, logistic regression model. RESULTS: From a total of 44 patients, NIPPV failed in 14 (32%); a Glasgow Coma Scale (GCS)<15 at HEMS arrival was associated independently with NIPPV failure (adjusted odds ratio 13.9; 95% CI, 2.4-80.3; P=.003). Mean scene times were significantly longer in patients who failed NIPPV when compared with patients in whom NIPPV was successful (95 minutes vs 51 minutes; 39.4 minutes longer; 95% CI, 16.2-62.5; P=.001). CONCLUSION: Patients with a decreased level of consciousness were more likely to fail NIPPV. Furthermore, patients who failed NIPPV had significantly longer scene times. The benefits of NIPPV should be balanced against risks of long scene times by HEMS providers. Knowing risk factors of NIPPV failure could assist HEMS providers to make the safest decision for patients on whether to initiate NIPPV or proceed directly to endotracheal intubation prior to transport. PMID- 25723379 TI - Strategies for effective feedback. AB - Provision of regular feedback to trainees on clinical performance by supervising providers is increasingly recognized as an essential component of undergraduate and graduate health sciences education; however, many individuals have not been formally trained in this pedagogical skill. At the bedside or in the clinic, effective performance feedback can be accomplished by following four key steps. Begin by setting expectations that incorporate the trainee's personal goals and external objectives. Delineate how and when you will provide feedback to the learner. Next, directly observe the trainee's performance. This can be challenging while engaged on a busy clinical service, but a focus on discrete activities or interactions (e.g., family meeting, intravascular volume assessment using bedside ultrasound, or obtaining informed consent) is helpful. The third step is to plan and prioritize the feedback session. Feedback is most effective when given in a timely fashion and delivered in a safe environment. Limit the issues addressed because learners often disengage if confronted with too many deficiencies. Finally, when delivering feedback, begin by listening to the trainee's self-evaluation and then take a balanced approach. Describe in detail what the trainee does well and discuss opportunities for improvement with emphasis on specific, modifiable behaviors. The feedback loop is completed with a plan for follow-up reassessment. Through the use of these relatively simple practices, both the trainee and teacher can have a more productive learning experience. PMID- 25723380 TI - Predictors of Echinococcus multilocularis Prevalence in Definitive and Intermediate Hosts: A Meta-Analysis Approach. AB - Echinococcus multilocularis (EM) is a pathogenic and potentially fatal cestode causing human alveolar echinococcosis (AE). A meta-analysis was conducted using a generalized estimation equation approach (GEE) to assess the effect of taxonomic, environmental, and diagnostic variables on EM prevalence in different hosts. Red foxes ( Vulpes vulpes ) had significantly higher prevalence of EM than domestic dogs ( Canis lupus familiaris), with the diagnostic method playing an important factor in assessing prevalence. For intermediate hosts genera was significantly associated with EM prevalence, although there was some indication of publication bias in this dataset. This study also highlights the possible importance of temperature and precipitation to EM transmission. This implies the possibility of a changing climate affecting the future distribution of the parasite. PMID- 25723381 TI - High-voltage cathode materials for lithium-ion batteries: freeze-dried LiMn0.8Fe0.1M0.1PO4/C (M = Fe, Co, Ni, Cu) nanocomposites. AB - Four LiMn0.8Fe0.1M0.1PO4/C (M = Fe, Co, Ni, Cu) cathode materials have been synthesized via a freeze-drying method. The samples have been characterized by powder X-ray diffraction, transmission electron microscopy, magnetic susceptibility, and electrochemical measurements. The composition and effective insertion of the transition-metal substituents in LiMnPO4 have been corroborated by elemental analysis, the evolution of the crystallographic parameters, and the magnetic properties. The morphological characterization of the composites has demonstrated that the phosphate nanoparticles are enclosed in a matrix of amorphous carbon. Among them, LiMn0.8Fe0.1Ni0.1PO4/C is the most promising cathode material, providing a good electrochemical performance in all aspects: high voltage and specific capacity values, excellent cyclability, and good rate capability. This result has been attributed to several factors, such as the suitable morphology of the sample, the good connection afforded by the in situ generated carbon, and the amelioration of the structural stress provided by the presence of Ni(2+) and Fe(2+) in the olivine structure. PMID- 25723382 TI - Unstable sitting in the workplace--are there physical activity benefits? AB - The increasingly popular practice of using a stability ball (exercise/fitness ball) as a sitting surface runs counter to conventional human factors/ergonomics guidelines for seated workspace design. Employees sitting on stability balls in an office environment present safety risks that might be justifiable if the practice has a definitive benefit to the promotion of health. However, the published studies and best evidence to date call into question even the theoretical basis for this practice and do not suggest significant health benefits. First, biomechanical studies do not confirm the intended trunk muscle activation. Second, energy expenditure studies show a small (if any) increase in metabolic demand that is unlikely to be effective in combating sedentary work risk factors. Until studies demonstrate more conclusive benefits, the practice of stability ball sitting should be viewed skeptically as a general workplace recommendation in the interest of health or wellness. PMID- 25723385 TI - Editor's desk: The coaction issue. PMID- 25723386 TI - Standing up to bullies. PMID- 25723387 TI - Genomic and phylogenetic characterization of novel, recombinant H5N2 avian influenza virus strains isolated from vaccinated chickens with clinical symptoms in China. AB - Infection of poultry with diverse lineages of H5N2 avian influenza viruses has been documented for over three decades in different parts of the world, with limited outbreaks caused by this highly pathogenic avian influenza virus. In the present study, three avian H5N2 influenza viruses, A/chicken/Shijiazhuang/1209/2013, A/chicken/Chiping/0321/2014, and A/chicken/Laiwu/0313/2014, were isolated from chickens with clinical symptoms of avian influenza. Complete genomic and phylogenetic analyses demonstrated that all three isolates are novel recombinant viruses with hemagglutinin (HA) and matrix (M) genes derived from H5N1, and remaining genes derived from H9N2-like viruses. The HA cleavage motif in all three strains (PQIEGRRRKR/GL) is characteristic of a highly pathogenic avian influenza virus strain. These results indicate the occurrence of H5N2 recombination and highlight the importance of continued surveillance of the H5N2 subtype virus and reformulation of vaccine strains. PMID- 25723389 TI - A human platelet calcium calculator trained by pairwise agonist scanning. AB - Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID- 25723390 TI - Effect of dietary selenium yeast supplementation on porcine circovirus type 2 (PCV2) infections in mice. AB - The present study was performed to determine the protective role of dietary selenium (Se) yeast supplementation in porcine circovirus type 2 (PCV2) infected mice. Forty-eight Kun Ming female mice were randomly assigned to Se yeast group (0.3%Se +basal diet, n = 24) and control group (basal diet, n = 24). After 3 days of adaptive feeding and 15 days treatment with the experimental feed, mice were challenged by intraperitioneal injection of PCV2 at the dosage of 2000 TCID50 (50% tissue culture infection dose, TCID50). Serum total superoxide dismutase (SOD) activity, malondialdehyde (MDA) level, tumor necrosis factor alpha (TNF alpha), C-reactive protein (CRP) and interleukin-1 beta (IL-1beta) levels were measured at 5, 10, 15, 20 days post infection (dpi). The PCV2 virus load in the liver, spleen and lung, and the microscopic lesions in the liver, spleen and lung also were determined on 5, 10, 15, and 20 dpi. Dietary Se yeast supplementation decreased (PMU0.05) the serum levels of TNF-alpha, but had no significant effect on the activity of SOD and the levels of MDA, CRP and IL-1beta between experimental and control groups. Dietary Se yeast supplementation had little effect on the PCV2 virus load in the liver, spleen and lung. However, mice in the selenium yeast group showed a significant decrease in microscopic lesion scores in the lung and spleen compared with those in the control group (PMU0.05). These data indicate Se yeast attenuated the PCV2 infection through altering the systemic inflammation and maintaining the normal organ morphology. PMID- 25723391 TI - Daily and seasonal rhythms in immune responses of splenocytes in the freshwater snake, Natrix piscator. AB - Present study was designed to examine daily and seasonal variability in the innate immune responses of splenocytes in the fresh water snake, Natrix piscator. Animals were mildly anesthetized and spleen was aseptically isolated and processed for macrophage phagocytosis, NBT reduction, nitrite production, splenocyte proliferation and serum lysozyme activity. Samples were collected at seven time points, viz., 0000, 0400, 0800, 1200, 1600, 2000 and 0000 h during three different seasons, namely summer, winter and spring. Cosinor analysis revealed that percent phagocytosis had a significant 24-h rhythm during summer and spring seasons. The peaks of rhythms in NBT reduction and nitrite release occurred in the morning hours at 10.88 h and 8.31 h, respectively, in winter. A significant 24-h rhythm was also observed in lysozyme concentration and splenocyte proliferation (both Basal and Concanavalin A stimulated) in all three seasons. A significant phase shift in splenocyte proliferation was obtained with a trend of delayed phase shift from winter to spring and from spring to summer. Of the nine variables, significant annual (seasonal) rhythms were detected in almost all variables, excluding phagocytic and splenosomatic indices. All rhythmic variables, except spleen cellularity, exhibited tightly synchronized peaks coinciding with the progressive and recrudescence phases of annual reproductive cycle. It is concluded that the snake synchronizes its daily and seasonal immune activity with the corresponding external time cues. The enhancement of immune function coinciding with one of its crucial reproductive phases might be helping it to cope with the seasonal stressors, including abundance of pathogens, which would otherwise jeopardize the successful reproduction and eventual survival of the species. PMID- 25723392 TI - Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia inducible factor-1alpha and Notch1 in head neck squamous cell carcinoma. AB - Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC). The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab induced epidermal growth factor receptor (EGFR) inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1alpha (HIF-1alpha) was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO) mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1alpha and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1alpha and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1alpha and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch induced angiogenesis may benefit HNSCC therapy. PMID- 25723393 TI - Selection of reference genes for qPCR- and ddPCR-based analyses of gene expression in Senescing Barley leaves. AB - Leaf senescence is a tightly regulated developmental or stress-induced process. It is accompanied by dramatic changes in cell metabolism and structure, eventually leading to the disintegration of chloroplasts, the breakdown of leaf proteins, internucleosomal fragmentation of nuclear DNA and ultimately cell death. In light of the global and intense reorganization of the senescing leaf transcriptome, measuring time-course gene expression patterns in this model is challenging due to the evident problems associated with selecting stable reference genes. We have used oligonucleotide microarray data to identify 181 genes with stable expression in the course of dark-induced senescence of barley leaf. From those genes, we selected 5 candidates and confirmed their invariant expression by both reverse transcription quantitative PCR and droplet digital PCR (ddPCR). We used the selected reference genes to normalize the level of the expression of the following senescence-responsive genes in ddPCR assays: SAG12, ICL, AGXT, CS and RbcS. We were thereby able to achieve a substantial reduction in the data variability. Although the use of reference genes is not considered mandatory in ddPCR assays, our results show that it is advisable in special cases, specifically those that involve the following conditions: i) a low number of repeats, ii) the detection of low-fold changes in gene expression or iii) series data comparisons (such as time-course experiments) in which large sample variation greatly affects the overall gene expression profile and biological interpretation of the data. PMID- 25723394 TI - N6-adenosine methylation in MiRNAs. AB - Methylation of N6-adenosine (m6A) has been observed in many different classes of RNA, but its prevalence in microRNAs (miRNAs) has not yet been studied. Here we show that a knockdown of the m6A demethylase FTO affects the steady-state levels of several miRNAs. Moreover, RNA immunoprecipitation with an anti-m6A-antibody followed by RNA-seq revealed that a significant fraction of miRNAs contains m6A. By motif searches we have discovered consensus sequences discriminating between methylated and unmethylated miRNAs. The epigenetic modification of an epigenetic modifier as described here adds a new layer to the complexity of the posttranscriptional regulation of gene expression. PMID- 25723395 TI - Evaluation of methyl bromide alternatives efficacy against soil-borne pathogens, nematodes and soil microbial community. AB - Methyl bromide (MB) and other alternatives were evaluated for suppression of Fusarium spp., Phytophthora spp., and Meloidogyne spp. and their influence on soil microbial communities. Both Fusarium spp. and Phytophthora spp. were significantly reduced by the MB (30.74 mg kg-1), methyl iodide (MI: 45.58 mg kg 1), metham sodium (MS: 53.92 mg kg-1) treatments. MS exhibited comparable effectiveness to MB in controlling Meloidogyne spp. and total nematodes, followed by MI at the tested rate. By contrast, sulfuryl fluoride (SF: 33.04 mg kg-1) and chloroform (CF: 23.68 mg kg-1) showed low efficacy in controlling Fusarium spp., Phytophthora spp., and Meloidogyne spp. MB, MI and MS significantly lowered the abundance of different microbial populations and microbial biomass in soil, whereas SF and CF had limited influence on them compared with the control. Diversity indices in Biolog studies decreased in response to fumigation, but no significant difference was found among treatments in PLFA studies. Principal component and cluster analyses of Biolog and PLFA data sets revealed that MB and MI treatments greatly influenced the soil microbial community functional and structural diversity compared with SF treatment. These results suggest that fumigants with high effectiveness in suppressing soil-borne disease could significantly influence soil microbial community. PMID- 25723396 TI - Investigating the cellular distribution and interactions of HIV-1 nucleocapsid protein by quantitative fluorescence microscopy. AB - The nucleocapsid protein (NCp7) of the Human immunodeficiency virus type 1 (HIV 1) is a small basic protein containing two zinc fingers. About 2000 NCp7 molecules coat the genomic RNA in the HIV-1 virion. After infection of a target cell, the viral core enters into the cytoplasm, where NCp7 chaperones the reverse transcription of the genomic RNA into the proviral DNA. As a consequence of their much lower affinity for double-stranded DNA as compared to single-stranded RNAs, NCp7 molecules are thought to be released in the cytoplasm and the nucleus of infected cells in the late steps of reverse transcription. Yet, little is known on the cellular distribution of the released NCp7 molecules and on their possible interactions with cell components. Hence, the aim of this study was to identify potential cellular partners of NCp7 and to monitor its intracellular distribution and dynamics by means of confocal fluorescence microscopy, fluorescence lifetime imaging microscopy, fluorescence recovery after photobleaching, fluorescence correlation and cross-correlation spectroscopy, and raster imaging correlation spectroscopy. HeLa cells transfected with eGFP-labeled NCp7 were used as a model system. We found that NCp7-eGFP localizes mainly in the cytoplasm and the nucleoli, where it binds to cellular RNAs, and notably to ribosomal RNAs which are the most abundant. The binding of NCp7 to ribosomes was further substantiated by the intracellular co-diffusion of NCp7 with the ribosomal protein 26, a component of the large ribosomal subunit. Finally, gradient centrifugation experiments demonstrate a direct association of NCp7 with purified 80S ribosomes. Thus, our data suggest that NCp7 molecules released in newly infected cells may primarily bind to ribosomes, where they may exert a new potential role in HIV-1 infection. PMID- 25723397 TI - Association of blood lead levels with methylenetetrahydrofolate reductase polymorphisms among Chinese pregnant women in Wuhan city. AB - BACKGROUND: Pregnancy is an important stimulus of bone lead release. Elevated blood lead levels (BLLs) may cause adverse pregnancy outcomes for mothers and harmful lead effects on fetuses. However, the reports about maternal BLL changes during pregnancy are conflicting to some extent. This article is to explore the variations in BLLs among pregnant women. The relationships of BLLs with methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms, which are associated with bone resorption, were also studied. A total of 973 women, including 234, 249, and 248 women in their first, second, and third trimesters, respectively, and 242 non-pregnant women, were recruited at the Wuhan Women and Children Medical Health Center. METHODS: BLLs were determined using a graphite furnace atomic absorption spectrometer. Single-nucleotide polymorphisms of MTHFR were identified with the TaqMan probe method. RESULTS: The geometric mean (geometric standard deviation) of BLLs was 16.2 (1.78) MUg/L for all participants. All the studied MTHFR alleles were in Hardy-Weinberg equilibrium. Multiple-linear regression analysis revealed the following results. Among the pregnant women, those that carried MTHFR 677CC (i.e. wild-genotype homozygote) and 1298CC (i.e. mutant-genotype homozygote) exhibited higher BLLs than those that carried 677CT/TT (standardized beta = 0.074, P = 0.042) and 1298AC/AA (standardized beta = 0.077, P = 0.035) when other covariates (e.g., age, no. of children, education and income, etc.) were adjusted. The BLLs of pregnant women consistently decreased during the pregnancy and these levels positively correlated with BMI (standard beta = 0.086-0.096, P<0.05). CONCLUSIONS: The 1298CC mutant-type homozygote in the MTHFR gene is a risk factor for high BLLs among low-level environmental lead-exposed Chinese pregnant women, whose BLLs consistently decreased during gestation. PMID- 25723398 TI - De Novo assembly of the Japanese flounder (Paralichthys olivaceus) spleen transcriptome to identify putative genes involved in immunity. AB - BACKGROUND: Japanese flounder (Paralichthys olivaceus) is an economically important marine fish in Asia and has suffered from disease outbreaks caused by various pathogens, which requires more information for immune relevant genes on genome background. However, genomic and transcriptomic data for Japanese flounder remain scarce, which limits studies on the immune system of this species. In this study, we characterized the Japanese flounder spleen transcriptome using an Illumina paired-end sequencing platform to identify putative genes involved in immunity. METHODOLOGY/PRINCIPAL FINDINGS: A cDNA library from the spleen of P. olivaceus was constructed and randomly sequenced using an Illumina technique. The removal of low quality reads generated 12,196,968 trimmed reads, which assembled into 96,627 unigenes. A total of 21,391 unigenes (22.14%) were annotated in the NCBI Nr database, and only 1.1% of the BLASTx top-hits matched P. olivaceus protein sequences. Approximately 12,503 (58.45%) unigenes were categorized into three Gene Ontology groups, 19,547 (91.38%) were classified into 26 Cluster of Orthologous Groups, and 10,649 (49.78%) were assigned to six Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, 40,928 putative simple sequence repeats and 47, 362 putative single nucleotide polymorphisms were identified. Importantly, we identified 1,563 putative immune-associated unigenes that mapped to 15 immune signaling pathways. CONCLUSIONS/SIGNIFICANCE: The P. olivaceus transciptome data provides a rich source to discover and identify new genes, and the immune-relevant sequences identified here will facilitate our understanding of the mechanisms involved in the immune response. Furthermore, the plentiful potential SSRs and SNPs found in this study are important resources with respect to future development of a linkage map or marker assisted breeding programs for the flounder. PMID- 25723400 TI - Ultrahigh surface area zirconium MOFs and insights into the applicability of the BET theory. AB - An isoreticular series of metal-organic frameworks (MOFs) with the ftw topology based on zirconium oxoclusters and tetracarboxylate linkers with a planar core (NU-1101 through NU-1104) has been synthesized employing a linker expansion approach. In this series, NU-1103 has a pore volume of 2.91 cc g(-1) and a geometrically calculated surface area of 5646 m(2) g(-1), which is the highest value reported to date for a zirconium-based MOF and among the largest that have been reported for any porous material. Successful activation of the MOFs was proven based on the agreement of pore volumes and BET areas obtained from simulated and experimental isotherms. Critical for practical applications, NU 1103 combines for the first time ultrahigh surface area and water stability, where this material retained complete structural integrity after soaking in water. Pressure range selection for the BET calculations on these materials was guided by the four so-called "consistency criteria". The experimental BET area of NU-1103 was 6550 m(2) g(-1). Insights obtained from molecular simulation suggest that, as a consequence of pore-filling contamination, the BET method overestimates the monolayer loading of NU-1103 by ~16%. PMID- 25723399 TI - Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells. AB - Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance. PMID- 25723401 TI - Non-invasive tools for the diagnosis of potentially life-threatening gynaecological emergencies: a systematic review. AB - OBJECTIVE: To identify non-invasive tools for diagnosis of the major potentially life-threatening gynaecological emergencies (G-PLEs) reported in previous studies, and to assess their diagnostic accuracy. METHODS: MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library) were searched to identify all eligible studies published in English or French between January 1990 and December 2012. Studies were considered eligible if they were primary diagnostic studies of any designs, with a gold standard and with sufficient information for construction of a 2 * 2 contingency table, concerning at least one of the following G-PLEs: complicated ectopic pregnancy, complicated pelvic inflammatory disease, adnexal torsion and haemoperitoneum of any gynaecological origin. Extraction of data and assessment of study quality were conducted by two independent reviewers. We set the thresholds for the diagnostic value of signs retrieved at Sensibility >= 95% and LR-<= 0.25, or Specificity >= 90% and LR+ >= 4. RESULTS: We identified 8288 reports of diagnostic studies for the selected G-PLEs, 45 of which met the inclusion criteria. The methodological quality of the included studies was generally low. The most common diagnostic tools evaluated were transvaginal ultrasound (20/45), followed by medical history (18/45), clinical examination (15/45) and laboratory tests (14/45). Standardised questioning about symptoms, systolic blood pressure<110 mmHg, shock index>0.85, identification of a mass by abdominal palpation or vaginal examination, haemoglobin concentration <10 g/dl and six ultrasound and Doppler signs presented high performances for the diagnosis of G-PLEs. Transvaginal ultrasound was the diagnostic tool with the best individual performance for the diagnosis of all G PLEs. CONCLUSION: This systematic review suggests that blood pressure measurement, haemoglobin tests and transvaginal ultrasound are cornerstone examinations for the diagnosis of G-PLEs that should be available in all gynaecological emergency care services. Standardised questioning about symptoms could be used for triage of patients. PMID- 25723403 TI - Landscape of pi-pi and sugar-pi contacts in DNA-protein interactions. AB - There were 1765 contacts identified between DNA nucleobases or deoxyribose and cyclic (W, H, F, Y) or acyclic (R, E, D) amino acids in 672 X-ray structures of DNA-protein complexes. In this first study to compare pi-interactions between the cyclic and acyclic amino acids, visual inspection was used to categorize amino acid interactions as nucleobase pi-pi (according to biological edge) or deoxyribose sugar-pi (according to sugar edge). Overall, 54% of contacts are nucleobase pi-pi interactions, which involve all amino acids, but are more common for Y, F, and R, and involve all DNA nucleobases with similar frequencies. Among binding arrangements, cyclic amino acids prefer more planar (stacked) pi-systems than the acyclic counterparts. Although sugar-pi interactions were only previously identified with the cyclic amino acids and were found to be less common (38%) than nucleobase-cyclic amino acid contacts, sugar-pi interactions are more common than nucleobase pi-pi contacts for the acyclic series (61% of contacts). Similar to DNA-protein pi-pi interactions, sugar-pi contacts most frequently involve Y and R, although all amino acids adopt many binding orientations relative to deoxyribose. These DNA-protein pi-interactions stabilize biological systems, by up to approximately -40 kJ mol(-1) for neutral nucleobase or sugar-amino acid interactions, but up to approximately -95 kJ mol(-1) for positively or negatively charged contacts. The high frequency and strength, despite variation in structure and composition, of these pi-interactions point to an important function in biological systems. PMID- 25723402 TI - Preventive effect of Ligularia fischerion inhibition of nitric oxide in lipopolysaccharide-stimulated RAW 264.7 macrophages depending on cooking method. AB - BACKGROUND: Ligularia fischeri (common name Gomchwi) is known for its pharmaceutical properties and used in the treatment of jaundice, scarlet-fever, rheumatoidal arthritis, and hepatic diseases; however, little is known about its anti-inflammatory effect. In this study the influence of blanching and pan-frying on the anti-inflammatory activity of Ligularia fischeri (LF) was evaluated. RESULTS: Fresh LF and cooked LF showed no significant effect on the viability of macrophages after 24 h incubation. Fresh LF was found to be the most potent inhibitor of nitric oxide (NO) production at 100 MUg/ml, while pan-fried LF showed little inhibitory effect on lipoloysaccharide (LPS) stimulated murine machrophage RAW264.7 cells. In contrast with its effect on NO production, pan fried LF showed significant attenuation of the expression of inducible nitiric oxide synthase (iNOS) compared with fresh LF. In the cooking method of LF, PGE2 production was not affected in the LPS-induced RAW 264.7 cells. In LPS-induced RAW 264.7 cells, pretreatment by fresh and cooked LF increased COX2 mRNA expression. The 3-O-caffeoylquinic acid content of blanching and pan-frying LF increased by 4.92 and 9.7 fold with blanching and pan-frying respectively in comparison with uncooked LF. CONCLUSIONS: Regardless of the cooking method, Ligularia fischeri exhibited potent inhibition of NO production through expression of iNOS in LPS-induced RAW264.7 cells. PMID- 25723404 TI - Singularity-free finite element model of bone through automated voxel-based reconstruction. AB - Computed tomography (CT) provides both anatomical and density information about tissues. Bone is segmented by raw images and Finite Element Method (FEM) voxel based meshing technique is achieved by matching each CT voxel to a single finite element (FE). As a consequence of the automated model reconstruction, unstable elements - i.e. elements insufficiently anchored to the whole model and thus potentially involved in partial rigid body motion - can be generated, a crucial problem in obtaining consistent FE models, hindering mechanical analyses. Through the classification of instabilities on topological connections between elements, a numerical procedure is proposed in order to avoid unconstrained models. PMID- 25723405 TI - Dendrimer nanofluids in the concentrated regime: from polymer melts to soft spheres. AB - Understanding dendrimer structures and their interactions in concentrated solutions is important to a wide range of applications, such as drug delivery and lubrication. However, controversy has persisted concerning whether, when confined to proximity, dendrimers would entangle as observed for polymer systems, or act as deformable spheres. Furthermore, how such behavior may be related to their size-dependent molecular architecture remains unclear. Using small-angle X-ray scattering (SAXS), the intermolecular interactions and structures in aqueous nanofluids containing three generations of carboxyl-terminated poly(amidoamine) (PAMAM) dendrimers (G0.5, Rg = 9.3 A; G3.5, Rg = 22.6 A; G5.5, Rg = 39.9 A, where Rg is the radius of gyration) over a mass fraction range 0.005 <= x <= 0.316 have been studied. In the highly concentrated regime (x >= 0.157), we observe that the solution properties depend on the dendrimer generation. Our results suggest that the smaller G0.5 dendrimers form a highly entangled polymer melt, while the larger dendrimers, G3.5 and G5.5, form densely packed and ordered structures, in which the individual dendrimers exhibit some degree of mutual overlap or deformation. Our results demonstrate the tunability of interdendrimer interactions via their molecular architecture, which in turn may be harnessed to control and tailor the physical properties of dendrimer nanofluids. PMID- 25723406 TI - Pump bleaching of Tm-doped fiber with 793 nm pump source. AB - We demonstrate, for the first time to our knowledge, the strong recovery of the optical-optical slope efficiency of gamma-ray-irradiated Tm-doped fiber under 793 nm laser diode (LD) pumping. The fiber optical-optical slope efficiency, the fiber cladding absorption spectra, and the fluorescence spectra of the Tm-doped fiber before and after 500 Gy gamma-ray irradiation have been measured for comparison. It is found that the fiber optical-optical slope efficiency had significant degradation from 56.3% to 26.7% after irradiation and recovered to 40.8% after 15 h pump bleaching. Based on comparative analysis of fiber cladding absorption spectra among pristine fiber, irradiation, and bleaching, the reasons for the strong recovery have also been discussed. PMID- 25723407 TI - Ultra-small wavelength splitters in a subwavelength plasmonic waveguide. AB - Miniaturizing optical devices beyond the diffraction limit is of great importance for high-integration photonic circuits. By directly fabricating a double-slit aperture structure of different sizes in a subwavelength plasmonic waveguide, an ultra-small plasmonic wavelength splitter is realized experimentally. Due to the different slit widths, the surface plasmon polaritons (SPPs) in the opposite directions exhibit anti-phase interferences. As a result, the SPPs excited at different wavelengths can be split to propagate in the opposite directions along the subwavelength plasmonic waveguide. The plasmonic wavelength splitter only occupies a footprint of about 1.4 MUm2 on the metal surface, and the splitting wavelengths and their separation can be easily varied by adjusting the structural parameters. This provides it with important applications in the areas of the optical modulating, sensing, and computing networks in highly integrated plasmonic circuits. PMID- 25723408 TI - Experimental analysis of distributed pump absorption and refractive index changes in Yb-doped fibers using acousto-optic interaction. AB - In-fiber acousto-optic interaction is used to characterize the refractive index changes at the C band in a single-mode ytterbium-doped optical fiber under 980 nm pumping. The transmission notch created by the acoustic-induced coupling between the core mode and a cladding mode shifts to longer wavelengths when the pump is delivered to the fiber. The electronic contribution to the refractive index change is quantified from the wavelength shift. Using a time-resolved acousto optic method, we investigate the distribution of pump absorption, and the resulting refractive index change profile, along sections of ytterbium-doped fiber exceeding 1 m long under different pump power levels. PMID- 25723409 TI - On a quasi-relativistic formula in polarization theory. AB - In a pure operatorial (nonmatrix) Pauli algebraic approach, this Letter shows that the Poincare vector of the light transmitted by a dichroic device can be expressed as function of the Poincare vectors of the incoming light and of the device by a composition law of the same kind as the composition law of the noncolinear relativistic velocities. This is, in fact, a general law of composition for three-dimensional (3D) vectors remaining in the Poincare ball (where they have a group-like structure). The differences between this problem and that of the composition law of two dichroic devices are pointed out and justified. PMID- 25723410 TI - Particles replaced axially in an optical trap. AB - Flow-based measures to automate optical trapping have significant limitations. A scheme is advanced here where a spherical bead is first located in a trap, and a second bead below the focus point is selectively drawn into the trap to replace the original particle. Experimentation conducted showed that it was possible to do so with little perturbation of other surrounding particles. Simulations done allowed for a clearer description of the exchange mechanism. PMID- 25723411 TI - Vortex Hermite-Gaussian laser beams. AB - We study elliptical vortex Hermite-Gaussian (vHG) beams, which are described by the complex amplitude proportional to the nth-order Hermite polynomial whose argument is a function of a real parameter a. At |a|<1, on the vertical axis of the beam cross section, there are n isolated optical nulls that produce optical vortices with topological charge +1(a<0) or -1(a>0). At |a|>1, similar isolated optical nulls of the vHG beams are found on the horizontal axis. At a=0, the vHG beam becomes identical to the HG mode of the order (0,n). We derive the orbital angular momentum (OAM) of the vHG beams, which depends on the parameter a and an ellipticity parameter of the Gaussian beam. The derived equation allows the transverse intensity of the vHG-beam to be changed without changing its OAM. The experimental and theoretical results are in good agreement. PMID- 25723412 TI - Fourier transform acousto-optic imaging with a custom-designed CMOS smart-pixels array. AB - We report acousto-optic imaging (AOI) into a scattering medium using a Fourier Transform (FT) analysis to achieve axial resolution. The measurement system was implemented using a CMOS smart-pixels sensor dedicated to the real-time analysis of speckle patterns. This first proof-of-principle of FT-AOI demonstrates some of its potential advantages, with a signal-to-noise ratio comparable to the one obtained without axial resolution, and with an acquisition rate compatible with a use on living biological tissue. PMID- 25723413 TI - Passive coherent combining of CEP-stable few-cycle pulses from a temporally divided hollow fiber compressor. AB - We demonstrate a simple and robust passive coherent combining technique for temporal compression of millijoule energy laser pulses down to few-cycle duration in a gas-filled hollow fiber. High combining efficiency is achieved by using carefully oriented calcite plates for temporal pulse division and recombination. Carrier-envelope phase (CEP)-stable, 6-fs, 800-nm pulses with more than 0.6 mJ energy are routinely generated. This method could aid in the energy scaling of CEP-stable hollow-fiber compressor systems. PMID- 25723414 TI - Electrically driving bandwidth tunable guided-mode resonance filter based on a twisted nematic liquid crystal polarization rotator. AB - A novel bandwidth-tunable filter is proposed based on nonpolarizing guided-mode resonance effect. The compact, electrically driving bandwidth-tunable optical filter is realized by taking advantage of the effect of bandwidth-to-polarization sensitivity and using a twisted nematic liquid crystal polarization rotator for simple and precise polarization control. The operation principle and the design of the device are presented. The center wavelength is fixed at 623.1 nm with a relatively symmetric line shape. The full-width at half-maximum bandwidth is tuned from 12 to 44.8 nm by controlling the voltage in the polarization rotator. PMID- 25723415 TI - Control of spectral interference patterns in broad Rabi sidebands toward quasi comb structures. AB - The pattern of spectral interference fringes in broad dynamic Rabi sidebands allows for a considerable degree of control by shaping the picosecond driving pulse. We demonstrate experimental evidence of such control and report an analytic and numerical investigation of possibilities to control the fringe pattern to produce a comb-like optical structure. The temporal phase and amplitude shaping of a picosecond driving pulse influence the spectrum envelope, fringe contrast, and fringe spacing variation in the sideband spectra. The sideband spectrum envelope depends on the sharpness of the driving pulse, that is, on the rate at which the temporal distance between the leading and trailing edges grows away from the pulse maximum. Increasing this parameter reduces the variation of the envelope amplitude across the sideband. The fringe contrast, defined by the maximum-to-minimum difference, depends strongly on the asymmetry of the driving pulse. The imbalance between the leading and trailing edges leads to a decrease of the contrast. The variation of interpeak distance within a sideband was controlled using the temporal shape of the driving pulse. In the particular case of a blue-shifted sideband emitted by excited oxygen atoms driven by a picosecond pulse of 800 nm carrier wavelength and ~5*1010 W cm-2 intensity, a Gaussian pulse shape results in an interpeak distance increasing almost five times over the interval from 1.60 to 1.66 eV, whereas a super-Gaussian shape leads to almost equidistant fringes producing a comb-like spectrum. PMID- 25723416 TI - Nonlinear pulse combining and pulse compression in multi-core fibers. AB - We demonstrate light pulse combining and pulse compression using a continuous discrete nonlinear system implemented in a multi-core fiber (MCF). It is shown that the pulses initially injected into all of the cores of a ring MCF are combined by nonlinearity into a small number of cores with simultaneous pulse compression. We demonstrate the combining of 77% of the energy into one core with pulse compression over 14* in a 20-core MCF. We also demonstrate that a suggested scheme is insensitive to the phase perturbations. Nonlinear spatio-temporal pulse manipulation in multi-core fibers can be exploited for various applications, including pulse compression, switching, and combining. PMID- 25723417 TI - Ultrahigh-contrast imaging by temporally modulated stimulated emission depletion. AB - Stimulated emission depletion (STED) is the key optical technology enabling super resolution microscopy below the diffraction limit. Here, we demonstrate that modulation of STED in the time domain, combined with properly designed lock-in detection, can radically enhance the contrast of fluorescent images of strongly autofluorescent biotissues. In our experiments, the temporally modulated STED technique, implemented with low-intensity continuous-wave laser sources, is shown to provide an efficient all-optical suppression of a broadband fluorescent background, allowing the contrast of fluorescent images of mammal brain tissues tagged with nitrogen-vacancy diamond to be increased by five orders of magnitude. PMID- 25723418 TI - Investigation of anti-Stokes Raman processes at phonon-polariton resonance: from Raman oscillation, frequency upconversion to Raman amplification. AB - Raman oscillation, frequency upconversion, and Raman amplification can be achieved in a second-order nonlinear medium at the phonon-polariton resonance. By beating two optical fields, a second-order nonlinear polarization is generated inside the medium. Such a polarization induces a spatially uniform nonpropagating electric field at the beat frequency, which in turn mixes with the input optical field at the lower frequency to generate or amplify the anti-Stokes optical field. Raman oscillation can be efficiently reached for the copropagating configuration. In comparison, efficient frequency upconversion and large amplifications are achievable for the counterpropagating configuration. These Raman processes can be used to effectively remove transverse-optical phonons before decaying to lower-frequency phonons, achieve laser cooling, and significantly enhance coherent anti-Stokes Raman scattering. The counterpropagating configuration offers advantages for amplifying extremely weak signals. PMID- 25723419 TI - Photonic crystal-enhanced fluorescence through the extraction of dually polarized modes. AB - In this Letter, we demonstrate that fluorescence detection by using surface-bound fluorescent molecules can be enhanced by coupling the fluorescence emission with dually polarized resonant modes of a photonic crystal (PC) substrate. The PC was fabricated through nanoreplica molding by using a plastic substrate. It was designed such that the transverse magnetic (TM)- and transverse electric (TE) polarized resonance coincided at a specific combination of the incident angle and the illumination wavelength. During excitation, the nonpolarized emission from cyanine-5 was simultaneously coupled with the TE and TM resonant modes and reradiated into the detection instrument, increasing the fluorescence collection efficiency and thus, enhancing the fluorescence detection. PMID- 25723420 TI - Bandpass integrated Bragg gratings in silicon-on-insulator with well-controlled amplitude and phase responses. AB - Bandpass filters with square shape amplitude responses and well-controlled dispersion characteristics are achieved by accurate apodization of Bragg grating structures in silicon-on-insulator waveguides. For these devices, precise tailoring of their frequency response typically requires low coupling coefficients and relatively long on-chip propagation lengths. These challenges are addressed by implementing apodization by phase-modulation and using wider strip waveguides to reduce phase noise. This design approach is demonstrated with a dispersion-less narrowband filter and a chirped bandpass filter. PMID- 25723421 TI - Optical properties of single diatom frustules revealed by confocal microspectroscopy. AB - Optical properties of single diatom frustule valves from two different Coscinodiscus species (C. wailesii and C. centralis) are studied by transmission confocal hyperspectral imaging and numerical calculations. Light convergence, concentration, and trapping effects are observed and depend on both the wavelength and the valve orientation. These effects seem to occur independently of the incident light angle. From our results, a wavelength-dependent multifocal lens behavior can be explained by light diffraction related to the radial symmetry of the multiscaled 3D nanostructure. PMID- 25723422 TI - Long-range surface plasmon resonance sensor based on dielectric/silver coated hollow fiber with enhanced figure of merit. AB - A long-range surface plasmon resonance (LRSPR) sensor based on dielectric/silver coated hollow fiber (HF) is proposed. It can detect the refractive index (RI) of sensed liquid filled in the hollow core of the sensor. A HF LRSPR sensor with 90 nm-thick silver layer and 260-nm-thick OC300 layer is fabricated. Experiments are taken to evaluate the performance of the sensor by measuring the transmission spectra. Theoretical analysis based on a ray model is also taken, and the results agree well with the experimental results. The proposed sensor has similar sensitivity but much smaller SPR dip width than the silver-coated HF SPR sensor. Thus figure of merit of the sensor is enhanced approximately five times. The stability of the sensor is also improved because the dielectric layer acts as a protection layer for the damageable silver layer. PMID- 25723423 TI - Thermal stress modification in regenerated fiber Bragg grating via manipulation of glass transition temperature based on CO2-laser annealing. AB - In this work, we have demonstrated thermal stress relaxation in regenerated fiber Bragg gratings (RFBGs) by using direct CO2-laser annealing technique. After the isothermal annealing and slow cooling process, the Bragg wavelength of the RFBG has been red-shifted. This modification is reversible by re-annealing and rapid cooling. It is repeatable with different cooling process in the subsequent annealing treatments. This phenomenon can be attributed to the thermal stress modification in the fiber core by means of manipulation of glass transition temperature with different cooling rates. This finding in this investigation is important for accurate temperature measurement of RFBG in dynamic environment. PMID- 25723424 TI - Lens-free inline holographic microscopy with numerical correction of layers with different refractive index. AB - Digital inline holographic microscopy is applied for lens-free imaging with high lateral resolution. Microfluidic chambers for the imaging of cells in water-like or native solutions, e.g., thick layers of glass and other materials with different refractive index, cause aberrations that limit the spatial resolution and change the magnification scale. In this Letter, a fast reconstruction technique considering parallel layer systems of different refractive indices is presented. In the experiments, properly scaled images of microbeads and red human blood cells with an optical resolution corresponding to a numerical aperture of about 0.62 were reconstructed. PMID- 25723425 TI - Photonic spin Hall effect in dielectric metasurfaces with rotational symmetry breaking. AB - Observation of photonic spin Hall effect (SHE) in dielectric metasurfaces whose local optical axes are spatially rotated is presented. The photonic SHE manifests itself as a spin-dependent splitting in momentum space due to the space-variant Pancharatnam-Berry phase. We show that no spin-dependent splitting occurs when keeping the rotational symmetry of local optical axes. However, the splitting can be observed when the rotational symmetry is broken. The spin-dependent splitting in position space can be observed in the far field due to the high transmission efficiency of dielectric metasurfaces. Moreover, it can be enhanced by increasing the rotation rate of local optical axes in the metasurfaces. PMID- 25723426 TI - Performance evaluation of analog signal transmission in an orbital angular momentum multiplexing system. AB - We propose and experimentally demonstrate analog signal transmission in an orbital angular momentum (OAM) multiplexing system. By employing two spatial light modulators (SLMs), each loaded with a complex phase pattern generating 4 OAM beams, an 8 OAM multiplexing system is established for analog signal transmissions. The crosstalk between each OAM channel is measured to assess the performance of the OAM multiplexing system. Using 3-GHz analog signals over 8 OAM beams, we evaluate the performance of OAM multiplexing analog signal transmissions. The spurious free dynamic range (SFDR) of the second-order harmonic distortion (SHD) and the third-order-harmonic distortion (THD) are measured and characterized for each OAM channel. PMID- 25723427 TI - Estimation of particle size variations for laser speckle rheology of materials. AB - Laser speckle rheology (LSR) is an optical technique for assessing the viscoelastic properties of materials with several industrial, biological, and medical applications. In LSR, the viscoelastic modulus, G*(omega), of a material is quantified by analyzing the temporal fluctuations of speckle patterns. However, the size of scattering particles within the material also influences the rate of speckle fluctuations, independent of sample mechanical properties, and complicates the accurate estimation of G*(omega). Here, we demonstrate that the average particle size may be retrieved from the azimuth-angle dependence of time averaged speckle intensities, permitting the accurate quantification of the viscoelastic moduli of materials with unknown particle size distribution using LSR. PMID- 25723428 TI - Tailoring between network rigidity and nanosecond transient absorption in a Ge(x)As(35-x)Se65 thin films. AB - In this Letter, we report the first observation of dramatic decrease in nanosecond (ns) pulsed laser-induced transient absorption (TA) in a-Ge(x)As(35 x)Se65 thin films by tuning the amorphous network from floppy to rigid. Our results provide the direct experimental evidence of a self-trapped exciton mechanism, where trapping of the excitons occurs through bond rearrangements. Taken together, a rigid amorphous network with more constraints than degrees of freedom are unable to undergo any such bond rearrangements and results in weaker TA. However, we also demonstrate that excitation fluence can be effectively utilized as a simple tool to lift up enough constraints to introduce large TA even in rigid networks. Apart from this, we also show that TA is tunable with network rigidity as it blueshifts when the mean coordination is increased from 2.35 to 2.6. PMID- 25723429 TI - Continuous-wave whispering-gallery optical parametric oscillator for high resolution spectroscopy. AB - We achieve a continuous operation of a whispering gallery optical parametric oscillator by stabilizing the resonator temperature T on the mK level and simultaneously locking the pump frequency to a cavity resonance using the Pound Drever-Hall technique. The millimeter-sized device converts several mW of a pump wave at 1040 nm wavelength to signal and idler waves around 2000 nm wavelength with more than 50% efficiency. Over 1 h, power and frequency of the signal wave vary by <+/-1% and by <+/-25 MHz, respectively. The latter can be tuned over 480 MHz without a mode hop by changing T over 120 mK. In order to prove the suitability for high-resolution spectroscopy, we scan the signal frequency across the resonance of a Fabry-Perot interferometer resolving nicely its 10 MHz linewidth. PMID- 25723430 TI - Sub-pm linewidth nanosecond Nd:GYSGG laser at 1336.6 nm. AB - We demonstrate a sub-pm linewidth acousto-optic (AO) Q-switched nanosecond Nd:GYSGG ring laser at 1336.6 nm side-pumped by 808-nm quasi-continuous wave (QCW) diode lasers for the first time. With incident pulse energy of 4.23 J at 10 Hz, a maximum output macropulse energy of 36.7 mJ at 1336.6 nm with linewidth of less than 0.85 pm and a micropulse width of 300 ns was obtained at a repetition rate of 80 Hz, corresponding to an average micropulse peak power of 15.3 kW. The M2 factors were measured to be 1.42 and 1.10 in x and y directions, respectively. It can be tuned from 1336.576 to 1336.652 nm with a tuning resolution of 1 pm. The 1336.632 nm can be converted to deep ultraviolet (DUV) laser at 167.079 nm through its eighth harmonics, which is very useful for the 27Al+ optical frequency standard. PMID- 25723431 TI - Quantitative study on propagation and healing of Airy beams under experimental conditions. AB - We investigate the propagation and healing of Airy beams in two dimensions that are obtainable under practical experimental conditions. We introduce an intensity similarity factor to quantitatively describe how an Airy beam retains its original shape. Based on such a figure of merit, we define a shape-retaining distance to quantify how far an Airy beam can keep the shape of its main lobe upon propagation and a healing distance to quantify how soon an initially partially blocked Airy beam can restore its main lobe profile. We perform an analysis on how these two distances scale with experimental parameters. We further use an interference picture to interpret the healing phenomenon of an Airy beam. Our work can serve as a guideline for quantitative performance analysis for applications of Airy beams and can be extended to other special beams in a straightforward fashion. PMID- 25723432 TI - All-fiber mode-locked laser based on microfiber polarizer. AB - A novel all-fiber mode-locked fiber laser based on microfiber polarizer is proposed and demonstrated. The microfiber polarizer is composed of two pieces of microfibers that are finely manipulated to be partly overlapped. Because of the asymmetric cross section, the microfiber polarizer shows a strong birefringence that ultimately induces a high polarization-selective feature. Compared with other polarizers, the microfiber polarizer owns the merits of simpler fabrication, lower cost, broader band, and more compact size. The polarization extinction ratio of the microfiber polarizer is 26 dB, and the stable pulse sequence with the duration of 2.9 ps is generated from this microfiber polarizer based all-fiber mode-locked laser. PMID- 25723433 TI - Probing the topological charge of a vortex beam with dynamic angular double slits. AB - When a vortex beam with a spiral phase structure passes through dynamic angular double slits (ADS), the interference pattern changes alternatively between destructive and constructive at the angular bisector of the ADS. This change is due to their phase difference. Based on this property, we experimentally demonstrate a simple method to precisely and efficiently determine the topological charge of vortex beams. Furthermore, this scheme allows for the simultaneous determination of the modulus and the sign of the topological charge of the vortex beams. PMID- 25723434 TI - Proximity effect assisted absorption enhancement in thin film with locally clustered nanoholes. AB - We focus on the light-trapping characteristics of a thin film with locally clustered nanoholes (NHs), considering that the clustering effect is usually encountered in preparing the nanostructures. Our full-wave finite-element simulation indicates that an intentionally introduced clustering effect could be employed for improving the light-trapping performance of the nanostructured thin film. For a 100 nm thick amorphous silicon film, an optimal clustering design with NH diameter of 100 nm is able to double the integrated optical absorption over the solar spectrum, compared to the planar counterpart, as well as show much improved optical performance over that of the nonclustered setup. A further insight into the underlying physics explains the outstanding light-trapping capability in terms of the increased available modes, a stronger power coupling efficiency, a higher fraction of electric field concentrated in absorbable material, and a higher density of photon states. PMID- 25723435 TI - Internal gain in Er-doped As2S3 chalcogenide planar waveguides. AB - Low-loss erbium-doped As2S3 planar waveguides are fabricated by cothermal evaporation and plasma etching. Internal gain in the telecommunications band is demonstrated for the first time in any chalcogenide glass and additionally in a thin film planar waveguide amplifier configuration. PMID- 25723436 TI - Universal axial fluctuations in optical tweezers. AB - Optical tweezers (OTs) allow the measurement of fluctuations at the nanoscale, in particular fluctuations in the end-to-end distance in single molecules. Fluctuation spectra can yield valuable information, but they can easily be contaminated by instrumental effects. We identify axial fluctuations, i.e., fluctuations of the trapped beads in the direction of light propagation, as one of these instrumental effects. Remarkably, axial fluctuations occur on a characteristic timescale similar to that of conformational (folding) transitions, which may lead to misinterpretation of the experimental results. We show that a precise measurement of the effect of force on both axial and conformational fluctuations is crucial to disentangle them. Our results on axial fluctuations are captured by a simple and general formula valid for all OT setups and provide experimentalists with a general strategy to distinguish axial fluctuations from conformational transitions. PMID- 25723437 TI - Generation of broadband noise-like pulse from Yb-doped fiber laser ring cavity. AB - We have demonstrated a generation of the noise-like pulse (NLP) with broadband spectrum in a nonlinear polarized evolution-based passive mode-locked Yb-doped fiber (YDF) ring laser. At the cavity dispersion of near zero, the NLP with spectrum bandwidth up to 131 nm (FWHM) was obtained at a central wavelength of 1070 nm with output power of 136 mW and 80 MHz repetition rate. To our best knowledge, this spectrum bandwidth of NLP is the broadest among the reported YDF lasers. The autocorrelation function of pulse contained the short (30 fs) and long (4.6 ps) components. This short coherence light source is well suited for the optical coherent tomography used for ophthalmology at a wavelength of ~1000 nm. PMID- 25723438 TI - Optimization and characterization of nonlinear excitation and collection through a gradient-index lens for high-resolution nonlinear endomicroscopy. AB - We report a study of gradient index (GRIN) lenses as a miniaturized micro objective for in vivo imaging in the context of the development of a nonlinear endomicroscope. A numerical study of the parameters influencing the lateral resolution, excitation, and collection efficiency, when GRIN lens is coupled with a double clad fiber (DCF), is exposed. Four commercial DCFs, previously identified from the literature as potential endoscopic fibers, are simulated. Then, an experimental study characterizes two GRIN lenses (one commercial, one homemade) by their dispersion and nonlinear effects, potential intrinsic fluorescence, and use for fluorescence lifetime measurements. Images of neural cells from brain tissues of mice through a GRIN lens are presented. PMID- 25723439 TI - Method for observing phase objects without halos or directional shadows. AB - A new microscopy method for observing phase objects without halos or directional shadows is proposed. The method is based on transformation of the surface profile of phase objects into a light intensity pattern. The key optical element is an annular aperture at the front focal plane of a condenser. The light flux passing through the annular aperture is changed by the specimen's surface profile and then passes through an objective and contributes to image formation. Theory and experimental results are presented. Phase images of induced pluripotent stem (iPS) cells with clear outlines were obtained with this method. PMID- 25723440 TI - Optical phase cloning by an integrated dual-parallel Mach-Zehnder modulator. AB - The use of a dual-parallel Mach-Zehnder modulator in a feed-forward configuration is shown to serve the purpose of cloning the optical phase of a master oscillator on a distributed-feed-back (DFB) slave laser exhibiting a multi-MHz-wide frequency noise spectrum. A residual phase error of 113 mrad is obtained together with an extremely high control bandwidth of hundreds of megahertz and a gigahertz level capture and tuning range. Besides offering a dramatic improvement over feedback loops, this approach is susceptible of hybrid integration in a cost effective compact device benefiting from the wide tunability of DFB lasers. PMID- 25723441 TI - Fabrication and characterization of cerium-doped terbium gallium garnet with high magneto-optical properties. AB - High optical quality (Tb((1-x))Ce(x))3Ga5O12 (TCGG) single crystal has been grown by the Czochralski method. The optical and magneto-optical properties of the TCGG are analyzed in detail and the Verdet constant (V) of TCGG is compared with that of undoped terbium gallium garnet (TGG) crystal. TCGG presents a very high transmittance, particularly in the visible-near infrared (VIS-NIR) region, and its V is obviously larger than that of TGG in the VIS-NIR region. The figure of merit and optical features point out the superior characteristics of TCGG with respect to TGG. PMID- 25723442 TI - Ultrastable fiber amplifier delivering 145-fs pulses with 6-MUJ energy at 10-MHz repetition rate. AB - A high-power femtosecond Yb:fiber amplifier operating with exceptional noise performance and long-term stability is demonstrated. It generates a 10-MHz train of 145-fs pulses at 1.03 MUm with peak powers above 36 MW. The system features a relative amplitude noise of 1.5.10-6 Hz(-1/2) at 1 MHz and drifts of the 60-W average power below 0.3% over 72 hours of continuous operation. The passively phase-stable Er:fiber seed system provides ultrabroadband pulses that are synchronized at a repetition rate of 40 MHz. This combination aims at new schemes for sensitive experiments in ultrafast scientific applications. PMID- 25723443 TI - Cherenkov-excited luminescence scanned imaging. AB - Ionizing radiation is commonly delivered by medical linear accelerators (LINAC) in the form of shaped beams, and it is able to induce Cherenkov emission in tissue. In fluorescence-based microscopy excitation from scanned spots, lines, or sheets can be used for fast high-resolution imaging. Here we introduce Cherenkov excited luminescence scanned imaging (CELSI) as a new imaging methodology utilizing 2-dimensional (~5-mm-thick) sheets of LINAC radiation to produce Cherenkov photons, which in turn excite luminescence of probes distributed in biological tissues. Imaging experiments were performed by scanning these excitation sheets in three orthogonal directions while recording Cherenkov excited luminescence. Tissue phantom studies have shown that single luminescent inclusions ~1 mm in diameter can be imaged within 20-mm-thick tissue-like media with minimal loss of spatial resolution. Using a phosphorescent probe for oxygen, PtG4 with the CELSI methodology, an image of partial pressure of oxygen (pO2) was imaged in a rat lymph node, quantitatively restoring pO2 values in differently oxygenated tissues. PMID- 25723444 TI - Electrically actuated liquid iris. AB - We report an adaptive iris using dielectric liquids and a radial-interdigitated electrode. A black liquid is confined by a circular gasket with a donut shape. The surrounding of the black liquid is filled with an immiscible liquid. In the relaxing state, the black liquid obtains the largest clear aperture. By applying a voltage, the surface of the black liquid is stretched by the generated dielectric force, resulting in a reduction of its aperture. For the demonstrated iris, the diameter of the aperture can be changed from ~4.7 mm to ~1.2 mm when the voltage is applied from 0 to 70 V(rms). The aperture ratio is ~94%. Owing to the radial-interdigitated electrode, the aperture size of the iris can be effectively switched with a reasonably fast response time. The optical switch is polarization-insensitive. The potential applications of our iris are light shutters, optical attenuators, biomimicry, and wearable devices. PMID- 25723445 TI - 574-647 nm wavelength tuning by second-harmonic generation from diode-pumped PPKTP waveguides. AB - We present a compact, all-room-temperature continuous-wave laser source in the visible spectral region between 574 and 647 nm by frequency doubling of a broadly tunable InAs/GaAs quantum-dot external-cavity diode laser in a periodically poled potassium titanyl phosphate crystal containing three waveguides with different cross-sectional areas (4*4, 3*5, and 2 MUm*6 MUm). The influence of a waveguide's design on tunability, output power, and mode distribution of second harmonic generated light, as well as possibilities to increase the conversion efficiency via an optimization of a waveguide's cross-sectional area, was systematically investigated. A maximum output power of 12.04 mW with a conversion efficiency of 10.29% at 605.6 nm was demonstrated in the wider waveguide with the cross-sectional area of 4 MUm*4 MUm. PMID- 25723446 TI - Nonlocal study of ultimate plasmon hybridization. AB - Within our recently proposed generalized nonlocal optical response (GNOR) model, where nonlocal response is included by taking into account both convective and diffusive currents of the conduction electrons, we revisit the fundamental problem of an optically excited plasmonic dimer. We consider the transition from separated dimers via touching dimers to finally overlapping dimers. In particular, we focus on the touching case, showing a fundamental limit on the hybridization of the bonding plasmon modes due to nonlocality. Using transformation optics, we determine a simple analytical equation for the resonance energies. PMID- 25723447 TI - Balancing of thermal lenses in enhancement cavities with transmissive elements. AB - Thermal lensing poses a serious challenge for the power scaling of enhancement cavities, in particular when these contain transmissive elements. We demonstrate the compensation of the lensing induced by thermal deformations of the cavity mirrors with the thermal lensing in a thin Brewster plate. Using forced convection to fine-tune the lensing in the plate, we achieve average powers of up to 160 kW for 250-MHz-repetition-rate picosecond pulses with a power-independent mode size. Furthermore, we show that the susceptibility of the cavity mode size to thermal lensing allows highly sensitive absorption measurements. PMID- 25723448 TI - Excitation of multiple resonances in 1D Anderson localized systems for efficient light amplification. AB - Excitation of hybridized multiple resonances can be an effective route for coherent light generation in irregular 1D systems larger than the localization length of light. Necklace states are often considered to have nonlocalized states. However, we propose that some hybridized/coupled states can have high resonant tunneling with spatially extended fields. If strong localization properties are preserved in hybridized resonances, the excitation of such states allows for deposition of the excitation energy deep into the structure and spatial overlap with local gain regions. This result could allow for better utilizing hybridized resonances in biological or natural photonic systems. PMID- 25723449 TI - Growth differentiation factor 9 and bone morphogenetic protein 15 expression in previtellogenic oocytes and during early embryonic development of Yellow-tail Kingfish Seriola lalandi. AB - BACKGROUND: During fish oocyte maturation, specific molecules are expressed and accumulated within oocyte until fertilization and embryo development. Special attention have been paid in members of the transforming growth factor (TGF-beta) superfamily; growth differentiation factor 9 (GDF9/gdf9) and bone morphogenetic protein 15 (BMP15/bmp15), which exert regulatory functions during oocyte maturation and follicle development. However, little attention has been paid to the involvement of these molecules during embryogenesis considering its importance for the formation of a good quality egg and subsequent embryo survival. The purpose of this study was to analyze the expression of gdf9 and bmp15 in previtellogenic oocytes and during early embryonic development in Seriola lalandi, a pelagic fish with increasing prospect for its aquaculture development, which however, show high mortality at embryo and larval stages. RESULTS: Through RT-qPCR it was found that gdf9 expression was higher in previtellogenic oocytes decreasing after ovulation. This expression profile agrees with its participation in early stages of the follicular development. The transcripts for bmp15 also showed the highest levels in previtellogenic oocytes, however this expression was lower than obtained with gdf9. Conversely, in recently spawned oocytes mRNA bmp15 levels were highest than observed to gdf9. This, is consequent with the main role proposed for this growth factor at the final fish oocyte maturation: avoid the ovulation of an immature oocyte. During embryo development, low levels of mRNA were detected to gdf9, with an increase in 48 H post-fertilization embryos. The bmp15 expression did not change throughout development and was higher than gdf9 at 16 cells, blastula and appearance embryos stages. CONCLUSIONS: Both (gdf9 and bmp15) expression profiles in previtellogenic oocytes and newly spawned eggs are consistent with the described functions for these growth factors in vertebrate ovarian physiology in early and late stages of the follicular development. So, these genes could be considered as quality biomarkers at these stages. However, further studies of these proteins throughout folliculogenesis, are necessaries to fully understand their functions during the oocyte formation. In addition, the persistent expression of these growth factors during development, allows us to speculate possible roles in embryonic processes, which must also be addressed. PMID- 25723450 TI - Fate by RNA methylation: m6A steers stem cell pluripotency. AB - The N 6-methyladenosine (m6A) modification of mRNA has a crucial function in regulating pluripotency in murine stem cells: it facilitates resolution of naive pluripotency towards differentiation. PMID- 25723452 TI - National Heart, Lung, and Blood Institute Strategic Visioning: setting an agenda together for the NHLBI of 2025. PMID- 25723451 TI - Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin. AB - BACKGROUND: Although analysis pipelines have been developed to use RNA-seq to identify long non-coding RNAs (lncRNAs), inference of their biological and pathological relevance remains a challenge. As a result, most transcriptome studies of autoimmune disease have only assessed protein-coding transcripts. RESULTS: We used RNA-seq data from 99 lesional psoriatic, 27 uninvolved psoriatic, and 90 normal skin biopsies, and applied computational approaches to identify and characterize expressed lncRNAs. We detect 2,942 previously annotated and 1,080 novel lncRNAs which are expected to be skin specific. Notably, over 40% of the novel lncRNAs are differentially expressed and the proportions of differentially expressed transcripts among protein-coding mRNAs and previously annotated lncRNAs are lower in psoriasis lesions versus uninvolved or normal skin. We find that many lncRNAs, in particular those that are differentially expressed, are co-expressed with genes involved in immune related functions, and that novel lncRNAs are enriched for localization in the epidermal differentiation complex. We also identify distinct tissue-specific expression patterns and epigenetic profiles for novel lncRNAs, some of which are shown to be regulated by cytokine treatment in cultured human keratinocytes. CONCLUSIONS: Together, our results implicate many lncRNAs in the immunopathogenesis of psoriasis, and our results provide a resource for lncRNA studies in other autoimmune diseases. PMID- 25723453 TI - Biological active ingredients of traditional Chinese herb Astragalus membranaceus on treatment of diabetes: a systematic review. AB - Diabetes mellitus (DM) is a serious chronic metabolic disease which disease afflicting at present now afflicts approximately 4% of world population worldwide. Nowadays, the need for more potent and safe drugs to supply the present anti-diabetic and treated drugs has become an imperative. Astragalus membranaceus, the most common Chinese herb and key-component of many Chinese herbal anti-diabetic formulas, is rich in anti-diabetic compounds: polysaccharides (APS), saponins (ASS), and flavonoids (ASF) etc. Because of its various biological activities, especially its antidiabetic properties, that continuously arouse different studies. Recent studies focused on type 1 and type 2 treatment, respectively caused by autoimmune destruction of pancreatic beta cells and insulin resistance and deficient glucose metabolism. Its total polysaccharides, saponins and flavonoids fractions and several isolated compounds have been the most studied. This paper discusses diabetic treatment and pharmacological action of the biological ingredients in relation to diabetes mellitus and diabetic complications. PMID- 25723454 TI - Secondary metabolites and bioactivities from higher fungi in China. AB - Higher fungi (i.e. macrofungi) do not form a natural taxonomic or ecological group. They are defined as those fungi that produce large, easily observed and collected sporocarps. Most of the higher fungi species are from the phyla Basidiomycota and Ascomycota. These fungi are of particular interest because of their importance as food resource and culture component in many places of the world. Therefore, study of their diverse natural products has become a hot topic. China has the most diverse fungi in the world. We investigated the chemical constituents of Basidiomycetes and Ascomycetes from China, and our ongoing search bioactive metabolites from higher fungi could potentially be developed into new 'lead' compounds. We review the isolation, structural elucidation and biologically activity of the rich natural products newly derived from higher fungi collected in China after July 2007. PMID- 25723455 TI - New approaches for the selection and evaluation of anti-prion organic compounds. AB - Transmissible spongiform encephalopathies (TSEs) are infectious neurodegenerative disorders for which symptomatic, curative, or prophylactic treatments are not available. TSEs arise as a consequence of the conversion of soluble cellular prion protein (PrP(C)) into the scrapie isoform (PrP(Sc)), which aggregates and accumulates in the central nervous system. Proposed drugs against TSEs range from small organic compounds to antibodies; various therapeutic strategies have been proposed, including blocking the conversion of PrP(C) to PrP(Sc), increasing PrP(Sc) clearance, and/or stabilizing PrP(C). While several compounds have been effective in vitro and in animal models, none have proven effective in clinical studies to date. Such lack of in vivo efficacy is attributable to high compound toxicity and the lack of permeability of the selected compounds across the blood brain barrier. In this review, we discuss recent advances in the screening and evaluation of organic compounds for anti-prion activity using multiple approaches, including initial screening in prion-infected cell cultures, in silico prediction of pharmacokinetic and physicochemical properties, ex vivo evaluation of cellular toxicity, and in vitro assays using purified recombinant prion proteins. The main challenges for effective discrimination of candidate lead compounds as therapeutic agents for TSEs, and the disadvantages of each screening strategy are discussed. We propose that a combination of in vitro, ex vivo, and in silico approaches would be useful for the rapid identification of novel anti-prion drug candidates with suitable pharmacokinetic and pharmacodynamic properties that would support their use as drugs. PMID- 25723456 TI - The processing of chitosan and its derivatives and their application for postoperative anti-adhesion. AB - The formation of peritoneal adhesions represents one of the most common complications after abdominal surgery, and it increases the difficulty of re operation. Thus, preventing postoperative adhesions is a major problem in the field of surgical medicine. Due to a lack of good predictive animal models and the complexity of adhesion pathogenesis, attempts to prevent or reduce peritoneal adhesions have been largely unsuccessful. As a result, the study of anti-adhesion drugs and materials has become a hot topic for experts and scholars. The processing and development of chitosan and its derivatives as new anti-adhesion materials is highly valued because chitosan is inexpensive, highly biocompatible, and not cytotoxic, making it a promising anti-adhesion material. Here, we review the sources and preparation of chitosan and the progress made toward producing different types of chitosan and its derivatives for preventing adhesion. PMID- 25723457 TI - Exploration of N-arylpiperazine Binding Sites of D2 Dopaminergic Receptor. AB - The crystal structures of the D3 dopamine receptor and several other G-protein coupled receptors (GPCRs) were published in recent times. Those 3D structures are used by us and other scientists as a template for the homology modeling and ligand docking analysis of related GPCRs. Our main scientific interest lies in the field of pharmacologically active N-arylpiperazines that exhibit antipsychotic and/or antidepressant properties, and as such are dopaminergic and serotonergic receptor ligands. In this short review article we are presenting synthesis and biological data on the new N-arylpipereazine as well our results on molecular modeling of the interactions of those N-arylpiperazines with the model of D2 dopamine receptors. To obtain that model the crystal structure of the D3 dopamine receptor was used. Our results show that the N-arylpiperazines binding site consists of two pockets: one is the orthosteric binding site where the N arylpiperazine part of the ligand is docked and the second is a non-canonical accessory binding site for N-arylpipereazine that is formed by a second extracellular loop (ecl2) of the receptor. Until now, the structure of this receptor region was unresolved in crystal structure analyses of the D3 dopamine receptor. To get a more complete picture of the ligand - receptor interaction, DFT quantum mechanical calculations on N-arylpiperazine were performed and the obtained models were used to examine those interactions. PMID- 25723458 TI - Sphingosine kinases signalling in carcinogenesis. AB - Sphingosine kinases (Sphk1 and 2) regulate the prodution of sphingosine-1 phosphate (S1P), that is key molecule in cancer development. SphK1, which is commonly overexpressed in malignant tumours, significantly contributes to the pathogenesis of various types of cancer as well as to resistance to different Tyrosine Kinase inibitors (TKIs). Even, SphK2 may promote apoptosis and inhibit cell growth but its role has not yet been fully understood in pathologic conditions. Different growth factorsinduced activation of receptor tyrosine kinases (RTKs) results in production of Sphk1 which catalyzes the phosphorylation of sphingosine. Such enzyme, in turn, is involved in many cellular processes by its five receptors. These are able to transactivate RTKs through amplification of a positive-feedback signaling loop. In conclusion, development of pharmacological inhibitors of SphK1 has been limited by the lack of completely understanding of the enzymatic activation mechanisms of SphK1. PMID- 25723459 TI - Discovery and Development of Hepatitis C Virus Inhibitors Targeting the NS5A Protein. AB - Hepatitis C virus infection is a major health and economic burden worldwide. The standard of care is associated with low sustained virological response and some adverse effects. As an important component of all-oral direct-acting antiviral regimes, inhibitors of NS5A demonstrate potent pan-genotypic activity in vitro and in vivo. This review summarized the discovery and development of NS5A inhibitors, including the early chemotypes for which resistance maps to the NS5A protein, as well as first- and second-generation NS5A inhibitors and other analogues. The mechanism of action of NS5A inhibitors and related clinical trials were also described. PMID- 25723460 TI - Phenolics and Terpenoids; the Promising New Search for Anthelmintics: A Critical Review. AB - Ailments caused by helminth parasites are global causing different types of clinical complications with permanent and long term morbidity in humans. Although huge advances have been made in medical sciences the effectiveness of available anthelmintics are still quite limited. Starting from the 50's, most importance was given to synthetic compounds for developing remedies from them, however, the traditional knowledge of medicine of different countries continued to provide us clues against this widespread health problem. Natural products or structural analogs with diverse structures are always been the major sources for discovering new therapeutics and in recent past different active compounds have also been identified form these plant sources having anthelmintic properties. Although compounds of diverse chemical nature and classes were identified most active ones belong to either phenol or terpene in broad chemical nature. The mechanism of action of these phytotherapeutics is usually multi-targeted and can act against the helminth parasites through diverse spectrum of activities. In this reviewwe summarized the effective anthelmintics belong to either phenolics or terpenoids and highlighted the major way of their effectiveness. This also highlights the recent development of new therapeutic strategies against helminth parasites in the light of recent advances of knowledge. In addition, developing efficient strategies to promote apoptosis and disturbing redox status in them by natural products can provide us a clue in antifilarial drug developmental research and crucial unmet medical need. PMID- 25723461 TI - Role of 2-methoxyestradiol, an Endogenous Estrogen Metabolite, in Health and Disease. AB - Estradiol (E2) is a steroid hormone whose physiological actions are mainly mediated by its interaction with intracellular estrogen receptors (ER) leading to modification on the mRNA and protein synthesis in its target cells. However, estrogens can also activate several intracellular signal transduction cascades by non-genomic mechanisms. Estrogens must be inactivated and removed from blood through its conversion to soluble compounds with an apparent low estrogenic activity and decreased affinity for ER. In this context, 2-methoxyestradiol (2ME2) is generated by a sequential hydroxylation of E2 via the enzyme cytochrome P450 isoform 1A1 to produce 2-hydroxyestradiol (2OHE2) followed by a conjugation reaction catalyzed by the enzyme Catechol-O-Methyltransferase generating 2ME2 from 2OHE2. Recent evidence indicates that physiological concentration of 2ME2 may regulate several biological processes while high concentrations of this metabolite may induce pathophysiological alterations in several tissues. In the last years, 2ME2 has also been described as a promising anticancer drug although its cellular and molecular mechanisms are still being disclosed. Herein, we will review the available literature concerning the role of 2ME2 in health and disease. We will focus on to describing the intracellular mechanisms by which 2ME2 exerts its effects on reproductive and non-reproductive tissues. The promising anticancer effects of 2ME2 and its synthetic derivatives will also be discussed. Finally, a group of 2ME2-target genes that could be used as biomarkers of 2ME2 under physiological or pathophysiological conditions will be reviewed. PMID- 25723462 TI - Emerging therapeutic approaches based on nanotechnology for the treatment of diseases associated with telomere dysfunction. AB - Telomeric diseases are a group of rare progeroid genetic syndromes, presenting premature aging phenotypes, characterized for defects on telomere maintenance. In humans, telomeres are heterochromatic structures consisting of long TTAGGG repeats located at the chromosomal ends, which shorten progressively after each DNA replication because of the 'end replication problem'. Critically short telomeres activate a DNA damage response that leads to the arrest of the cell cycle and resulting in cellular senescence or apoptosis. Furthermore, excessively short telomeres are prone to create telomeric fusions, causing genomic instability and malignant transformation. In order to counteract this process, there are two enzymatic complexes, the telomerase complex, with the capacity to elongate telomeres; and the shelterin complex, which protects them from being recognized as DNA breaks. Over the last few decades, several studies have confirmed that critically short telomeres and defects in telomere-associated enzymatic complexes are involved in the development of a group of rare human genetic diseases, with the accumulation of excessive telomere attrition as the underlying cause of these pathologies. Despite the severity of these disorders, there is no curative treatment for any of them. In light of this, this review summarizes the most important defective telomere diseases, their current management, and it presents possible therapeutic strategies based on nanotechnology which may open up new possibilities for their treatment. PMID- 25723463 TI - Vascular endothelium: functioning in norm, changes in atherosclerosis and current dietary approaches to improve endothelial function. AB - The endothelium represents not only a simple cellular monolayer that lines the vascular tree in humans and other vertebrates. Depending on the location, the endothelium shows significant morphological and functional heterogeneity through differentiated expression of pro- and anticoagulant factors, presence and frequency of intercellular contacts, variable contractility, cell shape, and volume. Altogether, these properties are crucial for adjustment of the endothelial function and further maintenance of the adequate homeostasis in response in local microenvironmental changes. Endothelial cells (ECs) play a critical role in coordinated regulation of blood flow. This is achieved due to the capacity of ECs to create the active anti-thrombotic surface that supports blood fluidity and transfer of blood cells and biomolecules. However, in certain vascular regions that can occur in inflamed sites or in sites with high hydrodynamic shear stress, ECs could lost their anti-thrombotic properties and switch their normal quiescent phenotype towards the prothrombotic, proadhesion, and proinflammatory state. In such an athero-prone site, the proper endothelial function is impaired that increases risk for formation of the atherosclerotic plaque. The endothelial dysfunction not only precedes atherosclerosis but greatly contributes to atherogenesis in all disease stages. Healthy lifestyle and regular intake of correct antioxidant-rich diet such as fresh fruits, vegetables, olive oil, red wine, and tea have beneficial effects on endothelial function and could therefore reduce the cardiovascular risk. PMID- 25723464 TI - Aryl- and heteroaryl substituted tandospirones as possible antidepressant drugs. AB - Nowadays, heterocyclic compounds which have a nitrogen atom on the structure, such as pharmacological products, pesticides and antimicrobials can be demonstrated by biologically-active groups that serve the pharmaceutical industry and they are still important in this field. Various cyclization reactions form the basis of the literature on the syntheses of heterocyclic compounds. NArylpiperazines are a class of heterocyclic compounds that play an important role in organic synthesis and are generally found as fragments in receptor ligands and natural products. They have been used extensively as reactive species for building chemical diversity. Arylpiperazines are also found in many pharmacologically-active molecules. Our research group has published numerous papers over the last two years on the synthesis of potentially bioactive tandospirone analogues which have a piperazine group by reductive Heck reactions. We also reported some important isoxazoline derivatives by 1,3-dipolar cycloadditions. Our work continued with potentially pharmacologically-active tandospirone analogues which have an exo-ring in the tricyclic system with an oxygen bridge and containing a 3-(trifluoromethyl)phenyl and 2,3-dichlorophenyl group on the aromatic ring. PMID- 25723466 TI - Consumer depletion alters seagrass resistance to an invasive macroalga. AB - Few field studies have investigated how changes at one trophic level can affect the invasibility of other trophic levels. We examined the hypothesis that the spread of an introduced alga in disturbed seagrass beds with degraded canopies depends on the depletion of large consumers. We mimicked the degradation of seagrass canopies by clipping shoot density and reducing leaf length, simulating natural and anthropogenic stressors such as fish overgrazing and water quality. Caulerpa racemosa was transplanted into each plot and large consumers were excluded from half of them using cages. Potential cage artifacts were assessed by measuring irradiance, scouring by leaf movement, water flow, and sedimentation. Algal invasion of the seagrass bed differed based on the size of consumers. The alga had higher cover and size under the cages, where the seagrass was characterized by reduced shoot density and canopy height. Furthermore, canopy height had a significant effect depending on canopy density. The alteration of seagrass canopies increased the spread of C. racemosa only when large consumers were absent. Our results suggest that protecting declining habitats and/or restoring fish populations will limit the expansion of C. racemosa. Because MPAs also enhance the abundance and size of fish consuming seagrass they can indirectly promote algal invasion. The effects of MPAs on invasive species are context dependent and require balancing opposing forces, such as the conservation of seagrass canopy structure and the protection of fish grazing the seagrass. PMID- 25723465 TI - Follow-up of an asymptomatic Chagas disease population of children after treatment with nifurtimox (Lampit) in a sylvatic endemic transmission area of Colombia. AB - BACKGROUND: Chagas disease is an anthropozoonosis caused by Trypanosoma cruzi. Two drugs are currently used for the etiological treatment of the disease: Nifurtimox (Lampit) and Benznidazole. This study presents a quasi-experimental trial (non-control group) of sixty-two patients who were treated for Chagas disease with Nifurtimox (Lampit), and were then followed for 30 months post treatment. The safety of Nifurtimox (Lampit) for Chagas disease in this group of children primarily between 4 and 19 years old was also evaluated. MATERIALS AND METHODS: The 62 patients included in the study were selected when resulted seropositive for two out of three fundamentally different serological tests. All children were treated during two months according to protocols established by WHO. Monitoring was performed every twenty days to evaluate treatment safety. In 43 patients, two different serological tests: ELISA and IFAT; and two parasitological tests: blood culture, and real time PCR, (qPCR) were performed to assess therapeutic response, defined as post-treatment serological negativization. PRINCIPAL FINDINGS: All patients completed the treatment successfully, and six patients abandoned the post-treatment follow-up. Adverse effects occurred in 74% of patients, but only 4.8% of cases required temporary suspension to achieve 100% adherence to the 60-day treatment, and all symptoms reverted after treatment completion. Both parasite load (measured through qPCR) and antibodies (ELISA absorbance) evidenced a significant median reduction 6 months after treatment from 6.2 to 0.2 parasite equivalents/mL, and from 0.6 to 0.2 absorbance units respectively (p<0.001). Serological negativization by ELISA was evident since 6 months post-treatment, whereas by IFAT only after 18 months. Serological negativization by the two tests (ELISA and IFAT) was 41.9% (95%CI: 26.5-57.3) after 30 months post-treatment. qPCR was positive in 88.3% of patients pre-treatment and only in 12.1% of patients after 30 months. Survival analysis indicated that only 26.3% (95%CI: 15.5-44.8) persisted with negative qPCR during the whole follow-up period. CONCLUSIONS: Nifurtimox was very well tolerated and successfully reduced parasite load and antibody titers. Re-infection, lysed parasites or a lack of anti-parasitic activity could explain these persistently positive qPCR cases. PMID- 25723468 TI - Vaccination with recombinant L7/L12-truncated Omp31 protein induces protection against Brucella infection in BALB/c mice. AB - Brucellosis is the most common bacterial zoonotic disease worldwide and no vaccine is available for the prevention of human brucellosis. In humans, brucellosis is mostly caused by Brucella melitensis and Brucella abortus. The Outer membrane protein 31 (Omp31) and L7/L12 are immunodominant and protective antigens conserved in human Brucella pathogens. In the present study, we evaluated the humoral and cellular immune responses induced by a fusion protein designed based on the Truncated form of Omp31 (TOmp31) and L7-L12 antigens. Vaccination of BALB/c mice with the recombinant fusion protein (rL7/L12-TOmp31) provided the significant protection level against B. melitensis and B. abortus challenge. Moreover, rL7/L12-TOmp31 elicited a strong specific IgG response (higher IgG2a titers) and significant IFN-gamma/IL2 production and T-cell proliferation was also observed. The T helper1 (Th1) oriented response persisted for 12 weeks after the first immunization. The rL7/L12-TOmp31 could be a new potential antigen candidate for the development of a subunit vaccine against B. melitensis and B. abortus. PMID- 25723469 TI - miR-203 protects microglia mediated brain injury by regulating inflammatory responses via feedback to MyD88 in ischemia. AB - Much evidence demonstrates that microglia mediated inflammatory responses play an important role in brain injury in ischemia. miRNA is the important factor in regulation of inflammation. However, the effect of miRNA in microglia mediated inflammatory responses has not been well studied. In the study, we demonstrate that miR-203 negatively regulates ischemia induced microglia activation by targeting MyD88, an important adapter protein involved in most Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) pathways. Through negative feedback, enforced expression of miR-203 or MyD88 siRNA silencing inhibits downstream NF-kappabeta signaling and microglia activation, thereby alleviating neuronal injury. These findings reveal that miR-203 represents a novel target regulating neuroinflammation and brain injury, thus offering a new therapeutical strategy for cerebral hypoxic diseases. PMID- 25723470 TI - [Pregnancy after breast cancer in germany - results of a retrospective database analysis]. AB - BACKGROUND: After the establishment of the FertiPROTEKT network in 2006, an impetus for possibilities of pregnancy during and after breast cancer was introduced. Nowadays, breast cancer survivors are confronted with the question how often women become pregnant after breast cancer and whether there have been significant changes in this respect during the past 10 years. The aim of the study was, therefore, to examine the change in frequency of pregnancies after breast cancer treatment and the time from the first breast cancer diagnosis to pregnancy over one decade, i. e., the period from 2010-2012 compared to the period from 2000-2002. METHODS: The study is based on data from the IMS Disease Analyzer database, which enables access to anonymous data from registered physicians. Data from 102 gynecological practices were available for the present study. The study included women aged 20-45 with breast cancer. RESULTS: A total of 179 pregnant women were included in this study from 2000-2002 and 2010-2012. 65 pregnancies were recorded in the period from 2000-2002, 114 pregnancies from 2010-2012. The time interval from the breast cancer diagnosis to pregnancy (analysed time period was 10 years) was 896 days (SD: 690) in the period from 2000-2002 and 552 days (SD: 696) in the period from 2010-2012 (p<0.001). CONCLUSION: There was a significant increase in pregnancies within the first 2 years after the breast cancer diagnosis. These data are consistent with the intensified consultations after the introduction of the FertiPROTEKT network. PMID- 25723471 TI - Quantitative analysis of ligand-EGFR interactions: a platform for screening targeting molecules. AB - Epidermal growth factor receptor (EGFR) is often constitutively stimulated in many cancers owing to the binding of ligands such as epidermal growth factor (EGF). Therefore, it is necessary to investigate the interaction between EGFR and its targeting biomolecules. The main aim of this study was to estimate the binding affinity and adhesion force of two targeting molecules, anti-EGFR monoclonal antibody (mAb LA1) and the peptide GE11 (YHWYGYTPQNVI), with respect to EGFR and to compare these values with those obtained for the ligand, EGF. Surface plasmon resonance (SPR) was used to determine the equilibrium dissociation constant (KD) for evaluating the binding affinity. Atomic force microscopy (AFM) was performed to estimate the adhesion force. In the case of EGFR, the KD of EGF, GE11, and mAb LA1 were 1.77 * 10-7, 4.59 * 10-4 and 2.07 * 10-9, respectively, indicating that the binding affinity of mAb LA1 to EGFR was higher than that of EGF, while the binding affinity of GE11 to EGFR was the lowest among the three molecules. The adhesion force between EGFR and mAb LA1 was 210.99 pN, which is higher than that observed for EGF (209.41 pN), while the adhesion force between GE11 and EGFR was the lowest (59.51 pN). These results suggest that mAb LA1 binds to EGFR with higher binding affinity than EGF and GE11. Moreover, the adhesion force between mAb LA1 and EGFR was greater than that observed for EGF and GE11. The SPR and AFM experiments confirmed the interaction between the receptor and targeting molecules. The results of this study might aid the screening of ligands for receptor targeting and drug delivery. PMID- 25723472 TI - Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection. AB - OBJECTIVE: To determine the durability over 96 weeks of safety and efficacy of lopinavir/ritonavir (LPV/r) and raltegravir (RAL) which was demonstrated to have non-inferior efficacy relative to a regimen of LPV/r with nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) (Control) in primary analysis at 48 weeks. DESIGN: Open label, centrally randomised trial. SETTING: Recruitment was from 37 primary and secondary care sites from Africa, Asia, Australia, Europe and Latin America. SUBJECTS: 541 HIV-1 infected adults virologically failing first line non-NRTI + 2N(t)RTI, with no previous exposure to protease inhibitors or integrase strand transfer inhibitors were analysed, 425 completed 96 weeks follow up on randomised therapy. INTERVENTION: Randomisation was 1:1 to Control or RAL. MAIN OUTCOME MEASURES: Differences between the proportion of participants with plasma HIV-1 RNA (VL) <200 copies/mL by intention to treat were compared with a non-inferiority margin of -12%. Differences in biochemical, haematological and metabolic changes were assessed using T-tests. RESULTS: VL <200 copies/mL at 96 weeks was: RAL 80.4%, Control 76.0% (difference: 4.4 [95%CI -2.6, 11.3]) and met non-inferiority criteria. The RAL arm had a significantly higher mean change (difference Control-RAL; 95%CI) in haemoglobin (-2.9; -5.7, -1.1), total lymphocytes (-0.2; -0.3, -0.0), total cholesterol (-0.5; -0.8, -0.3), HDL cholesterol (-0.1; -0.1, -0.0) and LDL cholesterol (-0.3; -0.5, -0.2). CONCLUSION: At 96 weeks, both RAL and Control maintained efficacy greater than 75% and continued to demonstrate similar safety profiles. These results support the use of a combination LPV/r and RAL regimen as an option following failure of 1st line NNRTI + 2N(t)RTIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00931463. PMID- 25723473 TI - Trehalose-6-phosphate and SNF1-related protein kinase 1 are involved in the first fruit inhibition of cucumber. AB - In cucumber (Cucumis sativus L.), the preexisting fruits inhibit the growth of subsequent fruits. To study the mechanism underlying this phenomenon, we examined the sink activity, the level of free sugars, and the activity of SNF1-related protein kinase 1 (SnRK1) in the peduncles of two types of fruits. In the two fruit cucumber plants, the growth rate and sink activity [evaluated by alkaline alpha-galactosidase (CsAGA) activity in the peduncle] of the first fruit were greater than those of the second fruit. The (14)C-labeling experiment revealed that assimilates produced by the leaves closer to the second fruit tended to move to the first fruit. Sucrose and trehalose-6-phosphate (T6P) levels in the peduncle of the first fruit were higher than those in the peduncle of the second fruit. The SnRK1 activity was lower in the peduncle of the first fruit than in that of the second fruit at 0-8 days after anthesis. The growth rate and sink activity of the second fruit were enhanced after the removal of the first fruit or after treatment with 6-benzyl aminopurine, as determined by comparison with an increase in the sucrose and T6P levels and a decrease in the SnRK1 activity in its peduncle. The SnRK1 activity was inhibited by T6P in an in vitro kinase assay, and the mRNA level of CsAGA1 in cucumber calli was up-regulated by exogenous trehalose treatment, confirming that the SnRK1 activity and CsAGA1 expression can be regulated by T6P levels. Our results suggest that the T6P- and SnRK1-mediated signaling functions are involved in the regulation of first-fruit inhibition in cucumber plants. PMID- 25723474 TI - Productivity, absorbed photosynthetically active radiation, and light use efficiency in crops: implications for remote sensing of crop primary production. AB - Vegetation productivity metrics such as gross primary production (GPP) at the canopy scale are greatly affected by the efficiency of using absorbed radiation for photosynthesis, or light use efficiency (LUE). Thus, close investigation of the relationships between canopy GPP and photosynthetically active radiation absorbed by vegetation is the basis for quantification of LUE. We used multiyear observations over irrigated and rainfed contrasting C3 (soybean) and C4 (maize) crops having different physiology, leaf structure, and canopy architecture to establish the relationships between canopy GPP and radiation absorbed by vegetation and quantify LUE. Although multiple LUE definitions are reported in the literature, we used a definition of efficiency of light use by photosynthetically active "green" vegetation (LUE(green)) based on radiation absorbed by "green" photosynthetically active vegetation on a daily basis. We quantified, irreversible slowly changing seasonal (constitutive) and rapidly day to-day changing (facultative) LUE(green), as well as sensitivity of LUE(green) to the magnitude of incident radiation and drought events. Large (2-3-fold) variation of daily LUE(green) over the course of a growing season that is governed by crop physiological and phenological status was observed. The day-to day variations of LUE(green) oscillated with magnitude 10-15% around the seasonal LUE(green) trend and appeared to be closely related to day-to-day variations of magnitude and composition of incident radiation. Our results show the high variability of LUE(green) between C3 and C4 crop species (1.43 g C/MJ vs. 2.24 g C/MJ, respectively), as well as within single crop species (i.e., maize or soybean). This implies that assuming LUE(green) as a constant value in GPP models is not warranted for the crops studied, and brings unpredictable uncertainties of remote GPP estimation, which should be accounted for in LUE models. The uncertainty of GPP estimation due to facultative and constitutive changes in LUE(green) can be considered as a critical component of the total error budget in the context of remotely sensed based estimations of GPP. The quantitative framework of LUE(green) estimation presented here offers a way of characterizing LUE(green) in plants that can be used to assess their phenological and physiological status and vulnerability to drought under current and future climatic conditions and is essential for calibration and validation of globally applied LUE algorithms. PMID- 25723475 TI - Low molecular weight heparin (LMWH) improves peritoneal function and inhibits peritoneal fibrosis possibly through suppression of HIF-1alpha, VEGF and TGF beta1. AB - BACKGROUND: Peritoneal fibrosis is the major cause of ultrafiltration failure, and intraperitoneal administration of Low Molecular Weight Heparin (LMWH) was reported to protect peritoneal function. But the exact mechanism of its influence on peritoneal structure and function is still unknown. METHODS: A fibrosis model of rat was established by intraperitoneal (IP) administration of PD fluid and Erythromycin Lactobionate. Fifty-two rats were randomly divided into 6 groups: (1) normal control group (CON, n = 6); (2) normal saline group (NS, n = 10); (3) high-glucose group (GLU, n = 10); (4) heparin group (HEP, n = 6); (5) low dose LMWH group (LLMWH, n = 10); (6) high dose LMWH group (HLMWH, n = 10). Two hour peritoneal equilibration test was performed after 28 days of intervention. The peritoneum, mesentery and omentum were harvested, and evaluated by Hematoxylin Eosin and Masson Trichrome staining. The expressions of HIF-1alpha, VEGF and TGF beta1 in parietal peritoneum were detected by IHC and RT-PCR (Reverse Transcriptase Polymerase Chain Reaction). RESULTS: Compared with group CON and NS, ultrafiltration volume and D2/D0 glucose in group GLU decreased significantly, D/Purea (Dialysate-Plasma ratio of urea), D/Palb (Dialysate-Plasma ratio of albumin), peritoneal thickness, neoangiogenesis and inflammatory reaction increased significantly (all P<0.05). Administration of heparin and LMWH markedly alleviated these above pathological changes. The protein and mRNA levels of HIF-1alpha, VEGF and TGF-beta1 increased significantly in group GLU, and decreased significantly after administration of LMWH in a dose-dependent manner. CONCLUSIONS: LMWH ameliorates peritoneal function and inhibits peritoneal fibrosis, possibly through suppression of HIF-1alpha, VEGF and TGF-beta1. PMID- 25723476 TI - Embryonic stem cells derived from in vivo or in vitro-generated murine blastocysts display similar transcriptome and differentiation potential. AB - The use of assisted reproductive technologies (ART) such as in vitro fertilization (IVF) has resulted in the birth of more than 5 million children. While children conceived by these technologies are generally healthy, there is conflicting evidence suggesting an increase in adult-onset complications like glucose intolerance and high blood pressure in IVF children. Animal models indicate similar potential risks. It remains unclear what molecular mechanisms may be operating during in vitro culture to predispose the embryo to these diseases. One of the limitations faced by investigators is the paucity of the material in the preimplantation embryo to test for molecular analysis. To address this problem, we generated mouse embryonic stem cells (mESC) from blastocysts conceived after natural mating (mESCFB) or after IVF, using optimal (KSOM + 5% O2; mESCKAA) and suboptimal (Whitten's Medium, + 20% O2, mESCWM) conditions. All three groups of embryos showed similar behavior during both derivation and differentiation into their respective mESC lines. Unsupervised hierarchical clustering of microarray data showed that blastocyst culture does not affect the transcriptome of derived mESCs. Transcriptomic changes previously observed in the inner cell mass (ICM) of embryos derived in the same conditions were not present in mESCs, regardless of method of conception or culture medium, suggesting that mESC do not fully maintain a memory of the events occurring prior to their derivation. We conclude that the fertilization method or culture media used to generate blastocysts does not affect differentiation potential, morphology and transcriptome of mESCs. PMID- 25723477 TI - Correction. Is the readmission rate a valid quality indicator? A review of the evidence. PMID- 25723478 TI - Altered esophageal histamine receptor expression in Eosinophilic Esophagitis (EoE): implications on disease pathogenesis. AB - Eosinophilic Esophagitis (EoE) is a chronic allergic disorder, whose pathobiology is incompletely understood. Histamine-producing cells including mast cells and basophils have been implicated in EoE. However, very little is currently known about the role of histamine and histamine receptor (HR) expression and signaling in the esophageal epithelium. Herein, we characterized HR (H1R, H2R, H3R, and H4R) expression in human esophageal biopsies and investigate the role of histamine signaling in inducible cytokine expression in human esophageal epithelial cells in vitro. HR expression was quantified in esophageal biopsies from non-EoE control (N = 23), inactive EoE (<15 eos/hpf, N = 26) and active EoE (>15 eos/hpf, N = 22) subjects using qRT-PCR and immunofluorescent localization. HR expression and histamine-mediated cytokine secretion were evaluated in human primary and telomerase-immortalized esophageal epithelial cells. H1R, H2R, and H4R expression were increased in active EoE biopsies compared to inactive EoE and controls. H2R was the most abundantly expressed receptor, and H3R expression was negligible in all 3 cohorts. Infiltrating eosinophils expressed H1R, H2R, and H4R, which contributed to the observed increase in HR in active subjects. H1R and H2R, but not H3R or H4R, were constitutively expressed by primary and immortalized cells, and epithelial histamine stimulation induced GM-CSF, TNFalpha, and IL-8, but not TSLP or eotaxin-3 secretion. Epithelial priming with the TLR3 ligand poly (I:C) induced H1R and H2R expression, and enhanced histamine induced GM-CSF, TNFalpha, and IL-8 secretion. These effects were primarily suppressed by H1R antagonists, but unaffected by H2R antagonism. Histamine directly activates esophageal epithelial cytokine secretion in vitro in an H1R dependent fashion. However, H1R, H2R and H4R are induced in active inflammation in EoE in vivo. While systemic antihistamine (anti-H1R) therapy may not induce clinical remission in EoE, our study suggests that further study of histamine receptor signaling in EoE is warranted and that targeting of additional histamine receptors may lead to novel treatment strategies for this important disease. PMID- 25723479 TI - Cofilin1 controls transcolumnar plasticity in dendritic spines in adult barrel cortex. AB - During sensory deprivation, the barrel cortex undergoes expansion of a functional column representing spared inputs (spared column), into the neighboring deprived columns (representing deprived inputs) which are in turn shrunk. As a result, the neurons in a deprived column simultaneously increase and decrease their responses to spared and deprived inputs, respectively. Previous studies revealed that dendritic spines are remodeled during this barrel map plasticity. Because cofilin1, a predominant regulator of actin filament turnover, governs both the expansion and shrinkage of the dendritic spine structure in vitro, it hypothetically regulates both responses in barrel map plasticity. However, this hypothesis remains untested. Using lentiviral vectors, we knocked down cofilin1 locally within layer 2/3 neurons in a deprived column. Cofilin1-knocked-down neurons were optogenetically labeled using channelrhodopsin-2, and electrophysiological recordings were targeted to these knocked-down neurons. We showed that cofilin1 knockdown impaired response increases to spared inputs but preserved response decreases to deprived inputs, indicating that cofilin1 dependency is dissociated in these two types of barrel map plasticity. To explore the structural basis of this dissociation, we then analyzed spine densities on deprived column dendritic branches, which were supposed to receive dense horizontal transcolumnar projections from the spared column. We found that spine number increased in a cofilin1-dependent manner selectively in the distal part of the supragranular layer, where most of the transcolumnar projections existed. Our findings suggest that cofilin1-mediated actin dynamics regulate functional map plasticity in an input-specific manner through the dendritic spine remodeling that occurs in the horizontal transcolumnar circuits. These new mechanistic insights into transcolumnar plasticity in adult rats may have a general significance for understanding reorganization of neocortical circuits that have more sophisticated columnar organization than the rodent neocortex, such as the primate neocortex. PMID- 25723481 TI - Investigations of anticholinestrase and antioxidant potentials of methanolic extract, subsequent fractions, crude saponins and flavonoids isolated from Isodon rugosus. AB - BACKGROUND: Based on the ethnomedicinal uses and the effective outcomes of natural products in various diseases, this study was designed to evaluate Isodon rugosus as possible remedy in oxidative stress, alzheimer's and other neurodegenerative diseases. Acetylecholinestrase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of crude methanolic extract (Ir.Cr), resultant fractions (n-hexane (Ir.Hex), chloroform (Ir.Cf), ethyl acetate (Ir.EtAc), aqueous (Ir.Aq)), flavonoids (Ir.Flv) and crude saponins (Ir.Sp) of I. rugosus were investigated using Ellman's spectrophotometric method. Antioxidant potential of I. rugosus was determined using DPPH, H2O2 and ABTS free radicals scavenging assays. Total phenolic and flavonoids contents of plant extracts were determined and expressed in mg GAE/g dry weight and mg RTE/g of dry sample respectively. RESULTS: Among different fractions Ir.Flv and Ir.Cf exhibited highest inhibitory activity against AChE (87.44 +/- 0.51, 83.73 +/- 0.64%) and BChE (82.53 +/- 0.71, 88.55 +/- 0.77%) enzymes at 1 mg/ml with IC50 values of 45, 50 for AChE and 40, 70 MUg/ml for BChE respectively. Activity of these fractions were comparable to galanthamine causing 96.00 +/- 0.30 and 88.61 +/- 0.43% inhibition of AChE and BChE at 1 mg/ml concentration with IC50 values of 20 and 47 MUg/ml respectively. In antioxidant assays, Ir.Flv, Ir.Cf, and Ir.EtAc demonstrated highest radicals scavenging activities in DPPH and H2O2 assays which were comparable to ascorbic acid. Ir.Flv was found most potent with IC50 of 19 and 24 MUg/ml against DPPH and H2O2 radicals respectively. Whereas antioxidant activates of plant samples against ABTS free radicals was moderate. Ir.Cf, Ir.EtAc and Ir.Cr showed high phenolic and flavonoid contents and concentrations of these compounds in different fractions correlated well to their antioxidant and anticholinestrase activities. CONCLUSION: It may be inferred from the current investigations that the Ir.Sp, Ir.Flv and various fractions of I. rugosus are good sources of anticholinesterase and antioxidant compounds. Different fractions can be subjected to activity guided isolation of bioactive compounds effective in neurological disorders. PMID- 25723482 TI - Health economic evaluations of visceral leishmaniasis treatments: a systematic review. AB - OBJECTIVE: The main objective of this study was to identify, describe, classify and analyze the scientific health economic evidence of VL-related technologies. METHODS: A web search of combinations of free text and Mesh terms related to the economic evaluation of visceral leishmaniasis was conducted on scientific publication databases (Web of Science, Scopus, Medline via the Pubmed and Lilacs). A manual search of references lists of articles previously identified by the authors was also included. Articles written in English, Portuguese, Spanish or French were considered suitable for inclusion. Articles that matched the inclusion criteria were screened by at least two researchers, who extracted information regarding the epidemiologic scenario and methodological issues on a standardized form. RESULTS: The initial search retrieved 107 articles, whose abstracts were inspected according to the inclusion criteria leading to a first selection of 49 (46%) articles. After the elimination of duplicates, the list was reduced to 21 (20%) articles. After careful reading and application of exclusion criteria, 14 papers were eligible according to the description, classification and analysis process proposed by the study. When classified by type of economic evaluation, articles were 7 (50%) cost-effectiveness, 5 (36%) cost-minimization, 1(7%) cost-benefit, and 1(7%) budget impact. When classified by methodology, studies were mainly nested to clinical-trials ("piggy back") 8(57%). Discount rates for outcomes and costs were present in 3 (43%) of the cost-effectiveness studies, and according to WHO's recommendations, the discount rate of 3% was used in all studies. CONCLUSIONS: This article showed that health economic evaluations on visceral leishmaniasis used a wide range of technologies and methods. Nevertheless it is important to point out the geographic concentration of studies, which makes their transferability uncertain to different epidemiological scenarios, especially those concerning visceral leishmaniasis caused by Leishmania infantum. PMID- 25723483 TI - Editorial: Rethinking the definition of diabetes for precision medicine. PMID- 25723485 TI - Corrigendum. Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice. PMID- 25723489 TI - Unstable chromosome aberrations do not accumulate in normal human fibroblast after fractionated x-irradiation. AB - We determined the frequencies of dicentric chromosomes per cell in non-dividing confluent normal human fibroblasts (MRC-5) irradiated with a single 1 Gy dose or a fractionated 1 Gy dose (10X0.1 Gy, 5X0.2 Gy, and 2X0.5 Gy). The interval between fractions was between 1 min to 1440 min. After the completion of X irradiation, the cells were incubated for 24 hours before re-plating at a low density. Then, demecolcine was administrated at 6 hours, and the first mitotic cells were collected for 42 hours. Our study demonstrated that frequencies of dicentric chromosomes in cells irradiated with a 1 Gy dose at different fractions were significantly reduced if the fraction interval was increased from 1 min to 5 min (p<0.05, chi2-test). Further increasing the fraction interval from 5 up to 1440 min did not significantly affect the frequency of dicentric chromosomes. Since misrejoining of two independent chromosome breaks introduced in close proximity gives rise to dicentric chromosome, our results indicated that such circumstances might be quite infrequent in cells exposed to fractionated X irradiation with prolonged fraction intervals. Our findings should contribute to improve current estimation of cancer risk from chronic low-dose-rate exposure, or intermittent exposure of low-dose radiation by medical exposure. PMID- 25723488 TI - Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. AB - Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1) linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt) induces p62 phosphorylation at its ubiquitin-association (UBA) domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington's disease. PMID- 25723490 TI - Study of integrated heterogeneous data reveals prognostic power of gene expression for breast cancer survival. AB - BACKGROUND: Studies show that thousands of genes are associated with prognosis of breast cancer. Towards utilizing available genetic data, efforts have been made to predict outcomes using gene expression data, and a number of commercial products have been developed. These products have the following shortcomings: 1) They use the Cox model for prediction. However, the RSF model has been shown to significantly outperform the Cox model. 2) Testing was not done to see if a complete set of clinical predictors could predict as well as the gene expression signatures. METHODOLOGY/FINDINGS: We address these shortcomings. The METABRIC data set concerns 1981 breast cancer tumors. Features include 21 clinical features, expression levels for 16,384 genes, and survival. We compare the survival prediction performance of the Cox model and the RSF model using the clinical data and the gene expression data to their performance using only the clinical data. We obtain significantly better results when we used both clinical data and gene expression data for 5 year, 10 year, and 15 year survival prediction. When we replace the gene expression data by PAM50 subtype, our results are significant only for 5 year and 15 year prediction. We obtain significantly better results using the RSF model over the Cox model. Finally, our results indicate that gene expression data alone may predict long-term survival. CONCLUSIONS/SIGNIFICANCE: Our results indicate that we can obtain improved survival prediction using clinical data and gene expression data compared to prediction using only clinical data. We further conclude that we can obtain improved survival prediction using the RSF model instead of the Cox model. These results are significant because by incorporating more gene expression data with clinical features and using the RSF model, we could develop decision support systems that better utilize heterogeneous information to improve outcome prediction and decision making. PMID- 25723492 TI - Inertia coupling analysis of a self-decoupled wheel force transducer under multi axis acceleration fields. AB - Wheel force transducer (WFT), which measures the three-axis forces and three-axis torques applied to the wheel, is an important instrument in the vehicle testing field and has been extremely promoted by researchers with great interests. The transducer, however, is typically mounted on the wheel of a moving vehicle, especially on a high speed car, when abruptly accelerating or braking, the mass/inertia of the transducer/wheel itself will have an extra effect on the sensor response so that the inertia/mass loads will also be detected and coupled into the signal outputs. The effect which is considered to be inertia coupling problem will decrease the sensor accuracy. In this paper, the inertia coupling of a universal WFT under multi-axis accelerations is investigated. According to the self-decoupling approach of the WFT, inertia load distribution is solved based on the principle of equivalent mass and rotary inertia, thus then inertia impact can be identified with the theoretical derivation. The verification is achieved by FEM simulation and experimental tests. Results show that strains in simulation agree well with the theoretical derivation. The relationship between the applied acceleration and inertia load for both wheel force and moment is the approximate linear, respectively. All the relative errors are less than 5% which are within acceptable and the inertia loads have the maximum impact on the signal output about 1.5% in the measurement range. PMID- 25723491 TI - The effects of knockdown of rho-associated kinase 1 and zipper-interacting protein kinase on gene expression and function in cultured human arterial smooth muscle cells. AB - Rho-associated kinase (ROCK) and zipper-interacting protein kinase (ZIPK) have been implicated in diverse physiological functions. ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes. To test the hypothesis that sequential activation of ROCK1 and ZIPK is commonly involved in regulatory pathways, we utilized siRNA to knock down ROCK1 and ZIPK in cultured human arterial smooth muscle cells (SMC). Microarray analysis using a whole-transcript expression chip identified changes in gene expression induced by ROCK1 and ZIPK knockdown. ROCK1 knockdown affected the expression of 553 genes, while ZIPK knockdown affected the expression of 390 genes. A high incidence of regulation of transcription regulator genes was observed in both knockdowns. Other affected groups included transporters, kinases, peptidases, transmembrane and G protein-coupled receptors, growth factors, phosphatases and ion channels. Only 76 differentially expressed genes were common to ROCK1 and ZIPK knockdown. Ingenuity Pathway Analysis identified five pathways shared between the two knockdowns. We focused on cytokine signaling pathways since ROCK1 knockdown up-regulated 5 and down-regulated 4 cytokine genes, in contrast to ZIPK knockdown, which affected the expression of only two cytokine genes (both down-regulated). IL-6 gene expression and secretion of IL-6 protein were up-regulated by ROCK1 knockdown, whereas ZIPK knockdown reduced IL-6 mRNA expression and IL-6 protein secretion and increased ROCK1 protein expression, suggesting that ROCK1 may inhibit IL-6 secretion. IL-1beta mRNA and protein levels were increased in response to ROCK1 knockdown. Differences in the effects of ROCK1 and ZIPK knockdown on cell cycle regulatory genes suggested that ROCK1 and ZIPK regulate the cell cycle by different mechanisms. ROCK1, but not ZIPK knockdown reduced the viability and inhibited proliferation of vascular SMC. We conclude that ROCK1 and ZIPK have diverse, but predominantly distinct regulatory functions in vascular SMC and that ROCK1-mediated activation of ZIPK is not involved in most of these functions. PMID- 25723493 TI - Circuit motifs for contrast-adaptive differentiation in early sensory systems: the role of presynaptic inhibition and short-term plasticity. AB - In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems. PMID- 25723495 TI - Napping reverses increased pain sensitivity due to sleep restriction. AB - STUDY OBJECTIVE: To investigate pain sensitivity after sleep restriction and the restorative effect of napping. DESIGN: A strictly controlled randomized crossover study with continuous polysomnography monitoring was performed. SETTING: Laboratory-based study. PARTICIPANTS: 11 healthy male volunteers. INTERVENTIONS: Volunteers attended two three-day sessions: "sleep restriction" alone and "sleep restriction and nap". Each session involved a baseline night of normal sleep, a night of sleep deprivation and a night of free recovery sleep. Participants were allowed to sleep only from 02:00 to 04:00 during the sleep deprivation night. During the "sleep restriction and nap" session, volunteers took two 30-minute naps, one in the morning and one in the afternoon. MEASUREMENTS AND RESULTS: Quantitative sensory testing was performed with heat, cold and pressure, at 10:00 and 16:00, on three areas: the supraspinatus, lower back and thigh. After sleep restriction, quantitative sensory testing revealed differential changes in pain stimuli thresholds, but not in thermal threshold detection: lower back heat pain threshold decreased, pressure pain threshold increased in the supraspinatus area and no change was observed for the thigh. Napping restored responses to heat pain stimuli in the lower back and to pressure stimuli in the supraspinatus area. CONCLUSIONS: Sleep restriction induces different types of hypersensitivity to pain stimuli in different body areas, consistent with multilevel mechanisms, these changes being reversed by napping. The napping restorative effect on pain thresholds result principally from effects on pain mechanisms, since it was independent of vigilance status. PMID- 25723494 TI - Differences in the direction of change of cerebral function parameters are evident over three years in HIV-infected individuals electively commencing initial cART. AB - BACKGROUND: Changes in cerebral metabolite ratios (CMR) measured on 1H-MRS and changes in cognitive function (CF) are described in subjects commencing combination antiretroviral therapy (cART), although the dynamics of such changes are poorly understood. METHODS: Neuroasymptomatic, HIV-infected subjects electively commencing cART were eligible. CMR were assessed in three anatomical voxels and CF assessed at baseline, week 48 and week 144. Overall differences in absolute change in CMRs and CF parameters between 0-48 and 48-144 weeks were assessed. RESULTS: Twenty-two subjects completed study procedures. Plasma HIV-RNA was <50 copies/mL in all at week 48 and in all, but two subjects at week 144. In general, between weeks 0-48 a rise in N-acetyl-aspartate(NAA)/Creatine(Cr) ratio and a decline in myo-Inositol(mI)/Cr ratio were observed. Between weeks 48-144, small rises in NAA/Cr ratio were observed in two anatomical voxels, whereas a rise in mI/Cr ratio was observed in all anatomical locations (0.31 (0.66) and 0.27 (1.35) between weeks 0-48 and 0.13 (0.91) and 1.13 (1.71) between weeks 48 144 for absolute changes in NAA/Cr and mI/Cr (SD) in frontal-grey voxel, respectively). Global CF score improved between weeks 0-48 and then declined between weeks 48-144 (0.63 (1.16) and -0.63 (0.1.41) for mean absolute change (SD) between weeks 0-48 and weeks 48-144, respectively). CONCLUSIONS: The direction of change of cerebral function parameters differs over time in HIV infected subjects commencing cART, highlighting the need for long-term follow-up in such studies. The changes we have observed between weeks 48-144 may represent the initial development of cerebral toxicities from cART. PMID- 25723496 TI - Nutritional evaluation of Australian microalgae as potential human health supplements. AB - This study investigated the biochemical suitability of Australian native microalgal species Scenedesmus sp., Nannochloropsis sp., Dunaliella sp., and a chlorophytic polyculture as nutritional supplements for human health. The four microalgal cultures were harvested during exponential growth, lyophilized, and analysed for proximate composition (moisture, ash, lipid, carbohydrates, and protein), pigments, and amino acid and fatty acid profiles. The resulting nutritional value, based on biochemical composition, was compared to commercial Spirulina and Chlorella products. The Australian native microalgae exhibited similar, and in several cases superior, organic nutritional properties relative to the assessed commercial products, with biochemical profiles rich in high quality protein, nutritious polyunsaturated fats (such as alpha-linolenic acid, arachidonic acid, and eicosapentaenoic acid), and antioxidant pigments. These findings indicate that the microalgae assessed have great potential as multi nutrient human health supplements. PMID- 25723499 TI - Growth of Au on Pt icosahedral nanoparticles revealed by low-dose in situ TEM. AB - A growth mode was revealed by an in situ TEM study of nucleation and growth of Au on Pt icosahedral nanoparticles. Quantitative analysis of growth kinetics was carried out based on real-time TEM data, which shows the process involves: (1) deposition of Au on corner sites of Pt icosahedral nanoparticles, (2) diffusion of Au from corners to terraces and edges, and (3) subsequent layer-by-layer growth of Au on Au surfaces to form Pt@Au core-shell nanoparticles. The in situ TEM results indicate diffusion of Au from corner islands to terraces and edges is a kinetically controlled growth, as evidenced by a measurement of diffusion coefficients for these growth processes. We demonstrated that in situ electron microscopy is a valuable tool for quantitative study of nucleation and growth kinetics and can provide new insight into the design and precise control of heterogeneous nanostructures. PMID- 25723497 TI - Description and utilization of the United States department of defense serum repository: a review of published studies, 1985-2012. AB - Specimens in the United States Department of Defense (DoD) Serum Repository have accumulated in frozen storage since 1985 when the DoD began universal screening for human immunodeficiency virus. Use of the stored serum for health research has been carefully controlled, but the resulting publications have never been systematically identified or described. The Armed Forces Health Surveillance Center (AFHSC) information systems and open (online) sites were used as data sources. Through 2012, the repository contained 54,542,658 serum specimens, of which 228,610 (0.42%) have been accessed for any purpose. Between 2001 (the first year that comprehensive, digital records were available) and 2012, 65.2% of all approved requests for serum were for healthcare or public health investigations, but greater than 99% of all shipped samples were for research. Using two different methods - a structure search of PubMed and an exhaustive online search based on records from AFHSC - we identified 76 articles published between October 1988 and March 2013 that covered a multitude of infectious diseases, injuries, environmental exposures and mental health conditions through analysis of antibodies, biological metabolic, signaling and regulatory substances, Vitamin D, organochlorines, dioxin, omega-3-fatty acid, and portions of human deoxyribonucleic acid. Despite its operational and scientific value, it appears that the DoD Serum Repository has been underutilized. Changes to policy and increased capacity for specimen processing could increase use of the repository without risking privacy or the availability of specimens for the healthcare of individual service members in the future. PMID- 25723500 TI - Pathological Response of Northern Bobwhites to Oxyspirura petrowi Infections. AB - The effects of Oxyspirura petrowi infections in northern bobwhites ( Colinus virginianus ) are not well understood. While studies have reported O. petrowi infections, none has histopathologically examined the eye surface and intraorbital glands to assess cellular-level impacts associated with infection. This study is the first to document the histopathology associated with O. petrowi infections. Oxyspirura petrowi occurred on the eye surface as well as in the conjunctiva, lacrimal ducts, lacrimal glands, and Harderian glands. Histopathology showed infections of O. petrowi caused cellular damage to these tissues, scarring and interstitial keratitis of the cornea, and acinar atrophy of the Harderian gland. PMID- 25723501 TI - A working model of how noroviruses infect the intestine. PMID- 25723502 TI - Inter-epidemic acquisition of Rift Valley fever virus in humans in Tanzania. AB - BACKGROUND: In East Africa, epidemics of Rift Valley fever (RVF) occur in cycles of 5-15 years following unusually high rainfall. RVF transmission during inter epidemic periods (IEP) generally passes undetected in absence of surveillance in mammalian hosts and vectors. We studied IEP transmission of RVF and evaluated the demographic, behavioural, occupational and spatial determinants of past RVF infection. METHODOLOGY: Between March and August 2012 we collected blood samples, and administered a risk factor questionnaire among 606 inhabitants of 6 villages in the seasonally inundated Kilombero Valley, Tanzania. ELISA tests were used to detect RVFV IgM and IgG antibodies in serum samples. Risk factors were examined by mixed effects logistic regression. FINDINGS: RVF virus IgM antibodies, indicating recent RVFV acquisition, were detected in 16 participants, representing 2.6% overall and in 22.5% of inhibition ELISA positives (n = 71). Four of 16 (25.0%) IgM positives and 11/71 (15.5%) of individuals with inhibition ELISA sero-positivity reported they had had no previous contact with host animals. Sero-positivity on inhibition ELISA was 11.7% (95% CI 9.2-14.5) and risk was elevated with age (odds ratio (OR) 1.03 per year; 95% CI 1.01-1.04), among milkers (OR 2.19; 95% CI 1.23-3.91), and individuals eating raw meat (OR 4.17; 95% CI 1.18-14.66). Households keeping livestock had a higher probability of having members with evidence of past infection (OR = 3.04, 95% CI = 1.42-6.48) than those that do not keep livestock. CONCLUSION: There is inter-epidemic acquisition of RVFV in Kilombero Valley inhabitants. In the wake of declining malaria incidence, these findings underscore the need for clinicians to consider RVF in the differential diagnosis for febrile illnesses. Several types of direct contact with livestock are important risk factors for past infection with RVFV in this study's population. However, at least part of RVFV transmission appears to have occurred through bites of infected mosquitoes. PMID- 25723503 TI - The crosstalk between miRNA and mammalian circadian clock. AB - Circadian clocks are present in most organisms to coordinate daily rhythms in physiology and behavior. The general molecular mechanisms are based on interlocked transcription-translation feedback loops driving rhythms in gene expression of a series of core clock genes. Multiple levels of regulations including transcriptional, posttranscriptional and post-translational mechanisms make circadian clock regulation more complex than once thought. Particularly, accumulating evidences have shown that miRNAs are significant players in regulating various aspects of circadian clock function. In this review, we will summarize the recent findings in the interplay of miRNAs and mammalian circadian clock and discuss future perspectives for research on the role of miRNAs played in circadian timing in health and disease. PMID- 25723504 TI - Considering autotaxin inhibitors in terms of 2D-QSAR and 3D-mapping- review and evaluation. AB - The potential role of Autotaxin (ATX) in physiological and pathological processes turned it in an attractive drug target for pharmacological therapeutic development. However, potent and selective non-lipid as well lipid inhibitors of ATX are currently not available as drugs. In this paper we tried to review all the known progress on ATX inhibition using two dimensional (2D)-Quantitative Structure Activity Relationship (QSAR) and three dimensional (3D) mapping techniques. Furthermore, we tried to compare and extract conclusions analyzing with 3D mapping techniques vastly diverse structures of non-lipid ATX inhibitors which have been reported in patents. McGowan's Volume (MgVol) molar volume and Molar Refractivity (MR) of substituents seems to govern the ATX inhibition. 3D mapping results point to the role of steric properties (Volume and Polar Surface Area-PSA). Steric factors are obviously important. The role of hydrophilicity was also highlighted. Electronic parameters are not found to be present. PMID- 25723505 TI - Inhibitors targeting the influenza virus hemagglutinin. AB - The annual flu season causes thousands of deaths and millions of hospitalizations, which pose a great burden to global health and economy. Moreover, a flu pandemic arising from reassortment viruses, such as H5N1 and H1N1, raises even greater concern due to the lack of effective vaccines at the initial stage of flu outbreak. The influenza virus is the causative agent of flu infection. Currently there are four drugs in use to combat influenza infection. Amantadine and rimantadine are M2 proton channel blockers that inhibit virus uncoating; oseltamivir and zanamivir are neuraminidase (NA) inhibitors that inhibit virus release. However, recent years have witnessed a drastic increase in instances of drug resistance, and flu strains that are resistant to both classes of drugs have been reported. Thus, there is a pressing need to develop the next generation of anti-influenza drugs. Among a handful of anti-influenza drug targets, the viral fusion protein hemagglutinin (HA) is one of the most advanced. This review discusses the biological roles of HA during viral replication and highlights peptide- and small molecule-based HA inhibitors, including recent computationally designed HA binders. The text is organized into four sections based on the maturation stages of HA: inhibitors targeting the glycosylation of HA, the proteolytic activation of HA, the attachment of HA to host cell receptors, and peptide- and small molecule-based inhibitors targeting HA-mediated membrane fusion. Of particular interest are advances in the areas of developing dual inhibitors targeting both HA and NA and broad-spectrum HA inhibitors targeting both groups of HAs. PMID- 25723506 TI - Necrosis Avidity of Organic Compounds: A Natural Phenomenon with Exploitable Theragnostic Potentials AB - Necrosis is an in vivo chaotic event distinguished by uncontrolled disintegration of the cell membrane leading to cytolysis, inflammation and tissue destruction followed by a healing or regenerating process. Targeting necrosis may offer potential diagnostic, therapeutic and/or theragnostic applications in translational medicine. This article reviews the current concept of necrosis including definition, etiology and pathophysiology. The evolution and development of a wide diversity of necrosis targeting agents and their potential applications in preclinical and clinical settings are also elaborated and discussed. PMID- 25723507 TI - Mechanisms of neurodegeration in type 2 diabetes and the neuroprotective potential of dipeptidyl peptidase 4 inhibitors. AB - Prospective epidemiological studies suggest that type 2 diabetes is a risk factor for neurodegenerative pathologies such as Alzheimer disease, vascular dementia, and Parkinson disease. Drugs that act as incretin receptor agonists or inhibit the proteolytic degradation of incretins (dipeptidyl peptidase 4 inhibitors) have been approved since 2005 for use in diabetes treatment. Dipeptidyl peptidase 4 (DPP4) cleaves N-terminal dipeptides from polypeptides when the second residue is proline, hydroxyproline, dehydroproline or alanine. The inhibition of DPP4 hydrolytic activities extends the halflife of these peptides by preventing their degradation. Several peptides have been identified as DPP4 substrates, including neuropeptides, chemokines, and the incretin hormones; hence the pleomorphic effects of DPP4 inhibition. Recently, the neuroprotective properties of these drugs have been evaluated in cell cultures and animal models, not yet in human trials. Although mechanisms distinct from glycaemic control alone have been claimed to account for protection against neuronal degeneration, the precise cellular mechanism by which DPP4 inhibitors exert their neuroprotective effects remain unknown. The present review is focused on the candidate pathways that could be involved in mediating DPP4 inhibitors-mediated protection against neuronal degeneration. PMID- 25723508 TI - Food addiction spectrum: a theoretical model from normality to eating and overeating disorders. AB - The authors comment on the recently proposed food addiction spectrum that represents a theoretical model to understand the continuum between several conditions ranging from normality to pathological states, including eating disorders and obesity, as well as why some individuals show a peculiar attachment to food that can become an addiction. Further, they review the possible neurobiological underpinnings of these conditions that include dopaminergic neurotransmission and circuits that have long been implicated in drug addiction. The aim of this article is also that at stimulating a debate regarding the possible model of a food (or eating) addiction spectrum that may be helpful towards the search of novel therapeutic approaches to different pathological states related to disturbed feeding or overeating. PMID- 25723509 TI - Potential role of natural compounds against skin aging. AB - Skin aging is an inevitable biological phenomenon of human life. Advancing age brings changes to all components of the integumentary system with consequent signs on the skin. Skin aging is mainly due to intrinsic (chronologic) and extrinsic aging (photo-aging). Photo-aging is a consequence of exposure to ultraviolet radiations. Despite variable economic conditions, the skin care market based on natural products continues to see strong growth. In this context, the research of naturally occurring anti-aging agents is greatly expanding and in recent years numerous plant-derived products have been investigated. This review article focuses on highlighting recent advances in current knowledge on anti aging natural products grouped and presented according to their family origin. Plants from 35 families were reviewed. A variety of phytomolecules, derived in particular from polyphenols, triterpenes and sterols classes, demonstrated a promising activity. Among them carnosic acid, curculigoside, curcumin, glycyrrhizic acid, mangiferin, mirkoin, asiaticoside, rosmarinic acid, tectorigenin, tyrosol etc., able to inhibit tyrosinase, hyaluronidase, elastase, and collagenase, to scavenge free radicals from skin cells, to prevent trans epidermal water loss, and to contribute to protect skin from wrinkles, were largely investigated and herein discussed. Extracts and pure compounds from Fabaceae, Asperaceae and Zingiberaceae families have shown particular interest and appear most promising in the development of anti-aging products. PMID- 25723510 TI - Recent trends in 1,2,3-Triazolo-nucleosides as promising anti-infective and anticancer agents. AB - The concept of click chemistry represented by the formation of the 1,2,3-triazole core has found wide application in drug discovery, particularly in the early discovery phases and the lead optimization process. 1,2,3-Triazoles ha ve attracted considerable attention in recent years because of their wide range of biological activities against various viruses, malignant cells, microorganisms and their inhibitory activities against several enzymes. This review emphasizes the recent advances on diverse and potent biological profiles of 1,2,3-triazolo nucleosides, along with emerging application of click chemistry in their synthesis, and their perspective in the development of new bioactive chemical entities in the future. The work is primarily addressed to antiviral, antimicrobial and anticancer potency of this important structural motifs in which the 1,2,3-triazole ring acts as a nucleobase surrogate or is linked to a nucleobase or a sugar/sugar mimic moiety. PMID- 25723511 TI - Mexiletine metabolites: a review. AB - Mexiletine belongs to class IB antiarrhythmic drugs and it is still considered a drug of choice for treating myotonias. However some patients do not respond to mexiletine or have significant side effects limiting its use; thus, alternatives to this drug should be envisaged. Mexiletine is extensive metabolized in humans via phase I and phase II reactions. Only a small fraction (about 10%) of the dose of mexiletine administered is recovered without modifications in urine. Although in the past decades Mex metabolites were reported to be devoid of biological activity, recent studies seem to deny this assertion. Actually, several hydroxylated metabolites showed pharmacological activity similar to that of Mex, thus contributing to its clinical profile. Purpose of this review is to summarize all the studies proposed till now about mexiletine metabolites, regarding structureactivity relationship studies as well as synthetic strategies. Biological and analytical studies will be also reported. PMID- 25723512 TI - Nucleic acid-based aptamers: applications, development and clinical trials. AB - Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases. PMID- 25723513 TI - High progesterone receptor expression in prostate cancer is associated with clinical failure. AB - BACKGROUND: Prostate cancer is a highly heterogeneous disease and one of the leading causes of mortality in developed countries. Specific prognostic and predictive markers for prostate cancer patients are still lacking. A causal relationship between androgens and the development of prostate cancer is generally considered biologically plausible, but androgens are not the sole effector in the complexity of prostate carcinogenesis. The aim of this study was to evaluate the prognostic significance of progesterone receptor in tumor tissue of T1-3N0 prostate cancer patients undergoing prostatectomy. METHODS: Tissue microarrays from 535 patients with prostate cancer were constructed. Duplicate cores of tumor cells and tumor stromal tissue from each resected specimen were extracted. Immunohistochemistry was used to evaluate the in-situ expression of progesterone receptor. RESULTS: In univariate analyses, high tumor cell density (p = 0.006) and high tumor stromal cell density level (p = 0.045) of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5, 95% CI: 1.2-5.2, p = 0.012). CONCLUSION: High progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure. PMID- 25723514 TI - Prodomain removal enables neto to stabilize glutamate receptors at the Drosophila neuromuscular junction. AB - Stabilization of neurotransmitter receptors at postsynaptic specializations is a key step in the assembly of functional synapses. Drosophila Neto (Neuropillin and Tolloid-like protein) is an essential auxiliary subunit of ionotropic glutamate receptor (iGluR) complexes required for the iGluRs clustering at the neuromuscular junction (NMJ). Here we show that optimal levels of Neto are crucial for stabilization of iGluRs at synaptic sites and proper NMJ development. Genetic manipulations of Neto levels shifted iGluRs distribution to extrajunctional locations. Perturbations in Neto levels also produced small NMJs with reduced synaptic transmission, but only Neto-depleted NMJs showed diminished postsynaptic components. Drosophila Neto contains an inhibitory prodomain that is processed by Furin1-mediated limited proteolysis. neto null mutants rescued with a Neto variant that cannot be processed have severely impaired NMJs and reduced iGluRs synaptic clusters. Unprocessed Neto retains the ability to engage iGluRs in vivo and to form complexes with normal synaptic transmission. However, Neto prodomain must be removed to enable iGluRs synaptic stabilization and proper postsynaptic differentiation. PMID- 25723515 TI - Morphogenesis of the compartmentalizing bone around the molar primordia in the mouse mandible during dental developmental stages between lamina, bell-stage, and root formation (E13-P20). AB - Despite increasing knowledge of the basic molecular aspects of bone formation and its regulation, the mechanisms of bone morphogenesis leading to a topologically specific shape remain unknown. The formation of the alveolar bone, which houses the dental primordia and later, the dental roots, may serve as a model to understand the formation of bone form in general. Thirty-eight heads of mice (C57 Bl/6J) ranging from stages E13-P20 were used to prepare histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia concomitantly with their surrounding bone. Special focus was given to recording the remodeling pattern. It has been shown that, in early stages (E13, E14), bone formation is characterized by apposition only. In stage E15, the bony crypt around the dental primordia is remodeled mostly by resorption of bone. In stage E18, the bone remodeling pattern shows resorption all along the bony gutter, which houses the molar primordia. The medial and lateral margins are characterized by apposition. At birth (stage P0), a bony septum has begun to form between the primordium m1 and of m2, arising from both sides and characterized by pure apposition of bone. In stage P4, the crypts of m1 and m2, and also that of m3, show bone resorption inside, while the medial and lateral bony margins show apposition of bone throughout. Generally, during development, the bone gradually encapsulates the dental primordia, in such a way that the bone reaches over the dental primordia and leaves only a continuous longish opening of about 200MUm width. The opening at the occlusal surface of m1, at the time of eruption, starting at stage P14, appears to have increased in size again. The distance between bone and dental primordium undergoes change during development. In erupted molars, it is around 100MUm, during early developmental stages, it may be as less as 20MUm. These data show the inevitability of bone remodeling. PMID- 25723516 TI - Anatomy in Cologne--Institutional development and body supply from the Weimar Republic to the early post-war period. AB - The Anatomical Institute of the University of Cologne was founded in 1925. This paper highlights its institutional development and the sources from which it procured bodies for dissection. A comparison is drawn between the first years of the institute's existence during the Weimar Republic (1925-1932) and its rebuilding after war damage in the early post-war period (1947-1954). The institute and its procurement of bodies have not previously been investigated for these two time periods. The Third Reich, for which a detailed study already exists, will be mentioned as well to allow better evaluation of the periods before and after National Socialism. Based on newly evaluated archival material and body journals which will be examined both quantitatively and qualitatively, it becomes apparent that the Cologne institute experienced a chronic shortage of bodies both during the Weimar Republic and the first post-war decade (even though the delivery facilities were mostly the same). However, the situation of the institute in terms of structure, organization and personnel as well as body supply in the aftermath of World War II proved much more challenging than during the time of the Weimar Republic. PMID- 25723517 TI - Embryonic hematopoietic stem cells and interstitial Cajal cells in the hindgut of late stage human embryos: evidence and hypotheses. AB - There have been few studies on human embryos describing a specific pattern of hindgut colonization by hematopoietic stem cells (HSCs) and interstitial Cajal cells (ICCs). We aimed to study CD34, CD45 and CD117/c-kit expression in late stage human embryos, to attain observational data that could be related to studies on the aorta-gonad-mesonephros (AGM)-derived HSCs, and data on hindgut ICCs. Antibodies were also applied to identify alpha-smooth muscle actin and neurofilaments. Six human embryos of 48-56 days were used. In the 48 day embryo, the hindgut was sporadically populated by c-kit+ ICCs, but, in all other embryos, a layer of myenteric ICCs had been established. Intraneural c-kit+ cells were found in pelvic nerves and vagal trunks, suggesting that the theory of Ramon y Cajal assuming that ICCs may be primitive neurons may not be so invalid. Also in the 48 day embryo, c-kit+/CD45+ perivascular cells were found along the pelvic neurovascular axes, suggesting that not only liver, but also other organs could be seeded with HSCs from the AGM region. CD45+ cells with dendritic morphologies were found in all hindgut layers, including the epithelium. This last evidence is suggestive of an AGM contribution to the tissue resident macrophages and could be related to processes of sprouting angiogenesis which, in turn, have been found to be guided by filopodia of endothelial tip cells. Further studies on human embryonic and fetal material should be performed to attempt to clarify whether the hindgut colonization with HSCs is a transitory or definitive process. PMID- 25723518 TI - Sex-differences of the healthy infra-patellar (Hoffa) fat pad in relation to intermuscular and subcutaneous fat content--data from the Osteoarthritis Initiative. AB - The infra-patellar fat pad (IPFP) is composed of intra-articular adipose tissue; it represents a potential source of pro-inflammatory cytokines and has been associated with osteoarthritis of the knee. Yet, to what extent the size of the IPFP differs between healthy men and women, and how sex differences compare to those in inter-muscular and subcutaneous fat tissue content is unknown. We studied healthy reference subjects from the Osteoarthritis Initiative, without knee pain, without radiographic signs or without risk factors of femorotibial osteoarthritis. Sagittal magnetic resonance images (MRIs) of 99 right knees were used to segment the IPFP; in a subset, axial images of the thigh were available to segment inter-muscular and subcutaneous fat. Healthy men (n=40) displayed a 41% greater (p<0.001) IPFP volume and a 9% greater (p<0.01) ratio of IPFP volume/body weight than women (n=59). Men (n=13) displayed 15% greater intermuscular fat content (not significant), and a 50% lesser (p<0.01) subcutaneous fat content than women (n=12); when related to total thigh cross sectional areas, these sex differences were +2% (not significant) and -53% (p<0.001). This is the first study to explore quantitative measures of the IPFP in healthy men and women, and to relate these to sex differences of inter muscular and subcutaneous fat tissue content. Men displayed a significantly greater ratio of IPFP volume/body weight than women, similar amounts of inter muscular fat, and strikingly less subcutaneous fat. These data provide a basis for further systematic studies of the variability of the IPFP with the body mass index and its role in knee osteoarthritis. PMID- 25723519 TI - Experimental and numerical analysis of the cooling performance of water spraying systems during a fire. AB - The water spray systems are effective protection systems in the confined or unconfined spaces to avoid the damage to building structures since the high temperature when fires occur. NFPA 15 and 502 have suggested respectively that the factories or vehicle tunnels install water spray systems to protect the machinery and structures. This study discussed the cooling effect of water spray systems in experimental and numerical analyses. The actual combustion of woods were compared with the numerical simulations. The results showed that although the flame continued, the cooling effects by water spraying process within 120 seconds were obvious. The results also indicated that the simulation results of the fifth version Fire Dynamics Simulator (FDS) overestimated the space temperature before water spraying in the case of the same water spray system. PMID- 25723520 TI - LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C. AB - In budding yeast, the Mitotic Exit Network (MEN) regulates anaphase promoting complex/cyclosome (APC/C) via the Dbf2-Cdc14 signaling cascade. Dbf2 kinase phosphorylates and activates Cdc14 phosphatase, which removes the inhibitory phosphorylation of the APC/C cofactor Cdh1. Although each component of the MEN was highly conserved during evolution, there is presently no evidence supporting direct phosphorylation of CDC14 by large tumor suppressor kinase 1 (LATS1), the human counterpart of Dbf2; hence, it is unclear how LATS1 regulates APC/C. Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly. Nocodazole-induced phosphorylation of T7 was reduced by knockdown of LATS1 and LATS2 in HeLa cells, indicating that both of these kinases contribute to the phosphorylation of CDC26 in vivo. The T7 residue of CDC26 is critical for its interaction with APC6, a tetratricopeptide repeat-containing subunit of APC/C, and mutation of this residue to Asp (T7D) reduced the interaction of CDC26 with APC6. Replacement of endogenous CDC26 in HeLa cells with exogenous phosphor-mimic T7D-mutated CDC26 increased the elution size of APC/C subunits in a gel filtration assay, implying a change in the APC/C assembly upon phosphorylation of CDC26. Furthermore, T7D-mutated CDC26 promoted the ubiquitination of polo-like kinase 1, a well-known substrate of APC/C. Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C. PMID- 25723521 TI - Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation. AB - BACKGROUND: Atrial fibrillation(AF) is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene. METHODS: A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs) (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097) were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study. RESULTS: In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678), compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF. CONCLUSIONS: Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor. PMID- 25723522 TI - Cytomegalovirus and Epstein-Barr virus in breast cancer. AB - Findings of polymerase chain reaction (PCR) studies of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) and breast cancer vary, making it difficult to determine whether either, both, or neither virus is causally associated with breast cancer. We investigated CMV and EBV in paired samples of breast cancer and normal breast tissue from 70 women using quantitative PCR. A serum sample from each woman was tested for CMV and EBV IgG. To place our results in context, we reviewed the existing literature and performed a meta-analysis of our results together with previous PCR studies of EBV, CMV, and breast cancer. Of the serology samples, 67 of 70 (96%) were EBV IgG positive and 49 of 70 (70%) were CMV IgG positive. QPCR detected EBV in 24 (34%) of the tumour and 9 (13%) of the paired normal specimens and CMV in 0 (0%) of the tumour and 2 (3%) of the paired normal specimens. Our findings, together with earlier results summarised in the meta-analysis, suggest several possibilities: variable findings may be due to limitations of molecular analyses; 'hit and run' oncogenesis may lead to inconsistent results; one or both viruses has a role at a later stage in breast cancer development; infection with multiple viruses increases breast cancer risk; or neither virus has a role. Future studies should focus on ways to investigate these possibilities, and should include comparisons of breast cancer tissue samples with appropriate normal tissue samples. PMID- 25723523 TI - Cyclin and DNA distributed cell cycle model for GS-NS0 cells. AB - Mammalian cell cultures are intrinsically heterogeneous at different scales (molecular to bioreactor). The cell cycle is at the centre of capturing heterogeneity since it plays a critical role in the growth, death, and productivity of mammalian cell cultures. Current cell cycle models use biological variables (mass/volume/age) that are non-mechanistic, and difficult to experimentally determine, to describe cell cycle transition and capture culture heterogeneity. To address this problem, cyclins-key molecules that regulate cell cycle transition-have been utilized. Herein, a novel integrated experimental modelling platform is presented whereby experimental quantification of key cell cycle metrics (cell cycle timings, cell cycle fractions, and cyclin expression determined by flow cytometry) is used to develop a cyclin and DNA distributed model for the industrially relevant cell line, GS-NS0. Cyclins/DNA synthesis rates were linked to stimulatory/inhibitory factors in the culture medium, which ultimately affect cell growth. Cell antibody productivity was characterized using cell cycle-specific production rates. The solution method delivered fast computational time that renders the model's use suitable for model-based applications. Model structure was studied by global sensitivity analysis (GSA), which identified parameters with a significant effect on the model output, followed by re-estimation of its significant parameters from a control set of batch experiments. A good model fit to the experimental data, both at the cell cycle and viable cell density levels, was observed. The cell population heterogeneity of disturbed (after cell arrest) and undisturbed cell growth was captured proving the versatility of the modelling approach. Cell cycle models able to capture population heterogeneity facilitate in depth understanding of these complex systems and enable systematic formulation of culture strategies to improve growth and productivity. It is envisaged that this modelling approach will pave the model-based development of industrial cell lines and clinical studies. PMID- 25723524 TI - A case for two-component signaling systems as antifungal drug targets. PMID- 25723525 TI - Sm29, but not Sm22.6 retains its ability to induce a protective immune response in mice previously exposed to a Schistosoma mansoni infection. AB - BACKGROUND: A vaccine against schistosomiasis would have a great impact in disease elimination. Sm29 and Sm22.6 are two parasite tegument proteins which represent promising antigens to compose a vaccine. These antigens have been associated with resistance to infection and reinfection in individuals living in endemic area for the disease and induced partial protection when evaluated in immunization trials using naive mice. METHODOLOGY/PRINCIPALS FINDINGS: In this study we evaluated rSm29 and rSm22.6 ability to induce protection in Balb/c mice that had been previously infected with S. mansoni and further treated with Praziquantel. Our results demonstrate that three doses of the vaccine containing rSm29 were necessary to elicit significant protection (26%-48%). Immunization of mice with rSm29 induced a significant production of IL-2, IFN-gamma, IL-17, IL-4; significant production of specific antibodies; increased percentage of CD4+ central memory cells in comparison with infected and treated saline group and increased percentage of CD4+ effector memory cells in comparison with naive Balb/c mice immunized with rSm29. On the other hand, although immunization with Sm22.6 induced a robust immune response, it failed to induce protection. CONCLUSION/SIGNIFICANCE: Our results demonstrate that rSm29 retains its ability to induce protection in previously infected animals, reinforcing its potential as a vaccine candidate. PMID- 25723526 TI - Simultaneous chirality sensing of multiple amines by (19)F NMR. AB - The rapid detection and differentiation of chiral compounds is important to synthetic, medicinal, and biological chemistry. Palladium complexes with chiral pincer ligands are demonstrated to have utility in determining the chirality of various amines. The binding of enantiomeric amines induces distinct (19)F NMR shifts of the fluorine atoms appended on the ligand that defines a chiral environment around palladium. It is further demonstrated that this method has the ability to evaluate the enantiomeric composition and discriminate between enantiomers with chiral centers several carbons away from the binding site. The wide detection window provided by optimized chiral chemosensors allows the simultaneous identification of as many as 12 chiral amines. The extraordinary discriminating ability of this method is demonstrated by the resolution of chiral aliphatic amines that are difficult to separate using chiral chromatography. PMID- 25723527 TI - Academic health centers and the growth of integrative medicine. PMID- 25723528 TI - Development of gel-filter method for high enrichment of low-molecular weight proteins from serum. AB - The human serum proteome has been extensively screened for biomarkers. However, the large dynamic range of protein concentrations in serum and the presence of highly abundant and large molecular weight proteins, make identification and detection changes in the amount of low-molecular weight proteins (LMW, molecular weight <= 30kDa) difficult. Here, we developed a gel-filter method including four layers of different concentration of tricine SDS-PAGE-based gels to block high molecular weight proteins and enrich LMW proteins. By utilizing this method, we identified 1,576 proteins (n = 2) from 10 MUL serum. Among them, 559 (n = 2) proteins belonged to LMW proteins. Furthermore, this gel-filter method could identify 67.4% and 39.8% more LMW proteins than that in representative methods of glycine SDS-PAGE and optimized-DS, respectively. By utilizing SILAC-AQUA approach with labeled recombinant protein as internal standard, the recovery rate for GST spiked in serum during the treatment of gel-filter, optimized-DS, and ProteoMiner was 33.1 +/- 0.01%, 18.7 +/- 0.01% and 9.6 +/- 0.03%, respectively. These results demonstrate that the gel-filter method offers a rapid, highly reproducible and efficient approach for screening biomarkers from serum through proteomic analyses. PMID- 25723529 TI - Impaired postural control in healthy men at moderate altitude (1630 m and 2590 m): data from a randomized trial. AB - OBJECTIVES: Intact postural control is essential for safe performance of mountain sports, operation of machinery at altitude, and for piloting airplanes. We tested whether exposure to hypobaric hypoxia at moderate altitude impairs the static postural control of healthy subjects. METHODS: In 51 healthy men, median age 24 y (quartiles 20;28), static control was evaluated on a balance platform in Zurich, 490 m, and during a 4-day sojourn in Swiss mountain villages at 1630 m and 2590 m, 2 days each. The order of altitude exposure was randomized. Total center of pressure path length (COPL) and sway amplitude measured in two directions by a balance platform, and pulse oximetry were recorded. Data were compared between altitudes. RESULTS: Median (quartiles) COPL during standing on both legs with eyes open at 490 m and in the evenings on the first and second days at 1630 and 2590 m, respectively were: 50 (45;57), 55 (48;62), 56 (49;61), 53 (47;59), 54 (48;60) cm, P<0.001 ANOVA. Corresponding arterial oxygen saturation was 97% (96;97), 95% (94;96), 95%(94;96), 92%(90;93), 93%(91;93), P<0.001. Anterior posterior sway amplitudes were larger at 1630 and 2590 m compared to 490 m, P<0.001. Multiple logistic regression analysis confirmed that higher altitudes (1630 and 2590m) were independently associated with increased COPL when controlled for the order of altitude exposure and age (P=0.001). CONCLUSIONS: Exposure to 1630 and 2590m was associated with impaired static postural control even when visual references were available. TRIAL REGISTRATION: ClinicalTrials.gov NCT01130948. PMID- 25723530 TI - Region-specific activation of oskar mRNA translation by inhibition of Bruno mediated repression. AB - A complex program of translational repression, mRNA localization, and translational activation ensures that Oskar (Osk) protein accumulates only at the posterior pole of the Drosophila oocyte. Inappropriate expression of Osk disrupts embryonic axial patterning, and is lethal. A key factor in translational repression is Bruno (Bru), which binds to regulatory elements in the osk mRNA 3' UTR. After posterior localization of osk mRNA, repression by Bru must be alleviated. Here we describe an in vivo assay system to monitor the spatial pattern of Bru-dependent repression, separate from the full complexity of osk regulation. This assay reveals a form of translational activation-region-specific activation-which acts regionally in the oocyte, is not mechanistically coupled to mRNA localization, and functions by inhibiting repression by Bru. We also show that Bru dimerizes and identify mutations that disrupt this interaction to test its role in vivo. Loss of dimerization does not disrupt repression, as might have been expected from an existing model for the mechanism of repression. However, loss of dimerization does impair regional activation of translation, suggesting that dimerization may constrain, not promote, repression. Our work provides new insight into the question of how localized mRNAs become translationally active, showing that repression of osk mRNA is locally inactivated by a mechanism acting independent of mRNA localization. PMID- 25723532 TI - Multiple-geographic-scale genetic structure of two mangrove tree species: the roles of mating system, hybridization, limited dispersal and extrinsic factors. AB - Mangrove plants comprise a unique group of organisms that grow within the intertidal zones of tropical and subtropical regions and whose distributions are influenced by both biotic and abiotic factors. To understand how these extrinsic and intrinsic processes influence a more fundamental level of the biological hierarchy of mangroves, we studied the genetic diversity of two Neotropical mangrove trees, Avicenniagerminans and A. schaueriana, using microsatellites markers. As reported for other sea-dispersed species, there was a strong differentiation between A. germinans and A. schaueriana populations sampled north and south of the northeastern extremity of South America, likely due to the influence of marine superficial currents. Moreover, we observed fine-scale genetic structures even when no obvious physical barriers were present, indicating pollen and propagule dispersal limitation, which could be explained by isolation-by-distance coupled with mating system differences. We report the first evidence of ongoing hybridization between Avicennia species and that these hybrids are fertile, although this interspecific crossing has not contributed to an increase in the genetic diversity the populations where A. germinans and A. schaueriana hybridize. These findings highlight the complex interplay between intrinsic and extrinsic factors that shape the distribution of the genetic diversity in these sea-dispersed colonizer species. PMID- 25723531 TI - Promoter hypermethylation-related reduced somatostatin production promotes uncontrolled cell proliferation in colorectal cancer. AB - BACKGROUND: Somatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line. METHODS: Colonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion. RESULTS: In case of normal aging SST mRNA expression did not alter, but decreased in cancer (p < 0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70% +/- 0.79%) compared to CRC (0% +/- 0%) (p < 0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2% +/- 11.6%) compared to healthy young individuals (3.5% +/- 1.9%) (p < 0.05). CONCLUSIONS: In cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation. PMID- 25723533 TI - Methylmercury in the breast milk of Japanese mothers and lactational exposure of their infants. AB - The human fetus is known to be exposed to methylmercury (MeHg), but little is known about the risk of infant exposure via breast milk. To evaluate the lactational exposure to MeHg via breast milk in Japanese infants, the levels of total mercury (THg) and MeHg were determined in breast milk and maternal blood using samples from a birth cohort study at the Tohoku Study of Child Development. Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively. The median THg (and MeHg) concentrations in maternal RBCs, plasma and breast milk were 17.8 ng g(-1) (17.8 ng g(-1)), 1.51 ng g(-1) (1.33 ng g(-1)) and 0.81 ng g(-1) (0.45 ng g(-1)), respectively (n=27). The median percentage of MeHg in THg was 54% in breast milk. Breast milk contained substantial amounts of MeHg, which was strongly associated with the internal accumulation of MeHg and the lipid content of the milk (r=0.684). The range of lipid contents in milk varied widely from 0.50 to 6.60 g/100 g of milk, with a median of 3.60 g/100 g. The median (range) weekly average intake of MeHg via breast milk was estimated to be 0.63 MUg kg(-1) (0.08-1.68 MUg kg(-1)) BW/week. Because the MeHg and lipid contents in milk substantially fluctuate, an investigation of the variations of MeHg and lipid content in breast milk may be required for a more precise risk assessment. PMID- 25723534 TI - Characterization of the major light-harvesting complexes (LHCBM) of the green alga Chlamydomonas reinhardtii. AB - Nine genes (LHCBM1-9) encode the major light-harvesting system of Chlamydomonas reinhardtii. Transcriptomic and proteomic analyses have shown that those genes are all expressed albeit in different amounts and some of them only in certain conditions. However, little is known about the properties and specific functions of the individual gene products because they have never been isolated. Here we have purified several complexes from native membranes and/or we have reconstituted them in vitro with pigments extracted from C. reinhardtii. It is shown that LHCBM1 and -M2/7 represent more than half of the LHCBM population in the membrane. LHCBM2/7 forms homotrimers while LHCBM1 seems to be present in heterotrimers. Trimers containing only type I LHCBM (M3/4/6/8/9) were also observed. Despite their different roles, all complexes have very similar properties in terms of pigment content, organization, stability, absorption, fluorescence and excited-state lifetimes. Thus the involvement of LHCBM1 in non photochemical quenching is suggested to be due to specific interactions with other components of the membrane and not to the inherent quenching properties of the complex. Similarly, the overexpression of LHCBM9 during sulfur deprivation can be explained by its low sulfur content as compared with the other LHCBMs. Considering the highly conserved biochemical and spectroscopic properties, the major difference between the complexes may be in their capacity to interact with other components of the thylakoid membrane. PMID- 25723535 TI - Protein sectors: statistical coupling analysis versus conservation. AB - Statistical coupling analysis (SCA) is a method for analyzing multiple sequence alignments that was used to identify groups of coevolving residues termed "sectors". The method applies spectral analysis to a matrix obtained by combining correlation information with sequence conservation. It has been asserted that the protein sectors identified by SCA are functionally significant, with different sectors controlling different biochemical properties of the protein. Here we reconsider the available experimental data and note that it involves almost exclusively proteins with a single sector. We show that in this case sequence conservation is the dominating factor in SCA, and can alone be used to make statistically equivalent functional predictions. Therefore, we suggest shifting the experimental focus to proteins for which SCA identifies several sectors. Correlations in protein alignments, which have been shown to be informative in a number of independent studies, would then be less dominated by sequence conservation. PMID- 25723536 TI - Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. AB - Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control. PMID- 25723538 TI - In vitro metabolic stability of exendin-4: pharmacokinetics and identification of cleavage products. AB - The aim of this study was to investigate the metabolic stability and cleavage sites of exendin-4 in rat tissue homogenates, as well as to identify the types of proteases involved in exendin-4 degradation. The stability of exendin-4 in kidney and liver homogenates from rats was evaluated using liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) with gradient elution. Furthermore, we used a combination of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and LC-ESI-MS/MS to identify the structures of the major degradation products of exendin-4, and peptidase inhibitors were used to characterize exendin-4 degradation in rat liver and kidney homogenates and to identify the proteases involved in exendin-4 metabolism. Exendin-4 had a half-life of 7.8 and 100.9 min in the kidney and liver homogenate, respectively. The enzymes most likely to be involved in the degradation of exendin-4 were aminopeptidases, serineproteases, and metalloproteases. Exendin-4(15-39) and exendin-4(16-39) were the predominant direct exendin-4 metabolites in the kidney, and the main product of exendin-4 metabolism in the liver was exendin-4(12-39). Our results indicated that the metabolism of exendin-4 involved an initial endoproteolytic cleavage and subsequent exoproteolytic digestion. The degradation of exendin-4 in the kidney and liver homogenates followed distinct patterns, and the primary cleavage sites of exendin-4 degradation in rat kidney homogenates were located after AA-14, and 15, whereas those in rat liver homogenates were located after AA-11. PMID- 25723540 TI - Lower virus infections in Varroa destructor-infested and uninfested brood and adult honey bees (Apis mellifera) of a low mite population growth colony compared to a high mite population growth colony. AB - A comparison was made of the prevalence and relative quantification of deformed wing virus (DWV), Israeli acute paralysis virus (IAPV), black queen cell virus (BQCV), Kashmir bee virus (KBV), acute bee paralysis virus (ABPV) and sac brood virus (SBV) in brood and adult honey bees (Apis mellifera) from colonies selected for high (HMP) and low (LMP) Varroa destructor mite population growth. Two viruses, ABPV and SBV, were never detected. For adults without mite infestation, DWV, IAPV, BQCV and KBV were detected in the HMP colony; however, only BQCV was detected in the LMP colony but at similar levels as in the HMP colony. With mite infestation, the four viruses were detected in adults of the HMP colony but all at higher amounts than in the LMP colony. For brood without mite infestation, DWV and IAPV were detected in the HMP colony, but no viruses were detected in the LMP colony. With mite infestation of brood, the four viruses were detected in the HMP colony, but only DWV and IAPV were detected and at lower amounts in the LMP colony. An epidemiological explanation for these results is that pre-experiment differences in virus presence and levels existed between the HMP and LMP colonies. It is also possible that low V. destructor population growth in the LMP colony resulted in the bees being less exposed to the mite and thus less likely to have virus infections. LMP and HMP bees may have also differed in susceptibility to virus infection. PMID- 25723539 TI - Drosophila casein kinase I alpha regulates homolog pairing and genome organization by modulating condensin II subunit Cap-H2 levels. AB - The spatial organization of chromosomes within interphase nuclei is important for gene expression and epigenetic inheritance. Although the extent of physical interaction between chromosomes and their degree of compaction varies during development and between different cell-types, it is unclear how regulation of chromosome interactions and compaction relate to spatial organization of genomes. Drosophila is an excellent model system for studying chromosomal interactions including homolog pairing. Recent work has shown that condensin II governs both interphase chromosome compaction and homolog pairing and condensin II activity is controlled by the turnover of its regulatory subunit Cap-H2. Specifically, Cap-H2 is a target of the SCFSlimb E3 ubiquitin-ligase which down-regulates Cap-H2 in order to maintain homologous chromosome pairing, chromosome length and proper nuclear organization. Here, we identify Casein Kinase I alpha (CK1alpha) as an additional negative-regulator of Cap-H2. CK1alpha-depletion stabilizes Cap-H2 protein and results in an accumulation of Cap-H2 on chromosomes. Similar to Slimb mutation, CK1alpha depletion in cultured cells, larval salivary gland, and nurse cells results in several condensin II-dependent phenotypes including dispersal of centromeres, interphase chromosome compaction, and chromosome unpairing. Moreover, CK1alpha loss-of-function mutations dominantly suppress condensin II mutant phenotypes in vivo. Thus, CK1alpha facilitates Cap-H2 destruction and modulates nuclear organization by attenuating chromatin localized Cap-H2 protein. PMID- 25723541 TI - Assessment of the direct effects of biogenic and petrogenic activated carbon on benthic organisms. AB - Activated carbon (AC) has long been associated with the capacity to effectively remove organic substances from aquatic and sediment matrices; however, its use in remediation purposes has drawn some concern due to possible impacts on benthic communities. Within the inner Oslofjord, the use of AC has been well documented for reducing the risks associated with dioxins or dioxin-like compounds from contaminated areas. However, benthic surveys performed on areas treated with AC have revealed that the abundance of organisms inhabiting these areas can be reduced significantly in the subsequent years following treatment. The reason for the reduction in the benthic communities is currently unknown, and therefore, an integrated approach to assess the effects of 2 different forms of AC (biogenic and petrogenic) on benthic organisms has been performed. A battery of 3 different benthic organisms with different feeding and life-cycle processes has been used encompassing sediment surface feeders, sediment ingestors, and sediment reworkers. Results of the tests indicated that although AC is not acutely toxic at concentrations up to 1000 mg/L, there may be physical effects of the substance on benthic dwelling organisms at environmentally relevant concentrations of AC at remediated sites. PMID- 25723542 TI - rDNA genetic imbalance and nucleolar chromatin restructuring is induced by distant hybridization between Raphanus sativus and Brassica alboglabra. AB - The expression of rDNA in hybrids inherited from only one progenitor refers to nucleolar dominance. The molecular basis for choosing which genes to silence remains unclear. We report genetic imbalance induced by distant hybridization correlates with formation of rDNA genes (NORs) in the hybrids between Raphanus sativus L. and Brassica alboglabra Bailey. Moreover, increased CCGG methylation of rDNA in F1 hybrids is concomitant with Raphanus-derived rDNA gene silencing and rDNA transcriptional inactivity revealed by nucleolar configuration restriction. Newly formed rDNA gene locus occurred through chromosomal in F1 hybrids via chromosomal imbalance. NORs are gained de novo, lost, and/or transposed in the new genome. Inhibition of methyltransferases leads to changes in nucleolar architecture, implicating a key role of methylation in control of nucleolar dominance and vital nucleolar configuration transition. Our findings suggest that gene imbalance and methylation-related chromatin restructuring is important for rDNA gene silencing that may be crucial for synthesis of specific proteins. PMID- 25723543 TI - Role of cortactin homolog HS1 in transendothelial migration of natural killer cells. AB - Natural Killer (NK) cells perform many functions that depend on actin assembly, including adhesion, chemotaxis, lytic synapse assembly and cytolysis. HS1, the hematopoietic homolog of cortactin, binds to Arp2/3 complex and promotes actin assembly by helping to form and stabilize actin filament branches. We investigated the role of HS1 in transendothelial migration (TEM) by NK cells. Depletion of HS1 led to a decrease in the efficiency of TEM by NK cells, as measured by transwell assays with endothelial cell monolayers on porous filters. Transwell assays involve chemotaxis of NK cells across the filter, so to examine TEM more specifically, we imaged live-cell preparations and antibody-stained fixed preparations, with and without the chemoattractant SDF-1alpha. We found small to moderate effects of HS1 depletion on TEM, including whether the NK cells migrated via the transcellular or paracellular route. Expression of HS1 mutants indicated that phosphorylation of HS1 tyrosines at positions 222, 378 and 397 was required for rescue in the transwell assay, but HS1 mutations affecting interaction with Arp2/3 complex or SH3-domain ligands had no effect. The GEF Vav1, a ligand of HS1 phosphotyrosine, influenced NK cell transendothelial migration. HS1 and Vav1 also affected the speed of NK cells migrating across the surface of the endothelium. We conclude that HS1 has a role in transendothelial migration of NK cells and that HS1 tyrosine phosphorylation may signal through Vav1. PMID- 25723544 TI - Dietary compositions and their seasonal shifts in Japanese resident birds, estimated from the analysis of volunteer monitoring data. AB - Determining the composition of a bird's diet and its seasonal shifts are fundamental for understanding the ecology and ecological functions of a species. Various methods have been used to estimate the dietary compositions of birds, which have their own advantages and disadvantages. In this study, we examined the possibility of using long-term volunteer monitoring data as the source of dietary information for 15 resident bird species in Kanagawa Prefecture, Japan. The data were collected from field observations reported by volunteers of regional naturalist groups. Based on these monitoring data, we calculated the monthly dietary composition of each bird species directly, and we also estimated unidentified items within the reported foraging episodes using Bayesian models that contained additional information regarding foraging locations. Next, to examine the validity of the estimated dietary compositions, we compared them with the dietary information for focal birds based on stomach analysis methods, collected from past literatures. The dietary trends estimated from the monitoring data were largely consistent with the general food habits determined from the previous studies of focal birds. Thus, the estimates based on the volunteer monitoring data successfully detected noticeable seasonal shifts in many of the birds from plant materials to animal diets during spring-summer. Comparisons with stomach analysis data supported the qualitative validity of the monitoring-based dietary information and the effectiveness of the Bayesian models for improving the estimates. This comparison suggests that one advantage of using monitoring data is its ability to detect dietary items such as fleshy fruits, flower nectar, and vertebrates. These results emphasize the potential importance of observation data collecting and mining by citizens, especially free descriptive observation data, for use in bird ecology studies. PMID- 25723546 TI - Polymer films removed from solid surfaces by nanostructured fluids: microscopic mechanism and implications for the conservation of cultural heritage. AB - Complex fluids based on amphiphilic formulations are emerging, particularly in the field of conservation of works of art, as effective and safe liquid media for the removal of hydrophobic polymeric coatings. The comprehension of the cleaning mechanism is key to designing tailored fluids for this purpose. However, the interaction between nanostructured fluids and hydrophobic polymer films is still poorly understood. In this study, we show how the combination of confocal laser scanning microscopy (CLSM) and atomic force microscopy (AFM) provides interesting and complementary insight into this process. We focused on the interaction between an ethyl methacrylate/methyl acrylate 70:30 copolymer film deposited onto a glass surface and a water/nonionic surfactant/2-butanone (MEK) ternary system, with MEK being a good solvent and water being a nonsolvent for the polymer. Our results indicate a synergy between the organic solvent and the surfactant assemblies: MEK rapidly swells the outer layers of the polymer film allowing for the subsequent diffusion of solvent molecules, while the amphiphile decreases the interfacial energy between the polymeric coating and the liquid phase, favoring dewetting and dispersion of swollen polymer droplets in the aqueous phase. The chemical nature of the surfactant and the microstructure of the assemblies determine both the kinetics and the overall efficiency of polymer removal, as assessed by comparing the behavior of similar formulations containing an anionic surfactant (sodium dodecyl sulfate, SDS). PMID- 25723545 TI - An integrated approach to reconstructing genome-scale transcriptional regulatory networks. AB - Transcriptional regulatory networks (TRNs) program cells to dynamically alter their gene expression in response to changing internal or environmental conditions. In this study, we develop a novel workflow for generating large-scale TRN models that integrates comparative genomics data, global gene expression analyses, and intrinsic properties of transcription factors (TFs). An assessment of this workflow using benchmark datasets for the well-studied gamma proteobacterium Escherichia coli showed that it outperforms expression-based inference approaches, having a significantly larger area under the precision recall curve. Further analysis indicated that this integrated workflow captures different aspects of the E. coli TRN than expression-based approaches, potentially making them highly complementary. We leveraged this new workflow and observations to build a large-scale TRN model for the alpha-Proteobacterium Rhodobacter sphaeroides that comprises 120 gene clusters, 1211 genes (including 93 TFs), 1858 predicted protein-DNA interactions and 76 DNA binding motifs. We found that ~67% of the predicted gene clusters in this TRN are enriched for functions ranging from photosynthesis or central carbon metabolism to environmental stress responses. We also found that members of many of the predicted gene clusters were consistent with prior knowledge in R. sphaeroides and/or other bacteria. Experimental validation of predictions from this R. sphaeroides TRN model showed that high precision and recall was also obtained for TFs involved in photosynthesis (PpsR), carbon metabolism (RSP_0489) and iron homeostasis (RSP_3341). In addition, this integrative approach enabled generation of TRNs with increased information content relative to R. sphaeroides TRN models built via other approaches. We also show how this approach can be used to simultaneously produce TRN models for each related organism used in the comparative genomics analysis. Our results highlight the advantages of integrating comparative genomics of closely related organisms with gene expression data to assemble large-scale TRN models with high-quality predictions. PMID- 25723547 TI - Enantioselective synthesis of functionalized pyrazoles by NHC-catalyzed reaction of pyrazolones with alpha,beta-unsaturated aldehydes. AB - The N-heterocyclic carbene (NHC)-organocatalyzed enantioselective annulation reaction of pyrazolones with alpha,beta-unsaturated aldehydes proceeding via the chiral alpha,beta-unsaturated acyl azolium intermediates under oxidative conditions is presented. The reaction afforded dihydropyranone-fused pyrazoles in moderate to good yields and good er values under operationally simple and base free conditions. PMID- 25723549 TI - Structure and function of water molecules buried in the protein core. AB - Although the formation of the apolar core is crucial for protein folding, protein interior is often packed sub-optimally and incorporates water molecules that leave the bulk solvent. On average, one buried water molecules is observed every 20-90 amino acids, depending on the protein dimension and structural class: more buried water molecules are observed in large proteins and less in alpha proteins. >From a structural perspective, it was shown that buried water molecules tend to be as rigid as buried protein atoms, incline to form hydrogen bonds with backbone residues of loops, and often are in contact with other buried water molecules. From a functional perspective, buried water molecules have a stabilizing effect by filling internal cavities and by interacting with polar atoms buried in the protein core and may also act as lubricants to favor loop dynamics. Their exchange kinetics with the bulk solvent is quite variable, ranging from few tens of nanoseconds to few tens of milliseconds. PMID- 25723548 TI - Bridging the epidemic: a comprehensive analysis of prevalence and correlates of HIV, hepatitis C, and syphilis, and infection among female sex workers in Guangxi Province, China. AB - INTRODUCTION: Female sex workers (FSWs) are at highest risk for contracting HIV and facilitating the current heterosexual HIV epidemic in Guangxi, China, yet little is known of the impact of recent harm reduction campaigns in the province. We analyzed sentinel surveillance data collected between 2010 and 2012 in Guangxi to explore correlations between the prevalence of HIV, hepatitis C (HCV), and syphilis and risk behaviors of different categories of FSWs in Guangxi. METHODS: The sentinel surveillance data for 5,1790 FSWs in all 14 prefectures and 64 city/county regions of Guangxi, China from 2010 to 2012 were collected. Differences between three categories of FSWs (grouped by venue) and disease trends (HIV, HCV, and syphilis) by year were analyzed using bivariate and multivariate logistic regression analyses as to evaluate risk factors correlated with HIV, HCV, or syphilis infection. RESULTS: HIV and HCV prevalence remained constant across the three FSW categories; however, syphilis prevalence showed a significant increase from 5.7% to 7.3% for low-tier FSWs. Most cases with HIV, HCV, syphilis and intravenous drug use were seen in low-tier FSWs. Testing positive for HIV and syphilis were most correlated with being HCV positive (AOR 4.12 and AOR 4.36), only completing elementary school (AOR 3.71 and AOR 2.35), low tier venues (AOR 2.02 and AOR 2.00), and prior STI (AOR 1.40 and AOR 3.56), respectively. HCV infection was correlated with ever injecting drugs (AOR 60.65) and testing positive for syphilis (AOR 4.16) or HIV (AOR 3.74). CONCLUSIONS: This study highlights that low tier FSWs with lower formal education levels are the most vulnerable population at risk for acquiring and transmitting HIV, HCV, and syphilis in Guangxi, China. Condom distribution with evolution to safer sex practices are the reasons to explain the non-increasing prevalence of HIV, HCV in Guangxi for 2010-2012. PMID- 25723550 TI - Revealing the sequence and resulting cellular morphology of receptor-ligand interactions during Plasmodium falciparum invasion of erythrocytes. AB - During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine. PMID- 25723551 TI - Influence of HCV and HIV on development of cryoglobulinemia. AB - Cryoglobulinemic syndrome refers to a systemic inflammatory process that involves small and medium-sized vessels accompanied by multi-organ damage. The aim of the present study was to determine the incidence of cryoglobulinemia among patients infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV) and HCV/HIV co-infection, as well as evaluation of cryoglobulinemia type. The association was evaluated between cryoglobulinemia and clinical symptoms, selected biochemical measures of liver and kidney function, virologic measures, as well as histopathological changes in the liver. One hundred and forty-one patients were enrolled (59 HCV mono-infected, 48 HIV mono-infected, and 34 HCV/HIV co-infected). Cryoglobulinemia was nearly five times less frequent among HIV mono-infected patients (10%) than HCV mono-infected (53%) and HCV/HIV co infected patients (59%). Cryoglobulinemia was more frequent in patients infected with genotype 1 HCV than genotype 3 (63% vs. 46%, p=0.12). There was a lower incidence of cryoglobulinemia in HIV mono-infected patients treated with antiretroviral drugs (p=0.04). Cryoglobulinemia correlated with ALT activity (p=0.01) and HIV viral load (p<0.001). Symptoms were significantly more frequent among cryoglobulinemic patients than those without cryoglobulinemia (38% vs. 9%, p<0.001). The most common symptoms related to cryoglobulinemia, regardless of cryoglobulinemia type, were fatigue (38%), arthralgia (20%), polineuropathy (18%), and skin lesions (14%). In conclusion, HCV mono-infection and HCV/HIV co infection, regardless of HCV genotype, are potent stimulators of cryoglobulinemia, with its symptomatic form occurring in about 40% of cases. Effective antiretroviral therapy seems to be protective against cryoglobulinemia development in HIV mono-infected patients. PMID- 25723553 TI - A polystyrene-supported 9-amino(9-deoxy)epi quinine derivative for continuous flow asymmetric Michael reactions. AB - A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions affording excellent levels of conversion and enantioselectivity using different nucleophiles and structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours without significant decrease in conversion and with improved enantioselectivity with respect to batch operation. The flow process has also been used for the sequential preparation of a small library of enantioenriched Michael adducts. PMID- 25723554 TI - Contribution of fatty acid transporter (CD36) genetic variant rs1761667 to body mass index, the TAMRISK study. AB - BACKGROUND: Human fatty acid transporter CD36 gene variations have previously been associated with fat preferences and obesity. These variations could thus cause overweight and hypothetically lead to hypertension. The association of CD36 SNP rs1761667 with body mass index (BMI) and hypertension was therefore studied in a Finnish cohort of adults. METHODS: The data were collected from the Tampere adult population cardiovascular risk study (TAMRISK). A total of 314 cases with diagnosed hypertension, and 422 non-hypertensive healthy controls were selected from a Finnish periodic 50-year-old health examination cohort. Most subjects had prior health examination data also from their 40- and 45-year examinations. DNA was extracted from buccal swabs and the human CD36 genetic variant was analyzed using KASP genotyping. RESULTS: The CD36 SNP rs1761667 variant AA was significantly associated with lower BMI, as compared to variants AG and GG at the ages of 40-, 45-, and 50 years (p < 0.001, p = 0.005 and p = 0.013, respectively). No association of this CD36 variation with hypertension was found. CONCLUSIONS: CD36 rs1761667 was associated with BMI in the TAMRISK study. Considering the multitude of roles of CD36 in processes related to fatty acid metabolism and sensing in the body, it is plausible that genetic variation in human fatty acid transporter CD36 can have effects on regulation of energy homeostasis. PMID- 25723552 TI - Oxidative stress responses in the human fungal pathogen, Candida albicans. AB - Candida albicans is a major fungal pathogen of humans, causing approximately 400,000 life-threatening systemic infections world-wide each year in severely immunocompromised patients. An important fungicidal mechanism employed by innate immune cells involves the generation of toxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. Consequently, there is much interest in the strategies employed by C. albicans to evade the oxidative killing by macrophages and neutrophils. Our understanding of how C. albicans senses and responds to ROS has significantly increased in recent years. Key findings include the observations that hydrogen peroxide triggers the filamentation of this polymorphic fungus and that a superoxide dismutase enzyme with a novel mode of action is expressed at the cell surface of C. albicans. Furthermore, recent studies have indicated that combinations of the chemical stresses generated by phagocytes can actively prevent C. albicans oxidative stress responses through a mechanism termed the stress pathway interference. In this review, we present an up-date of our current understanding of the role and regulation of oxidative stress responses in this important human fungal pathogen. PMID- 25723555 TI - Real-time cellular exometabolome analysis with a microfluidic-mass spectrometry platform. AB - To address the challenges of tracking the multitude of signaling molecules and metabolites that is the basis of biological complexity, we describe a strategy to expand the analytical techniques for dynamic systems biology. Using microfluidics, online desalting, and mass spectrometry technologies, we constructed and validated a platform well suited for sampling the cellular microenvironment with high temporal resolution. Our platform achieves success in: automated cellular stimulation and microenvironment control; reduced non-specific adsorption to polydimethylsiloxane due to surface passivation; real-time online sample collection; near real-time sample preparation for salt removal; and real time online mass spectrometry. When compared against the benchmark of "in culture" experiments combined with ultraperformance liquid chromatography electrospray ionization-ion mobility-mass spectrometry (UPLC-ESI-IM-MS), our platform alleviates the volume challenge issues caused by dilution of autocrine and paracrine signaling and dramatically reduces sample preparation and data collection time, while reducing undesirable external influence from various manual methods of manipulating cells and media (e.g., cell centrifugation). To validate this system biologically, we focused on cellular responses of Jurkat T cells to microenvironmental stimuli. Application of these stimuli, in conjunction with the cell's metabolic processes, results in changes in consumption of nutrients and secretion of biomolecules (collectively, the exometabolome), which enable communication with other cells or tissues and elimination of waste. Naive and experienced T-cell metabolism of cocaine is used as an exemplary system to confirm the platform's capability, highlight its potential for metabolite discovery applications, and explore immunological memory of T-cell drug exposure. Our platform proved capable of detecting metabolomic variations between naive and experienced Jurkat T cells and highlights the dynamics of the exometabolome over time. Upregulation of the cocaine metabolite, benzoylecgonine, was noted in experienced T cells, indicating potential cellular memory of cocaine exposure. These metabolomics distinctions were absent from the analogous, traditional "in culture" UPLC-ESI-IM-MS experiment, further demonstrating this platform's capabilities. PMID- 25723556 TI - Impaired increase of plasma abscisic Acid in response to oral glucose load in type 2 diabetes and in gestational diabetes. AB - The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8-12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8-12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control. PMID- 25723558 TI - The current impact of incidental findings found during neuroimaging on neurologists' workloads. AB - OBJECTIVE: Neuroimaging is an important diagnostic tool in the assessment of neurological disease, but often unmasks Incidental Findings (IFs). The negative impacts of IFs, such as 'patient' anxiety, present neurologists with management dilemmas, largely due to the limited knowledge base surrounding the medical significance of these IFs. In particular, the lack of evidence-based clinical trials investigating the efficacy of treatments for subclinical IFs makes management protocols challenging. The objective was to determine the impact IFs may have on neurologists' workloads and healthcare budgets and to examine neurologists' concerns regarding the clinical management of these 'patients'. METHODS: Qualitative research based on constructivist grounded theory. Data was collected through semi-structured interviews of purposively sampled neurologists, coded, and concurrent comparative analysis performed. A substantive theory of the 'IF impacts' was developed after concept saturation. RESULTS: Neurologists managed the escalating workload caused by an increased number of referrals of 'patients' with IFs found during neuroimaging; however it was unclear whether this was sustainable in the future. Neurologists experienced IF management dilemmas and spent more time with 'patients' affected by anxiety. The lack of information provided to those undergoing neuroimaging by the referring clinician regarding the possibility of discovering IFs was highlighted. CONCLUSION: The impact of IFs upon the neurologist, 'patient' and the health institution appeared considerable. Further research determining the natural history of subclinical IFs and the efficacy of intervention will help to alleviate these issues. PMID- 25723559 TI - The impact of mood symptomatology on pattern of substance use among homeless. AB - BACKGROUND: Homeless individuals are an extremely vulnerable and underserved population characterized by overlapping problems of mental illness and substance use. Given the fact that mood disorders are frequently associated with substance use disorders, we wanted to further highlight the role of excitement in substance abuse. Patterns of substance abuse among homeless suffering from unipolar and bipolar depression were compared. The "self-medication hypothesis" which would predict no-differences in substance preference by unipolar (UP) and bipolar (BP) depressed homeless was tested. METHODS: Homeless individuals from the Vancouver At Home/Chez Soi study were selected for lifetime UP and lifetime BP depression and patterns of substances abused in the previous 12 months were identified with the Mini-International Neuropsychiatric Interview. Differences in substance use between BP-depressed homeless and UP-depressed homeless were tested using Chi square and logistic regression techniques. RESULTS: No significant differences were observed between UP and BP homeless demographics. The bipolar depressed homeless (BDH) group displayed a higher percentage of Central Nervous System (CNS) Stimulants (chi 8.66, p=0.004) and Opiates (chi 6.41, p=0.013) as compared to the unipolar depressed homeless (UDH) group. CSN Stimulant was the only predictor within the BDH Group (chi(2) 8.74 df 1 p<0.003). LIMITATIONS: Data collected are self-reported and no urinalyses were performed. CONCLUSIONS: The results support the hypothesis that beyond the self-medication hypothesis, bipolarity is strictly correlated to substance use; this correlation is also verified in a homeless population. PMID- 25723560 TI - Comorbidity of ADHD and suicide attempts among adolescents and young adults with bipolar disorder: A nationwide longitudinal study. AB - BACKGROUND: Suicide is among the leading causes of death among people with bipolar disorder and has gained substantial attention in the psychiatric and public health fields. However, the role of attention deficit hyperactivity disorder (ADHD) in suicide among adolescents and young adults with bipolar disorder remains unknown. METHODS: Using Taiwan's National Health Insurance Research Database, we identified 500 adolescents and young adults from 2002 to 2008 aged between 15 and 24 years with bipolar disorder and ADHD. The sample was matched according to age and sex with 1500 (1:3) patients with bipolar disorder only and observed until the end of 2011. The patients who attempted suicide during the follow-up period were identified. RESULTS: Adolescents and young adults with bipolar disorder and ADHD had a greater incidence of attempted suicide than did those with bipolar disorder only (3.0% vs. 1.1%, p=0.005). After adjustment for demographic factors and psychiatric comorbidities, a Cox regression analysis determined that ADHD was an independent risk factor for attempted suicide (hazard ratio: 2.38, 95% confidence interval: 1.13-5.00) later in life among adolescents and young adults with bipolar disorder. DISCUSSION: Adolescents and young adults with bipolar disorder and ADHD had an increased likelihood of attempted suicide compared with adolescents and young adults with bipolar disorder only. Further study is required to investigate the possible pathophysiology among ADHD, bipolar disorder, and attempted suicide, and to assess whether prompt intervention for ADHD may reduce the risk of attempted suicide. PMID- 25723561 TI - Suicides and medically serious attempters are of the same population in Chinese rural young adults. AB - BACKGROUND: Suicide rates in China are among the highest in the world, although there has been a decreasing trend in the past few years. One practical approach to study the characteristics and risk factors of suicide is to interview the suicide attempters. It was to compare completed suicides with serious attempters that may shed lights on suicide prevention strategies. METHOD: This is a combination of two case control studies for suicide completers and suicide attempters respectively. After a sample of suicides (n=392) and community living controls (n=416) were obtained and studied in rural China, we collected in the same rural areas data of suicide attempt and studied 507 medically serious attempters and 503 community counterparts. RESULTS: Characteristics and previously observed risk factors were compared between the suicides and the attempters, and we found that the demographic characteristics and risk factors for the suicides were also for the medically serious attempters but at some lesser degrees for the attempters than for the suicides. It was especially true of suicide intent, deficient coping, negative life events, and impulsivity. While most of the demographic characteristics were not significantly different between the suicides and the attempters, most of the clinical variables could distinguish the two groups. CONCLUSIONS: The suicide victims and the serious attempters could be of the same group of people who were at the edge of fatal self-injury, and the same clinical risk factors but of different degrees have divided them into the life and death groups. PMID- 25723563 TI - O,N,N-pincer ligand effects on oxidatively induced carbon-chlorine coupling reactions at palladium. AB - The syntheses of two families of sterically tuneable O,N,N pro-ligands are reported, namely the 2-(phenyl-2'-ol)-6-imine-pyridines, 2-(C6H4-2'-OH),6 (CMe=NAr)C5H3N [Ar = 4-i-PrC6H4 (HL1(a)), 2,6-i-Pr2C6H3 (HL1(b))] and the 2 (phenyl-2'-ol)-6-(amino-prop-2-yl)pyridines, 2-(C6H4-2'-OH),6-(CMe2NHAr)C5H3N [Ar = 4-i-PrC6H4 (HL2(a)), 2,6-i-Pr2C6H3 (HL2(b))], using straightforward synthetic approaches and in reasonable overall yields. Interaction of HL1(a/c) and HL2(a/b) with palladium(II) acetate affords the O,N,N-pincer complexes, [{2-(C6H4-2'-O)-6 (CMe=NAr)C5H3N}Pd(OAc)] (Ar = 4-i-PrC6H4 (1a), 2,6-i-Pr2C6H3 (1b)) and [{2-(C6H4 2'-O)-6-(CMe2NHAr)C5H3N}Pd(OAc)] (Ar = 4-i-PrC6H4 (2a), 2,6-i-Pr2C6H3 (2b)), which can be readily converted to their chloride derivatives, [{2-(C6H4-2'-O)-6 (CMe=NAr)C5H3N}PdCl] (Ar = 4-i-PrC6H4 (3a), 2,6-i-Pr2C6H3 (3b)) and [{2-(C6H4-2' O)-6-(CMe2NHAr)C5H3N}PdCl] (Ar = 4-i-PrC6H4 (4a), 2,6-i-Pr2C6H3 (4b)), respectively, on reaction with an aqueous sodium chloride solution. Treating each of 3a, 3b, 4a and 4b with two equivalents of di-p-tolyliodonium triflate at 100 degrees C in a toluene/acetonitrile mixture affords varying amounts of 4 chlorotoluene along with the 4-iodotoluene by-product with the conversions highly dependent on the steric and backbone properties of the pincer complex employed (viz. 4a > 3a > 4b > 3b); notably, the least sterically bulky and most flexible amine-containing 4a reaches 90% conversion to 4-chlorotoluene in 15 h as opposed to 17% for imine-containing 3b. In the case of 3a, the inorganic palladium species recovered from the reaction has been identified as the Pd(II) salt [{2 (C6H4-2'-O)-6-(CMe=N(4-i-PrC6H4)C5H3N}Pd(NCMe)][O3SCF3] (5a), which was independently prepared by the reaction of 3a with silver triflate in acetonitrile. Single crystal X-ray structures are reported for HL1(a), HL2(a), 1a, 1b, 2a, 2b, 3a and 5a. PMID- 25723562 TI - Faith-adapted psychological therapies for depression and anxiety: Systematic review and meta-analysis. AB - BACKGROUND: Incorporating faith (religious or spiritual) perspectives into psychological treatments has attracted significant interest in recent years. However, previous suggestion that good psychiatric care should include spiritual components has provoked controversy. To try to address ongoing uncertainty in this field we present a systematic review and meta-analysis to assess the efficacy of faith-based adaptations of bona fide psychological therapies for depression or anxiety. METHODS: A systematic review and meta-analysis of randomised controlled trials were performed. RESULTS: The literature search yielded 2274 citations of which 16 studies were eligible for inclusion. All studies used cognitive or cognitive behavioural models as the basis for their faith-adapted treatment (F-CBT). We identified statistically significant benefits of using F-CBT. However, quality assessment using the Cochrane risk of bias tool revealed methodological limitations that reduce the apparent strength of these findings. LIMITATIONS: Whilst the effect sizes identified here were statistically significant, there were relatively a few relevant RCTs available, and those included were typically small and susceptible to significant biases. Biases associated with researcher or therapist allegiance were identified as a particular concern. CONCLUSIONS: Despite some suggestion that faith-adapted CBT may out-perform both standard CBT and control conditions (waiting list or "treatment as usual"), the effect sizes identified in this meta-analysis must be considered in the light of the substantial methodological limitations that affect the primary research data. Before firm recommendations about the value of faith adapted treatments can be made, further large-scale, rigorously performed trials are required. PMID- 25723564 TI - Microbial Bioburden of Orthokeratology Contact Lens Care System. AB - OBJECTIVE: To assess the bioburden in an orthokeratology contact lens (OK) care system (defined by microbial identification from OK case fluid) and to identify the risk factors causing high bioburden for pediatric OK wearers in southern Taiwan. METHODS: A prospective study for the investigation of bioburden in the OK care system was performed in a tertiary medical center in southern Taiwan. Microbial isolates from the case fluids soaking OKs were analyzed, and pathogenicity was determined. Age, gender, OK experiences, and contact lens care habits were considered the potential risk factors of microbial bioburden (colony forming units per milliliter) for causal analysis. RESULTS: Forty-one OK wearers (20 female and 21 male subjects) participated in this study. The mean age was 12.7 years, and the mean OK-wearing experience was 3.5 years. A total of 86 microbial strains were isolated from 38 culture-positive specimens. Frequently reported pathogens in contact lens-related microbial keratitis were less common in the current study, but still present, including 4 strains (5%) of Serratia marcescens, 1 strain (1%) of Pseudomonas aeruginosa, and 1 strain (1%) of Staphylococcus aureus. Microbial bioburden of the OK care system was significantly higher (P<0.05) in male subjects. CONCLUSIONS: The contamination rate of the OK care system was high, and many isolated microorganisms had potential pathogenicity. Reinforcement of proper contact lens care and education should be mandatory for OK wearers, particularly for male subjects, to decrease the risk of high bioburden of the OK care system. PMID- 25723557 TI - Spontaneous and post-treatment HCV clearance: relationships with health-related quality of life in HIV infection (ANRS-VESPA2 study). AB - BACKGROUND: Post-treatment clearance of HCV is associated with improved health related quality of life (HRQL) in HIV-HCV co-infection. However, the potential differences in HRQL between post-treatment and spontaneous clearers remain poorly documented. METHODS: Linear regression models were used to assess the relationships between HCV status and HRQL (PROQOL-HIV scale) in 411 co-infected adults followed-up in French hospitals in 2011 (ANRS-VESPA2 survey). RESULTS: After adjustment for socio-economic and clinical factors, patients previously exposed to HCV treatment showed better physical HRQL and better experience of HIV treatment than treatment-naive HCV-chronic patients. Post-treatment clearers showed better mental HRQL. Spontaneous clearers showed better experience of HIV treatment. CONCLUSION: Spontaneous and post-treatment HCV clearance may influence different dimensions of HRQL of HIV-HCV co-infected patients. Further studies in real-life settings are needed to document patient-reported outcomes in the era of direct-acting antiviral agents for HCV treatment. PMID- 25723565 TI - Impact of Cosmetics on the Physical Dimension and Optical Performance of Silicone Hydrogel Contact Lenses. AB - OBJECTIVES: To evaluate the impact of cosmetics on silicone hydrogel (SiHy) contact lens shape, lens power, and optical performance. METHODS: In this in vitro experiment, 7 SiHy materials were coated with 9 marketed brands of cosmetics, including hand creams (HCs) (3), eye makeup removers (MRs) (3), and mascaras (3). Diameter, sagittal depth, and base curve were determined using the Chiltern (Optimec Limited), whereas lens power and optical performance were assessed using the Contest Plus (Rotlex). Six replicates were used for each lens and cosmetic combination. Measurements were repeated after a cleaning cycle using a one-step hydrogen peroxide solution. RESULTS: Makeup removers had the greatest impact on diameter, sagittal depth, and base curve, resulting in changes of up to 0.5, 0.15, and 0.77 mm, respectively. The HCs and mascaras had little impact on these parameters; however, differences were observed between lens types. Optical performance was reduced with all mascaras, and a decrease of greater than 2 units on a 0 to 10 scale (10=uniform power distribution) was seen for 5 lens types exposed to waterproof mascara (P<0.01). Most HCs and MRs had minimal impact on image quality. Lens power did not change with any of the cosmetics (+/- 0.25 diopter; P>0.05). Lens cleaning resulted in some recovery of the lens parameters, and efficiency varied between cosmetics. CONCLUSION: Some eye MRs and waterproof mascaras changed the shape and optical performance of some SiHy lenses. Further research is needed to understand the clinical implications for SiHy lens wearers using cosmetics. PMID- 25723566 TI - Synthesis, spectroscopic and antimicrobial studies of La(III), Ce(III), Sm(III) and Y(III) Metformin HCl chelates. AB - Metal complexes of Metformin hydrochloride were prepared using La(III), Ce(III), Sm(III) and Y(III). The resulting complexes were discussed and synthesized to serve as potential insulin-mimetic. Some physical properties and analytical data of the four complexes were checked. The elemental analysis shows that La(III), Ce(III) Sm(III) and Y(III) formed complexes with Metformin in 1:3 (metal:MF) molar ratio. All the synthesized complexes are white and possess high melting points. These complexes are soluble in dimethylsulfoxide and dimethylformamide, partially soluble in hot methanol and insoluble in water and some other organic solvents. From the spectroscopic (infrared, UV-vis and florescence), effective magnetic moment and elemental analyses data, the formula structures are suggested. The results obtained suggested that Metformin reacted with metal ions as a bidentate ligand through its two imino groups. The molar conductance measurements proved that the Metformin complexes are slightly electrolytic in nature. The kinetic thermodynamic parameters such as: E(*), DeltaH(*), DeltaS(*) and DeltaG(*) were estimated from the DTG curves. The antibacterial evaluations of the Metformin and their complexes were also performed against some gram positive, negative bacteria as well as fungi. PMID- 25723567 TI - Biomarkers for screening of lung cancer and pre-neoplastic lesions in a high risk Chilean population. AB - BACKGROUND: The mortality of lung cancer (LC), increases each year in the world, in spite of any advances, in development of new drugs to advance stages of LC. The high incidence of LC has been associated with smoking habit, genetic diversity and environmental pollution. Antofagasta region has been reported to have the highest LC mortality rate in Chile and its inhabitants were exposed to arsenic in their drinking water in concentrations as high as 870 MUg/L. Non invasive techniques such as biomarkers (Automatic Quantitative Cytometry: AQC and DR70) and Auto Fluorescence Bronchoscopy (AFB) might be potentially useful as a supplementary diagnostic approach and early detection. Early detection is one of the most important factors to intervene and prevent cancer progression in LC. This is a work of an ongoing prospective bimodality cancer surveillance study in high risk LC volunteers. Enrolment was done in subjects from Antofagasta and Metropolitan regions. In addition, we enrolled subjects who were suspected of having lung cancer. AQC, DR70 and AFB were used as tools in the detection of pre neoplastic (PNL) and neoplastic lesions (NL). RESULTS: Half of the samples, classified as suspicious by AFB, were confirmed as metaplasia or dysplasia by histopathology. For LC, DR70 showed a higher sensitivity (95.8%) and specificity (91.9%) than AQC. However, for PNL AQC showed a higher sensitivity (91.9%) than DR70 (27.3%), although both with low PPV values. As a pre screener, both biomarkers might be employed as complementary tools to detect LC, especially as serially combined tests, with a sensitivity of 60% and a PPV of 65.2%. Additionally, the use of parallel combined tests might support the detection of PNL (sensitivity 91.2%; PPV 49.1%). CONCLUSION: This work adds information on cellular and molecular biomarkers to complement imaging techniques for early detection of LC in Latin America that might contribute to formulate policies concerning screening of LC. Supported by INNOVA-CORFO, Chile. PMID- 25723569 TI - A flexible lab-on-a-chip for the synthesis and magnetic separation of magnetite decorated with gold nanoparticles. AB - Magnetite decorated with gold nanoparticles (Fe3O4-AuNPs) is a ferrimagnetic material with unprecedented applications in immunosensors, as a contrast agent for imaging diagnosis, and for the photothermal ablation of tumor cells. Here, we show the preparation of controlled amounts of Fe3O4-AuNPs without organic solvents, surfactants, or heat treatment. For this, we have developed a customized natural-rubber-based microfluidic device (NRMD) as a flexible lab-on-a chip for the decoration of Fe3O4 with AuNPs. With a novel NRMD configuration, monodisperse Fe3O4-NPs (phi = 10 nm) decorated with AuNPs (phi = 4 nm) were readily obtained. The AuNPs were homogenous in terms of their size and their distribution on the Fe3O4-NP surfaces. Furthermore, the lab-on-a-chip was projected with an internal system for magnetic separation, an innovation in terms of aqueous/carrier phase separation. Finally, the nanomaterials produced with this NRMD are free of organic solvents and surfactants, allowing them to be used directly for medical applications. PMID- 25723568 TI - A comparison of the periodontal status in patients with type 2 diabetes based on glycated haemoglobin levels and other risk factors. AB - PURPOSE: The aim of this study was to compare the periodontal status in patients with type 2 diabetes based on glycated haemoglobin levels and other risk factors. MATERIAL/METHODS: 75 patients with DM2 were grouped according to glycemic control: 40 subjects with HbA1c<7.0% and 35 subjects with HbA1c>=7.0%. We performed measurements of HbA1c, C-reactive protein (CRP), Approximal Plaque Index (API), Gingival Severity Index (GSI), tooth mobility (TM) as well as periodontal parameters such as probing depth (PD) and clinical attachment level (CAL). Age, gender and duration of the disease were analyzed too. RESULTS: No significant differences in PD, CAL, API, GSI and TM were found between the analyzed groups. HbA1c positively correlated with CRP (p=0.046) and the duration of DM2 (p=0.012) but not with the periodontal parameters. Patients' age was positively correlated with both the duration of DM2 (p=0.002) and CAL (p=0.034). Regardless of HbA1c, men had significantly worse periodontal parameters compared to women (respectively: PD 2.73mm vs. 2.18mm, p=0.01; CAL 3.84mm vs. 2.54mm, p=0.005; proportion of deep pockets 9.06% vs. 2.97%, p=0.01; proportion of teeth with grade 2 mobility 9.14% vs. 2.8%, p=0.02). CONCLUSIONS: The selected group of patients attending the Diabetes Outpatient Clinic showed a similar periodontal status with regard to glycated haemoglobin levels and other risk factors except gender. Male gender turned out to be a significant risk factor for periodontal disease in patients with type 2 diabetes mellitus. PMID- 25723570 TI - Photoelectron spectroscopy and ab initio calculations of Li(H2O)n(-) and Cs(H2O)n(-) (n = 1-6) clusters. AB - The Li(H2O)n(-) and Cs(H2O)n(-) (n = 0-6) clusters were studied using anion photoelectron spectroscopy combined with ab initio calculations. It was found that Li tends to be surrounded by water molecules with no water-water H-bonds being formed in the first hydration shell; while Cs sticks on the surface of water-water H-bonds network. The Li atom in its anionic or neutral state is surrounded by four water molecules through Li-O interactions within the first hydration shell; while the case of Cs is different. For the anionic Cs(H2O)n(-) clusters, two types of structures, namely H-end and O-end structures, were identified, with nearly degenerate energies. For the neutral Cs(H2O)n clusters, only O-end structures exist and the first hydration shell of the Cs atom has four water molecules. The different hydration nature of Li and Cs atoms can be ascribed to the delicate balance between the alkali metal-water interactions and the water-water interactions as well as the effect of excess electron. PMID- 25723571 TI - MDM2-mediated degradation of p14ARF: a novel mechanism to control ARF levels in cancer cells. AB - We here show a new relationship between the human p14ARF oncosuppressor and the MDM2 oncoprotein. MDM2 overexpression in various cancer cell lines causes p14ARF reduction inducing its degradation through the proteasome. The effect does not require the ubiquitin ligase activity of MDM2 and preferentially occurs in the cytoplasm. Interestingly, treatment with inhibitors of the PKC (Protein Kinase C) pathway and use of p14ARF phosphorylation mutants indicate that ARF phosphorylation could play a role in MDM2 mediated ARF degradation reinforcing our previous observations that ARF phosphorylation influences its stability and biological activity. Our study uncovers a new potentially important mechanism through which ARF and MDM2 can counterbalance each other during the tumorigenic process. PMID- 25723572 TI - Reassessment of morphological diagnostic characters and species boundaries requires taxonomical changes for the genus orthopyxis L. Agassiz, 1862 (campanulariidae, hydrozoa) and some related campanulariids. AB - The genus Orthopyxis is widely known for its morphological variability, making species identification particularly difficult. A number of nominal species have been recorded in the southwestern Atlantic, although most of these records are doubtful. The goal of this study was to infer species boundaries in the genus Orthopyxis from the southwestern Atlantic using an integrative approach. Intergeneric limits were also tested using comparisons with specimens of the genus Campanularia. We performed DNA analyses using the mitochondrial genes 16S and COI and the nuclear ITS1 and ITS2 regions. Orthopyxis was monophyletic in maximum likelihood analyses using the combined dataset and in analyses with 16S alone. Four lineages of Orthopyxis were retrieved for all analyses, corresponding morphologically to the species Orthopyxis sargassicola (previously known in the area), Orthopyxis crenata (first recorded for the southwestern Atlantic), Orthopyxis caliculata (= Orthopyxis minuta Vannucci, 1949 and considered a synonym of O. integra by some authors), and Orthopyxis mianzani sp. nov. A re evaluation of the traditional morphological diagnostic characters, guided by our molecular analyses, revealed that O. integra does not occur in the study area, and O. caliculata is the correct identification of one of the lineages occurring in this region, corroborating the validity of that species. Orthopyxis mianzani sp. nov. resembles O. caliculata with respect to gonothecae morphology and a smooth hydrothecae rim, although it shows significant differences for other characters, such as perisarc thickness, which has traditionally been thought to have wide intraspecific variation. The species O. sargassicola is morphologically similar to O. crenata, although they differ in gonothecae morphology, and these species can only be reliably identified when this structure is present. PMID- 25723574 TI - Muscle energy technique for non-specific low-back pain. AB - BACKGROUND: Low-back pain (LBP) is responsible for considerable personal suffering due to pain and reduced function, as well as the societal burden due to costs of health care and lost work productivity. For the vast majority of people with LBP, no specific anatomical cause can be reliably identified. For these people with non-specific LBP there are numerous treatment options, few of which have been shown to be effective in reducing pain and disability. The muscle energy technique (MET) is a treatment technique used predominantly by osteopaths, physiotherapists and chiropractors which involves alternating periods of resisted muscle contractions and assisted stretching. To date it is unclear whether MET is effective in reducing pain and improving function in people with LBP. OBJECTIVES: To examine the effectiveness of MET in the treatment of people with non-specific LBP compared with control interventions, with particular emphasis on subjective pain and disability outcomes. SEARCH METHODS: CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers were searched from inception to May and June 2014 together with reference checking and citation searching of relevant systematic reviews. SELECTION CRITERIA: Randomised controlled trials assessing the effect of MET on pain or disability in patients with non-specific LBP were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted the data. Meta-analysis was performed where clinical homogeneity was sufficient. The quality of the evidence for each comparison was assessed with the GRADE approach. MAIN RESULTS: There were 12 randomised controlled trials with 14 comparisons included in the review, with a total sample of 500 participants across all comparisons. Included studies were typically very small (n = 20 to 72), all except one were assessed as being at high risk of bias, and all reported short-term outcomes. For the purposes of pooling, studies were divided into seven clinically homogenous comparisons according to the patient population (acute or chronic LBP) and the nature of the control intervention. Most of the comparisons (five out of seven) included only one study, one comparison had two studies, and one comparison included seven studies.The meta analyses provided low-quality evidence that MET provided no additional benefit when added to other therapies on the outcomes of chronic pain and disability in the short-term (weighted mean difference (WMD) for pain 0.00, 95% CI -2.97 to 2.98 on a 100-point scale; standardised mean difference (SMD) for disability 0.18, 95% CI -0.43 to 0.08, 7 studies, 232 participants). There was low-quality evidence that MET produced no clinically relevant differences in pain compared to sham MET (mean difference (MD) 14.20, 95% CI -10.14 to 38.54, 1 study, 20 participants). For the comparison of MET to other conservative therapies for acute non-specific LBP, there was very low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -10.72, 95% CI -32.57 to 11.13, 2 studies, 88 participants) and functional status (MD 0.87, 95% CI -6.31 to 8.05, 1 study, 60 participants). For the comparison of MET to other conservative therapies for chronic non-specific LBP, there was low-quality evidence of no clinically relevant difference for the outcomes of pain (MD -9.70, 95% CI -20.20 to 0.80, 1 study, 30 participants) and functional status (MD -4.10, 95% CI -9.53 to 1.33, 1 study, 30 participants). There was low-quality evidence of no clinically relevant difference for the addition of MET to other interventions for acute non-specific LBP for the outcome of pain (MD -3, 95% CI -11.37 to 5.37, 1 study, 40 participants) and low-quality evidence of an effect in favour of MET for functional status (MD -17.6, 95% CI -27.05 to -8.15, 1 study, 40 participants). For chronic non-specific LBP, there was low-quality evidence of an effect in favour of MET for the addition of MET to other interventions for the outcomes of pain (MD -34.1, 95% CI -38.43 to -29.77, 1 study, 30 participants) and functional status (MD -22, 95% CI -27.41 to -16.59, 1 study, 30 participants). Lastly, there was low-quality evidence of no difference for the addition of MET to another manual intervention compared to the same intervention with other conservative therapies for the outcomes of pain (MD 5.20, 95% CI -3.03 to 13.43, 1 study, 20 participants) and functional status (MD 6.0, 95% CI -0.49 to 12.49, 1 study, 20 participants).No study reported on our other primary outcome of general well-being. Seven studies reported that no adverse events were observed, whereas the other five studies did not report any information on adverse events. AUTHORS' CONCLUSIONS: The quality of research related to testing the effectiveness of MET is poor. Studies are generally small and at high risk of bias due to methodological deficiencies. Studies conducted to date generally provide low-quality evidence that MET is not effective for patients with LBP. There is not sufficient evidence to reliably determine whether MET is likely to be effective in practice. Large, methodologically-sound studies are necessary to investigate this question. PMID- 25723576 TI - [New minimally invasive approach for palmar plating in distal radius fractures]. AB - Distal radius fractures are among the most common fractures. Types A3 and C2 make up almost half of these. Volar fixed-angle plate fixation is the gold standard of treatment today. We wanted to minimise the approach to the distal radius through a transverse 2-3 cm incision in the wrist flexor fold, tunnelling beneath the pronator muscle. The operative technique is demonstrated here. 11 patients, averaging 70 years of age, underwent surgery for 7 A3 and 4 C2 type fractures. Average operating time was 50 minutes. Length of admission averaged 2.9 days. Using a visual analogue scale, pain decreased from 6/10 preoperatively to 3/10 on post-op day one and 2/10 on post-op day three. After 6 weeks, flexion and extension averaged 45-0-45 degrees , and radial and ulnar deviation 20-0-20 degrees . Pronation and supination averaged 85-0-85 degrees . Grip strength with manometer averaged 90 % compared to the contralateral side at 6 weeks and 96 % at 3 months. As comparison, from 1 January 2008 until 31 May 2013, we treated 908 patients with distal radius fractures with volar fixed-angle plates through a conventional longitudinal incision of 5-8 cm. The average skin to skin time was 46 minutes, with an average length of admission of 5.6 days. A minimally invasive approach to treat distal radius fractures with volar plate fixation and sparing of the pronator muscle is possible. The initial patients treated with this approach experienced minimal post-operative pain, shorter hospital admissions, and rapid grip strength recovery with almost undisturbed rotational motion. PMID- 25723573 TI - Pathway-based analysis of genome-wide siRNA screens reveals the regulatory landscape of APP processing. AB - The progressive aggregation of Amyloid-beta (Abeta) in the brain is a major trait of Alzheimer's Disease (AD). Abeta is produced as a result of proteolytic processing of the beta-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPalpha and the amyloidogenic peptides sAPPbeta, Abeta40, and Abeta42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Abeta40 production over Abeta42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPbeta production over sAPPalpha. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the "regulatory landscape" of APP. PMID- 25723577 TI - [Editorial for the Journal of Orthopaedics and Traumatology]. PMID- 25723575 TI - The amino-terminal conserved domain of 4-hydroxy-3-methylbut-2-enyl diphosphate reductase is critical for its function in oxygen-evolving photosynthetic organisms. AB - 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR), also known as isoprenoid synthesis H (IspH) or lysis-tolerant B (LytB), catalyzes the last step of the methylerythritol phosphate pathway to synthesize isopentenyl diphosphate and dimethylallyl diphosphate. The structure and reaction mechanism of IspH have been actively investigated in Escherichia coli but little is known in plants. Compared with the bacterial IspH, cyanobacterial and plant HDRs all contain an extra N-terminal conserved domain (NCD) that is essential for their function. Tyr72 in the NCD and several plant-specific residues around the central active site are critical for Arabidopsis HDR function. These results suggest that the structure and reaction mechanism of HDR/IspH may be different between plants and bacteria. The E. coli IspH is an iron-sulfur protein that is sensitive to oxygen. It is possible that the cyanobacterial HDR may independently evolve from the common ancestor of prokaryotes to obtain the NCD, which may protect the enzyme from high concentration of oxygen during photosynthesis. PMID- 25723578 TI - [Score-controlled duration of follow-up treatment after alloplastic hip and knee replacement]. AB - BACKGROUND: In the literature many studies can be found addressing the effectiveness of individual measures and therapies within the medical rehabilitation. The duration of the rehabilitation itself is rarely taken into account. Consequently the duration of postoperative inpatient medical rehabilitation after initial implantation of alloarthroplastic hip and knee replacements in osteoarthritis of the hip or knee was the object of our analysis. PATIENTS AND METHODS: In the present prospective study 100 patients each with osteoarthritis of the hip or knee were presented at a follow-up treatment postoperatively after primary implantation of alloarthroplastic hip and knee replacements. Two different scores were used (Staffelstein score, Lequesne score), which were collected at a weekly follow-up (T1-T4) to determine the degree of mobility in the initial examination of the patient and after three weeks. By setting a target score at admission of the patient to the CSO, which stood for achieving the rehabilitation objective, the rehabilitation period could be changed individually. RESULTS: Our study showed that the highest rehabilitation progress has been achieved in both the total hip replacement and total knee replacement in patients at the end of the second week of rehabilitation (T2-T3). Thus, in the Staffelstein score 74 % (n = 74) of hip replacement patients and 46 % (n = 46) of knee replacement patients had already reached their rehabilitation aim between T2 and T3. From the third week on there was a marked flattening of the rehabilitation progress. Also the Lequesne scores obtained confirmed these results. CONCLUSION: Based on the score-driven detection of mobility degree of rehabilitation at the beginning of the follow-up treatment, the individual design of the rehabilitation process with the active participation of the patient is possible. In a large number of cases a reduction of the rehabilitation period can be achieved to less than 21 days. This finding is particularly important in times of limited financial resources, because the saved resources can be used for other rehabilitation groups. Therefore, in a greater number of patients, a shortening of the duration of the rehabilitation is possible. PMID- 25723579 TI - [Total wrist arthroplasty--indications and state of the art]. AB - BACKGROUND: For decades design and development of TWA has been accompanied by quite a few failures, so that it has been rejected by most surgeons until today. The difficult and complex anatomy of the wrist led to different ways of development and often ended in an impasse. Compared to knee and hip arthroplasties which could be conceived and developed further, a consistent method could not be applied. But in the last years some new concepts have established themselves, so that TWA is now not only applied in individual cases. The indications could be expanded and standardised. PATIENTS/MATERIAL AND METHODS: At the Hand-Center Lingen more than 400 TWAs have been performed since 2005. This article describes the mid-term results (5 years since operation) of TWA in 162 patients. 41 % suffered from rheumatoid arthritis, the remaining diseases consisted of osteoarthritis, post-traumatic arthritis and osteoarthritis following distal radius fracture, scaphoid non-union, scapholunate dissociation and Kienbock's disease. RESULTS: Three different types of TWA have been applied and their benefits and disadvantages were examined. In the follow-up we found an improvement in the Quick-Dash of 34 points and 5.8 points on the VAS. The range of motion decreased in patients with RA, but it increased in patients with other diseases. In both groups of patients we found an increase of force. On the whole there was a rate of complications in an average rate of holding time of 3.7 %. There was no necessity for TWA removal and secondary wrist arthrodesis. CONCLUSIONS: Our own very positive experience corresponds with the international comparison and it further encourages a standardised indication in TWA as an equivalent treatment. PMID- 25723580 TI - [Anatomic reconstruction of hip joint biomechanics: conventional vs. short-stem prosthesis]. AB - BACKGROUND: Currently, short cementless femoral stems are alternative implants to treat osteoarthritis in young patients with sufficient bone quality in order to get a more proximal load transfer. The purpose of the present study was to biomechanically compare joint reconstructions resulting from implantations of a short-stemmed and a conventional hip replacement. METHODS: 100 patients (50 short stemmed and 50 conventional) were retrospectively examined. For evaluation of biomechanical parameters standardised pre- and postoperative X-rays (pelvic AP views) were used and digitally analysed. RESULTS: The horizontal femoral off-set increased within both groups (short: 2.0 mm and conventional: 3.3 mm), with a significant increase in the conventional group. The hip centre of rotation was significantly medialised after both procedures (short: 6.0 mm and conventional: 4.2 mm). Limb length was shorter preoperatively at the arthroplasty side, but increased thereafter (short: 2.1 mm and conventional: 2.6 mm). Compared to the native contralateral side the limb length was almost equal after THA (short: 0.7 mm and conventional: 0.8 mm). CONCLUSIONS: Our study shows that an almost anatomic reconstruction of hip joint biomechanics is possible with a short stemmed prosthesis compared to a conventional stem, regarding limb length, centre of rotation and offset. PMID- 25723581 TI - [Surgical treatment of 3- and 4-part fractures of the humeral head using a polyaxial-locking plate: results and patient satisfaction]. AB - INTRODUCTION: In recent years, new angle-stable plate implants with polyaxial screw direction were developed with the aim of an improved treatment of displaced 3- and 4-part fractures of the proximal humerus. There are only a few studies available about polyaxial implants in the treatment of 3- and 4-part proximal humerus fractures. Therefore, the aim of this study was to evaluate clinical results and complications of open reduction and internal fixation of displaced 3- and 4-part fractures using a polyaxial plate. PATIENTS AND METHODS: Within 51 months, 105 patients with a displaced 3- or 4-part fracture of the proximal humerus were treated with a polyaxial locking plate. The complications were evaluated and the Constant & Murley score was assessed and correlated with patient satisfaction ("very satisfied" to "not satisfied"). Additionally, the results were compared with those of monoaxial plates from the literature. Furthermore, the operative experience of the surgeons at the time of surgery was correlated with the objective results of the patients. RESULTS: 65 patients (average age: 71.3 +/- 11.4 years; average follow-up: 19,6 +/- 9,8 month [10-44 month]) with a displaced 3- or 4-part fracture were re-examined retrospectively (female: n = 54; male: n = 11). Overall, there were 27 3-part fractures and 38 4 part fractures. The Constant and Murley Score was on average 62.1 +/- 16.5 points and the complication rate was 26 %. The most frequent complication was screw perforation through the humeral head. Patient satisfaction with clinical outcome was high within the whole study group. 40 % of the patients were "very satisfied" with their shoulder function, 29 % were "satisfied" ("fair": 12 %, "not satisfied": 19 %). Additionally, the operative experience of the surgeons influenced the final clinical result. CONCLUSION: In comparison to the literature we could not delineate better clinical outcomes or lower complication rates with polyaxial implants compared to monoaxial plates in 3- and 4-part fractures. Nevertheless, the majority of patients were satisfied with the clinical result in the context of age-related shoulder function. In addition, a close correlation could be detected between the degree of satisfaction and the objectively measured shoulder function. A high level of operative experience is required to avoid typical complications and to achieve a good clinical result. PMID- 25723582 TI - [Case fatality rate and outcome in multiply injured patients after trauma: influence of specialisation from the first treating physician - an analysis of 198 patients from a national trauma centre]. AB - BACKGROUND: The treatment of multiple injured patients is a highly demanding process concerning the amount and speed of gathered information. Physicians have to evaluate the situation and begin a treatment immediately. There may be influencing variables in the pre-clinical treatment which are correlated to the specialisation of the first treating physician and influencing the outcome of the patient. The aim of this study was to examine the influence of the specialisation of the first treating physician on the pre-clinical treatment and the resulting outcome. PATIENTS AND METHODS: All trauma patients of our department from 2007 to 2010 who fulfilled the following criteria were included into our study: completely recorded DIVI-emergency protocol with declared specialisation of the first treating physician and inclusion into the trauma register of the DGU. This group of patients was divided into three groups according to the specialisation of the first treating physician (anaesthesia, surgery and other) and compared with one another. RESULTS: The study group consisted of 198 patients. 76 were treated by anaesthesiologists, 58 by surgeons, and 64 by physicians of other specialisations. The Injury Severity Score (ISS), the age and the distribution between the sexes showed no significant differences. Surgeons applied significantly less volume pre-clinically (794 ml [anesthesiologists: 1275 ml, others: 1231 ml; p value = 0.036]), the haemoglobin value was higher in the surgeon-treated group. This was also reflected in the applied blood transfusions at admission. The pre-clinical intubation rates (anaesthesiologists 48.7 %, others 37.5 %, surgeons 31 % [p value = 0.11]), the ventilator free days within the first 30 days after admission (anaesthesiologists 21.8, others 21.0, surgeons 25.8), intensive care unit free days within the first 30 days after admission (anaesthesiologists 18.4, others 18.5, surgeons 22.4) as well as the rescue time and case fatality rate showed no significant differences between the different groups. CONCLUSION: Multiply injured patients get a different treatment from the different specialised physicians in the pre-clinical phase. There were differences in the pre-clinical applied volume and haemoglobin value. Rescue time and intubation rate as well as outcome parameters were not statistically different. The case fatality rate in total was not significantly different between the 3 groups. PMID- 25723584 TI - [Clinical relevance of unloading in cartilage therapy of the knee--shoe insoles, knee braces or additional operative procedure?]. AB - Restoration of a neutral biomechanical environment and reduction of overload is an important factor contributing to the success of any cartilage repair procedure. Reduction of overload can by achieved by so called unloading procedures in order to reduce intraarticular pressure from the repair zone. Unloading can be achieved via loss of weight, wedged shoe insoles, knee braces or via operations such as osteotomies around the knee joint. The cartilage therapy and the concomitant unloading procedure should be adapted to the individual pathology and realistic aims of the patient. Wedged insoles and braces are the least invasive treatment methods. In comparison, however, beneficial effects of braces outline those of laterally wedged heels. Nevertheless long-term compliance with insoles and braces is poor. Concerning braces either because the positive effects of the braces are too small or because the adverse effects are too large. Unloading in the long run may only be achieved through operative procedures. When an osteotomy seems to be too invasive the arthroscopic release of the posterior oblique ligament might be an option. Patients with an intact contralateral chondral status, medium to slight malalignment who want to remain at high activity levels, remain good candidates for unloading osteotomies. PMID- 25723583 TI - [The German Cartilage Registry (KnorpelRegister DGOU) for evaluation of surgical treatment for cartilage defects: experience after six months including first demographic data]. AB - The German Cartilage Registry (KnorpelRegister DGOU) has been introduced in October 2013 and aims on the evaluation of patients who underwent cartilage repair for symptomatic cartilage defects. It represents a nation-wide cohort study which has been introduced by the working group "Tissue Regeneration" of the Germany Society of Orthopaedic Surgery and Traumatology and is technically based upon a web-based remote data entry (RDE) system. The present article describes first experiences with the registry including patient and treatment characteristics. Between October 2013 and April 2014, a total of 230 patients who had undergone surgical cartilage repair for symptomatic full-thickness cartilage defects of the knee has been included in the German Cartilage Registry from 23 cartilage repair centres. Mean age was 37.11 years (SD 13.61) and mean defect size was 3.68 cm(2) (SD 0.23). Since the introduction of the KnorpelRegister DGOU the total number of registered patients has increased steadily up to the most recent figure of 72 patients within one month. Patients were treated mainly according to the recommended therapies. The highest percentage in therapy is represented by the bone marrow stimulation techniques (55.02 %) as well as by the autologous chondrocyte transplantation (34.92 %). Unlike the patient collective in the majority of prospective randomised controlled trials, the patient population within the registry shows a high proportion of patients with accompanying pathologies, with an age of more than 50 years at the time of treatment and with unfavourably assessed accompanying pathologies such as an affection of the opposite cartilage surface or a previously resected meniscus. In summary, the technical platform and forms of documentation of the KnorpelRegister DGOU have proved to be very promising within the first six months. Unlike data from other clinical trials, the previous analysis of the patients' data and therapies reflects successfully the actual medical care situation of patients with cartilage defects of the knee joint. This analysis also provides new information on subgroups of patients that have not yet been recorded in the scientific literature. This will be part of the first analysis of clinical treatment data. An expansion of the KnorpelRegister DGOU to patients with cartilage defects of the ankle and hip joints is already decided upon and initialised. PMID- 25723585 TI - [Does coxitis fugax predispose for later Perthes' disease?--first results of an insurance data-based study]. AB - INTRODUCTION: For decades, it has been a matter of debate whether coxitis fugax (CF) may trigger the onset of Perthes' disease (PD). However, the low incidence of both conditions limits the validity of clinical studies. As a novel approach, an analysis of patient data provided by a private health insurance (PHI) was performed. After calculation of the frequencies of CF and PD possible correlations were statistically assessed. We hypothesised that CF predisposes to the development of PD. MATERIALS: A retrospective database analysis was conducted based on insurance data of patients aged between 1 and 14 years covering an observation period of 7 years. Cases of CF and PD were detected by a search algorithm based on the International Classification System of Diseases (ICD) encoding the ICD codes M12.85 to CF and M91.1 to PD, respectively. Cases where CF was followed by PD were separately assessed for plausibility considering the clinical course and the length of the symptom-free interval. Statistical analysis was performed by using the chi-square test with a significance level set at 5 %. RESULTS: Among a cohort of 407,875 children 960 cases of CF were detected. Of these, 876 (91.3 %) had one single event of CF whereas 84 (8.7 %) children had two or more episodes. The average incidence of CF was 0.24 % per year. The frequency of PD was calculated to be 15.7 cases per 100, 000 children per year. In eleven cases (all male) CF was found to be followed by PD, however, after checking for plausibility only three cases remained. Statistical analysis revealed that the incidence of PD in male children with a previous CF episode was 21-times higher compared to children without CF (p < 0.0001). DISCUSSION: The results of the hitherto largest study including more than 400 ,000 children showed a significantly higher rate of PD in male children with previous CF compared to boys without CF. However, different patterns of age distribution and the observation that multiple CF episodes do not trigger the development of PD contradict the assumption of a possible correlation between these two diseases. In two of the three cases where CF was followed by PD a so-called "late onset PD" was evident suggesting a misdiagnosed PD at initial presentation. The chosen study design using patient data provided by a PHI allows the acquisition and evaluation of large numbers of cases which may help to elucidate possible correlations between different medical conditions. To unambiguously answer the hypothesis of this study, the inclusion of additional insurance data is necessary. PMID- 25723586 TI - [Causes and calculated predictors of a Duchenne gait in adolescents and young adults with cerebral palsy]. AB - BACKGROUND: Adolescents with cerebral palsy often complain about a Duchenne gait, which increases the load on the spine, the energy consumption and therefore decreases gait efficiency. However the underlying causes of a Duchenne gait in patients with CP are not clearly researched yet. Nevertheless there is an assumption that excessive trunk lean might assist foot clearance to compensate for muscle weakness or contractures of the legs. In particular weakness, secondary to surgical soft tissue muscle tendon lengthening in childhood, might predispose patients to greater compensatory movements of the trunk. Therefore the aim of this study was to estimate the prevalence, underlying causes and calculated predictors for a Duchenne gait on CP patients with and without previous muscle tendon lengthening. PATIENTS, MATERIALS AND METHODS: 50 CP patients between 12 and 22 years with diplegia and GMFCS II (GMFCS: Gross Motor Function Classification System) participated in this study. 25 patients had no previous surgeries (CP-0). 25 patients had previous calf, hamstrings and/or adductor muscle tendon lengthening surgeries (CP-1). Data of 20 typically developed adolescents served as controls (TD). Gait was analysed using an instrumented gait analysis system (Vicon, Oxford, UK) The parameter "thorax obliquity range" (TOR) investigated the dimension of Duchenne gait. RESULTS: CP-0 showed a prevalence of 72 %, CP-1 of 66 % for Duchenne gait. TOR was 5 +/- 2 degrees , 16 +/- 8 degrees and 16 +/- 8 degrees , for TD, CP-0 and CP-1, respectively. CP-0 and CP-1 showed significant differences in TOR between TD (both p < 0.001), but not between CP-0 and CP-1 (p = 1.0). Passive hip abduction range of motion (ROM) showed no significant correlation to TOR in both groups, whereas hip abduction muscle strength revealed significant correlation (rs = - 0.37) in CP-0. Best gait predictors in CP-0 patients were increased hip generation work (stance = st) and ankle dorsi flexion (swing = sw), together explaining 47 % of the variance in TOR. In CP-1 best gait predictors were increased hip generation work (st) as well as reduced knee flexion (sw) and ankle generation work (st), explaining 31 % of the variance in TOR. CONCLUSION: With a prevalence of 66 % or higher Duchenne gait is a serious gait pathology in CP. Neither the hypothesis that previous muscle tendon lengthening nor that hip adductor contractures increase Duchenne gait could be confirmed in this study. Weak hip abductor muscle strength only showed a small correlation in CP-0. Best predictor in both groups was hip generation work (st). Certain hip abductors (M. gluteus medius ventral; M. gluteus minimus; M. tensor fasciae latae) function also as hip flexors and internal rotators. This leads to the hypothesis that during stance the Duchenne gait unloads the hip abductor muscles and therefore decreases the effect of internal rotation and hip flexion which leads to improved dynamic power of the hip for propulsion. In consequence the resultant hip extension moment increases by reducing the hip flexion moment. Presumably this is due to the fact that patients with CP show a reduced selective muscle control. For CP patients the negative effects of the common pelvis drop and internal rotation of the hip during gait decrease. PMID- 25723587 TI - [The Grice-Green subtalar arthrodesis using a fibular bone graft--follow-up of 92 patients]. AB - BACKGROUND: The Grice-Green subtalar arthrodesis is considered to be a valid treatment option of severe pes planovalgus deformity especially in children with cerebral palsy. The purpose of this study was to evaluate long term results using Grice-Green procedure with a fibular bone graft. MATERIAL AND METHODS: Between 3/07 and 11/12 92 patients (36 girls, 56 boys) with 127 feet underwent surgery. The average age of patients was 12.3 years (5-21 years). 68 patients had infantile cerebral palsy, 17 patients suffered from other neuromuscular diseases and 7 had idiopathic pes planovalgus deformities. The preoperative and postoperative radiographs with full weight bearing in the frontal and lateral planes were analysed. The mean follow-up was 22.6 months (6-64 months). In addition to that, 23 of the 92 patients (13 girls, 10 boys) were reviewed preoperatively, in the first year after operation and after more than 24 months. RESULTS: The mean lateral talocalcanear angle was reduced from 49.52 to 31.49 degrees . The calcaneal pitch angle changed from 2.95 to 7.55 degrees . The mean lateral talo-first-metatarsal angle improved from -36.98 to -12.32 degrees . The mean frontal talo-first-metatarsal-base-angle increased from -28.48 to -2.64 degrees and the TMT index from -66.46 to -14.96 degrees . All measured angles changed significantly (p < 0.0001). There was no significant change after 6-12 month and >= 24 month follow-up (p > 0.05). Eight feet were not corrected completely, three feet were overcorrected. In one case the fibular graft was reabsorbed. There were degenerative changes of the talus in three cases. 14 feet developed a dorsal bunion with extension deformity of the first metatarsal bone. CONCLUSIONS: The Grice-Green subtalar arthrodesis improves foot alignment and can achieve a significant correction also in long-term follow-up. PMID- 25723588 TI - Hydrotrope accumulation around the drug: the driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea. AB - Nicotinamide is an effective non-micellar hydrotrope (solubilizer) for drugs with low aqueous solubility. To clarify the molecular basis of nicotinamide's hydrotropic effectiveness, we present here a rigorous statistical thermodynamic theory, based on the Kirkwood-Buff theory of solutions, and our recent application of it to hydrotropy. We have shown that (i) nicotinamide self association reduces solubilization efficiency, contrary to the previous hypothesis which claimed that self-association drives solubilization and (ii) the minimum hydrotrope concentration (MHC), namely, the threshold concentration above which solubility suddenly increases, is caused not by the bulk-phase self association of nicotinamides as has been postulated previously, but by the enhancement of nicotinamide-nicotinamide interaction around the drug molecules. We have thus established a new view of hydrotropy - it is nicotinamide's non stoichiometric accumulation around the drug that is the basis of solubility increase above MHC. PMID- 25723589 TI - Stereodivergent synthesis and relative stereostructure of the C1-C13 fragment of symbiodinolide. AB - Four possible diastereomers of the C1-C13 fragment of symbiodinolide, which were proposed by the stereostructural analysis of the degraded product, were synthesized in a stereodivergent and stereoselective manner. The key transformations were aldol reaction of methyl acetoacetate with the aldehyde, diastereoselective reduction of the resulting beta-hydroxy ketone, and the stereoinversion at the C6 position. Comparison of the (1)H NMR data between the four synthetic products and the degraded product revealed the relative stereostructure of the C1-C13 fragment of symbiodinolide. PMID- 25723590 TI - CD95 rs1800682A/G variant and tumor risk in Asians: evidence from a meta-analysis of 36 case-control studies containing 22,438 samples. AB - BACKGROUND: The CD95 gene plays a key role in regulating cell growth and tumor genesis. To date, several publications have focused on the CD95 rs1800682A/G site polymorphism and various types of tumors in Asians; however, this association is still controversial and obscure. Therefore, a meta-analysis combined with all publications to clarify this association is necessary. MATERIAL/METHODS: A search in the PubMed and SinoMed databases was performed to detect all relevant included publications. Odds ratio (OR) and 95% confidence intervals (CI) revealed association strengths. RESULTS: Overall, 36 case-control studies were chosen based on the search criteria. There was no association of the CD95 rs1800682A/G site polymorphism with tumor risk in total and ethnicity subgroup analysis. However, further stratified analysis in the cancer subgroup revealed weakly significant associations in hepatocellular carcinoma (AA+AG vs. GG: OR=0.93, 95% CI=0.87-0.99, P=0.035; AG vs. GG: OR=0.89, 95% CI=0.80-0.99, P=0.036). CONCLUSIONS: The CD95 rs1800682A/G site polymorphism may be associated with hepatocellular carcinoma susceptibility. Further large-scale and well-designed studies regarding tumor types and ethnicities are still required to confirm our results. PMID- 25723591 TI - Survey of preventable disaster death at medical institutions in areas affected by the Great East Japan Earthquake: a retrospective preliminary investigation of medical institutions in Miyagi Prefecture. AB - PROBLEM: The 2011, magnitude (M) 9, Great East Japan Earthquake and massive tsunami caused widespread devastation and left approximately 18,500 people dead or missing. The incidence of preventable disaster death (PDD) during the Great East Japan Earthquake remains to be clarified; the present study investigated PDD at medical institutions in areas affected by the Great East Japan Earthquake in order to improve disaster medical systems. METHODS: A total of 25 hospitals in Miyagi Prefecture (Japan) that were disaster base hospitals (DBHs), or had at least 20 patient deaths between March 11, 2011 and April 1, 2011, were selected to participate based on the results of a previous study. A database was created using the medical records of all patient deaths (n=868), and PDD was determined from discussion with 10 disaster health care professionals. RESULTS: A total of 102 cases of PDD were identified at the participating hospitals. The rate of PDD was higher at coastal hospitals compared to inland hospitals (62/327, 19.0% vs 40/541, 7.4%; P<.01). No difference was observed in overall PDD rates between DBHs and general hospitals (GHs); however, when analysis was limited to cases with an in-hospital cause of PDD, the PDD rate was higher at GHs compared to DBHs (24/316, 7.6% vs 21/552, 3.8%; P<.05). The most common causes of PDD were: insufficient medical resources, delayed medical intervention, disrupted lifelines, deteriorated environmental conditions in homes and emergency shelters at coastal hospitals, and delayed medical intervention at inland hospitals. Meanwhile, investigation of PDD causes based on type of medical institution demonstrated that, while delayed medical intervention and deteriorated environmental conditions in homes and emergency shelters were the most common causes at DBHs, insufficient medical resources and disrupted lifelines were prevalent causes at GHs. CONCLUSION: Preventable disaster death at medical institutions in areas affected by the Great East Japan Earthquake occurred mainly at coastal hospitals. Insufficient resources (at GHs), environmental factors (at coastal hospitals), and delayed medical intervention (at all hospitals) constituted the major potential contributing factors. Further investigation of all medical institutions in Miyagi Prefecture, including those with fewer than 20 patient deaths, is required in order to obtain a complete picture of the details of PDD at medical institutions in the disaster area. PMID- 25723592 TI - The Bactrocera oleae genome: localization of nine genes on the polytene chromosomes of the olive fruit fly (Diptera: Tephritidae). AB - Four homologous and five heterologous gene-specific sequences have been mapped by in situ hybridization on the salivary gland polytene chromosomes of the olive fruit fly, Bactrocera oleae. The nine genes were dispersed on four of the five autosomal chromosomes, thus enriching the available set of chromosome landmarks for this major agricultural pest. Present data further supports the proposed chromosome homologies among B. oleae, Ceratitis capitata, and Drosophila melanogaster and the idea of the conservation of chromosomal element identity throughout dipteran evolution. PMID- 25723594 TI - Erratum to: The draft genome of a socially polymorphic halictid bee, Lasioglossum albipes. AB - During the type-setting of the final version of the article [1] some of the additional files were swapped, and several were completely replaced. The correct files are republished in this Erratum. PMID- 25723593 TI - Clinical, virological and immunological features from patients infected with re emergent avian-origin human H7N9 influenza disease of varying severity in Guangdong province. AB - BACKGROUND: The second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region. METHODS: Five patients with H7N9 virus infection admitted to our hospital during August 2013 to February 2014 were intensively investigated. Viral load in the respiratory tract was determined by quantitative polymerase chain reaction (Q-PCR) and cytokine levels were measured by bead-based flow cytometery. RESULTS: Four patients survived and one died. Viral load in different clinical specimens was correlated with cytokine levels in plasma and broncho-alveolar fluid (BALF), therapeutic modalities used and clinical outcome. Intravenous zanamivir appeared to be better than peramivir as salvage therapy in patients who failed to respond to oseltamivir. Higher and more prolonged viral load was found in the sputum or endotracheal aspirates compared to throat swabs. Upregulation of proinflammatory cytokines IP-10, MCP-1, MIG, MIP 1alpha/beta, IL-1beta and IL-8 was found in the plasma and BALF samples. The levels of cytokines in the plasma and viral load were correlated with disease severity. Reactivation of herpes simplex virus type 1(HSV-1) was found in three out of five patients (60%). CONCLUSION: Expectorated sputum or endotracheal aspirate specimens are preferable to throat swabs for detecting and monitoring H7N9 virus. Severity of the disease was correlated to the viral load in the respiratory tract as well as the extents of cytokinemia. Reactivation of HSV-1 may contribute to clinical outcome. PMID- 25723595 TI - Characterization of fetal antigen 1/delta-like 1 homologue expressing cells in the rat nigrostriatal system: effects of a unilateral 6-hydroxydopamine lesion. AB - Fetal antigen 1/delta-like 1 homologue (FA1/dlk1) belongs to the epidermal growth factor superfamily and is considered to be a non-canonical ligand for the Notch receptor. Interactions between Notch and its ligands are crucial for the development of various tissues. Moreover, FA1/dlk1 has been suggested as a potential supplementary marker of dopaminergic neurons. The present study aimed at investigating the distribution of FA1/dlk1-immunoreactive (-ir) cells in the early postnatal and adult midbrain as well as in the nigrostriatal system of 6 hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian adult rats. FA1/dlk1-ir cells were predominantly distributed in the substantia nigra (SN) pars compacta (SNc) and in the ventral tegmental area. Interestingly, the expression of FA1/dlk1 significantly increased in tyrosine hydroxylase (TH)-ir cells during early postnatal development. Co-localization and tracing studies demonstrated that FA1/dlk1-ir cells in the SNc were nigrostriatal dopaminergic neurons, and unilateral 6-OHDA lesions resulted in loss of both FA1/dlk1-ir and TH-ir cells in the SNc. Surprisingly, increased numbers of FA1/dlk1-ir cells (by 70%) were detected in dopamine-depleted striata as compared to unlesioned controls. The higher number of FA1/dlk1-ir cells was likely not due to neurogenesis as colocalization studies for proliferation markers were negative. This suggests that FA1/dlk1 was up-regulated in intrinsic cells in response to the 6-OHDA mediated loss of FA1/dlk1-expressing SNc dopaminergic neurons and/or due to the stab wound. Our findings hint to a significant role of FA1/dlk1 in the SNc during early postnatal development. The differential expression of FA1/dlk1 in the SNc and the striatum of dopamine-depleted rats could indicate a potential involvement of FA1/dlk1 in the cellular response to the degenerative processes. PMID- 25723596 TI - Prevalence of cigarette smoking and associated factors in a large sample of HIV positive patients receiving antiretroviral therapy in Vietnam. AB - BACKGROUND: Cigarette smoking presents a salient risk for HIV-positive populations. This study is among the first to examine smoking prevalence, nicotine dependence, and associated factors in a large sample of HIV-positive patients receiving antiretroviral therapy (ART) in Vietnam. METHODS: A cross sectional study of 1133 HIV-positive people was conducted from January to September 2013 at 8 ART clinics in Hanoi (the capital) and Nam Dinh (a rural area). Smoking history and nicotine dependence (Fagerstrom Test of Nicotine Dependence-FTND) were assessed by participant self-report. Logistic regression and Tobit linear regression were performed to identify factors significantly associated with smoking outcomes. RESULTS: Prevalence of current, former, and never smokers in the sample was 36.1%, 9.5%, and 54.4%, respectively. The current smoking proportion was higher in males (59.7%) than females (2.6%). The mean FTND score was 3.6 (SD = 2.1). Males were more likely to currently smoke than females (OR = 23.4, 95% CI = 11.6-47.3). Individuals with problem drinking (OR = 1.8, 95% CI = 1.1-2.9) and ever drug use (OR = 3.7, 95%CI = 2.5-5.7) were more likely to be current smokers. Older age and currently feeling pain were associated with lower nicotine dependence. Conversely, receiving care in Nam Dinh, greater alcohol consumption, ever drug use, and a longer smoking duration were associated with greater nicotine dependence. CONCLUSIONS: Given the high prevalence of smoking among HIV-positive patients, smoking screening and cessation support should be offered at ART clinics in Vietnam. Risk factors (i.e., substance use) linked with smoking behavior should be considered in prevention programs. PMID- 25723597 TI - The immunology of influenza virus-associated bacterial pneumonia. AB - Infection with influenza virus has been a significant cause of morbidity and mortality for more than a hundred years. Severe disease and increased mortality often results from bacterial super-infection of patients with influenza virus infection. Preceding influenza infection alters the host's innate and adaptive immune responses, allowing increased susceptibility to secondary bacterial pneumonia. Recent advances in the field have helped to define how influenza alters the immune response to bacteria through the dysregulation of phagocytes, antimicrobial peptides, and lymphocytes. Viral-induced interferons play a key role in altering the phenotype of the immune response. Potential genetic modifiers of disease will help to define additional immunologic mechanisms that predispose to viral, bacterial super-infection with the overarching goal of developing effective therapeutic strategies to prevent and treat disease. PMID- 25723598 TI - Four new Mn(II) inorganic-organic hybrid frameworks with diverse inorganic magnetic chain's sequences: syntheses, structures, magnetic, NLO, and dielectric properties. AB - Four new inorganic-organic hybrid manganese frameworks, formulated as [Mn(Am Hip)2].3H2O (1), [Mn2(ip)2(H2O)].CH3OH (2), [Mn2(OH-ip)2(DMF)].DMF (3), and (Me2NH2)[Mn4(sdba)4(Hsdba)(H2O)].3H2O.2DMF (4) (Am-H2ip = 5-aminoisophthalic acid, H2ip = isophthalic acid, OH-H2ip = 5-hydroxyisophthalic acid, and H2sdba = 4,4'-sulfonyldibenzoic acid), have been prepared by solvothermal reactions of Mn(II) ions with different polycarboxylate acids in the presence of LiNO3 or NH4NO3. Single-crystal X-ray diffraction studies reveal that the frameworks of 1 4 contain diverse Mn(II)-oxygen inorganic magnetic chain's sequences, -J1J1J1J1- for 1, -J1J2J1J2- for 2, -J1J1J2J2- for 3, and -J1J2J3J3- for 4. The sequence in 4 has never been seen for the magnetic chain compounds and is a new type of magnetic alternating sequence. Magnetic investigations indicate that these compounds all show weak antiferromagnetic couplings between the adjacent Mn(II) ions. Magnetostructural analyses based on the data of 1-4 and other related Mn(II) chain compounds imply that the magnitude of the magnetic coupling has some relationship with the Mn-O-Mn angle of the MU2-O bridge and the average Mn-O-C-O torsion angle of the carboxylate bridges. Compounds 2 and 4 crystallize in chiral and acentric space groups, and they both exhibit powder second harmonic generation (SHG) efficiencies approximately 0.6 and 0.9 times, respectively, that of the standard potassium dihydrogen phosphate (KDP) powder. In addition, the dielectric properties of 2 and 4 were also investigated. PMID- 25723600 TI - Dreaming and the default network: A review, synthesis, and counterintuitive research proposal. AB - This article argues that the default network, augmented by secondary visual and sensorimotor cortices, is the likely neural correlate of dreaming. This hypothesis is based on a synthesis of work on dream content, the findings on the contents and neural correlates of mind-wandering, and the results from EEG and neuroimaging studies of REM sleep. Relying on studies in the 1970s that serendipitously discovered episodes of dreaming during waking mind-wandering, this article presents the seemingly counterintuitive hypothesis that the neural correlates for dreaming could be further specified in the process of carrying out EEG/fMRI studies of mind-wandering and default network activity. This hypothesis could be tested by asking participants for experiential reports during moments of differentially high levels of default network activation, as indicated by mixed EEG/fMRI criteria. Evidence from earlier EEG/fMRI studies of mind-wandering and from laboratory studies of dreaming during the sleep-onset process is used to support the argument. PMID- 25723599 TI - Computerized PET/CT image analysis in the evaluation of tumour response to therapy. AB - Current cancer therapy strategy is mostly population based, however, there are large differences in tumour response among patients. It is therefore important for treating physicians to know individual tumour response. In recent years, many studies proposed the use of computerized positron emission tomography/CT image analysis in the evaluation of tumour response. Results showed that computerized analysis overcame some major limitations of current qualitative and semiquantitative analysis and led to improved accuracy. In this review, we summarize these studies in four steps of the analysis: image registration, tumour segmentation, image feature extraction and response evaluation. Future works are proposed and challenges described. PMID- 25723601 TI - [In Process Citation]. PMID- 25723602 TI - [Robot-assisted surgery in visceral and thoracic surgery gynaecology, urology- importantanaesthetic considerations]. AB - Robot-assisted surgery, as a development of laparoscopic surgery, has an increasing field of application. Beside urology, this technique has also been implemented in visceral and thoracic surgery and gynaecology. For the surgeon an enhanced view of the surgical field and a better mobility of the instruments are the most important advantages. Thus, it is possible to work more accurate and prevent inadvertent tissue damage. For the anaesthesiologist several characteristics are of importance. Limited access to the patient as a result of a special positioning requires adequate anaesthetic preparation. For many visceral and thoracic surgical interventions the head and airway of the patient is bedded remote from the anaesthesiologist. Therefore, a standardised order and protection of all i. v.-lines, cables and the ventilation-hose of the (double-lumen) tube is essential. After the roboter is connected to the patient, it is nearly impossible to change or extend patient monitoring. Especially in case of emergency, e. g. respiratory complications or heart failure, a close communication with the surgeon and a team approach are indispensable. PMID- 25723603 TI - [Community acquired pneumonia in the emergence department--do standardized care bundles improve quality of care?]. AB - Community acquired pneumonia (CAP) is associated with high in-hospital mortality. The initial correct diagnosis, risk assessment and initiation of treatment are responsibilities of the emergency department (ED). In Germany, emergency medicine is not well established nationwide and organized in a very heterogeneous manner. Therefore, systematic approaches to improve quality of care are scarce and standardisations of processes are required. Standardized care bundles for CAP identify patients at increased risk for an adverse outcome. Early detection of CAP in the emergency department is essential for initiating timely and appropriate treatment. As part of the nationwide CAP quality improvement program we use CRB-65 for initial risk stratification in the ED. In own investigations we demonstrated that implementation of systematic guideline based care bundles for pneumonia significantly improves quality of care in the ED subsequently leading to decreased mortality during hospitalization. Early standardized care bundles in the ED reduce length-of-stay in the hospital and the intensive care unit. Furthermore, those strategies are accompanied with an improvement of economic characteristics. PMID- 25723604 TI - [Perioperative management of patients with opioid tolerance and misuse]. AB - Patients with opioid pretreatment can be divided into different groups.While patients after successful drug addiction treatment with or without drug replacement therapy usually not require an extensive perioperative pain therapy, patients with persistent chronic pain and patients with an existing opioid addiction regularly are challenging for the anesthetist. Important pathophysiological issues among the patients include opioid tolerance, opioid induced hyperalgesia (OIH) as well as acute withdrawal symptomes. Pharmakokinetic properties of the opioid seems to be crucial the manifestation of an acute withdrawal syndrome following opioid administration, and thus the use of remifentanil has frequently been reported to induce withdrawal symptoms. While all established anesthetic procedures can be applied, regional anesthetic techniques should be included whenever possible. A common misstake when treating patients with a history of opioid abuse is an unwarranted restraint in using opioids. In patients with a ongoing opioid abuse, it may be efficient to apply methadone or buprenorphine even prior to surgery. While pregabalin and gabapentin are first line therapeutics for treatment of neuropathic pain, they also seem to be effective co-analgesics in patients suffering from chronic pain and undergo surgery. A similar statement applies to clonidine and dexmedetomidine, which probably induce analgesia by activation of the descending antinociceptive noradrenergic system. The intraoperative administration of S-ketamine is recommended for patients who either already have developed opioid tolerance or suffer from neuropathic pain, and by which postoperative pain is high and was already shown to be poorly adjusted. Other therapeutic options such as intraoperative administration of magnesium or lidocaine may be promising approaches. PMID- 25723605 TI - [Sepsis and multi-organ failure--recognize , understand and treat early]. PMID- 25723606 TI - [Pathophysiology of sepsis]. AB - Our understanding of the causes and pathophysiological basis of sepsis has been subject to constant change over the last decades. In today's understanding, sepsis is primarily a pathology of the immune system, triggered by an underlying infection but perpetuated by the host's response itself. Thereby, sepsis should not be categorized to be either a sole pro- or anti-inflammatory syndrome, but rather as a variable continuum of overlaying immune mechanisms. While a overshooting immune reaction predominates in early sepsis, this reaction is rapidly compensated, often leading to a immune dysfunction, rendering the host susceptible for secondary infections. This review aims to provide the reader with an overview of the broad molecular mechanisms contributing to the clinical picture of sepsis. PMID- 25723607 TI - [Blood culture diagnostic--challenge or routine standard of care?]. AB - Blood cultures are an essential diagnostic tool to investigate suspected cases of sepsis. However, several studies indicate that (compared with other countries) blood culture diagnostics is only rarely performed in German healthcare facilities. Reasons for this are unknown, but could include clinicians' perception that the turn-around time of results is delayed or that contamination rates are high. Therefore, this article aims to summarize important aspects involved in assuring quality of blood culture diagnostics as well as innovative approaches. PMID- 25723608 TI - [Sepsis and multiple organfailure--potential therapeutic interventions]. AB - Sepsis therapy is aiming to eliminate the focus of infection and to obtain or to restore microcirculation. Severe sepsis and septic shock have to be treated as fast and aggressively as hemorrhagic shock, because the time between onset of disease and initiating the therapy is crucial for the probability of survival. The bundle measures introduced by the Surviving-Sepsis-Campaign are able to reduce mortality significantly. The compliance with the bundle measures and consequent training of medical staff to predefined goal measures and therapy protocols is determining the success of sepsis therapy. The bundle measures of the first six hours (resuscitation bundle) deserve special attention. PMID- 25723609 TI - [The premedication visit--suggestions for a patient-friendly design]. AB - The premedication visit is often a difficult situation for the anaesthetist. On the one hand the patient needs to be informed in detail, but on the other he must not be alienated unnecessarily. Furthermore, a hospital stay represents an exceptional situation for the patient in which he behaves differently than in everyday life and shows a limited ability to process information. Following certain communication strategies allows to convey information to the patient in a comprehensible manner and to describe his individual anaesthesiological risk without needlessly creating fear. PMID- 25723610 TI - [Conference Report - 2. Induced hypothermia--a talk]. PMID- 25723613 TI - Simultaneous silencing of VEGF and KSP by siRNA cocktail inhibits proliferation and induces apoptosis of hepatocellular carcinoma Hep3B cells. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is involved in the growth of new blood vessels that feed tumors and kinesin spindle protein (KSP) plays a critical role in mitosis involving in cell proliferation. Simultaneous silencing of VEGF and KSP, an attractive and viable approach in cancer, leads on restricting cancer progression. The purpose of this study is to examine the therapeutic potential of dual gene targeted siRNA cocktail on human hepatocellular carcinoma Hep3B cells. RESULTS: The predesigned siRNAs could inhibit VEGF and KSP at mRNA level. siRNA cocktail showed a further downregulation on KSP mRNA and protein levels compared to KSP-siRNA or VEGF siRNA, but not on VEGF expression. It also exhibited greater suppression on cell proliferation as well as cell migration or invasion capabilities and induction of apoptosis in Hep3B cells than single siRNA simultaneously. This could be explained by the significant downregulation of Cyclin D1, Bcl-2 and Survivin. However, no sigificant difference in the mRNA and protein levels of ANG2, involving inhibition of angiogenesis was found in HUVECs cultured with supernatant of Hep3B cells treated with siRNA cocktail, compared to that of VEGF siRNA. CONCLUSION: Silencing of VEGF and KSP plays a key role in inhibiting cell proliferation, migration, invasion and inducing apoptosis of Hep3B cells. Simultaneous silencing of VEGF and KSP using siRNA cocktail yields promising results for eradicating hepatocellular carcinoma cells, a new direction for liver cancer treatment. PMID- 25723614 TI - Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn's disease: results from a randomized, multicenter, phase-3 study. AB - BACKGROUND: Adalimumab, a fully human monoclonal antibody (IgG1kappa) to tumor necrosis factor, has shown benefit in the treatment of inflammatory bowel disease. The purpose of this analysis was to evaluate the pharmacokinetics (PK) and the serum concentration-efficacy relationship of adalimumab in pediatric patients with moderate-to-severe Crohn's disease. METHODS: The safety, efficacy, and PK of adalimumab was evaluated in a phase-3, randomized, double-blind, 52 week study (IMAgINE-1, N = 192), which had a 4-week open-label induction phase (dose was determined by patient weight) followed by a 48-week double-blind maintenance phase (standard and low-dose arms, drug given every other week). Trough serum adalimumab (baseline, weeks 2, 4, 16, 26, and 52) and anti adalimumab antibody measurements (baseline, weeks 16, 26, and 52) were collected. Disease activity was assessed using the Pediatric Crohn's Disease Activity Index. RESULTS: At week 52, adalimumab trough concentrations (mean +/- SD) were higher for patients in the standard-dose (9.48 +/- 5.61 MUg/mL) compared with the low dose (3.51 +/- 2.21 MUg/mL) arm. In patients whose doses were increased from every other week to weekly, higher trough concentrations were observed after dose escalation. Higher body weight, baseline C-reactive protein, and lower baseline albumin levels were associated with greater clearance of adalimumab. An exposure (serum concentration)-efficacy relationship was observed, in which higher concentrations of adalimumab were associated with greater rates of remission. CONCLUSIONS: This study is the first to describe the PK of adalimumab in pediatric patients with moderate-to-severe Crohn's disease. A positive association between serum adalimumab concentration and remission/response was identified. PMID- 25723615 TI - Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease. AB - Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy. PMID- 25723616 TI - Exercise decreases risk of future active disease in patients with inflammatory bowel disease in remission. AB - BACKGROUND: Although exercise impacts quality of life in patients with inflammatory bowel disease, little is known about its role in disease activity. Among patients with inflammatory bowel disease in remission, we aimed to evaluate the association between exercise and subsequent active disease. METHODS: We performed a prospective study using the Crohn's and Colitis Foundation of America Partners' internet-based cohort of individuals with self-reported inflammatory bowel disease. We identified participants in remission, defined as short Crohn's disease activity index <150 or simple clinical colitis activity index <=2. The primary exposure was exercise status, measured using the validated Godin leisure time activity index. The primary study outcome, assessed after 6 months, was active disease defined using the above disease activity index thresholds. We used bivariate and multivariate analyses to describe the independent association between exercise and risk of active disease. RESULTS: We identified 1308 patients with Crohn's disease (CD) and 549 with ulcerative or indeterminate colitis (UC/IC) in remission, of whom 227 (17.4%) with CD and 135 (24.6%) with UC/IC developed active disease after 6 months. Higher exercise level was associated with decreased risk of active disease for CD (adjusted risk ratio: 0.72, 95% confidence interval: 0.55-0.94) and UC/IC (adjusted risk ratio: 0.78, 95% confidence interval: 0.54-1.13). CONCLUSIONS: In patients with CD in remission, those with higher exercise levels were significantly less likely to develop active disease at 6 months. In patients with UC/IC in remission, patients with higher exercise levels were less likely to develop active disease at 6 months; however this was not statistically significant. PMID- 25723617 TI - Serum prostate-specific antigen levels in men with prediabetes: a cross-sectional study. AB - BACKGROUND: Previous studies demonstrated that men with type 2 diabetes mellitus (T2DM) had significantly lower serum prostate-specific antigen (PSA) levels than healthy men. However, the influence of prediabetes (preDM) on serum PSA levels is unknown. The aim of this study was to investigate the relationships between preDM and serum PSA levels. METHODS: A cross-sectional analysis was conducted to determine the relationships between preDM and serum PSA levels. Data were obtained from men over 50 years of age who measured serum PSA levels in the physical examination center of Tianjin Union Medical Center from May to July 2014. Pearson's correlation analysis and multivariable linear regression analysis were utilized to calculate the correlations between PSA levels and various clinical and biochemical variables. RESULTS: In age-matched analysis, the mean PSA values were significantly higher in the preDM group compared with the normoglycemia (NG) and T2DM groups (1.429 ng/mL vs. 1.086 ng/mL and 1.071 ng/mL; p < 0.05). In addition, multivariable linear regression analysis demonstrated that PSA was positively correlated with age, total cholesterol (TC) and preDM (p < 0.05). Negative correlation existed between PSA and T2DM (p < 0.05). Men with preDM had PSA values 31.6% higher than men without the condition (p < 0.05), whereas PSA levels were 17.5% lower in men with T2DM than in those without the condition (p < 0.05). CONCLUSIONS: Our results suggest preDM was an independent determinant of high PSA levels and support that men with T2DM had decreased PSA levels. Further larger studies are needed. PMID- 25723618 TI - Driving performance on the descending limb of blood alcohol concentration (BAC) in undergraduate students: a pilot study. AB - Young drivers are overrepresented in collisions resulting in fatalities. It is not uncommon for young drivers to socially binge drink and decide to drive a vehicle a few hours after consumption. To better understand the risks that may be associated with this behaviour, the present study has examined the effects of a social drinking bout followed by a simulated drive in undergraduate students on the descending limb of their BAC (blood alcohol concentration) curve. Two groups of eight undergraduate students (n = 16) took part in this study. Participants in the alcohol group were assessed before drinking, then at moderate and low BAC as well as 24 hours post-acute consumption. This group consumed an average of 5.3 +/ 1.4 (mean +/- SD) drinks in an hour in a social context and were then submitted to a driving and a predicted crash risk assessment. The control group was assessed at the same time points without alcohol intake or social context.; at 8 a.m., noon, 3 p.m. and 8 a.m. the next morning. These multiple time points were used to measure any potential learning effects from the assessment tools (i.e. driving simulator and useful field of view test (UFOV)). Diminished driving performance at moderate BAC was observed with no increases in predicted crash risk. Moderate correlations between driving variables were observed. No association exists between driving variables and UFOV variables. The control group improved measures of selective attention after the third assessment. No learning effect was observed from multiple sessions with the driving simulator. Our results show that a moderate BAC, although legal, increases the risky behaviour. Effects of alcohol expectancy could have been displayed by the experimental group. UFOV measures and predicted crash risk categories were not sensitive enough to predict crash risk for young drivers, even when intoxicated. PMID- 25723620 TI - Structural studies of O-polysaccharide isolated from Cronobacter sakazakii Sequence Type 12 from a case of neonatal necrotizing enterocolitis. AB - The O-polysaccharide (OPS) of Cronobacter sakazakii NTU 696 (Sequence Type 12) from a case of neonatal necrotizing enterocolitis was isolated from the polysaccharide fraction obtained after lipopolysaccharide (LPS) hydrolysis. Purified OPS was analyzed by NMR spectroscopy ((1)H, COSY, TOCSY, NOESY, HSQC, HSQC-TOCSY and HMBC experiments) and chemical methods. Obtained monosaccharide derivatives analyzed by gas chromatography and gas chromatography-mass spectrometry allowed the identification of six sugar components. Performed experiments enabled to establish a structure of the OPS repeating unit of C. sakazakii NTU 696, as: [structure: see text]. PMID- 25723619 TI - The role of palliative care in population management and accountable care organizations. AB - By 2021, health care spending is projected to grow to 19.6% of the GDP, likely crowding out spending in other areas. The 2010 Affordable Care Act (ACA) attempts to curb health care spending by incentivizing high-value care through the creation of Accountable Care Organizations (ACOs), which assume financial risk for patient outcomes. With this financial risk, health systems creating ACOs will be motivated to pursue innovative care models that maximize the value of care. Palliative care, as an emerging field with a growing evidence base, is positioned to improve value in ACOs by increasing high-quality care and decreasing costs for the sickest patients. ACO leaders may find palliative care input valuable in optimizing high-quality patient-centered care in the accountable care environment; however, palliative care clinicians will need to adopt new models that extrapolate their direct patient care skills to population management strategies. We propose that palliative care specialists take on responsibilities for working with ACO leaders to broaden their mission for systemwide palliative care for appropriate patients by prospectively identifying patients with a high risk of death, high symptom burden, and/or significant psychosocial dysfunction, and developing targeted, "triggered" interventions to enhance patient-centered, goal-consistent, coordinated care. Developing these new population management competencies is a critical role for palliative care teams in the ACO environment. PMID- 25723621 TI - Structure and genetics of the O-antigen of Enterobacter cloacae G3054 containing di-N-acetylpseudaminic acid. AB - Mild acid degradation of the lipopolysaccharide of Enterobacter cloacae G3054 resulted in the cleavage of the O-polysaccharide at the linkage of residues of 5,7-diacetamido-3,5,7,9-tetradeoxy-L-glycero-L-manno-non-2-ulosonic acid (di-N acetylpseudaminic acid, Pse5Ac7Ac) in the main chain. The resultant oligosaccharide and an alkali-treated lipopolysaccharide were studied by sugar analysis along with (1)H and (13)C NMR spectroscopy, and the following structure of the branched pentasaccharide O-unit of the O-polysaccharide was established: [structure: see text] The O-antigen gene cluster of E. cloacae G3054 between conserved genes galF and gnd was sequenced. Most genes necessary for the O antigen synthesis were found in the cluster and their functions were tentatively assigned by comparison with sequences in the available databases. PMID- 25723622 TI - Characteristics of mannosylerythritol lipids and their environmental potential. AB - Mannosylerythritol lipids (MELs) are promising biosurfactants containing two glycosyl derivatives and various fatty acids, which are mainly secreted by Pseudozyma as well as Ustilago. In this review, the latest research is demonstrated on production conditions, structural diversity, self-assembling properties and versatile biochemical functions of MELs. The genetic study and synthetic pathways, which mainly influence the type and yield of MELs production. Due to the excellent surface activity, biocompatibility and restorative function, MELs can be used in enviornmental industry, which has not been widely noted. In this paper, the current status of research on enviornmental potential of MELs has been discussed including petroleum degradation, bioconversion of chemical wastes and enhanced bioremediation of amphiphilic wastes. PMID- 25723623 TI - Kinetic characterization of Aspergillus niger chitinase CfcI using a HPAEC-PAD method for native chitin oligosaccharides. AB - The abundant polymer chitin can be degraded by chitinases (EC 3.2.1.14) and beta N-acetyl-hexosaminidases (EC 3.2.1.52) to oligosaccharides and N-acetyl glucosamine (GlcNAc) monomers. Kinetic characterization of these enzymes requires product quantification by an assay method with a low detection limit, preferably compatible with the use of native, non-labeled substrates. Here we report a quantitative HPAEC-PAD method that allows fast separation of chitin oligosaccharides (COS) ranging from (GlcNac)1-6 at detection limits of 1-3 pmol and a linear range of 5-250 pmol. Quantification under intra- and interday precision conditions was performed with 2.1-5.4% relative standard deviation (RSD) and 1.2-10.3% RSD, respectively. This method was successfully used for the determination of the kinetic parameters of the Aspergillus niger chitinase CfcI with native COS. CfcI was recently shown to release GlcNAc from the reducing end of COS, a new activity for fungal chitinases. A Carbohydrate Binding Module of family 18 (CBM18) is inserted in the CfcI catalytic domain. Site directed mutagenesis was used to assess the functionality of this CfcI-CBM18: four of its key amino acids were replaced by glycine residues, yielding CfcISYNF. Comparison of the kinetic parameters of CfcI and CfcISYNF confirmed that this CBM18 is functionally involved in catalysis. PMID- 25723625 TI - Macrospirocyclic oligomer based on triphenylamine and diphenylphosphine oxide as a bipolar host for efficient blue electrophosphorescent organic light-emitting diodes (OLEDs). AB - A novel bipolar oligomer (TPA-PO)3 was prepared as a host material for efficient blue phosphorescent organic light-emitting diodes (OLEDs). Through the C-9s of the fluorene units, three triphenylamine units attached to diphenylphosphine oxide are connected in series to form a macrocyclic structure. The solution processed phosphorescent device based on FIrpic and (TPA-PO)3 achieved a maximum current efficiency of 19.4 cd A(-1) and a maximum luminance of 11,500 cd m(-2) with a relatively low efficiency roll-off. PMID- 25723624 TI - Hydrolysis of wheat flour arabinoxylan, acid-debranched wheat flour arabinoxylan and arabino-xylo-oligosaccharides by beta-xylanase, alpha-L-arabinofuranosidase and beta-xylosidase. AB - A range of alpha-L-arabinofuranosyl-(1-4)-beta-D-xylo-oligosaccharides (AXOS) were produced by hydrolysis of wheat flour arabinoxylan (WAX) and acid debranched arabinoxylan (ADWAX), in the presence and absence of an AXH-d3 alpha-L arabinofuranosidase, by several GH10 and GH11 beta-xylanases. The structures of the oligosaccharides were characterised by GC-MS and NMR and by hydrolysis by a range of alpha-L-arabinofuranosidases and beta-xylosidase. The AXOS were purified and used to characterise the action patterns of the specific alpha-L arabinofuranosidases. These enzymes, in combination with either Cellvibrio mixtus or Neocallimastix patriciarum beta-xylanase, were used to produce elevated levels of specific AXOS on hydrolysis of WAX, such as 3(2)-alpha-L-Araf-(1-4)-beta-D xylobiose (A(3)X), 2(3)-alpha-L-Araf-(1-4)-beta-D-xylotriose (A(2)XX), 3(3)-alpha L-Araf-(1-4)-beta-D-xylotriose (A(3)XX), 2(2)-alpha-L-Araf-(1-4)-beta-D xylotriose (XA(2)X), 3(2)-alpha-L-Araf (1-4)-beta-D-xylotriose (XA(3)X), 2(3) alpha-L-Araf-(1-4)-beta-D-xylotetraose (XA(2)XX), 3(3)-alpha-L-Araf-(1-4)-beta-D xylotetraose (XA(3)XX), 2(3),3(3)-di-alpha-L-Araf-(1-4)-beta-D-xylotriose (A(2+3)XX), 2(3),3(3)-di-alpha-L-Araf-(1-4)-beta-D-xylotetraose (XA(2+3)XX), 2(4),3(4)-di-alpha-L-Araf-(1-4)-beta-D-xylopentaose (XA(2+3)XXX) and 3(3),3(4)-di alpha-L-Araf-(1-4)-beta-D-xylopentaose (XA(3)A(3)XX), many of which have not previously been produced in sufficient quantities to allow their use as substrates in further enzymic studies. For A(2,3)XX, yields of approximately 16% of the starting material (wheat arabinoxylan) have been achieved. Mixtures of the alpha-L-arabinofuranosidases, with specific action on AXOS, have been combined with beta-xylosidase and beta-xylanase to obtain an optimal mixture for hydrolysis of arabinoxylan to L-arabinose and D-xylose. PMID- 25723626 TI - A functional extracellular transcriptome in animals? Implications for biology, disease and medicine. AB - Muneesh Tewari shares his views on possible functions and applications of RNA transport by extracellular vesicles in animals. PMID- 25723628 TI - A tribute to Hai-yan Wang (1937-2014). PMID- 25723630 TI - Kidney transplant results in children: progress made, but blacks lag behind. AB - Early kidney transplant results in children lagged behind corresponding results in adults. Multiple advances over the past three decades have eliminated that gap. Most children now have equal or superior long-term allograft and patient survival compared with adult recipients. However, black children in the United States continue to have allograft survival results inferior to those of non-black children, even after extensive adjustments for socioeconomic status and access to transplantation. PMID- 25723631 TI - Lessons from a rare disease: IgG subclass and disease severity in alloimmune antenatal membranous nephropathy. AB - Fetomaternal alloimmunization against neutral endopeptidase (NEP) is a rare cause of antenatal membranous nephropathy, yet lessons from such cases continue to elucidate important pathophysiologic points. Vivarelli and colleagues describe two recent cases of this disease and demonstrate that despite a common genetic cause, differences in maternal anti-NEP IgG subclass modulate disease severity through such mechanisms as complement activation and enzyme inhibition. PMID- 25723633 TI - Bone cells, sclerostin, and FGF23: what's bred in the bone will come out in the flesh. AB - Bone metabolism is linked to systemic diseases, and new research shows that the bone cells have endocrine functions that affect multiple organs. They secrete sclerostin, FGF23, prostaglandins, and osteocalcin. Pereira et al. examined gene expression of cells grown from bone biopsies of adolescents with renal osteodystrophy, as a first step to understanding how the bone-cell abnormalities contribute to cardiovascular and metabolic problems in these patients. PMID- 25723632 TI - Insulin resistance and hypertension: new insights. AB - Insulin resistance is associated with hypertension. Nakamura et al. demonstrate in rodents and humans with insulin resistance that while the stimulatory effect of insulin on glucose uptake in adipocytes, mediated via insulin receptor substrate 1 (IRS1), was severely diminished, its effect on salt reabsorption in the kidney proximal tubule, mediated via IRS2, was preserved. Compensatory hyperinsulinemia in individuals with insulin resistance may enhance salt absorption in the proximal tubule, resulting in a state of salt overload and hypertension. PMID- 25723634 TI - The authors reply:. PMID- 25723635 TI - Regarding 'Long-term risks for kidney donors'. PMID- 25723636 TI - Incretin-based drugs and renoprotection-is hyperfiltration key? PMID- 25723637 TI - Validation of the Oxford classification of IgA nephropathy: valid or invalid? PMID- 25723638 TI - The authors reply:. PMID- 25723639 TI - The authors reply:. PMID- 25723640 TI - A 4-year survey of the spectrum of renal disease at a National Referral Hospital Outpatient Clinic in Uganda. PMID- 25723641 TI - The author replies:. PMID- 25723642 TI - The vanishing kidneys return. PMID- 25723643 TI - A venous ulcer on the hand secondary to an arteriovenous fistula for hemodialysis treated successfully by transvenous embolization. PMID- 25723644 TI - The Case | A 48-year-old man with pulmonary-renal syndrome. PMID- 25723645 TI - The relation between self-reported worry and annoyance from air and road traffic. AB - Negative perceptions such as fear or worry are known to be an important determinant of annoyance. Annoyance caused by noise and odour has been analysed in relation to worry about safety or health due to environmental hazards, using responses to a health survey. In the survey area high environmental impacts come from air and road traffic. The survey results show a correlation between worry due to the airport or passing aircraft and noise and odour annoyance from aircraft (correlation coefficient (c.c.) close to 0.6). For the relation between worry about a busy street and annoyance from road traffic the correlation is lower (c.c. 0.4-0.5). Worries about different situations, such as living below sea level, close to an airport, busy street or chemical industry, are highly correlated (c.c. 0.5-0.9), also for situations that are not obviously related. Personal factors can also lead to more worry: being female, above 35 years of age, having a high risk for anxiety/depression and being in bad health increase the odds for being worried. The results thus suggest that worry about safety or health is correlated to both personal and environmental factors. PMID- 25723646 TI - Factors associated with atopy in toddlers: a case-control study. AB - In this case-control study the association between the approaches used to feed infants, together with known family and environmental factors, and the occurrence of atopic illness in toddlers between the ages of 4 months to 3 years in Hong Kong was examined. A total of 206 subjects were recruited from April to June of 2014. The results obtained by binary logistic regression indicated that atopy is associated with boys (OR 2.072, CI 1.089-3.941), the maternal use of antibiotics in utero or while breast feeding (OR 2.276, CI 1.151-4.504), the later commencement of mixed feeding (OR 2.497, CI 1.025-6.082), breast feeding exclusively for 3 months (OR 1.972, CI 1.009-3.857), and having a mother who was diagnosed with eczema (OR 4.510, CI 1.764-11.530). Although an exclusive reliance on breast feeding has been shown to be predictive of atopy among toddlers, the positive qualities of breast milk cannot be ignored. A further study of the contents and nutritional values of breast milk is warranted. PMID- 25723648 TI - Liquid marbles: topical context within soft matter and recent progress. AB - The study of particle stabilized interfaces has a long history in terms of emulsions, foams and related dry powders. The same underlying interfacial energy principles also allow hydrophobic particles to encapsulate individual droplets into a stable form as individual macroscopic objects, which have recently been called "Liquid Marbles". Here we discuss conceptual similarities to superhydrophobic surfaces, capillary origami, slippery liquids-infused porous surfaces (SLIPS) and Leidenfrost droplets. We provide a review of recent progress on liquid marbles, since our earlier Emerging Area article (Soft Matter, 2011, 7, 5473-5481), and speculate on possible future directions from new liquid-infused liquid marbles to microarray applications. We highlight a range of properties of liquid marbles and describe applications including detecting changes in physical properties (e.g. pH, UV, NIR, temperature), use for gas sensing, synthesis of compounds/composites, blood typing and cell culture. PMID- 25723647 TI - Physiological and psychological effects on high school students of viewing real and artificial pansies. AB - The relaxation effects of gardening have attracted attention; however, very few studies have researched its physiological effects on humans. This study aimed to clarify the physiological and psychological effects on high school students of viewing real and artificial pansies. Forty high school students (male: 19, female: 21) at Chiba Prefectural Kashiwanoha Senior High School, Japan, participated in this experiment. The subjects were presented with a visual stimulation of fresh yellow pansies (Viola x wittrockiana "Nature Clear Lemon") in a planter for 3 min. Artificial yellow pansies in a planter were used as the control. Heart rate variability was used as a physiological measurement and the modified semantic differential method was used for subjective evaluation. Compared with artificial pansies, visual stimulation with real flowers resulted in a significant decrease in the ratio of low- to high-frequency heart rate variability component, which reflects sympathetic nerve activity. In contrast, high frequency, which reflects parasympathetic nerve activity, showed no significant difference. With regard to the psychological indices, viewing real flowers resulted in "comfortable", "relaxed", and "natural" feelings. The findings indicate that visual stimulation with real pansies induced physiological and psychological relaxation effects in high school students. PMID- 25723649 TI - Attitudes of Pulmonary and Critical Care Training Program Directors toward Quality Improvement Education. AB - RATIONALE: Quality improvement (QI) is a required component of fellowship training in pulmonary, critical care, and sleep medicine. However, little is known about how training programs approach QI education. OBJECTIVES: We sought to understand the perceptions of pulmonary, critical care, and sleep medicine training program directors toward QI education. METHODS: We developed and fielded an internet survey of pulmonary, critical care, and sleep medicine training program directors during 2013. Survey domains included program characteristics, the extent of trainee and faculty involvement in QI, attitudes toward QI education, and barriers to successful QI education in their programs. MEASUREMENTS AND MAIN RESULTS: A total of 75 program directors completed the survey (response rate = 45.2%). Respondents represented both adult (n = 43, 57.3%) and pediatric (n = 32, 42.7%) programs. Although the majority of directors (n = 60, 80.0%) reported substantial fellow involvement in QI, only 19 (26.0%) reported having a formal QI education curriculum. QI education was primarily based around faculty mentoring (n = 46, 61.3%) and lectures (n = 38, 50.7%). Most directors agreed it is an important part of fellowship training (n = 63, 84.0%). However, fewer reported fellows were well integrated into ongoing QI activities (n = 45, 60.0%) or graduating fellows were capable of carrying out independent QI (n = 28, 50.7%). Key barriers to effective QI education included lack of qualified faculty, lack of interest among fellows, and lack of time. CONCLUSIONS: Training program directors in pulmonary, critical care, and sleep medicine value QI education but face substantial challenges to integrating it into fellowship training. PMID- 25723650 TI - The effect of coronary artery plaque composition, morphology and burden on Absorb bioresorbable vascular scaffold expansion and eccentricity - A detailed analysis with optical coherence tomography. AB - AIMS: Suboptimal stent expansion correlates with adverse cardiac events. There is limited information regarding Absorb bioresorbable vascular scaffold (BVS) expansion characteristics. Optical coherence tomography (OCT) allows for high resolution assessment of plaque morphology, composition and assessment of BVS expansion. This study evaluates coronary plaque composition, morphology and burden and their effect on Absorb BVS expansion using OCT. METHODS AND RESULTS: Two thousand three hundred and thirty four frames totalling 462.6 mm of BVS from twenty OCT-guided BVS implantations were examined. 200 MUm longitudinal cross sections of each BVS were analysed for lumen contours and plaque characteristics. The relationship between each plaque characteristic and scaffold expansion index (SEI) or scaffold eccentricity index (SEC) was analysed by repeated measures ANOVA. Forty-four fibrous and 265 calcific plaques were identified. Lower SEI was significantly (p<0.001) associated with greater calcific plaque (CP) area (mean SEI 78.9% vs. 80.0%), thickness (78.5% vs. 80.4%) and lower CP depth (78.3% vs. 80.2%). Lower SEC was significantly (p<0.001) associated with greater fibrous plaque (FP) area (0.84 vs. 0.85), thickness (0.83 vs. 0.86), arc angle (0.84 vs. 0.85), greater CP area (0.83 vs. 0.86), CP thickness (0.83 vs. 0.86), CP angle (0.84 vs. 0.85) and lower CP depth (0.84 vs. 0.85). Greater FP area was associated with greater SEI (81.0% vs. 80.0%, p<0.001), even after adjustment for target vessel size. Greater FP angle (80.7% vs 78.3%, p<0.001) and quadrants occupied were also associated (80.0% vs 78.5%, p<0.002) with greater SEI. CONCLUSION: BVS expansion and eccentricity are significantly impacted by plaque composition, morphology and burden. PMID- 25723651 TI - Characteristic myocardial strain identified in hypertrophic cardiomyopathy subjects with preserved left ventricular ejection fraction using a novel multi layer transthoracic echocardiography technique. AB - PURPOSE: In order to evaluate compensatory mechanisms in hypertrophic cardiomyopathy (HCM) subjects with preserved left-ventricular (LV) ejection fraction (EF), we measured myocardial percentage endocardial strain dependency, as represented by 2D LV global longitudinal (GLS) and circumferential-strain (GCS), using a novel, multi-layer, speckle-tracking transthoracic echocardiography (TTE) technique. METHODS: A total of 60 subjects (40 HCM with preserved LV EF (30 male; 62 +/- 15 years, all LV EF>50%)) and 20 controls (10 male; 59 +/- 10 years) underwent TTE (Vivid-E9). Quantitative strain-measurements of: endocardial, all and epicardial layers were performed at each-site. We defined percentage endocardial strain dependency as the ratio of endocardial strain to epicardial strain. RESULTS: Absolute GLS values at all views in all, endocardial and epicardial myocardial layers were significantly smaller in HCM subjects than in controls (all P<0.001). There were no significant differences between both-groups in absolute GCS values in the endocardial layers, at the mitral valve and papillary muscle levels. Percentage endocardial GCS dependency at all levels were greater in HCM subjects than in controls (all P<0.01). In HCM subjects, percentage endocardial GCS dependency at the mitral valve and papillary muscle levels revealed significant, moderate, negative correlations with LV end diastolic and systolic dimensions (correlation coefficients -0.505, -0.451 (mitral valve level) and -0.533, -0.591 (papillary muscle level), respectively). CONCLUSIONS: In HCM subjects with preserved LV EF, 2D LV GLS was lower than in controls, but endocardial GCS was maintained in compensation for reduction in endocardial GLS; thus percentage endocardial GCS dependency may increase, and the larger the LV size, the smaller this compensatory effect. PMID- 25723652 TI - Short-term pain for long-term gain: the role of experiential avoidance in the relation between anxiety sensitivity and emotional distress. AB - Research has provided evidence of an interactive effect between anxiety sensitivity (AS) and experiential avoidance (EA) in predicting both anxiety and posttraumatic stress (PTS) symptomatology. Additionally, theory suggests that EA alleviates distress in the short-term, but exacerbates it in the long-term. The present cross-sectional study was developed to replicate the noted findings and examine the interaction (EA * AS) in the context of an emotionally evocative task. It was predicted that, among high AS participants, high EA would (a) reduce the likelihood of experiencing short-term increases in negative affect following the task, and (b) increase the likelihood of anxiety and PTS symptomatology. Undergraduate participants (N=199) completed a battery of self-report questionnaires and an emotionally evocative task. As predicted, positive associations were observed between AS and both anxiety and PTS symptoms, but only among high EA participants. Additionally, AS only predicted increases in negative affect following the emotionally evocative task for those with lower levels of EA, thus providing empirical evidence of the affect regulatory function of EA among those who fear anxiety-related bodily sensations. These findings help to elucidate the motives for the use of avoidance among those high in AS. Conceptual and clinical implications are discussed. PMID- 25723653 TI - Coherent plasmon-exciton coupling in silver platelet-J-aggregate nanocomposites. AB - Hybrid nanostructures that couple plasmon and exciton resonances generate hybridized energy states, called plexcitons, which may result in unusual light matter interactions. We report the formation of a transparency dip in the visible spectra of colloidal suspensions containing silver nanoplatelets and a cyanine dye, 1,1'-diethyl-2,2'-cyanine iodide (PIC). PIC was electrostatically adsorbed onto the surface of silver nanoplatelet core particles, forming an outer J aggregate shell. This core-shell architecture provided a framework for coupling the plasmon resonance of the silver nanoplatelet core with the exciton resonance of the J-aggregate shell. The sizes and aspect ratios of the silver nanoplatelets were controlled to ensure the overlap of the plasmon and exciton resonances. As a measure of the plasmon-exciton coupling strength in the system, the experimentally observed transparency dips correspond to a Rabi splitting energy of 207 meV, among the highest reported for colloidal nanoparticles. The optical properties of the silver platelet-J-aggregate nanocomposites were supported numerically and analytically by the boundary-element method and temporal coupled mode theory, respectively. Our theoretical predictions and experimental results confirm the presence of a transparency dip for the silver nanoplatelet core J aggregate shell structures. Additionally, the numerical and analytical calculations indicate that the observed transparencies are dominated by the coupling of absorptive resonances, as opposed to the coupling of scattering resonances. Hence, we describe the suppressed extinction in this study as an induced transparency rather than a Fano resonance. PMID- 25723654 TI - Gene expression of osteogenic factors following gene therapy in mandibular lengthening. AB - This study investigated the effect of gene therapy on the expression of osteogenic mediators in mandibular distraction osteogenesis rabbits. Bilateral mandibular osteotomies were performed in 45 New-Zealand rabbits. After a latency of 3 days, the mandibles were elongated using distractors with a rate of 0.8 mm/d for 7 days. After the completion of distraction, the rabbits were randomly divided into 5 groups: 2 MUg (0.1 MUg/MUL) of recombinant plasmid pIRES-hVEGF165 hBMP-2, recombinant plasmid pIRES-hBMP2, recombinant plasmid pIRES-hVEGF165, pIRES, and the same volume of normal saline were injected into the distraction gap of groups A, B, C, D, and E, respectively, followed by electroporation. Three animals were killed at the 7th, 14th, and 28th day after gene transfected in different groups, respectively. The lengthened mandibles were harvested and processed for immunohistochemical examinations; the mean optic densities (MODs) and integral optical density of bone morphogenetic protein (BMP-2) and transforming growth factor beta1 (TGF-beta1)-positive cells were measured by CMIAS-2001A computerized image analyzer. The data were analyzed with SPSS (SPSS Inc, Chicago, IL). Bone morphogenetic protein 2 and TGF-beta1 staining was mainly located in inflammatory cells, monocytes, fibroblasts, osteoblasts, osteocytes, and chondrocytes in the distraction zones. Their strongest expression reached to the peak at the seventh day and decreased at the 14th day of consolidation stage; at the 28th day, they expressed weakly. Image analysis results show that, at the seventh day, the expression of BMP-2 in group B (0.26 +/- 0.03, 0.36 +/- 0.02) was the strongest; there was significant difference among them (P < 0.01), whereas the expression of TGF-beta1 in group C (0.38 +/- 0.06, 1.05 +/- 0.19) is strongest followed by group A (0.34 +/- 0.05, 0.95 +/- 0.16) and B (0.33 +/- 0.07, 0.90 +/- 0.19). At every time point, the level of expression of BMP-2 and TGF-beta1 in gene therapy groups (groups A, B, and C) was remarkably higher than those in non-gene therapy groups(groups D and E). There were significant differences between gene therapy groups and non-gene therapy groups (P < 0.05 or P < 0.001). These results indicated that local gene transfection can up-regulate the expression of osteogenic mediators (BMP-2 and TGF-beta1), which may promote cell differentiation and proliferation and stimulate extracellular matrix synthesis and new bone formation in distraction gap. PMID- 25723655 TI - The influence of gender and laterality on the incidence of hemifacial microsomia. AB - OBJECTIVE: The objective of this study was to identify the presence of gender and laterality bias in patients with hemifacial microsomia. METHODS: We performed a systematic search of PubMed, EMBASE, Cochrane Central Register of Systematic Reviews, and Cochrane Central Register of Controlled Trials to identify trials published up to January 2014. Data extracted from the literature were analyzed using Review Manager 5.0.24. RESULTS: Relevant data were extracted from 24 articles (1121 participants), and the finding revealed no significant difference in incidence according to gender with the male-to-female ratio being 1.09:1 (relative risk, 1.13; 95% confidence interval, 0.94-1.36; P < 0.00001; n = 908) There was no obvious difference in the laterality subgroup either, with the ratio of between the right and left sides of the head being 1.12 (relative risk, 1.08; 95% confidence interval, 0.94-1.24; P = 0.006; n = 977). CONCLUSIONS: This meta analysis reveals no difference in the incidence of hemifacial microsomia between male and female patients; in addition, there is no obvious difference in distribution between the left and right sides of the head. PMID- 25723656 TI - Congenital huge submandibular and neck teratoid cyst in newborn. AB - Head and neck teratoid cysts are the least common congenital cysts in the head and neck region, accounting for approximately 1.8% of all dermoid cysts. Teratoid cysts exhibiting mesodermal elements may be lined by gastric, intestinal, respiratory, squamous, or cilitated epithelium. We present a case of huge submandibular and neck teratoid cyst in newborn with airway obstruction and feeding difficulty. Surgical extirpation is the treatment of choice. However, before operation, some other cystic diseases in the head and neck region needs to be excluded. Fine-needle aspiration biopsy was necessary in differential diagnosis of lesions before treatment, especially that the principle of treatment of those diseases is different. PMID- 25723657 TI - Retrieval of root fragment in maxillary sinus via anterolateral wall of the sinus to preserve alveolar bone. AB - PURPOSE: The objective of this study was to present a functional surgery for retrieval of displaced root fragments from the maxillary sinus while preserving the alveolar bone. MATERIALS AND METHODS: Twenty-one patients with associated root fragments displaced into the maxillary sinus after tooth extraction were collected and reviewed retrospectively. All patients included in the study were subjected to surgical removal of the displaced root by the use of piezosurgery. In case the root fragment was barely detectable, endoscopy would be helpful. RESULTS: Eleven roots were removed via small windows and 10 roots via large windows. Endoscopy was used in 2 patients. Granulomatous tissues were found around 6 root fragments, and cyst formation was found in 1 patient. Only 1 patient had sinusitis temporarily. No patients developed complications such as facial paresthesia, facial asymmetry, or infection. CONCLUSIONS: The functional surgery for the retrieval of a displaced root from the maxillary sinus is recommended owing to quick recovery, preservation of alveolar bone, and minimal complications. PMID- 25723658 TI - Functional surgery for the treatment of dentigerous cyst in the maxillary sinus. AB - BACKGROUND: Dentigerous cyst (DC) in the maxillary sinus is rarely seen. Several complications are observed after the Caldwell-Luc operation, which is combined with endoscopy. Still, a more perfect treatment method is yet to be discovered. OBJECTIVES: The purpose of this study was to explore and assess a new functional surgical treatment with fewer complications, which not only insured normal maxillary sinus cilia restoration and bony integrity but also did little damage to maxillary sinus natural ostium. METHODS: Dentigerous cyst in the maxillary sinuses of 20 patients had conditions diagnosed through radiographic imaging and the locating of bone windows' positions according to preoperative 3-dimensional computed tomography (CT) (3D CT). All the patients underwent a functional surgery in which a bony lid was created anteriolaterally of maxillary sinus with piezosurgery and reimplanted by titanium plates after enucleating the cyst, leaving the maxillary sinus mucosa in place with or without endoscope's assistance. Therapeutic efficacy was evaluated by clinical examination and radiographic imaging at regular intervals; the longest follow-up was 24 months. RESULTS: All the patients recovered except for one, who underwent plate removal and radical maxillary sinusotomy owing to infection. Patients were asymptomatic, and CT images showed integrated maxillary bone. Extrusion deformation of the sinus was improved to different extents after 6 to 24 months of follow-up. CONCLUSIONS: Functional surgery for the treatment of DC in the maxillary sinus is a new approach and has the advantages of less surgical trauma, restoration of mucosa and bony wall, and more satisfactory results. PMID- 25723659 TI - Cranial bone deformity after forehead tissue expansion. AB - The expanded forehead flap is frequently used for nasal reconstruction. When expanding the forehead tissue, the underlying cranial bones are compressed by the inserted expander. Many effects of tissue expansion on the bone have been reported including bone remolding, erosion, displacement, and so forth. In this work, we report a peculiar patient of cranial bone deformity after forehead tissue expansion, which demanded a surgical revision. PMID- 25723660 TI - Magnesium sulfate for acute traumatic brain injury. AB - BACKGROUND: The purpose of this systematic review was to evaluate the effect of magnesium sulfate in the treatment of acute traumatic brain injury. MATERIALS AND METHODS: A systematic search of ClinicalTrials.gov, the Cochrane Library database, EMBASE, MEDLINE, Web of Science, and the World Health Organization trial registry, plus manual searches of gray literature, was undertaken in April 2013. Two reviewers independently extracted the data with a predefined data extraction form. RevMan 5 software was used to synthesize data and calculate the risk ratio for mortality with the 95% confidence interval. For the Glasgow Outcome Scale and posttreatment Glasgow Coma Scale data, the weighted mean difference was calculated with the 95% confidence interval. RESULTS: A total of 8 randomized controlled trials with a total of 786 patients were included. Meta analysis showed that there was no significant difference between the groups for mortality. The Glasgow Outcome Scale of the treatment group was higher than that of the control group, although the significance was borderline. The Glasgow Coma Scale score change posttreatment was significantly higher than that of the control. CONCLUSIONS: The present meta-analysis of existing randomized controlled trials does not identify a significant beneficial effect in the mortality of traumatic brain injury patients; however, it suggests that magnesium sulfate shows a tendency to improve the Glasgow Outcome Scale and Glasgow Coma Scale scores, which is a promising result for traumatic brain injury therapy. Further effort is necessary to explore which subgroup of traumatic brain injury patients could benefit from magnesium sulfate. PMID- 25723661 TI - Surgery can get favorable outcome in atypical Sturge-Weber syndrome with intractable epilepsy. PMID- 25723662 TI - Clinical analysis of transcranial orbitotomy approach on cranio-orbital tumors. AB - AIMS: The aims of this study were to investigate 21 cases of transcranial orbitotomy for cranio-orbital tumors and evaluate the clinical value of the surgical approach. METHODS: A retrospective study was done on 21 patients with cranio-orbital tumors. According to the tumors' location, shape, boundary, and invasion on the images, coronal scalp flap approach, subfrontal approach, or pterion approach for transcranial orbitotomy was performed. RESULTS: The surgical route was coronal scalp flap approach in 7 cases (including 3 cases combined with lateral orbitotomy), subfrontal approach in 6 cases, or pterion approach in 8 cases (including 1 case combined with evisceration of orbit). Tumors were en bloc resection in 4 cases, block resection or curettage in 13 cases, and incomplete resection in 4 cases. Postoperatively, the mean reduction in exophthalmos was 4 mm; maximum reduction was 11 mm. Ocular movement restriction was made better in 10 of 14 patients, whereas there was no change in 4 of 14 patients. Ophthalmoplegia occurred in 2 cases, complete ptosis occurred in 3 cases, and mydriasis occurred in 3 cases. No vision loss or cerebrospinal fluid leak was observed. Fourteen patients were followed up, including 2 patients with metastatic carcinoma who died dead because of systemic metastasis; 2 patients had a recurrence (schwannoglioma and meningioma). No recurrence was found in the other 10 patients. CONCLUSIONS: Cranio-orbital tumors can be removed effectively through transcranial orbitotomy, whereas operative approach is convenient to the surgical procedure and can offer better exposure. Being familiar with the tumors' location, adhesion, and invasion, coupled with the skilled surgical techniques, would improve the results and reduce serious complications. PMID- 25723663 TI - Mesenchymal stem cells secrete brain-derived neurotrophic factor and promote retinal ganglion cell survival after traumatic optic neuropathy. AB - OBJECTIVE: The study aimed to investigate whether intravitreal injection of mesenchymal stem cells (MSCs) cultivated in vitro could increase the number of survived retinal ganglion cells (RGCs) after traumatic optic neuropathy and sought to identify potential mechanisms underlying such growth. METHODS: The right eye of 24 cats in the MSC transplantation group accepted intravitreal injection of MSCs, and the other 24 cats in the phosphate buffer (PBS) control group received isotonic saline after traumatic optic neuropathy. The RGCs' survival rate in separated retinal and brain-derived neurotrophic factor (BDNF) expression were observed by Dil labeling and Enzyme-Linked Immuno Sorbent Assay (ELISA), respectively, at 3, 7, 14, and 28 days after transplantation. RESULTS: Quantitative analysis showed that RGCs were significantly attenuated at 3, 7, 14, and 28 days after transplantation in both areas of the retina (peripheral, P7d = 0.0011, P14d < 0.001, P28d < 0.001; central, P3d = 0.0437, P7d = 0.0067, P14d < 0.001, P28d < 0.001). Mean density of RGCs in the MSC transplantation group was significantly higher than that of the PBS control group after 14 days of treatment (P < 0.001). The homogenates BDNF (hBDNF) in the MSC transplantation group was obviously higher than that in the PBS control group at 14 and 28 days (P < 0.05). CONCLUSIONS: The MSCs transplanted into the retina of cats can slow down RGC apoptosis and steadily express BDNF. The MSC-mediated neuroprotection after optic nerve injury may be related to BNDF. PMID- 25723664 TI - Analysis of alar balance in secondary cleft lip with Z-plasty technique of nasal cartilage. AB - The cleft nasal deformity is a prevailing problem of complex challenge for plastic surgery, especially in the secondary correction. We mainly chose 40 patients with unilateral secondary cleft lip nasal deformity with alar collapse. Based on biomechanics and anatomy of nasal cartilage, we adapt a Z-plasty with cartilage mucosa using the deformed lateral crus of the upper lateral cartilage to support the collapse of lower lateral cartilage. All of our patients were satisfied with the aesthetic morphology after surgery, so we are confident that this method should be considered as an auxiliary treatment to rhinoplasty. PMID- 25723665 TI - Modified free latissimus dorsi musculocutaneous flap in the reconstruction of extensive postoncologic defects in the head and neck region. AB - Oncological resection of advanced carcinoma in the head and neck region results in vast defects. The free latissimus dorsi musculocutaneous flap (FLDMF) is one of the most commonly used flaps for the repair of complex head and neck defects. We tried to modify FLDMF to multiple segments or combine it with acellular dermis to fit through-and-through defects in the oral-facial region during the last decade. A retrospective review of patients with FLDMF reconstruction between 2004 and 2012 was undertaken. Demographics, histology, surgical management, disease control and overall survival, complications, radiotherapy, aesthetic outcome, as well as economic results were analyzed. The majority of the patients (66.7%) had recurrent tumors, and the rest of the patients had primary tumor with stage IV. Fourteen patients (38.9%) had a history of prior radiation therapy, whereas 27.8% of the patients had postoperative radiation therapy. The areas of the defects vary from 52 cm to 180 cm (mean, 86.4 cm). The flap failed in 1 of the 37 patients. The complications at the recipient site include hematoma (n = 6, 16.7%), venous insufficiency (n = 4, 11.1%), infection (n = 3, 8.3), and partial flap necrosis (n = 2, 5.5%). The donor-site complications include delayed healing, necrosis of skin graft, and limited shoulder function. The 5-year overall survival rate was 39.1%, and the 5-year disease-free survival rate was 22.1%. In conclusion, the FLDMF could be modified to fit vast defects where voluminous tissue is needed to be transferred in the head and neck region. PMID- 25723666 TI - Edge locked stitching between nostril ala and lateral cartilages with a mucochondrial Z-plasty in correction of unilateral cleft nasal deformity in secondary rhinoplasty. AB - BACKGROUND: Ala and nostril collapse are most raised complaints in secondary deformity of unilateral cleft patients. While a lot of techniques have been introduced so far, the purpose of this study was to evaluate the effectiveness of edge locked stitching between nostril ala and lateral cartilages with mucochondrial Z-plasty to correct the collapse in lower lateral cartilage in the ala and nostril shaping. METHODS: Fifty-seven patients with unilateral cleft nasal deformities were recruited. They all had primary surgery before and were left with nasal deformities. Based on the anatomic understanding, we operated on all the patients using edge locked stitching between nostril ala and lateral cartilages with a mucochondrial Z-plasty to correct the abnormal lateral collapse of nostril deformities. RESULTS: All the patients had an improvement in the shape of the ala and nostril immediately after the surgery. Follow-up at 6 months (or later) showed no severe relapse. CONCLUSION: The edge locked stitching between nostril ala and lateral cartilages with mucochondrial Z-plasty is effective to correct ala and nostril deformities in unilateral cleft. PMID- 25723667 TI - Unilateral microform cleft lip repair: application of muscle tension line group theory. AB - BACKGROUND: In microform cleft lip repair, reconstructing the elaborate structures is difficult. We describe a new technique of unilateral microform cleft lip repair that is based on the muscle tension line group theory. METHODS: According to the shape of Cupid bow, a different small incision is used without creating an obvious cutaneous scar. First, the nasolabial muscle around the nasal floor (the first auxiliary tension line group) is reconstructed, and then the orbicularis oris muscle around the philtrum (the second auxiliary tension line group) is reconstructed based on the muscle tension line group theory. RESULTS: From June 2006 to June 2012, the technique was used in 263 unilateral microform cleft lip repairs. For 18 months, 212 patients were followed up. The appearance of the nasal alar, nasal sill, philtrum, and Cupid bow peak improved. Most patients had a satisfactory appearance. CONCLUSIONS: Based on the muscle tension line group theory, using this technique offers the ability to adduct the nasal alar effectively to form a good nasal sill and philtrum. PMID- 25723669 TI - Alpine glacier change in the Eastern Altun mountains of Northwest China during 1972-2010. AB - Accurately mapping and monitoring glacier changes over decades is important for providing information to support sustainable use of water resource in arid regions of northwest China. Since 1970, glaciers in the Eastern Altun Mountains showed remarkable recession. Further study is indispensable to indicate the extent and amplitude of glacial change at basin and individual glacier scale. In this study, spatiotemporal glacier changes referring to the year 1972, 1990, 2000 and 2010 were studied for the Eastern Altun Mountains using Landsat MSS/TM/ETM+ images and glacier volume-area scaling. The results demonstrated that the total area and volume of glaciers in EAMs decreased significantly by 10.70+/-0.57 km2 (19.56+/-10.41%) and 0.61+/-0.03 km3 (23.19+/-11.40%) during 1972-2010, respectively. More than half of the total receding area occurred during 1990 2000, primarily due to higher temperature increasing. However, varied response of individual glaciers indicated that glacier change was also affected by glacier dynamics, which was related to local topography. In addition, five glaciers unrecorded in the glacier inventory of China were reported in this study. PMID- 25723668 TI - Different NaCl-induced calcium signatures in the Arabidopsis thaliana ecotypes Col-0 and C24. AB - A common feature of stress signalling pathways are alterations in the concentration of cytosolic free calcium ([Ca2+]cyt), which allow the specific and rapid transmission of stress signals through a plant after exposure to a stress, such as salinity. Here, we used an aequorin based bioluminescence assay to compare the NaCl-induced changes in [Ca2+]cyt of the Arabidopsis ecotypes Col-0 and C24. We show that C24 lacks the NaCl specific component of the [Ca2+]cyt signature compared to Col-0. This phenotypic variation could be exploited as a screening methodology for the identification of yet unknown components in the early stages of the salt signalling pathway. PMID- 25723670 TI - Effect of childhood victimization on occupational prestige and income trajectories. AB - BACKGROUND: Violence toward children (childhood victimization) is a major public health problem, with long-term consequences on economic well-being. The purpose of this study was to determine whether childhood victimization affects occupational prestige and income in young adulthood. We hypothesized that young adults who experienced more childhood victimizations would have less prestigious jobs and lower incomes relative to those with no victimization history. We also explored the pathways in which childhood victimization mediates the relationships between background variables, such as parent's educational impact on the socioeconomic transition into adulthood. METHODS: A nationally representative sample of 8,901 young adults aged 18-28 surveyed between 1999-2009 from the National Longitudinal Survey of Youth 1997 (NLSY) were analyzed. Covariate adjusted multivariate linear regression and path models were used to estimate the effects of victimization and covariates on income and prestige levels and on income and prestige trajectories. After each participant turned 18, their annual 2002 Census job code was assigned a yearly prestige score based on the 1989 General Social Survey, and their annual income was calculated via self-reports. Occupational prestige and annual income are time-varying variables measured from 1999-2009. Victimization effects were tested for moderation by sex, race, and ethnicity in the multivariate models. RESULTS: Approximately half of our sample reported at least one instance of childhood victimization before the age of 18. Major findings include 1) childhood victimization resulted in slower income and prestige growth over time, and 2) mediation analyses suggested that this slower prestige and earnings arose because victims did not get the same amount of education as non-victims. CONCLUSIONS: Results indicated that the consequences of victimization negatively affected economic success throughout young adulthood, primarily by slowing the growth in prosperity due to lower education levels. PMID- 25723671 TI - Surgical resection of a liver metastasis from breast cancer. AB - We report a case of a solitary liver metastasis from breast cancer in a 65-year old woman. The patient underwent a mastectomy and axillary lymph node clearance for right breast cancer in 1990. A solitary metastasis was found in the left lobe of the liver by ultrasonography, 20 years after the initial mastectomy. A left lateral segmentectomy was performed in January 2011 and adjuvant hormonal therapy was also initiated. At present, she remains disease free. This case demonstrates the implementation of liver resection to provide an effective treatment for metachronous metastatic breast cancer. We encourage surgeons to offer suitable patients this surgical treatment option, which is shown to provide a survival benefit. PMID- 25723672 TI - Acute paraspinal compartment syndrome as a rare cause of loin pain. AB - A significant proportion of emergency urological admissions are comprised of ureteric colic presenting as loin pain. A variety of alternative pathologies present in this manner and should be considered during systematic assessment. We report the case of a patient admitted with severe unilateral back and flank pain after strenuous deadlift exercise. Clinical examination and subsequent investigation following a significant delay demonstrated acute paraspinal compartment syndrome (PCS) after an initial misdiagnosis of ureteric colic. The patient was managed conservatively. We review the current literature surrounding the rare diagnosis of PCS and discuss the management options. PMID- 25723673 TI - The diagnostic dilemma of a parasympathetic schwannoma in the submandibular gland. AB - Schwannomas are benign soft tissue tumours that arise from nerve sheath cells. They are rare in the salivary glands and are thought to arise from the parasympathetic nerves. We report the case of a 69-year-old man who presented with a painless right submandibular mass that appeared to resemble a pleomorphic adenoma on ultrasonography and, on this basis, proceeded to surgical excision of the gland. We review the relevant literature and highlight the diagnostic pitfalls. PMID- 25723674 TI - Brachiocephalic artery haemorrhage during percutaneous tracheostomy. AB - Percutaneous tracheostomy was performed on a 69-year-old woman to facilitate weaning. Insertion of the size 7 tracheostomy tube resulted in profuse bleeding around the tracheostomy site. On inflation of the tracheostomy balloon, the bleeding stopped. Urgent computed tomography demonstrated the brachiocephalic artery was abnormally high and lying in an oblique fashion over the trachea, and the tracheostomy tube was displacing the trachea posteriorly. Surgical repair of the defect in the brachiocephalic artery was undertaken and a surgical tracheostomy was performed in theatre. This case raises important issues about the potential dangers of percutaneous tracheostomy in cases of abnormal anatomy. It also emphasises the importance of direct visualisation of the seeker needle using the endoscope. In cases where there is a suspicion of abnormal anatomy, it is safer to obtain preprocedural imaging or perform a surgical tracheostomy. PMID- 25723675 TI - Retrograde inversion stripping as a complication of the ClariVein mechanochemical venous ablation procedure. AB - The endovenous revolution has accelerated the development of new techniques and devices for the treatment of varicose veins. The ClariVein mechanochemical ablation device offers tumescentless treatment with a rotating ablation tip that can theoretically become stuck in tissue. We present the first report of retrograde stripping of the small saphenous vein without anaesthesia following attempted use of the ClariVein device, without adverse sequelae. PMID- 25723676 TI - Dashboard (in the) knee. AB - We present the case of a 19-year-old individual presenting to an orthopaedic outpatient clinic several months following a dashboard knee injury during a road traffic accident with intermittent mechanical symptoms. Despite unremarkable examination findings and normal magnetic resonance imaging, the patient was identified subsequently as having an intra-articular plastic foreign body consistent with a piece of dashboard on arthroscopic knee assessment, the retrieval of which resulted in a complete resolution of symptoms. PMID- 25723677 TI - Spontaneous splenic rupture four days after an open appendicectomy. AB - INTRODUCTION: Spontaneous splenic rupture is a rare but dangerous event that requires prompt diagnosis and frequently an emergency splenectomy. Previous case reports have described the occurrence in patients with medical conditions, anticoagulant treatments, endoscopic procedures, laparoscopic surgery or no particular predisposing factor. Our report is the first to describe the occurrence of spontaneous spleen rupture following a laparotomy conducted in the lower abdomen. CASE HISTORY: A 62-year-old woman presented with a 10-day history of right iliac fossa pain radiating to the right leg and associated vomiting. Following a routine blood check and computed tomography (CT), she underwent an open appendicectomy through a lower midline laparotomy for an appendicular abscess. Four days later, she experienced haemorrhagic shock and a second CT scan diagnosed a spontaneous splenic rupture that required a prompt splenectomy. CONCLUSIONS: Our case is the first that describes the spontaneous rupture of the spleen following an open procedure conducted in the lower quadrants. This entity must still be considered as a rare but potential cause for postoperative bleeding when no other obvious sources are identified. PMID- 25723678 TI - Laparoscopic features and repair of a combined left Spigelian hernia and left Morgagni diaphragmatic hernia. AB - Both Spigelian and Morgagni hernias cause serious morbidity so early diagnosis and timely treatment are necessary. These two types of hernia are more commonly found on the right side of patients. They are rare individually in adults and even rarer in combination. So far, an association between the two hernias has only been reported on the right. We describe the first case of a Spigelian hernia and a Morgagni hernia in a 62-year-old woman, both occurring on the left side. Our accompanying video describes several laparoscopic features that will help lead to early detection and diagnosis. PMID- 25723679 TI - Diaphragmatic hernia masquerading as a pulmonary metastasis. AB - Iatrogenic injury accounts for the second most common cause of acquired diaphragmatic hernias after penetrating trauma. An increased incidence of these hernias has been observed with the widespread use of laparoscopic surgery. We present the case of a 65-year-old woman who initially underwent sigmoid resection for an adenocarcinoma and a subsequent liver resection for metastasis. She was noted to have a left lower lobe pulmonary nodule on surveillance computed tomography, for which she underwent a mini-thoracotomy for a planned resection. At the time of surgery, the pulmonary nodule was discovered to be a diaphragmatic hernia, most probably of iatrogenic origin. We discuss the difficulty in diagnosis given her history and the location of such a lesion. PMID- 25723680 TI - Tongue metastasis from a poorly differentiated urothelial carcinoma of the bladder. AB - Chemotherapy may cause oral ulceration but a thorough investigation of symptoms and signs is important to determine the underlying diagnosis accurately. We describe a case of a patient with a poorly differentiated urothelial carcinoma of the bladder developing a tongue metastasis. This is a challenging diagnosis to make given the rarity of the presentation but it illustrates the need to evaluate any new symptoms fully. PMID- 25723681 TI - Ultra-low anterior resection with coloanal anastomosis for recurrent rectal prolapse in a young woman with colitis cystica profunda. AB - This case demonstrates the successful treatment of a young female patient with colitis cystica profunda causing rectal prolapse, after primary treatment with a Delorme procedure had failed. An ultra-low anterior resection with a temporary defunctioning ileostomy was carried out with good postoperative results. This case illustrates the possibility of carrying out sphincter preserving surgery rather than an abdominoperineal resection in the treatment of this condition, which may be preferable for patients. PMID- 25723682 TI - What are Journals for? AB - 'The secret is comprised in three words - work, finish, publish.' Michael Faraday There are many reasons doctors want to publish their work. For most at an early stage in their career, this may be to add a line to their curriculum vitae and advance their careers but for academics, publishing is an expectation. Many will believe they have something important to say, and wish to provoke debate and discussion; others wish to share knowledge and experiences, which in medicine can lead to a satisfying change in clinical practice. All serve to register one's idea and educate others. However, for some, the reason is as basic as money. As we celebrate the 350th anniversary of the first academic publication, perhaps we have come full circle when it comes to why people publish? Publishing is a flourishing business. There were approximately 28,100 active scholarly peer reviewed journals in mid-2012, collectively publishing about 1.8-1.9 million articles per year. The number of articles published each year and the number of journals have both grown steadily for more than two centuries, by about 3% and 3.5% per year respectively. (1) Journals have a responsibility to refine and define information and act as a scientific filter. Many of us will receive daily invitations in our email inbox from eclectic and new journals that are likely to take anything - is the filter now too porous? But this industry is like any other commercial activity and the supply still far outstrips the demand. Perhaps the internet revolution has merely fuelled our hunger to publish more? The launch of this exciting and innovative series about publishing coincides with the 350th celebration of the publication of the first academic journal. In the age of social media, the first question is 'What are journals for?', which Simon Rallison sets out to answer. Simon is Director of Publications at the Physiological Society, and was previously a journal publisher with Earthscan, Springer and Blackwell. Writing is hard work and, through this series, I hope the reader will get some useful insight into this service industry for academia. Jyoti Shah Commissioning Editor Reference 1. Ware M, Mabe M. The STM Report. 3rd edn. The Hague: International Association of Scientific, Technical and Medical Publishers; 2012. PMID- 25723683 TI - Diagnosis and management of schwannomas originating from the cervical vagus nerve. AB - INTRODUCTION: A schwannoma is a benign, slow growing, encapsulated nerve sheath tumour. Presentation of a schwannoma is a diagnostic and management challenge. METHODS: Internet searches of PubMed/MEDLINE((r)) for all articles listing schwannomas of the vagus nerve in the cervical/neck region (1980-2012) were undertaken to ascertain diagnostic pitfalls. The references of all articles were cross-checked to include all pertinent contributions. Further articles were traced through reference lists. RESULTS: Schwannomas are solitary, well circumscribed and medial to the carotid sheath. Preoperative diagnoses of schwannomas in the lateral part of the neck can cause confusion with its nerve of origin (ie whether it arises from the vagus nerve or a sympathetic chain). Computed tomography and magnetic resonance imaging reveal valuable information regarding the location and origin of the tumour as well as aiding surgical planning. The diagnosis can be confirmed intraoperatively. Postoperative recovery of neurological function is dependent on the type of surgery. Histopathological studies searching for classical features and immunohistochemical staining for S100 also confirm the diagnosis. CONCLUSIONS: Schwannomas should be considered in the differential diagnoses of unusual masses in the neck. Preoperative imaging elicits valuable information regarding the location and origin of schwannomas and histopathology confirms the diagnosis. PMID- 25723684 TI - When might an operative complication be regarded as acceptable? Part 1: Surgical factors that influence courts when finding fault during litigation. AB - In cases where surgeons face litigation over operative misadventure, the result of a trial is uncertain. In order to identify factors in cases of surgical litigation that have influenced the final decision of the courts, we have reviewed recent reported cases, noting both surgical and evidential influences on outcome. Taken together, these reveal that among other influential factors, the acceptability of more than one reasonable operative approach, the court's approach to inappropriate delegation and the uncertainties of expert evidence all play a role in the determination of the case. PMID- 25723685 TI - Neovascularisation is not an innocent bystander in recurrence after great saphenous vein surgery. AB - INTRODUCTION: This study sought to establish the causes of failure of great saphenous vein surgery among patients in whom there was confidence that accurate saphenofemoral ligation had been carried and the great saphenous vein had been stripped at least to knee level. METHODS: This was an observational study of 100 limbs (66 patients) operated on by a single surgeon 5-22 years previously (mean: 12 years). The index operation was primary in 54 limbs and for recurrence in 46 limbs. Thirty-two patients were studied having been re-referred for recurrence while 34 were recalled for review. All were examined clinically and with duplex ultrasonography, and all completed questionnaires (Aberdeen varicose vein questionnaire [AVVQ] and EQ-5D-3L). In order to measure the extent of visible recurrence, a scoring system similar to that in the venous clinical severity score was used but with a range of 0-8. RESULTS: There were visible varicosities in 77 of the 100 limbs. Duplex ultrasonography showed that recurrent saphenofemoral incompetence (SFI) was present in 27% of the limbs. This was judged to result from neovascularisation and was the most common source of reflux. AVVQ scores for the 27 limbs with recurrent SFI (median: 34, interquartile range [IQR]: 20-42) were higher than for the 73 with no recurrent SFI (median: 17, IQR: 11-29), which was a significant difference (Mann-Whitney U test, p<0.01). Analysing clinical scores with chi-squared tests indicated fewer visible varicosities in limbs without recurrent SFI than in those with recurrent SFI (p<0.01). CONCLUSIONS: Neovascularisation remains poorly understood but it cannot be considered an innocent bystander. PMID- 25723686 TI - Evaluation of robotic-assisted laparoscopic and open pyeloplasty in children: single-surgeon experience. AB - INTRODUCTION: Robotic-assisted laparoscopic pyeloplasty (RALP), the most commonly undertaken paediatric robotic urologic surgery, has not been compared against open pyeloplasty (OPN) by a single surgeon. Here, we describe our experience and outcomes. METHODS: Children undergoing RALP or OPN from 2007 to 2013 were reviewed. Clinical success was defined as resolution of presenting symptoms and improved/stable hydronephrosis on ultrasound. RESULTS: RALP and OPN cohorts comprised 52 and 40 patients, respectively. RALP patients were significantly older (6.8 vs 1.2 years, p<0.01) and heavier (28.4 vs 8.4 kg, p<0.01). Operative times for RALP were longer (203.3 vs 135.0 min, p<0.01), but decreased significantly with increasing experience (r(2)=0.42, p<0.01). Seven type-IIIb Clavien-Dindo complications occurred in RALP patients compared with two in OPN cases. There were no differences in postoperative narcotic administration (p=0.92) or duration of stay in hospital (DOSH) (p=0.93). A total of 11/40 (28%) OPN patients required epidural analgesia but none were placed in the RALP cohort. A total of 49/52 (94%) RALP patients and 40/40 OPN cases had successful outcomes. Three RALP patients required revision RALP. CONCLUSIONS: These data show that outcomes for RALP and OPN were comparable. An initial learning curve with RALP is to be expected, but operative times for RALP approached those for OPN. Previously reported benefits of RALP (reduced analgesic requirements, DOSH) were not observed. This difference may have been due to comparison of a heterogeneous cohort. Close evaluation of complications allowed for improved placement of stents in RALP. PMID- 25723687 TI - Female gender and diabetes mellitus increase the risk of recurrence after laparoscopic incisional hernia repair. AB - BACKGROUND: Laparoscopic hernia repair is used widely for the repair of incisional hernias. Few case studies have focussed on purely 'incisional' hernias. This multicentre series represents a collaborative effort and employed statistical analyses to provide insight into the factors predisposing to recurrence of incisional hernia after laparoscopic repair. A specific hypothesis (ie, laterality of hernias as well as proximity to the xyphoid process and pubic symphysis predisposes to recurrence) was also tested. METHODS: This was a retrospective study of all laparoscopic incisional hernias undertaken in six centres from 1 January 2004 to 31 December 2010. It comprised a comprehensive review of case notes and a follow-up using a structured telephone questionnaire. Patient demographics, previous medical/surgical history, surgical procedure, postoperative recovery, and perceived effect on quality of life were recorded. Repairs undertaken for primary ventral hernias were excluded. A logistic regression analysis was then fitted with recurrence as the primary outcome. RESULTS: A total of 186 cases (91 females) were identified. Median follow-up was 42 months. Telephone interviews were answered by 115/186 (62%) of subjects. Logistic regression analyses suggested that only female sex (odds ratio (OR) 3.53; 95% confidence interval (CI) 1.39-8.97) and diabetes mellitus (3.54; 1 12.56) significantly increased the risk of recurrence. Position of the defect had no statistical effect. CONCLUSIONS: These data suggest an increased risk of recurrence after laparoscopic incisional hernia repair in females and subjects with diabetes mellitus. These data will help inform surgeons and patients when considering laparoscopic management of incisional hernias. We recommend a centrally hosted, prospectively maintained national/international database to carry out additional research. PMID- 25723688 TI - Incidental non-inguinals hernias in totally extra-peritoneal hernia repair. AB - INTRODUCTION: Totally extra-peritoneal (TEP) inguinal hernia repair allows identification and repair of incidental non-inguinal groin hernias. We assessed the prevalence of incidental hernias during TEP inguinal hernia repair and identified the risk factors for incidental hernias. MATERIALS AND METHODS: Consecutive patients undergoing TEP repair from May 2005 to November 2012 were the study cohort. Inspection for ipsilateral femoral, obturator and rarer varieties of hernia was undertaken during TEP repair. Patient characteristics and operative findings were recorded on a prospectively collected database. RESULTS: A total of 1,532 TEP repairs were undertaken in 1,196 patients. Ninety-three patients were excluded due to incomplete data, leaving 1,103 patients and 1,404 hernias for analyses (1,380 male; 802 unilateral and 301 bilateral repairs; median age, 59 years). Among the 37 incidental hernias identified (2.6% of cases), the most common type of incidental hernia was femoral (n=32, 2.3%) followed by obturator (n=2, 0.1%). Increasing age was associated with an increased risk of incidental hernia, with a significant linear trend (p<0.01). The risk for patients >60 years of age was 4.0% vs 1.4% for those aged <60 years (p<0.01). Incidental hernias were found in 29.2% of females vs 2.2% of males, (p<0.0001). Risk of incidental hernia in those with a recurrent inguinal hernia was 3.0% vs 2.6% for primary repair (p=0.79). CONCLUSIONS: Incidental hernias during TEP inguinal hernia repair were found in 2.6% of cases and, though infrequent, could cause complications if left untreated. The risk of incidental hernia increased with age and was significantly higher in patients aged >60 years and in females. PMID- 25723689 TI - The epidemiology of and outcome from pancreatoduodenal trauma in the UK, 1989 2013. AB - INTRODUCTION: Pancreatoduodenal (PD) injury is an uncommon but serious complication of blunt and penetrating trauma, associated with high mortality. The aim of this study was to assess the incidence, mechanisms of injury, initial operation rates and outcome of patients who sustained PD trauma in the UK from a large trauma registry, over the period 1989-2013. METHODS: The Trauma Audit and Research Network database was searched for details of any patient with blunt or penetrating trauma to the pancreas, duodenum or both. RESULTS: Of 356,534 trauma cases, 1,155 (0.32%) sustained PD trauma. The median patient age was 27 years for blunt trauma and 27.5 years for penetrating trauma. The male-to-female ratio was 2.5:1. Blunt trauma was the most common type of injury seen, with a ratio of blunt-to-penetrating PD injury ratio of 3.6:1. Road traffic collision was the most common mechanism of injury, accounting for 673 cases (58.3%). The median injury severity score (ISS) was 25 (IQR: 14-35) for blunt trauma and 14 (IQR: 9 18) for penetrating trauma. The mortality rate for blunt PD trauma was 17.6%; it was 12.2% for penetrating PD trauma. Variables predicting mortality after pancreatic trauma were increasing age, ISS, haemodynamic compromise and not having undergone an operation. CONCLUSIONS: Isolated pancreatic injuries are uncommon; most coexist with other injuries. In the UK, a high proportion of cases are due to blunt trauma, which differs from US and South African series. Mortality is high in the UK but comparison with other surgical series is difficult because of selection bias in their datasets. PMID- 25723691 TI - The Nottingham Prognostic Index: five- and ten-year data for all-cause survival within a screened population. AB - INTRODUCTION: The Nottingham Prognostic Index (NPI) is an established prognostication tool in the management of breast cancers (BCs). Latest ten-year survival data have demonstrated an improved outlook for each NPI category and the latest UK five- and ten-year survival from BC has been reported to be 85% and 77%, respectively. We compared survival of each NPI category for BCs diagnosed within the national breast screening service in Wales (Breast Test Wales (BTW)) to the latest data, and reviewed its validity in unselected cases within a screened population. METHODS: All women screened between 1998 and 2001 within BTW were included. The NPI score for each cancer was calculated using the size, nodal status, and grade of the primary tumour. Survival data (all-cause) were calculated after ten years of follow-up. RESULTS: In the three-year screening period, 199,082 women were screened. A total of 1,712 cancers were diagnosed, and 1,546 had data available for calculating the NPI. Overall five-year and ten-year survival was 94% and 82%, respectively. CONCLUSIONS: Overall five-year and ten year survival (all-cause) has improved even when compared with UK data for BC specific survival. We found that the NPI remains valid for BC treatment, and that our data provide a reference for updating the all-cause survival of women diagnosed with BCs within a screened population. PMID- 25723690 TI - Implications of the index cholecystectomy and timing of referral for radical resection of advanced incidental gallbladder cancer. AB - INTRODUCTION: Advanced (pT2/T3) incidental gallbladder cancer is often deemed unresectable after restaging. This study assesses the impact of the primary operation, tumour characteristics and timing of management on re-resection. METHODS: The records of 60 consecutive referrals for incidental gallbladder cancer in a single tertiary centre from 2003 to 2011 were reviewed retrospectively. Decision on re-resection of incidental gallbladder cancer was based on delayed interval restaging at three months following cholecystectomy. Demographics, index cholecystectomy data, primary pathology, CA19-9 tumour marker levels at referral and time from cholecystectomy to referral as well as from referral to restaging were analysed. RESULTS: Thirty-seven patients with pT2 and twelve patients with pT3 incidental gallbladder cancer were candidates for radical re-resection. Following interval restaging, 24 patients (49%) underwent radical resection and 25 (51%) were deemed inoperable. The inoperable group had significantly more patients with positive resection margins at cholecystectomy (p=0.002), significantly higher median CA19-9 levels at referral (p=0.018) and were referred significantly earlier (p=0.004) than the patients who had resectable tumours. On multivariate analysis, urgent referral (p=0.036) and incomplete cholecystectomy (p=0.048) were associated significantly with inoperable disease following restaging. CONCLUSIONS: In patients with incidental, potentially resectable, pT2/T3 gallbladder cancer, inappropriate index cholecystectomy may have a significant impact on tumour dissemination. Early referral of breached tumours is not associated with resectability. PMID- 25723692 TI - Emergency oesophagectomy for oesophageal perforation after chemoradiotherapy for oesophageal cancer. AB - INTRODUCTION: Oesophageal perforation following chemoradiotherapy for oesophageal cancer is a devastating condition but there have been no studies investigating the role of emergency oesophagectomy for this life threatening situation. METHODS: This retrospective study comprised all cases of emergency oesophagectomy for oesophageal perforation after chemoradiotherapy for oesophageal carcinoma at a major centre for oesophageal surgery in Germany between 2004 and 2013. RESULTS: A total of 13 patients (mean age: 58.9 years) were identified. During the same time period, 356 elective oesophagectomies were performed. Tumour entities were squamous cell carcinoma (n=12) and adenocarcinoma of the oesophagus (n=1). Alcoholism (odds ratio [OR]: 25.79, 95% confidence interval [CI]: 6.70-121.70, p<0.0001) and chronic pulmonary disease (OR: 3.76, 95% CI: 1.06-14.96, p=0.027) were more common among the emergency cases. Oesophageal rupture was caused by perforation of an oesophageal stent (10 cases) or perforation during implantation of a percutaneous endoscopic gastrostomy tube (3 cases). Emergency oesophagectomy was carried out either as discontinuity resection (10/13) or oesophagectomy with immediate reconstruction (3/13). Compared with the elective cases, patients undergoing emergency oesophagectomy had significantly higher odds for sustaining perioperative sepsis (OR: 4.42, 95% CI: 1.23-16.45, p=0.01), acute renal failure (OR: 6.49, 95% CI: 1.57-24.15, p=0.005) and pneumonia (OR: 24.33, 95% CI: 3.52 1,046.65, p<0.0001). Furthermore, slow respiratory weaning was more common and there was a significantly higher tracheostomy rate (OR: 4.64, 95% CI: 1.14-16.98, p=0.02). Oesophageal discontinuity was eventually reversed in eight patients. Emergency oesophagectomy patients had odds that were three times higher for fatal outcome (OR: 3.59, 95% CI: 0.77-13.64, p=0.05). The overall mortality was 4/13. The remaining nine patients had a mean survival of 25.1 months (range: 5-46 months). The two-year-survival-rate was 38.5% (5/13). CONCLUSIONS: Despite the most unfavourable preconditions, the results of emergency oesophagectomy for oesophageal perforation after chemoradiotherapy are not desperate. The procedure is not only justified but life saving. PMID- 25723693 TI - The current role of staging laparoscopy in oesophagogastric cancer. AB - INTRODUCTION: Oesophagogastric cancers are known to spread rapidly to locoregional lymph nodes and by transcoelomic spread to the peritoneal cavity. Staging laparoscopy combined with peritoneal cytology can detect advanced disease that may not be apparent on other staging investigations. The aim of this study was to determine the current value of staging laparoscopy and peritoneal cytology in light of the ubiquitous use of computed tomography in all oesophagogastric cancers and the addition of positron emission tomography in oesophageal cancer. METHODS: All patients undergoing staging laparoscopy for distal oesophageal or gastric cancer between March 2007 and August 2013 were identified from a prospectively maintained database. Demographic details, preoperative staging, staging laparoscopy findings, cytology and histopathology results were analysed. RESULTS: A total of 317 patients were identified: 159 (50.1%) had gastric adenocarcinoma, 136 (43.0%) oesophageal adenocarcinoma and 22 (6.9%) oesophageal squamous carcinoma. Staging laparoscopy revealed macroscopic metastases in 36 patients (22.6%) with gastric adenocarcinoma and 16 patients (11.8%) with oesophageal adenocarcinoma. Positive peritoneal cytology in the absence of macroscopic peritoneal metastases was identified in a further five patients with gastric adenocarcinoma and six patients with oesophageal adenocarcinoma. There was no significant difference in survival between patients with macroscopic peritoneal disease and those with positive peritoneal cytology (p=0.219). CONCLUSIONS: Staging laparoscopy and peritoneal cytology should be performed routinely in the staging of distal oesophageal and gastric cancers where other investigations indicate resectability. Currently, in our opinion, patients with positive peritoneal cytology should not be treated with curative intent. PMID- 25723694 TI - Current outcomes of emergency large bowel surgery. AB - INTRODUCTION: Emergency large bowel surgery (ELBS) is known to carry an increased risk of morbidity and mortality. Previous studies have reported morbidity and mortality rates up to 14.3%. However, there has not been a recent study to document the outcomes of ELBS following several major changes in surgical training and provision of emergency surgery. The aim of this study was therefore to explore the current outcomes of ELBS. METHODS: A retrospective review was performed of a prospectively maintained database of the clinical records of all patients who had ELBS between 2006 and 2013. Data pertaining to patient demographics, ASA (American Society of Anesthesiologists) grade, diagnosis, surgical procedure performed, grade of operating surgeon and assistant, length of hospital stay, postoperative complications and in-hospital mortality were analysed. RESULTS: A total of 202 patients underwent ELBS during the study period. The mean patient age was 62 years and the most common cause was colonic carcinoma (n=67, 33%). There were 32 patients (15.8%) who presented with obstruction and 64 (31.7%) had bowel perforation. The overall in-hospital mortality rate was 14.8% (n=30). A consultant surgeon was involved in 187 cases (92.6%) as either first operator, assistant or available in theatre. CONCLUSIONS: ELBS continues to carry a high risk despite several major changes in the provision of emergency surgery. Further developments are needed to improve postoperative outcomes in these patients. PMID- 25723695 TI - A method of fabricating an antibiotic cement spacer using an elastic nail for the treatment of intramedullary osteomyelitis. PMID- 25723696 TI - Optimisation of internal thoracic artery exposure using a simple retraction method for extrapleural dissection. PMID- 25723697 TI - The useful distraction of mobile 'apps'. PMID- 25723698 TI - A simple technique of managing a urine bag. PMID- 25723699 TI - Topical use of tranexamic acid to control parastomal bleeding. PMID- 25723700 TI - Stryker intracompartmental pressure monitor in the triage of circumferential limb burns. PMID- 25723701 TI - A simple technique to reduce surgeon radiation exposure during the use of the mini C-arm fluoroscope. PMID- 25723702 TI - Greater palatine block in the treatment of acute epistaxis. PMID- 25723703 TI - The ABC guide for the safe use of mini C-arms. PMID- 25723704 TI - Challenging nasogastric tube insertion made easy. PMID- 25723705 TI - A versatile hip spacer for first stage revision in prosthetic joint infection. PMID- 25723706 TI - Technical tip in dynamic hip screw plate insertion. PMID- 25723707 TI - A simple purse string closure to maintain breast projection after central excision. PMID- 25723709 TI - A series of lanthanoid selenidoantimonates(V): rare examples of lanthanoid selenidoantimonates based on dinuclear lanthanide complexes. AB - A series of new lanthanoid selenidoantimonates(V) [Ln(en)(tepa)SbSe4] (Ln = La (Ia), Ce (Ib), Pr (Ic); en = ethylenediamine, tepa = tetraethylenepentamine) and [Ln2(tepa)2(MU-OH)2Cl2]-{[Ln(tepa)]2(MU-OH)2(SbSe4)2} (Ln = Y (IIa), Sm (IIb), Gd (IIc), Tb (IId), Dy (IIe), and Tm (IIf)) were solvothermally synthesized and structurally characterized. The structures of Ia-c consist of neutral molecules [Ln(en)(tepa)SbSe4], where the tetrahedral [SbSe4](3-) anion acts as a ligand to chelate the [Ln(en)(tepa)](3+) cation. The structures of IIa-f contain isolated dinuclear [Ln2(tepa)2(MU-OH)2Cl2](2+) cations built up from two [Ln(tepa)Cl](2+) ions linked by two -OH bridging groups and organic decorated {[Ln(tepa)]2(MU OH)2(SbSe4)2}(2-) anions based on two [Ln(tepa)SbSe4] units bridged by two -OH groups. Although a few lanthanoid selenidoantimonates(V) under solvothermal conditions have been reported, their lanthanide complexes normally appear mononuclear. Hence, IIa-f are rare examples of lanthanoid selenidoantimonates based on dinuclear lanthanide complexes. A preliminary investigation of nine lanthanoid selenidoantimonates(V) shows that the well-known lanthanide contraction has a significant influence on the formation of lanthanoid selenidoantimonates(V) under solvothermal conditions. The absorption edges of all compounds have been investigated by UV-vis spectroscopy, and density functional theory calculations for Ia and IIc have also been performed. PMID- 25723710 TI - Managing immune diseases in the smartphone era: how have apps impacted disease management and their future? AB - Immunology, similar to other areas of clinical science, is a data-rich discipline that involves a great deal of interaction between healthcare professionals and their patients. The focus of this editorial is to review the challenges and opportunities for mobile healthcare applications within immunology. It is clear that further research is required to fully maximize the potential of mobile apps (e.g., regulations and guidelines, electronic health). However, it is equally clear that mobile healthcare applications have had a positive impact on patient outcomes (better response rates, more efficient usage of time and more accurate diagnosis). Overall, healthcare applications have a fundamental role to play in the future management of diseases as they will help to ensure that we deliver more effective patient care. PMID- 25723711 TI - One-pot, bioinspired coatings to reduce the flammability of flexible polyurethane foams. AB - In this manuscript, natural materials were combined into a single "pot" to produce flexible, highly fire resistant, and bioinspired coatings on flexible polyurethane foam (PUF). In one step, PUF was coated with a fire protective layer constructed of a polysaccharide binder (starch or agar), a boron fire retardant (boric acid or derivative), and a dirt char former (montmorillonite clay). Nearly all coatings produced a 63% reduction in a critical flammability value, the peak heat release rate (PHRR). One formulation produced a 75% reduction in PHRR. This technology was validated in full-scale furniture fire tests, where a 75% reduction in PHRR was measured. At these PHRR values, this technology could reduce the fire threat of furniture from significant fire damage in and beyond the room of fire origin to being contained to the burning furniture. This flammability reduction was caused by three mechanisms-the gas-phase and condensed phase processes of the boron fire retardant and the condensed-phase process of the clay. We describe the one-pot coating process and the impact of the coating composition on flammability. PMID- 25723712 TI - Stress tolerant virulent strains of Cronobacter sakazakii from food. AB - BACKGROUND: Cronobacter sakazakii is considered as an emerging foodborne pathogen. The aim of this study was to isolate and characterize virulent strains of Cronobacter sakazakii from food samples of Bangladesh. RESULT: Six (6) Cronobacter sakazakii was isolated and identified from 54 food samples on the basis of biochemical characteristics, sugar fermentation, SDS-PAGE of whole cell protein, plasmid profile and PCR of Cronobacter spp. specific genes (esak, gluA, zpx, ompA, ERIC, BOX-AIR) and sequencing. These strains were found to have moderately high antibiotic resistance against common antibiotics and some are ESBL producer. Most of the C. sakazakii isolates were capable of producing biofilm (strong biofilm producer), extracellular protease and siderophores, curli expression, haemolysin, haemagglutinin, mannose resistant haemagglutinin, had high cell surface hydrophobicity, significant resistance to human serum, can tolerate high concentration of salt, bile and DNase production. Most of them produced enterotoxins of different molecular weight. The isolates pose significant serological cross-reactivity with other gram negative pathogens such as serotypes of Salmonella spp., Shigella boydii, Shigella sonnei, Shigella flexneri and Vibrio cholerae. They had significant tolerance to high temperature, low pH, dryness and osmotic stress. CONCLUSION: Special attention should be given in ensuring hygiene in production and post-processing to prevent contamination of food with such stress-tolerant virulent Cronobacter sakazakii. PMID- 25723713 TI - Predicting the outcome of Sjogren's syndrome-associated non-hodgkin's lymphoma patients. AB - BACKGROUND: Non-Hodgkin's lymphoma (NHL) development in Sjogren's syndrome (SS) remains a potentially lethal complication and efforts should focus on the identification of predictors that could aid in appropriate therapeutic decisions. METHODS: In order to identify potential prognostic factors for outcome in SS associated NHL, we retrospectively analyzed a cohort of 77 patients, diagnosed with NHL according to WHO classification criteria and meeting the American European Consensus Classification (AECC) criteria for SS and examined the effect of SS-activity (defined as the EULAR SS disease activity index-ESSDAI) in the prognosis of SS-related NHLs, as defined in terms of overall and event-free survivals (OS and EFS). An event was defined as lymphoma relapse, treatment failure, disease progression, histological transformation or death. The effect of NHL clinical and laboratory characteristics was also investigated. RESULTS: MALT lymphomas constituted the majority (66.2%) of lymphomas. During the follow-up (median = 57.93 months), the 5-year OS was 90.91% (95% CI: 82.14-95.80%) and the EFS was 77.92% (95% CI: 67.37-85.82%). Patients with high ESSDAI score at lymphoma diagnosis had a greater risk for death (OR = 5.241, 95% CI: 1.034 26.568) or for event (OR = 4.317, 95% CI: 1.146-9.699, p = 0.008). These patients had also significantly worse EFS (HR = 4.541, 95% CI: 1.772-11.637) and OS (HR = 5.946, 95% CI: 1.259-28.077). In addition, post-chemotherapy ESSDAI improvement was significantly lower in patients who had experienced an event (p = 0.005). An unfavorable International prognostic index (IPI) score (high-intermediate/high) was associated with high risk of death and event (OR = 13.867, 95% CI: 2.656 72.387 and OR = 12.589, 95% CI: 3.911-40.526, respectively), worse EFS (log-rank p<0.001, HR = 8.718, 95% CI: 3.477-21.858), as well as with worse OS (log-rank p<0.001, HR = 11.414, 95% CI: 2.414-53.974). After adjustment for identified risk factors, IPI score retained a significant prognostic role following by a strong effect of ESSDAI in survival outcomes. CONCLUSIONS: At the point of NHL diagnosis, IPI and ESSDAI might be proved useful predictive tools in SS associated lymphoma prognosis, directing to a more patient-tailored approach. PMID- 25723714 TI - Toxicity and DNA methylation changes induced by perfluorooctane sulfonate (PFOS) in sea urchin Glyptocidaris crenularis. AB - Perfluorooctane sulfonate (PFOS) is an ubiquitous persistent organic pollutant, which can be bioaccumulated and cause adverse effects on organisms. However, there is very limited information about the toxic effects of PFOS to marine organisms and its mechanisms. Therefore, in the present study, adult sea urchins Glyptocidaris crenularis were exposed to PFOS for 21 d, followed by a 7-d depuration period, in order to investigate the toxicity of PFOS to sea urchin and its potential epigenetic mechanisms. Sea urchins dropped spines, and lowered down the motor ability and feeding ability after the PFOS exposure. Superoxide dismutase activities in supernatant of coelomic fluid of sea urchin increased firstly and then dropped down, while the change of the catalase activity took an opposite trend during the exposure period. They both approached to the corresponding activity of the control after the depuration period. The DNA methylation polymorphism, methylation rate and demethylation rate in sea urchin gonad all increased following the prolonged exposure time, and then decreased after the depuration period. The demethylation rates were lower than the corresponding methylation rates, therefore methylation events were dominant during the whole experimental period. This might suggest that sea urchin have strong self-protection mechanisms and can survive from the PFOS exposure presented in this study. Further efforts are needed to more precisely investigate the DNA methylation effects of PFOS and the self-protection mechanism of sea urchin. PMID- 25723715 TI - Significance of Penicillium ochrochloron chitinase as a biocontrol agent against pest Helicoverpa armigera. AB - Penicillium ochrochloron chitinase purified by DEAE-cellulose ion exchange chromatography was evaluated for its antifeedant and growth inhibitory activities against Helicoverpa armigera at different concentrations of 2000, 1000, 500, 250 and 100 U mL(-1). It reduced the successful pupation and increased larval and pupal mortality, adult emergence in a dosage-dependent manner when applied topically. The highest mortalities were recorded for groups treated with 2000 U mL(-1) chitinase activity. The studies showed P.ochrochloron chitinase can affect the growth of H.armigera larvae. Since this insect pest species has developed resistance and resurgence to chemical insecticides, only alternate is the usage of enzyme-based pesticide formulations as an environmentally friendly pest management tool. PMID- 25723716 TI - Response of PAH-degrading genes to PAH bioavailability in the overlying water, suspended sediment, and deposited sediment of the Yangtze River. AB - The degrading genes of hydrophobic organic compounds (HOCs) serve as indicators of in situ HOC degradation potential, and the existing forms and bioavailability of HOCs might influence the distribution of HOC-degrading genes in natural waters. However, little research has been conducted to study the relationship between them. In the present study, nahAc and nidA genes, which act as biomarkers for naphthalene- and pyrene-degrading bacteria, were selected as model genotypes to investigate the response of polycyclic aromatic hydrocarbon (PAH)-degrading genes to PAH bioavailability in the overlying water, suspended sediment (SPS), and deposited sediment of the Yangtze River. The freely dissolved concentration, typically used to reflect HOC bioavailability, and total dissolved, as well as sorbed concentrations of PAHs were determined. Phylogenetic analysis showed that all the PAH-ring hydroxylating dioxygenase gene sequences of Gram-negative bacteria (PAH-RHD[GN]) were closely related to nahAc, nagAc, nidA, and uncultured PAH-RHD genes. The PAH-RHD[GN] gene diversity as well as nahAc and nidA gene copy numbers decreased in the following order: deposited sediment>SPS>overlying water. The nahAc and nidA gene abundance was not significantly correlated with environmental parameters but was significantly correlated with the bioavailable existing forms of naphthalene and pyrene in the three phases. The nahAc gene copy numbers in the overlying water and deposited sediment were positively correlated with freely dissolved naphthalene concentrations in the overlying and pore water phases, respectively, and so were nidA gene copy numbers. This study suggests that the distribution and abundance of HOC-degrading bacterial population depend on the HOC bioavailability in aquatic environments. PMID- 25723717 TI - Effect of low doses of precocene on reproduction and gene expression in green peach aphid. AB - Insect reproduction can be stimulated by exposure to sublethal doses of insecticide that kill the same insects at high doses. This bi-phasic dose response to a stressor is known as hormesis and has been demonstrated with many different insect-insecticide models. The specific mechanisms of the increased reproduction in insects following sublethal pesticide exposure are unknown, but may be related to juvenile hormone (JH), which has a major role in regulation of metamorphosis and reproductive development in insects. We tested the hypothesis that exposure to sublethal concentrations of precocene, an antagonist of JH, would not result in stimulated reproductive outputs in the green peach aphid, Myzus persicae, as can be demonstrated with many neurotoxic insecticides. We also measured JH titers and the expression of various developmental (FPPS I), stress response (Hsp60), and dispersal (OSD, TOL and ANT) genes in aphids following exposure to the same precocene treatments. We found that when aphid nymphs were treated with certain sublethal concentrations of precocene, 1.5- to 2-fold increased reproductive stimulation occurred when they became adults, but this effect subsided in the following generation. Precocene treatments to nymphs resulted in no measurable effects on JH levels in subsequent reproducing adults. Although we detected major effects on gene expression following some precocene treatments (e.g. 100- to 300-fold increased expression of some genes), there were no clear relationships between gene expression and reproductive responses for a given treatment. PMID- 25723718 TI - Long-term effects of bisphenol AF (BPAF) on hormonal balance and genes of hypothalamus-pituitary-gonad axis and liver of zebrafish (Danio rerio), and the impact on offspring. AB - Bisphenol AF (BPAF) is one of the analogues of bisphenol A (BPA) and is widely used as a raw material in the plastics industry. The potential toxicity to fish from exposure to BPAF in the aquatic environment is largely unknown. In this study, zebrafish (Danio rerio) were exposed to BPAF at 5, 25 and 125 MUg L(-1), from 4 hour-post-fertilization (hpf) to 120 day-post-fertilization (dpf), representing the period from embryo to adult. The levels of plasma hormones were measured and the expression of selected representative genes along the hypothalamus-pituitary-gonad (HPG) axis and liver were examined. The concentration of 17beta-estradiol (E2) was significantly increased in male and female fish and a significant decrease of testosterone (T) was observed in male fish. The mRNA expression of genes along the HPG axis and in liver tissues in F0 generation fish demonstrated that the steroid hormonal balances of zebrafish were modulated through the alteration of steroidgenesis. The significant decrease of egg fertilization among offspring indicates the possibility of sperm deterioration of parent following exposure to BPAF. The higher occurrence of malformation and lower survival rate in the offspring from the exposure group suggested a possibility of maternal transfer of BPAF, which could be responsible for the increased prevalence of adverse health signs in the offspring. The hatching delay in 5 MUg L(-1) BPAF indicated that parental exposure to environmentally relevant concentration of BPAF would result in delayed hatching of the offspring. A potential consequence of adverse effects in the offspring by BPAF deserves further investigation. PMID- 25723719 TI - Endocrine determinants of changes in insulin sensitivity and insulin secretion during a weight cycle in healthy men. AB - OBJECTIVE: Changes in insulin sensitivity (IS) and insulin secretion occur with perturbations in energy balance and glycemic load (GL) of the diet that may precede the development of insulin resistance and hyperinsulinemia. Determinants of changes in IS and insulin secretion with weight cycling in non-obese healthy subjects remain unclear. METHODS: In a 6wk controlled 2-stage randomized dietary intervention 32 healthy men (26+/-4y, BMI: 24+/-2kg/m2) followed 1wk of overfeeding (OF), 3wks of caloric restriction (CR) containing either 50% or 65% carbohydrate (CHO) and 2wks of refeeding (RF) with the same amount of CHO but either low or high glycaemic index at +/-50% energy requirement. Measures of IS (basal: HOMA-index, postprandial: Matsuda-ISI), insulin secretion (early: Stumvoll-index, total: tAUC-insulin/tAUC-glucose) and potential endocrine determinants (ghrelin, leptin, adiponectin, thyroid hormone levels, 24h-urinary catecholamine excretion) were assessed. RESULTS: IS improved and insulin secretion decreased due to CR and normalized upon RF. Weight loss-induced improvements in basal and postprandial IS were associated with decreases in leptin and increases in ghrelin levels, respectively (r = 0.36 and r = 0.62, p<0.05). Weight regain-induced decrease in postprandial IS correlated with increases in adiponectin, fT3, TSH, GL of the diet and a decrease in ghrelin levels (r-values between -0.40 and 0.83, p<0.05) whereas increases in early and total insulin secretion were associated with a decrease in leptin/adiponectin ratio (r = -0.52 and r = -0.46, p<0.05) and a decrease in fT4 (r = -0.38, p<0.05 for total insulin secretion only). After controlling for GL associations between RF-induced decrease in postprandial IS and increases in fT3 and TSH levels were no longer significant. CONCLUSION: Weight cycling induced changes in IS and insulin secretion were associated with changes in all measured hormones, except for catecholamine excretion. While leptin, adiponectin and ghrelin seem to be the major endocrine determinants of IS, leptin/adiponectin-ratio and fT4 levels may impact changes in insulin secretion with weight cycling. TRIAL REGISTRATION: ClinicalTrials.gov NCT01737034. PMID- 25723721 TI - Theoretical treatment of helix-coil transition of complexes DNA with two different ligands having different binding parameters. AB - The melting transition of DNA-ligand complexes, allowing for two binding mechanisms to different DNA conformations is treated theoretically. The obtained results express the behavior of the experimentally measurable quantities, degree of denaturation, and concentrations of bound ligands on the temperature. The range of binding parameters is obtained, where denaturation curves become multiphasic. The possible application to the nanocomposites crystallization is discussed. PMID- 25723720 TI - Rapid stress system drives chemical transfer of fear from sender to receiver. AB - Humans can register another person's fear not only with their eyes and ears, but also with their nose. Previous research has demonstrated that exposure to body odors from fearful individuals elicited implicit fear in others. The odor of fearful individuals appears to have a distinctive signature that can be produced relatively rapidly, driven by a physiological mechanism that has remained unexplored in earlier research. The apocrine sweat glands in the armpit that are responsible for chemosignal production contain receptors for adrenalin. We therefore expected that the release of adrenalin through activation of the rapid stress response system (i.e., the sympathetic-adrenal medullary system) is what drives the release of fear sweat, as opposed to activation of the slower stress response system (i.e., hypothalamus-pituitary-adrenal axis). To test this assumption, sweat was sampled while eight participants prepared for a speech. Participants had higher heart rates and produced more armpit sweat in the fast stress condition, compared to baseline and the slow stress condition. Importantly, exposure to sweat from participants in the fast stress condition induced in receivers (N = 31) a simulacrum of the state of the sender, evidenced by the emergence of a fearful facial expression (facial electromyography) and vigilant behavior (i.e., faster classification of emotional facial expressions). PMID- 25723722 TI - Erdheim-Chester disease mimicking an intracranial trigeminal schwannoma: case report. AB - Erdheim-Chester disease (ECD) is non-Langerhans histiocytosis that can affect multiple organ systems. It usually affects middle-aged patients, and only a few reports of ECD in children appear in the literature. Central nervous system involvement is a common feature that usually occurs as infiltration of the hypothalamus-pituitary axis, cerebellum, and/or brainstem. Meningeal involvement occurs less commonly. In this article, the authors discuss a rare pediatric case of ECD presenting as an infiltrative mass of the trigeminal nerve and resembling the clinical and imaging features of a trigeminal schwannoma. PMID- 25723723 TI - Fast dynamic imaging technique to identify obstructive lesions in the CSF space: report of 2 cases. AB - Disorders of CSF dynamics such as syringomyelia and obstructive hydrocephalus can be caused by thin mobile obstructive lesions not visible on traditional MRI sequences. New imaging techniques with balanced steady-state free precession (bSSFP) and dynamic imaging with bSSFP cine allow visualization of these pulsatile structures within the CSF space. The authors present 2 cases involving pediatric patients-one who developed presumed idiopathic syringomyelia and one with presumed communicating hydrocephalus in association with Pfeiffer syndrome who harbored thin dynamic obstructive lesions seen on bSSFP cine studies using 1.5-T MRI. In combination with traditional CSF cine studies and bSSFP, bSSFP cine sequence was able to detect dynamic membranous adhesions not seen on traditional MRI sequences. These previously undetectable lesions on traditional MRI sequences were the etiology of CSF obstruction, and tailored surgical approaches were performed to avoid shunting in both patients. These reports demonstrate the clinical utility for using these novel imaging tools for the detection of thin adhesions and dynamic lesions in the central nervous system. Balanced SSFP cine sequences can supplement conventional MR modalities to identify these otherwise poorly visualized lesions responsible for presumed communicating hydrocephalus or idiopathic syringomyelia. PMID- 25723724 TI - Hyponatremia and poor cognitive outcome following pediatric brain tumor surgery. AB - OBJECT: Pediatric intracranial neoplasms are common and cause substantial neurological morbidity. Postoperative hyponatremia is also common and may exacerbate neurological injury. The authors performed an exploratory analysis to evaluate an exposure-response relationship between hyponatremia severity and cognitive function at discharge. METHODS: A retrospective cohort of patients 0-19 years old who underwent a first intracranial neoplasm surgery at a pediatric tertiary care hospital was reviewed. Outcome was assessed by Pediatric Cerebral Performance Category (PCPC) score of 1-6 at hospital discharge. Poor outcome was defined as PCPC score 3-6, corresponding to moderate or worse disability. RESULTS: Of 319 total children, 80 (25%) had poor outcomes. One hundred thirty seven children (43%) had serum sodium concentrations <= 131-135 mEq/L and 39 (12%) had serum sodium concentrations <= 130 mEq/L. Lower nadir sodium concentration and longer duration of hyponatremia were significantly associated with worsening PCPC score (p < 0.001). Rapid sodium decreases and more hyponatremic episodes were also significantly associated with worsening PCPC score (p < 0.001). After adjustment for patient factors, tumor characteristics, and measures of sodium disruption, multivariable analysis revealed noncortical tumor locations and lower nadir sodium concentration (adjusted odds ratio 0.86, 95% confidence interval 0.78-0.95) were important independent risk factors for poor cognitive outcome. CONCLUSIONS: Neurocognitive disability and hyponatremia are common in children undergoing surgery for intracranial neoplasms. This study found a significant association between severity of hyponatremia and worsened cognitive outcome, with an apparent exposure-response relationship. These data support the need for careful postoperative monitoring of serum sodium. Further research is needed to determine if prevention and treatment of hyponatremia can improve outcomes in these children. PMID- 25723725 TI - Neoadjuvant chemotherapy for brain tumors in infants and young children. AB - OBJECT: Because of their large size and high vascularity, complete removal of brain tumors in infants and young children is often difficult. In most cases the degree of resection is associated with prognosis. Neoadjuvant chemotherapy may facilitate resection by reducing the vascularity of the tumor. The authors evaluated the effectiveness of neoadjuvant chemotherapy in the management of these tumors. METHODS: The authors performed a retrospective review of infants and young children who underwent tumor removal after neoadjuvant chemotherapy. RESULTS: Nine consecutive patients underwent resection after neoadjuvant chemotherapy during the period February 2004 to December 2012. The mean age at diagnosis was 18 months (range 2-50 months). The average largest tumor diameter was 71 mm (range 30-130 mm) at initial surgery. Five patients underwent partial resection, and 4 underwent biopsy as the initial surgery. The histopathological diagnoses were ependymoma in 2 patients, anaplastic ependymoma in 1, primitive neuroectodermal tumor (PNET) in 2, choroid plexus carcinoma in 1, atypical teratoid/rhabdoid tumor (AT/RT) in 1, glioblastoma in 1, and embryonal tumor with abundant neuropil and true rosettes in 1. After 2-4 courses of multiagent chemotherapy (mainly with vincristine, cyclophosphamide, etoposide, and cisplatin), the second-look surgery was performed. In 1 patient with a PNET, intratumoral hemorrhage was observed after 2 courses of chemotherapy. The mean interval between the initial and the second-look surgery was 3 months. The tumor volume was reduced to varying degrees in 5 patients (56%) after chemotherapy. Intraoperatively, the vascularity of the tumor was considerably reduced, and the tumor was more circumscribed in all cases. Gross-total resection was achieved in 8 patients (89%) and neartotal resection in 1 (11%). Histopathological examination demonstrated fibrotic tissue circumscribing the tumor in 6 of 9 cases (67%). The average blood loss was 20% of the estimated blood volume, and 3 patients (33%) required a blood transfusion. There was no surgical mortality. One patient had transient dysphasia postoperatively. The mean follow-up period was 28 months. At the last follow-up, 2 patients (22%) had died (1 died of tumor progression and 1 of sepsis), and 4 patients (44%) had no tumor recurrence. CONCLUSIONS: Neoadjuvant chemotherapy for brain tumors in infants and young children was effective in reduction of tumor vascularity and clarification of the tumor-brain interface, which significantly facilitated maximal tumor resection. PMID- 25723726 TI - Letter to the editor: Off-label rhBMP-2 use in pediatric spine deformity surgery. PMID- 25723727 TI - Experimental and density functional theory (DFT): a dual approach to study the various important properties of monohydrated l-proline cadmium chloride for nonlinear optical applications. AB - In the current work we have applied the experimental and quantum chemical techniques to study the electro-optical and nonlinear optical properties of l proline cadmium chloride monohydrate (LPCCM). Synthesis and good quality single crystals of LPCCM were grown (size=20mm*12mm*10mm). Crystal structure was confirmed by powder X-ray diffraction study. The calculated FT-IR and FT-Raman frequencies were analyzed. Detailed optical studies were carried out and various optical parameters are calculated. Using density functional theory, molecular geometry of LPCCM was optimized within framework of B3LYP/6-31G(*). The calculated HOMO-LUMO energy gap of 5.484eV and transition energy of 5.565eV has been found in semi-quantitative agreement with experimental results. The value of dipole moment and first hyperpolarizability of LPCCM are found to be 2 and 6 times respectively, higher than that of urea. The obtained results reveal that the titled compound is a good candidate for nonlinear applications having an excellent transparency trade-off value. PMID- 25723728 TI - The added diagnostic value of five different C-reactive protein point-of-care test devices in detecting pneumonia in primary care: A nested case-control study. AB - BACKGROUND: The results obtained from various point-of-care (POC) test devices for estimating C-reactive protein (CRP) levels in a laboratory setting differ when compared to a laboratory reference test. We aimed to determine whether such differences meaningfully affect the accuracy and added diagnostic value in predicting radiographic pneumonia in adults presenting with acute cough in primary care. METHODS: A nested case control study of adult patients presenting with acute cough in 12 different European countries (the Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe [GRACE] Network). Venous blood samples from 100 patients with and 100 patients without pneumonia were tested with five different POC CRP tests and a laboratory analyzer. Single test accuracy values and the added value of CRP to symptoms and signs were calculated. RESULTS: Single test accuracy values showed similar results for all five POC CRP tests and the laboratory analyzer. The area under the curve of the different POC CRP tests and the laboratory analyzer (range 0.79 0.80) were all comparable and higher than the clinical model without CRP (0.70). Multivariable odds ratios were the same (1.2) for all CRP tests. CONCLUSIONS: Five POC CRP test devices and the laboratory analyzer performed with similar accuracy in detecting pneumonia both as single test, and when used in addition to clinical findings. Variability in results obtained from standard CRP laboratory and POC test devices do not translate into clinically relevant differences when used for prediction of pneumonia in patients with acute cough in primary care. PMID- 25723729 TI - Karyogamy in rice zygotes: Actin filament-dependent migration of sperm nucleus, chromatin dynamics, and de novo gene expression. AB - In angiosperms, the fusion of a sperm cell with an egg cell, termed plasmogamy, triggers egg activation. Then, karyogamy, migration of the sperm nucleus toward the egg nucleus and their subsequent nuclear fusion, progresses, and de novo gene expression from the zygotic genome is initiated for early embryogenesis. Therefore, karyogamy is an important post-fusion event that bridges egg activation and de novo gene expression in fused gametes/zygotes. In this study, we monitored the progression of karyogamy in rice zygotes produced by in vitro fusion. The results indicated that the sperm nucleus migrated adjacent to the egg nucleus via an actin cytoskeleton, and the egg chromatin then appeared to move unidirectionally into the sperm nucleus through a possible nuclear connection. An enlargement of the sperm nucleus accompanied this possible chromatin remodeling. Then, 30-70 min after fusion, the sperm chromatin began to decondense, and karyogamy was completed. The development of early rice zygotes from plasmogamy to karyogamy could be divided into eight stages, and paternal and de novo synthesized transcripts were separately detectable in zygotes at early and late karyogamy stages, respectively, by RT-PCR using zygotes at each karyogamy stage. PMID- 25723730 TI - Assembling allopolyploid genomes: no longer formidable. AB - A combined approach of whole genome shotgun sequencing and ultra-high density linkage mapping using skim sequencing of a segregating population is effective for assembling allopolyploid genomes. PMID- 25723731 TI - Sleep-disordered Breathing in Neuromuscular Disease. AB - Sleep-disordered breathing in neuromuscular diseases is due to an exaggerated reduction in lung volumes during supine sleep, a compromised physiologic adaptation to sleep, and specific features of the diseases that may promote upper airway collapse or heart failure. The normal decrease in the rib cage contribution to the tidal volume during phasic REM sleep becomes a critical vulnerability, resulting in saw-tooth oxygen desaturation possibly representing the earliest manifestation of respiratory muscle weakness. Hypoventilation can occur in REM sleep and progress into non-REM sleep, with continuous desaturation and hypercarbia. Specific characteristics of neuromuscular disorders, such as pharyngeal neuropathy or weakness, macroglossia, bulbar manifestations, or low lung volumes, predispose patients to the development of obstructive events. Central sleep-disordered breathing can occur with associated cardiomyopathy (e.g., dystrophies) or from instability in the control of breathing due to diaphragm weakness. Mitigating factors such as recruitment of accessory respiratory muscles, reduction in REM sleep, and loss of normal REM atonia in some individuals may partially protect against sleep-disordered breathing. Noninvasive ventilation, a standard-of-care management option for sleep disordered breathing, can itself trigger specific sleep-disordered breathing events including air leaks, patient-ventilator asynchrony, central sleep apnea, and glottic closure. These events increase arousals, reduce adherence, and impair sleep architecture. Polysomnography plays an important role in addressing pitfalls in the diagnosis of sleep-disordered breathing in neuromuscular diseases, identifying sleep-disordered breathing triggered by noninvasive ventilation, and optimizing noninvasive ventilation settings. PMID- 25723732 TI - Effects of chronic exposure to microcystin-LR on hepatocyte mitochondrial DNA replication in mice. AB - Microcystins (MCs) are produced by cyanobacterial blooms, and microcystin-LR (MC LR) is the most toxic among the 80 MC variants. Data have shown that the liver is one of the specific target organs for MC-LR, which can cause mitochondrial DNA (mtDNA) damage, resulting in mitochondrial dysfunction. However, the underlying mechanism is still unclear. In the present study, we evaluated the genetic toxicity of MC-LR in mice drinking water at different concentrations (1, 5, 10, 20, and 40 MUg/L) for 12 months. Our results showed that long-term and persistent exposure to MC-LR increased the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels of DNA in liver cells, damaged the integrity of mtDNA and nuclear DNA (nDNA), and altered the mtDNA content. Notably, MC-LR exposure can change the expression of mitochondrial genes and nuclear genes that are critical for regulating mtDNA replication and repairing oxidized DNA. They also further impaired the function of mitochondria and liver cells. PMID- 25723733 TI - Scavenging of radioactive soluble gases from inhomogeneous atmosphere by evaporating rain droplets. AB - We analyze effects of inhomogeneous concentration and temperature distributions in the atmosphere, rain droplet evaporation and radioactive decay of soluble gases on the rate of trace gas scavenging by rain. We employ a one-dimensional model of precipitation scavenging of radioactive soluble gaseous pollutants that is valid for small gradients and non-uniform initial altitudinal distributions of temperature and concentration in the atmosphere. We assume that conditions of equilibrium evaporation of rain droplets are fulfilled. It is demonstrated that transient altitudinal distribution of concentration under the influence of rain is determined by the linear wave equation that describes propagation of a scavenging wave front. The obtained equation is solved by the method of characteristics. Scavenging coefficients are calculated for wet removal of gaseous iodine-131 and tritiated water vapor (HTO) for the exponential initial distribution of trace gases concentration in the atmosphere and linear temperature distribution. Theoretical predictions of the dependence of the magnitude of the scavenging coefficient on rain intensity for tritiated water vapor are in good agreement with the available atmospheric measurements. PMID- 25723734 TI - Influence of rootstocks on growth, yield, fruit quality and leaf mineral element contents of pear cv. 'Santa Maria' in semi-arid conditions. AB - BACKGROUND: Rootstocks play an essential role to determining orchard performance of fruit trees. Pyrus communis and Cydonia oblonga are widely used rootstocks for European pear cultivars. The lack of rootstocks adapted to different soil conditions and different grafted cultivars is widely acknowledged in pear culture. Cydonia rootstocks (clonal) and Pyrus rootstocks (seedling or clonal) have their advantages and disadvantages. In each case, site-specific environmental characteristics, specific cultivar response and production objectives must be considered before choosing the best rootstock. In this study, the influence of three Quince (BA 29, Quince A = MA, Quince C = MC) and a local European pear seedling rootstocks on the scion yield, some fruit quality characteristics and leaf macro (N, P, K, Ca and Mg) and micro element (Fe, Zn, Cu, Mn and B) content of 'Santa Maria' pear (Pyrus communis L.) were investigated. RESULTS: Trees on seedling rootstock had the highest annual yield, highest cumulative yield (kg tree(-1)), largest trunk cross-sectional area (TCSA), lowest yield efficiency and lowest cumulative yield (ton ha(-1)) in the 10(th) year after planting. The rootstocks had no significant effect on average fruit weight and fruit volume. Significantly higher fruit firmness was obtained on BA 29 and Quince A. The effect of rootstocks on the mineral element accumulation (N, K, Ca, Mg, Fe, Zn, Cu, Mn and B) was significant. Leaf analysis showed that rootstocks used had different mineral uptake efficiencies throughout the early season. CONCLUSION: The results showed that the rootstocks strongly affected fruit yield, fruit quality and leaf mineral element uptake of 'Santa Maria' pear cultivar. Pear seedling and BA 29 rootstock found to be more prominent in terms of several characteristics for 'Santa Maria' pear cultivar that is grown in highly calcareous soil in semi-arid climate conditions. We determined the highest N, P (although insignificant), K, Ca, Mg, Fe and Cu mineral element concentrations on the pear seedling and BA 29 rootstocks. According to the results, we recommend the seedling rootstock for normal density plantings (400 trees ha(-1)) and BA 29 rootstock for high-density plantings (800 trees ha(-1)) for 'Santa Maria' pear cultivar in semi-arid conditions. PMID- 25723735 TI - Reaction Kinetics of Meteoric Sodium Reservoirs in the Upper Atmosphere. AB - The gas-phase reactions of a selection of sodium-containing species with atmospheric constituents, relevant to the chemistry of meteor-ablated Na in the upper atmosphere, were studied in a fast flow tube using multiphoton ionization time-of-flight mass spectrometry. For the first time, unambiguous observations of NaO and NaOH in the gas phase under atmospheric conditions have been achieved. This enabled the direct measurement of the rate constants for the reactions of NaO with H2, H2O, and CO, and of NaOH with CO2, which at 300-310 K were found to be (at 2sigma confidence level): k(NaO + H2O) = (2.4 +/- 0.6) * 10(-10) cm(3) molecule (-1) s(-1), k(NaO + H2) = (4.9 +/- 1.2) * 10(-12) cm(3) molecule (-1) s( 1), k(NaO + CO) = (9 +/- 4) * 10(-11) cm(3) molecule (-1) s(-1), and k(NaOH + CO2 + M) = (7.6 +/- 1.6) * 10(-29) cm(6) molecule (-2) s(-1) (P = 1-4 Torr). The NaO + H2 reaction was found to make NaOH with a branching ratio >= 99%. A combination of quantum chemistry and statistical rate theory calculations are used to interpret the reaction kinetics and extrapolate the atmospherically relevant experimental results to mesospheric temperatures and pressures. The NaO + H2O and NaOH + CO2 reactions act sequentially to provide the major atmospheric sink of meteoric Na and therefore have a significant impact on the underside of the Na layer in the terrestrial mesosphere: the newly determined rate constants shift the modeled peak to about 93 km, i.e., 2 km higher than observed by ground-based lidars. This highlights further uncertainties in the Na chemistry cycle such as the unknown rate constant of the NaOH + H reaction. The fast Na-recycling reaction between NaO and CO and a re-evaluated rate constant of the NaO + CO2 sink should be now considered in chemical models of the Martian Na layer. PMID- 25723736 TI - Defining and managing expectations for early immunotherapy cancer trials. AB - This review discusses the concept of expectations in assessing direct benefit to participants in phase I immunotherapy studies. With the push toward a faster assessment of clinical benefit or efficacy, limiting phase I studies to safety determination only is now viewed as obsolete and has been replaced by designs that draw attention to therapeutic benefit or efficacy. While this approach is touted as being more flexible in trial conduct, these designs are particularly problematic for immunotherapy studies. Defining and managing expectations is paramount on understanding the key axioms that emerge that include i) understanding bias in models and mechanistic results, ii) that no test is perfect, iii) it is difficult to select a good predictive biomarker in the absence of clinical data, even for targeted therapies, iv) markers predictive for monotherapy may not be predictive for combination therapy, and v) all about improved patient selection. Considering the heterogeneity of cancers and the immune response of the host, we think that immunotherapy should be developed in parallel with the identification of different clinico-pathological models of immune response to cancer. This approach would accomplish two important goals: 1) provide a biological understanding of the complete in vivo environment, thereby giving investigators the opportunity to optimize and maximize the effect of a specific immunotherapy agent and 2) addressing host environment issues simultaneously so that safety data and perceived benefit can be achieved more quickly. PMID- 25723739 TI - Probing the conformational energetics of alkyl thiols on gold surfaces by means of a morphing/steering non-equilibrium tool. AB - In this work we show that a non-equilibrium statistical tool based on Jarzynski's equality (JE) can be applied to achieve a sufficiently accurate mapping of the torsion free energy, bond-by-bond, for an alkyl thiol ligand tethered to a gold surface and sensing the presence of the surrounding cluster of similar chains. The strength of our approach is the employment of a strategy to let grow the internal energetics of the whole system (namely, the "energy morphing" stage recently presented by us in J. Comput. Chem., 2014, 35, 1865-1881) before initiating the rotational steering, which yields accurate results in terms of statistical uncertainties and bias on the free energy profiles. The work is mainly methodological and illustrates the feasibility of this kind of inspection on nanoscale molecular clusters with conformational flexibility. The outcomes for the archetype of self-assembled-monolayers considered here, a regular pattern of 10-carbon alkyl thiols on an ideal gold surface, give information on the conformational mobility of the ligands. Notably, such information is unlikely to be obtained by means of standard equilibrium techniques or by conventional molecular dynamics simulations. PMID- 25723738 TI - Validation of Tuba1a as appropriate internal control for normalization of gene expression analysis during mouse lung development. AB - The expression ratio between the analysed gene and an internal control gene is the most widely used normalization method for quantitative RT-PCR (qRT-PCR) expression analysis. The ideal reference gene for a specific experiment is the one whose expression is not affected by the different experimental conditions tested. In this study, we validate the applicability of five commonly used reference genes during different stages of mouse lung development. The stability of expression of five different reference genes (Tuba1a, Actb Gapdh, Rn18S and Hist4h4) was calculated within five experimental groups using the statistical algorithm of geNorm software. Overall, Tuba1a showed the least variability in expression among the different stages of lung development, while Hist4h4 and Rn18S showed the maximum variability in their expression. Expression analysis of two lung specific markers, surfactant protein C (SftpC) and Clara cell-specific 10 kDA protein (Scgb1a1), normalized to each of the five reference genes tested here, confirmed our results and showed that incorrect reference gene choice can lead to artefacts. Moreover, a combination of two internal controls for normalization of expression analysis during lung development will increase the accuracy and reliability of results. PMID- 25723737 TI - Tumor progression locus 2 (Tpl2) kinase as a novel therapeutic target for cancer: double-sided effects of Tpl2 on cancer. AB - Tumor progression locus 2 (Tpl2) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that conveys various intra- and extra-cellular stimuli to effector proteins of cells provoking adequate adoptive responses. Recent studies have elucidated that Tpl2 is an indispensable signal transducer as an MAP3K family member in diverse signaling pathways that regulate cell proliferation, survival, and death. Since tumorigenesis results from dysregulation of cellular proliferation, differentiation, and apoptosis, Tpl2 participates in many decisive molecular processes of tumor development and progression. Moreover, Tpl2 is closely associated with cytokine release of inflammatory cells, which has crucial effects on not only tumor cells but also tumor microenvironments. These critical roles of Tpl2 in human cancers make it an attractive anti-cancer therapeutic target. However, Tpl2 contradictorily works as a tumor suppressor in some cancers. The double-sided effects of Tpl2 originate from the specific upstream and downstream signaling environment of each tumor, since Tpl2 interacts with various signaling components. This review summarizes recent studies concerning the possible roles of Tpl2 in human cancers and considers its possibility as a therapeutic target, against which novel anti-cancer agents could be developed. PMID- 25723741 TI - The Efficacy of Adjuvant Chemotherapy in Patients With Stage II/III Resected Rectal Cancer Treated With Neoadjuvant Chemoradiation Therapy. AB - INTRODUCTION: Patients with stage II/III rectal cancers are treated with neoadjuvant chemoradiation and surgical resection followed by adjuvant chemotherapy (CT) per practice guidelines. It is unclear whether adjuvant CT provides survival benefit, and the purpose of this study was to measure outcomes in patients who did and did not receive adjuvant CT. MATERIALS AND METHODS: We used a prospectively collected database for patients treated at The Ohio State University, and analyzed overall survival (OS), time to recurrence, patient characteristics, tumor features, and treatments. Survival curves were estimated using Kaplan-Meier method and compared by the log-rank test. Age was compared using the Wilcoxon test, and other categorical variables were compared using the chi or Fisher exact test. RESULTS: Between August 2005 and July 2011, 110 patients were identified and 71 patients had received adjuvant CT. There was no significant difference in sex, race, pathologic tumor stage, and pathologic complete response between the 2 patient groups. Although patient characteristics showed a difference in age (median age 54.3 vs. 62 y, P=0.01) and advanced pathologic nodal status (43% vs. 19%, P=0.02), there was a significant difference in OS. Median OS was 72.6 months with CT versus 36.4 months without CT (P=0.0003). Median time to recurrence has not yet been reached. CONCLUSIONS: In this retrospective analysis, adjuvant CT was associated with a longer OS despite more advanced pathologic nodal staging. Prospective randomized studies are warranted to determine whether adjuvant CT provides a survival benefit for patients across the spectrum of stage II and III rectal cancer. PMID- 25723740 TI - Hematologic Toxicity of Concurrent Administration of Radium-223 and Next generation Antiandrogen Therapies. AB - PURPOSE/OBJECTIVES: Radium-223 is a first-in-class radiopharmaceutical recently approved for the treatment of castration-resistant prostate cancer in patients with symptomatic bone metastases. Initial studies investigating Radium-223 primarily used nonsteroidal first-generation antiandrogens. Since that time, newer antiandrogen therapies have demonstrated improved survival in patients with castration-resistant prostate cancer. It has been suggested that the rational combination of these newly approved agents with Radium-223 may lead to improved response rates and clinical outcomes. Currently, there is lack of information regarding the safety of concurrent administration of these agents with radiopharmaceuticals. Here, we report on hematologic toxicity findings from our institution in patients receiving concurrent Radium-223 and next-generation antiandrogen therapies with either enzalutamide or abiraterone. MATERIALS/METHODS: In a retrospective study, we analyzed patients who received Radium-223 as part of an early-access trial, and following FDA approval in May 2013, patients receiving Radium-223 as part of standard care. Radium-223 was given at standard dosing of 50 kBq/kg each month for 6 total cycles. Complete blood counts were performed before treatment monthly and following each injection. Blood counts from patients receiving Radium alone and concurrently with next-generation antiandrogens were compared. To date, 25 total patients were analyzed, with a median of 5 monthly doses received per patient. Fourteen patients received concurrent therapy during monthly Radium-223 with either enzalutamide (n=8) or abiraterone (n=6). RESULTS: Six patients expired due to disease progression. Two patients discontinued treatment due to grade 3 myelosuppression. For patients receiving either Radium alone and with concurrent next-generation antiandrogen therapy, there did not appear to be any statistically significant differences between initial and nadir blood counts. Mean change from initial neutrophil count to nadir was 1.9*10/L in patients receiving Radium alone, versus 2.3*10/L in patients receiving concurrent therapy (P=0.77). Mean change from initial hemoglobin value to nadir was 1.5 g/L in patients receiving Radium alone, versus 1.8 g/L in patients receiving concurrent therapy (P=0.31). Mean change from initial platelet count to nadir was 52.3*10 cells/L in patients receiving Radium alone versus 70.6*10 cells/L in patients receiving concurrent therapy (P=0.39). Individual blood counts for each measured laboratory are included in the supplemental data. PSA was stable or decreased in 22% of patients receiving Radium alone versus 35% of patients receiving combination treatment (P=0.24). CONCLUSIONS: Concurrent administration of Radium 223 and next-generation antiandrogen therapies appears to be well tolerated with similar toxicities to standard administration of Radium-223 alone. This particular cohort of patients represents a high-risk, heavily pretreated group of patients with advanced metastatic disease and significant marrow burden. Despite these risk factors, hematologic toxicity was modest and was in the range expected for this risk group based on previous trials. To date, this is the first study investigating the toxicity of combination treatment. Further studies investigating the safety and efficacy of combination treatments are warranted. PMID- 25723742 TI - Personal choice vs. public health. PMID- 25723743 TI - An unusual lesion of the finger presenting to the emergency department. AB - INTRODUCTION: Squamous cell carcinoma (SCC) of the finger, especially those arising from the nail bed matrix and lateral skin folds are common, especially after the fifth decade of life. A variety of aetiological factors and associations have been described. The appearance can be so ambiguous and appear benign that it can lead to a delay in presentation and diagnosis. PRESENTATION OF THE CASE: We report a case of a 66 year old retired Engineer who presented to our Emergency Department with a 2-year history of a painless swelling of his left ring finger. Examination revealed a diffuse circumferential swelling of the left ring finger involving the middle and distal phalanx. The tip was insensate. The differential diagnoses included pyogenic granuloma, soft tissue sarcoma and chronic granulomatous infection. An excisional biopsy confirmed the diagnosis of a well differentiated squamous cell carcinoma. DISCUSSION: This case highlights how digital squamous cell carcinoma can appear benign, mimic a wide variety of conditions leading to a delay in diagnosis and treatment. It usually runs an indolent course but can be locally destructive. Excisional biopsy, providing a clear margin where possible is usually sufficient in the absence of metastatic spread. CONCLUSION: Chronic, non-healing lesions of the digits should be viewed with suspicion. Digital squamous cell carcinoma commonly mimics a variety of benign conditions and efforts should be made to rule out other possible diagnoses and to institute early treatment. PMID- 25723744 TI - Laparoscopic endoloop technique - A novel approach of managing iatrogenic caecal perforation and literature review. AB - INTRODUCTION: An iatrogenic caecal perforation is rare, but a serious complication associated with significant morbidity and mortality. We present a 4min and 50s video on a new improvisation undertaken during laparoscopic management of post-polypectomy caecal perforation. PRESENTATION OF CASE: Our patient presented with an acute abdomen following endoscopic polypectomy. At surgery, the site of caecal perforation was close to the appendicular base with devitalization tissue, secondary to diathermy usage. The hallmark of safety within this novel technique included fresh healthy tissue margins within the endoloop (detachable snare ligation) and ensuring no ischemic tissue was gathered. Complete freeing of the appendix and meso-appendicular base was required and securing three endoloops proximal to the site of perforation. The post-operative course was uneventful. DISCUSSION: The World Society of Emergency Surgery (WSES) 2013 guidelines suggested an early laparoscopic approach is a safe and effective treatment for colonoscopy-related colonic perforation. There are no national guidelines and the management is dictated by the clinical condition of the patient, co-morbidity, size and site of perforation as well as the scale of bowel preparation, and surgical experience. CONCLUSION: The endoloop technique described, undertaken during a laparoscopy is a novel approach. It is a simple and effective method, reminding clinicians to adapt techniques when necessary. Nevertheless, it is only limited to perforations around the appendicular base. PMID- 25723745 TI - A case of primary adenocarcinoma of the third portion of the duodenum resected by laparoscopic and endoscopic cooperating surgery. AB - INTRODUCTION: We report a case of primary adenocarcinoma in the third portion of the duodenum (D3) curatively resected by laparoscopic and endoscopic cooperating surgery (LECS). PRESENTATION OF CASE: A 65-year-old woman had a routine visit to our hospital for a follow-up of rectal cancer resected curatively 2 years ago. A routine screening gastroduodenal endoscopy revealed an elevated lesion of 20mm in diameter in the D3. The preoperative diagnosis was adenoma with high-grade dysplasia; however, suspicion about potential adenocarcinoma was undeniable. Curative resection was performed by LECS. Pathological examination revealed intramucosal adenocarcinoma arising from normal duodenal mucosa. The tumor was stage I (T1/N0/M0) in terms of the tumor, nodes, metastasis (TNM) classification. LECS for duodenal tumor has seldom been reported previously, and this is the first report of LECS for primary adenocarcinoma in the D3. The transverse mesocolon was removed from the head of pancreas to expose the duodenum, and the accessory right colic vein was cut; this was followed by the Kocher maneuver for mobilization of the lesion site. DISCUSSION: LECS enabled en bloc resection with adequate surgical margins and secure intra-abdominal suturing. Thorough mobilization of the mesocolon and pancreas head is essential for this procedure because it facilitates correct resection and suturing. CONCLUSION: LECS is a feasible treatment option for duodenal neoplasms, including intramucosal adenocarcinoma, even though it exists in the D3. PMID- 25723746 TI - Creation of gastric conduit free-graft with intraoperative perfusion imaging during pancreaticoduodenectomy in a patient post esophagectomy. AB - As surgery becomes more successful for complicated malignancies, patients survive longer and can unfortunately develop subsequent malignancies. Surgical resection in these settings can be treacherous and manipulations of the patient's anatomy need to be closely considered before embarking on major operations. We report a case of a patient who survived esophageal resection for locally advanced esophageal cancer only to develop a new pancreatic head malignancy. Careful upfront planning allowed for a successful resection with an uncomplicated recovery. She underwent open pancreaticoduodenectomy, and to maintain perfusion to the gastric conduit a microvascular anastomosis of the gastroepiploic pedicle was performed to the middle colic vessels. Intraoperative fluorescent imaging was used to evaluate the anastomosis as well as gastric and duodenal perfusion during the case. PMID- 25723747 TI - Treatment of giant hiatal hernia by laparoscopic Roux-en-Y gastric bypass. AB - INTRODUCTION: Obesity is a risk factor for hiatal hernia. In addition, much higher recurrence rates are reported after standard surgical treatment of hiatal hernia in morbidly obese patients. Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective surgical treatment for morbid obesity and is known to effectively control symptoms of gastroesophageal reflux (GERD). CASE PRESENTATION: Two patients suffering from giant hiatal hernias where a combined LRYGB and hiatal hernia repair (HHR) with mesh was performed are presented in this paper. There were no postoperative complications and at 1 year follow-up, there was no sign of recurrence of the hernia. DISCUSSION: The gold standard for all symptomatic reflux patients is still surgical correction of the paraesophageal hernia, including complete reduction of the hernia sac, resection of the sac, hiatal closure and fundoplication. However, HHR outcome is adversely affected by higher BMI levels, leading to increased HH recurrence rates in the obese. CONCLUSION: Concomitant giant hiatal hernia repair with LRYGB appears to be safe and feasible. Moreover, LRYGB plus HHR appears to be a good alternative for HH patients suffering from morbid obesity as well than antireflux surgery alone because of the additional benefit of significant weight loss and improvement of obesity related co-morbidity. PMID- 25723748 TI - A rare condition: Ectopic liver tissue with its unique blood supply encountered during laparoscopic cholecystectomy. AB - INTRODUCTION: Developmental abnormalities of liver including ectopic liver tissue (ELT) are rare conditions. Few cases presenting ELT have been reported in literature till now. Even though the most common area seen is gallbladder, it is detected both abdominal and thoracic sites. There is a relationship between HCC and ectopic liver that necessitates the removal. PRESENTATION OF CASE: A 51-year old female was hospitalized because of abdominal pain. Gallstone and bile duct dilatation were determined during ultrasonographic (USG) evaluation. The patient was operated for cholecystectomy following a successful endoscopic retrograde cholangiopancreatography (ERCP). During operation, a mass located on gallbladder with its unique vascular support was identified and resected together with gallbladder. The mass had a separate vascular stalk arising from liver parenchyma substance and it was clipped with laparoscopic staples. The histopathological examination revealed that the mass adherent to gallbladder was ectopic liver confirming the intraoperative observation. The postoperative course of patient was uneventfull and she was discharged at the second day after the operation. DISCUSSION: Ectopic liver tissue is incidentally found both in abdominal and thoracic cavity. ELT can rarely be diagnosed before surgical procedures or autopsies. It can be overlooked easily by radiological techniques. Although it does not usually produce any symptom clinically, it can rarely result in serious complications such as bleeding, pyloric and portal vein obstruction. ELT also has the capacity of malignant transformation to hepatocellular carcinoma that makes it essential to be removed. CONCLUSION: Although ELT is rarely seen, it should be removed when recognized in order to prevent the complications and malignant transformation. PMID- 25723749 TI - Gastric mesenteroaxial volvulus with partial eventration of left hemidiaphragm: A rare case report. AB - BACKGROUND: Eventration of diaphragm associated with gastric volvulus is an uncommon condition. CASE PRESENTATION: We reporting a case of a 16-year-old male having left sided diaphragmatic eventration associated with acute mesenteroaxial gastric volvulus. The patient presented with acute pain abdomen and upper abdomen fullness. Plication of left hemidiaphragm with anterior gastropexy was performed through an abdominal approach. Postoperatively the patient's recover uneventfully. CONCLUSION: Symptomatic gastric volvulus associated with diaphragmatic eventration is a surgical emergency and always requires surgical repair. PMID- 25723750 TI - Mobile Versus Fixed Deployment of Automated External Defibrillators in Rural EMS. AB - INTRODUCTION: There is no consensus on where automated external defibrillators (AEDs) should be placed in rural communities to maximize impact on survival from cardiac arrest. In the community of Stokes County, North Carolina (USA) the Emergency Medical Services (EMS) system promotes cardiopulmonary resuscitation (CPR) public education and AED use with public access defibrillators (PADs) placed mainly in public schools, churches, and government buildings. HYPOTHESIS/PROBLEM: This study tested the utilization of AEDs assigned to first responders (FRs) in their private-owned-vehicle (POV) compared to AEDs in fixed locations. METHODS: The authors performed a prospective, observational study measuring utilization of AEDs carried by FRs in their POV compared to utilization of AEDs in fixed locations. Automated external defibrillator utilization is activation with pads placed on the patient and analysis of heart rhythm to determine if shock/no-shock is indicated. The Institutional Review Board of Wake Forest University Baptist Health System approved the study and written informed consent was waived. The study began on December 01, 2012 at midnight and ended on December 01, 2013 at midnight. RESULTS: During the 12-month study period, 81 community AEDs were in place, 66 in fixed locations and 15 assigned to FRs in their POVs. No utilizations of the 66 fixed location AEDs were reported (0.0 utilizations/AED/year) while 19 utilizations occurred in the FR POV AED study group (1.27 utilizations/AED/year; P<.0001). Odds ratio of using a FR POV located AED was 172 times more likely than using a community fixed-location AED in this rural community. Discussion Placing AEDs in a rural community poses many challenges for optimal utilization in terms of cardiac arrest occurrences. Few studies exist to direct rural community efforts in placing AEDs where they can be most effective, and it has been postulated that placing them directly with FRs may be advantageous. CONCLUSIONS: In this rural community, the authors found that placing AED devices with FRs in their POVs resulted in a statistically significant increase in utilizations over AED fixed locations. PMID- 25723751 TI - Thermodynamics of random reaction networks. AB - Reaction networks are useful for analyzing reaction systems occurring in chemistry, systems biology, or Earth system science. Despite the importance of thermodynamic disequilibrium for many of those systems, the general thermodynamic properties of reaction networks are poorly understood. To circumvent the problem of sparse thermodynamic data, we generate artificial reaction networks and investigate their non-equilibrium steady state for various boundary fluxes. We generate linear and nonlinear networks using four different complex network models (Erdos-Renyi, Barabasi-Albert, Watts-Strogatz, Pan-Sinha) and compare their topological properties with real reaction networks. For similar boundary conditions the steady state flow through the linear networks is about one order of magnitude higher than the flow through comparable nonlinear networks. In all networks, the flow decreases with the distance between the inflow and outflow boundary species, with Watts-Strogatz networks showing a significantly smaller slope compared to the three other network types. The distribution of entropy production of the individual reactions inside the network follows a power law in the intermediate region with an exponent of circa -1.5 for linear and -1.66 for nonlinear networks. An elevated entropy production rate is found in reactions associated with weakly connected species. This effect is stronger in nonlinear networks than in the linear ones. Increasing the flow through the nonlinear networks also increases the number of cycles and leads to a narrower distribution of chemical potentials. We conclude that the relation between distribution of dissipation, network topology and strength of disequilibrium is nontrivial and can be studied systematically by artificial reaction networks. PMID- 25723753 TI - [Editorial]. PMID- 25723752 TI - [Robot-assisted minimally invasive lobectomy with systematic lymphadenectomy for lung cancer]. AB - BACKGROUND AND INTRODUCTION: Lobectomy for lung cancer is the standard therapy for lung cancer in limited stages. The adoption of minimally invasive lobectomy (video-assisted thoracic surgery or VATS lobectomy) has increased worldwide since its first description more than 15 years ago. However, the VATS technique has a long learning curve and sometimes limitations in terms of precise preparation and presentability of the central structures of the lung hilus due to the limited mobility of the standard thoracoscopic instruments. By using a four-arm robotic platform (DaVinci(r)), not only the preparation of the hilus structures but also the central lymphadenectomy can be performed in a comfortable and safe way under a clear and precise view. INDICATION: Surgical treatment of locally limited lung cancer in the right lower lobe (squamous cell carcinoma). PROCEDURE: Robot assisted, minimally invasive right lower lobectomy with systematic lymphadenectomy. CONCLUSION: Robot-assisted minimal invasive lobectomy is feasible with special regard to oncological and technical aspects. Especially the intrathoracic precise dissection of the tissue under a perfect view allow a comfortable and safe operation technique. PMID- 25723754 TI - [Report on the 139th Summer Conference of the Society of Northwest German Surgeons, June 19-21, 2014, in Bremen]. PMID- 25723755 TI - [What does the general and abdominal surgeon need to know about radiotherapy? - aspects of radiotherapy in general and abdominal surgery]. AB - Radiooncological therapies are an integral part of the multimodal oncological treatment concepts in general and abdominal surgery. These include therapeutic approaches with a curative intention such as the neoadjuvant (pre-operative) radiotherapy of locoregionally advanced and/or N+ oesophageal and rectal cancer, definitive combined chemoradiotherapy of locally advanced, unresectable oesophageal cancer or oesophageal tumour lesions of the upper third, definitive radiotherapy of anal cancer (sphincter sparing) and pre- or post-operative radiotherapy of soft tissue sarcoma on the one hand. A yT0 stage achieved as characteristic of a curative effect by radiation in oesophageal and rectal cancer (omitting subsequent surgical intervention, naturally under clinical and imaging based controls within short-term follow-up intervals) can be considered as a very interesting set-up with regard to its reasonable integration in daily clinical practice, which needs to be further and critically discussed. By integrating radiotherapy in interdisciplinary therapy concepts, improved tumour control and survival rates with clinically acceptable toxicity can be achieved. On the other hand, non-invasive, locally ablative radiooncological therapies such as extracranial stereotactic body radiotherapy constitute an effective and feasible treatment method for liver metastases in oligometastatic colorectal cancer or other tumour entities according to the decisions by the institutional tumour board, offering high local tumour control rates which can be part of multistep, multimodal procedures with curative intention. This review aims at providing an overview for the general and abdominal surgeon, outlining relevant radiooncological treatment aspects in the multimodal cancer therapy with a focus on the treatment of rectal, oesophageal and anal cancer as well as soft tissue sarcoma and hepatic metastases in oligometastatic colorectal cancer. PMID- 25723757 TI - [Therapy of bronchiectasis]. AB - The prevalence of bronchiectasis not due to cystic fibrosis (NCFB) increases with older age. Because of multifaceted etiology of bronchiectasis an extensive diagnostic approach is essential. This includes in-depth anamnesis and a high resolution CT scan of the chest (HRCT). The pathophysiological mechanism with infection, inflammation, secretion retention and destruction determine the therapeutic options. In patients with high rates of exacerbations and severe diseases physicians should think of inhaled antibiotics and macrolids. In case of localized bronchiectasis and failure of conventional therapy surgery of bronchiectasis is an effective treatment option. In some cases surgery is necessary due to haemoptysis, aspergilloma, lung abscess and pleuraempyema. To improve the treatment options of bronchiectasis results of epidemiological, basically and clinical research trials are expected and needed. PMID- 25723758 TI - Origin and evolution of a new retained intron on the vulcan gene in Drosophila melanogaster subgroup species. AB - Although numerous intron gains have been discovered, the mechanisms of intron creation have proven to be elusive. Previous study revealed that the vulcan gene of Drosophila melanogaster contained four exons in its coding region. In the current study, a newly created intron (Intron L) was identified on exon 2 of vulcan in D. melanogaster by comparing expression sequence tags. The RT-PCR experiment revealed that Intron L was associated with intron retention, in which two alternative transcripts of the gene differ by the inclusion or removal of an intron. It was found that Intron L was created by intronization of exonic sequence, and its donor and acceptor splice sites were created by synonymous mutation, leading to the origin of a new vulcan protein that is 22 amino acids shorter than the previously reported vulcan protein. Moreover, to track the origin of Intron L, 36 orthologous genes of species of Drosophila were cloned or annotated, and phylogenetic analysis was carried out. It indicated that the common ancestor of D. melangaster subgroup species created Intron L about 15 million years ago. PMID- 25723760 TI - Interventions for treating fractures of the patella in adults. AB - BACKGROUND: Fractures of the patella (kneecap) account for around 1% of all human fractures. The treatment of these fractures can be surgical or conservative (such as immobilisation with a cast or brace). There are many different surgical and conservative interventions for treating fractures of the patella in adults. OBJECTIVES: To assess the effects (benefits and harms) of interventions (surgical and conservative) for treating fractures of the patella in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (2 May 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 4), MEDLINE (1946 to April Week 4 2014), Ovid MEDLINE In-Process & Other Non-Indexed Citations (2 May 2014), Embase (1980 to 2014 Week 17), LILACS (1982 to 2 May 2014), trial registers and references lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi RCTs that evaluated any surgical or conservative intervention for treating adults with fractures of the patella were eligible for inclusion. The primary outcomes were patient-rated knee function and knee pain, and major adverse outcomes. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected eligible trials, assessed risk of bias and cross-checked data extraction. Where appropriate, results of comparable trials were pooled. MAIN RESULTS: We included five small trials involving 169 participants with patella fractures. Participant age ranged from 16 to 76 years. There were 68 females and 100 males; the gender of one participant was not reported. Two trials were conducted in China and one each in Finland, Mexico and Turkey.All five trials compared different surgical interventions. Two trials compared biodegradable versus metallic implants for treating displaced patella fractures; one trial compared patellectomy with advancement of vastus medialis obliquus versus simple patellectomy for treating comminuted patella fractures; and two trials compared percutaneous osteosynthesis (both procedures were 'novel' and one used a new device) versus open surgery for treating displaced patella fractures. All the trials had design flaws, such as lack of assessor blinding, which put them at high risk of bias, potentially limiting the reliability of their findings. No trial reported on health-related quality of life, return to previous activity or cosmetic appearance.Very low quality evidence from two trials (48 participants) comparing biodegradable versus metallic implants indicated little difference between the two interventions at two-year follow-up in the numbers of participants with occasional knee pain (1/23 versus 2/24), incurring adverse events (3/24 versus 1/24) or with reduced knee motion (2/23 versus 2/24). Neither trial reported patient-rated knee function scores. In one trial, as per routine practice, metallic implants were removed one year after surgery (four participants). The other trial did not report on this aspect.Very low quality evidence from one trial (28 participants) indicated that compared with simple patellectomy, patellectomy with advancement of vastus medialis obliquus surgery for treating comminuted patella fractures resulted in more participants with a 'good' result based on a subjectively rated score (12/12 versus 11/16; risk ratio (RR) 1.42, 95% confidence interval (CI) 1.01 to 2.01), fewer participants experiencing knee pain (5/12 versus 13/16; RR 3.11, 95% CI 1.01 to 9.60) and more participants with unlimited activity and no loss in quadriceps strength at four-year follow-up. The only adverse event reported was a patellar tendon subluxation in the simple patellectomy group.Neither trial comparing percutaneous osteosynthesis (using novel devices or methods) versus open surgery reported on patient-rated knee function scores. Very low quality evidence from two trials (93 participants) showed that percutaneous osteosynthesis improved knee pain measured using visual analogue scale (0 to 10 where 10 is worst pain) at one month (mean difference (MD) -2.24, 95% CI -2.80 to -1.68) and at up to three months (MD -1.87, 95% CI -2.45 to -1.29). This effect did not persist at six months (very low quality evidence from one trial). Very low quality evidence from the two trials showed significantly fewer participants with adverse events (loss of reduction, infection, hardware complications, delayed wound healing) after percutaneous surgery (8/47 versus 28/46; RR 0.28, 95% CI 0.14 to 0.55). Very low quality evidence from the two trials indicated better clinician-rated knee function scores after percutaneous fixation at two to three months and 12 months follow-up; however, the between-group difference was not clinically important at 24 months. Very low quality evidence showed a lower incidence of hardware removal in the percutaneous group at two years; however, the results in the two trials were heterogeneous and the reasons for removal were not given in detail. AUTHORS' CONCLUSIONS: There is very limited evidence from RCTs about the relative effects of different surgical interventions for treating fractures of the patella in adults. There is no evidence from RCTs evaluating the relative effects of surgical versus conservative treatment or different types of conservative interventions.Based on very low quality evidence, biodegradable implants seem to be no better than metallic implants for displaced patellar fractures; patellectomy with vastus medialis obliquus advancement may give better results than simple patellectomy for comminuted patellar fractures; and two novel methods of percutaneous osteosynthesis may give better results than conventional open surgery. However, until conclusive evidence becomes available, treatment options must be chosen on an individual patient basis, carefully considering the relative benefits and harms of each intervention and patient preferences. Further randomised trials are needed, but in order to optimise research effort, these should be preceded by research that aims to identify priority questions. PMID- 25723759 TI - Surfactant Driven Post-Deposition Spreading of Aerosols on Complex Aqueous Subphases. 1: High Deposition Flux Representative of Aerosol Delivery to Large Airways. AB - BACKGROUND: Aerosol drug delivery is a viable option for treating diseased airways, but airway obstructions associated with diseases such as cystic fibrosis cause non-uniform drug distribution and limit efficacy. Marangoni stresses produced by surfactant addition to aerosol formulations may enhance delivery uniformity by post-deposition spreading of medications over the airway surface, improving access to poorly ventilated regions. We examine the roles of different variables affecting the maximum post-deposition spreading of a dye (drug mimic). METHODS: Entangled aqueous solutions of either poly(acrylamide) (PA) or porcine gastric mucin (PGM) serve as airway surface liquid (ASL) mimicking subphases for in vitro models of aerosol deposition. Measured aerosol deposition fluxes indicate that the experimental delivery conditions are representative of aerosol delivery to the conducting airways. Post-deposition spreading beyond the locale of direct aerosol deposition is tracked by fluorescence microscopy. Aqueous aerosols formulated with either nonionic surfactant (tyloxapol) or fluorosurfactant (FS-3100) are compared with surfactant-free control aerosols. RESULTS: Significant enhancement of post-deposition spreading is observed with surfactant solutions relative to surfactant-free control solutions, provided the surfactant solution surface tension is less than that of the subphase. Amongst the variables considered--surfactant concentration, aerosol flow-rate, total deposited volume, time of delivery, and total deposited surfactant mass- surfactant mass is the primary predictor of maximum spread distance. This dependence is also observed for solutions deposited as a single, microliter-scale drop with a volume comparable to the total volume of deposited aerosol. CONCLUSIONS: Marangoni stress-assisted spreading after surfactant-laden aerosol deposition at high fluxes on a complex fluid subphase is capable of driving aerosol contents over significantly greater distances compared to surfactant-free controls. Total delivered surfactant mass is the primary determinant of the extent of spreading, suggesting a great potential to extend the reach of aerosolized medication in partially obstructed airways via a purely physical mechanism. PMID- 25723761 TI - Regioselective synthesis of substituted arenes via aerobic oxidative [3 + 3] benzannulation reactions of alpha,beta-unsaturated aldehydes and ketones. AB - Facile conversion of alpha,beta-unsaturated aldehydes and ketones into highly substituted arenes via a base-mediated, completely regioselective, air-oxidative [3 + 3] benzannulation reaction with readily available 4-sulfonylcrotonates or 1,3-bisphenylsulfonylpropene is reported. The reaction can also be carried out as a one-pot, three-component operation using 4-bromocrotonates, aryl sulfinates, and cinnamaldehyde. This open-flask, metal-free reaction does not require anhydrous solvents, proceeds under mild conditions, and uses atmospheric oxygen as the oxidant to afford high yields of the 3-(arylsulfonyl)benzoic acid esters. PMID- 25723762 TI - Acute type A aortic dissection repair with mild-to-moderate hypothermic circulatory arrest and selective cerebral perfusion. AB - AIM: The purpose of this study was to evaluate surgical results of aortic repair with antegrade selective cerebral perfusion (ASCP) and mild-to-moderate hypothermia (MH) from 28 to 31 degrees C comparing with previous series with hypothermia from 20 degrees C to 27 degrees C. METHODS: Between 2000 and 2011, 109 consecutive patients underwent surgical repair for acute type A aortic dissection with circulatory arrest and ASCP and MH in our institution. Mean patient age was 67+/-11 years old. Total arch replacement was performed in 85 patients (78%). Thirty (27%) patients had shock status preoperatively. The patients were divided into two different subsets, which is group A (circulatory arrest at less than 27.9 degrees C, N.=70), and group B (at more than 28 degrees C, N.=39). RESULTS: The mean extra-corporeal circulation time was 185+/ 47 minutes in group A and 155+/-38 minutes in group B (P<0.001). The hospital mortality was 11.4% in group A and 10.3% in group B (P>0.05). Permanent neurological deficit occurred in 10 patients (14.3%) in group A, and in 5 (12.8%) in group B (P>0.05). Two (2.8%) paraplegia occurred in group A, and none in group B (P>0.05). The incidence of renal failure requiring hemodialysis was 17.1% in group A and 7.7% in group B, (P>0.05). Respiratory failure after surgery occurred in 27.1% of patients in group A, and 5.1% in group B (P=0.005). CONCLUSION: Circulatory arrest at more than 28 degrees C offered sufficient cerebral and distal organ protection for acute type A aortic dissection. PMID- 25723763 TI - Visuomotor adaptation: how forgetting keeps us conservative. AB - Even when provided with feedback after every movement, adaptation levels off before biases are completely removed. Incomplete adaptation has recently been attributed to forgetting: the adaptation is already partially forgotten by the time the next movement is made. Here we test whether this idea is correct. If so, the final level of adaptation is determined by a balance between learning and forgetting. Because we learn from perceived errors, scaling these errors by a magnification factor has the same effect as subjects increasing the amount by which they learn from each error. In contrast, there is no reason to expect scaling the errors to affect forgetting. The magnification factor should therefore influence the balance between learning and forgetting, and thereby the final level of adaptation. We found that adaptation was indeed more complete for larger magnification factors. This supports the idea that incomplete adaptation is caused by part of what has been learnt quickly being forgotten. PMID- 25723766 TI - Abstracts of the Third Symposium on Primary Breast Cancer in Older Women, March 6, 2015, Nottingham, England. PMID- 25723765 TI - Pharmacokinetics of epsilon-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass. AB - BACKGROUND: Antifibrinolytic medications such as epsilon-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. METHODS: Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). RESULTS: Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h * (WT/70). Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg . kg . h, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. CONCLUSIONS: EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults. PMID- 25723764 TI - AtNIGT1/HRS1 integrates nitrate and phosphate signals at the Arabidopsis root tip. AB - Nitrogen and phosphorus are among the most widely used fertilizers worldwide. Nitrate (NO3(-)) and phosphate (PO4(3-)) are also signalling molecules whose respective transduction pathways are being intensively studied. However, plants are continuously challenged with combined nutritional deficiencies, yet very little is known about how these signalling pathways are integrated. Here we report the identification of a highly NO3(-)-inducible NRT1.1-controlled GARP transcription factor, HRS1, document its genome-wide transcriptional targets, and validate its cis-regulatory elements. We demonstrate that this transcription factor and a close homologue repress the primary root growth in response to P deficiency conditions, but only when NO3(-) is present. This system defines a molecular logic gate integrating P and N signals. We propose that NO3(-) and P signalling converge via double transcriptional and post-transcriptional control of the same protein, HRS1. PMID- 25723767 TI - Biosynthesis of ethyl (S)-4-chloro-3-hydroxybutanoate with an NADH-dependent reductase (ClCR) discovered by genome data mining using a modified colorimetric screening strategy. AB - An NADH-dependent reductase (ClCR) was discovered by genome data mining. After ClCR was overexpressed in E. coli BL21, recombinant E. coli CCZU-T15 with high reductase activity and excellent stereoselectivity for the reduction of ethyl 4 chloro-3-oxobutanoate (COBE) into ethyl (S)-4-chloro-3-hydroxybutanoate [(S) CHBE] was screened using a modified high-throughput colorimetric screening strategy. After the reaction optimization, a highly stereoselective bioreduction of COBE into (S)-CHBE (>99% ee) with the resting cells of E. coli CCZU-T15 was successfully demonstrated in toluene-water (50:50, v/v) biphasic system. Biotransformation of 1000 mM COBE for 24 h in the biphasic system, (S)-CHBE (>99% ee) could be obtained in the high yield of 96.4%. Significantly, E. coli CCZU-T15 shows high potential in the industrial production of (S)-CHBE (>99% ee). PMID- 25723768 TI - A novel photoelectrochemical sensor based on photocathode of PbS quantum dots utilizing catalase mimetics of bio-bar-coded platinum nanoparticles/G quadruplex/hemin for signal amplification. AB - Photocathode based on p-type PbS quantum dots (QDs) combing a novel signal amplification strategy utilizing catalase (CAT) mimetics was designed and utilized for sensitive photoelectrochemical (PEC) detection of DNA. The bio-bar coded Pt nanoparticles (NPs)/G-quadruplex/hemin exhibited high CAT-like activity following the Michaelis-Menten model for decomposing H2O2 to water and oxygen, whose activity even slightly exceeded that of natural CAT. The bio-bar-code as a catalytic label was conjugated onto the surface of PbS QDs modified electrodes through the formed sandwich-type structure due to DNA hybridization. Oxygen in situ generated by the CAT mimetics of the bio-bar-code of Pt NPs/G quadruplex/hemin acted as an efficient electron acceptor of illuminated PbS QDs, promoting charge separation and enhancing cathodic photocurrent. Under optimal conditions, the developed PEC biosensor for target DNA exhibited a dynamic range of 0.2pmol/L to 1.0nmol/L with a low detection limit of 0.08pmol/L. The high sensitivity of the method was resulted from the sensitive response of PbS QDs to oxygen and the highly efficient CAT-like catalytic activity of the bio-bar-coded Pt NPs/G-quadruplex/hemin. PMID- 25723769 TI - Porous carbon with defined pore size as anode of microbial fuel cell. AB - This paper reported a novel anode material, porous carbon with a defined pore size (DPC) matching bacteria, for microbial fuel cell (MFC). The DPC was prepared by using silica spheres as templates and sucrose as carbon precursor. The structure and morphology of the as-prepared DPC were characterized with X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM), and its performance as anode of MFC based on Escherichia coli (E. coli) was evaluated with chronoamperometry, cyclic voltammetry (CV) and polarization curve measurement. The result from SEM demonstrates that pores in the as-prepared DPC are well defined with an average diameter of 400nm, which is a little larger than that of E. coli, and the polarization curve measurement shows that the as-prepared DPC exhibits superior performance as anode material loaded on carbon felt, delivering a power output of 1606mWm(-2), compared to the 402mWm(-2) of naked carbon felt anode, in the solution containing 2g/L glucose. The excellent performance of the as-prepared DPC is attributed to its suitable pore size for accommodating E. coli strain, which facilitates the formation of bacterial biofilm and the electron transfer between bacteria and anode. PMID- 25723770 TI - [Cerebrospinal fluid analysis-based diagnosis in neuroinfections: an update]. PMID- 25723771 TI - [Differential diagnosis of bipolar disorder: historical and clinical implications and perspectives]. AB - In DSM-5, bipolar disorder (BS) is no longer conceptualised as a pure mood disorder together with unipolar depression, but as a bridge between schizophrenia and depressive disorders. This nosological classification is founded on the historical context of the 19th century. In addition to unipolar depression and schizophrenia, schizoaffective disorder, borderline personality disorder and attention-deficit hyperactivity disorder (ADHD) overlap with BS symptomatology. Overlap also exists with somatic diseases such as multiple sclerosis, Cushing's syndrome and syphilis as well as iatrogenic affective syndromes. PMID- 25723772 TI - [Pharmacological cognitive enhancement from a perspective of misuse and addiction]. AB - Pharmacological "cognitive enhancement" (CE) and "pharmacological neuroenhancement" (PN) are different terms to describe the use of diverse substances by healthy individuals aiming at an increase of individual cognitive skills. Targets of CE are an increase of vigilance, attention, concentration, memory and motivation. Substances used for pharmacological CE can be divided into two categories: stimulants and non-stimulants. The sub-group of methylxanthines like caffeine as well as the sub-group of amphetamines like prescription and illicit amphetamine as well as methylphenidate and modafinil belongs to the group of stimulants; antidementives, antidepressants, phytopharmaceutical products like Ginkgo biloba etc. belong to the group of non-stimulants. Prevalence rates depend on the (type of) study and (group of) substances used for CE. And they range from a 1 % lifetime prevalence rate up to 20 % one-year prevalence rate. This review presents stimulant and non-stimulant substances, their limited clinical effects on cognitive skills as well as their prevalence rates and the aspect of misuse and addiction of the above-mentioned substances which belongs to their respective category. PMID- 25723773 TI - [Ketamine--a new treatment option for therapy-resistant depression]. AB - The anaesthetic ketamine has been demonstrated to have an antidepressive effect in several randomised controlled studies. Patients with a severe therapy resistant depression showed response rates of up to 70 % after one single ketamine infusion. In contrast to all other antidepressant treatment options, this effect was already apparent at 24 hours post infusion. However, the antidepressant effect is limited and after two weeks the relapse rate is around 70 %. This review gives a summary of the clinical value of ketamine in the treatment of depression focussing on clinical trials and the therapeutic mechanism of action. PMID- 25723774 TI - [The Basel Interview for Psychosis (BIP): structure, reliability and validity]. AB - BACKGROUND: Although several instruments have been developed to identify patients with an at-risk mental state (ARMS) for psychosis and first episode of psychosis (FEP), up to now there were no instruments for a detailed assessment of risk factors and indicators of emerging psychosis and the temporal development of psychiatric symptoms over the whole life span in these patients. We therefore developed the Basle Interview for Psychosis (BIP). The aim of this study is to describe the development of the BIP and to report about its psychometric properties. METHODS: The BIP is a comprehensive semi-structured interview that was developed for the Basel early detection of psychoses (FePsy) study. Its items were derived from the most important risk factors and indicators of psychosis described in the literature and from several existing instruments. It contains the following six sections: 1) social and physical development and family, 2) signs and symptoms, 3) vulnerability, 4) help-seeking behavior, 5) illness insight, 6) evaluation of the interview. To estimate the inter-rater reliabilities of the items of sections 2 and 3, 20 interviews were conducted and rated by 8 well-trained raters. The factorial structure of the BIP section "signs and symptoms" was explored in a sample of 120 ARMS and 77 FEP patients. On the basis of the discovered factorial structure, we created new subscales and assessed their reliabilities and validities. RESULTS: Of the 153 studied items of sections 2 and 3, 150 (98 %) were rated with sufficiently high agreement (inter rater reliability > 0.4). The items of section "signs and symptoms" could be grouped into 5 subscales with predominantly good to very good internal consistencies, homogeneities, and discriminant and convergent validities. Predictive validities could be demonstrated for the subscales "Positive Psychotic Symptoms", "Disturbance of Thinking" and the total score. DISCUSSION: The BIP is the first interview for comprehensively assessing risk factors and indicators of emerging psychosis and the temporal development of psychiatric symptoms over the whole life span, which has been validated in ARMS and FEP patients. We could show that the BIP has excellent psychometric properties. PMID- 25723775 TI - [Cerebrospinal fluid diagnostics for neuroinfectious diseases]. AB - Cerebrospinal fluid analysis is of prime importance to establish an early diagnosis of central nervous system infections. Beside the basic diagnostics containing CSF white cell count, lactate concentration and protein analysis, the targeted search for agents of bacterial, viral or fungal CNS infectious diseases is essential. Decisive methods are bacterial and fungal staining techniques, microbiological culture methods, nucleic acid amplification and antigen detection methods or indirect identification of pathogens by serologic testings including the determination of pathogen-specific intrathecal immunoglobulin synthesis. Besides imparting basic principles of cerebrospinal fluid analysis, this article focuses on special aspects of detection of infectious agents. Well-directed questions and a close communication between clinician and laboratory allow optimal diagnostic analysis for successful confirmation of the diagnosis and for optimal treatment of the patient. PMID- 25723776 TI - Hebephilia as a sexual disorder. AB - BACKGROUND: The term "hebephilia" describes the sexual preference for minors at an early pubertal body age. For most clinicians the definition of hebephilia is not obvious and not integrated as a separate category in the DSM-5. METHOD: N = 222 self-motivated applicants from the community for the therapy program of the Prevention Project Dunkelfeld in Berlin were assessed concerning their sexual preference towards minors. RESULTS: Approximately two-thirds (n = 153) showed a sexual interest in early pubertal minors (15 % exclusively; 85 % non exclusively). Approximately 95 % reported having sexually abused children and/or having used child abusive images at least once in their lifetime. Hebephiles reported a significantly higher level of clinically relevant distress and personality characteristics, as well as more offense-supportive attitudes compared to normative samples. CONCLUSION: Hebephilia can be differentiated from pedophilia in terms of sexual interest for the body age of the minor. Associated personal distress, deviant personality characteristics as well as sexual behavior problems suggest that hebephilia can fulfill the criteria of a sexual disorder which should be considered in classification systems (DSM, ICD). PMID- 25723777 TI - Upconversion effective enhancement by producing various coordination surroundings of rare-Earth ions. AB - In this manuscript, we present a simple route to enhance upconversion (UC) emission by producing two different coordination sites of trivalent cations in a matrix material and adjusting crystal field asymmetry by Hf(4+) co-doping. A cubic phase, Y3.2Al0.32Yb0.4Er0.08F12, with these structural characteristics was synthesized successfully by introducing a small ion (Al(3+)) into YF3. X-ray diffraction (XRD), nuclear magnetic resonance (NMR), transmission electron microscopy (TEM), X-ray spectroscopy (XPS), and fluorescence spectrophotometry (FS) were employed for its crystalline structure and luminescent property analysis. As a result, the coordination environments of the rare-earth ions were varied more obviously than a hexagonal NaYF4 matrix with the same Hf(4+) co doping concentration, with vertical comparison, UC luminescent intensities of cubic Y3.2Al0.32Yb0.4Er0.08F12 were largely enhanced (~32-80 times greater than that of different band emissions), while the maximum enhancement of hexagonal NaYF4 was by a factor of ~12. According to our experimental results, the mechanism has been demonstrated involving the crystalline structure, crystal field asymmetry, luminescence lifetime, hypersensitive transition, and so on. The study may be helpful for the design and fabrication of high-performance UC materials. PMID- 25723778 TI - Outcome of robotic surgery for endometrial cancer as a function of patient age. AB - OBJECTIVE: This study aimed to evaluate and compare robot-assisted surgical staging on clinical outcomes, including quality of life and survival, as a function of patient age. METHODS: Evaluation and comparison of perioperative morbidity, survival, and postoperative quality of life after prospective accumulation of clinical information including outcome measures for patients with endometrial cancer during the first 5 years of a robotic program, based on the following 3 age categories: women older than 80 years, women between 70 and 80 years, and women younger than 70 years. RESULTS: All consecutive patients with endometrial cancer undergoing robotic surgery (n = 303) were included, with 197 women younger than 70 years, 75 women between 70 and 80 years, and 31 women older than 80 years. There were significantly more patients with advanced stage (stage II to IV in 17%, 34%, and 35%, P = 0.02) and grade 3 disease (26%, 43%, and 58%, P = 0.002) with increasing age. The perioperative data showed similar grade I or II complications (Clavien-Dindo classification) between the groups, but significantly more grade III and IV complications for women older than 80 years compared with women 80 years or younger (10% vs 1%, P = 0.004). The time needed to resume chore activities was significantly shorter for patients 70 years or older than patients younger than 70 years [8.9 (8.7) vs 18.8 (25.5) days, P = 0.048]. Overall, all patients irrespective of age were highly satisfied with the procedure. There was no difference between young and elderly patients for disease free survival (P = 0.99). CONCLUSIONS: Patient's age did not influence minor postoperative morbidity or overall satisfaction after robotic assisted surgery for endometrial cancer. Elderly patients had more major postoperative morbidity but resumed activities quicker than younger patients. PMID- 25723779 TI - Prevalence, classification, and risk factors for postoperative lower extremity lymphedema in women with gynecologic malignancies: a retrospective study. AB - OBJECTIVE: Lower extremity lymphedema (LEL) is a major long-term complication of radical surgery. We aimed to estimate the incidence and grading of LEL in women who underwent lymphadenectomy and to evaluate risk factors associated with LEL. MATERIALS AND METHODS: We retrospectively reviewed 358 patients with cervical, endometrial, and ovarian cancer who underwent transabdominal complete systematic pelvic and para-aortic lymphadenectomy between 1997 and 2011. Lower extremity lymphedema was graded according to criteria of the International Society of Lymphology. Incidence of LEL and its correlation with various clinical characteristics were investigated using Kaplan-Meier survival and Cox proportional hazards methods. RESULTS: Overall incidence of LEL was 21.8% (stage 1, 60%; stage 2, 32%; and stage 3, 8%). Cumulative incidence increased with observation period: 12.9% at 1 year, 20.3% at 5 years, and 25.4% at 10 years. Age, cancer type, stage (International Federation of Gynecology and Obstetrics), body mass index, hysterectomy type, lymphocyst formation, lymph node metastasis, and chemotherapy were not associated with LEL. Multivariate analysis confirmed that removal of circumflex iliac lymph nodes (hazard ratio [HR], 4.28; 95% confidence interval [CI], 2.09-8.77; P < 0.0001), cellulitis (HR, 3.48; 95% CI, 2.03-5.98; P < 0.0001), and number of removed lymph nodes (HR, 0.99; 95% CI, 0.98 0.99; P = 0.038) were independent risk factors for LEL. CONCLUSIONS: Postoperative LEL incidence increased over time. The results of the present study showed a significant correlation with removal of circumflex iliac lymph nodes and cellulitis with the incidence of LEL. Multicenter or prospective studies are required to clarify treatment efficacies. PMID- 25723780 TI - Psychometric properties of Internet-administered measures of health anxiety: an investigation of the Health Anxiety Inventory, the Illness Attitude Scales, and the Whiteley Index. AB - BACKGROUND: The Health Anxiety Inventory (HAI), the Illness Attitude Scales (IAS), and the Whiteley Index (WI) are three of the most widely used health anxiety measures, but their psychometric properties have not been investigated when administered via the Internet. METHODS: We investigated the three instruments' test-retest reliability, internal consistency, convergent, and discriminant validity and sensitivity to change using one sample (n=111) of participants with severe health anxiety and one sample of healthy controls (n=92). RESULTS: The HAI, IAS, and WI showed high test-retest reliability (rs>=.80), good convergent, and discriminant validity and were sensitive to detect change. The HAI and IAS (alphas>=.85), but not the WI (alphas<=.60) demonstrated high internal consistency. CONCLUSIONS: The HAI, IAS, and WI have good psychometric properties, except for the low internal consistency of WI, when used as Internet-administered measures of health anxiety. Using these measures over the Internet offers highly important advantages such as increased ease of administration, reduced attrition, and cost-efficient treatment evaluation. PMID- 25723781 TI - Molecular model of hemoglobin N from Mycobacterium tuberculosis bound to lipid bilayers: a combined spectroscopic and computational study. AB - A singular aspect of the 2-on-2 hemoglobin structures of groups I and II is the presence of tunnels linking the protein surface to the distal heme pocket, supporting the storage and the diffusion of small apolar ligands to/from the buried active site. As the solubility of apolar ligands is greater in biological membranes than in solution, the association of these proteins with biological membranes may improve the efficiency of ligand capture. As very little is known on this subject, we have investigated the interactions between hemoglobin N (HbN), a group I 2-on-2 hemoglobin from the pathogenic Mycobacterium tuberculosis (Mtb), and biological membranes using both experimental techniques and MD simulations. HbN has a potent nitric oxide dioxygenase activity (HbN-Fe2+-O2 + *NO + H2O -> HbN-Fe3+-OH2 + NO3-) that is thought to protect the aerobic respiration of Mtb from inhibition by *NO. Three different membrane compositions were chosen for the studies, representative of the mycobacterial plasma membrane and the mammalian cell membranes. Both the experimental and the modeling results agreed with each other and allow for a detailed molecular description of HbN in association with membranes of different compositions. The results indicated that HbN is a peripheral protein, and the association with the membranes occurred via the pre-A, G, and H helices. In addition, HbN would be allowed to modulate the binding to the membranes via electrostatic interactions between the lipid membranes and the Asp100 residue. In its membrane-bound form the short tunnel of HbN is oriented toward the membrane interior and the other tunnels point toward the solvent. Such protein orientation would facilitate the uptake of nonpolar substrates from the membrane and the release of products to the solvent. It is interesting to note that the pre-A, G, and H helices are conserved among HbN from a few other Mycobacteria. PMID- 25723782 TI - Ru(II)-catalyzed oxidative spiroannulation of 2-arylphenols with alkynes via a C H activation/dearomatization strategy. AB - An intermolecular spiroannulation reaction of appropriately substituted 2 arylphenols with internal alkynes has been developed by using a Ru(II) catalyst and an oxidant. This transformation was realized by a phenol-directed C-H activation, migratory insertion of the alkyne, and subsequent dearomatization of the phenolic ring, providing a broad range of highly functionalized spirocyclic compounds in moderate yields with high regioselectivity. PMID- 25723783 TI - In search for new bonding modes of the methylenedithiolato ligand: novel tri- and tetra-metallic clusters. AB - Building upon our earlier results on the chemistry of diruthenium analogue of pentaborane (9) with heterocumulenes, we continued to investigate the reactivity of arachno-[(Cp*Ru)2(B3H8)(CS2H)], 1, (Cp* = eta(5)-C5Me5) towards group 7 and 8 transition metal carbonyl compounds under photolytic and thermolytic conditions. The metal carbonyl compounds show diverse reactivity pattern with arachno-1. For example, the photolysis of arachno-1 with [Re2(CO)10] yielded [(Cp*Ru)2B3H5(CH2S2){Re(CO)4}2], 2, [(Cp*RuCO)2(MU-H)2(CH2S2){Re(CO)4}{Re(CO)3}], 3 and [(Cp*Ru)2(MU-CO)(MU-H)(CH2S2){Re(CO)3}], 4. The geometry of 2 with a nearly planar eight-membered ring containing heavier transition metals rhenium, ruthenium is unprecedented. Compounds 3 and 4 can be considered as M4 quadrilateral and M3-triangle with a methylenedithiolato ligand attached to the metal centres, respectively. [Mn2(CO)10], on the other hand, reacts with arachno 1 to yield heterometallic binuclear [(Cp*RuCO){Mn(CO)4}(MU-H)(SCH3)], 5 and homocubane [(Cp*Ru)2{Mn(CO)3}-(CS2H2)B3H4], 6. In an attempt to generate group 8 analogues of 2-5, we performed the reaction of arachno-1 with [Fe2(CO)9] and [Ru3(CO)12]. Although, the objective of isolating analogous compounds was not achieved, the reaction with [Fe2(CO)9] led to novel tetrahedral cluster [(Cp*RuCO){(Fe(CO)3}2S(MU-H)], 7. [Ru3(CO)12], in contrast, yielded known compounds [{Cp*Ru(CO)}2B2H6], 9 and [Cp*Ru(CO)2]2, 10. All the cluster compounds have been characterized by mass spectrometry, IR, and (1)H, (11)B, and (13)C NMR spectroscopy, and the geometric structures were unequivocally established by crystallographic analysis of 2-5 and 7. PMID- 25723784 TI - Nematic caps on colloidal particles in a nematogenic liquid under an electric field. AB - We examine the localized nematic regions (caps) on spherical colloidal particles suspended in a nematogenic liquid in the isotropic phase in the bulk by solving the Poisson equation with an orientation-dependent dielectric tensor. These caps appear and grow with an increasing applied electric field. We assume positive dielectric anisotropy of the nematogenic liquid and a high dielectric constant of the particles. Then, the electric field becomes the strongest near the poles of each particle along the field direction, leading to nematic caps. This cap formation occurs continuously for homeotropic anchoring, but is a discontinuous transition otherwise. We also discuss how the nematic caps can be observed in dielectric response, birefringence, and depolarized light scattering. PMID- 25723785 TI - Adsorption of cationic polyacrylamide at the cellulose-liquid interface: a neutron reflectometry study. AB - The layer thickness and density of high molecular weight cationic polyacrylamide (CPAM) adsorbed at the cellulose-water interface was quantified by neutron reflectometry. The thickness of a full monolayer of CPAM of constant molecular weight (13 MD) but different charge densities, adsorbed with or without NaCl (10( 3) M), was studied. Thin cellulose films (40+/-7 A) of roughness <10 A were produced by spin coating a cellulose acetate-acetone solution and regenerating by alkaline hydrolysis. Film smoothness was greatly improved by controlling the concentration of cellulose acetate (0.13 wt%) and the hydrolysis time in sodium methoxide. The adsorption thickness of CPAM (40% charge 13 MD) at the solid-D2O interface was 43+/-4 A on cellulose and 13+/-2 A on silicon, an order of magnitude smaller than the CPAM radius of gyration. At constant molecular weight, the thickness of the CPAM layer adsorbed on cellulose increases with polymer charge density (10+/-1 A at 5%). Addition of 10(-3) M NaCl decreased the thickness of CPAM layer already adsorbed on cellulose. However, the adsorption layer on cellulose of a CPAM solution equilibrated in 10(-3) M NaCl is much thicker (89+/-11 A for 40% CPAM). For high molecular weight CPAMs adsorbed from solution under constant conditions, the adsorption layer can be varied by 1 order of magnitude via control of the variables affecting electrostatic intra- and inter-polymer chain interactions. PMID- 25723786 TI - The dependence of phase change enthalpy on the pore structure and interfacial groups in hydrated salts/silica composites via sol-gel. AB - It was found that the procedures for incorporating hydrated salts into silica, including mixing with sol in an instant (S1 procedure), mixing with sol via drop by drop (S2 procedure) and mixing until the sol forming the gel (S3 procedure), had pronounced effects on the phase change enthalpy of hydrated salts/silica composite via sol-gel process. The discrepancy of phase change enthalpies of the composites with the same content of hydrated salts can be as high as 40 kJ/kg. To unveil the mechanism behind, the pore structure of silica matrix and interfacial functional groups were investigated extensively. It was revealed that different incorporation procedures resulted in distinct pore structure of silica matrix and different intensities of interfacial Si-OH groups. The S3 procedure was beneficial to induce the silica matrix with bigger pore size and fewer Si-OH groups. Consequently, the phase change enthalpy of the hydrated salts/silica composite prepared by this procedure was the highest because of its lower size confinement effects and weaker adsorption by Si-OH groups. This study will provide insight into the preparation of shape-stabilized phase change materials for thermal energy storage applications. PMID- 25723787 TI - Formation of transparent solid lipid nanoparticles by microfluidization: influence of lipid physical state on appearance. AB - HYPOTHESIS: This study investigated the influence of liquid-solid transition and particle size on the optical properties of nanoemulsions. The hypothesis was that the crystallization of lipid droplets influences the nanoemulsion appearance. EXPERIMENTS: Liquid and solid nanoemulsions (10 wt% octadecane, 1-5 wt% sodium dodecylsulfate) were formed by high-pressure microfluidization (5000-28,500 psi) at 45 degrees C. Solid lipid nanoparticles were formed by cooling the nanoemulsions to 5 degrees C and then heating to ambient temperature, whereas liquid nanoemulsions were formed by maintaining them at 25 degrees C. FINDINGS: Results indicated that lipid nanoparticles ranging from 136 nm down to 36 nm were generated, and were stable to particle aggregation. The melting and onset temperatures of the nanoparticles decreased with decreasing particle diameter. Upon crystallization of the lipid, the absorbance increased by about 140% for nanoemulsions with 136 nm particle diameter, but only 5% for nanoemulsions with 36 nm particle diameter. These results were explained in terms of changes in refractive index upon droplet solidification that alter their scattering behavior. These results show that solidification of nanoemulsions results in a shift of the transparent-to-turbid transition regime. The practical consequences for emulsion manufacturers are that solid nanoemulsions must be smaller than liquid nanoemulsions to remain transparent. PMID- 25723788 TI - Light diffusing films fabricated by strawberry-like PMMA/SiO2 composite microspheres for LED application. AB - This paper presents a facile method to fabricate volumetric light diffusing films with high transmittance and haze simultaneously by mimicking the micro- and nanostructure of compound eyes. Strawberry-like polymethyl methacrylate/SiO2 composite microspheres were first prepared via the electrostatic attraction between positively charged PMMA spheres and negatively charged SiO2 nanoparticles, and further blended with polyacrylate latex to produce light diffusing coatings. A novel light diffusing film with hemispherical surface was built by casting the light diffusing coatings on optical-grade PET film. Effects of the sizes of PMMA spheres and SiO2 nanoparticles on the optical properties of light diffusing film were investigated by a haze meter and application on a LED lamp. The best result (transmittance 94.6% and haze 84.2%) was achieved for the strawberry-like composite microspheres based on 1 MUm PMMA spheres and 50 nm SiO2 nanoparticles. The light-diffusing mechanism of the strawberry-like microspheres in the film was discussed. PMID- 25723789 TI - Differential effects of habitual chow-based and semi-purified diets on lipid metabolism in lactating rats and their offspring. AB - Diet during pregnancy and lactation is a critical factor in relation to the health of dams and their offspring. Currently, control diets used in metabolic imprinting studies differ in composition and type, i.e. semi-purified diets (SD) or chow-based diets (ND). The aim of the present study was to determine whether two widely used control diets, a SD and a ND, that mainly differ in fat content (5.08 and 3.26 %, respectively) and its sources (soyabean oil for the SD and cereals and fish for the ND), fibre (6 and 15 %, respectively), and cholesterol (26 and 69 mg/kg diet, respectively) can influence the lipid metabolism of dams and their offspring. Wistar rats were fed either the SD or the ND during pregnancy and lactation. At weaning, SD-fed dams presented severe hepatic steatosis and increased levels of circulating TAG, NEFA and insulin. Importantly, the offspring presented an altered plasma lipid profile. In contrast, the ND allowed for a normal gestation and lactation process, and did not affect the metabolism of offspring. In parallel, virgin rats fed the SD showed no metabolic alterations. A higher intake of SFA and MUFA and a lower consumption of PUFA observed in SD-fed dams during the lactation period could contribute to explaining the observed effects. In conclusion, two different control diets produced very different outcomes in the lipid metabolism of lactating rats and their offspring. The present results highlight the importance of the assessment of the metabolic state of dams when interpreting the results of metabolic programming studies. PMID- 25723790 TI - Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model. AB - An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A pharmacokinetic study in humans demonstrated the enhanced performance of the solid dispersion formulation relative to the HSWG formulation. The Cmax and AUC of the solid dispersion was 2.6 and 1.9 times greater, respectively, compared to the HSWG formulation. In the ASD, the solid dispersion formulation performance was characterized by three main phases: (1) rapid release in the stomach, creating a supersaturated concentration of drug, (2) precipitation in the stomach, and (3) rapid redissolution of the precipitate in the duodenum to concentration levels that are supersaturated relative to crystalline drug. A series of complementary experiments were employed to describe this performance behavior mechanistically. Imaging experiments with a pH indicating dye showed that local pH gradients from meglumine in the solid dispersion formulation were responsible for creating a high initial supersaturation concentration in the stomach. Upon dissipation of meglumine, the drug precipitated in the stomach as an amorphous solid. Because the precipitated drug is in an amorphous form, it can then rapidly redissolve as it transits to the more neutral environment of the duodenum. This unexpected sequence of physical state changes gives a mechanistic explanation for the enhanced in vivo performance of the solid dispersion formulation relative to the HSWG formulation. PMID- 25723791 TI - Prognostic value of MGMT promoter status in non-resectable glioblastoma after adjuvant therapy. AB - BACKGROUND: Methylation of MGMT promoter has been identified as a favourable predictive factor of benefit from XRT/TMZ -> TMZ. Patients with non-resectable glioblastoma (GBM) generally exhibit a poor prognosis, even after XRT/TMZ. Few data are available concerning the predictive value of MGMT promoter methylation in this population. METHODS: This is an observational retrospective study in patients with malignant brain glioma, treated between June 2008 and October 2011 and followed up until April 2012 at the Neurosurgery-Neurotraumatology Unit of the University Hospital of Parma and at the Neurosurgery Unit of IRCCS "ASMN" of Reggio Emilia, Italy. The medical records of an overall number of 174 patients with a newly diagnosed GBM were reviewed. Volumetry analysis of the lesions was performed on pre- and post-operative neuroimaging by Voxar 3D Ebit AET software. The genetic characterization was performed on paraffin embedded tissue from all resected tumours. Isolation of nucleic acids, bisulfite modification of DNA, methylation-specific PCR and sequencing analyses were done mainly on fresh tissue from biopsy withdrawals. Within 3-4 weeks after either biopsy or surgery, patients were assigned to receive XRT/TMZ->TMZ: treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m(2))/TMZ (150-200mg/m(2) per day for 5 days of every 28-day cycle). RESULTS AND DISCUSSION: A total of 55 consecutive patients (23 men, 22 women) fulfilled inclusion criteria consisting of age over 18 years, supratentorial histologically proven primary malignant glioma, complete determination of the MGMT methylation status, no prior history of surgery, XRT and/or chemotherapy, adequate clinical and radiological follow-up no lesser than 6 months. Twenty-three patients underwent neuronavigation needle biopsy (B Group) and thirty-two patients were operated with craniotomy for tumour resection (R Group). The pre-operative mean age was similar between groups (61.7 +/- 10.7 vs 60.3 +/- 11.8 years in the B and R groups respectively; p>0.05). The B groups showed a slightly lower KPS than the R Group (82.1 +/- 17.3 vs 90.3 +/- 14.1 respectively; p>0.05). The mean pre-operative volume of the tumour did not differ between groups (46.2 +/- 40.2 cm(3) vs 44.1 +/- 33.2 cm(3) in the R Group and B Group respectively; p>0.05). The MGMT promoter was methylated in 12 patients (51.2%) of B Group and in 17 patients (53.1%) of R Group. XRT/TMZ -> TMZ was accomplished in 11 patients (47.8%) of B Group and in 24 patients (75%) of R Group; in 24/29 methylated patients (82.8%) and in 11/26 unmethylated patients (42.3%). Survival analysis of methylated vs unmethylated tumours was statistically significant (Log Rank Mantel Cox: 0.019 in B Group and 0.023 in R Group). In B Group the mean overall survival (OS) of methylated patients was 11.4 months (IC 95% 6.5-16.4) vs 4.8 months (95% IC, 2.6-7.0) of unmethylated patients. In R Group the mean OS was 21.7 months (95% IC, 16.9-26.6) for methylated patients and 14.0 months (95% IC, 8.5-19.4) for unmethylated patients. At the multivariate Cox regression analysis conducted on the total population (55 patients), XRT and TMZ were found to be predictive of OS. In the R Group, KPS, XRT and TMZ correlated with a better outcome. In the B Group, XRT and MGMT promoter methylation were favourably related with OS. CONCLUSION: MGMT promoter unmethylation has a predominant unfavourable impact on clinical outcomes even in the subpopulation of patients with non-resectable GBM. The unmethylated MGMT promoter status could be considered the main predictor of poor prognosis in biopsied GBM, due to the greater probability of patients not having benefits from adjuvant therapies and not being able to accomplish XRT/TMZ -> TMZ. The frameless neuronavigation biopsy technique is safe and effective for predictive evaluation and could help in treatment decision making. PMID- 25723793 TI - Make time for writing. PMID- 25723792 TI - Combined measure of neighborhood food and physical activity environments and weight-related outcomes: The CARDIA study. AB - Engagement in healthy lifestyle behaviors likely reflects access to a diverse and synergistic set of food and physical activity resources, yet most research examines discrete characteristics. We characterized neighborhoods with respect to their composition of features, and quantified associations with diet, physical activity (PA), body mass index (BMI), and insulin resistance (IR) in a longitudinal biracial cohort (n=4143; aged 25-37; 1992-2006). We used latent class analysis to derive population-density-specific (=1750 people per sq km) clusters of neighborhood indicators: road connectivity, parks and PA facilities, and food stores/restaurants. In lower population density areas, a latent class with higher food and PA resource diversity (relative to other clusters) was significantly associated with higher diet quality. In higher population density areas, a cluster with relatively more natural food/specialty stores; fewer convenience stores; and more PA resources was associated with higher diet quality. Neighborhood clusters were inconsistently associated with BMI and IR, and not associated with fast food consumption, walking, biking, or running. PMID- 25723794 TI - Should mother-baby rooming-in be the standard of care? PMID- 25723796 TI - Parenting perceptions of low-income mothers. AB - PURPOSE: The purpose of this descriptive qualitative study was to gain understanding of perceptions of low-income pregnant women and mothers about parenting. STUDY DESIGN AND METHODS: Participants were 65 low-income, primarily African American, women in their 20s and 30s who were recruited from a faith based social service center in Memphis, Tennessee. Interviews were conducted by nursing, social work, and psychology students. The existential phenomenological method was used to analyze verbatim responses of participants to vignettes depicting parenting behaviors of hypothetical mothers. RESULTS: Five global themes were identified: (a) Focus on baby's development: "Because I'm the Mother, I'm the First Teacher"; (b) Focus on baby's safety/security: "The Baby Could Be Hurt"; (c) Focus on conveying love: "She Just Wants the Baby to Feel Her Love"; (d) Focus on learning the rules of good childcare: "It's Important to Know the Do's and Don'ts"; and (e) Focus on doing it differently (better) than parents did: "When You Know Better, You Do Better." CLINICAL IMPLICATIONS: Findings suggest that these mothers care deeply about providing a better life for their children than the life they have had. They desire to learn about being the best parents they can be. As nurses, we can help to provide educational opportunities for mothers through a variety of evidence-based interventions delivered across the childbearing years. PMID- 25723795 TI - Skin-to-skin care and breastfeeding in the perioperative suite. AB - Current trends are moving toward immediate skin-to-skin care after birth of a newborn. This is shown to be highly beneficial, both physiologically and emotionally, to the mother and the baby. Strategies and considerations for initiating skin-to-skin care in the perioperative suite immediately after cesarean birth, such as thermoregulation of the baby in the operative suite, equipment, baby and family positioning, and maternal monitoring, are presented. Initiating skin-to-skin care as soon as possible after birth is recommended. PMID- 25723797 TI - Doulas for childbearing women. AB - Doulas are sometimes sought to provide support to women during childbirth. Communication between nurses and doulas is essential to work together effectively and promote the best outcomes for the mother and baby. An understanding of the training and certification of doulas and potential roles and benefits of a doula assisted birth can be the foundation for developing strategies to improve communication and collaboration between doulas and nurses. PMID- 25723798 TI - New hypertension in pregnancy guidelines. PMID- 25723799 TI - Organic baby food. PMID- 25723800 TI - Big data science. PMID- 25723801 TI - Early childhood development in low-income countries. PMID- 25723803 TI - Maternal oxygen administration as an intrauterine resuscitation measure during labor. PMID- 25723807 TI - Anterior Synechiolysis with Healon Needle and Ophthalmic Viscosurgical Devices after Anterior Lamellar Dissection in Penetrating Keratoplasty. AB - PURPOSE: We described a technique to perform anterior synechiolysis with a healon needle and Viscoat(r) ophthalmic viscosurgical devices (OVDs) through anterior lamellar dissection in penetrating keratoplasty. METHODS: OVDs were gently injected between iridocorneal adhesions with a healon needle to make a blunt dissection after anterior lamellar corneal dissection. Anterior synechiolysis at 360 degrees was completed with a healon needle and OVDs. Subsequently, the deep corneal lamella was cut with right and left Troutman-Katzin corneal scissors. 24 interrupted sutures were made with 10-0 nylon suture to implant the donor cornea. RESULTS: In two eyes from two patients, with corneal opacity and nearly total anterior synechiae, clear grafts and relatively deep anterior chambers were achieved. Penetrating keratoplasty with anterior synechiolysis was thus successful with a healon needle and OVDs through lamellar dissection. CONCLUSIONS: Anterior synechiolysis with a healon needle and OVDs through lamellar dissection is a safe and efficient technique for keratoplasty in patients with corneal opacity with anterior synechiae. PMID- 25723808 TI - Contact-Lens-Associated Purpureocillium Keratitis: Risk Factors, Microbiologic Characteristics, Clinical Course, and Outcomes. AB - PURPOSE: To study the risk factors, microbiologic characteristics, clinical course, and outcomes of patients with Purpureocillium keratitis at a tertiary eye care center in south Florida. MATERIALS AND METHODS: All medical records during a seven-year period starting January 1, 2007, were reviewed. Twenty-eight culture proven Purpureocillium keratitis cases with complete medical records presenting to our institution were included in this retrospective, observational case series. Data collected included predisposing factors, therapeutic interventions, treatment duration, and visual outcomes. RESULTS: Twenty patients (71.4%) had a history of soft contact lens use, with only two for therapeutic use. Other identified risk factors were trauma and immunosuppression. Fifteen patients (53.6%) received topical corticosteroid treatment prior to the diagnosis of fungal keratitis. Thirteen patients (46.4%) were on Natamycin treatment prior to Purpureocillium identification. As a group, the average best-corrected visual acuity (BCVA) at presentation was 1.1 logMAR; upon the final evaluation, it was 1.0 logMAR. The BCVA on last evaluation for the eight patients presenting to our institution within two weeks of onset of symptoms was 0.3 log MAR, and all patients in this group responded to medical management. The final BCVA for 20 patients presenting two weeks after onset of symptoms was 1.2 logMAR. There was a significant difference in the final BCVA between Group 1 and Group 2 (p = 0.004), but no difference in steroid use or previous treatments. Previous steroid use tended to extend time to presentation and was significantly associated with a worse final visual outcome (1.2 versus 0.6 logMAR; p = 0.0474). Previous Natamycin use was significantly associated with a worse final visual outcome (1.4 versus 0.6 logMAR; p = 0.014). CONCLUSION: Purpureocillium keratitis can have devastating consequences to visual function and even lead to enucleation. Physicians should make every effort to arrive at an earlier microbiological diagnosis, as this is associated with better outcomes and less need for surgical intervention. The first line use of voriconazole is recommended, and steroid use should be avoided, as their previous use is associated with worse visual outcomes. PMID- 25723809 TI - Serum cystatin C level is associated with carotid intima-media thickening and plaque. AB - BACKGROUND AND AIM: Chronic kidney disease has recently been shown to be a major risk factor for cardiovascular disease and carotid intima-media thickness has been widely used as a biomarker for early detection of cardiovascular disease. The aim of this study was to confirm whether carotid thickening and carotid plaque are associated with preclinical chronic kidney disease in individuals without clinical cardiovascular disease and chronic kidney disease. MATERIAL AND METHODS: We conducted a cross-sectional study on participants from Maanshan City, China. All participants underwent carotid ultrasonography. Kidney function was measured using cystatin C, serum creatinine, blood urea nitrogen and blood uric acid. Demographics and risk factors for cardiovascular diseases were obtained from each participant. RESULTS: A total of 927 subjects were surveyed; 453 (48.87%) were men and 474 (51.13%) were women. A total of 525 (56.63%) of the participants were found to have carotid thickening of which 281 (53.52%) were men and 244 (46.48%) were women. Kidney function was strongly associated with carotid thickening and plaque in the unadjusted analysis. However, cystatin C was the only measure of kidney function that was significantly associated with carotid thickening and plaque in the adjusted analysis (in order to select risk factors from sex, age, BMI, hypertension, diabetes, smoking, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, apolipoprotein A, apolipoprotein B, cystatin C, creatinine, blood urea nitrogen, blood uric, estimated GFR). CONCLUSION: Cystatin C, an alternative measure of kidney function, was more strongly associated with carotid thickening and plaque than other measures of kidney function. PMID- 25723810 TI - Avianbase: a community resource for bird genomics. AB - Giving access to sequence and annotation data for genome assemblies is important because, while facilitating research, it places both assembly and annotation quality under scrutiny, resulting in improvements to both. Therefore we announce Avianbase, a resource for bird genomics, which provides access to data released by the Avian Phylogenomics Consortium. PMID- 25723811 TI - New approach to fully ordered fct-FePt nanoparticles for much enhanced electrocatalysis in acid. AB - Fully ordered face-centered tetragonal (fct) FePt nanoparticles (NPs) are synthesized by thermal annealing of the MgO-coated dumbbell-like FePt-Fe3O4 NPs followed by acid washing to remove MgO. These fct-FePt NPs show strong ferromagnetism with room temperature coercivity reaching 33 kOe. They serve as a robust electrocatalyst for the oxygen reduction reaction (ORR) in 0.1 M HClO4 and hydrogen evolution reaction (HER) in 0.5 M H2SO4 with much enhanced activity (the most active fct-structured alloy NP catalyst ever reported) and stability (no obvious Fe loss and NP degradation after 20 000 cycles between 0.6 and 1.0 V (vs RHE)). Our work demonstrates a reliable approach to FePt NPs with much improved fct-ordering and catalytic efficiency for ORR and HER. PMID- 25723812 TI - The Predictive Role of ERCC1 Status in Oxaliplatin Based Neoadjuvant Therapy for Metastatic Colorectal Cancer (mCRC) to the Liver. AB - Increased expression of excision repair cross-complementing 1 (ERCC1) in mCRC patients could be related to their response to Oxaliplatin based chemotherapy. We evaluated ERCC1 mRNA expression levels in primary bowel and liver metastases of 51 patients, and correlated with pathologic parameters and clinical outcomes. A significant negative correlation was detected between primary tumor ERCC1 and both the extent of clear surgical margins (P = 0.0011) and the percent of liver metastasis necrosis (P = 0.0167). No relationship was observed between ERCC1 expression and survival. Further study is needed to assess the promising role of ERCC1 expression as a predictive marker benefiting subgroups for Oxaliplatin. PMID- 25723813 TI - Previous physicochemical stress exposures influence subsequent resistance of Escherichia coli O157:H7, Salmonella enterica, and Listeria monocytogenes to ultraviolet-C in coconut liquid endosperm beverage. AB - This study investigated the influences of prior exposures to common physicochemical stresses encountered by microorganisms in food and food processing ecologies such as acidity, desiccation, and their combinations, on their subsequent susceptibility towards UV-C treatment in coconut liquid endosperm beverage. Cocktails of Escherichia coli O157:H7, Salmonella enterica, and Listeria monocytogenes were separately subjected to gradually acidifying environment (final pH 4.46), exposed to abrupt desiccation by suspension in saturated NaCl solution (aw=0.85) for 4, 8, and 24h, and sequential acidic and desiccated stresses before suspending in the coconut beverage for UV-C challenge. The exposure times (D) and UV-C energy dose values (DUV-C) necessary to reduce 90% of the population of the different test organisms varied with previous exposures to different sublethal stresses, indicating possible influence of implicit microbial factors towards resistance to UV-C. All tested individual and combined stresses resulted in increased resistance, albeit some were not statistically significant. Non-stressed cells had D values of 3.2-3.5s, and corresponding DUV-C values of 8.4-9.1 mJ/cm(2). Cells exposed to previous acid stress had D values of 4.1-4.8s and corresponding DUV-C values of 10.7-12.5 mJ/cm(2). Prior exposure to desiccation resulted in D values of 5.6-7.9s and DUV C values of 14.7-20.6 mJ/cm(2), while exposure to combined acid and desiccation stresses resulted in D values of 6.1-8.1s and DUV-C values of 15.9-21.0 mJ/cm(2). The D and DUV-C values of S. enterica after previous exposure to sequential acid (24 h) and desiccation (24 h) stresses were found significantly greatest, making the organism and physiological state an appropriate reference organism for the establishment of UV-C pasteurization process for the beverage. PMID- 25723814 TI - Rapid responses and mechanism of action for low-dose bisphenol S on ex vivo rat hearts and isolated myocytes: evidence of female-specific proarrhythmic effects. AB - BACKGROUND: Bisphenol S (BPS) has increasingly been used as a substitute for bisphenol A (BPA) in some "BPA-free" consumer goods and in thermal papers. Wide human exposure to BPS has been reported; however, the biological and potential toxic effects of BPS are poorly understood. OBJECTIVE: In this study, we sought to elucidate the sex-specific rapid effect of BPS in rat hearts and its underlying mechanism. METHODS: We examined the rapid effects of BPS in rat hearts using electrophysiology, confocal and conventional fluorescence imaging, and immunoblotting. Treatment was administered via acute perfusion of excised hearts or isolated cardiac myocytes. RESULTS: In female rat hearts acutely exposed to 10 9 M BPS, the heart rate was increased; in the presence of catecholamine-induced stress, the frequency of ventricular arrhythmia events was markedly increased. BPS-exposed hearts showed increased incidence of arrhythmogenic-triggered activities in female ventricular myocytes and altered myocyte Ca2+ handling, particularly spontaneous Ca2+ release from the sarcoplasmic reticulum. The dose responses of BPS actions were inverted U-shaped. The impact of BPS on myocyte Ca2+ handling was mediated by estrogen receptor beta signaling and by rapid increases in the phosphorylation of key Ca2+ handling proteins, including ryanodine receptor and phospholamban. The proarrhythmic effects of BPS were female specific; male rat hearts were not affected by BPS at the organ, myocyte, or protein levels. CONCLUSION: Rapid exposure to low-dose BPS showed proarrhythmic impact on female rat hearts; these effects at the organ, cellular, and molecular levels are remarkably similar to those reported for BPA. Evaluation of the bioactivity and safety of BPS and other BPA analogs is necessary before they are used as BPA alternatives in consumer products. PMID- 25723815 TI - Neutral space analysis for a Boolean network model of the fission yeast cell cycle network. AB - BACKGROUND: Interactions between genes and their products give rise to complex circuits known as gene regulatory networks (GRN) that enable cells to process information and respond to external stimuli. Several important processes for life, depend of an accurate and context-specific regulation of gene expression, such as the cell cycle, which can be analyzed through its GRN, where deregulation can lead to cancer in animals or a directed regulation could be applied for biotechnological processes using yeast. An approach to study the robustness of GRN is through the neutral space. In this paper, we explore the neutral space of a Schizosaccharomyces pombe (fission yeast) cell cycle network through an evolution strategy to generate a neutral graph, composed of Boolean regulatory networks that share the same state sequences of the fission yeast cell cycle. RESULTS: Through simulations it was found that in the generated neutral graph, the functional networks that are not in the wildtype connected component have in general a Hamming distance more than 3 with the wildtype, and more than 10 between the other disconnected functional networks. Significant differences were found between the functional networks in the connected component of the wildtype network and the rest of the network, not only at a topological level, but also at the state space level, where significant differences in the distribution of the basin of attraction for the G1 fixed point was found for deterministic updating schemes. CONCLUSIONS: In general, functional networks in the wildtype network connected component, can mutate up to no more than 3 times, then they reach a point of no return where the networks leave the connected component of the wildtype. The proposed method to construct a neutral graph is general and can be used to explore the neutral space of other biologically interesting networks, and also formulate new biological hypotheses studying the functional networks in the wildtype network connected component. PMID- 25723816 TI - Wavelength tunable microdisk cavity light source with a chemically enhanced MoS2 emitter. AB - In this work, we report an integrated narrowband light source based on thin MoS2 emissive material coupled to the high quality factor whispering gallery modes of a microdisk cavity with a spatial notch that enables easy out-coupling of emission while it yields high spatial coherence and a Gaussian intensity distribution. The active light emitting material consists of chemically enhanced bilayer MoS2 flakes with a thin atomic layer deposited SiO2 protective coating that yields 20-times brighter chemically enhanced photoluminescence compared to as-exfoliated monolayers on the microdisk. Quality factors ~ 1000 are observed as well as a high degree of spatial coherence. We also experimentally achieve effective index tuning of cavity coupled emission over a full free spectral range. The thermal response of this system is also studied. This work provides new insights for nanophotonic light sources with atomically thin active media. PMID- 25723817 TI - Critical effect of pore characteristics on capillary infiltration in mesoporous films. AB - Capillary phenomena governing the mass-transport (capillary filling, condensation/evaporation) has been experimentally investigated in around 20 different silica thin films exhibiting various porosities with pores dimension ranging from 2 to 200 nm. Films have been prepared by sol-gel chemistry combined with soft-templating approaches and controlled dip coating process. Environmental ellipsometric porosimetry combined with electronic microscopy were used to assess the porosity characteristics. Investigation of lateral capillary filling was performed by following the natural infiltration of water and ionic liquids at the edge of a sessile drop in open air or underneath a PDMS cover. The Washburn model was applied to the displacement of the liquid front within the films to deduce the kinetic constants. The role of the different capillary phenomena were discussed with respect to the porosity characteristics (porosity vol%, pore dimensions and constrictions). We show that correlation between capillary filling rate and pore dimensions is not straightforward. Generally, with a minimum of constrictions, faster filling is observed for larger pores. In the case of mesopores (<50 nm in diameter), the presence of bottle necks considerably slows down the infiltration rate. At such a small dimension, evaporation/capillary condensation dynamics, taking place at the meniscus inside the porosity, has to be considered to explain the transport mode. This fundamental study is of interest for applications involving liquids at the interface of mesoporous networks such as nanofluidics, purification, separation, water harvesting or heat transfer. PMID- 25723818 TI - Vitamin D, the gut microbiome, and the hygiene hypothesis. How does asthma begin? PMID- 25723819 TI - Predictive genetic profiles for beta-agonist therapy in asthma. A future under construction. PMID- 25723820 TI - Cysteinyl leukotrienes: an innate system for epithelial control of airway smooth muscle proliferation? PMID- 25723821 TI - The promise and peril of functional genomics in chronic obstructive pulmonary disease. PMID- 25723822 TI - Occupational exposures and chronic obstructive pulmonary disease. Causality established, time to focus on effect and phenotypes. PMID- 25723823 TI - On the tricks alveolar epithelial cells play to make a good lung. PMID- 25723824 TI - Disseminated tuberculosis in a patient treated with biologics. PMID- 25723825 TI - Diffuse cerebral microbleeds after extracorporeal membrane oxygenation support. PMID- 25723826 TI - Treating pulmonary silicosis by blocking interleukin 1. PMID- 25723827 TI - Air contamination with bacteria in cystic fibrosis clinics: implications for prevention strategies. PMID- 25723828 TI - Vascular receptor autoantibodies in pulmonary arterial hypertension. PMID- 25723829 TI - Reply: vascular receptor autoantibodies in pulmonary arterial hypertension. PMID- 25723830 TI - The future of nursing is now. PMID- 25723831 TI - Moving the needle forward: the imperative for collaboration in vascular access. PMID- 25723833 TI - A community collaborative to develop consensus guidelines to standardize out-of hospital maintenance care of central venous catheters. AB - Central venous catheter (CVC) maintenance is integral to preventing complications and improving outcomes. This process is made more challenging when patients transition from hospital to home care or to an outpatient infusion setting, because different CVC maintenance practices and care parameters confuse patients and care providers alike. Through collaboration and consensus building, a group of metropolitan home health and home infusion agencies developed a standardized approach to CVC maintenance care. This article discusses the multiagency collaborative and resulting guideline and other educational materials that better enable providers, patients, and families to maintain CVC integrity and achieve optimal outcomes. PMID- 25723832 TI - Transfusion reaction identification and management at the bedside. AB - Blood product transfusion is one of the most common invasive procedures performed in the health care setting. In contrast to pharmaceuticals, blood is actually a liquid transplant. Transfusion complications consequently encompass complex biological processes and infectious possibilities. Changes in vital signs are regularly seen during transfusion. Knowledge of common transfusion reaction signs and symptoms enables the clinical team to differentiate a normal patient response from a life-threatening reaction. Direct care nurses responsible for this procedure play a vital role in its success. Understanding the possible complications of transfusion and how to quickly recognize reactions at the bedside helps ensure the best patient outcomes. PMID- 25723834 TI - A comprehensive review of clinical nurse specialist-led peripherally inserted central catheter placement in Korea: 4101 cases in a tertiary hospital. AB - Peripherally inserted central catheters (PICCs) are expected to be convenient and reliable venous access devices. The purpose of this study was to analyze clinical nurse specialist (CNS)-led PICC placement and to describe its growth in a tertiary hospital. A computerized database identified 3508 patients who had PICCs placed between November 2001 and June 2010. One thousand, eight hundred ninety eight of the 4101 PICCs were available for complete follow-up, and 791 of 1898 PICCs were still in place. The mean dwell time of 1898 PICCs was 27.4 days (1~422 days). Most PICCs were removed after the completion of infusion therapy; the remainder were removed following death, occlusion, suspected infection, or phlebitis, or were removed by the patient. The study found that CNS-led PICC placement for infusion therapies was effective and safe with relatively low complication rates and that CNSs played important roles in the increased use of PICCs. PMID- 25723835 TI - Neonatal late-onset sepsis following peripherally inserted central catheter removal: association with antibiotic use and adverse line events. AB - The objective of the study was to evaluate incidence of and risk factors for sepsis following peripherally inserted central catheter (PICC) removal. The retrospective cohort study looked at neonatal intensive care unit patients with PICC placement between February 2003 and June 2010 at a single medical center in the United States. Results showed that 14/216 patients (6.5%) had sepsis within 5 days of PICC removal. PICC removal because of adverse events was significantly associated with sepsis (P = .017). Antibiotic use before PICC removal did not have a significant impact on sepsis. The conclusions of the study are that removal of PICCs because of adverse events is significantly associated with late onset neonatal sepsis and that antibiotic use at the time of PICC removal is not associated with a decline in sepsis rate. PMID- 25723836 TI - Development of an intravenous skills module for graduate nurses. AB - Graduate nurses (GNs) are a major part of hospital recruitment. Forty-two percent of new hires are likely to be GNs. Many GNs feel ill prepared in intravenous (i.v.) catheter insertion and central line care. The purpose of this evidence based practice project was to determine if an i.v. skills workshop would have a positive impact on GNs' comfort and skills. Casey-Fink Graduate Nurse Experience Survey data indicate that 29% of graduate nurse residents participating in the first cohort of this workshop list i.v. skills as most challenging. Postsurvey data showed that GN comfort level improved. Supporting the GN in this challenging transition by providing focused education and skills practice may alleviate this discomfort. PMID- 25723837 TI - The effect of a safe zone on nurse interruptions, distractions, and medication administration errors. AB - Patient safety is a health care priority. Yet medical errors are ranked the eighth leading cause of death. Medication administration errors (MAEs) often result from multiple environmental and individual factors. This quality improvement initiative adapted a protocol based on airline industry safety measures to decrease nurse distractions and interruptions during medication administration, with the goal of decreasing MAEs. Sources of distractions, interruptions, and MAEs were measured pre and post intervention. Patient satisfaction scores were measured concurrently. Results of this initiative differ from previous studies in which similar interventions reduced both distractions and MAEs. An unexpected finding was dramatically increased patient satisfaction. PMID- 25723839 TI - HNTf2-catalyzed regioselective preparation of polysubstituted naphthalene derivatives through alkyne-aldehyde coupling. AB - We report herein the preparation of polysubstituted naphthalene derivatives by the original Bronsted-acid-catalyzed benzannulation reaction of phenylacetaldehydes with alkynes. This reaction, which was usually performed with Lewis acids under thermal activation, is efficiently promoted by 15 mol % of triflimide (HNTf2) at room temperature under metal-free and mild reaction conditions and leads with a perfect regioselectivity to a wide variety of diversely functionalized naphthalenes in 41-78% yield. A catalytic cycle is proposed together with some further applications of this catalytic system in the related benzannulation transformations of epoxide and acetal derivatives. PMID- 25723841 TI - Binary and Bidisperse Polymer Brushes: Coexisting Surface States. AB - In the present work, we consider polydispersity effects on a mixed polymer brush. Two types of polymer chains with different solvent selectivity being densely grafted together onto an impenetrable surface are forming a binary mixed polymer brush. Using a numerical quasi off-lattice self-consistent field method for heterogeneous chains we study the brush profile upon varying the strength of solvent selectivity (e.g., temperature) and the degree of polymerization of the two chain types (N1 and N2, respectively). For a monodisperse brush (N1 = N2) it is well-known, that the two types of polymers segregate into a two-layer structure, if the difference in solvent selectivity is increased. The state where the chains exposed to their good solvent forming the top layer of the brush can be frustrated for shorter chains and an inversion of the layering takes place. In the inverted state, the top layer is formed by long chains exposed to poor solvent covering the layer of shorter chains. By varying the solvent selectivity of the long chains we show that coexistence of the two states occurs,which indicates a discontinuous phase transition scenario for the switching process. We consider further the case of a very low fraction of short chains and find these chains to undergo a conformational transition of first order from a "coil" state, found deep inside the compact brush layer, to a "flower" state, stretching to the top of the brush upon varying the strength of the solvent selectivity. At the transition both states are found to be quasi-stable with an energy barrier of the order of the chain length in units of kBT. The discontinuous nature of the switching process by combining solvent selectivity and bidispersity can be of high interest for the creation of stimuli-responsive surfaces. PMID- 25723840 TI - Trapping hydrogen sulfide (H2S) with diselenides: the application in the design of fluorescent probes. AB - Here we report a unique reaction between phenyl diselenide-ester substrates and H2S to form 1,2-benzothiaselenol-3-one. This reaction proceeded rapidly under mild conditions. Thiols could also react with the diselenide substrates. However, the resulted S-Se intermediate retained high reactivity toward H2S and eventually led to the same cyclized product 1,2-benzothiaselenol-3-one. Based on this reaction two fluorescent probes were developed and showed high selectivity and sensitivity for H2S. The presence of thiols was found not to interfere with the detection process. PMID- 25723842 TI - Screening for Chronic Obstructive Pulmonary Disease (COPD) in an Urban HIV Clinic: A Pilot Study. AB - Increased smoking and a detrimental response to tobacco smoke in the lungs of HIV/AIDS patients result in an increased risk for COPD. We aimed to determine the predictive value of a COPD screening strategy validated in the general population and to identify HIV-related factors associated with decreased lung function. Subjects at least 35 years of age at an HIV clinic in New York City completed a COPD screening questionnaire and peak flow measurement. Those with abnormal results and a random one-third of normal screens had spirometry. 235 individuals were included and 89 completed spirometry. Eleven (12%) had undiagnosed airway obstruction and 5 had COPD. A combination of a positive questionnaire and abnormal peak flow yielded a sensitivity of 20% (specificity 93%) for detection of COPD. Peak flow alone had a sensitivity of 80% (specificity 80%). Abnormal peak flow was associated with an AIDS diagnosis (p=0.04), lower nadir (p=0.001), and current CD4 counts (p=0.001). Nadir CD4 remained associated in multivariate analysis (p=0.05). Decreased FEV1 (<80% predicted) was associated with lower CD4 count nadir (p=0.04) and detectable current HIV viral load (p=0.01) in multivariate analysis. Questionnaire and peak flow together had low sensitivity, but abnormal peak flow shows potential as a screening tool for COPD in HIV/AIDS. These data suggest that lung function may be influenced by HIV-related factors. PMID- 25723843 TI - How do regulatory networks evolve and expand throughout evolution? AB - Throughout evolution, regulatory networks need to expand and adapt to accommodate novel genes and gene functions. However, the molecular details explaining how gene networks evolve remain largely unknown. Recent studies demonstrate that changes in transcription factors contribute to the evolution of regulatory networks. In particular, duplication of transcription factors followed by specific mutations in their DNA-binding or interaction domains propels the divergence and emergence of new networks. The innate promiscuity and modularity of regulatory networks contributes to their evolvability: duplicated promiscuous regulators and their target promoters can acquire mutations that lead to gradual increases in specificity, allowing neofunctionalization or subfunctionalization. PMID- 25723844 TI - Solvent-tuned dual emission: a structural and electronic interplay highlighting a novel planar ICT (OPICT). AB - Displaying a dual emission, a Phen-PENMe2 compound can be foreseen as a new model for fundamental studies. It is based on an excited state cumulene-type structure, involving orthogonal pi orbital (OPICT). In contrast to the "Twisted Intramolecular Charge Transfer" (TICT) emission, the OPICT emissive state is planar. This new compound is also a potential candidate for local ratiometric probes of medium polarity (mixture of solvents and biological systems) and white emission. PMID- 25723845 TI - Improved Surgical Outcomes for ACS NSQIP Hospitals Over Time: Evaluation of Hospital Cohorts With up to 8 Years of Participation. AB - BACKGROUND: The American College of Surgeons, National Surgical Quality Improvement Program (ACS NSQIP) surgical quality feedback models are recalibrated every 6 months, and each hospital is given risk-adjusted, hierarchical model, odds ratios that permit comparison to an estimated average NSQIP hospital at a particular point in time. This approach is appropriate for "relative" benchmarking, and for targeting quality improvement efforts, but does not permit evaluation of hospital or program-wide changes in quality over time. We report on long-term improvement in surgical outcomes associated with participation in ACS NSQIP. STUDY DESIGN: ACS NSQIP data (2006-2013) were used to create prediction models for mortality, morbidity (any of several distinct adverse outcomes), and surgical site infection (SSI). For each model, for each hospital, and for year of first participation (hospital cohort), hierarchical model observed/expected (O/E) ratios were computed. The primary performance metric was the within-hospital trend in logged O/E ratios over time (slope) for mortality, morbidity, and SSI. RESULTS: Hospital-averaged log O/E ratio slopes were generally negative, indicating improving performance over time. For all hospitals, 62%, 70%, and 65% of hospitals had negative slopes for mortality, morbidity, and any SSI, respectively. For hospitals currently in the program for at least 3 years, 69%, 79%, and 71% showed improvement in mortality, morbidity, and SSI, respectively. For these hospitals, we estimate 0.8%, 3.1%, and 2.6% annual reductions (with respect to prior year's rates) for mortality, morbidity, and SSI, respectively. CONCLUSIONS: Participation in ACS NSQIP is associated with reductions in adverse events after surgery. The magnitude of quality improvement increases with time in the program. PMID- 25723846 TI - Surface engineered CuO nanowires with ZnO islands for CO2 photoreduction. AB - Large arrays of massively parallel (10(8) cm(-2)) CuO nanowires were surface engineered with dense ZnO islands using a few pulsed cycles of atomic layer deposition (ALD). These nanowires were subjected to UV-vis radiation-based CO2 photoreduction under saturated humidity (CO2 + H2O mixture) conditions. We monitored CO2 to CO conversion, indicating the viability of these nanostructures as potential photocatalysts. High-resolution transmission electron microscopy and atomic force microscopy indicated an island growth mechanism of ZnO epitaxially depositing on pristine, single crystal CuO nanowire surface. Photoluminescence and transient absorption spectroscopy showed a very high density of defects on these ZnO islands which trapped electrons and enhanced their lifetimes. Peak CO conversion (1.98 mmol/g-cat/hr) and quantum efficiency (0.0035%) were observed in our setup when the ZnO islands impinged each other at 1.4 nm (8 cycles of ALD) diameter; at which point ZnO island perimeter lengths maximized as well. A mechanism whereby simultaneous H2O oxidation and CO2 reduction occurred in the active perimeter region between CuO nanowire and ZnO islands is proposed to explain the observed photoconversion of CO2 to CO. PMID- 25723847 TI - The induction of Ethylene response factor 3 (ERF3) in potato as a result of co inoculation with Pseudomonas sp. R41805 and Rhizophagus irregularis MUCL 41833 - a possible role in plant defense. AB - Colonization of plant rhizosphere/roots by beneficial microorganisms (e.g. plant growth promoting rhizobacteria - PGPR, arbuscular mycorrhizal fungi - AMF) confers broad-spectrum resistance to virulent pathogens and is known as induced systemic resistance (ISR) and mycorrhizal-induced resistance (MIR). ISR or MIR, an indirect mechanism for biocontrol, involves complex signaling networks that are regulated by several plant hormones, the most important of which are salicylic acid (SA), jasmonic acid (JA) and ethylene (ET). In the present study, we investigated if inoculation of potato plantlets with an AMF (Rhizophagus irregularis MUCL 41833) and a PGPR (Pseudomonas sp R41805) either alone or in combination, could elicit host defense response genes in the presence or absence of Rhizoctonia Solani EC-1, a major potato pathogen. RT-qPCR revealed the significant expression of ethylene response factor 3 (EFR3) in mycorrhized potato plantlets inoculated with Pseudomonas sp R41805 and also in mycorrhized potato plantlets inoculated with Pseudomonas sp R41805 and challenged with R. solani. The significance of ethylene response factors (ERFs) in pathogen defense has been well documented in the literature. The results of the present study suggest that the dual inoculation of potato with PGPR and AMF may play a part in the activation of plant systemic defense systems via ERF3. PMID- 25723848 TI - The potential of chiroptical and vibrational spectroscopy of blood plasma for the discrimination between colon cancer patients and the control group. AB - Colorectal cancer is one of the most abundant causes of cancer deaths in the world. At an early stage, the established clinical procedures have low reliability and sensitivity. Therefore, we tested a novel approach based on chiroptical methods such as electronic circular dichroism (ECD) and Raman optical activity (ROA). These methods are suitable for detecting slight changes in the 3D structure of chiral biomolecules, some of which may be caused by pathological processes occurring during cancer growth. Fifty-five blood plasma samples were analyzed using the combination of ECD and ROA supplemented by conventional Raman and FT-IR spectroscopy. All obtained spectra were evaluated together by linear discriminant analysis. The accuracy of sample discrimination reached 100% and the subsequent leave-one-out cross-validation resulted in 93% sensitivity and 81% specificity. The achieved results indicate that chiroptical methods supplemented by Raman and FT-IR spectroscopy might be new supporting and minimally invasive tools in the clinical diagnosis of colon cancer. PMID- 25723849 TI - Assembly and structure of Lys33-linked polyubiquitin reveals distinct conformations. AB - Ubiquitylation regulates a multitude of biological processes and this versatility stems from the ability of ubiquitin (Ub) to form topologically different polymers of eight different linkage types. Whereas some linkages have been studied in detail, other linkage types including Lys33-linked polyUb are poorly understood. In the present study, we identify an enzymatic system for the large-scale assembly of Lys33 chains by combining the HECT (homologous to the E6-AP C terminus) E3 ligase AREL1 (apoptosis-resistant E3 Ub protein ligase 1) with linkage selective deubiquitinases (DUBs). Moreover, this first characterization of the chain selectivity of AREL1 indicates its preference for assembling Lys33- and Lys11-linked Ub chains. Intriguingly, the crystal structure of Lys33-linked diUb reveals that it adopts a compact conformation very similar to that observed for Lys11-linked diUb. In contrast, crystallographic analysis of Lys33-linked triUb reveals a more extended conformation. These two distinct conformational states of Lys33-linked polyUb may be selectively recognized by Ub-binding domains (UBD) and enzymes of the Ub system. Importantly, our work provides a method to assemble Lys33-linked polyUb that will allow further characterization of this atypical chain type. PMID- 25723850 TI - Tyrosol prevents ischemia/reperfusion-induced cardiac injury in H9c2 cells: involvement of ROS, Hsp70, JNK and ERK, and apoptosis. AB - Ischemia-Reperfusion (I/R) injury causes ROS overproduction, creating oxidative stress, and can trigger myocyte death, resulting in heart failure. Tyrosol is an antioxidant abounded in diets and medicine. Our objective was to investigate the protective effect of tyrosol on I/R-caused mortality in H9c2 cardiomyocytes through its influence on ROS, Hsp70, ERK, JNK, Bcl-2, Bax and caspase-8. A simulated I/R model was used, myocytes loss was examined by MTT, and ROS levels were measured using DCFH-DA. Nuclear condensation and caspase-3 activity were assessed by DAPI staining and fluorometric assay. Phosphorylated ERK and JNK were determined by electrochemiluminescent ELISA, and Hsp70, Bcl-2, Bax and caspase-8 were examined by Western blotting. Results show that tyrosol salvaged myocyte loss, inhibited nuclear condensation and caspase-3 activity dose-dependently, indicating its protection against I/R-caused myocyte loss. Furthermore, tyrosol significantly inhibited ROS accumulation and activation of ERK and JNK, augmenting Hsp70 expression. Besides, tyrosol inhibited I/R-induced apoptosis, associated with retained anti-apoptotic Bcl-2 protein, and attenuated pro apoptotic Bax protein, resulting in a preservation of Bcl-2/Bax ratio. Finally, tyrosol notably decreased cleaved caspase-8 levels. In conclusion, cytoprotection of tyrosol in I/R-caused myocyte mortality was involved with the mitigation of ROS, prohibition of the activation of ERK, JNK and caspase-8, and elevation of Hsp70 and Bcl-2/Bax ratio. PMID- 25723851 TI - Targeting the Cryptococcus neoformans var. grubii cell wall using lectins: study of the carbohydrate-binding domain. AB - Cryptococcus neoformans var. grubii is considered to be the major cause of cryptococcosis in immunosuppressed patients. Understanding cell wall glycoproteins using lectins is of medical interest and can contribute to specific therapy. The aim of this study was to evaluate the carbohydrates on the cell wall of Cryptococcus neoformans var. grubii clinical isolates, using a fluorescein isothiocyanate-lectin binding protocol. Thirty yeast strains stocked in the culture collection were cultivated for 2 days at 30 degrees C with shaking. Cells were obtained by centrifugation, washed in phosphate-buffered saline, and a suspension of 107 cells/mL was obtained. To determine the binding profile of lectins, concanavalin A (Con A), wheat germ agglutinin (WGA), Ulex europaeus agglutinin I (UEA-I), and peanut agglutinin (PNA) conjugated to fluorescein were used. All the tested clinical isolates of Cryptococcus neoformans var. grubii were intensely stained by WGA, moderately stained by Con A, and weakly stained by PNA and UEA-I. Thus, Cryptococcus can be detected in clinical specimens such as blood and cerebrospinal fluid using the fluorescent lectin WGA, which may be considered as an option for detection in cases of suspected cryptococcosis with low laboratory sensitivity. Future applications may be developed using this basic tool. PMID- 25723852 TI - Obituary: Richard R. Bootzin (1940-2014). PMID- 25723854 TI - Immortal time bias in retrospective analysis: comment on 'Efficacy and safety of long-term treatment with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma'. PMID- 25723853 TI - B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy? AB - Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of kappa-B (NF-kappaB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916). PMID- 25723855 TI - Absence of natural intracellular retinoids in mouse bone marrow cells and implications for PML-RARA transformation. PMID- 25723856 TI - t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs. PMID- 25723858 TI - Focus on vitamin D and the adrenal gland. AB - The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. However, recent evidences have demonstrated that vitamin D may also play a role in a variety of nonskeletal disorders such as endocrine diseases and in particular type 1 diabetes, type 2 diabetes, adrenal diseases, and the polycystic ovary syndrome. Despite controversial results on an association of low vitamin D levels with cortisol and aldosterone overproduction, encouraging in vitro findings have been reported on vitamin D effects in adrenocortical cancer cells. The focus of this review is the role of vitamin D in adrenal diseases and the results of vitamin D supplementation studies in patients. Although many studies support a beneficial role of vitamin D in adrenal disease, randomized controlled trials and mechanistic studies are required to provide more insight into the efficacy and safety of vitamin D as a therapeutic tool. PMID- 25723857 TI - Expression of non-neuronal cholinergic system in maxilla of rat in vivo. AB - BACKGROUND: Acetylcholine (ACh) is known to be a key neurotransmitter in the central and peripheral nervous systems, which is also produced in a variety of non-neuronal tissues and cell. The existence of ACh in maxilla in vivo and potential regulation role for osteogenesis need further study. RESULTS: Components of the cholinergic system (ACh, esterase, choline acetyltransferase, high-affinity choline uptake, n- and mAChRs) were determined in maxilla of rat in vivo, by means of Real-Time PCR and immunohistochemistry. Results showed RNA for CarAT, carnitine/acylcarnitine translocase member 20 (Slc25a20), VAChT, OCTN2, OCT1, OCT3, organic cation transporter member 4 (Slc22a4), AChE, BChE, nAChR subunits alpha1, alpha2, alpha3, alpha5, alpha7, alpha10, beta1, beta2, beta4, gamma and mAChR subunits M1, M2, M3, M4, M5 were detected in rat's maxilla. RNA of VAChT, AChE, nAChR subunits alpha2, beta1, beta4 and mAChR subunits M4 had abundant expression (2(-DeltaCt) > 0.03). Immunohistochemical staining was conducted for ACh, VAChT, nAChRalpha7 and AChE. ACh was expressed in mesenchymal cells, chondroblast, bone and cartilage matrix and bone marrow cells, The VAChT expression was very extensively while ACh receptor alpha7 was strongly expressed in newly formed bone matrix of endochondral and bone marrow ossification, AchE was found only in mesenchymal stem cells, cartilage and bone marrow cells. CONCLUSIONS: ACh might exert its effect on the endochondral and bone marrow ossification, and bone matrix mineralization in maxilla. PMID- 25723859 TI - [Use of Balloon Enteroscopy-Guided ERCP in Postsurgically Changed Anatomy of the Upper GI Tract (Roux-en-Y Anastomosis) - A Comment on the Publications by Monkemuller et al. from a Surgical Perspective]. PMID- 25723860 TI - [How Steady are Hospitals in Complying with Minimum Volume Standards? A Retrospective Longitudinal Data Analysis of the Years 2006, 2008, and 2010]. AB - BACKGROUND: The outcome volume relationship has been analysed for more than 30 years and debated ever since. For German hospitals minimum volume standards (MVS) have been introduced for some procedures in 2004. Hospitals have to report procedure volumes in their quality reports. This study analyses for the first time how constant hospitals comply with minimum volume standards over time. MATERIALS AND METHODS: Data used are the reported volumes, which hospitals published in their quality reports in 2006, 2008, and 2010. The case volumes of complex oesophageal and pancreatic interventions, total knee replacements, and liver, kidney and stem cell transplantations (KTX, LTX, STX) are analysed in a retrospective, longitudinal study design. RESULTS: More than 80 % of hospitals conducting LTX, KTX, and total knee replacements are complying with MVS constantly, in STX 57 % of hospitals comply, and with complex pancreatic and oesophageal interventions compliance is 44 and 28 %, respectively. Twenty-seven to 36 % of hospitals conducting the three last mentioned procedures vary in complying with the MVS over time. 3.5 % (total knee replacements) up to 26 % (pancreatic interventions) and 37 % (oesophageal interventions) of all hospitals constantly fail to comply with MVS. Hospitals constantly over the MVS treat more than 80 % of all patients, except in complex oesophageal interventions. Hospitals with varying compliance in oesophageal and pancreatic interventions are mainly hospitals with 100 to 599 beds. Only very few hospitals of these two procedure types stop conducting the interventions after failing to comply with MVS earlier, the other some 120 hospitals for each intervention type treat 2 cases on average per year. CONCLUSION: The MVS on KTX, LTX, STX, and total knee replacement are almost constantly complied with. A considerable number of hospitals conducting oesophageal and pancreatic interventions never or rarely meet the MVS without discontinuing this type of intervention. At least for hospitals that never comply with MVS on oesophageal and pancreatic interventions, requirements and possibilities for a regional patient transfer should be studied in depth. PMID- 25723861 TI - [Extended Pathohistological Criteria for Assessment of the Long-Term Prognosis of Gastric Cancer]. AB - BACKGROUND: Gastric cancer is one of the most frequent tumour diseases worldwide. Despite numerous innovations in the diagnostic procedures and treatment the prognosis remains poor as the detection of the disease depends on tumour associated symptoms which develop rather late in the majority of cases. The treatment outcomes may be improved by a more differentiated and individualised evaluation of the tumour biology. We present a detailed analysis of potentially relevant factors. MATERIAL AND METHODS: From 1995 to 2011, data from 923 patients with gastric cancer have been collected in a prospective tumour database. We performed monovariate and multivariate analyses of factors. For the statistical analyses, SPSS software version 19.0 was used. The literature research was performed with Medline. RESULTS: 748 patients underwent surgical exploration. The resection rate was 87 % with a morbidity and mortality of 27 and 9 % (2004 to 2001: 13 and 5 %), respectively. 36 and 29 % of patients survived 5 years or 10 years, respectively. The 5-year and 10-year survival after curative resection was 58 and 46 %, respectively. TNM-associated criteria, tumour size, histological growth pattern, intestinal metaplasia, location of the tumour and classification according to Lauren were of significant influence in the monovariate analyses. In the multivariate analysis, tumour size, curative resection and lymph node involvement were independent prognostic factors. 90 % of the tumour recurrences developed within five years. The median recurrence-free interval was 16 months. Depending on the type of tumour, different survival times were identified. The 228 patients with node-negative curatively resected gastric cancer had a markedly better long-term prognosis. Diffuse type according to Lauren, tumour size, non tubular histological growth pattern, female sex and proof of serosa infiltration from the primary tumour were prognostic factors in the monovariate analysis. In the multivariate analysis, tumour size was an independent significant prognostic factor (p = 0.05). CONCLUSION: The data analyses showed that the evaluation of gastric cancer may be extended in a sensitive way by factors that have not been previously established. The benefit of an individualised structured treatment and follow-up on the basis of extended criteria should be investigated in future studies. PMID- 25723862 TI - [Implementation of the Perioperative WHO Safety Checklist at a Maximum Care Hospital - A Retrospective Analysis]. AB - BACKGROUND: In recent years there has been a significant increase of surgical procedures worldwide. Perioperative complication occurred in approximately 10 %, mortality was about 0.5 %. Half of these adverse events were considered to have been preventable. With the introduction of a perioperative checklist by the WHO in 2008, a significant reduction of morbidity and mortality could be achieved. The aim of this study was to investigate the success of the implementation process of the checklist at a maximum care hospital over a three-year period and to expose and analyse any occurring issues. PATIENTS AND METHODS: At various time points (introduction phase, five months, one year and three years after implementation) a total of 358 operations was investigated. First the presence and the handling of the checklist were investigated followed by an analysis of possible influencing factors on the processing. To examine a potential perioperative malpractice, three typical perioperative errors known from the literature on patient safety were analysed. RESULTS: The presence of the checklist improved significantly during the study. With the exception of the first column (signed by ward nurse) the checklist was processed more often among the participants (anaesthesia nurse, anaesthesia physician, surgeon) over the time. However the "sign out" column edited by the surgeon at the end of the operation fell below expectations. In addition to the duration after implementation the level of experience of the surgeon was a relevant factor for a properly completed checklist. During the study a malpractice was found in two cases, a checklist could not be detected. CONCLUSION: Within the study we could demonstrate the difficulties of introducing a surgical checklist at a maximum care hospital. Therefore involved nursing or medical staff must be aware of the usefulness of the checklist and should be motivated to use it. In addition, periodical lectures, training courses and role modelling of nursing and medical staff are required. The objective must be to establish the checklist into daily routine as it is a simple and efficient tool to reduce perioperative morbidity and mortality. PMID- 25723863 TI - [Prospective, Systematic Observational Study on the Daily Use of Cilostazol (Pletal) in Clinical Vascular Surgical Practice - Significant Improvement of Walking Distance and Quality of Life for Patients with PAOD, Stage II b]. AB - AIM, PATIENTS AND METHODS: Through a defined time period, all consecutive vascular surgical patients with indicated and initiated medication with cilostazol (PAOD, stage II b) were registered and controlled clinically within 3 month time intervals to investigate the therapeutic effect in a representative, specifically vascular surgical group of patients using a systematic prospective, unicentre clinical observational study. In particular, maximum walking distance, subjective (semiquantitative) assessment of the quality of life, impact of accompanying diseases as well as the occurrence of adverse effects and their impact onto the treatment were studied. RESULTS: Out of the 146 registered patients with initiated medication of cilostazol, 93 subjects were finally evaluated. Three months after initiation of cilostazol medication, maximum walking distance increased by 108 m (159.7 %) based on the initial 181 m. After 6 and 9 months, walking distance increased by 181 m (200 %) and 168 m (192.8 %), respectively. After 12 months, there was no further increase of the walking distance by 126 m (169.6 %) compared with months 6 and 9 but still with a significant difference to the initial distance. There was a trend of an improved walking distance from the 3rd to the 6th month (p = 0.1055) and a significant difference between the 3rd and the 9th month (p = 0.0094; no further significant differences between the time points 3rd/12th, 6th/9th, 6th/12th and 9th/12th month). While an improved quality of life was reported in 80.7 % of patients after 3 months, the rate varied between 82.6, 72.9 and 80.9 % at 6, 9 and 12 months, respectively, i.e., always in the majority of cases. There were no hints for safety concerns with regard to severe adverse effects, in particular, bleeding episodes. Subgroup analyses on accompanying diseases such as diabetes, hyperlipidemia or nicotine abuse did not reveal any impact on the improved walking distance (ABI - no feasible parameter). CONCLUSION: Medication with cilostazol led to a significant increase of the maximum walking distance (p < 0.0001) compared to the initial distance, which was further increased through one year (however, the effect became weaker) accompanied by a dominating improvement of the quality of life. The effects can be observed longer than 3-6 months. PMID- 25723864 TI - [Interdisciplinary Diagnosis and Treatment of Deep Infiltrating Endometriosis]. AB - Endometriosis is the second most common benign female genital disease after uterine myoma. This review discusses the interdisciplinary approach to the treatment of deep infiltrating endometriosis. Endometriosis has been defined as the presence of endometrial glands and stroma outside the internal epithelial lining of the cavum uteri. As a consequence, endometriosis can cause a wide range of symptoms such as chronic pelvic pain, subfertility, dysmenorrhea, deep dyspareunia, cyclical bowel or bladder symptoms (e.g., dyschezia, bloating, constipation, rectal bleeding, diarrhoea and hematuria), abnormal menstrual bleeding, chronic fatigue or low back pain. Approx. 50 % of teenagers and up to 32 % of women of reproductive age, operated for chronic pelvic pain or dysmenorrhoea, suffer from endometriosis. The time interval between the first unspecific symptoms and the medical diagnosis of endometriosis is about 7 years. This is caused not only by the non-specific nature of the symptoms but also by the frequent lack of awareness on the part of the cooperating disciplines with which the patients have first contact. As the pathogenesis of endometriosis is not clearly understood, a causal treatment is still impossible. Treatment options include expectant management, analgesia, hormonal medical therapy, surgical intervention and the combination of medical treatment before and/or after surgery. The correct treatment for each patient should take into account the severity of the disease and whether the patient desires to have children. The treatment should be as radical as necessary and as minimal as possible. The recurrence rate among treated patients lies between 5 and > 60 % and is very much dependent on the integrated management and surgical skills of the respective hospital. Consequently, to optimise the individual patient's treatment, a high degree of interdisciplinary cooperation in diagnosis and treatment is crucial and should, especially in the case of deep infiltrating endometriosis, be undertaken in appropriate centres. PMID- 25723865 TI - [Reconstruction options for pelvic defects after abdominal exenteration]. AB - Soft tissue defects after oncological pelvic exenteration still represent a significant problem. Because of the anatomic and functional peculiarities, the reconstruction of defects in the pelvic region is challenging and requires a differentiated approach. In this paper, current strategies and options for reconstructive procedures are presented considering preoperative conditions and factors related to surgical planning. The relevance of interdisciplinary collaboration and the resulting benefits are set out. The inclusion of the plastic surgeon already in the preoperative planning of tumour resection is recommended. PMID- 25723866 TI - Protein substitute for children and adults with phenylketonuria. AB - BACKGROUND: Phenylketonuria is an inherited metabolic disorder characterised by an absence or deficiency of the enzyme phenylalanine hydroxylase. The aim of treatment is to lower blood phenylalanine concentrations to the recommended therapeutic range to prevent developmental delay and support normal growth. Current treatment consists of a low-phenylalanine diet in combination with a protein substitute which is free from or low in phenylalanine. Guidance regarding the use, dosage, and distribution of dosage of the protein substitute over a 24 hour period is unclear, and there is variation in recommendations among treatment centres. This is an update of a Cochrane review first published in 2005, and previously updated in 2008. OBJECTIVES: To assess the benefits and adverse effects of protein substitute, its dosage, and distribution of dose in children and adults with phenylketonuria who are adhering to a low-phenylalanine diet. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which consists of references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. We also contacted manufacturers of the phenylalanine-free and low-phenylalanine protein substitutes for any data from published and unpublished randomised controlled trials.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 03 April 2014. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing: any dose of protein substitute with no protein substitute; an alternative dosage; or the same dose, but given as frequent small doses throughout the day compared with the same total daily dose given as larger boluses less frequently. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data and assessed trial quality. MAIN RESULTS: Three trials (69 participants) are included in this review. One trial investigated the use of protein substitute in 16 participants, while a further two trials investigated the dosage of protein substitute in a total of 53 participants. Due to issues with data presentation in each trial, described in full in the review, formal statistical analyses of the data were impossible. Investigators will be contacted for further information. AUTHORS' CONCLUSIONS: No conclusions could be drawn about the short- or long-term use of protein substitute in phenylketonuria due to the lack of adequate or analysable trial data. Additional data and randomised controlled trials are needed to investigate the use of protein substitute in phenylketonuria. Until further evidence is available, current practice in the use of protein substitute should continue to be monitored with care. PMID- 25723867 TI - Effect of monochloramine treatment on colonization of a hospital water distribution system by Legionella spp.: a 1 year experience study. AB - Contamination of hot water distribution systems by Legionella represents a great challenge due to difficulties associated with inactivating microorganisms, preserving the water characteristics. The aim of this study was to examine over the course of 1 year in 11 fixed sites, the impact of monochloramine disinfection on Legionella, heterotrophic bacteria (36 degrees C), Pseudomonas aeruginosa contamination, and chemical parameters of a plumbing system in an Italian hospital. Three days after installation (T0), in the presence of monochloramine concentration between 1.5 and 2 mg/L, 10/11 sites (91%) were contaminated by L. pneumophila serogroups 3 and 10. After these results, the disinfectant dosage was increased to between 6 and 10 mg/L, reducing the level of Legionella by three logarithmic unit by 2 months postinstallation (T2) until 6 months later (T3). One year later (T4), there was a significant reduction (p = 0.0002) at 8/11 (73%) sites. Our data showed also a significant reduction of heterotrophic bacteria (36 degrees C) in 6/11 (55%) sites at T4 (p = 0.0004), by contrast the contamination of P. aeruginosa found at T0 in two sites persisted up until T4. The results of the present study show that monochloramine is a promising disinfectant that can prevent Legionella contamination of hospital water supplies. PMID- 25723868 TI - Field pathogenomics reveals the emergence of a diverse wheat yellow rust population. AB - BACKGROUND: Emerging and re-emerging pathogens imperil public health and global food security. Responding to these threats requires improved surveillance and diagnostic systems. Despite their potential, genomic tools have not been readily applied to emerging or re-emerging plant pathogens such as the wheat yellow (stripe) rust pathogen Puccinia striiformis f. sp. tritici (PST). This is due largely to the obligate parasitic nature of PST, as culturing PST isolates for DNA extraction remains slow and tedious. RESULTS: To counteract the limitations associated with culturing PST, we developed and applied a field pathogenomics approach by transcriptome sequencing infected wheat leaves collected from the field in 2013. This enabled us to rapidly gain insights into this emerging pathogen population. We found that the PST population across the United Kingdom (UK) underwent a major shift in recent years. Population genetic structure analyses revealed four distinct lineages that correlated to the phenotypic groups determined through traditional pathology-based virulence assays. Furthermore, the genetic diversity between members of a single population cluster for all 2013 PST field samples was much higher than that displayed by historical UK isolates, revealing a more diverse population of PST. CONCLUSIONS: Our field pathogenomics approach uncovered a dramatic shift in the PST population in the UK, likely due to a recent introduction of a diverse set of exotic PST lineages. The methodology described herein accelerates genetic analysis of pathogen populations and circumvents the difficulties associated with obligate plant pathogens. In principle, this strategy can be widely applied to a variety of plant pathogens. PMID- 25723870 TI - Abundance and diversity of methanogens: potential role in high arsenic groundwater in Hetao Plain of Inner Mongolia, China. AB - To investigate the community diversity and abundance of methanogens and their potential role in high arsenic groundwater, 17 groundwater samples from Hetao Plain of Inner Mongolia were investigated with an integrated method including 16S rRNA gene clone library, quantitative polymerase chain reaction and geochemistry analyses. Total arsenic (AsTot) concentrations were 82.7-1088.7 MUg/L and arsenite (AsIII) mostly dominated in these samples with percentages of 0.04-0.79. CH4 concentrations ranged from 0.01 to 292 MUg/L and distinctly elevated only when AsTot were relatively high and SO4(2-) were distinctly low. Principal component analysis indicated that these samples were divided into three groups according to the variations of AsTot, CH4 and SO4(2-). AsTot concentrations were distinctly high in the group with high CH4 and low SO4(2-) comparing to the other two groups (one with high CH4 and high SO4(2-), the other with low CH4 and SO4(2 )). The mcrA gene (methyl coenzyme-M reductase gene) based phylogenetic analysis of methanogens population showed that methanogenic archaea was diverse but mainly composed of Methanomicrobiales, Methanosarcinales, Methanobacteria and unidentified groups, with Methanomicrobiales being distinctly dominant (50.6%). The mcrA gene abundance in high arsenic groundwater ranged from 3.01 * 10(3) to 3.80 * 10(6)copies/L and accounted for 0-30.2% of total archaeal 16S rRNA genes. The abundance of mcrA genes was positively correlated with the concentrations of AsTot (R=0.59), AsIII (R=0.57) and FeII (R=0.79), while it was negatively correlated with oxidation-reduction potential (R=-0.66) and SO4(2-) concentration (R=-0.64). These results implied that methanogenic archaea might accelerate As release in groundwater aquifers in Hetao Plain. PMID- 25723869 TI - Dbl oncogene expression in MCF-10 A epithelial cells disrupts mammary acinar architecture, induces EMT and angiogenic factor secretion. AB - The proteins of the Dbl family are guanine nucleotide exchange factors (GEFs) of Rho GTPases and are known to be involved in cell growth regulation. Alterations of the normal function of these proteins lead to pathological processes such as developmental disorders, neoplastic transformation, and tumor metastasis. We have previously demonstrated that expression of Dbl oncogene in lens epithelial cells modulates genes encoding proteins involved in epithelial-mesenchymal-transition (EMT) and induces angiogenesis in the lens. Our present study was undertaken to investigate the role of Dbl oncogene in epithelial cells transformation, providing new insights into carcinoma progression.To assess how Dbl oncogene can modulate EMT, cell migration, morphogenesis, and expression of pro-apoptotic and angiogenic factors we utilized bi- and 3-dimensional cultures of MCF-10 A cells. We show that upon Dbl expression MCF-10 A cells undergo EMT. In addition, we found that Dbl overexpression sustains Cdc42 and Rac activation inducing morphological alterations, characterized by the presence of lamellipodia and conferring a high migratory capacity to the cells. Moreover, Dbl expressing MCF 10 A cells form altered 3D structures and can induce angiogenesis by producing proangiogenic factors such as CCL2. These results support a role for Dbl oncogene in epithelial cell differentiation and transformation and suggest the relevance of GEF deregulation in tumor onset and progression. PMID- 25723871 TI - Reliable quantification of phthalates in environmental matrices (air, water, sludge, sediment and soil): a review. AB - Because of their widespread application, phthalates or phthalic acid esters (PAEs) are ubiquitous in the environment. Their presence has attracted considerable attention due to their potential impacts on ecosystem functioning and on public health, so their quantification has become a necessity. Various extraction procedures as well as gas/liquid chromatography and mass spectrometry detection techniques are found as suitable for reliable detection of such compounds. However, PAEs are ubiquitous in the laboratory environment including ambient air, reagents, sampling equipment, and various analytical devices, that induces difficult analysis of real samples with a low PAE background. Therefore, accurate PAE analysis in environmental matrices is a challenging task. This paper reviews the extensive literature data on the techniques for PAE quantification in natural media. Sampling, sample extraction/pretreatment and detection for quantifying PAEs in different environmental matrices (air, water, sludge, sediment and soil) have been reviewed and compared. The concept of "green analytical chemistry" for PAE determination is also discussed. Moreover useful information about the material preparation and the procedures of quality control and quality assurance are presented to overcome the problem of sample contamination and these encountered due to matrix effects in order to avoid overestimating PAE concentrations in the environment. PMID- 25723872 TI - Prevalence of microbiological contaminants in groundwater sources and risk factor assessment in Juba, South Sudan. AB - In low-income regions, drinking water is often derived from groundwater sources, which might spread diarrheal disease if they are microbiologically polluted. This study aimed to investigate the occurrence of fecal contamination in 147 improved groundwater sources in Juba, South Sudan and to assess potential contributing risk factors, based on bivariate statistical analysis. Thermotolerant coliforms (TTCs) were detected in 66% of the investigated sources, including 95 boreholes, breaching the health-based recommendations for drinking water. A significant association (p<0.05) was determined between the presence of TTCs and the depth of cumulative, long-term prior precipitation (both within the previous five days and within the past month). No such link was found to short-term rainfall, the presence of latrines or damages in the borehole apron. However, the risk factor analysis further suggested, to a lesser degree, that the local topography and on site hygiene were additionally significant. In summary, the analysis indicated that an important contamination mechanism was fecal pollution of the contributing groundwater, which was unlikely due to the presence of latrines; instead, infiltration from contaminated surface water was more probable. The reduction in fecal sources in the environment in Juba is thus recommended, for example, through constructing latrines or designating protection areas near water sources. The study results contribute to the understanding of microbiological contamination of groundwater sources in areas with low incomes and high population densities, tropical climates and weathered basement complex environments, which are common in urban sub-Saharan Africa. PMID- 25723873 TI - Evaluating Emergency Department Asthma Management Practices in Florida Hospitals. AB - OBJECTIVE: To assess gaps in emergency department (ED) asthma management at Florida hospitals. DESIGN: Survey instrument with open- and closed-ended questions. Topics included availability of specific asthma management modalities, compliance with national guidelines, employment of specialized asthma care personnel, and efforts toward performance improvement. SETTING: Emergency departments at 10 large hospitals in the state of Florida. PARTICIPANTS: Clinical care providers and health administrators from participating hospitals. MAIN OUTCOME MEASURES: Compliance with national asthma care guideline standards, provision of specific recommended treatment modalities and resources, employment of specialized asthma care personnel, and engagement in performance improvement efforts. RESULTS: Our results suggest inconsistency among sampled Florida hospitals' adherence to national standards for treatment of asthma in EDs. Several hospitals were refining their emergency care protocols to incorporate guideline recommendations. Despite a lack of formal ED protocols in some hospitals, adherence to national guidelines for emergency care nonetheless remained robust for patient education and medication prescribing, but it was weaker for formal care planning and medical follow-up. CONCLUSIONS: Identified deficiencies in emergency asthma care present a number of opportunities for strategic mitigation of identified gaps. We conclude with suggestions to help Florida hospitals achieve success with ED asthma care reform. Team-based learning activities may offer an optimal strategy for sharing and implementing best practices. PMID- 25723874 TI - Bridging Research, Practice, and Policy: The "Evidence Academy" Conference Model. AB - Innovative models to facilitate more rapid uptake of research findings into practice are urgently needed. Community members who engage in research can accelerate this process by acting as adoption agents. We implemented an Evidence Academy conference model bringing together researchers, health care professionals, advocates, and policy makers across North Carolina to discuss high impact, life-saving study results. The overall goal is to develop dissemination and implementation strategies for translating evidence into practice and policy. Each 1-day, single-theme, regional meeting focuses on a leading community identified health priority. The model capitalizes on the power of diverse local networks to encourage broad, common awareness of new research findings. Furthermore, it emphasizes critical reflection and active group discussion on how to incorporate new evidence within and across organizations, health care systems, and communities. During the concluding session, participants are asked to articulate action plans relevant to their individual interests, work setting, or area of expertise. PMID- 25723875 TI - A Logic Model for Evaluating the Academic Health Department. AB - Academic Health Departments (AHDs) are collaborative partnerships between academic programs and practice settings. While case studies have informed our understanding of the development and activities of AHDs, there has been no formal published evaluation of AHDs, either singularly or collectively. Developing a framework for evaluating AHDs has potential to further aid our understanding of how these relationships may matter. In this article, we present a general theory of change, in the form of a logic model, for how AHDs impact public health at the community level. We then present a specific example of how the logic model has been customized for a specific AHD. Finally, we end with potential research questions on the AHD based on these concepts. We conclude that logic models are valuable tools, which can be used to assess the value and ultimate impact of the AHD. PMID- 25723876 TI - Lessons Learned From Measuring Return on Investment in Public Health Quality Improvement Initiatives. AB - CONTEXT: The Center for Public Health Quality and its partner, North Carolina State University Industrial Extension Service, used 2 existing, yet similar quality improvement (QI) programs to provide technical assistance to conduct return on investment (ROI) and economic impact (EI) analyses so that they could estimate their QI projects' financial impacts. OBJECTIVES: The objectives of this article are to describe the approach and ongoing learning from applying ROI and EI analyses to public health QI projects and analyze the results in order to illustrate ROI potential in public health. DESIGN: We used a before-after study design for all ROI and EI analyses, spanning a 3-year time period. SETTING: The study was conducted as part of 2 existing public health QI training programs that included webinars, face-to-face workshops, on-site facilitation, and longitudinal coaching and mentoring. PARTICIPANTS: The QI training programs included multidisciplinary teams from local and state public health programs in North Carolina. MAIN OUTCOME MEASURE: Return on investment and EI calculations. RESULTS: Numerous adaptations were made over the 3 years of the ROI program to enhance participant's understanding and application. Results show an average EI of $149 000, and a total EI in excess of $5 million for the 35 projects studied. The average ROI per QI project was $8.56 for every $1 invested in the project. CONCLUSIONS: Adapting the ROI approach was important in helping teams successfully conduct their ROI analyses. This study suggests that ROI analyses can be effectively applied in public health settings, and the potential for financial return is substantial. PMID- 25723877 TI - Edge dislocation slows down oxide ion diffusion in doped CeO2 by segregation of charged defects. AB - Strained oxide thin films are of interest for accelerating oxide ion conduction in electrochemical devices. Although the effect of elastic strain has been uncovered theoretically, the effect of dislocations on the diffusion kinetics in such strained oxides is yet unclear. Here we investigate a 1/2<110>{100} edge dislocation by performing atomistic simulations in 4-12% doped CeO2 as a model fast ion conductor. At equilibrium, depending on the size of the dopant, trivalent cations and oxygen vacancies are found to simultaneously enrich or deplete either in the compressive or in the tensile strain fields around the dislocation. The associative interactions among the point defects in the enrichment zone and the lack of oxygen vacancies in the depletion zone slow down oxide ion transport. This finding is contrary to the fast diffusion of atoms along the dislocations in metals and should be considered when assessing the effects of strain on oxide ion conductivity. PMID- 25723878 TI - When to initialize enteral nutrition in patients with severe acute pancreatitis? A retrospective review in a single institution experience (2003-2013). AB - OBJECTIVE: The present retrospective study aimed to analyze the optimal time to initiate enteral nutrition (EN) in patients with severe acute pancreatitis at a single Chinese institution (China Medical University Hospital). METHODS: A total of 1196 patients with severe acute pancreatitis were admitted in the intensive care unit between November 2003 and June 2013; 1092 patients were selected and were divided into the early and delayed EN groups, according to their initial timing of EN. RESULTS: Five hundred sixty-six patients were administered with the delayed EN, and 526 with the early EN. Both groups had similar severity of pancreatic necrosis, but organ failure developed in 81% patients of the delayed EN group and 21% in the early EN group (P < 0.01). The numbers of septic necrosis and morbidity were significantly higher in the delayed EN group than in the early EN (P < 0.01). CONCLUSIONS: The early EN had significant benefits over the delayed EN in the decrease of organ failure and mortality; our findings suggested that the first 48 hours of administration in the intensive care unit was the optimal time to start EN. PMID- 25723879 TI - Bioaccumulation of 4-nonylphenol and effects on biomarkers, acetylcholinesterase, glutathione-S-transferase and glutathione peroxidase, in Mytilus galloprovincialis mussel gilla. AB - Wild marine mussels, Mytilus galloprovincialis showed a moderate bioaccumulation ability when exposed to waterborne 4-nonylphenol (4-NP), with a bioconcentration factor (BCF) of 6850 L Kg(-1) (dry weight). Kinetic and concentration-response experiments were performed and three enzymatic biomarkers in mussel gills were measured: Glutathione S-transferase (GST), glutathione peroxidase (GPx) and acetylcholinesterase (AChE). Exposure of mussels to environmentally relevant concentrations (25-100 MUg L(-1)) of 4-nonylphenol significantly inhibited the AChE activity and induced the GST and GPx activities. GST induction was dose dependent whilst GPx activity showed a less consistent pattern, but in both cases the induction remained after a 10 d depuration period. Mussels seem capable of eliminating 4-NP from their tissues through a mechanism involving GST induction. PMID- 25723880 TI - Frontier orbitals and transition states in the oxidation and degradation of L ascorbic acid: a DFT study. AB - DFT calculations were carried out to investigate reaction paths of L-ascorbic acid (AAH2), hydroxyl radicals and water clusters. Frontier-orbital analyses were also performed to examine the regioselectivity of the OH addition. Transition states of the electrolytic dissociation of AAH2 and intermediate carboxylic acids were found to have very small activation energies through proton transfers along hydrogen bonds. The ionized species (anions) are subject to the electrophilic attack of OH. The elementary processes of AAH2 -> A(-) -> dehydroascorbic acid -> diketogulonic acid -> threonic, oxalic, xylonic and lyxonic acids were investigated and discussed. The processes involved in the conversion of dehydroascorbic acid into a bicyclic hemiketal were also examined as a side-chain participating reaction. The oxidation and degradation of vitamin C up to threonic acid were described mainly as a donor (AAH2)-acceptor (OH) reaction. PMID- 25723881 TI - Prehospital emergency care training practices regarding lesbian, gay, bisexual, and transgender patients in Maryland (USA). AB - INTRODUCTION: Prehospital Emergency Medical Services (EMS) providers are expected to treat all patients the same, regardless of race, gender identity, sexual orientation, or religion. Some EMS personnel who are poorly trained in working with lesbian, gay, bisexual, and transgender (LGBT) patients are at risk for managing such patients incompletely and possibly incorrectly. During emergency situations, such mistreatment has meant the difference between life and death. METHODS: An anonymous survey was electronically distributed to EMS educational program directors in Maryland (USA). The survey asked participants if their program included training cultural sensitivity, and if so, by what modalities. Specific questions then focused on information about LGBT education, as well as related topics, that they, as program directors, would want included in an online training module. RESULTS: A total of 20 programs met inclusion criteria for the study, and 16 (80%) of these programs completed the survey. All but one program (15, 94%) included cultural sensitivity training. One-third (6, 38%) of the programs reported already teaching LGBT-related issues specifically. Three quarters of the programs that responded (12, 75%) were willing to include LGBT related material into their curriculum. All programs (16, 100%) identified specific aspects of LGBT-related emergency health issues they would be interested in having included in an educational module. CONCLUSION: Most EMS educational program directors in Maryland are receptive to including LGBT-specific education into their curricula. The information gathered in this survey may help guide the development of a short, self-contained, open-access module for EMS educational programs. Further research, on a broader scale and with greater geographic sampling, is needed to assess the practices of EMS educators on a national level. PMID- 25723882 TI - Disseminated emm Type 12 Group A Streptococcus and Review of Invasive Disease. AB - The authors present a case of invasive group A Streptococcus (GAS) in a previously healthy 63-year-old male complicated by trans-esophageal echocardiogram negative endocarditis, septic arthritis, and multiple cerebral septic emboli. Despite antibiotics and drainage of his largest brain abscess, the patient expired. This case highlights the potential mortality from invasive GAS disease. Included is a review of current literature regarding invasive GAS that addresses its presentation, prevalence, virulence and treatment. PMID- 25723883 TI - When Hodgkin comes to a head: Hodgkin central nervous system involvement. PMID- 25723884 TI - Dexrazoxane protects breast cancer patients with diabetes from chemotherapy induced cardiotoxicity. AB - BACKGROUND: To evaluate the cardioprotective effect of dexrazoxane (DEX) on chemotherapy in patients with breast cancer with concurrent type 2 diabetes mellitus (DM2). METHODS: Eighty female patients with breast cancer with DM2 were randomly assigned to receive chemotherapy only or chemotherapy plus DEX. All patients received 80 mg/m epirubicin and 500 mg/m cyclophosphamide by intravenous infusion every 3 weeks for a total of 6 cycles. The group assigned to receive chemotherapy alone received placebo 30 minutes before epirubicin administration. The group assigned to receive chemotherapy plus DEX received 800 mg/m DEX 30 minutes before epirubicin administration. Cardiac function and hematology before and after 6 cycles of chemotherapy were analyzed. RESULTS: There was no difference in baseline systole or diastole function between the 2 DM2 groups. Patients receiving chemotherapy alone experienced significantly greater reductions in Ea and significantly greater elevations in E/Ea and Tei index in comparison with patients receiving chemotherapy plus DEX. After chemotherapy, superoxide dismutase was significantly reduced, and serum malondialdehyde (MDA) was significantly increased in patients with DM2. Serum superoxide dismutase levels were comparable between the 2 groups before and after chemotherapy, MDA levels were comparable between the 2 groups before chemotherapy, whereas serum MDA was significantly higher after chemotherapy in the chemotherapy alone group in comparison with the group that received DEX. CONCULSIONS: DEX protects against cardiotoxicity induced by chemotherapy in patients with breast cancer with concurrent DM2. PMID- 25723885 TI - Sequential decolorization of azo dye and mineralization of decolorization liquid coupled with bioelectricity generation using a pH self-neutralized photobioelectrochemical system operated with polarity reversion. AB - A novel photobioelectrochemical system (PBES) was developed by acclimating algal bacterial biofilm in both anode and cathode using Chlorella vulgaris and indigenous wastewater bacteria as inoculums. The PBES was operated in polarity reversion mode depend on dark/light alternate reaction to achieve simultaneous pH self-neutralization, azo dye degradation (Congo red) and bioelectricity generation. The anodic accumulated acidity and cathodic accumulated alkalinity were self-neutralized after polarity reversion and hence eliminate the membrane pH gradient. The Congo red was first decolored in the dark anode and the resultant decolorization liquid was subsequently mineralized after the dark anode changing to the photo-biocathode. The presence of C. vulgaris significantly enhanced the two-stage degradation of Congo red, with 93% increases in decolorization rates and 8% increases in mineralization compared to the algae free BES. The PBES continuously generated stable voltage output over four months under repeatedly reversion of polarity. The maximum power density produced before and after polarity reversion was 78 and 61 mW/m(2), respectively. The synergy between C. vulgaris and mixed bacteria was responsible for the successful operation of the PBES which can be potentially applied to treat wastewater containing azo dye with benefits of enhanced azo dye degradation, high net power output and buffer minimization. PMID- 25723886 TI - Ammonia gas transport and reactions in unsaturated sediments: implications for use as an amendment to immobilize inorganic contaminants. AB - Use of gas-phase amendments for in situ remediation of inorganic contaminants in unsaturated sediments of the vadose zone may be advantageous, but there has been limited development and testing of gas remediation technologies. Treatment with ammonia gas has a potential for use in treating inorganic contaminants (such as uranium) because it induces a high pore-water pH, causing mineral dissolution and subsequent formation of stable precipitates that decrease the mobility of some contaminants. For field application of this treatment, further knowledge of ammonia transport in porous media and the geochemical reactions induced by ammonia treatment is needed. Laboratory studies were conducted to support calculations needed for field treatment design, to quantify advective and diffusive ammonia transport in unsaturated sediments, to evaluate inter-phase (gas/sediment/pore water) reactions, and to study reaction-induced pore-water chemistry changes as a function of ammonia delivery conditions, such as flow rate, gas concentration, and water content. Uranium-contaminated sediment was treated with ammonia gas to demonstrate U immobilization. Ammonia gas quickly partitions into sediment pore water and increases the pH up to 13.2. Injected ammonia gas advection front movement can be reasonably predicted by gas flow rate and equilibrium partitioning. The ammonia gas diffusion rate is a function of the water content in the sediment. Sodium, aluminum, and silica pore-water concentrations increase upon exposure to ammonia and then decline as aluminosilicates precipitate when the pH declines due to buffering. Up to 85% of the water-leachable U was immobilized by ammonia treatment. PMID- 25723887 TI - Effect of molecular structure of aniline-formaldehyde copolymers on corrosion inhibition of mild steel in hydrochloric acid solution. AB - Aniline-formaldehyde copolymers with different molecular structures have been prepared and investigated for the purpose of corrosion control of mild steel in hydrochloric acid. The copolymers were synthesized by a condensation polymerization process with different ratios of aniline to formaldehyde in acidic precursor solutions. The corrosion inhibition efficiency of as-synthesized copolymers for Q235 mild steel was investigated in 1.0 mol L(-1) hydrochloric acid solution by weight loss measurement, potentiodynamic polarization, and electrochemical impedance spectroscopy, respectively. All the results demonstrate that as-prepared aniline-formaldehyde copolymers are efficient mixed-type corrosion inhibitors for mild steels in hydrochloric acid. The corrosion inhibition mechanism is discussed in terms of the role of molecular structure on adsorption of the copolymers onto the steel surface in acid solution. PMID- 25723889 TI - Sonocatalytic degradation of RhB over LuFeO3 particles under ultrasonic irradiation. AB - LuFeO3 particles with an average particle size of ~200 nm were synthesized via a polyacrylamide gel route. The sonocatalytic activity of LuFeO3 particles was evaluated by the degradation of Rhodamine B (RhB) under ultrasonic irradiation, revealing that they exhibit a good sonocatalytic activity. The effects of various experimental factors including ultrasonic frequency (f), reaction solution temperature (T), catalyst dosage (Ccatalyst), initial RhB concentration (CRhB), and pH value on the sonocatalysis efficiency were investigated. It is found that the former four factors have an important influence on the sonocatalytic degradation of RhB, where the best degradation conditions are obtained to be f=60 kHz, T=40 degrees C, Ccatalyst=4 g L(-1), and CRhB=5 mg L(-1). The pH value has a relatively small effect on the sonocatalytic degradation of RhB compared with other experimental factors. Hydroxyl (.OH) radicals were detected by fluorimetry using terephthalic acid as a probe molecule, revealing that they are produced over the ultrasonic-irradiated LuFeO3 particles. The addition of ethanol leads to a quenching of .OH radicals and a simultaneous decrease in the RhB degradation. This indicates that .OH radicals are the primary active species responsible for the dye degradation. PMID- 25723888 TI - In situ growing directional spindle TiO2 nanocrystals on cellulose fibers for enhanced Pb(2+) adsorption from water. AB - TiO2/cellulose nanocomposite was synthesized by in situ generation of titanium dioxide (TiO2) nanocrystals on cellulose fibers (CF) via facile hydrolysis of TiOSO4. Cellulose was intended as a scaffold to immobilize TiO2 nanoparticles (NPs), but turned out surprisingly to be also a chemical template that directed the crystal growth. As a result, spindle rutile TiO2 crystals were nicely formed on the surface of cellulose. These crystals were further controlled to disperse uniformly without agglomeration for better use of their surface area to adsorb heavy metals. The TiO2/CF composite showed enhanced adsorption capacity, good regenerability and selectivity for lead (Pb(2+)) removal. In addition, the composite fibers were readily fabricated into a nonwoven filter bed through which dynamic filtration experiment was conducted. A 12-fold increase in filtered bed volume was achieved for TiO2/CF bed compared with pure CF bed before breakthrough took place. This work provides a green pathway for fabricating low cost, high efficiency and engineering application possible nanosorbents for water decontamination. PMID- 25723890 TI - Error identification in a high-volume clinical chemistry laboratory: Five-year experience. AB - INTRODUCTION: Quality indicators for assessing the performance of a laboratory require a systematic and continuous approach in collecting and analyzing data. The aim of this study was to determine the frequency of errors utilizing the quality indicators in a clinical chemistry laboratory and to convert errors to the Sigma scale. MATERIALS AND METHODS: Five-year quality indicator data of a clinical chemistry laboratory was evaluated to describe the frequency of errors. An 'error' was defined as a defect during the entire testing process from the time requisition was raised and phlebotomy was done until the result dispatch. An indicator with a Sigma value of 4 was considered good but a process for which the Sigma value was 5 (i.e. 99.977% error-free) was considered well controlled. RESULTS: In the five-year period, a total of 6,792,020 specimens were received in the laboratory. Among a total of 17,631,834 analyses, 15.5% were from within hospital. Total error rate was 0.45% and of all the quality indicators used in this study the average Sigma level was 5.2. Three indicators - visible hemolysis, failure of proficiency testing and delay in stat tests - were below 5 on the Sigma scale and highlight the need to rigorously monitor these processes. CONCLUSIONS: Using Six Sigma metrics quality in a clinical laboratory can be monitored more effectively and it can set benchmarks for improving efficiency. PMID- 25723891 TI - Is there room for improving the nutraceutical composition of apple? AB - In this study, we assessed the main bioactive compounds of a broad apple germplasm collection, composed by 247 accessions of wild (97) and domesticated (150) species. Among the stilbenes, trans- and cis-piceid were found to be ubiquitary components of both wild and cultivated apples. Apple was suggested to be the second dietary source of resveratrols. Results confirmed that the selection pressure of breeding and domestication did not uniformly affect all the phytochemicals contained in apples. For instance, organic acids (malic and ascorbic acid) and some phenolics (stilbenes, hydroxycinnamic acids, and dihydrochalcones) were significantly influenced by selection, while some relevant flavonoids (flavonols and flavan-3-ols) and triterpenoids (ursolic, oleanolic, and betulinic acids) were not. This comprehensive screening will assist in the selection of Malus accessions with specific nutraceutical traits suitable to establish innovative breeding strategies or to patent new functional foods and beverages. PMID- 25723892 TI - Tuning complex transition metal hydroxide nanostructures as active catalysts for water oxidation by a laser-chemical route. AB - Diverse transition metal hydroxide nanostructures were synthesized by laser induced hydrolysis in a liquid precursor solution for alkaline oxygen evolution reaction (OER). Several active OER catalysts with fine control of composition, structure, and valence state were obtained including (Lix)[Ni0.66Mn0.34(OH)2](NO3)(CO3) . mH2O, Lix[Ni0.67Co0.33(OH)2](NO3)0.25(ORO)0.35 . mH2O, etc. An operate overpotential less than 0.34 V at current density of 10 mA cm(-2) was achieved. Such a controllable laser-chemical route for assessing complex nanostructures in liquids opens many opportunities to design novel functional materials for advanced applications. PMID- 25723893 TI - Equilibrium state at supersaturated drug concentration achieved by hydroxypropyl methylcellulose acetate succinate: molecular characterization using (1)H NMR technique. AB - The maintenance mechanism of the supersaturated state of poorly water-soluble drugs, glibenclamide (GLB) and chlorthalidone (CLT), in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) solution was investigated at a molecular level. HPMC-AS suppressed drug crystallization from supersaturated drug solution and maintained high supersaturated level of drugs with small amount of HPMC-AS for 24 h. However, the dissolution of crystalline GLB into HPMC-AS solution failed to produce supersaturated concentrations, although supersaturated concentrations were achieved by adding amorphous GLB to HPMC-AS solution. HPMC-AS did not improve drug dissolution and/or solubility but efficiently inhibited drug crystallization from supersaturated drug solutions. Such an inhibiting effect led to the long-term maintenance of the amorphous state of GLB in HPMC-AS solution. NMR measurements showed that HPMC-AS suppressed the molecular mobility of CLT depending on their supersaturation level. Highly supersaturated CLT in HPMC-AS solution formed a gel-like structure with HPMC-AS in which the molecular mobility of the CLT was strongly suppressed. The gel-like structure of HPMC-AS could inhibit the reorganization from drug prenuclear aggregates to the crystal nuclei and delay the formation of drug crystals. The prolongation subsequently led to the redissolution of the aggregated drugs in aqueous solution and formed the equilibrium state at the supersaturated drug concentration in HPMC-AS solution. The equilibrium state formation of supersaturated drugs by HPMC-AS should be an essential mechanism underlying the marked drug concentration improvement. PMID- 25723894 TI - In response to: comparison of F(ab')2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial. PMID- 25723896 TI - Linear free energy relationships for the biotic and abiotic reduction of nitroaromatic compounds. AB - Nitroaromatic compounds (NACs) are ubiquitous environmental contaminants that are susceptible to biological and abiotic reduction. Prior works have found that for the abiotic reduction of NACs, the logarithm of the NACs' rate constants correlate with one-electron reduction potential values of the NACs (EH,NAC1) according to linear free energy relationships (LFERs). Here, we extend the application of LFERs to the bioreduction of NACs and to the abiotic reduction of NACs by bioreduced (and pasteurized) iron-bearing clay minerals. A linear correlation (R2=0.96) was found between the NACs' bioreduction rate constants (kobs) and EH,NAC1 values. The LFER slope of log kobs versus EH,NAC1/(2.303RT/F) was close to one (0.97), which implied that the first electron transfer to the NAC was the rate-limiting step of bioreduction. LFERs were also established between NAC abiotic reduction rate constants by bioreduced iron-bearing clay minerals (montmorillonite SWy-2 and nontronite NAu-2). The second-order NAC reduction rate constants (k) by bioreduced SWy-2 and NAu-2 were well correlated to EH,NAC1 (R2=0.97 for both minerals), consistent with bioreduction results. However, the LFER slopes of log k versus EH,NAC1/(2.303RT/F) were significantly less than one (0.48-0.50) for both minerals, indicating that the first electron transfer to the NAC was not the rate-limiting step of abiotic reduction. Finally, we demonstrate that the rate of 4-acetylnitrobenzene reduction by bioreduced SWy 2 and NAu-2 correlated to the reduction potential of the clay (EH,clay, R2=0.95 for both minerals), indicating that the clay reduction potential also influences its reactivity. PMID- 25723897 TI - Cytotoxic scalarane sesterterpenoids from the South China Sea sponge Carteriospongia foliascens. AB - Eleven new scalarane sesterterpenoids, including three 20,24-bishomo-25 norscalaranes, carteriofenones A-C (1-3), and eight 20,24-bishomoscalaranes, carteriofenones D-K (4-11), along with two known analogues (12 and 13), were obtained from the marine sponge Carteriospongia foliascens collected from the South China Sea. Their planar structures and relative configurations were elucidated by extensive NMR spectroscopic data. The absolute configuration of 3 was determined using the modified Mosher's method on its hydrolysis product. Scalarane sesterterpenoids with 4-methylpentanate or pentanoate substituents at the 12-position (1-8) were reported for the first time. Carteriofenones E-H (5-8) represented rare naturally occurring scalarane sesterterpenoids with a cyclobutane ring. Compound 4 showed cytotoxicity against the mouse lymphocytic leukemia cell line (P388) with an IC50 value of 0.96 MUM. PMID- 25723898 TI - Atmospheric mercury footprints of nations. AB - The Minamata Convention was established to protect humans and the natural environment from the adverse effects of mercury emissions. A cogent assessment of mercury emissions is required to help implement the Minamata Convention. Here, we use an environmentally extended multi-regional input-output model to calculate atmospheric mercury footprints of nations based on upstream production (meaning direct emissions from the production activities of a nation), downstream production (meaning both direct and indirect emissions caused by the production activities of a nation), and consumption (meaning both direct and indirect emissions caused by final consumption of goods and services in a nation). Results show that nations function differently within global supply chains. Developed nations usually have larger consumption-based emissions than up- and downstream production-based emissions. India, South Korea, and Taiwan have larger downstream production-based emissions than their upstream production- and consumption-based emissions. Developed nations (e.g., United States, Japan, and Germany) are in part responsible for mercury emissions of developing nations (e.g., China, India, and Indonesia). Our findings indicate that global mercury abatement should focus on multiple stages of global supply chains. We propose three initiatives for global mercury abatement, comprising the establishment of mercury control technologies of upstream producers, productivity improvement of downstream producers, and behavior optimization of final consumers. PMID- 25723900 TI - Reducing transmission risk through high-level disinfection of transvaginal ultrasound transducer handles. AB - Intracavity ultrasound transducer handles are not routinely immersed in liquid high-level disinfectants. We show that residual bacteria, including pathogens, persist on more than 80% of handles that are not disinfected, whereas use of an automated device reduces contamination to background levels. Clinical staff should consider the need for handle disinfection. PMID- 25723899 TI - The structural biology of CRISPR-Cas systems. AB - Prokaryotic CRISPR-Cas genomic loci encode RNA-mediated adaptive immune systems that bear some functional similarities with eukaryotic RNA interference. Acquired and heritable immunity against bacteriophage and plasmids begins with integration of ~30 base pair foreign DNA sequences into the host genome. CRISPR-derived transcripts assemble with CRISPR-associated (Cas) proteins to target complementary nucleic acids for degradation. Here we review recent advances in the structural biology of these targeting complexes, with a focus on structural studies of the multisubunit Type I CRISPR RNA-guided surveillance and the Cas9 DNA endonuclease found in Type II CRISPR-Cas systems. These complexes have distinct structures that are each capable of site-specific double-stranded DNA binding and local helix unwinding. PMID- 25723901 TI - Sodium thioether macrocyclic chemistry: remarkable homoleptic octathia coordination to Na(+). AB - Unprecedented homoleptic octathioether macrocyclic coordination to Na(+) in [Na([24]aneS8)](+) has been achieved by using Na[B{3,5-(CF3)2-C6H3}4] as a source of "naked" Na(+) ions and confirmed crystallographically, with d(Na-S) = 2.9561(15)-3.0524(15) A. Density functional theory calculations show that there is electron transfer from the S 3p and C 2p valence orbitals of the ligand to the 3s and 3p orbitals of the Na(+) ion upon complexation. PMID- 25723902 TI - Hybrid [n]arenes through thermodynamically driven macrocyclization reactions. AB - Hybrid [n]arenes, the class of medium-sized macrocyclic compounds consisting of different alkoxybenzene units, were obtained by a simple, one-pot, direct condensation of two different alkoxybenzenes with formaldehyde catalyzed by a Bronsted acid (trifluoroacetic acid). We have shown that, under Bronsted acid catalysis, this reaction is reversible and therefore governed by the relative stability of the products. The main macrocyclic products are hybrid [n]arenes consisting of four alkoxybenzene units of [2 + 2] or [3 + 1] stoichiometry. However, an unusual [3 + 2] hybrid macrocycle was also obtained as a main product of the condensation between 1,4-dimethoxybenzene, 1,3,5-trimethoxybenzene, and formaldehyde. The stability of the hybrid products and the reversibility of the reaction were further confirmed by a scrambling experiment, involving pillar[5]arene and per-O-methylated resorcin[4]arene. The scrambling experiment has given hybrid macrocycles in yields comparable with those obtained in condensation reactions. NMR spectra and X-ray structures of hybrid [n]arenes indicate that 1,2- and 1,3-dialkoxybenzene units are flexible parts of macrocyclic rings. However, the 1,4-dialkoxybenzene units present considerable steric hindrance, resulting in the formation of isomers and inherently chiral macrocycles due to inhibited rotation. The recognition properties toward various organic cations were also determined. Highly selective recognition of the N methylpyridinium cation was observed for the [3 + 2] hybrid macrocycle. PMID- 25723903 TI - Access to N-thioalkenyl and N-(o-thio)aryl-benzimidazol-2-ones by ring opening of thiazolobenzimidazolium and benzimidazobenzothiazolium salts and C-O bond cleavage of an alkoxide. AB - We report herein the synthesis of highly functionalized 1,3-dihydro-2H benzimidazol-2-ones via a ring opening of thiazolo[3,2-a]benzimidazolium or benzimidazo[2,1-b][1,3]benzothiazol-6-ium salts and an unusual C-O bond cleavage of an alkoxide. A large variety of benzimidazolones bearing an original N thioalkenyl or N-(o-thio)aryl group was obtained in high yields. The developed chemistry provides efficient and rapid access to the privileged benzimidazol-2 one scaffold. PMID- 25723904 TI - Elemental characterization of single-wall carbon nanotube certified reference material by neutron and prompt gamma activation analysis. AB - Instrumental neutron activation analysis with both relative and k0 standardization was used in four experienced laboratories to determine element mass fractions in single-wall carbon nanotube certified reference material (CRM) SWCNT-1. Results obtained were evaluated using the National Institute of Standards and Technology (NIST) "Type B On Bias" approach and yielded consensus values in agreement with National Research Council Canada (NRCC) certified values for Fe, Co, Ni, and Mo and provided mass fraction values for 13 additional elements, namely, Na, Mg, Al, K, Ca, Ti, V, Cr, Mn, Br, La, W, and Au. In addition, prompt gamma neutron activation analysis was employed to determine mass fractions of H, B, Co, Ni, and Mo. Results of this work provide a basis for the establishment of reference values of element mass fractions in CRM SWCNT-1, thus expanding its usability for more accurate characterization and benchmarking of similar nanotechnology materials. PMID- 25723905 TI - Comparative histometric analysis of the effects of high-intensity focused ultrasound and radiofrequency on skin. AB - INTRODUCTION: High-intensity focused ultrasound (HIFU) and radiofrequency (RF) are used for non-invasive skin tightening. Neocollagenesis and neoelastogenesis have been reported to have a mechanism of controlled thermal injury. OBJECTIVE: To compare neocollagenesis and neoelastogenesis in each layer of the dermis after each session of HIFU and monopolar RF. METHODS: We analyzed the area fraction of collagen and elastic fibers using the Masson's Trichrome and Victoria blue special stains, respectively, before and after 2 months of treatments. Histometric analyses were performed in each layer of the dermis, including the papillary dermis, and upper, mid, and deep reticular dermis. RESULTS: Monopolar RF led to neocollagenesis in the papillary dermis, and upper, mid, and deep reticular dermis, and neoelastogenesis in the papillary dermis, and upper and mid reticular dermis. HIFU led to neocollagenesis in the mid and deep reticular dermis and neoelastogenesis in the deep reticular dermis. Among these treatment methods, HIFU showed the highest level of neocollagenesis and neoelastogenesis in the deep reticular dermis. CONCLUSIONS: HIFU affects deep tissues and impacts focal regions. Monopolar RF also affects deep tissues, but impacts diffuse regions. We believe these data provide further insight into effective skin tightening. PMID- 25723906 TI - HIV patients' decision of switching to second-line antiretroviral therapy in India. AB - The objective is to examine when patients should switch to second-line antiretroviral therapy (ART) under health uncertainty and in the absence of viral load monitoring. We formalize and solve the therapeutic dilemma about whether or not, and when, to switch a therapy. The model's main value-added consists in the concrete application to patients with HIV in India. In our dynamic stochastic model, health level volatility can be understood as the variation in CD4 count and the trend of health level as increases in CD4 count and, thus, decreases in the incidence of opportunistic infections and mortality. The results of the empirical application suggest that the theoretical model can explain ART treatment switch. Treatment switch depends negatively on the volatility of patients' health, and on trend of health, i.e., the greater the variation in CD4 count and the more CD4 count increase, the fewer treatment switches one expects to occur. Treatment switch also depends negatively on the degree of irreversibility. Under irreversibility, low-risk patients must begin the second line treatment as soon as possible, which is precisely when the second-line treatment is least valuable. The existence of an option value means that ART first-line regimen may be the better choice when considering lifetime welfare. Conversely, treatment switch depends positively on the discount rate and on the correlation between the patient's health under first- and second-line treatments. This means that treatment switch is likelier to succeed in second-line treatments that are similar to the first-line treatments, implying that a decision-maker should not rely on treatment switch as a risk diversification tool. PMID- 25723908 TI - Oxidatively stable nanoporous silicon photocathodes with enhanced onset voltage for photoelectrochemical proton reduction. AB - Stable and high-performance nanoporous "black silicon" photoelectrodes with electrolessly deposited Pt nanoparticle (NP) catalysts are made with two metal assisted etching steps. Doubly etched samples exhibit an ~300 mV positive shift in photocurrent onset for photoelectrochemical proton reduction compared to oxide free planar Si with identical catalysts. We find that the photocurrent onset voltage of black Si photocathodes prepared from single-crystal planar Si wafers by an Ag-assisted etching process increases in oxidative environments (e.g., aqueous electrolyte) owing to a positive flat-band potential shift caused by surface oxidation. However, within 24 h, the surface oxide layer becomes a kinetic barrier to interfacial charge transfer that inhibits proton reduction. To mitigate this issue, we developed a novel second Pt-assisted etch process that buries the Pt NPs deep into the nanoporous Si surface. This second etch shifts the onset voltage positively, from +0.25 V to +0.4 V versus reversible hydrogen electrode, and reduces the charge-transfer resistance with no performance decrease seen for at least two months. PEC performance was stable owing to Pt NP catalysts that were buried deeply in the photoelectrode by the second etch, below a thick surface layer comprised primarily of amorphous SiO2 along with some degree of remaining crystalline Si as observed by scanning and transmission electron micrographs. Electrochemical impedance studies reveal that the second etch leads to a considerably smaller interfacial charge-transfer resistance than samples without the additional etch, suggesting that burying the Pt NPs improves the interfacial contact to the crystalline silicon surface. PMID- 25723909 TI - Carnitine supplementation alleviates lipid metabolism derangements and protects against oxidative stress in non-obese hereditary hypertriglyceridemic rats. AB - The aim of this study was to estimate the effect of carnitine supplementation on lipid disorders and peripheral tissue insulin sensitivity in a non-obese animal model of insulin resistance, the hereditary hypertriglyceridemic (HHTg) rat. Male HHTg rats were fed a standard diet, and half of them received daily doses of carnitine (500 mg.kg(-1) body weight) for 8 weeks. Rats of the original Wistar strain were used for comparison. HHTg rats exhibited increased urinary excretion of free carnitine and reduced carnitine content in the liver and blood. Carnitine supplementation compensated for this shortage and promoted urinary excretion of acetylcarnitine without any signs of (acyl)carnitine accumulation in skeletal muscle. Compared with their untreated littermates, carnitine-treated HHTg rats exhibited lower weight gain, reduced liver steatosis, lower fasting triglyceridemia, and greater reduction of serum free fatty acid content after glucose load. Carnitine treatment was associated with increased mitochondrial biogenesis and oxidative capacity for fatty acids, amelioration of oxidative stress, and restored substrate switching in the liver. In skeletal muscle (diaphragm), carnitine supplementation was associated with significantly higher palmitate oxidation and a more favorable complete to incomplete oxidation products ratio. Carnitine supplementation further enhanced insulin sensitivity ex vivo. No effects on whole-body glucose tolerance were observed. Our data suggest that some metabolic syndrome-related disorders, particularly fatty acid oxidation, steatosis, and oxidative stress in the liver, could be attenuated by carnitine supplementation. The effect of carnitine could be explained, at least partly, by enhanced substrate oxidation and increased fatty acid transport from tissues in the form of short-chain acylcarnitines. PMID- 25723910 TI - Cancer stem cells--the current status of an old concept: literature review and clinical approaches. AB - As regards their morphology and biology, tumours consist of heterogeneous cell populations. The cancer stem cell (CSC) hypothesis assumes that a tumour is hierarchically organized and not all of the cells are equally capable of generating descendants, similarly to normal tissue. The only cells being able to self-renew and produce a heterogeneous tumour cell population are cancer stem cells. CSCs probably derive from normal stem cells, although progenitor cells may be taken into consideration as the source of cancer stem cells. CSCs reside in the niche defined as the microenvironment formed by stromal cells, vasculature and extracellular matrix. The CSC assays include FACS sorting, xenotransplantation to immunodeficient mice (SCID), incubation with Hoechst 33342 dye, cell culture in non-adherent conditions, cell culture with bromodeoxyuridine. CSCs have certain properties that make them resistant to anticancer therapy, which suggests they may be the target for potential therapeutic strategies. PMID- 25723912 TI - Pediatric epilepsy and comorbid reading disorders, math disorders, or autism spectrum disorders: Impact of epilepsy on cognitive patterns. AB - INTRODUCTION: In pediatric epilepsy, comorbidities are reported to be frequent. The present study focusedon the cognitive patterns of children with isolated epilepsy, children with isolated neurodevelopmental disorders (reading disorders, math disorders, autism spectrum disorders), and children with epilepsy and these neurodevelopmental disorders as comorbidities. METHODS: Based on two samples of referred children, one with epilepsy, reading disorders, math disorders, or ASDs occurring in "isolation" (n=117) and one with reading disorders, math disorders, and ASDs occurring comorbid with epilepsy (n=171), cognitive patterns were compared. The patterns displayed by verbal and nonverbal abilities from the WISC series were studied with repeated measures ANOVA. Thereafter, an exploratory 2*3*2 factorial analysis was done to study the independent contribution of the type of comorbidity and of the presence or absence of epilepsy to the VIQ-PIQ pattern. RESULTS: In isolated epilepsy, a VIQ>PIQ pattern was found, which was not seen in the other disorders. When epilepsy and another disorder co-occurred, patterns were altered. They resembled partly the pattern seen in isolated epilepsy and partly the pattern seen in the isolated neurodevelopmental disorder. In comorbid reading disorders, the VIQ>PIQ pattern was mitigated; in comorbid math disorders, it was exacerbated. In comorbid ASDs, no clear pattern emerged. In the presence of epilepsy, patterns characteristic of isolated disorders appeared systematically shifted toward relatively lowered performance abilities or relatively spared verbal abilities. The similar "impact" exerted by epilepsy on the patterns of the various conditions suggested shared mechanisms. PMID- 25723913 TI - Oriented clay nanopaper from biobased components--mechanisms for superior fire protection properties. AB - The toxicity of the most efficient fire retardant additives is a major problem for polymeric materials. Cellulose nanofiber (CNF)/clay nanocomposites, with unique brick-and-mortar structure and prepared by simple filtration, are characterized from the morphological point of view by scanning electron microscopy and X-ray diffraction. These nanocomposites have superior fire protection properties to other clay nanocomposites and fiber composites. The corresponding mechanisms are evaluated in terms of flammability (reaction to a flame) and cone calorimetry (exposure to heat flux). These two tests provide a wide spectrum characterization of fire protection properties in CNF/montmorrilonite (MTM) materials. The morphology of the collected residues after flammability testing is investigated. In addition, thermal and thermo oxidative stability are evaluated by thermogravimetric analyses performed in inert (nitrogen) and oxidative (air) atmospheres. Physical and chemical mechanisms are identified and related to the unique nanostructure and its low thermal conductivity, high gas barrier properties and CNF/MTM interactions for char formation. PMID- 25723914 TI - Role of Bed Design and Head-of-Bed Articulation on Patient Migration. AB - The ramifications of patient migration toward the foot of the bed in intensive care units are not well understood. Migration may cause shear and friction between the patient and the mattress, reduce elevation of the patient's torso, and require frequent repositioning of the patient. This study assesses how bed design impacts both the amount of migration that patients undergo during head section articulation to 30 degrees and 45 degrees and the extent of torso compression following the articulation. PMID- 25723915 TI - A counterfactual p-value approach for benefit-risk assessment in clinical trials. AB - Clinical trials generally allow various efficacy and safety outcomes to be collected for health interventions. Benefit-risk assessment is an important issue when evaluating a new drug. Currently, there is a lack of standardized and validated benefit-risk assessment approaches in drug development due to various challenges. To quantify benefits and risks, we propose a counterfactual p-value (CP) approach. Our approach considers a spectrum of weights for weighting benefit risk values and computes the extreme probabilities of observing the weighted benefit-risk value in one treatment group as if patients were treated in the other treatment group. The proposed approach is applicable to single benefit and single risk outcome as well as multiple benefit and risk outcomes assessment. In addition, the prior information in the weight schemes relevant to the importance of outcomes can be incorporated in the approach. The proposed CPs plot is intuitive with a visualized weight pattern. The average area under CP and preferred probability over time are used for overall treatment comparison and a bootstrap approach is applied for statistical inference. We assess the proposed approach using simulated data with multiple efficacy and safety endpoints and compare its performance with a stochastic multi-criteria acceptability analysis approach. PMID- 25723916 TI - ENU mutagenesis in the mouse. AB - This article describes the treatment of laboratory mice with the mutagen N-ethyl N-nitrosourea (ENU) to induce very highly increased rates of mutation throughout the genome. Further, it describes several popular mating schemes designed to produce animals displaying phenotypes associated with the induced mutations. PMID- 25723917 TI - An overview of measuring impulsive behavior in mice. AB - Impulsive behavior is a key constituent of many psychiatric illnesses, with maladaptive response control being a feature of disorders such as ADHD, schizophrenia, mania, and addiction. In order to understand the neurological underpinnings of impulsivity, a number of behavioral tasks have been developed for use with animal models. Data from studies with rats and other animals have led to the idea of the existence of dissociable components of impulsivity, which in turn informs studies of human disorders and potentially the development of specific therapies. Increasingly, mouse models are being used to investigate the known genetic contribution to psychiatric disorders in which abnormal response control leads to altered impulsive behaviors. In order to maximize the potential of these mouse models, it is important that researchers take into account the non unitary nature of response control and impulsivity. In this article, we briefly review the tasks available to behavioral neuroscientists and how these can be used in order to tease apart the contribution of a specific genetic lesion into the discrete aspects of impulsive behavior. PMID- 25723918 TI - Transporting mouse embryos and germplasm as frozen or unfrozen materials. AB - The 21st century has seen a huge proliferation in the availability of genetically altered mice. The availability of these resources has been accompanied by ever greater opportunities for international collaborations between laboratories involving the exchange of mouse strains. This exchange can involve significant costs in terms of animal welfare and transportation expenses. In an attempt to mitigate some of these costs, the mouse community has developed a battery of techniques that can be used to avoid transporting live mice. Transporting frozen embryos and sperm at liquid nitrogen (LN2 ) temperatures using dry shippers has been common practice for some time. However, current advances in this field have refined transportation procedures and introduced new techniques for disseminating embryos and sperm: for example, shipping frozen sperm on dry ice, exchanging unfrozen epididymides from which sperm can be extracted, and transporting frozen/thawed embryos in isotonic media. This article discusses some of the current practices used by laboratories to transport mouse strains around the world without having to exchange live mice. PMID- 25723919 TI - In vitro fertilization in mice using the MBCD-GSH protocol. AB - Historically, timed mating of either naturally cycling or superovulated females has been the mainstay of pre-implantation embryo production. However, rising cage costs and the rapid expansion of biomedical research programs has necessitated the development of high-throughput approaches to mouse embryo production. In vitro fertilization (IVF) represents one such versatile tool offering many advantages to busy mouse facilities in terms of efficient use of space and resources. For example, strains can be taken off the shelf, frozen quickly as sperm, and recovered at a later date, small colonies can be rapidly expanded to meet demand, and IVF can be used to rescue strains that fail to breed or where the founder male is ill or has died suddenly. This article describes an IVF protocol currently used by many reproductive technologists to assist mouse biology programs. PMID- 25723920 TI - Model-based analysis of coupled equilibrium-kinetic processes: indirect kinetic studies of thermodynamic parameters using the dynamic data. AB - Thermodynamic studies of equilibrium chemical reactions linked with kinetic procedures are mostly impossible by traditional approaches. In this work, the new concept of generalized kinetic study of thermodynamic parameters is introduced for dynamic data. The examples of equilibria intertwined with kinetic chemical mechanisms include molecular charge transfer complex formation reactions, pH dependent degradation of chemical compounds and tautomerization kinetics in micellar solutions. Model-based global analysis with the possibility of calculating and embedding the equilibrium and kinetic parameters into the fitting algorithm has allowed the complete analysis of the complex reaction mechanisms. After the fitting process, the optimal equilibrium and kinetic parameters together with an estimate of their standard deviations have been obtained. This work opens up a promising new avenue for obtaining equilibrium constants through the kinetic data analysis for the kinetic reactions that involve equilibrium processes. PMID- 25723921 TI - Radiation damage to macromolecules: kill or cure? AB - Radiation damage induced by X-ray beams during macromolecular diffraction experiments remains an issue of concern in structural biology. While advances in our understanding of this phenomenon, driven in part by a series of workshops in this area, undoubtedly have been and are still being made, there are still questions to be answered. Eight papers in this volume give a flavour of ongoing investigations, addressing various issues. These range over: a proposed new metric derived from atomic B-factors for identifying potentially damaged amino acid residues, a study of the relative damage susceptibility of protein and DNA in a DNA/protein complex, a report of an indication of specific radiation damage to a protein determined from data collected using an X-ray free-electron laser (FEL), an account of the challenges in FEL raw diffraction data analysis, an exploration of the possibilities of using radiation damage induced phasing to solve structures using FELs, simulations of radiation damage as a function of FEL temporal pulse profiles, results on the influence of radiation damage during scanning X-ray diffraction measurements and, lastly, consideration of strategies for minimizing radiation damage during SAXS experiments. In this short introduction, these contributions are briefly placed in the context of other current work on radiation damage in the field. PMID- 25723922 TI - Identifying and quantifying radiation damage at the atomic level. AB - Radiation damage impedes macromolecular diffraction experiments. Alongside the well known effects of global radiation damage, site-specific radiation damage affects data quality and the veracity of biological conclusions on protein mechanism and function. Site-specific radiation damage follows a relatively predetermined pattern, in that different structural motifs are affected at different dose regimes: in metal-free proteins, disulfide bonds tend to break first followed by the decarboxylation of aspartic and glutamic acids. Even within these damage motifs the decay does not progress uniformly at equal rates. Within the same protein, radiation-induced electron density decay of a particular chemical group is faster than for the same group elsewhere in the protein: an effect known as preferential specific damage. Here, BDamage, a new atomic metric, is defined and validated to recognize protein regions susceptible to specific damage and to quantify the damage at these sites. By applying BDamage to a large set of known protein structures in a statistical survey, correlations between the rates of damage and various physicochemical parameters were identified. Results indicate that specific radiation damage is independent of secondary protein structure. Different disulfide bond groups (spiral, hook, and staple) show dissimilar radiation damage susceptibility. There is a consistent positive correlation between specific damage and solvent accessibility. PMID- 25723923 TI - Radiation damage to nucleoprotein complexes in macromolecular crystallography. AB - Significant progress has been made in macromolecular crystallography over recent years in both the understanding and mitigation of X-ray induced radiation damage when collecting diffraction data from crystalline proteins. In contrast, despite the large field that is productively engaged in the study of radiation chemistry of nucleic acids, particularly of DNA, there are currently very few X-ray crystallographic studies on radiation damage mechanisms in nucleic acids. Quantitative comparison of damage to protein and DNA crystals separately is challenging, but many of the issues are circumvented by studying pre-formed biological nucleoprotein complexes where direct comparison of each component can be made under the same controlled conditions. Here a model protein-DNA complex C.Esp1396I is employed to investigate specific damage mechanisms for protein and DNA in a biologically relevant complex over a large dose range (2.07-44.63 MGy). In order to allow a quantitative analysis of radiation damage sites from a complex series of macromolecular diffraction data, a computational method has been developed that is generally applicable to the field. Typical specific damage was observed for both the protein on particular amino acids and for the DNA on, for example, the cleavage of base-sugar N1-C and sugar-phosphate C-O bonds. Strikingly the DNA component was determined to be far more resistant to specific damage than the protein for the investigated dose range. At low doses the protein was observed to be susceptible to radiation damage while the DNA was far more resistant, damage only being observed at significantly higher doses. PMID- 25723924 TI - Indications of radiation damage in ferredoxin microcrystals using high-intensity X-FEL beams. AB - Proteins that contain metal cofactors are expected to be highly radiation sensitive since the degree of X-ray absorption correlates with the presence of high-atomic-number elements and X-ray energy. To explore the effects of local damage in serial femtosecond crystallography (SFX), Clostridium ferredoxin was used as a model system. The protein contains two [4Fe-4S] clusters that serve as sensitive probes for radiation-induced electronic and structural changes. High dose room-temperature SFX datasets were collected at the Linac Coherent Light Source of ferredoxin microcrystals. Difference electron density maps calculated from high-dose SFX and synchrotron data show peaks at the iron positions of the clusters, indicative of decrease of atomic scattering factors due to ionization. The electron density of the two [4Fe-4S] clusters differs in the FEL data, but not in the synchrotron data. Since the clusters differ in their detailed architecture, this observation is suggestive of an influence of the molecular bonding and geometry on the atomic displacement dynamics following initial photoionization. The experiments are complemented by plasma code calculations. PMID- 25723925 TI - XFEL diffraction: developing processing methods to optimize data quality. AB - Serial crystallography, using either femtosecond X-ray pulses from free-electron laser sources or short synchrotron-radiation exposures, has the potential to reveal metalloprotein structural details while minimizing damage processes. However, deriving a self-consistent set of Bragg intensities from numerous still crystal exposures remains a difficult problem, with optimal protocols likely to be quite different from those well established for rotation photography. Here several data processing issues unique to serial crystallography are examined. It is found that the limiting resolution differs for each shot, an effect that is likely to be due to both the sample heterogeneity and pulse-to-pulse variation in experimental conditions. Shots with lower resolution limits produce lower-quality models for predicting Bragg spot positions during the integration step. Also, still shots by their nature record only partial measurements of the Bragg intensity. An approximate model that corrects to the full-spot equivalent (with the simplifying assumption that the X-rays are monochromatic) brings the distribution of intensities closer to that expected from an ideal crystal, and improves the sharpness of anomalous difference Fourier peaks indicating metal positions. PMID- 25723926 TI - Towards RIP using free-electron laser SFX data. AB - Here, it is shown that simulated native serial femtosecond crystallography (SFX) cathepsin B data can be phased by rapid ionization of sulfur atoms. Utilizing standard software adopted for radiation-damage-induced phasing (RIP), the effects on both substructure determination and phasing of the number of collected patterns and fluences are explored for experimental conditions already available at current free-electron laser facilities. PMID- 25723927 TI - Simulations of radiation damage as a function of the temporal pulse profile in femtosecond X-ray protein crystallography. AB - Serial femtosecond X-ray crystallography of protein nanocrystals using ultrashort and intense pulses from an X-ray free-electron laser has proved to be a successful method for structural determination. However, due to significant variations in diffraction pattern quality from pulse to pulse only a fraction of the collected frames can be used. Experimentally, the X-ray temporal pulse profile is not known and can vary with every shot. This simulation study describes how the pulse shape affects the damage dynamics, which ultimately affects the biological interpretation of electron density. The instantaneously detected signal varies during the pulse exposure due to the pulse properties, as well as the structural and electronic changes in the sample. Here ionization and atomic motion are simulated using a radiation transfer plasma code. Pulses with parameters typical for X-ray free-electron lasers are considered: pulse energies ranging from 10(4) to 10(7) J cm(-2) with photon energies from 2 to 12 keV, up to 100 fs long. Radiation damage in the form of sample heating that will lead to a loss of crystalline periodicity and changes in scattering factor due to electronic reconfigurations of ionized atoms are considered here. The simulations show differences in the dynamics of the radiation damage processes for different temporal pulse profiles and intensities, where ionization or atomic motion could be predominant. The different dynamics influence the recorded diffracted signal in any given resolution and will affect the subsequent structure determination. PMID- 25723928 TI - On radiation damage in FIB-prepared softwood samples measured by scanning X-ray diffraction. AB - The high flux density encountered in scanning X-ray nanodiffraction experiments can lead to severe radiation damage to biological samples. However, this technique is a suitable tool for investigating samples to high spatial resolution. The layered cell wall structure of softwood tracheids is an interesting system which has been extensively studied using this method. The tracheid cell has a complex geometry, which requires the sample to be prepared by cutting it perpendicularly to the cell wall axis. Focused ion beam (FIB) milling in combination with scanning electron microscopy allows precise alignment and cutting without splintering. Here, results of a scanning X-ray diffraction experiment performed on a biological sample prepared with a focused ion beam of gallium atoms are reported for the first time. It is shown that samples prepared and measured in this way suffer from the incorporation of gallium atoms up to a surprisingly large depth of 1 um. PMID- 25723929 TI - Limiting radiation damage for high-brilliance biological solution scattering: practical experience at the EMBL P12 beamline PETRAIII. AB - Radiation damage is the general curse of structural biologists who use synchrotron small-angle X-ray scattering (SAXS) to investigate biological macromolecules in solution. The EMBL-P12 biological SAXS beamline located at the PETRAIII storage ring (DESY, Hamburg, Germany) caters to an extensive user community who integrate SAXS into their diverse structural biology programs. The high brilliance of the beamline [5.1 * 10(12) photons s(-1), 10 keV, 500 (H) um * 250 (V) um beam size at the sample position], combined with automated sample handling and data acquisition protocols, enable the high-throughput structural characterization of macromolecules in solution. However, considering the often significant resources users invest to prepare samples, it is crucial that simple and effective protocols are in place to limit the effects of radiation damage once it has been detected. Here various practical approaches are evaluated that users can implement to limit radiation damage at the P12 beamline to maximize the chances of collecting quality data from radiation sensitive samples. PMID- 25723930 TI - New methods in time-resolved Laue pump-probe crystallography at synchrotron sources. AB - Newly developed methods for time-resolved studies using the polychromatic and in particular the pink-Laue technique, suitable for medium and small-size unit cells typical in chemical crystallography, are reviewed. The order of the sections follows that of a typical study, starting with a description of the pink-Laue technique, followed by the strategy of data collection for analysis with the RATIO method. Novel procedures are described for spot integration, orientation matrix determination for relatively sparse diffraction patterns, scaling of multi crystal data sets, use of Fourier maps for initial assessment and analysis of results, and least-squares refinement of photo-induced structural and thermal changes. In the calculation of Fourier maps a ground-state structure model, typically based on monochromatic results, is employed as reference, and the laser ON structure factors for the Fourier summations are obtained by multiplying the reference ground-state structure factors by the square root of the experimental ON/OFF ratios. A schematic of the procedure followed is included in the conclusion section. PMID- 25723931 TI - Brightness of synchrotron radiation from undulators and bending magnets. AB - The maximum of the Wigner distribution (WD) of synchrotron radiation (SR) fields is considered as a possible definition of SR source brightness. Such a figure of merit was originally introduced in the SR community by Kim [(1986), Nucl. Instrum. Methods Phys. Res. A, 246, 71-76]. The brightness defined in this way is always positive and, in the geometrical optics limit, can be interpreted as the maximum density of photon flux in phase space. For undulator and bending magnet radiation from a single electron, the WD function can be explicitly calculated. In the case of an electron beam with a finite emittance the brightness is given by the maximum of the convolution of a single electron WD function and the probability distribution of the electrons in phase space. In the particular case when both electron beam size and electron beam divergence dominate over the diffraction size and the diffraction angle, one can use a geometrical optics approach. However, there are intermediate regimes when only the electron beam size or the electron beam divergence dominate. In these asymptotic cases the geometrical optics approach is still applicable, and the brightness definition used here yields back once more to the maximum photon flux density in phase space. In these intermediate regimes a significant numerical disagreement is found between exact calculations and the approximation for undulator brightness currently used in the literature. The WD formalism is extended to a satisfactory theory for the brightness of a bending magnet. It is found that in the intermediate regimes the usually accepted approximation for bending magnet brightness turns out to be inconsistent even parametrically. PMID- 25723932 TI - Thermal stress prediction in mirror and multilayer coatings. AB - Multilayer optics for X-rays typically consist of hundreds of periods of two types of alternating sub-layers which are coated on a silicon substrate. The thickness of the coating is well below 1 um (tens or hundreds of nanometers). The high aspect ratio (~10(7)) between the size of the optics and the thickness of the multilayer can lead to a huge number of elements (~10(16)) for the numerical simulation (by finite-element analysis using ANSYS code). In this work, the finite-element model for thermal-structural analysis of multilayer optics has been implemented using the ANSYS layer-functioned elements. The number of meshed elements is considerably reduced and the number of sub-layers feasible for the present computers is increased significantly. Based on this technique, single layer coated mirrors and multilayer monochromators cooled by water or liquid nitrogen are studied with typical parameters of heat-load, cooling and geometry. The effects of cooling-down of the optics and heating of the X-ray beam are described. It is shown that the influences from the coating on temperature and deformation are negligible. However, large stresses are induced in the layers due to the different thermal expansion coefficients between the layer and the substrate materials, which is the critical issue for the survival of the optics. This is particularly true for the liquid-nitrogen cooling condition. The material properties of thin multilayer films are applied in the simulation to predict the layer thermal stresses with more precision. PMID- 25723933 TI - A new extra-focus monochromator designed for high-performance VUV beamlines. AB - A new monochromator called an extra-focus constant-included-angle varied-line spacing (VLS) cylindrical-grating monochromator (extra-focus CIA-VCGM) is described. This monochromator is based on the Hettrick-Underwood scheme where the plane VLS grating is replaced by a cylindrical one in order to zero the defocus at three reference photon energies in the vacuum-ultraviolet range. It has a simple mechanical structure and a fixed focus spot with high performance over a wide energy range. Furthermore, its mechanical compatibility with a standard VLS plane-grating monochromator allows convenient extension into the soft-X-ray range. PMID- 25723934 TI - Pushing the limits: an instrument for hard X-ray imaging below 20 nm. AB - Hard X-ray microscopy is a prominent tool suitable for nanoscale-resolution non destructive imaging of various materials used in different areas of science and technology. With an ongoing effort to push the 2D/3D imaging resolution down to 10 nm in the hard X-ray regime, both the fabrication of nano-focusing optics and the stability of the microscope using those optics become extremely challenging. In this work a microscopy system designed and constructed to accommodate multilayer Laue lenses as nanofocusing optics is presented. The developed apparatus has been thoroughly characterized in terms of resolution and stability followed by imaging experiments at a synchrotron facility. Drift rates of ~2 nm h(-1) accompanied by 13 nm * 33 nm imaging resolution at 11.8 keV are reported. PMID- 25723935 TI - The influence of metallic brazing materials on the strain formation of internally water-cooled X-ray optics. AB - A study of metallic brazing material for internally cooled optics is presented. The study shows the influence of the different material properties on the final quality of the bond in terms of diffracted wavefront distortion, i.e. enlargement of the rocking curve. By choosing the proper brazing material and applying the proper brazing conditions, the influence of the brazing material can be fully eliminated. Furthermore the degradation of some brazing material due to the extreme working conditions of the optics is presented. Measurement results from ESRF and KEK confirm the importance of the proper brazing material choice. PMID- 25723936 TI - Comparative study of the X-ray reflectivity and in-depth profile of a-C, B4C and Ni coatings at 0.1-2 keV. AB - The use of soft X-rays near the carbon edge of absorption (270-300 eV) greatly enhances studies in various branches of science. However, the choice of reflecting coatings for mirrors operating in free-electron and X-ray free electron laser (FEL and XFEL) beamlines in this spectral range is not so evident and experimental justifications of the mirror efficiency are rather limited. In the present paper it is demonstrated experimentally that the reflectivity of B4C- and Ni-coated grazing-incidence mirrors is high enough for their operation in FEL or XFEL beamlines near the carbon K-edge of absorption. The minimal reflectivity of both mirrors proves to exceed 80% near the carbon absorption edge at a grazing angle of 0.6 degrees . An in-depth profile of the chemical elements composing the reflecting coatings is reconstructed based on analysis of a set of reflectivity curves measured versus the grazing angle at different photon energies in the soft X-ray spectral region. This allows us to predict correctly the mirror reflectivity at any X-ray energy and any grazing angle. PMID- 25723937 TI - Validation of a Geant4 model of the X-ray fluorescence microprobe at the Australian Synchrotron. AB - A Geant4 Monte Carlo simulation of the X-ray fluorescence microprobe (XFM) end station at the Australian Synchrotron has been developed. The simulation is required for optimization of the scan configuration and reconstruction algorithms. As part of the simulation process, a Gaussian beam model was developed. Experimental validation of this simulation has tested the efficacy for use of the low-energy physics models in Geant4 for this synchrotron-based technique. The observed spectral distributions calculated in the 384 pixel Maia detector, positioned in the standard back-scatter configuration, were compared with those obtained from experiments performed at three incident X-ray beam energies: 18.5, 11.0 and 6.8 keV. The reduced chi-squared (?chi^{2}_{?rm{red}}) was calculated for the scatter and fluorescence regions of the spectra and demonstrates that the simulations successfully reproduce the scatter distributions. Discrepancies were shown to occur in the multiple-scatter tail of the Compton continuum. The model was shown to be particularly sensitive to the impurities present in the beryllium window of the Maia detector and their concentrations were optimized to improve the ?chi^{2}_{?rm{red}} parametrization in the low-energy fluorescence regions of the spectra. PMID- 25723938 TI - In situ synchrotron X-ray diffraction investigation of the evolution of a PbO2/PbSO4 surface layer on a copper electrowinning Pb anode in a novel electrochemical flow cell. AB - This paper describes the quantitative measurement, by in situ synchrotron X-ray diffraction (S-XRD) and subsequent Rietveld-based quantitative phase analysis and thickness calculations, of the evolution of the PbO2 and PbSO4 surface layers formed on a pure lead anode under simulated copper electrowinning conditions in a 1.6 M H2SO4 electrolyte at 318 K. This is the first report of a truly in situ S XRD study of the surface layer evolution on a Pb substrate under cycles of galvanostatic and power interruption conditions, of key interest to the mining, solvent extraction and lead acid battery communities. The design of a novel reflection geometry electrochemical flow cell is also described. The in situ S XRD results show that beta-PbO2 forms immediately on the anode under galvanostatic conditions, and undergoes continued growth until power interruption where it transforms to PbSO4. The kinetics of the beta-PbO2 to PbSO4 conversion decrease as the number of cycles increases, whilst the amount of residual PbO2 increases with the number of cycles due to incomplete conversion to PbSO4. Conversely, complete transformation of PbSO4 to beta-PbO2 was observed in each cycle. The results of layer thickness calculations demonstrate a significant volume change upon PbSO4 to beta-PbO2 transformation. PMID- 25723939 TI - Noncrystalline structure of Ni-P nanoparticles prepared by liquid pulse discharge. AB - Noncrystalline nickel phosphide (Ni-P) nanoparticles have drawn great attention due to their high potential as catalysts. However, the structure of noncrystalline Ni-P nanoparticles is still unknown, which may shed light on explaining the catalysis mechanism of the Ni-P nanoparticles. In this paper, noncrystalline Ni-P nanoparticles were synthesized. Their morphology, particle size, element contents, local atomic structures, as well as the catalysis in the thermal decomposition of ammonium perchlorate were studied. The results demonstrate that the as-prepared Ni-P nanoparticles are spherical with an average diameter of about 13.5 nm. The Ni and P contents are, respectively, 78.15% and 21.85%. The noncrystalline nature of the as-prepared Ni-P nanoparticles can be attributed to cross-linkage between P-doping f.c.c.-like Ni centers and Ni3P-like P centers. The locally ordered Ni centers and P centers are the nuclei sites, which can explain well the origin of initial nuclei to form the crystalline phases after high-temperature annealing. The starting temperature of high temperature decomposition of ammonium perchlorate was found having a significant decrease in the presence of the noncrystalline Ni-P nanoparticles. Therefore, the as-prepared noncrystalline Ni-P nanoparticles can be used as a potential catalyst in the thermal decomposition of ammonium perchlorate. PMID- 25723940 TI - Stroboscopic detection of nuclear resonance in an arbitrary scattering channel. AB - The theory of heterodyne/stroboscopic detection of nuclear resonance scattering is developed, starting from the total scattering matrix as a product of the matrix of the reference sample and the sample under study. This general approach holds for all dynamical scattering channels. In the forward channel, which has been discussed in detail in the literature, the electronic scattering manifests itself only in an energy-independent diminution of the scattered intensity. In all other channels, complex resonance line shapes of the heterodyne/stroboscopic spectra are encountered, as a result of the interference of electronic and nuclear scattering. The grazing-incidence case will be evaluated and described in detail. Experimental data of classical X-ray reflectivity and their stroboscopically detected resonant counterpart spectra on the [(nat)Fe/(57)Fe]10 isotope periodic multilayer and antiferromagnetic [(57)Fe/Cr]20 superlattice are fitted simultaneously. PMID- 25723941 TI - Effective beam method for element concentrations. AB - There is a great diversity of research being conducted at synchrotron facilities around the world and a diverse set of beamlines to accommodate this research. Time is a precious commodity at synchrotron facilities; therefore, methods that can maximize the time spent collecting data are of value. At the same time the incident radiation spectrum, necessary for some research, may not be known on a given beamline. A preliminary presentation of a method applicable to X-ray fluorescence spectrocopic analyses that overcomes the lack of information about the incident beam spectrum that addresses both of these concerns is given here. The method is equally applicable for other X-ray sources so long as local conditions are considered. It relies on replacing the polychromatic spectrum in a standard fundamental parameters analysis with a set of effective monochromatic photon beams. A beam is associated with each element and can be described by an analytical function allowing extension to elements not included in the necessary calibration measurement(s). PMID- 25723942 TI - Planning, performing and analyzing X-ray Raman scattering experiments. AB - A compilation of procedures for planning and performing X-ray Raman scattering (XRS) experiments and analyzing data obtained from them is presented. In particular, it is demonstrated how to predict the overall shape of the spectra, estimate detection limits for dilute samples, and how to normalize the recorded spectra to absolute units. In addition, methods for processing data from multiple crystal XRS spectrometers with imaging capability are presented, including a super-resolution method that can be used for direct tomography using XRS spectra as the contrast. An open-source software package with these procedures implemented is also made available. PMID- 25723943 TI - Identification of the iron oxidation state and coordination geometry in iron oxide- and zeolite-based catalysts using pre-edge XAS analysis. AB - Analysis of the oxidation state and coordination geometry using pre-edge analysis is attractive for heterogeneous catalysis and materials science, especially for in situ and time-resolved studies or highly diluted systems. In the present study, focus is laid on iron-based catalysts. First a systematic investigation of the pre-edge region of the Fe K-edge using staurolite, FePO4, FeO and alpha-Fe2O3 as reference compounds for tetrahedral Fe(2+), tetrahedral Fe(3+), octahedral Fe(2+) and octahedral Fe(3+), respectively, is reported. In particular, high resolution and conventional X-ray absorption spectra are compared, considering that in heterogeneous catalysis and material science a compromise between high quality spectroscopic data acquisition and simultaneous analysis of functional properties is required. Results, which were obtained from reference spectra acquired with different resolution and quality, demonstrate that this analysis is also applicable to conventionally recorded pre-edge data. For this purpose, subtraction of the edge onset is preferentially carried out using an arctangent and a first-degree polynomial, independent of the resolution and quality of the data. For both standard and high-resolution data, multiplet analysis of pre-edge features has limitations due to weak transitions that cannot be identified. On the other hand, an arbitrary empirical peak fitting assists the analysis in that non-local transitions can be isolated. The analysis of the oxidation state and coordination geometry of the Fe sites using a variogram-based method is shown to be effective for standard-resolution data and leads to the same results as for high-resolution spectra. This method, validated by analysing spectra of reference compounds and their well defined mixtures, is finally applied to track structural changes in a 1% Fe/Al2O3 and a 0.5% Fe/BEA zeolite catalyst during reduction in 5% H2/He. The results, hardly accessible by other techniques, show that Fe(3+) is transformed into Fe(2+), while the local Fe-O coordination number of 4-5 is maintained, suggesting that the reduction involves a rearrangement of the oxygen neighbours rather than their removal. In conclusion, the variogram-based analysis of Fe K-edge spectra proves to be very useful in catalysis research. PMID- 25723944 TI - 57Fe polarization-dependent synchrotron Mossbauer spectroscopy using a diamond phase plate and an iron borate nuclear Bragg monochromator. AB - Energy-domain (57)Fe polarization-dependent synchrotron radiation Mossbauer spectroscopy was developed by using a diamond X-ray phase plate and an iron borate nuclear Bragg monochromator. The former controls the polarization of the incident synchrotron radiation X-rays and the latter filters the (57)Fe-Mossbauer radiation with a narrow bandwidth of ~3.4 Gamma0 (Gamma0 ? 4.7 neV: natural linewidth of the (57)Fe nucleus) from the broadband synchrotron radiation. The developed nuclear diffraction optics allowed (57)Fe-Mossbauer studies to be performed with various polarization states, i.e. linear polarization, circular polarization and non-polarization. In this paper, the spectrometer system, beam characterization, performance-test experiments and a grazing-incidence Mossbauer measurement of an isotope-enriched ((57)Fe: 95%) iron thin film are described. PMID- 25723945 TI - Strategies and limitations for fluorescence detection of XAFS at high flux beamlines. AB - The issue of detecting the XAFS signal from dilute samples is discussed in detail with the aim of making best use of high flux beamlines that provide up to 10(13) photons s(-1). Various detection methods are compared, including filters with slits, solid state detectors, crystal analyzers and combinations of these. These comparisons rely on simulations that use experimentally determined parameters. It is found that inelastic scattering places a fundamental limit on detection, and that it is important to take proper account of the polarization dependence of the signals. The combination of a filter-slit system with a solid state detector is a promising approach. With an optimized system good performance can be obtained even if the total count rate is limited to 10(7) Hz. Detection schemes with better energy resolution can help at the largest dilutions if their collection efficiency and count rate limits can be improved. PMID- 25723946 TI - Ancient administrative handwritten documents: X-ray analysis and imaging. AB - Handwritten characters in administrative antique documents from three centuries have been detected using different synchrotron X-ray imaging techniques. Heavy elements in ancient inks, present even for everyday administrative manuscripts as shown by X-ray fluorescence spectra, produce attenuation contrast. In most cases the image quality is good enough for tomography reconstruction in view of future applications to virtual page-by-page 'reading'. When attenuation is too low, differential phase contrast imaging can reveal the characters from refractive index effects. The results are potentially important for new information harvesting strategies, for example from the huge Archivio di Stato collection, objective of the Venice Time Machine project. PMID- 25723947 TI - Registration of the rotation axis in X-ray tomography. AB - There is high demand for efficient, robust and automated routines for tomographic data reduction, particularly for synchrotron data. Registration of the rotation axis in data processing is a critical step affecting the quality of the reconstruction and is not easily implemented with automation. Existing methods for calculating the center of rotation have been reviewed and an improved algorithm to register the rotation axis in tomographic data is presented. The performance of the proposed method is evaluated using synchrotron-based microtomography data on geological samples with and without artificial reduction of the signal-to-noise ratio. The proposed method improves the reconstruction quality by correcting both the tilting error and the translational offset of the rotation axis. The limitation of this promising method is also discussed. PMID- 25723948 TI - Profile etching for prefiguring X-ray mirrors. AB - A method to pre-shape mirror substrates through etching with a broad-beam ion source and a contoured mask is presented. A 100 mm-long elliptical cylinder substrate was obtained from a super-polished flat Si substrate with a 48 nm root mean-square (r.m.s.) figure error and a 1.5 A r.m.s. roughness after one profile etching process at a beam voltage of 600 V without iteration. A follow-up profile coating can be used to achieve a final mirror. Profile etching and profile coating combined provide an economic way to make X-ray optics, such as nested Kirkpatrick-Baez mirrors. PMID- 25723949 TI - A small and robust active beamstop for scattering experiments on high-brilliance undulator beamlines. AB - A small active in-vacuum beamstop has been developed to monitor the flux of intense third-generation synchrotron X-ray beams protecting the downstream detector from the direct beam. Standard active beamstops, where a built-in diode directly absorbs the beam, have limitations in size and lifetime. In the present design, a silicon PIN diode detects the photons back-scattered from a cavity in the beamstop. This approach drastically reduces the radiation dose on the diode and thus increases its lifetime. The beamstop with a diameter of 2 mm has been fabricated to meet the requirements for the P12 bioSAXS beamline of EMBL Hamburg at PETRA III (DESY). The beamstop is in regular user operation at the beamline and displays a good response over the range of energies tested (6-20 keV). Further miniaturization of the diode is easily possible as its size is not limited by the PIN diode used. PMID- 25723950 TI - CDApps: integrated software for experimental planning and data processing at beamline B23, Diamond Light Source. AB - The B23 Circular Dichroism beamline at Diamond Light Source has been operational since 2009 and has seen visits from more than 200 user groups, who have generated large amounts of data. Based on the experience of overseeing the users' progress at B23, four key areas requiring the most assistance are identified: planning of experiments and note-keeping; designing titration experiments; processing and analysis of the collected data; and production of experimental reports. To streamline these processes an integrated software package has been developed and made available for the users. The subsequent article summarizes the main features of the software. PMID- 25723951 TI - Coherent imaging at the diffraction limit. Erratum. PMID- 25723953 TI - Regional ozone impacts of increased natural gas use in the Texas power sector and development in the Eagle Ford shale. AB - The combined emissions and air quality impacts of electricity generation in the Texas grid and natural gas production in the Eagle Ford shale were estimated at various natural gas price points for the power sector. The increased use of natural gas in the power sector, in place of coal-fired power generation, drove reductions in average daily maximum 8 h ozone concentration of 0.6-1.3 ppb in northeastern Texas for a high ozone episode used in air quality planning. The associated increase in Eagle Ford upstream oil and gas production nitrogen oxide (NOx) emissions caused an estimated local increase, in south Texas, of 0.3-0.7 ppb in the same ozone metric. In addition, the potential ozone impacts of Eagle Ford emissions on nearby urban areas were estimated. On the basis of evidence from this work and a previous study on the Barnett shale, the combined ozone impact of increased natural gas development and use in the power sector is likely to vary regionally and must be analyzed on a case by case basis. PMID- 25723954 TI - Pre-processing of Fourier transform infrared spectra by means of multivariate analysis implemented in the R environment. AB - Pre-processing of Fourier transform infrared (FTIR) spectra is typically the first and crucial step in data analysis. Very often hyperspectral datasets include the regions characterized by the spectra of very low intensity, for example two-dimensional (2D) maps where the areas with only support materials (like mylar foil) are present. In that case segmentation of the complete dataset is required before subsequent evaluation. The method proposed in this contribution is based on a multivariate approach (hierarchical cluster analysis), and shows its superiority when compared to the standard method of cutting-off by using only the mean spectral intensity. Both techniques were implemented and their performance was tested in the R statistical environment - open-source platform - that is a favourable solution if the repeatability and transparency are the key aspects. PMID- 25723955 TI - Activation of group II metabotropic glutamate receptors blocks zinc release from hippocampal mossy fibers. AB - BACKGROUND: The hippocampal CA3 area contains large amounts of vesicular zinc in the mossy fiber terminals which is released during synaptic activity, depending on presynaptic calcium. Another characteristic of these synapses is the presynaptic localization of high concentrations of group II metabotropic glutamate receptors, specifically activated by DCG-IV. Previous work has shown that DCG-IV affects only mossy fiber-evoked responses but not the signals from associational-commissural afferents, blocking mossy fiber synaptic transmission. Since zinc is released from mossy fibers even for single stimuli and it is generally assumed to be co-released with glutamate, the aim of the work was to investigate the effect of DCG-IV on mossy fiber zinc signals. RESULTS: Studies were performed using the membrane-permeant fluorescent zinc probe TSQ, and indicate that DCG-IV almost completely abolishes mossy fiber zinc changes as it does with synaptic transmission. CONCLUSIONS: Zinc signaling is regulated by the activation of type II metabotropic receptors, as it has been previously shown for glutamate, further supporting the corelease of glutamate and zinc from mossy fibers. PMID- 25723956 TI - Health impact assessment of cyclone Bejisa in Reunion Island (France) using syndromic surveillance. AB - INTRODUCTION: On January 2, 2014, Cyclone Bejisa struck Reunion Island (France). This storm led to major material damages, such as power outages, disturbance of drinking water systems, road closures, and the evacuation of residents. In this context, the Regional Office of French Institute for Public Health Surveillance in Indian Ocean (Cire OI) set up an epidemiological surveillance in order to describe short-term health effects of the cyclone. METHODS: The assessment of the health impact was based mainly on a syndromic surveillance system, including the activity of all emergency departments (EDs) and the Emergency Medical Service (EMS) of the island. From these data, several health indicators were collected and analyzed daily and weekly. To complete this assessment, all medical charts recorded in the EDs of Reunion Island from January 2, 2014 through January 5, 2014 were reviewed in order to identify visits directly and indirectly related to the cyclone, and to determine mechanisms of injuries. RESULTS: The number of calls to the EMS peaked the day of the cyclone, and the number of ED visits increased markedly over the next two days. At the same time, a significant increase in visits for trauma, burns, and carbon monoxide poisoning was detected in all EDs. Among 1,748 medical records reviewed, eight visits were directly related to the cyclone and 208 were indirectly related. For trauma, the main mechanisms of injury were falls and injuries by machinery or tools during the clean-up and repair works. Due to prolonged power outages, several patients were hospitalized: some to assure continuity of care, others to take care of an exacerbation of a chronic disease. An increase in leptospirosis cases linked to post-cyclone clean-up was observed two weeks after the cyclone. CONCLUSION: Information based on the syndromic surveillance system allowed the authors to assess rapidly the health impact of Cyclone Bejisa in Reunion Island; however, an underestimation of this impact was still possible. In the near future, several lines of work will be planned by the authors in order to improve the assessment. PMID- 25723957 TI - Fruits and barks extracts of Zanthozyllum heitzii a spice from Cameroon induce mitochondrial dependent apoptosis and Go/G1 phase arrest in human leukemia HL-60 cells. AB - BACKGROUND: Zanthoxylum heitzii is a spice used to prepare several dishes and to treat tumors, syphilis, malaria, cardiac palpitations, urogenital infections in the west region of Cameroon, but the antitumor mechanisms and chemical composition are not yet investigated. This study was aimed to determine the antiproliferative effects of four extracts from the fruits and barks of Zanthoxyllum heitzii (Rutaceae) on apoptosis in human promyelocytic cells, their mechanisms and the chemical composition. The 3-(4, 5-dimethylthiazole-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay was used to determine the fifty percent inhibition (IC50) concentration of the cell lines after treatment. The effect on morphology was observed using a light or fluorescence microscopy. The rate of apoptosis and the cell cycle were measured using flow cytometry (FCM). The phytochemical analysis of the extract was carried with HPLC/MS methods. RESULTS: The phytochemical analysis of the extracts indicated the presence of four known polyphenols (Syringic acid, Juglon, Luteolin and Myricetin) in both fruits and barks of Z. heitzii but in different quantities. Syringic acid and Myricetin concentrations were between 17-21 fold higher in the fruits than the stem bark. Rhamnetin (393.35 MUg/mL) and Oleuropein (63.10 MUg/mL) were identified only in the stem barks of Z. heitzii. Among the four extracts tested for cytotoxicity properties, only the methanol extract of fruits and barks significantly inhibited cell proliferation of HL-60 cells with IC50 value of 20 MUg/mL and 12 MUg/mL respectively. HL-60 cells treated with Z. heitzii extracts significantly produced reactive oxygen species (ROS) with concurrent loss of mitochondrial membrane potential (MMP). Modifications in the DNA distribution and enhanced of G1/G0 phase cell cycle arrest were observed in a concentration dependent manner. CONCLUSIONS: Polyphenols from Z. heitzii plant exert inhibitory effect on HL-60 cells through the reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and cell cycle destabilization. PMID- 25723958 TI - Fractionation, transfer, and ecological risks of heavy metals in riparian and ditch wetlands across a 100-year chronosequence of reclamation in an estuary of China. AB - The effect of reclamation on heavy metal concentrations and the ecological risks in ditch wetlands (DWs) and riparian wetlands (RWs) across a 100-year chronosequence in the Pearl River Estuary of China was investigated. Concentrations of 4 heavy metals (Cd, Cu, Pb, and Zn) in soil and plant samples, and sequential extracts of soil samples were determined, using inductively coupled plasma atomic absorption spectrometry. Results showed that heavy metal concentrations were higher in older DW soils than in the younger ones, and that the younger RW soils contained higher heavy metal concentrations compared to the older ones. Although the increasing tendency of heavy metal concentrations in soil was obvious after wetland reclamation, the metals Cu, Pb, and Zn exhibited low or no risks to the environment based on the risk assessment code (RAC). Cd, on the other hand, posed a medium or high risk. Cd, Pb, and Zn were mainly bound to Fe-Mn oxide, whereas most of Cu remained in the residual phase in both ditch and riparian wetland soils, and the residual proportions generally increased with depth. Bioconcentration and translocation factors for most of these four heavy metals significantly decreased in the DWs with older age (p<0.05), whereas they increased in the RWs with younger age (p<0.05). The DW soils contained higher concentrations of heavy metals in the organic fractions, whereas there were more carbonate and residual fractions in the RW soils. The non-bioavailable fractions of Cu and Zn, and the organic-bound Cd and Pb significantly inhibited plant growth. PMID- 25723959 TI - Revegetation impacts soil nitrogen dynamics in the water level fluctuation zone of the Three Gorges Reservoir, China. AB - Revegetations in riparian ecosystem are important in regulating soil nitrogen (N) dynamics. However, impacts of revegetation on soil N cycling and thereby on ecosystem functioning are not fully understood. We conducted an in situ incubation in the water level fluctuation zone (WLFZ) of the Three Gorges Reservoir region to evaluate soil N transformation including net N mineralization rate, net ammonification rate, net nitrification rate, net denitrification rate, N leaching and plant N uptake as well as the soil inorganic N (NH4(+)-N and NO3( )-N) concentration in the top soils (0-20 cm) following revegetations (implementing tree, shrub and herb plantations) over two years. The soil inorganic N concentration and N leaching were lower in the tree soils than in herb and shrub soils. Tree plantations decreased net N mineralization rate and net ammonification rate compared to herb and shrub soils, possibly due to lower soil organic carbon (SOC) input and soil temperatures. Whereas tree plantations increased soil net denitrification rate compared to herb and shrub soils because of higher tree NO3(-)-N uptake together with higher net nitrification rate. The inorganic N in the tree and shrub soils were lower in fall and summer, respectively, which was dependent on the seasonal variations in plant N uptake, soil N transformation, and N leaching. Thus, our results suggest that tree plantations could decrease soil inorganic N concentration and N leaching by altering both the quantity and quality of SOC and thereby potentially improve water quality in the riparian zone. PMID- 25723960 TI - Interaction of human adenoviruses and coliphages with kaolinite and bentonite. AB - Human adenoviruses (hAdVs) are pathogenic viruses responsible for public health problems worldwide. They have also been used as viral indicators in environmental systems. Coliphages (e.g., MS2, PhiX174) have also been studied as indicators of viral pollution in fecally contaminated water. Our objective was to evaluate the distribution of three viral fecal indicators (hAdVs, MS2, and PhiChi174), between two different phyllosilicate clays (kaolinite and bentonite) and the aqueous phase. A series of static and dynamic experiments were conducted under two different temperatures (4, 25 degrees C) for a time period of seven days. HAdV adsorption was examined in DNase I reaction buffer (pH=7.6, and ionic strength (IS)=1.4mM), whereas coliphage adsorption in phosphate buffered saline solution (pH=7, IS=2mM). Moreover, the effect of IS on hAdV adsorption under static conditions was evaluated. The adsorption of hAdV was assessed by real-time PCR and its infectivity was tested by cultivation methods. The coliphages MS2 and PhiChi174 were assayed by the double-layer overlay method. The experimental results have shown that coliphage adsorption onto both kaolinite and bentonite was higher for the dynamic than the static experiments; whereas hAdV adsorption was lower under dynamic conditions. The adsorption of hAdV increased with decreasing temperature, contrary to the results obtained for the coliphages. This study examines the combined effect of temperature, agitation, clay type, and IS on hAdV adsorption onto clays. The results provide useful new information on the effective removal of viral fecal indicators (MS2, PhiX174 and hAdV) from dilute aqueous solutions by adsorption onto kaolinite and bentonite. Factors enabling enteric viruses to penetrate soils, groundwater and travel long distances within aquifers are important public health issues. Because the observed adsorption behavior of surrogate coliphages MS2 and PhiChi174 is substantially different to that of hAdV, neither MS2 nor PhiChi174 is recommended as a suitable model for adenovirus. PMID- 25723961 TI - Tracing contamination sources in soils with Cu and Zn isotopic ratios. AB - Copper (Cu) and zinc (Zn) are naturally present and ubiquitous in soils and are important micronutrients. Human activities contribute to the input of these metals to soils in different chemical forms, which can sometimes reach a toxic level for soil organisms and plants. Isotopic signatures could be used to trace sources of anthropogenic Cu and Zn pollution. The aim of this paper is to determine whether it is possible to identify (i) Cu and Zn contamination in soils and their sources, on the basis of their isotopic signatures, and (ii) situations that are a priori favorable or not for tracing Cu and Zn pollution using the isotopic approach. Therefore, we compiled data from the literature on Cu and Zn isotopes in soils, rocks and pollutants and added to this database the results of our own research. As only a few studies have dealt with agricultural contamination, we also studied a soil toposequence from Brittany, France, that experienced spreading of pig slurry for tens of years. In the surface horizons of the natural soils, the delta(65)Cu values vary from -0.15 to 0.440/00 and the delta(66)Zn from -0.03 to 0.430/00. Furthermore, vertical variations along soil profiles range from -0.95 to 0.440/00 for delta(65)Cu and from -0.53 to 0.640/00 for delta(66)Zn values. We concluded that pedogenetic processes can produce isotopic fractionation, yet, it is not always discernible and can be overprinted by an exogenous isotopic signature. Furthermore, some contaminants are enriched in heavy Cu or in light Zn compared to the rock or soil, but no generalization can be made. The anthropogenic inputs can be identified based on stable Cu and Zn isotope ratios if the isotope ratios of the sources are different from those of the soil, which needs to be tested for each individual case. PMID- 25723962 TI - Contemporary techniques for freezing mouse spermatozoa. AB - Each year, thousands of new mouse models are generated around the world to further biomedical research. Unfortunately, the cost of maintaining mouse colonies makes it uneconomical to keep strains on the shelf that are not part of active research programs. Ideally, these retired strains should be archived. If this is not done and the line is simply killed off, the genetics are lost to future generations of scientists. Traditionally, embryo freezing has been used to cryopreserve mice, but this is expensive, time consuming, requires large numbers of donor females, and usually involves invasive superovulation procedures. Sperm freezing circumvents all of these disadvantages and is rapidly becoming the technique of choice for many repositories. This has been made possible through the use of refined cryoprotective agents and the development of improved in vitro fertilization techniques. This article describes two popular sperm freezing techniques employed by mouse repositories to archive spermatozoa using cryoprotective agents supplemented with either L-glutamine or monothioglycerol. PMID- 25723963 TI - Overview of mouse models of Parkinson's disease. AB - Parkinson's disease is a neurodegenerative disorder characterized by the loss of neurons in specific regions of the nervous system, notably in the substantia nigra pars compacta and, in most cases, by the deposition of intraneuronal inclusions named Lewy bodies. These pathological alterations have profound effects on the brain function, leading to the progressive development of various symptoms, the most prominent being the impaired initiation of voluntary movements caused by the loss of dopamine signaling in the basal ganglia. Here, we provide an overview of the mouse models of Parkinson's disease, with the goal of guiding selection of the most appropriate model for studying the question at hand. Pharmacological approaches targeting dopamine signaling and toxins leading to selective degeneration of nigral neurons are used to validate symptomatic treatments that aim at restoring effective dopaminergic function for motor control. Alternative mouse models are based on genetic modifications that are meant to reproduce the inherited alterations associated with familial forms of Parkinson's disease. Although genetic models have most often failed to induce overt degeneration of nigral dopaminergic neurons, they provide essential tools to explore the multifactorial etiology of this complex neurodegenerative disorder. PMID- 25723964 TI - Real-time ultrasound-guided needle injection of the mouse jugular vein. AB - This unit describes a novel method for direct venous injection into mice that offers potentially significant advantages over commonly used mouse vein injection techniques. This is achieved via percutaneous needle placement into the mouse jugular vein under real-time B-mode ultrasound (US) imaging. Real-time US imaging of the injection process allows for immediate determination of the overall success of injection. Unique, and potentially significant, advantages of this technique over others include: (1) direct visual confirmation of needle tip placement in the lumen of the vein, (2) immediate visual detection of extravascular extravasation of injectate, when compared to blinded techniques, such as tail vein injections, and (3) reduced morbidity and mortality compared to surgical vascular access techniques (i.e., jugular vein cannulation). This technique may lead to more accurate determination of the success of the injection procedure for each mouse, thus improving the quality of acquired data in dependent mouse experiments. PMID- 25723965 TI - Palladium-catalyzed regio-selective oxidative C-H bond acylation of azoxybenzenes with alcohols. AB - A palladium-catalyzed regio-selective acylation of C-H bonds of azoxybenzenes with alcohols was developed using tert-butyl hydroperoxide (TBHP) as an oxidant. Alcohol derivatives can act as effective acyl precursors in situ, which are less toxic, inexpensive, stable, and commercially available. These transformations proceeded smoothly and could tolerate a variety of functional groups. PMID- 25723966 TI - Evidence for suppression of immunity as a driver for genomic introgressions and host range expansion in races of Albugo candida, a generalist parasite. AB - How generalist parasites with wide host ranges can evolve is a central question in parasite evolution. Albugo candida is an obligate biotrophic parasite that consists of many physiological races that each specialize on distinct Brassicaceae host species. By analyzing genome sequence assemblies of five isolates, we show they represent three races that are genetically diverged by ~1%. Despite this divergence, their genomes are mosaic-like, with ~25% being introgressed from other races. Sequential infection experiments show that infection by adapted races enables subsequent infection of hosts by normally non infecting races. This facilitates introgression and the exchange of effector repertoires, and may enable the evolution of novel races that can undergo clonal population expansion on new hosts. We discuss recent studies on hybridization in other eukaryotes such as yeast, Heliconius butterflies, Darwin's finches, sunflowers and cichlid fishes, and the implications of introgression for pathogen evolution in an agro-ecological environment. PMID- 25723968 TI - Identification of Genetic Variants of Gestational Diabetes in South Indians. AB - BACKGROUND: This study examined the association in a South Indian population with gestational diabetes mellitus (GDM) of type 2 diabetes risk variants that have previously conferred susceptibility to GDM in other populations. SUBJECTS AND METHODS: The study groups comprised 518 women with GDM and 910 pregnant women with normal glucose tolerance (NGT). Women with GDM were recruited from a tertiary diabetes center in Chennai, in south India, and NGT women were selected from antenatal clinics also in Chennai. Genomic DNA was isolated from whole blood using the phenol chloroform method. Twelve previously reported GDM-associated single nucleotide polymorphisms (SNPs) in or near nine loci were genotyped using the MassARRAYTM system (Sequenom, San Diego, CA). RESULTS: Among the 12 SNPs genotyped, 11 SNPs were in Hardy-Weinberg equilibrium and had a call rate of >95%. Of the 11 SNPs previously associated with GDM in other populations, significant association was observed only with the rs7754840 and rs7756992 SNPs of the CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) gene in this population. The minor alleles of the SNPs rs7754840 and rs7756992 showed significant susceptibility to GDM with an odds ratio of 1.34 (95% confidence interval, 1.12-1.60; P = 0.0013) and 1.45 (95% confidence interval, 1.21-1.72; P = 0.00004), respectively. CONCLUSIONS: The rs7754840 and rs7756992 SNPs of the CDKAL1 gene were found to be associated with GDM in this south Indian population. This is the first study describing genetic susceptibility of GDM in Asian Indians. PMID- 25723967 TI - Corelease of acetylcholine and GABA from cholinergic forebrain neurons. AB - Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons. PMID- 25723969 TI - [Therapeutic surgery of the cornea. Part 1: keratoplasty]. PMID- 25723970 TI - [Imaging of the Lacrimal Gland and the Lacrimal Drainage System]. PMID- 25723971 TI - [Episcleritis and scleritis]. PMID- 25723972 TI - Quality and severity of depression in borderline personality disorder: A systematic review and meta-analysis. AB - Depression in borderline personality disorder (BPD) is hypothesized to be distinct in quality and severity. This paper provides a systematic review of depression quality, and a meta-analysis of depression severity in BPD patients compared to those with depressive disorders (DeDs) only. Based on a systematic literature search, 26 studies were identified for systematic review and 35 studies (3425 participants) were included for meta-analysis. The review focused on different forms of depressive symptoms, affective impairment, self-evaluation, and negative interpersonal experiences. The meta-analysis examined age, gender, presence of comorbid DeDs in BPD patients, and type of depression scale as moderators of effect sizes. Findings indicate that depression quality in BPD is characterized by higher anger/hostility and self-criticism. There was no significant difference in depression severity between BPD and DeD groups, and a high level of heterogeneity. Moderator analyses revealed lower depression severity in BPD patients without comorbid DeDs, but higher severity in BPD patients with comorbid DeDs compared to depressed controls. Our results suggest high variability in depression severity across BPD patients, point toward the consideration of comorbid DeDs, and lend partial support to a BPD-specific depression quality. We discuss difficulties in research on depression in BPD, and offer directions for future studies. PMID- 25723973 TI - Reducing postpartum weight retention and improving breastfeeding outcomes in overweight women: a pilot randomised controlled trial. AB - Overweight and obesity is prevalent among women of reproductive age (42% BMI > 25 kg/m2) and parity is associated with risk of weight gain. Weight gain greater than that recommended by the Institute of Medicine (IOM )is also associated with lower rates of breastfeeding initiation and duration in women. The aim of this pilot randomised controlled trial is to examine the feasibility of recruiting and maintaining a cohort of pregnant women with the view of reducing postpartum weight retention and improving breastfeeding outcomes. Women (BMI of 25-35 kg/m2 (n = 36)) were recruited from the John Hunter Hospital antenatal clinic in New South Wales, Australia. Participants were stratified by BMI and randomised to one of three groups with follow-up to six months postpartum. Women received a dietary intervention with or without breastfeeding support from a lactation consultant, or were assigned to a wait-list control group where the dietary intervention was issued at three months postpartum. Feasibility and acceptability was assessed by participation rates and questionnaire. Analysis of variance and covariance was conducted to determine any differences between groups. Sixty-nine per cent of the participants were still enrolled at six months postpartum. This pilot demonstrated some difficulties in recruiting women from antenatal clinics and retaining them in the trial. Although underpowered; the results on weight; biomarkers and breastfeeding outcomes indicated improved metabolic health. PMID- 25723974 TI - Evaluating respondent-driven sampling as an implementation tool for universal coverage of antiretroviral studies among men who have sex with men living with HIV. AB - INTRODUCTION: The TRUST model based on experimental and observational data posits that integration of HIV prevention and universal coverage of antiretroviral treatment at a trusted community venue provides a framework for achieving effective reduction in HIV-related morbidity and mortality among men who have sex with men (MSM) living with HIV, as well as reducing HIV incidence. The analyses presented here evaluate the utility of respondent-driven sampling as an implementation tool for engaging MSM in the TRUST intervention. METHODS: The TRUST integrated prevention and treatment model was established at a trusted community center serving MSM in Abuja, Nigeria. Five seeds have resulted in 3-26 waves of accrual between March 2013 and August 2014, with results presented here characterizing HIV burden and engagement in HIV care for 722 men across study recruitment waves. For analytic purposes, the waves were collapsed into 5 groups: 4 equally spaced (0-4, 5-9, 10-14, and 15-19) and 1 ranging from the 20th to the 26th wave with significance assessed using Pearson chi2 test. RESULTS: In earlier waves, MSM were more likely to have reported testing for HIV (82.9% in waves 0-4, 47.7% in waves 20-26; P < 0.01). In addition, biologically confirmed HIV prevalence decreased from an average of 59.1% to 42.9% (P < 0.05) in later waves. In earlier waves, about 80% of participants correctly reported their HIV status as compared with less than 25% in the later waves (P < 0.01). Finally, participants reporting being on ART decreased from 50% to 22.2% in later waves (P < 0.01). CONCLUSIONS: Implementation science studies focused on demonstrating impact of universal HIV treatment programs among people living with HIV necessitate different accrual methods than those focused on preventing HIV acquisition. Here, respondent-driven sampling was shown to be an efficient method for reaching marginalized populations of MSM living with HIV in Nigeria, and engaging them in universal HIV treatment services. PMID- 25723975 TI - Uptake of treatment as prevention for HIV and continuum of care among HIV positive men who have sex with men in Nigeria. AB - BACKGROUND: Experimental evidence has shown that treatment of HIV infection with antiretroviral therapy (ART) prevents heterosexual transmission of HIV to an uninfected partner. However, the "real-world" application of this strategy to key populations such as men who have sex with men (MSM) has been limited. We report findings on acceptability of a treatment as prevention (TasP) strategy among HIV infected MSM at a Trusted Community Center providing comprehensive HIV prevention and treatment services to MSM in Abuja, Nigeria. METHODS: Using respondent-driven sampling (RDS), MSM who were 16 years and older and have engaged in either receptive or insertive anal intercourse within the previous 12 months were recruited into a prospective combination HIV prevention and treatment study (TRUST). Two weeks after enrollment, HIV testing and counseling was conducted. At each 3-month follow-up visits, HIV-infected individuals underwent clinical and laboratory evaluation, including CD4 count, plasma HIV viral load, immediate 3 weekly sessions of ART preparation, and then ART initiation per TasP strategy irrespective of CD4 count. Reasons for not engaging in pre-TasP preparation and TasP were documented. Characteristics associated with TasP engagement and loss to follow-up (LTFU) were determined using logistic and Cox regression, respectively. RESULTS: Of 186 HIV-positive MSM enrolled, 58 (31.2%) were on ART at the time of recruitment, whereas 128 (68.8%) were ART-naive and provided opportunity for engaging TasP. Of these, 70 (54.7%) engaged in TasP. Compared with MSM who did not engage in TasP, those who engaged had significantly lower mean CD4 count (P = 0.001), were more likely to be Christian (P = 0.01), and had disclosed being MSM to family (P = 0.02) or health care providers (P = 0.02). In multivariate models, disclosure of being MSM to health care providers remained significantly associated with uptake of TasP. Among individuals engaged in TasP, 10% were LTFU in care at 18 months since enrollment. Being engaged in TasP (relative hazards = 0.08, P < 0.001) and on ART (relative hazards = 0.17, P < 0.001) were associated with decreased risk of LTFU. CONCLUSIONS: Although there was high acceptance of HIV testing and low LTFU among individuals who were already on ART or engaged in TasP, a higher than expected proportion did not engage in TasP, suggesting the need for customized treatment preparation and an increase in enabling environments to support HIV treatment access with this key population. PMID- 25723976 TI - Drug use and sexual behavior: the multiple HIV vulnerabilities of men and women who inject drugs in Kumasi, Ghana. AB - BACKGROUND: Recent evidence suggests that injecting drug use presents a new challenge to HIV prevention in West Africa. Very little is known about the HIV vulnerability of people who inject drugs (PWID) in Ghana, and no HIV prevention efforts are currently targeting PWID. METHODS: Purposive sampling was used to recruit 30 (20 men and 10 women) PWID to participate in in-depth interviews in Kumasi, Ghana. Transcripts were coded and analyzed by theme. RESULTS: Half the men and more than half the women in this study reported sharing needles/syringes (N/S); most shared a common mixing container; and all said they shared N/S with intimate partners. Some PWID who said that they do not share N/S with other PWID, also said they routinely use N/S that they find on the ground at injecting sites or in the hospital dumpster. Nearly, all the women (9/10) and more than half the men (12/20) were currently sexually active; most had more than 1 partner in the last 6 months, but very few reported condom use. Three women said they exchanged sex for money and 3 men reported buying sex in the last year. Several PWID had no knowledge of HIV transmission through injecting. CONCLUSIONS: PWID in Kumasi are highly vulnerable to HIV because of N/S sharing and reuse, lack of condom use, low knowledge of HIV transmission, and lack of services. Program and policy recommendations include N/S and condom distribution, peer education, opioid substitution therapy, and training of health providers, police, and pharmacy staff. PMID- 25723978 TI - A short history of HIV prevention programs for female sex workers in Ghana: lessons learned over 3 decades. AB - BACKGROUND: Female sex workers (FSWs) in Ghana have a 10-fold greater risk for acquiring HIV than the general adult population, and they contribute a substantial proportion of the new HIV infections in the country. Although researchers have conducted behavioral and biological surveys, there has been no review of the contextual, programmatic, and epidemiological changes over time. METHODS: The authors conducted a historical review of HIV prevention programs in Ghana. We reviewed the use of different interventions for HIV prevention among FSWs and data from program monitoring and Integrated Biological and Behavioral Surveillance Surveys. In particular, we looked at changes in service access and coverage, the use of HIV testing and counseling services, and the changing prevalence of HIV and other sexually transmitted infections. RESULTS: HIV prevention interventions among FSWs increased greatly between 1987 and 2013. Only 72 FSWs were reached in a pilot program in 1987, whereas 40,508 FSWs were reached during a national program in 2013. Annual condom sales and the proportion of FSWs who used HIV testing and counseling services increased significantly, whereas the prevalence of gonorrhea and chlamydia decreased. The representation of FSWs in national HIV strategic plans and guidelines also improved. CONCLUSIONS: Ghana offers an important historical example of an evolving HIV prevention program that despite periods of inactivity-grew in breadth and coverage over time. The prevention of HIV infections among sex workers has gained momentum in recent years through the efforts of the national government and its partners-a trend that is critically important to Ghana's future. PMID- 25723977 TI - "It's all about making a life": poverty, HIV, violence, and other vulnerabilities faced by young female sex workers in Kumasi, Ghana. AB - OBJECTIVES: This study aimed to identify social, economic, structural, and individual-level vulnerabilities of female adolescents who sell sex in Kumasi, Ghana. METHODS: Twenty-four in-depth interviews and 4 focus group discussions were conducted with female sex workers of age 18-20 years who had been involved in sex work for at least 2 years. Total sample size was 48. FINDINGS: One-third of participants started sex work before age 15. Knowledge of HIV was accurate and most reported having intentions to use condoms consistently with clients; however, factors such as higher payments, drug and/or alcohol use, fear of violence, and police harassment affected condom use. They perceived violence and rape at the hands of clients as their greatest risk. They also reported abuse and exploitation by police. Respondents voiced strong concerns that girls and teens involved in sex work are at higher risk of unsafe sex, exploitation, and abuse than their older and more experienced counterparts. Unprotected sex with boyfriends was also common. DISCUSSION: The pathway to sex work followed a similar pattern for many study participants who left their rural homes for Kumasi in search of economic opportunity. While adolescents who sell sex appear to be abundant in Kumasi, they have been missed by HIV prevention and harm reduction programming. The findings from this study informed the design and implementation of a young female sex worker peer educator pilot program. Key elements of that program are presented, and recommendations for future program evaluation are made. PMID- 25723979 TI - Associations of stigma with negative health outcomes for people living with HIV in the Gambia: implications for key populations. AB - BACKGROUND: The HIV epidemic in the Gambia is concentrated among stigmatized key populations. This study explores the relationship between 3 types of HIV-related stigma and 3 health outcomes among people living with HIV (PLHIV) in the Gambia. METHODS: Three hundred seventeen PLHIV from PLHIV support groups in the Gambia were surveyed using the PLHIV Stigma Index. RESULTS: Enacted stigma in health care settings was significantly associated with avoiding or delaying seeking care [adjusted odds ratio (aOR) = 3.03, 95% confidence interval (CI) = 1.24 to 7.89]; enacted stigma in the household or community (aOR = 1.21, 95% CI = 0.98 to 1.49) and internal stigma (aOR = 1.47, 95% CI = 0.96 to 2.22) were marginally associated. Enacted stigma in health care settings was significantly associated with non-use of antiretroviral therapy (aOR = 0.52, 95% CI = 0.31 to 0.88), whereas internal stigma and enacted stigma in the household or community were not. Enacted stigma in the household or community (aOR = 0.75, 95% CI = 0.64 to 0.87) and internal stigma (aOR = 0.69, 95% CI = 0.50 to 0.93) were significantly associated with poorer self-reported health status, whereas enacted stigma in health care settings was not. CONCLUSIONS: PLHIV in the Gambia face stigma regardless of identity as members of key populations, who may face dual stigma. Stigma mitigation represents a potentially important component of a comprehensive package of services to improve the HIV care continuum in the Gambia. Targeted interventions that address stigma with health care workers could facilitate antiretroviral therapy use and timely care seeking for PLHIV. Interventions to address internal stigma and enacted stigma in the household and community may yield additional dividends for the overall health of PLHIV. Examining only 1 domain of stigma may not be sufficient to understand the effect of stigma on a specific health outcome. PMID- 25723980 TI - Mothers who sell sex: a potential paradigm for integrated HIV, sexual, and reproductive health interventions among women at high risk of HIV in Burkina Faso. AB - BACKGROUND: Antenatal care is a point of entry into the health system for women across Africa and may facilitate the uptake of HIV services among female sex workers (FSWs). This study aimed to evaluate the determinants of motherhood among FSWs, their sexual risks, and their engagement in health care. METHODS: A cross sectional study was conducted from January to July 2013 among FSWs in Ouagadougou and Bobo-Dioulasso, Burkina Faso. The study used respondent-driven sampling for HIV testing and behavioral data collection. Predictors of motherhood and the association of motherhood and sex work dynamics were assessed separately using logistic regression. RESULTS: Of the 696 women enrolled, the majority of participants (76.6%, n = 533) had at least 1 biological child. Mothers were more likely to have a nonpaying partner [adjusted odds ratio (aOR), 1.73; 95% confidence interval (CI): 1.20 to 2.49], and significantly less likely to currently desire to conceive (aOR, 0.21; 95% CI: 0.13 to 0.33). Motherhood was predictive of having reduced condomless vaginal or anal sex with a new client [age-adjusted odds ratio (aaOR), 0.80; 95% CI: 0.65 to 0.97] in the past 30 days, and increased condomless vaginal or anal sex with a nonpaying partner (aaOR, 1.49; 95% CI: 1.13 to 1.96). Motherhood was prognostic of a higher likelihood of ever being tested for HIV (aaOR, 1.89; 95% CI: 1.55 to 2.31). Motherhood was predictive of reporting limited difficulty when accessing health services (aaOR, 0.15; 95% CI: 0.67 to 0.34). CONCLUSIONS: Motherhood is common among FSWs. The results indicate that FSWs who are mothers may have more exposure to health care because of seeking antenatal/perinatal services, presenting important opportunities for inclusion in the HIV continuum of care and to prevent vertical transmission. PMID- 25723981 TI - Structural determinants of health among women who started selling sex as minors in Burkina Faso. AB - OBJECTIVES: To explore the prevalence of and factors associated with initiation of selling sex as a minor. DESIGN: Data were drawn from cross-sectional studies of adult female sex workers (FSW) recruited through respondent-driven sampling in Ouagadougou and Bobo-Dioulasso, Burkina Faso. METHODS: FSW completed a questionnaire that included a retrospective question regarding the age at which they started selling sex. Separate multivariate logistic regression analyses were conducted for each city to examine associations with initiation of selling sex as a minor (<18 year old), controlling for current age. RESULTS: Of study participants, 27.8% (194/698) reported selling sex as a minor, ranging from 24.4% (85/349) in Bobo-Dioulasso to 31.2% (85/349) in Ouagadougou. In Ouagadougou, early initiates were more than twice as likely to report someone ever forced them to have sex [age-adjusted odds ratio (aaOR): 2.54, 95% confidence interval (CI): 1.53 to 4.23]. In Bobo-Dioulasso, those who started as minors were more likely to report someone ever tortured them (aaOR: 2.29, 95% CI: 1.28 to 4.10). In both cities, early initiates were more likely to not use a condom with a client if offered more money (Ouagadougou aaOR: 2.34, 95% CI: 1.23 to 4.47; Bobo-Dioulasso aaOR: 2.37, 95% CI: 1.29 to 4.36). In Ouagadougou, women who had started selling sex at a young age were half as likely to have been tested for HIV more than once ever (aaOR: 0.50, 95% CI: 0.26 to 0.94). In Bobo-Dioulasso, early initiates were less likely to attend HIV-related talks or meetings (aaOR: 0.56, 95% CI: 0.33 to 0.97). CONCLUSIONS: A substantial proportion of FSW in Burkina Faso started selling sex as minors. The findings show that there are heightened vulnerabilities associated with selling sex below age 18 years, including physical and sexual violence, client-related barriers to condom use, and lower access to HIV-related services. PMID- 25723982 TI - Sexual violence, condom negotiation, and condom use in the context of sex work: results from two West African countries. AB - BACKGROUND: Female sex workers (FSWs) are vulnerable to violence within and beyond the workplace. Violence is associated with increased burden of HIV, possibly explained through physiologic or behavioral causal pathways. These analyses sought to determine the relationship between lifetime sexual violence with unprotected, condomless vaginal intercourse (UVI) among FSWs in West Africa. METHODS: FSWs (aged >=18 years) were recruited into a cross-sectional study through respondent-driven sampling in two West African countries, Togo and Burkina Faso. A total of 1380 participants were enrolled from January to July 2013, and completed a sociobehavioral questionnaire and HIV testing. Measures included sex work history, lifetime experiences of violence victimization, sexual practices, and UVI (past month). Crude and adjusted robust log binomial regression was conducted to estimate prevalence ratios (PrR) as a measure of association between UVI with clients and the primary exposure, forced sex. RESULTS: Self-reported lifetime physical abuse (47.3%), forced sex (33.0%), and any violence (57.9%) were common. Almost one-quarter (23.9%) reported recent UVI with clients. History of forced sex was independently associated with recent UVI with clients [vs. none, adjusted PrR: 1.49; 95% confidence interval (CI): 1.18 to 1.88], with evidence of partial mediation by difficult condom negotiation with regular (aPrR: 1.83; 95% CI: 1.43 to 2.34) and new clients (aPrR: 1.60; 95% CI: 1.13 to 2.29). DISCUSSION: These data demonstrate the significant relationship between sexual violence experienced by FSWs and unprotected sex with clients. Comprehensive interventions reducing vulnerabilities to violence combined with improved condom negotiation are needed to address the complex influences of condom use during sex work as a means of ultimately lowering HIV acquisition and transmission. PMID- 25723983 TI - Potential impact of existing interventions and of antiretroviral use in female sex workers on transmission of HIV in Burkina Faso: a modeling study. AB - BACKGROUND: The impact and cost-effectiveness of antiretroviral treatment (ART) as prevention is likely to vary depending on the local context. Burkina Faso has a concentrated mature HIV epidemic where female sex workers (FSW) are thought to have driven HIV transmission. METHODS: A dynamic HIV transmission model was developed using data from the Yerelon FSW cohort in Bobo-Dioulasso and population surveys. Compared with current ART provision [status quo (SQ)], the model estimated the proportion of HIV infections averted or incremental life-years gained per additional person-year of ART over 20 years for ART targeting different subgroups or expanding eligibility to all HIV-infected individuals compared with SQ. RESULTS: Modeling suggests that condom use within commercial sex has averted 40% of past HIV infections. Continuing SQ averts 35%-47% of new infections over 20 years compared with no ART. Expanding ART eligibility to all HIV-infected individuals and increasing recruitment (80% per year) could avert a further 65% of new infections, whereas targeting full-time FSW or all FSWs achieved less impact but was more efficient in terms of life-years gained per 100 person-years of ART. Local HIV elimination is possible with expanded ART provision to FSWs but requires condom use within commercial sex to be maintained at high levels. CONCLUSIONS: Increasing FSW recruitment onto ART could be a highly efficient method for reducing HIV transmission in concentrated epidemic settings but should not be undertaken at the expense of existing interventions for FSWs. Specialized clinics providing multiple interventions for FSWs should be a fundamental component of prevention in concentrated epidemics. PMID- 25723984 TI - Assessment of policy and access to HIV prevention, care, and treatment services for men who have sex with men and for sex workers in Burkina Faso and Togo. AB - BACKGROUND: In Burkina Faso and Togo, key populations of men who have sex with men (MSM) and sex workers (SW) have a disproportionately higher HIV prevalence. This study analyzed the 2 countries' policies impacting MSM and SW; to what extent the policies and programs have been implemented; and the role of the enabling environment, country leadership, and donor support. METHODS: The Health Policy Project's Policy Assessment and Advocacy Decision Model methodology was used to analyze policy and program documents related to key populations, conduct key informant interviews, and hold stakeholder meetings to validate the findings. RESULTS: Several policy barriers restrict MSM/SW from accessing services. Laws criminalizing MSM/SW, particularly anti-solicitation laws, result in harassment and arrests of even nonsoliciting MSM/SW. Policy gaps exist, including few MSM/SW supportive policies and HIV prevention measures, e.g., lubricant not included in the essential medicines list. The needs of key populations are generally not met due to policy gaps around MSM/SW participation in decision-making and funding allocation for MSM/SW-specific programming. Misaligned policies, eg, contradictory informed consent laws and protocols, and uneven policy implementation, such as stockouts of sexually transmitted infection kits, HIV testing materials, and antiretrovirals, undermine evidence-based policies. Even in the presence of a supportive donor and political community, public stigma and discrimination (S&D) create a hostile enabling environment. CONCLUSIONS: Policies are needed to address S&D, particularly health care provider and law enforcement training, and to authorize, fund, guide, and monitor services for key populations. MSM/SW participation and development of operational guidelines can improve policy implementation and service uptake. PMID- 25723985 TI - Outreach strategies for the promotion of HIV testing and care: closing the gap between health services and female sex workers in Benin. AB - BACKGROUND: Regular voluntary counseling and testing is a key component of the fight against HIV/AIDS. In Benin, the project SIDA-1/2/3 established to decrease HIV/sexually transmitted infection (STIs) among female sex workers (FSWs), implemented a multifaceted intervention, including outreach activities. The objective of this article was to present potential advantages and limitations of 3 categories of outreach interventions designed to increase the use of testing services among FSWs in Benin. METHODS: This analysis is based on ethnographic fieldwork conducted in Benin from June to December 2012. RESULTS: Sixty-six FSWs and 24 health care workers were interviewed. Their narratives revealed 3 main factors impeding the development of appropriate HIV testing behavior. These negative elements can be positioned along a continuum of health care behaviors, with each stage of this continuum presenting its own challenges: fear or lack of motivation to use testing services, inaccessibility of care when the decision to go has been made, and a perceived lack of quality in the care offered at the health care center. Many of these needs seem to be addressed in the outreach strategies tested. However, the study also exposed some potential barriers or limitations to the success of these strategies when applied in this specific context, due to social disruption, mobility, access to care, and hard to reach population. CONCLUSIONS: To increase the use of testing services, an outreach strategy based on community workers or peer educators, along with improved access to testing services, would be well adapted to this context and appreciated by both FSWs and health care workers. PMID- 25723986 TI - Understanding the intention to undergo regular HIV testing among female sex workers in Benin: a key issue for entry into HIV care. AB - BACKGROUND: HIV testing constitutes an entry point for HIV prevention and access to care. Although access to tests has increased in most low- and middle-income countries in recent years, regular HIV testing among high-risk populations remains a challenge. Understanding the determinants of regular HIV testing is the key to improving treatment-as-prevention programs and access to care. This study aimed to identify psychosocial factors associated with the intention to be HIV tested every 3 months among female sex workers (FSWs) in Benin. METHODS: We developed an interview questionnaire based on the Theory of Planned Behavior and other theoretical variables. We interviewed 450 FSWs in their work place. Using Amos software, we applied structural equation modeling to identify the determinants of intention. RESULTS: Previous testing was reported by 87% of FSWs, 40% of whom reported having been tested in the last 3 months. More than half of the FSWs (69%) showed a strong intention to be HIV tested during the next 3 months. The structural model indicates that 55% of the variance in intention is explained in descending order of importance (standardized coefficient weight, beta) by perceived control, descriptive norms, control beliefs, habits, attitude, risk perception, and normative beliefs. CONCLUSIONS: This is the first theoretically based study identifying determinants of intention to undergo regular HIV testing among FSWs in sub-Saharan Africa. The results can inform development of interventions to maintain and increase regular HIV testing among FSWs, thus reinforcing primary prevention and supporting early access to care. PMID- 25723987 TI - Reorienting the HIV response in Niger toward sex work interventions: from better evidence to targeted and expanded practice. AB - BACKGROUND: Niger's low-burden, sex-work-driven HIV epidemic is situated in a context of high economic and demographic growth. Resource availability of HIV/AIDS has been decreasing recently. In 2007-2012, only 1% of HIV expenditure was for sex work interventions, but an estimated 37% of HIV incidence was directly linked to sex work in 2012. The Government of Niger requested assistance to determine an efficient allocation of its HIV resources and to strengthen HIV programming for sex workers. METHODS: Optima, an integrated epidemiologic and optimization tool, was applied using local HIV epidemic, demographic, programmatic, expenditure, and cost data. A mathematical optimization algorithm was used to determine the best resource allocation for minimizing HIV incidence and disability-adjusted life years (DALYs) over 10 years. RESULTS: Efficient allocation of the available HIV resources, to minimize incidence and DALYs, would increase expenditure for sex work interventions from 1% to 4%-5%, almost double expenditure for antiretroviral treatment and for the prevention of mother-to child transmission, and reduce expenditure for HIV programs focusing on the general population. Such an investment could prevent an additional 12% of new infections despite a budget of less than half of the 2012 reference year. Most averted infections would arise from increased funding for sex work interventions. CONCLUSIONS: This allocative efficiency analysis makes the case for increased investment in sex work interventions to minimize future HIV incidence and DALYs. Optimal HIV resource allocation combined with improved program implementation could have even greater HIV impact. Technical assistance is being provided to make the money invested in sex work programs work better and help Niger to achieve a cost-effective and sustainable HIV response. PMID- 25723988 TI - West African female sex workers in Mali: reduction in HIV prevalence and differences in risk profiles of sex workers of differing nationalities of origin. AB - BACKGROUND: Female sex workers (FSW) in Mali are highly vulnerable to HIV. Their prevalence in 2009 was 9 times higher (24.2%) than that among pregnant women (2.7%). METHODS: Four Integrated HIV/sexually transmitted infection (STI) Surveillance and Behavioral Surveys among FSW in Mali (2000, 2003, 2006, and 2009) tracked demographic characteristics, behavior, and HIV and STI prevalence. Logistic regression using generalized estimating equations to control for the cluster effect identified factors associated with HIV-positive serostatus adjusting for potential confounding. RESULTS: Of 2430 FSW, 40.8% were Nigerian, 36.8% were Malian, and 22.4% were from other neighboring countries. Between 2003 and 2009, HIV prevalence dropped from 44.14% to 28.49% (P < 0.0001) among Malians, from 21.33% to 12.71% (P = 0.0082) among Nigerians, and from 43.42% to 33.67% (P = 0.0442) among "others." Between 2000 and 2009, condom availability increased (89.18%-99.3%; P < 0.0001) as did HIV testing (40%-75%; P < 0.0001). Consistent condom use with clients improved for Malians (72.3%-81.5%; P = 0.0092), but not among Nigerians (92.7%-90.94%; P = 0.8240) and "others" (88.9% 88.48%; P = 0.8452). Consistent condom use with boyfriends was low and improved only for Nigerians (9.8%-28.4%; P = 0.0003). Factors associated with HIV prevalence in the multivariate model were older age, study year (2003 and 2006), nationality, lack of education, mobility, STI symptoms, gonorrhea prevalence, and younger age at first sex. CONCLUSIONS: This study documents progress in the fight against HIV among FSW in Mali. The different vulnerabilities to HIV found for different nationality FSW should be considered in programming and future research. PMID- 25723989 TI - Antiretroviral treatment coverage for men who have sex with men and female sex workers living with HIV in Cameroon. AB - BACKGROUND: Men who have sex with men (MSM) and female sex workers (FSW) are more likely to be living with HIV and experience difficulty accessing HIV health services due to stigma and discrimination. Antiretroviral treatment and sustained viral suppression among individuals living with HIV is the last step in the continuum of HIV care, which has been shown to improve health outcomes and decrease the risk of onward transmission of HIV. METHODS: To calculate the numerator and denominator for antiretroviral therapy (ART) coverage estimates among MSM and FSW living with HIV, the Priority Locations for AIDS Control Efforts methods were modified to include individual quantitative interviews, health service assessment and mapping, and size estimation in 7 cities in Cameroon. MSM and FSW were recruited using peer referral and venue-based sampling. The numerator was calculated from interviews with MSM and FSW. Population size estimation of MSM and FSW was used to determine the denominator. RESULTS: Antiretroviral coverage varied by site from 0% to 25% among HIV infected MSM and FSW. ART provision to the general population was reported at a significantly greater proportion of HIV health centers (56.5%) than ART provision to MSM and FSW populations (13.2%). CONCLUSIONS: The majority of MSM and FSW living with HIV and eligible for treatment in Cameroon are not connected to ART care. Additionally, ART provision for MSM and FSW at HIV health centers is insufficient. Characterizing effective strategies to reach optimal levels of engagement in the continuum of HIV care among MSM and FSW is essential for an AIDS-free generation for Cameroon. PMID- 25723990 TI - Violence against female sex workers in Cameroon: accounts of violence, harm reduction, and potential solutions. AB - BACKGROUND: Female sex workers (FSWs) in Cameroon, and West Africa generally, suffer a disproportionate burden of HIV. Although violence against FSWs has been documented extensively in other parts of the world, data on violence from West African countries are lacking. The aim of this study was to qualitatively document violence and harm reduction strategies from the perspective of FSWs in Cameroon as well as to understand how experiences of violence may increase FSWs' HIV risk. METHODS: FSWs from 7 major cities in Cameroon (Douala, Yaounde, Bamenda, Bertoua, Nagoundere, Kribi, and Bafoussam) were purposively recruited. Data from 31 in-depth interviews and 7 focus groups (n = 70; with some overlapping participants from in-depth interviews) conducted with these FSWs in 6 of these 7 cities (excluding Kribi) were analyzed using a grounded theory approach. RESULTS: Transcripts revealed 3 primary themes related to violence: (1) sources and types of violence, including sexual, physical, and financial violence perpetrated by clients and police, (2) harm reduction strategies, including screening clients and safe work locations, receipt of payment before sexual act, and formation of an informal security network, and (3) recommendations on structural changes to reduce violence that emphasized sex work decriminalization and increased police accountability. CONCLUSIONS: As in other parts of the world, violence against FSWs is pervasive in Cameroon. Interventions targeting violence and HIV must address the forms of violence cited locally by FSWs and can build on FSWs' existing strengths and harm reduction strategies. Structural changes are needed to ensure access to justice for this population. PMID- 25723991 TI - Applying innovative approaches for reaching men who have sex with men and female sex workers in the Democratic Republic of Congo. AB - BACKGROUND: In the Democratic Republic of Congo (DRC), men who have sex with men (MSM) and female sex workers (FSW) have the highest HIV prevalence but have the least access to services due to their marginalization within Congolese society. METHODS: The Projet Integre de VIH/SIDA au Congo (ProVIC) aims to reduce the risk and impact of HIV in the DRC through community- and facility-based prevention, counseling and testing, and treatment strategies aimed at high-risk populations, including MSM and FSW. To more effectively meet the needs of key populations, ProVIC tailored the existing interventions to better suit MSM and FSW by offering mobile counseling and rapid HIV testing services at night in MSM and FSW "hotspots," targeting outreach to and mobilizing key populations through social networks of MSM and FSW peer educators and recruiters, and referring MSM and FSW who test HIV positive to "friendly" clinics. RESULTS: Through these approaches, ProVIC was able to reach 2,621 MSM and 12,746 FSW with targeted prevention messaging in 2013 and provide testing and counseling services to 4,366 MSM and 21,033 FSW from October 2012 to June 2014. CONCLUSIONS: By applying innovative adaptations geared toward key populations, ProVIC has been able to better reach MSM and FSW in the DRC. ProVIC's targeted interventions for MSM and FSW provide promising examples of programming that can be used to meet the HIV prevention and testing needs of key populations and improve referrals for care and treatment, particularly in complex and unstable settings similar to the DRC. PMID- 25723993 TI - Scaling-up HIV responses with key populations in West Africa. AB - BACKGROUND: Despite decades of HIV responses in pockets of West and Central Africa (WCA), the HIV response with key populations remains an understudied area. Recently, there has been a proliferation of studies highlighting epidemiologic and behavioral data that challenge attitudes of complacency among donors and country governments uncomfortable in addressing key populations. METHODS: The articles in this series highlight new studies that provide a better understanding of the epidemiologic and structural burden facing key populations in the WCA region and how to improve responses through more effective targeting. RESULTS: Key populations face pervasive structural barriers including institutional and sexual violence and an intersection of stigma, criminalization, and marginalization as sexual minorities. Despite decades of smaller interventions that have shown the importance of integrated services for key populations, there remains incongruent provision of outreach or testing or family planning pointing to sustained risk. There remains an incongruent resource provision for key populations where they shoulder the burden of HIV and their access to services alone could turn around HIV epidemics within the region. CONCLUSIONS: These proximal and distal determinants must be addressed in regional efforts, led by the community, and resourced for scale, targeting those most at risk for the acquisition and transmission of HIV. This special issue builds the knowledge base for the region focusing on interventions that remove barriers to service access including treatment uptake for those living with HIV. Better analysis and use of data for strategic planning are shown to lead to more effective targeting of prevention, care, and HIV treatment programs with key populations. These articles further demonstrate the immediate need for comprehensive action to address HIV among key populations throughout the WCA region. PMID- 25723994 TI - What really is a concentrated HIV epidemic and what does it mean for West and Central Africa? Insights from mathematical modeling. AB - BACKGROUND: HIV epidemics have traditionally been classified as "concentrated" among key populations if overall HIV prevalence was below 1% and as "generalized" otherwise. We aimed to objectively determine the utility of this classification by determining how high overall HIV prevalence can reach in epidemics driven by unprotected sex work (SW) and how estimates of the contribution of SW to HIV transmission changes over time in these epidemics. METHODS: We developed a deterministic model of HIV transmission specific to West and Central Africa to simulate 1000 synthetic HIV epidemics, where SW is the sole behavioral driver that sustains HIV in the population (ie, truly concentrated epidemics), and it is based on a systematic extraction of model parameters specific to West and Central Africa. We determined the range of plausible HIV prevalence in the total population over time and calculated the population attributable fraction (PAF) of SW over different time periods. RESULTS: In 1988 and 2008, HIV prevalence across the 1000 synthetic concentrated HIV epidemics ranged (5th-95th percentile) between 0.1%-4.2% and 0.1%-2.8%, respectively. The maximum HIV prevalence peaked at 12%. The PAF of SW measured from 2008 over 1 year was <5%-18% compared with 16%-59% over 20 years in these SW-driven epidemics. CONCLUSIONS: Even high HIV prevalence epidemics can be driven by unprotected SW and therefore concentrated. Overall, HIV prevalence and the short-term PAF are poor makers of underlying transmission dynamics and underestimate the role of SW in HIV epidemics and thus should not be used alone to inform HIV programs. PMID- 25723995 TI - A comprehensive review of available epidemiologic and HIV service data for female sex workers, men who have sex with men, and people who inject drugs in select West and Central African countries. AB - OBJECTIVE: To identify gaps in epidemiologic and HIV service coverage data for key populations (KP), including men who have sex with men (MSM), female sex workers (FSW), people who inject drugs (PWID), and transgender persons, in 8 West and Central Africa countries: Cameroon, Chad, Cote d'Ivoire, Democratic Republic of Congo, Ghana, Guinea-Bissau, Niger, and Nigeria. METHODS: A comprehensive search of peer-reviewed literature was conducted using PubMed and MEDLINE. This search was supplemented by an additional search of relevant non-peer-reviewed, or gray, literature. Available data on HIV prevalence, KP size estimates, HIV prevention service targets, and HIV prevention service coverage, including the availability of population-specific minimum packages of services, were included in the review. RESULTS: No data for transgender persons were found. HIV prevalence data and size estimates were more frequently available for FSW, followed by MSM. Only 2 countries (Ghana and Nigeria) had both KP size estimates and HIV prevalence data for PWID. The degree to which HIV prevention service targets were adopted was highly variable across the selected countries, and the collection of relevant HIV prevention service coverage data for those targets that were identified was inconsistent. Population-specific minimum packages of services were identified in 3 countries (Cote d'Ivoire, Ghana, and Nigeria), although only Ghana and Nigeria included services for PWID. CONCLUSIONS: Epidemiologic and HIV prevention service data for FSW, MSM, PWID, and transgender persons remain sparse, and these KP are inconsistently accounted for in-service delivery and nationally endorsed minimum packages of HIV services in West and Central Africa. The strengthening of data collection and reporting to consistently include KP and the inclusion of that data in national planning is imperative for effectively addressing the HIV epidemic. PMID- 25723996 TI - An urgent need for integration of family planning services into HIV care: the high burden of unplanned pregnancy, termination of pregnancy, and limited contraception use among female sex workers in Cote d'Ivoire. AB - BACKGROUND: HIV infection and unintended pregnancy are occupational risks of commercial female sex work (FSW). The burden of unintended pregnancy among FSW including maternal and infant outcomes in the context of HIV is largely unknown. METHODS: FSW >=18 years were recruited through respondent driven sampling into a cross-sectional study in Abidjan, Cote d'Ivoire. Participants completed a sociobehavioral questionnaire and HIV counseling and testing. Pregnancy history by HIV status and contraceptive use were described, and Poisson regression used to estimate correlates of termination of pregnancy (TOP). RESULTS: From March to July 2014, 466 FSW were enrolled. Unintended pregnancy was common, and 64% of participants had >=1 TOP. Half of FSW experiencing TOPs did so without a medical professional, resulting in frequent complications. Contraceptive use was lowest among younger FSW, and 37% of 20-24 year olds reported multiple TOPs. FSW with a TOP history reported 19% less consistent condom use with clients than women who never had a TOP (adjusted-prevalence ratio, 0.81; 95% confidence interval: 0.74 to 0.88), whereas use of reliable nonbarrier contraceptive methods was comparable between the groups. Although FSW were engaged in HIV testing and prevention services, only 59% of FSW had received HIV testing before childbirth during their last pregnancy, and 30% of HIV-infected FSW had lost >=1 children. CONCLUSIONS: Low contraceptive use and high burden of unintended pregnancy result in poor reproductive outcomes for FSW and avoidable mother-to-child HIV transmission risks. Integration of family planning and antenatal services into HIV prevention and care programs accessed by FSW could enhance reproductive outcomes and HIV prevention goals. PMID- 25723997 TI - Retention and risk factors for loss to follow-up of female and male sex workers on antiretroviral treatment in Ivory Coast: a retrospective cohort analysis. AB - BACKGROUND: Antiretroviral therapy (ART) for HIV-infected sex workers is an important HIV prevention strategy. However, sex workers may have additional challenges for retention in ART care. The objectives of this study were to assess retention of sex workers on ART in a routine setting in Ivory Coast and identify risk factors for loss to follow-up (LTFU). METHODS: The design was a retrospective cohort study. An analysis of clinic files was conducted in 2 sites providing ART services to sex workers in Ivory Coast. Demographic, behavior, and clinical data of female and male sex workers on ART were abstracted onto a standardized anonymous data collection form. Data collection took place between May 11 and 28, 2010. RESULTS: A total of 376 female and 38 male sex workers were included in the analysis. The retention probability was 75% at 6 months, 68% at 12 months, 55% at 24 months, and 47% at 36 months. Attrition was mainly because of LTFU. Factors significantly associated with LTFU in bivariate analysis were lower schooling level, later calendar year of starting ART, and not receiving initial adherence counseling. Later year of starting ART and not receiving adherence counseling at ART initiation remained significantly associated with LTFU in a multivariate Cox regression model. CONCLUSIONS: To improve the retention of sex workers on ART, there is a need for more in-depth investigation of the role of pre-ART counseling and the increasing rates of LTFU with each calendar year. PMID- 25723998 TI - The application of imaging technologies in the detection of trace evidence in forensic medical investigation. AB - In a country notorious for violent crime, it seems that South African medico legal laboratories make minimal application of technology in the death investigation process and little attention is given to trace evidence. Non destructive, non-invasive, portable and cost-effective tools are required. This study was conducted at the Pretoria Medico-Legal Laboratory. The surface area of the bodies and clothing of victims of fatal interpersonal violence were examined using a torch, magnifying lamp, portable digital microscope and alternate light source to gauge their potential for trace evidence detection. Most studies apply these and similar tools to inert surfaces, with few focusing on their application to human skin. There was a statistically significant difference in the detection of many of the evidence types between the naked-eye observation of the pathologists and the technologies. The different imaging technologies were compared as to their cost, evidence detection ability and ease of use. The most common evidence types discovered on the bodies and clothing of victims of fatal interpersonal violence, as well as the propensity of each tool to detect these, was evaluated in order to devise the best option for incorporation into the Pretoria Medico-Legal Laboratory routine. The digital microscope performed best overall followed by the magnifying lamp, torch and the Polilight((r)). This study aimed to justify the investment of more time, effort and funding into trace evidence recovery in the South African mortuary environment. PMID- 25723999 TI - Quantitative bloodstain analysis: differentiation of contact transfer patterns versus spatter patterns on fabric via microscopic inspection. AB - In crime scene reconstruction, it is often necessary to differentiate "contact transfer" and "spatter" bloodstain patterns found on clothing. Current methodologies, however, are qualitative and prone to context bias. In this work, we demonstrate that microscopic inspection of the stain orientations provides a quantitative differentiation of bloodstains resulting from spatter versus contact transfer. Specifically, common knitted fabrics are comprised of parallel rows of left loop legs, in an upward diagonal orientation (/), and right loop legs in a downward diagonal orientation (?). Our microscopic examination of more than 65,000 individual stained loop legs shows that spatter stains are approximately evenly distributed between left and right loop legs, but contact transfer stains are unevenly distributed: depending on the type of surface contacted, as many as 82% of the stains were preferentially located on the left loop legs. We further show that in these fabrics the left loop legs protrude further out than the right loop legs by approximately 50 MUm, indicating that the observation of left loop legs preferentially stained over right loop legs is associated with the topography of the fabric. These findings suggest that microscopic quantification of the relative loop leg stain distributions could provide an objective means of differentiating contact transfer versus spatter patterns in crime scene reconstruction. PMID- 25724000 TI - Sox10--a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors. AB - Sox10 transcription factor is expressed in schwannian and melanocytic lineages and is important in their development and can be used as a marker for corresponding tumors. In addition, it has been reported in subsets of myoepithelial/basal cell epithelial neoplasms, but its expression remains incompletely characterized. In this study, we examined Sox10 expression in 5134 human neoplasms spanning a wide spectrum of neuroectodermal, mesenchymal, lymphoid, and epithelial tumors. A new rabbit monoclonal antibody (clone EP268) and Leica Bond Max automation were used on multitumor block libraries containing 30 to 70 cases per slide. Sox10 was consistently expressed in benign Schwann cell tumors of soft tissue and the gastrointestinal tract and in metastatic melanoma and was variably present in malignant peripheral nerve sheath tumors. In contrast, Sox10 was absent in many potential mimics of nerve sheath tumors such as cellular neurothekeoma, meningioma, gastrointestinal stromal tumors, perivascular epithelioid cell tumor and a variety of fibroblastic-myofibroblastic tumors. Sox10 was virtually absent in mesenchymal tumors but occasionally seen in alveolar rhabdomyosarcoma. In epithelial tumors of soft tissue, Sox10 was expressed only in myoepitheliomas, although often absent in malignant variants. Carcinomas, other than basal cell-type breast cancers, were only rarely positive but included 6% of squamous carcinomas of head and neck and 7% of pulmonary small cell carcinomas. Furthermore, Sox10 was often focally expressed in embryonal carcinoma reflecting a primitive Sox10-positive phenotype or neuroectodermal differentiation. Expression of Sox10 in entrapped non-neoplastic Schwann cells or melanocytes in various neoplasms has to be considered in diagnosing Sox10 positive tumors. The Sox10 antibody belongs in a modern immunohistochemical panel for the diagnosis of soft tissue and epithelial tumors. PMID- 25724001 TI - Clinical impact of minimal micropapillary pattern in invasive lung adenocarcinoma: prognostic significance and survival outcomes. AB - Micropapillary subtype has recently been established to be a distinct marker for poor prognosis in lung adenocarcinomas. According to the current classification of lung adenocarcinomas, all subtypes are listed semiquantitatively in 5% increments. In other words, a minimal amount of the micropapillary pattern, precisely <5% of the entire tumor is disregarded. Therefore, we sought to assess the prognostic significance and survival outcomes in patients with a micropapillary pattern proportion of <5% of the entire tumor. A total of 525 patients with lung adenocarcinoma were classified into 3 subgroups according to the presence and proportion of micropapillary subtype: (1) >=5% of the micropapillary pattern (n=114); (2) <5% of the micropapillary pattern (n=115); and (3) absence (<1%) of the micropapillary pattern (n=296). Sex, TNM stage, lymph node status (N status), tumor size, and predominant subtype demonstrated a significant difference among the 3 subgroups. Overall survival (OS) and disease free survival (DFS) were significantly different among the 3 subgroups (P=0.009 and 0.001 for OS and DFS, respectively). Furthermore, OS was significantly better in patients without the micropapillary pattern (<1%) than in those with <5% (P=0.034). At multivariate analyses, age (P=0.005) and N status (P=0.005) were independent prognostic factors influencing OS. In conclusion, our results demonstrated that even a small proportion of the micropapillary pattern, specifically <5% of the entire tumor has a significant prognostic impact on OS. N status remained an independent prognostic factor that negatively influenced OS. PMID- 25724002 TI - Non-L-cell immunophenotype and large tumor size in rectal neuroendocrine tumors are associated with aggressive clinical behavior and worse prognosis. AB - According to the 2010 World Health Organization classification, all gastrointestinal neuroendocrine tumors (NETs) are classified as malignant except for L-cell-type (glucagon-like peptide [GLP] and peptide YY [PYY]-producing) NETs. However, L-cell immunophenotype in rectal NETs has not been widely studied previously. Immunohistochemical labeling of L-cell markers with GLP1 and PYY was performed in 208 surgically or endoscopically resected rectal NET cases with tissue microarrays and was compared with clinicopathologic features and patient survival. Rectal NETs with non-L-cell immunophenotype and large tumor size (>1 cm) were associated with increased tumor grading, advanced T category, lymphovascular and perineural invasions, and lymph node and distant metastases (P<0.001, each). Rectal NET patients with non-L-cell phenotype and measuring >1 cm had significantly worse survival outcome than other groups by univariate (P<0.001) and multivariate (P<0.001) analyses. In summary, non-L-cell immunophenotype and large tumor size are associated with increased tumor grading and staging, concurrently indicating that they are independently poor prognostic indicators in rectal NET patients. Therefore, combining L-cell phenotype and tumor size can demonstrate the clinical behavior of rectal NETs more precisely than use of L-cell immunophenotype alone. PMID- 25724003 TI - Invasive endocervical adenocarcinoma: a new pattern-based classification system with important clinical significance. AB - A new 3-tier pattern-based system to classify endocervical adenocarcinoma was recently presented. In short, pattern A tumors were characterized by well demarcated glands frequently forming clusters or groups with relative lobular architecture. Pattern B tumors demonstrated localized destructive invasion defined as desmoplastic stroma surrounding glands with irregular and/or ill defined borders or incomplete glands and associated tumor cells (individual or small clusters) within the stroma. Tumors with pattern C showed diffusely infiltrative glands with associated extensive desmoplastic response. In total, 352 cases (all FIGO stages) from 12 institutions were identified. Mean patient age was 45 years (range, 20 to 83 y). Forty-nine (13.9%) cases demonstrated lymph nodes (LNs) with metastatic endocervical carcinoma. Using this new system, 73 patients (20.7%) were identified with pattern A tumors (all stage I); none had LN metastases and/or recurrences. Ninety patients (25.6%) were identified with pattern B tumors (all stage I); only 4 (4.4%) had LN metastases; 1 had vaginal recurrence. The 189 (53.7%) remaining patients had pattern C tumors; 45 (23.8%) of them had LN metastases. This new classification system demonstrated 20.7% of patients (pattern A) with negative LNs, and patients with pattern A tumors can be spared of lymphadenectomy. Patients with pattern B tumors rarely presented with metastatic LNs, and sentinel LN examination could potentially identify these patients. Aggressive treatment is justified in patients with pattern C tumors. PMID- 25724004 TI - A Novel SDHA-deficient Renal Cell Carcinoma Revealed by Comprehensive Genomic Profiling. AB - Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is an emerging provisional entity included in the 2013 International Society of Urological Pathology Vancouver Classification. Most genomic alterations in patients with SDH deficient RCCs involve the SDHB subunit, and the associated renal tumors have loss of immunohistochemical SDHB expression and distinctive morphologic features. Renal tumors less commonly possess genomic alterations involving the SDHC and SDHD subunits, but no SDHA alterations have as yet been described. Here we identified a novel SDHA homozygous deletion in an aggressive variant of RCC diagnosed initially as unclassified type in a 54-year-old patient. A search for novel actionable mutations by comprehensive genomic profiling based on clinical next-generation sequencing evaluating entire coding regions of 315 cancer-related genes, including all SDH subunits, was performed. Sequencing identified a novel 17 kbp homozygous deletion of 9 SDHA exons on chromosome 5p15. SDHA and SDHB immunohistochemistry further confirmed that the homozygous deletion led to the loss of SDHA and SDHB protein expression. Histologically, the tumor had a mixed pattern of high-grade papillary and collecting duct carcinoma and distinctive pale eosinophilic cytoplasmic inclusions similar to those described in SDHB deficient RCC. This is the first report that identifies SDHA inactivation in RCC. Additional studies utilizing comprehensive genomic profiling, immunohistochemistry, and careful morphologic evaluation are needed both prospectively and retrospectively to identify the group of RCCs harboring SDHA genomic alterations. PMID- 25724005 TI - Supermolecular bent configuration composed of achiral flexible liquid crystal trimers exhibiting chiral domains with opposite handedness. AB - Chirality's effects on physical properties of materials and how chirality arises have persisted as attractive issues in chemistry. We prepared a homologous series of achiral liquid crystal trimers in which three phenylpyrimidine units are connected via flexible heptamethylene spacers. An equimolecular mixture of a trimer with a nematic (N) phase and that with smectic A (SmA), smectic C (SmC), and smectic B phases was found to exhibit an N phase, a SmC phase, and a B4 phase composed of chiral domains with opposite handedness. The chiral characteristics of the B4 phase were confirmed by uncrossing the polarizers in opposite directions. XRD measurements reveal that both SmC and B4 phases have an interdigitated layer structure. That molecular interdigitation might form a supermolecular bent configuration that can produce saddle splay curvature to drive the B4 phase. PMID- 25724007 TI - I control therefore I do: judgments of agency influence action selection. AB - Our sense of being agents, that is of willingly controlling both our own bodies and the external environment is ubiquitous if thin. Empirical and theoretical work on this 'sense of agency' has documented motivational, cognitive and neural influences on implicit (out of awareness) and explicit (conscious) judgments of agency. For example, fluency of action selection processes has been recently shown to affect judgments of one's degree of control over an external event. However, it is an open question whether and how such judgments of agency act as input to other processes. In this study we demonstrate that the opposite relationship between action selection and judgment of agency also exists. Specifically, we show that manipulating one's objective control over the environment influences both the speed and the frequency of performing an action associated with that control. This pattern bears a striking resemblance to the effect that tangible rewards have on action selection and suggests that positive control feedback is rewarding to the organism, consequently affecting action selection. If further corroborated this 'reward from control' may explain everyday addictions such as prolonged engagement in arcade games and pathological behaviors, such as stereotypy. PMID- 25724006 TI - De-regulated expression of the BRG1 chromatin remodeling factor in bone marrow mesenchymal stromal cells induces senescence associated with the silencing of NANOG and changes in the levels of chromatin proteins. AB - Stem cells have a peculiar chromatin architecture that contributes to their unique properties, including uncommitted status, multi/pluripotency and self renewal. We analyzed the effect of the de-regulation of the SWI/SNF chromatin remodeling complex in mesenchymal stromal cells (MSC) through the silencing and up-regulation of BRG1, which is the ATPase subunit of the complex. The altered expression of BRG1 promoted the senescence of MSC with suppression of the NANOG transcription, which is part of the transcriptional circuitry governing stem cell functions. To gain insight on the way NANOG was silenced, we evaluated how the de regulated BRG1 expression affect the binding of activators and repressors on the NANOG promoter. We found 4 E2F binding motifs on NANOG promoter, which can be occupied by RB1 and RB2/P130. These are members of the retinoblastoma gene family. In MSC with a silenced BRG1, the relative binding of the 2 retinoblastoma proteins increased, and this was associated with the recruitment of DNMT1. This induced the methylation of CpG on the NANOG promoter. Opposingly, when a high level of BRG1 was present, the same E2F binding motifs were docking sites for BRG1, which induced chromatin compaction without CpG methylation but with increased histone deacetylation, associated with the presence of HDAC1 on E2F binding sites. Besides the sharp regulation of the NANOG expression, we evidenced, through proteomic analysis, that the de-regulation of the SWI/SNF function affected the expression of histones and other nuclear proteins involved in "nuclear architecture," suggesting that BRG1 may act as global regulator of gene expression. PMID- 25724008 TI - North Atlantic storm track changes during the Last Glacial Maximum recorded by Alpine speleothems. AB - The European Alps are an effective barrier for meridional moisture transport and are thus uniquely placed to record shifts in the North Atlantic storm track pattern associated with the waxing and waning of Late-Pleistocene Northern Hemisphere ice sheets. The lack of well-dated terrestrial proxy records spanning this time period, however, renders the reconstruction of past atmospheric patterns difficult. Here we present a precisely dated, continuous terrestrial record of meteoric precipitation in Europe between 30 and 14.7 ka. In contrast to present-day conditions, our speleothem data provide strong evidence for preferential advection of moisture from the South across the Alps supporting a southward shift of the storm track during the local Last Glacial Maximum (that is, 26.5-23.5 ka). Moreover, our age control indicates that this circulation pattern preceded the Northern Hemisphere precession maximum by ~3 ka, suggesting that obliquity may have played a considerable role in the Alpine ice aggradation. PMID- 25724010 TI - Retinal Ganglion Cell Layer Analysis by Optical Coherence Tomography in Toxic and Nutritional Optic Neuropathy. AB - OBJECTIVE: To analyze the retinal ganglion cell layer (RGL) by optical coherence tomography (OCT) in toxic and nutritional optic neuropathy and to correlate its thickness and volume with functional damage. METHODS: We conducted an observational cross-sectional study in healthy subjects and in patients with toxic optic neuropathy observed in the Neuro-Ophthalmology Department of Central Lisbon Hospital Center. Complete ophthalmologic examination, OCT (Heidelberg Spectralis), and automated static perimetry were performed. Thickness and macular volume of RGL layer and inner plexiform layer were measured after manual segmentation. RESULTS: The study included 16 eyes of 12 healthy subjects and 16 eyes of 8 patients with toxic and nutritional optic neuropathy. Age and gender did not differ between the 2 groups. Ethambutol was the cause of toxic optic neuropathy in 4 patients and nutritional factors (tobacco-alcohol) in 4 patients. A statistically significant decrease in thickness and volume of RGL, in all quadrants at 2 and 3 mm, was detected in individuals with optic neuropathy compared with controls (P < 0.01). A positive correlation between RGL thickness and mean deviation (MD) and between RGL volume and MD was detected (P < 0.05). There was a negative correlation between MD and time of disease (r = 0.846 P = 0.001) and a positive correlation between MD and visual acuity in logMAR (r = 0.739 P = 0.006). A majority of the structural parameters also correlated negatively with time of disease (P < 0.05). CONCLUSIONS: Decreased RGL thickness and volume detected in this study support a mechanism of RGL toxicity. RGL analysis may contribute to the diagnosis and management of toxic and nutritional optic neuropathies. PMID- 25724009 TI - Recent advances clarifying the etiologies of strabismus. AB - BACKGROUND: Strabismus is commonly encountered in neuro-ophthalmology practice. Adult patients may present with symptoms including disabling diplopia and decreased quality of life. Although presentation to the neuro-ophthalmologist often prompts a thorough workup for a neurologic basis of ocular misalignment, advances in orbital imaging and understanding of orbital mechanics have revealed novel mechanical causes. A goal of this review is to clarify mechanical mechanisms of strabismus that were formerly assumed be neurologic in origin. EVIDENCE ACQUISITION: The authors combine their own research and clinical experience with a literature review using PubMed. RESULTS: Aberrant paths of the extraocular muscles can lead to strabismus. The extraocular muscles have connective tissue pulleys that control muscle paths and are, in turn, influenced by the extraocular muscle orbital layers. Orbital connective tissues, including the pulleys, constrain extraocular muscle paths. Abnormalities of these tissues may lead to strabismus that is not due to neurologic pathology. Some extraocular muscles are divided into independent neuromuscular compartments, so that partial motor nerve lesions may manifest as selective denervation of only 1 compartment, complicating the presentation of neuropathic strabismus. CONCLUSIONS: Strabismus in adults due to nonneurologic causes can result from recently described abnormalities of the orbital connective tissue pulley system. Advances in understanding of compartmental extraocular muscle anatomy and innervation can explain cyclovertical strabismus in partial nerve palsies. Recognition of the underlying pathogenesis of the strabismus can lead to improved treatments. PMID- 25724011 TI - Multiple sequential light and laser sources to activate aminolevulinic acid in the treatment of photodamage: A retrospective study. AB - INTRODUCTION: The aim of this study was to retrospectively evaluate photodynamic therapy (PDT) with aminolevulinic acid (ALA) for cutaneous photorejuvenation using blue light sequentially with red light, pulsed-dye laser (PDL), and/or intense pulsed light (IPL). MATERIALS AND METHODS: Ninety-six patients (121 treatments) had photodamage treated with field-directed ALA-PDT from 2001 to 2010 in this single-center study. Treatments were performed with blue light + PDL, blue light + IPL, blue light + PDL + IPL, or blue light + red light + PDL + IPL. Outcome measures were obtained via telephone questionnaire and graded on a four point scale. RESULTS: There were no significant differences in patient-reported improvement in photodamage, overall skin quality, and postprocedure adverse events between treatment arms. However, number of patients in the blue light + red light + PDL + IPL group was markedly smaller (n = 2) than that in the other groups (n = 14-46). DISCUSSION: Although results showed a trend toward greater efficacy with similar tolerability using multiple, sequential light and laser sources with ALA-PDT for photorejuvenation, the potential for recall bias and widely disparate number of patients between treatment groups and follow-up times between patients severely limit this retrospective study. Nevertheless, despite these major statistical flaws, the results may provide valuable information regarding the safety of multiple modalities with PDT of photodamage in a single session. PMID- 25724012 TI - Age-associated power decline from running, jumping, and throwing male masters world records. AB - BACKGROUND/STUDY CONTEXT: The capacity to perform everyday tasks is directly related to the muscular power the body can develop (see Appendix). The age related loss of power is a fact, but the characterization or the rate of muscle power loss remains an open issue. Data useful to study the decline of the skeletal muscles power are largely available from sources other than medical tests, e.g., from track and field competitions of Masters athletes. The aim of our study is to identify the age-related decline trend of the power developed by the athletes in carrying out the track and field events. METHODS: Absolute male world records of 16 events were collected along with world records of male Masters categories. Performance was normalized with respect to the absolute record; the performance of various age groups is consequently represented by a number ranging from 1 (world absolute records) to 0 (null performance). The performance of a jumping event is transformed into a parameter proportional to the power developed by the athletes: the displacement of the center of gravity of the athlete. Throwing events are further normalized for the decreasing weight of the implements with the increasing age of the Masters athletes. RESULTS: Most track and field events show a linear decline to 70 years. The annual rate of power decline for all the events (running, throwing, and jumping), using a simplified synthesis, is 1.25% per year. The events that involve mostly upper limbs (shot put, javelin throw) show a higher rate of decline (1.4% per year) compared to those where the lower limbs are mostly involved (long jump 1.1%, track events 0.6-0.7% per year). This analysis of muscle power decline is only partially in line with the results of works based on clinical tests. A clarification of the reasons for such discrepancy may provide clinically significant information. CONCLUSION: Human power decline in Masters athletes was analyzed, adopting a coherent approach based on an extended database. Skeletal muscle power starts declining after the age of 30, with slight variations depending on the events. This conclusion is in line with only some of the previous studies. The various trend lines point to 0 at the age of 110 years, which is in line with the present human survival age. The study can be further developed with a suitable database for male and female Masters performances to facilitate longitudinal studies, which are currently lacking. PMID- 25724013 TI - Relationships between strategy switching and strategy switch costs in young and older adults: a study in arithmetic problem solving. AB - BACKGROUND/STUDY CONTEXT: This study investigated age-related differences in within-item strategy switching (i.e., revising initial strategy choices to select a better strategy while solving a given problem) and in strategy switch costs (i.e., longer latencies when participants switch strategies than when they do not switch strategy during strategy execution). METHODS: In a computational estimation task, participants had to give approximate products to two-digit multiplication problems (e.g., 41*67) while rounding up (i.e., do 50*70 for 41*67) or rounding down (i.e., do 40*60 for 41*67) operands to their nearest decades. After executing a cued strategy during 1000 ms, participants had the possibility to switch to another strategy (or repeat the same strategy) in a selection condition. In an execution condition, participants were forced to repeat the same strategy or to switch to another strategy. RESULTS: It was found that (1) older adults were less able than young adults to switch strategy after starting to execute a cued strategy (36.1% vs. 45.8%); (2) older adults showed larger switch costs than young adults (422 vs. 223 ms); and (3) strategy switches and strategy switch costs correlated in older adults but not in young adults. CONCLUSION: These findings have important implications for our understanding of the mechanisms underlying within-item strategy switching and aging effects on these mechanisms as well as, more generally, of strategic variations during cognitive aging. PMID- 25724014 TI - Perceptions of competence: age moderates views of healthy aging and Alzheimer's disease. AB - BACKGROUND/STUDY CONTEXT: Older adults have more complex and differentiated views of aging than do younger adults, but less is known about age-related perceptions of Alzheimer's disease. This study investigated age-related perceptions of competence of an older adult labeled as "in good health" (healthy) or "has Alzheimer's disease" (AD), using a person-perception paradigm. It was predicted that older adults would provide more differentiated assessments of the two targets than would younger adults. METHODS: Younger (n=86; 18-36 years) and older (n=66; 61-95 years) adults rated activities of daily living (ADL), instrumental activities of daily living (IADL), and memory abilities of a female target aged 75 years, described as healthy or with AD. Data on anxiety about aging, knowledge of and experience with aging and AD, knowledge of memory aging, and positive and negative biases toward aging and AD were also collected. RESULTS: Older adults perceived the healthy target as more capable of cognitively effortful activities (e.g., managing finances) and as possessing better memory abilities than the AD target. As predicted, these differences were greater than differences between targets perceived by younger adults. The interaction effect remained significant after statistically controlling for relevant variables, including education and gender. Additionally, exploratory analyses revealed that older adults held less positively biased views of AD than younger adults, but negatively biased views were equivalent between age groups. CONCLUSION: The results demonstrate that mere labels of "healthy" and "Alzheimer's disease" produce significant and subtle age differences in perceived competencies of older adults, and that biases towards AD vary by age group and valence. Our findings extend the person-perception paradigm to an integrative analysis of aging and AD, are consistent with models of adult development, and complement current research and theory on stereotypes of aging. Future directions for research on perceptions of aging are suggested. PMID- 25724015 TI - Baseline cluster membership demonstrates positive associations with first occurrence of multiple gerontologic outcomes over 10 years. AB - BACKGROUND/STUDY CONTEXT: The potential of cluster analysis (CA) as a baseline predictor of multivariate gerontologic outcomes over a long period of time has not been previously demonstrated. METHODS: Restricting candidate variables to a small group of established predictors of deleterious gerontologic outcomes, various CA methods were applied to baseline values from 754 nondisabled, community-living persons, aged 70 years or older. The best cluster solution yielded at baseline was subsequently used as a fixed explanatory variable in time to-event models of the first occurrence of the following outcomes: any disability in four activities of daily living, any disability in four mobility measures, and death. Each outcome was recorded through a maximum of 129 months or death. Associations between baseline ordinal cluster level and first occurrence of all three outcomes were modeled over a 10-year period with proportional hazards regression and compared with the associations yielded by the analogous latent class analysis (LCA) solution. RESULTS: The final cluster-defining variables were continuous measures of cognitive status and depressive symptoms, and dichotomous indicators of slow gait and exhaustion. The best solution yielded by baseline values of these variables was obtained with a K-means algorithm and cosine similarity and consisted of three clusters representing increasing levels of impairment. After adjustment for age, sex, ethnic group, and number of chronic conditions, baseline ordinal cluster level demonstrated significantly positive associations with all three outcomes over a 10-year period that were equivalent to those from the corresponding LCA solution. CONCLUSION: These findings suggest that baseline clusters based on previously established explanatory variables have potential to predict multivariate gerontologic outcomes over a long period of time. PMID- 25724016 TI - Practice of aerobic sports is associated with better spatial memory in adults and older men. AB - BACKGROUND/STUDY CONTEXT: Cognitive abilities experience diverse age-related changes. Memory complaints are common in aging. The practice of sports is known to benefit brain functioning, improving memory among other abilities. Introduction of virtual reality tasks makes it possible to easily assess cognitive functions such as spatial memory, a hippocampus-dependent cognitive ability. METHODS: In this study, the authors applied a virtual reality-based task to study spatial reference memory in two groups of men, sportsmen (n=28) and sedentary (n=28), across three different age groups: 50-59, 60-69, and 70-77 years. RESULTS: The data showed that sportsmen outperformed sedentary participants. In addition, there was also a significant effect of the factor age. Hence, older men (70-77 years old) displayed a poorer performance in comparison with the other age groups. CONCLUSIONS: These results support the beneficial effect of habitual physical activity in spatial memory. PMID- 25724017 TI - Destination memory for emotional information in older adults. AB - BACKGROUND/STUDY CONTEXT: Destination memory, remembering the destination of the information that one tells, shows significant age-related decline. In the present paper, the authors sought to determine whether destination memory can be improved in older adults using emotional stimuli. This aim was motivated by findings showing better context memory for emotional than for neutral information in older adults. METHODS: Younger and older adults were asked to tell neutral facts to three types of faces: a neutral one, an emotionally positive one, and an emotionally negative one. On a later recognition test, participants were asked to associate each previously told fact with the face to whom it was told. RESULTS: Destination memory performance was better for facts told to negative than to positive faces, and the latter memory was better than for neutral faces in older adults. CONCLUSION: Older adults seem to place higher emphasis on emotional material relative to neutral faces, showing better memory for the association between statements and emotional faces. PMID- 25724018 TI - Oxidative methane activation over yttrium stabilised zirconia. AB - The methane C-H bond is extremely stable, requiring significant energy input in reforming processes. We present a novel mechanism for energetically favourable methane C-H bond breaking over yttrium stabilised zirconia in the presence of oxygen, based on results of Density Functional Theory (DFT) and HSE06 hybrid functional calculations. We argue that this mechanism will be relevant to C-H activation over many metal oxide catalyst materials. PMID- 25724019 TI - Ruthenium complexes as antimicrobial agents. AB - One of the major advances in medical science has been the development of antimicrobials; however, a consequence of their widespread use has been the emergence of drug-resistant populations of microorganisms. There is clearly a need for the development of new antimicrobials--but more importantly, there is the need for the development of new classes of antimicrobials, rather than drugs based upon analogues of known scaffolds. Due to the success of the platinum anticancer agents, there has been considerable interest in the development of therapeutic agents based upon other transition metals--and in particular ruthenium(II/III) complexes, due to their well known interaction with DNA. There have been many studies of the anticancer properties and cellular localisation of a range of ruthenium complexes in eukaryotic cells over the last decade. However, only very recently has there been significant interest in their antimicrobial properties. This review highlights the types of ruthenium complexes that have exhibited significant antimicrobial activity and discusses the relationship between chemical structure and biological processing--including site(s) of intracellular accumulation--of the ruthenium complexes in both bacterial and eukaryotic cells. PMID- 25724020 TI - Effects of a Tailored Positive Psychology Intervention on Well-Being and Pain in Individuals With Chronic Pain and a Physical Disability: A Feasibility Trial. AB - OBJECTIVES: To determine the feasibility, acceptability, and efficacy of a computer-based positive psychology intervention in individuals with a physical disability and chronic pain. METHODS: Individuals with spinal cord injury, multiple sclerosis, neuromuscular disease, or postpolio syndrome and chronic pain were randomly assigned to a positive psychology or a control condition. Participants in the intervention group were instructed to practice 4 personalized positive psychology exercises. Participants in the control group were instructed to write about life details for 8 weeks. Participants completed online well-being and pain-related questionnaires at baseline, posttreatment, and at the 2.5-month follow-up, and rated treatment satisfaction at posttreatment. RESULTS: Ninety-six participants were randomized and 68 (70%) completed follow-up assessments. Participants in the positive psychology intervention group reported significant pretreatment to posttreatment improvements in pain intensity, pain control, pain catastrophizing, pain interference, life satisfaction, positive affect, and depression. Improvements in life satisfaction, depression, pain intensity, pain interference, and pain control were maintained to the 2.5-month follow-up. Participants in the control group reported significant pretreatment to posttreatment improvements in life satisfaction, and pretreatment to follow-up improvements in pain intensity and pain control. Significant between-group differences, favoring the treatment group, emerged for pretreatment to posttreatment improvements in pain intensity and pain control. Participants were similarly satisfied with both treatments. DISCUSSION/CONCLUSIONS: The results support the feasibility, acceptability, and potential efficacy of a computer based positive psychology intervention for improving well-being and pain-related outcomes in individuals with physical disabilities and chronic pain, and indicate that a full trial of the intervention is warranted. PMID- 25724021 TI - Acupuncture Reduces Pain and Autonomic Distress During Injection of Local Anesthetic in Children: A Pragmatic Crossover Investigation. AB - OBJECTIVES: Stimulation of acupoint LI4 has been shown to result in analgesic effects in patients experiencing acute pain. We aimed to study the effectiveness of LI4 stimulation for pain relief in children receiving an injection of a local anesthetic (LA). MATERIALS AND METHODS: Children scheduled for dental treatment using LA received bilateral acupuncture at LI4 using indwelling fixed needles. During the treatment, the parents of the patients stimulated the needles by massage. Two different treatment regimes were compared: a standardized LA injection given 5 minutes after acupuncture, and an LA injection without acupuncture. The order of treatment was randomized, with the 2 treatments performed in a crossover manner on different days. Pain intensity during LA injection, assessed by the patient with the Verbal Rating Scale or Faces Pain Scale (0 to 10), was used as the primary endpoint. Parent-assessed and dentist assessed pain intensity and agitation, heart rate, and the patients' satisfaction with the therapy were also recorded. RESULTS: Data were obtained from 49 patients (22 female; mean age 10 y). Patients reported less pain when acupuncture was used: mean 2.3 (95% confidence interval, 1.5-3.1) versus 3.9 (95% confidence interval, 3.0-4.7); P<0.001. The patients' heart rate remained low throughout the dental treatment after LI4 stimulation, when compared with treatment without acupuncture (P<0.05). LI4 stimulation was safe and increased satisfaction levels in both the patients and their parents, when compared with LA injection alone (P<0.05). DISCUSSION: Stimulation of acupoint LI4 reduces pain and autonomic distress in children during LA injection in dental procedures. PMID- 25724023 TI - The master diagnostic anatomic pathologist. PMID- 25724022 TI - A Qualitative Examination of a New Combined Cognitive-Behavioral and Neuromuscular Training Intervention for Juvenile Fibromyalgia. AB - OBJECTIVES: Adolescents with juvenile fibromyalgia (JFM) are typically sedentary despite recommendations for physical exercise, a key component of pain management. Interventions such as cognitive-behavior therapy (CBT) are beneficial but do not improve exercise participation. The objective of this study was to obtain preliminary information about the feasibility, safety, and acceptability of a new intervention--Fibromyalgia Integrative Training for Teens (FIT Teens), which combines CBT with specialized neuromuscular exercise training modified from evidence-based injury prevention protocols. MATERIALS AND METHODS: Participants were 17 adolescent females (aged 12 to 18 y) with JFM. Of these, 11 completed the 8-week (16 sessions) FIT Teens program in a small-group format with 3 to 4 patients per group. Patients provided detailed qualitative feedback via individual semistructured interviews after treatment. Interview content was coded using thematic analysis. Interventionist feedback about treatment implementation was also obtained. RESULTS: The intervention was found to be feasible, well tolerated, and safe for JFM patients. Barriers to enrollment (50% of those approached) included difficulties with transportation or time conflicts. Treatment completers enjoyed the group format and reported increased self efficacy, strength, and motivation to exercise. Participants also reported decreased pain and increased energy levels. Feedback from participants and interventionists was incorporated into a final treatment manual to be used in a future trial. DISCUSSION: Results of this study provided initial support for the new FIT Teens program. An integrative strategy of combining pain coping skills via CBT enhanced with tailored exercise specifically designed to improve confidence in movement and improving activity participation holds promise in the management of JFM. PMID- 25724024 TI - Payment for cancer biomarker testing. PMID- 25724025 TI - Requisites to strategic planning. PMID- 25724026 TI - Pathologists' place in the electronic health record landscape. AB - With growth spurred by recent federal efforts, electronic health records (EHRs) are transforming the practice of medicine and have important implications for pathologists, their laboratories, and the patients they serve. Beyond new EHR related regulatory requirements, EHRs fundamentally alter the way clinicians interact with laboratory information, including test order entry and result reviewing. This article is the first in a series of 5 related articles whose goal is to provide a "framework" for empowering pathologists to adapt to, and to succeed in, the era of expanding EHR use. This series aims to describe the environment for EHR uptake, to raise awareness of EHR-related issues that pathologists and laboratories face, and to explore new professional roles for pathologists as stewards of patients' laboratory information in EHRs. PMID- 25724027 TI - Stand-alone laboratory information systems versus laboratory modules incorporated in the electronic health record. AB - The increasing availability of laboratory information management modules within enterprise electronic health record solutions has resulted in some institutional administrators deciding which laboratory information system will be used to manage workflow within the laboratory, often with minimal input from the pathologists. This article aims to educate pathologists on many of the issues and implications this change may have on laboratory operations, positioning them to better evaluate and represent the needs of the laboratory during this decision making process. The experiences of the authors, many of their colleagues, and published observations relevant to this debate are summarized. There are multiple dimensions of the interdependency between the pathology laboratory and its information system that must be factored into the decision. Functionality is important, but management authority and gap-ownership are also significant elements to consider. Thus, the pathologist must maintain an active role in the decision-making process to ensure the success of the laboratory. PMID- 25724028 TI - Management of laboratory data and information exchange in the electronic health record. AB - In the era of the electronic health record, the success of laboratories and pathologists will depend on effective presentation and management of laboratory information, including test orders and results, and effective exchange of data between the laboratory information system and the electronic health record. In this third paper of a series that explores empowerment of pathology in the era of the electronic health record, we review key elements of managing laboratory information within the electronic health record and examine functional issues pertinent to pathologists and laboratories in the exchange of laboratory information between electronic health records and both anatomic and clinical pathology laboratory information systems. Issues with electronic order-entry and results-reporting interfaces are described, and considerations for setting up these interfaces are detailed in tables. The role of the laboratory medical director as mandated by the Clinical Laboratory Improvement Amendments of 1988 and the impacts of discordance between laboratory results and their display in the electronic health record are also discussed. PMID- 25724029 TI - Accreditation and regulatory implications of electronic health records for laboratory reporting. AB - The Clinical Laboratory Improvement Amendments of 1988 include strict regulations for reporting content, and it falls on the named director to ensure that this content is available to the caregiver. With the electronic health record serving as the conduit to the end user of the laboratory data, the laboratory generally, and the director specifically, must verify accurate transmission of these content components. An understanding of regulatory and accreditation requirements is essential both to allow the proper discharge of these mandated responsibilities and to enforce the role and authority that the pathologist must have to ensure that these requirements are satisfied by the reporting system. The regulatory requirements will be discussed in the context of the Clinical Laboratory Improvement Amendments of 1988 standards; however, interpretation and expansion on these regulations exist both in Clinical Laboratory Improvement Amendments of 1988 inspection guidelines from the Centers for Medicare and Medicaid Services and in accreditation program requirements. This regulatory expectation both places the laboratory director in a position of risk and provides leverage to ensure meaningful and accurate communication of laboratory information. PMID- 25724030 TI - Pathologists as stewards of laboratory information. AB - Just as electronic health records are transforming the practice of medicine and health care information management, practicing in the era of the electronic health record offers opportunities, if not imperatives, for pathologists to take on new and "transformative" professional and leadership roles for the organizations they serve. Experience indicates that clinicians will perceive pathologists and laboratories as responsible for all aspects of laboratory testing and information management, including order entry and results reporting, even though such functions may fall beyond the control of the laboratory. As described and expanded upon in the previous 4 articles of this series, the use of electronic health records dictates changes in how clinicians interact with laboratory information. In this environment, pathologists are uniquely positioned to act as the stewards for laboratory information in electronic health records and throughout health care organizations. PMID- 25724031 TI - Best practices in diagnostic immunohistochemistry: workup of cutaneous lymphoid lesions in the diagnosis of primary cutaneous lymphoma. AB - CONTEXT: Primary cutaneous lymphoma is a common extranodal non-Hodgkin lymphoma. These lesions share common features with their nodal counterparts, but also have differences in morphology, unique clinical presentations, and immunohistochemical features. OBJECTIVE: To review the 2008 World Health Organization (WHO) and 2005 consensus WHO-EORTC (European Organisation for Research and Treatment of Cancer) classifications, and address the immunohistochemical findings in the most common primary cutaneous T- and B-cell lymphomas. Since clonality testing is commonly used as an ancillary test in the evaluation of cutaneous lymphoma, a brief section in the use and pitfalls of clonality testing is included. DATA SOURCES: The WHO and EORTC classification publications and the relevant recent literature were used to compile appropriate and practical guidelines in this review. CONCLUSIONS: The practice of dermatopathology and hematopathology varies widely. Thus, while this review provides an overview and guideline for the workup of lymphoid lesions of the skin, the practitioner should understand the importance of clinical correlation as well as appropriate utility of available resources (such as clonality testing) in arriving at a diagnosis in cutaneous lymphoid lesions. PMID- 25724032 TI - Red blood cell transfusion practices: a College of American Pathologists Q-Probes study of compliance with audit criteria in 128 hospitals. AB - CONTEXT: Most information on compliance with audit criteria for red blood cell (RBC) transfusions comes from single institutions; few studies have compared practices among many hospitals. OBJECTIVE: To survey a cross-section of hospitals in 2008 for criteria and compliance with RBC transfusion guidelines, using the College of American Pathologists Q-Probes format. DESIGN: One hundred twenty eight hospitals, representing about 4.5% (724,332 of 16,212,000) of all annual RBC usage in the United States, provided information on their RBC audit practices and their recent rates of compliance. They also each examined 50 RBC transfusion episodes for compliance with their guidelines. RESULTS: The participants' median, pretransfusion hemoglobin thresholds for audit review were 8.0 to 8.9 g/dL for most clinical settings and 9.0 to 9.9 g/dL for patients with underlying cardiopulmonary disease. For the transfusion episodes examined, 60% (2063 of 6518) were for a single unit. The median of the institutional averages for pretransfusion hemoglobin was 8.1 g/dL, and the median rate of compliance was 69% (range, 0%-100%). Involvement by a pathologist or transfusion medicine expert in the audit system was associated with more-strict audit criteria and better compliance. CONCLUSIONS: Median hemoglobin thresholds for RBC transfusion audits were somewhat higher than currently evolving recommendations, but opportunities for improvement were provided by expert involvement and by the growing frequency of 1-unit transfusions. PMID- 25724033 TI - An algorithmic approach to sellar region masses. AB - CONTEXT: Most sellar region masses (85%-90%) are pituitary adenomas; however, other neoplasms or even inflammatory or cystic nonneoplastic lesions may occasionally be encountered in this location. A practical, non-electron microscopically based approach is essential for the daily practice of diagnosing and subclassifying adenomatous and nonadenomatous sellar region lesions. OBJECTIVE: To provide an algorithmic approach to sellar region masses for the pathologist and to formulate a cost-effective, limited panel of stains and immunostains that can be used in daily practice at most small to medium-sized centers. DESIGN: Pool collective experience of 3 neuropathologists practicing at academic medical centers with expertise in diagnosis and treatment of sellar region masses to craft a single-page algorithmic diagram and to liberally illustrate the range of lesions present in the sellar region. RESULTS: After formulating a differential diagnosis, the general pathologist can generate a confident final diagnosis of adenoma using 1 histochemical (reticulin) and 1 immunohistochemical (synaptophysin) stain, supplemented by 5 immunohistochemical stains (CAM5.2, follicle-stimulating hormone, growth hormone, prolactin, and adrenocorticotropic hormone), which provide subtyping of the adenoma in the overwhelming majority of examples. CAM5.2 and clinical information further help identify clinically aggressive variants such as sparsely granulated growth hormone adenomas and silent adrenocorticotropic hormone adenomas, respectively. MIB-1, thyroid transcription factor 1, and S-100 protein can be of further assistance in select cases where increased mitotic activity or possible nonadenomatous spindle cell lesions are suspected. CONCLUSIONS: Adenomas, normal anterior or posterior gland, and nonadenomatous masses can be easily diagnosed in a nontertiary pathology laboratory setting. PMID- 25724034 TI - Bethesda System reporting rates for conventional Papanicolaou tests and liquid based cytology in a large Chinese, College of American Pathologists-certified independent medical laboratory: analysis of 1394389 Papanicolaou test reports. AB - CONTEXT: Reports that use the Bethesda System categories for Chinese Papanicolaou test results are rare. OBJECTIVE: To document and analyze rates reported in the Bethesda System for conventional Papanicolaou tests and liquid-based cytology between 2007 and 2012 in China's largest College of American Pathologists accredited laboratory. DESIGN: Results from 1,394,389 Papanicolaou tests, rendered between 2007 and 2012 by the Guangzhou Kingmed Diagnostics Cytology Laboratory, were documented by the Bethesda System report categories and Papanicolaou test methodology, which included both conventional Papanicolaou tests and 4 different liquid-based cytology preparations. RESULTS: Results were documented for 326,297 conventional Papanicolaou tests and 1,068,092 liquid-based cytology specimens, which included 928,884 ThinPrep (Hologic, Bedford, Massachusetts), 63,465 SurePath (BD Diagnostics, Franklin Lakes, New Jersey), 50,422 Liqui-Prep (LGM International, Melbourne, Florida), and 25,321 Lituo liquid-cytology (Lituo Biotechnology Co, Hunan, China) specimens. Abnormality rates reported were significantly higher with liquid-based cytology than they were with conventional Papanicolaou tests in all the Bethesda System categories (P < .001). Reporting rates were within the 2006 benchmark ranges from the College of American Pathologists, except for atypical glandular cells (low) and unsatisfactory rates for conventional Papanicolaou tests (low). CONCLUSION: Participation in the international College of American Pathologists Laboratory Accreditation Program provides laboratory quality standards not otherwise available in many international settings. PMID- 25724035 TI - High collagen I gene expression as an independent predictor of adverse renal outcomes in lupus nephritis patients with preserved renal function. AB - CONTEXT: The deposition of extracellular matrix is a major pathogenic mechanism leading to fibrosis and progressive decline in renal function in patients with lupus nephritis (LN). Currently, available clinicopathologic features cannot predict renal outcome consistently. OBJECTIVE: To test that the expression of renal fibrogenic genes correlates with renal fibrosis at the time of biopsy and is predictive of renal outcomes. DESIGN: Renal gene expression levels of transforming growth factor beta-1 (TGFB1), and collagen I (COL1) were studied by real-time multiplex quantitative polymerase chain reaction in a prospective cohort of patients with LN (n = 39). Extracellular matrix index (ECMI) and collagen I/III matrix index were measured from Picro-Sirius Red-stained slides under normal and polarized light, respectively. RESULTS: After follow-up (median, 43.9 months), renal failure (50% reduction in glomerular filtration rate [GFR] or dialysis) had developed in 13 subjects. The expression levels of renal fibrogenic genes were increased as compared to controls without LN. COL1 correlated with collagen I/III matrix index at baseline. Both high expression of TGFB1 or COL1 tended to predict renal failure by univariate analysis. By multivariate analysis, high ECMI and low GFR were predictive of renal failure. In patients with baseline GFR of 60 mL/min/1.73 m(2) or greater, high renal COL1 expression was an independent (hazard ratio = 4.4, P = .04) predictor of renal failure. CONCLUSIONS: High renal COL1 expression is a strong predictor of adverse renal outcome in patients with LN and preserved baseline GFR. These findings support larger prospective studies to confirm the benefits of COL1 in identifying patients at high risk of progression to renal disease. PMID- 25724036 TI - Anatomic distribution of sessile serrated adenoma/polyp with and without cytologic dysplasia. AB - CONTEXT: Sessile serrated adenomas/polyps (SSA/Ps) have been increasingly studied during the last 10 years. However, their detailed anatomic distribution pattern has not been studied, especially given newer (broader) criteria for the diagnosis. OBJECTIVES: To characterize the anatomic distribution of SSA/P with and without cytologic dysplasia and to assess the demographics of these patients in a nationwide database. DESIGN: We retrospectively analyzed the database of Miraca Life Sciences Research Institute for a 1-year period. Patients with a diagnosis of SSA/P, SSA/P with low-grade cytologic dysplasia (SSA/P-LGD), SSA/P with high-grade cytologic dysplasia (SSA/P-HGD), or SSA/P with adenocarcinoma (SSA/P-ACA) were retrieved, and patients' age, sex, and specific anatomic location were analyzed. RESULTS: A total of 11,201 patients were identified, of which 10,646 (95.0%) had SSA/P, 514 (4.6%) had SSA/P-LGD, 39 (0.35%) had SSA/P HGD, and 2 (0.018%) had SSA/P-ACA. All SSA/Ps and more advanced lesions were significantly more common in the proximal colon-SSA/P (61.2%), SSA/P-LGD (61.2%), SSA/P-HGD (80%), and SSA/P-ACA (100%)-than in either the transverse (18.8%, 17.8%, 10.0%, and 0%, respectively) or the distal (19.9%, 21.0%, 10.0%, and 0%, respectively) colon, P < .001. Sessile serrated adenoma/polyp with cytologic dysplasia was most commonly found in the ascending colon (LGD, 31.6%) and cecum (HGD, 37.5%). Advanced SSA/Ps were disproportionally more common among older women. CONCLUSIONS: Sessile serrated adenomas/polyps with and without cytologic dysplasia and carcinoma are predominantly found in the cecum and ascending colon, whereas there is low prevalence in both the transverse and distal colon. Confirmation of previously published data regarding demographics of advanced lesions among a different cohort and including newer (broader) criteria suggests these criteria are valid. PMID- 25724037 TI - The Pathology Residency Program of the Johns Hopkins University School of Medicine: a model of its kind. AB - CONTEXT: The Department of Pathology of the Johns Hopkins University pioneered in the late 19th century the application of the scientific method to the study of medicine and fostered the development of residency training programs. OBJECTIVE: To trace the history of the Johns Hopkins Pathology Residency Program and assess with quantifiable outcomes the performance of former residents. Design .- We reviewed archival and departmental records from September 1899 to June 2014 to create a database of pathology residents. We then analyzed resident in-service examinations, American Board of Pathology examinations, and career paths. RESULTS: In 115 years the department trained 555 residents who came from 133 medical schools located in 23 countries. Residents performed well on the in service examinations, obtaining mean scaled total scores that were significantly better (P = .02) than those of the national peer groups. Residents (371 of 396, 94%) passed their boards typically at the first attempt, a percentage pass that was higher than the national average for both anatomic (P < .001) and clinical (P = .002) pathology. Approximately half of the residents went into private practice, whereas a third followed an academic career. Of the latter group, 124 (75%) became professors of pathology, 31 (19%) chairs of pathology departments, 10 (6%) deans of medical schools, 5 (3%) were elected into the National Academy of Sciences, and 1 won the Nobel prize. CONCLUSIONS: While maintaining its original core values, the Johns Hopkins Pathology Residency Program has trained physicians to be outstanding researchers, diagnosticians, and leaders in pathology. PMID- 25724038 TI - Clear cell sarcoma-like tumor of the gastrointestinal tract: an evolving entity. AB - Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm that occurs in the wall of the small bowel, stomach, or large bowel, predominantly in young adults. It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. Clear cell sarcoma-like tumor of the gastrointestinal tract is positive for S100 protein, invariably negative for melanocyte-specific markers and is often also positive for neuroendocrine markers. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions. Here, we discuss the current status of CCSLGT, including histologic, immunophenotypic, and molecular findings. PMID- 25724039 TI - Sudden cardiac death: a modern pathology approach to hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is one of the most common causes of sudden cardiac death among young adults and adolescents. Unfortunately, the first manifestation of the condition may be sudden death during exertion, such as sporting activities. Other clinical symptoms include exertional dyspnea, angina, and syncope. Postmortem examination often reveals asymmetrical septal thickening and mural plaque formation in the left ventricular outflow tract. Histologic analysis shows cardiac myocyte hypertrophy, myofiber disarray, and interstitial and replacement fibrosis. Molecular analysis for known genetic abnormalities is essential to genetic counseling of living relatives of decedents to assess and reduce the risk of sudden cardiac death from hypertrophic cardiomyopathy. PMID- 25724040 TI - Groove pancreatitis: a brief review of a diagnostic challenge. AB - Groove pancreatitis is an uncommon, yet well-described, type of focal chronic pancreatitis, affecting "the groove"-the area between the head of the pancreas, the duodenum, and the common bile duct. Men aged 40 to 50 years are most commonly affected, with a history of alcohol abuse frequently disclosed. Clinical manifestations are similar to other forms of chronic pancreatitis, and vomiting secondary to duodenal stenosis is the main feature. It is postulated that pancreatitis in the groove area arises from obstruction of pancreatic juices in the ductal system, causing fibrosis and stasis with resultant inflammation of surrounding structures. The minor papilla is frequently the anatomic area of preferential involvement. Groove pancreatitis poses diagnostic challenges, forming a "pseudotumor" that mimics pancreatic carcinoma. The distinction is important, although often impossible to make because of their similar presentation, with groove pancreatitis usually affecting younger patients. Most patients are successfully treated with pancreaticoduodenectomy when definitive pathologic diagnoses can be made. PMID- 25724041 TI - Cost-effectiveness analysis parallel to a randomized controlled trial comparing vertical scar reduction and inverted T-shaped reduction mammaplasty. PMID- 25724042 TI - Reply: Cost-effectiveness analysis parallel to a randomized controlled trial comparing vertical scar reduction and inverted T-shaped reduction mammaplasty. PMID- 25724043 TI - Preemptive analgesia with bupivacaine in reduction mammaplasty: a prospective, randomized, double-blind, placebo-controlled trial. PMID- 25724044 TI - Reply: A systematic review and meta-analysis of single-stage augmentation mastopexy. PMID- 25724045 TI - Functional considerations in aesthetic eyelid surgery. PMID- 25724046 TI - Minimally Invasive Options in Dupuytren's Contracture: Aponeurotomy, Enzymes, Stretching, and Fat Grafting. PMID- 25724047 TI - Discussion: Financial conflicts of interest in plastic surgery: background, potential for bias, disclosure, and transparency. PMID- 25724048 TI - Reply: Financial conflict of interests in plastic surgery: background, potential for bias, disclosure, and transparency. PMID- 25724049 TI - Treatment of nipple-sparing mastectomy necrosis using hyperbaric oxygen therapy. PMID- 25724050 TI - The rib graft rhinoplasty: anchoring the extended columellar strut. PMID- 25724051 TI - Novel penile splint and its use in microsurgical penile replantation. PMID- 25724052 TI - The modified liposuction-curettage cannula for the treatment of secondary axillary bromhidrosis with subcutaneous scarring. PMID- 25724053 TI - Intrathoracic Breast Implant Migration following Video-Assisted Thorascopic Surgery. PMID- 25724054 TI - Eyelid finger manipulation in the treatment of overcorrected blepharoptosis and postblepharoplasty ectropion-retraction. PMID- 25724055 TI - Lymphedema of the Upper Extremity following Supraclavicular Lymph Node Harvest. PMID- 25724057 TI - Introducing the plastic surgery research network: a comprehensive online platform to facilitate interdisciplinary plastic surgery research. PMID- 25724056 TI - Long-Term (24-Month) Safety Evaluation of Poly-DL-Lactic Acid Filler Injection for the Nasolabial Fold: A Multicenter, Open, Randomized, Evaluator-Blind, Active Controlled Design. PMID- 25724058 TI - A tribute to the founding figures of the American Board of Plastic Surgery. AB - The American Board of Plastic Surgery recently celebrated its 75th anniversary as an established specialty board. This historical article provides an outline of the events that led to the formation of the American Board of Plastic Surgery and gives insight into the personalities and achievements of the key individuals whose unique talents coalesced into a common vision of making plastic surgery the diverse and well-respected specialty that it is today. This is a historical literature review outlining the circumstances leading to the formation of American Board of Plastic Surgery. The emphasis on the role of its founding fathers is reviewed and detailed in the article. The founding figures continue to inspire us through their unrelenting dedication to the field of plastic surgery. Over the past 75 years, the field of plastic surgery has been very well served by their successors, and these founding figures have fostered a surgical specialty of great repute. PMID- 25724059 TI - Reply: Chronic biofilm infection in breast implants is associated with an increased T-cell lymphocytic infiltrate: implications for breast implant associated lymphoma. PMID- 25724060 TI - Use of Diced Conchal Cartilage with Perichondrial Attachment in Rhinoplasty. AB - BACKGROUND: The conchal cartilage is favored in nasal tip surgery, but is limited in dorsal augmentation. The authors evaluated diced conchal cartilage with perichondrial attachment in augmentation of the nasal dorsum, radix, and/or tip. METHODS: The medical records of 37 patients who underwent rhinoplasty using diced conchal cartilage with perichondrial attachment as an augmentation material for the nasal dorsum, radix, or tip, at a tertiary academic institution, were reviewed retrospectively. Postoperative surgical outcomes were assessed by comparing facial photographs before and after surgery. In addition, complications were analyzed. RESULTS: Diced conchal cartilage with perichondrial attachment was used alone in 22 patients (59.5 percent) and in combination with autologous cartilage graft, homologous fascia lata, or expanded polytetrafluoroethylene in 15 patients (40.5 percent). Successful outcomes were achieved in 33 patients (89.2 percent). Dorsal augmentation with diced conchal cartilage with perichondrial attachment was performed in 30 patients (81.1 percent) and radix augmentation in nine patients (24.3 percent), and their dorsal and radix heights, respectively, were significantly increased after surgery (p < 0.01 each). Four patients (10.8 percent) who underwent tip surgery with diced conchal cartilage with perichondrial attachment showed successful aesthetic outcomes, although anthropometrically measured tip projection and rotation were not significantly affected (p > 0.05). Complications included hematoma and keloid at the conchal cartilage donor site, and poor aesthetic outcome in four patients (10.8 percent). CONCLUSION: Diced conchal cartilage with perichondrial attachment may be a valuable graft material with which to augment the nasal dorsum, radix, and/or tip in rhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25724061 TI - Differential contributions of graft-derived and host-derived cells in tissue regeneration/remodeling after fat grafting. AB - BACKGROUND: Recent research indicates that the adipose tissue of nonvascularized grafts is completely remodeled within 3 months, although origins of next generation cells are unclear. METHODS: Inguinal fat pads of green fluorescent protein mice and wild-type mice were cross-transplanted beneath the scalp. At 1, 2, 4, and 12 weeks after transplantation, grafted fat was harvested, weighed, and analyzed through immunohistochemistry, whole-mount staining, and flow cytometry of cell isolates. Bone marrow of green fluorescent protein mice was transplanted to wild-type mice (after irradiation). Eight weeks later, these mice also received fat grafts, which were analyzed as well. RESULTS: The majority of host derived cells detected during remodeling of grafted fat were macrophages (>90 percent at the early stage; 60 percent at 12 weeks). Cell origins were analyzed at 12 weeks (i.e., when completely regenerated). At this point, mature adipocytes were largely derived from adipose-derived stem/stromal cells of grafts. Although vascular wall constituents were chiefly graft derived, vascular endothelial cells originated equally from graft and host bone marrow. Adipose-derived stem/stromal cells of regenerated fat were an admixture of grafted, host nonbone marrow, and host bone marrow cells. CONCLUSIONS: The above findings underscore the importance of adipose stem/stromal cells in the grafted fat for adipocyte regeneration. Host bone marrow and local tissues contributed substantially to capillary networks and provided new adipose-derived stem/stromal cells. An appreciation of mechanisms that are operant in this setting stands to improve clinical outcomes of fat grafting and cell-based therapies. PMID- 25724062 TI - Volumetric changes in cranial vault expansion: comparison of fronto-orbital advancement and posterior cranial vault distraction osteogenesis. AB - BACKGROUND: Posterior cranial vault distraction osteogenesis has recently been introduced to treat patients with multisuture syndromic craniosynostosis and is believed to provide greater gains in intracranial volume. This study provides volumetric analysis to determine the gains in intracranial volume produced by this modality. METHODS: This was a two-center retrospective study of preprocedure and postprocedure computed tomography scans of two groups of 15 patients each with syndromic multisuture craniosynostosis treated with either fronto-orbital advancement or posterior cranial vault distraction osteogenesis. Scan data were analyzed volumetrically with Mimics software. Volumetric gains attributable to growth between scans were controlled for. RESULTS: The mean advancements were 12.5 mm for fronto-orbital advancement and 24.8 mm for distraction osteogenesis. The mean difference in volume between the preoperative and postoperative scans was 144 cm(3) for fronto-orbital advancement and 274 cm(3) for (p = 0.009). After controlling for growth, the corrected mean volume difference was 66 cm(3) for fronto-orbital advancement and 142 cm(3) for distraction osteogenesis (p = 0.0017). The corrected mean volume difference per millimeter of advancement was 4.6 cm(3) for fronto-orbital advancement and 5.8 cm(3) for distraction (p = 0.357). CONCLUSIONS: In this retrospective study, posterior cranial vault distraction osteogenesis provided statistically greater intracranial volume expansion than fronto-orbital advancement. The volume gains per millimeter advancement were similar between groups, with a trend toward greater gains per millimeter with distraction osteogenesis. Gradual expansion of the overlying soft tissues with posterior cranial vault distraction osteogenesis appears to be the primary mechanism for greater volume gains with this technique. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25724063 TI - Obesity-induced lymphedema: clinical and lymphoscintigraphic features. AB - The purpose of this study was to characterize obesity as a novel cause of lower extremity lymphedema. Fifty-one patients with a body mass index greater than 30 kg/m(2) without any potential cause of lymphedema were evaluated with lymphoscintigraphy. Group 1 patients (n = 33) were at their maximum body mass index; individuals with lymphatic dysfunction had a greater body mass index (72.0 kg/m(2)) compared with subjects with normal function (37.7 kg/m(2)) (p < 0.0001). Body mass index predicted the lymphoscintigram result, which was abnormal if the body mass index was greater than 60 kg/m(2) and normal if it was less than 50 kg/m(2). Group 2 patients (n = 18) had lost weight and were not at their maximum body mass index: patients who reduced their body mass index from greater than 60 kg/m to less than 50 kg/m(2) had normal (n = 4) or abnormal (n = 3) lymphatic function. Patients with obesity-induced lymphedema, or who were at risk for the condition, were referred to a surgical weight loss center. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 25724064 TI - Antibiotic prophylaxis for preventing surgical-site infection in plastic surgery: an evidence-based consensus conference statement from the American Association of Plastic Surgeons. AB - BACKGROUND: There is a growing concern for microbial resistance as a result of overuse of antibiotics. Although guidelines have focused on the use of antibiotics for surgery in general, few have addressed plastic surgery specifically. The objective of this expert consensus conference was to evaluate the evidence for efficacy and safety of antibiotic prophylaxis in plastic surgical procedures. METHODS: THE AUTHORS: searched for existing high-quality systematic reviews for antibiotic prophylaxis in the literature from the MEDLINE, Cochrane Library, and Embase databases. All synonyms for antibiotics were combined with terms for relevant plastic surgery procedures. The searches were not limited by language, and included all study designs. In addition, supplemental hand searches were performed of bibliographies of relevant articles, and extensive "related articles." Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons to reach consensus recommendations. RESULTS: Database searches identified 4300 articles, from which 2042 full-text articles were identified for eligibility. De novo meta analyses were performed for each plastic surgical category. In total, 67 studies met the inclusion criteria, including nine for breast surgery, 17 for head and neck surgery, 10 for orthognathic surgery, seven for rhinoplasty/septoplasty, 19 for hand surgery, five for skin surgery, and two for abdominoplasty. CONCLUSIONS: Systemic antibiotic prophylaxis is recommended for clean breast surgery and for contaminated surgery of the hand or the head and neck. It is not recommended to reduce infection in clean surgical cases of the hand, skin, head and neck, or abdominoplasty. PMID- 25724065 TI - How many perforators in a deep inferior epigastric artery perforator flap? The salvage of a perforator. PMID- 25724066 TI - Reply: How many perforators in a deep inferior epigastric artery perforator flap? The salvage of a perforator. PMID- 25724067 TI - Chronic biofilm infection in breast implants is associated with an increased T cell lymphocytic infiltrate: implications for breast implant-associated lymphoma. PMID- 25724069 TI - Student learning outcomes. PMID- 25724068 TI - The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity. AB - ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Here we demonstrate a role of ABCG1 as a mediator of tumour immunity. Abcg1(-/-) mice have dramatically suppressed subcutaneous MB49-bladder carcinoma and B16-melanoma growth and prolonged survival. We show that reduced tumour growth in Abcg1(-/-) mice is myeloid cell intrinsic and is associated with a phenotypic shift of the macrophages from a tumour-promoting M2 to a tumour-fighting M1 within the tumour. Abcg1(-/-) macrophages exhibit an intrinsic bias towards M1 polarization with increased NF-kappaB activation and direct cytotoxicity for tumour cells in vitro. Overall, our study demonstrates that the absence of ABCG1 inhibits tumour growth through modulation of macrophage function within the tumour, and illustrates a link between cholesterol homeostasis and cancer. PMID- 25724070 TI - Unique partnership and pediatric simulation facilitates learning for students. PMID- 25724071 TI - The National Council of State Boards of Nursing's Transition to Practice study: implications for educators. PMID- 25724072 TI - Use of the unfolding case study in teaching nurse educator master of science in nursing students. PMID- 25724073 TI - Long-term safety and efficacy of sapropterin: the PKUDOS registry experience. AB - The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 +/- 382 MUmol/L at baseline to 392 +/- 239 MUmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 +/- 959 mg/day (pre-sapropterin baseline) to 1539 +/- 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in <= 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance. PMID- 25724074 TI - Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. AB - PURPOSE: To describe a diagnostic protocol, surveillance and treatment guidelines, genetic counseling considerations and long-term follow-up data elements developed in preparation for X-linked adrenoleukodystrophy (X-ALD) newborn screening in New York State. METHODS: A group including the director from each regional NYS inherited metabolic disorder center, personnel from the NYS Newborn Screening Program, and others prepared a follow-up plan for X-ALD NBS. Over the months preceding the start of screening, a series of conference calls took place to develop and refine a complete newborn screening system from initial positive screen results to long-term follow-up. RESULTS: A diagnostic protocol was developed to determine for each newborn with a positive screen whether the final diagnosis is X-ALD, carrier of X-ALD, Zellweger spectrum disorder, acyl CoA oxidase deficiency or D-bifunctional protein deficiency. For asymptomatic males with X-ALD, surveillance protocols were developed for use at the time of diagnosis, during childhood and during adulthood. Considerations for timing of treatment of adrenal and cerebral disease were developed. CONCLUSION: Because New York was the first newborn screening laboratory to include X-ALD on its panel, and symptoms may not develop for years, long-term follow-up is needed to evaluate the presented guidelines. PMID- 25724075 TI - A cross-sectional survey to investigate the prevalence of pain in Japanese patients with major depressive disorder and schizophrenia. AB - We conducted a cross-sectional survey to assess the prevalence of physical pain in Japanese major depressive disorder (MDD) and schizophrenia (SZ) patients as well as in healthy controls (HCs). We also examined the association between their psychopathology and characteristics of pain according to a face-to-face survey by an experienced psychiatrist and psychologist. We analyzed 233 HCs, 94 MDD patients, and 75 SZ patients using the McGill Pain Questionnaire (MPQ) and SF-8 (all participants), the Hamilton Depression Rating Scale 21 items (MDD patients), and the Positive and Negative Symptom Scale (SZ patients). Although MDD patients experienced more pain than HCs, there was no difference in the prevalence of pain between SZ patients and HCs. Moreover, HCs with pain did not have higher SF-8 total scores than those without pain, whereas both MDD and SZ patients with pain had higher SF-8 total scores than those without pain. The severity of psychopathology in MDD and SZ patients was also positively associated with both the prevalence of pain and MPQ scores. MPQ scores were also associated with positive symptoms in SZ patients. Considering these results, physicians need to query MDD patients about physical pain during examination if they are to ensure a favorable and quick response to treatment. The severity of positive symptoms (i.e., clinical status) in SZ patients might also be associated with pain sensitivity, and warrants further investigation. PMID- 25724076 TI - Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review. AB - BACKGROUND: Overdose of amphetamine, related derivatives, and analogues (ARDA) continues to be a serious worldwide health problem. Patients frequently present to the hospital and require treatment for agitation, psychosis, and hyperadrenegic symptoms leading to pathologic sequelae and mortality. OBJECTIVE: To review the pharmacologic treatment of agitation, psychosis, and the hyperadrenergic state resulting from ARDA toxicity. METHODS: MEDLINE, PsycINFO, and the Cochrane Library were searched from inception to September 2014. Articles on pharmacologic treatment of ARDA-induced agitation, psychosis, and hyperadrenergic symptoms were selected. Evidence was graded using Oxford CEBM. Treatment recommendations were compared to current ACCF/AHA guidelines. RESULTS: The search resulted in 6082 articles with 81 eligible treatment involving 835 human subjects. There were 6 high-quality studies supporting the use of antipsychotics and benzodiazepines for control of agitation and psychosis. There were several case reports detailing the successful use of dexmedetomidine for this indication. There were 9 high-quality studies reporting the overall safety and efficacy of beta-blockers for control of hypertension and tachycardia associated with ARDA. There were 3 high-quality studies of calcium channel blockers. There were 2 level I studies of alpha-blockers and a small number of case reports for nitric oxide-mediated vasodilators. CONCLUSIONS: High-quality evidence for pharmacologic treatment of overdose from ARDA is limited but can help guide management of acute agitation, psychosis, tachycardia, and hypertension. The use of butyrophenone and later-generation antipsychotics, benzodiazepines, and beta-blockers is recommended based on existing evidence. Future randomized prospective trials are needed to evaluate new agents and further define treatment of these patients. PMID- 25724077 TI - Cost and sensitivity of on-farm versus slaughterhouse surveys for prevalence estimation and substantiating freedom from disease. AB - Within the framework of Swiss surveillance for epizootic diseases, dairy cattle are sampled using bulk tank milk while non-dairy cattle are sampled on the farm. The latter method is costly, time-demanding and dangerous for the personnel. However, slaughterhouses could be an alternative sampling point for this population. To assess the cost-effectiveness and sensitivity of such an approach, surveillance using slaughterhouse sampling was modelled with data from the 2012 Swiss animal movement database (AMD). We simulated a cross-sectional study for bluetongue (BT), and surveillance programmes to substantiate freedom from infectious bovine rhinotracheitis (IBR) and enzootic bovine leucosis (EBL) (combined) to compare the outcome of random on-farm sampling versus slaughterhouse sampling. We found that, under Swiss conditions, slaughterhouse sampling results in low herd-level sensitivities because animals are sent by owners to slaughter individually and not in large groups, restricting the number of samples per herd. This makes slaughterhouse sampling inappropriate for prevalence surveys at the herd-level. However, for prevalence surveys at the animal-level and for substantiation of freedom from disease, slaughterhouse surveillance is equally or more cost-efficient than on-farm sampling. PMID- 25724078 TI - High-attenuation crescent sign on computed tomography in acute abdominal aortic aneurysm. AB - We present an interesting radiologic finding in a 65-year-old gentleman who attended our emergency department (ED)with sudden-onset severe abdominal pain. Non-contrast-enhanced computed tomography of the abdomen revealed a 7-cm abdominal aortic aneurysm (AAA)which demonstrated the high-attenuation crescent sign (HACS). PMID- 25724079 TI - The differential diagnosis of acute pulmonary embolism and ST-segment inferior myocardial infarction. PMID- 25724080 TI - The fate of unscreened women in colon cancer: impact on staging and prognosis. AB - BACKGROUND: Several nationwide reports show lower female participation in colon cancer screening. We therefore assessed for outcome differences in women of screening age presenting for surgical treatment of colon cancer patients. METHODS: All patients over 50 years undergoing surgery for first-onset colon cancer at Massachusetts General Hospital (2004 to 2011) were included. Differences between (unscreened) women and the remaining population in presentation characteristics and subsequent morbidity and mortality were assessed. RESULTS: We included 919 patients (49.1% female). Women were less often diagnosed through screening (26.4 vs 32.7%, P = .036). Unscreened women were at significantly higher risk (all P < .001) for having high-grade tumors (Relative risk [RR] = 1.61), lymph node metastasis (RR = 1.36), and distant metastasis (RR = 2.26) on pathology, leading to higher colon cancer-related mortality (RR = 1.72). CONCLUSION: Unscreened women present with more advanced colon cancer and higher mortality, confirming that disparities in screening lead to ever increasing disparities in outcomes. PMID- 25724081 TI - Gracilins: Spongionella-derived promising compounds for Alzheimer disease. AB - Alzheimer disease (AD) is a neurodegenerative pathology that is strongly linked with oxidative stress and mitochondrial dysfunction. The unclear origin of AD lead researchers to study several drug targets and it has been proposed that a multi-target drug would be a more promising candidate. Gracilins are sponge derived diterpenoid compounds that have been described to act as antioxidants through mitochondrial targeting and through the induction of Nrf2 translocation. In this work gracilin H, A and L and tetrahydroaplysulphurin-1 have been studied in two neuroblastoma cellular models. First the BE(2)-M17 cell line has been used as a model for APP metabolism studies and next, SH-SY5Y-TMHT441 cells were used for AD drugs screening targeting tau phosphorylation. In vitro assays showed that gracilins were able to inhibit BACE1, reduce tau hyperphosphorylation and inhibit ERK. These positive results lead us to test gracilin H and L in 3xTg-AD mice. After chronic intraperitoneal treatments, a preliminary behavioral test pointed a positive trend on learning and spatial memory of mice treated with these compounds. Moreover in vivo assays confirmed the previous results. Amyloid-beta42 and hyperphosphorylated tau levels were decreased after treatments and the ERK inhibition was also observed. This research highlights new bioactivities for gracilins, such as BACE1 and ERK inhibition, and provides more evidence for their potential therapeutic application in neurodegenerative diseases due to their multi-target activities, especially in AD. PMID- 25724082 TI - Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain. AB - The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPgammaS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-beta (pGSK3beta(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPgammaS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1 stimulated GTPgammaS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3beta(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system. PMID- 25724084 TI - Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems. AB - Since their molecular cloning in the late 90's, Acid-Sensing Ion Channels (ASICs) have been shown to be involved in many aspects of nociception, both in peripheral and central neurons. In rodents, the combination of specific or non-specific pharmacological modulators of ASICs, together with in vivo knockdown and/or knockout animals has revealed their contribution to the detection, the modulation and the sensitization of the pain message by primary and secondary sensory neurons. Functional ASICs are homo or heterotrimers of different homologous subunits (ASIC1-3). Channels containing ASIC3 or ASIC1 subunits, appear to be important in peripheral nociceptors, where they are subject to intense regulation, while ASIC1a-containing channels also have a prominent role in central neurons, including spinal cord neurons that modulate and transmit the pain signal to the brain. In humans, experiments performed in healthy volunteers using drugs already used in the clinic and acting as poorly-selective inhibitors of ASICs, together with recent in vitro data obtained from stem cell-derived sensory neurons both support a role for these channels in nociception. These data thus suggest a real translational potential in the development of inhibitory strategies of ASICs for the treatment of pain. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. PMID- 25724083 TI - Neuropharmacology of purinergic receptors in human submucous plexus: Involvement of P2X1, P2X2, P2X3 channels, P2Y and A3 metabotropic receptors in neurotransmission. AB - RATIONALE: The role of purinergic signaling in human ENS is not well understood. We sought to further characterize the neuropharmacology of purinergic receptors in human ENS and test the hypothesis that endogenous purines are critical regulators of neurotransmission. EXPERIMENTAL APPROACH: LSCM-Fluo-4/(Ca(2+)) imaging of postsynaptic Ca(2+) transients (PSCaTs) was used as a reporter of synaptic transmission evoked by fiber tract electrical stimulation in human SMP surgical preparations. Pharmacological analysis of purinergic signaling was done in 1,556 neurons (identified by HuC/D-immunoreactivity) in 235 ganglia from 107 patients; P2XR-immunoreactivity was evaluated in 19 patients. Real-time MSORT (Di 8-ANEPPS) imaging tested effects of adenosine on fast excitatory synaptic potentials (fEPSPs). RESULTS: Synaptic transmission is sensitive to pharmacological manipulations that alter accumulation of extracellular purines: Apyrase blocks PSCaTs in a majority of neurons. An ecto-NTPDase-inhibitor 6-N,N diethyl-D-beta,gamma-dibromomethyleneATP or adenosine deaminase augments PSCaTs. Blockade of reuptake/deamination of eADO inhibits PSCaTs. Adenosine inhibits fEPSPs and PSCaTs (IC50 = 25 uM), sensitive to MRS1220-antagonism (A3AR). A P2Y agonist ADPbetaS inhibits PSCaTs (IC50 = 111 nM) in neurons without stimulatory ADPbS responses (EC50 = 960 nM). ATP or a P2X1,2,2/3 (alpha,beta-MeATP) agonist evokes fast, slow, biphasic Ca(2+) transients or Ca(2+) oscillations (ATP,EC50 = 400 mM). PSCaTs are sensitive to P2X1 antagonist NF279. Low (20 nM) or high (5 uM) concentrations of P2X antagonist TNP-ATP block PSCaTs in different neurons; proportions of neurons with P2XR-immunoreactivity follow the order P2X2 > P2X1 >> P2X3; P2X1 + P2X2 and P2X3 + P2X2 are co-localized. RT-PCR identified mRNA transcripts for P2X1-7, P2Y1,2,12-14R. CONCLUSIONS: Purines are critical regulators of neurotransmission in human ENS. Purinergic signaling involves P2X1, P2X2, P2X3 channels, P2X1 + P2X2 co-localization and inhibitory P2Y or A3 receptors. These are potential novel therapeutic targets for neurogastroenterology. PMID- 25724085 TI - Structural modeling and patch-clamp analysis of pain-related mutation TRPA1-N855S reveal inter-subunit salt bridges stabilizing the channel open state. AB - The ankyrin transient receptor potential channel TRPA1 is a polymodal sensor for noxious stimuli, and hence a promising target for treating chronic pain. This tetrameric six-transmembrane segment (S1-S6) channel can be activated by various pungent chemicals, such as allyl isothiocyanate or cinnamaldehyde, but also by intracellular Ca(2+) or depolarizing voltages. Within the S4-S5 linker of human TRPA1, a gain-of-function mutation, N855S, was recently found to underlie familial episodic pain syndrome, manifested by bouts of severe upper body pain, triggered by physical stress, fasting, or cold. To clarify the structural basis for this channelopathy, we derive a structural model of TRPA1 by combining homology modeling, molecular dynamics simulations, point mutagenesis and electrophysiology. In the vicinity of N855, the model reveals inter-subunit salt bridges between E854 and K868. Using the heterologous expression of recombinant wild-type and mutant TRPA1 channels in HEK293T cells, we indeed found that the charge-reversal mutants E854R and K868E exhibited dramatically reduced responses to chemical and voltage stimuli, whereas the charge-swapping mutation E854R/K868E substantially rescued their functionalities. Moreover, mutation analysis of highly conserved charged residues within the S4-S5 region revealed a gain-of function phenotype for R852E with an increased basal channel activity, a loss of Ca(2+)-induced potentiation and an accelerated Ca(2+)-dependent inactivation. Based on the model and on a comparison with the recently revealed atomic-level structure of the related channel TRPV1, we propose that inter-subunit salt bridges between adjacent S4-S5 regions are crucial for stabilizing the conformations associated with chemically and voltage-induced gating of the TRPA1 ion channel. PMID- 25724086 TI - Gene expression in hepatocellular carcinoma: pilot study of potential transarterial chemoembolization response biomarkers. AB - PURPOSE: To perform a feasibility study to explore the relationship between hepatocellular carcinoma genetics and transarterial chemoembolization treatment response to identify potential biomarkers associated with enhanced treatment efficacy. MATERIALS AND METHODS: In this single-institution study, pretreatment hepatocellular carcinoma biopsy specimens for tumors in 19 patients (14 men, five women; mean age, 59 y) treated with chemoembolization between 2007 and 2013 were analyzed for a panel of 60 chemotherapy-sensitivity, hypoxia, mitosis, and inflammatory genes with the QuantiGene Plex 2.0 mRNA detection assay. Demographic, disease, and procedure data and tumor response outcomes were collected. Quantitative mRNA levels were compared based on radiologic response between tumors exhibiting complete response (CR) versus partial response (PR). RESULTS: The study sample included 19 biopsy specimens from tumors (mean size, 3.0 cm; grade 1, n = 6; grade 2, n = 9; grade 3, n = 4) in patients treated with a mean of two conventional chemoembolization sessions. Thirteen and six tumors exhibited CR and PR, respectively, at a mean of 116 days after treatment. Tumors with CR showed a significant increase in (P < .05) or trend toward (P < .1) greater (range, 1.49-3.50 fold) pretreatment chemotherapy-sensitivity and mitosis (ATF4, BAX, CCNE1, KIF11, NFX1, PPP3CA, SNX1, TOP2A, and TOP2B) gene mRNA expression compared with tumors with PR, in addition to lower CXCL10 levels (0.48 fold), and had significantly (P < .05) higher (1.65-fold) baseline VEGFA levels. CONCLUSIONS: Genetic signatures may allow prechemoembolization stratification of tumor response probability, and gene analysis may therefore offer an opportunity to personalize locoregional therapy by enhancing treatment modality allocation. Further corroboration of identified markers and exploration of their respective predictive capacity thresholds is necessary. PMID- 25724087 TI - Source of errors and accuracy of a two-dimensional/three-dimensional fusion road map for endovascular aneurysm repair of abdominal aortic aneurysm. AB - PURPOSE: To evaluate the accuracy and source of errors using a two-dimensional (2D)/three-dimensional (3D) fusion road map for endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm. MATERIALS AND METHODS: A rigid 2D/3D road map was tested in 16 patients undergoing EVAR. After 3D/3D manual registration of preoperative multidetector computed tomography (CT) and cone beam CT, abdominal aortic aneurysm outlines were overlaid on live fluoroscopy/digital subtraction angiography (DSA). Patient motion was evaluated using bone landmarks. The misregistration of renal and internal iliac arteries were estimated by 3 readers along head-feet and right-left coordinates (z-axis and x-axis, respectively) before and after bone and DSA corrections centered on the lowest renal artery. Iliac deformation was evaluated by comparing centerlines before and during intervention. A score of clinical added value was estimated as high (z-axis < 3 mm), good (3 mm <= z-axis <= 5 mm), and low (z-axis > 5 mm). Interobserver reproducibility was calculated by the intraclass correlation coefficient. RESULTS: The lowest renal artery misregistration was estimated at x-axis = 10.6 mm +/- 11.1 and z-axis = 7.4 mm +/- 5.3 before correction and at x-axis = 3.5 mm +/- 2.5 and z-axis = 4.6 mm +/- 3.7 after bone correction (P = .08), and at 0 after DSA correction (P < .001). After DSA correction, residual misregistration on the contralateral renal artery was estimated at x-axis = 2.4 mm +/- 2.0 and z axis = 2.2 mm +/- 2.0. Score of clinical added value was low (n = 11), good (n= 0), and high (n= 5) before correction and low (n = 5), good (n = 4), and high (n = 7) after bone correction. Interobserver intraclass correlation coefficient for misregistration measurements was estimated at 0.99. Patient motion before stent graft delivery was estimated at x-axis = 8 mm +/- 5.8 and z-axis = 3.0 mm +/- 2.7. The internal iliac artery misregistration measurements were estimated at x axis = 6.1 mm +/- 3.5 and z-axis = 5.6 mm +/- 4.0, and iliac centerline deformation was estimated at 38.3 mm +/- 15.6. CONCLUSIONS: Rigid registration is feasible and fairly accurate. Only a partial reduction of vascular misregistration was observed after bone correction; minimal DSA acquisition is still required. PMID- 25724088 TI - Preliminary Results of Temporary Placement of Retrievable Expandable Metallic Stents during Preoperative Neoadjuvant Chemoradiotherapy in Patients with Resectable Esophageal Cancer. AB - PURPOSE: To evaluate the clinical efficacy of temporary placement of a retrievable expandable metallic stent (REMS) during preoperative neoadjuvant chemoradiotherapy (CRT) in patients with resectable esophageal cancer. MATERIALS AND METHODS: REMSs were placed in 25 patients who underwent preoperative neoadjuvant CRT for resectable esophageal cancer. Stent removal was scheduled between 4 and 6 weeks after starting neoadjuvant CRT. Clinical effectiveness was assessed using the following variables: technical and clinical success, dysphagia score before and after stent placement and removal, and complications and their management. RESULTS: REMS placement was technically successful in all patients, with 24 of 25 patients (96%) showing symptomatic improvement. Stents were removed electively 32 days (range, 27-42 d) after starting neoadjuvant CRT (n = 20; 80%) or after stent migration and exit through the anus with no evidence of symptom recurrence (n = 5; 20%). The dysphagia score (before stent, 3.1 +/- 0.5) improved by 3 days after stent placement (1.3 +/- 0.4; P < .001) and was maintained up to 1 month after stent removal (1.2 +/- 0.7; P < .001). The median survival was 18.6 months. CONCLUSIONS: In patients with resectable esophageal cancer, temporary placement of a REMS during preoperative neoadjuvant CRT showed clinical efficacy in the bridge to surgery. Stent removal between 4 and 6 weeks after starting neoadjuvant CRT seems to be a feasible time frame with symptom improvement. PMID- 25724089 TI - Use of multiple cell and tissue-level biomarkers in mussels collected along two gas fields in the northern Adriatic Sea as a tool for long term environmental monitoring. AB - As a consequence of the growing global demand of energy supplies, intense oil and gas exploration and exploitation programs have been carried out worldwide especially within the marine environments. The release of oil-derived compounds in the sea from anthropogenic sources both as effluents or accidental spill is perceived as a major environmental concern. An approach based on a combination of biomarkers and the distribution of some classes of environmentally relevant pollutants was used to investigate the occurrence of a stress syndrome in mussels (Mytilus galloprovincialis) collected at three gas platforms placed in two distinct oceanographic districts within the Adriatic Sea. Biological responses were integrated by a ranking algorithm which demonstrated both a range of biological effects reflecting exposure gradients and a temporal related trend in the investigated responses. The overall results demonstrate a moderate to absent pollution from studied gas platforms with low but remarkable biological disturbance in sentinel organisms. PMID- 25724090 TI - Whole genome sequencing and phylogenetic analysis of feline anelloviruses. AB - Torque teno felis virus (FcTTV) was detected in the cat population in the Czech Republic. A total of 110 serum samples were tested by a nested PCR technique using specific primers, situated in the highly conserved untranslated region of the virus genome. The frequency of feline TT virus in the Czech Republic was found to be 33.63%. Sequencing of PCR product from several virus strains showed that all of them are closely related and belong to the same virus species. Whole genome sequencing of three strains was performed to compare overall genetic heterogeneity of feline TT viruses. One of these three strains showed more that 10% difference at the nucleotide level. Furthermore we didn't find any correlation between FcTTV infection and sex or health status of examined animals. PMID- 25724091 TI - Molecular epidemiology of carbapenem non-susceptible Acinetobacter nosocomialis in a medical center in Taiwan. AB - The mechanism by which carbapenem non-susceptible Acinetobacter nosocomialis (CNSAN) is disseminated is rarely described in the literature. In this study, we delineated the molecular epidemiology of CNSAN isolated from patients in a medical center in Taiwan. Fifty-four non-duplicate bloodstream isolates of CNSAN were collected at the Taipei Veterans General Hospital between 2001 and 2007. Pulsed-field gel electrophoresis (PFGE) was performed to determine their clonal relationship. Carbapenem-resistance genes and associated genetic structures were detected by polymerase chain reaction (PCR) mapping. Southern hybridization was performed to determine the plasmid location of carbapenem-resistance genes. Transmissibility of these genes to Acinetobacterbaumannii was demonstrated by conjugation tests. The overall carbapenem non-susceptibility rate among A. nosocomialis isolates during the study period was 21.6% (54/250). PFGE revealed three major pulsotypes: H (n=23), I (n=10), and K (n=8). The most common carbapenem-resistance gene was blaOXA-58 (43/54, 79.6%), containing an upstream insertion sequence IS1006 and a truncated ISAba3 (IS1006-DeltaISAba3-like-blaOXA 58). All isolates belonging to the pulsotypes H, I, and K carried plasmid located IS1006-DeltaISAba3-like-blaOXA-58. A common plasmid carrying ISAba1-blaOXA-82 was found in six isolates, which belonged to five pulsotypes. A type 1 integron that carried blaIMP-1 was detected in different plasmids of seven isolates, which belonged to five pulsotypes. Plasmids carrying these carbapenem-resistant determinants were transmissible from A. nosocomialis to A. baumannii via conjugation. In this medical center, CNSAN mainly emerged through clonal dissemination; propagation of plasmids and integrons carrying carbapenem resistant determinants played a minor role. This study showed that plasmids carrying carbapenem-resistant determinants are transmissible from A. nosocomialis to A. baumannii. PMID- 25724092 TI - Pathologic evaluation of the response of mesorectal positive nodes to preoperative chemoradiotherapy in patients with rectal cancer. AB - BACKGROUND: The response of positive mesorectal lymph nodes to chemoradiotherapy remains largely unstudied in patients with rectal cancer. The aim of this study was to investigate the requirements of the total regression of positive nodes treated with chemoradiotherapy. METHODS: The response of the primary tumor was evaluated according to the tumor regression grade (TRG 0-4) in resected specimens, and positive lymph nodes were assessed according to the lymph node regression grade (LRG 1-3), with TRG 4 and LRG 3 indicating total regression. We investigated the relationships among TRG, LRG, and the sizes of positive lymph nodes. RESULTS: Among 178 patients, 68 (38.2%) had 200 positive lymph nodes. We first investigated the relationship of positive nodes to TRG and LRG and found that the response of the primary tumor to chemoradiotherapy correlated with the response of positive nodes. Next, we investigated the correlation between LRG and the size of positive nodes. At TRG 1 and 2, LRG score was not correlated with the positive node size. In contrast, at TRG 3, LRG score was correlated with the size of positive nodes. Next, our assessment of the relationship between the sizes of positive nodes and complete degeneration to LRG 3 showed that the most accurate cut-off score on receiver-operator-characteristics curve analysis was 6 mm in maximum diameter for TRG 3. CONCLUSION: The requirements of the total regression of positive nodes are 1) degeneration of the primary tumor to TRG 3 and 2) a positive node diameter of <6 mm. PMID- 25724093 TI - Protective effects of rosuvastatin in a rat model of lung contusion: Stimulation of the cyclooxygenase 2-prostaglandin E-2 pathway. AB - BACKGROUND: Lung contusion, which can occur in patients with blunt thoracic trauma, is a leading risk factor for development of acute lung injury (ALI) and acute respiratory distress syndrome. Statins are lipid-lowering drugs with many beneficial antiinflammatory and antioxidative effects. We therefore hypothesized that the administration of statins immediately after trauma will inhibit the production of inflammatory mediators, and thereby alleviate the severity of lung injury. METHODS: A model of blunt chest injury in rat was employed. The effects of statins (rosuvastatin) and cyclooxygenase-2 (COX-2) inhibitors (meloxicam) on ALI were assessed by measuring inflammatory mediator levels in the serum and in the bronchoalveolar space. Animals were killed at the end of day 3. Histologic evaluation of lung tissue was performed to confirm the presence and severity of lung contusion as well as the effects of statins, nonsteroidal antiinflammatory drugs, and their combination. RESULTS: Administration of meloxicam after lung contusion decreased the amount of neutrophil infiltration; however, marked hemorrhage and edema were still noticed. Administration of rosuvastatin decreased significantly cytokine levels that were increased after the blunt chest trauma. Rosuvastatin increased the expression of inducible nitric oxide (iNOS), COX-2, heme oxygenase-1 (HO-1), and prostaglandin E2 (PGE-2) in the bronchoalveolar lavage fluid of the rat contused lungs. Coadministration of meloxicam prevented these changes. CONCLUSION: Rosuvastatin treatment after lung contusion attenuated several features of ALI. The enhanced activity of iNOS, COX-2, and HO-1 in the lung may reflect the advent of protective processes that took place in the contused lung. To our knowledge, this is the first demonstration that prostaglandin pathways play an essential role in the effects of statins in lung injury. PMID- 25724094 TI - Development of a risk stratification system for the occurrence of prolonged postoperative ileus after colorectal surgery: a prospective risk factor analysis. AB - BACKGROUND: Management strategies for prolonged postoperative ileus (PPOI) are principally conservative and it is therefore valuable to shift attention to prevention. This study aimed to identify prospectively the perioperative risk factors for the development of PPOI and create a tool to predict its occurrence. METHODS: Patients undergoing elective colorectal surgery at Auckland District Health Board between September 2012 and June 2014 were enrolled. In total, 92 variables were investigated prospectively with uniform application of a standardized definition of PPOI. Logistic regression and area under receiver operating characteristic curves (AUC) were used to generate risk stratification models. RESULTS: PPOI occurred in 88 of 327 patients (26.9%). Independent predictors of PPOI were male gender (odds ratio [OR], 3.01), decreasing preoperative albumin (OR, 1.11 per g/L unit), open or converted technique (OR, 6.37 [vs laparoscopic]), increasing wound size (OR, 1.09 [per cm]), operative difficulty (OR, 1.28 [per unit on 10-point Likert scale]), operative bowel handling (OR, 1.38 [per unit on 10-point Likert scale]), red cell transfusion (OR, 1.84 [per unit]), intravenous crystalloid administration (OR, 1.55 [per liter]), and delayed first mobilization (OR, 1.39 [per day]). The I-Score assimilated preoperative and intraoperative variables to generate a score out of 6 with a 7-fold increase in risk from low-risk to high-risk strata and fair predictive capacity (AUC, 0.742; 95% CI, 0.684-0.799). CONCLUSION: Independent predictors for the development of PPOI have been identified prospectively and used to construct a novel risk stratification model. PMID- 25724095 TI - A novel whole-embryo culture model for pharmaceutical and developmental studies. AB - INTRODUCTION: This report introduces a new vertebrate whole-embryo culture model for the direct application of pharmaceuticals and/or toxins into developing embryos. This method uses a terrestrial amphibian system and therefore has eliminated the problem of mammalian placental and uterine concerns. To test the utility and effectiveness of this method, we investigated the effect of fluoxetine on craniofacial development. Fluoxetine is one of the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) on the market and treatment of depression during pregnancy is commonly deemed necessary. Previous studies have shown that SSRIs may promote developmental defects and congenital malformations of the heart. METHODS: This model utilized the egg/embryos of the directly developing Puerto Rican coqui frog, Eleutherodactylus coqui. The E. coqui embryo clutches were placed on filter paper in a Petri dish and were directly exposed (chronically) to fluoxetine concentrations ranging from 0.10mM to 1.0mM. Traditional whole-mount bone (Alizarin red) and cartilage (Alcian blue) staining was utilized to show the effect of fluoxetine on craniofacial development. RESULTS: Whole-mount staining revealed profound defects in cartilage development, particularly in the nasal capsule, mandible, and the brain case. Further, fluoxetine-treated embryos developed significantly slower compared to control animals. DISCUSSION: We found that the E. coqui culture model was an effective and sensitive technique for pharmaceutical studies, particularly since it allows the direct application of drugs and toxins into the developing embryo without the hindrance of the uterus and placenta. Chromatographic analysis revealed that fluoxetine infiltrated and penetrated embryonic tissue. It was found that altering serotonergic activity during development, via fluoxetine, stunted craniofacial development and organization. PMID- 25724096 TI - Health assessment of free-ranging endangered Australian sea lion (Neophoca cinerea) pups: effect of haematophagous parasites on haematological parameters. AB - Evaluation of the health status of free-ranging populations is important for understanding the impact of disease on individuals and on population demography and viability. In this study, haematological reference intervals were developed for free-ranging endangered Australian sea lion (Neophoca cinerea) pups within the context of endemic hookworm (Uncinaria sanguinis) infection and the effects of pathogen, host, and environment factors on the variability of haematological parameters were investigated. Uncinaria sanguinis was identified as an important agent of disease, with infection causing regenerative anaemia, hypoproteinaemia, and a predominantly lymphocytic-eosinophilic systemic inflammatory response. Conversely, the effects of sucking lice (Antarctophthirus microchir) were less apparent and infestation in pups appears unlikely to cause clinical impact. Overall, the effects of U. sanguinis, A. microchir, host factors (standard length, body condition, pup sex, moult status, and presence of lesions), and environment factors (capture-type and year of sampling) accounted for 26-65% of the total variance observed in haematological parameters. Importantly, this study demonstrated that anaemia in neonatal Australian sea lion pups is not solely a benign physiological response to host-environment changes, but largely reflects a significant pathological process. This impact of hookworm infection on pup health has potential implications for the development of foraging and diving behaviour, which would subsequently influence the independent survival of juveniles following weaning. The haematological reference intervals developed in this study can facilitate long-term health surveillance, which is critical for the early recognition of changes in disease impact and to inform conservation management. PMID- 25724097 TI - Extraocular spectral photosensitivity in the tentacles of Hydra vulgaris. AB - Previous electrophysiological studies on the cnidarian Hydra vulgaris have shown that hydra have a highly developed and specific photoresponse despite their lack of any structure recognizable as a traditional photoreceptor. In an effort to identify the site of hydra's photoreceptors, we recorded extracellularly from single excised tentacles and from ablated hypostomes lacking tentacles in absolute darkness and during exposure to light of various wavelengths. During recording, after an initial period of absolute darkness, tentacles or hypostomes were exposed to light from 450nm to 600nm, red, and white light. Exposure to light caused a change in the pattern and frequency of impulses in the tentacles that varied with color. The number of large tentacle pulses (TPs) increased at 550 and 600nm relative to darkness, whereas the number of small tentacle pulses (STPs) tended to decrease in 500nm light. Impulse frequency was significantly different among the different wavelengths. In addition to bursts of tentacle contraction pulses, long trains of pulses were observed. A change in lighting caused a switch from bursting to trains or vice versa. In contrast to excised tentacles, no change in electrical activity was seen in ablated hypostomes at any of the wavelengths relative to each other or relative to darkness. These results indicate that isolated tentacles can distinguish among and respond to various colors across the visible spectrum and suggest that electromagnetic information is transmitted from the tentacles to the hypostome where it may be integrated by the hypostomal nervous system, ultimately contributing to hydra's photoreceptive behavior. PMID- 25724098 TI - Permanent gas analysis using gas chromatography with vacuum ultraviolet detection. AB - The analysis of complex mixtures of permanent gases consisting of low molecular weight hydrocarbons, inert gases, and toxic species plays an increasingly important role in today's economy. A new gas chromatography detector based on vacuum ultraviolet (VUV) spectroscopy (GC-VUV), which simultaneously collects full scan (115-240 nm) VUV and UV absorption of eluting analytes, was applied to analyze mixtures of permanent gases. Sample mixtures ranged from off-gassing of decomposing Li-ion and Li-metal batteries to natural gas samples and water samples taken from private wells in close proximity to unconventional natural gas extraction. Gas chromatography separations were performed with a porous layer open tubular column. Components such as C1-C5 linear and branched hydrocarbons, water, oxygen, and nitrogen were separated and detected in natural gas and the headspace of natural gas-contaminated water samples. Of interest for the transport of lithium batteries were the detection of flammable and toxic gases, such as methane, ethylene, chloromethane, dimethyl ether, 1,3-butadiene, CS2, and methylproprionate, among others. Featured is the capability for deconvolution of co-eluting signals from different analytes. PMID- 25724099 TI - Selective removal of phosphate for analysis of organic acids in complex samples. AB - Accurate quantitation of compounds in samples of biological origin is often hampered by matrix interferences one of which occurs in GC-MS analysis from the presence of highly abundant phosphate. Consequently, high concentrations of phosphate need to be removed before sample analysis. Within this context, we screened 17 anion exchange solid-phase extraction (SPE) materials for selective phosphate removal using different protocols to meet the challenge of simultaneous recovery of six common organic acids in aqueous samples prior to derivatization for GC-MS analysis. Up to 75% recovery was achieved for the most organic acids, only the low pKa tartaric and citric acids were badly recovered. Compared to the traditional approach of phosphate removal by precipitation, SPE had a broader compatibility with common detection methods and performed more selectively among the organic acids under investigation. Based on the results of this study, it is recommended that phosphate removal strategies during the analysis of biologically relevant small molecular weight organic acids consider the respective pKa of the anticipated analytes and the detection method of choice. PMID- 25724100 TI - A new application of monolithic supports: the separation of viruses from one another. AB - The emergence of next-generation "deep" sequencing has enabled the study of virus populations with much higher resolutions. This new tool increases the possibility of observing mixed infections caused by combinations of plant viruses, which are likely to occur more frequently than previously thought. The biological impact of co-infecting viruses on their host has yet to be determined and fully understood, and the first step towards reaching this goal is the separation and purification of individual species. Ion-exchange monolith chromatography has been used successfully for the purification and concentration of different viruses, and number of them have been separated from plant homogenate or bacterial and eukaryotic lysate. Thus, the question remained as to whether different virus species present in a single sample could be separated. In this study, anion exchange chromatography using monolithic supports was optimized for fast and efficient partial purification of three model plant viruses: Turnip yellow mosaic virus, Tomato bushy stunt virus, and Tobacco mosaic virus. The virus species, as well as two virus strains, were separated from each other in a single chromatographic experiment from an artificially mixed sample. Based on A260/280 ratios, we were able to attribute specific peaks to a certain viral morphology/structure (icosahedral or rod-shaped). This first separation of individual viruses from an artificially prepared laboratory mixture should encourage new applications of monolithic chromatographic supports in the separation of plant, bacterial, or animal viruses from all kinds of mixed samples. PMID- 25724101 TI - Machine learning in computational docking. AB - OBJECTIVE: The objective of this paper is to highlight the state-of-the-art machine learning (ML) techniques in computational docking. The use of smart computational methods in the life cycle of drug design is relatively a recent development that has gained much popularity and interest over the last few years. Central to this methodology is the notion of computational docking which is the process of predicting the best pose (orientation + conformation) of a small molecule (drug candidate) when bound to a target larger receptor molecule (protein) in order to form a stable complex molecule. In computational docking, a large number of binding poses are evaluated and ranked using a scoring function. The scoring function is a mathematical predictive model that produces a score that represents the binding free energy, and hence the stability, of the resulting complex molecule. Generally, such a function should produce a set of plausible ligands ranked according to their binding stability along with their binding poses. In more practical terms, an effective scoring function should produce promising drug candidates which can then be synthesized and physically screened using high throughput screening process. Therefore, the key to computer aided drug design is the design of an efficient highly accurate scoring function (using ML techniques). METHODS: The methods presented in this paper are specifically based on ML techniques. Despite many traditional techniques have been proposed, the performance was generally poor. Only in the last few years started the application of the ML technology in the design of scoring functions; and the results have been very promising. MATERIAL: The ML-based techniques are based on various molecular features extracted from the abundance of protein ligand information in the public molecular databases, e.g., protein data bank bind (PDBbind). RESULTS: In this paper, we present this paradigm shift elaborating on the main constituent elements of the ML approach to molecular docking along with the state-of-the-art research in this area. For instance, the best random forest (RF)-based scoring function on PDBbind v2007 achieves a Pearson correlation coefficient between the predicted and experimentally determined binding affinities of 0.803 while the best conventional scoring function achieves 0.644. The best RF-based ranking power ranks the ligands correctly based on their experimentally determined binding affinities with accuracy 62.5% and identifies the top binding ligand with accuracy 78.1%. CONCLUSIONS: We conclude with open questions and potential future research directions that can be pursued in smart computational docking; using molecular features of different nature (geometrical, energy terms, pharmacophore), advanced ML techniques (e.g., deep learning), combining more than one ML models. PMID- 25724102 TI - The experiences of ICU patients during follow-up sessions--a qualitative study. AB - OBJECTIVE: Evidence supports the recommendation for follow-up session(s) for patients after discharge from an intensive care unit (ICU). The aim of these follow-up sessions is to allow patients to express and discuss their experiences and problems following their time in an ICU. To optimise the knowledge gained from the follow-up session experience, it is necessary to describe how patients experience these sessions. The aim of this study was to describe how ICU patients, experience a follow-up session. DESIGN/SETTING: This study adopted a qualitative design utilising semi-structured interviews, and which examined the experiences of seven men and five women. Qualitative content analysis was utilised. FINDINGS: The participants stated that the information gained from these sessions, which had previously seemed unclear to some of them, was, on the whole, now clarified and confirmed. A discernible difference was found between participants who were cared for on a general ward and those who were cared for on a rehabilitation ward and also were offered a meeting with a counsellor, following discharge their from the ICU. The findings also indicated that participants who were not offered psychosocial support showed a greater need for a follow-up session. CONCLUSION: This study has highlighted the need for increasing collaboration between intensive care staff and staff in other units to provide support to this patient group in order to reduce their suffering post intensive care experience. PMID- 25724103 TI - Prospective, randomised controlled trial comparing VersajetTM hydrosurgery and conventional debridement of partial thickness paediatric burns. AB - INTRODUCTION: Conventional surgical debridement of burn wounds consists of tangential excision of eschar using a knife or dermabrasion until viable dermis or punctate bleeding occurs. The VersajetTM (Smith and Nephew, St. Petersburg, FL, USA) hydrosurgery system has also been advocated for burn wound debridement, with the suggestion that enhanced preservation of dermal tissue might reduce subsequent scarring. METHODS: A prospective randomised controlled trial was undertaken comparing VersajetTM to conventional debridement. After excluding those with facial burns, 61 children <=16 years of age undergoing debridement and skin grafting for partial thickness burns were recruited. Adequacy of debridement was assessed by 2mm punch biopsies taken pre- and post-debridement. Surgical time, percentage graft take at day 10, time to healing, post-operative infection and scarring at 3 and 6 months were assessed. RESULTS: Thirty-one children underwent conventional debridement and 30 debridement using VersajetTM. There was a significant difference in the amount of viable dermal preservation between the two groups (p=0.02), with more viable tissue lost in the conventional group (median 325 MUm) versus the VersajetTM group (median 35 MUm). There was no significant difference between graft take at day 10 (p=0.9), post-operative wound infection (p=0.5), duration of surgery (p=0.6) or time to healing after grafting (p=0.6). Despite better dermal preservation in the VersajetTM group, there was no significant difference between scarring at 3 or 6 months (p=1.0, 0.1). CONCLUSIONS: These findings suggest that VersajetTM hydrosurgery appears a more precise method of burn wound debridement. Although dermal preservation may be a factor in reducing subsequent hypertrophic scarring, there were no significant differences found between scarring at 3 or 6 months after-injury. PMID- 25724104 TI - The safety of general anaesthesia in paediatric patients undergoing the application of Biobrane(r) for small scalds. AB - BACKGROUND: Each year more than 5000 children present to English and Welsh hospitals for the management of scalds; 60% of these are small scalds of less than 10% body surface area. There are no agreed UK care pathways for this injury. One method of management is to use a biosynthetic wound dressing after thorough wound cleaning. In children, this usually utilises general anaesthesia. This study investigates the incidence of adverse events during anaesthesia for the application of biosynthetic dressings in children with small-area scalds. METHODS: The medical records of 500 consecutive admissions to a tertiary care paediatric burn centre between July 1st 2007 and June 30th 2012 were analysed. The primary outcome was any patient-related adverse event incurred as a result of the general anaesthesia. Secondary outcomes included delays in discharge and any recovery sequelae to the adverse events. RESULTS: There were 21 (4.2%) documented adverse events associated with 500 episodes of anaesthesia. Of these, the majority (52%) were documented as self-resolving laryngospasm. All episodes were temporary with no recovery sequelae and did not delay discharge from the post anaesthetic recovery area. CONCLUSIONS: The use of general anaesthesia in this setting for the application of biosynthetic dressings in children with small-area scalds has a low incidence of anaesthesia-related complications with no associated long-term sequelae. This incidence is similar to that quoted for adverse events related to anaesthesia for other procedures and is lower than that reported for procedures using sedation. PMID- 25724105 TI - Association of influenza vaccine uptake with health, access to health care, and medical mistreatment among adults from low-income neighborhoods in New Haven, CT: a classification tree analysis. AB - OBJECTIVE: The aim of this study is to identify population subgroups under vaccinated for influenza through classification tree analysis to inform interventions aimed at improving future vaccine uptake. METHOD: A cross-sectional community health needs assessment was conducted from 09/2012 through 11/2012 among randomly selected households in six low-income neighborhoods in New Haven, CT (N=1300 adults, aged 18-65). Known correlates of influenza vaccine uptake plus experience of medical mistreatment were used to develop a classification tree to identify under-vaccinated population subgroups RESULTS: Forty-five percent of respondents reported receiving the influenza vaccine. The classification tree identified healthy adults and uninsured adults at increased risk of influenza complications as subgroups with low vaccine uptake (40% and 30%, respectively). The subgroup representing insured, high-risk adults who reported experience of medical mistreatment had moderate vaccine uptake (45%). Sensitivity of the classification tree was high (83%, 95% CI=80% to 86%), indicating a strong true positive rate using these subgroups. CONCLUSION: Results highlight the need for renewed attention to promoting the influenza vaccination recommendation for all adults, particularly among healthy adults, uninsured, high-risk adults and insured, high-risk adults who have experienced medical mistreatment. Further research is needed to better understand how to reach these population subgroups. PMID- 25724106 TI - Contrasts in active transport behaviour across four countries: how do they translate into public health benefits? AB - OBJECTIVE: Countries and regions vary substantially in transport related physical activity that people gain from walking and cycling and in how this varies by age and gender. This study aims to quantify the population health impacts of differences between four settings. METHOD: The Integrated Transport and Health Model (ITHIM) was used to estimate health impacts from changes to physical activity that would arise if adults in urban areas in England and Wales adopted travel patterns of Switzerland, the Netherlands, and California. The model was parameterised with data from travel surveys from each setting and estimated using Monte Carlo simulation. Two types of scenarios were created, one in which the total travel time budget was assumed to be fixed and one where total travel times varied. RESULTS: Substantial population health benefits would accrue if people in England and Wales gained as much transport related physical activity as people in Switzerland or the Netherlands, whilst smaller but still considerable harms would occur if active travel fell to the level seen in California. The benefits from achieving the travel patterns of the high cycling Netherlands or high walking Switzerland were similar. CONCLUSION: Differences between high income countries in how people travel have important implications for population health. PMID- 25724107 TI - Sulforaphane attenuation of experimental diabetic nephropathy involves GSK-3 beta/Fyn/Nrf2 signaling pathway. AB - Sulforaphane (SFN), the bioactive component of cruciferous vegetables, is a potent indirect antioxidant. Oxidative stress and activation of glycogen synthase kinase 3beta (GSK3beta) are two major contributors to the pathogenesis of diabetic nephropathy (DN). Here, we investigated whether and how SFN affected GSK3beta in experimental models of DN in vivo and in vitro. SFN treatment obviously prevented the increase in urine albumin excretion, matrix expansion, transforming growth factor-beta1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Simultaneously, the level of 8-oxo deoxyguanosine, an indicator of oxidative damage, was markedly lowered in SFN treated diabetic rats, together with a significant reduction in activity of the GSK-3beta/Fyn axis and an evident activation of Nrf2 signaling. Similarly, antifibrotic effects of SFN, parallel to enhanced inhibitory Ser9-phosphorylation of GSK3beta and Fyn/Nrf2 nuclear export/import, were observed in the cultured rat mesangial cells (RMC) exposed to high glucose. The salutary effects of SFN on high-glucose-stimulated RMC were abolished by overexpression of GSK3beta while being rescued by lithium chloride, a well-known GSK3beta inhibitor. Taken together, our findings suggested that SFN ameliorated experimental diabetic nephropathy, at least in part, via GSK3beta/Fyn/Nrf2 signaling pathway. PMID- 25724108 TI - Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice. AB - The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro inflammatory response (TNF-alpha, IL1-beta, IL-6 and pIkappaBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. PMID- 25724109 TI - Angiotensin II and its receptor in activated microglia enhanced neuronal loss and cognitive impairment following pilocarpine-induced status epilepticus. AB - Neuroinflammation plays a role in the pathology of epilepsy and in cognitive impairment. Angiotensin II (AII) and the angiotensin receptor type 1 (AT1) have been shown to regulate seizure susceptibility in different models of epilepsy. Inhibition of AT1 attenuates neuroinflammatory responses in different neurological diseases. In the present study, we showed that the protein expression of AII and AT1 was increased in activated microglia following lithium pilocarpine-induced status epilepticus (SE) in rats. Furthermore, the AT1 receptor antagonist, losartan, significantly inhibited SE-induced cognitive impairment and microglia-mediated inflammation. Losartan also prevented SE induced neuronal loss in the hippocampus and exerted neuroprotection. These data suggest that losartan improves SE-induced cognitive impairment by suppressing microglia mediated inflammatory responses and attenuating hippocampal neuronal loss. Overall, our findings provide a possible therapeutic strategy for the treatment of cognitive impairment in epilepsy. PMID- 25724110 TI - Staging Bilateral Total Knee Arthroplasty During the Same Hospitalization: The Impact of Timing. AB - The concept of staging during the same hospitalization for bilateral total knee arthroplasty (BTKA) has emerged as a practice to minimize perioperative risks, although with few data providing an evidence base. A total of 41,664 BTKA patients from Nationwide Inpatient Sample data between 1998 and 2010 were identified, and categorized into three groups, same day, staging 1-3 days, and staging 4-7 days BTKA. Staging BTKA 1-3 days apart was associated with increased rates for complications compared to same day BTKA, while staging 4-7 days BTKA was associated with similar complication profiles compared to same day BTKA. Our study suggests that same day BTKA for selective patient population is preferable, and staging BTKA either 1-3 days or 4-7 days apart should be discouraged. PMID- 25724111 TI - Rivaroxaban Versus Enoxaparin for Venous Thromboembolism Prophylaxis after Hip and Knee Arthroplasty. AB - The oral Factor Xa inhibitor rivaroxaban (Xarelto) has been the pharmacologic agent used for venous thromboembolism (VTE) prophylaxis after primary hip and knee arthroplasty (THA/TKA) at our institution since February 2012. The purpose of our study was to compare rates of VTE and major bleeding between rivaroxaban and our previous protocol of enoxaparin after THA/TKA. A retrospective cohort study was performed including 2406 consecutive patients at our institution between 1/1/11 and 9/30/13. Patients who did not have unilateral primary THA/TKA or who received other anticoagulants were excluded. Of the 1762 patients included, 1113 patients (63.2%) received enoxaparin and 649 patients (36.8%) received rivaroxaban. This study found no demonstrable differences between these two anticoagulants in rates of VTE, infection, reoperation, transfusion, or major bleeding. Therapeutic, Retrospective comparative study, Level III. PMID- 25724112 TI - Trunnion-Head Stresses in THA: Are Big Heads Trouble? AB - The effects of large heads on stresses at the THA trunnion-head junction and their impact on tribocorrosion/metal ion release remain controversial. A 12/14 3D model of a stem with different head sizes was investigated. Material properties of titanium were assigned to the trunnion and cobalt-chrome/alumina to the heads. A load simulating walking single-leg stand phase was applied to the head. A total contact head-trunnion interface was assumed. The area underneath the junction underwent significant elevations in stresses as head size increased from 28- to 40-mm. Maximum principal stress doubled between 28 and 40-mm heads, regardless of head material. Stress levels had a direct correlation to head diameter. Stress increases observed using increasingly larger heads will probably contribute to head-trunnion tribocorrosion and ion release. PMID- 25724113 TI - Characteristics and prognosis of pulmonary infection in patients with neurologic disease and hypoproteinemia. AB - OBJECTIVE: To examine the characteristics and the prognostic influence of pulmonary infections in neurologic disease patients with mild-to-severe hypoproteinemia. METHODS: We used a retrospective survey method to analyze the characteristics and prognoses of 220 patients with hypoproteinemia complicated with pulmonary infection in the Internal Medicine-Neurology Intensive Care Unit at the First Affiliated Hospital of Chongqing Medical University from January 2010 to December 2013. The patients were divided into mild, moderate and severe hypoproteinemia groups according to their serum albumin levels. The analysis included patient age, sex, acute physiology and chronic health evaluation (APACHE II score), and characteristics of the pulmonary infection, nutritional support and prognosis, among others. RESULTS: Differences in the general information of the 220 cases of hypoalbuminemia patients complicated with varying degrees of pulmonary infection (APACHE II score, age, disease distribution) were statistically significant. The pulmonary infection onset time and pathogen susceptibility in the patients with mild-to-severe hypoalbuminemia were not significantly different. Pulmonary infection onset was more frequently observed within the first 3-11 days following admission in all groups. The nutritional support method did not significantly influence serum albumin protein levels. However, the neurological intensive care unit stay length, total hospitalization cost and disease distribution were significantly different among the patient groups. CONCLUSIONS: Patients with cerebrovascular disease, intracranial infections and epilepsy complicated with pulmonary infection represent the high risk groups for hypoalbuminemia. The Acinetobacter baumannii complex represents the main group of pathogenic bacteria causing lung infections, and the high-risk period for lung infections is 3-11 days after the occurrence of hypoalbuminemia. Patients with severe hypoalbuminemia complicated with pulmonary infection have the worst prognoses. PMID- 25724114 TI - Radiographic caries detection: A systematic review and meta-analysis. AB - OBJECTIVES: This systematic review aimed at evaluating the accuracy of radiographic caries detection for different lesions at different locations. DATA: Studies reporting on the accuracy (sensitivity/specificity) of radiographic detection of natural primary caries lesions under clinical or in vitro conditions were included. Risk of bias was assessed using QUADAS-2. Pooled sensitivity, specificity and diagnostic odds ratios (DORs) were calculated using random effects meta-analysis. Analyses were performed separately for occlusal and proximal lesions, with further discrimination between any kind of lesions, dentine lesions, and cavitated lesions. SOURCES: Electronic databases (Medline, Embase, Cochrane Central) and grey literature were systematically searched, complemented by cross-referencing from bibliographies. STUDY SELECTION: From 947 identified articles, 442 were analyzed full-text. 117 studies (13,375 teeth, 19,108 surfaces) were included, the majority of them reporting on permanent teeth and having high risk of bias. The detection of any kind (i.e. also initial) lesions had low sensitivities (pooled DOR [95% CI]: 0.24 [0.21/0.26] to 0.42 [0.31/0.34]), but moderate to high specificities (0.70 [0.76/0.84] to 0.97 [0.95/0.98]). For dentine lesions, sensitivities were higher (from 0.36 [0.24/0.49] for proximal to 0.56 [0.53/0.59] for occlusal lesions), and specificities ranged between 0.87 [0.85/0.89] and 0.95 [0.94/0.96]. No studies reported on cavitated occlusal lesions, whilst for cavitated proximal lesions, sensitivities increased above 0.60, whilst sensitivities remained high (above 0.90). CONCLUSIONS: Radiographic caries detection is highly accurate for cavitated proximal lesions, and seems also suitable to detect dentine caries lesions. For detecting initial lesions, more sensitive methods could be considered in population with high caries risk and prevalence. CLINICAL SIGNIFICANCE: Radiographic caries detection is especially suitable for detecting more advanced caries lesions, and has limited risks for false positive diagnoses. For groups with high caries risk and prevalence, alternative detection methods with higher sensitivity for initial lesions might be considered. PMID- 25724115 TI - Validation of quantitative light-induced fluorescence-digital (QLF-D) for the detection of approximal caries in vitro. AB - OBJECTIVES: Detection of approximal caries lesions can be difficult due to their anatomical position. This study aimed to assess the ability of the quantitative light-induced fluorescence-digital (QLF-D) in detecting approximal caries, and to compare the performance with those of the International Caries Detection and Assessment System II (ICDAS II) and digital radiography (DR). METHODS: Extracted permanent teeth (n=100) were selected and mounted in pairs. The simulation pairs were assessed by one calibrated dentist using each detection method. After all the examinations, the teeth (n=95) were sectioned and examined histologically as gold standard. The modalities were compared in terms of sensitivity, specificity, areas under receiver operating characteristic curves (AUROC) for enamel (D1) and dentine (D3) levels. The intra-examiner reliability was assessed for all modalities. RESULTS: At D1 threshold, the ICDAS II presented the highest sensitivity (0.80) while the DR showed the highest specificity (0.89); however, the methods with the greatest AUC values at D1 threshold were DR and QLF-D (0.80 and 0.80 respectively). At D3 threshold, the methods with the highest sensitivity were ICDAS II and QLF-D (0.64 and 0.64 respectively) while the method with the lowest sensitivity was DR (0.50). However, with regard to the AUC values at D3 threshold, the QLF-D presented the highest value (0.76). All modalities showed to have excellent intra-examiner reliability. CONCLUSIONS: The newly developed QLF-D was not only able to detect proximal caries, but also showed to have comparable performance to the visual inspection and radiography in detecting proximal caries. CLINICAL SIGNIFICANCE: QLF-D has the potential to be a useful detection method for proximal caries. PMID- 25724117 TI - Effect of COPD on cognitive functions in patients with heart failure. PMID- 25724116 TI - Perspectives from mechanical circulatory support coordinators on the pre implantation decision process for destination therapy left ventricular assist devices. AB - OBJECTIVE: To understand mechanical circulatory support (MCS) coordinators' perspectives related to destination therapy left ventricular assist devices (DT LVAD) decision making. BACKGROUND: MCS coordinators are central to the team that interacts with patients considering DT LVAD, and are well positioned to comment upon the pre-implantation process. METHODS: From August 2012 to January 2013, MCS coordinators were recruited to participate in semi-structured, in-depth interviews. Established qualitative approaches were used to analyze and interpret data. RESULTS: Eighteen MCS coordinators from 18 programs were interviewed. We found diversity in coordinators' roles and high programmatic variability in how DT LVAD decisions are approached. Despite these differences, three themes were consistently recommended: 1) DT LVAD is a major patient-centered decision: "you're your best advocate... this may not be the best choice for you"; 2) this decision benefits from an iterative, multidisciplinary process: "It is not a one time conversation"; and 3) this process involves a tension between conveying enough detail about the process yet not overwhelming patients: "It's sometimes hard to walk that line to not scare them but not paint a rainbow and butterflies picture." CONCLUSIONS: MCS coordinators endorsed a shared decision-making process that starts early, uses non-biased educational materials, and involves a multidisciplinary team sensitive to the tension between conveying enough detail about the therapy yet not overwhelming patients. PMID- 25724118 TI - Metabolic reconfigurations aimed at the detoxification of a multi-metal stress in Pseudomonas fluorescens: implications for the bioremediation of metal pollutants. AB - Although the ability of microbial systems to adapt to the toxic challenge posed by numerous metal pollutants individually has been well documented, there is little detailed information on how bacteria survive in a multiple-metal environment. Here we describe the metabolic reconfiguration invoked by the soil microbe Pseudomonas fluorescens in a medium with millimolar amounts of aluminum (Al), iron (Fe), gallium (Ga), calcium (Ca), and zinc (Zn). While enzymes involved in the production of NADH were decreased, there was a marked increase in enzymatic activities dedicated to NADPH formation. A modified tricarboxylic acid (TCA) cycle coupled to an alternate glyoxylate shunt mediated the synthesis of adenosine triphosphate (ATP) with the concomitant generation of oxalate. This dicarboxylic acid was a key ingredient in the sequestration of the metals that were detoxified as a lipid complex. It appears that the microbe favors this strategy as opposed to a detoxification process aimed at each metal separately. These findings have interesting implications for bioremediation technologies. PMID- 25724119 TI - Charge-based engineering of hydrophobin HFBI: effect on interfacial assembly and interactions. AB - Hydrophobins are extracellular proteins produced by filamentous fungi. They show a variety of functions at interfaces that help fungi to adapt to their environment by, for example, adhesion, formation of coatings, and lowering the surface tension of water. Hydrophobins fold into a globular structure and have a distinct hydrophobic patch on their surface that makes these proteins amphiphilic. Their amphiphilicity implies interfacial assembly, but observations indicate that intermolecular interactions also contribute to their functional properties. Here, we used the class II hydrophobin HFBI from Trichoderma reesei as a model to understand the structural basis for the function of hydrophobins. Four different variants were made in which charged residues were mutated. The residues were chosen to probe the role of different regions of the hydrophilic part of the proteins. Effects of the mutations were studied by analyzing the formation and structure of self-assembled layers, multimerization in solution, surface adhesion, binding of secondary layers of proteins on hydrophobins, and the viscoelastic behavior of the air-water interface during formation of protein films; the comparison showed clear differences between variants only in the last two analyses. Surface viscoelasticity behavior suggests that the formation of surface layers is regulated by specific interactions that lead to docking of proteins to each other. One set of mutations led to assemblies with a remarkably high elasticity at the air-water interface (1.44 N/m). The variation of binding of secondary layers of protein on surface-adsorbed hydrophobins suggest a mechanism for a proposed function of hydrophobins, namely, that hydrophobins can act as a specific adhesive layer for the binding of macromolecules to interfaces. PMID- 25724120 TI - Staphylococcal protein A-formulated immune complexes suppress enterotoxin-induced cellular responses in nasal polyps. AB - BACKGROUND: Recent studies have revealed that Staphylococcus aureus and its components participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyps. OBJECTIVE: We sought to determine whether staphylococcal protein A (SpA) from S aureus regulated cellular responses in nasal polyps, especially when coupled to immunoglobulins in immune complexes (ICs). METHODS: Dispersed nasal polyp cells (DNPCs) or peripheral blood monocytes were cultured in vitro with SpA in the presence or absence of IgG, and IL-5, IL 13, IFN-gamma, IL-17A, and IL-10 levels were measured in the supernatants. The effect of SpA exposure on staphylococcal enterotoxin B-induced cytokine production by DNPCs in the presence and absence of IgG, IgA, and autologous serum was also examined. RESULTS: Exposure to SpA induced DNPCs to produce significantly higher IL-10, IL-13, and IL-17A levels than DNPCs without SpA, although the magnitude of the IL-17A increase was less than that of IL-10 and IL 13. SpA induced IL-10 production mainly from adherent DNPCs, and this was significantly enhanced in the presence of IgG; similar results were observed in peripheral blood monocytes. IC formation between SpA and IgG (SpA-IgG ICs) was confirmed by using native polyacrylamide gel electrophoresis. SpA-IgG ICs, but not SpA alone, almost completely suppressed staphylococcal enterotoxin B-induced IL-5, IL-13, IFN-gamma, and IL-17A production by DNPCs; similar inhibition was observed in DNPCs treated with SpA in the presence of either IgA or autologous serum. CONCLUSIONS: Our results suggest that SpA can regulate the pathogenesis of enterotoxin-induced inflammation in patients with chronic rhinosinusitis with nasal polyps through coupling to immunoglobulins. PMID- 25724121 TI - Reply: To PMID 25457150. PMID- 25724122 TI - Measuring histamine content and release at single-cell level during venom allergy immunotherapy. PMID- 25724124 TI - Somatic NOD2 mosaicism in Blau syndrome. PMID- 25724125 TI - Mandibular morphology in two archaeological human skeletal samples from northwest Europe with different masticatory regimes. AB - Mandibular morphology, assessed osteometrically, is studied in two historic human skeletal series (N = 64 individuals) from northwest Europe, one from Zwolle, the Netherlands (19th century CE), the other from Wharram Percy, England (10th-19th century). Both groups show greater dental wear than modern Western populations, but the rate of wear is greater at Wharram Percy than at Zwolle, suggesting a more vigorous masticatory regime. The aim is to evaluate any differences in mandibular morphology between the two groups that might relate to the inferred difference in biomechanical loading upon the chewing apparatus consequent upon the different physical properties of the diets consumed. Results indicate that the mandibles from Zwolle are generally smaller than those from Wharram Percy, especially in the gonial and ramus region and in the height of the post-canine corpus. These differences are consistent with those predicted on biomechanical grounds. That clear differences were observed in two samples whose masticatory regimes were distinct but not very different is an indication of the sensitivity of mandibular morphology to biomechanical input, and supports its value for investigating differences in physical properties of diets in palaeopopulations. PMID- 25724123 TI - The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. AB - BACKGROUND: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. OBJECTIVES: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. METHODS: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. RESULTS: DOCK8 deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/MUL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. CONCLUSIONS: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures. PMID- 25724126 TI - Clinical significance of fractional magnesium excretion (FEMg) as a predictor of interstitial nephropathy and its correlation with conventional parameters. AB - BACKGROUND: Elevated urine Mg excretion and its correlation with histological damage in tubulo-interstitial nephropathy (TIN) were reported. Here we investigated the clinical significance of the fractional excretion of Mg (FEMg) for the prediction of TIN. METHODS: We enrolled and assessed 94 adult patients with various renal diseases diagnosed principally by renal biopsy. RESULTS: Our stratified analysis based on the value of the conventional TIN parameter N acetylglucosaminidase (NAG) excretion showed that the high-NAG index group (more than median value of NAG-to-Cr ratio, n = 47) demonstrated significantly high FEMg values (p = 0.017). A univariate analysis revealed a significant correlation between the FEMg and the NAG index (R = 0.60) but not for other parameters. A multivariate regression analysis confirmed the significance of the FEMg as an effective predictor of the NAG index. The FEMg showed a significant correlation with the estimated glomerular filtration rate (eGFR) in the patients with eGFR <= 30 mL/min. The correlation of FEMg with the NAG index was not observed in the primary glomerulonephritis patients but was apparent in the patients with hypertensive nephrosclerosis or interstitial nephritis. CONCLUSION: Our findings may indicate that the combination of the FEMg and the NAG index can provide a specific, sensitive assessment for TIN in patients without renal insufficiency. PMID- 25724128 TI - Comparison of methods for the isolation of mycobacteria from water treatment plant sludge. AB - Nontuberculous mycobacteria (NTM) are ubiquitous organisms in all natural ecosystems, including water environments. Several of these species are potential pathogens which affect human health. NTM most commonly cause pulmonary, skin or soft tissue infections. Primary sludge obtained from the water treatment plants of four drinking water reservoirs were subjected to analysis for mycobacteria. Five decontamination methods (5% oxalic acid, modified Petroff, HCl-NaOH, N acetyl-L-cysteine-sodium hydroxide and 0.05% cetylpyridinium chloride), three growth media (Herrold's egg yolk medium with and without the antibiotic cocktail PANTA and Lowenstein-Jensen medium with sodium pyruvate) and three incubation temperatures (25, 30 and 37 degrees C) for isolation of mycobacteria were compared in the analysis of 18 sludge samples. To evaluate examined methods, the overall positive, negative, and contamination rate, and these rates in respect to localities are taken into account. Statistical analysis demonstrated that the best combination for the recovery of mycobacteria with the minimum number of contaminating microorganisms is 5% oxalic acid decontamination cultured on Herrold's egg yolk medium with the antibiotic cocktail PANTA at 25 degrees C. The least suitable is N-acetyl-L-cysteine-sodium hydroxide decontamination cultured on Lowenstein-Jensen medium with sodium pyruvate at 25 degrees C. From 18 sludge samples we isolated 27 mycobacterial species or groups; Mycobacterium algericum, M. arabiense, M. heraklionense, M. minnesotense, M. moriokaense, M. salmoniphilum and M. vulneris were isolated from the natural water environment for the first time. Because the natural water environment is the main source of potentially pathogenic mycobacteria for humans, it is important to direct particular focus to newly described mycobacterial species. PMID- 25724127 TI - The prognostic value of positive T-wave in lead aVR in hemodialysis patients. AB - BACKGROUND: Given that cardiac disease is the leading cause of mortality in hemodialysis (HD) patients, identification of patients at risk for cardiac mortality is crucial. The aim of this study was to determine if positive T-wave amplitude in lead aVR (TaVR) was predictive of cardiovascular (CV) mortality and sudden cardiac death (SCD) in a group of HD patients. METHODS AND RESULTS: After exclusion, 223 HD patients were prospectively followed-up for 25.43 +/- 3.56 months. Patients were divided into TaVR negative (n = 186) and TaVR positive (n = 37) groups. Myocardial infarction, diabetes and beta-blocker therapy were more frequent in positive TaVR patients. Patients with upright TaVR were older, had higher left ventricular mass index, lower ejection fraction, higher calcium * phosphate product, higher troponin T level, higher prevalence of ST-T abnormalities, and increased width of QRS complex and QT interval, compared with patients with negative TaVR. A Kaplan-Meier analysis showed that the cumulative incidences of CV mortality as well as SCD were higher in patients with positive TaVR compared with those with negative TaVR (log-rank, p < 0.001 in both cases). A multivariate analysis selected age [hazard ratio (HR) 1.71, p < 0.001], heart rate (HR 1.42, p = 0.016), and positive TaVR (HR 2.21, p = 0.001) as well as age (HR 1.88, p < 0.001), and positive TaVR (HR 1.53, p = 0.014) as independent predictors of CV mortality and SCD, respectively. CONCLUSION: In HD patients, positive TaVR is an independent and powerful predictor of CV mortality as well as SCD. This simple ECG parameter provides additional information beyond what is available with other known traditional risk factors and allows the identification of patients most at risk of CV events. PMID- 25724129 TI - Finding diagnostic phenotypic features of Photobacterium in the genome sequences. AB - Photobacterium species are ubiquitous in the aquatic environment and can be found in association with animal hosts including pathogenic and mutualistic associations. The traditional phenotypic characterization of Photobacterium is expensive, time-consuming and restricted to a limited number of features. An alternative is to infer phenotypic information directly from whole genome sequences. The present study evaluates the usefulness of whole genome sequences as a source of phenotypic information and compares diagnostic phenotypes of the Photobacterium species from the literature with the predicted phenotypes obtained from whole genome sequences. All genes coding for the specific proteins involved in metabolic pathways responsible for positive phenotypes of the seventeen diagnostic features were found in the majority of the Photobacterium genomes. In the Photobacterium species that were negative for a given phenotype, at least one or several genes involved in the respective biochemical pathways were absent. PMID- 25724130 TI - Improved oral therapeutic potential of nanoencapsulated cryptdin formulation against Salmonella infection. AB - An encapsulated system for cryptdin-2 (a Paneth cell antimicrobial peptide) was developed, with a view to help it sustain adverse gut conditions and to ensure its bioavailability on oral administration. The formulation was characterized on the basis of particle size, zeta potential and polydispersity index. Cryptdin-2 loaded nanoparticles of size 105+/-7 nm, formulated by ionotropic gelation method using chitosan: tripolyphosphate (5:2), revealed 60% drug entrapment efficiency with 65% in vitro release in 4.5 h. Developed system was evaluated for its therapeutic application against Salmonella Typhimurium infection in mice, on the basis of survivability of animals, bacterial load in tissues, histo-architecture and oxidative damage markers. Infected mice when treated with the encapsulated peptide showed 83% survivability and approximately 2 log unit reductions in the bacterial load in the tissues versus 100% mortality observed with the free peptide. The encapsulated cryptdin-2 also achieved a decrease in the level of oxidants, particularly nitrite by 3.25 folds and increased the level of antioxidant catalase by 2 folds when compared to the levels exhibited by the free peptide. The bacteriological and biochemical alterations illustrated by encapsulated peptide co-related well with the histo-architectural studies. The study is a first pre-clinical report on the oral effectiveness of cryptdin-2 by its suitable encapsulation and has potential for future clinical applications. PMID- 25724131 TI - Preserving the supersaturation generation capability of amorphous drug polysaccharide nanoparticle complex after freeze drying. AB - While the supersaturation generation capability of amorphous nanopharmaceuticals (NPs) in their aqueous suspension form has been well established, their supersaturation generation is adversely affected after drying. Herein we investigated the effects of freeze drying on the supersaturation generation capability of a new class of amorphous NPs referred to as drug nanoplex prepared and stabilized by electrostatic complexation of drug molecules with polysaccharides (dextran sulfate). Using ciprofloxacin as the model drug, two types of freeze-drying adjuvants were investigated, i.e., (1) highly water soluble excipient (trehalose, mannitol), whose role was to prevent irreversible NPs aggregations upon drying, and (2) crystallization inhibitor (hydroxypropylmethylcellulose (HPMC)), whose role was to suppress crystallization of the dissolved drug and the remaining solid phase. The results showed that dual adjuvant formulations (i.e. trehalose-HPMC and mannitol-HPMC) were required to preserve the supersaturation generation capability of the drug nanoplex suspension after drying. Freeze drying with only one adjuvant type, or incorporating HPMC as physical mixtures with the freeze-dried nanoplex, were ineffective in preserving the supersaturation. The dual-adjuvant formulations produced prolonged supersaturation levels over 240min at ~6-8* of the saturation solubility with comparable area under the curve (AUC) in the concentration versus time plot as that exhibited by the suspension form. PMID- 25724132 TI - Determination of the glycosylation-pattern of the middle ear mucosa in guinea pigs. AB - In the present study the glycosylation pattern of the middle ear mucosa (MEM) of guinea pigs, an approved model for middle ear research, was characterized with the purpose to identify bioadhesive ligands which might prolong the contact time of drug delivery systems with the middle ear mucosa (MEM). To assess the utility of five fluorescein labeled plant lectins with different carbohydrate specificities as bioadhesive ligands, viable MEM specimens were incubated at 4 degrees C and the lectin binding capacities were calculated from the MEM associated relative fluorescence intensities. Among all lectins under investigation, fluorescein-labeled wheat germ agglutinin (F-WGA) emerged as the highest bioadhesive lectin. In general, the accessibility of carbohydrate moieties of the MEM followed the order: sialic acid and N-acetyl-d-glucosamine (WGA)>>mannose and galactosamine (Lensculinaris agglutinin)>N-acetyl-d glucosamine (Solanumtuberosum agglutinin)>fucose (Ulexeuropaeus isoagglutinin I)>>terminal mannose alpha-(1,3)-mannose (Galanthusnivalis agglutinin). Competitive inhibition studies with the corresponding carbohydrate revealed that F-WGA-binding was inhibited up to 90% confirming specificity of the F-WGA-MEM interaction. The cilia of the MEM were identified as F-WGA binding sites by fluorescence imaging as well as a z-stack of overlays of transmission, F-WGA- and nuclei-stained images of the MEM. Additionally, co-localisation experiments revealed that F-WGA bound to acidic mucopolysaccharides of the MEM. All in all, lectin-mediated bioadhesion to the MEM is proposed as a new concept for drug delivery to prolong the residence time of the drug in the tympanic cavity especially for successful therapy for difficult-to-treat diseases such as otitis media. PMID- 25724133 TI - Trans-resveratrol and beta-carotene from sunscreens penetrate viable skin layers and reduce cutaneous penetration of UV-filters. AB - Cutaneous permeation is a critical parameter when topical application of sunscreens containing antioxidants is considered. The aim of this study was to evaluate the cutaneous penetration of most marketed UV-filters combined with trans-resveratrol (RES) and beta-carotene (BTC) since few studies report skin penetration when such compounds are applied. Formulations containing octocrylene, octyl methoxycinnamate, avobenzone and bemotrizinole were prepared and supplemented or not with BTC, or with RES, or with both compounds in combination. Penetration studies were performed using Franz vertical diffusion cells and porcine ear skin as the biological membrane. The quantification of UV-filters and antioxidants in the stratum corneum (SC), viable epidermis plus dermis and receptor fluid was performed by HPLC. Results suggested that UV-filters and antioxidants did not permeate the skin but were retained for 12h post application. About 90% and 80%, respectively, of the total penetrated amount of UV-filters and antioxidants was found in the SC. Interestingly, it was observed that BTC, alone or combined with RES, reduced the skin retention of UV-filters on average by 63%. In conclusion, this study demonstrated that the combination of antioxidants and UV-filters in sunscreens is advantageous for cutaneous penetration, since BTC and BTC+RES improved sunscreen safety by reducing delivery of the four UV-filters in the study into SC and viable epidermis. PMID- 25724135 TI - Enteric-coated capsules filled with mono-disperse micro-particles containing PLGA lipid-PEG nanoparticles for oral delivery of insulin. AB - The success of the oral delivery of insulin (INS) as a therapeutic protein drug would significantly improve the quality of life of diabetic patients who would otherwise receive multiple daily INS injections. The oral delivery of INS, however, is still limited in its delivery efficiency, which could be due to the chemical, enzymatic, and adsorption barriers. In this work, in an attempt to improve the delivery efficiency, the INS-loaded polymer-lipid hybrid nanoparticles (INS-PLGA-lipid-PEG NPs) were designed and constructed through a double-emulsion solvent evaporation technique, followed by formulation of the spherical micro-particles using a spray freeze dryer (SFD). This kind of dryers has a uniquely designed microfluidic aerosol nozzle (MFAN), ensuring the formation of uniform particles. The resulted particles of ~212 MUm could easily be reverted to discrete INS-PLGA-lipid-PEG NPs in an aqueous solution. The INS PLGA-lipid-PEG NPs created in this work showed a highly negative surface charge, excellent entrapment efficiency (92.3%) and a sustained drug release (~24 h). Confocal laser scanning microscopy and flow cytometer were used to show that the cellular uptake efficiency for the INS-PLGA-lipid-PEG NPs was more effective than the INS in Caco-2 cells. More importantly, the in vivo pharmacodynamics demonstrated that the orally delivered system induced a prolonged decrease in blood glucose levels among diabetic rats. The relative bioavailability of INS compared with subcutaneous injection in diabetic rats was found to be approximately 12%. These results suggested that the encapsulated INS-PLGA-lipid PEG NPs are promising and should be investigated further in the near future as an effective INS oral delivery system. PMID- 25724134 TI - Synthesis and characterization of silk fibroin microparticles for intra-articular drug delivery. AB - OBJECTIVE: To determine the utility of silk fibroin (SF) microparticles as sustained release vehicles for intra-articular delivery. DESIGN: SF formulations were varied to generate microparticle drug carriers that were characterized in vitro for their physical properties, release kinetics for a conjugated fluorophore (Cy7), and in vivo for intra-articular retention time using live animal, fluorescence in vivo imaging. RESULTS: SF microparticle carriers were spherical in shape and ranged from 598 nm to 21.5 MUm in diameter. SF microparticles provided for sustained release of Cy7 in vitro, with only 10% of the initial load released over 7 days. Upon intra-articular injection in rat knee joints, the SF microparticles were associated with an intra-articular fluorescence decay half-life of 43.3h, greatly increasing the joint residence over that for an equivalent concentration of SF-Cy7 in solution form. The SF microparticles also increase the localization of dye within the joint cavity as determined by image analysis of fluorescent gradients, significantly reducing distribution of the Cy7 to neighboring tissue as compared to SF-Cy7 in free solution. CONCLUSION: Silk microparticles act to provide for localized and sustained delivery of loaded small molecules following intra-articular injection, and may be an attractive strategy for delivering small molecule drugs for the treatment of arthritis. PMID- 25724136 TI - Core-shell structured gel-nanocarriers for sustained drug release and enhanced antitumor effect. AB - The present paper attempted to develop temperature-sensitive and core-shell structured gel-nanocarriers (gel-NCs) for paclitaxel (PTX) with 12-hydroxystearic acid (12-HSA) as an organic gelator, which aims at sustaining drug release over time and thus improves the therapeutic effect. The gel-NCs were prepared by a mechanical mixing and high-pressure homogenization method. The gelation transition temperature (Tgel) of the organic phase contained in the cores of the gel-NCs was optimized by a stirring method. The gel-NCs were characterized in terms of the particle size, morphology and in vitro drug release. The in vivo studies, including the antitumor effects on H22 tumor-bearing mice, biocompatibility and toxicity in mice, were performed. Gel-NCs with approximately 170 nm were prepared successfully, and the gelation of the liquid cores at 37 degrees C was achieved, while the amount of gelator was 3.75% (w/w). Due to the gelation of the cores, sustained drug release over time was obtained. Moreover, the PTX-loaded gel-NCs suppressed tumor growth more efficiently than the conventional nanocarriers with better in vivo biocompatibility and no toxicity to other healthy organs. In conclusion, the 12-HSA organogel-based NCs appear to be promising systems for the sustained release of active compounds for a long time and thus improve the therapeutic outcome. PMID- 25724137 TI - Conversion of solid dispersion prepared by acid-base interaction into free flowing and tabletable powder by using Neusilin(r) US2. AB - A novel method of greatly increasing solubility and dissolution rate of a model basic drug, haloperidol, by interacting it with water-soluble weak organic acids in aqueous media was previously reported in the literature. Amorphous solid dispersion (SD) was formed when solutions containing haloperidol and various acids were dried. However, the SDs were semisolid, viscous and sticky, especially when the drug load was high, and could not be processed into tablets. The drug release from SD was also incomplete since the viscous material did not readily mix with aqueous media. In the present study, a mesoporous metalosilicate, Neusilin((r)) US2, was incorporated in SDs prepared by using malic, tartaric and citric acids. The silicate constituted 40% w/w of the total solid mass. The addition of silicate converted SDs into powders, which were then characterized for flow properties, bulk and tap density, and tabletability. Their physical properties were found to be acceptable for the development of tablets. DSC and powder XRD showed that haloperidol and acids converted completely to amorphous forms, and they did not show any sign of crystallization during accelerated stability study at 40 degrees C/75% RH and 25 degrees C/60% RH for 9 months. Complete drug release under gastrointestinal pH conditions could be obtained from tablets prepared. PMID- 25724138 TI - Folate-polyethyleneimine functionalized mesoporous carbon nanoparticles for enhancing oral bioavailability of paclitaxel. AB - Polymer-functionalized carbon nanoparticles hold great promise for their use in enhancing the oral absorption of drugs with poor oral bioavailability. And since the abundant expression of folate receptors in intestinal tract, folic acid (FA) modified uniform mesoporous carbon spheres (UMCS) was used to improve oral absorption of paclitaxel, a chemotherapeutic drug with poor oral bioavailability. In this research, folate-polyethyleneimine (FA-PEI) was grafted onto acid-treated uniform mesoporous carbon spheres through one-step electrostatic attraction. PTX was loaded into mesopores of nanoparticles through solvent evaporation, present as amorphous. The release of PTX from the FA-PEI-UMCS nanoparticles exhibited an initial rapid release, followed by a sustained release. And release rate could be regulated by changing amount of FA-PEI complex on the UMCS. The uptake of PTX encapsulated nanoparticles was studied exploiting Caco-2 cells as an in vitro model. The results of confocal microscopy and flow cytometry demonstrated that folate functionalization enhanced internalization of nanoparticles by the cells. Moreover, PTX loaded in FA-PEI-UMCS nanoparticles resulted in a 5.37-fold increase in apparent permeability (Papp) across Caco-2 cell monolayers compared to Taxol((r)). And the in vivo results showed that FA-PEI-UMCS nanoparticles did not only improve the oral bioavailability of PTX, but also decrease the gastrointestinal toxicity of PTX. In conclusion, the FA-PEI-UMCS nanoparticles might be a potentially applicable system to improve oral absorption of drugs with poor oral bioavailability. PMID- 25724139 TI - Validation and applications of an expedited tablet friability method. AB - The harmonized monograph on tablet friability test in United States Pharmacopeia (USP), European Pharmacopeia (Pharm. Eur.), and Japanese Pharmacopeia (JP) is designed to assess adequacy of mechanical strength of a batch of tablets. Currently, its potential applications in formulation development have been limited due to the batch requirement that is both labor and material intensive. To this end, we have developed an expedited tablet friability test method, using the existing USP test apparatus. The validity of the expedited friability method is established by showing that the friability data from the expedited method is not statistically different from those from the standard pharmacopeia method using materials of very different mechanical properties, i.e., microcrystalline cellulose and dibasic calcium phosphate dihydrate. Using the expedited friability method, we have shown that the relationship between tablet friability and tablet mechanical strength follows a power law expression. Furthermore, potential applications of this expedited friability test in facilitating systematic and efficient tablet formulation and tooling design are demonstrated with examples. PMID- 25724140 TI - Habitat Fragmentation can Modulate Drought Effects on the Plant-soil-microbial System in Mediterranean Holm Oak (Quercus ilex) Forests. AB - Ecological transformations derived from habitat fragmentation have led to increased threats to above-ground biodiversity. However, the impacts of forest fragmentation on soils and their microbial communities are not well understood. We examined the effects of contrasting fragment sizes on the structure and functioning of soil microbial communities from holm oak forest patches in two bioclimatically different regions of Spain. We used a microcosm approach to simulate the annual summer drought cycle and first autumn rainfall (rewetting), evaluating the functional response of a plant-soil-microbial system. Forest fragment size had a significant effect on physicochemical characteristics and microbial functioning of soils, although the diversity and structure of microbial communities were not affected. The response of our plant-soil-microbial systems to drought was strongly modulated by the bioclimatic conditions and the fragment size from where the soils were obtained. Decreasing fragment size modulated the effects of drought by improving local environmental conditions with higher water and nutrient availability. However, this modulation was stronger for plant-soil microbial systems built with soils from the northern region (colder and wetter) than for those built with soils from the southern region (warmer and drier) suggesting that the responsiveness of the soil-plant-microbial system to habitat fragmentation was strongly dependent on both the physicochemical characteristics of soils and the historical adaptation of soil microbial communities to specific bioclimatic conditions. This interaction challenges our understanding of future global change scenarios in Mediterranean ecosystems involving drier conditions and increased frequency of forest fragmentation. PMID- 25724141 TI - Commemoration of the centenary of the birth of Mario Milletti (1914-1959), co founder of Acta Neurochirurgica. PMID- 25724142 TI - Asymmetric effect of automatic deviant detection: The effect of familiarity in visual mismatch negativity. AB - The visual mismatch negativity (vMMN) component is regarded as a prediction error signal elicited by events violating the sequential regularities of environmental stimulation. The aim of the study was to investigate the effect of familiarity on the vMMN. Stimuli were patterns comprised of familiar (N) or unfamiliar (I) letters. In a passive oddball paradigm, letters (N and I) were presented as either standard or deviant in separate conditions. VMMNs emerged in both conditions; peak latency of vMMN was shorter to the I deviant compared to the vMMN elicited by the N deviant. To test the orientation-specific effect of the oblique lines on the vMMN, we introduced a control experiment. In the control experiment, the patterns were constructed solely from oblique lines, identical to the oblique lines of the N and I stimuli. Contrary to the first experiment, there was no significant difference between the vMNNs elicited by the two orientations. Therefore, the differences in vMMNs to I and N deviants are not attributable to the physical difference between the I and N stimuli. Consequently, the vMMN is sensitive to the familiarity of the stimuli. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25724143 TI - miR-126 promotes angiogenesis and attenuates inflammation after contusion spinal cord injury in rats. AB - MicroRNAs are a class of small RNAs that regulate the expression of target mRNAs by inhibiting translation or destabilizing target mRNAs. miR-126 is a microRNA that is highly enriched in endothelial cells. miR-126 has been found to promote angiogenesis and inhibit vascular inflammation in endothelial cells by repressing three target genes Sprouty-related EVH1 domain-containing protein 1 (SPRED1), phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2), and vascular cell adhesion molecule 1 (VCAM1). Our previous study showed that the expression of miR 126 was downregulated after spinal cord injury (SCI). Therefore, we wanted to examine whether upregulation of miR-126 could promote angiogenesis, inhibit inflammation, and exert a positive effect on recovery after contusion SCI. In this study, we found that increased levels of miR-126 promoted angiogenesis, and inhibited leukocyte extravasation into the injured spinal cord, which was concurrent with downregulation of mRNA and protein expression of three validated miR-126 target genes, SPRED1, PIK3R2, and VCAM1. Moreover, a dose-dependent effect of miR-126 was observed in rescuing tissue damage and improving the functional deficit after SCI. Thus, the present study indicated that miR-126 played an important role in angiogenesis and inflammation after SCI. PMID- 25724144 TI - The effects of hyperbaric oxygen on macrophage polarization after rat spinal cord injury. AB - The immunoreactive responses are a two-edged sword after spinal cord injury (SCI). Macrophages are the predominant inflammatory cells responsible for this response. However, the mechanism underlying the effects of HBOT on the immunomodulation following SCI is unclear now. The present study was performed to examine the effects of hyperbaric oxygen therapy (HBOT) on macrophage polarization after the rat compressive injury of the spinal cord. HBOT was associated with significant increases in IL-4 and IL-13 levels, and reductions in TNF-alpha and IFN-gamma levels. This was associated simultaneously with the levels of alternatively activated macrophages (M2 phenotype: arginase-1- or CD206 positive), and decreased levels of classically activated macrophages (M1 phenotype: iNOS- or CD16/32-positive). These changes were associated with functional recovery in the HBOT-transplanted group, which correlated with preserved axons and increased myelin sparing. Our results suggested that HBOT after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, which may further promote the axonal extension and functional recovery. PMID- 25724145 TI - Inhibition of CaMKK2 reverses age-associated decline in bone mass. AB - Decline in bone formation is a major contributing factor to the loss of bone mass associated with aging. We previously showed that the genetic ablation of the tissue-restricted and multifunctional Ca(2+)/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) stimulates trabecular bone mass accrual, mainly by promoting anabolic pathways and inhibiting catabolic pathways of bone remodeling. In this study, we investigated whether inhibition of this kinase using its selective cell-permeable inhibitor STO-609 will stimulate bone formation in 32 week old male WT mice and reverse age-associated of decline in bone volume and strength. Tri-weekly intraperitoneal injections of saline or STO-609 (10 MUM) were performed for six weeks followed by metabolic labeling with calcein and alizarin red. New bone formation was assessed by dynamic histomorphometry whereas micro-computed tomography was employed to measure trabecular bone volume, microarchitecture and femoral mid-shaft geometry. Cortical and trabecular bone biomechanical properties were assessed using three-point bending and punch compression methods respectively. Our results reveal that as they progress from 12 to 32 weeks of age, WT mice sustain a significant decline in trabecular bone volume, microarchitecture and strength as well as cortical bone strength. However, treatment of the 32 week old WT mice with STO-609 stimulated apposition of new bone and completely reversed the age-associated decrease in bone volume, quality, as well as trabecular and cortical bone strength. We also observed that regardless of age, male Camkk2(-/-) mice possessed significantly elevated trabecular bone volume, microarchitecture and compressive strength as well as cortical bone strength compared to age-matched WT mice, implying that the chronic loss of this kinase attenuates age-associated decline in bone mass. Further, whereas STO-609 treatment and/or the absence of CaMKK2 significantly enhanced the femoral mid-shaft geometry, the mid-shaft cortical wall thickness and material bending stress remained similar among the cohorts, implying that regardless of treatment, the material properties of the bone remain similar. Thus, our cumulative results provide evidence for the pharmacological inhibition of CaMKK2 as a bone anabolic strategy in combating age-associated osteoporosis. PMID- 25724146 TI - Exploring the effect of vitamin C on sleep deprivation induced memory impairment. AB - In the current study, the possible beneficial effect of vitamin C (VitC) against sleep deprivation induced memory impairment was examined. Chronic sleep deprivation was induced via placing rats in a modified multiple platform apparatus for 8h/day for a period of 6 weeks. Concomitantly, VitC was administered to animals at doses of 150 and 500 mg/kg/day. After 6 weeks of treatment, the radial arm water maze (RAWM) was used to test for spatial learning and memory performance. Moreover, the hippocampus was dissected; and levels/activities of antioxidant defense biomarkers glutathione reduced (GSH), glutathione oxidized (GSSG), GSH/GSSG ratio, catalase, superoxide dismutase (SOD), and thiobarbituric acid reactive substances (TBARS), were evaluated. Results revealed that chronic sleep deprivation impaired short- and long-term memories (P<0.05). This impairment was prevented by chronic VitC treatments. In addition, VitC normalized sleep deprivation induced decreases in hippocamppal GSH/GSSG ratio (P<0.05), and activities of catalase, and SOD, and increase in GSSG levels (P<0.05). Collectively, spatial memory impairment was induced by chronic sleep deprivation, and VitC treatment prevented such impairment. This was possibly achieved via normalizing antioxidant defense mechanisms of the hippocampus. PMID- 25724147 TI - Cocaine enhances the conditioned rewarding effects of MDMA in adolescent mice. AB - Although the consumption of cocaine is frequent in young users of MDMA (3,4 methylenedioxymethamphetamine), the influence of exposure to cocaine on the rewarding effects of MDMA in adolescents has not been studied. The purpose of the present work was to evaluate the effect of co-administration of cocaine (1 and 10 mg/kg) and a sub-threshold dose of MDMA (1.25 mg/kg) on the acquisition of conditioned place preference (CPP) (experiment 1). In addition, the effect of pre treatment with cocaine on MDMA-induced CPP was evaluated (experiment 2). Levels of monoamines in striatum, hippocampus and cortex were measured in both experiments. Our hypotheses were that cocaine co-administration or pre-treatment would increase the rewarding effects of MDMA, and that these effects would be related with changes in brain monoamine levels. Our results showed that cocaine potentiated the rewarding effects of MDMA, since a sub-threshold dose of MDMA, which did not induce CPP by itself, induced a significant CPP in adolescent mice when administered along with cocaine during conditioning (experiment 1). Moreover, pre-treatment with cocaine several days before conditioning also increased the rewarding effects of MDMA (experiment 2). No significant changes in the levels of biogenic amines, which correlated with these behavioural effects, were observed. Our results confirm the involvement of the dopaminergic system in MDMA-induced CPP in adolescent mice and suggest that combined consumption with or pre-exposure to cocaine increases the conditioned rewarding effects of MDMA, which may enhance the capacity of MDMA to induce dependence. PMID- 25724148 TI - 9-Oxo-(10E,12E)-octadecadienoic acid, a cytotoxic fatty acid ketodiene isolated from eggplant calyx, induces apoptosis in human ovarian cancer (HRA) cells. AB - 9-Oxo-(10E,12E)-octadecadienoic acid (9-EE-KODE), which is isolated from the calyx of eggplants, exhibits cytotoxic activity against human ovarian cancer (HRA) cells. The aim of the present study is to clarify the action mechanism of 9 EE-KODE leading to cell death. After the treatment of 9-EE-KODE in HRA cells, we found intracellular DNA fragmentation, surface-exposure of phosphatidylserine in the outer cell membrane, and increased caspase-3/7 activities in the HRA cells. The dissipation of mitochondrial membrane potential, release of cytochrome c from mitochondria to cytosol, down-regulation of Bcl-2, and up-regulation of Bax levels were also found in 9-EE-KODE-treated cells in a dose-dependent manner. These results demonstrated that 9-EE-KODE induced apoptosis in HRA cells via the mitochondrial regulation pathway. PMID- 25724149 TI - Effects of Supplemental Acerola Juice on the Mineral Concentrations in Liver and Kidney Tissue Samples of Mice Fed with Cafeteria Diet. AB - We evaluated the impact of a supplemental acerola juice (unripe, ripe, and industrial) and its main pharmaceutically active components on the concentrations of minerals in the liver and kidney of mice fed with cafeteria diet. Swiss male mice were fed with a cafeteria (CAF) diet for 13 weeks. The CAF consisted of a variety of supermarket products with high energy content. Subsequently, animals received one of the following food supplements for 1 month: water, unripe acerola juice, ripe acerola juice, industrial acerola juice, vitamin C, or rutin. Mineral concentrations of the tissues were determined by particle-induced X-ray emission (PIXE). Our study suggests that the simultaneous intake of acerola juices, vitamin C, or rutin in association with a hypercaloric and hyperlipidic diet provides change in the mineral composition of organisms in the conditions of this study, which plays an important role in the antioxidant defenses of the body. This may help to reduce the metabolism of the fat tissue or even to reduce the oxidative stress. PMID- 25724150 TI - Stress, Place, and Allostatic Load Among Mexican Immigrant Farmworkers in Oregon. AB - Cumulative exposure to chronic stressors has been shown to contribute to immigrants' deteriorating health with more time in US residence. Few studies, however, have examined links among common psychosocial stressors for immigrants (e.g., acculturation-related) and contexts of immigrant settlement for physical health. The study investigated relationships among social stressors, stress buffers (e.g., family support), and allostatic load (AL)--a summary measure of physiological "wear and tear"--among 126 adult Mexican immigrant farm workers. Analyses examined social contributors to AL in two locales: (1) White, English speaking majority sites, and (2) a Mexican immigrant enclave. Our six-point AL scale incorporated immune, cardiovascular, and metabolic measures. Among men and women, older age predicted higher AL. Among women, lower family support related to higher AL in White majority communities only. Findings suggest that Latino immigrants' cumulative experiences in the US significantly compromise their health, with important differences by community context. PMID- 25724151 TI - "Can I Ask That?": Perspectives on Perinatal Care After Resettlement Among Karen Refugee Women, Medical Providers, and Community-Based Doulas. AB - This study characterized the perspectives of Karen refugee women in Buffalo, NY, their medical providers, and Karen interpreters/doulas on perinatal care for Karen women in resettlement. In-depth qualitative interviews with Karen women (14), Karen doulas/interpreters and key informants (8), and medical providers (6) were informed by the social contextual model and focused on women's questions about and opinions of perinatal care in Buffalo and on providers' experiences caring for Karen patients. Karen women expressed gratitude for and understanding of perinatal care in Buffalo, and providers described Karen patients as agreeable but shy. Karen doulas offered an alternative view that exposed women's many questions and concerns, and described how doula training empowered them as patients' advocates. Low self-efficacy, trauma histories, and cultural expectations may contribute to Karen women's seeming agreeability. Doulas/interpreters possess insider knowledge of women's concerns and facilitate communication between patients and the care team. PMID- 25724152 TI - Enhancing the interpretation of statistical P values in toxicology studies: implementation of linear mixed models (LMMs) and standardized effect sizes (SESs). AB - In this paper, we compare the traditional ANOVA approach to analysing data from 90-day toxicity studies with a more modern LMM approach, and we investigate the use of standardized effect sizes. The LMM approach is used to analyse weight or feed consumption data. When compared to the week-by-week ANOVA with multiple test results per week, this approach results in only one statement on differences in weight development between groups. Standardized effect sizes are calculated for the endpoints: weight, relative organ weights, haematology and clinical biochemistry. The endpoints are standardized, allowing different endpoints of the same study to be compared and providing an overall picture of group differences at a glance. Furthermore, in terms of standardized effect sizes, statistical significance and biological relevance are displayed simultaneously in a graph. PMID- 25724153 TI - Health economic evaluation of paricalcitol((r)) versus cinacalcet + calcitriol (oral) in Italy. [corrected]. AB - BACKGROUND AND OBJECTIVE: Chronic kidney disease (CKD) is a highly morbid disorder. The most severe form of CKD is end-stage renal disease (ESRD), in which the patient requires some form of renal replacement therapy to survive. The increasing incidence, prevalence, and costs of ESRD are major national healthcare concerns. The objective of this study was to determine the cost effectiveness of two innovative therapies, paricalcitol versus cinacalcet + calcitriol (oral) in patients with CKD stage 5 (CKD 5) in the healthcare setting in Italy in 2013. METHODS: A Markov process model was developed employing data sources from the published literature, paricalcitol clinical trials, official Italian price/tariff lists, and national population statistics. The analysis is based on a comparison of treatment with paricalcitol versus cinacalcet + calcitriol (oral) in CKD 5. The perspective of the study was that of the payer [Italian National Health Service (INHS)]. The primary efficacy outcomes in the paricalcitol and cinacalcet + calcitriol (oral) clinical trials (reduction of secondary hyperparathyroidism, complications, and mortality) were extrapolated to effectiveness outcomes: number of life-years gained (LYG) and number of quality-adjusted life-years (QALYs). Clinical and economic outcomes were discounted at 3 %. RESULTS: The base-case analysis is based on a 5-year time horizon. From the INHS perspective, the use of paricalcitol leads to a cost saving of ?1,853 and an increase in LYG (0.136) and a gain in QALYs (0.089). Consequently, the use of paricalcitol is dominant over the use of combination cinacalcet + calcitriol (oral paricalcitol leads to cost savings and a higher effectiveness). Sensitivity analyses confirmed the robustness of the model. CONCLUSION: The results showed that the favorable clinical benefit of paricalcitol results in positive health economic benefits. This study suggests that the use of paricalcitol in patients with ESRD may be cost effective from the perspective of the INHS. PMID- 25724154 TI - Effects of ethanol on the pharmacokinetics of extended-release oxycodone with sequestered naltrexone (ALO-02). AB - BACKGROUND AND OBJECTIVES: ALO-02 capsules, intended to deter abuse, contain pellets of extended-release oxycodone hydrochloride (HCl), an opioid agonist, surrounding sequestered naltrexone HCl, an opioid antagonist. The objective of this study was to determine the effects of administration of ALO-02 with 20 or 40 % ethanol on the pharmacokinetics of oxycodone. METHODS: This was an open-label, single-dose, randomized, three-way crossover study in 18 healthy fasting adults administered ALO-02 20/2.4 mg (oxycodone/naltrexone) with water, 20 % ethanol, or 40 % ethanol, each under naltrexone block. RESULTS: Median time to maximum concentration was 12 h postdose when ALO-02 was administered with water or 20 % ethanol and decreased to 8 h postdose with 40 % ethanol. Geometric mean area under the plasma concentration-time curve (AUC) from time zero extrapolated to infinity (AUCinfinity) and maximum concentration (Cmax) values were similar for ALO-02 administered with water or 20 % ethanol, and increased by about 13 and 37 %, respectively, for ALO-02 administered with 40 % ethanol versus water. The 90 % confidence intervals (CIs) for AUCinfinity and Cmax ratios of ALO-02 with 20 % ethanol versus water were within 80-125 %; upper 90 % CIs were >125 % for ALO-02 with 40 % ethanol versus water. The most common adverse events were mild-to moderate vomiting, nausea, headache, and somnolence. Incidence of adverse events increased for ALO-02 given with ethanol versus water. CONCLUSIONS: Oxycodone exposures (Cmax) were unaffected when ALO-02 was administered with 20 % ethanol but Cmax increased by 37 % with 40 % ethanol versus water. ALO-02 administered with ethanol under naltrexone block was generally well tolerated. PMID- 25724155 TI - Youth unemployment and economic recession in Spain: influence on health and lifestyles in young people (16-24 years old). AB - OBJECTIVES: To explore health status and lifestyles in young Spanish people in 2006 and 2012, the changes between these 2 years and the influence of employment status on health and lifestyles in this period. METHODS: Cross-sectional analysis of the Spanish National Health Surveys 2006 and 2011/12 in people 16-24 years old (3701). Regression analyses for pooled cross-sectional data were developed. Employment status was considered as explanatory variable of health (self-rated health, diagnosed morbidity and mental disorders) and lifestyles (overweight, tobacco and alcohol consumption). RESULTS: Male unemployment was associated with poor self-rated health (OR 1.88; CI 95 % 1.00-3.53), mental disorders (OR 2.42; CI 95 % 1.02-5.76) and tobacco consumption (OR 1.62; CI 95 % 1.00-2.62). During the economic recession, young people presented better health results than in 2006. Unemployed who had never worked consumed less tobacco and alcohol than short-term unemployed. CONCLUSIONS: Unemployment was associated in young men with poor self-rated health, mental illness and tobacco consumption. Despite the economic recession, young people presented better self-rated health, diagnosed morbidity and mental health in 2012 than in 2006, especially in women. PMID- 25724156 TI - The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. AB - PURPOSE: To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. METHODS: Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four way crossover study in 44 healthy participants. Study 2 was a randomized, repeat dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open label, sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participants. RESULTS: Administration of single-dose ibrutinib under fasting conditions (study 1) resulted in approximately 60 % of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (>=30 min before or 2 h after), exposures were slightly (~30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied. CONCLUSIONS: Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib. PMID- 25724157 TI - Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study. AB - Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 +/- 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued. PMID- 25724158 TI - Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug. AB - PURPOSE: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated. METHODS: Self association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables. RESULTS: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data. CONCLUSIONS: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation. PMID- 25724159 TI - Development of a Control Strategy for Benzene Impurity in HPMCAS-Stabilized Spray Dried Dispersion Drug Products Using a Science-Based and Risk-Based Approach. AB - PURPOSE: To develop a strategy to control benzene, an ICH Q3C Class 1 impurity that may be present in spray solvents at ppm concentration, in amorphous polymer stabilized spray-dried dispersion (SDD) products. METHODS: Risk assessments included determining the probability for benzene concentration in primary spray solvents, the physical properties of volatiles, and the potential enrichment of benzene from solution to solid. Mechanistic understanding of benzene removal was gained through a benzene-spiked fate and tolerance (F&T) study simulating worst case spray-drying conditions and application of diffusion models for secondary drying. RESULTS: The mass ratio of spray solution to solid presented the highest risk of benzene enrichment. With slow spray-drying kinetics, benzene was reduced about 700-fold. Under standard secondary-drying conditions to remove residual solvents, residual benzene was further removed. Using diffusion models, the maximum benzene concentration was approximated for SDDs dried to the in-process control (IPC) limit of primary solvents. CONCLUSIONS: Two critical control points were established to eliminate any risk of residual benzene reaching patients: (1) upstream control of benzene in solvents (<=10 ppm) and (2) IPC of residual solvents in polymer-stabilized SDDs. PMID- 25724160 TI - A Microfluidic Diffusion Cell for Fast and Easy Percutaneous Absorption Assays. AB - PURPOSE: Percutaneous absorption assays of molecules for pharmaceutical and cosmetology purposes are important to determine the bioavailability of new compounds, once topically applied. The current method of choice is to measure the rate of diffusion through excised human skin using a diffusion cell. This method however entails significant drawbacks such as scarce availability and poor reproducibility of the sample, low sampling rate, and tedious assay setup. METHODS: The objective of the present work is to propose an alternative method that overcomes these issues by integrating an experimental model of the skin (artificial stratum corneum) and online optical sensors into a microfluidic device. RESULTS: The measurement of the diffusion profile followed by the calculation of the permeability coefficients and time lag were performed on seven different molecules and obtained data positively fit with those available from literature on human skin penetration. The coating of the lipid mixture to generate the artificial stratum corneum also proved robust and reproducible. The results show that the proposed device is able to give fast, real-time, accurate, and reproducible data in a user-friendly manner, and can be produced at a large scale. CONCLUSION: These assets should help both the cosmetics and pharmaceutics fields where the skin is the target or a pathway of a formulated compound, by allowing more candidate molecules or formulations to be assessed during the various stages of their development. PMID- 25724161 TI - Curdlan-Conjugated PLGA Nanoparticles Possess Macrophage Stimulant Activity and Drug Delivery Capabilities. AB - PURPOSE: There is significant interest in the application of nanoparticles to deliver immunostimulatory signals to cells. We hypothesized that curdlan (immune stimulating polymer) could be conjugated to PLGA and nanoparticles from this copolymer would possess immunostimulatory activity, be non-cytotoxic and function as an effective sustained drug release system. METHODS: Carbodiimide chemistry was employed to conjugate curdlan to PLGA. The conjugate (C-PLGA) was characterized using (1)H and (13)C NMR, FTIR, DSC and TGA. Nanoparticles were synthesized using an emulsion-solvent evaporation technique. Immunostimulatory activity was characterized in THP-1 derived macrophages. MTT assay and real-time impedance measurements were used to characterize polymer and nanoparticle toxicity and uptake in macrophages. Drug delivery capability was assessed across Caco-2 cells using rifampicin as a model drug. RESULTS: Spectral characterization confirmed successful synthesis of C-PLGA. C-PLGA nanoparticles enhanced phosphorylated ERK production in macrophages indicating cell stimulation. Nanoparticles provided slow release of rifampicin across Caco-2 cells. Polymers but not nanoparticles altered the adhesion profiles of the macrophages. Impedance measurements suggested Ca(2+) dependent uptake of nanoparticles by the macrophages. CONCLUSIONS: PLGA nanoparticles with macrophage stimulating and sustained drug delivery capabilities have been prepared. These nanoparticles can be used to stimulate macrophages and concurrently deliver drug in infectious disease therapy. PMID- 25724162 TI - Evaluation of Matrix Tablets Based on Eudragit(r)E100/Carbopol(r)971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol. AB - The purpose of this work was to investigate the influence of Eudragit(r)E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol(r)971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Pi rotating paddle apparatus at 50 rpm and 37 degrees C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 +/- 0.4 Kp) compared to polymer-free tablets (3.4 +/- 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol(r)971P NF, Eudragit(r)E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit(r)E100 when combined with Carbopol(r)971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer-Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs. PMID- 25724163 TI - Sodium Ferulate Reduces Portal Pressure Through Inhibition of RhoA/Rho-Kinase and Activation of Endothelial Nitric Oxide Synthase in Cirrhotic Rats. AB - BACKGROUND AND AIMS: Recent studies have demonstrated that increased RhoA/Rho kinase activity and reduced nitric oxide activity have the necessary machinery to induce cirrhosis. However, it is unclear whether this regulates the functions of hepatic stellate cells (HSCs). In this study, we used sodium ferulate (SF) in a cirrhotic rat model and examined its roles in regulating RhoA activation in HSCs and the subsequent effects on contraction of HSCs. METHODS: Bile duct ligation method was used to induce cirrhosis in rats. Intrahepatic resistance was investigated in in situ perfused livers. Hepatic RhoA, Rho-kinase and eNOS expressions were studied by RT-PCR and Western blot. RhoA pull-down assay and collagen gel contraction assay of HSCs were performed by incubation with SF in the absence or presence of GGPP. RESULTS: We showed that in cirrhotic liver, SF can efficiently affect RhoA activation via lowering the synthesis of GGPP in HSCs. These actions effectively reduced basal intrahepatic resistance in cirrhotic rats. Our study further suggested that SF effectively decreased Rho kinase activity and increased activity of eNOS at both the mRNA and protein levels. SF treatment of HSCs reduced RhoA GTP without affecting the total RhoA protein level, and GGPP had the ability to block SF-induced protein expression. Furthermore, SF inhibited the contraction of activated HSCs and this inhibition was efficiently reversed by addition of GGPP. CONCLUSIONS: SF inhibits hepatic RhoA/Rho-kinase signaling and activates the NO/PKG pathway in cirrhotic rats. This may serve as a mechanism for reducing the contraction of activated HSCs upon SF treatment. PMID- 25724164 TI - Reduced Albumin Dosing During Large-Volume Paracentesis Is Not Associated with Adverse Clinical Outcomes. AB - BACKGROUND: LVP is used to manage diuretic-resistant ascites in cirrhotic patients. Albumin administration prevents complications including acute kidney injury and paracentesis-induced circulatory dysfunction, but the optimal dose is unclear. AIM: We sought to assess adherence to guidelines enacted in July 2011 at our center for reducing the albumin dose administered at large-volume paracentesis (LVP) and evaluate the cost and rate of complications of LVPs before and after guideline enactment. METHODS: All LVPs performed on cirrhotic patients in our center's Department of Radiology between July 2009 and January 2014 were studied. Outcomes included adherence to guidelines, LVP complications, and administered albumin cost. Groups were compared using Student's t tests for continuous data and Chi-square or Fisher's exact tests for categorical data. A repeated measurements model accounted for patients with multiple LVPs. RESULTS: Of the 935 LVPs, 288 occurred before guideline implementation (group 1) and 647 occurred after (group 2). The mean dose of albumin administered was 13.7 g/L of ascites removed in group 1 versus 10.3 g/L in group 2 (p < 0.0001). Of the group 2 LVPs, 235 (36.3 %) adhered to guidelines. There were no significant differences in LVP complications. CONCLUSIONS: Guidelines were followed in one-third of LVPs. Despite this limited adherence, a reduction in albumin administration and associated cost savings was still observed. There was no increase in LVP-related complications after guideline implementation or in the adherent group, suggesting that albumin dose can be safely reduced. Future efforts should be directed at enhancing guideline adherence and potentially further reducing albumin dosing. PMID- 25724165 TI - High Prevalence of Gastric Preneoplastic Lesions in East Asians and Hispanics in the USA. AB - BACKGROUND: The prevalence of H. pylori infection and the incidence of gastric cancer differ widely around the world, but it is unclear whether these differences are mirrored in the multiethnic population of the USA. AIMS: This study tested the hypothesis that the prevalence of both H. pylori infection and gastric preneoplastic lesions in US residents of Hispanic and Asian ancestry reflects the incidence of gastric cancer in their ancestral countries. METHODS: A total of 799,075 subjects with gastric biopsies extracted from a national pathology database were stratified into the following ancestries: Indian, Hispanic, Vietnamese, Chinese, Japanese Korean, and other Americans (Caucasian and African-American US residents). The prevalence of H. pylori, intestinal metaplasia, and atrophic gastritis was compared among different ethnic groups using age- and sex-adjusted odds ratios and linear regression. RESULTS: Patients of Indian, Hispanic, Vietnamese, Chinese, Japanese, and Korean ancestry had significantly higher prevalence rates of H. pylori gastritis, intestinal metaplasia, and atrophy than other Americans. The prevalence of intestinal metaplasia and atrophy among different ethnic groups did not correlate with H. pylori prevalence, but did correlate highly significantly with gastric cancer incidence in the patients' ancestral countries. CONCLUSIONS: Various US ethnic groups have significantly different prevalence rates of H. pylori gastritis and gastric preneoplastic lesions. Patients' ethnicity needs be considered in the prevention and early detection of gastric cancer. PMID- 25724166 TI - High Rate of Hospital Admissions Among Patients with Cirrhosis Seeking Care in US Emergency Departments. AB - BACKGROUND AND AIMS: Emergency Departments (ED) can serve as a gateway to specialty care for patients with cirrhosis with limited care access. We described the rates and characteristics of patients with cirrhosis who access United States (US) EDs, and identified factors associated with subsequent hospitalization. METHODS: Using data from the National Hospital Ambulatory Medical Care Survey, cirrhosis-related ED from 2000 to 2009 were identified and compared to all other ED visits. RESULTS: From 2000 to 2009, there were an estimated 1,029,693 cirrhosis and 877 million non-cirrhosis visits. Compared to the general ED population, those with cirrhosis were more frequently male (58 vs. 44 %, p = 0.02), Hispanic (18.6 vs. 10.6 %, p < 0.05), seeking care in urban areas (91.6 vs. 73.4 %, p < 0.05) and had Medicaid/no insurance (43 vs. 35 %, p < 0.01). Patients with cirrhosis were more frequently triaged immediately or emergently (72.3 vs. 54.2 %, p < 0.01). The majority were admitted or transferred to another hospital (66.8 vs. 17.4 %, p < 0.01). Among patients with cirrhosis, patients with age >= 65 years were more likely to be admitted (adjusted OR 2.49, 95 % CI 1.08-5.73), and Medicaid/uninsured (adjusted OR 0.34; 95 % CI 0.17-0.67) were less likely to be admitted, after adjusting for patient demographics, hospital characteristics, and triage score. CONCLUSIONS: Patient with cirrhosis account for approximately 100,000 US ED visits annually. The higher admission rates among patients with cirrhosis indicate a high acuity of illness. Older age among those admitted may reflect poorer functional status. Finally, high visit but low admission rates among those with Medicaid/no insurance suggest a gap in specialty care. PMID- 25724167 TI - Optimizing the interpretation of capsule endoscopic images: shortsighted or taking the long view? PMID- 25724168 TI - CRC screening, past, present, and future: a tribute to Emmet Keeffe. PMID- 25724170 TI - An analysis of variations in the bronchovascular pattern of the right upper lobe using three-dimensional CT angiography and bronchography. AB - OBJECTIVES: General thoracic surgeons must be familiar with anatomical variations in the pulmonary bronchi and vessels. We analyzed variations in the bronchovascular pattern of the right upper lung lobe using three-dimensional CT angiography and bronchography and then compared our results with those of previous reports. METHODS: We reviewed anatomical variations in the right upper pulmonary bronchus and vessels of 263 patients using 3DCT angiography and bronchography images obtained using a 64-channel multidetector CT and workstation running volume-rendering reconstruction software. RESULTS: Variations in the pulmonary vein were classified into four types: the "anterior-plus-central vein type" was the most common, noted in 219 cases (83.2 %). The "anterior vein type" was evident in 23 cases (8.8 %), a significantly lower incidence than in previous reports (p < 0.001). Also, the branching patterns of the segmental arteries of the pulmonary artery differed partially from those noted in previous reports. Furthermore, we identified some new variations. The "B(1)- or B(2)-defective branch type" bronchus was noted in 19 cases (7.2 %), which was a higher prevalence than that in previous reports. CONCLUSION: We explored the bronchovascular pattern and the frequency of variations in the right upper lobe using a large number of 3DCT images. The incidences of variations differed, sometimes significantly, from those noted by previous reports. Moreover, we report some new branching variations. Our data can be used by thoracic surgeons to perform safe and precise lung resections. PMID- 25724169 TI - Primary hypertension is a disease of premature vascular aging associated with neuro-immuno-metabolic abnormalities. AB - There is an increasing amount of data indicating that primary hypertension (PH) is not only a hemodynamic phenomenon but also a complex syndrome involving abnormal fat tissue distribution, over-activity of the sympathetic nervous system (SNS), metabolic abnormalities, and activation of the immune system. In children, PH usually presents with a typical phenotype of disturbed body composition, accelerated biological maturity, and subtle immunological and metabolic abnormalities. This stage of the disease is potentially reversible. However, long lasting over-activity of the SNS and immuno-metabolic alterations usually lead to an irreversible stage of cardiovascular disease. We describe an intermediate phenotype of children with PH, showing that PH is associated with accelerated development, i.e., early premature aging of the immune, metabolic, and vascular systems. The associations and determinants of hypertensive organ damage, the principles of treatment, and the possibility of rejuvenation of the cardiovascular system are discussed. PMID- 25724171 TI - Cholesterol in myelin biogenesis and hypomyelinating disorders. AB - The largest pool of free cholesterol in mammals resides in myelin membranes. Myelin facilitates rapid saltatory impulse propagation by electrical insulation of axons. This function is achieved by ensheathing axons with a tightly compacted stack of membranes. Cholesterol influences myelination at many steps, from the differentiation of myelinating glial cells, over the process of myelin membrane biogenesis, to the functionality of mature myelin. Cholesterol emerged as the only integral myelin component that is essential and rate-limiting for the development of myelin in the central and peripheral nervous system. Moreover, disorders that interfere with sterol synthesis or intracellular trafficking of cholesterol and other lipids cause hypomyelination and neurodegeneration. This review summarizes recent results on the roles of cholesterol in CNS myelin biogenesis in normal development and under different pathological conditions. This article is part of a Special Issue entitled Brain Lipids. PMID- 25724172 TI - Adolescent dietary intakes predict cardiometabolic risk clustering. AB - PURPOSE: To prospectively examine the relation between adolescent dietary intake and cardiometabolic risk (CMR) clustering at the end of adolescence. METHODS: Data from the NHLBI Growth and Health Study on 1369 girls enrolled at ages 9-10 in 1987-1988 and followed for 10 years were used to estimate the relative risk of having multiple (>=2 or >=3) risk factors in late adolescence associated with usual food intake patterns from 9 to 17 years of age. Mean food intakes were derived from multiple 3-day diet records and CMR factors included larger waist circumference, insulin resistance, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, high triglycerides, and elevated systolic or diastolic blood pressures. RESULTS: Of 1369 subjects, 18.4 % girls had 3-6 prevalent risk factors by the end of adolescence and 35.0 % had at least two. Higher intakes of fruit and non-starchy vegetables, dairy, and grains were independently associated with having fewer risk factors as were eating patterns characterized by higher combined intakes of these food groups. After adjusting for age, race, socio-economic status, height, physical activity, and television watching, girls with high intakes of dairy and fruits and non-starchy vegetables (vs. those with lower intakes of both) were nearly 50 % less likely to have three or more CMR factors in late adolescence; girls with higher intakes of grains plus fruits and non-starchy vegetables were nearly 60 % less likely. CONCLUSION: These results suggest that healthy food consumption patterns during adolescence may prevent accumulation of cardiometabolic risk. PMID- 25724174 TI - Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin model. Development of the SENS-IS assay. AB - Analysis of genes modulated during the sensitization process either on mice (LLNA) or human (blisters) combined with data mining has allowed the definition of a comprehensive panel of sensitization biomarkers. This set of genes includes already identified markers such as the ARE family and others not yet associated with the sensitization process (the so-called SENS-IS gene subset). The expression of this set of genes has been measured on reconstituted human epidermis models (Episkin) exposed to various sensitizers and non-sensitizers. Fine analysis of their expression pattern indicates that it is the number of modulated genes rather than the intensity of up-regulation that correlates best with the sensitization potential of a chemical. Moreover, sensitizers that are weak inductors of ARE genes tend to be relevant modulators of the SENS-IS subset. By combining the expression data obtained with both gene subsets, it is now possible to identify a wide variety of sensitizers on a test system (in vitro reconstructed human epidermis) that is very similar to the in vivo situation and compatible with a large variety of test substance characteristics. PMID- 25724173 TI - Multiple anti-inflammatory and anti-atherosclerotic properties of red wine polyphenolic extracts: differential role of hydroxycinnamic acids, flavonols and stilbenes on endothelial inflammatory gene expression. AB - PURPOSE: The aim of the study was to evaluate the vascular anti-inflammatory effects of polyphenolic extracts from two typical South Italy red wines, the specific contribution of individual polyphenols and the underlying mechanisms of action. METHODS: Human endothelial cells were incubated with increasing concentrations (1-50 MUg/mL) of Primitivo and Negroamaro polyphenolic extracts (PWPE and NWPE, respectively) or pure polyphenols (1-25 MUmol/L), including hydroxycinnamic acids (p-coumaric, caffeic and caftaric acids), flavonols (kaempferol, quercetin, myricetin) or stilbenes (trans-resveratrol, trans-piceid) before stimulation with lipopolysaccharide. Through multiple assays, we analyzed the endothelial-monocyte adhesion, the endothelial expression of adhesion molecules (ICAM-1, VCAM-1 and E-Selectin), monocyte chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF), as well as ROS intracellular levels and the activation of NF-kappaB and AP-1. RESULTS: Both PWPE and NWPE, already at 1 MUg/mL, inhibited monocyte adhesion to stimulated endothelial cells, a key event in triggering vascular inflammation. They down regulated the expression of adhesion molecules, ICAM-1, VCAM-1, E-Selectin, as well as MCP-1 and M-CSF, at mRNA and protein levels. All polyphenols reduced intracellular ROS, and everything, except caftaric acid, inhibited the endothelial expression of adhesion molecules and MCP-1, although with different potency. Flavonols and resveratrol significantly reduced also the endothelial expression and release of M-CSF. The decrease in endothelial inflammatory gene expression was related to the inhibition of NF-kappaB and AP-1 activation but not to intracellular oxidative stress. CONCLUSIONS: This study showed multiple anti inflammatory and anti-atherosclerotic properties of red wine polyphenolic extracts and indentified specific bioactive polyphenols which could counteract inflammatory diseases including atherosclerosis. PMID- 25724175 TI - Using rabies virus vaccine strain SRV9 as viral vector to express exogenous gene. AB - Rabies virus (RABV) can cause a fatal neurological disease in human and animals, and vaccines were generally applied for the immunoprophylaxis of rabies. Here, a recombinant viral vector carrying the exogenous gene expression component between phosphoprotein (P) and matrix protein (M) genes of RABV was constructed based on the vaccine strain SRV9 used in China. To develop a reverse genetic system, the full-length cDNA plasmids of SRV9 were constructed using the eukaryotic expression vector pCI or pcDNA3.1(+). However, recovery efficiency based on the pcDNA3.1 vector was significantly higher than that of the pCI vector. The exogenous gene expression component PE-PS-BsiWI-PmeI or PS-BsiWI-PmeI-PE was introduced in different locations between the P and M genes of SRV9. When the enhanced green fluorescent protein (eGFP) was used as a reporter gene, both locations could rescue recombinant RABV (rRABV) expressing eGFP with high efficiency. Characterization of rRABV expressing eGFP in vitro revealed that its growth was similar to that of the parental virus. Animal experiments showed that rRABV expressing eGFP could replicate and express eGFP in the brains of suckling mice. Furthermore, rRABV of SRV9 was nonpathogenic for 3-week-old mice and could be cleared from the central nervous system at 5 days post-inoculation. Our results showed that the recombinant SRV9 virus could be used as a useful viral vector for exogenous gene expression. PMID- 25724176 TI - Combination of intratypic and intertypic recombinant events in EV71: a novel evidence for the "triple-recombinant" strains of genotype A viruses in Mainland China from 2008 to 2010. AB - The first Enterovirus 71 (EV71) strain isolated in 1969 was classified as genotype A. It is interesting that the genotype A disappeared nearly 40 years until its re-emergence in mainland China in 2008-2010. Few studies on genetic characterization of the re-emerged genotype A viruses have been reported. In this study, a series of analyses were performed on molecular epidemiology and genome recombination of genotype A viruses in China. Phylogenetic analysis indicated that except for 17 reported genotype A strains and 3 orphan strains (C0, C3 and B5), almost all EV71 strains in mainland China were belonging to subgenotype C4 during 1987-2011. The subgenotype C4 was further divided into 3 clades C4a1, C4a2, and C4b. The genotype A viruses co-circulated with the predominant clade C4a2 and the re-emerged clade C4b both in eastern and central China in 2008-2009. Moreover, comprehensive recombination analysis showed that the genotype A viruses were "triple-recombinant" by combination of intratypic and intertypic recombination. Intertypic recombination between the oldest C4b strain (SHZH98) and Coxsackievirus A5 (CVA5) and intratypic recombination between the SHZH98 and C1 strains both with one junction in 5'-UTR were observed for some specific C4a2 strains and the re-emerged C4b strain, respectively. And intratypic recombination between the re-emerged C4b strain and the specific C4a2 strains with one junction in 5'-UTR was observed for the Chinese genotype A viruses. Taken together, these results provided potential explanations for the genesis of Chinese genotype A viruses which were significant for preventing and controlling outbreaks. PMID- 25724177 TI - Studies on differential behavior of cassava mosaic geminivirus DNA components, symptom recovery patterns, and their siRNA profiles. AB - Cassava mosaic disease caused by cassava mosaic geminiviruses (CMGs) with bipartite genome organization is a major constraint for production of cassava in the African continent and the Indian sub-continent. Currently, there are eleven recognized species of CMGs, and several diverse isolates represent them, with vast amount of sequence variability, reflecting into diversity of symptom severity/phenotypes. Here, we make a systematic effort to study the infection dynamics of several species of CMGs and their isolates. Further, we try to identify the genomic component of CMGs contributing to the manifestation of diverse patterns of symptoms and the molecular basis for the differential behavior of CMGs. The pseudo-recombination studies carried out by swapping of DNA A and DNA-B components of the CMGs revealed that the DNA-B component significantly contributes to the symptom severity. Past studies had shown that the DNA-A component of Sri Lankan cassava mosaic virus shows monopartite feature. Thus, the ability of DNA-A component alone, to replicate and move systemically in the host plant with inherent monopartite features was investigated for all the CMGs. Geminiviruses are known to trigger gene silencing and are also its target, resulting in recovery of the host plant from viral infection. In the collection of several different CMG species and isolates we had, there was a vast variability in their recovery and non-recovery phenotypes. To understand the molecular basis of this, the origin and distribution of virus-derived small interfering RNAs were mapped across their genome and across the CMG-infected symptomatic Nicotiana benthamiana. PMID- 25724178 TI - Paroxysmal Sympathetic Hyperactivity in Critically Ill Children with Encephalitis and Meningoencephalitis. AB - BACKGROUND: Autonomic dysfunction in pediatric patients with acquired brain injury is often encountered and greatly understudied. We sought to identify the incidence of Paroxysmal Sympathetic Hyperactivity (PSH) in critically ill pediatric patients with meningoencephalitis and encephalitis, associated risk factors and influence on outcome. METHODS: Children admitted to the pediatric intensive care unit (PICU) with a diagnosis of meningoencephalitis and/or encephalitis were identified from a single institution Neurocritical Care database. The patients were stratified as having a bacterial or non-bacterial cause of their meningoencephalitis/encephalitis. Data from their hospitalization was supplemented with a retrospective review of the electronic medical record. PSH was defined as episodic lability in heart rate and/or blood pressure, hyperthermia, diaphoresis, dystonic posturing, tachypnea and/or agitation without any other cause. Statistical analysis was performed using t-test and chi-squared to compare outcomes and risk factors between patients with PSH and without. RESULTS: PSH was found in 41 % of children studied. Subgroup analysis revealed patients with non-bacterial encephalitis were more likely to experience PSH (51 %) as compared to those with bacterial causes (27 %). Fever and/or seizures on presentation and female gender were associated with higher occurrence of PSH but only in the non-bacterial etiology group. There were trends toward increased length of PICU and overall hospital stay for patients with PSH. CONCLUSIONS: PSH was found in a high percentage of our patients with significant variation in risk factors and outcome noted between patients with bacterial and nonbacterial causes of their meningoencephalitis/encephalitis. PMID- 25724180 TI - TRIM24 is upregulated in human gastric cancer and promotes gastric cancer cell growth and chemoresistance. AB - The tripartite motif protein tripartite motif-containing 24 (TRIM24) is involved in human cancer progression. However, the expression pattern and biological roles of TRIM24 in human gastric cancer have not been studied. Here, we report that expression of TRIM24 protein was upregulated in 65 of 133 gastric cancer specimens. TRIM24 upregulation positively correlated with clinical stage, local invasion, and poor patient prognosis. We overexpressed TRIM24 by transfection in SGC-7901 cells and used an siRNA strategy to knock down TRIM24 in MKN-1 cells. MTT and colony formation assays showed that transfection of TRIM24 plasmid accelerated, while its depletion inhibited cell proliferation rate. TRIM24 overxpression also induced chemoresistance to 5-FU in gastric cancer cells. Further analysis showed that TRIM24 overexpression upregulated cyclin D1 and Akt phosphorylation. Akt inhibitor LY294002 reversed the role of TRIM24 on chemoresistance. In conclusion, our study shows that TRIM24 is overexpressed in human gastric cancer and accelerates cell growth as well as induce chemoresistance, possibly through the Akt pathway. PMID- 25724179 TI - Vitamin D: Implications for ocular disease and therapeutic potential. AB - Vitamin D is a multifunctional hormone that is now known to play a significant role in a variety of biological functions in addition to its traditional role in regulating calcium homeostasis. There are a large number of studies demonstrating that adequate vitamin D levels are important in maintaining health and show that vitamin D is able to be utilized at local tissue sites. In the eye, we have increasing evidence of the association between disease and vitamin D. In this narrative review, we summarize recent findings on vitamin D and its relationship to various ocular pathologies and the therapeutic potential for some of these, as well as examine the basic science studies that demonstrate that vitamin D is biologically relevant in the eye. PMID- 25724181 TI - In stage II/III lymph node-positive breast cancer patients less than 55 years of age, keratin 8 expression in lymph node metastases but not in the primary tumour is an indicator of better survival. AB - Axillary lymph node status is one of the most important prognostic variables for breast cancer (BC). To investigate and understand the clinical, histopathological and biological factors that affect prognosis in node-positive young breast cancer patients, we compared the phenotype of 100 primary tumours with their corresponding loco-regional lymph node (LN) metastases using conventional immunohistochemistry (IHC) markers currently in use for molecular classification of breast cancer. By comparing the expression of ER, PR, HER-2, Ki67, K8, K5/6 and vimentin, we found that expression of HER-2, Ki67, K8 and vimentin is frequently lost in lymph node metastases. Between the primary tumour and corresponding lymph node metastases, expression of keratins K8 and K5/6 significantly changed. Expression of K8 in lymph node metastases, but not in primary tumours, segregates patients in two sub-groups with different outcomes. Survival of patients with K8-positive LN metastases at 5 years in comparison with patients with K8-negative LN metastases was 75 vs 48 %, at 10 years 62 vs 22 % and at 20 years 53 vs 14 % (p < 0.001). K8 immunostaining of tissue from the lymph node metastasis allows defining a sub-group of lymph node-positive BC patients with a highly unfavourable outcome, for whom therapeutic options might have to be reconsidered. PMID- 25724182 TI - The clinical value of dynamic contrast-enhanced MRI in differential diagnosis of malignant and benign ovarian lesions. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used in preoperative diagnosis of various tumors. We investigated the clinical value of DCE-MRI in differential diagnosis of malignant and benign ovarian lesions. The study involved 48 subjects with surgical pathology-confirmed ovarian tumors with solid components. Early dynamic phase enhancement performances of the ovarian lesions in patients were assessed, including the enhancement pattern, time-signal intensity curve (TIC), signal intensity rate at the initial 60 s (SI60), time to peak within 200 s (TTP200), and slope ratio. There were significant differences in enhancement patterns between benign and malignant ovarian tumors (P < .05). A total of 30 malignant tumors (30/31) displayed type I TIC, 8 benign tumors (8/13) showed type III TIC, and significant differences were found in TIC type between malignant and benign ovarian lesions (P < 0.01). Benign ovarian tumors showed lower SI60 (%) and slope ratio, as well as significantly prolonged TTP20, compared to malignant ovarian tumors (all P < 0.01). The microvessel count (MVC) of malignant tumors was significantly higher than that of benign tumors (P < 0.05). Receiver operating characteristic (ROC) curve analyses revealed that DCE MRI provided an optimal diagnostic performance with threshold values of SI60 at 83.40 %, TTP200 at 77.65 s, and slope ratio at 4.12. These findings revealed that DCE-MRI provides critical information required for differential diagnosis of malignant and benign ovarian lesions. PMID- 25724183 TI - Ceramide production mediates cinobufotalin-induced growth inhibition and apoptosis in cultured hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a highly aggressive and lethal neoplasm with poor prognosis. The aim of this study is to investigate the anticancer activity of cinobufotalin, a bufadienolide isolated from toad venom, in cultured HCC cells, and to study the underlying mechanisms. We found that cinobufotalin (at nmol/L) significantly inhibited HCC cell growth and survival while inducing considerable cell apoptosis. Further, cinobufotalin inhibited sphingosine kinase 1 (SphK1) activity and induced pro-apoptotic ceramide production. Ceramide synthase-1 small hairpin RNA (shRNA)-depletion inhibited cinobufotalin-induced ceramide production and HCC cell apoptosis. On the other hand, the glucosylceramide synthase (GCS) inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1 propanol (PDMP) facilitated cinobufotalin-induced ceramide production and cell apoptosis. SphK1 inhibitor II (SKI-II), similar to cinobufotalin, increased cellular ceramide level and promoted HCC cell apoptosis. Finally, we observed that cinobufotalin inactivated Akt-S6K1 signaling in HepG2 cells, which was again inhibited by ceramide synthase-1 shRNA-depletion. In conclusion, the results of this study suggest that cinobufotalin induces growth inhibition and apoptosis in cultured HCC cells through ceramide production. Cinobufotalin may be investigated as a novel anti-HCC agent. PMID- 25724184 TI - Tobacco carcinogen-metabolizing genes CYP1A1, GSTM1, and GSTT1 polymorphisms and their interaction with tobacco exposure influence the risk of head and neck cancer in Northeast Indian population. AB - Genetic polymorphisms in tobacco-metabolizing genes may modulate the risk of head and neck cancer (HNC). In Northeast India, head and neck cancers and tobacco consumption remains most prevalent. The aim of the study was to investigate the combined effect of cytochrome P450 1A1 (CYP1A1) T3801C, glutathione S transferases (GSTs) genes polymorphisms and smoking and tobacco-betel quid chewing in the risk of HNC. The study included 420 subjects (180 cases and 240 controls) from Northeast Indian population. Polymorphisms of CYP1A1 T3801C and GST (M1 & T1) were studied by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR, respectively. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approach were applied for statistical analysis. LR analysis revealed that subjects carrying CYP1A1 TC/CC + GSTM1 null genotypes had 3.52-fold (P < 0.001) increase the risk of head and neck squamous cell carcinoma (HNSCC). Smokers carrying CYP1A1 TC/CC + GSTM1 null and CYP1A1 TC/CC + GSTT1 null genotypes showed significant association with HNC risk (odds ratio [OR] = 6.42; P < 0.001 and 3.86; P = 0.005, respectively). Similarly, tobacco-betel quid chewers carrying CYP1A1 TC/CC + GSTM1 null genotypes also had several fold increased risk of HNC (P < 0.001). In MDR analysis, the best model for HNSCC risk was the four-factor model of tobacco betel quid chewing, smoking, CYP1A1 TC/CC, and GSTM1 null genotypes (testing balance accuracy [TBA] = 0.6292; cross-validation consistency [CVC] = 9/10 and P < 0.0001). These findings suggest that interaction of combined genotypes of carcinogen-metabolizing genes with environmental factors might modulate susceptibility of HNC in Northeast Indian population. PMID- 25724185 TI - PTEN gene is infrequently hypermethylated in human esophageal squamous cell carcinoma. AB - Whether promoter hypermethylation of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is associated with loss of PTEN expression was not yet elucidated in esophageal squamous cell carcinoma (ESCC). The methylation status of PTEN gene was evaluated in 74 ESCC specimens and four esophageal cancer cell lines. Its association with clinicopathological factors or the prognosis was investigated by statistical analysis. We further measured messenger RNA (mRNA) and protein level of PTEN by quantitative RT-PCR and immunohistochemistry and studied the role of PTEN hypermethylation in loss of PTEN expression in clinical samples. Next, demethylation of PTEN gene with 5-azaC in EC9706 was performed to confirm the clinical findings. PTEN methylation was only found in 14 (18.9 %) of 74 ESCC tumor samples and one (EC9706) of four esophageal cancer cell lines. PTEN methylation was not statistically associated with clinicopathological factors and the prognosis (p > 0.05). In addition, 41 patients (55.4 %) and 38 patients (51.4 %) showed reduced mRNA level of PTEN and negative expression of PTEN protein in ESCC tumors, respectively. Detailed analysis indicated that PTEN methylation was a possible mechanism of loss of PTEN expression in ESCC, and further 5-azaC demethylation revealed inversed methylation status and increased mRNA or protein level of PTEN in EC9706. However, the role of PTEN methylation in loss of PTEN expression was still limited due to low frequency of methylation in ESCC. PTEN hypermethylation is a rare event and did not play an important role in the prognosis and loss of PTEN expression in ESCC. PMID- 25724186 TI - Androgen receptor promotes esophageal cancer cell migration and proliferation via matrix metalloproteinase 2. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in ESCC are poorly characterized. In the present study, Western blot analysis and real-time quantitative PCR were performed to identify differentially expressed AR in 40 ESCC tissue samples, which revealed that the messenger RNA (mRNA) and protein expression of AR is upregulated in the ESCC tissue samples. AR overexpression induced increases in ESCC cell invasion and proliferation in vitro. Silencing of AR inhibited the proliferation of KYSE450 cells which have a relatively high level of AR, and the invasion of KYSE450 cells was distinctly suppressed. Furthermore, AR knockdown led to substantial reductions in matrix metalloproteinase 2 (MMP2) and p-AKT levels in ESCC cell lines, but no significant change in AKT and MMP9 expression. These results suggest that AR is involved in tumor progression, and thus, AR could represent selective targets for the molecularly targeted treatments of ESCC. PMID- 25724187 TI - Transcriptome meta-analysis reveals dysregulated pathways in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a malignant cancer arising from the epithelial surface of the nasopharynx that mostly appears in advanced stages of the disease, leading to a poor prognosis. To date, a number of mRNA profiling investigations on NPC have been reported in order to identify suitable biomarkers for early detection. However, the results may be specific to each study with distinct sample types. In this study, an integrative meta-analysis of NPC transcriptome data was performed to determine dysregulated pathways, potentially leading to identification of molecular markers. Ten independent NPC gene expression profiling microarray datasets, including 135 samples from NPC cell lines, primary cell lines, and tissues were assimilated into a meta-analysis and cross validation to identify a cohort of genes that were significantly dysregulated in NPC. Bioinformatics analyses of these genes revealed the significant pathways and individual players involving in cellular metabolism, cell cycle regulation, DNA repair, as well as ErbB pathway. Altogether, we propose that dysregulation of these molecular pathways in NPC might play a role in the NPC pathogenesis, providing clues, which could eventually translate into diagnostic and therapeutic approaches. PMID- 25724188 TI - Activation of matrix metalloproteinase-9 (MMP-9) by neurotensin promotes cell invasion and migration through ERK pathway in gastric cancer. AB - Neurotensin (NT) is distributed throughout the brain and gastrointestinal tract. Although the relationship between NT and matrix metalloproteinase-9 (MMP-9) activity in gastric cancer has not been reported, the elevation of MMP-9 and NT is reported in the breast, lung, prostate, and gastric cancer. The aim of our study is to investigate the relationship between NT and MMP-9 activity and the underlying signaling mechanism in gastric cancer cell lines. Commercial ELISA kits were used for estimation of NT and MMP-9 expression, and fluorescence resonance energy transfer (FRET) assay was used for measurement of MMP-9 activity. Cell migration and invasion were determined by wound healing and transwell assay. The expression of signaling proteins was measured by Western blotting. Our study reveals a positive correlation between increased plasma NT and MMP-9 activity in both of patient's serum and gastric cancer cell lines. A dose-dependent elevation of MMP-9 activity was observed by NT treatment in gastric cancer cells (MKN-1 and MKN-45) compared to untreated gastric cancer and normal epithelial cell (HFE-145). Moreover, NT-mediated migration and invasion were observed in gastric cancer cells unlike in normal cell. The signaling mechanism of NT in gastric cancer cells was confirmed in protein kinase C (PKC), extracellular-signal regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K) pathway. In addition, pretreatment of gastric cancer cells with NTR1 inhibitor SR48692 was shown to significantly inhibit the NT-mediated MMP-9 activity, cell invasion, and migration. Our finding illustrated NTR1 could be a possible therapeutic target for gastric cancer. PMID- 25724190 TI - Does long-distance air travel associated with the Sevens World Series increase players' risk of injury? AB - OBJECTIVE: To assess whether players who cross >=6 time zones and/or undertake >=10 h air travel prior to competition experience a higher risk of injury during the Sevens World Series than players not required to undertake this level of travel. DESIGN: Five-year, prospective, cohort study. PARTICIPANTS: All players from nine core teams competing in the Sevens World Series from 2008/2009 to 2013/2014. RESULTS: A total of 436 match injuries and 3363 player-match-hours of exposure were recorded in the study, which corresponds to an overall incidence of 129.6 injuries/1000 player-match-hours, irrespective of the nature of pretournament travel. The incidence of injury for those players crossing >=6 time zones and undertaking >=10 h air travel prior to competition (99.3 injuries/1000 player-match-hours) was significantly lower than that of players undertaking >=10 h air travel but crossing <=2 time zones prior to competition (148.8 injuries/1000 player-match-hours; p=0.003) and of those undertaking <=3 h air travel and crossing <=2 time zones prior to competition (146.4 injuries/1000 player-match-hours; p=0.004). There was no significant difference in the incidence of injury for players crossing <=2 time zones in the week prior to competition, irrespective of whether the length of air travel was <=3 h or >=10 h (p=0.904). Precompetition air travel had no significant effect (p=0.879) on the performance of teams in terms of their final Tournament ranking positions. CONCLUSIONS: There was no evidence to suggest that players were exposed to a greater risk of injury following extensive air travel and crossing multiple time zones prior to Tournaments in the Sevens World Series. PMID- 25724189 TI - A Multiplexed Cell-Based Assay for the Identification of Modulators of Pre Membrane Processing as a Target against Dengue Virus. AB - The DenV pre-membrane protein (prM) is a crucial chaperone for the viral envelope protein, preventing premature fusion with vesicles during viral export. prM molecules in immature particles are cleaved by host proteases, leading to mature fusogenic virions. Blockade of prM cleavage would restrict fusion and represents a novel druggable opportunity against DenV. We have thus established a cell-based platform to monitor prM processing that relies on an engineered two-tag scaffold that travels to the cell surface through the secretory pathway. The assay discriminates between a single cell-surface tag when prM is cleaved and two tags when it is not, as detected through fluorescent-coupled antibodies by flow cytometry. The assay, miniaturized into a 96-well plate format, was multiplexed with the HIV-1 envelope boundary, also cleaved in the same pathway. A pilot screen against 1280 compounds was executed, leading to the identification of a potential active and corroborating the robustness of our assay for large-scale screening. We describe for the first time a cell-based assay that monitors DenV prM processing within the classical secretory pathway, which was exploited to identify a potential novel drug against DenV. PMID- 25724191 TI - Computing human optical point spread functions. AB - There is renewed interest in the role of optics in human vision. At the same time there have been advances that allow for routine standardized measurement of the wavefront aberrations of the human eye. Computational methods have been developed to convert these measurements to a description of the human visual optical point spread function (PSF), and to thereby calculate the retinal image. However, tools to implement these calculations for vision science are not widely available or widely understood. In this report we describe software to compute the human optical PSF, and we discuss constraints and limitations. PMID- 25724192 TI - The Predictive Validity of the Short-Term Assessment of Risk and Treatability (START) for Multiple Adverse Outcomes in a Secure Psychiatric Inpatient Setting. AB - The Short-Term Assessment of Risk and Treatability (START) aims to assist mental health practitioners to estimate an individual's short-term risk for a range of adverse outcomes via structured consideration of their risk ("Vulnerabilities") and protective factors ("Strengths") in 20 areas. It has demonstrated predictive validity for aggression but this is less established for other outcomes. We collated START assessments for N = 200 adults in a secure mental health hospital and ascertained 3-month risk event incidence using the START Outcomes Scale. The specific risk estimates, which are the tool developers' suggested method of overall assessment, predicted aggression, self-harm/suicidality, and victimization, and had incremental validity over the Strength and Vulnerability scales for these outcomes. The Strength scale had incremental validity over the Vulnerability scale for aggressive outcomes; therefore, consideration of protective factors had demonstrable value in their prediction. Further evidence is required to support use of the START for the full range of outcomes it aims to predict. PMID- 25724193 TI - A unique homodimeric NAD+-linked isocitrate dehydrogenase from the smallest autotrophic eukaryote Ostreococcus tauri. AB - In eukaryotes, NAD(+)-dependent isocitrate dehydrogenase (IDH) is strictly mitochondrial and is a key enzyme in the Krebs cycle. To date, all known NAD(+) specific IDHs (NAD-IDHs) in the mitochondria are believed to be heteromeric in solution. Here, a unique homodimeric NAD-IDH from Ostreococcus tauri (OtIDH), the smallest autotrophic picoeukaryote, was unveiled. Active OtIDH has a molecular weight of ~93 kDa with each subunit of 46.7 kDa. In the presence of Mn(2+) and Mg(2+), OtIDH displayed 42-fold and 51-fold preference for NAD(+) over NADP(+), respectively. Interestingly, OtIDH exhibited a sigmoidal kinetic behavior in response to isocitrate unlike other homodimeric homologs, and a remarkably high affinity for isocitrate (S0.5 < 10 MUM) unlike other hetero-oligomeric homologs. Furthermore, its coenzyme specificity can be completely converted from NAD(+) (ancient trait) to NADP(+) (adaptive trait) by rational mutagenesis based on the evolutionary trace. Mutants D344R and D344R/M345H displayed a 15-fold and 72-fold preference for NADP(+) over NAD(+), respectively, indicating that D344 and M345 are the determinants of NAD(+) specificity. These findings also suggest that OtIDH may be an ancestral form of type II IDHs (all reported members are NADP(+) linked enzymes) and may have evolved into NADP(+)-dependent IDH for adaptation to the increased demand of NADPH under carbon starvation. PMID- 25724194 TI - Inhibition of EZH2 expression is associated with the proliferation, apoptosis and migration of SW620 colorectal cancer cells in vitro. AB - Epigenetic changes have been recently recognized as important in many human cancers. Enhancer of zeste homologue 2 (EZH2) gene has shown overexpression in various human cancers, consistent with a straightforward role of EZH2 as an oncogene, but its function in carcinogenesis is partly contradictory. The role of EZH2 in development of human colorectal cancer (CRC) has not yet been clarified. In present study, we observed up-regulation of EZH2 expression in tumor tissues from CRC patients. The expression of EZH2 in CRC cell lines is consistent with the trend in cancer tissues using RT-PCR. We showed that TNM stage and lymph node metastasis in CRC patients are significantly correlated with EZH2 expression levels. EZH2 level of transcription and protein was inhibited by small interfering RNA (siRNA). More importantly, EZH2-siRNA inhibited the proliferation and migration of SW620 cells while promoting their apoptosis, and inducing G0/G1 cell cycle arrest of CRC cells. Collectively, our results suggest that up regulated EZH2 expression may contribute to the progression of the patients with CRC. A comprehensive study of epigenetic mechanisms and the relevance of EZH2 in CRC is important for fully understanding this disease and as a basis for developing new treatment options in patients with CRC. PMID- 25724195 TI - Special tests for assessing meniscal tears within the knee: a systematic review and meta-analysis. AB - BACKGROUND: Musculoskeletal knee pain is a large and costly problem, and meniscal tears make up a large proportion of diagnoses. 'Special tests' to diagnose torn menisci are often used in the physical examination of the knee joint. A large number of publications within the literature have investigated the diagnostic accuracy of these tests, yet despite the wealth of research their diagnostic accuracy remains unclear.Aim To synthesise the most current literature on the diagnostic accuracy of special tests for meniscal tears of the knee in adults. METHOD: An electronic search of MEDLINE, Cumulative Index to Nursing and Allies Health Literature (CINAHL), The Allied and Complementary Medicine Database (AMED) and SPORT Discus databases was carried out from inception to December 2014. Two authors independently selected studies and independently extracted data. Methodological quality was evaluated using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS) 2 tool. RESULTS: Nine studies were included (n=1234) and three special tests were included in the meta-analysis. The methodological quality of the included studies was generally poor. McMurray's had a sensitivity of 61% (95% CI 45% to 74%) and a specificity of 84% (95% CI 69%to 92%). Joint line tenderness had a sensitivity of 83%(95% CI 73% to 90%) and a specificity of 83% (95% CI 61% to 94%). Thessaly 20 degrees had a sensitivity of 75%(95% CI 53% to 89%) and a specificity of 87% (95% CI 65% to 96%). CONCLUSIONS: The accuracy of the special tests to diagnose meniscal tears remains poor. However, these results should be used with caution, due to the poor quality and low numbers of included studies and high levels of heterogeneity. PMID- 25724196 TI - Prosthetic vascular graft infection through a median sternotomy: a multicentre review ?. AB - OBJECTIVES: The aim of this study is to analyse the treatment outcomes of thoracic prosthetic graft infection. METHODS: A retrospective chart review was conducted at six hospitals and included the records of 68 patients treated for postoperative prosthetic vascular graft infection (mean age: 62.3 +/- 15.1, male 51) from January 2000 to December 2013. The number of patients and the locations of the treated infections were as follows: 13 for aortic root, 16 for ascending aorta, 35 for aortic arch and 4 for aortic root to arch. In-hospital infection occurred in 43 patients and after discharge in 25. RESULTS: The mean follow-up time was 2.0 +/- 2.3 years. The follow-up rate was 94.1%. The most commonly isolated micro-organism was Staphylococcus aureus (72.1%). Rereplacement of infectious graft was performed in 18 patients (Dacron graft in 12, homograft in 4 and rifampicin-bonded Dacron graft in 2). The overall hospital mortality rate was 35.3% (24/68). The mortality rate among the patients with graft rereplacement was 33.3% (6/18), with pedicled muscle flaps or pedicled omental flaps to cover the graft 25.9% (7/27), with irrigation 55.0% (11/20) and on antibiotic therapy only 0% (0/3). Our multivariate analysis demonstrated that the risk factors of hospital death increased in the absence of pedicled flaps (muscle or omentum) to cover the graft (P = 0.001), age over 55 (P = 0.003), time from onset of initial operation <1 week (P = 0.031) and period before 2008 (P = 0.001). The overall 1 year survival rate was 58.6%. CONCLUSIONS: The treatment outcomes of thoracic prosthetic vascular graft infection have not been satisfactory. However, the use of pedicled muscle or omental flaps to cover the graft could improve the outcomes. PMID- 25724197 TI - Determination of Toxic Metals in Little Cigar Tobacco with 'Triple Quad' ICP-MS. AB - Smoking remains the leading cause of preventable death in the USA. Much of the focus on harmful and potentially harmful constituents (HPHCs) in tobacco products has been on cigarettes. Little cigars gained popularity over the last decade until tobacco taxes made cigarettes more expensive in the USA. Many little cigar brands are similar in size with cigarettes and may be smoked in a similar manner. Scant data are available on HPHC concentrations in little cigars, therefore we developed and applied a new analytical method to determine concentrations of 10 toxic metals in little cigar tobacco. The method utilizes 'triple quadrupole' ICP MS. By optimizing octapole bias, energy discrimination and cell gas flow settings, we were able to accurately quantify a range of elements including those for which the cell gas reactions were endothermic. All standard modes (Single Quad No Gas, MS-MS NH3/He and MS-MS O2) were utilized for the quantitation of 10 toxic metals in little cigar tobacco, including uranium, which was added as an analyte in the new method. Because of the elimination of interfering ions at 'shifted analyte masses', detection limits were lower compared with a previous method. Tobacco selenium concentrations were below the limit of detection in the previous method, but the new technology made it possible to report all selenium concentrations. PMID- 25724198 TI - Tailoring the Blood Ordering Process for Cardiac Surgical Cases Using an Institution-Specific Version of the Maximum Surgical Blood Order Schedule. AB - BACKGROUND: Excess ordering of blood products for surgical cases is expensive and wasteful. Evidence has shown that institution-specific versions of the Maximum Surgical Blood Order Schedule (MSBOS) lead to better ordering practices. Most MSBOSs recommend a crossmatch for a minimum of 2 units of packed red blood cells (PRBCs) for cardiac surgical cases; however, studies have shown that >50% of these patients receive no transfusions. Our aim was to create a blood order algorithm for cardiac surgical cases that would decrease unnecessary crossmatching. METHODS: Retrospective data was collected for 264 patients from January 2011 through April 2012. The crossmatch-to-transfusion ratio (C:tx), transfusion probability (%T), and transfusion index (TI) were calculated for each type of procedure. RESULTS: All 264 patients were crossmatched and 98 patients were transfused, resulting in an overall transfusion probability (%T) of 37.12% (95% confidence interval 31.52-43.09). A total of 1175 units of blood were crossmatched, but only 370 units of blood were transfused, resulting in a C:tx of 3.17 (95% confidence interval 2.61-4.03). The average number of units transfused per procedure (transfusion index) was 1.40. C:tx was highest and TI was lowest for CABG, where approximately 11 units of blood were ordered for every 1 unit transfused (C:tx =11.70 +/- 3.04), and the TI was 0.32. CONCLUSIONS: Using the gold standard C:tx of >2:1 as an indicator of inappropriate blood utilization, our analysis confirmed that excessive crossmatching occurred for several procedures. Now a subset of cardiac surgical cases only requires a type and screen order prior to surgery. PMID- 25724199 TI - Single stem cell gene therapy for genetic skin disease. AB - Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz-Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings. PMID- 25724200 TI - A single epidermal stem cell strategy for safe ex vivo gene therapy. AB - There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for next-generation gene therapy. PMID- 25724201 TI - Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. AB - Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a task yet to be demonstrated by other neuroimaging approaches. Diffusion basis spectrum imaging-derived radial diffusivity (myelin integrity marker) and non-restricted isotropic diffusion fraction (oedema marker) correlated with magnetization transfer ratio, supporting previous reports that magnetization transfer ratio is sensitive not only to myelin integrity, but also to inflammation-associated oedema. Our results suggested that diffusion basis spectrum imaging-derived quantitative biomarkers are highly consistent with histology findings and hold promise to accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. Thus, diffusion basis spectrum imaging can potentially serve as a non invasive outcome measure to assess treatment effects on the specific components of underlying pathology targeted by new multiple sclerosis therapies. PMID- 25724203 TI - Study of murine experimental Jorge Lobo's disease by analysis of peritoneal lavage cells and footpad histopathology: early versus chronic lesions. AB - The murine model of Jorge Lobo's disease is characterized by histological alterations similar to those seen in human disease, including a large number of viable fungi. This study evaluated the immune response of mice with early and late macroscopic lesions (5 and 13 months post-inoculation [p.i.], respectively) by the analysis of peritoneal lavage cells and footpad (FP) histology. The FP of mice were inoculated with 1 * 10(6) fungi (viability index of 41%). At 5 and 13 months p.i., the granuloma mainly consisted of macrophages and multinucleated giant cells, but a larger number of neutrophils was observed at 5 months and lymphocytes at 13 months. The number of fungi in the FP and fungal viability were 1.8 +/- 1.1 * 10(6) fungi/ml and 38.5% at 5 months p.i. and 30.8 +/- 11.7 * 10(6) fungi/ml and 9% at 13 months (P < .05). Higher production of H2O2, O2(-), IL-10, and TNF-alpha were observed at 13 months (P < .05), but there was no significant difference in the production of NO, IL-2, IL-4, IL-12 and IFN-gamma. The results showed significant differences between early and late lesions and support the use of BALB/c mice for evaluation of the different phases of infection. PMID- 25724202 TI - Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep. AB - Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders. PMID- 25724204 TI - The inflammatory response of eosinophil-related fungal rhinosinusitis varies with inciting fungi. AB - Earlier studies demonstrated immunological response to Alternaria alternata in patients with eosinophil-related fungal rhinosinusitis (FRS). However, Aspergillus flavus rather than A. alternata is predominantly isolated from such patients in Asia. We compared immunological response to A. flavus and A. alternata in our patients with eosinophil related FRS. Total immunoglobulin E, absolute eosinophil count (AEC), cytokine response, and in vitro eosinophil degranulation in the presence of A. flavus/A. alternata were compared among patients with eosinophil-related FRS, non-eosinophilic rhinosinusitis (NECRS), and healthy individuals. Eosinophil-related FRS patients were subgrouped into: Group A - presence of mucin with fungus in tissues and positive immediate hypersensitivity; group B - presence of mucin with fungus in biopsies and no immediate hypersensitivity; and group C - presence of mucin without fungi and hypersensitivity. A. flavus was the predominant (89%) isolate. Significantly higher major basic protein (MBP) was induced by A. flavus in Group A (279.15 +/- 32.29 ng/2.5 * 10(5) cells) compared to Group B (254.9 +/- 17.14 ng), Group C (238.33 +/- 17.56 ng), NECRS (56.96 +/- 10.97 ng), and normal subjects (28.73 +/- 7.04 ng). A. alternata - eosinophil interaction failed to induce detectable MBP. AEC and serum cytokines, interleukin (IL)- 2, IL-4, IL-5, IL-10, tumor necrosis factor alpha, and interferon-gamma were significantly higher (P < 0.001) in eosinophil-related FRS compared to NECRS and control. Thus a mixed Th1 and Th2 cytokine response was observed in eosinophil-related FRS. In conclusion, immune response in eosinophil-related FRS depends on locally inciting fungi rather than A. alternata in all instances, and the categorization of this group appears to be arbitrary. PMID- 25724205 TI - Amplification of IL-21 signalling pathway through Bruton's tyrosine kinase in human B cell activation. AB - OBJECTIVE: B cells play an important role in the pathogenesis of autoimmune diseases. The role of Bruton's tyrosine kinase (Btk) in cytokine-induced human B cell differentiation and class-switch recombination remains incompletely defined. This study analysed the effect of Btk on human activated B cells. METHODS: Purified B cells from healthy subjects were stimulated with B cell receptor (BCR) and other stimuli with or without a Btk inhibitor and gene expression was measured. The B cell line BJAB was used to assess Btk-associated signalling cascades. Phosphorylated Btk (p-Btk) in peripheral blood B cells obtained from 10 healthy subjects and 41 patients with RA was measured by flow cytometry and compared with patient backgrounds. RESULTS: IL-21 signalling, in concert with BCR, CD40 and BAFF signals, led to robust expression of differentiation- and class-switch DNA recombination-related genes and IgG production in human B cells, all of which were significantly suppressed by the Btk inhibitor. Although phosphorylation of STAT1 and STAT3 was induced by co-stimulation with IL-21, BCR and CD40, STAT1 phosphorylation in the nucleus, but not in the cytoplasm, was exclusively impaired by Btk blockade. High levels of p-Btk were noted in B cells of RA patients compared with controls and they correlated significantly with titres of RF among RF-positive patients. CONCLUSION: The findings elucidate a model in which Btk not only plays a fundamental role in the regulation of BCR signalling, but may also mediate crosstalk with cytokine signalling pathways through regulation of IL-21-induced phosphorylation of STAT1 in the nuclei of human B cells. Btk appears to have pathological relevance in RA. PMID- 25724206 TI - Serum markers associated with disease activity in giant cell arteritis and polymyalgia rheumatica. AB - OBJECTIVE: To compare multiple serum markers for their ability to detect active disease in patients with GCA and in those with PMR. METHODS: Twenty-six markers related to immune cells that may be involved in GCA and PMR were determined by ELISA and multiplex assay in the serum of 24 newly diagnosed, untreated GCA/PMR patients, 14 corticosteroid (CS)-treated GCA/PMR patients in remission and 13 healthy controls. Receiver operating characteristic analysis with area under the curve and Spearman's correlation coefficients were performed. RESULTS: Serum B cell activating factor (BAFF), CXCL9 and IL-6 were increased in newly diagnosed GCA and PMR patients. Serum CCL2, CCL11, IL-10 and sIL-2R were modulated in GCA patients only and CXCL10 in PMR patients only. BAFF, CXCL9 and IL-6 accurately distinguished newly diagnosed GCA and PMR patients from healthy controls, as shown by area under the curve > 0.80. Upon CS-induced remission, serum BAFF and IL-6 decreased significantly in both GCA and PMR patients, whereas CXCL9 remained high. Serum BAFF and IL-6 correlated strongly with ESR and CRP in GCA and PMR patients. CONCLUSION: Among the serum markers tested, BAFF and IL-6 showed the strongest association with disease activity in both GCA and PMR patients. The diagnostic value of these markers should be evaluated in larger, longitudinal studies with GCA and PMR patients, and in patients with infections or other inflammatory conditions. PMID- 25724207 TI - DNA methylation and chromatin organization in insects: insights from the Ant Camponotus floridanus. AB - Epigenetic information regulates gene function and has important effects on development in eukaryotic organisms. DNA methylation, one such form of epigenetic information, has been implicated in the regulation of gene function in diverse metazoan taxa. In insects, DNA methylation has been shown to play a role in the regulation of gene expression and splicing. However, the functional basis for this role remains relatively poorly understood, and other epigenetic systems likely interact with DNA methylation to affect gene expression. We investigated associations between DNA methylation and histone modifications in the genome of the ant Camponotus floridanus in order to provide insight into how different epigenetic systems interact to affect gene function. We found that many histone modifications are strongly predictive of DNA methylation levels in genes, and that these epigenetic signals are more predictive of gene expression when considered together than when considered independently. We also found that peaks of DNA methylation are associated with the spatial organization of chromatin within active genes. Finally, we compared patterns of differential histone modification enrichment to patterns of differential DNA methylation to reveal that several histone modifications significantly covary with DNA methylation between C. floridanus phenotypes. As the first genomic comparison of DNA methylation to histone modifications within a single insect taxon, our investigation provides new insight into the regulatory significance of DNA methylation. PMID- 25724208 TI - Evolution of an epigenetic gene ensemble within the genus Anopheles. AB - Epigenetic control of gene expression has important implications for the regulation of developmental processes, for mediating homeostasis and responses to the external environment, and for transgenerational inheritance of gene expression patterns. Genes that mediate epigenetic control have been well characterized in Drosophila melanogaster, and we have identified and analyzed an orthologous gene ensemble in Anopheles gambiae that comprises 169 orthologs related to a 215-member epigenetic gene ensemble in D. melanogaster. We find that this ensemble is highly conserved among anopheline mosquitoes, as we identify only seven gene family expansion/contraction events within the ensemble among 12 mosquito species we have studied within the genus Anopheles. Comparative analyses of the epigenetic gene expression across the genera Drosophila and Anopheles reveal distinct tissue-associated expression patterns in the two genera, but similar temporal expression patterns. The A. gambiae complex and D. melanogaster subgroup epigenetic gene ensembles exhibit similar evolutionary rates, as assessed by their respective dN/dS values. These differences in tissue-associated expression patterns, in contrast to similarities in evolutionary rates and temporal expression patterns, may imply that some members of the epigenetic gene ensemble have been redeployed within one or both genera, in comparison to the most recent common ancestor of these two clades. Members of this epigenetic gene ensemble may constitute another set of potential targets for vector control and enable further reductions in the burden of human malaria, by analogy to recent success in development of small molecule antagonists for mammalian epigenetic machinery. PMID- 25724209 TI - Ancient traces of tailless retropseudogenes in therian genomes. AB - Transposable elements, once described by Barbara McClintock as controlling genetic units, not only occupy the largest part of our genome but are also a prominent moving force of genomic plasticity and innovation. They usually replicate and reintegrate into genomes silently, sometimes causing malfunctions or misregulations, but occasionally millions of years later, a few may evolve into new functional units. Retrotransposons make their way into the genome following reverse transcription of RNA molecules and chromosomal insertion. In therian mammals, long interspersed elements 1 (LINE1s) self-propagate but also coretropose many RNAs, including mRNAs and small RNAs that usually exhibit an oligo(A) tail. The revitalization of specific LINE1 elements in the mammalian lineage about 150 Ma parallels the rise of many other nonautonomous mobilized genomic elements. We previously identified and described hundreds of tRNA-derived retropseudogenes missing characteristic oligo(A) tails consequently termed tailless retropseudogenes. Additional analyses now revealed hundreds of thousands of tailless retropseudogenes derived from nearly all types of RNAs. We extracted 2,402 perfect tailless sequences (with discernible flanking target site duplications) originating from tRNAs, spliceosomal RNAs, 5S rRNAs, 7SK RNAs, mRNAs, and others. Interestingly, all are truncated at one or more defined positions that coincide with internal single-stranded regions. 5S ribosomal and U2 spliceosomal RNAs were analyzed in the context of mammalian phylogeny to discern the origin of the therian LINE1 retropositional system that evolved in our 150-Myr-old ancestor. PMID- 25724210 TI - Reduction in Rotavirus Disease and Sustained Predominance of G2P[4] Rotavirus Strain following Introduction of Rotavirus Vaccine in Recife, Brazil. AB - Rotavirus vaccination was introduced in Brazil in March 2006. We describe the distribution of rotavirus genotypes in children with acute gastroenteritis in a hospital in Recife, Brazil, during pre- and post-vaccination periods. There was a 43.8% reduction in the proportion of diarrhea episodes due to rotavirus. Nevertheless, we observed a sustained predominance of G2P[4] as the main genotype identified in the post-vaccination period. PMID- 25724211 TI - Patterns of distribution of childhood cancer in Africa. AB - BACKGROUND: Very little is known about the regional variation in the incidence of childhood malignancies in Africa. The aim of the study was to perform a comprehensive analysis of the distribution of childhood cancer in Sub-Saharan Africa and compare the results to the Globocan estimations. METHODS: A letter of invitation to participate was sent to all registry centers in Africa registered with the International Agency for Research on Cancer and to all African centers registered with AORTIC and SIOP Africa, requesting similar information as in CanReg 4. Childhood cancers were defined as those occurring below the age of 15 years. The data requested was from 2000 to 2010. The malignancies were classified and coded according to the International Classification of Childhood Cancer, 2004 system. Data obtained were analyzed using EpiInfo and Statistica 10 software. Information regarding the estimation of the numbers and incidence of the top 5 childhood cancers in specific countries was obtained from Globocan Web site. RESULTS: There were 21 centers included in the study from 18 Sub-Saharan African countries. The data analyzed differed from center to center and included cases from 1985 to 2011. The proportion of childhood cancer out of all cancers ranged between 1.4% in Ghana to 10.0% in Rwanda. In Southern Africa, Kaposi sarcoma was the most common malignancy in children in Mozambique (15.8% of all cases) and the second most common in Zambia (15.6%) and in Malawi (12.4%). In Eastern Africa, Uganda recorded Kaposi sarcoma as the most common tumor in children (22.0%), while two Kenyan centers reported mainly Burkitt lymphoma (25.1 and 37.1%, respectively). In Central Africa, Congo classified retinoblastoma as the most common childhood cancer with an incidence of 20.1%. In Western Africa, Non Hodgkin lymphoma was the most common in Ghana (53.6%), in Ivory Coast (73.6%) and in Mali (32.7%). Nephroblastoma remains the most common solid tumor in Africa exceeding 10% of total pediatric cancers in many countries (Rwanda 21.3%, Senegal 22%, Ivory Coast 14.5%, Mali 17.6%, Congo 15.5%, etc). CONCLUSION: Unlike developed countries, lymphomas, nephroblastoma, Kaposi sarcoma and retinoblastoma were the most common pediatric tumors in Africa. Globocan estimations despite bringing significant contribution to the registration map cannot replace the data from local hospital and population-based registries. All efforts should be directed in developing functional and reliable childhood cancer registries across the African continent. PMID- 25724212 TI - Undiagnosed congenital hypothyroidism in a newborn treated with dopamine infusion. AB - Medications administered during the neonatal period may mask the diagnosis of congenital hypothyroidism. Herein, we report a case of undiagnosed congenital hypothyroidism while the infant was on treatment with dopamine. Given the inhibitory effect of dopamine on thyroid-stimulating hormone, a high index of suspicion for potential congenital hypothyroidism is needed in such neonates. PMID- 25724213 TI - Probiotics Reduce Necrotizing Enterocolitis Severity in HIV-exposed Premature Infants. AB - OBJECTIVE: To assess the effect of probiotics on the incidence of necrotizing enterocolitis (NEC) in premature infants born to human immunodeficiency virus (HIV)-positive and HIV-negative women. PATIENTS AND METHODS: HIV-exposed and HIV unexposed premature infants were randomized to either the probiotic or the placebo group. The probiotic consisted of 1 * 10(9) colony-forming units, Lactobacillus rhamnosus GG and Bifidobacterium infantis per day. RESULTS: In total, 74 HIV-exposed and 110 HIV-unexposed infants were enrolled and randomized. The incidence of death [4 (5.4%) vs. 7 (6%); p = 0.79] and NEC [4 (5%) vs. 5 (5%); p = 0.76] did not differ significantly between the HIV-exposed and HIV unexposed groups. A significant difference was found for total NEC incidence between the study and control groups [3 (3%) vs. 6 (6%); p = 0.029]. The incidence of NEC in the HIV-exposed group differed significantly [Bells I 2 (5%) vs. Bells III 2 (5%); p = 0.045). CONCLUSION: Probiotic supplementation reduced the incidence of NEC in the premature very low birth weight infants; however, results failed to show a lower incidence of NEC in HIV-exposed premature infants. A reduction in the severity of disease was found in the HIV-exposed study group. PMID- 25724214 TI - Characteristics and prognosis of patients with thyroglobulin-positive and radioactive iodine whole-body scan-negative differentiated thyroid carcinoma. AB - OBJECTIVE: The prognosis of differentiated thyroid carcinoma is generally favorable. However, some patients have negative radioiodine whole-body scans and detectable serum thyroglobulin with biochemical radioiodine-refractory carcinoma and are candidates for treatment with a multikinase inhibitor, such as sorafenib. The purpose of this study is to investigate the characteristics and prognosis of differentiated thyroid carcinoma patients who are thyroglobulin positive and scan negative. METHODS: We retrospectively classified 153 patients treated for 15 years by serum thyroglobulin level and radioiodine scan results and examined the relationship between clinical characteristics and prognosis. RESULTS: Overall, 27% of the patients were classified as thyroglobulin positive/scan negative (positive/negative) while 61% were thyroglobulin negative/scan negative (double negative). Compared with double-negative patients, positive/negative patients were significantly older, predominantly male, had a higher pT and pN, stage, and had higher pre-operative thyroglobulin values. Positive/negative patients showed worse prognosis in terms of overall survival, disease-specific survival and disease-free survival than double-negative patients (10-year overall survival, 85 vs. 93%, P = 0.001; 10-year disease-specific survival, 94 vs. 100%, P = 0.03, 10 year disease-free survival, 77 vs. 93%, P < 0.001). Multivariate analysis revealed that positive/negative status was the only factor associated with disease-free survival, including age and TNM stage (hazard ratio: 6.37, 95% confidence interval: 1.22-33.3). However, the median duration of disease-free period for positive/negative patients was 14.2 years. CONCLUSIONS: Few patients among thyroglobulin-positive/scan-negative patients are candidates for sorafenib, despite the significant survival differences from double-negative patients. PMID- 25724215 TI - Multicenter observational cohort study of post-operative treatment for completely resected non-small-cell lung cancer of pathological Stage I (T1 >2 cm and T2 in TNM classification version 6). AB - Post-operative adjuvant chemotherapy has been considered an effective strategy to reduce cancer recurrence and improve survival for resected non-small-cell lung cancer. The Japan Clinical Oncology Group has completed patient accrual for a randomized Phase III study (JCOG0707), which compares the survival benefit of UFT and S-1 for completely resected pathological Stage I (T1 >2 cm and T2 in TNM classification version 6) non-small-cell lung cancer. However, there is a growing concern that those who participated in clinical trials are highly selected patients and do not represent the 'real-world' population. This multicenter observational cohort study aims to analyze the backgrounds, pattern of care and outcomes of the patients who were excluded from the JCOG0707 study during the accrual period. The results of this cohort study will be useful for external validity of the results of clinical trial such as JCOG0707. PMID- 25724216 TI - Risk of ischemic stroke after androgen deprivation therapy for prostate cancer in the Chinese population living in Hong Kong. AB - OBJECTIVE: Previous reports on the risk of stroke after androgen deprivation therapy for prostate cancer were largely based on Caucasians. We investigated the risk of ischemic stroke after androgen deprivation therapy for prostate cancer in the Chinese population. METHODS: All Chinese prostate cancer patients who were treated primarily with radical prostatectomy or radiotherapy, with (androgen deprivation therapy group) or without (non-androgen deprivation therapy group) further androgen deprivation therapy, at our hospital from year 2000-09 were reviewed. Potential risk factors of ischemic stroke including age, baseline prostate-specific antigen, Gleason score, clinical T stage, hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, history of stroke, use of androgen deprivation therapy and duration of androgen deprivation therapy were reviewed. The risk of ischemic stroke after androgen deprivation therapy was analyzed with Kaplan-Meier and multivariate Cox regression analyses. RESULTS: A total of 452 patients were included, consisting of 200 patients in the non androgen deprivation therapy group and 252 patients in the androgen deprivation therapy group. The androgen deprivation therapy group appeared to have increased risk of ischemic stroke when compared with the non-androgen deprivation therapy group (P = 0.063) upon Kaplan-Meier analysis. Upon multivariate Cox regression analyses, older age (hazard ratio 1.13, 95% confidence interval 1.04-1.22, P = 0.003), hyperlipidemia (hazard ratio 4.61, 95% confidence interval 2.01-10.54, P < 0.001) and the use of androgen deprivation therapy (hazard ratio 3.32, 95% confidence interval 1.14-9.67, P = 0.028) were associated with increased risk of ischemic stroke. CONCLUSIONS: There was increased risk of ischemic stroke after androgen deprivation therapy for prostate cancer in the Chinese population. The risk of ischemic stroke should be considered while deciding on androgen deprivation therapy, especially in older patients with known history of hyperlipidemia. PMID- 25724217 TI - Differences in the responses to pazopanib and the prognoses of soft tissue sarcomas by their histological eligibility for the PALETTE study. AB - OBJECTIVE: In Japan, pazopanib has been made available to soft tissue sarcoma patients, also to patients histologically diagnosed as ineligible for the international Phase 3 study (PALETTE). However, clinical evidence for the use of pazopanib in PALETTE-ineligible patients is currently insufficient. METHODS: We retrospectively reviewed medical records of soft tissue sarcoma patients treated with pazopanib at our institute. By pathological review, the patients' eligibility for the PALETTE study was evaluated and the differences in their responses to pazopanib and incidences of adverse events were investigated. RESULTS: From November 2012 to August 2014, a total of 47 patients received pazopanib, 38 (81%) of whom were histologically eligible for the PALETTE study, and 9 of whom (19%) were not. The median follow-up time was 7.5 months (range 1.4 20.3 months). An objective response was observed in both groups, but the patients' survival tended to be longer in the PALETTE-eligible patients; median progression-free survival was 4.5 months vs. 2.9 months (P = 0.15) and overall survival was 10.7 months vs. 7.8 months (P = 0.55), though these differences were not statistically significant. There were no significant differences in the incidence of adverse events by PALETTE eligibility, but dose skipping or dose reduction was more likely to be observed in PALETTE-ineligible patients. CONCLUSION: Pazopanib is tolerable to soft tissue sarcoma patients ineligible for the PALETTE study and some of them respond to pazopanib, but the prognoses of patients ineligible for the PALETTE study might be worse than those of PALETTE eligible patients. The indication of pazopanib for soft tissue sarcoma patients with PALETTE-ineligible histologies should be decided carefully. PMID- 25724218 TI - Hepatitis B virus infection in children. AB - For two decades, hepatitis B vaccine has been integrated into national routine childhood vaccination programs in almost all countries. The prevalence of HBsAg has decreased in children worldwide. However, there are children who miss the benefit of hepatitis B vaccine in some regions and countries. Long-term follow-up studies have revealed the clinical outcomes of chronic hepatitis B virus infection in children. A small percentage of chronically infected children develop liver cirrhosis and hepatocellular carcinoma. However, it is controversial who should be treated and when antiviral treatment should be initiated in children. Compared with adult studies, the data are insufficient to evaluate the pathogenesis of hepatitis B infection and the efficacy of antiviral treatment in childhood. New antiviral drugs have been approved for children and adults. Also, oral antiviral drugs are administered to pregnant women to reduce the hepatitis B virus mother-to-child transmission rate. PMID- 25724220 TI - Analysis of protein coatings on gold nanoparticles by XPS and liquid-based particle sizing techniques. AB - The precise use of nanoparticles in technological applications requires control over their surface properties. This implies the ability to quantitatively describe, for example, molecular coatings in terms of their thickness, areal mass, or number of molecules. Here, the authors describe two different approaches to the measurement of these parameters by using gold nanoparticles ranging in diameter from 10 to 80 nm and coated with three different proteins: immunoglobulin G, bovine serum albumin, and a peptide. One approach utilizes ultraviolet-visible spectroscopy, dynamic light scattering, and differential centrifugal sedimentation to measure the protein shell refractive indices and thicknesses, from which the number of molecules in the protein shell can be derived. The other approach employs x-ray photoelectron spectroscopy to measure the thickness of the dry molecular coatings and also to derive the number of molecules in the protein shell. The authors demonstrate that the two approaches, although very different, produce consistent measurement results. This finding is important to extend the quantitative analysis of nanoparticle molecular coatings to a wide range of materials. PMID- 25724221 TI - Angiogenic tube formation of bovine aortic endothelial cells grown on patterns formed by H2/He plasma treatment of the plasma polymerized hexamethyldisiloxane film. AB - Angiogenesis, the process to generate new vessels, is necessary for normal development in children as well as the wound healing and the tumor growth in adults. Therefore, it is physiologically and/or pathophysiologically significant to monitor angiogenesis. However, classical in vitro methods to evaluate angiogenesis take a long time and are expensive. Here, the authors developed a novel method to analyze the angiogenesis in a simple and economical way, using patterned films. In this study, the authors fabricated a plasma polymerized hexamethyldisiloxane (PPHMDSO) thin film deposited by capacitively coupled plasma chemical vapor deposition system with various plasma powers. The patterned PPHMDSO film was plasma treated by 10:90 H2/He mixture gas through a metal shadow mask. The films were characterized by water contact angle, atomic force microscopy, x-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy analyses. Our results show that the PPHMDSO film suppresses the cell adhesion, whereas surface modified PPHMDSO film enhances the cell adhesion and proliferation. From cell culture experiments, the authors found that the patterned film with 300 MUm line interval was most efficient to evaluate the tube formation, a sapient angiogenic indicator. This patterned film will provide an effective and promising method for evaluating angiogenesis. PMID- 25724219 TI - HIV-1 gp120 as a therapeutic target: navigating a moving labyrinth. AB - INTRODUCTION: The HIV-1 gp120 envelope (Env) glycoprotein mediates attachment of virus to human target cells that display requisite receptors, CD4 and co receptor, generally CCR5. Despite high-affinity interactions with host receptors and proof-of-principle by the drug maraviroc that interference with CCR5 provides therapeutic benefit, no licensed drug currently targets gp120. AREAS COVERED: An overview of the role of gp120 in HIV-1 entry and of sites of potential gp120 vulnerability to therapeutic inhibition is presented. Viral defenses that protect these sites and turn gp120 into a moving labyrinth are discussed together with strategies for circumventing these defenses to allow therapeutic targeting of gp120 sites of vulnerability. EXPERT OPINION: The gp120 envelope glycoprotein interacts with host proteins through multiple interfaces and has conserved structural features at these interaction sites. In spite of this, targeting gp120 for therapeutic purposes is challenging. Env mechanisms that have evolved to evade the humoral immune response also shield it from potential therapeutics. Nevertheless, substantial progress has been made in understanding HIV-1 gp120 structure and its interactions with host receptors, and in developing therapeutic leads that potently neutralize diverse HIV-1 strains. Synergies between advances in understanding, needs for therapeutics against novel viral targets and characteristics of breadth and potency for a number of gp120-targetting lead molecules bodes well for gp120 as a HIV-1 therapeutic target. PMID- 25724222 TI - [Mexican guidelines on the diagnosis and treatment of urticaria]. AB - BACKGROUND: Urticaria is a disease that a fifth of the population shallsuffer once in a lifetime. Recent clinical guidelines have proposed some fundamental changes in the diagnosis and treatment of urticaria, making the development of a national, multidisciplinary guideline, with wide acceptability among different professional groups -both specialists and primary health care workers-, necessary in Mexico. MATERIAL AND METHOD: Internationally recognized tools for guidelinedevelopment were used. An interdisciplinary group of clinical experts (some of them knowledgeable in methodology of guideline development) determined the objectives and scope of the Evidence Based Clinical Practice Guideline with SCOPE. It was decided to adapt and transculturize international guidelines on the diagnosis and treatment of urticaria. With AGREE-II three high-quality guidelines (Zuberbier 2014, Sanchez-Borges 2012, Powell 2007) were selected to function as basic guidelines (BG). A set of Clinical Questions was formulated that lead to recommendations/suggestions, based on these BG, taking into account the cultural and economic background of Mexico, according to GRADE recommendation development. RESULTS: By a formal process of discussion and voting during several working sessions, experts and first level healthcare physicians determined the wording of the final guideline, taking particularly care of developing a document, adjusted to the reality, values and preferences of the Mexican patients. The use of oral second generation, non-sedating antihistamines as first line treatment is emphasized. CONCLUSION: This document is an Evidence Based Clinical Practice Guideline for the diagnosis and treatment of acute and chronic urticaria, based on three, high quality, international guidelines. It was developed by a multidisciplinary group. Tables and algorithms make the guideline user-friendly for both, first line health care physicians and specialists. PMID- 25724223 TI - Thoracic central venous evaluation: comparison of first-pass direct versus delayed-phase indirect multidetector CT venography. AB - PURPOSE: The purpose was to compare first-pass and delayed-phase thoracic computed tomography (CT) venography for the evaluation of suspected central thoracic venous pathology. MATERIAL AND METHODS: CT images and medical records of all patients who underwent thoracic CT venography over a 5-year period were retrospectively reviewed. Both first-pass (18s) and delayed-phase (60s) venous images were obtained in all patients. The images were reviewed in random order by three readers using a semiquantitative visual grading scheme for image quality, including artifacts and the uniformity of venous enhancement. In addition, enhancement was quantitatively evaluated. The presence and type of venous pathology, and overall diagnostic confidence were recorded and compared. Reference verification was performed when available. RESULTS: Eighteen patients formed the study group, mean age 49.5years and 28% male. Dual-arm injection was successful in 72% of exams. All readers reported more streak artifacts on first pass imaging than delayed imaging (72%-94% vs. 27%-44%, respectively; P<.05). First-pass imaging had significantly higher measured enhancement across all central venous segments than delayed imaging (mean HU range 212-906 HU vs. 173 414 HU; P<.05) but also had significantly more heterogeneous enhancement (mean S.D. range 75-1058 HU vs. 67-378 HU; P<.05). For overall diagnosis, reader agreement, accuracy, and confidence levels were higher for delayed-phase images (P<.05). CONCLUSION: Indirect thoracic CT venography using delayed-phase imaging alone may be sufficient for evaluating clinically suspected central venous abnormality. PMID- 25724224 TI - Low-intensity late gadolinium enhancement predominates in hypertrophic cardiomyopathy. AB - AIM: Assess the extent of low- versus high-intensity late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM). METHODS: Low- versus high-intensity LGE indexed volumes in 19 HCM patients were compared to 23 myocardial infarction (MI) patients. RESULTS: Total, low-, and high-intensity LGE volumes in HCM vs. MI were 7.6ml/m(2), 4.7, and 2.4 vs. 11.2, 2.5, and 7.1, respectively. Total LGE volume did not differ (P=.13), though low- and high-intensity did (P=.05, .004). 67% versus 26% of all LGE was low-intensity in HCM versus MI (P<.001). CONCLUSIONS: LGE in HCM is predominantly low-intensity, so a low threshold may be the most appropriate. PMID- 25724225 TI - Y90 radioembolization of colorectal cancer liver metastases: response assessment by contrast-enhanced computed tomography with or without PET-CT guidance. AB - PURPOSE: To compare various computed tomography (CT) parameters to the positron emission tomography with computed tomography (PET-CT) response, with or without PET guidance for the response assessment of colorectal cancer (CRC) metastases treated by Y90 radioembolization. METHODS: Thirty-six CRC metastases were retrospectively evaluated on 18F-Fluoro-Deoxy-Glucose PET-CT and contrast enhanced computed tomography (CECT) performed at baseline and 2-3 months after Y90 radioembolization. RESULTS: Median SUVmax values decreased from 11.39 to 6.71 after radioembolization (P<.001), and 23/36 (64%) metastases were categorized metabolic responses according to European Organisation for Research and Treatment of Cancer criteria. Only a decrease of the mean attenuation in the structural (P<.001) and metabolic active volume (P<.001) was observed. The change in these criteria was correlated with the change of SUVmax. PMID- 25724226 TI - End-of-life palliative chemotherapy: where do we stand? AB - BACKGROUND: This study evaluates the use of palliative chemotherapy (PCT) and possible associated factors at the end of life. METHOD: The study includes all advanced non hematological cancer patients who died in the King Abdullah Medical City during the period from January 2011 to April 2014. Demographic and disease features were registered. RESULTS: 420 patients were included in the study, median age 62 years (range 17-108); 52% female and 48% male. 87.4% of patients were Saudis and 12.6% non Saudis. 124 (29.5%) patients received PCT at the last month before death (LM-PCT): 21.8%, 22.6% and 55.6% within one, two and four weeks of death, respectively. Place of death (critical care vs. regular ward) and mode of admission (ER vs. OPD vs. Transferred) had a strong association with LM PCT (p<0.0001, phi=0.35) and (p<0.0001, V=0.43), respectively. There was a gradual increase in the number of patients receiving LM-PCT from January 2011 to April 2014; 15.3%, 28.2%, 37.1% and 19.4%, respectively. CONCLUSION: In our center; at the end of life, there is a gradual increase in the number of patients receiving chemotherapy which significantly increased cancer patients' odds without clear predictive factors associated with its use, which calls into question the benefits of PCT in terminally ill cancer patients. PMID- 25724227 TI - A report of radioactivity measurements of freshwater fish samples from the National Capital Region of Canada. PMID- 25724228 TI - When a serum test overrides the clinical assessment. PMID- 25724229 TI - Varicella-zoster virus claims yet another painful scalp--Giant cell arteritis. PMID- 25724230 TI - Comment: New insights on cognition after deep brain stimulation in Parkinson disease. PMID- 25724231 TI - Yield of spinal imaging in nonaneurysmal, nonperimesencephalic subarachnoid hemorrhage. AB - OBJECTIVE: We studied the yield of MRI of the spinal neuraxis in patients with nonperimesencephalic subarachnoid hemorrhage (NPSAH). METHODS: In a prospective, multicenter study, we performed T1-weighted and T2-weighted MRI of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging. RESULTS: A spinal origin of the hemorrhage was found in 3 of 75 patients (4%; 95% confidence interval 0-8.4). The lesions were 1 lumbar ependymoma and 2 cervical cavernous malformations. All 3 patients presented without focal neurologic deficits and 2 had a CT-negative subarachnoid hemorrhage but positive lumbar puncture. Patients with a spinal origin were younger than patients without a spinal origin (38 vs 56 years; p < 0.05), which was the only significant difference between groups. CONCLUSIONS: The yield and clinical relevance of MRI of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MRI of the spinal axis in this patient population, but it might be justified in a subgroup of patients. PMID- 25724232 TI - A Canada-wide survey of chronic respiratory disease and spinal cord injury. AB - OBJECTIVE: The objective of this study was to evaluate the association between chronic respiratory diseases (asthma and chronic obstructive pulmonary disease) and spinal cord injury (SCI) in a large representative sample. METHODS: Data were compiled from more than 60,000 individuals from the 2010 cycle of the cross sectional Canadian Community Health Survey (CCHS). Multivariable logistic regression analysis was conducted to examine this relationship, adjusting for confounders, and using probability weighting to account for the CCHS sampling method. RESULTS: After adjusting for age, sex, and smoking status, SCI was associated with a significant increased odds of asthma (adjusted odds ratio = 1.59 [95% confidence interval 1.11, 2.26]; p < 0.05) and chronic obstructive pulmonary disease (1.87 [1.20, 2.91]; p < 0.05). CONCLUSIONS: These heightened odds highlight the exigent need for targeted interventions and prevention strategies for respiratory health among individuals with SCI. PMID- 25724233 TI - Neuropsychological outcome after deep brain stimulation for Parkinson disease. AB - OBJECTIVE: To assess the neuropsychological outcome 12 months after bilateral deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN) for advanced Parkinson disease. METHODS: We randomly assigned patients to receive either GPi DBS or STN DBS. Standardized neuropsychological tests were performed at baseline and after 12 months. Patients and study assessors were masked to treatment allocation. RESULTS: Univariate analysis of change scores indicated group differences on Stroop word reading and Stroop color naming (confidence interval [CI] 1.9-10.0 and 2.1-8.8), on Trail Making Test B (CI 0.5-10.3), and on Wechsler Adult Intelligence Scale similarities (CI -0.01 to 1.5), with STN DBS showing greater negative change than GPi DBS. No differences were found between GPi DBS and STN DBS on the other neuropsychological tests. Older age and better semantic fluency at baseline predicted cognitive decline after DBS. CONCLUSIONS: We found no clinically significant differences in neuropsychological outcome between GPi DBS and STN DBS. No satisfactory explanation is available for the predictive value of baseline semantic fluency for cognitive decline. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that there is no large difference in neuropsychological outcome between GPi DBS and STN DBS after 12 months. The study lacks the precision to exclude a moderate difference in outcomes. PMID- 25724234 TI - Distinct roles of the intraparietal sulcus and temporoparietal junction in attentional capture from distractor features: An individual differences approach. AB - Setting attention for an elementary visual feature, such as color or motion, results in greater spatial attentional "capture" from items with target compared with distractor features. Thus, capture is contingent on feature-based control settings. Neuroimaging studies suggest that this contingent attentional capture involves interactions between dorsal and ventral frontoparietal networks. To examine the distinct causal influences of these networks on contingent capture, we applied continuous theta-burst stimulation (cTBS) to alter neural excitability within the dorsal intraparietal sulcus (IPS), the ventral temporoparietal junction (TPJ) and a control site, visual area MT. Participants undertook an attentional capture task before and after stimulation, in which they made speeded responses to color-defined targets that were preceded by spatial cues in the target or distractor color. Cues appeared either at the target location (valid) or at a non-target location (invalid). Reaction times were slower for targets preceded by invalid compared with valid cues, demonstrating spatial attentional capture. Cues with the target color captured attention to a greater extent than those with the distractor color, consistent with contingent capture. Effects of cTBS were not evident at the group level, but emerged instead from analyses of individual differences. Target capture magnitude was positively correlated pre- and post-stimulation for all three cortical sites, suggesting that cTBS did not influence target capture. Conversely, distractor capture was positively correlated pre- and post-stimulation of MT, but uncorrelated for IPS and TPJ, suggesting that stimulation of IPS and TPJ selectively disrupted distractor capture. Additionally, the effects of IPS stimulation were predicted by pre stimulation attentional capture, whereas the effects of TPJ stimulation were predicted by pre-stimulation distractor suppression. The results are consistent with the existence of distinct neural circuits underlying target and distractor capture, as well as distinct roles for the IPS and TPJ. PMID- 25724235 TI - In vitro studies in VCP-associated multisystem proteinopathy suggest altered mitochondrial bioenergetics. AB - Mitochondrial dysfunction has recently been implicated as an underlying factor to several common neurodegenerative diseases, including Parkinson's disease, Alzheimer's and amyotrophic lateral sclerosis (ALS). Valosin containing protein (VCP)-associated multisystem proteinopathy is a new hereditary disorder associated with inclusion body myopathy, Paget disease of bone (PDB), frontotemporal dementia (FTD) and ALS. VCP has been implicated in several transduction pathways including autophagy, apoptosis and the PINK1/Parkin cascade of mitophagy. In this report, we characterized VCP patient and mouse fibroblasts/myoblasts to examine their mitochondrial dynamics and bioenergetics. Using the Seahorse XF-24 technology, we discovered decreased spare respiratory capacity (measurement of extra ATP that can be produced by oxidative phosphorylation in stressful conditions) and increased ECAR levels (measurement of glycolysis), and proton leak in VCP human fibroblasts compared with age- and sex-matched unaffected first degree relatives. We found decreased levels of ATP and membrane potential, but higher mitochondrial enzyme complexes II+III and complex IV activities in the patient VCP myoblasts when compared to the values of the control cell lines. These results suggest that mutations in VCP affect the mitochondria's ability to produce ATP, thereby resulting in a compensatory increase in the cells' mitochondrial complex activity levels. Thus, this novel in vitro model may be useful in understanding the pathophysiology and discovering new drug targets of mitochondrial dynamics and physiology to modify the clinical phenotype in VCP and related multisystem proteinopathies (MSP). PMID- 25724236 TI - Involvement of the paraventricular nucleus in the occurrence of arrhythmias in middle cerebral artery occlusion rats. AB - BACKGROUND: Ischemic stroke complicating with arrhythmia is one of the main causes of sudden death. To investigate the association between ischemic stroke induced arrhythmia and the activity of paraventricular nucleus (PVN), we used Fos protein as an objective indicator to illustrate the functional state of PVN neurons in middle cerebral artery occlusion (MCAO) rats, in single intracerebroventricular injection of l-glutamate rats and in application of MK 801 before l-glutamate injection and MCAO rats. METHODS: The standard limb II electrocardiography was continuously recorded by a biological signal collecting and processing system. The experimental cerebral ischemic animal model was established by occluding the right middle cerebral artery. The Fos protein expression was detected by immunohistochemistry and Western blot. RESULTS: The incidence of arrhythmia was significantly higher than that of controls (75.89% versus 0%), and Fos protein expression in the PVN also increased significantly in MCAO rats; both of them could be blocked by prior application of MK-801. Intracerebroventricular injection of l-glutamate induced changes in Fos protein expression and arrhythmia similar to that in the stroke, which could also be blocked by prior application of MK-801. CONCLUSIONS: It was concluded that activation of the PVN in MCAO rats is likely mediated by glutamate via activation of N-methyl-D-aspartic acid (NMDA) receptors, which causes arrhythmias. PMID- 25724237 TI - Cotard and Capgras syndrome after ischemic stroke. AB - Capgras and Cotard are delusional misidentification syndromes characterized by delusions about oneself, others, places, and objects. To date, there are few cases of comorbidity of both syndromes. We describe a case of aphasic stroke patient affected by cerebral ischemia localized in right temporoparietal region. The patient showed a typical clinical picture of delusional disorder attributable, through psychological assessment, to comorbidity of both Capgras and Cotard syndromes. PMID- 25724238 TI - Ischemic stroke with essential thrombocythemia: a case series. AB - BACKGROUND: Essential thrombocythemia (ET) is considered a rare cause of stroke partly because it is not detected if the platelet count is not elevated. However, early detection of ET is important because thrombosis can recur frequently, unless adequately treated. METHODS: We retrospectively collected data from 10 stroke cases with ET. Clinical characteristics, location of stroke, laboratory data (platelet and leukocyte count, hemoglobin, and JAK2 V617F mutation), and treatment were reviewed. RESULTS: The population consisted of 7 women and 3 men aged 18-83 years. Most patients had atherosclerotic risk factors. Half of the patients had a history of ischemic stroke. In 8 patients, ischemic stroke was the first manifestation of ET. Of 13 acute cerebrovascular events, 4 were transient ischemic attacks and 9 were cerebral infarctions. Three patients presented with watershed-type infarcts without large artery stenosis. Two patients had atherosclerotic stenosis of the large artery and experienced atherothrombotic infarction. The mean platelet count was 966 +/- 383 * 10(9)/L. JAK2 V617F mutation was found in 5 of 7 patients. Despite treatment with combined antiplatelet and cytoreductive therapy in all patients, 3 experienced recurrent ischemic stroke. CONCLUSIONS: These findings suggest that ET is an adjunctive risk factor for stroke and the patients with ET are subject to watershed-type infarcts even in the absence of large artery stenosis. Early diagnosis of ET and strict management of vascular risk factors may help prevent additional cerebrovascular events. PMID- 25724240 TI - Re: Cai et al, case misclassification in studies of spinal manipulation and arterial dissection, J Stroke Cerebrovascular Dis 2014. PMID- 25724239 TI - Sequence variants on chromosome 9p21 are associated with ischemic stroke and the lipids level in Chinese Han population. AB - BACKGROUND: Several studies have demonstrated that variants on chromosome 9p21 confer susceptibility to ischemic stroke (IS) disease. But, the results of variants' roles in Chinese IS population are blank or inconsistent. METHODS: We performed a case-control analysis in 116 patients with IS and 118 non-IS controls of Han background to determine whether 4 single nucleotide polymorphisms were associated with IS. DNA was extracted from saliva using a magnetic nanoparticles based method. RESULTS: After we adjusted for clinical parameters, we found that the rs10757278-GG genotype conveyed 1.88-fold (95% confidence interval [CI], 1.1 3.1; P = .015), the rs1537378-C allele conveyed 2.0-fold (95% CI, 1.2-3.5; P = .008), and the rs1333047-TT genotype conveyed 1.64-fold (95% CI, 1.02-2.6; P = .041) increased risk of IS, respectively. In addition, there is a significant difference of the lipids level between GG genotype compared with that of AA genotype in rs10757278 (P < .05). CONCLUSIONS: This study is the first one to demonstrate that the rs10757278-GG genotype, the rs1537378-C allele, and rs1333047-TT genotype are associated with IS in Chinese Han populations. More importantly, the variant of rs10757278 may have different degrees of influence on lipids level. PMID- 25724241 TI - Outcome assessment of hemiparesis due to intracerebral hemorrhage using diffusion tensor fractional anisotropy. AB - BACKGROUND: This study aimed to evaluate the prognostic efficacy of magnetic resonance diffusion tensor fractional anisotropy (FA) for patients with hemiparesis due to intracerebral hemorrhage. METHODS: Diffusion tensor FA brain images were acquired 14-21 days after putaminal and/or thalamic hemorrhage. The ratio of FA values within the cerebral peduncles of the affected and unaffected hemispheres (rFA) was calculated for each patient (n = 40) and assessed for correlation with Brunnstrom stage (BRS, 1-6), motor component of the functional independence measure (FIM-motor, 13-91), and the total length of stay (LOS) until discharge from rehabilitation (P < .05). Ordinal logistic regression analyses were conducted to determine the relationships between rFA and specific outcomes as measured by BRS range (poor, BRS 1 or 2; moderate, BRS 3 or 4; and good, BRS 5 or 6; P < .05). RESULTS: The rFA values were .571-1.043 (median, .856) and BRS scores were 1-6 (median, 4) for shoulder/elbow/forearm, 1-6 (median, 4) for hand, and 2-6 (median, 4) for lower extremities. FIM-motor scores were 58-86 (median, 78) and LOS ranged from 42 to 225 days (median, 175.5 days). Correlation coefficients were statistically significant between rFA and shoulder/elbow/forearm BRS (.696), hand BRS (.779), lower extremity BRS (.631), FIM-motor (.442), and LOS (-.598). Logistic model fit was moderate for shoulder/elbow/forearm BRS (R(2) = .221) and lower extremity BRS (R(2) = .277), but was much higher for hand BRS (R(2) = .441). CONCLUSIONS: Diffusion tensor FA values are predictive of clinical outcome from hemiparesis due to putaminal and/or thalamic hemorrhage, particularly hand function recovery. PMID- 25724242 TI - Intracranial versus extracranial artery dissection cases presenting with ischemic stroke. AB - BACKGROUND: To compare the clinical and radiologic characteristics, possible stroke mechanisms, and prognosis of intracranial artery dissections (IADs) with those of extracranial artery dissections (EADs) presenting with cerebral infarction. METHODS: Among 3250 adult patients with acute ischemic stroke (cerebral infarction), we prospectively recruited and categorized patients with cerebral infarction secondary to spontaneous cerebral artery dissection into IAD or EAD groups. The clinical and radiologic characteristics, possible stroke mechanisms according to the distributions of the infarctions based on diffusion weighted imaging, and prognosis were analyzed for both groups. RESULTS: There were 48 and 50 patients experiencing IAD and EAD, accounting for 1.5% and 1.5% of all ischemic stroke patients, respectively. Compression of the perforating artery was the most common possible stroke mechanism (33.3%) in IADs; thromboembolism was more common in EADs than that in IADs (36 of 50 versus 12 of 48; P < .001). Magnetic resonance imaging and angiography were used to investigate the arterial dissections in all IAD patients and 46 EAD patients. Based on magnetic resonance imaging and angiography, the IADs more frequently displayed dissecting aneurysm (6 of 48 versus 0 of 46; P = .027) and intimal flap or double lumen (21 of 48 versus 4 of 46; P < .001) than EADs. For the clinical characteristics and prognosis, there was no significant difference between the 2 groups. CONCLUSIONS: These results indicate that IAD is an important cause of ischemic stroke, and it displays unique radiologic characteristics and specific stroke mechanisms compared with EAD. PMID- 25724243 TI - Primary pontine hemorrhage in the acute stage: clinical features and a proposed new simple scoring system. AB - BACKGROUND: It is important to evaluate the likelihood of fatality in patients with acute primary pontine hemorrhage (PPH) in emergency departments. We aimed to evaluate the clinical symptoms and computed tomography findings of PPH to develop a simple grading scale for predicting the mortality of PPH. METHODS: Records of 101 consecutive patients admitted to our hospital with acute PPH between June 1, 2006, and January 31, 2014, were retrospectively reviewed. Independent predictors of 30-day mortality were identified by univariate and multivariate logistic regression analyses. A simple and easy clinical score (PPH score) was developed from independent factors to predict mortality in acute PPH. The PPH score was compared with the established intracerebral hemorrhage (ICH) score, which served as the reference scoring system. RESULTS: Overall mortality rate 30 days after onset was 58.4% (59 of 101). Factors independently associated with 30-day mortality were Glasgow Coma Scale (GCS) score of 6 or less (P = .0051), absence of pupillary light reflex (P = .0003), and blood glucose of 180 mg/dL or greater (P = .0312). The PPH score was the sum of independent factors, which were assigned 1 point each. The area under the receiver operating characteristic curve for predicting 30-day mortality was .90 (95% confidence interval [CI], .84-.95) for PPH score and .86 (95% CI, .78-.93) for ICH score. CONCLUSIONS: GCS score of 6 or less, absence of pupillary light reflex, and plasma glucose of 10 mmol/L or greater are independent mortality predictors of PPH. The PPH score is a simple and reliable clinical grading scale for predicting 30-day mortality. PMID- 25724244 TI - Response to Cassidy and Cote. PMID- 25724245 TI - Nonconvulsive partial status epilepticus mimicking recurrent infarction revealed by diffusion-weighted and arterial spin labeling perfusion magnetic resonance images. AB - "Non-convulsive" partial status epilepticus (SE) is an important pathologic condition that should be differentiated from cerebral infarction. Herein, we reported 2 patients who had partial SE associated with old infarction in the right parietal lobe. Each patient had 2 episodes of left hemiparesis and hemisensory disturbance without convulsion. On diffusion-weighted magnetic resonance images (DW-MRI), a hyperintense lesion was noted in the cortex around the old infarction lesion, and recurrent infarction was suspected. Although electroencephalography (EEG) failed to reveal ictal discharges or interictal paroxysmal activities in 3 of 4 episodes, perfusion images with arterial spin labeling (ASL) clearly demonstrated ictal hyperperfusion in the area corresponding to the cortical hyperintense lesion on DW-MRI. After appropriate anticonvulsant treatment based on the diagnosis of partial SE, clinical symptoms were completely improved. These data stress the importance of cortical hyperintensity on DW-MRI and ictal ASL hyperperfusion, even when SE cannot be determined from EEG. PMID- 25724246 TI - An ultrasound investigation of tongue shape in stroke patients with lingual hemiparalysis. AB - BACKGROUND: Stroke can cause hemilateral paresis of the tongue. The present study investigated the functional consequences of a lingual hemiparalysis on the symmetry and the grooving of the tongue in the coronal plane during the production of vowel-consonant-vowel sequences. The hypotheses were that, because of the lingual hemiparalysis, the stroke patients' tongue shapes would be (1) more asymmetrical and (2) less grooved than the tongues of the control speakers. METHODS: The participants in this prospective data collection were 9 stroke patients with lingual hemiparalysis and 6 control speakers. All participants produced vowel-consonant-vowel sequences with the vowels [a, i, and u] and the target consonants [k, t, ?, s, and r]. The tongue shape in the coronal plane was traced and measured. The outcome measures were asymmetry and midlingual concavity. The participants and controls were compared using repeated measures analyses of variance with post hoc Scheffe tests. RESULTS: There were no significant differences in asymmetry. There was significantly reduced midlingual concavity for the stroke patients (F[1, 13] = 8.78; P < .05). There was also a within-subjects effect for consonant (F[4, 50] = 14.26; P < .01). Post hoc testing with Scheffe tests indicated that the consonant [k] had significantly lower grooving than the other consonant sounds (P < .05). CONCLUSIONS: The hemilateral paresis affected not the symmetry but the midlingual grooving. Residual ipsilateral innervation in the hemiparalyzed tongue may help patients compensate. More research is needed to assess the impact of the intrinsic deformation of the tongue on speech acceptability and intelligibility in patients with a lingual hemiparalysis. PMID- 25724247 TI - [Bullet points of emergency attendances for cocaine-users in Spain]. PMID- 25724248 TI - [Clozapine-associated myocarditis]. PMID- 25724249 TI - [Encephalitis associated with anti-NMDA antibodies]. PMID- 25724250 TI - Adsorption and release of surfactant into and from multifunctional zwitterionic poly(NIPAm-co-DMAPMA-co-AAc) microgel particles. AB - We synthesize monodispersed zwitterionic microgel (ZI-MG) particles that undergo an extensive, reversible change in volume in response to environmental stimuli such as pH and temperature. These aqueous ZI-MG dispersions exhibit a minimum hydrodynamic diameter value at an adjustable isoelectric point (IEP). In addition, the study elucidates the controlled uptake and release of ionic and nonionic surfactants from these particle systems. The extent of surfactant loading and the ensuing relative swelling/deswelling behaviors within the colloidal polymer networks are explained in terms of their binding interactions. PMID- 25724251 TI - Donor transmission intestinal carcinoma after kidney transplantation: case report. AB - Tumor transmission is a rare complication of organ transplantation. Despite several improvements in excluding donor malignant disease, there continue to be reports of unknown tumors in the donors. The risk of having a donor with an undetected malignancy ranges between 1.3% and 2%. The cases of two kidney transplant recipients who had intestinal carcinoma transmitted from the same deceased donor are described. The clinical presentation, previous data, and management options are discussed. As a result of the increase in the overall donor pool, using extended criteria donors, donors of extreme ages, donors with prolonged intensive care admission, and donors who may potentially transmit disease to their recipients, the risk of tumor transmission and also infections should be considered. PMID- 25724252 TI - Adult living-donor liver transplantation for a recipient with a high preoperative 1,3-beta-D-glucan level and positive test result for Aspergillus antigen. AB - The patient was a 45-year-old man with underlying alcoholic liver cirrhosis. Two years prior, he was repeatedly hospitalized for liver failure symptoms and requested a living-donor liver transplantation (LDLT) because of end-stage cirrhosis. A pretransplantation blood test revealed a high 1,3-beta-d-glucan (BDG) value of 102.0 pg/mL (reference value <20.0 pg/mL) and a high blood Aspergillus antigen (AsAg) value of 1.6 cutoff index (COI; reference value <0.5 COI). Contrast-enhanced thoracoabdominal-pelvic computed tomography (CT) and cranial magnetic resonance imaging revealed no fungal infection. However, latent fungal infection could not be ruled out, hence preoperative antifungal agent treatment was administered. BDG and AsAg levels showed a decreasing trend after treatment initiation. However, normalization did not occur; the BDG and AsAg levels were 25.8 pg/mL and 1.0 COI, respectively. Although the possibility of latent fungal infection was judged low, we prophylactically administered antifungal agents after LDLT. The BDG level consistently increased at 35-39 pg/mL until postoperative day 5 but subsequently normalized. The AsAg level was higher than the limit of detection at 5.0 COI on postoperative day 3 but normalized to 0.2 COI on postoperative day 5 and did not subsequently increase. The postoperative course was uneventful despite bacterial pneumonia and the patient was discharged on postoperative day 35. A histopathologic examination (Grocott methenamine silver staining) and a fungal polymerase chain reaction assay were performed for the resected liver, but the results of both were negative. At 9 postoperative months, the patient was making ambulatory follow-up visits. Currently, the BDG and AsAg values remain normal and clinical progress is favorable. We found no reports of LDLT for a recipient with a high preoperative BDG level and positive test result for AsAg. Thus, we report on such a case with a discussion of the literature on the causes of high preoperative BDG and AsAg values. PMID- 25724253 TI - Unusual indication for extracorporeal membrane oxygenation immediately after successful sequential bilateral lung transplantation: a case report. AB - BACKGROUND: Ischemia-reperfusion injury-induced primary graft dysfunction after lung transplantation is a major cause of early morbidity and mortality. CASE REPORT: We report an unusual case of primary graft dysfunction grade III following uneventful off-pump bilateral sequential lung transplantation caused by paradoxical left ventricular failure due to systolic anterior motion of the mitral valve-induced left ventricular outflow tract obstruction. Cardiac failure was precipitated by profound dehydration and administration of high doses of vasopressin and norepinephrine. Immediate connection to extracorporeal membrane oxygenation treated the graft failure-associated respiratory-pulmonary hypoxia and reversed the cardiogenic shock syndrome. CONCLUSIONS: Hypovolemia together with a hyperdynamic state resulting from catecholamine administration may result in the development of dynamic left ventricular outflow tract obstruction even if baseline cardiac evaluation is unremarkable. Early detection and intensive efforts to reverse the underlying conditions including cessation of catecholamine therapy and correction of hypovolemia are essential. PMID- 25724254 TI - Pulmonary sarcomatoid carcinoma in a renal transplant recipient. AB - Sarcomatoid carcinomas (SC) are rare malignancies with concomitant occurrence of both carcinomatous and sarcomatous components. Although it may occur throughout the body, lungs are only very rarely involved. We present the first documented case of pulmonary SC (PSC) in a renal transplant recipient, and discuss clinical presentation, diagnostic procedures, treatment, and outcome. PMID- 25724255 TI - Successful term pregnancy in an intestine-pancreas transplant recipient with chronic graft dysfunction and parenteral nutrition dependence: a case report. AB - Pregnancy after solid organ transplantation is becoming more common, with the largest recorded numbers in renal and liver transplant recipients. Intestinal transplantation is relatively new compared to other solid organs, and reports of successful pregnancy are far less frequent. All pregnancies reported to date in intestinal transplant recipients have been in women with stable graft function. The case reported here involves the first reported successful term pregnancy in an intestine-pancreas transplant recipient with chronic graft dysfunction and dependence on both transplant immunosuppression and parenteral nutrition (PN) at the time of conception. Pregnancy was unplanned and unexpected in the setting of chronic illness and menstrual irregularities, discovered incidentally on abdominal ultrasound at approximately 18 weeks' gestation. Rapamune was held, tacrolimus continued, and PN adjusted to maintain consistent weight gain. A healthy female infant was delivered vaginally at term. Medical complications during pregnancy included anemia and need for tunneled catheter replacements. Ascites and edema were improved from baseline, with recurrence of large volume ascites shortly after delivery. Successful pregnancy is possible in the setting of transplant immunosuppression, chronic intestinal graft dysfunction, and long term PN requirement, but close monitoring is required to ensure the health of mother and child. PMID- 25724256 TI - Synovial chemokine expression and relationship with knee symptoms in patients with meniscal tears. AB - OBJECTIVE: In patients with knee OA, synovitis is associated with knee pain and symptoms. We previously identified synovial mRNA expression of a set of chemokines (CCL19, IL-8, CCL5, XCL-1, CCR7) associated with synovitis in patients with meniscal tears but without radiographic OA. CCL19 and CCR7 were also associated with knee symptoms. This study sought to validate expression of these chemokines and association with knee symptoms in more typical patients presenting for meniscal arthroscopy, many who have pre-existing OA. DESIGN: Synovial fluid (SF) and biopsies were collected from patients undergoing meniscal arthroscopy. Synovial mRNA expression was measured using quantitative RT-PCR. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was administered preoperatively. Regression analyses determined if associations between chemokine mRNA levels and KOOS scores were independent of other factors including radiographic OA. CCL19 in SF was measured by ELISA, and compared to patients with advanced knee OA and asymptomatic organ donors. RESULTS: 90% of patients had intra-operative evidence of early cartilage degeneration. CCL19, IL-8, CCL5, XCL1, CCR7 transcripts were detected in all patients. Synovial CCL19 mRNA levels independently correlated with KOOS Activities of Daily Living (ADL) scores (95% CI [-8.071, -0.331], P = 0.036), indicating higher expression was associated with more knee-related dysfunction. SF CCL19 was detected in 7 of 10 patients, compared to 4 of 10 asymptomatic donors. CONCLUSION: In typical patients presenting for meniscal arthroscopy, synovial CCL19 mRNA expression was associated with knee-related difficulty with ADL, independent of other factors including presence of radiographic knee OA. PMID- 25724257 TI - Comparison of four chondral repair techniques in the hip joint: a biomechanical study using a physiological human cadaveric model. AB - OBJECTIVE: The objective of this study was to assess the biomechanical stability of three types of chondral flap repair techniques as well as a hydrogel scaffold implantation on the acetabular articular surface using a physiological human cadaveric model. METHODS: Chondral flaps were created in the antero-superior zone of the acetabulum in a series of human cadaveric hip joints. The chondral flap was repaired by fibrin glue, cyanoacrylate, suture technique and an agarose hydrogel scaffold sealed with fibrin glue using six hips in each case. After each repair, the specimens were mounted in a validated jig and tested for 1500 gait cycles. In order to determine the stability of the repair, specimens were evaluated arthroscopically at specific intervals. RESULTS: The fibrin glue and cyanoacrylate techniques were technically the easiest to perform arthroscopically, all flaps repaired with fibrin were detached at 50 cycles while those repaired with cyanoacrylate lasted for an average of 635 cycles. On the other hand, both the suture repair and scaffold implantation techniques were more technically challenging but were both stable till the endpoint of 1500 cycles. CONCLUSION: Fibrin glue on its own does not provide sufficient fixation to repair chondral flaps on the acetabular surface. Cyanoacrylate repairs universally failed midway through the testing protocol employed here, raising doubts as to the effectiveness of that technique. The suture and hydrogel scaffold technique were the most reliable for chondral repair at any given cycle. The results of this biomechanical study demonstrate the relative effectiveness of chondral repair and fixation techniques. PMID- 25724258 TI - Association of patellar bone marrow lesions with knee pain, patellar cartilage defect and patellar cartilage volume loss in older adults: a cohort study. AB - AIM: To examine the cross-sectional and longitudinal associations of patellar bone marrow lesion (BMLs) with knee pain, cartilage defects and cartilage volume in older adults. METHODS: A total of 904 randomly selected subjects (mean 62.4 years, 49.9% female) were studied. Fat suppressed T1-weighted spoiled gradient recall and T2-weighted fast spin echo magnetic resonance imaging (MRI) sequences were used to assess cartilage volume, cartilage defects and/or BMLs at baseline (n = 904) and 2.6 (range: 1.4-4.8) years' follow-up (n = 414). Knee pain was assessed by self-administered Western Ontario McMaster Osteoarthritis Index (WOMAC) questionnaire at baseline (n = 904) and follow-up (n = 790). RESULTS: The prevalence of any patellar BMLs was 19% and was higher in those with tibiofemoral BMLs. In multivariable analyses, patellar BMLs were positively associated with any knee pain at baseline and an increase in knee pain when going up/down stairs (odds ratio (OR): 1.67, 95% confidence interval (CI): 1.08, 2.59) but not with other knee pain subscales. Patella BMLs were also associated with patellar cartilage defects both at baseline and change over time (OR: 1.76, 95% CI: 1.00, 3.70) but not tibiofemoral defects. Patellar BMLs were negatively associated with baseline and change in patella cartilage volume (beta: -2.10%, 95% CI: -3.39%, 0.80%). These associations remained significant after further adjustment for tibiofemoral BMLs. CONCLUSIONS: Patellar BMLs were consistently associated with increased knee pain especially going up/down stairs, increased patellar cartilage defects, and decreased patellar cartilage volume cross-sectionally and longitudinally, suggesting a predominantly compartment specific role for patellar BMLs. PMID- 25724259 TI - Do children with cerebral palsy change their gait when walking over uneven ground? AB - Independently ambulant children with Cerebral Palsy (CP) often report balance difficulties when walking in challenging settings. The aim of this study was to compare gait in children with CP to typically developing (TD) children walking over level ground and uneven ground, as an evaluation of dynamic balance. Thirty four children participated, 17 with CP (10 hemiplegia and 7 diplegia, mean age 10 years) and 17 TD (mean age 10 years 1 month). Three-dimensional kinematic and kinetic data of the lower limbs and trunk were captured during walking over level and uneven ground using Codamotion(r). Statistical analysis was performed using a mixed-effects model two-factor Analysis of Variance (Group*Surface). Over both surfaces, children with CP showed increased trunk movement in the sagittal (Group effect, p<0.001) and transverse planes (p<0.001), and increased pelvic movement in the coronal plane (p=0.008), indicating impaired trunk control. Peak separation between the centre of mass and centre of pressure was reduced in CP, indicating impaired dynamic balance (p=0.027). TD children made a number of significant adaptations to uneven ground, including reduced hip extension (mean difference 3.4 degrees , 95% CI [-5.3, -1.0] p=0.006), and reduced ankle movement in the sagittal (5.2 degrees , 95% CI [0.01, 10] p=0.049) and coronal planes (2.4 degrees , 95% CI [0.3, 4.5], p=0.029), but these adaptations were not measured in CP. A significant Group*Surface interaction was detected for knee sagittal range (p=0.009). The findings indicate that children with CP walk show impaired control of trunk movement and are less able to adapt their gait to uneven ground, particularly at the ankle. PMID- 25724260 TI - Plantar heel pain and foot loading during normal walking. AB - Plantar heel pain is aggravated by weight-bearing, yet limited evidence exists regarding how people with heel pain load their feet during walking. Knowledge of loading patterns in people with plantar heel pain would enhance the understanding of their foot function and assist in developing intervention strategies. Plantar pressure using the Emed-AT platform (Novel Gmbh, Germany) was collected from 198 people with plantar heel pain and 70 asymptomatic controls during normal walking. Maximum force, force-time integral, peak pressure, pressure-time integral and contact time were measured in four quadrants of the heel, the midfoot and the medial and lateral forefoot. The symptomatic group was sub-divided into equal low pain and high-pain groups using the Foot Health Status Questionnaire pain score. Following age and body mass comparison, multivariate analyses of covariance were performed to compare the heel pain group to the controls, and the low-pain group to the high-pain group, for each loading variable. The heel pain group displayed lower maximum force beneath the heel, lower peak pressure beneath the postero lateral heel and lower maximum force beneath the medial forefoot. Force-time integrals were lower beneath the posterior heel regions and higher at the lateral forefoot. People with heel pain also had longer midfoot and forefoot contact time. Higher pain level was associated with lower peak pressure and maximum force beneath regions of the heel. Compared to the controls, people with plantar heel pain demonstrated reduced heel loading and modified forefoot loading consistent with a strategy to offload the painful heel. PMID- 25724261 TI - Multiple resistant factors in lung cancer with primary resistance to EGFR-TK inhibitors confer poor survival. AB - OBJECTIVES: EGFR activating mutations have been recognized as the most important predictor of response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, 20 30% of patients harboring EGFR activating mutations show a poor response requiring investigation for underlying mechanisms. MATERIALS AND METHODS: Characteristics of 541 patients with lung cancer harboring EGFR activating mutations were analyzed to determine contributing factors that could differentiate responders and non-responders. In addition, previously suggested moleculo-pathologic factors of resistance such as IkappaB, IGF1R, PTEN, MET, AXL and BIM were evaluated in patients exhibiting primary resistance who had sufficient biopsied tissues available for analyses. RESULTS: Responders to EGFR TKIs had a higher incidence of deletion mutations and more frequent presence of EGFR amplifications than non-responders. The median OS was 21 months (95% CI 26.1 30.4) in responders compared to 8 months (95% CI 8.7-15.8) in non-responders (p<0.001). In analyses of patients with primary resistance, we found that 27.3% (6/22) of them exhibited decreased expression of IkappaB, and 9.1% (2/22) of patients showed increased expression of IGF1R. Loss of PTEN was noted in 54.5%, and BIM polymorphism was found in 19% of patients. No patients had MET amplification, while expression of AXL was detected in 5 patients. Two patients had simultaneous T790M EGFR or PIK3CA mutation alongside EGFR activating mutation. Most of patients exhibited multiple abnormalities of these factors. The overall survival was worse in the group with multiple resistant factors. CONCLUSION: Our study suggests that mechanisms of primary resistance may be more complex than those underlying acquired resistance, with several factors concomitantly contributing to primary resistance. PMID- 25724262 TI - Cancer-drug induced insulin resistance: innocent bystander or unusual suspect. AB - Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to reduce the efficacy of cancer therapy. Treatment with cancer therapeutics such as glucocorticoids, chemotherapy, hormonal therapies and targeted drugs can actually induce insulin resistance. The question arises whether cancer-therapy induced insulin resistance impairs anticancer treatment efficacy and disease outcome. Here, we review current literature regarding the incidence of cancer-therapy induced insulin resistance and describe the systemic and extra- and intracellular changes that occur in insulin signalling pathways and glucose metabolism. Subsequently, clinical and preclinical evidence for consequences of insulin resistance in terms of cancer progression and survival is presented. Finally, potential interventions including diabetes medication and limiting energy availability through diets and exercise are discussed. PMID- 25724263 TI - Diapause induces remodeling of the fatty acid composition of membrane and storage lipids in overwintering larvae of Ostrinia nubilalis, Hubn. (Lepidoptera: Crambidae). AB - Seasonal changes in the FA composition of triacylglycerols and phospholipids prepared from the whole bodies of non-diapausing and diapausing fifth instar larvae of Ostrinia nubilalis, Hubn. (Lepidoptera: Crambidae) were determined to evaluate the role of these lipids in diapause. Substantial changes in the FA composition of triacylglycerols and phospholipids were triggered by diapause development. This led to a significant increase in the overall FA unsaturation (UFAs/SFAs ratio), attributable to an increase in the relative proportion of MUFAs and the concomitant decrease in PUFAs and SFAs. In triacylglycerols, the significant changes in the FAs composition are the result of an increase in the relative proportions of MUFAs, palmitoleic acid (16:1n-7) and oleic acid (18:1n 9), and a concomitant reduction in the composition of SFAs and PUFAs, mainly palmitic acid (16:0) and linoleic acid (18:2n-6), respectively. Changes in the composition of phospholipids were more subtle with FAs contributing to the overall increase of FA unsaturation. Differential scanning calorimetry (DSC) analysis revealed that the melt transition temperatures of total lipids prepared from whole larvae, primarily attributable to the triacylglycerol component, were significantly lower during the time course of diapause compared with non diapause. These observations were correlated to the FA composition of triacylglycerols, most likely enabling them to remain functional during colder winter conditions. We conclude that O. nubilalis undergoes remodeling of FA profiles of both energy storage triacylglycerols and membrane phospholipids as an element of its overwintering physiology which may improve the ability to cold harden during diapause. PMID- 25724264 TI - Neuroprotective effect of thalidomide on MPTP-induced toxicity. AB - Thalidomide is a sedative with unique pharmacological properties; studies on epilepsy and brain ischemia have shown intense neuroprotective effects. We analyzed the effect of thalidomide treatment on the neurotoxicity caused by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahidropyridine (MPTP) in mice. Thalidomide was administered at two times; before and after the exposure to MPTP. In both circumstances thalidomide improved the neurotoxicity induced by MPTP as seen by a significant raise of the striatal contents of dopamine and simultaneous decrease of monoamine-oxidase-B (MAO-B). These results indicate that in the experimental model of Parkinson's disease the administration of thalidomide improves the functional damage on the nigrostriatal cell substratum as seen by the production of dopamine. This neuroprotective effect seems to be mediated by inhibition of excitotoxicity. Our results suggest that thalidomide could be investigated as potential adjuvant therapy for Parkinson's disease. PMID- 25724265 TI - Stereotactic body radiotherapy. PMID- 25724266 TI - Vapers' perspectives on electronic cigarette regulation in Australia. AB - BACKGROUND: The use of electronic cigarettes (e-cigarettes), also known as personal vaporisers (PVs), has increased rapidly in Australia despite legal barriers to the sale, possession and use of nicotine for non-therapeutic purposes. Australia is one of many countries in the process of developing regulations for these devices yet knowledge of consumers' views on e-cigarette regulation is lacking. METHODS: An online survey was completed by 705 e-cigarette users recruited online. Participants answered questions about their smoking history, e-cigarette use, as well as their opinions on appropriate regulation of e-cigarettes. RESULTS: Most participants were male (71%), employed (72%), and highly educated (68% held post-school qualification). They tended to be former heavy smokers who had stopped smoking entirely and were currently vaping. Participants generally agreed that the government should enforce minimum labelling and packaging standards and there was majority support for minimum quality standards. Most supported making e-cigarettes available for sale to anyone over the age of 18, but expressed concern about the government's motivation for regulating e-cigarettes. There was strong opposition to restricting sales to a medicines framework (prescription only or pharmacy only sales). CONCLUSION: E-cigarette users in Australia are in favour of e-cigarettes being regulated as long as those regulations do not impede their ability to obtain devices and refill solutions, which they view as important for them to remain smoke free. These views align with some aspects of appropriate policy designed to maximise the public health potential of e-cigarettes in society, but conflict with some of the proposed regulatory models. Governments should consider how future regulation of e-cigarettes will affect current consumers while helping to maximise the number of smokers who switch to e-cigarettes and minimise the possibility of non-smokers becoming addicted to nicotine. PMID- 25724267 TI - Nicotine levels in electronic cigarette refill solutions: A comparative analysis of products from the U.S., Korea, and Poland. AB - BACKGROUND: Electronic cigarettes vaporize nicotine dissolved in glycerine and/or propylene glycol (e-liquid). Due to a lack of regulations, e-liquids may contain inaccurately labelled nicotine levels. Our aim was to test nicotine levels in samples of e-liquids from three countries. METHODS: We measured nicotine concentration in 32, 29 and 30 e-liquids purchased between 2013 and 2014 from locations in the United States (US), South Korea, and Poland, respectively. RESULTS: Nicotine concentration in the US products varied from 0 to 36.6 mg/mL. Traces of nicotine were found in three US products labelled as 'nicotine free'. Two-thirds of South Korean products did not contain detectable amounts of nicotine, whereas nicotine concentration in other products varied from 6.4+/-0.7 to 150.3+/-7.9 (labelled as 'pure nicotine') mg/mL. In products from Poland, nicotine concentration varied from 0 to 24.7+/-0.1 mg/mL. Overall, we found significant discrepancies (>20%) in the labelled nicotine concentrations in 19% of analysed e-liquids. CONCLUSION: Most of the analysed samples had no significant discrepancies in labelled nicotine concentrations and contained low nicotine levels. However some products labelled as 'nicotine-free' had detectable levels of the substance, suggesting insufficient manufacturing quality control. We identified a single product labelled as 'pure nicotine' which contained significantly higher concentration of the drug, increasing the risk of accidental poisoning. The study reveals the need for quality standards of these new nicotine containing products. PMID- 25724268 TI - Interaction of PARP-2 with AP site containing DNA. AB - In eukaryotes the stability of genome is provided by functioning of DNA repair systems. One of the main DNA repair pathways in eukaryotes is the base excision repair (BER). This system requires precise regulation for correct functioning. Two members of the PARP family - PARP-1 and PARP-2, which can be activated by DNA damage - are widely considered as regulators of DNA repair processes, including BER. In contrast to PARP-1, the role of PARP-2 in BER has not been extensively studied yet. Since AP site is one of the most frequent type of DNA damage and a key intermediate of BER at the stage preceding formation of DNA breaks, in this paper we focused on the characterization of PARP-2 interaction with AP site containing DNAs. We demonstrated that PARP-2, like PARP-1, can interact with the intact AP site via Schiff base formation, in spite of crucial difference in the structure of the DNA binding domains of these PARPs. By cross-linking of PARPs to AP DNA, we determined that the N-terminal domains of both PARPs are involved in formation of cross-links with AP DNA. We have also confirmed that DNA binding by PARP-2, in contrast to PARP-1, is not modulated by autoPARylation. PARP-2, like PARP-1, can inhibit the activity of APE1 by binding to AP site, but, in contrast to PARP-1, this inhibitory influence is hardly regulated by PAR synthesis. At the same time, 5'-dRP lyase activity of both PARPs is comparable, although being much weaker than that of Pol beta, which is considered as the main 5'-dRP lyase of the BER process. PMID- 25724269 TI - Independent role of PP2A and mTORc1 in palmitate induced podocyte death. AB - Molecular mechanism behind palmitate associated insulin resistance (IR) and podocyte death is not yet fully understood. The present study shows that palmitate treatment induces IR, in human urine derived podocyte-like epithelial cells (HUPECs), which is characterised by decrease in insulin-induced p-AKT, p GSK3 beta and p-ERK1/2. This impairment in insulin signalling prevents insulin induced SIRT 1 expression and deacetylation of p53. Further, palmitate treatment prevents insulin induced phosphorylation of PP2A and FOXO1 but it potentiates the phosphorylation of mTOR at Ser 2448. Interestingly, selective inhibition of PP2A, by Okadaic acid at 5 nM, restored insulin induced phosphorylation of AKT, FOXO1, SIRT1 activity and p53 degradation. However, PP2A inhibition had no effect on mTOR phosphorylation at Ser 2448. On the other hand, partial inhibition of mTORc1, by low dose of Rapamycin (1 nM) also restored phosphorylation of AKT and SIRT1 activity, whereas no significant changes were observed in insulin induced phosphorylation of PP2A after mTORc1 inhibition. To the best of our knowledge this is the first report suggesting independent role of PP2A and mTORc1 in palmitate induced IR and associated podocyte death. Therefore, the best therapeutic approach for treatment of diabetic kidney disease should involve manipulating phosphorylation of both PP2A and mTORc1. PMID- 25724270 TI - Ayadualin, a novel RGD peptide with dual antihemostatic activities from the sand fly Lutzomyia ayacuchensis, a vector of Andean-type cutaneous leishmaniasis. AB - Sequence analysis of the Lutzomyia (Lu.) ayacuchensis salivary gland cDNA library identified a short peptide containing an RGD (Arg-Gly-Asp) sequence flanked by two cysteine residues in the C-terminal end as the most abundant transcript. In the present study, a recombinant protein of the RGD-containing peptide, designated ayadualin, was expressed in Escherichia coli and its activity was characterized. Ayadualin inhibited both collagen and ADP-induced platelet aggregations by interfering with the binding of integrin alphaIIbbeta3 to fibrinogen. The RGD sequence and cysteine residues located on both sides of the RGD sequence were essential for the inhibitory action. Moreover, ayadualin efficiently inhibited the intrinsic blood coagulation pathway irrespective of the RGD sequence. Measuring the enzymatic activity of coagulation factors using chromogenic substrates revealed that ayadualin efficiently inhibited factor XIIa (FXIIa) activity in a dose-dependent manner. In addition, pre-incubation of ayadualin with FXII inhibited FXIIa activity, while activated FXIIa was not affected by ayadualin, indicating that ayadualin inhibits the activation of FXII, but not enzymatic activity of FXIIa. These results indicated that ayadualin plays an important role in the blood feeding of Lu. ayacuchensis by inhibiting host hemostasis via dual mechanisms. PMID- 25724271 TI - The Edinburgh Postnatal Depression Scale for Fathers: A contribution to the validation for an Italian sample. AB - OBJECTIVE: The aims of the study are to contribute to the validation of the Edinburgh Postnatal Depression Scale (EPDS; Cox et al., 1987) on a sample of Italian fathers (both men in the perinatal period than those with grown-up children) and to analyze its factorial structure. METHODS: Four hundred thirty six fathers participated; specifically, we used two samples. The first was composed of 334 fathers, 39 of which were depressed new fathers. We conducted explorative factor analysis and receiver operator characteristic analysis. The second sample was composed of 102 fathers, 22 of which were depressed new fathers. We conducted confirmative factor analysis on this second sample. We administered the Italian version of the EPDS (Carpiniello et al., 1997; Benvenuti et al., 1999), the Beck Depression Inventory-II (Ghisi et al., 2006) and the Center for Epidemiological Studies Depression Scale (Fava, 1983). RESULTS: The test seems to detect not depression but a state of distress including depressive symptoms, anxiety and unhappiness. Results showed a two-factor structure, different from that of mothers. The optimal cutoff for Italian fathers is 12/13. CONCLUSIONS: The EPDS is a valid and reliable instrument, useful in the perinatal period for screening fathers at risk for perinatal distress and in need of psychological support. PMID- 25724273 TI - Remote control of the permeability of the blood-brain barrier by magnetic heating of nanoparticles: A proof of concept for brain drug delivery. AB - Despite advances in neurology, drug delivery to the brain remains a substantial challenge. This is mainly due to the insurmountable and selective nature of the blood-brain barrier (BBB). In this study, we show that the thermal energy generated by magnetic heating (hyperthermia) of commercially available magnetic nanoparticles (MNPs) in the brain capillaries of rats can transiently increase barrier permeability. Here, the fluorescent Evans Blue (EB) dye was used to verify the BBB integrity. Results indicate a substantial but reversible opening of the BBB where hyperthermia is applied. Also, in this investigation, analysis of CD68 immunoreactivity, an indicator of inflammation, implies that this technique is not associated with any inflammation. We have previously investigated theranostic (therapeutic and diagnostic) capabilities of the MNPs, therefore, the findings presented in this investigation are particularly encouraging for a novel targeted drug delivery system to the brain. PMID- 25724272 TI - Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study. AB - Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD+/-Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically relevant concentrations of doxorubicin (4.8+/-0.5MUg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10MUl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was delivered before sonication. In histology, the severe neurotoxicity observed in some previous studies with doxorubicin by other investigators was not observed here. However, four of the five rats who received FUS-BBBD and Lipo-DOX had regions (dimensions: 0.5-2mm) at the focal targets with evidence of minor prior damage, either a small scar (n=4) or a small cyst (n=1). The focal targets were unaffected in rats who received FUS-BBBD alone. The result indicates that while delivery of Lipo-DOX to the rat brain might result in minor damage, the severe neurotoxicity seen in earlier works does not appear to occur with delivery via FUS-BBB disruption. The damage may be related to capillary damage produced by inertial cavitation, which might have resulted in excessive doxorubicin concentrations in some areas. PMID- 25724275 TI - Cortical processes associated with continuous balance control as revealed by EEG spectral power. AB - Balance is a crucial component in numerous every day activities such as locomotion. Previous research has reported distinct changes in cortical theta activity during transient balance instability. However, there remains little understanding of the neural mechanisms underlying continuous balance control. This study aimed to investigate cortical theta activity during varying difficulties of continuous balance tasks, as well as examining the relationship between theta activity and balance performance. 37 subjects completed nine balance tasks with different levels of surface stability and base of support. Throughout the balancing task, electroencephalogram (EEG) was recorded from 32 scalp locations. ICA-based artifact rejection was applied and spectral power was analyzed in the theta frequency band. Theta power increased in the frontal, central, and parietal regions of the cortex when balance tasks became more challenging. In addition, fronto-central and centro-parietal theta power correlated with balance performance. This study demonstrates the involvement of the cerebral cortex in maintaining upright posture during continuous balance tasks. Specifically, the results emphasize the important role of frontal and parietal theta oscillations in balance control. PMID- 25724276 TI - Peripheral neuropathies: Moving closer to mechanism. PMID- 25724274 TI - Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries. AB - The environment within the spinal cord after injury, which changes in the progression from the acute to chronic stages, limits the extent of regeneration. The delivery of inductive factors to promote regeneration following spinal cord injury has been promising, yet, few strategies are versatile to allow delivery during acute or chronic injury that would facilitate screening of candidate therapies. This report investigates the intrathecal delivery of lentiviruses for long-term expression of regenerative factors. Lentivirus-filled sponges were inserted into the intrathecal space surrounding the spinal cord, with transgene expression observed within multiple cell types that persists for 12 weeks for both intact and injured spinal cord, without any apparent damage to the spinal cord tissue. Sponges loaded with lentivirus encoding for Sonic hedgehog (Shh) were investigated for acute (delivered at 0 weeks) and chronic (at 4 weeks) injuries, and for multiple locations relative to the injury. In an acute model, sponges placed directly above the injury increased oligodendrocyte and decreased astrocyte presence. Sponges placed caudal to the injury had reduced impact on oligodendrocytes and astrocytes in the injury. In a chronic model, sponges increased oligodendrocyte and decreased astrocyte presence. Furthermore, the effect of Shh was shown to be mediated in part by reduction of Bmp signaling, monitored with an Msx2-sensitive reporter vector. The implantation of lentivirus loaded biomaterials intrathecally provides the opportunity to induce the expression of a factor at a specified time without entering the spinal cord, and has the potential to promote gene delivery within the spinal cord, which can influence the extent of regeneration. PMID- 25724277 TI - Quantification of symbiotic contributions to lower termite lignocellulose digestion using antimicrobial treatments. AB - Animal-microbe co-evolution and symbiosis are broadly distributed across the animal kingdom. Insects form a myriad of associations with microbes ranging from vectoring of pathogens to intracellular, mutualistic relationships. Lower termites are key models for insect-microbe symbiosis because of the diversity, complexity and functionality of their unique tripartite symbiosis. This collaboration allows termites to live on a diet of nitrogen-poor lignocellulose. Recent functional investigations of lignocellulose digestion in lower termites have primarily focused on the contributions of the eukaryotic members of the termite holobiont (termite and protist). Here, using multiple antimicrobial treatments, we induced differing degrees of dysbiosis in the termite gut, leading to variably altered symbiont abundance and diversity, and lignocellulolytic capacity. Although protists are clearly affected by antimicrobial treatments, our findings provide novel evidence that the removal of distinct groups of bacteria partially reduces, but does not abolish, the saccharolytic potential of the termite gut holobiont. This is specifically manifested by reductions of 23-47% and 30-52% in glucose and xylose yields respectively from complex lignocellulose. Thus, all members of the lower termite holobiont (termite, protist and prokaryotes) are involved in the process of efficient, sustained lignocellulase activity. This unprecedented quantification of the relative importance of prokaryotes in this system emphasizes the collaborative nature of the termite holobiont, and the relevance of lower termites as models for inter-domain symbioses. PMID- 25724278 TI - Discrepant effects of acute cocaine on impulsive choice (delay discounting) in female rats during an increasing- and adjusting-delay procedure. AB - RATIONALE: The relationship between impulsive choice and cocaine use in humans has been well established, although the causal role between these variables is complex. To disentangle this relationship, studies using rats have focused on how acute or chronic cocaine alters impulsive choice. A predominance of studies has focused on chronic cocaine regimens, but few have assessed acute cocaine's effects on impulsive choice. OBJECTIVE: The current study assessed if acute cocaine administrations alter delay discounting of rats in two common impulsive choice procedures. METHOD: Baseline delay discounting rates were determined in female rats using both an increasing- and adjusting-delay procedure. Once stable, a range of acute cocaine injections (2, 5, and 15 mg/kg i.p.) was administered prior to both procedures. RESULTS: Baseline delay discounting rates were positively correlated between the increasing- and adjusting-delay procedures. Acute administrations of cocaine produced a dose-dependent decrease in preference for the large alternative in the increasing-delay procedure but had no effect in the adjusting-delay procedure. CONCLUSIONS: The concordance of delay discounting rates across the two choice procedures suggests that both quantify the same underlying components of impulsive choice. However, manipulations that disrupt large alternative preference may not be readily detected under the adjusting delay procedure unless control conditions are employed. PMID- 25724279 TI - Incidence of cystoid macular edema: femtosecond laser-assisted cataract surgery versus manual cataract surgery. PMID- 25724280 TI - Autophagy Alleviates Melamine-Induced Cell Death in PC12 Cells Via Decreasing ROS Level. AB - Since melamine was illegally added to raw milk for increasing the apparent protein content, such a scandal has not been quite blown out. Previous studies showed that melamine induced apoptosis and oxidative damage in both in vivo and in vitro experiments. It is well known that autophagy is closely related to oxidative stress. In the present study, we examined whether autophagy played an important role in protecting PC12 cells, which were damaged by melamine. Immunofluorescence assay showed that melamine enhanced the number of punctuate dot, indicating the increase of autophagosomes. Western blot assay presented that melamine significantly elevated the expression level of autophagy markers including LC3-II/LC3-I ratio, beclin-1, and Atg 7. Rapamycin further enhanced the effect, whereas 3-methyadenine (3-MA) inhibited it. MTT assay exhibited that rapamycin significantly enhanced the cell viability (P < 0.01), while 3-MA considerably reduced it in melamine-treated PC12 cells (P < 0.01). Furthermore, flow cytometry assay showed that rapamycin considerably reduced the reactive oxygen species (ROS) level of the cells (P < 0.01), but 3-MA increased the generation of ROS (P < 0.01). Additionally, the superoxide dismutase (SOD) activity was notably increased by rapamycin in melamine-treated PC12 cells (P < 0.01), while the activity of which was prominently decreased by 3-MA (P < 0.01). Malondialdehyde (MDA) assay showed that rapamycin remarkably decreased the MDA level of the cells (P < 0.05), while 3-MA increased it (P < 0.01). Consequently, this study demonstrated that autophagy protected PC12 cells from melamine-induced cell death via inhibiting the excessive generation of ROS. Regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine. PMID- 25724282 TI - Advanced voice function assessment: editorial introduction to this special issue. AB - ICT COST Action 2103 was an EU-funded collaborative network of speech processing engineers, laryngologists, and phoniatricians that started on 19 December 2006 and ended on 18 June 2011. The main objectives were to improve the clinical assessment of voice using new technologies; to encourage clinicians and technologists to work closely together to understand the needs and limitations of each other's fields and, in parallel, to acquire new data with a view to elaborating better voice production models. The papers in this special issue represent some of the outcomes of that partnership. This editorial introduces the background and context for COST Action 2103 and each of the papers. In conclusion we discuss the impact of the Action and what aspects of it may have a lasting effect on practice. PMID- 25724281 TI - Local anaesthetic infiltration for the rubber band ligation of early symptomatic haemorrhoids: a systematic review and meta-analysis. AB - The objective of this article is to systematically analyse the randomized, controlled trials evaluating the effectiveness of local anaesthetic infiltration prior to the rubber band ligation of early symptomatic haemorrhoids. Published randomized, controlled trials comparing the use of local anaesthetic (LA) versus no-local anaesthetic (NLA) for the rubber band ligation of early symptomatic haemorrhoids were analysed using RevMan(r), and the combined outcomes were expressed as odds ratios (OR) and standardized mean difference (SMD). Four randomized, controlled trials evaluating 387 patients were retrieved from the standard electronic databases. The risk of treatment failure (OR 0.44; 95% CI 0.07, 2.79; z = 0.87; p = 0.39) and post-procedure complications (OR 0.48; 95% CI 0.08, 2.76; z = 0.83; p = 0.41) was similar between two techniques. However, the post-procedure pain score (SMD -5.19; 95% CI -9.08, -1.30; z = 2.62; p < 0.009) was significantly lower in the group of patients undergoing rubber band ligation of haemorrhoids under local anaesthetic injection. The use of LA appears to have clinically measurable advantages over NLA in the rubber band ligation of early symptomatic haemorrhoids to lessen post-procedure pain. PMID- 25724283 TI - Two new naphthalene glucosides and other bioactive compounds from the carnivorous plant Nepenthes mirabilis. AB - Two new naphthalene diglucosides named nepenthosides A (1) and B (2), together with eleven known compounds (3-13), were isolated from the carnivorous plant Nepenthes mirabilis. The structures of these compounds were elucidated based on extensive spectroscopic analysis, including 1D- and 2D-NMR, and MS. The antioxidant activities of compounds 1-13 were evaluated in terms of their peroxyl radical-scavenging (trolox equivalent, TE) and reducing capacities. All isolates showed peroxyl radical-scavenging and reducing activities at concentrations of 1.0 and 10.0 MUM. Anti-osteoporotic activities were investigated using murine osteoclastic RAW 264.7 cells. Compounds 1-7 and 9-12 significantly suppressed tartrate-resistant acid phosphatase activity down to 91.13 +/- 1.18 to 42.39 +/- 1.11%, relative to the control (100%) in nuclear factor-kappaB ligand (RANkappaL) induced osteoclastic RAW 264.7 macrophage cells. PMID- 25724284 TI - Structure-based design, structure-activity relationship analysis, and antitumor activity of diaryl ether derivatives. AB - To identify novel therapeutic agents to treat cancer, we synthesized a series of diaryl ether derivatives. Structure-activity relationship studies revealed that the presence of a chlorine or hydroxyl at the para-position on the phenyl ring (5h or 5k) significantly enhanced antitumor activity. Compound 5h had stronger growth inhibitory activity in HepG2, A549, and HT-29 cells than compound 5k, with IC50 values of 2.57, 5.48, and 30.04 MUM, respectively. Compound 5h also inhibited the growth of other cells lines, including Hep3B, PLC/PRF5, SMMC-7721, HeLa, and A375, with IC50 values of 2.76, 4.26, 29.66, 18.86, and 10.21 MUM, respectively. The antitumor activity of compound 5h was confirmed by a colony forming assay. Further, our results indicated that the antitumor activity of compound 5h may be mediated by enhancing expression of p21 and cl-caspase3, and leading to apoptosis of cancer cells. PMID- 25724285 TI - The manganese-salen compound EUK-134 and N-acetyl cysteine rescue from zinc- and paraquat-induced toxicity in rat polymorphonuclear leukocytes. AB - Oxidative stress is implicated in toxicant-induced inflammation leading to chronic diseases. Polymorphonuclear leukocytes (PMNs) offer the first line of defense against infection in the mammals and protect against inflammation mediated pathological anomalies. Conversely, activated PMNs contribute to the oxidative stress-mediated damage and inflammation. The study aimed to investigate the status of oxidative stress and antioxidant defense system in the PMNs of rats treated with/without zinc (Zn) and/or paraquat (PQ) in the presence or absence of a synthetic superoxide dismutase/catalase mimetic, a manganese-salen compound-EUK 134 and/or a glutathione precursor, N-acetyl cysteine (NAC). While Zn and/or PQ elevated the total free radical generation, lipid peroxidation (LPO) and catalytic activity of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase alpha 4-4 (GSTA4-4), a pronounced decrease in reduced glutathione (GSH) and glutathione reductase (GR) activity was also observed. Zn and/or PQ augmented the expression of metallothionein-I and II and GSTA4-4. Pre-treatment of EUK-134 or NAC alone altered the level of total free radical generation, LPO, GSH content and catalytic activity of MPO, SOD, GR and GPx and the expression of metallothionein I and II towards normalcy. The alterations were more pronounced in the PMNs of rats treated with EUK-134 and NAC in combination. Catalytic activity/expression of GSTA4-4 remained unchanged in the PMNs of EUK-134 or NAC treated rats. The results demonstrate that EUK-134 and NAC protect PMNs from the toxic effects of Zn and PQ in rats and also suggest that metallothioneins I/II might contribute to antioxidant defense under GSH depleted conditions. PMID- 25724286 TI - Selected 4-phenyl hydroxycoumarins: in vitro cytotoxicity, teratogenic effect on zebrafish (Danio rerio) embryos and molecular docking study. AB - A study of structure cytotoxic-activity relationship of three hydroxy 4-phenyl coumarins and basic coumarin molecule against two human cell lines (MRC5 fibroblasts and A375 melanoma cells) is presented. Of all investigated compounds the highest cytotoxic activity in both cell lines was determined for 7,8 dihydroxy-4-phenyl coumarin. SAR studies revealed the influence of phenyl group and hydroxyl group's number and position on cytotoxic activity. In addition, to get an insight about their binding preferences at the active site of the receptor (catalytic subunit of cAMP-dependent protein kinase) molecular docking studies were performed. Docking studies suggest that 4-phenyl hydroxycoumarins are potent cAMP-dependent protein kinase inhibitors, better than their analogs without phenyl group. The teratogenic potential was assessed in zebrafish embryo toxicity test and results showed that 4-phenyl dihydroxycoumarins were more while 7 hydroxy-4-phenyl coumarin was less embryo toxic in comparison to coumarin. In order to examine selected 4-phenyl hydroxycoumarins as a new lead compounds the druglikeness of selected 4-phenyl hydroxycoumarins was estimated by using Lipinski's "rule of five". All selected 4-phenyl hydroxycoumarins proved to have satisfying pharmacokinetic profile. PMID- 25724287 TI - Resveratrol improves the quality of pig oocytes derived from early antral follicles through sirtuin 1 activation. AB - During oocyte growth, the number of mitochondria drastically increases and mitochondrial function profoundly affects the oocyte competence. Resveratrol is a well-known activator of sirtuin 1 (SIRT1), which has a role in cellular energy homeostasis and mitochondrial biogenesis. The main aim of the present study was to examine the effect of supplementation of culture media with resveratrol on oocyte development and mitochondrial number and functions. Lipid contents and developmental ability of the oocytes grown in vitro were also examined. Oocyte granulosa cell complexes were collected from early antral follicles of gilt ovaries and were cultured in medium containing 0 or 2 MUM resveratrol for 14 days. Immunostaining revealed that resveratrol enhanced SIRT1 expression in oocytes. Antrum formation during the culture period and survivability of the granulosa cells surrounding the developed oocytes did not differ between the two concentrations of resveratrol. In addition, the ability of oocytes to complete meiotic maturation did not differ between the two concentrations of resveratrol, whereas the ability of oocytes to develop to the blastocyst stage was improved significantly by resveratrol (7.4% vs. 1.6%; P < 0.05). Resveratrol upregulated the ATP content in oocytes grown in vitro, and the addition of 2 MUM of the SIRT1 inhibitor 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (EX527) diminished this effect although EX527 alone had no effect on ATP content. The mitochondrial DNA copy number in oocytes determined by quantitative real-time polymerase chain reaction increased during in vitro oocyte development, but resveratrol did not affect the kinetics of the mitochondrial DNA copy number. We found that resveratrol also increased the expression level of phospho-5' adenosine monophosphate-activated protein kinase in oocytes but decreased the lipid content in oocytes grown in vitro. These results suggest that resveratrol increased the ATP content in oocytes via energy homeostasis and improved the developmental ability of oocytes grown in vitro. PMID- 25724288 TI - Individual and seasonal variations in the quality of fractionated boar ejaculates. AB - Reproductive seasonality has been shown to affect the quality of boar semen. In this study, effects of seasonal variations in the characteristics of spermatozoa and seminal plasma (SP) of fractioned ejaculates from individual boars have been investigated. Fractionated ejaculates, designated as fraction 1 (F1), fraction 2 (F2), and fraction 3 (F3), were collected from five mature boars during the autumn-winter (October through March) and spring-summer periods (April through September). A total of 10 fractionated ejaculates (F1, F2, and F3) were collected from each boar within each seasonal period. Assessments of the sperm quality characteristics included computer-assisted sperm analysis motion patterns, mitochondrial membrane potential (MMP), plasma membrane integrity, normal apical ridge acrosomes, and DNA fragmentation. Besides SDS-PAGE and densitometric analyses of the SP proteins, the antiperoxidant activity was monitored. There were marked differences in the sperm quality characteristics among the boars, except for sperm MMP. Distinct seasonal differences (P < 0.05) were observed in the ejaculate volume of F3 during the autumn-winter and spring-summer periods (107.78 +/- 5.45 and 87.80 +/- 4.75 mL, respectively). Significantly higher (P < 0.05) sperm concentration and the total number of spermatozoa in the fraction were observed during the autumn-winter period. Seasonal effects in MMP and plasma membrane integrity were manifested in significantly higher (P < 0.05) percentages of spermatozoa with functional mitochondria and intact plasma membrane during the autumn-winter period. However, the seasonal effects were less marked in either sperm normal apical ridge acrosomes or sperm DNA fragmentation. Sodium dodecyl sulfate-PAGE and densitometric analyses revealed marked variations in the protein composition of the SP profiles among the boars, regardless of the ejaculate fraction and seasonal period. Distinct seasonal variations, observed in the SDS PAGE profiles, were associated with an abundance of protein fractions of low molecular and high-molecular weight components, particularly during the autumn winter period. There were wide variations in antiperoxidant activity in the SP among the boars, being significantly higher in the autumn-winter period, irrespective of the ejaculate fraction. It can be suggested that marked deterioration of the quality of fractionated ejaculates during the spring-summer period was probably caused by impaired reproductive function in the boar. PMID- 25724289 TI - Aggressive Costoclavicular Junction Decompression in Patients with Threatened AV Access. AB - BACKGROUND: A substantial number of patients with threatened arteriovenous (AV) access are found to have stenoses at the costoclavicular junction (CCJ), which frequently are resistant to angioplasty and stenting. We believe that stenoses in this location will not resolve unless bony decompression is performed to relieve the extrinsic compression on the vein. This article describes our short- to medium-term results following such decompression in patients with failing fistulae. METHODS: We reviewed a prospectively maintained database to identify all patients with threatened AV access operated on for stenoses at the CCJ. Pre- and postoperative course along with long-term follow-up were analyzed. RESULTS: Between July 2012 and December 2013, 24 patients with threatened access were operated on for CCJ stenoses at our institution. Fifteen had highly dysfunctional AV fistulae otherwise felt to need ligation, 10 had significant arm and/or head swelling, and 3 required access but had no contralateral options. In 6 patients, the subclavian vein was occluded and 18 stenotic; 5 of these had stents in place through the CCJ. Decompression was performed via claviculectomy in 3 patients, 2 of whom underwent reconstruction (one jugular vein, one prosthetic bypass) and 1 was stented. The other 21 patients underwent first rib resection, 20 via an infraclavicular exposure and 1 via a supraclavicular rib resection. A variety of interventions were performed in the arm, including aneurysm plication, cephalic to deep bypass, one prophylactic distal revascularization interval ligation, and several primary fistulae. 30-Day mortality was minimal: there was one significant hematoma and one hemothorax in a patient who underwent on-table thrombolysis and there were no deaths or cardiac, neurologic, or other significant morbidity. Median length of stay was 2 days. At follow-up up to 20 (median 10) months, 4 patients died of unrelated causes and 1 patient undergoing central reconstruction with prosthetic bypass required excision of this for infection and ligation of his fistula. Two other fistulae failed. One-year assisted primary patency of the fistula was 85%, and of the central bypass, 89%. At last follow-up, the index arm continued to be used for access in 85% of patients, and overall survival was 68%. Virtually all patients experienced dramatic symptom relief. CONCLUSIONS: In this group of high-risk patients whose access was judged otherwise nonsalvageable, excellent symptom relief and long-term fistula and ipsilateral arm use can be achieved with aggressive decompression of the bony CCJ followed by endovascular intervention as needed. PMID- 25724290 TI - Population pharmacokinetic and pharmacodynamic model of propofol externally validated in children. AB - There have been no pharmacokinetic parameters and blood-brain equilibration rate constant (k e0) of propofol obtained in a single population of children, by which propofol can be administered using a target effect-site concentration controlled infusion. Thirty-nine, American Society of Anesthesiologists Physical Status 1-2 children aged 2-12 years were given an intravenous bolus of propofol (3 mg kg( 1)), followed by infusion (200 ug kg(-1) min(-1)). Arterial drug concentrations and bispectral index (BIS) values were measured. Population pharmacokinetic and pharmacodynamic analysis was performed using nonlinear mixed effects modeling. External model validation was performed in a separate population of children. A two-compartment model and a sigmoid E max model directly linked by an effect compartment well described the time courses of propofol concentration and BIS. The estimates of parameters were: V 1 (L) = 1.69, V 2 (L) = 27.2 + 0.929 * (weight - 25), Cl (L min(-1)) = 0.893 * (weight/23.6)(0.966), Q (L min(-1)) = 1.3; E 0 = 76.9; E max = 35.4, Ce 50 (MUg mL(-1)) = 3.47 - (0.095 * age) - (1.63 * mean infusion rate of remifentanil in ug kg(-1) min(-1)); gamma = 2.1; and k e0 (min(-1)) = 0.371. Pooled biases (95 % CI) of the target effect-site concentration controlled infusion system of propofol was -20.2 % (-23.3 to -18.1 %) and pooled inaccuracy was 30.4 % (28.6-32.7 %). Pooled biases of BIS prediction was -6.8 % (-9.1 to -4.1 %) and pooled inaccuracies was 19.1 % (17.5 20.9 %).The altered weight-based dose requirements of propofol are well described pharmacokinetically, and pharmacodynamically. Predictive performances of the TCI system in this study were clinically acceptable. PMID- 25724291 TI - Population Pharmacokinetic Modeling of Guanfacine in Pediatric Patients. AB - INTRODUCTION: The population pharmacokinetics of guanfacine extended release were characterized in pediatric patients aged 6-17 years using NONMEM and evaluated by predictive check and bootstrap. METHODS: Data were described using a one compartment model. A covariate modeling approach that emphasized parameter estimation rather than stepwise hypothesis testing was implemented. A nonparametric bootstrap procedure and a predictive check method were used to evaluate the final model and parameter estimates. RESULTS: Typical population pharmacokinetic parameters (95 % confidence interval), given the reference covariates (Caucasian, male, age 12 years, weight 50 kg), were 33.1 (30.2-36.4) L/h for apparent clearance (CL/F), 804 (703-900) L for apparent volume of distribution, 0.552 (0.437-0.670) h(-1) for the absorption rate constant, and 0.651 (0.608-0.697) h for absorption lag time. DISCUSSION: The pharmacokinetics of guanfacine are similar in pediatric patients compared with adults when appropriately scaled by patient weight. The main predictor of guanfacine exposure, as determined by a change in CL/F, was weight. Effects of the other covariates (age, sex, and race) on CL/F were estimated with reasonable precision; however, the additional effects of age, sex, and race can be considered to have little to no clinical relevance. PMID- 25724292 TI - Propagation of maternal behavior across generations is associated with changes in non-maternal cognitive and behavioral processes. AB - Over a number of years we have studied the phenomenology of maternal behavior from endocrine, neural, experiential, and ontogenetic perspectives. Here, we focus on the effects of early life experiences with and without the mother on subsequent maternal and non-maternal behaviors of the offspring. We have used an artificial rearing procedure, which entails removing rat pups from their mother and raising them in isolation, while controlling and manipulating several aspects of their upbringing. As adults, mother-reared (MR) and artificially-reared (AR) rats are assessed on their own maternal behavior, as well several other behaviors. While both AR and MR rats nurse and successfully wean their young, the AR rats spend less time licking, grooming, and crouching over their young. Hence, being raised in social isolation does not seem to affect primary maternal motivational dynamics. Instead, isolation rearing produces alterations in the ongoing execution of the behavior and its effective organization. Here, we present evidence that changes in maternal behavior, as a result of social isolation from mother and siblings, are due to changes in top-down (e.g., sustained attention, flexibility) and bottom-up process (e.g., increased stimulus driven behavior). These changes are likely due to alterations in brain dopamine systems, which are sensitive to early life manipulations and are modulators of bottom-up and top-down processes. Finally, we draw parallels between the rat and human maternal behavior. This article is part of a Special Issue entitled: In Honor of Jerry Hogan. PMID- 25724293 TI - Frequency-specific coupling between trial-to-trial fluctuations of neural responses and response-time variability. AB - We assessed intra-individual variability of response times (RT) and single-trial P3 amplitudes following targets in healthy adults during a Flanker/NO-GO task. RT variability and variability of the neural responses coupled at the faster frequencies examined (0.07-0.17 Hz) at Pz, the target-P3 maxima, despite non significant associations for overall variability (standard deviation, SD). Frequency-specific patterns of variability in the single-trial P3 may help to understand the neurophysiology of RT variability and its explanatory models of attention allocation deficits beyond intra-individual variability summary indices such as SD. PMID- 25724294 TI - High doses of onabotulinumtoxinA in post-stroke spasticity: a retrospective analysis. AB - We retrospectively evaluated the efficacy and safety of high doses of onabotulinumtoxinA (from 600 to 800 units) in 26 patients affected by upper and/or lower limb post-stroke spasticity. They were assessed before, 30 and 90 days after treatment. We observed a significant muscle tone reduction and a significant functional improvement (assessed with the Disability Assessment Scale). No adverse events were reported. In our retrospective analysis the treatment with high doses of onabotulinumtoxinA showed to be effective and safe. PMID- 25724295 TI - Modeling and simulation of soft sensor design for real-time speed and position estimation of PMSM. AB - This paper deals with the design of a speed soft sensor for permanent magnet synchronous motor. At high speed, model-based soft sensor is used and it gives excellent results. However, it fails to deliver satisfactory performance at zero or very low speed. High-frequency soft sensor is used at low speed. We suggest to use a model-based soft sensor together with the high-frequency soft sensor to overcome the limitations of the first one at low speed range. PMID- 25724296 TI - Robust pole assignment using velocity-acceleration feedback for second-order dynamical systems with singular mass matrix. AB - In this paper the robust pole assignment problem using combined velocity and acceleration feedback for second-order linear systems with singular mass matrix is illustrated. This is promising for better applicability in several practical applications where the acceleration signals are easier to obtain than the proportional ones. First, the explicit parametric expressions of both the feedback gain controller and the eigenvector matrix are derived. The parametric solution involves manipulations only on the original second-order model. The available degrees of freedom offered by the velocity-acceleration feedback in selecting the associated eigenvectors are utilized to improve robustness of the closed-loop system. Straight-forward computational algorithms are introduced to demonstrate the effectiveness of the proposed approach. These algorithms are applicable for a dynamical system with mass matrices that can be either singular or nonsingular. Numerical examples are provided to illustrate the application of the proposed procedure. PMID- 25724297 TI - Transformation of the endophytic fungus Acremonium implicatum with GFP and evaluation of its biocontrol effect against Meloidogyne incognita. AB - Acremonium implicatum is an endophytic fungus with biocontrol potential against Meloidogyne incognita based on its opportunistic egg-parasitic, hatching inhibition, and toxic properties. To understand its mode of plant endophytism and opportunistic egg parasitism, GFP-tagged A. implicatum was constructed by PEG mediated protoplast transformation. By laser scanning confocal microscopy (LSCM), we evaluated the endophytism and opportunistic egg parasitism of a stable gfp transformant (Acr-1). Acr-1 could colonize epidermal tissue, cortical tissue, and xylem of roots and form a mutualistic symbiosis with tomato host plants. LSCM of Acr-1 infecting M. incognita eggs revealed that hyphae penetrated the shell and grew inside eggs to form trophic hyphae. A large number of hyphae enveloped parasitized eggs. In addition, the egg shell integrity was destroyed by fungal penetration. The percentage of egg parasitism was 33.8 %. There were no marked differences between the wild type and mutant in nematode second-stage juvenile mortality and egg hatching and in fungal control efficiency in a pot experiment. In conclusion, gfp-transformation did not change the nematicidal activity of A. implicatum and is a tool to examine the mode of plant endophytism and opportunistic egg parasitism of A. implicatum. PMID- 25724298 TI - Enhanced lipid accumulation and biodiesel production by oleaginous Chlorella protothecoides under a structured heterotrophic-iron (II) induction strategy. AB - A structured heterotrophic-iron (II) induction (HII) strategy was proposed to enhance lipid accumulation in oleaginous Chlorella protothecoides. C. protothecoides subjected to heterotrophic-iron (II) induction achieved a favorable lipid accumulation up to 62 % and a maximum lipid productivity of 820.17 mg/day, representing 2.78-fold and 3.64-fold increase respectively over heterotrophic cultivation alone. HII-induced cells produced significantly elevated levels of 16:0, 18:1(Delta9), and 18:2(Delta9,12) fatty acids (over 90 %). The lipid contents and plant lipid-like fatty acid compositions exhibit the potential of HII-induced C. protothecoides as biodiesel feedstock. Furthermore, 31 altered proteins in HII-induced algal cells were successfully identified. These differentially expressed proteins were assigned into nine molecular function categories, including carbohydrate metabolism, lipid biosynthesis, Calvin cycle, cellular respiration, photosynthesis, energy and transport, protein biosynthesis, regulate and defense, and unclassified. Analysis using the Kyoto encyclopedia of genes and genomes and gene ontology annotation showed that malic enzyme, acyltransferase, and ACP were key metabolic checkpoints found to modulate lipid accumulation in C. protothecoides. The results provided possible applications of HII cultivation strategy in other microalgal species and new possibilities in developing genetic and metabolic engineering microalgae for desirable lipid productivity. PMID- 25724299 TI - The role of oxytocin and vasopressin in conditioned mate guarding behavior in the female rat. AB - We have shown previously that female rats given their first copulatory experiences with the same male rat display mate guarding behavior in the presence of that male provided a female competitor is also present. Females given access to the familiar male show more Fos induction within regions of the brain that contain oxytocin (OT) and vasopressin (AVP) cell bodies, notably the supraoptic (SON) and paraventricular nuclei (PVN) relative to females given sexual experience with different males. The present experiments examined whether the Fos induction we previously observed within the SON and PVN occurred within OT and/or AVP neurons, and whether exogenous administration of OT or AVP prior to female rats first sexual experience could potentiate the acquisition of mate guarding behavior. Female rats that display conditioned mate guarding had significantly more double-labeled Fos/OT neurons in both SON and PVN, and significantly more Fos/AVP neurons in the PVN. Peripheral administration of OT or AVP prior to their first sexual experience with the familiar male facilitated different aspects of mate guarding: OT augmented affiliative behaviors and presenting responses whereas AVP augmented interference behavior. These results indicate that female rats' first experiences with sexual reward when paired with the same male induce changes to bonding networks in the brain. Moreover peripheral administration of OT or AVP during their first sexual experience can augment different aspects of mate guarding behavior. PMID- 25724301 TI - The Urea-to-Creatinine Ratio Is Predictive of Worsening Kidney Function in Ambulatory Heart Failure Patients. AB - BACKGROUND: Changes in kidney function in heart failure patients convey important prognostic information. We investigated the association of the urea-to-creatinine (BUN/Cr) ratio, the fractional excretion of urea (FeUr), and the fractional excretion of sodium (FeNa) and subsequent declines in kidney function in ambulatory heart failure patients. METHODS AND RESULTS: We prospectively enrolled adult patients with ejection fraction <40% at a multidisciplinary heart failure clinic and measured serial measurements of laboratory values from September 2008 to July 2011. The study outcome was changes in the estimated glomerular filtration rate (eGFR). In 138 patients contributing 10,350 patient-hours of follow-up, we found that participants with a decline of >25% in eGFR had higher mean BUN/Cr ratio (0.110 +/- 0.043 vs 0.086 +/- 0.026; P = .02) and no difference in the FeNa (1.81 vs 1.43; P = .2) or FeUr (32.3 vs 37.2; P = .9) compared with those with no change. There was an association of BUN/Cr ratio with the rate of change of eGFR (coefficient -25.67, 95% confidence interval [CI] -10.99 to 40.35; P < .0001). The BUN/Cr ratio was an independent predictor of eGFR drop >25% (odds ratio 1.19, 95% CI 1.07-1.32) and improved model discrimination (c statistic increased from 0.624 to 0.693) and reclassification (net reclassification index 11.38% [P < .0001], integrated discrimination improvement 5.24% [P = .02]). CONCLUSIONS: The BUN/Cr ratio is associated with worsening kidney function and adds incremental risk prediction information relative to traditional predictive measures in outpatients with heart failure at risk for worsening kidney disease. PMID- 25724300 TI - Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. AB - Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naive LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ associated mutation in one or more MMR genes was observed in five out of six TMZ treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency. PMID- 25724302 TI - Roles of nonclinical and clinical data in prediction of 30-day rehospitalization or death among heart failure patients. AB - BACKGROUND: Selecting heart failure (HF) patients for intensive management to reduce readmissions requires effective targeting. However, available prediction scores are only modestly effective. We sought to develop a prediction score for 30-day all-cause rehospitalization or death in HF with the use of nonclinical and clinical data. METHODS AND RESULTS: This statewide data linkage included all patients who survived their 1st HF admission (with either reduced or preserved ejection fraction) to a Tasmanian public hospital during 2009-2012. Nonclinical data (n = 1,537; 49.5% men, median age 80 y) included administrative, socioeconomic, and geomapping data. Clinical data before discharge were available from 977 patients. Prediction models were developed and internally and externally validated. Within 30 days of discharge, 390 patients (25.4%) died or were rehospitalized. The nonclinical model (length of hospital stay, age, living alone, discharge during winter, remoteness index, comorbidities, and sex) had fair discrimination (C-statistic 0.66 [95% confidence interval (CI) 0.63-0.69]). Clinical data (blood urea nitrogen, New York Heart Association functional class, albumin, heart rate, respiratory rate, diuretic use, angiotensin-converting enzyme inhibitor use, arrhythmia, and troponin) provided better discrimination (C statistic 0.72 [95% CI 0.68-0.76]). Combining both data sources best predicted 30 day rehospitalization or death (C-statistic 0.76 [95% CI 0.72-0.80]). CONCLUSIONS: Clinical data are stronger predictors than nonclinical data, but combining both best predicts 30-day rehospitalization or death among HF patients. PMID- 25724303 TI - Monitoring of the microbiota of fermented sausages by culture independent rRNA based approaches. AB - In Italy, fermented sausages (called "salami") are consumed in large quantities. Salami samples from a local meat factory in the area of Torino were analyzed at 0, 3, 7, 30 and 45 days of ripening. Swab samples from the production environment were also collected at the beginning of the experiment. The diversity of metabolically active microbiota occurring during the natural fermentation of salami was evaluated by using RT-PCR-DGGE coupled with RNA-based pyrosequencing of the 16S rRNA gene. A culture-dependent approach was also applied to identify and characterize isolated Staphylococcaceae and LAB populations. Staphylococcus succinus, Staphylococcus xylosus and Lactobacillus sakei were the species most frequently isolated during the maturation time. Rep-PCR analysis showed that S. succinus and S. xylosus isolated from swabs and salami samples clustered together, suggesting possible contamination during the production process. RT-PCR DGGE and rRNA-based pyrosequencing showed that the metabolically active populations were dominated by S. succinus, Lb. sakei and Leuconostoc carnosum. In this specific case study, only a few species belonging to Staphylococcaceae, Lactobacillaceae and Leuconostocaceae may be metabolically active and contribute to determine the final characteristics of the products. PMID- 25724305 TI - Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. AB - Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c.5074G>C/p.Asp1692His, c.5074G>A/p.Asp1692Asn, c.5074G>T/p.Asp1692Tyr, c.5332G>A/p.Asp1778Asn, c.5332G>T/p.Asp1778Tyr, and c.5408G>C/p.Gly1803Ala), whereas five BRCA1 variants had no effect on splicing (c.4985T>C/p.Phe1662Ser, c.5072C>A/p.Thr1691Lys, c.5153G>C/p.Trp1718Ser, c.5154G>T/p.Trp1718Cys, and c.5333A>G/p.Asp1778Gly). Eight of the variants having an effect on splicing (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5074G>C/p.Asp1692His, c.5074G>A/p.Asp1692Asn, c.5074G>T/p.Asp1692Tyr, c.5332G>A/p.Asp1778Asn, c.5332G>T/p.Asp1778Tyr, and c.5408G>C/p.Gly1803Ala) were previously determined to have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification of BRCA1 missense variants located close to exon/intron boundaries. PMID- 25724306 TI - Smoking and survival in female breast cancer patients. AB - The purpose of this study was to determine if smoking affects survival in female breast cancer patients, both overall and stratified by race, ethnicity, and socioeconomic status. We linked data from the 1996-2007 Florida cancer data system, the Florida Agency for Health Care Administration, and the U.S. census. Inclusion criteria were females >=18 years, diagnosed with breast cancer, and residing in Florida (n = 127,754). To analyze the association between smoking and survival, we performed sequential multivariate Cox proportional hazard regression models with progressive adjustment for main confounders. Compared to never smokers, worse survival was found in current (hazard ratio 1.33; 95 % CI 1.28 1.38) and former smokers (1.09; 1.06-1.13). Those who smoked <1, 1-2, and >2 packs/day had worse survival (HR 1.28; 1.20-1.36; HR 1.40; 1.33-1.47 and 1.70; 1.45-1.99, respectively) (p for linear trend <0.001), than never smokers. Among Whites, current and former smokers had worse survival (HR 1.38; 1.33-1.44 and HR 1.11; 1.07-1.15, respectively) than never smokers. Worse survival was also found for current and former smokers (HR 1.34; 1.29-1.40 and HR 1.10; 1.06-1.15, respectively) compared with never smokers among non-Hispanics; similarly, worse survival was found among current Hispanic smokers (HR 1.13; 1.01-1.26). The association was not significant for Blacks. Current smoking is associated with worse survival in White breast cancer patients and through all socioeconomic status categories and ethnicities compared to never smoking. Former smoking is associated with worse survival in White and non-Hispanic females. Blacks had similar survival regardless of smoking status. Nonetheless, all female breast cancer patients should be advised to quit smoking. PMID- 25724304 TI - Superresolution imaging of viral protein trafficking. AB - The endoplasmic reticulum (ER) membrane is closely apposed to the outer mitochondrial membrane (OMM), which facilitates communication between these organelles. These contacts, known as mitochondria-associated membranes (MAM), facilitate calcium signaling, lipid transfer, as well as antiviral and stress responses. How cellular proteins traffic to the MAM, are distributed therein, and interact with ER and mitochondrial proteins are subject of great interest. The human cytomegalovirus UL37 exon 1 protein or viral mitochondria-localized inhibitor of apoptosis (vMIA) is crucial for viral growth. Upon synthesis at the ER, vMIA traffics to the MAM and OMM, where it reprograms the organization and function of these compartments. vMIA significantly changes the abundance of cellular proteins at the MAM and OMM, including proteins that regulate calcium homeostasis and cell death. Through the use of superresolution imaging, we have shown that vMIA is distributed at the OMM in nanometer scale clusters. This is similar to the clusters reported for the mitochondrial calcium channel, VDAC, as well as electron transport chain, translocase of the OMM complex, and mitochondrial inner membrane organizing system components. Thus, aside from addressing how vMIA targets the MAM and regulates survival of infected cells, biochemical studies and superresolution imaging of vMIA offer insights into the formation, organization, and functioning of MAM. Here, we discuss these insights into trafficking, function, and organization of vMIA at the MAM and OMM and discuss how the use of superresolution imaging is contributing to the study of the formation and trafficking of viruses. PMID- 25724307 TI - Characterization of the activity of ultrasound emitted in a perpendicular liquid flow using Particle Image Velocimetry (PIV) and electrochemical mass transfer measurements. AB - The present work is dedicated to the study of the interactions between a liquid circulation and a perpendicular acoustic wave propagation. A specific experimental setup was designed to study one transducer operating at 20 kHz, with the help of electrochemical mass transfer measurements combined with Particle Image Velocimetry (PIV) determination. Electrodes were located on the wall opposite to the acoustic emission. Experiments were performed for various Reynolds numbers: from 0 to 21700 (different liquid flow rates and viscosities). Both PIV and electrochemical measurements methods were found to be relevant, and had delivered complementary information. Even if PIV showed that the plume due to streaming was highly deflected by the additional flow, electrochemical measurements showed that there was still an activity, higher than in silent conditions, on the wall facing the transducer. Thus the ultrasound contribution remained noticeable on the surface opposite to the transducer even for a disturbed hydrodynamic environment due to the presence of a liquid circulation perpendicular to the wave propagation. PMID- 25724308 TI - Non-linear response and viscoelastic properties of lipid-coated microbubbles: DSPC versus DPPC. AB - For successful in vivo contrast-enhanced ultrasound imaging (CEUS) and ultrasound molecular imaging, detailed knowledge of stability and acoustical properties of the microbubbles is essential. Here, we compare these aspects of lipid-coated microbubbles that have either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as their main lipid; the other components were identical. The microbubbles were investigated in vitro over the frequency range 1-4 MHz at pressures between 10 and 100 kPa, and their response to the applied ultrasound was recorded using ultrahigh-speed imaging (15 Mfps). Relative to DPPC-coated microbubbles, DSPC-coated microbubbles had (i) higher acoustical stability; (ii) higher shell elasticity as derived using the Marmottant model (DSPC: 0.26 +/- 0.13 N/m, DPPC: 0.06 +/- 0.06 N/m); (iii) pressure amplitudes twice as high at the second harmonic frequency; and (iv) a smaller amount of microbubbles that responded at the subharmonic frequency. Because of their higher acoustical stability and higher non-linear response, DSPC coated microbubbles may be more suitable for contrast-enhanced ultrasound. PMID- 25724309 TI - Influence of Hepatic Inflammation on FibroScan Findings in Diagnosing Fibrosis in Patients with Chronic Hepatitis B. AB - Hepatic inflammation may affect the performance of FibroScan. This prospective study investigated the influence of hepatic inflammation on liver stiffness measurement (LSM) values by assessing FibroScan and liver biopsy findings in 325 patients with chronic hepatitis B. Liver fibrosis and inflammation were classified into five stages (S0-S4) and grades (G0-G4) according to the Scheuer scoring system. LSM values were correlated with fibrosis stage and inflammation grade (r = 0.479, p < 0.001, and r = 0.522, p < 0.001, respectively). Although LSM values increased in parallel with inflammation grade, no significant differences were found between patients with significant fibrosis (S2-S4) (p > 0.05). For inflammation grades G0, G1, G2 and G3, areas under receiver operating characteristic curves of FibroScan for significant fibrosis were 0.8267 (p < 0.001), 0.6956 (p < 0.001), 0.709 (p = 0.0012) and 0.6947 (p = 0.137), respectively. Inflammation has a significant influence on LSM values in patients with chronic hepatitis B with mild fibrosis, but not in those with significant fibrosis. PMID- 25724310 TI - Fungal Morphology in Industrial Enzyme Production--Modelling and Monitoring. AB - Filamentous fungi are widely used in the biotechnology industry for the production of industrial enzymes. Thus, considerable work has been done with the purpose of characterizing these processes. The ultimate goal of these efforts is to be able to control and predict fermentation performance on the basis of "standardized" measurements in terms of morphology, rheology, viscosity, mass transfer and productivity. However, because the variables are connected or dependent on each other, this task is not trivial. The aim of this review article is to gather available information in order to explain the interconnectivity between the different variables in submerged fermentations. An additional factor which makes the characterization of a fermentation broth even more challenging is that the data obtained are also dependent on the way they have been collected meaning which technologies or probes have been used, and on the way the data is interpreted-i.e. which models were applied. The main filamentous fungi used in industrial fermentation are introduced, ranging from Trichoderma reesei to Aspergillus species. Due to the fact that secondary metabolites, like antibiotics, are not to be considered bulk products, organisms like e.g. Penicillium chrysogenum are just briefly touched upon for the description of some characterization techniques. The potential for development of different morphological phenotypes is discussed as well, also in view of what this could mean to productivity and-equally important-the collection of the data. An overview of the state of the art techniques for morphology characterization is provided, discussing methods that finally can be employed as the computational power has grown sufficiently in the recent years. Image analysis (IA) clearly benefits most but it also means that methods like near infrared measurement (NIR), capacitance and on-line viscosity now provide potential alternatives as powerful tools for characterizing morphology. These measuring techniques, and to some extent their combination, allow obtaining the data necessary for supporting the creation of mathematical models describing the fermentation process. An important part of this article will indeed focus on describing the different models, and on discussing their importance to fermentations of filamentous fungi in general. The main conclusion is that it has not yet been attempted to develop an overarching model that spans across strains and scales, as most studies indeed conclude that their respective results might be strain specific and not necessarily valid across scales. PMID- 25724311 TI - A non-phenomenological model of competition and cooperation to explain population growth behaviors. AB - This paper is an extension of a previous work which proposes a non phenomenological model of population growth that is based on the interactions among the individuals of a population. In addition to what had already been studied-that the individuals interact competitively-in the present work it is also considered that the individuals interact cooperatively. As a consequence of this new consideration, a richer dynamics is observed. For instance, besides getting the population models already reached from the original version of the model (as the Malthus, Verhulst, Gompertz, Richards, Bertalanffy and power-law growth models), the new formulation also reaches the von Foerster growth model and also a regime of divergence of the population at a finite time. An agent based model is also presented in order to give support to the analytical results. Moreover, this new approach of the model explains the Allee effect as an emergent behavior of the cooperative and competitive interactions among the individuals. The Allee effect is the characteristic of some populations of increasing the population growth rate in a small-sized population. Whereas the models presented in the literature explain the Allee effect with phenomenological ideas, the model presented here explains this effect by the interactions between the individuals. The model is tested with empirical data to justify its formulation. Another interesting macroscopic emergent behavior from the model proposed is the observation of a regime of population divergence at a finite time. It is interesting that this characteristic is observed in humanity's global population growth. It is shown that in a regime of cooperation, the model fits very well to the human population growth data from 1000 AD to nowadays. PMID- 25724312 TI - Formulation and optimization of efavirenz nanosuspensions using the precipitation ultrasonication technique for solubility enhancement. AB - Efavirenz is a non-nucleoside reverse transcriptase inhibitor, and is classified as BCS Class II API. Its erratic oral absorption and poor bioavailability make it a potential candidate for being formulated as a nanosuspension. The objective of this study was to formulate efavirenz nanosuspensions employing the antisolvent precipitation-ultrasonication method, and to enhance its solubility by reducing particle size to the nanometer range. The effects of different process parameters were studied and optimized with respect to particle size and poly dispersity index (PDI). The optimized formulation was also subjected to lyophilization, to further increase the solubility and stability, and the technology is potentially suited to a range of poorly water-soluble compounds. PMID- 25724313 TI - Cortical screw trajectory for instrumentation and fusion in the setting of osteopathic compression fracture allows for percutaneous kyphoplasty for adjacent level compression fractures. AB - Spinal fixation in the osteoporotic patient can be challenging due to the poor trabecular bone quality of the vertebral body. Patients with osteoporotic vertebral body compression fractures are at risk for future compression fractures at adjacent levels, especially after cement augmentation. The purpose of this technical report is to describe the utilization of a cortical screw trajectory along with kyphoplasty for a patient with an osteoporotic compression fracture as well as degenerative spinal disease. This trajectory allows for the possibility of percutaneous pedicle access in the event of future compression fractures. Our patient underwent a decompressive laminectomy and kyphoplasty at the level of an osteoporotic compression fracture. The fracture was stabilized with cortical screw instrumentation and fusion at a level above and a level below the fracture. Subsequently the patient developed an adjacent level fracture within the fusion construct. Due to the utilization of a cortical screw trajectory for the initial fusion, the traditional pedicle trajectory was still accessible. As a result, the new fracture was treated with a percutaneous kyphoplasty through a standard pedicle trajectory. In conclusion, the use of a cortical screw trajectory for stabilization of osteoporotic compression fractures provides for a stronger bone screw interface and avoids osteoporotic trabecular vertebral body bone. At the same time this trajectory allows for future percutaneous pedicular access in the event that the patient suffers future compression fractures. PMID- 25724314 TI - Comorbidities in Cushing's disease. AB - INTRODUCTION: Cushing's disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality. METHODS: Here we review the comorbidities associated with Cushing's disease and their impact on quality of life and mortality. RESULTS: Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbidity and a poor quality of life. Normalization of cortisol levels leads to significant improvement in comorbidities but long-term data regarding complete resolution are lacking and need further study. CONCLUSION: Early diagnosis and treatment of hypercortisolemia, aggressive management of comorbidities along with long-term follow-up is crucial for the optimal recovery of these patients. PMID- 25724315 TI - Surgical management of Cushing's disease. AB - BACKGROUND: Transsphenoidal selective adenomectomy is the first-line treatment for Cushing's disease. At experienced centers, early remission rates after transsphenoidal surgery range from 65 to 98%, however disease relapse frequently occurs with rates ranging from 2 to 35% at long-term follow up. METHODS: This article discusses recently reported studies on the surgical outcomes from transsphenoidal surgery for Cushing's disease. CONCLUSIONS: One of the keys to a successful long-term surgical outcome is meticulous dissection using the adenoma's pseudocapsule as a surgical plane for complete resection. MRI-negative and invasive ACTH-secreting adenomas pose particular challenges for pituitary surgeons. PMID- 25724316 TI - Seeing One's Own Painful Hand Positioned in the Contralateral Space Reduces Subjective Reports of Pain and Modulates Laser Evoked Potentials. AB - Studies report that viewing the body or keeping one's arms crossed while receiving painful stimuli may have an analgesic effect. Interestingly, changes in ratings of pain are accompanied by a reduction of brain metabolism or of laser evoked potentials amplitude. What remains unknown is the link between visual analgesia and crossed-arms related analgesia. Here, we investigated pain perception and laser evoked potentials in 3 visual contexts while participants kept their arms in a crossed or uncrossed position during vision of 1) one's own hand, 2) a neutral object in the same spatial location, and 3) a fixation cross placed in front of the participant. We found that having vision of the affected body part in the crossed-arms position was associated with a significant reduction in pain reports. However, no analgesic effect of having vision of the hand in an uncrossed position or of crossing the arms alone was found. The increase of the late vertex laser evoked potential P2 amplitude indexed a general effect of vision of the hand. Our results hint at a complex interaction between cross-modal input and body representation in different spatial frames of reference and at the same time question the effect of visual analgesia and crossed-arms analgesia alone. PERSPECTIVE: We found that nociceptive stimuli delivered to the hand in a crossed-arms position evoke less pain than in a canonical anatomic position. Yet we report no significant analgesic effect of vision or crossing the arms on their own. These findings foster the integration of visuospatial and proprioceptive information in rehabilitation protocols. PMID- 25724317 TI - KIR2DS5 in the presence of HLA-C C2 protects against endometriosis. AB - Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity. Several hypotheses have attempted to explain the etiology and pathogenesis of endometriosis. Recently, it has been suggested that a defect of the natural killer (NK) activity in the recognition and lysis of endometrial cells is one of the crucial points in the development of this disease. Natural killer cells can express killer immunoglobulin-like receptors (KIR), which recognize class I human leukocyte antigens on target cells. We asked whether polymorphisms in KIR, HLA-C, and HLA-B genes are risk factors for endometriosis. We tested 153 women with endometriosis diagnosed on the basis of laparoscopic and histological examination, and 213 control healthy women, who gave birth to at least one child. The frequency of KIR genes in patients was similar to that in controls except for KIR2DS5, which exerted a protective effect only in HLA-C C2 positive individuals. Moreover, KIR2DS5-positive women with endometriosis had 13 times lower chance that the disease would occupy the peritoneum than KIR2DS5- and KIR2DS4del-negative ones (OR = 0.077, P = 0.0061). Similarly, KIR2DS4del-positive endometriotic persons had 11 times lower chance for peritoneal disease (OR = 0.094, P < 0.001). Negative linkage disequilibrium between KIR2DS5 and KIR2DS4del indicates that these genes are mutually exclusive. Our data suggest that KIR2DS5 may be associated with protection from endometriosis, whereas KIR2DS4del seems to be associated with higher disease stages, possibly by exclusion of protective KIR2DS5. PMID- 25724318 TI - Erratum to: IL28B SNP screening and distribution in the French Canadian population using a rapid PCR-based test. PMID- 25724320 TI - A framework for analyzing the relationship between gene expression and morphological, topological, and dynamical patterns in neuronal networks. AB - BACKGROUND: A key point in developmental biology is to understand how gene expression influences the morphological and dynamical patterns that are observed in living beings. NEW METHOD: In this work we propose a methodology capable of addressing this problem that is based on estimating the mutual information and Pearson correlation between the intensity of gene expression and measurements of several morphological properties of the cells. A similar approach is applied in order to identify effects of gene expression over the system dynamics. Neuronal networks were artificially grown over a lattice by considering a reference model used to generate artificial neurons. The input parameters of the artificial neurons were determined according to two distinct patterns of gene expression and the dynamical response was assessed by considering the integrate-and-fire model. RESULTS: As far as single gene dependence is concerned, we found that the interaction between the gene expression and the network topology, as well as between the former and the dynamics response, is strongly affected by the gene expression pattern. In addition, we observed a high correlation between the gene expression and some topological measurements of the neuronal network for particular patterns of gene expression. COMPARISON WITH EXISTING METHODS: To our best understanding, there are no similar analyses to compare with. CONCLUSIONS: A proper understanding of gene expression influence requires jointly studying the morphology, topology, and dynamics of neurons. The proposed framework represents a first step towards predicting gene expression patterns from morphology and connectivity. PMID- 25724319 TI - Neurological counterparts of hyponatremia: pathological mechanisms and clinical manifestations. AB - Hyponatremia, defined as a serum sodium concentration <135 mEq/L, represents the most frequent electrolyte disorder in older hospitalized patients. Early recognition of hyponatremia is mandatory, since it represents an independent risk factor that increases hospital mortality by 40 %. Delayed correction of hyponatremia may worsen brain edema, resulting in different degrees of neural damage. However, an overly rapid correction of serum sodium levels can lead to osmotic demyelination syndrome (ODS), a dreadful neurological picture. In recent years, hyponatremia and ODS have received growing attention both in terms of clinical management and pathophysiology, leading to the discovery of new drugs and treatment algorithms. In this review, we recapitulate the pathogenetic background, clinical manifestations, and treatment guidelines of hyponatremia, focusing on the neurological alterations. Neurological symptoms may be neglected when they manifest as early signs of mild hyponatremia, while brain damage can irremediably affect patients' conditions in the context of ODS. PMID- 25724321 TI - Exploring task-related variability in fMRI data using fluctuations in power spectrum of simultaneously acquired EEG. AB - BACKGROUND: The paper deals with joint analysis of fMRI and scalp EEG data, simultaneously acquired during event-related oddball experiment. The analysis is based on deriving temporal sequences of EEG powers in individual frequency bands for the selected EEG electrodes and using them as regressors in the general linear model (GLM). NEW METHOD: Given the infrequent use of EEG spectral changes to explore task-related variability, we focused on the aspects of parameter setting during EEG regressor calculation and searched for such parameters that can detect task-related variability in EEG-fMRI data. We proposed a novel method that uses relative EEG power in GLM. RESULTS: Parameter, the type of power value, has a direct impact as to whether task-related variability is detected or not. For relative power, the final results are sensitive to the choice of frequency band of interest. The electrode selection also has certain impact; however, the impact is not crucial. It is insensitive to the choice of EEG power series temporal weighting step. Relative EEG power characterizes the experimental task activity better than the absolute power. Absolute EEG power contains broad spectrum component. Task-related relative power spectral formulas were derived. COMPARISON WITH EXISTING METHODS: For particular set of parameters, our results are consistent with previously published papers. Our work expands current knowledge by new findings in spectral patterns of different brain processes related to the experimental task. CONCLUSIONS: To make analysis to be sensitive to task-related variability, the parameters type of power value and frequency band should be set properly. PMID- 25724322 TI - Development of an exercise intervention to improve cognition in people with mild to moderate dementia: Dementia And Physical Activity (DAPA) Trial, registration ISRCTN32612072. AB - More than 800000 people in the UK have dementia, and it is a government priority to improve dementia care. Drug treatment options are relatively limited. The Dementia And Physical Activity (DAPA) study is a randomised trial which targets cognition in people with dementia, using an exercise programme. There is evidence to suggest that both aerobic and resistance exercise may be useful in improving cognition. Hence the intervention comprises a supervised part of twice-weekly exercise classes of one hour duration for 4 months, including aerobic exercise at moderate intensity on static bicycles, and resistance (weight training) exercise using weight vests, weight belts and dumbbells. Thereafter participants progress to unsupervised, independent exercise. Aids to behaviour modification have been incorporated into the intervention. The DAPA intervention has been designed to maximise likelihood of effectiveness and cost-effectiveness, and for delivery in the UK National Health Service. PMID- 25724323 TI - Effectiveness of land-based physiotherapy exercise following hospital discharge following hip arthroplasty for osteoarthritis: an updated systematic review. AB - BACKGROUND: Existing review required updating. OBJECTIVE: To evaluate the effectiveness of physiotherapy exercise after discharge from hospital on function, walking, range of motion, quality of life and muscle strength, for patients following elective primary total hip arthroplasty for osteoarthritis. DESIGN: Systematic review from January 2007 to November 2013. DATA SOURCES: AMED, CINAHL, EMBASE, MEDLINE, Kingsfund Database, and PEDro. Cochrane CENTRAL, BioMed Central (BMC), The Department of Health National Research Register and Clinical Trials.gov register. Searches were overseen by a librarian. Authors were contacted for missing information. No language restrictions were applied. ELIGIBILITY CRITERIA: Trials comparing physiotherapy exercise vs usual/standard care, or comparing two types of relevant exercise physiotherapy, following discharge from hospital after elective primary total hip replacement for osteoarthritis were reviewed. OUTCOMES: Functional activities of daily living, walking, quality of life, muscle strength and joint range of motion. STUDY APPRAISAL: Quality and risk of bias for studies were evaluated. Data were extracted and meta-analyses considered. RESULTS: 11 trials are included in the review. Trial quality was mixed. Newly included studies were assessed as having lower risk of bias than previous studies. Narrative review indicates that physiotherapy exercise after discharge following total hip replacement may potentially benefit patients in terms of function, walking and muscle strengthening. LIMITATIONS: The overall quality and quantity of trials, and their diversity, prevented meta-analyses. CONCLUSIONS: Disappointingly, insufficient evidence still prevents the effectiveness of physiotherapy exercise following discharge to be determined for this patient group. High quality, adequately powered, trials with long term follow up are required. PMID- 25724324 TI - The Phosphorylation State of GSK3beta Serine 9 Correlated to the Development of Valproic Acid-Associated Fetal Cardiac Teratogenicity, Fetal VPA Syndrome, Rescued by Folic Acid Administration. AB - The effects of the phosphorylation state of the glycogen synthase kinase 3beta involved in the cardiac myocytes (jelly-like cells) epithelial-mesenchymal transition-associated migration during heart-valve formation were examined through the valproic acid-induced cardiac teratogenicity of transgenic line A34 of Tg in a the Brachydanio rerio embryo model. Valproic acid is an effective anti epileptic drug; however, when taken by pregnant women to treat epilepsy, it can produce cardiac developmental defects in fetuses. In this study, the role of glycogen synthase kinase 3beta in valproic acid-induced cardiac teratogenicity was investigated. Transgenic line A34 of zebrafish embryos was used at 3 days postfertilization. The results show that 78% (18/23) of the embryos treated with 0.10 mM valproic acid (group A) had incomplete chamber formation with normal looping and 22 % (5/23) had abnormal looping. Bradycardia was also found in comparison with control embryos (P < 0.001). For the embryos treated with 0.25 mM valproic acid (group B), 92% (22/24) demonstrated chamber formation failure and looping abnormality. Pericardial effusion, noncontracting ventricles, and enlarged, slowly beating atriums were observed at 6 days postfertilization. Valproic acid inhibited phosphorylation of serine 9 in glycogen synthase kinase 3beta in a dose-dependent manner. According to immunochemical staining results, valproic acid was shown to inhibit the mass migration and proliferation of cardiomyocytes in the development of the heart-valve region through inhibition of the GSK3beta Ser 9 phosphorylation. Folic acid rescued the GSK3beta Ser 9 phosphorylation and reversed the valproic acid-induced cardiac morphological, functional, and biochemical defects. PMID- 25724325 TI - Protection of Luteolin-7-O-Glucoside Against Doxorubicin-Induced Injury Through PTEN/Akt and ERK Pathway in H9c2 Cells. AB - Luteolin-7-O-glucoside (LUTG) was isolated from the plants of Dracocephalum tanguticum Maxim. Previous research has showed that LUTG pretreatment had a significant protective effect against doxorubicin (DOX)-induced cardiotoxicity by reducing intracellular calcium overload and leakage of creatine kinase and lactate dehydrogenase. But the underlying mechanisms have not been completely elucidated. In the present study, we investigated the effects of LUTG on H9c2 cell morphology, viability, apoptosis, reactive oxygen species generation, and the mitochondrial transmembrane potentials. The expression of p-PTEN, p-Akt, p ERK, p-mTOR, and p-GSK-3beta were detected by Western blotting. Compared with DOX alone treatment group, the morphological injury and apoptosis of the cells in groups treated by DOX plus LUTG were alleviated, cell viability was increased, ROS generation was lowered remarkably, and mitochondrial depolarization was mitigated. In DOX group, the expression of p-PTEN was lower than normal group and the expression of p-Akt and p-ERK was higher than normal group. In the groups treated with LUTG (20 MUM), the expression of p-PTEN was upregulated and the expression of p-Akt, p-ERK, p-mTOR, and p-GSK-3beta was downregulated. These results indicated that the protective effects of LUTG against DOX-induced cardiotoxicity may be related to anti-apoptosis through PTEN/Akt and ERK pathway. PMID- 25724326 TI - Exosome and exosomal microRNA: trafficking, sorting, and function. AB - Exosomes are 40-100 nm nano-sized vesicles that are released from many cell types into the extracellular space. Such vesicles are widely distributed in various body fluids. Recently, mRNAs and microRNAs (miRNAs) have been identified in exosomes, which can be taken up by neighboring or distant cells and subsequently modulate recipient cells. This suggests an active sorting mechanism of exosomal miRNAs, since the miRNA profiles of exosomes may differ from those of the parent cells. Exosomal miRNAs play an important role in disease progression, and can stimulate angiogenesis and facilitate metastasis in cancers. In this review, we will introduce the origin and the trafficking of exosomes between cells, display current research on the sorting mechanism of exosomal miRNAs, and briefly describe how exosomes and their miRNAs function in recipient cells. Finally, we will discuss the potential applications of these miRNA-containing vesicles in clinical settings. PMID- 25724327 TI - Anxiety Sensitivity and Its Factors in Relation to Generalized Anxiety Disorder among Adolescents. AB - Anxiety psychopathology, one of the most prevalent classes of disorder among youth, is linked to detrimental outcomes. Accordingly, identifying factors that influence vulnerability to anxiety disorders is important. One promising factor, given emerging evidence for its transdiagnostic nature, is anxiety sensitivity (AS); however, relatively little is known about the linkage between AS and indicators of generalized anxiety disorder (GAD), particularly among youth. The aim of the current investigation was to address this gap in the literature using a community-based sample of adolescents aged 10-17 years (n = 165; M age = 14.49 years, SD = 2.26). Results indicated global AS and the AS-physical concerns dimension were significantly associated with worry, generalized anxiety symptoms, and GAD diagnosis assessed via a structured clinical interview, above and beyond key theoretically-relevant covariates. These findings add to a growing body of work underscoring the relevance of AS for multiple types of anxiety-related disorders among youth. PMID- 25724328 TI - Introduction to the Special Section: Biopsychosocial Processes in the Etiology and Development of Internalizing Problems. AB - In recent years, empirical attention to the etiology and development of internalizing problems has increased, alongside the growing recognition of their prevalence and severity. A comprehensive understanding of internalizing problems requires an integrative biopsychosocial perspective. The five empirical papers in this special section present findings from five longitudinal studies that reflect this perspective, and shed new light on the multiplicity of factors and processes that are involved in the development of internalizing problems. This brief introduction unpacks the biopsychosocial construct and highlights the points of conceptual commonality that link the articles. PMID- 25724329 TI - [Role of alpha-hemoglobin molecular chaperone in the hemoglobin formation and clinical expression of some hemoglobinopathies]. AB - Alpha-hemoglobin stabilizing protein (AHSP), described as a chaperone of alpha hemoglobin (alpha-Hb), is synthesized at a high concentration in the erythroid precursors. AHSP specifically recognizes the G and H helices of alpha-Hb and forms a stable complex with free alpha-Hb until its association with the partner beta-subunits. Unlike the free beta-Hb which are soluble and form homologous tetramers, freshly synthesized alpha-Hb chains are highly unstable molecular species which precipitate and generate reactive oxygen species within the erythrocyte precursors of the bone marrow leading to apoptosis and ineffective erythropoiesis. AHSP protects the free alpha-Hb chains in maintaining it in the soluble state. In this review, we report data from the literature and our laboratory concerning the key role of AHSP in the biosynthesis of Hb and its possible involvement in some disorders of the red blood cell as well as the hemoglobinopathies and we discuss its use as a prognostic tool in thalassemia syndromes. PMID- 25724330 TI - EEG biofeedback for autism spectrum disorders: a reply to a commentary by Coben and Ricca (2014). PMID- 25724331 TI - H2 genotypes of G4P[6], G5P[7], and G9[23] porcine rotaviruses show super-short RNA electropherotypes. AB - During group A rotavirus (RVA) surveillance of pig farms in Japan, we detected three RVA strains (G4P[6], G5P[7], and G9P[23] genotypes), which showed super short RNA patterns by polyacrylamide gel electrophoresis, in samples from a healthy eight-day-old pig and two pigs of seven and eight days old with diarrhea from three farms. Reverse transcription PCR and sequencing revealed that the full length NSP5 gene of these strains contained 952 or 945 nucleotides, which is consistent with their super-short electropherotypes. Due to a lack of whole genome data on Japanese porcine RVAs, we performed whole genomic analyses of the three strains. The genomic segments of these RVA strains showed typical porcine RVA constellations, except for H2 NSP5 genotype, (G4,5,9-P[6,7,23]-I5-R1-C1-M1-A8 N1-T1-E1-H2 representing VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5 genes). In phylogenetic analyses, these porcine RVA strains clustered with porcine and porcine-like human RVA strains and showed a typical porcine RVA backbone, except for the NSP5 gene; however, intra-genotype reassortment events among porcine and porcine-like human RVA strains were observed. The NSP5 gene segments of these strains were clustered within the H2b genotype with super-short human RVA strains. The H2 genotype has to date only been identified in human and lapine RVA strains. Thus, to our knowledge, this report presents the first case of H2 NSP5 genotype showing a super-short RNA pattern in porcine RVA. These data suggest the possibility of interspecies transmission between pigs and humans and imply that super-short porcine RVA strains possessing H2 genotype are circulating among both asymptomatic and diarrheic porcine populations in Japan. PMID- 25724332 TI - West Nile virus serosurveillance in pigs, wild boars, and roe deer in Serbia. AB - West Nile virus (WNV) is maintained in nature in an enzootic transmission cycle between birds and mosquitoes, but it also infects many other vertebrates, including humans and horses, in which it can induce severe neurological diseases; however, data about virus circulation in other mammals is scarce. WNV has a history of recent outbreaks in Europe, including Serbia, where it was identified for the first time in 2010 in mosquitoes and in 2012 in birds and humans, being responsible for over 300 confirmed human cases and 35 deaths there along 2013. To assess WNV circulation among mammals in the country, 688 samples obtained from 279 farm pigs, 318 wild boars, and 91 roe deer were investigated for the presence of antibodies to WNV by enzyme-linked immunosorbent assay (ELISA) and viral neutralization test (VNT), and the specificity of their reactivity was assayed against Usutu virus (USUV). ELISA-reactive sera were identified in 43 (15.4%) pigs, 56 (17.6%) wild boars, and 17 (18.7%) roe deer. Of these, 6 (14%), 33 (59%), and 4 (23.5%) respectively, neutralized WNV. One out of the 45 ELISA negative sera tested, from a roe deer, neutralized WNV. Cross-reactivity neutralization test indicated that all deer and pigs neutralizing sera were WNV specific, while in 5 (15.2%) of the wild boar samples the specificity could not be established. Four wild boar sera showed USUV specificity. All these data confirm the circulation of both flaviviruses in Serbia, and highlight the need for the implementation of global coordinated surveillance programs in the region. PMID- 25724333 TI - Understanding and managing bTB risk: perspectives from Ireland. AB - There is substantial variation in herd risk for bovine tuberculosis (bTB) in Ireland, with most herds playing little to no role in the ongoing endemic. In infected areas, bTB persistence (affecting one or a group of herds) is a key feature of the infection. In this paper, we present our current understanding and management of bTB risk in Ireland, based on a detailed review of research and policy. There is close interaction between science and policy in Ireland, seeking both to understand and effectively manage bTB risk. Detailed research on bTB persistence is presented, including current understanding of the relative importance of different infection sources, which can include residual infection in cattle and/or re-infection, either from local sources or following cattle introduction. In recent years, there have been three primary drivers for policy change, including scientific advances, ongoing improvements to programme supports, and ongoing programme review. In this review, three key future programme challenges are identified. Although good progress is being made, eradication has not yet been achieved. Firstly, a key question concerns the additional effort that will be required, to move towards final eradication. Secondly, a percentage of non-infected animals are falsely positive to current testing methods. This is an ongoing challenge, given the imperfect specificity of test methods but will become more so, as the positive predictive value falls with reducing bTB prevalence. Finally, there is a need to re-engage with the farming community, so that they play a much greater role in programme ownership. PMID- 25724334 TI - C-type lectin-like domain and fibronectin-like type II domain of phospholipase A(2) receptor 1 modulate binding and migratory responses to collagen. AB - Phospholipase A2 receptor 1 (PLA2R) mediates collagen-dependent migration. The mechanisms by which PLA2R interacts with collagen remain unclear. We produced HEK293 cells expressing full-length wild-type PLA2R or a truncated PLA2R that lacks fibronectin-like type II (FNII) domains or several regions of C-type lectin like domain (CTLD). We show that the CTLD1-2 as well as the FNII domain of PLA2R are responsible for binding to collagen and for collagen-dependent migration. Thus, multiple regions and domains of the extracellular portion of PLA2R participate in the responses to collagen. These data suggest a potentially new mechanism for PLA2R-mediated biological response beyond that of a receptor for secretory PLA2. PMID- 25724335 TI - Essential function of Aco2, a fusion protein of aconitase and mitochondrial ribosomal protein bL21, in mitochondrial translation in fission yeast. AB - A possible interaction between aconitase and a mitochondrial ribosomal protein was suggested in a genome-wide interactome study. In fission yeast Schizosaccharomyces pombe, the aco2(+) gene encodes a fusion protein between aconitase and a putative mitochondrial ribosomal protein bL21 (Mrpl49). Two types of aco2(+) transcripts are generated via alternative poly (A) site selection, producing both a single aconitase domain protein and the fusion form. The bL21 fused Aco2 protein resides in mitochondria as well as in the cytosol and the nucleus. The viability defect of aco2 mutation is complemented not by the aconitase domain but by the bL21 domain, which enables mitochondrial translation. PMID- 25724336 TI - Construction of allitol synthesis pathway by multi-enzyme coexpression in Escherichia coli and its application in allitol production. AB - An engineered strain for the conversion of D-fructose to allitol was developed by constructing a multi-enzyme coupling pathway and cofactor recycling system in Escherichia coli. D-Psicose-3-epimerase from Ruminococcus sp. and ribitol dehydrogenase from Klebsiella oxytoca were coexpressed to form the multi-enzyme coupling pathway for allitol production. The cofactor recycling system was constructed using the formate dehydrogenase gene from Candida methylica for continuous NADH supply. The recombinant strain produced 10.62 g/l allitol from 100 mM D-fructose. To increase the intracellular concentration of the substrate, the glucose/fructose facilitator gene from Zymomonas mobilis was incorporated into the engineered strain. The results showed that the allitol yield was enhanced significantly to 16.53 g/l with a conversion rate of 92 %. Through optimizing conversion conditions, allitol was produced effectively on a large scale by the whole-cell biotransformation system; the yield reached 48.62 g/l when 500 mM D-fructose was used as the substrate. PMID- 25724337 TI - Temperature effects on biomass, geosmin, and 2-methylisoborneol production and cellular activity by Nocardia spp. and Streptomyces spp. isolated from rainbow trout recirculating aquaculture systems. AB - Isolates of Nocardia cummidelens, Nocard ia fluminea, Streptomyces albidoflavus, and Streptomyces luridiscabiei attributed as the cause of "earthy-musty" off flavor in rainbow trout (Oncorhynchus mykiss) raised in recirculating aquaculture systems (RAS) were evaluated for the effect of temperature (10-30 degrees C) on biomass, geosmin, and 2-methylisoborneol (MIB) production and cellular activity. Cultures of these isolates were monitored over 7 days by measuring culture dry weight, geosmin, and MIB production using solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS), and ATP production via a luminometer. Compared to the other isolates, S. luridiscabiei had significantly (P < 0.05) higher biomass (8.17 +/- 0.35 mg/mL) at 15 degrees C (water temperature in the RAS) after 7 days incubation. In addition, S. luridiscabiei produced significantly (P < 0.05) higher geosmin (69,976 +/- 15,733 ng/L) at 15 degrees C. At 25 degrees C and 30 degrees C, S. albidoflavus produced significantly (P < 0.05) higher geosmin (182,074 +/- 60,272 ng/L and 399,991 +/- 102,262 ng/L, respectively). All isolates produced MIB at 15 degrees C, but S. luridiscabiei produced significantly (P < 0.05) higher MIB (97,143 +/- 28,972 ng/L) and ATP after 7 days. Therefore, S. luridiscabiei appears to be a likely contributor of geosmin and MIB in the RAS. PMID- 25724338 TI - Myricetin suppresses differentiation of 3 T3-L1 preadipocytes and enhances lipolysis in adipocytes. AB - Myricetin (MyR), a naturally occurring flavonol widely distributed in fruits, vegetables, and medicinal plants, has anticancer, anti-inflammatory, antihyperlipidaemic, and antiobesity activities. In the present study, we hypothesized that the antiobesity property of MyR is mediated via suppression of differentiation of preadipocytes into adipocytes and promotion of lipolysis of mature adipocytes, which effectively decrease the intracellular triglyceride concentration of adipocytes. Accordingly, the aim of this work was to investigate the effects of MyR on adipocyte differentiation and lipolysis in differentiated 3 T3-L1 adipocytes. Our results showed that MyR inhibited differentiation of 3 T3 L1 preadipocytes in a concentration-dependent manner. Myricetin downregulated the mRNA and protein levels of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma, both of which are major adipogenic transcription factors. Furthermore, the mRNA levels of other adipogenesis-related transcription factors, namely, CCAAT/enhancer-binding protein beta, sterin regulatory element binding protein 1-c, peroxisome proliferator-activated receptor gamma coactivator-1, adipocyte protein 2, lipoprotein lipase and glucose transporter 4, were also reduced by MyR treatment. Moreover, MyR significantly inhibited the phosphorylation of extracellular signal-regulated kinase, Jun N terminal kinase, and p38 during the differentiation process. On the other hand, MyR induced a dose-dependent increase in glycerol release in fully differentiated adipocytes, indicating its stimulatory effect on adipocyte lipolysis. Furthermore, MyR downregulated mRNA level of perilipin A and enhanced the phosphorylation level of extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 during lipolysis. Taken together, these findings indicate that MyR exerts antiobesity activity in adipocytes. PMID- 25724339 TI - Enhanced tolerance of Saccharomyces cerevisiae to multiple lignocellulose-derived inhibitors through modulation of spermidine contents. AB - Fermentation inhibitors present in lignocellulose hydrolysates are inevitable obstacles for achieving economic production of biofuels and biochemicals by industrial microorganisms. Here we show that spermidine (SPD) functions as a chemical elicitor for enhanced tolerance of Saccharomyces cerevisiae against major fermentation inhibitors. In addition, the feasibility of constructing an engineered S. cerevisiae strain capable of tolerating toxic levels of the major inhibitors without exogenous addition of SPD was explored. Specifically, we altered expression levels of the genes in the SPD biosynthetic pathway. Also, OAZ1 coding for ornithine decarboxylase (ODC) antizyme and TPO1 coding for the polyamine transport protein were disrupted to increase intracellular SPD levels through alleviation of feedback inhibition on ODC and prevention of SPD excretion, respectively. Especially, the strain with combination of OAZ1 and TPO1 double disruption and overexpression of SPE3 not only contained spermidine content of 1.1mg SPD/g cell, which was 171% higher than that of the control strain, but also exhibited 60% and 33% shorter lag-phase period than that of the control strain under the medium containing furan derivatives and acetic acid, respectively. While we observed a positive correlation between intracellular SPD contents and tolerance phenotypes among the engineered strains accumulating different amounts of intracellular SPD, too much SPD accumulation is likely to cause metabolic burden. Therefore, genetic perturbations for intracellular SPD levels should be optimized in terms of metabolic burden and SPD contents to construct inhibitor tolerant yeast strains. We also found that the genes involved in purine biosynthesis and cell wall and chromatin stability were related to the enhanced tolerance phenotypes to furfural. The robust strains constructed in this study can be applied for producing chemicals and advanced biofuels from cellulosic hydrolysates. PMID- 25724340 TI - An evolutionary metabolic engineering approach for enhancing lipogenesis in Yarrowia lipolytica. AB - Lipogenic organisms provide an ideal platform for biodiesel and oleochemical production. Through our previous rational metabolic engineering efforts, lipogenesis titers in Yarrowia lipolytica were significantly enhanced. However, the resulting strain still suffered from decreased biomass generation rates. Here, we employ a rapid evolutionary metabolic engineering approach linked with a floating cell enrichment process to improve lipogenesis rates, titers, and yields. Through this iterative process, we were able to ultimately improve yields from our prior strain by 55% to achieve production titers of 39.1g/L with upwards of 76% of the theoretical maximum yield of conversation. Isolated cells were saturated with up to 87% lipid content. An average specific productivity of 0.56g/L/h was achieved with a maximum instantaneous specific productivity of 0.89g/L/h during the lipid production phase in fermentation. Genomic sequencing of the evolved strains revealed a link between a decrease/loss of function mutation of succinate semialdehyde dehydrogenase, uga2, suggesting the importance of gamma-aminobutyric acid assimilation in lipogenesis. This linkage was validated through gene deletion experiments. This work presents an improved host strain that can serve as a platform for efficient oleochemical production. PMID- 25724341 TI - In-house PCR with DNA extracted directly from positive slides to confirm or exclude the diagnosis of tuberculosis: focus on biosafety. AB - The possibility to obtain DNA from smears is a valuable alternative to remedy the lack of samples when they are totally used for bacilloscopy; this technique solves the biosafety problem related to a possible accident with the transportation of flasks containing potentially transmissible clinical samples. Hence, the purpose of this study was to utilize the insertion sequence IS6110 for amplification of DNA from a smear-positive sample for tuberculosis (TB) diagnosis. Among the 52 positive bacilloscopies, sensitivity, specificity, positive predictive value and negative predictive value were 52.3%, 100%, 100% and 89.7%, respectively whereas accuracy was 90.7%. The IS6110-based PCR for TB diagnosis developed in DNA extracted from a positive smear is a fast, simple, specific, and safe method. PMID- 25724342 TI - The state of a central inhibition system predicts access to visual targets: An ERP study on distractor-induced blindness (DIB). AB - Distractor-induced blindness (DIB) is elicited in a temporal selection task based on rapid serial visual presentation: Following the onset of a central cue (color change of fixation), a target in a global stream has to be detected (orientation change of tilted bars). Distractors are occasional target-like events presented prior to the onset of the cue. Depending on the number of distractor episodes, a frontal ERP negativity (FN) is evoked, and the detection rate of the forthcoming target is reduced. Here, we provide a concise review of the DIBs' functional characteristics, and examine the relationship between FN activation on target processing and detectability. To this end, ERP responses collected in a set of participants (n=14) were analysed separately with respect to detection performance (hits vs. misses). A gradual increase in the amplitude of the FN with increasing number of distractor events was only observed for forthcoming misses, but not for hits. The FN activation can be linked to a target-related ERP component: The amplitude of a late centro-parietal positivity (LPC) was significantly diminished for misses. In sum, the data support the notion that the DIB reflects the controlled activation of a central inhibition system. Depending on its state of activation, conscious access to stimuli defined by distinctive visual features is restricted. PMID- 25724343 TI - Homocitrate synthase expression and lysine content in fruiting body of different developmental stages in Flammulina velutipes. AB - Homocitrate synthase (EC 2.3.3.14) regulates the first step of fungal lysine biosynthesis. The gene encoding homocitrate synthase was identified in whole genomic sequencing of Flammulina velutipes and contains seven introns. The homocitrate synthase gene of F. velutipes strain W23 (Fvhcs) is 1780 bp in length and encodes a 464 amino acid protein with a predicted molecular weight 50.7 kDa. Phylogenetic analysis of Fvhcs and other homocitrate synthase proteins from diverse fungi produced a topology congruent with the current best estimate of organismal phylogeny. Analysis of protein domains by InterProScan and a motif search found that Fvhcs gene encodes homocitrate synthase protein conserved across Agaricomycotina. In addition, we sequenced the transcriptome of different developmental stages and structures of the fruiting body to analyze the expression levels of the Fvhcs gene. The data showed a correlation between Fvhcs gene expression and lysine values in different developmental stages and structures of F. velutipes. PMID- 25724344 TI - Phenotypic and genotypic characterization of biofilm formation in Staphylococcus haemolyticus. AB - Staphylococcus haemolyticus is one of the most frequently isolated coagulase negative staphylococci. The ability to produce biofilm has contributed to its emergence as a nosocomial pathogen. In this study, some growth conditions were tested to determine their influence on biofilm formation. Brain-heart infusion (BHI) broth containing glucose was used to screen 64 clinical strains. A strong biofilm producer strain showed cells surrounded by a thick layer of extracellular matrix. The presence of atlE, fbp, bap, and icaA genes was analyzed. We concluded that S. haemolyticus biofilm production can be increased with cells grown in BHI, and highlighted that it could be an ica-independent process. PMID- 25724345 TI - Case study: a case of debilitating gout in the 1st metatarsophalangeal joint. AB - Gout is a painful arthritic condition that affects many people worldwide. The disease has been associated with hyperuricaemia and life style risk factors such as obesity, alcohol intake, meat and seafood consumption. We present a case of a 67-year-old male with a history of gout, who attended the clinic with a painful 1st metatarsophalangeal joint, which had progressively worsened in pain, mobility and deformity in the last 20 years. Although lifestyle changes had been advised by the GP some years earlier such as a low purine based diet, management had only consisted of NSAID's, which had not significantly improved symptoms. Surgical excision of chalky white material from around the 1st metatarsophalangeal joint rendered the patient symptom free with increased mobility after 6 weeks. Histopathology confirmed the excised tissue as gouty tophus. Following this, the patient was placed on allopurinol, a xanthine oxidase inhibitor to prevent recurrent attacks. This case study highlights the importance of early recognition and prophylactic management in gout sufferers. In joints where the disease process is well-established surgical excision of the gouty tophus may help mitigate further disease progression, and restore quality of life to individuals. PMID- 25724347 TI - The Expanded Four Habits Model-A teachable consultation model for encounters with patients in emotional distress. AB - OBJECTIVE: The study aims to develop a teachable consultation model for encounters with patients in emotional distress. METHODS: The Expanded Four Habits Model is designed for improving the consultations with patients in emotional distress or with other psychosocial concerns. The model represents an integration between the concept of Six Skills (Stensrud T, Gulbrandsen P, Mjaaland T, Skretting S, Finset A. Improving communication in general practice when mental health issues appear: piloting a set of six evidence-based skills. Patient Educ Couns 2014;95:69-75) and the Four Habits Model (Frankel RM, Stein T. Getting the most out of the clinical encounter: the four habits model. Permanente J. 1999;3:79-88). RESULTS: The proposed new model includes an expansion of the original Four Habits within three key psychological domains: emotion, cognition and coping. There is one explorative and one elaborative skill in each domain. The theoretical foundation of the model is presented. The six specific skills are described and research findings and literature supporting the model reviewed. As is the case with the original Four Habits model, the expanded model represents both a model of the consultation and a scheme for communication skills training. CONCLUSION: The Expanded Four Habits Model is a simple and teachable scheme to help the clinician to structure consultations with patients in emotional distress. PRACTICE IMPLICATIONS: The model should be tested as a communication skills training program based on training principles developed in the Four Habits training courses. PMID- 25724346 TI - Evaluation and selection of reference genes for ecotoxicogenomic study of the green alga Closterium ehrenbergii using quantitative real-time PCR. AB - The green alga Closterium ehrenbergii occurs in fresh water environments and has been suggested as a model for ecotoxicological assessment. Quantitative real-time PCR (qRT-PCR), with its high sensitivity and specificity, is a preferred method for reliable quantification of gene expression levels. qRT-PCR requires reference genes to normalize the transcription level of the target gene, and selection of appropriate references is crucial. Here, we evaluated nine housekeeping genes, that is, 18S rRNA, ACT, TUA, TUB, eIF, H4, UBQ, rps4, and GAPDH, using 34 RNA samples of C. ehrenbergii cultured in various environments (e.g. exposure to heat shock, UV, metals, and non-metallic chemicals). Each housekeeping gene tested displayed different ranges of C T values for each experimental condition. The gene stability was determined using the descriptive statistic software geNorm, which showed that ACT, H4, and TUA were the most suitable reference genes for all the conditions tested. In addition, at least three genes were required for proper normalization. With these references, we assessed the expression level of the heat shock protein 70 (HSP70) gene in C. ehrenbergii cells exposed to thermal and toxic contaminant stress and found that it was significantly up-regulated by these stressors. This study provides potential reference genes for gene expression studies on C. ehrenbergii with qRT-PCR. PMID- 25724348 TI - Evolving interpretation of the athlete's electrocardiogram: from European Society of Cardiology and Stanford criteria, to Seattle criteria and beyond. AB - Electrocardiographic (ECG) pre-participation screening can prevent sudden cardiac death in the athletes by early diagnosis and disqualification of affected individuals. Interpretation of the athlete's ECG should be based on specific criteria, because ECG changes that would be considered abnormal in the untrained population may develop in trained athletes as a physiologic and benign consequence of the heart's adaptation to exercise. In 2010, a stem document from the Section of Sports Cardiology of the European Society of Cardiology (ESC) proposed to classify the athlete's ECG changes according to the prevalence, relation to exercise training, association with an increased risk of cardiovascular disease and need for further investigations into two groups: "common and training-related" (Group 1) and "uncommon and training-unrelated" (Group 2). Over the last years, several efforts have been made to refine the ESC criteria for interpretation of the athlete's ECG in order to improve specificity maintaining good sensitivity, especially among elite and Afro-Caribbean athletes, which show the highest rate of false positives Group 2 ECG abnormalities. However, the balance between improvement in specificity and loss of sensitivity should be evaluated keeping in mind that the primary aim of the screening program is to save the athlete's lives rather than money. PMID- 25724349 TI - What are hydra effects? A response to Schroder et al. PMID- 25724350 TI - Impact of interfractional changes in head and neck cancer patients on the delivered dose in intensity modulated radiotherapy with protons and photons. AB - PURPOSE: To investigate the influence of interfractional changes on the delivered dose of intensity modulated proton (IMPT) and photon plans (IMXT). METHODS AND MATERIALS: Five postoperative head and neck cancer patients, previously treated with tomotherapy at our institute, were analyzed. The planning study is based on megavoltage (MV) control images. For each patient one IMPT plan and one IMXT plan were generated on the first MV-CT and recalculated on weekly control MV-CTs in the actual treatment position. Dose criteria for evaluation were coverage and conformity of the planning target volume (PTV), as well as mean dose to parotids and maximum dose to spinal cord. RESULTS: Considerable dosimetric changes were observed for IMPT and IMXT plans. Proton plans showed a more pronounced increase of maximum dose and decrease of minimum dose with local underdosage occurring even in the center of the PTV (worst IMPT vs. IMXT coverage: 66.7% vs. 85.0%). The doses to organs at risk (OARs) increased during the treatment period. However, the OAR doses of IMPT stayed below corresponding IMXT values at any time. For both modalities treatment plans did not necessarily worsen monotonically throughout the treatment. CONCLUSIONS: Although absolute differences between planned and reconstructed doses were larger in IMPT plans, doses to OARs were higher in IMXT plans. Tumor coverage was more stable in IMXT plans; IMPT dose distributions indicated a high risk for local underdosage during the treatment course. PMID- 25724351 TI - A novel method for dose distribution registration using fiducial marks made by a megavoltage beam in film dosimetry for intensity-modulated radiation therapy quality assurance. AB - PURPOSE: Photographic film is widely used for the dose distribution verification of intensity-modulated radiation therapy (IMRT). However, analysis for verification of the results is subjective. We present a novel method for marking the isocenter using irradiation from a megavoltage (MV) beam transmitted through slits in a multi-leaf collimator (MLC). METHODS: We evaluated the effect of the marking irradiation at 500 monitor units (MU) on the total transmission through the MLC using an ionization chamber and Radiochromic Film. Film dosimetry was performed for quality assurance (QA) of IMRT plans. Three methods of registration were used for each film: marking by irradiating with an MV beam through slits in the MLC (MLC-IC); marking with a fabricated phantom (Phantom-IC); and a subjective method based on isodose lines (Manual). Each method was subjected to local gamma-analysis. RESULTS: The effect of the marking irradiation on the total transmission was 0.16%, as measured by a ionization chamber at a 10-cm depth in a solid phantom, while the inter-leaf transmission was 0.3%, determined from the film. The mean pass rates for each registration method agreed within +/- 1% when the criteria used were a distance-to-agreement (DTA) of 3 mm and a dose difference (DD) of 3%. For DTA/DD criteria of 2mm/3%, the pass rates in the sagittal plane were 96.09 +/- 0.631% (MLC-IC), 96.27 +/- 0.399% (Phantom-IC), and 95.62 +/- 0.988% (Manual). CONCLUSION: The present method is a versatile and useful method of improving the objectivity of film dosimetry for IMRT QA. PMID- 25724352 TI - Glial U87 cells protect neuronal SH-SY5Y cells from indirect effect of radiation by reducing oxidative stress and apoptosis. AB - Recent studies have demonstrated the role of indirect effect of radiation in neurodegeneration. However, the role of glial cells in neuroprotection against indirect effect of radiation is still not clear, although they are known to protect neurons under stress conditions in central nervous system. Our study showed that indirect effect of radiation increased the oxidative stress that further enhances the expression of key apoptotic proteins and leads to neuronal cell death. We also investigated the indirect effect of radiation on neuronal cells in the presence of glial cells in a transwell co-culture system, while our analysis was focused on neuronal cells. Irradiated cell-conditioned medium (ICCM) was used as source of indirect radiation and neuroprotective effect was analyzed by various endpoints. It was observed that ICCM-induced reactive oxidative species level was significantly reduced in SH-SY5Y cells co-cultured with glial U87 cells, which might help to maintain the integrity of mitochondrial membrane potential. Increased levels of antioxidant enzyme superoxide dismutase and antioxidant glutathione were observed in SH-SY5Y cells co-cultured with glial U87 cells. Moreover, it was also observed that co-culture with glial cells inhibits the expression of ICCM-induced apoptotic proteins, i.e. Bax, cytochrome c, and caspase-3 in SH-SY5Y cells. Hence, it can be speculated that in co-culture system glial cells may protect the neuronal SH-SY5Y cells by reducing the ICCM-induced oxidative stress and apoptotic death. PMID- 25724353 TI - Ontogenic expression of human carboxylesterase-2 and cytochrome P450 3A4 in liver and duodenum: postnatal surge and organ-dependent regulation. AB - Human carboxylesterase-2 (CES2) and cytochrome P450 3A4 (CYP3A4) are two major drug metabolizing enzymes that play critical roles in hydrolytic and oxidative biotransformation, respectively. They share substrates but may have opposite effect on therapeutic potential such as the metabolism of the anticancer prodrug irinotecan. Both CES2 and CYP3A4 are expressed in the liver and the gastrointestinal tract. This study was conducted to determine whether CES2 and CYP3A4 are expressed under developmental regulation and whether the regulation occurs differentially between the liver and duodenum. A large number of tissues (112) were collected with majority of them from donors at 1-198 days of age. In addition, multi-sampling (liver, duodenum and jejunum) was performed in some donors. The expression was determined at mRNA and protein levels. In the liver, CES2 and CYP3A4 mRNA exhibited a postnatal surge (1 versus 2 months of age) by 2.7 and 29 fold, respectively. CYP3A4 but not CES2 mRNA in certain pediatric groups reached or even exceeded the adult level. The duodenal samples, on the other hand, showed a gene-specific expression pattern at mRNA level. CES2 mRNA increased with age but the opposite was true with CYP3A4 mRNA. The levels of CES2 and CYP3A4 protein, on the other hand, increased with age in both liver and duodenum. The multi-sampling study demonstrated significant correlation of CES2 expression between the duodenum and jejunum. However, neither duodenal nor jejunal expression correlated with hepatic expression of CES2. These findings establish that developmental regulation occurs in a gene and organ-dependent manner. PMID- 25724354 TI - Effectiveness of simplified 15-min refresher BLS training program: a randomized controlled trial. AB - OBJECTIVES: To evaluate the long-term effectiveness of 15-min refresher basic life support (BLS) training following 45-min chest compression-only BLS training. METHODS: After the 45-min chest compression-only BLS training, the participants were randomly assigned to either the refresher BLS training group, which received a 15-min refresher training 6 months after the initial training (refresher training group), or to the control group, which did not receive refresher training. Participants' resuscitation skills were evaluated by a 2-min case-based scenario test 1 year after the initial training. The primary outcome measure was the number of appropriate chest compressions during a 2-min test period. RESULTS: 140 participants were enrolled and 112 of them completed this study. The number of appropriate chest compressions performed during the 2-min test period was significantly greater in the refresher training group (68.9+/-72.3) than in the control group (36.3+/-50.8, p=0.009). Time without chest compressions was significantly shorter in the refresher training group (16.1+/-2.1 s versus 26.9+/ 3.7 s, p<0.001). There were no significant differences in time to chest compression (29.6+/-16.7 s versus 34.4+/-17.8 s, p=0.172) and AED use between the groups. CONCLUSIONS: A short-time refresher BLS training program 6 months after the initial training can help trainees retain chest compression skills for up to 1 year. Repeated BLS training, even if very short, would be adopted to keep acquired CPR quality optimal (UMIN-CTR UMIN 000004101). PMID- 25724355 TI - Inconsistent shock advisories for monomorphic VT and Torsade de Pointes--A prospective experimental study on AEDs and defibrillators. AB - BACKGROUND: Cardiovascular disease and sudden cardiac arrest are the leading causes of death in the United States. Early defibrillation is key to successful resuscitation for patients who experience shockable rhythms during a cardiac arrest. It is therefore vital that the shock advisory of AEDs (automated external defibrillators) or defibrillators in AED mode be reliable and appropriate. The goal of this study was to better understand the performance of multiple lay rescuer and hospital professional defibrillators in AED mode in their analysis of ventricular arrhythmias. The measurable objectives of this study sought to quantify: 1. No shock advisory for sinus rhythms at any rate. 2. Recognition and shock advisory for ventricular fibrillation (VF). 3. Recognition and shock advisory for monomorphic ventricular tachycardia (VT). 4. Recognition and shock advisory for Torsades de Pointes (TdP). METHODS: This is a prospective evaluation of two AEDs and four semi-automatic, hospital professional defibrillators. This study represents post-marketing evaluation of FDA approved devices. Each defibrillator was connected to multiple rhythm simulators and presented with simulated ECG waveforms 20 consecutive times at various rates when possible. RESULTS: All four defibrillators and both AEDs tested consistently recognized normal sinus rhythm (NSR) from all rhythm sources, and did not recommend a shock for NSR at any rate (from 80 to 220 bpm). All four defibrillators and both AEDs recognized VF from all rhythm sources tested and recommended a shock 100% of the time. Variations were found in the shock advisory rates among defibrillators when testing simulated VT heart rates at or below 150 bpm. One AED tested did not consistently advise a shock for monomorphic VT or TdP at any tested rate. CONCLUSION: Lay-rescuer AEDs and professional hospital defibrillators tested in AED mode did not reliably recommend a shock for sustained monomorphic VT or TdP at certain rates, despite the fact that it is a critical component of the currently recommended treatment. These findings require further examination of the risk benefit analysis of shocking or not shocking rhythms such as TdP or pulseless VT. PMID- 25724356 TI - Volume versus outcome: More emergency medical services personnel on-scene and increased survival after out-of-hospital cardiac arrest. AB - BACKGROUND AND AIM: The large regional variation in survival after treatment of out-of-hospital cardiac arrest (OHCA) is incompletely explained. Communities respond to OHCA with differing number of emergency medical services (EMS) personnel who respond to the scene. The effect of different numbers of EMS personnel on-scene upon outcomes is unclear. We sought to evaluate the association between number of EMS personnel on-scene and survival after OHCA. METHODS: We performed a retrospective review of prospectively collected data on 16,122 EMS-treated OHCA events from December 1, 2005 to May 31, 2007 from a combined population over 21 million people residing in an area of over 33,000 square miles in Canada and the United States. Number of EMS personnel on-scene was defined as the number of EMS personnel who responded to the scene of OHCA within 15 min after 9-1-1 call receipt and prior to patient death or transport away from the scene. Associations with survival to hospital discharge were assessed by using generalized estimating equations to construct multivariable logistic regression models. RESULTS: Compared to a reference number of EMS personnel on-scene of 5 or 6, 7 or 8 EMS personnel on-scene was associated with a higher rate of survival to hospital discharge, adjusted odds ratio [OR], 1.35 (95% CI: 1.05, 1.73). There was no significant difference in survival between 5 or 6 personnel on-scene versus fewer. CONCLUSION: More EMS personnel on-scene within 15 min of 9-1-1 call was associated with improved survival of out-of hospital cardiac arrest. It is unlikely that this finding was mediated solely by earlier CPR or earlier defibrillation. PMID- 25724357 TI - Implementation of a software for REmote COMparison of PARticlE and photon treatment plans: ReCompare. AB - PURPOSE: To guarantee equal access to optimal radiotherapy, a concept of patient assignment to photon or particle radiotherapy using remote treatment plan exchange and comparison - ReCompare - was proposed. We demonstrate the implementation of this concept and present its clinical applicability. MATERIALS AND METHODS: The ReCompare concept was implemented using a client-server based software solution. A clinical workflow for the remote treatment plan exchange and comparison was defined. The steps required by the user and performed by the software for a complete plan transfer were described and an additional module for dose-response modeling was added. RESULTS: The ReCompare software was successfully tested in cooperation with three external partner clinics and worked meeting all required specifications. It was compatible with several standard treatment planning systems, ensured patient data protection, and integrated in the clinical workflow. CONCLUSION: The ReCompare software can be applied to support non-particle radiotherapy institutions with the patient-specific treatment decision on the optimal irradiation modality by remote treatment plan exchange and comparison. PMID- 25724358 TI - Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation. AB - Iron accumulation occurs in the CNS in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying such iron accumulation are not fully understood. We studied the expression and cellular localization of molecules involved in cellular iron influx, storage, and efflux. This was assessed in two mouse models of EAE: relapsing-remitting (RR-EAE) and chronic (CH-EAE). The expression of molecules involved in iron homeostasis was assessed at the onset, peak, remission/progressive and late stages of the disease. We provide several lines of evidence for iron accumulation in the EAE spinal cord which increases with disease progression and duration, is worse in CH-EAE, and is localized in macrophages and microglia. We also provide evidence that there is a disruption of the iron efflux mechanism in macrophages/microglia that underlie the iron accumulation seen in these cells. Macrophages/microglia also lack expression of the ferroxidases (ceruloplasmin and hephaestin) which have antioxidant effects. In contrast, astrocytes which do not accumulate iron, show robust expression of several iron influx and efflux proteins and the ferroxidase ceruloplasmin which detoxifies ferrous iron. Astrocytes therefore are capable of efficiently recycling iron from sites of EAE lesions likely into the circulation. We also provide evidence of marked dysregulation of mitochondrial function and energy metabolism genes, as well as of NADPH oxidase genes in the EAE spinal cord. This data provides the basis for the selective iron accumulation in macrophage/microglia and further evidence of severe mitochondrial dysfunction in EAE. It may provide insights into processes underling iron accumulation in MS and other neurodegenerative diseases in which iron accumulation occurs. PMID- 25724359 TI - A mouse model of skin aging: fragmentation of dermal collagen fibrils and reduced fibroblast spreading due to expression of human matrix metalloproteinase-1. PMID- 25724360 TI - Melanocyte-specific cytotoxic T lymphocytes in patients with rhododendrol-induced leukoderma. PMID- 25724362 TI - Identification of HSP70-inducing activity in Arnica montana extract and purification and characterization of HSP70-inducers. AB - BACKGROUND: The expression of heat shock proteins (HSPs), particularly HSP70, is receiving considerable attention in the field of cosmetics, particularly given our recent report that ultraviolet-induced melanin production, skin damage and wrinkle formation were all suppressed in transgenic mice expressing HSP70. OBJECTIVE: In the present study, we searched for HSP70-inducers from a library of herbal extracts that have already been approved as quasi-pharmaceutical products in Japan. We selected an ethanol extract of Arnica montana (A. montana), based on its high HSP70-inducing activity and low cytotoxicity. METHODS: Cell viability was determined by MTT method and expression of HPS70 was monitored by immunoblotting analysis. RESULTS: From the extract, we purified and identified eight sesquiterpene lactones (AM1-8) as HSP70-inducers, among which AM-2 (helenalin 2-methylbutyrate) was selected due to its good HSP70-inducing properties and low cytotoxicity. Treatment of cultured mouse melanoma cells with AM-2 or A. montana extract up-regulated the expression of HSP70 in a dose dependent manner. This treatment also activated heat shock factor-1, a transcription factor for hsp genes. Furthermore, pre-treatment of cells with AM-2 or A. montana extract decreased melanin production and expression and activity of tyrosinase. CONCLUSION: These results suggest that AM-2 and A. montana extract could be beneficial for use in hypopigmenting cosmetics as a consequence of their stimulatory effects on HSP70 expression. PMID- 25724363 TI - In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases. AB - BACKGROUND: Bullous pemphigoid (BP) is an acquired autoimmune blistering disease characterized by subepidermal blister formation, in vivo linear deposition of immunoglobulin G (IgG) and complements at the dermal-epidermal junction (DEJ). The circulating IgG autoantibodies are directed against two epidermal hemidesmosomal glycoproteins: BP180, also known as type XVII collagen (COL17), and BP230. In addition, recent studies have shown that IgE autoantibodies may be involved in the pathogenesis of BP, although in vivo IgE deposition in lesional skin has not been fully characterized in large numbers of BP patients. OBJECTIVE: This study investigated the incidence of in vivo deposition of IgE autoantibodies at the DEJ in lesional skin from a large number of BP patients. METHODS: Peri lesional skin samples from 100 patients who met the clinical and histopathological criteria for BP were investigated by direct immunofluorescence for the deposition of autoantibodies and complement. Patients' sera were also investigated by enzyme-linked immunosorbent assay and indirect immunofluorescence. RESULTS: 18% of BP patients were found to show IgE deposition at the DEJ. Disease severity, clinical course and outcome did not differ between IgE-positive and IgE-negative patients. In 3 IgE-positive cases, IgG was undetectable in vivo, and these cases showed atypical manifestations. CONCLUSION: The results of in vivo IgE deposition may not be useful in predicting the disease course of BP, although predominant IgE deposition could alter the pattern of clinical manifestations. PMID- 25724364 TI - The Dutch version of the Child Posttraumatic Cognitions Inventory: validation in a clinical sample and a school sample. AB - BACKGROUND: With the inclusion of trauma-related cognitions in the DSM-5 criteria for posttraumatic stress disorder (PTSD), the assessment of these cognitions has become essential. Therefore, valid tools for the assessment of these cognitions are warranted. OBJECTIVE: The current study aimed at validating the Dutch version of the Child Posttraumatic Cognitions Inventory (CPTCI). METHOD: We included children aged 8-19 years in our study and assessed the factor structure, reliability and validity of the CPTCI in a clinical sample (n=184) and a school sample (n=318). RESULTS: Our results supported the two-factor structure of the CPTCI and showed good internal consistency for the total scale and the two subscales. We found significant positive correlations between the CPTCI and measures of PTSD, depression, and anxiety disorder. The CPTCI correlated negatively with a measure of quality of life. Furthermore, we found significantly higher scores in the clinical sample than in the school sample. For children who received treatment, we found that a decrease in CPTCI scores was accompanied by a decrease in posttraumatic stress symptoms and comorbid problems indicating that the CPTCI is able to detect treatment effects. CONCLUSION: Overall, our results suggest that the Dutch CPTCI is a reliable and valid instrument. PMID- 25724365 TI - Restoration of Wnt/beta-catenin signaling attenuates alcoholic liver disease progression in a rat model. AB - BACKGROUND & AIMS: Alcoholic liver disease (ALD) is characterized by the development of fatty liver, alcoholic hepatitis, fibrosis and cirrhosis. However, the underlying mechanism(s) associated with progression remains elusive. Pro inflammatory cytokines have been implicated in ALD progression due to pro apoptotic effects on hepatocytes. Wnt/beta-catenin signaling recently has been shown to promote inflammation and apoptosis, suggesting that activation of this signaling pathway may modulate ALD progression. The current study was designed to test whether pharmacological activation of Wnt/beta-catenin signaling altered ALD development and progression in a rat model. METHODS: Adult male Long Evans rats were fed with isocaloric liquid diets containing 0% or 37% ethanol for 8 weeks, and also treated with Wnt agonist during the last 3 weeks of the feeding regimen. Liver and blood samples were subjected to histology, TUNEL assay, immunoblot analysis, real-time quantitative PCR, and alanine transaminase (ALT) assay. RESULTS: Wnt/beta-catenin signaling was negatively correlated with Foxo3A expression and reduced steatosis, cellular injury and apoptosis in ALD rats. Mutation experiments demonstrated that Foxo3A was critical for modulating these effects. Activation of Wnt/beta-catenin signaling suppressed Foxo3A-induced apoptosis through upregulation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, pharmacological restoration of Wnt/beta-catenin signaling reduced ALD progression in vivo. CONCLUSIONS: Wnt/beta-catenin signaling plays a protective role in ALD progression via antagonizing Foxo3A-induced apoptosis, and activation of the Wnt/beta-catenin signaling cascade attenuates ALD progression. PMID- 25724367 TI - Liberte, liberte cherie. AB - As part of the Journal of Cell communication and Signaling publishing staff, we are very much attached to the freedom of expression given to our authors. This has been exemplified in our willingness to stimulate commentaries and open debates through the Bits and Bytes series published in JCCS.Without willing to take part in the debate regarding the nature of the drawings published in Charlie Hebdo, we recognize the worldwide response to the recent murdering of journalists as strong support of freedom of the press , however, we also felt that attempts to silence other forms of expression, which are numerous these days, should be reminded and fought against.In this editorial we pay homage to the victims of recent tragic events in Paris and to all who fight every day for freedom of expression. PMID- 25724366 TI - Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma. AB - BACKGROUND & AIMS: Obesity defined by body mass index (BMI) significantly increases the risk of hepatocellular carcinoma (HCC). In contrast, not only obesity but also underweight is associated with poor prognosis in patients with HCC. Differences in body composition rather than BMI were suggested to be true determinants of prognosis. However, this hypothesis has not been demonstrated conclusively. METHODS: We measured skeletal muscle index (SMI), mean muscle attenuation (MA), visceral adipose tissue index, subcutaneous adipose tissue index, and visceral to subcutaneous adipose tissue area ratios (VSR) via computed tomography in a large-scale retrospective cohort of 1257 patients with different stages of HCC, and comprehensively analyzed the impact of body composition on the prognoses. RESULTS: Among five body composition components, low SMI (called sarcopenia), low MA (called intramuscular fat [IMF] deposition), and high VSR (called visceral adiposity) were significantly associated with mortality, independently of cancer stage or Child-Pugh class. A multivariate analysis revealed that sarcopenia (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.18-1.96; p=0.001), IMF deposition (HR, 1.34; 95% CI, 1.05-1.71; p=0.020), and visceral adiposity (HR, 1.35; 95% CI, 1.09-1.66; p=0.005) but not BMI were significant predictors of survival. The prevalence of poor prognostic body composition components was significantly higher in underweight and obese patients than in normal weight patients. CONCLUSIONS: Sarcopenia, IMF deposition, and visceral adiposity independently predict mortality in patients with HCC. Body composition rather than BMI is a major determinant of prognosis in patients with HCC. PMID- 25724368 TI - Nutrition-dependent changes of mouse adipose tissue compositions monitored by NMR, MS, and chromatographic methods. AB - Many diseases nowadays are assumed to be genetically determined. Therefore, many knockout mouse models have been established and are widely used. Unfortunately, nutrition (in particular the fat content of food) is often neglected in studies on these disease models. In this study the effects of nutrition on the lipid (triacylglycerol, TAG) compositions of different mouse adipose tissues were investigated. Mice were subjected to different diets [high fat (HF) vs. standard diet (SD)] and different adipose tissue samples (brown, visceral, and subcutaneous fat) were isolated after 12 weeks. Subsequent to lipid extraction, the organic extracts were analyzed by mass spectrometry (MALDI and ESI), high resolution (1)H and (31)P NMR spectroscopy, high-performance thin-layer chromatography (HPTLC), and gas chromatography (GC). In adipose tissue of mice fed with HF diet, (a) decreased double bond contents and (b) decreased fatty acyl chain lengths of tissue TAGs were observed; this trend could be concomitantly monitored by all methods used. However, the adipose tissue still contained significant amounts of slightly unsaturated fatty acyl residues (18:1). Thus, a certain double bond content seems necessary to maintain the properties of adipose tissues. PMID- 25724369 TI - Quantitative urinary proteomics using stable isotope labelling by peptide dimethylation in patients with prostate cancer. AB - Prostate cancer (PCa) is the most commonly diagnosed malignancy in men. The current prevalent diagnosis method, prostate-specific antigen (PSA) screening test, has low sensitivity, specificity and is poor at predicting the grade of disease. Thus, new biomarkers are urgently needed to improve the PCa diagnosis and staging for the management of patients. The aim of this study is to investigate the first voided urinary sample after massage for biomarker discovery for PCa. In this work, untargeted metabolomic profiling of the first voided urinary sample after massage from 28 confirmed prostate cancer patients, 20 benign enlarged prostate patients and 6 healthy volunteers was performed using liquid chromatography coupled to high-resolution tandem mass spectrometry (LC MS/MS). Single and multiple peptide protein and cross-linking molecules were identified using PEAKS software. Analytical and diagnostic performance was tested using the Student's t test, Benjamini Hochberg correction and the receiver operating characteristic (ROC) curves. Using differential display analysis to compare peptides and cross-linking molecules of urinary samples between patients with benign, enlarged prostate and malignant cancer, we identified multiple peptides derived from osteopontin (SPP1) and prothrombin (F2) that are lower in PCa patients than in benign and enlarged prostate. The diagnosis accuracies of SPP1 and F2 peptides are 0.65-0.77 and 0.68-0.72, respectively. In addition to this, there are significant differences between PCa and benign/enlarged prostate patients in pyridinoline (PYD) and deoxypyridinoline (DPD) (p value = 0.001). Differences also, as shown in the excretion of these molecules for different stages of PCa (p value = 0.04) as the level of DPD and DPD/PYD ratio, were high in patients with locally advanced tumours. The study underscores the importance of proteomics analysis, and our results demonstrate that a urinary-based in depth proteomic approach allows the potential identification of dysregulated pathways and diagnostic biomarkers. PMID- 25724370 TI - Protein-losing enteropathy as a rare complication of the ketogenic diet. AB - INTRODUCTION: The ketogenic diet is a valuable therapy for patients with intractable epilepsy, but it can result in a variety of complications that sometimes limits its usefulness. Hypoproteinemia is one of the common adverse effects of this diet, although the underling mechanism is largely unknown except for the diet's reduced protein intake. Only one case of protein-losing enteropathy during the ketogenic diet has been reported. PATIENT DESCRIPTION: A previously healthy 9-year-old girl experienced fever for 5 days then suddenly developed convulsive seizures that subsequently evolved to severe refractory status epilepticus. After multiple antiepileptic drugs failed to improve the patient's condition, we introduced the ketogenic diet. Although her seizures diminished, her course was complicated by hypoproteinemia. An abdominal dynamic scintigraphy and colonoscopy findings indicated protein-losing enteropathy with nonspecific mucosal inflammation. Her nutritional status deteriorated; thus, we discontinued the ketogenic diet. Her nutritional status gradually improved, whereas her seizures increased. DISCUSSION: Hypoproteinemia during the ketogenic diet is common, but the underlying etiologies are not well understood. Abdominal dynamic scintigraphy could be valuable for clarifying the etiology of hypoproteinemia during the ketogenic diet. PMID- 25724371 TI - Prenatal cerebellar hemorrhage: fetal and postnatal neuroimaging findings and postnatal outcome. AB - BACKGROUND: Despite significant progress in fetal neuroimaging techniques, only a few well-documented examples of prenatal cerebellar hemorrhages are available in the literature. In the majority of these individuals, the diagnosis of prenatal cerebellar hemorrhages led to termination of pregnancy or death occurred in utero; data about postnatal outcome of children with prenatal diagnosis of cerebellar hemorrhages are scant. We describe fetal and postnatal neuroimaging findings and the neurodevelopmental outcome of a child with a large cerebellar hemorrhage that occurred at approximately 27 weeks' gestation. METHOD: Data about neurological features and neurodevelopmental outcome were collected from the clinical history and follow-up examination. All pre- and postnatal MRI data were qualitatively evaluated for infra- and supratentorial abnormalities. RESULTS: Fetal MRI at 27 weeks' gestation showed a T1-hyperintense and T2-hypointense lesion within the cerebellum suggestive of bilateral cerebellar hemorrhages with extension into the adjacent subarachnoid, subdural, and intraventricular spaces. The prenatal cerebellar hemorrhage was possibly related to maternal sepsis. Postnatal MRI showed encephalomalacic changes involving the vermis and both cerebellar hemispheres. Neurodevelopmental follow-up at 15 months of age was concerning for global developmental delay and significant right esotropia. CONCLUSION: This child illustrates (1) the role of prenatal neuroimaging in the diagnosis of fetal cerebellar hemorrhages, (2) the significance of cerebellar involvement for neurodevelopment, and (3) the importance of the collection of postnatal outcome data in children with prenatal diagnosis of cerebellar hemorrhage. PMID- 25724372 TI - Injury to insult: infarction after radiotherapy in the treatment of pediatric brain tumor. PMID- 25724373 TI - Phenotypic variability in childhood of skeletal muscle sodium channelopathies. AB - BACKGROUND: Mutations of the SCN4A gene cause several skeletal muscle channelopathies and overlapping forms of these disorders. However, the variability of the clinical presentation in childhood is confusing and not fully understood among pediatric neurologists. PATIENTS: We found three different mutations (p.V445M, p.I693L, and a novel mutation, p.V1149L) in SCN4A but not in the CLCN1 gene. The patient with p.V445M showed the clinical phenotype of sodium channel myotonia, but her clear symptoms did not appear until 11 years of age. Her younger sister and mother, who have the same mutation, displayed marked intrafamilial phenotypic heterogeneity from mild to severe painful myotonia with persistent weakness. The patient with p.I693L exhibited various symptoms that evolved with age, including apneic episodes, tonic muscular contractions during sleep, fluctuating severe episodic myotonia, and finally episodic paralyses. The patient with the novel p.V1149L mutation exhibited episodic paralyses starting at 3 years of age, and myotonic discharges were detected at 11 years of age for the first time. CONCLUSION: The present cohort reveals the complexity, variability, and overlapping nature of the clinical features of skeletal muscle sodium channelopathies. These are basically treatable disorders, so it is essential to consider genetic testing before the full development of a patient's condition. PMID- 25724374 TI - The potential risk of vessel infiltration and cervical lymph node metastasis in hypopharyngeal superficial squamous cell carcinoma: a retrospective observational study. AB - CONCLUSION: The depth of hypopharyngeal superficial cancer may predict vessel infiltration and potential risk of cervical lymph node metastasis. OBJECTIVES: To elucidate the histopathological predictors of vessel infiltration and the risk of regional lymph node metastasis in hypopharyngeal superficial cancer. METHODS: This study included 31 lesions from 30 patients who had undergone transoral en bloc resection in the hospital. Patients with intraepithelial neoplasia or muscular invasion were excluded. Patient characteristics, nodal status, state of vessel infiltration, state of perineural invasion, histopathological parameters, and post-operative cervical lymph node recurrence were retrospectively examined. The histopathological parameters measured were tumor diameter and the following three parameters: tumor thickness, depth from the mucosal surface, and depth from the basement membrane. Correlations between histopathological parameters and state of vessel infiltration were statistically analyzed. RESULTS: Of the 31 lesions examined, four had vessel infiltration. Three of the four lesions with vessel infiltration had regional lymph node metastasis as well as subsequent lymph node metastasis. Lesions with vessel infiltration were significantly deeper than those without. In contrast, there was no significant difference in lesion diameters. In addition, there was no correlation between the depth and the diameter of the lesion. PMID- 25724375 TI - Internal energy deposition for low energy, femtosecond laser vaporization and nanospray post-ionization mass spectrometry using thermometer ions. AB - The internal energy of p-substituted benzylpyridinium ions after laser vaporization using low energy, femtosecond duration laser pulses of wavelengths 800 and 1042 nm was determined using the survival yield method. Laser vaporization of dried benzylpyridinium ions from metal slides into a buffered nanospray with 75 MUJ, 800 nm laser pulses resulted in a higher extent of fragmentation than conventional nanospray due to the presence of a two-photon resonance fragmentation pathway. Using higher energy 800 nm laser pulses (280 and 505 MUJ) led to decreased survival yields for the four different dried benzylpyridinium ions. Analyzing dried thermometer ions with 46.5 MUJ, 1042 nm pulse-bursts resulted in little fragmentation and mean internal energy distributions equivalent to nanospray, which is attributable to the absence of a two-photon resonance that occurs with higher energy, 800 nm laser pulses. Vaporization of thermometer ions from solution with either 800 nm or 1042 nm laser pulses resulted in comparable internal energy distributions to nanospray ionization. PMID- 25724376 TI - An Evaluation of Cerebral and Systemic Predictors of 18-Month Outcomes for Neonates With Hypoxic Ischemic Encephalopathy. AB - Amplitude-integrated EEG (aEEG) is a commonly used predictor of outcome after hypoxic ischemic encephalopathy. Cerebral and systemic near-infrared spectroscopy and acute kidney injury might also have prognostic value. The authors monitored neonates with aEEG, cerebral and systemic near-infrared spectroscopy during therapeutic hypothermia, assigned an acute kidney injury stage, and measured neurodevelopmental outcome. For 18 infants, cerebral near-infrared spectroscopy variables did not differentiate between those with favorable (n = 13) versus adverse (death or moderate-severe disability; n = 5) 18-month outcomes. However, systemic rSO2 variability was higher during hours 48-72 of cooling among those with favorable outcomes (.02 < P < .03). Mean aEEG amplitude during hours 24 to 48 of cooling was higher among those with good outcomes (.027 < P < .032). The aEEG lower margin was also higher during hours 12 to 48 for those with good outcomes (.014 < P < .035). Acute kidney injury did not predict outcome (P > .05). aEEG is a useful prognostic tool for outcomes after neonatal hypoxic ischemic encephalopathy, but the role of near-infrared spectroscopy in the hypothermia-treated population remains uncertain. PMID- 25724377 TI - A Potential Epigenetic Therapy for NSCLC. AB - New research shows that inhibiting the histone modifier EZH2 may make non-small cell lung cancers harboring BRG1 or EGFR mutations more sensitive to etoposide, a common chemotherapy. PMID- 25724379 TI - Violence and vulnerability of female migrants in drop houses in Arizona: the predictable outcome of a chain reaction of violence. AB - This qualitative research study examines the experiences of immigrant women crossing the U.S./Mexico border and the proliferation of "drop houses" in Arizona as a new phenomenon, one that is often marked by kidnappings and sexual assault. Little research has been published on the violence women face on their journey, and the drop houses have almost completely escaped scholarly analysis. We argue that the drop houses must be seen as a consequence of a "state of emergency" declared by policy makers that led to changes in U.S. national and local immigration policies that fueled what we call a "chain reaction of violence." PMID- 25724378 TI - KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome. AB - We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis. PMID- 25724381 TI - Green serum and pregnancy: Case report. AB - OBJECTIVES: This report investigates the etiology of green serum within pregnancy. PATIENT AND METHODS: A 24-year-old patient applied to our clinic for a routine control examination at her 25th week of pregnancy. In her repeated blood analysis, green serum was observed after centrifugation of the blood sample taken for an oral glucose tolerance test. After that, records of the patient's blood samples collected at the 9th and 12th weeks of pregnancy to verify that these serum samples were yellow were retrospectively examined. RESULTS: In the literature, no green serum case without an accompanying increase in serum ceruloplasmin level has been reported. The routine blood biochemistry of alanine transaminase: 8 U/L (10-40 U/L), aspartate amino transferase: 10 U/L (10-40 U/L), gamma glutamyl transferase: 17 U/L (7-40 U/L), indirect bilirubin 5.13 MUmol/L (0.0-18 MUmol/L), and total bilirubin 11.9 MUmol/L (0.0-24 MUmol/L). The level of serum copper detected was 0.172 MUmol/L (0.14-0.173 MUmol/L) and of ceruloplasmin was 600 mg/L (260-630 mg/L) within the normal reference interval. CONCLUSIONS: This case proves that generation of green serum in pregnancy is not only due to an increased serum ceruloplasmin but can also be caused by other factors. Additional studies need to be performed to understand the pathophysiological mechanism and future effects of the appearance of green serum during pregnancy. PMID- 25724380 TI - Potent degradation of neuronal miRNAs induced by highly complementary targets. AB - MicroRNAs (miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, target mRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacy of target RNA-directed miRNA degradation (TDMD) in rodent primary neurons. Coincident with degradation, and while still bound to Argonaute, targeted miRNAs are 3' terminally tailed and trimmed. Absolute quantification of both miRNAs and their decay-inducing targets suggests that neuronal TDMD is multiple turnover and does not involve co-degradation of the target but rather competes with miRNA-mediated decay of the target. Moreover, mRNA silencing, but not TDMD, relies on cooperativity among multiple target sites to reach high efficacy. This knowledge can be harnessed for effective depletion of abundant miRNAs. Our findings bring insight into a potent miRNA degradation pathway in primary neurons, whose TDMD activity greatly surpasses that of non-neuronal cells and established cell lines. Thus, TDMD may be particularly relevant for miRNA regulation in the nervous system. PMID- 25724382 TI - Efficient multiple-trait association and estimation of genetic correlation using the matrix-variate linear mixed model. AB - Multiple-trait association mapping, in which multiple traits are used simultaneously in the identification of genetic variants affecting those traits, has recently attracted interest. One class of approaches for this problem builds on classical variance component methodology, utilizing a multitrait version of a linear mixed model. These approaches both increase power and provide insights into the genetic architecture of multiple traits. In particular, it is possible to estimate the genetic correlation, which is a measure of the portion of the total correlation between traits that is due to additive genetic effects. Unfortunately, the practical utility of these methods is limited since they are computationally intractable for large sample sizes. In this article, we introduce a reformulation of the multiple-trait association mapping approach by defining the matrix-variate linear mixed model. Our approach reduces the computational time necessary to perform maximum-likelihood inference in a multiple-trait model by utilizing a data transformation. By utilizing a well-studied human cohort, we show that our approach provides more than a 10-fold speedup, making multiple trait association feasible in a large population cohort on the genome-wide scale. We take advantage of the efficiency of our approach to analyze gene expression data. By decomposing gene coexpression into a genetic and environmental component, we show that our method provides fundamental insights into the nature of coexpressed genes. An implementation of this method is available at http://genetics.cs.ucla.edu/mvLMM. PMID- 25724383 TI - Release and protein binding of components from resin based composites in native saliva and other extraction media. AB - OBJECTIVES: Unpolymerized (co)monomers and additives can be released from resin based composites (RBCs) and can enter the human organism. In this study, the binding of ingredients from composites to salivary proteins and plasma proteins was investigated. METHODS: The composites investigated were Admira((r)) flow, Venus((r)) Diamond flow, FiltekTM Supreme XTE flow, Tetric EvoCeram((r)), Tetric EvoFlow((r)). The samples (n=4) were polymerized according to the instructions of the manufacturer of RBCs. The samples were immersed into native saliva, protein free saliva (artificial saliva), water and ethyl acetate, and incubated at 37 degrees C for 24h or 72h. The eluates were analyzed by gas chromatography/mass spectrometry. To determine the binding to salivary proteins, the concentration of (co)monomers and additives detected in native saliva was compared to the concentration of (co)monomers and additives detected in protein-free saliva, water and ethyl acetate respectively. To assess the affinity of TEGDMA, EGDMA, DEGDMA, PMGDMA, BPA, and DCHP to human serum albumin (HSA) and human alpha1-acid glycoprotein (AGP), a plasma protein binding assay (ABNOVA, Transil XL PPB Prediction Kit TMP-0212-2096) was performed. The statistical significance (p<0.05) of the difference between the experimental groups was tested using the one-way-analysis of variance (ANOVA), followed by Tukey's analysis. RESULTS: The concentration of TEGDMA, GMA and CyHEMA released in native saliva was significantly lower than the concentration released in protein-free saliva or water (Admira((r)) flow: concentration of TEGDMA after 72h: 0.08 mmol/L (native saliva), 0.34 mmol/L (protein-free saliva), 0.39 mmol/L (water)). The concentrations of HEMA, EGDMA, DDDMA and CQ released in native saliva remained even below the detection limit, compared to the other extraction media. Protein binding of the tested methacrylates to HSA+AGP was 82-85%, the binding of DCHP was 96.6%, and the binding of BPA was 95.2%. SIGNIFICANCE: Artificial saliva or water as extraction medium does not reflect the real physiological situation in the body. Salivary and plasma proteins may bind (co)monomers and additives and may thereby contribute to a lower bioavailability of leachables from RBCs in vivo than previously thought. PMID- 25724384 TI - Hesperidin ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting HMGB1 release. AB - Hesperidin (HDN), a flavanone glycoside, possesses anti-inflammatory properties and has been suggested to be able to modulate the lipopolysaccharide (LPS) induced acute lung injury (ALI). High-mobility group box 1 (HMGB1) serves as an inflammatory cytokine when released extracellularly and is involved in the pathogenesis of diverse inflammatory disorders. The current study aimed to investigate the involvement of HMGB1 in HDN-induced immunoregulation of ALI. ALI in male BALB/c mice was induced by intranasal administration of LPS (0.5mg/kg). HDN (500mg/kg) was administered intragastrically 10days prior to LPS exposure. HDN significantly protected animals from LPS-induced ALI as evidenced by decreased elevation of the lung wet to dry weight ratio, total cells, neutrophils, macrophages, and myeloperoxidase (MPO) activity, associated with reduced lung histological damage. In the meantime, HDN pretreatment markedly inhibited the production of pro-inflammatory cytokines and chemokine, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Furthermore, HDN pretreatment dramatically inhibited the infiltration of macrophages and suppressed the expression and release of HMGB1 in vivo and in vitro. In addition, intranasal application of exogenous HMGB1 could result in lung injury which was also alleviated by HDN administration. These results suggest that HDN pretreatment protects mice from LPS-induced ALI via inhibiting the production of TNF-alpha and IL-6. Moreover, we found that HDN could inhibit the expression and release of HMGB1 via suppressing the infiltration of macrophages and production of MCP-1. PMID- 25724385 TI - Augmentation of Treatment As Usual with online Cognitive Bias Modification of Interpretation training in adolescents with Obsessive Compulsive Disorder: A pilot study. AB - BACKGROUND AND OBJECTIVES: Cognitive Behavioral Therapy for children and adolescents with Obsessive Compulsive Disorder (OCD) is effective. However, since almost half of patients remain symptomatic after treatment, there remains room for improvement. Cognitive Bias Modification training of Interpretations (CBM-I) is a promising new intervention, as it targets misinterpretation of intrusions, which is seen as an important characteristic in OCD. To date, there have been no published studies of CBM-I in adolescents with OCD. The aim of the current pilot study was to examine the added value of online CBM-I training as an adjunctive treatment to the Treatment As Usual (TAU; that included CBT and pharmacotherapy) in adolescents with OCD. METHODS: Patients receiving TAU were randomly assigned to either an additional CBM-I training (n = 9), or to an additional placebo variant of this procedure (n = 7). RESULTS: Immediate, on-line interpretations changed in response to the CBM-I training, while no such effects were observed on slower retrospective off-line interpretations. Patients in the CBM-I training condition reported fewer obsessive compulsive symptoms after training, and clinicians rated them as having fewer obsessive symptoms (corresponding to medium large effect sizes). No such changes were observed in the placebo group. LIMITATIONS: The small sample size precludes strong conclusions and replication is necessary to test the robustness of the findings. CONCLUSIONS: This small randomized controlled trial is suggestive, although not conclusive, regarding the promising additive value of OC-related CBM-I training as an adjunctive intervention to TAU in an adolescent clinical population. PMID- 25724386 TI - Antineuronal antibodies against neurotransmitter receptors and synaptic proteins in schizophrenia: current knowledge and clinical implications. AB - When Eugen Bleuler coined the term 'schizophrenia' he believed that various causes of illness may underlie this disease. Currently, neurodevelopmental abnormalities and consecutive impairments in dopaminergic and glutamatergic neurotransmission are considered as major causes of schizophrenia. However, there are various indications for involvement of immune processes, at least in subgroups of patients. Circulating antineuronal antibodies provide a promising link between the well-described disturbances in neurotransmission and the immune hypothesis of schizophrenia. This review summarizes important studies that have examined the role of glutamate, dopamine, acetylcholine and serotonin receptor autoantibodies, and other antineuronal antibodies against synaptic proteins in the serum of patients diagnosed with schizophrenia. Currently, it is not known whether the presence of antineuronal antibodies in blood should be considered as a causal or disease-modulating factor in schizophrenia. Due to emerging evidence regarding the important role of the blood-brain barrier, combined testing of serum and cerebrospinal fluid is likely to be more appropriate to answer this question than pure serum analyses. We suggest implementation of such testing in first-onset and treatment-resistant patients as part of the diagnostic process. In addition, future clinical trials should evaluate if immunotherapy (e.g. cortisone pulse therapy, intravenous immunoglobulins, plasmapheresis, rituximab, or cyclophosphamide) is helpful in cases with a neuroinflammatory component. PMID- 25724387 TI - A Single Amino Acid in the Hinge Loop Region of the FOXP Forkhead Domain is Significant for Dimerisation. AB - The forkhead box (FOX) proteins are a family of transcription factors that interact with DNA via a winged helix motif that forms part of the forkhead domain. The FOXP (FOXP1-4) subfamily is unique in the family in that the forkhead domains of these proteins are able to dimerise via domain swapping. In this event, structural elements are exchanged via extension of the hinge loop region. Despite the high sequence homology among the FOXP subfamily members, the stability of their forkhead domain dimers varies, with FOXP3 forming the most stable dimer. An amino acid difference is observed in the hinge region of the FOXP subfamily where a tyrosine in all members is replaced with a phenylalanine in FOXP3. In this work, the role of phenylalanine at this position in the hinge region was investigated. This was done by creating the Y540F variant of the FOXP2 forkhead domain. The effect of the Y540F mutation on the structure, dimerisation propensity and DNA binding ability of the FOXP subfamily was investigated. The mutation altered the structure of the protein by decreasing the disorder of the backbone as measured by circular dichroism spectroscopy and by altering the local environment of the hinge region as measured by tryptophan fluorescence. The propensity of the forkhead domain to form a dimer was improved ~9.5 fold by the mutation. This was attributed to increased hydrophobicity at the dimer interface as well as altered tension in the hinge loop region. DNA binding assays indicated that the affinity for DNA was decreased by the mutation. Taken together, these findings suggest that domain swapping may modulate DNA binding. PMID- 25724389 TI - Exposure to fluconazole and risk of congenital malformations in the offspring: A systematic review and meta-analysis. AB - Vulvovaginal candidiasis (VVC) affects up to 75% of women at least once during their lifetime, mostly during the reproductive age, and recurrence rate is about 50%. Because half of all pregnancies are unplanned and pregnant women have an increased risk of VVC recurrence, the likelihood of inadvertently being exposed to fluconazole in pregnancy is increased. Thus, we aimed to examine the risk of congenital malformations in the offspring of women exposed to fluconazole in the first trimester of pregnancy. The rate for overall malformations was 1.10 (95% CI 0.98-1.25), for heart defect was 1.29 (95% CI 1.05-1.58), for craniofacial defects was 1.25 (95% CI 0.88-1.77), and for limb/musculoskeletal defects was 0.82 (95% CI 0.59-1.13). In conclusion, the use of fluconazole in the first trimester does not appear to increase the overall risk for congennital malformations. More studies are needed to address the potential increased rate of heart defects. PMID- 25724388 TI - Ethanol modulates the synthesis and catabolism of retinoic acid in the rat prostate. AB - All-trans retinoic acid (atRA) maintains physiological stability of the prostate, and we reported that ethanol intake increases atRA in the rat prostate; however the mechanisms underlying these changes are unknown. We evaluated the impact of a low- and high-dose ethanol intake (UChA and UChB strains) on atRA metabolism in the dorsal and lateral prostate. Aldehyde dehydrogenase (ALDH) subtype 1A3 was increased in the dorsal prostate of UChA animals while ALDH1A1 and ALDH1A2 decreased in the lateral prostate. In UChB animals, ALDH1A1, ALDH1A2, and ALDH1A3 increased in the dorsal prostate, and ALDH1A3 decreased in the lateral prostate. atRA levels increased with the low activity of CYP2E1 and decreased with high CYP26 activity in the UChB dorsal prostate. Conversely, atRA was found to decrease when the activity of total CYP was increased in the UChA lateral prostate. Ethanol modulates the synthesis and catabolism of atRA in the prostate in a concentration-dependent manner. PMID- 25724390 TI - Peptide length and folding state govern the capacity of staphylococcal beta-type phenol-soluble modulins to activate human formyl-peptide receptors 1 or 2. AB - Most staphylococci produce short alpha-type PSMs and about twice as long beta type PSMs that are potent leukocyte attractants and toxins. PSMs are usually secreted with the N-terminal formyl group but are only weak agonists for the leukocyte FPR1. Instead, the FPR1-related FPR2 senses PSMs efficiently and is crucial for leukocyte recruitment in infection. Which structural features distinguish FPR1 from FPR2 ligands has remained elusive. To analyze which peptide properties may govern the capacities of beta-type PSMs to activate FPRs, full length and truncated variants of such peptides from Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis were synthesized. FPR2 activation was observed even for short N- or C-terminal beta-type PSM variants once they were longer than 18 aa, and this activity increased with length. In contrast, the shortest tested peptides were potent FPR1 agonists, and this property declined with increasing peptide length. Whereas full-length beta-type PSMs formed alpha-helices and exhibited no FPR1-specific activity, the truncated peptides had less-stable secondary structures, were weak agonists for FPR1, and required N-terminal formyl-methionine residues to be FPR2 agonists. Together, these data suggest that FPR1 and FPR2 have opposed ligand preferences. Short, flexible PSM structures may favor FPR1 but not FPR2 activation, whereas longer peptides with alpha-helical, amphipathic properties are strong FPR2 but only weak FPR1 agonists. These findings should help to unravel the ligand specificities of 2 critical human PRRs, and they may be important for new, anti-infective and anti inflammatory strategies. PMID- 25724391 TI - Depression and anxiety symptoms of mothers of preterm infants are decreased at 4 months corrected age with Family Nurture Intervention in the NICU. AB - Preterm delivery can precipitate maternal psychological morbidities. Family Nurture Intervention (FNI) was designed to minimize these by facilitating the emotional connection between mother and infant, beginning early in the infant's neonatal intensive care unit (NICU) stay. We examined depression and anxiety symptoms of mothers of preterm infants at 4 months infant corrected age (CA). One hundred fifteen mothers who delivered between 26 and 34 weeks gestational age were randomized to receive standard care (SC) or standard care plus FNI. Mothers' self-reported depressive symptoms (Center for Epidemiologic Studies Depression Scale: CES-D) and state anxiety (Spielberger State-Trait Anxiety Inventory: STAI) symptoms were assessed at enrollment, near to term age, and 4 months (CA). At 4 months CA, mean CES-D and STAI scores were significantly lower in FNI mothers compared to SC mothers. Effectiveness of FNI can only be evaluated as an integrated intervention strategy as it was not possible to control all aspects of FNI activities. Although there was considerable loss to follow-up, analyses suggest that resulting biases could have masked rather than inflated the measured effect size for depressive symptoms. FNI may be a feasible and practicable way to diminish the impact of premature delivery on maternal depressive and anxiety symptoms. PMID- 25724392 TI - Distinguishing the dominant species of pathogen in maxillary sinusitis by sequencing DNA dataset analysis. AB - This study determined the microbial composition in maxillary sinusitis and determined the predominant fungal and bacterial species. Samples were obtained from 11 patients with fungal sinusitis and 2 healthy patients. The 13 samples were sequenced using an Illumina Hi-Seq 2000, and mapping to the human, bacterial, and the fungal genomes were based on several steps. Bioinformatics and statistical analyses were then performed for bacterial and fungal expressions in the samples. All samples were cultures for fungal growth. The sequencing data revealed that Aspergillus flavus and Aspergillus oryzae were the dominant fungal strains in the rhinosinusitis samples, and Bacillus cereus and Bacillus thuringiensis were the dominant bacterial strains. Indeed, the fungi and bacteria were associated with the development of fungal rhinosinusitis. Furthermore, B. cereus and B. thuringiensis may cooperate with Pseudomonas aeruginosa to inhibit the growth of fungal mycelia. Knowledge of the microbial composition can provide a diagnostic reference for patients with maxillary sinusitis. PMID- 25724393 TI - Pre- and post-natal muscle microRNA expression profiles of two pig breeds differing in muscularity. AB - miRNAs regulate the expression of target genes in diverse cellular processes and hence play important roles in physiological processes including developmental timing, patterning, embryogenesis, organogenesis, cell lineage, myogenesis and growth control. A comparative expression analysis of miRNAs expressed in the longissimus dorsi muscle at two prenatal stages (63 and 91 days post-conception (dpc)), and one adult stage (180 days post-natum) in both German Landrace (DL) and Pietrain (Pi) pig breeds was performed using a custom-designed array. During the prenatal stages, miR-199 and the miR-17 families were significantly up regulated at 63 dpc, whereas miR-1 and miR-133a were overexpressed at 91 dpc. The abundance of several miRNAs was increased in the adult stage compared to 91 dpc including miR-1, miR-133, miR-22(a/b) and miR-29a. Some miRNAs were breed specific, such as miR-199 and the miR-17 families which were all up-regulated in Pi pigs, while miR-133, miR-181 and miR-214 were up-regulated in DL pigs. Several pathways related to muscle development were enriched with predicted targets for the differentially expressed miRNAs. The dynamic expression and breed-associated regulation of porcine muscle miRNAs suggests a functional role for miRNA-mediated gene regulation during muscle development and phenotypic variations of muscle traits. PMID- 25724394 TI - Performance of QF-PCR in targeted prenatal aneuploidy diagnosis: Indian scenario. AB - OBJECTIVE: Among the rapid aneuploidy detection methods, QF-PCR has now become an alternative tool for prenatal aneuploidy diagnosis concomitant with karyotyping. This method has been validated in many of the western clinics but in India no study was conducted to assess its utility as standalone procedure. The study was designed to answer the question whether QF-PCR can be implemented as a standalone diagnostic method for rapid aneuploidy diagnosis in our present clinical setup? MATERIALS AND METHODS: Study was conducted during March 2012 to August 2014 consisting of 270 prenatal samples that underwent for aneuploidy diagnosis. In addition to karyotyping, QF-PCR was also performed on these samples and the results were compared. RESULTS: Of 270 samples screened, 262 samples showed euploid genome (125 normal male and 137 normal female). Eight samples were consistent with aneuploidy--four trisomy 21 male sample, 2 trisomy 21 female sample, 1 trisomy 18 samples and 1 Klinefelter sample. The specificity, sensitivity, positive prediction value and negative prediction values were 100% while false positive rate and false negative rate were 0%. CONCLUSION: Outcome of this study strongly suggests that QF-PCR can be used as standalone procedure for targeted rapid aneuploidy diagnosis. PMID- 25724395 TI - Generation of insulin-producing cells from C3H10T1/2 mesenchymal progenitor cells. AB - Mesenchymal stem cells (MSCs) have been reported to be an attractive source for the generation of transplantable surrogate beta cells. A murine embryonic mesenchymal progenitor cell line C3H10T1/2 has been recognized as a model for MSCs, because of its multi-lineage differentiation potential. The purpose of this study was to explore whether C3H/10T1/2 cells have the potential to differentiate into insulin-producing cells (IPCs). Here, we investigated and compared the in vitro differentiation of rat MSCs and C3H10T1/2 cells into IPCs. After the cells underwent IPC differentiation, the expression of differentiation markers were detected by immunocytochemistry, reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR (qRT-PCR) and Western blotting. The insulin secretion was evaluated by enzyme-linked immunosorbent assay (ELISA). Furthermore, these differentiated cells were transplanted into streptozotocin induced diabetic mice and their biological functions were tested in vivo. This study reports a 2-stage method to generate IPCs from C3H10T1/2 cells. Under specific induction conditions for 7-8 days, C3H10T1/2 cells formed three dimensional spheroid bodies (SBs) and secreted insulin, while generation of IPCs derived from rat MSCs required a long time (more than 2 weeks). Furthermore, these IPCs derived from C3H10T1/2 cells were injected into diabetic mice and improves basal glucose, body weight and exhibited normal glucose tolerance test. The present study provided a simple and faithful in vitro model for further investigating the mechanism underlying IPC differentiation of MSCs and cell replacement therapy for diabetes. PMID- 25724396 TI - Firearms, bullets, and wound ballistics: an imaging primer. AB - Based on its intrinsic mass and velocity, a bullet has an upper limit of wounding potential. Actual wound severity is a function of the bullet construction and trajectory, as well as the properties of the tissues traversed. Interpreting physicians must evaluate the bullet trajectory and describe patterns of injury resulting from the effect of energy transfer from the projectile into living tissue. A basic understanding of firearms, projectiles, and wound ballistics can help the interpreting physicians in conceptualizing these injuries and interpreting these cases. PMID- 25724397 TI - Injury patterns of medial patellofemoral ligament and correlation analysis with articular cartilage lesions of the lateral femoral condyle after acute lateral patellar dislocation in children and adolescents: An MRI evaluation. AB - OBJECTIVES: The purpose of this study was to investigate the injury characteristics of medial patellofemoral ligament (MPFL), and to analyse the correlations between the injury patterns of MPFL and articular cartilage lesions of the lateral femoral condyle in children and adolescents with acute lateral patellar dislocation (LPD). METHODS: Magnetic resonance (MR) images were prospectively obtained in 127 consecutive children and adolescents with acute LPD. Images were acquired using standardised protocols and these were independently evaluated by two radiologists. RESULTS: Fifty-four cases of partial MPFL tear and 69 cases of complete MPFL tear were identified. Injuries occurred at an isolated patellar insertion (PAT) in 47 cases, an isolated femoral attachment (FEM) in 41 cases and an isolated mid-substance (MID) in four cases. More than one site of injury to the MPFL (COM) was identified in 31 cases. The prevalence rate of chondral and osteochondral lesions of the lateral femoral condyle were 23.4% (11/47) and 29.8% (14/47) in the PAT subgroup, 7.3% (3/41) and 9.8% (4/41) in the FEM subgroup and 25.8% (8/31) and 32.3% (10/31) in the COM subgroup, respectively. The PAT and COM subgroups showed significantly higher prevalence rate of chondral and osteochondral lesions in the lateral femoral condyle when compared with the FEM subgroup. The prevalence rate of chondral and osteochondral lesions of the lateral femoral condyle were 17.4% (12/69) and 30.4% (21/69) in the complete MPFL tear subgroup and 20.4% (11/54) and 13% (7/54) in the partial MPFL tear subgroup, respectively. The subgroup of the complete MPFL tear showed significantly higher prevalence rate of osteochondral lesions in the lateral femoral condyle when compared with the subgroup of the partial MPFL tear. CONCLUSIONS: Firstly, the MPFL is most easily injured at the PAT, and secondly at the FEM in children and adolescents after acute LPD. The complete MPFL tear is more often concomitant with osteochondral lesions of the lateral femoral condyle than the partial MPFL tear. The isolated patellar-sided MPFL tear and the combined MPFL tear are more easily concomitant with chondral lesions and osteochondral lesions of the lateral femoral condyle than the isolated femoral sided MPFL tear. PMID- 25724398 TI - Prognostic factors, morbidity and mortality in pancreatic trauma: a critical appraisal of 432 consecutive patients treated at a Level 1 Trauma Centre. AB - BACKGROUND: This large retrospective observational cohort study evaluated prognostic factors, 30-day morbidity and mortality and complications related to the pancreas in patients who had sustained pancreatic injuries. METHODS: The records of 432 consecutive patients treated for pancreatic injuries at an urban Level 1 Trauma Centre in Cape Town between January 1982 and December 2012 were reviewed. Primary endpoints were postoperative morbidity and death. Bivariate and multivariate logistic regression analyses were used to assess significant predictors of morbidity and mortality. RESULTS: Overall mortality in 432 patients [394 men, median age 26, median RTS 7.8] was 15.7% and morbidity 66%. Bivariate logistic regression analysis showed that nine factors, age, RTS, presence of shock, need for a transfusion, volume of blood transfused, damage control surgery, AAST grade of pancreatic injury, an associated vascular injury and a repeat laparotomy were significant predictors of morbidity. In the final multivariate logistic regression analysis model however only two variables, AAST grade of pancreatic injury and a repeat laparotomy were significant predictors of morbidity. When factors associated with mortality were considered, logistic regression analysis found that 11 variables, age, RTS, the presence of shock, patients who required a major blood transfusion, the median number of units transfused, the need for a damage control laparotomy, AAST grade 3, 4, 5 pancreatic injuries, associated vascular injuries, the number of associated injuries, postoperative complications and days in ICU were significant. However in the final stepwise multivariate logistic regression analysis model only five variables, age, shock, median number of units transfused and the presence of associated complications were significant factors associated with mortality. CONCLUSIONS: Morbidity was 64% and AAST grade of pancreatic injury and a repeat laparotomy were significant predictors of morbidity. Overall mortality was 15.7%. Most deaths were due to associated injuries and were unrelated to the pancreatic injury. Five variables, age, shock, median number of units transfused and the presence of associated complications were significant factors associated with mortality. These data indicate that the magnitude of blood loss and haemorrhagic shock are primary determinants for survival and that urgent reversal of shock and control of bleeding are essential to reduce mortality in this cohort of patients. PMID- 25724399 TI - Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth. AB - OBJECTIVE: Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. STUDY DESIGN: Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. RESULTS: EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 +/- 4122 vs 1455 +/- 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (rho = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). CONCLUSION: This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas. PMID- 25724400 TI - Competing risks model in screening for preeclampsia by maternal characteristics and medical history. AB - OBJECTIVE: The purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history. STUDY DESIGN: This was a screening study of 120,492 singleton pregnancies at 11-13 weeks' gestation, including 2704 pregnancies (2.2%) that experienced preeclampsia. A survival-time model for the gestational age at delivery with preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of preeclampsia. A 5-fold cross validation study was conducted to compare the performance of the new model with the National Institute for Health and Clinical Excellence (NICE) guidelines. RESULTS: In the new model, increased risk for preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racial origin, medical history of chronic hypertension, diabetes mellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of preeclampsia, and conception by in vitro fertilization. The risk for preeclampsia decreases with increasing maternal height and in parous women with no previous preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total preeclampsia and preeclampsia requiring delivery at <37 and <34 weeks' gestation, respectively, which were significantly higher than the respective values of 35%, 40%, and 44% achieved by application of NICE guidelines. CONCLUSION: A new model that is based on maternal characteristics and medical history has been developed for the estimation of patient-specific risks for preeclampsia. Such estimation of the a priori risk for preeclampsia is an essential first step in the use of Bayes theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of screening for the disease. PMID- 25724401 TI - Neonatal outcome of very preterm twins: policy of planned vaginal or cesarean delivery. AB - OBJECTIVE: The objective of the study was to compare neonatal mortality and morbidity in very preterm twins with the first twin in cephalic presentation in hospitals with a policy of planned vaginal delivery (PVD) and those with a policy of planned cesarean delivery (PCD). STUDY DESIGN: Women with preterm cephalic first twins delivered after preterm labor and/or premature preterm rupture of membranes from 26(0/7) to 31(6/7) weeks of gestation were identified from the databases of 6 perinatal centers and classified as PVD or PCD according to the center's management policy from 1999 to 2010. Severe neonatal morbidity was defined as any of the following: intraventricular hemorrhage grades 3-4, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, and hospital death. The independent effect of the planned mode of delivery, defined by the center's management policy, was tested and quantified with a 2-level multivariable logistic regression. RESULTS: The PVD group included 248 women, and the PCD group 63. Maternal characteristics did not differ between the 2 groups. The rate of vaginal delivery was 85.9% (213 of 248) vs 20.6% (13 of 63) (P < .001), and the rate of cesarean delivery for the second twin was 1.6% (4 of 248) vs 4.8% (3 of 63) (P = .13) for PVD and PCD. PVD had no independent effect on either newborn hospital mortality or severe neonatal composite morbidity. CONCLUSION: A policy of planned vaginal delivery of very preterm twins with the first twin in cephalic presentation does not increase either severe neonatal morbidity or mortality. PMID- 25724402 TI - Global epidemiology of hysterectomy: possible impact on gynecological cancer rates. AB - Despite the fact that hysterectomy is the most common surgical procedure worldwide in gynecology, national reporting of the incidence rate of gynecological cancers rarely removes the proportion no longer at risk of the disease from the population-at-risk-denominator (ie, women who have had a hysterectomy). The incidence rate of gynecological cancers is thus likely underestimated. Because hysterectomy, as well as oophorectomy, incidence varies across countries, age, and over time, meaningful comparison of gynecological cancer incidence rates may be compromised. Without accurate estimates of gynecological cancer incidence rates, performed via removing the proportion of hysterectomized or oophorectomized women from the population-at-risk-denominator, the impact of prevention strategies may be masked or misinterpreted. Furthermore, because national cervical cancer screening guidelines are at least in part based on the national reporting of cervical cancer incidence, it is important that the incidence rate reflects the true population at risk. PMID- 25724403 TI - Prolapse and continence surgery in countries of the Organization for Economic Cooperation and Development in 2012. AB - OBJECTIVE: The purpose of this study was to report the rates and types of pelvic organ prolapse (POP) and female continence surgery performed in member countries of the Organization for Economic Co-operation and Development (OECD) in 2012. STUDY DESIGN: The published health outcome data sources of the 34 OECD countries were contacted for data on POP and female continence interventions from 2010 2012. In nonresponding countries, data were sought from national or insurer databases. Extracted data were entered into an age-specific International Classification of Disease, edition 10 (ICD-10)-compliant Excel spreadsheet by 2 authors independently in English-speaking countries and a single author in non English-speaking countries. Data were collated centrally and discrepancies were resolved by mutual agreement. RESULTS: We report on 684,250 POP and 410,352 continence procedures that were performed in 15 OECD countries in 2012. POP procedures (median rate, 1.38/1000 women; range, 0.51-2.55 prolapse procedures/1000 women) were performed 1.8 times more frequently than continence procedures (median rate, 0.75/1000 women; range, 0.46-1.65 continence procedures/1000 women). Repairs of the anterior vaginal compartment represented 54% of POP procedures; posterior repairs represented 43% of the procedures, and apical compartment repairs represented 20% of POP procedures. Median rate of graft usage was 15.7% of anterior vaginal repairs (range, 3.3-25.6%) and 8.5% (range, 3.2-17%) of posterior vaginal repairs. Apical compartment repairs were repaired vaginally at a median rate of 70% (range, 35-95%). Sacral colpopexy represented a median rate of 17% (range, 5-65%) of apical repairs; 61% of sacral colpopexies were performed minimally invasively. Between 2010 and 2012, there was a 3.7% median reduction in transvaginal grafts, a 4.0% reduction in midurethral slings, and a 25% increase in sacral colpopexies that were performed per 1000 women. Midurethral slings represented 82% of female continence surgeries. CONCLUSION: The 5-fold variation in the rate of prolapse interventions within OECD countries needs further evaluation. The significant heterogeneity (>10 times) in the rates at which individual POP procedures are performed indicates a lack of uniformity in the delivery of care to women with POP and demands the development of uniform guidelines for the surgical management of prolapse. In contrast, the midurethral slings were the standard female continence surgery performed throughout OECD countries in 2012. PMID- 25724404 TI - A simple, semi-deterministic approximation to the distribution of selective sweeps in large populations. AB - In large populations, the distribution of the trajectory of allele frequencies under selection and genetic drift approaches a semi-deterministic behavior: a deterministic trajectory started and ended at stochastic boundary values. This provides simple yet accurate approximations for the distribution of allelic frequencies over time (conditional on fixation), and of extinction and fixation times, for both hard and soft sweeps, and under arbitrary inbreeding and dominance. PMID- 25724405 TI - Cyclical succession in grazed ecosystems: the importance of interactions between different-sized herbivores and different-sized predators. AB - Body size of vertebrate herbivores is strongly linked to other life history traits, most notably (1) tolerance of low quality forage and (2) vulnerability to predation, which both impact the composition and dynamics of natural communities. However, no study has thus far explored how the combination of these two body size related traits affects the long-term composition and dynamics of the herbivore and plant communities. We made a simple model of ordinary differential equations and simulated a grassland system with three herbivore species (small, medium, large) and two predator species (small, large) to investigate how the combination of low-quality tolerance and predation-vulnerability structure the herbivore and plant community. We found that facilitation and competition between different-sized herbivores and predation by especially small predators stimulate coexistence among herbivore species. Furthermore, the interaction between different-sized herbivores and predators generated cyclical succession in the plant community, i.e. alternating periods of short vegetation dominated by high quality plants, with periods of tall vegetation dominated by low-quality plants. Our results suggest that cyclical succession in plant communities is more likely to occur when a predator predominantly preys on small herbivore species. Large predators also play an important role, as their addition relaxed the set of conditions under which cyclical succession occurred. Consequently, our model predictions suggest that a diverse predator community plays an important role in the long-term dynamics and maintenance of diversity in both the herbivore and plant community. PMID- 25724406 TI - Optical Imaging of Tumor Response to Hyperbaric Oxygen Treatment and Irradiation in an Orthotopic Mouse Model of Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: Hyperbaric oxygen therapy (HBOT) is used in the treatment of radiation induced tissue injury but its effect on (residual) tumor tissue is indistinct and therefore investigated in this study. PROCEDURES: Orthotopic FaDu tumors were established in mice, and the response of the (irradiated) tumors to HBOT was monitored by bioluminescence imaging. Near infrared fluorescence imaging using AngioSense750 and Hypoxisense680 was applied to detect tumor vascular permeability and hypoxia. RESULTS: HBOT treatment resulted in accelerated growth of non-irradiated tumors, but mouse survival was improved. Tumor vascular leakiness and hypoxia were enhanced after HBOT, whereas histological characteristics, epithelial-to-mesenchymal transition markers, and metastatic incidence were not influenced. CONCLUSIONS: Squamous cell carcinoma responds to HBOT with respect to tumor growth, vascular permeability, and hypoxia, which may have implications for its use in cancer patients. The ability to longitudinally analyze tumor characteristics highlights the versatility and potential of optical imaging methods in oncological research. PMID- 25724407 TI - Efficacy and safety of oral palonosetron compared with IV palonosetron administered with dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid tumors receiving cisplatin-based highly emetogenic chemotherapy (HEC). AB - PURPOSE: This study aims to compare the efficacy and safety of oral palonosetron with intravenous (IV) palonosetron for the prevention of cisplatin-related chemotherapy-induced nausea and vomiting (CINV). METHODS: A multinational, randomized, double-blind study enrolling adult chemotherapy-naive patients with malignant solid tumors scheduled to receive cisplatin-based highly emetogenic chemotherapy (HEC). Patients received oral palonosetron (0.50 mg) or IV palonosetron (0.25 mg), each with oral dexamethasone. The primary objective was to demonstrate non-inferiority in terms of patients with a complete response (CR, no emesis/no rescue medication) within the acute phase (0-24 h after chemotherapy administration). RESULTS: Of the 743 patients randomized, 739 received study medications and 738 were included in the full analysis set. The CR rate in the acute phase was high for both groups (oral 89.4 %; IV 86.2 %). As this difference in proportions (stratum-adjusted Cochran-Mantel-Haenszel method) was 3.21 % (99 % confidence interval (CI) -2.74 to 9.17 %), non-inferiority was demonstrated (since the lower limit of the 99 % CI was closer to zero than the predefined margin of 15 %). Treatment-emergent adverse events (TEAEs) related to the study drug were rare (oral 3.2 %; IV 6.5 %). No TEAEs related to study drug leading to discontinuation were reported. CONCLUSION: Non-inferiority of oral versus IV palonosetron was demonstrated. The CR rate in the acute phase was >86 % in both patient groups. The safety profiles were comparable. PMID- 25724408 TI - Symptom burden and integrative medicine in cancer survivorship. AB - PURPOSE: The purpose of the study was to learn about the level of experience with, interest in, and desire for knowledge about integrative medicine (IM) among cancer survivors. METHODS: Cancer survivors attending the 2014 National Cancer Survivors Day in Rochester, MN, were recruited to participate in a one-page survey about their ongoing health concerns and symptoms, as well as their experience with, interest in, and desire for knowledge about IM. Two-sided t test was used for univariate analyses of impact of sex, time since diagnosis, and age. RESULTS: Among the 260 cancer survivors, 171 persons (female, 74 %; male, 26 %) completed the survey (mean age, 64.6 years). Symptoms most commonly somewhat or more bothersome were fear of recurrence (52 %), stress (43 %), fatigue (43 %), difficulty sleeping (33 %), and weight gain (31 %). The most used IM resources were exercise (75 %), improved nutrition and diet (66 %), stress management (42 %), dietary supplementation (33 %), meditation (25 %), and massage (22 %). Older patients (age, >=65 years) were less experienced with, interested in, and desiring of knowledge about IM techniques. Sex and time since diagnosis were not strongly predictive of most survey response categories. CONCLUSIONS: Cancer survivors have adverse effects for years into survivorship. They use and express interest in various IM techniques to help manage symptoms. It is critical that oncology providers help survivors address ongoing health concerns. Education about and access to evidence-based IM techniques may have important roles in comprehensive cancer survivorship programs. PMID- 25724409 TI - Exercise and dietary advice intervention for survivors of triple-negative breast cancer: effects on body fat, physical function, quality of life, and adipokine profile. AB - PURPOSE: Regular exercise and healthy eating are routinely recommended for breast cancer survivors, and past studies show benefits in quality of life and decreased inflammation. However, this has not been tested specifically in triple-negative breast cancer survivors. Increasing physical activity and losing body fat are thought to positively affect inflammatory biomarkers that have been associated with breast cancer. Therefore, the primary purpose of this study was to determine if participation in an exercise and dietary counseling program can improve body fat, physical function, and quality of life in survivors of this aggressive breast cancer. Secondarily, we sought to determine if participation in the program had beneficial effects on obesity-related markers of the adipokine profile. METHODS: Sixty-six survivors of triple-negative breast cancer with BMI >25 were invited to participate. Twenty-eight enrolled and 23 completed the randomized, controlled trial (13 intervention, 10 control). Moderate-intensity aerobic exercise (150 min per week, for 12 weeks) and diet counseling were compared to usual care, education only. The primary outcome of interest was weight loss (body mass, BMI, % fat), and secondary outcomes included physical function (exercise capacity), quality of life (Function After Cancer Therapy Breast (FACT-B)), cytokines (C-reactive protein (CRP), TNF-alpha, IL-6), and adipokine profile (leptin, adiponectin, insulin). RESULTS: Participants in the program lost more body fat (2.4 % loss vs. 0.4 % gain, p < 0.05) than the control group. The intervention group also improved quality of life (FACT-B total score +14 pts) and decreased sedentary time but did not improve peak exercise capacity. The intervention had no effect on serum cytokines and adipokines after 12 weeks in the program. However, serum leptin and adiponectin and their ratio were significantly correlated with BMI in the intervention group (p < 0.05). CONCLUSIONS: Exercise and dietary counseling led to loss of body fat and improved quality of life in survivors of triple-negative breast cancer. BMI was associated with favorable changes in leptin and adiponectin which may reflect a change in adiposity with intervention. Exercise and healthy eating may be equally effective in this high-risk population as in other breast cancer survivors and should be encouraged as a part of a cancer survivorship program. PMID- 25724410 TI - Inpatient infectious disease consultations requested by surgeons at a comprehensive cancer center. AB - PURPOSE: The aim of this study was to describe the value of infectious disease specialist consultations for surgeons at comprehensive cancer centers. METHODS: A total of 151 cancer surgery inpatients were retrospectively assessed during a 12 month period. We focused on the characteristics of the infectious disease consultations from surgical departments: the referring surgical divisions, the referral phases, and the reasons for the infectious disease consultations. RESULTS: Three-quarters of all consultation requests were made after the day of surgery. Approximately, 60 % of these requests were made within 30 days after surgery for cancer. The reasons for the infectious disease consultations could be classified into three categories: diagnosis and management (54 %), management of established infections (44 %), and surgical antimicrobial prophylaxis (3 %). The most requested reason for consultations was the diagnosis and management of fever or elevated inflammatory markers of unknown etiology. Among the management of established infections, the antimicrobial management of surgical site infections was most frequently requested. CONCLUSIONS: Many surgeons would prefer infectious disease specialists to assume a more direct role in the care of difficult or perplexing cases (such as fevers of unknown origin) while also maintaining a traditional relationship in which the consultant recommends antimicrobial agents during a perioperative period. Particularly at cancer centers where oncology specialists account for a significant proportion of the providers, the knowledge and skill of infectious disease physicians are valued. PMID- 25724411 TI - Can larger-bodied cemented femoral components reduce periprosthetic fractures? A biomechanical study. AB - INTRODUCTION: The risk for late periprosthetic femoral fractures is higher in patients treated for a neck of femur fracture compared to osteoarthritis. It has been hypothesised that osteopaenia and consequent decreased stiffness of the proximal femur are responsible for this. We investigated whether a femoral component with a bigger body would increase the torque to failure in a biaxially loaded composite Sawbone model. MATERIALS AND METHODS: A biomechanical bone analogue was used. Two different body sizes (Exeter 44-1 versus 44-4) of a polished tapered cemented femoral stem were implanted by an experienced surgeon in seven bone analogues each and internally rotated at 40 degrees /s until failure. Torque to fracture and fracture energy were measured using a biaxial materials testing device (Instron 8874, MI, USA). The data were non-parametric and therefore tested with the Mann-Whitney U test. RESULTS: The median torque to fracture was 156.7 Nm (IQR 19.7) for the 44-1 stem and 237.1 Nm (IQR 52.9) for the 44-4 stem (p = 0.001). The median fracture energy was 8.5 J (IQR 7.3) for the 44-1 stem and 19.5 J (IQR 8.8) for the 44-4 stem (p = 0.014). CONCLUSION: The use of large body polished tapered cemented stems for neck of femur fractures increases the torque to failure in a biomechanical model and therefore is likely to reduce late periprosthetic fracture risk in this vulnerable cohort. PMID- 25724412 TI - Chronic BDNF deficiency leads to an age-dependent impairment in spatial learning. AB - Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neural plasticity and, consequently, of memory formation. In hippocampus-dependent learning tasks BDNF also seems to play an essential role. However, there are conflicting results concerning the spatial learning ability of aging BDNF(+/-) mice in the Morris water maze paradigm. To evaluate the effect of chronic BDNF deficiency in the hippocampus on spatial learning throughout life, we conducted a comprehensive study to test differently aged BDNF(+/-) mice and their wild type littermates in the Morris water maze and to subsequently quantify their hippocampal BDNF protein levels as well as expression levels of TrkB receptors. We observed an age-dependent learning deficit in BDNF(+/-) animals, starting at seven months of age, despite stable hippocampal BDNF protein expression and continual decline of TrkB receptor expression throughout aging. Furthermore, we detected a positive correlation between hippocampal BDNF protein levels and learning performance during the probe trial in animals that showed a good learning performance during the long-term memory test. PMID- 25724413 TI - Combination of exosomes and circulating microRNAs may serve as a promising tumor marker complementary to alpha-fetoprotein for early-stage hepatocellular carcinoma diagnosis in rats. AB - PURPOSE: Due to unsatisfying prognosis of AFP for hepatocellular carcinoma (HCC), we aim to evaluate the prognostic value of combination of exosomes and miRNAs in detecting HCC. METHODS: HCC was induced with diethylnitrosamine in rats and using a scoring system based on histological examination six different stages (normal liver, degeneration, fibrosis, cirrhosis, early HCC and late HCC) were identified in the development of HCC. The expression levels of AFP, exosomes and miRNAs (miRNA-10b, miRNA-21, miRNA-122 and miRNA-200a) were detected in both tissue and blood samples from those six stages. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the power of each parameter and their different combinations in diagnosing HCC or cirrhosis. RESULTS: A change in the expression of both exosomes and miRNAs was observed during cirrhosis, which in contrast with AFP starts showing up until the early HCC stage. Interestingly, the expressions of exosomes and the selected four miRNAs at early HCC stage obtained more remarkably alterations than the level of AFP (P < 0.05). On correlation analysis, four selected miRNAs had a significant closer relationship with exosomes when compared with AFP. The different combinations of AFP, exosomes, serous miRNAs and exosomal miRNAs had stronger power in predicting HCC than AFP (area under the curve of ROC, 0.943 vs 0.826). CONCLUSION: To conclude, the combination of circulating miRNAs and exosomes might serve as promising biomarkers for non-virus infected HCC screening and cirrhosis discrimination. PMID- 25724414 TI - Use of the Persuasive Health Message framework in the development of a community based mammography promotion campaign. AB - PURPOSE: We describe how the Persuasive Health Message (PHM) framework was used to guide the formative evaluation informing development of messages and materials used in a community-based multi-media campaign intended to motivate low-income African American women to obtain low- or no-cost mammograms through the CDC's National Breast and Cervical Cancer Early Detection Program. METHODS: Seventy eight African American women were recruited for eight focus groups that discussed breast cancer screening. The moderator guide was developed in accordance with the PHM framework and solicited information on perceived threat and efficacy, cues, salient beliefs and referents, and barriers to self-efficacy. RESULTS: We created persuasive messages to emphasize that African American women are susceptible to the threat of breast cancer, but that their personal action in obtaining regular mammograms may lead to early detection, subsequent treatment, and reduced cancer mortality. The messages addressed concerns of self-efficacy by emphasizing that uninsured women can also obtain high-quality low- or no-cost mammograms. In an attempt to combat the sentiment that breast cancer is a death sentence, the messages indicated that breast cancer can be successfully treated, especially when detected early. CONCLUSIONS: The PHM framework consists of three steps: (1) determine information about threat and efficacy; (2) develop an audience profile; and (3) construct a persuasive message. It offered our team easy-to-follow, flexible steps to create a persuasive and effective campaign promoting awareness and use of mammogram screening among low-income African American women. PMID- 25724415 TI - Breast and cervical cancers diagnosed and stage at diagnosis among women served through the National Breast and Cervical Cancer Early Detection Program. AB - PURPOSE: To assess cancers diagnosed and the stage of cancer at the time of diagnosis among low-income, under-insured, or uninsured women who received services through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). METHODS: Using the NBCCEDP database, we examined the number and percent of women diagnosed during 2009-2011 with in situ breast cancer, invasive breast cancer, and invasive cervical cancer by demographic and clinical characteristics, including age, race and ethnicity, test indication (screening or diagnostic), symptoms (for breast cancer), and screening history (for cervical cancer). We examined these characteristics by stage at diagnosis, a new variable included in the database obtained by linking with state-based central cancer registries. RESULTS: There were 11,569 women diagnosed with invasive breast cancer, 1,988 with in situ breast cancer, and 583 with invasive cervical cancer through the NBCCEDP. Women who reported breast symptoms or who had diagnostic mammography were more likely to be diagnosed with breast cancer, and at a later stage, than those who did not have symptoms or who had screening mammography. Women who had been rarely or never screened for cervical cancer were more likely to be diagnosed with cervical cancer, and at a later stage, than women who received regular screenings. CONCLUSIONS: Women served through the NBCCEDP who have not had prior screening or who have symptoms were more often diagnosed with late-stage disease. PMID- 25724416 TI - Beta genus papillomaviruses and skin cancer. AB - A role for the beta genus HPVs in keratinocyte carcinoma (KC) remains to be established. In this article we examine the potential role of the beta HPVs in cancer revealed by the epidemiology associating these viruses with KC and supported by oncogenic properties of the beta HPV proteins. Unlike the cancer associated alpha genus HPVs, in which transcriptionally active viral genomes are invariably found associated with the cancers, that is not the case for the beta genus HPVs and keratinocyte carcinomas. Thus a role for the beta HPVs in KC would necessarily be in the carcinogenesis initiation and not in the maintenance of the tumor. PMID- 25724417 TI - Silencing the alarms: Innate immune antagonism by rotavirus NSP1 and VP3. AB - The innate immune response involves a broad array of pathogen sensors that stimulate the production of interferons (IFNs) to induce an antiviral state. Rotavirus, a significant cause of childhood gastroenteritis and a member of the Reoviridae family of segmented, double-stranded RNA viruses, encodes at least two direct antagonists of host innate immunity: NSP1 and VP3. NSP1, a putative E3 ubiquitin ligase, mediates the degradation of cellular factors involved in both IFN induction and downstream signaling. VP3, the viral capping enzyme, utilizes a 2H-phosphodiesterase domain to prevent activation of the cellular oligoadenylate synthase (OAS)/RNase L pathway. Computational, molecular, and biochemical studies have provided key insights into the structural and mechanistic basis of innate immune antagonism by NSP1 and VP3 of group A rotaviruses (RVA). Future studies with non-RVA isolates will be essential to understand how other rotavirus species evade host innate immune responses. PMID- 25724419 TI - The European Association Of Urology Robotic Training Curriculum: The Journey Has Only Just Begun. PMID- 25724420 TI - Carbon dioxide receptor genes in cotton bollworm Helicoverpa armigera. AB - Carbon dioxide (CO2) is important in insect ecology, eliciting a range of behaviours across different species. Interestingly, the numbers of CO2 gustatory receptors (GRs) vary among insect species. In the model organism Drosophila melanogaster, two GRs (DmelGR21a and DmelGR63a) have been shown to detect CO2. In the butterfly, moth, beetle and mosquito species studied so far, three CO2 GR genes have been identified, while in tsetse flies, four CO2 GR genes have been identified. In other species including honeybees, pea aphids, ants, locusts and wasps, no CO2 GR genes have been identified from the genome. These genomic differences may suggest different mechanisms for CO2 detection exist in different insects but, with the exception of Drosophila and mosquitoes, limited attention has been paid to the CO2 GRs in insects. Here, we cloned three putative CO2 GR genes from the cotton bollworm Helicoverpa armigera and performed phylogenetic and expression analysis. All three H. armigera CO2 GRs (HarmGR1, HarmGR2 and HarmGR3) are specifically expressed in labial palps, the CO2-sensing tissue of this moth. HarmGR3 is significantly activated by NaHCO3 when expressed in insect Sf9 cells but HarmGR1 and HarmGR2 are not. This is the first report characterizing the function of lepidopteran CO2 receptors, which contributes to our general understanding of the molecular mechanisms of insect CO2 gustatory receptors. PMID- 25724418 TI - Reaching the melting point: Degradative enzymes and protease inhibitors involved in baculovirus infection and dissemination. AB - Baculovirus infection of a host insect involves several steps, beginning with initiation of virus infection in the midgut, followed by dissemination of infection from the midgut to other tissues in the insect, and finally culminating in "melting" or liquefaction of the host, which allows for horizontal spread of infection to other insects. While all of the viral gene products are involved in ultimately reaching this dramatic infection endpoint, this review focuses on two particular types of baculovirus-encoded proteins: degradative enzymes and protease inhibitors. Neither of these types of proteins is commonly found in other virus families, but they both play important roles in baculovirus infection. The types of degradative enzymes and protease inhibitors encoded by baculoviruses are discussed, as are the roles of these proteins in the infection process. PMID- 25724421 TI - Taurine ameliorates 5-flourouracil-induced intestinal mucositis, hepatorenal and reproductive organ damage in Wistar rats: A biochemical and histological study. AB - 5-Fluorouracil is one of the most commonly used anticancer drugs for the treatment of various types of cancer but has potential adverse effects such as intestinal mucositis, renal, hepatic, and reproductive organ toxicity. Attention has been given to approaches to reduce the side effects and improve the therapeutic effectiveness of chemotherapeutic drugs. In this study, we have investigated the protective effect of taurine (Tau) on 5-fluorouracil (5-FU) induced adverse effects in Wistar rats. Animals were divided into four groups with six animals (n = 6) in each group. Group I received vehicle only and served as control group. Groups II, III, and IV animals were given oral gavage of 5-FU at 50 mg/kg body weight for 4 days. Tau was given to the animals of groups III and IV 30 min prior to 5-FU administration. We observed marked elevation in the myeloperoxidase (MPO) activity after 5-FU administration, which was reversed by Tau pretreatment. Histological observation of liver, kidney, intestine, testis, and prostate revealed that 5-FU administration resulted in anomalies like distortion of normal cellular architecture, infiltration of inflammatory cells, and loss of cellular integrity. These histopathological changes were markedly suppressed by Tau treatment. In conclusion, biochemical and histological findings of this study suggest that Tau has strong preventive potential against complications of anticancer drug 5-FU and hence Tau may play an important role in combinational chemotherapy to enhance the therapeutic efficacy of anticancer drugs. PMID- 25724422 TI - The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication. AB - BACKGROUND AND OBJECTIVE: Amitriptyline, a frequently used tricyclic antidepressant agent, has powerful cardiotoxic effects especially in high doses. Serum and urine levels of amitriptyline dosages are not correlated with severity of toxicity; therefore, it increases the importance of electrocardiography (ECG) abnormalities. The prolongation of QTc can be a predictive marker for cardiotoxicity. Hence, in this study, it is aimed to evaluate possible effects of metoprolol and diltiazem in amitriptyline toxicity. MATERIALS AND METHODS: The rats were separated into four groups. First one was control group, the second was the amitriptyline + saline group, third one was the amitriptyline + metoprolol group, and forth one was the amitriptyline + diltiazem group. ECG were recorded on rats under anesthesia. RESULTS: In amitriptyline group, QTc duration was prolonged compared with all other groups. The prolongation of QTc was shorter in amitriptyline + metoprolol group and amitriptyline + diltiazem group than amitriptyline group (p < 0.01 and p < 0.01, respectively). CONCLUSION: According to the results, it is possible to report ameliorating effects of both metoprolol and diltiazem on QTc prolongation related with amitriptyline intoxication. With further studies, these agents may be used for amitriptyline toxicity and besides, they may be used for patients in cardiovascular risk groups who take amitriptyline treatment regularly. PMID- 25724423 TI - Nonobstructive hydrocolpos due to vesicovaginal reflux: expanding the differential diagnosis. AB - We report the clinical details and imaging findings for a case of vesicovaginal reflux presenting as gross urocolpos in a 15-year-old female. Findings included a large fluid-filled vagina on full-bladder scan in the absence of any anatomical abnormality, which disappeared completely after micturition. It is important for radiologists to be aware of this entity as it is rarely encountered and leads to very confusing findings, which could result in an erroneous diagnosis. PMID- 25724424 TI - Salivary cortisol and cortisone responses to tetracosactrin (synacthen). AB - BACKGROUND: To establish cutoff values for salivary liquid chromatography tandem mass spectroscopy cortisol and cortisone in defining adequate adrenocortical function during a standard synacthen test. METHODS: We compared salivary liquid chromatography tandem mass spectroscopy cortisol and cortisone responses to those of serum cortisol measured on the Roche E170 immunoassay analyser and the Abbott Architect i2000 before and 30 min and 60 min following 0.25 mg of intravenous synacthen. RESULTS: Correlations of salivary cortisol and cortisone were bimodal and linear, respectively. Based on these correlations, adequate salivary cortisol and cortisone responses to synacthen were extrapolated from a serum cortisol (Roche) cut-off of 550 nmol/L and defined as 15 nmol/L and 45 nmol/L, respectively. The Abbott method correlated well with the Roche but gave results that were about 20% lower than the Roche method. CONCLUSIONS: Measurement of salivary cortisol and cortisone responses offers an alternative to those of serum cortisol during a synacthen test in the investigation of adrenal hypofunction. PMID- 25724425 TI - Combining intraoperative carmustine wafers and Stupp regimen in multimodal first line treatment of primary glioblastomas. AB - BACKGROUND: The study investigated if intraoperative use of carmustine wafers, particularly in combination with Stupp regimen, is a viable and safe first-line treatment option of glioblastomas. METHODS: Eighty-three consecutive adult patients (50 men; mean age 60 years) with newly diagnosed supratentorial primary glioblastomas that underwent surgical resection with intraoperative carmustine wafers implantation (n = 7.1 +/- 1.7) were retrospectively studied. RESULTS: The median overall survival (OS) was 15.8 months with 56 patients dying over the course of the study. There was no significant association between the number of implanted carmustine wafers and complication rates (four surgical site infections, one death). The OS was significantly longer in Stupp regimen patients (19.5 months) as compared with patients with other postoperative treatments (13 months; p = 0.002). In addition patients with eight or more implanted carmustine wafers survived longer (24.5 months) than patients with seven or less implanted wafers (13 months; p = 0.021). Finally, regardless of the number of carmustine wafers, median OS was significantly longer in patients with a subtotal or total resection (21.5 months) than in patients with a partial resection (13 months; p = 0.011). CONCLUSIONS: The intraoperative use of carmustine wafers in combination with Stupp regimen is a viable first-line treatment option of glioblastomas. The prognostic value of this treatment association should be evaluated in a multicenter trial, ideally in a randomized and placebo-controlled one. PMID- 25724427 TI - Significance of post-resection tissue shrinkage on surgical margins of oral squamous cell carcinoma. AB - BACKGROUND: Resecting oral squamous cell carcinoma (SCC) with an appropriate margin of uninvolved tissue is critical in preventing local recurrence and in making decisions regarding postoperative radiation therapy. This task can be difficult due to the discrepancy between margins measured intraoperatively and those measured microscopically by the pathologist after specimen processing. MATERIAL AND METHODS: A total of 61 patients underwent resective surgery with curative intent for primary oral SCC were included in this study. All patients underwent resection of the tumor with a measured 1-cm margin. Specimens were then submitted for processing and reviewing, and histopathologic margins were measured. The closest histopathologic margin was compared with the in situ margin (1 cm) to determine the percentage discrepancy. RESULTS: The mean discrepancy between the in situ margins and the histopathological margins of all close and positive margins were 47.6% for the buccal mucosa (with a P value corresponding to 0.05 equaling 2.1), which is statistically significant, 4.8% for the floor of mouth, 9.5% for the mandibular alveolus, 4.8% for the retromolar trigon, and 33.3% for the tongue. CONCLUSION: There is a significant difference among resection margins based on tumor anatomical location. Margins shrinkage after resection and processing should be considered at the time of the initial resection. Tumors located in the buccal mucosa show significantly greater discrepancies than tumors at other sites. These findings suggest that it is critical to consider the oral site when outlining margins to ensure adequacy of resection. Buccal SCC is an aggressive disease, and should be considered as an aggressive subsite within the oral cavity, requiring a radical and aggressive resective approach. PMID- 25724426 TI - Ectopic expression of a phytochrome B gene from Chinese cabbage (Brassica rapa L. ssp. pekinensis) in Arabidopsis thaliana promotes seedling de-etiolation, dwarfing in mature plants, and delayed flowering. AB - Phytochrome B (phyB) is an essential red light receptor that predominantly mediates seedling de-etiolation, shade-avoidance response, and flowering time. In this study, we isolate a full-length cDNA of PHYB, designated BrPHYB, from Chinese cabbage (Brassica rapa L. ssp. pekinensis), and we find that BrphyB protein has high amino acid sequence similarity and the closest evolutionary relationship to Arabidopsis thaliana phyB (i.e., AtphyB). Quantitative reverse transcription (RT)-PCR results indicate that the BrPHYB gene is ubiquitously expressed in different tissues under all light conditions. Constitutive expression of the BrPHYB gene in A. thaliana significantly enhances seedling de etiolation under red- and white-light conditions, and causes dwarf stature in mature plants. Unexpectedly, overexpression of BrPHYB in transgenic A. thaliana resulted in reduced expression of gibberellins biosynthesis genes and delayed flowering under short-day conditions, whereas AtPHYB overexpression caused enhanced expression of FLOWERING LOCUS T and earlier flowering. Our results suggest that BrphyB might play an important role in regulating the development of Chinese cabbage. BrphyB and AtphyB have conserved functions during de-etiolation and vegetative plant growth and divergent functions in the regulation of flowering time. PMID- 25724428 TI - Detection of Tumor Suppressor Genes in Cancer Development by a Novel shRNA-Based Method. AB - Pancreatic cancer is one of the deadliest cancers with poor survival rates and limited therapeutic options. To improve the understanding of this disease's biology, a prerequisite for the generation of novel therapeutics, new platforms for rapid and efficient genetic and therapeutic screening are needed. Therefore, a combined in vitro/in vivo hybrid shRNA assay was developed using isolated murine primary pancreatic ductal cells (PDCs), in which oncogenic Kras(G12D) could be activated in vitro by genomic recombination through 4OH-tamoxifen induced nuclear translocation of Cre-ERT2 expressed under control of the ROSA26 promoter. Further genetic manipulation was achieved through selective and stable RNAi against the tumor suppressors p16(Ink4a) (CDKN2A) or Trp53 (TP53) using lentiviral gene delivery. Treatment of PDCs with 4OH-tamoxifen increased phosphorylation of ERK downstream of KRAS, and subsequent lentiviral transduction resulted in sustained target gene repression. Double-mutant PDCs were then reintroduced into the pancreata of NOD-SCID-gamma (NSG) mice and monitored for tumor growth. Orthotopic implantation of PDCs carrying the activated Kras(G12D) allele and shRNA against p16(Ink4a) or Trp53 resulted in tumor growth, metastasis, and reduced survival of NSG mice. In contrast, Kras(G12D) alone was not sufficient to induce tumor growth. IMPLICATIONS: The combinatory in vitro/in vivo approach described in this study allows for rapid and efficient identification of genes involved in carcinogenesis and opens new avenues for the development of therapeutic strategies to improve cancer treatment. PMID- 25724430 TI - Congenital cervical vertebrae clefts in Klippel-Feil syndrome. PMID- 25724431 TI - Primary extraosseous Ewing sarcoma of the lumbar spine presenting with left leg weakness. PMID- 25724429 TI - The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression. AB - Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased beta-catenin expression, and TCF4 promoter activity, and reduced NF-kappaB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro-2-deoxy-D-glucose-deoxyglucose positron emission tomography (FDG PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth-promoting and antiapoptotic signaling properties. IMPLICATIONS: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. PMID- 25724432 TI - Unusual tonsillar herniation; extending to third thoracic vertebrae. PMID- 25724433 TI - Preoperative imaging for staging bladder cancer. AB - Accurate preoperative staging of bladder cancer is essential in determining the extent of disease and optimal treatment. The current gold standard of transurethral resection of bladder tumor (TURBT) followed by computed tomography (CT) imaging provides excellent staging specificity, but often understages the disease, leading to pathologic upstaging and adverse outcomes in patients undergoing radical cystectomy. Newer imaging modalities, such as multiparametric magnetic resonance (MR) imaging and positron emission tomography (PET) combined with CT or MR provides promising imaging alternatives which may improve accuracy of staging both local and distant disease. PMID- 25724434 TI - Production, purification, and capsid stability of rhinovirus C types. AB - The rhinovirus C (RV-C) were discovered in 2006 and these agents are an important cause of respiratory morbidity. Little is known about their biology. RV-C15 (C15) can be produced by transfection of recombinant viral RNA into cells and subsequent purification over a 30% sucrose cushion, even though yields and infectivity of other RV-C genotypes with this protocol are low. The goal of this study was to determine whether poor RV-C yields were due to capsid instability, and moreover, to develop a robust protocol suitable for the purification of many RV-C types. Capsid stability assays indicated that virions of RV-C41 (refractory to purification) have similar tolerance for osmotic and temperature stress as RV A16 (purified readily), although C41 is more sensitive to low pH. Modification to the purification protocol by removing detergent increased the yield of RV-C. Addition of nonfat dry milk to the sucrose cushion increased the virus yield but sacrificed purity of the viral suspension. Analysis of virus distribution following centrifugation indicated that the majority of detectable viral RNA (vRNA) was found in pellets refractory to resuspension. Reduction of the centrifugal force with commiserate increase in spin-time improved the recovery of RV-C for both C41 and C2. Transfection of primary lung fibroblasts (WisL cells) followed by the modified purification protocol further improved yields of infectious C41 and C2. Described herein is a higher yield purification protocol suitable for RV-C types refractory to the standard purification procedure. The findings suggest that aggregation-adhesion problems rather than capsid instability influence RV-C yield during purification. PMID- 25724435 TI - Performance evaluation of AnyplexTMII HPV28 detection kit in a routine diagnostic setting: comparison with the HPV Sign(r) Genotyping Test. AB - AnyplexTMII HPV28 is a new PCR assay designed for HPV genotyping. It can detect 28 HPV types including 19 high-risk and 9 low-risk types. This study evaluated the performance of AnyplexTMII HPV28 on 123 fresh cervical samples screened in parallel with HPV Sign(r) Genotyping Test. Of the 123 samples screened, 93 were positive, 15 negative, and 15 discordant. The total number of HPV positive samples combined was 108: 38 single infections and 70 multiple infections. The agreement between the two tests was 87.8%, kappa=0.592. Genotype specific agreement was strong for HPV 16 (k=0.761), HPV 18 (k=0.674), and HPV 35 (k=0.796). Sensitivity and specificity of AnyplexTMII HPV28 assay using HPV Sign(r) Genotyping Test as reference was 84.8% and 94%; conversely, sensitivity and specificity of HPV Sign(r) Genotyping Test was 29% and 99.5%. AnyplexTMII HPV28 assay is a sensitive and specific assay suitable for HPV genotyping but requires clinical validation. PMID- 25724436 TI - Urban agriculture: long-term strategy or impossible dream?: Lessons from Prospect Farm in Brooklyn, New York. AB - Proponents of urban agriculture have identified its potential to improve health and the environment but in New York City and other densely developed and populated urban areas, it faces huge challenges because of the shortage of space, cost of land, and the lack of contemporary local food production. However, large portions of the city and metropolitan region do have open land and a history of agricultural production in the not-too-distant past. Local food movements and concerns about food security have sparked a growing interest in urban farming. Policies in other sectors to address diet-related illnesses, environmental quality and climate change may also provide opportunities to expand urban farming. Nevertheless, for any major advances in urban agriculture, significant changes in local and regional land use policies are needed. These do not appear to be forthcoming any time soon unless food movements amplify their voices in local and national food policy. Based on his experiences as founder of a small farm in Brooklyn, New York and his engagement with local food movements, the author analyzes obstacles and opportunities for expanding urban agriculture in New York. PMID- 25724437 TI - Rates of homicide-followed-by-suicide among White, African American, and Hispanic men. PMID- 25724438 TI - Cardiovascular disease and diabetes mortality, and their relation to socio economical, environmental, and health behavioural factors in worldwide view. AB - BACKGROUND: Today, non-communicable diseases, mainly cardiovascular diseases and diabetes, represent a leading threat to human health and development. This study observed mortality trends in all income group countries in relation to a wide variety of related factors like economical and environmental factors, health behaviour and health risk factors. STUDY DESIGN: Ecological study. METHOD: Data were analysed for 72 countries using the ecological study method. Data were collected from various sources including WHO, World Bank and previous studies. Cardiovascular disease and diabetes mortality rates for males and females were used as the dependent variables. GDP, GINI, literacy rate, urbanization, health expenditure, the number of physicians and the number of beds, BMI, western diet, blood glucose, blood pressure, serum cholesterol, physical inactivity, alcohol, and smoking were used as the independent variables initially. The final model was decided on the basis of availability of complete data and result of co-linearity test. Correlation test and linear regression were employed to identify the affecting factors for the dependent variables. RESULT: Analysis showed that cardiovascular disease and diabetes mortality was more concentrated in middle- and low-income countries and was negatively associated with GDP, GINI, and western diet. Countries with high average blood pressure had higher mortality rates showing a positive relationship. CONCLUSION: Non-communicable disease mortality rate is strongly associated with many economical, social, environmental, and behavioural factors. More comprehensive preventive and diagnostic strategies are needed to decrease mortality especially in low- and middle-income countries. PMID- 25724439 TI - Bladder Varices Caused by Portal Hypertension. AB - This report presents a rare case of bladder varices caused by portal hypertension in a patient with no past history of surgery. The objective is to describe the diagnosis and management of such cases. A 63-year-old man with a 7-month history of intermittent painless gross hematuria and a 9-year history of hepatic cirrhosis was admitted to our hospital. Physical examination showed no abnormalities, lab tests revealed decreased platelets (56 * 10(9)/L), and ultrasound examination showed gross splenomegaly (5.8 cm thick, 14 cm long). On the left and front walls of his bladder, a network structure filled with blood was detected covering the area of approximately 7.0 * 2.4 cm. This structure stretched toward the outer upper quadrant of the left side of his bladder and connected with a large vein. Cystoscopic examination showed venous varices of about 3 * 5 cm in size in the left and front walls of his bladder. The CT and angiographic exams revealed that varicose vessels of the bladder were connected with the inferior mesenteric veins, and that blood from those vessels emptied into the portal veins. The patient was diagnosed with hepatic cirrhosis, portal hypertension, and vesicle venous varices. Perivesical devascularization was conducted. At the 1-month follow-up, varicose veins were no longer seen on the ultrasound exam. In conclusion, bladder varices can occur in patients with hepatic cirrhosis or portal hypertension with no previous history of surgery. In such patients, perivesical devacularization is a safe and effective treatment. PMID- 25724440 TI - The Effect of Hydroxycamptothecin on Wound Healing Following Reduction of the Knee Intra-Articular Adhesion in Rabbits. AB - Topical application of 10-hydroxycamptothecin (HCPT) can reduce intra-articular scar adhesion after knee surgery, but the effect of HCPT on wound healing has not yet been elucidated. The study investigates the effect of the topical application of HCPT on wound healing after knee surgery in rabbits. Forty New Zealand white rabbits were divided into five groups: 2.0, 1.0, 0.5, and 0.1 mg/ml HCPT groups and control group. Approximately 10 mm * 10 mm of the cortical bone was removed from both sides of the femoral condyle, and the underneath of the cancellous bone was exposed. HCPT in various concentrations or saline was applied to the decorticated sites. Two weeks after surgery, the intra-articular adhesion was evaluated by Masson's trichrome staining. The blood vessel density and the fibroblast counting were evaluated by hematoxylin-eosin staining. The Vascular endothelial growth factor (VEGF) expression was evaluated by immunohistochemical staining and mRNA measurement. The recovery of all rabbits was stable after surgery. Topical application of HCPT could reduce intra-articular adhesion after 2 weeks. The blood vessel density, the number of fibroblast, and the level of VEGF expression in 2.0 and 1.0 mg/ml HCPT groups were lower than those of 0.5 mg/ml HCPT group, 0.1 mg/ml HCPT group, and the control group. However, there was no difference in multiple parameters between 1.0 and 2.0 mg/ml HCPT groups. Topical application of HCPT could reduce intra-articular scar adhesion in rabbits, but HCPT with concentrations above 1.0 mg/ml may affect the wound healing process by inhibiting the angiogenesis and fibroblast proliferation. PMID- 25724441 TI - Subcutaneous Injections of the Mannose-Sensitive Hemagglutination Pilus Strain of Pseudomonas aeruginosa Stimulate Host Immunity, Reduce Bladder Cancer Size and Improve Tumor Survival in Mice. AB - We wished to evaluate the effects of Pseudomonas aeruginosa (mannose-sensitive hemagglutination pilus strain, PA-MSHA) as an immunostimulating and anti-tumor agent for treatment of bladder cancer. Immunostimulating effects were assessed by the in vitro proliferation assay of murine splenic lymphocytes. Anti-tumor effects were studied in a subcutaneous tumor model established in female C57BL/6 mice using the MB49 bladder cell line. These mice received subcutaneous injections of normal saline (control group) or PA-MSHA (high, medium, or low dose, respectively, 1.6-2.0 * 10(9), 3.2- .0 * 10(8), 6.4-8.0 * 10(7) CFU/ml) twice a week for 3 weeks. Mice survival, tumor volume, vascular endothelial growth factor (VEGF) expression, microvessel density (MVD), serum levels of TNF alpha and IFN-gamma, and blood CD4(+) /CD8(+) counts were the study outcomes. We observed that PA-MSHA promoted the growth of splenic lymphocytes in vitro. In the murine tumor model, PA-MSHA prolonged mice survival and reduced tumor growth. Furthermore, VEGF and MVD were also diminished by PA-MSHA. Mice that received high and medium dose of PA-MSHA had significantly higher serum levels of IFN gamma and TNF-alpha (days 21 and 28), and higher levels of CD4(+) /CD8(+) cells (days 21 and 28). In conclusion, PA-MSHA exerts beneficial effects on increasing proliferation of murine splenic lymphocytes in vitro and inhibits the growth of bladder tumor in a murine model. Therefore, PA-MSHA may be useful an immunostimulating and anti-tumor agent for bladder cancer therapy. PMID- 25724442 TI - Advances in the Traditional Chinese Medicine-Based Management of Viral Myocarditis. AB - Viral myocarditis (VMC) is a common clinical condition; however, no specific treatment has been available from the perspective of modern western medicine, and typically only symptomatic treatment is provided in clinical settings. The traditional Chinese medicine (TCM) has shown certain advantages in treating VMC. Last few years have witnessed certain advances in the TCM-based research on the etiology and pathogenesis of VMC and its clinical management. This article reviews the clinical advances made in the TCM-based management of VMC in the last 5 years. PMID- 25724443 TI - Icariin Exerts Protective Effect Against Myocardial Ischemia/Reperfusion Injury in Rats. AB - Icariin, a plant-derived flavonoid, has multiple beneficial actions on the cardiovascular system. The current study investigated whether icariin postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. In in vivo rat model of myocardial ischemia/reperfusion, we found that postconditioning with icariin significantly reduced myocardial infarct size, serum level of TNF-alpha and IL-10, TNF-alpha and IL-10 expression, and apoptosis. Moreover, our results showed that icariin postconditioning exerts cardioprotective effect against myocardial I/R injury through activating PI3K/Akt using PI3K/Akt inhibitor LY294002. PMID- 25724444 TI - RGD-mimetic poly(amidoamine) hydrogel for the fabrication of complex cell-laden micro constructs. AB - The potential of the 3D cell culture approach for creating in vitro models for drug screening and cellular studies, has led to the development of hydrogels that are able to mimic the in vivo 3D cellular milieu. To this aim, synthetic polymer based hydrogels, with which it is possible to fine-tune the chemical and biophysical properties of the cell microenvironment, are becoming more and more acclaimed. Of all synthetic materials, poly(amidoamine)s (PAAs) hydrogels are known to have promising properties. In particular, PAAs hydrogels containing the 2,2-bisacrylamidoacetic acid-agmatine monomeric unit are capable of enhancing cellular adhesion by interacting with the RGD-binding alphaVbeta3 integrin. The synthesis of a new photocrosslinkable, biomimetic PAA-Jeffamine(r)-PAA triblock copolymer (PJP) hydrogel is reported in this paper with the aim of improving the optical, biocompatibility and cell-adhesion properties of previously studied PAA hydrogels and providing an inexpensive alternative to the RGD peptide based hydrogels. The physicochemical properties of PJP hydrogels are extensively discussed and the behavior of 2D and 3D cell cultures was analyzed in depth with different cell types. Moreover, cell-laden PJP hydrogels were patterned with perfusable microchannels and seeded with endothelial cells, in order to investigate the possibility of using PJP hydrogels for fabricating cell laden tissue-like micro constructs and microfluidic devices. Overall the data obtained suggest that PJP could ultimately become a useful tool for fabricating improved in vitro models in order to potentially enhance the effectiveness of drug screening and clinical treatments. PMID- 25724445 TI - Physician Perspectives on Providing Primary Medical Care to Adults with Autism Spectrum Disorders (ASD). AB - We conducted in-depth case studies of 10 health care professionals who actively provide primary medical care to adults with autism spectrum disorders. The study sought to understand their experiences in providing this care, the training they had received, the training they lack and their suggestions for encouraging more physicians to provide this care. Qualitative data were gathered by phone using a structured interview guide and analyzed using the framework approach. Challenges to providing care were identified at the systems, practice and provider, and education and training levels. Solutions and interventions targeting needed changes at each level were also proposed. The findings have implications for health care reform, medical school and residency training programs, and the development of best practices. PMID- 25724446 TI - [Shear waves elastography of the placenta in pregnant baboon]. AB - OBJECTIVES: To evaluate tissue characteristics of the placenta by transabdominal ShearWave Elastography in pregnant baboon. MATERIALS AND METHOD: For 9 months (03/2013-12/2013) two operators (EQ, GG) performed ultrasound of the placenta during pregnancy pregnant baboons station partner primatology project. The identification of the placenta was performed previously in 2D ultrasound. The elastography method was then activated. Three measurements were carried out by operator for each placenta. The intraclass correlation coefficients within and between observers were calculated for the objective assessment (elastography) of placental maturity. RESULTS: During the study period, 21 pregnant baboons were included and ultrasounds were performed between 1 and 3 times each. The measurements have been carried out by two operators in 100% of cases. The intra- and inter-observer ICC for single values are respectively 0.657 - 95% CI (0.548 to 0.752) and 0.458 - 95% CI (0.167 to 0.675). The intra- and inter-observer ICC for average values are respectively 0.852 - 95% CI (0.784 to 0.901) and 0.628 - 95% CI (0.286 to 0.806). CONCLUSION: The study by transabdominal ShearWave Elastography of placenta's pregnant baboons is possible. The intra- and inter operator reproducibility of this method is good using the average of three measurements. The objective study via elastography ShearWave of the degree of placental maturity seems not yet be used in clinical practice. Studies of larger cohorts are needed. PMID- 25724447 TI - [Impact of thyroid function on fertility]. AB - Until recently, anovulation or recurrent miscarriages were the only situations for screening a thyroid dysfunction in an infertile patient. Recent U.S. guidelines published in 2011 identify infertile women as being at risk for thyroid dysfunction. This paper proposes, on the occasion of the new recommendations, a review of the literature data on the known impact of thyroid dysfunction on fertility, on the first trimester of pregnancy and on the way to treat them. PMID- 25724448 TI - [In vitro fertilization and perinatal risk, what's new?]. PMID- 25724449 TI - [Cesarean scar ectopic pregnancies: combined modality therapies with uterine artery embolization before surgical procedure]. AB - OBJECTIVES: To offer a therapeutic management of cesarean scar pregnancies (GSC) in the first trimester of pregnancy with a first approach by uterine artery embolization (UAE) PATIENTS AND METHODS: This study describes seven cases of GSC diagnosed between 2009 and 2013 in the clinic of the University Hospital of the Hospital of Croix-Rousse. We present the symptoms and how imagery has led to the diagnosis and the therapeutic management conducted. RESULTS: The mean gestational age at diagnosis was 9 weeks gestation. There were ongoing pregnancies with cardiac activity present for each patient. An additional MRI was performed in five patients. Five patients were treated with methotrexate injection, two patients received the Mifegyne. All patients then received a selective uterine artery embolization. Finally within 48hours, suction curettage was performed in 6 patients. A patient at 13 WA+1 required a subtotal hysterectomy for placenta accreta. Intra-operative complications were represented by a bladder injury, two bleeding of 1000mL in patients at 13 WA+1 and 12 WA. For the 6 cases of GSC with a gestational age less than 10 WA, average blood loss was less than 500mL. Three patients underwent resection of scar isthmocele confirmed by EVAC. An intrauterine pregnancy was carried to term after care. DISCUSSION AND CONCLUSION: Cesarean scar pregnancies is a diagnostic and therapeutic challenge, which should be diagnosed as early as soon as possible with care in a medical facility with a uterine artery embolization technical platform. Our protocol combining Mifegyne and methotrexate for termination of pregnancy and uterine artery embolization (UAE) followed by curettage for evacuation of pregnancy allows conservative treatment while minimizing the risk of bleeding (for GSC diagnosed before 10 WA). PMID- 25724450 TI - [How I do...a nerve stimulator-guided pudendal nerve block]. PMID- 25724451 TI - Characteristics of youth who report early sexual experiences in Sweden. AB - Early timing of first sex is a common risk factor for adverse sexual and reproductive health (SRH) outcomes. This study explored characteristics and circumstances associated with early sexual experience (at or below age 14) among Swedish youth. Data were drawn from UngKAB09, a national study of youth SRH in Sweden. 24,000 youth 16-28 years were randomly selected for a web-based survey with a response rate of 24%. Post-stratification weights were used to correct for over- and underrepresentation in response. Adjusted logistic regression was used to model associations with early sexual experience, by gender. In the final sample (N = 5,321, 49% girls), 9 in 10 were sexually experienced, of whom 21% reported early first sex. In multivariate analysis, early sex was significantly associated with 7 of the 9 predictor variables selected for the model among boys and 14 of 15 selected factors among girls. Early sex was positively associated with low educational attainment, early pubertal onset, bisexual identity and (girls only) rural residence. For girls, first generation immigrant status, greater religiosity, conservative sexual attitudes and low Chlamydia knowledge decreased the odds of early sex. Early experience was more common if youth had older partners and, among girls, felt that sex was expected. Being in love, feelings of intimacy, alcohol use at first sex, and (girls only) causal sexual partner and wantedness of first sex were inversely associated with early first sex. The findings and implications are discussed in relation to the European and global literature on early sexual experiences. PMID- 25724452 TI - Effects of estradiol-17beta implantation on ovarian growth, sex steroid levels and vitellogenin proxies in previtellogenic sturgeon Huso huso. AB - Sexual development in female great sturgeon (Huso huso) is arrested at the previtellogenic stage for many years. The present study investigated the effects of different levels of estradiol-17beta (E2) on gonadal development, levels of sex steroids and proxies of vitellogenin in 3-year-old cultured previtellogenic great sturgeon. Fish were intraperitoneally implanted every 1.5 months over a 6 month period from January to July with capsules filled with 0, 3, 6 or 12 mg E2/kg body mass as control, low, mid and high experimental groups, respectively. Blood sampling was performed at the start of experimentation and 3 weeks after each implantation for quantification of sex steroid levels and of vitellogenin associated variables (triacylglycerol, cholesterol, calcium, phosphorus). Gonad biopsy samples were taken at the beginning and the end of the experiment in order to determine the gonad stage and oocyte morphometrical measures were taken to evaluate treatment effects. E2 implants produced a significant elevation in serum concentrations of E2, calcium, triacylglycerol, cholesterol and phosphorus. A rapid significant decrease was observed in serum testosterone levels in a dose independent manner, so that the highest testosterone concentrations were observed in control fish throughout the experiment. There were no significant differences in oocyte stage or morphometric end points among the treated fish. We conclude that E2 implants do not stimulate ovarian growth, and hence, E2 implants alone are insufficient to reducing the time until onset of sexual maturation in previtellogenic great sturgeon. PMID- 25724453 TI - Targeting the FXR nuclear receptor to treat liver disease. PMID- 25724454 TI - Topical therapy in ulcerative colitis: always a bridesmaid but never a bride? PMID- 25724456 TI - The rationale and growth of advanced training in inflammatory bowel disease. PMID- 25724455 TI - Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. AB - BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 MUg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 MUg/mL (43.7%). Of 76 patients with TCs <3 MUg/mL, 69 patients (91%) achieved TCs of 3-7 MUg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 MUg/mL, 67 patients (93%) achieved TCs of 3-7 MUg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 MUg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38. PMID- 25724457 TI - Management of pancreatic cysts: the evidence is not here yet. PMID- 25724458 TI - Homeostatic restoration of desmoplastic stroma rather than its ablation slows pancreatic cancer progression. PMID- 25724459 TI - Fibrolamellar hepatocellular carcinoma: a rare but distinct type of liver cancer. PMID- 25724460 TI - Managing pancreatic cysts: less is more? PMID- 25724461 TI - Management of pancreatic cysts in an evidence-based world. PMID- 25724462 TI - Practical clinical skills assessment for a cohort of 680 2nd year human medicine students. Is it feasible? AB - In clinical skills training objective structured clinical examinations (OSCEs) are the method of choice to foster learning. Hence, implementing them is challenging and expensive. Thus it is investigated how an alternative procedure that keeps OSCE's essential elements, but assigns less stations to each student, works in terms of validity and justifiability.Data of n = 694 students, each taking five tasks drawn semi-randomized out of a pool of 26 tasks, strictly aligned with learning objectives, are analyzed. Despite unsurprisingly low overall reliability, a justifiable pass/fail decision is possible for 480 students (69 %). The remaining group (n = 210, 30 %) is indeed larger than with longer OSCEs, and would need ongoing assessment. The tasks' psychometric quality contributes to exams construct validity. Resource preserving short practical skills assessment is educationally valid and feasible with MedUniVienna's human medicine cohorts of n = 680. PMID- 25724463 TI - A Health Belief Model delivered by nurses improves health outcomes for people with chronic obstructive pulmonary disease in China. PMID- 25724464 TI - Modifiable risk factors for miscarriage identified. PMID- 25724465 TI - Women's health locus of control during pregnancy may predict risk for postpartum depression. PMID- 25724467 TI - Sleep disturbances predict future sickness absence among individuals with lower back or neck-shoulder pain: a 5-year prospective study. AB - BACKGROUND: Musculoskeletal pain is one of the most common causes of sickness absence. Sleep disturbances are often co-occurring with pain, but the relationship between sleep and pain is complex. Little is known about the importance of self-reported sleep, when predicting sickness absence among persons with musculoskeletal pain. This study aims to study the association between self reported sleep quality and sickness absence 5 years later, among individuals stratified by presence of lower back pain (LBP) and neck and shoulder pain (NSP). METHODS: The cohort (n = 2286) in this 5-year prospective study (using data from the MUSIC-Norrtalje study) was stratified by self-reported pain into three groups: no LBP or NSP, solely LBP or NSP, and concurrent LBP and NSP. Odds ratios (ORs) for the effect of self-reported sleep disturbances at baseline on sickness absence (> 14 consecutive days), 5 years later, were calculated. RESULTS: Within all three pain strata, individuals reporting the most sleep problems showed a significantly higher OR for all-cause sickness absence, 5 years later. The group with the most pronounced sleep problems within the concurrent LBP and NSP stratum had a significantly higher OR (OR 2.00; CI 1.09-3.67) also for long-term sickness absence (> 90 days) 5 years later, compared to the group with the best sleep. CONCLUSIONS Sleep disturbances predict sickness absence among individuals regardless of co-existing features of LBP and/or NSP. The clinical evaluation of patients should take possible sleep disturbances into account in the planning of treatments. PMID- 25724466 TI - Bisphenol A exposure and behavioral problems among inner city children at 7-9 years of age. AB - BACKGROUND: Bisphenol A (BPA) is a ubiquitous endocrine disrupting compound. Several experimental and epidemiological studies suggest that gestational BPA exposure can lead to neurodevelopmental and behavioral problems in early-life, but results have been inconsistent. We previously reported that prenatal BPA exposure may affect child behavior and differently among boys and girls at ages 3 5 years. OBJECTIVES: We investigated the association of prenatal and early childhood BPA exposure with behavioral outcomes in 7-9 year old minority children and hypothesized that we would observe the same sex-specific pattern observed at earlier ages. METHODS: African-American and Dominican women enrolled in an inner city prospective cohort study and their children were followed from mother's pregnancy through children's age 7-9 years. Women during the third trimester of pregnancy and children at ages 3 and 5 years provided spot urine samples. BPA exposure was categorized by tertiles of BPA urinary concentrations. The Child Behavioral Checklist (CBCL) was administered at ages 7 and 9 to assess multiple child behavior domains. Associations between behavior and prenatal (maternal) BPA concentrations and behavior and postnatal (child) BPA concentration were assessed via Poisson regression in models stratified by sex. These models accounted for potential confounders including prenatal or postnatal urinary BPA concentrations, child age at CBCL assessment, ethnicity, gestational age, maternal intelligence, maternal education and demoralization, quality of child's home environment, prenatal environmental tobacco smoke exposure, and prenatal mono-n-butyl phthalate concentration. RESULTS: The direction of the associations differed between boys and girls. Among boys (n=115), high prenatal BPA concentration (upper tertile vs. lower two tertiles) was associated with increased internalizing (beta=0.41, p<0.0001) and externalizing composite scores (beta=0.40, p<0.0001) and with their corresponding individual syndrome scales. There was a general decrease in scores among girls that was significant for the internalizing composite score (beta=-0.17, p=0.04) (n=135). After accounting for possible selection bias, the results remained consistent for boys. Conversely, high postnatal BPA concentration was associated with increased behaviors on both the internalizing composite (beta=0.30, p=0.0002) and externalizing composite scores (beta=0.33, p<0.0001) and individual subscores in girls but fewer symptoms in boys. These results remained significant in girls after accounting for selection bias. CONCLUSION: These results suggest BPA exposure may affect childhood behavioral outcomes in a sex-specific manner and differently depending on timing of exposure. PMID- 25724468 TI - Work participation in Q-fever patients and patients with Legionnaires' disease: a 12-month cohort study. AB - AIMS: The aim of the study was to assess long-term work participation of Q-fever patients and patients with Legionnaires' disease, and to identify which factors are associated with a reduced work participation in Q-fever patients. METHODS: Q fever patients participated at four time points until 12 months after onset of illness, patients with Legionnaires' disease only at 12 months. Data were self reported using questionnaires on the amount of hours that patients worked, and on socio-demographic, medical, psychosocial and lifestyle aspects. RESULTS: Our study included 336 Q-fever patients and 190 patients with Legionnaires' disease. There was a decrease in the proportion of Q-fever patients with reduced work participation over time, from 45% at 3 months to 19% at 12 months (versus 15% of patients with Legionnaires' disease at 12 months). Factors associated with reduced work participation of Q-fever patients in a multivariate model were having symptoms, a higher level of sorrow, being a former smoker (compared to never smoking), not consuming any alcohol and following additional treatment for the long-term health effects of Q-fever. CONCLUSIONS: Despite an increase in work participation of Q-fever patients over time, almost one in five Q-fever patients and one in six patients with Legionnaires' disease still suffer from reduced work participation at 12 months. Occupational and insurance physicians need to be aware of the long-term impact of these diseases on work participation. PMID- 25724469 TI - Social, lifestyle and demographic inequalities in hypertension care. AB - AIMS: Recent nationwide in-depth analyses on inequalities in hypertension prevalence and care are scarce. This study assessed sociodemographic and lifestyle factors associated with the prevalence, awareness, treatment and control of hypertension in Finland. METHODS: A representative nationwide sample (participation rate 58%) of the Finnish adult population underwent a health examination and interview in 2011. After excluding participants with missing data, 4230 people were included in the analyses. Weighted regression modelling was used to explore the associations of sociodemographic and lifestyle factors with the prevalence, awareness, treatment and control of hypertension. RESULTS: The prevalence, awareness, treatment and control rates of hypertension (blood pressure ?140/90 mmHg or antihypertensive medication) in Finland were 47%, 57%, 51% and 48%, respectively. Older age, male sex, lower education, retirement, higher BMI, never-smoking and heavy alcohol use were associated with a higher prevalence of hypertension (p<0.05). In contrast, younger age, non-retirement, lower BMI, smoking and high physical activity were associated with lower awareness and treatment rates (p<0.05). In addition, male sex was associated with lower awareness rates (p<0.01). Hypertension control was better in younger participants (p<0.05). CONCLUSIONS: In addition to high prevalence and moderate treatment rates of hypertension, serious sociodemographic and lifestyle inequities in hypertension care exist in Finland. Hypertension is more prevalent in older people of lower socio-economic status with adverse lifestyles. However, hypertension is more often unrecognised and untreated among people with low risk of hypertension. PMID- 25724470 TI - Nimesulide inhibits the growth of human esophageal carcinoma cells by inactivating the JAK2/STAT3 pathway. AB - Although selective COX-2 inhibitors have cancer-preventive effects and induce apoptosis, the mechanisms underlying these effects are not fully understood. This study investigated the effects of nimesulide, a selective COX-2 inhibitor, on apoptosis and on the JAK/STAT signaling pathway in Eca-109 human esophageal squamous carcinoma cells. The effects and mechanisms of nimesulide on Eca-109 cell growth were studied in culture and in nude mice with Eca-109 xenografts. Cells were cultured with or without nimesulide and/or the JAK2 inhibitor AG490. Cell proliferation was evaluated using the MTT assay, and apoptosis was investigated. COX-2 mRNA expression was measured using reverse transcription polymerase chain reaction, and protein expression was detected by Western blot analysis, immunohistochemistry, and flow cytometry. Nimesulide significantly inhibited Eca-109 cell viability in vitro in a dose- and time-dependent manner (P<0.05). Nimesulide also induced apoptosis, which was accompanied by a significant decrease in the expression of COX-2 and survivin and an increase in caspase-3 expression. Nimesulide downregulated the phosphorylation levels of JAK2 and STAT3, and JAK2 inhibition by AG490 significantly augmented both nimesulide induced apoptosis and the downregulation of COX-2 and survivin (P<0.05). In vivo, nimesulide inhibited the growth of Eca-109 tumors and the expression of p-JAK2 and p-STAT3. Thus, nimesulide downregulates COX-2 and survivin expression and upregulates caspase-3 expression in Eca-109 cells, by inactivating the JAK2/STAT3 pathway. These effects may mediate nimesulide-induced apoptosis and growth inhibition in Eca-109 cells in vitro and in vivo. PMID- 25724471 TI - Recurrence of Hypertrophic Abductor Digiti Minimi Muscle of the Foot After Subtotal Resection. AB - Soft tissue tumors of the foot are rare, and the diagnosis is often difficult. Surgery is indicated if pain, discomfort, or functional impairment is present or to rule out malignancy. We present the case of a 14-year-old female with a painless swelling at the lateral aspect of her right foot. After radiologic imaging, including ultrasonography and magnetic resonance imaging (MRI), we performed a subtotal resection of the abductor digiti minimi muscle, preserving its motor nerve. Four months later, recurrence of the soft tissue mass was observed. MRI revealed hypertrophy of the small muscles of the foot, including the abductor digiti minimi, quadratus plantae, and flexor digiti minimi brevis. Functional impairment resulted in complete excision of the remnant abductor digiti minimi muscle and partial excision of the flexor digiti minimi brevis muscle another 7 months later. Twelve months after the secondary surgery, neither clinical nor radiologic signs of a second recurrence were found. At the last follow-up visit, the patient was satisfied with the contour of her foot and not hindered at all during sporting activities. Our findings demonstrate that subtotal resection of a bulky muscle, preserving its motor nerve, can result in reactive hypertrophy of the remnant muscle part. The patient must be informed that partial excision of an innervated muscle could result in reactive hypertrophy and must be contrasted with radical muscle excision that might be more likely to result in functional impairment. PMID- 25724472 TI - Polymorphisms in the glucocorticoid receptor gene and in the glucocorticoid induced transcript 1 gene are associated with disease activity and response to glucocorticoid bridging therapy in rheumatoid arthritis. AB - Glucocorticoids (GC) are widely used in rheumatoid arthritis (RA). Ongoing active disease due to GC resistance may unfavorably influence long-term disease outcome in RA. We studied the association between the presence of glucocorticoid receptor (GR) and glucocorticoid-induced transcript 1 (GLCCI1) gene polymorphisms, which modulate GC sensitivity, and baseline disease activity score (DAS) and efficacy of GC bridging therapy in RA. We prospectively studied in vivo GC sensitivity in 138 patients with recent-onset or longstanding RA. In vivo GC sensitivity was expressed as the relative decrease in DAS following 2 weeks of standardized GC therapy. All patients were genotyped for the GR polymorphisms BclI (rs41423247), N363S (rs6195), 9beta (rs6198), ER22/23EK (rs6189 + rs6190), and the GLCCI1 variant rs37972 and subsequently divided in groups carrying a polymorphism associated with increased GC sensitivity (BclI-G allele, N363S-G allele, GLCCI1-C allele) or decreased GC sensitivity (9beta-G allele, ER22/23EK-A/A allele, GLCCI1 T allele). Differences in baseline DAS and relative decrease in DAS in the different genotype groups were analyzed using analysis of covariance and linear regression. Baseline DAS was higher in patients who carried polymorphisms of the GR and GLCCI1 genes associated with decreased GC sensitivity. GLCCI1 genotype, but not GR genotypes, was associated with improvement in DAS in male patients with RA. The GLCCI1 gene minor allele (rs37972) may be associated with less efficient GC bridging therapy in male RA patients. Carriers of the BclI-G, N363S G, or GLCCI1-C alleles had lower levels of baseline disease activity, suggesting a role for the GLCCI1 and GR gene in regulation of GC sensitivity to endogenously produced cortisol. PMID- 25724473 TI - A confidence ellipse for the Net Reclassification Improvement. AB - The Net Reclassification Improvement (NRI) has become a popular metric for evaluating improvement in disease prediction models through the past years. The concept is relatively straightforward but usage and interpretation has been different across studies. While no thresholds exist for evaluating the degree of improvement, many studies have relied solely on the significance of the NRI estimate. However, recent studies recommend that statistical testing with the NRI should be avoided. We propose using confidence ellipses around the estimated values of event and non-event NRIs which might provide the best measure of variability around the point estimates. Our developments are illustrated using practical examples from EPIC-Potsdam study. PMID- 25724474 TI - Nut consumption and risk of stroke. AB - Nut consumption has been inconsistently associated with risk of stroke. Our aim was to carry out a meta-analysis of prospective studies to assess the relation between nut consumption and stroke risk and mortality. Pertinent studies were identified by a search of PubMed and Embase through June 2014 and by reviewing the references of retrieved articles. Prospective cohort studies that reported relative risks (RRs) with 95% confidence intervals (CIs) for the association between nut consumption and risk of stroke were included. Six articles including nine independent prospective cohorts with 476,181 participants were included in the meta-analysis. The pooled RR of stroke was 0.90 (95% CI 0.83-0.98) comparing the highest with the lowest nut consumption. Stratifying by gender, significant inverse association was observed for females (RR 0.88; 95% CI 0.78-0.98). Sensitivity analysis restricted to studies with adjustment for common confounding factors showed similar results, strengthening the association between nut consumption and stroke risk. Moreover, we observed a trend toward an inverse association between higher nut consumption and stroke mortality (RR 0.86; 95% CI 0.69-1.06), although it is not significant. Current evidence indicated that nut consumption is inversely associated with risk of stroke. PMID- 25724475 TI - Electron dose distributions caused by the contact-type metallic eye shield: Studies using Monte Carlo and pencil beam algorithms. AB - A metallic contact eye shield has sometimes been used for eyelid treatment, but dose distribution has never been reported for a patient case. This study aimed to show the shield-incorporated CT-based dose distribution using the Pinnacle system and Monte Carlo (MC) calculation for 3 patient cases. For the artifact-free CT scan, an acrylic shield machined as the same size as that of the tungsten shield was used. For the MC calculation, BEAMnrc and DOSXYZnrc were used for the 6-MeV electron beam of the Varian 21EX, in which information for the tungsten, stainless steel, and aluminum material for the eye shield was used. The same plan was generated on the Pinnacle system and both were compared. The use of the acrylic shield produced clear CT images, enabling delineation of the regions of interest, and yielded CT-based dose calculation for the metallic shield. Both the MC and the Pinnacle systems showed a similar dose distribution downstream of the eye shield, reflecting the blocking effect of the metallic eye shield. The major difference between the MC and the Pinnacle results was the target eyelid dose upstream of the shield such that the Pinnacle system underestimated the dose by 19 to 28% and 11 to 18% for the maximum and the mean doses, respectively. The pattern of dose difference between the MC and the Pinnacle systems was similar to that in the previous phantom study. In conclusion, the metallic eye shield was successfully incorporated into the CT-based planning, and the accurate dose calculation requires MC simulation. PMID- 25724476 TI - HPV-related squamous cell carcinoma of the head and neck: An update on testing in routine pathology practice. AB - Oropharyngeal squamous cell carcinoma caused by high-risk types of human papillomavirus (HPV) is now a well-recognized tumor entity whose incidence is on the rise. Most HPV-related oropharyngeal squamous cell carcinomas have a distinct histomorphology, and most patients fit a typical clinical profile. Importantly, HPV-related oropharyngeal carcinoma patients overall have significantly improved outcomes when compared to their HPV-negative counterparts, and the differences in tumor biology may soon lead to modifications in how they are treated. While high risk HPV can be detected in a significant minority of head and neck squamous cell carcinomas across anatomic subsites in the head and neck, it has become clear in recent years that the biologically and clinically favorable features are limited to tumors that harbor transcriptionally active, high-risk HPV, something that occurs predominantly (but certainly not exclusively) in the oropharynx. It is now acknowledged that detecting transcriptionally active, high-risk HPV is a necessity in routine clinical practice, but there is considerable confusion among pathologists and clinicians alike about the subsites and settings in which HPV testing should be performed. Compounding this lack of clarity is the fact that there are multiple HPV testing options available, but currently there is no clear consensus on which test or combination of tests is optimal for routine diagnostic use. This review serves as an update for practicing pathologists on the current status of HPV (and surrogate marker) testing in head and neck cancers. PMID- 25724477 TI - [SMILE: refractive lenticule extraction for myopic correction]. AB - PURPOSE: It is currently possible to obtain refractive correction without using an excimer laser; the technique is called ReLEx((r)) (Refractive Lenticule extraction) and uses the femtosecond laser VisuMax((r)) (Carl Zeiss Meditec, Jena, Germany). We present initial clinical experience with small-incision (4mm) lenticule extraction (SMILE) for the treatment of moderate to high myopia via a retrospective study of 106 myopic and astigmatic eyes. MATERIALS AND METHODS: This retrospective study of 106 eyes measures postoperative visual acuity to determine the safety, efficacy and predictability of the technique. For SMILE, an intrastromal lenticule is cut with the VisuMax((r)) femtosecond laser; it is then dissected and detached from the anterior and posterior stromal planes and finally removed through a 4mm incision. This procedure does not require the creation of a flap. The study is based on 106 eyes of 54 patients who underwent the surgery for moderate to high myopia, with or without associated astigmatism. Patient selection was the same as for LASIK. RESULTS: The average age of the patients was 33 +/- 9 (20-54). The mean preoperative spherical equivalent was -6.22 +/- 1.6 ( 3; -9.75 D). The mean preoperative sphere was -5.88 D +/- 1.52 (-3; -9.75 D) with a mean cylinder of -0.68 D +/- 0.58 (0.00; -2.25). Postoperatively, 95% of patients had distance vision greater than or equal to 8/10. No loss of BCVA was noted. The mean postoperative spherical equivalent was -0.16 +/- 0.35 D (-1.38; +0.88) with a mean sphere of 0.00 +/- 0.34 D (-1,25; +1) and a mean cylinder of 0.31 +/- 0.37 D (0; -1.5). One eye was converted to PRK because the incision site was covered by conjunctiva during the last 5 seconds of the laser phase. CONCLUSION: SMILE is a predictable and safe technique for the surgical correction of moderate to high myopia. PMID- 25724478 TI - Gene expression levels of Casein kinase 1 (CK1) isoforms are correlated to adiponectin levels in adipose tissue of morbid obese patients and site-specific phosphorylation mediated by CK1 influences multimerization of adiponectin. AB - White adipose tissue has now been recognized as an important endocrine organ secreting bioactive molecules termed adipocytokines. In obesity, anti inflammatory adipocytokines like adiponectin are decreased while pro-inflammatory factors are over-produced. These changes contribute to the development of insulin resistance and obesity-associated diseases. Since members of the casein kinase 1 (CK1) family are involved in the regulation of various signaling pathways we ask here whether they are able to modulate the functions of adiponectin. We show that CK1delta and epsilon are expressed in adipose tissue and that the expression of CK1 isoforms correlates with that of adiponectin. Furthermore, adiponectin co immunoprecipitates with CK1delta and CK1epsilon and is phosphorylated by CK1delta at serine 174 and threonine 235, thereby influencing the formation of adiponectin oligomeric complexes. Furthermore, inhibition of CK1delta in human adipocytes by IC261 leads to an increase in basal and insulin-stimulated glucose uptake. In summary, our data indicate that site-specific phosphorylation of adiponectin, especially at sites targeted by CK1delta in vitro, provides an additional regulatory mechanism for modulating adiponectin complex formation and function. PMID- 25724480 TI - Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link? AB - Metabolic syndrome (MetS) is a disease composed of different risk factors such as obesity, type 2 diabetes or dyslipidemia. The prevalence of this syndrome is increasing worldwide in parallel with the rise in obesity. Nonalcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in western countries, affecting more than 30% of the general population. NAFLD encompasses a spectrum of liver manifestations ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. There is accumulating evidence supporting an association between NAFLD and MetS. Indeed, NAFLD is recognized as the liver manifestation of MetS. Insulin resistance is increasingly recognized as a key factor linking MetS and NAFLD. Insulin resistance is associated with excessive fat accumulation in ectopic tissues, such as the liver, and increased circulating free fatty acids, which can further promote inflammation and endoplasmic reticulum stress. This in turn aggravates and maintains the insulin resistant state, constituting a vicious cycle. Importantly, evidence shows that most of the patients developing NAFLD present at least one of the MetS traits. This review will define MetS and NAFLD, provide an overview of the common pathophysiological mechanisms linking MetS and NAFLD, and give a perspective regarding treatment of these ever growing metabolic diseases. PMID- 25724479 TI - Brain GLP-1 and insulin sensitivity. AB - Type 2 diabetes is often treated with a class of drugs referred to as glucagon like peptide-1 (GLP-1) analogs. GLP-1 is a peptide secreted by the gut that acts through only one known receptor, the GLP-1 receptor. The primary function of GLP 1 is thought to be lowering of postprandial glucose levels. Indeed, medications utilizing this system, including the long-acting GLP-1 analogs liraglutide and exenatide, are beneficial in reducing both blood sugars and body weight. GLP-1 analogs were long presumed to affect glucose control through their ability to increase insulin levels through peripheral action on beta cells. However, multiple lines of data point to the ability of GLP-1 to act within the brain to alter glucose regulation. In this review we will discuss the evidence for a central GLP-1 system and the effects of GLP-1 in the brain on regulating multiple facets of glucose homeostasis including glucose tolerance, insulin production, insulin sensitivity, hepatic glucose production, muscle glucose uptake, and connections of the central GLP-1 system to the gut. Although the evidence indicates that GLP-1 receptors in the brain are not necessary for physiologic control of glucose regulation, we discuss the research showing a strong effect of acute manipulation of the central GLP-1 system on glucose control and how it is relevant to type 2 diabetic patients. PMID- 25724481 TI - Transcriptional activation of LON Gene by a new form of mitochondrial stress: A role for the nuclear respiratory factor 2 in StAR overload response (SOR). AB - High output of steroid hormone synthesis in steroidogenic cells of the adrenal cortex and the gonads requires the expression of the steroidogenic acute regulatory protein (StAR) that facilitates cholesterol mobilization to the mitochondrial inner membrane where the CYP11A1/P450scc enzyme complex converts the sterol to the first steroid. Earlier studies have shown that StAR is active while pausing on the cytosolic face of the outer mitochondrial membrane while subsequent import of the protein into the matrix terminates the cholesterol mobilization activity. Consequently, during repeated activity cycles, high level of post-active StAR accumulates in the mitochondrial matrix. To prevent functional damage due to such protein overload effect, StAR is degraded by a sequence of three to four ATP-dependent proteases of the mitochondria protein quality control system, including LON and the m-AAA membranous proteases AFG3L2 and SPG7/paraplegin. Furthermore, StAR expression in both peri-ovulatory ovarian cells, or under ectopic expression in cell line models, results in up to 3-fold enrichment of the mitochondrial proteases and their transcripts. We named this novel form of mitochondrial stress as StAR overload response (SOR). To better understand the SOR mechanism at the transcriptional level we analyzed first the unexplored properties of the proximal promoter of the LON gene. Our findings suggest that the human nuclear respiratory factor 2 (NRF-2), also known as GA binding protein (GABP), is responsible for 88% of the proximal promoter activity, including the observed increase of transcription in the presence of StAR. Further studies are expected to reveal if common transcriptional determinants coordinate the SOR induced transcription of all the genes encoding the SOR proteases. PMID- 25724482 TI - Chaperone mediated autophagy to the rescue: A new-fangled target for the treatment of neurodegenerative diseases. AB - One of the main pathways of lysosomal proteolysis is chaperone-mediated autophagy (CMA), which represents a selective mechanism for the degradation of specific soluble proteins within lysosomes. Along with the other two lysosomal pathways, macro- and micro-autophagy, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. The two intrinsic characteristics of CMA are the selective targeting and the direct translocation of substrate proteins into the lysosomal lumen, in a fine-tuned manner through the orchestrated action of a chaperone/co-chaperone complex localized both at the cytosol and the lysosomes. Even though CMA was originally identified as a stress induced pathway, basal CMA activity is detectable in most cell types analyzed so far, including neurons. Additionally, CMA activity declines with age and this may become a major aggravating factor contributing to neurodegeneration. More specifically, it has been suggested that CMA impairment may underlie the accumulation of misfolded/aggregated proteins, such as alpha-synuclein or LRRK2, whose levels or conformations are critical to Parkinson's disease pathogenesis. On the other hand, CMA induction might accelerate clearance of pathogenic proteins and promote cell survival, suggesting that CMA represents a viable therapeutic target for the treatment of various proteinopathies. In the current review, we provide an overview of the current state of knowledge regarding the role of CMA under physiological and pathological conditions of the nervous system and discuss the implications of these findings for therapeutic interventions for Parkinson's disease and other neurodegenerative disorders. This article is part of Special Issue entitled "Neuronal Protein". PMID- 25724483 TI - The Susd2 protein regulates neurite growth and excitatory synaptic density in hippocampal cultures. AB - Complement control protein (CCP) domains have adhesion properties and are commonly found in proteins that control the complement immune system. However, an increasing number of proteins containing CCP domains have been reported to display neuronal functions. Susd2 is a transmembrane protein containing one CCP domain. It was previously identified as a tumor-reversing protein, but has no characterized function in the CNS. The present study investigates the expression and function of Susd2 in the rat hippocampus. Characterization of Susd2 during development showed a peak in mRNA expression two weeks after birth. In hippocampal neuronal cultures, the same expression profile was observed at 15days in vitro for both mRNA and protein, a time consistent with synaptogenesis in our model. At the subcellular level, Susd2 was located on the soma, axons and dendrites, and appeared to associate preferentially with excitatory synapses. Inhibition of Susd2 by shRNAs led to decreased numbers of excitatory synaptic profiles, exclusively. Also, morphological parameters were studied on young (5DIV) developing neurons. After Susd2 inhibition, an increase in dendritic tree length but a decrease in axon elongation were observed, suggesting changes in adhesion properties. Our results demonstrate a dual role for Susd2 at different developmental stages, and raise the question whether Susd2 and other CCP containing proteins expressed in the CNS could be function-related. PMID- 25724484 TI - Association of norepinephrine transporter (NET, SLC6A2) genotype with ADHD related phenotypes: findings of a longitudinal study from birth to adolescence. AB - Variation in the gene encoding for the norepinephrine transporter (NET, SLC6A2) has repeatedly been linked with ADHD, although there is some inconsistency regarding the association with specific genes. The variants for which most consistent association has been found are the NET variants rs3785157 and rs28386840. Here, we tested for their association with ADHD diagnosis and ADHD related phenotypes during development in a longitudinal German community sample. Children were followed from age 4 to age 15, using diagnostic interviews to assess ADHD. Between the ages of 8 and 15 years, the Child Behavior Checklist (CBCL) was administered to the primary caregivers. The continuous performance task (CPT) was performed at age 15. Controlling for possible confounders, we found that homozygous carriers of the major A allele of the functional promoter variant rs28386840 displayed a higher rate of ADHD lifetime diagnosis. Moreover, homozygous carriers of the minor T allele of rs3785157 were more likely to develop ADHD and showed higher scores on the CBCL externalizing behavior scales. Additionally, we found that individuals heterozygous for rs3785157 made fewer omission errors in the CPT than homozygotes. This is the first longitudinal study to report associations between specific NET variants and ADHD-related phenotypes during the course of development. PMID- 25724485 TI - Sodium valproate for the treatment of Tourette's syndrome in children: a systematic review and meta-analysis. AB - The aims are to evaluate the efficacy and safety of sodium valproate for children with Tourette's syndrome (TS). We searched PubMed, EMBASE, the Cochrane library, Cochrane Central, CBM, CNKI, VIP, WANG FANG database and relevant reference lists. Five RCTs (N=247) and five case series (N=163) studies were included. Only one RCT (93 patients) evaluated total YGTSS scores and there was significant difference in the reduction of total YGTSS scores between sodium valproate and the control group (3.50+/-4.59 vs 7.86+/-7.03, P<0.01). One RCT (30 patients) evaluated motor and vocal tics, and there was significant difference in the reduction of motor and vocal tics scores between sodium valproate and haloperidol (10.45+/-4.15 vs 14.92+/-3.01, P<0.01). Meta-analysis of three RCTs (N=124) showed there was no significant difference in the reduction of the number of tics between sodium valproate and the positive control group [Relative Risk (RR)=1.09, 95%CI (0.92, 1.30), P=0.30]. The pooled proportion in five case series studies which used tics symptom improvement self-defined by authors was 80.7% (95% CI: 73.7-86.2, I(2)=0). No fatal side effects were reported. In conclusion, based on the limited evidence, the routine use of sodium valproate for treatment of TS in children is not recommended. Further well-conducted trials that examine long-term outcomes are required. PMID- 25724486 TI - Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder- data from an association study of suicide attempts with clock genes. AB - Suicidal behavior exhibits both circadian and annual rhythms. We were seeking an association between selected candidate clock genes and suicidal behavior in bipolar patients. The study included 441 bipolar patients and 422 controls and we genotyped 41 SNPs of the CLOCK, ARNTL, TIMELESS, PER3 genes. The main positive findings built up associations between selected polymorphisms and. PMID- 25724487 TI - Progress in mind: focus on alcohol use disorders, an elsevier resource centre. AB - Harmful use of alcohol is one of the top five risks for burden of disease globally and in Europe; in 2012, 3.3 million net deaths (approximately 6% of all global deaths) were attributable to this risk factor. It is also linked to the development of a wide spectrum of alcohol use disorders, ranging from mild manifestations to a severe disease known as alcohol dependence. Alcohol dependence is a progressive, chronic, and relapsing brain disease resulting from the prolonged effects of alcohol on the brain. Alcohol dependence imposes a significant societal burden, with indirect societal costs reaching up to 0.64% of European countries' annual gross domestic product. With these facts in mind, it is important to recognize and manage alcohol dependence. Although the biological mechanisms behind the development of alcohol dependence are not fully known, factors that have been shown to influence its development include genetic predisposition, psychological problems, and social interactions. Alcohol use has also been linked to the development of hypertension, liver cirrhosis, chronic pancreatitis, multiple types of cancer, and psychiatric comorbidities such as depression and anxiety disorders. With such severe effects on both individuals and society, it is important to recognize the characteristic signs and symptoms of alcohol dependence and explore new ways to better manage patients with this brain disease. Effective treatment approaches for alcohol dependence include biological, behavioral, and social components addressing the multiple aspects of this disease. Comprehensive, educational platforms in which to explore the many facets of this disease such as the Progress in Mind: Focus on Alcohol Use Disorders Resource Centre, will provide clinicians with the tools necessary for recognizing patients with alcohol dependence and managing their disease along with related comorbidities. Online Access: http://progressinmind.elsevierresource.com. PMID- 25724488 TI - The role of coronary microvascular disorder in congestive heart failure. PMID- 25724489 TI - New investigator editorial: Acquiring writing and reviewing skills for your communication toolbox. PMID- 25724490 TI - Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice. AB - This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors l-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin resistant mice. PMID- 25724491 TI - Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines. AB - Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca(2+) homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4-6 wk of age. To assess Ca(2+) handling, isolated cardiomyocytes were loaded with fluo-4. Q510E SHP2 expression increased Ca(2+) transient amplitudes during excitation contraction coupling and increased sarcoplasmic reticulum Ca(2+) content concurrent with increased expression of sarco(endo)plasmic reticulum Ca(2+) ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force velocity relationships and power-load curves were shifted upward. The peak power generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca(2+) cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2 associated HCM. PMID- 25724492 TI - Angiotensin-(1-7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy. AB - In diabetic patients, left ventricular (LV) remodeling is highly prevalent; however, little is known about the impact of diabetes on right ventricular (RV) structure and function. We recently found that overexpression of angiotensin (ANG)-converting enzyme 2 (ACE2), which metabolizes ANG-II to ANG-(1-7) and ANG-I to ANG-(1-9), may improve LV remodeling in diabetic cardiomyopathy (DCM). Here, we aimed to assess whether LV remodeling and dysfunction are paralleled by RV alterations and the effects of ANG-(1-7) on RV remodeling in DCM. After 12 wk of diabetes induced by a single intraperitoneal injection of streptozotocin, rats were treated with saline, ANG-(1-7), perindopril, ANG-(1-7) plus perindopril, ANG (1-7) plus Mas receptor antagonist A779, or ANG-(1-7) plus ANG-II type 2 receptor antagonist PD123319 for 4 wk. RV remodeling in diabetic rats was indicated by fibrosis of the RV free wall in the absence of hypertrophy and apoptosis. Treatment with ANG-(1-7) prevented diabetes-induced RV fibrosis and dysfunction. ANG-(1-7) (800 ng.kg(-1).min(-1)) was superior to perindopril in improving RV fibrosis. The major mechanisms involved a complex interaction of ANG-II type 2 and Mas receptors for subsequent downregulation of ACE expression and activity and ANG-II type 1 receptor expression, as well as upregulation of ACE2 expression and activity and the expression of ANG-II type 2 receptor and sarco(endo)plasmic reticulum Ca(2+)-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations. PMID- 25724493 TI - Regulation of inflammation and fibrosis by macrophages in lymphedema. AB - Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4(+) cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4(+) cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function. PMID- 25724494 TI - Platelet-derived growth factor-BB enhances MSC-mediated cardioprotection via suppression of miR-320 expression. AB - Delivery of bone marrow-derived mesenchymal stem cells (MSCs) to myocardium protects ischemic tissue through the paracrine release of beneficial angiogenic and cytoprotective factors. Platelet-derived growth factor (PDGF)-BB, a potent mitogen of MSCs, is involved in the pathophysiology of ischemic heart disease. However, the role(s) of PDGF in MSC-mediated cardioprotection remains unknown. Here, we found that PDGF treatment of MSCs resulted in rapid activation of both Akt and ERK (central intracellular signal mediators), upregulated VEGF, and induced phosphorylation of the activator protein-1 (AP-1) transcription factor c Jun. Examination of several microRNA genes having predicted promoter c-Jun binding sites showed that PDGF treatment resulted in upregulation of miR-16-2 and downregulation of miRs-23b, -27b, and -320b. To examine possible PDGF augmentation of therapeutic potential, we evaluated the effects of PDGF using an ex vivo isolated mouse heart ischemia-reperfusion model. Human MSCs, with or without PDGF preconditioning, were infused into the coronary circulation of isolated mouse hearts. The hearts that received PDGF-treated MSCs exhibited a greater functional recovery compared with naive MSC-infused hearts, following ischemia-reperfusion injury. This enhanced functional recovery was abolished by overexpression of miR-320, a microRNA we found downregulated by PDGF-activated c Jun. Overexpression of miR-320 also resulted in upregulation of insulin-like growth factor binding protein (IGFBP) family members, suggesting PDGF "cross talk" with the mitogenic IGF signaling pathway. Collectively, we conclude that PDGF enhances MSC-mediated cardioprotection via a c-Jun/miR-320 signaling mechanism and PDGF MSC preconditioning may be an effective therapeutic strategy for cardiac ischemia. PMID- 25724495 TI - Exercise excess pressure and exercise-induced albuminuria in patients with type 2 diabetes mellitus. AB - Exercise-induced albuminuria is common in patients with type 2 diabetes mellitus (T2DM) in response to maximal exercise, but the response to light-moderate exercise is unclear. Patients with T2DM have abnormal central hemodynamics and greater propensity for exercise hypertension. This study sought to determine the relationship between light-moderate exercise central hemodynamics (including aortic reservoir and excess pressure) and exercise-induced albuminuria. Thirty nine T2DM (62 +/- 9 yr; 49% male) and 39 nondiabetic controls (53 +/- 9 yr; 51% male) were examined at rest and during 20 min of light-moderate cycle exercise (30 W; 50 revolutions/min). Albuminuria was assessed by the albumin-creatinine ratio (ACR) at rest and 30 min postexercise. Hemodynamics recorded included brachial and central blood pressure (BP), aortic stiffness, augmented pressure (AP), aortic reservoir pressure, and excess pressure integral (Pexcess). There was no difference in ACR between groups before exercise (P > 0.05). Exercise induced a significant rise in ACR in T2DM but not controls (1.73 +/- 1.43 vs. 0.53 +/- 1.0 mg/mol, P = 0.002). All central hemodynamic variables were significantly higher during exercise in T2DM (i.e., Pexcess, systolic BP and AP; P < 0.01 all). In T2DM (but not controls), exercise Pexcess was associated with postexercise ACR (r = 0.51, P = 0.002), and this relationship was independent of age, sex, body mass index, heart rate, aortic stiffness, antihypertensive medication, and ambulatory daytime systolic BP (beta = 0.003, P = 0.003). Light moderate exercise induced a significant rise in ACR in T2DM, and this was independently associated with Pexcess, a potential marker of vascular dysfunction. These novel findings suggest that Pexcess could be important for appropriate renal function in T2DM. PMID- 25724496 TI - Heterogeneous patterns of vasoreactivity in the middle cerebral and internal carotid arteries. AB - This study compared changes in cross-sectional area (CSA) and flow (Q) between the middle cerebral artery (MCA) and the internal carotid artery (ICA) at baseline and during 5 min of hypercapnia (HC; 6% CO2) and hypocapnia (HO; hyperventilation) and quantified how these changes contribute to estimates of cerebrovascular reactivity (CVR). Measures of MCA CSA were made using 3T magnetic resonance imaging. On a separate day, MCA flow velocity was measured with transcranial Doppler ultrasound and ICA diameters and flow velocity were measured with duplex ultrasound. Fourteen subjects (23 +/- 3 yr, 7 females) participated, providing data for 11 subjects during HC and 9 subjects during HO. An increase in MCA CSA (P < 0.05) was observed within the first minute of HC. During HO, the decrease in MCA CSA (P < 0.05) was delayed until minute 4. No changes were observed in ICA CSA during HC or HO. The relative changes in QICA and QMCA were similar during HC and HO. Therefore, the MCA, but not ICA, dilates and constricts during 5 min of HC and HO, respectively. The consequent impact on QMCA significantly affects estimates of CVR, and reactivity cannot be attributed solely to changes in smaller arterioles. PMID- 25724497 TI - Redox signaling and splicing dependent change in myosin phosphatase underlie early versus late changes in NO vasodilator reserve in a mouse LPS model of sepsis. AB - Microcirculatory dysfunction may cause tissue malperfusion and progression to organ failure in the later stages of sepsis, but the role of smooth muscle contractile dysfunction is uncertain. Mice were given intraperitoneal LPS, and mesenteric arteries were harvested at 6-h intervals for analyses of gene expression and contractile function by wire myography. Contractile (myosin and actin) and regulatory [myosin light chain kinase and phosphatase subunits (Mypt1, CPI-17)] mRNAs and proteins were decreased in mesenteric arteries at 24 h concordant with reduced force generation to depolarization, Ca(2+), and phenylephrine. Vasodilator sensitivity to DEA/nitric oxide (NO) and cGMP under Ca(2+) clamp were increased at 24 h after LPS concordant with a switch to Mypt1 exon 24- splice variant coding for a leucine zipper (LZ) motif required for PKG 1alpha activation of myosin phosphatase. This was reproduced by smooth muscle specific deletion of Mypt1 exon 24, causing a shift to the Mypt1 LZ+ isoform. These mice had significantly lower resting blood pressure than control mice but similar hypotensive responses to LPS. The vasodilator sensitivity of wild-type mice to DEA/NO, but not cGMP, was increased at 6 h after LPS. This was abrogated in mice with a redox dead version of PKG-1alpha (Cys42Ser). Enhanced vasorelaxation in early endotoxemia is mediated by redox signaling through PKG 1alpha but in later endotoxemia by myosin phosphatase isoform shifts enhancing sensitivity to NO/cGMP as well as smooth muscle atrophy. Muscle atrophy and modulation may be a novel target to suppress microcirculatory dysfunction; however, inactivation of inducible NO synthase, treatment with the IL-1 antagonist IL-1ra, or early activation of alpha-adrenergic signaling did not suppressed this response. PMID- 25724499 TI - Convenience and the hierarchy of meal preparation. Cooking and domestic education in the Netherlands, 1910-1930. AB - The concept of convenience in food products and meal preparation has changed rapidly during the twentieth century. However, there is little investigation into the way attitudes towards this concept have changed, which curbs our understanding of the importance of, and need for, convenience today. This paper uses the magazine of the Dutch schools of domestic education to examine their stance on convenience in meal preparation during the 1910s and 1920s. Recipes and articles are quantitatively and qualitatively analysed to estimate the importance of convenience in food preparation and consumption. The results of this analysis show that there was a hierarchy of values with regard to food choice: convenience was definitely valued, but matters of frugality and nutrition generally dominated. This provides not just a nuanced image of the role of domestic education (demanding yet flexible), but it also gives insight into the mechanics of food choice, which may at least partly still apply today. PMID- 25724498 TI - A role for matrix stiffness in the regulation of cardiac side population cell function. AB - The mechanical properties of the local microenvironment may have important influence on the fate and function of adult tissue progenitor cells, altering the regenerative process. This is particularly critical following a myocardial infarction, in which the normal, compliant myocardial tissue is replaced with fibrotic, stiff scar tissue. In this study, we examined the effects of matrix stiffness on adult cardiac side population (CSP) progenitor cell behavior. Ovine and murine CSP cells were isolated and cultured on polydimethylsiloxane substrates, replicating the elastic moduli of normal and fibrotic myocardium. Proliferation capacity and cell cycling were increased in CSP cells cultured on the stiff substrate with an associated reduction in cardiomyogeneic differentiation and accelerated cell ageing. In addition, culture on stiff substrate stimulated upregulation of extracellular matrix and adhesion proteins gene expression in CSP cells. Collectively, we demonstrate that microenvironment properties, including matrix stiffness, play a critical role in regulating progenitor cell functions of endogenous resident CSP cells. Understanding the effects of the tissue microenvironment on resident cardiac progenitor cells is a critical step toward achieving functional cardiac regeneration. PMID- 25724500 TI - Micronutrients and diarrhea. PMID- 25724501 TI - Fever in Children and Fever of Unknown Origin. AB - Fever is the most common symptom in children and can be classified as fever with or without focus. Fever without focus can be less than 7 d and is subclassified as fever without localizing signs and fever of unknown origin (FUO). FUO is defined as a temperature greater than 38.3 degrees C, for more than 3 wk or failure to reach a diagnosis after 1 wk of inpatient investigations. The most common causes of FUO in children are infections, connective tissue disorders and neoplasms. Infectious diseases most commonly implicated in children with FUO are salmonellosis, tuberculosis, malaria and rickettsial diseases. Juvenile rheumatic arthritis is the connective tissue disease frequently associated with FUO. Malignancy is the third largest group responsible for FUO in children. Diagnostic approach of FUO includes detailed history and examination supported with investigations. Age, history of contact, exposure to wild animals and medications should be noted. Examination should include, apart from general appearance, presence of sweating, rashes, tonsillitis, sinusitis and lymph node enlargement. Other signs such as abdominal tenderness and hepatosplenomegly should be looked for. The muscles and bones should be carefully examined for connective tissue disorders. Complete blood count, blood smear examination and level of acute phase reactants should be part of initial investigations. Radiological imaging is useful aid in diagnosing FUO. Trials of antimicrobial agents should not be given as they can obscure the diagnosis of the disease in FUO. PMID- 25724502 TI - Analysis of Prognostic Factors and Mortality in Children with Esophageal Atresia. AB - OBJECTIVE: The survival rate in newborns with congenital esophageal atresia (EA) is about 85-90 %, and it raises over 95 % in the developed countries. The survival rate in developing countries is much lower and the authors describe their experience with 60 newborns. METHODS: Medical records of 60 newborns (40 boys and 20 girls) with congenital EA were reviewed for the prognostic factors and mortality. RESULTS: The birth weight, mean Apgar score (AS) value, gestational age and birth-operative treatment time had significant influence on the mortality of treated patients (p < 0.05). Thirty five percent newborns had aspirational pneumonia at the moment of hospitalization and 86.7 % of them were operated during the first 48 h. The presence of associated anomalies considerably affected the death rate of treated patients (p < 0.05). The incidence of postoperative complications was similar to those in developed countries but the total mortality was higher (28.3 %); sepsis being the main cause of mortality. The postoperative complications and sepsis significantly influenced the mortality of patients (p < 0.05). CONCLUSIONS: Total mortality in newborns with EA was high; sepsis being the most frequent cause of death. The high total mortality was also caused by prematurity, delay in diagnosis, increased incidence of the aspiration pneumonia and shortage of qualified nurses. PMID- 25724503 TI - Review: an urgent need for research on factors impacting adherence to and retention in care among HIV-positive youth and adolescents from key populations. AB - INTRODUCTION: The 50% increase in HIV-related deaths in youth and adolescents (aged 10-24) from 2005 to 2012 highlights the need to improve HIV treatment and care in this population, including treatment adherence and retention. Youth and adolescents from key populations or young key populations (YKP) in particular are highly stigmatized and may face additional barrier(s) in adhering to HIV treatment and services. We reviewed the current knowledge on treatment adherence and retention in HIV care among YKP to identify gaps in the literature and suggest future directions to improve HIV care for YKP. METHODS: We conducted a comprehensive literature search for YKP and their adherence to antiretroviral therapy (ART) and retention in HIV care on PsycInfo (Ovid), PubMed and Google Scholar using combinations of the keywords HIV/AIDS, ART, adolescents, young adults, adherence (or compliance), retention, men who have sex with men, transgender, injection drug users, people who inject drugs and prisoners. We included empirical studies on key populations defined by WHO; included the terms youth and adolescents and/or aged between 10 and 24; examined adherence to or retention in HIV care; and published in English-language journals. All articles were coded using NVivo. RESULTS AND DISCUSSION: The systematic search yielded 10 articles on YKP and 16 articles on behaviourally infected youth and adolescents from 1999 to 2014. We found no studies reporting on youth and adolescents identified as sex workers, transgender people and prisoners. From existing literature, adherence to ART was reported to be influenced by age, access to healthcare, the burden of multiple vulnerabilities, policy involving risk behaviours and mental health. A combination of two or more of these factors negatively impacted adherence to ART among YKP. Collectively, these studies demonstrated that future programmes need to be tailored specifically to YKP to ensure adherence. CONCLUSIONS: There is an urgent need for more systematic research in YKP. Current limited evidence suggests that healthcare delivery should be tailored to the unique needs of YKP. Thus, research on YKP could be used to inform future interventions to improve access to treatment and management of co-morbidities related to HIV, to ease the transition from paediatric to adult care and to increase uptake of secondary prevention methods. PMID- 25724504 TI - Adolescent girls and young women: key populations for HIV epidemic control. AB - INTRODUCTION: At the epicentre of the HIV epidemic in southern Africa, adolescent girls and young women aged 15-24 contribute a disproportionate ~30% of all new infections and seroconvert 5-7 years earlier than their male peers. This age-sex disparity in HIV acquisition continues to sustain unprecedentedly high incidence rates, and preventing HIV infection in this age group is a pre-requisite for achieving an AIDS-free generation and attaining epidemic control. DISCUSSION: Adolescent girls and young women in southern Africa are uniquely vulnerable to HIV and have up to eight times more infection than their male peers. While the cause of this vulnerability has not been fully elucidated, it is compounded by structural, social and biological factors. These factors include but are not limited to: engagement in age-disparate and/or transactional relationships, few years of schooling, experience of food insecurity, experience of gender-based violence, increased genital inflammation, and amplification of effects of transmission co-factors. Despite the large and immediate HIV prevention need of adolescent girls and young women, there is a dearth of evidence-based interventions to reduce their risk. The exclusion of adolescents in biomedical research is a huge barrier. School and community-based education programmes are commonplace in many settings, yet few have been evaluated and none have demonstrated efficacy in preventing HIV infection. Promising data are emerging on prophylactic use of anti-retrovirals and conditional cash transfers for HIV prevention in these populations. CONCLUSIONS: There is an urgent need to meet the HIV prevention needs of adolescent girls and young women, particularly those who are unable to negotiate monogamy, condom use and/or male circumcision. Concerted efforts to expand the prevention options available to these young women in terms of the development of novel HIV-specific biomedical, structural and behavioural interventions are urgently needed for epidemic control. In the interim, a pragmatic approach of integrating existing HIV prevention efforts into broader sexual reproductive health services is a public health imperative. PMID- 25724505 TI - Mental health and support among young key populations: an ecological approach to understanding and intervention. AB - INTRODUCTION: The patterning of the HIV epidemic within young key populations (YKPs) highlights disproportionate burden by mental disorders in these populations. The mental wellbeing of YKPs is closely associated with biological predispositions and psychosocial factors related to YKPs' sexual and gender identities and socio-economic status. The purpose of this paper is to highlight sources of risk and resilience, as well as identify treatment and supports for mental health disorders (MHDs) among YKPs. DISCUSSION: This paper utilizes Bronfenbrenner's Bioecological Systems Theory and the Social Stress Model to explore the risk and protective factors for MHDs across YKPs' ecological systems, and identify current gaps in treatment and support for MHDs among these youth. We emphasize the fluidity and intersections across these categorizations which reinforce the vulnerability of these populations, the lack of concrete data to inform mental health interventions among YKPs, and the need to ground YKP interventions and programmes with human rights principles stipulated in the convention on the rights of a child. CONCLUSIONS: We put forth recommendations for future research and strategies to address the mental wellbeing of YKPs, including the need for integrated interventions that address the multiplicity of risk factors inherent in the multiple group membership, rather than single-focus interventions whilst addressing the unique needs or challenges of YKPs. PMID- 25724506 TI - HIV testing and linkage to services for youth. AB - INTRODUCTION: HIV testing is the portal to serostatus knowledge that can empower linkage to care for HIV treatment and HIV prevention. However, young people's access to HIV testing is uneven worldwide. The objective of this paper is to review the context and concerns faced by youth around HIV testing in low- as well as high-income country settings. DISCUSSION: HIV testing is a critical entry point for primary and secondary prevention as well as care and treatment for young people including key populations of vulnerable youth. We provide a framework for thinking about the role of testing in the continuum of prevention and care for young people. Brief case study examples from Kenya and the US illustrate some of the common barriers and issues involved for young people. CONCLUSIONS: Young people worldwide need more routine access to HIV testing services that effectively address the developmental, socio-political and other issues faced by young women and men. PMID- 25724508 TI - "First, do no harm": legal guidelines for health programmes affecting adolescents aged 10-17 who sell sex or inject drugs. AB - INTRODUCTION: There is a strong evidence base that the stigma, discrimination and criminalization affecting adolescent key populations (KPs) aged 10-17 is intensified due to domestic and international legal constructs that rely on law enforcement-based interventions dependent upon arrest, pre-trial detention, incarceration and compulsory "rehabilitation" in institutional placement. While there exists evidence and rights-based technical guidelines for interventions among older cohorts, these guidelines have not yet been embraced by international public health actors for fear that international law applies different standards to adolescents aged 10-17 who engage in behaviours such as selling sex or injecting drugs. DISCUSSION: As a matter of international human rights, health, juvenile justice and child protection law, interventions among adolescent KPs aged 10-17 must not involve arrest, prosecution or detention of any kind. It is imperative that interventions not rely on law enforcement, but instead low threshold, voluntary services, shelter and support, utilizing peer-based outreach as much as possible. These services must be mobile and accessible, and permit alternatives to parental consent for the provision of life-saving support, including HIV testing, treatment and care, needle and syringe programmes, opioid substitution therapy, safe abortions, antiretroviral therapy and gender-affirming care and hormone treatment for transgender adolescents. To ensure enrolment in services, international guidance indicates that informed consent and confidentiality must be ensured, including by waiver of parental consent requirements. To remove the disincentive to health practitioners and researchers to engaging with adolescent KPs aged 10-17 government agencies and ethical review boards are advised to exempt or grant waivers for mandatory reporting. In the event that, in violation of international law and guidance, authorities seek to involuntarily place adolescent KPs in institutions, they are entitled to judicial process. Legal guidelines also provide that these adolescents have influence over their placement, access to legal counsel to challenge the conditions of their detention and regular visitation from peers, friends and family, and that all facilities be subject to frequent and periodic review by independent agencies, including community-based groups led by KPs. CONCLUSIONS: Controlling international law specifies that protective interventions among KPs aged 10-17 must not only include low-threshold, voluntary services but also "protect" adolescent KPs from the harms attendant to law-enforcement-based interventions. Going forward, health practitioners must honour the right to health by adjusting programmes according to principles of minimum intervention, due process and proportionality, and duly limit juvenile justice and child protection involvement as a measure of last resort, if any. PMID- 25724507 TI - Tailored combination prevention packages and PrEP for young key populations. AB - INTRODUCTION: Young key populations, defined in this article as men who have sex with men, transgender persons, people who sell sex and people who inject drugs, are at particularly high risk for HIV. Due to the often marginalized and sometimes criminalized status of young people who identify as members of key populations, there is a need for HIV prevention packages that account for the unique and challenging circumstances they face. Pre-exposure prophylaxis (PrEP) is likely to become an important element of combination prevention for many young key populations. OBJECTIVE: In this paper, we discuss important challenges to HIV prevention among young key populations, identify key components of a tailored combination prevention package for this population and examine the role of PrEP in these prevention packages. METHODS: We conducted a comprehensive review of the evidence to date on prevention strategies, challenges to prevention and combination prevention packages for young key populations. We focused specifically on the role of PrEP in these prevention packages and on young people under the age of 24, and 18 in particular. RESULTS AND DISCUSSION: Combination prevention packages that include effective, acceptable and scalable behavioural, structural and biologic interventions are needed for all key populations to prevent new HIV infections. Interventions in these packages should meaningfully involve beneficiaries in the design and implementation of the intervention, and take into account the context in which the intervention is being delivered to thoughtfully address issues of stigma and discrimination. These interventions will likely be most effective if implemented in conjunction with strategies to facilitate an enabling environment, including increasing access to HIV testing and health services for PrEP and other prevention strategies, decriminalizing key populations' practices, increasing access to prevention and care, reducing stigma and discrimination, and fostering community empowerment. PrEP could offer a highly effective, time-limited primary prevention for young key populations if it is implemented in combination with other programs to increase access to health services and encourage the reliable use of PrEP while at risk of HIV exposure. CONCLUSIONS: Reductions in HIV incidence will only be achieved through the implementation of combinations of interventions that include biomedical and behavioural interventions, as well as components that address social, economic and other structural factors that influence HIV prevention and transmission. PMID- 25724509 TI - Young key populations and HIV: a special emphasis and consideration in the new WHO Consolidated Guidelines on HIV Prevention, Diagnosis, Treatment and Care for Key Populations. PMID- 25724510 TI - "We don't need services. We have no problems": exploring the experiences of young people who inject drugs in accessing harm reduction services. AB - INTRODUCTION: Evidence suggests that people who inject drugs often begin their drug use and injecting practices in adolescence, yet there are limited data available on the HIV epidemic and the responses for this population. The comprehensive package of interventions for the prevention, treatment and care of HIV infection among people who inject drugs first laid out in 2009 (revised in 2012) by World Health Organization, United Nations Office of Drugs and Crime and Joint United Nations Programme on HIV/AIDS, does not consider the unique needs of adolescent and young people. In order to better understand the values and preferences of young people who inject drugs in accessing harm reduction services and support, we undertook a series of community consultations with young people with experience of injecting drugs during adolescence. METHODS: Community consultations (4-14 persons) were held in 14 countries. Participants were recruited using a combined criterion and maximum variation sampling strategy. Data were analyzed using collaborative qualitative data analysis. Frequency analysis of themes was conducted. RESULTS: Nineteen community consultations were organized with a total of 132 participants. All participants had experienced injecting drugs before the age of 18. They had the following age distribution: 18 20 (37%), 21-25 (48%) and 26-30 (15%). Of the participants, 73.5% were male while 25.7% were female, with one transgender participant. Barriers to accessing the comprehensive package included: lack of information and knowledge of services, age restrictions on services, belief that services were not needed, fear of law enforcement, fear of stigma, lack of concern, high cost, lack of outreach, lack of knowledge of HCV/TB and lack of youth friendly services. CONCLUSIONS: The consultations provide a rare insight into the lived experiences of adolescents who inject drugs and highlight the dissonance between their reality and current policy and programmatic approaches. Findings suggest that harm reduction and HIV policies and programmes should adapt the comprehensive package to reach young people and explore linkages to other sectors such as education and employment to ensure they are fully supported and protected. Continued participation of the community of young people who inject drugs can help ensure policy and programmes respond to the social exclusion and denial of rights and prevent HIV infection among adolescents who inject drugs. PMID- 25724512 TI - Building our youth for the future. AB - Adolescents and young adults are at increased risk for HIV due to the many developmental, psychological, social, and structural transitions that converge in this period of the lifespan. In addition, adolescent deaths resulting from HIV continue to rise despite declines in other age groups. There are also young key populations (YKPs) that bear disproportionate burdens of HIV and are the most vulnerable, including young men who have sex with men (MSM), transgender youth, young people who inject drugs, and adolescent and young adult sex workers. As a society, we must do more to stop new HIV infections and untimely HIV-related deaths through both primary and secondary prevention and better management approaches. Using an interwoven prevention and treatment cascade approach, the starting point for all interventions must be HIV counselling and testing. Subsequent interventions for both HIV-negative and HIV-positive youth must be "adolescent-centred," occur within the socio-ecological context of young people and take advantage of the innovations and technologies that youth have easily incorporated into their daily lives. In order to achieve the global goals of zero infections, zero discrimination and zero deaths, a sustained focus on HIV research, policy and advocacy for YKPs must occur. PMID- 25724513 TI - The effect of transcranial direct current stimulation on task processing and prioritisation during dual-task gait. AB - The relationship between cognition and gait is often explored using a dual-task gait paradigm, which represents the ability to divide cognitive resources during walking. Recent evidence has suggested that the prefrontal cortex is involved in the allocation of cognitive resources during dual-task gait, though its precise role is unclear. Here, we used anodal and cathodal transcranial direct current stimulation (tDCS) to probe the role of the prefrontal cortex in the control of stride time variability (STV), trunk RoM and cognitive task performance during dual-task gait. As task difficulty has been shown to mediate the dual-task cost, we also manipulated walking speed to see whether the effects of tDCS on dual-task gait were influenced by walking difficulty. Ten adults performed a serial subtraction task when walking at either preferred walking speed or 25 % of preferred walking speed, before and after receiving tDCS of the left prefrontal cortex. Anodal tDCS reduced STV and the dual-task cost on STV and improved cognitive task performance. Cathodal tDCS increased STV and appeared to increase the dual-task cost on STV, but did not affect cognitive task performance. There was no effect of tDCS on trunk RoM, and the effects of tDCS were not mediated by walking speed. The effect of dual-task gait on stride time variability and cognitive task performance was altered by the application of tDCS, and these effects were polarity dependent. These results highlight the role of the prefrontal cortex in biasing task performance during dual-task gait and indicate that tDCS may be a useful tool for examining the role of the cortex in the control of dual-task gait. PMID- 25724511 TI - Providing comprehensive health services for young key populations: needs, barriers and gaps. AB - INTRODUCTION: Adolescence is a time of physical, emotional and social transitions that have implications for health. In addition to being at high risk for HIV, young key populations (YKP) may experience other health problems attributable to high-risk behaviour or their developmental stage, or a combination of both. METHODS: We reviewed the needs, barriers and gaps for other non-HIV health services for YKP. We searched PubMed and Google Scholar for articles that provided specific age-related data on sexual and reproductive health; mental health; violence; and substance use problems for adolescent, youth or young sex workers, men who have sex with men, transgender people, and people who inject drugs. RESULTS: YKP experience more unprotected sex, sexually transmitted infections including HIV, unintended pregnancy, violence, mental health disorders and substance use compared to older members of key populations and youth among the general population. YKP experience significant barriers to accessing care; coverage of services is low, largely because of stigma and discrimination experienced at both the health system and policy levels. DISCUSSION: YKP require comprehensive, integrated services that respond to their specific developmental needs, including health, educational and social services within the context of a human rights-based approach. The recent WHO Consolidated Guidelines on HIV Prevention, Diagnosis, Treatment and Care for Key Populations are an important first step for a more comprehensive approach to HIV programming for YKP, but there are limited data on the effective delivery of combined interventions for YKP. Significant investments in research and implementation will be required to ensure adequate provision and coverage of services for YKP. In addition, greater commitments to harm reduction and rights-based approaches are needed to address structural barriers to access to care. PMID- 25724514 TI - Safety and feasibility of initial frequency mapping within 24 hours after cochlear implantation. AB - CONCLUSION: Switch-on within 24 h after cochlear implantation can be safely and practically performed. The minimally invasive approach presented here also brought about benefits such as nonstop rehabilitation programs and shorter duration of uncertainty/worry for patients and their families about surgical outcomes. Those were important factors for international patients. Our research invites further studies to show whether instant commencement of electrical stimulation helps to expedite long-term hearing/speech performance in cochlear implantees. OBJECTIVES: Initial switch-on generally could not launch until weeks after cochlear implantation due to factors associated with wound conditions. Commencement of electrical stimulation within 24 h after the surgery has long been performed in our department on a routine basis. The idea issued from the need to sew-and-go for international patients. This study presents the safety and feasibility of the procedure. METHODS: Charts of 79 subjects with profound hearing impairment were studied. A minimally invasive approach was used for cochlear implantation, with an intention to control wound condition and tissue swelling. Hearing threshold was measured preoperatively and postoperatively. RESULTS: Initial switch-on within 24 h was done in all patients. Good hearing gain was obtained. No major complication occurred. There was no significant difference in hearing postoperatively that was attributable to the early switch on. PMID- 25724515 TI - Regression-Based Norms for a Bi-factor Model for Scoring the Brief Test of Adult Cognition by Telephone (BTACT). AB - The current study developed regression-based normative adjustments for a bi factor model of the The Brief Test of Adult Cognition by Telephone (BTACT). Archival data from the Midlife Development in the United States-II Cognitive Project were used to develop eight separate linear regression models that predicted bi-factor BTACT scores, accounting for age, education, gender, and occupation-alone and in various combinations. All regression models provided statistically significant fit to the data. A three-predictor regression model fit best and accounted for 32.8% of the variance in the global bi-factor BTACT score. The fit of the regression models was not improved by gender. Eight different regression models are presented to allow the user flexibility in applying demographic corrections to the bi-factor BTACT scores. Occupation corrections, while not widely used, may provide useful demographic adjustments for adult populations or for those individuals who have attained an occupational status not commensurate with expected educational attainment. PMID- 25724516 TI - Tactile search for change has less memory than visual search for change. AB - Haptic perception of a 2D image is thought to make heavy demands on working memory. During active exploration, humans need to store the latest local sensory information and integrate it with kinesthetic information from hand and finger locations in order to generate a coherent perception. This tactile integration has not been studied as extensively as visual shape integration. In the current study, we compared working-memory capacity for tactile exploration to that of visual exploration as measured in change-detection tasks. We found smaller memory capacity during tactile exploration (approximately 1 item) compared with visual exploration (2-10 items). These differences generalized to position memory and could not be attributed to insufficient stimulus-exposure durations, acuity differences between modalities, or uncertainty over the position of items. This low capacity for tactile memory suggests that the haptic system is almost amnesic when outside the fingertips and that there is little or no cross-position integration. PMID- 25724517 TI - A general formula for computing maximum proportion correct scores in various psychophysical paradigms with arbitrary probability distributions of stimulus observations. AB - Proportion correct (Pc) is a fundamental measure of task performance in psychophysics. The maximum Pc score that can be achieved by an optimal (maximum likelihood) observer in a given task is of both theoretical and practical importance, because it sets an upper limit on human performance. Within the framework of signal detection theory, analytical solutions for computing the maximum Pc score have been established for several common experimental paradigms under the assumption of Gaussian additive internal noise. However, as the scope of applications of psychophysical signal detection theory expands, the need is growing for psychophysicists to compute maximum Pc scores for situations involving non-Gaussian (internal or stimulus-induced) noise. In this article, we provide a general formula for computing the maximum Pc in various psychophysical experimental paradigms for arbitrary probability distributions of sensory activity. Moreover, easy-to-use MATLAB code implementing the formula is provided. Practical applications of the formula are illustrated, and its accuracy is evaluated, for two paradigms and two types of probability distributions (uniform and Gaussian). The results demonstrate that Pc scores computed using the formula remain accurate even for continuous probability distributions, as long as the conversion from continuous probability density functions to discrete probability mass functions is supported by a sufficiently high sampling resolution. We hope that the exposition in this article, and the freely available MATLAB code, facilitates calculations of maximum performance for a wider range of experimental situations, as well as explorations of the impact of different assumptions concerning internal-noise distributions on maximum performance in psychophysical experiments. PMID- 25724518 TI - Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. AB - PURPOSE: The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. EXPERIMENTAL DESIGN: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNalpha. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus. CONCLUSIONS: In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice. PMID- 25724519 TI - miR-137 and miR-197 Induce Apoptosis and Suppress Tumorigenicity by Targeting MCL 1 in Multiple Myeloma. AB - PURPOSE: Deregulation of miRNA has been implicated in the pathogenesis of multiple myeloma. We identified miR-137 and miR-197, mapped to the chromosome 1p (12)-(21) deletion region, and examined their antimyeloma activity as tumor suppressors. EXPERIMENTAL DESIGN: The expression of miR-137/197 was examined in multiple myeloma and normal plasma cells by qRT-PCR. Functional effect of miR 137/197 was analyzed by cell viability, apoptosis, clonogenic, and migration assays. Antimyeloma activity of miR-137/197 was further evaluated in vivo by lentiviral-based or lipid-based delivery in a mouse xenograft model of multiple myeloma. RESULTS: miR-137/197 expression was significantly lower in multiple myeloma cell lines and multiple myeloma patient samples compared with normal plasma cells. Transfection of miR-137/197 resulted in reduction of MCL-1 protein expression, as well as alteration of apoptosis-related genes, and induction of apoptosis, inhibition of viability, colony formation, and migration in multiple myeloma cells. MCL-1 was further validated as a direct target of miR-137/197. Conversely, overexpression of MCL-1 partially reverted the effect of miR-137/197. Importantly, in vivo lentiviral-mediated or intratumor delivery of miR-137/197 induced regression of tumors in murine xenograft models of multiple myeloma. CONCLUSIONS: Our study reveals a novel role of miR-137/197 as tumor suppressors in mediating apoptosis in multiple myeloma cells by targeting MCL-1. Our findings provide a proof-of-principle that lentivirus-based or formulated synthetic miR 137/197 exerts therapeutic activity in preclinical models, and support a framework for development of miR-137/197-based treatment strategies in patients with multiple myeloma. PMID- 25724520 TI - PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy +/- Cetuximab in Cervical Cancer Patients. AB - PURPOSE: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. EXPERIMENTAL DESIGN: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6 week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients. RESULTS: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18). CONCLUSIONS: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups. PMID- 25724521 TI - Treatment Planning and Fracture Prediction in Patients with Skeletal Metastasis with CT-Based Rigidity Analysis. AB - PURPOSE: Pathologic fractures could be prevented if reliable methods of fracture risk assessment were available. A multicenter prospective study was conducted to identify significant predictors of physicians' treatment plan for skeletal metastasis based on clinical fracture risk assessments and the proposed CT-based Rigidity Analysis (CTRA). EXPERIMENTAL DESIGN: Orthopedic oncologists selected a treatment plan for 124 patients with 149 metastatic lesions based on the Mirels method. Then, CTRA was performed, and the results were provided to the physicians, who were asked to reassess their treatment plan. The pre- and post CTRA treatment plans were compared to identify cases in which the treatment plan was changed based on the CTRA report. Patients were followed for a 4-month period to establish the incidence of pathologic fractures. RESULTS: Pain, lesion type, and lesion size were significant predictors of the pre-CTRA plan. After providing the CTRA results, physicians changed their plan for 36 patients. CTRA results, pain, and primary source of metastasis were significant predictors of the post CTRA plan. Follow-up of patients who did not undergo fixation resulted in 7 fractures; CTRA predicted these fractures with 100% sensitivity and 90% specificity, whereas the Mirels method was 71% sensitive and 50% specific. CONCLUSIONS: Lesion type and size and pain level influenced the physicians' plans for the management of metastatic lesions. Physicians' treatment plans and fracture risk predictions were significantly influenced by the availability of CTRA results. Due to its high sensitivity and specificity, CTRA could potentially be used as a screening method for pathologic fractures. PMID- 25724522 TI - Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression. AB - PURPOSE: Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists. EXPERIMENTAL DESIGN: Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination. RESULTS: Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model. CONCLUSIONS: Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780-91. (c)2015 AACR. PMID- 25724523 TI - Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384. AB - PURPOSE: Radiation remains a mainstay for the treatment of nonmetastatic head and neck squamous cell carcinoma (HNSCC), a malignancy characterized by a high rate of PI3K/mTOR signaling axis activation. We investigated the ATP-competitive dual PI3K/mTOR inhibitor, PF-05212384, as a radiosensitizer in preclinical HNSCC models. EXPERIMENTAL DESIGN: Extent of radiation enhancement of two HNSCC cell lines (UMSCC1-wtP53 and UMSCC46-mtP53) and normal human fibroblast (1522) was assessed by in vitro clonogenic assay with appropriate target inhibition verified by immunoblotting. Radiation-induced DNA damage repair was evaluated by gammaH2AX Western blots with the mechanism of DNA double-strand break repair abrogation investigated by cell cycle analysis, immunoblotting, and RT-PCR. PF-05212384 efficacy in vivo was assessed by UMSCC1 xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. RESULTS: PF 05212384 effectively inhibited PI3K and mTOR, resulting in significant radiosensitization of exponentially growing and plateau-phase cells with 24-hour treatment following irradiation, and variable radiation enhancement with 24-hour treatment before irradiation. Tumor cells radiosensitized to a greater extent than normal human fibroblasts. Postirradiation PF-05212384 treatment delays gammaH2AX foci resolution. PF-05212384 24-hour exposure resulted in an evident G1 S phase block in p53-competent cells. Fractionated radiation plus i.v. PF 05212384 synergistically delayed nude mice bearing UMSCC1 xenograft regrowth, with potential drug efficacy biomarkers identified, including pS6, pAkt, p4EBP1, and Ki67. CONCLUSIONS: Taken together, our results of significant radiosensitization both in vitro and in vivo validate the PI3K/mTOR axis as a radiation modification target and PF-05212384 as a potential clinical radiation modifier of nonmetastatic HNSCC. PMID- 25724524 TI - Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy. AB - PURPOSE: BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and alpha-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for beta-genus HPV is suspected in BRAFi cSCC. Cutaneous beta-HPV may act in concert with host and environmental factors in BRAFi-cSCC. EXPERIMENTAL DESIGN: Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology. RESULTS: Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, beta-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel beta-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected. CONCLUSIONS: We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; beta-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered beta HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general. PMID- 25724525 TI - A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia. AB - PURPOSE: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. RESULTS: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P <= 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. CONCLUSIONS: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. PMID- 25724526 TI - Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib. AB - PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents. EXPERIMENTAL DESIGN: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib. RESULTS: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4-10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1-694). The mPFS on ceritinib was 7.8 months (6.5-9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4-9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5-19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5-63.1). CONCLUSIONS: Ceritinib has significant antitumor activity in ALK-positive NSCLC-even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. PMID- 25724527 TI - A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors. AB - PURPOSE: Enoticumab (REGN421) is a fully human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. EXPERIMENTAL DESIGN: Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W). RESULTS: Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non-small cell lung cancer bronchoalveolar-type with a beta-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3> 6 months). CONCLUSIONS: Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. Clin Cancer Res; 21(12); 2695-703. (c)2015 AACR. PMID- 25724528 TI - Physical parameters, modeling, and methodological details in using IR laser pulses to warm frozen or vitrified cells ultra-rapidly. AB - We report additional details of the thermal modeling, selection of the laser, and construction of the Cryo Jig used for our ultra-rapid warming studies of mouse oocytes (Jin et al., 2014). A Nd:YAG laser operating at 1064 nm was selected to deliver short 1ms pulses of sufficient power to produce a warming rate of 1*10(7) degrees C/min from -190 degrees C to 0 degrees C. A special Cryo Jig was designed and built to rapidly remove the sample from LN2 and expose it to the laser pulse. India ink carbon black particles were required to increase the laser energy absorption of the sample. The thermal model reported here is more general than that previously reported. The modeling reveals that the maximum warming rate achievable via external warming across the cell membrane is proportional to (1/R(2)) where R is the cell radius. PMID- 25724529 TI - Bionic reconstruction to restore hand function after brachial plexus injury: a case series of three patients. AB - BACKGROUND: Brachial plexus injuries can permanently impair hand function, yet present surgical reconstruction provides only poor results. Here, we present for the first time bionic reconstruction; a combined technique of selective nerve and muscle transfers, elective amputation, and prosthetic rehabilitation to regain hand function. METHODS: Between April 2011, and May 2014, three patients with global brachial plexus injury including lower root avulsions underwent bionic reconstruction. Treatment occurred in two stages; first, to identify and create useful electromyographic signals for prosthetic control, and second, to amputate the hand and replace it with a mechatronic prosthesis. Before amputation, the patients had a specifically tailored rehabilitation programme to enhance electromyographic signals and cognitive control of the prosthesis. Final prosthetic fitting was applied as early as 6 weeks after amputation. FINDINGS: Bionic reconstruction successfully enabled prosthetic hand use in all three patients. After 3 months, mean Action Research Arm Test score increased from 5.3 (SD 4.73) to 30.7 (14.0). Mean Southampton Hand Assessment Procedure score improved from 9.3 (SD 1.5) to 65.3 (SD 19.4). Mean Disabilities of Arm, Shoulder and Hand score improved from 46.5 (SD 18.7) to 11.7 (SD 8.42). INTERPRETATION: For patients with global brachial plexus injury with lower root avulsions, who have no alternative treatment, bionic reconstruction offers a means to restore hand function. FUNDING: Austrian Council for Research and Technology Development, Austrian Federal Ministry of Science, Research & Economy, and European Research Council Advanced Grant DEMOVE. PMID- 25724530 TI - Bionic hand transplantation: linking the cortex to the hand. PMID- 25724531 TI - Gene mdpC plays a regulatory role in the methyl-tert-butyl ether degradation pathway of Methylibium petroleiphilum strain PM1. AB - Among the few bacteria known to utilize methyl tert-butyl ether (MTBE) as a sole carbon source, Methylibium petroleiphilum PM1 is a well-characterized organism with a sequenced genome; however, knowledge of the genetic regulation of its MTBE degradation pathway is limited. We investigated the role of a putative transcriptional activator gene, mdpC, in the induction of MTBE-degradation genes mdpA (encoding MTBE monooxygenase) and mdpJ (encoding tert-butyl alcohol hydroxylase) of strain PM1 in a gene-knockout mutant mdpC(-). We also utilized quantitative reverse transcriptase PCR assays targeting genes mdpA, mdpJ and mdpC to determine the effects of the mutation on transcription of these genes. Our results indicate that gene mdpC is involved in the induction of both mdpA and mdpJ in response to MTBE and tert-butyl alcohol (TBA) exposure in PM1. An additional independent mechanism may be involved in the induction of mdpJ in the presence of TBA. PMID- 25724532 TI - Whole genome sequence of Enterobacter ludwigii type strain EN-119T, isolated from clinical specimens. AB - Enterobacter ludwigii strain EN-119(T) is the type strain of E. ludwigii, which belongs to the E. cloacae complex (Ecc). This strain was first reported and nominated in 2005 and later been found in many hospitals. In this paper, the whole genome sequencing of this strain was carried out. The total genome size of EN-119(T) is 4952,770 bp with 4578 coding sequences, 88 tRNAs and 10 rRNAs. The genome sequence of EN-119(T) is the first whole genome sequence of E. ludwigii, which will further our understanding of Ecc. PMID- 25724533 TI - Pyrosequencing analysis of aerobic anoxygenic phototrophic bacterial community structure in the oligotrophic western Pacific Ocean. AB - Aerobic anoxygenic phototrophic bacteria (AAPB) represent a widespread functional bacterial group defined by their obligate aerobic and facultative photoheterotrophic abilities. They are an active part of the marine microbial community as revealed by a large number of previous investigations. Here, we made an in-depth comparison of AAPB community structures in the subsurface water and the upper twilight zone of the western Pacific Ocean using high-throughput sequencing based on the pufM gene. Approximately, 100 000 sequences, grouped into 159 OTUs (94% cut-off value), included 44 and 24 OTUs unique to the subsurface and the upper twilight zone, respectively; 92 OTUs were common to both subsurface and twilight zone, and 3 OTUs were found in all samples. Consistent with previous studies, AAPB belonging to the Gammaproteobacteria were the dominant group in the whole water column, followed by the alphaproteobacterial AAPB. Comparing the relative abundance distribution patterns of different clades, an obvious community-structure separation according to deeper or shallower environment could be observed. Sulfitobacter-like, Loktanella-like, Erythrobacter-like, Dinoroseobacter-like and Gamma-HIMB55-like AAPB preferred the high-light subsurface water, while Methylobacterium-like, 'Citromicrobium'-like, Roseovarius like and Bradyrhizobium-like AAPB, the dim light environment. PMID- 25724534 TI - Isolation and transposition properties of ISBlo11, an active insertion sequence belonging to the IS3 family, from Bifidobacterium longum 105-A. AB - Transposon mutagenesis systems are still under development in bifidobacteria, partly because intrinsic active insertion sequences are not well characterized in bifidobacteria. Here, we isolated an active insertion sequence, ISBlo11, from Bifidobacterium longum 105-A using a sacB-based counterselection system, which is generally used to screen for active insertion sequences from bacterial genomes. ISBlo11 is 1432 bp long and belongs to the IS3 family. It has a single ORF encoding a transposase and 25-bp inverted repeats at its termini. Full-length copies of ISBlo11 are specifically conserved among certain B. longum genomes and exist in different sites. Transposition analysis of an artificial ISBlo11 transposon using an Escherichia coli conjugation system revealed that ISBlo11 has adequate transposition activity, comparable to the reported activity of IS629, another IS3 family element initially isolated from Shigella sonnei. ISBlo11 also showed low transposition selectivity for non-conserved 3- or 4-bp target sequences. These characteristics of ISBlo11 seem suitable for the development of a new transposon mutagenesis system in bifidobacteria. PMID- 25724535 TI - The SfaNI restriction-modification system from Enterococcus faecalis NEB215 is located on a putative mobile genetic element. AB - A type IIS restriction-modification (R-M) system SfaNI from Enterococcus faecalis NEB215 has been characterized. The sfaNIM gene was cloned by the methylase selection method. Methyltransferase SfaNI, a protein of 695 amino acids, consists of two domains responsible for different DNA-strand recognition and modification, and a putative DNA-binding HTH domain located in the N-terminal part of the protein. The sfaNIR gene, located adjacent to the gene of the cognate modification methyltransferases, encodes a protein of 648 amino acids. The enzyme has been purified to apparent homogeneity and its biochemical characteristics have been described. The R-M system SfaNI is flanked by a transposase gene at its 5(') end, and a cassette chromosome recombinase (ccr) gene complex, encoding serine recombinases CcrA and CcrB, at the 3(') end. Both proteins are specifically involved in genome rearrangement and are widely distributed among staphylococcal species. These results suggested that the R-M system SfaNI is present on the putative mobile element. PMID- 25724536 TI - Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout. AB - Febuxostat (Adenuric((r)), Uloric((r)), Feburic((r))) is an orally-active, potent, non-purine, selective xanthine oxidase inhibitor. In the EU, it is indicated in adults for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred. Unlike allopurinol, the prototypical xanthine oxidase inhibitor that is the cornerstone therapy for chronic gout, febuxostat does not require dosage adjustment in patients with mild or moderate renal impairment. In randomized, double-blind studies, 6-12 months' treatment with febuxostat at dosages approved for use in the EU (80 and 120 mg/day) was significantly more effective in lowering serum uric acid (sUA) levels in patients with hyperuricaemia and gout than allopurinol at dosages commonly prescribed in practice (100-300 mg/day); febuxostat demonstrated greater urate-lowering efficacy than allopurinol in patients with renal impairment. In open-label extension studies, 3-5 years' treatment with febuxostat maintained a target sUA level of <6.0 mg/dL in most patients; sustained reduction in sUA level was associated with near elimination of gout flares and improved tophus status. Febuxostat therapy was generally well tolerated during clinical development; frequently reported adverse events included liver function abnormalities, diarrhoea and rash. Cardiovascular (CV) events were the most common serious adverse events; the comparative safety of febuxostat and allopurinol is being examined further in large, ongoing trials in patients with gout who already have, or are at risk of developing, CV disease. In conclusion, febuxostat is a well established antihyperuricaemic agent that provides an effective alternative to allopurinol for the management of chronic gout. PMID- 25724537 TI - Clusters of Factors Identify A High Prevalence of Pregnancy Involvement Among US Adolescent Males. AB - The study purpose was to use recursive partitioning analysis (RPA) to identify factors that, when clustered, are associated with a high prevalence of pregnancy involvement among US adolescent males. The National Survey of Family Growth is a nationally representative survey of individuals 15-44 years old. RPA was done for the 2002 and 2006-2010 cycles to identify factors which, when combined, identify adolescent males with the highest prevalence of pregnancy involvement. Pregnancy involvement prevalence among adolescent males was 6 %. Two clusters of adolescent males have the highest pregnancy-involvement prevalence, at 84-87 %. In RPA, the highest pregnancy-involvement prevalence (87 %) was seen in adolescent males who ever HIV tested, had >4 lifetime sexual partners, reported less than an almost certain chance of feeling less physical pleasure with condom use, had an educational attainment of <11th grade, and had <=2 sexual partners in the past 12 months. Adolescent males who ever HIV tested, had >4 lifetime sexual partners, reported less than an almost certain chance of feeling less physical pleasure with condom use, had an educational attainment >=11th grade, were >17 years old, and had their first contraceptive education >=10th grade, had a pregnancy involvement prevalence of 84 %. Pregnancy-prevention efforts among adolescent males who have been involved in a pregnancy may need to target risk factors identified in clusters with the highest pregnancy prevalence to prevent subsequent pregnancies in these adolescent males and improve their future outcomes. PMID- 25724538 TI - Parental Perceptions of Family Centered Care in Medical Homes of Children with Neurodevelopmental Disabilities. AB - Life course theory sets the framework for strong inclusion of family centered care (FCC) in quality medical homes of children with neurodevelopmental disabilities (CNDD). The purpose of this study was to explore the perceptions of families with their experiences of FCC in medical homes for CNDD. Using a structured questionnaire, the Family-Centered Care Self-Assessment Tool developed by Family Voices, this study surveyed 122 parents of CNDD in a large urban area during 2010-2012. Data collected information on FCC in the provision of primary health care services for CNDD and focused on family-provider partnerships, care setting practices and policies, and community services. Frequency analysis classified participants' responses as strengths in the "most of the time" range, and weaknesses in the "never" range. Only 31 % of parents were satisfied with the primary health care their CNDD received. Based on an accepted definition of medical home services, 16 % of parents reported their CNDD had most aspects of a medical home, 64 % had some, and 20 % had none. Strengths in FCC were primarily evident in the family-provider partnership and care settings when focused on meeting the medical care needs of the child. Weaknesses in FCC were noted in meeting the needs of families, coordination, follow-up, and support with community resources. Improvements in key pediatric health care strategies for CNDD are recommended. CNDD and their families have multifaceted needs that require strong partnerships among parents, providers, and communities. Quality medical homes must include FCC and valued partnerships with diverse families and community-based providers. PMID- 25724539 TI - Opportunities and Challenges for Adolescent Health Under the Affordable Care Act. AB - The purpose of this commentary is to highlight some of the key policy changes under the Patient Protection and Affordable Care Act (ACA) that have the potential to improve health care services for adolescents as well as to draw attention to challenges that have yet to be addressed. This commentary stems from our prior policy research, which examined the extent to which the health care needs of adolescents were being considered in the early implementation phases of the ACA. This study was informed by a literature review and interviews with health care administrators, health policy researchers, and adolescent medicine specialists. The ACA has significantly expanded health insurance access; however, inequities in coverage and access remain. Primarily, the structure and financing of adolescent health care needs to be improved to better support the delivery of patient-centered, comprehensive care for this special population. Additionally, improvements in youths' awareness of their benefits under the ACA as well as a greater appreciation of preventive visits are critical. Furthermore, an unanticipated consequence of the ACA is that it exacerbates the risk of confidentiality breaches through explanation of benefits and electronic health records, which can compromise adolescents' access and utilization of health care services. Greater attention to improving and sustaining health promoting behaviors within the context of the ACA is critical for it to truly have a positive impact on adolescent health. PMID- 25724540 TI - Parvalbumin expression in the claustrum of the adult dog. An immunohistochemical and topographical study with comparative notes on the structure of the nucleus. AB - Although the detailed structure and function of the claustrum remain enigmatic, its extensive reciprocal connection with the cortex suggests a role in the integration of multisensory information. Claustrum samples, obtained from necropsy of four dogs, were formalin fixed for paraffin embedding. Sections were either stained for morpho-histological analysis or immunostained for parvalbumin (PV). We focused on PV because in cortical and hippocampal areas it is a marker of the fast-spiking interneurons which have an important role in the information transmission and processing. Soma area, perimeter and circularity were considered as morphological parameters to quantitatively group the PV positive somata by k means clustering. The histological investigation revealed a superior pyramidoid puddle and a posterior puddle characterized by a "cloud" of neurons in its dorso lateral part. Immunostaining showed positive somata and fibers throughout the rostro-caudal extent of the dog claustrum, localized principally in the dorsal region. k-Means clustering analysis enabled neuron classification according to size, identifying respectively big (radius=11.42+/-1.99MUm) and small (radius=6.33+/-1.08MUm) cells. No statistical differences in soma shape were observed. The topographical distribution of PV immunoreactivity suggests that the dog dorsal claustrum might be functionally related to the processing of visual inputs. Taken together our findings may help in the understanding the physiology of claustrum when compared with anatomical and functional data obtained in other species. PMID- 25724541 TI - Efficacy of enrofloxacin for the treatment of acute clinical mastitis caused by Escherichia coli in dairy cows. AB - Evidence for the efficacy of antimicrobial treatments in Escherichia coli mastitis is limited. The aim of this double-blinded field trial was to investigate the efficacy of enrofloxacin compared with placebo, with a special focus on survival, in dairy cows with acute clinical mastitis caused by E. coli. Dairy cows (n=116) with acute clinical mastitis were included in the study. A clinical examination was performed and a milk sample from the affected udder quarter was collected for investigation of somatic cell count (SCC) and bacteriology on the first day of treatment (day 0) and at day 3 (clinical examination only), day 22 and day 28. Data regarding culled cows, SCC and daily milk yield were retrieved from monthly milk recording each month until 180 days after treatment. All cows were treated with either enrofloxacin or placebo once a day for three days, starting at day 0. After culturing, 56 cows with confirmed E. coli mastitis remained in the study. Nine (16 per cent) of them died within the first week. Enrofloxacin-treated cows had lower SCC compared with placebo-treated cows at first monthly milk recordings after being treated for mastitis. Treatment with enrofloxacin did not result in a higher probability of survival compared with placebo. PMID- 25724542 TI - A practical tool for locomotion scoring in sheep: reliability when used by veterinary surgeons and sheep farmers. AB - A four-point locomotion scoring tool for sheep was developed and tested on 10 general practice veterinary surgeons (VS) and 10 sheep farmers. Thirty-four video clips of sheep displaying different locomotion scores were recorded and randomly assorted. Following a set period of training using four other video clips typical of the four locomotion scores, participants then scored the 34 test clips. The participants repeated the training and the exercise one month later. There were high levels of intraobserver repeatability: weighted kappa (kappaW) 0.81 for VS and 0.83 for farmers. There was no difference in intraobserver repeatability between vets and farmers (Wilcoxon signed rank P=0.8). When considering the overall distribution of scores within the video package, there were high levels of interobserver repeatability: mean kappaW 0.73 for VS and 0.72 for farmers. However, the repeatability for the individual locomotion scores was only fair to moderate. It is therefore recommended that when observations are repeated on different occasions they are made by the same observer. PMID- 25724543 TI - Characteristics of sheep flocks affected by Streptococcus dysgalactiae arthritis. PMID- 25724544 TI - Field study of pneumonia in vaccinated cattle associated with incorrect vaccination and Pasteurella multocida infection. AB - This field study used data on the vaccine courses against bovine respiratory disease sold by one pharmaceutical company in conjunction with pharmacovigilance data to explore reported suspected lack of expected efficacy and the reasons for this. The study ran from May 1, 2007, to April 30, 2010, and covered vaccines sold in Scotland and part of Northumberland. In total, 83 groups of cattle reported suspected lack of expected efficacy, representing 1.6 per cent of the 804,618 vaccine courses sold. It was possible to investigate 45 of these outbreaks in depth using a standard questionnaire and diagnostic protocol. Vaccine usage outwith the specific product characteristics (SPC) occurred in 47 per cent of cases (21/45). The proportion of vaccination courses used where a pathogen contained in the vaccine was detected in the diseased cattle and vaccine use was consistent with the SPC was estimated at 0.12 per cent of the courses sold. Pasteurella multocida was the most common pathogen detected and was found in 21 of the outbreaks. For outbreaks where a pathogen contained in the vaccine was detected, P. multocida was found at a significantly greater frequency (P=0.03) where vaccine use was compliant with the SPC (five of six outbreaks) compared with outbreaks where vaccine use had not been compliant with the SPC (one of seven outbreaks). The limitations of the study, including the diagnostic tests employed and definition of vaccination outwith the SPC, are discussed. PMID- 25724545 TI - In vitro assessment of aiming bias in the frontal plane during orthopaedic drilling procedures. AB - Drilling trials were performed using drilling boards incorporating pairs of 22 mm polyethylene tubes mounted horizontally. The tubes were premarked with 20, 0.5 mm deep notches along the centre of their upper surface representing the starting point for each drilling trial. Volunteers were instructed to drill 20 straight holes across the tube until they penetrated both walls. Kirschner wires were inserted through each of the drill holes until they made indentations into the base board. Deviation of each mark from mid-line was measured using digital callipers. The measured values were used to calculate deviation angles to the left (negative values) or right (positive values). Trials were performed with the drill and guide held in the surgeon's line-of-sight (LOS) and with 300 mm offset (OFF). A systematic error (aiming bias) was identified in all individuals. Overall, left-hander's drilling action was skewed to the left and right-hander's drilling action was skewed to the right. Using LOS technique, mean overall bias was 2.3 degrees (range 0 degrees -7.7 degrees ) to the left for left-handers and 1.5(o) (range 0.3 degrees -3.1 degrees ) to the right for right-handers. Surprisingly, aiming bias was greater for LOS than for OFF, although the difference for this comparison was not statistically significant. PMID- 25724546 TI - Affective processing bias in youth with primary bipolar disorder or primary attention-deficit/hyperactivity disorder. AB - High rates of comorbidity and overlapping diagnostic criteria between pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) contribute to diagnostic and treatment confusion. To advance what is known about both disorders, we compared effect of emotional stimuli on response control in children with primary BD, primary ADHD and typically developing controls (TDC). Participants included 7-17 year olds with either "narrow-phenotype" pediatric BD (n = 25), ADHD (n = 25) or TDC (n = 25). Groups were matched on participant age and FSIQ. The effect of emotional stimuli on response control was assessed using the Cambridge Neuropsychological Test Automated Battery Affective Go/No-Go task (CANTAB AGN). We found a group by target valence interaction on commission errors [F(2,71) = 5.34, p < 0.01, n p (2) = 0.13] whereby ADHD, but not TDC participants, made more errors on negative than positive words [t(24) = -2.58, p < 0.05, r = 0.47]. In contrast, there was a nonsignificant trend for BD participants to make fewer errors on negative versus positive words compared to ADHD and TDC participants. Between-subjects effects showed that ADHD participants made more errors than TDC, but not BD participants. Our main finding advances what is known about the effect of emotional stimuli on response control in children with ADHD. Our results suggesting a positive affective processing bias in children with ADHD compliment emerging literature show that difficulties with emotional processing and regulation may be core features of ADHD. Further, given the observed pattern of results in children with ADHD compared to BD children, our behavioral results suggest the importance of examining differences in the brain-behavior mechanisms involved in affective processing in children with ADHD compared to BD children. PMID- 25724547 TI - Off-label prescribing of psychotropic drugs in a Danish child and adolescent psychiatric outpatient clinic. AB - This study aimed to describe the level of off-label treatment with psychotropic drugs at a child and adolescent psychiatric outpatient clinic in Denmark. We performed a cross-sectional study assessing records on patients treated with medicine at two outpatient clinics at the child and adolescent psychiatric ward, on 1 day in 2014. Prescriptions of drugs from ATC group N05-N06 were classified according to label status. Six hundred and fifteen drug prescriptions distributed on nine different drugs were prescribed to 503 children eligible for this study. Overall results showed that 170 of the 615 prescriptions were off-label, which corresponds to 27.6 %. Attention deficit hyperkinetic disorder (ADHD) drugs were prescribed 450 times (73.2 %) of which 11 prescriptions were off-label (2.4 %). Other psychotropic drugs comprised 165 (26.8 %) prescriptions and of these 159 (96.4 %) were off-label. With 106 prescriptions, melatonin was the most prescribed of these drugs; all prescriptions were off-label. The main reasons for classifying prescriptions as off-label were age and indication of treatment. This cross-sectional study reveals that medical treatment of children with other psychotropic drugs than ADHD drugs is usually off-label. ADHD drugs were, as the only drug group, primarily prescribed on-label. Although off-label prescription may be rational and even evidence based, the responsibility in case of, e.g. adverse drug reactions is a challenge, and clinical trials in children should be incited. PMID- 25724548 TI - Effects of exposure to benzo[a]pyrene on metastasis of breast cancer are mediated through ROS-ERK-MMP9 axis signaling. AB - Metastasis is the leading cause of deaths in patients with breast cancer. Benzo[a]pyrene is a cumulative carcinogen and ubiquitous environmental pollutant with potent carcinogenic properties. As we report here, we established an accumulative mouse model mimicking the cumulative effects of benzo[a]pyrene exposure in human breast carcinogenesis. Our focus was on elucidating the mechanisms by which benzo[a]pyrene contributes to the process of breast cancer metastasis. Our study indicated that benzo[a]pyrene increased the migration of breast cancer cells both in vitro and in vivo. Specifically, we demonstrated that benzo[a]pyrene enhances breast cancer cell migration and invasion by up regulating ROS-induced ERK signaling, leading to the activation of matrix metalloproteinases 9. Our results suggest that benzo[a]pyrene-induced mammary gland cancer metastasis is an important and intricate process facilitated by cumulative benzo[a]pyrene exposure leading to activation of the ROS-ERK-MMP9 signaling pathway. PMID- 25724549 TI - Tracking a protein following dissociation from a protein-protein complex using a split SNAP-tag system. AB - Protein-protein interactions (PPIs) are important for various biological processes in living cells. Several methods have been developed for the visualization of PPIs in vivo; however, these methods are unsuitable for visualization of post-PPI events such as dissociation and translocation. In this study, we applied a split SNAP-tag system for the visualization of post-PPI events. This method enabled tracking of the protein following dissociation from the protein-protein complex. Thus, the split SNAP-tag system should prove to be a useful tool for visualization of post-PPI events. PMID- 25724550 TI - Effect of oral health education programs for caregivers on oral hygiene of the elderly: A systemic review and meta-analysis. AB - OBJECTIVES: To evaluate the effects of oral health education for caregivers on the oral health status of the elderly. DESIGN: A systematic review and meta analysis. DATA SOURCES: The Medline, EMBASE, Cochrane Library (CENTRAL), PsycINFO, CINAHL were searched up to September, 2014. REVIEW METHODS: Randomized controlled trials or comparative before-and-after studies involving an oral health education program for caregivers of the elderly (>=65 years old) were identified by two independent reviewers. Primary outcome was the percentage of patients with normal mucosa in the oral cavity. The secondary outcomes were the percentage of patients with no visible plaque and the percentage of patients without denture stomatitis. RESULTS: A total of five studies, involving 602 elders, met the eligible criteria for inclusion in the meta-analysis. It was found that the percentage of residents with normal oral mucosa (odds ratio (OR)=1.81, P=0.027), no visible plaque (OR=1.54, P=0.001), and no detectable denture stomatitis (OR=2.89, P<0.001) significantly increased after the group was treated by caregivers who had received a recent oral health education program. CONCLUSIONS: The systemic review and meta-analysis found limited evidence that oral health education for caregivers may be effective for improving the oral health of the elderly. PMID- 25724551 TI - Regulation of ozone-induced lung inflammation and injury by the beta-galactoside binding lectin galectin-3. AB - Macrophages play a dual role in ozone toxicity, contributing to both pro- and anti-inflammatory processes. Galectin-3 (Gal-3) is a lectin known to regulate macrophage activity. Herein, we analyzed the role of Gal-3 in the response of lung macrophages to ozone. Bronchoalveolar lavage (BAL) and lung tissue were collected 24-72h after exposure (3h) of WT and Gal-3(-/-) mice to air or 0.8ppm ozone. In WT mice, ozone inhalation resulted in increased numbers of proinflammatory (Gal-3(+), iNOS(+)) and anti-inflammatory (MR-1(+)) macrophages in the lungs. While accumulation of iNOS(+) macrophages was attenuated in Gal-3( /-) mice, increased numbers of enlarged MR-1(+) macrophages were noted. This correlated with increased numbers of macrophages in BAL. Flow cytometric analysis showed that these cells were CD11b(+) and consisted mainly (>97%) of mature (F4/80(+)CD11c(+)) proinflammatory (Ly6GLy6C(hi)) and anti-inflammatory (Ly6GLy6C(lo)) macrophages. Increases in both macrophage subpopulations were observed following ozone inhalation. Loss of Gal-3 resulted in a decrease in Ly6C(hi) macrophages, with no effect on Ly6C(lo) macrophages. CD11b(+)Ly6G(+)Ly6C(+) granulocytic (G) and monocytic (M) myeloid derived suppressor cells (MDSC) were also identified in the lung after ozone. In Gal-3(-/ ) mice, the response of G-MDSC to ozone was attenuated, while the response of M MDSC was heightened. Changes in inflammatory cell populations in the lung of ozone treated Gal-3(-/-) mice were correlated with reduced tissue injury as measured by cytochrome b5 expression. These data demonstrate that Gal-3 plays a role in promoting proinflammatory macrophage accumulation and toxicity in the lung following ozone exposure. PMID- 25724552 TI - Effects of nondipping pattern on systemic inflammation in obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a highly prevalent chronic systemic disease in the general population with high morbidity and mortality. Nondipping pattern-failure to drop blood pressure levels in nighttime-is also seen in OSAS patients. We aim to investigate dipping and nondipping patterns of OSAS patients and to compare inflammatory markers. MATERIALS AND METHODS: Patients with the confirmed diagnosis of OSAS with polysomnography underwent ambulatory blood pressure monitoring. During monitoring, patients with decreased nighttime mean systolic blood pressures 10 % or more were defined as dippers, and the patients without this amount of decrease were defined as nondippers. Peripheral venous blood samples were collected for the analysis of IL-2, IL-6, IL 8, IL-10, IL-12, and TNF-alpha. Results were compared with convenient statistical tests. RESULTS: According to monitoring results, 34 of 62 OSAS patients were dipper and 28 of 62 patients were nondipper. Demographic characteristics, OSAS severity, and Apnea Hypopnea Index were similar in both groups. When inflammatory markers were compared between two groups, IL-2 levels were found to be significantly different (p = 0.014). CONCLUSION: In conclusion, nondipping pattern appears to be associated with increased serum IL-2 levels indicating the increased inflammatory response independently from OSAS severity, and this pattern should be evaluated carefully for possible cardiovascular complications. PMID- 25724553 TI - IGF-1: a potential biomarker for efficacy of sleep improvement with automatic airway pressure therapy for obstructive sleep apnea? AB - BACKGROUND: Positive airway pressure (PAP) reverses obstructive sleep apnea (OSA) related hypoxia and restores slow wave sleep (SWS). Insulin-like growth factor 1 (IGF-1) is a neuropeptide that facilitates the repair of neurons from hypoxia and improves sleep regulation. IGF-1 concentrations are lower in OSA, and likely increase following PAP treatment; however, this relationship has not yet been determined in a younger cohort of OSA patients. METHODS: This was a prospective, observational pilot study of 58 young men, who were diagnosed with OSA and provided PAP as an intervention. Adherence to PAP treatment over 3 months was objectively measured, as well as changes in the apnea-hypopnea index (AHI). Serum concentrations of IGF-1and C-reactive protein (CRP) were measured and correlated with PAP adherence. RESULTS: IGF-1 concentrations at baseline were similar between PAP adherent 55.5 +/- 34.4 ng/ml and PAP nonadherent participants 61.2 +/ 27.1 ng/ml (p = 0.4), with the overall mean IGF-1 concentration of 59.0 +/- 29.9 ng/ml. At follow-up, adherent participants had concentrations of IGF-1 that were significantly higher 128 +/- 59.5 ng/ml compared to nonadherent participants 86.0 +/- 47.4 ng/ml (p < 0.01). Increases in IGF-1 concentrations were significantly associated with reductions in AHI (Spearman's rho = -0.409, p = 0.015). Conversely, CRP concentrations did not differ between baseline and follow-up measurements in either group. CONCLUSIONS: Adherence to PAP treatment leads to significant increases in IGF-1 concentrations in young men with OSA. While an objective measure of adherence exists, PAP usage does not allow for measure of sleep improvement. IGF-1 may serve as a potential biomarker for the efficacy of PAP therapy on improved sleep. PMID- 25724554 TI - Chronic intermittent hypoxia leads to insulin resistance and impaired glucose tolerance through dysregulation of adipokines in non-obese rats. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine whether chronic intermittent hypoxia (CIH) could affect the secretion of adipokines, such as resistin, leptin, and adiponectin, in non-obese rats and to investigate the potential mechanisms. METHODS: An established rodent model of CIH was utilized, in which rats were exposed to varying oxygen levels (7-21 %) respectively over a period of 5 weeks. The area under the curve (AUCG) and the insulin resistance index (homeostasis model of assessment for insulin resistance index, HOMA-IR) were calculated. The levels of several secretory factors in the blood were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA levels and protein expression in adipose tissues was measured by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Glucose tolerance and the levels of adiponectin in non-obese rats were decreased in the CIH group both in the serum and adipose tissue compared with the controls, while the insulin resistance index and the levels of resistin and leptin were increased. Moreover, the expressions of hypoxia inducible factor-1alpha and lactate dehydrogenase A were significantly higher in chronic intermittent hypoxia rats than in control rats, suggesting the presence of adipose tissue hypoxia. CONCLUSIONS: These results show that CIH leads to insulin resistance (IR) and impaired glucose tolerance (IGT) in a non obese rodent model of obstructive sleep apnea-hypopnea syndrome, and these effects may be due to the dysregulation of adiponectin, resistin, and leptin. PMID- 25724555 TI - Promotion of Dental Pulp Cell Migration and Pulp Repair by a Bioceramic Putty Involving FGFR-mediated Signaling Pathways. AB - Mineral trioxide aggregate is the currently recommended material of choice for clinical pulp repair despite several disadvantages, including handling inconvenience. Little is known about the signaling mechanisms involved in bioceramic-mediated dental pulp repair-particularly, dental pulp cell (DPC) migration. This study evaluated the effects of iRoot BP Plus, a novel ready-to use nanoparticulate bioceramic putty, on DPC migration in vitro and pulp repair in vivo, focusing on possible involvement of fibroblast growth factor receptor (FGFR)-related signaling, including mitogen-activated protein kinase and Akt pathways. Treatment with iRoot BP Plus extracts enhanced horizontal and vertical migration of DPCs, which was comparable with the effects induced by mineral trioxide aggregate extracts. The DPCs exposed to iRoot BP Plus extracts demonstrated no evident apoptosis. Importantly, treatment with iRoot BP Plus extracts resulted in rapid activation of FGFR, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK), and Akt signaling in DPCs. Confocal immunofluorescence staining revealed that iRoot BP Plus stimulated focal adhesion formation and stress fiber assembly in DPCs, in addition to upregulating the expression of focal adhesion molecules, including p-focal adhesion kinase, p-paxillin, and vinculin. Moreover, activation of FGFR, ERK, JNK, and Akt were found to mediate the upregulated expression of focal adhesion molecules, stress fiber assembly, and enhanced DPC migration induced by iRoot BP Plus. Consistent with the in vitro results, we observed induction of homogeneous dentin bridge formation and expression of p-focal adhesion kinase, p-FGFR, p-ERK 1/2, p-JNK, and p-Akt near injury sites by iRoot BP Plus in an in vivo pulp repair model. These data demonstrate that iRoot BP Plus can promote DPC migration and pulp repair involving the FGFR-mediated ERK 1/2, JNK, and Akt pathways. These findings provide valuable insights into the signaling mechanisms underlying nanoparticulate bioceramic-mediated pulp repair. PMID- 25724556 TI - Migration of splenic lymphocytes promotes liver fibrosis through modification of T helper cytokine balance in mice. AB - BACKGROUND: Sustained liver injury causes liver fibrosis and eventually cirrhosis. Understanding the pathophysiological mechanisms of liver fibrosis and interventions in the fibrotic process is crucial for improving the prognosis of patients with chronic liver diseases. Although studies have shown that splenectomy suppresses liver fibrosis, the mechanism by which this occurs is poorly understood. The present study focuses on the immunological functions of the spleen to investigate its role in liver fibrosis. METHODS: BALB/c and severe combined immunodeficiency (SCID) mice underwent splenectomies or sham operations prior to induction of liver fibrosis with carbon tetrachloride or thioacetamide. RESULTS: Sirius red staining and hydroxyproline assays showed that splenectomy suppressed liver fibrogenesis in BALB/c mice. Reverse transcription PCR analysis of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines demonstrated that splenectomy shifted the Th1/Th2 balance in the liver towards Th1 dominance. In SCID mice, the inhibitory effect on liver fibrosis was abrogated. The number of CD4(+) T helper lymphocytes in the spleen decreased after liver injury. Green fluorescent protein positive (GFP(+)) splenocytes were transplanted into the spleens of syngeneic wild-type mice to trace their destination after fibrosis induction. GFP(+)CD4(+) lymphocytes appeared in the liver after induction of fibrosis, and flow cytometry revealed the vast majority of them were Th2 lymphocytes. Transfer of splenocytes via the portal vein into syngeneic splenectomized mice cancelled the suppressive effect of splenectomy on liver fibrosis. CONCLUSIONS: The present study demonstrated that Th2-dominant splenic lymphocytes migrate into the liver and promote liver fibrosis by shifting the cytokine balance towards Th2 dominance. Splenectomy suppresses the progression of fibrosis at least partly by restoring the Th1/Th2 balance. PMID- 25724557 TI - Conducting Research With Community Groups. AB - Nurse scientists are increasingly recognizing the necessity of conducting research with community groups to effectively address complex health problems and successfully translate scientific advancements into the community. Although several barriers to conducting research with community groups exist, community based participatory research (CBPR) has the potential to mitigate these barriers. CBPR has been employed in programs of research that respond in culturally sensitive ways to identify community needs and thereby address current health disparities. This article presents case studies that demonstrate how CBPR principles guided the development of (a) a healthy body weight program for urban, underserved African American women; (b) a reproductive health educational intervention for urban, low-income, underserved, ethnically diverse women; and (c) a pilot anxiety/depression intervention for urban, low-income, underserved, ethnically diverse women. These case studies illustrate the potential of CBPR as an orientation to research that can be employed effectively in non-research intensive academic environments. PMID- 25724558 TI - Healthcare outsourcing from NHS to independent sector rose from 4.8% of market in 2009 to 7% in 2014, report shows. PMID- 25724559 TI - Stress is a bad advisor. Stress primes poor decision making in deluded psychotic patients. AB - Stress is implicated in the onset of psychosis but the complex links between stress and psychotic breakdown are yet poorly understood. For the present study, we examined whether two prominent cognitive biases in psychosis, jumping to conclusions and distorted attribution, in conjunction with neuropsychological deficits play a role in this process. Thirty participants with schizophrenia and acute delusional symptoms were compared with 29 healthy controls across three conditions involving a noise stressor, a social stressor or no stressor. Under each condition participants had to perform parallel versions of cognitive bias tasks and neuropsychological tests including a probabilistic reasoning task (jumping to conclusions), the revised Internal, Personal and Situational Attributions Questionnaire (IPSAQ-R; attributional style), and the Corsi block tapping task (nonverbal memory). Stress, particularly noise, aggravated performance differences of patients relative to controls on memory. Participants with psychosis demonstrated an escalated jumping to conclusion bias under stress. At a medium effect size, patients made more monocausal attributions, which increased under social stress. The present study is partially in line with prior studies. It suggests that stress negatively affects cognition in psychosis more than in controls, which is presumably insufficiently realized by patients and thus not held in check by greater response hesitance. Raising patients' awareness about these response tendencies and encouraging them to be more cautious in their judgments under conditions of increased stress may prove beneficial for improving positive symptoms. PMID- 25724560 TI - The impact of emotional faces on social motivation in schizophrenia. AB - Impairments in emotion recognition and psychosocial functioning are a robust phenomenon in schizophrenia and may affect motivational behavior, particularly during socio-emotional interactions. To characterize potential deficits and their interplay, we assessed social motivation covering various facets, such as implicit and explicit approach-avoidance tendencies to facial expressions, in 27 patients with schizophrenia (SZP) and 27 matched healthy controls (HC). Moreover, emotion recognition abilities as well as self-reported behavioral activation and inhibition were evaluated. Compared to HC, SZP exhibited less pronounced approach avoidance ratings to happy and angry expressions along with prolonged reactions during automatic approach-avoidance. Although deficits in emotion recognition were replicated, these were not associated with alterations in social motivation. Together with additional connections between psychopathology and several approach avoidance processes, these results identify motivational impairments in SZP and suggest a complex relationship between different aspects of social motivation. In the context of specialized interventions aimed at improving social cognitive abilities in SZP, the link between such dynamic measures, motivational profiles and functional outcomes warrants further investigations, which can provide important leverage points for treatment. Crucially, our findings present first insights into the assessment and identification of target features of social motivation. PMID- 25724561 TI - Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics. AB - Autophagy in cancer is an intensely debated concept in the field of translational research. The dual nature of autophagy implies that it can potentially modulate the pro-survival and pro-death mechanisms in tumor initiation and progression. There is a prospective molecular relationship between defective autophagy and tumorigenesis that involves the accumulation of damaged mitochondria and protein aggregates, which leads to the production of reactive oxygen species (ROS) and ultimately causes DNA damage that can lead to genomic instability. Moreover, autophagy regulates necrosis and is followed by inflammation, which limits tumor metastasis. On the other hand, autophagy provides a survival advantage to detached, dormant metastatic cells through nutrient fueling by tumor-associated stromal cells. Manipulating autophagy for induction of cell death, inhibition of protective autophagy at tissue-and context-dependent for apoptosis modulation has therapeutic implications. This review presents a comprehensive overview of the present state of knowledge regarding autophagy as a new approach to treat cancer. PMID- 25724562 TI - Exosomes and their roles in immune regulation and cancer. AB - Exosomes, a subset of extracellular vesicles (EVs), function as a mode of intercellular communication and molecular transfer. Exosomes facilitate the direct extracellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells in vitro and in vivo. The immunological activities of exosomes affect immunoregulation mechanisms including modulating antigen presentation, immune activation, immune suppression, immune surveillance, and intercellular communication. Besides immune cells, cancer cells secrete immunologically active exosomes that influence both physiological and pathological processes. The observation that exosomes isolated from immune cells such as dendritic cells (DCs) modulate the immune response has enforced the way these membranous vesicles are being considered as potential immunotherapeutic reagents. Indeed, tumour- and immune cell-derived exosomes have been shown to carry tumour antigens and promote immunity, leading to eradication of established tumours by CD8(+) T cells and CD4(+) T cells, as well as directly suppressing tumour growth and resistance to malignant tumour development. Further understanding of these areas of exosome biology, and especially of molecular mechanisms involved in immune cell targeting, interaction and manipulation, is likely to provide significant insights into immunorecognition and therapeutic intervention. Here, we review the emerging roles of exosomes in immune regulation and the therapeutic potential in cancer. PMID- 25724564 TI - Association of processes of primary care and hospitalisation for people with diabetes: A record linkage study. AB - AIMS: To explore the association of primary care and hospitalisation for people with diabetes. METHODS: The study comprised 20,433 diabetic participants in the Sax Institute's 45 and Up Study. Data on processes of care at recruitment (15 months) were extracted from the Department of Human Services Medicare database. Processes included continuity of primary care (47.1%), and claims for completion of an annual cycle of care (25.0%), GP management plan/team care arrangement (GPMP/TCA, 41.3%), review of GPMP/TCA (24.0%), and monitoring including HbA1c (62.7%). Hospitalisation (12 months) following recruitment was extracted from administrative data held by NSW Ministry of Health. Adjusted incidence rate ratios (aIRR) with 95% confidence interval were calculated. RESULTS: A hospital admission was reported for 33.0% of participants. Continuity of care (aIRR: 0.92 (95%CI: 0.89-0.96)), or claims for an annual cycle of care (aIRR: 0.77 (0.74 0.80)) or HbA1c testing (aIRR: 0.92 (0.89-0.96) were associated with a reduced likelihood of hospitalisation. While claims for preparation of GPMP/TCA were not associated with hospitalisation, a claim for review of GPMP/TCA was associated with a reduced likelihood of hospitalisation (aIRR: 0.92 (95%CI: 0.89 0.96)). CONCLUSIONS: This study has implications for hospital avoidance programmes suggesting that strengthening primary care may be more important than care coordination for this group of patients. PMID- 25724563 TI - Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity. AB - Liver X receptor (LXR)alpha and LXRbeta play key roles in hepatic de novo lipogenesis through their regulation of lipogenic genes, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate responsive element binding protein (ChREBP). LXRs activate lipogenic gene transcription in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-hexosamine-derived O-linked beta-N acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin-independent effects of feeding on LXR-mediated lipogenic gene expression in vivo, we subjected control and streptozotocin-treated LXRalpha/beta(+/+) and LXRalpha/beta(-/-) mice to a fasting-refeeding regime. We show that under hyperglycemic and hypoinsulinemic conditions, LXRs maintain their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPalpha, and the newly identified shorter isoform ChREBPbeta. Furthermore, glucose-dependent increases in LXR/retinoid X receptor-regulated luciferase activity driven by the ChREBPalpha promoter was mediated, at least in part, by O GlcNAc transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPalpha promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose metabolic sensors upstream of ChREBP by modulating GK expression, nuclear O-GlcNAc signaling, and ChREBP expression and activity. PMID- 25724565 TI - Seasonal variation in infestations by ixodids on Siberian chipmunks: effects of host age, sex, and birth season. AB - In mammalian hosts, macroparasite aggregation is highly heterogeneous over space and time and among individuals. While the exact causes of this heterogeneity remain unclear, it has mainly been attributed to individual differences in exposure and susceptibility. Although some extrinsic (e.g., parasite availability) and intrinsic (e.g., sex or age) factors are well known to affect infestation patterns, the joint and possibly interacting effects of these factors are poorly understood. Here, we study the infestation of hard ticks (mainly Ixodes ricinus) in a small rodent, the Siberian chipmunk (Tamias sibiricus), introduced to an oak-hornbeam forest in France. We investigate the seasonal variation in infestation according to the sex, age, birth season (spring-born or summer-born), and body weight of individual hosts while controlling for interannual variability. During the 10-year study period, 3421 tick count events were recorded involving 1017 chipmunks monitored by the capture-mark-recapture procedure. Our results reveal a male-biased parasitism in the Siberian chipmunk, which is not consistent among individuals born in different seasons. This sex bias is observed among spring-born juveniles from July to the beginning of hibernation. For adults, this difference becomes apparent along the reproduction period (May-September) for summer-born adults only. These complex interactions between sex, age, and birth season suggest overall that the seasonal variation of tick load is critically linked to the reproductive behavior of this small ground sciurid. PMID- 25724566 TI - Optical coherence tomography features of angiographic complex and smooth lesions in acute coronary syndromes. AB - Plaque rupture (PR) and superimposed thrombosis have been shown as the most frequent underlying substrate in acute coronary syndromes (ACS). Coronary angiography is a luminogram not able to define in vivo features of the culprit plaques. The aim of the study was to use optical coherence tomography (OCT) to investigate the pathology underlying complex (CL) and non-complex angiographic lesions (NCL). We retrospectively enrolled 107 ACS patients admitted to our institution; 83 with non-ST elevation ACS (NSTE-ACS) and 24 with ST-elevation myocardial infarction. Coronary angiography was performed and culprit lesions were classified according to Ambrose criteria into NCL (n = 47) and CL (n = 60). OCT imaging was then performed to better identify plaque morphology; either PR or intact fibrous cap, the presence of superimposed thrombosis, lipid rich plaque, and thin cap fibroatheroma (TCFA). OCT analysis showed that 58 lesions (54.2%) were classified as PR and 48 lesions (44.9%) were associated with thrombi. Lipid rich plaques were identified in 62 lesions (57.9%). PR, intracoronary thrombi, lipid rich plaques and TCFA were more frequent in CL compared with NCL (71.7 vs 31.9%, 63.3 vs 21.3%, 71.7 vs 40.4% and 46.7 vs 21.3% respectively), but PR with superimposed thrombus may be also detected in NCL. OCT demonstrates PR and thrombosis in the majority of ACS patients presenting with CL. However, one-third of NCL show PR by OCT, suggesting that additional intracoronary imaging by OCT may better identify the underlying mechanism of coronary instability than coronary angiography alone. PMID- 25724567 TI - Coronary plaque progression of non-culprit lesions after culprit percutaneous coronary intervention in patients with moderate to advanced chronic kidney disease: intravascular ultrasound and integrated backscatter intravascular ultrasound study. AB - Previous studies have suggested that the deterioration of renal function increases the risk of major adverse clinical events not only in culprit lesions but also in non-culprit lesions (NCLs) after percutaneous coronary intervention (PCI). This study evaluated serial coronary plaque change of NCL in patients with different stages of chronic kidney disease (CKD) using intravascular ultrasound (IVUS) and integrated backscatter IVUS (IB-IVUS). In 113 patients (113 NCLs) underwent both IVUS-guided PCI and follow-up IVUS, volumetric IVUS analyses were performed at proximal reference NCLs in de novo target vessels post PCI and at 8 month follow-up. NCLs were divided into 4 groups based on baseline CKD stage: CKD 1, n = 18; CKD-2, n = 42; CKD-3, n = 29; and CKD4-5, n = 24. We compared serial changes of plaque burden and composition among groups under statin treatment. Plaque progression occurred in CKD-3 (+4.6 mm(3), p < 0.001) and CKD4-5 (+9.8 mm(3), p < 0.001) despite anti-atherosclerotic treatment, whereas plaque regression occurred in CKD-1 (-5.4 mm(3), p = 0.002) and CKD-2 (-3.2 mm(3), p = 0.001) mainly due to initiate statin treatment after PCI. Plaque volume change was correlated with eGFR (p < 0.0001). Multivariate analysis showed CKD stage 3-5 was an independent predictor of plaque progression. Regarding IB-IVUS analyses, lipid plaque increased in CKD-3 (+4.6 mm(3), p < 0.001) and CKD4-5 (+5.4 mm(3), p < 0.001), but decreased in CKD-2 (-2.7 mm(3), p < 0.05). Fibrotic plaque also increased in CKD4-5 (+3.4 mm(3), p < 0.001). Moderate to advanced CKD was associated with coronary plaque progression characterized by greater lipid and fibrotic plaque volumes in NCL under statin treatment after culprit PCI. PMID- 25724568 TI - Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling. AB - ERG and PTEN biomarkers are increasingly being analyzed on prostate core biopsies (NBXs); ERG as a marker of clonality and number of separately arising tumor foci and PTEN for prognostic information. Yet, in patients with multiple biopsy cores positive for cancer (PCa), there is no standardized approach for interrogation of these biomarkers in terms of the number of positive cores to evaluate. A total of 194 NBX cases containing more than one positive core with cancer were evaluated for ERG overexpression and PTEN loss by immunostaining (immunohistochemistry) of all positive cores. ERG overexpression or PTEN loss in at least one cancer core was present in 111 (57%) and 69 (36%) cases respectively. ERG overexpression was significantly associated with PTEN loss (P < .0001), and PTEN loss was associated with a high Gleason score (P < .0001). Inter- and intra-tumor core staining heterogeneity for ERG overexpression occurred in 42% and 5% cases and for PTEN loss both intra- and inter-tumor core heterogeneity was 68%. PTEN staining was highly discordant between PCa sites regardless of laterality. When the Gleason score was non-uniform across PCa sites, the combination of cores showing the highest Gleason score and largest tumor volume provided the best representation of ERG overexpression (92%) and PTEN loss (98%). When grades were uniform across cancer sites, the highest tumor volume core was generally representative of ERG overexpression (90%) but was less representative for PTEN loss (76%). Our results suggest that knowledge of this heterogeneity is critical for developing optimal yet cost-effective strategies to identify these underlying molecular abnormalities. PMID- 25724569 TI - High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial. AB - AIMS/HYPOTHESIS: High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet). METHODS: In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (<10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner. RESULTS: Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUCglucose) throughout the day was 20% lower, whereas AUCinsulin, AUCC-peptide and AUCtGLP-1 were 20% higher for the Bdiet than the Ddiet. Glucose AUC0-180min and its peak were both lower by 24%, whereas insulin AUC0-180min was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet. CONCLUSIONS/INTERPRETATION: High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes. Trial registration ClinicalTrials.gov NCT01977833 Funding No specific funding was received for the study. PMID- 25724570 TI - Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. AB - AIMS/HYPOTHESIS: Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk factors for and impact of CAND in glucose intolerance and diabetes. METHODS: Among 1,332 eligible participants aged 55-74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs. RESULTS: In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG-IGT (IFG-IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG-IGT and i-IFG than in those with NGT (p < 0.05). The rates of CAND (>=2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG-IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% (p < 0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV (p < 0.05 vs normal HRV). CONCLUSIONS/INTERPRETATION: In the general population aged 55-74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG-IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice. PMID- 25724571 TI - A Cluster Randomized Trial of Interventions to Improve Work Conditions and Clinician Burnout in Primary Care: Results from the Healthy Work Place (HWP) Study. AB - BACKGROUND: Work conditions in primary care are associated with physician burnout and lower quality of care. OBJECTIVE: We aimed to assess if improvements in work conditions improve clinician stress and burnout. SUBJECTS: Primary care clinicians at 34 clinics in the upper Midwest and New York City participated in the study. STUDY DESIGN: This was a cluster randomized controlled trial. MEASURES: Work conditions, such as time pressure, workplace chaos, and work control, as well as clinician outcomes, were measured at baseline and at 12-18 months. A brief worklife and work conditions summary measure was provided to staff and clinicians at intervention sites. INTERVENTIONS: Diverse interventions were grouped into three categories: 1) improved communication; 2) changes in workflow, and 3) targeted quality improvement (QI) projects. ANALYSIS: Multilevel regressions assessed impact of worklife data and interventions on clinician outcomes. A multilevel analysis then looked at clinicians whose outcome scores improved and determined types of interventions associated with improvement. RESULTS: Of 166 clinicians, 135 (81.3%) completed the study. While there was no group treatment effect of baseline data on clinician outcomes, more intervention clinicians showed improvements in burnout (21.8% vs 7.1% less burned out, p = 0.01) and satisfaction (23.1% vs 10.0% more satisfied, p = 0.04). Burnout was more likely to improve with workflow interventions [Odds Ratio (OR) of improvement in burnout 5.9, p = 0.02], and with targeted QI projects than in controls (OR 4.8, p = 0.02). Interventions in communication or workflow led to greater improvements in clinician satisfaction (OR 3.1, p = 0.04), and showed a trend toward greater improvement in intention to leave (OR 4.2, p = 0.06). LIMITATIONS: We used heterogeneous intervention types, and were uncertain how well interventions were instituted. CONCLUSIONS: Organizations may be able to improve burnout, dissatisfaction and retention by addressing communication and workflow, and initiating QI projects targeting clinician concerns. PMID- 25724572 TI - Reconstruction of the naso-orbital-ethmoid (NOE) complex using the osteocutaneous radial forearm flap (OCRFF). AB - OBJECTIVES: Describe the utility of osteocutaneous forearm flaps in reconstruction of naso-orbito-ethmoid (NOE) defects. STUDY DESIGN: Case series with chart review. SETTING: Tertiary medical centers. SUBJECTS AND METHODS: The study was conducted on patients treated between the years 2000 and 2014 undergoing NOE resection with reconstruction using the radial forearm flap. Decision making, technical feasibility, need for revisions, and patient disease outcomes were included to assess the durability of reconstruction over remaining survival period. RESULTS: Fifteen patients underwent NOE reconstruction in the timeframe studied. Five recent patients reported poor nasal airway but no diplopia or immediately clinically evident enopthalmus after NOE reconstruction in mean follow-up of 17.3 months. One-third of patients succumbed to disease in the study period, 3 without revision, and all but 2 surviving patients required revisions. CONCLUSION: Osteocutaneous radial forearm flap (OCRFF) is a cosmetically acceptable method of reconstructing NOE defects. Though a 1-step reconstruction can be serviceable without multiple additional procedures, longer surviving patients frequently receive revision surgery as with more traditional planned staged procedures. PMID- 25724573 TI - Transcriptional activity of HPV in inverted papilloma demonstrated by in situ hybridization for E6/E7 mRNA. AB - OBJECTIVE: Assess human papilloma virus (HPV) transcriptional activity in inverted Schneiderian papillomas (IPs). STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care center. SUBJECTS AND METHODS: Retrospective clinicopathologic review of 19 cases of IP in patients undergoing surgical excision from 1995 to 2013 at Mayo Clinic in Rochester, Minnesota. Surgical pathology archival material was histopathologically reviewed using hematoxylin and eosin-stained slides. Formalin-fixed, paraffin-embedded material from each case was evaluated for p16 expression using immunohistochemistry as well as HPV DNA and E6/E7 messenger RNA (mRNA) transcription using polymerase chain reaction (PCR) and in situ hybridization (via RNAscope technology), respectively. RESULTS: Eight patients were female (42%), with an average age of 53 years (range, 23-82 years). Three demonstrated malignancy, and 5 subsequently recurred. Average follow-up was 49 months (range, 0-200 months), and 1 patient died from squamous cell carcinoma arising from the IP. RNAscope detected HPV mRNA transcripts exclusively within IP in 100% of cases; however, in 11 patients (58%), less than 1% of cells exhibited transcriptional activity. Only 2 of 19 cases (11%) demonstrated mRNA activity in 50% or more cells. HPV DNA was detected in only 2 specimens by PCR. CONCLUSIONS: This study reveals wide prevalence but limited transcriptional activity of HPV in IP. No correlation between HPV transcriptional activity and progression, recurrence, or malignant transformation was identified. These data suggest that transcription of HPV may contribute to the pathogenesis of IP, but prospective data are needed to definitively demonstrate this connection. These results also suggest that RNAscope may be more sensitive than PCR in detecting HPV activity in IP. PMID- 25724574 TI - Reliability and validity of measurements on digital study models and plaster models. AB - OBJECTIVE: To compare manual plaster cast and digitized model analysis for accuracy and efficiency. MATERIAL AND METHODS: Nineteen plaster models of orthodontic patients in permanent dentition were analyzed by two calibrated examiners. Analyses were performed with a diagnostic calliper and computer assisted analysis after digitization of the plaster models. The reliability and efficiency of different examiners and methods were compared statistically using a mixed model. RESULTS: Statistically significant differences were found for comparisons of all 28 teeth (P < 0.001), mandibular intermolar width (IMW, P = 0.0453), and overjet (P < 0.001 to P = 0.0329). Single-tooth measurements tended to have larger values when measured manually and the SD was between 0.06 and 1.33mm. Digital analyses gave significantly higher values for mandibular IMW and overjet. Less time was needed for digital measurements. CONCLUSION: Clinical significance of the differences between the methods compared did not appear significant. 3D laser-scanned plaster model analysis appears to be an adequate, reliable, and time saving alternative to analogue model analysis using a calliper. PMID- 25724575 TI - New perspectives on the relationship between mandibular and statural growth. AB - BACKGROUND: Condylar and somatic growth have similar growth curves. The aim of this study was to compare both growth curves in untreated subjects at different ages and investigate if a correlation factor (CF) could be established. MATERIAL AND METHODS: Semi-longitudinal records (cephalograms and body height) of 418 untreated, healthy children (193 girls and 225 boys) from a craniofacial growth study were analyzed. Incremental changes of three mandibular measurements from articulare and three from condylion were compared to statural growth changes separately. Based on the assumption that mandibular and somatic growth both follow a parallel line, a CF was postulated and checked for validity and reliability. RESULTS: Mandibular growth spurt could be observed in all six different mandibular measurements, but distances from condylion were more informative. Gonial measurements were not as indicative as symphyseal distances. Mandibular growth did not coincide with somatic growth precisely, and condylar peak velocity preceded statural peak velocity in boys and was slightly delayed in girls. CF was close to the value of 0.4, and its validity could be ascertained when using the condylion-gnathion distance for all ages in girls and up to the age of 12 in boys. Reliability, however, proved to be poor owing to heterogeneity of the sample. CONCLUSIONS: Although the relationship between mandibular and statural growth increments can be expressed as a CF with some degree of adequacy, the variance rendered CF unreliable. When evaluating growth-related changes, condylion should be preferred as condylar reference, and symphyseal landmarks should be favoured over gonion. PMID- 25724576 TI - Supplementing diet with blackberry extract causes a catabolic response with increments in insulin sensitivity in rats. AB - Blackberry (Rubus sp.) fruit has a high content of anthocyanins, but its health benefits have not been sufficiently explored in healthy individuals. Thus, the aim of the study was to determine the effects of blackberry extract on lipid and glucose variables in female and male rats. Sprague Dawley rats were given a standard pellet (SD) or cafeteria (CD) diet supplemented (SD+R and CD+R) or not with Rubus extract for 80 days. Female rats given SD+R had lower body and liver weights than SD females; both sexes given SD+R showed lower plasma glucose and insulin, higher plasma NEFA, glycerol and 3-hydroxybutyrate, and higher liver concentration of triacylglycerols than SD rats. The homeostasis model of insulin resistance (HOMA) was lower in SD+R rats than in SD rats, but higher in CD rats. No effects of Rubus extract were observed in CD rats. In conclusion, Rubus extract, in rats given SD, decreased glycemia and increased insulin sensitivity. It also increased lipid breakdown in adipose tissue. The effects were greater in females than in males. No effect was seen in rats given CD, probably as a result of their high insulin resistance. PMID- 25724579 TI - The use of natural products in colorectal cancer drug discovery. AB - INTRODUCTION: Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a strategy of developing targeted agents by screening libraries of synthetic compounds. However, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and was applied in standard regimens for metastatic colorectal cancer (CRC) worldwide. Additionally, polysaccharide K is approved for CRC in Japan and Taiwan in combination with cytotoxic agents. However, after the approval of irinotecan in 1996, no anti cancer agents derived from NPs have been approved for CRC. AREAS COVERED: This review discusses NPs that are currently under investigation for the treatment of CRC. In addition, other NPs derived as purified ingredients and crude extracts are listed and also discussed. EXPERT OPINION: The use of NPs for the discovery of anti-cancer agents has not been fully investigated. New technologies that are currently applied for synthetic compounds may be utilized for anti-cancer drug discovery including NPs for CRC. PMID- 25724578 TI - CD133 marks a stem cell population that drives human primary myelofibrosis. AB - Primary myelofibrosis is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, extramedullary hematopoiesis, and transformation to acute myeloid leukemia. To date the stem cell that undergoes the spatial and temporal chain of events during the development of this disease has not been identified. Here we describe a CD133(+) stem cell population that drives the pathogenesis of primary myelofibrosis. Patient-derived circulating CD133(+) but not CD34(+)CD133(-) cells, with a variable burden for JAK2 (V617F) mutation, had multipotent cloning capacity in vitro. CD133(+) cells engrafted for up to 10 months in immunocompromised mice and differentiated into JAK2-V617F(+) myeloid but not lymphoid progenitors. We observed the persistence of human, atypical JAK2-V617F(+) megakaryocytes, the initiation of a prefibrotic state, bone marrow/splenic fibrosis and transition to acute myeloid leukemia. Leukemic cells arose from a subset of CD133(+) cells harboring EZH2 (D265H) but lacking a secondary JAK2 (V617F) mutation, consistent with the hypothesis that deregulation of EZH2 activity drives clonal growth and increases the risk of acute myeloid leukemia. This is the first characterization of a patient-derived stem cell population that drives disease resembling both chronic and acute phases of primary myelofibrosis in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in primary myelofibrosis and indicate a new therapeutic target for myeloproliferative neoplasms. PMID- 25724580 TI - Characterizing and optimizing human anticancer drug targets based on topological properties in the context of biological pathways. AB - One of the challenging problems in drug discovery is to identify the novel targets for drugs. Most of the traditional methods for drug targets optimization focused on identifying the particular families of "druggable targets", but ignored their topological properties based on the biological pathways. In this study, we characterized the topological properties of human anticancer drug targets (ADTs) in the context of biological pathways. We found that the ADTs tended to present the following seven topological properties: influence the number of the pathways related to cancer, be localized at the start or end of the pathways, interact with cancer related genes, exhibit higher connectivity, vulnerability, betweenness, and closeness than other genes. We first ranked ADTs based on their topological property values respectively, then fused them into one global-rank using the joint cumulative distribution of an N-dimensional order statistic to optimize human ADTs. We applied the optimization method to 13 anticancer drugs, respectively. Results demonstrated that over 70% of known ADTs were ranked in the top 20%. Furthermore, the performance for mercaptopurine was significant: 6 known targets (ADSL, GMPR2, GMPR, HPRT1, AMPD3, AMPD2) were ranked in the top 15 and other four out of the top 15 (MAT2A, CDKN1A, AREG, JUN) have the potentialities to become new targets for cancer therapy. PMID- 25724577 TI - Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective "Lymphomes Malins B" protocols. A Societe Francaise des Cancers de l'Enfant study. AB - To describe relapsed B-cell lymphoma or leukemia in children/adolescents treated with a "Lymphomes Malins B" regimen and their outcome and to identify prognostic factors for survival, we studied relapses in the LMB89, 96 and 2001 studies of the Societe Francaise d'Oncologie Pediatrique (Societe Francaise des Cancers de l'Enfant). Therapeutic guidelines at relapse were to obtain a second complete remission and to consolidate the remission with high-dose chemotherapy followed by autologous stem-cell transplantation. Between July 1989 and March 2007, 67 patients of 1322 (5%) relapsed: 57 had Burkitt lymphoma and 10 had large-cell histology. Three patients were initially treated in risk group A, 41 in group B and 23 in group C. Thirty-three patients had a relapse in one site (15 in the central nervous system) and 34 at multiple sites. Sixty-five patients received salvage chemotherapy and 33 achieved complete remission. Forty-one patients also received high-dose chemotherapy followed by autologous (n=33) or allogeneic (n=8) transplantation. With a median follow-up of 6.4 years, the 5-year survival rate was 29.9%. Nineteen patients were still alive, all but one (group A) received consolidation treatment. Multivariate analysis showed the following factors to be significantly associated with better survival: relapse at one site (P=0.0006), large-cell histology (P=0.012), initial prognostic group A or B with lactate dehydrogenase level below twice the normal value (P=0.005), and time to relapse more than 6 months (P=0.04). PMID- 25724581 TI - Practical approach to management of intracranial atherosclerosis. AB - OPINION STATEMENT: Intracranial atherosclerosis (ICAS) is one of the most frequent causes of stroke worldwide and has a high incidence of recurrent stroke. The therapeutic approaches for treating this high-risk disease have been evolving over time. The most recent, evidence-based approach is to focus on aggressive medical management of vascular risk factors and includes short-term dual antiplatelet treatment for 90 days followed by antiplatelet monotherapy. The role of endovascular therapy in the treatment of ICAS has not been established and is currently reserved only for patients who have failed aggressive medical management with recurrent ischemic events. There are no currently recommended surgical options to treat ICAS; however, investigational treatments such as encephaloduroarteriosynagiosis (EDAS) may hold promise. Despite aggressive medical management with short-term dual antiplatelet therapy, there remains a subset of patients with severe ICAS who will have recurrence of ischemic events. Further research is needed to better identify this high-risk subset and develop novel treatments to prevent further stroke and death. PMID- 25724582 TI - Sigma factor WhiGch positively regulates natamycin production in Streptomyces chattanoogensis L10. AB - The roles of many sigma factors are unclear in regulatory mechanism of secondary metabolism in Streptomyces. Here, we report the regulation network of a group 3 sigma factor, WhiGch, from a natamycin industrial strain Streptomyces chattanoogensis L10. WhiGch regulates the growth and morphological differentiation of S. chattanoogensis L10. The whiG ch deletion mutant decreased natamycin production by about 30 % and delayed natamycin production more than 24 h by delaying the growth. Overexpression of the whiG ch gene increased natamycin production in large scale production medium by about 26 %. WhiGch upregulated the transcription of natamycin biosynthetic gene cluster and inhibited the expression of migrastatin and jadomycin analog biosynthetic polyketide synthase genes. WhiGch positively regulated natamycin biosynthetic gene cluster by directly binding to the promoters of scnC and scnD, which were involved in natamycin biosynthesis, and these binding sites adjacent to translation start codon were determined. Thus, this paper further elucidates the high natamycin yield mechanisms of industrial strains and demonstrates that a valuable improvement in the yield of the target metabolites can be achieved through manipulating the transcription regulators. PMID- 25724583 TI - Comparison of the validity of the use of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder in males and females. AB - The spontaneously hypertensive rat (SHR) is a commonly used and well-studied rodent model of attention deficit hyperactivity disorder (ADHD). Sex differences in the cognitive symptoms of ADHD are reported. However, the female SHR rat is much less studied than its male counterpart. The goal of the current study was to assess the validity of the SHR rodent model of ADHD by examining attentional performance, inhibitory control, and hyperactivity in both male and female SHR rats. Adult SHR and control Wistar-Kyoto rats were trained on the 5-choice serial reaction time task, a self-paced test of attention and inhibitory control. This task requires animals to identify the location of a brief light stimulus among five possible locations under several challenging conditions. Analyses of percent correct revealed that attentional performance in SHR females was not significantly different from control females, whereas attentional performance in SHR males was significantly different from control males. Analyses of the number of premature responses revealed that SHR rats made more inhibitory control errors than did control rats and that this decrease in inhibitory control was present in both SHR males and females. Analyses of activity in the open field revealed that SHR rats were more hyperactive than were control rats and that this increased hyperactivity was present in both SHR males and females. The current findings have implications for the study of sex differences in ADHD and for the use of SHR rats as a model of ADHD in females. PMID- 25724584 TI - [Does ultrasonographic volume of the thyroid gland correlate with difficult intubation? An observational study]. AB - BACKGROUND AND OBJECTIVES: Preoperative ultrasonographic evaluation of the thyroid gland done by surgeons could let us foresee airway management challenges. The aim of this observational study was to evaluate the effects of thyroid related parameters assessed preoperatively by surgeons via ultrasonography and chest X-ray on intubation conditions. METHODS: Fifty patients undergoing thyroid surgery were enrolled. Thyromental distance, Mallampati score, neck circumference and range of neck movement were evaluated before the operation. Thyroid volume, signs of invasion or compression and tracheal deviation on chest X-ray were also noted. The intubation conditions were assessed with Cormack and Lehane score and the intubation difficulty scale. Statistical analyses were done with SPSS 15.0 software. RESULTS: The mean thyroid volume of the patients was 26.38+/-14mL. The median intubation difficulty scale was 1 (0-2). Thyromental distance (p=0.011; r=0.36; 95% CI 0.582-0.088), Mallampati score (p=0.041; r=0.29; 95% CI 0.013 0.526), compression or invasion signs (p=0.041; r=0.28; 95% CI 0.006-0.521) and tracheal deviation on chest X-ray (p=0.041; r=0.52; 95% CI 0.268-0.702) were correlated with intubation difficulty scale. Also patients were classified into two groups related to their intubation difficulty scale (Group I, n=19: intubation difficulty scale=0; Group II, n=31: 1 T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FHL1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. [2013]. PMID- 25724587 TI - Homozygous missense mutation in STYXL1 associated with moderate intellectual disability, epilepsy and behavioural complexities. AB - The introduction of massive parallel sequencing has led to the identification of multiple novel genes for intellectual disability (ID) as well as epilepsy. Whereas dominant de novo mutations have been proven to be a leading cause for these disorders, they do not apply to families suggestive of an autosomal recessive inheritance pattern. In this study, we combined the use of linkage analysis with exome sequencing to elucidate the cause of moderate non-syndromic ID, epilepsy and behavioural problems in a consanguineous Asian family. A founder missense mutation was identified in STYXL1. We propose this as a novel candidate gene involved in ID, accompanied by seizures and behavioural problems. Our findings further confirm the genetic heterogeneity of cognitive disorders and genetic epilepsy. PMID- 25724588 TI - Fertility status of Hodgkin lymphoma patients treated with chemotherapy and adjuvant gonadotropin-releasing hormone analogues. AB - PURPOSE: Aim of this prospective observational study was to analyze fertility status of Hodgkin lymphoma (HL) patients treated with different types of chemotherapy while receiving GnRH analogues to preserve ovarian function. METHODS: Fertility status was assessed among 108 females in reproductive age treated by curative chemotherapy for freshly diagnosed HL between 2005 and 2010 in university-based tertiary fertility and oncology center. All patients received GnRH analogues during chemotherapy to preserve their ovarian function. Their reproductive functions were assessed by follicle-stimulating hormone (FSH) measurement and pregnancy achievement. Ovarian function was determined separately in three groups with increasing gonadotoxicity of chemotherapy. RESULTS: One year following the treatment, normal ovarian function was found in 89 (82.4%) of patients. Two years after chemotherapy, 98 (90.7%) of patients retained their ovarian function, and 23 (21.3%) achieved clinical pregnancy during the follow-up period. Average FSH after chemotherapy was 11.6 +/- 17.9 IU/l 1 year after the treatment resp. 9.0 +/- 13.8 at the 2 years interval. There were significantly more patients with chemotherapy induced diminished ovarian reserve (chDOR) among the group receiving escalated BEACOPP chemotherapy in comparison with the other types of treatment (58.1% vs. 87.9% resp. 95.5%). CONCLUSION: The rate of chDOR is significantly higher after EB poly-chemotherapy and there is no tendency for improvement in time. The 2 + 2 chemotherapy with GnRH-a required for more advanced HL retained ovarian function significantly better after 2 years. Another important advantage of GnRH-a co-treatment is the excellent control of patient's menstrual cycle. PMID- 25724589 TI - Characterization of putative multidrug resistance transporters of the major facilitator-superfamily expressed in Salmonella Typhi. AB - Multidrug resistance mediated by efflux pumps is a well-known phenomenon in infectious bacteria. Although much work has been carried out to characterize multidrug efflux pumps in Gram-negative and Gram-positive bacteria, such information is still lacking for many deadly pathogens. The aim of this study was to gain insight into the substrate specificity of previously uncharacterized transporters of Salmonella Typhi to identify their role in the development of multidrug resistance. S. Typhi genes encoding putative members of the major facilitator superfamily were cloned and expressed in the drug-hypersensitive Escherichia coli strain KAM42, and tested for transport of 25 antibacterial compounds, including representative antibiotics of various classes, antiseptics, dyes and detergents. Of the 15 tested putative transporters, STY0901, STY2458 and STY4874 exhibited a drug-resistance phenotype. Among these, STY4874 conferred resistance to at least ten of the tested antimicrobials: ciprofloxacin, norfloxacin, levofloxacin, kanamycin, streptomycin, gentamycin, nalidixic acid, chloramphenicol, ethidium bromide, and acriflavine, including fluoroquinolone antibiotics, which were drugs of choice to treat S. Typhi infections. Cell-based functional studies using ethidium bromide and acriflavine showed that STY4874 functions as a H(+)-dependent exporter. These results suggest that STY4874 may be an important drug target, which can now be tested by studying the susceptibility of a STY4874-deficient S. Typhi strain to antimicrobials. PMID- 25724590 TI - Comparing Alternative Biometric Models with and without Gene-by-Measured Environment Interaction in Behavior Genetic Designs: Statistical Operating Characteristics. AB - To extend Purcell's well known ACE model in testing gene by measured environment interactions (GxM) in behavior genetic designs, Rathouz et al. considered a broader class of models for quantifying and testing such interactions. Only a sub group of these extended models have been investigated for their statistical operating characteristics by Van Hulle et al. due to lack of closed form likelihood. With an estimation procedure developed using numerical techniques in a companion paper, we study statistical operating characteristics of these extended models, especially those with non-linear effects. Type I error analysis shows the likelihood ratio test for GxM to be conservative in testing models extended from the bivariate Cholesky model, and to be liberal for models extended from the bivariate correlated factors model. Parameter estimation for all models is very good, with little bias exhibited for most models and parameters. Comparisons among alternative models under various simulated conditions show that it is relatively more difficult to confirm the existence of gene by environment interactions versus to detect non-linear effects which exclude such interactions. PMID- 25724591 TI - Genome size evolution in macroparasites. AB - Reduction in genome size has been associated not only with a parasitic lifestyle in intracellular microparasites but also in some macroparasitic insects and nematodes. We collected the available data on genome size for flatworms, annelids, nematodes and arthropods, compared those with available data for the phylogenetically closest free-living taxa and found evidence of smaller genome sizes for parasites in six of nine comparisons. Our results suggest that despite great differences in evolutionary history and life cycles, parasitism as a lifestyle promotes convergent genome size reduction in macroparasites. We discuss factors that could be associated with small genome size in parasites which require further exploration in the future. PMID- 25724592 TI - Vitamin D concentration and its association with past, current and future depression in older men: The Health In Men Study. AB - BACKGROUND: Vitamin D deficiency has been associated with depression in later life, but it remains unclear whether this association is truly causal. METHODS: Observational study examining the retrospective, cross-sectional and prospective associations between vitamin D concentration and depressed mood in a community derived sample of 3105 older men living in metropolitan Perth, Western Australia. We measured the plasma concentration of 25-hydroxyvitamin D using standard procedures. Past depression was ascertained by direct questioning and through the use of administrative health data linkage. A geriatric depression scale score equal or greater 7/15 established the presence of current depression. Incident depression was established by a patient health questionnaire (PHQ-9) score >= 10 or by administrative health data linkage during the 6-year follow up (range 0.1 10.9 years). RESULTS: Vitamin D concentration <50 nmol/L was associated with greater odds of current (OR=1.65, 95% CI=1.13, 2.42) but not past depression (OR=1.15, 95% CI=0.83, 1.58). Of the 2740 men with no past or current history of depression, 81 developed clinically significant symptoms during follow up. The adjusted hazard ratio of incident depression for men with plasma vitamin D <50 nmol/L was 1.03 (95% CI=0.59, 1.79; adjusted for age, living arrangements, season, and prevalent cardiovascular diseases). CONCLUSIONS: Our results do not support a role for vitamin D in the causation of depression, although a small antidepressant effect of vitamin D cannot be entirely discarded. Large randomised placebo-controlled trials are required to dismiss or establish with certainty the causal link between vitamin D deficiency and depression. PMID- 25724593 TI - Patterns of stove use in the context of fuel-device stacking: rationale and implications. AB - The implementation of clean fuel and stove programs that achieve sustained use and tangible health, environmental, and social benefits to the target populations remains a key challenge. Realization of these benefits has proven elusive because even when the promoted fuels-stoves are used in the long term they are often combined (i.e., "stacked") with the traditional ones to fulfill all household needs originally met with open fires. This paper reviews the rationale for stacking in terms of the roles of end uses, cooking tasks, livelihood strategies, and the main patterns of use resulting from them. It uses evidence from case studies in different countries and from a 1-year-long field study conducted in 100 homes in three villages of Central Mexico; outlining key implications for household fuel savings, energy use, and health. We argue for the implementation of portfolios of clean fuels, devices and improved practices tailored to local needs to broaden the use niches that stove programs can cover and to reduce residual open fire use. This allows to integrate stacking into diagnosis tools, program monitoring, evaluation schemes, and implementation strategies and establish critical actions that researchers and project planners can consider when faced with actual or potential fuel-device stacking. PMID- 25724594 TI - Safety and effectiveness of therapeutic magnetic resonance in the management of postsurgical lesion of the diabetic foot. AB - To evaluate the safety and effectiveness of therapeutic magnetic resonance (TMR) in the management of the diabetic foot (DF), we treated a group of consecutive type 2 diabetic inpatients with wide postsurgical lesions (Group A: N = 10; age 67.7 +/- 18.9 years, duration of diabetes 22.3 +/- 6.6 years, 8.1 +/- 1.1%, body mass index 29.4 +/- 2.1 kg/m(2)), for 2 consecutive weeks, while admitted, with a low-intensity magnetic resonance equipment, in addition to standard treatment. Patients, compared with a matched control group with the same clinical characteristics (Group B), were then followed monthly for 6 months to evaluate healing rate (HR), healing time (HT), rate of granulation tissue (GT) at 3 months, and adverse events. HR was of 90% in Group A and 30% in Group B (P < .05); GT was 73.7 +/- 13.2% in Group A versus 51.84 +/- 18.77% in Group B (P < .05). HT in Group A was 84.46 +/- 54.38 days versus 148.54 +/- 78.96 days in Group B (P < .01). No difference in adverse events (5 in Group A and 6 in Group B) was observed throughout the study period. In this pilot study, the use of TMR at this dose and duration was safe. The results also permit the observation that TMR plus standard care offered a faster healing rate compared with standard care alone. PMID- 25724595 TI - Survey of Wound-Healing Centers and Wound Care Units in China. AB - The purpose of this study is to report the Chinese experience of establishing hospital-based wound care centers over 15 years. A total of 69 wound-healing centers (WHCs) and wound care units (WCUs) were involved. Questionnaires were diverged to the principal directors of these sites; data extracted for this study included origin, year of establishment, medical staff, degree of hospitals, wound etiology, wound-healing rate, hospital stay, and outcomes data. The period of data extraction was defined as before and after 1 year of the establishment of WHCs and WCUs. The earliest WHC was established in 1999, and from 2010 the speeds of establishing WHCs and WCUs rapidly increased. The majority of WHCs were divisions of burn departments, and all WHCs came from departments of outpatient dressing rooms. Full-time multidisciplinary employees of WHCs differed greatly to WCUs. Types of wound and outcomes vary with those of centers reported from Western countries and the United States. Improvement in wound healing caused by the establishment of WHCs and WCUs in China occurred without doubt. Some advices include the following: rearrange and reorganize the distribution of WHCs and WCUs; enact and generalize Chinese guidelines for chronic wounds; utilize medical resources reasonably; improve multidisciplinary medical staff team; draw up and change some medical and public policies and regulations. PMID- 25724596 TI - [Off-label use of calcium channel blockers as tocolytic agent. CNGOF Workgroup (Short text)]. PMID- 25724597 TI - [One day diagnosis for breast lesions: Medical and psychological assessment- EVADIASEIN study]. AB - INTRODUCTION: Breast cancer is the most frequent feminine cancer in France and its incidence increases steadily. The time of access to medical care is an indicator of the quality of the treatments recommended by the Plan Cancer 2009 2013, as it influences the diagnosis and reduces psychological morbidity during the pre-diagnosis phase. The one-day diagnosis is a recently initiated concept, which offers to get the results of the biopsy on the day it is performed and facilitates the setting-up of therapeutic care with the surgeon met during the one-day medical consultations. The aim of this study is to evaluate the satisfaction of patients who benefited from a one-day breast lesion diagnosis, as well as confirm the decrease of time of access to medical treatment. METHODS: This is an observational, non-interventional and single-centre study based on 27 patients who benefited from one-day breast lesions diagnosis over two years. The patients were only included who had a classified lesion ACR 4 or 5 and visible in the ultrasound. We analyzed the histological concordance between the biopsy and the definitive histology, the time of access to medical care, and the therapeutic treatments We analyzed the psychological impact of such an organization by sending to the patients a questionnaire including the Psychological Consequence Questionnaire (PCQ) and the Breast Cancer Anxiety Indicator (BCA) allowing to estimate the anxiety generated by the pre-diagnostic phase, the DC-Sat allowing to estimate the satisfaction of the consultation of announcement, as well as the same day diagnosis benefit. RESULTS: The patients were 59.8 years old in average [33-87]. The average time between the date of the mammography and the one-day diagnosis consultation (including the biopsy) was 15.0 days [0-60]. Fifty-seven percent of the patients considered this time as short. The average time between the biopsy date and the start of the treatment was 15.9 days [4-30]. The one-day diagnosis took an average of 1.6 days [1-5]. The results of the PCQ showed an important emotional impact during the diagnosis phase, and the average BCA score reached an average of 3.9 on a scale of 5. However, the patients were very satisfied with the diagnosis consultation with an average of 8.7 on a scale of 10, and 95% think the one-day diagnosis is beneficial to the patients. DISCUSSION: This study shows that the one-day breast-damage diagnosis enables to improve the time of access to care, and meets the current recommendations. Even though faster access to treatment does not reduce the psychological morbidity of awaiting diagnosis, the patients express their satisfaction and find the rapidity of the pre-diagnosis phase beneficial. CONCLUSION: In view of this study, the one day breast-damage diagnosis appears to be a quality feature in the process of access to care and treatment of the patients. PMID- 25724598 TI - [Off-label treatments in obstetrics: Tocolysis with calcium channel blockers]. PMID- 25724599 TI - [Distribution of blood loss during vaginal delivery and cesarean section]. AB - OBJECTIVES: To describe the distribution of the volume of blood loss during vaginal and cesarean deliveries among women who delivered after 24 weeks of gestation. MATERIALS AND METHODS: A descriptive study of the distribution of blood loss by delivery route and for all patients after 24 weeks of gestation over a period of two years in a type III maternity. Patient and delivery characteristics were collected and blood loss was measured prospectively based on weighing pads and the use of a collector bag for vaginal deliveries, a suction cannula for cesareans sections. The following parameters were calculated: the mean (+/-SD), the median, interquartile range (IQR), the 5th and 95th percentile. RESULTS: Seven thousand nine hundreds and eight patients were included. After vaginal delivery (n=6134), the mean volume of bleeding was equal to 180.1 mL (+/- 224.7 mL), the median to 100mL (IQR [100-200]), the 95th percentile to 500 mL [CI 95% 500-550]. For cesarean sections (n=1774), the mean volume of bleeding was equal to 557.9mL (+/- 496.2 mL), the median volume of blood loss to 400 mL (IQR [300-700]), the 95th percentile to 1300 mL [CI 95% 1200-1500]. CONCLUSION: The distribution of blood loss after cesarean was significantly higher than the distribution of blood loss after vaginal delivery. PMID- 25724600 TI - [Feasibility of outpatient laparoscopy in gynaecology. A prospective study about 50 cases]. AB - OBJECTIVES: To evaluate the feasibility of outpatient laparoscopy in gynaecology. MATERIALS AND METHODS: This prospective monocentric study included 50 patients. Postoperative pain was evaluated by the visual analogic scale (VAS). Reasons for hospital stay and emergency consultation rates in the first postoperative month were noted. Patient's satisfaction was recorded at the postoperative visit one month after the intervention. RESULTS: The following procedures were included in the study: cystectomy, oophorectomy+/-salpingectomy, explorative laparoscopy for chronic pelvic pain and tubal sterilization. Mean operative time never exceeded 90 minutes (mean 60+/-26.5min). A resident performed 70% of the procedures. No intraoperative complication was reported. Only one patient stayed hospitalised overnight. On the first and second postoperative days, the VAS was 4.89 (+/-2.25) and 4.14 (+/-2.20) respectively. Twenty-five patients (50%) were very satisfied of the medical care, 23 patients (46%) were satisfied and one patient (2%) was not much satisfied. CONCLUSION: The outpatient laparoscopy in gynaecology seems feasible with a high level of satisfaction. It can be proposed to patients after good information. PMID- 25724601 TI - [Epidemioclinical and legal aspects and cost management of sexual abuse among minors in Dakar, Senegal]. AB - OBJECTIVES: Specify epidemioclinical and legal aspects of sexual abuse among minors and evaluate the cost of care in Dakar. MATERIALS AND METHODS: This is a retrospective multicenter cross-sectional study on sexual abuse among minors over a period of four years from 1st January 2006 to 31st December 2009. Four maternities were targeted: the Social Hygiene Institute of Medina, health center Roi-Baudouin Guediawaye, the Pikine hospital and health center Youssou-Mbargane Diop of Rufisque. RESULTS: During the study period, 252 child victims of sexual abuse were supported at four health facilities on a total of 272 sexual abuses of all ages, a frequency of 92.64%. The epidemiological profile of our patients was a child of 11 years old on average, female (100%) and living in the suburbs of Dakar (68.1%). Children were often abused during working hours (31.7%), outside the family environment and often by someone known to the victim (72.6%). Genito genital contact was the most common mode of sexual contact (80.9%) with vaginal penetration in 61% of cases. Almost all of the victims (92.1%) came to consult, accompanied by their parents, between the 1st and 4th day after the sexual abuse (70%). The examination usually revealed a hymenal trauma (59.9%) of which nearly half (49%) consisted of old lesions. 56.9% of victims had a post-traumatic stress disorder and 31.1%, mutism. We recorded six (6) pregnancies, 2% of our sample. A case of HIV infection was recorded on a sample taken 72hours after sexual abuse. Control of three months HIV serology was requested in 7.1% of cases and only 20% of children had received antiretroviral prophylaxis. Antibiotic prophylaxis had been performed in 13.7% of cases using doxycycline as drug of choice (75%). Only 29% of our patients had received emergency contraception progestin and psychological care concerned only 22% of children. On the legal aspects, 46% of our patients had filed a complaint. Prosecutions were 38%, 45% of which were convicted and 21% were acquitted. The rate of out-of-court settlement was 35% and the time limit for settlement by the justice was on average 6 months with extremes of one month and 24 months. The average cost of care was estimated at 17,010 CFA francs (26 euros) taking into account the consumables used for clinical examination (sterile gloves, catheter, syringe), analysis and prescription drugs. CONCLUSION: The sexual abuse of minors is a disturbing reality that raises rightly universal reprobation. In Senegal, this mainly affects children and its magnitude is increasing over the years. Improved support for victims necessarily involves raising public awareness through the media and the development of specialized structures in the management of sexual abuse. PMID- 25724602 TI - [Pregnancy and bariatric surgery: Critical points]. AB - More than 200,000 people underwent obesity surgery in France. Most of them are women. Pregnancy after bariatric surgery is becoming a common situation. This surgery results in major nutritional and gastro-intestinal tract modifications that may influence or be influenced by pregnancy, and yields benefits as well as complications. A multidisciplinary management including a nutritionist, an obstetrician, an anesthesiologist, and a bariatric surgeon is required. The aim of this review is to analyze the impact of bariatric surgery on pregnancy and vice versa, and to identify the key points of this management. PMID- 25724603 TI - Factors associated with pulmonary embolism within 72 hours of admission after trauma: a multicenter study. AB - BACKGROUND: Recent studies using thromboelastography indicate that patients are at risk for hypercoagulability early after injury. Pulmonary embolism (PE) is also well known to cause significant morbidity and mortality after injury and can occur within 72 hours of admission (early PE). Despite this risk, prophylactic anticoagulation is often delayed in patients with certain injuries due to concerns about bleeding. STUDY DESIGN: This was a retrospective study of injured patients with a PE from 2007 to 2013 at 3 level I trauma centers. Data collected included patient demographics, injury patterns, length of stay, timing of prophylaxis for deep vein thrombosis (DVT), and diagnosis of PE. Patients with early PE (<= 3 days) were compared with those with late PE (>3 days) using bivariate and multivariable analysis. RESULTS: A total of 54,964 patients were admitted to the 3 centers during the study period, and 144 (0.26%) were diagnosed with a PE. Eleven were excluded from the study due to a lack of critical data, leaving 133 patients (43% early PE). Factors associated with early PE included long bone fractures in the lower extremity and an Abbreviated Injury Score (AIS) Extremity >= 3. Higher Injury Severity Score, severe chest and head trauma (AIS >= 3), and not receiving DVT prophylaxis within 48 hours of hospital admission were not associated with early PE. CONCLUSIONS: Early PE is a significant clinical entity occurring in nearly half the patients who suffered a PE. Early PE is associated with long bone fractures and severe extremity trauma, but not severe thoracic injury. Timing of prophylactic anticoagulation had no impact on early PE. If further studies confirm this incidence of unsuspected early PE, all admitted trauma patients should be assessed for a hypercoagulable state after injury. PMID- 25724605 TI - The evolving role of the surgeon scientist. PMID- 25724604 TI - High tidal volume decreases adult respiratory distress syndrome, atelectasis, and ventilator days compared with low tidal volume in pediatric burned patients with inhalation injury. AB - BACKGROUND: Inhalation injury, which is among the causes of acute lung injury and acute respiratory distress syndrome (ARDS), continues to represent a significant source of mortality in burned patients. Inhalation injury often requires mechanical ventilation, but the ideal tidal volume strategy is not clearly defined in burned pediatric patients. The aim of this study was to determine the effects of low and high tidal volume on the number of ventilator days, ventilation pressures, and incidence of atelectasis, pneumonia, and ARDS in pediatric burned patients with inhalation injury within 1 year post burn injury. METHODS: From 1986 to 2014, inhalation injury was diagnosed by bronchoscopy in pediatric burned patients (n = 932). Patients were divided into 3 groups: unventilated (n = 241), high tidal volume (HTV, 15 +/- 3 mL/kg, n = 190), and low tidal volume (LTV, 9 +/- 3 mL/kg, n = 501). RESULTS: High tidal volume was associated with significantly decreased ventilator days (p < 0.005) and maximum positive end expiratory pressure (p < 0.0001) and significantly increased maximum peak inspiratory pressure (p < 0.02) and plateau pressure (p < 0.02) compared with those in patients with LTV. The incidence of atelectasis (p < 0.0001) and ARDS (p < 0.02) was significantly decreased with HTV compared with LTV. However, the incidence of pneumothorax was significantly increased in the HTV group compared with the LTV group (p < 0.03). CONCLUSIONS: High tidal volume significantly decreases ventilator days and the incidence of both atelectasis and ARDS compared with low tidal volume in pediatric burned patients with inhalation injury. Therefore, the use of HTV may interrupt sequences leading to lung injury in our patient population. PMID- 25724606 TI - Two thousand consecutive pancreaticoduodenectomies. AB - BACKGROUND: The first successful local resection of a periampullary tumor was performed by Halsted in 1898. Kausch performed the first regional resection in 1909, and the operation was popularized by Whipple in 1935. The operation was infrequently performed until the 1980s and 1990s. STUDY DESIGN: Two thousand consecutive pancreaticoduodenectomies performed by 1 surgeon (JLC) from the 1960s to the 2000s were retrospectively reviewed from a prospectively maintained database. The first 1,000 were performed over a period of 34 years, the second 1,000 over a period of 9 years. RESULTS: The most common indication throughout was adenocarcinoma of the head of the pancreas (PDAC, 46%). Benign intraductal papillary mutinous neoplasm (IPMN) increased from 1% (1990s) to 8% (2000s) (p = 0.002). Age range was 13 years to 103 years. Mean age increased from 59 years (1980s) to 66 (2000s) (p = 0.001), as did those older than 80 (3% to 12%, p = 0.002). Thirty-day mortality was 1.4%; hospital mortality was 1.7%. Delayed gastric emptying (23%), pancreatic fistulas (16%), and wound infections (11%), were the most frequent morbidity, and have not decreased. The median number of blood transfusions decreased from 2 (1980s) to 0 (1990s and 2000s) (p = 0.004). Length of stay decreased from 21 days (1980s) to 13 (1990s) days to 10 days (2000s) (p = 0.002). Five-year survival for PDAC increased from 19% (1990s) to 24% (2000s) (p = 0.02), and 5-year survival for node-negative, margin-negative PDAC patients was 39%. CONCLUSIONS: The volume of pancreatic pathology has attracted 22 basic and clinical scientists to Hopkins, which has $28.5 million of direct support and more than $30 million in endowments, to support research in pancreatic cancer. The volume of clinical material has also supported the training of many young surgeons, 15 of whom have become department chairmen, and more than 20 have become division chiefs. PMID- 25724607 TI - Value of primary operative drain placement after major hepatectomy: a multi institutional analysis of 1,041 patients. AB - BACKGROUND: The value of routine primary (intraoperative) drain placement after major hepatectomy remains unclear. We sought to determine if primary drainage led to decreased rates of complications, specifically, intra-abdominal biloma or infection requiring a secondary (postoperative) drainage procedure. STUDY DESIGN: All patients who underwent major hepatectomy (>=3 hepatic segments) at 3 institutions, from 2000 to 2012, were identified. Patients with biliary anastomoses were excluded. Primary outcomes were any complication, rate of secondary drainage procedures, bile leak, and 30-day readmission. RESULTS: There were 1,041 patients who underwent major hepatectomy without biliary anastomosis; 564 (54%) had primary drains placed at the surgeon's discretion. Primary drain placement was associated with increased complications (56% vs 44%; p < 0.001), bile leaks (7.3% vs 4.2%; p = 0.048), and 30-day readmissions (16.4% vs 8.0%; p < 0.001), but was not associated with a decrease in secondary drainage procedures (8.0% vs 5.9%; p = 0.23). Patients with primary drains demonstrated higher American Society of Anesthesioloigsts (ASA) class, greater blood loss, more transfusions, and larger resections. After accounting for these significant clinicopathologic variables on multivariate analysis, primary drain placement was not associated with increased risk of any complications. Primary drainage was, however, independently associated with increased risk of bile leak (hazard ratio [HR] 2.04; 95% CI1.02 to 4.09; p = 0.044) and 30-day readmission (HR 1.79; 95% CI1.14 to 2.80; p = 0.011). There still was no reduction in the need for secondary drainage procedures (HR 0.98; p = 0.96). CONCLUSIONS: Primary intraoperative drain placement after major hepatectomy does not decrease the need for secondary drainage procedures and may be associated with increased bile leaks and 30-day readmissions. Routine drain placement is not warranted. PMID- 25724608 TI - Concurrent chart review provides more accurate documentation and increased calculated case mix index, severity of illness, and risk of mortality. AB - BACKGROUND: Case mix index (CMI) is calculated to determine the relative value assigned to a Diagnosis-Related Group. Accurate documentation of patient complications and comorbidities and major complications and comorbidities changes CMI and can affect hospital reimbursement and future pay for performance metrics. STUDY DESIGN: Starting in 2010, a physician panel concurrently reviewed the documentation of the trauma/acute care surgeons. Clarifications of the Centers for Medicare and Medicaid Services term-specific documentation were made by the panel, and the surgeon could incorporate or decline the clinical queries. A retrospective review of trauma/acute care inpatients was performed. The mean severity of illness, risk of mortality, and CMI from 2009 were compared with the 3 subsequent years. Mean length of stay and mean Injury Severity Score by year were listed as measures of patient acuity. Statistical analysis was performed using ANOVA and t-test, with p < 0.05 for significance. RESULTS: Each year demonstrated an increase in severity of illness, risk of mortality, and CMI compared with baseline values (p < 0.05). Length of stay was not significantly different, reflecting similar patient populations throughout the study. Injury Severity Score decreased in 2011 and 2012 compared with 2009, reflecting a lower level of injury in the trauma population. CONCLUSIONS: A concurrent documentation review significantly increases severity of illness, risk of mortality, and CMI scores in a trauma/acute care service compared with pre-program levels. These changes reflect more accurate key word documentation rather than a change in patient acuity. The increased scores might impact hospital reimbursement and more accurately stratify outcomes measures for care providers. PMID- 25724609 TI - Has intraoperative cholangiography during laparoscopic cholecystectomy become obsolete in the era of preoperative endoscopic retrograde and magnetic resonance cholangiopancreatography? AB - BACKGROUND: Preoperative ERCP, magnetic resonance cholangiopancreatography (MRCP), and intraoperative cholangiography (IOC) are standard procedures in evaluating patients with suspected choledocholithiasis. This study evaluates the changing practice patterns over time of these 3 procedures in a large cohort of patients undergoing laparoscopic cholecystectomy (LC) at a single tertiary care center. STUDY DESIGN: Data from all patients undergoing an LC with or without preoperative ERCP, MRCP, or an IOC from January 1, 2004 to December 31, 2013 were retrospectively reviewed from billing data obtained by CPT code and analyzed by chi-square testing. RESULTS: During 10 years, 7,427 patients underwent successful LC. The number of patients undergoing successful IOC (11.9% to 7.6%) or preoperative ERCP (7.2% to 1.5%) decreased significantly during that time interval (p < 0.01). In the last 6 years, 4,506 patients underwent successful LC. The number of patients from this group undergoing a preoperative MRCP (0.9% to 8.6%) or MRCP and ERCP (0.4% to 3.6%) increased significantly (p < 0.001). CONCLUSIONS: Despite a shift from IOC and preoperative ERCP to preoperative MRCP alone or with ERCP, a significant percentage (7.6%) of patients still underwent IOC in 2013. Use of IOC during LC has decreased but is not considered obsolete, rather, it remains a valuable tool for the evaluation of bile duct anatomy, bile duct injury, or suspected choledocholithiasis. Intraoperative cholangiography during uncomplicated LC should be emphasized in teaching programs to insure general surgery resident competency with the procedure. PMID- 25724610 TI - Community organizing and community health: piloting an innovative approach to community engagement applied to an early intervention project in south London. AB - BACKGROUND: The importance of community engagement in health is widely recognized, and key themes in UK National Institute for Health and Clinical Excellence (NICE) recommendations for enhancing community engagement are co production and community control. This study reports an innovative approach to community engagement using the community-organizing methodology, applied in an intervention of social support to increase social capital, reduce stress and improve well-being in mothers who were pregnant and/or with infants aged 0-2 years. METHODS: Professional community organizers in Citizens-UK worked with local member civic institutions in south London to facilitate social support to a group of 15 new mothers. Acceptability of the programme, adherence to principles of co-production and community control, and changes in the outcomes of interest were assessed quantitatively in a quasi-experimental design. RESULTS: The programme was found to be feasible and acceptable to participating mothers, and perceived by them to involve co-production and community control. There were no detected changes in subjective well-being, but there were important reductions in distress on a standard self-report measure (GHQ-12). There were increases in social capital of a circumscribed kind associated with the project. CONCLUSIONS: Community organizing provides a promising model and method of facilitating community engagement in health. PMID- 25724611 TI - Public health coming home. PMID- 25724612 TI - Re: World J Urol. 2014 Nov 22. [Epub ahead of print]. HoLEP has come of age. Vincent MW, Gilling PJ. PMID- 25724614 TI - Discussion. PMID- 25724613 TI - Antibodies against malondialdehyde-acetaldehyde adducts can help identify patients with abdominal aortic aneurysm. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is a pathologic dilation of the aorta. Inflammation of the aortic wall has been shown to be involved in AAA formation. Malondialdehyde-acetaldehyde (MAA) adducts are MAA/protein hybrids with immunogenic, proinflammatory, and profibrotic properties. Levels of MAA adducts are elevated in patients with coronary artery disease; however, the role of MAA adducts in AAA is unclear. We hypothesize that levels of circulating antibodies against MAA adducts are increased in patients with AAA. METHODS: Plasma samples were collected from mice and patients with AAA and control patients with atherosclerosis but not AAA. AAA was induced in mice by a standard CaCl2 protocol, with matching sham mice. Plasma levels of anti-MAA antibodies were quantified by enzyme-linked immunosorbent assay. RESULTS: Patients with AAA exhibited higher levels of immunoglobulin G and immunoglobulin A anti-MAA antibody subtypes (P = .049 and .026, respectively) compared with control patients. Conversely, immunoglobulin M anti-MAA antibodies in AAA patients were lower compared with control patients (P = .018). In CaCl2-treated mice, immunoglobulin G anti-MAA antibodies were elevated after AAA formation (P = .006). CONCLUSIONS: The pattern of anti-MAA antibodies is able to distinguish between patients with AAA and patients with atherosclerosis but no AAA. These results demonstrate that MAA adducts are associated with AAA and suggest that they may play a role in either initiating or propagating chronic inflammation in AAA. PMID- 25724615 TI - Evaluation of carotid artery outward remodeling by T1-weighted magnetic resonance imaging in carotid endarterectomy and stenting. AB - OBJECTIVE: We evaluated carotid artery outward remodeling and plaque relative signal intensity (rSI) using T1-weighted magnetic resonance imaging (T1-MRI) to investigate their clinical significance in carotid revascularization. METHODS: From 86 patients undergoing carotid endarterectomy (CEA) or carotid artery stenting (CAS), 88 lesions (51 lesions treated with CEA and 37 lesions treated with CAS) were analyzed retrospectively. We evaluated the preoperative carotid artery remodeling index (CRI), determined by a ratio of the external cross sectional vessel area at maximum stenosis and the reference cross-sectional vessel area at the distal portion of the internal carotid artery, and the plaque rSI, which is quantified as the ratio between the signal intensities of plaque and adjacent muscle using T1-MRI. We divided carotid lesions into four groups using the median values of CRI and rSI: L/L (CRI < 1.8, rSI < 2.5), H/L (CRI >= 1.8, rSI < 2.5), L/H (CRI < 1.8, rSI >= 2.5), and H/H (CRI >= 1.8, rSI >= 2.5). The primary end point was detection of acute ipsilateral ischemia on diffusion weighted imaging (DWI) within 72 hours of treatment. RESULTS: Mean CRI and rSI were significantly higher in lesions treated with CEA than in those treated with CAS. Postoperative DWI abnormalities were observed in 4 CEA cases (7.8%) and 10 CAS cases (27.0%) (P = .01). In the CAS group, the frequency of DWI abnormalities was 5.5% for the L/L, 40.0% for the H/L and L/H, and 55.5% for the H/H group (P = .009). Multivariate analysis showed that the degree of stenosis and H/H lesion were independent risk factors for cerebral embolism. No correlation was found between plaque parameters and postoperative DWI findings in the CEA group. CONCLUSIONS: CRI and rSI provide complementary information for the prediction of high-risk plaques associated with CAS but not with CEA. Preoperative evaluation with T1-MRI facilitates the selection of a treatment strategy for carotid artery stenosis. PMID- 25724616 TI - Upper limb vascular calcification score as a predictor of mortality in diabetic hemodialysis patients. AB - OBJECTIVE: This study evaluated the correlation between an upper limb vascular calcification (Vc) score (VcS) and late all-cause mortality in diabetic hemodialysis patients with distal upper limb arteries medial wall sclerosis (Monckeberg disease). METHODS: We retrospectively reviewed Vc in bilateral upper limb plain radiographs and in duplex ultrasound images performed before radial cephalic fistula (RCF) creation in diabetic hemodialysis patients. Only medial linear calcifications outlining the vessel wall were considered positive on X-ray images, whereas for ultrasound reviews, only continuous highly echogenic plaques producing bright white echos with shadowing were considered to be medial calcification. A VcS was then applied in each patient. Every half of each of the three main arterial conduits (brachial, radial, and ulnar arteries) in each arm was counted as 1 if it contained >= 6 cm of linear calcification, whereas absence of calcification or minimum calcification (length <6 cm) was counted as 0. Long term all-cause mortality was compared between patients with a low or moderate VcS <8 (group I), patients with a high VcS >= 8 (group II), and patients with VcS = 0 (control group). Kaplan-Meier statistics were used for comparisons among the groups. RESULTS: Nineteen patients had a VcS <8, 21 had VcS >= 8, and 43 patients had VcS = 0. The study patients had a mean age of 68 +/- 10 years (range, 42-83 years; P = .23). Before early conversion to a RCF, dialysis therapy in 59 (71.1%) had already been initiated through central venous catheters (CVCs). The mean follow-up for groups I, II, and controls was 41.4 +/- 41.2 months (range, 4-144 months), 34.15 +/- 31.3 months (range, 1-108 months), and 66.7 +/- 32.5 months (range, 12-126 months), respectively (P = .0009). Forty-seven patients died during the follow-up period (12 in group II and 24 in the controls; P = .88). Survival rates at 12, 24, 36, and 48 months were 78.3%, 65.7%, 54.8%, and 48.1% for group I; 75.2%, 58.8%, 49.3%, and 42% for group II; and 97.7%, 93.1%, 76.8%, and 71.8% for the control group, respectively (P = .013 for all groups; P = .044 for group II vs controls). Patients with (subgroups) or without CVCs at baseline had similar late mortality rates. Patients with CVCs/Vc had lower survival rates than those with CVCs/no Vc at 1 year (73.3% vs 96.5%) and at 3 years (47.7% vs 75.8%; P = .038). CVCs were related to increased risk of death only in subgroup II patients compared with the subcontrol group patients (75.4% vs 37.9% at 5 years, respectively; P = .034). CONCLUSIONS: Diabetic hemodialysis patients exposed to high levels of upper extremity arterial medial VcSs upon receiving RCFs have an increased long-term mortality risk compared with diabetic hemodialysis patients with no Vc and receiving the same access. Patients with CVCs/Vc had the lowest survival rates. PMID- 25724617 TI - Lead in soil and agricultural products in the Huainan Coal Mining Area, Anhui, China: levels, distribution, and health implications. AB - Heavy metal accumulation in agricultural soil is of great concern, as heavy metals can be finally transferred to the human body through the food chain. A field survey was conducted to investigate the lead (Pb) levels and distribution in soil, agricultural products (wheat, paddy, and soybean), and fish, in the Huainan Coal Mining Area (HCMA), Anhui Province, China, to provide reference information to local inhabitants. The daily intake and target hazard quotients of Pb through food consumption were assessed. Results showed that the mean Pb concentration in soil was higher than the Huainan soil background Pb value but lower than the maximum allowance Pb concentration for agricultural soil (GB 15618 2008). The elevated Pb in soil, especially in rainy months (June to August in Huainan), might be related to Pb leaching from ambient coal gangue piles. Excessive Pb concentration was found in the grains of food crops, which would pose a potential health risk to local inhabitants. Therein, wheat showed higher Pb bioaccumulation ability than other crops. With regard to the Pb levels in muscles, fishes were considered to be safe for consumption. The calculations on daily intake and tolerable hazard quotient of Pb suggest that the potential health hazard posed by Pb is currently insignificant for the inhabitants in the HCMA. PMID- 25724618 TI - Occurrence of triclosan in the tropical rivers receiving the effluents from the hospital wastewater treatment plant. AB - The objective of this study was to determine the occurrence of triclosan in the tropical rivers where received the effluents from a hospital wastewater treatment plant (HWWTP) in southern Taiwan. Three and ten sampling sites were selected at the Jiaosu River (S0-S2) and Dian-Bao River (S3-S12), respectively. The samples of the HWWTP influent, effluent and receiving river water and sediment were collected and analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/ MS). Results showed that the triclosan level in surface water of the Jiaosu River and Dian-Bao River ranged from 3 to 68 ng/L and ranged from <2.7 to 51 ng/L, respectively. The hospital did contribute a loading of triclosan to the neighboring river. The mean value of triclosan concentration in the downstream surface water of the Jiaosu River (S1 20.2 ng/L) was approximately three times higher than that of the background level (S0 6.0 ng/L) (p = 0.011). The concentrations of triclosan in two surface water samples were over the predicted no effect concentration (PNEC) of 50 ng/L for algae. In addition, significant seasonal differences of triclosan in surface water of Jiaosu River (p = 0.020) and the HWWTP effluents (p = 0.302) were also observed. The concentrations of triclosan in sediments of these two rivers seemed stable. On average, triclosan was detected in 86 % of the sediment samples with a range from <1.1 to 13 ng/g. Triclosan in surface water and sediments of the tropical rivers might be rapidly photolyzed due to plenty of sunshine. It is worth to further investigate the occurrence and fate of triclosan photoproduct in the aquatic environment of the tropics. PMID- 25724619 TI - [The method of selection of the residents in Spain. Analysis of the examination MIR and offer of a new methodology]. AB - INTRODUCTION: The method for selecting medical graduates for residency positions has a strong influence on teaching and learning strategies in medical schools. The methodology currently used in Spain does not seem appropriate for ranking the candidates or improving curriculum development. Thus, and taking into account the most consistent methodologies used in the United Kingdom and USA, we have designed a new method to be used in our country. OBJECTIVES: To analyze the limitations of the methodology used in Spain, and propose a new one aimed to improve the accuracy of selection itself and avoiding the negative influence of the current method on curricular development. In addition, we emphasize the necessity of improving teaching and learning in the clinical context to assure that graduating students reach an adequate level of clinical competence. CONCLUSIONS: The method for selecting candidates to residency post currently used in Spain, which relies mainly on testing theoretical knowledge, should be changed for an alternative methodology taking into account student,s performance through the course and assessing his/her ability for clinical contextualization of knowledge and level of clinical competence. PMID- 25724620 TI - [Choroid plexus tumour treatment at Hospital Infantil Nino Jesus in Madrid: Our experience over the last three decades]. AB - OBJECTIVE: To review childhood patients with choroid plexus tumors (CPT) who underwent surgery at Hospital Infantil Nino Jesus of Madrid since January 1981 to September 2014. MATERIAL AND METHODS: Registered charts were analyzed based on the epidemiology, tumor grade, clinical profile, location, dissemination characteristics, therapy, prognosis and complications. RESULTS: Seventeen childhood patients were recorded with CPT. Cases were distributed so that 9 cases were choroid plexus-papilloma (CPP) (52.9%), 2 cases atypical CPP (11.7%) and 6 cases choroid plexus-carcinoma (CPC) (35.2%). Age at diagnosis was less than 2 years in 14 of the 17 patients (82.3%) and the incidence was higher in males (82.3% of the cases). Gross total resection was performed in 16 patients (94.1%). Adjuvant treatment was used in 6 patients (all this cases with CPC) (35.2%). Two of the 17 patients died (11.7%), showing an incidence density of 0.01 deaths/year. CONCLUSIONS: Our case series is consistent with previous published in scientific literature regarding epidemiology, tumor grade, clinical presentation, radiological features and therapeutic approach. Gross total resection is considered the therapeutic gold standard for choroid plexus tumors. Chemotherapy and radiotherapy should be used as adjuvant treatment in CPC and recurrent or remaining atypical CPP. PMID- 25724621 TI - Can a Clinical Prediction Rule Reliably Predict Pediatric Bacterial Meningitis? PMID- 25724622 TI - Do Glycoprotein IIb/IIIa Inhibitors Improve Outcomes in Acute Ischemic Stroke? PMID- 25724623 TI - "Just a few seconds of your time..." at least 130 million times a year. PMID- 25724624 TI - Can Children With Uncomplicated Acute Appendicitis Be Treated With Antibiotics Instead of an Appendectomy? PMID- 25724625 TI - Kindlin-2 induced by TGF-beta signaling promotes pancreatic ductal adenocarcinoma progression through downregulation of transcriptional factor HOXB9. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths with no effective therapeutics. Invasion and metastasis are the major characteristics of PDAC. However, mechanisms underlying PDAC invasion and metastasis are elusive. In this report, we found that Kindlin-2 is a target protein of transforming growth factor beta (TGF-beta) signaling and is upregulated by TGF-beta1 in PDAC cells. TGF-beta1-upregulated Kindlin-2 promotes PDAC cell growth, migration and invasion, whereas Kindlin-2 upregulates transforming growth factor receptor I (TbetaRI), a key component of TGF-beta signaling. Thereby Kindlin-2 and TGF-beta signaling constitute a positive feedback loop. Mechanistically, Kindlin-2 promotes PDAC progression by downregulation of HOXB9 and E-cadherin. For clinical relevance, enhanced expression of Kindlin-2 predicts a poor overall survival for PDAC patients. Gene expression levels of Kindlin-2, TGF-beta, TbetaRI and HOXB9 are all correlated with the overall survival of PDAC patients in an Oncomine dataset. Taken together, our findings demonstrated that TGF-beta1-induced Kindlin-2 expression promotes PDAC progression by downregulation of HOXB9 and E-cadherin. PMID- 25724626 TI - Ethnicity differences in breast cancer stage at the time of diagnosis in Norway. AB - BACKGROUND AND AIMS: Several studies have demonstrated that breast cancer survival rates differ with ethnicity. Most of these studies analyzed discrepancies between African-American and Caucasian-American women and were performed in the United States. There are increasing concerns about differences in breast cancer survival among immigrants from Asia and Africa living in Europe, including those living in Scandinavian countries. There are few data on breast cancer survival in relation to race or ethnicity in Scandinavian countries, even though immigrants from Asia and Africa have lived in Scandinavian countries for decades. The aim of this study was to identify variations in breast cancer incidence, treatment modalities, relapse, and survival among women from Pakistan, Sri Lanka, and Somalia compared to ethnic Norwegian women. MATERIAL AND METHODS: The incidence, treatment modalities, relapse, and survival of breast cancer were analyzed in women from Pakistan, Sri Lanka, and Somalia in a nation-based study over a period of 7 ears. Results for women from Pakistan, Sri Lanka, and Somalia were compared with those from a group of ethnic Norwegian women during the same period. In our study, 63 patients from Pakistan, Sri Lanka, and Somalia were diagnosed with breast cancer during the period 2002-2009 in Norway. RESULTS AND CONCLUSION: Comparison between women from Pakistan, Sri Lanka, and Somalia and ethnic women from Norway revealed significant differences in cancer stage at the time of diagnosis, age at diagnosis, type of surgical treatment, and relapse and breast cancer mortality rates. The findings of this study demonstrate that the outcome after a breast cancer diagnosis is significantly worse for women from Pakistan, Sri Lanka, and Somalia than for ethnic Norwegian women. In addition, the mean age at the breast cancer diagnosis was lower for women from Pakistan, Sri Lanka, and Somalia, especially those from Sri Lanka and Somalia, than for ethnic Norwegian women. PMID- 25724627 TI - Molecular cloning and characterization of Mj-mov-10, a putative RNA helicase involved in RNAi of kuruma shrimp. AB - Identification and characterization of the RNAi-related genes is the key to understanding RNAi mechanism in shrimp. In this study, we have identified and characterized a novel putative RNA helicase gene, Mj-mov-10 from the kuruma shrimp, Marsupenaeus japonicus and its implication in shrimp RNAi was demonstrated. The full-length Mj-mov-10 gene contained 3536bp, including 239 bp of 5'UTR, 2895 bp of the open reading frame (ORF) and 402bp of 3'UTR, respectively. An ORF of Mj-mov-10 could be translated to a 109-kDa protein which consists of a single helicase core domain containing seven signature motifs of the RNA helicase superfamily-1. Mj-MOV-10 protein shared 47% and 40% identity with mammalian MOV-10 and plant SDE3, respectively. Expression of Mj-mov-10 gene was significantly up-regulated upon dsRNA and white spot syndrome virus (WSSV) challenge. In vivo gene knockdown of Mj-mov-10 resulted in an increase of a susceptibility of shrimp to WSSV infection. Our results implied the functional significance of Mj-MOV-10 in dsRNA-mediated gene silencing and antiviral defense mechanism in shrimp. PMID- 25724628 TI - Synergistic effects of fosfomycin and carbapenems against carbapenem-resistant Pseudomonas aeruginosa clinical isolates. PMID- 25724629 TI - The impact of ventilation tubes in otitis media on the risk of cholesteatoma on a national level. AB - OBJECTIVE: To estimate the impact of treatment with middle ear ventilation tube insertion (VTI) in children with otitis media (OM) on the risk of cholesteatoma on a national level. METHODS: Data were obtained from the Danish National Patient Register, the National Health Service Register and Statistics Denmark. Cumulative incidence proportions were estimated by the Kaplan-Meier method and hazard ratios with Cox regression analysis. The first surgically treated middle ear cholesteatoma in a child (STMEC1) was considered an event. RESULTS: A total of 217,206 children, born after December 31, 1996, who had VTI from January 1, 1997 to August 31, 2011 were identified. Of these, 374 subsequently had a STMEC1. A corresponding 36,981 children without any VTI were identified for comparison using a random 5% sample of the Danish population. Of these, 5 had a STMEC1. The cumulative incidence proportion with STMEC1 at 12 years of age for children with 0, 1, 2, 3, and >=4 VTI's was 0.04% (95% confidence interval 0.02-0.12%), 0.21% (0.18-0.26%), 0.35% (0.28-0.43%), 0.40% (0.30-0.54%), and 0.55% (0.44-0.70%), respectively. In the regression model each additional year of age before the first VTI increased the risk of STMEC1 by 54% (47-63%), while each additional year between two successive tube insertions increased the risk by 28% (15-43%). CONCLUSION: We found that prolonged OM requiring multiple VTIs was associated with an increased risk of STMEC1. Early age at first VTI and short time between two VTIs was associated with a lower risk of STMEC1. This may be the result of reduced time with negative middle ear pressure and OM. However, these findings may be susceptible to selection bias, as age at first VTI and time between VTIs, as well as the outcome variable, STMEC1, may all depend on the underlying indication for VTI. In short the present study suggests that treatment with VTI in children with OM reduces the risk of STMEC1 on a population level. However, for the individual child the absolute risk reduction is very small, and the decision of treatment with VTI must always rely on the symptoms and clinical findings in the individual child. PMID- 25724630 TI - Adequate formal language performance in unilateral cochlear implanted children: is it indicative of complete recovery in all linguistic domains? Insights from referential communication. AB - OBJECTIVES: Referential communication (RC) is a key element in achieving a successful communication. This case series aimed to evaluate RC in children with unilateral cochlear implants (CIs) with formal language skills within the normal range. METHODS AND MATERIALS: A total of 31 children with CIs, with language development within the normal range, were assessed using the Pragmatic Language Skills test (MEDEA). RESULTS: Of the children with CIs, 83.9% reached performance levels appropriate for their chronological ages. The results confirmed a positive effect of cochlear implantation on RC development, although difficulties remained in some CI users. CONCLUSIONS: The outcomes emphasize the need to pay greater attention to the pragmatic aspects of language, assessing them with adequate testing in the early phase after cochlear implantation. Clear knowledge of children's communicative competence is the key in optimizing their communicative environments in order to create the basis for future successful interpersonal exchanges and social integration. PMID- 25724631 TI - Government-funded universal newborn hearing screening and genetic analyses of deafness predisposing genes in Taiwan. AB - OBJECTIVE: To investigate the association of eight connexin genes (GJB2, GJB4, GJA1P1, GJB6, GJB3, GJA1, GJB1, and GJC3) and the SLC26A4 gene with congenital hearing impairment among infants in a universal newborn hearing screening program. METHOD: From September 2009 to October 2013, the consecutive neonates born in all six branches of Taipei City Hospital were enrolled. Infants who failed the newborn hearing screening and were diagnosed with hearing impairment underwent the genetic analyses. RESULT: 15,404 neonates were born at Taipei City Hospital, and 15,345 neonates underwent newborn hearing screening. Among them, 32 infants were diagnosed with unilateral or bilateral hearing impairment. 26 of them underwent analyses of the connexin genes and the SLC26A4 gene. Of the connexin genes, two infants carried a GJB3 mutation (heterozygous c.580G>A and heterozygous c.520G>A, respectively). Only one infant carried a GJB2 mutation (homozygous c.235delC). One infant carried a GJA1P1 mutation (heterozygous c.929delC) and another carried a GJB4 mutation (heterozygous c.302G>A). Additionally, one infant carried a GJA1P1 novel variant (heterozygous c.1081C>T). Another infant carried a GJA1 novel variant (heterozygous c.1-33C>G). Of the SLC26A4 gene, one infant carried heterozygous c.919-2A>G mutation and a novel variant (heterozygous c.164+1G>C), and high-resolution computed tomography (HRCT) of the temporal bone revealed bilateral enlarged vestibular aqueducts. One infant carried heterozygous c.919-2A>G mutation and no inner ear anomalies were demonstrated by HRCT of the temporal bone. Another infant carried a novel variant (heterozygous c.818C>T). CONCLUSION: These results provide a genetic profile of the connexin genes and SLC26A4 gene among infants with hearing impairment detected by a universal newborn hearing screening program in Taiwan. Further studies and long-term follow up of this cohort are warranted to determine the pathogenicity of each variants and the long-term hearing consequence. PMID- 25724632 TI - Acute and subchronic (28 days) oral toxicity studies of Codonopsis lanceolata extract in Sprague-Dawley rats. AB - Codonopsis lanceolata is a perennial plant that has been used as a food and in traditional medicine for the treatment of cough, bronchitis, and inflammation in East Asia including Korea, Japan, and China. However, information regarding its toxicity is limited. Therefore, we performed a safety evaluation of aqueous C. lanceolata root extract (CLE) in Sprague-Dawley rats. Assessment of acute toxicity revealed that CLE did not influence mortality, clinical appearance, body weight gain, or necropsy findings at a dose of 5000 mg/kg body weight. In the subchronic oral toxicity, data revealed that several significant alteration in food consumption, water consumption, protein excretion, WBCs levels, TGs, BUN levels, and the absolute and relative weights in the liver, spleen and lungs. However, these changes were transient and were not considered treatment related because they showed no apparent dose dependent. These results suggest that CLE (1250, 2500, and 5000 mg/kg body weight/day) administered orally does not cause acute or subchronic toxicity to male or female rats. The 50% lethal dose (LD50) of CLE was determined to be greater than 5000 mg/kg. PMID- 25724633 TI - Survey on the state of otoneurology in Spain. AB - Otoneurology is a subspecialty of otolaryngology-neurology, which has experienced extraordinary progress in the last 50 years and is currently fully consolidated in our environment. Through this study, prepared by the Otoneurology Commission of the Spanish Society of Otorhinolaryngology (SEORL), we have attempted to design an approach to provide information on what the current situation regarding the exercise in Spain is, trying to determine who practice it and where, what resources are available and what the teaching and scientific productions are. The results obtained are generally satisfactory and reflect the strength of the exercise of otoneurology. The number of centres with otoneurology units is significant and the majority of centres that lack such a unity consider it necessary. However, there are aspects to establish related to minimum requirements for its performance in satisfactory conditions, as well as determining future guidelines to ensure improved teaching and increased scientific production. PMID- 25724634 TI - Baseline Attitudes About Prostate Cancer Screening Moderate the Impact of Decision Aids on Screening Rates. AB - BACKGROUND: The impact of decision aids on prostate cancer screening outcomes has been inconsistent. PURPOSE: We assessed whether pre-existing attitudes moderated the impact of decision aids on screening. METHODS: Men aged 45-70 (56.2% Caucasian, 39.9% African-American) were randomly assigned to a print decision aid (N = 630), a web decision aid (N = 631), or usual care (N = 632). Telephone interviews assessed pro/con screening attitudes and screening behaviors at baseline, 1-month and 13-months post-randomization. RESULTS: Logistic regression analyses revealed significant arm by attitude interactions: Higher baseline cons scores predicted lower screening in the print (OR = 0.60 (95% CI: 0.40, 0.92)) and web (OR = 0.61 (95% CI: 0.40, 0.91)) arms but not in usual care (OR = 1.34 (95% CI: 0.90, 2.00)). CONCLUSIONS: The decision aids amplified the impact of men's baseline attitudes about limitations of screening: Compared to the usual care arm, men in both decision aid arms were less likely to be screened when they perceived more limitations of screening. PMID- 25724635 TI - Real-Time Associations Between Engaging in Leisure and Daily Health and Well Being. AB - BACKGROUND: Engagement in leisure has a wide range of beneficial health effects. Yet, this evidence is derived from between-person methods that do not examine the momentary within-person processes theorized to explain leisure's benefits. PURPOSE: This study examined momentary relationships between leisure and health and well-being in daily life. METHODS: A community sample (n = 115) completed ecological momentary assessments six times a day for three consecutive days. At each measurement, participants indicated if they were engaging in leisure and reported on their mood, interest/boredom, and stress levels. Next, participants collected a saliva sample for cortisol analyses. Heart rate was assessed throughout the study. RESULTS: Multilevel models revealed that participants had more positive and less negative mood, more interest, less stress, and lower heart rate when engaging in leisure than when not. CONCLUSIONS: Results suggest multiple mechanisms explaining leisure's effectiveness, which can inform leisure based interventions to improve health and well-being. PMID- 25724636 TI - Arabidopsis chloroplast mini-ribonuclease III participates in rRNA maturation and intron recycling. AB - RNase III proteins recognize double-stranded RNA structures and catalyze endoribonucleolytic cleavages that often regulate gene expression. Here, we characterize the functions of RNC3 and RNC4, two Arabidopsis thaliana chloroplast Mini-RNase III-like enzymes sharing 75% amino acid sequence identity. Whereas rnc3 and rnc4 null mutants have no visible phenotype, rnc3/rnc4 (rnc3/4) double mutants are slightly smaller and chlorotic compared with the wild type. In Bacillus subtilis, the RNase Mini-III is integral to 23S rRNA maturation. In Arabidopsis, we observed imprecise maturation of 23S rRNA in the rnc3/4 double mutant, suggesting that exoribonucleases generated staggered ends in the absence of specific Mini-III-catalyzed cleavages. A similar phenotype was found at the 3' end of the 16S rRNA, and the primary 4.5S rRNA transcript contained 3' extensions, suggesting that Mini-III catalyzes several processing events of the polycistronic rRNA precursor. The rnc3/4 mutant showed overaccumulation of a noncoding RNA complementary to the 4.5S-5S rRNA intergenic region, and its presence correlated with that of the extended 4.5S rRNA precursor. Finally, we found rnc3/4-specific intron degradation intermediates that are probable substrates for Mini-III and show that B. subtilis Mini-III is also involved in intron regulation. Overall, this study extends our knowledge of the key role of Mini-III in intron and noncoding RNA regulation and provides important insight into plastid rRNA maturation. PMID- 25724637 TI - Activation of symbiosis signaling by arbuscular mycorrhizal fungi in legumes and rice. AB - Establishment of arbuscular mycorrhizal interactions involves plant recognition of diffusible signals from the fungus, including lipochitooligosaccharides (LCOs) and chitooligosaccharides (COs). Nitrogen-fixing rhizobial bacteria that associate with leguminous plants also signal to their hosts via LCOs, the so called Nod factors. Here, we have assessed the induction of symbiotic signaling by the arbuscular mycorrhizal (Myc) fungal-produced LCOs and COs in legumes and rice (Oryza sativa). We show that Myc-LCOs and tetra-acetyl chitotetraose (CO4) activate the common symbiosis signaling pathway, with resultant calcium oscillations in root epidermal cells of Medicago truncatula and Lotus japonicus. The nature of the calcium oscillations is similar for LCOs produced by rhizobial bacteria and by mycorrhizal fungi; however, Myc-LCOs activate distinct gene expression. Calcium oscillations were activated in rice atrichoblasts by CO4, but not the Myc-LCOs, whereas a mix of CO4 and Myc-LCOs activated calcium oscillations in rice trichoblasts. In contrast, stimulation of lateral root emergence occurred following treatment with Myc-LCOs, but not CO4, in M. truncatula, whereas both Myc-LCOs and CO4 were active in rice. Our work indicates that legumes and non-legumes differ in their perception of Myc-LCO and CO signals, suggesting that different plant species respond to different components in the mix of signals produced by arbuscular mycorrhizal fungi. PMID- 25724638 TI - In planta variation of volatile biosynthesis: an alternative biosynthetic route to the formation of the pathogen-induced volatile homoterpene DMNT via triterpene degradation in Arabidopsis roots. AB - Plant-derived volatile compounds such as terpenes exhibit substantial structural variation and serve multiple ecological functions. Despite their structural diversity, volatile terpenes are generally produced from a small number of core 5 to 20-carbon intermediates. Here, we present unexpected plasticity in volatile terpene biosynthesis by showing that irregular homo/norterpenes can arise from different biosynthetic routes in a tissue specific manner. While Arabidopsis thaliana and other angiosperms are known to produce the homoterpene (E)-4,8 dimethyl-1,3,7-nonatriene (DMNT) or its C16-analog (E,E)-4,8,12-trimethyl 1,3,7,11-tridecatetraene by the breakdown of sesquiterpene and diterpene tertiary alcohols in aboveground tissues, we demonstrate that Arabidopsis roots biosynthesize DMNT by the degradation of the C30 triterpene diol, arabidiol. The reaction is catalyzed by the Brassicaceae-specific cytochrome P450 monooxygenase CYP705A1 and is transiently induced in a jasmonate-dependent manner by infection with the root-rot pathogen Pythium irregulare. CYP705A1 clusters with the arabidiol synthase gene ABDS, and both genes are coexpressed constitutively in the root stele and meristematic tissue. We further provide in vitro and in vivo evidence for the role of the DMNT biosynthetic pathway in resistance against P. irregulare. Our results show biosynthetic plasticity in DMNT biosynthesis in land plants via the assembly of triterpene gene clusters and present biochemical and genetic evidence for volatile compound formation via triterpene degradation in plants. PMID- 25724639 TI - An upstream open reading frame is essential for feedback regulation of ascorbate biosynthesis in Arabidopsis. AB - Ascorbate (vitamin C) is an essential antioxidant and enzyme cofactor in both plants and animals. Ascorbate concentration is tightly regulated in plants, partly to respond to stress. Here, we demonstrate that ascorbate concentrations are determined via the posttranscriptional repression of GDP-l-galactose phosphorylase (GGP), a major control enzyme in the ascorbate biosynthesis pathway. This regulation requires a cis-acting upstream open reading frame (uORF) that represses the translation of the downstream GGP open reading frame under high ascorbate concentration. Disruption of this uORF stops the ascorbate feedback regulation of translation and results in increased ascorbate concentrations in leaves. The uORF is predicted to initiate at a noncanonical codon (ACG rather than AUG) and encode a 60- to 65-residue peptide. Analysis of ribosome protection data from Arabidopsis thaliana showed colocation of high levels of ribosomes with both the uORF and the main coding sequence of GGP. Together, our data indicate that the noncanonical uORF is translated and encodes a peptide that functions in the ascorbate inhibition of translation. This posttranslational regulation of ascorbate is likely an ancient mechanism of control as the uORF is conserved in GGP genes from mosses to angiosperms. PMID- 25724642 TI - Gaming the system: how hungry nematodes get plants to produce feeding sites for them. PMID- 25724641 TI - The rice CK2 kinase regulates trafficking of phosphate transporters in response to phosphate levels. AB - Phosphate transporters (PTs) mediate phosphorus uptake and are regulated at the transcriptional and posttranslational levels. In one key mechanism of posttranslational regulation, phosphorylation of PTs affects their trafficking from the endoplasmic reticulum (ER) to the plasma membrane. However, the kinase(s) mediating PT phosphorylation and the mechanism leading to ER retention of phosphorylated PTs remain unclear. In this study, we identified a rice (Oryza sativa) kinase subunit, CK2beta3, which interacts with PT2 and PT8 in a yeast two hybrid screen. Also, the CK2alpha3/beta3 holoenzyme phosphorylates PT8 under phosphate-sufficient conditions. This phosphorylation inhibited the interaction of PT8 with PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR1, a key cofactor regulating the exit of PTs from the ER to the plasma membrane. Additionally, phosphorus starvation promoted CK2beta3 degradation, relieving the negative regulation of PT phosphorus-insufficient conditions. In accordance, transgenic expression of a nonphosphorylatable version of OsPT8 resulted in elevated levels of that protein at the plasma membrane and enhanced phosphorus accumulation and plant growth under various phosphorus regimes. Taken together, these results indicate that CK2alpha3/beta3 negatively regulates PTs and phosphorus status regulates CK2alpha3/beta3. PMID- 25724643 TI - Clarifying the opaque: identification of direct targets of maize opaque2. PMID- 25724644 TI - Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects. AB - PURPOSE: The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. METHODS: Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg * 3 days followed by 40 mg * 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at -2, -1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. RESULTS: The geometric mean ratio and 90% confidence interval of Cmax and AUC of acetaminophen were within 80-125% suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. CONCLUSION: In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by ~1.25 h without affecting Cmax or AUC. PMID- 25724645 TI - Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. AB - PURPOSE: Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine. METHODS: In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics. RESULTS: A three-compartment model for both S ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8% (11% interindividual variability), and its clearance was high, 95 L/h/70 kg (13% interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine. CONCLUSIONS: Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain. PMID- 25724640 TI - Coordinated rates of evolution between interacting plastid and nuclear genes in Geraniaceae. AB - Although gene coevolution has been widely observed within individuals and between different organisms, rarely has this phenomenon been investigated within a phylogenetic framework. The Geraniaceae is an attractive system in which to study plastid-nuclear genome coevolution due to the highly elevated evolutionary rates in plastid genomes. In plants, the plastid-encoded RNA polymerase (PEP) is a protein complex composed of subunits encoded by both plastid (rpoA, rpoB, rpoC1, and rpoC2) and nuclear genes (sig1-6). We used transcriptome and genomic data for 27 species of Geraniales in a systematic evaluation of coevolution between genes encoding subunits of the PEP holoenzyme. We detected strong correlations of dN (nonsynonymous substitutions) but not dS (synonymous substitutions) within rpoB/sig1 and rpoC2/sig2, but not for other plastid/nuclear gene pairs, and identified the correlation of dN/dS ratio between rpoB/C1/C2 and sig1/5/6, rpoC1/C2 and sig2, and rpoB/C2 and sig3 genes. Correlated rates between interacting plastid and nuclear sequences across the Geraniales could result from plastid-nuclear genome coevolution. Analyses of coevolved amino acid positions suggest that structurally mediated coevolution is not the major driver of plastid nuclear coevolution. The detection of strong correlation of evolutionary rates between SIG and RNAP genes suggests a plausible explanation for plastome-genome incompatibility in Geraniaceae. PMID- 25724646 TI - Zebrafish foxc1a plays a crucial role in early somitogenesis by restricting the expression of aldh1a2 directly. AB - Foxc1a is a member of the forkhead transcription factors. It plays an essential role in zebrafish somitogenesis. However, little is known about the molecular mechanisms underlying its controlling somitogenesis. To uncover how foxc1a regulates zebrafish somitogenesis, we generated foxc1a knock-out zebrafish using TALEN (transcription activator-like effector nuclease) technology. The foxc1a null embryos exhibited defective somites at early development. Analyses on the expressions of the key genes that control processes of somitogenesis revealed that foxc1a controlled early somitogenesis by regulating the expression of myod1. In the somites of foxc1a knock-out embryos, expressions of fgf8a and deltaC were abolished, whereas the expression of aldh1a2 (responsible for providing retinoic acid signaling) was significantly increased. Once the increased retinoic acid level in the foxc1a null embryos was reduced by knocking down aldh1a2, the reduced expression of myod1 was partially rescued by resuming expressions of fgf8a and deltaC in the somites of the mutant embryos. Moreover, a chromatin immunoprecipitation assay on zebrafish embryos revealed that Foxc1a bound aldh1a2 promoter directly. On the other hand, neither knocking down fgf8a nor inhibiting Notch signaling affected the expression of aldh1a2, although knocking down fgf8a reduced expression of deltaC in the somites of zebrafish embryos at early somitogenesis and vice versa. Taken together, our results demonstrate that foxc1a plays an essential role in early somitogenesis by controlling Fgf and Notch signaling through restricting the expression of aldh1a2 in paraxial mesoderm directly. PMID- 25724647 TI - delta-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions. AB - The ability of neurons to maintain spine architecture and modulate it in response to synaptic activity is a crucial component of the cellular machinery that underlies information storage in pyramidal neurons of the hippocampus. Here we show a critical role for delta-catenin, a component of the cadherin-catenin cell adhesion complex, in regulating spine head width and length in pyramidal neurons of the hippocampus. The loss of Ctnnd2, the gene encoding delta-catenin, has been associated with the intellectual disability observed in the cri du chat syndrome, suggesting that the functional roles of delta-catenin are vital for neuronal integrity and higher order functions. We demonstrate that loss of delta-catenin in a mouse model or knockdown of delta-catenin in pyramidal neurons compromises spine head width and length, without altering spine dynamics. This is accompanied by a reduction in the levels of synaptic N-cadherin. The ability of delta-catenin to modulate spine architecture is critically dependent on its ability to interact with cadherin and PDZ domain-containing proteins. We propose that loss of delta catenin during development perturbs synaptic architecture leading to developmental aberrations in neural circuit formation that contribute to the learning disabilities in a mouse model and humans with cri du chat syndrome. PMID- 25724648 TI - Specific amyloid beta clearance by a catalytic antibody construct. AB - Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid beta (Abeta)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Abeta C terminus noncovalently and hydrolyzed Abeta rapidly, with no reactivity to the Abeta precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Abeta dipeptide unit. The catabody dissolved preformed Abeta aggregates and inhibited Abeta aggregation more potently than an Abeta-binding IgG. Intravenous catabody treatment reduced brain Abeta deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Abeta hydrolysis appears to be an innate immune function that could be applied for therapeutic Abeta removal. PMID- 25724649 TI - Sul1 and Sul2 sulfate transceptors signal to protein kinase A upon exit of sulfur starvation. AB - Sulfate is an essential nutrient with pronounced regulatory effects on cellular metabolism and proliferation. Little is known, however, about how sulfate is sensed by cells. Sul1 and Sul2 are sulfate transporters in the yeast Saccharomyces cerevisiae, strongly induced upon sulfur starvation and endocytosed upon the addition of sulfate. We reveal Sul1,2-dependent activation of PKA targets upon sulfate-induced exit from growth arrest after sulfur starvation. We provide two major arguments in favor of Sul1 and Sul2 acting as transceptors for signaling to PKA. First, the sulfate analogue, d-glucosamine 2-sulfate, acted as a non-transported agonist of signaling by Sul1 and Sul2. Second, mutagenesis to Gln of putative H(+)-binding residues, Glu-427 in Sul1 or Glu-443 in Sul2, abolished transport without affecting signaling. Hence, Sul1,2 can function as pure sulfate sensors. Sul1(E427Q) and Sul2(E443Q) are also deficient in sulfate induced endocytosis, which can therefore be uncoupled from signaling. Overall, our data suggest that transceptors can undergo independent conformational changes, each responsible for triggering different downstream processes. The Sul1 and Sul2 transceptors are the first identified plasma membrane sensors for extracellular sulfate. High affinity transporters induced upon starvation for their substrate may generally act as transceptors during exit from starvation. PMID- 25724650 TI - From Protease to Decarboxylase: THE MOLECULAR METAMORPHOSIS OF PHOSPHATIDYLSERINE DECARBOXYLASE. AB - Phosphatidylserine decarboxylase (PSDs) play a central role in the synthesis of phosphatidylethanolamine in numerous species of prokaryotes and eukaryotes. PSDs are unusual decarboxylase containing a pyruvoyl prosthetic group within the active site. The covalently attached pyruvoyl moiety is formed in a concerted reaction when the PSD proenzyme undergoes an endoproteolytic cleavage into a large beta-subunit, and a smaller alpha-subunit, which harbors the prosthetic group at its N terminus. The mechanism of PSD proenzyme cleavage has long been unclear. Using a coupled in vitro transcription/translation system with the soluble Plasmodium knowlesi enzyme (PkPSD), we demonstrate that the post translational processing is inhibited by the serine protease inhibitor, phenylmethylsulfonyl fluoride. Comparison of PSD sequences across multiple phyla reveals a uniquely conserved aspartic acid within an FFXRX6RX12PXD motif, two uniquely conserved histidine residues within a PXXYHXXHXP motif, and a uniquely conserved serine residue within a GS(S/T) motif, suggesting that PSDs belong to the D-H-S serine protease family. The function of the conserved D-H-S residues was probed using site-directed mutagenesis of PkPSD. The results from these mutagenesis experiments reveal that Asp-139, His-198, and Ser-308 are all essential for endoproteolytic processing of PkPSD, which occurs in cis. In addition, within the GS(S/T) motif found in all PSDs, the Gly-307 residue is also essential, but the Ser/Thr-309 is non-essential. These results define the mechanism whereby PSDs begin their biochemical existence as proteases that execute one autoendoproteolytic cleavage reaction to give rise to a mature PSD harboring a pyruvoyl prosthetic group. PMID- 25724651 TI - The N terminus of pro-endothelial monocyte-activating polypeptide II (EMAP II) regulates its binding with the C terminus, arginyl-tRNA synthetase, and neurofilament light protein. AB - Pro-endothelial monocyte-activating polypeptide II (EMAP II), one component of the multi-aminoacyl tRNA synthetase complex, plays multiple roles in physiological and pathological processes of protein translation, signal transduction, immunity, lung development, and tumor growth. Recent studies have determined that pro-EMAP II has an essential role in maintaining axon integrity in central and peripheral neural systems where deletion of the C terminus of pro EMAP II has been reported in a consanguineous Israeli Bedouin kindred suffering from Pelizaeus-Merzbacher-like disease. We hypothesized that the N terminus of pro-EMAP II has an important role in the regulation of protein-protein interactions. Using a GFP reporter system, we defined a putative leucine zipper in the N terminus of human pro-EMAP II protein (amino acid residues 1-70) that can form specific strip-like punctate structures. Through GFP punctum analysis, we uncovered that the pro-EMAP II C terminus (amino acids 147-312) can repress GFP punctum formation. Pulldown assays confirmed that the binding between the pro EMAP II N terminus and its C terminus is mediated by a putative leucine zipper. Furthermore, the pro-EMAP II 1-70 amino acid region was identified as the binding partner of arginyl-tRNA synthetase, a polypeptide of the multi-aminoacyl tRNA synthetase complex. We also determined that the punctate GFP pro-EMAP II 1-70 amino acid aggregate colocalizes and binds to the neurofilament light subunit protein that is associated with pathologic neurofilament network disorganization and degeneration of motor neurons. These findings indicate the structure and binding interaction of pro-EMAP II protein and suggest a role of this protein in pathological neurodegenerative diseases. PMID- 25724652 TI - Identification of a novel HIV-1 inhibitor targeting Vif-dependent degradation of human APOBEC3G protein. AB - APOBEC3G (A3G) is a cellular cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA and by deamination-independent mechanisms. HIV-1 Vif binds to A3G, resulting in its degradation via the 26 S proteasome. Therefore, this interaction represents a potential therapeutic target. To identify compounds that inhibit interaction between A3G and HIV-1 Vif in a high throughput format, we developed a homogeneous time-resolved fluorescence resonance energy transfer assay. A 307,520 compound library from the NIH Molecular Libraries Small Molecule Repository was screened. Secondary screens to evaluate dose-response performance and off-target effects, cell-based assays to identify compounds that attenuate Vif-dependent degradation of A3G, and assays testing antiviral activity in peripheral blood mononuclear cells and T cells were employed. One compound, N.41, showed potent antiviral activity in A3G(+) but not in A3G(-) T cells and had an IC50 as low as 8.4 MUM and a TC50 of >100 MUM when tested against HIV-1Ba-L replication in peripheral blood mononuclear cells. N.41 inhibited the Vif-A3G interaction and increased cellular A3G levels and incorporation of A3G into virions, thereby attenuating virus infectivity in a Vif dependent manner. N.41 activity was also species- and Vif-dependent. Preliminary structure-activity relationship studies suggest that a hydroxyl moiety located at a phenylamino group is critical for N.41 anti-HIV activity and identified N.41 analogs with better potency (IC50 as low as 4.2 MUM). These findings identify a new lead compound that attenuates HIV replication by liberating A3G from Vif regulation and increasing its innate antiviral activity. PMID- 25724653 TI - Ancestral AlaX editing enzymes for control of genetic code fidelity are not tRNA specific. AB - Accurate protein synthesis requires the hydrolytic editing of tRNAs incorrectly aminoacylated by aminoacyl-tRNA synthetases (ARSs). Recognition of cognate tRNAs by ARS is less error-prone than amino acid recognition, and, consequently, editing domains are generally believed to act only on the tRNAs cognate to their related ARSs. For example, the AlaX family of editing domains, including the editing domain of alanyl-tRNA synthetase and the related free-standing trans editing AlaX enzymes, are thought to specifically act on tRNA(Ala), whereas the editing domains of threonyl-tRNA synthetases are specific for tRNA(Thr). Here we show that, contrary to this belief, AlaX-S, the smallest of the extant AlaX enzymes, deacylates Ser-tRNA(Thr) in addition to Ser-tRNA(Ala) and that a single residue is important to determine this behavior. Our data indicate that promiscuous forms of AlaX are ancestral to tRNA-specific AlaXs. We propose that former AlaX domains were used to maintain translational fidelity in earlier stages of genetic code evolution when mis-serylation of several tRNAs was possible. PMID- 25724655 TI - Review of empagliflozin monotherapy for previously untreated patients with type 2 diabetes mellitus: Comparison with sitagliptin. AB - This Practice Pearl provides a review and brief commentary of the 24-week, double blind, parallel-group, randomized, Phase III study by Roden et al., which assessed the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin, 10 mg or 25 mg as monotherapy, versus placebo and the dipeptidyl peptidase-4 inhibitor sitagliptin, in previously untreated patients with type 2 diabetes mellitus (T2DM). Compared to placebo, empagliflozin improved glycemic control, with additional benefits on bodyweight and systolic blood pressure, versus placebo and sitagliptin. Treatment was well tolerated. The authors concluded that empagliflozin is a potential new approach to treat patients with T2DM who are inadequately controlled with diet and exercise alone. This paper advances our understanding of empagliflozin, which so far, appears to be a promising therapeutic option for the management of patients with T2DM. PMID- 25724654 TI - A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference. AB - The noradrenergic and p38 mitogen-activated protein kinase (p38 MAPK) systems are implicated in cocaine-elicited behaviors. Previously, we demonstrated a role for p38 MAPK-mediated norepinephrine transporter (NET) Thr(30) phosphorylation in cocaine-induced NET up-regulation (Mannangatti, P., Arapulisamy, O., Shippenberg, T. S., Ramamoorthy, S., and Jayanthi, L. D. (2011) J. Biol. Chem. 286, 20239 20250). The present study explored the functional interaction between p38 MAPK mediated NET regulation and cocaine-induced behaviors. In vitro cocaine treatment of mouse prefrontal cortex synaptosomes resulted in enhanced NET function, surface expression, and phosphorylation. Pretreatment with PD169316, a p38 MAPK inhibitor, completely blocked cocaine-mediated NET up-regulation and phosphorylation. In mice, in vivo administration of p38 MAPK inhibitor SB203580 completely blocked cocaine-induced NET up-regulation and p38 MAPK activation in the prefrontal cortex and nucleus accumbens. When tested for cocaine-induced locomotor sensitization and conditioned place preference (CPP), mice receiving SB203580 on cocaine challenge day or on postconditioning test day exhibited significantly reduced cocaine sensitization and CPP. A transactivator of transcription (TAT) peptide strategy was utilized to test the involvement of the NET-Thr(30) motif. In vitro treatment of synaptosomes with TAT-NET-Thr(30) (wild type peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In vivo administration of TAT-NET-Thr(30) peptide but not TAT NET-T30A (mutant peptide) completely blocked cocaine-mediated NET up-regulation and phosphorylation. In the cocaine CPP paradigm, mice receiving TAT-NET-Thr(30) but not TAT-NET-T30A on postconditioning test day exhibited significantly reduced cocaine CPP. Following extinction, TAT-NET-Thr(30) when given prior to cocaine challenge significantly reduced reinstatement of cocaine CPP. These results demonstrate that the direct inhibition of p38 MAPK or the manipulation of NET Thr(30) motif/phosphorylation via a TAT peptide strategy prevents cocaine-induced NET up-regulation, locomotor sensitization, and CPP, suggesting a role for Thr(30)-linked NET regulation in cocaine-elicited behaviors. PMID- 25724656 TI - Effects of ghrelin treatment on exertional dyspnea in COPD: an exploratory analysis. AB - A substudy of ghrelin treatment in a multicenter trial previously revealed that administration of ghrelin improves the exercise capacity of underweight COPD patients. To clarify exertional dyspnea more precisely, exploratory analysis was conducted on data from the substudy. Of 20 underweight COPD patients who were randomized to pulmonary rehabilitation with intravenous ghrelin (2 MUg/kg, n = 10) or placebo (n = 10) twice daily for 3 weeks in the substudy, 16 (ghrelin = 9, placebo = 7) could be investigated for dyspnea break-point on the dyspnea-ratio (%) of Deltaoxygen uptake ([Formula: see text]) (= peak minus resting [Formula: see text]) curve. A significant treatment effect of ghrelin on percentage [Formula: see text] at the dyspnea break-point to Delta[Formula: see text] (p = 0.049) was achieved. In conclusion, underweight COPD patients benefitted from ghrelin treatment in terms of shifts to the early exercise phase of the dyspnea break-point during a standardized exercise program. PMID- 25724659 TI - Over three decades of longitudinal research on the development of foster children: a meta-analysis. AB - Large numbers of children over the world experience foster care each year. How best to satisfy their developmental needs and how to avoid placement breakdowns and negative consequences of foster care are important challenges. In this study, a series of four meta-analyses is performed to examine the longitudinal developmental outcomes of children in foster care. The focus is on adaptive functioning and behavioral outcomes. A literature search identified 11 studies suitable for inclusion in the meta-analysis on adaptive functioning (N=1,550), 24 studies for the meta-analysis on internalizing problems (N=1,984), 21 studies for the meta-analysis on externalizing problems (N=1,729) and 25 studies for the meta analysis on total behavior problems (N=2,523). No overall improvement or deterioration was found for adaptive functioning. However, studies with a timespan longer than one year and studies with larger sample sizes showed development toward more negative adaptive functioning than studies with shorter timespans or smaller samples. No overall increases or decreases in internalizing, externalizing or total behavior problems were found. Based on these results, it is concluded that foster care does not negatively or positively affect foster children's developmental trajectories. Given that many children enter foster care with problems, this is a worrying situation. Further longitudinal research to find the factors necessary for improving foster children's developmental chances is recommended. Furthermore, routine screening and targeted foster-care interventions are adviseable to ensure that all children, who cannot be raised by their own parents, receive the support conducive to their positive development. PMID- 25724658 TI - Modeling risk for child abuse and harsh parenting in families with depressed and substance-abusing parents. AB - Children with substance abusing parents are at considerable risk for child maltreatment. The current study applied an actor-partner interdependence model to examine how father only (n=52) and dual couple (n=33) substance use disorder, as well as their depressive symptomology influenced parents' own (actor effects) and the partner's (partner effects) overreactivity in disciplinary interactions with their children, as well as their risk for child maltreatment. Parents completed the Center for Epidemiologic Studies Depression Scale (CES-D; Radloff, 1977), the overreactivity subscale from the Parenting Scale (Arnold, O'Leary, Wolff, & Acker, 1993), and the Brief Child Abuse Potential Inventory (Ondersma, Chaffin, Mullins, & LeBreton, 2005). Results of multigroup structural equation models revealed that a parent's own report of depressive symptoms predicted their risk for child maltreatment in both father SUD and dual SUD couples. Similarly, a parent's report of their own depressive symptoms predicted their overreactivity in disciplinary encounters both in father SUD and dual SUD couples. In all models, partners' depressive symptoms did not predict their partner's risk for child maltreatment or overreactivity. Findings underscore the importance of a parent's own level of depressive symptoms in their risk for child maltreatment and for engaging in overreactivity during disciplinary episodes. PMID- 25724657 TI - Xenopus pax6 mutants affect eye development and other organ systems, and have phenotypic similarities to human aniridia patients. AB - Mutations in the Pax6 gene cause ocular defects in both vertebrate and invertebrate animal species, and the disease aniridia in humans. Despite extensive experimentation on this gene in multiple species, including humans, we still do not understand the earliest effects on development mediated by this gene. This prompted us to develop pax6 mutant lines in Xenopus tropicalis taking advantage of the utility of the Xenopus system for examining early development and in addition to establish a model for studying the human disease aniridia in an accessible lower vertebrate. We have generated mutants in pax6 by using Transcription Activator-Like Effector Nuclease (TALEN) constructs for gene editing in X. tropicalis. Embryos with putative null mutations show severe eye abnormalities and changes in brain development, as assessed by changes in morphology and gene expression. One gene that we found is downregulated very early in development in these pax6 mutants is myc, a gene involved in pluripotency and progenitor cell maintenance and likely a mediator of some key pax6 functions in the embryo. Changes in gene expression in the developing brain and pancreas reflect other important functions of pax6 during development. In mutations with partial loss of pax6 function eye development is initially relatively normal but froglets show an underdeveloped iris, similar to the classic phenotype (aniridia) seen in human patients with PAX6 mutations. Other eye abnormalities observed in these froglets, including cataracts and corneal defects, are also common in human aniridia. The frog model thus allows us to examine the earliest deficits in eye formation as a result of pax6 lesions, and provides a useful model for understanding the developmental basis for the aniridia phenotype seen in humans. PMID- 25724660 TI - Cognitive performance in community-dwelling older adults with stroke and the contribution of age and diffuse subcortical damage: a population-based study in rural Ecuador (The Atahualpa Project). AB - BACKGROUND: Cognitive impairment is common among stroke survivors. However, there is controversy on the role of the stroke itself or the associated subcortical damage in post-stroke cognitive decline. AIM: To assess the independent contribution and the interaction of age, the stroke itself and diffuse subcortical damage in the poor cognitive performance observed in patients with stroke. METHODS: Atahualpa residents aged >=60 years were identified during a door-to-door survey and invited to undergo brain MRI for identification of stroke lesions and white matter hyperintensities (WMH) of presumed vascular origin. Cognitive performance was evaluated by the use of the Montreal Cognitive Assessment (MoCA). Using a generalized linear model, we examined the association between MoCA score, stroke and WMH, after adjusting for demographics, education, vascular risk factors, depression and edentulism. RESULTS: Out of 311 persons aged >=60 years, 242 (78 %) were enrolled. MRI showed strokes in 39 (16 %) and moderate-to-severe WMH in 52 (22 %) cases. Mean MoCA score was 18.5 +/- 4.7 in the entire population. When participants were stratified according to the median age of the population (67 years), the generalized linear model showed that MoCA scores were not different in younger persons irrespective of the presence of stroke or WMH. In contrast, increased age associated with lower MoCA scores in persons with WMH (p = 0.002) or with both stroke and WMH (p = 0.003), but not in those with stroke without WMH (p = 0.087). CONCLUSIONS: Interaction of age and diffuse subcortical damage are major determinants for poor cognitive performance among stroke patients. PMID- 25724661 TI - Pediatric lipid screening rates in the US are low: what can labs do to help? PMID- 25724662 TI - Saccadic model of eye movements for free-viewing condition. AB - In this paper, we propose a new framework to predict visual scanpaths of observers while they freely watch a visual scene. The visual fixations are inferred from bottom-up saliency and several oculomotor biases. Bottom-up saliency is represented by a saliency map whereas the oculomotor biases (saccade amplitudes and saccade orientations) are modeled using public eye tracking datasets. Our experiments show that the simulated scanpaths exhibit similar trends of human eye movements in a free-viewing condition. The generated scanpaths are more similar to human scanpaths than those generated by two existing methods. In addition, we show that computing saliency maps from simulated visual scanpaths allows to outperform existing saliency models. PMID- 25724663 TI - Minimum phi -Divergence Estimation in Constrained Latent Class Models for Binary Data. AB - The main purpose of this paper is to introduce and study the behavior of minimum phi -divergence estimators as an alternative to the maximum-likelihood estimator in latent class models for binary items. As it will become clear below, minimum phi -divergence estimators are a natural extension of the maximum-likelihood estimator. The asymptotic properties of minimum phi -divergence estimators for latent class models for binary data are developed. Finally, to compare the efficiency and robustness of these new estimators with that obtained through maximum likelihood when the sample size is not big enough to apply the asymptotic results, we have carried out a simulation study. PMID- 25724664 TI - Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. PMID- 25724665 TI - High turnover of tissue factor enables efficient intracellular delivery of antibody-drug conjugates. AB - Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach. PMID- 25724666 TI - betaIII-Tubulin Regulates Breast Cancer Metastases to the Brain. AB - Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (betaIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of betaIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as beta3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells. PMID- 25724667 TI - Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway. AB - NISCH encodes the imidazoline receptor Nischarin and is a known tumor suppressor in many human malignancies; however, its roles in ovarian cancer are still largely unknown. Here, we aim to investigate the biologic functions of NISCH in ovarian cancer. We found that NISCH was significantly downregulated, which correlated considerably with advanced tumor stage, poor differentiation, lymph node metastasis, and the serous/mucinous subtypes in a panel of ovarian cancer tissues. Moreover, NISCH gene silencing was mainly the product of promoter hypermethylation, which could be reversed by treatment with 5-aza-dC. In vitro, NISCH overexpression suppressed cell proliferation and colony formation by hindering cell-cycle progression, whereas the opposite was observed in NISCH knockdown counterparts. In vivo, abundant NISCH expression hindered the growth of HO8910 xenografts, whereas NISCH knockdown accelerated the growth of SKOV3 xenografts. In addition, NISCH significantly attenuated cell invasion by inhibiting the phosphorylation of FAK and ERK, which could be neutralized by PF 562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knockdown xenografts exhibited increased peritoneal/pelvic metastases that were not present in counterparts treated with PF-562271. Furthermore, NISCH expression in primary ovarian cancer cells predicted a cellular resistance to PF-562271. In conclusion, we showed that NISCH was frequently silenced by promoter hypermethylation in human ovarian cancer. NISCH manipulated cellular proliferation and invasion by arresting cell cycle and inhibiting the FAK signal. Our findings revealed the biologic functions of NISCH in ovarian cancer, and might be useful for treating patients with aberrant expression of NISCH. PMID- 25724668 TI - Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells. AB - Multiple pulmonary conditions are characterized by an abnormal misbalance between various tissue components, for example, an increase in the fibrous connective tissue and loss/increase in extracellular matrix proteins (ECM). Such tissue remodeling may adversely impact physiological function of airway smooth muscle cells (ASMCs) responsible for contraction of airways and release of a variety of bioactive molecules. However, few efforts have been made to understand the potentially significant impact of tissue remodeling on ASMCs. Therefore, this study reports how ASMCs respond to a change in mechanical stiffness of a matrix, to which ASMCs adhere because mechanical stiffness of the remodeled airways is often different from the physiological stiffness. Accordingly, using atomic force microscopy (AFM) measurements, we found that the elastic modulus of the mouse bronchus has an arithmetic mean of 23.1 +/- 14 kPa (SD) (median 18.6 kPa). By culturing ASMCs on collagen-conjugated polyacrylamide hydrogels with controlled elastic moduli, we found that gels designed to be softer than average airway tissue significantly increased cellular secretion of vascular endothelial growth factor (VEGF). Conversely, gels stiffer than average airways stimulated cell proliferation, while reducing VEGF secretion and agonist-induced calcium responses of ASMCs. These dependencies of cellular activities on elastic modulus of the gel were correlated with changes in the expression of integrin-beta1 and integrin-linked kinase (ILK). Overall, the results of this study demonstrate that changes in matrix mechanics alter cell proliferation, calcium signaling, and proangiogenic functions in ASMCs. PMID- 25724669 TI - Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1. AB - Cytokines drive many inflammatory diseases, including asthma. Understanding the molecular mechanisms responsible for cytokine secretion will allow us to develop novel strategies to repress inflammation in the future. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study, we investigate the p38 MAPK-mediated regulatory interaction of two anti-inflammatory proteins, mitogen-activated protein kinase phosphatase 1 (MKP-1) and tristetraprolin (TTP), in the context of asthmatic inflammation. Using primary cultures of airway smooth muscle cells in vitro, we explored the temporal regulation of IL-6 cytokine mRNA expression upon stimulation with TNF-alpha. Intriguingly, the temporal profile of mRNA expression was biphasic. This was not due to COX-2-derived prostanoid upregulation, increased expression of NLRP3 inflammasome components, or upregulation of the cognate receptor for TNF-alpha TNFR1. Rather, the biphasic nature of TNF-alpha-induced IL-6 mRNA expression was regulated temporally by the RNA-destabilizing molecule, TTP. Importantly, TTP function is controlled by p38 MAPK, and our study reveals that its expression in airway smooth muscle cells is p38 MAPK-dependent and its anti-inflammatory activity is also controlled by p38 MAPK-mediated phosphorylation. MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally distinct manner, MKP-1 ensures that TTP is expressed and made functional at precisely the correct time to repress cytokine expression. Together, p38 MAPK, MKP-1, and TTP may form a regulatory network that exerts significant control on cytokine secretion in proasthmatic inflammation through precise temporal signaling. PMID- 25724671 TI - Family Caregivers' Experiences of Caring for a Relative With Younger Onset Dementia: A Qualitative Systematic Review. AB - Family caregiving for people with younger onset dementia affects everyone in the family unit. This article presents findings of a qualitative systematic review exploring the experiences of family caregivers of persons with younger onset dementia. A systematic search resulted in the inclusion of five relevant articles, and two groups within the family unit were identified-child caregivers and adult and spousal caregivers. Using the thematic synthesis approach, five themes emerged: dementia damage, grief for loss of relationship, changes in family roles, positive and negative impacts of family caregiving, and transition to formal care. The review findings support increasing evidence that despite the stress of caring for a person with dementia damage, family members have the capacity to cope, adapt, and grow through their experiences. Nurses can assist families to identify their unique strengths and enhance family resiliency so they can navigate the "lonely road" of younger onset dementia. PMID- 25724670 TI - Analysis of the history and spread of HIV-1 in Uganda using phylodynamics. AB - HIV prevalence has decreased in Uganda since the 1990s, but remains substantial within high-risk groups. Here, we reconstruct the history and spread of HIV subtypes A1 and D in Uganda and explore the transmission dynamics in high-risk populations. We analysed HIV pol sequences from female sex workers in Kampala (n = 42), Lake Victoria fisher-folk (n = 46) and a rural clinical cohort (n = 74), together with publicly available sequences from adjacent regions in Uganda (n = 412) and newly generated sequences from samples taken in Kampala in 1986 (n = 12). Of the sequences from the three Ugandan populations, 60 (37.1 %) were classified as subtype D, 54 (33.3 %) as subtype A1, 31 (19.1 %) as A1/D recombinants, six (3.7 %) as subtype C, one (0.6 %) as subtype G and 10 (6.2 %) as other recombinants. Among the A1/D recombinants we identified a new candidate circulating recombinant form. Phylodynamic and phylogeographic analyses using BEAST indicated that the Ugandan epidemics originated in 1960 (1950-1968) for subtype A1 and 1973 (1970-1977) for D, in rural south-western Uganda with subsequent spread to Kampala. They also showed extensive interconnection with adjacent countries. The sequence analysis shows both epidemics grew exponentially during the 1970s-1980s and decreased from 1992, which agrees with HIV prevalence reports in Uganda. Inclusion of sequences from the 1980s indicated the origin of both epidemics was more recent than expected and substantially narrowed the confidence intervals in comparison to previous estimates. We identified three transmission clusters and ten pairs, none of them including patients from different populations, suggesting active transmission within a structured transmission network. PMID- 25724672 TI - The a subunit of the A1AO ATP synthase of Methanosarcina mazei Go1 contains two conserved arginine residues that are crucial for ATP synthesis. AB - Like the evolutionary related F1FO ATP synthases and V1VO ATPases, the A1AO ATP synthases from archaea are multisubunit, membrane-bound transport machines that couple ion flow to the synthesis of ATP. Although the subunit composition is known for at least two species, nothing is known so far with respect to the function of individual subunits or amino acid residues. To pave the road for a functional analysis of A1AO ATP synthases, we have cloned the entire operon from Methanosarcina mazei into an expression vector and produced the enzyme in Escherichia coli. Inverted membrane vesicles of the recombinants catalyzed ATP synthesis driven by NADH oxidation as well as artificial driving forces. [Formula: see text] as well as DeltapH were used as driving forces which is consistent with the inhibition of NADH-driven ATP synthesis by protonophores. Exchange of the conserved glutamate in subunit c led to a complete loss of ATP synthesis, proving that this residue is essential for H+ translocation. Exchange of two conserved arginine residues in subunit a has different effects on ATP synthesis. The role of these residues in ion translocation is discussed. PMID- 25724673 TI - Expression profiling of cadmium response genes in ramie (Boehmeria nivea L.) root. AB - Ramie (Boehmeria nivea), a perennial herb belongs to Urticaceae family, is a rapid growth and high biomass crop with highly tolerant and accumulative to heavy metals. However, the gene expression and regulation caused by cadmium (Cd) in ramie has not been well studied. In the present study, a gene expression database of ramie root in the absence (control) or presence of 100 MUM Cd was established. Solexa high-throughput sequencing technology showed that 3,654,395 and 3,572,333 tags have been obtained from control and Cd treatment respectively. In total, 3887 genes were detected with significant differential expression levels, in which 2883 genes were up-regulated and 1004 genes were down-regulated. Gene ontology and pathway-based analyses were performed to determine and further to understand the biological functions of those differentially expressed genes. Fifteen genes were selected and their expression levels were confirmed by quantitative RT-PCR, and twelve of them showed consistent expression patterns with the digital gene expression data. Results on these expression profiling of genes lay the basis for biotechnological modification of new transgenic plants with improved phytoremediation capacity. PMID- 25724674 TI - Statin use is associated with lower risk of liver cancer, study shows. PMID- 25724675 TI - Children Who are Anxious in Silence: A Review on Selective Mutism, the New Anxiety Disorder in DSM-5. AB - Selective mutism (SM) is a relatively rare childhood disorder characterized by a consistent failure to speak in specific settings (e.g., school, social situations) despite speaking normally in other settings (e.g., at home). The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5) lists SM among the anxiety disorders. This makes sense as the current review of the literature confirms that anxiety is a prominent symptom in many children suffering from this condition. Further, research on the etiology and treatment of SM also corroborates the conceptualization of SM as an anxiety disorder. At the same time, critical points can be raised regarding the classification of SM as an anxiety disorder. We explore a number of such issues in this review. Recommendations for dealing with this diagnostic conundrum are made for psychologists, psychiatrists, and other mental health workers who face children with SM in clinical practice, and directions for future research are highlighted. PMID- 25724676 TI - Stochastic rat lung dosimetry for inhaled radon progeny: a surrogate for the human lung for lung cancer risk assessment. AB - Laboratory rats are frequently used in inhalation studies as a surrogate for human exposures. The objective of the present study was therefore to develop a stochastic dosimetry model for inhaled radon progeny in the rat lung, to predict bronchial dose distributions and to compare them with corresponding dose distributions in the human lung. The most significant difference between human and rat lungs is the branching structure of the bronchial tree, which is relatively symmetric in the human lung, but monopodial in the rat lung. Radon progeny aerosol characteristics used in the present study encompass conditions typical for PNNL and COGEMA rat inhalation studies, as well as uranium miners and human indoor exposure conditions. It is shown here that depending on exposure conditions and modeling assumptions, average bronchial doses in the rat lung ranged from 5.4 to 7.3 mGy WLM(-1). If plotted as a function of airway generation, bronchial dose distributions exhibit a significant maximum in large bronchial airways. If, however, plotted as a function of airway diameter, then bronchial doses are much more uniformly distributed throughout the bronchial tree. Comparisons between human and rat exposures indicate that rat bronchial doses are slightly higher than human bronchial doses by about a factor of 1.3, while lung doses, averaged over the bronchial (BB), bronchiolar (bb) and alveolar interstitial (AI) regions, are higher by about a factor of about 1.6. This supports the current view that the rat lung is indeed an appropriate surrogate for the human lung in case of radon-induced lung cancers. Furthermore, airway diameter seems to be a more appropriate morphometric parameter than airway generations to relate bronchial doses to bronchial carcinomas. PMID- 25724677 TI - "(Not) all (dead) things share the same breath": identification of cell death mechanisms in anticancer therapy. AB - During the last decades, the knowledge of cell death mechanisms involved in anticancer therapy has grown exponentially. However, in many studies, cell death is still described in an incomplete manner. The frequent use of indirect proliferation assays, unspecific probes, or bulk analyses leads too often to misunderstandings regarding cell death events. There is a trend to focus on molecular or genetic regulations of cell demise without a proper characterization of the phenotype that is the object of this study. Sometimes, cancer researchers can feel overwhelmed or confused when faced with such a corpus of detailed insights, nomenclature rules, and debates about the accuracy of a particular probe or assay. On the basis of the information available, we propose a simple guide to distinguish forms of cell death in experimental settings using cancer cell lines. PMID- 25724678 TI - RIP1 Kinase Is an Oncogenic Driver in Melanoma. AB - Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-kappaB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage independent cell growth in an NF-kappaB-dependent manner. We identified DNA copy number gain and constitutive ubiquitination by a TNFalpha autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-kappaB-dependent activation mechanism as a novel approach to treat this disease. PMID- 25724679 TI - Heat shock factor 1 in protein homeostasis and oncogenic signal integration. AB - Heat shock factor 1 (HSF1) is a stress-inducible transcription factor and has been described as a multi-faceted modulator of tumorigenesis. Heat shock, accumulation of misfolded proteins, or malignant transformation promotes the activation and nuclear translocation of HSF1, where it binds to the promoters of heat shock proteins and an array of nonheat shock-regulated proteins to upregulate their transcription. These stress-responsive and tumor-promoting genes in turn alter the ability of tumor cells to respond to a variety of stresses and enable them to thrive in less than favorable growth conditions. Although a direct role for HSF1 in promoting mRNA transcription of tumor-promoting genes has been suggested, it appears that this property is context- and cell-type dependent. Furthermore, recent studies have demonstrated a direct involvement of mTOR signaling in regulating HSF1-mediated transcription, thus establishing a direct link between protein translation and HSF1 activity. Interestingly, there is a growing understanding of the signaling pathways that are modulated by HSF1 in a variety of tumor types and the co-option of these survival pathways by HSF1 to promote tumorigenesis. This review will focus on the role of HSF1 in protein homeostasis and HSF1-mediated oncogenic signaling pathways that together promote tumorigenesis. PMID- 25724680 TI - Meta-analysis of associations between functional prolactin -1149 G/T polymorphism and susceptibility to rheumatoid arthritis and systemic lupus erythematosus. AB - The aim of this study was to determine whether the prolactin -1149 G/T polymorphism confers susceptibility to systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). A meta-analysis was conducted for examining the associations between prolactin -1149 G/T polymorphism and susceptibility to SLE or RA using allele contrast, recessive and dominant models, and homozygote contrast. A total of 10 comparative studies, consisting of 4 SLE and 6 RA studies, involving 4252 patients and 4949 controls, were included in the meta analysis. No association between the prolactin -1149 G allele and SLE was found when all study subjects were considered together (OR = 1.019, 95 % CI = 1.841 1.236, p = 0.845). Stratification by ethnicity also indicated no association between the prolactin G allele and SLE in either Caucasian or Latin American populations. In contrast, a significant association was observed between the prolactin G allele and RA in all subjects (OR = 1.123, 95 % CI = 1.052-1.198, p = 4.6 * 10(-5)). After stratification by ethnicity, the G allele was found to be significantly associated with RA in Caucasians (OR = 1.112, 95 % CI = 1.041 1.189, p = 0.002). Furthermore, the prolactin -1149 G/T polymorphism was found to be associated with RA in Caucasians under the dominant model and under homozygote contrast. This meta-analysis demonstrates that the prolactin -1149 G/T polymorphism is associated with susceptibility to RA, but not SLE, in Caucasians. PMID- 25724681 TI - The association between RANKL and Osteoprotegerin gene polymorphisms with breast cancer. AB - Breast cancer is the most common cause of cancer death among women (522,000 deaths in 2012). Imbalance between RANKL and OPG is observed in many cancers, including breast cancer. Consequently, SNPs in the genes of RANKL and OPG may be involved in breast cancer development. This study included 276 subjects. Group I (n = 100) healthy females as a control group, group II (n = 96) breast cancer patients without bone metastases, and group III (n = 80) breast cancer patients with bone metastases. RANKL rs9533156, OPG rs2073618, and OPG rs2073617 SNPs and their serum protein levels were studied for a possible association with breast cancer development. The allele frequency [(OR: 4.832 CI 2.18-10.71, P = 0.001) and genotype distribution (P = 0.001)] of OPG SNP rs2073618 showed a highly significant difference between breast cancer patients and healthy controls. The allele C is more common in breast cancer patients. The allele frequency [(OR: 0.451 CI 0.232-0.879, P = 0.018) and genotype distribution (P = 0.003)] of RANKL SNP rs9533156 differed significantly between breast cancer patients and healthy controls. The allele T is more common in breast cancer patients. The allele frequency [(OR: 0.36 CI 0.184-0.705, P = 0.002) and genotype distribution (P = 0.011)] of OPG SNP rs2073617 differed significantly between breast cancer patients and healthy controls. The allele T is more common in breast cancer patients. The C allele of OPG SNP rs2073618 may be associated with breast cancer development. No association was found between any of the SNPs and the serum protein levels of RANKL and OPG. PMID- 25724682 TI - Does proteasome regulate the level of microRNA-1 in cardiomyocytes? Application to anoxia-reoxygenation. AB - Proteasome and microRNAs play a critical role in almost all processes in a living organism, including pathology of the heart; however, their interaction is still in question. In the present study, we have found that proteasome inhibitor provoked increase of mature but not immature microRNA-1 in cultured cardiomyocytes, and tested the hypothesis that mature microRNA-1 can be a substrate for endonuclease activity of proteasome. In our in vitro experiments, we have found that proteasome fraction II is able to degrade both mature and primary but not precursor microRNA-1. However, this in vitro effect was not abolished by chemical inhibitor of proteolytic activities of proteasome. These data let us summarize that proteasome has the complex effect on the level of microRNA-1. PMID- 25724683 TI - Tocopherol isoforms (alpha-, gamma-, and delta-) show distinct capacities to control Nrf-2 and NfkappaB signaling pathways that modulate inflammatory response in Caco-2 intestinal cells. AB - We recently showed that alpha-, gamma-, and delta-tocopherols (Toc) were isoform dependent in modulating an inflammatory response in differentiated human Caco-2 intestinal cells. Here, we aim to investigate the relative capacity of Toc isoforms to modify the stress-activated NfkappaB and Nrf-2 signaling pathways that regulate the expression of pro-inflammatory cytokines and antioxidant enzymes, respectively, in this well-established in vitro model of the small intestine The modulation of IFNgamma/phorbol myristate acetate (PMA)-induced inflammatory responses, determined by the expression of IL8 mRNA and protein, corresponded to the extent by which different Toc isoforms altered intracellular oxidative status in Caco-2 cells. alpha Toc was more effective at suppressing IFNgamma/PMA-induced NfkappaB activation than gamma-Toc, while delta-Toc was ineffective. On the other hand, only delta-Toc and to a lesser extent gamma-Toc promoted IFNgamma/PMA-induced Nrf-2 activation. Up-regulation of Nrf-2 by delta Toc coincided with a decrease in GSH/GSSG ratio, thus pointing to pro-oxidant activity of delta-Toc isoform in IFNgamma/PMA-stimulated Caco-2 cells. The induction of oxidative stress in IFNgamma/PMA-treated cells by delta-Toc was lowered (P < 0.05) in the presence of ascorbic acid. Ascorbic acid also enabled a greater suppression of IL8 secretion than when cells were treated with delta-Toc isoform alone. Our findings show that delta-Toc uniquely promoted oxidative stress which translated to Toc isoform-specific modulation of the stress activated Nrf-2 and NfkappaB signaling pathway and an influence on IL8 expression. PMID- 25724684 TI - MAPKs' status at early stages of renal carcinogenesis and tumors induced by ferric nitrilotriacetate. AB - Renal cell carcinoma (RCC) is asymptomatic at early stages, and thus, initial diagnosis frequently occurs at advanced or even metastatic stages, leading to a high rate of mortality. Ferric nitrilotriacetate (FeNTA)-induced RCC model is a useful tool to analyze molecular events at different stages of the carcinogenesis process in vivo. MAPKs' alterations seem to play an important role in the development and maintenance of human RCC tumors. Based on the above, p38alpha/beta/gamma, JNK1/2, and ERK1/2 statuses were studied at early stages of FeNTA-induced renal carcinogenesis (1 and 2 months of carcinogen treatment) as well as in tumor tissue. MAPKs showed distinct response along carcinogenesis process, either as total proteins and/or as their phosphorylated forms. While the increase in total and phospho-p38alpha/beta levels became lower as carcinogenesis progressed, p38gamma overexpression grew. Instead, total JNK2 diminished, but JNK1 was elevated at all studied times, and p-JNK1 levels increased at early stages, but not in tumors. In contrast, p-JNK2 rose at 2 months of treatment and in tumor tissue. Increased levels of p-ERK1/2 were observed at all stages analyzed. Very interestingly, at 1 and 2 months of FeNTA treatment, no alterations in MAPKs were found in liver or lung, where no primary tumors are induced with the scheme of FeNTA administration followed here. In conclusion, MAPKs' behavior evolved differentially as renal carcinogenesis advanced, even among isoforms of the same family, but it did not change in other tissues. All this strongly suggests a role of these kinases in FeNTA-induced RCC tumor development and maintenance. PMID- 25724685 TI - Reproducibility and repeatability of a new computerized software for sagittal spinopelvic and scoliosis curvature radiologic measurements: Keops((r)). AB - PURPOSE: The purpose of this study was to evaluate the inter- and intra-observer variability of the computerized radiologic measurements using Keops((r)) and to determine the bias between the software and the standard paper measurement. METHODS: Four individuals measured all frontal and sagittal variables on the 30 X rays randomly selected on two occasions (test and retest conditions). The Bland Altman plot was used to determine the degree of agreement between the measurement on paper X-ray and the measurement using Keops((r)) for all reviewers and for the two measures; the intraclass correlation coefficient (ICC) was calculated for each pair of analyses to assess interobserver reproducibility among the four reviewers for the same patient using either paper X-ray or Keops((r)) measurement and finally, concordance correlation coefficient (rc) was calculated to assess intraobserver repeatability among the same reviewer for one patient between the two measure using the same method (paper or Keops((r))). RESULTS: The mean difference calculated between the two methods was minimal at -0, 4 degrees +/- 3.41 degrees [-7.1; 6.4] for frontal measurement and 0.1 degrees +/- 3.52 degrees [-6.7; 6.8] for sagittal measurement. Keops((r)) has a better interobserver reproducibility than paper measurement for determination of the sagittal pelvic parameter (ICC = 0.9960 vs. 0.9931; p = 0.0001). It has a better intraobserver repeatability than paper for determination of Cobbs angle (rc = 0.9872 vs. 0.9808; p < 0.0001) and for pelvic parameter (rc = 0.9981 vs. 0.9953; p < 0.0001). CONCLUSIONS: We conclude that Keops((r)) has no bias compared to the traditionally paper measurement, and moreover, the repeatability and the reproducibility of measurements with this method is much better than with similar standard radiologic measures done manually in both frontal and sagittal plane and that the use of this software can be recommended for clinical application. LEVEL OF EVIDENCE: Diagnostic, level III. PMID- 25724686 TI - Answer to the Letter to the Editor of Jianqiang Ni et al. concerning "Anterior stand-alone fusion revisited: a prospective clinical, X-ray and CT investigation" by Siepe C.J., et al. Eur Spine J (2014): DOI 10.1007/s00586-014-3642-y. PMID- 25724687 TI - A proposed adhesin AoMad1 helps nematode-trapping fungus Arthrobotrys oligospora recognizing host signals for life-style switching. AB - The nematode-trapping fungus Arthrobotrys oligospora is an important natural enemy of nematodes. It can capture nematodes by producing a special mycelial structure called adhesive network or trap. The trap is also a signature of the fungus switching from the saprophytic lifestyle to the predacious lifestyle. At present, little is known about the mechanism of lifestyle switch in nematode trapping fungi. Here we describe the effect of a cell wall protein called AoMad1 on lifestyle switch. The disruption of the AoMad1-encoding gene in A. oligospora resulted in the formation of more traps in the presence of nematodes. Interestingly, the mutant strain was more sensitive to certain nitrogen sources as trap inducers than the wild type strain. The microscopic examinations revealed that the AoMad1-deletion mutant lacked cell surface adhesive materials and the cell wall structures were more porous than wild-type strains. A great of genes were differentially expressed by transcriptomic analysis when trap formation was induced by sodium nitrate compared to the wild type strain, many of them were related to nitrogen metabolism, host-pathogen interaction and mycelia development. The results suggest that AoMad1 plays an important role in life style switching in A. oligospora. PMID- 25724688 TI - Importance of punishment frequency in the Iowa gambling task: an fMRI study. AB - It has been widely found that in the Iowa Gambling Task (IGT; Bechara et al. Cognition, 50(1), 7-15 1994) normal subjects would gradually learn to prefer obtaining rewards for long-term benefits than seeking immediate rewards to maximize the overall profit. The current study aimed to gain an understanding of how punishment frequency in the IGT would be processed and its association with subjects' reward preferences. In this study, we employed the clinical version of the IGT, in which response options are not only different in the long-term outcome, but also associated with different punishment frequencies. Event-related functional Magnetic Resonance Imaging (fMRI) was used to capture the subjects' brain activity when performing the IGT. A total of 24 male subjects (mean age = 21.7 years, SD = 1.8 years), who were university students, participated in the experiment. It is found that subjects learned to select more from the decks that were advantageous in the long-term, but they were more sensitive to the effect of long-term outcome under the condition of high punishment frequency. The corresponding brain activation showed that the Anterior Cingulate Cortex (ACC) had significantly higher activation during the disadvantageous choices than the advantageous choices. Such activity difference between the two conditions of long term outcome was more prominent with high punishment frequency than low punishment frequency; and this brain activity difference was significantly correlated with the behavioral performance under the condition of high punishment frequency. The results suggested that only in the context with high punishment frequency, there would be increased neural activity in ACC when subjects intended to select from the disadvantageous choices so that these choices would be inhibited and advantageous choices would be selected. PMID- 25724689 TI - Neuroimaging of the developing brain. PMID- 25724690 TI - Inorganic nitrite attenuates NADPH oxidase-derived superoxide generation in activated macrophages via a nitric oxide-dependent mechanism. AB - Oxidative stress contributes to the pathogenesis of many disorders, including diabetes and cardiovascular disease. Immune cells are major sources of superoxide (O2(?-)) as part of the innate host defense system, but exaggerated and sustained O2(?-) generation may lead to progressive inflammation and organ injuries. Previous studies have proven organ-protective effects of inorganic nitrite, a precursor of nitric oxide (NO), in conditions manifested by oxidative stress and inflammation. However, the mechanisms are still not clear. This study aimed at investigating the potential role of nitrite in modulating NADPH oxidase (NOX) activity in immune cells. Mice peritoneal macrophages or human monocytes were activated by lipopolysaccharide (LPS), with or without coincubation with nitrite. O2(?-) and peroxynitrite (ONOO(-)) formation were detected by lucigenin-based chemiluminescence and fluorescence techniques, respectively. The intracellular NO production was measured by DAF-FM DA fluorescence. NOX isoforms and inducible NO synthase (iNOS) expression were detected by qPCR. LPS increased both O2(?-) and ONOO(-) production in macrophages, which was significantly reduced by nitrite (10umol/L). Mechanistically, the effects of nitrite are (1) linked to increased NO generation, (2) similar to that observed with the NO donor DETA-NONOate, and (3) can be abolished by the NO scavenger carboxy-PTIO or by the xanthine oxidase (XO) inhibitor febuxostat. Nox2 expression was increased in activated macrophages, but was not influenced by nitrite. However, nitrite attenuated LPS induced upregulation of iNOS expression. Similar to that observed in mice macrophages, nitrite also reduced O2(?-) generation in LPS-activated human monocytes. In conclusion, XO-mediated reduction of nitrite attenuates NOX activity in activated macrophages, which may modulate the inflammatory response. PMID- 25724691 TI - Understanding mammalian glutathione peroxidase 7 in the light of its homologs. AB - The glutathione peroxidase homologs (GPxs) efficiently reduce hydroperoxides using electrons from glutathione (GSH), thioredoxin (Trx), or protein disulfide isomerase (PDI). Trx is preferentially used by the GPxs of the majority of bacteria, invertebrates, plants, and fungi. GSH or PDI, instead, is preferentially used by vertebrate GPxs that operate by Sec or Cys catalysis, respectively. Mammalian GPx7 and GPx8 are unique homologs that contain a peroxidatic Cys (CP). Being reduced by PDI and located within the endoplasmic reticulum (ER), these enzymes have been involved in oxidative protein folding. Kinetic analysis indicates that oxidation of PDI by recombinant GPx7 occurs at a much faster rate than that of GSH. Nonetheless, activity measurement suggests that, at physiological concentrations, a competition between these two substrates takes place, with the rate of PDI oxidation by GPx7 controlled by the concentration of GSH, whereas the GSSG produced in the competing reaction contributes to the ER redox buffer. A mechanism has been proposed for GPx7 involving two Cys residues, in which an intramolecular disulfide of the CP is formed with an alleged resolving Cys (CR) located in the strongly conserved FPCNQ motif (C86 in humans), a noncanonical position in GPxs. Kinetic measurements and comparison with the other thiol peroxidases containing a functional CR suggest that a resolving function of C86 in the catalytic cycle is very unlikely. We propose that GPx7 is catalytically active as a 1-Cys-GPx, in which CP both reduces H2O2 and oxidizes PDI, and that the CP-C86 disulfide has instead the role of stabilizing the oxidized peroxidase in the absence of the reducing substrate. PMID- 25724693 TI - Two genes conferring resistance to Pythium stalk rot in maize inbred line Qi319. AB - Stalk rots are destructive diseases in maize around the world, and are most often caused by the pathogen Pythium, Fusarium and other fungi. The most efficient management for controlling stalk rots is to breed resistant cultivars. Pythium stalk rot can cause serious yield loss on maize, and to find the resistance genes from the existing germplasm is the basis to develop Pythium-resistance hybrid lines. In this study, we investigated the genetic resistance to Pythium stalk rot in inbred line Qi319 using F2 and F2:3 population, and found that the resistance to Pythium inflatum in Qi319 was conferred by two independently inherited dominant genes, RpiQI319-1 and RpiQI319-2. Linkage analysis uncovered that the RpiQI319-1 co-segregated with markers bnlg1203, and bnlg2057 on chromosome 1, and that the RpiQI319-2 locus co-segregated with markers umc2069 and bnlg1716 on chromosome 10. The RpiQI319-1 locus was further mapped into a ~500-kb interval flanked by markers SSRZ33 and SSRZ47. These results will facilitate marker assisted selection of Pythium stalk rot-resistant cultivars in maize breeding. To our knowledge, this is the first report on the resistance to P. inflatum in the inbred line Qi319, and is also the first description of two independently inherited dominant genes conferring the resistance of Pythium stalk rot in maize. PMID- 25724692 TI - Pathways associated with lignin biosynthesis in lignomaniac jute fibres. AB - We generated the bast transcriptomes of a deficient lignified phloem fibre mutant and its wild-type jute (Corchorus capsularis) using Illumina paired-end sequencing. A total of 34,163 wild-type and 29,463 mutant unigenes, with average lengths of 1442 and 1136 bp, respectively, were assembled de novo, ~77-79 % of which were functionally annotated. These annotated unigenes were assigned to COG (~37-40 %) and GO (~22-28 %) classifications and mapped to 189 KEGG pathways (~19 21 %). We discovered 38 and 43 isoforms of 16 and 10 genes of the upstream shikimate-aromatic amino acid and downstream monolignol biosynthetic pathways, respectively, rendered their sequence similarities, confirmed the identities of 22 of these candidate gene families by phylogenetic analyses and reconstructed the pathway leading to lignin biosynthesis in jute fibres. We also identified major genes and bast-related transcription factors involved in secondary cell wall (SCW) formation. The quantitative RT-PCRs revealed that phenylalanine ammonia-lyase 1 (CcPAL1) was co-down-regulated with several genes of the upstream shikimate pathway in mutant bast tissues at an early growth stage, although its expression relapsed to the normal level at the later growth stage. However, cinnamyl alcohol dehydrogenase 7 (CcCAD7) was strongly down-regulated in mutant bast tissues irrespective of growth stages. CcCAD7 disruption at an early growth stage was accompanied by co-up-regulation of SCW-specific genes cellulose synthase A7 (CcCesA7) and fasciclin-like arabinogalactan 6 (CcFLA6), which was predicted to be involved in coordinating the S-layers' deposition in the xylan type jute fibres. Our results identified CAD as a promising target for developing low-lignin jute fibres using genomics-assisted molecular approaches. PMID- 25724694 TI - Expression pattern of RAGE and IGF-1 in the human fetal ovary and ovarian serous carcinoma. AB - The expression pattern of RAGE and IGF-1 proteins in different ovarian cell lineages was histologically analyzed in six fetal, nine adult human ovaries, and nine serous ovarian carcinomas (OSC) using immunohistochemical methods. Mild expression of IGF-1 in ovarian surface epithelium (Ose) and oocytes in the 15 week human ovaries increased to moderate or strong in the stromal cells, oocytes and follicular cells in week 22. Occasional mild RAGE expression was observed in Ose during week 15, while strong expression characterized primordial follicles in week 22. In the reproductive human ovary, IGF-1 was mildly to moderately expressed in all ovarian cell lineages except in theca cells of the tertiary follicle where IGF-1 was negative. RAGE was strongly positive in the granulosa cells and some theca cells of the tertiary follicle, while negative to mildly positive in all cells of the secondary follicle. In the postmenopausal human ovary IGF-1 and RAGE were mildly expressed in Ose and stroma. In OSC, cells were strongly positive to IGF-1 and RAGE, except for some negative stromal cells. Different levels of IGF-1 and RAGE co-expression characterized fetal ovarian cells during development. In reproductive ovaries, IGF-1 and RAGE were co localized in the granulosa and theca interna cells of tertiary follicles, while in postmenopausal ovaries and OSC, IGF-1 and RAGE were co-localized in Ose and OSC cells respectively. Our results indicate that intracellular levels of IGF-1 and RAGE protein might regulate the final destiny of the ovarian cell populations prior and during folliculogenesis, possibly controlling the metastatic potential of OSC as well. PMID- 25724695 TI - Advanced treatment of biologically pretreated coal gasification wastewater by a novel integration of heterogeneous Fenton oxidation and biological process. AB - Laboratorial scale experiments were conducted in order to investigate a novel system integrating heterogeneous Fenton oxidation (HFO) with anoxic moving bed biofilm reactor (ANMBBR) and biological aerated filter (BAF) process on advanced treatment of biologically pretreated coal gasification wastewater (CGW). The results indicated that HFO with the prepared catalyst (FeOx/SBAC, sewage sludge based activated carbon (SBAC) which loaded Fe oxides) played a key role in eliminating COD and COLOR as well as in improving the biodegradability of raw wastewater. The surface reaction and hydroxyl radicals (OH) oxidation were the mechanisms for FeOx/SBAC catalytic reaction. Compared with ANMBBR-BAF process, the integrated system was more effective in abating COD, BOD5, total phenols (TPs), total nitrogen (TN) and COLOR and could shorten the retention time. Therefore, the integrated system was a promising technology for engineering applications. PMID- 25724696 TI - Consistency of prediction across generation: explaining quality of life by family functioning and health-promoting behaviors. AB - PURPOSE: The study aimed to investigate the consistency of relationship between family functioning, health-promoting behaviors, and quality of life across generations in joint families. METHOD: The sample comprises of 79 joint families (N = 316 members, n = 79 grandparents (grandfathers = 27, grandmothers = 52) n = 158 parents (fathers = 79, mothers = 79), and n = 79 grandchildren (girls = 61, boys = 18)). Data were collected on Self-Report Family Inventory, SFI, Health Promoting Lifestyle Profile II, HPLP-II, and World Health Organization Quality of Life Scale BREF WHO QOL BREF. All three variables, i.e., family functioning, health-promoting behaviors, and quality of life, were modeled as latent variables. Analyses were conducted separately for each group. RESULTS: Results showed that in grandparents, family functioning predicted (beta = .44, p < .01,) health-promoting behaviors (R (2) = .20), which in turn predicted (beta = .26, p < .05) quality of life (R (2) = .85). Family functioning appears to have significant indirect effects (beta = .34, p < .01) through health-promoting behaviors on quality of life. The model fit indices showed a good fit (IFI = .917, CFI = .910, RMSEA = .078) of the model of the data. For all other groups, i.e., fathers, mothers, and grandchildren, family functioning and health promoting behaviors independently predicted quality of life (R (2) = .55, .67, and .54, respectively). CONCLUSION: Our results showed that family functioning and health-promoting behaviors are consistent predictors of quality of life across generations. PMID- 25724697 TI - Association between single-nucleotide polymorphisms in growth factor genes and quality of life in men with prostate cancer and the general population. AB - PURPOSE: Improved survival for men with prostate cancer has led to increased attention to factors influencing quality of life (QOL). As protein levels of vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF 1) have been reported to be associated with QOL in people with cancer, we sought to identify whether single-nucleotide polymorphisms (SNPs) of these genes were associated with QOL in men with prostate cancer. METHODS: Multiple linear regression of two data sets (including approximately 750 men newly diagnosed with prostate cancer and 550 men from the general population) was used to investigate SNPs of VEGF and IGF-1 (10 SNPs in total) for associations with QOL (measured by the SF-36v2 health survey). RESULTS: Men with prostate cancer who carried the minor 'T' allele for IGF-1 SNP rs35767 had higher mean Role-Physical scale scores (>=0.3 SD) compared to non-carriers (p < 0.05). While this association was not identified in men from the general population, one IGF-1 SNP rs7965399 was associated with higher mean Bodily Pain scale scores in men from the general population that was not found in men with prostate cancer. Men from the general population who carried the rare 'C' allele had higher mean Bodily Pain scale scores (>=0.3 SD) than non-carriers (p < 0.05). CONCLUSIONS: Through identifying SNPs that are associated with QOL in men with prostate cancer and men from the general population, this study adds to the mapping of complex interrelationships that influence QOL and suggests a role for IGF-I in physical QOL outcomes. Future research may identify biomarkers associated with increased risk of poor QOL that could assist in the provision of pre-emptive support for those identified at risk. PMID- 25724698 TI - Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes. AB - INTRODUCTION: Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S transferase 1. AREAS COVERED: Herein, the authors summarize the standard of care in order to build the framework for therapeutic advancements. The purpose of this paper is to review the body of preclinical and clinical research literature on the investigational agent ezatiostat hydrochloride (TLK199) for the treatment of MDSs. The article includes details of the pathophysiology, pharmacology, toxicity and efficacy of ezatiostat hydrochloride from controlled studies in patients with myelodysplasia. EXPERT OPINION: MDS clonal heterogeneity and clonal architecture complexity has presented a significant technical challenge in developing effective therapies. Ezatiostat offers a unique and specific mechanism to improve the transfusion burden associated with myelodysplasia. Since it is tolerable as a monotherapy, combining ezatiostat with agents such as lenalidomide may have the most potential benefit. PMID- 25724699 TI - Effectiveness and Safety of Immunomodulators With Anti-Tumor Necrosis Factor Therapy in Crohn's Disease. AB - BACKGROUND & AIMS: The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD. METHODS: We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti TNF monotherapy via propensity score and compared by using 3 metrics of effectiveness-surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery-and 2 metrics of safety-serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses. RESULTS: Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR], 1.20; 95% confidence interval, 0.73-1.96), hospitalization (HR, 0.82; 0.57-1.19), discontinuation of anti-TNF therapy or surgery (HR, 1.09; 0.88-1.34), and serious infection (HR, 0.93; 0.88-1.34) did not differ between users of anti TNF combination therapy and monotherapy. However, the risks of opportunistic infection (HR, 2.64; 1.21-5.73) and herpes zoster (HR, 3.16; 1.25-7.97) were increased with combination therapy. CONCLUSIONS: We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection. PMID- 25724700 TI - Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. AB - BACKGROUND & AIMS: The phytochemical compound curcumin was reported to be effective in maintaining remission in patients with ulcerative colitis (UC). We investigated curcumin's efficacy in inducing remission in patients with active mild-to-moderate UC. METHODS: We performed a multicenter randomized, placebo controlled, double-blind study of 50 mesalamine-treated patients with active mild to-moderate UC (defined by the Simple Clinical Colitis Activity Index [SCCAI]) who did not respond to an additional 2 weeks of the maximum dose of mesalamine oral and topical therapy. Patients were randomly assigned to groups who were given curcumin capsules (3 g/day, n = 26) or an identical placebo (n = 24) for 1 month, with continued mesalamine. The primary outcome was the rate of clinical remission (SCCAI <=2) at week 4. Clinical and endoscopic responses were also recorded. RESULTS: In the intention-to-treat analysis, 14 patients (53.8%) receiving curcumin achieved clinical remission at week 4, compared with none of the patients receiving placebo (P = .01; odds ratio [OR], 42; 95% confidence interval [CI], 2.3-760). Clinical response (reduction of >=3 points in SCCAI) was achieved by 17 patients (65.3%) in the curcumin group vs. 3 patients (12.5%) in the placebo group (P < .001; OR, 13.2; 95% CI, 3.1-56.6). Endoscopic remission (partial Mayo score <=1) was observed in 8 of the 22 patients evaluated in the curcumin group (38%), compared with none of 16 patients evaluated in the placebo group (P = .043; OR, 20.7; 95% CI, 1.1-393). Adverse events were rare and comparable between the 2 groups. CONCLUSIONS: Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects. Curcumin may be a safe and promising agent for treatment of UC. Clinicaltrials.gov number: NCT01320436. PMID- 25724702 TI - A Curious Cause of Acute Encephalopathy. PMID- 25724703 TI - Changes in the Gastric Mucosa With Aging. AB - BACKGROUND & AIMS: We aimed to characterize age-related changes in the gastric mucosa and investigate the contribution of Helicobacter pylori infection to these changes. METHODS: We collected data from a large national pathology database of 895,323 subjects who underwent esophagogastroduodenoscopy with gastric biopsies from January 2008 through December 2013 at endoscopy centers throughout the United States. The prevalence of various types of gastric histopathology was expressed as percent of the total study population, stratified by sex, age, and state. RESULTS: Over a lifetime, the gastric mucosa became abnormal in 50% of subjects. A higher proportion of people in areas with a high prevalence of H pylori infection acquired gastric abnormalities. H pylori-associated chronic active gastritis and mucosal changes caused by infection were observed in 22% of biopsies; these were the most common gastric abnormalities observed. Reactive gastropathy, which was detected in 18% of biopsies, increased with age and was the second most common factor of gastric pathology observed. CONCLUSIONS: On the basis of an analysis of biopsies collected by esophagogastroduodenoscopy in the United States, gastric abnormalities increase with age. Most pathologic conditions detected by histologic analysis are caused by H pylori infection, but the causes of many others are unknown. PMID- 25724701 TI - Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity. AB - BACKGROUND & AIMS: Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians and patients adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Centers for Disease Control's (CDC) isoniazid severe adverse events program. METHODS: We analyzed Drug-Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities. RESULTS: Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 of these met inclusion criteria. The median age of cases was 49 years (range, 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range, 0-99 days). Thirty-three cases (55%) continued taking isoniazid for more than 7 days after the ATS criteria for stopping were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting criteria for stopping. A delay in stopping was associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for more than 7 days after meeting criteria for stopping. Only 1 of 25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC was reported. CONCLUSIONS: Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the United States, and its hepatotoxicity is under reported significantly. PMID- 25724704 TI - Integrated Care Increases Treatment and Improves Outcomes of Patients With Chronic Hepatitis C Virus Infection and Psychiatric Illness or Substance Abuse. AB - BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infection with psychiatric disorders and/or substance abuse face significant barriers to antiviral treatment. New strategies are needed to improve treatment rates and outcomes. We investigated whether an integrated care (IC) protocol, which includes multidisciplinary care coordination and patient case management, could increase the proportion of patients with chronic HCV infection who receive antiviral treatment (a combination of interferon-based and direct-acting antiviral agents) and achieve a sustained virologic response (SVR). METHODS: We performed a prospective randomized trial at 3 medical centers in the United States. Participants (n = 363 patients attending HCV clinics) had been screened and tested positive for depression, post-traumatic stress disorder, and/or substance use; they were assigned randomly to groups that received IC or usual care (controls) from March 2009 through February 2011. A midlevel mental health practitioner was placed at each HCV clinic to provide IC with brief mental health interventions and case management, according to formal protocol. The primary end point was SVR. RESULTS: Of the study participants, 63% were non-white, 51% were homeless in the past 5 years, 64% had psychiatric illness, 65% were substance abusers within 1 year before enrollment, 57% were at risk for post-traumatic stress disorder, 71% had active depression, 80% were infected with HCV genotype 1, and 23% had advanced fibrosis. Over a mean follow-up period of 28 months, a greater proportion of patients in the IC group began receiving antiviral therapy (31.9% vs 18.8% for controls; P = .005) and achieved a SVR (15.9% vs 7.7% of controls; odds ratio, 2.26; 95% confidence interval, 1.15-4.44; P = .018). There were no differences in serious adverse events between groups. CONCLUSIONS: Integrated care increases the proportion of patients with HCV infection and psychiatric illness and/or substance abuse who begin antiviral therapy and achieve SVRs, without serious adverse events. ClinicalTrials.gov # NCT00722423. PMID- 25724705 TI - Ultrasonography and Transmural Healing in Crohn's Disease. PMID- 25724706 TI - Gender Differences in Fecal Immunochemical Test Performance for Early Detection of Colorectal Neoplasia. AB - BACKGROUND & AIMS: Fecal immunochemical tests (FITs) are used widely in colorectal cancer screening. Programs use the same fecal hemoglobin threshold for colonoscopy referral for men and women, but it is unclear whether FIT performs equally in both sexes. We therefore assessed FIT performance in men and women. METHODS: A prospective cohort study was performed, in which a total of 10,008 average-risk subjects (age, 50-74 y) were invited for first-round screening and 8316 average-risk subjects (age, 51-74 y) were invited for second-round screening with a single FIT. Subjects with a hemoglobin (Hb) level of 10 MUg hemoglobin (Hb)/g (or >=50 ng/mL) feces or higher were referred for colonoscopy. The test characteristics were assessed by sex for a range of FIT cut-off values. RESULTS: In total, 59.8% of men and 64.6% of women participated in the first round (P < .001). At a cut-off level of 10 MUg Hb/g feces, the positivity rate was significantly higher among men (10.7%) compared with women (6.3%; P < .001) in the first round. The detection rate of advanced neoplasia was 4.4% for men and 2.2% for women (P < .001) in the first round. The positive predictive value for advanced neoplasia in the first round was 42% for men and 37% for women (P = .265). A significantly higher false-positive rate in men (6.3%) than in women (4.1%; P < .001) was found. Similar differences in these test characteristics were seen in the second round. CONCLUSIONS: At a cut-off level of 10 MUg Hb/g feces the FIT positivity rate was higher in men, reflected by both a higher detection rate and a higher false-positive rate. The use of the same cut-off value in men and women in FIT screening is recommended based on equal test performance in terms of positive predictive value. PMID- 25724707 TI - An Unexpected Cause of Dysphagia. PMID- 25724708 TI - Diagnostic Accuracy of a Qualitative Fecal Immunochemical Test Varies With Location of Neoplasia But Not Number of Specimens. AB - BACKGROUND & AIMS: We compared the accuracy of a qualitative fecal immunochemical test (FIT) in identifying patients with proximal vs distal advanced neoplasia and evaluated whether analysis of 2 specimens performed better than analysis of 1 specimen. Distal advanced neoplasia was defined as colorectal cancer (CRC), any colorectal adenoma >=10 mm in diameter, high-grade dysplasia, or a lesion with villous or tubulovillous histologic characteristics in a location distal to the splenic flexure, including the descending colon, the rectosigmoid, and the rectum. METHODS: We collected data from 5343 subjects (50-70 years old) who received 2 FITs (Hemosure; cutoff value, 10 MUg hemoglobin/g feces) before colonoscopy in an invitational CRC screening program in Hong Kong from 2008 through 2012. We calculated the FIT's sensitivity, specificity, positive predictive value (PPV), and negative predictive value in detecting colorectal neoplasia. RESULTS: Of the participants, 13.6%, 12.2%, and 6.0% had distal, proximal, and synchronous distal or proximal neoplasia, respectively. Advanced neoplasia was detected in 291 subjects (5.4%); 22 (0.4%) had CRC. FIT detected distal advanced adenoma with 39.7% sensitivity (95% confidence interval [CI], 32.0%-48.0%) vs proximal advanced adenoma with 25.0% sensitivity (95% CI, 17.3% 34.6%; P = .014), distal advanced neoplasia with 40.0% sensitivity (95% CI, 32.5% 47.9%) vs proximal advanced neoplasia with 27.9% sensitivity (95% CI, 20.0% 37.4%; P = .039), and any distal adenoma >=10 mm, irrespective of other lesion characteristics, with 39.5% sensitivity (95% CI, 31.0%-48.7%) vs. proximal adenoma with 25.3% sensitivity (95% CI, 16.5%-36.6%; P = .038). The specificity of FIT in detecting CRC was similar between the proximal and distal colon. FIT detected distal lesions with higher PPV than proximal lesions. One FIT detected advanced neoplasia with 31.8% sensitivity (95% CI, 25.9%-38.4%) and 92.4% specificity (95% CI, 91.6%-93.2%), whereas 2 FITs detected advanced neoplasia with 34.1% sensitivity (95% CI, 28.0%-40.8%; P = .617) and 91.9% specificity (95% CI, 91.0%-92.7%; P = .327). FIT detected distal advanced neoplasia with greater sensitivity and higher PPV than proximal advanced neoplasia. CONCLUSIONS: In an analysis of data from subjects who underwent CRC screening in Hong Kong, FIT detected distal advanced neoplasia with higher sensitivity than proximal advanced neoplasia. Analysis of 1 vs 2 specimens by FIT identified advanced neoplasia with similar test characteristics. PMID- 25724709 TI - Increased Risk of Esophageal Eosinophilia and Eosinophilic Esophagitis in Patients With Active Celiac Disease on Biopsy. AB - BACKGROUND & AIMS: The possible association between eosinophilic esophagitis (EoE) and celiac disease is controversial because prior results have been contradictory. We aimed to determine the relationship between EoE and celiac disease among patients with concomitant esophageal and duodenal biopsies. METHODS: We conducted a cross-sectional study in a U.S. national pathology database by using data from January 2009 through June 2012. Our primary case definition was defined by the presence of esophageal eosinophilia with >=15 eosinophils per high-power field. The crude and adjusted (for age and sex) odds of esophageal eosinophilia for patients with active celiac disease were compared with those without celiac disease. Sensitivity analyses were performed by using more stringent case definitions and by estimating the associations between celiac disease and reflux esophagitis and celiac disease and Barrett's esophagus. RESULTS: Of 292,621 patients in the source population, 88,517 with both esophageal and duodenal biopsies were studied. Four thousand one hundred one (4.6%) met criteria for EoE, and 1203 (1.4%) met criteria for celiac disease. Odds of EoE were 26% higher in patients with celiac disease than in patients without celiac disease (adjusted odds ratio [aOR], 1.26; 95% confidence interval [CI], 0.98-1.60). The magnitude of association varied according to EoE case definition, but all definitions showed a weak positive association between the 2 conditions. There was no association between celiac disease and reflux esophagitis (aOR, 0.95; 95% CI, 0.85-1.07) or Barrett's esophagus (aOR, 0.89; 95% CI, 0.69-1.14) and celiac disease. CONCLUSIONS: There is a weak increase in EoE in patients with celiac disease. This association strengthened with increasingly stringent definitions of EoE and was not observed for other esophageal conditions. In patients with celiac disease, concomitant EoE should be considered in the correct clinical setting. PMID- 25724710 TI - Attitudes Toward Pre-implantation Genetic Diagnosis (PGD) for Genetic Disorders Among Potential Users in Malaysia. AB - While pre-implantation genetic diagnosis (PGD) is available and legal in Malaysia, there is an ongoing controversy debate about its use. There are few studies available on individuals' attitudes toward PGD, particularly among those who have a genetic disease, or whose children have a genetic disease. To the best of our knowledge, this is, in fact, the first study of its kind in Malaysia. We conducted in-depth interviews, using semi-structured questionnaires, with seven selected potential PGD users regarding their knowledge, attitudes and decisions relating to the use PGD. The criteria for selecting potential PGD users were that they or their children had a genetic disease, and they desired to have another child who would be free of genetic disease. All participants had heard of PGD and five of them were considering its use. The participants' attitudes toward PGD were based on several different considerations that were influenced by various factors. These included: the benefit-risk balance of PGD, personal experiences of having a genetic disease, religious beliefs, personal values and cost. The study's findings suggest that the selected Malaysian participants, as potential PGD users, were supportive but cautious regarding the use of PGD for medical purposes, particularly in relation to others whose experiences were similar. More broadly, the paper highlights the link between the participants' personal experiences and their beliefs regarding the appropriateness, for others, of individual decision-making on PGD, which has not been revealed by previous studies. PMID- 25724712 TI - Transient epileptic amnesia: Update on a slowly emerging epileptic syndrome. AB - Transient epileptic amnesia (TEA) is a recently individualized, late-onset, pharmaco-sensitive form of mesial temporal lobe epilepsy with recurrent episodes of acute memory loss, but also interictal memory disturbances characterized by autobiographical and topographical memory impairment and a long-term consolidation deficit. In this article, we review the main clinical and electrophysiological characteristics of TEA, discuss its putative neuroanatomical substrate and mechanisms, common features and how it differs from related concepts, with the overall aim to defend the idea that TEA deserves to be recognized as a distinct epilepsy syndrome. While the pathophysiological basis remains largely unknown, emotional and/or dysimmune factors may have a potential influence. Most importantly, the concept of TEA is highly relevant to tertiary epilepsy and memory clinics, but also to routine neurology practice, leading to an adequate diagnosis and management of epilepsy-related, acute and long-standing memory deficits. PMID- 25724711 TI - Hippocampus and epilepsy: Findings from human tissues. AB - Surgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often enhanced and GABAergic inhibition is preserved. Typically epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in the neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated, not in the hippocampus but in the subiculum, an output region, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity. PMID- 25724713 TI - Malignant Perivascular Epithelioid Cell Tumor (PEComa) of the Adrenal Gland: Report of a Rare Case Posing Diagnostic Challenge with the Role of Immunohistochemistry in the Diagnosis. AB - Histological diagnosis of adrenal tumors is often challenging as diverse groups of tumors, both primaries and metastatic, may be seen in the adrenal gland with overlapping morphological features. Immunohistochemistry (IHC) plays the most important role in their diagnosis. Perivascular epithelioid cell tumor (PEComa), a rarely reported tumor in the adrenal gland, shares many features with another rare tumor sarcomatoid adrenocortical carcinoma (ACC). Extensive immunohistochemical study is required to distinguish this tumor from adrenocortical carcinoma and from other morphologically similar tumors. The unique combination of immunoreactivity for melanocytic markers, such as HMB-45 and Melan A, and myogenic markers, such as smooth muscle actin, is the hallmark of PEComas biological behavior, and prognosis of malignant PEComas is yet to be fully understood. Few cases of malignant PEComa have been reported in the adrenal gland. We report a case of malignant PEComa of the adrenal gland posing diagnostic challenge and compare its morphological and immunohistochemical features with those of sarcomatoid ACC. PMID- 25724714 TI - MDCT of extranodal mantle cell lymphoma: a single institute experience. AB - OBJECTIVE: To study the pattern of extranodal and particularly gastrointestinal (GI) involvement of mantle cell lymphoma (MCL) on MDCT MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, MDCT features of 78 patients (62 males and 16 females, mean age 57 years) with MCL including 28 patients at presentation were reviewed. Clinical and histopathological (blastoid vs. non-blastoid) data were noted from medical records. RESULTS: Extranodal involvement was present in overall 51/78 patients on CT (65%), 18/28 (64%) patients at presentation. Spleen (21/78-27%) and bowel (19/78-24%) were the most common sites of extranodal involvement by MCL on imaging, followed by lungs (10/78-13%) and skin/subcutaneous tissue (9/78-12%). Bowel involvement was either in the form of endophytic polypoidal lesions (n = 11, mean size 3.1 cm), as focal mild bowel wall thickening (n = 5, mean thickness 1.4 cm), or as combination of the two (n = 3). Blastoid histology was present in 14/78 (24%) patients and was statistically associated with skin/subcutaneous involvement (p < 0.05; Fisher's exact t test). Median follow-up was 72 months during which 21 patients died with median survival of 48 months (26 months for blastoid histology vs. 47 months for non-blastoid histology). There was no statistical correlation between sites of involvement and survival. CONCLUSIONS: MCL has a predilection for extranodal disease, predominantly involving the spleen, bowel, lungs, and subcutaneous tissue. GI involvement on CT is in the form of endoluminal polypoidal lesions and mild bowel wall thickening. Skin/subcutaneous involvement was statistically more common with blastoid histology in our study. PMID- 25724715 TI - Biotransformation of rutin to isoquercitrin using recombinant alpha-L rhamnosidase from Bifidobacterium breve. AB - OBJECTIVES: To biotransform rutin into isoquercitrin. RESULTS: A alpha-L rhamnosidase from Bifidobacterium breve was produced by using Escherichia coli BL21 for biotransformation of rutin to isoquercitrin. The enzyme was purified by Ni(2+)-NTA chromatography to yield a soluble protein with a specific activity of 56 U protein mg(-1). The maximum enzyme activities were at pH 6.5, 55 degrees C, 20 mM rutin, and 1.2 U enzyme ml(-1). Under optimal conditions, the half-life of the enzyme was 96 h. The K m and V max values were 2.2 mM, 56.4 MUmol mg(-1) min( 1) and 2.1 mM, 57.5 MUmol mg(-1) min(-1) using pNP-Rha and rutin as substrates, respectively. The kinetic behavior indicated that the recombinant alpha-L rhamnosidase has good catalytic performance for producing isoquercitrin. 20 mM rutin was biotransformed into 18.25 and 19.87 mM isoquercitrin after 60 and 240 min. CONCLUSION: The specific biotransformation of rutin to isoquercitrin using recombinant alpha-L-rhamnosidase from B. breve is a feasible method for use in industrial processes. PMID- 25724716 TI - A simple and rapid approach to manipulate pseudorabies virus genome by CRISPR/Cas9 system. AB - OBJECTIVES: The broad host range of pseudorabies virus (PRV) and large capacity for foreign DNA make it a promising vector for the development of vaccines and agents of gene therapy. RESULTS: We show that up to 100 % viral gene disrupting efficiency was achieved by simple co-transfection of the purified PRV genomes with the clustered regularly-interspaced, short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) into cells. Furthermore, CRISPR/Cas9 mediated knock-in of >4-kb-long DNA cassettes into the PRV genome at a positive rate of 50 % by a homology-independent DNA repair mechanism without constructing homology arms. This approach requires only a simple plasmid construction and is applicable to knock-in of other foreign genes. CONCLUSION: Our studies offered simple and efficient methods to manipulate PRV. PMID- 25724717 TI - Enhanced production of poly-3-hydroxybutyrate by Escherichia coli over-expressing multiple copies of NAD kinase integrated in the host genome. AB - OBJECTIVES: With the help of attB-attP recombination technique, multiple copies of yfjB gene encoding the NAD kinase of Escherichia coli were inserted into the host chromosome to promote NADPH-dependent poly-3-hydroxybutyrate (PHB) production. RESULTS: The yfjB integration mutant E. coli T2 harbored a similar metabolic profile to that of the wild type control. When PHB biosynthesis operon was introduced, the yfjB integration mutant produced 3 g PHB l(-1) from 18.2 g glucose l(-1), while the wild type consumed 15.7 g glucose l(-1) to afford 2.34 g PHB l(-1) in 48 h of shake-flask cultivation. Transcriptional analysis showed that the transcription levels of genes within the PHB biosynthesis operon were increased by six to eightfold with yfj Bover-expression, which may be the primary reason for the improved PHB production. CONCLUSION: A practical method is demonstrated to construct genetically-stable strains harboring extra copies of NAD kinase to enhance NADPH-dependent reactions. PMID- 25724718 TI - Purification and characterization of a novel alpha-glucosidase from Malbranchea cinnamomea. AB - OBJECTIVES: To characterize a novel alpha-glucosidase from the thermophilic fungus Malbranchea cinnamomea. RESULTS: The enzyme was purified to homogeneity with purification fold of 40 and a recovery of 7.2 %. It was a monomer with molecular mass of 65.7 kDa on SDS-PAGE. It was optimally active at pH 6 and 50 degrees C (measured over 10 min) and exhibited a wide range of substrate specificity with the highest specific activity of 47.4 U mg(-1) for p-nitrophenyl alpha-D-glucopyranoside (pNPGlu) followed by isomaltose, panose and sucrose, suggesting that the enzyme belongs to the type I alpha-glucosidases. The K m values of the alpha-glucosidase for pNPGlu and isomaltose were 1.1 and 19.3 mM, respectively. CONCLUSION: Because of its unique properties, the alpha-glucosidase may have a potential in several industrial applications. PMID- 25724719 TI - Generation by reverse genetics of an effective attenuated Newcastle disease virus vaccine based on a prevalent highly virulent Chinese strain. AB - OBJECTIVES: To investigate whether the differences between the circulating Newcastle disease virus (NDV) isolates and the used vaccine might account for the current ND outbreaks in vaccinated poultry flocks. RESULTS: A reverse genetics system using prevalent genotype VIId isolate SG10 was constructed and a mutant virus, named aSG10, was developed by changing the virulent F protein cleavage site motif "(112)RRQKR?F(117)" into an avirulent motif "(112)GRQGR?L(117)". The attenuated pathogenicity of aSG10 was confirmed from the mean death time and intracerebral pathogenicity index. aSG10 and LaSota both protected vaccinated birds from death after challenge with highly virulent genotype VII NDV, strain SG10. However, aSG10 significantly reduced the challenge virus shedding from the vaccinated birds compared to LaSota vaccine. We also generated a recombinant virus, aSG10-enhanced green fluorescent protein (EGFP), which expresses EGFP. aSG10-EGFP stably expressed EGFP for at least 10 passages. CONCLUSIONS: The mutant, aSG10, can be safely used as a vaccine vector and is a potential vaccine candidate in increasing the protective efficacy for the control of current ND epidemic in China. PMID- 25724720 TI - Strategy for enhancing adenosine production under the guidance of transcriptional and metabolite pool analysis. AB - OBJECTIVES: To rationally identify targets for enhancing adenosine production, transcription level of genes involved in adenosine synthesis of Bacillus subtilis XGL was detected during the fermentation process, complemented with metabolite pool analysis. RESULTS: PurR-regulated genes (pur operon and purA) and prs were down-regulated and 5-phosphoribosyl 1-pyrophosphate (PRPP) decreased considerably after 24 h when adenosine significantly accumulated. Since PRPP could strongly antagonize the binding of PurR to its targets, it was inferred that down regulation of pur operon and purA might be due to a low PRPP pool, which was confirmed by metabolite analysis. So desensitized prs responsible for PRPP synthesis was overexpressed, resulting in increased PRPP concentration and pur operon transcription. To further enhance the adenosine production, desensitized purF and prs were co-overexpressed with integrating additional copy of purA to B. subtilis XGL genome, resulting in 24.3 % (1.29 g/g DCW) higher adenosine production than that by B. subtilis XG. CONCLUSIONS: Overexpression of prs, purF and purA under the guidance of transcriptional and metabolite pool analysis significantly increased adenosine production. Strategies used in this study have potential applications for rational modification of industrial microorganisms. PMID- 25724721 TI - Safety and efficacy outcomes of protamine administration for heparin reversal following cryoballoon-based pulmonary vein isolation. AB - PURPOSE: Anticoagulation with heparin is required during catheter ablation of atrial fibrillation (AF) to reduce systemic thromboembolism. In this study, we aim to compare safety and efficacy outcomes between patients who receive protamine administration for reversal of heparin and those who do not, following cryoballoon-based pulmonary vein isolation (PVI) for AF. METHODS: Patients with symptomatic paroxysmal or persistent AF despite >=1 antiarrhythmic drug(s) were scheduled for PVI per the recent consensus recommendations. Some patients were administered protamine at the end of the procedure depending on the operator's choice. RESULTS: Among 380 patients [48.2% male, 56 (20-86) years] that were enrolled, 188 patients received protamine at the end of the procedure. Baseline characteristics did not differ between groups (p > 0.05). Mean protamine dose was 39.1 +/- 6.4 mg. Only 1 patient developed rash following protamine infusion. Hospital stay was significantly shorter in patients who were administered protamine (1 [1-5] vs. 2 [1-7] days, p < 0.001). Hematoma/pseudoaneurysm or femoral AV fistula requiring surgical or interventional repair in the femoral access site occurred in 2 (1.1 %) patients who received protamine and 12 (6.3%) patients who did not (p = 0.011). Deep vein thrombosis was seen in 1 patient in whom protamine was not administered (p = 0.499). CONCLUSION: To the best of our knowledge, this is one of the largest series showing that protamine administration for heparin reversal in patients undergoing cryoballoon-based PVI allows quicker sheath removal and minimizes the risk of potential vascular complications without causing an increase in thrombotic events. PMID- 25724722 TI - Identification of novel cyclic nucleotide binding proteins in Trypanosoma cruzi. AB - Cyclic AMP has been implicated as second messenger in a wide range of cellular processes. In the protozoan parasite Trypanosoma cruzi, cAMP is involved in the development of the parasite's life cycle. While cAMP effectors have been widely studied in other eukaryotic cells, little is known about cAMP's mechanism of action in T. cruzi. To date, only a cAMP-dependent protein kinase A (PKA) has been cloned and characterised in this parasite; however experimental evidence indicates the existence of cAMP-dependent, PKA-independent events. In order to identify new cAMP binding proteins as potential cAMP effectors, we carried out in silico studies using the predicted T. cruzi proteome. Using a combination of search methods 27 proteins with putative cNMP binding domains (CBDs) were identified. Phylogenetic analysis of the CBDs presented a homogeneous distribution, with sequences segregated into two main branches: one containing kinases-like proteins and the other gathering hypothetical proteins with different function or no other known. Comparative modelling of the strongest candidates provides support for the hypothesis that these proteins may give rise to structurally viable cyclic nucleotide binding domains. Pull-down and nucleotide displacement assays strongly suggest that TcCLB.508523.80 could bind cAMP and eventually be a new putative PKA-independent cAMP effector in T. cruzi. PMID- 25724723 TI - Chromatin methylation and cardiovascular aging. AB - DNA and histone methylation are well characterized epigenetic marks that are altered during the aging process. In aged cells and tissues, DNA cytosine tagging by methylation undergoes the so-called "epigenetic drift", in parallel with a change in the methylated histone profile. Despite the large body of knowledge regarding age-dependent epigenetic changes, there are few reports related to this topic in the cardiovascular field. This review summarizes age-dependent changes in DNA and histone methylation with a specific focus on age-related cardiovascular diseases (CVDs). PMID- 25724725 TI - Transplantation of adipose tissue-derived stem cells improves cardiac contractile function and electrical stability in a rat myocardial infarction model. AB - The transplantation of adipose tissue-derived stem cells (ADSCs) improves cardiac contractility after myocardial infarction (MI); however, little is known about the electrophysiological consequences of transplantation. The purpose of this study was to clarify whether the transplantation of ADSCs increases or decreases the incidence of ventricular tachyarrhythmias (VT) in a rat model of MI. MI was induced experimentally by permanent occlusion of the left anterior descending artery of Lewis rats. ADSCs were harvested from GFP-transgenic rats, and were cultured until passage four. ADSCs (10*10(6)) resuspended in 100MUL saline or pro survival cocktail (PSC), which enhances cardiac graft survival, were injected directly into syngeneic rat hearts 1week after MI. The recipients of ADSCs suspended in PSC had a larger graft area compared with those receiving ASDCs suspended in saline at 1week post-transplantation (number of graft cells/section: 148.7+/-10.6 vs. 22.4+/-3.4, p<0.05, n=5/group). Thereafter, all ADSC recipients were transplanted with ASDCs in PSC. ADSCs were transplanted into infarcted hearts, and the mechanical and electrophysiological functions were assessed. Echocardiography revealed that ADSC recipients had improved contractile function compared with those receiving PSC vehicle (fractional shortening: 21.1+/-0.9 vs. 14.1+/-1.2, p<0.05, n>=12/group). Four weeks post-transplantation, VT was induced via in vivo programmed electrical stimulation. The recipients of ADSCs showed a significantly lower incidence of induced VT compared with the control (31.3% vs. 83.3%, p<0.05, n>=12/group). To understand the electrical activity following transplantation, we performed ex vivo optical mapping using a voltage sensitive dye, and found that ADSC transplantation decreased conduction velocity and its dispersion in the peri-infarct area. These results suggest that ADSC transplantation improved cardiac mechanical and electrophysiological functions in subacute MI. PMID- 25724724 TI - beta-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model. AB - A five-state model of myofilament contraction was integrated into a well established rabbit ventricular myocyte model of ion channels, Ca(2+) transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by beta adrenergic stimulation (beta-AS). beta-AS effect on sarcoplasmic reticulum Ca(2+) handling, Ca(2+), K(+) and Cl(-) currents, and Na(+)/K(+)-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca(2+) sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental beta-AS responses on action potentials and Ca(2+) transient amplitude and kinetics. It also replicated the behavior of force-Ca(2+), release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The beta-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing beta-AS effects on L-type Ca(2+) channels or phospholamban limited Ca(2+) transients and contractile responses in parallel, while blocking phospholemman and K(+) channel (IKs) effects enhanced Ca(2+) and inotropy. Removal of beta-AS effects from XBCa enhanced contractile force while decreasing peak Ca(2+) (due to greater Ca(2+) buffering), but had less effect on shortening. Conversely, preventing beta-AS effects on XBcy preserved Ca(2+) transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of beta-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. beta-AS effects on XBCa and XBcy have greater impact on isometric and isotonic contraction, respectively. PMID- 25724726 TI - Prostate cancer-associated autoantibodies in serum against tumor-associated antigens as potential new biomarkers. AB - The limitations of the current prostate cancer (PCa) screening tests demands new biomarkers for early diagnosis of PCa. In this study, we aim to investigate serum autoantibody signatures as PCa specific biomarkers. PCa proteins were resolved by 2-DE and then transferred onto polyvinylidene difluoride membrane, which were subsequently incubated with either pooled serum from PCa patients or from normal controls. Mass spectrometry results have identified 18 antigens from 21 different 2-DE spots associated with PCa. Autoantibody response to antigens PRDX2, PRDX6 and ANXA11 in PCa patient's sera was confirmed using recombinant antigens. Further validation with an independent set of PCa patient's sera have shown relatively increased abundance of PRDX6 and ANXA11 antibodies in PCa patients. Formal concept analysis method was applied to assess whether the abundance of these autoantibodies could influence the classification of patients. However, sensitivity of the single antibody to discriminate prostate tumor and healthy controls varies from 70% to 80%, whereas combination of both PRDX6 and ANXA11 antibodies increased sensitivity to 90% for tumors and 100% for healthy controls. Therefore, we hereby report that the detection of these antibodies in PCa patient's serum in combination with the existing non-invasive diagnostic procedures may have significance in PCa diagnosis. BIOLOGICAL SIGNIFICANCE: The present study aimed to investigate serum autoantibody signatures as new biomarkers for early diagnosis of prostate cancer (PCa). To investigate serum autoantibodies in patients with PCa, we used proteomics approach based on two dimensional gel electrophoresis (2-DE) and mass spectrometry. Total tissue proteins extracted from prostate were separated by 2-DE and then transferred onto polyvinylidene difluoride (PVDF) membrane, which were subsequently incubated with either pooled serum from PCa patients or from normal controls with no history for PCa. Proteomic analysis results have identified 18 antigens that showed antibody response specifically to cancer patient's serum. For validation experiments using recombinant antigens, confirmed autoantibody response to three antigens PRDX2, PRDX6 and ANXA11. Further validation using a second independent set of PCa patient's sera has shown relatively increased abundance of PRDX6 and ANXA11 antibodies specifically in PCa patients. Partition analysis of patients based on abundance of autoantibodies highlighted a combination of both PRDX6 and ANXA11 antibodies in serum with 90% sensitivity in case of tumors and 100% in case of healthy controls. Therefore, we hereby report that the detection of these antibodies in PCa patient's serum in combination with known markers may have significance in diagnosis of PCa with further validation in larger cohort of samples. PMID- 25724727 TI - Quantitative proteomics of nuclear phosphoproteins in the root tip of soybean during the initial stages of flooding stress. AB - Soybean is sensitive to flooding stress, which has affected many proteins in roots. To identify the upstream events controlling the regulation of flooding responsive proteins, nuclear phosphoproteomics of soybean-root tip was performed. Nuclei were isolated from the root tip of 2-day-old soybeans treated with flooding for 3h. The purity of nuclear fractions was confirmed by Western blotting and enzyme-activity assays for subcellular-specific enzymes. Phosphopeptides in the fractions were enriched and analyzed using gel-free proteomic technique. Fourteen phosphoproteins significantly changed in root tip in response to flooding stress. Of these phosphoproteins, 10 proteins including 5 protein synthesis-related proteins were predicted to be localized in the nucleus. In particular, zinc finger/BTB domain-containing protein 47, glycine-rich protein, and rRNA processing protein Rrp5, which are related to abscisic acid (ABA) response, were clearly phosphorylated in response to flooding stress. The mRNA expression levels of these nuclear phosphoproteins were down-regulated in root tip exposed to flooding stress with ABA. In addition, the fresh weight of soybean decreased under flooding stress with ABA, although the fresh weight of plant increased during the initial stage of flooding stress. These results suggest that ABA may affect the flooding response of early-stage soybean through the regulation of nuclear-localized phosphoproteins. BIOLOGICAL SIGNIFICANCE: This study reported nuclear phosphoprotein analysis of root tip under initial flooding stress using gel-free quantitative proteomics. The main findings of this study are as follows: (i) Fourteen nuclear phosphoproteins in soybean root tip cells were significantly changed in the initial stages of flooding stress; (ii) Zinc finger protein, glycine-rich protein, and Rrp5 were phosphorylated in the nuclei of root tip in response to flooding; and (iii) The mRNA expression levels of these genes were down-regulated by ABA under flooding conditions. These results suggest that ABA may be involved in the initial responses of early-stage soybean to flooding stress by altering the phosphorylation of nuclear-localized phosphoproteins. This study provides not only the nuclear phosphoproteomic analysis but also the molecular mechanism underlying the initial flooding responsive nuclear phosphoproteins functions in the root tip of soybean. PMID- 25724728 TI - Alterations of protein expression in serum of infants with intrauterine growth restriction and different gestational ages. AB - Intrauterine growth restriction (IUGR) is associated with increased morbidity and metabolic anomalies in adults. The serum proteome of venous blood was compared in 43 IUGR and 45 adequate gestational age (AGA) infants, separated into three gestational age groups, "Very Preterm" 29-32weeks, "Moderate Preterm" 33-36w, and, "Term" >=37weeks, in samples drawn three times from birth to 1month of life. After depleting the abundant serum proteins (ProteoMiner(TM)), expression changes were studied by 2-DE, image analysis (Proteomweaver 4.0(TM)), and identification by MALDI-TOF/TOF. Significant expression differences were found in thirty-four proteins, and thirty-three were identified. Lysophospholipid acyltransferase 7 (MBOAT7), was detected exclusively in IUGR of all gestational ages and sampling times; seven other proteins were found only in AGA. Another twenty-five proteins had intensity changes >=2.5 folds in IUGR: twenty were upregulated and five downregulated. Western blots confirmed the identification of several proteins: MBOAT7 increased 20.5-fold in IUGR, while AGA had 11.2-fold higher levels of SUMO3 and sumoylated proteins and 13.7-fold higher levels of APOL1. Upregulation of MBOAT7 in IUGR neonates could be an adaptive response to protect the brain from an adverse environment. BIOLOGICAL SIGNIFICANCE: There are significant protein expression differences between IUGR and AGA at different gestational age groups and blood extraction times. The extensive upregulation of lysophospholipid acyltransferase 7 in all IUGR gestational ages and extraction times might be an adaptative response to an adverse fetal environment, reminiscent of Barker's fetal programming theory. Two serotransferrins were also upregulated in IUGR of all gestational ages. Just at birth "Very Preterm" IUGR showed nine upregulated proteins, including five albumins, apolipoprotein E, keratin type I cytoskeletal 10, solute carrier family member 2 fragment, and anaphase-promoting complex subunit 2. PMID- 25724729 TI - Comparative proteomic analysis of Listeria monocytogenes ATCC 7644 exposed to a sublethal concentration of nisin. AB - Listeria monocytogenes infections have been frequently reported in many food poisoning outbreaks around the world. In this work, the protein repertoires of L. monocytogenes ATCC 7644 cells treated or not with a 10(-3)mg/mL nisin sublethal concentration, established by antimicrobial susceptibility tests, were analyzed by LC-MS/MS. Overall, 179 proteins were identified, 9 of them more abundant in nisin-treated samples, and 4 more abundant in non-treated control samples. In nisin treated cells, proteins associated to oxidative stress response showed higher abundance. Also, the higher abundance of an enzyme related to the production of cell membrane lipids upon nisin exposure is suggestive of both a failure in conventional cell division mechanism and the activation of an alternative L-form mediated division mechanism. Finally, flagellar and motility proteins' overexpression upon nisin exposure is indicative of increased bacterial motility in response to the bacteriocin. Taken together, these results provide new insights on nisin effects on L. monocytogenes cells and on how this bacterium may overcome a bacteriocin-containing environment. BIOLOGICAL SIGNIFICANCE: The antimicrobial mechanism of nisin on target bacterial cells has been extensively studied since discovery of this bacteriocin. The nisin pore-forming mechanism is mediated by its binding to the pyrophosphate portion of membrane lipid II [1], but some evidences point out to alternative mechanisms. Results from assays with mutacin 1140 hybrids [2] showed that the portion of nisin that is not involved with lipid II binding could damage the bacterial cell, independently of pore formation [3,4]. Moreover, there are insufficient data to explain how nisin affects the bacterial survival. In this scenario, proteomics is an interesting approach, as a comparison between treated and untreated cells may provide insights of both antimicrobial mechanisms of action and bacterial response mechanisms [5]. PMID- 25724730 TI - Quantitative proteomic study of Aspergillus Fumigatus secretome revealed deamidation of secretory enzymes. AB - Aspergillus sp. plays an essential role in lignocellulosic biomass recycling and is also exploited as cell factories for the production of industrial enzymes. This study profiled the secretome of Aspergillus fumigatus when grown with cellulose, xylan and starch by high throughput quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ). Post translational modifications (PTMs) of proteins play a critical role in protein functions. However, our understanding of the PTMs in secretory proteins is limited. Here, we present the identification of PTMs such as deamidation of secreted proteins of A. fumigatus. This study quantified diverse groups of extracellular secreted enzymes and their functional classification revealed cellulases and glycoside hydrolases (32.9%), amylases (0.9%), hemicellulases (16.2%), lignin degrading enzymes (8.1%), peptidases and proteases (11.7%), chitinases, lipases and phosphatases (7.6%), and proteins with unknown function (22.5%). The comparison of quantitative iTRAQ results revealed that cellulose and xylan stimulates expression of specific cellulases and hemicellulases, and their abundance level as a function of substrate. In-depth data analysis revealed deamidation as a major PTM of key cellulose hydrolyzing enzymes like endoglucanases, cellobiohydrolases and glucosidases. Hemicellulose degrading endo 1,4-beta-xylanase, monosidases, xylosidases, lignin degrading laccase, isoamyl alcohol oxidase and oxidoreductases were also found to be deamidated. BIOLOGICAL SIGNIFICANCE: The filamentous fungi play an essential role in lignocellulosic biomass recycling and fungal strains belonging to Aspergillus were also exploited as cell factories for the production of organic acids, pharmaceuticals, and industrially important enzymes. In this study, extracellular proteins secreted by thermophilic A. fumigatus when grown with cellulose, xylan and starch were profiled using isobaric tags for relative and absolute quantification (iTRAQ) by adopting liquid chromatography tandem mass spectrometry. The comparison of quantitative iTRAQ results revealed that cellulose and xylan stimulate expression of specific cellulases and hemicellulases, and expression level as a function of substrate. Post translational modifications revealed deamidation of key cellulases including endoglucanases, cellobiohydrolases and glucosidases; and hemicellulases and lignin degrading enzymes. The knowledge on deamidated enzymes along with specific sites of modifications could be crucial information for further functional studies of these enzymes of A. fumigatus. PMID- 25724731 TI - N-Sulfonylation of amines, imides, amides and anilides using p-TsCl in presence of atomized sodium in EtOH-THF under sonic condition. AB - A simple, facile and an efficient procedure for the N-sulfonylation of amines, imides, amides and anilides using p-TsCl in the presence of atomized sodium in a mixture of EtOH-THF under sonic condition is developed. The method is rapid, mild and inexpensive; yields are high and the reactions go to completion within 2-8 min. PMID- 25724732 TI - The synthesis of cadmium sulfide nanoplatelets using a novel continuous flow sonochemical reactor. AB - A continuous flow sonochemical reactor was developed capable of producing metastable cadmium sulfide (CdS) nanoplatelets with thicknesses at or below 10nm. The continuous flow sonochemical reactor included the passive in-line micromixing of reagents prior to sonochemical reaction. Synthesis results were compared with those from reactors involving batch conventional heating and batch ultrasound induced heating. The continuous sonochemical synthesis was found to result in high aspect ratio hexagonal platelets of CdS possessing cubic crystal structures with thicknesses well below 10nm. The unique shape and crystal structure of the nanoplatelets are suggestive of high localized temperatures within the sonochemical process. The particle size uniformity and product throughput are much higher for the continuous sonochemical process in comparison to the batch sonochemical process and conventional synthesis processes. PMID- 25724733 TI - Robotic-assisted gait training in neurological patients: who may benefit? AB - Regaining one's ability to walk is of great importance for neurological patients and is a major goal of all rehabilitation programs. Gait training of severely affected patients after the neurological event is technically difficult because of their motor weakness and balance disturbances. An innovative locomotor training that incorporates high repetitions of task-oriented practice by the use of body weight-supported treadmill training (BWSTT) was developed to overcome these obstacles. To facilitate the delivery of BWSTT, a motorized robotic driven gait orthosis (robotic-assisted gait training-RAGT) was developed. Two types of robotic gait devices were developed, end-effector and exoskeleton devices. Several randomized controlled trials have been published regarding the usage of RAGT in patients after stroke, spinal cord injury (SCI), multiple sclerosis (MS) and other neurological diseases. According to these trials, the usage of RAGT in combination with conventional rehabilitation treatment has some additive beneficial effect on the ambulation abilities mainly in sub-acute stroke and sub acute SCI patients. No difference was found between the two types of robotic gait devices. No sufficient data regarding an optimal protocol of RAGT is available, however a longer duration and a higher intensity of RAGT seem to have more beneficial effect on the final functional ambulation outcomes. Larger controlled studies are still required to determine the optimal timing and protocol design for the maximal efficacy and long-term outcome of RAGT in neurological patients. PMID- 25724734 TI - Metastasis to submandibular glands in oral cavity cancers: Can we preserve the gland safely? AB - OBJECTIVE: To analyze submandibular gland (SMG) involvement in cases of oral cavity cancers and decide whether to remove submandibular glands while performing neck dissections for oral cavity cancers to decrease the incidence of xerostomia, a common issue post-operatively. METHODS: Retrospective analysis of 157 neck dissections out of 204 neck dissections performed for oral cavity carcinomas in the Department of Otolaryngology and Head and Neck Surgery from 2008 to 2013 was done. SMG was bilaterally removed in 6 dissections, hence a total of 163 glands were analyzed. Those involved by tumor in histopathology were further studied for the pattern of involvement. RESULTS: 3.68% (6/163) glands showed involvement by the tumor. 9.20% (15/163) showed chronic sialo-adenitic changes. Four of the six involved glands showed direct contiguous spread from primary lesion, one showed extra-capsular spread from level IB lymph nodes and evidence of both modes of spread was seen in one. Evidence of metastasis was not seen in any of the glands (0%). Literature review showed a metastasis rate of 0.096% (2/2074). CONCLUSION: Metastatic involvement of submandibular gland is extremely rare. Submandibular gland preservation, in the absence of evidence of gross contiguous involvement, does not affect survival. Hence, SMG can be safely spared during neck dissections for oral cavity squamous cell cancers except in certain situations such as close proximity of the primary lesion to gland, presence of intra-capsular lymph nodes in radiology, gross intraoperative evidence of invasion of the SMG and in salvage surgeries performed in post-irradiated and recurrent cases. PMID- 25724735 TI - Early growth response-1 facilitates enterovirus 71 replication by direct binding to the viral genome RNA. AB - Enterovirus 71 (EV71) infections can cause hand, foot and mouth disease (HFMD), meningoencephalitis, neonatal sepsis, and even fatal encephalitis in children. Unfortunately, there is currently no effective treatment for EV71 infection due to the lack of understanding of viral replication and infection; and viral infections have emerged as an imperative global hazard. Thus, it is extremely important to understand the mechanism of EV71 replication in order to prevent and control the diseases associated with EV71 infections. Early growth response-1 (EGR1) is a multifunctional transcription factor that regulates diverse biological functions, including inflammation, apoptosis, differentiation, tumorigenesis, and even viral infection. Here, we provide new insight into the role of EV71 infection in regulating EGR1 production; and reveal a novel mechanism by which EGR1 facilitates EV71 replication. We demonstrate that EV71 activates EGR1 expression during infection by stimulating the protein kinase A/protein kinase CE/phosphoinositide 3-kinase/Akt (PKA/PKCE/PI3K/Akt) cascade. We further reveal that EV71-activated EGR1, in turn, regulates the internal ribosomal entry site (IRES) of EV71 to enhance viral replication. In addition, EGR1 facilitates EV71 replication by binding directly to stem-loops I and IV of EV71 5'-untranslated region (5'UTR) with its first two zinc fingers. Moreover, EGR1 protein co-localizes with EV71 RNA in the cytoplasm of infected cells to facilitate viral replication. Our results reveal an important new role of EGR1 in viral infection, provide new insight into the novel mechanism underlying the regulation of EV71 replication, and suggest a potential application of EGR1 in the control of EV71 infection. PMID- 25724736 TI - Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis. AB - Understanding the mechanisms responsible for the resistance against chemotherapy induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation is known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anticancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA-MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxol induced UPR activation differently according to the different UPR pathways (PERK, ATF6, and IRE1alpha). The putative involvement of these signaling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, which occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxol-induced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors. PMID- 25724737 TI - Polo-like kinase 3 (PLK3) mediates the clearance of the accumulated PrP mutants transiently expressed in cultured cells and pathogenic PrP(Sc) in prion infected cell line via protein interaction. AB - Polo-like kinases (PLKs) family has long been known to be critical for cell cycle and recent studies have pointed to new dimensions of PLKs function in the nervous system. Our previous study has verified that the levels of PLK3 in the brain are severely downregulated in prion-related diseases. However, the associations of PLKs with prion protein remain unclear. In the present study, we confirmed that PrP protein constitutively interacts with PLK3 as determined by both in vitro and in vivo assays. Both the kinase domain and polo-box domain of PLK3 were proved to bind PrP proteins expressed in mammalian cell lines. Overexpression of PLK3 did not affect the level of wild-type PrP, but significantly decreased the levels of the mutated PrPs in cultured cells. The kinase domain appeared to be responsible for the clearance of abnormally aggregated PrPs, but this function seemed to be independent of its kinase activity. RNA-mediated knockdown of PLK3 obviously aggravated the accumulation of cytosolic PrPs. Moreover, PLK3 overexpression in a scrapie infected cell line caused notable reduce of PrP(Sc) level in a dose dependent manner, but had minimal effect on the expression of PrP(C) in its normal partner cell line. Our findings here confirmed the molecular interaction between PLK3 and PrP and outlined the regulatory activity of PLK3 on the degradation of abnormal PrPs, even its pathogenic isoform PrP(Sc). We, therefore, assume that the recovery of PLK3 in the early stage of prion infection may be helpful to prevent the toxic accumulation of PrP(Sc) in the brain tissues. PMID- 25724738 TI - Self-identification of the clinical fertile window and the ovulation period. AB - OBJECTIVE: To assess the sensitivity and specificity of the self-identified fertile window. DESIGN: Observational study. SETTING: Not applicable. PATIENT(S): A total of 107 women. INTERVENTION(S): Women recorded cervical mucus observation and basal body temperature daily while undergoing daily ovarian ultrasound. MAIN OUTCOME MEASURE(S): The biological fertile window, defined as the 6 days up to and including the day of ovulation; and the 2-day ovulation window, defined as the day before and the day of ovulation. RESULT(S): The self-identification of the biological fertile window by the observation of any type of cervical mucus provides 100% sensitivity but poor specificity, yielding a clinical fertile window of 11 days. However, the identification of the biological fertile window by peak mucus (defined as clear, slippery, or stretchy mucus related to estrogen) yielded 96% sensitivity and improved specificity. The appearance of the peak mucus preceded the biological fertile window in less than 10% of the cycles. Likewise, this type of mucus identified the ovulation window with 88% sensitivity. CONCLUSION(S): These results suggest that, when perceived accurately, more accurate clinical self-detection of the fertile window can be obtained by identification of peak mucus. This may improve efforts to focus intercourse in the fertile phase for couples with fertility concerns. PMID- 25724739 TI - G protein-coupled estrogen receptor 1 agonist G-1 induces cell cycle arrest in the mitotic phase, leading to apoptosis in endometriosis. AB - OBJECTIVE: To demonstrate the effects of the selective G protein-coupled estrogen receptor 1 (GPER) agonist G-1 in human ovarian endometriotic stromal cells (ESCs). DESIGN: Experimental in vitro study. SETTING: University hospital. PATIENT(S): A total of 33 patients with ovarian endometrioma. INTERVENTION(S): Endometriotic stromal cells from ovarian chocolate cysts were treated with the GPER agonist G-1. MAIN OUTCOME MEASURE(S): The primary outcomes were cell proliferation, measured using the WST-8 assay; cell cycle, as analyzed using flow cytometry, fluorescent immunocytochemistry, and cytotoxicity; caspase activity, as measured by fluorescent and luminescent enzyme assays; and protein expression levels, as determined by Western blot analysis. RESULT(S): G-1 suppressed ESC proliferation in a concentration-dependent manner. The inhibitory effect was not blocked when GPER signaling pathways, including the GPER itself, were inhibited. G-1 induced cell cycle arrest and accumulation in the sub-G1 phase in ESCs. Immunofluorescence analysis demonstrated that G-1 interrupted microtubule assembly at the mitotic phase. G-1 also induced caspase-3-dependent apoptosis without significant cytotoxicity. CONCLUSION(S): G-1 suppressed proliferation and induced apoptosis in ESCs, suggesting the potential use of this compound as a therapeutic drug for the treatment of endometriosis. PMID- 25724740 TI - Avoiding ovarian hyperstimulation syndrome with the use of gonadotropin-releasing hormone agonist trigger. AB - Ovarian hyperstimulation syndrome (OHSS) is one of the most serious, and potentially lethal, complications of controlled ovarian stimulation (COS). Induction of final oocyte maturation with a bolus of gonadotropin-releasing hormone (GnRH) agonist (GnRHa), instead of the criterion standard hCG, in patients undergoing ovarian stimulation significantly reduces the risk of OHSS and could be considered to be more physiologic. A bolus of GnRHa used in this context also acts as a luteolytic agent. From a clinical point of view, the most significant benefit of GnRHa trigger is its ability to induce quick and reversible luteolysis and thus reducing the risk of OHSS development. This paper describes the pathophysiology of OHSS, focusing specifically on the luteolytic benefits of using GnRHa to decrease OHSS and the possible corpus luteum rescue modalities available. PMID- 25724741 TI - Multiple pregnancy: changing expectations for patients and patterns for physicians. PMID- 25724742 TI - Perinatal factors associated with the development of cow's milk protein allergy. AB - The prevalence of cow's milk protein allergy (CMPA) has increased in recent years, and is associated with antimicrobial use during the perinatal period, prematurity, the type of childbirth, and the decrease in breastfeeding. The aim of this study was to analyze whether there is any association between these factors and the development of CMPA. MATERIAL AND METHODS: A retrospective, comparative, cross-sectional, observational study was conducted by reviewing the case records of 101 children diagnosed with CMPA and seen at the Department of Gastroenterology and Nutrition of the Instituto Nacional de Pediatria within the time frame of January 2012 and August 2013. The following variables were included: age, sex, weeks of gestation, history of maternal infection and antimicrobial use during the pregnancy, type of delivery, and feeding with human milk, and its duration. Likewise, the case records of 90 children were reviewed as a control group on not having CMPA or any other allergy. The chi-square test was used for proportions, and the Mann-Whitney U test was used for comparing means in the statistical analysis. RESULTS: The factors associated with CMPA were the use of antimicrobials during gestation and breastfeeding duration in months. Both factors were statistically significant (P<.001). No association was found between CMPA and gestational age or type of delivery. CONCLUSIONS: The statistically significant associated factors were breastfeeding duration and the use of antimicrobials during the gestational stage. These results underline the necessity for prospective studies. PMID- 25724743 TI - Chelativorans intermedius sp. nov. and proposal to reclassify Thermovum composti as Chelativorans composti comb. nov. AB - Two Gram-stain-negative, non-endospore-forming, rod-shaped bacteria, strains CC MHSW-5(T) and A1392, were isolated from water of coastal hot springs located in Taiwan and China, respectively, and investigated for their taxonomic position. The two strains shared identical 16S rRNA gene sequences, a DNA-DNA hybridization value >80% and similar genomic DNA G+C contents (64.3 and 64.6 mol%), but showed different genomic fingerprint patterns generated by BOX-PCR and three random amplification polymorphic DNA PCRs. The strains shared highest 16S rRNA gene sequence similarities with the type strains of Chelativorans multitrophicus (96.7 and 96.1%), Thermovum composti (96.2 and 96.1%) and Chelativorans oligotrophicus (96.1 and 95.8%). Phylogenetic trees (based on 16S rRNA and recA gene sequence comparisons) showed a distinct clustering of both strains with the type strains of species of the genus Chelativorans and T. composti Nis3(T). The quinone systems of strains CC-MHSW-5(T) and Nis3(T) contained ubiquinone Q-10 as the major component. The major polyamine in both strains was sym-homospermidine. Putrescine, spermidine and, for strain CC-MHSW-5(T), spermine were found in minor concentrations. Their polar lipid profiles consisted of phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and diphosphatidylglycerol. The fatty acid profile contained major amounts of C18 : 1omega7c and C19 : 0 cyclo omega8c. On the basis of these results, the two strains are considered to represent a novel species of the genus Chelativorans , for which the name Chelativorans intermedius sp. nov. is proposed. The type strain is CC-MHSW-5(T) ( =CCM 8543(T) =LMG 28482(T) =DSM 29391(T) =CIP 110825(T)). Based on both genotypic and phenotypic characters, it is proposed that T. composti be reclassified within the genus Chelativorans as Chelativorans composti comb. nov. PMID- 25724744 TI - Blastomonas aquatica sp. nov., a bacteriochlorophyll-containing bacterium isolated from lake water. AB - Yellow or orange-to-brown pigmented, ovoid or rod-shaped, Gram-negative staining, aerobic strains PE 4-5(T) and N5-10 m-1 were isolated from brackish water in Lake Peng Co and fresh to brackish water in Lake Namtso on the Tibetan Plateau, China. Bacteriochlorophyll a was produced by the isolates. The predominant cellular fatty acids were C16 : 1, C17 : 1 and C18 : 1 unsaturated fatty acids, C17 : 1omega6c (55.3%), C17 : 1omega8c (13.0%) and C18 : 1omega7c (10.4%) for PE 4-5(T) and C18 : 1omega7c (54.7%) and C16 : 1omega7c (18.0%) for N5-10 m-1. The polar lipid profiles of strains PE 4-5(T) and N5-10 m-1 were composed of diphosphatidylglycerol, phosphatidylcholine (not detected in N5-10 m-1), phosphatidyldimethylethanolamine, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol, sphingoglycolipid and an unknown phospholipid. The predominant respiratory quinone was ubiquinone Q10 and the DNA G+C content was 66.0 mol% for both strains. The16S rRNA gene sequence of strain PE 4-5(T) shared 99.0% similarity with that of N5-10 m-1, and 97.56% similarity with those of Blastomonas natatoria LMG 17322(T) and Blastomonas ursincola DSM 9006(T), respectively. The DNA-DNA hybridization relatedness between strains PE 4-5(T) and N5-10 m-1 was 79.0 +/- 1.0%, but below 70% with the type strains in the genus Blastomonas . Based on the variability of phylogenetic and phenotypic characteristics, the isolates should be classified as representatives of a novel species of the genus Blastomonas; the name Blastomonas aquatica sp. nov. is proposed. The type strain is PE 4-5(T) ( =JCM 30179(T) =CGMCC 1.12851(T)). PMID- 25724745 TI - Planctomicrobium piriforme gen. nov., sp. nov., a stalked planctomycete from a littoral wetland of a boreal lake. AB - An aerobic, budding, non-pigmented and rosette-forming bacterium was isolated from a littoral wetland of a boreal lake located in Valaam Island, northern Russia, and designated strain P3(T). Ellipsoidal to pear-shaped cells of this bacterium were covered with crateriform pits and possessed stalks suggesting a planctomycete morphotype. 16S rRNA gene sequence analysis confirmed that strain P3(T) was a member of the order Planctomycetales and belonged to a phylogenetic lineage defined by the genus Planctomyces , with 89 and 86% sequence similarity to Planctomyces brasiliensis and Planctomyces maris , respectively. Strain P3(T) was a mildly acidophilic, mesophilic organism capable of growth at pH values between pH 4.2 and 7.1 (with an optimum at pH 6.0-6.5) and at temperatures between 10 and 30 degrees C (optimum at 20-28 degrees C). Most sugars, a number of polysaccharides and several organic acids were the preferred growth substrates. Compared with Planctomyces brasiliensis and Planctomyces maris , which require NaCl for growth, strain P3(T) was salt-sensitive and did not develop at NaCl concentrations above 0.5% (w/v). The major fatty acids were C16 : 0 and C16 : 1omega7c; the cells also contained significant amounts of C18 : 1omega7c and C18 : 0. The major intact polar lipids were diacylglycerol-O-(N,N,N trimethyl)homoserine (DGTS) lipids; the major neutral lipids were long-chain 1,(omega-1)-diols and C31 : 9 hydrocarbon. The quinone was MK-6, and the G+C content of the DNA was 59.0 mol%. Strain P3(T) differed from Planctomyces brasiliensis and Planctomyces maris by cell morphology, substrate utilization pattern and a number of physiological characteristics. Based on these data, the novel isolate should be considered as representing a novel genus and species of planctomycetes, for which the name Planctomicrobium piriforme gen. nov., sp. nov., is proposed. The type strain is P3(T) ( =DSM 26348(T) =VKM B-2887(T)). PMID- 25724746 TI - Sulfitobacter undariae sp. nov., isolated from a brown algae reservoir. AB - A Gram-stain-negative, aerobic, non-spore-forming, non-flagellated and coccoid, ovoid or rod-shaped bacterial strain, W-BA2(T), was isolated from a brown algae reservoir in Wando of South Korea. Strain W-BA2(T) grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of approximately 2.0-3.0% (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain W-BA2(T) fell within the clade comprising the type strains of species of the genus Sulfitobacter , clustering coherently with the type strains of Sulfitobacter donghicola and Sulfitobacter guttiformis showing sequence similarity values of 98.0-98.1%. Sequence similarities to the type strains of the other species of the genus Sulfitobacter were 96.0-97.4%. Strain W-BA2(T) contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids of strain W-BA2(T) were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain W-BA2(T) was 55.0 mol% and its DNA-DNA relatedness values with the type strains of Sulfitobacter donghicola , Sulfitobacter guttiformis and Sulfitobacter mediterraneus were 16-23%. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain W-BA2(T) is separated from other species of the genus Sulfitobacter . On the basis of the data presented, strain W-BA2(T) is considered to represent a novel species of the genus Sulfitobacter, for which the name Sulfitobacter undariae sp. nov. is proposed. The type strain is W-BA2(T) ( = KCTC 42200(T) = NBRC 110523(T)). PMID- 25724747 TI - Polaribacter undariae sp. nov., isolated from a brown alga reservoir. AB - A Gram-stain-negative, non-flagellated, non-gliding, aerobic and rod-shaped or ovoid bacterial strain, designated W-BA7(T), was isolated from a brown alga reservoir on the South Sea in South Korea. This strain grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of approximately 2.0% (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain W-BA7(T) belonged to the genus Polaribacter, clustering coherently with the type strain of Polaribacter sejongensis, showing 99.3% sequence similarity. Strain W-BA7(T) exhibited 16S rRNA gene sequence similarity of 93.4-98.6% to the type strains of the other species of the genus Polaribacter. Strain W-BA7(T) contained MK-6 as the predominant menaquinone and iso-C15 : 0 3-OH and anteiso C15 : 0 as the major fatty acids. The major polar lipids of strain W-BA7(T) were phosphatidylethanolamine, three unidentified lipids, one unidentified glycolipid, one unidentified aminolipid and one unidentified aminophospholipid. The DNA G+C content of strain W-BA7(T) was 31.9 mol%, and the mean DNA-DNA relatedness with the type strains of four phylogenetically related species of the genus Polaribacter was 12-27%. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain W-BA7(T) is separated from recognized species of the genus Polaribacter. On the basis of the data presented, strain W-BA7(T) is considered to represent a novel species of the genus Polaribacter, for which the name Polaribacter undariae sp. nov. is proposed. The type strain is W-BA7(T) ( =KCTC 42175(T) =CECT 8670(T)). PMID- 25724748 TI - Oleiagrimonas soli gen. nov., sp. nov., a genome-sequenced gammaproteobacterium isolated from an oilfield. AB - A yellow-pigmented strain, designated strain 3.5X(T), was isolated from oil contaminated saline soil in Gudao, Shandong Province, China, and was characterized taxonomically. The results showed that the isolate was a Gram-stain negative, aerobic, motile, rod-shaped cell with a polar flagellum. Phylogenetic analysis of 16S rRNA gene sequences revealed the strain belonged to the family Xanthomonadaceae in the class Gammaproteobacteria and represented an independent taxon separated from other genera. The closest relative of strain 3.5X(T) was Fulvimonas soli DSM 14263(T) (94% similarity). The genomic DNA G+C content was 67 mol% by thermal denaturation and 66.3 mol% from genome sequences. The cells mainly consisted of branched fatty acids, with iso-C17 : 0, iso-C15 : 0, iso-C17 : 1omega9c and/or C16 : 010-methyl and iso-C11 : 0 as the major fatty acids. The main polar lipids were phosphatidylmonomethylethanolamine, diphosphatidylglycerol and phosphatidylethanolamine. In addition, ubiquinone Q-8 was the major component of the quinone system and the polyamine pattern contained the major compound spermidine plus minor amounts of putrescine and spermine. On the basis of phenotypic, genotypic and phylogenetic distinctiveness, it is proposed that the isolate represents a novel species in a novel genus, namely Oleiagrimonas soli gen. nov., sp. nov. The type strain is 3.5X(T) ( =NBRC 110685(T) =KCTC 42351(T) =CPCC 100614(T)). PMID- 25724749 TI - Use of statins by medicare beneficiaries post myocardial infarction: poor physician quality or patient-centered care? AB - Even though guidelines strongly recommend that patients receive a statin for secondary prevention after an acute myocardial infarction (MI), many elderly patients do not fill a statin prescription within 30 days of discharge. This paper assesses whether patterns of statin use by Medicare beneficiaries post discharge may be due to a mix of high-quality and low-quality physicians. Our data come from the Centers for Medicare & Medicaid Services (CMS) Chronic Condition Data Warehouse (CCW) and include 100% of Medicare beneficiaries hospitalized for an acute myocardial infarction in 2008 or 2009. Our study sample included physicians treating at least 10 Medicare fee-for-service beneficiaries during their MI institutional stay. Physician-specific statin fill rates (the proportion of each physician's patients with a statin within 30 days post discharge) were calculated to assess physician quality. We hypothesized that if the observed statin rates reflected a mix of high-quality and low-quality physicians, then physician-specific statin fill rates should follow a u-shaped or bimodal distribution. In our sample, 62% of patients filled a statin prescription within 30 days of discharge. We found that the distribution of statin fill rates across physicians was normal, with no clear distinctions in physician quality. Physicians, especially cardiologists, with relatively younger and healthier patient populations had higher rates of statin use. Our results suggest that physicians were engaging in patient-centered care, tailoring treatments to patient characteristics. PMID- 25724750 TI - Evaluation outcomes of a sex education strategy in high schools of Pavia (Italy). AB - AIM: We aimed to provide process and effectiveness evaluations of a sex education intervention realized with interactive techniques in high schools of Pavia (Italy). METHODS: Six public high schools, divided into 'treated' and 'control' units, voluntarily joined this mixed-methods study. Only second-year classes were enrolled: treated adolescents followed a sex education course, performed by trained 'near-peer educators' (undergraduate medical students) with interactive techniques. All adolescents compiled an anonymous effectiveness evaluation questionnaire at baseline (pre-test) and 3 months later (post-test). Sexual knowledge and reported behavioural changes were compared between the two groups through linear mixed-effects models. The process was assessed through a satisfaction questionnaire for treated students, monitoring cards for working group members and cards/diaries for educators. RESULTS: The final sample consisted of 547 treated and 355 control adolescents (mean age = 15.28 +/- 0.61 years). Highly significant changes (p < 0.001) from pre-test to post-test, with strong improvements of treated adolescents, were evident for all knowledge items. No significant changes for behavioural items were reported. Process evaluation showed positive results in adolescents' satisfaction, highlighting the need for more youth gathering places. Working group members and educators generally provided positive evaluations, although difficult communication was perceived. CONCLUSIONS: The intervention was effective in improving adolescents' sexual knowledge. The present work highlighted that in Italy sex education in adolescence is still neglected: this could encourage misinformation and health risk behaviour. Young people perceive the need for a serious health-promoting action in which they could play an active role, spreading educational messages with organized interactive methods. PMID- 25724751 TI - Salud mental en desastres naturales: estrategias interventivas con adultos mayores en sectores rurales de Chile. AB - En el presente articulo se da a conocer una estrategia de intervencion llevada a cabo con adultos mayores en la comuna de Paredones, sexta region de Chile, con posterioridad al terremoto y tsunami del 27 de febrero 2010 en Chile, en el contexto de una investigacion sobre fortalezas y vulnerabilidades desplegadas por este grupo etario, con posterioridad a un desastre natural. Se presenta una descripcion del desarrollo metodologico de la intervencion y de los sustentos teoricos y conceptuales en los que se basa. Como resultado de este proceso, se propone una estrategia que trabaje a traves de la identificacion de las propias experiencias y fortalezas de los sujetos. De tal forma se minimizan los efectos negativos de los determinantes sociales de la salud (como la edad y el lugar de residencia) en contexto de crisis; permitiendo a los adultos mayores fortalecer sus recursos individuales y colectivos, en pro de su bienestar psicosocial. PMID- 25724752 TI - Housing influences among sleep-related infant injury deaths in the USA. AB - This article examines the role of housing conditions in sleep-related infant injury death, a leading cause of infant mortality in the USA. The use of an unsafe sleep surface is a major risk factor for sleep-related infant injury. This exploratory study examined contextual circumstances, specifically those related to the physical environment, which may contribute to caregivers' decisions to place an infant on an unsafe sleep surface. It employed a retrospective review of 255 sleep-related infant injury death cases in a large urban area from 2004 to 2010 where an infant was found sleeping on an unsafe sleep surface, including 122 cases where a crib or bassinet was identified in the home. Quantitative findings indicated no differences in demographic or risk characteristics between infants with cribs or bassinets and those without them. Qualitative findings suggested the lack of crib or bassinet use may be related to environmental factors influenced by poverty, specifically crowded living space, room temperature and vermin infestation. This study suggests that infants may be at risk of sleep related injury deaths even when a crib or bassinet is present in the home and supports the consideration of housing conditions in health promotion efforts to reduce infant mortality. Understanding environmental factors that may contribute to infants sleeping on an unsafe surface can help maternal child health and public health professionals develop more appropriate interventions that address deleterious living conditions. PMID- 25724753 TI - Linear shock wave therapy in the treatment of erectile dysfunction. AB - INTRODUCTION: Linear Shock Wave Therapy (LSWT) is a new noninvasive therapy that uses low-intensity shock waves to induce local angiogenesis promising modality in the treatment of erectile dysfunction (ED). OBJECTIVE: To evaluate the effectiveness of LSWT in men with vasculogenic erectile dysfunction (ED), in a Tertiary Care Center. MATERIAL AND METHODS: Included 15 men aged 45-70 years, sexually active with mild and moderate vascular ED evaluated with the International Index of Erectile Function (IIEF). The study was conducted in three stage: screening, treatment and results. Treatment stage: 4 weekly sessions LSWT (RENOVA (r)) 5000 waves (.09mJ/mm(2)). Erectile function was assessed with IIEFF EF, SEP (Sexual Encounter Profile) and GAQ (Global Assessment Questions) at one and six months after treatment. RESULTS: The rate of success was 80% (12/15). Patients with mild ED (6/15) 40% and moderate ED (9/15) 60%. We found a positive association between IIEF-Basal (average 14.23 pts) and IIEF at one month and six months after therapy (19.69 pts) a difference of 5.46 pts. (P<.013). CONCLUSIONS: The feasibility and tolerability of this treatment, and rehabilitation potential features, make it this an attractive new treatment option for patients with ED. PMID- 25724754 TI - [Introduction of an accreditation system for hospital informed consent forms]. AB - OBJECTIVE: To describe an accreditation system for informed consent forms (ICF) in a tertiary hospital, as an intervention to improve their quality, and to check the improvements achieved. MATERIAL AND METHODS: Following an external evaluation of the ICF quality in a public hospital in Murcia (Spain), an accreditation committee set the ICF requirements and associated procedures. Effectiveness is assessed by comparing two external evaluations carried out by the EMCA Program (2011 and 2013) and based on 19 criteria and a sample of 60 ICF for every public hospital in Murcia Region. RESULTS: To be accredited, every ICF must meet the 19 external criteria plus 5 based on legibility, readability and scientific and technical validity. A form to fill in the contents of every ICF was agreed, which would be reviewed, approved and validated for five years. Before the implementation, 8.2 defects/ICF were detected. The accreditation system obtained an 89% improvement (0.9 defects/ICF) and achieved significant improvements in 18 criteria, 16 of which are benchmarked. DISCUSSION: The accreditation system achieved a substantial improvement in the ICF (obtaining a better result in external evaluations) and guarantees their contents, legibility and readability. This system needs to be extended to other hospitals, since it is not clear whether common ICFs would be suitable. However, this improvement is structural and does not guarantee that the overall information/consent procedure is done properly, thus complementary strategies for measurement and improvement are required. PMID- 25724755 TI - AP endonuclease knockdown enhances methyl methanesulfonate hypersensitivity of DNA polymerase beta knockout mouse embryonic fibroblasts. AB - Apurinic/apyrimidinic (AP) endonuclease (Apex) is required for base excision repair (BER), which is the major mechanism of repair for small DNA lesions such as alkylated bases. Apex incises the DNA strand at an AP site to leave 3'-OH and 5'-deoxyribose phosphate (5'-dRp) termini. DNA polymerase beta (PolB) plays a dominant role in single nucleotide (Sn-) BER by incorporating a nucleotide and removing 5'-dRp. Methyl methanesulfonate (MMS)-induced damage is repaired by Sn BER, and thus mouse embryonic fibroblasts (MEFs) deficient in PolB show significantly increased sensitivity to MMS. However, the survival curve for PolB knockout MEFs (PolBKOs) has a shoulder, and increased sensitivity is only apparent at relatively high MMS concentrations. In this study, we prepared Apex knockdown/PolB-knockout MEFs (AKDBKOs) to examine whether BER is related to the apparent resistance of PolBKOs at low MMS concentrations. The viability of PolBKOs immediately after MMS treatment was significantly lower than that of wild type MEFs, but there was essentially no effect of Apex-knockdown on cell viability in the presence or absence of PolB. In contrast, relative counts of MEFs after repair were decreased by Apex knockdown. Parental PolBKOs showed especially high sensitivity at >1.5 mM MMS, suggesting that PolBKOs have another repair mechanism in addition to PolB-dependent Sn-BER, and that the back-up mechanism is unable to repair damage induced by high MMS concentrations. Interestingly, AKDBKOs were hypersensitive to MMS in a relative cell growth assay, suggesting that MMS-induced damage in PolB-knockout MEFs is repaired by Apex-dependent repair mechanisms, presumably including long-patch BER. PMID- 25724756 TI - The GETA technique: a novel technique protecting the dura against the distractors for early cranial expansion. AB - PURPOSE: Posterior cranial vault distraction profoundly enlarges intracranial volume. To perform this procedure during the first year of life, the cranium is too thin to fix the distractors. Sometimes, the screws penetrate the bone, which risks scratching the dura during distraction. To solve this problem, we developed an implant fixation technique using bioabsorbable screws and plates, and named it the GETA technique. METHODS: In cases in which the bone is thinner than the screws, a resorbable sheet is placed between the bone and the dura to protect the dura from the tips of the screws. RESULTS: We used this technique for cranial distraction in four patients, with satisfactory results and without complications. CONCLUSIONS: The technique described here allows craniofacial surgeons to fix the distractors without injuring the dura. PMID- 25724758 TI - "Domain gauges": A reference system for multivariate profiling of brain fMRI activation patterns induced by psychoactive drugs in rats. AB - Pharmacological magnetic resonance imaging (phMRI) of the brain has become a widely used tool in both preclinical and clinical drug research. One of its challenges is to condense the observed complex drug-induced brain-activation patterns into semantically meaningful metrics that can then serve as a basis for informed decision making. To aid interpretation of spatially distributed activation patterns, we propose here a set of multivariate metrics termed "domain gauges", which have been calibrated based on different classes of marketed or validated reference drugs. Each class represents a particular "domain" of interest, i.e., a specific therapeutic indication or mode of action. The drug class is empirically characterized by the unique activation pattern it evokes in the brain-the "domain profile". A domain gauge provides, for any tested intervention, a "classifier" as a measure of response strength with respect to the domain in question, and a "differentiator" as a measure of deviation from the domain profile, both along with error ranges. Capitalizing on our in-house database with an unprecedented wealth of standardized perfusion-based phMRI data obtained from rats subjected to various validated treatments, we exemplarily focused on 3 domains based on therapeutic indications: an antipsychotic, an antidepressant and an anxiolytic domain. The domain profiles identified as part of the gauge definition process, as well as the outputs of the gauges when applied to both reference and validation data, were evaluated for their reconcilability with prior biological knowledge and for their performance in drug characterization. The domain profiles provided quantitative activation patterns with high biological plausibility. The antipsychotic profile, for instance, comprised key areas (e.g., cingulate cortex, nucleus accumbens, ventral tegmental area, substantia nigra) which are believed to be strongly involved in mediating an antipsychotic effect, and which are in line with network-level dysfunctions observed in schizophrenia. The domain gauges plausibly positioned the vast majority of the pharmacological and even non-pharmacological treatments. The results also suggest the segregation of sub-domains based on, e.g., the mode of action. Upon judicious selection of domains and careful calibration of the gauges, our approach represents a valuable analytical tool for biological interpretation and decision making in drug discovery. PMID- 25724757 TI - Dynamic causal modelling for functional near-infrared spectroscopy. AB - Functional near-infrared spectroscopy (fNIRS) is an emerging technique for measuring changes in cerebral hemoglobin concentration via optical absorption changes. Although there is great interest in using fNIRS to study brain connectivity, current methods are unable to infer the directionality of neuronal connections. In this paper, we apply Dynamic Causal Modelling (DCM) to fNIRS data. Specifically, we present a generative model of how observed fNIRS data are caused by interactions among hidden neuronal states. Inversion of this generative model, using an established Bayesian framework (variational Laplace), then enables inference about changes in directed connectivity at the neuronal level. Using experimental data acquired during motor imagery and motor execution tasks, we show that directed (i.e., effective) connectivity from the supplementary motor area to the primary motor cortex is negatively modulated by motor imagery, and this suppressive influence causes reduced activity in the primary motor cortex during motor imagery. These results are consistent with findings of previous functional magnetic resonance imaging (fMRI) studies, suggesting that the proposed method enables one to infer directed interactions in the brain mediated by neuronal dynamics from measurements of optical density changes. PMID- 25724759 TI - The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24. AB - Hereditary colorectal cancer accounts for approximately 30% of all colorectal cancers, but currently only 5% of these families can be explained by highly penetrant, inherited mutations. In the remaining 25% it is not possible to perform a gene test to identify the family members who would benefit from prophylactic screening. Consequently, all family members are asked to follow a screening program. The purpose of this study was to localize a new gene which causes colorectal cancer. We performed a linkage analysis using data from a SNP6.0 chip in one large family with 12 affected family members. We extended the linkage analysis with microsatellites (STS) and single nucleotide polymorphisms (SNP's) and looked for the loss of heterozygosity in tumour tissue. Furthermore, we performed the exome sequencing of one family member and we sequenced candidate genes by use of direct sequencing. Major rearrangements were excluded after karyotyping. The linkage analysis with SNP6 data revealed three candidate areas, on chromosome 2, 6 and 11 respectively, with a LOD score close to two and no negative LOD scores. After extended linkage analysis, the area on chromosome 6 was excluded, leaving areas on chromosome 2 and chromosome 11 with the highest possible LOD scores of 2.6. Two other studies have identified 11q24 as a candidate area for colorectal cancer susceptibility and this area is supported by our results. PMID- 25724761 TI - Working memory training triggers delayed chromatin remodeling in the mouse corticostriatothalamic circuit. AB - Working memory is a cognitive function serving goal-oriented behavior. In the last decade, working memory training has been shown to improve performance and its efficacy for the treatment of several neuropsychiatric disorders has begun to be examined. Neuroimaging studies have contributed to elucidate the brain areas involved but little is known about the underlying cellular events. A growing body of evidence has provided a link between working memory and relatively long lasting epigenetic changes. However, the effects elicited by working memory training at the epigenetic level remain unknown. In this study we establish an animal model of working memory training and explore the changes in histone H3 acetylation (H3K9,14Ac) and histone H3 dimethylation on lysine 27 (H3K27Me2) triggered by the procedure in the brain regions of the corticostriatothalamic circuit (prelimbic/infralimbic cortex (PrL/IL), dorsomedial striatum (DMSt) and dorsomedial thalamus (DMTh)). Mice trained on a spontaneous alternation task showed improved alternation scores when tested with a retention interval that disrupts the performance of untrained animals. We then determined the involvement of the brain areas of the corticostriatothalamic circuit in working memory training by measuring the marker of neuronal activation c-fos. We observed increased c-fos levels in PrL/IL and DMSt in trained mice 90min after training. These animals also presented lower immunoreactivity for H3K9,14Ac in DMSt 24h but not 90min after the procedure. Increases in H3K27Me2, a repressive chromatin mark, were found in the DMSt and DMTh 24h after the task. Altogether, we present a mouse model to study the cellular underpinnings of working memory training and provide evidence indicating delayed chromatin remodeling towards repression triggered by the procedure. PMID- 25724762 TI - The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury. AB - Methamphetamine is a psychostimulant that was initially synthesized in 1920. Since then it has been used to treat attention deficit hyperactive disorder (ADHD), obesity and narcolepsy. However, methamphetamine has also become a major drug of abuse worldwide. Under conditions of abuse, which involve the administration of high repetitive doses, methamphetamine can produce considerable neurotoxic effects. However, recent evidence from our laboratory indicates that low doses of methamphetamine can produce robust neuroprotection when administered within 12h after severe traumatic brain injury (TBI) in rodents. Thus, it appears that methamphetamine under certain circumstances and correct dosing can produce a neuroprotective effect. This review addresses the neuroprotective potential of methamphetamine and focuses on the potential beneficial application for TBI. PMID- 25724760 TI - Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end? AB - Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists' mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2. PMID- 25724763 TI - Nociceptin and the nociceptin receptor in learning and memory. AB - There are many processes in which the neuropeptide nociceptin/orphanin FQ (N/OFQ or nociceptin) is involved in the brain. The role of nociceptin in learning and memory holds promise in modulating these processes in health and disease in the human brain. This review summarizes the body of research focused on N/OFQ and its specific receptor, the nociceptin receptor (NOP receptor), in learning and memory, and its potential mechanisms of action, in which acetylcholine, NMDA receptor, and noradrenaline may be critical. Finally, the association between NOP receptor and posttraumatic stress disorder (PTSD), a psychiatric disorder with altered fear learning, is examined as one of the potential outcomes resulting from pathological consequences of dysregulation of N/OFQ-NOP receptor in the brain. PMID- 25724764 TI - Traumatic brain injury in the elderly: morbidity and mortality trends and risk factors. AB - An estimated 1.7 million people sustain a traumatic brain injury (TBI) annually in the United States. We sought to examine factors contributing to mortality among TBI patients aged >=65 y in the United States. TBI data from the Nationwide Inpatient Sample were combined from 2000-2010. Patients were stratified by age, sex, mechanism of injury, payer status, comorbidity, injury severity, and other factors. Odds of death were explored using an adjusted multivariable logistic regression. A total of 950,132 TBI-related hospitalizations and 107,666 TBI related deaths occurred among adults aged >=65 y from 2000-2010. The most common mechanism of injury was falling, and falls were more common among the oldest age groups. Logistic regression analysis showed highest odds of death among male patients, those whose mechanism of injury was motor vehicle related, patients with three or more comorbidities, and patients who were designated as self paying. PMID- 25724765 TI - A noninvasive hemoglobin monitor in the pediatric intensive care unit. AB - BACKGROUND: Critically ill pediatric patients frequently require hemoglobin monitoring. Accurate noninvasive Hb (SpHb) would allow practitioners to decrease anemia from repeated blood draws, traumatic blood draws, and a decreased number of laboratory Hb (LabHb) medical tests. The Food and Drug Administration has approved the Masimo Pronto SpHb and associated Rainbow probes; however, its use in the pediatric intensive care unit (PICU) is controversial. In this study, we define the degree of agreement between LabHb and SpHb using the Masimo Pronto SpHb Monitor and identify clinical and demographic conditions associated with decreased accuracy. MATERIALS AND METHODS: We performed a prospective, observational study in a large PICU at an academic medical center. Fifty-three pediatric patients (30-d and 18-y-old), weighing >3 kg, admitted to the PICU from January-April 2013 were examined. SpHb levels measured at the time of LabHb blood draw were compared and analyzed. RESULTS: Only 83 SpHb readings were obtained in 118 attempts (70.3%) and 35 readings provided a result of "unable to obtain." The mean LabHb and SpHb were 11.1 g/dL and 11.2 g/dL, respectively. Bland-Altman analysis showed a mean difference of 0.07 g/dL with a standard deviation of +/ 2.59 g/dL. Pearson correlation is 0.55, with a 95% confidence interval between 0.38 and 0.68. Logistic regression showed that extreme LabHb values, increasing skin pigmentation, and increasing body mass index were predictors of poor agreement between SpHb and LabHb (P < 0.05). Separately, increasing body mass index, hypoxia, and hypothermia were predictors for undetectable readings (P < 0.05). CONCLUSIONS: The Masimo Pronto SpHb Monitor provides adequate agreement for the trending of hemoglobin levels in critically ill pediatric patients. However, the degree of agreement is insufficient to be used as the sole indicator for transfusion decisions and should be used in context of other clinical parameters to determine the need for LabHb in critically ill pediatric patients. PMID- 25724766 TI - Dynamic pathology for leukocyte-platelet formation in sepsis model. AB - BACKGROUND: This study aimed to evaluate the dynamic pathology for in vivo real time leukocyte-endothelium-platelet aggregation in a mouse model of sepsis. MATERIALS AND METHODS: A lipopolysaccharide-induced model of sepsis was analyzed in green fluorescent protein transgenic mice using two-photon laser-scanning microscopy (TPLSM). The real-time process of leukocyte-endothelium-platelet complex (LEPC) formation was assessed in vivo using blood flow dynamics. RESULTS: TPLSM allowed direct visualization of LEPC formation at the single-platelet level. Leukocytes rolling number and speed, blood flow velocity, and shear rate gradually decreased with time during the acute phase of sepsis compared with those in the control groups. The number of adherent leukocytes and platelet counts gradually increased over time in the septic group. In the septic group, microcirculatory dysfunction was seen in the postcapillary venules before the capillaries. CONCLUSIONS: In vivo real-time imaging and analysis of LEPC formation can be achieved with little inter-experimental variation using TPLSM. In the acute phase of sepsis, new treatment strategies should target the postcapillary venules because their LEPC formation and blood flow dynamics start to change before those in the capillaries. PMID- 25724767 TI - Effect of aging on the osteoinductive activity of recombinant human bone morphogenetic protein-2 in rats. AB - BACKGROUND: Bone morphogenetic proteins may hold broad potential for use in the reconstruction of bone defects resulting from tumor resection or trauma and in assisting bone healing thanks to methods enabling the synthesis of recombinant human bone morphogenetic protein-2 (rhBMP-2). METHODS: rhBMP-2 was implanted with atelopeptide type I collagen as a carrier into the calf muscles of 3-, 8-, and 48 wk-old Wistar/ST male rats. After 21 d, the formation of ectopic neoplastic bone was examined in soft x-ray imaging, and the bone mineral content, bone area, and bone mineral density (BMD) were measured by dual-energy x-ray absorptiometry. In addition, hematoxylin-eosin and von Kossa staining and proliferation cell nuclear antigen immunostaining were performed. RESULTS: BMD values determined by dual energy x-ray absorptiometry were 29.40 (standard deviation +/-5.47), 24.15 (+/ 2.33), and 19.01 (+/-2.02) mg/cm(2) in the 3-, 8-, and 48-wk-old rats, respectively, demonstrating that BMD significantly decreased with aging (P < 0.05). The von Kossa stain-positive area decreased significantly with aging (P < 0.01). The number of proliferation cell nuclear antigen-positive cells also decreased significantly with aging (P < 0.01). CONCLUSIONS: The capacity of rhBMP 2 to induce ectopic bone formation decreases with aging. These findings will be of considerable benefit in the development of clinical treatments for the regeneration of cranio-maxillofacial bone in elderly patients. PMID- 25724768 TI - Radiofrequency ablation versus surgical resection for intrahepatic hepatocellular carcinoma recurrence: a meta-analysis. AB - BACKGROUND: To compare the clinical efficacy and safety of radiofrequency ablation (RFA) versus surgical resection (SR) for intrahepatic hepatocellular carcinoma (HCC) recurrence by meta-analytical techniques. METHODS: Literature documenting a comparison of RFA and SR for intrahepatic HCC recurrence was identified by searching PubMed, Embase, Cochrane Library, and Web of Science databases, for those from inception to July 2014 with no limits. The heterogeneity was tested by the Cochrane Q statistic; the pooled estimates were measured using either fixed or random effect model. Furthermore, subgroup and sensitivity analyses were conducted to explore heterogeneity between studies and to assess the efficacy of different studies. RESULTS: Seven studies were included with a total of 718 patients (359 treated with RFA and 359 treated with SR). Our meta-analysis showed that the 1-, 3-, and 5-y overall survival rate and procedure related mortality rate were similar in patients treated with RFA or SR. Meanwhile, SR was associated with significantly higher 1-, 3-, and 5-y re recurrence-free survival rate and procedure-related morbidity rate compared with RFA. In the subgroup analysis of patients in China, the results concerning overall and re-recurrence-free survival were similar to the outcomes of the meta analysis without regional restriction. In the subgroup analysis of intrahepatic recurrent HCC <=3 cm, the 1-, 3-, and 5-y overall survival rate did not differ significantly in the comparison of RFA and SR. CONCLUSIONS: Although RFA was associated with lower re-recurrence-free survival, it seems to be as effective as SR for the treatment of intrahepatic HCC recurrence owing to comparable overall survival benefits. The advantages of being less invasive, highly target selective, and repeatable may render RFA a preferred treatment option for selected patients. PMID- 25724769 TI - Exogenous carcinoembryonic antigen-related cell adhesion molecule 1 suppresses 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in mice. AB - BACKGROUND: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is known to play an immunomodulatory role in a variety of tumors, but its role in ulcerative colitis (UC) remains to be elucidated. The present study aimed to investigate the effects of exogenous CEACAM1 on UC using a mouse model. MATERIALS AND METHODS: UC in female Balb/c mice was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Hundred microliters of 1% TNBS was supplied through abdominal smearing for sensitization. Then after 7 d, 100 MUL 0.5% TNBS was administered by a transrectal injection. After injection, the mice were placed in an upside-down position for 1 min. The CEACAM1 treatment was performed by receiving a transrectal injection of 10(9) pfu of CEACAM1. The mice were weighed, and the colonic mucosa damage was scored. The effects of exogenous CEACAM1 expression on mouse colon inflammation, apoptosis, and CD4 T lymphocyte infiltration in UC were examined. RESULTS: CEACAM1 expression was significantly reduced in the colon tissue of mice with UC, and the expression of exogenous CEACAM1 improved the symptoms of UC, as evidenced by hematoxylin-eosin staining and histopathologic scores. Moreover, exogenous CEACAM1 reduced the levels of inflammatory cytokines, suppressed CD4 T cell infiltration, and effectively inhibited apoptosis in the colon of TNBS-induced UC mice. CONCLUSIONS: The expression of exogenous CEACAM1 effectively rescues the symptoms of TNBS-induced UC in mice by inhibiting inflammation, T cell infiltration, and apoptosis in the colon. PMID- 25724770 TI - Effect of products of PLA2 catalyzed hydrolysis of DLPC on motion of rising bubbles. AB - Local velocities of rising bubbles decrease with the increasing concentration in solution of surface-active, water-soluble species. Therefore, it is possible to use this phenomenon to monitor products of enzymatic reactions, which meet such criteria. In this study, hydrolysis of 1,2-dilauroyl-sn-glycero-3 phosphatidylcholine (DLPC) catalyzed by calcium-dependent phospholipase A2 (PLA2) (EC3.1.1.4) from porcine pancreas was used as model reaction. The products of this reaction are lauric acid (LA) and 1-lauroyl-2-hydroxy-sn-glycero-3 phosphatidylcholine (Lyso-PC). DLPC was dispersed in a chloroform/methanol mixture that was spread on a free PLA2 solution surface. Air bubbles were then formed at a capillary orifice and the local velocity of rising bubbles as a function of the distance from the capillary tip was monitored. Local velocity profiles were compared with profiles recorded for solutions of pure enzymatic reaction products and their mixtures. Our experiments showed that the product, which had a dominating effect on bubble motion retardation, was lyso phosphatidylcholine. This can be explained by differences in the kinetics of lauric acid and lyso-phosphatidylcholine transfer from the spread layer to the solution. PMID- 25724771 TI - Chronic conditions, disability, and quality of life in older adults with multimorbidity in Spain. AB - BACKGROUND: As the population ages, the prevalence of multimorbidity also increases, with consequences to several health outcomes such as disability and quality of life (QoL). This study aimed at analyzing the relationships between chronic conditions, disability, and QoL of older adults with multimorbidity in Spain. METHOD: Data on older adults aged 65 years or more, with at least two chronic health conditions were drawn from three cohort studies. Sample size was 705, 443, and 4995, respectively. For each cohort, the impact of the following chronic health conditions was analyzed: asthma, cancer, cardiac, diabetes, hypertension, mental health disorders, osteoarticular conditions, and stroke. Disability and QoL measures varied according to the survey. RESULTS: In older adults with multimorbidity, the most prevalent conditions were osteoarticular (59.08-67.80%) and hypertension (50.64-60.03%). The presence of disability was significantly associated to having osteoarticular (OR range: 1.53 to 2.646), diabetes (OR: 1.86 to 1.71), or mental health disorders (OR: 2.19 to 3.36) in most cohorts. Disability (OR: 1.67 to 7.67), osteoarticular conditions (OR: 3.37 to 5.10), and mental health disorders (OR: 1.83 to 4.27) showed the highest effects on lower QoL than the population. CONCLUSION: The presence of disability and diverse chronic conditions has a negative effect on QoL of older adults affected by multimorbidity in Spain. Public health and primary care interventions focusing on the integrated care of older adults with multimorbidity might give special attention to mental health and osteoarticular conditions. PMID- 25724772 TI - Sentinel Lymph Node Detection With the Use of Intradermal Microbubbles in Vulvar Cancer. PMID- 25724773 TI - Morphological Effects Induced In Vitro by Propranolol on Human Erythrocytes. AB - Despite the extended use and well-documented information, there are insufficient reports concerning the effects of propranolol on the structure and functions of cell membranes, particularly those of human erythrocytes. Aimed to better understand the molecular mechanisms of its interactions with cell membranes, human erythrocyte and molecular models of the red cell membrane were utilized. The latter consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. The capacity of propranolol to perturb the multibilayer structures of DMPC and DMPE was evaluated by X-ray diffraction. Moreover, we took advantage of the capability of differential scanning calorimetry to detect the changes in the thermotropic phase behavior of lipid bilayers resulting from propranolol interaction with DMPC and DMPE multilamellar vesicles. In an attempt to further elucidate their effects on cell membranes, the present work also examined their influence on the morphology of intact human erythrocytes by means of defocusing and scanning electron microscopy. Results indicated that propranolol induced morphological changes to human erythrocytes and interacted in a concentration-dependent manner with phospholipid bilayer. PMID- 25724774 TI - Alternative treatments for muscle injury: massage, cryotherapy, and hyperbaric oxygen. AB - Current evidence suggests that popular alternative therapies such as massage, cryotherapy, and hyperbaric oxygen exposure as currently practiced on humans have little effect on recovery from minor muscle damage such as induced by exercise. While further research is still needed, hyperbaric oxygen exposure shows clear promise for potentially being a successful adjunct treatment for enhancing muscle repair and recovery from more severe crush on contusion injury in humans. Cryotherapy or icing, as currently practiced, will not likely be successful in cooling muscle sufficiently to have any significant influence on muscle repair regardless of the degree of injury. However, based on studies in animal models, it may be that if sufficient muscle cooling could be achieved in humans, it could actually delay recovery and increase muscle scarring following significant muscle damage. Conclusions about the effectiveness of massage on influencing muscle recovery from more severe injury cannot yet be made due to a lack of experimental evidence with a more significant muscle damage model. PMID- 25724775 TI - Draft genome of a Xanthomonas perforans strain associated with pith necrosis. AB - Xanthomonas perforans causes bacterial spot of tomato and pepper. A genome draft of an unusual isolate (strain 4P1S2), differing in that it was associated with stem pith necrosis, was assembled from Illumina MiSeq sequencing data using the draft of X. perforans strain 91-118 as a reference. The resulting draft (accession number JRWW00000000) largely overlapped with the reference draft. In addition, the reads not mapping on the reference assembly were selected and used for a further assembly, that revealed a large putative plasmid. The analysis of the predicted proteins showed only few gene features that could be potentially implicated in the switch of a phytopathological behavior. PMID- 25724776 TI - Draft genome sequences of two Aeromonas salmonicida subsp. salmonicida isolates harboring plasmids conferring antibiotic resistance. AB - The bacterium Aeromonas salmonicida is the etiological agent of furunculosis, a widespread fish disease causing important economic losses to the fish farming industry. Antibiotic treatments in fish farms may be challenging given the existence of multidrug-resistant isolates of this bacterium. Here, we report the draft genome sequences of the 2004-05MF26 and 2009-144K3 isolates, which harbor plasmids conferring antibiotic resistance. Both isolates also carry the large plasmid pAsa5, which is known to encode a type three secretion system (TTSS) and the pAsal1 plasmid which has the aopP gene producing a TTSS effector. These two isolates are good representatives of the plasmid diversity in A. salmonicida subsp. salmonicida. PMID- 25724777 TI - Immunogenicity and protective effect of recombinant Brucella abortus Ndk (rNdk) against a virulent strain B. abortus 544 infection in BALB/c mice. AB - In this study, we particularly evaluated the protective effect of recombinant protein encoded by Brucella abortus 544 ndk (nucleoside diphosphate kinase) gene against B. abortus infection in the BALB/c mice. Cloning and expression of B. abortus Ndk was accomplished by PCR amplification into a pMAL expression system, and purification of a recombinant Ndk (rNdk). As for the determination of IgG responses, rNdk induced vigorous IgG production, especially higher in IgG2a compared to IgG1 with titers of 5.2 and 4.8, respectively, whereas titers of these in mice immunized with MBP were 2.4 of IgG2a and 2.6 of IgG1. The analysis of cytokine has revealed that rNdk can strongly induce production of IFN-gamma as well as proinflammatory cytokines (TNF, MCP1 and IL-6) but not much IL-10, suggesting rNdk elicited predominantly cell-mediated immune responses. Furthermore, the spleen proliferation and bacterial burden in the spleen of rNdk immunized mice were significantly lower than those of MBP-immunized mice against virulent B. abortus challenge (P < 0.01). Conclusionly, rNdk immunization enables to elicit both of the humoral and cellular response, ultimately enhancing protection level in experimental mice, suggesting that rNdk of B. abortus might be a useful candidate for subunit vaccine for brucellosis in animals. PMID- 25724778 TI - msaABCR operon positively regulates biofilm development by repressing proteases and autolysis in Staphylococcus aureus. AB - Staphylococcus aureus is an important human pathogen that causes nosocomial and community-acquired infections. One of the most important aspects of staphylococcal infections is biofilm development within the host, which renders the bacterium resistant to the host's immune response and antimicrobial agents. Biofilm development is very complex and involves several regulators that ensure cell survival on surfaces within the extracellular polymeric matrix. Previously, we identified the msaABCR operon as an additional positive regulator of biofilm formation. In this study, we define the regulatory pathway by which msaABCR controls biofilm formation. We demonstrate that the msaABCR operon is a negative regulator of proteases. The control of protease production mediates the processing of the major autolysin, Atl, and thus regulates the rate of autolysis. In the absence of the msaABCR operon, Atl is processed by proteases at a high rate, leading to increased cell death and a defect in biofilm maturation. We conclude that the msaABCR operon plays a key role in maintaining the balance between autolysis and growth within the staphylococcal biofilm. PMID- 25724779 TI - Draft genome sequence of the first acid-tolerant sulfate-reducing deltaproteobacterium Desulfovibrio sp. TomC having potential for minewater treatment. AB - The sulfidogenic bacterium Desulfovibrio sp. TomC was isolated from acidic waste at the abandoned gold ore mining site in the Martaiga gold ore belt, Western Siberia. This bacterium, being the first reported acid-tolerant gram-negative sulfate-reducer of the order Deltaproteobacteria, is able to grow at pH as low as 2.5 and is resistant to high concentrations of metals. The draft 5.3 Mb genome sequence of Desulfovibrio sp. TomC has been established and provides the genetic basis for application of this microorganism in bioreactors and other bioremediation schemes for the treatment of metal-containing wastewater. PMID- 25724780 TI - Relation of delayed recovery of myocardial function after takotsubo cardiomyopathy to subsequent quality of life. AB - Takotsubo cardiomyopathy (TTC) has generally been regarded as a relatively transient disorder, characterized by reversible regional left ventricular systolic dysfunction. However, most patients with TTC experience prolonged lassitude or dyspnea after acute attacks. Although this might reflect continued emotional stress, myocardial inflammation and accentuated brain-type natriuretic peptide (BNP) release persist for at least 3 months. We therefore tested the hypotheses that this continued inflammation is associated with (1) persistent contractile dysfunction and (2) consequent impairment of quality of life. Echocardiographic parameters (global longitudinal strain [GLS], longitudinal strain rate [LSR], and peak apical twist [AT]) were compared acutely and after 3 months in 36 female patients with TTC and 19 age-matched female controls. Furthermore, correlations were sought between putative functional anomalies, inflammatory markers (T2 score on cardiovascular magnetic resonance, plasma NT proBNP, and high-sensitivity C-reactive protein levels), and the physical composite component of SF36 score (SF36-PCS). In TTC cases, left ventricular ejection fraction returned to normal within 3 months. GLS, LSR, and AT improved significantly over 3-month recovery, but GLS remained reduced compared to controls even at follow-up (-17.9 +/- 3.1% vs -20.0 +/- 1.8%, p = 0.003). Impaired GLS at 3 months was associated with both persistent NT-proBNP elevation (p = 0.03) and reduced SF36-PCS at >=3 months (p = 0.04). In conclusion, despite normalization of left ventricular ejection fraction, GLS remains impaired for at least 3 months, possibly as a result of residual myocardial inflammation. Furthermore, perception of impaired physical exercise capacity >=3 months after TTC may be explained by persistent myocardial dysfunction. PMID- 25724781 TI - Factors driving anticoagulant selection in patients with atrial fibrillation in the United States. AB - With the introduction of novel oral anticoagulants (NOACs), the factors driving anticoagulant selection in atrial fibrillation (AF) in real-world practice are unclear. The goal was to examine whether and to what extent utilization has been driven by predictions of stroke risk (treatment benefit), bleeding risk (treatment harm), or prescription benefits' coverage. We extracted a cohort of patients with nonvalvular AF initiating anticoagulation from October 2010 to December 2012 from a large US database of commercial and Medicare supplement claims. Multivariable regression examined associations between ischemic stroke (CHA2DS2-VASc) and bleeding (Anticoagulation and Risk Factors in Atrial Fibrillation [ATRIA]) risk scores and benefits' generosity (proportion of costs covered by patients relative to total) with warfarin and novel oral anticoagulant (NOAC) selection and also between dabigatran and rivaroxaban. C-statistics and partial chi-square statistics were used to assess the variation explained. Of 70,498 patients initiating anticoagulation, 29.9% and 7.9% used dabigatran and rivaroxaban, respectively. Compared with warfarin, patients were less likely to receive an NOAC with high ischemic stroke risk (CHA2DS2-VASc >=2; adjusted relative risk [aRR] 0.75, 95% confidence interval [CI] 0.72 to 0.77) and high bleeding risk (ATRIA >=5; aRR 0.66, 95% CI 0.64 to 0.69) but more likely with good benefits' generosity (<=20% of costs borne by patient; aRR 2.03, 95% CI 1.92 to 2.16). Prescription generosity explained almost twice the model variation as either risk score. Compared with dabigatran, patients were more likely to fill rivaroxaban with high bleeding risk (aRR 1.16, 95% CI 1.09 to 1.24). In conclusion, patients with greater bleeding and ischemic stroke risk were more likely to initiate warfarin, but generous benefits more strongly predicted NOAC usage and drove more selection. PMID- 25724782 TI - Trends in management and outcomes of ST-elevation myocardial infarction in patients with end-stage renal disease in the United States. AB - Acute myocardial infarction in patients with end-stage renal disease (ESRD) is associated with increased risk of morbidity and mortality. Limited data are available on the contemporary trends in management and outcomes of ST-elevation myocardial infarction (STEMI) in patients with ESRD. We analyzed the 2003 to 2011 Nationwide Inpatient Sample databases to examine the temporal trends in STEMI, use of mechanical revascularization for STEMI, and in-hospital outcomes in patients with ESRD aged >=18 years in the United States. From 2003 to 2011, whereas the number of patients with ESRD admitted with the primary diagnosis of acute myocardial infarction increased from 13,322 to 20,552, there was a decrease in the number of STEMI hospitalizations from 3,169 to 2,558 (ptrend <0.001). The overall incidence rate of cardiogenic shock in patients with ESRD and STEMI increased from 6.6% to 18.3% (ptrend <0.001). The use of percutaneous coronary intervention for STEMI increased from 18.6% to 37.8% (ptrend <0.001), whereas there was no significant change in the use of coronary artery bypass grafting (ptrend = 0.32). During the study period, in-hospital mortality increased from 22.3% to 25.3% (adjusted odds ratio [per year] 1.09; 95% confidence interval 1.08 to 1.11; ptrend <0.001). The average hospital charges increased from $60,410 to $97,794 (ptrend <0.001), whereas the average length of stay decreased from 8.2 to 6.5 days (ptrend <0.001). In conclusion, although there have been favorable trends in the utilization of percutaneous coronary intervention and length of stay in patients with ESRD and STEMI, the incidence of cardiogenic shock has increased threefold, with an increase in risk-adjusted in-hospital mortality, likely because of the presence of greater co-morbidities. PMID- 25724783 TI - Meta-analysis of multivessel versus culprit-only percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndrome and multivessel coronary disease. AB - Even in the era of contemporary drug-eluting stents, it is not clear whether percutaneous coronary intervention (PCI) for nonculprit lesions can improve long term outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) with multivessel coronary disease. Relevant studies published through August 2014 were searched and identified in the electronic databases. Summary estimates were obtained using a random-effects model. From 368 initial citations, 8 observational studies with 8,425 patients (3,227 multivessel and 5,198 culprit only PCI) were included. Mean follow-up duration was 18 months. There were no significant differences in all-cause mortality (odds ratios [ORs] 0.85, 95% confidence interval [CI] 0.70 to 1.04) and myocardial infarction (OR 0.86, 95% CI 0.55 to 1.35). However, multivessel PCI was associated with a significantly lower rate of repeat revascularization (OR 0.75, 95% CI 0.56 to 1.00). Comparison of multivessel versus culprit-only PCI disclosed OR for major adverse cardiac events of 0.74 (95% CI 0.57 to 0.97). In conclusion, multivessel PCI reduced repeat revascularization without significant benefits in terms of mortality or myocardial infarction at the long-term follow-up in patients with NSTE-ACS and multivessel coronary disease. Future randomized studies that examine the safety and efficacy of multivessel PCI in NSTE-ACS are warranted. PMID- 25724784 TI - Analysis of the bypass angioplasty revascularization investigation trial using a multistate model of clinical outcomes. AB - Current cardiovascular randomized trials typically use composite outcomes. We hypothesized that the Bypass Angioplasty Revascularization Investigation (BARI) outcomes and conclusions would differ using a multistate model relative to the intervention for the composite outcome of death (D) and nonfatal Q-wave myocardial infarction (MI). We used a multistate model which uses transition paths to simultaneously assess multiple end points. Using the 10-year follow-up BARI data, we post hoc analyzed outcomes according to 3 transition paths: (1) from intervention to MI; (2) from intervention to death; and (3) from MI to death. Of 1,829 patients randomized to the intervention of percutaneous transluminal coronary angioplasty or coronary artery bypass grafting (CABG), 700 (38%) experienced the composite event D/MI which included 230 (13%) nonfatal MI and 470 (26%) death without antecedent nonfatal MI, whereas 79 of 230 (34%) experienced death after nonfatal MI. Outcomes of the 3 individual transition paths were analyzed by a multistate model. In contrast to standard survival analyses, after adjustment for baseline clinical covariates, outcomes after percutaneous transluminal coronary angioplasty or CABG were not significantly different for intervention to MI (p = 0.33) or intervention to death (p = 0.23), but MI to death favored CABG (p = 0.02). Deconstruction of the BARI data using a multistate model identifies a significant difference in individual transition stage outcomes and therefore trial conclusions in contrast to the standard methods of survival analysis. These observations suggest multistate models should be considered in the design and analysis of randomized cardiovascular trials which use composite outcomes. PMID- 25724785 TI - Doxycycline ameliorates aggregation of collagen and atrial natriuretic peptide in murine post-infarction heart. AB - Heart failure after myocardial infarction (MI) is associated with the aggregation of collagen and some misfolded proteins. This study was aimed to assess the therapeutic efficacy of doxycycline (Dox) in MI-induced heart failure and elucidate the potential mechanisms involved. A heart failure model of animals was established by ligating the left anterior descending coronary artery of rats. The administration of Dox via drinking water (25mg/kg/day) was initiated after surgery and lasted for two weeks. After cardiac function evaluation by echocardiography, all animals were killed to assess the aggregation of type I collagen, atrial natriuretic peptide (ANP), and the activities of matrix metalloproteinases (MMPs), autophagosomes and microtubule-associated protein 1 light chain 3 (LC3). Dox treatment significantly improved cardiac function and attenuated cardiac hypertrophy. Histological observation revealed that Dox significantly reduced the expression of collagen and ANP in the heart. Further investigation showed that Dox significantly inhibited the activities of MMP-2 and MMP-9, increased autophagosomes and enhanced LC3-II in post-infarction hearts. This study revealed that Dox treatment could promote autophagy, reduce ANP aggregation in post-infarction hearts, and inhibit MMP-2 and MMP-9 activities. Dox might act as a potential therapeutic drug for preventing proteotoxicity and cardiac dysfunction. PMID- 25724787 TI - Thymol attenuates inflammation in isoproterenol induced myocardial infarcted rats by inhibiting the release of lysosomal enzymes and downregulating the expressions of proinflammatory cytokines. AB - Inflammation plays an important role in the development of myocardial infarction (MI). The current study dealt with the protective effects of thymol on inflammation in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pre and co-treated with thymol (7.5mg/kg body weight) daily for 7 days. ISO (100mg/kg body weight) was injected subcutaneously into rats at an interval of 24h for two days (6th and 7th day) to induce MI. ISO induced myocardial infarcted rats showed increased levels of serum cardiac troponin-T, high sensitive C-reactive protein (hsCRP), lysosomal thiobarbituric acid reactive substances (TBARS) and elevated ST-segments. Also, the activities of lysosomal enzymes such as beta-glucuronidase, beta-galactosidase, cathepsin-B and D, the stimulators of inflammatory mediators were increased in the serum and heart of ISO induced myocardial infarcted rats. Furthermore, ISO up regulates the expressions of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) genes in the myocardium of rats analyzed by reverse transcription polymerase chain reaction (RT-PCR). Pre and co-treatment with thymol (7.5mg/kg body weight) near normalized the levels of lysosomal TBARS, activities of serum and heart lysosomal enzymes and downregulates the expressions of pro-inflammatory cytokines in the myocardium of ISO induced myocardial infarcted rats. Histopathological and transmission electron microscopic findings were also found in line with biochemical findings. Thus, the results of our study revealed that thymol attenuates inflammation by inhibiting the release of lysosomal enzymes and downregulates the expressions of pro-inflammatory cytokines by its potent anti-inflammatory effect. PMID- 25724786 TI - Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice. AB - Patients with sickle cell disease (SCD) can have recurrent episodes of vaso occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid responsive mechanisms. Dexmedetomidine, a specific alpha2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P<=0.006). In sickle, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickle and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickle and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickle compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients. PMID- 25724788 TI - Dopamine receptor partial agonists and addiction. AB - Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction. PMID- 25724789 TI - Increased postoperative day one discharges after implementation of a hysterectomy enhanced recovery pathway: a retrospective cohort study. AB - PURPOSE: In 2011, the hysterectomy enhanced recovery (HER) pathway, a multi disciplinary, evidence-based care plan designed to improve recovery after open gynecologic surgery for non-malignant lesions, was introduced at The Ottawa Hospital (TOH). This before-and-after study examined the impact of the HER pathway on postoperative day (POD) 1 hospital discharge. METHODS: Ethical approval was obtained. This retrospective cohort study included patients who had undergone open abdominal gynecologic surgery for non-malignant lesions at TOH Civic Campus between July 2010 and September 2012 (the year before and year after HER implementation). Patients were analyzed in either a pre-HER or post-HER group depending on their surgery date. Patients with chronic pain and emergent surgery were excluded. Data were obtained via medical chart review. Our primary outcome was the percentage of POD 1 discharges before and after HER implementation. Secondary outcomes included return to hospital within 30 days of discharge, median length of stay (LOS), clinician compliance with HER, and an exploratory analysis with multivariable modelling to evaluate which aspects of the HER independently predicted POD 1 discharge. Variables used included American Society of Anesthesiologists physical status (>= II), prior abdominal surgery, body mass index, use of transversus abdominis plane blocks, and anesthetic type. RESULTS: Among the 223 patients, significantly more POD 1 discharges occurred for post-HER compared to pre-HER patients (34% vs 7%, respectively; adjusted odds ratio [OR] = 7.33; 95% confidence interval [CI] = 3.05 to 17.62). Rates of return to hospital at 30 days were similar between the groups (10% post-HER and 13% pre-HER; adjusted OR = 0.74; 95% CI = 0.32 to 1.74). The median length of stay was two days in the post-HER group and three days in the pre-HER group (P < 0.0001). Only inhalational general anesthesia was independently associated with decreased odds of POD 1 discharge (adjusted OR = 0.16, 95% CI = 0.04 to 0.65). CONCLUSION: For patients undergoing abdominal hysterectomy, implementation of a HER pathway is associated with a higher POD 1 discharge rate, with no increase in the early return to hospital rate. PMID- 25724790 TI - Safety-engineered intravenous catheter utilization among Canadian pediatric anesthesiologists. AB - INTRODUCTION: Compared with other specialties, anesthesiologists are at increased risk of acquiring a blood-borne pathogen (BBP) through needle-stick injuries (NSIs). Safety-engineered intravenous catheters (SEICs) have been designed to reduce NSIs but have not been well received. Our objective was to determine SEIC usage by pediatric anesthesiologists, including availability, utilization, perceived utility, and sources of NSI before and after legislation mandating their use in Canada. METHODS: After Ethics Committee approval, we conducted two electronic surveys of Canadian pediatric anesthesiologists (CPAs) based in tertiary care settings. Survey responses from May through August 2012 and June through September 2006 were considered. In addition to SEIC use and perceived utility, respondents described factors influencing SEIC adoption and workplace NSIs. Standard metrics of survey validity and reliability were employed. RESULTS: Completed questionnaires were returned by 154 (69%) and 124 (53%) respondents in 2012 and 2006, respectively, representing 15 of 16 Canadian pediatric tertiary care centres. Reported SEIC availability increased in hospitals (82% vs 98%; difference in proportion 16%, 95% confidence interval [CI]: 9 to 24%; P < 0.001) and in operating rooms (62% vs 86%; difference in proportion 24%, 95% CI: 13 to 34%; P < 0.001) Respondents' report of "routine" personal use of SEICs increased from 43 of 76 (56%) to 112 of 132 (85%) (difference in proportion 29%, 95% CI: 16 to 41%; P < 0.001). Attitudes concerning perceived utility of SEICs remained unchanged and evenly split between respondents. "Awkward handling" remained the primary reason for non-use. In all, 71 (48%) and 60 (48%) respondents reported recent contaminated NSIs in 2012 and 2006, respectively. The majority were related to a needle on a disposable syringe. DISCUSSION: Despite only moderate perceived utility, SEIC uptake among CPAs is high. However, NSIs remain common. Several opportunities to reduce the risk for work-related BBP transmission among CPAs were evident. PMID- 25724791 TI - Engineering solutions for safety: not always as simple as they seem. PMID- 25724792 TI - The predictive validity of neonatal MRI for neurodevelopmental outcome in very preterm children. AB - Very preterm children are at a high risk for neurodevelopmental impairments, but there is variability in the pattern and severity of outcome. Neonatal magnetic resonance imaging (MRI) enhances the capacity to detect brain injury and altered brain development and assists in the prediction of high-risk children who warrant surveillance and early intervention. This review describes the application of conventional and advanced MRI with very preterm neonates, specifically focusing on the relationship between neonatal MRI findings and later neurodevelopmental outcome. Research demonstrates that conventional MRI is strongly associated with neurodevelopmental outcome in childhood. Further studies are needed to examine the role of advanced MRI techniques in predicting outcome in very preterm children, but early research findings are promising. In conclusion, neonatal MRI is predictive of later neurodevelopment but is dependent on appropriately trained specialists and should be interpreted in conjunction with other clinical and social information. PMID- 25724793 TI - Preoperative imaging of uterine malignancy: A low-value service. AB - OBJECTIVE: The aim of this study is to examine the value of computed tomography (CT) or magnetic resonance imaging (MRI) before surgical treatment of uterine malignancy. METHODS: Retrospective chart review was undertaken of women who underwent hysterectomy for uterine cancer at the University of Virginia. Radiologic reports were examined for evidence of cervical or extrauterine disease or incidental findings and correlated with detection of extrauterine disease at surgery. RESULTS: Overall, 204 of 448 patients (45%) had preoperative imaging. Scans were ordered nearly evenly by referring clinicians and gynecologic oncologists (GO) (95 vs. 122, 44% vs. 56%). Imaging was most common among patients with grade 3 endometrioid or non-endometrioid histology (86 of 101, 85%). Women referred with low grade disease had more false positive (4 of 112, 4%) than true positive scans (2 of 113, 2%). Overall, 23 of 190 (12%) reviewed preoperative scans indicated suspected extrauterine disease. Two of these 23 women were low risk by intra-operative "Mayo criteria" and had stage 1A disease; 14 of 23 (61%) had stage II or greater disease. CONCLUSIONS: Preoperative CT or MRI is of low value in predicting extra-uterine disease among uterine cancer patients with low grade disease. Women with low grade disease had false positive results more frequently than true detection of extrauterine disease. Abnormal imaging findings are more common and predictive of extrauterine disease in women with grade 3 or non-endometrioid histology but the value of these scans remains unclear. PMID- 25724794 TI - Shoulder ring complaints as a rare first symptom of malignant pleural mesothelioma. AB - The prevalence of malignant pleural mesothelioma is often encountered in the areas highly exposed to asbestos. The aim of this paper was a retrospective analysis of shoulder pain as a rare, first symptom of pleural mesothelioma, which constitutes an interdisciplinary diagnostic problem concerning both orthopedics and pulmonology. The research was based on a retrospective review of the patients' medical records. The considered period of time included the years 2006 2012. The study group included a total of 49 patients. Seven patients (14.3%) presented a complain of shoulder pain, as the first symptom of mesothelioma. The remaining 42 mesothelioma patients, without this symptom, constituted a reference group. The intensity of shoulder pain was, on average, 4/10 on an analog scale. A concomitant limitation of mobility was observed in five out of the seven subjects. In one case, limitation of motion and dysfunction of the shoulder joint were at an advanced stage. Neuralgia of upper limbs was found in two cases. We conclude that shoulder pain may be a manifesting symptom of malignant pleural mesothelioma. The neoplasm appears to have a pleiotropic effect on human body, reflected in different ways of its primary manifestation which may also include the motor system. PMID- 25724795 TI - Compliance with Vaccination Against Influenza Among the Elderly. AB - Protective vaccination against influenza is one of the most beneficial methods of preventing this viral disease. The use of vaccines brings not only the health benefits but also has positive implications related to diminishing the costs of treatment, prolonged hospitalization or post-influenza complications. Promoting vaccinations against influenza among the elderly is especially important. The article concerns the perception of these vaccinations and evaluation of the general knowledge on influenza among listeners of a university of the third age in Warsaw, Poland. It aims also at assessing the potential to change opinions and decisions regarding vaccinations against influenza and widely understood influenza prevention among this target group. The research tool, apart from the scientific lecture-like presentation rich in examples, was a self-reported questionnaire designed by the authors specifically for this study purpose. This paper presents the results of survey conducted with the questionnaire completed by 29 persons over 60 years of age. We found that the recent vaccination rate against influenza was just was about 20% in the studied sample of the elderly. The study demonstrates that educational training through a professional lecture presentation facilitates the promotion of health and vaccination coverage against influenza in the elderly. PMID- 25724796 TI - Progress in the Diagnosis and Control of Ebola Disease. AB - Ebola hemorrhagic fever is one of numerous viral hemorrhagic fevers. It is a severe, often fatal disease in humans and nonhuman primates (gorillas and chimpanzees). This article discusses the history of Ebola disease, already known routes of infection together with defining prevention methods and treatment trials. The importance of increasing awareness of the risk of disease among people who do not inhabit endemic regions is emphasized. This risk is associated especially with the increasing popularity of tourism to African countries, even to those where the virus is endemic. The research conducted over the years shows that three species of frugivorous bats are subjected to contamination by Ebola, but the infection is asymptomatic in them. It is believed that the saliva of these mammals and other body fluids may be a potential source of infection for primates and humans. In the laboratory, infection through small-particle aerosols has been demonstrated in primates, and airborne spread among humans is strongly suspected, although it has not yet been conclusively demonstrated. The importance of this route of transmission remains unclear. Poor hygienic conditions can aid the spread of the virus. These observations suggest approaches to the study of routes of transmission to and among humans. PMID- 25724797 TI - Detection of Chlamydophila Pneumoniae and Typical Bacteria in Patients with Chronic Cough. AB - The aim of research was to analyze the results of microbiological tests for typical and atypical bacteria in patients with symptoms of chronic cough. A total of 214 outpatients aged from 2 to 94 years (110 women, 64 men, and 40 children) with chronic cough were studied. Four hundred twenty eight throat swabs were examined for atypical bacteria antigen (Chlamydophila pneumoniae) (n=214) and typical pathogens (n=214). Chl. pneumoniae detection was performed using indirect immunofluorescence test. Classical microbiological culture was used for typical bacteria detection. Chl. pneumoniae antigen was detected in 55/214 (26.0%) patients with chronic cough (in 31 (28.2%) women, 14 (21.9%) men, and 10 (25.0%) children). Positive culture for typical pathogens was observed in 30 (27.3%) women, 22 (34.4%) men, and 21 (52.5%) children. Simultaneous occurrence of Chl. pneumoniae and typical pathogens (Staphylococcus aureus strain MSSA, Streptococcus pyogenes, or Moraxella catarrhalis) was found in 16 (7.5%) patients. The findings show that in patients with chronic cough Chl. pneumoniae infection, although less than that with typical pathogens, is rather frequent. Further, the performance of test for Chl. pneumoniae in throat swabs from patients with chronic cough is good and provides an efficient way to diagnose the infection and implement appropriate therapy. PMID- 25724798 TI - Prevalence of Brucella antibodies on a previously acute brucellosis infected population: sensitivity, specificity and predictive values of Rose Bengal and Wright standard tube agglutination tests. AB - PURPOSE: Brucellosis is a zoonosis with worldwide distribution. The presence of antibodies after acute infection and the prevalence of positive serology in endemic area are not well documented. METHODS: Patients hospitalized with acute brucellosis were relocated 3-13 years after the initial infection. Hospital records of the initial infection were retrieved, and examination of Brucella antibodies using Rose Bengal test (RBT) and Wright standard tube agglutination (STA) test was performed. RESULTS: Eighty-three patients were hospitalized from 2000 to 2010; 50.6 % were farmers and 37.4 % livestock farmers. All had febrile illness and various focal complications. All had positive serology, and 82.2 % had positive blood cultures; 91.5 % were treated with streptomycin plus doxycycline. Seventy-two (86.7 %) were relocated on follow-up. Nine (12.5 %) had positive RBT and STA up to 1/320. Occupational history was associated with positive serology (p = 0.0172), and 8/9 of the positive individuals were livestock farmers (38.0 % of the livestock farmers checked). Residence, years after the infection, clinical presentation of brucellosis and treatment were not associated with serology results. Both tests had excellent sensitivity (nearly 100 %), specificity 87.5 % and excellent negative predictive value (nearly 100 %); however, positive predictive value was only 11.4 %. CONCLUSIONS: Rapid and low-cost tests as RBT and STA are still very useful in diagnosing acute brucellosis; however, every positive test must be examined together with clinical symptoms and occupational history. The tests can be used as screening tests in endemic populations to rule out acute brucellosis. PMID- 25724799 TI - Definite (microbiologically confirmed) tuberculous meningitis: predictors and prognostic impact. AB - BACKGROUND: Microbiological confirmation cannot be obtained in approximately two third patients with tuberculous meningitis. In this study, we sought to identify epidemiological, clinical, cerebrospinal fluid, and imaging parameters that could indicate the possibility of microbiological confirmation among patients with suspected tuberculous meningitis. MATERIALS AND METHODS: In this prospective observational study, patients with tuberculous meningitis were evaluated for clinical, laboratory (cerebrospinal fluid microscopy, culture, and polymerase chain reaction), and neuroimaging parameters. All patients received anti tuberculosis drugs and corticosteroids. The patients were followed for a period of 6 months. RESULTS: Among 118 cases of tuberculous meningitis, there were 43 (36 %) definite (microbiologically confirmed) cases, 59 (50 %) probable and 16 (14 %) possible cases. Among 43 definite cases, tuberculosis polymerase chain reaction (PCR) was positive in 42 (35 %) patients, culture was positive in 1 case and microscopy, after Ziehl-Neelsen staining, was positive in 3 cases. Three factors, modified Barthel index score at admission <=12 (p = 0.008), cerebrospinal fluid total cell count >100/mm(3) (p = 0.016), and basal exudates on imaging (p = 0.015), were significantly associated with definite tuberculous meningitis. Among 20 patients who died within 6 months, 13 belonged to definite tuberculous meningitis group (p < 0.001). Stage III tuberculous meningitis (p = 0.004), baseline-modified Barthel index score <=12 (p = 0.013), and positive tuberculosis PCR (p = 0.007) were independently associated with poor outcome on multivariate analysis. CONCLUSION: Severe disability, cerebrospinal fluid cells >100 mm(3), and basal exudates are significantly related to the presence of microbiologically confirmed definite tuberculous meningitis. Microbiologically confirmed tuberculous meningitis is associated with poorer outcome. PMID- 25724800 TI - Effects of the size and morphology of zinc oxide nanoparticles on the germination of Chinese cabbage seeds. AB - The toxicity of four zinc oxide nanoparticles (i.e., spheric ZnO-30, spheric ZnO 50, columnar ZnO-90, and hexagon rod-like ZnO-150) to the seed germination of Chinese cabbage (Brassica pekinensis L.) was investigated in this study. The results showed that zinc oxide nanoparticles (nano-ZnOs) did not affect germination rates at concentrations of 1-80 mg/L but significantly inhibited the root and shoot elongation of Chinese cabbage seedlings, with the roots being more sensitive. The inhibition was evident mainly during seed incubation rather than the seed soaking process. Both the production of free hydroxyl groups (.OH) and the Zn bioaccumulation in roots or shoots resulted in toxicity of nano-ZnOs to Chinese cabbage seedlings. The toxicity of nano-ZnOs was affected significantly by their primary particle sizes in the minimum dimensionality, but large columnar ZnO-90 and small spherical ZnO-50 had comparable toxicities. Therefore, both the particle size and morphology affected the toxicity of nano-ZnOs. PMID- 25724801 TI - Green alga Ulva pertusa--a new source of bioactive compounds with antialgal activity. AB - We tested the effects of solvent fractions (FA, FB, FC, and FD), which partitioned by liquid-liquid extraction from the methanol extract of Ulva pertusa, on the growth of red tide microalgae (Karenia mikimitoi, Skeletonema costatum, Alexandrium tamarense, Heterosigma akashiwo, Prorocentrum donghaiense), and FA, FB, and FC exhibited significantly antialgal activity. The chemical constituent analysis showed the existence of bioactive compounds such as phenols and alkaloids. Further, four solvent fractions were applied to silica gel column and repeated preparative TLC to produce 13 samples and their purity qualified as thin-layer chromatographic grade. Among these purified samples, FA111, FB411, FC411, FD111, and FD211 exhibited stronger antialgal activity. Furthermore, their functional groups were analyzed by colorimetric methods and UV spectra data. FD111 and FD211 were temptatively identified as alkaloids; the others were initially identified as phenolic acids. This is a preliminary study and the structure identification of these purified samples requires further investigation. While concentration of these purified samples in this algae was very small, they showed excellent effects against red tide microalgae. PMID- 25724802 TI - Functional assessments for decision-making regarding return to sports following ACL reconstruction. Part II: clinical application of a new test battery. AB - PURPOSE: The purpose of this study was to utilize a novel functional test system to facilitate determining the time of return to sports following ACL reconstruction. METHODS: Sixty-nine patients with unilateral ACL reconstruction were included in this pilot study. All the patients performed a standardized test battery consisting of one- and two-legged stability tests, counter movement jumps, speedy jumps, plyometric jumps and a quick feed test. The first test was administered on average 170.7 +/- 75.1 days post-operatively, and the retest was administered on average 239.1 +/- 79.7 days post-operatively. The values of the subtests were compared with the normative data of healthy gender- and age-matched controls to determine the functional capacities of patients following ACL reconstruction. RESULTS: After the first and second test, 15.9 and 17.4 % of the patients met the criteria for a "return to non-competitive sports". One patient fulfilled the criteria for a "return to competitive sports" after the second test battery. The most limiting factor was a poor LSI value of <90 % if the dominant leg was involved and <80 % if the non-dominant leg was involved. CONCLUSION: This test battery demonstrates that, in terms of neuromuscular abilities, most patients, compared to healthy controls, are most likely not ready for a safe return to sports, even 8 months post-operatively. This should be considered in the future to determine when it is safe to return to sports and should avoid a premature return to competitive sports. LEVEL OF EVIDENCE: III. PMID- 25724803 TI - Emotion Regulation in Sexually Abused Preschoolers. AB - Emotion regulation is closely related to mental health in children and adults. Low emotion regulation competencies have been found in school-aged sexually abused girls. The aim of the present study was to investigate emotion regulation competencies in sexually abused preschool girls and boys using a multi-informant approach. Emotion regulation was assessed in 62 sexually abused and 65 non-abused preschoolers using the Emotion Regulation Checklist and the MacArthur Story Stem Battery. Both parents and educators reported lower emotion regulation competencies in sexually abused preschoolers, especially boys, than in non-abused children. The narrative task completed by the children also revealed lower emotion regulation competencies in sexually abused boys. These findings could have an important impact on intervention programs offered to these at-risk children. PMID- 25724804 TI - A systematic review and meta-analysis of cognitive behavioral and psychodynamic therapy for depression in Parkinson's disease patients. AB - Numerous practice guidelines have recommended cognitive behavioral therapy (CBT) and psychodynamic therapy as a treatment of choice for depression in Parkinson's disease (PD). However, no recent meta-analysis has examined the effects of brief psychotherapy (which includes both CBT and psychodynamic therapy) for adult depression in PD. We decided to conduct such a systematic review and meta analysis. We included randomized controlled trials (RCTs) examining the effects of brief psychotherapy compared with control groups, other support nursing, or pharmacotherapy. The quality of included studies was strictly evaluated. Twelve studies including 766 patients met all inclusion criteria. The result showed that brief psychotherapy could evidently improve the HAMD (p < 0.00001) and Moca scale (p = 0.006). There was no statistical significance in PDQ-39 scale (p = 0.31). In the subgroup analysis by types of brief psychotherapy, the efficacy of psychodynamic psychotherapy was better than CBT (SMD = -2.02 vs SMD = -0.90) for the outcome measure according to HAMD scale. Meanwhile, we found brief psychotherapy in China was more effective than in US (SMD = -1.54 vs SMD = 1.23), and in low quality studies was more efficacious than in high quality studies (SMD = -1.50 vs SMD = -1.33). Time of brief psychotherapy treatment above 6 weeks was superior to studies with less than 6 weeks treatment. We found brief psychotherapy is probable effective in the management of depression in PD patients. But one reason to undermine the validity of findings is high clinical heterogeneity and low methodological quality of the included trials. PMID- 25724805 TI - Chronic inflammatory demyelinating polyneuropathy mimicking an acute painful diabetic neuropathy. PMID- 25724806 TI - Electrical stimulation characteristics of denervated orbicularis oculi muscle. AB - This research is to study the electrical stimulation characteristics of orbicularis oculi muscle and the characteristics of the mechanical contraction. We observed the stimulus current diffusion regularity and its relationship with mechanical contraction in the orbicularis oculi muscle using an electrode gathering line. Under different stimulus intensities of 2 or 4 mA, the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. In addition, current conduction across the muscle fiber was studied. Under different stimulus intensities of 2 or 4 mA, it was found that the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. The transverse current reached a maximum 4 mA range, and increasing the current intensity did not increase the propagation range. Under different stimulation intensities, the larger the stimulus intensity, the greater is the potential change and the faster is the attenuation. Longitudinal current, even in the range of 6 mm, can still record electrical activity. While a transverse current diffuser has a maximum range of 4 mm, increasing the current intensity does not increase the propagation range. PMID- 25724808 TI - Reply to: Li J, Cao Y "Serum ferritin as a biomarker for diabetes and insulin resistance: a further study". PMID- 25724809 TI - Age and sex differences in the effect of parental stroke on the progression of carotid intima-media thickness. AB - BACKGROUND AND PURPOSE: Parental stroke is a risk factor for stroke among the offspring. Carotid artery intima-media thickness (IMT) is a widely regarded surrogate marker for atherosclerosis and a predictive marker for stroke. This study examines whether parental stroke is associated with IMT progression. METHODS: This longitudinal study had two measures of IMT that were taken upon enrollment of the 521 subjects and after an average follow-up of 4.1 years. The rate of IMT progression was tested for associations with parental stroke and cardiovascular risk factors using ANCOVA models. Age and sex were also tested as effect modifiers. The subjects were allocated into the young or old group using the age of 55 years. RESULTS: Parental history of stroke was significantly associated with progression of common carotid artery (CCA) IMT compared with no parental stroke history (13.52 vs. 10.43 MUm/year, adjusted p = 0.035). The parental effect on IMT progression of the bifurcation and internal carotid artery was dependent on age group. Young subjects had faster progression, whereas older subjects with parental stroke had slower progression. There was a three-way interaction among sex, age, and parental stroke in CCA IMT progression, such that young women with parental stroke had a 69.7% faster progression than young women without parental stroke (15.58 vs. 9.18 MUm/year). However, this difference was not found in young men or old subjects with and without parental stroke. CONCLUSIONS: Parental stroke is associated with carotid artery IMT progression and is more obvious in the young, especially among women. The results emphasize the clinical significance of parental stroke risk on atherosclerosis in young women. PMID- 25724810 TI - Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes. AB - Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann Steiner, Kabuki, and Adams-Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers. PMID- 25724811 TI - Hair follicle bulge cultures yield class III beta-tubulin-positive melanoglial cells. AB - Class III beta-tubulin (TUBB3)-positive cells from the hair follicle bulge are thought to be neuronal cells derived from a local neural crest stem cell. However, TUBB3 has recently been shown to be expressed in the melanocytic lineage. To evaluate the neural-crest-associated immunophenotype of TUBB3 positive cells from hair follicle bulge explants, we dissected hair follicle bulges out from mouse whisker pads and cultured for 1 month and assessed outgrowing cells by means of immunocytochemistry using the biomarkers TUBB3, nestin, NGFR, SOX9, TYRP1 and laminin. Large amounts of TUBB3-positive cells could be cultured that co-expressed nestin, NGFR, SOX9 and, to a lesser degree, TYRP1, matching a melanoglial phenotype. In addition, a small population of TUBB3 negative but laminin-positive cells was found, which presumably are of glial origin. It can be concluded that cells of melanoglial origin can easily be obtained from hair follicle bulge explants. These cells may be of use in experimental animal or human disease and wound healing models. Notably, the TUBB3 positive cells are of melanoglial rather than neuronal origin. PMID- 25724812 TI - Ultrastructural changes in the progress of natural Scrapie regardless fixation protocol. AB - Because few studies regarding ultrastructural pathological changes associated with natural prion diseases have been performed, the present study primarily intended to determine consistent lesions at the subcellular level and to demonstrate whether these changes are evident regardless of the fixation protocol. Thus far, no assessment method has been developed for classifying the possible variations according to the disease stage, although such an assessment would contribute to clarifying the pathogenesis of this neurodegenerative disease. Therefore, animals at different disease stages were included here. This study presents the first description of lesions associated with natural Scrapie in the cerebellum. Vacuolation, which preferentially occurs around Purkinje cells and which displays a close relation with glial cells, is one of the most novel observations provided in this study. The disruption of hypolemmal cisterns in this neuronal type and the presence of a primary cilium in the granular layer both represent the first findings concerning prion diseases. The possibility of including samples regardless of their fixation protocol is confirmed in this work. Therefore, a high proportion of tissue bank samples that are currently being wasted can be included in ultrastructural studies, which constitute a valuable source for information regarding physiological and pathological samples. PMID- 25724813 TI - Sleeve-forming gastrectomy is the right terminology. AB - Gastric sleeve is the final result when a vertical or sleeve-forming gastrectomy is performed. There is controversy about the nomination of the procedure to make a lesser curvature gastric sleeve (LCS) since the term sleeve gastrectomy, used commonly, is grammatically a misnomer. Lexicon incorrectness should not be accepted scientifically for any nomination. The Spanish Royal Academy of Medicine and seven leaders of the International Federation for the Surgery of Obesity (IFSO) were consulted. Four past IFSO presidents, four chief editors of the Obesity Surgery journal and two presidents of national associations all agree that the sleeve gastrectomy term is a misnomer and sleeve-forming gastrectomy is proposed as the correct term. PMID- 25724814 TI - The Role of FTO and Vitamin D for the Weight Loss Effect of Roux-en-Y Gastric Bypass Surgery in Obese Patients. AB - BACKGROUND: A recent study in children demonstrated that the rs9939609 single nucleotide polymorphism in the fat mass and obesity (FTO) gene influences prospective weight gain, however, only in those who were vitamin D-deficient. If this might also be the case for Roux-en-Y gastric bypass (RYGB), surgery-induced weight loss is however unknown. The objective of this study is to examine if the magnitude of RYGB surgery-induced weight loss after 2 years depends on patients' FTO rs9939609 genotype (i.e., TT, AT, and AA) and presurgery vitamin D status (<50 nmol/L equals deficiency). METHODS: Before and at 24 months after RYGB surgery, BMI was measured in 210 obese patients (mean BMI 45 kg/m(2), 72 % females). Serum 25-hydroxyvitamin D3 levels were also repeatedly measured. Following surgery, vitamin D was supplemented. Possible weight loss differences between genotypes were tested with multiple linear regressions. RESULTS: The per allele effect of each FTO A-allele on excessive BMI loss (EBMIL) was 3 % (P = 0.02). When split by baseline status, the EBMIL of vitamin D-deficient patients carrying AA exceeded that of vitamin D-deficient patients carrying TT by ~14 % (P = 0.03). No such genotypic differences were found in patients without presurgery vitamin D deficiency. Post-surgery serum levels of vitamin D did not differ between groups. CONCLUSIONS: Our data suggest that presurgery vitamin D levels influence the size of genotype effects of FTO rs9939609 on RYGB surgery-induced weight loss in obese patients. PMID- 25724815 TI - Understanding bacterial resistance to antimicrobial peptides: From the surface to deep inside. AB - Resistant bacterial infections are a major health problem in many parts of the world. The major commercial antibiotic classes often fail to combat common bacteria. Although antimicrobial peptides are able to control bacterial infections by interfering with microbial metabolism and physiological processes in several ways, a large number of cases of resistance to antibiotic peptide classes have also been reported. To gain a better understanding of the resistance process various technologies have been applied. Here we discuss multiple strategies by which bacteria could develop enhanced antimicrobial peptide resistance, focusing on sub-cellular regions from the surface to deep inside, evaluating bacterial membranes, cell walls and cytoplasmic metabolism. Moreover, some high-throughput methods for antimicrobial resistance detection and discrimination are also examined. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 25724816 TI - Reduced graphene oxide directed self-assembly of phospholipid monolayers in liquid and gel phases. AB - The response of cell membranes to the local physical environment significantly determines many biological processes and the practical applications of biomaterials. A better understanding of the dynamic assembly and environmental response of lipid membranes can help understand these processes and design novel nanomaterials for biomedical applications. The present work demonstrates the directed assembly of lipid monolayers, in both liquid and gel phases, on the surface of a monolayered reduced graphene oxide (rGO). The results from atomic force microscopy indicate that the hydrophobic aromatic plane and the defect holes due to reduction of GO sheets, along with the phase state and planar surface pressure of lipids, corporately determine the morphology and lateral structure of the assembled lipid monolayers. The DOPC molecules, in liquid phase, probably spread over the rGO surface with their tails associating closely with the hydrophobic aromatic plane, and accumulate to form circles of high area surrounding the defect holes on rGO sheets. However, the DPPC molecules, in gel phase, prefer to form a layer of continuous membrane covering the whole rGO sheet including defect holes. The strong association between rGO sheets and lipid tails further influences the melting behavior of lipids. This work reveals a dramatic effect of the local structure and surface property of rGO sheets on the substrate directed assembly and subsequent phase behavior of the supported lipid membranes. PMID- 25724817 TI - Which factors affect the choice of the inhaler in chronic obstructive respiratory diseases? AB - Inhalation is the preferred route of drug administration in chronic respiratory diseases because it optimises delivery of the active compounds to the targeted site and minimises side effects from systemic distribution. The choice of a device should be made after careful evaluation of the patient's clinical condition (degree of airway obstruction, comorbidities), as well as their ability to coordinate the inhalation manoeuvre and to generate sufficient inspiratory flow. These patient factors must be aligned with the specific advantages and limitations of each inhaler when making this important choice. Finally, adherence to treatment is not the responsibility of the patient alone, but should be shared also by clinicians. Clinicians have access to a wide selection of pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) that can be used effectively when matched to the needs of individual patients; this should be perceived as an opportunity rather than a limitation. PMID- 25724818 TI - Toxicological assessments of rats exposed prenatally to inhaled vapors of gasoline and gasoline-ethanol blends. AB - The primary alternative to petroleum-based fuels is ethanol, which may be blended with gasoline in the United States at concentrations up to 15% for most automobiles. Efforts to increase the amount of ethanol in gasoline have prompted concerns about the potential toxicity of inhaled ethanol vapors from these fuels. The well-known sensitivity of the developing nervous and immune systems to ingested ethanol and the lack of information about the neurodevelopmental toxicity of ethanol-blended fuels prompted the present work. Pregnant Long-Evans rats were exposed for 6.5h/day on days 9-20 of gestation to clean air or vapors of gasoline containing no ethanol (E0) or gasoline blended with 15% ethanol (E15) or 85% ethanol (E85) at nominal concentrations of 3000, 6000, or 9000 ppm. Estimated maternal peak blood ethanol concentrations were less than 5mg/dL for all exposures. No overt toxicity in the dams was observed, although pregnant dams exposed to 9000 ppm of E0 or E85 gained more weight per gram of food consumed during the 12 days of exposure than did controls. Fuel vapors did not affect litter size or weight, or postnatal weight gain in the offspring. Tests of motor activity and a functional observational battery (FOB) administered to the offspring between post-natal day (PND) 27-29 and PND 56-63 revealed an increase in vertical activity counts in the 3000- and 9000-ppm groups in the E85 experiment on PND 63 and a few small changes in sensorimotor responses in the FOB that were not monotonically related to exposure concentration in any experiment. Neither cell-mediated nor humoral immunity were affected in a concentration related manner by exposure to any of the vapors in 6-week-old male or female offspring. Systematic concentration-related differences in systolic blood pressure were not observed in rats tested at 3 and 6 months of age in any experiment. No systematic differences were observed in serum glucose or glycated hemoglobin A1c (a marker of long-term glucose homeostasis). These observations suggest a LOEL of 3000 ppm of E85 for vertical activity, LOELs of 9000 ppm of E0 and E85 for maternal food consumption, and NOELs of 9000 ppm for the other endpoints reported here. The ethanol content of the vapors did not consistently alter the pattern of behavioral, immunological, or physiological responses to the fuel vapors. The concentrations of the vapors used here exceed by 4-6 orders of magnitude typical exposure levels encountered by the public. PMID- 25724819 TI - Neural representation of dynamic frequency is degraded in older adults. AB - Older adults, even with clinically normal hearing sensitivity, often report difficulty understanding speech in the presence of background noise. Part of this difficulty may be related to age-related degradations in the neural representation of speech sounds, such as formant transitions. Frequency-following responses (FFRs), which are dependent on phase-locked neural activity, were elicited using sounds consisting of linear frequency sweeps, which may be viewed as simple models of formant transitions. Eighteen adults (ten younger, 22-24 years old, and nine older, 51-67 years old) were tested. FFRs were elicited by tonal sweeps in six conditions. Two directions of frequency change, rising or falling, were used for each of three rates of frequency change. Stimulus-to response cross correlations revealed that older adults had significantly poorer representation of the tonal sweeps, and that FFRs became poorer for faster rates of change. An additional FFR signal-to-noise ratio analysis based on time windows revealed that across the FFR waveforms and rates of frequency change, older adults had smaller (poorer) signal-to-noise ratios. These results indicate that older adults, even with clinically-normal hearing sensitivity, have degraded phase-locked neural representations of dynamic frequency. PMID- 25724821 TI - Autism and vaccination: The value of the evidence base of a recent meta-analysis. PMID- 25724820 TI - Hepatitis B vaccination among adolescents 13-17 years, United States, 2006-2012. AB - BACKGROUND: Hepatitis B (HepB) vaccination is the most effective measure to prevent HBV infection. Routine HepB vaccination was recommended for infants in 1991 and catch-up vaccination has been recommended for adolescents since in 1995. The purpose of this study is to assess HepB vaccination among adolescents 13-17 years. METHODS: The 2006-2012 NIS-Teen were analyzed. Vaccination trends and coverage by birth cohort among adolescents were evaluated. Multivariable logistic regression and predictive marginal models are used to identify factors independently associated with HepB vaccination. RESULTS: HepB vaccination coverage increased from 81.3% in 2006 to 92.8% in 2012. Coverage varied by birth cohort and 79-83% received vaccination before 2 years of age for those who were born during 1995 and 1999. Among those who had not received vaccination by 11 years of age, for the 1993-1995 birth cohorts, 9-15% were vaccinated during ages 11-12 years, and 27-37% had been vaccinated through age 16 years. Coverage among adolescents 13-17 years in 2012 ranged by state from 84.4% in West Virginia to 98.7% in Florida (median 93.3%). Characteristics independently associated with a higher likelihood of HepB vaccination included living more than 5 times above poverty level, living in Northeastern or Southern region of the United States, and having a mixed facility as their vaccination provider. Those with a hospital listed as their vaccination provider and those who did not have a well-child visit at age 11-12 years were independently associated with a lower likelihood of HepB vaccination. CONCLUSIONS: Efforts focused on groups with lower coverage may reduce disparities in coverage and prevent hepatitis B infection. Parents and providers should routinely review adolescent immunizations. Routine reminder/recall, expanded access in health care settings, and standing order programs should be incorporated into routine clinical care of adolescents. PMID- 25724822 TI - Thrombophilia: clinical-practical aspects. AB - No consensus exists as to who should be tested for thrombophilia, mainly due to the lack of good quality clinical outcome data in relationship to presence or absence of a given thrombophilia. Testing may be considered if (a) finding a thrombophilia predicts recurrent thrombosis and, thus, influences length of anticoagulation treatment decisions; (b) identifying a thrombophilia has implications on management of asymptomatic family members who are carriers of the detected thrombophilia; (c) a patient wishes to better understand why a thrombotic event occurred. Testing may be helpful in patients with venous thromboembolism at intermediate risk of recurrence in whom the finding of a strong thrombophilia can be one of the arguments for long-term anticoagulation- the "risk-of-recurrence-triangle" may be a useful aid in this decision process. Patients whose venous thromboembolism was provoked by a major transient risk factor should not be tested for thrombophilia. Thrombophilia tests should only be ordered by health care professionals who can provide the "4P": (a) appropriately select which patient to test, (b) provide pre-test counseling, (c) properly interpret the test results, and (d) provide education and advice to the patient. If testing is embarked on in patients with venous thromboembolism, it is advisable to be done at the time of decision making whether to stop or continue anticoagulation, i.e. typically after 3 months of anticoagulant therapy. Thrombophilia testing is best not done at the time of an acute thrombotic event and while a patient is on an anticoagulant. PMID- 25724823 TI - The effects of reduced copayments on discontinuation and adherence failure to statin medication in Australia. AB - This paper assesses whether the concession card, which offers discounted out-of pocket costs for prescription medicines in Australia, affects discontinuation and adherence to statin therapy. The analysis uses data from the Australian Hypertension and Absolute Risk Study (AusHEART), which involves patients aged 55 years and over who visited a GP between April and June 2008. Socioeconomic and clinical information was collected and linked to administrative data on pharmaceutical use. Patients without a concession card were 63% more likely (hazard ratio (HR) 95% confidence interval (CI): 1.14-2.33) to discontinue and 60% (odds ratio (OR) CI: 1.04-2.44) more likely to fail to adhere to therapy compared to concessional patients. Smokers were 2.12 (HR CI: 1.39-3.22) times more likely to discontinue use and 2.23 (OR CI: 1.35-3.71) times more likely to fail to adhere compared to non-smokers. Patients who had recently initiated statin medication were also 2.28 (HR CI: 1.22-4.28) times more likely to discontinue use. In conclusion, higher copayments act as a disincentive for persistent and adherent use of statin medication. PMID- 25724824 TI - Bottom-up priority setting revised. A second evaluation of an institutional intervention in a Swedish health care organisation. AB - BACKGROUND: Transparent priority setting in health care based on specific ethical principles is requested by the Swedish Parliament since 1997. Implementation has been limited. In this case, transparent priority setting was performed for a second time round and engaged an entire health care organisation. AIMS: Objectives were to refine a bottom-up priority setting process, reach a political decision on service limits to make reallocation towards higher prioritised services possible, and raise systems knowledge. METHODS: An action research approach was chosen. The national model for priority setting was used with addition of dimensions costs, volumes, gender distribution and feasibility. The intervention included a three step process and specific procedures for each step which were created, revised and evaluated regarding factual and functional aspects. Evaluations methods included analyses of documents, recordings and surveys. RESULTS: Vertical and horizontal priority setting occurred and resources were reallocated. Participants' attitudes remained positive, however less so than in the first priority setting round. Identifying low-priority services was perceived difficult, causing resentment and strategic behaviour. The horizontal stage served to raise quality of the knowledge base, level out differences in ranking of services and raise systems knowledge. CONCLUSIONS: Existing health care management systems do not meet institutional requirements for transparent priority setting. Introducing transparent priority setting constitutes a complex institutional reform, which needs to be driven by management/administration. Strong managerial commitment is required. PMID- 25724826 TI - In vitro and in silico evaluation of twelve newly-synthesized 1-acetamide-5 methoxy-2-oxindoles as 5-Ht7 receptor ligands. AB - Based on in vitro studies of twelve newly-synthesized 1-acetamide-5-methoxy-2 oxindoles as 5-Ht7 receptor ligands, Structure Affinity Relationship (SAR) and Quantitative Structure Affinity Relationship model (QSAR) are provided. Also, a ligand-based pharmacophore model is proposed through molecular docking techniques and Nucleus Independent Chemical Shift DFT calculations (NICS). PMID- 25724825 TI - Design, synthesis and evaluation of novel 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids as potential multifunctional agents for the treatment of Alzheimer's disease. AB - A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BuChE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Abeta) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8 nM, potent inhibition of self-induced Abeta1-42 aggregation with inhibition ratio of 33.8% at 25 MUM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD. PMID- 25724827 TI - Design, synthesis and biological evaluation of GY3-based derivatives for anti type 2 diabetes activity. AB - A series of indole carboxylic acid derivatives were designed and synthesized. Their anti-type 2 diabetes activity was evaluated in HepG2 cell and db/db mice. The results showed that compounds 8c, 17a, 17b, 15a and 15b could significantly increase glucose consumption in HepG2 cell. Furthermore, compound 8c was able to lower the blood glucose level and induce less weight gain in db/db mice. PMID- 25724828 TI - Molecular dynamics simulation to rationalize regioselective hydroxylation of aromatic substrates by soluble methane monooxygenase. AB - Soluble methane monooxygenase (sMMO) is a bacterial multicomponent enzyme that oxidizes a diverse range of substrates, including aromatic hydrocarbons. We have investigated enzyme-substrate interactions that govern oxidation regioselectivity at various sites of aromatic compounds using substrate docking and molecular dynamics (MD) simulations. Here, we studied the hydroxylation of toluene and ethyl benzene by two forms of Methylosinus trichosporium OB3b (sMMO), that is, wild-type (WT) and two active site mutants (L110Y/G). The two substrates, toluene and ethyl benzene, were docked into the active site of the WT and the L110Y/G mutant models of M. trichosporium OB3b sMMO using the available X-ray structure (PDB id 1 MHZ). The trends observed in the formation of the experimental product were highly correlated with the results obtained from the relatively short MD simulation. These results show that our approach could be an attractive computational tool to rationalize the prediction of product ratios and specificities. PMID- 25724829 TI - Does maternal asthma contribute to racial/ethnic disparities in obstetrical and neonatal complications? AB - PURPOSE: To examine whether maternal asthma contributes to racial/ethnic differences in obstetrical and neonatal complications. METHODS: Data on white (n = 110,603), black (n = 50,284), and Hispanic (n = 38,831) singleton deliveries came from the Consortium on Safe Labor. Multilevel logistic regression models, with an interaction term for asthma and race/ethnicity, estimated within-group adjusted odds ratios (aORs) for gestational diabetes, gestational hypertension, pre-eclampsia, placental abruption, premature rupture of membranes, preterm delivery, maternal hemorrhage, neonatal intensive care unit admissions, small for gestational age, apnea, respiratory distress syndrome, transient tachypnea of the newborn, anemia, and hyperbilirubinemia after adjustment for clinical and demographic confounders. Nonasthmatics of the same racial/ethnic group were the reference group. RESULTS: Compared with nonasthmatics, white asthmatics had increased odds of pre-eclampsia (aOR, 1.28; 95% confidence interval [CI], 1.15 1.43) and maternal hemorrhage (aOR, 1.14; 95% CI, 1.04-1.23). White and Hispanic infants were more likely to have neonatal intensive care unit admissions (aOR, 1.19; 95% CI, 1.11-1.28; aOR, 1.16; 95% CI, 1.02-1.32, respectively) and be small for gestational age (aOR, 1.11; 95% CI, 1.02-1.20; aOR, 1.26; 95% CI, 1.10-1.44, respectively), and Hispanic infants were more likely to have apnea (aOR, 1.32; 95% CI, 1.02-1.69). CONCLUSIONS: Maternal asthma did not affect most obstetrical and neonatal complication risks within racial/ethnic groups. Despite their increased risk for both asthma and many complications, our findings for black women were null. Asthma did not contribute to racial/ethnic disparities in complications. PMID- 25724831 TI - ATX-101 for reduction of submental fat. AB - INTRODUCTION: Facial esthetics are important for self-esteem. Undesired submental fat (SMF) deposits lead to an unappealing submental profile associated with aging and overweight. Compound ATX-101 is a proprietary formulation of purified synthetic deoxycholic acid for pharmacological submental contouring. Review areas covered: This reviews covers anatomy of SMF, biochemistry of deoxycholic acid related to adipose tissue and tissue response to injection of ATX-101. Data from clinical trials were analyzed for efficacy and safety. METHODOLOGY: Published studies using PubMed((c)) database 2000 - 2014 have been analyzed. The terms 'deoxycholate', 'deoxycholic acid', 'ATX-101' and 'injection lipolysis' were used. RESULTS: Deoxycholic acid causes adipocyte breakdown and an inflammatory tissue reaction leading to fat cell reduction and limited fibrosis. Four large clinical Phase III trials demonstrated efficacy of ATX-101 in reduction of SMF measured by validated scales and objective measurements. Patients reported improved psychological features and feeling. Adverse effects were mild and temporary. EXPERT OPINION: Adipocytolysis of SMF by ATX-101 is an important step forward to the development of approved drugs for reduction of localized fat pads. This could become a growing market. PMID- 25724830 TI - Female and male differences in AIDS diagnosis rates among people who inject drugs in large U.S. metro areas from 1993 to 2007. AB - PURPOSE: We estimated female and male incident AIDS diagnosis rates (IARs) among people who inject drugs (PWID) in U.S. metropolitan statistical areas (MSAs) over time to assess whether declines in IARs varied by sex after combination antiretroviral therapy (cART) dissemination. METHODS: We compared IARs and 95% confidence intervals for female and male PWID in 95 of the most populous MSAs. To stabilize estimates, we aggregated data across three-year periods, selecting a period immediately preceding cART (1993-1995) and the most recent after the introduction of cART for which data were available (2005-2007). We assessed disparities by comparing IAR 95% confidence intervals for overlap, female-to-male risk ratios, and disparity change scores. RESULTS: IARs declined an average of 58% for female PWID and 67% for male PWID between the pre-cART and cART periods. Among female PWID, IARs were significantly lower in the later period relative to the pre-cART period in 48% of MSAs. Among male PWID, IARs were significantly lower over time in 86% of MSAs. CONCLUSIONS: IARs among female PWID in large U.S. MSAs have declined more slowly than among male PWID. This suggests a need for increased targeting of prevention and treatment programs and for research on MSA level conditions that may drive differences in declining AIDS rates among female and male PWID. PMID- 25724833 TI - Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome. AB - BACKGROUND: Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. OBJECTIVE: The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. METHODS: We simultaneously recorded surface ECG and unipolar electrograms at baseline and after dofetilide in a canine model of dofetilide-induced LQT2 (6 male mongrel dogs). Standard ECG variables, T-wave duration, and moments of peaks of bifid T waves (Tp1 and Tp2) were correlated with moments of local repolarization. Epicardial electrograms were recorded over the left ventricular (LV) and right ventricular (RV) anterior walls (11 * 11 electrode grid, 5-mm interelectrode distance). In 5 of the 6 hearts, we also recorded intramural unipolar electrograms (n = 4-7 needles per heart). In each unipolar recording, we determined activation time, repolarization time (RTs), and activation-recovery interval. In addition, we studied RT response to heart rate changes. RESULTS: Dofetilide prolonged QT and QTc, induced bifid T waves in 4 of 6 animals, and prolonged RT heterogeneously in LV and RV, resulting in increased interventricular and LV intraventricular RT dispersion. Dofetilide did not induce a disparate response in activation-recovery interval across the transmural axis. Dofetilide-induced separation of RT across the RV-LV interface concurred with the moments of T-wave peaks. Dofetilide-induced steepening of restitution slopes was larger in LV than RV. CONCLUSION: Dofetilide-induced bifid T waves result from interventricular RT dispersion. PMID- 25724832 TI - Protein kinase Calpha mediates erlotinib resistance in lung cancer cells. AB - Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for advanced patients with EGFR-activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of protein kinase C (PKC) isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymal-like morphology driven by transforming growth factor-beta signaling. We found that H1650-M3 cells display remarkable PKCalpha upregulation and PKCdelta downregulation. Notably, silencing PKCalpha from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-to-mesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCalpha RNA interference depletion and PKCdelta restoring sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCalpha in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused downregulation of PKCdelta expression, suggesting a unidirectional crosstalk. Finally, mechanistic studies revealed that PKCalpha upregulation in H1650-M3 cells is driven by transforming growth factor-beta. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCalpha as a potential target for lung cancer treatment. PMID- 25724834 TI - Pulmonary vein signal interpretation during cryoballoon ablation for atrial fibrillation. PMID- 25724835 TI - Editorial: large database studies--what they can do, what they cannot do, and which ones we will publish. PMID- 25724837 TI - Confidence intervals, P values, and statistical significance. PMID- 25724836 TI - Which Surgical Treatment for Open Tibial Shaft Fractures Results in the Fewest Reoperations? A Network Meta-analysis. AB - BACKGROUND: Open tibial shaft fractures are one of the most devastating orthopaedic injuries. Surgical treatment options include reamed or unreamed nailing, plating, Ender nails, Ilizarov fixation, and external fixation. Using a network meta-analysis allows comparison and facilitates pooling of a diverse population of randomized trials across these approaches in ways that a traditional meta-analysis does not. QUESTIONS/PURPOSES: Our aim was to perform a network meta-analysis using evidence from randomized trials on the relative effect of alternative approaches on the risk of unplanned reoperation after open fractures of the tibial diaphysis. Our secondary study endpoints included malunion, deep infection, and superficial infection. METHODS: A network meta analysis allows for simultaneous consideration of the relative effectiveness of multiple treatment alternatives. To do this on the subject of surgical treatments for open tibial fractures, we began with systematic searches of databases (including EMBASE and MEDLINE) and performed hand searches of orthopaedic journals, bibliographies, abstracts from orthopaedic conferences, and orthopaedic textbooks, for all relevant material published between 1980 and 2013. Two authors independently screened abstracts and manuscripts and extracted the data, three evaluated the risk of bias in individual studies, and two applied Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria to bodies of evidence. We included all randomized and quasirandomized trials comparing two (or more) surgical treatment options for open tibial shaft fractures in predominantly (ie, > 80%) adult patients. We calculated pooled estimates for all direct comparisons and conducted a network meta-analysis combining direct and indirect evidence for all 15 comparisons between six stabilization strategies. Fourteen trials published between 1989 and November 2011 met our inclusion criteria; the trials comprised a total of 1279 patients surgically treated for open tibial shaft fractures. RESULTS: Moderate confidence evidence showed that unreamed nailing may reduce the likelihood of reoperation compared with external fixation (network odds ratio [OR], 0.38; 95% CI, 0.23-0.62; p < 0.05), although not necessarily compared with reamed nailing (direct OR, 0.74; 95% CI, 0.45-1.24; p = 0.25). Only low- or very low-quality evidence informed the primary outcome for other treatment comparisons, such as those involving internal plate fixation, Ilizarov external fixation, and Ender nailing. Method ranking based on reoperation data showed that unreamed nailing had the highest probability of being the best treatment, followed by reamed nailing, external fixation, and plate fixation. CIs around pooled estimates of malunion and infection risk were very wide, and therefore no conclusive results could be made based on these data. CONCLUSION: Current evidence suggests that intramedullary nailing may be superior to other fixation strategies for open tibial shaft fractures. Use of unreamed nails over reamed nails also may be advantageous in the setting of open fractures, but this remains to be confirmed. Unfortunately, these conclusions are based on trials that have had high risk of bias and poor precision. Larger and higher-quality head-to-head randomized controlled trials are required to confirm these conclusions and better inform clinical decision-making. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 25724838 TI - Systematic analysis of the radiologic findings of aortic dissections on unenhanced postmortem computed tomography. AB - The aim of this study was to evaluate the diagnostic criteria and to identify the radiological signs (derived from known radiological signs) for the detection of aortic dissections using postmortem computed tomography (PMCT). Thirty-three aortic dissection cases were retrospectively evaluated; all underwent PMCT and autopsy. The images were initially evaluated independently by two readers and were subsequently evaluated in consensus. Known radiological signs, such as dislocated calcification and an intimomedial flap, were identified. The prevalence of the double sedimentation level in the true and false lumen of the dissected aorta was assessed and defined as a postmortem characteristic sign of aortic dissection. Dislocated calcification was detected in 85% of the cases with aortic calcification; whereas in 54% of the non-calcified aortas, the intimomedial flap could also be recognized. Double sedimentation was identified in 16/33 of the cases. Overall, in 76% (25/33) of the study cases, the described signs, which are indicative for aortic dissection, could be identified. In this study, three diagnostic criteria of aortic dissection were identified using non enhanced PMCT images of autopsy-confirmed dissection cases. PMID- 25724839 TI - Bilateral spontaneous pneumothorax secondary to aspiration pneumonia induced by a wristwatch lodged at the pharyngoesophageal junction. AB - Bilateral spontaneous pneumothorax secondary to disease is rare and seldom encountered in forensic autopsies; however, traumatic bilateral pneumothorax occurs often. Herein, we present a forensic case involving a 50-year-old woman who died 4 days after ingesting a wristwatch. Postmortem computed tomography and autopsy findings demonstrated that the wristwatch was lodged at the pharyngoesophageal junction, that she had a bilateral pneumothorax unaccompanied by any thoracic wound, and that macular hemorrhagic lesions on the lung surfaces were responsible for the pneumothorax. A histological examination of the macular lesions revealed that they were aspiration pneumonia foci with many birefringent foreign materials. Furthermore, a necrotic process secondary to aspiration pneumonia with a one way check-valve hyperinflation caused by foreign materials in the bronchioles was the most probable pathogenesis of her pneumothorax. To our knowledge, this is the first reported case of a bilateral secondary spontaneous pneumothorax caused by a large foreign body at the pharyngoesophageal junction leading to death. PMID- 25724840 TI - siRNA silencing of PD-1 ligands on dendritic cell vaccines boosts the expansion of minor histocompatibility antigen-specific CD8(+) T cells in NOD/SCID/IL2Rg(null) mice. AB - Allogeneic stem cell transplantation (allo-SCT) can be a curative therapy for patients suffering from hematological malignancies. The therapeutic efficacy is based on donor-derived CD8(+) T cells that recognize minor histocompatibility antigens (MiHAs) expressed by patient's tumor cells. However, these responses are not always sufficient, and persistence and recurrence of the malignant disease are often observed. Therefore, application of additive therapy targeting hematopoietic-restricted MiHAs is essential. Adoptive transfer of MiHA-specific CD8(+) T cells in combination with dendritic cell (DC) vaccination could be a promising strategy. Though effects of DC vaccination in anti-cancer therapy have been demonstrated, improvement in DC vaccination therapy is needed, as clinical responses are limited. In this study, we investigated the potency of program death ligand (PD-L) 1 and 2 silenced DC vaccines for ex vivo priming and in vivo boosting of MiHA-specific CD8(+) T cell responses. Co-culturing CD8(+) T cells with MiHA-loaded DCs resulted in priming and expansion of functional MiHA specific CD8(+) T cells from the naive repertoire, which was augmented upon silencing of PD-L1 and PD-L2. Furthermore, DC vaccination supported and expanded adoptively transferred antigen-specific CD8(+) T cells in vivo. Importantly, the use of PD-L silenced DCs improved boosting and further expansion of ex vivo primed MiHA-specific CD8(+) T cells in immunodeficient mice. In conclusion, adoptive transfer of ex vivo primed MiHA-specific CD8(+) T cells in combination with PD-L silenced DC vaccination, targeting MiHAs restricted to the hematopoietic system, is an interesting approach to boost GVT immunity in allo SCT patients and thereby prevent relapse. PMID- 25724841 TI - Preclinical activity of anti-CCR7 immunotherapy in patients with high-risk chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) with deletions of the p53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring CCR7 surface expression and complement-dependent cytotoxicity. Our results demonstrate that CCR7 is highly expressed in challenging and heavily treated CLL patients. In addition, the complement-mediated mechanism of action of this mAb effectively eradicates CLL cells while sparing subsets of T cells in these patients. Moreover, this mAb outperformed the activity of alemtuzumab, the mAb with the highest efficacy in these groups. Finally, in vitro activity was also demonstrated in patients with a disease refractory to both fludarabine and alemtuzumab, and patients harboring 11q22 deletion. Our results propose that anti CCR7 mAb is an effective and promising future treatment in high-risk CLL. PMID- 25724842 TI - Transverse relaxation dispersion of the p7 membrane channel from hepatitis C virus reveals conformational breathing. AB - The p7 membrane protein encoded by hepatitis C virus (HCV) assembles into a homo hexamer that selectively conducts cations. An earlier solution NMR structure of the hexameric complex revealed a funnel-like architecture and suggests that a ring of conserved asparagines near the narrow end of the funnel are important for cation interaction. NMR based drug-binding experiments also suggest that rimantadine can allosterically inhibit ion conduction via a molecular wedge mechanism. These results suggest the presence of dilation and contraction of the funnel tip that are important for channel activity and that the action of the drug is attenuating this motion. Here, we determined the conformational dynamics and solvent accessibility of the p7 channel. The proton exchange measurements show that the cavity-lining residues are largely water accessible, consistent with the overall funnel shape of the channel. Our relaxation dispersion data show that residues Val7 and Leu8 near the asparagine ring are subject to large chemical exchange, suggesting significant intrinsic channel breathing at the tip of the funnel. Moreover, the hinge regions connecting the narrow and wide regions of the funnel show strong relaxation dispersion and these regions are the binding sites for rimantadine. Presence of rimantadine decreases the conformational dynamics near the asparagine ring and the hinge area. Our data provide direct observation of MUs-ms dynamics of the p7 channel and support the molecular wedge mechanism of rimantadine inhibition of the HCV p7 channel. PMID- 25724843 TI - Cancer-associated mutants of RNA helicase DDX3X are defective in RNA-stimulated ATP hydrolysis. AB - The DEAD-box RNA helicase DDX3X is frequently mutated in pediatric medulloblastoma. We dissect how these mutants affect DDX3X function with structural, biochemical, and genetic experiments. We identify an N-terminal extension ("ATP-binding loop", ABL) that is critical for the stimulation of ATP hydrolysis by RNA. We present crystal structures suggesting that the ABL interacts dynamically with ATP and confirming that the interaction occurs in solution by NMR chemical shift perturbation and isothermal titration calorimetry. DEAD-box helicases require interaction between two conserved RecA-like helicase domains, D1 and D2 for function. We use NMR chemical shift perturbation to show that DDX3X interacts specifically with double-stranded RNA through its D1 domain, with contact mediated by residues G302 and G325. Mutants of these residues, G302V and G325E, are associated with pediatric medulloblastoma. These mutants are defective in RNA-stimulated ATP hydrolysis. We show that DDX3X complements the growth defect in a ded1 temperature-sensitive strain of Schizosaccharomyces pombe, but the cancer-associated mutants G302V and G325E do not complement and exhibit protein expression defects. Taken together, our results suggest that impaired translation of important mRNA targets by mutant DDX3X represents a key step in the development of medulloblastoma. PMID- 25724844 TI - Combination of driselase and lysing enzyme in one molar potassium chloride is effective for the production of protoplasts from germinated conidia of Fusarium verticillioides. AB - Various cell wall degrading enzymes and the protoplasting media were evaluated for the production of protoplast in Fusarium verticillioides. Among the various enzymes tested, driselase at 12.5 mg/ml in 1 M KCl protoplasting medium produced the maximum number of protoplast. Next to driselase, lysing enzyme at 10 mg/ml in 1.2 M MgSO4 protoplasting medium was found to be the second best enzyme for the production of protoplast. More interestingly, the combined use of driselase @ 12.5 mg/ml and lysing enzyme @ 10 mg/ml in 1 M KCl exhibited the additive effect on protoplast formation. Germinated conidia of F. verticillioides are the most susceptible fungal material for protoplast production. The use of sucrose at 1.2 M in the regeneration medium supported the maximum regeneration of protoplast. From the present study, we recommend driselase (12.5 mg/ml) and lysing enzyme (10 mg/ml) in 1 M KCl protoplasting medium and germinated conidia of F. verticillioides for the maximum production of protoplasts and 1.2 M sucrose is the best osmoticum for the regeneration of protoplasts. PMID- 25724845 TI - Learning how the electron transport chain works: independent and interactive effects of instructional strategies and learners' characteristics. AB - In order to develop an expert-like mental model of complex systems, causal reasoning is essential. This study examines the differences between forward and backward instructional strategies' in terms of efficiency, students' learning and progression of their mental models of the electronic transport chain in an undergraduate metabolism course (n = 151). Additionally, the participants' cognitive flexibility, prior knowledge, and mental effort in the learning process are also investigated. The data were analyzed using a series of general linear models to compare the strategies. Although the two strategies did not differ significantly in terms of mental model progression and learning outcomes, both groups' mental models progressed significantly. Mental effort and prior knowledge were identified as significant predictors of mental model progression. An interaction between instructional strategy and cognitive flexibility revealed that the backward instruction was more efficient than the conventional (forward) strategy for students with lower cognitive flexibility, whereas the conventional instruction was more efficient for students with higher cognitive flexibility. The results are discussed and suggestions for future research on the possible moderating role of cognitive flexibility in the area of health education are presented. PMID- 25724846 TI - Pattern of disease progression in atypical form of pantothenate-kinase-associated neurodegeneration (PKAN) - Prospective study. AB - INTRODUCTION: Classic form of pantothenate-kinase-associated neurodegeneration (PKAN), caused by mutation in PANK2 gene, is characterized by early onset, severe neurological impairment and rapid disease progression. In less precisely described form of atypical PKAN, clinical course is associated with late onset, less severe motor impairment and slower disease evolution. The aim of this study was to assess a pattern of disease progression in atypical PKAN, by following development of specific milestones. METHODS: The clinical characteristics and the disease course of 9 genetically confirmed patients with atypical form of PKAN were evaluated. Time latencies from the disease onset to the appearance of specific clinical milestones were estimated in order to assess the disease progression. RESULTS: Most frequent disease presentation in our patients was characterized with early and prominent oromandibular dystonia (OMD), followed by severe generalized dystonia and early loss of mobility within the first five years of prolonged disease duration (18.7 +/- 10.0 years). Eight out of 9 patients reached 7 significant clinical milestones (OMD, generalized dystonia, dysarthria, dysphagia, postural instability, gait difficulties, ADL dependency) in the first 4.6 years of disease course. Afterwards, a long-lasting, relatively stable period of slower progression was complicated predominantly with skeletal deformities (developed after 7.0 +/- 2.8 years). CONCLUSIONS: Majority of milestones which might significantly influence functional abilities and quality of life in patients with atypical form of PKAN developed in the course of the first five years of the disease, followed by a long-lasting, relatively stable period of slower progression. PMID- 25724847 TI - Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). AB - RATIONALE: Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking. OBJECTIVE: To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes). MEASUREMENTS AND METHODS: 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St George's Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes. MAIN RESULTS: 206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. CONCLUSIONS: Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency. TRIAL REGISTRATION NUMBER: NCT00978315 (ClinicalTrials.gov). PMID- 25724848 TI - The inverse fallacy and interpreting P values. PMID- 25724850 TI - Acute Disseminated Encephalomyelitis in an Adult: An Uncommon Case of Paroxysmal Sympathetic Hyperactivity. AB - Acute disseminated encephalomyelitis (ADEM) is an uncommon acute, rapidly progressive autoimmune demyelinating disease of the central nervous system that is most often due to infection or immunization. Generally, it is monophasic, but there is potential for recurrence and risk for development of multiple sclerosis. Although there has been literature documenting autonomic dysreflexia and hypertensive emergency in 2 pediatric cases of ADEM, to our knowledge there has not been a case detailing paroxysmal sympathetic hyperactivity in an adult patient with ADEM. This case report describes a fulminant case of ADEM and serves to expand the list of diagnoses associated with paroxysmal sympathetic hyperactivity. PMID- 25724849 TI - Myofascial Trigger Points Then and Now: A Historical and Scientific Perspective. AB - The intent of this article is to discuss the evolving role of the myofascial trigger point (MTrP) in myofascial pain syndrome (MPS) from both a historical and scientific perspective. MTrPs are hard, discrete, palpable nodules in a taut band of skeletal muscle that may be spontaneously painful (i.e., active) or painful only on compression (i.e., latent). MPS is a term used to describe a pain condition that can be acute or, more commonly, chronic and involves the muscle and its surrounding connective tissue (e.g. fascia). According to Travell and Simons, MTrPs are central to the syndrome-but are they necessary? Although the clinical study of muscle pain and MTrPs has proliferated over the past two centuries, the scientific literature often seems disjointed and confusing. Unfortunately, much of the terminology, theories, concepts, and diagnostic criteria are inconsistent, incomplete, or controversial. To address these deficiencies, investigators have recently applied clinical, imaging (of skeletal muscle and brain), and biochemical analyses to systematically and objectively study the MTrP and its role in MPS. Data suggest that the soft tissue milieu around the MTrP, neurogenic inflammation, sensitization, and limbic system dysfunction may all play a role in the initiation, amplification, and perpetuation of MPS. The authors chronicle the advances that have led to the current understanding of MTrP pathophysiology and its relationship to MPS, and review the contributions of clinicians and researchers who have influenced and expanded our contemporary level of clinical knowledge and practice. PMID- 25724851 TI - Occupational Therapy Workforce in the United States: Forecasting Nationwide Shortages. AB - BACKGROUND: As the baby boomer generation retires in growing numbers, the demand for occupational therapists specializing in geriatrics will be particularly strong. Currently, there is evidence that a workforce shortage exists in the field of occupational therapy (OT), and few studies have been published in this area to systematically examine the status of the OT workforce. OBJECTIVE: To examine current and future OT job surplus/shortage trends within the United States. DESIGN: Forecast models and grading methodology were developed to evaluate individual state OT job shortages from 2008 to 2030. SETTING: Not applicable. PARTICIPANTS: Not applicable. MAIN OUTCOME MEASUREMENTS: OT shortages, OT shortage ratios, and a report card were generated and compared among the 50 states in the United States. RESULTS: On the basis of current trends, demand for OT services will outpace the supply of occupational therapists within the United States. Shortages are expected to increase for all 50 states through 2030. The number of states with a grade D or below will increase from 3 in 2010, to 18 in 2020, to 37 in 2030, respectively. By 2030, the 3 states with the greatest shortage ratios will be Arizona, Hawaii, and Utah. The 3 states with the largest OT shortages (the number of OT jobs) will be California, Florida, and Texas. States in the northeast are projected to have the smallest shortages whereas states in the south and west are projected to have the largest shortages. CONCLUSION: This study serves to provide health care professionals, policy makers, and stakeholders with a means of assessing current and future OT needs. Discussion of the issues surrounding OT shortages and ongoing assessment of supply and demand must ensue to mitigate the projected shortages. PMID- 25724852 TI - Diagnostic utility of interferon-gamma release assay in extrapulmonary tuberculosis. AB - Early diagnosis of extrapulmonary tuberculosis (EP-TB) is essential. However, diagnosis of EP-TB is difficult. We evaluated the diagnostic utility of an interferon-gamma release assay (IGRA) in diagnosing active EP-TB among suspected patients in Korea. We retrospectively reviewed the clinical records of all patients with suspected EP-TB at Gangnam Severance Hospital in Seoul, Korea. Of the 418 patients with suspected EP-TB, 324 had active EP-TB. The tuberculosis (TB) group had a higher percentage of positive IGRAs (70.2%, 33/47) than the non TB group (33.3%, 3/9) (P=0.034). The IGRA sensitivity and specificity were 70.2% (63.7-74.8%) and 66.7% (32.9-90.6%), respectively. The sensitivity and specificity of IGRAs in patients with TB lymphadenitis were 81.8% (61.4-90.4%) and 80.0% (35.1-98.9%), but 38.5% (31.2-45.7%) and 50.0% (2.7-97.3%) in patients with TB pleurisy. The diagnostic performance of IGRAs may vary depending on the site of EP-TB involvement. IGRA was potentially valuable for diagnosis of active EP-TB in TB lymphadenopathy. PMID- 25724853 TI - Comparison of the performance of 2 commercial multiplex PCR platforms for detection of respiratory viruses in upper and lower tract respiratory specimens. AB - The performance of the CLART(r) PneumoVir system with that of the Luminex xTAG RVP Fast v1 assay for detection of most common respiratory viruses in upper and lower tract respiratory specimens (n=183) from unique patients with influenza like syndrome or lower tract respiratory infection. Nested PCR coupled to automated sequencing was used for resolution of discrepancies. Fully concordant results were obtained for a total of 122 specimens, whereas 56 specimens gave partially (n=21) or fully discordant (n=35) results (Kappa coefficient, 0.62). The overall specificity of the Luminex xTAG RVP Fast v1 assay was slightly higher than that of the CLART(r) PneumoVir assay for human bocavirus, influenza A virus/H3N2, influenza B virus, human metapneumovirus, and parainfluenza virus, whereas the sensitivity of the latter was higher for most targeted viruses except, notably, for picornaviruses. This was irrespective of either the origin of the respiratory specimen or the age group to which the patients belonged. PMID- 25724854 TI - Surrogate analysis of vancomycin to predict susceptible categorization of dalbavancin. AB - Dalbavancin (DAL) represents a recently approved addition for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Newly released antimicrobial agents are rarely found on commercial susceptibility testing devices, and surrogate testing may be an option for clinical microbiology laboratories. A total of 33,688 Staphylococcus aureus, 2800 viridans group streptococci (VGS), and 5722 beta-hemolytic streptococci (BHS) were included in this cross-susceptibility (DAL versus vancomycin [VAN]) analysis as well as 4576 coagulase-negative staphylococci and 6515 enterococci (nonindicated species groups). Isolates were collected as part of the SENTRY Antimicrobial Surveillance Program for the United States (USA) and Europe (2011-2013). Susceptibility testing followed CLSI (M07-A9 and M100-S24) methods. USA Food and Drug Administration (DAL) and CLSI (VAN) breakpoint criteria were used for correlations between DAL and VAN susceptibility results. A categorical agreement (CA; susceptible) rate of 99.9% was observed between DAL and VAN when testing S. aureus. Only 48 (0.14%) very major (false-susceptible) errors were noted against VAN-susceptible isolates that displayed a DAL-nonsusceptible (MIC, 0.25 or 0.5 MUg/mL) phenotype. When susceptible MIC correlations were analyzed against indicated BHS species (Streptococcus agalactiae and Streptococcus pyogenes), an overall CA rate of 97.7-100.0% was obtained. Complete (100.0%) CA was documented for S. pyogenes, as well as against all VGS isolates, including the indicated Streptococcus anginosus group (758 strains). In conclusion, high susceptible CA rates between DAL and VAN were observed when testing a contemporary collection of indicated clinical isolates found in ABSSSI. VAN-susceptible isolates can be inferred to be inhibited by DAL (97.7-100.0%) at the regulatory agency-approved susceptible interpretive breakpoint of <=0.12 MUg/mL. PMID- 25724855 TI - Integrative taxonomy of central European parasitic flatworms of the family Prosthogonimidae Luhe, 1909 (Trematoda: Plagiorchiida). AB - Species of the family Prosthogonimidae are considered the most pathogenic poultry trematodes worldwide, affecting particularly low intensity farming in rural areas. Adults of Prosthogonimus occur mainly in the bursa of Fabricius, oviduct and cloaca of ducks, geese, fowl and other birds feeding at least occasionally on dragonflies or damselflies (Odonata). We analyzed the central European species of the Prosthogonimidae, namely Prosthogonimus cuneatus, Prosthogonimus ovatus, Prosthogonimus pellucidus and Prosthogonimus rarus. We sequenced three nuclear (ITS2) and mitochondrial (CO1, ND1) DNA loci of four species isolated from Anas clypeata, Anas strepera, Anas platyrhynchos, Aythya ferina, Passer domesticus and Turdus merula. Intra- and inter-specific sequence variability revealed that all four species represent distinct well-defined entities. Our data, combined with previously published studies, suggest the return of the name Prosthogonimus rarus Braun, 1901 for Schistogonimus rarus (Braun, 1901). The genus name Schistogonimus Luhe, 1909 is considered a junior synonym of Prosthogonimus Luhe, 1899. We identified the existence of two clades, one represented by P. cuneatus and P. pellucidus, and another one formed by P. ovatus and P. rarus. We also provide comparative measurements of these four central European prosthogonimids, and address their tissue specificity, host-specific prevalence (based on the extensive bird cohort examined in years 1962-2014), and for some bird hosts we address also differences in the prevalence of Prosthogonimus spp. in natural and near-natural wetlands in comparison with fishponds utilized for intense carp production. We provide an updated key to European Prosthogonimus spp. based on their morphological characters. PMID- 25724856 TI - Experimental centrocestiasis: Worm burden, morphology and fecundity of Centrocestus formosanus (Trematoda: Heterophyidae) in dexamethasone immunosuppressed mice. AB - Centrocestus formosanus is an intestinal foodborne trematode with medical and veterinary importance that remains with the pathological and immunological aspects of the infection in definitive host poorly studied. In the present study, we evaluated the effects of pharmacological immunosuppression by glucocorticoids in experimental centrocestiasis. Mice of the AKR/J strain were orally inoculated with 100 metacercariae of C. formosanus obtained in naturally infected fish (Australoheros facetus) collected in an urban reservoir from Brazil. Treatment with dexamethasone (25 mg/kg, via subcutaneous injection) was started 1h before infection of mice and then continued daily during 14 days post-infection. Untreated mice also infected with C. formosanus were used as control. At the end of the treatment course, all rodents were euthanized and adult parasites recovered from host intestines were subjected to morphological and morphometric analysis under optical microscopy. The worm burden in dexamethasone treated group [70+/-14 (41-85)] was significantly greater (p<0.0001) than that in the control group [15+/-4 (10-22)]. In addition, the parasites recovered from immunosuppressed mice were larger, with more developed reproductive structures and greater number of intrauterine eggs than in control mice. These parasite developmental changes induced by dexamethasone treatment are reported for the first time in experimental centrocestiasis. Moreover the higher parasite fecundity induced by glucocorticoid treatment had so far not been reported for any heterophyid species, which can have implications for the pathology and morbidity in infections caused by these parasites. PMID- 25724857 TI - Is there an association between clinical features, response to diagnostic analgesia and radiological findings in horses with a magnetic resonance imaging diagnosis of navicular disease or other injuries of the podotrochlear apparatus? AB - Previous descriptions of the clinical features of navicular disease occurred before the widespread use of magnetic resonance imaging (MRI) allowed a more definitive diagnosis of foot pain. The objective of this study was to compare the clinical features of horses with lesions of the podotrochlear apparatus with those with other causes of foot pain. It was hypothesised that primary navicular bone disease would be associated with more advanced radiological findings than other diagnoses. A retrospective study was performed of all horses examined at a referral centre with a definitive diagnosis of foot pain based on MRI +/- post mortem examination. Clinical examination findings, response to diagnostic analgesia and radiological grading of the navicular bone were compared among five diagnosis groups: (1) primary navicular bone pathology (NB); (2) lesions of the collateral sesamoidean ligament and/or distal sesamoidean impar ligament (CSL + DSIL); (3) primary deep digital flexor tendon injury (DDFT); (4) navicular bone pathology and other lesions of the podotrochlear apparatus +/- DDFT (PTA) and (5) Other. There were 702 horses (NB, 62; CSL + DSIL, 180; DDFT, 69; PTA, 92; Other, 299). Horses with PTA injuries were more frequently unilaterally lame than other groups (P = 0.04). Horses with DDFT injury were more likely to exhibit pain on turning than other groups (P <0.01). There were no associations between response to diagnostic analgesia and diagnostic group, and no association between radiological grade and diagnostic group. Clinical examination findings generally did not discriminate between diseases of the PTA and other causes of foot pain. Overall radiological scores of the navicular bone did not accurately predict navicular bone pathology. PMID- 25724858 TI - Cushing syndrome: establishing a timely diagnosis. PMID- 25724859 TI - [Clinical characteristics and 30-day survival decompensated heart failure of hospitalized elderly patients in Colombia]. PMID- 25724860 TI - [Inhaled colistin in elderly patients with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa bronchial infection]. AB - BACKGROUND: Bronchiectasis is a frequent cause of admission for elderly patients and chronic respiratory diseases. Although some guidelines recommend long-term treatment with inhaled antibiotics in non-cystic fibrosis bronchiectasis with chronic Pseudomonas aeruginosa (P. aeruginosa) infection, there is limited evidence supporting these prolonged antibiotic treatments in this population. The aim of this study was to assess the effectiveness of inhaled colistin in elderly patients with bronchiectasis and chronic bronchial P. aeruginosa infection in reducing hospital readmissions. MATERIAL AND METHODS: A prospective, controlled and open label study was conducted on patients with bronchiectasis diagnosed by computed tomography and persistence of P. aeruginosa in sputum after appropriate antimicrobial therapy. All patients received education, and physiotherapy training. The intervention group also received nebulized colistin 1 million IU twice a day for one year. Data were collected on the demographics, clinical and functional characteristics, admissions in previous year, and sputum microbiology. Patients were followed up every two months for one year, with readmissions, microbiological results, functional tests, and deaths being evaluated. RESULTS: The study included 39 patients, of whom 20 received nebulized colistin and 19 conventional therapy. There were no differences between the two groups in baseline clinical and functional characteristics or previous hospital stay. The mean age was 77.7+/-5, Charlson index 2.85, and FEV1% 41.3+/-15. Five patients (25%) stopped the nebulized treatment because of adverse effects. P. aeruginosa was eradicated in 45% of the colistin treated patients, and in only one of the control group (statistically significant), but at the end of the study year, there were no differences in the number of hospital admissions (control group 1.6+/-1.7 and 2.7+/-3 colistin group), or days of stay (19+/-31 and 23+/-20). There were no differences in lung function or clinical symptoms between the two groups No significant changes were observed in P. aeruginosa A antibiotic sensitivity or in sputum flora. CONCLUSIONS: More patients in the treatment group achieved Pseudomonas eradication, but benefits in clinical symptoms, lung function or use of healthcare resources in our elderly patients, could not be demonstrated. Adverse effects were common. Further studies are needed in order to identify factors associated with response, or subgroups of patients with bronchiectasis and chronic infection with P. aeruginosa, who benefit from (expensive) long term treatments with inhaled antibiotics. PMID- 25724861 TI - [Fungal infections and ureteral material: How to manage?]. AB - INTRODUCTION: Urinary tract infections due to Candida species are mostly encountered in hospital environment. The management of candiduria on ureteral catheter is not consensual. The objective of our work was to make a review of medical literature related to definition, physiopathology, management and prevention of candiduria on ureteral catheter. MATERIAL AND METHODS: The research was made on Medline using the following keywords: Candida; fungal; urinary tract infection; ureteral stent; ureteric stent; double-J pigtail. RESULTS: The threshold defining candiduria is 10(5) CFU/mL. Candiduria corresponds to many different clinical presentations from colonization to candidemia. Species found are mostly Candida albicans (19-72%) and Candida glabrata (15.6-49.4%). The colonization of ureteral stent due to Candida is of 10% and comes with candiduria in 40% of the cases, due to the presence of biofilm. Prevention of infections on ureteral stents requires a regular change of material every 3-6 months depending on the patients risk groups. In case of symptomatic candiduria on ureteral stent, an anti-fungal therapy should be initiated 48 hours to 3 weeks before the change of the stent, in order to get a sterilization of urines and prevent the recolonization of the stent. Fluconazole is the drug of choice to use. CONCLUSION: Colonization of ureteral stents due to Candida is common and can be responsible of symptomatic infection. Anti-fungal therapy should be introduced before the change of the stent but a consensual duration of treatment before surgery is not found in the literature. PMID- 25724862 TI - [Ejaculation capacity in spinal cord injured patients carrying an endo-urethral stent for incontinentation: Descriptive study]. AB - OBJECTIVES: To assess the impact of endo-urethral stent (EUP) of incontinentation in spinal cord injured (SCI) men on ejaculation capacity. FIRST CRITERIA: Presence of ejaculation after EUP. SECONDARY CRITERIA: Modification on ejaculation type, stimulation mode, possibility of sperm conservation in the same population. POPULATION AND METHODS: A descriptive monocentric study including SCI subjects which underwent placement or change of temporary (MemokathTM or AlliumTM) or definitive (MemothermTM) EUP between January 2004 and January 2014 with at least one ejaculatory test. Are identified for each patient: the presence of ejaculation, type of ejaculation, stimulation mode used, number of frozen specimen and results from semen analysis. RESULTS: Over 11 men with tetraplegia, complete for motricity, there were 8 (72%) for whom ejaculation was possible after laying EUP. Of these, 6 (55%) had an antegrade or antero-retrograde ejaculation. It was not possible to make a freezing straw in four of them due to infection of semen (2) or terato-oligo-astenospermia (1) or absence of reproductive project (1). CONCLUSION: In this small sample, it was found that over 70% ejaculation have been preserved after laying EUP and more than 50% with antegrade or antero-retrograde ejaculation. A larger study would identify how EUP may alter the ejaculatory capacity or quality of the ejaculate. LEVEL OF EVIDENCE: 4. PMID- 25724863 TI - [Surveillance of stage I testicular seminoma: 20 years oncological results]. AB - INTRODUCTION AND OBJECTIVE: The objective of this study was to assess the oncological results of a population of patients which undergo surveillance after diagnosis of stage I testicular seminoma (2, 5 and 8 years overall, specific and recurrence free survival). We also research recurrence risk factors. PATIENTS AND METHODS: We have looked at the data of all patients treated in our center since 1993 for a grade I testicular seminoma. We focused on age at diagnosis, biological (tumoral markers) and pathological (tumor size, rete testis, lymphovascular, tunica albuginea or spermatic cord invasion) data. During surveillance, we noted the number, the localization and the interval until recurrence and death. We calculated 2, 5 and 8 years overall, specific and recurrence-free survival and searched recurrence risk factors. RESULTS: Sixty nine patients (mean age: 37) were followed during a mean time of 97 months. Sixty three per cent of the tumours were less than 4 cm (50 lesions). Lymphovascular, rete testis, spermatic cord and tunica albuginea invasion were present in respectively 21%, 33%, 4% and 29% of the cases. LDH and HCG were above normal rate in respectively 44 and 27% of the cases. Eighteen patients (23%) relapsed at a mean time of 12 months. Recurrence-free survival was respectively 81%, 77% and 77% at 2, 5 and 8 years. Tumor size<4 cm (P = 0.002), rete testis invasion (P = 0.03) and stage >= pT2 (P = 0.012) were associated with recurrence in univariate analysis. Using multivariate analysis, only tumor size >4 cm was a recurrence risk factor (risk multiplied by 3). At the end of the study, 77 patients are alive (97.5%). Overall and specific survival was 97.5% at 2, 5 and 8 years. CONCLUSION: We show here the interest of surveillance in case of stage 1 testicular seminoma. The overall and specific survivals are the same as after chemotherapy or radiotherapy. Furthermore, we confirm the role of tumor size to stratify recurrence risk. PMID- 25724864 TI - [About a rare tumor of the kidney: Malignant mixed epithelial and stromal tumor]. AB - Mixed epithelial and stromal tumor of the kidney is a recently described neoplasm that predominantly affects perimenopausal women. Few cases with malignant features have been reported. Here, we report the case of malignant mixed epithelial and stromal tumor of the kidney with sarcomatous transformation arising in a 27-year-old female. She presented with abdominal discomfort. Computed tomography of the abdomen revealed a large compressive mass arisen from the left kidney with solid and focal cystic components. The patient underwent left radical nephrectomy. Histologic sections showed benign and malignant components. The benign component consisted of multiple tubules and variably sized cysts lined by benign epithelium. The malignant component was composed of undifferentiated cellular spindle cell sarcoma. By immunohistochemical studies, the epithelial component was positive for cytokeratins and epithelial membrane antigen (EMA). The stromal component displayed strong immunohistochemical expression of vimentin, CD99, bcl2; and was negative for cytokeratins, desmin, SMA, S-100, estrogen receptor (ER) and progesterone receptor (PR). Analysis by reverse transcriptase polymerase chain reaction (RT-PCR) failed to identify the SYT-SSX1 or SYT-SSX2 fusion transcripts characteristic of synovial sarcoma. PMID- 25724865 TI - Management of pediatric hand burns. AB - PURPOSE: Hand burns are common in the pediatric population. Optimal hand function is a crucial component of a high-quality survival after burn injury. This can only be achieved with a coordinated approach to the injuries. The aim of this study was to review the management algorithm and outcomes of pediatric hand burns at our institution. METHODS: In total, 70 children fulfilling our study criteria were treated for a burn hand injury in our Burn Care Center between January 2008 and May 2013. RESULTS: 14 of the 70 pediatric patients underwent surgery because of the depth of the hand burns. The management algorithm depending on the depth of the burn is described. Two patients underwent correction surgery due to burn contractures later. CONCLUSION: For a successful outcome of the burned hand, the interdisciplinary involvement and cooperation of the plastic and pediatric surgeon, hand therapist, burn team, patient and their parents are crucial. PMID- 25724866 TI - Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice. AB - Ginseng serves as a potential candidate for the treatment of aging-related memory decline or memory loss. However, the related mechanism is not fully understood. In this study, we applied an intraperitoneal injection of ginsenoside Rg1, an active compound from ginseng in middle-aged mice and detected memory improvement and the underlying mechanisms. Our results showed that a period of 30-day administration of ginsenoside Rg1 enhanced long-term memory in the middle-aged animals. Consistent with the memory improvement, ginsenoside Rg1 administration facilitated weak theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in acute hippocampal slices from middle-aged animals. Ginsenoside Rg1 administration increased the dendritic apical spine numbers and area in the CA1 region. In addition, ginsenoside Rg1 administration up-regulated the expression of hippocampal p-AKT, brain-derived neurotrophic factor (BDNF), proBDNF and glutamate receptor 1 (GluR1), but not p-ERK. Interestingly, the phosphatase and tensin homolog deleted on chromosome ten (PTEN) inhibitor (bpV) mimicked the ginsenoside Rg1 effects, including increasing p-AKT expression, promoting hippocampal basal synaptic transmission, LTP and memory. Taken together, our data suggest that ginsenoside Rg1 treatment improves memory in middle-aged mice possibly through regulating the PI3K/AKT pathway, altering apical spines and facilitating hippocampal LTP. PMID- 25724867 TI - Species on the rocks: Systematics and biogeography of the rock-dwelling Ptyodactylus geckos (Squamata: Phyllodactylidae) in North Africa and Arabia. AB - The understanding of the diversity of species in the Palearctic and the processes that have generated it is still weak for large parts of the arid areas of North Africa and Arabia. Reptiles are among their most remarkable representatives, with numerous groups well adapted to the diverse environments. The Ptyodactylus geckos are a strictly rock-dwelling genus with homogeneous morphology distributed across mountain formations and rocky plateaus from the western African ranges in Mauritania and the Maghreb to the eastern tip of the Arabian Peninsula, with an isolated species in southern Pakistan. Here, we use a broad sampling of 378 specimens, two mitochondrial (12S and cytb) and four nuclear (c-mos, MC1R, ACM4, RAG2) markers in order to obtain the first time-calibrated molecular phylogeny of the genus and place its diversification in a temporal framework. The results reveal high levels of intraspecific variability, indicative of undescribed diversity, and they do not support the monophyly of one species (P. ragazzii). Ptyodactylus species are allopatric across most of their range, which may relate to their high preference for the same type of structural habitat. The onset of their diversification is estimated to have occurred in the Late Oligocene, while that of several deep clades in the phylogeny took place during the Late Miocene, a period when an increase in aridification in North Africa and Arabia initiated. PMID- 25724868 TI - Molecular cloning and characterization of gonadotropin subunits (GTHalpha, FSHbeta and LHbeta) and their regulation by hCG and GnRHa in Japanese sea bass (Lateolabrax japonicas) in vivo. AB - In this study, three cDNA sequences encoding common glycoprotein alpha subunit (GTHalpha), follicle-stimulating hormone beta subunit (FSHbeta) and luteinizing hormone beta subunit (LHbeta) were isolated from Japanese sea bass (Lateolabrax japonicas). Comparison of the deduced amino acid sequences with other gonadotropic hormones (GTHs) indicated that their cysteine residues and potential N-linked glycosylation sites were highly conserved, and high homology with those of other perciformes was showed in phylogenetic analysis. GTHs transcripts were present highly in the pituitary and brain and weakly in testis and other tissues. During testicular development, GTHs transcriptional levels in pituitary and brain (expect FSHbeta subunit in brain) were significantly increased at spermiation period, stage V. Subsequently, the effects of hCG and GnRHa on the mRNA levels of GTHs subunits were examined. In brain, both hormones were detected to improve the expression of GTHalpha subunit mRNA. In pituitary, three GTHs subunits increased parallelly and abruptly in two hormone treatment groups. In testis, hCG was suggested to improve three GTHs subunits expression in Japanese sea bass for the first time. These results suggest that both gonadotropins are probably involved in the control of Japanese sea bass spermatogenesis and provide a framework for better understanding of the mechanisms of hormone-mediated reproduction control in Japanese sea bass and other teleosts. PMID- 25724871 TI - Reversal of leukoencephalopathy induced by liposomal amphotericin B in a patient with cryptococcal meningitis. PMID- 25724869 TI - Establishment and characterization of a gonad cell line from half-smooth tongue sole Cynoglossus semilaevis pseudomale. AB - A new cell line was established from half-smooth tongue sole Cynoglossus semilaevis pseudomale gonad (CSPMG). Primary culture was initiated from gonad tissues pieces, and the CSPMG cells were cultured at 24 degrees C in Dulbecco's modified Eagle medium/F12 medium (1:1) (pH7.0), supplemented with 20 % fetal bovine serum, basic fibroblast growth factor, epidermal growth factor, insulin like growth factor-I, 2-mercaptoethanol, penicillin and streptomycin. The cultured CSPMG cells, in fibroblast shape, proliferated to 100 % confluency 10 days later and had been subcultured to passage 109. Chromosome analyses indicated that the CSPMG cells exhibited chromosomal aneuploidy with a modal chromosome number of 42, which displayed the normal diploid karyotype of half-smooth tongue sole (2n = 42t, NF = 42). Reverse transcription polymerase chain reaction revealed CSPMG cells could express gonad somatic cell functional genes Sox9a, Wt1a and weakly germ cell marker gene Vasa, but not male specific gene Dmrt1. Transfection experiment demonstrated that CSPMG cells transfected with pEGFP-N3 plasmid and small RNA could express green and red fluorescence signals with high transfection efficiency. In conclusion, a continuous CSPMG cell line has been established successfully. The cell line might serve as a valuable tool for studies on the mechanism of sex determination, sex reversal and gonad development in flatfish. PMID- 25724870 TI - Incidence and related factors of traffic accidents among the older population in a rapidly aging society. AB - OBJECTIVE: To estimate the incidence of traffic accidents and find related factors among the older population. METHODS: We used the cross-sectional data from the Korean Community Health Survey (KCHS), which was conducted between 2008 and 2010 and completed by 680,202 adults aged 19 years or more. And we used individuals aged 60 years or above (n=210,914). The incidence of traffic accidents was estimated as number of traffic accidents experienced per thousand per year by a number of factors including age, sex, residential area, education, employment status, and diagnosis with chronic diseases. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each potential risk factor adjusted for the others. RESULTS: Incidence of traffic accidents was estimated as 11.74/1,000 per year for men, and 7.65/1,000 per year for women. It tended to decline as age increased among women; compared to the youngest old age group (60-64), the older old groups (70-74 and 80+) were at lower risk for traffic accidents. Depressive symptom was the strongest predictor for both men (OR=1.83, 95% CI=1.28-2.61) and women (1.70, 1.23-2.35). Risk of traffic accident was greater in employed men (1.76, 1.40 2.22) and women diagnosis with arthritis (1.36, 1.06-1.75). CONCLUSION: Given that the incidence of and factors associated with traffic accidents differ between men and women, preventive strategies, such as driver education and traffic safety counseling for older adults, should be modified in accordance with these differences. PMID- 25724872 TI - Parkinsonism, cognitive deficit and behavioural disturbance caused by a novel mutation in the polymerase gamma gene. AB - Polymerase gamma (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 (http://genetics.bwh.hardvard.edu/pph2/) predicted that this change is probably damaging, with a score of 1.0 (0-1). PMID- 25724873 TI - Alpha-fetoprotein producing gastric cancer. PMID- 25724874 TI - Respiratory dysfunction in multiple sclerosis. AB - Respiratory dysfunction frequently occurs in patients with advanced multiple sclerosis (MS), and may manifest as acute or chronic respiratory failure, disordered control of breathing, respiratory muscle weakness, sleep disordered breathing, or neurogenic pulmonary edema. The underlying pathophysiology is related to demyelinating plaques involving the brain stem or spinal cord. Respiratory complications such as aspiration, lung infections and respiratory failure are typically seen in patients with long-standing MS. Acute respiratory failure is uncommon and due to newly appearing demyelinating plaques extensively involving areas of the brain stem or spinal cord. Early recognition of MS patients at risk for respiratory complications allows for the timely implementation of care and measures to decrease disease associated morbidity and mortality. PMID- 25724875 TI - Harsh Parenting As a Potential Mediator of the Association Between Intimate Partner Violence and Child Disruptive Behavior in Families With Young Children. AB - Young children living with intimate partner violence (IPV) are often also exposed to harsh parenting. Both forms of violence increase children's risk for clinically significant disruptive behavior, which can place them on a developmental trajectory associated with serious psychological impairment later in life. Although it is hypothesized that IPV behaviors may spillover into harsh parenting, and thereby influence risk for disruptive behavior, relatively little is known about these processes in families with young children. The current study examines the overlap of the quality and frequency of psychological and physical forms of IPV and harsh parenting, and tests whether harsh parenting mediates the relationship between IPV and child disruptive behavior in a diverse cross sectional sample of 81 children ages 4 to 6 years. Results suggest that mothers reporting a greater occurrence of psychologically aggressive IPV (e.g., yelling, name-calling) more often engage in psychological and physical aggression toward their children (odds ratios [ORs] = 4.6-9.9). Mothers reporting a greater occurrence of IPV in the form of physical assault more often engage in mild to more severe forms of physical punishment with potential harm to the child (ORs = 3.8-5.0). Psychological and physical forms of IPV and harsh parenting all significantly correlated with maternal reports of child disruptive behavior (r = .29-.40). Psychological harsh parenting partially mediated the association between psychological IPV and child disruptive behavior. However, a significant direct effect of psychological IPV on preschool children's disruptive behavior remained. Implications for child welfare policy and practice and intervention, including the need for increased awareness of the negative impact of psychological IPV on young children, are discussed. PMID- 25724876 TI - X Views and Counting: Interest in Rape-Oriented Pornography as Gendered Microaggression. AB - Academics and activists called to attention decades prior the importance of identifying, analyzing, and tracking the transmission of attitudes, behaviors, and norms correlated with violence against women. A specific call to attention reflected the media as a mode of transmission. This research builds on prior studies of media, with an emphasis on Internet search queries. Using Google search data, for the period 2004 to 2012, this research provides regional analysis of associated interest in rape-oriented pornography and pornographic hubs. Results indicate minor regional variations in interest, including the use of "BDSM" or "bondage/discipline, dominance/submission, and sadomasochism" as a foundational query for use in trend analysis. Interest in rape-oriented pornography by way of pornographic hubs is discussed in the context of microaggression. PMID- 25724877 TI - Attrition and Rape Case Characteristics: A Profile and Comparison of Female Sex Workers and Non-Sex Workers. AB - The attrition of rape cases from the criminal justice system (CJS) remains high and there is a paucity of research in relation to marginalized groups. Sex workers (SWs) are vulnerable to sexual violence due to the nature of their work. They are also unlikely to report such violence to police for a range of reasons. Two stages of research sought to describe the victim, perpetrator, and offense characteristics of SW rape and to examine the attrition of these cases. All rapes and attempted rapes (N = 1,146) reported to police in a large city in the South West of England over a 21-year period were examined; 67 cases involved SWs. Data were extracted from police files in line with the variables of interest. Secondary analysis of the total number of SW rapes (n = 67) resulted in a profile of these cases. A matched pairs study revealed significant differences in victim, perpetrator, and assault characteristics between SW (n = 62) and non-sex-worker (NSW) samples (n = 62). Although no significant difference was found in terms of attrition from the CJS, SW cases were observed to secure more convictions for rape than NSW cases. The implications of the findings for practice and future research are discussed. PMID- 25724878 TI - Sometimes more competent, but always less warm: Perceptions of biologically oriented mental-health clinicians. AB - BACKGROUND AND AIMS: Biological conceptualizations of psychopathology are ascendant, including among mental-health clinicians. However, it is unknown how this might affect people's perceptions of clinicians, which in turn could have considerable public-health implications. The present studies sought to address this issue. METHODS: In the present research, participants imagined that they or their loved ones were suffering from a mental disorder and then rated their perceptions of one clinician espousing the view that 'mental disorders are brain diseases' and another describing them as 'disorders of thoughts and emotions'. RESULTS: Biologically oriented clinicians were perceived as more competent and effective only when the disorder in question was judged to be biologically caused. Otherwise, there was no significant difference in perceived competence, and biologically oriented clinicians were rated less effective. Regardless, all participants perceived the biologically oriented clinician as significantly less warm on average than the psychosocially oriented clinician. CONCLUSION: These findings may have important clinical implications for the crucial therapeutic alliance between therapists and patients. PMID- 25724879 TI - Group patient education: effectiveness of a brief intervention in people with type 2 diabetes mellitus in primary health care in Greece: a clinically controlled trial. AB - This study aims to assess the impact of a brief patient group education intervention in people with type 2 diabetes mellitus. The sample, 193 people with type 2 diabetes mellitus who were patients at the diabetic clinic of a primary health care setting in Attica, was assigned to two groups, intervention (138 individuals) and control group (55 individuals). The intervention group, instead of receiving standard care, attended a structured group educational programme using Conversation Maps while the control group had standard care. The main outcome measures were HbA1c, body mass index (BMI), triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL), measured at baseline and 6 months after the intervention. After 6 months, significant differences in changes of the studied parameters were observed between the groups in HbA1c, 1.4 (95% CI: 1.1, 1.7), (P < 0.001) and HDL -4.4 (95% CI: -8.1, -0.8), (P < 0.001) in favour of group education. Within the groups, the intervention group presented a significant reduction in HbA1c, -0.6 (95% CI: -0.8, -0.3), (P < 0.001), in BMI, 0.7 (95% CI: -0.9, -0.1), (P = 0.007), in triglycerides, -21.1 (95% CI: -47.1, 9.9), (P = 0.003) and LDL, -10.0 (95% CI: -22.5, -5.7), (P < 0.001), while in the control group significant reductions were observed in HbA1c, -0.5 (95% CI: -0.5, 0.3), (P = 0.003), in HLD, -4.1 (95% CI: -7.7, -2.3), (P = 0.001) and in LDL, 9.4 (95% CI: -19.9, -3.9), (P = 0.018). Group-based patient education using Conversation Maps for people with type 2 diabetes is more effective, compared with individual education, in diabetes self-management. PMID- 25724880 TI - Results of a fast-track referral system for urgent outpatient hepatology visits. AB - OBJECTIVE: In 2011, our regional district adopted an experimental system for fast referral (within 72 h) by general practitioners to several outpatient specialist evaluations including hepatology. The aim of this study was to assess the characteristics and appropriateness of urgent hepatology visits. DESIGN: Retrospective study. SETTING: Hospital-based study in Italy. PARTICIPANTS: A total of 192 subjects referred to our outpatient hepatology clinic classified as 'urgent' were compared with 397 patients evaluated with standard referral. A comparison with 200 patients visited just before the adoption of the new system was also included. MAIN OUTCOME MEASURES: Patients' features and appropriateness of referral in urgent and non-urgent groups using the new system. RESULTS: Increase in liver enzymes was the main factor that leads to specialist hepatology consultation and was more frequent in the urgent group (37% vs. 27.1%, P < 0.001). Liver malignancies were identified in 2.6% of patients in the urgent group, whereas this percentage was 10 times lower in the non-urgent group (P = 0.01). Urgent patients required inpatient admission more frequently compared with non-urgent patients (4.2% vs. 0.5%; P = 0.003). Inappropriate referral was recorded in 41% of cases in the urgent group (no reason for urgency 27%; condition not attributable to liver 13.5%). In the non-urgent group, consultations were inappropriate in 20.1% of cases (condition not attributable to liver). In comparison with the old system, the new one allocated >85% of patients with serious illness to urgent group. CONCLUSIONS: This strategy is helpful in selecting patients with more serious hepatic conditions. Appropriateness of referral represents a crucial issue. PMID- 25724881 TI - GREAT-a randomized aneurysm trial. Design of a randomized controlled multicenter study comparing HydroSoft/HydroFrame and bare platinum coils for endovascular aneurysm treatment. AB - The effectiveness of a hybrid hydrogel platinum detachable coil (HydroCoil; MicroVention Inc., Tustin, CA) for endovascular aneurysm treatment has been proven in a recently published RCT. Due to technical restrictions (coil stiffness, time restriction for placement), the HydroSoft coil as well as a corresponding 3D framing coil, the HydroFrame coil (MicroVention Inc., Tustin, CA), a class of new softer coils containing less hydrogel and swelling more slowly than the HydroCoil, have been developed and brought to clinical practice. The present study aims to compare the effectiveness of endovascular aneurysm treatment with coil embolization between patients allocated HydroSoft/HydroFrame versus bare platinum coiling. GREAT is a randomized, controlled, multicentre trial in patients bearing cerebral aneurysms to be treated by coil embolization. Eligible patients were randomized to either coil embolization with HydroSoft/HydroFrame coils (>50 % of administered coil length), or bare platinum coils. Inclusion criteria were as follows: age 18-75, ruptured aneurysm (WFNS 1 3) and unruptured aneurysm with a diameter between 4 and 12 mm. Anatomy such that endovascular coil occlusion deemed possible and willingness of the neurointerventionalist to use either HydroSoft/HydroFrame or bare platinum coils. Exclusion criteria were as follows: aneurysms previously treated by coiling or clipping. Primary endpoint is a composite of major aneurysm recurrence on follow up angiography and poor clinical outcome (modified Rankin scale 3 or higher), both assessed at 18 months post treatment. Risk differences for poor outcomes will be estimated in a modified intention-to-treat analysis stratified by rupture status (DRKS-ID: DRKS00003132). PMID- 25724882 TI - Phytochemical and in vitro and in vivo biological investigation on the antihypertensive activity of mango leaves (Mangifera indica L.). AB - AIMS: The aim of this study was to investigate the antihypertensive effect of leaves Mangifera indica L. using in vitro and in vivo assays. METHODOLOGY: The ethanol extract of leaves of M. indica was fractionated to dichloromethanic, n butyl alcohol and aqueous fractions. The chemical composition of ethanolic extract and dichloromethanic fraction were evaluated by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Antioxidant activity was evaluated in the DPPH scavenging activity assay. Angiotensin-converting enzyme (ACE) inhibitory activity was investigated using in vitro and in vivo assays. The chronic antihypertensive assay was performed in spontaneously hypertensive rats (SHRs) and Wistar rats treated with enalapril (10 mg/kg), dichloromethanic fraction (100 mg/kg; twice a day) or vehicle control for 30 days. The baroreflex sensitivity was evaluated through the use of sodium nitroprusside and phenylephrine. Cardiac hypertrophy was evaluated by morphometric analysis. RESULTS: The dichloromethanic fraction exhibited the highest flavonoid, total phenolic content and high antioxidant activity. Dichloromethanic fraction elicited ACE inhibitory activity in vitro (99 +/- 8%) similar to captopril. LC MS/MS analysis revealed the presence of ferulic acid (48.3 +/- 0.04 ug/g) caffeic acid (159.8 +/- 0.02 ug/g), gallic acid (142.5 +/- 0.03 ug/g), apigenin (11.0 +/- 0.01 ug/g) and quercetin (203.3 +/- 0.05 ug/g). The chronic antihypertensive effects elicited by dichloromethanic fraction were similar to those of enalapril, and the baroreflex sensitivity was normalized in SHR. Plasma ACE activity and cardiac hypertrophy were comparable with animals treated with enalapril. CONCLUSIONS: Dichloromethanic fraction of M. indica presented an antihypertensive effect, most likely by ACE inhibition, with benefits in baroreflex sensitivity and cardiac hypertrophy. Altogether, the results of the present study suggest that the dichloromethanic fraction of M. indica leaves may have potential as a promoting antihypertensive agent. PMID- 25724883 TI - Antibody Drug Conjugates: Preclinical Considerations. AB - The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg(r), the first in class FDA-approved ADC, are highlighted. PMID- 25724884 TI - Defining the morphology and mechanism of the hemoglobin transport pathway in Plasmodium falciparum-infected erythrocytes. AB - Hemoglobin degradation during the asexual cycle of Plasmodium falciparum is an obligate process for parasite development and survival. It is established that hemoglobin is transported from the host erythrocyte to the parasite digestive vacuole (DV), but this biological process is not well characterized. Three dimensional reconstructions made from serial thin-section electron micrographs of untreated, trophozoite-stage P. falciparum-infected erythrocytes (IRBC) or IRBC treated with different pharmacological agents provide new insight into the organization and regulation of the hemoglobin transport pathway. Hemoglobin internalization commences with the formation of cytostomes from localized, electron-dense collars at the interface of the parasite plasma and parasitophorous vacuolar membranes. The cytostomal collar does not function as a site of vesicle fission but rather serves to stabilize the maturing cytostome. We provide the first evidence that hemoglobin transport to the DV uses an actin myosin motor system. Short-lived, hemoglobin-filled vesicles form from the distal end of the cytostomes through actin and dynamin-mediated processes. Results obtained with IRBC treated with N-ethylmaleimide (NEM) suggest that fusion of hemoglobin-containing vesicles with the DV may involve a soluble NEM-sensitive factor attachment protein receptor-dependent mechanism. In this report, we identify new key components of the hemoglobin transport pathway and provide a detailed characterization of its morphological organization and regulation. PMID- 25724885 TI - Control of Plasma Membrane Permeability by ABC Transporters. AB - ATP-binding cassette transporters Pdr5 and Yor1 from Saccharomyces cerevisiae control the asymmetric distribution of phospholipids across the plasma membrane as well as serving as ATP-dependent drug efflux pumps. Mutant strains lacking these transporter proteins were found to exhibit very different resistance phenotypes to two inhibitors of sphingolipid biosynthesis that act either late (aureobasidin A [AbA]) or early (myriocin [Myr]) in the pathway leading to production of these important plasma membrane lipids. These pdr5Delta yor1 strains were highly AbA resistant but extremely sensitive to Myr. We provide evidence that these phenotypic changes are likely due to modulation of the plasma membrane flippase complexes, Dnf1/Lem3 and Dnf2/Lem3. Flippases act to move phospholipids from the outer to the inner leaflet of the plasma membrane. Genetic analyses indicate that lem3Delta mutant strains are highly AbA sensitive and Myr resistant. These phenotypes are fully epistatic to those seen in pdr5Delta yor1 strains. Direct analysis of AbA-induced signaling demonstrated that loss of Pdr5 and Yor1 inhibited the AbA-triggered phosphorylation of the AGC kinase Ypk1 and its substrate Orm1. Microarray experiments found that a pdr5Delta yor1 strain induced a Pdr1-dependent induction of the entire Pdr regulon. Our data support the view that Pdr5/Yor1 negatively regulate flippase function and activity of the nuclear Pdr1 transcription factor. Together, these data argue that the interaction of the ABC transporters Pdr5 and Yor1 with the Lem3-dependent flippases regulates permeability of AbA via control of plasma membrane protein function as seen for the high-affinity tryptophan permease Tat2. PMID- 25724888 TI - Platelet inhibitors influence cardioprotection: importance in preclinical study design: reply. PMID- 25724886 TI - Role of phosphatidylinositol phosphate signaling in the regulation of the filamentous-growth mitogen-activated protein kinase pathway. AB - Reversible phosphorylation of the phospholipid phosphatidylinositol (PI) is a key event in the determination of organelle identity and an underlying regulatory feature in many biological processes. Here, we investigated the role of PI signaling in the regulation of the mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. Lipid kinases that generate phosphatidylinositol 4-phosphate [PI(4)P] at the Golgi (Pik1p) or PI(4,5)P2 at the plasma membrane (PM) (Mss4p and Stt4p) were required for filamentous-growth MAPK pathway signaling. Introduction of a conditional allele of PIK1 (pik1-83) into the filamentous (Sigma1278b) background reduced MAPK activity and caused defects in invasive growth and biofilm/mat formation. MAPK regulatory proteins that function at the PM, including Msb2p, Sho1p, and Cdc42p, were mislocalized in the pik1-83 mutant, which may account for the signaling defects of the PI(4)P kinase mutants. Other PI kinases (Fab1p and Vps34p), and combinations of PIP (synaptojanin-type) phosphatases, also influenced the filamentous-growth MAPK pathway. Loss of these proteins caused defects in cell polarity, which may underlie the MAPK signaling defect seen in these mutants. In line with this possibility, disruption of the actin cytoskeleton by latrunculin A (LatA) dampened the filamentous-growth pathway. Various PIP signaling mutants were also defective for axial budding in haploid cells, cell wall construction, or proper regulation of the high-osmolarity glycerol response (HOG) pathway. Altogether, the study extends the roles of PI signaling to a differentiation MAPK pathway and other cellular processes. PMID- 25724887 TI - Neurotoxin-induced DNA damage is persistent in SH-SY5Y cells and LC neurons. AB - Degeneration of the noradrenergic neurons has been reported in the brain of patients suffering from neurodegenerative diseases. However, their pathological characteristics during the neurodegenerative course and underlying mechanisms remain to be elucidated. In the present study, we used the neurotoxin camptothecin (CPT) to induce the DNA damage response in neuroblastoma SH-SY5Y cells, normal fibroblast cells, and primarily cultured locus coeruleus (LC) and raphe neurons to examine cellular responses and repair capabilities after neurotoxin exposure. To our knowledge, the present study is the first to show that noradrenergic SH-SY5Y cells are more sensitive to CPT-induced DNA damage and deficient in DNA repair, as compared to fibroblast cells. Furthermore, similar to SH-SY5Y cells, primarily cultured LC neurons are more sensitive to CPT-induced DNA damage and show a deficiency in repairing this damage. Moreover, while N-(2 chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) exposure also results in DNA damage in cultured LC neurons, neither CPT nor DSP4 induce DNA damage in neuronal cultures from the raphe nuclei. Taken together, noradrenergic SH-SY5Y cells and LC neurons are sensitive to CPT-induced DNA damage and exhibit a repair deficiency, providing a mechanistic explanation for the pathological characteristics of LC degeneration when facing endogenous and environmental DNA damaging insults in vivo. PMID- 25724889 TI - Status of P2Y12 treatment must be considered in evaluation of myocardial ischaemia/reperfusion injury. PMID- 25724890 TI - MicroRNA biogenesis and cellular proliferation. AB - Given the fundamental roles of microRNAs (miRNAs) in physiological, developmental, and pathologic processes, we hypothesized that genes involved in miRNA biogenesis contribute to human complex traits. For 13 such genes, we evaluated the relationship between transcription and 2 classes of complex traits, namely cellular growth and sensitivity to various chemotherapeutic agents in a set of lymphoblastoid cell lines. We found a highly significant correlation between argonaute RNA-induced silencing complex catalytic component 2 (AGO2) expression and cellular growth rate (Bonferroni-adjusted P < 0.05), and report additional miRNA biogenesis genes with suggestive associations with either cellular growth rate or chemotherapeutic sensitivity. AGO2 expression was found to be correlated with multiple drug sensitivity phenotypes. Furthermore, small interfering RNA knockdown of AGO2 resulted in cellular growth inhibition in an ovarian cancer cell line (OVCAR-3), supporting the role of this miRNA biogenesis gene in cell proliferation in cancer cells. Expression quantitative trait loci mapping indicated that genetic variation (in the form of both single-nucleotide polymorphisms and copy number variations) that may regulate the expression of AGO2 can have downstream effects on cellular growth-dependent complex phenotypes. PMID- 25724891 TI - Progesterone antagonizes the positive influence of estrogen on Chlamydia trachomatis serovar E in an Ishikawa/SHT-290 co-culture model. AB - Studies indicate that estrogen enhances Chlamydia trachomatis serovar E infection in genital epithelial cells. Hormones have direct and indirect effects on endometrial epithelial cells. Estrogen and progesterone exposure induces endometrial stromal cells to release effectors that subsequently regulate growth and maturation of uterine epithelial cells. Estrogen enhances C. trachomatis infection by aiding entry and intracellular development in endometrial epithelial cell (Ishikawa, IK)/SHT-290 stromal cell co-culture. Enhanced chlamydial infection was mediated by direct estrogen-stimulated signaling events in epithelial cells and indirectly via estrogen-induced stromal cell effectors. The current study investigates the effects of hormones on chlamydial development using culture conditions representative of the menstrual cycle. Chlamydia trachomatis-infected IK or IK/SHT-290 cultures were exposed to 10(-8) M estrogen (E2), 10(-7) M progesterone (P4) or a combination of both hormones (10(-8) M E2 followed by 10(-9) M E2/10(-7) M P4). Chlamydial infectivity and progeny production were significantly decreased (30-66%) in cultures exposed to progesterone or estrogen/progesterone combination compared to estrogen alone. Thus, progesterone antagonized the positive effects of estrogen on chlamydial infection. These data indicate the susceptibility of endometrial epithelial cells to C. trachomatis infection during the menstrual cycle is altered by phase specific actions of sex hormones in the genital tract. PMID- 25724892 TI - Role of Proteus mirabilis MR/P fimbriae and flagella in adhesion, cytotoxicity and genotoxicity induction in T24 and Vero cells. AB - Proteus mirabilis is frequently associated with complicated urinary tract infections (UTI). It is proposed that several virulence factors are associated with P. mirabilis uropathogenicity. The aim of this work was to elucidate genotoxic and cytotoxic effects mediated by MR/P fimbriae and flagella in eukaryotic cells in vitro. Two cell lines (kidney- and bladder-derived) were infected with a clinical wild-type P. mirabilis strain and an MR/P and a flagellar mutant. We evaluated adhesion, genotoxicity and cytotoxicity by microscopy, comet assay and triple staining technique, respectively. Mutant strains displayed lower adhesion rates than the P. mirabilis wild-type strain and were significantly less effective to induce genotoxic and cytotoxic effects compared to the wild type. We report for the first time that P. mirabilis MR/P fimbriae and flagella mediate genotoxic and cytotoxic effects on eukaryotic cells, at least in in vitro conditions. These results could contribute to design new strategies for the control of UTI. PMID- 25724893 TI - Characterising the epigenome as a key component of the fetal exposome in evaluating in utero exposures and childhood cancer risk. AB - Recent advances in laboratory sciences hold a promise for a 'leap forward' in understanding the aetiology of complex human diseases, notably cancer, potentially providing an evidence base for prevention. For example, remarkable advances in epigenomics have an important impact on our understanding of biological phenomena and importance of environmental stressors in complex diseases. Environmental and lifestyle factors are thought to be implicated in the development of a wide range of human cancers by eliciting changes in the epigenome. These changes, thus, represent attractive targets for biomarker discovery intended for the improvement of exposure and risk assessment, diagnosis and prognosis and provision of short-term outcomes in intervention studies. The epigenome can be viewed as an interface between the genome and the environment; therefore, aberrant epigenetic events associated with environmental exposures are likely to play an important role in the onset and progression of different human diseases. The advent of powerful technologies for analysing epigenetic patterns in both cancer tissues and normal cells holds promise that the next few years will be fundamental for the identification of critical cancer- and exposure associated epigenetic changes and for their evaluation as new generation of biomarkers. Here, we discuss new opportunities in the current age of 'omics' technologies for studies with prospective design and associated biospecimens that represent exciting potential for characterising the epigenome as a key component of the fetal exposome and for understanding causal pathways and robust predictors of cancer risk and associated environmental determinants during in utero life. Such studies should improve our knowledge concerning the aetiology of childhood cancer and identify both novel biomarkers and clues to causation, thus, providing an evidence base for cancer prevention. PMID- 25724894 TI - Including auxiliary item information in longitudinal data analyses improved handling missing questionnaire outcome data. AB - OBJECTIVES: Previous studies show that missing values in multi-item questionnaires can best be handled at item score level. The aim of this study was to demonstrate two novel methods for dealing with incomplete item scores in outcome variables in longitudinal studies. The performance of these methods was previously examined in a simulation study. The two methods incorporate item information at the background when simultaneously the study outcomes are estimated. STUDY DESIGN AND SETTING: The investigated methods include the item scores or a summary of a parcel of available item scores as auxiliary variables while using the total score of the multi-item questionnaire as the main focus of the analysis in a latent growth model. That way the items help estimating the incomplete information of the total scores. The methods are demonstrated in two empirical data sets. RESULTS: Including the item information results in more precise outcomes in terms of regression coefficient estimates and standard errors, compared with not including item information in the analysis. CONCLUSION: The inclusion of a parcel summary is an efficient method that does not overcomplicate longitudinal growth estimates. Therefore, it is recommended in situations where multi-item questionnaires are used as outcome measure in longitudinal clinical studies with incomplete scores because of missing item scores. PMID- 25724895 TI - Response to letter by Forike et al.: more rigorous, not less, external validation is needed. PMID- 25724896 TI - Extra L2m is needed to improve mental healthcare intelligence, conference hears. PMID- 25724897 TI - Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: implications for xenograft models of human prostate cancer. AB - BACKGROUND: Ephrin-B2 is the sole physiologically-relevant ligand of the receptor tyrosine kinase EphB4, which is over-expressed in many epithelial cancers, including 66% of prostate cancers, and contributes to cancer cell survival, invasion and migration. Crucially, however, the cancer-promoting EphB4 signalling pathways are independent of interaction with its ligand ephrin-B2, as activation of ligand-dependent signalling causes tumour suppression. Ephrin-B2, however, is often found on the surface of endothelial cells of the tumour vasculature, where it can regulate angiogenesis to support tumour growth. Proteolytic cleavage of endothelial cell ephrin-B2 has previously been suggested as one mechanism whereby the interaction between tumour cell-expressed EphB4 and endothelial cell ephrin B2 is regulated to support both cancer promotion and angiogenesis. METHODS: An in silico approach was used to search accessible surfaces of 3D protein models for cleavage sites for the key prostate cancer serine protease, KLK4, and this identified murine ephrin-B2 as a potential KLK4 substrate. Mouse ephrin-B2 was then confirmed as a KLK4 substrate by in vitro incubation of recombinant mouse ephrin-B2 with active recombinant human KLK4. Cleavage products were visualised by SDS-PAGE, silver staining and Western blot and confirmed by N-terminal sequencing. RESULTS: At low molar ratios, KLK4 cleaved murine ephrin-B2 but other prostate-specific KLK family members (KLK2 and KLK3/PSA) were less efficient, suggesting cleavage was KLK4-selective. The primary KLK4 cleavage site in murine ephrin-B2 was verified and shown to correspond to one of the in silico predicted sites between extracellular domain residues arginine 178 and asparagine 179. Surprisingly, the highly homologous human ephrin-B2 was poorly cleaved by KLK4 at these low molar ratios, likely due to the 3 amino acid differences at this primary cleavage site. CONCLUSION: These data suggest that in in vivo mouse xenograft models, endogenous mouse ephrin-B2, but not human tumour ephrin-B2, may be a downstream target of cancer cell secreted human KLK4. This is a critical consideration when interpreting data from murine explants of human EphB4+/KLK4+ cancer cells, such as prostate cancer cells, where differential effects may be seen in mouse models as opposed to human clinical situations. PMID- 25724898 TI - CIAPIN1 targets Na+/H+ exchanger 1 to mediate MDA-MB-231 cells' metastasis through regulation of MMPs via ERK1/2 signaling pathway. AB - Cytokine-induced antiapoptotic inhibitor 1 (CIAPIN1) was recently identified as an essential downstream effector of the Ras signaling pathway and has been confirmed to be closely associated with various malignant tumors. However, its potential role in regulating breast cancer metastasis remains unclear. Matrix metalloproteinases (MMPs) are a broad family of zinc-biding endopeptidases that participate in the extracellular matrix (ECM) degradation that accompanies cancer cell invasion, metastasis and angiogenesis. In this study, we found up-regulation of CIAPIN1 by lentiviral expression vector inhibited the migration, invasion and MMPs expression of MDA-MB-231 cells. Further, CIAPIN1 over-expression decreased NHE1 (Na(+)/H(+) exchanger 1) expression and ERK1/2 phosphorylation. Importantly, treating CIAPIN1 over-expressed MDA-MB-231 cells with the NHE1 specific inhibitor, Cariporide, further inhibited the metastatic capacity, MMPs expression and phosphorylated ERK1/2. Treatment with the MEK1 specific inhibitor, PD98059, induced nearly the same suppression of CIAPIN1 over-expression-dependent migration, invasion and MMPs expression as was observed with Cariporide. Further, Cariporide and PD98059 synergistically suppressed migration, invasion and MMPs expression of CIAPIN1 over-expressed MDA-MB-231 cells. Thus, our results revealed the mechanism by which CIAPIN1 targeted NHE1 to mediate migration and invasion of MDA-MB-231 cells through regulation of MMPs via ERK1/2 signaling pathway. PMID- 25724899 TI - Interferon-alpha and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL induced apoptosis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-alpha) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-alpha exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-alpha on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN alpha synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-alpha upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-alpha reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-alpha- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-alpha and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-alpha and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors. PMID- 25724900 TI - Retinal differentiation of human bone marrow-derived stem cells by co-culture with retinal pigment epithelium in vitro. AB - The goal of this study was to assess the in vitro differentiation capacity of human bone marrow-derived stem cells (hBMSCs) along retinal lineages. Mononuclear cells (MNC) were isolated from bone marrow (BM) and mobilized peripheral blood (mPB) using Ficoll-Paque density gradient centrifugation, and were sorted by magnetic-activated cell sorting (MACS) for specific stem cell subsets (CD34(+)CD38(+)/CD34(+)CD38(-)). These cells were then co-cultured on human retinal pigment epithelial cells (hRPE) for 7 days. The expression of stem cell, neural and retina-specific markers was examined by immunostaining, and the gene expression profiles were assessed after FACS separation of the co-cultured hBMSCs by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, in vitro functionality of the differentiated cells was analyzed by quantifying phagocytosis of CY5-labeled photoreceptor outer segments (POS). After 7 days of co-culture, hBMSCs adopted an elongated epithelial-like morphology and expressed RPE-specific markers, such as RPE65 and bestrophin. In addition, these differentiated cells were able to phagocytose OS, one of the main characteristics of native RPE cells. Our data demonstrated that human CD34(+)CD38(-) hBMSC may differentiate towards an RPE-like cell type in vitro and could become a new type of autologous donor cell for regenerative therapy in retinal degenerative diseases. PMID- 25724901 TI - EphB4 localises to the nucleus of prostate cancer cells. AB - The EphB4 receptor tyrosine kinase is over-expressed in a variety of different epithelial cancers including prostate where it has been shown to be involved in survival, migration and angiogenesis. We report here that EphB4 also resides in the nucleus of prostate cancer cell lines. We used in silico methods to identify a bipartite nuclear localisation signal (NLS) in the extracellular domain and a monopartite NLS sequence in the intracellular kinase domain of EphB4. To determine whether both putative NLS sequences were functional, fragments of the EphB4 sequence containing each NLS were cloned to create EphB4NLS-GFP fusion proteins. Localisation of both NLS-GFP proteins to the nuclei of transfected cells was observed, demonstrating that EphB4 contains two functional NLS sequences. Mutation of the key amino residues in both NLS sequences resulted in diminished nuclear accumulation. As nuclear translocation is often dependent on importins we confirmed that EphB4 and importin-alpha can interact. To assess if nuclear EphB4 could be implicated in gene regulatory functions potential EphB4 binding genomic loci were identified using chromatin immunoprecipitation and Lef1 was confirmed as a potential target of EphB4-mediated gene regulation. These novel findings add further complexity to the biology of this important cancer associated receptor. PMID- 25724902 TI - Kinesin superfamily proteins (KIFs): Various functions and their relevance for important phenomena in life and diseases. AB - Kinesin superfamily proteins (KIFs) largely serve as molecular motors on the microtubule system and transport various cellular proteins, macromolecules, and organelles. These transports are fundamental to cellular logistics, and at times, they directly modulate signal transduction by altering the semantics of informational molecules. In this review, we will summarize recent approaches to the regulation of the transport destinations and to the physiological relevance of the role of these proteins in neuroscience, ciliary functions, and metabolic diseases. Understanding these burning questions will be essential in establishing a new paradigm of cellular functions and disease pathogenesis. PMID- 25724903 TI - A geometric approach to aortic root surgical anatomy. AB - OBJECTIVES: The aim of this study was the analysis of the geometrical relationships between the different structures constituting the aortic root, with particular attention to interleaflet triangles, haemodynamic ventriculo-arterial junction and functional aortic annulus in normal subjects. METHODS: Sixteen formol-fixed human hearts with normal aortic roots were studied. The aortic root was isolated, sectioned at the midpoint of the non-coronary sinus, spread apart and photographed by a high-resolution digital camera. After calibration and picture resizing, the software AutoCAD 2004 was used to identify and measure all the elements of the interleaflets triangles and of the aortic root that were objects of our analysis. Multiple comparisons were performed with one-way analysis of variance for continuous data and with Kruskal-Wallis analysis for non continuous data. Linear regression and Pearson's product correlation were used to correlate root element dimensions when appropriate. Student's t-test was used to compare means for unpaired data. Heron's formula was applied to estimate the functional aortic annular diameters. RESULTS: The non coronary-left coronary interleaflets triangles were larger, followed by inter-coronary and right-non coronary ones. The apical angle is <60 degrees and its standard deviation can be considered an asymmetry index. The sinu-tubular junction was shown to be 10% larger than the virtual basal ring (VBR). The mathematical relationship between the haemodynamic ventriculo-arterial junction and the VBR calculated by linear regression and expressed in terms of the diameter was: haemodynamic ventriculo arterial junction = 2.29 VBR (diameter) + 47. DISCUSSION: Conservative aortic surgery is based on a better understanding of aortic root anatomy and physiology. The relationships among its elements are of paramount importance during aortic valve repair/sparing procedures and they can be useful also in echocardiographic analysis and in computed tomography reconstruction. PMID- 25724904 TI - From baby to man with a piggyback heart: long-term success of heterotopic heart transplantation. AB - We present a case of a young man, who underwent heterotopic heart transplantation 20 years ago, when he was 6 months old. The baby suffered from severe intractable cardiomyopathy. In this desperate situation only a miniature, compromised donor heart became available. Today, the young man is fully active under minimal immunosuppression. His surgical course is reviewed and described. PMID- 25724905 TI - Extra-anatomic revascularization for preoperative cerebral malperfusion due to distal carotid artery occlusion in acute type A aortic dissection. AB - OBJECTIVES: Management of patients with acute aortic dissection type A (AADA) and cerebral malperfusion secondary to occlusion or stenosis of the left common carotid artery (LCCA) or right common carotid artery (RCCA) is a significant challenge. The aim of this study is to present our institutional strategy and postoperative results for this high-risk patient cohort. METHODS: Between November 2005 and July 2013, 23 of 354 consecutively operated AADA patients [median age: 66.3; interquartile range (IQR): 55.2-69.9] suffered from cerebral malperfusion due to bilateral (n = 1) or unilateral occlusion of the LCCA/RCCA (n = 22). AADA repair comprised hemi- (n = 14) or total (n = 9) arch replacement in combination with aortic valve repair (n = 7) or replacement (n = 11), root replacement (n = 15) and coronary bypass (n = 3). Extra-anatomic aorto-carotid bypass was performed in all patients. Aorto-carotid bypass was performed at the beginning of the procedure to allow for unilateral selective cerebral perfusion (n = 17; 73.9%) or during the procedure if persisting malperfusion was suspected by near-infrared spectroscopy (n = 6; 26.1%). RESULTS: The median follow-up was 15.2 months (IQR: 4.8-34.1) and 100% complete. Median hospital stay and ICU stay were 16.0 (IQR: 12.5-26.0) and 13.7 (IQR: 2.0-16.5) days, respectively. Rethoracotomy for haemorrhage or cardiac tamponade was performed in 6 (26.1%) patients. Other postoperative complications comprised low cardiac output with extracorporeal membrane oxygenation (n = 2; 8.7%), sepsis (n = 4; 17.4%), respiratory insufficiency (n = 10; 43.5%), renal failure with temporary dialysis (n = 7; 30.4%) and visceral malperfusion (n = 2; 8.7%) requiring stent grafting (n = 1) or laparotomy with intestinal resection (n = 1). New stroke with or without permanent sensory or motor deficit was diagnosed in 8 (34.8%) patients. Temporary neurological deficits were seen in 9 (39.1%) individuals. Hospital and 1-year mortality rates were 13.0 and 30.4%, respectively. Overall survival after 36 months of the 23 patients (Group I = Extra-anatomic bypass) versus the remaining 331 AADA patients without distal RCCA/LCCA occlusion (Group II = no extra-anatomic bypass) was 69.6% (n = 16) in Group I vs 72.5% (n = 240) in Group II (P = 0.90). CONCLUSION: Extra-anatomic bypass for LCCA or RCCA occlusion allows for early selective cerebral perfusion during AADA repair, and may reduce the risk of neurological complications in patients with preoperative cerebral malperfusion. PMID- 25724906 TI - External validation of the Ferguson pulmonary risk score for predicting major pulmonary complications after oesophagectomy?. AB - OBJECTIVES: Pulmonary complications remain a frequent cause of morbidity in patients undergoing oesophagectomy. Risk screening tools assist in patient stratification. Ferguson proposed a risk score system to predict major pulmonary complications after oesophagectomy. Our objective was to externally validate this risk score system. METHODS: We analysed our institutional database for patients undergoing oesophagectomy for cancer from August 2009 to December 2012. We analysed patients who had complete documentation of variables used in the Ferguson risk score calculation: forced expiratory volume in the 1 s, diffusion capacity of the lung for carbon monoxide, performance status and age. One hundred and thirty-six patients qualified for analysis in the validation study. Outcome variables measured included major pulmonary complications, defined as need for reintubation for respiratory failure and pneumonia. The risk score was then calculated for each individual based on the model. Incidence of major pulmonary events was assessed in the five risk class groupings to assess the discriminative ability of the Ferguson score. RESULTS: Major pulmonary complications occurred in 35% of patients (47/136). Overall mortality was 6% (8/136). Patients were grouped into five risk categories according to their Ferguson pulmonary risk score: 0-2, 8 patients (6%); 3-4, 24 patients (18%); 5-6, 49 patients (36%); 29 patients (21%); 9-14, 26 patients (19%). The incidence of major pulmonary complications in these categories was 0, 17, 20, 41 and 77%, respectively. The accuracy of the risk score system for predicting major pulmonary complications was 76% (P < 0.0001). CONCLUSIONS: This pulmonary risk scoring system is a reliable instrument to be used during the preoperative phase to differentiate patients who may be at higher risk for pulmonary complications after oesophagectomy. These data can assist in patient selection, and in patient education/informed consent and can guide postoperative management. PMID- 25724907 TI - Outcomes and risk factors for heart transplantation in children with end-stage cardiomyopathy?. AB - OBJECTIVES: Heart transplantation (HT) is the treatment of choice in children with end-stage cardiomyopathy. Several clinical, morphological, demographic, donor and recipient transplant factors have been demonstrated to affect survival in those patients following listing for HT and following HT. We aim to report our single institution results of HT in children with cardiomyopathy, and explore variables affecting survival and the need for heart retransplantation (RHT). METHODS: Between 1988 and 2013, 125 children with cardiomyopathy underwent HT. Competing risks analysis modelled events after HT (RHT, death without RHT). Multivariable regression analysis examined risk factors affecting outcomes and parametric models were used to compare survival between diverse groups of patients. RESULTS: There were 62 males (50%). Cardiomyopathy types were dilated (n = 104, 83%), restrictive (n = 10, 8%), chemotherapy-induced (n = 7, 6%), and other (n = 4, 3%). Median age at listing was 6.9 years and median age at HT was 7.0 years with median waiting list duration of 29 days. Thirty-four patients were infants <1 year. At time of HT, 106 patients (85%) were at United Network for Organ Sharing status-1, 25 (20%) were ventilated and 17 (14%) had mechanical circulatory support. There was 1 operative death. Competing risks analysis showed that at 10 years following HT, 10% of patients have undergone RHT, 32% have died without RHT and 58% of patients were alive without RHT. On multivariable analysis, risk factors for death following HT were panel-reactive antibodies >10% {hazard ratio [HR]: 4.1 [95% confidence interval (CI): 1.7-9.9], P = 0.002}, age group >10 years [HR: 3.2 (95% CI: 1.4-8.1), P = 0.009] and pre-HT mechanical circulatory support [HR: 2.9 (95% CI: 1.1-7.7), P = 0.033]. Additionally, earlier era <2000 was a significant risk factor for early phase mortality [HR: 8.7 (95% CI: 1.8-42.5), P = 0.017] but not for constant or late phase mortality [HR: 0.8 (95% CI 0.3-1.8), P = 0.6]. Following RHT, 6/11 (55%) expired yielding overall parametric survival estimates of 92, 77 and 57% at 1, 5 and 15 years, respectively. CONCLUSIONS: Despite remarkable improvement in operative mortality and 1-year survival of children undergoing HT for cardiomyopathy in the current era, that advantage is reduced at the later follow-up, especially in teenagers indicating ongoing compliance and chronic management challenges. In children requiring pre-HT mechanical support, mid-term attrition is higher despite low operative mortality. PMID- 25724909 TI - Multiplexed, Quantitative Workflow for Sensitive Biomarker Discovery in Plasma Yields Novel Candidates for Early Myocardial Injury. AB - We have developed a novel plasma protein analysis platform with optimized sample preparation, chromatography, and MS analysis protocols. The workflow, which utilizes chemical isobaric mass tag labeling for relative quantification of plasma proteins, achieves far greater depth of proteome detection and quantification while simultaneously having increased sample throughput than prior methods. We applied the new workflow to a time series of plasma samples from patients undergoing a therapeutic, "planned" myocardial infarction for hypertrophic cardiomyopathy, a unique human model in which each person serves as their own biologic control. Over 5300 proteins were confidently identified in our experiments with an average of 4600 proteins identified per sample (with two or more distinct peptides identified per protein) using iTRAQ four-plex labeling. Nearly 3400 proteins were quantified in common across all 16 patient samples. Compared with a previously published label-free approach, the new method quantified almost fivefold more proteins/sample and provided a six- to nine-fold increase in sample analysis throughput. Moreover, this study provides the largest high-confidence plasma proteome dataset available to date. The reliability of relative quantification was also greatly improved relative to the label-free approach, with measured iTRAQ ratios and temporal trends correlating well with results from a 23-plex immunoMRM (iMRM) assay containing a subset of the candidate proteins applied to the same patient samples. The functional importance of improved detection and quantification was reflected in a markedly expanded list of significantly regulated proteins that provided many new candidate biomarker proteins. Preliminary evaluation of plasma sample labeling with TMT six plex and ten-plex reagents suggests that even further increases in multiplexing of plasma analysis are practically achievable without significant losses in depth of detection relative to iTRAQ four-plex. These results obtained with our novel platform provide clear demonstration of the value of using isobaric mass tag reagents in plasma-based biomarker discovery experiments. PMID- 25724908 TI - Proteomic analysis of the soybean symbiosome identifies new symbiotic proteins. AB - Legumes form a symbiosis with rhizobia in which the plant provides an energy source to the rhizobia bacteria that it uses to fix atmospheric nitrogen. This nitrogen is provided to the legume plant, allowing it to grow without the addition of nitrogen fertilizer. As part of the symbiosis, the bacteria in the infected cells of a new root organ, the nodule, are surrounded by a plant-derived membrane, the symbiosome membrane, which becomes the interface between the symbionts. Fractions containing the symbiosome membrane (SM) and material from the lumen of the symbiosome (peribacteroid space or PBS) were isolated from soybean root nodules and analyzed using nongel proteomic techniques. Bicarbonate stripping and chloroform-methanol extraction of isolated SM were used to reduce complexity of the samples and enrich for hydrophobic integral membrane proteins. One hundred and ninety-seven proteins were identified as components of the SM, with an additional fifteen proteins identified from peripheral membrane and PBS protein fractions. Proteins involved in a range of cellular processes such as metabolism, protein folding and degradation, membrane trafficking, and solute transport were identified. These included a number of proteins previously localized to the SM, such as aquaglyceroporin nodulin 26, sulfate transporters, remorin, and Rab7 homologs. Among the proteome were a number of putative transporters for compounds such as sulfate, calcium, hydrogen ions, peptide/dicarboxylate, and nitrate, as well as transporters for which the substrate is not easy to predict. Analysis of the promoter activity for six genes encoding putative SM proteins showed nodule specific expression, with five showing expression only in infected cells. Localization of two proteins was confirmed using GFP-fusion experiments. The data have been deposited to the ProteomeXchange with identifier PXD001132. This proteome will provide a rich resource for the study of the legume-rhizobium symbiosis. PMID- 25724912 TI - A Concise Protocol for siRNA-Mediated Gene Suppression in Human Embryonic Stem Cells. AB - Human embryonic stem cells hold great promise for future biomedical applications such as disease modeling and regenerative medicine. However, these cells are notoriously difficult to culture and are refractory to common means of genetic manipulation, thereby limiting their range of applications. In this protocol, we present an easy and robust method of gene repression in human embryonic stem cells using lipofection of small interfering RNA (siRNA). PMID- 25724910 TI - Quantitative proteomics reveals protein-protein interactions with fibroblast growth factor 12 as a component of the voltage-gated sodium channel 1.2 (nav1.2) macromolecular complex in Mammalian brain. AB - Voltage-gated sodium channels (Nav1.1-Nav1.9) are responsible for the initiation and propagation of action potentials in neurons, controlling firing patterns, synaptic transmission and plasticity of the brain circuit. Yet, it is the protein protein interactions of the macromolecular complex that exert diverse modulatory actions on the channel, dictating its ultimate functional outcome. Despite the fundamental role of Nav channels in the brain, information on its proteome is still lacking. Here we used affinity purification from crude membrane extracts of whole brain followed by quantitative high-resolution mass spectrometry to resolve the identity of Nav1.2 protein interactors. Of the identified putative protein interactors, fibroblast growth factor 12 (FGF12), a member of the nonsecreted intracellular FGF family, exhibited 30-fold enrichment in Nav1.2 purifications compared with other identified proteins. Using confocal microscopy, we visualized native FGF12 in the brain tissue and confirmed that FGF12 forms a complex with Nav1.2 channels at the axonal initial segment, the subcellular specialized domain of neurons required for action potential initiation. Co-immunoprecipitation studies in a heterologous expression system validate Nav1.2 and FGF12 as interactors, whereas patch-clamp electrophysiology reveals that FGF12 acts synergistically with CaMKII, a known kinase regulator of Nav channels, to modulate Nav1.2-encoded currents. In the presence of CaMKII inhibitors we found that FGF12 produces a bidirectional shift in the voltage-dependence of activation (more depolarized) and the steady-state inactivation (more hyperpolarized) of Nav1.2, increasing the channel availability. Although providing the first characterization of the Nav1.2 CNS proteome, we identify FGF12 as a new functionally relevant interactor. Our studies will provide invaluable information to parse out the molecular determinant underlying neuronal excitability and plasticity, and extending the relevance of iFGFs signaling in the normal and diseased brain. PMID- 25724911 TI - Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. AB - The data-independent acquisition (DIA) approach has recently been introduced as a novel mass spectrometric method that promises to combine the high content aspect of shotgun proteomics with the reproducibility and precision of selected reaction monitoring. Here, we evaluate, whether SWATH-MS type DIA effectively translates into a better protein profiling as compared with the established shotgun proteomics. We implemented a novel DIA method on the widely used Orbitrap platform and used retention-time-normalized (iRT) spectral libraries for targeted data extraction using Spectronaut. We call this combination hyper reaction monitoring (HRM). Using a controlled sample set, we show that HRM outperformed shotgun proteomics both in the number of consistently identified peptides across multiple measurements and quantification of differentially abundant proteins. The reproducibility of HRM in peptide detection was above 98%, resulting in quasi complete data sets compared with 49% of shotgun proteomics. Utilizing HRM, we profiled acetaminophen (APAP)(1)-treated three-dimensional human liver microtissues. An early onset of relevant proteome changes was revealed at subtoxic doses of APAP. Further, we detected and quantified for the first time human NAPQI-protein adducts that might be relevant for the toxicity of APAP. The adducts were identified on four mitochondrial oxidative stress related proteins (GATM, PARK7, PRDX6, and VDAC2) and two other proteins (ANXA2 and FTCD). Our findings imply that DIA should be the preferred method for quantitative protein profiling. PMID- 25724913 TI - Sensitization of the trigeminovascular system following environmental irritant exposure. AB - BACKGROUND: Air pollution is linked to increased emergency room visits for headache, and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that nasal administration of environmental irritants acutely increases meningeal blood flow via a TRPA1-dependent mechanism involving the trigeminovascular system. Here, we examine whether chronic environmental irritant exposure sensitizes the trigeminovascular system. METHODS: Male rats were exposed to acrolein, a TRPA1 agonist, or room air by inhalation for four days prior to meningeal blood flow measurements. Some animals were injected daily with a TRPA1 antagonist, AP-18, or vehicle prior to inhalation exposure. Trigeminal ganglia were isolated following blood flow measurements for immunocytochemistry and/or qPCR determination of TRPV1, TRPA1 and CGRP levels. RESULTS: Acrolein inhalation exposure potentiated blood flow responses both to TRPA1 and TRPV1 agonists compared to room air. Acrolein exposure did not alter TRPV1 or TRPA1 mRNA levels or TRPV1 or CGRP immunoreactive cell counts in the trigeminal ganglion. Acrolein sensitization of trigeminovascular responses to a TRPA1 agonist was attenuated by pre-treatment with AP-18. INTERPRETATION: These results suggest trigeminovascular sensitization as a mechanism for enhanced headache susceptibility after chemical exposure. PMID- 25724914 TI - Mechanisms of glyceryl trinitrate provoked mast cell degranulation. AB - BACKGROUND: Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache. METHODS: Using a newly developed rat model mimicking the human glyceryl trinitrate headache model, we have investigated the occurrence of dural mast cell degranulation after a clinically relevant dose of glyceryl trinitrate. RESULTS: A 6-fold increase in degranulation was observed starting at 2 hours after glyceryl trinitrate infusion. Interestingly, pre treatment with the effective anti-migraine substances L-nitro-arginine methyl ester and sumatriptan prevented glyceryl trinitrate-induced mast cell degranulation whereas the calcitonin gene-related peptide-receptor antagonist olcegepant and the substance P receptor antagonist L-733,060 did not affect mast cell degranulation. However, topical application of two different nitric oxide donors did not cause mast cell degranulation ex vivo. CONCLUSIONS: Direct application of an exogenous nitric oxide donor on dural mast cells does not cause mast cell degranulation ex vivo. In vivo application of the nitric oxide donor glyceryl trinitrate leads to a prominent level of degranulation via a yet unknown mechanism. This effect can be completely blocked by inhibition of the endogenous nitric oxide production and by 5-HT1B/1D receptor agonists but is unaffected by calcitonin gene-related peptide and substance P receptor antagonists. PMID- 25724915 TI - An evaluation of a community living initiative in Ireland. AB - One of the central principles underpinning Irish intellectual disability policy is that of decongregation. Allied to this is the belief that life in community settings offers greater opportunities and richer experiences than does life in institutional settings. This study explores the experiences of a group of adults with intellectual disabilities who moved from residential settings to living units in the community. Using a qualitative descriptive approach, it considers the significance of that move for them and seeks to understand the extent to which their lives have changed. Whereas it emerges that this was a positive period in their lives, it is clear that a number of issues remain to be addressed and these provide useful information for similar developments in the future. PMID- 25724918 TI - Measuring the cost effectiveness of HIV prevention interventions in the US: pitfalls and problems. PMID- 25724917 TI - The professional experiences of peer specialists in the Georgia Mental Health Consumer Network. AB - There has been an increase in the number of peer-led services within the mental health care system. There however remains little information about the experiences of peers serving in such helping roles. This study explored the professional experiences of peer specialists including the basic roles, benefits, and potential challenges of the peer specialist role. Peer specialists (N = 84) completed a battery of surveys and questionnaires. Qualitative analysis of participants' responses indicated that peer specialists face difficulties such as poor compensation, limited employment opportunities, work stress, emotional stress in helping others, and maintaining personal wellness. Quantitative analyses revealed that recovery attitudes may confer clinical and psychosocial benefits for peer specialists and employment may contribute to hope, empowerment, social engagement, and competence. Peer specialists would benefit from resources and supports aimed at their continued training and supervision. Fostering the vocational advancement of peer specialists could potentially enhance their experiential recovery and community functioning. PMID- 25724919 TI - Variation in Clinical Practice: A Priority Setting Approach to the Staged Funding of Quality Improvement. AB - Variation in adherence to clinical guidelines, and in the organisation and delivery of health care significantly impact patient outcomes and health service costs. Despite mounting evidence of variation in clinical practice, the funds allocated to improve the quality of existing services remain small, relative to the resources allocated to new technologies. Quality improvement is a complex intervention, with a lack of focus on outcomes, and greater uncertainty around its effects. These factors have contributed to a relatively narrow, mainstream view of quality improvement as focussing on safety, with efforts to improve adherence to best practice limited to high profile clinical areas. This paper presents an analysis of linked, routinely collected data to identify variation in patient outcomes and processes of care across hospitals for patients presenting with low-risk chest pain. Such analyses provide a low cost, broadly applicable approach to identifying potentially important areas of variation in clinical practice, to inform the prioritisation of more detailed analyses to validate, and further investigate the causes of variation. PMID- 25724916 TI - Biomarkers for glioma immunotherapy: the next generation. AB - The term "biomarker" historically refers to a single parameter, such as the expression level of a gene or a radiographic pattern, used to indicate a broader biological state. Molecular indicators have been applied to several aspects of cancer therapy: to describe the genotypic and phenotypic state of neoplastic tissue for prognosis, to predict susceptibility to anti-proliferative agents, to validate the presence of specific drug targets, and to evaluate responsiveness to therapy. For glioblastoma (GBM), immunohistochemical and radiographic biomarkers accessible to the clinical lab have informed traditional regimens, but while immunotherapies have emerged as potentially disruptive weapons against this diffusely infiltrating, heterogeneous tumor, biomarkers with strong predictive power have not been fully established. The cancer immunotherapy field, through the recently accelerated expansion of trials, is currently leveraging this wealth of clinical and biological data to define and revise the use of biomarkers for improving prognostic accuracy, personalization of therapy, and evaluation of responses across the wide variety of tumors. Technological advancements in DNA sequencing, cytometry, and microscopy have facilitated the exploration of more integrated, high-dimensional profiling of the disease system-incorporating both immune and tumor parameters-rather than single metrics, as biomarkers for therapeutic sensitivity. Here we discuss the utility of traditional GBM biomarkers in immunotherapy and how the impending transformation of the biomarker paradigm-from single markers to integrated profiles-may offer the key to bringing predictive, personalized immunotherapy to GBM patients. PMID- 25724920 TI - Influence of FkpA variants on survival and replication of Cronobacter spp. in human macrophages. AB - Members of the genus Cronobacter are responsible for cases of meningitis and bacteremia with high fatality rates in neonates. Macrophage uptake of invading microbes is an innate process, and it has been proposed that macrophage infectivity potentiator (Mip) like proteins enhance the ability of pathogens to survive within macrophages. Cronobacter harbor the mip-like gene fkpA, but its role in intracellular survival of these bacteria in human macrophages has not yet been studied. Application of gentamicin exclusion assays and human THP-1 macrophage cells revealed significant differences in the capablility of Cronobacter species to survive and replicate within macrophages. Analysis to the amino acid level revealed both length and sequence variations in FkpA proteins among species. In this study, we addressed the possible influence of FkpA variants in intracellular survival of Cronobacter spp. in human macrophages, by knocking out the fkpA genes in two different Cronobacter strains and subsequent complementation with variants of the fkpA genes. Our results provide strong evidence that, in Cronobacter spp., FkpA must be considered a virulence factor, but its influence on macrophage survival and replication varies among strains and/or species due to the presence of amino acid variations. PMID- 25724922 TI - Persistent negative illness perceptions despite long-term biochemical control of acromegaly: novel application of the drawing test. AB - CONTEXT AND OBJECTIVE: Patients with acromegaly have persistent complaints despite long-term biochemical control. Drawings can be used to assess patients' perceptions about their disease. We aimed to explore the utility of the drawing test and its relation to illness perceptions and quality of life (QoL) in patients after long-term remission of acromegaly. DESIGN: A cross-sectional study was conducted to evaluate the utility of the drawing test. METHODS: A total of 50 patients after long-term remission (mean+/-s.e.m., 16+/-1.2 years) of acromegaly were included in this study. Patients completed the drawing test (two retrospective drawings of their body perception before acromegaly and during the active phase of acromegaly, and one drawing on the current condition after long term remission), Illness Perception Questionnaire-Revised, Physical Symptom Checklist, EuroQoL-5D, and AcroQoL. RESULTS: Patients perceived a dramatic change in body size during the active state of the disease compared with the healthy state before the awareness of acromegaly. Patients reported that their body did not completely return to the original proportions after long-term remission. In addition, larger drawings indicated more negative consequences (P<0.05), a higher score on emotional representations (P<0.05), and more perceived symptoms that were attributed to acromegaly (P<0.01). Larger drawings also indicated more impaired QoL, especially disease-specific QoL (all P<0.05). CONCLUSION: There are strong correlations among the drawing test, illness perceptions, and QoL. The drawing test appears to be a novel and relatively easy tool to assess the perception of patients after long-term remission of acromegaly. The assessment of drawings may enable health care providers to appreciate the perceptions of patients with long-term remission of acromegaly, and enable discussion of symptoms and remission. PMID- 25724921 TI - Pharmacokinetic evaluation of the equivalency of gavage, dietary, and drinking water exposure to manganese in F344 rats. AB - Concerns exist as to whether individuals may be at greater risk for neurotoxicity following increased manganese (Mn) oral intake. The goals of this study were to determine the equivalence of 3 methods of oral exposure and the rate (mg Mn/kg/day) of exposure. Adult male rats were allocated to control diet (10 ppm), high manganese diet (200 ppm), manganese-supplemented drinking water, and manganese gavage treatment groups. Animals in the drinking water and gavage groups were given the 10 ppm manganese diet and supplemented with manganese chloride (MnCl(2)) in drinking water or once-daily gavage to provide a daily manganese intake equivalent to that seen in the high-manganese diet group. No statistically significant difference in body weight gain or terminal body weights was seen. Rats were anesthetized following 7 and 61 exposure days, and samples of bile and blood were collected. Rats were then euthanized and striatum, olfactory bulb, frontal cortex, cerebellum, liver, spleen, and femur samples were collected for chemical analysis. Hematocrit was unaffected by manganese exposure. Liver and bile manganese concentrations were elevated in all treatment groups on day 61 (relative to controls). Increased cerebellum manganese concentrations were seen in animals from the high-manganese diet group (day 61, relative to controls). Increased (relative to all treatment groups) femur, striatum, cerebellum, frontal cortex, and olfactory bulb manganese concentrations were also seen following gavage suggesting that dose rate is an important factor in the pharmacokinetics of oral manganese. These data will be used to refine physiologically based pharmacokinetic models, extending their utility for manganese risk assessment by including multiple dietary exposures. PMID- 25724923 TI - Toward revealing the controversy of bacterial biosynthesis versus bactericidal properties of silver nanoparticles (AgNPs): bacteria and other microorganisms do not per se viably synthesize AgNPs. AB - In the last two decades, a large number of literature had focused on the biosynthesis of silver nanoparticles (AgNPs) from silver ions by bacteria and other microorganisms. This study infers that bacteria and other microorganisms do not per se synthesize AgNPs. All tested auto- and heterotrophic microorganisms in this study were killed by silver ions and could not as viable cells produce AgNPs. Microbial cell viability represented in colony-forming units and metabolic viability represented in aerobic respiration in all investigated microorganisms as well as photosynthesis in photoautotrophic microorganisms ceased by silver ions too early before AgNPs formation. The time required for AgNPs synthesis inversely related to the incubation temperature of the investigated microorganisms with silver ions where it requires only few minutes for nanoparticles formation at high temperature or autoclaving. The minimum inhibitory and minimum bactericidal and fungicidal concentrations of silver ions were significantly lower than AgNPs, indicating that silver ions are more efficient antimicrobial. The results presented in this study indicate that formation of AgNPs by eubacteria, cyanobacteria and fungi is not a vitally regulated cellular metabolic process and the mechanism occurs via bioreduction of silver ions to nanoparticles by organics released from the dead cells. PMID- 25724924 TI - Estimating the economic impact of Trypanosoma evansi infection on production of camel herds in Somaliland. AB - The traditional livestock sector in Somalia is based on nomadic pastoralism where sheep, goats and camels are herded in large numbers. Data from 1609 females (27 % lactating) and 550 males (26 % exported) belonging to 40 pastoralists were analysed in this study. The expected amount of revenue the herders could lose per year in the studied area was estimated at US$404,630 being made up of US$314,630 from decreased milk yield and US$90,000 from reduced market value of exported animals. However, all the camels in Somaliland are at risk of acquiring surra infection, and therefore extrapolating the current findings to the total population could potentially lose US$223,164,000. This highlights the loss in the magnitude of US$164,253,600 from decreased milk yield and US$58,910,400 from body condition loss. Overall, the benefit in controlling Trypanosoma evansi infection in the study area was US$398,880 (n = 2159). On average, US$720 was saved per head per year from improved milk production in treated animals and US$615 from the increased value of exported camels. It is concluded that all three-treatment options evaluated were economically beneficial strategies; however, the biannual treatment of seropositive camels in the herds was the best financial option. PMID- 25724925 TI - Effect of some non-genetic factors on milk yield and composition of Draa indigenous goats under an intensive system of three kiddings in 2 years. AB - With 5 millions heads, goats occupy the second place after sheep in Morocco. The indigenous populations are generally raised for meat, except Draa goat that is raised as a dual purpose doe. The objective of this study was to assess milk yield and composition of Draa indigenous goat breed under an intensive system of three kiddings in 2 years and to evaluate the effects of non-genetic factors. Data were collected on 381 lactations between 2006 and 2012 and on 174 samples for milk composition between 2008 and 2010. The highest milk yield was recorded in does of 36-48 months old (84.3 +/- 4.78), those suckling more than one kid (80.0 +/- 3.39) and those kidding in spring (80.4 +/- 3.60) and summer (79.9 +/- 3.67). Except protein content, milk composition was not affected by age of does. Dry matter and fat content increased significantly with the lactation stage, protein content decreased from early to middle/late lactation, and lactose content was high in middle lactation. The highest dry matter and fat and lactose contents were obtained for summer kiddings, while the highest percent of protein was recorded for autumnal kiddings. It was concluded that under the three kiddings in 2-year system, Draa does produce enough milk with an interesting milk composition, indicating that this system may be used with success to improve farmers' income. PMID- 25724926 TI - Effects of calving month, pasture conditions and management on the growth of Holstein-Friesian * Ankole crossbred calves in a semi-arid rangeland. AB - Daily weight gain of crossbred calves was studied in relation to seasonal changes in pasture quality and quantity, and management routines. A total of 171 and 56 calves were monitored up to the ages of 6 and 9 months, respectively, on ten farms in a semi-arid region of Uganda. Daily weight gains of calves were 288, 315 and 442 g/day at ages 0-2, 2-6 and 6-9 months, respectively. Average live weights of calves at ages 6 and 9 months were around 90 and 120 kg, respectively. Daily weight gain of calves at ages 6-9 months increased by 81 g for each additional percentage of crude protein in pasture (p < 0.05). At ages 0-2 (p < 0.05) and 0-6 (p < 0.05) months, crosses with >75 % Holstein-Friesian (HF) had 30 and 60 g lower daily weight gain, respectively, than crosses with 75 % HF and 25 % Ankole. Birth month (August-January) and the number of days with low pasture quantity (<800 kg dry matter (DM)/ha) had no significant effect on calf weight gain. A significantly higher weight gain was obtained for calves with the opportunity to suckle twice daily, compared with once. This indicates that suckling is beneficial for calves in semi-arid environments where seasonal pasture shortage regularly occurs. PMID- 25724927 TI - Discovery of the Meanings, Expressions, and Practices Related to Malaria Care Among the Maasai. AB - PURPOSE: Although malaria is preventable and treatable, morbidity and mortality from this disease continue among the Maasai of Southern Kenya. Prior to this study, the Maasai's generic and professional malaria care/cure practices were largely unknown. The purpose of this study was to discover, describe, and systematically analyze meanings, expressions, and practices that promote culturally congruent malaria care among this population. DESIGN: The qualitative, ethnonursing research method was used to conduct in-depth examination of the Maasai ethnohistory and culture relevant to malaria care and analyze data from 48 interviews conducted in Maasailand. FINDINGS: Guided by the "culture care theory," four themes were discovered related to Maasai community, traditional, spiritual, and professional care/cure practices. These significant findings filled a research gap and contribute to nursing knowledge and caring practice. PRACTICE IMPLICATIONS: These study findings have implications for culturally congruent malaria care education, practice, research, policy, and partnership with traditional and professional caregivers. PMID- 25724928 TI - Experiences of Patients Living With Heart Failure: A Descriptive Qualitative Study. AB - The purpose of this study was to explore the experiences, needs, and coping strategies of patients living with heart failure in Singapore. A descriptive qualitative design was used. A purposive sample of 15 informants was recruited from two cardiology wards of a tertiary public hospital in Singapore. Individual face-to-face interviews were conducted with a semistructured interview guideline that was developed based on a review of the literature and a pilot study. Content analysis was adopted to analyze the data, and four main categories were identified: perceived causes, manifestations, and prognosis; enduring emotions; managing the condition; and needs from health care professionals. The informants were overwhelmed with the experience of living with heart failure due to the disruptive and uncertain nature of the condition. This study offers health care professionals practical and useful suggestions when providing holistic care for patients with heart failure. PMID- 25724929 TI - Delivering nanomedicines to patients: a practical guide. AB - This is a perspective on the current state of development of nanomedicines in Europe. The view is expressed that a much higher translational success rate could be achieved, with rewards for all stakeholders, if researchers understood the industrial decision points required for new drugs. Getting a drug through the clinic will not help patients unless it is developable by industry. This article is written in the hope that it will help researchers and SMEs to decide where they are in the established process, whether they are making progress and to determine what to do next. It attempts to map the early stages from ideation to first (time) in man (FIM). FROM THE CLINICAL EDITOR: The field of nanomedicine has come a long way in the past decade. The overall dream of any researcher in this field remains the realization of concept to clinical product. In this paper, the authors outlined for the readers, the underlying problems and actions that need to be done, so that current challenges can be solved. PMID- 25724930 TI - IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color. AB - Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north western European origin (aged 51-99 years, 45% male). Physicians graded the number of AK into four severity levels: none (76%), 1-3 (14%), 4-9 (6%) and >=10 (5%), and skin color was quantified using a spectrophotometer on sun-unexposed skin. A GWAS for AK severity was conducted, where promising signals at IRF4 and MC1R (P < 4.2 * 10(-7)) were successfully replicated in an additional cohort of 623 RS individuals (IRF4, rs12203592, Pcombined = 6.5 * 10(-13) and MC1R, rs139810560, Pcombined = 4.1 * 10(-9)). Further, in an analysis of ten additional well-known human pigmentation genes, TYR also showed significant association with AK (rs1393350, P = 5.3 * 10(-4)) after correction for multiple testing. Interestingly, the strength and significance of above-mentioned associations retained largely the same level after skin color adjustment. Overall, our data strongly suggest that IRF4, MC1R and TYR genes likely have pleiotropic effects, a combination of pigmentation and oncogenic functions, resulting in an increased risk of AK. PMID- 25724931 TI - Efficacy of a nutritional education program to improve diet in patients attending a cardiac rehabilitation program: outcomes of a one-year follow-up. AB - Dietary habits are widely reported to play a primary role in the occurrence of coronary artery disease (CAD). Cardiac rehabilitation is a multidisciplinary intervention that includes nutritional education. Proper nutrition plays an important role in cardiovascular health outcomes and in decreasing morbidity and mortality of cardiovascular diseases (CVD) as highlighted in the literature. The aim of this study was to assess the efficacy of an educational program to improve the diet of cardiac rehabilitation patients compared to usual treatment. 160 patients with CAD, (124 M, 36 F) were randomized into two groups. Data analysis was conducted on 133 patients (11 % dropped out). All enrolled patients attended two educational seminars about proper nutrition and cardiovascular prevention, and completed a questionnaire about dietary habits (before CAD). The Body Mass Index (BMI) was calculated, and basal glycaemia and plasma lipids were assessed at the beginning and at the end of the study (12 months after hospital discharge). The intervention group patients underwent a mid-term evaluation of nutrient intakes, BMI, and received a personalized educational reinforcement by a dietitian. At the end of the study, the intervention group was shown to have significantly reduced their daily caloric intake (reduction of total proteins, total fat, carbohydrate, alcohol), and showed a significant reduction of weight and BMI compared to the control group. Individual nutritional counseling session as a reinforcement of a standard educational program is effective in reducing caloric intake and BMI, which may reduce cardiovascular risk factors in cardiovascular patients. PMID- 25724932 TI - DRESS syndrome and reversible liver function abnormalities in patients with systemic lupus erythematosus treated with the highly selective JAK-1 inhibitor GSK2586184. PMID- 25724933 TI - Acute temperature sensitivity in optic nerve axons explained by an electrogenic membrane potential. AB - Classical work in squid axon reports resting membrane potential is independent of temperature, but our findings suggest that this is not the case for axons in mammalian optic nerve. Refractory period duration changes over 10 times between 37 degrees C and room temperature, and afterpotential polarity is also acutely temperature sensitive, inconsistent with changes in temperature impacting nerve function only through altered rates of ion channel gating kinetics. Our evidence suggests that the membrane potential is enhanced by warming, an effect reduced by exposure to ouabain. The temperature dependence can be explained if axonal Na(+)/K(+) ATPase continuously expels Na(+) ions that enter axons largely electroneutrally, thereby adding a substantial electrogenic component to the membrane potential. Block of the Na(+) transporter NKCC1 with bumetanide increases refractoriness, like depolarization, indicating that this is a probable route by which Na(+) enters, raising the expectation that the rate of electroneutral Na(+) influx increases with temperature and suggesting a temperature-dependent transmembrane Na(+) cycle that contributes to membrane potential. PMID- 25724936 TI - Longitudinal monitoring for respiratory pathogens in broiler chickens reveals co infection of Chlamydia psittaci and Ornithobacterium rhinotracheale. AB - Chlamydia psittaci is prevalent in broiler chicken production. However, the role of C. psittaci in the respiratory disease complex needs to be clarified. Our aim was to identify the time point when a C. psittaci infection appeared on a broiler farm and to examine the presence of other respiratory pathogens at that time. We focused on the 'major' respiratory pathogens occurring in Belgian broilers, namely infectious bronchitis virus (IBV), avian metapneumovirus (aMPV), Ornithobacterium rhinotracheale, Mycoplasma gallisepticum and Mycoplasma synoviae, and examined their co-occurrence with C. psittaci on three commercial broiler farms. For all farms, 1-day-old broilers showed high maternal antibody titres against C. psittaci in the presence of viable C. psittaci. Maternal antibodies seemed to protect against respiratory signs. Maternal antibodies declined and clinical outbreaks could be identified serologically even before maternal antibodies completely disappeared. Mixed infections with genotypes B/C and B/C/D were observed. Broilers with C. psittaci antibody increases showed conjunctivitis, signs of upper respiratory disease and dyspnoea. C. psittaci always preceded an O. rhinotracheale infection. Infections with aMPV, IBV or Mycoplasma spp. were not observed. Evidence was provided that C. psittaci could occur at an early age in broilers without a predisposing respiratory infection. Both C. psittaci and O. rhinotracheale should be considered when developing prevention strategies for respiratory disease in broilers. PMID- 25724935 TI - House officers' attitude towards family medicine and its choice as a career in Egypt. AB - BACKGROUND: Family medicine (FM) specialty is new to Egyptian medical education and its choice as a career option is still unclear. This study aims to assess perceptions, expectations and level of information amongst house officers (HOs) in relation to FM and its choice as a future career. METHODS: This cross sectional descriptive study was conducted during an orientation program implemented to HOs before joining work in primary health care. Data were collected using an anonymous self-administered questionnaire. FINDINGS: More than half of respondents considered FM to have an essential social function. The most influential factor on HOs' opinions regarding FM were their own experiences during the course of study (52.6%), the opinion of family physicians (43.8%). More than two fifths of HOs reported that training sessions in health centers would be useful and 29.5% stated that at least 25-50% of the total practical training in medical school should be dedicated to FM. Nearly half of HOs (48.2%) suggested that training should take place during the fourth year of medical school. Before orientation 15.8% of HOs mentioned that they will choose FM as a career, this increased to 50.4% after orientation. Rural residence and low grades in public health are the independent predictors of choosing FM as a career (OR = 1.9 and 1.7, respectively). CONCLUSION: FM is developing rapidly as a specialty. Frequent training programs directed to HOs may encourage them to consider FM as a career. PMID- 25724934 TI - Activation of Toll-like receptor 3 increases mouse aortic vascular smooth muscle cell contractility through ERK1/2 pathway. AB - Activation of Toll-like receptor 3 (TLR3), a pattern recognition receptor of the innate immune system, is associated with vascular complications. However, whether activation of TLR3 alters vascular contractility is unknown. We, therefore, hypothesized that TLR3 activation augments vascular contractility and activates vascular smooth muscle cell (VSMC) contractile apparatus proteins. Male mice were treated with polyinosinic-polycytidylic acid (Poly I:C group, 14 days), a TLR3 agonist; control mice received saline (vehicle, 14 days). At the end of protocol, blood pressure was measured by tail cuff method. Aortas were isolated and assessed for contractility experiments using a wire myograph. Aortic protein content was used to determine phosphorylated/total interferon regulatory factor 3 (IRF3), a downstream target of TLR3 signaling, and ERK1/2 using Western blot. We investigated the TLR3/IRF3/ERK1/2 signaling pathway and contractile-related proteins such as phosphorylated/total myosin light chain (MLC) and caldesmon (CaD) in aortic VSMC primary cultures. Poly I:C-treated mice exhibited (vs. vehicle-treated mice) (1) elevated systolic blood pressure. Moreover, Poly I:C treatment (2) enhanced aortic phenylephrine-induced maximum contraction, which was suppressed by PD98059 (ERK1/2 inhibitor), and (3) increased aortic levels of phosphorylated IRF3 and ERK1/2. Stimulation of mouse aortic VSMCs with Poly I:C resulted in increased phosphorylation of IRF3, ERK1/2, MLC, and CaD. Inhibition of ERK1/2 abolished Poly I:C-mediated phosphorylation of MLC and CaD. Our data provide functional evidence for the role of TLR3 in vascular contractile events, suggesting TLR3 as a potential new therapeutic target in vascular dysfunction and regulation of blood pressure. PMID- 25724937 TI - Inter-subject variability effects on the primary stability of a short cementless femoral stem. AB - This paper is concerned with the primary stability of the Furlong Evolution((r)) cementless short stem across a spectrum of patient morphology. A computational tool is developed that automatically selects and positions the most suitable stem from an implant system made of a total of 48 collarless stems to best match a 3D model based on a library of CT femur scans (75 males and 34 females). Finite Element contact models of reconstructed hips, subjected to physiologically-based boundary constraints and peak loads of walking mode, were simulated using a coefficient of friction of 0.4 and an interference-fit of 50 MUm. Maximum and average implant micromotions across the subpopulation were predicted to be 100+/ 7 MUm and 7+/-5 MUm with ranges [15 MUm, 350 MUm] and [1 MUm, 25 MUm], respectively. The computed percentage of implant area with micromotions greater than reported critical values of 50 MUm, 100 MUm and 150 MUm never exceeded 14%, 8% and 7%, respectively. To explore the possible correlations between anatomy and implant performance, response surface models for micromotion metrics were constructed. Detailed morphological analyses were conducted and a clear nonlinear decreasing trend was observed between implant average micromotion and both the metaphyseal canal flare indices and average densities in Gruen zones. The present study demonstrates that the primary stability and tolerance of the short stem to variability in patient anatomy were high, reducing the need for patient stratification. In addition, the developed tool could be utilised to support implant design and planning of femoral reconstructive surgery. PMID- 25724938 TI - Declining body, institutional life, and making home-are they at odds? The lived experiences of moving through staged care in long-term care settings. AB - This study examines elderly residential life in long-term care settings, focusing on the ways residents interact with their physical and social environments. It further proposes that the residential environment is an important player for everyday ethics in long-term care settings, and is also an important factor in enhancing the quality of life for residents. By employing the theories of place identity and environmental meanings and listening to the voices of the elderly collected through an ethnographic field study in elderly homes of life care, the study reveals the residents' experiences of going through declining health and moving through the stages of care. Two major themes were identified. The first theme of liminal life portrays the elders' fears as they move through the stages of care. This theme includes four sub-themes: (1) the loss of home and the loss of autonomy; (2) impending loss and its constant reminders; (3) the social classification of "us" and "them"; (4) the irreversibility of moving. The second theme of relational life describes the keys to successful transitions as experienced and told by the residents. The second theme includes three sub themes: (1) shifting identity and the acceptance of old age; (2) human interdependence and building trust; (3) an accompanied death. Study implications are further discussed, including specific suggestions for social programs and revisions to the physical environments. A more fundamental question about place based staged care is also raised so as to serve as a point of departure for reflections and discussions amongst health professionals, planners and designers, and other decision-makers. PMID- 25724939 TI - Effects of sleeve gastrectomy and gastric banding on the hypothalamic feeding center in an obese rat model. AB - PURPOSE: Laparoscopic sleeve gastrectomy (SG) and gastric banding (GB) are popular bariatric procedures for treating morbid obesity. This study aimed to investigate changes in the hypothalamic feeding center after these surgeries in a diet-induced obese rat model. METHODS: Obesity was induced in 60 Sprague-Dawley rats using a high-energy diet for 6 weeks. These rats were divided into four groups: the sham-operated (SO) control, pair-fed (PF) control, SG and GB groups. Six weeks after the surgery, metabolic parameters, the plasma levels of leptin, ghrelin, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) and the hypothalamic mRNA expressions of neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) were measured. RESULTS: Compared with those observed in the SO group, the body and fat tissue weights were significantly decreased and the metabolic parameters were significantly improved in the PF, SG and GB groups 6 weeks after surgery. The plasma ghrelin levels were significantly lower and the PYY and GLP-1 levels were significantly higher in the SG group than in the PF, GB and SO groups. Compared with that seen in the PF and GB groups, the hypothalamic mRNA expression of NPY was significantly lower and the expression of POMC was significantly higher in the SG group. CONCLUSIONS: SG may affect the neurological pathway associated with appetite in the hypothalamus and thereby control ingestive behavior. PMID- 25724940 TI - What is the difference between the inferior labial artery and the horizontal labiomental artery? AB - BACKGROUND: The inferior labial artery (ILA) and horizontal labiomental artery (HLA) can be regarded as the main arteries used in the lower lip pedicle for the perioral reconstruction. However, the courses of the ILA and HLA are described in diverse ways, and there is no obvious standard for distinguishing between them. The aim of this study was to elucidate the distribution patterns of the ILA and HLA, and the significance of the HLA in the vascularization of the lower lip. MATERIALS AND METHODS: Sixty-three hemifaces from 18 Korean and 19 Thai cadavers were used in this study. The distribution patterns of the arteries of the lower lip area were classified based on the assumption that the HLA travels in the middle of the lower lip area, while the ILA runs along the lower lip border. The arterial distribution pattern of the HLA was classified into three types (I-III): type I, where the HLA ran horizontally in the lower lip area; type II, where the HLA curved upward to the vermilion border of the lower lip; and type III, where the HLA bifurcated into two branches. The ILA was also classified into three types (A-C): type A, where the ILA was not observed; type B, ILA was ramified from facial artery at the level of mouth corner; and type C, ILA arose from the superior labial artery (SLA) and supplied the lower lip vermillion border. RESULTS: Types I, II, and III were observed in 52.4 % (33/63), 39.7 % (25/63), and 7.9 % (5/63) of cases, respectively; and types A, B, and C were observed in 52.4 % (33/63), 36.5 % (23/63), and 11.1 % (7/63) of cases. Consideration of the two artery classifications together revealed seven types: type IA (14.3 %, 9/63), type IB (28.6 %, 18/63), type IC (9.5 %, 6/63), type IIA (30.2 %, 19/63), type IIB (7.9 %, 5/63), type IIC (1.6 %, 1/63), and type III (7.9 %, 5/63). The distance between the HLA and the midpoint between the mouth corner and the inferior mandibular margin was 0.4 +/- 3.1 mm (mean +/- SD) inferior to this point. CONCLUSION: The ILA and HLA should be differentiated according to the location of their origin rather than their terminating areas. The HLA could be considered as the main artery supplying the lower lip mucosa. PMID- 25724941 TI - Motor branches of the ulnar nerve to the forearm: an anatomical study and guidelines for selective neurectomy. AB - PURPOSE: Precise knowledge of motor nerve branches is critical to plan selective neurectomies for the treatment of spastic limbs. Our objective is to describe the muscular branching pattern of the ulnar nerve in the forearm and suggest an ideal surgical approach for selective neurectomy of the flexor carpi ulnaris. METHODS: The ulnar nerve was dissected under loop magnification in 20 upper limbs of fresh frozen cadavers and its branches to the flexor carpi ulnaris muscle (FCU) and to the flexor digitorum profundus muscle (FDP) were quantified. We measured their diameter, length and distance between their origin and the medial epicondyle. The point where the ulnar artery joined the nerve was observed. The position in which the ulnar nerve gave off each branch was noted (ulnar, posterior or radial) and the Martin-Gruber connection, when present, had its origin observed and its diameter measured. RESULTS: The ulnar nerve gave off two to five muscular branches, among which, one to four to the FCU and one or two to the FDP. In all cases, the first branch was to the FCU. It arose on average 1.4 cm distal to the epicondyle, but in four specimens it arose above or at the level of the medial epicondyle (2.0 cm above in one case, 1.5 cm above in two cases, and at the level of the medial epicondyle in one). The first branch to the FDP arose on average 5.0 cm distal to the medial epicondyle. All the branches to FDP but one arose from the radial aspect of the ulnar nerve. A Martin-Gruber connection was present in nine cases. All motor branches arose in the proximal half of the forearm and the ulnar nerve did not give off branches distal to the point where it was joined by the ulnar artery. CONCLUSIONS: The number of motor branches of the ulnar nerve to the FCU varies from 2 to 4. An ideal approach for selective neurectomy of the FCU should start 4 cm above the medial epicondyle, and extend distally to 50% of the length of the forearm or just to the point where the ulnar artery joins the nerve. PMID- 25724943 TI - 2015 Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Nashville, Tennessee, USA, 15-18 April 2015 : Video Presentations. PMID- 25724942 TI - Aberrant internal carotid artery associated with occipital artery arising from the internal carotid artery. AB - We present an extremely rare case of an aberrant course of the petrous internal carotid artery (ICA) associated with the ipsilateral occipital artery arising from the cervical ICA, a combination not previously reported by magnetic resonance (MR) angiography. The patient was a 53-year-old woman with no symptoms related to the anomalous ICA. Source images and partial maximum-intensity projection images of MR angiography are useful in diagnosing these variations. Source images and curved multiplanar reconstruction images of computed tomography angiography are important for the accurate evaluation of reduced arterial diameter and the relationship between the anomalous artery and petrous bone. PMID- 25724944 TI - Proteolysis of decellularized extracellular matrices results in loss of fibronectin and cell binding activity. AB - Excessive inflammation in the chronic wound bed is believed to result in increased fibronectin (FN) proteolysis and poor tissue repair. However, FN fragments can prime the immune response and result in higher protease levels. The reciprocity between FN proteolysis and inflammation makes it challenging to determine the specific contribution of FN proteolysis in the extracellular matrix (ECM) on tissue responses. We studied the impact of proteolysis of decellularized extracellular matrices (dECMs) obtained from NIH 3T3 mouse fibroblasts on FN level and activity. The dECMs were treated with alpha chymotrypsin and proteolysis was stopped at different time points. The protease solution was obtained, the remaining dECM was scrapped and examined by immunoblotting and Bicinchoninic Acid assays. Fibronectin was 9.4 +/- 1.8% of the total protein content in the dECM but was more susceptible to proteolysis. After 15 min of protease treatment there was a 67.6% and 11.1% decrease in FN and total protein, respectively, in the dECMs. Fibronectin fragments were present both in the proteolysis solution and in the dECM. Cell adhesion, spreading and actin extensions on dECMs decreased with increasing proteolysis time. Interestingly, the solutions obtained after proteolysis of the dECMs supported cell adhesion and spreading in a time dependent manner, thus demonstrating the presence of FN cell binding activity in the protease solution of dECMs. This study demonstrates the susceptibility of FN in the ECM to proteolysis and the resulting loss of cell adhesion due to the decrease of FN activity and places weight on bioengineering strategies to stabilize FN against proteolysis. PMID- 25724945 TI - CD109 attenuates TGF-beta1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells. AB - CD109 is a glycosylphosphatidylinositol-anchored cell surface protein that is frequently detected in squamous cell carcinomas. CD109 is a negative regulator of TGF-beta1 signaling in human keratinocytes, and the N-terminal fragment of CD109 secreted from cells after cleavage by the furin protease is important for modulating TGF-beta1 signaling. Previously, we found that CD109 is expressed in human glioblastoma cells; however, the role of CD109 in glioblastoma cells is not established. Here, we describe the effects of CD109 in human glioblastoma cell lines. Three glioblastoma cell lines, SK-MG-1, U251MG and MG178, were tested and CD109 overexpression attenuated TGF-beta1 signaling and enhanced EGF signaling in SK-MG-1, but not in U251MG or MG178. The N-terminal CD109 fragment in SK-MG-1 was hyperglycosylated compared with that in MG178 or U251MG. The conditioned medium of CD109-overexpressing SK-MG-1, containing the secreted N-terminal CD109, had a negative effect on TGF-beta1 signaling in wild-type SK-MG-1 and MG178, whereas it did not show any effect on EGF signaling. In addition, cell surface CD109 interacts with EGF receptor in SK-MG-1 overexpressing CD109, and exhibited enhanced cell migration and invasion. These findings suggest that CD109 attenuates TGF-beta1 signaling and enhances EGF signaling in SK-MG-1 cells and that the membrane-anchored CD109 may play major roles in the EGF signaling pathway. PMID- 25724946 TI - Crystal structure of ATP-binding subunit of an ABC transporter from Geobacillus kaustophilus. AB - The ATP binding cassette (ABC) transporters, represent one of the largest superfamilies of primary transporters, which are very essential for various biological functions. The crystal structure of ATP-binding subunit of an ABC transporter from Geobacillus kaustophilus has been determined at 1.77 A resolution. The crystal structure revealed that the protomer has two thick arms, (arm I and II), which resemble 'L' shape. The ATP-binding pocket is located close to the end of arm I. ATP molecule is docked into the active site of the protein. The dimeric crystal structure of ATP-binding subunit of ABC transporter from G. kaustophilus has been compared with the previously reported crystal structure of ATP-binding subunit of ABC transporter from Salmonella typhimurium. PMID- 25724947 TI - The Effect of Dining Room Physical Environmental Renovations on Person-Centered Care Practice and Residents' Dining Experiences in Long-Term Care Facilities. AB - This qualitative study evaluated the effect of dining room physical environmental changes on staff practices and residents' mealtime experiences in two units of a long-term care facility in Edmonton, Canada. Focus groups with staff (n = 12) and individual interviews with unit managers (n = 2) were conducted. We also developed and used the Dining Environment Assessment Protocol (DEAP) to conduct a systematic physical environmental evaluation of the dining rooms. Four themes emerged on the key influences of the renovations: (a) supporting independence and autonomy, (b) creating familiarity and enjoyment, (c) providing a place for social experience, and (d) challenges in supporting change. Feedback from the staff and managers provided evidence on the importance of physical environmental features, as well as the integral nature of the role of the physical environment and organizational support to provide person-centered care for residents. PMID- 25724948 TI - DriveSafe and DriveAware Assessment Tools Are a Measure of Driving-Related Function and Predicts Self-Reported Restriction for Older Drivers. AB - Safety concerns together with aging of the driving population has prompted research into clinic-based driving assessments. This study investigates the relationship between the DriveSafe and DriveAware assessments and restriction of driving. Community-dwelling adults aged more than 75 (n = 380) were recruited in New South Wales, Australia. Questionnaires were administered to assess driving habits and functional assessments to assess driving-related function. Self reported restriction was prevalent in this cross-sectional sample (62%) and was related to DriveSafe scores and personal circumstances but not DriveAware scores. DriveSafe scores were correlated with better performance on the Trail-Making Test (TMT; beta = -2.94, p < .0001) and better contrast sensitivity (beta = 48.70, p < .0001). Awareness was associated with better performance on the TMT (beta = 0.08, p < .0001). Our data suggest that DriveSafe and DriveAware are sensitive to deficits in vision and cognition, and drivers with worse DriveSafe scores self report restricting their driving. PMID- 25724949 TI - The role of defoliation and root rot pathogen infection in driving the mode of drought-related physiological decline in Scots pine (Pinus sylvestris L.). AB - Drought-related tree die-off episodes have been observed in all vegetated continents. Despite much research effort, however, the multiple interactions between carbon starvation, hydraulic failure and biotic agents in driving tree mortality under field conditions are still not well understood. We analysed the seasonal variability of non-structural carbohydrates (NSCs) in four organs (leaves, branches, trunk and roots), the vulnerability to embolism in roots and branches, native embolism (percentage loss of hydraulic conductivity (PLC)) in branches and the presence of root rot pathogens in defoliated and non-defoliated individuals in a declining Scots pine (Pinus sylvestris L.) population in the NE Iberian Peninsula in 2012, which included a particularly dry and warm summer. No differences were observed between defoliated and non-defoliated pines in hydraulic parameters, except for a higher vulnerability to embolism at pressures below -2 MPa in roots of defoliated pines. No differences were found between defoliation classes in branch PLC. Total NSC (TNSC, soluble sugars plus starch) values decreased during drought, particularly in leaves. Defoliation reduced TNSC levels across tree organs, especially just before (June) and during (August) drought. Root rot infection by the fungal pathogen Onnia P. Karst spp. was detected but it did not appear to be associated to tree defoliation. However, Onnia infection was associated with reduced leaf-specific hydraulic conductivity and sapwood depth, and thus contributed to hydraulic impairment, especially in defoliated pines. Infection was also associated with virtually depleted root starch reserves during and after drought in defoliated pines. Moreover, defoliated and infected trees tended to show lower basal area increment. Overall, our results show the intertwined nature of physiological mechanisms leading to drought-induced mortality and the inherent difficulty of isolating their contribution under field conditions. PMID- 25724950 TI - Speciation of uranium in compartments of living cells. AB - Depleted uranium used as ammunition corrodes in the environment forming mineral phases and then dissolved uranium species like uranium carbonates (Schimmack et al., in Radiat Environ Biophys 46:221-227, 2007) and hydroxides. These hydroxide species were contacted with plant cells (canola). After 24 h contact time the cells were fractionated and the uranium speciation in the fraction was determined by time resolved laser-induced fluorescence spectroscopy at room temperature as well at 150 K. It could be shown that the uranium speciation in the fractions is different to that in the nutrient solution. Comparison of the emission bands with literature data allows assignment of the uranium binding forms. PMID- 25724951 TI - Lessons from bloodless worms: heme homeostasis in C. elegans. AB - Heme is an essential cofactor for proteins involved in diverse biological processes such as oxygen transport, electron transport, and microRNA processing. Free heme is hydrophobic and cytotoxic, implying that specific trafficking pathways must exist for the delivery of heme to target hemoproteins which reside in various subcellular locales. Although heme biosynthesis and catabolism have been well characterized, the pathways for trafficking heme within and between cells remain poorly understood. Caenorhabditis elegans serves as a unique animal model for uncovering these pathways because, unlike vertebrates, the worm lacks enzymes to synthesize heme and therefore is crucially dependent on dietary heme for sustenance. Using C. elegans as a genetic animal model, several novel heme trafficking molecules have been identified. Importantly, these proteins have corresponding homologs in vertebrates underscoring the power of using C. elegans, a bloodless worm, in elucidating pathways in heme homeostasis and hematology in humans. Since iron deficiency and anemia are often exacerbated by parasites such as helminths and protozoa which also rely on host heme for survival, C. elegans will be an ideal model to identify anti-parasitic drugs that target heme transport pathways unique to the parasite. PMID- 25724952 TI - pH influences the importance of niche-related and neutral processes in lacustrine bacterioplankton assembly. AB - pH is an important factor that shapes the structure of bacterial communities. However, we have very limited information about the patterns and processes by which overall bacterioplankton communities assemble across wide pH gradients in natural freshwater lakes. Here, we used pyrosequencing to analyze the bacterioplankton communities in 25 discrete freshwater lakes in Denmark with pH levels ranging from 3.8 to 8.8. We found that pH was the key factor impacting lacustrine bacterioplankton community assembly. More acidic lakes imposed stronger environmental filtering, which decreased the richness and evenness of bacterioplankton operational taxonomic units (OTUs) and largely shifted community composition. Although environmental filtering was determined to be the most important determinant of bacterioplankton community assembly, the importance of neutral assembly processes must also be considered, notably in acidic lakes, where the species (OTU) diversity was low. We observed that the strong effect of environmental filtering in more acidic lakes was weakened by the enhanced relative importance of neutral community assembly, and bacterioplankton communities tended to be less phylogenetically clustered in more acidic lakes. In summary, we propose that pH is a major environmental determinant in freshwater lakes, regulating the relative importance and interplay between niche-related and neutral processes and shaping the patterns of freshwater lake bacterioplankton biodiversity. PMID- 25724953 TI - Pseudomonas fluorescens pirates both ferrioxamine and ferricoelichelin siderophores from Streptomyces ambofaciens. AB - Iron is essential in many biological processes. However, its bioavailability is reduced in aerobic environments, such as soil. To overcome this limitation, microorganisms have developed different strategies, such as iron chelation by siderophores. Some bacteria have even gained the ability to detect and utilize xenosiderophores, i.e., siderophores produced by other organisms. We illustrate an example of such an interaction between two soil bacteria, Pseudomonas fluorescens strain BBc6R8 and Streptomyces ambofaciens ATCC 23877, which produce the siderophores pyoverdine and enantiopyochelin and the siderophores desferrioxamines B and E and coelichelin, respectively. During pairwise cultures on iron-limiting agar medium, no induction of siderophore synthesis by P. fluorescens BBc6R8 was observed in the presence of S. ambofaciens ATCC 23877. Cocultures with a Streptomyces mutant strain that produced either coelichelin or desferrioxamines, as well as culture in a medium supplemented with desferrioxamine B, resulted in the absence of pyoverdine production; however, culture with a double mutant deficient in desferrioxamines and coelichelin production did not. This strongly suggests that P. fluorescens BBbc6R8 utilizes the ferrioxamines and ferricoelichelin produced by S. ambofaciens as xenosiderophores and therefore no longer activates the production of its own siderophores. A screening of a library of P. fluorescens BBc6R8 mutants highlighted the involvement of the TonB-dependent receptor FoxA in this process: the expression of foxA and genes involved in the regulation of its biosynthesis was induced in the presence of S. ambofaciens. In a competitive environment, such as soil, siderophore piracy could well be one of the driving forces that determine the outcome of microbial competition. PMID- 25724954 TI - Extended-spectrum-beta-lactamase-producing Enterobacteriaceae isolated from vegetables imported from the Dominican Republic, India, Thailand, and Vietnam. AB - To examine to what extent fresh vegetables imported into Switzerland represent carriers of extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae, 169 samples of different types of fresh vegetables imported into Switzerland from the Dominican Republic, India, Thailand, and Vietnam were analyzed. Overall, 25.4% of the vegetable samples yielded one or more ESBL-producing Enterobacteriaceae, 78.3% of which were multidrug resistant. Sixty isolates were obtained: Escherichia coli, 26; Klebsiella pneumoniae, 26; Enterobacter cloacae, 6; Enterobacter aerogenes, 1; and Cronobacter sakazakii, 1. We found 29 isolates producing CTX-M-15, 8 producing CTX-M-14, 7 producing CTX-M-55, 3 producing CTX-M 65, 1 each producing CTX-M-1, CTX-M-3, CTX-M-27, and CTX-M-63, 5 producing SHV-2, 3 producing SHV-12, and 1 producing SHV-2a. Four of the E. coli isolates belonged to epidemiologically important clones: CTX-M-15-producing B2:ST131 (1 isolate), D:ST405 (1 isolate), and D:ST38 (2 isolates). One of the D:ST38 isolates belonged to the extraintestinal enteroaggregative E. coli (EAEC) D:ST38 lineage. Two of the K. pneumoniae isolates belonged to the epidemic clones sequence type 15 (ST15) and ST147. The occurrence of antibiotic-resistant pathogenic and commensal Enterobacteriaceae in imported agricultural foodstuffs constitutes a source of ESBL genes and a concern for food safety. PMID- 25724955 TI - Sialic acid-mediated gene expression in Streptococcus pneumoniae and role of NanR as a transcriptional activator of the nan gene cluster. AB - In this study, we investigated the transcriptomic response of Streptococcus pneumoniae D39 to sialic acid (N-acetylneuraminic acid [Neu5Ac]). Transcriptome comparison of wild-type D39 grown in M17 medium with and without sialic acid revealed the elevated expression of various genes and operons, including the nan gene cluster (nan operon I and nanA gene). Our microarray analysis and promoter lacZ fusion studies showed that the transcriptional regulator NanR acts as a transcriptional activator of nan operon I and the nanA gene in the presence of sialic acid. The putative regulatory site of NanR in the promoter region of nan operon I is predicted and confirmed by promoter truncation experiments. Furthermore, the role of CcpA in the regulation of the nan gene cluster is demonstrated through microarray analysis and promoter-lacZ fusion studies, suggesting that in the presence of sialic acid and glucose, CcpA represses the expression of nan operon I while the expression of the nanA gene is CcpA independent. PMID- 25724956 TI - Constitutive cylindrospermopsin pool size in Cylindrospermopsis raciborskii under different light and CO2 partial pressure conditions. AB - Cylindrospermopsin (CYN) and 7-deoxy-cylindrospermopsin (dCYN) are potent hepatotoxic alkaloids produced by numerous species of cyanobacteria, including the freshwater Cylindrospermopsis raciborskii. C. raciborskii is an invasive cyanobacterium, and the study of how environmental parameters drive CYN production has received significant interest from water managers and health authorities. Light and CO2 affect cell growth and physiology in photoautotrophs, and these are potential regulators of cyanotoxin biosynthesis. In this study, we investigated how light and CO2 affect CYN and dCYN pool size as well as the expression of the key genes, cyrA and cyrK, involved in CYN biosynthesis in a toxic C. raciborskii strain. For cells growing at different light intensities (10 and 100 MUmol photons m(-2) s(-1)), we observed that the rate of CYN pool size production (MUCYN) was coupled to the cell division rate (MUc) during batch culture. This indicated that CYN pool size under our experimental conditions is constant and cell quotas of CYN (QCYN) and dCYN (QdCYN) are fixed. Moreover, a lack of correlation between expression of cyrA and total CYN cell quotas (QCYNs) suggests that the CYN biosynthesis is regulated posttranscriptionally. Under elevated CO2 (1,300 ppm), we observed minor effects on QCYN and no effects on expression of cyrA and cyrK. We conclude that the CYN pool size is constitutive and not affected by light and CO2 conditions. Thus, C. raciborskii bloom toxicity is determined by the absolute abundance of C. raciborskii cells within the water column and the relative abundance of toxic and nontoxic strains. PMID- 25724957 TI - Organic cultivation of Triticum turgidum subsp. durum is reflected in the flour sourdough fermentation-bread axis. AB - Triticum turgidum subsp. durum was grown according to four farming systems: conventional (CONV), organic with cow manure (OMAN) or green manure (OLEG), and without inputs (NOINPUT). Some chemical and technological characteristics differed between CONV and organic flours. As shown by two-dimensional electrophoresis (2-DE) analysis, OMAN and OLEG flours showed the highest number of gliadins, and OMAN flour also had the highest number of high-molecular-mass glutenins. Type I sourdoughs were prepared at the laboratory level through a back slopping procedure, and the bacterial ecology during sourdough preparation was described by 16S rRNA gene pyrosequencing. Before fermentation, the dough made with CONV flour showed the highest bacterial diversity. Flours were variously contaminated by genera belonging to the Proteobacteria, Firmicutes, and Actinobacteria. Mature sourdoughs were completely and stably dominated by lactic acid bacteria. The diversity of Firmicutes was the highest for mature sourdoughs made with organic and, especially, NOINPUT flours. Beta diversity analysis based on the weighted UniFrac distance showed differences between doughs and sourdoughs. Those made with CONV flour were separated from the other with organic flours. Lactic acid bacterium microbiota structure was qualitatively confirmed through the culturing method. As shown by PCR-denaturing gradient gel electrophoresis (DGGE) analysis, yeasts belonging to the genera Saccharomyces, Candida, Kazachstania, and Rhodotorula occurred in all sourdoughs. Levels of bound phenolic acids and phytase and antioxidant activities differed depending on the farming system. Mature sourdoughs were used for bread making. Technological characteristics were superior in the breads made with organic sourdoughs. The farming system is another determinant affecting the sourdough microbiota. The organic cultivation of durum wheat was reflected along the flour-sourdough fermentation-bread axis. PMID- 25724958 TI - Extensive genetic variability linked to IS26 insertions in the fljB promoter region of atypical monophasic variants of Salmonella enterica serovar Typhimurium. AB - Fifty-nine monophasic Salmonella enterica serovar Typhimurium isolates, collected in Belgium during the period from 2008 to 2011, have been serotyped as 4,[5]:i:- and shown to harbor an fljB coding sequence. The genetic differences between these strains and phenotypically biphasic Salmonella Typhimurium were analyzed through PCR and DNA sequencing. Genetic alterations in the fljB promoter region affecting expression of the phase 2 flagellin were observed in 53 isolates. Other genetic events in the invertible region carrying the fljB promoter were observed in 2 isolates. For the remaining 4 isolates, no molecular differences with a reference biphasic Salmonella Typhimurium strain could be observed. Next generation sequencing of one representative isolate affected in the fljB promoter region revealed a 26-kb IS26 composite transposon insertion along with a local genomic rearrangement. Several other IS26 element-mediated alterations of this genomic region were observed. This group of monophasic Salmonella Typhimurium isolates was genetically heterogeneous, as revealed by multilocus variable-number tandem-repeat analysis (MLVA), PCR, and sequencing. Pigs and pork represented a major source of such monophasic isolates in Belgium, as reported in other countries. Three out of 5 isolates of human origin presented genetic profiles identical to those of food isolates, demonstrating the pathogenic potential of the newly characterized variants and potential dissemination along the food chain. This study highlighted the key role played by IS26 insertions in the loss of phase 2 flagellin expression and the subsequent generation of multiple monophasic variant lineages from biphasic Salmonella Typhimurium ancestors. PMID- 25724959 TI - Phylogenetically distinct phylotypes modulate nitrification in a paddy soil. AB - Paddy fields represent a unique ecosystem in which regular flooding occurs, allowing for rice cultivation. However, the taxonomic identity of the microbial functional guilds that catalyze soil nitrification remains poorly understood. In this study, we provide molecular evidence for distinctly different phylotypes of nitrifying communities in a neutral paddy soil using high-throughput pyrosequencing and DNA-based stable isotope probing (SIP). Following urea addition, the levels of soil nitrate increased significantly, accompanied by an increase in the abundance of the bacterial and archaeal amoA gene in microcosms subjected to SIP (SIP microcosms) during a 56-day incubation period. High throughput fingerprints of the total 16S rRNA genes in SIP microcosms indicated that nitrification activity positively correlated with the abundance of Nitrosospira-like ammonia-oxidizing bacteria (AOB), soil group 1.1b-like ammonia oxidizing archaea (AOA), and Nitrospira-like nitrite-oxidizing bacteria (NOB). Pyrosequencing of 13C-labeled DNA further revealed that 13CO2 was assimilated by these functional groups to a much greater extent than by marine group 1.1a associated AOA and Nitrobacter-like NOB. Phylogenetic analysis demonstrated that active AOB communities were closely affiliated with Nitrosospira sp. strain L115 and the Nitrosospira multiformis lineage and that the 13C-labeled AOA were related to phylogenetically distinct groups, including the moderately thermophilic "Candidatus Nitrososphaera gargensis," uncultured fosmid 29i4, and acidophilic "Candidatus Nitrosotalea devanaterra" lineages. These results suggest that a wide variety of microorganisms were involved in soil nitrification, implying physiological diversification of soil nitrifying communities that are constantly exposed to environmental fluctuations in paddy fields. PMID- 25724960 TI - A replicative plasmid vector allows efficient complementation of pathogenic Leptospira strains. AB - Leptospirosis, an emerging zoonotic disease, remains poorly understood because of a lack of genetic manipulation tools available for pathogenic leptospires. Current genetic manipulation techniques include insertion of DNA by random transposon mutagenesis and homologous recombination via suicide vectors. This study describes the construction of a shuttle vector, pMaORI, that replicates within saprophytic, intermediate, and pathogenic leptospires. The shuttle vector was constructed by the insertion of a 2.9-kb DNA segment including the parA, parB, and rep genes into pMAT, a plasmid that cannot replicate in Leptospira spp. and contains a backbone consisting of an aadA cassette, ori R6K, and oriT RK2/RP4. The inserted DNA segment was isolated from a 52-kb region within Leptospira mayottensis strain 200901116 that is not found in the closely related strain L. mayottensis 200901122. Because of the size of this region and the presence of bacteriophage-like proteins, it is possible that this region is a result of a phage-related genomic island. The stability of the pMaORI plasmid within pathogenic strains was tested by passaging cultures 10 times without selection and confirming the presence of pMaORI. Concordantly, we report the use of trans complementation in the pathogen Leptospira interrogans. Transformation of a pMaORI vector carrying a functional copy of the perR gene in a null mutant background restores the expression of PerR and susceptibility to hydrogen peroxide comparable to that of wild-type cells. In conclusion, we demonstrate the replication of a stable plasmid vector in a large panel of Leptospira strains, including pathogens. The shuttle vector described will expand our ability to perform genetic manipulation of Leptospira spp. PMID- 25724961 TI - Metatranscriptomic analysis of diminutive Thiomargarita-like bacteria ("Candidatus Thiopilula" spp.) from abyssal cold seeps of the Barbados Accretionary Prism. AB - Large sulfur-oxidizing bacteria in the family Beggiatoaceae are important players in the global sulfur cycle. This group contains members of the well-known genera Beggiatoa, Thioploca, and Thiomargarita but also recently identified and relatively unknown candidate taxa, including "Candidatus Thiopilula" spp. and "Ca. Thiophysa" spp. We discovered a population of "Ca. Thiopilula" spp. colonizing cold seeps near Barbados at a ~4.7-km water depth. The Barbados population consists of spherical cells that are morphologically similar to Thiomargarita spp., with elemental sulfur inclusions and a central vacuole, but have much smaller cell diameters (5 to 40 MUm). Metatranscriptomic analysis revealed that when exposed to anoxic sulfidic conditions, Barbados "Ca. Thiopilula" organisms expressed genes for the oxidation of elemental sulfur and the reduction of nitrogenous compounds, consistent with their vacuolated morphology and intracellular sulfur storage capability. Metatranscriptomic analysis further revealed that anaerobic methane-oxidizing and sulfate-reducing organisms were active in the sediment, which likely provided reduced sulfur substrates for "Ca. Thiopilula" and other sulfur-oxidizing microorganisms in the community. The novel observations of "Ca. Thiopilula" and associated organisms reported here expand our knowledge of the globally distributed and ecologically successful Beggiatoaceae group and thus offer insight into the composition and ecology of deep cold seep microbial communities. PMID- 25724962 TI - Site-directed mutagenesis of HgcA and HgcB reveals amino acid residues important for mercury methylation. AB - Methylmercury is a potent neurotoxin that is produced by anaerobic microorganisms from inorganic mercury by a recently discovered pathway. A two-gene cluster, consisting of hgcA and hgcB, encodes two of the proteins essential for this activity. hgcA encodes a corrinoid protein with a strictly conserved cysteine proposed to be the ligand for cobalt in the corrinoid cofactor, whereas hgcB encodes a ferredoxin-like protein thought to be an electron donor to HgcA. Deletion of either gene eliminates mercury methylation by the methylator Desulfovibrio desulfuricans ND132. Here, site-directed mutants of HgcA and HgcB were constructed to determine amino acid residues essential for mercury methylation. Mutations of the strictly conserved residue Cys93 in HgcA, the proposed ligand for the corrinoid cobalt, to Ala or Thr completely abolished the methylation capacity, but a His substitution produced measurable methylmercury. Mutations of conserved amino acids near Cys93 had various impacts on the methylation capacity but showed that the structure of the putative "cap helix" region harboring Cys93 is crucial for methylation function. In the ferredoxin like protein HgcB, only one of two conserved cysteines found at the C terminus was necessary for methylation, but either cysteine sufficed. An additional, strictly conserved cysteine, Cys73, was also determined to be essential for methylation. This study supports the previously predicted importance of Cys93 in HgcA for methylation of mercury and reveals additional residues in HgcA and HgcB that facilitate the production of this neurotoxin. PMID- 25724964 TI - Development of the honey bee gut microbiome throughout the queen-rearing process. AB - The European honey bee (Apis mellifera) is used extensively to produce hive products and for crop pollination, but pervasive concerns about colony health and population decline have sparked an interest in the microbial communities that are associated with these important insects. Currently, only the microbiome of workers has been characterized, while little to nothing is known about the bacterial communities that are associated with queens, even though their health and proper function are central to colony productivity. Here, we provide a large scale analysis of the gut microbiome of honey bee queens during their developmental trajectory and through the multiple colonies that host them as part of modern queen-rearing practices. We found that queen microbiomes underwent a dramatic shift in size and composition as they aged and encountered different worker populations and colony environments. Queen microbiomes were dominated by enteric bacteria in early life but were comprised primarily of alphaproteobacteria at maturity. Furthermore, queen gut microbiomes did not reflect those of the workers who tended them and, indeed, they lacked many of the bacteria that are considered vital to workers. While worker gut microbiotas were consistent across the unrelated colony populations sampled, the microbiotas of the related queens were highly variable. Bacterial communities in mature queen guts were similar in size to those of mature workers and were characterized by dominant and specific alphaproteobacterial strains known to be associated with worker hypopharyngeal glands. Our results suggest a model in which queen guts are colonized by bacteria from workers' glands, in contrast to routes of maternal inoculation for other animal microbiomes. PMID- 25724963 TI - Red soils harbor diverse culturable actinomycetes that are promising sources of novel secondary metabolites. AB - Red soils, which are widely distributed in tropical and subtropical regions of southern China, are characterized by low organic carbon, high content of iron oxides, and acidity and, hence, are likely to be ideal habitats for acidophilic actinomycetes. However, the diversity and biosynthetic potential of actinomycetes in such habitats are underexplored. Here, a total of 600 actinomycete strains were isolated from red soils collected in Jiangxi Province in southeast China. 16S rRNA gene sequence analysis revealed a high diversity of the isolates, which were distributed into 26 genera, 10 families, and 7 orders within the class Actinobacteria; these taxa contained at least 49 phylotypes that are likely to represent new species within 15 genera. The isolates showed good physiological potentials for biosynthesis and biocontrol. Chemical screening of 107 semirandomly selected isolates spanning 20 genera revealed the presence of at least 193 secondary metabolites from 52 isolates, of which 125 compounds from 39 isolates of 12 genera were putatively novel. Macrolides, polyethers, diketopiperazines, and siderophores accounted for most of the known compounds. The structures of six novel compounds were elucidated, two of which had a unique skeleton and represented characteristic secondary metabolites of a putative novel Streptomyces phylotype. These results demonstrate that red soils are rich reservoirs for diverse culturable actinomycetes, notably members of the families Streptomycetaceae, Pseudonocardiaceae, and Streptosporangiaceae, with the capacity to synthesize novel bioactive compounds. PMID- 25724965 TI - Mono- and dialkyl glycerol ether lipids in anaerobic bacteria: biosynthetic insights from the mesophilic sulfate reducer Desulfatibacillum alkenivorans PF2803T. AB - Bacterial glycerol ether lipids (alkylglycerols) have received increasing attention during the last decades, notably due to their potential role in cell resistance or adaptation to adverse environmental conditions. Major uncertainties remain, however, regarding the origin, biosynthesis, and modes of formation of these uncommon bacterial lipids. We report here the preponderance of monoalkyl- and dialkylglycerols (1-O-alkyl-, 2-O-alkyl-, and 1,2-O-dialkylglycerols) among the hydrolyzed lipids of the marine mesophilic sulfate-reducing proteobacterium Desulfatibacillum alkenivorans PF2803T grown on n-alkenes (pentadec-1-ene or hexadec-1-ene) as the sole carbon and energy source. Alkylglycerols account for one-third to two-thirds of the total cellular lipids (alkylglycerols plus acylglycerols), depending on the growth substrate, with dialkylglycerols contributing to one-fifth to two-fifths of the total ether lipids. The carbon chain distribution of the lipids of D. alkenivorans also depends on that of the substrate, but the chain length and methyl-branching patterns of fatty acids and monoalkyl- and dialkylglycerols are systematically congruent, supporting the idea of a biosynthetic link between the three classes of compounds. Vinyl ethers (1 alken-1'-yl-glycerols, known as plasmalogens) are not detected among the lipids of strain PF2803T. Cultures grown on different (per)deuterated n-alkene, n alkanol, and n-fatty acid substrates further demonstrate that saturated alkylglycerols are not formed via the reduction of hypothetic alken-1'-yl intermediates. Our results support an unprecedented biosynthetic pathway to monoalkyl/monoacyl- and dialkylglycerols in anaerobic bacteria and suggest that n alkyl compounds present in the environment can serve as the substrates for supplying the building blocks of ether phospholipids of heterotrophic bacteria. PMID- 25724966 TI - A novel triplex quantitative PCR strategy for quantification of toxigenic and nontoxigenic Vibrio cholerae in aquatic environments. AB - Vibrio cholerae is a severe human pathogen and a frequent member of aquatic ecosystems. Quantification of V. cholerae in environmental water samples is therefore fundamental for ecological studies and health risk assessment. Beside time-consuming cultivation techniques, quantitative PCR (qPCR) has the potential to provide reliable quantitative data and offers the opportunity to quantify multiple targets simultaneously. A novel triplex qPCR strategy was developed in order to simultaneously quantify toxigenic and nontoxigenic V. cholerae in environmental water samples. To obtain quality-controlled PCR results, an internal amplification control was included. The qPCR assay was specific, highly sensitive, and quantitative across the tested 5-log dynamic range down to a method detection limit of 5 copies per reaction. Repeatability and reproducibility were high for all three tested target genes. For environmental application, global DNA recovery (GR) rates were assessed for drinking water, river water, and water from different lakes. GR rates ranged from 1.6% to 76.4% and were dependent on the environmental background. Uncorrected and GR-corrected V. cholerae abundances were determined in two lakes with extremely high turbidity. Uncorrected abundances ranged from 4.6*10(2) to 2.3*10(4) cell equivalents liter(-1), whereas GR-corrected abundances ranged from 4.7*10(3) to 1.6*10(6) cell equivalents liter(-1). GR-corrected qPCR results were in good agreement with an independent cell-based direct detection method but were up to 1.6 log higher than cultivation-based abundances. We recommend the newly developed triplex qPCR strategy as a powerful tool to simultaneously quantify toxigenic and nontoxigenic V. cholerae in various aquatic environments for ecological studies as well as for risk assessment programs. PMID- 25724967 TI - Fistula-tract Laser Closure (FiLaCTM): long-term results and new operative strategies. AB - BACKGROUND: Fistula-tract Laser Closure (FiLaCTM) is a sphincter-saving technique for the treatment of anal fistulas that has been shown to be successful in the short and middle term. However, the long-term success rate is unknown. This study aimed to report long-term results in performing FiLaCTM. METHODS: This study was performed as a retrospective observational study. Forty-five patients who underwent FiLaCTM between July 2010 and May 2014 were evaluated. In all cases, FiLaCTM was performed with a diode laser at a wavelength of 1470 nm by means of a radial fiber. Patients and fistula characteristics, previous treatments, healing rates, failures and postoperative incontinence were reviewed. RESULTS: Median follow-up time was 30 months (range 6-46 months). Thirty-five patients (78%) had a history of previous surgery for their fistulas. Primary healing was observed in 32 patients (71.1%), and the median healing time was 5 weeks (range 3-8 weeks). Eleven of the 13 failures (85%) were early failures (persistent symptoms). No patient reported postoperative incontinence. The best healing rate was observed in patients who had been previously treated with loose seton (19/24, 79%). CONCLUSIONS: Long-term follow-up after FiLaCTM seems to confirm the favorable short-term success rates reported for this procedure. Although sealing of chronic anal fistulas may be obtained with FiLaCTM in a single treatment, our current strategy consists of placing a loose seton into the fistula tract a few weeks prior to laser treatment. Seton treatment facilitates the following laser procedure and seems to have favorable effects on healing. PMID- 25724968 TI - Invited comment on van der Steeg et al.: European consensus meeting of ARM-Net members concerning diagnosis and early management of newborns with anorectal malformations. PMID- 25724969 TI - Race and referral to diabetes education in primary care patients with prediabetes and diabetes. AB - PURPOSE: The purpose of the study was to determine whether there are any race related disparities in the prevalence of provisions for diabetes education in primary care clinics for patients with diabetes and prediabetes. METHODS: A retrospective cross-sectional study of 3967 patients aged 14 to >89 years with prediabetes and diabetes. Medical record data from patient encounters within primary care clinics at a large academic medical health system between July 1, 2008, and July 31, 2013, were used to determine rates of referral for diabetes education by race. Multivariate logistic regression models were used to assess associations between race and referral to diabetes education. Separate regression models were computed for patients who were prediabetic and diabetic. Adjusted models included age, sex, A1C, health care utilization, smoking, and diagnosis for depression, hyperlipidemia, hypertension, vascular disease, and obesity. RESULTS: Compared to that of white patients, a significantly higher prevalence of African American patients with prediabetes were referred to diabetes education, and this association was also observed in patients with diabetes. In fully adjusted models, white patients with prediabetes were significantly less likely to be referred. CONCLUSIONS: Being African American independently increased the likelihood of referral for diabetes education in patients with prediabetes and patients with diabetes. After adjusting for patient comorbidities and risk factors, this association remained significant for patients with prediabetes. Additional research is needed to determine if provider beliefs and attitudes regarding race and diabetes education account for this association. PMID- 25724970 TI - Securidaca longipedunculata Fresen (Polygalaceae): a review of its ethnomedicinal uses, phytochemistry, pharmacological properties and toxicology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Securidaca longipedunculata Fresen (Polygalaceae) is a multi-purpose plant with a long history of use in African traditional medicine to treat various sexually transmitted infections, hernias, coughs, fever, ascariasis, constipation, headaches, rheumatism, stomach ache, malaria, tuberculosis, pain, epilepsy, pneumonia, skin infections, and it is also used as an aphrodisiac for men. The current paper provides an overview of the present phytochemistry, toxicology, ethnomedicinal uses and pharmacological properties of S. longipedunculata. MATERIALS AND METHODS: The information reported in this paper was collected from a literature search using various computerised databases including ScienceDirect, Scopus, Scielo, PubMed and Google Scholar. The extra information was sourced from various academic dissertations, theses and botanical books. RESULTS: Phytochemically, extracts from various parts of S. longipedunculata, especially the root bark, contain numerous valuable compounds including xanthones, some benzyl benzoates and triterpene saponins amongst others. Toxicity studies, both in vivo and in vitro, revealed that extracts are only toxic at relatively high concentrations. Furthermore, extracts have antimicrobial, antioxidant, antiparasitic, anti-diabetic, anti-inflammatory, antimalarial, insecticidal, pesticidal, and anticonvulsant properties. CONCLUSIONS: S. longipedunculata is an important plant species with potential benefits in the treatment of transmissible and infectious diseases, including malaria, tuberculosis, and those caused by community acquired microorganisms. Although extracts from this species generally have little toxicity at low concentrations, further efforts are required to investigate the potential toxicity of S. longipedunculata. The antimicrobial properties of extracts and purified compounds against microorganisms causing sexually transmitted infections are also deserving of further research. Moreover, the pharmacokinetic properties of extracts and compounds of the species need to be explored as there is insufficient data available on these aspects. PMID- 25724971 TI - Morphological and functional maturation of Leydig cells: from rodent models to primates. AB - BACKGROUND: Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed 'mini-puberty' precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic-pituitary-testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates. METHODS: Pubmed, Scopus, Web of Science and Google Scholar databases were searched between December 2012 and October 2014. Studies published in languages other than English or German were excluded, as were data in abstract form only. Studies available on primates were primarily examined and compared with available data from specific animal models with emphasis on rodents. RESULTS: Expression of different marker genes in rodents provides evidence that at least two distinct progenitor lineages give rise to the fetal LC (FLC) population, one arising from the coelomic epithelium and the other from specialized vascular-associated cells along the gonad-mesonephros border. There is general agreement that the formation and functioning of the FLC population in rodents is gonadotrophin-responsive but not gonadotrophin-dependent. In contrast, although there is in primates some controversy on the role of gonadotrophins in the formation of the FLC population, there is consensus about the essential role of gonadotrophins in testosterone production. Like the FLC population, adult Leydig cells (ALC) in rodents arise from stem cells, which have their origin in the fetal testis. In contrast, in primates the ALC population is thought to originate from FLC, which undergo several cycles of regression and redifferentiation before giving rise to the mature ALC population, as well as from differentiation of stem cells/precursor cells. Despite this difference in origin, both in primates and rodents the formation of the mature and functionally active ALC population is critically dependent on the pituitary gonadotrophin, LH. From studies on rodents considerable knowledge has emerged on factors that are involved besides LH in the regulation of this developmental process. Whether the same factors also play a role in the development of the mature primate LC population awaits further investigation. CONCLUSION: Distinct populations of LC develop along the life span of males, including fetal, neonatal (primates) and ALC. Despite differences in the LC lineages of rodents and primates, the end product is a mature population of LC with the main function to provide androgens necessary for the maintenance of spermatogenesis and extra-gonadal androgen actions. PMID- 25724972 TI - Rho4 interaction with exocyst and septins regulates cell separation in fission yeast. AB - Rho GTPases are small proteins present in all eukaryotic cells, from yeast to mammals, with a function in actin organization and morphogenetic processes. Schizosaccharomyces pombe Rho4 is not essential but it displays a role during cell separation at high temperature. In fact, Rho4 is involved in the secretion of the hydrolytic enzymes that are required for cell septum degradation during this process. In rho4Delta cells, vesicles accumulate in the septum area and the glucanases Eng1 and Agn1 are not secreted to the culture medium. The localization of Eng1 and Agn1 depends on the exocyst and the septins. The exocyst is a conserved multiprotein complex important for the targeting and fusion of Golgi derived vesicles with the plasma membrane. Septins are a family of GTP-binding proteins conserved in eukaryotes that function during cytokinesis. Here we show that Rho4 is required for the proper localization of the exocyst and septins at high temperature. Moreover, pull-down experiments demonstrate that Rho4 can interact with exocyst subunits, such as Sec8 and Exo70, and septin proteins, such as Spn3. We observe that Sec8 preferentially binds to activated GTP-Rho4, suggesting that Sec8 could be an effector of this GTPase. We propose that the interaction of Rho4 with the exocyst and septins confers a precise regulation for the secretion of glucanases at the appropriate place and time during the cell cycle. PMID- 25724973 TI - Conserved expression of truncated telethonin in a patient with limb-girdle muscular dystrophy 2G. AB - Limb-girdle muscular dystrophy 2G is caused by mutations in the TCAP gene that encodes for telethonin. Here we describe a 49 year-old male patient of Indian descent presenting a classical LGMD phenotype. He had normal motor milestones but became noticeably slower in his early teens and was wheelchair bound by age 44. The muscle biopsy showed myopathic features and absence of labeling with an antibody to the C-terminal portion of telethonin. Sequence analysis of the TCAP gene revealed a novel homozygous mutation in exon 2, predicted to generate a truncated protein of 81 amino acids. Interestingly, an antibody for the full length protein showed labeling on sections and a single band of ~10 kDa on Western blot. The truncated protein co-localized with filamin C at the Z-line. Our findings indicate that mutant telethonin can be incorporated into the sarcomere and that other LGMD2G patients with retention of telethonin expression may exist. PMID- 25724974 TI - Adolescents' Communication with Parents, Other Adult Family Members and Teachers on Sexuality: Effects of School-Based Interventions in South Africa and Tanzania. AB - Cluster-randomized controlled trials were carried out to examine effects on sexual practices of school-based interventions among adolescents in three sites in sub-Saharan Africa. In this publication, effects on communication about sexuality with significant adults (including parents) and such communication as a mediator of other outcomes were examined. Belonging to the intervention group was significantly associated with fewer reported sexual debuts in Dar es Salaam only (OR 0.648). Effects on communication with adults about sexuality issues were stronger for Dar es Salaam than for the other sites. In Dar, increase in communication with adults proved to partially mediate associations between intervention and a number of social cognition outcomes. The hypothesized mediational effect of communication on sexual debut was not confirmed. Promoting intergenerational communication on sexuality issues is associated with several positive outcomes and therefore important. Future research should search for mediating factors influencing behavior beyond those examined in the present study. PMID- 25724975 TI - Improving cell growth and lipid accumulation in green microalgae Chlorella sp. via UV irradiation. AB - Microalgae with high biomass and high lipid content are the ideal feedstock for biodiesel production. To obtain such microalgae, ultraviolet (UV) irradiation was applied to Chlorella sp. to induce mutagenesis. The growth characteristics, total nitrogen (TN), and biochemical compositions of the control and UV mutation strains were analyzed. Compared to the control strain, the biomass for the UV mutation strain was 7.6 % higher and it presented a higher growth rate. The lipid content of the UV mutation strain showed different levels of increase and reached the maximum value of 28.1 % on day 15. Furthermore, the lipid productivity of the UV mutation strain showed a desired increase. The nitrogen consumption and Acetyl CoA carboxylase (ACC) activity contributed to the lipid production by UV. All these results indicate that UV mutagenesis is an efficient method to improve probability for using Chlorella sp. as the potential raw material for biodiesel production. PMID- 25724976 TI - Enhanced biological straw saccharification through coculturing of lignocellulose degrading microorganisms. AB - Lignocellulosic waste (LCW) is an abundant, low-cost, and inedible substrate for the induction of lignocellulolytic enzymes for cellulosic bioethanol production using an efficient, environmentally friendly, and economical biological approach. In this study, 30 different lignocellulose-degrading bacterial and 18 fungal isolates were quantitatively screened individually for the saccharification of four different ball-milled straw substrates: wheat, rice, sugarcane, and pea straw. Rice and sugarcane straws which had similar Fourier transform-infrared spectroscopy profiles were more degradable, and resulted in more hydrolytic enzyme production than wheat and pea straws. Crude enzyme produced on native straws performed better than those on artificial substrates (such as cellulose and xylan). Four fungal and five bacterial isolates were selected (based on their high strawase activities) for constructing dual and triple microbial combinations to investigate microbial synergistic effects on saccharification. Combinations such as FUNG16-FUNG17 (Neosartorya fischeri-Myceliophthora thermophila) and RMIT10-RMIT11 (Aeromonas hydrophila-Pseudomonas poae) enhanced saccharification (3- and 6.6-folds, respectively) compared with their monocultures indicating the beneficial effects of synergism between those isolates. Dual isolate combinations were more efficient at straw saccharification than triple combinations in both bacterial and fungal assays. Overall, co-culturing can result in significant increases in saccharification which may offer significant commercial potential for the use of microbial consortia. PMID- 25724977 TI - Multistep synthesis of UDP-glucose using tailored, permeabilized cells of E. coli. AB - We constructed and applied a recombinant, permeabilized Escherichia coli strain for the multistep synthesis of UDP-glucose. Sucrose phosphorylase (E.C. 2.4.1.7) of Leuconostoc mesenteroides was over expressed and the pgm gene encoding for phosphoglucomutase (E.C. 5.4.2.2) was deleted in E. coli to yield the E. coli JW 0675-1 SP strain. The cells were permeabilized with the detergent Triton X-100 at 0.05 % v/v. The synthesis of UDP-glucose with permeabilized cells was then optimized with regard to pH, cell density during the synthesis and growth phase during cell harvest, metal cofactor, other media components, and temperature. In one configuration sucrose, phosphate, UMP, and ATP were used as substrates. At pH 7.8, 27 mg/ml cell dry weight, cell harvest during the early stationary phase of growth and Mn(2+) as cofactor a yield of 37 % with respect to UMP was achieved at 33 degrees C. In a second step, ATP was regenerated by feeding glucose and using only catalytic amounts of ATP and NAD(+). A UDP-glucose yield of 60 % with respect to UMP was obtained using this setup. With the same setup but without addition of external ATP, the yield was 54%. PMID- 25724978 TI - Numerical modeling of drug delivery in a dynamic solid tumor microvasculature. AB - The complicated capillary network induced by angiogenesis is one of the main reasons of unsuccessful cancer therapy. A multi-scale mathematical method which simulates drug transport to a solid tumor is used in this study to investigate how capillary network structure affects drug delivery. The mathematical method involves processes such as blood flow through vessels, solute and fluid diffusion, convective transport in extracellular matrix, and extravasation from blood vessels. The effect of heterogeneous dynamic network on interstitial fluid flow and drug delivery is investigated by this multi-scale method. The sprouting angiogenesis model is used for generating capillary network and then fluid flow governing equations are implemented to calculate blood flow through the tumor induced capillary network and fluid flow in normal and tumor tissues. Finally, convection-diffusion equation is used to simulate drug delivery. Three approaches are used to simulate drug transport based on the developed mathematical method: without a vascular network, using a static vascular network, and a dynamic vascular network. The avascular approach predicts more uniform and higher drug concentration than vascular approaches since the simplified assumptions are implemented in this method. The dynamic network which uses more realistic assumptions predicts more irregular blood vessels, high interstitial pressure, and more heterogeneity in drug distribution than other two approaches. PMID- 25724979 TI - Microvascular blood flow resistance: Role of red blood cell migration and dispersion. AB - Microvascular blood flow resistance has a strong impact on cardiovascular function and tissue perfusion. The flow resistance in microcirculation is governed by flow behavior of blood through a complex network of vessels, where the distribution of red blood cells across vessel cross-sections may be significantly distorted at vessel bifurcations and junctions. In this paper, the development of blood flow and its resistance starting from a dispersed configuration of red blood cells is investigated in simulations for different hematocrit levels, flow rates, vessel diameters, and aggregation interactions between red blood cells. Initially dispersed red blood cells migrate toward the vessel center leading to the formation of a cell-free layer near the wall and to a decrease of the flow resistance. The development of cell-free layer appears to be nearly universal when scaled with a characteristic shear rate of the flow. The universality allows an estimation of the length of a vessel required for full flow development, lc ? 25D, for vessel diameters in the range 10 MUm < D < 100 MUm. Thus, the potential effect of red blood cell dispersion at vessel bifurcations and junctions on the flow resistance may be significant in vessels which are shorter or comparable to the length lc. Aggregation interactions between red blood cells generally lead to a reduction of blood flow resistance. The simulations are performed using the same viscosity for both external and internal fluids and the RBC membrane viscosity is not considered; however, we discuss how the viscosity contrast may affect the results. Finally, we develop a simple theoretical model which is able to describe the converged cell-free-layer thickness at steady-state flow with respect to flow rate. The model is based on the balance between a lift force on red blood cells due to cell-wall hydrodynamic interactions and shear-induced effective pressure due to cell-cell interactions in flow. We expect that these results can also be used to better understand the flow behavior of other suspensions of deformable particles such as vesicles, capsules, and cells. PMID- 25724980 TI - Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) drives and synchronizes daily rhythms at the cellular level via transcriptional-translational feedback loops comprising clock genes such as Bmal1 and Period (Per). Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, phosphorylates at least 5 core clock proteins and shows diurnal variation in phosphorylation state (inactivation) of the GSK3beta isoform. Whether phosphorylation of the other primary isoform (GSK3alpha) varies across the subjective day-night cycle is unknown. The purpose of this study was to determine if the endogenous rhythm of GSK3 (alpha and beta) phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. Significant circadian rhythmicity of phosphorylated GSK3 (alpha and beta) was observed in the SCN from wild-type mice housed in constant darkness for 2 weeks. Importantly, chronic activation of both GSK3 isoforms impaired rhythmicity of the GSK3 target BMAL1. Furthermore, chronic pharmacological inhibition of GSK3 with 20 uM CHIR-99021 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. These results support the model that GSK3 activity status is regulated by the circadian clock and that GSK3 feeds back to regulate the molecular clock amplitude in the SCN. PMID- 25724981 TI - A review of the international Burn Injury Database (iBID) for England and Wales: descriptive analysis of burn injuries 2003-2011. AB - OBJECTIVE: To describe, for the first time, distribution (by geography, age, sex) and time trends in burn injury in England and Wales over the period that the international Burn Injury Database (iBID) has been in place. SETTING: Data from the iBID for the years 2003-2011 were used for a retrospective descriptive observational study of specialised services workload and admissions in England and Wales. PARTICIPANTS: All patients who have been visited or admitted to the burn injury specialised health service of England and Wales during the time period 2003-2011. Data cleaning was performed omitting patients with incomplete records (missingness never exceeded 5%). OUTCOME MEASURES: Workload, admissions, mortality, length of stay (LOS), geographical distribution, sex differences, age differences, total burn surface area, mechanism of Injury. RESULTS: During 2003 2011, 81,181 patients attended the specialised burn service for assessment and admission in England and Wales. Of these, 57,801 were admitted to the services. Males accounted for 63% of the total workload in specialised burn injury services, and females for 37%. The median (IQR) burn surface area was 1.5% (3.5%). The most frequent reason for burn injury was scald (38%). The median (IQR) age for all the referred workload for both genders was 21 (40). The overall mortality of the admitted patients was 1.51% and the median (IQR) LOS was 1 (5) days. CONCLUSIONS: Mortality from burn injuries in England and Wales is decreasing in line with western world trends. There is an observed increase in admissions to burn services but that could be explained in various ways. These results are vital for service development and planning, as well as the development and monitoring of prevention strategies and for healthcare commissioning. PMID- 25724982 TI - An assessment of driving fitness in patients with visual impairment to understand the elevated risk of motor vehicle accidents. AB - OBJECTIVE: To assess the driving fitness of patients with glaucoma by identifying specific areas and degrees of visual field impairment that threaten safe driving. DESIGN: Case-control study. SETTING, AND PARTICIPANTS: This prospective study included 36 patients with advanced glaucoma, defined as Humphrey field analyzer (HFA; 24-2 SITA standard program) measurements of mean deviation in both eyes of worse than -12 dB, and 36 age-matched and driving exposure time-matched normal subjects. All participants underwent testing in a novel driving simulator (DS) system. Participants were recruited between September 2010 and January 2012. MAIN OUTCOME MEASURES: The number of collisions with simulated hazards and braking response time in 14 DS scenarios was recorded. Monocular HFA 24-2 test results from both eyes were merged to calculate the binocular integrated visual field (IVF). The position of the IVF subfields in which the collision-involved patients had lower sensitivity than the collision-uninvolved patients was compared with the track of the hazard. The cut-off value to predict an elevated risk of collisions was determined, as were its sensitivity and specificity, with the area under the receiver operating characteristic (AUROC) curve. RESULTS: Patients with advanced glaucoma were involved in a significantly higher number of collisions in the DS than the age-matched and driving exposure time-matched normal subjects (119 vs 40, respectively, p<0.0001), especially in four specific DS scenarios. In these four scenarios, IVF sensitivity was significantly lower in the collision involved patients than in the collision-uninvolved patients in subfields on or near the track of the simulated hazard (p<0.05). The subfields with the largest AUROC curve had values ranging from 0.72 to 0.91 and were located in the paracentral visual field just below the horizontal. CONCLUSIONS: Our novel DS system effectively assessed visual impairment, showing that simulators may have future potential in educating patients. PMID- 25724983 TI - Perspectives on enhancing physical activity and diet for health promotion among at-risk urban UK South Asian communities: a qualitative study. AB - OBJECTIVES: To explore perspectives on enhancing physical activity and diet among South Asians in urban deprived communities at high risk of chronic disease and to inform development of culturally appropriate health promotion intervention. DESIGN: Qualitative study using semistructured one-to-one and family group interviews with thematic analysis of data. SETTING: Urban disadvantaged communities in the East Midlands of the UK. PARTICIPANTS: 45 respondents, including 34 people of South Asian origin (16 at-risk individuals, six family groups involving 18 relatives), of mainly Pakistani and Indian origin, including 16 non-English speakers; and 11 health professionals working locally with communities of concern. RESULTS: South Asian participants underlined the challenges of requiring family members across generations to engage in modifying dietary behaviours, and the central role of communal eating of traditional 'Asian' food in their cultural lives. Barriers to increasing physical activity included cost, personal safety and lack of time outside of long working hours and carer commitments. However, increasing walking activity was regarded as feasible by both community and health professional participants. Respondents emphasised using a social approach for potential interventions, undertaking activity with family or friends and with bilingual community peers to facilitate engagement, motivation and support. Spoken content and delivery of interventions was favoured, including personal stories and multilingual audio-visual information; within local informal rather than provider settings, including the home; and aided by pedometers for self-monitoring. CONCLUSIONS: Focusing on physical activity by increasing walking may hold promise as health promotion in this deprived South Asian community context. Further intervention development, with exploration of feasibility and acceptability of the social approach and elements suggested, is merited. PMID- 25724984 TI - Cost-effectiveness analyses of self-harm strategies aimed at reducing the mortality of pesticide self-poisonings in Sri Lanka: a study protocol. AB - INTRODUCTION: An estimated 803,900 people worldwide died as a result of self-harm in 2012. The deliberate ingestion of pesticides has been identified as the method most frequently used to commit fatal self-harm globally. In Sri Lanka, it is estimated that up to 60% of all suicides are committed using this method. The aim of the present study is to assess the cost-effectiveness of an ongoing safe storage intervention currently taking place in a rural Sri Lankan district and to model the cost-effectiveness of implementing the safe storage intervention as well as four potential interventions (legislative, medical management, follow-up contact and mobile phone contact) on a national level. METHODS AND ANALYSIS: Study design for all the strategies is a cost-effectiveness analysis. A governmental perspective is adopted. The time horizon for tracking the associated costs and health outcomes of the safe storage intervention on district level runs over 3 years. The time horizon is extended to 5 years when modelling a full national roll-out of the respective interventions. The discounting of costs and health outcomes are undertaken at the recommended real rate of 3%. Threshold analyses of the modelled strategies are employed to assess the strategies potential for cost-effectiveness, running scenarios with health outcome improvements ranging from 1% to 100%. Sensitivity analyses are also performed. The main outcome measures of the safe storage intervention are incremental cost effectiveness ratios. ETHICS AND DISSEMINATION: Ethical approval was granted for the safe storage project from the University of Peradeniya, Sri Lanka, in March of 2008. An amendment for the present study was granted from Rajarata University of Sri Lanka in November of 2013. Findings will be disseminated to public and private stakeholders in local and national government in Sri Lanka as well as the wider academic audience through peer-reviewed publications and international conferences. TRIAL REGISTRATION NUMBER: The safe storage cluster trial is registered with the Clinical Trials, ref: NCT1146496 (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT1146496). PMID- 25724986 TI - Measuring antimicrobial prescribing quality in Australian hospitals: development and evaluation of a national antimicrobial prescribing survey tool. AB - OBJECTIVES: Antimicrobial stewardship (AMS) programmes have been developed with the intention of reducing inappropriate and unnecessary use of antimicrobials, while improving the quality of patient care and locally helping prevent the development of antimicrobial resistance. An important aspect of AMS programmes is the qualitative assessment of prescribing through antimicrobial prescribing surveys (APS), which are able to provide information about the prescribing behaviour within institutions. Owing to lack of standardization of audit tools and the resources required, qualitative methods for the assessment of antimicrobial use are not often performed. The aim of this study was to design an audit tool that was appropriate for use in all Australian hospitals, suited to local user requirements and included an assessment of the overall appropriateness of the prescription. METHODS: In November 2011, a pilot APS was conducted across 32 hospitals to assess the usability and generalizability of a newly designed audit tool. Following participant feedback, this tool was revised to reflect the requirements of the respondents. A second pilot study was then performed in November 2012 across 85 hospitals. RESULTS: These surveys identified several areas that can be targets for quality improvement at a national level, including: documentation of indication; surgical prophylaxis prescribed for >24 h; compliance with prescribing guidelines; and the appropriateness of the prescription. CONCLUSIONS: By involving the end users in the design and evaluation, we have been able to provide a practical and relevant APS tool for quantitative and qualitative data collection in a wide range of Australian hospital settings. PMID- 25724987 TI - Systematic analysis of the role of bacterial Hfq-interacting sRNAs in the response to antibiotics. AB - OBJECTIVES: To systematically analyse the interplay between the expression of Hfq associated small non-coding RNAs (sRNAs) and antibiotic susceptibility in Gram negative bacteria. METHODS: To identify the roles of sRNAs in the antibiotic susceptibility of Escherichia coli and Salmonella species, susceptibility tests, growth analyses and viability assays were performed using E. coli Hfq-associated sRNAs from overexpression libraries. Prediction, susceptibility testing of gene knockouts and expression analysis of target genes under conditions of sRNA overexpression or knockout were performed to identify candidate targets for modulating antibiotic susceptibility. RESULTS: The susceptibilities of E. coli strains overexpressing each of the 26 known Hfq-dependent sRNAs to major classes of antibiotics were determined. Induced expression of 17 sRNAs modulated the susceptibility of E. coli to antibiotics. Among them, four sRNA knockout strains partially or completely reversed susceptibility phenotypes of sRNA overexpression. The phenotype of OxyS, RseX or MicF was not entirely dependent on the presence of Hfq protein, in contrast to the dependency of previously characterized roles. The function of eight of nine sRNAs was found to be conserved in the response to antibiotics in Salmonella. Some MicF- or RyeB mediated cellular target genes and pathways that may be important for the regulation of antibiotic susceptibility were identified. Finally, the overexpression of RyeB potentiated the efficacy of levofloxacin against MDR strains. CONCLUSIONS: Our data indicate that Hfq-associated sRNAs potentially enable bacteria to adapt to antibiotic challenges via multifaceted approaches. Therefore, sRNA-based applications will form a new antibiotic arsenal for combating the rise in antibiotic resistance. PMID- 25724985 TI - Safety and immunogenicity of a modified vaccinia Ankara-based HIV-1 vaccine (MVA B) in HIV-1-infected patients alone or in combination with a drug to reactivate latent HIV-1. AB - OBJECTIVES: The safety, immunogenicity, impact on the latent reservoir and rebound of viral load after therapeutic HIV-1 vaccination with recombinant modified vaccinia Ankara-based (MVA-B) HIV-1 vaccine expressing monomeric gp120 and the fused Gag-Pol-Nef polyprotein of clade B with or without a drug to reactivate latent HIV-1 (disulfiram) were assessed. METHODS: HIV-1-infected patients were randomized to receive three injections of MVA-B (n = 20) or placebo (n = 10). Twelve patients (eight who received vaccine and four who were given placebo) received a fourth dose of MVA-B followed by 3 months of disulfiram. Combined ART (cART) was discontinued 8 weeks after the last dose of MVA-B. Clinical Trials.gov identifier: NCT01571466. RESULTS: MVA-B was safe and well tolerated. A minor, but significant, increase in the T cell responses targeting vaccine inserts of Gag was observed [a median of 290, 403 and 435 spot-forming cells/10(6) PBMCs at baseline, after two vaccinations and after three vaccinations, respectively; P = 0.02 and P = 0.04]. After interruption of cART, a modest delay in the rebound of the plasma viral load in participants receiving vaccine but not disulfiram was observed compared with placebo recipients (P = 0.01). The dynamics of the viral load rebound did not change in patients receiving MVA-B/disulfiram. No changes in the proviral reservoir were observed after disulfiram treatment. CONCLUSIONS: MVA-B vaccination was a safe strategy to increase Gag-specific T cell responses in chronically HIV-1-infected individuals, but it did not have a major impact on the latent reservoir or the rebound of plasma viral load after interruption of cART when given alone or in combination with disulfiram. PMID- 25724988 TI - Modeling the effect of transcriptional noise on switching in gene networks in a genetic bistable switch. AB - Gene regulatory networks in cells allow transitions between gene expression states under the influence of both intrinsic and extrinsic noise. Here we introduce a new theoretical method to study the dynamics of switching in a two state gene expression model with positive feedback by explicitly accounting for the transcriptional noise. Within this theoretical framework, we employ a semi classical path integral technique to calculate the mean switching time starting from either an active or inactive promoter state. Our analytical predictions are in good agreement with Monte Carlo simulations and experimental observations. PMID- 25724989 TI - Investigation of iron-containing products from natural and laboratory cultivated Sphaerotilus-Leptothrix bacteria. AB - Bacterial biomass collected from sheath-forming bacteria of the genera Sphaerotilus and Leptothrix was collected from a high-mountain natural stream water source. The elemental constitution and oxide phases of the products after selective cultivation of the bacteria on two different elective media using neutron activation analysis (NAA), electron microscopy (SEM, TEM), and X-ray diffraction (XRD) were studied. A high enrichment level of iron was revealed by the NAA technique in cultivated isolates as compared to the reference sample from nature. Three types of iron oxide compounds were established after cultivation in Adler's medium: lepidocrocite (gamma-FeOOH), magnetite (Fe3O4), and goethite (alpha-FeOOH). The cultivation in the Isolation medium yielded a single phase, that of goethite, excluding one sample with a distinguishable amount of lepidocrocite. XRD and EM investigations show that the biogenic oxides are nanosized. Our study exemplifies the possibilities of the biotechnology approach for obtaining, under artificial conditions, large quantities of iron-containing by-products that could be of further used in appropriate nano- and biotechnologies. PMID- 25724990 TI - Emotional Health Predicts Changes in Body Mass Index (BMI-z) Among Black and Latino Youth. PMID- 25724991 TI - A 21/2-Year-Old Girl With a Diffuse Erythematous Rash and Fever. PMID- 25724992 TI - Pediatricians Transitioning Practices, Youth With Special Health Care Needs in New York State. AB - OBJECTIVE: To assess current practices of New York State pediatricians as they transition youth with special health care needs to adult-oriented medical care. METHODS: A survey of New York State pediatricians included 6 critical steps from 2002 consensus statement, 11 essential steps adapted from recent literature, and questions targeting age of starting transition and availability of transition policy. RESULTS: Of 181 respondents, only 11% have a transition policy. Most assist patients in transition process; identify an adult provider (92%); and create portable medical summary (57%). Only 3% start planning process at recommended age. No respondents are compliant with all 6 critical steps; subspecialists were more likely to report compliance to more than 4 steps. CONCLUSIONS: Participating pediatricians are making gains, yet effort is needed, to incorporate the essential steps into practice for transitioning youth with special health care needs. Recognition of barriers, use of electronic tools, and clarifying subspecialist's approach, may improve compliance with transition recommendations. PMID- 25724993 TI - Rates of Complications After Newborn Circumcision in a Well-Baby Nursery, Special Care Nursery, and Neonatal Intensive Care Unit. AB - OBJECTIVE/METHOD: To determine rates of complications after newborn circumcision by performing a retrospective chart review of patients circumcised at a well-baby nursery, neonatal intensive care units (NICU), and special care nursery (SCN) from 2007 to 2012. RESULT: A total of 5129 babies (73%) were circumcised at the well-baby nursery and 1909 babies (27%) at the NICU and SCN. Forty-seven patients (0.67%, 95% CI 0.49% to 0.89%) had circumcision-related complications: 5 (0.07%) patients with acute and 42 (0.6%) with late complications. Babies in the NICU/SCN had increased odds of complication (OR 4.00, 95% CI 2.23 to 7.19) compared with those in well-baby nursery. There were increased odds of complications in babies with Caucasian ethnicity (OR 2.60, 95% CI 1.48 to 4.89) compared with African American babies and in babies with private insurance (OR 4.0, 95% CI 2.1 to 7.5) compared with nonprivate insurance. CONCLUSIONS: The rates of complications after newborn circumcisions were low. Babies in the NICU/SCN had increased odds of complication. PMID- 25724994 TI - Maternal Beliefs and Parenting Practices Regarding Their Preschool Child's Television Viewing: An Exploration in a Sample of Low-Income Mexican-Origin Mothers. AB - OBJECTIVE: To explore maternal beliefs about television (TV) viewing and related parenting practices in low-income Mexican-origin mothers of preschoolers. METHODS: Semistructured interviews were conducted with 21 low-income Mexican origin mothers of preschoolers. Interviews were audio recorded and analyzed using a theoretically based thematic analytic approach. RESULTS: Mothers described strong beliefs about the positive and negative impact of TV content. Mothers emphasized the educational value of specific programming. Content restrictions were common. Time restrictions were not clearly defined; however, many mothers preferred short versus long episodes of viewing. Mothers spoke positively about family viewing and the role of TV viewing in enabling mothers to accomplish household tasks. DISCUSSION: These findings have implications for intervening in this population. Interventionists should consider the value mothers place on the educational role of TV viewing, the direct benefit to mothers of viewing time, the lack of clear time limits, and the common practice of family co-viewing. PMID- 25724995 TI - A new species of Meliolinites associated with Buxus leaves from the Oligocene of Guangxi, southern China. AB - A new species of Meliolinites (fossil Meliolaceae), M. buxi sp. nov., is reported from the Oligocene Ningming Formation of Guangxi, South China. The fungus has hyphopodia characteristics of extant Meliolaceae, such as thick-walled, branching hyphae with appressoria and phialides. However, these fossils entirely lack mycelial or perithecial setae and have only a few phialides, thereby distinguishing the new species from most known species. The fungus was discovered on the adaxial and abaxial cuticles of several fossilized Buxus leaves. Thickening and twisting of cell walls in the Buxus leaf cuticle, along with the parasitic feeding strategy of the extant Meliolaceae, suggest that a parasitic interaction between Buxus and M. buxi seems feasible. The distribution of modern Meliolaceae suggests that they live in warm, humid subtropical-tropical climates. It is possible that the presence of M. buxi indicates a similar climatic condition. The co-occurrence of large-leaf Buxus and floristic comparisons of the Ningming assemblage also corroborate this conclusion. PMID- 25724996 TI - Two amino acid sequences direct Aspergillus nidulans protein kinase C (PkcA) localization to hyphal apices and septation sites. AB - The Aspergillus nidulans ortholog of protein kinase C (pkcA) is involved in the organism's putative cell wall integrity (CWI) pathway, and PkcA also is highly localized at growing tips and forming septa. In the present work we identify the regions within PkcA that are responsible for its localization to hyphal tips and septation sites. To this end, we used serially truncated pkcA constructs and expressed them as green fluorescent protein (GFP) chimeras and identified two regions that direct PkcA localization. The first region is a 10 amino-acid sequence near the carboxyl end of the C2 domain that is required for localization to hyphal tips. Proteins containing this sequence also localize to septation sites. A second region between C2 and C1B (encompassing C1A) is sufficient for localization to septation sites but not to hyphal tips. We also report that localization to hyphal tips and septation sites alone is not sufficient for truncated constructs to complement hypersensitivity to the cell wall compromising agent calcofluor white in a strain bearing a mutation in the pkcA gene. Taken together, these results suggest that localization and stress response might be independent. PMID- 25724997 TI - Toward monophyletic generic concepts in Magnaporthales: species with Harpophora asexual states. AB - We investigated the phylogenetic relationships among Magnaporthales fungi with harpophora-like asexual states based on DNA sequences of ITS, MCM7, RPB1 and TEF1 genes. The results indicated that these species are polyphyletic. Based on the four-gene phylogeny, the type species of Harpophora, H. radicicola, belongs to Gaeumannomyces and thus Harpophora is treated as a synonym of Gaeumannomyces. In addition, a monotypic new genus, Falciphora, is established based on F. oryzae, previous referred as Harpophora oryzae. PMID- 25724998 TI - Molecular phylogeny of Ascotricha, including two new marine algae-associated species. AB - Phylogenetic analyses based on a broad taxonomic sampling of Ascotricha were conducted using the sequences of nuc rDNA region encompassing the internal transcribed spacers 1 and 2, along with the 5.8S rDNA (ITS), partial nuc 18S rDNA (18S) and partial beta-tubulin gene (TUB2). Hypoxyloid Xylariaceae and xylarioid Xylariaceae were inferred as two distinct lineages in the Xylariaceae in the combined ITS-TUB2 phylogeny. Within xylarioid Xylariaceae species of Ascotricha form a monophyletic group. Two new marine algae-associated fungi, Ascotricha longipila and A. parvispora, are described on the basis of morphological and molecular characters and the combination, A. sinuosa, is proposed. A synopsis of the morphological characters and a dichotomous key to Ascotricha species are provided. PMID- 25724999 TI - First comprehensive phylogenetic analysis of the genus Erysiphe (Erysiphales, Erysiphaceae) I. The Microsphaera lineage. AB - The genus Erysiphe (including powdery mildew fungi only known as anamorph, Pseudoidium) is the largest genus in the Erysiphaceae and contains more than 50% of all species in this family. Little is known about the phylogenetic structure of this genus. We conducted a comprehensive phylogenetic analysis of the Microsphaera-lineage, a monophyletic group including species of sects. Microsphaera and Erysiphe, using 401 sequences of nuc ITS1-5.8S-ITS2 and the 28S rDNA regions. This analysis gave many small clades delimited by the host plant genus or family. We identified two deep branches, albeit with moderate bootstrap supports, that divided the 401 sequences into three large groups. In addition, we identified four large clades consisting of homogeneous sequences of powdery mildews from a wide range of host plants beyond family level, namely, the E. aquilegiae clade, the E. alphitoides clade, the E. quercicola clade, and the E. trifoliorum s. lat. clade. Isolates from herbaceous plants were mostly situated in the E. aquilegiae clade and in Group III that was located at the most derived position of the Microsphaera-lineage. On the other hand, the basal part of the Microsphaera-lineage was occupied by isolates from woody plants except for E. glycines that was used as an outgroup taxon. This supports our previous hypothesis that tree-parasitic powdery mildews are phylogenetically primitive in the Erysiphaceae in general, and host-shift from trees to herbs occurred many times independently during the evolution of powdery mildews. Molecular clock analyses suggested that the divergence of the Microsphaera-lineage began ca. 20 million years ago in the Miocene Epoch of the Neogene Period. PMID- 25725000 TI - Evolution of virulence in fungal plant pathogens: exploiting fungal genomics to control plant disease. AB - The propensity of a fungal pathogen to evolve virulence depends on features of its biology (e.g. mode of reproduction) and of its genome (e.g. amount of repetitive DNA). Populations of Leptosphaeria maculans, a pathogen of Brassica napus (canola), can evolve and overcome disease resistance bred into canola within three years of commercial release of a cultivar. Avirulence effector genes are key fungal genes that are complementary to resistance genes. In L. maculans these genes are embedded within inactivated transposable elements in genomic regions where they are readily mutated or deleted. The risk of resistance breakdown in the field can be minimised by monitoring disease severity of canola cultivars and virulence of fungal populations using high throughput molecular assays and by sowing canola cultivars with different resistance genes in subsequent years. This strategy has been exploited to avert yield losses due to blackleg disease in Australia. PMID- 25725001 TI - Studies in the genus Glutinoglossum. AB - Glutinoglossum is a recently described genus in Geoglossomycetes, characterized by viscid black fruiting bodies. Glutinoglossum was described based on molecular evidence showing that the fungus formerly known as Geoglossum glutinosum formed a well-supported clade separate from Geoglossum. This study provides a comprehensive examination of Glutinoglossum based on maximum-likelihood and Bayesian analyses of a dataset that includes nuc rDNA internal transcribed spacer and partial 28S regions and the nuc genes for RNA polymerase II largest subunit (RPB1) and minichromosome maintenance complex component 7 (MCM7). Four new species are described, an emended description of Glutinoglossum glutinosum and a key to the genus Glutinoglossum is provided. PMID- 25725002 TI - Shame, hope, intimacy and growth: Dementia distress and growth in families from the perspective of senior aged care professionals. AB - Minimal research explores the impact of dementia and a dementia diagnosis on families from the unique vantage of senior health professionals. The participants of this study, eight senior aged care professionals, provided unique interpretative insights into family dynamics and sense-making on the journey with dementia, and their own role in that journey. Both positive and negative perspectives were sought. Data from semi-structured interviews were analysed using Interpretative Phenomenological Analysis (IPA). One superordinate theme, Dementia naivete; redefined intimacy, overarched Embarrassed shame; Maintaining hope; Redefining a model of intimacy; and Redefined relational intimacy and growth Within these themes, the participants shed light on hurtful embarrassment and shame experienced by families associated with the diagnostic label given to a loved one. This label was perceived to either trigger separation, hurt and immobility through ignorance, or precipitate a frenzy of naive yet hopeful energy for seeking that elusive cure. The participants saw their role as one of enacting a new way of connecting what was with what could be. Thus, they modelled advocacy, integral care and relational intimacy. Validation came in witnessing a redefining of intimacy in many families who were able to embrace that holistic and empathic approach to the shifting presentation of dementia. Psychological well-being was observed to occur when families embraced growthful domains, e.g. acceptance, hope, relational closeness and altruistic concern for other families. Implications for future care models are discussed. PMID- 25725003 TI - An exploration of the properties of the CORE problem list subset and how it facilitates the implementation of SNOMED CT. AB - OBJECTIVE: Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) is the emergent international health terminology standard for encoding clinical information in electronic health records. The CORE Problem List Subset was created to facilitate the terminology's implementation. This study evaluates the CORE Subset's coverage and examines its growth pattern as source datasets are being incorporated. METHODS: Coverage of frequently used terms and the corresponding usage of the covered terms were assessed by "leave-one-out" analysis of the eight datasets constituting the current CORE Subset. The growth pattern was studied using a retrospective experiment, growing the Subset one dataset at a time and examining the relationship between the size of the starting subset and the coverage of frequently used terms in the incoming dataset. Linear regression was used to model that relationship. RESULTS: On average, the CORE Subset covered 80.3% of the frequently used terms of the left-out dataset, and the covered terms accounted for 83.7% of term usage. There was a significant positive correlation between the CORE Subset's size and the coverage of the frequently used terms in an incoming dataset. This implies that the CORE Subset will grow at a progressively slower pace as it gets bigger. CONCLUSION: The CORE Problem List Subset is a useful resource for the implementation of Systematized Nomenclature of Medicine Clinical Terms in electronic health records. It offers good coverage of frequently used terms, which account for a high proportion of term usage. If future datasets are incorporated into the CORE Subset, it is likely that its size will remain small and manageable. PMID- 25725004 TI - Parameterizing time in electronic health record studies. AB - BACKGROUND: Fields like nonlinear physics offer methods for analyzing time series, but many methods require that the time series be stationary-no change in properties over time.Objective Medicine is far from stationary, but the challenge may be able to be ameliorated by reparameterizing time because clinicians tend to measure patients more frequently when they are ill and are more likely to vary. METHODS: We compared time parameterizations, measuring variability of rate of change and magnitude of change, and looking for homogeneity of bins of temporal separation between pairs of time points. We studied four common laboratory tests drawn from 25 years of electronic health records on 4 million patients. RESULTS: We found that sequence time-that is, simply counting the number of measurements from some start-produced more stationary time series, better explained the variation in values, and had more homogeneous bins than either traditional clock time or a recently proposed intermediate parameterization. Sequence time produced more accurate predictions in a single Gaussian process model experiment. CONCLUSIONS: Of the three parameterizations, sequence time appeared to produce the most stationary series, possibly because clinicians adjust their sampling to the acuity of the patient. Parameterizing by sequence time may be applicable to association and clustering experiments on electronic health record data. A limitation of this study is that laboratory data were derived from only one institution. Sequence time appears to be an important potential parameterization. PMID- 25725005 TI - Using age, triage score, and disposition data from emergency department electronic records to improve Influenza-like illness surveillance. AB - OBJECTIVE: Markers of illness severity are increasingly captured in emergency department (ED) electronic systems, but their value for surveillance is not known. We assessed the value of age, triage score, and disposition data from ED electronic records for predicting influenza-related hospitalizations. MATERIALS AND METHODS: From June 2006 to January 2011, weekly counts of pneumonia and influenza (P&I) hospitalizations from five Montreal hospitals were modeled using negative binomial regression. Over lead times of 0-5 weeks, we assessed the predictive ability of weekly counts of 1) total ED visits, 2) ED visits with influenza-like illness (ILI), and 3) ED visits with ILI stratified by age, triage score, or disposition. Models were adjusted for secular trends, seasonality, and autocorrelation. Model fit was assessed using Akaike information criterion, and predictive accuracy using the mean absolute scaled error (MASE). RESULTS: Predictive accuracy for P&I hospitalizations during non-pandemic years was improved when models included visits from patients >=65 years old and visits resulting in admission/transfer/death (MASE of 0.64, 95% confidence interval (95% CI) 0.54-0.80) compared to overall ILI visits (0.89, 95% CI 0.69-1.10). During the H1N1 pandemic year, including visits from patients <18 years old, visits with high priority triage scores, or visits resulting in admission/transfer/death resulted in the best model fit. DISCUSSION: Age and disposition data improved model fit and moderately reduced the prediction error for P&I hospitalizations; triage score improved model fit only during the pandemic year. CONCLUSION: Incorporation of age and severity measures available in ED records can improve ILI surveillance algorithms. PMID- 25725006 TI - Is precipitation a trigger for the onset of xylogenesis in Juniperus przewalskii on the north-eastern Tibetan Plateau? AB - BACKGROUND AND AIMS: A series of studies have shown that temperature triggers the onset of xylogenesis of trees after winter dormancy. However, little is known about whether and how moisture availability influences xylogenesis in spring in drought-prone areas. METHODS: Xylogenesis was monitored in five mature Qilian junipers (Juniperus przewalskii) by microcore sampling from 2009 to 2011 in a semi-arid area of the north-eastern Tibetan Plateau. A simple physical model of xylem cell production was developed and its sensitivity was analysed. The relationship between climate and growth was then evaluated, using weekly wood production data and climatic data from the study site. KEY RESULTS: Delayed onset of xylogenesis in 2010 corresponded to a negative standardized precipitation evapotranspiration index (SPEI) value and a continuous period without rainfall in early May. The main period of wood formation was in June and July, and drier conditions from May to July led to a smaller number of xylem cells. Dry conditions in July could cause early cessation of xylem differentiation. The final number of xylem cells was mainly determined by the average production rate rather than the duration of new cell production. Xylem growth showed a positive and significant response to precipitation, but not to temperature. CONCLUSIONS: Precipitation in late spring and summer can play a critical role in the onset of xylogenesis and xylem cell production. The delay in the initiation of xylogenesis under extremely dry conditions seems to be a stress-avoidance strategy against hydraulic failure. These findings could thus demonstrate an evolutionary adaptation of Qilian juniper to the extremely dry conditions of the north-eastern Tibetan Plateau. PMID- 25725007 TI - The relationship between cell division and elongation during development of the nectar-yielding petal spur in Centranthus ruber (Valerianaceae). AB - BACKGROUND AND AIMS: Floral spurs are hollow, tubular outgrowths that typically conceal nectar. By their involvement in specialized pollinator interactions, spurs have ecological and evolutionary significance, often leading to speciation. Despite their importance and diversity in shape and size among angiosperm taxa, detailed investigations of the mechanism of spur development have been conducted only recently. METHODS: Initiation and growth of the nectar-yielding petal spur of Centranthus ruber 'Snowcloud' was investigated throughout seven stages, based on bud size and developmental events. The determination of the frequency of cell division, quantified for the first time in spurs, was conducted by confocal microscopy following 4',6-diamidino-2-phenylindole (DAPI) staining of mitotic figures. Moreover, using scanning electron microscospy of the outer petal spur surface unobstructed by trichomes, morphometry of epidermal cells was determined throughout development in order to understand the ontogeny of this elongate, hollow tube. KEY RESULTS: Spur growth from the corolla base initially included diffuse cell divisions identified among epidermal cells as the spur progressed through its early stages. However, cell divisions clearly diminished before a petal spur attained 30 % of its final length of 4.5 mm. Thereafter until anthesis, elongation of individual cells was primarily responsible for the spur's own extension. Consequently, a prolonged period of anisotropy, wherein epidermal cells elongated almost uniformly in all regions along the petal spur's longitudinal axis, contributed principally to the spur's mature length. CONCLUSIONS: This research demonstrates that anisotropic growth of epidermal cells - in the same orientation as spur elongation - chiefly explains petal spur extension in C. ruber. Representing the inaugural investigation of the cellular basis for spur ontogeny within the Euasterids II clade, this study complements the patterns in Aquilegia species (order Ranunculales, Eudicots) and Linaria vulgaris (order Lamiales, Euasterids I), thereby suggesting the existence of a common underlying mechanism for petal spur ontogeny in disparate dicot lineages. PMID- 25725010 TI - Receptors and routes of dengue virus entry into the host cells. AB - Dengue is the most prevalent arthropod-borne viral disease, caused by dengue virus, a member of the Flaviviridae family. Its worldwide incidence is now a major health problem, with 2.5 billion people living in risk areas. In this review, we integrate the structural rearrangements of each viral protein and their functions in all the steps of virus entry into the host cells. We describe in detail the putative receptors and attachment factors in mammalian and mosquito cells, and the recognition of viral immunocomplexes via Fcgamma receptor in immune cells. We also discuss that virus internalization might occur through distinct entry pathways, including clathrin-mediated or non-classical clathrin independent endocytosis, depending on the host cell and virus serotype or strain. The implications of viral maturation in virus entry are also explored. Finally, we discuss the mechanisms of viral genome access to the cytoplasm. This includes the role of low pH-induced conformational changes in the envelope protein that mediate membrane fusion, and original insights raised by our recent work that supports the hypothesis that capsid protein would also be an active player in this process, acting on viral genome translocation into the cytoplasm. PMID- 25725008 TI - A last stand in the Po valley: genetic structure and gene flow patterns in Ulmus minor and U. pumila. AB - BACKGROUND AND AIMS: Ulmus minor has been severely affected by Dutch elm disease (DED). The introduction into Europe of the exotic Ulmus pumila, highly tolerant to DED, has resulted in it widely replacing native U. minor populations. Morphological and genetic evidence of hybridization has been reported, and thus there is a need for assessment of interspecific gene flow patterns in natural populations. This work therefore aimed at studying pollen gene flow in a remnant U. minor stand surrounded by trees of both species scattered across an agricultural landscape. METHODS: All trees from a small natural stand (350 in number) and the surrounding agricultural area within a 5-km radius (89) were genotyped at six microsatellite loci. Trees were morphologically characterized as U. minor, U. pumila or intermediate phenotypes, and morphological identification was compared with Bayesian clustering of genotypes. For paternity analysis, seeds were collected in two consecutive years from 20 and 28 mother trees. Maximum likelihood paternity assignment was used to elucidate intra- and interspecific gene flow patterns. KEY RESULTS: Genetic structure analyses indicated the presence of two genetic clusters only partially matching the morphological identification. The paternity analysis results were consistent between the two consecutive years of sampling and showed high pollen immigration rates (~0.80) and mean pollination distances (~3 km), and a skewed distribution of reproductive success. Few intercluster pollinations and putative hybrid individuals were found. CONCLUSIONS: Pollen gene flow is not impeded in the fragmented agricultural landscape investigated. High pollen immigration and extensive pollen dispersal distances are probably counteracting the potential loss of genetic variation caused by isolation. Some evidence was also found that U. minor and U. pumila can hybridize when in sympatry. Although hybridization might have beneficial effects on both species, remnant U. minor populations represent a valuable source of genetic diversity that needs to be preserved. PMID- 25725011 TI - The battle for chitin recognition in plant-microbe interactions. AB - Fungal cell walls play dynamic functions in interaction of fungi with their surroundings. In pathogenic fungi, the cell wall is the first structure to make physical contact with host cells. An important structural component of fungal cell walls is chitin, a well-known elicitor of immune responses in plants. Research into chitin perception has sparked since the chitin receptor from rice was cloned nearly a decade ago. Considering the widespread nature of chitin perception in plants, pathogens evidently evolved strategies to overcome detection, including alterations in the composition of cell walls, modification of their carbohydrate chains and secretion of effectors to provide cell wall protection or target host immune responses. Also non-pathogenic fungi contain chitin in their cell walls and are recipients of immune responses. Intriguingly, various mutualists employ chitin-derived signaling molecules to prepare their hosts for the mutualistic relationship. Research on the various types of interactions has revealed different molecular components that play crucial roles and, moreover, that various chitin-binding proteins contain dissimilar chitin binding domains across species that differ in affinity and specificity. Considering the various strategies from microbes and hosts focused on chitin recognition, it is evident that this carbohydrate plays a central role in plant fungus interactions. PMID- 25725013 TI - Microbial ecology of hot desert edaphic systems. AB - A significant proportion of the Earth's surface is desert or in the process of desertification. The extreme environmental conditions that characterize these areas result in a surface that is essentially barren, with a limited range of higher plants and animals. Microbial communities are probably the dominant drivers of these systems, mediating key ecosystem processes. In this review, we examine the microbial communities of hot desert terrestrial biotopes (including soils, cryptic and refuge niches and plant-root-associated microbes) and the processes that govern their assembly. We also assess the possible effects of global climate change on hot desert microbial communities and the resulting feedback mechanisms. We conclude by discussing current gaps in our understanding of the microbiology of hot deserts and suggest fruitful avenues for future research. PMID- 25725014 TI - Role of bacterial volatile compounds in bacterial biology. AB - Bacterial interactions with neighboring microorganisms via production of small metabolites enable bacteria to respond and adapt to environmental changes. The study of intercellular interactions primarily focused on soluble metabolites, but bacteria also produce and release into their headspace a wide variety of volatile secondary metabolites, the ecological roles of which have generally been overlooked. However, bacterial volatile compounds are known to contribute to interkingdom interactions (plant, fungi and nematodes), and recent studies also identified their at-a-distance influence on bacterial behavior. The present review describes the biological roles of bacterial volatile compounds in inter- and intraspecies bacterial interactions, a new and yet unexplored research area, with potential clinical and industrial applications. PMID- 25725016 TI - It's time to think about the head and heart! PMID- 25725012 TI - Illumination of growth, division and secretion by metabolic labeling of the bacterial cell surface. AB - The cell surface is the essential interface between a bacterium and its surroundings. Composed primarily of molecules that are not directly genetically encoded, this highly dynamic structure accommodates the basic cellular processes of growth and division as well as the transport of molecules between the cytoplasm and the extracellular milieu. In this review, we describe aspects of bacterial growth, division and secretion that have recently been uncovered by metabolic labeling of the cell envelope. Metabolite derivatives can be used to label a variety of macromolecules, from proteins to non-genetically-encoded glycans and lipids. The embedded metabolite enables precise tracking in time and space, and the versatility of newer chemoselective detection methods offers the ability to execute multiple experiments concurrently. In addition to reviewing the discoveries enabled by metabolic labeling of the bacterial cell envelope, we also discuss the potential of these techniques for translational applications. Finally, we offer some guidelines for implementing this emerging technology. PMID- 25725015 TI - Viscoelasticity of biofilms and their recalcitrance to mechanical and chemical challenges. AB - We summarize different studies describing mechanisms through which bacteria in a biofilm mode of growth resist mechanical and chemical challenges. Acknowledging previous microscopic work describing voids and channels in biofilms that govern a biofilms response to such challenges, we advocate a more quantitative approach that builds on the relation between structure and composition of materials with their viscoelastic properties. Biofilms possess features of both viscoelastic solids and liquids, like skin or blood, and stress relaxation of biofilms has been found to be a corollary of their structure and composition, including the EPS matrix and bacterial interactions. Review of the literature on viscoelastic properties of biofilms in ancient and modern environments as well as of infectious biofilms reveals that the viscoelastic properties of a biofilm relate with antimicrobial penetration in a biofilm. In addition, also the removal of biofilm from surfaces appears governed by the viscoelasticity of a biofilm. Herewith, it is established that the viscoelasticity of biofilms, as a corollary of structure and composition, performs a role in their protection against mechanical and chemical challenges. Pathways are discussed to make biofilms more susceptible to antimicrobials by intervening with their viscoelasticity, as a quantifiable expression of their structure and composition. PMID- 25725017 TI - Impact of participation in randomized trials of reperfusion therapy on the time to reperfusion and hospital mortality in ST-segment elevation myocardial infarction: A single-centre cohort study. AB - AIM: There is uncertainty as to whether consenting and randomizing patients in randomized clinical trials (RCTs) in acute ST-segment elevation myocardial infarction (STEMI) delays reperfusion and increases mortality. The aim of this study was to determine whether participation of patients with STEMI in RCTs is associated with delay in implementation of reperfusion therapy and increased hospital mortality. METHODS AND RESULTS: A consecutive sample of 2523 patients, admitted within 6 hours of symptom onset without cardiogenic shock, was recruited from a single tertiary academic centre. They were categorized according to participation (n=392, 15.5%) or nonparticipation (n=2131, 84.5%) in RCTs of reperfusion therapy. Primary outcome was hospital mortality. Additional outcome was time from symptom onset to receipt of reperfusion therapy. Trial participants were more likely to receive fibrinolysis with a 37 min delay in comparison with patients not included in RCTs. Time from symptom onset to reperfusion (minutes) was longer for trial participants than nonparticipants (246 +/- 85 vs 233 +/- 93, p=0.01). Hospital mortality was 3.61% for nonparticipants. Expected mortality (based on risk modeling) for trial participants was 2.74% (p=0.014 vs nonparticipants). Observed mortality was 1.53% (p=0.034 vs nonparticipants; p=0.16 vs expected mortality). In a multivariable analysis using logistic regression, participation in a RCT was not an independent correlate of hospital mortality (odds ratio 0.54, 95% confidence interval 0.23-2.43, p=0.16). CONCLUSIONS: In this consecutive cohort, despite a longer delay to reperfusion, there was no indication that participation in a RCT, starting before initiation of reperfusion therapy, was associated with a detectable increase in risk of hospital mortality among patients with STEMI. These data suggest that it is possible to consent and randomize patients with STEMI into RCTs without jeopardizing their survival. PMID- 25725018 TI - Alcohol outlet density, drinking contexts and intimate partner violence: a review of environmental risk factors. AB - Alcohol use is a robust predictor of intimate partner violence (IPV). A critical barrier to progress in preventing alcohol-related IPV is that little is known about how an individual's specific drinking contexts (where, how often, and with whom one drinks) are related to IPV, or how these contexts are affected by environmental characteristics, such as alcohol outlet density and neighborhood disadvantage. The putative mechanism is the social environment in which drinking occurs that may promote or strengthen aggressive norms. Once these contexts are known, specific prevention measures can be put in place, including policy oriented (e.g., regulating outlet density) and individually oriented (e.g., brief interventions to reduce risk for spousal aggression) measures targeting at-risk populations. This paper reviews applicable theories and empirical research evidence that links IPV to drinking contexts and alcohol outlet density, highlights research gaps, and makes recommendations for future research. PMID- 25725019 TI - Protective Behavioral Strategies and Alcohol Use Outcomes Among College Women Drinkers: Does Disordered Eating and Race Moderate This Association? AB - The current study examined the degree to which associations that protective behavioral strategy use had with alcohol consumption and alcohol-related negative consequences were moderated by disordered eating and race. Participants were 382 female undergraduates (ages 18-25) who had consumed alcohol at least once within the previous month. Participants completed online self-report measures concerning their use of protective behavioral strategies, disordered eating, weekly alcohol consumption, harmful drinking patterns, and alcohol-related negative consequences. White non-Hispanic women who used the fewest protective behavioral strategies reported the highest levels of alcohol consumption and harmful drinking patterns. Protective behavioral strategy use was associated with lower levels of alcohol-related negative consequences except for African American women with low levels of disordered eating behaviors. For interventions targeting drinking among college women, disordered eating behaviors may increase risky behaviors and qualify relationships between protective behavioral strategies and alcohol-related negative consequences. Thus, assessment of disordered eating behavior as part of drinking interventions may be helpful. PMID- 25725020 TI - Metabolic remodeling: a pyruvate transport affair. AB - Metabolic remodeling is a major determinant for many cell fate decisions, and a switch from respiration to aerobic glycolysis is generally considered as a hallmark of cancer cell transformation. Pyruvate is a key metabolite at the major junction of carbohydrate metabolism between cytosolic glycolysis and the mitochondrial Krebs cycle. In this issue of The EMBO Journal, Bender et al show that yeast cells regulate pyruvate uptake into mitochondria, and thus its metabolic fate, by expressing alternative pyruvate carrier complexes with different activities. PMID- 25725023 TI - Uptake of inorganic phosphate is a limiting factor for Saccharomyces cerevisiae during growth at low temperatures. AB - The fermenting ability of Saccharomyces at low temperatures is crucial for the development of alcoholic beverages, but the key factors for the cold tolerance of yeast are not well known. In this report, we present the results of a screening for genes able to confer cold tolerance by overexpression in a laboratory yeast strain auxotrophic for tryptophan. We identified genes of tryptophan permeases (TAT1 and TAT2), suggesting that the first limiting factor in the growth of tryptophan auxotrophic yeast at low temperatures is tryptophan uptake. This fact is of little relevance to industrial strains which are prototrophic for tryptophan. Then, we screened for genes able to confer growth at low temperatures in tryptophan-rich media and found several genes related to phosphate uptake (PHO84, PHO87, PHO90 and GTR1). This suggests that without tryptophan limitation, uptake of inorganic phosphate becomes the limiting factor. We have found that overexpression of the previously uncharacterized ORF YCR015c/CTO1 increases the uptake of inorganic phosphate. Also, genes involved in ergosterol biosynthesis (NSG2) cause improvement of growth at 10 degrees C, dependent on tryptophan uptake, while the gluconeogenesis gene PCK1 and the proline biosynthesis gene PRO2 cause an improvement in growth at 10 degrees C, independent of tryptophan and phosphate uptake. PMID- 25725024 TI - Saccharomyces cerevisiae: a nomadic yeast with no niche? AB - Different species are usually thought to have specific adaptations, which allow them to occupy different ecological niches. But recent neutral ecology theory suggests that species diversity can simply be the result of random sampling, due to finite population sizes and limited dispersal. Neutral models predict that species are not necessarily adapted to specific niches, but are functionally equivalent across a range of habitats. Here, we evaluate the ecology of Saccharomyces cerevisiae, one of the most important microbial species in human history. The artificial collection, concentration and fermentation of large volumes of fruit for alcohol production produce an environment in which S. cerevisiae thrives, and therefore it is assumed that fruit is the ecological niche that S. cerevisiae inhabits and has adapted to. We find very little direct evidence that S. cerevisiae is adapted to fruit, or indeed to any other specific niche. We propose instead a neutral nomad model for S. cerevisiae, which we believe should be used as the starting hypothesis in attempting to unravel the ecology of this important microbe. PMID- 25725025 TI - Microcyclosporella mali: a novel fungal keratitis in a post-penetrating keratoplasty patient. AB - An 86-year-old woman underwent penetrating keratoplasty for pseudophakic bullous keratopathy and presented with an acute corneal ulcer thereafter. Examination demonstrated a fluffy white infiltrate and epithelial defect with subsequent endothelial plaque formation and anterior chamber inflammation. The ulcer was cultured, and fortified topical vancomycin and tobramycin were initiated but failed to significantly improve the clinical course. Cultures were ultimately positive for fungus Microcyclosporella mali that responded well to topical natamycin with stabilisation of the ulcer after 6 weeks of topical therapy. This is the first reported case of fungal keratitis due to M. mali. PMID- 25725027 TI - Successful primary coronary angioplasty for acute inferior myocardial infarction in a patient with RII-type single coronary artery. PMID- 25725026 TI - Adipofascial radial artery perforator flap interposition to treat post-traumatic radioulnar synostosis in a patient with head injury. AB - We report this 47-year-old man who presented with polytrauma following a fall from a roof in March 2011. He sustained a head injury and a complex, comminuted forearm fracture. He underwent an open reduction and internal fixation of the fracture at the time of injury, but later developed a rigid type 2 diaphyseal radioulnar synostosis, with loss of forearm rotation. Synostosis excision and a radial artery perforator-based adipofascial interposition flap to prevent recurrence has resulted in a good functional outcome and no recurrence at 2.5 years follow-up. PMID- 25725028 TI - Type I allergic hypersensitivity reactions due to ethylene oxide sterilised leucocyte filters in patients with thalassaemia: report of four cases. AB - Ethylene oxide (EO) is a highly reactive gas used in sterilisation of heat sensitive medical devices, such as infusion sets, cannulae, intubation materials, ventriculoperitoneal shunts, dialysis catheters and stents. Allergic reactions due to EO have been reported in haemodialysis patients, patients undergoing extracorporeal photopheresis and donors of plasmapheresis. Clinical manifestations vary considerably and generally do not allow differentiation between IgE-mediated anaphylaxis and anaphylactoid reactions. We report four patients with thalassaemia who experienced anaphylaxis during transfusion due to ethylene oxide sterilised leucocyte filters. The aim of this report is to highlight the fact that frequently transfused patients can have allergic reactions due to EO particles left in leucocyte filters. PMID- 25725029 TI - Parietal bone osteomyelitis in melioidosis. AB - We report a case of a 55-year-old man with uncontrolled diabetes who presented with pneumonia. During his hospital stay his clinical status worsened and he had a focal seizure. MRI showed central nervous system involvement and parietal bone osteomyelitis. As the patient's blood culture and endotracheal aspirate grew Burkholderia pseudomallei, melioidosis was diagnosed. He was treated with meropenem after failure to respond to ceftazidime. He gradually improved over a period of 4 weeks and was discharged. Early diagnosis and therapy resulted in improved outcome. PMID- 25725030 TI - HIV-associated primary effusion lymphoma presenting as a paracardial mass. AB - Primary effusion lymphoma (PEL), a rare type of non-Hodgkin's lymphoma, is an AIDS-defining illness and always associated with human herpesvirus 8 (HHV-8). Classic presentations involve the pleural, pericardial or peritoneal cavities. Infrequently, extracavitary solid tumours develop. Treatment of PEL requires chemotherapy and highly active antiretroviral therapy (HAART). We report a case of a 46-year-old man, who presented with right-sided chest pain, dyspnoea and night sweats. Evaluation revealed decreased breath sounds and dullness to percussion on the right side of the chest. Imaging demonstrated a 6.1 cm*6.3 cm right paracardial mass and right-sided pleural effusion. Pleural fluid was HHV-8 positive. The patient was diagnosed with PEL with extracavitary involvement and treated with chemotherapy and concurrent HAART. This case is the first reported case of extracavitary paracardial involvement and adds new insight to the accepted treatment for PEL with extracavitary lesions. PMID- 25725031 TI - Disseminated hydatidosis. PMID- 25725032 TI - An unexpected diagnosis of adenomyosis in the subfertile woman. AB - A 38-year-old nulliparous female presented to an assisted conception clinic with subfertility and a long-standing history of dysmenorrhoea. Transvaginal ultrasound revealed two lesions in the body of the uterus, which were presumed to be fibroids. A decision was made to remove these lesions prior to attempting in vitro fertilisation (IVF). However, on laparotomy, deeply penetrating adenomyosis was discovered, resulting in an unexpected hysterectomy and significant blood loss. Based on our experience, we highlight the importance of suspecting a diagnosis of adenomyosis preoperatively and the methods by which this diagnosis can be made, in order to avoid potential unforeseen outcomes as described in this case. We discuss conservative management options for this condition, particularly in women wishing to preserve fertility. PMID- 25725033 TI - Left atrium compression due to oesophageal dilation can induce acute heart failure. PMID- 25725034 TI - A Baker's dozen. PMID- 25725035 TI - Increased Platelet to Lymphocyte Ratio is Related to Slow Coronary Flow. AB - Previous studies showed that both inflammation and platelets have a role in development of slow coronary flow (SCF). Platelet to lymphocyte ratio (PLR) as an emerging inflammatory indicator was significantly associated with adverse cardiovascular events. Therefore, we aimed to assess the relationship between PLR and SCF. Patients who had angiographically normal coronary arteries were enrolled in this retrospective study (n = 221 as SCF group and n = 293 as control group). Patients who had thrombolysis in myocardial infarction frame counts (TFC) above the normal cutoffs were considered to have SCF. Both PLR and C-reactive protein (CRP) were significantly higher in the SCF group. In correlation analysis, PLR has a significantly positive correlation with the left anterior descending artery TFC (P = .001), circumflex artery TFC (P < .001), right coronary artery TFC (P < .001), and serum CRP level (P < .001). In multiple logistic regression analysis, PLR was independently associated with presence of SCF (odds ratio: 1.014, P < .001). In conclusion, higher PLR levels were significantly and independently related to the presence of SCF. Besides, PLR was positively correlated with serum CRP level as a conventional marker for systemic inflammation. PMID- 25725036 TI - Feeling depleted and powerless: the construal-level mechanism. AB - Individuals exercise self-control daily to achieve desired goals; at the same time, people engage in social interaction daily and influence (feel powerful) or are influenced (feel powerless) by others. Does controlling the self have an unforeseen consequence for people's perception of their capacity to control others? Five studies-one correlational and four experimental-demonstrate that ego depletion from prior self-control determines one's personal sense of power; low level, concrete mental construals account for this relationship. Our results showed that people with higher trait self-control reported a greater sense of power (Study 1). People who had depleted their self-control-related regulatory resources (vs. those who had not) experienced a lower sense of power (Study 2). The relationship between ego depletion and low sense of power was mediated by construal level (Study 3) and observed only when low-level, concrete construals were present, but not under high-level, abstract construals (Studies 4 and 5). PMID- 25725037 TI - Comparing the Efficacy of Ophthalmic NSAIDs in Common Indications: A Literature Review to Support Cost-effective Prescribing. AB - OBJECTIVE: To review the commercially available ophthalmic nonsteroidal anti inflammatory drugs (NSAIDs), identify opportunities for therapeutic substitutions within and outside of their Food and Drug Administration (FDA)-approved indications, and identify clinically superior drugs within the class for specific indications. DATA SOURCE: A PubMed search (1992 through January 2014) was performed on the terms diclofenac, ketorolac, flurbiprofen, bromfenac, and nepafenac. STUDY SELECTION AND DATA EXTRACTION: Clinical trials, meta-analyses, and review articles were evaluated if they were written in English and pertained to human subjects. Studies were excluded if they were in vitro studies, solely evaluated pharmacokinetic or pharmacodynamic properties, did not relate to the topical ophthalmic route, did not evaluate the FDA-approved indications of any available ophthalmic NSAID, or compared a reviewed drug with a nonreviewed drug (without placebo comparison). DATA SYNTHESIS: A total of 67 articles met the criteria for evaluation. Article quality, study design, and dosing of the medications were assessed to determine the clinical applicability of the results. The quality of the article was determined using the Oxford Centre for Evidence based Medicine Levels of Evidence 1. CONCLUSIONS: Many formulations of the 5 reviewed NSAIDs have been studied across the 4 primary indications. These indications are (1) pain and inflammation associated with cataract surgery, (2) pain associated with corneal refractive surgery, (3) inhibition of intraoperative miosis, and (4) seasonal allergic conjunctivitis. Several studies have directly compared drugs within this class and have identified instances in which certain selections are therapeutically superior or equivalent to another. This information provides practitioners with guidance in selecting an optimal medication. PMID- 25725038 TI - Tinnitus Holistic Simplified Classification (THoSC): A New Assessment for Subjective Tinnitus, With Diagnostic and Therapeutic Implications. AB - OBJECTIVE: One of the most debated topics in tinnitus is its standard and practical classification. The most popular classification distinguishes subjective from objective tinnitus. Other classifications are based on different features. On the whole, they seem incomplete, and the diagnostic and therapeutic algorithms are often difficult for practical purposes. The aim of this work is to develop a new diagnostic and therapeutic algorithm. METHODS: Our model is based on 10 years of experience. In particular, the starting point is the data retrieved from 212 consecutive patients in our Tinnitus Unit between May and December 2013: We found a clear auditory disorder in 74.5% of the population, muscolo-skeletal disorders and/or trigeminal disease in 57.1%, and psychiatric comorbidities in 43.8%. Different features coexisted in 59.9% of the population. RESULTS: Following such data we propose the Tinnitus Holistic Simplified Classification, which takes into account the different tinnitogenic mechanisms and the interactions between them. It differentiates tinnitus that arises from: (1) auditory alterations (Auditory Tinnitus), (2) complex auditory-somatosensory interactions (Somatosensory Tinnitus), (3) psychopathological-auditory interactions (Psychopathology-related Tinnitus), and (4) 2 or all of the previous mechanisms (Combined Tinnitus). CONCLUSIONS: In our opinion this classification provides an accurate and easy tailored path to manage tinnitus patients. PMID- 25725039 TI - Endometriosis mimicking colonic stromal tumor. AB - Endometriosis is defined as the presence of endometrial glands and stroma at extra-uterine sites; it is a common disease affecting women of reproductive age. Endometrial tissue can implant itself to various organs, including the gastrointestinal tract, and can cause significant gastrointestinal symptoms. These ectopic endometrial tissue implants are usually located in the pelvis but can be present almost anywhere in the body. Endometriosis seems to be the most frequent cause of chronic pelvic pain in women of reproductive age and may cause prolonged suffering and disability that negatively affect health-related quality of life. We report a case in a generally healthy young female patient who presented for evaluation of diarrhea. PMID- 25725040 TI - Primary sclerosing cholangitis and the risk of colon neoplasia in patients with Crohn's colitis. AB - BACKGROUND AND AIM: Crohn's colitis (CC) is associated with primary sclerosing cholangitis (PSC). However the risk of colon cancer or dysplasia in CC and PSC is unclear. Our aim was to study the risk of colon neoplasia in CC in patients with and without PSC. METHODS: This is a nested, case-control cohort study of all patients diagnosed with concurrent CC and PSC, seen at the Cleveland Clinic between 1985 and 2012. Forty-three patients with both CC and PSC were compared with a random sample of 159 CC controls without PSC during the same period. RESULTS: Seven (16.3%) of 43 CC patients with PSC developed colon cancer or dysplasia, compared with 22 (13.8%) of 159 controls (P = 0.98). Of seven colon neoplasia cases in the PSC group, 100% occurred proximal to the splenic flexure, compared with 50% (11/22) cases of colon neoplasia in controls occurring in the proximal colon (P = 0.001). Based on Cox regression analysis, male gender independently increased the risk of neoplasia [hazard ratio (HR) = 2.68; 95% confidence interval (CI) 1.30-5.54; P = 0.008], as did age at CC diagnosis (HR = 1.29; 95% CI 1.14-1.47; P < 0.001), while the use of azathioprine/6 mercaptopurine was protective (HR = 0.30; 95% CI 0.13-0.70; P = 0.005). The presence of PSC did not increase the risk for colon neoplasia (HR = 0.45; 95% CI 0.18-1.13; P = 0.09). CONCLUSIONS: CC patients with PSC appear not to be at increased risk of developing colon neoplasia. Among patients in our cohort with colon neoplasia and concurrent PSC, the neoplasia occurred in the proximal colon in all cases. PMID- 25725041 TI - Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials. AB - Celiac disease is a lifelong disorder for which there is currently only one known, effective treatment: a gluten-free diet. New treatment approaches have recently emerged; several drugs are in Phase 2 trials and results appear promising; however, discussion around regulatory endpoints is in its infancy. We will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints, such as patient-reported outcomes, histology, serology, gene expression analysis and other tests. We will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials, with a particular emphasis on current thinking in regulatory agencies. We conclude our paper with recommendations and a glossary of regulatory terms, to enable readers who are less familiar with regulatory language to take maximum advantage of this review. PMID- 25725042 TI - Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment. AB - Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimer's disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM. PMID- 25725043 TI - Phosphene Perception Relates to Visual Cortex Glutamate Levels and Covaries with Atypical Visuospatial Awareness. AB - Phosphenes are illusory visual percepts produced by the application of transcranial magnetic stimulation to occipital cortex. Phosphene thresholds, the minimum stimulation intensity required to reliably produce phosphenes, are widely used as an index of cortical excitability. However, the neural basis of phosphene thresholds and their relationship to individual differences in visual cognition are poorly understood. Here, we investigated the neurochemical basis of phosphene perception by measuring basal GABA and glutamate levels in primary visual cortex using magnetic resonance spectroscopy. We further examined whether phosphene thresholds would relate to the visuospatial phenomenology of grapheme-color synesthesia, a condition characterized by atypical binding and involuntary color photisms. Phosphene thresholds negatively correlated with glutamate concentrations in visual cortex, with lower thresholds associated with elevated glutamate. This relationship was robust, present in both controls and synesthetes, and exhibited neurochemical, topographic, and threshold specificity. Projector synesthetes, who experience color photisms as spatially colocalized with inducing graphemes, displayed lower phosphene thresholds than associator synesthetes, who experience photisms as internal images, with both exhibiting lower thresholds than controls. These results suggest that phosphene perception is driven by interindividual variation in glutamatergic activity in primary visual cortex and relates to cortical processes underlying individual differences in visuospatial awareness. PMID- 25725044 TI - De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. AB - BACKGROUND: Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. METHODS: The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses. RESULTS: The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. CONCLUSIONS: Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing. PMID- 25725045 TI - Bilateral vestibular schwannomas in older patients: NF2 or chance? AB - BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant condition with high spontaneous mutation rate which predisposes to the development of multiple nerve sheath tumours (schwannomas), meningiomas and ependymoma. The cardinal feature and main diagnostic criterion for the diagnosis of NF2 remains the development of bilateral vestibular schwannoma (BVS). With increasing use of MRI screening the possibility of a 'chance' diagnosis of BVS has been mooted with a potential frequency of one in two million people in their lifetime. Until now, however, no evidence for such an event has been published. We aimed to demonstrate that chance occurrence can occur and to estimate its frequency among those with just BVS late in life. METHODS: Two vestibular schwannomas from the same patient were DNA sequenced and underwent loss of heterozygosity analysis. RESULTS: We show that a man who developed BVS, at ages 52 and 67 years developed these tumours sporadically by demonstrating that there were no molecular events in common between the two tumours. Furthermore from a database of over 1200 patients with NF2, we have estimated that ~25% of cases of BVS over 50 years and 50% over 70 years of age where no other features of NF2 are present represent a chance occurrence rather than due to an underlying mosaic or constitutional NF2 mutation. CONCLUSIONS: Patients presenting with BVS later in life should be appraised of the potential likelihood they may not have NF2 and the resultant further reduction in risks of transmission to offspring. PMID- 25725047 TI - A mother and newborn with brown blood. PMID- 25725048 TI - Commentary. PMID- 25725046 TI - Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)?. AB - BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT. PMID- 25725049 TI - Commentary. PMID- 25725050 TI - A 72-year-old woman with markedly increased ferritin. PMID- 25725051 TI - Where did the globulins go? PMID- 25725052 TI - Interpretation of Alvin Coburn's Ezra in pen and ink. PMID- 25725053 TI - The exquisite personal work space of Federigo da Montefeltro. PMID- 25725054 TI - Nonspecific (Heterologous) Protection of Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection and Sepsis. AB - BACKGROUND: Bacille Calmette-Guerin (BCG) vaccination has been suggested to have nonspecific beneficial effects in children from developing countries, reducing morbidity and mortality caused by unrelated pathogens. OBJECTIVE: We aimed to assess the heterologous protective effects of BCG vaccination against respiratory infection (RI) and sepsis not attributable to tuberculosis in children born in Spain. METHODS: We conducted a retrospective epidemiological study using data from the Official Spanish Registry of Hospitalizations (CMBD-HA) to identify differences in hospitalization rates (HR) in BCG-vaccinated children (Basque Country, where neonatal BCG is part of the immunization schedule and has a 100% coverage) as compared to non-BCG-vaccinated children (from the rest of Spain, where BCG is not used). RESULTS: A total of 464 611 hospitalization episodes from 1992 to 2011 were analyzed. The HR due to RI not attributable to tuberculosis in BCG-vaccinated children was significant lower compared to non-BCG-vaccinated children for all age groups, with a total preventive fraction (PF) of 41.4% (95% confidence interval: 40.3-42.5; P-value <.001). According to age group, PF was 32.4% (30.9-33.9; P-value <.001) for children under 1 year old, 60.1% (58.5-61.7; P-value <.001) for children between 1 and 4 years old, 66.6% (62.8-70.2; P-value <.001) for children between 5 and 9 years old, and 69.6% (63.3-75.0; P-value <.001) for children between 10 and 14 years old. The HR due to sepsis not attributable to tuberculosis in BCG-vaccinated children under 1 year of age was also significantly lower, with a PF of 52.8% (43.8-60.7; P-value <.001). CONCLUSIONS: BCG vaccination at birth may decrease hospitalization due to RI and sepsis not related to tuberculosis through heterologous protection. PMID- 25725055 TI - Editorial Commentary: Nonspecific Beneficial Effects of BCG Vaccination in High income Countries, Should We Extend Recommendation of BCG Vaccination? PMID- 25725056 TI - Stevens DL et al (Clin Infect Dis 2014; 59:147-59). PMID- 25725057 TI - Determining similarity of scientific entities in annotation datasets. AB - Linked Open Data initiatives have made available a diversity of scientific collections where scientists have annotated entities in the datasets with controlled vocabulary terms from ontologies. Annotations encode scientific knowledge, which is captured in annotation datasets. Determining relatedness between annotated entities becomes a building block for pattern mining, e.g. identifying drug-drug relationships may depend on the similarity of the targets that interact with each drug. A diversity of similarity measures has been proposed in the literature to compute relatedness between a pair of entities. Each measure exploits some knowledge including the name, function, relationships with other entities, taxonomic neighborhood and semantic knowledge. We propose a novel general-purpose annotation similarity measure called 'AnnSim' that measures the relatedness between two entities based on the similarity of their annotations. We model AnnSim as a 1-1 maximum weight bipartite match and exploit properties of existing solvers to provide an efficient solution. We empirically study the performance of AnnSim on real-world datasets of drugs and disease associations from clinical trials and relationships between drugs and (genomic) targets. Using baselines that include a variety of measures, we identify where AnnSim can provide a deeper understanding of the semantics underlying the relatedness of a pair of entities or where it could lead to predicting new links or identifying potential novel patterns. Although AnnSim does not exploit knowledge or properties of a particular domain, its performance compares well with a variety of state-of-the-art domain-specific measures. Database URL: http://www.yeastgenome.org/ PMID- 25725058 TI - FR database 1.0: a resource focused on fruit development and ripening. AB - Fruits form unique growing period in the life cycle of higher plants. They provide essential nutrients and have beneficial effects on human health. Characterizing the genes involved in fruit development and ripening is fundamental to understanding the biological process and improving horticultural crops. Although, numerous genes that have been characterized are participated in regulating fruit development and ripening at different stages, no dedicated bioinformatic resource for fruit development and ripening is available. In this study, we have developed such a database, FR database 1.0, using manual curation from 38 423 articles published before 1 April 2014, and integrating protein interactomes and several transcriptome datasets. It provides detailed information for 904 genes derived from 53 organisms reported to participate in fleshy fruit development and ripening. Genes from climacteric and non-climacteric fruits are also annotated, with several interesting Gene Ontology (GO) terms being enriched for these two gene sets and seven ethylene-related GO terms found only in the climacteric fruit group. Furthermore, protein-protein interaction analysis by integrating information from FR database presents the possible function network that affects fleshy fruit size formation. Collectively, FR database will be a valuable platform for comprehensive understanding and future experiments in fruit biology. Database URL: http://www.fruitech.org/ PMID- 25725059 TI - LocSigDB: a database of protein localization signals. AB - LocSigDB (http://genome.unmc.edu/LocSigDB/) is a manually curated database of experimental protein localization signals for eight distinct subcellular locations; primarily in a eukaryotic cell with brief coverage of bacterial proteins. Proteins must be localized at their appropriate subcellular compartment to perform their desired function. Mislocalization of proteins to unintended locations is a causative factor for many human diseases; therefore, collection of known sorting signals will help support many important areas of biomedical research. By performing an extensive literature study, we compiled a collection of 533 experimentally determined localization signals, along with the proteins that harbor such signals. Each signal in the LocSigDB is annotated with its localization, source, PubMed references and is linked to the proteins in UniProt database along with the organism information that contain the same amino acid pattern as the given signal. From LocSigDB webserver, users can download the whole database or browse/search for data using an intuitive query interface. To date, LocSigDB is the most comprehensive compendium of protein localization signals for eight distinct subcellular locations. Database URL: http://genome.unmc.edu/LocSigDB/ PMID- 25725060 TI - MnTEdb, a collective resource for mulberry transposable elements. AB - Mulberry has been used as an economically important food crop for the domesticated silkworm for thousands of years, resulting in one of the oldest and well-known plant-herbivore interactions. The genome of Morus notabilis has now been sequenced and there is an opportunity to mine the transposable element (TE) data. To better understand the roles of TEs in structural, functional and evolutionary dynamics of the mulberry genome, a specific, comprehensive and user friendly web-based database, MnTEdb, was constructed. It was built based on a detailed and accurate identification of all TEs in mulberry. A total of 5925 TEs belonging to 13 superfamilies and 1062 families were deposited in this database. MnTEdb enables users to search, browse and download the mulberry TE sequences. Meanwhile, data mining tools, including BLAST, GetORF, HMMER, Sequence Extractor and JBrowse were also integrated into MnTEdb. MnTEdb will assist researchers to efficiently take advantage of our newly annotated TEs, which facilitate their studies in the origin, amplification and evolution of TEs, as well as the comparative analysis among the different species. Database URL: http://morus.swu.edu.cn/mntedb/ PMID- 25725061 TI - Automatic concept recognition using the human phenotype ontology reference and test suite corpora. AB - Concept recognition tools rely on the availability of textual corpora to assess their performance and enable the identification of areas for improvement. Typically, corpora are developed for specific purposes, such as gene name recognition. Gene and protein name identification are longstanding goals of biomedical text mining, and therefore a number of different corpora exist. However, phenotypes only recently became an entity of interest for specialized concept recognition systems, and hardly any annotated text is available for performance testing and training. Here, we present a unique corpus, capturing text spans from 228 abstracts manually annotated with Human Phenotype Ontology (HPO) concepts and harmonized by three curators, which can be used as a reference standard for free text annotation of human phenotypes. Furthermore, we developed a test suite for standardized concept recognition error analysis, incorporating 32 different types of test cases corresponding to 2164 HPO concepts. Finally, three established phenotype concept recognizers (NCBO Annotator, OBO Annotator and Bio-LarK CR) were comprehensively evaluated, and results are reported against both the text corpus and the test suites. The gold standard and test suites corpora are available from http://bio-lark.org/hpo_res.html. Database URL: http://bio-lark.org/hpo_res.html. PMID- 25725062 TI - PathCards: multi-source consolidation of human biological pathways. AB - The study of biological pathways is key to a large number of systems analyses. However, many relevant tools consider a limited number of pathway sources, missing out on many genes and gene-to-gene connections. Simply pooling several pathways sources would result in redundancy and the lack of systematic pathway interrelations. To address this, we exercised a combination of hierarchical clustering and nearest neighbor graph representation, with judiciously selected cutoff values, thereby consolidating 3215 human pathways from 12 sources into a set of 1073 SuperPaths. Our unification algorithm finds a balance between reducing redundancy and optimizing the level of pathway-related informativeness for individual genes. We show a substantial enhancement of the SuperPaths' capacity to infer gene-to-gene relationships when compared with individual pathway sources, separately or taken together. Further, we demonstrate that the chosen 12 sources entail nearly exhaustive gene coverage. The computed SuperPaths are presented in a new online database, PathCards, showing each SuperPath, its constituent network of pathways, and its contained genes. This provides researchers with a rich, searchable systems analysis resource. Database URL: http://pathcards.genecards.org/ PMID- 25725063 TI - PreDREM: a database of predicted DNA regulatory motifs from 349 human cell and tissue samples. AB - PreDREM is a database of DNA regulatory motifs and motifs modules predicted from DNase I hypersensitive sites in 349 human cell and tissue samples. It contains 845-1325 predicted motifs in each sample, which result in a total of 2684 non redundant motifs. In comparison with seven large collections of known motifs, more than 84% of the 2684 predicted motifs are similar to the known motifs, and 54-76% of the known motifs are similar to the predicted motifs. PreDREM also stores 43 663-20 13 288 motif modules in each sample, which provide the cofactor motifs of each predicted motif. Compared with motifs of known interacting transcription factor (TF) pairs in eight resources, on average, 84% of motif pairs corresponding to known interacting TF pairs are included in the predicted motif modules. Through its web interface, PreDREM allows users to browse motif information by tissues, datasets, individual non-redundant motifs, etc. Users can also search motifs, motif modules, instances of motifs and motif modules in given genomic regions, tissue or cell types a motif occurs, etc. PreDREM thus provides a useful resource for the understanding of cell- and tissue-specific gene regulation in the human genome. Database URL: http://server.cs.ucf.edu/predrem/. PMID- 25725064 TI - Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9. AB - Loss of neurons that express the neuropeptide hypocretin (Hcrt) has been implicated in narcolepsy, a debilitating disorder characterized by excessive daytime sleepiness and cataplexy. Cell replacement therapy, using Hcrt-expressing neurons generated in vitro, is a potentially useful therapeutic approach, but factors sufficient to specify Hcrt neurons are unknown. Using zebrafish as a high throughput system to screen for factors that can specify Hcrt neurons in vivo, we identified the LIM homeobox transcription factor Lhx9 as necessary and sufficient to specify Hcrt neurons. We found that Lhx9 can directly induce hcrt expression and we identified two potential Lhx9 binding sites in the zebrafish hcrt promoter. Akin to its function in zebrafish, we found that Lhx9 is sufficient to specify Hcrt-expressing neurons in the developing mouse hypothalamus. Our results elucidate an evolutionarily conserved role for Lhx9 in Hcrt neuron specification that improves our understanding of Hcrt neuron development. PMID- 25725065 TI - Eph-Pak2a signaling regulates branching of the pharyngeal endoderm by inhibiting late-stage epithelial dynamics. AB - Branching morphogenesis depends on the precise temporal and spatial control of epithelial dynamics. In the vertebrate head, endodermal branches, called pharyngeal pouches, form through the transient stratification, collective migration and reorganization of epithelial cells into bilayers. Here, we report novel requirements for the EphrinB ligands B2a and B3b, the Ephb4a receptor and the Pak2a kinase in the development of pouches and the posterior facial skeleton that depends on pouches for its segmentation. Time-lapse imaging in zebrafish shows that EphB-Pak2a signaling is required to stabilize pouch epithelial cells at the end of branching morphogenesis. Transgenic rescue experiments further demonstrate that endodermal Eph-ephrin signaling promotes pouch integrity by targeting Pak2a to the plasma membrane, where subsequent activation by Wnt4a Cdc42 signaling increases junctional E-cadherin in maturing pouches. Integration of Eph-ephrin and Wnt4a signaling through Pak2a thus signals the end of branching morphogenesis by increasing intercellular adhesion that blocks further epithelial rearrangements. PMID- 25725066 TI - Female-to-male sex reversal in mice caused by transgenic overexpression of Dmrt1. AB - Genes related to Dmrt1, which encodes a DNA-binding DM domain transcription factor, act as triggers for primary sex determination in a broad range of metazoan species. However, this role is fulfilled in mammals by Sry, a newly evolved gene on the Y chromosome, such that Dmrt1 has become dispensable for primary sex determination and instead maintains Sertoli cell phenotype in postnatal testes. Here, we report that enforced expression of Dmrt1 in XX mouse fetal gonads using a Wt1-BAC transgene system is sufficient to drive testicular differentiation and male secondary sex development. XX transgenic fetal gonads showed typical testicular size and vasculature. Key ovarian markers, including Wnt4 and Foxl2, were repressed. Sertoli cells expressing the hallmark testis determining gene Sox9 were formed, although they did not assemble into normal testis cords. Other bipotential lineages differentiated into testicular cell types, including steroidogenic fetal Leydig cells and non-meiotic germ cells. As a consequence, male internal and external reproductive organs developed postnatally, with an absence of female reproductive tissues. These results reveal that Dmrt1 has retained its ability to act as the primary testis-determining trigger in mammals, even though this function is no longer normally required. Thus, Dmrt1 provides a common thread in the evolution of sex determination mechanisms in metazoans. PMID- 25725067 TI - Tbx6, Mesp-b and Ripply1 regulate the onset of skeletal myogenesis in zebrafish. AB - During embryonic development, the paraxial mesoderm becomes segmented into somites, within which proliferative muscle progenitors and muscle fibers establish the skeletal musculature. Here, we demonstrate that a gene network previously implicated in somite boundary formation, involving the transcriptional regulators Tbx6, Mesp-b and Ripply1, also confers spatial and temporal regulation to skeletal myogenesis in zebrafish. We show that Tbx6 directly regulates mesp-b and ripply1 expression in vivo, and that the interactions within the regulatory network are largely conserved among vertebrates. Mesp-b is necessary and sufficient for the specification of a subpopulation of muscle progenitors, the central proportion of the Pax3(+)/Pax7(+) dermomyotome. Conditional ubiquitous expression indicates that Mesp-b acts by inhibiting myogenic differentiation and by inducing the dermomyotome marker meox1. By contrast, Ripply1 induces a negative-feedback loop by promoting Tbx6 protein degradation. Persistent Tbx6 expression in Ripply1 knockdown embryos correlates with a deficit in dermomyotome and myotome marker gene expression, suggesting that Ripply1 promotes myogenesis by terminating Tbx6-dependent inhibition of myogenic maturation. Together, our data suggest that Mesp-b is an intrinsic upstream regulator of skeletal muscle progenitors and that, in zebrafish, the genes regulating somite boundary formation also regulate the development of the dermomyotome in the anterior somite compartment. PMID- 25725068 TI - teashirt is required for head-versus-tail regeneration polarity in planarians. AB - Regeneration requires that the identities of new cells are properly specified to replace missing tissues. The Wnt signaling pathway serves a central role in specifying posterior cell fates during planarian regeneration. We identified a gene encoding a homolog of the Teashirt family of zinc-finger proteins in the planarian Schmidtea mediterranea to be a target of Wnt signaling in intact animals and at posterior-facing wounds. Inhibition of Smed-teashirt (teashirt) by RNA interference (RNAi) resulted in the regeneration of heads in place of tails, a phenotype previously observed with RNAi of the Wnt pathway genes beta-catenin 1, wnt1, Dvl-1/2 or wntless. teashirt was required for beta-catenin-1-dependent activation of posterior genes during regeneration. These findings identify teashirt as a transcriptional target of Wnt signaling required for Wnt-mediated specification of posterior blastemas. PMID- 25725069 TI - Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity. AB - We have previously described the creation and analysis of a Notch1 activity-trap mouse line, Notch1 intramembrane proteolysis-Cre6MT or N1IP::Cre(LO), that marked cells experiencing relatively high levels of Notch1 activation. Here, we report and characterize a second line with improved sensitivity (N1IP::Cre(HI)) to mark cells experiencing lower levels of Notch1 activation. This improvement was achieved by increasing transcript stability and by restoring the native carboxy terminus of Cre, resulting in a five- to tenfold increase in Cre activity. The magnitude of this effect probably impacts Cre activity in strains with carboxy terminal Ert2 fusion. These two trap lines and the related line N1IP::Cre(ERT2) form a complementary mapping tool kit to identify changes in Notch1 activation patterns in vivo as the consequence of genetic or pharmaceutical intervention, and illustrate the variation in Notch1 signal strength from one tissue to the next and across developmental time. PMID- 25725070 TI - Drosophila MAGI interacts with RASSF8 to regulate E-Cadherin-based adherens junctions in the developing eye. AB - Morphogenesis is crucial during development to generate organs and tissues of the correct size and shape. During Drosophila late eye development, interommatidial cells (IOCs) rearrange to generate the highly organized pupal lattice, in which hexagonal ommatidial units pack tightly. This process involves the fine regulation of adherens junctions (AJs) and of adhesive E-Cadherin (E-Cad) complexes. Localized accumulation of Bazooka (Baz), the Drosophila PAR3 homolog, has emerged as a critical step to specify where new E-Cad complexes should be deposited during junction remodeling. However, the mechanisms controlling the correct localization of Baz are still only partly understood. We show here that Drosophila Magi, the sole fly homolog of the mammalian MAGI scaffolds, is an upstream regulator of E-Cad-based AJs during cell rearrangements, and that Magi mutant IOCs fail to reach their correct position. We uncover a direct physical interaction between Magi and the Ras association domain protein RASSF8 through a WW domain-PPxY motif binding, and show that apical Magi recruits the RASSF8-ASPP complex during AJ remodeling in IOCs. We further show that this Magi complex is required for the cortical recruitment of Baz and of the E-Cad-associated proteins alpha- and beta-catenin. We propose that, by controlling the proper localization of Baz to remodeling junctions, Magi and the RASSF8-ASPP complex promote the recruitment or stabilization of E-Cad complexes at junction sites. PMID- 25725072 TI - Corrections. PMID- 25725074 TI - Isolation, identification, and whole genome sequencing of reticuloendotheliosis virus from a vaccine against Marek's disease. AB - According to the requirements of the Ministry of Agriculture of China, all vaccines must be screened for exogenous virus contamination before commercialization. A freeze-dried vaccine against Marek's disease was used to inoculate specific pathogen-free chickens, from which serum samples were collected after 42 days. The results were positive for reticuloendotheliosis virus antibody, which was indicative of reticuloendotheliosis virus contamination. After neutralization with serum positive for Marek's disease virus, chicken embryo fibroblasts were inoculated with the vaccine. Afterward, viral isolation and identification were performed. One reticuloendotheliosis virus strain (MD-2) was isolated and verified using an immunofluorescence assay. Polymerase chain reaction amplification of the provirus MD-2 genome was performed using seven overlapping fragments as primers. The amplified products were sequenced and spliced to obtain the whole MD-2 genome sequence. The full genome length of MD-2 was 8,284 bp, which had an identity greater than 99% with the prairie chicken isolate APC-566 from the US, the goose-derived isolate 3410/06 from Taiwan, and the chicken-derived reticuloendotheliosis virus isolate HLJR0901 from Heilongjiang Province, China. The MD-2 was phylogenetically close to these isolates. The identity with REV isolate HA9901 from Jiangsu Province of China was 96.7%. The MD-2 had the lowest identity with duck-derived Sin Nombre virus from the United States, with the value of only 93.5%. The main difference lay in the U3 region of the long terminal repeat. The present research indicated that some vaccines produced during specific periods in China might be contaminated by reticuloendotheliosis virus. The reticuloendotheliosis virus strain isolated from the vaccine was phylogenetically close to the prevalent strain, with only minor variations. PMID- 25725071 TI - GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression. AB - Farnesoid X receptor (FXR) functions as a regulator of bile acid and lipid homeostasis and is recognized as a promising therapeutic target for metabolic diseases. The biologic function of FXR is mediated in part by a small heterodimer partner (SHP); ligand-activated FXR enhances SHP expression, and SHP in turn represses the activity of multiple transcription factors. This study aimed to investigate the effect of FXR activation on expression of the major drug metabolizing enzyme CYP3A4. The effects of 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2 chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), a synthetic agonist of FXR, on the expression and activity of CYP3A4 were examined in primary human hepatocytes by using quantitative real-time polymerase chain reaction and S9 phenotyping. In human hepatocytes, treatment of GW4064 (1 MUM) for 48 hours resulted in a 75% decrease in CYP3A4 mRNA expression and a 25% decrease in CYP3A4 activity, accompanied by ~3-fold increase in SHP mRNA expression. In HepG2 cells, SHP repressed transactivation of CYP3A4 promoter by pregnane X receptor (PXR), constitutive androstane receptor (CAR), and glucocorticoid receptor. Interestingly, GW4064 did not repress expression of CYP2B6, another target gene of PXR and CAR; GW4064 enhanced CYP2B6 promoter activity. In conclusion, GW4064 represses CYP3A4 expression in human hepatocytes, potentially through upregulation of SHP expression and subsequent repression of CYP3A4 promoter activity. Clinically significant drug-drug interaction involving FXR agonists and CYP3A4 substrates may occur. PMID- 25725075 TI - Are peripheral Mott cells an indication of stress or inefficient immunity? AB - Atypical plasmacytes having distinctive cytoplasmic vacuoles (Mott cells) were detected in 77/1,000 (7.7%) of commercial hens housed conventionally, in aviaries, or in enriched environments. The earliest Mott positive peripheral blood samples were at placement (18 wk) from 2 consecutive commercial flocks. Additional samples obtained at 32, 48, 56, and 77 wk were positive. Most Mott cells came from hens with high total white blood cell counts as a component of leukocytosis. However, Mott cells were found in hens with low total white blood cell counts, and low heterophil/lymphocyte ratios. Phagocytosis of bacteria by some Mott cells was a remarkable feature. Many of the Mott positive hens had polymicrobial bacteremia and a few had fungemia likely accounting for the leukocytosis. In other cases, free-swimming bacteria were located near to a Mott cell. These atypical cells were in the peripheral blood samples from other poultry; a tom at slaughter (17 wk), experimental toms (10 wk), and experimental ducklings. Examples are included.As descriptions of avian Mott cells are few, the purpose of describing these cells is their contribution to hematology, immunology, and cytology. Mott cells like other atypia are sentinels, frank cytological indicators of an unusual hemogram, and consequently infer stress. Therefore, they bear directly on welfare issues. PMID- 25725076 TI - Antibiotic resistance profiles among mesophilic aerobic bacteria in Nigerian chicken litter and associated antibiotic resistance genes1. AB - The effect of global antibiotic use practices in livestock on the emergence of antibiotic resistant pathogens is poorly understood. There is a paucity of data among African nations, which suffer from high rates of antibiotic resistant infections among the human population. Escherichia (29.5%), Staphylococcus (15.8%), and Proteus (15.79%) were the dominant bacterial genera isolated from chicken litter from four different farms in Zaria, Nigeria, all of which contain human pathogenic members. Escherichia isolates were uniformly susceptible to augmentin and cefuroxime, but resistant to sulfamethoxazole (54.5%), ampicillin (22.7%), ciprofloxacin (18.2%), cephalothin (13.6%) and gentamicin (13.6%). Staphylococcus isolates were susceptible to ciprofloxacin, gentamicin, and sulfamethoxazole, but resistant to tetracycline (86.7%), erythromycin (80%), clindamycin (60%), and penicillin (33.3%). Many of the isolates (65.4%) were resistant to multiple antibiotics, with a multiple antibiotic resistance index (MARI) >= 0.2. sul1, sul2, and vanA were the most commonly detected antibiotic resistance genes among the isolates. Chicken litter associated with antibiotic use and farming practices in Nigeria could be a public health concern given that the antibiotic resistant patterns among genera containing pathogens indicate the potential for antibiotic treatment failure. However, the MARI values were generally lower than reported for Escherichia coli from intensive poultry operations in industrial nations. PMID- 25725079 TI - Non-small cell lung cancer in young adults: presentation and survival in the English National Lung Cancer Audit. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) in young adults is a rare but devastating illness with significant socioeconomic implications, and studies of this patient subgroup are limited. AIM: This study employed the National Lung Cancer Audit to compare the clinical features and survival of young adults with NSCLC with the older age groups. DESIGN: A retrospective cohort review using a validated national audit dataset. METHODS: Data were analysed for the period between 1 January 2004 and 31 December 2011. Young adults were defined as between 18 and 39 years, and all others were divided into decade age groups, up to the 80 years and above group. We performed logistic and Cox regression analyses to assess clinical outcomes. RESULTS: Of a total of 1 46 422 patients, 651 (0.5%) were young adults, of whom a higher proportion had adenocarcinoma (48%) than in any other age group. Stage distribution of NSCLC was similar across the age groups and 71% of young patients had stage IIIb/IV. Performance status (PS) was 0 1 for 85%. Young adults were more likely to have surgery and chemotherapy compared with the older age groups and had better overall and post-operative survival. The proportion with adenocarcinoma, better PS and that receiving surgery or chemotherapy diminished progressively with advancing decade age groups. CONCLUSION: In our cohort of young adults with NSCLC, the majority had good PS despite the same late-stage disease as older patients. They were more likely to have treatment and survive longer than older patients. PMID- 25725080 TI - Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. PMID- 25725081 TI - Erratum. PMID- 25725082 TI - Paternal obesity in a rodent model affects placental gene expression in a sex specific manner. AB - Fetal growth restriction (FGR) is a major obstetric complication stemming from poor placental development. We have previously demonstrated that paternal obesity in mice is associated with impaired embryo development and significantly reduced fetal and placental weights. We hypothesised that the FGR observed in our rodent model of paternal diet-induced obesity is associated with alterations in metabolic, cell signalling and stress pathways. Male C57BL/6 mice were fed either a normal or high-fat diet for 10 weeks before sperm collection for IVF and subsequent embryo transfer. On embryonic day 14, placentas were collected and RNA extracted from both male and female placentas to assess mRNA expression of 24 target genes using custom RT-qPCR arrays. Peroxisome proliferator-activated receptor alpha (Ppara) and caspase-12 (Casp12) expression were significantly altered in male placentas from obese fathers compared with normal (P<0.05), but not female placentas. PPARA and CASP12 proteins were localised within the placenta to trophoblast giant cells by immunohistochemistry, and relative protein abundance was determined by western blot analysis. DNA was also extracted from the same placentas to determine methylation status. Global DNA methylation was significantly increased in female placentas from obese fathers compared with normal (P<0.05), but not male placentas. In this study, we demonstrate for the first time that paternal obesity is associated with changes in gene expression and methylation status of extraembryonic tissue in a sex-specific manner. These findings reinforce the negative consequences of paternal obesity before conception, and emphasise the need for more lifestyle advice for prospective fathers. PMID- 25725083 TI - Germination and ultrastructural studies of seeds produced by a fast-growing, drought-resistant tree: implications for its domestication and seed storage. AB - Seed ageing during storage is one of the main causes of reduction in seed quality and this results in loss of vigour and failure to thrive. Finding appropriate storage conditions to ameliorate deterioration due to ageing is, therefore, essential. Ultrastructural changes in cellular organelles during storage and seed germination rates are valuable indices of damage that occurs during seed ageing. There is increasing interest in Moringa oleifera Lam. because of its multiple uses as an agroforestry crop. Seeds of this species lose their viability within 6 12 months of harvest but no scientific information is available on the longevity of seed stored in the fruit (capsules). In most undeveloped countries, seeds are still stored inside the fruit by traditional methods in special handmade structures. In this experiment we tried to simulate these traditional storage conditions. Capsules of Moringa were stored at ambient room temperature for 12, 24 and 36 months. The ultrastructure, solute leakage and viability of seed were investigated. The ultrastructure of 1-year-old seed showed no sign of deterioration. It was evident, however, that some cells of the 3-year-old seed had deteriorated. The remnants of the outer and inner two integuments that remain tightly attached to the cotyledons probably play a role in seed dormancy. No significant difference was found between germination percentage of fresh and 1 year-old seed. The germination percentage decreased significantly from 2 years of storage onward. The decrease in seed viability during storage was associated with a loss in membrane integrity which was evidenced by an increase in electrolyte leakage. Our findings indicate that the longevity of M. oleifera seeds can be maintained if they are stored within their capsules. PMID- 25725084 TI - Mutualism-disrupting allelopathic invader drives carbon stress and vital rate decline in a forest perennial herb. AB - Invasive plants can negatively affect belowground processes and alter soil microbial communities. For native plants that depend on soil resources from root fungal symbionts (RFS), invasion could compromise their resource status and subsequent ability to manufacture and store carbohydrates. Herbaceous perennials that depend on RFS-derived resources dominate eastern North American forest understories. Therefore, we predict that forest invasion by Alliaria petiolata, an allelopathic species that produces chemicals that are toxic to RFS, will diminish plant carbon storage and fitness. Over a single growing season, the loss of RFS could reduce a plant's photosynthetic physiology and carbon storage. If maintained over multiple growing seasons, this could create a condition of carbon stress and declines in plant vital rates. Here we characterize the signals of carbon stress over a short timeframe and explore the long-term consequence of Alliaria invasion using Maianthemum racemosum, an RFS-dependent forest understory perennial. First, in a greenhouse experiment, we treated the soil of potted Maianthemum with fresh leaf tissue from either Alliaria or Hesperis matronalis (control) for a single growing season. Alliaria-treated plants exhibit significant overall reductions in total non-structural carbohydrates and have 17 % less storage carbohydrates relative to controls. Second, we monitored Maianthemum vital rates in paired experimental plots where we either removed emerging Alliaria seedlings each spring or left Alliaria at ambient levels for 7 years. Where Alliaria is removed, Maianthemum size and vital rates improve significantly: flowering probability increases, while the probability of plants regressing to non-flowering stages or entering prolonged dormancy are reduced. Together, our results are consistent with the hypothesis that disruption of a ubiquitous mutualism following species invasion creates symptoms of carbon stress for species dependent on RFS. Disruption of plant-fungal mutualisms may generally contribute to the common, large-scale declines in forest biodiversity observed in the wake of allelopathic invaders. PMID- 25725085 TI - Ecotypic variation in growth responses to simulated herbivory: trade-off between maximum relative growth rate and tolerance to defoliation in an annual plant. AB - It has been hypothesized that slow-growing plants are more likely to maximize above-ground biomass and fitness when defoliated by herbivores than those with an already high relative growth rate (RGR). Some populations of the annual herb Datura stramonium L. can tolerate foliar damage better than others. The physiological basis of this difference is examined here in a comparative study of two ecotypes that differ in tolerance and maximum growth rate, using a growth analytical approach. One hundred and fifty-four plants of each ecotype grown under controlled conditions were suddenly defoliated (35 % of total leaf area removed) and a similar sample size of plants remained undefoliated (control). Ontogenetic plastic changes in RGR and its growth components [net assimilation rate (NAR), specific leaf area and leaf weight ratio (LWR)] after defoliation were measured to determine whether these plastic changes maximize plant growth and fitness. Different ontogenetic phases of the response were discerned and increased RGR of defoliated plants was detected at the end of the experimental period, but brought about by a different growth component (NAR or LWR) in each ecotype. These changes in RGR are putatively related to increases in fitness in defoliated environments. At the intra-specific scale, data showed a trade-off between the ability to grow under benign environmental conditions and the ability to tolerate resource limitation due to defoliation. PMID- 25725088 TI - American Heart Association's Life's Simple 7 and risk of venous thromboembolism: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. AB - BACKGROUND: The American Heart Association's Life's Simple 7 metric is being used to track the population's cardiovascular health (CVH) toward a 2020 goal for improvement. The metric includes body mass index (BMI), blood pressure, cholesterol, glucose, physical activity (PA), cigarette smoking, and diet. We hypothesized a lower risk of venous thromboembolism (VTE) with favorable Life's Simple 7 scores. METHODS AND RESULTS: REGARDS recruited 30,239 black and white participants >=45 years of age across the United States in 2003-2007. A 14-point summary score for Life's Simple 7 classified participants into inadequate (0 to 4 points), average (5 to 9 points), and optimal (10 to 14 points) categories. Hazard ratios (HRs) of incident VTE were calculated for these categories, adjusting for age, sex, race, income, education, and region of residence. For comparison, HRs of VTE were calculated using the Framingham 10-year coronary risk score. There were 263 incident VTE cases over 5.0 years of follow-up; incidence rates per 1000 person-years declined from 2.9 (95% confidence interval [CI], 2.3 to 3.7) among those in the inadequate category to 1.8 (95% CI, 1.4 to 2.4) in the optimal category. Compared to the inadequate category, participants in the average category had a 38% lower VTE risk (95% CI, 11 to 57) and participants in the optimal category had a 44% lower risk (95% CI, 18 to 62). The individual score components related to lower VTE risk were ideal PA and BMI. There was no association of Framingham Score with VTE. CONCLUSIONS: Life's Simple 7, a CVH metric, was associated with reduced VTE risk. Findings suggest that efforts to improve the population's CVH may reduce VTE incidence. PMID- 25725089 TI - Variation in critical care unit admission rates and outcomes for patients with acute coronary syndromes or heart failure among high- and low-volume cardiac hospitals. AB - BACKGROUND: Little is known about cross-hospital differences in critical care units admission rates and related resource utilization and outcomes among patients hospitalized with acute coronary syndromes (ACS) or heart failure (HF). METHODS AND RESULTS: Using a population-based sample of 16,078 patients admitted to a critical care unit with a primary diagnosis of ACS (n=14,610) or HF (n=1467) between April 1, 2003 and March 31, 2013 in Alberta, Canada, we stratified hospitals into high (>250), medium (200 to 250), or low (<200) volume based on their annual volume of all ACS and HF hospitalization. The percentage of hospitalized patients admitted to critical care units varied across low, medium, and high-volume hospitals for both ACS and HF as follows: 77.9%, 81.3%, and 76.3% (P<0.001), and 18.0%, 16.3%, and 13.0% (P<0.001), respectively. Compared to low volume units, critical care patients with ACS and HF admitted to high-volume hospitals had shorter mean critical care stays (56.6 versus 95.6 hours, P<0.001), more critical care procedures (1.9 versus 1.2 per patient, <0.001), and higher resource-intensive weighting (2.8 versus 1.5, P<0.001). No differences in in hospital mortality (5.5% versus 6.2%, adjusted odds ratio 0.93; 95% CI, 0.61 to 1.41) were observed between high- and low-volume hospitals; however, 30-day cardiovascular readmissions (4.6% versus 6.8%, odds ratio 0.77; 95% CI, 0.60 to 0.99) and cardiovascular emergency-room visits (6.6% versus 9.5%, odds ratio 0.80; 95% CI, 0.69 to 0.94) were lower in high-volume compared to low-volume hospitals. Outcomes stratified by ACS or HF admission diagnosis were similar. CONCLUSIONS: Cardiac patients hospitalized in low-volume hospitals were more frequently admitted to critical care units and had longer hospitals stays despite lower resource-intensive weighting. These findings may provide opportunities to standardize critical care utilization for ACS and HF patients across high- and low-volume hospitals. PMID- 25725090 TI - SimSeq: a nonparametric approach to simulation of RNA-sequence datasets. AB - MOTIVATION: RNA sequencing analysis methods are often derived by relying on hypothetical parametric models for read counts that are not likely to be precisely satisfied in practice. Methods are often tested by analyzing data that have been simulated according to the assumed model. This testing strategy can result in an overly optimistic view of the performance of an RNA-seq analysis method. RESULTS: We develop a data-based simulation algorithm for RNA-seq data. The vector of read counts simulated for a given experimental unit has a joint distribution that closely matches the distribution of a source RNA-seq dataset provided by the user. We conduct simulation experiments based on the negative binomial distribution and our proposed nonparametric simulation algorithm. We compare performance between the two simulation experiments over a small subset of statistical methods for RNA-seq analysis available in the literature. We use as a benchmark the ability of a method to control the false discovery rate. Not surprisingly, methods based on parametric modeling assumptions seem to perform better with respect to false discovery rate control when data are simulated from parametric models rather than using our more realistic nonparametric simulation strategy. AVAILABILITY AND IMPLEMENTATION: The nonparametric simulation algorithm developed in this article is implemented in the R package SimSeq, which is freely available under the GNU General Public License (version 2 or later) from the Comprehensive R Archive Network (http://cran.rproject.org/). CONTACT: sgbenidt@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25725091 TI - GlycoProfileAssigner: automated structural assignment with error estimation for glycan LC data. AB - MOTIVATION: Sequencing glycan structures is a difficult problem that requires the use of multiple experimental approaches. One powerful approach to glycan sequencing is the combination of liquid chromatography with sequential exoglycosidase digestions; however, interpreting this can be difficult and time consuming. To aid this process, we introduce GlycoProfileAssigner, software for automated structural assignment of glycan profile data from liquid chromatography experiments. RESULTS: GlycoProfileAssigner has been tested on human IgG data, and can retrieve the correct structure in 14 out of 16 peaks tested. AVAILABILITY AND IMPLEMENTATION: The programme and its source code is available at https://bitbucket.org/fergaljd/glycoprofileassigner CONTACT: : pauline.rudd@nibrt.ie SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25725092 TI - The Effect of Self-Monitoring of Blood Pressure on Medication Adherence and Lifestyle Factors: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Self-monitoring of blood pressure (SMBP) can contribute to reduced blood pressure in people with hypertension. Potential mediators include increased medication, improved adherence, and changes in lifestyle factors including dietary change and increased physical activity. The objective of this review was to determine the effect of SMBP on medication adherence, medication persistence, and lifestyle factors in people with hypertension. METHODS: Electronic bibliographic databases were searched through February 2014 to identify randomized controlled trials that compared SMBP to control/usual care in ambulatory hypertensive patients and reported medication or nonpharmacologic treatment adherence measures. RESULTS: Twenty-eight trials with 7,021 participants fulfilled the inclusion criteria. Medication adherence was assessed in 25 trials (89%), dietary outcomes in 8 (29%), physical activity in 6 (21%), and medication persistence in 1 (4%). Blood pressure was assessed in 26 studies (93%). Follow-up ranged from 2 weeks to 12 months. Pooled results of 13 studies demonstrated a small but significant overall effect on medication adherence in favor of SMBP interventions (standardized mean difference 0.21, 95% CI 0.08, 0.34), with moderate heterogeneity (I2 = 43%). Standardized mean difference was used to express the size of intervention effect in each study relative to the variability observed, and was used to combine the results of studies where different measures of medication adherence were used. Where SMBP interventions had a significant effect on lifestyle factor change, the effect was unlikely to be clinically significant. Pooled results of 11 studies demonstrate a significant overall effect on diastolic blood pressure in favor of SMBP (weighted mean difference -2.02, 95% CI -2.93, -1.11), with low heterogeneity (I2 = 0%). A test for subgroup differences showed no difference when studies were grouped according to whether medication adherence was significantly improved or not. CONCLUSIONS: SMBP may contribute to improvements in medication adherence in hypertensives. However, evidence for the effect of SMBP on lifestyle change and medication persistence is scarce, of poor quality, and suggests little clinically relevant benefit. PMID- 25725093 TI - Current perspective on protein S-acylation in plants: more than just a fatty anchor? AB - Membranes are an important signalling platform in plants. The plasma membrane is the point where information about the external environment must be converted into intracellular signals, while endomembranes are important sites of protein trafficking, organization, compartmentalization, and intracellular signalling. This requires co-ordinating the spatial distribution of proteins, their activation state, and their interacting partners. This regulation frequently occurs through post-translational modification of proteins. Proteins that associate with the cell membrane do so through transmembrane domains, protein protein interactions, lipid binding motifs/domains or use the post-translational addition of lipid groups as prosthetic membrane anchors. S-acylation is one such lipid modification capable of anchoring proteins to the membrane. Our current knowledge of S-acylation function in plants is fairly limited compared with other post-translational modifications and S-acylation in other organisms. However, it is becoming increasingly clear that S-acylation can act as more than just a simple membrane anchor: it can also act as a regulatory mechanism in signalling pathways in plants. S-acylation is, therefore, an ideal mechanism for regulating protein function at membranes. This review discusses our current knowledge of S acylated proteins in plants, the interaction of different lipid modifications, and the general effects of S-acylation on cellular function. PMID- 25725094 TI - Membrane nanodomains in plants: capturing form, function, and movement. AB - The plasma membrane is the interface between the cell and the external environment. Plasma membrane lipids provide scaffolds for proteins and protein complexes that are involved in cell to cell communication, signal transduction, immune responses, and transport of small molecules. In animals, fungi, and plants, a substantial subset of these plasma membrane proteins function within ordered sterol- and sphingolipid-rich nanodomains. High-resolution microscopy, lipid dyes, pharmacological inhibitors of lipid biosynthesis, and lipid biosynthetic mutants have been employed to examine the relationship between the lipid environment and protein activity in plants. They have also been used to identify proteins associated with nanodomains and the pathways by which nanodomain-associated proteins are trafficked to their plasma membrane destinations. These studies suggest that plant membrane nanodomains function in a context-specific manner, analogous to similar structures in animals and fungi. In addition to the highly conserved flotillin and remorin markers, some members of the B and G subclasses of ATP binding cassette transporters have emerged as functional markers for plant nanodomains. Further, the glycophosphatidylinositol anchored fasciclin-like arabinogalactan proteins, that are often associated with detergent-resistant membranes, appear also to have a functional role in membrane nanodomains. PMID- 25725095 TI - Greasy tactics in the plant-pathogen molecular arms race. AB - The modification of proteins by the attachment of fatty acids is a targeting tactic involved in mechanisms of both plant immunity and bacterial pathogenesis. The plant plasma membrane (PM) is a key battleground in the war against disease causing microbes. This membrane is armed with an array of sensor proteins that function as a surveillance system to detect invading pathogens. Several of these sensor proteins are directed to the plasma membrane through the covalent addition of fatty acids, a process termed fatty acylation. Phytopathogens secrete effector proteins into the plant cell to subvert these surveillance mechanisms, rendering the host susceptible to infection. The targeting of effectors to specific locales within plant cells, particularly the internal face of the host PM, is critical for their virulence function. Several bacterial effectors hijack the host fatty acylation machinery to be modified and directed to this contested locale. To find and fight these fatty acylated effectors the plant leverages lipid-modified intracellular sensors. This review provides examples featuring how fatty acylation is a battle tactic used by both combatants in the molecular arms race between plants and pathogens. Also highlighted is the exploitation of a specific form of host-mediated fatty acid modification, which appears to be exclusively employed by phytopathogenic effector proteins. PMID- 25725097 TI - STAT-1 facilitates the ATM activated checkpoint pathway following DNA damage. PMID- 25725096 TI - JCS Editor changes. PMID- 25725098 TI - The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis. AB - Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are a diverse family of pattern recognition receptors that are essential mediators of inflammation and host defense in the gastrointestinal system. Recent studies have identified a subgroup of inflammasome forming NLRs that modulate the mucosal immune response during inflammatory bowel disease (IBD) and colitis associated tumorigenesis. To better elucidate the contribution of NLR family members in IBD and cancer, we conducted a retrospective analysis of gene expression metadata from human patients. These data revealed that NLRP1, an inflammasome forming NLR, was significantly dysregulated in IBD and colon cancer. To better characterize the function of NLRP1 in disease pathogenesis, we used Nlrp1b(-/-) mice in colitis and colitis-associated cancer models. In this paper, we report that NLRP1 attenuates gastrointestinal inflammation and tumorigenesis. Nlrp1b(-/-) mice demonstrated significant increases in morbidity, inflammation, and tumorigenesis compared with wild-type animals. Similar to data previously reported for related inflammasome forming NLRs, the increased inflammation and tumor burden was correlated with attenuated levels of IL-1beta and IL-18. Further mechanistic studies using bone marrow reconstitution experiments revealed that the increased disease pathogenesis in the Nlrp1b(-/-) mice was associated with nonhematopoietic derived cells and suggests that NLRP1 functions in the colon epithelial cell compartment to attenuate tumorigenesis. Taken together, these data identify NLRP1 as an essential mediator of the host immune response during IBD and cancer. These findings are consistent with a model whereby multiple NLR inflammasomes attenuate disease pathobiology through modulating IL-1beta and IL-18 levels in the colon. PMID- 25725099 TI - Egress of mature murine regulatory T cells from the thymus requires RelA. AB - The mechanism of egress of mature regulatory T cells (Tregs) from the thymus to the periphery remains enigmatic, as does the nature of those factors expressed in the thymic environment. In this study, we examined the fate of thymic Tregs in TNF-alpha/RelA double-knockout (TA-KO) mice, because TA-KO mice retain a Treg population in the thymus but have only a small Treg population at the periphery. Transplantation of whole TA-KO thymus to under the kidney capsule of Rag1-null mice failed to induce the production of donor-derived splenic Tregs expressing neuropilin-1, which is reported to be a marker of naturally occurring Tregs, indicating that TA-KO thymic Tregs either do not leave the thymus or are lost at the periphery. We next transplanted enriched TA-KO thymic Tregs to the peripheries of TA-KO mice and traced mouse survival. Transplantation of TA-KO thymic Tregs rescued the lethality in TA-KO mice, demonstrating that TA-KO thymic Tregs remained functional at the periphery. The TA-KO thymic Treg population had highly demethylated CpG motifs in the foxp3 locus, indicating that the cells were arrested at a late mature stage. Also, the population included a large subpopulation of Tregs expressing IL-7Ralpha, which is a possible marker of late stage mature Tregs. Finally, TA-KO fetal liver chimeric mice developed a neuropilin-1(+) splenic Treg population from TA-KO cells, suggesting that Treg arrest was caused by a lack of RelA in the thymic environment. Taken together, these results suggest that egress of mature Tregs from the thymus depends on RelA in the thymic environment. PMID- 25725101 TI - Group V secreted phospholipase A2 is upregulated by IL-4 in human macrophages and mediates phagocytosis via hydrolysis of ethanolamine phospholipids. AB - Studies on the heterogeneity and plasticity of macrophage populations led to the identification of two major polarization states: classically activated macrophages or M1, induced by IFN-gamma plus LPS, and alternatively activated macrophages, induced by IL-4. We studied the expression of multiple phospholipase A2 enzymes in human macrophages and the effect that polarization of the cells has on their levels. At least 11 phospholipase A2 genes were found at significant levels in human macrophages, as detected by quantitative PCR. None of these exhibited marked changes after treating the cells with IFN-gamma plus LPS. However, macrophage treatment with IL-4 led to strong upregulation of the secreted group V phospholipase A2 (sPLA2-V), both at the mRNA and protein levels. In parallel with increasing sPLA2-V expression levels, IL-4-treated macrophages exhibited increased phagocytosis of yeast-derived zymosan and bacteria, and we show that both events are causally related, because cells deficient in sPLA2-V exhibited decreased phagocytosis, and cells overexpressing the enzyme manifested higher rates of phagocytosis. Mass spectrometry analyses of lipid changes in the IL-4-treated macrophages suggest that ethanolamine lysophospholipid (LPE) is an sPLA2-V-derived product that may be involved in regulating phagocytosis. Cellular levels of LPE are selectively maintained by sPLA2-V. By supplementing sPLA2-V deficient cells with LPE, phagocytosis of zymosan or bacteria was fully restored in IL-4-treated cells. Collectively, our results show that sPLA2-V is required for efficient phagocytosis by IL-4-treated human macrophages and provide evidence that sPLA2-V-derived LPE is involved in the process. PMID- 25725100 TI - Inhibiting STAT5 by the BET bromodomain inhibitor JQ1 disrupts human dendritic cell maturation. AB - Maturation of dendritic cells (DCs) is required to induce T cell immunity, whereas immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. In this study, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs, as indicated by defective upregulation of costimulatory molecules and CD83, as well as reduced secretion of IL-12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83, and IL-12. The activation of STAT5 in Mo-DCs is mediated by GM-CSF produced following LPS stimulation. Activated STAT5 then leads to increased expression of both GM-CSF and GM-CSFR, triggering an autocrine loop that further enhances STAT5 signaling and enabling Mo-DCs to acquire a more mature phenotype. JQ1 decreases the ability of Mo-DCs to induce allogeneic CD4(+) and CD8(+) T cell proliferation and production of proinflammatory cytokines. Furthermore, JQ1 leads to a reduced generation of inflammatory CD8(+) T cells and decreased Th1 differentiation. Thus, JQ1 impairs LPS-induced Mo-DC maturation by inhibiting STAT5 activity, thereby generating cells that can only weakly stimulate an adaptive-immune response. Therefore, JQ1 could have beneficial effects in treating T cell mediated inflammatory diseases. PMID- 25725102 TI - CXCL10 triggers early microglial activation in the cuprizone model. AB - A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology. PMID- 25725103 TI - Biased agonism as a novel strategy to harness the proresolving properties of melanocortin receptors without eliciting melanogenic effects. AB - There is a need for novel approaches to control pathologies with overexuberant inflammatory reactions. Targeting melanocortin (MC) receptors represents a promising therapy for obesity and chronic inflammation, but lack of selectivity and safety concerns limit development. A new way to increase selectivity of biological effects entails the identification of biased agonists. In this study, we characterize the small molecule AP1189 as a biased agonist at receptors MC1 and MC3. Although not provoking canonical cAMP generation, AP1189 addition to MC1 or MC3, but not empty vector, transfected HEK293 cells caused ERK1/2 phosphorylation, a signaling responsible for the proefferocytic effect evoked in mouse primary macrophages. Added to macrophage cultures, AP1189 reduced cytokine release, an effect reliant on both MC1 and MC3 as evident from the use of Mc1r(-/ ) and Mc3r(-/-) macrophages. No melanogenesis was induced by AP1189 in B16-F10 melanocytes. In vivo, oral AP1189 elicited anti-inflammatory actions in peritonitis and, upon administration at the peak of inflammation, accelerated the resolution phase by ~3-fold. Finally, given the clinical efficacy of adrenocorticotropin in joint diseases, AP1189 was tested in experimental inflammatory arthritis, where this biased agonist afforded significant reduction of macroscopic and histological parameters of joint disruption. These proof-of concept analyses with AP1189, an active oral anti-inflammatory and resolution promoting compound, indicate that biased agonism at MC receptors is an innovative, viable approach to yield novel anti-inflammatory molecules endowed with a more favorable safety profile. PMID- 25725105 TI - Properdin provides protection from Citrobacter rodentium-induced intestinal inflammation in a C5a/IL-6-dependent manner. AB - Citrobacter rodentium is an attaching and effacing mouse pathogen that models enteropathogenic and enterohemorrhagic Escherichia coli in humans. The complement system is an important innate defense mechanism; however, only scant information is available about the role of complement proteins during enteric infections. In this study, we examined the impact of the lack of properdin, a positive regulator of complement, in C. rodentium-induced colitis. Following infection, properdin knockout (P(KO)) mice had increased diarrhea and exacerbated inflammation combined with defective epithelial cell-derived IL-6 and greater numbers of colonizing bacteria. The defect in the mucosal response was reversed by administering exogenous properdin to P(KO) mice. Then, using in vitro and in vivo approaches, we show that the mechanism behind the exacerbated inflammation of P(KO) mice is due to a failure to increase local C5a levels. We show that C5a directly stimulates IL-6 production from colonic epithelial cells and that inhibiting C5a in infected wild-type mice resulted in defective epithelial IL-6 production and exacerbated inflammation. These outcomes position properdin early in the response to an infectious challenge in the colon, leading to complement activation and C5a, which in turn provides protection through IL-6 expression by the epithelium. Our results unveil a previously unappreciated mechanism of intestinal homeostasis involving complement, C5a, and IL-6 during bacteria triggered epithelial injury. PMID- 25725104 TI - c-FLIP protects T lymphocytes from apoptosis in the intrinsic pathway. AB - Apoptosis can be induced by either death receptors on the plasma membrane (extrinsic pathway) or the damage of the genome and/or cellular organelles (intrinsic pathway). Previous studies suggest that cellular caspase 8 (FLICE) like inhibitory protein (c-FLIP) promotes cell survival in death receptor-induced apoptosis pathway in T lymphocytes. Independent of death receptor signaling, mitochondria sense apoptotic stimuli and mediate the activation of effector caspases. Whether c-FLIP regulates mitochondrion-dependent apoptotic signals remains unknown. In this study, c-FLIP gene was deleted in mature T lymphocytes in vitro, and the role of c-FLIP protein in intrinsic apoptosis pathway was studied. In resting T cells treated with the intrinsic apoptosis inducer, c-FLIP suppressed cytochrome c release from mitochondria. Bim-deletion rescued the enhanced apoptosis in c-FLIP-deficient T cells, whereas inhibition of caspase 8 did not. Different from activated T cells, there was no necroptosis or increase in reactive oxygen species in c-FLIP-deficient resting T cells. These data suggest that c-FLIP is a negative regulator of intrinsic apoptosis pathway in T lymphocytes. PMID- 25725106 TI - Collagen induces maturation of human monocyte-derived dendritic cells by signaling through osteoclast-associated receptor. AB - Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-kappaB-dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR-collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs. PMID- 25725107 TI - IL-1 receptor type 2 suppresses collagen-induced arthritis by inhibiting IL-1 signal on macrophages. AB - IL-1alpha and IL-1beta (in this article referred to as IL-1) play important roles in host defense against infection and inflammatory diseases. IL-1R1 is the receptor for IL-1, and IL-1R2 is suggested to be a decoy receptor, because it lacks the signal-transducing TIR domain in the cytoplasmic part. However, the roles of IL-1R2 in health and disease remain largely unknown. In this study, we generated EGFP-knock-in Il1r2(-/-) mice and showed that they were highly susceptible to collagen-induced arthritis, an animal model for rheumatoid arthritis in which the expression of IL-1R2 is augmented in inflammatory joints. Il1r2 was highly expressed in neutrophils but had only low expression in other cells, including monocytes and macrophages. Ab production and T cell responses against type II collagen were normal in Il1r2(-/-) mice. Despite the high expression in neutrophils, no effects of Il1r2 deficiency were observed; however, we found that production of inflammatory mediators in response to IL-1 was greatly enhanced in Il1r2(-/-) macrophages. These results suggest that IL-1R2 is an important regulator of arthritis by acting specifically on macrophages as a decoy receptor for IL-1. PMID- 25725108 TI - Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center. AB - Long-lasting Ab responses rely on the germinal center (GC), where B cells bearing high-affinity Ag receptors are selected from a randomly mutated pool to populate the memory and plasma cell compartments. Signaling downstream of the BCR is dampened in GC B cells, raising the possibility that Ag presentation and competition for T cell help, rather than Ag-dependent signaling per se, drive these critical selection events. In this study we use an in vivo reporter of BCR signaling, Nur77-eGFP, to demonstrate that although BCR signaling is reduced among GC B cells, a small population of cells exhibiting GC light zone phenotype (site of Ag and follicular helper T cell encounter) express much higher levels of GFP. We show that these cells exhibit somatic hypermutation, gene expression characteristic of signaling and selection, and undergo BCR signaling in vivo. PMID- 25725109 TI - Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis. AB - Complement is implicated in the pathogenesis of rheumatoid arthritis (RA); elevated levels of complement activation products have been measured in plasma, synovial fluid, and synovial tissues of patients. Complement polymorphisms are associated with RA in genome-wide association studies. Coding-region polymorphisms may directly impact protein activity; indeed, we have shown that complement polymorphisms affecting a single amino acid change cause subtle changes in individual component function that in combination have dramatic effects on complement activity and disease risk. In this study, we explore the functional consequences of a single nucleotide polymorphism (SNP) (rs17611) encoding a V802I polymorphism in C5 and propose a mechanism for its link to RA pathology. Plasma levels of C5, C5a, and terminal complement complex were measured in healthy and RA donors and correlated to rs17611 polymorphic status. Impact of the SNP on C5 functionality was assessed. Plasma C5a levels were significantly increased and C5 levels significantly lower with higher copy number of the RA risk allele for rs17611, suggesting increased turnover of C5 V802. Functional assays using purified C5 variants revealed no significant differences in lytic activity, suggesting that increased C5 V802 turnover was not mediated by complement convertase enzymes. C5 is also cleaved in vivo by proteases; the C5 V802 variant was more sensitive to cleavage with elastase and the "C5a" generated was biologically active. We hypothesize that this SNP in C5 alters the rate at which elastase generates active C5a in rheumatoid joints, hence recruiting neutrophils to the site thus maintaining a state of inflammation in arthritic joints. PMID- 25725110 TI - Proinflammatory responses and higher IL-10 production by T cells correlate with protection against malaria during pregnancy and delivery outcomes. AB - Pregnancy triggers immunological changes aimed to tolerate the fetus. However, it has not been properly addressed whether similar changes occur in tropical areas with high infection pressure and whether these changes render women more susceptible to infectious diseases. We compared the frequencies of T cell subsets, including regulatory T cells, in pregnant and nonpregnant women from Papua New Guinea, a high malaria transmission area, and from Spain, a malaria free country. We also assessed the relationship among these cellular subsets, malaria infection, and delivery outcomes. CD4(+)FOXP3(+)CD127(low) T cells (Tregs) were decreased in pregnant women in both countries but were not associated with malaria infection or poor delivery outcomes. An expansion of IFN gamma-producing cells and intracytoplasmic IFN-gamma levels was found in pregnant compared with nonpregnant women only in Papua New Guinea. Increased CD4(+)IL 10(+)IFN-gamma(+) frequencies and Treg-IFN-gamma production were found in women with current Plasmodium falciparum infection. Higher CD4(+)IL-10(-)IFN-gamma(+) T cells frequencies and production of proinflammatory cytokines (including TNF and IL-2) at recruitment (first antenatal visit) had a protective association with birth weight and future (delivery) P. falciparum infection, respectively. Higher intracellular IL-10 levels in T cells had a protective association with future P. falciparum infection and hemoglobin levels at delivery. The protective associations were found also with nonmalaria-specific T cell responses. Treg frequencies positively correlated with plasma eotaxin concentrations, but this subset did not express eotaxin receptor CCR3. Thus, an activated immune system during pregnancy might contribute to protection against malaria during pregnancy and poor delivery outcomes. PMID- 25725111 TI - CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. AB - We had previously demonstrated the role of CD103 integrin on lung tumor infiltrating lymphocyte (TIL) clones in promoting specific TCR-mediated epithelial tumor cell cytotoxicity. However, the contribution of CD103 on intratumoral T cell distribution and functions and the prognosis significance of TIL subpopulations in non-small cell lung carcinoma (NSCLC) have thus far not been systematically addressed. In this study, we show that an enhanced CD103(+) TIL subset correlates with improved early stage NSCLC patient survival and increased intraepithelial lymphocyte infiltration. Moreover, our results indicate that CD8(+)CD103(+) TIL, freshly isolated from NSCLC specimens, display transcriptomic and phenotypic signatures characteristic of tissue-resident memory T cells and frequently express PD-1 and Tim-3 checkpoint receptors. This TIL subset also displays increased activation-induced cell death and mediates specific cytolytic activity toward autologous tumor cells upon blockade of the PD 1-PD-L1 interaction. These findings emphasize the role of CD8(+)CD103(+) tissue resident memory T cells in promoting intratumoral CTL responses and support the rationale for using anti-PD-1 blocking Ab to reverse tumor-induced T cell exhaustion in NSCLC patients. PMID- 25725112 TI - A molecular phylogeny of Aeridinae (Orchidaceae: Epidendroideae) inferred from multiple nuclear and chloroplast regions. AB - The subtribe Aeridinae, which contains approximately 90 genera, is one of the most diverse and taxonomically puzzling groups in Orchidaceae. In the present study, the phylogenetic relationships of Aeridinae were reconstructed utilizing five DNA sequences (ITS, atpI-H, matK, psbA-trnH, and trnL-F) from 211 taxa in 74 genera. The results of the phylogenetic analyses indicate that Aeridinae is monophyletic and that the subtribe can primarily be grouped into 10 clades: (1) Saccolabium clade, (2) Chiloschista clade, (3) Phalaenopsis clade, (4) Thrixspermum clade, (5) Vanda clade, (6) Aerides clade, (7) Trichoglottis clade, (8) Abdominea clade, (9) Gastrochilus clade, and (10) Cleisostoma clade. In our examination, most genera of Aeridinae were well-supported as monophyletic, and several genera, namely, Pteroceras, Cleisostoma, Vandopsis, Diploprora, Malleola, and Robiquetia, were found to be polyphyletic as currently circumscribed. In addition, several classifications of intra-genera, such as the subgenus Codonosepalum of Taeniophyllum and the section Gastrochilus of Gastrochilus, were also revealed to be paraphyletic. Due to the many questions raised by our phylogenies, the present study may serve as a reference for future taxonomic studies of Aeridinae. PMID- 25725113 TI - Functional effects of beta3-adrenoceptor on pacemaker activity in interstitial cells of Cajal from the mouse colon. AB - We investigated the presence of beta3-adrenoceptor and its functional effects on pacemaker potentials in colonic interstitial cells of Cajal (ICCs) from mice. The whole-cell patch clamp technique was used to record pacemaker potentials in cultured ICCs and reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the mRNA transcript levels beta-adrenoceptors. The beta3 adrenoceptor agonist, BRL37344, reduced the frequency of pacemaker potentials in a concentration-dependent manner. The inhibitory effects of BRL37344 were blocked by the pretreatment of propranolol, a nonspecific beta-adrenoceptor antagonist, but not by the selective beta1-adrenoceptor antagonist atenolol and the selective beta2-adrenoceptor antagonist butoxamine. beta3-adrenoceptor antagonists SR59230A and L748337 blocked the inhibitory effects of BRL37344. RT-PCR revealed mRNA transcripts of beta1- and beta3-adrenoceptor, but not beta2-adrenoceptor, in c kit- and Ano-1-positive colonic ICCs. The K(+) channel blockers tetraethylammonium, apamin, and glibenclamide did not block the effects of BRL37344. N(omega)-Nitro-l-arginine methyl ester hydrochloride (L-NAME), an NO synthase inhibitor, and chelerythrine, a protein kinase C inhibitor, also did not block the effects of BRL37344. Noradrenaline mimicked the effects of BRL37344 in colonic ICCs. However, the inhibitory effects of noradrenaline on pacemaker potentials were blocked only by pretreatment with atenolol but not by butoxamine, SR59230A, or L748337. In small intestinal ICCs, BRL37344 had no effect on pacemaker potentials and mRNA transcripts of beta1-and beta2-adrenoceptor, but not beta3-adrenoceptor were detected. These results suggest that beta3 adrenoceptors are present in colonic ICCs and may play a role in regulating gastrointestinal motility by the inhibition of pacemaker potentials. PMID- 25725114 TI - The effect of R-(-)-deprenyl administration on reproductive parameters of rat males. AB - The aim of the study was to investigate the effect of R-(-)-deprenyl administration on the reproductive parameters of rat males. After 30 days of intraperitoneal administration of saline or 0.0025mg/kg (10(-5)mol/l) of R-(-) deprenyl dissolved in saline, males were mated with females of the same strain. Subsequently, animals were killed by thiopental, and their blood and sperm were collected. We found that epididymis of males exposed to R-(-)-deprenyl had higher sperm count (P<0.05), and females who mated with these males gave birth to a greater number of offspring (P<0.05) compared to control. The blood of experimental animals contained higher levels of testosterone (P<0.05), FSH (P<0.01), and total antioxidants (P<0.01). We did not detect sperm DNA fragmentation in control or in experimental males. Interestingly, round spermatids were often observed inside seminiferous tubules of experimental animals, but obviously without any negative consequences on male fertility. Our findings could be verified on a sample of human male volunteers treated for infertility, because human organism tolerate higher doses of R-(-)-deprenyl, which is a selective inhibitor of monoamine oxidase B employed in our experiment and used in the therapy of Parkinson's disease, rather well. PMID- 25725115 TI - Pharmacogenomics and targeted therapy of cancer: Focusing on non-small cell lung cancer. AB - Recent studies have been established high degree of genetic diversity in solid organ tumors among individuals and even between individual tumor cells. This intratumor and intertumor genetic diversity results in a heterogeneous tumor with unique characteristics which potentially allows effective drug therapy. The goal of pharmacogenomics is to elucidate the genetic network(s) that underlie drug efficacy and drug resistance. Advances in targeted and personalized therapy play an increasingly important role in many common cancers, notably lung cancer, due to the high incidence, prevalence, mortality and the greater tendency towards drug resistance seen in these patients. Non-small cell lung cancer (NSCLC) is characterized by mutations in the epidermal growth factor receptor (EGFR) and or downstream kinase pathways. This has led to the development of highly selective monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs) to prevent cancer initiation, proliferation, differentiation, angiogenesis, survival, and invasion. However, resistance to many of these new treatments is induced and further pharmacogenomic analysis has revealed mutations associated with increased or reduced drug efficacy. Combinations of kinase inhibitors or potentially the targeting of cancer stem cells may further increase the success of pharmacogenomics in treating patients with lung cancer. PMID- 25725116 TI - Pathogenicity of bacteria isolated from gut of Spodoptera litura (Lepidoptera: Noctuidae) and fitness costs of insect associated with consumption of bacteria. AB - Gut microbes contribute to the health of insects and perturbations in the composition or location of gut microbiota can lead to pathological states and host mortality. We explored the culturable bacterial community in the gut of Spodoptera litura (Fab.) larvae, which is a polyphagous pest. Bacterial isolates were identified as Microbacterium arborescens (SL6), Enterococcus casseliflavus (SL10) and Enterobacter cloacae (SL11) by using culture dependent technique based on 16S rRNA gene sequencing. Screening of these three isolates for insecticidal potential against the same host i.e. S. litura indicated the highest larval mortality in E. cloacae (73.33%). Further, we assessed the effect of E. cloacae (SL11) infection on growth and development of S. litura. A significant effect of E. cloacae was observed on various biological parameters viz. larval and pupal period, total development period and reproductive potential of S. litura. E. cloacae significantly influenced the immune response of S. litura. A marked decrease in total hemocyte count was observed in larvae infected with E. cloacae whereas lysozyme and phenoloxidase activity increased initially followed by a decline. The gut microbial diversity in larvae infected with E. cloacae differed from control larvae. The population of E. cloacae in the gut of infected larvae exceeded over the other two microbes and resulted in pathogenicity and death of S. litura larvae. This indicates that E. cloacae can have the potential to be used as a promising biological control agent. PMID- 25725117 TI - Domesticated horses differ in their behavioural and physiological responses to isolated and group housing. AB - The predominant housing system used for domestic horses is individual stabling; however, housing that limits social interaction and requires the horse to live in semi-isolation has been reported to be a concern for equine welfare. The aim of the current study was to compare behavioural and physiological responses of domestic horses in different types of housing design that provided varying levels of social contact. Horses (n = 16) were divided equally into four groups and exposed to each of four housing treatments for a period of five days per treatment in a randomized block design. The four housing treatments used were single housed no physical contact (SHNC), single housed semi-contact (SHSC), paired housed full contact (PHFC) and group housed full contact (GHFC). During each housing treatment, adrenal activity was recorded using non-invasive faecal corticosterone metabolite analysis (fGC). Thermal images of the eye were captured and eye temperature was assessed as a non-invasive measure of the stress response. Behavioural analysis of time budget was carried out and an ease of handling score was assigned to each horse in each treatment using video footage. SHNC horses had significantly higher (p = 0.01) concentrations of fGC and were significantly (p = 0.003) more difficult to handle compared to the other housing types. GHFC horses, although not significantly different, had numerically lower concentrations of fGC and were more compliant to handling when compared to all other housing treatments. Eye temperature was significantly (p = 0.0001) lower in the group housed treatment when compared to all other treatments. These results indicate that based on physiological and behavioural measures incorporating social contact into the housing design of domestic horses could improve the standard of domestic equine welfare. PMID- 25725118 TI - Trait anxiety moderates the association between estradiol and dominance in women. AB - The aim of the study was to investigate the relationship between self-assessed social dominance trait and levels of free basal sex steroids: estradiol and testosterone, in reproductive age women. Polish urban women aged 24-35 (N = 72) filled in Trait Dominance-Submissiveness Scale (TDS) and State and Trait Anxiety Inventory (STAI). They also gave a single blood sample during the follicular phase of the following menstrual cycle. The blood sample was analyzed for concentration of free testosterone (T), estradiol (E2) and cortisol (C). We found that self-assessed social dominance was negatively associated with free E2 and E2 to T ratio. This general relationship was moderated by Trait Anxiety. Higher social dominance was associated with lower E2 and lower E2 to T ratio in moderate and highly anxious women. No such relationship was found in low anxious women. Results of this study evidence important contribution of estradiol and question the independent role of testosterone in shaping dominance in women. They might also suggest important biological and psychological cost of maintaining high social dominance in reproductive age women. PMID- 25725119 TI - Physiological state influences evaporative water loss and microclimate preference in the snake Vipera aspis. AB - Animals typically respond to environmental variation by adjusting their physiology, behavior, or both. Ectothermic animals are particularly sensitive to microclimatic conditions and behaviorally thermoregulate to optimize physiological performance. Yet, thermoregulation can be costly and may obligate a physiological tradeoff with water loss. Presumably, this tradeoff intensifies when animals undergo necessary life-history events (e.g., pregnancy or digestion) that impose significant behavioral and physiological changes, including shifts in behavioral thermoregulation and increased metabolic rate. Thus, behavioral responses, such as modified microclimatic preferences, may help mitigate the physiological tradeoff between thermoregulation and water loss. Herein, we examined the influence of major physiological states (specifically, pregnancy, ecdysis, and digestion) on evaporative water loss and on behavioral adjustments in a viviparous snake, Vipera aspis. First, we used open-flow respirometry to measure the effects of physiological states and microclimatic conditions (temperature and humidity) on the rate of total evaporative water loss (TEWL) and metabolic rate (rate of O2 consumption, VO2). Then, we experimentally tested the influence of physiological state on microclimate selection. We found that energy demanding physiological states were associated with i) an increased rate of TEWL and VO2 compared to control states and ii) a slight preference (statistically marginal) for both warm and humid conditions compared to controls, suggesting a state-specificity in behavioral response. Overall our results underline the impact of physiological state on water loss and demonstrate the potential for behavior to mitigate the physiological tradeoff between thermoregulation and water balance. PMID- 25725120 TI - Inert gas narcosis disrupts encoding but not retrieval of long term memory. AB - Exposure to increased ambient pressure causes inert gas narcosis of which one symptom is long-term memory (LTM) impairment. Narcosis is posited to impair LTM by disrupting information encoding, retrieval (self-guided search), or both. The effect of narcosis on the encoding and retrieval of LTM was investigated by testing the effect of learning-recall pressure and levels of processing (LoP) on the free-recall of word lists in divers underwater. All participants (n=60) took part in four conditions in which words were learnt and then recalled at either low pressure (1.4-1.9atm/4-9msw) or high pressure (4.4-5.0atm/34-40msw), as manipulated by changes in depth underwater: low-low (LL), low-high(LH), high-high (HH), and high-low (HL). In addition, participants were assigned to either a deep or shallow processing condition, using LoP methodology. Free-recall memory ability was significantly impaired only when words were initially learned at high pressure (HH & HL conditions). When words were learned at low pressure and then recalled at low pressure (LL condition) or high pressure (LH condition) free recall was not impaired. Although numerically superior in several conditions, deeper processing failed to significantly improve free-recall ability in any of the learning-recall conditions. This pattern of results support the hypothesis that narcosis disrupts encoding of information into LTM, while retrieval appears to be unaffected. These findings are discussed in relation to similar effects reported by some memory impairing drugs and the practical implications for workers in pressurised environments. PMID- 25725121 TI - Hormones orchestrated pre- and post-copulatory sexual traits in male Mongolian gerbils. AB - Parker's sperm competition model predicts a negative relationship between pre copulatory (social status) and post-copulatory (sperm quality and quantity) sexually selected traits, however, empirical studies have revealed considerable inconsistency in this relationship. We hypothesized that there was a trade-off between pre- and post-copulatory sexually selected traits, and hormones (corticosterone, CORT; testosterone, T) orchestrate this relationship. In this study, we measured energetic parameters in the dominant-subordinate Mongolian gerbils (Meriones unguiculatus), whose relationship was established under chronic social encounters in a neutral arena, and then tested the relationship between their social status and sperm quality and quantity. Our results showed that dominant males initiated attack sooner and displayed more aggression, self grooming and locomotion behaviors in daily social encounters across seven consecutive days. Dominant gerbils also had more and better quality of sperm than that of subordinate males, yet showed no significant differences in energy intake and RMR in comparison with subordinate individuals. In addition, dominant males had higher concentrations of serum T than subordinate males, whereas the concentrations of CORT showed a reverse pattern. The frequency and duration of aggression (indicative of social status) increased with elevated T concentrations. Sperm quality in terms of number and activity were associated with higher concentrations of serum T in dominant gerbils, whereas small sperm counts and poor-quality sperm were associated with relatively higher concentrations of serum CORT in subordinate gerbils. Together, our data indicated that there was no trade-off between pre- and post-copulatory sexually selected traits but hormones orchestrated the relationship between these traits in male Mongolian gerbils. PMID- 25725122 TI - A differentiable reformulation for E-optimal design of experiments in nonlinear dynamic biosystems. AB - Informative experiments are highly valuable for estimating parameters in nonlinear dynamic bioprocesses. Techniques for optimal experiment design ensure the systematic design of such informative experiments. The E-criterion which can be used as objective function in optimal experiment design requires the maximization of the smallest eigenvalue of the Fisher information matrix. However, one problem with the minimal eigenvalue function is that it can be nondifferentiable. In addition, no closed form expression exists for the computation of eigenvalues of a matrix larger than a 4 by 4 one. As eigenvalues are normally computed with iterative methods, state-of-the-art optimal control solvers are not able to exploit automatic differentiation to compute the derivatives with respect to the decision variables. In the current paper a reformulation strategy from the field of convex optimization is suggested to circumvent these difficulties. This reformulation requires the inclusion of a matrix inequality constraint involving positive semidefiniteness. In this paper, this positive semidefiniteness constraint is imposed via Sylverster's criterion. As a result the maximization of the minimum eigenvalue function can be formulated in standard optimal control solvers through the addition of nonlinear constraints. The presented methodology is successfully illustrated with a case study from the field of predictive microbiology. PMID- 25725123 TI - Analysis of virotherapy in solid tumor invasion. AB - Cancer treatment is an inexact science despite traditional cancer therapies. The traditional cancer treatments have high levels of toxicity and relatively low efficacy. Current research and clinical trials have indicated that virotherapy, a procedure which uses replication-competent viruses to kill cancer cells, has less toxicity and a high efficacy. However, the interaction dynamics of the tumor host, the virus, and the immune response is poorly understood due to its complexity. We present a mathematical analysis of models that study tumor-immune virus interactions in the form of differential equations with spatial effects. A stability analysis is presented and we obtained analytical traveling wave solutions. Numerical simulations were obtained using fourth order Runge-Kutta and Crank-Nicholson methods. We show that the use of viruses as a cancer treatment can reduce the tumor cell concentration to a very low cancer dormant steady state or possibly deplete all tumor cells in body tissue. The traveling waves indicated an exponential increase and decrease in the cytotoxic-T-lymphocytes (CTLs) density and tumor load in the long term respectively. PMID- 25725124 TI - A cryptic three-way translocation t(10;19;11)(p12.31;q13.31;q23.3) with a derivative Y-chromosome in an infant with acute myeloblastic leukemia (M5b). AB - Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the malignant transformation of hematopoietic precursors to a pathogenic cell clone. Chromosomal band 11q23 harboring MLL (=mixed lineage leukemia) gene is known to be involved in rearrangements with variety of genes as activating partners of MLL in different AML subtypes. Overall, an unfavorable prognosis is associated with MLL abnormalities. Here we investigated an 11-month-old male presenting with hyperleukocytosis being diagnosed with AML subtype FAB-M5b. In banding cytogenetics a der(19)t(19;?)(q13.3;?) and del(Y)(q11.23) were found as sole aberrations. Molecular cytogenetics revealed that the MLL gene was disrupted and even partially lost due to a t(10;19;11)(p12.31;q13.31;q23.3), an MLL/MLLT10 fusion appeared, and the der(Y) was an asymmetric inverted duplication with breakpoints in Yp11.2 and Yq11.23. The patient got hematopoietic stem cell transplantation from his haploidentical mother. Still three months afterwards 15% of blasts were detected in bone marrow and later the patient was lost during follow-up. The present case highlights the necessity to exclude MLL rearrangements, even when there seems to be no actual hint from banding cytogenetics. PMID- 25725125 TI - Molecular characterization and expression profile of methionine sulfoxide reductase gene family in maize (Zea mays) under abiotic stresses. AB - Methionine (Met) oxidation to methionine sulfoxide (MetSO) is a common form of damage caused by reactive oxygen species (ROS) accumulation via various environmental stresses. Methionine sulfoxide reductase (MSR) repairs oxidized Met and protects organisms from oxidative damage. Two types of MSR, A and B, have been identified based on substrate stereo specificity; they share no sequence similarity. In the present study, we characterized six genes encoding the putative MSR from two public databases. We compared them with MSRs from 6 species, and evaluated molecular characterization, phylogenetic analysis, tertiary structure and conserved motifs. On the basis of in silico and the qRT PCR experimental data, we analyzed cDNA sequences and expression patterns of ZmMSR genes in different organs in maize. We found that ZmMSR genes were induced by polyethylene glycol (PEG) and NaCl, both known to generate oxidative stress. The results show that MSRs are conserved in different species, suggesting that MSRs across different species share common mechanisms related to diverse defense responses. PMID- 25725126 TI - Soft computing model for optimized siRNA design by identifying off target possibilities using artificial neural network model. AB - The ability of small interfering RNA (siRNA) to do posttranscriptional gene regulation by knocking down targeted genes is an important research topic in functional genomics, biomedical research and in cancer therapeutics. Many tools had been developed to design exogenous siRNA with high experimental inhibition. Even though considerable amount of work has been done in designing exogenous siRNA, design of effective siRNA sequences is still a challenging work because the target mRNAs must be selected such that their corresponding siRNAs are likely to be efficient against that target and unlikely to accidentally silence other transcripts due to sequence similarity. In some cases, siRNAs may tolerate mismatches with the target mRNA, but knockdown of genes other than the intended target could make serious consequences. Hence to design siRNAs, two important concepts must be considered: the ability in knocking down target genes and the off target possibility on any nontarget genes. So before doing gene silencing by siRNAs, it is essential to analyze their off target effects in addition to their inhibition efficacy against a particular target. Only a few methods have been developed by considering both efficacy and off target possibility of siRNA against a gene. In this paper we present a new design of neural network model with whole stacking energy (DeltaG) that enables to identify the efficacy and off target effect of siRNAs against target genes. The tool lists all siRNAs against a particular target with their inhibition efficacy and number of matches or sequence similarity with other genes in the database. We could achieve an excellent performance of Pearson Correlation Coefficient (R=0. 74) and Area Under Curve (AUC=0.906) when the threshold of whole stacking energy is >=-34.6 kcal/mol. To the best of the author's knowledge, this is one of the best score while considering the "combined efficacy and off target possibility" of siRNA for silencing a gene. The proposed model shall be useful for designing exogenous siRNA for therapeutic applications and gene silencing techniques in the area of bioinformatics. The software is developed as a desktop application and available at http://opsid.in/opsid/. PMID- 25725127 TI - Phylogenic analysis revealed an expanded C2H2-homeobox subfamily and expression profiles of C2H2 zinc finger gene family in Verticillium dahliae. AB - C2H2 zinc finger (CZF) proteins are a major class of transcription factors that play crucial roles in fungal growth, development, various stress responses, and virulence. Little genome-wide data is available regarding the roles of CZF proteins in Verticillium dahliae, a destructive pathogen that causes vascular wilt disease in more than 200 plant species. We identified a total of 79 typical CZF genes in V. dahliae. Comparative analysis revealed that four plant pathogenic fungi, V. dahliae, Fusarium oxysporum, Magnaporthe oryzae, and Botrytis cinerea, have comparable numbers of predicted CZF genes with similar characteristics. Phylogenetic analysis identified a C2H2-homeobox subfamily in V. dahliae containing seven genes with similar gene structures. V. dahliae and F. oxysporum (Hypocreomycetidae) have more genes of this subfamily than M. oryzae (Sordariomycetidae) and B. cinerea (Leotiomycetes). Furthermore, gene-expression analysis of the smoke tree wilt fungus V. dahliae strain XS11 using digital gene expression profiling and RT-qPCR revealed that a number of CZF genes were differentially expressed during microsclerotia formation, nutritional starvation, and simulated in planta conditions. Furthermore, the expression profiles revealed that some CZF genes were overrepresented during multiple stages, indicating that they might play diverse roles. Our results provide useful information concerning the functions of CZF genes in microsclerotia formation, nutritional stress responses, and pathogenicity in V. dahliae, and form a basis for future functional studies of these genes. PMID- 25725128 TI - Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease of unknown etiology that is currently untreatable. In this study we aim to characterize the potential of extracellular/circulating microRNAs (miRNAs) in serum as biomarkers for IPF. METHODS: Total serum RNAs were isolated from serum from healthy control subjects (n=12), rapid progressive (n=12) and slowly progressive IPF patients (n=12). Serum RNA was analyzed by using TaqMan microRNA assays containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis on the significant differential miRNAs were performed using DIANA mirPath. RESULTS: We found 47 significantly differentially expressed serum miRNAs (p<0.05) in rapid progressive or slowly progressive IPF patients compared to healthy controls, including 21 up-regulated miRNAs and 26 down-regulated miRNAs. Bioinformatic analysis by DIANA-mirPath demonstrated that 53 KEGG biological processes were significantly enriched (p < 0.05, FDR corrected) among differentially expressed serum miRNAs, including TGF-beta signaling pathway (p < 0.0001), MAPK signaling pathway (p < 0.0001), PI3K-Akt signaling pathway (p < 0.0001), Wnt signaling pathway (p < 0.0001), HIF-1 signaling pathway (p < 0.0001), Regulation of actin cytoskeleton (p < 0.0001), Jak-STAT signaling pathway (p < 0.0001), Notch signaling pathway (p < 0.0001), and Cytokine-cytokine receptor interaction (p = 0.0062). We further validated six miRNAs (miR-21, miR 199a-5p, miR-200c, miR-31, let-7a, and let-7d) for further validation using an independent cohort of 20 rapid progressive IPF, 24 slowly progressive IPF patients and 20 healthy controls. In agreement with the preliminary data from miRNA assay, miR-21, miR-199a-5p, and miR-200c were significantly increased in serums of IPF patients while miR-31, let-7a, and let-7d were significantly under expressed in serums of IPF patients compared to healthy controls. CONCLUSIONS: These studies demonstrated that extracellular/circulating miRNAs in serum could be potentially served as novel regulators influencing disease progression of IPF. PMID- 25725129 TI - MicroRNA-33b, upregulated by EF24, a curcumin analog, suppresses the epithelial to-mesenchymal transition (EMT) and migratory potential of melanoma cells by targeting HMGA2. AB - Diphenyl difluoroketone (EF24), a curcumin analog, exhibits potent anti-tumor activities by arresting cell cycle and inducing apoptosis. However, the efficacy and modes of action of EF24 on melanoma metastasis remain elusive. In this study, we found that at non-cytotoxic concentrations, EF24 suppressed cell motility and epithelial-to-mesenchymal Transition (EMT) of melanoma cell lines, Lu1205 and A375. EF24 also suppressed HMGA2 expression at mRNA and protein levels. miR-33b directly bound to HMGA2 3' untranslated region (3'-UTR) to suppress its expression as measured by dual-luciferase assay. EF24 increased expression of E cadherin and decreased STAT3 phosphorylation and expression of the mesenchymal markers, vimentin and N-cadherin. miR-33b inhibition or HMGA2 overexpression reverted EF24-mediated suppression of EMT phenotypes. In addition, EF24 modulated the HMGA2-dependent actin stress fiber formation, focal adhesion assembly and FAK, Src and RhoA activation by targeting miR-33b. Thus, the results suggest that EF24 suppresses melanoma metastasis via upregulating miR-33b and concomitantly reducing HMGA2 expression. The observed activities of EF24 support its further evaluation as an anti-metastatic agent in melanoma therapy. PMID- 25725130 TI - GAPDH-knockdown reduce rotenone-induced H9C2 cells death via autophagy and anti oxidative stress pathway. AB - BACKGROUND: GAPDH, well known for its house-keeping functions, has also been shown to be involved in cell injury, apoptosis and death under conditions of stress such as starvation, chemical injury and oxidative stress. This study examines the effect of GAPDH knockdown on cell injury in response to Rotenone. METHODS: GAPDH was knocked down in H9C2 cardiomyoblasts using siRNA prior to exposure to rotenone (0 nM, 20 nM, 40 nM and 80 nM). Autophagy was detected by western blot for autophagy proteins (Beclin-1, Atg5, LC-3A/B and p62) and MDC staining for acidic substances. Pro-apoptosis protein and flow cytometry were used to assess cell apoptosis and death and intracellular ATP relative concentration was measured. Oxidant stress was assessed by measuring DCFH-DA, TBARS, GSH and SOD. RESULTS: In this study, GAPDH-knockdown enhanced autophagy in rotenone-induced H9C2 cells, decreased oxidant stress and increased antioxidant pathways; and reduced cell apoptosis and death. Furthermore, GAPDH-knockdown preserved cell energy. CONCLUSION: siRNA-mediated GAPDH knockdown reduced rotenone-induced H9C2 cell death occurring via autophagy and anti-oxidative stress pathway. This study enriches the understanding of GAPDH pathophysiology role, and provides potential new therapeutic targets for cardiac disease states characterized by oxidative stress. PMID- 25725131 TI - Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. AB - Almost exactly 20 years after their discovery, the BRCA1 and BRCA2 genes have become the target of the first "personalized" therapy available for patients with ovarian cancer. In December 2014, a poly(ADP-ribose) polymerase (PARP) inhibitor was granted expedited approved by the United States Food and Drug Administration for use in advanced ovarian cancer patients with germline BRCA1/2 mutations who have received three or more prior lines of chemotherapy. This review article will discuss (1) the BRCA1 and BRCA2 genes within the larger context of homologous recombination deficiency; (2) the advances in our understanding of hereditary cancer risk and the dramatic shifts that have occurred in the genetic testing landscape since the landmark 2013 Supreme Court ruling invalidating patents on BRCA1 and BRCA2 genetic testing; and (3) the clinical trials leading to the approval of olaparib, the first in human PARP inhibitor. PMID- 25725132 TI - Locomotor activity and sensory-motor developmental alterations in rat offspring exposed to arsenic prenatally and via lactation. AB - Arsenic (As) is one of the most toxic naturally occurring contaminants in the environment. The major source of human exposure to inorganic As (iAs) is through contaminated drinking water. Although both genotoxicity and carcinogenicity derived from this metalloid have been thoroughly studied, the effects of iAs on the development and function of the central nervous system (CNS) have received less attention and only a few studies have focused on neurobehavioral effects. Thus, in order to characterize developmental and behavioral alterations induced by iAs exposure, pregnant Wistar rats were exposed to 0.05 and 0.10 mg/L iAs through drinking water during gestation and lactation. Sensory-motor reflexes in each pup were analyzed and the postnatal day when righting reflex, cliff aversion and negative geotaxis were recorded. Functional Observational Battery (FOB) and locomotor activity in an open field were assessed in 90-day-old offspring. Results show that rats exposed to low iAs concentrations through drinking water during early development evidence a delay in the development of sensory-motor reflexes. Both FOB procedure and open-field tests showed a decrease in locomotor activity in adult rats. This study reveals that exposure to the above-mentioned iAs concentrations produces dysfunction in the CNS mechanisms whose role is to regulate motor and sensory development and locomotor activity. PMID- 25725133 TI - Calcium is an organizer of cell polarity in plants. AB - Cell polarity is a fundamental property of pro- and eukaryotic cells. It is necessary for coordination of cell division, cell morphogenesis and signaling processes. How polarity is generated and maintained is a complex issue governed by interconnected feed-back regulations between small GTPase signaling and membrane tension-based signaling that controls membrane trafficking, and cytoskeleton organization and dynamics. Here, we will review the potential role for calcium as a crucial signal that connects and coordinates the respective processes during polarization processes in plants. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25725134 TI - Multiparametric temporal analysis of the Caco-2/TC7 demonstrated functional and differentiated monolayers as early as 14 days of culture. AB - Reducing the differentiation period for obtaining an in vitro intestinal barrier model is required to reduce the duration and cost for drug screening assays. In this frame, the Caco-2/TC7 subclone differentiation state was investigated from day 0 (D0) to day 32 (D32). As such, the expression of 45 genes (including cell junction, cell polarization, cell functionality, drug transport and metabolism genes) was followed throughout the 32 days. In parallel, the monolayer polarization and the formation of the cellular junctions were characterized by the immuno-staining of occludin, claudin-1 and actin proteins. The cell monolayer permeability was analyzed via transepithelial electric resistance measurements and paracellular transport of Lucifer Yellow. The P-gp efflux efficiency was assessed by rhodamine 123 transport. Alkaline phosphate activity was quantified to assess the cell differentiation. Three stages of differentiation were observed using the clustering of principal component analysis of the RTqPCR data and the overall assays. From D0 to D10, cells were in a proliferation stage and under differentiated; from D14 to D21 a stable differentiation stage was reached; from D25 to D32 the epithelium seemed to enter into a post-differentiated stage. This study demonstrates that Caco-2/TC7 cells are functional and ready for use in drug screening permeability assays from 14 days in culture when compared with conventional 21 days for Caco-2 cells. In addition, this study provides a refined set of data allowing temporal and multi scale investigations, due to the intracellular kinetics and mRNA levels that can be correlated with membrane protein kinetics and functional extracellular activities. Therefore, shorter time in culture combined with a better knowledge of the cells during the time in culture will in turn help to improve the quality and cost of Caco-2/TC7 assays for drug development. PMID- 25725135 TI - Prevalence of High risk Human Papillomavirus in cervical dysplasia and cancer samples from twin cities in Pakistan. AB - INTRODUCTION: Human Papilloma Virus (HPV) is small DNA virus mostly infecting mucosa and cutaneous keratinocytes. So far, more than 200 Human papillomaviruses are known. HPV have been divided into high- and low-risk on the basis of their oncogenic potential. High risk HPV is considered to be the main etiological cause for cervical cancer. OBJECTIVE: The current study was designed to screen the local cervical cancer patients from the twin cities of Pakistan for the occurance of high risk HPV. METHODOLOGY: A total of 67 formalin fixed paraffin-embedded samples of cervical cancer biopsies were obtained from the government hospitals in Islamabad and Rawalpindi. Cervical cancer biopsies were examined for the presence of HPV DNA. Polymerase chain reaction (PCR) was used for the amplification of a region in the HPV-L1 gene for the general detection of the Papilloma virus and for the genotype specific detection of high risk HPV 16 and 18 using the GP5/GP6 primers and genotype specific primers, respectively. RESULTS: HPV DNA was detected in 59 out of 67 samples analyzed. 30 samples showed the presence of HPV16 while 22 samples were positive for HPV18. HPV subtype could not be determined in 7 samples. CONCLUSION: Our results show a strong association between HPV infection and cervical cancer among women in twin cities of Pakistan. One way to minimize the disease burden in relation to HPV infection in Pakistani population is the use of prophylactic vaccines and routine screening. An early diagnosis of HPV infection will allow better health management to reduce the risk of developing cervical cancer. PMID- 25725136 TI - Factors affecting the opinions of family physicians regarding generic drugs--a questionnaire based study. AB - A range of factors are believed to exert a negative influence on opinions of physicians about generic drugs.The aim of this study was to survey the opinions of primary care doctors on generics, and determine the factors which may affect them. A questionnaire comprising thirty eight questions was distributed among primary care doctors working in seventy out-patient clinics of the Lodzkie province, Poland, during the period of January 1, 2010 - December 31, 2010. A total of 170 of 183 participants completed the survey (average age 48.5; 70.0% women): a 92.9% response rate. While 38.8% of physicians claimed that generics were worse than brand name drugs, 54.1% considered them to be better. However, 36.5% of the doctors did not choose generics for their own use. Two key opinions were identified among the responses concerning the effectiveness of generic drugs: use of generic drugs by the physician (p<0.001), and their opinion that pharmacists do inform patients about generic drugs (p<0.05). Although existing evidence confirms that generic and brand name drugs are equally effective, many physicians doubt this, which prevents them from being used as cost effective drug therapy. In order to increase healthcare savings through the use of generics, these factors should be addressed: for example, convincing a physician to adopt generics for personal use may be an efficient way to support more cost effective treatment of his patients. PMID- 25725138 TI - TaqIB and severity of coronary artery disease in the Turkish population: a pilot study. AB - The cholesteryl ester transfer protein (CETP) plays a crucial role in high density lipoprotein (HDL) metabolism. Genetic variants that alter CETP concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration. In this case-control study, we analyzed the genotype frequencies of CETP Taq1B polymorphisms in coronary artery disease patients (CAD; n=210) and controls (n=100). We analyzed the role of the CETP Taq1B variant in severity of CAD, and its association with plasma lipids and CETP concentration. DNA was extracted from 310 patients undergoing coronary angiography. The Taq1B polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis. Lipid concentrations were measured by an auto analyzer and CETP level by a commercial enzyme-linked immunosorbent assay (ELISA) kit. In our study population, the B2 allele frequency was higher in control subjects than patients with single, double or triple vessel disease. B2B2 genotype carriers had a significantly higher high-density lipoprotein cholesterol (HDL-C) concentration than those with the B1B1 genotype in controls (51.93+/ 9.47versus 45.34+/-9.93; p<0.05) and in CAD patients (45.52+/-10.81 versus 40.38+/-9.12; p<0.05). B2B2 genotype carriers had a significantly lower CETP concentration than those with the B1B1 genotype in controls (1.39+/-0.58 versus 1.88+/-0.83; p< 0.05) and in CAD patients (2.04+/-1.39versus 2.81+/-1.68; p< 0.05). Our data suggest that the B2 allele is associated with higher concentrations of HDL-C and lower concentrations of CETP, which confer a protective effect on coronary artery disease. PMID- 25725137 TI - Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an autosomal dominant vascular disorder. Diagnosis and follow-up in patients with CADASIL are based mainly on magnetic resonance imaging (MRI). MRI shows white matter hyperintensities (WMHs), lacunar infarcts and cerebral microbleeds (CMBs). WMHs lesions tend to be symmetrical and bilateral, distributed in the periventricular and deep white matter. The anterior temporal lobe and external capsules are predilection sites for WMHs, with higher specificity and sensitivity of anterior temporal lobe involvement compared to an external capsule involvement. Lacunar infarcts are presented by an imaging signal that has intensity of cerebrospinal fluid in all MRI sequences. They are localized within the semioval center, thalamus, basal ganglia and pons. CMBs are depicted as focal areas of signal loss on T2 images which increases in size on the T2*-weighted gradient echo planar images ("blooming effect"). PMID- 25725140 TI - Structural changes in the rat placenta during the last third of gestation discovered by stereology. AB - Structural changes in the rat placenta during the last third of gestation were for the first time assessed by stereology. Fischer female rats were euthanized on the day 16 or day 19 of gestation, and 35 placentas were collected. Three randomly selected placentas from each group were stereologically analyzed for the absolute volume. The proportion of the glycogenic cells and the trophoblast giant cells (TGC) in the basal part of the placenta was calculated using volume density. The absolute volume of the rat placenta on the day 16 of gestation was determined as 0.0638 cm3. The labyrinth comprised 0.0274 cm3, the basal plate 0.0271 cm3 and the decidua 0.0093 cm3. On the day 19 of gestation, the absolute volume of the placenta was 0.1627 cm3, the labyrinth occupied 0.0922 cm3, the basal plate 0.0596 cm3 and the decidua 0.0109 cm3. The volume density of trophoblast giant cells was 0.174 cm0 on the day 16 and 0.107 cm0 on the day 19 of gestation. The glycogenic cells comprised 0.379 percentage of the basal plate on the day 16 and 0.236 on the day 19 of gestation. We conclude that the absolute volume of the whole placenta and the labyrinth has increased from day 16 to the day 19 of gestation. In contrast, the volume density of glycogenic cells and trophoblast giant cells was higher on the day 16 than on the day 19 of gestation, probably due to the intensive trophoblast invasion during that time. PMID- 25725139 TI - Effect and mechanisms of zinc supplementation in protecting against diabetic cardiomyopathy in a rat model of type 2 diabetes. AB - Diabetic cardiomyopathy is a prominent cause of heart failure in patients with diabetes mellitus. Currently, there is no specific treatment for diabetic cardiomyopathy. This study aimed to investigate the effect and underlying mechanisms of Zinc (Zn) supplementation in the protection against diabetic cardiomyopathy in a rat model of type 2 diabetes mellitus (T2DM). T2DM-like lesions in male Wistar rats were induced by introducing the high-fat diet and by administration of streptozocin (STZ). After STZ induction, animals with fasting plasma glucose level >=16.7 mM were considered as diabetic, and randomly assigned to the group receiving physiological saline (control) or ZnSO4 for 56 days. On days 0, 7, 28 and 56 of treatment, animals were weighed, and their blood samples were analyzed. On day 56, hemodynamic assessment was performed right before the sacrifice of animals. Cardiac tissue specimens were collected and subjected to pathologic assessment, metallothionein (MT) concentration measurement and Western blot analysis of microtubule-associated protein light chain 3 (LC3), the marker of autophagy, and glucose-regulated protein-78 (GRP78), an oxidative stress marker. High-fat diet feeding followed by STZ administration resulted in weight loss, hyperglycemia, polydipsia, polyphagia, hemodynamic anomalies and a significant increase in the myocardial content of LC3 and GRP78 proteins, but not in MT protein. Zn supplementation effectively attenuated all these aberrations induced by high-fat diet and STZ. These findings suggest that Zn might be a protective factor in diabetic cardiomyopathy, acting in two ways: at least partially, through inhibiting autophagy and by endoplasmic reticulum stress. PMID- 25725141 TI - Dichloromethane fractions of Scrophularia oxysepala extract induce apoptosis in MCF-7 human breast cancer cells. AB - Breast cancer is a prevalent malignancy among women, especially in developing countries. A large number of anticancer agents with herbal origins have been reported. Hence, herbals may play an essential role in prevention and treatment of cancers. We investigated cytotoxic effects of dichloromethane fractions of Scrophularia oxysepala extract on the MCF-7 breast cancer cell line. The cytotoxic activity of Scrophularia oxysepala fractions on the MCF-7 cells was assessed using Trypan Blue dye exclusion and MTT (3-(4, 5-dimetylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide) assays. In addition, apoptosis induction was determined using TUNEL (terminal deoxy transferase (TdT)-mediated dUTP nick- end labeling) assay and DNA fragmentation analysis. Quantitative Real-Time PCR was also used for analyzing the changes in Caspase-3, Caspase-9, and Bcl-2 genes' expression. Results revealed an effective inhibition of growth and viability in MCF-7 cells treated with dichloromethane fractions. Cell death assay and DNA fragmentation analysis using the TUNEL test confirmed the induction of apoptosis in the MCF-7 cell line. Further, the fractions have resulted in an increased expression of Caspase-3 and Caspase-9 mRNA, which highlights the possibility of apoptosis in the treatments. The expression study of Caspase-9 mRNA confirmed that, the fractions have triggered apoptosis via intrinsic mitochondrial pathway. In summary, fractions of Scrophularia oxysepala extract were found to be promising in growth inhibition and induction of apoptosis in MCF-7 breast cancer cells. PMID- 25725142 TI - Trefoil factor family peptides TFF1 and TFF3 in the nervous tissues of developing mouse embryo. AB - Trefoil factor family peptides (TFF1, TFF2, and TFF3) are predominantly found in mucous epithelia of various organs. However, they have also been reported in the nervous tissue, particularly mouse, rat, porcine, and human brain. The aim of this research was to determine the presence of TFF1 and TFF3 in the nervous system of developing mouse embryo. Mouse embryos, at the stages E15 to E17 were isolated, fixed in 4% paraformaldehyde and embedded in paraffin blocks. Sagittal 6um sections were made, processed for immunohistochemistry, and incubated with anti-TFF1 or anti-TFF3 primary polyclonal rabbit antibodies. Labeled streptavidin biotin method was used for TFF detection. TFF1 and 3 were found in the cytoplasm of ganglion cell somata, while TFF3 staining was also visible in the cytoplasm of neurons in different areas and nuclei of brain and medulla oblongata. Neurons in the gray matter of spinal cord were also TFF1 and TFF3 positive, and signal for both peptides was found in the choroid plexus. TFF peptides might be involved in the complex processes of nervous system development and differentiation and brain plasticity. PMID- 25725143 TI - Neuroprotective effects of sildenafil in experimental spinal cord injury in rabbits. AB - Neuroprotective agents such as methylprednisolone and sildenafil may limit damage after spinal cord injury. We evaluated the effects of methylprednisolone and sildenafil on biochemical and histologic changes after spinal cord injury in a rabbit model. Female New Zealand rabbits (32 rabbits) were allocated to 4 equal groups: laminectomy only (sham control) or laminectomy and spinal trauma with no other treatment (trauma control) or treatment with either methylprednisolone or sildenafil. Gelsolin and caspase-3 levels in cerebrospinal fluid and plasma were determined, and spinal cord histology was evaluated at 24 hours after trauma. There were no differences in mean cerebrospinal fluid or plasma levels of caspase 3 between the groups or within the groups from 0 to 24 hours after injury. From 0 to 24 hours after trauma, mean cerebrospinal fluid gelsolin levels significantly increased in the sildenafil group and decreased in the sham control and the trauma control groups. Mean plasma gelsolin level was significantly higher at 8 and 24 hours after trauma in the sildenafil than other groups. Histologic examination indicated that general structural integrity was better in the methylprednisolone in comparison with the trauma control group. General structural integrity, leptomeninges, white and grey matter hematomas, and necrosis were significantly improved in the sildenafil compared with the trauma control group. Caspase-3 levels in the cerebrospinal fluid and blood were not increased but gelsolin levels were decreased after spinal cord injury in trauma control rabbits. Sildenafil caused an increase in gelsolin levels and may be more effective than methylprednisolone at decreasing secondary damage to the spinal cord. PMID- 25725144 TI - Interleukin 6 and fetal fibronectin as a predictors of preterm delivery in symptomatic patients. AB - Preterm delivery is the leading cause of neonatal mortality and morbidity. The rate of preterm births has been estimated to be about 15 million, which accounts for 11.1% of all live births worldwide. The purpose of this study was to evaluate the cervico-vaginal (CVF) cytokine IL-6 and fetal fibronectin (fFN) status as predictors of preterm delivery in patients with symptoms of preterm labor. Patients with symptoms suggestive of preterm labor were recruited from September 2013 to March 2014. Vaginal swabs were taken for fetal fibronectin test (fFN) and CVF IL-6. Antibiotics, steroids and tocolytics were administered, where appropriate. The outcome was measured by the occurrence of preterm delivery within 14 days from the day of hospital admission. Cut-off value of 1305 pg/mL for the concentration of IL-6 in the CVF was the best predictor of preterm delivery, with the sensitivity of 69.4% and specificity of 68.2%. Patients with positive fFN test had the OR of 6.429 (95%CI 1.991-20.758) to deliver prematurely. The multivariate analysis of combined fFN and CVF IL-6 tests resulted in risk of 86.7% to deliver prematurely, if both tests were positive. The combination of both tests performed better than the individual tests and decreased the false positive rate, which in turn reduced the chances for inappropriate patient treatment, bringing down the costs. PMID- 25725145 TI - Nicolau syndrome after intramuscular injection of non-steroidal anti-inflammatory drugs (NSAID). AB - Nicolau syndrome is a rare complication of intramuscular injection that leads to local ischemic necrosis of the skin and adipose tissue. In this paper, we discuss etiologies, risk factors, and treatment options for gluteal Nicolau syndrome referring to patients treated in our hospital. Our study includes 17 women who visited our clinic with symptoms of gluteal necrosis secondary to intramuscular injection. The following variables were taken into account: injection site, drug administered, frequency of injections, the person who administered the injections, needle size, and needle tip color. Magnetic resonance images obtained in the aftermath of intramuscular injection application were carefully analyzed for presence of necrosis, cyst formation and the thickness of the gluteal fat tissue layer. Drugs that had been received in intramuscular injection were exclusively non-steroidal anti-inflammatory drugs. Mean patient BMI was 41.8 (all patients were considered as obese), and mean gluteal fat thickness was 54 mm. Standard length of needles (3.8 cm) had been used in procedures. The wounds were treated with primary closure in 11 patients and with local flap therapy in 6 patients. The observed necrosis was a consequence of misplaced gluteal injection, where drugs were injected into the adipose tissue instead of the muscle due to the extreme thickness of the fat layer, on one hand, and the inappropriate length of standard needles, on the other hand. Intramuscular injection should be avoided in obese patients whenever possible: if it is necessary, proper injection technique should be used. PMID- 25725146 TI - Evaluation of conventional imaging techniques on preoperative localization in primary hyperparathyroidism. AB - We aimed to evaluate the diagnostic and preoperative localization capacity of 99mTc methoxyisobutylnitrile (MIBI) parathyroid scintigraphy and ultrasonography (USG) in enlarged parathyroid glands in the primary hyperparathyroidism (pHPT) as well as the relationship between the success rate of these techniques and biochemical values. In this study, we retrospectively evaluated 39 patients with clinical and biological evidence of pHPT who referred to the university hospital for MIBI parathyroid scintigraphy. Patients were examined with USG and double phase MIBI parathyroid scintigraphy for the detection of enlarged parathyroid glands. Preoperative serum intact parathyroid hormone (iPTH) levels, calcium (Ca), phosphate and alkaline phosphatase measurements were obtained. A total of 45 parathyroid lesions in 39 patients were reviewed. Thirty-four patients had a single adenoma and 5 patients with multi-gland disease had 11 abnormal parathyroid glands including three adenomas, whereas the remaining 8 glands showed hyperplasia. The overall sensitivities of MIBI parathyroid scintigraphy, USG and combined techniques were 85.3%, 72.5% and 90.4%, respectively; the positive predictive values (PPV) were 89.7%, 85.2% and 92.6%, respectively. The most successful approach for detection of enlarged parathyroid glands in hyperparathyroidism is the concurrent application of USG and MIBI parathyroid scintigraphy modalities. The concomitancy of thyroid diseases decreases the sensitivity of both MIBI parathyroid scintigraphy and USG in enlarged parathyroid glands. PMID- 25725148 TI - Fusion activity of African henipavirus F proteins with a naturally occurring start codon directly upstream of the signal peptide. AB - Compared to the fusion proteins of pathogenic Nipah and Hendra viruses, the F protein of prototype African henipavirus GH-M74a displays a drastically reduced surface expression and fusion activity. A probable reason for limited F expression is the unusually long sequence located between the gene start and the signal peptide (SP) not present in other henipaviruses. Such a long pre-SP extension can prevent efficient ER translocation or protein maturation and processing. As its truncation can therefore enhance surface expression, the recent identification of a second in-frame start codon directly upstream of the SP in another African henipavirus F gene (GH-UP28) raised the question if such a naturally occurring minor sequence variation can lead to the synthesis of a pre SP truncated translation product, thereby increasing the production of mature F proteins. To test this, we analyzed surface expression and biological activity of F genes carrying the second SP-proximal start codon of GH-UP28. Though we observed minor differences in the expression levels, introduction of the additional start codon did not result in an increased fusion activity, even if combined with further mutations in the pre-SP region. Thus, limited bioactivity of African henipavirus F protein is maintained even after sequence changes that alter the gene start allowing the production of F proteins without an unusually long pre-SP. PMID- 25725147 TI - Association between serum vitamin D levels and subclinical coronary atherosclerosis and plaque burden/composition in young adult population. AB - Evidence suggests that low 25-OH vitamin D 25(OH)D concentrations may increase the risk of several cardiovascular diseases such as hypertension, peripheral vascular disease, diabetes mellitus, obesity, myocardial infarction, heart failure and cardiovascular mortality. Recent studies suggested a possible relationship between vitamin D deficiency and increased carotid intima-media wall thickness and vascular calcification. We hypothesized that low 25(OH)D may be associated with coronary atherosclerosis and coronary plaque burden and composition, and investigated the relationship between serum vitamin D levels and coronary atherosclerosis, plaque burden or structure, in young adult patients by using dual-source 128x2 slice coronary computed tomography angiography (CCTA). We included 98 patients with coronary atherosclerosis and 110, age and gender matched, subjects with normal findings on CCTA examinations. Patients with subclinical atherosclerosis had significantly higher serum total cholesterol, triglycerides, hs-CRP, uric acid, HbA1c and creatinine levels and lower serum 25(OH)D levels in comparison with controls. There was no significant correlation between 25(OH)D and plaque morphology. There was also a positive relationship between 25(OH)D and plaque burden of coronary atherosclerosis. In multivariate analysis, coronary atherosclerosis was associated high hs-CRP (adjusted OR: 2.832), uric acid (adjusted OR: 3.671) and low 25(OH)D (adjusted OR: 0.689). Low levels of 25(OH)D were associated with coronary atherosclerosis and plaque burden, but there was no significant correlation between 25(OH)D and plaque morphology. PMID- 25725149 TI - Genome sequence heterogeneity of Lake Sinai Virus found in honey bees and Orf1/RdRP-based polymorphisms in a single host. AB - Honey bees (Apis mellifera) are susceptible to a wide range of pathogens, including a broad set of viruses. Recently, next-generation sequencing has expanded the list of viruses with, for instance, two strains of Lake Sinai Virus. Soon after its discovery in the USA, LSV was also discovered in other countries and in other hosts. In the present study, we assemble four almost complete LSV genomes, and show that there is remarkable sequence heterogeneity based on the Orf1, RNA-dependent RNA polymerase and capsid protein sequences in comparison to the previously identified LSV 1 and 2 strains. Phylogenetic analyses of LSV sequences obtained from single honey bee specimens further revealed that up to three distinctive clades could be present in a single bee. Such superinfections have not previously been identified for other honey bee viruses. In a search for the putative routes of LSV transmission, we were able to demonstrate the presence of LSV in pollen pellets and in Varroa destructor mites. However, negative-strand analyses demonstrated that the virus only actively replicates in honey bees and mason bees (Osmia cornuta) and not in Varroa mites. PMID- 25725150 TI - Expression of fluorescent proteins within the repeat long region of the Marek's disease virus genome allows direct identification of infected cells while retaining full pathogenicity. AB - Marek's disease virus (MDV) is a lymphotropic alphaherpesvirus and causes Marek's disease (MD) in chickens. RLORF4 is an MDV-specific gene located in the repeat long (RL) regions of the genome and is directly involved in attenuation. In this report, we generated recombinant (r)MDVs in which eGFP or mRFP was inserted in frame of the 3' end of the RLORF4 gene. In vitro growth was unaffected and infected cells could be identified by using fluorescent microscopy. Interestingly, though inserted in-frame with RLORF4, eGFP and mRFP were expressed alone, confirming mRNA expression and splicing within the RL of MDV is complex. In vivo, rMDVs expressing mRFP or eGFP caused tumors similar to wild-type MDV. Fluorescent protein expression could be seen in spleen, tumor, and feather follicle epithelial cells. These results show that expression of fluorescent proteins within the RL region results in fluorescent rMDVs that still maintains full pathogenicity in the chicken. PMID- 25725151 TI - Structural and biophysical analysis of sequence insertions in the Venezuelan Equine Encephalitis Virus macro domain. AB - Random transposon insertions in viral genomes can be used to reveal genomic regions important for virus replication. We used these genomic data to evaluate at the protein level the effect of such insertions on the Venezuelan Equine Encephalitis Virus nsP3 macro domain. The structural analysis showed that transposon insertions occur mainly in loops connecting the secondary structure elements. Some of the insertions leading to a temperature sensitive viral phenotype (ts) are close to the cleavage site between nsP2 and nsP3 or the ADP ribose binding site, two important functions of the macro domain. Using four mutants mimicking the transposon insertions, we confirmed that these insertions can affect the macro domain properties without disrupting the overall structure of the protein. PMID- 25725152 TI - Coagulase-negative staphylococcal bloodstream infections: Does vancomycin remain appropriate empiric therapy? AB - OBJECTIVES: It is unknown if vancomycin minimal inhibitory concentrations (MICs) have increased in coagulase-negative staphylococci (CoNS) or whether vancomycin remains appropriate empiric therapy. METHODS: We performed a retrospective study at a single tertiary care center over 8 years. Adult inpatients with >=2 positive blood cultures for CoNS within a 48-h period were eligible. Susceptibilities were performed by automated broth based-microdilution. Changes in antimicrobial susceptibility were analyzed using logistic regression. The clinical characteristics and outcomes of patients with bloodstream infections (BSI) were compared by MIC. RESULTS: Of 308 episodes of possible CoNS bacteremia, the vancomycin MIC was <=1 MUg/mL in 80 (26%) isolates, 2 MUg/mL in 223 (72.4%) isolates and 4 MUg/mL in 5 (1.6%) isolates. No isolates were resistant. We observed an 11-fold increased chance of having an isolate with a vancomycin MIC <=1 MUg/mL in 2009-2011 compared with 2004-2008 (OR 10.8, 95% CI 6.0-19.5, p < 0.05). In 152 patients with BSI, the median days of bacteremia, hospital mortality and readmissions at 30 days were similar in BSI caused by isolates with high vancomycin MICs (2-4 MUg/mL) and low vancomycin MICs (<=1 MUg/mL). CONCLUSIONS: We conclude vancomycin is still appropriate empiric therapy for CoNS BSIs. CoNS vancomycin MICs decreased over the study period despite widespread use of vancomycin. PMID- 25725153 TI - Masking autoprocessing of Clostridium difficile toxin A by the C-terminus combined repetitive oligo peptides. AB - Clostridium difficile toxin A and B (TcdA and TcdB) are the major virulence factors of the bacterium, both of which consist of two enzymatic domains: an effector glucosyltransferase domain (GTD) and a cysteine protease domain (CPD) responsible for autocleavage and release of GTD. Although the CPDs from both toxins share a similar structure and mechanism of hexakisphosphate (InsP6) induced activation, TcdA is substantially less sensitive to the autocleavage as compared with TcdB. In this study, we provided evidence of inter-domain regulation of CPD activity of TcdA and its autoprocessing. The C-terminus combined repetitive oligo peptides (CROPs) of TcdA reduced the accessibility of TcdB CPD to its substrate in a chimeric toxin TxB-Ar, consequently blocking autoprocessing. Moreover, interference of antibodies with the CROPs of full length TcdA efficiently enhanced its GTD release. In conclusion, by utilizing chimeric toxins and specific antibodies, we identified that the CROPs of TcdA plays a crucial role in controlling the InsP6-mediated activation of CPD and autocleavage of GTD. Our data provides insights on the molecular mode of action of the C. difficile toxins. PMID- 25725154 TI - Transcriptome sequencing and differential gene expression analysis in Viola yedoensis Makino (Fam. Violaceae) responsive to cadmium (Cd) pollution. AB - Viola yedoensis Makino is an important Chinese traditional medicine plant adapted to cadmium (Cd) pollution regions. Illumina sequencing technology was used to sequence the transcriptome of V. yedoensis Makino. We sequenced Cd-treated (VIYCd) and untreated (VIYCK) samples of V. yedoensis, and obtained 100,410,834 and 83,587,676 high quality reads, respectively. After de novo assembly and quantitative assessment, 109,800 unigenes were finally generated with an average length of 661 bp. We then obtained functional annotations by aligning unigenes with public protein databases including NR, NT, SwissProt, KEGG and COG. In addition, 892 differentially expressed genes (DEGs) were investigated between the two libraries of untreated (VIYCK) and Cd-treated (VIYCd) plants. Moreover, 15 randomly selected DEGs were further validated with qRT-PCR and the results were highly accordant with the Solexa analysis. This study firstly generated a successful global analysis of the V. yedoensis transcriptome and it will provide for further studies on gene expression, genomics, and functional genomics in Violaceae. PMID- 25725155 TI - TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. AB - The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in TBX5 have been associated with various congenital heart diseases and arrhythmias in humans. However, whether mutated TBX5 contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons and flanking introns of the TBX5 gene were sequenced in 190 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX5. The functional characteristics of the mutant TBX5 were explored in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.S154A, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across various species. Functional assays revealed that the mutant TBX5 had significantly decreased transcriptional activity. Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM. This study firstly associates TBX5 loss-of-function mutation with enhanced susceptibility to DCM, providing novel insight into the molecular mechanisms of DCM, and suggesting the potential implications in the development of new treatment strategies for this common form of myocardial disorder. PMID- 25725156 TI - mRNA m6A methylation downregulates adipogenesis in porcine adipocytes. AB - Fat Mass and Obesity-associated protein (FTO), associated with obesity, is proved to demethylate N6-methyladenosine (m(6)A), which raises questions regarding whether m(6)A plays vital roles in adipogenesis. To prove this, overexpression and knockdown of FTO and METTL3, as well as the chemical treatment in procine adipocytes were conducted. The results showed FTO negatively regulated m(6)A levels and positively regulated adipogenesis, while METTL3 positively correlated with m(6)A levels and negatively with adipogenesis. To remove the potential effect of FTO and METTL3 gene, chemical reagents of methylation inhibitor cycloleucine and methyl donor betaine were used to test the regulation effect of m(6)A on adipogenesis. The results showed the inverse effect of m(6)A on lipid accumulation in porcine adipocytes. These findings provide compelling evidence that m(6)A plays a critical role in the regulation of adipogenesis. PMID- 25725157 TI - Cancer cell-associated cytoplasmic B7-H4 is induced by hypoxia through hypoxia inducible factor-1alpha and promotes cancer cell proliferation. AB - Aberrant B7-H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7-H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7-H4 transcription in primary CD138(+) multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7-H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7-H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatin immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1alpha (HIF-1alpha) to proximal hypoxia-response element (HRE) sites within the B7-H4 promoter. Knockdown of HIF-1alpha and pharmacological inhibition of HIF-1alpha diminished B7-H4 expression. Furthermore, knockdown of cytoplasmic B7-H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7-H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7-H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment. PMID- 25725158 TI - Plasmodium infections and fluctuating asymmetry among children and teenagers from Senegal. AB - Although fluctuating asymmetry is a sensitive indicator of stress, its links with health remains controversial, especially in humans. Here, we explored for the first time the association between fluctuating asymmetry and malaria infections in humans, from 107 participants involved in a long term medical survey in Senegal. No clear relationship was detected. Depending on traits considered, associations were not significant, or (marginally) significant but not in the same directions. We discuss the possible reasons for the global weakness of the signals detected in this study. PMID- 25725159 TI - Molecular and antigenic characteristics of Newcastle disease virus isolates from domestic ducks in China. AB - Newcastle disease (ND) is one of the most devastating diseases to the poultry industry. The causative agents of ND are virulent strains of Newcastle disease virus (NDV), which are members of the genus Avulavirus within the family Paramyxoviridae. Waterfowl, such as ducks and geese, are generally considered potential reservoirs of NDV and may show few or no clinical signs when infected with viruses that are obviously virulent in chickens. However, ND outbreaks in domestic waterfowl have been frequently reported in many countries in the past decade. In this study, 18 NDV strains isolated from domestic ducks in southern and eastern China, between 2005 and 2013, were genetically and phylogenetically characterized. The complete genomes of these strains were sequenced, and they exhibited genome sizes of 15,186 nucleotides (nt), 15,192 nt, and 15,198 nt, which follow the "rule of six" that is required for the replication of NDV strains. Based on the cleavage site of the F protein and pathogenicity tests in chickens, 17 of our NDV isolates were categorized as lentogenic viruses, and one was characterized as a velogenic virus. Phylogenetic analysis based on the partial sequences of the F gene and the complete genome sequences showed that there are at least four genotypes of NDV circulating in domestic ducks; GD1, AH224, and AH209 belong to genotypes VIId, Ib, and II of class II NDVs, respectively, and the remaining 15 isolates belong to genotype 1b of class I NDVs. Cross-reactive hemagglutination inhibition tests demonstrated that the antigenic relatedness between NDV strains may be associated with their genotypes, rather than their hosts. These results suggest that though those NDV isolates were from duck, they still don't form a phylogenetic group because they came from the same species; however, they may play an important role in promoting the evolution of NDVs. PMID- 25725160 TI - Loss of T cells influences sex differences in behavior and brain structure. AB - Clinical and animal studies demonstrate that immune-brain communication influences behavior and brain function. Mice lacking T cell receptor beta and delta chains were tested in the elevated plus maze, open field, and light-dark test and showed reduced anxiety-like behavior compared to wild type. Interestingly sex differences were observed in the behavioural phenotype of TCRbeta-/-delta- mice. Specifically, female TCRbeta-/-delta- mice spent more time in the light chamber compared to wild type females, whereas male TCRbeta-/-delta- spent more time in the center of the open field compared to wild type males. In addition, TCRbeta-/-delta- mice did not show sex differences in activity-related behaviors observed in WT mice. Ex vivo brain imaging (7 Tesla MRI) revealed volume changes in hippocampus, hypothalamus, amygdala, periaqueductal gray, and dorsal raphe and other brain regions between wild type and T cell receptor knockout mice. There was also a loss of sexual dimorphism in brain volume in the bed nucleus of the stria terminalis, normally the most sexually dimorphic region in the brain, in immune compromised mice. These data demonstrate the presence of T cells is important in the development of sex differences in CNS circuitry and behavior. PMID- 25725161 TI - The Evolving Treatment Paradigm for Metastatic Spine Disease. PMID- 25725162 TI - Vitamin D Deficiency in Spinal Surgery: Can It Compromise the Outcome? PMID- 25725163 TI - Are External Ventricular Drains Better than Parenchymal Intracranial Pressure Monitors in Trauma Patients? PMID- 25725164 TI - Going Big to Explore the Detail. PMID- 25725165 TI - Intracranial Inflammatory Pseudotumors Associated with Immunoglobulin G4-Related Disease Mimicking Multiple Meningiomas: A Case Report and Review of the Literature. AB - BACKGROUND: Immunoglobulin G (IgG)4-related disease is a syndrome that forms inflammatory pseudotumors with increasing IgG4-positive plasma cells and lymphocytes infiltrating the exocrine gland and other organs. The concept of this disease gradually has gained more recognition. However, reports of intracranial pseudotumors associated with IgG4-related disease are very rare. The purpose of this report is to provide further information helpful in distinguishing IgG4 related disease from multiple meningiomas. CASE DESCRIPTION: We report a case of a 62-year-old man who presented with visual disturbance and quadrantanopia of the right eye. Magnetic resonance imaging revealed uniformly enhancing masses located near the right paraclinoid at the right Meckel's cave and along the left foramen magnum. He had experienced autoimmune pancreatitis 7 years previously, and the condition had responded to steroid therapy. Laboratory data revealed elevation of IgG (1877 mg/dL) and IgG4 (405 ng/dL). The right paraclinoidal lesion causing visual disturbance was subtotally removed, which provided sufficient decompression of the right optic nerve. IgG4 was strongly positive on immunohistochemical staining, and we started oral corticosteroid medication. Consequently, all lesion masses shrank remarkably within 1 month. CONCLUSION: There have been a growing number of reports of such multiple pseudotumors associated with IgG4-related disease. In differential diagnosis, this disease entity requires special attention when multiple dural-based tumors are observed. Preoperative presumption is very important because this disease is likely to respond to steroid therapy. PMID- 25725166 TI - Activity-dependent expression of miR-132 regulates immediate-early gene induction during olfactory learning in the greater short-nosed fruit bat, Cynopterus sphinx. AB - The activity-dependent expression of immediate-early genes (IEGs) and microRNA (miR)-132 has been implicated in synaptic plasticity and the formation of long term memory (LTM). In the present study, we show that olfactory training induces the expression of IEGs (EGR-1, C-fos, C-jun) and miR-132 at similar time scale in olfactory bulb (OB) of Cynopterus sphinx. We examined the role of miR-132 in the OB using antisense oligodeoxynucleotide (AS-ODN) and demonstrated that a local infusion of AS-ODN in the OB 2h prior to training impaired olfactory memory formation in C. sphinx. However, the infusion of AS-ODN post-training did not cause a deficit in memory formation. Furthermore, the inhibition of miR-132 reduced the olfactory training-induced expression of IEGs and post synaptic density protein-95 (PSD-95) in the OB. Additionally, we show that miR-132 regulates the activation of calcium/calmodulin-dependent protein kinase-II (CaMKII) and cAMP response element binding protein (CREB), possibly through miR 148a. These data suggest that olfactory training induces the expression of miR 132 and IEGs, which in turn activates post-synaptic proteins that regulate olfactory memory formation. PMID- 25725167 TI - Effects of temporal and spatial cueing on anticipatory postural control in a rapid interceptive task. AB - Balance disruptions induced by voluntary focal arm actions are accommodated via anticipatory postural adjustments, but how this coordinated control is organized by the central nervous system remains unclear: either as combined or separate streams of postural-focal motor commands. For example, a focal arm task that dictates extremely tight temporal constraints may induce a focal response in absence of an anticipatory postural adjustment, providing evidence for separate focal-postural control streams. This study sought to probe the organization of focal-postural control via an interceptive task with very little available response time, and to determine whether focal-postural coordination depends on temporal and/or spatial foreknowledge of the task. Ten healthy young adults (5 males and 5 females; 20-29 years) reacted to catch a ball when standing under four conditions of temporal and spatial foreknowledge. Response onset was characterized by muscle activity from both postural and focal arm muscles. The catching task resulted in rapid muscle responses, but there was no difference between the fastest focal and postural muscle onsets. As expected, temporal cuing resulted in faster focal and postural onsets compared to spatial and control cuing trials. The accompaniment and time-locking of focal and postural muscle onsets, suggests that postural-focal coupling remains intact even under external time constraints and provides evidence for a single combined command stream of postural and focal control under such circumstances. PMID- 25725168 TI - The metabolic trinity, glucose-glycogen-lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression. AB - Glucose, glycogen, and lactate are traditionally identified with brain energetics, ATP turnover, and pathophysiology. However, recent studies extend their roles to include involvement in astrocytic signaling, memory consolidation, and gene expression. Emerging roles for these brain fuels and a readily diffusible by-product are linked to differential fluxes in glycolytic and oxidative pathways, astrocytic glycogen dynamics, redox shifts, neuron-astrocyte interactions, and regulation of astrocytic activities by noradrenaline released from the locus coeruleus. Disproportionate utilization of carbohydrate compared with oxygen during brain activation is influenced by catecholamines, but its physiological basis is not understood and its magnitude may be affected by technical aspects of metabolite assays. Memory consolidation and gene expression are impaired by glycogenolysis blockade, and prevention of these deficits by injection of abnormally-high concentrations of lactate was interpreted as a requirement for astrocyte-to-neuron lactate shuttling in memory and gene expression. However, lactate transport was not measured and evidence for presumed shuttling is not compelling. In fact, high levels of lactate used to preserve memory consolidation and induce gene expression are sufficient to shut down neuronal firing via the HCAR1 receptor. In contrast, low lactate levels activate a receptor in locus coeruleus that stimulates noradrenaline release that may activate astrocytes throughout brain. Physiological relevance of exogenous concentrations of lactate used to mimic and evaluate metabolic, molecular, and behavioral effects of lactate requires close correspondence with the normal lactate levels, the biochemical and cellular sources and sinks, and specificity of lactate delivery to target cells. PMID- 25725169 TI - Sex differences in depression-like behavior after nerve injury are associated with differential changes in brain-derived neurotrophic factor levels in mice subjected to early life stress. AB - We recently demonstrated that exposure to early life stress exacerbates nerve injury-induced thermal and mechanical hypersensitivity in adult male and female mice. Accumulating evidence suggests that chronic pain causes emotional dysfunction, such as anxiety and depression. In the present study, we investigated the impact of early life stress on depression-like behavior after nerve injury in mice. In addition, we examined the expression of brain-derived neurotrophic factor (BDNF), which is known to be involved in the pathogenesis of depression. Early life stress was induced by maternal separation between 2 and 3 weeks of age combined with social isolation after weaning (MSSI). At 9 weeks of age, the sciatic nerve was partially ligated to elicit neuropathic pain. Depression-like behavior was evaluated using the forced swim test at 12 weeks of age. Tissue samples from different regions of the brain were collected at the end of maternal separation (3 weeks of age) or after the forced swim test (12 weeks of age). At 12 weeks of age, immobility time in the forced swim test was increased only in MSSI-stressed female mice with nerve injury. BDNF expression was increased in male, but not female, MSSI-stressed mice at 3 weeks of age. However, MSSI stress did not impact BDNF expression in male or female mice at 12 weeks of age. Our findings suggest that exposure to early life stress exacerbates emotional dysfunction induced by neuropathic pain in a sex-dependent manner. Changes in BDNF expression after early life stress may be associated with neuropathic pain-induced depression-like behavior in adulthood. Furthermore, sex differences in BDNF expression after exposure to early life stress may contribute to sex-specific susceptibility to neuropathic pain-induced emotional dysfunction. PMID- 25725170 TI - Pain in Fabry disease: Plasma lipids sensitise nociceptors. PMID- 25725171 TI - Long-term oral administration of the NMDA receptor antagonist memantine extends life span in spinocerebellar ataxia type 1 knock-in mice. AB - Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by extension of a CAG repeat in the Sca1gene. Although the mechanisms underlying the symptoms of SCA1 have not been determined, aberrant neuronal activation potentially contributes to the neuronal cell death characteristic of the disease. Here we examined the potential involvement of extrasynaptic N-methyl d-aspartate receptor (NMDAR) activation in the pathogenesis of SCA1 by administering memantine, a low-affinity noncompetitive NMDAR antagonist, in SCA1 knock-in (KI) mice. In KI mice, the exon in the ataxin 1 gene is replaced with abnormally expanded 154CAG repeats. Memantine was administered orally to the SCA1 KI mice from 4 weeks of age until death. The treatment significantly attenuated body-weight loss and prolonged the life span of SCA1 KI mice. Furthermore, memantine significantly suppressed the loss of Purkinje cells in the cerebellum and motor neurons in the dorsal motor nucleus of the vagus, which are critical for motor function and parasympathetic function, respectively. These findings support the contribution of aberrant activation of extrasynaptic NMDARs to neuronal cell death in SCA1 KI mice and suggest that memantine may also have therapeutic benefits in human SCA1 patients. PMID- 25725173 TI - In Vivo praying and catastrophizing mediate the race differences in experimental pain sensitivity. AB - Black individuals have a lower tolerance for experimental pain than white individuals. Black and white individuals also differ in their use of pain coping strategies, which may explain the race differences in pain sensitivity. We examined the extent to which situation-specific pain coping mediated black-white differences in pain sensitivity. We hypothesized that 1) black participants would demonstrate lower pain tolerance than white participants, 2) black participants would use different pain coping strategies than white participants, and 3) the differential use of these strategies would mediate the relationship between race and pain tolerance. Healthy college undergraduates (N = 190) participated in a cold pressor task and then completed the Coping Strategies Questionnaire-Revised to assess their situation-specific pain coping. Compared with white participants, black participants demonstrated lower pain tolerance, engaged in more situation specific catastrophizing and praying, and ignored pain less frequently. Catastrophizing and praying were inversely related to pain tolerance and were significant mediators of the relationship between race and pain tolerance. The indirect effect of praying was stronger than that of catastrophizing. Race differences in pain sensitivity may be due, in part, to differences in the use of catastrophizing and praying as coping strategies. These results may help guide treatments addressing maladaptive pain coping. PERSPECTIVE: This study suggests that race differences in pain sensitivity may be due, in part, to the differential use of catastrophizing and praying strategies. Psychosocial treatments for pain should encourage patients to take an active role in their pain management. PMID- 25725174 TI - "Compassion, pleasantry, and hope": a process evaluation of a volunteer-based nonprofit. AB - As funders continue to emphasize the importance of documented results, nonprofit organizations must work to complete program evaluations that are both valuable and feasible. The purpose of this paper is to document a practical process evaluation of a southeastern nonprofit, a local Meals on Wheels. Using a mixed methods approach, we sought to answer four evaluation questions: (1) What are the essential program components, as identified by key stakeholders; (2) To what extent are volunteers implementing the identified essential components as intended; (3) What is the level of volunteer satisfaction with the program; and (4) What suggestions do stakeholders have for improving the program? Our findings indicate that most aspects of the program were implemented as intended, but inconsistencies occurred when volunteers were unsure of their assigned duties. In addition, volunteers had high levels of satisfaction and specific suggestions for improvement. From these results, we developed a conceptual model of factors contributing to quality of implementation and volunteer satisfaction that may be generalizable to other volunteer-based nonprofits. Specifically, we identified three factors that helped to facilitate satisfaction and performance: leadership, social contact, and fulfillment. Finally, this process evaluation demonstrates the feasibility of developing and implementing evaluation tools in similar organizations. PMID- 25725172 TI - Disrupted sleep is associated with altered pain processing by sex and ethnicity in knee osteoarthritis. AB - Studies indicate that improving sleep decreases reported pain in patients with knee osteoarthritis, but it is unclear if this association extends to experimentally induced pain responses. A community-based sample of 88 African American and 52 non-Hispanic white adults (45-76 years) with knee osteoarthritis completed the Insomnia Severity Index and the arousal subscale of the Sleep Hygiene and Practices Scale. Participants underwent quantitative sensory testing, including measures of pain sensitivity and facilitation at the knee, and pain inhibition. Outcomes were analyzed with multiple Tobit hierarchical regression models, with adjustment for relevant covariates. Ethnicity and sex by sleep interactions were also entered into the models. After covariate adjustment, main associations were not observed. However, sex interacted with insomnia severity to predict greater temporal summation of heat and punctate pressure pain among women and lower heat temporal summation among men. Men and women who engaged in frequent arousal-associated sleep behaviors demonstrated higher and lower heat temporal summation, respectively. Non-Hispanic whites with greater insomnia severity displayed lower pressure pain thresholds and pain inhibition. Our findings are the first to demonstrate that disrupted sleep is associated with altered pain processing differentially by sex and ethnicity/race among people with knee osteoarthritis. PERSPECTIVE: This article presents the association between insomnia severity, maladaptive sleep behaviors, and experimentally induced pain responses among people with knee osteoarthritis. Disrupted sleep was associated with altered pain processing by sex and ethnicity/race. Offering sleep interventions may help ameliorate pain, but treatment may need to be tailored by sex and ethnicity/race. PMID- 25725176 TI - Helicobacter pylori Infection and atherosclerosis: a systematic review. AB - Helicobacter pylori (H. pylori) is a spiral-shaped gram negative bacterium that naturally colonizes the human gastric epithelium. In recent years, large evidence has come to the literature strongly proposing causal link between H. pylori and extra gastric disorders. Cardiovascular system is one of the extra gastric organs that can be affected by H. pylori infection. The first evidence suggestive of such an association comes from seroepidemiological evaluations, but histopathological and eradication studies have strongly confirmed existence of a causal association between H. pylori infection and cardiovascular events. PMID- 25725177 TI - Chronic lithium treatment increased intracellular S100beta levels in rat primary neuronal culture. AB - S100beta? a neurotrophic factor mainly released by astrocytes, has been implicated in the pathogenesis of bipolar disorder. Thus, lithium may exert its neuroprotective effects to some extent through S100beta. Furthermore, the possible effects of lithium on astrocytes as well as on interactions between neurons and astrocytes as a part of its mechanisms of actions are unknown. This study was undertaken to determine the effect of lithium on S100beta in neurons, astrocytes and a mixture of neurons and astrocytes. Rat primary astrocyte, neuronal and mixed neuro-astroglia cultures were prepared from cortices of 18 day's embryos. Cell cultures were exposed to lithium (1mM) or vehicle for 1day (acute) or 7 days (chronic). RT-PCR and ELISA determined S100beta mRNA and intra- and extracellular protein levels. Chronic lithium treatment significantly increased intracellular S100beta in neuronal and neuro-astroglia cultures in comparison to control cultures (P<0.05). Acute and chronic lithium treatments exerted no significant effects on intracellular S100beta protein levels in astrocytes, and extracellular S100beta protein levels in three studied cultures as compared to control cultures. Acute and chronic lithium treatments did not significantly alter S100beta mRNA levels in three studied cultures, compared to control cultures. Chronic lithium treatment increased intracellular S100beta protein levels in a cell-type specific manner which may favor its neuroprotective action. The findings of this study suggest that lithium may exert its neuroprotective action, at least partly, by increasing neuronal S100beta level, with no effect on astrocytes or interaction between neurons and astrocytes. PMID- 25725178 TI - Comparison of glyburide and insulin in women with gestational diabetes mellitus and associated perinatal outcome: a randomized clinical trial. AB - Insulin is currently the drug of choice in treating patients with gestational diabetes mellitus but insulin is expensive, inconvenient to store and use and probably associated with more risks of asymptomatic hypoglycemia in comparison with some oral agents. This randomized clinical trial was conducted to evaluate the efficacy and safety of glyburide in patients with gestational diabetes mellitus in comparison with insulin therapy. Pregnant women aged between 18-45 years with singleton pregnancies and in their 24-36 weeks of gestation were assessed for eligibility. Women with gestational diabetes mellitus were randomly allocated to two insulin and glyburide groups and compared with maternal and neonatal outcome. Ninety-six women with gestational diabetes mellitus enrolled in the study. At screen and treated fasting and post-prandial blood glucose levels were similar in both groups. Time for beginning the treatment to control the glycemic index was 28.30 (+/-20.60) days in the insulin group and 22.56 (+/ 18.86) in the glyburide group. There was no statistically significant difference in time-to-control the blood glucose level in two studied group. Time, between beginning the treatment of GDM and delivery, was 53.22 (+/-28.96) days in the insulin group and 56.67 (+/-30.47) in the glyburide group. There was no statistically significant difference between the times of treatment-to-delivery in two studied groups. There were no statistically significant differences between maternal and neonatal outcomes in two studied groups. Glyburide can effectively and safely control the glycemic index in women with gestational diabetes mellitus in comparison with insulin. PMID- 25725179 TI - The effect of continuous low dose methylprednisolone infusion on inflammatory parameters in patients undergoing coronary artery bypass graft surgery: a randomized-controlled clinical trial. AB - This trial was performed to determine if a continuous low-dose infusion of methylprednisolone is as effective as its bolus of high-dose in reducing inflammatory response. The study was single-center, double-blinded randomized clinical trial and performed in a surgical intensive care unit of an academic hospital. In this study, 72 consecutive patients undergoing elective coronary artery bypass grafting (CABG) were assigned to receive either a methylprednisolone loading dose (1mg/kg) followed by continuous infusion (2mg/Kg/24 hours for 1 day) (low-dose regime) or a single dose of methylprednisolone (15 mg/kg) before cardiopulmonary bypass (high dose regime). Serum concentrations of IL-6 and C- reactive protein (CRP) were measured preoperatively and 6, 24 and 48 hours after surgery, and serum creatinine was measured before the operation and 24, 48 and 72 hours postoperatively. The measurements were then compared between the groups to evaluate the efficacy of each regimen. The basic characteristics and measurements were not different between the study groups. There was no significant difference in IL-6 and CRP elevation (P=0.52 and P=0.46, respectively). Early outcomes such as the length of stay in the intensive care unit, intubation time, changes in serum creatinine and blood glucose levels, inotropic support, insulin requirements, and rate of infection were also similar in both groups. A continuous low dose infusion of methylprednisolone was as effective as a single high dose methylprednisolone in reducing the inflammatory response after CABG with extracorporeal circulation with no significant difference in the postoperative measurements and outcomes. PMID- 25725180 TI - Is the GSTM1 null polymorphism a risk factor for primary angle-closure glaucoma among Iranian population? AB - Glutathione S-transferases (GSTs) are members of multigenic family which have the essential functionin cells as an antioxidant. In the present study we studied the polymorphism of GSTT1 and GSTM1 deletion genotypes in Iranian patients with primary closed angle glaucoma (PCAG) compared to healthy subjects. We conducted a study of 41 PCAG patients (24 women, 17 men) and 100 healthy participants (57 women, 43 men) to determine the prevalence of GSTT1 and GSTM1 deletion genotypes and the risk of PCAG, which were determined by multiplex polymerase chain reaction. Genotypes of GSTM1 and GSTT1 null deletions were determined in 22 (53.7%) and 7 (17.1%) patients with PCAG and 34 (34%) and 15 (15%) in healthy participants. Comparison of patients and healthy ones regarding GSTM1 and GSTT1 genotypes revealed increase of GSTM1 null deletions genotypes' in patients with PCAG (P=0.03). It was concluded that the increased frequencies of GSTM1 null in patients with PCAG could be associated with a risk factor for incidence of PCAG in the Iranian population. PMID- 25725181 TI - A comparison to facilitate insertion of the laryngeal mask: term of recovery and postoperative nausea and vomiting after anesthesia with propofol- atracurium and thiopental-atracurium. AB - Laryngeal mask is a supraglothic instrument for ventilation of patients who are under anesthesia. Insertion of laryngeal mask requires maintaining sufficient depth of anesthesia to avoid airway reflex (gagging, coughing and spasms). The present study investigated two techniques of anesthesia with propofol-atracurium and thiopental-atracurium to facilitate insertion of the laryngeal mask, term of recovery and postoperative nausea and vomiting. In this prospective, randomized and double-blinded clinical trial, 224 patients undergoing elective laparoscopic class ASA one and two were studied. Patients were divided into two groups of 112 patients - one group with propofol anesthetic and thiopental-atracurium. Then after the induction of anesthesia neuromuscular hemodynamic changes, airway reflex (gagging, coughing and spasms), the ease of insertion of laryngeal mask and the frequency of patient movements' were recorded. The data were analyzed by SPSS V.18. Results indicated that anesthetic technique with propofol-atracurium provides better and more comfortable condition for insertion of laryngeal mask significantly (P<0.05). Hemodynamic changes during induction of anesthesia and five minutes after insertion of the laryngeal mask in first group was more than second one (P<0.05), and nausea and vomiting during recovery in propofol group was significantly lower than thiopental group (P<0.05). Using techniques of anesthesia with propofol - atracurium in inserting laryngeal mask airway in patients who have an indication for the use of this technique is better than anesthesia with thiopental -atracurium. PMID- 25725182 TI - Comparison of body mass index in children of two different regions of welfare. AB - Socioeconomic basis of children obesity is of high importance for preventive policies. This study aimed to compare the prevalence of obesity among children living in two different levels of welfare regions in Mashhad northeast of Iran. A total of 625 primary school girls and boys aged 78-127 months were randomly selected, and values of their body mass index (BMI) were measured. The prevalence of both overweight and obesity were higher among students of enriched area in comparison with that of resource restricted (P<0.05).The prevalence of overweight concerns in urban and rural areas. These results highlight the relation between socio-economic status and prevalence of obesity among children. PMID- 25725183 TI - Prominent complaint: a guide to medical therapy of overactive bladder syndrome in older women. AB - To evaluate Overactive bladder (OAB) with detrusor overactivity (DOA) following oxybutynin or tolterodine treatment in recommended doses at a four-week course. A total of 100 Iranian women 45 years or older with urgency that also showed idiopathic detrusor overactivity (IDO) in the filling phase of their cystometry were included in the current study. In this double-blinded trial two parallel groups were randomized by using two kinds of the antimuscarinic drugs for a four- week course [oxybutinin 5mg, t.d.s. or Tolterodin 2mg, b.i.d.] in the same packages. Data were collected from three-day frequency volume chart (FVC) one month before and after the treatment course. The effectiveness of each drug was compared using the paired, samples t-test. Patients' improvement regarding urinary urgency, frequency and urge incontinence after treatment in both groups was seen, but mean improvements in the terms of urgency and urge incontinence were larger in patients who were treated by oxybutynin. Night-time frequency was shown to be improved by a significantly larger score by tolterodine. Discontinuation of treatment due to adverse events had no significant difference in two groups. Four-week treatment with oxybutynin was better than tolterodine IR in improving urgency and urge incontinence, but there were not statistically significant difference between them. In planning a course of treatment especially in the elderly, the difference in the group of symptoms that reduce patients' quality of life should be considered. Physicians should consider the patient's prominent symptom in selection of anti-muscarinic drugs for the treatment of overactive bladder syndrome especially in elderly patients. PMID- 25725184 TI - Use of antihypertensive medications in patients with type -2 diabetes in Ajman, UAE. AB - Optimal reduction in blood pressure with antihypertensive agents helps to prevent microvascular and macrovascular complications of diabetes. The objective of the study was to evaluate the current utilization pattern of antihypertensive medications among patients with diabetes and coexistent hypertension as per the JNC seventh report guidelines. A Cross-sectional survey was conducted among patients with diabetes attending outpatient department of Internal Medicine at a hospital at Ajman. Medical records of patients were used to obtain diagnostic, demographic and drug use information. Univariate analysis was performed using Chi square and t- test followed by logistic regression to compute independent predictors. Of 132 patients with diabetes, uncomplicated hypertension (HTN) was coexistent in 81% (107/132) of patients. Males constituted 49.5% (53/107) of the total. Mean (SD) age of patients with HTN was 55.1(10.1) years higher than those without HTN 49.6 (9.9) years (P<0.01). Higher number of patients with HTN had duration of diabetes<5 years than those>5 years (P=0.04). While adjusting the significant factors, only duration of diabetes was statistically significant (adjusted OR=1.06; CI 95% (1.003-1.116) P= 0.03 among patients with HTN. 63.6% (68/107) prescriptions contained one drug antihypertensive drug, 27.1 % (29/107) two drugs and 7.4% (8/107) no anti-hypertensive drug were prescribed. Angiotensin converting enzyme inhibitors/ Angiotensin receptor blockers (ACEI/ARBs) followed by diuretics were commonly prescribed drugs. ARBs with diuretics were the most frequent two drug combinations. The antihypertensive utilization pattern was similar in both gender and age groups. Results represent the current prescribing trend for anti-hypertensive agents among patients with diabetes that is in accordance with JNC-7 recommendations. PMID- 25725185 TI - The effect of massage with medium-chain triglyceride oil on weight gain in premature neonates. AB - Prematurity and poor weight gaining are important causes for neonatal hospitalization. The present study aimed to investigate the role of medium-chain triglyceride (MCT) oil via massage therapy as a supplementary nutritional method on the weight gain of Neonatal Intensive Care Units (NICU)-hospitalized neonates. This randomized clinical trial performed among 121 stable premature neonates hospitalized in the NICU of Qaem Educational Hospital, Mashhad, Iran. They were randomly divided into three groups: oil-massage, massage alone and control groups. These groups were compared on the basis of weight gain during a one-week interval. The three groups were matched for sex, mean gestational age, birth weight, head circumference, delivery, and feeding type (P>0.05). The mean weight gain on the 7th day in the oil massage group was 105+/-1.3gr and 52+/-0.1gr in the massage group; whereas 54+/-1.3gr weight loss was observed in the control group. Significant differences were observed between the oil-massage group and the other two groups, respectively (P=0.002 and P=0.000). The findings of this study suggest that transcutaneous feeding with MCT oil massage therapy in premature neonates can result in accelerated weight gain in this age group with no risk of NEC. PMID- 25725186 TI - A proximal femur aneurysmal bone cyst resulting in amputation: a rare case report. AB - Aneurysmal bone cyst (ABC) is blood filled expansile cystic lesion that most commonly occurs in patients during the second decade of their lives. Traditionally it has been described as a benign lesion but can be locally aggressive and result in the destruction of the involved bone. Treatment methods include surgical excision and curettage with or without bone grafting. We report a proximal femur aneurysmal bone cyst, which resulted in the amputation of the lower extremity, even though all available classic methods of treatment were applied for it. PMID- 25725187 TI - Comments on: predictive value of having positive family history of cardiovascular disorders, diabetes mellitus, dyslipidemia, and hypertension in non-alcoholic fatty liver disease patients. PMID- 25725188 TI - Direct behavioral and neural evidence for an offset-triggered conscious perception. AB - Many previous theories of perceptual awareness assume that a conscious representation of a stimulus is created from sensory information carried by an onset (appearance) of the stimulus. In contrast, here we provide behavioral and neural evidence for a new phenomenon in which conscious perception is directly triggered by an offset (disappearance) of a stimulus. When a stimulus made invisible by inter-ocular suppression physically disappeared from a screen, subjects reported an appearance (not disappearance) of that stimulus, correctly reporting a color of the disappeared stimulus. Measurements of brain activity further confirmed that the physical offset of an invisible stimulus evoked neural activity reflecting conscious perception of that stimulus. Those results indicate a new role of a stimulus offset to facilitate (rather than inhibit) an emergence of consciousness. PMID- 25725189 TI - The effect of goals and vision on movements: a case study of optic ataxia and limb apraxia. AB - Normally we can perform a variety of goal-directed movements effortlessly. However, damage to the parietal cortex may dramatically reduce this ability, giving rise to optic ataxia and limb apraxia. Patients with optic ataxia show clear misreaches towards targets when presented in the peripheral visual field, whereas limb apraxia refers to the inability to use common tools or to imitate simple gestures. In the present paper we describe the case of a left-brain damaged patient, who presented both symptoms. We systematically investigated both spatial and temporal parameters of his movements, when asked to reach and grasp common objects to move (Experiment 1) or to use them (Experiment 2), presented either in the central or peripheral visual field. Different movement parameters changed in relation to the goal of the task (grasp to move vs. grasp to use), reflecting a normal modulation of the movement to accomplish tasks with different goals. On the other hand, grip aperture appeared to be more affected from both task goal and viewing condition, with a specific decrement observed when CF was asked to use objects presented peripherally. On the contrary, a neat effect of the viewing condition was observed in the spatial distribution of the end-points of the movements, and of the horizontal end point in particular, which were shifted towards the fixation point when reaching towards peripheral targets. We hypothesized that optic ataxia and limb apraxia have a differential effect on the patient's performance. The specific presence of optic ataxia would have an effect on the movement trajectory, but both symptoms might interact and influence the grasping component of the movement. As a 'cognitive side of motor control impairment', the presence of limb apraxia may have increased the task demands in grasping to use the objects thus exacerbating optic ataxia. PMID- 25725190 TI - Modified Fusarium mycotoxins unmasked: From occurrence in cereals to animal and human excretion. AB - Modified mycotoxins formed by plants, fungi and during some food processing steps may remain undetected by analytical methods, potentially causing underestimation of mycotoxin exposure and risk. Furthermore, due to altered physico-chemical characteristics of modified mycotoxins, these compounds might have different gastro-intestinal absorption compared to the unmodified forms, leading to altered modified mycotoxin plasma concentrations. Additionally, modified mycotoxins can be converted back into their corresponding unmodified forms by in vivo hydrolysis upon oral ingestion. This review aims to describe the current knowledge on the production, occurrence, toxicity and toxicokinetic properties of the modified Fusarium mycotoxins. The need for more occurrence data to correctly assess the risks associated with these modified mycotoxins is clearly indicated, including differences between commodities as well as geographical and climatological influences. Research on toxicity of these modified forms demonstrates the possibility of significant decreases as well as increases in the toxic effects of these compounds compared with those of the unmodified forms. Their toxicokinetics demonstrates that a decreased (increased) polarity of modified mycotoxins might cause enhanced (decreased) oral absorption. The possibility of in vivo hydrolysis, altered toxicity and their wide-spread occurrence makes modified mycotoxins a complex threat for which a risk assessment will require prospective multi-disciplinary efforts. PMID- 25725191 TI - Pilot clinic study of Project EX for smoking cessation with Spanish adolescents. AB - INTRODUCTION: Despite efforts to prevent smoking, the prevalence of smoking in Spanish adolescents remains high. So far, there are no evidence-based smoking cessation programs for adolescents in Spain. METHODS: This study describes the evaluation of Project EX, an eight-session school-based clinic smoking cessation program, with Spanish cigarette smokers 13-19 years of age, from 9 schools (four program condition schools and five control condition schools). A group-randomized controlled trial was used. There were 211 smokers at baseline (112 program group, and 99 control group). Evaluation involved an immediate pretest and posttest survey (administered five-weeks later) and six-month follow-up (after the immediate posttest). RESULTS: At immediate posttest, Project EX significantly reduced future nicotine dependence scores (mFTQ; p<.001), and increased intention to quit smoking (p<.001), and led to a higher previous day (prior to assessment) quit rate (p<.03). At the six-month follow-up, the percentage of quitters in the program group was 14.28%, whereas no smokers quit smoking in the control group (p<.04), and Project EX had a significant influence on future smoking expectation (p=.006) and overall level of 30-day smoking. CONCLUSIONS: Results for the Project EX school-based clinic are promising for adolescent smokers in Spain, although difficulties in recruitment and high attrition are of concern. Findings and limitations are discussed and suggestions for future research are suggested. PMID- 25725192 TI - An ecological approach to cognitive enhancement: complex motor training. AB - Cognitive training has received a lot of attention recently, yielding findings that can be conflicting and controversial. In this paper, we present a novel approach to cognitive training based on complex motor activities. In a randomized controlled design, participants were assigned to one of three conditions: aerobic exercise, working memory training or designed sport--an intervention specifically tailored to include both physical and cognitive demands. After training for eight weeks, the designed sport group showed the largest gains in all cognitive measures, illustrating the efficacy of complex motor activities to enhance cognition. Designed sport training also revealed impressive health benefits, namely decreased heart rate and blood pressure. In this period of skepticism over the efficacy of computerized cognitive training, we discuss the potential of ecological interventions targeting both cognition and physical fitness, and propose some possible applications. PMID- 25725193 TI - Timing matters: negative emotion elicited 5 min but not 30 min or 45 min after learning enhances consolidation of internal-monitoring source memory. AB - Two experiments examined the time-dependent effects of negative emotion on consolidation of item and internal-monitoring source memory. In Experiment 1, participants (n=121) learned a list of words. They were asked to read aloud half of the words and to think about the remaining half. They were instructed to memorize each word and its associative cognitive operation ("reading" versus "thinking"). Immediately following learning they conducted free recall and then watched a 3-min either neutral or negative video clip when 5 min, 30 min or 45 min had elapsed after learning. Twenty-four hours later they returned to take surprise tests for item and source memory. Experiment 2 was similar to Experiment 1 except that participants, without conducting an immediate test of free recall, took tests of source memory for all encoded words both immediately and 24 h after learning. Experiment 1 showed that negative emotion enhanced consolidation of item memory (as measured by retention ratio of free recall) regardless of delay of emotion elicitation and that negative emotion enhanced consolidation of source memory when it was elicited at a 5 min delay but reduced consolidation of source memory when it was elicited at a 30 min delay; when elicited at a 45 min delay, negative emotion had little effect. Furthermore, Experiment 2 replicated the enhancement effect on source memory in the 5 min delay even when participants were tested on all the encoded words. The current study partially replicated prior studies on item memory and extends the literature by providing evidence for a time-dependent effect of negative emotion on consolidation of source memory based on internal monitoring. PMID- 25725195 TI - Exposure to metals and congenital anomalies: a biomonitoring study of pregnant Bedouin-Arab women. AB - BACKGROUND: The Bedouin-Arab population in Israel comprises a low socio-economic society in transition. Smoking among males and consanguineous marriages are frequent. A previous study showed elevated rates of major malformations within groups from this population residing near an industrial park, where high ambient values of arsenic (As) and nickel (Ni) were detected, compared to groups living in remote localities. OBJECTIVES: We estimated the extent of exposure to metals in pregnant Bedouin-Arab women in relation to congenital malformations. METHODS: We collected maternal urine samples from 140 Bedouin women who gave birth in a local hospital. Patient medical history, type of marriage (consanguineous or non consanguineous), and parental exposure history were collected by interview and medical records. RESULTS: Aluminum (Al) was detected in 37 women (26.4%), cadmium (Cd) in 2 (1.4%), As in 10 (7.1%), and Ni in 1 woman (0.7%). The detected rate of Cd exposure was low, though more than 92% of the fathers reported smoking. Concentrations of Al were higher for women residing within 10 km of the local industrial park (Prevalence Ratio (PR)=1.12, p-value=0.012) or who reported using a wood burning stove (PR=1.37, p-value=0.011) and cooking over an open fire (PR=1.16, p-value=0.076). Exposure to Al was adversely associated with minor anomalies (OR=3.8, p-value=0.046) after adjusting for history of abortions (OR=6.1, p-value=0.007). Fetuses prenatally exposed to As were born prematurely (p-value=0.001) and at lower weights (pv=0.023). CONCLUSIONS: The study population of pregnant women is exposed to high levels of metals mainly of household origin. Our findings may be generalized to similar populations in developing countries. PMID- 25725194 TI - miR-491-5p functions as a tumor suppressor by targeting JMJD2B in ERalpha positive breast cancer. AB - The involvement of miR-491-5p in breast cancer development is unclear. This study showed that miR-491-5p is significantly downregulated in ERalpha-positive breast cancer tissues and cell lines and is generally hypermethylated in ERalpha positive breast cancer. MiR-491-5p overexpression significantly suppressed estrogen signaling and estrogen-stimulated proliferation of breast cancer cells. Furthermore, the histone demethylase JMJD2B was identified as a direct target of miR-491-5p. The ectopic expression of JMJD2B abrogated the phenotypic changes induced by miR-491-5p in breast cancer cells. Collectively, our data indicate that miR-491-5p plays a tumor suppressor role in the development and progression of breast caner and may be a novel therapeutic target against ERalpha-positive breast cancer. PMID- 25725196 TI - Indicators of airborne fungal concentrations in urban homes: understanding the conditions that affect indoor fungal exposures. AB - Indoor fungal exposure can compromise respiratory health. Low-income urban areas are of concern because of high asthma and allergy rates and housing disrepair. Understanding the conditions that affect indoor fungal exposures is important for assessing health risks and for developing mitigation strategies. We examined the types and concentrations of airborne fungi inside and outside of homes in low income areas of Syracuse, NY as well as the effect of snow cover on fungal levels. At 103 homes, air samples for viable fungi were collected, occupants were interviewed and homes were inspected for visible mold, musty odors, water problems and other factors. Multivariable logistic regression was used to relate high fungal levels to home conditions. Predominant indoor fungi included Cladosporium, Penicillium, Aspergillus, Alternaria and hyaline unknowns. Basidiomycetes and an uncommon genus Acrodontium were also found frequently due to analysis methods developed for this project. With snow cover, outdoor total fungal levels were depressed and indoor concentrations were three times higher than outdoor on average with a maximum of 29 times higher. Visible mold was related to elevated levels of Penicillium (OR 4.11 95% CI 1.37-14.0) and bacteria (OR 3.79 95% CI 1.41-11.2). Musty, moldy odors were associated with elevated concentrations of total fungi (OR 3.48 95% CI 1.13-11.6) and basidiomycetes. Cockroaches, an indicator of moisture, were associated with elevated levels of Penicillium (OR 3.66 95% CI 1.16-13.1) and Aspergillus (OR 4.36 95% CI 1.60 13.4). Increasing relative humidity was associated with higher concentrations of Penicillium, yeasts and basidiomycetes. Visible mold, musty odors, indoor humidity and cockroaches are modifiable factors that were important determinants of indoor fungal exposures. Indoor air investigators should interpret indoor:outdoor fungal ratios cautiously when snow cover is present. PMID- 25725197 TI - Developing an intervention strategy to reduce phthalate exposure in Taiwanese girls. AB - Children in Taiwan seem to be exposed to higher concentrations of phthalates than do children in Western countries. We developed intervention strategies to reduce the exposure of phthalates in Taiwanese girls. Thirty girls 4-13 years old who had been exposed to high levels of phthalates were selected from prior studies. To reduce their phthalate-exposure sources, we developed seven intervention strategies: handwashing, not using plastic containers, not eating food with a plastic bag/plastic-wrap cover, not microwaving food, not taking nutrition supplements, and reducing use of cosmetics/personal care products. Pre- and post intervention urine samples were collected during a one-week study. HPLC-MS/MS was used to analyze urinary phthalate metabolites. The dominant urinary phthalate metabolite was mono-n-butyl phthalate (MBP), followed by mono-(2-ethyl-5 hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). Post-intervention concentrations of eight urinary phthalate metabolites were significantly lower. Girls in the high-frequency handwashing group had significantly lower urinary MBP (p=0.009) and mono-methyl phthalate (MMP) (p=0.07) than did girls in the low-frequency handwashing group. Girls who drank fewer beverages from plastic cups had significantly lower urinary MBP (p=0.016), MEHHP (p=0.038), and MECPP (p=0.012). Girls who used less shampoo and shower gel also had marginally significantly lower urinary MBP (p=0.06) and mono-ethyl phthalate (MEP) (p=0.06). The intervention strategies that we set up in this study were effective for reducing exposure to phthalates in children. Handwashing and drinking fewer beverages from plastic cups were the most effective strategies for reducing phthalate metabolites in urine, especially MBP and di(2-ethylhexyl) phthalate (DEHP) metabolites. Education and voluntary self-restraint were useful for reducing the body burden of phthalates. PMID- 25725198 TI - A critical review of protocols for moss biomonitoring of atmospheric deposition: sampling and sample preparation. AB - Currently, the most important guideline for the application of the moss technique to monitor the atmospheric deposition of heavy metals is the "Heavy metals, nitrogen and POPs in European mosses: 2015 survey" published by the UNECE ICP Vegetation. Two main problems have been identified with this guideline: i) some of the recommendations regarding the methodological aspects involved in the application of the moss technique are not based on scientific criteria; and, ii) some recommendations in the manual are very vague and some aspects are even left out (e.g., elevation, distance to the coast). As a result there exists a high variability in the application of the protocol and many scientists adapt it to the specific conditions in the studied areas without evaluating how changes affect the results obtained. Therefore, in this article a total of 369 studies were reviewed including both methodological and application studies of the passive biomonitoring of the atmospheric deposition of heavy metals with terrestrial mosses. The results of this review have shown on the one hand, that none of the articles completely accomplished the ICP-Vegetation protocol suggestions, either because the information regarding some aspects was lacking or simply because the authors did not follow the manual suggestions. On the other hand, it was found that the results of methodological studies sometimes contradicted the ICP Vegetation manual recommendations. Thus, a new protocol in which each suggestion has been carefully and rigorously contrasted with the available literature has been proposed in this paper. In addition, practical and economic issues have also been considered and much more concise suggestions have been proposed which would facilitate its fulfilment in a more objective way. PMID- 25725199 TI - Exploring the interaction between O3 and NOx pollution patterns in the atmosphere of Barcelona, Spain using the MCR-ALS method. AB - This work focuses on understanding the behaviour and patterns of three atmospheric pollutants namely, nitric oxide (NO), nitrogen dioxide (NO2), and ozone (O3) along with their mutual interactions in the atmosphere of Barcelona, North Spain. Hourly samples were collected for NO, NO2 and O3 from the same city location for three consecutive years (2010-2012). The study explores the seasonal, annual and weekday-weekend variations in their diurnal profiles along with the possible identification of their source and mutual interactions in the region. Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) was applied to the individual datasets of these pollutants, as well as to all of them simultaneously (augmented mode) to resolve the profiles related to their source and variation patterns in the atmosphere. The analysis of the individual datasets confirmed the source pattern variations in the concerned pollutant's profiles; and the resolved profiles for augmented datasets suggested for the mutual interaction of the pollutants along with their patterns variations, simultaneously. The study suggests vehicular pollution as the major source of atmospheric nitrogen oxides and presence of weekend ozone effect in the region. PMID- 25725200 TI - Observation of color center peaks in calcium fluoride. AB - Alkali halides such as calcium fluoride all have color center defects that absorb light in the visible region. Using a moncochromator equipped, aberration corrected, scanning transmission electron microscope (STEM) we recorded spectra showing the time evolution of the generation of F and H centers in calcium fluoride. The final stage of electron beam irradiation is the formation of metallic calcium nanoparticles. High resolution low loss spectra for the Vacuum Ultraviolet region were also recorded. PMID- 25725201 TI - The use of adenosine and adenosine triphosphate testing in the diagnosis, risk stratification and management of patients with syncope: current evidence and future perspectives. AB - Syncope is a significant source of cardiovascular-related morbidity yet the etiology is frequently obscure and the identification of patients at highest risk is challenging. Adenosine (AD) and adenosine triphosphate (ATP) administrations have been suggested as potentially useful non-invasive tools in the diagnostic workup of patients with neurally-mediated or bradycardia-related syncope. It has been postulated that both compounds by modulating the autonomic innervation in the heart and exerting negative chronotropic and dromotropic effects in the conduction system, may unmask the mechanism of syncope. However, the clinical implications derived from the efficacy of both tests in the investigation of syncope remain unclear mainly due to inconclusive and occasionally contradictory results of published studies. This review article summarizes recent and past information in the use of ATP and AD in the investigation of syncope with emphasis on clinical trials. We present the current level of evidence for the use of these agents in clinical practice, identify areas where further research is warranted and highlight the future perspectives of these agents as complements to an accurate risk-stratification of patients with syncope. PMID- 25725202 TI - Degradation rates of benzotriazoles and benzothiazoles under UV-C irradiation and the advanced oxidation process UV/H2O2. AB - Benzotriazoles (BTs) and benzothiazoles (BTHs) are extensively used chemicals found in a wide range of household and industrial products. They are chemically stable and are therefore ubiquitous in the aquatic environment. The present study focuses on the potential of ultraviolet (UV) irradiation, alone or in combination with hydrogen peroxide (H2O2), to remove BTs and BTHs from contaminated waters. Six compounds, three out of each chemical class, were investigated using a low pressure mercury lamp (main emission at 254 nm) as the radiation source. Initially, the direct phototransformation kinetics and quantum yield in dilute aqueous solution was studied over the pH range of 4-12. All BTs and BTHs, except for benzothiazole, exhibited pH-dependent direct phototransformation rate constants and quantum yields in accordance to their acid-base speciation (7.1 < pKa < 8.9). The direct phototransformation quantum yields (9.0 * 10(-4)-3.0 * 10( 2) mol einstein(-1)), as well as the photon fluence-based rate constants (1.2-48 m(2) einstein(-1)) were quite low. This suggests that UV irradiation alone is not an efficient method to remove BTs and BTHs from impacted waters. The second-order rate constants for the reaction of selected BTs and BTHs with the hydroxyl radical were also determined, and found to fall in the range of 5.1-10.8 * 10(9) M(-1) s(-1), which is typical for aromatic contaminants. Finally, the removal of BTs and BTHs was measured in wastewater and river water during application of UV irradiation or the advanced oxidation process UV/H2O2. The latter process provided an efficient removal, mostly due to the effect of the hydroxyl radical, that was comparable to other aromatic aquatic contaminants, in terms of energy requirement or treatment costs. PMID- 25725203 TI - The eAND process: enabling simultaneous nitrogen-removal and disinfection for WWTP effluent. AB - To mitigate potential eutrophication risk caused by nitrogen species in the effluent of wastewater treatment plant (WWTP), nitrogenous compounds failed to be removed during biological wastewater treatment should be further eliminated. In this paper, an electrochemical process for ammonia-oxidation, nitrate-reduction and disinfection (eAND process) of WWTP effluent was developed and its performance for tertiary treatment of synthetic wastewater and actual effluent was evaluated. Results indicated ammonia and nitrate removal efficiencies in actual effluent reached 96% and 36% at 1.23 Ah l(-1), while coliforms were totally inactivated at 0.072 Ah l(-1) under the optimal operation conditions. Ammonia removal due to the anodic indirect oxidation followed a pseudo first kinetic, while the modified model expressed as exponential decay fitted well to the experimental data with the presence of nitrate. The coliforms inactivation was attributed to the in situ generated active chlorine, indicating no extra addition of disinfectant. Nitrate reduction in cathodic area fitted to pseudo first order kinetic with kinetic constants of 0.13-0.54 l A(-1) h(-1). These results clearly showed the potential of this eAND process to serve as a tertiary treatment of WWTP effluent for simultaneous removal of ammonia, nitrate and disinfection. PMID- 25725204 TI - Concerning the role of cell lysis-cryptic growth in anaerobic side-stream reactors: the single-cell analysis of viable, dead and lysed bacteria. AB - In the Anaerobic Side-Stream Reactor (ASSR), part of the return sludge undergoes alternating aerobic and anaerobic conditions with the aim of reducing sludge production. In this paper, viability, enzymatic activity, death and lysis of bacterial cells exposed to aerobic and anaerobic conditions for 16 d were investigated at single-cell level by flow cytometry, with the objective of contributing to the understanding of the mechanisms of sludge reduction in the ASSR systems. Results indicated that total and viable bacteria did not decrease during the anaerobic phase, indicating that anaerobiosis at ambient temperature does not produce a significant cell lysis. Bacteria decay and lysis occurred principally under aerobic conditions. The aerobic decay rate of total bacteria (bTB) was considered as the rate of generation of lysed bacteria. Values of bTB of 0.07-0.11 d(-1) were measured in anaerobic + aerobic sequence. The enzymatic activity was not particularly affected by the transition from anaerobiosis to aerobiosis. Large solubilisation of COD and NH4(+) was observed only under anaerobic conditions, as a consequence of hydrolysis of organic matter, but not due to cell lysis. The observations supported the proposal of two independent mechanisms contributing equally to sludge reduction: (1) under anaerobic conditions: sludge hydrolysis of non-bacterial material, (2) under aerobic conditions: bacterial cell lysis and oxidation of released biodegradable compounds. PMID- 25725205 TI - Lymphomagenesis in Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) accounts for approximately 0.6% of all new cancer cases, 10% of all lymphomas in the USA, leading to an approximate 9000 new cases per year. It is very unique in that the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of classical HL account for only 1% of the tumor tissue in most cases, with various inflammatory cells including B-cells, T-cells, mast cells, macrophages, eosinophils, neutrophils, and plasma cells comprising the tumor microenvironment. Recent research has identified germinal center B-cells to be the cellular origin of HRS cells. Various transcription factor dysregulation in these neoplastic cells that explains for the loss of B-cell phenotype as well as acquisition of survival and anti-apoptotic features of HRS cells has been identified. Aberrant activation of nuclear factor-kappa B (NF-kappaB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphoinositide 3-kinase (PI3K) pathways play a central role in HL pathogenesis. Both intrinsic genetic mechanisms as well as extrinsic signals have been identified to account for the constitutive activation of these pathways. The extrinsic factors that regulate the activation of transcription pathways in HRS cells have also been studied in detail. Cytokines and chemokines produced both by the HRS cells as well as cells of the microenvironment of HL work in an autocrine and/or paracrine manner to promote survival of HRS cells as well as providing mechanisms for immune escape from the body's antitumor immunity. The understanding of various mechanisms involved in the lymphomagenesis of HL including the importance of its microenvironment has gained much interest in the use of these microenvironmental features as prognostic markers as well as potential treatment targets. In this article, we will review the pathogenesis of HL starting with the cellular origin of neoplastic cells and the mechanisms supporting its pathogenesis, especially focusing on the microenvironment of HL and its associated cytokines. PMID- 25725206 TI - Facioscapulohumeral muscular dystrophy as a genetic cause of pectus excavatum. PMID- 25725207 TI - Understanding intercultural transitions of medical students. AB - OBJECTIVE: The aim of this research was to explore the transition of medical students to an international branch campus of a medical university established in Bahrain. METHODS: In order to gain insights into this transition, we explored two culturally diverse systems of learning of the university and the local schools in Bahrain, using Communities of Practice as a lens for understanding transitions. Focus groups were conducted with secondary school teachers and first year medical students. Additionally, semi-structured interviews were conducted with university lecturers. RESULTS: The findings suggest that, while Communities of Practice have been influential in contextualising transitions to university, this model does not seem to help us to fully understand intercultural transitions to the case study university. CONCLUSIONS: The research emphasises that more attention should be given to learner individual agency within this theory as a framework for understanding transitions. It also challenges approaches within medical education that attempt to standardise systems of learning through acquisition of established practices. PMID- 25725208 TI - Orthogonal hydrogen/halogen bonding in 1-(2-methoxyphenyl)-1H-imidazole-2(3H) thione-I2 adduct: an experimental and theoretical study. AB - The molecular complex between 1-(2-methoxyphenyl)-1H-imidazole-2(3H)-thione (Hmim(OMe)) and iodine (I2) was investigated. Single crystal of [(Hmim(OMe))I2] adduct was grown by slow evaporation technique from chloroform at room temperature. Spectroscopic techniques such as FT-IR and Raman techniques, as well as elemental and thermal analysis were used to characterize the complex. The crystal structure shows that the formed adduct stabilized by two noncovalent interactions, namely, hydrogen bond (HB) and halogen bond (XB). Orthogonal HB/XB associated with iodine atom (I) was observed and fully characterized. The ability of iodine to behave as hydrogen bond acceptor and halogen bond donor was held responsible for the orthogonal HB/XB presence. In addition, the structure of Hmim(OMe)I2 was investigated theoretically using MP2/aug-cc-pVDZ level of theory. Natural bond orbital analysis (NBO) was used to investigate the molecular orbitals interactions and orbitals stabilization energies. PMID- 25725209 TI - Synthesis, crystal structures HOMO-LUMO analysis and DFT calculation of new complexes of p-substituted dibenzyltin chlorides and 1,10-phenanthroline. AB - In the present work, the complex formation of p-substituted dibenzyltin dichlorides with 1,10-phenanthroline. The reaction of (p-MeBz)2SnCl2 with 1,10 phenanthroline results (p-MeBz)2SnCl2-1,10-phenanthroline complex, (2a). Likewise (p-ClBz)2SnCl2 with 1,10-phenanthroline results (p-ClBz)2SnCl2-1,10 phenanthroline complex, (2b), in the similar reaction conditions. The IR, (1)H NMR, (13)C NMR, (119)Sn NMR spectral analyses indicate that the formation of hexacoordinated tin(IV) complexes in 1:1 ratio. The crystal structures of complexes 2a and 2b show that the tin atom is in regular octahedral geometry with the benzyl groups in the equidirectional positions. A comparison was made with the structural data of other R2SnX2-1,10-phenathroline derivatives. Fourier transforms infrared and Raman spectral studies were performed for analyzing and assigning the vibrations and to identify the functional groups. Optimized geometrical parameters, harmonic vibrational frequencies, frontier molecular orbitals were obtained by DFT/B3LYP method combined with LanL2DZ basis set. PMID- 25725210 TI - A Combined theoretical and experimental study of conformational and spectroscopic profile of 2-acetamido-5-aminopyridine. AB - Present work aims at identifying the conformational and spectroscopic profile of 2-acetamido-5-aminopyridine compound by means of experimental and computational methods. To achieve this, three-dimensional potential energy scan (PES) was performed by varying the selected dihedral angles at B3LYP/6-31+G(d,p) level of theory and thus stable conformers of the title compound were determined. The most stable conformer was further optimized at higher level and vibrational wavenumbers were calculated. Experimentally, vibrational features of title compound were determined by FT-IR and FT-Raman spectroscopic methods in the solid phase while the electronic absorption spectrum was recorded in methanol solution. On the basis of these investigations, the conformational and spectroscopic attributes of 2-acetamido-5-aminopyridine were interpreted. PMID- 25725211 TI - RETRACTED: Green synthesis of zinc oxide nanoparticles using Moringa oleifera leaf extract and evaluation of its antimicrobial activity. AB - The development of semiconductor materials made a considerable progress of catalytic technologies. In the present study, a simple and eco-friendly chemical direction for the synthesis of zinc oxide nanoparticles (ZnO NPs) using leaf extract of Moringa oleifera has been used. The prepared ZnO NPs were characterized various techniques such as UV-Vis absorption spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray analysis (EDX), Fourier transform infrared spectroscopy (FT-IR) and photoluminescence spectroscopy (PL). XRD analysis revealed the wurtzite hexagonal structure of ZnO NPs. FT-IR confirmed the presence of functional groups of both leaf extract and ZnO NPs. The particles size, morphology and topography determined from FE-SEM. The intense and narrow width of zinc and oxygen have high purity and crystalline were identified using EDX. UV-Vis absorption showed the characteristic absorption peak of ZnO NPs. The results of antimicrobial activities revealed that maximum zones of inhibition was observed Gram (+ve) positive bacteria and followed by the Gram (-ve) negative bacteria and fungal at concentration of 200MUg/mL of ZnO NPs. PMID- 25725212 TI - Feeding the human brain model. AB - The goal of the Human Brain Project is to develop, during the next decade, an infrastructure capable of simulating a draft human brain model based on available experimental data. One of the key issues is therefore to integrate and make accessible the experimental data necessary to constrain and fully specify this model. The required data covers many different spatial scales, ranging from the molecular scale to the whole brain and these data are obtained using a variety of techniques whose measurements may not be directly comparable. Furthermore, these data are incomplete, and will remain so at least for the coming decade. Here we review new neuroinformatics techniques that need to be developed and applied to address these issues. PMID- 25725213 TI - TRP channels. AB - Evidence is accumulating on the role of transient receptor potential (TRP) channels, namely TRPV1, TRPA1, TRPV4 and TRPM8, expressed by C- and Adelta-fibres primary sensory neurons, in cough mechanism. Selective stimuli for these channels have been proven to provoke and, more rarely, to inhibit cough. More importantly, cough threshold to TRP agonists is increased by proinflammatory conditions, known to favour cough. Off-target effects of various drugs, such as tiotropium or desflurane, seem to produce their protective or detrimental actions on airway irritation and cough via TRPV1 and TRPA1, respectively. Thus, TRPs appear to encode the process that initiates or potentiates cough, activated by exogenous irritants and endogenous proinflammatory mediators. More research on TRP channels may result in innovative cough medicines. PMID- 25725214 TI - Anticoagulant therapy: present and future. PMID- 25725215 TI - A comparison of the surface nanostructure from two different types of gram negative cells: Escherichia coli and Rhodobacter sphaeroides. AB - Bacteria have been studied using different microscopy methods for many years. Recently, the developments of high-speed atomic force microscopy have opened the doors to study bacteria in new ways due to the fact that it uses much less force on the sample while imaging. This makes the high-speed atomic force microscope an indispensable technique for imaging the surface of living bacterial cells because it allows for the high-resolution visualization of surface proteins in their natural condition without disrupting the cell or the activity of the proteins. Previous work examining living cells of Magnetospirillum magneticum AMB-1 demonstrated that the surface of these bacteria was covered with a net-like structure that is mainly composed of porin molecules. However, it was unclear whether or not this feature was unique to other living bacteria. In this study we used the high-speed atomic force microscope to examine the surface of living cells of Escherichia coli and Rhodobacter sphaeroides to compare their structure with that of M. magneticum. Our research clearly demonstrated that both of these types of cells have an outer surface that is covered in a network of nanometer sized holes similar to M. magneticum. The diameter of the holes was 8.0+/-1.5 nm for E. coli and 6.6+/-1.1 nm for R. sphaeroides. The results in this paper confirm that this type of outer surface structure exists in other types of bacteria and it is not unique to Magnetospirillum. PMID- 25725216 TI - Venous stenosis in chronic dialysis patients with a well-functioning arteriovenous fistula. AB - PURPOSE: It is not clear whether patient who is dialyzing with a well-functioning vascular access may appear venous stenosis. The aim is to see the prevalence of central or other vein stenoses/occlusions in patients with asymptomatic, normal functioning fistulas. METHODS: A total of 54 patients met the inclusion criteria. We performed angiography examinations for these patients and reviewed venography of the superficial and deep venous systems. RESULTS: Among these patients, 21 (39%) were detected positive cases by the angiography, the remainder was negative cases. Thirteen of 54 (24%) had mild central venous stenosis (stenosis <50% diameter with or without collateral branch), 7/54 (13%) had upper arm vein system occlusion or stenosis, another one had anastomotic stenosis. There were no differences in fistula flow dynamics between those with venous abnormalities and those without such as blood flow rate, venous pressures, brachial arterial velocity, and brachial arterial flow rate. We also observed no significant differences in other variables between these two groups (including BMI, hemoglobin, albumin, gender, primary disease, URR, spKt/V P > 0.05). CONCLUSION: The frequency of venous lesion is not low in hemodialysis patients with a well functioning AVF. To value the impact of these abnormalities on access, prognosis needs longer time follow-up. PMID- 25725218 TI - Critical assessment of genome-scale metabolic networks: the need for a unified standard. AB - Genome-scale metabolic networks have been reconstructed for several organisms. These metabolic networks provide detailed information about the metabolism inside the cells, coupled with the genomic, proteomic and thermodynamic information. These networks are widely simulated using 'constraint-based' modelling techniques and find applications ranging from strain improvement for metabolic engineering to prediction of drug targets in pathogenic organisms. Components of these metabolic networks are represented in multiple file formats and also using different markup languages, with varying levels of annotations; this leads to inconsistencies and increases the complexities in comparing and analysing reconstructions on multiple platforms. In this work, we critically examine nearly 100 published genome-scale metabolic networks and their corresponding constraint based models and discuss various issues with respect to model quality. One of the major concerns is the lack of annotations using standard identifiers that can uniquely describe several components such as metabolites, genes, proteins and reactions. We also find that many models do not have complete information regarding constraints on reactions fluxes and objective functions for carrying out simulations. Overall, our analysis highlights the need for a widely acceptable standard for representing constraint-based models. A rigorous standard can help in streamlining the process of reconstruction and improve the quality of reconstructed metabolic models. PMID- 25725217 TI - Behavioral Pediatrics Feeding Assessment Scale in Young Children With Autism Spectrum Disorder: Psychometrics and Associations With Child and Parent Variables. AB - OBJECTIVE: The factor structure and validity of the Behavioral Pediatrics Feeding Assessment Scale (BPFAS; Crist & Napier-Phillips, 2001) were examined in preschoolers with autism spectrum disorder (ASD). METHODS: Confirmatory factor analysis was used to examine the original BPFAS five-factor model, the fit of each latent variable, and a rival one-factor model. None of the models was adequate, thus a categorical exploratory factor analysis (CEFA) was conducted. Correlations were used to examine relations between the BPFAS and concurrent variables of interest. RESULTS: The CEFA identified an acceptable three-factor model. Correlational analyses indicated that feeding problems were positively related to parent-reported autism symptoms, behavior problems, sleep problems, and parenting stress, but largely unrelated to performance-based indices of autism symptom severity, language, and cognitive abilities, as well as child age. CONCLUSION: These results provide evidence supporting the use of the identified BPFAS three-factor model for samples of young children with ASD. PMID- 25725219 TI - Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations. AB - The interaction between T-cell receptors (TCRs) and major histocompatibility complex (MHC)-bound epitopes is one of the most important processes in the adaptive human immune response. Several hypotheses on TCR triggering have been proposed. Many of them involve structural and dynamical adjustments in the TCR/peptide/MHC interface. Molecular Dynamics (MD) simulations are a computational technique that is used to investigate structural dynamics at atomic resolution. Such simulations are used to improve understanding of signalling on a structural level. Here we review how MD simulations of the TCR/peptide/MHC complex have given insight into immune system reactions not achievable with current experimental methods. Firstly, we summarize methods of TCR/peptide/MHC complex modelling and TCR/peptide/MHC MD trajectory analysis methods. Then we classify recently published simulations into categories and give an overview of approaches and results. We show that current studies do not come to the same conclusions about TCR/peptide/MHC interactions. This discrepancy might be caused by too small sample sizes or intrinsic differences between each interaction process. As computational power increases future studies will be able to and should have larger sample sizes, longer runtimes and additional parts of the immunological synapse included. PMID- 25725220 TI - GKN1 inhibits cell invasion in gastric cancer by inactivating the NF-kappaB pathway. AB - Metastasis is a relatively early event and a major cause of death in gastric cancer (GC) patients. Gastrokine 1 (GKN1) is a stomach-specific protein that is normally expressed in gastric mucosa but not in primary tumors or cell lines. We and others have demonstrated that GKN1 inhibits cell growth; however, its role in metastasis is not clear. In this study, we explored the role of GKN1 in cell invasion. Immunohistochemistry (IHC) was used to measure the expression of GKN1 in precancerous lesions and in GCs. The cell invasion assay was employed to examine the effect of GKN1 on cell invasion. The molecular mechanism of GKN1 in inhibiting GC cell invasion in vitro was explored by western blotting. We noted a gradual decrease in GKN1 expression from normal mucosa to dysplastic gastric tissue to GC, and that low GKN1 expression was associated with metastasis (P=0.003). We showed that GKN1 inhibits cell invasion by downregulating MMP2 expression through the NF-kappaB pathway. These results provide molecular evidence that GKN1 inhibits metastasis in GC cells, and indicate that GKN1 is a potential novel therapeutic target for gastric cancer. PMID- 25725221 TI - Epigenetics in atherosclerosis: a clinical perspective. AB - Significant progress has been made in understanding in the pathogenesis of atherosclerosis. Nevertheless, atherosclerosis remains a great threat to human health worldwide. Epigenetic mechanisms, which involve DNA methylation, histone modification, and microRNA, have significantly enhanced our understanding of the pathological process of atherosclerosis. More importantly, epigenetic processes (in contrast to genetic alterations) are reversible and thus provide a potential therapeutic target in atherosclerosis treatment. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. This review aims to present an overview of current epigenetic mechanisms involved in the pathogenesis of atherosclerosis, and discuss points in these processes where therapeutic interventions likely bear fruition. PMID- 25725222 TI - The guts of obesity: progress and challenges in linking gut microbes to obesity. AB - The sharp rise in prevalence of obesity in recent decades has been suggestively labeled as an "epidemic," and the lack of fully explanatory causal factors has challenged existing understandings of obesity's etiology from a purely energetic standpoint. Much recent attention has been focused on the microbial members of the human gut for insights into their role in potentially causing or promoting obesity. The human gut is home to trillions of microbes, among which hundreds of distinct species of bacteria interact to form the human gut microbiome, and numerous studies in humans and animal models have linked shifts in the gut microbiome to obesity. In this review we explore contemporary understandings of the relationship between obesity and the microbiome from a high-level ecological and functional perspective, along with a survey of recently proposed interventions. We highlight areas of consensus and areas for further study in the field. PMID- 25725223 TI - The impact of anti-HBV treatment on the occurrence and recurrence of hepatocellular carcinoma: focus on Asian studies. AB - Chronic hepatitis B virus (CHB) infection can cause persistent hepatic inflammation and cirrhosis, which may lead to hepatocellular carcinoma (HCC). CHB is considered the dominant cause of HCC in Asia because of the endemic status of hepatitis B virus (HBV) infection. A persistently high viral load, long duration of infection, and cirrhosis are the major risk factors for developing HCC in CHB patients. Antiviral therapies using interferon (IFN) and nucleos(t)ide analogues (NAs) could suppress viral replication, reduce liver injury, and preserve liver function, thereby lowering the risk of developing HCC. Recurrence of HCC after therapy is closely related to high levels of HBV DNA at the initial stage. Western studies have found that persistent antiviral treatments on CHB patients could not only reduce their risk of developing HCC, but also prevent or delay HCC recurrence after liver transplantation, hepatic resection, or radiation therapies. This review will focus on Asian clinical studies, where there is a higher prevalence of CHB and HCC. The outcomes of antiviral therapies on HCC in these Asian studies were compared to those in the Western studies. PMID- 25725224 TI - Targeted therapy for genetic cancer syndromes: Fanconi anemia, medullary thyroid cancer, tuberous sclerosis, and RASopathies. AB - With the advent of genomics-based treatment in recent years, the use of targeted therapies in the treatment of various malignancies has increased exponentially. Though much data is available regarding the efficacy of targeted therapies for common malignancies, genetic cancer syndromes remain a somewhat unexplored topic with comparatively less published literature. This review seeks to characterize targeted therapy options for the following genetic cancer syndromes: Fanconi anemia, inherited medullary thyroid cancer, tuberous sclerosis, and RASopathies. By understanding the pathophysiology of these conditions as well as available molecularly targeted therapies, oncologists, in collaboration with geneticists and genetic counsellors, can begin to develop effective clinical management options and therapy regimens for the patients with these genetic syndromes that they may encounter in their practice. PMID- 25725225 TI - Targeted therapy for genetic cancer syndromes: Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome. AB - Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome are cancer syndromes which affect multiple organs and lead to significant decline in quality of life in affected patients. These syndromes are rare and typically affect the adolescent and young adult population, resulting in greater cumulative years of life lost. Improved understanding of the underpinnings of the genetic pathways underlying these syndromes and the rapid evolution of targeted therapies in general have made it possible to develop therapeutic options for these patients and other genetic cancer syndromes. Targeted therapies especially antiangiogenics and inhibitors of the PIK3CA/AKT/mTOR signaling pathway have shown activity in selected group of patients affected by these syndromes or in patients harboring specific sporadic mutations which are otherwise characteristic of these syndromes. Unfortunately due to the rare nature, patients with these syndromes are not the focus of clinical trials and unique results seen in these patients can easily go unnoticed. Most of the data suggesting benefits of targeted therapies are either case reports or small case series. Thus, a literature review was indicated. In this review we explore the use of molecularly targeted therapy options in Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome. PMID- 25725226 TI - T cell chemokine receptor patterns as pathogenic signatures in autoimmunity. AB - Autoimmune diseases arise from aberrant activation of immune cells directed against endogenous autoantigens expressed throughout the human body. While the initiating triggers remain poorly understood, the self-perpetuating phase of these diseases is directly linked to the ongoing recruitment of inflammatory cells that traffic to the affected anatomical sites. T lymphocytes are prominent drivers of many autoimmune diseases and the targeted trafficking of these cells to infiltrate the affected organs is often a common denominator. The regulation of T cell trafficking involves the coordinated expression of specific patterns of chemokines and the reciprocal expression of cognate chemokine receptors on T cell membranes. Thereby, chemokines direct the specific trafficking of a wide array of responsive activated immune cells. Specific patterns of chemokine receptor expression can correlate with disease activity in an autoimmune disease, confirming the importance of further characterizing the T cells that infiltrate specific sites of autoimmunity. Herein, we will review our current understanding of the roles of chemokines in two common autoimmune diseases: rheumatoid arthritis and multiple sclerosis. We also discuss the implications for chemokine receptor signatures in autoimmune pathogenesis, and how these may provide novel targets for therapeutic intervention. PMID- 25725227 TI - Unwinding the role of senataxin in neurodegeneration. AB - Interest in senataxin biology began in 2004 when mutations were first identified in what was then a novel protein. Dominantly inherited mutations were documented in rare juvenile-onset, motor neuron disease pedigrees in a familial form of amyotrophic lateral sclerosis (ALS4), while recessive mutations were found to cause a severe early-onset ataxia with oculomotor apraxia (AOA2) that is actually the second most common recessive ataxia after Freidreich's ataxia. From earlier studies of sen1p, the yeast ortholog of senataxin, a range of important RNA processing functions have been attributed to this protein. Like sen1p, senataxin contains a helicase domain to interact with RNA and an amino-terminal domain for critical protein interactions. Senataxin also joins a group of important proteins responsible for maintaining RNA transcriptome homeostasis, including FUS, TDP-43, and SMN that can all cause familial forms of motor neuron disease (MND). Independent of this association, senataxin is gaining attention for its role in maintaining genomic stability. Senataxin has been shown to resolve R-Loop structures, which form when nascent RNA hybridizes to DNA, displacing the non transcribed strand. But in cycling cells, senataxin is also found at nuclear foci during the S/G2 cell-cycle phase, and may function at sites of specific collision between components of the replisome and transcription machinery. Which of these important processes is most critical to prevent neurodegeneration remains unknown, but our evolving understanding of these processes will be crucial not only for understanding senataxin's role in neurological disease, but also in a number of fundamentally important cellular functions. PMID- 25725229 TI - Making students' marks fair: standard setting, assessment items and post hoc item analysis. PMID- 25725228 TI - Pathogenesis, newly recognized etiologies, and management of idiopathic anaphylaxis. AB - Idiopathic anaphylaxis (IA) is a life-threatening allergic disease and the most common diagnosis given to patients following an anaphylactic event. The inability of the healthcare provider and the patient to identify the trigger for anaphylaxis makes standard allergen avoidance measures ineffectual. IA is diagnosed after other causes of anaphylaxis have been excluded. Mast cell activation syndromes (MCAS), mastocytosis, IgE to galactose-alpha-1,3-galactose (alpha-gal), and certain medications have recently been recognized as causes of anaphylaxis that were previously labeled idiopathic. This review will describe the epidemiology and proposed theories of pathogenesis for IA, its diagnostic approach, its clinical management, and examine newly recognized disorders that were previously labeled as idiopathic anaphylaxis. PMID- 25725231 TI - Kidney disease in disadvantaged populations: an unconquered challenge. PMID- 25725230 TI - A report of an adult case of tubulointerstitial nephritis and uveitis (TINU) syndrome, with a review of 102 Japanese cases. AB - BACKGROUND: Although TINU syndrome is characterized by idiopathic TIN with bilateral anterior uveitis, few reports have provided a comprehensive summary of the features of this disorder. Previous reports have suggested that many Japanese patients had HLA-A2 and -A24 (7), but there is no evidence. CASE REPORT: A 44 year-old female was referred to our hospital due to renal dysfunction in March 2012. After admission, her symptoms improved spontaneously without medication within 2 weeks. In the outpatient clinic, she was diagnosed with idiopathic bilateral anterior uveitis in May, and her renal dysfunction relapsed in November. A renal biopsy showed diffuse TIN. We made a diagnosis of TINU syndrome because we could not explain the origin, and treated her with a systemic corticosteroid. Her renal function and ocular symptoms have been improving. The patient had HLA-A24, -B7, -DR1, -C*07: 02 and -DQB1*05: 01: 01. We collected 102 Japanese cases in PubMed, Ovid MEDLINE, and the Japanese Medical Abstracts Society and compared our case with the previous cases. CONCLUSIONS: This disorder affects primarily young females (median age, 14 years), and the most common symptom is fever (44/102 cases). We conducted a statistical analysis using contingency table and Pearson's chi-square test, for HLA-A2 and A24, and calculated the odds ratio (OR). There are no significant differences (A2 was present in 7/22 cases and in 19/50 controls, p value (P) 0.61, OR 0.76 (95% confidence interval (CI)) 0.27-2.2; A24 was present in 10/22 cases and in 33/50 controls, P 0.10, OR 0.43, CI 0.16-1.2). PMID- 25725232 TI - Burden of disease: prevalence and incidence of ESRD in Latin America. AB - INTRODUCTION: Chronic kidney disease (CKD) represents a major challenge for Latin America (LA), due to its epidemic proportions and high burden to the population affected and to public health systems. METHODS: Our methods have been reported previously: This paper shows the data for the last 10 years until 2010, from the Latin American Dialysis and Renal Transplantation Registry (RLADTR). RESULTS: 20 countries participated in the surveys, covering 99% of Latin America (LA). The prevalence of end-stage renal disease (ESRD) under renal replacement therapy (RRT) in LA increased from 119 patients per million population (pmp) in 1991 to 660 pmp in 2010 (hemodialysis (HD) 413 pmp, peritoneal dialysis (PD) 135 pmp, and LFG 111 pmp). HD proportionally increased more than PD and transplant and continues to be the treatment of choice in the region (75%). The kidney transplant rate increased from 3.7 pmp in 1987 to 6.9 pmp in 1991 and to 19.1 in 2010. The total number of transplants in 2010 was 10,397, with 58% being deceased donors. The total RRT prevalence correlated positively with gross national income (GNI) (r = 0.86; p < 0.05) and life expectancy at birth (r = 0.58; p < 0.05). The global incidence rate correlated significantly only with GNI (r = 0.56; p < 0.05). Diabetes remained the leading cause of ESRD. CONCLUSION: The prevalence and incidence of RRT continues to increase. In countries with 100% public health or insurance coverage for RRT the rates are comparable to those displayed by developed countries with better GNI. PD is still an underutilized strategy for RRT in the region. Diagnostic and prevention programs for hypertension and diabetes, appropriate policies promoting the expansion of PD and organ procurement as well as transplantation as cost effective forms of RRT are needed in the region. PMID- 25725233 TI - ESRD burden in South Asia: the challenges we are facing. AB - South Asia, one of the most populous regions of the world, suffers from a large and increasing burden of untreated endstage renal disease (ESRD). Tropical ecology and increasing burden of non-communicable diseases are major drivers. Disease is diagnosed late, and access to treatment has been limited due to socioeconomic reasons but is increasing. System-level solutions, such as development of low-cost techniques and training of manpower to provide care to these patients are required. Individuals at high risk of developing progressive kidney disease should be identified early so that preventive measures can be instituted in a timely manner. This requires use of technology and workforce re engineering to strengthen community-based prevention efforts. PMID- 25725234 TI - ESRD management in Africa during the last decade. AB - AIMS: This study was initiated under the auspices of the African Association of Nephrology to evaluate end-stage renal disease (ESRD) development by using data collected in 3 successive surveys performed during the last decade. MATERIALS AND METHODS: Questionnaires were sent in 2004, 2006, and 2012 to national renal societies and to leading nephrologists. Data were also collected from dialysis supply companies, personal communication, and by using research on Medline, Pubmed, etc. So data could be obtained from 33 countries. RESULTS: During the last decade the total number of nephrologists increased from 1,022 to 2,500 in 33 countries - i.e., an average growth rate of 15% per year. But there are still few hospital units dedicated to renal healthcare. The number of dialysis units increased from 1,200 to 1,600 and the number of dialysis patients (97% on hemodialysis) grew from 36,000 to 87,400 i.e., an average growth rate of 14% per year. Peritoneal dialysis, which covers less than 3% of RRT, increased from 1,300 to 2,400 with a yearly growth rate of 8% but it is still located in few countries. Renal transplant is implemented mainly in public hospitals in 5 North African and 7 sub. Saharan and South African countries. Only 5 countries have sustained programs that perform more than 100 operations per year. CONCLUSION: During the last decade, several countries improved the quality and quantity of care offered to ESRD patients. It is hoped that there will be a sustained improvement with a greater emphasis on education and development of kidney transplantation. PMID- 25725235 TI - Silent kidney disease and hypertension in Cambodia--a pilot study in Mercy Medical Center Cambodia. AB - The incidence and prevalence of end-stage renal disease (ESRD) has been increasing in most developed countries. In developing countries, however, there has been a lack of reliable data. AIM: To assess the frequency of unsuspected urine abnormality and hypertension in Cambodia. METHOD: From April to December 2012, 1,013 new patient records of the Mercy Medical Center (MMC) in Cambodia were reviewed. 915 patients aged >= 18 years were included for analysis. Patients with history of hypertension (HT) were excluded for blood pressure (BP) analysis. Patients with history of diabetes mellitus (DM), hypertension (HT), chronic kidney disease (CKD), or with symptoms of renal disease were excluded for urinalysis study. RESULTS: 820 patients had no history of HT. Among this group, 73 (8.9%) had abnormal BP with 60 (7.3%) having BP >= 140/90 mmHg and 13 (1.6%) having isolated systolic HT (BP >= 140/ 5/high power field (HPF)), 156 (30.6%) having either significant proteinuria or hematuria; and 199 (39.0%) had urine white blood cell count (WBC) >= 1+. Overall, 275 patients (53.9%) had 1 or more urinary abnormalities on urinalysis. CONCLUSION: Abnormal urinalysis (53.9%) and abnormal BP measurement (8.9%) were common findings among asymptomatic patients referred to the MMC. Unlike findings in other countries, no association of family history of DM, HT, or CKD and the risk of kidney disease or abnormal BP was found. A comprehensive community screening program for HT and kidney disease is urgently needed to prevent ESRD in Cambodia. PMID- 25725236 TI - Current ESRD burden and its future trend in Beijing, China. AB - AIMS: To report the trend of incidence, prevalence, and mortality of end-stage renal disease (ESRD) patients on maintenance hemodialysis (MHD) in Beijing, China from 2007 to 2013. METHODS: Patient-level data was collected from Beijing hemodialysis (HD) facilities by the Beijing Hemodialysis Quality Control and Improvement Center (BJHDQCIC). Rates for incidence, prevalence, and mortality were calculated. RESULTS: The incidence rate declined from 136.3 per million population (pmp) in 2009 to 94.4 pmp in 2013. From 2010, the leading cause of incident ESRD has changed from chronic glomerulonephritis to diabetes mellitus. The prevalence rate showed an increasing trend and reached 579 pmp at the end of 2013. Chronic glomerulonephritis was still the leading cause of ESRD in prevalent MHD patients. The annual mortality rate showed a declining trend and reached 6.4% in 2013. CONCLUSIONS: In Beijing, there is a declining incidence rate, increasing prevalence rate, and declining mortality for MHD patients. PMID- 25725237 TI - Latin American special project: kidney health cooperation project between Uruguay and Bolivia. AB - Uruguay and Bolivia are two countries that show heterogenicity of the Latin American region, including the national income, the expenditure on health and the services for renal care. In Bolivia, there is manpower shortage for renal care with only 5 nephrologists per million people (pmp) and the prevalence of patients on dialysis is only 200 pmp. This is much lower than the mean prevalence rate of renal replacement therapy for Latin America as a whole. Uruguay on the other hand has more dedicated renal resources with 50 nephrologists pmp, and renal replacement therapy is provided to ~ 1,000 dialysis patients pmp. In November 2012, a collaborative project financed by the Uruguayan International Cooperation Agency was signed by both the Uruguay and Bolivia Ministries of Health, and the goal was to develop a comprehensive program for the prevention and management of all stages of chronic kidney disease (CKD) in Bolivia. The specific objectives were to: a) promote renal healthcare in the primary healthcare setting, b) identify kidney disease in populations at risk, and c) optimize patient care at all stages of CKD, including dialysis and transplantation supported with a national ESRD registry in Bolivia. As a first step, delegates from the Bolivian Health Ministry, visited Uruguay in April 2014, primarily to strengthen the development of tools required for developing and maintaining a national registry. In addition, during this visit, a meeting with the president of the Latin American Society of Nephrology and Hypertension (SLANH) culminated in designing a training program for peritoneal dialysis. This highly cooperative relationship is advancing the prevention and care of CKD in Bolivia and may serve as a model for international approaches to advance system level CKD care in countries with limited healthcare resources. PMID- 25725238 TI - Epidemiological characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities of El Salvador. AB - INTRODUCTION: In El Salvador end-stage renal disease (ESRD) was the first cause of hospital mortality overall, the first cause of hospital deaths in men, and the fifth cause of hospital mortality in women in 2013. In agricultural communities, chronic kidney disease (CKD) occurs predominantly in male agricultural workers, but it also affects women to a lesser degree, even those who are not involved in agricultural work. Internationally, most epidemiological CKD studies emphasize men and no epidemiological studies focused exclusively on women. OBJECTIVE: To describe the epidemiological characteristics of CKD in females in agricultural communities of El Salvador. METHODS: A cross-sectional epidemiological study was carried out in 2009 - 2011 based on active screening for CKD and risk factors in women aged >= 18 years in 3 disadvantaged populations of El Salvador: Bajo Lempa (Usulutan Department), Guayapa Abajo (Ahuachapan Department), and Las Brisas (San Miguel Department). Epidemiological and clinical data were gathered through personal history, as well as urinalysis for renal damage markers, determinations of serum creatinine and glucose, and estimation of glomerular filtration rates. CKD cases were confirmed at 3 months. RESULTS: Prevalence of CKD was 13.9% in 1,412 women from 1,306 families studied. Chronic kidney disease of nontraditional causes (CKDu), not attributed to diabetes mellitus, hypertension, or proteinuric primary glomerulopathy (proteinuria > 1 g/L) was 6.6%. Prevalence of chronic renal failure was 6.8%. Prevalence of renal damage markers was 9.8% (microalbuminuria (30 - 300 mg/L) 5.7%; macroalbuminuria (> 300 mg/L) 2%; and hematuria, 2.1%. Prevalence of chronic kidney disease risk factors was: diabetes mellitus, 9.3%; hypertension, 23%; family history of CKD, 16%; family history of diabetes mellitus (DM), 18.7%; family history of hypertension (HT), 31.9%; obesity, 21%; central obesity, 30.7%; NSAID use, 84.3%; agricultural occupation, 15.2%; and contact with agrochemicals, 33.1%. CONCLUSIONS: CKD in women of Salvadoran agricultural communities is associated with disadvantaged populations, traditional (DM, HT, obesity) and non-traditional causes (environmental and occupational exposure to toxic agents and inadequate working conditions). Our results reinforce the hypotheses emerging from other studies, suggesting a multifactorial etiopathology including environmental and occupational nephrotoxic exposure. PMID- 25725239 TI - HIV and chronic kidney disease. AB - Chronic kidney disease (CKD) is a frequent complication of HIV infection, occurring in 3.5 - 48.5%, and occurs as a complication of HIV infection, other co morbid disease and infections and as a consequence of therapy of HIV infection and its complications. The classic involvement of the kidney by HIV infection is HIV-associated nephropathy (HIVAN), occurring typically in young adults of African ancestry with advanced HIV disease in association with APOL1 high-risk variants. HIV-immune complex disease is the second most common diagnosis obtained from biopsies of patients with HIV-CKD. CKD is mediated by factors related to the virus, host genetic predisposition and environmental factors. The host response to HIV infection may influence disease phenotype through activation of cytokine pathways. With the introduction of antiretroviral therapy (ART), there has been a decline in the incidence of HIVAN, with an increasing prevalence of focal segmental glomerulosclerosis. Several studies have demonstrated the overall improvement in kidney function when initiating ART for HIV CKD. Progression to end stage kidney disease has been reported to be more likely when high grade proteinuria, severely reduced eGFR, hepatitis B and/C co-infection, diabetes mellitus, extensive glomerulosclerosis, and chronic interstitial fibrosis are present. Improved renal survival is associated with use of renin angiotensin system blockers and viral suppression. Many antiretroviral medications are partially or completely eliminated by the kidney and require dose adjustment in CKD. Certain drug classes, such as the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors, are metabolized by the liver and do not require dose adjustment. HIV-infected patients requiring either hemo- or peritoneal dialysis, who are stable on ART, are achieving survival rates comparable to those of dialysis patients without HIV infection. Kidney transplantation has been performed successfully in HIV-infected patients; graft and patient survival appears to be similar to that of HIV-uninfected recipients. Early detection of kidney disease by implementation of screening on diagnosis of HIV infection and annual screening thereafter will have an impact on the burden of disease, together with access to ART to those who require it. Programs for prevention of HIV infection are essential to prevent this lethal disease. PMID- 25725240 TI - Transplantation in resource-limited setting: using HIV-positive donors for HIV positive patients. AB - BACKGROUND: A HIV positive-to-positive program was started in South Africa in 2008. The program was started because dialysis is not freely available to everyone, but severely limited and only available to a selected group of patients. PATIENTS AND METHODS: Between September 2008 and March 2015, 29 patients were transplanted from HIV-positive brain-dead donors at Groote Schuur Hospital transplant team. Donors were either naive to anti-retroviral therapy or on first line therapy. The recipients were selected to have undetectable plasma HIV type 1 RNA levels and be on a stable antiretroviral regimen. CD4+ T-cell counts of at least 200/mm3 in last 6 months prior to transplant, with no previous serious opportunistic infections. RESULTS: Survivors in the study were followed for a median of 2.4 years. The rate of patient survival was 84% at 1 year and 74% at 5 years. The corresponding graft survival rate was 93% and 84%. CONCLUSION: Using HIV-positive donors might resolve some of the problems we are experiencing in getting enough donors for our patients wit ESRD. In the USA the HOPE act was accepted in 2014 and this might now also impact on the use of HIV positive donors elsewhere in the world. PMID- 25725241 TI - Need for chronic kidney disease prevention programs in disadvantaged populations. AB - Chronic kidney disease (CKD) is a key determinant of the poor health outcomes for major non-communicable diseases that are the leading cause of death in the world. CKD is a worldwide threat to public health, but the size of the problem is not fully appreciated. Early recognition of CKD and concomitant co-morbid conditions, can potentially slow progression to renal failure, increase longevity, improve quality of life, and reduce healthcare costs. Although screening programmes are attractive, there is no consensus yet on which individuals should be prioritized (high-risk group for CKD, or general population) especially in resourcepoor regions. In these settings there is not a unique blueprint of screening strategy, so that the approaches should be adapted on single-nation conditions and socioeconomic status. Effective multimodal tools are available to prevent CKD by managing its risk factors, and to slow or even halt disease progression to end stage renal failure, as well as reduce the associated risk of cardiovascular morbidity and mortality. They can be adapted even to the poorest populations who are at the highest risk of CKD. Where management strategies have been implemented, the incidence of end-stage renal disease (ESRD) has been reduced. The hope is that all these efforts will assist to make major advances in addressing the neglected aspect of renal health, especially of poor and disadvantaged populations worldwide. Beside saving young lives, such action would minimize the present health inequity that arises mainly from the unaffordable cost of renal replacement therapy if ESRD is not prevented. PMID- 25725242 TI - Early detection and prevention programs for kidney diseases in Hong Kong. AB - Two local studies were performed in Hong Kong for early detection and prevention of chronic kidney disease (CKD) which demonstrated the efficacy for screening asymptomatic individuals in the population for silent kidney disease while first degree relatives of known CKD patients should have a higher priority on future screening in view of their higher prevalence of silent CKD. Simple measures like urine dipstick tests and blood pressure measurement would suffice for screening. Regular health education programs are useful for conveying the key messages of kidney protection to the general public. PMID- 25725243 TI - The Kidney Early Evaluation Program (KEEP) of Japan. AB - The International Kidney Evaluation Association Japan (IKEAJ) was created to improve public health awareness of chronic kidney disease (CKD) by screening high risk CKD populations. This study aimed to retrospectively examine data from KEEP Japan and detect the CKD risk factors for the onset and the progression of CKD. A total of 1,947 participants (mean age: 56.9 +/- 16.4 years) to KEEP Japan were enrolled. More than 70% of the participants had no CKD. However, 7.5% of the participants were classified as high risk. The participants with a history of hypertension and older than 60 years had significantly higher odds ratio for occurrence of CKD. In addition, the participants with history of diabetes or cardiovascular disease, high blood pressure (BP), anemia, and low HDL-C had high odds ratios. It is therefore suggested that the appropriate control of BP, blood glucose, anemia, and HDL-C is important for populations with CKD risk factors to reduce the likelihood of CKD. PMID- 25725244 TI - Clinical characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities in El Salvador. AB - INTRODUCTION: A chronic kidney disease of non-traditional causes (CKDu) has emerged in Central America and elsewhere, predominantly affecting male farmworkers. In El Salvador (2009), it was the second cause of death in men > 18 years old. Causality has not been determined. Most available research focused on men and there is scarce data on women. OBJECTIVES: Describe the clinical and histopathologic characteristics of CKDu in women of agricultural communities in El Salvador. METHODOLOGY: A descriptive study was carried out in 10 women with CKDu stages 2, 3a, and 3b. Researchers studied demographics, clinical examination; hematological and biochemical analyses, urine sediment, renal injury markers, and assessed renal, cardiac, and peripheral arteries, liver, pancreas, and lung anatomy and functions. Kidney biopsy was performed in all. Data was collected on the Lime Survey platform and exported to SPSS 19.0. RESULTS: Patient distribution by stages: 2 (70%), 3a (10%), 3b (20%). Occupation: agricultural 7; non-agricultural 3. RISK FACTORS: agrochemical exposure 100%; farmworkers 70%; incidental malaria 50%, NSAIDs use 40%; hypertension 40%. SYMPTOMS: nocturia 50%; dysuria 50%; arthralgia 70%; asthenia 50%; cramps 30%, profuse sweating 20%. Renal markers: albumin creatinine ratio (ACR) > 300 mg/g 90%; beta microglobulin and neutrophil gelatinase- associated lipocalin (NGAL) presence in 40%. Kidney function: hypermagnesuria 100%; hyperphosphaturia 50%, hypercalciuria 40%; hypernatriuria 30%; hyponatremia 60%, hypocalcemia 50%. Doppler: tibial artery damage 40%. Neurological: reflex abnormalities 30%; Babinski and myoclonus 20%. Neurosensorial hypoacusis 70%. Histopathology: damage restricted mostly to the tubulo-interstitium, urine was essentially bland. CONCLUSIONS: CKDu in women is a chronic tubulointerstitial nephropathy with varied extrarenal symptoms. PMID- 25725245 TI - Balkan nephropathy. AB - Balkan endemic nephropathy (BN), frequently associated to upper urothelial cancer, is a familial chronic tubulointerstitial disease with insidious onset and slow progression to end-stage renal disease. After 60 years of research, its cause remains the major unanswered question. Etiology assumes polygenic susceptibility to the disease in interaction with multiple environmental factors. Chronic intoxication with Aristolochia is the major environmental risk factor for this disease. The mycotoxin hypothesis considers that BN is produced by ochratoxin A. The Pliocene lignite hypothesis assumes that the disease is caused by long-term exposure to organic toxins leached from coal nearby the endemic villages. Exome sequencing of 22,000 genes revealed that mutant genes (CELA1, HSPG2, and KCNK5) in BN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, which are tightly connected to the process of angiogenesis. SEC61G, IL17RA, and HDAC11 proved to be differently methylated throughout all patient-control pairs. The acetylation of histone lysine residues was detected and found increased at specific sites of H3 and total H4 histones isolated from urothelial cells of patients with BN. The results of molecular biological research will allow the discovery of genetic markers of BN and associated urothelial cancer, permitting early detection of BN predisposing mutations and identification of susceptible individuals who might be at risk of exposure to environmental agents. The research of gene-gene and gene environment interactions could lead to further studies to determine the precise risk for BN. PMID- 25725246 TI - Acute kidney injury in children in Nigeria. AB - AIM: To highlight the epidemiologic characteristics and therapeutic challenges of childhood acute kidney injury (AKI) in Nigeria. METHOD: A review of AKI publications on Nigerian children between January 1990 and December 2012 was carried out. RESULTS: Mean age at presentation varied between 3.1 +/- 2.6 and 6.28 +/- 4 (0.05 - 16) years. Male/female ratio ranged between 1.38 and 2.5 to 1. Hospital-acquired AKI (hAKI) and community-acquired AKI (cAKI) accounted for 17.1 - 27.2% and 72.8 - 82.9% of all AKI cases, respectively. 12 - 35 new AKI cases are seen per year. A single-center study puts cAKI and hAKI incidences at 9.8 per million children population (pmcp)/year (0.46%) and 3.7 pmcp/ year (0.17%), respectively; cAKI and hAKI prevalence rates were 49.2 pmcp (2.23%) and 18.3 pmcp (0.84%), respectively. Leading causes of AKI, accounting for 80.0% of all etiologies, were nephrotoxins (29.0%), infection (20.0%), intravascular volume depletion (17.9%), and glomerular disease (13.1%). Financial constraints, late presentation, presence of >= 2 comorbidities, need for dialysis, non-dialysis when indicated, severe hypertension, white cell count > 15 000/mm3, and platelet count < 100 000/mm3 are significant mortality risk factors in childhood AKI in our environment. Mean all-cause mortality rate from pooled data was 50.4 +/- 25.2% (range: 28.4 - 86.5%). CONCLUSION: AKI incidence and its leading causes, in Nigerian children, can be significantly reduced if attention is paid to public health education, enforcement of environmental sanitation laws, and prompt utilization of healthcare services during sickness. PMID- 25725247 TI - The multideterminant model of renal disease in a remote Australian Aboriginal population in the context of early life risk factors: lower birth weight, childhood post-streptococcal glomerulonephritis, and current body mass index influence levels of albuminuria in young Aboriginal adults. AB - BACKGROUND: Australian Aborigines in remote areas have very high rates of kidney disease, which is marked by albuminuria. We describe a "multihit" model of albuminuria in young adults in one remote Aboriginal community. METHODS: Urinary albumin/creatinine ratios (ACR) were measured in all subjects who volunteered to participate in a community-wide health screen. Subjects for this study were young adults who had birth weights recorded and whose medical records were inspected for a history of post-streptococcal glomerulonephritis (PSGN). Urine ACR levels were evaluated in the context of birth weights, PSGN history and current BMI. RESULTS: 580 subjects (335 males and 245 females) who were aged 18 - 39 years at time of screening and qualified for inclusion. 26% of subjects had birth weights of < 2.5 kg, and the median birth weight was 2.8 kg. 23% of subjects had a remote history of PSGN, all 3 or more years earlier. Median BMI for the group was 21 kg/m2. Urine ACR levels exceeded the microalbuminuria threshold of 3.4 g/mol in 35.5% of subjects. Birth weight (inversely), remote PSGN, and current BMI were all independent predictors of ACR levels. Median levels of ACR were lowest in those with birth weights >= 2.5 kg, and no history of PSGN, intermediate in those with either birth weights < 2.5 kg or a history of PSGN, and highest in those with both low birth weights and a PSGN history. ACR levels were higher in those with BMIs above the median values, most notably in those with lower birth weights or a PSGN history or both. INTERPRETATION: Much of the great excess of disease in this population is explained by high rates of the early life risk factors, low birth weight and PSGN. Their effects are expressed through amplification of ACR in the context of increasing age, and are further moderated by levels of current body size. Both early life risk factors are potentially modifiable. PMID- 25725248 TI - Comprehensive approach to pediatric kidney diseases in Guatemala. AB - The Foundation for Children with Kidney Diseases (FUNDANIER) has been the driving force that has facilitated changes in the Guatemalan health system in order to establish a comprehensive pediatric nephrology program. We previously described the creation and early phases of the FUNDANIER project. This article describes the recent accomplishments of the project with the intention of sharing a model that might be applicable in other developing countries. PMID- 25725249 TI - Transplant commercialism and organ trafficking: the Declaration of Istanbul with special relevance to disadvantaged populations living with kidney disease. AB - This paper provides a historical perspective on organ trafficking and transplant commercialism, an overview of the Declaration of Istanbul [1, 2], and an update on current state. We highlight the importance of this problem pertaining to disadvantaged populations living with or at risk for kidney disease. It was presented during the Kidney Disease in Disadvantaged Populations Satellite Symposium of the World Congress of Nephrology in Hong Kong 2013 (www.theisn.org). PMID- 25725250 TI - Development of a kidney transplantation program--inverted funnel approach. AB - INTRODUCTION: The history of organ shortage has been approached differently by different countries. This review tries to discuss the inverted funnel approach of Iran. METHODS: The whole history of transplants in the country can be divided in three phases of legally regulated living unrelated kidney donation, legislation of brain death donation and lastly how it has been implemented. In each phase, there have been attempts to clarify the role of each sector: the government, professionals, and the public. RESULTS: Based on more than 20 years of experience, it has been shown that kidney transplants from brain dead donors (BDDs) increased from 0.4 per million population (pmp) in 2000 to 2.9 pmp in 2005, 7.9 in 2010, and 15.1 pmp in 2013 and it could eventually change the rate from living source from 20.1 pmp, 24.5 pmp, 21.8 pmp, and 19.5 pmp in these years, respectively. DISCUSSION: It has been shown that the government began to take part when it was convinced that an organ procurement program from BDDs is not a luxury program but can lessen the economic burden on the health budget and be supported by legislations and budget allocation. Professionals took the responsibility not only to make decision makers and the public aware of the subject and adapt the national protocols to consider the general population concerns, but also to train as many medical teams as possible nationwide. Persistence and publishing the results can pave the way for the public to accept the program and take their own responsibilities to solve the problem of organ shortage by taking the opportunity to give life to others after the death of a loved one. PMID- 25725251 TI - Systemic cytokine storm in severe eosinophilic dermatitis. PMID- 25725252 TI - The prognostic significance of Src and p-Src expression in patients with osteosarcoma. AB - BACKGROUND: The expression of Src and phospho-Src (p-Src) is closely related to tumor invasion and metastasis. The aim of the present study was to investigate the expression of these molecules in osteosarcoma and their relationship with each other, to provide a theoretical basis to understand the prognosis of osteosarcoma. MATERIAL AND METHODS: We selected surgically resected osteosarcoma specimens from 116 patients of Zhongnan Hospital of Wuhan University and Hubei Cancer Hospital, Hubei, China, between January 2000 and January 2010 with detailed follow-up data. Twenty osteochondroma specimens from the corresponding period were used as controls. Expression of Src and p-Src was detected in osteosarcoma and osteochondroma by immunohistochemistry. We analyzed the relationship of the 2 proteins and osteosarcoma patient prognosis. RESULTS: The expression of Src and p-Src in osteosarcoma was significantly higher than the expression level in osteochondroma (P<0.05). The expression levels of the 2 proteins, clinical stage, and tumor metastasis were significantly associated with survival time (P<0.05), but there was no correlation between age or sex and survival time. The expression of Src and p-Src in osteosarcoma was positively correlated. CONCLUSIONS: Src and p-Src can be used as an auxiliary indicator to determine a malignant phenotype of bone tumors, and the combined detection of Src and p-Src may indicate the prognosis of osteosarcoma. PMID- 25725254 TI - Efficient mechanochemical complexation of various steroid compounds with alpha-, beta- and gamma-cyclodextrin. AB - Mechanochemical technology enables solvent-free micronized solid dispersions and efficient molecular host-guest inclusion complexes to be formed in matrices which contain cyclodextrins (CDs). This type of complexation has been studied using alpha-, beta- and gamma-cyclodextrin with the dual aims of improving overall solubility and enhancing the bioavailability of common steroid compounds, such as cholic acids and beta-sitosterols or lowering cholesterol content in products of animal origin. Several parameters have been studied and optimized: CD/compound molar ratio (1:1, 1:2, 2:1 and 3:1) in function of the cavity sizes of the three different CDs, milling time (from 5 to 40 min) and rotation speed (from 100 to 300 rpm). DSC (differential scanning calorimetry) analyses have revealed that inclusion complexes were efficiently formed after 40 min milling (200 rpm) for beta-CD/cholesterol and beta-CD/ugrsodeoxycholic acid (encapsulation efficiency 96% and 77% respectively). Besides steroid encapsulation/vehiculation, the mechanochemical technique may pave the way for new ideas in solventless steroid extraction from vegetal matrices with CDs. PMID- 25725253 TI - Dynein and intraflagellar transport. PMID- 25725255 TI - Epidemiologic studies of estrogen metabolism and breast cancer. AB - Early epidemiologic studies of estrogen metabolism measured only 2-hydroxyestrone and 16alpha-hydroxyestrone and relied on direct enzyme immunoassays without purification steps. Eight breast cancer studies have used these assays with prospectively collected blood or urine samples. Results were inconsistent, and generally not statistically significant; but the assays had limited specificity, especially at the low concentrations characteristic of postmenopausal women. To facilitate continued testing in population-based studies of the multiple laboratory-based hypotheses about the roles of estrogen metabolites, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to measure concurrently all 15 estrogens and estrogen metabolites in human serum and urine, as unconjugated and total (glucuronidated+sulfated+unconjugated) concentrations. The assay has high sensitivity (lower limit of quantitation ~1-2 pmol/L), reproducibility (coefficients of variation generally ?5%), and accuracy. Three prospective studies utilizing this comprehensive assay have demonstrated that enhanced 2-hydroxylation of parent estrogens (estrone+estradiol) is associated with reduced risk of postmenopausal breast cancer. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort, the serum ratio of 2-hydroxylation pathway metabolites to parent estrogens was associated with a 28% reduction in breast cancer risk across extreme deciles (p-trend=.05), after adjusting for unconjugated estradiol and breast cancer risk factors. Incorporating this ratio into a risk prediction model already including unconjugated estradiol improved absolute risk estimates substantially (by ?14%) in 36% of the women, an encouraging result that needs replication. Additional epidemiologic studies of the role of estrogen metabolism in the etiology of hormone-related diseases and continued improvement of estrogen metabolism assays are justified. PMID- 25725256 TI - Tissue content of vitamin D3 and 25-hydroxy vitamin D3 in minipigs after cutaneous synthesis, supplementation and deprivation of vitamin D3. AB - Information regarding the endogenous storages of vitamin D3 after cutaneous vitamin D synthesis compared to oral vitamin D3 supplementation is sparse. Furthermore it is not known whether vitamin D3 can be stored for later use during periods of shortages of vitamin D3. To investigate the endogenous storages of vitamin D3 two studies were carried out in Gottingen minipigs. In study 1 one group of minipigs (n=2) was daily exposed to UV light corresponding to 10-20 min of midday sun and another group (n=2) of pigs were fed up to 60 MUg vitamin D3/day corresponding to 3.7-4.4 MUg/kg body weight. Study 1 demonstrated that daily UV-exposure of minipigs stimulated the cutaneous synthesis of vitamin D3 and resulted in increasing serum vitamin D3 and 25-hydroxy vitamin D3, but also carcasses containing vitamin D3 and 25-hydroxy vitamin D3. The vitamin D3 content in adipose tissue from the UV-exposed minipigs was 150-260 ng/g and the content was 90-150 ng/g in the orally supplemented minipigs. In study 2, minipigs were UV exposed daily for 49 days. Subsequently, one group (n=2) was fed a vitamin D-free diet and another group (n=2) was dosed daily with 13C-labeled vitamin D3. The concentrations of vitamin D3 and 25-hydroxy vitamin D3 in serum and skin- and subcutaneous adipose tissue biopsies were repeatedly monitored. Vitamin D3 and 25 hydroxy vitamin D3 were eliminated from the skin and the adipose tissue after UV exposure was ceased. Supplementation of 13C-vitamin D3 did not seem to affect the decline in the endogenous vitamin D3 in the adipose tissue formed during UV exposure. PMID- 25725257 TI - Pilosulins: a review of the structure and mode of action of venom peptides from an Australian ant Myrmecia pilosula. AB - Myrmecia pilosula is an endemic Australian ant whose sting is a frequent cause of insect allergy in southeast Australia, and several deaths due to M. pilosula sting envenomation have been documented. In this review, we discuss the composition and bioactivity of M. pilosula venom. In addition to various enzymes and pharmacologically active constituents, the venom contains four families of highly basic low molecular weight peptides trivially named Pilosulins. These peptides are unique and have low structural homology to other Hymenoptera venom peptides. Moreover, M. pilosula venom is relatively simple in its composition with 5 predominant peptides making up about 90% by weight. These peptides display cytotoxic, hypotensive, histamine-releasing and antimicrobial activities. Within the M. pilosula venom, Pilosulin 3 has been classified as a major allergen and [Ile(5)]pilosulin 1 and Pilosulin 4.1 are classified as minor allergens. Several uncharacterised higher molecular weight components with allergenic activities have also been identified. The revised naming of M. pilosula venom peptides according to the International Union of Immunological Societies (IUIS) criteria for allergen nomenclature is discussed in this review. PMID- 25725258 TI - Human brain microvascular endothelial cells resist elongation due to shear stress. AB - Endothelial cells in straight sections of vessels are known to elongate and align in the direction of flow. This phenotype has been replicated in confluent monolayers of bovine aortic endothelial cells and human umbilical vein endothelial cells (HUVECs) in cell culture under physiological shear stress. Here we report on the morphological response of human brain microvascular endothelial cells (HBMECs) in confluent monolayers in response to shear stress. Using a microfluidic platform we image confluent monolayers of HBMECs and HUVECs under shear stresses up to 16 dyne cm(-2). From live-cell imaging we quantitatively analyze the cell morphology and cell speed as a function of time. We show that HBMECs do not undergo a classical transition from cobblestone to spindle-like morphology in response to shear stress. We further show that under shear stress, actin fibers are randomly oriented in the cells indicating that there is no cytoskeletal remodeling. These results suggest that HBMECs are programmed to resist elongation and alignment under shear stress, a phenotype that may be associated with the unique properties of the blood-brain barrier. PMID- 25725259 TI - Tomosyn is a novel Akt substrate mediating insulin-dependent GLUT4 exocytosis. AB - Insulin triggers glucose uptake into skeletal muscle and adipose tissues by gaining the available number of glucose transporter 4 (GLUT4) on the cell surface. GLUT4-loaded vesicles are targeted to plasma membrane from the intracellular reservoir through multiple trafficking and fusion processes that are mainly regulated by Akt. However, it is still largely unknown how GLUT4 expression in the cell surface is promoted by insulin. In the present study, we identified tomosyn at Ser-783 as a possible Akt-substrate motif and examined whether the phosphorylation at Ser-783 is involved in the regulation of GLUT4 expression. Both Akt1 and Akt2 phosphorylated the wild-type tomosyn, but not the mutant tomosyn in which Ser-783 was replaced with Ala. Phosphorylation of tomosyn at Ser-783 was also observed in the intact cells by insulin stimulation, which was blocked by PI3K inhibitor, LY294002. In vitro pull-down assay showed that phosphorylation of tomosyn at Ser-783 by Akt inhibited the interaction with syntaxin 4. Insulin stimulation increased GLUT4 in the cell surface of CHO-K1 cells to promote glucose uptake, however exogenous expression of the mutant tomosyn attenuated the increase by insulin. These results suggest that Ser-783 of tomosyn is a target of Akt and is implicated in the interaction with syntaxin 4. PMID- 25725260 TI - Next-generation pathology--surveillance of tumor microecology. AB - A tumor is a heterogeneous population of cells that provides an environment in which every cell resides in a microenvironmental niche. Microscopic evaluation of tissue sections, based on histology and immunohistochemistry, has been a cornerstone in pathology for decades. However, the dawn of novel technologies to investigate genetic aberrations is currently adopted in routine molecular pathology. We herein describe our view on how recent developments in molecular technologies, focusing on proximity ligation assay and padlock probes, can be applied to merge the two branches of pathology, allowing molecular profiling under histologic observation. We also discuss how the use of image analysis will be pivotal to obtain information at a cellular level and to interpret holistic images of tissue sections. By understanding the cellular communications in the microecology of tumors, we will be at a better position to predict disease progression and response to therapy. PMID- 25725261 TI - Absorption improvement of tranilast by forming highly soluble nano-size composite structures associated with alpha-glucosyl rutin via spray drying. AB - Tranilast (TL) composite particles with alpha-glucosyl rutin (Rutin-G) were developed to improve the solubility and oral bioavailability of TL. Composite formulation of TL/Rutin-G was prepared using the spray-drying method, and their physicochemical properties were evaluated with respect to the morphology, particle size distribution, solubility and crystallinity. The nanostructure formation of Rutin-G was characterized by dynamic light scattering and transmission electron microscopy when Rutin-G or TL/Rutin-G spray-dried particles (SDPs) were introduced into water. A pharmacokinetic study was also performed to assess the improvement of oral absorption in rats. TL/Rutin-G SDPs were spherical particles with a diameter of 5.5MUm. Even in the acidic condition, the remarkable improvement in solubility of TL was achieved, as evidenced by a 32.2-fold increase in solubility compared with untreated TL. The median size of Rutin-G nanostructures in water was 2nm. The formation of Rutin-G nanostructures and their drug inclusion properties may enhance the solubility and dissolution behavior of TL. A drastic increase was found in the exposure of TL in rats, with an increase in Cmax and AUC values of 114- and 36.4-fold, respectively, compared with those of untreated TL. These findings indicated that a TL formulation spray dried with Rutin-G could enhance its solubility and absorption and thus its therapeutic properties. PMID- 25725262 TI - Nanotherapies for the treatment of ocular diseases. AB - The topical route is the most frequent and preferred way to deliver drugs to the eye. Unfortunately, the very low ocular drug bioavailability (less than 5%) associated with this modality of administration, makes the efficient treatment of several ocular diseases a significant challenge. In the last decades, it has been shown that specific nanocarriers can interact with the ocular mucosa, thereby increasing the retention time of the associated drug onto the eye, as well as its permeability across the corneal and conjunctival epithelium. In this review, we comparatively analyze the mechanism of action and specific potential of the most studied nano-drug delivery carriers. In addition, we present the success achieved until now using a number of nanotherapies for the treatment of the most prevalent ocular pathologies, such as infections, inflammation, dry eye, glaucoma, and retinopathies. PMID- 25725263 TI - Antibody therapies and their challenges in the treatment of age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world. This multifactorial disease results from the combined contributions of age, environment and genetic predisposition. Antibody-based treatment of late-stage neovascular AMD with inhibitors of vascular endothelial growth factor has had great success, which is now the goal for currently untreatable AMD manifestations. The existence of an immune-privileged environment in the eye supports the feasibility of localized antibody therapy. Many different antibodies against various targets are being developed for the treatment of AMD, which reflects the etiological complexity of the disease. This review provides an overview of 19 potential therapeutic antibodies targeting angiogenesis, the complement system, inflammation or amyloid beta deposition in the eye. It summarizes the immunoglobulin structure, the specific target and study outcomes for each approach. The latter include beneficial results or adverse effects in AMD models and patients. Finally, this article discusses the challenges in the development of antibody-based drugs to treat degenerative processes in the posterior eye. In spite of these difficulties, to date, the following four antibodies have overcome the technical and preclinical hurdles and are being tested in active clinical studies: Lampalizumab, Sonepcizumab, GSK933776 and LFG316. We conclude that, while there are some antibody-based drugs that have made it into clinical practice, a successful transfer from bench to beside is still pending for many promising approaches. PMID- 25725264 TI - Beneficial effect of honokiol on lipopolysaccharide induced anxiety-like behavior and liver damage in mice. AB - Anxiety disorders are commonly occurring co-morbid neuropsychiatric disorders with chronic inflammatory conditions such as live damage. Numerous studies revealed that peripheral inflammation, oxidative stress and brain derived neurotrophic factor (BDNF) play important roles in the pathophysiology of anxiety disorders. Honokiol (HNK) is a polyphenol, possessing multiple biological activities including antioxidant, anti-inflammatory, anxiolytic, antidepressant and hepatoprotection. The present study was designed to investigate the effect of HNK, in lipopolysaccharide (LPS)-induced anxiety-like behavior and liver damage in mice. Mice (n=6-10/group) were pre-treated with different doses of HNK (2.5 and 5mg/kg; i.p.) for two days, and challenged with saline or LPS (0.83mg/kg; i.p.) on third day. Anxiety-like behavior was monitored using elevated plus maze (EPM) and open field test (OFT). Animals were sacrificed to evaluate various biochemical parameters in plasma and liver. HNK pre-treatment provided significant (P<0.01) protection against LPS-induced reduction in body weight, food and water intake in mice. HNK at higher dose significantly (P<0.05) attenuated LPS-induced anxiety-like behavior by increasing the number of entries and time spent in open arm in EPM test, and by increasing the frequency in central zone in OFT. HNK pre-treatment ameliorated LPS-induced peripheral inflammation by reducing plasma IL-1beta, IL-6, TNF-alpha level, and also improved the plasma BDNF level, prevented liver damage via attenuating transaminases (AST, ALT), liver oxidative stress and TNF-alpha activity in LPS challenged mice. In conclusion, the current investigation suggests that HNK provided beneficial effect against LPS-induced anxiety-like behavior and liver damage which may be governed by inhibition of cytokines production, oxidative stress and depletion of plasma BDNF level. Our result suggests that HNK could be a therapeutic approach for the treatment of anxiety and other neuropsychiatric disorders associated with inflammation and oxidative stress. PMID- 25725266 TI - On the pathway of mineral deposition in larval zebrafish caudal fin bone. AB - A poorly understood aspect of bone biomineralization concerns the mechanisms whereby ions are sequestered from the environment, concentrated, and deposited in the extracellular matrix. In this study, we follow mineral deposition in the caudal fin of the zebrafish larva in vivo. Using fluorescence and cryo-SEM microscopy, in combination with Raman and XRF spectroscopy, we detect the presence of intracellular mineral particles located between bones, and in close association with blood vessels. Calcium-rich particles are also located away from the mineralized bone, and these are also in close association with blood vessels. These observations challenge the view that mineral formation is restricted to osteoblast cells juxtaposed to bone, or to the extracellular matrix. Our results, derived from observations performed in living animals, contribute a new perspective to the comprehensive mechanism of bone formation in vertebrates, from the blood to the bone. More broadly, these findings may shed light on bone mineralization processes in other vertebrates, including humans. PMID- 25725267 TI - Role of eaq-, .OH and H. in radiolytic degradation of atrazine: a kinetic and mechanistic approach. AB - The degradation of atrazine was investigated in aqueous solution by gamma-ray irradiation. 8.11 MUM initial atrazine concentration could be completely removed in N2 saturated solution by applying 3500 Gy radiation dose at a dose rate of 296 Gy h(-1). Significant removal of atrazine (i.e., 39.4%) was observed at an absorbed dose of 1184 Gy in air saturated solution and the removal efficiency was promoted to 50.5 and 65.4% in the presence of N2O and N2 gases, respectively. The relative contributions of hydrated electron, hydroxyl radical and hydrogen radical toward atrazine degradation were determined as ratio of observed dose constant (kobs) and found to be 5: 3: 1 for keaq(-): k.OH: kH., respectively. The degradation efficiency of atrazine was 69.5, 55.6 and 37.3% at pH 12.1, 1.7 and 5.7, respectively. A degradation mechanism was proposed based on the identified degradation by-products by gas chromatography-mass spectrometry. Taking the relative contributions of oxidative and reductive species to atrazine degradation into account, reductive pathway proved to be a better approach for the radiolytic treatment of atrazine contaminated water. PMID- 25725265 TI - Dynamic interplay between bone and multiple myeloma: emerging roles of the osteoblast. AB - Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e., any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. PMID- 25725268 TI - Development of a PCR assay based on the 16S-23S rDNA internal transcribed spacer for identification of strictly anaerobic bacterium Zymophilus. AB - PCR-primers were designed for identification of strictly anaerobic bacteria of the genus Zymophilus based on genus-specific sequences of the 16S-23S rDNA internal transcribed spacer region. The specificity of the primers was tested against 37 brewery-related non-target microorganisms that could potentially occur in the same brewery specimens. None DNA was amplified from any of the non Zymophilus strains tested including genera from the same family (Pectinatus, Megasphaera, Selenomonas), showing thus 100% specificity. PCR assay developed in this study allows an extension of the spectra of detected beer spoilage microorganisms in brewery laboratories. PMID- 25725269 TI - Extracellular expression of YlLip11 with a native signal peptide from Yarrowia lipolytica MSR80 in three different yeast hosts. AB - Lipase YlLip11 from Yarrowia lipolytica was expressed with a signal peptide encoding sequence in Arxula adeninivorans, Saccharomyces cerevisiae and Hansenula polymorpha using the Xplor(r)2 transformation/expression platform and an expression module with the constitutive Arxula-derived TEF1 promoter. The YlLip11 signal peptide was functional in all of the yeast hosts with 97% of the recombinant enzyme being secreted into the culture medium. However, recombinant YlLip11 with His Tag fused at C-terminal was not active. The best recombinant YlLip11 producing A. adeninivorans G1212/YRC102-YlLip11 transformant cultivated in shake flasks produced 2654 U/L lipase, followed by S. cerevisiae SEY6210/YRC103-YlLip11 (1632U/L) and H. polymorpha RB11/YRC103-YlLip11 (1144U/L). Although the biochemical parameters of YlLip11 synthesized in different hosts were similar, their glycosylation level and thermo stability differed. The protein synthesized by the H. polymorpha transformant had the highest degree of glycosylation and with a t1/2 of 60min at 70 degrees C, exhibited the highest thermostability. PMID- 25725270 TI - New enzymatic pathways for the reduction of reactive oxygen species in Entamoeba histolytica. AB - BACKGROUND: Entamoeba histolytica, an intestinal parasite that is the causative agent of amoebiasis, is exposed to elevated amounts of highly toxic reactive oxygen and nitrogen species during tissue invasion. A flavodiiron protein and a rubrerythrin have been characterized in this human pathogen, although their physiological reductants have not been identified. METHODS: The present work deals with biochemical studies performed to reach a better understanding of the kinetic and structural properties of rubredoxin reductase and two ferredoxins from E. histolytica. RESULTS: We complemented the characterization of two different metabolic pathways for O2 and H2O2 detoxification in E. histolytica. We characterized a novel amoebic protein with rubredoxin reductase activity that is able to catalyze the NAD(P)H-dependent reduction of heterologous rubredoxins, amoebic rubrerythrin and flavodiiron protein but not ferredoxins. In addition, the protein exhibited an NAD(P)H oxidase activity, which generates hydrogen peroxide from molecular oxygen. We describe how different ferredoxins were also efficient reducing substrates for both flavodiiron protein and rubrerythrin. CONCLUSIONS: The enzymatic systems herein characterized could contribute to the in vivo detoxification of O2 and H2O2, playing a key role for the parasite defense against reactive oxidant species. GENERAL SIGNIFICANCE: To the best of our knowledge this is the first characterization of a eukaryotic rubredoxin reductase, including a novel kinetic study on ferredoxin-dependent reduction of flavodiiron and rubrerythrin proteins. PMID- 25725271 TI - Risk-Adjusted Meta-analysis of 30-Day Mortality of Endovascular Versus Open Repair for Ruptured Abdominal Aortic Aneurysms. AB - BACKGROUND: In recent years, the relative benefits of endovascular repair (EVAR) in the treatment of ruptured abdominal aortic aneurysms (rAAAs) compared with those of open repair have been postulated. However, sufficient quantification and evidence-based validation of the role of EVAR in the care pathway for these patients is still lacking. The aim of the present meta-analysis was to investigate the impact of hemodynamic instability and other potential risk factors on 30-day mortality of EVAR versus open repair for rAAAs by performing a meta-regression analysis of previously published data. METHODS: Studies comparing perioperative outcomes of endovascular and open repair of ruptured infrarenal or juxtarenal abdominal aortic aneurysm were considered for analysis. All types of comparative studies, including prospective or retrospective, observational studies, or randomized controlled trials (RCTs), were included. Meta-analysis was undertaken using the Mantel-Haenszel method, with a standard continuity correction of 0.5. A random-effects model was used owing to the variability in baseline characteristics in each article. Furthermore, an odds ratio (OR) for 30 day mortality adjusted for patients' hemodynamic condition at presentation in the hospital was calculated by performing a meta-regression analysis. RESULTS: The entire meta-analysis population comprised 81,681 patients (63 studies), of whom 13,706 underwent EVAR and the remaining 67,975 had an open repair of their rAAA. Without correction for hemodynamic instability, patients undergoing EVAR had a significantly lower 30-day mortality rate than patients having open repair (OR, 0.512; 95% confidence interval [CI], 0.457-0.574; P < 0.01). Moderate heterogeneity among the studies was identified (I(2) = 53.303%), and the likelihood of publication bias was low (P = 0.183). In the RCTs alone (3 studies), patients undergoing EVAR had no significantly lower 30-day mortality rate than patients with open repair (OR, 0.930; 95% CI, 0.691-1.253; P < 0.633). In all studies available, after adjustment for patients' hemodynamic condition at presentation to the hospital, the OR for 30-day mortality was 0.872 (95% CI, 0.598-1.270; P = 0.474), as well, indicating no significant difference between the 2 therapeutic options. CONCLUSIONS: Because a hemodynamically unstable condition may result in poorer clinical outcome, we calculated the 30-day mortality OR adjusted for patients' hemodynamic condition. After adjustment, there was no benefit in 30-day mortality for EVAR compared with that in open surgery. PMID- 25725272 TI - "Two is better than one": a composite graft made of two different vascular prostheses for urgent hemodialysis access in a troublesome case. AB - BACKGROUND: Multiple failed hemodialysis access and poor vascular anatomy can jeopardize an end-stage renal disease patient's survival, frequently leading to the urgent need for rapid and durable new vascular access. In these circumstances, the extensive use of central venous catheters (CVC) can led to serious complications, such as infection, thrombosis, and often vessel scarring with obstruction of the central veins. More recently, new self-sealing prosthetic grafts may be cannulated within a few days after implantation, avoiding the need for extensive CVC. However, similar to all synthetic arteriovenous grafts (AVG), the new grafts are prone to rapid and aggressive venous neointimal hyperplasia (VNH), which is responsible for outflow stenosis and access thrombosis. Endoluminal sutureless anastomosis has been demonstrated to have better hemodynamics at the venous outflow with a supposed reduction of VNH, thus potentially improving graft patency. METHODS: We report a case of a successful creation of a composite prosthetic access in a patient with severe comorbidities and nearly complete exhaustion of all vascular sites and with the need for immediate access for hemodialysis. Two relatively novel vascular expanded polytetrafluoroethylene prostheses were used jointly in this patient for a brachial-axillary AVG to allow early cannulation and with the aim of being less vulnerable to outflow stenosis. A multilayer self-sealing graft and a graft with a nitinol reinforced section, which permits endoluminal sutureless anastomosis, were sewed together to create a unique prosthesis with both features. RESULTS: The composite graft was cannulated 48 hr after implantation and continued to function well at 10 months of follow-up without signs of venous stenosis. CONCLUSIONS: This simple technique allows the creation of a customized composite graft with self-sealing properties and improved hemodynamics at the venous outflow. PMID- 25725273 TI - Pharmacomechanical thrombectomy in the management of deep vein thrombosis using the cleaner device: an initial single-center experience. AB - BACKGROUND: Pharmacomechanical thrombectomy (PMT) has appeared as an effective treatment modality for deep venous thrombosis (DVT). The study aimed to assess the efficacy of the CleanerTM thrombectomy device for acute DVT. METHODS: Sixteen consecutive patients presenting with extensive iliofemoral and/or femoropopliteal acute DVT and managed at our institution between February 2013 and May 2014 were retrospectively reviewed. The patients underwent PMT with the Cleaner device after insertion of vena caval filters. For underlying stenotic lesions, balloon angioplasty and/or stent placement was performed. RESULTS: PMT with the Cleaner device was successful in 14 patients with complete restoration of flow. No clinical signs of pulmonary thromboembolism was recorded after the procedure. Thrombectomy failed in 2 patients. For the rest of the patients, balloon angioplasty was performed to relieve underlying stenotic lesions. Nine of them underwent additional stenting. CONCLUSIONS: Our initial experience suggests that the Cleaner device can be used in acute DVT. However, further studies involving larger patient populations are warranted to determine long-term results. PMID- 25725274 TI - Interleukins and inflammatory markers in in-stent restenosis after femoral percutaneous transluminal angioplasty. AB - BACKGROUND: Inflammatory activity may influence results of percutaneous transluminal angioplasty (PTA). The purpose of this study was to evaluate the relationship between (1) proinflammatory markers (interleukin [IL]-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and highly sensitive C-reactive protein [CRP]); (2) type 1 T helper cell marker (IL-12); and (3) Type 2 T helper cell marker (transforming growth factor-beta [TGF-beta]) and in-stent restenosis, 6 months after femoral PTA with stent implantation. METHODS: We performed a single center prospective study with 26 patients with peripheral artery disease requiring PTA and stenting. As control, we studied 26 patients who were submitted to diagnostic angiography. Serum samples were collected before stent implantation, 24 hr and 6 months after the procedure. To detect restenosis, a new angiography was obtained at 6 months. RESULTS: Restenosis was observed in 10 (38.5%) patients who underwent PTA and stenting. There was a trend to increased levels of IL-6, TNF-alpha, TGF-beta, and IL-12 24 hr after PTA and stenting compared with pretreatment. IL-8 levels showed a statistically significant reduction 24 hours after versus pretreatment (P < 0.05), 6 months vs. pretreatment, and 6 months vs. 24 hr (P < 0.01). There was no statistical difference between cytokine levels when comparing restenosis and no restenosis groups. CRP levels were already high at pretreatment. CONCLUSIONS: No inflammatory marker was independently identified as risk factor for in-stent restenosis, 6 months after femoral PTA with stent implantation. The question that remains is whether acute phase reactants will be clinically useful to predict the individual risk for in-stent restenosis. PMID- 25725275 TI - Early vascular consultation in the setting of oncologic resections: benefit for patients and a continuing source of open vascular surgical training. AB - BACKGROUND: Oncologic surgeons have become more aggressive at tumor resections that often require complex open vascular interventions. Vascular surgeons may be consulted preoperatively to aid in these cases, or commonly called into the operating room for an urgent consult. These operations provide a challenge to the vascular surgeon and also an opportunity for open vascular surgical training of residents. We present our experience with vascular surgical interventions during oncologic resections. METHODS: A retrospective review of a prospectively maintained vascular registry was performed to identify patients undergoing vascular surgery in the setting of oncologic resections. Tumor histology, location, type of vascular intervention, vascular, and oncologic outcomes were recorded and reviewed. RESULTS: Over a 7-year period, 21 oncologic cases involving vascular surgeons were identified. Tumor types included sarcoma (9), adenocarcinoma (4), germ cell (4), paraganglioma (2), and others (2). Tumor locations included abdominal/pelvic (15), cervical (3), and extremity (3). Complete resection was achieved in 18 of the 19 patients; 2 patients underwent exploration alone for carcinomatosis. Vascular surgical procedures included bypass grafts in 7 patients, resection with primary repair in 5 patients, ligation/excision in 4 patients, and arterial mobilization in 3 patients. No major vascular complications occurred. Short-term patency rates were 100%. Survival rates following therapeutic resection were 90%, 80%, and 80% at 1, 3, and 5 years, respectively. Vascular surgeons were involved in the preoperative planning in 11 cases (52%). Patients with preoperative vascular consultation had significantly fewer vascular injuries, a nonsignificant trend toward lower blood loss, and a nonsignificant trend toward improved survival than those with urgent intraoperative vascular consultation. CONCLUSIONS: Vascular interventions can lead to favorable long-term outcomes during definitive oncologic resection of diverse tumor histologies and locations. Vascular surgeons must be prepared to participate, frequently urgently, in oncologic procedures. Standard open techniques employing all aspects of vascular exposures continue to be integral to vascular surgery training. Preoperative consultation between the oncologic and vascular surgeons may lead to improved outcomes. PMID- 25725276 TI - The impact of a massive transfusion protocol on outcomes among patients with abdominal aortic injuries. AB - BACKGROUND: Injuries of the abdominal aorta are uncommon and associated with a high mortality. The purpose of this study was to examine the impact of an institutional massive transfusion protocol (MTP) on outcomes in patients with injuries of the abdominal aorta. METHODS: A 12.5-year retrospective analysis of a Level 1 trauma center database to identify patients with abdominal aortic injuries was conducted. Demographics, associated injuries and severity, operative procedures, resuscitation requirements, and outcomes were compared among patients before and after implementation of an MTP. RESULTS: Of the 46 patients with abdominal aortic injuries, 29 (63%) were in the pre-MTP group and 17 (37%) were in the post-MTP group. The mean age of the entire cohort was 32 +/- 17 years and the two most common mechanisms of injury were gunshot wounds (63%) followed by motor vehicle collisions (24%). Thirteen patients (28%) underwent an emergency department thoracotomy and 11 patients (24%) sustained concomitant inferior vena cava injuries. There was a significant reduction in the volume of pre- and intraoperative crystalloids administered between the pre- and post-MTP groups. Intraoperatively, the use of tranexamic acid was increased in the post-MTP group (P < 0.001). A statistically significant difference in achievement of a low packed red blood cells to fresh frozen plasma ratio was observed for the post- versus the pre-MTP group (88% vs. 30%, P = 0.015). Overall survival was improved among post- versus pre-MTP patients (47% vs. 14%, P = 0.03). CONCLUSIONS: Abdominal aortic injuries continue to represent a challenge and remain associated with a high mortality. Modern improvements in damage control resuscitation techniques including implementation of an institutional MTP may improve outcomes in patients with these injuries. PMID- 25725278 TI - Bilateral cervical ribs causing cerebellar stroke and arterial thoracic outlet syndrome: a case report and review of the literature. AB - Stroke is an exceedingly rare presentation of arterial thoracic outlet syndrome (aTOS). This report describes a case of cerebellar stroke secondary to aTOS and reviews the literature. A 56-year-old woman with no previous history of stroke or arm ischemia presented with vertigo. Computed tomography (CT) and magnetic resonance imaging confirmed a left cerebellar ischemic stroke. She subsequently developed ischemia of her left arm, which was treated by a thromboembolectomy. CT angiography revealed bilateral cervical ribs along with bilateral subclavian artery aneurysms. Staged resection of the cervical ribs and reconstruction of the subclavian arteries were performed. Symptomatic arterial thoracic outlet syndrome most commonly presents as arm ischemia because of embolization of intramural clot from a subclavian artery aneurysm or because of thrombosis of the subclavian artery aneurysm itself. In rare cases, the clot can propagate retrograde, resulting in stroke. In young patients presenting with ischemic stroke, arterial thoracic outlet syndrome should be considered as part of the differential diagnosis. PMID- 25725277 TI - A Primary Primitive Neuroectodermal Tumor Arising from Left Subclavian Vein and Extending along Left Brachiocephalic Vein and Superior Vena Cava into Right Atrium. AB - Primitive neuroectodermal tumor (PNET) is an extremely rare malignancy thought to be derived from fetal neuroectodermal precursor cells. It usually occurs in central and peripheral nervous system or soft tissue and bone, while intravenous or intracavitary PNET is considered as an extremely rare tumor. We reported a case of a 44-year-old woman who presented with the left unilateral facial and neck swelling. Magnetic resonance imaging revealed a tape-shaped solid mass within left subclavian vein, left brachiocephalic vein, superior vena cava, and right atrium; the proximal end proportion occupied almost the entire right atrium with a pedicle flip protruded into the right ventricle. Ultrasonography revealed an irregular hypoechnoic mass arising from the left subclavian vein, which extended along the left brachiocephalic vein and superior vena cava into the right atrium and up to the right ventricle. Positron emission tomography-computed tomography revealed several hypermetabolic thyroid nodules with no evidence of intravenous hyperactive lesion. The patient underwent tumor resection under cardiopulmonary bypass. At 15 days postoperatively, total thyroidectomy and resection of the left subclavian vein were simultaneously performed. The patient received chemotherapy and radiotherapy later. Histologically, the neoplasm displayed small, round, blue cells with hyperchromatic nuclei and scant cytoplasm. The neoplastic cells showed a strong immunopositivity for CD99, synaptophysin, CD56, CD57, and friend leukemia integration 1, thus confirming a diagnosis of the PNET. Histopathological examination of the thyroid showed papillary carcinoma. Thus, this PNET had no definitive organ or tissue of origin, which primarily originated from the left subclavian vein with tumor extension along the superior vena cava to the right ventricle. PMID- 25725279 TI - Domains that Determine Quality of Life in Vascular Amputees. AB - BACKGROUND: Although patients with critical limb ischemia (CLI) commonly undergo major limb amputation, the quality of life (QOL) of this group remains poorly described. Therefore, we sought to describe which domains vascular amputees consider important in determining their health-related QOL. METHODS: We performed 4 focus groups in patients who had major lower extremity amputations resulting from CLI. They were conducted at 4 distinct centers across the United States to ensure broad geographic, socioeconomic, and ethnic representation. RESULTS: Of 26 patients (mean age, 64 years), 19 (73%) were Caucasian, 6 (23%) were African American, and 1 (4%) was Native American. Nearly, three-quarter of patients were men (n = 19, 73%) and had a high-school education or more (n = 19, 73%). Overall, 8 (31%) were double amputees and 17 (65%) had diabetes. Time since amputation varied across patients and ranged from 3 months to more than 27 years (mean, 4.3 years). Patients stated that their current QOL was determined by impaired mobility (65%), pain (60%), progression of disease in the remaining limb (55%), and depression/frustration (54%). Across 26 patients, more than half (n = 16, 62%) described multiple prior revascularization procedures. Although most felt that their physician did his/her best to salvage the affected leg (85%), a sizable minority would have preferred an amputation earlier in their CLI treatment course (27%). Furthermore, when asked how their care might have been improved, patients reported that facilitating peer support (88%), more extensive rehabilitation and prosthetist involvement (71%), earlier mention of amputation as a possible outcome (54%), and the early discontinuation of narcotics (54%) were potential areas of improvement. CONCLUSIONS: Although QOL in vascular amputees seems primarily determined by mobility impairment, pain, and emotional perturbation, our focus groups identified that physician-controlled factors such as the timing of amputation, informed decision making, and postamputation support may also play an important role. The assessment of patient preferences regarding maintenance of mobility at the cost of increased pain versus relief of pain with amputation at a cost of diminished mobility is central to shared decision making in CLI treatment. PMID- 25725280 TI - Multislice Computed Tomography Angiography of an Extremely Uncommon Variation of Hepatic Arteries: Michel's Type XI. AB - Variations of hepatic vascular system have been more important with improvements in some clinical procedures such as hepatic transplantation or radiologic chemoembolization of hepatic tumors. Multidetector computed tomography is a useful noninvasive imaging tool for differentiating such variations. PMID- 25725281 TI - Clinical efficacy of percutaneous transluminal renal artery stenting for the treatment of renovascular hypertension associated with Takayasu arteritis. AB - BACKGROUND: This study aims to observe and analyze the clinical efficacy of interventional therapy for patients with Takayasu arteritis (TA) experiencing renovascular hypertension (RH). METHODS: Eight TA patients with RH underwent percutaneous transluminal renal artery stenting (PTRAS). Patients were followed up 1, 6, 12, and 24 months postoperatively for levels of blood pressure, number of antihypertensive drugs being taken, levels of serum creatinine, and the presence of renal artery restenosis. RESULTS: All 8 patients were successfully followed up 1, 6, and 12 months postoperatively, but 1 was lost to follow-up at 24 months. All patients had significantly lower average blood pressure levels compared with those at baseline (P < 0.05); treatment efficacy rates (recovery or improvement) at 1, 6, 12, and 24 months were 94%, 90%, 80%, and 80%, respectively. The average number of antihypertensive drugs being taken was 3.5 at baseline, 1.0 at 1 month, 0.5 at 6 months, 1.0 at 12 months, and 1.5 at 24 months. Serum creatinine levels during the follow-up period were not significantly different from those at the baseline. No patient developed renal artery restenosis during the follow-up period. CONCLUSIONS: PTRAS is a safe and effective treatment for TA-associated RH, with a high technical success rate and a low complication rate. This interventional therapy can effectively control TA related hypertension and can also preserve and even improve kidney function. PMID- 25725282 TI - Endovascular treatment of an aortic saddle embolism resulting in full neurologic recovery. AB - Aortic saddle embolism (ASE) and aortic saddle thrombosis are rare and occasionally associated with spinal ischemia and paraplegia. Patients have traditionally been treated with transfemoral balloon thromboembolectomy. In the following case report, we present a patient with suspected ASE and paraplegia, who was successfully treated by an endovascular approach using covered stents. Following intervention, the patient regained full neurologic function. To our knowledge, it is the first time that this type of endovascular treatment for ASE has been applied successfully. PMID- 25725283 TI - Venous ulcer: late complication of a traumatic arteriovenous fistula. AB - Arteriovenous fistula (AVF) formation after penetrating trauma is a well described phenomenon. However, diagnosis of traumatic AVF is frequently delayed as patients often do not have hard signs of vascular injury at the initial presentation. Late complications of traumatic AVF include arterial and venous dilatation, distal ischemia, venous congestion, and congestive heart failure. This case report describes a traumatic femoral AVF causing distal venous ulceration 3 years after the injury. The AVF was treated with open repair. In the operating room, the Nicoladoni-Branham sign was elicited. The ulcer healed at 1 month and has not recurred at 1-year follow-up. PMID- 25725284 TI - Sodium-reduced lean sausages with fish oil optimized by a mixture design approach. AB - A partial NaCl replacement by KCl and sodium tripolyphosphate on low-fat meat sausages formulated with fish oil was studied using a mixture design. Thermal behavior by modulated differential scanning calorimetry, physicochemical, and textural properties were determined; afterwards they were mathematically modeled as a function of salts content. The thermo-rheological behavior of the different formulations was also studied in a control-stress rheometer. The optimal sodium reduction was found employing a desirability function approach. This formulation was experimentally validated and employed for microstructure analysis by environmental scanning microscopy. The results obtained in this work revealed that partial sodium replacement affected the matrix microstructure, but this change had no impact on sensory acceptability. In comparison with US and Argentinean commercial sausages, our product has 58% and 70% less Na(+) respectively. PMID- 25725285 TI - Cytoskeletal rearrangement and Src and PI-3K-dependent Akt activation control GABA(B)R-mediated chemotaxis. AB - The gamma-amino butyric acid (GABA) type B receptors (GABA(B)R) function as chemoattractant receptors in response to GABA(B)R agonists in human neutrophils. The goal of this study was to define signaling mechanisms regulating GABA(B)R mediated chemotaxis and cytoskeletal rearrangement. In a proteomic study we identified serine/threonine kinase Akt, tyrosine kinases Src and Pyk2, microtubule regulator kinesin and microtubule affinity-regulating kinase (MARK) co-immunoprecipitating with GABA(B)R. To define the contributions of these candidate signaling events in GABA(B)R-mediated chemotaxis, we used rat basophilic leukemic cells (RBL-2H3 cells) stably transfected with human GABA(B1b) and GABA(B2) receptors. The GABA(B)R agonist baclofen induced Akt phosphorylation and chemotaxis by binding to its specific GABA(B)R since pretreatment of cells with CGP52432, a GABA(B)R antagonist, blocked such effects. Moreover, baclofen induced Akt phosphorylation was shown to be dependent upon PI-3K and Src kinases. Baclofen failed to stimulate actin polymerization in suspended RBL cells unless exposed to a baclofen gradient. However, baclofen stimulated both actin and tubulin polymerization in adherent RBL-GABA(B)R cells. Blockade of actin and tubulin polymerization by treatment of cells with cytochalasin D or nocodazole respectively, abolished baclofen-mediated chemotaxis. Furthermore, baclofen stimulated Pyk2 and STAT3 phosphorylation, both known regulators of cell migration. In conclusion, GABA(B)R stimulation promotes chemotaxis in RBL cells which is dependent on signaling via PI3-K/Akt, Src kinases and on rearrangement of both microtubules and actin cytoskeleton. These data define mechanisms of GABA(B)R-mediated chemotaxis which may potentially be used to therapeutically regulate cellular response to injury and disease. PMID- 25725287 TI - Sec8 regulates cytokeratin8 phosphorylation and cell migration by controlling the ERK and p38 MAPK signalling pathways. AB - Cell migration is involved in numerous biological processes, including morphogenesis, wound healing and inflammatory responses, and is regulated by harmonic modulations of cellular cytoskeletal elements. The intermediate filament cytokeratin8 is one cytoskeletal element that has been implicated in cell migration. Sec8 is a component of an exocyst complex and is associated with various phenomena, such as cell migration, invadopodia formation, cytokinesis, glucose uptake and neural development. However, the relationship between Sec8 and cytokeratin8 remains to be elucidated. In this study, depleting Sec8 in HSC3 cells suppressed their migration by controlling the phosphorylation of cytokeratin8 at Ser73. This reduced cytokeratin8 phosphorylation at Ser73 is regulated by the activation of ERK and p38 mitogen-activated protein kinases (MAPK) signalling pathways via the downregulation of p21-activated kinases by p53 induced RING-H2 (Pirh2) and seven-in-absentia homologue 1 (Siah1) under conditions of Sec8 knockdown. PMID- 25725286 TI - EHT 1864, a small molecule inhibitor of Ras-related C3 botulinum toxin substrate 1 (Rac1), attenuates glucose-stimulated insulin secretion in pancreatic beta cells. AB - Glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cells entails a variety of signaling mechanisms including activation of small GTP-binding proteins (G-proteins). Previous studies from our laboratory in human islets, rodent islets and clonal beta-cells have demonstrated that G-proteins (e.g., Arf6, Cdc42 and Rac1) play novel roles in cytoskeletal remodeling, which is a critical step in the trafficking of insulin-laden secretory granules for fusion with plasma membrane and release of insulin. To further understand regulatory roles of Rac1 in GSIS, we utilized, herein, EHT 1864, a small molecule inhibitor, which attenuates Rac1 activation by retaining the G-protein in an inert/inactive state, thereby preventing activation of its downstream effector proteins. We demonstrate that EHT 1864 markedly attenuated GSIS in INS-1 832/13 cells. In addition, EHT 1864 significantly reduced glucose-induced activation and membrane targeting of Rac1 in INS-1 832/13 cells. This Rac1 inhibitor also suppressed glucose-induced activation of ERK1/2 and p53, but not Akt. Lastly, unlike the inhibitors of protein prenylation (simvastatin), EHT 1864 did not exert any significant effects on cell morphology (cell rounding) under the conditions it attenuated Rac1-sensitive signaling steps leading to GSIS. Based on these findings, we conclude that EHT 1864 specifically inhibits glucose-induced Rac1 activation and membrane association and associated downstream signaling events culminating in inhibition of GSIS. PMID- 25725288 TI - Nek5 interacts with mitochondrial proteins and interferes negatively in mitochondrial mediated cell death and respiration. AB - Mitochondria are involved in energy supply, signaling, cell death and cellular differentiation and have been implicated in several human diseases. Neks (NIMA related kinases) represent a family of mammal protein kinases that play essential roles in cell-cycle progression, but other functions have recently been related. A yeast two-hybrid (Y2H) screen was performed to identify and characterize Nek5 interaction partners and the mitochondrial proteins Cox11, MTX-2 and BCLAF1 were retrieved. Apoptosis assay showed protective effects of stable hNek5 expression from Hek293-T's cell death after thapsigargin treatment (2 MUM). Nek5 silenced cells as well as cells expressing a "kinase dead" version of Nek5, displayed an increase in ROS formation after 4 h of thapsigargin treatment. Mitochondrial respiratory chain activity was found decreased upon stable hNek5expression. Cells silenced for hNek5 on the other hand presented 1.7 fold increased basal rates of respiration, especially at the electrons transfer steps from TMPD to cytochrome c and at the complex II. In conclusion, our data suggest for the first time mitochondrial localization and functions for Nek5 and its participation in cell death and cell respiration regulation. Stable expression of hNek5 in Hek293T cells resulted in enhanced cell viability, decreased cell death and drug resistance, while depletion of hNek5by shRNA overcame cancer cell drug resistance and induced apoptosis in vitro. Stable expression of hNek5 also inhibits thapsigargin promoted apoptosis and the respiratory chain complex IV in HEK293T cells. PMID- 25725289 TI - Adenosine A1 receptor activation modulates human equilibrative nucleoside transporter 1 (hENT1) activity via PKC-mediated phosphorylation of serine-281. AB - Equilibrative nucleoside transporter subtype 1 (ENT1) is critical for the regulation of the biological activities of endogenous nucleosides such as adenosine, and for the cellular uptake of chemotherapeutic nucleoside analogs. Previous studies have implicated protein kinase C (PKC) in the regulation of ENT1 expression/function. It was hypothesized that hENT1 activity at the plasma membrane is regulated by PKC-mediated phosphorylation of Ser281. WT (wild-type) hENT1 or S281A-hENT1 was stably transfected into a PK15 cell variant that is deficient in nucleoside transport. Using [(3)H]nitrobenzylthioinosine (NBMPR) binding and [(3)H]2-chloroadenosine uptake analyses, it was determined that S281A hENT1 exhibited functional characteristics similar to WT-hENT1. Direct activation of PKC with PMA or indirect activation with the adenosine A1 receptor agonist 2 chloro-N(6)-cyclopentyladenosine (CCPA) led to significant increases in [(3)H]NBMPR binding and [(3)H]2-chloroadenosine uptake in WT-hENT1 transfected cells. The PKC inhibitor Go6983 blocked these effects of both PMA and CCPA, and the CCPA-mediated increase was also blocked by the A1 adenosine receptor antagonist DPCPX. In contrast, neither PMA nor CCPA affected [(3)H]NBMPR binding or [(3)H]2-chloroadenosine uptake in cells transfected with S281A-hENT1. shRNAi silencing studies implicated PKCdelta in this regulation of hENT1 activity. Immunocytochemical analysis and cell surface biotinylation assays showed that activation of PKC with PMA, but not CCPA, led to a significant increase in the plasma membrane localization of hENT1. These data suggest that phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1. This signaling pathway represents a feedback loop whereby adenosine receptor signaling can lead to increased adenosine reuptake into cells via hENT1. PMID- 25725290 TI - Early growth response gene 1, a TRBP binding protein, is involved in miRNA activity of miR-125a-3p in human cells. AB - BACKGROUND: MicroRNAs (miRNAs) are key regulators of many cellular pathways. However, the picture for components or regulators involved in the process of miRNA biogenesis and function remains to be further elucidated. Early growth response gene 1 (Egr1) has long been considered as tumor suppressor and transcriptional factor involved in cell proliferation and regulation of apoptosis. RESULTS: Here we show that Egr1 is able to modulate guide strand loading of certain miRNAs or siRNAs in human HEK293 and A549 cells, which is related with thermodynamic parameters of miRNA or siRNA. Further, we found that Egr1 modulates the silencing activity of miR-125a-3p in vivo. Immunoprecipitation experiment demonstrated that Egr1 could bind miRNA biogenesis protein TAR RNA binding protein2 (TRBP2), and knockdown TRBP by RNAi abolished the regulating effects of Egr1 on miR-125a-3p efficiency. Further experiments revealed that deleting sequence 97-227aa containing dsRBD B domain of TRBP eliminated the binding phenomenon between Egr1 and TRBP and impaired the effect of Egr1 on miR 125a-3p efficiency. CONCLUSIONS: Taken together, our study has demonstrated that Egr1 is able to regulate miRNA activity of miR-125a-3p in human cells through binding TRBP, which highlights an unexpected function of Egr1 in miRNA pathway. PMID- 25725291 TI - Downregulation of PEA-15 reverses G1 arrest, and nuclear and chromatin changes of senescence phenotype via pErk1/2 translocation to nuclei. AB - We previously showed that senescent cells respond to TPA with translocation of senescence associated-pErk1/2 (SA-pErk1/2) into nuclei along with reversal of senescence morphology. Here, we describe that the reversal of senescence phenotype was manifested by knockdown of cytoplasmic PEA-15 expression, a sequestrator of cytoplasmic pErk1/2. Transfection of short-interfering RNA to PEA 15 (siPEA-15) significantly induced nuclear translocation of SA-pErk1/2, and siPEA-15 with TPA co-treatment further increased the translocation. Moreover, the reversal of senescence phenotype, such as expressions of SA-beta-galactosidase, p53, p21(WAF1), PML body, 53BP1 and H3K9me2, was modified by either knockdown of PEA-15 or TPA treatment, indicating that nuclear translocation of SA-pErk1/2 might inhibit senescence progression. Indeed, knockdown of PEA-15 or TPA treatment significantly induced progression of G1 arrested cells to S-phase in human diploid fibroblast (HDF) senescent cells, examined by immunocytochemistry, FACS and immunoblot analyses. In conclusion, downregulation of PEA-15 expression reverses senescence phenotypes via nuclear translocation of SA-pErk1/2, which suggests in vivo maintenance of senescence phenotype by sequestration of pErk1/2 in cytoplasm. PMID- 25725292 TI - Mitochondria and NADPH oxidases are the major sources of TNF-alpha/cycloheximide induced oxidative stress in murine intestinal epithelial MODE-K cells. AB - TNF-alpha/cycloheximide (CHX)-induced apoptosis of the mouse intestinal epithelial cell line MODE-K corresponds with the production of reactive oxygen species (ROS). The aim of the study is to investigate the sources of ROS production contributing to apoptotic cell death during TNF-alpha/CHX-induced oxidative stress in MODE-K cells. Total ROS or mitochondrial superoxide anion production was measured simultaneously with cell death in the absence or presence of pharmacological inhibitors of various ROS-producing systems, and of ROS scavengers/antioxidants. The influence of TNF-alpha/CHX on mitochondrial membrane potential (Psi(m)) and cellular oxygen consumption was also studied. TNF alpha/CHX time-dependently increased intracellular total ROS and mitochondrial superoxide anion production in MODE-K cells, starting from 2h. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) by a pan-NOX inhibitor (VAS-2870) and a specific inhibitor of Rac1 (NSC23766) significantly reduced TNF-alpha/CHX-induced total ROS and cell death levels. The mitochondrial electron transport chain inhibitors, amytal (IQ site of complex I) and TTFA (Qp site of complex II) showed a pronounced decrease in TNF-alpha/CHX-induced total ROS, mitochondrial superoxide anion and cell death levels. TNF-alpha/CHX treatment caused an immediate decrease in mitochondrial respiration, and a loss of Psi(m) and increase in mitochondrial dysfunction from 1 h on. The results suggest that mitochondria and NOX are the two major sources of ROS overproduction during TNF-alpha/CHX-induced cell death in MODE-K cells, with superoxide anions being the major ROS species. Particularly, the quinone-binding sites of mitochondrial complex I (site I(Q)) and complex II (site Qp) seem to be the major sites of mitochondrial ROS production. PMID- 25725294 TI - Management of asymptomatic neoplastic pancreatic cysts: clinical decision support tool. PMID- 25725293 TI - Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands. AB - BACKGROUND & AIMS: Helicobacter pylori infection is the main risk factor for gastric cancer. We characterized the interactions of H pylori with gastric epithelial progenitor and stem cells in humans and mice and investigated how these interactions contribute to H pylori-induced pathology. METHODS: We used quantitative confocal microscopy and 3-dimensional reconstruction of entire gastric glands to determine the localizations of H pylori in stomach tissues from humans and infected mice. Using lineage tracing to mark cells derived from leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5(+)) stem cells (Lgr5-eGFP-IRES-CreERT2/Rosa26-TdTomato mice) and in situ hybridization, we analyzed gastric stem cell responses to infection. Isogenic H pylori mutants were used to determine the role of specific virulence factors in stem cell activation and pathology. RESULTS: H pylori grow as distinct bacterial microcolonies deep in the stomach glands and interact directly with gastric progenitor and stem cells in tissues from mice and humans. These gland-associated bacteria activate stem cells, increasing the number of stem cells, accelerating Lgr5(+) stem cell proliferation, and up-regulating expression of stem cell related genes. Mutant bacteria with defects in chemotaxis that are able to colonize the stomach surface but not the antral glands in mice do not activate stem cells. In addition, bacteria that are unable to inject the contact-dependent virulence factor CagA into the epithelium colonized stomach glands in mice, but did not activate stem cells or produce hyperplasia to the same extent as wild type H pylori. CONCLUSIONS: H pylori colonize and manipulate the progenitor and stem cell compartments, which alters turnover kinetics and glandular hyperplasia. Bacterial ability to alter the stem cells has important implications for gastrointestinal stem cell biology and H pylori-induced gastric pathology. PMID- 25725295 TI - Achieving safe hands-on defibrillation using electrical safety gloves--a clinical evaluation. AB - INTRODUCTION: Safe hands-on defibrillation (HOD) will allow uninterrupted chest compression during defibrillation and may improve resuscitation success. We tested the ability of electrical insulating gloves to protect the rescuer during HOD using a 'worst case' electrical scenario. MATERIALS AND METHOD: Leakage current flowing from the patient to the 'rescuer' during antero-lateral defibrillation of patients undergoing elective cardioversion was measured. The 'rescuer' maintained firm (20 kgf) contact with the patient during defibrillation, wearing Class 1 electrical insulating gloves while simulating an inadvertent contact with the patient, through an additional wired contact between 'rescuer' and patient. RESULTS: Data from 61 shocks from 43 different patients were recorded. The median leakage current from all defibrillations was 20.0 MUA, (range: 2.0-38.5). In total, 18 of the shocks were delivered at 360 J and had a median leakage current of 27.0 MUA (range: 14.3-38.5). CONCLUSION: When using Class 1 electrical insulating gloves for hands-on defibrillation, rescuer leakage current is significantly below the 1 mA safe threshold, allowing safe hands-on defibrillation if the rescuer makes only one other point of contact with the patient. PMID- 25725296 TI - Interaction effects between hypothermia and diabetes mellitus on survival outcomes after out-of-hospital cardiac arrest. AB - OBJECTIVES: Mild therapeutic hypothermia (MTH) is the core hospital intervention to enhance neurological outcome after out-of-hospital cardiac arrest (OHCA). Diabetes mellitus (DM) has been known to be a harmful risk factor on survival after OHCA. This study aimed to investigate whether the effect of MTH on brain recovery after OHCA differed between patients with or without DM. METHODS: We used a Korean national OHCA database composed of hospital and ambulance data. We included adult OHCA patients who survived to admission with presumed cardiac etiology during the study period from 2009 to 2013. We excluded cases without hospital outcome data. The primary exposure was MTH, which included all kinds of cooling methods that had been initiated within 6h after return of spontaneous circulation. DM was coded positive when the patient had a clinical history diagnosed by a physician before an OHCA event. The endpoints were discharge with good neurological recovery (cerebral performance category 1 or 2) and survival to discharge. We compared outcomes between MTH vs. non-MTH groups using multivariable logistic regression with an interaction term between MTH and DM for calculating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) after adjusting for potential confounders. RESULTS: Among 9735 patients following OHCA survived to hospital admission with cardiac etiology, MTH was performed in 16.5%. History of DM was observed in 25.4% among MTH group and 27.4% in non-MTH group (p=0.09). MTH group showed better outcomes than non-MTH group; 23.6% vs. 15.7% for good neurological recovery (p<0.01). AOR (95% CI) of MTH for good neurological recovery for all study groups was 1.23 (1.03-1.47). In the interaction model, AOR (95% CI) of MTH for good neurological recovery was 1.40 (1.16-1.70) in patients without DM vs. 0.69 (0.46-1.04) in patients with DM. For survival to discharge, the effects of MTH were different in patients without DM (1.97 (1.70-2.29)) and patients with DM (1.23 (0.96-1.57)). CONCLUSION: DM modified the effect of MTH on survival and neurological outcomes for OHCA survivors. MTH is significantly associated with good neurological recovery in patients without DM, but not in patients with DM. PMID- 25725297 TI - Delayed and intermittent CPR for severe accidental hypothermia. AB - INTRODUCTION: Cardiac arrest (CA) in patients with severe accidental hypothermia (core temperature <28 degrees C) differs from CA in normothermic patients. Maintaining CPR throughout the prehospital period may be impossible, particularly during difficult evacuations. We have developed guidelines for rescuers who are evacuating and treating severely hypothermic CA patients. METHODS: A literature search was performed. The authors used the findings to develop guidelines. RESULTS: Full neurological recovery is possible even with prolonged CA if the brain was already severely hypothermic before CA occurred. Data from surgery during deep hypothermic CA and prehospital case reports underline the feasibility of delayed and intermittent CPR in patients who have arrested due to severe hypothermia. CONCLUSIONS: Continuous CPR is recommended for CA due to primary severe hypothermia. Mechanical chest-compression devices should be used when available and CPR-interruptions avoided. Only if this is not possible should CPR be delayed or performed intermittently. Based on the available data, a patient with a core temperature <28 degrees C or unknown with unequivocal hypothermic CA, evidence supports alternating 5 min CPR and <=5 min without CPR. With core temperature <20 degrees C, evidence supports alternating 5 min CPR and <=10 min without CPR. PMID- 25725298 TI - Out-of-hospital pediatric airway management in the United States. AB - OBJECTIVE: The objective of this study was to characterize pediatric out-of hospital airway management interventions, success rates, and complications in the United States using the 2012 National Emergency Medical Services Information System (NEMSIS) dataset. METHODS: In 2012, NEMSIS collected data from Emergency Medical Services (EMS) encounters in 40 states. We included all patients less than 18 years of age and identified all patients who had airway interventions including endotracheal intubation (ETI), bag-valve-mask ventilation (BVM), continuous positive airway pressure/bilevel positive airway pressure (CPAP/BiPAP) and alternate airways (Combitube, King LT, Laryngeal Mask Airway (LMA), esophageal obturator airway, and cricothyroidotomy). Success and complication rates were analyzed and compared across pediatric age groups, by race, ethnicity, clinical condition, and geographic region. RESULTS: We identified a total of 949,301 pediatric patient care events in the NEMSIS 2012 dataset. 4.5% had airway management procedures (42,936 events). Invasive airway management or ventilation (ETI, cricothyroidotomy, alternate airway, CPAP/BiPAP, BVM and other ventilation) took place in 1.5% of patient care events (14,107). Of those who had invasive airway management, 29.9% were less than 1 year of age, 58.1% were male, 42.3% were white, and 83.6% were in urban areas. ETI occurred in 3124 of patient care events (329 per 100,000; 95% CI 318-341). Overall success of ETI was 81.1% (95% CI 79.7-82.6). Lower success was noted in patients with cardiac arrest (75.5%, 95% CI 72.6-78.3) and those aged 1-12 months (72.1%, 95% CI 68.3-75.6). CONCLUSIONS: Out-of-hospital pediatric advanced airway procedures were infrequently performed. Success rates are lowest in patients aged 1-12 months. PMID- 25725299 TI - Triphenyl phosphate-induced developmental toxicity in zebrafish: potential role of the retinoic acid receptor. AB - Using zebrafish as a model, we previously reported that developmental exposure to triphenyl phosphate (TPP) - a high-production volume organophosphate-based flame retardant - results in dioxin-like cardiac looping impairments that are independent of the aryl hydrocarbon receptor. Using a pharmacologic approach, the objective of this study was to investigate the potential role of retinoic acid receptor (RAR) - a nuclear receptor that regulates vertebrate heart morphogenesis - in mediating TPP-induced developmental toxicity in zebrafish. We first revealed that static exposure of zebrafish from 5-72h post-fertilization (hpf) to TPP in the presence of non-toxic concentrations of an RAR antagonist (BMS493) significantly enhanced TPP-induced toxicity (relative to TPP alone), even though identical non-toxic BMS493 concentrations mitigated retinoic acid (RA)-induced toxicity. BMS493-mediated enhancement of TPP toxicity was not a result of differential TPP uptake or metabolism, as internal embryonic doses of TPP and diphenyl phosphate (DPP) - a primary TPP metabolite - were not different in the presence or absence of BMS493. Using real-time PCR, we then quantified the relative change in expression of cytochrome P450 26a1 (cyp26a1) - a major target gene for RA-induced RAR activation in zebrafish - and found that RA and TPP exposure resulted in a ~5-fold increase and decrease in cyp26a1 expression, respectively, relative to vehicle-exposed embryos. To address whether TPP may interact with human RARs, we then exposed Chinese hamster ovary cells stably transfected with chimeric human RARalpha-, RARbeta-, or RARgamma to TPP in the presence of RA, and found that TPP significantly inhibited RA-induced luciferase activity in a concentration-dependent manner. Overall, our findings suggest that zebrafish RARs may be involved in mediating TPP-induced developmental toxicity, a mechanism of action that may have relevance to humans. PMID- 25725300 TI - Hydroxylated polychlorinated biphenyls decrease circulating steroids in female polar bears (Ursus maritimus). AB - As a top predator in the Arctic food chain, polar bears (Ursus maritimus) are exposed to high levels of persistent organic pollutants (POPs). Because several of these compounds have been reported to alter endocrine pathways, such as the steroidogenesis, potential disruption of the sex steroid synthesis by POPs may cause implications for reproduction by interfering with ovulation, implantation and fertility. Blood samples were collected from 15 female polar bears in Svalbard (Norway) in April 2008. The concentrations of nine circulating steroid hormones; dehydroepiandrosterone (DHEA), androstenedione (AN), testosterone (TS), dihydrotestosterone (DHT), estrone (E1), 17alpha-estradiol (alphaE2), 17beta estradiol (betaE2), pregnenolone (PRE) and progesterone (PRO) were determined. The aim of the study was to investigate associations among circulating levels of specific POP compounds and POP-metabolites (hydroxylated PCBs [OH-PCBs] and hydroxylated PBDEs [OH-PBDEs]), steroid hormones, biological and capture variables in female polar bears. Inverse correlations were found between circulating levels of PRE and AN, and circulating levels of OH-PCBs. There were no significant relationships between the steroid concentrations and other analyzed POPs or the variables capture date and capture location (latitude and longitude), lipid content, condition and body mass. Although statistical associations do not necessarily represent direct cause-effect relationships, the present study indicate that OH-PCBs may affect the circulating levels of AN and PRE in female polar bears and that OH-PCBs thus may interfere with the steroid homeostasis. Increase in PRO and a decrease in AN concentrations suggest that the enzyme CYP17 may be a potential target for OH-PCBs. In combination with natural stressors, ongoing climate change and contaminant exposure, it is possible that OH-PCBs may disturb the reproductive potential of polar bears. PMID- 25725301 TI - Transcriptional profiling and biological pathway analysis of human equivalence PCB exposure in vitro: indicator of disease and disorder development in humans. AB - BACKGROUND AND AIMS: Our earlier gene-expression studies with a Slovak PCBs exposed population have revealed possible disease and disorder development in accordance with epidemiological studies. The present investigation aimed to develop an in vitro model system that can provide an indication of disrupted biological pathways associated with developing future diseases, well in advance of the clinical manifestations that may take years to appear in the actual human exposure scenario. METHODS: We used human Primary Blood Mononuclear Cells (PBMC) and exposed them to a mixture of human equivalence levels of PCBs (PCB-118, -138, -153, -170, -180) as found in the PCBs-exposed Slovak population. The microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (IPA) to associate the affected genes with their mechanistic pathways. High-throughput qRT PCR Taqman Low Density Array (TLDA) was done to further validate the selected 6 differentially expressed genes of our interest, viz., ARNT, CYP2D6, LEPR, LRP12, RRAD, TP53, with a small population validation sample (n=71). RESULTS: Overall, we revealed a discreet gene expression profile in the experimental model that resembled the diseases and disorders observed in PCBs-exposed population studies. The disease pathways included endocrine system disorders, genetic disorders, metabolic diseases, developmental disorders, and cancers, strongly consistent with the evidence from epidemiological studies. INTERPRETATION: These gene finger prints could lead to the identification of populations and subgroups at high risk for disease, and can pose as early disease biomarkers well ahead of time, before the actual disease becomes visible. PMID- 25725303 TI - MRI noise estimation and denoising using non-local PCA. AB - This paper proposes a novel method for MRI denoising that exploits both the sparseness and self-similarity properties of the MR images. The proposed method is a two-stage approach that first filters the noisy image using a non local PCA thresholding strategy by automatically estimating the local noise level present in the image and second uses this filtered image as a guide image within a rotationally invariant non-local means filter. The proposed method internally estimates the amount of local noise presents in the images that enables applying it automatically to images with spatially varying noise levels and also corrects the Rician noise induced bias locally. The proposed approach has been compared with related state-of-the-art methods showing competitive results in all the studied cases. PMID- 25725302 TI - Historical exposure to persistent organic pollutants and risk of incident hypertension. AB - The aim of this study was to assess the influence of adipose tissue concentrations of a group of persistent organic pollutants (POPs) on the risk of hypertension in an adult cohort of residents of Granada (Southern Spain) over a 10-year follow-up. No chemical was significantly associated with the risk of hypertension in the overall population or when models were stratified by sex or median age. However, we found positive associations between log-transformed POP concentrations and hypertension risk in participants with body mass index (BMI) above the median value of 26.3kg/m(2), which were statistically significant for hexachlorobenzene (HR=1.26, 95% CI=1.03-1.56), beta-hexachlorocyclohexane (HR=1.25, 95% CI=1.03-1.51), and polychlorinated biphenyl congeners -138 (HR=1.32, 95% CI=1.04-1.69) and -153 (HR=1.36, 95% CI=1.00-1.84). Inverse associations were observed in the subgroup with BMI<=26.3kg/m(2), but none was statistically significant. More research and a longer follow-up period are warranted to verify these associations and elucidate the role of obesity as a potential effect modifier. Given the elevated worldwide frequency of POP exposure and hypertension, the public health impact of this relationship may be substantial. PMID- 25725304 TI - Analysis of variations in band positions for normalization in across-gel denaturing gradient gel electrophoresis. AB - Variation in band position between gels is a well-known problem in denaturing gradient gel electrophoresis (DGGE). However, few reports have evaluated the degree of variation in detail. In this study, we investigated the variation in band positions of DNA samples extracted from soil, normalized using reference positions within marker lanes for DGGE in three organismal (bacterial, fungal, and nematode) conditions. For sample lanes, marker DNA (as a control) and sample DNA were used. The test for normality of distribution showed that the position data of a large percentage of bands were normally distributed but not for certain bands. For the normally-distributed data, their variations [standard deviation of marker bands (SDM) and standard deviation of sample bands (SDS), respectively] were assessed. For all organismal conditions, the degree of within-gel variation were similar between SDMs and SDSs, while between-gel variations in SDSs were larger than those in SDMs. Due to the large effect of between-gel variations, the total variations in SDSs were more varied between sample bands, and the mean variations of all sample bands were higher than those in the markers. We found that the total variation in the fungal and nematode SDSs decreased when the intervals between marker bands were narrowed, suggesting that band interval is important for reducing total variation in normalized band positions. For the non normally distributed data, the distribution was examined in detail. This study provided detailed information on the variation of band positions, which could help to optimize markers for reducing band position variation, and could aid in the accurate identification of bands in across-gel DGGE analyses. PMID- 25725305 TI - Transcriptomics of mRNA and egg quality in farmed fish: Some recent developments and future directions. AB - Maternal mRNA transcripts deposited in growing oocytes regulate early development and are under intensive investigation as determinants of egg quality. The research has evolved from single gene studies to microarray and now RNA-Seq analyses in which mRNA expression by virtually every gene can be assessed and related to gamete quality. Such studies have mainly focused on genes changing two to several-fold in expression between biological states, and have identified scores of candidate genes and a few gene networks whose functioning is related to successful development. However, ever-increasing yields of information from high throughput methods for detecting transcript abundance have far outpaced progress in methods for analyzing the massive quantities of gene expression data, and especially for meaningful relation of whole transcriptome profiles to gamete quality. We have developed a new approach to this problem employing artificial neural networks and supervised machine learning with other novel bioinformatics procedures to discover a previously unknown level of ovarian transcriptome function at which minute changes in expression of a few hundred genes is highly predictive of egg quality. In this paper, we briefly review the progress in transcriptomics of fish egg quality and discuss some future directions for this field of study. PMID- 25725306 TI - Anti-Ro/SSA antibodies and cardiac rhythm disturbances: Present and future perspectives. AB - Several case reports, small case series, and original research papers have recently suggested that the action of certain auto-antibodies related to connective tissue diseases may be responsible for significant cardiac rhythm disturbances in adults. The relationship between anti-Ro/SSA antibodies and congenital complete atrioventricular block is well recognized in the fetal heart. Herein we review the emerging evidences of the link to increased levels of anti Ro/SSA antibodies with rhythm disorders of unknown origin in the adult. Confirmation of this distinct etiology may eventually be the basis for new therapies. PMID- 25725307 TI - A comparison of stroke and coronary risks in Chinese and American. PMID- 25725308 TI - Innate immune perturbations, accumulating DAMPs and inflammasome dysregulation: A ticking time bomb in ageing. AB - Ageing has pronounced effects on the immune system, including on innate immune cells. Whilst most studies suggest that total numbers of different innate immune cell populations do not change dramatically during ageing, many of their functions such as phagocytosis, antigen presentation and inflammatory molecule secretion decline. In contrast, many endogenous damage-associated molecular patterns (DAMPs) accumulate during ageing. These include reactive oxygen species (ROS) released from damaged mitochondria, extracellular nucleotides like ATP, high mobility group box (HMGB) 1 protein, oxidized low density lipoprotein, amyloid-beta (Abeta), islet amyloid polypeptide and particulates like monosodium urate (MSU) crystals and cholesterol crystals. Some of these DAMPs trigger the activation of inflammasomes, cytosolic danger sensing signalling platforms that drive both the maturation of specific pro-inflammatory mediators such as IL 1beta, as well as the initiation of pro-inflammatory pyroptotic cell death. Herein, we review the evidence that dysregulated inflammasome activation, via altered innate immune cell functions and elevated levels of DAMPs, contributes to the establishment of chronic, low-grade inflammation (characterized by elevated levels of IL-6 and C-reactive protein) and the development of age-related pathological processes. PMID- 25725309 TI - Microfluidic-controlled manufacture of liposomes for the solubilisation of a poorly water soluble drug. AB - Besides their well-described use as delivery systems for water-soluble drugs, liposomes have the ability to act as a solubilizing agent for drugs with low aqueous solubility. However, a key limitation in exploiting liposome technology is the availability of scalable, low-cost production methods for the preparation of liposomes. Here we describe a new method, using microfluidics, to prepare liposomal solubilising systems which can incorporate low solubility drugs (in this case propofol). The setup, based on a chaotic advection micromixer, showed high drug loading (41 mol%) of propofol as well as the ability to manufacture vesicles with at prescribed sizes (between 50 and 450 nm) in a high-throughput setting. Our results demonstrate the ability of merging liposome manufacturing and drug encapsulation in a single process step, leading to an overall reduced process time. These studies emphasise the flexibility and ease of applying lab-on a-chip microfluidics for the solubilisation of poorly water-soluble drugs. PMID- 25725310 TI - Cultural-based biases of the GAD-7. AB - The GAD-7 is a popular measure of generalized anxiety disorder (GAD) symptoms that has been used across many cultural groups. Existing evidence demonstrates that the prevalence of GAD varies across self-identified ethnic/cultural groups, a phenomenon that some researchers attribute to cross-cultural measurement error rather than to actual differences in rates of GAD. Nonetheless, the effect of culture on factor structure and response patterns to the GAD-7 have not been examined and could result over- or under-estimated GAD-7 scores across different cultural groups. The current investigation assessed the factor structure of the GAD-7 in White/Caucasian, Hispanic, and Black/African American undergraduates and tested for cultural-based biases. A modified one-factor model exhibited good fit across subsamples. Results revealed that Black/African American participants with high GAD symptoms scored lower on the GAD-7 than other participants with similar GAD symptoms. Results highlight the need for culturally sensitive GAD screening tools. PMID- 25725311 TI - Cleaning of biomaterial surfaces: protein removal by different solvents. AB - The removal of biofilms or protein films from biomaterials is still a challenging task. In particular, for research investigations on real (applied) surfaces the reuse of samples is of high importance, because reuse allows the comparison of the same sample in different experiments. The aim of the present study was to evaluate the cleaning efficiency of different solvents (SDS, water, acetone, isopropanol, RIPA-buffer and Tween-20) on five different biomaterials (titanium, gold, PMMA (no acetone used), ceramic, and PTFE) with different wettability which were covered by layers of two different adsorbed proteins (BSA and lysozyme). The presence of a protein film after adsorption was confirmed by transmission electron microscopy (TEM). After treatment of the surfaces with the different solvents, the residual proteins on the surface were determined by BCA-assay (bicinchoninic acid assay). Data of the present study indicate that SDS is an effective solvent, but for several protein-substrate combinations it does not show the cleaning efficiency often mentioned in literature. RIPA-buffer and Tween 20 were more effective. They showed very low residual protein amounts after cleaning on all examined material surfaces and for both proteins, however, with small differences for the respective substrate-protein combinations. RIPA-buffer in combination with ultrasonication completely removed the protein layer as confirmed by TEM. PMID- 25725312 TI - Distribution, source characterization and inventory of perfluoroalkyl substances in Taihu Lake, China. AB - The levels, distribution, possible sources, and inventory of perfluoroalkyl acids (PFAAs) in the eutrophic freshwater Taihu Lake, East China were investigated in this study. Among the target 11 PFAAs, perfluorooctanoic acid (PFOA) (2.15-73.9 ng L(-1)) and perfluorohexanoic acid (PFHxA) (0.760, P<0.001), while there was no correlation with HDL-cholesterols. The levels of total cholesteryl ester were closely associated with triglyceride (r=0.763, P<0.001). Quantitative results indicate that childhood obesity may increase cholesterol synthesis while maintaining overall cholesterol homeostasis. PMID- 25725318 TI - Bisphenol A, 4-t-octylphenol, and 4-nonylphenol determination in serum by Hybrid Solid Phase Extraction-Precipitation Technology technique tailored to liquid chromatography-tandem mass spectrometry. AB - A rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and optimized for the simultaneous determination of bisphenol A, 4-t octylphenol and 4-nonylphenol in human blood serum. For the first time, the electrospray ionization (ESI) parameters of probe position, voltage potential, sheath gas flow rate, auxiliary gas flow rate, and ion transfer tube temperature were thoroughly studied and optimized for each phenol by a univariate approach. As a consequence, low instrumental limits of detection were reported, demonstrating at 0.2 ng/mL (in solvent matrix) excellent injection repeatability (RSD<14.5%) and a confirmation peak for all target phenols. Extraction and purification of serum was performed by the novel Hybrid Solid Phase Extraction Precipitation Technology technique (Hybrid SPE-PPT). The limits of detection in human blood serum were 0.80, 1.3 and 1.4 ng/mL for BPA, 4-t-OP and 4-NP, respectively. PMID- 25725316 TI - Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study. AB - OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels. METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-beta (TGF beta) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-beta and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998. RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-beta was associated with incident PAD (hazard ratio [HR] = 1.36 per doubling of TGF-beta, 95% confidence interval [CI] = 1.04, 1.78) and retinal venular diameter (1.63 MUm per doubling of TGF-beta, CI = 0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102 mm per doubling of PIIINP, CI = 0.029, 0.174) and impaired brachial artery reactivity (-0.20% change per doubling of PIIINP, CI = -0.39, 0.02). Neither TGF-beta nor PIIINP were associated with retinal arteriolar diameter or retinopathy. CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults. PMID- 25725319 TI - Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify serum voriconazole. AB - BACKGROUND: Voriconazole is an azole antifungal drug indicated for use in the treatment of invasive aspergillosis. Due to the large intra- and interindividual variation seen in voriconazole pharmacokinetics along with a high probability of drug-drug interactions, therapeutic drug monitoring is of considerable clinical value. As such, we developed and validated a LC-MS/MS assay to quantify serum voriconazole to improve turnaround time and decrease costs. METHODS: After protein precipitation with D3-voriconazole (deuterated internal standard) in acetonitrile was performed, samples were separated by gradient elution and injected into the mass spectrometer with a total run-time of 4 min per sample. Multiple reaction monitoring was employed using Q1/Q3 transitions of 350/127 and 350/281 for voriconazole and 353/284 and 353/127 for D3-voriconazole. RESULTS: Sample preparation took 30 min for 6 patient samples. The limit of quantitation was 0.1 MUg/mL and the linearity ranged from 0.1 MUg/mL to 10.0 MUg/mL. Extraction recovery was ~69% and ion suppression ~13%. Intra- and inter-assay imprecision (%CV) was <5% at the limit of quantitation and <4% through the rest of the linear range. Method comparisons between our assay and two reference laboratory methods, HPLC-UV and LC-MS/MS, revealed mean biases of 11% and 4%, respectively. CONCLUSIONS: We have developed an accurate, rapid, and sensitive LC MS/MS assay for quantification of human serum voriconazole. Our assay reduces current specimen volume requirements, decreases result turnaround time, and saves institutional funds. PMID- 25725320 TI - Simultaneous quantification of two canthinone alkaloids of Picrasma quassioides in rat plasma by liquid chromatography-tandem mass spectrometry and its application to a rat pharmacokinetic study. AB - Picrasma quassioides (D. Don) Benn. is used in traditional Chinese medicine for the treatment of inflammation. Characteristic components of the medicinal extract are canthinone alkaloids. In this study, a sensitive and rapid liquid chromatography with tandem mass spectrometry method has been developed for simultaneous quantification of two major canthinone alkaloids, 5-hydroxy-4 methoxycanthin-6-one and 4,5-dimethoxycanthin-6-one, in rat plasma after oral administration of P. quassioides extract (200 mg/kg). The chromatographic separation was performed on a C18 column using acetonitrile-aqueous 0.1% formic acid (90:10, v/v) as the mobile phase. Plasma samples were prepared for analysis using a simple liquid-liquid extraction with ethyl acetate. Analytes were detected using tandem mass spectrometry in positive multiple reaction monitoring mode. Method validation revealed excellent linearity over the range 1.25-900 ng/mL for 5-hydroxy-4-methoxycanthin-6-one and 0.5-800 ng/mL for 4,5 dimethoxycanthin-6-one with satisfactory intra- and inter-day precision, accuracy and recovery. Samples were stable under the conditions tested. The pharmacokinetic profiles of the analytes in rats showed that both canthinones were rapidly absorbed and that 4,5-dimethoxycanthin-6-one was eliminated faster than 5-hydroxy-4-methoxycanthin-6-one. PMID- 25725321 TI - Simultaneous determination of ezetimibe and its glucuronide metabolite in human plasma by solid phase extraction and liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was developed to quantify ezetimibe (EZM) and its major glucuronide (ezetimibe glucuronide, EZM G) in human plasma simultaneously. The analytes were purified by solid phase extraction (SPE) without hydrolysis. Separation of the analytes was achieved using acetonitrile-water (0.08% formic acid) (70:30, v/v) as the mobile phase at a flow rate of 0.8 mL/min on an Agilent Extend C18 column. The analytes were detected by LC-MS/MS using negative ionization in multiple reaction monitoring (MRM) mode. The mass transition pairs of m/z 408.4->271.0 and m/z 584.5->271.0 were used to detect EZM and EZM-G, respectively. The analytical method was linear over the concentration range of 0.1-20 ng/mL for EZM and 0.5-200 ng/mL for EZM-G. Within- and between-run precision for EZM was no more than 8.6% and 12.8%; and for EZM-G was no more than 9.0% and 8.7%, respectively. This method was reproducible and reliable, and was successfully used to analyze human plasma samples for application in a bioequivalence study. PMID- 25725322 TI - Comparative genome analysis of a thermotolerant Escherichia coli obtained by Genome Replication Engineering Assisted Continuous Evolution (GREACE) and its parent strain provides new understanding of microbial heat tolerance. AB - Heat tolerance of microbes is of great importance for efficient biorefinery and bioconversion. However, engineering and understanding of microbial heat tolerance are difficult and insufficient because it is a complex physiological trait which probably correlates with all gene functions, genetic regulations, and cellular metabolisms and activities. In this work, a novel strain engineering approach named Genome Replication Engineering Assisted Continuous Evolution (GREACE) was employed to improve the heat tolerance of Escherichia coli. When the E. coli strain carrying a mutator was cultivated under gradually increasing temperature, genome-wide mutations were continuously generated during genome replication and the mutated strains with improved thermotolerance were autonomously selected. A thermotolerant strain HR50 capable of growing at 50 degrees C on LB agar plate was obtained within two months, demonstrating the efficiency of GREACE in improving such a complex physiological trait. To understand the improved heat tolerance, genomes of HR50 and its wildtype strain DH5alpha were sequenced. Evenly distributed 361 mutations covering all mutation types were found in HR50. Closed material transportations, loose genome conformation, and possibly altered cell wall structure and transcription pattern were the main differences of HR50 compared with DH5alpha, which were speculated to be responsible for the improved heat tolerance. This work not only expanding our understanding of microbial heat tolerance, but also emphasizing that the in vivo continuous genome mutagenesis method, GREACE, is efficient in improving microbial complex physiological trait. PMID- 25725324 TI - Is dream recall underestimated by retrospective measures and enhanced by keeping a logbook? A review. AB - There are two methods commonly used to measure dream recall in the home setting. The retrospective method involves asking participants to estimate their dream recall in response to a single question and the logbook method involves keeping a daily record of one's dream recall. Until recently, the implicit assumption has been that these measures are largely equivalent. However, this is challenged by the tendency for retrospective measures to yield significantly lower dream recall rates than logbooks. A common explanation for this is that retrospective measures underestimate dream recall. Another is that keeping a logbook enhances it. If retrospective measures underestimate dream recall and if logbooks enhance it they are both unlikely to reflect typical dream recall rates and may be confounded with variables associated with the underestimation and enhancement effects. To date, this issue has received insufficient attention. The present review addresses this gap in the literature. PMID- 25725323 TI - The eye movement measure of memory and its relationship with explicit measures. AB - This study examined whether the eye movement can be used to measure memory of past events and its relationship with the explicit measures. In Experiment 1, after studying a list of Chinese characters, the participants received a recognition memory test. For each trial the participants had to indicate, among one studied character and two nonstudied homonyms, which character they had studied. Participants' eye movements were monitored while they viewed the three character test display. Both the time-course and response-locked measures showed that participants viewed the studied character longer than the nonstudied character regardless of their explicit response. Experiment 2 used a wagering task to assess participants' conscious awareness and found that wagering points predicted viewing time for the target better than the recognition accuracy did. These findings suggest that the effect of memory on viewing time occurs automatically and is weakly associated with subsequent conscious awareness of the studied event. PMID- 25725325 TI - Colour vision in marine organisms. AB - Colour vision in the marine environment is on average simpler than in terrestrial environments with simple or no colour vision through monochromacy or dichromacy. Monochromacy is found in marine mammals and elasmobranchs, including whales and sharks, but not some rays. Conversely, there is also a greater diversity of colour vision in the ocean than on land, examples being the polyspectral stomatopods and the many colour vision solutions found among reef fish. Recent advances in sequencing reveal more opsin (visual pigment) types than functionally useful at any one time. This diversity arises through opsin duplication and conversion. Such mechanisms allow pick-and-mix adaptation that tunes colour vision on a variety of very short non-evolutionary timescales. At least some of the diversity in marine colour vision is best explained as unconventional colour vision or as neutral drift. PMID- 25725326 TI - Studying the response of a plastic scintillator to gamma rays using the Geant4 Monte Carlo code. AB - To determine the gamma ray response function of an NE-102 scintillator and to investigate the gamma spectra due to the transport of optical photons, we simulated an NE-102 scintillator using Geant4 code. The results of the simulation were compared with experimental data. Good consistency between the simulation and data was observed. In addition, the time and spatial distributions, along with the energy distribution and surface treatments of scintillation detectors, were calculated. This simulation makes us capable of optimizing the photomultiplier tube (or photodiodes) position to yield the best coupling to the detector. PMID- 25725327 TI - Sudden unexpected death in children with epilepsy: focus on dietary supplementation with omega-3 polyunsaturated fatty acids. PMID- 25725328 TI - Perceptions of epilepsy surgery: a systematic review and an explanatory model of decision-making. AB - BACKGROUND: Clear evidence supports the benefits of surgery over medical therapy for patients with refractory focal epilepsy. Surgical procedures meet the needs of fewer than 2% of those eligible. Referral to a tertiary epilepsy center early in the course of disease is recommended; however, patients live with disabling and life-threatening seizures for an average of 22years before considering surgical treatment. Reasons for this treatment gap are unclear. PURPOSE: A critical analysis of the literature addressing perceptions of surgical treatment for epilepsy is placed in the context of a brief history and current treatment guidelines. Common conceptual themes shaping perceptions of epilepsy surgery are identified. DATA SOURCES: Data sources used for this study were PubMed-MEDLINE and PsycINFO from 2003 to December 2013; hand searches of reference lists. DATA SYNTHESIS: Nine papers that addressed patient perceptions of surgery for epilepsy and three papers addressing physician attitudes were reviewed. Treatment misperceptions held by both patients and physicians lead to undertreatment and serious health consequences. Fear of surgery, ignorance of treatment options, and tolerance of symptoms emerge as a triad of responses central to weighing treatment risks and benefits and, ultimately, to influencing treatment decision making. Our novel explanatory framework serves to illustrate and explain relationships among contributory factors. LIMITATION: Comparisons across studies are limited by the heterogeneity of study populations and by the fact that no instrument has been developed to consistently measure disability in refractory focal epilepsy. CONCLUSION: Exploring the components of decision-making for the management of refractory focal epilepsy from the patient's perspective presents a new angle on a serious contemporary challenge in epilepsy care and may lead to explanation as to why there is reluctance to embrace a safe and effective treatment. PMID- 25725329 TI - A European survey on current practices in epilepsy monitoring units and implications for patients' safety. AB - OBJECTIVE: This study aimed to survey current practices in European epilepsy monitoring units (EMUs) with emphasis on safety issues. METHODS: A 37-item questionnaire investigating characteristics and organization of EMUs, including measures for prevention and management of seizure-related serious adverse events (SAEs), was distributed to all identified European EMUs plus one located in Israel (N=150). RESULTS: Forty-eight (32%) EMUs, located in 18 countries, completed the questionnaire. Epilepsy monitoring unit beds are 1-2 in 43%, 3-4 in 34%, and 5-6 in 19% of EMUs; staff physicians are 1-2 in 32%, 3-4 in 34%, and 5-6 in 19% of EMUs. Personnel operating in EMUs include epileptologists (in 69% of EMUs), clinical neurophysiologists trained in epilepsy (in 46% of EMUs), child neurologists (in 35% of EMUs), neurology and clinical neurophysiology residents (in 46% and in 8% of EMUs, respectively), and neurologists not trained in epilepsy (in 27% of EMUs). In 20% of EMUs, patients' observation is only intermittent or during the daytime and primarily carried out by neurophysiology technicians and/or nurses (in 71% of EMUs) or by patients' relatives (in 40% of EMUs). Automatic detection systems for seizures are used in 15%, for body movements in 8%, for oxygen desaturation in 33%, and for ECG abnormalities in 17% of EMUs. Protocols for management of acute seizures are lacking in 27%, of status epilepticus in 21%, and of postictal psychoses in 87% of EMUs. Injury prevention consists of bed protections in 96% of EMUs, whereas antisuffocation pillows are employed in 21%, and environmental protections in monitoring rooms and in bathrooms are implemented in 38% and in 25% of EMUs, respectively. The most common SAEs were status epilepticus reported by 79%, injuries by 73%, and postictal psychoses by 67% of EMUs. CONCLUSIONS: All EMUs have faced different types of SAEs. Wide variation in practice patterns and lack of protocols and of precautions to ensure patients' safety might promote the occurrence and severity of SAEs. Our findings highlight the need for standardized and shared protocols for an effective and safe management of patients in EMUs. PMID- 25725330 TI - A technique to remove a stable all-polyethylene cemented acetabular liner in revision hip arthroplasty: A case report. AB - INTRODUCTION: The removal of a well-fixed acetabular component in a total hip arthroplasty can cause bone fractures, excessive bleeding, as well as extended bone loss. The reimplantation of a new acetabular component may be compromised. PRESENTATION OF CASE: We report a technique using 2 cork-screws for removal a stable cemented acetabular component for the treatment of a recurrent dislocation of a cemented total hip arthroplasty, due to acetabular malposition. DISCUSSION: A diversity of approaches and tools has been used for extraction of the acetabular prosthesis. Using 2 cork-screws it is possible to create fissures and fractures into the cement mantle, and greater manual control is obtained facilitating the manipulation of the acetabular component in different directions. The cup-cemented bond can be disrupted, the host bone is preserved and the risks of complications are minimized. CONCLUSION: This technique is simple, available in any environment, reproducible, non-costly, non-timing consuming and safe. PMID- 25725331 TI - Primary ectopic frontotemporal craniopharyngioma. AB - INTRODUCTION: Primary ectopic craniopharyngiomas have only rarely been reported. Craniopharyngiomas involve usually the sellar and suprasellar region, but can be originated from cell remnants of the obliterated craniopharyngeal duct or metaplastic change of andenohypophyseal cells. We present the first case of a primary ectopic frontotemporal craniopharyngioma. PRESENTATION OF CASE: A 35-year old woman presented with a one-year history of headache and diplopia. MRI showed a large frontotemporal cystic lesion. Tumor resection was performed with a keyhole endoscopic frontal lateral approach. The pathological features showed an adamantinomatous craniopharyngioma with a cholesterol granuloma reaction. DISCUSSION: There have been reported different localizations for primary ectopic craniopharyngioma. Our case presented a lobulated frontotemporal cystic mass formed by a dense eosinophilic proteinaceous material dystrophic calcifications and cholesterol crystals, with epithelial remnants. No tumor regrowth was observed in the magnetic resonance image 27 months postoperatively. CONCLUSION: Primary ectopic craniopharyngioma is a rare entity with a pathogenesis that remains uncertain. This is an unusual anatomic location associated with unique clinical findings. PMID- 25725332 TI - GraphVar: a user-friendly toolbox for comprehensive graph analyses of functional brain connectivity. AB - BACKGROUND: Graph theory provides a powerful and comprehensive formalism of global and local topological network properties of complex structural or functional brain connectivity. Software packages such as the Brain-Connectivity Toolbox have contributed to graph theory's increasing popularity for characterization of brain networks. However, comparably comprehensive packages are command-line based and require programming experience; this precludes their use by users without a computational background, whose research would otherwise benefit from graph-theoretical methods. NEW METHOD: "GraphVar" is a user-friendly GUI-based toolbox for comprehensive graph-theoretical analyses of brain connectivity, including network construction and characterization, statistical analysis on network topological measures, network based statistics, and interactive exploration of results. RESULTS: GraphVar provides a comprehensive collection of graph analysis routines for analyses of functional brain connectivity in one single toolbox by combining features across multiple currently available toolboxes, such as the Brain Connectivity Toolbox, the Graph Analysis Toolbox, and the Network Based Statistic Toolbox (BCT, Rubinov and Sporns, 2010; GAT, Hosseini et al., 2012; NBS, Zalesky et al., 2010). GraphVar was developed under the GNU General Public License v3.0 and can be downloaded at www.rfmri.org/graphvar or www.nitrc.org/projects/graphvar. COMPARISON WITH EXISTING METHODS: By combining together features across multiple toolboxes, GraphVar will allow comprehensive graph-theoretical analyses in one single toolbox without resorting to code. CONCLUSIONS: GraphVar will make graph theoretical methods more accessible for a broader audience of neuroimaging researchers. PMID- 25725333 TI - Encapsulation of testosterone and its aliphatic and aromatic dimers by milk beta lactoglobulin. AB - The encapsulation of testosterone and it aliphatic dimer (alip) and aromatic dimer (arom) with milk beta-lactoglobulin (beta-LG) was studied in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize testosterone beta-LG binding and protein aggregation process. Spectroscopic analysis showed that steroids bind beta-LG via hydrophobic and H-bonding interactions with overall binding constants K test-beta-LG = 5.6 (+/- 0.6) * 10(4)M(-1), K test dimeralip-beta-LG = 4.8 (+/- 0.5) * 10(3)M(-1) and K test-dimer-arom-beta-LG = 2.9 (+/- 0.4) * 10(4)M(-1). The binding affinity was testosterone > testosterone dimer-aromatic > testosterone dimer-aliphatic. Transmission electron microscopy showed major changes in protein morphology as testosterone-protein complexation occurred with increase in the diameter of the protein aggregate indicating encapsulation of steroids by beta-LG. Modeling showed the presence of H-bonding stabilized testosterone-beta-LG complexes with the free binding energy of -9.82 Kcal/mol indicating that the interaction process is spontaneous at room temperature. PMID- 25725334 TI - Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice. AB - Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour. PMID- 25725335 TI - The neuroprotective effect of a novel agent N2 on rat cerebral ischemia associated with the activation of PI3K/Akt signaling pathway. AB - Ischemic stroke is the third leading cause of death and the main reason for severe disabilities in the world today. N2, 4 - (2 - (1H - imidazol - 1 - yl) ethoxy) - 3 - methoxybenzoic acid is considered as a novel potent agent for cerebral ischemia due to its effect in preventing neuronal cell death after ischemic stroke. In the present study, we investigated the post-ischemic neuroprotective effect of N2 and its underlying mechanisms. Using a MCAO rat model, we found that N2 reversed brain infarct size, reduced cerebral edema and decreased the neurological deficit score significantly. Moreover, N2 diminished TUNEL positive cells, down-regulated bax expression and up-regulated bcl-2 expression notably. In addition, we evaluated the oxygen glucose deprivation/reoxygenation (OGD/R) injury induced neuron cell death in rat primary cortical neuron and assessed the neuroprotective effect of our drug. N2 increased cell viability, ameliorated neuron cell injury by decreasing LDH activity, and inhibited cell apoptotic rate while suppressed apoptotic signaling via inhibiting the bax expression, and elevating the bcl-2 expression. Furthermore, the neuroprotective effect of N2 was associated with the PI3K/Akt pathway which was proved by the use of PI3K inhibitor LY294002. The combination of our findings disclosed that N2 can be used as an effective neuroprotective agent for ischemic stroke due to its significant effect on preventing neuronal cell death after cerebral ischemia both in vivo and in vitro and the effectiveness was dose dependent. PMID- 25725337 TI - Long-term toxic effects of deltamethrin and fenvalerante in soil. AB - In this study, the long-term toxic effects of pyrethroids on the earthworm Eisenia fetida were evaluated. Earthworms were exposed to moist filter paper and soil for 14 days to evaluate the survival, exposed to soil for 56 days to assess the reproductive success and for 28 days to identify the cytotoxicity. Results showed that the earthworm survival rate decreased with increasing the concentration of either deltamethrin or fenvalerate in both filter paper test and soil test. No worms survived at 602.15 MUg cm(-2) of deltamethrin and 0.86 MUg cm(-2) of fenvalerate in the filter paper test, however 100-125 mg kg(-1) of both chemicals resulted in the maximum mortality of 90% in the soil test. The CYP3A4 enzyme activity responded significantly to deltamethrin and fenvalerante in soil at low concentration levels, however, the toxicity response of worms under the long-term exposure conflicted with the degradation of deltamethrin and fenvalerate in soil, indicating the possible formation of more toxic pyrethroid metabolites. This study gave an insight into the toxicological effects profile of pyrethroids for a better risk assessment of pyrethroids deltamethrin and fenvalerante in soil. PMID- 25725336 TI - Role of alpha5-containing nicotinic receptors in neuropathic pain and response to nicotine. AB - Nicotinic receptors in the central nervous system (nAChRs) are known to play important roles in pain processing and modulate behavioral responses to analgesic drugs, including nicotine. The presence of the alpha5-neuronal nicotinic accessory subunit in the nicotinic receptor complex is increasingly understood to modulate reward and aversive states, addiction, and possibly pathological pain. In the current study, using alpha5-knockout (KO) mice and subunit-specific antibodies, we assess the role of alpha5-containing neuronal nicotinic receptors in neuropathic pain and in the analgesic response to nicotine. After chronic constriction injury (CCI) or partial sciatic nerve ligation (PSNL), no differences in mechanical, heat, or cold hyperalgesia were found in wild-type (WT) versus alpha5-KO littermate mice. The number of alpha5-containing nAChRs was decreased (rather than increased) after CCI in the spinal cord and in the thalamus. Nevertheless, thermal analgesic response to nicotine was marginally reduced in CCI alpha5-KO mice at 4 days after CCI, but not at later timepoints or after PSNL. Interestingly, upon daily intermittent nicotine injections in unoperated mice, WT animals developed tolerance to nicotine-induced analgesia to a larger extent than alpha5-KO mice. Our results suggest that alpha5-containing nAChRs mediate analgesic tolerance to nicotine but do not play a major role in neuropathic pain. PMID- 25725338 TI - Controlled leaching with prolonged activity for Co-LDH supported catalyst during treatment of organic dyes using bicarbonate activation of hydrogen peroxide. AB - The effluents from industries are commonly non-biodegradable and produce various hazardous intermediate products by chemical reactions that have direct impact on environment. In the present investigation, a series of Co-Mg/AL ternary LDH catalysts with fixed Mg/Al ratio were prepared by co-precipitation method. The effect of Co on the activity of the catalyst was monitored on the degradation of methylene blue (MB) as model compound at batch level using bicarbonate activation of H2O2 (BAP) system. On bench level, the best CoMgAl-4 catalyst can completely decolorize both methylene blue (MB) and methylene orange (MO) in short time, while in fixed bed, the catalyst was found stable for over 300 h with nearly 100% decolorization and excellent chemical oxygen demand (COD) removal. No leaching of Co was detected for the entire fixed experiment which may be accounted for long life stability and good activity of the catalyst. The ternary LDH catalysts were characterized by AES, XRD, FTIR, BET, and SEM for its compositional, phase structure, optical properties, textural, and surface morphology respectively. The XRD analysis confirmed characteristic pattern of hydrotalcite like structures without impurity phases. The formation of superoxide and hydroxyl radical as ROS was proposed with CoMgAl-4 by radical's scavengers. PMID- 25725339 TI - Polyvinyl alcohol-immobilized Phanerochaete chrysosporium and its application in the bioremediation of composite-polluted wastewater. AB - A novel biosorbent, polyvinyl alcohol (PVA)-immobilized Phanerochaete chrysosporium, was applied to the bioremediation of composite-polluted wastewater, containing both cadmium and 2,4-dichlorophenol (2,4-DCP). The optimum removal efficiency achieved was 78% for Cd(II) and 95.4% for 2,4-DCP at initial concentrations of 20 mg/L Cd(II) and 40 mg/L 2,4-DCP. PPBs had significantly enhanced the resistance of P. chrysosporium to 2,4-DCP, leading to the degradation rates of 2,4-DCP beyond 90% with varying initial 2,4-DCP concentrations. This research demonstrated that 2,4-DCP and secreted proteins might be used as carbon and nitrogen sources by PVA-immobilized P. chrysosporium beads (PPBs) for Cd(II) removal. Fourier transform infrared spectroscopy analysis showed that hydroxyl and carboxyl groups on the surface of PPBs were dominant in Cd(II) binding. The mechanism underlying the degradation of 2,4-DCP into fumaric acid and 1-hexanol was investigated. The adsorption-desorption studies indicated that PPBs kept up to 98.9% of desorption efficiency over three cycles. PMID- 25725340 TI - Development of an activated carbon filter to remove NO2 and HONO in indoor air. AB - To obtain the optimum removal efficiency of NO2 and HONO by coated activated carbon (ACs), the influencing factors, including the loading rate, metal and non metal precursors, and mixture ratios, were investigated. The NOx removal efficiency (RE) for K, with the same loading (1.0 wt.%), was generally higher than for those loaded with Cu or Mn. The RE of NO2 was also higher when KOH was used as the K precursor, compared to other K precursors (KI, KNO3, and KMnO4). In addition, the REs by the ACs loaded with K were approximately 38-55% higher than those by uncoated ACs. Overall, the REs (above 95%) of HONO and NOx with 3% KOH were the highest of the coated AC filters that were tested. Additionally, the REs of NOx and HONO using a mixing ratio of 6 (2.5% PABA (p-aminobenzoic acid)+6% H3PO4):4 (3% KOH) were the highest of all the coatings tested (both metal and non metal). The results of this study show that AC loaded with various coatings has the potential to effectively reduce NO2 and HONO levels in indoor air. PMID- 25725341 TI - Variation in arsenic accumulation and translocation among wheat cultivars: the relationship between arsenic accumulation, efflux by wheat roots and arsenate tolerance of wheat seedlings. AB - Fifty-seven wheat cultivars were used to investigate the differences in arsenic (As) accumulation, efflux and translocation among wheat cultivars and their relationship with arsenate (As(V)) tolerance under hydroponic condition. The relationship between wheat root As accumulation, As(V) uptake, arsenite (As(III)) efflux and As(V) tolerance of 14 wheat cultivars were also investigated. The results showed there were significant (p<0.001) differences in As(V) tolerance, As accumulation and translocation among 57 wheat cultivars. Arsenate tolerance of wheat seedlings was positively correlated with As(V) uptake (p<0.05), root As concentration (p<0.001), but negatively correlated (p<0.05) with TFs and relative As(III) efflux. No significant correlation between As(III) efflux and As(V) tolerance was found (p=0.442). 56-83% of total As taken up by roots was extruded to nutrient solution. Root As concentration was positively correlated with As(V) uptake (not significant, p=0.100), negatively correlated (p<0.001) with relative As(III) efflux, whereas not significantly correlated (p=0.773) with As(III) efflux. The results indicated that As(V) tolerant wheat cultivars have much higher capacity of root As accumulation. Arsenic detoxification in root cells is important for wheat seedlings under As(V) exposure. PMID- 25725342 TI - A new integrated evaluation method of heavy metals pollution control during melting and sintering of MSWI fly ash. AB - Evaluations of technologies for heavy metal control mainly examine the residual and leaching rates of a single heavy metal, such that developed evaluation method have no coordination or uniqueness and are therefore unsuitable for hazard control effect evaluation. An overall pollution toxicity index (OPTI) was established in this paper, based on the developed index, an integrated evaluation method of heavy metal pollution control was established. Application of this method in the melting and sintering of fly ash revealed the following results: The integrated control efficiency of the melting process was higher in all instances than that of the sintering process. The lowest integrated control efficiency of melting was 56.2%, and the highest integrated control efficiency of sintering was 46.6%. Using the same technology, higher integrated control efficiency conditions were all achieved with lower temperatures and shorter times. This study demonstrated the unification and consistency of this method. PMID- 25725343 TI - Interaction of toxic azo dyes with heme protein: biophysical insights into the binding aspect of the food additive amaranth with human hemoglobin. AB - A biophysical study on the interaction of the food colorant amaranth with hemoglobin was undertaken. Spectrophotometric and spectrofluorimetric studies proposed for an intimate binding interaction between the dye and the protein. The dye quenched the fluorescence of the protein remarkably and the mechanism of quenching was found to be static in nature. Synchronous fluorescence studies suggested that the polarity around the tryptophan residues was altered in the presence of amaranth whereas the polarity around tyrosine residues remained largely unaltered. 3D fluorescence, FTIR and circular dichroism results suggested that the binding reaction caused conformational changes in hemoglobin. The negative far-UV CD bands exhibited a significantly large decrease in magnitude in the presence of amaranth. From calorimetry studies it was established that the binding was driven by a large positive entropic contribution and a small but favorable enthalpy change. PMID- 25725344 TI - Modified natural diatomite and its enhanced immobilization of lead, copper and cadmium in simulated contaminated soils. AB - Natural diatomite was modified through facile acid treatment and ultrasonication, which increased its electronegativity, and the pore volume and surface area achieved to 0.211 cm(3) g(-1) and 76.9 m(2) g(-1), respectively. Modified diatomite was investigated to immobilize the potential toxic elements (PTEs) of Pb, Cu and Cd in simulated contaminated soil comparing to natural diatomite. When incubated with contaminated soils at rates of 2.5% and 5.0% by weight for 90 days, modified diatomite was more effective in immobilizing Pb, Cu and Cd than natural diatomite. After treated with 5.0% modified diatomite for 90 days, the contaminated soils showed 69.7%, 49.7% and 23.7% reductions in Pb, Cu and Cd concentrations after 0.01 M CaCl2 extraction, respectively. The concentrations of Pb, Cu and Cd were reduced by 66.7%, 47.2% and 33.1% in the leaching procedure, respectively. The surface complexation played an important role in the immobilization of PTEs in soils. The decreased extractable metal content of soil was accompanied by improved microbial activity which significantly increased (P<0.05) in 5.0% modified diatomite-amended soils. These results suggested that modified diatomite with micro/nanostructured characteristics increased the immobilization of PTEs in contaminated soil and had great potential as green and low-cost amendments. PMID- 25725345 TI - The distribution of sialic acid receptors of avian influenza virus in the reproductive tract of laying hens. AB - The susceptibility of the host to influenza virus is determined by the distribution of the sialic acid (SA) receptors on host cell membrane. Avian influenza virus (AIV) preferentially binds to SA alpha-2,3-galactose (SA alpha2,3 gal) linked receptors, while human strains bind to sialic acid alpha2,6-galactose (SA alpha2,6-gal) linked receptors. Here, we describe the SA patterns and distributions in the reproductive tract of hens by employing two specific lectins, Maackia amurensis agglutinin (MAA) for SA alpha2,3-gal and sambucus nigra agglutinin (SNA) for SA alpha 2,6-gal receptors. Our results revealed that both SA alpha2,3-gal and SA alpha2,6-gal receptors exist in the reproductive tract of hens, including magnum, isthmus, uterus and vagina except for infundibulum. The distribution of SAalpha-2,3-gal receptor was more abundantly in the columnar epithelium cells of magnum, isthmus and uterus. Only minimal positive results for SA alpha-2,6-gal receptors were detected in the columnar epithelium cells of magnum, isthmus, uterus and vagina. Furthermore, AIV in tissues of the reproductive tract tissues of laying hens were detected by SYBR green-based reverse transcription and polymerase chain reaction (RT-PCR). Results showed that both viral loads and pathological changes in different parts of the reproductive tract were positively correlated with the expression of both receptors. Our results revealed that the reproductive tract of hens may provide an environment for the replication of both avian and human influenza viruses. PMID- 25725346 TI - Relationship between aggregation of rewards and the possibility of polymorphism in continuous snowdrift games. AB - The existence of intra-population variations in cooperation level has often been reported by some empirical studies. Evolutionary conditions of polymorphism in cooperation have been investigated by using a framework of the continuous snowdrift game. However, our insights from this framework have been limited because of an assumption that the cooperative reward is a function of total amount of investments within an interacting group. In many cases, payoffs may actually depend on the interactions between the effects of such investments, such as members share the sum of beneficial effects that are individually produced from their own investments. Alternatively, payoffs may depend multiplicatively on investment, such as when investments are complementary. In the present paper, we investigated the influence of such difference on the evolution of cooperation with respect to three aspects of the aggregating process of individuals' contributions for reward, i.e. (i) additive or multiplicative, (ii) aggregation of either investments or effects, and (iii) promotion of advantage or suppression of disadvantage. We analytically show that the possibilities of the emergence of polymorphism are different depending on the type of aggregation process classified from these three aspects. Polymorphism of cooperation level never emerges unless the aggregation process is the aggregation of investment or the multiplicative aggregation of effect with suppression of disadvantage. Our results show the necessary condition for the emergence of polymorphic cooperation levels that are observed in various taxonomic groups. PMID- 25725347 TI - Cue-based and algorithmic learning in common carp: A possible link to stress coping style. AB - Common carp that had been screened for stress coping style using a standard behavioural test (response to a novel environment) were given a learning task in which food was concealed in one of two compartments, its location randomised between trials and its presence in a given compartment signalled by either a red or a yellow light. All the fish learned to find food quickly, but did so in different ways. Fifty five percent learned to use the light cue to locate food; the remainder achieved the same result by developing a fixed movement routine. To explore this variation, we related learning strategy to stress coping style. Time to find food fell identically with successive trials in carp classified as reactive or proactive, but reactive fish tended to follow the light cue and proactive fish to adopt a fixed routine. Among fish that learned to follow the light, reactive individuals took fewer trials to reach the learning criterion than did proactive fish. These results add to the growing body of information on within-species variation in learning strategies and suggest a possible influence of stress coping style on the use of associative learning as opposed to algorithmic searching during foraging. PMID- 25725348 TI - The perception of regularity in an isochronous stimulus in zebra finches (Taeniopygia guttata) and humans. AB - Perceiving temporal regularity in an auditory stimulus is considered one of the basic features of musicality. Here we examine whether zebra finches can detect regularity in an isochronous stimulus. Using a go/no go paradigm we show that zebra finches are able to distinguish between an isochronous and an irregular stimulus. However, when the tempo of the isochronous stimulus is changed, it is no longer treated as similar to the training stimulus. Training with three isochronous and three irregular stimuli did not result in improvement of the generalization. In contrast, humans, exposed to the same stimuli, readily generalized across tempo changes. Our results suggest that zebra finches distinguish the different stimuli by learning specific local temporal features of each individual stimulus rather than attending to the global structure of the stimuli, i.e., to the temporal regularity. PMID- 25725349 TI - Dimethyl fumarate attenuates cerebral edema formation by protecting the blood brain barrier integrity. AB - Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema. PMID- 25725350 TI - Development of stage-dependent glycans on the Fc domains of IgG antibodies of ALS animals. AB - We recently revealed a unique glycan on the Fc domain of IgG antibodies in ALS patients that mediates antibody-dependent cell cytotoxicity (ADCC). This glycan has a bi-antennary structure that lacks the core fucose and sialic acid residues but contains a bisecting GlcNAc (A2BG2). Little is known, however, about the incidence of A2BG2 expression and IgG cytotoxicity under ALS conditions within well-defined clinical stages. Here, we characterize the IgG antibodies produced in ALS Tg mice by detecting intra- and extra-cellular antigens of motor neurons that express different glycan patterns during the disease. The increased number of innate immune cells found at the disease onset was insufficient to induce an optimal systemic T-cell response. Nevertheless, IgG antibodies were produced against intracellular antigens at the pre-symptomatic stage in the secondary lymphoid organs under the conditions of a poor systemic immune response. Moreover, while the glycosyltransferases of plasma B-cells that synthesize the Fc glycans were regulated by IL-2 or IL-4, the observed glycosyltransferase pattern did not match that found in ALS Tg mice. We further found that A2BG2 glycan is specific for ALS, its quantity increased with disease progression and that the IgG antibodies identifying extracellular motor neuron antigens were developed at the final stage of the disease. Therefore, the most effective ADCC of motor neurons was observed at the end stage of the disease. We conclude that in ALS, IgG antibodies are produced despite the poor systemic immune response and that the frequency and quantity of A2BG2 glycan expression on the Fc domain depends on the clinical stage. Therefore, A2BG2 is a potential prognostic biomarker for ALS. PMID- 25725351 TI - Regeneration of sensory but not motor axons following visceral nerve injury. AB - Following peripheral nerve injury, restoration of function may occur via the regeneration of injured axons or compensatory sprouting of spared axons. Injury to visceral nerves that control urogenital organs is a common consequence of pelvic surgery, however their capacity to reinnervate organs is poorly understood. To determine if and how sensory and motor connections to the bladder are re-established, a novel surgical model of visceral nerve injury was performed unilaterally in adult male Wistar rats. Bladder-projecting motor and sensory neurons in pelvic ganglia and lumbosacral dorsal root ganglia, respectively, were identified and characterised by retrograde tracing and immunofluorescence. Application of tracers ipsi- and contralateral to injury distinguished the projection pathways of new connections in the bladder. In naive animals, the majority of sensory and motor neurons project ipsilaterally to the bladder, while ~20 % project contralaterally and ~5 % bilaterally. Injured axons of motor neurons were unable to regenerate by 4weeks after transection. In contrast, by this time many injured sensory neurons regrew axons to reform a substantial plexus within the detrusor and suburothelial tissues. These regeneration responses were also indicated by upregulation of activating transcription factor 3 (ATF-3), which was sustained in motor neurons but transient in sensory bladder projecting neurons. Axotomy had little or no effect on the survival of bladder projecting sensory and motor neurons. We also found evidence that uninjured motor and sensory neurons develop additional projections to the denervated bladder tissue and return connectivity, likely by undergoing compensatory growth. In conclusion, our results show that visceral sensory and motor neurons have a different capacity to regenerate axons following axotomy, however in both components of the circuit uninjured bladder neurons spontaneously grow new axon collaterals to replace the lost terminal field within the organ. For a full functional recovery, understanding the environmental and cellular mechanisms that reduce the ability of pelvic ganglion cells to undergo axonal regeneration is needed. PMID- 25725352 TI - Statistical considerations for preclinical studies. AB - Research studies must always have proper planning, conduct, analysis and reporting in order to preserve scientific integrity. Preclinical studies, the first stage of the drug development process, are no exception to this rule. The decision to advance to clinical trials in humans relies on the results of these studies. Recent observations show that a significant number of preclinical studies lack rigor in their conduct and reporting. This paper discusses statistical aspects, such as design, sample size determination, and methods of analyses, that will help add rigor and improve the quality of preclinical studies. PMID- 25725353 TI - Reduced photoreceptor death and improved retinal function during retinal degeneration in mice lacking innate immunity adaptor protein MyD88. AB - The injury inflammatory response mediated by the innate immune system is an important contributor to neurodegeneration in the central nervous system (CNS) and retina. A major branch of the innate immune system is regulated by the Toll like receptors (TLRs), which are receptors for endogenous damage associated molecules released from injured cells as well as pathogen-derived molecules, and interleukin-1 receptors (IL-1R), which are activated by IL-1alpha, IL-1beta and IL-18 cytokines. TLRs and IL-1R are expressed on immune and non-immune cell types and act as first responders to cell damage, which results in tissue repair, or inflammation and apoptosis. Both TLR and IL-1R require the adaptor protein myeloid differentiation primary response gene 88 (MyD88) for signaling. Although inflammation is implicated in neuronal death in the retina, the role of MyD88 dependent TLR and IL-1R signaling in retinal degeneration is unknown. Therefore, the purpose of this study was to investigate the role of MyD88-mediated signaling in neuronal degeneration in the retinal degeneration 1 (rd1) mouse model, which exhibits a phenotype of rapid photoreceptor death and inflammation. To generate rd1 mice lacking the MyD88 gene, rd1 were bred with MyD88 knockout mice (MyD88(-/ )) for several generations to produce rd1/MyD88(+/+) and rd1/MyD88(-/-) genotypes. Chemokine mRNA expression levels were analyzed by qRT-PCR, and recruitment of activated microglia was quantified by immunodetection of the IBA-1 protein. Retinal outer nuclear layer cell counts were performed to quantify photoreceptor degeneration, and retinal function was assessed using electroretinograms (ERG). Our results revealed that retinal expression of Ccl2, Ccl4, Ccl7 and Cxcl10 was reduced by 2 to 8-fold in rd1/MyD88(-/-) mice compared with rd1/MyD88(+/+) mice (p<0.05), which coincided with attenuated microglial activation, higher numbers of photoreceptors and higher retina responses to photopic and scotopic stimuli. At later ages, rd1/MyD88(-/-) had reduced chemokine expression and higher photopic responses but no change in microglial recruitment compared with rd1 mice with functional MyD88. In conclusion, lack of MyD88-mediated signaling increased photoreceptor survival and retina function in rd1 mice, which implicates MyD88-mediated innate immunity pathways as an important pathogenic factor during retinal degeneration. PMID- 25725355 TI - Impact of treatment duration and lesion size on effectiveness of chondroitinase treatment post-SCI. AB - The effects of 2weeks of intralesional chondroitinase abc (ch'abc) treatment on anatomical plasticity and behavioral recovery are examined in adult cats and compared to results achieved with 4weeks of treatment following tightly controlled lateral hemisection injuries. Analyses also were completed using 35 cats with a range of hemisection magnitudes to assess relationships between treatment duration, lesion size and functional recovery. Results indicate that both 2 and 4weeks of treatment significantly increased the number of rubrospinal tract (RuST) neurons with axons below the lesion, but neither affected the number of corticospinal tract neurons. Similarly, both treatment periods also accelerated recovery of select motor tasks, which carries considerable importance with respect to human health care and rehabilitation. Four weeks of treatment promoted recovery beyond that seen with 2weeks in its significant impact on accuracy of movement critical for placement of the ipsilateral hindlimb onto small support surfaces during the most challenging locomotor tasks. Analyses, which extended to a larger group of cats with a range of lesion magnitudes, indicate that 4weeks of ch'abc treatment promoted earlier recovery as well as significantly greater targeting accuracy even in cats with larger lesions. Together, these results support the potential for ch'abc to promote anatomical and behavioral recovery and suggest that intraspinal treatment with ch'abc continues to enhance motor recovery and performance beyond the subacute injury period and diminishes the impact of lesion size. PMID- 25725354 TI - Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats. AB - Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3 degrees C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6. In sensorimotor activity assessments, rats in the HPI201 treated group exhibited improved functional recovery after TBI versus controls. These data support that PIH therapy using our NTR agonist is effective in reducing neuronal and BBB damage, attenuating inflammatory response and detrimental cellular signaling, and promoting functional recovery after TBI in the developing brain, supporting its potential for further evaluation towards clinical development. PMID- 25725356 TI - A saw is first identified as an object used on wood: ERP evidence for temporal differences between Thematic and Functional similarity relations. AB - The role of functional and motor information in manipulable artifact object semantic organization is still poorly understood. In particular, several types of semantic relations involving object functional knowledge may be distinguished. Functional similarity relations group objects with similar functions at relatively specific (e.g. saw-axe, both used to cut wood) or general (saw-knife, both used to cut) levels. Thematic relations group objects based on their complementarity in events (saw used upon/with wood). Recent eye-tracking data showed distinct temporal time courses for the different semantic relations, with fastest processing of thematic relations and slowest processing of general function similarity relations. Behavioral data suggest the involvement of distinct cognitive mechanisms in manipulable artifact object semantic processing. The aim of the present study was to assess the neural correlates of thematic, and specific and general function similarity relation processing. Specifically, we investigated whether time course differences between semantic relations could be highlighted at the neurophysiological level. We used a protocol combining semantic priming with electroencephalography, and manipulated the type of semantic relation and the duration of the interval between prime and target objects. Two consistent and complementary results were shown. On N1 and P3 components, semantic priming was observed for thematic relations only. On N400 component, the type of semantic relation interacted with interval duration, and semantic priming was visible for all 3 relations after the longest interval only. Results revealed graded processing time courses for thematic, specific function similarity, and general function similarity relations at the neural level, and further indicate that thematic relations impact object processing during the early stages of object recognition. Findings suggest a hierarchical organization of three types of semantic relations based on functional knowledge. The parallel between semantic relations involving manipulable artifact objects and levels of action representations is discussed. PMID- 25725357 TI - Detection of BMAA in the human central nervous system. AB - Amyotrophic lateral sclerosis (ALS) is an extremely devastating neurodegenerative disease with an obscure etiology. The amino acid beta-N-methylamino-l-alanine (BMAA) produced by globally widespread phytoplankton has been implicated in the etiology of human motor neuron diseases [corrected]. BMAA was recently proven to be present in Baltic Sea food webs, ranging from plankton to larger Baltic Sea organisms, some serving as important food items (fish) for humans. To test whether exposure to BMAA in a Baltic Sea setting is reflected in humans, blood and cerebrospinal fluid (CSF) from individuals suffering from ALS were analyzed, together with sex- and age-matched individuals not inflicted with ALS. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and multiple reaction monitoring (MRM), in conjunction with diagnostic transitions revealed BMAA in three (12%) of the totally 25 Swedish individuals tested, with no preference for those suffering from ALS. The three BMAA-positive samples were all retrieved from the CSF, while BMAA was not detected in the blood. The data show that BMAA, potentially originating from Baltic Sea phytoplankton, may reach the human central nervous system, but does not lend support to the notion that BMAA is resident specifically in ALS-patients. However, while dietary exposure to BMAA may be intermittent and, if so, difficult to detect, our data provide the first demonstration of BMAA in the central nervous system of human individuals ante mortem quantified with UHPLC-MS/MS, and therefore calls for extended research efforts. PMID- 25725358 TI - Effects of 5alpha-cholestan-3-one on the synaptic vesicle cycle at the mouse neuromuscular junction. AB - We have investigated the effects of 5alpha-cholesten-3-one (5Ch3, 200 nM) on synaptic transmission in mouse diaphragm. 5Ch3 had no impact on the amplitude or frequency of miniature endplate currents (MEPCs, spontaneous secretion), but decreased the amplitude of EPCs (evoked secretion) triggered by single action potentials. Treatment with 5Ch3 increased the depression of EPC amplitude and slowed the unloading of the dye FM1-43 from synaptic vesicles (exocytosis rate) during high-frequency stimulation. The estimated recycling time of vesicles did not change, suggesting that the decline of synaptic efficiency was due to the reduction in the size of the population of vesicles involved in release. The effects of 5Ch3 on synaptic transmission may be related to changes in the phase properties of the membrane. We have found that 5Ch3 reduces the staining of synaptic regions with the B-subunit of cholera toxin (a marker of lipid rafts) and increases the fluorescence of 22-NBD-cholesterol, indicating a phase change within the membrane. Manipulations of membrane cholesterol (saturation or depletion) strongly reduced the influence of 5Ch3 on both FM1-43 dye unloading and staining with the B-subunit of cholera toxin. Thus, 5Ch3 reduces the number of vesicles which are actively recruited during synaptic transmission and alters membrane properties. These effects of 5Ch3 depend on membrane cholesterol. PMID- 25725359 TI - A mass spectrometry-based method for the assay of ceramide synthase substrate specificity. AB - The acyl composition of sphingolipids is determined by the specificity of the enzyme ceramide synthase (EC 2.3.1.24). Ceramide contains a long-chain base (LCB) linked to a variety of fatty acids to produce a lipid class with potentially hundreds of structural variants. An optimized procedure for the assay of ceramide synthase in yeast microsomes is reported that uses mass spectrometry to detect any possible LCB and fatty acid combination synthesized from unlabeled substrates provided in the reaction. The assay requires the delivery of substrates with bovine serum albumin for maximum activity within defined limits of substrate concentration and specific methods to stop the reaction and extract the lipid that avoid the non-enzymatic synthesis of ceramide. The activity of ceramide synthase in yeast microsomes is demonstrated with the four natural LCBs found in yeast along with six saturated and two unsaturated fatty acyl-coenzyme As from 16 to 26 carbons in length. The procedure allows for the determination of substrate specificity and kinetic parameters toward natural substrates for ceramide synthase from potentially any organism. PMID- 25725360 TI - Laser mimicking mosquito bites for skin delivery of malaria sporozoite vaccines. AB - Immunization with radiation-attenuated sporozoites (RAS) via mosquito bites has been shown to induce sterile immunity against malaria in humans, but this route of vaccination is neither practical nor ethical. The importance of delivering RAS to the liver through circulation in eliciting immunity against this parasite has been recently verified by human studies showing that high-level protection was achieved only by intravenous (IV) administration of RAS, not by intradermal (ID) or subcutaneous (SC) vaccination. Here, we report in a murine model that ID inoculation of RAS into laser-illuminated skin confers immune protection against malarial infection almost as effectively as IV immunization. Brief illumination of the inoculation site with a low power 532 nm Nd:YAG laser enhanced the permeability of the capillary beneath the skin, owing to hemoglobin-specific absorbance of the light. The increased blood vessel permeability appeared to facilitate an association of RAS with blood vessel walls by an as-yet-unknown mechanism, ultimately promoting a 7-fold increase in RAS entering circulation and reaching the liver over ID administration. Accordingly, ID immunization of RAS at a laser-treated site stimulated much stronger sporozoite-specific antibody and CD8(+)IFN-gamma(+) T cell responses than ID vaccination and provided nearly full protection against malarial infection, whereas ID immunization alone was ineffective. This novel, safe, and convenient strategy to augment efficacy of ID sporozoite-based vaccines warrants further investigation in large animals and in humans. PMID- 25725362 TI - Assessment of long-term remission in lupus nephritis patients: a retrospective analysis over 30 years. AB - OBJECTIVE: To review the likelihood of very long-term remission in patients with biopsy-proven LN attempting to identify good prognostic features. METHODS: We reviewed patients with LN whose renal biopsies showed World Health Organization (WHO) classes III, IV and V and who had a follow-up of at least 5 years between 1973 and 2008. We analysed demographic, clinical, laboratory and therapeutic parameters comparing those patients with (group A) and without (group B) 5 year remission. RESULTS: Of 191 LN patients followed, 105 patients met the strict inclusion criteria. Ninety-five patients were female. Mean age at diagnosis of lupus was 24.1 years (s.d. 10.7). ean age at diagnosis of LN was 28.4 years (s.d. 11.3). The mean duration of follow-up was 13.7 years (s.d. 14.1). Forty (38%) patients achieved 5 year remission, of whom 17 (16.2%) had remission for >=15 years. The incidence of flares per year from 5 to 15 years was 7.9%; however, no flares were observed after 15 years of remission. The only distinguishing feature found in this study was the association of WHO class IV on kidney biopsy with LN progression (P = 0.03). CONCLUSION: Renal histology with WHO class IV predicted a poor long-term remission rate. Age, sex, ethnicity, serological parameters and treatment received did not predict long-term remission. Renal flares can occur up to 15 years after a patient has gone into remission. PMID- 25725361 TI - Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation. AB - The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2 oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100nm are excellently suited for parenteral administration. Moreover, a selected formulation with the taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d*4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214. PMID- 25725363 TI - Early physiological responses of Pinus pinea L. seedlings infected by Heterobasidion sp.pl. in an ozone-enriched atmospheric environment. AB - The presence of the American root-rot disease fungus Heterobasidion irregulare Garbel. & Otrosina was detected in Italian coastal pine forests (Pinus pinea L.) in addition to the common native species Heterobasidion annosum (Fries) Brefeld. High levels of tropospheric ozone (O3) as an atmospheric pollutant are usually experienced in Mediterranean pine forests. To explore the effect of interaction between the two Heterobasidion species and ozone pollution on P. pinea, an open top chamber (OTC) experiment was carried out. Five-year-old P. pinea seedlings were inoculated with the fungal species considered (H. irregulare, H. annosum and mock-inoculation as control), and then exposed in charcoal-filtered open-top chambers (CF-OTC) and non-filtered ozone-enriched chambers (NF+) from July to the first week of August 2010 at the experimental facilities of Curno (North Italy). Fungal inoculation effects in an ozone-enriched environment were assessed as: (i) the length of the inoculation lesion; (ii) chlorophyll a fluorescence (ChlF) responses; and (iii) analysis of resin terpenes. Results showed no differences on lesion length between fungal and ozone treatments, whereas the short-term effects of the two stress factors on ChlF indicate an increased photosynthetic efficiency, thus suggesting the triggering of compensation/repair processes. The total amount of resin terpenes is enhanced by fungal infection of both species, but depressed by ozone to the levels observed in mock-inoculated plants. Variations in terpene profiles were also induced by stem base inoculations and ozone treatment. Ozone might negatively affect terpene defences making plants more susceptible to pathogens and insects. PMID- 25725364 TI - High cervical spinal subdural hemorrhage as a harbinger of craniocervical arteriovenous fistula: an unusual clinical presentation. AB - BACKGROUND CONTEXT: Craniocervical dural arteriovenous fistula (dAVF) is rare as compared with the typical thoracolumbar dAVFs of the spine and usually presents with hemorrhagic manifestation, predominantly intracranial subarachnoid hemorrhage. PURPOSE: We describe the first case of craniocervical dAVF with initial presentation as neck pain and spinal subdural hemorrhage. STUDY DESIGN: Case report. METHODS: We present the case of a 59-year-old woman who presented with sudden onset of neck pain at an outside institution emergency department (ED) and was discharged after negative cervical spine radiographs. Magnetic resonance imaging of the cervical spine performed because of persistent pain demonstrated presence of high cervical spinal subdural hematoma and she was managed conservatively. She subsequently presented to our ED a week later with headache and was found to have an intraventricular hemorrhage on computed tomography scan of the head, which on subsequent workup with an angiography revealed the presence of a craniocervical dAVF. RESULTS: Surgical obliteration of the fistula was performed with use of intraoperative angiography as an adjunct to confirm complete fistula obliteration. She had an excellent clinical outcome with no deficits at her last follow-up at 9 months. CONCLUSIONS: Even though hemorrhagic presentation is fairly common in craniocervical dAVFs, there is no report of a craniocervical dAVF presenting with spinal subdural hemorrhage. The present case further highlights the propensity of these vascular lesions to bleed and emphasizes the clinical importance of including these lesions in the differential diagnosis of hemorrhage in the vicinity of foramen magnum region, whether subarachnoid or subdural in location. Physicians treating spinal pathologies should be aware of this entity and clinical presentation, as an angiography needs to be considered in these cases to direct appropriate referral and treatment. PMID- 25725365 TI - MRI-based morphological evidence of spinal cord tethering predicts curve progression in adolescent idiopathic scoliosis. AB - BACKGROUND CONTEXT: Existing prognostic factors for adolescent idiopathic scoliosis (AIS) patients have focused mainly on curve, maturity, and bone-related factors. Previous studies have shown significant associations between curve severity and morphological evidences of relative shorter spinal cord tethering in AIS, and increased prevalence of abnormal somatosensory cortical-evoked potentials and low-lying cerebellar tonsil in severe AIS. Earlier evidence suggests that there might be neural morphological predictors for curve progression. PURPOSE: The purpose of this study was to identify any morphological predictors associated with cord tethering, as measured by magnetic resonance imaging (MRI), for curve progression in AIS patients. STUDY DESIGN/SETTING: This is a prospective cohort study. PATIENT SAMPLE: A total of 81 female AIS subjects between 10 and 14 years were included, without surgical intervention during the follow-up period. OUTCOME MEASURES: Magnetic resonance imaging scans of hindbrain and whole spine and areal bone mineral density (BMD) at bilateral femoral necks were performed. METHODS: All AIS patients were longitudinally followed up starting from initiation of bracing beyond skeletal maturity in 6-month intervals. Clinical and radiographic data were recorded at each clinic visit. Bone mineral density and MRI measurements including ratio of spinal cord to vertebral column length, ratio of anteroposterior (AP) and transverse (TS) diameter of cord, lateral cord space (LCS) ratio, cerebellar tonsil level, and conus medullaris position were obtained at baseline. Only compliant patients with a minimum 2-year follow-up were analyzed. Adolescent idiopathic scoliosis girls were assigned into three groups according to bracing outcome: Group A, nonprogression (curvature increase of less than or equal to 5 degrees ); Group B, progression (curvature increase of greater than or equal to 6 degrees ); Group C, progression with surgery indication (Cobb angle of greater than or equal to 50 degrees after skeletal maturity despite bracing). The predictors for curve progression were evaluated using univariate analysis and multivariate ordinal regression model. RESULTS: The average duration of follow-up was 3.4 (range, 2.0 5.6) years. There were 46 girls (57%) in Group A, 19 (23%) in Group B, and 16 (20%) in Group C. No significant intergroup differences were found in spinal cord length, tonsil level, and conus position. Group C had significantly longer vertebral column length, smaller cord-vertebral length ratio, and higher AP/TS cord ratio compared with Group A, whereas LCS ratio in Group C was significantly increased compared with both Group A and Group B. In regression model, five significant independent predictors including cord-vertebral length ratio (odds ratio [OR]: 1.993 [95% confidence interval {CI}: 1.053-3.771], p=.034), LCS ratio (OR: 2.639 [95% CI: 1.128-6.174], p=.025), initial Cobb angle (OR: 1.156 [95% CI: 1.043-1.281], p=.006), menarche age (OR: 1.688 [95% CI: 1.010-2.823], p=.046), and BMD (OR: 2.960 [95% CI: 1.301-6.731], p=.010) and a marginally significant predictor namely AP/TS cord ratio (OR: 1.463 [95% CI: 0.791-2.706], p=.096) were obtained. CONCLUSIONS: On baseline MRI measurement, cord-vertebral length ratio and LCS ratio are identified as new significant independent predictors for curve progression in AIS, whereas AP/TS cord ratio is suggested as a potential predictor requiring further validations. The earlier MRI parameters can be taken into accounts for prognostication of bracing outcome. PMID- 25725366 TI - Restoration of the spinopelvic sagittal balance in isthmic spondylolisthesis: posterior lumbar interbody fusion may be better than posterolateral fusion. AB - BACKGROUND CONTEXT: More and more orthopedic surgeons recognize the importance of the sagittal balance of the spine. PURPOSE: To analyze the pre- and postoperative sagittal and deformity parameters of low-grade isthmic spondylolisthesis and evaluate the effect of posterolateral fusion (PLF) and posterior lumbar interbody fusion (PLIF) on spinopelvic sagittal balance. STUDY DESIGN: Nonrandomized controlled prospective study with a historical control. PATIENT SAMPLE: A total of 99 patients with low-grade L5-S1 isthmic spondylolisthesis were treated surgically; 36 patients (mean age, 60.2+/-5.2 years) received the PLF operation, and 63 patients (mean age, 57.1+/-6.9 years) chose the PLIF operation. The healthy control group was composed of 60 volunteers (mean age, 44.5+/-8.4 years). OUTCOME MEASURES: The pre- and postoperative spinopelvic and deformity parameters. METHODS: All patients had radiographs that allowed measurement of spinopelvic parameters before and after the operation. All the spinopelvic and deformity parameters were measured. Two radiologists measured the parameters with the Cobb method. RESULTS: All of the preoperative spinopelvic parameters showed no difference between the PLIF and PLF groups in this study (p>.05). In both of the operation groups, the preoperative pelvic incidence, pelvic tilt (PT), sacral slope, lumbar lordosis (LL), and L5 incidence (L5I) were significantly higher than in the control group (p<.01); the height of the intervertebral disc (HOD) was significantly lower than the controls. There were no significant differences in PT among PLIF, PLF, and control groups after the operation (p>.05). LL increased in the PLIF group and decreased in the PLF group. The slip degree (SD) and L5I were restored significantly in both groups. The HOD of the PLIF group increased 5.04 mm, the postoperative HOD of the PLF group had no significant change. In both PLIF and PLF groups, the correction of SD was correlated with the change of LL (r=-0.398, p=.007; r=0.365, p=.022). The restoration of HOD in the PLIF group correlated with the change of LL (r=0.334, p=.011). No significant differences could be found between the short-term clinical outcomes of the PLF and PLIF. CONCLUSION: Either PLF or PLIF would lead a great change in spinopelvic parameters and deformity parameters. The decrease of PT may be an important role for the short-term surgical outcome. The PLIF could increase the LL and form a more reasonable sagittal alignment. From the point of the sagittal spinopelvic balance, the PLIF may be better than the PLF for patients with isthmic spondylolisthesis. PMID- 25725367 TI - Effect of serum nicotine level on posterior spinal fusion in an in vivo rabbit model. AB - BACKGROUND CONTEXT: Cigarette smoking has a deleterious effect on spinal fusion. Although some studies have implied that nicotine is primarily responsible for poor fusion outcomes, other studies suggest that nicotine may actually stimulate bone growth. Hence, there may be a dose-dependent effect of nicotine on posterior spinal fusion outcomes. PURPOSE: The purpose of this study was to determine if such a relationship could be shown in an in vivo rabbit model. STUDY DESIGN/SETTING: This is a prospective in vivo animal study. METHODS: Twenty-four adult male New Zealand white rabbits were randomly divided into four groups. All groups received a single-level posterolateral, intertransverse process fusion at L5-L6 with autologous iliac crest bone. One group served as controls and only underwent the spine fusion surgery. Three groups received 5.25-, 10.5-, and 21-mg nicotine patches, respectively, for 5 weeks. Serum nicotine levels were recorded for each group. All animals were euthanized 5 weeks postoperatively, and spinal fusions were evaluated radiographically, by manual palpation, and biomechanically. Statistical analysis evaluated the dose response effect of outcomes variables and nicotine dosage. This study was supported by a portion of a $100,000 grant from the Orthopaedic Research and Education Foundation. Author financial disclosures were completed in accordance with the journal's guidelines; there were no conflicts of interests disclosed that would have led to bias in this work. RESULTS: The average serum levels of nicotine from the different patches were 7.8+/-1.9 ng/mL for the 5.25-mg patch group; 99.7+/-17.7 ng/mL for the 10.5-mg patch group; and 149.1+/-24.6 ng/mL for the 21-mg patch group. The doses positively correlated with serum concentrations of nicotine (correlation coefficient=0.8410, p<.001). The 5.25-mg group provided the best fusion rate, trabeculation, and stiffness. On the basis of the palpation tests, the fusion rates were control (50%), 5.25 mg (80%), 10.5 mg (50%), and 21 mg (42.8%). Radiographic assessment of trabeculation and bone incorporation and biomechanical analysis of bending stiffness ratio were also greatest in the 5.25-mg group. Radiographic evaluation showed a significant (p=.0446) quadratic effect of nicotine dose on spinal fusion. CONCLUSIONS: The effects of nicotine on spinal fusion are complex, may be dose dependent, and may not always be detrimental. The uniformly negative effects of smoking reported in patients undergoing spinal fusion may possibly be attributed to the other components of cigarette smoke. PMID- 25725368 TI - Mesenchymal stem cell allograft as a fusion adjunct in one- and two-level anterior cervical discectomy and fusion: a matched cohort analysis. AB - BACKGROUND CONTEXT: Live mesenchymal stem cell (MSC) allograft-containing allogeneic bone grafts have recently gained popularity and currently account for greater than 17% of all bone grafts and bone graft substitutes used in spinal surgery. Although the claim of cellular bone matrices containing osteogenic cells with osteoinductive properties is attractive, little is known about their clinical success when used in anterior cervical discectomy and fusion (ACDF). PURPOSE: The objective of this study was to report on the radiographic fusion rates in one- and two-level instrumented ACDF using an MSC. STUDY DESIGN/SETTING: This was a retrospective review of prospectively matched cohort of patients with radiologic assessment of fusion as the primary end point. PATIENT SAMPLE: Two matched cohorts of adult patients who underwent ACDF with MSC or standard allograft were included. OUTCOMES MEASURES: The outcome measures included radiographic and clinical evidence of healing at 1 year. METHODS: A consecutive series of 57 patients who underwent a one- or two-level instrumented ACDF procedure between 2010 and 2012 were retrospectively analyzed. All fusion constructs comprised an interbody allograft, an anterior plate, and Osteocel (NuVasive, San Diego, CA, USA). These patients were matched to a control group of 57 patients. RESULTS: Of the 57 cases in both cohorts, 29 (50.9%) were single level, and 28 (49.1%) were two-level instrumented ACDFs. There were no significant differences in patient age (p=.71), gender, comorbidity burden (Charlson Comorbidity Index [CCI]: 1.95; 2.42, p=.71) or body mass index (p=.79). At the 1-year follow-up, 50 of 57 (87.7%) patients in the Osteocel cohort demonstrated a solid fusion compared with 54 of 57 (94.7%) in the control group (p=.19). Seven (12.3%) patients in the Osteocel cohort were reported as having a failed fusion at 1 year. CONCLUSIONS: This is the first non-industry sponsored study to analyze a matched cohort assessing the 1-year arthrodesis rates associated with a nonstructural MSC allograft in one- and two-level ACDF procedures. Although not statistically significant, patients treated with MSC allografts demonstrated lower fusion rates compared with a matched non-MSC cohort. PMID- 25725370 TI - Visual, haptic and bimodal scene perception: evidence for a unitary representation. AB - Participants studied seven meaningful scene-regions bordered by removable boundaries (30s each). In Experiment 1 (N = 80) participants used visual or haptic exploration and then minutes later, reconstructed boundary position using the same or the alternate modality. Participants in all groups shifted boundary placement outward (boundary extension), but visual study yielded the greater error. Critically, this modality-specific difference in boundary extension transferred without cost in the cross-modal conditions, suggesting a functionally unitary scene representation. In Experiment 2 (N = 20), bimodal study led to boundary extension that did not differ from haptic exploration alone, suggesting that bimodal spatial memory was constrained by the more "conservative" haptic modality. In Experiment 3 (N = 20), as in picture studies, boundary memory was tested 30s after viewing each scene-region and as with pictures, boundary extension still occurred. Results suggest that scene representation is organized around an amodal spatial core that organizes bottom-up information from multiple modalities in combination with top-down expectations about the surrounding world. PMID- 25725369 TI - Cell death in genome evolution. AB - Inappropriate survival of abnormal cells underlies tumorigenesis. Most discoveries about programmed cell death have come from studying model organisms. Revisiting the experimental contexts that inspired these discoveries helps explain confounding biases that inevitably accompany such discoveries. Amending early biases has added a newcomer to the collection of cell death models. Analysis of gene-dependent death in yeast revealed the surprising influence of single gene mutations on subsequent eukaryotic genome evolution. Similar events may influence the selection for mutations during early tumorigenesis. The possibility that any early random mutation might drive the selection for a cancer driver mutation is conceivable but difficult to demonstrate. This was tested in yeast, revealing that mutation of almost any gene appears to specify the selection for a new second mutation. Some human tumors contain pairs of mutant genes homologous to co-occurring mutant genes in yeast. Here we consider how yeast again provide novel insights into tumorigenesis. PMID- 25725371 TI - Retinoic acid potentiates inflammatory cytokines in human mast cells: identification of mast cells as prominent constituents of the skin retinoid network. AB - Retinoic acid (RA), the active vitamin-A-metabolite, has well-established functions in skin homeostasis and in the immune system. Skin mast cells (MCs) combine traits of both structures, being of hematopoietic origin, but functional in the skin environment. It remains largely unknown whether mature MCs are targeted by the retinoid network. Here, we demonstrate that human skin MCs display substantial susceptibility to RA by which they are instructed to increase pro-inflammatory mediators (IL-1beta, IL-8, TNF-alpha) but not histamine release. The effects are observed at physiological RA levels, in different microenvironments, and are largely donor-independent. RA susceptibility is owed to the cells' abundant expression of RARA, the receptor mediating MC cytokine responses. Unexpectedly, bioinformatics calculations on the FANTOM5 expression atlas revealed general enrichment of retinoid network components in MCs against other skin cells, and MCs rapidly upregulated RA responsive genes. In conclusion, MCs are important yet hitherto overlooked retinoid targets in the skin. PMID- 25725372 TI - Transmembrane tumor necrosis factor-alpha sensitizes adipocytes to insulin. AB - Transmembrane TNF-alpha (tmTNF-alpha) acts both as a ligand, delivering 'forward signaling' via TNFR, and as a receptor, transducing 'reverse signaling'. The contradiction of available data regarding the effect of tmTNF-alpha on insulin resistance may be due to imbalance in both signals. Here, we demonstrated that high glucose-induced impairment of insulin-stimulated glucose uptake by 3T3-L1 adipocytes was concomitant with decreased tmTNF-alpha expression and increased soluble TNF-alpha (sTNF-alpha) secretion. However, when TACE was inhibited, preventing the conversion of tmTNF-alpha to sTNF-alpha, this insulin resistance was partially reversed, indicating a salutary role of tmTNF-alpha. Treatment of 3T3-L1 adipocytes with exogenous tmTNF-alpha promoted insulin-induced phosphorylation of IRS-1 and Akt, facilitated GLUT4 expression and membrane translocation, and increased glucose uptake while addition of sTNF-alpha resulted in the opposite effect. Furthermore, tmTNF-alpha downregulated the production of IL-6 and MCP-1 via NF-kappaB inactivation, as silencing of A20, an inhibitor for NF-kappaB, by siRNA, abolished this effect of tmTNF-alpha. However, tmTNF-alpha upregulated adiponectin expression through the PPAR-gamma pathway, as inhibition of PPAR-gamma by GW9662 abrogated both tmTNF-alpha-induced adiponectin transcription and glucose uptake. Our data suggest that tmTNF-alpha functions as an insulin sensitizer via forward signaling. PMID- 25725374 TI - Discovery and optimization of novel dual dithiocarbamates as potent anticancer agents. AB - A series of dual dithiocarbamates were synthesized and evaluated for their in vitro anticancer activities on human non-small cell lung cancer cell line H460. Nine compounds exhibited significant antiproliferative activities with IC50 less than 1 MUM. Among them, compound 14m showed the highest inhibitory activity against H460 cell and inhibited the growth of nine types of tumor cells with IC50 values less than 1 MUM. It also achieved IC50 of 54 nM and 23 nM against HepG2 and MCF-7 cell lines, respectively. Preliminary structure-activity relationship study indicated that: a) when the methyl group (region A) is substituted with benzene rings, ortho substitution on the benzene ring is favored for activity; b) substitution with heterocyclic structures at region A exhibited greater impact on the anti-tumor activity of compounds, in which pyridine ring, thiazole ring, coumarin and benzo[b]thiophene are favored and quinoline ring is the most favored; c) substitution with different amines (region B) also showed marked effect on the activity of compounds and dimethylamine and morpholine are preferred to other tested amines. PMID- 25725373 TI - Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERalpha-dependent in ERalpha-negative human breast cancer cells. AB - Available treatment strategies against estrogen receptor (ER)-negative breast cancer patients are limited due to their poor response to hormonal therapy. We have shown previously that the combinations of green tea polyphenols (GTPs), a dietary DNA methyltransferase inhibitor, and sulforaphane (SFN), a dietary histone deacetylase inhibitor, reactivate ERalpha expression in ERalpha-negative MDA-MB-231 cells. Here, we investigated the functional significance of ERalpha reactivation in the reactivation of silenced tumor suppressor genes (TSGs) in ERalpha-negative human breast cancer cells. We found that the treatment of MDA-MB 231 cells with the combinations of GTPs and SFN leads to the reactivation of silenced TSGs such as p21(CIP1/WAF1) and KLOTHO through active chromatin modifications. Further, GTPs- and SFN-mediated reactivation of TSGs was, at least in part, dependent on ERalpha reactivation in ERalpha-negative MDA-MB-231 cells. Collectively, our findings suggest that a novel combination of bioactive dietary supplements could further be explored as an effective therapeutic option against hormonal refractory breast cancer. PMID- 25725375 TI - Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO). AB - Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7 dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay. PMID- 25725376 TI - An efficient synthesis of new caffeine-based chalcones, pyrazolines and pyrazolo[3,4-b][1,4]diazepines as potential antimalarial, antitrypanosomal and antileishmanial agents. AB - A new series of chalcones 5a-f were synthesized from caffeine-based aldehyde 3 and substituted acetophenones 4a-f. Treatment of compounds 5a-f with hydrazine hydrate led to pyrazolines 6a-f, and their subsequent reaction with acetic anhydride or formic acid afforded the corresponding N-substituted pyrazolines 7a f and 8a-f respectively. Additionally, the regioselective cyclocondensation reaction of chalcones 5a-f with 4,5-diaminopyrazole 9 afforded the diazepine derivatives 10a-f. Synthesis of the above novel compounds was carried out through a simple procedure involving an easy work-up and mild reaction conditions. In vitro antimalarial activity against Plasmodium falciparum was evaluated for the obtained compounds. Among of them, just pirazoline 6a showed an outstanding growth inhibition percentage 85.2 +/- 5.4%, while diazepines 10a-f showed remarkable growth inhibitions in the range of 80.3 +/- 13.5 to 94.2 +/- 0.2% when were tested at 20 MUg/mL. Compounds 5b, 5e, 7c and 7f showed remarkable activities against Leishmania panamensis with growth inhibition of 88.3 +/- 1.5, 82.6 +/- 2.2, 82.8 +/- 1.7 and 87.6 +/- 0.5% respectively, at 20 MUg/mL. In vitro assays against Trypanozoma cruzi showed that pyrazoline 6d displayed a growth inhibition of 61.9 +/- 7.8% at 20 MUg/mL while chalcone 5f was considered especially active with a growth inhibition of 9.7 +/- 1.5% for a very low concentration of 1.0 MUg/mL. PMID- 25725377 TI - Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction. AB - Studying neural networks and behavioral indices such as potentiated startle responses during fear conditioning has a long tradition in both animal and human research. However, most of the studies in humans do not link startle potentiation and neural activity during fear acquisition and extinction. Therefore, we examined startle blink responses measured with electromyography (EMG) and brain activity measured with functional MRI simultaneously during differential conditioning. Furthermore, we combined these behavioral fear indices with brain network activity by analyzing the brain activity evoked by the startle probe stimulus presented during conditioned visual threat and safety cues as well as in the absence of visual stimulation. In line with previous research, we found a fear-induced potentiation of the startle blink responses when elicited during a conditioned threat stimulus and a rapid decline of amygdala activity after an initial differentiation of threat and safety cues in early acquisition trials. Increased activation during processing of threat cues was also found in the anterior insula, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). More importantly, our results depict an increase of brain activity to probes presented during threatening in comparison to safety cues indicating an involvement of the anterior insula, the ACC, the thalamus, and the PAG in fear potentiated startle processing during early extinction trials. Our study underlines that parallel assessment of fear-potentiated startle in fMRI paradigms can provide a helpful method to investigate common and distinct processing pathways in humans and animals and, thus, contributes to translational research. PMID- 25725378 TI - Postural control during gait initiation and termination of adults with incomplete spinal cord injury. AB - Gait initiation and termination are potentially challenging tasks for balance due to the transition from a quasi-static bipedal phase to a dynamic single-support phase. The purpose of this study was to compare the bipedal and single-support phases of gait initiation and termination in individuals with incomplete spinal cord injury (ISCI). Twelve individuals with ISCI were evaluated on the dynamic and postural components of balance using the stabilizing and destabilizing forces during gait initiation, termination and natural gait. Phase comparisons were made using non parametric tests. Visual inspection of the force profile of the factors explaining the forces was also conducted. Gait termination challenged more the postural control during the single-support phase than the bipedal phase for the dynamic component of the stabilizing/destabilizing forces model (p=.002). For gait initiation, the most challenging phase varied with the components analyzed (single-support phase for the dynamic component, bipedal phase for the postural component) (p?.008). The single support phase is more challenged during gait termination (both components) (p?.015) while the bipedal phase is more challenged during gait initiation (dynamic components) (p=.012). The stabilizing force and the speed of the center of mass on the one hand, and destabilizing force and the distance between the center of pressure and the base of support on the other hand, had a similar profile. The single-support phase of gait termination was the most challenging among all phases evaluated, being as challenging as the single support phase of level natural gait. This phase should be targeted in rehabilitation in order to improve balance and decrease the risk of falling in this population. PMID- 25725379 TI - Sensorimotor synchronization with tempo-changing auditory sequences: Modeling temporal adaptation and anticipation. AB - The current study investigated the human ability to synchronize movements with event sequences containing continuous tempo changes. This capacity is evident, for example, in ensemble musicians who maintain precise interpersonal coordination while modulating the performance tempo for expressive purposes. Here we tested an ADaptation and Anticipation Model (ADAM) that was developed to account for such behavior by combining error correction processes (adaptation) with a predictive temporal extrapolation process (anticipation). While previous computational models of synchronization incorporate error correction, they do not account for prediction during tempo-changing behavior. The fit between behavioral data and computer simulations based on four versions of ADAM was assessed. These versions included a model with adaptation only, one in which adaptation and anticipation act in combination (error correction is applied on the basis of predicted tempo changes), and two models in which adaptation and anticipation were linked in a joint module that corrects for predicted discrepancies between the outcomes of adaptive and anticipatory processes. The behavioral experiment required participants to tap their finger in time with three auditory pacing sequences containing tempo changes that differed in the rate of change and the number of turning points. Behavioral results indicated that sensorimotor synchronization accuracy and precision, while generally high, decreased with increases in the rate of tempo change and number of turning points. Simulations and model-based parameter estimates showed that adaptation mechanisms alone could not fully explain the observed precision of sensorimotor synchronization. Including anticipation in the model increased the precision of simulated sensorimotor synchronization and improved the fit of model to behavioral data, especially when adaptation and anticipation mechanisms were linked via a joint module based on the notion of joint internal models. Overall results suggest that adaptation and anticipation mechanisms both play an important role during sensorimotor synchronization with tempo-changing sequences. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25725380 TI - The effect of lifelong bilingualism on regional grey and white matter volume. AB - Lifelong bilingualism is associated with the delayed diagnosis of dementia, suggesting bilingual experience is relevant to brain health in aging. While the effects of bilingualism on cognitive functions across the lifespan are well documented, less is known about the neural substrates underlying differential behaviour. It is clear that bilingualism affects brain regions that mediate language abilities and that these regions are at least partially overlapping with those that exhibit age-related decline. Moreover, the behavioural advantages observed in bilingualism are generally found in executive function performance, suggesting that the frontal lobes may also be sensitive to bilingualism, which exhibit volume reductions with age. The current study investigated structural differences in the brain of lifelong bilingual older adults (n=14, mean age=70.4) compared with older monolinguals (n=14, mean age=70.6). We employed two analytic approaches: 1) we examined global differences in grey and white matter volumes; and, 2) we examined local differences in volume and cortical thickness of specific regions of interest previously implicated in bilingual/monolingual comparisons (temporal pole) or in aging (entorhinal cortex and hippocampus). We expected bilinguals would exhibit greater volume of the frontal lobe and temporal lobe (grey and white matter), given the importance of these regions in executive and language functions, respectively. We further hypothesized that regions in the medial temporal lobe, which demonstrate early changes in aging and exhibit neural pathology in dementia, would be more preserved in the bilingual group. As predicted, bilinguals exhibit greater frontal lobe white matter compared with monolinguals. Moreover, increasing age was related to decreasing temporal pole cortical thickness in the monolingual group, but no such relationship was observed for bilinguals. Finally, Stroop task performance was positively correlated with frontal lobe white matter, emphasizing the importance of preserved white matter in maintaining executive function in aging. These results underscore previous findings implicating an association between bilingualism and preserved frontal and temporal lobe function in aging. This article is part of a Special Issue entitled SI: Memory A. PMID- 25725381 TI - Endothelial progenitor cells and revascularization following stroke. AB - Brain injury after ischemia induces the mobilization of endothelial progenitor cells (EPCs), a population of bone marrow-derived cells with angio-vasculogenic capabilities. These cells have been also tested in pre-clinical models and proposed for neurorepair therapy aiming to treat patients in the delayed phases of stroke disease. Promising results in the pre-clinical field encourage the translation into a clinical therapeutic approach. In this review, we will describe EPCs actions for enhanced revascularization and neurorepair, which on one hand are by their direct incorporation into new vascular networks/structures or by direct cell-cell interactions with other brain cells, but also to indirect cell-cell communication thorough EPCs secreted growth factors. All these actions contribute to potentiate neurovascular remodeling and neurorepair. The data presented in this review encourages for a deep understanding of the mechanisms of the cross-talks between EPCs and other brain and progenitor cells, which deserves additional investigations and efforts that may lead to new EPCs-based therapies for stroke patients. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25725382 TI - Treadmill running restores MDMA-mediated hyperthermia prevented by inhibition of the dorsomedial hypothalamus. AB - The contribution of exercise to hyperthermia mediated by MDMA is not known. We recently showed that inhibiting the dorsomedial hypothalamus (DMH) attenuated spontaneous locomotion and hyperthermia and prevented deaths in rats given MDMA in a warm environment. The goal of this study was to confirm that restoring locomotion through a treadmill would reverse these effects thereby confirming that locomotion mediated by the DMH contributes to MDMA-mediated hyperthermia. Rats were randomized to receive bilateral microinjections, into the region of the DMH, of muscimol (80pmol/100nl) or artificial CSF followed by a systemic dose of either MDMA (7.5mg/kg, i.v.) or saline. Immediately after the systemic injection, rats were placed on a motorized treadmill maintained at 32 degrees C. Rats were exercised at a fixed speed (10m/min) until their core temperature reached 41 degrees C. Our results showed that a fixed exercise load abolished the decreases in temperature and mortality, seen previously with inhibition of the DMH in freely moving rats. Therefore, locomotion mediated by neurons in the DMH is critical to the development of hyperthermia from MDMA. PMID- 25725383 TI - Deletion of PdMit1, a homolog of yeast Csg1, affects growth and Ca(2+) sensitivity of the fungus Penicillium digitatum, but does not alter virulence. AB - GDP-mannose:inositol-phosphorylceramide (MIPC) and its derivatives are important for Ca(2+) sensitization of Saccharomyces cerevisiae and for the virulence of Candida albicans, but its role in the virulence of plant fungal pathogens remains unclear. In this study, we report the identification and functional characterization of PdMit1, the gene encoding MIPC synthase in Penicillium digitatum, one of the most important pathogens of postharvest citrus fruits. To understand the function of PdMit1, a PdMit1 deletion mutant was generated. Compared to its wild-type control, the PdMit1 deletion mutant exhibited slow radial growth, decreased conidia production and delayed conidial germination, suggesting that PdMit1 is important for the growth of mycelium, sporulation and conidial germination. The PdMit1 deletion mutant also showed hypersensitivity to Ca(2+). Treatment with 250 mmol/l Ca(2+) induced vacuole fusion in the wild-type strain, but not in the PdMit1 deletion mutant. Treatment with 250mmol/lCaCl2 upregulated three Ca(2+)-ATPase genes in the wild-type strain, and this was significantly inhibited in the PdMit1 deletion mutant. These results suggest that PdMit1 may have a role in regulating vacuole fusion and expression of Ca(2+) ATPase genes by controlling biosynthesis of MIPC, and thereby imparts P. digitatum Ca(2+) tolerance. However, we found that PdMit1 is dispensable for virulence of P. digitatum. PMID- 25725384 TI - Monitoring of Legionella pneumophila viability after chlorine dioxide treatment using flow cytometry. AB - The viability of three Legionella pneumophila strains was monitored after chlorine dioxide (ClO2) treatment using a flow cytometric assay. Suspensions of L. pneumophila cells were submitted to increasing concentrations of ClO2. Culturable cells were still detected when using 4 mg/L, but could no longer be detected after exposure to 6 mg/L of ClO2, although viable but not culturable (VBNC) cells were found after exposure to 4-5 mg/L of ClO2. When testing whether these VBNC were infective, two of the strains were resuscitated after co-culture with Acanthamoeba polyphaga, but neither of them could infect macrophage-like cells. PMID- 25725385 TI - Disappearance of circumscribed choroidal hemangiomas with photodynamic therapy. PMID- 25725386 TI - Removal of COD and nitrogen from animal food plant wastewater in an intermittently-aerated structured-bed reactor. AB - This study evaluated the performance of a continuous flow structured-bed reactor in the simultaneous removal of total nitrogen (TN) and chemical oxygen demand (COD) in the effluent from an animal food plant. The reactor had an intermittent aeration system; hydraulic retention time (HRT) of one day; temperature of 30 degrees C; and recirculation ratio of five times the flow. An experimental central composite rotational delineation (CCRD) type design was used to define the aeration conditions and nitrogen load (factors) to be studied. Response surface methodology was used to analyse the influence of the factors above the results, the removal of TN and COD. It was observed that the aeration factor showed the greatest significance for the results and that the affluent TKN concentration did not have a significant effect, at a 95% level of confidence, on COD removal. Throughout the experiment, the COD/N ratio remained between 3.2 and 3.8. The best results for COD and TN removal, 80% and 88%, respectively, were obtained with 158 min of aeration on a cycle of 180 min and 255 mg L(-1) of Total Kjeldahl Nitrogen (TKN) in the substrate. PMID- 25725387 TI - Prediction of forest fires occurrences with area-level Poisson mixed models. AB - The number of fires in forest areas of Galicia (north-west of Spain) during the summer period is quite high. Local authorities are interested in analyzing the factors that explain this phenomenon. Poisson regression models are good tools for describing and predicting the number of fires per forest areas. This work employs area-level Poisson mixed models for treating real data about fires in forest areas. A parametric bootstrap method is applied for estimating the mean squared errors of fires predictors. The developed methodology and software are applied to a real data set of fires in forest areas of Galicia. PMID- 25725388 TI - Characteristics of H2S emission from aged refuse after excavation exposure. AB - Hydrogen sulfide (H2S(g)) emission from landfills is a widespread problem, especially when aged refuse is excavated. H2S(g) emission from aged refuse exposed to air was investigated and the results showed that large amounts of H2S(g) can be released, especially in the first few hours after excavation, when H2S(g) concentrations in air near refuse could reach 2.00 mg m(-3). Initial exposure to air did not inhibit the emission of H2S(g), as is generally assumed, but actually promoted it. The amounts of H2S(g) emitted in the first 2 d after excavation can be very dangerous, and the risks associated with the emission of H2S(g) could decrease significantly with time. Unlike a large number of sulfide existed under anaerobic conditions, the sulfide in aged municipal solid waste can be oxidized chemically to elemental sulfur (but not sulfate) under aerobic conditions, and its conversion rate was higher than 80%. Only microorganisms can oxidize the reduced sulfur species to sulfate, and the conversion rate could reach about 50%. Using appropriate techniques to enhance these chemical and biological transformations could allow the potential health risks caused by H2S(g) after refuse excavation to be largely avoided. PMID- 25725389 TI - Reading disabilities in children: A selective meta-analysis of the cognitive literature. AB - This article synthesizes literature that compares the academic, cognitive, and behavioral performance of children with and without reading disabilities (RD). Forty-eight studies met the criteria for the meta-analysis, yielding 735 effect sizes (ESs) with an overall weighted ES of 0.98. Small to high ESs in favor of children without RD emerged on measures of cognition (rapid naming [ES = 0.89], phonological awareness [ES = 1.00], verbal working memory [ES = 0.79], short-term memory [ES = 0.56], visual-spatial memory [ES = 0.48], and executive processing [ES = 0.67]), academic achievement (pseudoword reading [ES = 1.85], math [ES = 1.20], vocabulary [ES = 0.83], spelling [ES = 1.25], and writing [ES = 1.20]), and behavior skills (ES = 0.80). Hierarchical linear modeling indicated that specific cognitive process measures (verbal working memory, visual-spatial memory, executive processing, and short-term memory) and intelligence measures (general and verbal intelligence) significantly moderated overall group effect size differences. Overall, the results supported the assumption that cognitive deficits in children with RD are persistent. PMID- 25725390 TI - Joint-dependent response to impact and implications for post-traumatic osteoarthritis. AB - OBJECTIVE: The prevalence of osteoarthritis (OA) varies between joints. Cartilage in eight different joints was evaluated to elucidate the disparate susceptibilities between joints to post-traumatic OA (PTOA) and provide evidence for joint-specific clinical treatments. The hypothesis was that cartilage in different joints would have varying cell death and anabolic gene expression profiles after injury. METHODS: Adult equine cartilage explants were harvested from shoulder (SH), elbow (EL), carpal (CA), metacarpophalangeal (MC), patellofemoral (FP), tarsal (TA), metatarsophalangeal (MT), and proximal interphalangeal (PP) joints, and injured by loading with 30 MPa within 1 s. Fractional dissipated energy, cell density, cell death, and gene expression were quantified. RESULTS: PP had the highest fractional dissipated energy (94%, 95% confidence interval [CI] 88 to 101%). Cell density was highest in the superficial zone in all samples, with MC and MT having the highest peak density. Injured samples had significantly increased cell death (13.5%, 95% CI 9.1 to 17.9%) than non-injured samples (6.8%, 95% CI 2.5 to 11.1%, P = 0.016); however, cell death after injury was not significantly different between joints. Gene expression was significantly different between joints. CD-RAP expression in normal cartilage was lowest in FP (Cp = 21, 95% CI -80 to 122). After injury, the change in CD-RAP expression increased and was highest in FP (147% relative increase after injury, 95% CI 64 to 213). CONCLUSION: Different joints have different baseline characteristics, including cell density and gene expression, and responses to injury, including energy dissipation and gene expression. These unique characteristics may explain differences in OA prevalence and suggest differences in susceptibility to PTOA. CLINICAL RELEVANCE: Understanding differences in the response to injury and potential susceptibility to OA can lead to the development of preventative or treatment strategies. KEY TERMS: Gene expression, cartilage injury, chondrocyte, multiphoton microscopy, cartilage biomechanical properties, PTOA. WHAT IS KNOWN ABOUT THE SUBJECT: The prevalence of OA is variable among joints; however, most laboratory studies are performed on a single joint - most commonly the knee, and extrapolated to other joints such as the ankle or shoulder. A small number of studies have compared knee and ankle cartilage and reported differences in mechanical properties and gene expression. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE: There are differences in baseline cell density and gene expression, and differences in response to injury, including gene expression and cell death. This suggests that there are inherent differences leading to varying susceptibilities in OA prevalence among joints. Joint-specific treatments may improve OA therapies. PMID- 25725391 TI - Meniscal biomechanical alterations in an ACLT rabbit model of early osteoarthritis. AB - OBJECTIVE: The purpose of this study was to analyze the early biomechanical alterations of menisci during the early stage of osteoarthritis (OA) development and to correlate them with the chemical composition and matrix alteration. A particular focus was paid to pathological changes in glycosaminoglycan (GAG) content and collagen fiber architecture. DESIGN: Menisci (n = 24) were removed from rabbits' knee joints 6 weeks following surgical anterior cruciate ligament transection (ACLT). Both the anterior and posterior regions of medial and lateral menisci were characterized using indentation tests, Raman microspectroscopy (RM), biphotonic confocal microscopy (BCM) and histology. RESULTS: Mechanical and matrix alterations occurred in both regions of medial and lateral menisci. A significant decrease in the mechanical properties was observed in OA menisci, with a mean reduced modulus from 2.3 to 1.1 MPa. Microstructural observations revealed less organized and less compact collagen bundles in operated menisci than in contralateral menisci, as well as a loss of fiber tension. GAG content was increased in OA menisci, especially in the damaged areas. Neither changes in the secondary structure of collagen nor mineralization were detected through RM at this stage of OA. CONCLUSION: ACLT led to a disorganization of the collagen framework at the early stage of OA development, which decreases the mechanical resistance of the menisci. GAG content increases in response to this degradation. All of these results demonstrate the strong correlation between matrix and mechanical alterations. PMID- 25725392 TI - Outcomes associated with early post-traumatic osteoarthritis and other negative health consequences 3-10 years following knee joint injury in youth sport. AB - OBJECTIVE: Post-traumatic osteoarthritis (PTOA) commonly affects the knee joint. Although the risk of PTOA substantially increases post-joint injury, there is little research examining PTOA outcomes early in the period between joint injury and disease onset. Improved understanding of this interval would inform secondary prevention strategies aimed at preventing and/or delaying PTOA progression. This study examines the association between sport-related knee injury and outcomes related to development of PTOA, 3-10 years post-injury. DESIGN: This preliminary analysis of the first year of a historical cohort study includes 100 (15-26 years) individuals. Fifty with a sport-related intra-articular knee injury sustained 3-10 years previously and 50 uninjured age, sex and sport matched controls. The primary outcome was the 'Symptoms' sub-scale of the Knee Osteoarthritis and Injury Outcome Score (KOOS). Secondary outcomes included; the remaining KOOS subscales, body mass index (BMI), hip abductor/adductor and knee extensor/flexor strength, estimated aerobic capacity (VO2max) and performance scores on three dynamic balance tests. Descriptive statistics (mean within-pair difference; 95% Confidence interval (CI) and conditional odds ratio (OR, 95% CI; BMI) were used to compare study groups. RESULTS: Injured participants demonstrated poorer KOOS outcomes [symptoms -9.4 (-13.6, -5.2), pain -4.0 (-6.8, 1.2), quality-of-life -8.0 (-11.0, -5.1), daily living -3.0 (-5.0, -1.1) and sport/recreation -6.9 (-9.9, -3.8)], were 3.75 times (95% CI 1.24, 11.3) more likely to be overweight/obese and had lower triple single leg hop scores compared to controls. No significant group differences existed for remaining balance scores, estimated VO2max, hip or knee strength ratios or side-to-side difference in hip abductor/adductor or quadricep/hamstring strength. CONCLUSIONS: This study provides preliminary evidence that youth/young adults following sport-related knee injury report more symptoms and poorer function, and are at greater risk of being overweight/obese 3-10 years post-injury compared to matched uninjured controls. PMID- 25725393 TI - Europium-doped Gd2O3 nanotubes cause the necrosis of primary mouse bone marrow stromal cells through lysosome and mitochondrion damage. AB - With the wide applications of europium-doped Gd2O3 nanoparticles (Gd2O3:Eu(3+) NPs) in biomedical fields, it will inevitably increase the chance of human exposure. It was reported that Gd2O3:Eu(3+) NPs could accumulate in bone. However, there have been few reports about the potential effect of Gd2O3:Eu(3+) NPs on bone marrow stromal cells (BMSCs). In this study, the Gd2O3:Eu(3+) nanotubes were prepared and characterized by powder X-ray diffraction (XRD), photoluminescence (PL) excitation and emission spectra, scanning electron microscope (SEM), and transmission electron microscopy (TEM). The cytotoxicity of Gd2O3:Eu(3+) nanotubes on BMSCs and the associated mechanisms were further studied. The results indicated that they could be uptaken into BMSCs by an energy dependent and macropinocytosis-mediated endocytosis process, and primarily localized in lysosome. Gd2O3:Eu(3+) nanotubes effectively inhibited the viability of BMSCs in concentration and time-dependent manners. A significant increase in the percentage of late apoptotic/necrotic cells, lactate dehydrogenase (LDH) leakage and the number of PI-stained cells was found after BMSCs were treated by 10, 20, and 40MUg/mL of Gd2O3:Eu(3+) nanotubes for 12h. No obvious DNA ladders were detected, but a dispersed band was observed. The above results revealed that Gd2O3:Eu(3+) nanotubes could trigger cell death by necrosis instead of apoptosis. Two mechanisms were involved in Gd2O3:Eu(3+) nanotube-induced BMSCs necrosis: lysosomal rupture and release of cathepsins B; and the overproduction of reactive oxygen species (ROS) injury to the mitochondria and DNA. The study provides novel evidence to elucidate the toxicity mechanisms and may be beneficial to more rational applications of these nanomaterials in the future. PMID- 25725394 TI - Aquatic hazard, bioaccumulation and screening risk assessment for 6:2 fluorotelomer sulfonate. AB - This study assessed the aquatic toxicity and bioaccumulation potential of 6:2 fluorotelomer sulfonate (6:2 FTSA). Acute and chronic aquatic hazard endpoints indicate 6:2 FTSA is not classified for aquatic hazard according to GHS or European CLP legislation. The aqueous bioconcentration factors for 6:2 FTSA were <40 and the dietary assimilation efficiency, growth corrected half-life and dietary biomagnification factor (BMF) were 0.435, 23.1d and 0.295, respectively. These data indicate that 6:2 FTSA is not bioaccumulative in aquatic organisms. Comparison of PNECs with the reported surface water concentrations (non-spill situations) suggests low risk to aquatic organisms from 6:2 FTSA. Future studies are needed to elucidate the biotic and abiotic fate of commercial AFFF surfactants in the environment. PMID- 25725395 TI - The plasticizer benzyl butyl phthalate (BBP) alters the ecdysone hormone pathway, the cellular response to stress, the energy metabolism, and several detoxication mechanisms in Chironomus riparius larvae. AB - Butyl benzyl phthalate (BBP) has been extensively used worldwide as a plasticizer in the polyvinyl chloride (PVC) industry and the manufacturing of many other products, and its presence in the aquatic environment is expected for decades. In the present study, the toxicity of BBP was investigated in Chironomus riparius aquatic larvae. The effects of acute 24-h and 48-h exposures to a wide range of BBP doses were evaluated at the molecular level by analysing changes in genes related to the stress response, the endocrine system, the energy metabolism, and detoxication pathways, as well as in the enzyme activity of glutathione S transferase. BBP caused a dose and time-dependent toxicity in most of the selected biomarkers. 24-h exposures to high doses affected larval survival and lead to a significant response of several heat-shock genes (hsp70, hsp40, and hsp27), and to a clear endocrine disrupting effect by upregulating the ecdysone receptor gene (EcR). Longer treatments with low doses triggered a general repression of transcription and GST activity. Furthermore, delayed toxicity studies were specially relevant, since they allowed us to detect unpredictable toxic effects, not immediately manifested after contact with the phthalate. This study provides novel and interesting results on the toxic effects of BBP in C. riparius and highlights the suitability of this organism for ecotoxicological risk assessment, especially in aquatic ecosystems. PMID- 25725396 TI - The use of cryopreserved sea urchin embryos (Paracentrotus lividus) in marine quality assessment. AB - We have established for first time an ecotoxicological bioassay using cryopreserved sea urchin embryos (Paracentotus lividus) and provided a comparison to the already standardized sea urchin embryo-larval bioassay, using selected (organic and inorganic) pollutants and sediment elutriates from 4 different locations from Ria de Vigo harbour (Galicia, NW Iberian Peninsula). A cryopreservation protocol was designed in order to enable the successful cryopreservation and cryobanking of gametes and embryos to be used for marine quality assessment and ensure the accessibility to high quality reproductive material all year round, as an option to conditioning adults for out of season reproduction. The calculated EC50 using the cryopreserved blastula was 53.7 MUg L(-1) for copper, 81.0 MUg L(-1) for lead, 300.6 MUg L(-1) for BP-3 and 300.6 MUg L(-1) for 4-MBC. The sensitivity of the classic sea urchin embryo-larval bioassay was compared with the bioassay conducted with cryopreserved blastula. The results showed that the use of cryopreserved blastula bioassay allows detecting lower concentrations of pollutants in comparison with the classic bioassay. PMID- 25725397 TI - A novel and green process for the production of tin oxide quantum dots and its application as a photocatalyst for the degradation of dyes from aqueous phase. AB - Green synthesis of SnO2 quantum dots (QDs) was developed by microwave heating method using the amino acids, namely, aspartic and glutamic acid. This method resulted in the formation of spherical SnO2 quantum dots with an average diameter less than the exciton Bohr radius of SnO2. The average diameter of SnO2 quantum dots formed using glutamic acid is ~1.6 nm and is smaller than that formed using aspartic acid (~2.6 nm). In the electronic spectra, a clear blue shift in the band gap energy from 4.33 to 4.4 eV is observed with a decrease in particle size (2.6-1.6 nm) due to three dimensional quantum confinement effects. The synthesized SnO2 QDs were characterized by transmission electron microscopy (TEM), selected area electron diffraction (SAED), X-ray diffraction (XRD) and Fourier transformed infrared spectroscopy (FT-IR). The optical properties were investigated using UV-visible spectroscopy. The synthesized SnO2 QDs act as an efficient photocatalyst in the degradation of Rose Bengal and Eosin Y dye under direct sunlight. For the first time, Rose Bengal dye was degraded using SnO2 QDs as a photocatalyst by solar irradiation. PMID- 25725398 TI - A synthetically modified hydrophobin showing enhanced fluorous affinity. AB - Hydrophobins are natural surfactant proteins endowed with exceptional surface activity and film-forming capabilities and their use as effective "fluorine-free fluorosurfactants" has been recently reported. In order to increase their fluorophilicity further, here we report the preparation of a unique fluorous modified hydrophobin, named F-HFBI. F-HFBI was found to be more effective than its wild-type parent protein HFBI at reducing interface tension of water at both air/water and oil/water interfaces, being particularly effective at the fluorous/water interface. F-HFBI was also found to largely retain the exceptionally good capability of forming strong and elastic films, typical of the hydrophobin family. Further studies by interface shear rheology and isothermal compression, alongside Quartz Crystal Microbalance and Atomic Force Microscopy, demonstrated the tendency of F-HFBI to form thicker films compared to the wild type protein. These results suggest that F-HFBI may function as an effective compatibilizer for biphasic systems comprising a fluorous phase. PMID- 25725399 TI - Free-standing carbon nanotube-titania photoactive sheets. AB - We report on the development of a new photoactive material via titania (TiO2) nanoparticle deposition on free-standing aligned carbon nanotube (CNT) sheets. Controlling homogeneous dispersion of negatively charged TiO2 nanoparticles, achieved by adjusting pH higher than the point of zero charge (PZC), influenced electrochemical deposition of TiO2 on CNT sheets substrate. Varying deposition time with constant voltage, 5 V allowed different thickness of TiO2 to be deposited layer on the CNT sheets. The thickness and morphology of CNT-TiO2 sheets was verified by scanning electron microscopy (SEM), energy dispersive X ray spectroscopy (EDS) and X-ray diffraction (XRD). Electrochemical experiments show that diffusion coefficient of Fe(CN)6(3-) was 5.56*10(-6) cm(2) s(-1) at pristine CNT sheets and 2.19*10(-6) cm(2) s(-1) at the CNT-TiO2 sheets. Photocatalytic activity for CNT-TiO2 sheets exhibits high photocurrent density (when deposition time=30 min, 4.3 MUA cm(-2) in N2, 13.4 MUA cm(-2) in CO2). This paper proved a possibility to use CNT-TiO2 sheets based on highly-aligned CNT sheets substrate as new photoactive material. PMID- 25725400 TI - The effect of fabric and stabbing variables on severance appearance. AB - During a stabbing, apparel fabrics are usually damaged and may be penetrated. Despite numerous studies considering forces required to penetrate skin and human stabbing performance, none have systematically evaluated which variables affect severance appearance from a textile science perspective using a human stabbing participant assessment. Although the human performance aspects of stabbing attacks have been previously studied, there has been a bias towards male assailants. The effects of fabric elasticity and tension applied have been identified as major factors influencing the severance profile in the fabric resulting from a stab attack. However, previous studies have considered limited fabric types with little emphasis on the physical and mechanical textile properties. The purpose of the current research was to use a human participant study (male n=5; female n=5) to determine the effect of fabric extension (0%, 10%) on the severance profile. Fabric type (single jersey; 100% cotton; 93% cotton/7% elastane), age (not laundered; laundered 60 times) and knife type (carving, bread) were also considered. Severance length was affected by participant sex, fabric type, laundering and knife type. The severances formed in this study were not significantly affected by the amount a fabric was extended when stabbed. Variability was observed in the severance appearance among participants where prior training influenced the angle of impact and knife withdrawal technique. PMID- 25725401 TI - Differences on the biological function of three Ig isotypes in zebrafish: a gene expression profile. AB - LPS challenge experiment was conducted to compare the different biological function of three Ig isotypes by checking the expression of Ig heavy chain in zebrafish adult and larvae. Overall, IgM and IgZ expression exceeded IgD in both the larvae and adult, and IgM expression exceeded IgZ in the larvae at later development stages and adult. Moreover, LPS challenge induced significant up regulation of all the three Ig isotypes in adult zebrafish, and the increase range of IgM and IgZ significantly exceeded that of IgD, indicating that the former two Ig isotypes played more important immunological role in response to antigen invasion. In additon, LPS challenge induced marked responses of all the Ig isotypes in the larvae since 21 dpf onwards. The response pattern of three Ig isotypes after LPS challenge was very similar in the larvae on 21 dpf, but the response range of IgZ exceeded IgM and IgD, and IgZ responded to LPS challenge a bit faster than the other Ig isotypes in the larvae on 28 dpf, which might be related to its important role in the mucosal immunity that was firstly induced by LPS immersion. PMID- 25725402 TI - The impact of Aeromonas salmonicida infection on innate immune parameters of Atlantic salmon (Salmo salar L). AB - Enzyme activities and gene expression of a number of innate immune parameters in the serum, mucus and skin of Atlantic salmon (Salmo salar) were investigated after challenge with a pathogenic strain of Aeromonas salmonicida (A. salmonicida). Fish were injected in the dorsal muscle with either 100 MUl bacterium solution, about 3.05 * 10(7) CFU/ml A. salmonicida, or 100 MUl 0.9% NaCl (as control group) and tissue samples were collected at days 0, 2, 4 and 6 post-injection. Lysozyme (LSZ) and alkaline phosphatase (AKP) activities in serum, mucus and skin, and LSZ and AKP mRNA expression in skin of the challenged fish were higher than those of the control at most of the experimental time, with significant differences at several time points (P < 0.05), indicating the involvement of LSZ and AKP in the innate immunity of Atlantic salmon to A. salmonicida. Superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities in mucus and skin, along with the SOD, POD and CAT mRNA expression in skin significantly decreased at day 4 and 6, indicating the decreased antioxidant capacity of the challenged fish. Glutamate pyruvate transaminase (GPT) and glutamic oxalacetic transaminase (GOT) activities in serum, mucus and skin of the challenged group were all higher than those of the control after the injection, and at several time points significant differences were found between the two groups, suggesting organs of fish were impaired after the pathogen infection. The changes of the GPT and GOT activities could be used as potential biomarkers for the impairment of physiological functions caused by the pathogen infection. Identified biomarkers of the immune responses will contribute to the early warning system of the disease. So this study will not only provide a theoretical basis for vaccine development, but also provide basic data for the establishment of early warning systems for diseases caused by A. salmonicida in Atlantic salmon rearing. PMID- 25725403 TI - Thermo-mechanical properties of poly epsilon-caprolactone/poly L-lactic acid blends: addition of nalidixic acid and polyethylene glycol additives. AB - The search for ideal biomaterials is still on-going for tissue regeneration. In this study, blends of poly epsilon-caprolactone (PCL) with poly l-lactic acid (PLLA), nalidixic acid (NA) and polyethylene glycol (PEG) were prepared. Mechanical and thermal properties of the blends were investigated by tensile and flexural analysis, DSC, TGA, WXRD, MFI, BET, SEM and hot stage optical microscopy. Results showed that the loading of PLLA caused a significant decrease in tensile strength and almost total eradication of the elongation at break of PCL matrix, especially after PEG and NA addition. Increased stiffness was also noted with additional NA, PEG and PLLA, resulting in an increase in the flexural modulus of the blends. Isothermal degradation indicated that bulk PCL, PLLA and the blends were thermally stable at 200 degrees C for the duration of 2h making extrusion of the blends at this temperature viable. Morphological study showed that increasing the PLLA content and addition of the very low viscosity PEG and powder NA decreased the Melt Flow Indexer and increased the viscosity. At the higher temperature, the PLLA begins to soften and eventually melts allowing for increased flow and, coupling this with, the natural increase in MFI caused by temperature is enhanced further. The PEG and NA addition increased dramatically the pore volume which is important for cell growth and flow transport of nutrients and metabolic waste. PMID- 25725404 TI - Proteomic analysis of the skin of Chinese giant salamander (Andrias davidianus). AB - The Chinese giant salamander (Andrias davidianus), renowned as a living fossil, is the largest and longest-lived amphibian species in the world. Its skin has developed mucous gland which could secrete a large amount of mucus under the scraping and electric stimulation, and the molting is the degraded skin stratum corneum. Although several proteomic studies have focused on functional proteomes of mammalian and frog skin, the skin proteome of Chinese giant salamander has not yet been carefully studied. To establish the functional skin proteome of Chinese giant salamander, two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS) were applied to detect the composition and relative abundance of the proteins in the skin, mucus and molting. Our findings indicated that 249 proteins were identified in the skin, 155 proteins in the mucus, and 97 proteins in the molting. Furthermore, Gene Ontology (GO) analysis showed that these proteins participated in various physiological activities, including extracellular matrix organization, defense, immune response, wound healing, respiration, etc. In conclusion, the proteomic results provide new insight in the aspects of the proteomes in the skin, mucus and the molting of Chinese giant salamander. BIOLOGICAL SIGNIFICANCE: This was the first study to examine the protein expression abundance in the skin, mucus and molting of Chinese giant salamander by a proteomics approach. Meantime, the identification of a more global proteome in normal skin may provide a basis for characterizing and comparing the skin proteomes from other amphibian species. PMID- 25725405 TI - Protist--continuity and change. PMID- 25725406 TI - Integration of pyrolysis and anaerobic digestion--use of aqueous liquor from digestate pyrolysis for biogas production. AB - Anaerobic digestion of aqueous pyrolysis liquor derived from pyrolysis of solid digestate was tested in batch mode using an un-adapted inoculum. Three pyrolysis liquors produced at 330 degrees C, 430 degrees C and 530 degrees C in four COD based concentrations of 3, 6, 12 and 30 g L(-1) were investigated. The three lower concentrations showed considerable biogas production, whereas the 30 g L( 1) dosage caused process inhibition. The highest methane yield of 199.1+/-18.5 mL g(COD)(-1) (COD removal: 56.9+/-5.3%) was observed for the 330 degrees C pyrolysis liquor, followed by the 430 degrees C sample with only slightly lower values. The 530 degrees C sample dropped to a yield of 129.3+/-19.7 mL g(COD)(-1) (COD removal: 36.9+/-5.6%). Most VOCs contained in the pyrolysis liquor (i.e. furfural, phenol, catechol, guaiacol, and levoglucosan) were reduced below detection limit (cresol by 10-60%). Consequently, integrated pyrolysis and anaerobic digestion in addition to thermochemical conversion of digestate also promises bioconversion of pyrolysis liquors. PMID- 25725407 TI - Bio-aviation fuel production from hydroprocessing castor oil promoted by the nickel-based bifunctional catalysts. AB - Bio-aviation fuel was firstly synthesized by hydroprocessing castor oil in a continuous-flow fixed-bed microreactor with the main objective to obtain the high yield of aviation fuel and determine the elemental compositions of the product phases as well as the reaction mechanism. Highest aviation range alkane yields (91.6 wt%) were achieved with high isomer/n-alkane ratio (i/n) 4.4-7.2 over Ni supported on acidic zeolites. In addition, different fuel range alkanes can be obtained by adjusting the degree of hydrodeoxygenation (HDO) and hydrocracking. And the observations are rationalized by a set of reaction pathways for the various product phases. PMID- 25725408 TI - Comparison of different pretreatments for the production of bioethanol and biomethane from corn stover and switchgrass. AB - In this study the efficiency of mild ionic liquid (IL) pretreatment and pressurized hot water (PHW) is evaluated and compared in terms of bioethanol and biomethane yields, with corn stover (CS) and switchgrass (SG) as model bioenergy crops. Both feedstocks pretreated with the IL 1-ethyl-3-methylimidazolium acetate [C2C1Im][OAc] at 100 degrees C for 3h exhibited lower glucose yield that those treated with harsher pretreatment conditions previously used. Compared to PHW, IL pretreatment demonstrated higher bioethanol yields; moreover IL pretreatment enhanced biomethane production. Taking into consideration both bioethanol and biomethane productions, results indicated that when using IL pretreatment, the total energy produced per kg of total solids was higher compared to untreated biomasses. Specifically energy produced from CS and SG was +18.6% and +34.5% respectively, as compared to those obtained by hot water treatment, i.e. +2.3% and +23.4% for CS and SG, respectively. PMID- 25725409 TI - Reduction of pyruvate orthophosphate dikinase activity is associated with high temperature-induced chalkiness in rice grains. AB - Global warming affects both rice (Oryza sativa) yields and grain quality. Rice chalkiness due to high temperature during grain filling would lower the grain quality. The biochemical and molecular mechanisms responsible for the increased occurrence of chalkiness under high temperature are not fully understood. Previous research suggested that cytosolic pyruvate orthophosphate dikinase (cyPPDK, EC 2.7.9.1) in rice modulates carbon metabolism. The objective of this study was to determine the relationship between cyPPDK and high temperature induced chalkiness. High temperature treatments were applied during the grain filling of two rice cultivars (9311 and TXZ-25) which had different sensitivity of chalkiness to high temperature. Chalkiness was increased significantly under high temperature treatment, especially for TXZ-25. A shortened grain filling duration and a decreased grain weight in both cultivars were caused by high temperature treatment. A reduction in PPDK activities due to high temperature was observed during the middle and late grain filling periods, accompanied by down regulated cyPPDK mRNA and protein levels. The temperature effects on the developmental regulation of PPDK activity were confirmed at transcription, translation and post-translational levels. PPDK activities were insensitive to variation in PPDK levels, suggesting the rapid phosphorylation mechanism of this protein. The two varieties showed similar responses to the high temperature treatment in both PPDK activities and chalkiness. We concluded that high temperature-induced chalkiness was associated with the reduction of PPDK activity. PMID- 25725410 TI - MhNCED3, a gene encoding 9-cis-epoxycarotenoid dioxygenase in Malus hupehensis Rehd., enhances plant tolerance to Cl- stress by reducing Cl- accumulation. AB - High Cl(-) concentrations in tissues can be toxic to crop plants and may lead to reduced growth rates and yields. 9-cis-epoxycarotenoid dioxygenase (NCED) is thought to be involved in the biosynthesis of abscisic acid (ABA), which is an important regulator of plant adaptive responses to stress. Here, the expression of MhNCED3 in Malus hupehensis Rehd. and the effects of MhNCED3 on plant tolerance to Cl(-) stress were explored. The results showed that MhNCED3 expression and ABA biosynthesis in M. hupehensis Rehd. were induced by Cl(-) stress. Ectopic expression of MhNCED3 in Arabidopsis complemented the phenotypic defects of the 129B08/nced3 mutant and enhanced WT tolerance to Cl(-) stress. The transgenic Arabidopsis showed improved growth and developmental status, increased ABA contents, and reduced transpiration rates and relative water content. Furthermore, ectopic expression of MhNCED3 decreased Cl(-) accumulation and oxidative damage, and up-regulated the expression levels of AtCLCc (chloride channel protein) and AtSLAH3 (slow anion channel 1 homolog 3) genes in Arabidopsis. These observations suggest that MhNCED3 has critical role in enhancing plant tolerance to Cl(-) stress by reducing Cl(-) accumulation. PMID- 25725411 TI - Cosmetics alter biologically-based factors of beauty: evidence from facial contrast. AB - The use of cosmetics by women seems to consistently increase their attractiveness. What factors of attractiveness do cosmetics alter to achieve this? Facial contrast is a known cue to sexual dimorphism and youth, and cosmetics exaggerate sexual dimorphisms in facial contrast. Here, we demonstrate that the luminance contrast pattern of the eyes and eyebrows is consistently sexually dimorphic across a large sample of faces, with females possessing lower brow contrasts than males, and greater eye contrast than males. Red-green and yellow-blue color contrasts were not found to differ consistently between the sexes. We also show that women use cosmetics not only to exaggerate sexual dimorphisms of brow and eye contrasts, but also to increase contrasts that decline with age. These findings refine the notion of facial contrast, and demonstrate how cosmetics can increase attractiveness by manipulating factors of beauty associated with facial contrast. PMID- 25725412 TI - Attentive tracking of moving objects in real 3D space. AB - Results of earlier multiple object tracking (MOT) studies imply that humans can track several moving targets in a 2D environment simultaneously. Recently, a study suggested that stereoscopic depth has positive effect on tracking multiple objects when the objects are presented separately on multiple planes. However, it remains unclear whether or not humans can track moving targets in a real 3D environment. In this study, we investigated this issue displaying four targets and four distractors on near and/or far depth planes separated physically by 6, 10 or 50 cm using a half-mirror and two CRT-monitors. In addition we also tested whether participants could track the targets when either a target or a distractor changed depth during tracking. Our results suggested that performance dropped if the targets were presented on both depth planes especially when the distance between the planes was 50 cm. In addition, participants could track a depth changed target if targets were presented on both planes before the start of a motion phase regardless of whether the initial state of targets distribution randomly varied or not, whereas they failed to track the target if all targets were presented on a single plane before MOT. In conclusion, humans have the ability to set attention on a wide range for MOT in a real 3D environment, with the provision that the efficiency of the tracking is critically dependent not only on the distance in depth but also on an initial state of distribution of the targets without the predictability of the initial state. PMID- 25725414 TI - An effective tool for identifying HIV-1 subtypes B, C, CRF01_AE, their recombinant forms, and dual infections in Southeast Asia by the multi-region subtype specific PCR (MSSP) assay. AB - The RV144 Thai vaccine trial has been the only vaccine study to show efficacy in preventing HIV infection. Ongoing molecular surveillance of HIV-1 in Southeast Asia is vital for vaccine development and evaluation. In this study a novel tool, the multi-region subtype specific PCR (MSSP) assay, that was able to identify subtypes B, C, CRF01_AE for Thailand, other Southeast Asian countries, India and China is described. The MSSP assay is based on a nested PCR strategy and amplifies eight short regions distributed along the HIV-1 genome using subtype specific primers. A panel of 41 clinical DNA samples obtained primarily from opiate users in northern Thailand was used to test the assay performance. The MSSP assay provided 73-100% sensitivity and 100% specificity for the three subtypes in each genome region. The assay was then field-tested on 337 sera from HIV infected northern Thai drug users collected between 1999 and 2002. Subtype distribution was CRF01_AE 77.4% (n=261), subtype B 3.3% (n=11), CRF01_AE/B recombinant 12.2% (n=41), CRF01_AE/C recombinant 0.6% (n=2), and non-typeable 6.5% (n=22). The MSSP assay is a simple, cost-effective, and accurate genotyping tool for laboratory settings with limited resources and is sensitive enough to capture the recombinant genomes and dual infections. PMID- 25725413 TI - Equivalence of influenza A virus RNA recovery from nasal swabs when lysing the swab and storage medium versus storage medium alone. AB - Surveillance of healthy individuals at high risk for zoonotic influenza A transmission is important for tracking trends in influenza A epidemiology. Practical measurement methods that maximize viral recovery and produce low variability are essential when low viral loads are expected. For this study, lysing both a nasal swab and its storage medium was compared to lysing the storage medium alone to determine which method results in greater influenza A virus recovery. Independent results from two laboratories suggest that including the swab in the lysis step does not lead to higher influenza A virus recovery, and that recovery is less variable when only the swab storage medium is extracted. These results indicate that simply lysing the swab storage medium is an effective extraction method for nasal swabs collected during studies of influenza A virus exposure among healthy populations. PMID- 25725415 TI - Emotion processing deficits: a liability spectrum providing insight into comorbidity of mental disorders. AB - Epidemiological studies have revealed that mental disorders are highly comorbid; almost half of the people with a mental disorder also meet the criteria of another disorder. The explanation of this high comorbidity has remained a scientific puzzle. We propose 'disrupted emotion processing' as a liability spectrum that underlies many different mental disorders. Emotion processing deficits have been reported in different disorders and result in difficulties in regulating emotions and at the perceptual level in attentional biases and impaired recognition of emotional expressions. This article provides a detailed overview of the literature on disrupted emotion processing in clinical groups on the behavioral and neurological level. In the discussion, the similarities and differences between these disorders are discussed in the context of common neuro endocrine, genetic and environmental factors and ideas are put forward on how future research may advance. Most importantly, more interdisciplinary research is needed in which different techniques, tasks and clinical populations are combined to get a better understanding of disrupted emotion processing as a liability spectrum underlying various different mental disorders. PMID- 25725416 TI - A neuropsychological investigation of decisional certainty. AB - The certainty that one feels following a decision increases decision-making efficiency, but can also result in decreased decision accuracy. In the current study, a neuropsychological approach was used to examine the impact of damage to the ventromedial prefrontal cortex (vmPFC) on core psychological processes promoting decision certainty: selective exposure, overconfidence, and decisiveness. Given previous research demonstrating that vmPFC damage disrupts the generation of negative emotional (somatic) states that have been associated with selective exposure and overconfidence, it was hypothesized that damage to the vmPFC would disrupt engagement in selective exposure, decrease overconfidence, and increase indecision. Individuals with vmPFC damage exhibited increased indecision, but contrary to our hypothesis, engaged in similar levels of selective exposure and overconfidence as the comparison groups. These results indicate that indecision may be an important psychological mechanism involved in decision-making impairments associated with vmPFC injury. The results also suggest that the vmPFC may not be critical for selective exposure or overconfidence, which provides support for a recent "desirability" account of selective exposure. PMID- 25725417 TI - Manganese (III) meso-tetrakis N-ethylpyridinium-2-yl porphyrin acts as a pro oxidant to inhibit electron transport chain proteins, modulate bioenergetics, and enhance the response to chemotherapy in lymphoma cells. AB - The manganese porphyrin, manganese (III) meso-tetrakis N-ethylpyridinium-2-yl porphyrin (MnTE-2-PyP(5+)), acts as a pro-oxidant in the presence of intracellular H2O2. Mitochondria are the most prominent source of intracellular ROS and important regulators of the intrinsic apoptotic pathway. Due to the increased oxidants near and within the mitochondria, we hypothesized that the mitochondria are a target of the pro-oxidative activity of MnTE-2-PyP(5+) and that we could exploit this effect to enhance the chemotherapeutic response in lymphoma. In this study, we demonstrate that MnTE-2-PyP(5+) modulates the mitochondrial redox environment and sensitizes lymphoma cells to antilymphoma chemotherapeutics. MnTE-2-PyP(5+) increased dexamethasone-induced mitochondrial ROS and oxidation of the mitochondrial glutathione pool in lymphoma cells. The combination treatment induced glutathionylation of Complexes I, III, and IV in the electron transport chain, and decreased the activity of Complexes I and III, but not the activity of Complex IV. Treatment with the porphyrin and dexamethasone also decreased cellular ATP levels. Rho(0) malignant T-cells with impaired mitochondrial electron transport chain function were less sensitive to the combination treatment than wild-type cells. These findings suggest that mitochondria are important for the porphyrin's ability to enhance cell death. MnTE-2-PyP(5+) also augmented the effects of 2-deoxy-D-glucose (2DG), an antiglycolytic agent. In combination with 2DG, MnTE-2-PyP(5+) increased protein glutathionylation, decreased ATP levels more than 2DG treatment alone, and enhanced 2DG-induced cell death in primary B-ALL cells. MnTE-2-PyP(5+) did not enhance dexamethasone- or 2DG-induced cell death in normal cells. Our findings suggest that MnTE-2-PyP(5+) has potential as an adjuvant for the treatment of hematologic malignancies. PMID- 25725419 TI - Radical Prostatectomy Findings in Men on Active Surveillance: Variable Findings Dependent on Reason for Surgery and Entry Criteria. AB - PURPOSE: We studied adverse radical prostatectomy findings in men on an active surveillance program with different entry and exit criteria. MATERIALS AND METHODS: The study included 80 men with biopsy progression, 33 who opted out for personal reasons and 24 who initially did not meet entry criteria mainly due to increased prostate specific antigen density. RESULTS: Of men who opted out 78.8% had a higher Gleason score of 6 than men who progressed on biopsy (46.2%, p = 0.002) and men with high prostate specific antigen density (45.8%, p = 0.02). Men with high prostate specific antigen density had less organ confined disease than the group that opted out (p <0.006) and a trend compared to the biopsy progression group (p = 0.07). Mean dominant tumor volume was lower in men who opted out than in those with biopsy progression (0.56 vs 1.1 cc, p = 0.03). The incidence of insignificant cancer was higher in men who opted out (48.4%) than in those with biopsy progression (28.4%, p = 0.05) and those with high prostate specific antigen density (20.8%, p = 0.035). There was a higher incidence of anterior tumor in men with high prostate specific antigen density (55.0%) than with biopsy progression (21.3%, p = 0.009) and a trend compared to those who opted out (27.3%, p = 0.06). CONCLUSIONS: The majority of men with biopsy progression still had tumors with features of curable disease. Men who opted out without biopsy progression had even less adverse findings, which supports counseling men to stay on active surveillance while they meet followup criteria. Men with elevated prostate specific antigen density had more anterior tumors and less organ confined cancer, substantiating that the ideal patients for active surveillance are those who meet all entry criteria. PMID- 25725418 TI - Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer. AB - Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(*-), an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer. PMID- 25725420 TI - alpha-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease. AB - The unfolded protein response (UPR) monitors the folding environment within the endoplasmic reticulum (ER). Accumulation of misfolded proteins within the ER activates the UPR resulting in the execution of adaptive or non-adaptive signaling pathways. alpha-Synuclein (alpha-syn) whose accumulation and aggregation define the pathobiology of Parkinson's disease (PD) has been shown to inhibit ER-Golgi transit of COPII vesicles. ATF6, a protective branch of the UPR, is processed via COPII mediated ER-Golgi transit following its activation via ER stress. Using cellular PD models together with biochemical reconstitution assays, we showed that alpha-syn inhibited processing of ATF6 directly through physical interactions and indirectly through restricted incorporation into COPII vesicles. Impaired ATF6 signaling was accompanied by decreased ER-associated degradation (ERAD) function and increased pro-apoptotic signaling. The mechanism by which alpha-syn inhibits ATF6 signaling expands our understanding of the role ER stress and the UPR play in neurodegenerative diseases such as PD. PMID- 25725421 TI - Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development. AB - Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy along with delayed psychomotor development and heightened premature mortality. A primary monogenic cause is mutation of the SCN1A gene, which encodes the voltage gated sodium channel subunit Nav1.1. The nature and timing of changes caused by SCN1A mutation in the hippocampal dentate gyrus (DG) network, a core area for gating major excitatory input to hippocampus and a classic epileptogenic zone, are not well known. In particularly, it is still not clear whether the developmental deficit of this epileptogenic neural network temporally matches with the progress of seizure development. Here, we investigated the emerging functional and structural deficits of the DG network in a novel mouse model (Scn1a(E1099X/+)) that mimics the genetic deficit of human DS. Scn1a(E1099X/+) (Het) mice, similarly to human DS patients, exhibited early spontaneous seizures and were more susceptible to hyperthermia-induced seizures starting at postnatal week (PW) 3, with seizures peaking at PW4. During the same period, the Het DG exhibited a greater reduction of Nav1.1-expressing GABAergic neurons compared to other hippocampal areas. Het DG GABAergic neurons showed altered action potential kinetics, reduced excitability, and generated fewer spontaneous inhibitory inputs into DG granule cells. The effect of reduced inhibitory input to DG granule cells was exacerbated by heightened spontaneous excitatory transmission and elevated excitatory release probability in these cells. In addition to electrophysiological deficit, we observed emerging morphological abnormalities of DG granule cells. Het granule cells exhibited progressively reduced dendritic arborization and excessive spines, which coincided with imbalanced network activity and the developmental onset of spontaneous seizures. Taken together, our results establish the existence of significant structural and functional developmental deficits of the DG network and the temporal correlation between emergence of these deficits and the onset of seizures in Het animals. Most importantly, our results uncover the developmental deficits of neural connectivity in Het mice. Such structural abnormalities likely further exacerbate network instability and compromise higher-order cognitive processing later in development, and thus highlight the multifaceted impacts of Scn1a deficiency on neural development. PMID- 25725422 TI - Anthelmintic efficacy, plasma and milk kinetics of eprinomectin following topical and subcutaneous administration to yaks (Bos grumniens). AB - Eprinomectin is recommended for use as an anti-parasitic agent in livestock, including cattle. Yaks are a member of the cattle family living in the high altitude mountains of China and adjacent countries; however, there have been no clinical trials of the anthelmintic efficacy and pharmacokinetics of eprinomectin in yaks. The purpose of this study was to investigate the endectocidal efficacy and pharmacokinetics of eprinomectin following topical (at 0.5 mg/kg) and subcutaneous (at 0.2 mg/kg) administration in the yak. After topical administration, plasma eprinomectin reached a peak value of 15.31 +/- 3.71 ng/ml (Cmax) at 3.01 +/- 1.22 days (Tmax). In milk, the Cmax was 3.74 +/- 1.05 ng/ml at 3.00 +/- 0.88 days. The AUC0-t for plasma was 193.84 +/- 26.34 ng d/ml and for milk AUC(0-t) was 46.24 +/- 10.37 ng d/ml. The mean residence time (MRT) was 10.74 +/- 1.44 days and 10.90 +/- 3.87 days in plasma and milk, respectively. After subcutaneous administration, the Cmax was 35.78 +/- 10.53 ng/ml at 0.91 +/- 0.39 days in plasma and 9.10 +/- 3.61 ng/ml at 1.61 +/- 1.05 days in milk. The MRTs in plasma and milk were 3.07 +/- 1.50 and 3.64 +/- 1.15 days, respectively. The AUC(0-t) was 133.71 +/- 32.51 ng d/ml for plasma and 43.85 +/- 14.16 ng d/ml for milk. Both the pour-on and injectable formulation of eprinomectin were similarly efficacious (minimum egg count reductions of 94% and 96.4%, respectively) at each post-treatment time point. However, Tmax, MRT and t(1/2el) were longer, and Cmax of eprinomectin in the plasma and milk were lower, following topical administration compared to those after subcutaneous administration. In conclusion, these results support the use of eprinomectin in yaks. The pour-on formulation of eprinomectin can be recommended for nematode control in lactating yaks with no milk-withdrawal period because of its low residue profile and good efficacy. PMID- 25725423 TI - Visual guidance during bicycle steering through narrow lanes: a study in children. AB - Recently, Vansteenkiste et al. (2013) explored how visual behaviour guides bicycle steering when cycling at different speeds through 15m long lanes of 10, 25 and 40cm wide. Participants were found to shift their gaze direction towards the end of the lanes at higher speeds, towards the near pathway on narrow lanes and more towards irrelevant areas on wider lanes. To investigate to what extent young learner bicyclists adapt their visual behaviour in a similar way as adults, the experiment was repeated with seven eight-year-old children, and results were compared to the adult data. Children were found to cycle slower through narrow lanes than adults. However, with increasing lane width and cycling speed, children made the same shifts of visual gaze direction as the adults. These results suggest that for a simple precision steering task, children are able to adopt a similar visual-motor strategy as adults, provided that they cycle at their own pace. PMID- 25725424 TI - Associations between driving under the influence of alcohol or drugs, speeding and seatbelt use among fatally injured car drivers in Norway. AB - Since 2005, all fatal road traffic crashes in Norway have been analyzed in-depth by multidisciplinary investigation teams organized by the Norwegian Public Roads Administration (NPRA). During the period 2005-2010, 608 drivers of cars or vans were killed in road traffic crashes. Blood samples were collected from 372 (61%) of the drivers and analyzed for alcohol and a large number of psychoactive drugs at the Norwegian Institute of Public Health (NIPH). After coupling the analytical results with the NPRA crash database, 369 drivers with a fatal outcome were identified and included. Alcohol or drug concentrations in blood above the legal limits were found in 39.8% of the drivers who were investigated for alcohol or drug impairment; 33.9% had blood alcohol concentrations above 0.5g/L or concentrations of drugs above the equivalent Norwegian legal impairment limits or concentrations of amphetamines above 200MUg/L. Among drivers with a fatal outcome who had been impaired by alcohol or drugs, 64.6% were unbelted and 71.7% were speeding when the crash occurred; whereas 24.2% and 33.2% of the sober drivers were unbelted or speeding, respectively. Statistically significant associations were found between impairment by alcohol or amphetamines and driving unbelted or speeding. Excessive speeding is one of the main reasons for road traffic crashes and together with being unbelted the main reasons for a fatal outcome. This behavior might in many cases be due to increased risk-taking or negligence of safety measures as a result of alcohol or drug use. PMID- 25725425 TI - Exposure to social defeat stress in adolescence improves the working memory and anxiety-like behavior of adult female rats with intrauterine growth restriction, independently of hippocampal neurogenesis. AB - Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. PMID- 25725426 TI - Loneliness predicts postprandial ghrelin and hunger in women. AB - Loneliness is strongly linked to poor health. Recent research suggests that appetite dysregulation provides one potential pathway through which loneliness and other forms of social disconnection influence health. Obesity may alter the link between loneliness and appetite-relevant hormones, one unexplored possibility. We examined the relationships between loneliness and both postmeal ghrelin and hunger, and tested whether these links differed for people with a higher versus lower body mass index (BMI; kg/m(2)). During this double-blind randomized crossover study, women (N=42) ate a high saturated fat meal at the beginning of one full-day visit and a high oleic sunflower oil meal at the beginning of the other. Loneliness was assessed once with a commonly used loneliness questionnaire. Ghrelin was sampled before the meal and postmeal at 2 and 7h. Self-reported hunger was measured before the meal, immediately postmeal, and then 2, 4, and 7h later. Lonelier women had larger postprandial ghrelin and hunger increases compared with less lonely women, but only among participants with a lower BMI. Loneliness and postprandial ghrelin and hunger were unrelated among participants with a higher BMI. These effects were consistent across both meals. These data suggest that ghrelin, an important appetite-regulation hormone, and hunger may link loneliness to weight gain and its corresponding negative health effects among non-obese people. PMID- 25725427 TI - Male fidelity expressed through rapid testosterone suppression of ultrasonic vocalizations to novel females in the monogamous California mouse. AB - The steroid hormone testosterone (T) is a well-known mediator of male sexual behavior in vertebrates. However, less is known about T's rapid effects on sexual behavior, particularly those involving ultrasonic vocalizations (USVs), a mode of communication that can influence mate acquisition in rodents. Using the monogamous California mouse, Peromyscus californicus, we tested whether T rapidly alters male USV production by giving T or saline injections to non-paired (sexually naive) males and paired (paternally experienced and pair-bonded) males immediately prior to a brief exposure to an unrelated, novel female. Among non paired males, no differences in the total number of USVs were observed; however, T increased the proportion of simple sweeps produced. Among paired males, T decreased the number of USVs produced, and this change was driven by a reduction in simple sweeps. These results suggest a differential rapid effect of T pulses between non-paired and paired males upon exposure to a novel female. Additionally, we observed a positive correlation in the production of USVs made between males and novel females, and this relationship was altered by T. Given the importance of USVs in sexual communication, our study supports an essential concept of monogamy in that mate fidelity is reinforced by decreased responsiveness to prospective mates outside of the pair bond. The central mechanism in pair bonded males that decreases their responsiveness to novel females appears to be one that T can trigger. This is among the first studies to demonstrate that T can inhibit sexually related behaviors and do so rapidly. PMID- 25725428 TI - Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rgamma(null) mice optimizes humanized mice that mount adaptive antibody responses. AB - Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rgamma(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications. PMID- 25725429 TI - A "developmental hourglass" in fungi. AB - The "developmental hourglass" concept suggests that intermediate developmental stages are most resistant to evolutionary changes and that differences between species arise through divergence later in development. This high conservation during middevelopment is illustrated by the "waist" of the hourglass and it represents a low probability of evolutionary change. Earlier molecular surveys both on animals and on plants have shown that the genes expressed at the waist stage are more ancient and more conserved in their expression. The existence of such a developmental hourglass has not been explored in fungi, another eukaryotic kingdom. In this study, we generated a series of transcriptomic data covering the entire lifecycle of a model mushroom-forming fungus, Coprinopsis cinerea, and we observed a molecular hourglass over its development. The "young fruiting body" is the stage that expresses the evolutionarily oldest (lowest transcriptome age index) transcriptome and gives the strongest signal of purifying selection (lowest transcriptome divergence index). We also demonstrated that all three kingdoms-animals, plants, and fungi-display high expression levels of genes in "information storage and processing" at the waist stages, whereas the genes in "metabolism" become more highly expressed later. Besides, the three kingdoms all show underrepresented "signal transduction mechanisms" at the waist stages. The synchronic existence of a molecular "hourglass" across the three kingdoms reveals a mutual strategy for eukaryotes to incorporate evolutionary innovations. PMID- 25725430 TI - Sexual dimorphism and the evolution of sex-biased gene expression in the brown alga ectocarpus. AB - Males and females often have marked phenotypic differences, and the expression of these dissimilarities invariably involves sex differences in gene expression. Sex biased gene expression has been well characterized in animal species, where a high proportion of the genome may be differentially regulated in males and females during development. Male-biased genes tend to evolve more rapidly than female-biased genes, implying differences in the strength of the selective forces acting on the two sexes. Analyses of sex-biased gene expression have focused on organisms that exhibit separate sexes during the diploid phase of the life cycle (diploid sexual systems), but the genetic nature of the sexual system is expected to influence the evolutionary trajectories of sex-biased genes. We analyze here the patterns of sex-biased gene expression in Ectocarpus, a brown alga with haploid sex determination (dioicy) and a low level of phenotypic sexual dimorphism. In Ectocarpus, female-biased genes were found to be evolving as rapidly as male-biased genes. Moreover, genes expressed at fertility showed faster rates of evolution than genes expressed in immature gametophytes. Both male- and female-biased genes had a greater proportion of sites experiencing positive selection, suggesting that their accelerated evolution is at least partly driven by adaptive evolution. Gene duplication appears to have played a significant role in the generation of sex-biased genes in Ectocarpus, expanding previous models that propose this mechanism for the resolution of sexual antagonism in diploid systems. The patterns of sex-biased gene expression in Ectocarpus are consistent both with predicted characteristics of UV (haploid) sexual systems and with the distinctive aspects of this organism's reproductive biology. PMID- 25725433 TI - Bioassay-guided isolation and mechanistic action of anti-inflammatory agents from Clerodendrum inerme leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Clerodendrum inerme (L.) Gaertn. have commonly been used in Thai traditional medicine for treatment of inflammatory diseases. However, the bioactive compounds responsible for the anti inflammatory effect of leaves have not been yet determined. The objective of the present study was to isolate these bioactive compounds by bioassay-guided isolation technique and to determine the mode of action of isolated compounds in LPS-induced macrophages. MATERIALS AND METHODS: Anti-inflammatory effect of various fractions (hexane, ethyl acetate and water) of ethanol extract of C. inerme leaves was determined from the production of nitric oxide (NO) in RAW 264.7 macrophage stimulated with LPS. The mRNA and protein levels were determined also by real-time reverse transcription-polymerase chain reaction and western blot analysis, respectively. Leaf bioactive compounds were isolated by bioassay guided fractionation technique using column chromatography. RESULTS: The ethyl acetate fraction (EA) among solvent extracts provided the most potent inhibitory activity on NO production. Also, EA reduced the mRNA and protein expressions of inducible nitric oxide synthase (iNOS) in LPS-stimulated macrophages. Three known flavones, acacetin (1), hispidulin (2) and diosmetin (3), were isolated based on inhibition of NO production. Furthermore, hispidulin also inhibited PGE2 production as well as iNOS and cyclooxygenase-2 expressions via the blockade of NF-kappaB DNA-binding activity and JNKway. CONCLUSIONS: Our results found acacetin (1), hispidulin (2) and diosmetin (3), were responsible for the anti inflammatory properties of C. inerme leaves. We provide scientific evidence to support the usefulness of C. inerme leaves in traditional medicine for the treatment of inflammation-related diseases. PMID- 25725431 TI - Sphingolipids, Transcription Factors, and Conserved Toolkit Genes: Developmental Plasticity in the Ant Cardiocondyla obscurior. AB - Developmental plasticity allows for the remarkable morphological specialization of individuals into castes in eusocial species of Hymenoptera. Developmental trajectories that lead to alternative caste fates are typically determined by specific environmental stimuli that induce larvae to express and maintain distinct gene expression patterns. Although most eusocial species express two castes, queens and workers, the ant Cardiocondyla obscurior expresses diphenic females and males; this provides a unique system with four discrete phenotypes to study the genomic basis of developmental plasticity in ants. We sequenced and analyzed the transcriptomes of 28 individual C. obscurior larvae of known developmental trajectory, providing the first in-depth analysis of gene expression in eusocial insect larvae. Clustering and transcription factor binding site analyses revealed that different transcription factors and functionally distinct sets of genes are recruited during larval development to induce the four alternative trajectories. In particular, we found complex patterns of gene regulation pertaining to sphingolipid metabolism, a conserved molecular pathway involved in development, obesity, and aging. PMID- 25725432 TI - Digestive organ in the female reproductive tract borrows genes from multiple organ systems to adopt critical functions. AB - Persistent adaptive challenges are often met with the evolution of novel physiological traits. Although there are specific examples of single genes providing new physiological functions, studies on the origin of complex organ functions are lacking. One such derived set of complex functions is found in the Lepidopteran bursa copulatrix, an organ within the female reproductive tract that digests nutrients from the male ejaculate or spermatophore. Here, we characterized bursa physiology and the evolutionary mechanisms by which it was equipped with digestive and absorptive functionality. By studying the transcriptome of the bursa and eight other tissues, we revealed a suite of highly expressed and secreted gene products providing the bursa with a combination of stomach-like traits for mechanical and enzymatic digestion of the male spermatophore. By subsequently placing these bursa genes in an evolutionary framework, we found that the vast majority of their novel digestive functions were co-opted by borrowing genes that continue to be expressed in nonreproductive tissues. However, a number of bursa-specific genes have also arisen, some of which represent unique gene families restricted to Lepidoptera and may provide novel bursa-specific functions. This pattern of promiscuous gene borrowing and relatively infrequent evolution of tissue-specific duplicates stands in contrast to studies of the evolution of novelty via single gene co-option. Our results suggest that the evolution of complex organ-level phenotypes may often be enabled (and subsequently constrained) by changes in tissue specificity that allow expression of existing genes in novel contexts, such as reproduction. The extent to which the selective pressures encountered in these novel roles require resolution via duplication and sub/neofunctionalization is likely to be determined by the need for specialized reproductive functionality. Thus, complex physiological phenotypes such as that found in the bursa offer important opportunities for understanding the relative role of pleiotropy and specialization in adaptive evolution. PMID- 25725434 TI - Anti-diabetic nephropathy compounds from Cinnamomum cassia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Cinnamomum cassia, called 'Rou-Gui', a traditional spice and medicine in China, is used to treat diseases resulted from kidney yang deficiency, including diabetic nephropathy. The aim of this study is to investigate the anti-diabetic nephropathy activity of Rou-Gui and the active compounds in it. MATERIALS AND METHODS: The air-dried bark of C. cassia was extracted with 90% EtOH, the obtained residue was successively partitioned by petroleum ether, EtOAc, and n-BuOH followed by concentrating to give petroleum ether (RG-1), EtOAc (RG-2), n-BuOH (RG-3), and water fraction (RG-4), respectively. The anti-diabetic nephropathy activity of fraction (RG-1-4) was evaluated in vitro by inhibiting the expression of fibronectin, monocyte chemoattractant protein-1 and interleukin-6 in high-glucose-induced mesangial cells. By bioassay screenings, repeated column chromatography on fractions of RG 1, 2, and 3, led to the isolation of 23 compounds, whose structures were determined by extensive spectroscopic analyses, and the anti-diabetic nephropathy activity of the isolated compounds was also evaluated. RESULTS: Four new sesquiterpenoids, cinnamoids A-D (1-4), a new natural product (5), and 18 known compounds (6-23) were isolated from the EtOH extract of the bark of C. cassia under the bioassay-guided screenings. The anti-diabetic nephropathy activity assay showed that fractions of RG-1, 2, and 3 could significantly inhibit the production of fibronectin, monocyte chemoattractant protein-1 and interleukin-6 in high-glucose-stimulated mesangial cells at the concentration of 50 MUg/ml; and sesquiterpenoids 5, 6, 14 and compound 20 could significantly inhibit the expression of fibronectin, monocyte chemoattractant protein-1 and interleukin-6 at the concentration of 50 MUM. CONCLUSIONS: The results revealed that sesquiterpenoids may be the active compounds in C. cassia bark on diabetic nephropathy which provided new evidences for the traditional use of this herb to treat diabetic nephropathy and associated kidney diseases. PMID- 25725435 TI - Anti-mycobacterial triterpenes from the Canadian medicinal plant Alnus incana. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alnus incana, commonly known as the gray or speckled alder, is a medicinal plant used by some Canadian First Nations to treat symptoms associated with tuberculosis. The aim of this study was to assess the anti-mycobacterial activity of an Alnus incana bark extract and to identify the active constituents of the extract. MATERIALS AND METHODS: Methanolic extracts of the bark of A. incana were subjected to bioassay guided fractionation using Mycobacterium tuberculosis (H37Ra). The active constituents were identified by NMR and MS. RESULTS: Four pentacyclic lupane triterpenes were isolated and were identified as betulin, betulinic acid, betulone and lupenone. Betulin displayed a MIC of 12.5 MUg/mL and an IC50 of 2.4 MUg/mL against M. tuberculosis (H37Ra). Betulinic acid and betulone showed lower anti-mycobacterial activities with IC50 values of 84 and 57 MUg/mL respectively. Lupenone was inactive against M. tuberculosis (H37Ra). CONCLUSIONS: Betulin, betulinic acid and betulone were identified as the major anti-mycobacterial constituents in the bark of A. incana and the functionality at carbons 3 and 28 of the lupane skeleton would seem to be important in determining the anti-mycobacterial activity of the triterpenes. This work supports the ethnopharmacological use of A. incana by Canadian First Nations communities as a treatment for tuberculosis. PMID- 25725436 TI - Large-scale genetic analysis of chloroplast biogenesis in maize. AB - BACKGROUND: Chloroplast biogenesis involves a collaboration between several thousand nuclear genes and ~100 genes in the chloroplast. Many of the nuclear genes are of cyanobacterial ancestry and continue to perform their ancestral function. However, many others evolved subsequently and comprise a diverse set of proteins found specifically in photosynthetic eucaryotes. Genetic approaches have been key to the discovery of nuclear genes that participate in chloroplast biogenesis, especially those lacking close homologs outside the plant kingdom. SCOPE OF REVIEW: This article summarizes contributions from a genetic resource in maize, the Photosynthetic Mutant Library (PML). The PML collection consists of ~2000 non-photosynthetic mutants induced by Mu transposons. We include a summary of mutant phenotypes for 20 previously unstudied maize genes, including genes encoding chloroplast ribosomal proteins, a PPR protein, tRNA synthetases, proteins involved in plastid transcription, a putative ribosome assembly factor, a chaperonin 60 isoform, and a NifU-domain protein required for Photosystem I biogenesis. MAJOR CONCLUSIONS: Insertions in 94 maize genes have been linked thus far to visible and molecular phenotypes with the PML collection. The spectrum of chloroplast biogenesis genes that have been genetically characterized in maize is discussed in the context of related efforts in other organisms. This comparison shows how distinct organismal attributes facilitate the discovery of different gene classes, and reveals examples of functional divergence between monocot and dicot plants. GENERAL SIGNIFICANCE: These findings elucidate the biology of an organelle whose activities are fundamental to agriculture and the biosphere. This article is part of a Special Issue entitled: Chloroplast Biogenesis. PMID- 25725437 TI - Possible function of VIPP1 in maintaining chloroplast membranes. AB - A protein designated as VIPP1 is found widely in organisms performing oxygenic photosynthesis, but its precise role in chloroplasts has remained somewhat mysterious. Based on its structural similarity, it presumably has evolved from bacterial Phage shock protein A (PspA) with a C-terminal extension of approximately 40 amino acids. Both VIPP1 and PspA are membrane-associated despite the lack of transmembrane helices. They form an extremely large homo-complex that consists of an oligomeric ring unit. Although PspA is known to respond to membrane stress and although it acts in maintaining proton motive force through membrane repair, the multiple function of VIPP1, such as vesicle budding from inner envelope to deliver lipids to thylakoids, maintenance of photosynthetic complexes in thylakoid membranes, biogenesis of Photosystem I, and protective role of inner envelope against osmotic stress, has been proposed. Whatever its precise function in chloroplasts, it is an important protein because depletion of VIPP1 in mutants severely affects photoautotrophic growth. Recent reports of the relevant literature describe that VIPP1 becomes highly mobile when chloroplasts receive hypotonic stress, and that VIPP1 is tightly bound to lipids, which implies a crucial role of VIPP1 in membrane repair through lipid transfer. This review presents a summary of our current knowledge related to VIPP1, particularly addressing the dynamic behavior of complexes against stress and its property of lipid binding. Those data altogether suggest that VIPP1 acts a priori in chloroplast membrane maintenance through its activity to transfer lipids rather than in thylakoid formation through vesicles. This article is part of a Special Issue titled: Chloroplast Biogenesis. PMID- 25725438 TI - Prognostic nomogram for patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization. AB - BACKGROUND & AIMS: To establish an effective prognostic nomogram for patients with unresectable hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). METHODS: The nomogram was constructed based on data obtained from a retrospective study on 2938 patients who received TACE as an initial therapy from 2000 to 2008. The predictive accuracy and discriminative ability of the nomogram were compared with seven current commonly used staging systems on HCC by using data obtained from a prospective study on a cohort of 647 patients treated from January 2011 to December 2011 at the same institution. Additional external validation was performed using a data set (n=221) from another institution. RESULTS: Portal vein invasion, tumor number, tumor capsule, alpha fetoprotein, aspartate aminotransferase, and indocyanine green retention at 15 min formed the basis of the nomogram. The concordance index (C-index) of the nomogram was 0.755, which was significantly better than the American Joint Committee on Cancer seventh edition (0.612), the Barcelona Clinic Liver Cancer system (0.692), the Okuda system (0.579), the Japan Integrated Staging system (0.637), Cancer of the Liver Italian Program system (0.683), the Chinese University Prognostic Index (0.637) and the Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (0.577) (p<0.001 for all). The calibration curve for predicting probability of survival showed a good agreement between the nomogram and actual observation. The findings were supported by the external validation cohort. The nomogram gave better discrimination than the seven staging systems. CONCLUSIONS: The proposed nomogram gave accurate prognostic prediction in patients with unresectable HCC after treatment with TACE. PMID- 25725439 TI - Coagulation and fibrosis: A potential non-negligible target of statins in chronic hepatitis. PMID- 25725440 TI - Can Colonoscopy Reduce the Risk of Colon Cancer and Mortality in Patients With Inflammatory Bowel Disease? PMID- 25725441 TI - Cumulative Sum Analysis and Endoscopic Ultrasound Training Competency: A Requiem for Expert Opinion? PMID- 25725442 TI - Predicting microscopic colitis before colon biopsies: a look into the crystal ball? PMID- 25725443 TI - Surveillance Endoscopy Definition Critical to the Nomogram. PMID- 25725444 TI - Bridging the gap between host immune response and intestinal dysbiosis in inflammatory bowel disease: does immunoglobulin A mark the spot? AB - Inflammatory bowel disease (IBD) is a chronic, debilitating condition characterized by relapsing and remitting episodes of gastrointestinal inflammation. As the incidence and prevalence have increased, so has our understanding of the pathophysiology of this complex, immunologically mediated disease. With advances in bacterial and human gene sequencing technologies, a significant amount of work has focused on how alterations in the intestinal microbiome affect disease onset and progression. A recent study in Cell suggests that it may be possible to identify specific bacteria responsible for promoting a proinflammatory state by assessing the degree to which they are coated by the immunoglobulin (Ig) A. A combination of antibody-based bacterial cell sorting, flow cytometry, and 16s ribosomal RNA gene sequencing was used to identify IgA coated bacteria from stool of specific pathogen-free mice. This technique was used to demonstrate that IgA-coated bacteria were indeed detectable and increased in a mouse model of colitis. Stool from patients with IBD was then used to generate 2 groups of IgA+ and IgA- bacterial consortia. When transplanted into specific pathogen-free mice, no initial clinical differences were noted. However, when mice with dextran sodium sulfate-induced colitis were transplanted with the IgA+ bacterial strains, they exhibited severe exacerbation of intestinal inflammation, whereas the IgA- group developed minimal symptoms. These findings suggest that bacteria highly coated with IgA are potentially responsible for driving gut inflammation in patients with IBD. These results may represent a critical advance in our understanding of the complex interactions between the host immune system and commensal microorganisms as it relates to the development and disease course of IBD. Future work will focus on how these findings can be translated into the development of individualized, microbiota-specific therapies. PMID- 25725446 TI - Missing data imputation on the 5-year survival prediction of breast cancer patients with unknown discrete values. AB - Breast cancer is the most frequently diagnosed cancer in women. Using historical patient information stored in clinical datasets, data mining and machine learning approaches can be applied to predict the survival of breast cancer patients. A common drawback is the absence of information, i.e., missing data, in certain clinical trials. However, most standard prediction methods are not able to handle incomplete samples and, then, missing data imputation is a widely applied approach for solving this inconvenience. Therefore, and taking into account the characteristics of each breast cancer dataset, it is required to perform a detailed analysis to determine the most appropriate imputation and prediction methods in each clinical environment. This research work analyzes a real breast cancer dataset from Institute Portuguese of Oncology of Porto with a high percentage of unknown categorical information (most clinical data of the patients are incomplete), which is a challenge in terms of complexity. Four scenarios are evaluated: (I) 5-year survival prediction without imputation and 5-year survival prediction from cleaned dataset with (II) Mode imputation, (III) Expectation Maximization imputation and (IV) K-Nearest Neighbors imputation. Prediction models for breast cancer survivability are constructed using four different methods: K-Nearest Neighbors, Classification Trees, Logistic Regression and Support Vector Machines. Experiments are performed in a nested ten-fold cross validation procedure and, according to the obtained results, the best results are provided by the K-Nearest Neighbors algorithm: more than 81% of accuracy and more than 0.78 of area under the Receiver Operator Characteristic curve, which constitutes very good results in this complex scenario. PMID- 25725445 TI - Quantifying maternally derived respiratory syncytial virus specific neutralising antibodies in a birth cohort from coastal Kenya. AB - BACKGROUND: Severe respiratory syncytial virus (RSV) disease occurs predominantly in children under 6 months of age. There is no licensed RSV vaccine. Protection of young infants could be achieved by a maternal vaccine to boost titres of passively transferred protective antibodies. Data on the level and kinetics of functional RSV-specific antibody at birth and over the early infant period would inform vaccine product design. METHODS: From a birth cohort study (2002-2007) in Kilifi, Kenya, 100 participants were randomly selected for whom cord blood and 2 subsequent 3-monthly blood samples within the first year of life, were available. RSV antibodies against the A2 strain of RSV were assayed and recorded as the logarithm (base 2) plaque reduction neutralisation test (PRNT) titre. Analysis by linear regression accounted for within-person clustering. RESULTS: The geometric mean neutralisation antibody titre was 10.6 (SD: 1.13) at birth with a log-linear decay over the first 6 months of life. The estimated rate of decay was -0.58 (SD: 0.20) log2PRNT titre per month and a half-life of 36 days. There was no significant interaction between cord titre and rate of decay with age. Mean cord titres rose and fell in a pattern temporally tracking community virus transmission. CONCLUSIONS: In this study population, RSV neutralising antibody titres decay approximately two-fold every one month. The rate of decay varies widely by individual but is not related to titre at birth. RSV specific cord titres vary seasonally, presumably due to maternal boosting. PMID- 25725447 TI - Synthesis and characterization studies of MgO:CuO nanocrystals by wet-chemical method. AB - In this report, we examine the progress in adapting these nanomaterials for several predominantly photonics device fabrication by wet-chemical method. Nanocomposite of magnesium oxide (MgO) with copper oxide (CuO) doped nanoparticles were characterized by X-ray powder diffraction (XRD) and the observed peaks are quite agreeable with the pure phase cubic structure. High resolution transmission electron microscopic (HR-TEM) results reveal that the resultant nanopowders are porous and agglomerated with polycrystalline nano entities. Field emission of selected-area electron diffraction (SAED) studies showed that the average size of the nanoparticles were 20nm. Photoluminescence spectra of MgO:CuO were investigated, showing emission peaks around 375nm relating to new energy levels induced by defects or defect levels generation and confocal micro-Raman images indicated that the chemical molecular vibrational band structure and morphology of the product which is spherical shaped nanoparticles with an average particle size of ~25nm with standard deviation. The electrochemical response of MgO:CuO which is proves that the nano copper/magnesium has high functionality due to the small size and it has higher electrochemical activity without any modifications. PMID- 25725448 TI - Synthesis, characterization, X-ray crystal structure, DFT calculation, DNA binding, and antimicrobial assays of two new mixed-ligand copper(II) complexes. AB - Two new Cu(II) complexes, [Cu(L)(phen)] (1), [Cu(L)(bipy)] (2), where L(2-)=(3 methoxy-2oxidobenzylidene)benzohydrazidato, phen=1,10 phenanthroline, and bipy=2,2' bipyridine, were prepared and fully characterized using elemental analyses, FT-IR, molar conductivity, and electronic spectra. The structures of both complexes were also determined by X-ray diffraction. It was found that, both complexes possessed square pyramidal coordination environment in which, Cu(II) ions were coordinated by donor atoms of HL and two nitrogens of heterocyclic bases. Computational studies were performed using DFT calculations at B3LYP/6 311+G(d,p) level of theory. DNA binding activities of these complexes were also investigated using electronic absorption, competitive fluorescence titration and cyclic voltammetry studies. The obtained results indicated that binding of the complexes to DNA was of intercalative mode. Furthermore, antimicrobial activities of these compounds were screened against microorganisms. PMID- 25725449 TI - Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295. AB - Human kinesin CENP-E is an attractive target for cancer chemotherapy. The allosteric CENP-E inhibitor GSK923295 was proposed as a promising anticancer compound with potent cytostatic effect. In our work, we have analyzed the influence of the Pgp efflux pump on the cytostatic effect of GSK923295. We have demonstrated that multidrug resistant MESSA Dx5 cells overexpressing Pgp are 70 80 times more resistant to GSK923295 than their parental counterpart MESSA cells. Addition of 20 uM verapamil restored the drug sensibility of MESSA Dx5 cells. Combinations of GSK923295 with verapamil showed nearly additive effects in MESSA and synergistic effects in MESSA Dx5 cells. Our results demonstrate that tumors possessing Pgp could be more resistant to GSK923295, and that overexpression of Pgp can decrease the therapeutic effect of this drug. Development of structural analogs of GSK923295 which would not be a substrate of the Pgp efflux pump or addition of Pgp pump inhibitors can significantly improve the cytostatic effect of this drug. PMID- 25725450 TI - Vemurafenib resistance selects for highly malignant brain and lung-metastasizing melanoma cells. AB - V600E being the most common mutation in BRAF, leads to constitutive activation of the MAPK signaling pathway. The majority of V600E BRAF positive melanoma patients treated with the BRAF inhibitor vemurafenib showed initial good clinical responses but relapsed due to acquired resistance to the drug. The aim of the present study was to identify possible biomarkers associated with the emergence of drug resistant melanoma cells. To this end we analyzed the differential gene expression of vemurafenib-sensitive and vemurafenib resistant brain and lung metastasizing melanoma cells. The major finding of this study is that the in vitro induction of vemurafenib resistance in melanoma cells is associated with an increased malignancy phenotype of these cells. Resistant cells expressed higher levels of genes coding for cancer stem cell markers (JARID1B, CD271 and Fibronectin) as well as genes involved in drug resistance (ABCG2), cell invasion and promotion of metastasis (MMP-1 and MMP-2). We also showed that drug-resistant melanoma cells adhere better to and transmigrate more efficiently through lung endothelial cells than drug-sensitive cells. The former cells also alter their microenvironment in a different manner from that of drug-sensitive cells. Biomarkers and molecular mechanisms associated with drug resistance may serve as targets for therapy of drug-resistant cancer. PMID- 25725451 TI - Sex, women and the menopause: are specialist trainee doctors up for it? A survey of views and attitudes of specialist trainee doctors in Community Sexual & Reproductive Health and Obstetrics & Gynaecology around sexuality and sexual healthcare in the (peri)menopause. AB - Sexual health, function and pleasure can contribute significantly towards the wellbeing of (peri-)menopausal women. Healthcare professionals specialising in women's health should therefore be able to provide 'sex-positive' menopause care, which proactively addresses any sexual issues and assesses the need for contraception and prevention of sexually transmitted infections. A survey was used to investigate the views and attitudes of specialist trainee doctors in Community Sexual & Reproductive Health (cSRH) and Obstetrics & Gynaecology towards sexual health in the (peri)menopause as they play a key role in promoting the sexual wellbeing of their patients. The results showed that both study groups had positive attitudes towards sexuality and sexual healthcare of mid-life and older women. However, cSRH trainees had significantly more confidence in dealing with psychosexual problems and perceived significantly less barriers to deliver comprehensive menopausal care within the mostly community-based Sexual & Reproductive Healthcare settings they are working in compared to their mainly hospital-based gynaecological colleagues. Profiting from seemingly better training in the topic cSRH trainees also noticed considerably less embarrassment from their patients when addressing sexual issues. Nonetheless, training needs were identified in both trainee groups. PMID- 25725452 TI - Why would we use the Sediment Isotope Tomography (SIT) model to establish a 210Pb based chronology in recent-sediment cores? AB - After half a century, the use of unsupported (210)Pb ((210)Pbexc) is still far off from being a well established dating tool for recent sediments with widespread applicability. Recent results from the statistical analysis of time series of fluxes, mass sediment accumulation rates (SAR), and initial activities, derived from varved sediments, place serious constraints to the assumption of constant fluxes, which is widely used in dating models. The Sediment Isotope Tomography (SIT) model, under the assumption of non post-depositional redistribution, is used for dating recent sediments in scenarios in that fluxes and SAR are uncorrelated and both vary with time. By using a simple graphical analysis, this paper shows that under the above assumptions, any given (210)Pbexc profile, even with the restriction of a discrete set of reference points, is compatible with an infinite number of chronological lines, and thus generating an infinite number of mathematically exact solutions for histories of initial activity concentrations, SAR and fluxes onto the SWI, with these two last ranging from zero up to infinity. Particularly, SIT results, without additional assumptions, cannot contain any statistically significant difference with respect to the exact solutions consisting in intervals of constant SAR or constant fluxes (both being consistent with the reference points). Therefore, there is not any benefit in its use as a dating tool without the explicit introduction of additional restrictive assumptions about fluxes, SAR and/or their interrelationship. PMID- 25725453 TI - On the lognormality of radionuclide deposition. AB - The influence of the variation of soil density and the uncertainty of activity measurements on the statistical distribution of radionuclide concentrations on a site is considered. It is demonstrated that the influence of these factors adequately explains the observed deviation of radionuclide empirical probability distribution functions (empirical PDFs) from lognormal. In all probability lognormality of activity density distributions is the consequence of the atmospheric fallout process, as observed for deposition from Chernobyl and Fukushima. The results obtained are in no way specific to radioactive contaminants, and are consequently applicable for depositions of non-radioactive pollutants as well. PMID- 25725454 TI - Rare disease policies to improve care for patients in Europe. AB - Rare diseases are those with a particularly low prevalence; in Europe, diseases are considered to be rare when they affect not more than 5 in 10000 persons in the European Union. The specificities of rare diseases make the area a veritable public health challenge: the limited number of patients and scarcity of knowledge and expertise single rare diseases out as a distinctive domain of high European added-value. The Orphan Medicinal Product Regulation of 1999 was the first European legislative text concerning rare diseases, followed by many initiatives, including recommendations by the Council of Ministers of the European Union in 2009. These initiatives contributed to the development of rare diseases policies at European and national level aimed at improving care for patients with rare diseases. A review of the political framework at European level and in European countries is provided to demonstrate how legislation has created a dynamic that is progressively improving care for patients with rare diseases. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". PMID- 25725456 TI - Evaluating the developmental trajectory of the episodic buffer component of working memory and its relation to word recognition in children. AB - The creation of temporary bound representation of information from different sources is one of the key abilities attributed to the episodic buffer component of working memory. Whereas the role of working memory in word learning has received substantial attention, very little is known about the link between the development of word recognition skills and the ability to bind information in the episodic buffer of working memory and how it may develop with age. This study examined the performance of Grade 2 children (8 years old), Grade 3 children (9 years old), and young adults on a task designed to measure their ability to bind visual and auditory-verbal information in working memory. Children's performance on this task significantly correlated with their word recognition skills even when chronological age, memory for individual elements, and other possible reading-related factors were taken into account. In addition, clear developmental trajectories were observed, with improvements in the ability to hold temporary bound information in working memory between Grades 2 and 3, and between the child and adult groups, that were independent from memory for the individual elements. These findings suggest that the capacity to temporarily bind novel auditory verbal information to visual form in working memory is linked to the development of word recognition in children and improves with age. PMID- 25725455 TI - True (but not false) memories are subject to retrieval-induced forgetting in children. AB - Veridical and false memories of children aged 6 to 15 years were studied in two experiments with the retrieval-induced forgetting paradigm. Using the Deese Roediger-McDermott (DRM) false memory word lists, children's reports of true, but not false, memories showed evidence of retrieval-induced forgetting. These differences were observed across delays as long as 2 days following word list presentation. The lack of observation of retrieval-induced forgetting in children's false memories provides evidence that a key assumption in the theory of retrieval-induced forgetting, cue independence, might not consistently apply. These experiments underscore the need for both practical and theoretically motivated study of true and false memories. PMID- 25725457 TI - Complete genome sequence of Bacillus amyloliquefaciens L-H15, a plant growth promoting rhizobacteria isolated from cucumber seedling substrate. AB - Bacillus amyloliquefaciens L-H15 is a plant growth promoting rhizobacteria (PGPR) isolated from the cucumber seedling substrate collected in Beijing, China. The complete genome of B. amyloliquefaciens L-H15 consists of one single circular chromosome (3,864,316 bp) without any plasmid. From the genome, we identified clusters responsible for non-ribosomal synthesis of secondary metabolites, and genes related to the plant growth promotion hormone such as indole-3-acetic acid (IAA) and acetoin secretion. In addition, genes that contribute to biofilm formation were also found on the genome of L-H15. Complete genome information enables further study on the beneficial interactions between B. amyloliquefaciens L-H15 and host plants, and the future application of B. amyloliquefaciens L-H15 as biofertilizer and biocide. PMID- 25725458 TI - 10-Day survival of Hyalella azteca as a function of water quality parameters. AB - Estuarine systems are among the most impacted ecosystems due to anthropogenic contaminants; however, they present unique challenges to toxicity testing with regard to varying water quality parameters. The euryhaline amphipod species, Hyalella azteca, is widely used in toxicity testing and well suited for testing estuarine water samples. Nevertheless, the influence of relevant water quality parameters on test endpoints must be quantified in order to efficiently use this species for routine monitoring. Here, we studied the influence of five water quality parameters: electrical conductivity, pH, un-ionized ammonia, dissolved oxygen and temperature, on H. azteca survival in a water column toxicity test. A model was developed to quantify and predict the independent and interacting effects of water quality variables on 10-day survival. The model allows simultaneous assessment of multiple potential predictors recorded during the tests. Data used for modeling came from 1089 tests performed on ambient water samples over a period of three years (2006-2008). The final model reflects significant effects of predictors and their two-way interactions. The effect of each level of all predictors on survival probability of H. azteca was examined by comparing levels of each predictor at a time, while holding all others at their lowest (reference) level. This study showed that predictors of survival in water column tests should not be evaluated in isolation in the interpretation of H. azteca water column tests. Our model provides a useful tool to predict expected control survival based on relevant water quality parameters, and thus enables the use of H. azteca tests for toxicity monitoring in estuaries with a wide range of water quality conditions. PMID- 25725459 TI - A comparative study of digital RT-PCR and RT-qPCR for quantification of Hepatitis A virus and Norovirus in lettuce and water samples. AB - Sensitive and quantitative detection of foodborne enteric viruses is classically achieved by quantitative RT-PCR (RT-qPCR). Recently, digital PCR (dPCR) was described as a novel approach to genome quantification without need for a standard curve. The performance of microfluidic digital RT-PCR (RT-dPCR) was compared to RT-qPCR for detecting the main viruses responsible for foodborne outbreaks (human Noroviruses (NoV) and Hepatitis A virus (HAV)) in spiked lettuce and bottled water. Two process controls (Mengovirus and Murine Norovirus) were used and external amplification controls (EAC) were added to examine inhibition of RT-qPCR and RT-dPCR. For detecting viral RNA and cDNA, the sensitivity of the RT-dPCR assays was either comparable to that of RT-qPCR (RNA of HAV, NoV GI, Mengovirus) or slightly (around 1 log10) decreased (NoV GII and MNV-1 RNA and of HAV, NoV GI, NoV GII cDNA). The number of genomic copies determined by dPCR was always from 0.4 to 1.7 log10 lower than the expected numbers of copies calculated by using the standard qPCR curve. Viral recoveries calculated by RT-dPCR were found to be significantly higher than by RT-qPCR for NoV GI, HAV and Mengovirus in water, and for NoV GII and HAV in lettuce samples. The RT-dPCR assay proved to be more tolerant to inhibitory substances present in lettuce samples. This absolute quantitation approach may be useful to standardize quantification of enteric viruses in bottled water and lettuce samples and may be extended to quantifying other human pathogens in food samples. PMID- 25725460 TI - Local contamination, and not feeding preferences, explains elevated PCB concentrations in Labrador ringed seals (Pusa hispida). AB - Polychlorinated biphenyls (PCBs) in high trophic level species typically reflect the contributions of myriad sources, such that source apportionment is rarely possible. The release of PCBs by a military radar station into Saglek Bay, Labrador contaminated the local marine food web. For instance, while heavier (higher chlorinated) PCB profiles in some ringed seals (Pusa hispida) were previously attributed to this local source, differences in feeding preferences among seals could not be ruled out as a contributing factor. Herein, similar fatty acid profiles between those seals with 'local' PCB profiles and those with 'long-range' or background profiles indicate little support for the possibility that differential feeding ecologies underlay the divergent PCB profiles. Ringed seals appeared to feed predominantly on zooplankton (Mysis oculata and Themisto libellula), followed by the dusky snailfish (Liparis gibbus), arctic cod (Boreogadus saida), and shorthorn sculpin (Myoxocephalus scorpius). Principal components analysis (PCA) and PCB homolog profiles illustrated the extent of contamination of the Saglek food web, which had very different (and much heavier) PCB profiles than those food web members contaminated by 'long-range' sources. Locally contaminated prey had PCB levels that were higher (2- to 544-fold) than prey contaminated by 'long-range' sources and exceeded wildlife consumption guidelines for PCBs. The application of multivariate analyses to two distinct datasets, including PCB congeners (n=50) and fatty acids (n=65), afforded the opportunity to clearly distinguish the contribution of locally-released PCBs to a ringed seal food web from those delivered via long-ranged transport. Results from the present study strongly suggest that habitat use rather than differences in prey selection is the primary mechanism explaining the divergent PCB patterns in Labrador ringed seals. PMID- 25725461 TI - Personal history of dieting and family history of obesity are unrelated: implications for understanding weight gain proneness. AB - Identifying predictors of future weight gain is important in obesity prevention efforts. Both family history of obesity and personal dieting history have been established as predictors of future weight gain; however, it is unknown if they are independent or overlapping predictors. The purpose of this study was to examine the degree of overlap between these two predictors using cross-sectional data. Baseline data from four studies were examined separately and in combination for a total of 561 female participants, and analyses were conducted to examine parent anthropometric variables by dieting status within and across studies. All participants were female university students between the ages of 17 and 30. For each study, as well as for the entire sample combined, parent anthropometric variables were examined by dieting status using factorial ANOVAs. No meaningful pattern was found when examining parent anthropometric variables by dieting status, which suggests that the two risk factors are largely independent. This suggests that the processes associated with the development of future weight gain by each variable are different; therefore, future research should use a longitudinal study to test the hypothesis that using both variables to predict future weight gain would account for more variance than using either variable alone. PMID- 25725462 TI - A SERS/fluorescence dual-mode nanosensor based on the human telomeric G quadruplex DNA: Application to mercury (II) detection. AB - DNA-metal nanoparticle conjugates have been increasingly exploited for sensing purposes over the past decades. However, most of the existing strategies are operated with canonical DNA structures, such as single-stranded forms, stem-loop structures, and double helix structures. There is intense interest in the development of nano-system based on high order DNA secondary structures. Herein, we propose a SERS/fluorescence dual-mode nanosensor, where the signal transduction mechanism is based on the conformational switching of the human telomeric G-quadruplex DNA. The nanosensor exhibits excellent SERS/fluorescence responses to the complementary strands of G-quadruplexes. Based on T-Hg(2+)-T coordination chemistry, this sensor is effectively applied to determination of Hg(2+) in buffer solution and real samples. It achieves a limit of detection (LOD) as low as 1ppt, which is ~100 times more sensitive than conventional optical sensors. We anticipate that the proposed G-quadruplex-based nanosensor could be applied to the analysis of other metal ions and small molecules in environmental samples and biological systems. PMID- 25725463 TI - Aptamer-based competitive electrochemical biosensor for brevetoxin-2. AB - Brevetoxins (BTXs) are very potent marine neurotoxins that increased in geographical distribution in the past decade causing the illness clinically described as neurological shellfish poisoning (NSP). The ethical problems as well as the technical difficulties associated with the currently employed analysis methods for marine toxins are encouraging the research for suitable alternatives to be applied in a regulatory monitoring regime. Here, we report an electrochemical biosensor platform for BTX-2 detection utilising aptamer as specific receptor. Using in vitro selection, high affinity DNA aptamers to BTX-2 were successfully selected for the first time from a large pool of random sequences. The binding of BTX-2 to aptamer pools/clones was monitored using fluorescence and electrochemical impedance spectroscopy (EIS). The aptamer BT10 exhibited the highest binding affinity to BTX-2, with a dissociation constant of 42nM. The effects of the incubation time, pH and metal ions concentrations on the aptamer-toxin binding were studied. The aptamer BT10 was used to construct a label-free competitive impedimetric biosensor for BTX-2 achieving a detection limit of 106pg/ml. We observed a high degree of cross reactivity of the selected aptamer to the two similar congeners, BTX-2 and -3, whereas no cross reactivity to other marine toxins was obtained. Moreover, the aptasensor was applied for the detection of BTX-2 in spiked shellfish extract showing a very high recovery percentage. We believe that the proposed aptasensor will facilitate the routine detection of BTX-2 in food samples. PMID- 25725464 TI - Alcohol oxidase protein mediated in-situ synthesized and stabilized gold nanoparticles for developing amperometric alcohol biosensor. AB - A simple one step method for the alcohol oxidases (AOx) protein mediated synthesis of gold nano-particles (AuNPs) in alkaline (pH 8.5) condition with simultaneous stabilization of the nanoparticles on the AOx protein surface under native environment has been developed. The formation of the AOx conjugated AuNPs was confirmed by advanced analytical and spectroscopic techniques. The significant increase in zeta potential (zeta) value of -57mV for the synthesized AOx-AuNPs conjugate from the AOx (pI 4.5) protein (zeta, -30mV) implied good stability of the in-situ synthesized nano-conjugate. The AOx-AuNPs conjugate showed steady stability in alkaline (upto pH 8.5) and NaCl (up to 10(-1)M) solutions. The efficiency (Kcat/Km) of the AuNP conjugated AOx was increased by 18% from the free enzyme confirming the activating role of the surface stabilized AuNPs for the enzyme. The AuNPs-AOx conjugate was encapsulated with polyaniline (PANI) synthesized by oxidative polymerization of aniline using H2O2 generated in situ from the AOx catalysed oxidation of alcohol. The PANI encapsulated AuNPs-AOx assembly was stabilized on a glassy carbon electrode (GCE) by chitosan-Nafion mixture and then utilized the fabricated bioelectrode for detection of alcohol amperometrically using H2O2 as redox indicator at +0.6V. The constructed biosensor showed high operational stability (6.3% loss after 25 measurements), wide linear detection range of 10uM-4.7mM (R(2)=0.9731), high sensitivity of 68.3+/-0.35uAmM(-1) and low detection limit of 7+/-0.027uM for ethanol. The fabricated bioelectrode was successfully used for the selective determination of alcohol in beverage samples. PMID- 25725465 TI - Whole-cell method for phenol detection based on the color reaction of phenol with 4-aminoantipyrine catalyzed by CotA laccase on endospore surfaces. AB - A green method for phenol spectrophotometric determination was developed based on the color reaction of phenol with 4-aminoantipyrine catalyzed by addition of Bacillus amyloliquefaciens endospores in the presence of O2. The catalytic activity of the endospores may be attributed to the presence of coat protein A on the cell surfaces. This deduction was confirmed by cotA gene knock-out from B. amyloliquefaciens using the homologous double-exchange method. Under optimal conditions, linear responses were obtained over phenol concentrations ranging from 5.0*10(-5)gL(-1) to 1.0*10(-2)gL(-1) (r=0.9984) with a detection limit of 2.1*10(-5)gL(-1) (3sigma). Repeatability measurements of 1.0mgL(-1) phenol provided reproducible results with a relative standard deviation of 5.3% (n=11). Standard addition tests indicated recoveries ranging from 92.78% to 107.60%. The proposed whole-cell method was successfully used to detect total phenol in synthetic samples. Results confirmed the potential use of the developed method in practical applications. PMID- 25725466 TI - The wandering brain: meta-analysis of functional neuroimaging studies of mind wandering and related spontaneous thought processes. AB - The neural basis and cognitive functions of various spontaneous thought processes, particularly mind-wandering, are increasingly being investigated. Although strong links have been drawn between the occurrence of spontaneous thought processes and activation in brain regions comprising the default mode network (DMN), spontaneous thought also appears to recruit other, non-DMN regions just as consistently. Here we present the first quantitative meta-analysis of neuroimaging studies of spontaneous thought and mind-wandering in order to address the question of their neural correlates. Examining 24 functional neuroimaging studies of spontaneous thought processes, we conducted a meta analysis using activation likelihood estimation (ALE). A number of key DMN areas showed consistent recruitment across studies, including medial prefrontal cortex, posterior cingulate cortex, medial temporal lobe, and bilateral inferior parietal lobule. Numerous non-DMN regions, however, were also consistently recruited, including rostrolateral prefrontal cortex, dorsal anterior cingulate cortex, insula, temporopolar cortex, secondary somatosensory cortex, and lingual gyrus. These meta-analytic results indicate that DMN activation alone is insufficient to adequately capture the neural basis of spontaneous thought; frontoparietal control network areas, and other non-DMN regions, appear to be equally central. We conclude that further progress in the cognitive and clinical neuroscience of spontaneous thought will therefore require a re-balancing of our view of the contributions of various regions and networks throughout the brain, and beyond the DMN. PMID- 25725467 TI - Disrupted developmental organization of the structural connectome in fetuses with corpus callosum agenesis. AB - Agenesis of the corpus callosum is a model disease for disrupted connectivity of the human brain, in which the pathological formation of interhemispheric fibers results in subtle to severe cognitive deficits. Postnatal studies suggest that the characteristic abnormal pathways in this pathology are compensatory structures that emerge via neural plasticity. We challenge this hypothesis and assume a globally different network organization of the structural interconnections already in the fetal acallosal brain. Twenty fetuses with isolated corpus callosum agenesis with or without associated malformations were enrolled and fiber connectivity among 90 brain regions was assessed using in utero diffusion tensor imaging and streamline tractography. Macroscopic scale connectomes were compared to 20 gestational age-matched normally developing fetuses with multiple granularity of network analysis. Gradually increasing connectivity strength and tract diffusion anisotropy during gestation were dominant in antero-posteriorly running paramedian and antero-laterally running aberrant pathways, and in short-range connections in the temporoparietal regions. In fetuses with associated abnormalities, more diffuse reduction of cortico cortical and cortico-subcortical connectivity was observed than in cases with isolated callosal agenesis. The global organization of anatomical networks consisted of less segregated nodes in acallosal brains, and hubs of dense connectivity, such as the thalamus and cingulate cortex, showed reduced network centrality. Acallosal fetal brains show a globally altered connectivity network structure compared to normals. Besides the previously described Probst and sigmoid bundles, we revealed a prenatally differently organized macroconnectome, dominated by increased connectivity. These findings provide evidence that abnormal pathways are already present during at early stages of fetal brain development in the majority of cerebral white matter. PMID- 25725468 TI - Cortical thickness gradients in structural hierarchies. AB - MRI, enabling in vivo analysis of cortical morphology, offers a powerful tool in the assessment of brain development and pathology. One of the most ubiquitous measures used-the thickness of the cortex-shows abnormalities in a number of diseases and conditions, but the functional and biological correlates of such alterations are unclear. If the functional connotations of structural MRI measures are to be understood, we must strive to clarify the relationship between measures such as cortical thickness and their cytoarchitectural determinants. We therefore sought to determine whether patterns of cortical thickness mirror a key motif of the cortex, specifically its structural hierarchical organisation. We delineated three sensory hierarchies (visual, somatosensory and auditory) in two species-macaque and human-and explored whether cortical thickness was correlated with specific cytoarchitectural characteristics. Importantly, we controlled for cortical folding which impacts upon thickness and may obscure regional differences. Our results suggest that an easily measurable macroscopic brain parameter, namely, cortical thickness, is systematically related to cytoarchitecture and to the structural hierarchical organisation of the cortex. We argue that the measurement of cortical thickness gradients may become an important way to develop our understanding of brain structure-function relationships. The identification of alterations in such gradients may complement the observation of regionally localised cortical thickness changes in our understanding of normal development and neuropsychiatric illnesses. PMID- 25725469 TI - New extender for cryopreservation of Siberian sturgeon (Acipenser baerii) semen. AB - The goal of this study was to develop a simple glucose-methanol extender for cryopreservation of Siberian sturgeon (Acipenser baerii) semen. Semen quality was assessed by determining post-thaw sperm motility and fertilizing ability at hatching stage. We tested the effect of glucose concentration (0, 0.10, 0.15, 0.20 and 0.30 M) in a methanol extender on post-thaw sperm motility. Sperm motility parameters and fertilizing ability of semen cryopreserved in 0.1 M glucose in 15% methanol (GM) were compared to previously described Tris-sucrose KCl in 10% - methanol extender (TSKM). Additionally, sperm motility and fertilizing ability in relation to 30 min equilibration in GM extender before cryopreservation and 30 min of post-thaw storage were determined. The beneficial effect of the glucose for semen cryopreservation was related to its concentration with a quite narrow optimum of 0.1 to -0.15 M. The fertilization rates of frozen/thawed sperm were similar for both (TSKM and GM) tested extenders. The sperm motility and fertilization rate were not affected either by 30 min equilibration in GM extender or by 30 min of post-thaw storage. Our work indicates that the use a simple extender consisting of 0.1M glucose in 15% methanol can be an alternative cryopreservation method to those previously described for sturgeons. The use of an equilibration period and the possibility of post-thaw semen storage can improve organization of hatchery work and help with logistics of large-scale hatchery operations. PMID- 25725470 TI - Use of cryotubes for the cryopreservation of tambaqui fish semen (Colossoma macropomum). AB - Tambaqui (Colossoma macropomum) is a freshwater fish of great importance to aquaculture in several South American countries. Recent studies have developed a protocol for semen cryopreservation in 0.25 and 0.5 mL straws; however, this technique has limitations for fingerling production at a large scale due to the high fecundity of tambaqui. The main objective of this study was to evaluate the feasibility of using cryotubes (1.6 and 4.5 mL) for tambaqui semen cryopreservation. Semen samples were diluted in freezing solution (5% glucose solution, 10% methylglycol, 5% egg yolk), stored in 1.6 and 4.5 mL cryotubes, frozen in liquid nitrogen vapor at -175 degrees C and transferred to a cryogenic container at -196 degrees C. The cryotubes were thawed in a water bath at 60 degrees C for 70 or 90 s and the motility (total motility - TM; progressive motility - PM; curvilinear velocity - VCL; straight line velocity - VSL and average path velocity - VAP) and the viability of sperm were evaluated. There was no significant difference in sperm motility and viability post-thawing between 1.6 and 4.5m L cryotubes, except for TM (47% and 40%, respectively). Thawing for 90 s provided better results, being used in fertilization trials. Although the fertilization rate did not differ between the cryotubes (41-45%), it was significantly lower than that for fresh semen (74%). A strong positive correlation was observed between the sperm motility and fertilization rate (r=0.69-0.89). We conclude that 1.6 and 4.5 mL cryotubes have high potential for tambaqui semen cryopreservation when thawed for a minimum time of 90 s at 60 degrees C. PMID- 25725471 TI - Equilibrium water and solute uptake in silicone hydrogels. AB - Equilibrium water content of and solute partitioning in silicone hydrogels (SiHys) are investigated using gravimetric analysis, fluorescence confocal laser scanning microscopy (FCLSM), and back extraction with UV/Vis-absorption spectrophotometry. Synthesized silicone hydrogels consist of silicone monomer, hydrophilic monomer, cross-linking agent, and triblock-copolymer macromer used as an amphiphilic compatibilizer to prevent macrophase separation. In all cases, immiscibility of the silicone and hydrophilic polymers results in microphase separated morphologies. To investigate solute uptake in each of the SiHy microphases, equilibrium partition coefficients are obtained for two hydrophilic solutes (i.e., theophylline and caffeine dissolved in aqueous phosphate-buffered saline) and two oleophilic solutes (i.e., Nile Red and Bodipy Green dissolved in silicone oil), respectively. Measured water contents and aqueous-solute partition coefficients increase linearly with increasing solvent-free hydrophilic-polymer volume fraction. Conversely, oleophilic-solute partition coefficients decrease linearly with rising solvent-free hydrophilic-polymer volume fraction (i.e., decreasing hydrophobic silicone-polymer fraction). We quantitatively predict equilibrium SiHy water and solute uptake assuming that water and aqueous solutes reside only in hydrophilic microdomains, whereas oleophilic solutes partition predominately into silicone microdomains. Predicted water contents and solute partition coefficients are in excellent agreement with experiment. Our new procedure permits a priori estimation of SiHy water contents and solute partition coefficients based solely on properties of silicone and hydrophilic homopolymer hydrogels, eliminating the need for further mixed-polymer-hydrogel experiments. PMID- 25725472 TI - Decellularized periosteum as a potential biologic scaffold for bone tissue engineering. AB - Bone grafting or bone substitute is typically used to bridge a bone defect that has been caused by trauma, tumor resection, pathological degeneration, or congenital deformations. However, bone graft healing and remodeling is always a major concern of orthopedic surgeons. Because the periosteum has a remarkable regenerative capacity and is widely recognized to be essential for the initiation of bone graft healing and remodeling, the present study aimed to produce a rabbit decellularized periosteum (D-periosteum) to be used as a biologic scaffold for future bone tissue engineering. We obtained the D-periosteum by employing a combination of commonly used decellularization processes, which include physical methods as well as chemical and enzymatic solutions. The cellular components were effectively removed, and this removal was demonstrated using current decellularization criteria (H&E staining, DAPI staining, DNA quantification and agarose gel electrophoresis); however, there were no significant alterations of the native extracellular matrix (ECM) properties (collagen, glycosaminoglycan (GAG), microarchitecture and mechanical properties). Periosteum-derived cells (PDCs) could adhere, proliferate and infiltrate into the D-periosteum in vitro. The allogenic D-periosteum was implanted subcutaneously into the backs of rabbits over 28 days to study the biocompatibility in vivo. The D-periosteum did not elicit a severe immunogenic response. In summary, a biologic scaffold composed of ECM from periosteum has been successfully developed. The D-periosteum maintains biocompatibility in vitro and in vivo and, therefore, can provide a naturally compatible scaffold for use in future bone tissue engineering. PMID- 25725473 TI - Fall-related injuries in a low-income setting: Results from a pilot injury surveillance system in Rawalpindi, Pakistan. AB - This study assessed the characteristics and emergency care outcomes of fall related injuries in Pakistan. This study included all fall-related injury cases presenting to emergency departments (EDs) of the three teaching hospitals in Rawalpindi city from July 2007 to June 2008. Out of 62,530 injury cases, 43.4% (N=27,109) were due to falls. Children (0-15 years) accounted for about two out of five of all fall-related injuries. Compared with women aged 16-45 years, more men of the same age group presented with fall-related injuries (50% vs. 42%); however, compared with men aged 45 years or more, about twice as many women of the same age group presented with fall-related injuries (16% vs. 9%, P<0.001). For each reported death due to falls (n=57), 43 more were admitted (n=2443, 9%), and another 423 were discharged from the EDs (n=24,142, 91%). Factors associated with death or inpatient admission were: aged 0-15 years (adjusted odds ratio [aOR]=1.35), aged 45 years or more (aOR=1.94), male gender (aOR=1.15), falls occurring at home (aOR=3.38), in markets (aOR=1.43), on work sites (aOR=4.80), and during playing activities (aOR=1.68). This ED-based surveillance study indicated that fall prevention interventions in Pakistan should target children, older adult women, homes, and work sites. PMID- 25725474 TI - Expression of fructose 1,6-bisphosphatase and phosphofructokinase is induced in hepatopancreas of the white shrimp Litopenaeus vannamei by hypoxia. AB - Marine organisms are exposed to hypoxia in natural ecosystems and during farming. In these circumstances marine shrimp survive and synthesize ATP by anaerobic metabolism. Phosphofructokinase (PFK) and fructose 1,6-bisphosphatase (FBP) are key enzymes in carbohydrate metabolism. Here we report the cDNA of FBP from the shrimp Litopenaeus vannamei hepatopancreas and expression of PFK and FBP under normoxia and hypoxia. Hypoxia induces PFK and FBP expression in hepatopancreas but not in gills and muscle. Induction in hepatopancreas of the glycolytic and gluconeogenic key enzymes, PFK and FBP, suggests that PFK could be a key factor for increasing anaerobic rate, while FBP is probably involved in the activation of gluconeogenesis or the pentose-phosphates pathway during hypoxia in the highly active metabolism of hepatopancreas. PMID- 25725475 TI - Imaging Congestion With a Pocket Ultrasound Device: Prognostic Implications in Patients With Chronic Heart Failure. AB - BACKGROUND: Venous congestion is common in patients with chronic heart failure (HF). We used a pocket-sized ultrasound imaging device (PID) to assess the patients' congestive status and related our findings to prognosis. METHODS AND RESULTS: One hundred four consecutive outpatients from an HF outpatient clinic were studied. Interstitial lung water (ILW), pleural effusion (PE), and the diameter of the inferior vena cava (VCI) were assessed with the use of a PID. ILW was assessed by demonstration of B-lines (comet tail artifact (CTA). Out of the 104 patients, 28 had CTA and 8 had PE. Median VCI diameter was 18 mm (interquartile range 14-22 mm). Each of these parameters correlated weakly (r = 0.26-0.37; P < .05) with the HF biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP). During the median follow-up time of 530 days, 18 hospitalizations and 14 deaths were registered. Findings of CTA, PE, or both increased the risk of death or hospitalization (hazard ratio 3-4; P < .05). After adjustment for age, cardiac systolic function, and NT-proBNP, this difference remained significant for CTA alone and CTA + PE combined, but not for PE alone. CONCLUSIONS: With the use of a handheld ultrasound device, signs of pulmonary congestion could be demonstrated. When found, these had a significant prognostic impact in clinically stable HF. PMID- 25725476 TI - Right ventricular myocardial biomarkers in human heart failure. AB - BACKGROUND: Right ventricular (RV) dysfunction contributes to mortality in chronic heart failure (HF). However, the molecular mechanisms of RV failure remain poorly understood, and RV myocardial biomarkers have yet to be developed. METHODS AND RESULTS: We performed RNA sequencing (RNA-seq) on 22 explanted human HF RVs and 5 unused donor human heart RVs (DON RV) and compared results to those recently reported from 16 explanted human LVs We used Bowtie-Tophat for transcript alignment and transcriptome assembly, DESeq for identification of differentially expressed genes (DEGs) and Ingenuity for exploration of gene ontologies. In the HF RV, RNA-seq identified 130,790 total RNA transcripts including 13,272 protein coding genes, 10,831 long non-coding RNA genes and 8,605 pseudogenes. There were 800-1000 DEGs between DON and HF RV comparison groups with differences concentrated in cytoskeletal, basement membrane, extracellular matrix (ECM), inflammatory mediator, hemostasis, membrane transport and transcription factor genes, lncRNAs and pseudogenes. In an unbiased approach, the top 10 DEGs SERPINA3, SERPINA5, LCN6, LCN10, STEAP4, AKR1C1, STAC2, SPARCL1, VSIG4 and F8 exhibited no overlap in read counts between DON and HF RVs, high sensitivities, specificities, predictive values and areas under the receiver operating characteristic curves. STEAP4, SPARCL1 and VSIG4 were differentially expressed between RVs and LVs, supporting their roles as RV-specific myocardial biomarkers. CONCLUSIONS: Unbiased, comprehensive profiling of the RV transcriptome by RNA-seq suggests structural changes and abnormalities in inflammatory processes and yields specific, novel HF RV vs HF LV myocardial biomarkers not previously identified by more limited transcriptome profiling approaches. PMID- 25725477 TI - Electrochemistry of LB films of mixed MGDG:UQ on ITO. AB - The electrochemical behaviour of biomimetic monolayers of monogalactosyldiacylglycerol (MGDG) incorporating ubiquinone-10 (UQ) has been investigated. MGDG is the principal component in the thylakoid membrane and UQ seems a good substitute for plastoquinone-9, involved in photosynthesis chain. The monolayers have been performed using the Langmuir and Langmuir-Blodgett (LB) techniques and the redox behaviour of the LB films, transferred at several surface pressures on a glass covered with indium-tin oxide (ITO), has been characterized by cyclic voltammetry. The cyclic voltammograms show that UQ molecules present two redox processes (I and II) at high UQ content and high surface pressures, and only one redox process (I) at low UQ content and low surface pressures. The apparent rate constants calculated for processes I and II indicate a different kinetic control for the reduction and the oxidation of UQ/UQH2 redox couple, being k(Rapp)(I) = 2.2 . 10(-5) s(-1), k(Rapp)(II) = 5.1 . 10(-14) k(Oapp)(I) = 3.3 . 10(-3) s(-1) and k(Oapp)(II) = 6.1 . 10(-6) s(-1), respectively. The correlation of the redox response with the physical states of the LB films allows determining the positions of the UQ molecules in the biomimetic monolayer, which change with the surface pressure and the UQ content. These positions are known as diving and swimming. PMID- 25725478 TI - High throughput sequencing analysis of Trypanosoma brucei DRBD3/PTB1-bound mRNAs. AB - Trypanosomes are early-branched eukaryotes that show an unusual dependence on post-transcriptional mechanisms to regulate gene expression. RNA-binding proteins are crucial in controlling mRNA fate in these organisms, but their RNA substrates remain largely unknown. Here we have analyzed on a global scale the mRNAs associated with the Trypanosoma brucei RNA-binding protein DRBD3/PTB1, by capturing ribonucleoprotein complexes using UV cross-linking and subsequent immunoprecipitation. DRBD3/PTB1 associates with many transcripts encoding ribosomal proteins and translation factors. Consequently, silencing of DRBD3/PTB1 expression altered the protein synthesis rate. DRBD3/PTB1 also binds to mRNAs encoding the enzymes required to obtain energy through the oxidation of proline to succinate. We hypothesize that DRBD3/PTB1 is a key player in RNA regulon-based gene control influencing protein synthesis in trypanosomes. PMID- 25725479 TI - Some characteristics of activity of potential chemotherapeutics--benzimidazole derivatives. AB - In this work, the biological activity of some benzimidazoles and benzimidazole 4,7-diones was compared. These two groups of compounds were evaluated as potential chemotherapeutics and their characteristic relationship structure to biological activity was discussed. The authors compared their effect into the cytotoxic, apoptosis and DNA destruction approach. Their cytotoxic effect on the human lung adenocarcinoma A549 cells line was determined by WST-1 test. Next the cytotoxic way of tumor cells death was determined by caspase 3/7 test. The last point referred to the DNA destruction of A549 cells and test in situ DNA Assay Kit was applied. Two of the examined compounds (B2 and D2) show a very good correlation of the cytotoxic effect normoxia to hypoxia and they have been found as the potential agents of the DNA damage. The most cytotoxic feature possesses N oxide benzimidazole derivatives (D and B groups). The screening test of the DNA damage established that N-oxide benzimidazole derivatives (D and B groups) can be more potent as the hypoxia-selective agents for tumor cells than benzimidazole derivatives (A and C groups). Additionally, the test of the caspase-dependent apoptosis proved that the exposure of benzimidazole-4,7-diones against A549 cells, especially in hypoxia, promotes apoptotic cell death. PMID- 25725480 TI - Sex-differences in the incidence of stroke: should we change our traditional belief? PMID- 25725481 TI - Risk factors for post lumbar puncture headache. AB - BACKGROUND: Lumbar puncture (LP) is complicated by headache in about one-third of patients. The aim of the study was to evaluate potential risk factors for post-LP headache. METHODS: 144 Patients undergoing diagnostic LP at a tertiary medical center completed questionnaires on fear of the procedure, pre-existing headache, and post-LP headache. Data on patient demographics, operator experience, and other procedure-related parameters were collected from hospital files. RESULTS: The post-LP headache group (n=37, 27.6%) was characterized by a significantly younger age and higher proportion of women relative to the no-headache group (n=97); body mass index was similar. Both groups had similar levels of fear of the procedure and there was no correlation between intensity of patients' anxiety to the procedure and its occurrence. Patients with high opening pressure had higher levels of post-LP headache (28.6% vs. 18% p=0.078) and a history of headaches was significantly more prevalent in the post-LP-headache group (66.6% vs. 38.1%, p=0.003). CONCLUSIONS: Fear of the procedure does not predispose to occurrence of post-LP headache while a history of headache and elevated intracranial pressure does. These findings may be related to the possible pathophysiology of the condition, namely a change in compliance and pressure gradients with resultant venous distention. PMID- 25725482 TI - Fbxo25 controls Tbx5 and Nkx2-5 transcriptional activity to regulate cardiomyocyte development. AB - The ubiquitin-proteasome system (UPS) plays an important role in protein quality control, cellular signalings, and cell differentiation through the regulated turnover of key transcription factors in cardiac tissue. However, the molecular mechanism underlying Fbxo25-mediated ubiquitination of cardiac transcription factors remains elusive. We report that an Fbxo25-mediated SCF ubiquitination pathway regulates the protein levels and activities of Tbx5 and Nkx2-5 based on our studies using MG132, proteasome inhibitor, and the temperature sensitive ubiquitin system in ts20 cells. Our data indicate that Fbxo25 directly interacts with Tbx5 and Nkx2-5 in vitro and in vivo. In support of our findings, a dominant negative mutant of Fbxo25, Fbxo251-236, prevents Tbx5 degradation and increases Tbx5 transcriptional activity in a Tbx5 responsive luciferase assay. Therefore, Fbxo25 facilitates Tbx5 degradation in an SCF-dependent manner. In addition, the silencing of endogenous Fbxo25 increases Tbx5 and Nkx2-5 mRNA levels and suppresses mESC-derived cardiomyocyte differentiation. Likewise, the exogenous expression of FBXO25 downregulates NKX2-5 level in human ESC-derived cardiomyocytes. In myocardial infarction model, Fbxo25 mRNA decreases, whereas the mRNA and protein levels of Tbx5 and Nkx2-5 increase. The protein levels of Tbx5 and Nkx2-5 are regulated negatively by Fbxo25-mediated SCF ubiquitination pathway. Thus, our findings reveal a novel mechanism for regulation of SCFFbox25 dependent Nkx2-5 and Tbx5 ubiquitination in cardiac development and provide a new insight into the regulatory mechanism of Nkx2-5 and Tbx5 transcriptional activity. PMID- 25725484 TI - Association of food environment and food retailers with obesity in US adults. AB - The food environment has been shown to be a factor affecting the obesity rate. We studied the association of density of food retailer type with obesity rate in U.S. adults in local regions controlling for socioeconomic factors. Parametric nonlinear regression was used on publically available data (year=2009) at the county level. We used the results of this association to estimate the impact of the addition of a new food retailer type in a geographic region. Obesity rate increased in supercenters (0.25-0.28%) and convenience stores (0.05%) and decreased in grocery stores (0.08%) and specialized food stores (0.27-0.36%). The marginal measures estimated in this work could be useful in identifying regions where interventions based on food retailer type would be most effective. PMID- 25725485 TI - What are the main barriers to healthy eating among families? A qualitative exploration of perceptions and experiences of Tehranian men. AB - Despite women playing a pivotal role in shaping nutritional patterns in their families, it is the men whose ideas and preferences, after children, influence the selection and consumption of daily foods among Iranian families. This study focused on exploring the main barriers to healthy eating as experienced by male participants of the Tehran Lipid Glucose Study (TLGS). A grounded theory approach was used for analyzing participants' experiences and their perceptions regarding these barriers. Participants were 98 men, aged 25-65 years, selected and recruited from the TGLS cohort. Data collection was conducted through fourteen semi-structured focus group discussions, between 2008 and 2009. All interviews and focus group discussions were audio recorded and transcribed verbatim. Constant comparative analysis of the data was conducted manually according to the Strauss and Corbin analysis method. The most important barriers to healthy eating were: (i) Personal factors, which included two subthemes--lack of knowledge and personal taste, (ii) Communication and modeling included two subthemes--other individuals and media/advertisements; (iii) Modernization included two subthemes- nutrition transition and women's role; and (iv) Lack of access to healthy foods, which included four subthemes--Inadequate confidence, perceived risk, high cost and time limitations. Appropriate attention and prioritized policy-making to modify the socio-environmental barriers to healthy eating were explored in the current study, along with effective educational programs that could help to promote healthy eating among Iranian families. PMID- 25725483 TI - Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox containing gene associated with breast cancer. AB - HOXC6 is a homeobox-containing gene associated with mammary gland development and is overexpressed in variety of cancers including breast and prostate cancers. Here, we have examined the expression of HOXC6 in breast cancer tissue, investigated its transcriptional regulation via estradiol (E2) and bisphenol-A (BPA, an estrogenic endocrine disruptor) in vitro and in vivo. We observed that HOXC6 is differentially over-expressed in breast cancer tissue. E2 induces HOXC6 expression in cultured breast cancer cells and in mammary glands of Sprague Dawley rats. HOXC6 expression is also induced upon exposure to BPA both in vitro and in vivo. Estrogen-receptor-alpha (ERalpha) and ER-coregulators such as MLL histone methylases are bound to the HOXC6 promoter upon exposure to E2 or BPA and that resulted in increased histone H3K4-trimethylation, histone acetylation, and recruitment of RNA polymerase II at the HOXC6 promoter. HOXC6 overexpression induces expression of tumor growth factors and facilitates growth 3D-colony formation, indicating its potential roles in tumor growth. Our studies demonstrate that HOXC6, which is a critical player in mammary gland development, is upregulated in multiple cases of breast cancer, and is transcriptionally regulated by E2 and BPA, in vitro and in vivo. PMID- 25725486 TI - Investigation of lifestyle choices of individuals following a vegan diet for health and ethical reasons. AB - The proportion of individuals choosing to follow a vegan diet has increased in recent years. The choice is made for different reasons, primarily concern for animals (ethics) and health, which may impact both specific food choices and other lifestyle behaviors linked to health outcomes. To determine the extent to which the reason for following a vegan diet was associated with health behaviors, we conducted an online survey recruiting an international sample of 246 individuals who reported adhering to a vegan diet. We hypothesized that compared to those following the diet for ethical reasons, those doing so for health reasons would consume foods with higher nutritional value and engage in other healthier lifestyle behaviors. Our hypotheses were partially supported in that those citing health reasons (n = 45) reported eating more fruit (U = 3503.00, p = 0.02) and fewer sweets (U = 3347.00, p <0.01) than did those citing ethical reasons (n = 201). Individuals endorsing ethical reasons reported being on the diet longer (U = 3137.00, p <0.01), and more frequent consumption of soy (U = 2936.00, p <0.01), foods rich in vitamin D (U = 3441.00, p = 0.01), high polyphenol beverages (U = 3124.50, p <0.01), and vitamin supplements (vitamin D: chi(2)=4.65, p = 0.04; vitamin B12: chi(2)=4.46, p = 0.03) than did those endorsing health reasons. As these factors may affect outcome in studies investigating the impact of vegan diets on health, they should be taken into account when studying persons following a vegan diet. PMID- 25725487 TI - Two inhibitory control training interventions designed to improve eating behaviour and determine mechanisms of change. AB - Inhibitory control training has been shown to influence eating behaviour in the laboratory; however, the reliability of these effects is not yet established outside the laboratory, nor are the mechanisms responsible for change in behaviour. Two online Stop-Signal Task training interventions were conducted to address these points. In Study 1, 72 participants completed baseline and follow up measures of inhibitory control, self-regulatory depletion, fat intake and body mass index. Participants were randomly assigned to complete one of three Stop Signal Tasks daily for ten days: food-specific inhibition--inhibition in response to unhealthy food stimuli only, general inhibition--inhibition was not contingent on type of stimuli, and control--no inhibition. While fat intake did not decrease, body-mass index decreased in the food-specific condition and change in this outcome was mediated by changes in vulnerability to depletion. In Study 2, the reliability and longevity of these effects were tested by replicating the intervention with a third measurement time-point. Seventy participants completed baseline, post-intervention and follow-up measures. While inhibitory control and vulnerability to depletion improved in both training conditions post intervention, eating behaviour and body-mass index did not. Further, improvements in self-regulatory outcomes were not maintained at follow-up. It appears that while the training paradigm employed in the current studies may improve self regulatory outcomes, it may not necessarily improve health outcomes. It is suggested that this may be due to the task parameters, and that a training paradigm that utilises a higher proportion of stop-signals may be necessary to change behaviour. In addition, improvements in self-regulation do not appear to persist over time. These findings further current conceptualisations of the nature of self-regulation and have implications for the efficacy of online interventions designed to improve eating behaviour. PMID- 25725488 TI - Real-time monitoring of binding events on a thermostabilized human A2A receptor embedded in a lipid bilayer by surface plasmon resonance. AB - Membrane proteins (MPs) are prevalent drug discovery targets involved in many cell processes. Despite their high potential as drug targets, the study of MPs has been hindered by limitations in expression, purification and stabilization in order to acquire thermodynamic and kinetic parameters of small molecules binding. These bottlenecks are grounded on the mandatory use of detergents to isolate and extract MPs from the cell plasma membrane and the coexistence of multiple conformations, which reflects biochemical versatility and intrinsic instability of MPs. In this work ,we set out to define a new strategy to enable surface plasmon resonance (SPR) measurements on a thermostabilized and truncated version of the human adenosine (A2A) G-protein-coupled receptor (GPCR) inserted in a lipid bilayer nanodisc in a label- and detergent-free manner by using a combination of affinity tags and GFP-based fluorescence techniques. We were able to detect and characterize small molecules binding kinetics on a GPCR fully embedded in a lipid environment. By providing a comparison between different binding assays in membranes, nanodiscs and detergent micelles, we show that nanodiscs can be used for small molecule binding studies by SPR to enhance the MP stability and to trigger a more native-like behaviour when compared to kinetics on A2A receptors isolated in detergent. This work provides thus a new methodology in drug discovery to characterize the binding kinetics of small molecule ligands for MPs targets in a lipid environment. PMID- 25725489 TI - High tolerated paclitaxel nano-formulation delivered by poly (lactic-co-glycolic acid)-g-dextran micelles to efficient cancer therapy. AB - The amphiphilic graft copolymer poly (lactic-co-glycolic acid)-g-dextran (Dex PLGA) was successfully synthesized to fabricate micelles for the delivery of paclitaxel with low critical micelle concentration (CMC). The sizes of paclitaxel loaded Dex-PLGA (Dex-PLGA/PTX) micelles were kept below 100nm with a relatively narrow size distribution. This novel PTX nano-formulation was found to exhibit slightly stronger in vitro cytotoxicity against SKOV-3, OVCAR-8 and MCF-7 cells with Taxol(r). However, it could overcome the drug resistance of multi-drug resistant human breast carcinoma cells (MCF-7/Adr cells). The maximum tolerated dose (MTD) of Dex-PLGA/PTX after a single dose was more than 200mg PTX/kg, which were 8-fold higher than that of Paclitaxel Injection. The in vivo antitumor activity results indicated that Dex-PLGA/PTX micelles treatments effectively suppressed the tumor growth and highly reduced the toxicity against animals than Taxol(r) and could eliminate the SKOV-3 tumor by highly increasing the drug dose. FROM THE CLINICAL EDITOR: Chemotherapy for cancer has always been hampered the toxic side effect of the drugs. Nanotechnology has helped to produce various drug delivery systems to minimize these side effects. In this article, the authors designed dextran-based micelles loaded with paclitaxel. They showed effective anti-tumor activity in both in vitro and in vivo experiments with significant lower systemic toxicity. PMID- 25725490 TI - Toxicity studies of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide) as a colonoscopic imaging agent in rats. AB - We are investigating an imaging agent that detects early-stage primary colorectal cancer on the mucosal surface in real time under colonoscopic observation. The imaging agent, which is named the nanobeacon, is fluorescent nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide). Its potential use as an imaging tool for colorectal cancer has been thoroughly validated in numerous studies. Here, toxicities of the nanobeacon were assessed in rats. The nanobeacon was prepared according to the synthetic manner which is being established as the Good Manufacturing Practice-guided production. The rat study was performed in accordance with Good Laboratory Practice regulations. No nanobeacon treatment-related toxicity was observed. The no observable adverse effect levels (NOAEL) of the nanobeacon in 7-day consecutive oral administration and single intrarectal administration were estimated to be more than 1000mg/kg/day and 50mg/kg/day, respectively. We concluded that the nanobeacon could be developed as a safe diagnostic agent for colonoscopy applications. FROM THE CLINICAL EDITOR: Colon cancer remains a major cause of death. Early detection can result in early treatment and thus survival. In this article, the authors tested potential systemic toxicity of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin (PNA) and poly(N-vinylacetamide) (PNVA), which had been shown to bind specifically to colonic cancer cells and thus very promising in colonoscopic detection of cancer cells. PMID- 25725492 TI - The prevalence and correlates of syphilis and HIV among homosexual and bisexual men in Shijiazhuang, China. AB - Bisexual men (men who have sex with men and women) are potential epidemiological bridges responsible for the spread of HIV and other sexually transmitted infections from men who have sex with men only to the heterosexual population. We aimed to estimate the prevalence of syphilis and HIV and the factors associated with syphilis infection among men who have sex with men and women and men who have sex with men only from Shijiazhuang, China. In 2011-2013, a cross-sectional cohort of 427 men who have sex with men was recruited by a snowball sampling method and tested for syphilis and HIV. Chi square and logistic regression were performed to identify syphilis risk factors. Among the 427 men who have sex with men, 71 (16.6%) cases were syphilis-positive and 16 cases (3.7%) were HIV positive. The proportions of men who have sex with men and women and men who have sex with men only in the total sample were 31.4% and 68.6%, respectively. Men who have sex with men and women exhibited double the syphilis prevalence of men who have sex with men only and were more likely to practice insertive anal sex. Higher education level, being married, having more male partners, and both receptive and insertive anal sex roles were associated with syphilis among men who have sex with men and women. Residing in suburban areas, being married, being HIV positive, and an absence of desire to change sexual orientation were associated with syphilis among men who have sex with men only. Therefore, men who have sex with men and women represent an important sub-group in the syphilis epidemic and further interventions should be developed to reduce risk among different sub-sets of men who have sex with men. PMID- 25725494 TI - GeLL: a generalized likelihood library for phylogenetic models. AB - Phylogenetic models are an important tool in molecular evolution allowing us to study the pattern and rate of sequence change. The recent influx of new sequence data in the biosciences means that to address evolutionary questions, we need a means for rapid and easy model development and implementation. Here we present GeLL, a Java library that lets users use text to quickly and efficiently define novel forms of discrete data and create new substitution models that describe how those data change on a phylogeny. GeLL allows users to define general substitution models and data structures in a way that is not possible in other existing libraries, including mixture models and non-reversible models. Classes are provided for calculating likelihoods, optimizing model parameters and branch lengths, ancestral reconstruction and sequence simulation. AVAILABILITY AND IMPLEMENTATION: http://phylo.bio.ku.edu/GeLL under a GPL v3 license. PMID- 25725493 TI - Socio-demographics, sexual behaviours, and use of HIV prevention services among men who have sex with men and women in Western China. AB - This paper looks into the differences of sexual risk behaviours and prevention services among men who have sex with men and women and men who have sex with men only. The data from a cross-sectional survey of 159 men who have sex with men and women and 1186 men who have sex with men only in western China is analysed. It is found that men who have sex with men and women, with multiple anal sex partners, have higher rates of selling and buying sex than men who have sex with men only, but obtain less HIV-related knowledge from partners or HIV consulting and testing services. More efforts should be made to promote safer sexual behaviours and reduce the barriers for access to health services. PMID- 25725491 TI - Cre recombinase-regulated Endothelin1 transgenic mouse lines: novel tools for analysis of embryonic and adult disorders. AB - Endothelin-1 (EDN1) influences both craniofacial and cardiovascular development and a number of adult physiological conditions by binding to one or both of the known endothelin receptors, thus initiating multiple signaling cascades. Animal models containing both conventional and conditional loss of the Edn1 gene have been used to dissect EDN1 function in both embryos and adults. However, while transgenic Edn1 over-expression or targeted genomic insertion of Edn1 has been performed to understand how elevated levels of Edn1 result in or exacerbate disease states, an animal model in which Edn1 over-expression can be achieved in a spatiotemporal-specific manner has not been reported. Here we describe the creation of Edn1 conditional over-expression transgenic mouse lines in which the chicken beta-actin promoter and an Edn1 cDNA are separated by a strong stop sequence flanked by loxP sites. In the presence of Cre, the stop cassette is removed, leading to Edn1 expression. Using the Wnt1-Cre strain, in which Cre expression is targeted to the Wnt1-expressing domain of the central nervous system (CNS) from which neural crest cells (NCCs) arise, we show that stable chicken beta-actin-Edn1 (CBA-Edn1) transgenic lines with varying EDN1 protein levels develop defects in NCC-derived tissues of the face, though the severity differs between lines. We also show that Edn1 expression can be achieved in other embryonic tissues utilizing other Cre strains, with this expression also resulting in developmental defects. CBA-Edn1 transgenic mice will be useful in investigating diverse aspects of EDN1-mediated-development and disease, including understanding how NCCs achieve and maintain a positional and functional identity and how aberrant EDN1 levels can lead to multiple physiological changes and diseases. PMID- 25725495 TI - Mammalian genome evolution is governed by multiple pacemakers. AB - Genomic evolution is shaped by a dynamic combination of mutation, selection and genetic drift. These processes lead to evolutionary rate variation across loci and among lineages. In turn, interactions between these two forms of rate variation can produce residual effects, whereby the pattern of among-lineage rate heterogeneity varies across loci. The nature of rate variation is encapsulated in the pacemaker models of genome evolution, which differ in the degree of importance assigned to residual effects: none (Universal Pacemaker), some (Multiple Pacemaker) or total (Degenerate Multiple Pacemaker). Here we use a phylogenetic method to partition the rate variation across loci, allowing comparison of these pacemaker models. Our analysis of 431 genes from 29 mammalian taxa reveals that rate variation across these genes can be explained by 13 pacemakers, consistent with the Multiple Pacemaker model. We find no evidence that these pacemakers correspond to gene function. Our results have important consequences for understanding the factors driving genomic evolution and for molecular-clock analyses. AVAILABILITY AND IMPLEMENTATION: ClockstaR-G is freely available for download from github (https://github.com/sebastianduchene/clockstarg). PMID- 25725496 TI - hiHMM: Bayesian non-parametric joint inference of chromatin state maps. AB - MOTIVATION: Genome-wide mapping of chromatin states is essential for defining regulatory elements and inferring their activities in eukaryotic genomes. A number of hidden Markov model (HMM)-based methods have been developed to infer chromatin state maps from genome-wide histone modification data for an individual genome. To perform a principled comparison of evolutionarily distant epigenomes, we must consider species-specific biases such as differences in genome size, strength of signal enrichment and co-occurrence patterns of histone modifications. RESULTS: Here, we present a new Bayesian non-parametric method called hierarchically linked infinite HMM (hiHMM) to jointly infer chromatin state maps in multiple genomes (different species, cell types and developmental stages) using genome-wide histone modification data. This flexible framework provides a new way to learn a consistent definition of chromatin states across multiple genomes, thus facilitating a direct comparison among them. We demonstrate the utility of this method using synthetic data as well as multiple modENCODE ChIP-seq datasets. CONCLUSION: The hierarchical and Bayesian non parametric formulation in our approach is an important extension to the current set of methodologies for comparative chromatin landscape analysis. AVAILABILITY AND IMPLEMENTATION: Source codes are available at https://github.com/kasohn/hiHMM. Chromatin data are available at http://encode x.med.harvard.edu/data_sets/chromatin/. PMID- 25725497 TI - IVA: accurate de novo assembly of RNA virus genomes. AB - MOTIVATION: An accurate genome assembly from short read sequencing data is critical for downstream analysis, for example allowing investigation of variants within a sequenced population. However, assembling sequencing data from virus samples, especially RNA viruses, into a genome sequence is challenging due to the combination of viral population diversity and extremely uneven read depth caused by amplification bias in the inevitable reverse transcription and polymerase chain reaction amplification process of current methods. RESULTS: We developed a new de novo assembler called IVA (Iterative Virus Assembler) designed specifically for read pairs sequenced at highly variable depth from RNA virus samples. We tested IVA on datasets from 140 sequenced samples from human immunodeficiency virus-1 or influenza-virus-infected people and demonstrated that IVA outperforms all other virus de novo assemblers. AVAILABILITY AND IMPLEMENTATION: The software runs under Linux, has the GPLv3 licence and is freely available from http://sanger-pathogens.github.io/iva PMID- 25725498 TI - L-GRAAL: Lagrangian graphlet-based network aligner. AB - MOTIVATION: Discovering and understanding patterns in networks of protein-protein interactions (PPIs) is a central problem in systems biology. Alignments between these networks aid functional understanding as they uncover important information, such as evolutionary conserved pathways, protein complexes and functional orthologs. A few methods have been proposed for global PPI network alignments, but because of NP-completeness of underlying sub-graph isomorphism problem, producing topologically and biologically accurate alignments remains a challenge. RESULTS: We introduce a novel global network alignment tool, Lagrangian GRAphlet-based ALigner (L-GRAAL), which directly optimizes both the protein and the interaction functional conservations, using a novel alignment search heuristic based on integer programming and Lagrangian relaxation. We compare L-GRAAL with the state-of-the-art network aligners on the largest available PPI networks from BioGRID and observe that L-GRAAL uncovers the largest common sub-graphs between the networks, as measured by edge-correctness and symmetric sub-structures scores, which allow transferring more functional information across networks. We assess the biological quality of the protein mappings using the semantic similarity of their Gene Ontology annotations and observe that L-GRAAL best uncovers functionally conserved proteins. Furthermore, we introduce for the first time a measure of the semantic similarity of the mapped interactions and show that L-GRAAL also uncovers best functionally conserved interactions. In addition, we illustrate on the PPI networks of baker's yeast and human the ability of L-GRAAL to predict new PPIs. Finally, L-GRAAL's results are the first to show that topological information is more important than sequence information for uncovering functionally conserved interactions. AVAILABILITY AND IMPLEMENTATION: L-GRAAL is coded in C++. Software is available at: http://bio-nets.doc.ic.ac.uk/L-GRAAL/. CONTACT: n.malod-dognin@imperial.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25725499 TI - Mining viral proteins for antimicrobial and cell-penetrating drug delivery peptides. AB - MOTIVATION: The need for more effective and safer pharmaceuticals is a persistent quest. Microbial adaptations create the need to permanently develop new antimicrobials (AMPs), for instance. Similarly, intracellular delivery of drugs is still a challenge and translocation of membranes for drug delivery is an area of intense research. Peptides can be used both as AMP drug leads and drug carrier systems for intracellular delivery. Multifunctional proteins are abundant in viruses but, surprisingly, have never been thoroughly screened for bioactive peptide sequences. RESULTS: Using the AMPA and CellPPD online tools, we have evaluated the propensity of viral proteins to comprise AMP or cell-penetrating peptides (CPPs). Capsid proteins from both enveloped and non-enveloped viruses, and membrane and envelope proteins from enveloped viruses, in a total of 272 proteins from 133 viruses, were screened to detect the presence of potential AMP and CPP sequences. A pool of 2444 and 426 CPP and AMP sequences, respectively, were discovered. The capsids of flaviviruses are the best sources of these peptides reaching more than 80% of CPP sequence coverage per protein. Selected sequences were tested experimentally and validated the results. Overall, this study reveals that viruses form a natural multivalent biotechnological platform still underexplored in drug discovery and the heterogeneous abundance of CPP/AMP sequences among viral families opens new avenues in viral biology research. PMID- 25725500 TI - Elder and caregiver solutions to improve medication adherence. AB - Medication mismanagement is a growing public health concern, especially among elders. Annually, it is a major contributor to emergency hospitalization and nursing home placement. Elders and their caregivers, as healthcare consumers and stakeholders in this issue, are uniquely qualified to inform strategies to improve medication adherence. We conducted a qualitative study to ascertain caregiver and elder perceptions of barriers to medication management and to identify community-derived solutions to improve medication management. Nine focus groups (N = 65, mean age = 71) were conducted with caregivers or elders from five communities. Participants were recruited by key informants utilizing snowball sampling methodology. The following themes were identified in the participant recommended proposed solutions improving medication adherence: (i) use of personal systems to overcome barriers to medication adherence, (ii) various solutions to address cost concerns, (iii) the need for regular review of medications by doctors or pharmacists to eliminate unnecessary medications, (iv) desire for community-driven support systems, and (v) using medical advocates. Elders and caregivers recognized medication non-adherence as a community-wide issue and were eager to offer solutions they thought would work in their communities. These solutions can lend credibility to strategies currently being developed/utilized and offer innovative recommendations for future interventions. PMID- 25725501 TI - Characterization of immune cells and cytokine localization in the rat utero placental unit mid- to late gestation. AB - The success of pregnancy is dependent on the precise regulation of the immune response within the utero-placental environment. Rats are beginning to be widely used as a model for human immune-related pregnancy complications. However, our knowledge of immune cells and cytokine localization in the rat utero-placental tissue is limited. The current study aimed to localize the immune cell populations, including uterine natural killer (uNK) cells, neutrophils, and macrophages within the rat utero-placental unit at two crucial gestational ages, gestational days 15.5 and 18.5. In addition, we characterized the distribution of the cytokines TNFalpha, IFNgamma, and IL-10 in the utero-placental regions at both the above-mentioned gestational ages. Our study has demonstrated co localization TNFalpha and IFNgamma with uNK cells in perivascular regions of the rat mesometrial triangle at both gestational ages. Neutrophils and IL-10-positive cells were localized at the maternal-fetal interface and in the spiral artery lumen of the rat mesometrial triangle at both gestational ages. TNFalpha and IL 10 demonstrated a temporal change in the localization from GD15.5 to GD18.5, which coincides with the leading edge of trophoblast invasion into the mesometrial triangle. The current study furthers our knowledge of the localization of uterine immune cells and relevant cytokines, and provides a base from which to research the function of these immune cells and cytokines during rat pregnancy as a model to study human immune-related pregnancy complications. PMID- 25725502 TI - Outdoor areas of Australian residential aged care facilities do not facilitate appropriate sun exposure. AB - OBJECTIVE: The aim of the present study was to assess whether the outdoor areas of residential aged care facilities used for a sunlight intervention trial had the design features that encouraged participants' use of these spaces. METHODS: The design principles recommended in the 'Vitamin D and the Built Environment in Victoria' guidelines were used to assess the outdoor spaces of residential aged care facilities that were used in a randomised controlled trial (RCT) of sunlight exposure. Attendance rates in the sunlight RCT were analysed in relation to global impression scores of the facilities using one-way analysis of variance. RESULTS: Thirty-six outdoor areas of 31 facilities were assessed. The facilities met the guidelines for sun exposure, and were generally safe and accessible. However, many lacked privacy, security and aesthetic appeal. Most of the outdoor spaces were not used for regularly scheduled activities. Attendance rates were higher in those facilities with the highest global impression scores compared with those with the lowest scores (F(2,367) = 3.262, P = 0.039). CONCLUSIONS: The physical environment of the outdoor areas of residential aged care facilities was associated with their use for sunlight exposure. Suitably designed or modified spaces have the potential to encourage their greater use, and residential aged care facilities should also plan regular activities in those areas. These measures can facilitate safe sun exposure, as well as physical activity and social interaction in older people. PMID- 25725503 TI - Comparison of VMAT and IMRT strategies for cervical cancer patients using automated planning. AB - BACKGROUND AND PURPOSE: In a published study on cervical cancer, 5-beam IMRT was inferior to single arc VMAT. Here we compare 9, 12, and 20 beam IMRT with single and dual arc VMAT. MATERIAL AND METHODS: For each of 10 patients, automated plan generation with the in-house Erasmus-iCycle optimizer was used to assist an expert planner in generating the five plans with the clinical TPS. RESULTS: For each patient, all plans were clinically acceptable with a high and similar PTV coverage. OAR sparing increased when going from 9 to 12 to 20 IMRT beams, and from single to dual arc VMAT. For all patients, 12 and 20 beam IMRT were superior to single and dual arc VMAT, with substantial variations in gain among the study patients. As expected, delivery of VMAT plans was significantly faster than delivery of IMRT plans. CONCLUSIONS: Often reported increased plan quality for VMAT compared to IMRT has not been observed for cervical cancer. Twenty and 12 beam IMRT plans had a higher quality than single and dual arc VMAT. For individual patients, the optimal delivery technique depends on a complex trade off between plan quality and treatment time that may change with introduction of faster delivery systems. PMID- 25725504 TI - The utility of pathologic evaluation of adult hernia specimens. AB - BACKGROUND: Pathological examination of hernia sac specimens adds additional steps and cost to a surgical procedure but has no proven benefit. Although well studied in pediatrics, there are limited data in the adult literature pertaining to this practice. METHODS: This is a retrospective analysis from a single institution referral center over a 4-year period (2007 to 2011). All inguinal, incisional, ventral, and umbilical hernia repairs greater than 18 years of age were included. RESULTS: A total of 1,216 inguinal (55.4%), incisional (11.4%), umbilical (21.5%), or ventral hernia (11.7%) repairs were included. In 246 cases (20.2%), hernia sac specimens were sent to pathology (open 96.7%; laparoscopic 3.3%). There were no cases in which management of the patient changed because of the final results. CONCLUSION: The rarity of changes in diagnosis and treatment from routine pathologic examination of a hernia sac does not justify this practice and indicates that it may be omitted except in unique circumstances. PMID- 25725505 TI - Idle time: an underdeveloped performance metric for assessing surgical skill. AB - BACKGROUND: The aim of this study was to evaluate validity evidence using idle time as a performance measure in open surgical skills assessment. METHODS: This pilot study tested psychomotor planning skills of surgical attendings (n = 6), residents (n = 4) and medical students (n = 5) during suturing tasks of varying difficulty. Performance data were collected with a motion tracking system. Participants' hand movements were analyzed for idle time, total operative time, and path length. We hypothesized that there will be shorter idle times for more experienced individuals and on the easier tasks. RESULTS: A total of 365 idle periods were identified across all participants. Attendings had fewer idle periods during 3 specific procedure steps (P < .001). All participants had longer idle time on friable tissue (P < .005). CONCLUSIONS: Using an experimental model, idle time was found to correlate with experience and motor planning when operating on increasingly difficult tissue types. Further work exploring idle time as a valid psychomotor measure is warranted. PMID- 25725506 TI - Role of the catechol group in the antioxidant and neuroprotective effects of virgin olive oil components in rat brain. AB - The aim of the present study was to determine the role of the catechol group in the antioxidant and neuroprotective effects of minor components of virgin olive oil in rat brain tissue. Hydroxytyrosol ethyl ether (HT, 2 OH), tyrosol ethyl ether (Ty, 1 OH) and 3,4-di-ortho-methylidene-hydroxytyrosol ethyl ether (MET, no OH) were compared. Oxidative stress was induced with ferrous salts (lipid peroxidation induction), diethylmaleate (depletion of glutathione) and hypoxia reoxygenation in brain slices. Lipid peroxidation was inhibited in direct proportion to the number of OH groups: HT>Ty>MET. Exposure to HT led to partial recovery of the glutathione system after chemical inhibition or hypoxia reoxygenation. All three compounds inhibited cell death in hypoxia-reoxygenation experiments (HT>=Ty>MET). Peroxynitrite formation (3-nitrotyrosine) and inflammatory mediators (prostaglandin E2 and interleukin 1beta) were inhibited by all three compounds. In conclusion, the presence of OH groups in the molecule of these phenolic compounds from virgin olive oil is a determinant factor in their antioxidant effect in brain tissue, but this antioxidant effect is not the only explanation for their neuroprotective effect. PMID- 25725507 TI - High prevalence of pathologic copy number variants detected by chromosomal microarray in Swiss-Italian children with autism spectrum disorders. PMID- 25725508 TI - The management of renal artery stenosis: an alternative interpretation of ASTRAL and CORAL. AB - OBJECTIVES: To assess the literature on intervention for renal artery stenosis (RAS), with special emphasis on the last two and largest randomized trials, the ASTRAL and CORAL trials. DESIGN: A review of renal physiology, pathology, and pathophysiology of RAS and a critical analysis of the randomized trials. MATERIALS: Published literature for renal physiology and RAS were assessed. METHODS: Renal physiology, renal intervention, and the limitations and challenges of both ASTRAL and CORAL are analysed. RESULTS: The last two reported, and largest randomized trials of percutaneous renal artery intervention for RAS were the ASTRAL and the CORAL trials; both generated much debate and much controversy, however both trials had methodological shortcomings, and assumed a simplistic approach to renal physiology. Both trials were hampered by slow recruitment, and there were protocol changes to accommodate, and CORAL was not powered for subgroup analysis. The primary outcome measure for ASTRAL was the reciprocal of serum creatinine levels and CORAL a complex composite endpoint of cardiovascular or renal events. In ASTRAL, 25% of patients had normal renal function and 40% almost normal renal function; and in CORAL, 50% of the cohort had either no renal failure, or were Stage I or Stage II CKD, (i.e. eGFR of >60 mls/min/1.73 m(2)). In ASTRAL, 41% of patients had a stenosis of <70%; and an interim analysis of 611 patients (of 947 enrolled) in CORAL revealed that 55% had <70% renal artery stenosis. CONCLUSIONS: Best evidence still supports intervention for patients with RAS of >80% with a significant trans-lesional pressure gradient; difficult to control blood pressure with more than three antihypertensives, especially in younger patients; and those with truncal rather than ostial stenosis; patient with a rapid deterioration of renal function; flash pulmonary oedema; and post transplant RAS. PMID- 25725509 TI - Re: 'Why do health systems not fund supervised exercise programmes for intermittent claudication?'. PMID- 25725510 TI - Distinct neural networks underlying empathy for pleasant and unpleasant touch. AB - In spite of considerable progress in the understanding of the neural mechanisms underlying the experience of empathy, the majority of previous investigations have focused on how we share negative affective states (and in particular pain) of others, whereas only few studies have targeted empathy for positive emotions. This bias has precluded addressing one of the central tenets of the shared representations account of empathy, which is that different networks should be engaged when empathizing with emotions that are represented on different neural levels. The aim of the present study was to overcome this limitation and to test whether empathy for pleasant and unpleasant affective touch is underpinned by different neural networks. To this end we used functional magnetic resonance imaging (fMRI), with two independent replication experiments (N = 18, N = 32), and a novel paradigm enabling the joint investigation of first-hand and vicarious responses to pleasant and unpleasant affect induced via visuo-tactile stimulation. This revealed that empathy is subserved by distinct neural networks, with those regions recruited in the first-hand experience of positive or negative affective states also being specifically recruited when empathizing with these respective states in others. More specifically, the first-hand and vicarious experience of pleasant touch commonly recruited medial orbitofrontal cortex (OFC), while unpleasant touch was associated with shared activation in the right fronto-insular cortex. The observation that specifically tailored subsystems of the human brain are engaged to share positive versus negative touch of others brings fresh evidence to one of the major goals of the social neuroscience of empathy: to identify which specific aspects of the affective states of others are shared, and what role this plays in enabling the understanding of the emotions of others. PMID- 25725511 TI - Commentary on "Neural correlates of mirth and laughter: A direct electrical cortical stimulation study" by Yamao and colleagues. PMID- 25725512 TI - [Factors associated with colon cleansing measured with the Boston scale in routine clinical practice]. AB - INTRODUCTION: The Boston scale is useful to standardize colon cleansing at colonoscopy. The aim of this study was to analyze the degree of preparation before colonoscopy and the factors associated with cleansing in routine clinical practice. MATERIAL AND METHODS: We included colonoscopies performed from January to June 2013. Exclusion criteria were age <15 years, a history of colon surgery, inflammatory bowel disease, and active gastrointestinal bleeding. The standard preparation was CitraFleet. The parameters related to the degree of bowel cleansing (using the Boston scale) were age, sex, indication, colonoscopy shift (morning or afternoon), patient origin (outpatient or hospitalized), and colonoscopy findings. RESULTS: We analyzed 947 colonoscopies, with exclusion of 297. A total of 5.8% (38/650) of the colonoscopies were incomplete, 50% due to lack of preparation. The mean age of the patients was 61.27 years (SD: 16.1), and 51.8% were women. The distribution of the Boston scale was 0-3 in 6.3%, 4-5 in 12.6%, 6-7 in 30.6%, and 8-9 in 50.4%, with a mean 7.04 (SD: 2.03). On multivariate analysis, the factors statistically associated with better preparation were younger age, afternoon colonoscopy and the outpatient setting. The percentage of polyps in patients with a Boston scale score <=5 was 10% compared with 27.8% in patients with a score > 5 (P=.014). CONCLUSION: In clinical practice, 80% of patients had an acceptable level of preparation. Older patients, those undergoing colonoscopy in the morning and hospitalized patients would be candidates for measures to improve the degree of colonic preparation. PMID- 25725513 TI - Mechanistic chemical perspective of hydrogen sulfide signaling. AB - Hydrogen sulfide is now a well-appreciated master regulator in a diverse array of physiological processes. However, as a consequence of the rapid growth of the area, sulfide biology suffers from an increasing number of controversial observations and interpretations. A better understanding of the underlying molecular pathways of sulfide's actions is key to reconcile controversial issues, which calls for rigorous chemical/biochemical investigations. Protein sulfhydration and coordination/redox chemical interactions of sulfide with heme proteins are the two most extensively studied pathways in sulfide biochemistry. These pathways are important mediators of protein functions, generate bioactive sulfide metabolites, contribute to sulfide storage/trafficking and carry antioxidant functions. In addition, inorganic polysulfides, which are oxidative sulfide metabolites, are increasingly recognized as important players in sulfide biology. This chapter provides an overview of our mechanistic perspective on the reactions that govern (i) sulfide's bioavailability (including the delicate enzyme machineries that orchestrate sulfide production and consumption and the roles of the large sulfide-storing pools as biological buffers), (ii) biological significance and mechanisms of persulfide formation (including the reduction of disulfides, condensation with sulfenic acids, oxidation of thiols with polysulfides and radical-mediated pathways), (iii) coordination and redox chemical interactions of sulfide with heme proteins (including cytochrome c oxidase, hemoglobins, myoglobins and peroxidases), and (iv) the chemistry of polysulfides. PMID- 25725514 TI - Measurement of H2S in vivo and in vitro by the monobromobimane method. AB - The gasotransmitter hydrogen sulfide (H2S) is known as an important regulator in several physiological and pathological responses. Among the challenges facing the field is the accurate and reliable measurement of hydrogen sulfide bioavailability. We have reported an approach to discretely measure sulfide and sulfide pools using the monobromobimane (MBB) method coupled with reversed phase high-performance liquid chromatography (RP-HPLC). The method involves the derivatization of sulfide with excess MBB under precise reaction conditions at room temperature to form sulfide dibimane (SDB). The resultant fluorescent SDB is analyzed by RP-HPLC using fluorescence detection with the limit of detection for SDB (2 nM). Care must be taken to avoid conditions that may confound H2S measurement with this method. Overall, RP-HPLC with fluorescence detection of SDB is a useful and powerful tool to measure biological sulfide levels. PMID- 25725515 TI - Hydrogen sulfide detection using nucleophilic substitution-cyclization-based fluorescent probes. AB - While previously known as a toxic pollutant, hydrogen sulfide (H2S) has been recently classified as an important signaling molecule with potent cytoprotective actions. The study on H2S is a rapidly growing field in biomedical research. Nevertheless, the detection of H2S in biological samples is still a challenge. Fluorescent assays can be very useful in this field owing to their high sensitivity and convenience. Based on the dual nucleophilicity of hydrogen sulfide, a series of reaction-based fluorescence "turn-on" probes have been developed by our lab. In this chapter, we provide an overview of the reactivity/property of these probes and detailed protocols for the use of them in experiments. PMID- 25725516 TI - Azide-based fluorescent probes: imaging hydrogen sulfide in living systems. AB - Hydrogen sulfide is a redox active sulfur species that is endogenously generated in mammalian systems as an antioxidant and signaling molecule to support cellular function. The fundamental and ubiquitous actions of hydrogen sulfide demand sensitive and specific methods to track this biomolecule as it is produced within living organisms with temporal and spatial regulation. In this context, the hydrogen sulfide-mediated reduction of an azide to an amine is a useful method for organic synthesis, and this reaction has successfully been exploited to yield biocompatible fluorescent probes for hydrogen sulfide detection in vitro and in cells. This chapter provides protocols and guidelines for applying azide-based fluorescence probes to detecting hydrogen sulfide in living systems, including a protocol that was used to detect endogenous hydrogen sulfide in living single cells using a confocal microscope. PMID- 25725518 TI - Quantification of hydrogen sulfide concentration using methylene blue and 5,5' dithiobis(2-nitrobenzoic acid) methods in plants. AB - Hydrogen sulfide (H2S) has long been considered as a phytotoxin but, nowadays, as a novel signaling molecule at low concentration in plants, which is involved in plant growth, development, and the acquisition of tolerance to abiotic and biotic stresses. H2S is commonly found only in very small amounts in most biological systems. To further understand H2S functions, accurate measurement of H2S concentration in plants is very important. In this chapter, quantificational methods of H2S in plant tissues, namely, methylene blue (MB) and 5,5'-dithiobis(2 nitrobenzoic acid) (DTNB) methods, are introduced; the former has higher sensitivity than that of the latter, and the determination limits of MB and DTNB methods are 1.5*10(-7)M (0.005 MUg/ml) and 3.7*10(-6)M (0.13 MUg/ml), respectively, hoping to stimulate more research into H2S signal molecule in plants. PMID- 25725517 TI - Chemiluminescent detection of enzymatically produced H2S. AB - Hydrogen sulfide (H2S) has emerged as an important biological signaling molecule. To better understand the multifaceted biological roles of H2S, the development of selective and sensitive biocompatible assays for H2S is becoming increasingly important. Motivated by these challenges, our laboratory is developing new methods to further detect and monitor biological H2S. Here, we describe in detail our recent advances in the development and the use of chemiluminescence-based H2S sensors to assist other investigators with use of these chemical tools. We highlight the use of these tools use by displaying their selectivity and high sensitivity toward H2S and provide examples of assays we have developed to detect enzymatically produced H2S. PMID- 25725519 TI - H2S analysis in biological samples using gas chromatography with sulfur chemiluminescence detection. AB - Hydrogen sulfide (H2S) is a metabolite and signaling molecule in biological tissues that regulates many physiological processes. Reliable and sensitive methods for H2S analysis are necessary for a better understanding of H2S biology and for the pharmacological modulation of H2S levels in vivo. In this chapter, we describe the use of gas chromatography coupled to sulfur chemiluminescence detection to measure the rates of H2S production and degradation by tissue homogenates at physiologically relevant concentrations of substrates. This method allows separation of H2S from other sulfur compounds and provides sensitivity of detection to ~15 pg (or 0.5 pmol) of H2S per injected sample. PMID- 25725520 TI - Use of phosphorodithioate-based compounds as hydrogen sulfide donors. AB - Synthetic hydrogen sulfide (H2S) donors are useful research tools as well as potential therapeutic agents. In this chapter, we report the detailed protocols for the synthesis and evaluation of a series of phosphorodithioate-based H2S donors. Fluorescence assays were used to determine H2S release from the donors in both aqueous buffers and in cultured cells. These donors were found to be slow release donors, much like the well-known GYY4137. These donors also showed some protective effects against hydrogen peroxide (H2O2)-induced oxidative damage in myocytes. PMID- 25725521 TI - GYY4137, a novel water-soluble, H2S-releasing molecule. AB - Hydrogen sulfide (H2S) is now recognized as the so called "third gasotransmitter" taking its place alongside nitric oxide and carbon monoxide. In recent years, H2S has been reported to exhibit a diverse range of pharmacological effects in biological systems. Much of this evidence is derived from a combination of conventional pharmacological and genetic approaches coupled with the use of chemical compounds such as sodium hydrosulfide, a rapid H2S releasing donor. Developments in the design of new drug entities which attempt to take into account physicochemical properties, targeting to specific cellular organelles, triggering of H2S release upon specific chemical reactions in the cell, and controlling the release of H2S over extended periods of time have been described. For most of these molecules, little or no work has been conducted to determine their biological activity or possible therapeutic effects. It is therefore not clear whether such molecules have therapeutic potential which highlights the need for further in vivo studies. One exception to the general rule is GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate), a slow releasing H2S donor, which has been evaluated for activity in a range of pharmacological models both in vitro and in vivo. GYY4137 was first reported to release H2S and exhibit vasodilator activity over 5 years ago and, to date, GYY4137 is becoming increasingly employed as a pharmacological "tool" to explore the biological functions of H2S. PMID- 25725522 TI - Neuroprotective effects of hydrogen sulfide in Parkinson's disease animal models: methods and protocols. AB - Hydrogen sulfide (H2S) was first proposed to be a neuromodulator in 1996. After that, multiple biological functions of H2S have been revealed. In brain, it regulates intracellular calcium, intracellular pH, and cAMP level in different brain cells via regulation of the functions of different proteins. In pathological situations, H2S produces anti-inflammatory, -oxidant, and -apoptotic effects, and therefore is potentially used to treat neurodegenerative diseases, especially Parkinson's disease (PD). In this chapter, we summarized the methods commonly used to create PD animal models followed by description of evaluations of PD pathology. The PD models described in this chapter included those caused by various neurotoxins like 6-hydroxydopamine, rotenone, and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine. Methods for examination of dopaminergic neuron loss and microglial activation in both substantia nigra and striatum are also described. The role of H2S and its therapeutic potentials are discussed in the last section of this chapter. PMID- 25725523 TI - Assay methods for H2S biogenesis and catabolism enzymes. AB - H2S is produced from sulfur-containing amino acids, cysteine and homocysteine, or a catabolite, 3-mercaptopyruvate, by three known enzymes: cystathionine beta synthase, gamma-cystathionase, and 3-mercaptopyruvate sulfurtransferase. Of these, the first two enzymes reside in the cytoplasm and comprise the transsulfuration pathway, while the third enzyme is found both in the cytoplasm and in the mitochondrion. The following mitochondrial enzymes oxidize H2S: sulfide quinone oxidoreductase, sulfur dioxygenase, rhodanese, and sulfite oxidase. The products of the sulfide oxidation pathway are thiosulfate and sulfate. Assays for enzymes involved in the production and oxidative clearance of sulfide to thiosulfate are described in this chapter. PMID- 25725524 TI - Oxidation of H2S in mammalian cells and mitochondria. AB - Hydrogen sulfide (H2S) is the third gasotransmitter described in mammals. These gasotransmitters (H2S, CO, and NO) are small molecules able to diffuse freely across membranes and thus susceptible to reach easily intracellular targets, one of which is the respiratory enzyme cytochrome oxidase subject to complete inhibition by low micromolar concentrations of these gases. However in contrast to NO or CO, H2S can be metabolized by a sulfide quinone reductase feeding the mitochondrial respiratory chain with the hydrogen atoms of sulfide. Sulfide is thus a two-sided molecule: substrate or poison according to the concentration. The aim of this chapter is to present a mean to monitor sulfide oxidation by isolated mitochondria or cells and to summarize how the properties of this amazing couple (mitochondria and sulfide) translate into practical and conceptual consequences. PMID- 25725525 TI - Redox regulation of mammalian 3-mercaptopyruvate sulfurtransferase. AB - A cystine-catabolizing enzyme, 3-mercaptopyruvate sulfurtransferase catalyzes the trans-sulfuration reaction of mercaptopyruvate or thiosulfate to thiol-containing compounds or cyanide. During the catalytic process, persulfide is formed at the catalytic site cysteine residue and a sulfur-acceptor substrate donates the outer sulfur of the persulfide to form a new persulfide molecule. Subsequently, the molecule can be reduced by thioredoxin to form hydrogen sulfide. The enzyme is regulated by redox changes via two redox-sensing molecular switches consisting redox-sensitive cysteine residues. One switch is the catalytic cysteine in itself, which is oxidized to form a cysteine-sulfenate resulting in inhibition of catalytic activity. The sulfenate can be reduced by thioredoxin resulting in restoration of the activity. The redox potential of sulfenate is lower than that of glutathione and greater than that of thioredoxin. The other switch involves cysteine residues positioned on the surface of the enzyme. The oxidation the intermolecular disulfide linkage at these cysteine residues, leading to dimer formation, inhibits enzyme activity. On the other hand, reduction-associated monomer formation increases catalytic activity. Thioredoxin reduces the disulfide bond more effectively than dithiothreitol, although the specificity mechanism has not been identified. Congenital defects in this enzyme result in, mercaptolactate cysteine disulfiduria associated with or without mental retardation. However, the pathogenesis has not been identified. Because 3-mercaptopyruvate sulfurtransferase serves as a cellular antioxidative protein, the other biological functions related to the inhabitant disease are being investigated. PMID- 25725526 TI - Role of human sulfide: quinone oxidoreductase in H2S metabolism. AB - The first step in the mammalian metabolism of H2S is catalyzed by sulfide:quinone oxidoreductase (SQOR). Human SQOR is an integral membrane protein, which presumably interacts with the inner mitochondrial membrane in a monotopic fashion. The enzyme is a member of a family of flavoprotein disulfide oxidoreductases (e.g., glutathione reductase) that utilize a Cys-S-S-Cys disulfide bridge as an additional redox center. SQOR catalyzes a two-electron oxidation of H2S to sulfane sulfur using coenzyme Q as electron acceptor. The enzyme also requires a third substrate to act as the acceptor of the sulfane sulfur from a cysteine persulfide intermediate. Here, we describe a method for the bacterial expression of human SQOR as a catalytically active membrane-bound protein, procedures for solubilization and purification of the recombinant protein to >95% homogeneity, and spectrophotometric assays to monitor SQOR mediated H2S oxidation in reactions with different sulfane sulfur acceptors. PMID- 25725528 TI - Preface. PMID- 25725527 TI - H2S regulation of nitric oxide metabolism. AB - Nitric oxide (NO) and hydrogen sulfide (H2S) are two major gaseous signaling molecules that regulate diverse physiological functions. Recent publications indicate the regulatory role of H2S on NO metabolism. In this chapter, we discuss the latest findings on H2S-NO interactions through formation of novel chemical derivatives and experimental approaches to study these adducts. This chapter also addresses potential H2S interference on various NO detection techniques, along with precautions for analyzing biological samples from various sources. This information will facilitate critical evaluation and clearer insight into H2S regulation of NO signaling and its influence on various physiological functions. PMID- 25725529 TI - Long-term survival of Cryptococcus neoformans and Cryptococcus gattii in stored environmental samples from Colombia. AB - BACKGROUND: Both Cryptococcus neoformans and Cryptococcus gattii have been isolated from a variety of environmental sources in Colombia. AIM: To determine the viability of C. neoformans/C. gattii isolates in stored soil samples, filtrates and bird droppings from which these yeasts were previously recovered. METHODS: A total of 964 samples collected between 2003 and 2009, and kept at room temperature were processed. From them, 653 samples were from trees decaying wood, 274 from soil filtrates and 37 from bird droppings. When C. neoformans or C. gattii were recovered, the molecular type of each isolate was established by PCR fingerprinting using the single primer (GTG)5. RESULTS: Among the processed samples, 161 isolates were recovered. From those, 81 (50.3%) corresponded to C. gattii recovered from decaying wood of Eucalyptus spp., Corymbia ficifolia, Terminalia catappa and Ficus spp. trees, and 80 (49.7%) corresponded to C. neoformans recovered from Ficus spp. and eucalyptus trees, as well as from bird droppings. The most prevalent molecular type among the C. gattii and C. neoformans isolates was VGII and VNI, respectively. CONCLUSIONS: The re-isolation of C. neoformans/C. gattii from 10-year stored samples suggests that these yeasts are able to keep viable in naturally colonized samples. PMID- 25725530 TI - Past, present, and future of craniofacial superimposition: Literature and international surveys. AB - In this manuscript, the past, present and future of the identification of human remains based on craniofacial superimposition is reviewed. An analysis of the different technological approaches developed over time is offered in conjunction with a new classification based on the technology implemented throughout the diverse phases of the process. The state of the art of the technique, in the academic and forensic realms, is reflected in an extensive international survey that includes over one hundred experts worldwide. The results of the survey indicate the current relative importance of the technique, despite of its controversial nature within the scientific community. Finally, the future challenges to be faced to justify the use of this technique for either profiling, exclusion or identification purposes are discussed. PMID- 25725531 TI - Fatal mechanical asphyxia induces changes in energy utilization in the rat brain: An (18)F-FDG-PET study. AB - PURPOSE: This study was designed to evaluate changes in brain glucose metabolism in rats following ligature strangulation. MATERIALS AND METHODS: Thirteen male Wistar rats were used in the present study, divided into control (n=7) and asphyxia groups (n=6, ligature strangulation). Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) was used to evaluate brain glucose metabolism. Rats were scanned for PET-CT, and image data co-registered with a T2WI MRI template using SPM8 software. Image J was employed to draw regions of interest (ROIs) from the MRI template and acquire ROI activity information from the PET images. RESULTS: In the asphyxia group vs. controls, (18)F-FDG uptake (FU) was decreased in the substantia nigra (25.26%, p<0.001), rhombencephalon (pons/medulla oblongata, 13.92%, p<0.01), hypothalamus (22.06%, p<0.01), ventral tegmentum (10.12%, p<0.05) and amygdala (12.74%, p<0.05); however, FU was increased in motor (18.21%, p<0.05) and visual cortices (19.2%, p<0.05). CONCLUSIONS: The glucose metabolism distribution map in the asphyxiated rat brains were substantially changed versus controls. PET with (18)F-FDG can demonstrate excitement and inhibition of different brain areas even in cases of ligature strangulation. PMID- 25725532 TI - Patient safety in anesthesia: learning from the culture of high-reliability organizations. AB - There has been an increased awareness of and interest in patient safety and improved outcomes, as well as a growing body of evidence substantiating medical error as a leading cause of death and injury in the United States. According to The Joint Commission, US hospitals demonstrate improvements in health care quality and patient safety. Although this progress is encouraging, much room for improvement remains. High-reliability organizations, industries that deliver reliable performances in the face of complex working environments, can serve as models of safety for our health care system until plausible explanations for patient harm are better understood. PMID- 25725533 TI - Intraoperative cardiac emergencies. AB - Intraoperative cardiac emergencies require prompt recognition and management in order to optimize patient safety and recovery. This article addresses the perioperative management of hypertension, myocardial infarction, arrhythmias, autonomic dysreflexia, tamponade, and tension pneumothorax. These complications can occur in patients with underlying coexisting disease, but can also occur in surgical patients regardless of the underlying disorder. PMID- 25725534 TI - Critical care nursing in acute postoperative neurosurgical patients. AB - The nursing discipline is vital throughout patients' hospital progression. One of the most critical moments in the hospital stay is the postoperative period. Neurosurgical patients require a high level of nursing care and vigilance and additional postoperative monitoring in intensive care units designed specifically for this demographic. In the postoperative setting, patient care must be transferred from anesthesia to nursing in a manner that is continuous and safe. This article focuses on neurosurgical patients in the postoperative period, the assessment of these patients, and critical care nursing, with emphasis on common issues and interventions for this dynamic patient population. PMID- 25725535 TI - Massive transfusion for hemorrhagic shock: what every critical care nurse needs to know. AB - Massive transfusion is defined as complete replacement of a patient's blood volume or approximately 10 units of packed red blood cells within a 24-hour period or one red blood cells volume in 24 hours for a pediatric patient. This article reviews the most recent understanding and recommendations in massive transfusion along with the unintended consequences in the management of patients with profound hemorrhage. PMID- 25725536 TI - Management of the difficult airway. AB - Airway management skills are critical to patient care in many settings. Patients with a difficult airway present unique challenges and considerations, and clinicians should assess for this condition by obtaining a thorough history and physical examination. Familiarity with difficult airway management guidelines, algorithms, tools, and techniques is essential to formulating a safe and effective plan for intubation as well as extubation. This article focuses on airway evaluation, identification, planning, extubation, and care of the patient with a difficult airway. PMID- 25725537 TI - Intraoperative fluid management. AB - Evidence-based medicine has been slow to address the critically important issue of intraoperative fluid maintenance for surgical patients. A "rule" published by Holliday and colleagues in 1957 was the accepted practice for the initial calculation of fluid maintenance for nearly 50 years. Using this formula, the nil per os fluid deficit was based on how long it had been since the preoperative patient had last consumed anything by mouth, even water. New technology and monitoring modalities are being used to guide evidence-supported intraoperative care, leading to better outcomes for surgical patients. PMID- 25725538 TI - Infection control in the operating room. AB - Surgical site infections (SSIs) occur in 160,000 to 300,000 patients per year, at a rate of 2% to 5%. SSIs increase postoperative hospitalization stay and the likelihood of postoperative mortality by a factor of 2- to 11-fold. The estimated financial impact of SSIs on the health care system ranges from $3.5 to $45.0 billion annually. Anesthesia providers have the potential to increase the patient's risk for developing an SSI. The use of antibiotics, attention to patient normothermia, and sound hand hygiene have been shown to decrease the rate of postoperative SSI. PMID- 25725539 TI - Operative care of obstetric patients. AB - The operative care of pregnant patients, whether for delivery of the neonate or for a nonobstetric surgical procedure, must take into consideration many variables. An awareness of maternal physiologic changes, fetal requirements, effects of anesthetic agents on both the mother and the fetus, and the potential for complications is essential for obstetric anesthetists. In addition, a comprehensive evaluation of the parturient, ample preparation of drugs and equipment in the operative suite, and cooperation with the obstetrician and the surgical team are of major importance in ensuring the safe and effective anesthetic care of this special patient population. PMID- 25725540 TI - Pediatric emergencies. AB - It is important that pediatric critical care nurses possess a thorough understanding of their patient and be able to provide exceptional care, especially during emergent situations in the operating room. This care is accomplished by assessing the pediatric patient, dosing medications accurately and effectively, and performing effective Pediatric Advanced Life Support. Pediatric patients present with unique anatomy, physiology, and pathophysiology. Emergencies are reviewed according to organ system, with a focus on definition, presentation, pathophysiology, management, and special considerations. PMID- 25725541 TI - Management of the patient with chronic pain. AB - Chronic pain is a significant complex problem in the perioperative environment. The management of patients with chronic pain has presented new challenges to anesthesia providers in the perioperative setting. The treatment of pain is often inadequate, and patients with preexisting chronic pain are not being managed properly. Although numerous techniques for intraoperative analgesia have been established, no official guidelines have been published for the growing population of patients with chronic pain. This article provides insight into and awareness of the various elements that should be addressed, along with interventions for the patient with chronic pain in the perioperative setting. PMID- 25725542 TI - Sedation options for intubated intensive care unit patients. AB - A common requirement for intubated patients in the intensive care unit (ICU) is sedation and pain management to facilitate patient safety and timely, atraumatic healing. The Society of Critical Care Medicine guidelines for management of pain, sedation, and delirium in adult ICU patients provide assessment scales for pain, sedation, and delirium; medications for sedation and pain management, and protocols for weaning sedation, are discussed. Proficient assessment skills, pharmacologic knowledge of medications administered to provide sedation, and an understanding of the importance of nonpharmacologic interventions can help the registered nurse provide patient advocacy, safety, and improved outcomes. PMID- 25725543 TI - Mechanical ventilation of the anesthetized patient. AB - Patients who require general anesthesia to undergo a surgical procedure often require mechanical ventilation during the perioperative period. Ventilators incorporated into modern anesthesia machines offer various options for patient management. The unique effects of general anesthesia and surgery on pulmonary physiology must be considered when selecting an individualized plan for mechanical ventilation during the perioperative period. In this article, the pulmonary effects of general anesthesia are reviewed and available options for mechanical ventilation of the anesthetized patient during the perioperative period are presented. PMID- 25725544 TI - Certified registered nurse anesthesia: critical care nursing in the operating room. PMID- 25725545 TI - Rethinking responsibility in offenders with acquired paedophilia: punishment or treatment? AB - This article reviews the current neurobiological literature on the aetiology of developmental and acquired paedophilia and examines what the consequences could be in terms of responsibility and treatment for the latter. Addressing the question of responsibility and punishment of offenders with acquired paedophilia from a neurobiological perspective is controversial. Consequently it is essential to avoid hasty conclusions based strictly on neurobiological abnormality justifications. This study establishes a distinction between developmental and acquired paedophilia. The article investigates whether offenders who fulfil the diagnosis of acquired paedophilia should be held fully responsible, particularly in cases where the offender's conduct appears to result from volitionally controlled behaviour that is seemingly incompatible with a neurological cause. Moreover, the article explores how responsibility can be compromised when offenders with acquired paedophilia have (partially) preserved moral knowledge despite their sexual disorder. The article then examines the option of offering mandatory treatment as an alternative to imprisonment for offenders with acquired paedophilia. Furthermore, the article addresses the ethical issues related to offering any form of quasi-coercive treatment as a condition of release. This study concludes that decisions to fully or partially excuse an individual who fulfil the diagnosis of acquired paedophilia should take all relevant information into account, both neurobiological and other environmental evidence, and should proceed on a careful case by case analysis before sentencing or offering treatment. PMID- 25725546 TI - Rapid selection for beta-tubulin alleles in codon 200 conferring benzimidazole resistance in an Ostertagia ostertagi isolate on pasture. AB - Resistance to benzimidazoles (BZs) is widespread in sheep nematodes and increasing in those of cattle. Several reasons including the predominant use of pour-on anthelmintics and lack of scales in field conditions lead to under-dosing of cattle and therefore to increased selection pressure. In an field experiment the frequency of BZ-resistance associated allele (TAC) in codon 200 in the beta tubulin isotype 1 gene of Ostertagia ostertagi was monitored over one grazing season (approximately 30 weeks). Group 1, consisting of four calves, was experimentally infected with a pure O. ostertagi population displaying ~50% of the TAC allele. The subsequently following groups of calves (four groups of two calves each) acquired natural infections by grazing contaminated pastures. Each group was treated with increasing percentages of sub-therapeutic dosages of albendazole (35-65%). Larvae obtained from faecal cultures pre and post treatment were subjected to species/genus-specific PCR as well as pyrosequencing to determine allele frequencies. PCR revealed the presence of Ostertagia, Trichostrongylus, Haemonchus and Cooperia in pre-treatment samples and predominantly Ostertagia as well as some Trichostrongylus in post treatment samples. Faecal egg count reduction was always less than 90% 7-10 days post treatment. In naturally infected calves TAC allele frequencies were significantly increased (p<0.05) after treatment and they also rapidly increased during the grazing season (pre: 15-63%; post: 55-89%). The more than 4-fold increase in resistant genotypes before treatment indicates how fast selection for BZ resistance can occur when sub-therapeutic dosages are combined with a high treatment frequency, even under moderated climatic conditions and in the presence of a refugium. PMID- 25725547 TI - Uses and limitations of faecal egg count for assessing worm burden in wild boars. AB - The most widely used technique to assess helminth infection in both domestic and wild mammals is the faecal egg count (FEC). Most efforts to test the reliability of FEC as a proxy for parasite load are in small ruminant studies and limited work has evaluated the use of FEC in pigs. The aim of this study was to explore whether FEC is a reliable indicator of helminth load, and to evaluate the effects of sample storage on FEC accuracy in 59 wild boars. Though FEC was useful for assessing most helminth infections (e.g., Metastrongylus spp., Ascaris suum, Trichuris suis), stomach nematodes were often missed. The accuracy of FEC decreased over time, and thus it is recommended that samples be processed within 5 days of collection. PMID- 25725548 TI - Persistent challenge with Trichostrongylus colubriformis and Haemonchus contortus larvae does not affect growth of meat-breed lambs suppressively treated with anthelmintics when grazing. AB - This experiment tested the hypothesis that persistent challenge with anthelmintic susceptible Trichostrongylus colubriformis and Haemonchus contortus larvae would not affect growth of grazing, meat-breed lambs when suppressively treated with anthelmintics. The experiment was a 2*2 factorial design using 6-7 months old White Suffolk X Border Leicester/Merino (meat-breed) lambs which were either infected with 2000 T. colubriformis and 300 H. contortus L3/week (IF) or remained uninfected (UIF) for 9 weeks and were either treated (TX) with a combination of short and long-acting anthelmintics or remained untreated (UTX). Lambs grazed as one flock and were rotated between paddocks to avoid autoinfection from pasture. Lambs were humanely euthanised on day 63 and the abomasum and small intestine collected to determine total worm burdens and tissue antibody response specific to T. colubriformis. As expected, worm egg count (WEC) and worm burden were significantly higher in IF UTX lambs (p<0.001). WEC was dominated by H. contortus and peaked at 2,325 epg on day 63 but remained at zero for the other treatment groups for the duration of the experiment. Tissue antibody responses were evident in IF lambs (titres; 9982 vs 2767, p=0.012) but treatment had no effect (titres; 5912 vs 5349, p=0.829). Lambs grew an average of 2.6 kg during the experiment with no difference between IF TX and UIF TX groups (p=0.432). Elevated tissue antibody responses were not associated with differences in growth. Results from this experiment support the hypothesis that persistent larval challenge with anthelmintic susceptible H. contortus and T. colubriformis will not affect growth of grazing, meat-breed lambs when suppressively treated with effective anthelmintics. Therefore the use of sheep suppressively treated with effective anthelmintics appears to be a valid substitute for gastrointestinal nematode-free lambs in field experiments. PMID- 25725549 TI - Radiation-/hypoxia-induced solid tumor metastasis and regrowth inhibited by hypoxia-specific upconversion nanoradiosensitizer. AB - Tumor resistance to ionizing irradiation and cancer cell's metastasis stimulated by radiation often lead to anti-cancer failure, and can be negatively caused by a key role--cellular hypoxia. In this regard, the exploitation of hypoxia-specific cytotoxic agents which assist to potentiate the anti-tumor effect of radiotherapy (RT) as well as efficiently counteract radiation-/hypoxia-induced cancer cell metastasis, becomes especially important, but has been widely overlooked. Herein, a core/shell-structured multifunctional nanoradiosensitizer with upconversion nanoparticle (UCNP) as an inside core, mesoporous silica as the shell and a cavity in between, has been constructed, in which UCNP core serves as radiation dose amplifiers and bio-reductive pro-drug--tirapazamine (TPZ) loaded in cavity is an hypoxia-selective cytotoxin and the silica shell provides the protection and diffusion path for TPZ. Such nanoradiosensitizer has been employed to inhibit the hypoxia-reoxygenation and the subsequent replication of cancer cells that often occurs after a single unaccompanied RT at low doses, and to silence the expression of transcription factors that support the progression of malignancy in cancer. This study confirms the radiotherapeutic benefits of utilizing nanoradiosensitizer as adjuvant to low-dose RT, and the results demonstrate the highly efficient hypoxia-specific killing in oxygen-dependent anti-tumor therapies. PMID- 25725550 TI - Development of a biological scaffold engineered using the extracellular matrix secreted by skeletal muscle cells. AB - The performance of implantable biomaterials derived from decellularized tissue, including encouraging results with skeletal muscle, suggests that the extracellular matrix (ECM) derived from native tissue has promising regenerative potential. Yet, the supply of biomaterials derived from donated tissue will always be limited, which is why the in-vitro fabrication of ECM biomaterials that mimic the properties of tissue is an attractive alternative. Towards this end, our group has utilized a novel method to collect the ECM that skeletal muscle myoblasts secrete and form it into implantable scaffolds. The cell derived ECM contained several matrix constituents, including collagen and fibronectin that were also identified within skeletal muscle samples. The ECM was organized into a porous network that could be formed with the elongated and aligned architecture observed within muscle samples. The ECM material supported the attachment and in vitro proliferation of cells, suggesting effectiveness for cell transplantation, and was well tolerated by the host when examined in-vivo. The results suggest that the ECM collection approach can be used to produce biomaterials with compositions and structures that are similar to muscle samples, and while the physical properties may not yet match muscle values, the in-vitro and in-vivo results indicate it may be a suitable first generation alternative to tissue derived biomaterials. PMID- 25725551 TI - PET imaging of a collagen matrix reveals its effective injection and targeted retention in a mouse model of myocardial infarction. AB - Injectable biomaterials have shown promise for cardiac regeneration therapy. However, little is known regarding their retention and distribution upon application in vivo. Matrix imaging would be useful for evaluating these important properties. Herein, hexadecyl-4-[(18)F]fluorobenzoate ((18)F-HFB) and Qdot labeling was used to evaluate collagen matrix delivery in a mouse model of myocardial infarction (MI). At 1 wk post-MI, mice received myocardial injections of (18)F-HFB- or Qdot-labeled matrix to assess its early retention and distribution (at 10 min and 2h) by positron emission tomography (PET), or fluorescence imaging, respectively. PET imaging showed that the bolus of matrix at 10 min redistributed evenly within the ischemic territory by 2h. Ex vivo biodistribution revealed myocardial matrix retention of ~ 65%, which correlated with PET results, but may be an underestimate since (18)F-HFB matrix labeling efficiency was ~ 82%. For covalently linked Qdots, labeling efficiency was ~ 96%. Ex vivo Qdot quantification showed that ~ 84% of the injected matrix was retained in the myocardium. Serial non-invasive PET imaging and validation by fluorescence imaging confirmed the effectiveness of the collagen matrix to be retained and redistributed within the infarcted myocardium. This study identifies matrix targeted imaging as a promising modality for assessing the biodistribution of injectable biomaterials for application in the heart. PMID- 25725552 TI - Molecular interference of fibrin's divalent polymerization mechanism enables modulation of multiscale material properties. AB - Protein based polymers provide an exciting and complex landscape for tunable natural biomaterials through modulation of molecular level interactions. Here we demonstrate the ability to modify protein polymer structural and mechanical properties at multiple length scales by molecular 'interference' of fibrin's native polymerization mechanism. We have previously reported that engagement of fibrin's polymerization 'hole b', also known as 'b-pockets', through PEGylated complementary 'knob B' mimics can increase fibrin network porosity but also, somewhat paradoxically, increase network stiffness. Here, we explore the possible mechanistic underpinning of this phenomenon through characterization of the effects of knob B-fibrin interaction at multiple length scales from molecular to bulk polymer. Despite its weak monovalent binding affinity for fibrin, addition of both knob B and PEGylated knob B at concentrations near the binding coefficient, Kd, increased fibrin network porosity, consistent with the reported role of knob B-hole b interactions in promoting lateral growth of fibrin fibers. Addition of PEGylated knob B decreases the extensibility of single fibrin fibers at concentrations near its Kd but increases extensibility of fibers at concentrations above its Kd. The data suggest this bimodal behavior is due to the individual contributions knob B, which decreases fiber extensibility, and PEG, which increase fiber extensibility. Taken together with laser trap-based microrheological and bulk rheological analyses of fibrin polymers, our data strongly suggests that hole b engagement increases in single fiber stiffness that translates to higher storage moduli of fibrin polymers despite their increased porosity. These data point to possible strategies for tuning fibrin polymer mechanical properties through modulation of single fiber mechanics. PMID- 25725553 TI - Novel human-derived extracellular matrix induces in vitro and in vivo vascularization and inhibits fibrosis. AB - The inability to vascularize engineered organs and revascularize areas of infarction has been a major roadblock to delivering successful regenerative medicine therapies to the clinic. These investigations detail an isolated human extracellular matrix derived from the placenta (hPM) that induces vasculogenesis in vitro and angiogenesis in vivo within bioengineered tissues, with significant immune reductive properties. Compositional analysis showed ECM components (fibrinogen, laminin), angiogenic cytokines (angiogenin, FGF), and immune-related cytokines (annexins, DEFA1) in near physiological ratios. Gene expression profiles of endothelial cells seeded onto the matrix displayed upregulation of angiogenic genes (TGFB1, VEGFA), remodeling genes (MMP9, LAMA5) and vascular development genes (HAND2, LECT1). Angiogenic networks displayed a time dependent stability in comparison to current in vitro approaches that degrade rapidly. In vivo, matrix-dosed bioscaffolds showed enhanced angiogenesis and significantly reduced fibrosis in comparison to current angiogenic biomaterials. Implementation of this human placenta derived extracellular matrix provides an alternative to Matrigel and, due to its human derivation, its development may have significant clinical applications leading to advances in therapeutic angiogenesis techniques and tissue engineering. PMID- 25725554 TI - Dynamic stiffening of poly(ethylene glycol)-based hydrogels to direct valvular interstitial cell phenotype in a three-dimensional environment. AB - Valvular interstitial cells (VICs) are active regulators of valve homeostasis and disease, responsible for secreting and remodeling the valve tissue matrix. As a result of VIC activity, the valve modulus can substantially change during development, injury and repair, and disease progression. While two-dimensional biomaterial substrates have been used to study mechanosensing and its influence on VIC phenotype, less is known about how these cells respond to matrix modulus in a three-dimensional environment. Here, we synthesized MMP-degradable poly(ethylene glycol) (PEG) hydrogels with elastic moduli ranging from 0.24 kPa to 12 kPa and observed that cell morphology was constrained in stiffer gels. To vary gel stiffness without substantially changing cell morphology, cell-laden hydrogels were cultured in the 0.24 kPa gels for 3 days to allow VIC spreading, and then stiffened in situ via a second, photoinitiated thiol-ene polymerization such that the gel modulus increased from 0.24 kPa to 1.2 kPa or 13 kPa. VICs encapsulated within soft gels exhibited alphaSMA stress fibers (~ 40%), a hallmark of the myofibroblast phenotype. Interestingly, in stiffened gels, VICs became deactivated to a quiescent fibroblast phenotype, suggesting that matrix stiffness directs VIC phenotype independent of morphology, but in a manner that depends on the dimensionality of the culture platform. Collectively, these studies present a versatile method for dynamic stiffening of hydrogels and demonstrate the significant effects of matrix modulus on VIC myofibroblast properties in three-dimensional environments. PMID- 25725555 TI - Nasal ectomesenchymal stem cells: multi-lineage differentiation and transformation effects on fibrin gels. AB - Ectomesenchymal stem cells (EMSCs) are novel adult stem cells derived from the cranial neural crest. However, their stemness and multi-lineage differentiation potential on three-dimensional fibrin gels has not yet been explored. The objective of this study was to investigate induced differentiation of EMSCs on fibrin gels and their remodeling effects on the scaffolds during the induced differentiation process. The results indicated that CD133(+)/nestin(+)/CD44(+) EMSCs were extensively distributed in the lamina propria of the nasal mucosa. The passaged cells could be induced to differentiate to a greater degree into neurons, Schwann cells and osteoblasts on three-dimensional fibrin gels than on two-dimensional glass slides. More importantly, the induced Schwann cells and osteoblasts exerted channelized and calcified remodeling effects, respectively, on the fibrin gels. Thus, these reshaped scaffolds have desirable biological properties, such as good cell adhesion, biocompatibility and guidance over the cell behavior, providing a tissue-committed niche for specific tissue generation. PMID- 25725556 TI - Matrix stiffness determines the fate of nucleus pulposus-derived stem cells. AB - Intervertebral disc (IVD) degeneration and consequent low-back pain present a major medical challenge. Nucleus pulposus-derived stem cells (NP-SCs) may lead to a novel therapy for this severe disease. It was recently shown that survival and function of mature NP cells are regulated in part by tissue stiffness. We hypothesized that modification of matrix stiffness will influence the ability of cultured NP-SCs to proliferate, survive, and differentiate into mature NP cells. NP-SCs were subcultured in three-dimensional matrices of varying degrees of stiffness as measured by the material's shear storage modulus. Cell survival, activity, and rate of differentiation toward the chondrogenic or osteogenic lineage were analyzed. NP-SCs were found to proliferate and differentiate in all matrices, irrespective of matrix stiffness. However, matrices with a low shear storage modulus (G' = 1 kPa) promoted significantly more proliferation and chondrogenic differentiation, whereas matrices with a high modulus (G' = 2 kPa) promoted osteogenic differentiation. Imaging performed via confocal and scanning electron microscopes validated cell survival and highlighted stiffness-dependent cell-matrix interactions. These results underscore the effect of the matrix modulus on the fate of NP-SCs. This research may facilitate elucidation of the complex cross-talk between NP-SCs and their surrounding matrix in healthy as well as pathological conditions. PMID- 25725557 TI - Nerve guides manufactured from photocurable polymers to aid peripheral nerve repair. AB - The peripheral nervous system has a limited innate capacity for self-repair following injury, and surgical intervention is often required. For injuries greater than a few millimeters autografting is standard practice although it is associated with donor site morbidity and is limited in its availability. Because of this, nerve guidance conduits (NGCs) can be viewed as an advantageous alternative, but currently have limited efficacy for short and large injury gaps in comparison to autograft. Current commercially available NGC designs rely on existing regulatory approved materials and traditional production methods, limiting improvement of their design. The aim of this study was to establish a novel method for NGC manufacture using a custom built laser-based microstereolithography (MUSL) setup that incorporated a 405 nm laser source to produce 3D constructs with ~ 50 MUm resolution from a photocurable poly(ethylene glycol) resin. These were evaluated by SEM, in vitro neuronal, Schwann and dorsal root ganglion culture and in vivo using a thy-1-YFP-H mouse common fibular nerve injury model. NGCs with dimensions of 1 mm internal diameter * 5 mm length with a wall thickness of 250 MUm were fabricated and capable of supporting re innervation across a 3 mm injury gap after 21 days, with results close to that of an autograft control. The study provides a technology platform for the rapid microfabrication of biocompatible materials, a novel method for in vivo evaluation, and a benchmark for future development in more advanced NGC designs, biodegradable and larger device sizes, and longer-term implantation studies. PMID- 25725558 TI - Profiling bone morphogenetic proteins and transforming growth factor-betas by hTGF-beta3 pre-treated coral-derived macroporous bioreactors: the power of one. AB - To study the expression profile of bone morphogenetic proteins and transforming growth factor-betas (BMPs and TGFbetas), coral-derived calcium carbonate-based macroporous bioreactors with limited conversion to hydroxyapatite (7% HA/CC) were pre-loaded with and without 250 MUg hTGF-beta3 and implanted in the rectus abdominis of 3 non-human primates Papio ursinus euthanized on day 60. To investigate the required dose of hNoggin, a BMPs antagonist that controls the induction of bone formation, 7% HA/CC were pre-loaded with 150 MUg hNoggin, with 125 MUg hTGF-beta3/150 MUg hNoggin, with or without 125 MUg hTGF-beta3 and implanted in the r. abdominis of 3 additional animals euthanized on day 90. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) evaluated the expression' profile of BMP-2, BMP-3, BMP-4, BMP-6, BMP-7 and TGF-beta1, beta2, and -beta3 in tissue generating bioreactors as well as in the adjacent r. abdominis muscle. On day 60, 250 MUg hTGF-beta3 induced bone formation at the periphery of the implanted bioreactors only. On day 90, 125 MUg hTGF beta3/treated bioreactors showed the induction of bone formation throughout the macroporous spaces. Untreated bioreactors induced bone, 4.11% vs. 2.00% on days 60 and 90, respectively. In hTGF-beta3/treated bioreactors, BMP-2 and BMP-3 were up-regulated at both time periods, both in the homogenized constructs and in the adjacent r. abdominis muscle whilst BMP-4 in the homogenized construct only. In untreated 7% HA/CC constructs, BMP-2 was up-regulated in the macroporous construct only. On day 60, 250 MUg hTGF-beta3/treated and untreated macroporous constructs showed up-regulation of TGF-beta1 with a six fold increase vs. TGF beta1 expression in adjacent muscle of untreated constructs. TGF-beta2 was down regulated in both untreated and 250 MUg hTGF-beta3/treated bioreactors. On day 60, 250 MUg hTGF-beta3/treated bioreactors showed TGF-beta3 expression in untreated, treated and adjacent muscle tissues. On day 90, BMP-2 was up regulated, with BMP-3 up-regulation both with and without hNoggin. BMP-4 expression was reduced, with down-regulation of BMP-6 and BMP-7 with and without hNoggin. BMPs expression is finely tuned by hNoggin that blocks BMPs resulting in minimal if any induction of bone formation. The primary differentiating events in untreated bioreactors develop within the macroporous spaces after stem cells invasion and differentiation with lack of BMP-2 expression in the adjacent muscle. In hTGF-beta3/treated bioreactors, both the adjacent muscle and the macroporous bioreactor show BMP-2 up-regulation, correlating with the temporo/spatial rapid induction of bone formation at the periphery of the bioreactors only. The latter may be the result of the initiation of a sequential chain of cellular induction rapidly recruiting pericytic perivascular myoblastic cells adjacent to the implanted bioreactors directly transformed into secreting osteoblasts. PMID- 25725560 TI - Micro-structured, spontaneously eroding hydrogels accelerate endothelialization through presentation of conjugated growth factors. AB - Growth factors represent highly potent and highly efficacious means of communication to cells. At the same time, these proteins are fragile and relatively small sized--rendering their immobilization and controlled release from biomaterials challenging. In this work, we establish a method to incorporate growth factors into the physical hydrogels based on poly(vinyl alcohol), PVA. The latter have a long and successful history of biomedical applications and approval for diverse use in human patients, but are also characterized with scant opportunities for bioconjugation and functionalization. Herein, we develop the conjugation of growth factors to the micro-structured, spontaneously eroding physical hydrogels based on PVA. Protein conjugation was elaborated using model substrates, albumin and lysozyme, which aided to reveal specificity of chemical reactions and benign, non-harmful nature of the established protocols. Surface adhered format of hydrogel analyses allowed to quantify bioconjugation reactions and enzymatic activity of the immobilized proteins and to visualize the hydrogels with immobilized cargo. In cell culture, immobilized growth factors were effective in communicating to adhering cells and specifically enhanced proliferation rates of the cells containing the corresponding receptors. At the same time, proliferation of the cells devoid of these receptors was un-altered. PMID- 25725559 TI - Composite scaffolds of nano-hydroxyapatite and silk fibroin enhance mesenchymal stem cell-based bone regeneration via the interleukin 1 alpha autocrine/paracrine signaling loop. AB - Composite scaffolds of nano-hydroxyapatite (nHAp) and silk fibroin (SF) have been reported to promote bone regeneration mainly through signaling pathways associated with cell-biomaterial interaction. However, it is unclear whether soluble factors also play a role in osteoinduction with nHAp-SF. In this study, we confirmed the biocompatibility and superior osteoinductivity of nHAp-SF scaffolds versus SF scaffolds both in vitro and on a calvarial defect model in vivo. This was followed by further analysis with microarray assay. The cDNA microarray results identified 247 differentially expressed genes in bone marrow mesenchymal stem cells (BMSCs) cultured on SF-nHAp scaffolds versus SF scaffolds. The greatest disparity in gene expression levels were observed with Il1alpha and Ilr2. Real-time PCR assay validated the results. The addition of IL-1alpha into cultures of BMSCs with SF significantly increased both Bmp2 and Ilr2 expression. However, with BMSCs alone, the Il1r2 expression increased substantially, whereas Bmp2 expression exhibited a decrease rather than increase. These data suggested that nHAp may exert osteoinductive effects on BMSCs via the secretion of IL 1alpha in an autocrine/paracrine fashion, and IL-1alpha activity could be regulated through the synthesis of IL1R2 by BMSCs upon interaction with nHAp. These results complemented our understanding of the underlying mechanisms of biomaterial osteoinductivity. PMID- 25725561 TI - Tailoring the stealth properties of biocompatible polysaccharide nanocontainers. AB - Fundamental development of a biocompatible and degradable nanocarrier platform based on hydroxyethyl starch (HES) is reported. HES is a derivative of starch and possesses both high biocompatibility and improved stability against enzymatic degradation; it is used to prepare nanocapsules via the polyaddition reaction at the interface of water nanodroplets dispersed in an organic miniemulsion. The synthesized hollow nanocapsules can be loaded with hydrophilic guests in its aqueous core, tuned in size, chemically functionalized in various pathways, and show high shelf life stability. The surface of the HES nanocapsules is further functionalized with poly(ethylene glycol) via different chemistries, which substantially enhanced blood half-life time. Importantly, methods for precise and reliable quantification of the degree of functionalization are also introduced, which enable the precise control of the chemistry on the capsules' surface. The stealth properties of these capsules is studied both in-vitro and in-vivo. The functionalized nanocapsules serve as a modular platform for specific cell targeting, as they show no unspecific up-taken by different cell types and show very long circulating time in blood (up to 72 h). PMID- 25725562 TI - Biodegradable poly-lactic acid based-composite reinforced unidirectionally with high-strength magnesium alloy wires. AB - Biodegradable poly-lactic acid (PLA)--based composites reinforced unidirectionally with high-strength magnesium alloy wires (MAWs) are fabricated by a heat-compressing process and the mechanical properties and degradation behavior are studied experimentally and theoretically. The composites possess improved strengthening and toughening properties. The bending strength and impact strength of the composites with 40 vol% MAWs are 190 MPa and 150 kJ/m(2), respectively, although PLA has a low viscosity and an average molecular weight of 60,000 g/mol. The mechanical properties of the composites can be further improved by internal structure modification and interface strengthening and a numerical model incorporating the equivalent section method (ESM) is proposed for the bending strength. Micro arc oxidization (MAO) of the MAWs is an effective interfacial strengthening method. The composites exhibit high strength retention during degradation and the PLA in the composite shows a smaller degradation rate than pure PLA. The novel biodegradable composites have large potential in bone fracture fixation under load-bearing conditions. PMID- 25725563 TI - Maternal and congenital syphilis in selected Latin America and Caribbean countries: a multi-country analysis using data from the Perinatal Information System. AB - Background Maternal syphilis has an important impact on reproductive health. In 2010, World Health Organization (WHO)/Pan American Health Organization (PAHO) member countries approved the Strategy and Plan of Action for Elimination of Mother-to-Child Transmission of HIV and Congenital Syphilis in the Americas by 2015. This paper aims to describe epidemiological and programmatic characteristics related to maternal and congenital syphilis in selected countries of Latin America and Caribbean for the period 2010-12. METHODS: The report is based on a multi-country, quantitative and qualitative analysis from data collected from several sources, representing a compilation of country reports from nine countries as part of the 2012 mid-term evaluation of the Strategy. Data was collected based on standardised procedures at country level. RESULTS: Results are variable among countries. All countries have a strategic national plan to eliminate congenital syphilis, with some distinct characteristics for each country. Protocols and guidelines for the management and treatment of maternal and congenital syphilis in all countries were updated between 2011 and 2013. A high rate of missing information for all countries for some indicators was noticed. CONCLUSIONS: The main limitation of the analyses is the huge amount of missing data. Countries must continue to be supported to build capacity for collecting high-quality data on intervention coverage and inequities, and to use it as a basis for decisions about how best to reach women and children with interventions. A high level political commitment is necessary to put into practice the Regional Initiative to Eliminate Congenital Syphilis, with the support of Health Ministries. PMID- 25725564 TI - Efficacy of low-dose intratympanic dexamethasone for sudden hearing loss. AB - OBJECTIVE: Intratympanic steroids (ITSs) are recommended for treatment of sudden sensorineural hearing loss (SSNHL). On the other hand, the dosage, frequency and duration of the intratympanic therapy are still not clear. We aimed to evaluate the efficacy of low-dose intratympanic steroid (ITS) treatment of SSNHL. METHODS: Seventy patients (ears) treated for SSNHL were involved in the study. The patients were divided into four groups: the systemic steroid, combined, intratympanic initial (ITSi) and intratympanic salvage (ITSs). The demographic data, accompanying symptoms, treatment onset duration, the treatment protocol, and pre- and post-treatment pure tone audiometry results were recorded. RESULTS: The mean treatment onset was 60 days in the ITSs group, which is statistically later than the other groups (p<0.001). The treatment response was assessed based on Siegel's criteria. Hearing recovery was statistically higher in the combined group than the systemic steroid group (p=0.042). 87.5% of the ITSi group showed full recovery, which is a statistically significantly higher difference than the other groups (p<0.001). In the salvage treatment group, the use of low-dose ITS was observed to be inadequate for the treatment (p<0.001). The post-treatment pure tone average gains in dB were analyzed at 500, 1000, 2000, and 4000Hz and the recovery determined for each of the four groups was found to be statistically significant (p<0.001 to p<0.031). CONCLUSION: The ITS administration as the initial treatment for mild to moderate hearing loss is adequate while low dose of dexamethasone used as a salvage treatment is inadequate. The use of low-dose ITS in the combined treatment may increase the hearing gain. PMID- 25725565 TI - Beyond the physical: a qualitative assessment of the burden of symptomatic uterine fibroids on women's emotional and psychosocial health. AB - OBJECTIVE: To qualitatively assess the burden of uterine fibroids on women's emotional health. METHODS: Sixty women (n = 60) with symptomatic uterine fibroids were recruited from an urban academic medical center and community-based organizations. Women completed qualitative, semi-structured interviews and demographic surveys. Interviews were recorded and transcribed verbatim. Using a grounded theory approach, three coders independently identified major themes and subthemes that emerged from the interviews. RESULTS: The kappa among coders was 0.94. The mean age of participants was 43.0 +/- 6.8. 61.7% of participants self identified as African-American, 25.0% as Caucasian, 8.3% as Hispanic and 5.0% as Asian. Most participants exhibited a significant emotional response to their fibroids, including fear, anxiety, anger, and depression. Half of the women felt helpless and believed that they had no control over their fibroids. Many women possessed a negative self-image and cited concern over appearing less attractive, which led to difficulties becoming intimate. Several women felt that they lacked substantial support to help them deal with these issues. CONCLUSION: In addition to the known high prevalence and severe physical impact of uterine fibroids, there is a significant psychological impact on women. Many women lack support to help them deal with these issues and very few seek help from a mental health professional. There is an opportunity and a need for the mental health community to address the concerns in this population, in order to improve psychological health and quality of life in patients living with this chronic condition. PMID- 25725566 TI - Office-based screening of common psychiatric conditions. AB - Depression and anxiety disorders are common conditions with significant morbidity. Many screening tools of varying length have been well validated for these conditions in the office-based setting. Novel instruments, including Internet-based and computerized adaptive testing, may be promising tools in the future. The best evidence for cost-effectiveness currently is for screening of major depression linked with the collaborative care model for treatment. Data are not conclusive regarding comparative cost-effectiveness of screening for multiple conditions at once or for other conditions. This article reviews screening tools for depression and anxiety disorders in the ambulatory setting. PMID- 25725567 TI - Screening for depression in the primary care population. AB - Despite strong efforts, the diagnosis and treatment of depression bring many challenges in the primary care setting. Screening for depression has been shown to be effective only if reliable systems of care are in place to ensure appropriate treatment by clinicians and adherence by patients. New evidence-based models of care for depression exist, but spread has been slow because of inadequate funding structures and conflicts within current clinical culture. The Affordable Care Act introduces potential opportunities to reorganize funding structures, conceivably leading to increased adoption of these collaborative care models. Suicide screening remains controversial. PMID- 25725568 TI - Posttraumatic stress in older adults: when medical diagnoses or treatments cause traumatic stress. AB - Most older patients adapt after catastrophic medical diagnoses and treatments, but a significant number may develop posttraumatic stress disorder (PTSD) symptoms. PTSD symptoms create added burden for the individual, family, and health care system for the patient's recovery. Medical-related PTSD may be underdiagnosed by providers who may be unaware that these health problems can lead to PTSD symptoms. Treatment research is lacking, but pharmacologic and nonpharmacologic approaches to treatment may be extrapolated and adjusted from the literature focusing on younger adults. Additional study is needed. PMID- 25725569 TI - The interface of child mental health and juvenile diabetes mellitus. AB - Diabetes mellitus is a common childhood illness, and its management is often complicated by mental health challenges. Psychiatric comorbidities are common, including anxiety, depression, and eating disorders. The illness can profoundly affect the developing brain and family functioning and have lifelong consequences. The child mental health provider can provide valuable assistance to support the child and family and assessment and treatment of comorbid mental health problems and to promote positive family functioning and normal developmental progress. PMID- 25725570 TI - Mental health and quality-of-life concerns related to the burden of food allergy. AB - As food allergy increases, more research is devoted to its influence on patient and family mental health and quality of life (QoL). This article discusses the effects on parent and child QoL, as well as distress, while appraising the limitations of knowledge given the methods used. Topics include whether QoL and distress are affected compared with other illnesses, assessment of distress and QoL in parents compared with children, concerns about food allergy-related bullying, and the necessity for evidence-based interventions. Suggestions are offered for how to improve QoL and reduce distress on the way to better coping with food allergy. PMID- 25725571 TI - Cognitive functioning, mental health, and quality of life in ICU survivors: an overview. AB - Critical illness can and often does lead to significant cognitive impairment and to the development of psychological disorders. These conditions are persistent and, although they improve with time, often fail to completely abate. Although the functional correlates of cognitive and psychological morbidity (depression, anxiety, and posttraumatic stress disorder) have been studied, they may include poor quality of life, inability to return to work or to work at previously established levels, and inability to function effectively in emotional and interpersonal domains. The potential etiologies of cognitive impairment and psychological morbidity in ICU survivors are particularly poorly understood and may vary widely across patients. Potential contributors may include the potentially toxic effects of sedatives and narcotics, delirium, hypoxia, glucose dysregulation, metabolic derangements, and inflammation. Patients with preexisting vulnerabilities, including predisposing genetic factors, and frail elderly populations may be at particular risk for emergence of acceleration of conditions such as mild cognitive impairment. PMID- 25725572 TI - Physical and psychiatric recovery from burns. AB - Burn injuries pose complex biopsychosocial challenges to recovery and improved comprehensive care. The physical and emotional sequelae of burns differ, depending on burn severity, individual resilience, and stage of development when they occur. Most burn survivors are resilient and recover, whereas some are more vulnerable and have complicated outcomes. Physical rehabilitation is affected by orthopedic, neurologic, and metabolic complications and disabilities. Psychiatric recovery is affected by pain, mental disorders, substance abuse, and burn stigmatization. Individual resilience, social supports, and educational or occupational achievements affect outcomes. PMID- 25725573 TI - The future of the psychiatric mental health clinical nurse specialist: evolution or extinction. AB - The role of the psychiatric mental health clinical nurse specialist (PMHCNS) is now in a precarious position. At first glance, some may say it is on the verge of extinction. In this article, a brief history of the role of the PMHCNS is reviewed along with current education, practice, role, and American Nurses Credentialing Center certification of the PMHCNS. The future implications and considerations of the unique functions of the PMHCNS for an advanced practice registered nurse with a psychiatric mental health specialization are discussed. PMID- 25725574 TI - Indicators of resilience in family members of adults with serious mental illness. AB - This integrative review summarizes current research on resilience in adult family members who have a relative with a diagnosed mental disorder considered serious. Within the context of resilience theory, studies identifying risk/vulnerability and positive/protective factors in family members are summarized, and studies examining 7 indicators of resilience, including acceptance, hardiness, hope, mastery, self-efficacy, sense of coherence, and resourcefulness, are described. Implications for clinical practice and recommendations for future research are presented. PMID- 25725575 TI - Teaching clinical interviewing skills using role-playing: conveying empathy to performing a suicide assessment: a primer for individual role-playing and scripted group role-playing. AB - This article provides a useful introduction to the art of role-playing in both the individual format and the group format using scripted group role-playing (SGRP). Role-playing can provide powerful learning opportunities, but to do so it must be done well. This article imparts guidance toward this goal. SGRP may greatly enhance the acquisition of critical complex interviewing skills, such as suicide assessment and uncovering domestic violence, in health care providers across all disciplines, an educational goal that has not been achievable to date. Although research is at an early stage of development, the hope represented by SGRP is tangible. PMID- 25725576 TI - Mental health in the medical setting: service delivery, workforce needs, and emerging best practices. PMID- 25725577 TI - A Wright-Fisher model with indirect selection. AB - We study a generalization of the Wright-Fisher model in which some individuals adopt a behavior that is harmful to others without any direct advantage for themselves. This model is motivated by studies of spiteful behavior in nature, including several species of parasitoid hymenoptera in which sperm-depleted males continue to mate despite not being fertile. We first study a single reproductive season, then use it as a building block for a generalized Wright-Fisher model. In the large population limit, for male-skewed sex ratios, we rigorously derive the convergence of the renormalized process to a diffusion with a frequency-dependent selection and genetic drift. This allows a quantitative comparison of the indirect selective advantage with the direct one classically considered in the Wright-Fisher model. From the mathematical point of view, each season is modeled by a mix between samplings with and without replacement, and analyzed by a sort of "reverse numerical analysis", viewing a key recurrence relation as a discretization scheme for a PDE. The diffusion approximation is then obtained by classical methods. PMID- 25725578 TI - Optical monitoring of chemical processes in turbid biogenic liquid dispersions by Photon Density Wave spectroscopy. AB - In turbid biogenic liquid material, like blood or milk, quantitative optical analysis is often strongly hindered by multiple light scattering resulting from cells, particles, or droplets. Here, optical attenuation is caused by losses due to absorption as well as scattering of light. Fiber-based Photon Density Wave (PDW) spectroscopy is a very promising method for the precise measurement of the optical properties of such materials. They are expressed as absorption and reduced scattering coefficients (MU a and MU s', respectively) and are linked to the chemical composition and physical properties of the sample. As a process analytical technology, PDW spectroscopy can sense chemical and/or physical processes within such turbid biogenic liquids, providing new scientific insight and process understanding. Here, for the first time, several bioprocesses are analyzed by PDW spectroscopy and the resulting optical coefficients are discussed with respect to established mechanistic models of the chosen processes. As model systems, enzymatic casein coagulation in milk, temperature-induced starch hydrolysis in beer mash, and oxy- as well as deoxygenation of human donor blood were investigated by PDW spectroscopy. The findings indicate that also for very complex biomaterials (i.e., not well-defined model materials like monodisperse polymer dispersions), obtained optical coefficients allow for the assessment of a structure/process relationship and thus for a new analytical access to biogenic liquid material. This is of special relevance as PDW spectroscopy data are obtained without any dilution or calibration, as often found in conventional spectroscopic approaches. PMID- 25725580 TI - One-step solvent extraction followed by liquid chromatography-atmospheric pressure photoionization tandem mass spectrometry for the determination of polycyclic aromatic hydrocarbons in edible oils. AB - A method for rapid analysis of 16 polycyclic aromatic hydrocarbons (PAHs) in edible oils has been developed on the basis of a simplified solvent extraction and liquid chromatography-atmospheric pressure photoionization tandem mass spectrometry performed in multiple reaction monitoring mode. The briefness of the experimental procedure, the use of milliliters of acetonitrile for extraction without any further cleanup process, the short analysis time, and the excellent sensitivity and selectivity demonstrated the advantages of this practical and environmentally friendly method. All the analytes exhibited satisfactory recoveries at three spiking levels (the recoveries ranged from 77.8 to 106.4%), and the relative standard deviations were lower than 10%. The limits of quantitation of this method for the 16 PAHs were in the range of 0.02-0.43 MUg/kg. The validated method was successfully applied for the determination of PAHs in coconut oil reference material (BCR-458) and real edible oil samples. The results suggested that a large-scale investigation of the concentration of PAHs in vegetable oils in China is required. PMID- 25725579 TI - Improved method for quantitative analysis of methylated phosphatidylethanolamine species and its application for analysis of diabetic-mouse liver samples. AB - N-monomethyl phosphatidylethanolamine (MMPE) and N,N-dimethyl phosphatidylethanolamine (DMPE) species are intermediates of phosphatidylcholine (PC) de-novo biosynthesis through methylation of phosphatidylethanolamine (PE). This synthesis pathway for PC is especially important in the liver when choline is deficient in the diet. Despite some efforts focused on the analysis of MMPE and DMPE species, a cost-effective and high-throughput method for determination of individual MMPE and DMPE species, including their regioisomeric structures, is still missing. Therefore we adopted and improved the "mass-tag" strategy for determining these PE-like species by methylating PE, MMPE, and DMPE molecules with deuterated methyl iodide to generate PC molecules with nine, six, and three deuterium atoms, respectively. On the basis of the principles of multidimensional mass-spectrometry-based shotgun lipidomics we could directly identify and quantify these methylated PE species, including their fatty-acyl chains and regiospecific positions. The method provided remarkable sensitivity, with a limit of detection at 0.5 fmol MUL(-1), high specificity, and a broad linear-dynamics range of >2500 folds. By applying this method to liver samples from streptozotocin (STZ)-induced diabetic mice and controls, we found that the levels of PC species tended to decrease and the amounts of PE species tended to increase in the liver of STZ-induced diabetic mice compared with controls, but no significant changes in MMPE and DMPE species were determined. However, remodeling of fatty-acyl chains in the determined lipids was observed in the liver of STZ induced diabetic mice, with reduction in 16:1 and increases in 18:2, 18:1, and 18:0 acyl chains. These results indicated the improved method to be a powerful tool to reveal the function of the PC de-novo biosynthesis pathway through methylation of PE species in biological systems. PMID- 25725581 TI - A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation. AB - Genetic variants in il2 and il2ra have been associated with autoimmune disease susceptibility in both genome-wide association studies (GWAS) in humans and in genetic linkage studies in experimental models of autoimmunity. Specifically, genetic variants resulting in a low IL-2 phenotype are susceptibility alleles while variants resulting in a high IL-2 phenotype are resistance alleles. The association of high IL-2 phenotypes with resistance has been attributed primarily to the T cell intrinsic promotion of regulatory T cell development, maintenance, and function; however, IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells. Here, we have uncovered a novel T cell extrinsic mechanism whereby IL-2 promotes both IFN-gamma and IL-27 production from tissue resident macrophages which in turn dampen the differentiation of pathogenic Th17 cells. PMID- 25725582 TI - External validation of a risk assessment model to adjust the frequency of eye screening visits in patients with diabetes mellitus. AB - AIMS: To validate a sight-threatening diabetic retinopathy (STDR) risk assessment model to adjust the frequency of eye-screening visits in patients with diabetes mellitus. METHODS: Retrospective follow-up study of patients with diabetes mellitus attending a diabetes center. Anonimyzed data on gender, type and duration of diabetes, HbA1c, blood pressure and the presence and grade of diabetic retinopathy were gathered to estimate risk for STDR for each individual's worse eye over time by means of a prediction model. Receiver operating characteristics (ROC) analysis was performed to determine the diagnostic ability of the model, and a calibration graph was done to see the model fit. RESULTS: 508 screening intervals were analyzed, median diabetes duration was 10years, 87% were type 2 diabetes mellitus, and 3.1% developed STDR before the next screening visit. The area under the ROC curve was 0.74, and the calibration graph showed that model had a good fit. The reduction in screening frequency was 40% compared with fixed annual screening. CONCLUSIONS: Current prediction model used to estimate the risk of developing STDR in patients with diabetes performed well. A personalized screening frequency for diabetic retinopathy could be implemented in practice. PMID- 25725583 TI - Dynamic control of type I IFN signalling by an integrated network of negative regulators. AB - Whereas type I interferons (IFNs) have critical roles in protection from pathogens, excessive IFN responses contribute to pathology in both acute and chronic settings, pointing to the importance of balancing activating signals with regulatory mechanisms that appropriately tune the response. Here we review evidence for an integrated network of negative regulators of IFN production and action, which function at all levels of the activating and effector signalling pathways. We propose that the aim of this extensive network is to limit tissue damage while enabling an IFN response that is temporally appropriate and of sufficient magnitude. Understanding the architecture and dynamics of this network, and how it differs in distinct tissues, will provide new insights into IFN biology and aid the design of more effective therapeutics. PMID- 25725584 TI - Upregulation of miR-24 promotes cell proliferation by targeting NAIF1 in non small cell lung cancer. AB - Recent studies have implied that aberration of miR-24 is linked to various human cancers. However, its role in non-small cell lung cancer (NSCLC) remains obscure. Here, we found that miR-24 was significantly upregulated in NSCLC tissues and patients' serum. High expression of miR-24 in patients' serum was independently correlated with a shorter overall survival of NSCLC patients. Depletion of miR-24 inhibited cell proliferation and anchorage-independent survival ability in lung cancer cell lines and reduced tumor formation ability in nude mice. Nuclear apoptosis-inducing factor 1 (NAIF1) was identified to be a functional target of miR-24 in the human lung. Next, we observed that the NAIF1 mRNA expression level in NSCLC tissues was suppressed in comparison to that in adjacent normal tissues. Restoration of NAIF1 in lung cancer cell inhibited cell proliferation and anchorage-independent survival ability, which were found to be similar with those from transfecting a miR-24 inhibitor into lung cancer cells. In conclusion, our study demonstrated that miR-24 was upregulated in NSCLC, and suppressing the expression of miR-24 inhibited tumor characteristics. MiR-24 acted as an oncomir, at least partially through regulation of its functional target NAIF1 in NSCLC. MiR-24 may serve as a novel potential biomarker for NSCLC diagnosis and prognosis. PMID- 25725585 TI - Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer. AB - Galectin-1, a beta-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for alpha-SMA and vimentin, and galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-beta, and IFN-gamma) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-beta and IFN-gamma), compared with hNPSCs. Immunohistochemical staining indicated that galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells. PMID- 25725586 TI - Tau and PTEN status as predictive markers for response to trastuzumab and paclitaxel in patients with HER2-positive breast cancer. AB - Trastuzumab (H)-based chemotherapy has been an active treatment in patients with HER2-positive breast cancer; however, primary and secondary resistance has occurred in patients treated with H alone or in combination with chemotherapy. Biomarkers were searched using tissue microarrays (TMA) in HER2-positive advanced breast cancer patients treated with H and paclitaxel (P) combination chemotherapy between October 2004 and August 2010. Tumor blocks were analyzed for Tau-protein, beta-III tubulin, PTEN, p27, IGF-1R, c-Met, CD44, and MUC4 by immunohistochemical (IHC) analysis. The correlation between IHC status and clinical outcomes, including response rate (RR), progression free survival (PFS), and overall survival (OS), was investigated. With a median follow-up duration of 54.1 months (range, 42.3-72.7 months), 65 patients received H + P chemotherapy. The overall RR was 63 % (95 % CI, 51-75 %), and seven patients (11 %) with high Tau/low PTEN expression showed a significantly lower RR (14 % vs. 69 %; p = 0.008). The odds ratio for a poor response was 13.3 (95 % CI, 1.5-119.0; p = 0.020). In addition, patients with high Tau/low PTEN showed a trend of poor survival in terms of PFS (6.6 months vs. 9.6 months, p = 0.052). Subsequent multivariate analysis showed that high Tau/low PTEN (hazard ratio [HR] 2.40, 95 % CI, 1.06-5.47; p = 0.037) was the poor prognostic factor independently associated with PFS after adjusting for possible confounding factors such as recurrence/metastasis, age, performance status, visceral metastasis, and hormone receptor status. High Tau-protein and low PTEN expression showed a significant association with poor response to H + P chemotherapy in patients with HER2-positive advanced breast cancer. PMID- 25725587 TI - Response evaluation after chemoradiotherapy for advanced nodal disease in head and neck cancer using diffusion-weighted MRI and 18F-FDG-PET-CT. AB - OBJECTIVES: Evaluation of accuracy and interobserver variation of diffusion weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDGPET-CT) to detect residual lymph node metastases after chemoradiotherapy (CRT) in advanced staged head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Retrospectively, routinely performed DW-MRI (n=73) and 18F-FDG-PET-CT (n=58) 3months after CRT in HNSCC-patients with advanced nodal disease (N2-N3) were assessed by two radiologists and two nuclear medicine physicians (individually and in consensus). Imaging was scored dichotomously and on a five-point Likert scale. We also explored different scenarios for the potential added value of DW-MRI to PET-CT using the consensus Likert scale. Histopathology and a follow-up of 9months after CRT served as reference standard. RESULTS: Five patients (7%) had residual regional disease. DW-MRI showed a sensitivity of 60% and a specificity of 93%, vs. 100% and 84% for PET-CT, respectively. DW-MRI and PET-CT observers had 'moderate' and 'substantial' interobserver agreement (kappa=0.58 and kappa=0.64, respectively) with the dichotomous system. The combination of PET-CT and DW-MRI showed a sensitivity of 100% and a specificity of 95%. CONCLUSION: The high sensitivity of PET-CT authorizes a neck dissection in all patients with a positive test result and the high specificity of DW-MRI justifies avoidance of invasive neck dissections if the test is negative. Interobserver agreement varied as a function of test positivity criteria. Adding DW-MRI to PET-CT seemed to increase the specificity of PET-CT alone, thereby ensuring that less patients are exposed to unnecessary neck dissections. PMID- 25725588 TI - Mechanisms of and therapeutic approaches for overcoming resistance to epidermal growth factor receptor (EGFR)-targeted therapy in squamous cell carcinoma of the head and neck (SCCHN). AB - The majority of squamous cell carcinoma of the head and neck (SCCHN) overexpress epidermal growth factor receptor (EGFR), which has been associated with poor treatment response and survival. However, only modest success has been achieved with the use of single agents that target EGFR, possibly due to primary and acquired resistance. This review will discuss key mechanisms of and therapeutic approaches to overcoming resistance to EGFR-targeted therapy in SCCHN. Recent preclinical and clinical investigations have demonstrated that other ErbB family receptors (eg, HER2 and HER3) and other horizontal resistance mechanisms, as well as activation of downstream signaling pathways, epigenetic events, and nuclear EGFR, are possible mediators of resistance to anti-EGFR therapeutics. Key downstream pathways that may be implicated in EGFR resistance include phosphatidylinositol-3-kinase/protein kinase B, vascular endothelial growth factor (VEGF), and mammalian target of rapamycin (mTOR). Multiple agents that target EGFR and other ErbB family members (ie, lapatinib, afatinib, and dacomitinib), as well as combination therapies that target EGFR and selected other pathways (eg, VEGF, mTOR, and c-Met) are being investigated clinically. In addition, several phase II and III trials continue to investigate strategies to enhance the efficacy of EGFR-targeted therapy in SCCHN. PMID- 25725589 TI - Examination and treatment of a professional ballet dancer with a suspected acetabular labral tear: A case report. AB - Dancers are at risk for developing groin pain that is due to acetabular labral tears. Although surgical management of labral tears has been reported extensively, conservative management has been poorly described. This case report describes the examination, diagnosis, and treatment of groin pain in a professional ballet dancer with a suspected acetabular labral tear. Treatment focused on decreasing anterior hip joint stresses and improving the precision of hip motion through correction of alignment and movement impairments noted during functional activities and dance. Successful outcomes included a reduction in pain and return to professional ballet dancing. PMID- 25725590 TI - Identifying prognostic factors predicting outcome in patients with chronic neck pain after multimodal treatment: A retrospective study. AB - OBJECTIVES: This study was conducted to identify possible prognostic factors to predict drop-out and favorable outcome in patients following a multimodal treatment program at an outpatient rehabilitation clinic. METHODS: A retrospective cohort study was conducted on 437 patients with chronic neck pain involved in an exercise-based rehabilitation program of an outpatient rehabilitation center between January 2008 and November 2011. Prognostic factors were analyzed through a univariate and a multivariate logistic regression analysis. RESULTS: Multivariate logistic regression revealed that a higher age (OR=0.960), presence of headache (OR=0.436) or low back pain (OR=0.525), and having low levels of depression (OR=1.044) increase the odds to complete the multimodal treatment program. A high NDI-score (OR=0.945), a high NRS-score for pain in the upper extremities (OR=0.862), a low NRS score for pain in the neck (OR=1.372), and a trauma in the patient's history (OR=0.411) decrease the odds of having a favorable outcome after the given treatment program. CONCLUSION: It is important to assess these prognostic factors as they may help therapists to identify patients with a good prognosis or patients at risk. For those at risk, this would allow the treatment approach to be redirected to address their specific needs. PMID- 25725591 TI - Social media in the emergency medicine residency curriculum: social media responses to the residents' perspective article. AB - In July to August 2014, Annals of Emergency Medicine continued a collaboration with an academic Web site, Academic Life in Emergency Medicine (ALiEM), to host an online discussion session featuring the 2014 Annals Residents' Perspective article "Integration of Social Media in Emergency Medicine Residency Curriculum" by Scott et al. The objective was to describe a 14-day worldwide clinician dialogue about evidence, opinions, and early relevant innovations revolving around the featured article and made possible by the immediacy of social media technologies. Six online facilitators hosted the multimodal discussion on the ALiEM Web site, Twitter, and YouTube, which featured 3 preselected questions. Engagement was tracked through various Web analytic tools, and themes were identified by content curation. The dialogue resulted in 1,222 unique page views from 325 cities in 32 countries on the ALiEM Web site, 569,403 Twitter impressions, and 120 views of the video interview with the authors. Five major themes we identified in the discussion included curriculum design, pedagogy, and learning theory; digital curation skills of the 21st-century emergency medicine practitioner; engagement challenges; proposed solutions; and best practice examples. The immediacy of social media technologies provides clinicians the unique opportunity to engage a worldwide audience within a relatively short time frame. PMID- 25725592 TI - Impact of an Electronic Clinical Decision Support Tool for Emergency Department Patients With Pneumonia. AB - STUDY OBJECTIVE: Despite evidence that guideline adherence improves clinical outcomes, management of pneumonia patients varies in emergency departments (EDs). We study the effect of a real-time, ED, electronic clinical decision support tool that provides clinicians with guideline-recommended decision support for diagnosis, severity assessment, disposition, and antibiotic selection. METHODS: This was a prospective, controlled, quasi-experimental trial in 7 Intermountain Healthcare hospital EDs in Utah's urban corridor. We studied adults with International Classification of Diseases, Ninth Revision codes and radiographic evidence for pneumonia during 2 periods: baseline (December 2009 through November 2010) and post-tool deployment (December 2011 through November 2012). The tool was deployed at 4 intervention EDs in May 2011, leaving 3 as usual care controls. We compared 30-day, all-cause mortality adjusted for illness severity, using a mixed-effect, logistic regression model. RESULTS: The study population comprised 4,758 ED pneumonia patients; 14% had health care-associated pneumonia. Median age was 58 years, 53% were female patients, and 59% were admitted to the hospital. Physicians applied the tool for 62.6% of intervention ED study patients. There was no difference overall in severity-adjusted mortality between intervention and usual care EDs post-tool deployment (odds ratio [OR]=0.69; 95% confidence interval [CI] 0.41 to 1.16). Post hoc analysis showed that patients with community-acquired pneumonia experienced significantly lower mortality (OR=0.53; 95% CI 0.28 to 0.99), whereas mortality was unchanged among patients with health care-associated pneumonia (OR=1.12; 95% CI 0.45 to 2.8). Patient disposition from the ED postdeployment adhered more to tool recommendations. CONCLUSION: This study demonstrates the feasibility and potential benefit of real-time electronic clinical decision support for ED pneumonia patients. PMID- 25725593 TI - European Psychiatric Association (EPA) guidance on quality assurance in mental healthcare. AB - PURPOSE: To advance the quality of mental healthcare in Europe by developing guidance on implementing quality assurance. METHODS: We performed a systematic literature search on quality assurance in mental healthcare and the 522 retrieved documents were evaluated by two independent reviewers (B.J. and J.Z.). Based on these evaluations, evidence tables were generated. As it was found that these did not cover all areas of mental healthcare, supplementary hand searches were performed for selected additional areas. Based on these findings, fifteen graded recommendations were developed and consented by the authors. Review by the EPA Guidance Committee and EPA Board led to two additional recommendations (on immigrant mental healthcare and parity of mental and physical healthcare funding). RESULTS: Although quality assurance (measures to keep a certain degree of quality), quality control and monitoring (applying quality indicators to the current degree of quality), and quality management (coordinated measures and activities with regard to quality) are conceptually distinct, in practice they are frequently used as if identical and hardly separable. There is a dearth of controlled trials addressing ways to optimize quality assurance in mental healthcare. Altogether, seventeen recommendations were developed addressing a range of aspects of quality assurance in mental healthcare, which appear usable across Europe. These were divided into recommendations about structures, processes and outcomes. Each recommendation was assigned to a hierarchical level of analysis (macro-, meso- and micro-level). DISCUSSION: There was a lack of evidence retrievable by a systematic literature search about quality assurance of mental healthcare. Therefore, only after further topics and search had been added it was possible to develop recommendations with mostly medium evidence levels. CONCLUSION: Evidence-based graded recommendations for quality assurance in mental healthcare were developed which should next be implemented and evaluated for feasibility and validity in some European countries. Due to the small evidence base identified corresponding to the practical obscurity of the concept and methods, a European research initiative is called for by the stakeholders represented in this Guidance to improve the educational, methodological and empirical basis for a future broad implementation of measures for quality assurance in European mental healthcare. PMID- 25725594 TI - Predicted effect size of lisdexamfetamine treatment of attention deficit/hyperactivity disorder (ADHD) in European adults: Estimates based on indirect analysis using a systematic review and meta-regression analysis. AB - BACKGROUND: There are few approved therapies for adults with attention deficit/hyperactivity disorder (ADHD) in Europe. Lisdexamfetamine (LDX) is an effective treatment for ADHD; however, no clinical trials examining the efficacy of LDX specifically in European adults have been conducted. Therefore, to estimate the efficacy of LDX in European adults we performed a meta-regression of existing clinical data. METHODS: A systematic review identified US- and Europe based randomized efficacy trials of LDX, atomoxetine (ATX), or osmotic-release oral system methylphenidate (OROS-MPH) in children/adolescents and adults. A meta regression model was then fitted to the published/calculated effect sizes (Cohen's d) using medication, geographical location, and age group as predictors. The LDX effect size in European adults was extrapolated from the fitted model. Sensitivity analyses performed included using adult-only studies and adding studies with placebo designs other than a standard pill-placebo design. RESULTS: Twenty-two of 2832 identified articles met inclusion criteria. The model estimated effect size of LDX for European adults was 1.070 (95% confidence interval: 0.738, 1.401), larger than the 0.8 threshold for large effect sizes. The overall model fit was adequate (80%) and stable in the sensitivity analyses. CONCLUSION: This model predicts that LDX may have a large treatment effect size in European adults with ADHD. PMID- 25725595 TI - The relevance of EPA guidance papers in the framework of the European Psychiatric Association. PMID- 25725596 TI - EPA guidance on cultural competence training. AB - The stress of migration as well as social factors and changes related to the receiving society may lead to the manifestation of psychiatric disorders in vulnerable individuals after migration. The diversity of cultures, ethnicities, races and reasons for migration poses a challenge for those seeking to understand how illness is experienced by immigrants whose backgrounds differ significantly from their clinicians. Cultural competence represents good clinical practice and can be defined as such that a clinician regards each patient in the context of the patient's own culture as well as from the perspective of the clinician's cultural values and prejudices. The EPA Guidance on cultural competence training outlines some of the key issues related to cultural competence and how to deal with these. It points out that cultural competence represents a comprehensive response to the mental health care needs of immigrant patients and requires knowledge, skills and attitudes which can improve the effectiveness of psychiatric treatment. To reach these aims, both individual and organizational competence are needed, as well as teaching competence in terms of educational leadership. The WPA Guidance on Mental Health and Mental Health Care for Migrants and the EPA Guidance on Mental Health Care for Migrants list a series of recommendations for policy makers, service providers and clinicians; these are aimed at improving mental health care for immigrants. The authors of this paper would like to underline these recommendations and, focusing on cultural competency and training, believe that they will be of positive value. PMID- 25725597 TI - A multiregional registry experience using an electronic medical record to optimize data capture for longitudinal outcomes in endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: Registries have been proven useful to assess clinical outcomes, but data entry and personnel expenses are challenging. We developed a registry to track patients undergoing endovascular aortic aneurysm repair (EVAR) in an integrated health care system, leveraging an electronic medical record (EMR) to evaluate clinical practices, device performance, surgical complications, and medium-term outcomes. This study describes the registry design, data collection, outcomes validation, and ongoing surveillance, highlighting the unique integration with the EMR. METHODS: EVARs in six geographic regions of Kaiser Permanente were entered in the registry. Cases were imported using a screening algorithm of inpatient codes applied to the EMR. Standard note templates containing data fields were used for surgeons to enter preoperative, postoperative, and operative data as part of normal workflows in the operating room and clinics. Clinical content experts reviewed cases and entered any missing data of operative details. Patient comorbidities, aneurysm characteristics, implant details, and surgical outcomes were captured. Patients entered in the registry are followed up for life, and all relevant events are captured. RESULTS: Between January 2010 and June 2013, 2112 procedures were entered in the registry. Surgeon compliance with data entry ranges from 60% to 90% by region but has steadily increased over time. Mean aneurysm size was 5.9 cm (standard deviation, 1.3). Most patients were male (84%), were hypertensive (69%), or had a smoking history (79%). The overall reintervention rate was 10.8%: conversion to open repair (0.9%), EVAR revision (2.6%), other surgical intervention (7.3%). Of the reinterventions, 27% were for endoleaks (I, 34.3%; II, 56.9%; III, 8.8%; IV and V, 0.0%), 10.5% were due to graft malfunction, 3.4% were due to infection, and 2.3% were due to rupture. CONCLUSIONS: Leveraging an EMR provides a robust platform for monitoring short-term and midterm outcomes after abdominal aortic aneurysm repair. Use of standardized templates in the EMR allows data entry as part of normal workflow, improving compliance, accuracy, and data capture using limited but expert personnel. Assessment of patient demographics, device performance, practice variation, and postoperative outcomes benefits clinical decision-making by providing complete and adjudicated event reporting. The findings from this large, community-based EVAR registry augment other studies limited to perioperative and short-term outcomes or small patient cohorts. PMID- 25725598 TI - The presence of variant genotype of the mannose-binding lectin gene (MBL2) is not associated with increased restenosis rate in carotid surgery. AB - BACKGROUND: We investigated the role of mannose-binding lectin (MBL) variant genotypes in patients with significant carotid restenosis after carotid endarterectomy (CEA) and who underwent a revision CEA. METHODS: This was a cross sectional analysis of 97 patients enrolled between 2001 and 2013. Three groups were investigated: group A included patients with internal carotid artery restenosis, group B included patients without restenosis after CEA, and group C included patients with peripheral arterial disease but without any signs of a carotid stenosis. Venous blood samples were drawn for the genotyping for MBL2 by polymerase chain reaction and for the determination of the MBL serum concentration by enzyme-linked immunoabsorbent assay. RESULTS: The serum concentration of MBL was higher in patients with the normal genotype than in those with the genotype variants of MBL (95% confidence interval, 272.8-1008.7 MUg/L; P = .001). There was no statistically significant difference among groups A, B, or C with respect to the presence of a variant genotype. Similarly, there was no significant gender difference regarding the presence of a variant genotype (P = .325). CONCLUSIONS: The presence of a variant genotype of the MBL2 gene (and the correspondingly lower serum concentration of this molecule) was not correlated with the development of carotid restenosis after CEA beyond a follow up of 12 months. PMID- 25725599 TI - Reflective, causal, and composite indicators of quality of life: A conceptual or an empirical distinction? AB - Items (or indicators) that constitute "quality of life" instruments can be classified as either reflective (manifestations of some underlying construct), causal (the construct is an effect of the indicators), or composite (the construct is an exact linear combination of the indicators). Psychometric methods based on inter-item associations are only appropriate for reflective indicators, whereas other statistical and non-statistical validation methods can be used for composite or causal indicators. Thus, the distinction has important practical, as well as theoretical, implications. Attempts have been made to empirically identify which items of the EORTC QLQ-C30, a cancer-specific instrument, are causal and which are reflective. Such attempts, however, first require commitment to a particular definition of quality of life, of which there are many. Whether an indicator forms a composite, is causal or reflective of quality of life will depend on the definition adopted, and therefore, the reflective-composite-causal distinction is, arguably, best established on conceptual rather empirical grounds, guided by the "mental experiments" suggested by Bollen (Structural equations with latent variables, Wiley, New York, 1989). Conceptual models of health status and quality of life, as well as a cognitive-linguistic approach to quality of life assessment, may make some contribution to this practice. Theoretical consideration of indicator content can guide not only instrument development and validation, but also the selection of an appropriate instrument. PMID- 25725600 TI - [Chest wall tuberculosis: report of 3 cases]. AB - Despite the dramatic decline in the incidence of tuberculosis during the last decades, the disease remains a significant public health problem especially in developing countries. Chest wall tuberculosis is a very rare location. Clinically, it can present as a pyogenic abscess or soft tumor, making diagnosis difficult, particularly in the absence of warning signs. Optimal therapeutic management is controversial. Medical treatment alone in often insufficient and must be associated with a surgical excision or debridement. PMID- 25725601 TI - [Concomitant discovery of lung cancer and tuberculosis in a cannabis smoker]. AB - INTRODUCTION: The coexistence of lung cancer and active tuberculosis is relatively rare. We report a case of concomitant discovery of lung cancer and tuberculosis in the context of addiction to tobacco and cannabis. OBSERVATION: A 50-year-old man, smoking tobacco and cannabis since the age of 18, was hospitalized for hemoptysis. Physical examination revealed cachexia, hyperthermia and decreased breath sounds on auscultation of the left lung field. The chest X ray objectified atelectasis of the left upper lobe. The CT scan revealed a left upper lobe atelectasis and a cavity surrounded opacities taking a tree in bud appearance located at the apex of the left lower lobe. Endoscopy showed an obstruction by a bud located at the upper left lobe. Histology of bronchial biopsy revealed squamous cell carcinoma. Direct examination of bacteriological samples found BAAR and culture confirmed tuberculosis. The contamination could occur via a close relative, smoking cannabis and being treated for tuberculosis. After a 6-month treatment for tuberculosis, the patient underwent a course of chemotherapy, but refused further treatment. Death occurred 3months later. CONCLUSION: This observation relates the concomitant discovery of lung cancer and tuberculosis. It also highlights the possible role of cannabis addiction in the transmission of tuberculosis and the occurrence of lung cancer in combination with tobacco. PMID- 25725602 TI - Young Children's Ritualistic Compulsive-Like Behavior and Executive Function: A Cross Sectional Study. AB - The goal of this study was to test whether the development of executive function in young children could add to the explained variance in child ritualistic behavior beyond child and maternal traits previously found to have explanatory power. Routinized, ritualistic behavior is common and normative in young children between the ages of 2 and 5, after which it subsides. In this cross-sectional study, maternal reports on 1345 children between the ages of 2 and 6 included child variables such as temperament, fears, and behavioral problems. Mother's characteristics included perfectionism, her attachment style, and trait anxiety. The sample included ultra-orthodox families, an understudied minority, and thus it was possible to compare their ritualistic behavior with that of children from other rearing environments. Ultraorthodox children had more ritualistic behavior than age-matched children. This finding offers support for an environmental influence on level of ritualistic behavior in children. For the entire sample, we found that young children's ritualistic behavior was associated with shy and emotional temperament, fears, pervasive developmental behavioral problems, and that executive function delays in shifting and emotion regulation had an additional contribution. Ritualistic child behavior was only weakly related to maternal variables. The results were consistent with a maturational process for the trajectory of ritualistic behavior, rather than with an environmentally induced behavior. The development of executive function may be the process mediating the decline of ritualistic behavior over development. PMID- 25725603 TI - New insights from major prospective cohort studies with cardiac CT. AB - Each year, 11 million patients present in the USA with new symptoms suggestive of obstructive coronary artery disease (CAD). Most undergo stress testing but <10% demonstrate myocardial ischemia. Moreover, up to 60% will have CAD which adversely affects outcomes. Cardiac computed tomography (CCT) is being used increasingly as an alternative to stress testing to rule out obstructive CAD in symptomatic patients, and large cohort studies in asymptomatic patients have identified burden of coronary atherosclerosis as a predictor of major adverse cardiovascular events (MACE). This review article will critically evaluate major clinical studies on the use of CCT in both symptomatic and asymptomatic patients and discuss the lessons for the clinical use of CCT. PMID- 25725604 TI - An overview of left atrial appendage occlusion devices. AB - Atrial fibrillation (AF) places patients at increased risk of thromboembolic events that can be devastating. The left atrial appendage (LAA) has been identified as the source of thrombus formation in nonvalvular AF. Traditionally, systemic anticoagulation has been used to reduce the risk of stroke and systemic embolism. However, anticoagulation is not well tolerated in all patients and is underutilized. As a potential alternative to anticoagulation, novel therapies have been developed to remove the LAA. Three main techniques are being utilized to accomplish LAA exclusion: percutaneous intracardiac, percutaneous epicardial, and surgical approaches. Emerging evidence suggests that LAA exclusion may be an effective means of reducing the risk of stroke in patients with nonvalvular AF. PMID- 25725605 TI - Constrictive pericarditis: old disease, new approaches. AB - Constrictive pericarditis is a disorder of cardiac filling caused by an inelastic pericardium. This treatable cause of heart failure should be considered in all patients with unexplained right heart failure symptoms or signs, especially when the left ventricular ejection fraction is preserved. Diagnosing constrictive pericarditis remains challenging, and the most effective tools are designed to identify its unique pathophysiologic mechanisms: dissociation of intrathoracic and intracardiac pressures and enhanced ventricular interaction. The cornerstone of the diagnostic work-up remains comprehensive echocardiography with Doppler, but cross-sectional imaging and invasive hemodynamic assessment may be necessary in some cases. Cardiac MRI is particularly helpful in identifying those patients who may have inflammatory constriction that would resolve with anti-inflammatory therapy. Complete surgical pericardiectomy remains the only definitive treatment for patients with chronic constriction. PMID- 25725606 TI - Echocardiographic evaluation of the right ventricle: a 2014 perspective. AB - The ability to properly evaluate the right ventricular size and function can have important consequences for clinical management and prognosis. Echocardiography is and will remain the leading method of right ventricle (RV) assessment due to its ease of use and wealth of diagnostic information provided. Understanding the various strengths and limitations of the diverse echocardiographic methods of RV assessment can allow a systematic approach to resolve situations where one's quantitative parameters are not necessarily concordant. Quantification of RV volume can be done by two-dimensional (2D) and three-dimensional (3D) echocardiography. Measurements of RV systolic function include fractional area change (FAC), right-sided index of myocardial performance (RIMP), RV ejection fraction (RVEF), tricuspid annular plane excursion by M-Mode (TAPSE), tricuspid annular systolic longitudinal velocity by tissue Doppler (S'), and regional strain and strain rate. RVEF can also be assessed volumetrically by 3D echocardiography. This article will review the current methods used in contemporary echocardiography laboratories, with an emphasis on a guideline-based approach as well as emerging techniques. PMID- 25725607 TI - 2-Benzisothiazolylimino-5-benzylidene-4-thiazolidinones as protective agents against cartilage destruction. AB - We report the synthesis, the antioxidant and the inhibitory activity (IC50) on metalloproteinases (MMPs) 3 and 13 of 2-benzo[d]isothiazolylimino-5-benzylidene-4 thiazolidinones. Their potential as protective agents in osteoarthritis (OA) was evaluated by biological assays on chondrocytes cultures, stimulated by IL-1beta. The chondroprotective capability, related both to antioxidant activity and to inhibition of MMPs, was studied in vitro, by determining nitric oxide production and glycosaminoglycans release. Moreover, selected derivatives 1h and 1g was studied for nuclear factor kappaB (NF-kappaB) inhibition by Western Blot analysis and for MMP-3 protein release using ELISA test. The structure-activity relationship of tested compounds demonstrates a favorable effect of the para substitution on the 5-benzilydene ring. Compound 1g shows a potent and selective activity on MMP-3 versus MMP-13. Accordingly, 1g possesses high antioxidant effect, NO lowering and GAGs restoring capability and also reduces the production of MMPs and NF-kappaB expression. Thus 1g can be considered as new potential chondroprotective agents. PMID- 25725608 TI - N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity. AB - We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158nM), good correlation with beta-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance. PMID- 25725610 TI - Commentary to "Lower radiation burden in state of the art fluoroscopic cystography compared to direct isotope cystography in children". PMID- 25725609 TI - Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures. AB - Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2, respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2MUM against the Calu-6 human lung adenocarcinoma line, and 4.8MUM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b-6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents. PMID- 25725611 TI - Environmental, parental and gestational factors that influence the occurrence of hypospadias in male patients. AB - OBJECTIVE: Hypospadias is a congenital defect, which affects normal development of the male urogenital external tract. In this malformation, the urethral orifice of the penis is positioned ventrally, thus interfering with normal urination and creating, in some adults, problems during sexual intercourse. Heritability of hypospadias has been shown in some reports, and the abnormality has been associated with the presence of mutations in one of the genes involved in urogenital development. However, even for patients who were born in families with a higher incidence rate of this defect, no evident genetic alteration could be identified in known genes, indicating that the list of loci involved is still incomplete. To further complicate matters, recent reports also underline that epigenetic changes, without any identifiable gene sequence mutation, may be involved in gene function impairment. Therefore, the inheritance of most hypospadias cases is not evident, suggesting that the genetic background is not the only cause of this malformation; indeed, the majority of hypospadias cases are classified as sporadic and idiopathic. MATERIALS AND METHODS: Evidence has accumulated highlighting the role of the environment and of its relationships with the genome in the etiology of this abnormality. In particular, the interaction between some chemicals, which are able to mimic endogenous molecules such as sexual hormones--for this reason called endocrine disrupting compounds (EDC)--and specific receptors has been extensively investigated during the pregnancy. Additionally, several articles have shown that parental and gestational factors play a significant role too. Indeed, physiological alterations, such as body weight of the mother and/or of the newborn, mother's diabetes, impaired father fertility, and exposure of one parent to job-related pollutants, show in many cases a direct correlation with hypospadias incidence. The overall prevalence of this condition has been studied in many countries, suggesting that at least in some periods and/or in specific populations there are detectable fluctuations, probably mirroring the different natural environments. However, many articles present data that do not agree with these findings and, consequently, most causes of hypospadias are still highly debated. RESULTS: In this review, we summarize the developmental steps involved in urogenital tract formation, with a particular emphasis on the genes that most frequently are associated with this condition, or that are subject to environmental stress, or that may be the targets of hormone-like, exogenous molecules. Then, we make an overview of the identified factors able to impair the function of important genes, even in the absence of their mutations, including those for which contradictory reports have been published. Finally, we propose an explanation of sporadic cases of hypospadias that reconciles these contradictions and suggest some steps for moving forward in the research focused on this condition. CONCLUSION: We hypothesize that most patients develop hypospadias because of gene environment interactions acting on polymorphic genes that, in the absence of environmental stimuli, would otherwise cause no developmental anomaly during urogenital development. PMID- 25725612 TI - Does augmentation cystoplasty with continent reconstruction at a young age increase the risk of complications or secondary surgeries? AB - INTRODUCTION AND OBJECTIVE: Lower urinary tract reconstruction with augmentation cystoplasty (AC) is an effective strategy for achieving urinary continence in children with neurogenic or severely compromised bladder. We compared complications and need for secondary surgeries in children 3-5 years of age undergoing AC with continent reconstruction to those >= 6 years old. STUDY DESIGN: Medical charts of children undergoing AC with continent urinary diversion between 2003 and 2011 were reviewed. Complications and secondary surgeries were analyzed according to patient age. Patient demographics, etiology of bladder dysfunction, bowel segment used, and concomitant procedures were also assessed. RESULTS: One hundred and eight children underwent AC with continent urinary diversion. Mean age at augmentation was 8.5 years (range 3-20). Twenty-eight children (25.9%) were 3-5 years old and 80 (74.1%) were >= 6 years. Mean follow up was 6.93 years (range 1.6-10 years). Bowel segment used included ileum in 59 (54.6%), sigmoid in 33 (30.6%), cecum in 4 (3.7%) and composite in 12 (11.1%). Major complications included bowel obstruction in 6 (5.6%), bladder perforation in 3 (2.8%) and fistula in 2 (1.9%). There was no difference in major complications based on bowel segment utilized (p = 0.804, OR 0.894) or age (p = 0.946, OR 0.969). Fifty children (46.3%) required no additional surgeries; the remaining 58 underwent 137 procedures post-augmentation. Surgeries included urolithiasis management (58/137, 42.3%), appendicovesicostomy revision including stoma revision or redo for persistent leakage between catheterizations in (34/137, 24.8%), bladder neck procedures (26/137, 19%) and revision of MACE (19/137, 13.9%) [Figure]. Incidence of stones in patients 3-5 years (32.1%) was not significantly different than children >= 6 years of age (25%, p = 0.463, OR 0.704). Mean number of secondary surgeries for those 3-5 years was 1.21 +/- 1.34, which was not statistically different than those >= 6 (1.3 +/- 1.82, p = 0.154). Children with myelomeningocele (MMC) were statistically more likely to require secondary surgeries than those with other bladder pathology (p = 0.01). DISCUSSION: Augmentation enterocystoplasty with cutaneous continent catheterizable channel is performed both to protect the upper urinary tract and afford the patient the option of social continence. Continent lower urinary tract reconstruction has been proven technically feasible and safe in preschool-aged children however, the ideal age for augmentation remains unknown. Urolithiasis accounted for over 40% of additional procedures in our series, with 26.9% of patients requiring one or more surgeries for stone disease. The incidence of stone disease in patients 3-5 years of age at the time of augmentation was comparable to that seen in older children. The overall need for additional post augment procedures was not influenced by patient age or bowel segment utilized, however children with MMC were significantly more likely to require future surgeries than those with a different underlying etiology of bladder dysfunction. Our study has several limitations that warrant mention. Children with neurogenic bladder represent a heterogeneous population, and their surgical outcomes are inherently influenced by underlying disease processes and severity. Complications and secondary surgeries were assessed; however success rates were not evaluated in the current study. Patient and caregiver adherence with CIC and daily bladder irrigation was not assessed; whether noncompliance affected complication rates (i.e. stone formation) is unknown. CONCLUSION: Whether performed at a young or older age, families must be adequately counseled regarding the daily management responsibilities and potential risks associated with lower urinary tract reconstruction including bladder augmentation. Augmentation with continent urinary diversion in selected patients 3-5 years of age confers complication and secondary surgery risk equal to that observed in their older counterparts. PMID- 25725613 TI - Is routine voiding cystourethrogram necessary following double hit for primary vesicoureteral reflux? AB - INTRODUCTION AND OBJECTIVE: Current AUA guidelines recommend voiding cystourethrogram (VCUG) following endoscopic treatment of vesicoureteral reflux (VUR). We evaluated the clinical and radiographic outcomes of children undergoing Double HIT (hydrodistention implantation technique) for primary VUR to determine success rates and the necessity of postoperative VCUG. STUDY DESIGN: Children with a history of febrile urinary tract infection (fUTI) undergoing Double HIT for primary VUR between 2009 and 2012 were identified. Patients were prospectively classified as high or low clinical and radiographic risk. Children were categorized as high clinical risk if they had >= 3 fUTIs or documented bladder bowel dysfunction (BBD). High radiographic risk included those <2 years of age or with grade 4-5 VUR. Initially, all children underwent postoperative VCUG ("routine" group), while only those with an indication (high radiographic risk or clinical failure) did so during the latter portion of the study ("indicated" group). Clinical success was defined as no postoperative fUTI and radiographic success as negative postoperative VCUG. Average clinical follow-up was 34.7 +/- 17.2 months. RESULTS: Two hundred and twenty-two children (198 girls, 24 boys) underwent Double HIT at a mean age of 4.1 +/- 2.7 years. Mean maximum VUR grade was 3 +/- 0.8. Sixty-eight children (30.6%) had documented BBD. Fourteen children (6.3%) experienced postoperative fUTI, for a clinical success rate of 93.7%. One hundred and fourteen patients (51.4%) underwent postoperative VCUG; 76 were "routine" and 38 were "indicated" [Figure]. Of children classified as low clinical/radiographic risk, 96.6% did not have a postoperative fUTI, compared to 91.1% for high risk patients (P = 0.771). Odds of clinical success for routine VCUG group were 9.9 times higher than for the indicated VCUG group (95% CI, 2-50). Odds of radiographic success for the routine cohort were 13 times higher than for the indicated group (95% CI, 4.2-40). Nine children (4.1%) underwent additional procedures. DISCUSSION: We found no difference in clinical success among the different risk groups; the number of children with postoperative fUTI was relatively few so there was not statistical power to discern any differences between patients who experienced clinical success versus clinical failure. However, children with an "indicated" VCUG (i.e. those less than 2 years of age, grade 4-5 VUR or those with a fUTI) were 13 times more likely to experience a radiographic failure. This cohort of 38 patients had a 50% radiographic cure rate and a 78.9% clinical cure rate, compared to the overall long-term clinical success rate of 93.7%. Our data demonstrates that we can predict failures with relatively high sensitivity, and it may therefore be prudent to selectively obtain postoperative VCUG rather than recommend it for all children undergoing dextranomer hyaluronic acid co-polymer (Dx/HA) injection. Our study has several limitations that warrant consideration. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. Incidence of fUTI may also be artificially low, as some radiographic failures proceeded directly to another injection or reimplantation. While we were able to demonstrate that children undergoing an "indicated" VCUG were more likely to experience radiographic failure, a larger patient cohort is necessary to determine whether age or VUR grade is more predictive of failure. Finally all patients underwent endoscopic Dx/HA injection, therefore the incidence "spontaneous resolution" is unknown. CONCLUSION: Long-term clinical success following Double HIT for the endoscopic correction of primary VUR is high, and the majority of children avoid additional procedures. Unless indicated by high grade, young age, clinical failure, or family/surgeon preference, consideration should be given to making postoperative VCUG an option rather than a recommendation in children undergoing endoscopic treatment of primary VUR using the Double HIT method. PMID- 25725614 TI - Laparoscopic approach in the management of anorectal malformations. AB - Seventeen years have passed since the first description of the laparoscopic approach for anorectal malformation and approximately 68 articles have been published on the subject. In this review article, we aim to describe the advantages as well as the indications and contraindications of this approach when dealing with each specific type of anorectal malformation, according to what has been described in the literature and to our own experience. The ideal and undisputable indication for laparoscopy remains for cases in which the abdomen needs to be entered to repair the malformation. Only 10% of male patients with anorectal malformation are born with a recto-bladder neck fistula that requires an abdominal approach, this represents an ideal indication for laparoscopy. In females, only the complex cloacae with a common channel length greater than 3 cm are the ones that require a laparotomy; they represent about 30% of the cloacae. However, the repair of this type of cloacae also requires sophisticated and technically demanding maneuvers that have never been done laparoscopically. In cases of recto-urethral prostatic fistulas the malformation can be repaired either way: laparoscopically or posterior sagitally. In all other malformations: recto-perineal fistula, recto-urethral bulbar fistula, anorectal malformation without fistula, rectal atresia, recto-vestibular fistula; no justification for laparoscopy could be found; and in some cases, laparoscopy is contraindicated. In the published reports, there is no evidence supporting the idea that laparoscopic repair results in better functional results when compared with non-laparoscopic operation; there is a tendency to omit information relevant to bowel control such as the characteristics of the sacrum and the presence or absence of tethered cord; and most authors do not compare results between comparable malformations. PMID- 25725615 TI - Performance of screening tools in detecting major depressive disorder among patients with coronary heart disease: a systematic review. AB - BACKGROUND: Eligible studies published before 31 Dec 2013 were identified from the following databases: Ovid Medline, EMBASE, PsycINFO, Scopus, Cochrane Library, CINAHL Plus, and Web of Science. MATERIAL AND METHODS: Eligible studies published before 31, Dec 2013 were identified from the following databases: Ovid Medline, EMBASE, psycINFO, Scopus, Cochrane Library, CINAHL Plus, and Web of Science. RESULTS: Eight studies aiming to identify MDD in CHD patients were included, and there were 10 self-reporting questionnaires (such as PHQ-2, PHQ-9, PHQ categorical algorithm, HADS-D, BDI, BDI-II, BDI-II-cog, CES-D, SCL-90, 2 simple yes/no items) and 1 observer rating scale (Ham-D). For MDD alone, the sensitivity and specificity of various screening tools at the validity and optimal cut-off point varied from 0.34 [0.19, 0.52] to 0.96 [0.78, 1.00] and 0.69 [0.65, 0.73] to 0.97 [0.93, 0.99]. Results showed PHQ-9 (>=10), BDI-II (314 or >=16), and HADS-D (>=5 or >=4) were widely used for screening MDD in CHD patients. CONCLUSIONS: There is no consensus on the optimal screening tool for MDD in CHD patients. When evaluating the performance of a screening tool, balancing the high sensitivity and negative predictive value (NPV) between specificity and positive predictive value (PPV) for screening or diagnostic purpose should be considered. After screening, further diagnosis, appropriate management, and necessary referral may also improve cardiovascular outcomes. PMID- 25725617 TI - Systematic review and meta-analysis of histopathological predictive factors for lymph node metastasis in T1 colorectal cancer. AB - BACKGROUND: In this study we examined whether histopathological findings, specifically lymphatic vessel invasion identified by an anti-human podoplanin antibody, and several other factors are associated with lymph node metastasis in T1 colorectal cancer. METHODS: We searched PubMed and Cochrane Library, and also handsearched relevant journals, for reports written in English and published between 1998 and 2012, utilizing combination headings, such as 'colorectal cancer,' 'lymph node metastasis,' and 'risk factors.' For the report to be included in our study, the following criteria had to be met: (1) data on the frequency of lymph node metastasis in T1 colorectal cancer in relation to histopathological factors were reported; (2) patients had undergone bowel resection and had histologically diagnosed T1 colorectal cancer; (3) lymphatic vessel invasion was identified by immunohistochemistry with an anti-human podoplanin antibody rather than by hematoxylin and eosin staining; (4) univariate and multivariate analyses were conducted. Studies investigating molecular markers were excluded. The independent predictive factors were confirmed in at least one study included in the meta-analysis in the present systematic review. Microsoft Excel 2013 for Windows was used for the statistical analysis. RESULTS: Initially, 369 publications were identified in the database searches and handsearches, of which five ultimately met all of the inclusion criteria and selected for this systematic review. The meta-analysis revealed that only two factors were significantly associated with T1 colorectal cancer lymph node metastasis: (1) lymphatic vessel invasion identified by an anti-human podoplanin antibody [Mantel Haenszel odds ratio (OR) 5.19; (95% confidence interval (CI) 3.31-8.15; P = 0.01]; (2) tumor budding (OR 7.45; 95 % CI 4.27-13.02; P = 0.0077). CONCLUSION: Our meta-analysis revealed that lymphatic vessel invasion identified by an anti human podoplanin antibody and tumor budding were significantly associated with T1 colorectal cancer lymph node metastasis. PMID- 25725616 TI - High salt intake as a multifaceted cardiovascular disease: new support from cellular and molecular evidence. AB - Scientists worldwide have disseminated the idea that increased dietary salt increases blood pressure. Currently, salt intake in the general population is ten times higher than that consumed in the past and at least two times higher than the current recommendation. Indeed, a salt-rich diet increases cardiovascular morbidity and mortality. For a long time, however, the deleterious effects associated with high salt consumption were only related to the effect of salt on blood pressure. Currently, several other effects have been reported. In some cases, the deleterious effects of high salt consumption are independently associated with other common risk factors. In this article, we gather data on the effects of increased salt intake on the cardiovascular system, from infancy to adulthood, to describe the route by which increased salt intake leads to cardiovascular diseases. We have reviewed the cellular and molecular mechanisms through which a high intake of salt acts on the cardiovascular system to lead to the progressive failure of a healthy heart. PMID- 25725618 TI - Clinical usefulness of endocytoscopy in the remission stage of ulcerative colitis: a pilot study. AB - BACKGROUND: Histopathology can be used to detect ulcerative colitis (UC) relapse, but diagnosis of the disease activity by histopathology requires multiple biopsies to be taken. Magnifying endocytoscopy provides a method for real-time ultra-magnifying imaging. It was recently reported that the endocytoscopy system score (ECSS) correlates well with the histopathology of UC. Here we evaluated the clinical usefulness of endocytoscopy for accurately monitoring UC during remission. METHODS: We performed endocytoscopy on 26 patients with UC in remission that had been diagnosed by conventional colonoscopy at our institution between January and April 2013. Endocytoscopy was performed at the area of the rectum where UC had been detected with conventional endoscopy. Biopsies were also taken from the same area and histopathology was evaluated by a single pathologist according to the Matts' grading system. The correlation between the relapse rate of UC and both the ECSS and the Matts' histopathological grade was evaluated. RESULTS: The ECSS of the intestinal mucosa in UC showed a correlation with the Matts' histopathological grade (Spearman's |r| = 0.647). The patients were classified into two groups: those with an ECSS of 0-2 (Grade A, 12 cases) and those with an ECSS of 3-6 (Grade B, 10 cases). To date, three Grade B cases have relapsed and no Grade A cases have relapsed. The average post-endocytoscopy surveillance period was 446 +/- 92 days. CONCLUSIONS: The ECSS may be a predictive indicator for UC relapse since there was a correlation between the ECSS and the degree of inflammation as determined by histopathology. PMID- 25725619 TI - Influence of anterior chamber depth, anterior chamber volume, axial length, and lens density on postoperative endothelial cell loss. AB - PURPOSE: To evaluate the influence of anterior chamber depth (ACD), anterior chamber volume (ACV), lens density (LD), and axial length (AL) as risk factors on endothelial cell loss 3 months after cataract surgery. METHODS: We enrolled 47 patients with senile cataract who were operated between July 2012 and March 2013 by the same surgeon using torsional phacoemulsification. Preoperatively, we measured ACD, ACV, and LD using the Oculus Pentacam(r). The AL was determined using the IOL Master(r). Primary outcomes were central endothelial density (ECD) and corrected distance visual acuity (CDVA) 3 months after surgery We evaluated the effect of ACD, ACV, LD, and AL as possible risk factors of postoperative percentage endothelial cell loss (ECL). RESULTS: The median age was 72 years. The median CDVA before surgery was 0.5 improving to 1.0 postoperatively. The median ECL was 5.2 % (range 1.7 %-7.6 %). These results are comparable to our previous study (median ECL 6.9 % after 3 months) [Reuschel et al. (2010) J Cataract Refract Surg]. The median ACD in our study was 2.56 mm (range 2.26 mm-2.8 mm). Median ACV was 144 mm(3) (range 121 mm(3)-158 mm(3)]. The median LD was 12.4 (range 11.4-13.7). Median AL was 23.1 mm (range 22.7 mm-23.9 mm). Our correlation analysis showed no significant correlation between ACD, ACV, LD, AL, and postoperative ECL. CONCLUSION: ACD, ACV, AL, and LD were not identified as risk factors of postoperative endothelial cell loss in our analysis. PMID- 25725620 TI - Clinical features of psoriatic uveitis in Japanese patients. AB - PURPOSE: To investigate the clinical features of psoriatic uveitis in Japanese patients. METHODS: Clinical features of 13 consecutive patients with psoriatic uveitis treated at our facility were retrospectively examined using medical records. In this study, we collected data about psoriasis type, uveitis laterality, onset type, HLA types, visual acuity, ocular inflammation localization, anterior segment findings, funduscopy findings, complications, recurrence, and medical treatments for uveitis and skin diseases. RESULTS: The cohort comprised ten males and three females (43.6 +/- 7.1 years old), and types of psoriasis included psoriasis vulgaris (seven cases), psoriatic arthritis (four cases), pustular psoriasis (three cases) and psoriatic erythroderma (one case). Two cases represented complicated cases of pustular psoriasis and psoriatic arthritis. Seven cases were unilateral, and six cases were bilateral. All cases had acute non-granulomatous anterior uveitis, whereas panuveitis occurred in one case. Furthermore, macular edema and vascular leakage on fluorescein angiography occurred in four cases, and hyperemic disc occurred in two cases. Recurrence occurred in nine cases. In addition to topical corticosteroid treatment, eight cases underwent oral immunosuppressive treatment or biologics. All six cases undergoing HLA typing were HLA-A2 positive. CONCLUSIONS: Cases of psoriatic uveitis in Japan appear to present with acute non-granulomatous uveitis; other symptoms may include macular edema, retinal vasculitis, or hyperemic disc. PMID- 25725621 TI - Carbamylated erythropoietin mediates retinal neuroprotection in streptozotocin induced early-stage diabetic rats. AB - PURPOSE: The neuroprotective effect of carbamylated erythropoietin (CEPO), an erythropoietin (EPO) derivative, in diabetic retinopathy (DR) has not been clearly verified. We conducted this study to investigate the potential neuroprotective role of CEPO in a streptozotocin-induced diabetic rat model. METHODS: Streptozotocin-induced diabetic rats and blank controls were treated with or without CEPO and EPO for 4 weeks. Retinal functional and histological changes were quantified by electroretinogram, light microscopy, and terminal dUTP nick end labeling assay. Gene and protein levels of colony-stimulating factor 2 receptor beta, low-affinity (CD131), EPO receptor (EPOR), THY1, glial fibrillary acidic protein (GFAP), and vascular endothelial growth factor (VEGF-A) in retinal tissues were determined by real-time PCR and western blotting, respectively. Vascular penetration was assessed by fluorescein retinal angiography. RESULTS: Diabetic rats had decreased retinal thickness, decreased ganglion cells, and increased retinal neuron apoptosis. CEPO increased CD131 and THY1 expression, while EPO increased EPOR expression. High glucose increased GFAP expression in the diabetic group, but both CEPO and EPO attenuated the trend for increase. CEPO downregulated VEGF-A expression. The amplitudes of b-wave and oscillatory potentials were decreased in the untreated diabetic group, whereas neither parameter decreased in diabetic rats after CEPO or EPO treatment. Vascular leakage and microaneurysms in the diabetic group were significantly improved following CEPO treatment. CONCLUSIONS: CEPO has similar anti-apoptotic effects to EPO in DR, but CEPO does not induce neovascularization. CEPO may exert neuroprotective effects via its receptor CD131. PMID- 25725622 TI - Identification and characterization of two novel germline RET variants associated with medullary thyroid carcinoma. AB - Activating germline mutations in the RET proto-oncogene are responsible for about 98 % of the familial forms of medullary thyroid carcinoma (MTC), which represent 25 % of all MTC cases. The search for germline mutations in this gene is important for the recognition of hereditary forms of MTC and further identification of at-risk relatives who may benefit from early clinical intervention. Genotype-phenotype correlations are well established for most disease-causing RET mutations, allowing risk stratification. The association of a new RET variant with the MTC phenotype and familial predisposition requires the assessment of its functional and clinical significance. The aim of this study was to evaluate the oncogenic potential of two newly identified RET germline variants associated with late-onset MTC. In vitro functional assays were designed to address the transforming potential of novel RET variants, through their expression in non-transformed cells, and comparing their effect with wild-type RET. The new variants were identified in codons 515 (p.C515W) and 636 (p.T636M) located, respectively, in exons 8 and 11, thus resulting in amino acid substitutions in the extracellular region of the tyrosine kinase receptor RET. Through functional assays, we observed increased cell growth and proliferation, loss of contact inhibition, and a stimulation of cell migration, suggesting that these new RET variants hold some relevant transforming potential. The transforming potential of these novel RET variants was of low-grade, when compared to that of RET MEN2A-causing mutation p.C634R, probably explaining the mild phenotype characterized by late onset and low clinical aggressiveness. PMID- 25725623 TI - Pathophysiology of diabetic dyslipidaemia: where are we? AB - Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus, with a two- to fourfold increase in cardiovascular disease risk compared with non-diabetic individuals. Abnormalities in lipid metabolism that are observed in the context of type 2 diabetes are among the major factors contributing to an increased cardiovascular risk. Diabetic dyslipidaemia includes not only quantitative lipoprotein abnormalities, but also qualitative and kinetic abnormalities that, together, result in a shift towards a more atherogenic lipid profile. The primary quantitative lipoprotein abnormalities are increased triacylglycerol (triglyceride) levels and decreased HDL-cholesterol levels. Qualitative lipoprotein abnormalities include an increase in large, very low-density lipoprotein subfraction 1 (VLDL1) and small, dense LDLs, as well as increased triacylglycerol content of LDL and HDL, glycation of apolipoproteins and increased susceptibility of LDL to oxidation. The main kinetic abnormalities are increased VLDL1 production, decreased VLDL catabolism and increased HDL catabolism. In addition, even though LDL-cholesterol levels are typically normal in patients with type 2 diabetes, LDL particles show reduced turnover, which is potentially atherogenic. Although the pathophysiology of diabetic dyslipidaemia is not fully understood, the insulin resistance and relative insulin deficiency observed in patients with type 2 diabetes are likely to contribute to these lipid changes, as insulin plays an important role in regulating lipid metabolism. In addition, some adipocytokines, such as adiponectin or retinol-binding protein 4, may also contribute to the development of dyslipidaemia in patients with type 2 diabetes. PMID- 25725624 TI - Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance. AB - AIMS/HYPOTHESIS: Type 2 diabetes has been associated with upper gastrointestinal motility dysfunction, but the relationship with diabetes duration and glucose control is less well understood. Gastric emptying, oesophageal motility and gastrointestinal symptoms were examined in volunteers with diabetes, prediabetes (impaired fasting glucose [IFG] or impaired glucose tolerance [IGT]) and normal glucose tolerance (NGT). METHODS: The study included 41 patients with type 2 diabetes, 17 individuals with IFG/IGT and 31 individuals with NGT. A gastric emptying breath test and high-resolution oesophageal manometry were performed. Gastrointestinal symptoms were assessed using questionnaires. RESULTS: Gastric emptying was delayed in individuals with IFG/IGT (p < 0.05) but was normal in the diabetic group. Amongst the diabetic patients, gastric emptying rate was fastest in those with longer diabetes duration and the highest HbA1c levels (p < 0.001). Oesophageal motility variables were similar between the groups. However, the lower oesophagus resting pressure was reduced in patients with longer diabetes duration (p = 0.01). Abdominal pain/discomfort was more frequent amongst patients with diabetes (p = 0.04) but was unrelated to gastric emptying. Significant associations between various oesophageal motility variables and gastrointestinal symptoms were observed. CONCLUSIONS/INTERPRETATION: Gastric emptying and oesophageal motility are not generally altered in patients with type 2 diabetes. In more advanced disease stages, however, gastric emptying and oesophageal motility may be disturbed, probably as a consequence of autonomic neuropathy. Delayed gastric emptying in IFG/IGT individuals might be secondary to acute hyperglycaemia. Determination of gastric emptying and oesophageal manometry should be considered for the diagnostic workup of patients with diabetes and gastrointestinal symptoms. PMID- 25725625 TI - Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity. AB - AIMS/HYPOTHESIS: Brown adipose tissue (BAT) activation increases energy expenditure and may have therapeutic potential to combat obesity. The primary activating and adaptive signal for BAT is via beta-adrenergic signalling. We previously demonstrated that human BAT is acutely responsive to oral administration of the sympathomimetic, ephedrine. Here we aimed to determine whether adaptive thermogenesis can be induced via chronic treatment with ephedrine. METHODS: Twenty-three healthy young men, recruited from the general public in Melbourne, Australia, who were non-smokers, physically inactive and non medicated with no prior history of cardiovascular disease or diabetes were recruited for this study. They were assigned to receive either 1.5 mg kg(-1) day( 1) ephedrine ('active' group; n = 12, age 23 +/- 1 years, BMI 24 +/- 1 kg/m(2)) or placebo (n = 11; 22 +/- 2 years, 23 +/- 2 kg/m(2)) for 28 days in a randomised (computer-generated random order sequence), placebo-controlled, parallel-group trial. Participants and all investigators were blinded to treatments. Body composition was measured before and after the intervention by dual energy X-ray absorptiometry. BAT activity, measured via (18)F-fluorodeoxyglucose positron emission tomography-computed tomography, in response to a single dose of 2.5 mg/kg ephedrine, was the primary outcome measure to be determined before and after the 28 day treatment period. RESULTS: Twenty-eight individuals were randomised and consented to the study. Twenty-three completed the trial and only these participants were included in the final analyses. After 28 days of treatment, the active group lost a significant amount of total body fat (placebo 1.1 +/- 0.3 kg, ephedrine -0.9 +/- 0.5 kg; p < 0.01) and visceral fat (placebo 6.4 +/- 19.1 g, ephedrine -134 +/- 43 g; p < 0.01), with no change in lean mass or bone mineral content compared with the placebo group. In response to acute ephedrine, BAT activity (change in mean standardised uptake value: placebo -3 +/- 7%, ephedrine -22 +/- 6%) and the increase in systolic blood pressure were significantly reduced (p < 0.05) in the active group compared with placebo. CONCLUSIONS/INTERPRETATION: Chronic ephedrine treatment reduced body fat content, but this was not associated with an increase in BAT activity. Rather, chronic ephedrine suppressed BAT glucose disposal, suggesting that chronic ephedrine treatment decreased, rather than increased, BAT activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02236962 FUNDING: This study was funded by the National Health and Medical Research Council of Australia Program Grant (1036352) and the OIS scheme from the Victorian State Government. PMID- 25725627 TI - Impaired spatial working memory after anterior thalamic lesions: recovery with cerebrolysin and enrichment. AB - Lesions to the anterior thalamic nuclei (ATN) in rats produce robust spatial memory deficits that reflect their influence as part of an extended hippocampal system. Recovery of spatial working memory after ATN lesions was examined using a 30-day administration of the neurotrophin cerebrolysin and/or an enriched housing environment. As expected, ATN lesions in standard-housed rats given saline produced severely impaired reinforced spatial alternation when compared to standard-housed rats with sham lesions. Both cerebrolysin and enrichment substantially improved this working memory deficit, including accuracy on trials that required attention to distal cues for successful performance. The combination of cerebrolysin and enrichment was more effective than either treatment alone when the delay between successive runs in a trial was increased to 40 s. Compared to the intact rats, ATN lesions in standard-housed groups produced substantial reduction in c-Fos expression in the retrosplenial cortex, which remained low after cerebrolysin and enrichment treatments. Evidence that multiple treatment strategies restore some memory functions in the current lesion model reinforces the prospect for treatments in human diencephalic amnesia. PMID- 25725626 TI - Historical review of research on plant cell dedifferentiation. AB - Plant cell dedifferentiation has long attracted interest as a key process for understanding the plasticity of plant development. In early studies, typical examples of plant cell dedifferentiation were described as physiological and cytological changes associated with wound healing or regenerative development. Subsequently, plant tissue and cell culture techniques, in which exciting progress was achieved after discovery of the hormonal control of cell proliferation and organogenesis in vitro in the 1950s, have been used extensively to study dedifferentiation. The pioneer studies of plant tissue/cell culture led to the hypothesis that many mature plant cells retain totipotency and related dedifferentiation to the initial step of the expression of totipotency. Plant tissue/cell cultures have provided experimental systems not only for physiological analysis, but also for genetic and molecular biological analysis, of dedifferentiation. More recently, proteomic, transcriptomic, and epigenetic analyses have been applied to the study of plant cell dedifferentiation. All of these works have expanded our knowledge of plant cell dedifferentiation, and current research is contributing to unraveling the molecular mechanisms. The present article provides a brief overview of the history of research on plant cell dedifferentiation. PMID- 25725628 TI - Detecting COPD exacerbations early using daily telemonitoring of symptoms and k means clustering: a pilot study. AB - COPD places an enormous burden on the healthcare systems and causes diminished health-related quality of life. The highest proportion of human and economic cost is associated with admissions for acute exacerbation of respiratory symptoms (AECOPD). Since prompt detection and treatment of exacerbations may improve outcomes, early detection of AECOPD is a critical issue. This pilot study was aimed to determine whether a mobile health system could enable early detection of AECOPD on a day-to-day basis. A novel electronic questionnaire for the early detection of COPD exacerbations was evaluated during a 6-months field trial in a group of 16 patients. Pattern recognition techniques were applied. A k-means clustering algorithm was trained and validated, and its accuracy in detecting AECOPD was assessed. Sensitivity and specificity were 74.6 and 89.7 %, respectively, and area under the receiver operating characteristic curve was 0.84. 31 out of 33 AECOPD were early identified with an average of 4.5 +/- 2.1 days prior to the onset of the exacerbation that was considered the day of medical attendance. Based on the findings of this preliminary pilot study, the proposed electronic questionnaire and the applied methodology could help to early detect COPD exacerbations on a day-to-day basis and therefore could provide support to patients and physicians. PMID- 25725630 TI - Numerical assessment of bone remodeling around conventionally and early loaded titanium and titanium-zirconium alloy dental implants. AB - The aim of this study was to investigate conventionally and early loaded titanium and titanium-zirconium alloy implants by three-dimensional finite element stress analysis. Three-dimensional model of a dental implant was created and a thread area was established as a region of interest in trabecular bone to study a localized part of the global model with a refined mesh. The peri-implant tissues around conventionally loaded (model 1) and early loaded (model 2) implants were implemented and were used to explore principal stresses, displacement values, and equivalent strains in the peri-implant region of titanium and titanium-zirconium implants under static load of 300 N with or without 30 degrees inclination applied on top of the abutment surface. Under axial loading, principal stresses in both models were comparable for both implants and models. Under oblique loading, principal stresses around titanium-zirconium implants were slightly higher in both models. Comparable stress magnitudes were observed in both models. The displacement values and equivalent strain amplitudes around both implants and models were similar. Peri-implant bone around titanium and titanium-zirconium implants experiences similar stress magnitudes coupled with intraosseous implant displacement values under conventional loading and early loading simulations. Titanium-zirconium implants have biomechanical outcome comparable to conventional titanium implants under conventional loading and early loading. PMID- 25725629 TI - Effects of severity and location of stenosis on the hemodynamics in human aorta and its branches. AB - Pulsatile blood flow is studied in a three-dimensional model of human thoracic aorta at different stages of atherosclerotic lesion growth, taking into account the effect of atherosclerotic plaque location and peripheral symmetry. The model is reconstructed from the computed tomography images. The wall shear stress (WSS), time-averaged WSS, and the oscillatory shear index are applied to determine susceptible sites for the onset of early atherosclerosis. Then, two different degrees of stenosis severity, 50 and 80 %, are introduced to vulnerable areas of the healthy aorta geometry. The overriding issue addressed is that the WSS distribution and magnitude are strongly affected by the atherosclerotic plaque size, its symmetric features, and the location, i.e., the branch it is formed. The present study, for the first time, is capable of providing information on the high shear environment that may exist upon the rupture of plaque surface and any thrombosis due to platelet deposition. The magnitude of WSS and its distribution at the throat of 50 % stenosed aortic arch are in agreement with the previous numerical study (Huang et al. in Exp Fluids 48(3):497 508, 2010). Results show that WSS values exceed 50 Pa at the throat of 80 % stenosed left common carotid and brachiocephalic arteries. PMID- 25725631 TI - Effects of bioaugmentation in para-nitrophenol-contaminated soil on the abundance and community structure of ammonia-oxidizing bacteria and archaea. AB - Pseudomonas sp. strain WBC-3 mineralizes the priority pollutant para-nitrophenol (PNP) and releases nitrite (NO2 (-)), which is probably involved in the nitrification. In this study, the rate of PNP removal in soil bioaugmented with strain WBC-3 was more accelerated with more NO2 (-) accumulation than in uninoculated soils. Strain WBC-3 survived well and remained stable throughout the entire period. Real-time polymerase chain reaction (real-time PCR) indicated a higher abundance of ammonia-oxidizing bacteria (AOB) than ammonia-oxidizing archaea (AOA), suggesting that AOB played a greater role in nitrification in the original sampled soil. Real-time PCR and multivariate analysis based on the denaturing gradient gel electrophoresis showed that PNP contamination did not significantly alter the abundance and community structure of ammonia oxidizers except for inhibiting the AOB abundance. Bioaugmentation of PNP-contaminated soil showed a significant effect on AOB populations and community structure as well as AOA populations. In addition, ammonium (NH4 (+)) variation was found to be the primary factor affecting the AOB community structure, as determined by the correlation between the community structures of ammonia oxidizers and environmental factors. It is here proposed that the balance between archaeal and bacterial ammonia oxidation could be influenced significantly by the variation in NH4 (+) levels as caused by bioaugmentation of contaminated soil by a pollutant containing nitrogen. PMID- 25725632 TI - 4-Hydroxyisoleucine production of recombinant Corynebacterium glutamicum ssp. lactofermentum under optimal corn steep liquor limitation. AB - 4-Hydroxyisoleucine (4-HIL) is a nonproteinogenic amino acid that exhibits insulinotropic biological activity. Here, L-isoleucine dioxygenase gene (ido) derived from Bacillus thuringiensis YBT-1520 was cloned and expressed in an L isoleucine-producing strain, Corynebacterium glutamicum ssp. lactofermentum SN01, in order to directly convert its endogenous L-isoleucine (Ile) into 4-HIL through single-step fermentation. The effects of corn steep liquor limitation as well as ido and truncated idoDelta6 overexpression on 4-HIL production were researched. 4 HIL production by ido-overexpressing strain was improved to 65.44 +/- 2.27 mM after fermented for 144 h under corn steep liquor-subsufficient condition, obviously higher than that under corn steep liquor-rich and insufficient conditions. The conversion ratio of Ile to 4-HIL increased to 0.85 mol/mol. In addition, 4-HIL production by ido-overexpressing strain was higher than that by idoDelta6-overexpressing strain, in accord with the relatively higher affinity of Ido as compared to IdoDelta6. This research generated a novel system for 4-HIL de novo biosynthesis and demonstrated corn steep liquor limitation as a useful strategy for improving 4-HIL production in recombinant C. glutamicum ssp. lactofermentum. PMID- 25725633 TI - Erratum to: Use of a whole-cell bioreporter, Acinetobacter baylyi, to estimate the genotoxicity and bioavailability of chromium(VI)-contaminated soils. PMID- 25725634 TI - Clinical and laboratory characteristics of active and healthy aging (AHA) in octogenarian men. AB - OBJECTIVES: To investigate clinical and laboratory variables associated with good subjective and objective health ("active and healthy aging", AHA) in a cohort of octogenarian men. DESIGN: Cross-sectional analyses of a longitudinal study. SETTING: The Helsinki Businessmen Study in Finland. PARTICIPANTS: A socioeconomically homogenous cohort of men (baseline n = 3293), born in 1919 1934, has been followed up from the 1960s. From 2000, the men have been regularly sent mailed questionnaires and mortality has been retrieved from national registers. MEASUREMENTS: In 2010 survey, AHA was defined as independently responding to the mailed survey, feeling happy without cognitive or functional impairments and without major diseases. In 2010/11, a random subgroup men was clinically investigated and survivors with healthy and nonhealthy aging were compared. RESULTS: By 2010, 1788 men of the baseline cohort had died, and 894 men responded to the mailed survey. 154 (17.2 %) of those fulfilled the present AHA criteria. Increasing number of criteria were negatively (P < 0.001) related to short-term mortality. In 2011, a random sample of 458 men were clinically investigated, 90 of them with AHA. Men with AHA had higher serum LDL cholesterol and diastolic blood pressure (partially explained by less frequent drug use) but no significant difference was observed in other risk factors. Men with AHA had significantly faster walking speed (P < 0.001), stronger handgrip (P = 0.017), better self-rated health and less phenotypic frailty (P = 0.02). CONCLUSION: Less than 5 % enjoyed active and healthy aging over their life course, which was significantly related to markers of frailty but not to the traditional vascular risk factors. PMID- 25725635 TI - Liraglutide-related cholelithiasis. AB - Liraglutide is a glucagon-like peptide-1 analog and recently started to be using as an incretin-based treatment for diabetes mellitus. Liraglutide causes some adverse affects including nausea, vomiting, acute nasopharyngitis and acute pancreatitis. However, development of liraglutide-dependent cholelithiasis has not been reported in the literature. A 75-year-old female patient had been diagnosed with type 2 diabetes mellitus for 10 years and she has been treated by liraglutide for 6 months. The patient was admitted to the emergency service due to sudden onset of abdominal pain. After laboratory and imaging studies, she was diagnosed with acute cholecystitis and cholelithiasis. And then patient's oral intake was stopped, intravenous fluid and ceftriaxone 2 g/day were started. Furthermore, liraglutide treatment discontinued and ursodeoxycholic acid (UDCA) was started to treat cholelithiasis. During follow-up, abdominal pain completely relieved. Hepatobiliary ultrasonography in sixth month follow-up showed entirely regression of cholelithiasis. Any liraglutide-related cholelithiasis case has not been reported in the literature previously. Therefore, our case is the first case. Especially, elderly diabetic patients who are started to liraglutide treatment should be monitored closely for the formation of cholelithiasis. UDCA treatment would be an alternative prior to surgical treatment for liraglutide related cholelithiasis. PMID- 25725636 TI - The international contribution to occupational health research. AB - OBJECTIVE: The importance of international occupational health research is established in achieving the World Health Organization's vision of "occupational health for all". The aim of this short communication is to describe the geographical distribution of research published in leading occupational health journals. METHODS: Seven leading occupational health journals were identified, based on citation rates and impact factors. All research papers published in these journals in 2011 and 2012 were identified and attributed to a country, based on the affiliation of the first author. The crude rate and rates adjusted by GDP and population were calculated for each country. RESULTS: A total of 1466 papers were identified, with first authors based in 56 different countries. Over half of the papers were published by first authors based in 4 countries (USA, UK, the Netherlands and Japan). The leading 10 countries contributed 76% of the total number of papers and the leading 20 countries 94%. Of the 1466 papers, 89% were published by authors based in high-income countries. An analysis of the adjusted rates of publications by population and GDP revealed dominance by the Scandinavian countries. CONCLUSIONS: The data are consistent with results of previous studies showing that a large proportion of papers are produced by researchers in the USA, but that the highest rates adjusted by GDP are from Scandinavian countries and the Netherlands. This indicates that a small number of countries continue to dominate research published in leading occupational health journals. As a result, the areas of research risk being biased to the needs of those countries rather than the wider international community. PMID- 25725637 TI - Chaos in an imperfectly premixed model combustor. AB - This article reports nonlinear bifurcations observed in a laboratory scale, turbulent combustor operating under imperfectly premixed mode with global equivalence ratio as the control parameter. The results indicate that the dynamics of thermoacoustic instability correspond to quasi-periodic bifurcation to low-dimensional, deterministic chaos, a route that is common to a variety of dissipative nonlinear systems. The results support the recent identification of bifurcation scenarios in a laminar premixed flame combustor (Kabiraj et al., Chaos: Interdiscip. J. Nonlinear Sci. 22, 023129 (2012)) and extend the observation to a practically relevant combustor configuration. PMID- 25725638 TI - Brand effect versus competitiveness in hypernetworks. AB - A few of evolving models in hypernetworks have been proposed based on uniform growth. In order to better depict the growth mechanism and competitive aspect of real hypernetworks, we propose a model in term of the non-uniform growth. Besides hyperdegrees, the other two important factors are introduced to underlie preferential attachment. One dimension is the brand effect and the other is the competitiveness. Our model can accurately describe the evolution of real hypernetworks. The paper analyzes the model and calculates the stationary average hyperdegree distribution of the hypernetwork by using Poisson process theory and a continuous technique. We also address the limit in which this model has a condensation. The theoretical analyses agree with numerical simulations. Our model is universal, in that the standard preferential attachment, the fitness model in complex networks and scale-free model in hypernetworks can all be seen as degenerate cases of the model. PMID- 25725639 TI - Determination of multifractal dimensions of complex networks by means of the sandbox algorithm. AB - Complex networks have attracted much attention in diverse areas of science and technology. Multifractal analysis (MFA) is a useful way to systematically describe the spatial heterogeneity of both theoretical and experimental fractal patterns. In this paper, we employ the sandbox (SB) algorithm proposed by Tel et al. (Physica A 159, 155-166 (1989)), for MFA of complex networks. First, we compare the SB algorithm with two existing algorithms of MFA for complex networks: the compact-box-burning algorithm proposed by Furuya and Yakubo (Phys. Rev. E 84, 036118 (2011)), and the improved box-counting algorithm proposed by Li et al. (J. Stat. Mech.: Theor. Exp. 2014, P02020 (2014)) by calculating the mass exponents tau(q) of some deterministic model networks. We make a detailed comparison between the numerical and theoretical results of these model networks. The comparison results show that the SB algorithm is the most effective and feasible algorithm to calculate the mass exponents tau(q) and to explore the multifractal behavior of complex networks. Then, we apply the SB algorithm to study the multifractal property of some classic model networks, such as scale free networks, small-world networks, and random networks. Our results show that multifractality exists in scale-free networks, that of small-world networks is not obvious, and it almost does not exist in random networks. PMID- 25725640 TI - Controllability and observability of Boolean networks arising from biology. AB - Boolean networks are currently receiving considerable attention as a computational scheme for system level analysis and modeling of biological systems. Studying control-related problems in Boolean networks may reveal new insights into the intrinsic control in complex biological systems and enable us to develop strategies for manipulating biological systems using exogenous inputs. This paper considers controllability and observability of Boolean biological networks. We propose a new approach, which draws from the rich theory of symbolic computation, to solve the problems. Consequently, simple necessary and sufficient conditions for reachability, controllability, and observability are obtained, and algorithmic tests for controllability and observability which are based on the Grobner basis method are presented. As practical applications, we apply the proposed approach to several different biological systems, namely, the mammalian cell-cycle network, the T-cell activation network, the large granular lymphocyte survival signaling network, and the Drosophila segment polarity network, gaining novel insights into the control and/or monitoring of the specific biological systems. PMID- 25725641 TI - Experimental study of complex mixed-mode oscillations generated in a Bonhoeffer van der Pol oscillator under weak periodic perturbation. AB - Bifurcations of complex mixed-mode oscillations denoted as mixed-mode oscillation incrementing bifurcations (MMOIBs) have frequently been observed in chemical experiments. In a previous study [K. Shimizu et al., Physica D 241, 1518 (2012)], we discovered an extremely simple dynamical circuit that exhibits MMOIBs. Our model was represented by a slow/fast Bonhoeffer-van der Pol circuit under weak periodic perturbation near a subcritical Andronov-Hopf bifurcation point. In this study, we experimentally and numerically verify that our dynamical circuit captures the essence of the underlying mechanism causing MMOIBs, and we observe MMOIBs and chaos with distinctive waveforms in real circuit experiments. PMID- 25725642 TI - Exotic equilibria of Harary graphs and a new minimum degree lower bound for synchronization. AB - This work is concerned with stability of equilibria in the homogeneous (equal frequencies) Kuramoto model of weakly coupled oscillators. In 2012 [R. Taylor, J. Phys. A: Math. Theor. 45, 1-15 (2012)], a sufficient condition for almost global synchronization was found in terms of the minimum degree-order ratio of the graph. In this work, a new lower bound for this ratio is given. The improvement is achieved by a concrete infinite sequence of regular graphs. Besides, non standard unstable equilibria of the graphs studied in Wiley et al. [Chaos 16, 015103 (2006)] are shown to exist as conjectured in that work. PMID- 25725643 TI - Hierarchical clustering in minimum spanning trees. AB - The identification of clusters or communities in complex networks is a reappearing problem. The minimum spanning tree (MST), the tree connecting all nodes with minimum total weight, is regarded as an important transport backbone of the original weighted graph. We hypothesize that the clustering of the MST reveals insight in the hierarchical structure of weighted graphs. However, existing theories and algorithms have difficulties to define and identify clusters in trees. Here, we first define clustering in trees and then propose a tree agglomerative hierarchical clustering (TAHC) method for the detection of clusters in MSTs. We then demonstrate that the TAHC method can detect clusters in artificial trees, and also in MSTs of weighted social networks, for which the clusters are in agreement with the previously reported clusters of the original weighted networks. Our results therefore not only indicate that clusters can be found in MSTs, but also that the MSTs contain information about the underlying clusters of the original weighted network. PMID- 25725644 TI - Network synchronization of time-delayed coupled nonlinear systems using predictor based diffusive dynamic couplings. AB - We study the problem of controlled network synchronization of coupled semipassive systems in the case when the outputs (the coupling variables) and the inputs are subject to constant time-delay (as it is often the case in a networked context). Predictor-based dynamic output feedback controllers are proposed to interconnect the systems on a given network. Using Lyapunov-Krasovskii functional and the notion of semipassivity, we prove that under some mild assumptions, the solutions of the interconnected systems are globally ultimately bounded. Sufficient conditions on the systems to be interconnected, on the network topology, on the coupling dynamics, and on the time-delays that guarantee global state synchronization are derived. A local analysis is provided in which we compare the performance of our predictor-based control scheme against the existing static diffusive couplings available in the literature. We show (locally) that the time delay that can be induced to the network may be increased by including the predictors in the loop. The results are illustrated by computer simulations of coupled Hindmarsh-Rose neurons. PMID- 25725645 TI - Modulational instability of co-propagating internal wavetrains under rotation. AB - Weakly-nonlinear unidirectional long internal waves in a non-rotating frame are well described by the Korteweg-de Vries equation (KdV). Within the KdV framework, all isolated monochromatic wavetrains are stable to modulational instability. However, analysis of a coupled nonlinear Schrodinger equation system (CNLS) has shown that all systems of two co-propagating monochromatic wavetrains in the KdV are modulationally unstable. To take into account the effect of the background rotation of the Earth on long internal waves, this analysis is extended here to derive the CNLS for the rotation-modified KdV, or Ostrovsky, equation. Rotation stabilises wavetrain pairs when the wavelengths of both waves comprising the wavetrains are longer than the linear wave with maximum group velocity. The particular case when the wavetrains have different wavenumbers but the same linear group speed is emphasised. PMID- 25725646 TI - Phase and amplitude dynamics of nonlinearly coupled oscillators. AB - This paper addresses the amplitude and phase dynamics of a large system of nonlinearly coupled, non-identical damped harmonic oscillators, which is based on recent research in coupled oscillation in optomechanics. Our goal is to investigate the existence and stability of collective behaviour which occurs due to a play-off between the distribution of individual oscillator frequency and the type of nonlinear coupling. We show that this system exhibits synchronisation, where all oscillators are rotating at the same rate, and that in the synchronised state the system has a regular structure related to the distribution of the frequencies of the individual oscillators. Using a geometric description, we show how changes in the non-linear coupling function can cause pitchfork and saddle node bifurcations which create or destroy stable and unstable synchronised solutions. We apply these results to show how in-phase and anti-phase solutions are created in a system with a bi-modal distribution of frequencies. PMID- 25725647 TI - Distance metric learning for complex networks: towards size-independent comparison of network structures. AB - Real networks show nontrivial topological properties such as community structure and long-tail degree distribution. Moreover, many network analysis applications are based on topological comparison of complex networks. Classification and clustering of networks, model selection, and anomaly detection are just some applications of network comparison. In these applications, an effective similarity metric is needed which, given two complex networks of possibly different sizes, evaluates the amount of similarity between the structural features of the two networks. Traditional graph comparison approaches, such as isomorphism-based methods, are not only too time consuming but also inappropriate to compare networks with different sizes. In this paper, we propose an intelligent method based on the genetic algorithms for integrating, selecting, and weighting the network features in order to develop an effective similarity measure for complex networks. The proposed similarity metric outperforms state of the art methods with respect to different evaluation criteria. PMID- 25725648 TI - Interactions of bright and dark solitons with localized PT-symmetric potentials. AB - We study collisions of moving nonlinear-Schrodinger solitons with a PT-symmetric dipole embedded into the one-dimensional self-focusing or defocusing medium. Accurate analytical results are produced for bright solitons, and, in a more qualitative form, for dark ones. In the former case, an essential aspect of the approximation is that it must take into regard the intrinsic chirp of the soliton, thus going beyond the framework of the simplest quasi-particle description of the soliton's dynamics. Critical velocities separating reflection and transmission of the incident bright solitons are found by means of numerical simulations, and in the approximate semi-analytical form. An exact solution for the dark soliton pinned by the complex PT-symmetric dipole is produced too. PMID- 25725649 TI - Oseledets' splitting of standard-like maps. AB - For the class of differentiable maps of the plane and, in particular, for standard-like maps (McMillan form), a simple relation is shown between the directions of the local invariant manifolds of a generic point and its contribution to the finite-time Lyapunov exponents (FTLE) of the associated orbit. By computing also the point-wise curvature of the manifolds, we produce a comparative study between local Lyapunov exponent, manifold's curvature and splitting angle between stable/unstable manifolds. Interestingly, the analysis of the Chirikov-Taylor standard map suggests that the positive contributions to the FTLE average mostly come from points of the orbit where the structure of the manifolds is locally hyperbolic: where the manifolds are flat and transversal, the one-step exponent is predominantly positive and large; this behaviour is intended in a purely statistical sense, since it exhibits large deviations. Such phenomenon can be understood by analytic arguments which, as a by-product, also suggest an explicit way to point-wise approximate the splitting. PMID- 25725650 TI - Diffusion and mobility of anisotropic particles in tilted periodic structures. AB - We numerically investigated the transport of anisotropic particles in tilted periodic structures. The diffusion and mobility of the particles demonstrate distinct behaviors dependence on the shape of the particles. In two-dimensional (2D) periodic potentials, we find that the mobility is influenced a little by the anisotropy of the particle, while the diffusion increases monotonically with the increasing of the particle anisotropy for large enough biased force. However, due to the sensitivity of the channels for the particle anisotropy, the transport in smooth channels is obviously different from that in energy potentials. The mobility decreases monotonically with the increasing of the particle anisotropy, while the diffusion can be a non-monotonic function of the particle anisotropy with a peak under appropriate biased force. PMID- 25725651 TI - Subharmonic generation, chaos, and subharmonic resurrection in an acoustically driven fluid-filled cavity. AB - Traveling wave solutions of the nonlinear acoustic wave equation are obtained for the fundamental and second harmonic resonances of a fluid-filled cavity. The solutions lead to the development of a non-autonomous toy model for cavity oscillations. Application of the Melnikov method to the model equation predicts homoclinic bifurcation of the Smale horseshoe type leading to a cascade of period doublings with increasing drive displacement amplitude culminating in chaos. The threshold value of the drive displacement amplitude at tangency is obtained in terms of the acoustic drive frequency and fluid attenuation coefficient. The model prediction of subharmonic generation leading to chaos is validated from acousto-optic diffraction measurements in a water-filled cavity using a 5 MHz acoustic drive frequency and from the measured frequency spectrum in the bifurcation cascade regime. The calculated resonant threshold amplitude of 0.2 nm for tangency is consistent with values estimated for the experimental set-up. Experimental evidence for the appearance of a stable subharmonic beyond chaos is reported. PMID- 25725652 TI - Dynamic changes in network synchrony reveal resting-state functional networks. AB - Experimental functional magnetic resonance imaging studies have shown that spontaneous brain activity, i.e., in the absence of any external input, exhibit complex spatial and temporal patterns of co-activity between segregated brain regions. These so-called large-scale resting-state functional connectivity networks represent dynamically organized neural assemblies interacting with each other in a complex way. It has been suggested that looking at the dynamical properties of complex patterns of brain functional co-activity may reveal neural mechanisms underlying the dynamic changes in functional interactions. Here, we examine how global network dynamics is shaped by different network configurations, derived from realistic brain functional interactions. We focus on two main dynamics measures: synchrony and variations in synchrony. Neural activity and the inferred hemodynamic response of the network nodes are simulated using a system of 90 FitzHugh-Nagumo neural models subject to system noise and time-delayed interactions. These models are embedded into the topology of the complex brain functional interactions, whose architecture is additionally reduced to its main structural pathways. In the simulated functional networks, patterns of correlated regional activity clearly arise from dynamical properties that maximize synchrony and variations in synchrony. Our results on the fast changes of the level of the network synchrony also show how flexible changes in the large scale network dynamics could be. PMID- 25725653 TI - Commentary on "clinical characteristics and adequate treatment of familial adenomatous polyposis combined with desmoid tumors". PMID- 25725654 TI - Reply to commentary on "clinical characteristics and adequate treatment of familial adenomatous polyposis combined with desmoid tumors". PMID- 25725655 TI - New activity-based funding model for Australian private sector overnight rehabilitation cases: the rehabilitation Australian National Sub-Acute and Non Acute Patient (AN-SNAP) model. AB - Traditional overnight rehabilitation payment models in the private sector are not based on a rigorous classification system and vary greatly between contracts with no consideration of patient complexity. The payment rates are not based on relative cost and the length-of-stay (LOS) point at which a reduced rate applies (step downs) varies markedly. The rehabilitation Australian National Sub-Acute and Non-Acute Patient (AN-SNAP) model (RAM), which has been in place for over 2 years in some private hospitals, bases payment on a rigorous classification system, relative cost and industry LOS. RAM is in the process of being rolled out more widely. This paper compares and contrasts RAM with traditional overnight rehabilitation payment models. It considers the advantages of RAM for hospitals and Australian Health Service Alliance. It also considers payment model changes in the context of maintaining industry consistency with Electronic Claims Lodgement and Information Processing System Environment (ECLIPSE) and health reform generally. PMID- 25725657 TI - Measuring what matters: quality in gynecologic surgery. PMID- 25725656 TI - Gynecological manifestations, histopathological findings, and schistosoma specific polymerase chain reaction results among women with Schistosoma haematobium infection: a cross-sectional study in Madagascar. AB - BACKGROUND: The pathophysiology of female genital schistosomiasis (FGS) is only partially understood. This study aims to describe the histopathological findings, polymerase chain reaction (PCR) results, and gynecological manifestations of FGS in women with different intensities of Schistosoma haematobium infection. METHODS: Women aged 15-35 years living in an S. haematobium-endemic area in Madagascar underwent pelvic and colposcopic examinations. Small biopsy specimens were obtained from lesions and examined histopathologically. Schistosoma PCR was done on urine, biopsy, cervicovaginal lavage, and genital mucosal surface specimens. RESULTS: Sandy patches and rubbery papules were found in 41 of 118 women (35%). Rubbery papules reflected an intense cellular immune reaction dominated by eosinophils, epithelial erosion, and viable ova. There was a significant decrease in the prevalence of rubbery papules with age, even after adjustment for urinary ova excretion. The sandy patches with grains showed moderate cellular immune reaction and ova (viable and/or calcified). They were most prevalent in cases with low-intensity urinary S. haematobium infection. Forty-two percent of women with Schistosoma-negative urine specimens had at least 1 genital specimen test positive for Schistosoma by PCR. CONCLUSIONS: The results indicate a diversity of lesions caused by S. haematobium and a dynamic evolution of the genital lesions. Schistosoma PCR may give an indication of the diagnosis. PMID- 25725658 TI - Induction of labor versus expectant management for women with a prior cesarean delivery. AB - OBJECTIVE: Previous studies of induction of labor in the setting of trial of labor after cesarean have compared women undergoing trial of labor after cesarean to those undergoing spontaneous labor. However, the clinically relevant comparison is to those undergoing expectant management. The objective of this study was to compare obstetric outcomes between women undergoing induction of labor and those undergoing expectant management >=39 weeks of gestation. STUDY DESIGN: This was a secondary analysis of data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Cesarean Registry that included women with singleton gestations at a gestational age of >=39 weeks and a history of 1 low transverse cesarean delivery. Outcomes of induction at 39, 40, and 41 weeks were compared to expectant management beyond each gestational age period using univariable and multivariable analyses. Women with scheduled repeat cesarean deliveries done for the indication of prior cesarean delivery were excluded from the analysis. RESULTS: In all, 12,676 women were eligible for analysis. The rate of vaginal birth after cesarean (VBAC) was higher among women undergoing induction of labor at 39 weeks compared to expectant management (73.8% vs 61.3%, P < .001). The risk of uterine rupture also was higher among women undergoing induction of labor at 39 weeks compared to expectant management (1.4% vs 0.5%, P = .006, respectively). In multivariable analysis, induction of labor at 39 weeks remained associated with a significantly higher chance of VBAC and uterine rupture (odds ratio, 1.31; 95% confidence interval, 1.03-1.67; and odds ratio, 2.73; 95% confidence interval, 1.22-6.12, respectively). CONCLUSION: Induction of labor at 39 weeks, when compared to expectant management, was associated with a higher chance of VBAC but also of uterine rupture. PMID- 25725659 TI - Weight gain in pregnancy: does the Institute of Medicine have it right? AB - OBJECTIVE: We aimed to examine whether women who adhered to Institute of Medicine (IOM) guidelines for gestational weight gain (GWG) had improved perinatal outcomes. STUDY DESIGN: This is a population-based retrospective cohort study of nulliparous women with term singleton vertex births in the United States from 2011 through 2012. Women with medical or obstetric complications were excluded. Prepregnancy body mass index was calculated using reported weight and height. Women were categorized into 4 groups based on GWG and prepregnancy body mass index: (1) weight gain less than, (2) weight gain within, (3) weight gain 1-19 lb in excess of, and (4) weight gain >=20 lb in excess of the IOM guidelines. The chi(2) test and multivariable logistic regression analysis were used for statistical comparisons. RESULTS: Compared to women who had GWG within the IOM guidelines, women with excessive weight gain, particularly >=20 lb, were more likely to have adverse maternal outcomes (preeclampsia: adjusted odds ratio [aOR], 2.78; 95% confidence interval [CI], 2.82-2.93; eclampsia: aOR, 2.51; 95% CI, 2.27-2.78; cesarean: aOR, 2.1; 95% CI, 2.14-2.19), blood transfusion (aOR, 1.22; 95% CI, 1.11-1.33), and neonatal outcomes (5-minute Apgar <4: aOR, 1.22; 95% CI, 1.14-1.31; ventilation use >6 hours: aOR, 1.24; 95% CI, 1.15-1.33; seizure: aOR, 1.53; 95% CI, 1.24-1.89). Women who gained less than IOM guidelines had lower risks of hypertensive disorders of pregnancy and obstetric interventions but were more likely to have small-for-gestational-age neonates (aOR, 1.55; 95% CI, 1.52-1.59). CONCLUSION: Women whose GWG is in excess of IOM guidelines have higher risk of adverse maternal and neonatal outcomes, particularly in women with >=20 lb excess weight gain above guidelines while women who had weight gain below the IOM guidelines were less likely to have maternal morbidity but had higher odds of small for gestational age. PMID- 25725661 TI - Musculoskeletal disorder (MSD) among agricultural workers. AB - Farming is a large and main industry in Bangladesh. Large numbers of people are directly involved in farming and have very unique exposure compare to other sectors. Musculoskeletal problems among farmer population are not infrequent. This study was carried out among 200 farmers in one selected district. The study revealed that musculoskeletal problems were common among the farmers working in a traditional way. All the respondents were male. The age of all respondents lie between 20-60 years. Among them 22.5% farmers were illiterate, about 45.5% below Class V. About half (42%) of the respondents had reported pain in different parts of the body at least one or more times during working in land. And about two third (65.5%) of the farmers had history of joint pain and stiffness in last 12 month. Most of the farmers who suffered from musculoskeletal symptoms were 41-60 years. Specially who worked more then 20 years (82.6%) and average 6 hours per day (66.7%). The occurrence of musculoskeletal problems in various part of the body included Knee pain - 48.1%, Back pain (back ache) - 22.9%, Waist pain (low back ache) - 13.3%, Neck pain - 18.3% and shoulder pain - 10.7%. Length of work in year and daily average working hours were found significant association with musculoskeletal pain. It was found that musculoskeletal pain were more common among the farmers when they worked in squatting position (52%) and specially during weeding of plants (31%). Among them only 22% also engaged in other business. Most of the farmers complained dull aching pain (40.6%), only 2.3% noticed severe acute pain, but about 86% farmers' temporary stop their work for pain and 80% get relief after discontinue of work. About 75% respondents visited doctors for their pain which was statistically significant (p=0.001). It was found that the rates of musculoskeletal complaints are more among those individuals who worked relatively bad ergonomic condition, such as body position probably play an important role. PMID- 25725662 TI - Placental changes in pregnancy induced hypertension and its impacts on fetal outcome. AB - A descriptive cross sectional study was carried out in the Gynae and Obstetrics & Pathology department of Mymensingh Medical College & Hospital (MMCH) to see the placental changes in normal & pregnancy induced hypertension (PIH) and its impacts on fetus for one year period. Total 80 placentas were collected, 40 from normal pregnant mothers having no hypertension and 40 from PIH group (one from gestational hypertension, 17 from pre-eclampsia and 22 from eclampsia. Macroscopic study of the placenta revealed placental weight, surface area and number of cotyledons were less in study group. Mean placental weight in study group was 419.50gm and in control group was 477.50 (p<0.001). Mean surface area in study group & control group were 232.29cm2 and 304.80cm2 respectively (p<0.001). Mean number of cotyledons were 15.39 and 17.40 in study & control group respectively (P<0.001) and lower diameter of umbilical cord (p<0.04667). But in the present study placental thickness was not significant (p<0.539). There was a single umbilical artery present in one patient in PIH group .In PIH group syncytial knots (95%), fibrinoid necrosis (80%), VSM (vasculosyncytial membrane) formation, sclerosis, chorangiosis and calcification were more marked. Infarction was present in placenta of PIH 34(85%) and in control group 8(20%). There was a tendency of lowering the weight of neonate 2.47kg in study group and 3.06kg in control group (p<0.001), number of asphyxiated babies and perinatal morbidity and mortality( still birth was 7.5 and neonatal death was 15%) were more marked in PIH group. In PIH group placental changes were related with fetal outcome. Common placental changes were significant in this study. PMID- 25725660 TI - Vitamin C supplementation ameliorates the adverse effects of nicotine on placental hemodynamics and histology in nonhuman primates. AB - OBJECTIVE: We previously demonstrated that prenatal nicotine exposure decreases neonatal pulmonary function in nonhuman primates, and maternal vitamin C supplementation attenuates these deleterious effects. However, the effect of nicotine on placental perfusion and development is not fully understood. This study utilizes noninvasive imaging techniques and histological analysis in a nonhuman primate model to test the hypothesis that prenatal nicotine exposure adversely effects placental hemodynamics and development but is ameliorated by vitamin C. STUDY DESIGN: Time-mated macaques (n = 27) were divided into 4 treatment groups: control (n = 5), nicotine only (n = 4), vitamin C only (n = 9), and nicotine plus vitamin C (n = 9). Nicotine animals received 2 mg/kg per day of nicotine bitartrate (approximately 0.7 mg/kg per day free nicotine levels in pregnant human smokers) from days 26 to 160 (term, 168 days). Vitamin C groups received ascorbic acid at 50, 100, or 250 mg/kg per day with or without nicotine. All underwent placental dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) at 135-140 days and Doppler ultrasound at 155 days to measure uterine artery and umbilical vein velocimetry and diameter to calculate uterine artery volume blood flow and placental volume blood flow. Animals were delivered by cesarean delivery at 160 days. A novel DCE-MRI protocol was utilized to calculate placental perfusion from maternal spiral arteries. Placental tissue was processed for histopathology. RESULTS: Placental volume blood flow was significantly reduced in nicotine-only animals compared with controls and nicotine plus vitamin C groups (P = .03). Maternal placental blood flow was not different between experimental groups by DCE-MRI, ranging from 0.75 to 1.94 mL/mL per minute (P = .93). Placental histology showed increased numbers of villous cytotrophoblast cell islands (P < .05) and increased syncytiotrophoblast sprouting (P < .001) in nicotine-only animals, which was mitigated by vitamin C. CONCLUSION: Prenatal nicotine exposure significantly decreased fetal blood supply via reduced placental volume blood flow, which corresponded with placental histological findings previously associated with cigarette smoking. Vitamin C supplementation mitigated the harmful effects of prenatal nicotine exposure on placental hemodynamics and development, suggesting that its use may limit some of the adverse effects associated with smoking during pregnancy. PMID- 25725663 TI - Prevalence of microalbuminuria in relation to glycemic control in type-2 diabetic patients in Mymensingh. AB - Microalbuminuria is a renal marker of generalized vascular endothelial damage and early atherosclerosis. Patients with microalbuminuria are at increased risk of microvascular and macrovascular complications of diabetes mellitus like myocardial infarction, stroke and nephropathy. Poor glycemic control increases the risk of microalbuminuria. This study was conducted to determine the frequency of microalbuminuria in type 2 diabetes and compare the frequency of microalbuminuria in poor and good glycemic control in type 2 diabetes. One Hundred and twenty two type 2 diabetic patients were included in the study. Data on age, gender, duration of diabetes, microalbuminuria and HbA1c were recorded. Urine and blood samples were collected and analyzed for microalbuminuria, blood glucose and HbA1c. All patients of both genders with type 2 diabetes for over 2 years were selected in this study. Patients with other causes of proteinuria were excluded. Out of 120 cases 93(77.5%) were male and 27(22.5%) were female. Mean age of patients was 57.8+/-14.7 years and average duration of diabetes was 9.2 years. Microalbuminuria was found 76.9% of male and 23.1% of female. Patients with poor glycemic control and good glycemic control have frequency of microalbuminuria of 55% and 54% respectively. Uncontrolled diabetes is strongly associated with prevalence of microalbuminuria. Screening for microalbuminuria and HbA1c test should be done both in newly and already diagnosed type 2 diabetic patients as an early marker of renal dysfunction and glycemic control. PMID- 25725664 TI - Morphometric study of dentate nucleus of cerebellum in Bangladeshi cadaver. AB - This cross sectional descriptive study was done by using nonprobability sampling technique and performed by examining 63 (sixty three) cerebellum. Out of them 40 postmortem human cerebellum collected from Bangladeshi cadavers of both sexes (male 25 and female 15) age ranging from 5 to 60 years and 23 cerebellums from caesarian section of intrauterine death cases of both sexes (male 14 and female 9) age ranging from 34 to 41 weeks of gestation. Specimens were collected from dead bodies autopsied on different dates from April' 2009 to September' 2009 at the autopsy laboratory of department of Forensic Medicine and prenatal cases from Gynaecology and Obstetrics Department of Mymensingh Medical College, Mymensingh. The collected specimens were grouped into three age groups like Group A (28 to 42 weeks of gestation), Group B (5 to 30 years) and Group C (31 to 60 years) and, two sex groups (male and female) and two sides (right and left). A transverse section was made at the level of horizontal fissure, and length and breadth of dentate nucleus were measured by divider and scale. The mean (+/-SD) length and breadth of dentate nucleus was 8.619+/-2.995mm and 14.770+/-3.604mm respectively and it was observed that length and breadth of dentate nucleus increased with age upto certain level then slightly decreased in the late age Group C. In this study, differences of the mean length of dentate nucleus on both right and left sides were statistically moderately significant between age Groups A&B. The differences of mean breadth of dentate nucleus on both right and left side were statistically highly significant between age Groups A&B and moderately significant between age Groups A&C on right side and only significant on left side. The differences between male & female were statistically insignificant in length and breadth of dentate nucleus. PMID- 25725665 TI - Blood pressure and serum creatinine in obese female. AB - Obesity is increasing in developed as well as in developing countries. This analytical cross sectional study was carried out to document the relation between blood pressure, serum creatinine and body mass index in female and to assess potential health differences among obese female and normal weight female. This study was done in the Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh from July 2012 to June 2013. Seventy female persons volunteered as subjects. Among them 35 were within normal weight (BMI 18.5 24.9kg/m2) and 35 were obese (BMI>=30kg/m2). Non probability purposive type of sampling technique was used to select the subjects. Measurement of body mass index and blood pressure were done as per procedure. Serum creatinine level was estimated by enzymatic colorimetric method. The results were calculated and analyzed by using SPSS (statistical package for social science, version 17.0), scientific electronic calculator and simultaneously with a computer assisted program like Microsoft excel. Unpaired 't' test was applied to find the significance of difference regarding serum creatinine and blood pressure levels in obese female. The value of p was 1% to indicate highly significant and 5% to indicate simply significant or statistically significant. The mean+/-SE of systolic blood pressure, diastolic blood pressure and serum creatinine levels were 135.71+/-1.58mmHg, 88.74+/-0.95mmHg and 1.03+/-0.01mg/dl respectively; significant at 1% level for obese group of BMI (p<0.0001). The examinations and biochemical investigations revealed that high BMI is significantly related to increased levels of serum creatinine & blood pressure in obese female which indicate the obese subjects are prone to cardiovascular & metabolic risk. PMID- 25725666 TI - Acute inferior myocardial infarction with right ventricular infarction is more prone to develop cardiogenic shock. AB - Cardiogenic shock is rare in isolated acute inferior myocardial infarction but there is relationship of cardiogenic shock with inferior myocardial infarction if associated with right ventricular infarction. A prospective study was carried out to see the association of cardiogenic shock with inferior myocardial infarction if associated with right ventricular infarction. This study was conducted from January 2011 to November 2011. A total of 100 cases were selected as study population which was taken from the Department of Cardiology, Mymensingh Medical College Hospital, Mymensingh, Bangladesh. Among them 50 were in Group A and 50 were in Group B. Group A was the patients of acute myocardial infarction with right ventricular infarction. Group B was the patients of acute myocardial infarction without right ventricular infarction. It revealed that 9(18%) in Group A and 3(6%) in Group B developed cardiogenic shock which is statistically significant (p<0.05). The study concluded that AMI (Inf) with RVI is significantly associated with cardiogenic shock. PMID- 25725667 TI - Genetic testing for spinocerebellar ataxias in patients diagnosed as Parkinson's disease in Bangladesh. AB - This study was conducted to find out Spinocerebellar Ataxias (SCA) by genetic analysis from those patients presenting with Parkinsonism in the Neurology department of Mymensingh Medical College Hospital, Bangladesh. A sample of about 5ml blood was collected by venipuncture in EDTA tube after having informed consent from each patients and healthy individual, with due Institutional Ethical committee approval for genetic study of 7 healthy people and 9 patients. The neurological disorder along with a complete physical and/or psychological, as well as family history and demographic data was recorded with a prescribed questionnaire by the neurologists of Mymensingh Medical College Hospital. Extraction of genomic DNA from the venous blood using Flexi Gene DNA kit (Qiagen, Japan) was performed in Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh. The extracted DNA was stored, accumulated and then were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat was performed for the SCA1, SCA2, SCA3, SCA6 loci using primers SCA1N-F1 and SCA1N-R1, SCA2-F1 and SCA2-R1, MJDF1 and MJDR1, SCA6-F1 and SCA6-R1, respectively. SCA1 PCR of both healthy individual and suspected Parkinsons Disease (PD) patients DNA was found 250 bp (no. of CAG repeats=36). SCA2 PCR products reveal the DNA products of about 150 bp (no. of CAG repeats=23) except one patient that was suspected and it was sequenced and revealed 175bp (no. of CAG repeats=30). SCA3 PCR product size of both healthy individual and patient DNA was within 250 (no. of CAG repeats=11) to 300 bp (no. of CAG repeats=28) except one patient which was about 320 bp and its CAG repeats was about 34. SCA6 PCR product size of both healthy individual and patient DNA was about 150 bp (no. of CAG repeats=16). PMID- 25725668 TI - Length of papillary muscles in both ventricles of different age group on Bangladeshi cadaver. AB - Papillary muscle rupture and dysfunction can lead to complications of prolapsed atrioventricular valve and valvular regurgitation. Morphology, measurements and attachments of papillary muscles in both tricuspid and bicuspid valve gains utmost importance in cardiac surgeries and variations in the papillary muscle morphology is one of causes for myocardial infarction in recent time. Therefore, it is important to know both the normal anatomy and variations of papillary muscles. The study was carried out in the department of Anatomy, Mymensingh Medical College, Mymensingh from July 2013 to June 2014. A total 80 human hearts were collected by purposive sampling method, among them 49 were male and 31 were female. The specimens were collected from Bangladeshi cadavers of age ranging from 6 months to 60 years, from autopsy laboratory of the Department of Forensic Medicine of Mymensingh Medical College. All the specimens were grouped into three categories Group A (upto 20 years), Group B (21 to 40 years) and Group C (41 to 60 years) according to age. Dissection was performed according to standard autopsy techniques. Length of each papillary muscle was measured in both ventricles in different age groups. In present study the mean length of the anterior papillary muscles of right ventricle was higher than both the posterior and septal papillary muscles among the age groups. The mean+/-SD length of the anterior papillary muscle was 1.07+/-0.48, 1.50+/-0.37 and 1.60+/-0.25cm in Group A, B and C respectively. The mean+/-SD length of the posterior papillary muscle was 1.02+/-0.35, 1.31+/-0.40 and 1.37+/-0.34cm in Group A, B & C respectively. The mean+/-SD length of the septal papillary muscle in right ventricle was 0.51+/ 0.42, 0.65+/-0.31 and 0.81+/-0.35cm in Group A, B & C respectively. It was also observed that the mean length of anterior, posterior and septal papillary muscle was increased with age. In present study the mean length of the anterior papillary muscles in left ventricle was higher than that of the posterior papillary muscle among the age groups. The mean+/-SD length of the anterior papillary muscle was 1.53+/-0.34, 2.05+/-0.39 and 2.01+/-0.25cm in Group A, B and C respectively. The mean+/-SD length of the posterior papillary muscle was 1.33+/ 0.34, 1.95+/-0.89 and 1.81+/-0.76cm in Group A, B and C respectively and it was also observed that the mean length of both anterior and posterior papillary muscle was increased with age. In statistical analysis, differences between age groups were calculated by using one way ANOVA test. PMID- 25725669 TI - Comparison of arthroscopic anterior cruciate ligament reconstruction by bone patellar tendon-bone graft with or without using interferential screw in general population. AB - Rupture of the Anterior Cruciate Ligament (ACL) is common, resulting reduced quality of life, increasing the meniscal injury risk, knee instability and early degenerative joint disease. Bone-Patellar Tendon-Bone (BPTB) became the gold standard surgery where conservative management failed. Adding interferential screw provides rigid fixation which is important for early accelerated rehabilitation program in athletes but we have carried out this prospective interventional study in Bangabandhu Sheikh Mujib Medical University (BSMMU) and our private settings from January 2007 to December 2011 to assess whether interferential screws provide any clinical and functional advantage in general population. Sixty six male patients of 21-40 years age, with ACL deficient knees were reconstructed with BPTB graft where 40 cases were augmented by interferential screws and 26 cases without and followed up for minimum 2 years. The clinical and functional outcome (by Lysholm Knee Scoring), post-operative knee stability (by clinical tests) and complications were assessed and recorded. There was significant (p<0.05, paired 't' test) improvement of knee function (limp, walking, stair climbing, squatting, thigh atrophy) in both groups but no significant difference between them (p>0.05, chi squared test) regarding clinical, functional outcome and knee stability. The complications were insignificant (p>0.05, chi squared test) in both groups but there were few cases of screw related complications with augmentation and pronounced anterior knee laxity without it. So, ACL reconstruction by BPTB grafts with or without augmentation results consistent and comparable outcome in general population. PMID- 25725670 TI - Quality and quantity of infertility care in Bangladesh. AB - Infertility is an important health issue which has been neglected in the developing countries. First test-tube babies (triplet) in Bangladesh were born on 30th May, 2001. Although there is no tertiary level infertility center in the public sector, several private centers have come up with the facilities. The objective of the study was to find i) the quality and quantity of infertility care in Bangladesh and ii) the cause of infertility in the attending patients iii) the treatment seeking behaviors iv) and the reasons for not taking treatment among the attending patients. There are now 10 tertiary level Infertility centers in Bangladesh. The information was collected in a preformed datasheet about the facilities and the profile of the patients and the treatment seeking behavior of the attending patients. Out of the ten centers two centers refused to respond and did not disclose their data. Around 16700 new patients are enrolled in a year in the responsive clinics. Five percent (5%) of the patients underwent ART, 7% of the patients gave only one visit, 84% of the patients completed their evaluation, 76% of the patients took treatment. Causes of infertility in the patients taking treatment were male factor in 36.4%, bilateral tubal block in 20.2%, PCOS and anovulation in 31.7%, endometriosis in 19.6%, unexplained in 10.95, combined in 3.5%, ovarian failure in 1.4%, testicular failure in 0.33%, congenital anomaly in 0.3%. The main reason for not taking treatment was financial constrainment. The quality and quantity of infertility care is dependent on the available resources and on the use of the resources by the patients. In developing countries the resources are merging and confined to specified areas which cannot meet the demand of their population. The study gives us the idea of the need and the demand of the services in the country. PMID- 25725671 TI - Outcome of modified Bristow-Laterjet procedure in post-traumatic recurrent anterior shoulder dislocation in young population. AB - Anterior shoulder dislocation (ASD) is a common injury of young population which may progress to recurrent episodes. The treatment is initially conservative but surgery is indicated when it fails. Out of more than 150 techniques, modified Bristow-Latarjet procedure has become most favorable even to arthroscopic techniques. We have intended to retrospectively assess the outcome of it in post traumatic recurrent ASD of young non-athletes, performed at our different private settings between January 2007 and July 2012; which included 15 male patients of 20-39 years with minimum 2 years follow up. Clinical, functional, radiological and overall outcome status were evaluated. There was significant improvement of shoulder stability (p<0.05, chi-square test) despite significant deterioration (p<0.05, paired t-test) of external rotation (21.67 degrees +/-00.61 degrees loss). The patient self assessed pain and instability had highly significant (p<0.001, paired t-test) and all components of activities of daily living (except above shoulder weight carrying and overhead throwing) had significant improvement (p<0.05, paired t-test). Despite of intra-operative difficulties, radiological transplant errors (33.33%) and post-operative complications (06.67%), overall satisfactory outcome (86.67%) had been significant (p<0.05, chi-square test). PMID- 25725672 TI - Pregnancy outcome following myomectomy. AB - In developing countries, abdominal myomectomy is still a modality of treatment for large and symptomatic uterine fibroid in women who wish to retain their fertility and preserve uterus. In order to assess the outcome of pregnancies after myomectomy, a prospective observational study was carried out in the Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from July 1999 and June 2011. Study included 40 married women of reproductive age, suffering either from primary or secondary subfertility, and who had uterine fibroid and strongly wished to conceive shortly after myomectomy using microsurgical procedure with no existence of other male and female subfertility factor. These women were followed up at 3, 6, 12 and 24 month intervals over telephone and outdoor visits. Data were recorded on preformed questionnaires. Post myomectomy hysterosalpingography was done at about 16 weeks after myomectomy. Patients were advised to try for pregnancy after 16 weeks of operation. Maximum number of women belonged to age group 31-35 years (n=14, 35%); primary subfertility was 67.5% and secondary 32.5%; in maximum number of cases duration of subfertility was 2-5 years (n=22, 55%); type of fibroid were solitary (52.5%) and multiple (47.5%); type of myoma were intramural (75%), submucous (2.5%) and combined (22.5%); location of myoma were fundal (5%), anterior wall (25%), posterior wall (20%) and combined (50%); diameter of removed myoma were <5cm (2.5%), 5-8cm (67.5%), >8-10(20%) and >10cm (10%); uterine size before myomectomy were (in weeks) <12(22.5%), 12-14 (27.5%), 15-20 (32.5%), 21-25 (15%) and >25 (2.5%). Hysterosalpingography was done in 16(40%) cases, and the findings were both tube patent (62.5%), unilateral tubal block (31.2%) and bilateral tubal block (6.2%). Menorrhagia after myomectomy was present only in 5% cases. After uterine myomectomy, 14(35%) women conceived, common time interval between myomectomy and conception was 1-2 years (42.9%), conception was spontaneous in 71.4%. Out of 14 who conceived after myomectomy 12(85.7%) delivered live babies by LUCS, and most of the babies weighed >3kg (58.3%). PMID- 25725673 TI - Role of USG-guided fine needle aspiration cytology in the diagnosis of abdominal mass. AB - The present study was carried out with the aims to diagnose abdominal masses by FNAC with the help of ultrasonography guidance and to determine the diagnostic accuracy of FNAC. One hundred consecutive patients were studied during the period from January 2005 to December 2005. Histopathological examination was done to correlate with the cytologic diagnosis. The results of comparative study of USG guided FNAC and histopathology were significant (P value was <0.001). In USG guided FNAC, it was found that 64 were malignant tumors, 5 were benign tumors, 28 were inflammatory and 3 were inadequate material. Histopathology of 3 inadequate materials showed 1 was adenoma and 2 were leiomyoma. As a whole test results of USG-guided FNAC were sensitivity 95.52%, specificity 100%, positive predictive value 100%, negative predictive value 91.67% and accuracy 97%. USG-guided FNAC has been proved to be a rapid, reliable and cost-effective diagnostic method. PMID- 25725674 TI - Comparison between retrograde and transeptal approach in radiofrequency catheter ablation of left accessory pathways. AB - To study a series of patients submitted to radiofrequency catheter ablation (RFA) of left accessory pathways (AP) using the transeptal approach (TSA) as compared to the conventional retrograde arterial approach (RAA). Sixty consecutive patients (44 male; mean age of 35.60+/-11.63 years) with 60 left APs (39 overt and 21 concealed) underwent catheter ablation using the TS method (30 patients) and the RAA method (30 patients) in an alternate fashion. The analysis was performed according to the intention-to-treat principle. The transeptal puncture was successfully performed in 29 patients (96%). This access allowed primary success in the ablation in all the patients without any complication. When we compared this approach with the RAA there was no difference as regards the primary success (p=0.103), fluoroscopy time (p=0.565) and total time (p=0.1917). Three patients in the RAA group presented a vascular complication. The TSA allowed shorter ablation times (p=0.006) and smaller number of radiofrequency applications (p=0.042) as compared to the conventional RAA. The patients who had unsuccessful ablation in the first session in each approach underwent with the opposite technique (cross-over), with a final ablation success rate of 100%.The TS and RA approaches showed similar efficacy and safety for the ablation of left accessory pathways. The TSA allowed shorter ablation times and smaller number of radiofrequency applications. When the techniques were used in a complementary fashion, they increased the final efficacy of the ablation. PMID- 25725675 TI - Maternal mortality in obstetrics and gynaecology in a tertiary care hospital. AB - Maternal mortality is the leading causes of death and disability of reproductive age in the developing countries. Bangladesh is one of the developing countries where maternal mortality is very high. The purpose of the present study was to see the causes of maternal deaths at Obstetrics and Gynaecology ward. This retrospective study was carried out in the Department of Obstetrics and Gynaecology at Dhaka Medical College Hospital (DMCH). All maternal deaths were included in this study from July 2003 to June 2004 for a period of one year. The incidence of maternal death was 18.5/1000 live birth. Hypertensive disorder of pregnancy (41.84%) was the most common cause of maternal death followed by unsafe abortions (21.4%), PPH (10.2%), obstructed labour (8.2%). Among 98 patients 36(36.7%) cases are died due to eclampsia. Death due to pre-eclampsia (5.1%), unsafe Abortion (21.4%), Obstetric haemorrhage (18.4%) and obstructed labour (8.3%) were commonly found in this study. The study permits to conclude that Hypertensive disorder of pregnancy is the leading cause of pregnancy related deaths followed by unsafe abortions and obstetric haemorrhage. Other causes include obstructed labour, anaesthetic complications and others. PMID- 25725676 TI - Non-Hodgkin's lymphoma by immunohistochemistry. AB - Non Hodgkin's lymphomas (NHL) constitute a heterogeneous group of neoplasm of the lymphoid system. There are many histological subtype of NHL based on WHO classification of hematopoietic and lymphoid neoplasm. This cross-sectional study was carried out in the department of Pathology, Dhaka Medical College, Dhaka from January 2009 to December 2010 to observe the different subtypes of NHL using immunohistochemistry (IHC) with CD3. A total of 50 microscopically diagnosed case of NHL irrespective of age and sex were included in the study. The diagnostic morphologic criteria of each lymphoma subcategory were compiled and diagnosis was made. Mean age of the study subjects were 42.0+/-19.7 years with range 3-75 years and male female ratio was 1.8:1. Nodal NHL was 66% and extranodal cases were 34%. Maximum number of histolgic subtypes belonged to diffuse large B-cell lymphoma (DLBCL) and male was predominant in all histological subtypes, except peripheral T-cell lymphoma (PTCL). DLBCL was predominant in all B-cell NHL whereas PTCL was predominant in all T-cell NHL. The most childhood patients belonged to lymphoblastic lymphoma. Regarding cell lineage B-cell NHL was more common than T cell NHL (88% vs. 12%), but high grade pattern was more predominant in T-cell type (83.3% vs. 65.9%). Among 50 study subjects histological (H & E) diagnosis reveals 46 cases as B-cell NHL and 4 as T-cell NHL but IHC confirms 6 cases as T cell NHL. PMID- 25725677 TI - Role of D-dimer in determining coagulability status in pre-eclamptic and normotensive pregnant women. AB - A cross sectional study was carried out from January 2007 to December 2008 in the department of Obstetrics and Gynaecology, Dhaka Medical College Hospital, Dhaka in collaboration with Department of Haematology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Pregnant women with pre-eclampsia attending at Out-patient Department (OPD) and admitted in In-patient Department of Obstetrics and Gynaecology Dhaka Medical College Hospital, Dhaka were selected as cases. Healthy and uncomplicated pregnant women admitted in the same hospital were taken as controls. The study showed that 26-30 years and 21-25 years age category was higher in the case and control groups and the mean age was significantly higher in case group compared to control group (p=0.025). The study showed that 44% of case group had a significantly high level of plasma D-dimer (>0.5MUg/ml) as opposed to control group (8%) (p<0.001). Estimation of odds ratio demonstrates that pre-eclamptic women (case) had 9 times (95% of CI = 2.8 - 28.9) more risk of having plasma D-dimer >0.5MUg/ml than that of normal pregnant women (control). The mean systolic and diastolic blood pressures in patients with plasma D-dimer >0.5MUg/ml were considerably higher than those who had plasma D dimer <=0.5MUg/ml (p<0.001). The study showed that majority (81.8%) of pre eclamptic women with plasma D-dimer >0.5MUg/ml had systolic blood pressure >= 160 mm Hg compared to 46.4% of those who had plasma D-dimer <=0.5MUg/ml (p=0.010). And ninety percent of pre-eclamptic women with plasma D-dimer >0.5MUg/ml had exhibited severe proteinuria as opposed to 53.6% of those who had plasma D-dimer <=0.5MUg/ml (p=0.017). The study concludes that plasma D-dimer level can easily be used in screening for the hypercoagulable state in pre-eclamptic patients which have preventive and therapeutic implications. PMID- 25725678 TI - Circadian rhythm of onset of stroke - in 50 cases of ischemic stroke. AB - Stroke is a leading cause of death and disability worldwide. While the immediate consequence of stroke include permanent cognitive deficits, paralysis, visual impairment and sensory disturbances; stroke also results in long term dysregulation of sleep and mood, which may be equally disabling. The influence of ischemic stroke on circadian rhythm regulation, which is strongly linked to sleep and mood, may thus potentially influence long term recovery in stroke patients. Stroke induces immediate changes in the timing of pineal melatonin secretion, indicating that cortical and basal ganglia infarction impacts the timing of melatonin rhythms. This study was done to find out the time of onset of most of the ischemic stroke attack and to determine the outcome of ischemic stroke during hospital stay. All ischemic stroke patients admitted in Medicine wards in Comilla Medical College Hospital during the period of 1st November 2010 to 30th April 2011 included in this study. After admission, a careful history and a thorough clinical examination was carried out. Data collection was done on a preset questionnaire which involved to identify the risk factors, the time of onset of ischemic stroke, and outcome during hospital stay. All the cases were investigated. Among the 50 ischemic stroke patients, 68% were male and 32% female. Maximum age groups were 61-70 years (50%). By occupational category, maximum were retired persons (46%); 68% were hypertensive, 38% smoker and 16% had diabetes. Dyslipidemia was present in 44% patients. Most of the ischemic stroke (44%) occurred in the morning to late morning (6:01AM-12:00PM) and majority (80%) of the patients was discharged with residual neurological dysfunction. This study supports the presence of a circadian pattern in the onset of ischemic stroke, with higher risk in the morning to late morning. Most of the patients were discharged with residual neurological dysfunction. PMID- 25725679 TI - Correlation of hyperinsulinemia with hyperandrogenemia in primary infertile women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of the reproductive age and is the most common form of anovulatory infertility. Hyperinsulinemia and hyperandrogenemia are the characteristic features of PCOS, but the association between hyperinsulinemia and hyperandrogenemia is not well established. To find out any causal association between Hyperinsulinemia and hyperandrogenemia, a retrospective study was done on primary infertile women suffering from PCOS in the department of Biochemistry, Bangabandhu Sheikh Mujib Medical University. A total of 80 subjects were selected, among them 60 were cases and 20 were controls. Depending on their body mass index, the cases were divide into two groups, obese (n=30) and non-obese (n=30). Age and BMI matched controls were taken for both age groups. Observations derived from the study suggested that hyperinsulinemia and hyperandrogenemia are characteristic features of PCOS but significant correlation was not found between hyperinsulinemia and hyperandrogenemia. However, we cannot negate any possible association between the two and thereby we recommend further study to be done with a larger sample size. PMID- 25725680 TI - Soft tissue tumours and tumour like lesions - a demographic and clinicopathologic study of 461 cases from different regions of Bangladesh. AB - Soft tissue tumours and tumour like lesions are relatively rare. They pose diagnostic difficulty due to wide morphological variation as well as overlapping clinical and pathological features. The relative frequency of soft tissue tumours varies throughout world. This study was undertaken to find out the distribution of soft tissue tumours and tumour like lesions in Babgladesh. Four hundred and sixty one cases of soft tissue tumour and tumour like lesions were studied to see the demographic and clinicopathologic pattern. Benign 320(69.4%) and malignant 141(30.6%) cases were recorded. Of all cases mean age was 31.07+/-16.87 years with M:F ratio of 1:0.71 (p=0.001). Upper extremity was the most common site. Majority of the benign cases (84.1%) were superficially located whereas majority of malignant cases (89.2%) were deep seated (p=0.001). Lipoma and fibrosarcoma was the most common benign and malignant tumour respectively observed in this study. In childhood group, rhabdomyosarcona was the commonest one. The distribution pattern of soft tissue tumours in Bangladeshi population is roughly similar to that described in other countries with few exceptions. PMID- 25725681 TI - Genotypes of hepatitis C virus infection in Bangladeshi population. AB - Hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide also in Bangladesh. Prevalence of Hepatitis C virus infection in rural adult population of Bangladesh is reported to be 0.6% but the exact pattern of existing genotype has not been well studied. Genotyping of HCV is important for the planning of treatment duration and predicting the response to treatment in HCV infection. This study was done to identify the existing HCV genotypes in the diagnosed cases of chronic hepatitis C infection in Bangladesh. This study was a prospective as well as retrospective cross-sectional observational study done in the department of Gastroenterology of Bangabandhu Sheikh Mujib Medical University, Dhaka Bangladesh. Cases were also taken from department of Hepatology of Bangabandhu Sheikh Mujib Medical University and Square General Hospital, Dhaka. The study was from January 2010 to March 2011. In total, 417 patients having chronic HCV confirmed by positive anti-HCV and HCV-RNA tests attending to above mentioned institutions were included in this study. Out of the 417 study subjects, 303 were males (72.66%) and 114 (27.34%) were females between 05 to 78 years of age. Most cases were in the age group 30-50 years (57.06%). The study showed that 209 (50.19%) were infected with Genotype 3. Next common identified genotype of HCV was a combination of type 3 & 4, which accounted for 120 (28.77%) and genotype -1 represented 59 (14.14%) of the cases. Other less common identified genotypes were 2, 4, 5 and mixed genotypes -1 & 3, 5 & 6 and 2 & 3; the figure being 12(2.87%), 8(1.91%), 1(0.23%), 5(1.19%), 2(0.47%) and 1(0.23%) respectively. Several subtypes were also found. Genotype 3 was the commonest HCV genotype among the Bangladeshi population. Different HCV genotypes will give a good idea regarding the plan of treatment and possible response rate as well as prognosis of HCV infection in Bangladesh. This study had some limitation like relatively smaller sample size and shorter period for the study. Further studies over a larger population are needed to draw any conclusive opinion. PMID- 25725682 TI - Role and efficacy of diffusion weighted imaging in evaluation of intracranial pathologies. AB - This study aims to assess the role & efficacy of Diffusion-weighted imaging in evaluation of intracranial pathologies. After achieving patient's informed consent and Institutional review board approval, total 80 cases of various intracranial pathologies of all age groups and either sex were evaluated. All MR images were obtained with a 1.5-T superconducting system (Siemens Medical Healthcare) using a circularly polarized head coil. Out of 80 cases, 2 cases showed no findings on MR (conventional and diffusion MR), and a total of 125 lesions was found in 78 cases. Infarct (68%) was the commonest lesion seen in our study. Of these, acute infarcts which presented within 24 hours of onset of ictus represented 70%, Hyper-acute infarcts (9.41%), Sub-acute infarcts (10.5%) and Chronic infarcts (9.41%) were less common. In cases of acute infarcts of the total 60 lesions, Conventional MR (T2WI) and FLAIR could detect 96.6% of the lesions and diffusion MR had 100% detection rate for acute infarcts. Diffusion MR, conventional MR and FLAIR had equal (100%) detection rate. Both conventional and diffusion MR (100%) had equal detection rate for chronic infarcts. Among the non-infarct lesions, Meningioma were most common with 10 lesions (8%) detected on DW MR. Least common lesions detected by DW MR included Medulloblastoma & Subdural Empyema -1 Lesion (0.8%) each. DWI is more sensitive & diagnostic in cases of acute infarct when comparatively evaluated with conventional MR & FLAIR. PMID- 25725683 TI - Obesity with irregular menstrual cycle in young girls. AB - Obesity is one of the leading causes of morbidity and mortality worldwide. Obese women are at increased risk of developing Type 2 Diabetes, cardiovascular diseases, hyperlipidemia, rectal carcinoma and gynecological problems including sub fertility, menstrual dysfunction and polycystic ovarian disease. The aim of this study was to assess relationship of obesity with menstrual irregularity in young girls that can help to create awareness among young girls about obesity and how it can affect fertility. It was a case controlled cross sectional study comprising of 220 participants from different colleges and universities of Karachi and from outpatients department of private clinic and Civil Hospital Karachi. A questionnaire was designed to assess the relationship of obesity with irregular menstrual cycle. Questionnaires were filled by co-authors after taking verbal consent. Data was collected from March 2013 to December 2013 and entered and analyzed on SPSS 16.0. Out of 220 participants obese and overweight were 67(30.4%) and 49(22.2%) respectively. Significant association was found between body composition and menstrual cycle irregularity as menstrual irregularity was present in only 9.5% when the BMI was normal and 14.09% and 24% girls in the overweight and obese categories respectively. Waist to hip ratio was found increased in 61.36% of girls. Sixty four point forty four percent (64.44%) of the girls with increased waist to hip ratio reported menstrual irregularity which makes 39.55% of the total sample population. Dysmenorrhea was reported by 63.6% of participants and family history was positive in 77.3%. Hirsutism was reported in 36.7% and 49.2%, acne in 34.6% and 43.2%, weight gain tendency in 85.7% and 98.5%, types 2 diabetes in 0% and 4.4% and hypertension in 8.16% and 31.3% of overweight and obese participants respectively. This study shows considerable association between overall and central obesity with menstrual cycle irregularity. This study provides the grounds on which foundation of health promotion and awareness programs can be laid for targeted age group. PMID- 25725685 TI - Conjoined twins with single heart and liver - a case report. AB - Twin pregnancy is common but conjoined twins are an extremely rare congenital malformation without any known genetic predisposition. The incidence of conjoined twins is estimated to be around 1 in 250,000 live births with a female predilection. We presented an extremely rare case of abdomino-thoracopagus with single heart and liver. In this paper, the imaging of conjoined twins both antenatally and postnatally is reviewed, in particular taking into consideration recent advances with gray scale and color Doppler ultrasound. This case is of particular interest because of the rarity of abdomino-thoracopagus twins with single heart and liver, in literature. PMID- 25725684 TI - A 7 years old girl with abdominal lump and per-vaginal bleeding of hypothyroidism. AB - Hypothyroidism is a common endocrine disorder resulting from decreased secretion of thyroid hormone. The diagnosis of hypothyroidism is suggested from the clinical and laboratory findings. Here we present a case report on this disease with rare presentation of abdominal lump and pervaginal bleeding in childhood. A 7 years old girl admitted in a tertiary level hospital with abdominal lump and irregular per vaginal bleeding. Abdominal swelling was gradually increasing in size & associated with lower abdominal pain for last 5 months. On examination the girl was moderately anaemic, mildly oedematous, distended lower abdomen and a mass in left iliac region. Her thyroid function test, serum FSH, serum LH, serum Prolactin was done and high FSH, LH, Prolactin levels were found. Ultrasonography of lower abdomen revealed bulky uterus and bilateral ovarian cysts. MRI of Brain showed feature of pituitary microadenoma. Finally the patient was diagnosed as primary hypothyroidism and bilateral follicular ovarian cyst with pituitary adenoma developed as its consequence. The case is reported for clinical awareness & to share our experience. PMID- 25725686 TI - Parotid gland metastasis - an unusual presentation of adenocarcinoma of lung. AB - Lung cancer is the most frequent malignant disease and the most common cause of cancer death in the world. Primary carcinoma of the lung was an uncommon cancer until the 1930s. Common cell types in bronchial carcinoma are squamous 35%, Adenocarcinoma 30%, Small-cell 20%, Large-cell 15%. We present a case of a bronchial neoplasm metastasis to the parotid gland. A 50 years old male patient presented with a 7*5cm painless parotid mass that was metastatic adenocarcinoma on histopathology. Then we thoroughly examined the patient and he was investigated accordingly. There was an abnormal shadow in the lung on chest x ray, CT revealed a lung tumour on left side. Metastasis to the parotid gland from any distant primary site is quite unusual. We are going to present this case in the journal because of its rarity. Parotid gland metastasis from the lung is rare & if a careful examination is not performed primary focus may be overlooked, negatively affecting the lifetime survival rate & the prognosis of the patient. PMID- 25725687 TI - Endometrial stromal nodule - a case report. AB - Among the endometrial tumour endometrial stromal nodule are very rare. It is one of the form of endometrial stromal tumour. There are no definite presurgical diagnosis and diagnosis in most instances by microscopy. Hysterectomy is the treatment of choice to evaluate the tumour margin to differentiate it from stromal sarcoma. We present a case of 40 years woman, ultrasonographically diagnosed as leiomyoma and ovarian cystadenoma, underwent a total abdominal hysterectomy with one sided salpingo-oophorectomy. Microscopic examination show an endometrial stromal nodule and serous cystadenoma of the ovary. Though it is a benign tumour margin should be carefully examined to differentiate from stromal sarcoma, whose treatment and prognosis is totally different. PMID- 25725688 TI - Sixty years old man with primary cutaneous lymphoma. AB - Cutaneous lymphomas are uncommon skin tumors. Which may be primary or secondary and T-cell or B-cell according to cell type the former type being less frequent. The term "primary cutaneous lymphoma" refers to cutaneous lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. In this report, we describe a 60-year-old man with primary cutaneous lymphoma, who presented with multiple painless reddish nodular skin lesion on the different sites of his body and there was no evidence of systemic involvement. PMID- 25725689 TI - Gastrointestinal manifestations as initial presenting features in a 40 years old woman with systemic lupus erythematosus. AB - Gastrointestinal (GI) symptoms are common in patients with systemic lupus erythematosus (SLE). These symptoms can be due to primary GI disorders like peptic ulcer disease, pancreatitis or intestinal obstruction. But they can be due to SLE itself or complications of treatment of SLE. In this case report, we describe a 40 years old woman who presented initially with GI complaints. Later she was diagnosed as a case of SLE with chronic intestinal pseudo-obstruction (CIPO). The problems related to diagnosis and management is also discussed. PMID- 25725690 TI - A middle aged lady with recurrent low trauma fracture due to parathyroid adenoma. AB - A 48 year old lady was referred to BIRDEM Hospital, Dhaka, Bangladesh by her local physician for evaluation of hypercalcaemia and increased serum parathyroid hormone (PTH) in the background history of low trauma fracture. Ultrasound of neck and parathyroid scintigraphy with 99mTc-MIBI revealed a parathyroid adenoma. Parathyroidectomy was done. Histopathology report showed features consistent with parathyroid adenoma. Primary hyperparathyroidism should be kept in mind in all patients presenting with history of bone problems ranging from simple bone pain to spontaneous or low trauma fracture associated with hypercalcemia. By the help of appropriate localization technique it can be localized and cured by parathyriodectomy. PMID- 25725691 TI - Primary malignant melanoma of the penis with secondary to adrenal. AB - Primary malignant melanoma of penis with secondaries to the adrenal gland is rare. Here we report a case of malignant melanoma of penis in a 60 years old man who presented with intermittent gross, episodic haematuria of 11 months duration and a hard indurated pigmented fungating lesion over the glans penis. Following an initial tissue biopsy from the penile growth which revealed malignant melanoma the patient underwent partial Panectomy. Few days after recovery the patient underwent laparotomy and incisional biopsy from adrenal mass revealed metastatic malignant melanoma histopathologically. PMID- 25725692 TI - Autoimmune polyglandular syndrome type II - a case report. AB - Autoimmune polyglandular syndrome also known as autoimmune polyendocrine syndrome (APS) type II is characterized by the presence of Addison's disease, in association with autoimmune thyroid disease and/or type I diabetes mellitus. Here a 14 year old girl is reported with Addison's disease, autoimmune hypothyroidism and primary hypogonadism. Autoimmune polyendocrine syndrome (APS) type II occurs most often in middle aged female and is quite rare in children but one should think to autoimmune polyglandular syndrome type II in patient at any age especially in patients with Addison's disease. PMID- 25725693 TI - Uterus didelphys with unilateral obstructed hemivagina and haematocolpos with ipsilateral renal agenesis - a case report. AB - Mullerian anomalies are a relatively uncommon occurrence with implication for adolescents and adults as they may result in specific gynaecologic, fertility and obstetrical issues. Uterus didelphys with blind hemivagina and ipsilateral renal agenesis is a rare congenital anomaly. Patient may be asymptomatic and unaware of having double uterus or may present with severe dysmenorrhoea or dyspareunia or a palpable mass due to unilateral haematocolpos. We report a case of 12 year old girl with this condition who was diagnosed as uterus didelphys with unilateral haematocolpos with ipsilateral renal agenesis on the basis of clinical association, physical examination and sonography and intravenous urogram. PMID- 25725694 TI - Testicular tumour - a review article. AB - Painless scrotal masses must be investigated with ultrasound imaging and tumour marker assay before being treated with radical inguinal orchidectomy. For unknown reasons, the incidence of this cancer increased in Caucasian population. The incidence of testicular germ cell tumour has doubled in past 40 years. An annual increase of 3-6% is reported in Caucasian population. But the mortality rate has been stable or decreasing due to improvement in treatment. In the past, metastatic testicular cancer was usually fatal, but recent advances in treatment, including high-dose chemotherapy and stem cell rescue, have considerably improved the prognosis. Indeed, testicular cancer is a bright spot in the oncological landscape and is now considered the model for the treatment of solid tumors. We looked into the epidemiology, presentation, classification, work up, staging, various treatment modalities and prognosis of testicular tumour in this article. PMID- 25725695 TI - Genital tuberculosis in the infertile women - an update. AB - Tuberculosis is endemic in many developing countries of the world including Bangladesh. Genital tuberculosis is a significant cause of infertility in the women of these countries. The diagnosis of genital tuberculosis in infertile women is difficult as most of the cases are usually asymptomatic. A high index of clinical suspicion is required. Genital tuberculosis always affects the fallopian tubes. It affects the endometrium in half of the cases. In addition to tuberculin skin tests and interferon gamma release assays, procedures like hysterosalpingography, laparoscopy-dye test, endometrial curettage and laparoscopy with multiple sampling for smear microscopy and culture for mycobacterium tuberculosis can detect the cases. In recent years diagnosis has been improved by polymerase chain reaction targeted against mycobacterium tuberculosis DNA. Following early diagnosis, treatment with anti-tubercular drugs is favourable for fertility only when tubal and endometrial damage is minimal. In cases where the organs are more severely involved the outcome is poor even with in- vitro fertilization. PMID- 25725696 TI - Pressure injury in Australian public hospitals: a cost-of-illness study. AB - OBJECTIVE: Pressure injuries (PI) are largely preventable and can be viewed as an adverse outcome of a healthcare admission, yet they affect millions of people and consume billions of dollars in healthcare spending. The existing literature in Australia presents a patchy picture of the economic burden of PI on society and the health system. The aim of the present study was to provide a more comprehensive and updated picture of PI by state and severity using publicly available data. METHODS: A cost-of-illness analysis was conducted using a prevalence approach and a 1-year time horizon based on data from the existing literature extrapolated using simulation methods to estimate the costs by PI severity and state subgroups. RESULTS: The treatment cost across all states and severity in 2012-13 was estimated to be A$983 million per annum, representing approximately 1.9% of all public hospital expenditure or 0.6% of the public recurrent health expenditure. The opportunity cost was valued at an additional A$820 million per annum. These estimates were associated with a total number of 121 645 PI cases in 2012-13 and a total number of 524 661 bed days lost. CONCLUSIONS: The costs estimated in the present study highlight the economic waste for the Australian health system associated with a largely avoidable injury. Wastage can also be reduced by preventing moderate injuries (Stage I and II) from developing into severe cases (Stage III and IV), because the severe cases, accounting for 12% of cases, mounted to 30% of the total cost. PMID- 25725697 TI - Role of anti-inflammatory cytokines IL-4 and IL-13 in systemic sclerosis. AB - OBJECTIVE: The aim of this paper is to review the anti-inflammatory cytokines IL 4 and IL-13 and their receptor signals; we discuss new insight into their possible roles in systemic sclerosis (SSc) and their overlapping function in SSc. INTRODUCTION: SSc is a connective tissue disease characterized by fibrosis. The exact etiology of SSc is unknown, and no therapy has been proved effective in modifying its course. Recently the roles of IL-4 and IL-13 in the development of SSc have been extensively considered. The possible roles of IL-4 and IL-13, especially their overlapping function, in SSc are not well documented. METHODS: A literature survey was performed using a PubMed database search to gather complete information regarding IL-4 and IL-13 and their role in inflammation. RESULTS AND CONCLUSIONS: The participation of complex pathways of IL-4 and IL-13 in the process of inflammation and fibrosis action in SSc is still not very clear, and some pathogenesis of regulation found in vitro needs to be further proved. There is still more work which could be done to achieve useful developments with therapeutic benefit in SSc. PMID- 25725699 TI - Recent advances in the pathogenesis and treatment of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukaemia (CLL) is a common lymphoid malignancy characterized by the expansion and progressive accumulation of mature autoreactive B lymphocytes. The disease is clinically heterogeneous and incurable by standard chemotherapy. A major feature of the disease is the marked dependence of the leukaemic cells on various microenvironmental stimuli, which promote leukaemia cell growth, survival, and drug-resistance. Recently, considerable progress has been made in the understanding of the molecular mechanisms that drive CLL. The identification of recurrent genetic lesions using next generation sequencing technology has provided new data on the pathophysiology of the disease and has improved its prognostication. The recognition of the critical role of the B cell receptor (BCR) in driving the disease has resulted in the development of BCR pathway inhibitors that have the potential to completely transform CLL treatment in the near future. Other novel therapeutic agents, such as BCL2 antagonists and chimeric antigen receptor (CAR)-modified T-cells, are also showing great promise in clinical trials. In this review, we summarize some of these recent advances, with a particular focus on the BCR and corresponding pathway inhibitors. PMID- 25725698 TI - Histamine receptor expression in human renal tubules: a comparative pharmacological evaluation. AB - OBJECTIVE AND DESIGN: The aim of this study is to evaluate the expression of the histamine receptors, particularly focusing on the H4R in human renal tubules. MATERIAL: The ex vivo evaluation was carried on specimens from human renal cortex. Primary and immortalized tubular epithelial cells (TECs) and the HK-2 cell line were used as in vitro models. TREATMENT: Cells were pretreated for 10 min with chlorpheniramine maleate 10 MUM (H1R antagonist), ranitidine 10 uM (H2R antagonist), GSK189254 1 uM (H3R antagonist) or JNJ7777120 10 uM (H4R antagonist), and then exposed to histamine (3 pM-10 nM) for 30 min. METHODS: The ex vivo evaluation on specimens from human renal cortex was performed by immunohistochemistry. The expression of histamine receptors on primary and immortalized TECs and the HK-2 cell line was evaluated at both gene (RT-PCR) and protein (immunocytofluorescence) levels. The pharmacological analysis was performed by TR-FRET measurements of second messenger (IP3 and cAMP) production induced by histamine with or without the selective antagonists. RESULTS: Our data revealed the presence of all histamine receptors in human tubules; however, only TECs expressed all the receptors. Indeed, histamine elicited a sigmoid dose response curve for IP3 production, shifted to the right by chlorpheniramine maleate, and elicited a double bell-shaped curve for cAMP production, partially suppressed by the selective H2R, H3R and H4R antagonists when each added alone, and completely ablated when combined together. CONCLUSIONS: Herein, we report the identification of all four histamine receptors in human renal tubules. PMID- 25725700 TI - Genotype variability and haplotype profile of ABCB1 (MDR1) gene polymorphisms in Macedonian population. AB - The aim of this study was to evaluate the most common ABCB1 (MDR1, P glycoprotein) polymorphisms in the population of R. Macedonia and compare the allele and haplotype frequencies with the global geographic data reported from different ethnic populations. The total of 107 healthy Macedonian individuals from the general population was included. Genotypes for the ABCB1 for three polymorphisms C1236T [rs1128503], G2677A/T [rs2032582] and C3435T [rs1045642] were analyzed by Real-Time PCR. Obtained allele frequencies for these three SNPs were similar to those observed in other European Caucasians. The detected genotype frequencies were 33.6% for 1236CC, 44.9% for 1236CT and 21.5% for 1236TT in exon 12; 32.7%, 44.9% and 22.4% for 2677GG, 2677GT and 2677GT consecutively in exon 21; and 25.2% for 3435CC, 52.3% for 3435CT and 22.5% for 3435TT in exon 26.Strong LD was observed in our study among all three SNPs with the highest association confirmed for C1236T and G2677T ((D'=0.859, r2=0.711). Eight different haplotypes were identified and the most prominent was the CGC haplotype (45.3%). Our study was the first to have documented the distribution of ABCB1 alleles, genotypes and haplotypes in the population of R. Macedonia. The obtained results can help in the prediction of different response to the drugs that are P glycoprotein substrates. Additionally, in the era of individualized medicine the determination of the P-glycoprotein genotype might be a good predictive marker for determination of the subpopulations with higher risk to certain diseases. PMID- 25725701 TI - Histological structure of the thyroid gland in apolipoprotein E deficient female mice after levothyroxine application. AB - The aim of this study was to determine the histological characteristics of the thyroid gland in ApoE KO-/- mice following the application of levothyroxine (l thyroxine). A total of 12 female ApoE KO-/- mice were divided into two groups. A control group of mice received distilled water and the experimental group received l-thyroxine dissolved in drinking water at a daily dose of 2 ug/ml, over 12 weeks. The paraffin sections were processed with the usual haematoxilin-eosin technique of staining. Qualitative histological analysis demonstrated: the presence of large distended follicles in the peripheral areas of the gland; fulfillment of the lumen of follicles with an ample amount of colloid; complete absence of resorptive vacuoles in the colloid; a flattened follicullar epithelium. Morphometric assessment showed a significant increase in the diameters of follicles in the peripheral areas of the gland and a significant decrease in the height of the follicullar epithelium (p<0,001). Our results demonstrated that l-thyroxine causes characteristic morphological changes in the structure of the thyroid gland in the direction of the occurrence of hyperthyroidism. PMID- 25725702 TI - Ischaemia-driven optimal therapeutic approach in asymptomatic patients with high cardiovascular risk: the value of clinical, laboratory and myocardial spect imaging findings. AB - BACKGROUND: We wanted to evaluate the presense of myocardial ischaemia in asymptomatic patients with high cardiovascular risk, the influencing clinical and laboratory factors and the impact of ischaemia on final management decision. MATERIAL AND METHODS: We evaluated 60 asymptomatic patients with high CV risk, who underwent SPECT myocardial perfusion imaging (MPI) for detection of suspected CAD. We used the 17 segment model for quantitative and semiquantitative scan perfusion and function analysis using perfusion scores. All patients had full blood laboratory analyses including lipid values, presence of albuminuria, rest and stress ECG. Logistic regression analysis was used to assess the impact of clinical and laboratory parameters on myocardial ischaemia prevalence. RESULTS: Stress-inducible ischaemia was found in 19 pts (33%), fixed defects were found in 13% and mixed defects in 9% of cases. The average ischaemia amount was 10%. Mild ischaemia was found in 12 patients (64%)--summed stress score (SDS)<4, moderate ischaemia in 5 patients (26%)--SDS 5-7 and severely abnormal scans in 2 patients (10%)--SDS>7. Severe ischaemia was only related to the duration of diabetes. Six pts with severe ischaemia had ST depression>2 mm on stress study, and a higher wall motion index and LVEF fall>5% during stress study (p<0.01). Stepwise logistic regression analysis for prediction of stress-induced ischaemia showed OR 2.4 (95% CI 1.7-3.6) for stress-induced ECG changes and OR 3.9 for presence of DM over 10 y (95% CI 2.3-6.6). Seven patients with ischaemia>10%, were referred for coronary angiography. CONCLUSIONS: MPI is a valuable method for preclinical assessment of myocardial ischaemia in patients with high CV risk, which can improve prognosis and guide treatment decision. PMID- 25725703 TI - Carotid artery disease in diabetic patients. AB - There are two points of view on the interplay between carotid artery disease and diabetes mellitus: Diabetes mellitus has been recognized as one of the main determinants for the presence and progression of asymptomatic and symptomatic carotid artery disease; and carotid intima-media thickness has been defined as a useful tool for risk stratification of this population. Hyperglycaemia, duration of diabetes, arterial hypertension, cholesterol and inflammatory markers have previously been determined as independent factors for carotid atherosclerosis in diabetes, and aging as its predictor in this population by our own results. This paper focuses on the particularities of risk factors in diabetic patients (especially in type 2) and evidence-based guidelines for the management and risk reduction of these patients with stroke and/or carotid artery disease. At present, carotid ultrasound is recommended in diabetic patients with cerebrovascular symptoms. Since the prevalence of diabetes increases constantly, we attempt to address refreshment of criteria for screening of carotid artery disease in the diabetic population. It could be recommended for diabetic patients with at least one more risk factors and for diabetic patients above 60 years of age. PMID- 25725704 TI - Can clinical supervision sustain our workforce in the current healthcare landscape? Findings from a Queensland study of allied health professionals. AB - OBJECTIVE: Clinical supervision is widely recognised as a mechanism for providing professional support, professional development and clinical governance for healthcare workers. There have been limited studies about the effectiveness of clinical supervision for allied health and minimal studies conducted within the Australian health context. The aim of the present study was to identify whether clinical supervision was perceived to be effective by allied health professionals and to identify components that contributed to effectiveness. Participants completed an anonymous online questionnaire, administered through the health service's intranet. METHODS: A cross-sectional study was conducted with community allied health workers (n = 82) 8 months after implementation of structured clinical supervision. Demographic data (age, gender), work-related history (profession employment level, years of experience), and supervision practice (number and length of supervision sessions) were collected through an online survey. The outcome measure, clinical supervision effectiveness, was operationalised using the Manchester Clinical Supervision Scale-26 (MCSS-26). Data were analysed with Pearson correlation (r) and independent sample t-tests (t) with significance set at 0.05 (ie the probability of significant difference set at P < 0.05). RESULTS: The length of the supervision sessions (r(s) >= 0.44), the number of sessions (r(s) >= 0.35) and the total period supervision had been received (r(s) >= 0.42) were all significantly positively correlated with the MCSS-26 domains of clinical supervision effectiveness. Three individual variables, namely 'receiving clinical supervision', 'having some choice in the allocation of clinical supervisor' and 'having a completed clinical supervision agreement', were also significantly associated with higher total MCSS-26 scores (P(s) < 0.014). CONCLUSION: The results of the study demonstrate that when clinical supervision uses best practice principles, it can provide professional support for allied health workers, even during times of rapid organisational change. PMID- 25725705 TI - Perspective: Vibrational-induced steric effects in bimolecular reactions. AB - The concept of preferred collision geometry in a bimolecular reaction is at the heart of reaction dynamics. Exemplified by a series of crossed molecular beam studies on the reactions of a C-H stretch-excited CHD3(v1 = 1) with F, Cl, and O((3)P) atoms, two types of steric control of chemical reactivity will be highlighted. A passive control is governed in a reaction with strong anisotropic entry valley that can significantly steer the incoming trajectories. This disorientation effect is illustrated by the F and O((3)P) + CHD3(v1 = 1) reactions. In the former case, the long-range anisotropic interaction acts like an optical "negative" lens by deflecting the trajectories away from the favored transition-state geometry, and thus inhibiting the bond rupture of the stretch excited CHD3. On the contrary, the interaction between O((3)P) and CHD3(v1 = 1) behaves as a "positive" lens by funneling the large impact-parameter collisions into the cone of acceptance, and thereby enhances the reactivity. As for reactions with relatively weak anisotropic interactions in the entry valley, an active control can be performed by exploiting the polarization property of the infrared excitation laser to polarize the reactants in space, as demonstrated in the reaction of Cl with a pre-aligned CHD3(v1 = 1) reactant. A simpler case, the end-on versus side-on collisions, will be elucidated for demonstrating a means to disentangle the impact-parameter averaging. A few general remarks about some closely related issues, such as mode-, bond-selectivity, and Polanyi's rules, are made. PMID- 25725706 TI - Dynamic properties of force fields. AB - Molecular-dynamics simulations are increasingly used to study dynamic properties of biological systems. With this development, the ability of force fields to successfully predict relaxation timescales and the associated conformational exchange processes moves into focus. We assess to what extent the dynamic properties of model peptides (Ac-A-NHMe, Ac-V-NHMe, AVAVA, A10) differ when simulated with different force fields (AMBER ff99SB-ILDN, AMBER ff03, OPLS-AA/L, CHARMM27, and GROMOS43a1). The dynamic properties are extracted using Markov state models. For single-residue models (Ac-A-NHMe, Ac-V-NHMe), the slow conformational exchange processes are similar in all force fields, but the associated relaxation timescales differ by up to an order of magnitude. For the peptide systems, not only the relaxation timescales, but also the conformational exchange processes differ considerably across force fields. This finding calls the significance of dynamic interpretations of molecular-dynamics simulations into question. PMID- 25725707 TI - Correlation consistent basis sets for the atoms In-Xe. AB - In this work, the correlation consistent family of Gaussian basis sets has been expanded to include all-electron basis sets for In-Xe. The methodology for developing these basis sets is described, and several examples of the performance and utility of the new sets have been provided. Dissociation energies and bond lengths for both homonuclear and heteronuclear diatomics demonstrate the systematic convergence behavior with respect to increasing basis set quality expected by the family of correlation consistent basis sets in describing molecular properties. Comparison with recently developed correlation consistent sets designed for use with the Douglas-Kroll Hamiltonian is provided. PMID- 25725708 TI - A continued fraction resummation form of bath relaxation effect in the spin-boson model. AB - In the spin-boson model, a continued fraction form is proposed to systematically resum high-order quantum kinetic expansion (QKE) rate kernels, accounting for the bath relaxation effect beyond the second-order perturbation. In particular, the analytical expression of the sixth-order QKE rate kernel is derived for resummation. With higher-order correction terms systematically extracted from higher-order rate kernels, the resummed quantum kinetic expansion approach in the continued fraction form extends the Pade approximation and can fully recover the exact quantum dynamics as the expansion order increases. PMID- 25725709 TI - Gaussian Markov transition models of molecular kinetics. AB - The slow processes of molecular dynamics (MD) simulations--governed by dominant eigenvalues and eigenfunctions of MD propagators--contain essential information on structures of and transition rates between long-lived conformations. Existing approaches to this problem, including Markov state models and the variational approach, represent the dominant eigenfunctions as linear combinations of a set of basis functions. However the choice of the basis functions and their systematic statistical estimation are unsolved problems. Here, we propose a new class of kinetic models called Markov transition models (MTMs) that approximate the transition density of the MD propagator by a mixture of probability densities. Specifically, we use Gaussian MTMs where a Gaussian mixture model is used to approximate the symmetrized transition density. This approach allows for a direct computation of spectral components. In contrast with the other Galerkin type approximations, our approach can automatically adjust the involved Gaussian basis functions and handle the statistical uncertainties in a Bayesian framework. We demonstrate by some simulation examples the effectiveness and accuracy of the proposed approach. PMID- 25725710 TI - Non-pairwise additivity of the leading-order dispersion energy. AB - The leading-order (i.e., dipole-dipole) dispersion energy is calculated for one dimensional (1D) and two-dimensional (2D) infinite lattices, and an infinite 1D array of infinitely long lines, of doubly occupied locally harmonic wells. The dispersion energy is decomposed into pairwise and non-pairwise additive components. By varying the force constant and separation of the wells, the non pairwise additive contribution to the dispersion energy is shown to depend on the overlap of density between neighboring wells. As well separation is increased, the non-pairwise additivity of the dispersion energy decays. The different rates of decay for 1D and 2D lattices of wells is explained in terms of a Jacobian effect that influences the number of nearest neighbors. For an array of infinitely long lines of wells spaced 5 bohrs apart, and an inter-well spacing of 3 bohrs within a line, the non-pairwise additive component of the leading-order dispersion energy is -0.11 kJ mol(-1) well(-1), which is 7% of the total. The polarizability of the wells and the density overlap between them are small in comparison to that of the atomic densities that arise from the molecular density partitioning used in post-density-functional theory (DFT) damped dispersion corrections, or DFT-D methods. Therefore, the nonadditivity of the leading-order dispersion observed here is a conservative estimate of that in molecular clusters. PMID- 25725711 TI - Electron transfer statistics and thermal fluctuations in molecular junctions. AB - We derive analytical expressions for probability distribution function (PDF) for electron transport in a simple model of quantum junction in presence of thermal fluctuations. Our approach is based on the large deviation theory combined with the generating function method. For large number of electrons transferred, the PDF is found to decay exponentially in the tails with different rates due to applied bias. This asymmetry in the PDF is related to the fluctuation theorem. Statistics of fluctuations are analyzed in terms of the Fano factor. Thermal fluctuations play a quantitative role in determining the statistics of electron transfer; they tend to suppress the average current while enhancing the fluctuations in particle transfer. This gives rise to both bunching and antibunching phenomena as determined by the Fano factor. The thermal fluctuations and shot noise compete with each other and determine the net (effective) statistics of particle transfer. Exact analytical expression is obtained for delay time distribution. The optimal values of the delay time between successive electron transfers can be lowered below the corresponding shot noise values by tuning the thermal effects. PMID- 25725712 TI - H + H2 quantum dynamics using potential energy surfaces based on the XYG3 type of doubly hybrid density functionals: validation of the density functionals. AB - The potential energy surfaces for the H + H2 exchange reaction are determined, using the standard Becke-3_parameter-Lee-Yang-Parr (B3LYP) hybrid exchange correlation functional and the recently developed XYG3 type (xDH) doubly hybrid functionals. Quantum dynamical results calculated on these density functional theory surfaces revealed that the accuracy for the surfaces from the xDH functionals is quite satisfactory as compared to the benchmark Boothroyd-Keogh Martin-Peterson-2 surface, whereas B3LYP is wholly inadequate in describing this simplest reaction despite the fact that it has been widely used to study reactions in complex systems. It is shown that further improvements can be achieved if the xDH functional parameters are fine-tuned to be reaction specific. PMID- 25725713 TI - Mesoscale simulations of shockwave energy dissipation via chemical reactions. AB - We use a particle-based mesoscale model that incorporates chemical reactions at a coarse-grained level to study the response of materials that undergo volume reducing chemical reactions under shockwave-loading conditions. We find that such chemical reactions can attenuate the shockwave and characterize how the parameters of the chemical model affect this behavior. The simulations show that the magnitude of the volume collapse and velocity at which the chemistry propagates are critical to weaken the shock, whereas the energetics in the reactions play only a minor role. Shock loading results in transient states where the material is away from local equilibrium and, interestingly, chemical reactions can nucleate under such non-equilibrium states. Thus, the timescales for equilibration between the various degrees of freedom in the material affect the shock-induced chemistry and its ability to attenuate the propagating shock. PMID- 25725714 TI - Surface hopping with a manifold of electronic states. I. Incorporating surface leaking to capture lifetimes. AB - We investigate the incorporation of the surface-leaking (SL) algorithm into Tully's fewest-switches surface hopping (FSSH) algorithm to simulate some electronic relaxation induced by an electronic bath in conjunction with some electronic transitions between discrete states. The resulting SL-FSSH algorithm is benchmarked against exact quantum scattering calculations for three one dimensional model problems. The results show excellent agreement between SL-FSSH and exact quantum dynamics in the wide band limit, suggesting the potential for a SL-FSSH algorithm. Discrepancies and failures are investigated in detail to understand the factors that will limit the reliability of SL-FSSH, especially the wide band approximation. Considering the easiness of implementation and the low computational cost, we expect this method to be useful in studying processes involving both a continuum of electronic states (where electronic dynamics are probabilistic) and processes involving only a few electronic states (where non adiabatic processes cannot ignore short-time coherence). PMID- 25725715 TI - Surface hopping with a manifold of electronic states. II. Application to the many body Anderson-Holstein model. AB - We investigate a simple surface hopping (SH) approach for modeling a single impurity level coupled to a single phonon and an electronic (metal) bath (i.e., the Anderson-Holstein model). The phonon degree of freedom is treated classically with motion along--and hops between--diabatic potential energy surfaces. The hopping rate is determined by the dynamics of the electronic bath (which are treated implicitly). For the case of one electronic bath, in the limit of small coupling to the bath, SH recovers phonon relaxation to thermal equilibrium and yields the correct impurity electron population (as compared with numerical renormalization group). For the case of out of equilibrium dynamics, SH current voltage (I-V) curve is compared with the quantum master equation (QME) over a range of parameters, spanning the quantum region to the classical region. In the limit of large temperature, SH and QME agree. Furthermore, we can show that, in the limit of low temperature, the QME agrees with real-time path integral calculations. As such, the simple procedure described here should be useful in many other contexts. PMID- 25725716 TI - Generic expansion of the Jastrow correlation factor in polynomials satisfying symmetry and cusp conditions. AB - Jastrow correlation factors play an important role in quantum Monte Carlo calculations. Together with an orbital based antisymmetric function, they allow the construction of highly accurate correlation wave functions. In this paper, a generic expansion of the Jastrow correlation function in terms of polynomials that satisfy both the electron exchange symmetry constraint and the cusp conditions is presented. In particular, an expansion of the three-body electron electron-nucleus contribution in terms of cuspless homogeneous symmetric polynomials is proposed. The polynomials can be expressed in fairly arbitrary scaling function allowing a generic implementation of the Jastrow factor. It is demonstrated with a few examples that the new Jastrow factor achieves 85%-90% of the total correlation energy in a variational quantum Monte Carlo calculation and more than 90% of the diffusion Monte Carlo correlation energy. PMID- 25725717 TI - Charge-displacement analysis via natural orbitals for chemical valence: charge transfer effects in coordination chemistry. AB - We recently devised a simple scheme for analyzing on quantitative grounds the Dewar-Chatt-Duncanson donation and back-donation in symmetric coordination complexes. Our approach is based on a symmetry decomposition of the so called Charge-Displacement (CD) function quantifying the charge flow, upon formation of a metal (M)-substrate (S) bond, along the M-S interaction axis and provides clear cut measures of donation and back-donation charges in correlation with experimental observables [G. Bistoni et al., Angew. Chem., Int. Ed. 52, 11599 (2013)]. The symmetry constraints exclude of course from the analysis most systems of interest in coordination chemistry. In this paper, we show how to entirely overcome this limitation by taking advantage of the properties of the natural orbitals for chemical valence [M. Mitoraj and A. Michalak, J. Mol. Model. 13, 347 (2007)]. A general scheme for disentangling donation and back-donation in the CD function of both symmetric and non-symmetric systems is presented and illustrated through applications to M-ethyne (M = Au, Ni and W) coordination bonds, including an explicative study on substrate activation in a model reaction mechanism. PMID- 25725718 TI - Counting the number of excited states in organic semiconductor systems using topology. AB - Exciton scattering theory attributes excited electronic states to standing waves in quasi-one-dimensional molecular materials by assuming a quasi-particle picture of optical excitations. The quasi-particle properties at branching centers are described by the corresponding scattering matrices. Here, we identify the topological invariant of a scattering center, referred to as its winding number, and apply topological intersection theory to count the number of quantum states in a quasi-one-dimensional system. PMID- 25725719 TI - An efficient implementation of the localized operator partitioning method for electronic energy transfer. AB - The localized operator partitioning method [Y. Khan and P. Brumer, J. Chem. Phys. 137, 194112 (2012)] rigorously defines the electronic energy on any subsystem within a molecule and gives a precise meaning to the subsystem ground and excited electronic energies, which is crucial for investigating electronic energy transfer from first principles. However, an efficient implementation of this approach has been hindered by complicated one- and two-electron integrals arising in its formulation. Using a resolution of the identity in the definition of partitioning, we reformulate the method in a computationally efficient manner that involves standard one- and two-electron integrals. We apply the developed algorithm to the 9-((1-naphthyl)-methyl)-anthracene (A1N) molecule by partitioning A1N into anthracenyl and CH2-naphthyl groups as subsystems and examine their electronic energies and populations for several excited states using configuration interaction singles method. The implemented approach shows a wide variety of different behaviors amongst the excited electronic states. PMID- 25725720 TI - Tunneling splittings in formic acid dimer: an adiabatic approximation to the Herring formula. AB - Small symmetric molecules and low-dimensional model Hamiltonians are excellent systems for benchmarking theories to compute tunneling splittings. In this work, we investigate a three dimensional model Hamiltonian coupled to a harmonic bath that describes concerted proton transfer in the formic acid dimer. The three modes include the symmetric proton stretch, the symmetric dimer rock, and the dimer stretch. These modes provide a paradigm for the symmetric and anti symmetric coupled tunneling pathways, these being recognized in the literature as two of the more important classes of coupling. The effects of selective vibrational excitation and coupling to a bath on the tunneling splittings are presented. The splittings for highly excited states are computed using a novel method that makes an adiabatic approximation to the Herring estimate. Results, which are in excellent agreement with the exact splittings, are compared with those obtained using the Makri-Miller approach. This latter method has been shown to provide quality results for tunneling splittings including highly excited vibrational states. PMID- 25725721 TI - A correction for the Hartree-Fock density of states for jellium without screening. AB - We revisit the Hartree-Fock (HF) calculation for the uniform electron gas, or jellium model, whose predictions--divergent derivative of the energy dispersion relation and vanishing density of states (DOS) at the Fermi level--are in qualitative disagreement with experimental evidence for simple metals. Currently, this qualitative failure is attributed to the lack of screening in the HF equations. Employing Slater's hyper-Hartree-Fock (HHF) equations, derived variationally, to study the ground state and the excited states of jellium, we find that the divergent derivative of the energy dispersion relation and the zero in the DOS are still present, but shifted from the Fermi wavevector and energy of jellium to the boundary between the set of variationally optimised and unoptimised HHF orbitals. The location of this boundary is not fixed, but it can be chosen to lie at arbitrarily high values of wavevector and energy, well clear from the Fermi level of jellium. We conclude that, rather than the lack of screening in the HF equations, the well-known qualitative failure of the ground state HF approximation is an artifact of its nonlocal exchange operator. Other similar artifacts of the HF nonlocal exchange operator, not associated with the lack of electronic correlation, are known in the literature. PMID- 25725722 TI - Free-complement local-Schrodinger-equation method for solving the Schrodinger equation of atoms and molecules: basic theories and features. AB - The free-complement (FC) method is a general method for solving the Schrodinger equation (SE): The produced wave function has the potentially exact structure as the solution of the Schrodinger equation. The variables included are determined either by using the variational principle (FC-VP) or by imposing the local Schrodinger equations (FC-LSE) at the chosen set of the sampling points. The latter method, referred to as the local Schrodinger equation (LSE) method, is integral-free and therefore applicable to any atom and molecule. The purpose of this paper is to formulate the basic theories of the LSE method and explain their basic features. First, we formulate three variants of the LSE method, the AB, HS, and H(T)Q methods, and explain their properties. Then, the natures of the LSE methods are clarified in some detail using the simple examples of the hydrogen atom and the Hooke's atom. Finally, the ideas obtained in this study are applied to solving the SE of the helium atom highly accurately with the FC-LSE method. The results are very encouraging: we could get the world's most accurate energy of the helium atom within the sampling-type methodologies, which is comparable to those obtained with the FC-VP method. Thus, the FC-LSE method is an easy and yet a powerful integral-free method for solving the Schrodinger equation of general atoms and molecules. PMID- 25725723 TI - Towards time-dependent current-density-functional theory in the non-linear regime. AB - Time-Dependent Density-Functional Theory (TDDFT) is a well-established theoretical approach to describe and understand irradiation processes in clusters and molecules. However, within the so-called adiabatic local density approximation (ALDA) to the exchange-correlation (xc) potential, TDDFT can show insufficiencies, particularly in violently dynamical processes. This is because within ALDA the xc potential is instantaneous and is a local functional of the density, which means that this approximation neglects memory effects and long range effects. A way to go beyond ALDA is to use Time-Dependent Current-Density Functional Theory (TDCDFT), in which the basic quantity is the current density rather than the density as in TDDFT. This has been shown to offer an adequate account of dissipation in the linear domain when the Vignale-Kohn (VK) functional is used. Here, we go beyond the linear regime and we explore this formulation in the time domain. In this case, the equations become very involved making the computation out of reach; we hence propose an approximation to the VK functional which allows us to calculate the dynamics in real time and at the same time to keep most of the physics described by the VK functional. We apply this formulation to the calculation of the time-dependent dipole moment of Ca, Mg and Na2. Our results show trends similar to what was previously observed in model systems or within linear response. In the non-linear domain, our results show that relaxation times do not decrease with increasing deposited excitation energy, which sets some limitations to the practical use of TDCDFT in such a domain of excitations. PMID- 25725724 TI - Time-resolved phase-sensitive second harmonic generation spectroscopy. AB - A methodology based on time-resolved, phase-sensitive second harmonic generation (SHG) for probing the excited state dynamics of species at interfaces is presented. It is based on an interference measurement between the SHG from the sample and a local oscillator generated at a reference together with a lock-in measurement to remove the large constant offset from the interference. The technique is characterized by measuring the phase and excited state dynamics of the dye malachite green at the water/air interface. The key attributes of the technique are that the observed signal is directly proportional to sample concentration, in contrast to the quadratic dependence from non-phase sensitive SHG, and that the real and imaginary parts of the 2nd order non-linear susceptibility can be determined independently. We show that the method is highly sensitive and can provide high quality excited state dynamics in short data acquisition times. PMID- 25725726 TI - Collision-induced Raman scattering and the peculiar case of neon: anisotropic spectrum, anisotropy, and the inverse scattering problem. AB - Owing in part to the p orbitals of its filled L shell, neon has repeatedly come on stage for its peculiar properties. In the context of collision-induced Raman spectroscopy, in particular, we have shown, in a brief report published a few years ago [M. Chrysos et al., Phys. Rev. A 80, 054701 (2009)], that the room temperature anisotropic Raman lineshape of Ne-Ne exhibits, in the far wing of the spectrum, a peculiar structure with an aspect other than a smooth wing (on a logarithmic plot) which contrasts with any of the existing studies, and whose explanation lies in the distinct way in which overlap and exchange interactions interfere with the classical electrostatic ones in making the polarizability anisotropy, alpha? - alpha?. Here, we delve deeper into that study by reporting data for that spectrum up to 450 cm(-1) and for even- and odd-order spectral moments up to M6, as well as quantum lineshapes, generated from SCF, CCSD, and CCSD(T) models for alpha? - alpha?, which are critically compared with the experiment. On account of the knowledge of the spectrum over the augmented frequency domain, we show how the inverse scattering problem can be tackled both effectively and economically, and we report an analytic function for the anisotropy whose quantum lineshape faithfully reproduces our observations. PMID- 25725725 TI - Investigation of Compton profiles of molecular methane and ethane. AB - The Compton profiles of methane and ethane molecules have been determined at an incident photon energy of 20 keV based on the third generation synchrotron radiation, and the statistical accuracy of 0.2% is achieved near pz = 0. The density functional theory with aug-cc-pVTZ basis set was used to calculate the Compton profiles of methane and ethane. The present experimental Compton profiles are in better agreement with the theoretical calculations in the whole pz region than the previous experimental results, which indicates that the present experimental Compton profiles are accurate enough to serve as the benchmark data for methane and ethane molecules. PMID- 25725727 TI - The exact forces on classical nuclei in non-adiabatic charge transfer. AB - The decomposition of electronic and nuclear motion presented in Abedi et al. [Phys. Rev. Lett. 105, 123002 (2010)] yields a time-dependent potential that drives the nuclear motion and fully accounts for the coupling to the electronic subsystem. Here, we show that propagation of an ensemble of independent classical nuclear trajectories on this exact potential yields dynamics that are essentially indistinguishable from the exact quantum dynamics for a model non-adiabatic charge transfer problem. We point out the importance of step and bump features in the exact potential that are critical in obtaining the correct splitting of the quasiclassical nuclear wave packet in space after it passes through an avoided crossing between two Born-Oppenheimer surfaces and analyze their structure. Finally, an analysis of the exact potentials in the context of trajectory surface hopping is presented, including preliminary investigations of velocity-adjustment and the force-induced decoherence effect. PMID- 25725728 TI - 5D quantum dynamics of the H2@SWNT system: quantitative study of the rotational translational coupling. AB - The dynamics of the dihydrogen molecule when confined in carbon nanotubes with different chiralities and diameters are studied by using a 5 dimensional model considering the most relevant degrees of freedom of the system. The nuclear eigenstates are calculated for an (8,0) and a (5,0) carbon nanotubes by the State Average Multiconfigurational Time-dependent Hartree, and then studied using qualitative tools (mapping of the total wave functions onto given subspaces) and more rigorous analysis (different kinds of overlaps with reference functions). The qualitative analysis is seen to fail due to a strong coupling between the internal and translational degrees of freedom. Using more accurate tools allows us to gain a deeper insight into the behaviour of confined species. PMID- 25725729 TI - Collision-induced absorption with exchange effects and anisotropic interactions: theory and application to H2 - H2. AB - We discuss three quantum mechanical formalisms for calculating collision-induced absorption spectra. First, we revisit the established theory of collision-induced absorption, assuming distinguishable molecules which interact isotropically. Then, the theory is rederived incorporating exchange effects between indistinguishable molecules. It is shown that the spectrum can no longer be written as an incoherent sum of the contributions of the different spherical components of the dipole moment. Finally, we derive an efficient method to include the effects of anisotropic interactions in the computation of the absorption spectrum. This method calculates the dipole coupling on-the-fly, which allows for the uncoupled treatment of the initial and final states without the explicit reconstruction of the many-component wave functions. The three formalisms are applied to the collision-induced rotation-translation spectra of hydrogen molecules in the far-infrared. Good agreement with experimental data is obtained. Significant effects of anisotropic interactions are observed in the far wing. PMID- 25725730 TI - Quantum mechanical calculation of the collision-induced absorption spectra of N2 N2 with anisotropic interactions. AB - We present quantum mechanical calculations of the collision-induced absorption spectra of nitrogen molecules, using ab initio dipole moment and potential energy surfaces. Collision-induced spectra are first calculated using the isotropic interaction approximation. Then, we improve upon these results by considering the full anisotropic interaction potential. We also develop the computationally less expensive coupled-states approximation for calculating collision-induced spectra and validate this approximation by comparing the results to numerically exact close-coupling calculations for low energies. Angular localization of the scattering wave functions due to anisotropic interactions affects the line strength at low energies by two orders of magnitude. The effect of anisotropy decreases at higher energy, which validates the isotropic interaction approximation as a high-temperature approximation for calculating collision induced spectra. Agreement with experimental data is reasonable in the isotropic interaction approximation, and improves when the full anisotropic potential is considered. Calculated absorption coefficients are tabulated for application in atmospheric modeling. PMID- 25725731 TI - Unusual behavior in magnesium-copper cluster matter produced by helium droplet mediated deposition. AB - We demonstrate the ability to produce core-shell nanoclusters of materials that typically undergo intermetallic reactions using helium droplet mediated deposition. Composite structures of magnesium and copper were produced by sequential condensation of metal vapors inside the 0.4 K helium droplet baths and then gently deposited onto a substrate for analysis. Upon deposition, the individual clusters, with diameters ~5 nm, form a cluster material which was subsequently characterized using scanning and transmission electron microscopies. Results of this analysis reveal the following about the deposited cluster material: it is in the un-alloyed chemical state, it maintains a stable core shell 5 nm structure at sub-monolayer quantities, and it aggregates into unreacted structures of ~75 nm during further deposition. Surprisingly, high angle annular dark field scanning transmission electron microscopy images revealed that the copper appears to displace the magnesium at the core of the composite cluster despite magnesium being the initially condensed species within the droplet. This phenomenon was studied further using preliminary density functional theory which revealed that copper atoms, when added sequentially to magnesium clusters, penetrate into the magnesium cores. PMID- 25725732 TI - Analysis of the S2<-S0 vibronic spectrum of the ortho-cyanophenol dimer using a multimode vibronic coupling approach. AB - The S2<-S0 vibronic spectrum of the ortho-cyanophenol dimer (oCP)2 is analyzed in a joint experimental and theoretical investigation. Vibronic excitation energies up to 750 cm(-1) are covered, which extends our previous analysis of the quenching of the excitonic splitting in this and related species [Kopec et al., J. Chem. Phys. 137, 184312 (2012)]. As we demonstrate, this necessitates an extension of the coupling model. Accordingly, we compute the potential energy surfaces of the ortho-cyanophenol dimer (oCP)2 along all relevant normal modes using the approximate second-order coupled cluster method RI-CC2 and extract the corresponding coupling constants using the linear and quadratic vibronic coupling scheme. These serve as the basis to calculate the vibronic spectrum. The theoretical results are found to be in good agreement with the experimental highly resolved resonant two-photon ionization spectrum. This allows to interpret key features of the excitonic and vibronic interactions in terms of nodal patterns of the underlying vibronic wave functions. PMID- 25725733 TI - Observation of structural relaxation during exciton self-trapping via excited state resonant impulsive stimulated Raman spectroscopy. AB - We detect the change in vibrational frequency associated with the transition from a delocalized to a localized electronic state using femtosecond vibrational wavepacket techniques. The experiments are carried out in the mixed-valence linear chain material [Pt(en)2][Pt(en)2Cl2]?(ClO4)4 (en = ethylenediamine, C2H8N2), a quasi-one-dimensional system with strong electron-phonon coupling. Vibrational spectroscopy of the equilibrated self-trapped exciton is carried out using a multiple pulse excitation technique: an initial pump pulse creates a population of delocalized excitons that self-trap and equilibrate, and a time delayed second pump pulse tuned to the red-shifted absorption band of the self trapped exciton impulsively excites vibrational wavepacket oscillations at the characteristic vibrational frequencies of the equilibrated self-trapped exciton state by the resonant impulsive stimulated Raman mechanism, acting on the excited state. The measurements yield oscillations at a frequency of 160 cm(-1) corresponding to a Raman-active mode of the equilibrated self-trapped exciton with Pt-Cl stretching character. The 160 cm(-1) frequency is shifted from the previously observed wavepacket frequency of 185 cm(-1) associated with the initially generated exciton and from the 312 cm(-1) Raman-active symmetric stretching mode of the ground electronic state. We relate the frequency shifts to the changes in charge distribution and local structure that create the potential that stabilizes the self-trapped state. PMID- 25725735 TI - Resonant two-photon ionization spectroscopy of Al atoms and dimers solvated in helium nanodroplets. AB - Resonant two-photon ionization (R2PI) spectroscopy has been applied to investigate the solvation of Al atoms in helium droplets. The R2PI spectra reveal vibrational progressions that can be attributed to Al-He(n) vibrations. It is found that small helium droplets have very little chance to pick up an aluminum atom after collision. However, the pick-up probability increases with the size of the helium droplets. The absorption band that is measured by monitoring the ions on the mass of the Al dimer is found to be very little shifted with respect to the Al monomer band (~400 cm(-1)). However, using the same laser wavelength, we were unable to detect any Al(n) photoion with n larger than two. PMID- 25725734 TI - A high-resolution XAS study of aqueous Cu(II) in liquid and frozen solutions: pyramidal, polymorphic, and non-centrosymmetric. AB - High-resolution EXAFS (k = 18 A(-1)) and MXAN XAS analyses show that axially elongated square pyramidal [Cu(H2O)5](2+) dominates the structure of Cu(II) in aqueous solution, rather than 6-coordinate JT-octahedral [Cu(H2O)6](2+). Freezing produced a shoulder at 8989.6 eV on the rising XAS edge and an altered EXAFS spectrum, while 1s -> 3d transitions remained invariant in energy position and intensity. Core square pyramidal [Cu(H2O)5](2+) also dominates frozen solution. Solvation shells were found at ~3.6 A (EXAFS) or ~3.8 A (MXAN) in both liquid and frozen phases. However, MXAN analysis revealed that about half the time in liquid solution, [Cu(H2O)5](2+) associates with an axially non-bonding 2.9 A water molecule. This distant water apparently organizes the solvation shell. When the 2.9 A water molecule is absent, the second shell is undetectable to MXAN. The two structural arrangements may represent energetic minima of fluxional dissolved aqueous [Cu(H2O)5](2+). The 2.9 A trans-axial water resolves an apparent conflict of the [Cu(H2O)5](2+) core model with a dissociational exchange mechanism. In frozen solution, [Cu(H2O)5](2+) is associated with either a 3.0 A axial non bonded water molecule or an axial ClO4(-) at 3.2 A. Both structures are again of approximately equal presence. When the axial ClO4(-) is present, Cu(II) is ~0.5 A above the mean O4 plane. This study establishes [Cu(H2O)5](2+) as the dominant core structure for Cu(II) in water solution, and is the first to both empirically resolve multiple extended solution structures for fluxional [Cu(H2O)5](2+) and to provide direct evidence for second shell dynamics. PMID- 25725736 TI - The infrared spectrum of the He-C2D2 complex. AB - Spectra of the helium-acetylene complex are elusive because this weakly bound system lies close to the free rotor limit. Previously, limited assignments of He C2D2 transitions in the R(0) region of the nu3 fundamental band (~2440 cm(-1)) were published. Here, new He-C2D2 infrared spectra of this band are obtained using a tunable optical parametric oscillator laser source to probe a pulsed supersonic slit jet expansion from a cooled nozzle, and the analysis is extended to the weaker and more difficult P(1) and R(1) regions. A term value approach is used to obtain a consistent set of "experimental" energy levels. These are compared directly with calculations using two recently reported ab initio intermolecular potential energy surfaces, which exhibit small but significant differences. Rovibrational energies for the He-C2H2 complex are also calculated using both surfaces. A Coriolis model, useful for predicting spectral intensities, is used to interpret the energy level patterns, and a comparison with the isoelectronic complex He-CO is made. PMID- 25725737 TI - Use of density functional theory method to calculate structures of neutral carbon clusters Cn (3 <= n <= 24) and study their variability of structural forms. AB - In this work, we present modifications to the well-known basin hopping (BH) optimization algorithm [D. J. Wales and J. P. Doye, J. Phys. Chem. A 101, 5111 (1997)] by incorporating in it the unique and specific nature of interactions among valence electrons and ions in carbon atoms through calculating the cluster's total energy by the density functional tight-binding (DFTB) theory, using it to find the lowest energy structures of carbon clusters and, from these optimized atomic and electronic structures, studying their varied forms of topological transitions, which include a linear chain, a monocyclic to a polycyclic ring, and a fullerene/cage-like geometry. In this modified BH (MBH) algorithm, we define a spatial volume within which the cluster's lowest energy structure is to be searched, and introduce in addition a cut-and-splice genetic operator to increase the searching performance of the energy minimum than the original BH technique. The present MBH/DFTB algorithm is, therefore, characteristically distinguishable from the original BH technique commonly applied to nonmetallic and metallic clusters, technically more thorough and natural in describing the intricate couplings between valence electrons and ions in a carbon cluster, and thus theoretically sound in putting these two charged components on an equal footing. The proposed modified minimization algorithm should be more appropriate, accurate, and precise in the description of a carbon cluster. We evaluate the present algorithm, its energy-minimum searching in particular, by its optimization robustness. Specifically, we first check the MBH/DFTB technique for two representative carbon clusters of larger size, i.e., C60 and C72 against the popular cut-and-splice approach [D. M. Deaven and K. M. Ho, Phys. Rev. Lett. 75, 288 (1995)] that normally is combined with the genetic algorithm method for finding the cluster's energy minimum, before employing it to investigate carbon clusters in the size range C3-C24 studying their topological transitions. An effort was also made to compare our MBH/DFTB and its re-optimized results carried out by full density functional theory (DFT) calculations with some early DFT-based studies. PMID- 25725738 TI - Final state-resolved mode specificity in HX + OH -> X + H2O (X = F and Cl) reactions: a quasi-classical trajectory study. AB - The state-to-state dynamics of the title reactions are investigated using a quasi classical trajectory method on recently developed accurate global potential energy surfaces. Although both produce the H2O product, these two reactions have very different characteristics in the reaction energy, barrier location, and barrier height. It is shown that the H2O product is moderately excited in its three vibrational modes in the HF + OH reaction, but its stretching modes are highly excited in the HCl + OH reaction. For both reactions, the OH vibrational degree of freedom is essentially a spectator, which sequesters its energy throughout the reaction. On the other hand, the HF vibrational excitation has almost no impact on the H2O vibrational distribution while HCl converts some of its vibrational energy into the stretching modes of H2O. These mode specific correlations can be rationalized by the recently proposed Sudden Vector Projection model. PMID- 25725739 TI - Ion transport and structural dynamics in homologous ammonium and phosphonium based room temperature ionic liquids. AB - Charge transport and structural dynamics in a homologous pair of ammonium and phosphonium based room temperature ionic liquids (ILs) have been characterized over a wide temperature range using broadband dielectric spectroscopy and quasi elastic light scattering spectroscopy. We have found that the ionic conductivity of the phosphonium based IL is significantly enhanced relative to the ammonium homolog, and this increase is primarily a result of a lower glass transition temperature and higher ion mobility. Additionally, these ILs exhibit pronounced secondary relaxations which are strongly influenced by the atomic identity of the cation charge center. While the secondary relaxation in the phosphonium IL has the expected Arrhenius temperature dependence characteristic of local beta relaxations, the corresponding relaxation process in the ammonium IL was found to exhibit a mildly non-Arrhenius temperature dependence in the measured temperature range-indicative of molecular cooperativity. These differences in both local and long-range molecular dynamics are a direct reflection of the subtly different inter-ionic interactions and mesoscale structures found in these homologous ILs. PMID- 25725740 TI - Valence-bond non-equilibrium solvation model for a twisting monomethine cyanine. AB - We propose and analyze a two-state valence-bond model of non-equilibrium solvation effects on the excited-state twisting reaction of monomethine cyanines. Suppression of this reaction is thought responsible for environment-dependent fluorescence yield enhancement in these dyes. Fluorescence is quenched because twisting is accompanied via the formation of dark twisted intramolecular charge transfer (TICT) states. For monomethine cyanines, where the ground state is a superposition of structures with different bond and charge localizations, there are two possible twisting pathways with different charge localizations in the excited state. For parameters corresponding to symmetric monomethines, the model predicts two low-energy twisting channels on the excited-state surface, which leads to a manifold of TICT states. For typical monomethines, twisting on the excited state surface will occur with a small barrier or no barrier. Changes in the solvation configuration can differentially stabilize TICT states in channels corresponding to different bonds, and that the position of a conical intersection between adiabatic states moves in response to solvation to stabilize either one channel or the other. There is a conical intersection seam that grows along the bottom of the excited-state potential with increasing solvent polarity. For monomethine cyanines with modest-sized terminal groups in moderately polar solution, the bottom of the excited-state potential surface is completely spanned by a conical intersection seam. PMID- 25725741 TI - Thermal collapse and hierarchy of polymorphs in a faujasite-type zeolite and its analogous melt-quenched glass. AB - We examine the route of structural collapse and re-crystallization of faujasite type (Na,K)-LSX zeolite. As the first step, a rather stable amorphous high density phase HDAcollapse is generated through an order-disorder transition from the original zeolite via a low density phase LDAcollapse, at around 790 degrees C. We find that the overall amorphization is driven by an increase in the bond angle distribution within T-O-T and a change in ring statistics to 6-membered TO4 (T = Si(4+), Al(3+)) rings at the expense of 4-membered rings. The HDAamorph transforms into crystalline nepheline, though, through an intermediate metastable carnegieite phase. In comparison, the melt-derived glass of similar composition, HDAMQ, crystallizes directly into the nepheline phase without the occurrence of intermediate carnegieite. This is attributed to the higher structural order of the faujasite-derived HDAcollapse which prefers the re-crystallization into the highly symmetric carnegieite phase before transformation into nepheline with lower symmetry. PMID- 25725742 TI - Molecular simulation of fluids with non-identical intermolecular potentials: thermodynamic properties of 10-5 + 12-6 Mie potential binary mixtures. AB - General methods for combining interactions between particles characterised by non identical intermolecular potentials are investigated. The combination methods are tested by performing molecular dynamics simulations to determine the pressure, energy, isochoric and isobaric heat capacities, thermal expansion coefficient, isothermal compressibility, Joule-Thomson coefficient, and speed of sound of 10-5 + 12-6 Mie potential binary mixtures. In addition to the two non-identical Mie potentials, mixtures are also studied with non-identical intermolecular parameters. The combination methods are compared with results obtained by simply averaging the Mie exponents. When either the energy or size parameters are non identical, very significant differences emerge in the thermodynamic properties predicted by the alternative combination methods. The isobaric heat capacity is the thermodynamic property that is most affected by the relative magnitude of the intermolecular potential parameters and the method for combining non-identical potentials. Either the arithmetic or geometric combination of potentials provides a simple and effective way of performing simulations involving mixtures of components characterised by non-identical intermolecular potentials, which is independent of their functional form. PMID- 25725743 TI - Phase diagram of water confined in MCM-41 up to 700 MPa. AB - On the basis of measurements of NMR signal intensity and T1 and T2(*) relaxation times as a function of temperature (290 K-170 K) and pressure (0.1 MPa-700 MPa), the p-T phase diagram was made for the sample containing water inside and outside MCM-41 pores of 1.81 nm in radius. The temperature of nucleation of water confined in nanopores under normal pressure was 230 K. With increasing pressure this temperature decreased to 200 K under 300 MPa, but with further increase in pressure it did not change. PMID- 25725744 TI - What can be learned from optical two-color diffusion and thermodiffusion experiments on ternary fluid mixtures? AB - A number of optical techniques have been developed during the recent years for the investigation of diffusion and thermodiffusion in ternary fluid mixtures, both on ground and on-board the International Space Station. All these methods are based on the simultaneous measurement of refractive index changes at two different wavelengths. Here, we discuss and compare different techniques with the emphasis on optical beam deflection (OBD), optical digital interferometry, and thermal diffusion forced Rayleigh scattering (TDFRS). We suggest to formally split the data evaluation into a phenomenological parameterization of the measured transients and a subsequent transformation from the refractive index into the concentration space. In all experiments, the transients measured at two different detection wavelengths can be described by four amplitudes and two eigenvalues of the diffusion coefficient matrix. It turns out that these six parameters are subjected to large errors and cannot be determined reliably. Five good quantities, which can be determined with a high accuracy, are the stationary amplitudes, the initial slopes as defined in TDFRS experiments and by application of a heuristic criterion for similar curves, a certain mean diffusion coefficient. These amplitudes and slopes are directly linked to the Soret and thermodiffusion coefficients after transformation with the inverse contrast factor matrix, which is frequently ill-conditioned. Since only five out of six free parameters are reliably determined, including the single mean diffusion coefficient, the determination of the four entries of the diffusion matrix is not possible. We apply our results to new OBD measurements of the symmetric (mass fractions 0.33/0.33/0.33) ternary benchmark mixture n dodecane/isobutylbenzene/1,2,3,4-tetrahydronaphthalene and existing literature data for the same system. PMID- 25725745 TI - The onset of sub-surface oxidation induced by defects in a chemisorbed oxygen layer. AB - We investigate the onset of internal oxidation of a Cu(110) surface induced by oxygen subsurface adsorption via defects in the Cu(110)-(2 * 1)-O chemisorbed layer. The presence of a boundary formed by merged add-row structure domains due to a mismatch of half unit-cell leads to preferred oxygen adsorption at the subsurface tetrahedral sites. The resulting distorted Cu-O tetrahedra along the domain boundary have comparable bond length and angles to those of the bulk oxide phase of Cu2O. Our results indicate that the presence of defects in the oxygen chemisorbed adlayer can lead to the internal oxidation via the formation of Cu2O like tetrahedra in between the topmost and second outermost atomic layers at the oxygen coverage theta = 0.53 and the second and third outermost atomic layers at theta = 0.56. These results show that the internal oxidation of a metal surface can occur in the very beginning of the oxygen chemisorption process enabled by the presence of defects in the oxygen chemisorbed layer. PMID- 25725746 TI - Surface activity of octanoic acid in ethanol-water solutions from molecular simulation and experiment. AB - The surface activity of a typical surfactant, octanoic acid (OA), in ethanol water solutions is investigated with a combined experimental and molecular simulation approach. The experiments show that OA reduces the surface tension of ethanol-water solutions at low ethanol concentration, but the effectiveness decreases with increasing ethanol concentration and vanishes for ethanol concentrations above 60%. Molecular dynamics simulations are used to obtain free energy landscapes for OA as a function of the distance from the surface. The free energy driving force pushing OA to the surface decreases with increasing ethanol concentration, and becomes insignificant (i.e., less than kT) for ethanol concentrations above 70%. Thus, the decrease in the effectiveness of OA in reducing the surface tension at higher ethanol concentrations can be attributed to the decrease in the free energy driving force keeping OA at the surface. We expect these results to apply generally to hydrocarbon-based surfactants. PMID- 25725747 TI - Interference enhanced thermoelectricity in quinoid type structures. AB - Quantum interference (QI) effects in molecular junctions may be used to obtain large thermoelectric responses. We study the electrical conductance G and the thermoelectric response of a series of molecules featuring a quinoid core using density functional theory, as well as a semi-empirical interacting model Hamiltonian describing the pi-system of the molecule which we treat in the GW approximation. Molecules with a quinoid type structure are shown to have two distinct destructive QI features close to the frontier orbital energies. These manifest themselves as two dips in the transmission, that remain separated, even when either electron donating or withdrawing side groups are added. We find that the position of the dips in the transmission and the frontier molecular levels can be chemically controlled by varying the electron donating or withdrawing character of the side groups as well as the conjugation length inside the molecule. This feature results in a very high thermoelectric power factor S(2)G and figure of merit ZT, where S is the Seebeck coefficient, making quinoid type molecules potential candidates for efficient thermoelectric devices. PMID- 25725749 TI - Electric response of a metal-molecule-metal junction to laser pulse by solving hierarchical equations of motion. AB - We have combined the quantum dissipative theory and the time dependent density functional theory to perform the first principle calculation of laser induced quantum dynamical electron transport through a molecule weak bridged to two electrodes. The formalism of hierarchical equations of motion based on non equilibrium Green's function theory has been taken in this work. Numerical simulations of optical absorption spectra of benzene, laser induced transient current without and with bias, charge pumping effect, as well as the spectrum analysis from the current in Au-benzene-Au molecular junction are presented and discussed. PMID- 25725748 TI - Influence of string-like cooperative atomic motion on surface diffusion in the (110) interfacial region of crystalline Ni. AB - Although we often think about crystalline materials in terms of highly organized arrays of atoms, molecules, or even colloidal particles, many of the important properties of this diverse class of materials relating to their catalytic behavior, thermodynamic stability, and mechanical properties derive from the dynamics and thermodynamics of their interfacial regions, which we find they have a dynamics more like glass-forming (GF) liquids than crystals at elevated temperatures. This is a general problem arising in any attempt to model the properties of naturally occurring crystalline materials since many aspects of the dynamics of glass-forming liquids remain mysterious. We examine the nature of this phenomenon in the "simple" case of the (110) interface of crystalline Ni, based on a standard embedded-atom model potential, and we then quantify the collective dynamics in this interfacial region using newly developed methods for characterizing the cooperative dynamics of glass-forming liquids. As in our former studies of the interfacial dynamics of grain-boundaries and the interfacial dynamics of crystalline Ni nanoparticles (NPs), we find that the interface of bulk crystalline Ni exhibits all the characteristics of glass forming materials, even at temperatures well below the equilibrium crystal melting temperature, Tm. This perspective offers a new approach to modeling and engineering the properties of crystalline materials. PMID- 25725750 TI - Full-dimensional multilayer multiconfigurational time-dependent Hartree study of electron transfer dynamics in the anthracene/C60 complex. AB - Electron transfer at the donor-acceptor heterojunctions plays a critical role in the photoinduced process during the solar energy conversion in organic photovoltaic materials. We theoretically investigate the electron transfer process in the anthracene/C60 donor-acceptor complex by using quantum dynamics calculations. The electron-transfer model Hamiltonian with full dimensionality was built by quantum-chemical calculations. The quantum dynamics calculations were performed using the multiconfigurational time-dependent Hartree (MCTDH) theory and multilayer (ML) MCTDH methods. The latter approach (ML-MCTDH) allows us to conduct the comprehensive study on the quantum evolution of the full dimensional electron-transfer model including 4 electronic states and 246 vibrational degrees of freedom. Our quantum dynamics calculations exhibit the ultrafast anthracene -> C60 charge transfer process because of the strong coupling between excitonic and charge transfer states. This work demonstrates that the ML-MCTDH is a very powerful method to treat the quantum evolution of complex systems. PMID- 25725751 TI - Dynamics of polymer translocation through kinked nanopores. AB - Polymer translocation through nanopore has potential technological applications for DNA sequencing, where one challenge problem is to slow down translocation speed. Inspired by experimental findings that kinked nanopores exhibit a large reduction in translocation velocity compared with their straight counterparts, we investigate the dynamics of polymer translocation through kinked nanopores in two dimensions under an applied external field. With increasing the tortuosity of an array of nanopores, our analytical results show that the translocation probability decreases. Langevin dynamics simulation results support this prediction and further indicate that with increasing the tortuosity, translocation time shows a slow increase followed by a rapid increase after a critical tortuosity. This behavior demonstrates that kinked nanopores can effectively reduce translocation speed. These results are interpreted by the roles of the tortuosity for decreasing the effective nanopore diameter, increasing effective nanopore length, and greatly increasing the DNA-pore friction. PMID- 25725752 TI - Charged dendrimers under the action of AC electric fields: breathing characteristics of molecular size, polarizations, and ion distributions. AB - Langevin dynamics simulations are performed to study the response of charged dendrimers in alternating current electric fields in 3:1 salt solutions. Time evolutions of molecular size show breathing characteristics which take saw-tooth like patterns in square-wave electric fields and undulated sine-function ones in sine-wave fields. Detailed study reveals how the dendrimer and condensed ions oscillate in the electric fields, which result in polarization of the molecule. To effect a significant deformation of the dendrimer, the applied field amplitude must be larger than some critical strength Ecrit and the field frequency smaller than a threshold fcrit. The response behavior is characterized by two relaxation times in square-wave fields, both of which decrease linearly with the strong field strength larger than Ecrit. In sine-wave fields, the molecular size exhibits interesting hysteretic behavior in plotting the curves with the field variation. A Maxwell-Wagner type polarization theory is derived and proved by simulations, which connects fcrit with the strength of the applied electric field. PMID- 25725753 TI - Self-assembly and structural relaxation in a model ionomer melt. AB - Molecular dynamics simulations are used to understand the self-assembly and structural relaxation in ionomer melts containing less than 10% degree of ionization on the backbone. The self-assembly of charged sites and counterions shows structural ordering and agglomeration with a range of structures that can be achieved by changing the dielectric constant of the medium. The intermediate scattering function shows a decoupling of charge and counterion relaxation at longer length scales for only high dielectric constant and at shorter length scales for all dielectric constants. Overall, the slow structural decay of counterions in the strongly correlated ionomer system closely resembles transport properties of semi-flexible polymers. PMID- 25725754 TI - From the depletion attraction to the bridging attraction: the effect of solvent molecules on the effective colloidal interactions. AB - Depletion attraction induced by non-adsorbing polymers or small particles in colloidal solutions has been widely used as a model colloidal interaction to understand aggregation behavior and phase diagrams, such as glass transitions and gelation. However, much less attention has been paid to study the effective colloidal interaction when small particles/molecules can be reversibly attracted to large colloidal particles. At the strong attraction limit, small particles can introduce bridging attraction as it can simultaneously attach to neighbouring large colloidal particles. We use Baxter's multi-component method for sticky hard sphere systems with the Percus-Yevick approximation to study the bridging attraction and its consequence to phase diagrams, which are controlled by the concentration of small particles and their interaction with large particles. When the concentration of small particles is very low, the bridging attraction strength increases very fast with the increase of small particle concentration. The attraction strength eventually reaches a maximum bridging attraction (MBA). Adding more small particles after the MBA concentration keeps decreasing the attraction strength until reaching a concentration above which the net effect of small particles only introduces an effective repulsion between large colloidal particles. These behaviors are qualitatively different from the concentration dependence of the depletion attraction on small particles and make phase diagrams very rich for bridging attraction systems. We calculate the spinodal and binodal regions, the percolation lines, the MBA lines, and the equivalent hard sphere interaction line for bridging attraction systems and have proposed a simple analytic solution to calculate the effective attraction strength using the concentrations of large and small particles. Our theoretical results are found to be consistent with experimental results reported recently. PMID- 25725755 TI - Self-assembly of patchy colloidal dumbbells. AB - We employ Monte Carlo simulations to investigate the self-assembly of patchy colloidal dumbbells interacting via a modified Kern-Frenkel potential by probing the system concentration and dumbbell shape. We consider dumbbells consisting of one attractive sphere with diameter sigma1 and one repulsive sphere with diameter sigma2 and center-to-center distance d between the spheres. For three different size ratios, we study the self-assembled structures for different separations l = 2d/(sigma1 + sigma2) between the two spheres. In particular, we focus on structures that can be assembled from the homogeneous fluid, as these might be of interest in experiments. We use cluster order parameters to classify the shape of the formed structures. When the size of the spheres is almost equal, q = sigma2/sigma1 = 1.035, we find that, upon increasing l, spherical micelles are transformed to elongated micelles and finally to vesicles and bilayers. For size ratio q = 1.25, we observe a continuously tunable transition from spherical to elongated micelles upon increasing the sphere separation. For size ratio q = 0.95, we find bilayers and vesicles, plus faceted polyhedra and liquid droplets. Our results identify key parameters to create colloidal vesicles with attractive dumbbells in experiments. PMID- 25725756 TI - Systematic characterization of protein folding pathways using diffusion maps: application to Trp-cage miniprotein. AB - Understanding the mechanisms by which proteins fold from disordered amino-acid chains to spatially ordered structures remains an area of active inquiry. Molecular simulations can provide atomistic details of the folding dynamics which complement experimental findings. Conventional order parameters, such as root mean-square deviation and radius of gyration, provide structural information but fail to capture the underlying dynamics of the protein folding process. It is therefore advantageous to adopt a method that can systematically analyze simulation data to extract relevant structural as well as dynamical information. The nonlinear dimensionality reduction technique known as diffusion maps automatically embeds the high-dimensional folding trajectories in a lower dimensional space from which one can more easily visualize folding pathways, assuming the data lie approximately on a lower-dimensional manifold. The eigenvectors that parametrize the low-dimensional space, furthermore, are determined systematically, rather than chosen heuristically, as is done with phenomenological order parameters. We demonstrate that diffusion maps can effectively characterize the folding process of a Trp-cage miniprotein. By embedding molecular dynamics simulation trajectories of Trp-cage folding in diffusion maps space, we identify two folding pathways and intermediate structures that are consistent with the previous studies, demonstrating that this technique can be employed as an effective way of analyzing and constructing protein folding pathways from molecular simulations. PMID- 25725757 TI - Water organization between oppositely charged surfaces: implications for protein sliding along DNA. AB - Water molecules are abundant in protein-DNA interfaces, especially in their nonspecific complexes. In this study, we investigated the organization and energetics of the interfacial water by simplifying the geometries of the proteins and the DNA to represent them as two equally and oppositely charged planar surfaces immersed in water. We found that the potential of mean force for bringing the two parallel surfaces into close proximity comprises energetic barriers whose properties strongly depend on the charge density of the surfaces. We demonstrated how the organization of the water molecules into discretized layers and the corresponding energetic barriers to dehydration can be modulated by the charge density on the surfaces, salt, and the structure of the surfaces. The 1-2 layers of ordered water are tightly bound to the charged surfaces representing the nonspecific protein-DNA complex. This suggests that water might mediate one-dimensional diffusion of proteins along DNA (sliding) by screening attractive electrostatic interactions between the positively charged molecular surface on the protein and the negatively charged DNA backbone and, in doing so, reduce intermolecular friction in a manner that smoothens the energetic landscape for sliding, and facilitates the 1D diffusion of the protein. PMID- 25725758 TI - Publisher's Note: "A model-free temperature-dependent conformational study of n pentane in nematic liquid crystals" [J. Chem. Phys. 142, 024904 (2015)]. PMID- 25725759 TI - Publisher's Note: "Phase behavior of a family of truncated hard cubes" [J. Chem. Phys. 142, 054904 (2015)]. PMID- 25725760 TI - Women and children first. AB - Women and children first! is a phrase rather infamously associated with the sinking Titanic. Although without basis in maritime law, it reflects an ethical imperative to protect those who historically are perceived as the most vulnerable in times of peril, diametrically opposed to the skewed survival-of-the-fittest posture. (Women are of course as fit or fitter than men, but that would take another editorial.) Global commitment to protecting maternal and child health (MCH) is integral to public health, and to sustainable social and economic development as well. The World Bank estimates that the global economic burden of disease could be reduced by up to 30% with optimal implementation of half a dozen cost-effective and affordable public health and clinical services: family planning, antenatal and delivery care, immunization, integrated management of childhood illness and HIV/AIDS prevention. The UN recognized MCH as integral to its Millennium Development Goals. Then last year, the Open Working Group on Sustainable Development Goals post-2015 set specific MCH targets for the world: Goal 3 (Ensure healthy lives and promote wellbeing for all at all ages) includes ending preventable neonatal and under-5 mortality by 2030 and reducing the global maternal mortality ratio to 70 per 100,000 live births (Cuba's was 38.9 in 2013). PMID- 25725761 TI - Meet Cuban Ebola fighters: interview with Felix Baez and Jorge Perez. A MEDICC Review exclusive. AB - Tramping through the Himalayan snows to treat patients after the 2005 Pakistan earthquake, internist Felix Baez could never have imagined he would be on the front lines of Ebola in Sierra Leone nine years later....much less that he would contract the deadly virus, live to tell the story and also to return to his team in Africa to continue the fight. At his side in the Geneva University Hospital, where he was airlifted, was Dr Jorge Perez, today director of Cuba's Pedro Kouri Tropical Medicine Institute (IPK), but best known as "Cuba's AIDS doctor." Times have changed for both physicians, and Ebola is first on their minds as it rages on. At this writing, while there is cautious optimism in Liberia, the epidemic is not yet under control. Ebola has already infected nearly 22,000 people, taken over 8600 lives; Sierra Leone is one of the countries hardest hit. Among the sick and dying have been too many local health workers: 103 of the 138 infected, at last count. The first to sound the global alarm was Doctors Without Borders, which, like Cuba, already had health professionals on the ground in Africa; they were joined by many more, and Cuba was the country that offered the most assistance once WHO called for nations to step up with funds and, most importantly, human resources. Cuba sent 256 volunteers, all with significant international emergency experience: 38 to Guinea, 53 to Liberia and 165 to Sierra Leone. And more wait in the wings, specially-trained disaster medical workers who have already received their first round of Ebola courses at IPK. These Cuban and other international volunteers are bringing patients back from the brink of death, assisting national health workers and community educators. And people like Jorge Perez are working to get to the bottom of Ebola to help prevent its spread throughout Africa and to other parts of the world. But to keep an epidemic like this from happening again, it will take more, much more. Not only could the global community have done a better job this time around. But as Jim Kim, President of the World Bank admonished, Ebola didn't start with disease, but rather with historic inequalities, the virus festering within health systems barely able to function. A lesson for us all. Hours before Dr Baez's return to Sierra Leone-where he is now-MEDICC Review interviewed him and Dr Perez at IPK in Havana. PMID- 25725762 TI - Lowering infant mortality in Cuba: Fernando Dominguez MD PhD. Neonatologist, Ramon Gonzalez Coro University Maternity Hospital, Havana. AB - Neonatologist Dr Fernando Dominguez served two years in a remote municipality of Cuba's Guantanamo Province upon graduation from medical school in 1973. Continuing his commitment to vulnerable populations, he joined the Cuban team in the Democratic Republic of the Congo, serving as a family doctor attending neonates and children. After returning to Cuba, he completed his pediatric residency and later became head of the neurodevelopment department at Havana's Ramon Gonzalez Coro University Maternity Hospital, where he has worked for over three decades. Dr Dominguez holds a doctorate in medical sciences, and since 1995 has served on the board of the Cuban Society of Pediatrics, where he was President from 2005-2011. He is also a member of the Ministry of Public Health's National Bioethics Commission; President of the Scientific Council of the Manuel Fajardo Medical School; on the Executive Board of the Latin American Association of Pediatrics; and a member of the Permanent Commission of the International Pediatric Association (IPA). Since 2010, he has served on IPA's Commission for Child Environmental Health and is the Editor-in-Chief of the pediatric section of Infomed, Cuba's national health portal. PMID- 25725763 TI - Neurodevelopment of very low birth weight infants in the first two years of life in a Havana tertiary care hospital. AB - INTRODUCTION: Improved survival rates of neonates with very low birth weight (<1500 g) have led to a higher incidence of neurodevelopmental sequelae. OBJECTIVE: Examine neurodevelopment outcomes over the first two years of life of infants who weighed <1500 g at birth, in relation to birth weight, gestational age and 1-minute and 5-minute Apgar scores, in a Havana tertiary care hospital. METHODS: A case-series study was conducted to assess neurodevelopment outcomes of very low birth weight infants over their first two years of life. The study population comprised 116 surviving neonates with very low birth weight (<1500 g), born in the Dr Ramon Gonzalez Coro University Maternity Hospital in Havana, Cuba, 2006-2010. A longitudinal, multidisciplinary and interdisciplinary follow up of all infants' neurodevelopment was performed, from hospital discharge to age two years, corrected for gestational age at birth. Data on each infant's perinatal variables were collected: birth weight in grams, gestational age at birth, and 1 minute and 5-minute Apgar scores. Patients were classified as having normal neurodevelopment, mild abnormalities and moderate-to-severe abnormalities. Pearson's chi-square test was used to determine possible relationships between perinatal variables studied and neurodevelopment, with exact sampling distribution and 95% confidence level. RESULTS: Normal neurodevelopment was observed in 69% of very low birth weight infants, 25.9% had mild abnormalities, and 5.2% displayed moderate-to-severe abnormalities. The results demonstrate a statistically significant relationship between gestational age and neurodevelopmental outcomes; more neurodevelopmental abnormalities were found in infants born at earlier gestational age (<30 weeks). CONCLUSIONS: Surviving very low birth weight neonates with lower gestational age at birth face a higher risk of neurodevelopmental abnormalities. PMID- 25725764 TI - New references for neonatal weight by gestational age and sex, Holguin, Cuba. AB - INTRODUCTION: Birth weight is considered to be the best predictor of an infant's health status in the neonatal phase. In the Americas, several studies have set the foundation for determining references birth weights. In Cuba there is a report on anthropometric patterns in neonates in 1990 from a maternity ward in Havana, but there are no updated neonatal weight distribution curves by gestational age and sex, as suggested by WHO. OBJECTIVE: Create birth weight percentile distribution tables and curves for neonates by gestational age and sex in Holguin Municipality, capital of the eastern Cuban province of the same name. METHODS: A retrospective longitudinal study was designed in a universe of 16,018 neonates born alive, delivered within a gestational range of 30 to 42 weeks in the maternity unit of the V.I. Lenin University General Hospital in Holguin Municipality between January 2008 and December 2012. Included were neonates born in the study hospital living in Holguin Municipality; neonates from multiple births were excluded. Variables included gestational age, sex, and birth weight. Gestational age- and sex-specific weight percentile distribution tables and curves were constructed based on observed values. A third-degree polynomial was applied via weighted least squares regression to smooth distribution curves. Analysis of variance was conducted to compare four years (2008, 2009, 2010 and 2011) and the coefficient of variation was calculated for each week of gestation. RESULTS: The average weight of neonates of both sexes rose from week 30 to week 42. The coefficient of variation between weeks 34 and 42 was 11.6%-19% in girls and 12.1%-21.3% in boys. The 10th percentile value at 36 weeks of gestation was 2140 g for girls and 2200 g for boys. For girls, cutoff points for the 10th percentile (small for gestational age infant) were higher at 34-42 weeks and for boys at 36-42 weeks. Applying our cutoff points to this population identified 47% more low birth weight infants than did previously applied standards. CONCLUSIONS: Marked differences were found when comparing our tables with tables from other countries. The higher references values for the 10th percentile (compared to previous ones in Cuba) in mean more neonates fall in the low birth weight category, providing greater opportunities to reduce morbidity and mortality in this high-risk group. PMID- 25725765 TI - HPLC for confirmatory diagnosis and biochemical monitoring of Cuban patients with hyperphenylalaninemias. AB - INTRODUCTION: Hyperphenylalaninemias are inborn errors of phenylalanine metabolism caused by deficiency of L-phenylalanine hydroxylase (the enzyme that converts phenylalanine to tyrosine), resulting in increased serum phenylalanine (>4 mg/dL or 240 umol/L). Phenylketonuria, or PKU, is the most common form. Untreated PKU is associated with progressive neurodevelopmental delay, evolving towards intellectual impairment. Cuba introduced a national newborn screening program for PKU in 1986. It has enabled early diagnosis and initiation of dietary treatment, reducing appearance of intellectual impairment in these patients. Originally, confirmatory diagnosis was done only by quantifying serum phenylalanine. In 2010, however, an HPLC method for quantifying serum phenylalanine and tyrosine simultaneously was validated at the National Medical Genetics Center, to perform confirmatory and differential diagnosis of hyperphenylalaninemias, as well as biochemical monitoring of patients diagnosed. OBJECTIVES: Describe experience using HPLC confirmatory diagnosis for positive cases from the National Neonatal Screening Program for Phenylketonuria and in biochemical monitoring of diagnosed patients after initiation of dietary treatment. METHODS: A descriptive retrospective case-series study was conducted from June 2010 through June 2012. The study population comprised 531 infants who tested positive in the National Neonatal Screening Program for Phenylketonuria. Variables used were serum phenylalanine concentration (first criterion of positivity) and tyrosine, phenylalanine/tyrosine ratio (second criterion, both detected by reverse-phase HPLC with direct fluorescence), hyperphenylalaninemia classification, year of diagnosis, sex, and province of origin. RESULTS: Of the samples, 97.7% (519/531) were confirmed as false positives, and 10.4% (55/531) had transient neonatal tyrosinemia. Hyperphenylalaninemia was diagnosed in 12 infants (2.2%): 1.3% (7/531) presented classical PKU, with 34.7 +/- 14.7 mg/dL phenylalanine in serum and phenylalanine/tyrosine ratio of 18.9 +/- 12.7; and 0.9% (5/531) had persistent hyperphenylalaninemia, with 8.9 +/- 3.4 mg/dL of phenylalanine and phenylalanine/tyrosine ratio of 4.5 +/- 1.6. Matanzas Province contributed more cases than any of Cuba's 14 other provinces (3/12, 25%) and there was a slight predominance of male sex (7/12, 58.3%). During biochemical monitoring, 83.3% of patients (10/12) reduced their levels of phenylalanine (<=5 mg/dL or 300 umol/L): 5 with classical PKU and all 5 with persistent hyperphenylalaninemia. The incidence of neonatal hyperphenylalaninemias was 1/22,503 live births and 1/38,577 for classical PKU. CONCLUSIONS: HPLC for simultaneous quantification of phenylalanine and tyrosine in serum meets the needs of a confirmatory test for patients testing positive in Cuba's National Neonatal Screening Program for Phenylketonuria (which has high false positive rates). It has enabled introduction in Cuba of a second PKU diagnostic criterion of positivity for both the classification of hyperphenylalaninemias and the biochemical monitoring of diagnosed patients. PMID- 25725766 TI - Cytomegalovirus and herpes simplex infections in mothers and newborns in a Havana maternity hospital. AB - INTRODUCTION: Cytomegalovirus and herpes simplex virus are associated with congenital or perinatal infection, causing potential damage to the newborn. OBJECTIVES: Determine the prevalence of active or latent infection by cytomegalovirus and herpes simplex virus in a population of mothers, congenital infection by these agents in their infants, and association between prevalence of virus infection in mothers and in their newborns. METHODS: A cross-sectional study was conducted from June to September 2012 in a population of 95 pregnant women admitted to the Dr Ramon Gonzalez Coro University Maternity Hospital during the third trimester of pregnancy, and their infants (98). Patients were tested for antibodies specific to these viruses; vaginal swabs and urine from the women and serum and urine from the newborns were tested for viral genome. The Fisher exact test with 95% confidence interval was used for comparisons. RESULTS: Of the women studied, 89.5% tested positive for cytomegalovirus and 83.2% for herpes simplex. Active infection from cytomegalovirus was detected in 16.7%, and from herpes simplex in 3.2%. Congenital cytomegalovirus infection was detected in 4.1% of newborns; no herpes simplex virus infection was found in this group. Two newborns of women with active cytomegalovirus infection were congenitally infected. CONCLUSIONS: Serology demonstrated that most of the women were immune to both viruses. Active cytomegalovirus infections are common in this population, and newborns of women with active cytomegalovirus infection during pregnancy are at increased risk of congenital infection. PMID- 25725767 TI - Factors related to antiretroviral therapy adherence in children and adolescents with HIV/AIDS in Cuba. AB - INTRODUCTION: In recent years, global initiatives to address the AIDS epidemic have produced promising advances through access to effective treatment programs. However, lack of adherence to antiretroviral therapy is a problem for pediatric patients. OBJECTIVE: Explore antiretroviral therapy adherence in children and adolescents living with HIV/AIDS in Cuba and examine its relationship with psychosocial, individual and treatment factors. METHODS: A qualitative study was carried out of 21 caregivers of children and adolescents with HIV/AIDS. Demographics and information on treatment regimen were collected by chart review. In-depth interviews were conducted to assess adherence and examine its relationship with psychosocial, individual and treatment factors. Interviews were transcribed and the information was grouped by factor category. Adherence was analyzed in relation to these three sets of factors. RESULTS: Caregivers interviewed reported adequate adherence in 17 of the 21 children. Lack of adherence was linked primarily to psychosocial factors such as additional responsibility taken on by the caregiver while grappling with his or her own illness, the presence of untreated psychological symptoms in the caregiver, perceived difficulties with family support, the child's age, and assigning treatment responsibilities to the child without taking into account his/her psychological maturity. CONCLUSIONS: The study revealed a high level of antiretroviral therapy adherence. It reconfirmed the fundamental importance of the caregiver and family support for therapeutic success in children and adolescents living with HIV/AIDS. These results, as well as the factors identified in cases of nonadherence, can contribute to a framework for assessment and specialized interventions to optimize pediatric antiretroviral adherence. PMID- 25725768 TI - Development of hypertension in a cohort of Cuban adolescents. AB - INTRODUCTION: Primary hypertension has its origins in childhood and is a risk factor for atherosclerosis; it is considered an important health problem because of its high prevalence worldwide. OBJECTIVE: Describe the development of hypertension during adolescence, including some factors that influence its persistence and progression in Cuban adolescents. METHODS: A cohort study was conducted in an intentional sample of 252 apparently healthy adolescents from the catchment area of the Heroes del Moncada Polyclinic in Plaza de la Revolucion Municipality, Havana. They were assessed in two cross-sectional studies in 2004 and 2008. Mean age at first assessment was 13.2 years, 17.1 years at the second. Variables were weight, height, body mass index, waist circumference, blood pressure, smoking, family history of hypertension and birth weight. Correlation coefficients and growth curve analyses were applied to assess blood pressure persistence. Risk of developing prehypertension and hypertension was estimated in the second assessment, based on predictors identified in the 2004 cut. Forecasting models with these factors were developed using classification trees as analytical tools. RESULTS: Of the six adolescents categorized as hypertensive in the first assessment, five still showed blood pressure alterations after four years. The main factors related to hypertension in those aged 16-19 were blood pressure itself and a body mass index >90th percentile, followed by low birth weight and abdominal obesity. Prognostic models for predicting this condition at the end of adolescence demonstrated the importance of blood pressure alterations at age 12-15 years. CONCLUSIONS: High rates of persistence and progression of hypertension during adolescence highlights the need for systematic blood pressure screening at the primary health care level and adoption of primary prevention strategies beginning in childhood. PMID- 25725769 TI - Acute liver failure in Cuban children. AB - INTRODUCTION: Acute liver failure is rare in pediatric patients and is one of the most challenging medical emergencies due to its prognostic and therapeutic implications. The best scientific evidence worldwide comes from multicenter studies in developed countries. In Cuba, there are no prior studies of this disorder in children. OBJECTIVES: Describe the main clinical features of Cuban children treated at a national referral center for acute liver failure, as defined by recognized diagnostic criteria for pediatric patients. METHODS: A case series study was conducted comprising patients diagnosed with acute liver failure treated from 2005 to 2011 in the hepatology and liver transplant service at Havana's William Soler University Children's Hospital. Variables were age group, etiology of acute liver failure, grade of hepatic encephalopathy, blood chemistry variables, and clinical outcome (whether or not spontaneous recovery of liver function occurred). Associations between variables were assessed using contingency tables, and case fatality was calculated, as well as relative risk with its 95% confidence interval. The Mann-Whitney U test was used to compare means of laboratory test results. RESULTS: Median age of the 31 patients studied (14 boys and 17 girls) was 24 months (range 1-180). Time between symptom onset and diagnosis of acute liver failure was 25.1 days (SD 16.8). Infection was the most common etiology, present in 61.3% of cases (19/31); nonhepatotropic viruses, especially cytomegalovirus, predominated in infants. Spontaneous recovery occurred in 15 patients (48.4%), 3 (9.7%) received transplants, and 13 died, for a case fatality of 41.9%. Outcome was not associated with etiology (p = 0.106), but was statistically associated with degree of hepatic encephalopathy (p <0.01): 77.8% of patients (7/9) with grades III-IV encephalopathy died, for a relative risk of 4.0 (95% CI 1.15-13.8), versus 11.1% (1/9) with grade II or less encephalopathy. Cholesterol levels were significantly lower in patients who failed to recover spontaneously (p <0.01). CONCLUSIONS: Patients' clinical characteristics in this case series were similar to those described in developed countries.The fact that nonhepatotropic viruses (basically, cytomegalovirus in infants) are the main cause of acute liver failure in Cuban children calls for further epidemiologic study and identification of local underlying determinants of this phenomenon. PMID- 25725770 TI - Lung cancer diagnostic delay in a Havana hospital. AB - INTRODUCTION: Lung cancer is one of the leading causes of death worldwide and in Cuba, where its incidence and mortality are on the rise. Diagnostic delay is a variable linked to survival and prognosis. Quantifying this delay and comparing it with data from other national and international sources may lead to planning actions to reduce its impact. OBJECTIVE: Assess diagnostic delay of lung cancer in patients at the Joaquin Albarran Clinical-Surgical Teaching Hospital, Havana, Cuba, from 2007 to 2010. METHODS: A retrospective descriptive study was conducted based on administrative data from patients diagnosed with lung cancer. The length of overall diagnostic delay was determined, as well delay between symptom onset and the patient's first contact with the health system, and delay at the primary and secondary levels of the national health system. Descriptive statistics were used to summarize the different time intervals. RESULTS: The study comprised a total of 54 patients; 74.1% were men; the largest age group was 51-60 years. Of the total, 61.1% sought care first at the primary level. Total diagnostic delay for these patients was 67.4 days: 24.3 days due to patient delay (SD 32.8), 16.2 days due to primary care delay (SD 5.2), and 26.9 days due to secondary care delay (SD 20.1). The total delay for patients first seen at the secondary care level was 79.1 days (SD 81.8): 47.8 days due to patient delay (SD 25.6), and 31.3 days due to secondary level delay (SD 14.4). CONCLUSIONS: Diagnostic delay in lung cancer is high. Patients who went directly to hospital did not benefit from shorter delay in diagnosis. PMID- 25725771 TI - Global comparisons for developing a national dementia registry in Cuba. AB - A review/analysis of current literature on exemplary multicenter registries of clinical dementias was conducted as a comparative basis for a proposed Cuban registry on cognitive impairment and dementia. The study of mental health disorders has been predominantly based on clinical concepts and criteria, and only in recent years a public health approach has been applied. Traditional epidemiological studies do not reveal patterns of cognitive impairment and behavioral disorders (particularly dementias) in routine clinical practice in a defined geographic area, which would provide essential information for long-term planning and allocation of health and social resources. Thus, multicenter clinical registries have become an important source of clinical and epidemiological data on dementias in recent decades. This article addresses the Cuban proposal for an automated national dementia registry, comparing it to others internationally. The registry would be housed in the Neurology and Neurosurgery Institute, and would include a duly protected surveillance network hosted on the Institute's website. Such a multicenter dementia registry based on epidemiological surveillance methods and limited to a defined area would provide new, valid, representative and current data on dementia occurrence patterns by subtype, flow of case identification and referral from primary care, as well as the main clinical features of patients at the time of their first contact with health services. This information would support development of health planning policies for implementation of programs aimed at improved distribution of social and health resources in the affected population, monitoring of the disorder's natural evolution and identification of preventive measures. The scientific benefits would be equally important: production of new knowledge, generation of hypotheses for clinical research projects, standardization of diagnostic criteria, and promotion of multicenter research in both national and multinational centers. PMID- 25725772 TI - Zero in on postpartum hemorrhage to reduce Cuba's maternal mortality. AB - Postpartum hemorrhage (PPH) is the most frequent cause of severe maternal morbidity (SMM) and the first direct cause of maternal death in most countries. In Africa and Asia, it accounts for about one third of all maternal deaths. Put more graphically: worldwide, one woman dies every minute from PPH. Defined as blood loss of >=500 mL after vaginal birth or >=1000 mL after cesarean delivery, PPH can be fatal in just two hours. In Cuba, between 2000 and 2012, maternal deaths directly related to obstetric causes totaled 410, 24.1% of which occurred postpartum, with PPH the leading cause.[1] While Cuba is among the Latin American countries with lowest maternal mortality, the decline has been slow over the last 20 years: in 1998, direct maternal mortality was 26.5 per 100,000 live births and in 2012, the rate was 21.5. This is troubling and deserves careful study, especially given that Cuba has a single, unified health system supported by significant political will-determining factors in important advances made in maternal-child health on par with wealthier countries. PMID- 25725773 TI - Michaelis-Menten elimination kinetics of etanercept, rheumatoid arthritis biologics, after intravenous and subcutaneous administration in rats. AB - Etanercept was approved by the Food and Drug Administration (FDA) in 2010 as a biologic agent for the treatment of rheumatoid arthritis (RA). The aim of the study was to investigate the pharmacokinetic properties of etanercept after intravenous and subcutaneous injection in rats. The plasma concentration of etanercept was determined using an enzyme-linked immunosorbent assay (ELISA). Intravenous and subcutaneous administration of 2 mg/kg of etanercept to rats showed that etanercept was slowly absorbed (time to reach the peak drug concentration [T max] = 1.60 days, bioavailability [F] = 47.18 %) and slowly eliminated (half-life [t 1/2], 2.33 days after intravenous administration and 3.31 days after subcutaneous administration). The area under the curve values on day 13 (AUC13day) were 121.25 +/- 14.37 and 48.56 +/- 6.78 MUg day/mL after intravenous and subcutaneous administration, respectively. A two-compartment model with Michaelis-Menten elimination kinetics (V max = 94.28 ug/day; K m = 10.88 ug/mL) was used to describe the pharmacokinetic profile of etanercept. Our results describe the pharmacokinetic profile of etanercept, and these results could be used for the development of etanercept biosimilars. PMID- 25725774 TI - (Dis-)Harmony in movement: effects of musical dissonance on movement timing and form. AB - While the origins of consonance and dissonance in terms of acoustics, psychoacoustics and physiology have been debated for centuries, their plausible effects on movement synchronization have largely been ignored. The present study aimed to address this by investigating whether, and if so how, consonant/dissonant pitch intervals affect the spatiotemporal properties of regular reciprocal aiming movements. We compared movements synchronized either to consonant or to dissonant sounds and showed that they were differentially influenced by the degree of consonance of the sound presented. Interestingly, the difference was present after the sound stimulus was removed. In this case, the performance measured after consonant sound exposure was found to be more stable and accurate, with a higher percentage of information/movement coupling (tau coupling) and a higher degree of movement circularity when compared to performance measured after the exposure to dissonant sounds. We infer that the neural resonance representing consonant tones leads to finer perception/action coupling which in turn may help explain the prevailing preference for these types of tones. PMID- 25725775 TI - CT characteristics and pathological implications of early stage (T1N0M0) lung adenocarcinoma with pure ground-glass opacity. AB - OBJECTIVES: To analyze the CT characteristics and pathological classification of early lung adenocarcinoma (T1N0M0) with pure ground-glass opacity (pGGO). METHODS: Ninety-four lesions with pGGO on CT in 88 patients with T1N0M0 lung adenocarcinoma were selected from January 2010 to December 2012. All lesions were confirmed by pathology. CT appearances were analyzed including lesion location, size, density, uniformity, shape, margin, tumour-lung interface, internal and surrounding malignant signs. Lesion size and density were compared using analysis of variance, lesion size also assessed using ROC curves. Gender of patients, lesion location and CT appearances were compared using chi2-test. RESULTS: There were no significant differences in gender, lesion location and density with histological invasiveness (P > 0.05). The ROC curve showed that the possibility of invasive lesion was 88.73% when diameter of lesion was more than 10.5 mm. There was a significant difference between lesion uniformity and histological invasiveness (P = 0.01). There were significant differences in margin, tumour lung interface, air bronchogram with histological invasiveness ( P = 0.02,P = 0.00,P = 0.048). The correlation index of lesion size and uniformity was r = 0.45 (P = 0.00). CONCLUSIONS: The lesion size and uniformity, tumour-lung interface and the air bronchogram can help predict invasive extent of early stage lung adenocarcinoma with pGGO. KEY POINTS: * CT characteristics and pathological classification of pGGO lung adenocarcinoma smaller than 3 cm * The optimal cut off value for discriminating preinvasive from invasive lesions was 10.5 mm * Uniformity was significant difference between histological subtypes and correlated with lesion size * Tumour margin, tumour-lung interface and air bronchogram showed different between histological types * No significant difference in gender, lesion location and density with histological subtypes. PMID- 25725776 TI - High prevalence of peripheral arterial disease in patients with obstructive sleep apnoea. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) merits increasing attention as cardiovascular risk factor. Whereas carotid and coronary artery disease have been associated with OSA, occurrence of peripheral arterial disease (PAD) in OSA remains undefined. METHODS: We screened 100 patients with suspected OSA for PAD. After polysomnography, each patient underwent standardized angiological testing including ankle-brachial index (ABI), central pulse wave velocity, pulse wave index and duplex sonography. RESULTS: Among total study population, PAD prevalence accounted for 88%, of those 68% had asymptomatic plaques and 20% were symptomatic Fontaine >= IIa. In confirmed OSA, prevalence raised up to 98%. Except for smoking habits, distribution of established risk factors did not differ between OSA groups (patients without, mild, intermediate and severe OSA). Presence of plaque, Fontaine PAD stages and intermittent claudication exhibited significant gain with increasing AHI. A logistic regression model revealed that age (OR = 1.199, 95% CI [1.066; 1.348]) and the logarithmically transformed AHI (OR = 5.426, 95% CI [1.068; 27.567]) had the strongest influence on plaque presence. Central pulse wave velocity as marker of arterial stiffness was positively correlated with AHI. CONCLUSION: OSA is associated with a high prevalence of PAD. This implies substantial diseases under-recognition and a presumable atherogenic role of OSA in the pathogenesis of PAD. However, vasoprotective impact of OSA treatment remains to be determined. PMID- 25725777 TI - Intravenous morphine administration and reperfusion success in ST-elevation myocardial infarction: insights from cardiac magnetic resonance imaging. AB - AIMS: Intravenous (IV) morphine has been shown to be independently associated with adverse clinical outcome in patients with non-STEMI. Currently, there are no data on the association of IV morphine and reperfusion success in STEMI. Thus, we thought to analyse the impact of IV morphine on ischemic injury and salvaged myocardium assessed by cardiac magnetic resonance imaging (CMR) in patients with STEMI reperfused by primary coronary intervention (PCI). METHODS AND RESULTS: STEMI patients reperfused by primary PCI (n = 276) within 12 h after symptom onset underwent CMR 3 days after the index event [interquartile range (IQR) 2-4]. IV morphine administration was recorded in all patients. IV morphine was administered in 44.7% (n = 123) of all patients. Patients in the IV morphine group displayed larger infarct size, higher extent of MO and lower myocardial salvage index (MSI) in comparison to the non-IV morphine group (all p < 0.05). In multivariable logistic regression analysis adjusted for TIMI-flow pre-PCI, time from symptom onset to PCI, Killip class and left ventricular ejection fraction, IV morphine was identified as an independent predictor for MSI = grade II was observed in 0 and 7.7% (2/26; p = 0.49). CONCLUSIONS: TF-TAVI without pre-dilatation was feasible and safe in this consecutive series of patient regardless of aortic valve morphology, for example. extent of valvular calcification or baseline EOA. This technique resulted in significantly lower fluoroscopy times and amounts of contrast agent while yielding non-inferior hemodynamic and clinical outcome. PMID- 25725779 TI - Effective method of continuous rocuronium administration based on effect-site concentrations using a pharmacokinetic/pharmacodynamic model during propofol remifentanil anesthesia. AB - BACKGROUND: Rocuronium bromide (Rb) is a rapid onset, intermediate-acting neuromuscular blocking agent that is suitable for continuous administration. The appropriate rate of rocuronium administration is, however, difficult to determine due to large interindividual differences in sensitivity to rocuronium. The aim of this study was to clarify whether the simulated rocuronium concentration at the time of recovery to %T1 > 0 % after the initial administration of rocuronium is a good indicator of optimal effect-site concentrations during continuous rocuronium administration. METHODS: Twenty-one patients were anesthetized with propofol. After induction, Rb 0.6 mg/kg was administered intravenously, and nerve stimulation using the single stimulation mode was conducted every 15 s. When %T1 recovered to >0 % after the initial administration of Rb, the effect-site concentration of rocuronium, calculated by pharmacokinetic simulation with Wierda's set of parameters, was recorded and defined as the recovery concentration (Rb r.c.). The administration rate of rocuronium was adjusted to maintain the Rb r.c. during surgery. Rb administration was discontinued just before the end of surgery, and the recovery time until %T1 > 25 % was recorded. Plasma Rb concentrations were measured at 1 and 3 h after the initiation of continuous Rb administration. RESULT: The mean Rb r.c. was 1.56 +/- 0.35 MUg/ml, with minimum and maximum values of 1.09 and 2.08 MUg/ml, respectively. The %T1 did not increase above 10 % in any of the patients during continuous administration of Rb, and the recovery period to %T1 > 25 % ranged from 9 to 29 min. The effect-site concentrations of Rb calculated with Wierda's parameters significantly correlated with plasma concentrations (P < 0.01) at both 1 and 3 h after the initial administration of Rb. CONCLUSION: The results suggest that our method may be one of the most reliable protocols for the continuous administration of Rb described to date for maintaining suitable muscle relaxation during surgery without excessively prolonged effects. PMID- 25725780 TI - Transversus abdominis plane block with 0.25 % levobupivacaine: a prospective, randomized, double-blinded clinical study. AB - PURPOSE: Because blood concentrations of local anesthetics sometimes reach toxic levels after transversus abdominis plane (TAP) block, reduction of the dose has been necessary to reduce the risk of systemic toxicity. We therefore investigated the effects of TAP block with 0.25 % levobupivacaine (100 mg) on postoperative pain and measured its plasma concentration after gynecological surgery. METHODS: Forty women undergoing elective open gynecological surgery were randomized to receive bilateral TAP block with 20 ml 0.25 % levobupivacaine on each side (TAP group) or not (non-TAP group) before surgery. Postoperative pain was treated with intravenous patient-controlled analgesia by use of morphine. Patients were evaluated 3 and 24 h after the end of surgery. Visual analog scale (VAS) for pain at rest and with movement, and morphine consumption were recorded. Plasma concentrations of levobupivacaine after TAP block were measured. RESULTS: Three hours after surgery, total morphine consumption was significantly lower in the TAP group (2.8 +/- 1.6 mg) than in the non-TAP group (6.4 +/- 4.8 mg, P = 0.03). There were no significant differences between VAS in the two groups. Mean plasma concentration of levobupivacaine peaked 10 min after TAP block (0.99 +/- 0.43 MUg/ml), and the highest concentration was 1.99 MUg/ml. CONCLUSION: TAP block with 100 mg levobupivacaine is a safe and efficacious multimodal analgesic regimen for postoperative pain after open gynecological surgery. PMID- 25725781 TI - Patterns of daily energy management at work: relations to employee well-being and job characteristics. AB - PURPOSE: The present study aimed at identifying subgroups of employees with similar daily energy management strategies at work and finding out whether well being indicators and job characteristics differ between these subgroups. METHODS: The study was conducted by electronic questionnaire among 1122 Finnish employees. First, subgroups of employees with unique and distinctive patterns of energy management strategies were identified using latent profile analysis. Second, differences in well-being indicators and job characteristics between the subgroups were investigated by means of ANCOVA. RESULTS: Four subgroups (i.e., patterns) were identified and named: Passives (n = 371), Averages (n = 390), Casuals (n = 272) and Actives (n = 89). Passives used all three (i.e., work related, private micro-break and physical micro-break) strategies less frequently than other subgroups, whereas Actives used work-related and physical energy management strategies more frequently than other subgroups. Averages used all strategies on an average level. Casuals' use of all strategies came close to that of Actives, notably in a shared low use of private micro-break strategies. Active and Casual patterns maintained vigor and vitality. Autonomy and social support at work played a significant role in providing opportunities for the use of beneficial energy management strategies. CONCLUSIONS: Autonomy and support at work seem to support active and casual use of daily energy management, which is important in staying energized throughout the working day. PMID- 25725782 TI - Immigrating to Canada During Early Childhood Associated with Increased Risk for Mood Disorders. AB - This study explored the impact of age at time of immigration on mental health in Canada. The Canadian Community Health Survey (CCHS) 2011 was analyzed to determine prevalence rates for mood disorders for those who immigrated during early childhood, middle childhood, adolescence, and adulthood. Multivariable logistic regression analysis was carried out on pooled CCHS 2007-2011 data to calculate risk of mood disorders. Those who immigrated during early childhood (before the age of six) had a significantly higher prevalence rate of mood disorders (6.83 %, 95 % CI 6.77-6.89) compared to those who immigrated later in life (4.83-4.88 %, 95 % CI 4.56-4.93). Immigrating during early childhood was also associated with elevated risk of mood disorders (OR 1.40, 95 % CI 1.04-1.88) compared to those who immigrated as adults after adjusting for key factors. Mental health services need to consider the factors associated with early childhood migration and the implications for early intervention programming. PMID- 25725783 TI - Organic Anion Transporter 1 Deficiency Accelerates Learning and Memory Impairment in tg2576 Mice by Damaging Dendritic Spine Morphology and Activity. AB - To investigate whether and how organic anion transporter 1 (OAT1) is involved in the process of Alzheimer's disease (AD), we crossbred OAT1 knockout mice with tg2576, the widely used AD model mice. Results here showed the heterozygous OAT1 deficient tg2576 mice developed a learning- and memory-related behavior deficiency and higher soluble Abeta amount in early stage (3 months old). Furthermore, the heterozygous mice brain slice also showed impaired long-term potentiation (LTP) and spontaneous excitatory postsynaptic currents (sEPSC). By crossbreeding heterozygous OAT1-deficient tg2576 mice with Thy-1 YFP mice, we got autofluoresced (layer 4/5 cortical neuron) heterozygous mice. By using two-photon microscope in the direct observation of mice brain in vivo or single photon confocal on slices, compared with control tg2576 mice, we found that the OAT1 deficient mice showed a higher spine numbers but with a much lesser maturity extent. Finally, by using glutamate uncaging method, we induced chemical LTP in brain slices and found that OAT1-deficient mice showed abnormal chemical-induced LTP, which meant that the deficient behavior may be caused by abnormal spine morphology and activity. Our results indicated OAT1 may be involved in AD process by regulating spine morphology and activity. PMID- 25725784 TI - Overexpression of SIRT1 Induced by Resveratrol and Inhibitor of miR-204 Suppresses Activation and Proliferation of Microglia. AB - Microglia activation plays an important role in neuroinflammation. Sirtuin1 (SIRT1) has been shown to play a role in regulation of inflammation. Resveratrol, a potent SIRT1 activator, has anti-inflammation property. MicroRNA (miRNA or miR) related to inflammation pathways has been shown to be a promising therapeutic approach for septic encephalopathy (SE). The miR mediated mechanism of regulation of SIRT1 expression in encephalitis. However, the mechanism of was unknown. To address this question, we investigated whether miRNAs and resveratrol regulate the SIRT1 and the functional changes of mice microglia cell lines pre-treated with or without lipopolysaccharide (LPS). The research about direct role of miR 204 and resveratrol on expression of SIRT1 in mice microglia cell lines (N9 and BV2) pre-treated with or without LPS had been performed. Mice microglia cell lines were transfected with miR-204 mimics and inhibitors or treated with resveratrol, and the effects on cell growth, proliferation, and apoptosis of cells were assessed. LPS induced inflammation and activation of mice microglia. Through overexpression of SIRT1, resveratrol, and inhibitor of miR-204 inhibited inflammation process, proliferation of mice microglia cells and promoted its apoptosis. We identified if resveratrol and miR-204 could repress inflammation process and proliferation of mice microglia cell through promoting the expression of SIRT1. PMID- 25725785 TI - Inhibition of the GABAA Receptor by Sulfated Neurosteroids: A Mechanistic Comparison Study between Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate. AB - The gamma-aminobutyric acid type A receptor (GABAAR) is negatively modulated by two structurally similar neurosteroids, pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS). This study attempted to ascertain the molecular mechanisms of inhibition of the GABA-ergic current by neurosteroids. We demonstrated that the presence of the gamma subunit in GABAAR enhances the efficacy of DHEAS without altering its binding affinity. A saturating concentration of DHEAS blocked approximately 75 % of currents mediated by GABAAR, which is composed of human alpha1, beta1, and gamma2S subunits, whereas the inhibition was only 35 % in GABAAR containing only alpha1 and beta1 subunits. The IC50 values of DHEAS with and without the gamma subunit were almost identical. In contrast to DHEAS, neither the affinity nor the efficacy of PS was altered by the gamma subunit. When Val256 of alpha1 subunit was mutated to Ser, the mutant channel became resistant to inhibition by both DHEAS and PS. PS exerted its inhibitory effect by enhancing the desensitization kinetics of GABAAR possibly through promoting the interaction between the M2-M3 linker and extracellular loop 7/loop 2. Mutant alpha1, containing double Cys in loop 2/loop 7 and the M2-M3 linker, formed disulfide bonds three times as much fast, when treated with saturating GABA+PS, compared with GABA alone or with GABA+DHEAS. We demonstrated that PS, but not DHEAS, mediates GABA-ergic inhibition by promoting collisions between the structural elements involved in receptor desensitization, i.e., loop 2, loop 7, and the M2-M3 linker, thus following different inhibitory mechanisms. PMID- 25725786 TI - The Anti-Edematous Effect of Ghrelin in Brain Hypoxia is Associated with Decreasing Expression of Vascular Endothelial Growth Factor. AB - There is increasing evidence that vascular endothelial growth factor (VEGF) has a role in the development of vascular leakage in the hypoxic brain. Our recent work showed an anti-edematous effect of ghrelin on brain hypoxia. However, the underlying mechanisms by which ghrelin exerts its anti-edematous effect are still unclear. For this purpose, we examined the effects of ghrelin on VEGF expression in the hypoxic brain. Adult male Wistar rats were divided into acute or chronic controls, acute or chronic hypoxia, and ghrelin-treated acute or chronic hypoxia groups. Systemic hypoxia was induced in rats by a hypoxic chamber (O2 10-11 %) for 2 days (acute) or 10 days (chronic). Effects of ghrelin on VEGF expression were evaluated using immunoblotting. Our data revealed that acute and chronic hypoxia increased VEGF expression in both acute and chronic hypoxia (P < 0.001). Ghrelin significantly reduced this expression in hypoxic conditions (P < 0.001). Our findings demonstrated the beneficial effects of ghrelin might be mediated, at least in part, through a decline in VEGF production. PMID- 25725787 TI - Cognitive Improvement Induced by Environment Enrichment in Chronic Cerebral Hypoperfusion Rats: a Result of Upregulated Endogenous Neuroprotection? AB - Environment enrichment (EE) has been demonstrated to improve the cognitive impairment that is induced by chronic cerebral hypoperfusion (CCH), but the underlying mechanism has not yet been elucidated. This study aimed to investigate the role of endogenous neuroprotection in EE-induced cognitive improvement in rats with CCH. Permanent bilateral common carotid artery occlusions (2-vessel occlusions (2VOs)) were performed to induce CCH in male adult Wistar rats. Four weeks after the surgeries, the rats were exposed to enriched environments for 4 weeks (6 h/day). Subsequently, we assessed the effects of EE on cognitive function, brain histone acetylation levels, neuroprotection-related transcription factors (i.e., cAMP response element-binding protein (CREB), phospho-CREB (p CREB), hypoxia-inducible factor 1 (HIF-1) alpha, and nuclear regulatory factor 2 (Nrf2)), and oxidative stress and histological changes in the brain. After 2VO, the rats exposed to the EE treatment exhibited increased acetylation of histone 4 and increased p-CREB and Nrf2 protein levels in the brain. HIF-1alpha levels were increased after 2VO and reduced after EE treatment. The oxidative damage, histopathological changes in the brain, and spatial learning and memory impairments induced by 2VO were subsequently restored after EE treatment. These data indicate that EE promotes the acetylation of histone 4, regulates some neuroprotection-related transcription factors, attenuates oxidative damage, and protects against the histopathological damage to the brain induced by CCH. Together, the effects of EE in CCH rats might contribute to the recovery of spatial learning and memory. PMID- 25725788 TI - Myostatin induces interstitial fibrosis in the heart via TAK1 and p38. AB - Myostatin, a member of the TGF-beta superfamily of secreted growth factors, is a negative regulator of skeletal muscle growth. In the heart, it is expressed at lower levels compared to skeletal muscle but up-regulated under disease conditions. Cre recombinase-mediated inactivation of myostatin in adult cardiomyocytes leads to heart failure and increased mortality but cardiac function of surviving mice is restored after several weeks probably due to compensatory expression in non-cardiomyocytes. To study long-term effects of increased myostatin expression in the heart and to analyze the putative crosstalk between cardiomyocytes and fibroblasts, we overexpressed myostatin in cardiomyocytes. Increased expression of myostatin in heart muscle cells caused interstitial fibrosis via activation of the TAK-1-MKK3/6-p38 signaling pathway, compromising cardiac function in older mice. Our results uncover a novel role of myostatin in the heart and highlight the necessity for tight regulation of myostatin to maintain normal heart function. PMID- 25725789 TI - Accuracy of MRI for the diagnosis of metastatic cervical lymphadenopathy in patients with thyroid cancer. AB - PURPOSE: The aim of this study was to systematically compare a comprehensive array of magnetic resonance (MR) imaging features in terms of their sensitivity and specificity to diagnose cervical lymph node metastases in patients with thyroid cancer. MATERIALS AND METHODS: The study included 41 patients with thyroid malignancy who underwent surgical excision of cervical lymph nodes and had preoperative MR imaging <=4weeks prior to surgery. Three head and neck neuroradiologists independently evaluated all the MR images. Using the pathology results as reference, the sensitivity, specificity and interobserver agreement of each MR imaging characteristic were calculated. RESULTS: On multivariate analysis, no single imaging feature was significantly correlated with metastasis. In general, imaging features demonstrated high specificity, but poor sensitivity and moderate interobserver agreement at best. CONCLUSIONS: Commonly used MR imaging features have limited sensitivity at correctly identifying cervical lymph node metastases in patients with thyroid cancer. A negative neck MR scan should not dissuade a surgeon from performing a neck dissection in patients with thyroid carcinomas. PMID- 25725790 TI - Non-mass-like lesions on breast ultrasound: classification and correlation with histology. AB - PURPOSE: Owing to advances in ultrasound (US) technology, optimal US techniques with a high-frequency transducer can identify more and more breast lesions. However, some lesions show up as non-mass-like lesions, which are difficult to be correctly identified and often result in missed diagnosis and misdiagnosis. The purpose of the present study was to develop a classification of the US features of non-mass-like breast lesions correlated with pathology, so as to improve the diagnostic accuracy of US in non-mass-like breast lesions. MATERIALS AND METHODS: A total of 854 breast lesions in 836 consecutive women scheduled for US-guided core-needle biopsy or US-guided vacuum-assisted biopsy between May 2008 and October 2011 were initially included in this study. Finally, 80 breast lesions in 78 women were classified as non-mass-like lesion and included in this study. The US features of the 80 non-mass-like breast lesions were classified and their correlation with pathology was analysed. RESULTS: Of the 80 non-mass-like breast lesions, 43 cases (53.8 %) were malignant and 37 cases (46.2 %) were benign. Fifty-two cases (73.7 %) appeared as a hypoechoic area, 22 cases (21.1 %) appeared as a hypoechoic area with sporadic or clustered microcalcification, four cases appeared as architectural distortion, and two cases appeared as solid echogenicity within a duct. The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of US for non-mass-like breast lesions were 71.25, 95.35, 43.24, 66.13 and 88.89 %, respectively. The finding of a hypoechoic area with microcalcification showed a statistically significant association with malignant lesions and its positive predictive value for carcinoma was 78.26 %. CONCLUSION: Non-mass-like breast lesions usually appeared as a hypoechoic area or a hypoechoic area with microcalcification. The finding of a hypoechoic area with microcalcification had a close correlation with malignant lesions. US had a high sensitivity but a low specificity in the diagnosis of non-mass-like breast lesions and a definitive diagnosis requires a US-guided biopsy. PMID- 25725791 TI - Vascular Doppler ultrasonographic indices in cirrhosis: a case-control study with emphasis on the common carotid arteries. AB - PURPOSE: To compare vascular Doppler waveform indices, particularly in the common carotid arteries, between cirrhotic and healthy subjects. MATERIALS AND METHODS: A total of 60 patients with Class-B cirrhosis and 60 healthy matched counterparts were enrolled in this prospective study. Vascular Doppler waveform parameters including resistance and/or pulsatility indices (RI and PI, respectively) were obtained from the common carotid, renal, celiac, superior mesenteric, femoral and brachial arteries. RESULTS: Compared to patients, healthy subjects had significantly higher mean PI and RI obtained from the common carotid (1.53 +/- 0.20 vs. 1.43 +/- 0.14, p = 0.03; 0.75 +/- 0.02 vs. 0.72 +/- 0.02, p < 0.001, respectively) and celiac arteries (2.00 +/- 0.36 vs. 1.81 +/- 0.34, p = 0.03; 0.80 +/- 0.03 vs. 0.78 +/- 0.02, p < 0.001, respectively). Both the mean PI and RI derived from the renal arteries, in contrast, were significantly higher in patients compared to that in controls (1.05 +/- 0.13 vs. 1.11 +/- 0.07, p = 0.03; 0.59 +/- 0.03 vs. 0.63 +/- 0.03, p < 0.001, respectively). The mean vascular impedance values obtained from the remaining arteries were comparable between the two groups. CONCLUSIONS: Blood flow increases in the common carotid and celiac arteries of Class-B cirrhotic patients with elevated renovascular impedance. PMID- 25725793 TI - Dynamic enhancement pattern of intrahepatic cholangiocarcinoma on contrast enhanced ultrasound: the correlation with cirrhosis and tumor size. AB - PURPOSE: To retrospectively evaluate the dynamic enhancement pattern of contrast enhanced ultrasound (CEUS) in intrahepatic cholangiocarcinoma (ICC) of varying sizes and hepatic backgrounds. MATERIALS AND METHODS: CEUS was performed in 98 pathologically confirmed ICCs (n = 39 < 30 mm, n = 59 > 30 mm; n = 45 with cirrhosis and n = 53 with normal liver). The dynamic enhancement pattern of CEUS was retrospectively analyzed. RESULTS: In the arterial phase, heterogeneous hyper enhancement was more frequent in ICCs with cirrhosis (21/45, 46.7% vs. 11/53, 20.8% in ICCs with normal liver, p = 0.009), while peripheral hyper-enhancement and hypo-enhancement were more common in ICCs with normal liver (14/53, 26.4%; 11/53, 20.8% vs. 2/45, 4.4%; 2/45, 4.4% in ICCs with cirrhosis, p = 0.005 and 0.033, respectively). There were no significant differences between portal and delayed phases. In ICCs < 30 mm, homogeneous hyper-enhancement was more frequently identified (27/39, 69.2% vs. 10/59, 16.9% in ICCs > 30 mm, p < 0.001), whereas in ICCs > 30 mm, heterogeneous, and peripheral hyper-enhancement were more commonly observed (26/59, 44.1% vs. 6/39, 15.4% in ICCs < 30 mm, p = 0.004, and 14/59, 23.7% vs. 2/39, 5.1% in ICCs < 30 mm, p = 0.023, respectively). The washout pattern in portal and delayed phases were not significantly different in ICCs with different sizes. 60.7% (17/28) ICCs < 30 mm and 85.2% (23/27) ICCs > 30 mm with cirrhosis, together with 66.7% (14/21) ICCs < 30 mm with normal liver displayed intense contrast agent uptake (homogeneous or heterogeneous hyper enhancement) in arterial phase followed by washout in portal and delayed phase, which was much higher than that in ICCs > 30 mm with normal liver (34.4%, 11/32, p < 0.001, <0.001 and =0.027, respectively). CONCLUSION: The CEUS dynamic enhancement pattern of ICC varies with size and hepatic background. The enhancement pattern is indistinguishable from hepatocellular carcinoma on CEUS in most ICCs with cirrhosis and in most ICCs < 30 mm with normal liver. PMID- 25725792 TI - The E23K and A190A variations of the KCNJ11 gene are associated with early-onset type 2 diabetes and blood pressure in the Chinese population. AB - Conflicting associations between define (KCNJ11) variations and susceptibility to late-onset (>40 years old) type 2 diabetes mellitus (T2DM) have been reported in different ethnic groups. We investigated whether the E23K (G->A, rs5219) or A190A (C->T, rs5218) variations in KCNJ11 are associated with early-onset T2DM and blood pressure in the Chinese population. Case-control study of 175 unrelated Chinese patients with early-onset T2DM (age of onset <40 years old) who receive (ins+, n = 57) or do not receive insulin (ins-, n = 118), and 182 non-diabetic control subjects. PCR-direct sequencing was performed to genotype E23K and A190A; the genotypic frequencies and associations with clinical characteristics were analyzed. The genotypic frequencies of E23K-GA+AA were higher and A190A-TT was lower in the early-onset T2DM group, especially the T2D-ins+ group, compared to the non-diabetic control group (p < 0.01 or 0.05, respectively). In non-diabetic subjects, E23K-AA carriers had significantly higher 2 h plasma glucose and lower 2 h insulin than E23K-GG carriers (both p < 0.05). A190A-TT or E23K-GG carriers had higher systolic blood pressure (SBP) than CC or AA carriers in the non diabetic control and T2DM groups (both p < 0.05). In the T2DM ins+ group, E23K-AA carriers had lower onset age and duration of diabetes and higher BMI than GG carriers, and A190A-TT carriers had higher SBP than CC carriers (all p < 0.05). The E23K-GA or AA genotypes may increase the susceptibility to early-onset T2DM, while A190A-TT may protect against early-onset T2DM. On the other hand the A190A TT or E23K-GG genotypes may increase the risk of hypertension in the Chinese population. PMID- 25725794 TI - Observer performance for adaptive, image-based denoising and filtered back projection compared to scanner-based iterative reconstruction for lower dose CT enterography. AB - PURPOSE: The purpose of this study was to compare observer performance for detection of intestinal inflammation for low-dose CT enterography (LD-CTE) using scanner-based iterative reconstruction (IR) vs. vendor-independent, adaptive image-based noise reduction (ANLM) or filtered back projection (FBP). METHODS: Sixty-two LD-CTE exams were performed. LD-CTE images were reconstructed using IR, ANLM, and FBP. Three readers, blinded to image type, marked intestinal inflammation directly on patient images using a specialized workstation over three sessions, interpreting one image type/patient/session. Reference standard was created by a gastroenterologist and radiologist, who reviewed all available data including dismissal Gastroenterology records, and who marked all inflamed bowel segments on the same workstation. Reader and reference localizations were then compared. Non-inferiority was tested using Jackknife free-response ROC (JAFROC) figures of merit (FOM) for ANLM and FBP compared to IR. Patient-level analyses for the presence or absence of inflammation were also conducted. RESULTS: There were 46 inflamed bowel segments in 24/62 patients (CTDIvol interquartile range 6.9-10.1 mGy). JAFROC FOM for ANLM and FBP were 0.84 (95% CI 0.75-0.92) and 0.84 (95% CI 0.75-0.92), and were statistically non-inferior to IR (FOM 0.84; 95% CI 0.76-0.93). Patient-level pooled confidence intervals for sensitivity widely overlapped, as did specificities. Image quality was rated as better with IR and AMLM compared to FBP (p < 0.0001), with no difference in reading times (p = 0.89). CONCLUSIONS: Vendor-independent adaptive image-based noise reduction and FBP provided observer performance that was non-inferior to scanner-based IR methods. Adaptive image-based noise reduction maintained or improved upon image quality ratings compared to FBP when performing CTE at lower dose levels. PMID- 25725795 TI - Clinical value of spectral CT in diagnosis of negative gallstones and common bile duct stones. AB - OBJECTIVE: To investigate the clinical value of spectral CT in diagnosis of negative gallstones and common bile duct stones primarily. METHODS: All patients diagnosed with negative biliary stones were analyzed and examined by spectral CT scanner retrospectively. Based on acquired raw imaging data, image series were reconstructed as described below: the optimal contrast-to-noise ratio monochromatic energy images, calcium- and fat- based material decomposition images and spectral curve images. All these imaging series were analyzed quantitatively and qualitatively. RESULTS: The contrast between negative stones and adjacent bile was 6.87 +/- 5.48 HU on hybrid energy CT images and 47.30 +/- 24.05 HU on optimal monochromatic energy CT images. The mean concentration of calcium in bile and negative stones was 19.36 +/- 5.12 and 3.88 +/- 6.60 mg/mL, and the fat in bile and negative stones was 998.48 +/- 11.79 and 1035.68 +/- 15.36 mg/mL. Effective atomic number Z of negative stones (6.60 +/- 0.45) was lower than that of bile (7.65 +/- 0.13). The slopes of the spectral curves for negative stones were k 90-40KeV = 1.43 +/- 0.63 and k 140-90KeV = 0.19 +/- 0.08, and for bile, they were k 90-40KeV = -0.27 +/- 0.09 and k 140-90KeV = -0.04 +/- 0.01. The same stone showed different densities in different imaging groups. The positive rate of conventional CT images was lower than that of other imaging groups. CONCLUSION: Spectral CT has a high diagnostic value for negative gallstones or bile duct stones, and material decomposition CT images and spectral curves can make an accurate diagnosis. PMID- 25725796 TI - Omental infarction and its mimics: imaging features of acute abdominal conditions presenting with fat stranding greater than the degree of bowel wall thickening. AB - The segmental omental infarction is a rare self-limited disorder presenting with aspecific clinical symptoms that may mimic several acute abdominal conditions. Therefore, a correct noninvasive diagnosis is important because treatment approaches range from monitoring to surgery. As omental infarction results in an important fat stranding that is much greater than the degree of bowel wall thickening, it suggests a narrower differential diagnosis: appendicitis, diverticulitis, epiploic appendagitis, and mesenteric panniculitis. In this pictorial essay, we point out the importance of imaging in identifying this typical sign allowing alternate diagnoses such as segmental omental infarction that can be conservatively managed. PMID- 25725797 TI - Investigation of the multifaceted iron acquisition strategies of Burkholderia cenocepacia. AB - Burkholderia cenocepacia is a bacterial pathogen which causes severe respiratory infections in cystic fibrosis (CF). These studies were aimed at gaining an insight into the iron acquisition strategies of B. cenocepacia. In iron restricted conditions, genes associated with the synthesis and utilisation of ornibactin (pvdA, orbA, orb F) were significantly upregulated compared to the expression of pyochelin associated genes (pchD, fptA). In the absence of alternative iron sources, B. cenocepacia J2315 and 715j utilised ferritin and haemin, but not transferrin or lactoferrin for growth. Significantly, mutants unable to produce ornibactin, (715j-orbI) or ornibactin and pyochelin, (715j pobA), utilised haemin and ferritin more efficiently than the wild-type. Moreover, both mutants were also able to utilise lactoferrin for growth (P <= 0.01) and additionally 715j-pobA utilised transferrin (P <= 0.01), potentially facilitating adaptation to the host environment. Furthermore, B. cenocepacia increased ornibactin gene expression in response to pyoverdine from Pseudomonas aeruginosa (P <= 0.01), demonstrating the capacity to compete for iron in co colonised niches. Pyoverdine also significantly diminished the growth of B. cenocepacia (P < 0.001) which was related to its iron chelating activity. In a study of three B. cenocepacia sequential clonal isolates obtained from a CF patient over a 3.5 year period, ornibactin upregulation in response to pyoverdine was less pronounced in the last isolate compared to the earlier isolates, as was growth in the presence of haemin and ferritin, indicating alternative iron acquisition mechanism(s) may dominate as chronic infection progresses. These data demonstrate the multifaceted iron acquisition strategies of B. cenocepacia and their capacity to be differentially activated in the presence of P. aeruginosa and during chronic infection. PMID- 25725798 TI - Biotransformation of indole and its derivatives by a newly isolated Enterobacter sp. M9Z. AB - In this study, a novel bacterial strain M9Z with the ability of producing indigoids from indole and its derivatives was isolated from activated sludge and identified as Enterobacter sp. according to 16S ribosomal RNA (rRNA) sequence analysis. UV-vis spectrometry and high-performance liquid chromatography-mass spectrometry analysis indicated that the products produced from indole, 5 methylindole, 7-methylindole, and 5-methoxyindole were indigo with different substituent groups, and the possible biotransformation pathways of indole derivatives, i.e., indole(s)-cis-indole-2,3-dihydrodiol(s)-indoxyl(s)-indigoids, were proposed. The conditions of indole transformation and indigo biosynthesis by strain M9Z were optimized, and the maximal indigo yield (68.1 mg/L) was obtained when using 150 mg/L indole, 200 mg/L naphthalene, and 5 g/L yeast extract. The transformation rates of 5-methylindole, 7-methylindole, and 5-methoxyindole by strain M9Z were all close to 100 % under certain conditions, making strain M9Z an efficient indigoid producer. This is the first study of indole biotransformation and indigoid biosynthesis by genus Enterobacter. PMID- 25725799 TI - Saccharification of beta-chitin from squid pen by a fermentation method using recombinant chitinase-secreting Escherichia coli. AB - Two strains [BL21(DE3) and HMS174(DE3)] of Escherichia coli harboring the recombinant chitinase expression plasmid pVP-Chi, which contains Vibrio parahaemolyticus chitinase gene with an attached signal sequence, were prepared. These E. coli transformants produced a large amount of recombinant chitinase, which hydrolyzes chitin to yield di-N-acetylchitobiose (GlcNAc)2, under the presence of isopropyl-1-thio-beta-D-galactopyranoside (IPTG), and secreted the enzyme into their culture fluid with the aid of the signal peptide. Cultivation of these E. coli transformants in Luria-Bertani medium containing squid pen beta chitin and IPTG gave rise to the decomposition of this polysaccharide and the accumulation of (GlcNAc)2 in the culture fluid. Through these experiments, we confirmed that the use of strain HMS174(DE3) was preferable for the stable accumulation of (GlcNAc)2 in the culture fluid during cultivation owing to lower (GlcNAc)2 assimilation compared to BL21(DE3). Next, using E. coli HMS174(DE3) transformants, we conducted saccharification of different forms (fluffy fiber, flake, and powder) of beta-chitin samples prepared from squid pens in Bacterion-N KS(B)K medium containing 2 % of each sample under the presence of IPTG. In these experiments, (GlcNAc)2 was isolated with a more than 20 % stoichiometric yield from each culture supernatant through charcoal column chromatography followed by recrystallization. PMID- 25725800 TI - Heavy metal removal from multicomponent system by the cyanobacterium Nostoc muscorum: kinetics and interaction study. AB - In this study, Nostoc muscorum, a native cyanobacterial species isolated from a coal mining site, was employed to remove Cu(II), Zn(II), Pb(II) and Cd(II) from aqueous solution containing these metals in the mixture. In this multicomponent study, carried out as per the statistically valid Plackett-Burman design of experiments, the results revealed a maximum removal of both Pb(II) (96.3 %) and Cu(II) (96.42 %) followed by Cd(II) (80.04 %) and Zn(II) (71.3 %) at the end of the 60-h culture period. Further, the removal of these metals was attributed to both passive biosorption and accumulation by the actively growing N. muscorum biomass. Besides, the specific removal rate of these metals by N. muscorum was negatively correlated to its specific growth rate. For a better understanding of the effect of these metals on each other's removal by the cyanobacteria, the results were statistically analyzed in the form of analysis of variance (ANOVA) and Student's t test. ANOVA of the metal bioremoval revealed that the main (individual) effect due to the metals was highly significant (P value <0.05) on each other's removal. Student's t test results revealed that both Zn(II) and Pb(II) strongly inhibited both Cu(II) removal (P value <0.01) and Cd(II) removal (P value <0.02). All these results not only demonstrated a very good potential of the cyanobacteria in the bioremoval of these metals but also the effect of individual metals on each other's removal in the multicomponent system. PMID- 25725801 TI - In the absence of its cytosolic domain, the CD28 molecule still contributes to T cell activation. AB - The CD28 costimulatory receptor has a pivotal role in T cell biology as this molecule amplifies T cell receptor (TCR) signals to provide an efficient immune T cell response. There is a large debate about how CD28 mediates these signals. Here, we designed a CD28 gene-targeted knock-in mouse strain lacking the cytoplasmic tail of CD28. As is the case in CD28-deficient (CD28 knock-out) mice, regulatory T cell homeostasis and T cell activation are altered in these CD28 knock-in mice. Unexpectedly, the presence of a CD28 molecule deprived of its cytoplasmic tail could partially induce some early activation events in T cells such as signaling events or expression of early activation markers. These results unravel a new mechanism of T cell costimulation by CD28, independent of its cytoplasmic tail. PMID- 25725803 TI - 'Drug users stick together': HIV testing in peer-based drop-in centres among people who inject drugs in Thailand. AB - Introduction Although there is a well recognised need for novel approaches to HIV testing, particularly for marginalised populations at high risk for HIV infection, there remains a dearth of information on the acceptability of peer based HIV testing among people who inject drugs (PWID). METHODS: Between July 2011 and June 2012, 22 in-depth interviews were conducted with PWID participating in the Mitsampan Community Research Project in Bangkok, Thailand. Semi-structured interviews explored willingness to access rapid HIV testing delivered by a healthcare professional or a trained peer within peer-based drop-in centres. Audio-recorded interviews were transcribed verbatim and a thematic analysis was conducted. RESULTS: All participants indicated interest in accessing rapid HIV testing by a healthcare professional at peer-based drop-in centres due to the advantage of receiving immediate results. Experiencing stigma and discrimination by healthcare workers and wanting to avoid administrative barriers in hospitals were also reported as reasons for why PWID preferred HIV testing in peer-based settings. Peer support and shared lived experiences were repeatedly mentioned as benefits of peer-based testing. However, some concerns regarding peer-delivered testing were expressed and included a fear of peers' violating confidentiality and concerns regarding peers' qualifications for conducting an HIV test. CONCLUSION: Many PWID in this study sample noted the value of a peer-based approach to receiving testing and indicated their willingness to access rapid HIV testing in peer-based drop-in centres. The findings from this study highlight the potential for novel peer-based methods to complement existing HIV services in an effort to improve access to testing among this population. PMID- 25725802 TI - Dual-reporter surrogate systems for efficient enrichment of genetically modified cells. AB - Isolation of genetically modified cells generated by designed nucleases are challenging, since they are often phenotypically indistinguishable from their parental cells. To efficiently enrich genetically modified cells, we developed two dual-reporter surrogate systems, namely NHEJ-RPG and SSA-RPG based on NHEJ and SSA repair mechanisms, respectively. Repair and enrichment efficiencies of these two systems were compared using different nucleases. In both CRISPR-Cas9- and ZFNs-induced DSB repair studies, we found that the efficiency and sensitivity of the SSA-RPG reporter with direct repeat length more than 200 bp were much higher than the NHEJ-RPG reporter. By utilizing the SSA-RPG reporter, we achieved the enrichment for indels in several endogenous loci with 6.3- to 34.8-fold of non-selected cells. Thus, the highly sensitive SSA-RPG reporter can be used for activity validation of designed nucleases and efficient enrichment of genetically modified cells. Besides, our systems offer alternative enrichment choices either by puromycin selection or FACS. PMID- 25725804 TI - Evaluation of the NanoCHIP(r) Infection Control Panel test for direct detection and screening of methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria and vancomycin-resistant Enterococcus (VRE). AB - PURPOSE: Rapid detection of infection control targets is needed and several bacterial target assays are commercially available. Detection of patients colonized with Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae (KPC-CRE), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE) comprises an essential part of infection control programs. This study evaluated the performance and feasibility of a novel molecular-based diagnostic screening test, the NanoCHIP((r)) Infection Control Panel (ICP) assay (Savyon Diagnostics, Israel), which enables simultaneous detection of KPC-CRE, MRSA and VRE directly from swab samples and compares its sensitivity and specificity to culture. METHODS: Prospective direct swab analysis of 338 (70 CRE, 198 MRSA and 70 VRE) screening swab samples. RESULTS: Including all targets and all valid samples, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the NanoCHIP((r)) ICP assay were 91.1, 99.5, 99.1 and 94.9 %, respectively. CONCLUSIONS: As far as we know, this is the first report regarding a single molecular-based system that detects all three targets (CRE-KPC, MRSA and VRE) simultaneously, directly from swab samples, using the same reaction and platform. Overall, the assay was easy to perform, enabling medium- to high-throughput screening. Same day results enable efficient infection control interventions, such as carrier isolation. PMID- 25725806 TI - A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin. AB - Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures, and skull deformities. Mutation in the gene encoding cathepsin K (CTSK), which is a lysosomal cysteine protease, has been found to be responsible for this disease. Here we reported a consanguineous Chinese family with 1 affected individual demonstrating autosomal recessive pycnodysostosis with recurrent kidney stone, a new clinical manifestation which has not been reported in patients of pycnodysostosis before. To identify the pathogenic mutation, we evaluated the patient clinically, biochemically, and radiographically. To screen for mutations in the CTSK gene of the patient and his family members, all of its exons and exon intron junctions were PCR amplified from genomic DNA and sequenced. Sequence analysis of the patient's CTSK gene revealed homozygosity for a missense mutation (c.746T>C) in exon 6, which leads to amino change (p.Ile249Thr) in the mature CTSK protein. This mutation was firstly reported by Michela Donnarumma and his colleagues in 2007 in a Spanish family. Our study strengthens the role of this particular mutation in the pathogenesis of pycnodysostosis. PMID- 25725805 TI - Rat aortic smooth muscle cells cultured on hydroxyapatite differentiate into osteoblast-like cells via BMP-2-SMAD-5 pathway. AB - Vascular calcification is an important pathological condition associated with increased risk of cardiovascular mortality. Hydroxyapatite (HA) found in such deposits is the same polymorph of calcium (Ca) found in bone, indicating calcification may involve mechanisms akin to bone formation. Vascular smooth muscle cells (Vsmcs) have been shown to undergo phenotypic change to osteoblast like cells. However, the mechanisms underlying this phenotypic change are unclear, and whether the stimulus to become osteogenic is a result of loss of mineralization inhibitors or early mineral deposits is not known. Our aim in this study is to identify mechanisms and signal transduction pathways that cause differentiation of Vsmcs into osteoblast-like cells in the presence of HA. We first characterized vascular origin of Vsmcs by studying the expression of smooth muscle cell markers: myosin heavy chain and smooth muscle actin along with SM22alpha at both mRNA and protein levels. Vsmcs grown on HA exhibited progressive change in cellular morphology at 3-, 7-, and 14-day time points. Culturing of Vsmcs on HA disc resulted in decrease in media Ca levels and increased expression of Ca-sensing receptor (CaSR) on Vsmcs resulting in upregulation of intracellular CaSR signaling leading to increased BMP-2 secretion. BMP-2 pathway mediated differentiation of Vsmcs to osteoblast-like cells shown by expression of osteogenic markers like runt-related transcription factor 2, osteocalcin, and alkaline phosphatase at mRNA and protein levels. Blocking CaSR by NPS-2143 reduced BMP-2 secretion and blocking the BMP-2 pathway by LDN-193189, a BMP inhibitor, modulated expression of osteogenic markers confirming their role in osteogenesis of Vsmcs. PMID- 25725807 TI - Utilization of a novel valveless trocar system during robotic-assisted laparoscopic prostatectomy. AB - PURPOSE: To evaluate the effect of a novel valveless trocar system (VTS) on perioperative outcomes in patients undergoing robotic-assisted laparoscopic prostatectomy (RALP). METHODS: A single-institution retrospective review was performed of 792 patients undergoing RALP. Preoperative patient variables, tumor characteristics, and perioperative variables were collected and analyzed. The first 150 patients were excluded from analysis to account for the learning curve of robotic surgery. Univariate and multivariate linear regression models were used to assess factors affecting operative time (ORT). RESULTS: A total of 257 and 385 patients underwent RALP utilizing the VTS and conventional insufflation, respectively. There were no significant differences in American Society of Anesthesiologist score, body mass index (BMI), prostate volume, final Gleason score, estimated blood loss, and complications between the cohorts. The only difference noted was a significantly shorter mean ORT in the VTS cohort (149.5 vs. 170.1 min, p < 0.0001). In light of this finding, further analysis was performed to identify associations with ORT. Multivariable analysis demonstrated that VTS, BMI, final Gleason score, prostate volume, surgeon, and node dissection were significantly associated with ORT. The use of the VTS decreased mean ORT by 23.2 min when controlling for confounding factors (p < 0.001). The performance of a nerve sparing operation was found to decrease ORT by 15.9 min (p < 0.001), though more often performed for lower-risk disease. CONCLUSION: The use of a novel VTS demonstrated decreased ORT in patients undergoing RALP when controlling for confounding factors. Prospective randomized trials are needed to evaluate its ultimate benefit in various surgical cohorts. PMID- 25725808 TI - Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress. AB - Ischemic heart disease (IHD) is a leading cause of death worldwide, and regenerative therapies through exogenous stem cell delivery hold promising potential. One limitation of such therapies is the vulnerability of stem cells to the oxidative environment associated with IHD. Accordingly, manipulation of stem cell mitochondrial metabolism may be an effective strategy to improve survival of stem cells under oxidative stress. MitoNEET is a redox-sensitive, mitochondrial target of thiazolidinediones (TZDs), and influences cellular oxidative capacity. Pharmacological targeting of mitoNEET with the novel TZD, mitoNEET Ligand-1 (NL 1), improved cardiac stem cell (CSC) survival compared to vehicle (0.1% DMSO) during in vitro oxidative stress (H2O2). 10 MUM NL-1 also reduced CSC maximal oxygen consumption rate (OCR) compared to vehicle. Following treatment with dexamethasone, CSC maximal OCR increased compared to baseline, but NL-1 prevented this effect. Smooth muscle alpha-actin expression increased significantly in CSC following differentiation compared to baseline, irrespective of NL-1 treatment. When CSCs were treated with glucose oxidase for 7 days, NL-1 significantly improved cell survival compared to vehicle (trypan blue exclusion). NL-1 treatment of cells isolated from mitoNEET knockout mice did not increase CSC survival with H2O2 treatment. Following intramyocardial injection of CSCs into Zucker obese fatty rats, NL-1 significantly improved CSC survival after 24 h, but not after 10 days. These data suggest that pharmacological targeting of mitoNEET with TZDs may acutely protect stem cells following transplantation into an oxidative environment. Continued treatment or manipulation of mitochondrial metabolism may be necessary to produce long-term benefits related to stem cell therapies. PMID- 25725809 TI - Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. AB - Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IalphaI/IIIalphaI, connective tissue growth factor, fibronectin, TGF-beta3) and inflammatory (IL-10, IL-1beta, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3beta and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP 1 signalling may be required to realise its clear therapeutic potential for post MI heart failure. PMID- 25725810 TI - The efficacy of conservative treatment of osteoporotic compression fractures on acute pain relief: a systematic review with meta-analysis. AB - PURPOSE: The aim of this study is to systematically evaluate the efficacy of commonly used non-surgical treatments in acute care of adults with osteoporotic vertebral compression fractures (VCFs). METHODS: A systematic approach was used to search eight electronic databases for randomized controlled trials (RCTs) examining analgesic medications, passive physical therapies, bed rest or orthoses. Data on pain, activity/participation and adverse events were extracted. Methodological quality and quality of evidence were assessed with the Physiotherapy Evidence Database (PEDro) scale (score range 0-10) and the GRADE criteria, respectively. RESULTS: Five RCTs (total n = 350) were identified including one placebo-controlled and four controlled trials examining analgesics (2 studies) and orthoses (3). PEDro scores ranged from 4 to 7. The overall quality of evidence ranged from very low to low. In two trials, spinal orthoses provided significantly higher medium-term pain relief [pooled standardized mean differences (SMD): -1.47, 95 % confidence interval (CI) -1.82, -1.13; I (2) = 0 %] and disability reduction (pooled SMD: -1.73, 95 % CI -2.09, -1.37; I (2) = 0 %) than no intervention. Immediate- and short-term pain effects of diclofenac (a non-steroidal anti-inflammatory drug) and tramadol (a strong opioid) were demonstrated when compared to a Chinese medicine, whereas non-significant effects were found for oxycodone and tapentadol (strong opioids) in a placebo-controlled trial. Low/insufficient statistical power, co-interventions and potential conflict of interest might have influenced the results. CONCLUSIONS: At present, there is insufficient evidence to inform conservative care for acute pain related to VCF. Large, multinational, placebo/sham-controlled trials to address this gap in evidence are needed. PMID- 25725811 TI - Automated classification of neurological disorders of gait using spatio-temporal gait parameters. AB - OBJECTIVE: Automated pattern recognition systems have been used for accurate identification of neurological conditions as well as the evaluation of the treatment outcomes. This study aims to determine the accuracy of diagnoses of (oto-)neurological gait disorders using different types of automated pattern recognition techniques. METHODS: Clinically confirmed cases of phobic postural vertigo (N = 30), cerebellar ataxia (N = 30), progressive supranuclear palsy (N = 30), bilateral vestibulopathy (N = 30), as well as healthy subjects (N = 30) were recruited for the study. 8 measurements with 136 variables using a GAITRite((r)) sensor carpet were obtained from each subject. Subjects were randomly divided into two groups (training cases and validation cases). Sensitivity and specificity of k-nearest neighbor (KNN), naive-bayes classifier (NB), artificial neural network (ANN), and support vector machine (SVM) in classifying the validation cases were calculated. RESULTS: ANN and SVM had the highest overall sensitivity with 90.6% and 92.0% respectively, followed by NB (76.0%) and KNN (73.3%). SVM and ANN showed high false negative rates for bilateral vestibulopathy cases (20.0% and 26.0%); while KNN and NB had high false negative rates for progressive supranuclear palsy cases (76.7% and 40.0%). CONCLUSIONS: Automated pattern recognition systems are able to identify pathological gait patterns and establish clinical diagnosis with good accuracy. SVM and ANN in particular differentiate gait patterns of several distinct oto-neurological disorders of gait with high sensitivity and specificity compared to KNN and NB. Both SVM and ANN appear to be a reliable diagnostic and management tool for disorders of gait. PMID- 25725812 TI - Community and Social Participation Among Individuals with Autism Spectrum Disorder Transitioning to Adulthood. AB - Individuals with Autism Spectrum Disorders (ASDs) are at increased risk for poor psychosocial outcomes as adults. We described community and social participation in adolescents with ASDs as they transitioned from adolescence to adulthood, and identified adolescent factors associated with community and social participation outcomes in adulthood. We performed a secondary data analysis of a nationally representative cohort using the National Longitudinal Transition Study 2 and observed a significant decrease in community participation from adolescence to adulthood (63 to 46%); social participation remained stable. The presence of case management in adolescence was associated with increased community and social participation in adulthood. Case management may be crucial for optimal levels of participation among adults with ASDs. PMID- 25725813 TI - Intensity-modulated radiotherapy and volumetric-modulated arc therapy have distinct clinical advantages in non-small cell lung cancer treatment. AB - This study was conducted to compare the efficacy of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in delivering the planned dosage in the treatment of non-small cell lung cancer (NSCLC). Between September 2013 and March 2014, 125 NSCLC patients were randomly chosen and allocated to the IMRT group (n = 65) and VMAT group (n = 60). We compared multiple parameters such as target dose, organ dosimetry, monitor unit (MU) and time of therapy between IMRT and VMAT groups. The prescribed dose coverage of both planning techniques was 95 % of the planning target volumes (PTVs). PTV 95 % and homogeneous index in IMRT plan were greater than those in VMAT plan (both P < 0.05), while no significant difference in conformity index was observed (P > 0.05). The mean total lung V5 and V10 in VMAT group were markedly higher than those in IMRT group, but the V20, V30, and V40 in VMAT group were significantly lower (all P < 0.05), but no statistically significant difference was observed in V15 and V20 (P > 0.05). Furthermore, the planning spine and esophagus at risk volume showed no statistical significances in both groups (P > 0.05). MU of IMRT plan was about 4.2 % less than that of VMAT plan, which was statistically significant (P < 0.001). Both IMRT and VMAT had significant advantages in the treatment of NSCLC. The IMRT may be better for NSCLC patients with poor pulmonary function, and VMAT may be recommended for NSCLC patients with normal pulmonary function. PMID- 25725814 TI - A decimated minimum variance beamformer applied to ultrasound imaging. AB - Minimum variance beamforming has performed significant improvement in the resolution of the ultrasound images. However, its computational complexity is a serious problem. This paper introduces a new implementation of the minimum variance beamformer for ultrasound imaging with a focused transmit beam. In this method, a decimated aperture data instead of full of it, is used as the beamformer input, on which the minimum variance beamforming is applied, with the covariance matrix estimated using the full aperture data. In this way, the method can give a linear complexity while it can show a performance comparable to that of the full array implementation of the minimum variance beamforming, as the simulation and experimental results confirm this. Therefore, this adaptive beamforming method can be viewed as an approximate implementation of the minimum variance beamforming with a linear computational complexity. PMID- 25725815 TI - Morphological alterations in the freshwater rotifer Brachionus calyciflorus Pallas 1766 (Rotifera: Monogononta) caused by vinclozolin chronic exposure. AB - Vinclozolin (VZ) is a dicarboximide fungicide widely used on fruits, vegetables and wines, effective against fungi plagues. In this study we characterized the effects of VZ using a 4-day reproductive chronic assay with the freshwater rotifer Brachionus calyciflorus. The assay included observations of several features of asexual and sexual reproduction. Our results indicate that VZ: (a) increased asexual and sexual reproduction, (b) caused severe abnormality in females and (c) these abnormalities were inherited by sexual and asexual reproduction. At 1.2 mg/L three abnormal females were found out of 457 total females (0.66 %). This low percentage is consistent and reproducible according to further analysis, where we increased the number of replicates and total females exposed to 1.2 mg/L of VZ, and found 18 abnormal females out of 2868 total females (0.63 % abnormality). Interestingly, abnormal females found at 5.6 mg/L VZ exposure, were able to show mating behavior. Our results suggest that VZ behaves as a strong endocrine disruptor whose effects show the characteristic inverted-U-shape exposure concentration response curve regarding the intrinsic population increase and the percentage of abnormalities as endpoints. PMID- 25725817 TI - Frequency division color characterization apparatus for anisotropic leaky mode light modulators. AB - This paper presents an optical apparatus for characterizing frequency multiplexing of color in leaky mode, anisotropic waveguide modulators. This type of characterization is particularly useful for informing the design of full color holographic video displays. The primary function of the apparatus is to map the frequency response and angular overlap of red, green, and blue outputs. The apparatus also allows measurements of other parameters such as scan center frequency, optical and RF bandwidth, and scan linearity. PMID- 25725816 TI - Impaired brachial artery endothelial function in young healthy women following an acute painful stimulus. AB - INTRODUCTION: Impaired endothelial function has been observed during and immediately following an acutely painful stimulus. However, the extent to which this persists following pain dissipation is unclear. PURPOSE: To determine whether painful ischemic handgrip exercise (pain task) causes impaired flow mediated dilation (FMD) after the sensation of pain and hemodynamic responses have abated. A second purpose was to determine whether the response to pain differed with a predisposition to magnify, ruminate, and feel helpless about pain (pain catastrophizing status). METHODS: Brachial artery FMD stimulated by reactive hyperemia was assessed via ultrasound in 18 (9 high catastrophizing) healthy, women (20 +/- 1 years) before and 15 min after a 3 min pain task. The shear stress stimulus for FMD was estimated as shear rate (blood velocity/brachial artery diameter). RESULTS (MEAN +/- SD): None of the variables were significantly impacted by pain catastrophizing status and are presented pooled across group. The pain task increased pain ratings [1 +/- 1-6 +/- 3 (0-10 scale) (p < 0.001)], mean arterial pressure (MAP) (p < 0.001) and heart rate (HR) (p < 0.001), all returning to pre-pain levels <=2-min post-pain task (pre-pain vs. 2-min post-pain: pain rating p = 1.000; MAP p = 0.142; HR p = 0.992). The shear rate stimulus was not different between pre- and post-pain task FMD tests (p = 0.200). FMD decreased post-pain task (10.8 +/- 4.6 vs. 7.0 +/- 2.7 %, p < 0.001). CONCLUSION: These results indicate that, regardless of pain catastrophizing status, painful ischemic handgrip exercise has a deleterious impact on endothelial function that persists after the pain sensation and hemodynamic responses have abated. PMID- 25725818 TI - Radial distribution of charged particles in a magnetic field. AB - The radial spread of charged particles emitted from a point source in a magnetic field is a potential source of systematic error for any experiment where magnetic fields guide charged particles to detectors with finite size. Assuming uniform probability as a function of the phase along the particle's helical trajectory, an analytic solution for the radial probability distribution function follows which applies to experiments in which particles are generated throughout a volume that spans a sufficient length along the axis of a homogeneous magnetic field. This approach leads to the same result as a different derivation given by Dubbers et al., Nucl. Instrum. Methods Phys. Res., Sect. A 763, 112-119 (2014). But the constant phase approximation does not strictly apply to finite source volumes or fixed positions, which lead to local maxima in the radial distribution of emitted particles at the plane of the detector. A simple method is given to calculate such distributions, then the effect is demonstrated with data from a (207)Bi electron-conversion source in the superconducting solenoid magnet spectrometer of the Ultracold Neutron facility at the Los Alamos Neutron Science Center. Implications for neutron beta decay spectroscopy are discussed. PMID- 25725819 TI - Measurement of spherical and cylindrical power in ophthalmic lenses based in the change of lateral amplification. AB - In this article, we present a new technique to measure spherical and cylindrical power in ophthalmic lenses. This method is based in the change of lateral amplification produced by an optical system when introducing an ophthalmic lens. Ophthalmic lens power is calculated by considering the change in image size from a reference object and its own image seen through the ophthalmic lens. Mathematical analysis is presented along with the experimental setup and the obtained results. Several algorithms were applied to the obtained results as a method to compensate the error in order to fit into ISO 8598 specifications. PMID- 25725820 TI - Solid optical ring interferometer for high-throughput feedback-free spectral analysis and filtering. AB - We describe a simple and inexpensive optical ring interferometer for use in high resolution spectral analysis and filtering. It consists of a solid cuboid, reflection-coated on two opposite sides, in which constructive interference occurs for waves in a rhombic trajectory. Due to its monolithic design, the interferometer's resonance frequencies are insensitive to environmental disturbances over time. Additional advantages are its simplicity of alignment, high-throughput, and feedback-free operation. If desired, it can be stabilized with a secondary laser without disturbance of the primary signal. We illustrate the use of the interferometer for the measurement of the spectral Mollow triplet from a quantum dot and characterize its long-term stability for filtering applications. PMID- 25725821 TI - Effusive atomic oven nozzle design using an aligned microcapillary array. AB - We present a simple and inexpensive design for a multichannel effusive oven nozzle which provides improved atomic beam collimation and thus extended oven lifetimes. Using this design, we demonstrate an atomic lithium source suitable for trapped-atom experiments. At a nozzle temperature of 525 degrees C, the collimated atomic beam flux directly after the nozzle is 1.2 * 10(14) atoms/s with a peak beam intensity greater than 5.0 * 10(16) atoms/s/sr. This suggests an oven lifetime of several decades of continuous operation. PMID- 25725822 TI - Spectrometer for cluster ion beam induced luminescence. AB - A spectrometer to detect the ultra-weak luminescence originated by the collision of cluster ions on the surfaces of solid materials was constructed. This spectrometer consists of 11 photomultipliers with band-pass interference filters that can detect the luminescence within the wavelength ranging from 300 to 700 nm and of a photomultiplier without filter. The calibration of the detection system was performed using the photons emitted from a strontium aluminate fluorescent tape and from a high temperature tungsten filament. Preliminary measurements show the ability of this spectrometer to detect the cluster ion beam induced luminescence. PMID- 25725823 TI - Light depolarization in off-specular reflection on submicro rough metal surfaces with imperfectly random roughness. AB - Depolarization at a rough surface relates to its roughness and irregularity (e.g., sags and crests) besides the material property. However, there is still lack of general theory to clearly describe the relationship between depolarization ratios and surface conditions, and one important reason is that the mechanism of depolarization relates to geometric parameters such as microcosmic height/particle distributions of sub-micro to nm levels. To study the mechanism in more detail, a compact laser instrument is developed, and depolarization information of a linearly polarized incident light is used for analyzing the roughness, during which a He-Ne laser source (lambda = 632.8 nm) is used. Three nickel specimens with RMS roughness (Rq) less than lambda/4 are fabricated and tested. Six different areas in each specimen are characterized in detail using an AFM. Rq are in the range of 34.1-155.0 nm, and the heights are non-Gaussian distribution in the first specimen and near-Gaussian distribution in the others. Off-specular inspection is carried out exactly on these 18 characterized areas, and results show that the cross-polarization ratios match quite well with Rq values of the first sample that has Rq <= lambda/10 (or Rt <= lambda), while they match well with maximum height, Rt, values of the other two that have Rt > lambda (the maximum derivation is 11%). In addition, since this instrument is simple, portable, stable, and low-cost, it has great potential for practical online roughness testing after a linear calibration. PMID- 25725824 TI - Introduction of DC line structures into a superconducting microwave 3D cavity. AB - We report a technique that can noninvasively add multiple DC wires into a 3D superconducting microwave cavity for electronic devices that require DC electrical terminals. We studied the influence of our DC lines on the cavity performance systematically. We found that the quality factor of the cavity is reduced if any of the components of the electrical wires cross the cavity equipotential planes. Using this technique, we were able to incorporate a quantum dot (QD) device into a 3D cavity. We then controlled and measured the QD transport signal using the DC lines. We have also studied the heating effects of the QD by the microwave photons in the cavity. PMID- 25725825 TI - The method for measuring the groove density of variable-line-space gratings with elimination of the eccentricity effect. AB - To eliminate the eccentricity effect, a new method for measuring the groove density of a variable-line-space grating was adapted. Based on grating equation, groove density is calculated by measuring the internal angles between zeroth order and first-order diffracted light for two different wavelengths with the same angle of incidence. The measurement system mainly includes two laser sources, a phase plate, plane mirror, and charge coupled device. The measurement results of a variable-line-space grating demonstrate that the experiment data agree well with theoretical values, and the value of measurement error (DeltaN/N) is less than 2.72 * 10(-4). PMID- 25725826 TI - Measurement of the density profile of pure and seeded molecular beams by femtosecond ion imaging. AB - Here, we report on femtosecond ion imaging experiments to measure the density profile of a pulsed supersonic molecular beam. Ion images are measured for both a molecular beam and bulk gas under identical experimental conditions via femtosecond multiphoton ionization of Xe atoms. We report the density profile of the molecular beam, and the measured absolute density is compared with theoretical calculations of the centre line beam density. Subsequently, we discuss reasons accounting for the differences between measurements and calculations and propose that strong skimmer interference is the most probable cause for the differences. Furthermore, we report on experiments measuring the centre line density of seeded supersonic beams. The femtosecond ion images show that seeding the heavy Xe atom at low relative seed fractions (1%-10%) in a light carrier gas like Ne results in strong relative enhancements of up to two orders of magnitude. PMID- 25725827 TI - Quartz-enhanced photoacoustic spectroscopy sensor for ethylene detection with a 3.32 MUm distributed feedback laser diode. AB - An antimonide distributed feedback quantum wells diode laser operating at 3.32 MUm at near room temperature in the continuous wave regime has been used to perform ethylene detection based on quartz enhanced photoacoustic spectroscopy. An absorption line centered at 3007.52 cm(-1) was investigated and a normalized noise equivalent absorption coefficient (1sigma) of 3.09 10(-7) cm(-1) W Hz(-1/2) was obtained. The linearity and the stability of the detection have been evaluated. Biological samples' respiration has been measured to validate the feasibility of the detection setup in an agronomic environment, especially on ripening apples. PMID- 25725828 TI - Simultaneous broadband laser ranging and photonic Doppler velocimetry for dynamic compression experiments. AB - A diagnostic was developed to simultaneously measure both the distance and velocity of rapidly moving surfaces in dynamic compression experiments, specifically non-planar experiments where integrating the velocity in one direction does not always give the material position accurately. The diagnostic is constructed mainly from fiber-optic telecommunications components. The distance measurement is based on a technique described by Xia and Zhang [Opt. Express 18, 4118 (2010)], which determines the target distance every 20 ns and is independent of the target speed. We have extended the full range of the diagnostic to several centimeters to allow its use in dynamic experiments, and we multiplexed it with a photonic Doppler velocimetry (PDV) system so that distance and velocity histories can be measured simultaneously using one fiber-optic probe. The diagnostic was demonstrated on a spinning square cylinder to show how integrating a PDV record can give an incorrect surface position and how the ranging diagnostic described here obtains it directly. The diagnostic was also tested on an explosive experiment where copper fragments and surface ejecta were identified in both the distance and velocity signals. We show how the distance measurements complement the velocity data. Potential applications are discussed. PMID- 25725829 TI - A linear optical trap with active medium for experiments with high power laser pulses. AB - A linear optical trap for circulating high power laser pulses and tuning these pulses to high repetition frequency of several tens of MHz has been developed. A ns excimer pumped dye laser pulse has been injected with help of a Wollaston prism and a synchronized Pockels cell into an optical trap formed by two highly reflecting mirrors in a linear configuration. The test was done at lambda = 580 nm, but the optical trap can be used without limitations in a broad band of optical wavelengths (400-700 nm). Power considerations give an increase of the efficiency of the optical trap of about 7 times compared to single passage of the laser pulse through the experimental section. The time structure of the trapped laser pulses can be controlled by changing the distance between the two high reflecting mirrors. The efficiency of the optical trap strongly depends upon optical losses. To compensate the optical losses, an amplifying cell was introduced, and the efficiency was about 60 times higher than that by single passage of the laser pulse through the experimental section. PMID- 25725830 TI - Limitations of electron cyclotron resonance ion source performances set by kinetic plasma instabilities. AB - Electron cyclotron resonance ion source (ECRIS) plasmas are prone to kinetic instabilities due to anisotropy of the electron energy distribution function stemming from the resonant nature of the electron heating process. Electron cyclotron plasma instabilities are related to non-linear interaction between plasma waves and energetic electrons resulting to strong microwave emission and a burst of energetic electrons escaping the plasma, and explain the periodic oscillations of the extracted beam currents observed in several laboratories. It is demonstrated with a minimum-B 14 GHz ECRIS operating on helium, oxygen, and argon plasmas that kinetic instabilities restrict the parameter space available for the optimization of high charge state ion currents. The most critical parameter in terms of plasma stability is the strength of the solenoid magnetic field. It is demonstrated that due to the instabilities the optimum Bmin-field in single frequency heating mode is often <=0.8BECR, which is the value suggested by the semiempirical scaling laws guiding the design of modern ECRISs. It is argued that the effect can be attributed not only to the absolute magnitude of the magnetic field but also to the variation of the average magnetic field gradient on the resonance surface. PMID- 25725831 TI - Rapid measurement of charged particle beam profiles using a current flux grating. AB - The principle and physics issues of charged particle beam diagnostics using a current flux grating are presented. Unidirectional array of conducting channels with interstitial insulating layers of spacing d is placed in the beam path to capture flux of charge and electronically reproduce an exact beam current profile with density variation. The role of secondary electrons due to the impinging particle beam (both electron and ion) on the probe is addressed and a correction factor is introduced. A 2-dimensional profile of the electron beam is obtained by rotating the probe about the beam axis. Finally, a comparison of measured beam profile with a Gaussian is presented. PMID- 25725832 TI - An efficient, movable single-particle detector for use in cryogenic ultra-high vacuum environments. AB - A compact, highly efficient single-particle counting detector for ions of keV/u kinetic energy, movable by a long-stroke mechanical translation stage, has been developed at the Max-Planck-Institut fur Kernphysik (Max Planck Institute for Nuclear Physics, MPIK). Both, detector and translation mechanics, can operate at ambient temperatures down to ~10 K and consist fully of ultra-high vacuum compatible, high-temperature bakeable, and non-magnetic materials. The set-up is designed to meet the technical demands of MPIK's Cryogenic Storage Ring. We present a series of functional tests that demonstrate full suitability for this application and characterise the set-up with regard to its particle detection efficiency. PMID- 25725833 TI - A versatile apparatus for the fine-tuned synthesis of cluster-based materials. AB - In this paper, a custom-designed experimental setup for the fine-tuned synthesis of various cluster-based materials is presented. Providing custom-designed deposition stages and special sample holders it offers a high degree of control over the sample characteristics such as the cluster size, cluster amounts, and sample homogeneity in combination with high sample purity. The system is capable of producing thin films of pure clusters and various cluster-matrix combinations with cluster sizes ranging from single atoms up to aggregates of several thousand atoms. Two custom-designed deposition stages are available, one utilizes the full cluster beam, yielding micrograms of pure clusters within a few hours and the second one uses mass-separated clusters (mass-resolution between 2% and 10%), yielding nanograms of pure clusters in the same timescale. Furthermore, at the second deposition stage, a variety of matrix materials can be co-deposited at a controlled sample temperature between 153 K and 673 K. In order to prove the capabilities of the apparatus, a series of experiments with Fe clusters embedded in Ag matrices with different volume fractions of clusters were carried out. Energy dispersive X-ray spectroscopy measurements revealed that the amount of deposited clusters as well as the sample homogeneity can be controlled with an outstanding accuracy of 10%. Additional measurements of the magnetic properties indicated the presence of separated clusters for volume fractions of clusters around 2 volume percent (vol. %), while above this concentration (10 vol. %) a partial aggregation of the clusters was observed. It was also shown that the resulting thin films are nearly oxygen free, which ascertains that oxygen sensitive materials can be safely handled in this newly developed apparatus. PMID- 25725834 TI - A zero dead-time multi-particle time and position sensitive detector based on correlation between brightness and amplitude. AB - A new multi-particle time and position sensitive detector using only a set of microchannel plates, a waveform digitizer, a phosphor screen, and a CMOS camera is described. The assignment of the timing information, as taken from the microchannel plates by fast digitizing, to the positions, as recorded by the camera, is based on the COrrelation between the BRightness of the phosphor screen spots, defined as their integrated intensity and the Amplitude of the electrical signals (COBRA). Tests performed by observing the dissociation of HeH, the fragmentation of H3 into two or three fragments, and the photo-double-ionization of Xenon atoms are presented, which illustrate the performances of the COBRA detection scheme. PMID- 25725835 TI - Feasibility of a 90 degrees electric sector energy analyzer for low energy ion beam characterization. AB - A simple formula to calculate refocusing by locating the output slit at a specific distance away from the exit of 90 degrees ion deflecting electric sector is given. Numerical analysis is also performed to calculate the ion beam trajectories for different values of the initial angular deviation of the beam. To validate the theory, a compact (90 mm * 5.5 mm * 32 mm) 90 degrees sector ESA is fabricated which can fit through the inner diameter of a conflat 70 vacuum flange. Experimental results show that the dependence of resolution upon the distance between the sector exit and the Faraday cup agrees with the theory. The fabricated 90 degrees sector electrostatic energy analyzer was then used to measure the space resolved ion energy distribution functions of an ion beam with the energy as low as 600 eV. PMID- 25725836 TI - Development of Thomson scattering system on Shenguang-III prototype laser facility. AB - A Thomson scattering diagnostic system, using a 263 nm laser as the probe beam, is designed and implemented on Shenguang-III prototype laser facility. The probe beam is provided by an additional beam line completed recently. The diagnostic system allows simultaneous measurements of both ion feature and red-shifted electron feature from plasmas in a high-temperature (>=2 keV) and high-density (>=10(21) cm(-3)) regime. Delicate design is made to satisfy the requirements for successful detection of the electron feature. High-quality ion feature spectra have already been diagnosed via this system in recent experiments with gas-filled hohlraums. PMID- 25725837 TI - Design of polarizers for a mega-watt long-pulse millimeter-wave transmission line on the large helical device. AB - The polarizer is one of the critical components in a high-power millimeter-wave transmission line. It requires full and highly efficient coverage of any polarization states, high-power tolerance, and low-loss feature. Polarizers with rounded shape at the edge of the periodic groove surface are designed and fabricated by the machining process for a mega-watt long-pulse millimeter-wave transmission line of the electron cyclotron resonance heating system in the large helical device. The groove shape of lambda/8- and lambda/4-type polarizers for an 82.7 GHz transmission line is optimally designed in an integral method developed in the vector theories of diffraction gratings so that the efficiency to realize any polarization state can be maximized. The dependence of the polarization states on the combination of the two polarizer rotation angles (Philambda/8, Philambda/4) is examined experimentally in a low-power test with the newly developed polarization monitor. The results show that the measured polarization characteristics are in good agreement with the calculated ones. PMID- 25725838 TI - Development of compact rapid charging power supply for capacitive energy storage in pulsed power drivers. AB - High energy capacitor bank is used for primary electrical energy storage in pulsed power drivers. The capacitors used in these pulsed power drivers have low inductance, low internal resistance, and less dc life, so it has to be charged rapidly and immediately discharged into the load. A series resonant converter based 45 kV compact power supply is designed and developed for rapid charging of the capacitor bank with constant charging current up to 150 mA. It is short circuit proof, and zero current switching technique is used to commute the semiconductor switch. A high frequency resonant inverter switching at 10 kHz makes the overall size small and reduces the switching losses. The output current of the power supply is limited by constant on-time and variable frequency switching control technique. The power supply is tested by charging the 45 kV/1.67 MUF and 15 kV/356 MUF capacitor banks. It has charged the capacitor bank up to rated voltage with maximum charging current of 150 mA and the average charging rate of 3.4 kJ/s. The output current of the power supply is limited by reducing the switching frequency at 5 kHz, 3.3 kHz, and 1.7 kHz and tested with 45 kV/1.67 MUF capacitor bank. The protection circuit is included in the power supply for over current, under voltage, and over temperature. The design details and the experimental testing results of the power supply for resonant current, output current, and voltage traces of the power supply with capacitive, resistive, and short circuited load are presented and discussed. PMID- 25725839 TI - A flowing liquid lithium limiter for the Experimental Advanced Superconducting Tokamak. AB - A program involving the extensive and systematic use of lithium (Li) as a "first," or plasma-facing, surface in Tokamak fusion research devices located at Institute of Plasma Physics, Chinese Academy of Sciences, was started in 2009. Many remarkable results have been obtained by the application of Li coatings in Experimental Advanced Superconducting Tokamak (EAST) and liquid Li limiters in the HT-7 Tokamak-both located at the institute. In furtherance of the lithium program, a flowing liquid lithium (FLiLi) limiter system has been designed and manufactured for EAST. The design of the FLiLi limiter is based on the concept of a thin flowing film which was previously tested in HT-7. Exploiting the capabilities of the existing material and plasma evaluation system on EAST, the limiter will be pre-wetted with Li and mechanically translated to the edge of EAST during plasma discharges. The limiter will employ a novel electro-magnetic pump which is designed to drive liquid Li flow from a collector at the bottom of limiter into a distributor at its top, and thus supply a continuously flowing liquid Li film to the wetted plasma-facing surface. This paper focuses on the major design elements of the FLiLi limiter. In addition, a simulation of incoming heat flux has shown that the distribution of heat flux on the limiter surface is acceptable for a future test of power extraction on EAST. PMID- 25725840 TI - Measurement of plasma momentum exerted on target by a small helicon plasma thruster and comparison with direct thrust measurement. AB - Momentum, i.e., force, exerted from a small helicon plasma thruster to a target plate is measured simultaneously with a direct thrust measurement using a thrust balance. The calibration coefficient relating a target displacement to a steady state force is obtained by supplying a dc to a calibration coil mounted on the target, where a force acting to a small permanent magnet located near the coil is directly measured by using a load cell. As the force exerted by the plasma flow to the target plate is in good agreement with the directly measured thrust, the validity of the target technique is demonstrated under the present operating conditions, where the thruster is operated in steady-state. Furthermore, a calibration coefficient relating a swing amplitude of the target to an impulse bit is also obtained by pulsing the calibration coil current. The force exerted by the pulsed plasma, which is estimated from the measured impulse bit and the pulse width, is also in good agreement with that obtained for the steady-state operation; hence, the thrust assessment of the helicon plasma thruster by the target is validated for both the steady-state and pulsed operations. PMID- 25725841 TI - Electron temperature measurement in Maxwellian non-isothermal beam plasma of an ion thruster. AB - Published electron temperature profiles of the beam plasma from ion thrusters reveal many divergences both in magnitude and radial variation. In order to know exactly the radial distributions of electron temperature and understand the beam plasma characteristics, we applied five different experimental approaches to measure the spatial profiles of electron temperature and compared the agreement and disagreement of the electron temperature profiles obtained from these techniques. Experimental results show that the triple Langmuir probe and adiabatic poly-tropic law methods could provide more accurate space-resolved electron temperature of the beam plasma than other techniques. Radial electron temperature profiles indicate that the electrons in the beam plasma are non isothermal, which is supported by a radial decrease (~2 eV) of electron temperature as the plume plasma expands outward. Therefore, the adiabatic "poly tropic law" is more appropriate than the isothermal "barometric law" to be used in electron temperature calculations. Moreover, the calculation results show that the electron temperature profiles derived from the "poly-tropic law" are in better agreement with the experimental data when the specific heat ratio (gamma) lies in the range of 1.2-1.4 instead of 5/3. PMID- 25725842 TI - Density modulation experiment to determine transport coefficients on Joint-TEXT Tokamak. AB - Density modulation experiments have been conducted on Joint-TEXT (J-TEXT) Tokamak Ohmic discharge to investigate particle transport based on a model with constant diffusion plus inward convection. Like the HCN interferometer, the newly developed three-wave polarimeter-interferometer system (POLARIS) is used to measure the perturbed density. The comparison of results between the HCN interferometer and POLARIS is given. The consistent results indicate the validity of the analysis scheme. At lower densities, the typical particle confinement time taup is found to increase with electron density, while it saturates at higher densities. PMID- 25725843 TI - Studies on characteristics of resistive power calculated with discrete Fourier transform in a pulse-modulated radio frequency discharge. AB - In a pulse-modulated (PM) radio-frequency (RF) capacitively coupled plasma, the DFT (Discrete Fourier Transform)-calculated RF power and the corresponding phase shift between voltage and current measured with calibrated voltage and current probes present oscillations in the pulse rising and falling edges. The oscillating phase shift between voltage and current obtained in the falling edge is outside the expected value for a resistive-capacitive RF discharge. Numerical simulation and analytical analysis are made to interpret these abnormal characteristics and seek an approach to obtaining the reliable resistive (active) RF power. The oscillation is proved to be originated from the oscillating non zero reactive RF power of the capacitor(s) in the load. At the time instant when the reactive RF power within an integer RF period is not zero, the reactive RF power is mistakenly regarded as the active RF power in the DFT analysis, as a result, the corresponding phase is thus incorrect and even outside the expected value for a resistive-capacitive load. The resistive RF power and the phase can be only correctly calculated at the time instant when the reactive RF power is zero. For a series (or parallel) RC (resistor-capacitor) load and a combined RC load with the dominated series (or parallel) RC impedance, the time instant of the zero reactive RF power is calculated with one of the two proposed empirical formulae. In practice, the DFT-calculated resistive RF power is obtained according to the following procedures: (1) applying DFT to the measured RF voltage and current signals to obtain the power and time instants for minimal phase shifts between voltage and current; (2) selecting the empirical formula to calculate time instants of the zero reactive RF power; (3) getting resistive powers at time instants of the zero reactive RF power. In real PM RF capacitively coupled plasmas, the empirical formula for the series RC load is selected to calculate the resistive RF power. The accuracy of DFT-calculated resistive RF power is proved to be related to two kinds of errors. The first is the error of the time instant of the zero reactive RF power calculated using the empirical formula. This error is relatively lower when the requirement that the dominated parallel or series RC impedance is met and is almost independent of the impedance phase angle of a combined RC load. The second is the error of the DFT-calculated resistive RF power compared with the corresponding time integral RF power at the real zero reactive RF power. This error is independent of the load type or the load impedance but varies with the slope of PM RF voltage amplitude vs. time. The two kinds of errors both increase in the pulse rising and falling edges. PMID- 25725844 TI - Application of visible bremsstrahlung to Z(eff) measurement on the Experimental Advanced Superconducting Tokamak. AB - The multi-channel visible bremsstrahlung measurement system has been developed on Experimental Advanced Superconducting Tokamak (EAST). In addition to providing effective ion charge Zeff as a routine diagnostic, this diagnostic can also be used to estimate other parameters. With the assumption that Zeff can be seen as constant across the radius and does not change significantly during steady state discharges, central electron temperature, averaged electron density, electron density profile, and plasma current density profile have been obtained based on the scaling of Zeff with electron density and the relations between Zeff and these parameters. The estimated results are in good coincidence with measured values, providing an effective and convenient method to estimate other plasma parameters. PMID- 25725845 TI - Profile measurements in the plasma edge of mega amp spherical tokamak using a ball pen probe. AB - The ball pen probe (BPP) technique is used successfully to make profile measurements of plasma potential, electron temperature, and radial electric field on the Mega Amp Spherical Tokamak. The potential profile measured by the BPP is shown to significantly differ from the floating potential both in polarity and profile shape. By combining the BPP potential and the floating potential, the electron temperature can be measured, which is compared with the Thomson scattering (TS) diagnostic. Excellent agreement between the two diagnostics is obtained when secondary electron emission is accounted for in the floating potential. From the BPP profile, an estimate of the radial electric field is extracted which is shown to be of the order ~1 kV/m and increases with plasma current. Corrections to the BPP measurement, constrained by the TS comparison, introduce uncertainty into the ER measurements. The uncertainty is most significant in the electric field well inside the separatrix. The electric field is used to estimate toroidal and poloidal rotation velocities from E * B motion. This paper further demonstrates the ability of the ball pen probe to make valuable and important measurements in the boundary plasma of a tokamak. PMID- 25725846 TI - Ultrahigh-spatial-resolution chemical and magnetic imaging by laser-based photoemission electron microscopy. AB - We report the first experiments carried out on a new chemical and magnetic imaging system, which combines the high spatial resolution of a photoemission electron microscope (PEEM) with a continuous-wave deep-ultraviolet laser. Threshold photoemission is sensitive to the chemical and magnetic structures of the surface of materials. The spatial resolution of PEEM is limited by space charging when using pulsed photon sources as well as aberrations in the electron optics. We show that the use of a continuous-wave laser enabled us to overcome such a limit by suppressing the space-charge effect, allowing us to obtain a resolution of approximately 2.6 nm. With this system, we demonstrated the imaging of surface reconstruction domains on Si(001) by linear dichroism with normal incidence of the laser beam. We also succeeded in magnetic imaging of thin films with the use of magnetic circular dichroism near the Fermi level. The unique features of the ultraviolet laser will give us fast switching of the incident angles and polarizations of the photon source, which will be useful for the characterization of antiferromagnetic materials as well as ferromagnetic materials. PMID- 25725847 TI - A sample holder with integrated laser optics for an ELMITEC photoemission electron microscope. AB - We present a new sample holder compatible with ELMITEC Photoemission Electron Microscopes (PEEMs) containing an optical lens and a mirror. With the integrated optical elements, a laser beam is focused from the back side of the sample at normal incidence, yielding a minimum spot size of about 1 MUm. This opens up new possibilities for local laser excitations in PEEM experiments such as imaging all optical magnetization switching at a small length scale. PMID- 25725848 TI - Sub-nanosecond time-resolved near-field scanning magneto-optical microscope. AB - We report on the development of a new magnetic microscope, time-resolved near field scanning magneto-optical microscope, which combines a near-field scanning optical microscope and magneto-optical contrast. By taking advantage of the high temporal resolution of time-resolved Kerr microscope and the sub-wavelength spatial resolution of a near-field microscope, we achieved a temporal resolution of ~50 ps and a spatial resolution of <100 nm. In order to demonstrate the spatiotemporal magnetic imaging capability of this microscope, the magnetic field pulse induced gyrotropic vortex dynamics occurring in 1 MUm diameter, 20 nm thick CoFeB circular disks has been investigated. The microscope provides sub wavelength resolution magnetic images of the gyrotropic motion of the vortex core at a resonance frequency of ~240 MHz. PMID- 25725849 TI - A highly contrasting scanning helium microscope. AB - We present a scanning helium microscope equipped to make use of the unique contrast mechanisms, surface sensitivity, and zero damage imaging the technique affords. The new design delivers an order of magnitude increase in the available helium signal, yielding a higher contrast and signal-to-noise ratio. These improvements allow the microscope to produce high quality, intuitive images of samples using topological contrast, while setting the stage for investigations into further contrast mechanisms. PMID- 25725850 TI - High-stroke silicon-on-insulator MEMS nanopositioner: control design for non raster scan atomic force microscopy. AB - A 2-degree of freedom microelectromechanical systems nanopositioner designed for on-chip atomic force microscopy (AFM) is presented. The device is fabricated using a silicon-on-insulator-based process and is designed as a parallel kinematic mechanism. It contains a central scan table and two sets of electrostatic comb actuators along each orthogonal axis, which provides displacement ranges greater than +/-10 MUm. The first in-plane resonance modes are located at 1274 Hz and 1286 Hz for the X and Y axes, respectively. To measure lateral displacements of the stage, electrothermal position sensors are incorporated in the design. To facilitate high-speed scans, the highly resonant dynamics of the system are controlled using damping loops in conjunction with internal model controllers that enable accurate tracking of fast sinusoidal set points. To cancel the effect of sensor drift on controlled displacements, washout controllers are used in the damping loops. The feedback controlled nanopositioner is successfully used to perform several AFM scans in contact mode via a Lissajous scan method with a large scan area of 20 MUm * 20 MUm. The maximum scan rate demonstrated is 1 kHz. PMID- 25725851 TI - Alternative configuration scheme for signal amplification with scanning ion conductance microscopy. AB - Scanning Ion Conductance Microscopy (SICM) is an emerging nanotechnology tool to investigate the morphology and charge transport properties of nanomaterials, including soft matter. SICM uses an electrolyte filled nanopipette as a scanning probe and detects current changes based on the distance between the nanopipette apex and the target sample in an electrolyte solution. In conventional SICM, the pipette sensor is excited by applying voltage as it raster scans near the surface. There have been attempts to improve upon raster scanning because it can induce collisions between the pipette sidewalls and target sample, especially for soft, dynamic materials (e.g., biological cells). Recently, Novak et al. demonstrated that hopping probe ion conductance microscopy (HPICM) with an adaptive scan method can improve the image quality obtained by SICM for such materials. However, HPICM is inherently slower than conventional raster scanning. In order to optimize both image quality and scanning speed, we report the development of an alternative configuration scheme for SICM signal amplification that is based on applying current to the nanopipette. This scheme overcomes traditional challenges associated with low bandwidth requirements of conventional SICM. Using our alternative scheme, we demonstrate successful imaging of L929 fibroblast cells and discuss the capabilities of this instrument configuration for future applications. PMID- 25725852 TI - An improved phase shift reconstruction algorithm of fringe scanning technique for X-ray microscopy. AB - The X-ray phase imaging method has been applied to observe soft biological tissues, and it is possible to image the soft tissues by using the benefit of the so-called "Talbot effect" by an X-ray grating. One type of the X-ray phase imaging method was reported by combining an X-ray imaging microscope equipped by a Fresnel zone plate with a phase grating. Using the fringe scanning technique, a high-precision phase shift image could be obtained by displacing the grating step by step and measuring dozens of sample images. The number of the images was selected to reduce the error caused by the non-sinusoidal component of the Talbot self-image at the imaging plane. A larger number suppressed the error more but increased radiation exposure and required higher mechanical stability of equipment. In this paper, we analyze the approximation error of fringe scanning technique for the X-ray microscopy which uses just one grating and proposes an improved algorithm. We compute the approximation error by iteration and substitute that into the process of reconstruction of phase shift. This procedure will suppress the error even with few sample images. The results of simulation experiments show that the precision of phase shift image reconstructed by the proposed algorithm with 4 sample images is almost the same as that reconstructed by the conventional algorithm with 40 sample images. We also have succeeded in the experiment with real data. PMID- 25725853 TI - A novel technique for investigation of complete and partial anisotropic wetting on structured surface by X-ray microtomography. AB - An experimental study about the anisotropic wetting behavior of a surface patterned with parallel grooves is presented as an application example of a novel technique for investigation of complete and partial anisotropic wetting on structured surface by X-ray microtomography. Shape of glycerin droplets on such surface is investigated by X-ray micro computed tomography (microCT) acting as a non-intrusive, full volume 3D microscope with micrometric spatial resolution. The reconstructed drop volumes enable to estimate the exact volumes of the drops, their base contours, and 3D static contact angles, based on true cross-sections of the drop-surface couple. Droplet base contours are compared to approximate geometrical contour shapes proposed in the literature. Contact angles along slices parallel and perpendicular to the grooves direction are compared with each other. The effect of the sessile drop volume on the wetting behavior is discussed. The proposed technique, which is applicable for any structured surface, enables the direct measure of Wenzel ratio based on the microCT scan in the wetted region usually inapproachable by any others. Comparisons with simplified models are presented and congruence of results with respect to the minimum resolution needed is evaluated and commented. PMID- 25725854 TI - Measuring droplet size distributions from overlapping interferometric particle images. AB - Interferometric particle imaging provides a simple way to measure the probability density function (PDF) of droplet sizes from out-focus images. The optical setup is straightforward, but the interpretation of the data is a problem when particle images overlap. We propose a new way to analyze the images. The emphasis is not on a precise identification of droplets, but on obtaining a good estimate of the PDF of droplet sizes in the case of overlapping particle images. The algorithm is tested using synthetic and experimental data. We next use these methods to measure the PDF of droplet sizes produced by spinning disk aerosol generators. The mean primary droplet diameter agrees with predictions from the literature, but we find a broad distribution of satellite droplet sizes. PMID- 25725855 TI - A simple microviscometric approach based on Brownian motion tracking. AB - Viscosity-an integral property of a liquid-is traditionally determined by mechanical instruments. The most pronounced disadvantage of such an approach is the requirement of a large sample volume, which poses a serious obstacle, particularly in biology and biophysics when working with limited samples. Scaling down the required volume by means of microviscometry based on tracking the Brownian motion of particles can provide a reasonable alternative. In this paper, we report a simple microviscometric approach which can be conducted with common laboratory equipment. The core of this approach consists in a freely available standalone script to process particle trajectory data based on a Newtonian model. In our study, this setup allowed the sample to be scaled down to 10 MUl. The utility of the approach was demonstrated using model solutions of glycerine, hyaluronate, and mouse blood plasma. Therefore, this microviscometric approach based on a newly developed freely available script can be suggested for determination of the viscosity of small biological samples (e.g., body fluids). PMID- 25725857 TI - Small angle scattering methods to study porous materials under high uniaxial strain. AB - We developed a high pressure cell for the in situ study of the porosity of solids under high uniaxial strain using neutron small angle scattering. The cell comprises a hydraulically actioned piston and a main body equipped with two single-crystal sapphire windows allowing for the neutron scattering of the sample. The sample cavity is designed to allow for a large volume variation as expected when compressing highly porous materials. We also implemented a loading protocol to adapt an existing diamond anvil cell for the study of porous materials by X-ray small angle scattering under high pressure. The two techniques are complementary as the radiation beam and the applied pressure are in one case perpendicular to each other (neutron cell) and in the other case parallel (X-ray cell). We will illustrate the use of these two techniques in the study of lamellar porous systems up to a maximum pressure of 0.1 GPa and 0.3 GPa for the neutron and X-ray cells, respectively. These devices allow obtaining information on the evolution of porosity with pressure in the pore dimension subdomain defined by the wave-numbers explored in the scattering process. The evolution with the applied load of such parameters as the fractal dimension of the pore matrix interface or the apparent specific surface in expanded graphite and in expanded vermiculite is used to illustrate the use of the high pressure cells. PMID- 25725856 TI - A high throughput array microscope for the mechanical characterization of biomaterials. AB - In the last decade, the emergence of high throughput screening has enabled the development of novel drug therapies and elucidated many complex cellular processes. Concurrently, the mechanobiology community has developed tools and methods to show that the dysregulation of biophysical properties and the biochemical mechanisms controlling those properties contribute significantly to many human diseases. Despite these advances, a complete understanding of the connection between biomechanics and disease will require advances in instrumentation that enable parallelized, high throughput assays capable of probing complex signaling pathways, studying biology in physiologically relevant conditions, and capturing specimen and mechanical heterogeneity. Traditional biophysical instruments are unable to meet this need. To address the challenge of large-scale, parallelized biophysical measurements, we have developed an automated array high-throughput microscope system that utilizes passive microbead diffusion to characterize mechanical properties of biomaterials. The instrument is capable of acquiring data on twelve-channels simultaneously, where each channel in the system can independently drive two-channel fluorescence imaging at up to 50 frames per second. We employ this system to measure the concentration dependent apparent viscosity of hyaluronan, an essential polymer found in connective tissue and whose expression has been implicated in cancer progression. PMID- 25725858 TI - Spin echo small angle neutron scattering using a continuously pumped (3)He neutron polarisation analyser. AB - We present a new instrument for spin echo small angle neutron scattering (SESANS) developed at the Low Energy Neutron Source at Indiana University. A description of the various instrument components is given along with the performance of these components. At the heart of the instrument are a series of resistive coils to encode the neutron trajectory into the neutron polarisation. These are shown to work well over a broad range of neutron wavelengths. Neutron polarisation analysis is accomplished using a continuously operating neutron spin filter polarised by Rb spin-exchange optical pumping of (3)He. We describe the performance of the analyser along with a study of the (3)He polarisation stability and its implications for SESANS measurements. Scattering from silica Stober particles is investigated and agrees with samples run on similar instruments. PMID- 25725859 TI - Mossbauer cell for low-temperature studies of catalysts under reaction conditions. AB - Mossbauer spectroscopy is an essential tool to investigate the structure of Fe supported catalysts and their changes, when they are used in the Fischer-Tropsch synthesis. A cell, that allows keeping the samples in the same atmosphere of the reduction treatment, was designed in order to characterize the Fe species without changing the working atmosphere avoiding the oxidation. It allows to measure at low temperatures in a helium closed-cycle refrigerator. Besides, this cell is useful to perform Mossbauer measurements on the used catalysts, preserving the oxidation of its species, using an inert atmosphere. In this work, we describe the details of this new cell and, as an example of its utility, we present the results obtained with a system of 12 nm iron oxide nanoparticles supported on a mesoporous silica matrix. PMID- 25725860 TI - Implementation of a spark plasma sintering facility in a hermetic glovebox for compaction of toxic, radiotoxic, and air sensitive materials. AB - Spark plasma sintering (SPS) is a rapidly developing method for densification of powders into compacts. It belongs to the so-called "field assisted sintering techniques" that enable rapid sintering at much lower temperatures than the classical approaches of pressureless sintering of green pellets or hot isostatic pressing. In this paper, we report the successful integration of a SPS device into a hermetic glovebox for the handling of highly radioactive material containing radioisotopes of U, Th, Pu, Np, and Am. The glovebox implantation has been facilitated by the replacement of the hydraulic system to apply pressure with a compact electromechanical unit. The facility has been successfully tested using UO2 powder. Pellets with 97% of the theoretical density were obtained at 1000 degrees C for 5 min, significantly lower than the ~1600 degrees C for 5-10 h used in conventional pellet sintering. PMID- 25725861 TI - A magnetic tunnel to shelter hyperpolarized fluids. AB - To shield solutions carrying hyperpolarized nuclear magnetization from rapid relaxation during transfer through low fields, the transfer duct can be threaded through an array of permanent magnets. The advantages are illustrated for solutions containing hyperpolarized (1)H and (13)C nuclei in a variety of molecules. PMID- 25725862 TI - Gas diffusion electrode setup for catalyst testing in concentrated phosphoric acid at elevated temperatures. AB - We present a detailed description of the construction and testing of an electrochemical cell setup allowing the investigation of a gas diffusion electrode containing carbon supported high surface area catalysts. The setup is designed for measurements in concentrated phosphoric acid at elevated temperature, i.e., very close to the actual conditions in high temperature proton exchange membrane fuel cells (HT-PEMFCs). The cell consists of a stainless steel flow field and a PEEK plastic cell body comprising the electrochemical cell, which exhibits a three electrode configuration. The cell body and flow field are braced using a KF-25 vacuum flange clamp, which allows an easy assembly of the setup. As demonstrated, the setup can be used to investigate temperature dependent electrochemical processes on high surface area type electrocatalysts, but it also enables quick screening tests of HT-PEMFC catalysts under realistic conditions. PMID- 25725863 TI - Constant-current control method of multi-function electromagnetic transmitter. AB - Based on the requirements of controlled source audio-frequency magnetotelluric, DC resistivity, and induced polarization, a constant-current control method is proposed. Using the required current waveforms in prospecting as a standard, the causes of current waveform distortion and current waveform distortion's effects on prospecting are analyzed. A cascaded topology is adopted to achieve 40 kW constant-current transmitter. The responsive speed and precision are analyzed. According to the power circuit of the transmitting system, the circuit structure of the pulse width modulation (PWM) constant-current controller is designed. After establishing the power circuit model of the transmitting system and the PWM constant-current controller model, analyzing the influence of ripple current, and designing an open-loop transfer function according to the amplitude-frequency characteristic curves, the parameters of the PWM constant-current controller are determined. The open-loop transfer function indicates that the loop gain is no less than 28 dB below 160 Hz, which assures the responsive speed of the transmitting system; the phase margin is 45 degrees , which assures the stabilization of the transmitting system. Experimental results verify that the proposed constant-current control method can keep the control error below 4% and can effectively suppress load change caused by the capacitance of earth load. PMID- 25725864 TI - Tuner and radiation shield for planar electron paramagnetic resonance microresonators. AB - Planar microresonators provide a large boost of sensitivity for small samples. They can be manufactured lithographically to a wide range of target parameters. The coupler between the resonator and the microwave feedline can be integrated into this design. To optimize the coupling and to compensate manufacturing tolerances, it is sometimes desirable to have a tuning element available that can be adjusted when the resonator is connected to the spectrometer. This paper presents a simple design that allows one to bring undercoupled resonators into the condition for critical coupling. In addition, it also reduces radiation losses and thereby increases the quality factor and the sensitivity of the resonator. PMID- 25725865 TI - The thirty gigahertz instrument receiver for the Q-U-I Joint Tenerife experiment: concept and experimental results. AB - This paper presents the analysis, design, and characterization of the thirty gigahertz instrument receiver developed for the Q-U-I Joint Tenerife experiment. The receiver is aimed to obtain polarization data of the cosmic microwave background radiation from the sky, obtaining the Q, U, and I Stokes parameters of the incoming signal simultaneously. A comprehensive analysis of the theory behind the proposed receiver is presented for a linearly polarized input signal, and the functionality tests have demonstrated adequate results in terms of Stokes parameters, which validate the concept of the receiver based on electronic phase switching. PMID- 25725866 TI - Ultrastable low-noise current amplifier: a novel device for measuring small electric currents with high accuracy. AB - An ultrastable low-noise current amplifier (ULCA) is presented. The ULCA is a non cryogenic instrument based on specially designed operational amplifiers and resistor networks. It involves two stages, the first providing a 1000-fold current gain and the second performing a current-to-voltage conversion via an internal 1 MOmega reference resistor or, optionally, an external standard resistor. The ULCA's transfer coefficient is highly stable versus time, temperature, and current amplitude within the full dynamic range of +/-5 nA. The low noise level of 2.4 fA/?Hz helps to keep averaging times short at small input currents. A cryogenic current comparator is used to calibrate both input current gain and output transresistance, providing traceability to the quantum Hall effect. Within one week after calibration, the uncertainty contribution from short-term fluctuations and drift of the transresistance is about 0.1 parts per million (ppm). The long-term drift is typically 5 ppm/yr. A high-accuracy variant is available that shows improved stability of the input gain at the expense of a higher noise level of 7.5 fA/?Hz. The ULCA also allows the traceable generation of small electric currents or the calibration of high-ohmic resistors. PMID- 25725867 TI - Investigation of DC hybrid circuit breaker based on high-speed switch and arc generator. AB - A new design of DC hybrid circuit breaker based on high-speed switch (HSS) and arc generator (AG), which can drastically profit from low heat loss in normal state and fast current breaking under fault state, is presented and analyzed in this paper. AG is designed according to the magnetic pinch effect of liquid metal. By utilizing the arc voltage generated across AG, the fault current is rapidly commutated from HSS into parallel connected branch. As a consequence, the arcless open of HSS is achieved. The post-arc conducting resume time (Delta tc) of AG and the commutation original voltage (Uc), two key factors in the commutation process, are investigated experimentally. Particularly, influences of the liquid metal channel diameter (Phi) of AG, fault current rate of rise (di/dt) and Uc on Delta tc are focused on. Furthermore, a suitable Uc is determined during the current commutation process, aiming at the reliable arcless open of HSS and short breaking time. Finally, the fault current breaking test is carried out for the current peak value of 11.8 kA, and the validity of the design is confirmed by the experimental results. PMID- 25725868 TI - Preliminary investigation of an improved metal-dielectric cathode for magnetically insulated transmission line oscillator. AB - In order to explore the cathode with good repetition quality for the magnetically insulated transmission line oscillators, an improved metal-dielectric cathode is proposed and investigated experimentally. The cathode is designed to be step-like shape, and thin copper plated boards are periodically and compactly arrayed on the surface of the cathode base, which ensures the uniformity of the electrons emitted from the cusps of the copper plated boards. According to the numerical simulation results, the step-like shape is beneficial to convert the kinetic energy of the magnetic insulating current partially and enhance the beam-wave interaction efficiency. Finally, a preliminary experiment of an L-band magnetically insulated transmission line oscillator (MILO) with the improved metal-dielectric cathode is carried out. A high power microwave (HPM) with an average power of 1.95 GW is generated from the MILO, with an efficiency of 13.5%. Under the same experiment condition, the output power and main frequency with the presented cathode are almost the same to those with the velvet cathode. Apart from that, metal-dielectric cathode has the merits of small outgassing and long lifetime, and all of these make the improved metal-dielectric cathode significantly promising for the MILO repetition operation. PMID- 25725869 TI - Efficient and robust analysis of complex scattering data under noise in microwave resonators. AB - Superconducting microwave resonators are reliable circuits widely used for detection and as test devices for material research. A reliable determination of their external and internal quality factors is crucial for many modern applications, which either require fast measurements or operate in the single photon regime with small signal to noise ratios. Here, we use the circle fit technique with diameter correction and provide a step by step guide for implementing an algorithm for robust fitting and calibration of complex resonator scattering data in the presence of noise. The speedup and robustness of the analysis are achieved by employing an algebraic rather than an iterative fit technique for the resonance circle. PMID- 25725870 TI - A miniature microcontroller curve tracing circuit for space flight testing transistors. AB - This paper describes a novel miniature microcontroller based curve tracing circuit, which was designed to monitor the environmental effects on Silicon Carbide Junction Field Effect Transistor (SiC JFET) device performance, while exposed to the low earth orbit environment onboard the International Space Station (ISS) as a resident experiment on the 7th Materials on the International Space Station Experiment (MISSE7). Specifically, the microcontroller circuit was designed to operate autonomously and was flown on the external structure of the ISS for over a year. This curve tracing circuit is capable of measuring current vs. voltage (I-V) characteristics of transistors and diodes. The circuit is current limited for low current devices and is specifically designed to test high temperature, high drain-to-source resistance SiC JFETs. The results of each I-V data set are transmitted serially to an external telemetered communication interface. This paper discusses the circuit architecture, its design, and presents example results. PMID- 25725871 TI - Thermal characterization and analysis of microliter liquid volumes using the three-omega method. AB - Thermal phenomena in many biological systems offer an alternative detection opportunity for quantifying relevant sample properties. While there is substantial prior work on thermal characterization methods for fluids, the push in the biology and biomedical research communities towards analysis of reduced sample volumes drives a need to extend and scale these techniques to these volumes of interest, which can be below 100 pl. This work applies the 3omega technique to measure the temperature-dependent thermal conductivity and heat capacity of de-ionized water, silicone oil, and salt buffer solution droplets from 24 to 80 degrees C. Heater geometries range in length from 200 to 700 MUm and in width from 2 to 5 MUm to accommodate the size restrictions imposed by small volume droplets. We use these devices to measure droplet volumes of 2 MUl and demonstrate the potential to extend this technique down to pl droplet volumes based on an analysis of the thermally probed volume. Sensitivity and uncertainty analyses provide guidance for relevant design variables for characterizing properties of interest by investigating the tradeoffs between measurement frequency regime, device geometry, and substrate material. Experimental results show that we can extract thermal conductivity and heat capacity with these sample volumes to within less than 1% of thermal properties reported in the literature. PMID- 25725872 TI - Sensitivity enhancement of surface thermal lens technique with a short-wavelength probe beam: experiment. AB - Surface thermal lens is a highly sensitive photothermal technique to measure low absorption losses of various solid materials. In such applications, the sensitivity of surface thermal lens is a key parameter for measuring extremely low absorption. In this paper, we experimentally investigated the influence of probe beam wavelength on the sensitivity of surface thermal lens for measuring the low absorptance of optical laser components. Three probe lasers with wavelength 375 nm, 633 nm, and 1570 nm were used, respectively, to detect the surface thermal lens amplitude of a highly reflective coating sample excited by a cw modulated Gaussian beam at 1064 nm. The experimental results showed that the maximum amplitude of surface thermal lens signal obtained at corresponding optimized detection distance was inversely proportional to the wavelength of the probe beam, as predicted by previous theoretical model. The sensitivity of surface thermal lens could, therefore, be improved by detecting surface thermal lens signal with a short-wavelength probe beam. PMID- 25725873 TI - Characterization of the temperature dependence of the thermoreflectance coefficient for conductive thin films. AB - We describe a novel approach for calibration of the thermoreflectance coefficient, ideally suited for measurements in a vacuum thermostat, and present the high temperature thermoreflectance coefficients for several metals commonly encountered in electronic devices: gold, platinum, and aluminum. The effect of passivation on these metals is also examined, and we demonstrate the signal to noise ratio of a thermoreflectance measurement can be improved with informed selection of the dielectric layer thickness. Furthermore, the thermo-optic coefficients of the metals are extracted over a wide temperature range. The results presented here can be utilized in the optimization of experimental configurations for high temperature thermoreflectance imaging. PMID- 25725874 TI - A novel compact heat exchanger using gap flow mechanism. AB - A novel, compact gap-flow heat exchanger (GFHE) using heat-transfer fluid (HTF) was developed in this paper. The detail design of the GFHE coaxial structure which forms the annular gap passage for HTF is presented. Computational fluid dynamics simulations were introduced into the design to determine the impacts of the gap width and the HTF flow rate on the GFHE performance. A comparative study on the GFHE heating rate, with the gap widths ranged from 0.1 to 1.0 mm and the HTF flow rates ranged from 100 to 500 ml/min, was carried out. Results show that a narrower gap passage and a higher HTF flow rate can yield a higher average heating rate in GFHE. However, considering the compromise between the GFHE heating rate and the HTF pressure drop along the gap, a 0.4 mm gap width is preferred. A testing loop was also set up to experimentally evaluate the GFHE capability. The testing results show that, by using 0.4 mm gap width and 500 ml/min HTF flow rate, the maximum heating rate in the working chamber of the as made GFHE can reach 18 degrees C/min, and the average temperature change rates in the heating and cooling processes of the thermal cycle test were recorded as 6.5 and 5.4 degrees C/min, respectively. These temperature change rates can well satisfy the standard of IEC 60068-2-14:2009 and show that the GFHE developed in this work has sufficient heat exchange capacity and can be used as an ideal compact heat exchanger in small volume desktop thermal fatigue test apparatus. PMID- 25725875 TI - Research on temperature measurement technology for graphite-cone-absorption cavity absolute calorimeter. AB - The nonlinear effect of materials and sensors in high-energy laser calorimeters is especially obvious-due to the steep temperature gradients of their absorbers. Significant measurement errors occur when traditional integral temperature sensors and methods are utilized. In an effort to remedy this, a method is proposed in this paper in which an absorption cavity is divided into many parts and multiple discrete thermocouple sensors are used to measure the temperature rise of the absorbers. The temperature distribution in the absorbers is theoretically analyzed, numerically simulated, and verified through experimentation. Energy measurement results are compared according to the temperature distribution for different layouts of thermocouples. A high-accuracy calorimeter is developed by setting and optimizing thermocouple layout, as well as correcting various elements such as the specific heat of graphite and responsivity of thermocouples. The calorimeter employing this measurement method is calibrated against a standard energy meter, resulting in correction coefficient of 1.027 and relative standard deviation of the correction coefficient of only 0.8%. Theoretical analysis, numerical simulation, and experimental verification all prove that the proposed method successfully improves measurement accuracy. PMID- 25725876 TI - An approach to selecting the optimal sensing coil configuration structure for switched reluctance motor rotor position measurement. AB - Accurate rotor position signal is highly required for controlling the switched reluctance motor (SRM). The use of galvanic isolated sensing coils can provide independent circuit for position estimation without affecting the SRM actuation. However, the cross-coupling between main winding and sensing coil, and the mutual coupling between adjacent phase sensing coils may affect the position estimation performance seriously. In this paper, three sensing coil configurations in a 12/8 structure SRM are analyzed and compared for selecting an optimal configuration that can effectively minimize the bad effects of the cross-coupling factors. The finite element analysis and experimental results are provided for verification. PMID- 25725877 TI - Online technique for detecting state of onboard fiber optic gyroscope. AB - Although angle random walk (ARW) of fiber optic gyroscope (FOG) has been well modeled and identified before being integrated into the high-accuracy attitude control system of satellite, aging and unexpected failures can affect the performance of FOG after launch, resulting in the variation of ARW coefficient. Therefore, the ARW coefficient can be regarded as an indicator of "state of health" for FOG diagnosis in some sense. The Allan variance method can be used to estimate ARW coefficient of FOG, however, it requires a large amount of data to be stored. Moreover, the procedure of drawing slope lines for estimation is painful. To overcome the barriers, a weighted state-space model that directly models the ARW to obtain a nonlinear state-space model was established for FOG. Then, a neural extended-Kalman filter algorithm was implemented to estimate and track the variation of ARW in real time. The results of experiment show that the proposed approach is valid to detect the state of FOG. Moreover, the proposed technique effectively avoids the storage of data. PMID- 25725878 TI - A magnetic micro-manipulator for application of three dimensional forces. AB - Magnetic manipulation finds diverse applications in actuation, characterization, and manipulation of micro- and nano-scale samples. This paper presents the design and development of a novel magnetic micro-manipulator for application of three dimensional forces on a magnetic micro-bead. A simple analytical model is proposed to obtain the forces of interaction between the magnetic micro manipulator and a magnetic micro-bead. Subsequently, guidelines are proposed to perform systematic design and analysis of the micro-manipulator. The designed micro-manipulator is fabricated and evaluated. The manipulator is experimentally demonstrated to possess an electrical bandwidth of about 1 MHz. The ability of the micro-manipulator to apply both in-plane and out-of-plane forces is demonstrated by actuating permanent-magnet micro-beads attached to micro cantilever beams. The deformations of the micro-cantilevers are also employed to calibrate the dependence of in-plane and out-of-plane forces on the position of the micro-bead relative to the micro-manipulator. The experimentally obtained dependences are found to agree well with theory. PMID- 25725879 TI - Parameter-induced stochastic resonance based on spectral entropy and its application to weak signal detection. AB - The parameter-induced stochastic resonance based on spectral entropy (PSRSE) method is introduced for the detection of a very weak signal in the presence of strong noise. The effect of stochastic resonance on the detection is optimized using parameters obtained in spectral entropy analysis. Upon processing employing the PSRSE method, the amplitude of the weak signal is enhanced and the noise power is reduced, so that the frequency of the signal can be estimated with greater precision through spectral analysis. While the improvement in the signal to-noise ratio is similar to that obtained using the Duffing oscillator algorithm, the computational cost reduces from O(N(2)) to O(N). The PSRSE approach is applied to the frequency measurement of a weak signal made by a vortex flow meter. The results are compared with those obtained applying the Duffing oscillator algorithm. PMID- 25725880 TI - A simplified high figure-of-merit prism-free surface plasmon resonance refractive index sensor based on self adaptive angular interrogation. AB - We propose a simplified prism-free surface plasmon resonance (SPR) refractive index sensor based on self adaptive angular interrogation. An orthogonal V-shaped box with liquid sample is designed to achieve the functions of prism, sample cell, and mirror in a single setup. The rotator taking the self adaptive sample box is the sole mobile part in the system, which simplifies the structure greatly. A glass slide coated with Ag film is employed in this sample box as the sensing chip, in which the Ag film is isolated from the sample and air to prevent oxidation and pollution. According to the experimental results, the system can attain the figure-of-merit with 312.3/RIU, which is almost triple as high as that of the conventional prism-based sensor with the same samples. The proposed configuration could also be potentially utilized for the microminiaturization of the SPR sensor. PMID- 25725881 TI - Hot-wire anemometry for superfluid turbulent coflows. AB - We report the first evidence of an enhancement of the heat transfer from a heated wire to an external turbulent coflow of superfluid helium. We used a standard Pt Rh hot-wire anemometer and overheat it up to 21 K in a pressurized liquid helium turbulent round jet at temperatures between 1.9 K and 2.12 K. The null-velocity response of the sensor can be satisfactorily modeled by the counterflow mechanism, while the extra cooling produced by the forced convection is found to scale similarly as the corresponding extra cooling in classical fluids. We propose a preliminary analysis of the response of the sensor and show that contrary to a common assumption-such sensor can be used to probe local velocity in turbulent superfluid helium. PMID- 25725882 TI - Homogeneous heating of a sample space by a modified heating assembly in a belt type high-pressure apparatus. AB - To create homogeneous heating in the sample space in a belt-type high-pressure apparatus, modified heating assemblies under pressure of 2.5 GPa and temperature up to 1700 degrees C were examined. Counterbores (with several diameters) were made at both ends of a cylindrical graphite heater to suppress the temperature gradient along the cylindrical axis of the heater. Temperature distributions within the heaters were measured by thermocouples and geothermometers. Both sets of measurements revealed that the temperature distribution in the sample space (6.9 mm outside diameter/12 mm length) was homogenized (i.e., variation of less than 10 degrees C under heating at 1700 degrees C) by optimizing the heater shape. PMID- 25725883 TI - Experimental platform for solidification and in-situ magnetization measurement of undercooled melt under strong magnetic field. AB - An experimental platform for solidification of undercooled melt and synchronous measurement of magnetization under strong magnetic field is reported. The facility can be used for in-situ measurement of the magnetization of the undercooled melts and to studying the non-equilibrium solidification from deeply undercooled metals and alloys in magnetic field. The key advantages of this apparatus are first, we can obtain large undercooling in high fields by glass fluxing technique in combination with cyclical superheating and supercooling method, which is comparable to the maximum undercooling obtained by traditional method without magnetic field. Second, we can have a controlled thermal history with linear heating and cooling speed with high accuracy. Third, the temperature and magnetization measurement system are fast and on-line, which is very suitable for the investigation of both the structure transitions in the liquid in a wide temperature range (overheated and undercooled state) and the solid state phase transformations. PMID- 25725884 TI - Level monitoring system with pulsating sensor--application to online level monitoring of dashpots in a fast breeder reactor. AB - An innovative continuous type liquid level monitoring system constructed by using a new class of sensor, viz., pulsating sensor, is presented. This device is of industrial grade and it is exclusively used for level monitoring of any non conducting liquid. This instrument of unique design is suitable for high resolution online monitoring of oil level in dashpots of a sodium-cooled fast breeder reactor. The sensing probe is of capacitance type robust probe consisting of a number of rectangular mirror polished stainless steel (SS-304) plates separated with uniform gaps. The performance of this novel instrument has been thoroughly investigated. The precision, sensitivity, response time, and the lowest detection limit in measurement using this device are <0.01 mm, ~100 Hz/mm, ~1 s, and ~0.03 mm, respectively. The influence of temperature on liquid level is studied and the temperature compensation is provided in the instrument. The instrument qualified all recommended tests, such as environmental, electromagnetic interference and electromagnetic compatibility, and seismic tests prior to its deployment in nuclear reactor. With the evolution of this level measurement approach, it is possible to provide dashpot oil level sensors in fast breeder reactor for the first time for continuous measurement of oil level in dashpots of Control & Safety Rod Drive Mechanism during reactor operation. PMID- 25725885 TI - A highly accurate dynamic contact angle algorithm for drops on inclined surface based on ellipse-fitting. AB - To improve the accuracy in the calculation of dynamic contact angle for drops on the inclined surface, a significant number of numerical drop profiles on the inclined surface with different inclination angles, drop volumes, and contact angles are generated based on the finite difference method, a least-squares ellipse-fitting algorithm is used to calculate the dynamic contact angle. The influences of the above three factors are systematically investigated. The results reveal that the dynamic contact angle errors, including the errors of the left and right contact angles, evaluated by the ellipse-fitting algorithm tend to increase with inclination angle/drop volume/contact angle. If the drop volume and the solid substrate are fixed, the errors of the left and right contact angles increase with inclination angle. After performing a tremendous amount of computation, the critical dimensionless drop volumes corresponding to the critical contact angle error are obtained. Based on the values of the critical volumes, a highly accurate dynamic contact angle algorithm is proposed and fully validated. Within nearly the whole hydrophobicity range, it can decrease the dynamic contact angle error in the inclined plane method to less than a certain value even for different types of liquids. PMID- 25725886 TI - Monolithically integrated two-axis microgripper for polarization maintaining in optical fiber assembly. AB - Polarization maintaining optical fiber (PMOF) is a kind of special optical fiber that is designed to transmit the linearly polarized light. Unlike the general optical fiber, it is critical to conduct the rotational alignment between two PMOFs to guarantee the efficiency of light transmission. Until now, this alignment task still cannot be addressed with an efficient and economical way. Hence, we propose a monolithically integrated two-axis flexure-based microgripper that has the grasping and rubbing functions. To achieve a compact structure, the microgripper is designed with an asymmetric architecture. In this paper, the pseudo-rigid body model approach and finite element analysis are conducted to provide the essential guideline to accomplish the theoretical design. The prototype is fabricated by wire electrical discharge machining, with which two experiments are conducted to validate the performance of the microgripper. The experimental results demonstrate that the proposed microgripper can firmly grasp the optical fiber with the diameter of 250 MUm and meanwhile can rub it more than 90 degrees accurately and effectively, which indicate that it can satisfy the operating requirements well in the PMOF assembly. PMID- 25725887 TI - A novel device based on a fluorescent cross-responsive sensor array for detecting lung cancer related volatile organic compounds. AB - In this paper, a novel, simple, rapid, and low-cost detection device for lung cancer related Volatile Organic Compounds (VOCs) was constructed. For this task, a sensor array based on cross-responsive mechanism was designed. A special gas chamber was made to insure sensor array exposed to VOCs sufficiently and evenly, and FLUENT software was used to simulate the performance of the gas chamber. The data collection and processing system was used to detect fluorescent changes of the sensor arrays before and after reaction, and to extract unique patterns of the tested VOCs. Four selected VOCs, p-xylene, styrene, isoprene, and hexanal, were detected by the proposed device. Unsupervised pattern recognition methods, hierarchical cluster analysis and principal component analysis, were used to analyze data. The results showed that the methods could 100% discriminate the four VOCs. What is more, combined with artificial neural network, the correct rate of quantitative detection was up to 100%, and the device obtained responses at concentrations below 50 ppb. In conclusion, the proposed detection device showed excellent selectivity and discrimination ability for the VOCs related to lung cancer. Furthermore, our preliminary study demonstrated that the proposed detection device has brilliant potential application for early clinical diagnosis of lung cancer. PMID- 25725888 TI - A flux extraction device to measure the magnetic moment of large samples; application to bulk superconductors. AB - We report the design and construction of a flux extraction device to measure the DC magnetic moment of large samples (i.e., several cm(3)) at cryogenic temperature. The signal is constructed by integrating the electromotive force generated by two coils wound in series-opposition that move around the sample. We show that an octupole expansion of the magnetic vector potential can be used conveniently to treat near-field effects for this geometrical configuration. The resulting expansion is tested for the case of a large, permanently magnetized, type-II superconducting sample. The dimensions of the sensing coils are determined in such a way that the measurement is influenced by the dipole magnetic moment of the sample and not by moments of higher order, within user determined upper bounds. The device, which is able to measure magnetic moments in excess of 1 A m(2) (1000 emu), is validated by (i) a direct calibration experiment using a small coil driven by a known current and (ii) by comparison with the results of numerical calculations obtained previously using a flux measurement technique. The sensitivity of the device is demonstrated by the measurement of flux-creep relaxation of the magnetization in a large bulk superconductor sample at liquid nitrogen temperature (77 K). PMID- 25725889 TI - Reconstruction of the in-plane mode shape of a rotating tire with a continuous scanning measurement using the Hilbert-Huang transform. AB - Generally, the dynamic characteristics (natural frequency, damping, and mode shape) of a structure can be estimated by experimental modal analysis. Among these dynamic characteristics, mode shape requires multiple measurements of the structure at different positions, which increases the experimental cost and time. Recently, the Hilbert-Huang transform (HHT) method has been introduced to extract mode-shape information from a continuous measurement, which requires vibration measurements from one position to another position continuously with a non contact sensor. In this research study, an effort has been made to estimate the mode shapes of a rolling tire with a single measurement instead of using the conventional experimental setup (i.e., measurement of the vibration of a rolling tire at multiple positions similar to the case of a non-rotating structure), which is used to estimate the dynamic behavior of a rolling tire. For this purpose, HHT, which was used in the continuous measurement of a non-rotating structure in previous research studies, has been used for the case of a rotating system in this study. Ambiguous mode combinations can occur in this rotating system, and therefore, a method to overcome this ambiguity is proposed in this study. In addition, the specific phenomenon for a rotating system is introduced, and the effect of this phenomenon with regard to the obtained results through HHT is investigated. PMID- 25725890 TI - Designing an optimum pulsed magnetic field by a resistance/self inductance/capacitance discharge system and alignment of carbon nanotubes embedded in polypyrrole matrix. AB - In this work, an optimized pulsed magnetic field production apparatus is designed based on a RLC (Resistance/Self-inductance/Capacitance) discharge circuit. An algorithm for designing an optimum magnetic coil is presented. The coil is designed to work at room temperature. With a minor physical reinforcement, the magnetic flux density can be set up to 12 Tesla with 2 ms duration time. In our design process, the magnitude and the length of the magnetic pulse are the desired parameters. The magnetic field magnitude in the RLC circuit is maximized on the basis of the optimal design of the coil. The variables which are used in the optimization process are wire diameter and the number of coil layers. The coil design ensures the critically damped response of the RLC circuit. The electrical, mechanical, and thermal constraints are applied to the design process. A locus of probable magnetic flux density values versus wire diameter and coil layer is provided to locate the optimum coil parameters. Another locus of magnetic flux density values versus capacitance and initial voltage of the RLC circuit is extracted to locate the optimum circuit parameters. Finally, the application of high magnetic fields on carbon nanotube-PolyPyrrole (CNT-PPy) nano composite is presented. Scanning probe microscopy technique is used to observe the orientation of CNTs after exposure to a magnetic field. The result shows alignment of CNTs in a 10.3 Tesla, 1.5 ms magnetic pulse. PMID- 25725891 TI - Neutron resonance spin-echo upgrade at the three-axis spectrometer FLEXX. AB - We describe the upgrade of the neutron resonance spin-echo setup at the cold neutron triple-axis spectrometer FLEXX at the BER II neutron source at the Helmholtz-Zentrum Berlin. The parameters of redesigned key components are discussed, including the radio frequency (RF) spin-flip coils, the magnetic shield, and the zero field coupling coils. The RF-flippers with larger beam windows allow for an improved neutron flux transfer from the source to the sample and further to the analyzer. The larger beam cross sections permit higher coil inclination angles and enable measurements on dispersive excitations with a larger slope of the dispersion. Due to the compact design of the spin-echo units in combination with the increased coil tilt angles, the accessible momentum-range in the Larmor diffraction mode is substantially enlarged. In combination with the redesigned components of the FLEXX spectrometer, including the guide, the S bender polarizer, the double focusing monochromator, and a Heusler crystal analyzer, the count rate increased by a factor of 15.5, and the neutron beam polarization is enhanced. The improved performance extends the range of feasible experiments, both for inelastic scattering on excitation lifetimes in single crystals, and for high-resolution Larmor diffraction. The experimental characterization of the instrument components demonstrates the reliable performance of the new neutron resonance spin-echo option, now available for the scientific community at FLEXX. PMID- 25725892 TI - Low-jitter wide-range integrated time interval/delay generator based on combination of period counting and capacitor charging. AB - We present the design, operation, and test results of a new time interval/delay generator that provides the resolution of 0.3 ps, jitter below 10 ps (rms), and wide delay range of 10 s. The wide range has been achieved by counting periods of a reference clock while the high resolution and low jitter have been obtained through the two-time use of inner interpolation. This interpolation, based on charging of a single capacitor, provides both the precise external trigger synchronization and accurate generation of residual time interval. A combination of both processes virtually eliminates triggering indeterminacy. The jitter between the trigger and output is below 1 ps, which ensures a high performance delay. The generator is integrated in a single application specific integrated circuit chip using a standard cost-effective 0.35 MUm CMOS process. PMID- 25725893 TI - In-situ temperature-controllable shear flow device for neutron scattering measurement--an example of aligned bicellar mixtures. AB - We have designed and constructed a temperature-controllable shear flow cell for in-situ study on flow alignable systems. The device has been tested in the neutron diffraction and has the potential to be applied in the small angle neutron scattering configuration to characterize the nanostructures of the materials under flow. The required sample amount is as small as 1 ml. The shear rate on the sample is controlled by the flow rate produced by an external pump and can potentially vary from 0.11 to 3.8 * 10(5) s(-1). Both unidirectional and oscillational flows are achievable by the setting of the pump. The instrument is validated by using a lipid bicellar mixture, which yields non-alignable nanodisc like bicelles at low T and shear-alignable membranes at high T. Using the shear cell, the bicellar membranes can be aligned at 31 degrees C under the flow with a shear rate of 11.11 s(-1). Multiple high-order Bragg peaks are observed and the full width at half maximum of the "rocking curve" around the Bragg's condition is found to be 3.5 degrees -4.1 degrees . It is noteworthy that a portion of the membranes remains aligned even after the flow stops. Detailed and comprehensive intensity correction for the rocking curve has been derived based on the finite rectangular sample geometry and the absorption of the neutrons as a function of sample angle [See supplementary material at http://dx.doi.org/10.1063/1.4908165 for the detailed derivation of the absorption correction]. The device offers a new capability to study the conformational or orientational anisotropy of the solvated macromolecules or aggregates induced by the hydrodynamic interaction in a flow field. PMID- 25725894 TI - Note: control of liquid helium supply to cryopanels of Kolkata superconducting cyclotron. AB - The Kolkata superconducting cyclotron utilises liquid helium to cool the main magnet niobium-titanium (NbTi) coil and the cryopanels. Three liquid helium cooled cryopanels, placed inside the dees of the radio-frequency system, maintain the high vacuum in the acceleration region of the superconducting cyclotron. The small cryostat placed inside the cryogenic distribution manifold located at the basement of the superconducting cyclotron building supplies liquid helium in parallel branches to three cold heads, used for cooling their associated cryopanels. The level in the cryostat has to be maintained at an optimum value to ensure uninterrupted flow of liquid helium to these three cold heads. This paper describes the transfer function of the overall system, its tuning parameters, and discusses the actual control of cryostat level by using these parameters. PMID- 25725895 TI - Note: ultra-stable digitally controlled oven. AB - This paper describes design and characterization of a digitally controlled double oven system. This allows setting the turnover point of crystal oscillators automatically. Developed for metrological purposes of active phase noise measurements, this type of thermostat with a crystal oscillator is an ultra stable digitally controlled oven crystal oscillator. PMID- 25725896 TI - Note: Background Oriented Schlieren as a diagnostics for airflow control by plasma actuators. AB - Background Oriented Schlieren (BOS) is an optical technique sensitive to the first spatial derivative of the refractive index inside a light-transmitting medium. Compared to other Schlieren-like techniques, BOS is more versatile and allows to capture bi-dimensional gradients rather than just one spatial component. We propose to adopt BOS for studying the capabilities of surface dielectric barrier discharges to work like plasma actuators in flow control applications. The characteristics of the BOS we implemented at this purpose are discussed, together with few results concerning the ionic wind produced by the discharge in absence of an external airflow. PMID- 25725897 TI - Note: advancement in tip etching for preparation of tunable size scanning tunneling microscopy tips. AB - The two aspects of a scanning tunneling microscopy tip, the macroscopic profile and the nanoscale apex, can be tailored by controlling the tension during electrochemical etching and the solution-electrode contact area via acetone vapor. The apex diameter is shown to be proportional to the square root of the tension, and is demonstrated over apex diameters of 150-500 nm. The apex was found to be created in four distinct shapes where a secondary etching can reshape the tip into a single geometry. Improvement in tip height and stability of the profile are demonstrated versus a non-acetone fabrication control. PMID- 25725898 TI - Note: design and development of improved indirectly heated cathode based strip electron gun. AB - An improved design of indirectly heated solid cathode based electron gun (200 kW, 45 kV, 270 degrees bent strip type electron gun) has been presented. The solid cathode is made of thoriated tungsten, which acts as an improved source of electron at lower temperature. So, high power operation is possible without affecting structural integrity of the electron gun. The design issues are addressed based on the uniformity of temperature on the solid cathode and the single long filament based design. The design approach consists of simulation followed by extensive experimentation. In the design, the effort has been put to tailor the non-uniformity of the heat flux from the filament to the solid cathode to obtain better uniformity of temperature on the solid cathode. Trial beam experiments have been carried out and it is seen that the modified design achieves one to one correspondence of the solid cathode length and the electron beam length. PMID- 25725899 TI - Note: strain sensitivity comparison between fiber Bragg gratings inscribed on 125 and 80 micron cladding diameter fibers, case study on the solidification monitoring of a photo-curable resin. AB - The influence of fiber Bragg grating diameter when measuring strain is investigated and quantified. Two fiber Bragg gratings with bare cladding diameter of 125 MUm and 80 MUm are produced by excimer laser irradiation through a phase mask, and are used to simultaneously monitor the Bragg wavelength shift due to the strain produced by the solidification of a photo-curable resin during light exposure. It is found that the ratio of the measured strains in the two fiber Bragg gratings is close to the inverse ratio of the fiber's cladding diameter. These results represent a direct simultaneous comparison between 125 MUm and 80 MUm diameter fiber Bragg grating strain sensors, and demonstrate the feasibility of strain measurements in photo-curable resins using bare 80 MUm cladding diameter fiber Bragg gratings with an increased sensitivity and spatial resolution compared with standard 125 MUm diameter fiber Bragg gratings. PMID- 25725901 TI - A Coxsackie B4 virus isolated in Yunnan in 2009 is a recombinant. AB - Coxsackievirus B4 is a member of the species Enterovirus B in the Enterovirus genus of the Picornaviridae family. So far, there are only seven complete genome sequences of CVB4 published in GenBank database. In the study, the complete genome analysis of a Coxsackievirus B4 strain A155/YN/CHN/2009 isolated from a child with aseptic meningitis in Yunnan Province was performed. It had 85.1 and 83.3 % nucleotide similarity with prototype strain J.V.B Benschoten in the VP1 region and the complete genome, respectively. Phylogenetic analysis of VP1 region showed that A155/YN/CHN/2009 belongs to Genotype V circulating only in mainland of China. The results of Simplot and Bootscanning analysis implicated that A155 has recombined with other HEV-B viruses. PMID- 25725902 TI - [Diabetes, depression and dementia. Three interrelated "d's" in the elderly]. PMID- 25725903 TI - [Results of a physical therapy program in nursing home residents: A randomized clinical trial]. AB - INTRODUCTION: The maintenance of the physical functionality is a key factor in the care of the elderly. Inactive people have a higher risk of death due to diseases associated with inactivity. In addition, the maintenance of optimal levels of physical and mental activity has been suggested as a protective factor against the development and progression of chronic illnesses and disability. The objective of this study is to assess the effectiveness of an 8-week exercise program with elastic bands, on exercise capacity, walking and balance in nursing home residents. MATERIAL AND METHODS: A nursing home sample was divided into two groups, intervention group (n=26) and control group (n=25). The intervention group was included in an 8-week physical activity program using elastic bands, twice a week, while the control group was took part in a walking programme. Outcome measurements were descriptive variables (anthropometric characteristics, quality of life, fatigue, fear of movement) and fundamental variables (exercise capacity, walking and balance). RESULTS: A significant improvement in balance and walking speed was observed after the programme. Additionally, exercise capacity improved significantly (P<=.001), and the patients showed an improvement in perceived dyspnea after the physical activity programme in the intervention group. CONCLUSION: The exercise program was safe and effective in improving dyspnea, exercise capacity, walking, and balance in elderly. PMID- 25725904 TI - [Collaborative innovation networks and the future of Calidad Asistencial]. PMID- 25725906 TI - Biofilm formation by vaginal Lactobacillus in vivo. AB - Biofilm formation by nonpathogenic bacteria is responsible for their stable maintenance in vivo ecosystems as it promotes long-term permanence on the host's vaginal mucosa. Biofilm formation by Lactobacilli has been reported in vitro but not in vivo. We hypothesize the presence of biofilm formation in vivo could be also documented by microscope photographs (MP) of wet mounts obtained from uninfected vaginal samples satisfying rigorous scientific identification criteria. We analyzed 400 MP from our database, and we were able to determine that 12 MP from 6 different patients contained clues of the formation of biofilm by Lactobacilli. The most probable lactobacillus involved is presumed to be Lactobacillus jensenii. The documentation of biofilm formation by vaginal Lactobacilli at fresh wet mount preparation is significant and has several important clinical preventive and therapeutic implications. PMID- 25725905 TI - The key role of aquaporin 3 and aquaporin 10 in the pathogenesis of pompholyx. AB - Pompholyx remains a chronic skin affliction without a compelling pathophysiological explanation. The disease is characterized by the sudden onset of vesicles exclusively in the palms and soles which generally resolves. However, the disease may progress and the vesicles may expand and fuse; with chronicity there is deep fissuring. Multiple therapeutic approaches are available, but the disease is often resistant to conventional treatments. Currently, oral alitretinoin is used for patients with resistant chronic disease; however, this therapy is only approved for use in the UK, Europe and Canada. In this paper we wish to put forward a hypothesis: exposure to water and the subsequent steep osmotic gradient imbalance are key factors driving skin dehydration seen in pompholyx patients once the disease becomes chronic. The mechanistic explanation for the epidermal fissuring might lie in the over-expression across the mid and upper epidermis, including the stratum corneum, of two water/glycerol channel proteins aquaporin 3 and aquaporin 10, expressed in the keratinocytes of afflicted pompholyx patients. The over-expression of these two aquaporins may bridge the abundantly hydrated dermis and basal epidermis to the outer environment allowing cutaneous water and glycerol to flow outward. The beneficial effects reported in alitretinoin-treated patients with chronic hand eczemas may be due potential regulation of aquaporin 3 and aquaporin 10 by alitretinoin. PMID- 25725907 TI - Darwin and Spencer on the origin of music: is music the food of love? AB - Finding an evolutionary explanation for the origins of music serves as a rich test of broader ideas on the emergence of mind and the evolution of mental processes. Charles Darwin and Herbert Spencer both offered evolutionary explanations for the origins of music, indicating the importance of the question for these two leading nineteenth-century students of "descent with modification." Their discussion unfolded between the publication of Spencer's "The origin and function of music" in 1857 and Darwin's commentaries on music in The Descent of Man in 1871 with an addendum Spencer offered to his original article in light of Darwin's views. They had conflicting views on the lines of causation, asked differing questions, and had fundamentally different approaches. Their exchange laid the foundation for the discussion among contemporary adaptationists and nonadaptationists and contributed to the thinking of those who argue for Mixed Origins of Music or that it is a Transformative Technology of Mind. PMID- 25725908 TI - Music evolution and neuroscience. AB - There have been many attempts to discuss the evolutionary origins of music. We review theories of music origins and take the perspective that music is originally derived from emotional signals. We show that music has adaptive value through emotional contagion, social cohesion, and improved well-being. We trace the roots of music through the emotional signals of other species suggesting that the emotional aspects of music have a long evolutionary history. We show how music and speech are closely interlinked with the musical aspects of speech conveying emotional information. We describe acoustic structures that communicate emotion in music and present evidence that these emotional features are widespread among humans and also function to induce emotions in animals. Similar acoustic structures are present in the emotional signals of nonhuman animals. We conclude with a discussion of music designed specifically to induce emotional states in animals. PMID- 25725910 TI - Expert music performance: cognitive, neural, and developmental bases. AB - In this chapter, we explore what happens in the brain of an expert musician during performance. Understanding expert music performance is interesting to cognitive neuroscientists not only because it tests the limits of human memory and movement, but also because studying expert musicianship can help us understand skilled human behavior in general. In this chapter, we outline important facets of our current understanding of the cognitive and neural basis for music performance, and developmental factors that may underlie musical ability. We address three main questions. (1) What is expert performance? (2) How do musicians achieve expert-level performance? (3) How does expert performance come about? We address the first question by describing musicians' ability to remember, plan, execute, and monitor their performances in order to perform music accurately and expressively. We address the second question by reviewing evidence for possible cognitive and neural mechanisms that may underlie or contribute to expert music performance, including the integration of sound and movement, feedforward and feedback motor control processes, expectancy, and imagery. We further discuss how neural circuits in auditory, motor, parietal, subcortical, and frontal cortex all contribute to different facets of musical expertise. Finally, we address the third question by reviewing evidence for the heritability of musical expertise and for how expertise develops through training and practice. We end by discussing outlooks for future work. PMID- 25725911 TI - Apollo's curse: neurological causes of motor impairments in musicians. AB - Performing music at a professional level is probably one of the most complex human accomplishments. Extremely fast and complex, temporo-spatially predefined movement patterns have to be learned, memorized, and retrieved with high reliability in order to meet the expectations of listeners. Performing music requires not only the integration of multimodal sensory and motor information, and its precise monitoring via auditory and kinesthetic feedback, but also emotional communicative skills, which provide a "speaking" rendition of a musical masterpiece. To acquire these specialized auditory-sensory-motor and emotional skills, musicians must undergo extensive training periods over many years, which start in early childhood and continue on through stages of increasing physical and strategic complexities. Performance anxiety, linked to high societal pressures such as the fear of failure and heightened self-demands, frequently accompanies these learning processes. Motor disturbances in musicians are common and include mild forms, such as temporary motor fatigue with short-term reduction of motor skills, painful overuse injuries following prolonged practice, anxiety related motor failures during performances (choking under pressure), as well as more persistent losses of motor control, here termed "dynamic stereotypes" (DSs). Musician's dystonia (MD), which is characterized by the permanent loss of control of highly skilled movements when playing a musical instrument, is the gravest manifestation of dysfunctional motor programs, frequently linked to a genetic susceptibility to develop such motor disturbances. In this review chapter, we focus on different types of motor failures in musicians. We argue that motor failures in musicians develop along a continuum, starting with subtle transient degradations due to fatigue, overuse, or performance stress, which transform by and by into more permanent, still fluctuating motor degradations, the DSs, until a more irreversible condition, MD manifests. We will review the epidemiology and the principles of medical treatment of MD and discuss prevention strategies. PMID- 25725909 TI - Musicians and music making as a model for the study of brain plasticity. AB - Playing a musical instrument is an intense, multisensory, and motor experience that usually commences at an early age and requires the acquisition and maintenance of a range of sensory and motor skills over the course of a musician's lifetime. Thus, musicians offer an excellent human model for studying behavioral-cognitive as well as brain effects of acquiring, practicing, and maintaining these specialized skills. Research has shown that repeatedly practicing the association of motor actions with specific sound and visual patterns (musical notation), while receiving continuous multisensory feedback will strengthen connections between auditory and motor regions (e.g., arcuate fasciculus) as well as multimodal integration regions. Plasticity in this network may explain some of the sensorimotor and cognitive enhancements that have been associated with music training. Furthermore, the plasticity of this system as a result of long term and intense interventions suggest the potential for music making activities (e.g., forms of singing) as an intervention for neurological and developmental disorders to learn and relearn associations between auditory and motor functions such as vocal motor functions. PMID- 25725912 TI - Music and its association with epileptic disorders. AB - The association between music and epileptic seizures is complex and intriguing. Musical processing within the human brain recruits a network which involves many cortical areas that could activate as part of a temporal lobe seizure or become hyperexcitable on musical exposure as in the case of musicogenic epilepsy. The dichotomous effect of music on seizures may be explained by modification of dopaminergic circuitry or counteractive cognitive and sensory input in ictogenesis. Research has explored the utility of music as a therapy in epilepsy and while limited studies show some evidence of an effect on seizure activity; further work is required to ascertain its clinical potential. Sodium channel blocking antiepileptic drugs, e.g., carbamazepine and oxcarbazepine, appear to effect pitch perception particularly in native-born Japanese, a rare but important adverse effect, particularly if a professional musician. Temporal lobe surgery for right lateralizing epilepsy has the capacity to effect all facets of musical processing, although risk and correlation to resection area need further research. There is a need for the development of investigative tools of musical processing that could be utilized along the surgical pathway. Similarly, work is also required in devising a musical paradigm as part of electroencephalography to improve surveillance of musicogenic seizures. These clinical applications could aid the management of epilepsy and preservation of musical ability. PMID- 25725913 TI - Treatment and prevention of music performance anxiety. AB - Music performance anxiety (MPA) regularly occurs when musicians present themselves before an audience in performance situations, and thus, it plays an important role in the careers of professional musicians. MPA is expressed on the emotional and physical level, as well as on the levels of thinking and behavior, and extends along a continuum of varying severity. Its performance-impairing, afflicting form is considered to be a specific type of social phobia, which requires therapy. There are different psychological theories, which contribute to the understanding of the phenomenon of MPA and provide basic principles for the various treatment approaches. Current "best practice," in our clinical experience, is a personal- and problem-oriented approach within a multimodal therapy model, including the range of psychoanalytic and cognitive behavioral therapies, body-oriented methods, and mental techniques. In order to avoid severe MPA, prevention in the field of music pedagogic is very important. Thus, the concepts of dealing positively with MPA should be implemented very early into the instrumental and vocal education of musicians. PMID- 25725914 TI - Music as therapy in early history. AB - The notion of music as therapy is based on ancient cross-cultural beliefs that music can have a "healing" effect on mind and body. Explanations for the therapeutic mechanisms in music have almost always included cultural and social science-based causalities about the uses and functions of music in society. However, it is also important to note that the view of music as "therapy" was also always strongly influenced by the view and understanding of the concepts and causes of disease. Magical/mystical concepts of illness and "rational" medicine probably lived side by side for thousands of years. Not until the late-nineteenth and early-twentieth centuries were the scientific foundations of medicine established, which allowed the foundations of music in therapy to progress from no science to soft science and most recently to actual brain science. Evidence for "early music therapy" will be discussed in four broad historical-cultural divisions: preliterate cultures; early civilizations in Mesopotamia, Egypt, Israel; Greek Antiquity; Middle Ages, Renaissance, and Baroque. In reviewing "early music therapy" practice, from mostly unknown periods of early history (using preliterate cultures as a window) to increasingly better documented times, including preserved notation samples of actual "healing" music, five theories and applications of early music therapy can be differentiated. PMID- 25725915 TI - An Enlightenment proposal for music therapy: Richard Brocklesby on music, spirit, and the passions. AB - In 1749, the London physician Richard Brocklesby (1722-1797) published his Reflections on Antient [sic] and Modern Musick, an essay that not only sought to compare these practices in terms of their effects, but also to gather evidence supporting the use of music in treating mania and other mental diseases. As might be expected, Brocklesby's discussion of music therapy has already received attention by authors looking back to the origins of this practice, not least because he offers an account of a successful musical cure that took place in his own time (Rorke, 2001). My chapter, however, seeks to broaden the discussion of the Reflections, in order to show how Brocklesby's projected musical cures fit into his larger worldview, one that was influenced as much by Plato and other ancient philosophers as it was by modern thinkers such as Isaac Newton and his followers. Brocklesby's argument was essentially that music acted as a link between the mind and body and therefore could restore their intrinsic harmony, a connection that was mediated by the animal spirits, which also served as the vehicle of the passions. The movements and proportions of music could arouse or quell the passions by their effect on these (imaginary) spirits, which flowed through the nerves and brain and acted as the agent for the mind or soul. I show how his account of music in antiquity led him to reflect on the way that music was perceived and responded to in his own time, both as a stimulus to mental and bodily action, and as a source of esthetic pleasure through the cultivation of musical taste. PMID- 25725916 TI - Neurological implications and neuropsychological considerations on folk music and dance. AB - Neurological and neuropsychological aspects of folk music and traditional dance have been poorly investigated by historical and scientific literature. Some of these performances could be indeed the manifestation of latent pathological conditions or the expression of liberation rituals. This chapter aimed at analyzing the relationships between traditional dance, folk music, and neurological and psychiatric disorders. Since ancient times, dance has been used in the individual or collective as treatment of some diseases, including epilepsy and movement disorders (dyskinesia, chorea, etc.). Dionysia in Ancient Greece, St. Vitus dance in the Middle Age, tarantism and other traditional dances of southern Italy and of non-Western countries might be credited as curative rituals of these neurological and psychiatric conditions. During the nineteenth century, dance was also used for the treatment of psychiatric patients; the relationship between dance and insanity could also be reflected in classical ballets and music of that period. Nowadays, neuropsychiatric manifestations could also be evidenced in modern dances (mass fainting at rock concerts, flash mobs); some ballroom dances are commonly used for the rehabilitation of patients suffering from neurodegenerative and psychiatric conditions. Interdisciplinary research on these subjects (ethnomusicology and cultural anthropology, clinical neurology and dynamic psychology, neuroradiology and neurophysiology, and socioneurology and neuromusicology) should be increased. PMID- 25725917 TI - Music and dementia. AB - There is an increasing incidence of dementia in our aging population, and consequently an urgent need to develop treatments and activities that may alleviate the symptoms of dementia. Accumulating evidence shows that persons with dementia enjoy music, and their ability to respond to music is potentially preserved even in the late or severe stages of dementia when verbal communication may have ceased. Media interest in this topic has contributed to the public perception that music abilities are an "island of preservation" in an otherwise cognitively impaired person with dementia. In this chapter, we review the current literature on music cognition in dementia and show that there has been very scarce rigorous scientific investigation of this issue, and that various types of music memory exist and are differentially impaired in the different types of dementia. Furthermore, we discuss the recent development of music activities as a nonpharmacological treatment for dementia and highlight the methodological limitations of the current literature on this topic. While it has been reported that music activities can improve behavior, (particularly agitation), mood, and cognition in persons with dementia, recent large-scale randomized control studies have questioned the specificity of the effect of music and found that it is no more beneficial than other pleasant activities. Nevertheless, music is unique in its powerful ability to elicit both memories and emotions. This can provide an important link to individual's past and a means of nonverbal communication with carers, which make it an ideal stimulus for persons with dementia. PMID- 25725919 TI - The discovery of human auditory-motor entrainment and its role in the development of neurologic music therapy. AB - The discovery of rhythmic auditory-motor entrainment in clinical populations was a historical breakthrough in demonstrating for the first time a neurological mechanism linking music to retraining brain and behavioral functions. Early pilot studies from this research center were followed up by a systematic line of research studying rhythmic auditory stimulation on motor therapies for stroke, Parkinson's disease, traumatic brain injury, cerebral palsy, and other movement disorders. The comprehensive effects on improving multiple aspects of motor control established the first neuroscience-based clinical method in music, which became the bedrock for the later development of neurologic music therapy. The discovery of entrainment fundamentally shifted and extended the view of the therapeutic properties of music from a psychosocially dominated view to a view using the structural elements of music to retrain motor control, speech and language function, and cognitive functions such as attention and memory. PMID- 25725918 TI - Apollo's gift: new aspects of neurologic music therapy. AB - Music listening and music making activities are powerful tools to engage multisensory and motor networks, induce changes within these networks, and foster links between distant, but functionally related brain regions with continued and life-long musical practice. These multimodal effects of music together with music's ability to tap into the emotion and reward system in the brain can be used to facilitate and enhance therapeutic approaches geared toward rehabilitating and restoring neurological dysfunctions and impairments of an acquired or congenital brain disorder. In this article, we review plastic changes in functional networks and structural components of the brain in response to short- and long-term music listening and music making activities. The specific influence of music on the developing brain is emphasized and possible transfer effects on emotional and cognitive processes are discussed. Furthermore, we present data on the potential of using musical tools and activities to support and facilitate neurorehabilitation. We will focus on interventions such as melodic intonation therapy and music-supported motor rehabilitation to showcase the effects of neurologic music therapies and discuss their underlying neural mechanisms. PMID- 25725920 TI - Preface. PMID- 25725921 TI - [Is Herceptin((r)) (trastuzumab) by subcutaneous a mini revolution? Pharmaco economic study]. AB - Herceptin((r)) injected by intravenous (IV) is one of the key treatment of breast cancer HER2+. The improvement of galenic form allowed a new way of administration, the sub-cutaneous way (SC), authorized by EMEA in 2013. This new way enables a 5-minute infusion, a fixed dose and a fixed volume of preparation. On 2012, saving-time and financial impacts were calculated by extrapolation of the IV way in a cancer treatment center. The study showed a preparing time-saving of 7.5min/loading dose and of 6.5min/maintenance dose, and a nurse time-saving of 4.5min/loading dose and 4.25min/maintenance dose. Moreover, it can be added a saving of consumable of 13,31? per injection in case of monotherapy. The SC leads to a new adaptation and reorganization in the preparation of monoclonal antibodies and day hospitals. PMID- 25725922 TI - [Environmental and genetic risk factors for endometrial carcinoma]. AB - In France, endometrial cancer is at the first rank of gynecological cancers for cancer incidence, before ovarian and cervical cancers. In fact, the number of incident cases has been estimated to 7275 for the year 2012; the number of death due to endometrial cancer to 2025. This cancer is hormone-dependent and endogenous (reproductive factors) or exogenous (oral combined contraceptives, hormone replacement therapy) causes of exposition to estrogens are the major environmental risk factors for both types of endometrial cancers: type I or well differentiated endometrioid adenocarcinomas; and type II including all other histological types: papillary serous adenocarcinomas, clear cell adenocarcinomas and carcinosarcomas, also known as malignant mixed Mullerian tumor, MMMT. Obesity, diabetes mellitus and adjuvant treatment of breast cancer with tamoxifen are also associated with an increased risk of endometrial cancer. Genetic factors may also be implicated in the pathogenesis of endometrial cancer either as "minor genetic factors" (susceptibility factors), which remain largely unknown and are responsible for the increased observed risk in relatives of women affected with endometrial cancer; or as major genetic factors responsible for hereditary forms and namely for Lynch syndrome whose genetic transmission is of autosomic dominant type. The appropriate recognition of Lynch syndrome is of critical importance because affected patients and their relatives should benefit from specific care. The aims of this review is to describe major environmental and genetic risk factors for endometrial cancer with specific attention to most recent advances in this field and to describe recommendations for care of at-risk women. PMID- 25725923 TI - [An atypical necrotic wound]. PMID- 25725924 TI - A comparative study of antimicrobial resistance rates and phylogenetic groups of community-acquired versus hospital-acquired invasive Escherichia coli. AB - OBJECTIVES: Escherichia coli is the leading cause of various infections, both in community and nosocomial settings. Our objective was to determine the antibiotic resistance rates and the phylogenetic groups of invasive E. coli and to assess the relationship between these characteristics according to the community or nosocomial origin of the strains. MATERIALS AND METHODS: One hundred non redundant E. coli strains, causing invasive infections, were collected and investigated between 2010 and 2012. The phylogenetic groups were determined by triplex PCR. The statistical analysis was performed with Pearson chi(2) test and P-values below 0.05 were considered as statistically significant. RESULTS: Sixty three strains were community-acquired (CA) and 37 were hospital-acquired (HA). The resistance rates among CA and HA strains were respectively: cefotaxime (11.1/37.8%), ciprofloxacin (19/43.2%), amikacin (3.2/27.2%), and cotrimoxazole (42.8/64.8%). E. coli strains caused bacteremia (CA=34.9%; HA=83.7%), peritonitis (CA=58.7%; HA=13.5%), appendicitis (CA=3.2%; HA=2.7%), and cholecystitis (CA=3.2%; HA=0%). The distribution of phylogenetic groups among CA and HA strains was: A (25.4/18.9%), B1 (9.5/16.2%), B2 (23.8/37.8%), and D group (41.3/27%). High resistance rates to cefotaxime (P=0.02), ciprofloxacin (P=0.01), amikacin (P=0.001), and cotrimoxazole (P=0.05) were statistically significantly associated with a nosocomial origin. CONCLUSION: Our results prove the diversity of phylogroups among E. coli invasive strains whatever their origin, and a higher antibiotic resistance rate in nosocomial strains. An adequate use of antibiotics and applying strict hygiene measures would limit the transmission and selection of these bacteria in hospital as well as in community settings. PMID- 25725925 TI - Outcomes of anomalous left coronary artery from pulmonary artery repair: beyond normal function. AB - BACKGROUND: Anomalous left coronary artery from pulmonary artery (ALCAPA) is associated with high mortality if left uncorrected. We describe long-term outcomes after surgical repair and ventricular function changes on long-term follow-up. METHODS: A retrospective review of patients who had ALCAPA repair from January 1996 to December 2011 was completed. Ventricular function was assessed by shortening fraction and ejection fraction, left ventricular end-diastolic dimension, and severity of mitral regurgitation. Speckle tracking echocardiography served as a marker of early myocardial dysfunction. RESULTS: In total, 34 patients underwent ALCAPA repair at median age of 5 months (range, 3 days to 39 years). Surgical interventions included coronary translocation in 31 patients (91%), Takeuchi repair in 2 (6%), and coronary ligation in 1 patient (3%). Concomitant mitral valve repair was performed in 5 patients (15%). No patient required mechanical circulatory support postoperatively. There was no early mortality. At median follow-up of 6 years (range, 1 month to 14 years), there were 5 reoperations: 2 heart transplants (6%), 1 mitral valve replacement (3%), 1 coronary artery bypass graft (3%), and 1 ventricular septal defect closure (3%); there was 1 death 2 years after surgery. Ejection fraction improved from 21% +/- 6% to 60% +/- 7% (p = 0.008), mean shortening fraction from 25% +/- 14% to 38% +/- 5% (p = 0.01), mean left ventricular end-diastolic dimension Z score from 6.0 +/- 3.8 to 0.9 +/- 0.7 (p < 0.001), and number of patients with moderate-severe mitral regurgitation from 44% (15 of 34) to 5% (1 of 21). All patients had normal ejection fraction and shortening fraction at last follow-up. Speckle tracking echocardiography showed decreased global longitudinal (p = 0.01) and circumferential strain (p = 0.03) for 11 of 14 patients (79%). CONCLUSIONS: Excellent outcomes are achieved with repair of ALCAPA without mechanical circulatory support and with low reintervention rates. Normal ejection fraction and shortening fraction do not accurately convey myocardial dysfunction in these patients. PMID- 25725926 TI - The radial artery: a forgotten conduit. AB - We reviewed the published literature on the clinical and angiographic outcome of radial artery (RA) grafts and on the comparison between the RA and the other conduits used in coronary operations. The RA is a better graft than the saphenous vein and comparable to the right internal thoracic artery (RITA); moreover, the RA seems a better choice than the RITA in patients at risk of sternal or pulmonary complications. We conclude that the RA should be preferred to the saphenous vein and considered at least equivalent to the RITA as the second conduit during every elective coronary artery bypass procedure. PMID- 25725927 TI - Outcome of right ventricle to pulmonary artery conduit for biventricular repair. AB - BACKGROUND: The objective of this study was to assess the outcomes of the right ventricle to pulmonary artery conduit for biventricular repair. METHODS: This is a retrospective review of all right ventricle to pulmonary artery conduit operations for biventricular repair of congenital heart disease between 1982 and 2013 at a single institution. Results were compared among the conduit size and materials. RESULTS: A total of 476 physiologic right ventricle to pulmonary artery conduit operations were identified, with 195 pulmonary homografts, 105 handmade valved expanded polytetrafluoroethylene conduits, 103 Medtronic Hancock (Minneapolis, MN) bioprosthetic valved conduits, 38 non-valved expanded polytetrafluoroethylene tubes, and 35 others. The actuarial survival was 92.4% and the freedom from conduit reoperation was 33.0% at 20 years. The freedom from conduit reoperation was significantly different among conduit materials (76.8%, 92.1%, 81.9%, 80.6%, and 63.8% for pulmonary homograft, valved expanded polytetrafluoroethylene conduit, Hancock conduit, non-valved expanded polytetrafluoroethylene tube, and others at 5 years, p = 0.0001). The Cox proportional hazards model showed that age (p < 0.001 and p = 0.04), preoperative diagnosis (p < 0.001 and p < 0.001), conduit size (p < 0.001 and p < 0.001), and conduit material (the valved expanded polytetrafluoroethylene conduit versus combined other materials; p = 0.01 and p = 0.02, respectively) were significant factors for the freedom from conduit reoperation both when treating conduit size as a categoric predictor and as a quantitative predictor. CONCLUSIONS: The handmade valved expanded polytetrafluoroethylene conduit showed excellent early outcome as a right ventricle to pulmonary artery conduit for biventricular repair. A longer follow-up and a randomized study will be necessary to explore the advantages of the valved expanded polytetrafluoroethylene conduit. PMID- 25725928 TI - Osteopontin-expressing macrophages in non-small cell lung cancer predict survival. AB - BACKGROUND: Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltration in the tumor microenvironment. Osteopontin is related to tumor metastasis and proliferation. Osteopontin is expressed not only by tumor cells but also by TAMs. The purpose of the current study was to assess the prognostic significance of osteopontin expressed by TAMs (TOPN) in patients with non-small cell lung cancer. METHODS: Tissue microarray was used to detect the expression of TOPN, TAMs, and microvascular density in 159 patients with non small cell lung cancer undergoing complete pulmonary resection in our hospital between 2003 and 2006. The correlations between TOPN, TAMs, and clinicopathologic data were analyzed with chi(2) tests. Quantitation of TAMs or TOPN and microvascular density analyses was performed using Bonferroni correction and the Student's t test. The prognostic value of TOPN was evaluated by univariate Kaplan Meier survival analysis and multivariate Cox proportional hazard model analysis. RESULTS: In the recurrence and metastasis group, microvascular density was higher than that in the control group (14.4 +/- 1.06 versus 8.9 +/- 1.02; p = 0.0002). In the TOPN-positive group, microvascular density was increased compared with that in the TOPN-negative group (14.3 +/- 1.37 versus 10.7 +/- 0.91; p = 0.0273). Osteopontin expressed by TAMs was an independent predictor for overall survival (p = 0.017) and disease-free survival (p < 0.001), especially for stage I non small cell lung cancer. The 6-year overall and disease-free survival rates in TOPN-positive patients were 22.64% and 16.98%, respectively, which were significantly lower than those of TOPN-negative patients (50.00% and 39.62%, respectively). CONCLUSIONS: Osteopontin expressed by TAMs is a valuable independent predictor of tumor recurrence and survival in patients with non-small cell lung cancer. PMID- 25725929 TI - Decompression of enlarged mediastinal lymph nodes due to mycobacterium tuberculosis causing severe airway obstruction in children. AB - BACKGROUND: Large airway compression by enlarged tuberculosis (TB) lymph nodes results in life-threatening airway obstruction in a small proportion of children. The indications, safety, and efficacy of TB lymph node decompression are inadequately described. This study aims to describe the indications and efficacy of TB lymph node decompression in children with severe airway compression and investigate variables influencing outcome. METHODS: A prospective cohort of children (aged 3 months to 13 years) with life-threatening airway obstruction resulting from TB lymph node compression of the large airways were enrolled. The site and degree of airway obstruction were assessed by bronchoscopy and chest computed tomography scan. RESULTS: Of the 250 children enrolled, 34% (n = 86) required transthoracic lymph node decompression, 29% as an urgent procedure and 71% (n = 63) after failing 1 month of antituberculosis treatment that included glucosteroids. Compression (less than 75%) of the bronchus intermedius (odds ratio 2.28, 95% confidence interval: 1.29 to 4.02) and left main bronchus (odds ratio 3.34, 95% confidence interval: 1.73 to 6.83) were the best predictors for lymph node decompression. Human immunodeficiency virus status, drug resistance, and malnutrition were not associated with decompression. Few complications (self limiting, 8%) or treatment failures (2%) resulted from the decompression. There were no deaths. CONCLUSIONS: In one third of children with TB, severe airway obstruction caused by enlarged lymph nodes requires decompression. Transthoracic decompression can be safely performed with low complication, failure, and fatality rates. PMID- 25725930 TI - A meta-analysis of resected metachronous second non-small cell lung cancer. AB - This meta-analysis was designed to determine the effect of surgical treatment on overall survival of patients treated surgically for a second non-small cell lung cancer (NSCLC) that occurred after resection of an initial NSCLC. PubMed and Scopus databases were queried. Nine studies were identified. Meta-analyses revealed pooled operative mortality of 7% for the second resection, pooled 5-year overall survival of 46% after resection of the second NSCLC, and 79% after resection of the first NSCLC. These results suggest that surgical resection can be considered for patients who have a second primary NSCLC after resection of an initial lung cancer. PMID- 25725931 TI - Neurobiological studies on the relationship between toxoplasmosis and neuropsychiatric diseases. AB - Toxoplasma gondii is a widespread protozoan parasite infecting approximately one third of the world population. After proliferation of tachyzoites during the acute stage, the parasite forms tissue cysts in various anatomical sites including the Central Nervous tissue, and establishes a chronic infection. Clinical spectrum normally ranges from a completely asymptomatic infection to severe multi-organ involvement. Many studies have suggested T. gondii infection as a risk factor for the development of some neuropsychiatric disorders, particularly schizophrenia. During the last years, a potential link with other neurobiological diseases such as Parkinson disease and Alzheimer disease has also been suggested. This review will focus on neurobiological and epidemiological data relating infection with T. gondii to neuropsychiatric diseases. PMID- 25725932 TI - Associations of lifetime abstention and past and current alcohol use with late life mental health: a propensity score analysis. AB - BACKGROUND: Compared to the extensive research on the effects of alcohol intake on physical health, little research has been done on the effects of alcohol use/nonuse patterns on mental disorders in late life. This study examined associations between mental disorders and alcohol use/nonuse patterns among individuals aged 65+ years. METHODS: Data came from the public use files of the 2008 to 2012 National Survey on Drug Use and Health. Alcohol use/nonuse groups were lifetime abstainers, ex-drinkers, bingers, and nonbingers. Mental health problems were lifetime major depressive episode (MDE) and anxiety disorder, past year MDE and anxiety disorder, and past-year serious suicidal ideation. To minimize selection biases resulting from a complex array of covariates, we implemented a generalized boosted model to generate propensity score weights on covariates. Then we employed logistic regression models with mental health outcomes as the dependent variables. RESULTS: The four alcohol use/nonuse groups did not differ in past-year MDE. However, odds ratios show that, relative to non binge drinking, lifetime abstention decreased the odds of lifetime MDE by more than 60% (OR = 0.39, 95% CI = 0.23-0.68, p = .001) and the odds of lifetime anxiety disorder by almost half (OR = 0.55, 95% CI = 0.38-0.79, p = .002). Ex drinkers were more likely than nonbingers to report past-year serious suicidal thoughts (OR = 2.29, 95% CI = 1.45-3.62, p < .001). CONCLUSIONS: While lifetime abstainers had significantly better lifetime mental health histories than nonbingers, ex-drinkers had worse past-year mental health status. Since lifetime abstainers and ex-drinkers have significantly different characteristics, researchers should distinguish between these groups. PMID- 25725933 TI - Effect of oral THC pretreatment on marijuana cue-induced responses in cannabis dependent volunteers. AB - BACKGROUND: The current study tested whether oral Delta(9)-tetrahydrocannabinol (THC: 0-, 10-, and 20-mg) pretreatment would attenuate polysensory cue-induced craving for marijuana. METHODS: Cannabis dependent participants (7 males and 7 females, who smoked on average 5.4 +/- 1.1 blunts daily) completed 3 experimental sessions (oral THC pretreatment dose; counterbalanced order) using a placebo controlled within-subject crossover design. During each session, participants completed a baseline evaluation and were first exposed to neutral cues then marijuana cues while physiological measures and subjective ratings of mood, craving, and drug effect were recorded. RESULTS: Following placebo oral THC pretreatment, marijuana (vs. neutral) cues significantly increased ratings of marijuana craving (desire and urge to use, Marijuana Craving Questionnaire (MCQ) Compulsivity scale), anxious mood and feeling hungry. Males also reported feeling more "Down" during marijuana cues relative to females. Pretreatment with oral THC (10-mg and/or 20-mg vs. placebo) significantly attenuated marijuana cue-induced increases in craving and anxiety but not hunger. Oral THC attenuation of the cue induced increase in MCQ-Compulsivity ratings was observed in females only. Oral THC produced statistically (but not clinically) significant increases in heart rate and decreases in diastolic blood pressure, independent of cues. CONCLUSIONS: These marijuana-cue findings replicate earlier results and further demonstrate that oral THC can attenuate selected effects during marijuana multi-cue exposure, and that some of these effects may be sex-related. Results of this study suggest oral THC may be effective for reducing marijuana cue-elicited (conditioned) effects. Further study is needed to determine whether females may selectively benefit from oral THC for this purpose. PMID- 25725935 TI - Assessing clinical reasoning (ASCLIRE): Instrument development and validation. AB - Clinical reasoning is an essential competency in medical education. This study aimed at developing and validating a test to assess diagnostic accuracy, collected information, and diagnostic decision time in clinical reasoning. A norm referenced computer-based test for the assessment of clinical reasoning (ASCLIRE) was developed, integrating the entire clinical decision process. In a cross sectional study participants were asked to choose as many diagnostic measures as they deemed necessary to diagnose the underlying disease of six different cases with acute or sub-acute dyspnea and provide a diagnosis. 283 students and 20 content experts participated. In addition to diagnostic accuracy, respective decision time and number of used relevant diagnostic measures were documented as distinct performance indicators. The empirical structure of the test was investigated using a structural equation modeling approach. Experts showed higher accuracy rates and lower decision times than students. In a cross-sectional comparison, the diagnostic accuracy of students improved with the year of study. Wrong diagnoses provided by our sample were comparable to wrong diagnoses in practice. We found an excellent fit for a model with three latent factors diagnostic accuracy, decision time, and choice of relevant diagnostic information with diagnostic accuracy showing no significant correlation with decision time. ASCLIRE considers decision time as an important performance indicator beneath diagnostic accuracy and provides evidence that clinical reasoning is a complex ability comprising diagnostic accuracy, decision time, and choice of relevant diagnostic information as three partly correlated but still distinct aspects. PMID- 25725934 TI - Probability and predictors of treatment-seeking for substance use disorders in the U.S. AB - BACKGROUND: Little is known about to what extent treatment-seeking behavior varies across individuals with alcohol abuse, alcohol dependence, drug abuse, and drug dependence. METHODS: The sample included respondents from the Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) who reported a lifetime diagnosis alcohol abuse, alcohol dependence, drug abuse, or drug dependence. Unadjusted and adjusted hazard ratios are presented for time to first treatment contact by sociodemographic characteristics and comorbid psychiatric disorders. Individuals were censored from the analyses if their condition remitted prior to seeking treatment. RESULTS: In the first year after disorder onset, rates of treatment-seeking were 13% for drug dependence, 5% for alcohol dependence, 2% for drug abuse, and 1% for alcohol abuse. The lifetime probability of seeking treatment among individuals who did not remit was also highest for drug dependence (90%), followed by drug abuse (60%), alcohol dependence (54%), and alcohol abuse (16%). Having had previous treatment contact for a substance use disorder (SUD) increased the probability of seeking treatment for another SUD. By contrast, an early age of SUD onset, belonging to an older cohort, and a higher level of education decreased the lifetime probability of treatment contact for SUD. The role of comorbid mental disorders was more complex, with some disorders increasing and other decreasing the probability of seeking treatment. CONCLUSIONS: Given high rates of SUD and their substantial health and economic burden, these patterns suggest the need for innovative approaches to increase treatment access for individuals with SUD. PMID- 25725936 TI - Breast sparganosis and incidentally detected subcutaneous and intramuscular sparganosis at several sites: case report and literature review. AB - Sparganosis is an infestation caused by a tapeworm belonging to the genus Spirometra. We describe a surgically confirmed case of sparganosis in several organs including the breast, both lower extremities, anterior chest wall, inguinal area, and the psoas and gluteus muscles. Mammography, ultrasonography, and MRI imaging findings for our patient were characteristic of sparganosis. Ultrasonography revealed multiple elongated tubular hypoechoic structures with surrounding increased echogenicity. Mammographic findings included tortuous, lobular, and tubular densities. Short tau inversion recovery (STIR) MR images contained several elongated tubular tracts of high signal intensity. These imaging features were highly consistent with pathology results. PMID- 25725937 TI - Increased expression of perforin, granzyme B, and C5b-9 in villitis of unknown etiology. AB - INTRODUCTION: Villitis of unknown etiology (VUE) is associated with fetal growth restriction. However, the underlying mechanisms of villous injury in placentas with VUE are still largely unknown. We aimed to verify whether apoptosis-related factors are increased in VUE placentas. Furthermore, we determined apoptosis of villous cells. METHODS: Six placentas with VUE and 3 control placentas were stained using immunohistochemistry with antibodies for CD3, CD4, CD8, CD68, CD163, perforin, granzyme B, granzyme K, and C5b-9. TUNEL assay analysis was also performed with these placentas. The percentage of cells that stained positive, CD163/CD68 ratio, percentage of C5b-9 positive area, and apoptosis index were quantified and compared between the inflammatory lesions of the VUE placentas, non-VUE inflammatory lesions of the VUE placentas, and control placentas. RESULTS: The percentages of CD3, CD4, CD8 CD68, CD163, perforin, and granzyme B positive cells were significantly higher in the inflammatory lesions of the VUE placentas (p < 0.05). The intravillous CD163/CD68 ratio was higher in the inflammatory lesions compared with the non-inflammatory lesion of the VUE placentas (p < 0.05). The percentage of granzyme K-positive cells was not significantly different between the groups. C5b-9 deposition was higher in the inflammatory lesions of the VUE placentas (p < 0.05). TUNEL-positive cells were significantly higher in the inflammatory lesions of the VUE placentas (p < 0.05). DISCUSSION: To the best of our knowledge, this is the first report to assess villous injury, especially from a viewpoint of villous apoptosis in VUE placentas. An activated perforin/granzyme pathway and C5b-9 are suggested as possible mechanisms of apoptosis. PMID- 25725938 TI - Hospital admission associates with higher total IgE level in pediatric patients with asthma. PMID- 25725939 TI - Mobile health applications for asthma. PMID- 25725940 TI - Oral Immunotherapy for Egg Allergy: A Double-Blind Placebo-Controlled Study, with Postdesensitization Follow-Up. AB - BACKGROUND: Oral immunotherapy (OIT) may be an effective treatment for food allergy in children. It is not clear if the OIT-induced effect is achieved by desensitization (transient state dependent on regular antigen exposure), or by tolerance (persistent condition where the ability to consume the food is retained even after a period of withdrawal). OBJECTIVE: The aim of this study was to investigate the efficacy of OIT-egg desensitization in a double-blind placebo controlled study, and to evaluate if, after desensitization, tolerance can be maintained. METHODS: Children with egg allergy were randomized to OIT or placebo for 4 months. At the end of the controlled phase, a double-blind food challenge was repeated to confirm the achieved desensitization. Those subjects found to be desensitized were placed on an egg-containing diet for 6 months, followed by an egg avoidance phase for 3 months, when the food challenge was repeated to determine the maintained tolerance. RESULTS: A total of 31 children were randomized to OIT with dehydrated egg white (n = 17) or placebo (n = 14). Of the 17 active patients (1 dropout), 16 achieved desensitization and started the 6 month egg-containing diet. After 3-month of egg avoidance, 31% remained tolerant. In the control group, only 1 passed the final food challenge. Egg-specific IgG4 increased only in the active group. Five active OIT patients had side effects. CONCLUSION: Egg OIT results in desensitization in almost all subjects, although tolerance was maintained in only 1/3 of them after a 3-month period of withdrawal. Side effects were encountered, but the procedure appeared safe. In hen egg allergy, OIT is effective for desensitization. PMID- 25725941 TI - Rapid subcutaneous desensitization for the management of local and systemic hypersensitivity reactions to etanercept and adalimumab in 12 patients. PMID- 25725943 TI - Head trauma in sport and neurodegenerative disease: an issue whose time has come? AB - A number of small studies and anecdotal reports have been suggested that sports involving repeated head trauma may have long-term risks of neurodegenerative disease. There are now plausible mechanisms for these effects, and a recognition that these problems do not just occur in former boxers, but in a variety of sports involving repeated concussions, and possibly also in sports in which low level head trauma is common. These neurodegenerative effects potentially include increased risks of impaired cognitive function and dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Many would argue for taking a precautionary approach and immediately banning or restricting sports such as boxing. However, there are important public health issues in terms of how wide the net should be cast in terms of other sports, and what remedial measures could be taken? This in turn requires a major research effort involving both clinical and basic research to understand the underlying mechanisms, leading from head trauma to neurodegenerative disease and epidemiologic studies to assess the long-term consequences. PMID- 25725942 TI - A noninflammatory immune response in aged DNA Abeta42-immunized mice supports its safety for possible use as immunotherapy in AD patients. AB - Aging in the immune system results in tendency to proinflammatory responses. Intradermal DNA immunization showed Th2 polarized noninflammatory immune responses. We tested here 18-month-old mice which were immunized with Abeta42 peptide, DNA Abeta42 trimer, or 2 different prime boost protocols identical to previous experiments. High Abeta42 antibody levels were found in aged mice which had received peptide immunizations (900 MUg/mL plasma), and in mice which had received peptide prime and DNA boost immunizations (500 MUg/mL), compared with antibodies in DNA Abeta42 immunized mice with 50 MUg/mL. Although we found T-cell proliferation and inflammatory cytokines in mice which had received peptide or prime boost immunization, these were not found in DNA-immunized mice. The results are concordant with proinflammatory responses because of immunosenescence and contraindicate the use of Abeta42 peptide immunizations or prime boost immunization protocols for the use in elderly Alzheimer's disease patients. DNA Abeta42 immunization only on the other hand does lead to effective levels of antibodies without inflammatory cytokine or T-cell responses in the aged animal model tested. PMID- 25725944 TI - HMSN-P caused by p.Pro285Leu mutation in TFG is not confined to patients with Far East ancestry. AB - Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare disease so far identified only in individuals of Far East ancestry. Here, genome-wide linkage analysis and exome sequencing in an Iranian pedigree with 16 members affected with a neuromuscular disease led to identification of a mutation in TFG that causes p.Pro285Leu as cause of disease. The very same mutation was reported as cause of HMSN-P during the course of the study. Phenotypic analysis in conjunction with genetic data revealed that the Iranian patients were also affected with HMSN-P. Therefore, HMSN-P is not confined to the Far East and may simply not have been diagnosed in other populations. Haplotype analysis suggests at least 3 independent origins for mutated alleles that cause p.Pro285Leu. The phenotypic data gathered included subjective, biochemical, nerve conduction, electromyography, and muscle magnetic resonance imaging data. Comparison with patients with same disease in previous publications showed that clinical variability exists, sensory nerves are prominently affected, and proximal and distal muscles are involved. PMID- 25725945 TI - Curbside radiology consults: how does the time allotted for review, level of training, and subspecialization affect interpretation accuracy? AB - The interpretation accuracy of resident and attending radiologists was assessed based on time allotted for study review, level of training, and subspecialization. Twelve cases were presented in a time-constrained and a time unconstrained fashion to eight residents and six attendings. Overall, timed and untimed diagnostic accuracy was similar for all groups tested. Attendings sometimes performed worse than residents and in-field attendings when reviewing out-of-field studies. Residents often had greater specialty-specific accuracy than out-of-field attendings. Residents are capable of providing accurate "curbside" consultations to referring clinicians even under time-constrained conditions. Highly subspecialized attending radiologists should be cognizant of their out-of-field limitations. PMID- 25725946 TI - Multimodality imaging of Epstein-Barr virus-associated inflammatory pseudotumor like follicular dendritic cell tumor of the spleen: case report and literature review. AB - Inflammatory pseudotumors (IPTs) are rare tumors of unknown etiology; however, there is a strong association with the Epstein-Barr virus (EBV). EBV-positive IPTs are typically found in the liver and spleen. While many EBV-positive splenic IPTs contain follicular dendritic cell (FDC) proliferations, they are not aggressive such as with conventional FDC tumors. EBV-positive splenic IPTs have been reported with low malignant potential. We present a case with multimodality imaging of an EBV-positive IPT-like tumor with FDC features. PMID- 25725947 TI - Clinical utility of dual-energy CT for gout diagnosis. AB - OBJECTIVE: The present study was to evaluate the clinical value of dual-energy computed tomography (DECT) for detecting monosodium urate crystals in patients with gouty arthritis. METHODS: Two hundred and two patients, who experienced arthrocele and (or) joint pain, were enrolled into our study. DECT scans of upper or lower extremity were performed. One hundred and sixty one patients who conformed to the American College of Rheumatology classification standard were defined as the gout group. The rest (41) of the patients were regarded as the without-gout group. DE (80kV/140kV) datasets were reconstructed via DE gout software. Images were reviewed independently by two senior radiologists. RESULTS: In the gout group, DECT scans revealed a total of 379 areas of urate deposition in 121 patients. In the without-gout group, 3 areas of green urate deposition were detected. The sensitivity and specificity were 75.2% and 92.7%, respectively; when we increased the ratio to 1.32 and decreased the range to 3, the number of patients with green urate deposition increased, and the areas of urate deposition were more extensive. The sensitivity and specificity were 91.9% and 85.4%. DECT images could illustrate the palpable reduction in the tissue urate deposits compared to baseline images before and after treatment. CONCLUSIONS: DECT has comparable sensitivity and specificity for the detection of gouty arthritis in a clinical setting, and DECT can monitor the clinical treatment. However, DECT results should be interpreted carefully because there could be some false-negative or false-positive findings. PMID- 25725948 TI - Understanding Rift Valley fever: contributions of animal models to disease characterization and control. AB - Rift Valley fever (RVF) is a mosquito-borne viral zoonosis with devastating health impacts in domestic ruminants and humans. Effective vaccines and accurate disease diagnostic tools are key components in the control of RVF. Animal models reproducing infection with RVF virus are of upmost importance in the development of these disease control tools. Rodent infection models are currently used in the initial steps of vaccine development and for the study of virus induced pathology. Translation of data obtained in these animal models to target species (ruminants and humans) is highly desirable but does not always occur. Small ruminants and non-human primates have been used for pathogenesis and transmission studies, and for testing the efficacy of vaccines and therapeutic antiviral compounds. However, the molecular mechanisms of the immune response elicited by RVF virus infection or vaccination are still poorly understood. The paucity of data in this area offers opportunities for new research activities and programs. This review summarizes our current understanding with respect to immunity and pathogenesis of RVF in animal models with a particular emphasis on small ruminants and non-human primates, including recent experimental infection data in sheep. PMID- 25725949 TI - Analysis of waste hierarchy in the European waste directive 2008/98/EC. AB - Loss of recoverable resources in linear resource flow systems is likely to contribute to the depletion of natural resources and environmental degradation. The 'waste hierarchy' in the European Commission's latest Waste Framework Directive 2008/98/EC (WFD2008) makes recommendations on how to address this issue. The WFD2008 is analysed in this work for its adequacy in ensuring return of 'recoverable waste' as a 'resource' into the productive system. Despite the release of guidance documents by the DG Environment, DEFRA and WRAP UK on the interpretation of key provisions of the WFD2008, lack of clarity still exists around the WFD2008 'waste hierarchy'. There is also an overlap between measures such as 'prevention' and 'reduction', 'preparing for reuse' and 'reuse' and lack of clarity on why the measure of 'reuse' is included in the WFD2008 definition of 'prevention'. Finally, absence of the measures of 'recovery' and 'reuse' from the WFD2008 'waste hierarchy' reduces its effectiveness as a resource efficiency tool. Without clarity on the WFD2008 'waste hierarchy', it is challenging for decision makers to take direct action to address inefficiencies existing within their operations or supply chains. This paper proposes the development of an alternative 'hierarchy of resource use' and alternative 'definitions' that attempt to fill identified gaps in the WFD2008 and bring clarity to the key measures of waste prevention, reduction and recovery. This would help the key stakeholders in driving resource effectiveness, which in turn would assist in conservation of natural resources and prevention of environmental degradation. PMID- 25725950 TI - No standard is set for older women with breast cancer. PMID- 25725951 TI - Rocky Vista University, College of Osteopathic Medicine Hyperrealistic Simulation Center, Parker, Colorado. PMID- 25725952 TI - The Simulation Centre at Rigshospitalet, Copenhagen, Denmark. PMID- 25725953 TI - A polar-embedded C30 stationary phase: preparation and evaluation. AB - A novel polar-embedded C30 stationary phase has been synthesized and characterized. The polar carbamate group was generated homogeneously in situ by the catalytic reaction between isocyanate and primary alcohol. The simple one-pot synthetic strategy provided an efficient and effective strategy for modification of silica spheres. Efficiency, selectivity and silanol activity of the resulting column were characterized in detail with different classes of analytes that included Standard Reference Materials (SRM) 870, SRM 869b and SRM 1647e, alkylbenzene congeners, as well as polar-substituted aromatics. The polar embedded C30 stationary phase was found to exhibit excellent shape selectivity. PMID- 25725954 TI - Circulating ultrasound-assisted extraction, countercurrent chromatography, and liquid chromatography for the simultaneous extraction, isolation, and analysis of the constituents of Uncaria tomentosa. AB - A hyphenated automated technique for the online extraction, isolation, analysis, and identification of natural organic compounds was established. Circulating ultrasound-assisted extraction (CUAE) was coupled with countercurrent chromatography (CCC), high performance liquid chromatography (HPLC), and a diode array detector (DAD). This approach was applied to the fractionation and purification of alkaloids from Uncaria tomentosa. A biphasic solvent system of chloroform-methanol-water (6:4:5, v:v:v) was used for the CUAE and CCC separation of compounds from 500 g of U. tomentosa. Two CUAE/CCC/HPLC/DAD modes were established. Either the upper aqueous phase or the lower organic phase of the solvent system could be used as the extraction solvent. The target compounds were extracted by CUAE, and the extract was pumped into a sample loop before being directly injected into the CCC column, or pre-purified using a flash chromatography column before injection. The target compounds were eluted using either the organic or aqueous phase of the solvent system and the fractions were monitored using a UV detector. The target fractions were collected by a sample loop via a six-port valve, and analyzed by HPLC/DAD for purity and structural identification. This system isolated of 8.2mg, 7.4 mg, and 12.9 mg of rhynchophylline, corynoxine, and corynoxine B with HPLC purities of 96.15%, 95.34%, and 95.49%, respectively via the first mode; and isolated 26.6 mg, 24.6 mg, and 45.3mg of rhynchophylline, corynoxine, and corynoxine B with a HPLC purities of 98.22%, 97.18%, and 97.93% via the second mode. PMID- 25725955 TI - Interfacing supercritical fluid reaction apparatus with on-line liquid chromatography: monitoring the progress of a synthetic organic reaction performed in supercritical fluid solution. AB - An interface has been developed that connects a supercritical fluid reaction (SFR) vessel directly on-line to a liquid chromatograph. The combined SFR-LC system has enabled the progress of the esterification reaction between phenol and benzoyl chloride to synthesize phenyl benzoate in supercritical fluid carbon dioxide solution to be dynamically monitored. This was achieved by the periodic SFR-LC analysis of samples directly withdrawn from the esterification reaction mixture. Using the series of SFR-LC analysis results obtained for individual esterification reactions, the reaction progress profile for each esterification reaction was obtained by expressing the measured yield of phenyl benzoate as a function of reaction time. With reaction temperature fixed at 75 degrees C, four sets (n=3) of SFR-LC reaction progress profiles were obtained at four different SFR pressures ranging from 13.79 to 27.58 MPa. The maximum SFR yield obtained for phenyl benzoate using a standard set of reactant concentrations was 85.2% (R.S.D. 4.2%) when the reaction was performed at 13.79 MPa for 90 min. In comparison, a phenyl benzoate yield of less than 0.3% was obtained using the same standard reactant concentrations after 90 min reaction time at 75 degrees C using either: heptane, ethyl acetate or acetonitrile as conventional organic reaction solvents. PMID- 25725956 TI - Preparation and chromatographic evaluation of a newly designed steviol glycoside modified-silica stationary phase in hydrophilic interaction liquid chromatography and reversed phase liquid chromatography. AB - A diterpene glycoside compound, rebaudioside A (commonly abbreviated as RA), was immobilized onto porous silica surface through "thiol-ene" click chemistry strategy. The successful immobilization of the RA on the silica support was confirmed by FT-IR and elemental analysis. Chromatographic characteristics of the new stationary phase, named Click TE-RA, were evaluated by a set of diverse analytes such as carbohydrates, nucleosides, and organic acids in hydrophilic interaction liquid chromatography (HILIC) mode. The effects of water content, buffer pH and concentration were investigated and a typical HILIC retention feature of Click TE-RA was observed at high organic modifier content. The Click TE-RA stationary phase was further studied by a series of glycoside compounds. Tunable retention mechanisms from hydrophilic to hydrophobic interactions were observed. Separation of very polar compounds including oligosaccharides, nucleic acid bases and nucleosides using Click TE-RA in HILIC mode was successfully accomplished. In addition, separation of saponins both in HILIC and reversed phase liquid chromatography (RPLC) modes was performed, demonstrating the presence of orthogonality between two different modes on Click TE-RA column. The multiple interactions induced by polar sugar group and hydrophobic aglycone group allowed this Click TE-RA to serve as a multi-mode stationary phase in two dimensional liquid chromatography. PMID- 25725957 TI - In situ synthesis of homochiral metal-organic framework in capillary column for capillary electrochromatography enantioseparation. AB - Homochiral metal-organic frameworks (MOFs) are promising as porous stationary phase for open-tubular capillary electrochromatography (OT-CEC) enantioseparation owing to their fine-tuned pore sizes and large surface areas. In this work, the homochiral MOF AlaZnCl was successfully coated on the inner wall of fused silica capillary by an in situ, layer-by-layer self-assembly approach at room temperature. The results of scanning electron microscopy (SEM), X-ray diffraction (XRD), streaming potential (SP) and Fourier-transform infrared spectroscopy (FT IR) indicated that the homochiral MOF AlaZnCl was successfully coated on the capillary inner wall. To evaluate the performance of the homochiral MOF AlaZnCl coated capillary column, the enantioseparation was carried out by using six amine drugs and monoamine neurotransmitters as model analytes and excellent enantioseparation efficiency was achieved. Run-to-run, day-to-day, and column-to column relative standard deviations (RSDs) were all less than 5%. Moreover, the separation efficiency of the homochiral MOF AlaZnCl coated capillary column did not decrease obviously over 100 runs. PMID- 25725958 TI - Screening of mammalian target of rapamycin inhibitors in natural product extracts by capillary electrophoresis in combination with high performance liquid chromatography-tandem mass spectrometry. AB - In this study, capillary electrophoresis (CE) combined with HPLC-MS/MS were used as a powerful platform for screening of inhibitors of mammalian target of rapamycin (mTOR) in natural product extracts. The screening system has been established by using 5-carboxyfluorescein labeled substrate peptide F-4EBP1, a known mTOR inhibitor AZD8055, and a small chemical library consisted of 18 natural product extracts. Biochemical screening of natural product extracts was performed by CE with laser induced fluorescence detection. The CE separation allowed a quantitative measurement of the phosphorylated product, hence the quantitation of enzymatic inhibition as well as inhibition kinetics. The hits are readily identified as long as the peak area of the phosphorylated product is reduced in comparison with the negative control. Subsequent assay-guided isolation of the active natural product extract was performed with HPLC-MS/MS to track the particular active components. The structures of the identified active components were elucidated by the molecular ions and fragmentation information provided by MS/MS analysis. The CE-based assay method only requires minute pure compounds, which can be readily purified by HPLC. Therefore, the combination of CE and HPLC-MS/MS provides a high-throughput platform for screening bioactive compounds from the crude nature extracts. By taking the advantage of the screening system, salvianolic acid A and C in extract of Salvia miltiorrhiza were discovered as the new mTOR inhibitors. PMID- 25725959 TI - Pyrolysis-gas chromatography-isotope ratio mass spectrometry of polyethylene. AB - Polyethylene is probably the most used plastic material in daily life and its accurate analysis is of importance. In this communication the chemical structure of polyethylenes is studied in detail using conventional analytical pyrolysis (Py GC/MS), bulk stable isotopic analysis (IRMS) and pyrolysis compound specific stable isotopic analysis (Py-CSIA) to measure stable isotope proportions (delta(13)C, delta(15)N and deltaD) of polyethylene pyrolysis compounds. Polyethylene pyrolysis yields triplet peaks of n-alkanes, alpha-alkenes and alpha,omega-alkanedienes. No differences were found for bulk delta(13)C among different polyethylene types. However, conspicuous differences in deltaD were evident. It was possible to assign structure delta(13)C and deltaD values to specific polyethylene pyrolysis products in the range 12-18 carbon chain length. Conspicuous differences were found for the pyrolysis products with unsaturated moieties showing significant higher deltaD values than saturated chains (alkanes) that were deuterium depleted. In addition, a full isotopic fingerprinting (delta(13)C, delta(15)N and deltaD) for a dye (o-chloroaniline) contained in a polyethylene is reported. To the best of our knowledge this is the first application Py-CSIA to the study of a synthetic polymer. This hyphenated analytical technique is a promising tool to study synthetic materials, providing not only a fingerprinting, but also allowing the traceability of the polymerization process and the origin of the materials. PMID- 25725960 TI - A modified commercial gas chromatograph for the continuous monitoring of the thermal degradation of sunflower oil and off-line solid phase extraction gas chromatography-mass spectrometry characterization of released volatiles. AB - A homemade flow cell attached to a commercial Gas Chromatograph equipped with a Flame Ionization Detector (FID) has been designed for the continuous monitoring of volatile compounds released during heating edible oils. Analytical parameters such as mass of sample, temperature and flow rates have been optimized and the obtained results have been compared with the corresponding thermographs from standard TG systems. Results show that under optimum conditions, the profiles of volatiles released upon heating are comparable to the profiles of TG curves, suggesting that the FID based system could be an alternative to TGA. Additionally, volatiles have been retained in a Lichrolut EN((r)) resin, eluted and analyzed by Gas Chromatography-Mass Spectrometry. In this case, forty five compounds have been identified (acids, alcohols, alkanes, aldehydes, ketones and furans) and compared with the FID signals, working both in air or nitrogen atmosphere. It has been concluded that the oxidative thermal degradation is prevented in the presence of a nitrogen atmosphere. PMID- 25725961 TI - Evaluation of phytochemical composition of fresh and dried raw material of introduced Chamerion angustifolium L. using chromatographic, spectrophotometric and chemometric techniques. AB - Due to the wide spectrum of biological activities, Chamerion angustifolium L. as medicinal plant is used for the production of food supplements. However, it should be kept in mind that quality (biological activity) of the herb depends on its geographic origin, the way of raw material preparation or extraction and chemotype. The purpose of this study was to evaluate and compare the compositions of volatile, non-volatile compounds and antioxidant activities of C. angustifolium grown in Kaunas Botanical Garden after the introduction from different locations in Lithuania. The compositions of fresh and air-dried samples were compared. The profile of volatile compounds was analyzed using headspace solid phase microextraction coupled with GC/MS. trans-2-Hexenal (16.0-55.9% of all volatiles) and trans-anethole (2.6-46.2%) were determined only in the dried samples, while cis-3-hexenol (17.5-68.6%) only in fresh samples. Caryophyllenes (alpha- and beta-) were found in all analyzed samples, contributing together from 2.4% to 52.3% of all volatiles according to the origin and preparation (fresh or dried) of a sample. Total amount of phenolic compounds, total content of flavonoids and radical scavenging activity (using 2,2-diphenyl-1-picrylhydrazyl (DPPH)) were determined using spectrophotometric assays. The variation of total phenolic compounds content was dependent on the sample origin, moreover, drying reduced amount of phenolics 1.5-3.5 times. The DPPH free radical scavenging activity was in the range of 238.6-557.1mg/g (expressed in rutin equivalents) in the fresh samples and drastically reduced to 119.9-124.8 mg/g after drying. The qualitative analysis of phenolic compounds in the aqueous methanolic extracts of C. angustifolium was performed by means of HPLC with UV detection. Oenothein B and rutin were predominant in the samples; also caffeic and chlorogenic acids, and quercetin were determined. Chemometric methods, namely principal component analysis, hierarchical cluster analysis and K-means clustering analysis, were applied for evaluation of the results. Chemometric analysis showed existence of different chemotypes of C. angustifolium L. and their relation to the geographic origin. PMID- 25725962 TI - Filiferol, a chalconoid analogue from Washingtonia filifera possibly involved in the defence against the Red Palm Weevil Rhynchophorus ferrugineus Olivier. AB - A chalconoid analogue, 1,3,5-benzentriol 2-[(2S,3R)-3-(3,4-dihydroxylphenyl)-2,3 dihydroxylpropyl], named filiferol (1), has been isolated and purified for the first time from the leaf basal tissues of the palm species Washingtonia filifera. The chemical structure of the isolated compound has been elucidated unambiguously by spectroscopic and chemical methods. Filiferol has been based on a flavonol structure with the reduction of the common flavonoid keto group to give an unprecedented methylene carbon on the three carbon chain. An analogous compound with S stereochemistry at C3 has been obtained as synthetic intermediate for developing an enantioselective synthesis of (2R,3S)-(+)-catechin. Even though 1 proved to be deprived of antifungal properties, it displays a very effective larvicidal activity against Red Palm Weevil, Rhynchophorus ferrugineus, an important pest affecting cultivated and ornamental palms. 1 has been isolated from leaf tissues of W. filifera, a species resistant to this pest, but this molecule seems instead undetectable in tissues of other palm species susceptible to the parasite. The presence of 1 could therefore account for W. filifera natural resistance to the attacks of the Red Palm Weevil (R. ferrugineus). PMID- 25725963 TI - Effect of implant geometry on range of motion in reverse shoulder arthroplasty assessed using glenohumeral separation distance. AB - BACKGROUND: Whereas reverse shoulder arthroplasty has been successful in treating patients with cuff tear arthropathy, implant impingement after the procedure often causes complications, including reduced range of motion, bone loss, and instability. Attempts to simulate this problem in vitro typically rely on subjective visual methods to detect impingement. The purpose of this study was to determine the effect of humeral neck-shaft angle, implant diameter, humeral cup depth, and glenoid component eccentricity on minimum abduction angle and range of motion using an implant-tracking method for impingement detection. METHODS: Tests were performed in a kinematic shoulder simulator with actuated cables representing the deltoid. The humerus was manually adducted and abducted past the point of impingement in either direction. Centers of the implant components were tracked with optical motion capture and processed with a thresholding algorithm to determine the minimum abduction angle where impingement occurred. RESULTS: Humeral cup depth had the largest effect on minimum abduction angle and range of motion, with a retentive cup reducing range of motion by 26 degrees . A decreased neck-shaft angle reduced minimum abduction angle by 10 degrees but had little effect on overall range of motion. Diameter and eccentricity had little effect. CONCLUSION: A reduced neck-shaft angle reduces minimum abduction angle but does not improve overall range of motion. A more retentive humeral cup increases minimum abduction angle significantly. Although retentive cups are intended to improve joint stability, the reduced range of motion that they impart to the joint may partly counteract the benefits of increased constraint. PMID- 25725964 TI - Contact analysis of the native radiocapitellar joint compared with axisymmetric and nonaxisymmetric radial head hemiarthroplasty. AB - BACKGROUND: Radial head (RH) implants are manufactured from stiff materials, resulting in reduced radiocapitellar contact area that may lead to cartilage degeneration. Although the native RH is nonaxisymmetric, most implants are axisymmetric, potentially contributing to altered contact mechanics. This study compared the joint contact area (Ac) and maximum contact stress (sigmamax) of axisymmetric and nonaxisymmetric RH implants to the native radiocapitellar joint. METHODS: The contact mechanics of intact elbows derived from cadaveric computed tomography data (n = 15) were compared with axisymmetric (size: 18, 20, 22 mm) and nonaxisymmetric (size: 16 * 18, 18 * 20, 20 * 22 mm) RH hemiarthroplasty reconstructed elbows using Abaqus finite element software. Under a 100 N load, Ac and sigmamax were computed for +/-90 degrees pronation-supination and 0 degrees , 45 degrees , 90 degrees , and 135 degrees flexion. RESULTS: Compared with native, both hemiarthroplasty models produced significantly lower Ac and higher sigmamax (P < .001). In the best orientation, the nonaxisymmetric RH provided significantly larger Ac at 0 degrees and 135 degrees flexion (P = .03, P = .007) and reduced levels of sigmamax at 45 degrees and 90 degrees flexion (P = .003, P < .001). However, there was also a worst orientation that reduced Ac and increased sigmamax for all flexion angles (P < .003 for all). The native RH was less sensitive to rotation than the nonaxisymmetric RH in terms of sigmamax (P < .001). The axisymmetric RH was not sensitive to rotation. CONCLUSIONS: Whereas a nonaxisymmetric RH can provide improved contact mechanics at certain forearm rotations and flexions, there are also orientations where Ac is reduced and sigmamax is increased. Axisymmetric designs are more consistent throughout forearm rotation and therefore may be more forgiving than the nonaxisymmetric RH implant design used in this study. PMID- 25725965 TI - The influence of humeral head inclination in reverse total shoulder arthroplasty: a systematic review. AB - BACKGROUND: Humeral component inclination may play an important role in implant stability and the incidence of scapular notching in reverse total shoulder arthroplasty (RTSA). This study was conducted to determine if a difference exists between RTSA prostheses with a 135 degrees vs 155 degrees humeral component inclination angle with respect to dislocation rates and scapular notching rates. We hypothesized that the rate of dislocation would be significantly higher with the 135 degrees inclination design and that the rate of scapular notching would be significantly higher with the 155 degrees inclination design. METHODS: A systematic review was registered with PROSPERO and performed with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines using 3 publicly available free databases. Therapeutic clinical outcome investigations reporting the number of dislocations, number of patients with scapular notching, and postoperative range of motion after RTSA with levels of evidence I to IV were eligible for inclusion. All study and subject demographics were analyzed. Statistics were calculated using 2-proportion z tests. RESULTS: Thirty-eight studies including 2222 shoulders (average age, 70.3 +/- 3.91 years; 67% female) undergoing RTSA were included. Of these, 1762 (79.3%) used the 155 degrees inclination prosthesis and 460 (20.7%) used the 135 degrees inclination prosthesis with a lateralized glenosphere. The rate of scapular notching was 2.83% in the 135 degrees group and 16.80% in the 155 degrees group (P < .0001, z = -7.7107). The rate of dislocation was 1.74% in the 135 degrees group and 2.33% in the 155 degrees group (P = .4432, z = -0.7669). CONCLUSIONS: Our systematic review of 38 studies and 2222 shoulders found that the rate of scapular nothing was significantly higher with the 155 degrees prosthesis than with the 135 degrees prosthesis with a lateralized glenosphere, with no difference in dislocation rates between prostheses. PMID- 25725966 TI - Hyperosmolar irrigation compared with a standard solution in a canine shoulder arthroscopy model. AB - BACKGROUND: A hyperosmolar irrigation solution may decrease fluid extravasation during arthroscopic procedures. Demonstrating the safety of a hyperosmolar irrigation solution with respect to chondrocyte viability and cartilage water content was deemed necessary before designing a clinical efficacy study. METHODS: We designed a translational animal model study in which hyperosmolar arthroscopy irrigation fluid (1.8%, 600 mOsm/L) was compared with normal saline (0.9%, 300 mOsm/L). Purpose-bred research dogs (n = 5) underwent bilateral shoulder arthroscopy. Irrigation fluid was delivered to each shoulder joint (n = 10) at 40 mm Hg for 120 minutes using standard ingress and egress portals. The percentage change in shoulder girth was documented at the completion of 120 minutes. Articular cartilage sections from the glenoid and humeral head were harvested from both shoulders. Chondrocyte viability and tissue water content were evaluated. Differences between groups and compared with time 0 controls were determined, with significance set at P <.05. RESULTS: The mean percentage change in shoulder girth was higher in the isotonic control group (13.3%) than in the hyperosmolar group (10.4%). Chondrocyte viability and tissue water content for glenoid and humeral head cartilage were well maintained in both treatment groups, and differences were not statistically significant. CONCLUSIONS: The data from this study suggest that doubling the osmolarity of the standard irrigation solution used for arthroscopy was not associated with any detrimental effects on chondrocyte viability or tissue water content after 2 hours of arthroscopic irrigation. On the basis of potential benefits in conjunction with the safety demonstrated in these data, clinical evaluation of a hyperosmolar solution for irrigation during shoulder arthroscopy appears warranted. PMID- 25725967 TI - How do revised shoulders that are culture positive for Propionibacterium differ from those that are not? AB - BACKGROUND: Many shoulder arthroplasties revised for pain, stiffness, or component loosening are culture positive for Propionibacterium. The culture results are unknown until days or weeks after surgery, too late to inform intraoperative surgical decisions and immediate postsurgical antibiotic treatment. The objective of this study was to identify preoperative and intraoperative characteristics that may alert surgeons to an increased likelihood of positive cultures. METHODS: We analyzed the records of 132 shoulders that underwent surgical revision of a shoulder arthroplasty, 66 of which became culture positive for Propionibacterium and 66 did not. RESULTS: Propionibacterium positive and Propionibacterium-negative shoulders were similar with respect to many characteristics; however, Propionibacterium-negative shoulders were revised sooner after the index procedure and were significantly more likely to be female, to have sustained a fall, to have instability, and to have rotator cuff deficiency. Intraoperatively, Propionibacterium-positive shoulders demonstrated more glenoid erosions, glenoid osteolysis, glenoid loosening, and a higher incidence of a soft tissue membrane between the humeral component and humeral endosteum. Shoulders culture positive for Propionibacterium were more likely to be culture positive for another bacteria. CONCLUSIONS: Although Propionibacterium positive and Propionibacterium-negative shoulders have many similarities, factors such as male gender, delayed presentation, glenoid osteolysis and loosening, humeral membrane, and the absence of instability or cuff failure should arouse suspicion of Propionibacterium and suggest the need for deep cultures and consideration of aggressive surgical and medical treatment. PMID- 25725968 TI - New tumor phenotypes reported in the larynx in the last decades: a critique. PMID- 25725969 TI - Mastication accelerates Go/No-go decisional processing: An event-related potential study. AB - OBJECTIVE: The purpose of the present study was to investigate the effect of mastication on Go/No-go decisional processing using event-related potentials (ERPs). METHOD: Thirteen normal subjects underwent seven sessions of a somatosensory Go/No-go paradigm for approximately 4min; Pre, and Post 1, 2, 3, 4, 5, and 6. The Control condition included the same seven sessions. The RT and standard deviation were recorded, and the peak amplitude and latency of the N140 and P300 components were analyzed. RESULTS: The RT was significantly shorter in Mastication than in Control at Post 1-3 and 4-6. The peak latency of N140 was earlier in Mastication than in Control at Post 4-6. The latency of N140 was shortened by repeated sessions in Mastication, but not by those in Control. The peak latency of P300 was significantly shorter in Mastication than in Control at Post 4-6. The peak latency of P300 was significantly longer in Control with repeated sessions, but not in Mastication. CONCLUSIONS: These results suggest that mastication may influence response execution processing in Go trials, as well as response inhibition processing in No-go trials. SIGNIFICANCE: Mastication accelerated Go/No-go decisional processing in the human brain. PMID- 25725970 TI - [Multiple pulmonary emboli complicating infective endocarditis in a child with congenital heart disease]. AB - Pulmonary embolism in children is a rare condition, associated with high mortality. Clinical presentation is nonspecific. Pulmonary embolism may present initially similar to bacterial endocarditis of the right heart, septic thrombophlebitis, or osteomyelitis. We report the case of a 6-year-old girl who had dyspnea over the four months before consultation, complicated three months later by hemoptysis. She was diagnosed with subacute bacterial endocarditis secondary to group D Streptococcus, developed upon a ventricular septal defect. Two weeks later, the child had sudden chest pain and tachypnea. Lung scintigraphy showed multiple pulmonary embolisms. The therapeutic approach was to continue antibiotics without anticoagulant treatment. The outcome was favorable with apyrexia and stabilization on the respiratory level. Pulmonary embolism is a rare disease in children with an incidence of 3.7%. Classically, it presents with fever, hemoptysis, and nonspecific infiltrates on chest X-ray. These signs were noted in our patient, although the infiltrates on the chest X-ray were hidden by the pulmonary edema associated with heart failure. The persistence of these left basal opacities after antidiuretic treatment suggested an infectious origin. Subsequently, lung scintigraphy showed that it was a pulmonary infarct. The therapy of septic pulmonary embolism is the same as that for infective endocarditis. Antibiotic treatment alone was maintained without anticoagulants because of the high risk of bleeding at the seat of the pulmonary embolism and the insubstantial significant benefit of this therapy. Pulmonary embolism in children is a rare disease, but its incidence is underestimated. Better knowledge on its actual impact and etiologies in children is necessary. Multicenter studies are needed to establish recommendations. PMID- 25725971 TI - [Childhood eruptive nevi: a case report]. AB - "Eruptive nevi" is a phenomenon characterized by a rapid appearance of multiple melanocytic nevi. It is mainly developed in three groups of patients: those with systemic immunosuppression, bullous cutaneous disorders, and a melanocytic stimulation drug. We report on the case of an 11-year-old boy who was diagnosed with acute lymphoblastic leukemia. A few months after the beginning of the chemotherapy, he developed multiple pigmented lesions over the skin. Eruptive nevi syndrome has been described in the literature in 29 cases in the context of severe bullous disease and in immunosuppression. Nevi most often appear on the trunk and extremities, notably on the feet in the context of immunosuppression. They are localized in areas of bullous lesions in bullous diseases. Due to an increased melanocytic stimulation in eruptive nevi patients, long-term surveillance of individuals who have developed eruptive nevi is required, and increased sun prevention should be suggested. PMID- 25725973 TI - [Disseminated lymphangiomatosis: a rare cause of anemia]. AB - Disseminated lymphangiomatosis is a congenital lymphovenous vascular malformation. It can occur in different regions, some of which are unusual. The treatment of this vascular malformation is based on surgical excision, sclerotherapy, or recombinant interferon therapy. We report the case of disseminated lymphangiomatosis in a 13-year-old girl who presented with anemia. PMID- 25725972 TI - [Knowledge of adolescents with inflammatory bowel disease: Results of a multicenter cross-sectional survey]. AB - AIM: To assess knowledge acquired by adolescents about their inflammatory bowel disease (IBD). METHODS: An anonymous questionnaire was given during consultation to adolescents followed for IBD by pediatricians from 13 hospitals between 1 September 2012 and 1 July 2013. After parental consent, these physicians completed a form at the inclusion of each patient, in which the characteristics of IBD were detailed. The patients mailed back their questionnaire. RESULTS: A total of 124 patients from 12 to 19 years of age were included with a response rate of 82% (all anonymous); 23% of the patients thought that diet was a possible cause of IBD and 22% that one of the targets of their treatment was to cure their disease for good. Of the patients reported having Crohn disease, 46% knew the anoperineal location and 14% knew that Crohn disease can affect the entire digestive tract. Twenty-five percent of the patients were able to name one side effect of azathioprine (88% had already received this treatment), 24% were able to name one side effect of infliximab (54% had already received this treatment), 70% of the adolescents knew that smoking worsens Crohn disease, 68% declared they had learned about their IBD from their pediatrician, and 81% said they would like to receive more information. CONCLUSION: Adolescents with IBD have gaps in their general knowledge and the different treatments of their disease. Their main source of information is their pediatrician, warranting the implementation of customized patient education sessions. PMID- 25725974 TI - [Airbag-related death in a toddler. A poorly known danger?]. AB - We report the case of an 8-month-old baby killed by the deployment of an airbag. He was correctly positioned, in a safety seat designed for his age class, on the passenger side, and rear-facing. The accident occurred at low speed, on the left front of the car, without provoking any harm to the mother who was driving the vehicle, but the impact led to airbag deployment. A CT scan showed an occipital fracture, hemorrhagic parenchymal contusions, subarachnoid hemorrhage and edema, which quickly led to fatal intracranial hypertension. Severe retinal hemorrhages were also noted. Brain death was declared 24h later. Both direct impact and violent projection of the head are involved in the severity of brain lesions. Retinal hemorrhages are similar to what is observed in shaken-baby syndrome. To our knowledge, this is the first French publication on this topic in childhood. In France, children are allowed to be positioned on the passenger side seat, but the airbag, if present, is supposed to be deactivated, which is not always possible. In recent cars, depowering the airbag is easy, with on/off switches, but these systems are not uniform between models. Moreover, it is very likely that this possibility is ignored by numerous parents. A widespread communication on this topic should be initiated in France to prevent such events. Banning infants from front passenger seats completely does not seem possible. Nevertheless, greater attention on the part of police departments and better information to drivers appear necessary. PMID- 25725975 TI - [Prophylaxis of mother-to-infant transmission of hepatitis B virus]. AB - Hepatitis B virus (HBV) infection is a worldwide health problem and mother-to infant (or vertical) transmission is the main source of chronic infection in Asian countries. Administration of HBV vaccine to the infant at birth, with or without concurrent specific immunoglobulin, efficiently prevents such transmission (efficacy>90%). In France, testing Ag HBs is mandatory during pregnancy in all pregnant women. Infants born to Ag HBs-positive mothers should receive the first injection of vaccine and one injection of specific immunoglobulins at birth. Vaccination should thereafter be completed according to a three-injection protocol (at 1 and 6 months) or a four-injection protocol in case of prematurity. Failure of immunoprophylaxis can be observed when the viral load is very high in the mother during pregnancy (HBV-DNA levels>200,000 IU/mL). In such women, antiviral therapy with analogs (lamivudine, telbivudine, or tenofovir) during the third trimester of pregnancy and 1 month post-partum, in association with accurate immunoprophylaxis, may prevent vertical transmission. The optimal cut-off value of maternal viral load for antiviral therapy in late pregnancy and post-partum to prevent vertical transmission is still under debate. PMID- 25725976 TI - [Vulvar lichen sclerosus in children misdiagnosed as sexual abuse]. AB - INTRODUCTION: With the frequency of lawsuits for sexual abuse increasing, high quality care for victims is of utmost importance. Genital examination is difficult to perform, especially on children, but is a key item for diagnosis. A case report is presented herein to illustrate this issue. CASE PRESENTATION: A sexual assault was suspected on 2.5-year-old female twins. Clinical examination primarily detected vulvar micro-hematoma and hypopigmentation, discreetly sclerosing, as well as atrophic labia and a beginning of lichenification on one of them. The other twin showed an unspecific and erythematous lesion. Elimination of the supposedly dangerous environment and a remote consultation brought out a paradoxical development to the story and confirmed the diagnosis of vulvar lichen sclerosus. DISCUSSION: Traumatic lesions caused by sexual abuse are uncommon. Coexisting allegations and lesions in the genital area lend support to the hypothesis of sexual abuse. However, genital-anal tropism dermatosis can mimic traumatic injuries. Lichen sclerosus is an example of a differential diagnosis of vulvar traumatic lesions, which is quite often unknown to physicians, including pediatricians. This case report shows that taking the appropriate time in multidisciplinary councils can suggest a differential diagnosis. Nonetheless, it should be remembered that identifying the pathology behind the lesions cannot allow the physician to negate the child's story about potentially sexual acts, although the truth of this story and the perpetrator must still be proven by a court of law. PMID- 25725977 TI - Acute myocardial infarction: 'telomerasing' for cardioprotection. AB - Reactivating the telomerase gene through gene therapy after acute myocardial infarction (AMI) has been recently reported to improve survival in mice. Given that regular physical exercise also activates this gene, therapeutic and lifestyle interventions targeting telomerase need to be explored as possible additions to the current armamentarium for myocardial regeneration. PMID- 25725978 TI - [Ipilimumab and metastatic lung cancer: Can we change the natural history of the disease?]. AB - INTRODUCTION: Ipilimumab (anti CTLA-4 antibody) aims to activate antitumor immunity. This treatment is being evaluated in non-small cell lung cancer. CASE REPORT: We report a case of a stage IV adenocarcinoma patient randomized in 2008 in the phase II trial CA 184-104 evaluating the combination of ipilimumab to chemotherapy with carboplatin and paclitaxel. After an initial partial response to chemotherapy, the patient achieved a complete response with ipilimumab as maintenance therapy. However, it was complicated by grade 3 gastro-intestinal toxicity leading to stop the ipilimumab. However, this complete response persists after 6 years. CONCLUSIONS: Our case illustrates the contribution of immunotherapy at least in some patients. The mechanisms of action, relationship between efficacy and toxicity and predictors of efficacy remain to be defined. PMID- 25725979 TI - [Pituitary metastasis revealing a lung cancer]. AB - INTRODUCTION: Pituitary metastases are rare and difficult to diagnose. Their optimal approach and management remains to be defined. CASE REPORT: We report the case of a 56-year-old patient suffering from squamous cell lung carcinoma who developed pituitary metastasis with secondary hypopituitarism, the symptoms of which were initially attributed to depression. CONCLUSION: Pituitary metastases can be difficult to diagnose, which may lead to delays in care, which can be fatal. PMID- 25725980 TI - [Influence of chest physiotherapy on gastro-oesophageal reflux in children]. AB - INTRODUCTION: Chest physiotherapy is regularly prescribed for children, particularly in cystic fibrosis. Gastro-oesophageal reflux is common in this disease and is associated with certain chest physiotherapy manoeuvres. AIM OF THE STUDY: To evaluate the influence of two chest physiotherapy techniques on gastro oesophageal reflux in children. MATERIAL AND METHOD: Twenty-nine children were investigated by routine pHmetry. During the examination, they performed two chest physiotherapy manoeuvres in a seated position for 10 minutes each with a 5 minutes rest between them. The two manoeuvres used were a slow expiration technique (ELPr) and positive expiratory pressure (PEP). It was a prospective study and the order of manoeuvres was randomised. The pH traces were analysed blindly when all the studies had been completed. RESULTS: In the sample, 21% of children had gastro-oesophageal reflux during the physiotherapy session. No relationship was found between reflux during physiotherapy and pathological reflux (P=0.411) nor the physiotherapy technique used (P=0.219). CONCLUSION: The use of these two chest physiotherapy techniques in children in a seated position can produce gastro-oesophageal reflux. PMID- 25725981 TI - [The management of complicated parapneumonic effusions in France]. AB - INTRODUCTION: There are no French guidelines for the management of complicated parapneumonic effusions. A national observational study was carried out to assess the main features of current clinical practice for this condition. MATERIAL AND METHODS: A questionnaire was sent by email to the 1500 members of the Societe de Pneumologie de Langue Francaise (SPLF) between 15th November and 15th December 2012. RESULTS: There were 92 responders, i.e. a response rate of 6%. Of these, 87 physicians mentioned that they were involved in the management of patients with complicated parapneumonic effusions with a median number of cases of 10 per year (IQR: 5-20). Chest tube drainage was the main approach used for pleural fluid aspiration (n=51/87), followed by repeated thoracentesis (n=29/87) and early surgery (1/87). Five physicians answered both chest tube drainage or repeated thoracentesis and one physician either chest tube drainage or early surgery. Pleural fibrinolytics were never used by 20% of physicians, only in case of loculations by 70% and by 10% of respondents in all cases. Only 3 physicians combined fibrinolytics with DNAse. A double antibiotic dose was used by one third of physicians. All the physicians used respiratory physiotherapy during hospitalization and to aid recovery. Follow-up practices were heterogeneous. CONCLUSIONS: The management of complicated parapneumonic effusions varies significantly in France. National guidelines may be helpful to define best practice and aid in its implementation. PMID- 25725982 TI - [Mediastinal fat necrosis]. AB - Epicardial fat necrosis is a rare cause of benign chest pain. Its physiopathological mechanism is unknown. Diagnosis is easily performed through radiological investigations that show a round opacity of fat density limited by a dense pseudo-capsule in the anterior mediastinum, close to the heart. PMID- 25725983 TI - Automated radiosynthesis of GMP quality [18F]HX4 for PET imaging of hypoxia. AB - INTRODUCTION: [(18)F]HX4 is a 2-nitroimidazole based investigational radiotracer for imaging hypoxia. METHODS: A two-step, one-pot synthetic procedure was developed on a GE Tracerlab MX-FDG with a disposable cassette. Nucleophilic substitution of a nosylate group with [(18)F]fluoride was followed by solvent evaporation and acidic removal of the acetyl protecting group. HPLC purification in a bio-compatible solvent mixture was developed. RESULTS AND CONCLUSIONS: Using starting activities of 80-110 GBq [(18)F]fluoride, GMP compliant [(18)F]HX4 was produced in non-decay corrected radiochemical yields of 12 +/- 3% (n = 9) in 55 min including HPLC purification. No reformulation steps were required. The mean specific activity of the final product was 2450 GBq/MUmol. Modifications to the process and final formulation were included to prevent decomposition of the product, and these changes resulted in an improved stability of the formulated [(18)F]HX4, with a shelf-life of at least 8h post-synthesis. The product consistently passed all required quality control tests to determine that the [(18)F]HX4 was suitable for clinical use. Using a 90 minute target bombardment, and 80-110 GBq starting [(18)F]fluoride, the method produced multiple patient doses. PMID- 25725984 TI - A strategy for improving FDG accumulation for early detection of metastasis from primary pancreatic cancer: stimulation of the Warburg effect in AsPC-1 cells. AB - INTRODUCTION: Early detection and/or prediction of metastasis provide more prognostic relevance than local recurrence. Direct spread into the peritoneum is frequently found in pancreatic cancer patients, but positron emission tomography (PET) with 2-deoxy-2-fluoro-d-glucose (FDG) is not useful for identifying such metastasis. We investigated a method to enhance FDG accumulation using AsPC-1 human ascites tumor cells. METHODS: (14)C-FDG accumulation was assessed under the following conditions: 1) characteristics of (14)C-FDG transport were examined using phloridzin, a Na(+)-free buffer, and various hexoses, and 2) accumulation of (14)C-FDG was measured in cells that were pretreated with hexose for various time periods, and activity of 6-phosphofructo-1-kinase (PFK-1) was assayed. RESULTS: (14)C-FDG transport into AsPC-1 cells was mediated primarily by a Na(+) independent transport mechanism. Aldohexoses such as d-glucose, D-mannose, and D galactose inhibited (14)C-FDG transport. Cells pretreated with d-glucose, D mannose, or D-fructose exhibited augmented (14)C-FDG accumulation. Pretreatment with higher concentrations of D-glucose or D-fructose tended to increase PFK-1 activity. CONCLUSIONS: Very little information has been published about the association between PFK-1 and FDG accumulation, and we confirmed the impacts of various hexoses on the activity of PFK-1 and FDG accumulation in AsPC-1 cells. Clarifying the relevance of PFK-1 in FDG accumulation will contribute to developing new features of FDG-PET, because PFK-1 is the main regulator of glycolysis. PMID- 25725985 TI - Risk of hemoptysis in cystic fibrosis clinical trials: A retrospective cohort study. AB - BACKGROUND: Cystic fibrosis (CF) is characterized by airway infection and inflammation resulting in respiratory complications including hemoptysis. The objectives of this study were to characterize the risk of hemoptysis attributable to underlying disease and in the presence of standard of care therapy. METHODS: This retrospective cohort study estimated hemoptysis rates overall and by relevant risk factors utilizing adverse event data from longitudinal prospective CF clinical trials. RESULTS: Of the 1008 participants, 73% were <=18 years old; of 929 with available spirometry, 27% had an FEV1<70% predicted. During the average 8.2 months of follow-up, 8% experienced >=1 hemoptysis events (95% CI: 6%, 10%). Of the 125 events, 76% were mild in severity and only 9% were serious. Hemoptysis rates were greater among adults than children, those with FEV1<70% predicted, and participants infected with P. aeruginosa but not with S. aureus. CONCLUSIONS: Hemoptysis is a common adverse event among CF clinical trial participants, and particularly in adults with more severe lung disease. These results can be used to predict event occurrence in future clinical trials. PMID- 25725986 TI - Impact of storage conditions on metabolite profiles of sputum samples from persons with cystic fibrosis. AB - BACKGROUND: Although recent studies have begun to elucidate how airway microbial community structure relates to lung disease in cystic fibrosis (CF), microbial community activity and the host's response to changes in this activity are poorly understood. Metabolomic profiling provides a means to investigate microbial activity and human cell activity within diseased airways. However, variables in sample storage and shipping likely affect downstream analyses and standards for sample handling are lacking. METHODS: We assessed the impact of sample storage conditions on liquid chromatography mass spectrometry analysis of CF sputum samples. RESULTS: Significant changes in global metabolomic profiles occurred in samples stored at room temperature or at 4 degrees C for longer than one day. Untargeted metabolomic profiles were stable in sputum samples stored at -20 degrees C or -80 degrees C for at least 28 days. Quorum sensing molecules and phenazines, both considered important to the in vivo activity of Pseudomonas during airway infection, were detected after sample storage at room temperature for five days. CONCLUSIONS: Sputum samples can be stored at -20 degrees C or -80 degrees C for weeks with minimal effect on global metabolomic profiles. This observation provides guidance in designing metabolomic studies that have the potential to deepen our understanding of how airway microbial communities impact lung disease progression in CF. PMID- 25725987 TI - Characterization of a high TNF-alpha phenotype in children with moderate-to severe asthma. PMID- 25725988 TI - Reply: To PMID 24997637. PMID- 25725989 TI - Natural history of peanut allergy and predictors of resolution in the first 4 years of life: A population-based assessment. AB - BACKGROUND: There are no prospectively collected data available on the natural history of peanut allergy in early childhood. Previous studies of predictors of tolerance development have been biased by failure to challenge high-risk children when IgE antibody levels are high, therefore potentially introducing bias to persistent allergy. OBJECTIVES: We sought to describe the natural history of peanut allergy between 1 and 4 years of age and develop thresholds for skin prick test (SPT) results and specific IgE (sIgE) levels measured at age 1 and 4 years that have 95% positive predictive value (PPV) or negative predictive value for the persistence or resolution of peanut allergy. METHODS: One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the population-based, longitudinal HealthNuts Study (n = 5276) were followed up at 4 years of age with repeat oral food challenges, SPTs, and sIgE measurements (n = 103). Challenges were undertaken in all peanut-sensitized children at 1 and 4 years of age, irrespective of risk profile. RESULTS: Peanut allergy resolved in 22% (95% CI, 14% to 31%) of children by age 4 years. Decreasing wheal size predicted tolerance, and increasing wheal size was associated with persistence. Thresholds for SPT responses and sIgE levels at age 1 year with a 95% PPV for persistent peanut allergy are an SPT-induced response of 13 mm or greater and an sIgE level of 5.0 kU/L or greater. Thresholds for SPT and sIgE results at age 4 years with a 95% PPV for persistent peanut allergy are an SPT response of 8 mm or greater and an sIgE level of 2.1 kU/L or greater. Ara h 2, tree nut, and house dust mite sensitization; coexisting food allergies; eczema; and asthma were not predictive of persistent peanut allergy. CONCLUSION: These thresholds are the first to be generated from a unique data set in which all participants underwent oral food challenges at both diagnosis and follow-up, irrespective of SPT and sIgE results. PMID- 25725990 TI - Key stages of bone marrow B-cell maturation are defective in patients with common variable immunodeficiency disorders. PMID- 25725991 TI - IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (NPs) in Western populations is associated with TH2 cytokine polarization. IL-25, an IL-17 family cytokine, was recently reported to induce TH2-type immune responses and to contribute to several allergic diseases, such as atopic dermatitis and asthma. However, the role of IL-25 in Asian patients with nasal polyposis remains unclear. OBJECTIVE: We sought to determine the role of IL-25 in Asian patients with nasal polyposis and CRS. METHODS: We investigated IL-25 expression and its cellular origins in NPs of human subjects using immunohistochemistry (IHC), quantitative RT-PCR, and ELISA of NP tissues. Correlations between IL-25 expression and expression of other inflammatory markers in NP tissues were also explored. Anti-IL-25 neutralizing antibody was administered in an ovalbumin- and staphylococcal enterotoxin B-induced murine NP model to confirm the function of IL-25 during nasal polypogenesis. RESULTS: IL-25 expression was upregulated in NP mucosa from patients with CRS with NPs compared with uncinate process tissue from control subjects and those with CRS without NPs. Overexpression of epithelial IL 25 was confirmed by using IHC, and double IHC staining showed that tryptase positive cells were one of the main sources of IL-25 among immune cells. Furthermore, IL-17 receptor B levels were also increased in immune cells of patients with NPs compared with those in control subjects. In NPs IL-25 mRNA expression positively correlated with the expression of several inflammatory markers, including T-box transcription factor, RAR-related orphan receptor C, GATA3, eosinophil cationic protein, TGF-beta1, and TGF-beta2. IL-25 was more abundant in the murine NP model compared with control mice, and similar correlations between IL-25 and inflammatory markers were observed in murine models. Anti-IL-25 treatment reduced the number of polyps, mucosal edema thickness, collagen deposition, and infiltration of inflammatory cells, such as eosinophils and neutrophils. This treatment also inhibited expression of local inflammatory cytokines, such as IL-4 and IFN-gamma. Furthermore, expression of CCL11, CXCL2, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the nasal mucosa was suppressed in the anti-IL-25-treated group. CONCLUSION: Our results suggest that IL-25 secreted from the sinonasal epithelia and infiltrating mast cells plays a crucial role in the pathogenesis of CRS with NPs in Asian patients. In addition, our results suggest the novel possibility of treating nasal polyposis with anti-IL-25 therapy. PMID- 25725992 TI - Is the localized seminal plasma hypersensitivity the mucosal aspect of protein contact dermatitis? PMID- 25725993 TI - Comment on "study of quality and stability of ursodeoxycholic acid formulations for oral pediatric administration" by Santovena et al. [Int. J. Pharm. 477 (2014) 32-38]. PMID- 25725994 TI - Cyclic AMP prevents decrease of phosphorylated ezrin/radixin/moesin and chloride intracellular channel 5 expressions in injured podocytes. AB - BACKGROUND: Our previous in vitro studies suggested that cyclin AMP (cAMP) signaling protects against podocyte injury. However, the molecular mechanisms remain unknown. The aim of the present study was to explore the role of forskolin, an agonist for adenylate cyclase, on ezrin/radixin/moesin (ERM) phosphorylation and chloride intracellular channel 5 (CLIC5) expressions in injured podocytes. METHODS: ADR nephrosis model were induced by adriamycin (ADR) injection in BalB/C mice. Parts of ADR nephrosis mice were pretreated with forskolin. Albuminuria was estimated by urine Coomassie blue stain. Nephrin, synaptopodin, CLIC5, phosphorylated ERM and podocalyxin were measured by confocal microscopy. CLIC5 and phosphorylated ERM also were studied using western blotting. RhoA and Rac1 were estimated by G-Lisa kit. RESULTS: We found that forskolin partially alleviated albuminuria and width of foot processes. Nephrin, synaptopodin, phosphorylated-ERM (p-ERM) and CLIC5 expression were decreased in ADR mice, which were improved by forskolin pretreatment. In vitro studies, pretreatment of podocytes with pCPT-cAMP(PKA-selective cAMP analogue)prevented puromycin aminonucleoside (PAN)-induced CLIC5 downregulation. 8-pCPT-2'-O-Me-cAMP (2Me-cAMP, an Epac-selective cAMP analogue) blocked PAN-induced p-ERM downregulation. PAN inhibited RhoA activation in podocytes, which could be prevented by pCPT-cAMP pretreatment. Y-27632, a Rho inhibitor, decreased CLIC5 expression in podocytes. CONCLUSION: Activation cAMP signaling might attenuate albuminuria in ADR-induced nephrosis mice. Different downstream signaling pathway might mediate cAMP protection on CLIC5 and p-ERM expression, respectively. PMID- 25725995 TI - Epidemiology of coronary heart disease in HIV-infected versus uninfected individuals in developed countries. AB - The widespread use of combination antiretroviral therapy (cART) among people living with HIV in developed countries has lead to significantly improved life expectancy. However, extensive use of the effective cART coincides with increasing reports of coronary heart disease (CHD) among people living with HIV, and CHD has become a major cause of death. CHD results from a complex and multifactorial atherosclerotic process involving the over-representation of traditional cardiovascular risk factors, particularly smoking, uncontrolled viral replication, chronic inflammation, immune activation, and exposure to antiretroviral drugs. Consequently careful selection of antiretroviral drugs, cardiovascular risk reduction, and lifestyle modifications are needed. In individuals living with HIV, cardiovascular risk assessment is becoming an important element of care. PMID- 25725996 TI - French Hajj pilgrims' experience with pneumococcal infection and vaccination: A knowledge, attitudes and practice (KAP) evaluation. AB - BACKGROUND: Transmission of respiratory infections poses a major public health challenge during the Hajj and Umrah in the Kingdom of Saudi Arabia. Acquisition of Streptococcus pneumoniae during Hajj has been studied in the past and recommendations for vaccination against S. pneumoniae have been made for high risk groups. METHODS: The purpose of this study was to assess the knowledge and attitudes of French Hajj pilgrims towards pneumococcal vaccination. Adult pilgrims departing from Marseille, France to Mecca for the 2014 Hajj season were administered a face-to-face questionnaire to ascertain their knowledge and attitudes towards pneumococcal vaccination before departing for Hajj. RESULTS: A total of 300 participants took part. Their overall knowledge about the severity of pneumonia and the existence of the vaccine was very low. Out of 101 participants who had an indication for pneumococcal vaccination, irrespective of their travel status, only 7% were advised to have the vaccine by their general practitioner. CONCLUSIONS: These results reinforce the need for better dissemination of information either before or during the pre-travel counselling. The visit to the travel clinic for receiving the mandatory meningococcal vaccination for Hajj is a good opportunity to update routine immunizations, including pneumococcal vaccination. PMID- 25725997 TI - Taurine enhances excitability of mouse cochlear neural stem cells by selectively promoting differentiation of glutamatergic neurons over GABAergic neurons. AB - Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues, and has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in inner ear neural development is still largely unknown. Here we report that taurine enhanced the viability and proliferation of in vitro mouse cochlear neural stem cell culture, as well as improved neurite outgrowth. Moreover, prolonged taurine treatment also increased the neural electrical activity by escalating changes of intracellular calcium concentration, the number of spontaneous Ca(2+) oscillations in cells, and the frequencies of Ca(2+) spikes. Most importantly, we found that this escalated neural excitability by taurine was due to combined effect of increase in the population of excitatory glutamatergic neuron and decrease in inhibitory GABAergic neuron population. This is the first report on the effect of taurine to selectively promote neural stem cell differentiation by altering neuron type commitment. Our study has supported the potential of taurine as treatment against hearing loss caused by neuron degeneration, or even as an agent to improve sensitivity of hearing by increasing overall excitability of auditory nervous system. PMID- 25725998 TI - Clinical applications of cerebral function monitoring in neonates. AB - The cerebral function monitor is a device for trend monitoring of changes in the amplitude of the electroencephalogram, typically recorded from one or two pairs of electrodes. Initially developed and introduced to monitor cerebral activity in encephalopathic adult patients or during anaesthesia, it is now most widely used in newborns to assess the severity of encephalopathy and for determining prognosis. The duration and severity of abnormalities of the amplitude-integrated electroencephalogram tracing is highly predictive of subsequent neurologic outcome following neonatal hypoxic-ischemic encephalopathy, including in newborns receiving neuroprotective treatment with prolonged moderate hypothermia. The cerebral function monitor is also used for seizure detection and to monitor response to anticonvulsant therapies. Amplitude-integrated electroencephalography compares well with standard electroencephalography when used to assess the severity of neonatal encephalopathy, but a standard electroencephalogram is still required to provide important information about changes in frequency, and in the synchrony and distribution and other characteristics of cerebral cortical activity. The role of the amplitude-integrated electroencephalogram to identify brain injury in preterm infants remains to be determined. PMID- 25725999 TI - Characterisation of the late blight resistance in potato differential MaR9 reveals a qualitative resistance gene, R9a, residing in a cluster of Tm-2 (2) homologs on chromosome IX. AB - KEY MESSAGE: The durable late blight resistance in potato plant Ma R9 is genetically characterized. A novel R -gene is mapped. The monogenic nature and map positions of R9 are negated and rectified. Late blight of potato (Solanum tuberosum), caused by Phytophthora infestans, can effectively be managed by genetic resistance. The MaR9 differential plant provides durable resistance to a broad spectrum of late blight strains. This resistance is brought about by at least seven genes derived from S. demissum including R1, Rpi-abpt1, R3a, R3b, R4, R8 and, so far uncharacterized resistance gene(s). Here we set out to genetically characterize this additional resistance in MaR9. Three BC1 populations derived from MaR9 were identified that segregated for IPO-C resistance but that lacked R8. One BC1 population showed a continuous scale of resistance phenotypes, suggesting that multiple quantitative resistance genes were segregating. In two other BC1 populations resistance and susceptibility were segregating in a 1:1 ratio, suggesting a single qualitative resistance gene (R9a). A chromosome IX PCR marker, 184-81, fully co-segregated with R9a. The map position of R9a on the distal end of the lower arm of chromosome IX was confirmed using PCR markers GP101 and Stm1021. Successively, cluster-directed profiling (CDP) was carried out, revealing six closely linked markers. CDP(Sw)58, CDP(Sw)59 and CDP(Sw5)10 flanked the R9a gene at the distal end (5.8 cM) and, as expected, were highly homologous to Sw-5. CDP(Tm2)2 flanked R9a on the proximal side (2.9 cM). CDP(Tm2)6 and CDP(Tm2)7 fully co-segregated with resistance and had high homology to Tm-2 (2) , showing that R9a resides in a cluster of NBS-LRR genes with homology to Tm-2 (2) . Besides R9a, additional resistance of quantitative nature is found in MaR9, which remains to be genetically characterized. PMID- 25726000 TI - Chromosome engineering, mapping, and transferring of resistance to Fusarium head blight disease from Elymus tsukushiensis into wheat. AB - KEY MESSAGE: This manuscript describes the transfer and molecular cytogenetic characterization of a novel source of Fusarium head blight resistance in wheat. Fusarium head blight (FHB) caused by the fungus Fusarium graminearum Schwabe [telomorph = Gibberella zeae (Schwein. Fr.) Petch] is an important disease of bread wheat, Triticum aestivum L. (2n = 6x = 42, AABBDD) worldwide. Wheat has limited resistance to FHB controlled by many loci and new sources of resistance are urgently needed. The perennial grass Elymus tsukushiensis thrives in the warm and humid regions of China and Japan and is immune to FHB. Here, we report the transfer and mapping of a major gene Fhb6 from E. tsukushiensis to wheat. Fhb6 was mapped to the subterminal region in the short arm of chromosome 1E(ts)#1S of E. tsukushiensis. Chromosome engineering was used to replace corresponding homoeologous region of chromosome 1AS of wheat with the Fhb6 associated chromatin derived from 1E(ts)#1S of E. tsukushiensis. Fhb6 appears to be new locus for wheat as previous studies have not detected any FHB resistance QTL in this chromosome region. Plant progenies homozygous for Fhb6 had a disease severity rating of 7 % compared to 35 % for the null progenies. Fhb6 has been tagged with molecular markers for marker-assisted breeding and pyramiding of resistance loci for effective control of FHB. PMID- 25726001 TI - Ultrasonography can quantify the extent of osteochondroplasty after treatment of Cam-type femoroacetabular impingement. AB - PURPOSE: Surgical resection of femoroacetabular Cam impingement (cam-FAI) is now a generally accepted treatment, producing adequate hip score increases. Insufficient resection at the head-neck junction is the main reason for revision. The anterolateral region of the head-neck junction is visualized only suboptimally by radiography, which can be inadequate for monitoring resection results postoperatively. Our aim was to investigate the extent of Cam resection by ultrasonography (US) and determine if there is any correlation with clinical outcome. METHODS: Altogether, 40 consecutive patients (mean age 39 years) were enrolled in this prospective study following arthroscopic Cam resection. All patients underwent standardized US examination in the ventral longitudinal section at 20 degrees external rotation, neutral position, and 20 degrees internal rotation the day before arthroscopy and two days afterward. Alpha angle, anterior offset, offset ratio, and anterior femoral distance were measured on sonograms. Hip Disability and Osteoarthritis Outcome Score (HOOS) and Western Ontario and McMaster University Index of Osteoarthritis (WOMAC) were conducted the day before surgery and 6 weeks postoperatively (at the earliest). RESULTS: Alpha angle was significantly smaller on postoperative US in all hip joint positions. At 20 degrees internal rotation, the alpha angle decreased from 65.6 to 36.9 degrees (p < 0.0001). All but two (5%) patients had alpha angles <50 degrees . Anterior offset increased significantly on US in neutral position and at 20 degrees internal rotation. HOOS and WOMAC increased significantly. No correlation was found between measurements for Cam-FAI and the scores. CONCLUSIONS: US may be a useful tool for monitoring Cam-FAI resection results postoperatively. PMID- 25726003 TI - Low immunogenicity in non-small cell lung cancer; do new developments and novel treatments have a role? AB - Approximately 1.6 million new cases of lung cancer are diagnosed annually (Jemal et al. CA: A Cancer Journal for Clinicians, 61, 69-90, 2011) and it remains the leading cause of cancer-related mortality worldwide. Despite decades of bench and clinical research to attempt to improve outcome for locally advanced, good performance status patients, the 5-year survival remains less than 15 % (Molina et al. 2008). Immune checkpoint inhibitor (ICH) therapies have shown a significant promise in preclinical and clinical trails to date in the treatment of non-small cell lung cancer (NSCLC). The idea of combining these systemic immune therapies with local ablative techniques is one that is gaining momentum. Electrochemotherapy (ECT) is a unique atraumatic local therapy that has had very promising objective response rates and a number of advantages including but not limited to its immunostimulatory effects. ECT in combination with ICHs offers a novel approach for dealing with this difficult disease process. PMID- 25726004 TI - Effect of Sodium Fluoride on the Proliferation and Gene Differential Expression in Human RPMI8226 Cells. AB - Although fluoride is known to reduce the incidence of caries, chronic excessive fluoride exposure can impair human health, even resulting in fluorosis. Now the underlying mechanisms of fluoride-induced toxicity are not fully understood. So, we conducted this study with the purpose of investigating the effect of sodium fluoride (NaF) in human RPMI8226 cells. In this experiment, human RPMI8226 cells were cultured with varied doses of fluoride (10, 20, 40, 80, 160, 320 MUM). After 48 h exposure, the change of cell viability was examined by CCK-8 assay, and also the messenger RNA (mRNA) expression of relevant genes was assessed by QRT-PCR. Compared to the control group, fluoride exposure increased the human RPMI8226 cells viability at relatively lower levels (10-160 MUM); however, when the concentration reached to 320 MUM, the cell proliferation was significantly inhibited (p < 0.05). In addition, the genes mRNA expression, including ANKRD1, CRSP6, KLF2, SBNO2, ZNF649, FANCM, PDGFA, RNF152, CDK10, and CETN2 changed in a concentration-dependent manner and increased with fluoride exposure concentration. The results suggest that overexposure to fluoride (160-320 MUM) can induce cytotoxicity and regulate relevant genes expression. Our findings provide novel insights into the mechanisms of action of fluoride-induced toxicity. PMID- 25726005 TI - Earlier induction of labour in post term pregnancies--A historical cohort study. AB - OBJECTIVE: to evaluate a change of guideline for earlier induction of labour in post term pregnancies and its possible impact on selected birth interventions and outcome of the newborn. DESIGN: a historical cohort study. SETTINGS: Department of Obstetrics at Aarhus University Hospital in Denmark. PARTICIPANTS: 18,247 women giving birth between 1 January 2009 and 12 December 2012. METHODS: to compare induction of labour in two consecutive time periods before and after implementation of a new guideline on induction of labour (42 weeks versus 41 weeks plus five days gestational age) in post term pregnancy. t-Test and chi(2) were used to calculate means of gestational age and relative risk (RR) of selected birth and newborn outcomes. Stratification by Mantel-Haenszel-analysis was used to adjust for possible confounders. Robson's classification system 'Ten Group Classification System' was used to create comparable groups within the performed analysis. FINDINGS: a difference in means of three gestational days after implementation of the new guideline on earlier induction of labour was found together with an overall unadjusted decrease in emergency caesarean section rate of 30% (RR 0.70, 95% CI; 0.54-0.91). Stratified analysis on parity showed a reduction in emergency caesarean section but only in nulliparous women (RR 0.78, 95% CI; 0.66-0.92), whereas the analysis in multiparous women showed a non statistically significant increased risk of emergency caesarean section (RR 1.39, 95% CI; 0.89-2.18). No differences were found in assisted vaginal childbirths and outcome in newborns concerning Apgar score, pH and standard base excess in women induced in 42 weeks versus 41 weeks plus five days gestational age. CONCLUSION: the findings of this study suggest that earlier induction of labour due to post term pregnancy has a positive influence, but only in nulliparous women, by lowering the risk of emergency caesarean section evidently without increasing the risk on adverse outcome in newborns. PMID- 25726006 TI - Barriers to breast-feeding in obese women: A qualitative exploration. AB - OBJECTIVE: to explore the factors that influence breast-feeding practices in obese women who had either stopped breast-feeding or were no longer exclusively breast-feeding 6-10 weeks following the birth of their babies, despite an original intention to do so for 16 weeks or longer. Specifically (i) to identify the barriers to successful breast-feeding and reasons for introducing formula and/or stopping breast-feeding, and (ii) to explore the women's views and experiences of current breast-feeding support services. DESIGN: descriptive, qualitative study comprising semi-structured face-to-face interviews. Interviews were audio recorded and transcribed. The data were analysed using thematic analysis. SETTING: participants recruited from one large maternity unit in Scotland and interviewed in their homes. PARTICIPANTS: 28 obese women at 6-10 weeks following birth. FINDINGS: three major themes emerged from the data analysis: the impact of birth complications, a lack of privacy, and a low uptake of specialist breast-feeding support. Impact of birth complications: 19 of 28 women had given birth by caesarean section and some felt this led to feeling 'out of it' post-operatively, a delay in establishing skin-to-skin contact, and in establishing breast-feeding. Lack of privacy; several women described reluctance to breast feed in front of others, difficulties in achieving privacy, in hospital, at home and in public. Low uptake of postnatal breast-feeding support; despite experiencing problems such as physical difficulties during breast-feeding or a perception of low milk supply, breast-feeding support services were underused by this sample of women. A small number of the women in this study used breast-feeding clinics and reported finding these useful. A further small number felt they benefitted from the support of a friend who was successfully breast feeding. CONCLUSION AND IMPLICATIONS FOR PRACTICE: midwives should be mindful of the presence of additional factors alongside maternal obesity, such as caesarean delivery, physical difficulties when breast-feeding, poor body image, and lack of confidence about sufficient milk supply. Scope for innovation within hospital policies with regard to both the facilitation of early skin-to-skin contact and privacy in postnatal accommodation could be explored in future research. Women should be provided with information about the provision and specific purpose of breast-feeding support groups and services and encouraged to access these services when appropriate. Future research could assess the usefulness of sustained breast-feeding support by health professionals, as well as partner involvement and formal peer support for this group of women. The education and training needs of health professionals in terms of supporting this group of women to breast feed may also usefully be explored. PMID- 25726007 TI - Domestic violence during pregnancy: Midwives' experiences. AB - OBJECTIVE: the aim of this qualitative study was to explore midwives' knowledge and clinical experience of domestic violence among pregnant women, with particular emphasis on their perceptions of their professional role. DESIGN: the data collected for this phenomenological-hermeneutical qualitative study were collected using semi-structured interviews, and analysed according to Denzin and Lincoln (2011). SETTING AND PARTICIPANTS: fifteen hospital and community midwives working in the local health district of Monza and Brianza in northern Italy were recruited between July and October 2012. FINDINGS: three main themes emerged: 'it is difficult to recognise domestic violence' because of a limited knowledge of the most common signs and symptoms of violence, a lack of training, cultural taboos, and the women's unwillingness to disclose abuse; 'we have a certain number of means of identifying violence', such as relationships with the woman, specific professional training and screening tools, which have advantages and disadvantages; 'the professionals involved' in identifying and managing family violence highlight the importance of a interdisciplinary approach. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: midwives acknowledge their crucial role in identifying and managing domestic violence but are still unprepared to do so and indicate various barriers that need to be overcome. There is a need to implement basic university education on the subject and provide specific professional training. PMID- 25726008 TI - Effects of Acute Exposure to Endosulfan (Organochlorine Pesticides) on Hematology of African Mud Catfish, Clarias gariepinus (Burchell, 1822). AB - Changes in the blood parameters of fingerlings of Clarias gariepinus were investigated after 24 and 96-h of exposures to endosulfan. 180 fingerlings of C. gariepinus [mean weight (10.5+/-1.3 g); total length (11.2+/-1.2 cm)] were exposed to five different concentrations (1.00, 2.20, 4.80, 11.00, 23.00 ug/L) of endosulfan and a control for 96 h after being acclimatized for 21 days. After 24 h of exposure, microcytic hypochromic anemia was observed and all erythrocyte profiles tested showed significant variation (p<0.05) among the treatments except thrombocyte and mean corpuscular hemoglobin concentration. Macrocytic hyperchromic anemia was noticed after 96 h of exposure and all the hematological parameters varied significantly (p<0.05) except packed cell volume and red blood cell count. The study shows that endosulfan alters the hematology of C. gariepinus fingerlings. Therefore, awareness on the hazards associated with the use of endosulfan should be intensified and sound sustainable alternatives to endosulfan should be developed. PMID- 25726009 TI - Antioxidant Responses and Nuclear Deformations in Freshwater Fish, Oreochromis niloticus, Facing Degraded Environmental Conditions. AB - Two sites of collection along river Nile, nearby metal-related factories (site2) and 7 km downstream (site3) were compared to unpolluted reference fish farm (site1). Metals concentration (Cu, Zn, Pb, Fe, Mn and Cd) in water and sediment samples showed highly significant (p < 0.01) differences among sites. According to contamination factor and pollution load index values, overall pollution was ordered as site2 > site3 > site1. Compared with Oreochromis niloticus of site1, activities of superoxide dismutase, catalase and glutathione-S-transferase as well as malondialdehyde formation were significantly (p < 0.01) increased in both liver and gills of fish collected from metal contaminated sites. This increment showed a tissue-specific pattern with higher rate of increment in liver than in gills. While reduced glutathione level was sharply decreased in site2 and site3. Micronucleus test was assessed as an environmental genotoxic endpoint in erythrocytes. Assessment of eight nuclear deformations showed gradient frequencies related to the distance from the industrial discharges. PMID- 25726010 TI - Sample Size Requirements for Discrete-Choice Experiments in Healthcare: a Practical Guide. AB - Discrete-choice experiments (DCEs) have become a commonly used instrument in health economics and patient-preference analysis, addressing a wide range of policy questions. An important question when setting up a DCE is the size of the sample needed to answer the research question of interest. Although theory exists as to the calculation of sample size requirements for stated choice data, it does not address the issue of minimum sample size requirements in terms of the statistical power of hypothesis tests on the estimated coefficients. The purpose of this paper is threefold: (1) to provide insight into whether and how researchers have dealt with sample size calculations for healthcare-related DCE studies; (2) to introduce and explain the required sample size for parameter estimates in DCEs; and (3) to provide a step-by-step guide for the calculation of the minimum sample size requirements for DCEs in health care. PMID- 25726011 TI - Focus Groups in Elderly Ophthalmologic Patients: Setting the Stage for Quantitative Preference Elicitation. AB - OBJECTIVES: Patients suffering from age-related macular degeneration (AMD) are rarely actively involved in decision-making, despite facing preference-sensitive treatment decisions. This paper presents a qualitative study to prepare quantitative preference elicitation in AMD patients. The aims of this study were (1) to gain familiarity with and learn about the special requirements of the AMD patient population for quantitative data collection; and (2) to select/refine patient-relevant treatment attributes and levels, and gain insights into preference structures. METHODS: Semi-structured focus group interviews were performed. An interview guide including preselected categories in the form of seven potentially patient-relevant treatment attributes was followed. To identify the most patient-relevant treatment attributes, a ranking exercise was performed. Deductive content analyses were done by two independent reviewers for each attribute to derive subcategories (potential levels of attributes) and depict preference trends. RESULTS: The focus group interviews included 21 patients. The interviews revealed that quantitative preference surveys in this population will have to be interviewer assisted to make the survey feasible for patients. The five most patient-relevant attributes were the effect on visual function [ranking score (RS): 139], injection frequency (RS: 101), approval status (RS: 83), side effects (RS: 79), and monitoring frequency (RS: 76). Attribute and level refinement was based on patients' statements. Preference trends and dependencies between attributes informed the quantitative instrument design. CONCLUSION: This study suggests that qualitative research is a very helpful step to prepare the design and administration of quantitative preference elicitation instruments. It especially facilitated familiarization with the target population and its preferences, and it supported attribute/level refinement. PMID- 25726013 TI - Ultrasound-guided joint injections for MR arthrography in pediatric patients: how we do it. AB - In children, MR arthrography is typically performed using fluoroscopic guidance. This article explores the role of US-guided joint injections as an alternative for MR arthrography in children, discussing its advantages and disadvantages compared to standard methods. We describe techniques for performing US-guided injection of the shoulder, elbow, hip, knee, ankle and posterior subtalar joints, highlighting pertinent anatomy, routes of access and unique considerations for this modality in children. Written descriptions, images and links to video clips are used to illustrate proper arthrographic technique. We conclude that US provides effective guidance for intra-articular injection prior to MR arthrography, with the advantages of improved visualization of internal structures, reduced radiation exposure, convenience of performing the procedure portably and ease of performance. Although this paper does not address therapeutic steroid injections, these techniques could easily be translated for such purposes. We propose US guidance as a viable alternative to fluoroscopic technique for arthrography in children. PMID- 25726014 TI - What you need to know about statistics, part II: reliability of diagnostic and screening tests. AB - The foundation for the usefulness of any diagnostic test should be that it is both reliable and accurate in its clinical diagnosis. In this article we present the second of a two-part series on validity and reliability, discussing the assessment of reliability among raters of diagnostic tests and between diagnostics tests themselves. To examine reproducibility (reliability) among raters of diagnostic tests we present the calculation of two statistical procedures: (1) the kappa coefficient statistic when presented with categorical data for the presence or absence of a clinical diagnosis and (2) the intraclass correlation coefficient (ICC) for continuously scaled data among raters. The accuracy among diagnostic tests (i.e. their interchangeability) can be evaluated by application of (1) a Bland-Altman plot procedure (with its 95% limits of agreement) and (2) the Passing-Bablok regression procedure (for the identification and evaluation of systematic and proportional differences). When deciding whether to select a diagnostic test one must evaluate its ability to provide more precise information than a gold standard test, and whether in clinical practice it would be more beneficial for patients to adopt it. PMID- 25726016 TI - Salt concentration and solar orientation in two supralittoral sandhoppers: Talitrus saltator (Montagu) and Talorchestia ugolinii Bellan Santini and Ruffo. AB - The influence of salt concentration in the seawater on solar orientation in Talitrus saltator and Talorchestia ugolinii was studied in a confined environment (transparent plexiglass bowls). Sodium and calcium concentrations strongly affect both sea-land orientation and the sun compass mechanism in T.saltator, whereas the behaviour of T. ugolinii is less influenced. The absence of Na(+) does not influence the sun compass mechanism, but causes an inversion in the mean direction of orientation in T. saltator. In T. ugolinii, there was no influence on the compass mechanism for solar orientation and no inversion in the directional choice. In the absence of Ca(2+), a photonegative tendency was observed for T saltator together with marked reduction in the capacity to go in any direction. However, the effect of Ca(2+) absence on the orientation capacity of T. saltator is reversible and the orientation capacity can be reduced in a few minutes. The different behaviour of the two species of sandhoppers is discussed. PMID- 25726017 TI - Level-tolerant duration selectivity in the auditory cortex of the velvety free tailed bat Molossus molossus. AB - It has been reported previously that in the inferior colliculus of the bat Molossus molossus, neuronal duration tuning is ambiguous because the tuning type of the neurons dramatically changes with the sound level. In the present study, duration tuning was examined in the auditory cortex of M. molossus to describe if it is as ambiguous as the collicular tuning. From a population of 174 cortical 104 (60 %) neurons did not show duration selectivity (all-pass). Around 5 % (9 units) responded preferentially to stimuli having longer durations showing long pass duration response functions, 35 (20 %) responded to a narrow range of stimulus durations showing band-pass duration response functions, 24 (14 %) responded most strongly to short stimulus durations showing short-pass duration response functions and two neurons (1 %) responded best to two different stimulus durations showing a two-peaked duration-response function. The majority of neurons showing short- (16 out of 24) and band-pass (24 out 35) selectivity displayed "O-shaped" duration response areas. In contrast to the inferior colliculus, duration tuning in the auditory cortex of M. molossus appears level tolerant. That is, the type of duration selectivity and the stimulus duration eliciting the maximum response were unaffected by changing sound level. PMID- 25726018 TI - A novel surgical management of hypopharyngeal branchial anomalies. AB - OBJECTIVE: To review our experience treating hypopharyngeal branchial anomalies utilizing an open transcervical approach that: (1) includes recurrent laryngeal nerve (RLN) monitoring and identification if needed; (2) resection of tract if present; and (3) a superiorly based sternothyroid muscle flap for closure. METHODS: A retrospective chart review was performed to identify all patients at a tertiary level children's hospital with branchial anomalies from 2005 to 2014. The clinical presentation, evaluation, treatment and outcome were analyzed for those patients with hypopharyngeal branchial anomalies. RESULTS: Forty-seven patients who underwent excision of branchial anomalies with a known origin were identified. Thirteen patients had hypopharyngeal branchial anomalies. Six of these patients were treated by the authors of this study and are the focus of this analysis. All six underwent an open transcervical procedure with a sternothyroid muscle flap closure of a piriform sinus opening over a nine year period. Definitive surgery included a microlaryngoscopy and an open transcervical approach to close a fistula between the piriform sinus and neck with recurrent laryngeal nerve monitoring or dissection. A superiorly based sternothyroid muscle flap was used to close the sinus opening. There were no recurrences, recurrent laryngeal nerve injuries or other complications from these procedures. CONCLUSIONS: This study supports complete surgical extirpation of the fistula tract using an open cervical approach, recurrent laryngeal nerve monitoring or identification, and rotational muscle flap closure to treat patients with hypopharyngeal branchial anomalies. PMID- 25726019 TI - Sense of coherence, social networks, and mental health among children with a cochlear implant. AB - OBJECTIVE: The aim of this study was to explore the personal and social resources of children with a cochlear implant from a child's perspective. METHOD: This descriptive cross-sectional study included 19 children with cochlear implants, aged 9-12 years. Data was collected, using the children's sense of coherence (CSOC) scale, the Network map, and the strengths and difficulties questionnaire (SDQ). The data was analyzed using descriptive and correlation statistics. RESULTS: Most children had a strong sense of coherence. School life was an important arena for their social network. The mental health was comparable to normal hearing children. Still, some of the children with implants had low SOC and poor mental health. High SOC and closeness of the social network, especially in school, were associated with good mental health. CONCLUSION: This study shows that Swedish school-aged children with cochlear implants as a group have access to personal and social resources as strong sense of coherence and social networks. Still, there are individual children with psychosocial problems who need support and treatment. PMID- 25726020 TI - POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) treated with autologous hematopoietic stem cell transplantation: a case report and literature review. AB - BACKGROUND: POEMS syndrome is a rare systemic pathology of paraneoplastic origin that is associated with plasma cell dyscrasia. It is characterized by the presence of sensorimotor polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes, and other systemic manifestations. The pathogenesis of the syndrome is unknown but over-production of vascular endothelial growth factor is probably responsible for most of the more characteristic symptoms. There is no standard treatment for POEMS syndrome and no randomized controlled clinical trials of treatment exist in the available literature. High-dose melphalan with autologous hematopoietic stem cell transplantation should be considered for younger patients with widespread osteosclerotic lesions, and for patients with rapidly progressive neuropathy. CASE REPORT: This is the case of a 62-year-old Caucasian man who was admitted to our center presenting pretibial edema accompanied by significant weight loss and difficulty walking. POEMS criteria were present and an immunofixation test confirmed the presence of a monoclonal plasmaproliferative disorder. After autologous hematopoietic stem cell transplantation, the monoclonal component disappeared and the patient's clinical status improved markedly. CONCLUSIONS: Autologous hematopoietic stem cell transplantation following high-dose melphalan is an effective therapy for younger patients with widespread osteosclerotic lesions in POEMS syndrome. PMID- 25726021 TI - Sport-specific trunk muscle profiles in soccer players of different skill levels. AB - INTRODUCTION: Physical fitness and trunk stability are essential factors for successful soccer competition. MATERIALS AND METHODS: We investigated the impact of soccer exposure on the trunk muscle profile of players of different skill levels. Professional and amateur soccer players were examined for trunk flexibility and maximum isometric muscle strength in the midseason period 2011. RESULTS: 24 professional soccer players who had not participated in any specific trunk muscle training programmes had significantly higher isometric trunk muscle strength in the sagittal plane (Ext: p = 0.003, Flex: p = 0.014), the frontal plane (Lat. right: p = 0.001, left: p = 0.003) and the transverse plane (Rotation right and left: p < 0.001) than 83 amateur soccer players. Professional players also had higher trunk flexibility in the sagittal plane (Flex: p = 0.001) and the transverse plane (Rotation right: p = 0.02, left: p = 0.002) than amateur players. The side of the dominant kicking leg had no influence on muscle strength and flexibility of the trunk. CONCLUSION: Trunk flexibility and stability as necessary factors for avoiding physical overstress and injuries are differently trained in player of different soccer skill levels. PMID- 25726022 TI - Functional deterioration from the premorbid period to 2 years after the first episode of psychosis in early-onset psychosis. AB - The aim of the study was to analyze changes in functional adjustment from childhood to 2 years after the first episode of psychosis (FEP) in patients with early-onset schizophrenia spectrum disorders (SSD) and affective psychoses (AFP) and a good or intermediate level of premorbid adjustment. We followed 106 adolescents (aged 12-17 years) with FEP for 2 years after recruitment. Premorbid adjustment in childhood was assessed in 98 patients with the childhood subscale of the Cannon-Spoor Premorbid Adjustment Scale (c-PAS). Global functioning was assessed 2 years after the FEP with the Children's Global Assessment Scale (c GAS) or the Global Assessment of Functioning scale (GAF), as appropriate. Functional deterioration was defined as a downward shift in the level of functional adjustment from childhood to 2 years after the FEP. In patients with good or intermediate premorbid adjustment, functional deterioration was observed in 28.2 % (26.5 % of the AFP group, 29.4 % of the SSD group). Longer duration of untreated psychosis (Beta = 0.01; P = 0.01) and higher symptom severity at the FEP, as measured with the Clinical Global Impression Scale (Beta = 1.12; P = 0.02), significantly predicted the presence of functional deterioration, accounting for 21.4 % of the variance. Irrespective of diagnosis (SSD or AFP), almost one-third of adolescents with FEP and good or intermediate premorbid adjustment showed functional deterioration from the premorbid period to 2 years after the FEP. PMID- 25726023 TI - Trends in the effectiveness of endovascular recanalization for acute stroke: is a change taking place? AB - BACKGROUND: Despite recent technical advances in endovascular recanalization, there is skepticism regarding its clinical effectiveness compared with intravenous thrombolysis for treating acute ischemic stroke. We aimed to delineate its effectiveness and safety and their change over time. METHODS: Using a prospective, multicenter stroke registry database, we identified 872 patients with ischemic stroke who underwent recanalization therapy with intravenous thrombolysis alone (IVT; n = 533) or endovascular recanalization with or without intravenous thrombolysis (EVT; n = 339) between April 2008 and January 2012. All subjects had National Institute of Health Stroke Scale score of 10 or more and arrived at the hospital within 4.5 hours of onset. Propensity score was used to address baseline imbalances between treatment groups, but balance adjustment was not performed for subgroup analyses. RESULTS: The primary outcome was modified Rankin Scale score of 0-2 at discharge. The year-by-year effectiveness and safety of EVT and IVT were compared. Before 2010, the primary outcome was not associated with the recanalization method. However, in 2011, EVT increased the odds of having a primary outcome compared with IVT (adjusted odds ratio [OR], 1.87; 95% confidence interval [CI], 1.08-3.23). In 2011, EVT was superior to IVT regarding the achievement of a favorable outcome at 3 months after stroke (OR, 1.99; 95% CI, 1.10-3.59). The odds of in-hospital mortality and 3-month mortality were not different over 4 years. CONCLUSIONS: There might have been a change in the effectiveness of endovascular recanalization compared with intravenous thrombolysis, but the results remain tentative until prospectively evaluated. PMID- 25726024 TI - BEDAM binding free energy predictions for the SAMPL4 octa-acid host challenge. AB - The binding energy distribution analysis method (BEDAM) protocol has been employed as part of the SAMPL4 blind challenge to predict the binding free energies of a set of octa-acid host-guest complexes. The resulting predictions were consistently judged as some of the most accurate predictions in this category of the SAMPL4 challenge in terms of quantitative accuracy and statistical correlation relative to the experimental values, which were not known at the time the predictions were made. The work has been conducted as part of a hands-on graduate class laboratory session. Collectively the students, aided by automated setup and analysis tools, performed the bulk of the calculations and the numerical and structural analysis. The success of the experiment confirms the reliability of the BEDAM methodology and it shows that physics-based atomistic binding free energy estimation models, when properly streamlined and automated, can be successfully employed by non-specialists. PMID- 25726025 TI - The effect of co-administration of Lawsonia inermis extract and octreotide on experimental hepatocellular carcinoma. AB - OBJECTIVES: To investigate the effect of Lawsonia inermis total methanolic extract (LIE) and octreotide (OC) on hepatocellular carcinoma (HCC) progression, depending on somatostatin receptor 2 (SSTR-2) and Alfa fetoprotein (AFP) perturbations. METHODS: Sixty albino mice, divided into five groups (12/each); all except control were injected with single diethyl nitrosamine (DENA) dose of 90 mg/kg body weight, intraperitoneally (IP). DENA group was killed at the last day of week 18. LIE group was given 200 mg/100 ml drinking water from first day of DENA injection until end of week 18. OC group received OC (0.1 mg/kg body weight, twice daily by subcutaneous injection, SC from the first day of week 17 till end of week 18. LIE + OC was given medications till the last day of week 18. Serum AFP, liver tissue SSTR-2 mRNA, its protein expression, reduced glutathione (GSH) and malondialdehyde (MDA) were analyzed. RESULTS: A significant increase in plasma AFP and hepatic mRNA, associated to liver tissue neoplastic changes, SSTR 2 expression and MDA with decreased hepatic GSH were observed in DENA group. These changes were significantly improved by LIE and/or OC. CONCLUSIONS: LIE and/or OC treatment has effective chemopreventive action due to their ability to alleviate oxidative stress, desensitizing cellular growth receptor to SST. PMID- 25726026 TI - Surgical resection of metastases to the adrenal gland: a single center experience. AB - BACKGROUND: Only limited data exist on the treatment and outcome of adrenal metastases that derive from different primary tumor entities. Due to the lack of evidence, it is difficult to determine the indication for surgical resection. METHODS: We assessed the outcome of 45 patients (28 men, 17 women) with adrenal metastases who underwent surgery (1990-2014). The median age at the time of adrenal surgery was 62 years (range 44-77 years). We were able to evaluate follow up data of 41 patients. RESULTS: Primary tumor types were liver n = 12 (hepatocellular carcinoma n = 9, cholangiocellular carcinoma n = 2, sarcoma n = 1), upper GI tract n = 5 (esophagus n = 2, stomach n = 3), lung n = 9, kidney n = 6, neuroendocrine tumors n = 3, colon n = 2, ovarial n = 2, melanoma n = 2, others n = 4. The overall median survival time was 14 months (95 % CI 8.375 19.625). The survival rates at 1, 2, 5, and 10 years were 60, 31, 21, and 11 %, respectively. There were statistically significant differences in the survival time according to the resection status (R0 vs. R1/R2) (p < 0.001) and the type of the primary tumor (p = 0.009), while the metachronous or synchronous occurrence of adrenal metastases did not affect the prognosis. CONCLUSIONS: Resection of adrenal metastases can improve the survival if patients are carefully selected, the tumor is completely resected, and the intervention is integrated into a multidisciplinary oncologic treatment strategy. PMID- 25726027 TI - Risk assessment of pesticide usage by farmers in Commewijne, Suriname, South America: a pilot study for the Alkmaar and Tamanredjo regions. AB - Limited scientific work is available on pesticide use and exposure in Suriname. Therefore, research was conducted to assess the application, safety practices (use of personal protective equipment (PPEs)), and potential risk of pesticide use by means of a face-to-face questionnaire and determination of the international estimated short-term intake (IESTI)). The amount of pesticide used was compared with the label and the in the European Union (EU) authorized dose. The majority of the farmers was male between 41 and 60 years and followed a primary education only. Less than 5 % of farmers used non-authorized pesticides. Results showed that most farmers (58 up to 100 %) apply a dose, which is within 0 100 % of the regulated dose (label and EU). Good results were obtained for the use of most PPEs. Statistical analysis did not reveal a significant difference between the different age classes, the different levels of education, and the use of PPEs. Pesticide residue analysis of four major crops showed that 22 % of the samples contained pesticides (13 % imidacloprid and 9 % chlorothalonil). The results for imidacloprid were higher than their respective maximum residue levels (MRLs) and were used for calculation of the IESTI. The highest observed IESTI value was 74.5 % of the EU acute reference dose (ARfD), giving rise to concern about pesticide usage. In Suriname, educational programs, good agricultural practices (GAP) training, sustainable agricultural practices, food monitoring studies, and legislative control mechanisms are urgently needed to protect farmer's health and the environment and to ensure food safety. PMID- 25726028 TI - Assessment of pharmacists' views on biosimilar naming conventions. AB - BACKGROUND: As the date for the introduction of biosimilars in the United States approaches, questions remain regarding the naming, coding, and approval process for these agents that will need to be carefully considered. OBJECTIVES: To (a) ascertain pharmacists' awareness of and comfort level with biosimilars and (b) determine the impact of identical or different nonproprietary names on pharmacists' confidence in substituting interchangeable biologics. METHODS: The Academy of Managed Care Pharmacy, the American Pharmacists Association, and the American Society of Health-System Pharmacists fielded a survey to their membership or a partial segment of their membership. The survey consisted of 2 sections: (1) current processes for reporting biologics being dispensed and (2) familiarity and preferences regarding biosimilars. RESULTS: A substantial majority (70.1%) of respondents reported regularly using National Drug Code numbers as the identifier for biological products dispensed to patients; however, 10.4% of respondents reported using either the nonproprietary name or the Healthcare Common Procedure Coding System code as the identifier. When presented with 3 scenarios for naming conventions of interchangeable biosimilars and asked to rate their level of confidence (1 = not confident, 5 = very confident) to substitute, 74.6% of pharmacists indicated that they would be confident or very confident in substituting an interchangeable biosimilar with the reference product if both shared the same active ingredient or nonproprietary name of the reference biologic; 25.3% of pharmacists were confident in substituting when the nonproprietary name is not shared with the biologic; and 37.3% of pharmacists expressed confidence in substituting when the biologic and biosimilar product did not share the same nonproprietary name because of a prefix or suffix. CONCLUSIONS: The imminent entry of biosimilars into the U.S. market highlights the need to carefully evaluate current processes of identification, reporting, and recording of the biological products dispensed. The results of this survey indicate that the ultimate decision on the naming convention for biosimilars may influence dispensing pharmacists, with the majority of respondents being most comfortable with biosimilars having the same nonproprietary name as the reference biologic. PMID- 25726029 TI - Patterns of medication utilization and costs associated with the use of etanercept, adalimumab, and ustekinumab in the management of moderate-to-severe psoriasis. AB - BACKGROUND: Dose escalations of biologic agents may be attempted in the management of moderate-to-severe psoriasis. This has implications for the real world cost of treatment. OBJECTIVE: To examine the utilization patterns and costs associated with the use of etanercept, adalimumab, and ustekinumab among patients with moderate-to-severe psoriasis. METHODS: This was a retrospective cross sectional study. Patients with 2 or more medical claims with a diagnosis of psoriasis (excluding psoriatic arthritis) who were enrolled in large employer sponsored health plans (including a pharmacy benefit) in the United States from January 2007 to March 2012 were identified and extracted from the MarketScan Commercial Encounters Database. Patients aged at least 18 years were required to have 2 or more pharmacy claims for etanercept, adalimumab, or ustekinumab; the index date was the first biologic fill date. Demographics and comorbidities were identified during the 1-year pre-index period, and medication utilization and costs were evaluated in the 1-year post-index period after a titration period according to the product prescribing information (2 weeks to 12 weeks). Medication utilization parameters such as dose escalation, dose reduction, persistence, switching, discontinuation, and restarts were assessed at 6, 9, and 12 months from the end of the dose titration window. RESULTS: A total of 4,309 patients were included with a mean average age of 46 years, and 55% were male. Fifty-seven percent of the patients were started on etanercept, 39% on adalimumab, and 5% on ustekinumab. Patients had substantial dose escalation rates (etanercept: 41%; adalim-umab: 37%; ustekinumab: 36%, P less than 0.05) and discontinuation rates (etanercept: 35%; adalimumab: 27%; ustekinumab: 16%, P less than 0.05) over the 12-month post-titration period. Many patients also restarted the same biologic (etanercept: 37%; adalimumab: 10%; ustekinumab: 6%, P less than 0.05) or switched to another biologic (etanercept: 15%; adalimumab: 10%; ustekinumab: 5%, P less than 0.05) over the 12-month post-titration period. The persistence rates over 12 months were 19%, 53%, and 71% for etanercept, adalimumab, and ustekinumab, respectively (P less than 0.05). Close to one-third of the patients at 6 months and 39% at 12 months postdose titration experienced a dose escalation. Approximately half of the patients who experienced a dose escalation also had a discontinuation or a dose reduction over the 12 month post-titration period. CONCLUSIONS: Over one-third of psoriasis patients experienced a dose escalation of their biologic agents, and most of the dose escalation occurred during the first 6 months. Restarting, switching, and discontinuing index biologics were also common. PMID- 25726030 TI - Increased relapse activity for multiple sclerosis natalizumab users who become nonpersistent: a retrospective study. AB - BACKGROUND: Natalizumab disease-modifying therapy for relapsing-remitting multiple sclerosis (MS) is efficacious in randomized controlled trials. Few studies have estimated the association between real-world natalizumab persistence behavior and relapse-related outcomes. OBJECTIVES: To (a) examine the impact of using natalizumab consistently (i.e., persistent) on relapse-related outcomes as compared with transitioning to inconsistent natalizumab use (i.e., nonpersistent) and (b) examine the impact of other treatment patterns on relapse-related outcomes for those who initiated natalizumab. METHODS: Using the IMS PharMetrics Plus claims database (years 2006-2012), we identified MS subjects who initiated natalizumab (no natalizumab claims in year prior) and had at least 2 years of follow-up. Persistence in annual follow-up periods was defined as no 90-day or greater gap in natalizumab therapy. Relapse was an MS-related hospitalization or outpatient visit with intravenous or oral steroid burst claim within 7 days. Analyses compared observations based on changes in natalizumab persistence and natalizumab nonpersistence status from 1 year to the next (e.g., transitioning from persistent to nonpersistent), estimating differences in mean annual relapses and mean annual relapse-related costs. RESULTS: A total of 2,407 natalizumab initiators had at least 2 years of follow-up, yielding 4,770 year-to-year natalizumab treatment patterns where each subject contributed 1, 2, or 3 year-to year treatment patterns. In the year prior, 3,187 treatment patterns were persistent; 731 (22.9%) of these transitioned to nonpersistence. The remaining 1,583 treatment patterns were nonpersistent in the year prior; 132 (8.3%) of these transitioned to persistence. Persistent to nonpersistent treatment patterns were associated with a mean relapse-rate increase of 0.23 (95% CI = 0.12, 0.35), and a mean increase in relapse-related costs of $1,346 (95% CI = $97, $2,595). Nonpersistent to persistent treatment patterns were associated with a mean relapse-rate decrease of -0.15 (95% CI = -0.32, 0.017) and a mean decrease in relapse-related costs of -$1,369 (95% CI = -$2,761, $23). CONCLUSIONS: Findings suggest that real-world persistent natalizumab users who become nonpersistent have statistically significant increases in annual relapses and relapse-related costs. Those who transition from nonpersistent to persistent have nonsignificant reductions in relapses and their associated costs. PMID- 25726031 TI - Resource utilization and costs associated with using insulin therapy within a newly diagnosed type 2 diabetes mellitus population. AB - BACKGROUND: Although oral antidiabetic medications are the mainstay for managing type 2 diabetes mellitus (T2DM), patients often require insulin therapy to achieve optimal glycemic control. Given the prevalence of insulin use among patients with T2DM, this study evaluated the economic impact of this treatment modality in patients treated in a managed care setting. OBJECTIVE: To estimate costs and resource utilization associated with using insulin therapy among patients with newly diagnosed T2DM who were initially treated with other noninsulin antidiabetic (NIAD) medications. METHODS: An observational, retrospective study design was implemented using integrated medical and pharmacy claims data. Adults with a diagnosis of T2DM from July 1, 2003, through March 31, 2008, were identified. The date of first diagnosis was deemed the index date. The 24-month period after the index date was used to assess treatment patterns. Based on the treatment patterns, the following 2 cohorts were selected: NIAD-only cohort, users who received greater than 1 NIAD class medication but never received insulin, and insulin-use cohort, NIAD users who switched to/added on insulin therapy (duration >= 60 days). Patients were matched in a 1:3 (insulin use:NIAD-only) ratio based on propensity scores and other key covariates of interest. Hypoglycemia rates, monthly costs, and resource use during the outcome assessment period were compared between cohorts. RESULTS: After matching, 1,400 patients (350 insulin users and 1,050 NIAD-only users) were included in the analysis (42% women; mean age, 56 years). After controlling for covariates, the insulin-use cohort incurred $71 per patient per month higher total T2DM-specific costs than the NIAD-only cohort ($241/month vs. $170/month, P = 0.0003). Pharmacy costs and utilization of physician visits were drivers of cost differences between cohorts. The rate of hypoglycemic events was 10.2 per 100 person-years for the insulin-use cohort versus 2.9 per 100 person-years in the NIAD-only cohort (P less than 0.0001). CONCLUSIONS: Use of insulin therapy is associated with increased hypoglycemic events, increased pharmacy and medical costs, and greater utilization of T2DM-specific health care services. PMID- 25726032 TI - Association of visit-to-visit variability of hemoglobin A1c and medication adherence. AB - BACKGROUND: Medication nonadherence is widespread, but there are few efficient means of detecting medication nonadherence at the point of care. Visit-to-visit variability in clinical biomarkers has shown inconsistent efficiency to predict medication adherence. OBJECTIVE: To examine the performance of visit-to-visit variability (VVV) of hemoglobin A1c to predict nonadherence to antidiabetic medications. METHODS: In this cross-sectional study using a clinical and administrative database, adult members of a managed care plan at a safety-net medical center from 2008 to 2012 were included if they had >= 3 noninsulin antidiabetic prescription fills within the same class and >= 3 A1c measurements between the first and last prescription fills. The independent variable was VVV of A1c (within-subject standard deviation of A1c), and the dependent variable was medication adherence (defined by medication possession ratio) determined from pharmacy claims. Unadjusted and adjusted multivariate logistic regression models were created to examine the relationship between VVV of A1c and medication nonadherence. Receiver-operating characteristic (ROC) curves assessed the performance of the adjusted model at discriminating adherence from nonadherence. RESULTS: Among 632 eligible subjects, mean A1c was 7.7% +/- 1.3%, and 83% of the sample was nonadherent to antidiabetic medications. Increasing quintiles of VVV of A1c and medication nonadherence were both associated with increased within subject mean A1c and younger subject age. The logistic regression model (adjusted for age, sex, race/ethnicity, within-subject mean A1c, number of A1c measurements, number of days between the first and last antidiabetic medication prescription fills, and rate of primary care visits during the study period) showed a nonsignificant association of VVV of A1c and medication nonadherence (OR = 1.19, 95% CI = 0.42-3.38 for the highest quintile of VVV). Adding VVV of A1c to a model including age, sex, and race only modestly improved the C-statistic of the ROC curve from 0.6786 to 0.7064. CONCLUSIONS: VVV of A1c is not a robust predictor of antidiabetic medication nonadherence. Further innovation is needed to develop novel methods of detecting nonadherence. PMID- 25726033 TI - Association between hypoglycemia and fall-related events in type 2 diabetes mellitus: analysis of a U.S. commercial database. AB - BACKGROUND: Hypoglycemia is a major barrier to achieving optimal glycemic control and managing diabetes successfully in patients with diabetes. Falls are the most significant consequences caused by hypoglycemia episodes. Both hypoglycemia and falls lead to substantial economic burden on the health care system in the United States. OBJECTIVE: To examine the association of hypoglycemia with fall-related outcomes in elderly patients with type 2 diabetes mellitus (T2DM). METHODS: Records were obtained for T2DM patients (N = 1,147,937) from January 1, 2008, to December 31, 2011. The nonhypoglycemia patients were randomly matched 1:1 by age and gender to the hypoglycemia patients. Fall-related events (composite of fall related outcomes) were defined using ICD-9-CM codes. Conditional logistic regression models were used to compare the fall-related events within 30 days, 90 days, 180 days, and 365 days between the 2 cohorts. RESULTS: A total of 21,613 hypoglycemia patients were matched with 21,613 nonhypoglycemic patients. Patients with hypoglycemia had higher fall-related events within 30 days, 90 days, 180 days, and 365 days (P less than 0.001 for all frequency differences). Conditional logistic regression analyses showed an elevated risk for fall-related events over 365 days (aOR = 1.95, 95% CI = 1.70-2.24). Subgroup analysis showed elevated risk for patients aged less than 75 years and >= 75 years. Elevated risks were also seen for individual fall-related outcomes of fractures, head injuries, long-term care placement, and hospital admissions. CONCLUSIONS: The risk of fall-related events over 365 days increased 2-fold among elderly patients with diabetes who experienced hypoglycemia. PMID- 25726034 TI - Pharmacist-coordinated multidisciplinary hospital follow-up visits improve patient outcomes. AB - BACKGROUND: The Affordable Care Act of 2010 allows for the adjustment of reimbursement to health care centers based on 30-day readmission rates. High readmission rates may be explained by multiple events at discharge, including medication errors that occur during the transition of care from inpatient to outpatient. Pharmacist involvement at discharge has been shown to improve health outcomes in patients with chronic disease; however, there is limited knowledge regarding the benefits of a clinic appointment with a pharmacist postdischarge. OBJECTIVE: To compare hospital readmission rates and interventions in a multidisciplinary team visit coordinated by a clinical pharmacist practitioner with those conducted by a physician-only team within an internal medicine hospital follow-up program. METHODS: A retrospective observational study was completed. Patients seen between May 2012 and January 2013 in 1 of the 2 hospital follow-up program models (multidisciplinary team or physician-only team) were included. RESULTS: A total of 140 patient visits were included for 124 patients. Patients seen by the multidisciplinary team had a 30-day readmission rate of 14.3% compared with 34.3% by the physician-only team (P=0.010). Interventions completed during the visits, including addressing nonadherence, initiating a new medication, and discontinuing a medication were also statistically different between the groups, with the multidisciplinary team completing these interventions more frequently. CONCLUSIONS: Hospital follow-up visits coordinated by the multidisciplinary team decreased 30-day hospital readmission rates compared with follow-up visits by a physician-only team. PMID- 25726035 TI - Comparative effects of inorganic and organic nitrogen on the growth and microcystin production of Microcystis aeruginosa. AB - Nitrogen causes the frequent occurrence of harmful algal blooms and possible microcystin production. The effects of ammonia and alanine (Ala) on the growth and microcystin production of Microcystis aeruginosa were investigated using an isotope tracer ((15)N). The results indicated that Ala was directly used by M. aeruginosa and contributed to biomass formation amounting to 2.1 * 10(7) cells mL(-1) on day 48, compared with only 6.2 * 10(6) cells mL(-1) from ammonia alone. Microcystin-LR production with Ala was less than that of ammonia, which peaked at 50.2 fg cell(-1) on day 6. Liquid chromatographic analysis with tandem mass spectrometry of (15)N-microcystin-LR suggested that (15)N from ammonia was probably synthesized into the arginine residue. By contrast, (15)N from Ala was assimilated into the Ala, leucine, the iso-linked (2R,3S)-3-methylaspartic acid, arginine, and certain unusual C20 amino acid residues. The results represent the forward steps in the determination of the nitrogen forms that fuel toxin production and blooms. PMID- 25726036 TI - Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney. AB - BACKGROUND: Nephronophthisis 13 (NPHP 13) is associated with mutations in the WDR19 gene, which encodes for a protein in the intraflagellar transport complex. Herein, we describe six additional cases accompanied by Caroli syndrome or disease. METHODS: Targeted exome sequencing covering 96 ciliopathy-related genes was performed for 48 unrelated Korean patients with a clinical suspicion of NPHP. Mutations were confirmed by Sanger sequencing. We evaluated the expression of WDR19 in the biopsied kidney by immunohistochemistry in patients and controls. RESULTS: We detected three (3/48, 6.3 %) unrelated index cases with WDR19 mutations. One of the cases involved two siblings with the same mutation. Later, we detected an additional index case with a similar phenotype of kidney and liver involvement by Sanger sequencing of WDR19. The p.R1178Q mutation was common in all patients. All of the six affected patients from four families progressed to chronic kidney disease. Of note, all six patients had Caroli syndrome or disease. Immunohistochemistry for WDR19 showed localized expression along the luminal borders of the renal tubular epithelium in controls, whereas it showed diffuse cytoplasmic staining in the affected patients. CONCLUSIONS: Caroli disease is a major extra-renal phenotype associated with mutations in WDR19 in the Korean population. In this study, we visually validated the expression pattern of mutant WDR19 protein in the kidneys of NPHP 13 patients. More data are needed to identify the true frequency of p.R1178Q. Functional studies including transfection assay will provide solid grounds for the pathogenicity of each mutation. PMID- 25726037 TI - [Streptococcus pneumoniae: serotype distribution, antimicrobial susceptibility, risk factors and mortality in Galicia over a two year-period]. AB - INTRODUCTION: To examine the epidemiology of pneumococcal infection in Galicia (Spain) after the incorporation of the pneumococcal conjugate vaccine, and to determine serotype distribution, antibiotic susceptibility, risk factors and associated mortality in cases of invasive pneumococcal disease (IPD) during 2011 and 2012. METHODS: All strains causing IPD in Galicia were studied. Serotyping was performed by agglutination and Quellung reaction. Antibiotic sensitivity to penicillin, cefotaxime, erythromycin, vancomycin, and levofloxacin was determined. The risk factors considered were chronic respiratory disease, heart disease, liver disease, kidney disease, diabetes mellitus, and HIV and non-HIV immunodeficiency. RESULTS: A total of 555 strains were collected, with 43 different serotypes being found. The most frequently isolated ones were: serotype3 (17.5%), serotype7F (12.6%), serotype19A (9.4%), serotype14 (4.1%), serotype6C (4.1%), serotype11A (4%) and serotype22F (3.8%). 57.1% of isolates were serotypes included in VNC-13V. Two non-penicillin-sensitive strains and two others were not sensitive to cefotaxime, and 24.7% of the strains were not susceptible to erythromycin (26.9% in 2011 and 22.5% in 2012). The case fatality rate was 16.5%, reaching 23.3% in patients over 75years. Diseases with a statistically significant risk of mortality were: liver, kidney and immunodeficiency without HIV. CONCLUSIONS: Serotype3 was the most frequent in Galicia. Very few strains were not susceptible to penicillin. Erythromycin resistance decreased from 2011 to 2012. It is highlighted that mortality increases with age. Liver disease, renal disease and non-HIV immunodeficiency increases the mortality risk. PMID- 25726038 TI - The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis. AB - The diagnostic use of procalcitonin for bacterial infections remains a matter of debate. Most studies have used ambiguous outcome measures such as sepsis instead of infection. We performed a systematic review and meta-analysis to investigate the diagnostic accuracy of procalcitonin for bacteraemia, a proven bloodstream infection. We searched all major databases from inception to June 2014 for original, English language, research articles that studied the diagnostic accuracy between procalcitonin and positive blood cultures in adult patients. We calculated the area under the summary receiver-operating characteristic (SROC) curves and pooled sensitivities and specificities. To minimize potential heterogeneity we performed subgroup analyses. In total, 58 of 1567 eligible studies were included in the meta-analysis and provided a total of 16,514 patients, of whom 3420 suffered from bacteraemia. In the overall analysis the area under the SROC curve was 0.79. The optimal and most widely used procalcitonin cut-off value was 0.5 ng/mL with a corresponding sensitivity of 76% and specificity of 69%. In subgroup analyses the lowest area under the SROC curve was found in immunocompromised/neutropenic patients (0.71), the highest area under the SROC curve was found in intensive-care patients (0.88), sensitivities ranging from 66 to 89% and specificities from 55 78%. In spite of study heterogeneity, procalcitonin had a fair diagnostic accuracy for bacteraemia in adult patients suspected of infection or sepsis. In particular low procalcitonin levels can be used to rule out the presence of bacteraemia. Further research is needed on the safety and efficacy of procalcitonin as a single diagnostic tool to avoid taking blood cultures. PMID- 25726039 TI - Molecular identification of Mucorales in human tissues: contribution of PCR electrospray-ionization mass spectrometry. AB - Molecular methods are crucial for mucormycosis diagnosis because cultures are frequently negative, even if microscopy suggests the presence of hyphae in tissues. We assessed PCR/electrospray-ionization mass spectrometry (PCR/ESI-MS) for Mucorales identification in 19 unfixed tissue samples from 13 patients with proven or probable mucormycosis and compared the results with culture, quantitative real-time PCR, 16S-23S rRNA gene internal transcribed spacer region (ITS PCR) and 18S PCR sequencing. Concordance with culture identification to both genus and species levels was higher for PCR/ESI-MS than for the other techniques. Thus, PCR/ESI-MS is suitable for Mucorales identification, within 6 hours, for tissue samples for which microscopy results suggest the presence of hyphae. PMID- 25726040 TI - Characteristics of vertebral osteomyelitis after liver transplantation. AB - We performed a retrospective single-centre 1:3 case-control study to investigate the characteristics of vertebral osteomyelitis (VO) occurring in orthotopic liver transplant (OLT) recipients between 2000 and 2012. Nine cases were identified in 752 OLT recipients (1.2%), with a median time from OLT to VO of 12 weeks. In comparison with 27 VO not occurring in OLT patients (controls), VO occurring in OLT recipients was characterized by decreased levels of inflammation biomarkers (average C-reactive protein 65.1 mg.L(-1) vs. 167 mg.L(-1), p 0.02; average white blood cell count 4.8 * 10(9).L(-1) vs. 12.9 * 10(9).L(-1), p < 0.001), higher rate of fungal infections (3/9 vs. 0/27, p 0.01), lower rate of bacterial infections (3/9 vs. 25/27, p 0.001) and decreased proportion of positive blood cultures (1/9 vs. 16/27, p 0.02) despite a trend towards higher rate of multifocal infection. Microbiologic outcomes were similar between the two groups. Overall, VO in OLT patients was more difficult to diagnose as a result of altered inflammation response and specific microbial epidemiology of causal microorganisms. PMID- 25726041 TI - Enteropathogenic Escherichia coli: foe or innocent bystander? AB - Enteropathogenic Escherichia coli (EPEC) remain one the most important pathogens infecting children and they are one of the main causes of persistent diarrhoea worldwide. Historically, typical EPEC (tEPEC), defined as those isolates with the attaching and effacement (A/E) genotype (eae(+)), which possess bfpA(+) and lack the stx(-) genes are found strongly associated with diarrhoeal cases. However, occurrence of atypical EPEC (aEPEC; eae(+)bfpA(-)stx(-)) in diarrhoeal and asymptomatic hosts has made investigators question the role of these pathogens in human disease. Current epidemiological data are helping to answer the question of whether EPEC is mainly a foe or an innocent bystander during infection. PMID- 25726042 TI - Predictors and outcomes of venous thromboembolism in hospitalized lung cancer patients: A Nationwide Inpatient Sample database analysis. AB - BACKGROUND: Patients with lung cancer are at high risk of developing venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism. We sought to characterize the clinical factors associated with development of VTE and the impact of VTE on outcomes for hospitalized lung cancer patients. METHODS: We analyzed data captured in the Nationwide Inpatient Sample (NIS) database of the Agency of Healthcare Research and Quality (AHRQ). The study included all lung cancer patients hospitalized between 2006 and 2010 who had VTE captured as one of the top three discharge diagnoses. Demographics and outcomes of this population were compared to those of inpatient lung cancer patients without a VTE diagnosis. All analyses were performed using SAS version 9.3. RESULTS: Out of 570,304 lung cancer hospitalizations, 20,672 had a clinically relevant diagnosis of VTE, accounting for 3.6% of all events. The median age of lung cancer patients with VTE was 68 years; 48% were females, 79% were Caucasians, and 43% had metastatic disease. When compared to a lung cancer cohort without VTE (n=502,153), patients with VTE had significantly longer length of stay (LOS) (7.15 days vs. 6.05 days, OR 1.12), higher inpatient mortality (10.03% vs. 8.69%, OR 1.06), higher total hospital charges ($43,800 vs. $37,800, OR 1.07), and greater likelihood of moderate to severe disability upon discharge (55% vs. 49%, OR 1.23). CONCLUSIONS: VTE in hospitalized lung cancer patients is associated with longer LOS, higher inpatient mortality rates, increased cost and greater disability upon discharge compared to other inpatient lung cancer patients. PMID- 25726043 TI - Factors associated with a poor response to gefitinib in the NEJ002 study: smoking and the L858R mutation. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective response rate (ORR) than carboplatin plus paclitaxel. However, several cases showed no response. In this study, we performed further analysis of the characteristics of these non responders. METHODS: Available data from NEJ002 on maximum changes in tumour size were obtained from 103 cases (90.4%) and 110 cases (96.5%) in the carboplatin paclitaxel and gefitinib groups, respectively. Waterfall plots of maximum tumour size changes were created for non-responders. RESULTS: Five (4.9%) and 9 (8.2%) cases in the carboplatin-paclitaxel and gefitinib groups were non-responders, respectively. The mean pack years of the non-responders in the carboplatin paclitaxel and gefitinib groups were 0.33 and 31.7, respectively. The ORR of total smokers (61.5%) and heavy smokers (over 40 pack years, 52.6%) in the gefitinib group were significantly lower compared to people who have never smoked (80.0%) (P=0.044 and P=0.020, respectively). Smoker cases also showed a tendency towards lower PFS and overall survival (OS). In addition, the EGFR common mutation types did not affect PFS and OS in gefitinib-treated cases in NEJ002. However, in this study, the ORR and waterfall plots showed that gefitinib-treated non-responders who had a deletion in exon 19 in the EGFR gene exhibited a tendency towards a higher response compared to those with a L858R mutation. CONCLUSIONS: NSCLC patients with a smoking history or the EGFR L858R mutation may demonstrate a poorer response to gefitinib treatment. PMID- 25726045 TI - Shoulder arthroscopy: the basics. AB - Shoulder arthroscopy is a commonly performed and accepted procedure for a wide variety of pathologies. Surgeon experience, patient positioning, knowledge of surgical anatomy, proper portal placement, and proper use of instrumentation can improve technical success and minimize complication risks. This article details the surgical anatomy, indications, patient positioning, portal placement, instrumentation, and complications for basic shoulder arthroscopy. PMID- 25726044 TI - A nomogram to predict brain metastasis as the first relapse in curatively resected non-small cell lung cancer patients. AB - OBJECTIVES: Development of brain metastasis results in a significant reduction in overall survival. However, there is no an effective tool to predict brain metastasis in non-small cell lung cancer (NSCLC) patients. We conducted this study to develop a feasible nomogram that can predict metastasis to the brain as the first relapse site in patients with curatively resected NSCLC. MATERIAL AND METHODS: A retrospective review of NSCLC patients who had received curative surgery at National Cancer Center (Goyang, South Korea) between 2001 and 2008 was performed. We chose metastasis to the brain as the first relapse site after curative surgery as the primary endpoint of the study. A nomogram was modeled using logistic regression. RESULTS: Among 1218 patients, brain metastasis as the first relapse developed in 87 patients (7.14%) during the median follow-up of 43.6 months. Occurrence rates of brain metastasis were higher in patients with adenocarcinoma or those with a high pT and pN stage. Younger age appeared to be associated with brain metastasis, but this result was not statistically significant. The final prediction model included histology, smoking status, pT stage, and the interaction between adenocarcinoma and pN stage. The model showed fairly good discriminatory ability with a C-statistic of 69.3% and 69.8% for predicting brain metastasis within 2 years and 5 years, respectively. Internal validation using 2000 bootstrap samples resulted in C-statistics of 67.0% and 67.4% which still indicated good discriminatory performances. CONCLUSION: The nomogram presented here provides the individual risk estimate of developing metastasis to the brain as the first relapse site in patients with NSCLC who have undergone curative surgery. Surveillance programs or preventive treatment strategies for brain metastasis could be established based on this nomogram. PMID- 25726046 TI - Opportunities for the ECOG-ACRIN Cancer Research Group within the new National Clinical Trials Network. PMID- 25726047 TI - Pancreatic ductal adenocarcinoma treatment--the past, present, and future. PMID- 25726048 TI - Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. AB - Pancreatic cancer (PC) will affect 48,960 persons in the United States and will result in 40,560 deaths in 2015, according to the American Cancer Society. On a global basis, at least 337,000 persons will be diagnosed with PC. The incidence of PC has increased slightly in the United States, though worldwide cases are likely to increase substantially due to the influence of cigarette smoking, rising obesity and type II diabetes. The development of PC is related to a state of chronic inflammation and insulin resistance. Well-established environmental and personal risk factors for PC include advancing age, cigarette smoking, second hand tobacco smoke exposure, obesity, inherited familial cancer syndromes, Ashkenazi Jewish heritage, chronic pancreatitis, dietary factors, and diabetes. Other identified associations are human immunodeficiency virus infection, ABO blood group polymorphisms, hepatitis B virus, and Helicobacter pylori. PMID- 25726049 TI - Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDA) frequently presents at an advanced and incurable stage of the disease. Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting. Diagnostic workup includes serum chemistries and CA19-9, primarily to monitor disease status and response to treatment. Imaging studies are performed to assess resectability and stage disease, and pancreatic protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) are the preferred imaging studies for this purpose. Conventional staging is based on the American Joint Cancer Committee (AJCC) Staging System, 7th Edition and informs prognosis, while surgical staging systems focus specifically on assessing the likelihood of a complete (negative margins) resection with operative management. Herein, we review the presenting signs and symptoms, the diagnostic evaluation, and staging of PDA. PMID- 25726051 TI - Cross-sectional imaging and the role of positron emission tomography in pancreatic cancer evaluation. AB - Pancreatic cancer is an extraordinarily morbid malignancy with a poor prognosis. As a result, it is imperative that imaging examinations correctly identify tumors when they are relatively small and potentially still resectable, as well as accurately stage tumors to determine which patients should undergo definitive surgery. Multidetector computed tomography (MDCT) has been established as the most important modality for both initial diagnosis and staging, although positron emission tomography (PET) and magnetic resonance imaging (MRI) both play important ancillary roles. This review discusses how these three modalities play complementary roles in tumor diagnosis and staging. PMID- 25726052 TI - Endosonographic workup and preoperative biliary drainage for pancreatic cancer. AB - Computed tomography (CT) is the primary imaging modality for initial evaluation of pancreatic cancer (PC). Endoscopic ultrasound (EUS) has a higher sensitivity for detection of PC and is better especially for lesions<3 cm. It should be the next step if the CT scan is indeterminate, or negative in the presence of high suspicion of PC based on clinical and laboratory data. EUS-guided fine-needle aspiration (FNA) should be performed for lesions found on EUS after negative or indeterminate CT, for borderline resectable pancreatic cancer (BRPC) and unresectable cancer, or if the patient is being considered for neoadjuvant or palliative chemotherapy. EUS elastography and contrast-enhanced harmonic EUS are new and promising EUS technologies that may detect lesions missed by other modalities and may help guide EUS-FNA to target lesions. PMID- 25726050 TI - Pathological and molecular evaluation of pancreatic neoplasms. AB - Pancreatic neoplasms are morphologically and genetically heterogeneous and include a wide variety of tumors ranging from benign to malignant with an extremely poor clinical outcome. Our understanding of these pancreatic neoplasms has improved significantly with recent advances in cancer sequencing. Awareness of molecular pathogenesis brings new opportunities for early detection, improved prognostication, and personalized gene-specific therapies. Here we review the pathological classification of pancreatic neoplasms from the molecular and genetic perspectives. PMID- 25726053 TI - Premalignant cystic neoplasms of the pancreas. AB - Due to increasing utilization of cross-sectional imaging, asymptomatic pancreatic cysts are frequently being diagnosed. Many of these cysts have premalignant potential and offer a unique opportunity for cancer prevention. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are the major premalignant cystic neoplasms of pancreas. The prediction of the risk of malignancy (incidental and future risk of malignant transformation) and balancing the risks of watchful waiting with that of operative management with associated mortality and morbidity is the key to the management of these lesions. We review the literature that has contributed to the development of our approach to the management of these cystic neoplasms. We provide an overview of the key features used in diagnosis and in predicting malignancy. Particular attention is given to the natural history and management decision making. PMID- 25726054 TI - Neoadjuvant therapy for non-metastatic pancreatic ductal adenocarcinoma. AB - Treatment of pancreatic cancer is increasingly multimodal, with patients receiving chemotherapy, radiation, and surgical extirpation in hope of long-term cure. There is ongoing debate over the timing, sequence, and necessity of these treatments as they pertain to the spectrum of local-regional disease. Current guidelines support a neoadjuvant strategy in patients with locally advanced and borderline resectable disease. Although there is currently no high-level evidence to recommend neoadjuvant therapy for all patients, there are data to suggest that wider application of neoadjuvant therapy may be beneficial. Random-assignment prospective trials are ongoing. In this review we examine the literature addressing a neoadjuvant approach to potentially resectable, borderline resectable, and locally advanced pancreatic cancer and highlight the outcomes of preoperative emergence of latent metastatic disease, attempted resection rates, margin negative resection rates, and pathologic response to treatment. PMID- 25726055 TI - Surgical management of pancreatic cancer--pancreaticoduodenectomy. AB - Pancreaticoduodenectomy, the Whipple resection, is a complex operation that is commonly performed for patients with pancreatic ductal adenocarcinoma and other malignant or benign lesions in the head of the pancreas. It can be done with low morbidity and mortality rates, particularly when performed at high-volume hospitals and by high-volume surgeons. While it has been conventionally reserved for patients with early-stage malignant disease, it is being used increasingly for patients with locally extensive tumors who have undergone neoadjuvant therapy and downstaging. This article summarizes the role of pancreaticoduodenectomy for the treatment of patients with pancreatic cancer. It highlights the surgical staging of disease, the technical aspects of the operation and perioperative care, and the oncologic outcome. PMID- 25726056 TI - Surgical management of pancreatic cancer--distal pancreatectomy. AB - Distal pancreatectomy is the standard procedure for tumors located in the body and tail of the pancreas. In the last three decades, significant progress has been made with regard to technical aspects as well as perioperative care so that excellent mortality and morbidity rates can be achieved. Recently, there is growing evidence that distal pancreatectomy may be performed laparoscopically in selected patients, offering the advantages of minimally invasive surgery. Unfortunately, the oncologic outcomes for pancreatic adenocarcinoma remain poor, in part due to the late stage of presentation in most patients. We review the history of distal pancreatectomy, discuss current indications for performing this procedure, compare operative techniques in performing distal pancreatectomy, and review both the early complications seen in patients who have undergone a distal pancreatectomy and the long-term metabolic and oncologic outcomes of these patients. PMID- 25726057 TI - Minimally invasive pancreatic surgery. AB - Pancreatic resection is a complex procedure that involves exposure of the retroperitoneal gland, dissection around major vascular structures, and management of an intricate organ, all of which results in a procedure associated with a high morbidity. The application of minimally invasive techniques to pancreatic resection have been studied only relatively recently. This analysis of the current concepts in minimally invasive pancreatic surgery focuses on a select look at currently published series or reviews from centers and groups that have the most experience with this procedure. We aim to present a comprehensive review gained from the experiences of those who are on the leading edge of the learning curve, with an emphasis on describing the similarities and differences between the minimally invasive and open pancreatic procedure. Minimally invasive distal pancreatectomy appears to be on the verge of widespread acceptance and shows clear benefits over its open counterpart. Minimally invasive proximal (right sided) pancreatectomy, on the other hand, appears to be limited to select centers that have been able to demonstrate promising results despite its challenges. Additionally, minimally invasive central pancreatectomy and enucleation appear feasible as experience is gained in laparoscopic and robotic pancreatic resection. PMID- 25726058 TI - Adjuvant and neoadjuvant systemic therapy for pancreas adenocarcinoma. AB - The last two decades of research in the adjuvant setting of pancreas adenocarcinoma have established the value of adjuvant systemic therapy as being able to delay recurrence and increase overall survival. International standards of care in the adjuvant setting include either 6 months of gemcitabine or 5 fluorouracil and leucovorin. The added value of additional agents in the adjuvant setting is being evaluated in several large adjuvant studies. The role of a targeted agent in the adjuvant setting remains investigational. Other major areas of exploration include the integration of adjuvant immunotherapeutic approaches, which provide promise in a setting of micrometastatic disease volumes where such approaches may have greatest value. PMID- 25726059 TI - The role of radiation therapy in pancreatic ductal adenocarcinoma in the neoadjuvant and adjuvant settings. AB - Pancreatic adenocarcinoma (PCA) is associated with high rates of cancer-related morbidity and mortality. Yet despite modern treatment advances, the only curative therapy remains surgical resection. The adjuvant therapeutic standard of care for PCA in the United States includes both chemotherapy and chemoradiation; however, an optimal regimen has not been established. For patients with resectable and borderline resectable PCA, recent investigation has focused efforts on evaluating the feasibility and efficacy of neoadjuvant therapy. Neoadjuvant therapy allows for early initiation of systemic therapy and identification of patients who harbor micrometastatic disease, thus sparing patients the potential morbidities associated with unnecessary radiation or surgery. This article critically reviews the data supporting or refuting the role of radiation therapy in the neoadjuvant and adjuvant settings of PCA management, with a particular focus on determining which patients may be more likely to benefit from radiation therapy. PMID- 25726060 TI - Endoscopic and operative palliation strategies for pancreatic ductal adenocarcinoma. AB - Malignant biliary obstruction, duodenal, and gastric outlet obstruction, and tumor-related pain are the complications of unresectable pancreatic adenocarcinoma that most frequently require palliative intervention. Surgery involving biliary bypass with or without gastrojejunostomy was once the mainstay of treatment in these patients. However, advances in non-operative techniques most notably the widespread availability of endoscopic biliary and duodenal stents-have shifted the paradigm of treatment away from traditional surgical management. Questions regarding the efficacy and durability of endoscopic stents for biliary and gastric outlet obstruction are reviewed and demonstrate high rates of therapeutic success, low rates of morbidity, and decreased cost. Surgery remains an effective treatment modality, and still produces the most durable relief in appropriately selected patients. PMID- 25726061 TI - Novel targets in pancreatic cancer research. AB - The initiation and progression of pancreatic ductal adenocarcinoma (PDA) occurs as a result of molecular alterations that typically result in fluctuations of transcription, protein expression, and ultimately dysregulated signaling pathways. For example, PDA is driven by key activating, gain-of-function mutations in proto-oncogenes (eg, K-Ras) along with loss of function of tumor suppressor genes (eg, p16, SMAD4). With the advent of whole-exome sequencing of PDA genomes, several key genetic alterations have been identified as drivers of PDA. While these findings have led to groundbreaking discoveries in the etiology of PDA, they have failed to provide feasible, targetable therapeutic approaches. Additionally, recent advances in PDA research have uncovered the role of the tumor microenvironment (the non-epithelial tumor cells) in PDA progression by promoting potent, acute changes in gene expression. Herein, this chapter is aimed at discussing the key genetic and non-genetic mechanisms responsible for PDA initiation and progression. Thus based on these mechanisms, we will put forth investigated and novel therapeutic targets in PDA. PMID- 25726062 TI - Case series: five individuals diagnosed with breast and gastrointestinal cancers: are they "related"? PMID- 25726063 TI - [Surgical treatment of the primary tumor in stage IV breast cancer]. AB - INTRODUCTION: The aim of the study was to analyze the impact of loco-regional surgery on survival of patients with stage IV breast cancer. PATIENTS AND METHODS: Retrospective study that included patients with breast cancer and synchronous metastases. Patients with ECOG above 2 and high-risk patients were excluded. The following variables were evaluated: age, tumor size, nodal involvement, histological type, histological grade, hormone receptor status, HER2 overexpression, number of affected organs, location of metastases and surgical treatment. The impact of surgery and several clinical and pathologic variables on survival was analyzed by Cox regression model. RESULTS: A total of 69 patients, of whom 36 (52.2%) underwent surgery (study group) were included. After a mean follow-up of 34 months, the median survival of the series was 55 months and no significant differences between the study group and the group of patients without surgery (P=0.187) were found. Two factors associated with worse survival were identified: the number of organs with metastases (HR=1.69, IC 95%: 1.05-2.71) and triple negative breast cancer (HR=3.49, IC 95%: 1.39-8.74). Loco-regional surgery, however, was not associated with survival. CONCLUSIONS: Loco-regional surgical treatment was not associated with improved survival inpacientes with stage IV breast cancer. The number of organs with metastases and tumors were triple negative prognostic factors for survival. PMID- 25726064 TI - The indications for screening chest radiography after failed thoracic central venous catheterization. PMID- 25726065 TI - Upper extremity fractures among hospitalized pediatric road traffic accident victims. AB - BACKGROUND: Upper extremity fractures (UEFs) associated with road traffic accidents (RTAs) may result in long-term disability. Previous studies have examined UEF profiles with small patient populations. The objective of this study was to examine the injury profiles of UEFs in all mechanisms of injury related to RTAs in the pediatric population. METHODS: Data on 27 831 RTA hospitalized pediatric patients between 1997 and 2012 whose records were entered in a centralized country trauma database were reviewed. Data on UEFs related to mechanism of injury (car, motorcycle, bicycle, and pedestrian) including associated injuries, multiple UEFs, and frequency of UEF were analyzed. RESULTS: Of 27 831 pediatric RTA cases recorded in 1997-2012, 3666 (13.2%) included UEFs. Motorcycle (18%) and bicycle riders (18%) had a greater risk for UEF (P < .0001). Of 3666 patients with UEFs, 2047 (56%) had other injuries. The pedestrians (82%) and the motorcycle riders (78%) had a greater risk for associated injuries (P < .0001). Most of the injuries were head/face/neck (70%), lower extremities (36%), and chest (28%) injuries (P < .0001). Twenty-two percent of all cases had multiple UEFs. The bicycle riders (28%) had a greater risk for multiple UEFs (P < .0001). Of 3666 patients with UEFs, we found 4612 UEFs. most of the fractures in the radius (27%), humerus (25%), ulna (18%) and clavicle (17%) (P < .0001). CONCLUSIONS: This study contributes the largest database on reported pediatric UEFs related to all mechanisms of injury in RTAs and finds the comparative epidemiology of associated injuries, multiple UEFs, and frequency of UEFs. PMID- 25726066 TI - Calculation of species sensitivity values and their precision in marine benthic faunal quality indices. AB - A challenging aspect of benthic quality indices used for assessing the marine environment has been to compile reliable measures of the species' sensitivity to disturbances. Sensitivity values and their uncertainties can be calculated, but a problem to cope with is that the results may depend on the actual proportion of samples from disturbed and undisturbed environments. Here we calculated sensitivity values for each species along an artificial disturbance gradient created by bootstrapping varying numbers of samples from disturbed and undisturbed environments. The values were increasing, decreasing, or more or less constant along this gradient. The lowest value with the lowest uncertainty was adopted as the species sensitivity value. Analyses of the uncertainties indicated that the accuracy rather than the precision might be a concern. We suggest a method to exclude species for which the uncertainty is outside predefined limits as a precaution to reduce bias in the environmental status classification. PMID- 25726067 TI - Spatial distribution, sources and ecological risk assessment of polycyclic aromatic hydrocarbons in surface seawater from Yangpu Bay, China. AB - The occurrence of 14 polycyclic aromatic hydrocarbons (PAHs) listed by the United States Environmental Protection Agency was investigated in surface seawater of Yangpu Bay, China in November 2013 (winter) and May 2014 (summer). Seventy-two samples were collected from 12 sampling sites. The total concentrations of PAHs in Yangpu Bay showed obvious variations in different seasons, which varied from 582.8 to 2208.3 ng L(-1) in winter and 952.4 to 1201.7 ng L(-1) in summer, respectively. Two-ring PAHs accounted for more than 91.6% of total PAHs in winter, and three-ring PAHs were dominant with 81.6% of total PAHs in summer. Molecular indices analyses indicated that the main source of PAHs in Yangpu Bay could be petrogenic contamination. The ecological risk assessment by Risk quotients (RQNCs and RQMPCs) showed a potential ecological risk of PAHs in Yangpu Bay, indicating a close attention should be paid to pollution of PAHs in the coastal area of Yangpu. PMID- 25726068 TI - Tolerance of the VocaLogTM Vocal Monitor by Healthy Persons and Individuals With Parkinson Disease. AB - OBJECTIVE: To assess subject tolerance of extended use of the VocaLogTM vocal monitor (VM), a device marketed to log calibrated decibel sound pressure level. STUDY DESIGN: Prospective between-subjects design including two age- and sex matched groups: individuals with Parkinson disease (IWPD) and healthy persons. METHODS: After an initial session to calibrate the device and demonstrate its use, participants wore the VM during waking hours for five consecutive days. At a second visit to return the VM, participants completed a survey and a short interview regarding their experience with and perceptions of the device. RESULTS: Those with PD and control subjects reported relatively few issues with use of the VM. There were no group differences regarding convenience, others' reactions, technical issues, or future participation in similar studies. Participants with PD indicated similar frequency of discomfort issues but higher severity ratings for discomfort during VM use compared with healthy participants. CONCLUSIONS: The VocaLogTM offers a method to monitor vocal loudness during everyday activities for several consecutive days. The device was well tolerated by participants from both groups. IWPD reported greater discomfort than controls, possibly reflecting altered sensory perceptions associated with PD. The current data offer some reassurance that this VM can be tolerated by both healthy persons and those with PD for clinical and research purposes. PMID- 25726069 TI - Speech Articulation of Low-Dose Oral Contraceptive Users. AB - OBJECTIVES: In the female life cycle, hormonal fluctuations may result in impaired verbal efficiency and vocal worsening during the premenstrual phase. Oral contraceptives may interfere with vocal range. Voice, resonance, and articulation variations clarify speech content. To investigate the phonoarticulatory sounds produced by oral contraceptive users aged between 20 and 30 years. STUDY DESIGN: This is a cross-sectional study. METHODS: Our study included four groups of women (n = 66): two groups used low-dose oral contraceptives and two groups did not use any oral contraceptives. Questionnaires and sound records were used. Acoustic analysis was performed using the Computerized Speech Laboratory program, Model 4341 (Kay Elemetrics Corp, Lincoln Park, New Jersey). The statistical analysis of the SPPS database, version 13.0, was performed by means of generalized estimating equation. RESULTS: In the groups that did not use oral contraceptives, sustained vowel tones were more acute in the two phases and cycles of women older than 25 years (w/oOC1, 175 +/- 74 to 190 +/- 55 Hz; w/oOC2, 194 +/- 56 to 210 +/- 32 Hz). At the midfollicular phase (Fph) and midluteal phase (Lph) of the two cycles, the speed of the speech was slower in this group (w/oOC1: Fph, 5.3 +/- 1.6/s and Lph, 5.4 +/- 1.4/s; w/oOC2: Fph, 4.5 +/- 1.7/s and Lph, 4.8 +/- 1.1/s). In both groups that used oral contraceptives, there was a higher modulation frequency in the sentences when compared with nonusers (OC1, 33 +/- 10 Hz; w/oOC1, 28 +/- 10 Hz; OC2, 34 +/- 10 Hz; w/oOC2, 27 +/- 10 Hz). Vocal intensity was closer between the OC1 (62 +/- 4 dB), w/oOC1 (61 +/- 3 dB), and OC2 (63 +/- 4 dB) groups when compared with the w/oOC2 (67 +/- 6 dB) group. CONCLUSIONS: We demonstrated hormonal influences on speech articulation of contraceptive users and nonusers. PMID- 25726070 TI - Delivery of Intensive Voice Therapy for Vocal Fold Nodules Via Telepractice: A Pilot Feasibility and Efficacy Study. AB - OBJECTIVES: This pilot study examined voice outcomes and patient perceptions after intensive voice therapy for vocal fold nodules via telepractice. STUDY DESIGN: Pilot, within-subjects experimental trial. METHODS: Participants included 10 women diagnosed with bilateral vocal fold nodules who received intensive voice treatment via a free videoconferencing platform Skype, (Microsoft Corp., Redmond, WA). All participants completed one vocal hygiene session in person, followed by eight sessions of therapy via telepractice over 3 weeks. Before and immediately after treatment, patients attended a clinic in person to complete perceptual, stroboscopic, acoustic, and physiological assessments of vocal function. Analyses were performed by a speech-language pathologist and an otolaryngologist independent to and blinded to the study. Participants also completed the Voice Handicap Index and a telepractice satisfaction questionnaire, or an anticipated satisfaction questionnaire, before and after the treatment. RESULTS: Significant improvements were found in perceptual, vocal fold function, acoustic, and physiological parameters as well as nodule sizes and patient perceptions of voice related quality of life post-treatment. Participants were highly positive about their first experience with telepractice. Results were similar to those from a separate study investigating the effects of an intensive voice therapy delivered in conventional face-to-face (FTF) format. CONCLUSIONS: This study is consistent with possible benefits of telepractice in the delivery of intensive treatment for vocal fold nodules. Pending final verification with a FTF comparison group, telepractice could be recommended as an alternate treatment modality for patients with vocal fold nodules. PMID- 25726071 TI - Reprint of: Early and late outcomes of acute type A aortic dissection with intramural hematoma. AB - INTRODUCTION: Controversy remains regarding management of acute type A dissection with intramural hematoma (IMH). Our purpose was to analyze our experience and report outcomes after repair of acute type A aortic dissection with IMH. METHODS: We analyzed all patients from a single center who underwent open repair for acute type A aortic dissection with IMH. RESULTS: Between 2000 and 2013, we performed 418 repairs for acute type A aortic dissection. These were divided into 2 groups of patients: 64 patients (15%) with type A IMH and 354 patients (85%) with typical dissection. Those with IMH were older (62.4 +/- 13.9 years vs 56.7 +/- 14.7 years; P < .0046) and presented with reduced renal function (ie, glomerular filtration rate) (P < .0341), less frequently with distal malperfusion, and less frequently with rupture (P < .0116). With IMH, the time from presentation to repair was, by strategy, longer (median, 67 vs 6 hours; P < .0001), but no mortality occurred within 3 days of presentation. Mortality with IMH did not differ from typical dissection: 7 out of 64 patients (10.9%) versus 52 out of 354 patients (14.7%; P = .4276). A lower incidence of postoperative dialysis in the IMH group approached significance: 6 out of 63 patients (9.5%) versus 64 out of 347 patients (18.4%; P = .0820). When adjusted for age and renal function, late survival was improved with IMH (P < .0343). CONCLUSIONS: Repair of acute type A aortic dissection with IMH is associated with significant early morbidity and mortality, differing minimally from typical aortic dissection. Although expectant repair within 3 days may be applied, the purposeful delay imparted little advantage. Improved late outcomes may be seen with IMH, but continued long-term surveillance is required for verification. PMID- 25726072 TI - Reprint of: A is A. PMID- 25726073 TI - Distal aortic interventions after repair of ascending dissection: the argument for a more aggressive approach. AB - OBJECTIVE: Survivors of ascending aortic dissection repair frequently require downstream aortic interventions. Because of a paucity of data, we assessed early and long-term outcomes, and risk factors, of these distal procedures. METHODS: From January 1993 to January 2011, 305 patients underwent 429 distal aortic interventions after acute type A (95% DeBakey type I) dissection repair performed 3.8 years earlier (median); 11% of interventions used an endovascular approach. Maximum aortic size was 5.9 +/- 1.3 cm. Median follow-up was 3.6 years. RESULTS: Hospital mortality was 6.1%. Risk factors included graft infection, concomitant coronary artery bypass grafting, combined open arch and descending procedures, and lower distal anastomotic site. Within 10 years, the probability of patients undergoing a reintervention was 38%, with a cumulative incidence of 55 per 100 patients; however, 40 (9.3%) were stage-II elephant trunks. Patients with larger aortic diameters distal to the initial repair, and a stage-I elephant trunk, were more likely to undergo distal interventions. Survival was 65% at 10 years. Higher body mass index, a longer time between reinterventions, graft infection, combined open arch and descending procedures, and lower distal anastomosis sites were risk factors. The extent of aorta replaced was not associated with increased morbidity or mortality, unless it involved a combined open arch and descending aorta procedure. CONCLUSIONS: Distal interventions after ascending aortic dissection repair are feasible, but they are associated with early morbidity and subsequent reinterventions. Rigorous follow-up with early reintervention is important for improving short- and long-term outcomes. An extended hybrid endovascular repair for initial dissection warrants study. PMID- 25726074 TI - Reprint of: Renal and visceral protection in thoracoabdominal aortic surgery. AB - OBJECTIVES: Open thoracoabdominal aortic aneurysm (TAAA) repair traditionally carries substantial perioperative morbidity and mortality, primarily from distal aortic ischemia. Advances in surgical techniques, adjuncts, and strategies have greatly improved outcomes. METHODS: We analyzed outcomes of 1267 open consecutive TAAA repairs between January 2005 and September 2013. We provided cold crystalloid renal perfusion whenever the renal ostia were accessible; according to extent of repair, we selectively used left heart bypass and provided isothermic blood to the celiac axis and superior mesenteric artery. Repair was extensive (Crawford extent I and II) in 717 cases (57%). Left heart bypass was used in 645 (51%) cases, cold crystalloid renal perfusion in 987 (78%), and isothermic visceral perfusion in 318 (25%). Additional patient-specific surgical adjuncts included endarterectomy of renal or visceral vessels, open stent placement within these vessels, or use of both techniques; at least one was used in 447 repairs (35%). RESULTS: Thirty-day survival was 95% (1198/1267); overall operative mortality was 8% (104/1267). Acute renal dysfunction occurred in 155 (12%), renal failure requiring hemodialysis at hospital discharge in 84 (7%), and bowel ischemia in 9 (<1%). Extent II and III TAAA repairs carried the highest risks of postoperative renal dysfunction and renal failure requiring hemodialysis at hospital discharge. CONCLUSIONS: Contemporary protective strategies allow open TAAA repair with substantially fewer renal and visceral ischemic complications. Although bowel ischemia is uncommon, renal failure remains a concern, especially in extent II and extent III TAAA repairs. Additional studies are needed to identify and improve renal protection strategies. PMID- 25726075 TI - Surgery for congenital diseases of the aorta. AB - Congenital diseases of the aorta tend to be obstructive when they present early in life, and aneurysmal when they present later in life. The latter group also tends to be associated with connective tissue disorders and with repaired conotruncal lesions. The indications for intervention in the aneurysm group are still in evolution but are clearly age- and lesion-dependant. Disorders such as Loeys-Dietz syndrome and Turner syndrome may deserve aggressive prophylactic surgery, as well as Marfan syndrome to a lesser extent. The natural history of the dilated aorta after repair of congenital heart lesions is probably more benign than de novo aneurysms and therefore should be treated conservatively. PMID- 25726076 TI - Thoracic endovascular aortic repair versus open surgery for type-B chronic dissection. AB - An aging population, increased awareness, high-resolution imaging, and improving access to care all mean that more people are being diagnosed with acute aortic dissection. A better understanding of the role of initial medical therapy, improved surgical techniques, and the addition of endovascular approaches to the treatment algorithm, have resulted in more patients surviving the acute phase of disease. During the chronic phase, patients with residual dissection are challenged by the competing risks of reoperation or death. Open repair for chronic type-B dissection can be performed safely but is a relatively morbid operation. For this reason, surgery is often postponed until patients develop very late complications. Despite encouraging results for thoracic endovascular aortic repair of acute type-B dissection, chronic type-B dissection poses unique challenges that make application of endovascular technology more difficult. As our understanding of the disease and its natural history evolves, the ways in which these 2 methods of treatment complement each other need to be better understood. The benefits and limitations of each therapy, and how and when to apply each in the setting of chronic distal dissection, are discussed. PMID- 25726077 TI - Thoracic endovascular aortic repair for chronic distal aortic dissection: the jury is still out. PMID- 25726078 TI - Reprint of: Rationale and results of the Stanford modification of the David V reimplantation technique for valve-sparing aortic root replacement. PMID- 25726079 TI - Reprint of: Valve-sparing aortic root replacement: too many cooks? PMID- 25726080 TI - Reprint of: Reoperations on the total aortic arch in 119 patients: short- and mid term outcomes, focusing on composite adverse outcomes and survival analysis. AB - OBJECTIVES: To determine the preoperative and perioperative risk factors that significantly predict adverse outcomes after total arch replacement in patients with previous proximal aortic surgery and to analyze patient survival. METHODS: We performed univariate analysis and logistic regression on data extracted from a prospectively maintained database for 119 patients who had undergone total arch operations during a 7.5-year period. All patients had undergone previous proximal aortic surgery. The adverse outcome was defined as a single composite endpoint comprising operative mortality, permanent neurologic deficit, and renal failure necessitating permanent hemodialysis. RESULTS: The incidence of the composite endpoint was 13.5% (16 of 119 patients). The univariate predictors were preoperative pulmonary disease (P = .010), cardiac ischemia time (P = .032), and cardiopulmonary bypass (CPB) time (P = .073). On multivariate analysis, the following were predictors of the composite endpoint: preoperative pulmonary disease (P = .036), CPB time (P = .039), concomitant coronary artery bypass (P = .0057), previous aortic valve replacement (P = .027), and previous thoracoabdominal aortic aneurysm surgery (P = .057). Multivariate analysis showed that the CPB time predicted mortality (P = .0044), and previous thoracoabdominal aortic aneurysm surgery predicted stroke (P = .034). The overall survival was 85.3% during a median follow-up of 4.76 years (95% confidence interval, 4.2-5.1). CONCLUSIONS: Aortic arch reoperations, although technically demanding, can produce acceptable results. Preoperative pulmonary disease, CPB time, and concomitant coronary artery bypass predicted an adverse outcome. The CPB time predicted mortality, and previous thoracoabdominal aortic surgery predicted stroke. PMID- 25726081 TI - Investigation of possible molecular mechanisms underlying the regulation of adhesion in Vibrio alginolyticus with comparative transcriptome analysis. AB - Adhesion capability to fish mucus, which can be affected by environmental conditions, is considered to be a key virulence factor of Vibrio alginolyticus although the molecular mechanism is still unclear. In the present study, V. alginolyticus was treated with stress conditions including Cu(2+) (50 mg/L), Pb(2+) (100 mg/L), Hg(2+) (50 mg/L) and low pH (pH 5). We found these stress treatments were capable of reducing the adhesion of V. alginolyticus, while the expression levels of multiple genes were significantly changed according to the results of high throughput sequencing. The expression of randomly selected genes was confirmed by QPCR, which reinforced the reliability of the sequencing data. Ontology assignments and KEGG pathway analysis indicated that stress treatments affect pathways that may be related to adhesion. Our results identified genes which might play a key role in the adhesion process of V. alginolyticus, which could lay a foundation for further functional analysis of these genes in the process of adhesion. As these genes were sensitive to environmental factors, this may explain why the adhesion process can be influenced by environmental factors. PMID- 25726082 TI - Transcriptional regulation of the iac locus from Acinetobacter baumannii by the phytohormone indole-3-acetic acid. AB - The iac locus is involved in indole-3-acetic acid (IAA) catabolism in Acinetobacter baumannii. Nine structural genes of iac are transcribed in the same direction, whereas iacR, which encodes a MarR-type transcriptional regulator, is transcribed in the opposite direction. The IacA protein, which is encoded by the second structural gene of the iac locus, is expressed in an IAA-dependent manner. Here, we characterized gene expression from this locus in wild type A. baumannii and in an iacR mutant; this revealed that the iacH promoter is negatively regulated by IacR. The transcriptional site of iacH was determined by using 5' rapid amplification of cDNA ends; one IacR-binding site was identified between positions -35 and +28 of the iacH promoter. Sequence analysis and an electrophoretic mobility shift assay indicated that recombinant IacR binds specifically to a sequence with dyad symmetry in the iacR-iacH overlapping promoters in the absence of IAA. In addition, a two-plasmid expression system in Escherichia coli showed that IAA probably serves as a ligand that binds to IacR and releases it from the iacH promoter, thereby allowing RNA polymerase to transcribe iac. Thus, iac is expressed in order to promote IAA degradation, whereas free IacR is required for iac repression. We conclude that IacR serves as a key regulator of IAA degradation in A. baumannii in the rhizosphere. These results provide new insights into the possible role of A. baumannii in the environment. PMID- 25726083 TI - Early mortality in acute myeloid leukemia. AB - The Southwest Oncology Group (SWOG) described the expected early mortality rate (EMR) for patients with non-M3 AML by age enrolled in clinical trials, but it is unclear how generalizable this data is. We sought to compare SWOG's reported EMR to that of the general population by utilizing the case listing session of SEER 18 matched to the accrual periods of the SWOG studies. 26,272 patients were identified within SEER compared to 968 in the SWOG cohort with mortality data. The EMR was 26.7% (7022 events) in the SEER cohort versus 12.2% (116) in the SWOG cohort. The EMR was higher in the SEER cohort in every studied age group and definition of EMR. Stepwise logistic regression analysis identified increasing age, black race (OR 1.15, CI 1.03-1.29, p<0.01), and monocytic differentiation (OR 1.55, CI 1.27-1.89, p<0.01) as predictors of higher EMR. This study demonstrates that EMR in patients with non-M3 AML is higher in the general patient population than reported in SWOG clinical trials. PMID- 25726084 TI - Overexpression of survivin via activation of ERK1/2, Akt, and NF-kappaB plays a central role in vincristine resistance in multiple myeloma cells. AB - The acquisition of anti-cancer drug resistance is a major limitation of chemotherapy for multiple myeloma (MM) and it is thus important to identify the mechanisms by which MM cells develop such drug resistance. In a previous study, we showed that multidrug resistance (MDR) involves the overexpression of MDR1 and survivin in vincristine-resistant RPMI8226/VCR cells. However, the underlying mechanism of MDR remains unclear. In this study, we investigated the mechanism of MDR in RPMI8226/VCR cells, and found that RPMI8226/VCR cells exhibit increased levels of activated ERK1/2, Akt, and NF-kappaB, while the levels of activated mTOR, p38MAPK, and JNK do not differ between RPMI8226/VCR cells and their vincristine-susceptible counterparts. In addition, the inhibition of ERK1/2, Akt, or NF-kappaB by inhibitors reversed the drug-resistance of RPMI8226/VCR cells via the suppression of survivin expression, but did not affect MDR1 expression; RNA silencing of survivin expression completely reversed vincristine resistance, while MDR1 silencing only weakly suppressed vincristine resistance in RPMI8226/VCR cells. These results indicate that enhanced survivin expression via the activation of ERK1/2, Akt, and NF-kappaB plays a critical role in vincristine resistance in RPMI8226/VCR cells. Our findings suggest that ERK1/2, Akt, and NF kappaB inhibitors are potentially useful as anti-MDR agents for the treatment of vincristine-resistant MM. PMID- 25726086 TI - Host-directed therapy: tuberculosis vaccine development. PMID- 25726085 TI - Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies. AB - BACKGROUND: Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis. METHODS: We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling. FINDINGS: We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to >=24]; log-rank p<0.0001). Furthermore, conversion status at 6 months (adjusted OR 14.07 [95% CI 10.05-19.71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4.12 [95% CI 2.25-7.54]) or who had unknown HIV infection (3.59 [1.96-6.58]), but not in those who were HIV positive (0.38 [0.12-1.18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27.3% [95% confidence limit 16.6-41.4]) and high specificity (89.8% [82.3-94.4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91.8% [85.9-95.4]), but moderate specificity (57.8% [42.5-71.6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment. INTERPRETATION: Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis. FUNDING: US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention. PMID- 25726087 TI - Sputum culture conversion as a tuberculosis biomarker: a glass half empty or half full? PMID- 25726089 TI - Graves' disease: a review of surgical indications, management, and complications in a cohort of 59 patients. AB - An analysis of 59 patients who underwent total thyroidectomy for the treatment of Graves' disease over a 6-year period was conducted in order to assess the current indications and identify any specific factors that may influence the patient's decision to opt for surgical treatment. A comparison of outcomes between the current study and a similar one from Hong Kong was also attempted. Patient preference was the most common reason for opting for surgery over radioactive iodine in both studies. Other indications for surgery, such as Graves' ophthalmopathy, patient refusal for radioactive iodine, large goitre with pressure symptoms, planning for pregnancy, young age, and intolerance to anti thyroid drugs, were also similar in the two groups. There were no statistically significant differences in laryngeal nerve palsy between the two groups. The rates of permanent hypoparathyroidism in patients in Hong Kong and in the present study were 5.4% and 5.1%, respectively. No patient in either study had recurrent Graves' disease after total thyroidectomy. Our findings confirmed that patient preference is the leading indication for surgery, implicating a continuous misconception of radioactive substances and increasing confidence in surgical outcomes. In experienced hands, the risks of recurrent laryngeal nerve injury and permanent hypoparathyroidism remain minimal. PMID- 25726090 TI - Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. AB - The aim of this systematic review was to answer the question: What are the treatments available for bisphosphonate-related osteonecrosis of the jaws (BRONJ) and their outcomes? A literature search of PubMed, Cochrane Library, and Web of Science databases was conducted in accordance with the PRISMA statement, search phrases were ('jaw osteonecrosis' OR 'bisphosphonate-related osteonecrosis' OR 'bisphosphonate osteonecrosis') AND ('treatment' OR 'outcomes'). Ninety-seven articles published between 2003 and February 2014 were reviewed. The studies reported 4879 cases of BRONJ. The mean age of the patients was 66.5 +/- 4.7 years. The male to female ratio was 1:2. The mean duration of bisphosphonate (BP) administration was 38.2 +/- 15.7 months. The quality of the publications was good, with some moderate and poor. Minimally invasive surgical treatment was the treatment most used. Medical treatment was also used. Adjunctive treatments included laser, growth factors, hyperbaric oxygen and ozone. The articles provided a broad range of outcome variables to assess the treatment of BRONJ and the outcomes of each treatment. Considerable heterogeneity was found regarding study design, sample size, and treatment modalities. Clinical trials with larger samples are required to provide sufficient information for each treatment modality to predict the outcomes of each treatment. PMID- 25726088 TI - Safety, immunogenicity, and efficacy of the candidate tuberculosis vaccine MVA85A in healthy adults infected with HIV-1: a randomised, placebo-controlled, phase 2 trial. AB - BACKGROUND: HIV-1 infection is associated with increased risk of tuberculosis and a safe and effective vaccine would assist control measures. We assessed the safety, immunogenicity, and efficacy of a candidate tuberculosis vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in adults infected with HIV-1. METHODS: We did a randomised, double-blind, placebo controlled, phase 2 trial of MVA85A in adults infected with HIV-1, at two clinical sites, in Cape Town, South Africa and Dakar, Senegal. Eligible participants were aged 18-50 years, had no evidence of active tuberculosis, and had baseline CD4 counts greater than 350 cells per MUL if they had never received antiretroviral therapy or greater than 300 cells per MUL (and with undetectable viral load before randomisation) if they were receiving antiretroviral therapy; participants with latent tuberculosis infection were eligible if they had completed at least 5 months of isoniazid preventive therapy, unless they had completed treatment for tuberculosis disease within 3 years before randomisation. Participants were randomly assigned (1:1) in blocks of four by randomly generated sequence to receive two intradermal injections of either MVA85A or placebo. Randomisation was stratified by antiretroviral therapy status and study site. Participants, nurses, investigators, and laboratory staff were masked to group allocation. The second (booster) injection of MVA85A or placebo was given 6-12 months after the first vaccination. The primary study outcome was safety in all vaccinated participants (the safety analysis population). Safety was assessed throughout the trial as defined in the protocol. Secondary outcomes were immunogenicity and vaccine efficacy against Mycobacterium tuberculosis infection and disease, assessed in the per-protocol population. Immunogenicity was assessed in a subset of participants at day 7 and day 28 after the first and second vaccination, and M tuberculosis infection and disease were assessed at the end of the study. The trial is registered with ClinicalTrials.gov, number NCT01151189. FINDINGS: Between Aug 4, 2011, and April 24, 2013, 650 participants were enrolled and randomly assigned; 649 were included in the safety analysis (324 in the MVA85A group and 325 in the placebo group) and 645 in the per-protocol analysis (320 and 325). 513 (71%) participants had CD4 counts greater than 300 cells per MUL and were receiving antiretroviral therapy; 136 (21%) had CD4 counts above 350 cells per MUL and had never received antiretroviral therapy. 277 (43%) had received isoniazid prophylaxis before enrolment. Solicited adverse events were more frequent in participants who received MVA85A (288 [89%]) than in those given placebo (235 [72%]). 34 serious adverse events were reported, 17 (5%) in each group. MVA85A induced a significant increase in antigen 85A-specific T-cell response, which peaked 7 days after both vaccinations and was primarily monofunctional. The number of participants with negative QuantiFERON-TB Gold In Tube findings at baseline who converted to positive by the end of the study was 38 (20%) of 186 in the MVA85A group and 40 (23%) of 173 in the placebo group, for a vaccine efficacy of 11.7% (95% CI -41.3 to 44.9). In the per-protocol population, six (2%) cases of tuberculosis disease occurred in the MVA85A group and nine (3%) occurred in the placebo group, for a vaccine efficacy of 32.8% (95% CI -111.5 to 80.3). INTERPRETATION: MVA85A was well tolerated and immunogenic in adults infected with HIV-1. However, we detected no efficacy against M tuberculosis infection or disease, although the study was underpowered to detect an effect against disease. Potential reasons for the absence of detectable efficacy in this trial include insufficient induction of a vaccine-induced immune response or the wrong type of vaccine-induced immune response, or both. FUNDING: European & Developing Countries Clinical Trials Partnership (IP.2007.32080.002), Aeras, Bill & Melinda Gates Foundation, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium. PMID- 25726091 TI - Distinct effects of anti-inflammatory and anti-thrombotic drugs on cancer characteristics at diagnosis. AB - BACKGROUND: A previous study showed that regular use of low-dose aspirin was associated with smaller tumour size and fewer metastases for colorectal and lung cancer. We aim to explain these distinct effects in terms of the anti inflammatory and anti-thrombotic properties of aspirin. METHODS: From the Swedish Cancer Register, we identified patients diagnosed with colorectal and lung cancers between 1st October 2006 and 31st December 2009; each cancer was assessed in terms of tumour size/extent (T), lymph-node (N) and metastatic (M) status. Linkage with the Swedish Prescribed Drug Register was performed to obtain information on the use of low-dose aspirin, anti-inflammatory and anti-thrombotic drugs prior to cancer diagnosis. RESULTS: We identified 14,743 individuals with colorectal cancer and 5888 with lung cancer. For low-dose aspirin users we observed a statistically significant association with smaller tumour size and fewer metastases. For both cancers, the use of non-aspirin anti-inflammatory drugs was associated with smaller tumour size in all categories T2-T4 odds ratio (OR = 0.76, 95% confidence interval (CI) 0.63-0.92 for T2 versus T1 in colorectal cancer), but not with metastatic status (OR = 0.94, 95% CI 0.84-1.06 in colorectal cancer). In contrast, anti-thrombotic drug use was associated with fewer metastases, but not with tumour categories T2 and T3. CONCLUSIONS: The results suggest that the use of anti-inflammatories is associated with tumour growth inhibition at the primary site, while the use of anti-thrombotics is associated with restriction of cancer-cell metastasising capability. These have clinical implications on the potential use of these drugs for chemoprevention or chemotherapy. PMID- 25726092 TI - Movement of Retinal Vessels to Optic Nerve Head with Intraocular Pressure Elevation in a Child. PMID- 25726093 TI - Retinal vein occlusion and the risk of stroke development: a 9-year nationwide population-based study. AB - PURPOSE: To evaluate the risk of stroke development after retinal vein occlusion (RVO). DESIGN: Nationwide, population-based 9-year longitudinal study. PARTICIPANTS: National registry data were collected from the Korean National Health Insurance Research Database, comprising 1 025 340 (~2.2%) random subjects who were selected from 46 605 433 Korean residents in 2002. METHODS: Patients diagnosed with RVO or stroke in 2002 were excluded. The RVO group was composed of patients with an initial diagnosis of central or branch RVO between January 2003 and December 2005 (n = 344 in 2003, 375 in 2004, and 312 in 2005). The comparison group was composed of randomly selected patients (5 per patient with RVO; n = 1696 in 2003, 1854 in 2004, and 1524 in 2005) who were matched to the RVO group according to age, sex, residential area, household income, and year of RVO diagnosis. Each sampled patient was tracked until 2010. Cox proportional hazard regressions were used to calculate the overall survival rate for stroke development after adjusting for potential confounders, including hypertension, diabetes mellitus, and chronic kidney disease. MAIN OUTCOME MEASURES: Retinal vein occlusion and ischemic or hemorrhagic stroke based on the International Classification of Disease codes. RESULTS: Stroke developed in 16.8% of the RVO group and in 10.7% of the comparison group. Retinal vein occlusion was associated with an increased risk of stroke development (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.24-1.76). Hypertension, diabetes mellitus, and chronic kidney disease also increased the risk of stroke development. In addition, RVO increased the risk of both ischemic stroke (HR, 1.51; 95% CI, 1.24 1.84) and hemorrhagic stroke (HR, 1.30; 95% CI, 0.83-2.05), although this result was not significant for hemorrhagic stroke. In terms of age, the effect size of the HR was largest among younger adults, aged <50 years (HR, 2.69), compared with middle-aged adults, aged 50 to 69 years (HR, 1.33), and older adults, aged >=70 years (HR, 1.46). CONCLUSIONS: Retinal vein occlusion was significantly associated with stroke development after adjusting for potential confounders. These findings are limited by uncontrolled confounding and need to be replicated by other observational studies. PMID- 25726094 TI - Food and Drug Administration tobacco regulation and product judgments. AB - BACKGROUND: The Family Smoking Prevention and Tobacco Control Act granted the Food and Drug Administration (FDA) the authority to regulate tobacco products in the U.S. However, little is known about how regulation may be related to judgments about tobacco product-related risks. PURPOSE: To understand how FDA tobacco regulation beliefs are associated with judgments about tobacco product related risks. METHODS: The Health Information National Trends Survey is a national survey of the U.S. adult population. Data used in this analysis were collected from October 2012 through January 2013 (N=3,630) by mailed questionnaire and analyzed in 2013. Weighted bivariate chi-square analyses were used to assess associations among FDA regulation belief, tobacco harm judgments, sociodemographics, and smoking status. A weighted multinomial logistic regression was conducted where FDA regulation belief was regressed on tobacco product judgments, controlling for sociodemographic variables and smoking status. RESULTS: About 41% believed that the FDA regulates tobacco products in the U.S., 23.6% reported the FDA does not, and 35.3% did not know. Chi-square analyses showed that smoking status was significantly related to harm judgments about electronic cigarettes (p<0.0001). The multinomial logistic regression revealed that uncertainty about FDA regulation was associated with tobacco product harm judgment uncertainty. CONCLUSIONS: Tobacco product harm perceptions are associated with beliefs about tobacco product regulation by the FDA. These findings suggest the need for increased public awareness and understanding of the role of tobacco product regulation in protecting public health. PMID- 25726095 TI - Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: a semi-mechanistically-based, nonlinear mixed-effect modeling. AB - Neonatal loading studies with tetrahydrobiopterin (BH4) are used to detect hyperphenylalaninemia due to BH4 deficiency by evaluating decreases in blood phenylalanine (Phe) concentrations post BH4 load. BH4 responsiveness in phenylalanine hydroxylase (PAH)-deficient patients introduced a new diagnostic aspect for this test. In older children, a broad spectrum of different levels of responsiveness has been described. The primary objective of this study was to develop a pharmacodynamic model to improve the description of individual sensitivity to BH4 in the neonatal period. Secondary objectives were to evaluate BH4 responsiveness in a large number of PAH-deficient patients from a neonatal screening program and in patients with various confirmed BH4 deficiencies from the BIODEF database. Descriptive statistics in patients with PAH deficiency with 0-24-h data available showed that 129 of 340 patients (37.9%) had a >30% decrease in Phe levels post load. Patients with dihydropteridine reductase deficiency (n = 53) could not be differentiated from BH4-responsive patients with PAH deficiency. The pharmacologic turnover model, "stimulation of loss" of Phe following BH4 load, fitted the data best. Using the model, 193 of 194 (99.5%) patients with a proven BH4 synthesis deficiency or recycling defect were classified as BH4 sensitive. Among patients with PAH deficiency, 216 of 375 (57.6%) patients showed sensitivity to BH4, albeit with a pronounced variability; PAH-deficient patients with blood Phe <1200 MUmol/L at time 0 showed higher sensitivity than patients with blood Phe levels >1200 MUmol/L. External validation showed good correlation between the present approach, using 0-24-h blood Phe data, and the published 48-h prognostic test. Pharmacodynamic modeling of Phe levels following a BH4 loading test is sufficiently powerful to detect a wide range of responsiveness, interpretable as a measure of sensitivity to BH4. However, the clinical relevance of small responses needs to be evaluated by further studies of their relationship to long-term response to BH4 treatment. PMID- 25726096 TI - Effects of slow-release urea and rumen-protected methionine and histidine on performance of dairy cows. AB - This experiment was conducted with the objective to investigate the effects of slow-release urea and rumen-protected (RP) Met and His supplementation of a metabolizable protein (MP)-deficient diet (according to NRC, 2001) on lactation performance of dairy cows. Sixty lactating Holstein cows were used in a 10-wk randomized complete block-design trial. Cows were fed a covariate diet for 2 wk and then assigned to one of the following treatments for an 8-wk experimental period: (1) MP-adequate diet [AMP; 107% of MP requirements, based on the National Research Council (NRC, 2001)]; (2) MP-deficient diet (DMP; 95% of MP requirements); (3) DMP supplemented with slow-release urea (DMPU); (4) DMPU supplemented with RPMet (DMPUM); and (5) DMPUM supplemented with RPHis (DMPUMH). Total-tract apparent digestibility of dry matter, organic matter, neutral detergent fiber, and crude protein, and urinary N and urea-N excretions were decreased by DMP, compared with AMP. Addition of slow-release urea to the DMP diet increased urinary urea-N excretion. Dry matter intake (DMI) and milk yield (on average 44.0+/-0.9kg/d) were not affected by treatments, except DMPUMH increased DMI and numerically increased milk yield, compared with DMPUM. Milk true protein concentration and yield were increased and milk fat concentration tended to be decreased by DMPUMH, compared with DMPUM. Cows gained less body weight on the DMP diet, compared with AMP. Plasma concentrations of His and Lys were not affected by treatments, whereas supplementation of RPMet increased plasma Met concentration. Plasma concentration of 3-methylhistidine was or tended to be higher for DMP compared with AMP and DMPU, respectively. Addition of RPHis to the DMPUM diet tended to increase plasma glucose and creatinine. In conclusion, feeding a 5% MP-deficient diet (according to NRC, 2001) did not decrease DMI and yields of milk and milk components, despite a reduction in nutrient digestibility. Supplementation of RPHis increased DMI and milk protein concentration and yield. These results are in line with our previous data and suggest that His may have a positive effect on voluntary feed intake and milk production and composition in high-yielding dairy cows fed MP-deficient diets. PMID- 25726097 TI - Saturated fat supplementation interacts with dietary forage neutral detergent fiber content during the immediate postpartum period in Holstein cows: Energy balance and metabolism. AB - Forty-eight multiparous cows were used in a randomized complete block design experiment with a 2*2 factorial arrangement of treatments to determine the interaction between a highly saturated free FA supplement (SFFA) and dietary forage NDF (fNDF) content on energy balance and metabolic responses in postpartum cows. Treatment diets were offered from 1 to 29 d postpartum and contained 20 or 26% fNDF and 0 or 2% SFFA (Energy Booster 100; 96.1% FA: 46.2% C18:0, and 37.0% C16:0). Overall, low fNDF versus high fNDF and 2% SFFA versus 0% SFFA increased digestible energy intake (DEI; 67.5 vs. 62.2 Mcal/d and 68.1 vs. 61.6 Mcal/d, respectively). The low fNDF diet with SFFA increased energy balance compared with the other treatments early during the treatment period, but treatment differences diminished over time. Overall, low fNDF versus high fNDF diets and 2% SFFA versus 0% SFFA improved energy balance (-13.0 vs. -16.3 Mcal/d and -12.0 vs. -17.3, respectively) decreasing efficiency of utilization of DEI for milk (milk NEL/DEI; 0.575 vs. 0.634 and 0.565 vs. 0.643). Low fNDF diets increased plasma insulin (308 vs. 137ug/mL) and glucose concentrations (50.5 vs. 45.7mg/dL) and decreased plasma nonesterified FA (606 vs. 917uEq/L) and beta-hydroxybutyrate (9.29 vs. 16.5mg/dL) concentrations and liver triglyceride content. Compared with 0% SFFA, 2% SFFA decreased plasma nonesterified FA concentration during the first week postpartum (706 vs. 943uEq/L) and tended to decrease plasma nonesterified FA overall throughout the treatment period, but did not affect liver triglyceride content. During a glucose tolerance test, 2% SFFA increased plasma insulin concentration more in the low fNDF diet (84.5 vs. 44.6uIU/mL) than in the high fNDF diet (40.4 vs. 38.0uIU/mL). After glucose infusion, 2% SFFA increased insulin area under the curve by 64% when included in the low fNDF diet, but only by 5.2% when included in the high fNDF diet. Even though 2% SFFA did not affect weekly plasma insulin concentration, it increased plasma insulin baseline concentration before the tolerance tests. Supplementation of 2% SFFA and low fNDF diets increased DEI and improved energy balance, but decreased apparent efficiency of utilization of DEI for milk production. Fat supplementation affected energy partitioning, increasing energy balance and decreasing body condition score loss, especially in the lower fNDF diet. The decrease in body condition score loss observed was likely related to an increase in plasma insulin concentration. Feeding SFFA in a low fNDF diet during the first 29 d postpartum might have primed the cows to limit fat mobilization at the expense of milk. PMID- 25726098 TI - Bovine subclinical intramammary infection caused by coagulase-negative staphylococci increases somatic cell count but has no effect on milk yield or composition. AB - The aim of this study was to evaluate the effect of subclinical intramammary infection (IMI) caused by coagulase-negative staphylococci (CNS) as a group and by specific CNS species on milk yield and composition and somatic cell count (SCC) of dairy cows. Selection of cows with IMI caused by CNS was performed by microbiological cultures of composite samples collected from 1,242 dairy cows distributed in 21 dairy herds. After selection of cows, milk yield was measured and milk samples were collected at the mammary quarter level (i.e., 1,140 mammary samples collected from 285 cows) for analysis of milk composition and SCC. In total, 108 isolates of CNS were identified at the species level by PCR-RFLP analysis. Forty-one pairs of contralateral mammary quarters, with and without IMI, were used to evaluate the effect of CNS on milk yield and composition. Mammary quarters infected with CNS had higher geometric mean SCC (306,106 cells/mL) than noninfected contralateral mammary quarters (62,807 cells/mL). Intramammary infection caused by CNS had no effect on milk yield or on contents of fat, crude protein, casein, lactose, total solids, and solids-not-fat. Staphylococcus chromogenes was the most prevalent CNS species in this study and the only species that allowed within-cow evaluation. The IMI caused by S. chromogenes increased SCC but had no effect on milk yield and composition at the quarter level. In conclusion, subclinical mastitis caused by CNS increased the SCC but had no effect on milk yield and composition of dairy cows. PMID- 25726099 TI - Effect of camelina oil or live yeasts (Saccharomyces cerevisiae) on ruminal methane production, rumen fermentation, and milk fatty acid composition in lactating cows fed grass silage diets. AB - The potential of dietary supplements of 2 live yeast strains (Saccharomyces cerevisiae) or camelina oil to lower ruminal methane (CH4) and carbon dioxide (CO2) production and the associated effects on animal performance, rumen fermentation, rumen microbial populations, nutrient metabolism, and milk fatty acid (FA) composition of cows fed grass silage-based diets were examined. Four Finnish Ayrshire cows (53+/-7 d in milk) fitted with rumen cannula were used in a 4*4 Latin square with four 42-d periods. Cows received a basal total mixed ration (control treatment) with a 50:50 forage-to-concentrate ratio [on a dry matter (DM) basis] containing grass silage, the same basal total mixed ration supplemented with 1 of 2 live yeasts, A or B, administered directly in the rumen at 10(10) cfu/d (treatments A and B), or supplements of 60g of camelina oil/kg of diet DM that replaced concentrate ingredients in the basal total mixed ration (treatment CO). Relative to the control, treatments A and B had no effects on DM intake, rumen fermentation, ruminal gas production, or apparent total-tract nutrient digestibility. In contrast, treatment CO lowered DM intake and ruminal CH4 and CO2 production, responses associated with numerical nonsignificant decreases in total-tract organic matter digestibility, but no alterations in rumen fermentation characteristics or changes in the total numbers of rumen bacteria, methanogens, protozoa, and fungi. Compared with the control, treatment CO decreased the yields of milk, milk fat, lactose, and protein. Relative to treatment B, treatment CO improved nitrogen utilization due to a lower crude protein intake. Treatment A had no influence on milk FA composition, whereas treatment B increased cis-9 10:1 and decreased 11-cyclohexyl 11:0 and 24:0 concentrations. Treatment CO decreased milk fat 8:0 to 16:0 and total saturated FA, and increased 18:0, 18:1, 18:2, conjugated linoleic acid, 18:3n-3, and trans FA concentrations. Decreases in ruminal CH4 production to treatment CO were related, at least in part to lowered DM intake, whereas treatments had no effect on ruminal CH4 emission intensity (g/kg of digestible organic matter intake or milk yield). Results indicated that live yeasts A and B had no influence on animal performance, ruminal gas production, rumen fermentation, or nutrient utilization in cows fed grass silage-based diets. Dietary supplements of camelina oil decreased ruminal CH4 and CO2 production, but also lowered the yields of milk and milk constituents due to an adverse effect on intake. PMID- 25726100 TI - Short communication: Genomic selection for hoof lesions in first-parity US Holsteins. AB - Hoof lesions contributing to lameness are crucial economic factors that hinder the profitability of dairy enterprises. Producer-recorded hoof lesions data of US Holsteins were categorized into infectious (abscess, digital and interdigital dermatitis, heel erosion, and foot rot) and noninfectious (korn, corkscrew, sole and toe ulcer, sole hemorrhage, white line separation, fissures, thin soles, and upper leg lesions) categories of hoof lesions. Pedigree- and genomic-based univariate analyses were conducted to estimate the variance components and heritability of infectious and noninfectious hoof lesions. A threshold sire model was used with fixed effects of year-seasons and random effects of herd and sire. For genomic-based analysis, a single-step procedure was conducted, incorporating H matrix to estimate genomic variance components and heritability for hoof lesions. The pedigree-based analysis produced heritability estimates of 0.11 (+/ 0.05) for infectious hoof lesions and 0.08 (+/-0.05) for noninfectious hoof lesions. The single-step genomic analysis produced heritability estimates of 0.14 (+/-0.06) for infectious hoof lesions and 0.12 (+/-0.08) for noninfectious hoof lesions. Approximated genetic correlations between hoof lesion traits and hoof type traits along with productive life and net merit were all low and ranged between -0.25 and 0.14. Sire reliabilities increased, on average, by 0.24 and 0.18 for infectious and noninfectious hoof lesions, respectively, with incorporation of genomic data. PMID- 25726102 TI - Saturated fat supplementation interacts with dietary forage neutral detergent fiber content during the immediate postpartum and carryover periods in Holstein cows: Production responses and digestibility of nutrients. AB - Forty-eight multiparous cows were used in a randomized complete block design experiment with a 2*2 factorial arrangement of treatments to determine the interaction between a highly saturated free FA supplement (SFFA) and dietary forage neutral detergent fiber (fNDF) content on production responses and nutrient digestibility of dairy cows in the postpartum period. Treatment diets were offered from 1 to 29d postpartum (postpartum period; PP) and contained 20 or 26% fNDF (50:50 corn silage:alfalfa silage and hay, dry matter basis) and 0 or 2% SFFA [Energy Booster 100 (Milk Specialties Global, Eden Prairie, MN); 96.1% FA: 46.2% C18:0 and 37.0% C16:0]. From 30 to 71d postpartum (carryover period), a common diet (~23% fNDF, 0% SFFA) was offered to all cows to evaluate carryover effects of the treatment diets early in lactation. During the PP, higher fNDF decreased dry matter intake (DMI) by 2.0 kg/d, whereas SFFA supplementation increased it by 1.4kg/d. In addition, high fNDF with 0% SFFA decreased DMI compared with the other diets and this difference increased throughout the PP. Treatments did not affect 3.5% fat-corrected milk yield during the PP but did during the carryover period when SFFA supplementation decreased 3.5% fat corrected milk yield for the low-fNDF diet (51.1 vs. 58.7kg/d), but not for the high-fNDF diet (58.5 vs. 58.0kg/d). During the PP, lower fNDF and SFFA supplementation decreased body condition score loss. A tendency for an interaction between fNDF and SFFA indicated that low fNDF with 2% SFFA decreased body condition score loss compared with the other diets (-0.49 vs. -0.89). During the PP, lower fNDF and 2% SFFA supplementation decreased feed efficiency (3.5% fat-corrected milk/DMI) by 0.30 and 0.23 units, respectively. The low-fNDF diet with 2% SFFA decreased feed efficiency compared with other diets early in the PP, but this difference decreased over time. Supplementation of SFFA in the PP favored energy partitioning to body reserves and limited DMI depression for the high-fNDF diet, which might allow higher-fNDF diets to be fed to cows in the PP. However, SFFA supplemented in the low-fNDF diet during the PP affected production negatively in the carryover period. Dietary fNDF and SFFA interacted, affecting performance in the PP with carryover effects when cows were fed a common diet in early lactation. PMID- 25726101 TI - Short communication: Glucagon-like peptide-2 and coccidiosis alter tight junction gene expression in the gastrointestinal tract of dairy calves. AB - Tight junction (TJ) proteins are integral factors involved in gut barrier function, and therapy with glucagon-like peptide-2 (GLP-2) enhances gut integrity. Our aim was to assess effects of GLP-2 treatment on mRNA expression of 8 TJ complex proteins in the intestine of dairy calves not infected or infected with Eimeria bovis at 11+/-3d of age. Mucosal epithelium from jejunum, ileum, and cecum was collected at slaughter from Holstein bull calves assigned to 4 groups: noninfected, buffer-treated (n=5); noninfected, GLP-2 treated (n=4); E. bovis infected, buffer-treated (n=5); and E. bovis-infected, GLP-2-treated (n=4). Infected calves were orally dosed with 100,000 to 200,000 sporulated E. bovis oocysts on d 0; GLP-2-treated calves received 50 ug of GLP-2/kg of body weight subcutaneously twice daily for 10d beginning on d 18; and buffer-treated calves received an equal injection volume of 0.01 M Na bicarbonate buffer. All calves were killed on d 28. The mRNA expression of coxsackie and adenovirus receptor (CXADR), claudins 1, 2, and 4 (CLDN1, CLDN2, and CLDN4), F11 receptor (F11R), junction adhesion molecule 2 (JAM2), occludin (OCLN), and tight junction protein ZO-1 (TJP1) was determined by real-time quantitative PCR. In jejunum and ileum, an interaction of E. bovis infection and GLP-2 treatment on gene expression was noted. In jejunum of noninfected calves, GLP-2 increased CXADR, CLDN2, OCLN, and TJP1 mRNA expression but had no effect on mRNA expression in infected calves. Treatment with GLP-2 also increased tight junction protein ZO-1 protein expression in jejunum of noninfected calves as determined by immunohistochemistry. In ileum, E. bovis decreased expression of JAM2, OCLN, and TJP1 in buffer-treated calves, and GLP-2 increased TJP1 expression in infected calves. In cecum, E. bovis infection reduced expression of CXADR, CLDN4, F11R, and OCLN, and GLP-2 therapy increased expression of CLDN4, F11R, OCLN, and TJP1. Results are consistent with studies in nonruminants showing decreased expression of TJ complex proteins in the intestinal tract during pathogen-induced diarrhea and increased TJ protein expression in intestinal tissues in response to GLP-2 treatment. In conclusion, E. bovis reduces gene expression of TJ proteins primarily in cecum of calves 28d postinfection, and GLP-2 increases expression of selected TJ genes in intestinal tissues. Use of GLP-2 to improve gut barrier function in ruminants during pathogen-induced diarrhea warrants additional study. PMID- 25726103 TI - Yeast product supplementation modulated humoral and mucosal immunity and uterine inflammatory signals in transition dairy cows. AB - The transition from late gestation to early lactation is characterized by substantial metabolic stress and altered immune function. The objective of this study was to assess the effects of supplementing a yeast product derived from Saccharomyces cerevisiae on immunity and uterine inflammation in transition cows. Forty multiparous Holstein cows were blocked by expected parturition date and randomly assigned within block to 1 of 4 treatments (n=10) from 21d before expected parturition to 42d postpartum. Rations were top-dressed with a product containing yeast culture plus enzymatically hydrolyzed yeast (YC-EHY; Celmanax, Vi-COR, Mason City, IA) at the rate of 0, 30, 60, or 90g/d throughout the experiment. Cows were injected subcutaneously with ovalbumin on d -21, -7, and 14 to assess their humoral response. Data were analyzed using mixed models with repeated measures over time. Concentrations of colostrum IgG were unaffected by treatments. A treatment * week interaction was observed for somatic cell linear score, reflecting a tendency for a quadratic dose effect on wk 1 (2.34, 2.85, 1.47, and 4.06+/-0.59 for 0, 30, 60, and 90g/d, respectively) and a quadratic dose effect on wk 5 (1.36, -0.15, -1.07, and 0.35+/-0.64 for 0, 30, 60, and 90g/d, respectively). Platelet count was increased by YC-EHY. Increasing YC-EHY dose linearly increased plasma anti-ovalbumin IgG levels following 3 ovalbumin challenges, suggesting that treatments enhanced humoral immunity. Increasing YC EHY dose also quadratically increased fecal IgA concentrations in early lactation, suggesting that 30 and 60g/d doses enhanced mucosal immunity. Uterine neutrophil populations were much greater in samples collected on d 7 compared with those on d 42 (32.1 vs. 7.6+/-3.5% of cells), reflecting neutrophil infiltration immediately after calving, but no treatment effect was detected. Significant day effects were detected for mRNA of IL-6, IL-8, neutrophil myeloperoxidase (MPO), and neutrophil elastase (ELANE) in the uterine samples, reflecting greater abundance of these transcripts collected on d 7 compared with d 42. A quadratic dose effect was detected for IL-6, indicating that 30 and 60g/d doses decreased uterine IL-6 mRNA. The mRNA abundance of MPO and ELANE was increased linearly by YC-EHY. Supplementation with YC-EHY enhanced measures of humoral and mucosal immunity and modulated uterine inflammatory signals and mammary gland health in transition dairy cows. PMID- 25726104 TI - Effect of microencapsulated sodium butyrate in the close-up diet on performance of dairy cows in the early lactation period. AB - Two trials were conducted to determine the effect of sodium butyrate microencapsulated within triglyceride matrix (Na-butyrate) in the close-up period on performance of dairy cows and rumen papillae development. In trial 1, 26 Holstein-Friesian cows were randomly allocated to 2 groups (13 cows/group) and fed prepartum a total mixed ration (TMR) without or with 300g of Na-butyrate/d from 30 d before expecting calving to parturition. After calving, the same lactational TMR without Na-butyrate was offered to both treatments. Dry matter intake and milk yield were monitored daily to 60 d in milk, and body condition of cows was scored on d 30, 21, and 4 before parturition and d 14, 31, and 60 after parturition. On d 15, 10, and 5 before parturition blood samples were collected from 6 cows randomly chosen from each group and analyzed for plasma beta hydroxybutyrate and nonesterified fatty acids concentrations. No differences in dry matter (DM) intake, milk yield, body condition score, or plasma beta hydroxybutyrate and nonesterified fatty acids concentrations was observed between treatments; however, in the last 5 d before parturition the cows receiving Na butyrate ate 1.7kg of DM/d more, on average, as compared with control cows. In trial 2, 12 Holstein-Friesian growing bulls (404+/-48; body weight +/- SD) were used to determine the effect of Na-butyrate inclusion in the diet on rumen papillae development. Bulls were randomly allocated to 2 groups (6 bulls/group) and fed TMR without or with 2% (on a dry matter basis) of Na-butyrate for 21 d. At the end of the study, bulls were killed and rumen fluid and rumen tissue samples from dorsal and ventral sac of the rumen were collected. No effect of Na butyrate supplementation on BW of bulls and DMI during the trial period was observed. Sodium butyrate supplementation increased total short-chain fatty acid concentration in the rumen but had no effect on rumen pH, molar proportions of short-chain fatty acids, and NH3-N concentration. In dorsal sac of the rumen, papillae length and papillae cross-section surface area were increased as a result of Na-butyrate supplementation, whereas in the ventral sac a reverse effect was observed (significant treatment * location in the rumen interaction). Both in the dorsal and ventral sac of the rumen, dietary Na-butyrate increased rumen muscle layer thickness. Altogether, results of this study suggest that Na butyrate supplementation in the close-up diet may have a potential to enhance rumen papillae growth and rumen adaptation to postpartum diet but lactation performance was not affected under conditions of the current study. PMID- 25726105 TI - Effects of day of gestation and feeding regimen in Holstein * Gyr cows: II. Maternal and fetal visceral organ mass. AB - This study investigated the influence of day of gestation (DG) and feeding regimens (FR) on maternal and fetal visceral organ mass in Holstein * Gyr cows. Forty-four pregnant multiparous Holstein * Gyr cows with an average initial body weight of 480+/-10.1 kg and an average initial age of 5+/-0.5 yr were allocated to 1 of 2 FR: ad libitum (AL; n=20) or maintenance level (ML; n=24). Maintenance level was considered to be 1.15% of body weight (dry matter basis) and met 100% of the energy requirements; AL provided 190% of the total net energy requirements. Cows were individually fed a corn silage and concentrate-based diet composed of 93% roughage and 7% concentrate (dry matter basis) as a total mixed ration twice daily. Pregnant cows were slaughtered at 4 DG: 139 (n=11), 199 (n=11), 241 (n=11), and 268 (n=11) d, which was followed by necropsy. Mass of heart, liver, and gastrointestinal tract was heavier in AL- than in ML-fed cows. Mammary gland mass was heavier in AL- than in ML-fed cows, and the heaviest mass was observed at 268 d of gestation. Feeding regimen did not influence fetal body weight in this study. The majority of the visceral organ masses were similar in fetuses from cows fed AL or ML. These data indicate that maternal feed restriction does not affect the development of most fetal organs or fetal development; however, some maternal organs are affected by the FR provided. Moreover, the negative effect on mammary gland mass caused by ML feeding will probably not affect the subsequent lactation because the crude protein concentration in the mammary gland increased with ML feeding. However, we suggest that the AL diet in pregnant dry cows should be provided with caution because the amount of fat in the mammary gland increased at 268 d of gestation. PMID- 25726106 TI - Concentration of anti-Mullerian hormone in dairy heifers is positively associated with productive herd life. AB - Reliable biomarkers predictive of productive herd life (time in herd after birth of first calf) have heretofore not been discovered in dairy cattle. However, circulating concentrations of anti-Mullerian hormone (AMH) are positively associated with number of follicles or antral follicle count (AFC), ovarian function, and fertility, and approximately 25% of cows have a relatively low AFC and low AMH concentrations. The present study tested the hypothesis that heifers with the lowest AMH concentrations have suboptimal fertility and are removed from a herd for poor reproductive performance at a greater rate, and therefore have a shorter productive herd life compared with age-matched herdmates with higher AMH. To test this hypothesis, 11- to 15-mo-old Holstein heifers (n=281) were subjected to a single measurement of AMH. All heifers not removed from the herd had the opportunity to complete 2 lactations and start their third lactation after calving. During this time, performance and health parameters for each individual were recorded daily by herd managers. Results showed that the quartile of heifers with the lowest AMH concentration also had, on average, a shorter productive herd life (by 196 d), a reduced survival rate after birth of the first calf, the lowest level of milk production (first lactation), the lowest total percentage of cows pregnant (across all lactations), the highest culling rates (first and second lactations and overall), and the highest culling rate for poor reproduction (first lactation) compared with age-matched herdmates with higher AMH. We concluded that a single determination of AMH concentration in young adult dairy heifers may be a simple diagnostic method to predict herd longevity, and AMH may be a useful phenotypic marker to improve longevity of dairy cows. PMID- 25726107 TI - Short communication: Evaluation of amino acid consumption and necessary profiles of Streptococcus thermophilus T1C2 in controlled pH batch fermentations. AB - The objective of the present study was to elucidate the relationship between amino acid consumption and necessary profiles of Streptococcus thermophilus T1C2 to guide the design of media for high-cell-density culture. The amino acid consumption and necessary patterns of S. thermophilus T1C2 were investigated in the complete chemically defined medium. For amino acid consumption profiles throughout the growth of S. thermophilus T1C2, the most abundantly consumed amino acids were Gln and Arg, which accounted for 19 and 20% of total amino acids consumed, respectively. Asparagine, Thr, Ser, Ala, Val, Met, Leu, and Lys, consumptions of which ranged from 3 to 10% of total amino acids consumed, were the second most intensively consumed amino acids. For necessary amino acid patterns, the amount of Cys, which counted for 11% of total amino acids needed, was significantly higher than the amounts required for other amino acids in growth of S. thermophilus T1C2. The necessary amounts of Asp, Asn, Glu, Gln, Arg, Ala, Met, and Tyr ranked second, ranging from 5 to 8% of total amino acids needed. Compared with necessary amounts, the consumption of Asn, Thr, Ser, Gln, Arg, Ala, Val, Leu, Lys, His, and Phe exceeded the necessary amounts for growth of S. thermophilus T1C2 remarkably. Consumption of Gly, Met, Ile, Trp, and Pro was slightly higher than the necessary amounts. Consumption of Asp, Glu, Tyr, and Cys was lower than the necessary amounts. The overall consumption of amino acids exceeded the required amount for growth of S. thermophilus T1C2 almost 2.43 times, which implied a significant nitrogen wasting. PMID- 25726108 TI - Outbreak of staphylococcal food poisoning among children and staff at a Swiss boarding school due to soft cheese made from raw milk. AB - On October 1, 2014, children and staff members at a Swiss boarding school consumed Tomme, a soft cheese produced from raw cow milk. Within the following 7h, all 14 persons who ingested the cheese fell ill, including 10 children and 4 staff members. Symptoms included abdominal pain and violent vomiting, followed by severe diarrhea and fever. We aim to present this food poisoning outbreak and characterize the causative agent. The duration of the incubation period was dependent of the age of the patient: 2.5h in children under 10 yr of age, 3.5h in older children and teenagers, and 7h in adults. The soft cheese exhibited low levels of staphylococcal enterotoxin (SE) A (>6ng of SEA/g of cheese) and high levels of staphylococcal enterotoxin D (>200ng of SED/g of cheese). Counts of 10(7) cfu of coagulase-positive staphylococci per gram of cheese were detected, with 3 different Staphylococcus aureus strains being present at levels >10(6) cfu/g. The 3 strains were characterized using spa typing and a DNA microarray. An enterotoxin-producing strain exhibiting sea and sed was identified as the source of the outbreak. The strain was assigned to spa type tbl 3555 and clonal complex 8, and it exhibited genetic criteria consistent with the characteristics of a genotype B strain. This genotype comprises bovine Staph. aureus strains exclusively associated with very high within-herd prevalence of mastitis and has been described as a major contaminant in Swiss raw milk cheese. It is therefore highly likely that the raw milk used for Tomme production was heavily contaminated with Staph. aureus and that levels further increased due to growth of the organism and physical concentration effects during the cheese-making process. Only a few staphylococcal food poisoning outbreaks involving raw milk products have been described. Still, in view of this outbreak and the possible occurrence of other foodborne pathogens in bovine milk, consumption of raw milk and soft cheese produced from raw milk constitutes a health risk, particularly when young children or other members of sensitive populations are involved. PMID- 25726109 TI - Population structure of Lactobacillus helveticus isolates from naturally fermented dairy products based on multilocus sequence typing. AB - Lactobacillus helveticus is an economically important lactic acid bacterium used in industrial dairy fermentation. In the present study, the population structure of 245 isolates of L. helveticus from different naturally fermented dairy products in China and Mongolia were investigated using an multilocus sequence typing scheme with 11 housekeeping genes. A total of 108 sequence types were detected, which formed 8 clonal complexes and 27 singletons. Results from Structure, SplitsTree, and ClonalFrame software analyses demonstrated the presence of 3 subpopulations in the L. helveticus isolates used in our study, namely koumiss, kurut-tarag, and panmictic lineages. Most L. helveticus isolates from particular ecological origins had specific population structures. PMID- 25726110 TI - Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. AB - We reported previously that microRNA (miRNA) are present in whey fractions of human breast milk, bovine milk, and rat milk. Moreover, we also confirmed that so many mRNA species are present in rat milk whey. These RNA were resistant to acidic conditions and to RNase, but were degraded by detergent. Thus, these RNA are likely packaged in membrane vesicles such as exosomes. However, functional extracellular circulating RNA in bodily fluids, such as blood miRNA, are present in various forms. In the current study, we used bovine raw milk and total RNA purified from exosomes (prepared by ultracentrifugation) and ultracentrifuged supernatants, and analyzed them using miRNA and mRNA microarrays to clarify which miRNA and mRNA species are present in exosomes, and which species exist in other forms. Microarray analyses revealed that most mRNA in milk whey were present in exosomes, whereas miRNA in milk whey were present in supernatant as well as exosomes. The RNA in exosomes might exert functional effects because of their stability. Therefore, we also investigated whether bovine milk-derived exosomes could affect human cells using THP-1 cells. Flow cytometry and fluorescent microscopy studies revealed that bovine milk exosomes were incorporated into differentiated THP-1 cells. These results suggest that bovine milk exosomes might have effects in human cells by containing RNA. PMID- 25726111 TI - Short communication: Bovine-derived proteins activate STAT3 in human skeletal muscle in vitro. AB - Bovine milk contains biologically active peptides that may modulate growth and development within humans. In this study, targeted bovine-derived proteins were evaluated for their effects on signal transducer and activator of transcription-3 (STAT3) phosphorylation in human skeletal muscle cells. Following an acute exposure, bovine-derived acidic fibroblast growth factor-1 (FGF) and leukemia inhibitory factor (LIF) activated STAT3 in differentiating myotubes. Chronic exposure to FGF and LIF during the proliferative phase reduced myoblast proliferation and elevated MyoD and creatine kinase (CKM) mRNA expression without altering apoptotic genes. In mature myotubes, neither FGF nor LIF elicited any action. Together, these data indicate that a reduction in proliferation in the presence of bovine-derived FGF or LIF may stimulate early maturation of myoblasts. PMID- 25726112 TI - Effects of day of gestation and feeding regimen in Holstein * Gyr cows: I. Apparent total-tract digestibility, nitrogen balance, and fat deposition. AB - This study investigated how feeding regimen (FR) alters apparent total-tract digestibility, performance, N balance, excretion of purine derivatives, and fat deposition in Holstein * Gyr cows at different days of gestation (DG). Forty-four pregnant multiparous Holstein * Gyr cows with an average initial body weight of 480+/-10.1 kg and an initial age of 5+/-0.5 yr old were allocated to 1 of 2 FR: ad libitum (AL; n=20) and maintenance level (ML; n=24). Maintenance level was considered to be 1.15% of body weight on a dry matter (DM) basis and met 100% of the energy requirements, whereas AL provided 190% of total net energy requirements. Data for hot and cold carcass dressing, fat deposition, average daily gain, empty body gain, and average daily gain without the gravid uterus were analyzed as a 4*2 factorial design. Intake, apparent total-tract digestibility, N balance, urinary concentration of urea, and purine derivatives data were analyzed as repeated measurements taken over the 28-d period (122, 150, 178, 206, 234, and 262 d of gestation). Cows were individually fed a corn silage concentrate based diet composed of 93% roughage and 7% concentrate (DM basis) as a total mixed ration. Pregnant cows were slaughtered on 4 different DG: 139 (n=11), 199 (n=11), 241 (n=11), and 268 d (n=11). Overall, DM intake decreased as DG increased. This decrease observed in DM intake may be associated with the reduction in ruminal volume caused by the rapid increase in fetal size during late gestation. We observed an interaction for DM and organic matter apparent total-tract digestibility between FR and DG; at 150, 178, and 206 d of gestation, ML-fed cows had greater DM and organic matter apparent total-tract digestibility values than AL-fed cows. Rib fat thickness, mesentery, and kidney, pelvic, and heart fat were greater in AL-fed than in ML-fed cows at all DG, with the exception of rib fat thickness on d 139. Ad libitum-fed cows excreted more N in their feces and urine compared with ML-fed cows. Pregnant cows that were fed at maintenance had greater digestibility during some DG, excreted less N in feces and less N and urea in urine, and deposited less fat in the body. We therefore recommend ML (1.15% of body weight with 93% of roughage) as a FR for pregnant dry cows; however, during the last month of gestation, AL seems to be the most appropriate FR to avoid loss of body weight. PMID- 25726113 TI - The function of the milk-clotting enzymes bovine and camel chymosin studied by a fluorescence resonance energy transfer assay. AB - Enzymatic coagulation of bovine milk can be divided in 2 steps: an enzymatic step, in which the Phe105-Met106 bond of the milk protein bovine kappa-casein is cleaved, and an aggregation step. The aspartic peptidases bovine and camel chymosin (EC 3.4.23.4) are typically used to catalyze the enzymatic step. The most commonly used method to study chymosin activity is the relative milk clotting activity test that measures the end point of the enzymatic and aggregation step. This method showed that camel chymosin has a 2-fold higher milk clotting activity toward bovine milk than bovine chymosin. To enable a study of the enzymatic step independent of the aggregation step, a fluorescence resonance energy transfer assay has been developed using a peptide substrate derived from the 98-108 sequence of bovine kappa-casein. This assay and Michaelis-Menten kinetics were employed to determine the enzymatic activity of camel and bovine chymosin under milk clotting-like conditions (pH 6.65, ionic strength 80 mM). The results obtained show that the catalytic efficiency of camel chymosin is 3-fold higher than bovine chymosin. The substrate affinity and catalytic activity of bovine and camel chymosin increase at lower pH (6.00 and 5.50). The glycosylation of bovine and camel chymosin did not affect binding of the fluorescence resonance energy transfer substrate, but doubly glycosylated camel chymosin seems to have slightly higher catalytic efficiency. In the characterization of the enzymes, the developed assay is easier and faster to use than the traditionally used relative milk-clotting activity test method. PMID- 25726114 TI - Effects of a high-energy diet on oocyte quality and in vitro embryo production in Bos indicus and Bos taurus cows. AB - The effects of different dietary energy levels [100 and 170% for maintenance (M) and high energy (1.7M), respectively] on metabolic, endocrine, and reproductive parameters were evaluated in nonlactating Bos indicus (Gir; n=14) and Bos taurus (Holstein; n=14) cows submitted to ultrasound-guided ovum pick-up followed by in vitro embryo production. The oocyte donor cows were housed in a tiestall system and fed twice daily (0800 and 1600 h). Twenty-one days before the beginning of the experiment, the animals were fed with a maintenance diet for adaptation followed by the experimental diets (M and 1.7M), and each cow underwent 9 ovum pick-up procedures 14 d apart. The recovered oocytes were cultured in vitro for 7 d. We measured glucose and insulin concentrations and performed glucose tolerance tests and the relative quantification of transcripts (PRDX1, HSP70.1, GLUT1, GLUT5, IGF1R, and IGF2R) from the oocytes recovered at the end of the experimental period. No interactions were observed between the effects of genetic groups and dietary energy level on the qualitative (viable oocytes, quality grade, and oocyte quality index) and quantitative (oocytes recovered) oocyte variables. There were no effects of dietary energy level on the qualitative and quantitative oocyte variables. However, Bos indicus cows had greater numbers of recovered structures, viable oocytes, and A and B oocyte grades as well as better oocyte quality index scores and lower DNA fragmentation rates compared with Bos taurus donors. In vitro embryo production (cleavage and blastocyst rates and number of embryos) was similar between diets, but the 1.7M diet reduced in vitro embryo production in Bos indicus cows after 60 d of treatment. Moreover, Bos indicus cows on the 1.7M diet showed lower transcript abundance for the HSP70.1, GLUT1, IGF1R, and IGF2R genes. All cows fed 1.7M diets had greater glucose and insulin concentrations and greater insulin resistance according to the glucose tolerance test. In conclusion, increasing dietary energy did not interfere with oocyte numbers and quality, but the 1.7M diet reduced in vitro embryo production in Bos indicus cows after 60 d of treatment. Finally, Bos indicus cows had greater oocyte quality, greater numbers of viable oocytes and greater in vitro embryo yield than Bos taurus. PMID- 25726115 TI - Pulsed electric field processing preserves the antiproliferative activity of the milk fat globule membrane on colon carcinoma cells. AB - The present work evaluated the effect of processing on the antiproliferative activities of milk fat globule membrane (MFGM) extracts. The antiproliferative activity on human adenocarcinoma HT-29 cells of untreated MFGM extracts were compared with those extracted from pasteurized cream, thermally treated cream, or cream subjected to pulsed electrical field (PEF) processing. The PEF with a 37 kV/cm field strength applied for 1,705MUs at 50 and 65 degrees C was applied to untreated cream collected from a local dairy. Heating at 50 or 65 degrees C for 3min (the passage time in the PEF chamber) was also tested to evaluate the heating effect during PEF treatments. The MFGM extracted from pasteurized cream did not show an antiproliferative activity. On the other hand, isolates from PEF treated cream showed activity similar to that of untreated samples. It was also shown that PEF induced interactions between beta-lactoglobulin and MFGM proteins at 65 degrees C, whereas the phospholipid composition remained unaltered. This work demonstrates the potential of PEF not only a means to produce a microbiologically safe product, but also as a process preserving the biofunctionality of the MFGM. PMID- 25726116 TI - Short communication: Variable number of tandem repeat polymorphisms in DGAT1 gene of buffaloes (Bubalus bubalis) is associated with milk constituents. AB - The diacylglycerol-O-transferase 1 gene is a positional and functional candidate for milk composition traits. The objective of this study was to evaluate the segregation of the variable number of tandem repeat polymorphisms in the regulatory region of diacylglycerol-O-transferase 1 gene in a water buffalo herd, and to assess the association of this mutation with milk production traits. For this purpose, 196 Murrah buffalo cows were genotyped by PCR. The association of the marker with total milk, fat, and protein yields at 305 d of lactation, milk fat and protein percentage, and somatic cell scores were evaluated by single trait analyses using a generalized mixed model. Two segregating alleles were identified in the population. The allele with 2 repeats affected fat percentage favorably. The present results suggest that this polymorphism is an interesting marker to include in the genetic evaluation of buffaloes. PMID- 25726117 TI - Changes in quality of nonaged pasta filata Mexican cheese during refrigerated vacuum storage. AB - Six batches of Oaxaca cheese (a Mexican pasta filata cheese) from 3 dairy plants were sampled and vacuum-packaged at 8 degrees C up to 24d. Counts of principal microbial groups, pH, levels of sugars, organic acids, lipolytic and proteolytic indices, and texture, color, and meltability values of cheeses were studied at d 1, 8, 16 and 24 of storage. A descriptive sensory analysis of selected taste, odor, and texture characteristics was also carried out. The main changes in the cheeses during the storage were decreases in pH, hardness, elasticity, and whiteness, and an increase in meltability. Neither lipolytic nor proteolytic activities were evident during the storage of cheeses. Storage time resulted in a gradual quality loss of unmelted cheeses. This loss of quality might be related to the decrease of hardness and the appearance off-flavors. PMID- 25726118 TI - Internal transcribed spacer sequence-based rapid molecular identification of Prototheca zopfii and Prototheca blaschkeae directly from milk of infected cows. AB - The increasing incidence of rare mastitis-causing pathogens has urged the implementation of fast and efficient diagnostic and control measures. Prototheca algae are known to be associated with diseases in humans and animals. In the latter, the most prevalent form of protothecosis is bovine mastitis with Prototheca zopfii and Prototheca blaschkeae representing the most common pathogenic species. These nonphotosynthetic and colorless green algae are ubiquitous in different environments and are widely resistant against harmful conditions and antimicrobials. Hence, the association of Prototheca with bovine mastitis represents a herd problem, requiring fast and easy identification of the infectious agent. The purpose of this study was to develop a reliable and rapid method, based on the internal transcribed spacer (ITS) sequences of ribosomal DNA, for molecular identification and discrimination between P. zopfii and P. blaschkeae in bovine mastitic milk. The complete ITS sequences of 32 Prototheca isolates showed substantial interspecies but moderate intraspecies variability facilitating the design of species-specific PCR amplification primers. The species-specific PCR was successfully applied to the identification of P. zopfii and P. blaschkeae directly from milk samples. The intraspecific ITS phylogeny was compared for each species with the geographical distribution of the respective Prototheca isolates, but no significant correlation was found. PMID- 25726119 TI - Parasites and parasite management practices of organic and conventional dairy herds in Minnesota. AB - The objective of this study was to describe the prevalence and practices used to manage internal helminth parasites and external arthropod parasites on organic and conventional dairy herds in Minnesota. All organic (ORG) dairy herds in Minnesota (n=114) and a convenience sample of conventional herds were invited to participate in the study. Thirty-five ORG herds and 28 conventional herds were visited once in summer and fall of 2012. Conventional dairy herds were split into small conventional (SC,<200 cows) and medium-sized conventional herds (MC, >=200 cows) so that SC herds were comparable in size to the ORG herds. Dairy managers were surveyed to assess their farm management practices and perceptions about parasites, hygiene scores were recorded for adult stock, and fecal samples were collected from a nominal 20 breeding-age heifers to characterize abundance of internal parasites. Nonparametric tests were used to compare fecal egg counts per gram (FEC) among farms grouped by management systems and practices. Organic farms had more designated pasture and were more likely to use rotational grazing compared with conventional farms, but the stocking densities of animals on pasture were similar among farm types. The overall FEC were very low, and only a few individual ORG heifers had FEC >500 eggs/gram. Samples from heifers on ORG farms had significantly more strongyle-type eggs than those on SC and MC farms (ORG: 6.6+/-2.1; SC: 0.5+/-0.3; MC: 0.8+/-0.7), but egg counts of other types of gastrointestinal parasites did not differ significantly among the 3 herd groups. Fly control measures were applied mainly to milking cows and preweaned calves and were used on 88.6% of ORG herds, 60.0% of SC herds, and 91.7% of MC herds. Approximately half of the producers reported having seen skin conditions suggestive of lice or tail mange in their cattle during the previous winter (ORG: 48.6%, SC: 57.1%, MC: 53.9%). Although most conventional producers reported treating these skin conditions, most organic producers stated they had not treated them. In conclusion, gastrointestinal parasite egg counts were low overall at the time of the survey, and most surveyed producers did not perceive gastrointestinal parasites to be a problem for their animals' health. Independent of the herd type, fly control was mostly targeted at the lactating herd and preweaned calves. PMID- 25726120 TI - Short communication: Effect of inhibition of fatty acid synthase on triglyceride accumulation and effect on lipid metabolism genes in goat mammary epithelial cells. AB - The role of fatty acid synthase (FASN) on de novo fatty acid synthesis has been well established. In monogastrics, unlike acetyl-coenzyme A carboxylase, FASN is primarily controlled at the transcriptional level. However, no data exist on ruminant mammary cells evaluating effects of FASN knockdown on mRNA expression of lipogenic genes. Inhibition of FASN in mammary cells by C75-mediated interference, a synthetic inhibitor of FASN activity, and short hairpin RNA mediated interference markedly reduced cellular triglyceride content at least in part by decreasing the expression of genes related to triglyceride synthesis (GPAT, AGPAT6, and DGAT2) and enhancing the expression of lipolysis-related genes (ATGL and HSL). Consistent with the markedly lower expression of genes related to lipid droplet formation and secretion (TIP47, ADFP, BTN1A1, and XDH), cellular lipid droplets also were reduced sharply after incubation with C75 or adenovirus short-hairpin-RNA. The results underscored the essential role of FASN in the overall process of milk-fat formation in goat mammary epithelial cells. PMID- 25726121 TI - Institutional food as a lever for improving health in cities: the case of New York City. AB - OBJECTIVES: To describe and examine the factors that most facilitate and impede the provision of healthy foods in a complex institutional food system. STUDY DESIGN: Comparative case study of three institutional food settings in New York City. METHODS: Document review and interviews with relevant city government staff. RESULTS: Factors that facilitate and impede the provision of healthy food vary across institutional food settings, and particularly between centralized and decentralized settings. Generally pro-health factors include centralized purchasing and the ability to work with vendors to formulate items to improve nutritional quality, though decentralized purchasing may offer more flexibility to work with vendors offering healthier food items and to respond to consumer preferences. Factors most often working against health in more centralized systems include financing constraints that are unique to particular settings. In less centralized systems, factors working against health may include both financing constraints and factors that are site-specific, relating to preparation and equipment. CONCLUSIONS: Making changes to institutional food systems that will meaningfully influence public health requires a detailed understanding of the diverse systems supporting and shaping public food provision. Ultimately, the cases in this study demonstrate that agency staff typically would like to provide healthier foods, but often feel limited by the competing objectives of affordability and consumer preference. Their ability to address these competing objectives is shaped by a combination of both forces external to the institution, like nutritional regulations, and internal forces, like an agency's structure, and motivation on the part of staff. PMID- 25726122 TI - National diabetes prevention program (DEHKO): awareness and self-reported lifestyle changes in Finnish middle-aged population. AB - OBJECTIVES: The national development programme for the prevention and care of diabetes was carried out in Finland during 2000-2010. One of the programme goals was to raise awareness of diabetes and its risk factors in the whole population through various activities, e.g. media campaigns and health fares. In addition, a targeted implementation project on the prevention of type 2 diabetes, FIN-D2D, was carried out in selected districts during 2003-2008. The aim of this analysis was to examine the changes in overall awareness of the programme and its association with self-reported lifestyle changes within the adult population during the FIN-D2D project period in the FIN-D2D area compared with the area not participating in the FIN-D2D (the control area). STUDY DESIGN: Health behaviour and health among the Finnish Adult Population -postal survey. METHODS: The structured questionnaire mailed to a random population sample included questions on participants' sociodemographic background, medical history, health habits, and recent lifestyle changes. Awareness of the national diabetes programme was also enquired. Data (n = 10 831) from the 2004-2008 postal surveys were used for this investigation. RESULTS: In the FIN-D2D area, 25% (347/1384) of men and 48% (797/1674) of women reported being aware of the programme. In the control area, the proportions were 20% (702/3551) and 36% (1514/4222), respectively. The overall awareness increased among both genders and in all areas during the project period, but the level of awareness was consistently higher in the FIN-D2D area. Female gender and higher age were associated with increasing awareness of the programme in both areas. Self-reported lifestyle changes were more common among women, but associated with the level of awareness of the programme more often among men than women. CONCLUSIONS: The awareness of diabetes and its risk factors increased among men and women in both implementation and control areas during the FIN-D2D project period. The activities of the implementation project may at least partly explain the differences in lifestyle changes between areas, especially among men. The results suggest that health promotion campaigns increase the population awareness about the prevention of chronic diseases and as a result, especially men may be prompted to make beneficial lifestyle changes. PMID- 25726123 TI - Living in a cold and damp home: frameworks for understanding impacts on mental well-being. AB - OBJECTIVE: To carry out a review of recent studies that have explored relationships between mental well-being and how this may be affected by living in cold and damp homes. Attention is focused on intervention studies in which heating and insulation improvements were carried out and impacts on well-being assessed. STUDY DESIGN: Drawing mainly on a Cochrane Review published in 2013, nine studies of sound methodology are identified and significant effects discussed. METHODS: The review outlines the current frameworks for understanding mental well-being which prevail in psychology and psychiatry, describing the distinctions that can be made between mental well-being and its elements, namely positive mental health and negative mental health (the latter also known as mental disorder). The review then organizes findings from nine studies into the separate domains of positive and negative mental health, giving due consideration to the quality of the research, instruments used to measure mental health, methodological, and ethical issues. RESULTS: These first nine studies indicate early consensus. Living in cold and damp housing contributes to a variety of different mental health stressors, including persistent worry about debt and affordability, thermal discomfort, and worry about the consequences of cold and damp for health. Improvements to energy efficiency are often associated with significant improvements in mental well-being. CONCLUSIONS: Impacts affect both positive and negative mental health. A cumulative stress framework is hypothesized, within which the mental health impacts of improved energy efficiency can be better understood. PMID- 25726124 TI - Retrospective cohort study of liver transplantation in the United Kingdom between 1994 and 2010: the impact of hepatitis C infection. AB - BACKGROUND: Liver transplantation is an important and established treatment option for chronic hepatitis C virus (HCV) related end-stage liver disease (HCV related ESLD). This study describes trends in elective liver transplantation among persons with HCV-related ESLD. STUDY DESIGN: Retrospective cohort. METHODS: Analyses of United Kingdom (UK) Transplant Registry data for the period 1994 to 2010, with follow-up information extending to 2011. RESULTS: Annual registrations for liver transplantation increased linearly and alcoholic liver cirrhosis (2075, 24%) and HCV-related ESLD (1213, 14%) were the most common indications. HCV related ESLD patients were mainly aged 40-49 years (32%) and 50-59 years (43%); males (76%); and of white ethnicity (74%). Overall, 75% (956/1213) received a liver transplant with a linear increase over the period (OR 1.11, 95% CI 1.08, 1.13). Pre transplant mortality was unchanged (adjusted OR 1.0, 95% CI 0.96, 1.05) and post-transplant mortality decreased in both HCV-related (adjusted OR 0.77, 95% CI 0.68, 0.88) and non-HCV-related ESLD (adjusted OR 0.82, 95% CI 0.75, 0.89) patients. CONCLUSION: The increase in demand for and receipt of liver transplants among persons with HCV-related ESLD requires coordinated efforts to increase not only organ donation, but investment in HCV prevention programmes and improved access to hepatitis C treatment services. PMID- 25726125 TI - Census categories for mixed race and mixed ethnicity: impacts on data collection and analysis in the US, UK and NZ. PMID- 25726126 TI - Superior peroneal retinacular injuries in calcaneal fractures. AB - Calcaneal fractures are injuries that occur generally as the result of high energy mechanisms, and, as such, the presence of concurrent injuries should be suspected. The presence of peroneal tendon and superior retinacular injuries has been underreported. We sought to report the incidence of peroneal tendon pathologic features in our population of patients with calcaneal fractures, with emphasis on the method of identification. Furthermore, we sought to identify whether specific fracture patterns were more commonly associated with this pathologic finding. Of the 97 cases, 13 (13.4%) required repair of the superior peroneal retinaculum, 11 of which demonstrated the Sanders A fracture line. Our findings have demonstrated an incidence of pathologic features, in particular, with the presence of the Sanders A fracture line, that warrants attention to potentially help improve the outcome of these devastating injuries. PMID- 25726128 TI - Lack of optimum practice among health care workers regarding tuberculosis in Iran: A knowledge, attitude, and practice study. AB - BACKGROUND: Lack of knowledge toward tuberculosis (TB) among health care workers (HCWs) increases the risk of developing TB. The aim of this study was to assess the level of knowledge, attitude, and practice of HCWs in Iran. METHODS: We conducted a cross-sectional study in 50 universities of medical sciences throughout Iran. A questionnaire was developed to assess the knowledge, attitude, and practice of participants. The values of Cronbach alpha coefficients for the knowledge and attitude questions were .76 and .75, respectively. RESULTS: The mean scores of knowledge, attitude, and practice among TB laboratory staff regarding TB was 82.6 (95% confidence interval [CI], 82.0-83.7), 87.6 (95% CI, 87.1-88.0), and 57.9 (95% CI, 56.9-58.9), respectively. The mean scores of knowledge, attitude, and practice among non-TB laboratory staff regarding TB was 69.5 (95% CI, 67.9-71.1), 50.7 (95% CI, 50.1-51.4), and 40.82 (95% CI, 38.2 43.4), respectively. CONCLUSION: TB laboratory staff scored relatively well in knowledge and attitude of TB, but they scored lower in practice regarding TB. Non TB laboratory staff had lower scores than TB laboratory staff in knowledge, attitude, and practice. There is a major gap between knowledge and attitude and practice in both groups. It is therefore essential to plan for the continuing in service training of HCWs and public training of the general population regarding TB. PMID- 25726127 TI - Urinary phthalate metabolite concentrations and blood glucose levels during pregnancy. AB - PURPOSE: To examine associations between phthalate metabolite urinary concentrations during early pregnancy and blood glucose levels obtained at the time of screening for gestational diabetes mellitus (GDM). METHODS: Upon initiation of prenatal care, women with a mean gestational age of 12.8 weeks were recruited for a study of environmental chemical exposures (n = 110) and provided a spot urinary specimen. Blood glucose concentrations (mg/dl) were obtained from the electronic medical record for those patients who did not experience a pregnancy loss and did not transfer care to another facility prior to glucose screening (n = 72). Urinary concentrations of nine phthalate metabolites and creatinine were measured at the US Centers for Disease Control and Prevention. Associations between tertiles of phthalate metabolites concentrations and blood glucose levels were estimated using linear regression. RESULTS: Compared to pregnant women in the lowest concentration tertile, women with the highest urinary concentrations (>= 3 rd tertile) of mono-iso-butyl phthalate (tertile: >= 15.3 MUg/l, beta = -18.3, 95% CI: -35.4, -1.2) and monobenzyl phthalate (tertile: >= 30.3 MUg/l, beta = -17.3, 95% CI: -34.1, -0.4) had lower blood glucose levels at the time of GDM screening after adjustment for urinary creatinine and demographic covariates. CONCLUSION: Because maternal glucose levels increase during pregnancy to provide adequate nutrition for fetal growth and development, these findings may have implications for fetal health. However, given the limitations of our study, findings should be interpreted cautiously. PMID- 25726129 TI - Disinfecting personal protective equipment with pulsed xenon ultraviolet as a risk mitigation strategy for health care workers. AB - The doffing of personal protective equipment (PPE) after contamination with pathogens such as Ebola poses a risk to health care workers. Pulsed xenon ultraviolet (PX-UV) disinfection has been used to disinfect surfaces in hospital settings. This study examined the impact of PX-UV disinfection on an Ebola surrogate virus on glass carriers and PPE material to examine the potential benefits of using PX-UV to decontaminate PPE while worn, thereby reducing the pathogen load prior to doffing. Ultraviolet (UV) safety and coverage tests were also conducted. PX-UV exposure resulted in a significant reduction in viral load on glass carriers and PPE materials. Occupational Safety and Health Administration-defined UV exposure limits were not exceeded during PPE disinfection. Predoffing disinfection with PX-UV has potential as an additive measure to the doffing practice guidelines. The PX-UV disinfection should not be considered sterilization; all PPE should still be considered contaminated and doffed and disposed of according to established protocols. PMID- 25726130 TI - Increasing potential risks of contamination from repetitive use of endoscope. AB - BACKGROUND: Medical devices inserted into the human body can be divided into single-use devices and reusable medical devices (RMDs) depending on the method of use. RMDs are applied to >1 patient, and users reprocess them prior to repeat use. Therefore, reprocessing of RMDs has become more difficult, and issues related to infection risk have become more prevalent. METHODS: Research was performed to compare differences in surface alterations between not-aged (NA) samples and accelerated-aging (AA) samples. NA and AA samples were exposed to potential contaminants and treated with the same cleaning conditions. Then the residual contaminants were analyzed, and adhesion characteristics were investigated. RESULTS: Significant differences between the 2 sample groups were observed in the pattern of physical surface alterations. Similar to the endoscope for clinical use, a deep crack was found in the surface of the AA sample. According to the binding affinity test, highly likely potential contaminants were found more frequently on AA samples. CONCLUSION: The results suggest the necessity of limiting the duration of time that RMDs may be used, considering the potential risk of infection from repetitive use of RMDs, and also raised the possibility of applying this simulation model of AA. This methodology can be applied to various RMDs, including endoscopes. PMID- 25726131 TI - Methicillin-resistant Staphylococcus aureus nasal colonization in a level III neonatal intensive care unit: Incidence and risk factors. AB - OBJECTIVE: To describe epidemiologic features and identify risk factors for methicillin-resistant Staphylococcus aureus (MRSA) acquisition in a level III neonatal intensive care unit (NICU). SETTING: A prospective, cohort study in a university-affiliated NICU with an infection control program including weekly nasal cultures of all neonates. METHODS: Demographic, clinical, and microbiologic data were prospectively collected between June 2009 and June 2013. Molecular characterization of MRSA isolates was done by multilocus variable number tandem repeat fingerprinting, staphylococcal cassette chromosome mec typing, and on representative isolates by multilocus sequence typing and spa typing. RESULTS: Of 949 neonates, 217 (22.87%) had a culture growing MRSA, including 117 neonates testing positive at their first sampling. Of these latter infants, 96 (82.05%) were inborn and 59 (50.43%) had been transferred from the nursery. Length of stay and colonization pressure were strong independent predictors of MRSA acquisition. Among MRSA isolates, 7 sequence types were identified, with ST22-IVa, spa type t223, being the predominant strain. CONCLUSIONS: In an endemic area, early MRSA acquisition and high colonization pressure, likely related to an influx of colonized infants from a well-infant nursery, can support persistence of MRSA in NICUs. Surveillance, molecular tracking of strains, and reinforcement of infection control practices, involving well-infant nurseries in a comprehensive infection control program, could be helpful in containing MRSA transmission. PMID- 25726132 TI - Trends in emergency department management of skin abscesses. AB - BACKGROUND: Abscess is a distinct skin and soft tissue infection (SSTI) requiring incision and drainage (I&D). Previous national surveys combined all SSTIs to estimate abscess and evaluate management. We hypothesized that antibiotic rates are declining in response to evidence that antibiotics are unnecessary for most SSTIs requiring I&D. METHODS: Emergency department (ED) patients included in the National Hospital Ambulatory Medical Care Survey from 2007-2010 with diagnosis codes for cutaneous abscess or SSTI were filtered using a procedure code for I&D available since 2007. The number of patients with SSTI, the percentage of patients receiving I&D, and the percentage of patients receiving antibiotics were determined. Antibiotics were characterized based on efficacy to methicillin resistant Staphylococcus aureus (MRSA). RESULTS: ED visits for SSTI increased from 3.55 million (95% confidence interval [CI], 3.24 million-3.86 million) in 2007 to 4.21 million (95% CI, 3.89 million-4.55 million) in 2010. Incidences of I&D rose from 736,000 (95% CI, 602,000-869,000) to 1.48 million (95% CI, 1.30 million-1.65 million) and comprised 32.2% of SSTI visits over the 4 years. In 2007, 85.1% (95% CI, 82.6%-87.7%) of patients received antibiotics after I&D with no change over 4 years. In 2010, 15.5% (95% CI, 12.1%-18.7%) received >=2 antibiotics. Commonly prescribed antibiotics were trimethoprim-sulfamethoxazole (mean, 50.4%) followed by cephalexin (mean, 17.2%) and clindamycin (mean, 16.3%). CONCLUSION: ED visits for SSTIs continue to rise. Despite mounting evidence, antibiotic use in SSTIs requiring I&D is high, and many patients receive multiple antibiotics, including drugs with no efficacy on MRSA. PMID- 25726133 TI - Comparison of 3 in vivo methods for assessment of alcohol-based hand rubs. AB - BACKGROUND: Alcohol-based hand rubs (ABHRs) are the primary method of hand hygiene in health-care settings. ICPs increasingly are assessing ABHR product efficacy data as improved products and test methods are developed. As a result, ICPs need better tools and recommendations for how to assess and compare ABHRs. METHODS: Two ABHRs (70% ethanol) were tested according to 3 in vivo methods approved by ASTM International: E1174, E2755, and E2784. Log10 reductions were measured after a single test product use and after 10 consecutive uses at an application volume of 2 mL. RESULTS: The test method used had a significant influence on ABHR efficacy; however, in this study the test product (gel or foam) did not significantly influence efficacy. In addition, for all test methods, log10 reductions obtained after a single application were not predictive of results after 10 applications. CONCLUSIONS: Choice of test method can significantly influence efficacy results. Therefore, when assessing antimicrobial efficacy data of hand hygiene products, ICPs should pay close attention to the test method used, and ensure that product comparisons are made head to head in the same study using the same test methodology. PMID- 25726134 TI - Profound increase in longitudinal displacements of the porcine carotid artery wall can take place independently of wall shear stress: a continuation report. AB - The mechanisms underlying longitudinal displacements of the arterial wall, that is, displacements of the wall layers along the artery, and the resulting intramural shear strain remain largely unknown. We have already found that these displacements undergo profound changes in response to catecholamines. Wall shear stress, closely related to wall shear rate, represents the viscous drag exerted on the vessel wall by flowing blood. The aim of the work described here was to study possible relations between the wall shear rate and the longitudinal displacements. We investigated the carotid arteries of five anesthetized pigs in different hemodynamic situations using in-house developed non-invasive ultrasound techniques. The study protocol included administration of epinephrine, norepinephrine and beta-blockade (metoprolol). No significant correlation between longitudinal displacement of the intima-media complex and wall shear rate was found. This result suggests that one or multiple pulsatile forces other than wall shear stress are also working along arteries, strongly influencing arterial wall behavior. PMID- 25726135 TI - Ultrasonographic assessment of optic nerve sheath diameter during pediatric laparoscopy. AB - This study investigated the extent of the raised intracranial pressure resulting from carbon dioxide (CO2) pneumoperitoneum by ultrasonographically measuring optic nerve sheath diameter (ONSD) in children undergoing laparoscopic surgery. Twenty-five children aged less than 9 y (53.1 +/- 23.3 mo, mean +/- standard deviation) and scheduled for an elective laparoscopic surgery participated. ONSD was assessed using ocular ultrasonography 10 min after induction of anesthesia (T0), 10 min after induction of CO2 pneumoperitoneum at 10 mm Hg intra-abdominal pressure (T1) and in an anesthetized state without CO2 pneumoperitoneum at the conclusion of the surgery (T2). During CO2 pneumoperitoneum, ONSD increased significantly compared with ONSD after anesthesia induction (T0: 4.3 +/- 0.3 mm, T1: 4.6 +/- 0.3 mm, p < 0.05). In all enrolled patients, any neurologic complications were not observed during the intra-operative or post-operative period. In children undergoing laparoscopic surgery, an increase in ONSD was ascertained during CO2 pneumoperitoneum, and thus the corresponding increase in intracranial pressure could be predicted. PMID- 25726136 TI - Evaluating undergraduate nursing students' self-efficacy and competence in writing: Effects of a writing intensive intervention. AB - While professional nurses are expected to communicate clearly, these skills are often not explicitly taught in undergraduate nursing education. In this research study, writing self-efficacy and writing competency were evaluated in 52 nontraditional undergraduate baccalaureate completion students in two distance mediated 16-week capstone courses. The intervention group (n = 44) experienced various genres and modalities of written assignments set in the context of evidence-based nursing practice; the comparison group (n = 8) received usual writing undergraduate curriculum instruction. Self-efficacy, measured by the Post Secondary Writerly Self-Efficacy Scale, indicated significant improvements for all self-efficacy items (all p's = 0.00). Writing competency, assessed in the intervention group using a primary trait scoring rubric (6 + 1 Trait Writing Model((r)) of Instruction and Assessment), found significant differences in competency improvement on five of seven items. This pilot study demonstrated writing skills can improve in nontraditional undergraduate students with guided instruction. Further investigation with larger, culturally diverse samples is indicated to validate these results. PMID- 25726137 TI - Solving challenges in inter- and trans-disciplinary working teams: Lessons from the surgical technology field. AB - INTRODUCTION: Engineering a medical technology is a complex process, therefore it is important to include experts from different scientific fields. This is particularly true for the development of surgical technology, where the relevant scientific fields are surgery (medicine) and engineering (electrical engineering, mechanical engineering, computer science, etc.). Furthermore, the scientific field of human factors is important to ensure that a surgical technology is indeed functional, process-oriented, effective, efficient as well as user- and patient-oriented. Working in such trans- and inter-disciplinary teams can be challenging due to different working cultures. The intention of this paper is to propose an innovative cooperative working culture for the interdisciplinary field of computer-assisted surgery (CAS) based on more than ten years of research on the one hand and the interdisciplinary literature on working cultures and various organizational theories on the other hand. METHODOLOGY: In this paper, a retrospective analysis of more than ten years of research work in inter- and trans-disciplinary teams in the field of CAS will be performed. This analysis is based on the documented observations of the authors, the study reports, protocols, lab reports and published publications. To additionally evaluate the scientific experience in an interdisciplinary research team, a literature analysis regarding scientific literature on trans- and inter-disciplinarity was performed. Own research and literature analyses were compared. RESULTS: Both the literature and the scientific experience in an interdisciplinary research team show that consensus finding is not always easy. It is, however, important to start trans- and interdisciplinary projects with a shared mental model and common goals, which include communication and leadership issues within the project teams, i.e. clear and unambiguous information about the individual responsibilities and objectives to attain. This is made necessary due to differing leadership cultures within the cooperating disciplines. Another research outcome is the relevance of a cooperative learning culture throughout the complete duration of the project. Based on this cooperation, new ideas and projects were developed, i.e. a training concept for surgical trainers including technological competence for surgeons. DISCUSSION: An adapted innovative paradigm for a cooperating working culture in CAS is based on a shared mental model and common goals from the very beginning of a project. CONCLUSIONS: All actors in trans- and inter-disciplinary teams need to be interested in cooperation. This will lead to a common view on patients and technology models. PMID- 25726138 TI - Towards social acceptance of plant breeding by genome editing. AB - Although genome-editing technologies facilitate efficient plant breeding without introducing a transgene, it is creating indistinct boundaries in the regulation of genetically modified organisms (GMOs). Rapid advances in plant breeding by genome-editing require the establishment of a new global policy for the new biotechnology, while filling the gap between process-based and product-based GMO regulations. In this Opinion article we review recent developments in producing major crops using genome-editing, and we propose a regulatory model that takes into account the various methodologies to achieve genetic modifications as well as the resulting types of mutation. Moreover, we discuss the future integration of genome-editing crops into society, specifically a possible response to the 'Right to Know' movement which demands labeling of food that contains genetically engineered ingredients. PMID- 25726139 TI - Letter to the Editor on "Trends in Total Knee Arthroplasty Implant Utilization". PMID- 25726140 TI - Counterpoint: maintenance of certification: focus on physician concerns. PMID- 25726141 TI - Point: twin dogmas of maintenance of certification. PMID- 25726142 TI - Genotoxicity testing of 3,4,5-trimethylfuran-2(5H)-one, a compound from plant derived smoke with germination inhibitory activity. AB - Plant-derived smoke and certain smoke compounds improve seed germination and enhance seedling growth of many species. Thus, smoke-infused water and the active smoke-derived compounds have the potential to be used in different agricultural and horticultural applications. However, despite these interesting and potentially practical properties, it should also be ascertained whether such compounds may pose a health risk, particularly if they are to be used in the production of food or fodder crops. Amongst some of the aspects that would be important to understand are any possible genotoxic properties that the compounds may possess due to potential carry-over effects. Here, we report on a genotoxicity study of 3,4,5-trimethylfuran-2(5H)-one, a compound from plant derived smoke previously shown to have germination inhibitory activity. Using two in vitro tests, namely the bacterial VITOTOX(r) test (with/without S9 metabolic activation) and the cytome assay on human C3A cells, no genotoxicity or toxicity was found. Furthermore, these results support a previous study where a related smoke-derived compound with germination promoting properties was investigated. PMID- 25726143 TI - Rejoining kinetics of bleomycin-induced DNA single-strand breaks in agarose-bound human blood cells. AB - The rejoining kinetics of individual DNA single-strand breaks (SSBs) are difficult to measure, in biomonitoring studies, because SSB rejoining is rapid and hard to control. We have detected early (0, 1, 2, 5, 10 and 30 min) events in SSB rejoining in human leukocytes, with the alkaline comet assay, at a low concentration of bleomycin (BLM; 0.5 MUg/ml). Background Tail DNA% (percentage of DNA that remained in the comet tail) of the subjects was 1.23% (25th-75th percentile: 0.72-1.64). BLM treatment increased this to 62.4% (25th-75th percentile: 57.8-70.4) at t=0, decreasing to the background level by 30 min. Analysis of 45 subjects showed that the fastest return to the background level occurred in 5 min, whereas the slowest return took approximately 30 min. The early rejoining kinetics of SSBs may show multiple patterns, varying among individuals. PMID- 25726144 TI - Genotoxic testing of titanium dioxide anatase nanoparticles using the wing-spot test and the comet assay in Drosophila. AB - Titanium dioxide nanoparticles (TiO2 NPs) are widely used for preparations of sunscreens, cosmetics, food and personal care products. However, the possible genotoxic risk associated with this nano-scale material exposure is not clear, especially in whole organisms. In the present study, we explored the in vivo genotoxic activity of TiO2 NPs as well as their TiO2 bulk form using two well established genotoxic assays, the wing spot test and the comet assay in Drosophila melanogaster. To determine the extent of tissue damage induced by TiO2 NPs in Drosophila larvae, the trypan blue dye exclusion test was also applied. Both compounds were supplied to third instar larvae by ingestion at concentration ranging from 0.08 to 1.60 mg/mL. The results obtained in the present study indicate that TiO2 NPs can reach and induce cytotoxic effects on midgut and imaginal disc tissues of larvae, but they do not promote genotoxicity in the wing spot test of Drosophila. However, when both nano- and large-size forms of TiO2 were evaluated with the comet assay in Drosophila hemocytes, a significant increase in DNA damage, with a direct dose-response pattern, was observed for TiO2 NPs. The results obtained with the comet assay suggest that the primary DNA damage associated with TiO2 NPs exposure in Drosophila could be associated with specific physico-chemical properties of nano-TiO2, since no effects were observed with the bulk form. This study remarks the usefulness of using more than one genetic end-point in the evaluation of the genotoxic potential of nanomaterials. PMID- 25726145 TI - 6-Hydroxydopamine and lipopolysaccharides induced DNA damage in astrocytes: involvement of nitric oxide and mitochondria. AB - The present study was conducted to investigate the effect of the neurotoxins 6 hydroxydopamine and lipopolysaccharide on astrocytes. Rat astrocyte C6 cells were treated with different concentration of 6-hydroxydopamine (6 OHDA)/lipopolysaccharides (LPS) for 24 h. Both neurotoxins significantly decreased the viability of astrocytes, augmented the expression of inducible nitric oxide synthase (iNOS) and the astrocyte marker--glial fibrillar acidic protein. A significantly decreased mitochondrial dehydrogenase activity, mitochondrial membrane potential, augmented reactive oxygen species (ROS) level, caspase-3 mRNA level, chromatin condensation and DNA damage was observed in 6 OHDA/LPS treated astroglial cells. 6-OHDA/LPS treatment also caused the significantly increased expression of iNOS and nitrite level. Findings showed that 6-OHDA/LPS treatment caused mitochondrial dysfunction mediated death of astrocytes, which significantly involve the nitric oxide. Since we have observed significantly increased level of iNOS along with mitochondrial impairment and apoptotic cell death in astrocytes, therefore to validate the role of iNOS, the cells were co-treated with iNOS inhibitor aminoguanidine (AG, 100 MUM). Co treatment of AG significantly attenuated the 6-OHDA/LPS induced cell death, mitochondrial activity, augmented ROS level, chromatin condensation and DNA damage. GFAP and caspase-3 expression were also inhibited with co-treatment of AG, although the extent of inhibition was different in both experimental sets. In conclusion, the findings showed that iNOS mediated increased level of nitric oxide acts as a key regulatory molecule in 6-OHDA/LPS induced mitochondrial dysfunction, DNA damage and apoptotic death of astrocytes. PMID- 25726146 TI - Dynamic regulation of cerebral DNA repair genes by psychological stress. AB - Neuronal genotoxic insults from oxidative stress constitute a putative molecular link between stress and depression on the one hand, and cognitive dysfunction and dementia risk on the other. Oxidative modifications to DNA are repaired by specific enzymes; a process that plays a critical role for maintaining genomic integrity. The aim of the present study was to characterize the pattern of cerebral DNA repair enzyme regulation after stress through the quantification of a targeted range of gene products involved in different types of DNA repair. 72 male Sprague-Dawley rats were subjected to either restraint stress (6 h/day) or daily handling (controls), and sacrificed after 1, 7 or 21 stress sessions. The mRNA expression of seven genes (Ogg1, Ape1, Ung1, Neil1, Xrcc1, Ercc1, Nudt1) involved in the repair of oxidatively damaged DNA was determined by quantitative real time polymerase chain reaction in the prefrontal cortex (PFC) and hippocampus (HC). DNA repair gene expression in PFC exhibited a general trend towards an induction after acute stress and a decrease after subchronic exposure compared to control animals. After chronic stress, a normalization towards control levels was observed. A similar pattern was seen in HC, but with overall smaller effects and without the induction after acute stress. Nuclear DNA damage from oxidation as measured by the comet assay was unaffected by stress in both regions. We conclude that psychological stress have a dynamic influence on brain DNA repair gene expression; however, since we were unable to identify concurrent changes in DNA damage from oxidation, the down-stream consequences of this regulation, if any, remains unclear. PMID- 25726147 TI - Characterization of an area of reference for inhalable particulate matter (PM2.5) associated with genetic biomonitoring in children. AB - Humans are exposed to health-impairing air pollutants, especially children who are more sensitive to cancer-causing toxins. This study described an area of reference for inhalable particulates (PM2.5) by chemical (polycyclic aromatic hydrocarbons) and mutagenic characterization associated with the genetic biomonitoring of children (aged 5-11 years). The area studied was in a small town in Brazil, used as reference in previous studies. Organic matter of PM2.5 (extracted with dichloromethane) was evaluated for mutagenesis in a Salmonella/microsome (microsuspension) assay, in strains measuring frameshift error (TA98, YG1021 and YG1024) and base pair substitution (TA100) of DNA, in the presence and absence of rat liver metabolization fraction (S9). Exposure was studied analyzing a sample of 45 children using comet assay (peripheral blood lymphocytes) and micronucleus (exfoliated buccal mucosa cells). PM2.5 concentration for the period was 9% (25.89-64.71 MUg/m3) events above WHO limit value (25 MUg/m3). Mutagenesis responses (revertants/m3) varied from negative (spring) to 8.3+/-0.69 (autumn) (-S9) and 5.4+/-0.36 (winter) (+S9), in strain TA98, and for TA100, in spring, from negative to 14.8+/-4.23 (-S9) and 17.5+/ 2.72 (+S9). YG strain results show mononitroarenes and aromatic amines. Mean biomonitoring values were established for MN, 0.3+/-0.41 (0/00) and for other cell types a variation from 0.6+/-0.73 (0/00), nuclear buds to 57.5+/-24.92 (0/00), karyorrhexis. Comet assay means were 23.1+/-12.44; 7.3+/-11.66 and 0.9+/ 2.30 for tail length, intensity and moment, respectively. There was no difference for sex and age for the different parameters. A significant difference in confounding factors was observed for passive smoking and MN induction. PAHs and mutagenesis in the air may be related to local vehicular emissions. These results challenge the definition of areas of reference for air pollution associated with human biomonitoring including the region studied. PMID- 25726148 TI - Diagnostic capacity of non-echo planar diffusion-weighted MRI in the detection of primary and recurrent cholesteatoma. AB - INTRODUCTION AND AIMS: the aim of this study was to determine the certainty of non-echo-planar imaging diffusion-weighted magnetic resonance imaging (non-EPI DW MRI) in the diagnosis of primary and recurrent cholesteatoma in patients with clinical suspicion of cholesteatoma, assessing the sensitivity and specificity of the test in both groups. METHODS: Seventy-five patients with clinical suspicion of cholesteatoma were included in our study. Forty-eight cases had primary suspicion of cholesteatoma and 27 cases had recurrent suspicion of cholesteatoma. All patients received non-EPI DW MRI tests before surgery, and radiological and surgical findings were compared. RESULTS: Sensitivity, specificity and the positive and negative predictive value for primary diagnosis of cholesteatoma group were 91.2%, 50%, 81.6% and 70%, respectively. For the recurrent cholesteatoma group these results were 100%, 66.7%, 90.9% and 100%, respectively. CONCLUSION: Non-echo-planar imaging diffusion-weighted magnetic resonance imaging is a high sensitivity imaging test for detecting cholesteatoma, for both primary diagnosis and for recurrent cases. PMID- 25726149 TI - Nuclei fluorescence microscopic observation on early embryonic development of mitogynogenetic diploid induced by hydrostatic pressure treatment in olive flounder (Paralichthys olivaceus). AB - Sperm genetic material of olive flounder (Paralichthys olivaceus) was inactivated by ultraviolet irradiation. The nuclear phase changes during early embryonic development of diploid, haploid, and mitogynogenetic diploid induced by hydrostatic pressure treatment were observed under fluorescent microscope with 4',6-diamidino-2-phenylindole staining. The parameters of hydrostatic pressure treatment were 600 kg/cm(2) for 6 minutes at prometaphase stage. The data showed that developmental timing sequence of diploid and haploid fertilized eggs was similar. The cell cycle was about 48 minutes, including interphase (about 21 minutes), prophase (about 3 minutes), prometaphase (about 6 minutes), metaphase (about 6 minutes), anaphase (around 9 minutes), and telophase (about 3 minutes). After entering the fertilized egg, ultraviolet-inactivated sperm formed a male pronucleus and became a dense chromatin body in the cytoplasm. Dense chromatin body did not participate in nuclear division and unchanged all the time. For hydrostatic pressure-treated embryos, the first nuclear division and cytokinesis after treatment proceeded normally after about 15 minutes recovery. During the second mitosis, having undergone interphase, prophase, and prometaphase stage, chromosomes began to slowly spread around and scattered in the cell but not entered into metaphase and anaphase. The second nuclear division and cytokinesis was inhibited. The occurrence frequency of developmentally delayed embryos also showed that the second cleavage of about 80% treated eggs was inhibited. The inhibition of the second cleavage resulted to chromosome set doubling. So chromosome set doubling for mitogynogenetic flounder diploid induced by hydrostatic pressure treatment, performed at prometaphase stage, was mainly due to inhibition of the second mitosis rather than the first one. PMID- 25726150 TI - Reduced-rank models of growth and reproductive traits in Nelore cattle. AB - In beef cattle genetic evaluation, principal component models of the additive genetic effect could be used to incorporate several traits in the same analysis, without an important increase in the number of parameters to be estimated. In this study, multitrait (MT) and reduced-rank models were compared for their ability to estimate parameters and predict breeding values for weaning weight, yearling weight, weaning hip height, yearling hip height, weaning to yearling weight gain, scrotal circumference, and age at the first calving. Data obtained were from 74,388 Nelore animals, born to 1441 sires and 28,502 cows. Six analyses were performed using a MT model that incorporated all the traits simultaneously and five reduced-rank models for the genetic additive direct (co)variance matrix, fitting the first one (PC1), two (PC2), three (PC3), four (PC4), and five (PC5) principal components. The model considering the first three principal components (PC3) provided the best fit. Direct and maternal heritability and the respective standard errors obtained from the MT and PC3 models were similar. In general, the PC3 model provided slightly stronger genetic correlations between the traits when compared with those obtained with the MT model. The rank correlations between the breeding values predicted with the MT and PC3 models for the different traits ranged from 0.93 to 0.99. When 2% and 10% of the best sires were selected on the basis of breeding values predicted by the MT model, the degree of concordance with the PC3 model ranged from 86% to 97%. The first three principal components explained most of the genetic variation among animals, suggesting that major changes should not be expected in the sire's classification on the basis of breeding values predicted for growth and reproductive traits. Models of principal components could be used for beef cattle genetic evaluation, especially when considering several economic traits in the same analysis. PMID- 25726151 TI - Influence of wheel configuration on wheelchair basketball performance: wheel stiffness, tyre type and tyre orientation. AB - The aim of the current investigation was to explore the lateral stiffness of different sports wheelchair wheels available to athletes in 'new' and 'used' conditions and to determine the effect of (a) stiffness, (b) tyre type (clincher vs. tubular) and (c) tyre orientation on the physiological and biomechanical responses to submaximal and maximal effort propulsion specific to wheelchair basketball. Eight able-bodied individuals participated in the laboratory-based testing, which took place on a wheelchair ergometer at two fixed speeds (1.1 and 2.2 m s(-1)). Outcome measures were power output and physiological demand (oxygen uptake and heart rate). Three participants with experience of over-ground sports wheelchair propulsion also performed 2 * 20 m sprints in each wheel configuration. Results revealed that wheels differed significantly in lateral stiffness with the 'new' Spinergy wheel shown to be the stiffest (678.2 +/- 102.1 N mm(-1)). However the effects of stiffness on physiological demand were minimal compared to tyre type whereby tubular tyres significantly reduced the rolling resistance and power output in relation to clincher tyres. Therefore tyre type (and subsequently inflation pressure) remains the most important aspect of wheel specification for athletes to consider and monitor when configuring a sports wheelchair. PMID- 25726152 TI - Improving understanding, promoting social inclusion, and fostering empowerment related to epilepsy: Epilepsy Foundation public awareness campaigns--2001 through 2013. AB - It is a significant public health concern that epilepsy, the fourth most common neurological disorder in the United States, is generally poorly understood by both the public and those living with the condition. Lack of understanding may magnify the challenges faced by those with epilepsy, including limiting treatment opportunities, effective management of symptoms, and full participation in daily life activities. Insufficient awareness of epilepsy and appropriate seizure first aid among the public and professionals can result in insufficient treatment, inappropriate seizure response, physical restraint, social exclusion, or other negative consequences. To address the need for increased public education and awareness about epilepsy, the national Epilepsy Foundation, supported by the Centers for Disease Control and Prevention, has conducted yearly multifaceted public education and awareness campaigns designed to reach the broad population and targeted segments of the population including youth, young adults, racial/ethnic groups (i.e., African-, Hispanic-, and Asian-Americans), and people with epilepsy and their caregivers. Campaign channels have included traditional media, social media, and community opinion leaders and celebrity spokespersons. The key activities of these campaigns, conducted from 2001 to 2013, are summarized in this report. PMID- 25726153 TI - Implementation of a school-based social and emotional learning intervention: understanding diffusion processes within complex systems. AB - Sporadic and inconsistent implementation remains a significant challenge for social and emotional learning (SEL) interventions. This may be partly explained by the dearth of flexible, causative models that capture the multifarious determinants of implementation practices within complex systems. This paper draws upon Rogers (2003) Diffusion of Innovations Theory to explain the adoption, implementation and discontinuance of a SEL intervention. A pragmatic, formative process evaluation was conducted in alignment with phase 1 of the UK Medical Research Council's framework for Developing and Evaluating Complex Interventions. Employing case-study methodology, qualitative data were generated with four socio economically and academically contrasting secondary schools in Wales implementing the Student Assistance Programme. Semi-structured interviews were conducted with 15 programme stakeholders. Data suggested that variation in implementation activity could be largely attributed to four key intervention reinvention points, which contributed to the transformation of the programme as it interacted with contextual features and individual needs. These reinvention points comprise the following: intervention training, which captures the process through which adopters acquire knowledge about a programme and delivery expertise; intervention assessment, which reflects adopters' evaluation of an intervention in relation to contextual needs; intervention clarification, which comprises the cascading of knowledge through an organisation in order to secure support in delivery; and intervention responsibility, which refers to the process of assigning accountability for sustainable delivery. Taken together, these points identify opportunities to predict and intervene with potential implementation problems. Further research would benefit from exploring additional reinvention activity. PMID- 25726154 TI - The rectus sheath and serratus fascia "reverse" fashion flap for the coverage of the lower pole in immediate implant-based breast reconstruction. PMID- 25726155 TI - Direct geniculo-extrastriate pathways: a review of the literature. AB - PURPOSE: The aim of this paper is to review the literature on direct geniculo extrastriate pathways with special attention to 3D extrastriate visual areas. METHODS: A literature review was realized using PubMed and Google Scholar. "Lateral geniculate nucleus", "geniculo-extrastriate pathways" and "white matter fiber tracts" were among the keywords used. RESULTS: Existence of geniculo extrastriate connections was first hypothesized by the clinical observations of Riddoch's syndrome in patients with striate cortex (primary visual area, V1) lesions. Robust histological proof of geniculo-extrastriate pathways exists in monkeys. In humans, these pathways were tested through functional magnetic resonance imaging (fMRI), electro- and magneto-physiological paradigms. Conversely, only indirect proof of the connection between lateral geniculate nucleus and V5 exists. To our knowledge there were not any anatomical studies of geniculo-extrastriate connections in humans. CONCLUSION: Few human studies take interest in geniculo-extrastriate pathways. Only indirect proof of geniculo extrastriate pathways exists in humans. PMID- 25726156 TI - An Updated Meta-Analysis of the Effects of the Endothelial Nitric Oxide synthase Gene G894T Polymorphism and Erectile Dysfunction Risk. AB - Erectile dysfunction (ED) is a common disorder leading to a serious and negative impact on the patient's quality of life. The gene encoding endothelial nitric oxide synthase (eNOS) is an interesting candidate gene for understanding the physiopathology of ED. However, an association between eNOS G894T polymorphism and ED risk is uncertain and should be updated. Therefore, a meta-analysis of the current literature was necessary to clarify this relationship. We searched Pubmed and China National Knowledge Infrastructure (CNKI) (last search updated on Dec 12, 2013) using 'nitric oxide synthase,' 'polymorphism or variant,' 'genotype,' and 'ED' as keywords. We also searched reference lists of studies corresponding to the inclusion criteria for the meta-analysis. These studies involved the total number of 1,445 ED men and 1,459 healthy control men subjects. Odds ratio (OR) and 95 % confidence intervals (CIs) were used to evaluate this relationship. Statistical analysis was performed with STATA10.0. In the overall analysis, significantly decreased associations between ED risk and eNOS G894T polymorphism were found. Moreover, in the subgroup analysis based on ethnicity, similar significant associations were detected in both Caucasians (such as GG+GT vs. TT: OR 0.92, 95 %CI 0.86-0.97) and Asians (such as GG+GT vs. TT: OR 0.24, 95 % CI 0.07-0.85). The Egger's test did not reveal the presence of a publication bias. Our investigations demonstrate that eNOS G894T polymorphism might protect men against ED risk. Further studies based on larger sample size and gene-environment interactions should be conducted. PMID- 25726157 TI - The Expression and Significance of CXCR5 and MMP-13 in Colorectal Cancer. AB - The objective of the study is to investigate the CXCR5 and MMP-13 expression in colorectal cancer and explore its correlation between the clinicopathological characteristics and prognosis. The expressions of CXCR5 and MMP-13 proteins in 236 paired specimens of colorectal cancer and incisal edge normal tissues as well as 62 samples of colorectal adenoma tissues were analyzed by immunohistochemistry. The CXCR5 and MMP-13 positive expression rate in colorectal cancer tissues was 43.6 and 80.5 %, respectively. Both rates were higher than those in the incisal edge healthy intestinal mucosal tissues (4.2 and 13.1 %) and colorectal adenoma tissues (24.2 and 64.5 %), P < 0. 05 in both cases. The expressions of the CXCR5 and MMP-13 proteins were positively related to the lymph node and distal metastasis, tumor stage and relapse, P < 0. 05. The expression of the CXCR5 protein was positively related to MMP-13, P < 0. 05. The median and overall survival in the patients with positive CXCR5 and MMP-13 expression were significantly shorter than those with negative expression: median survival, 20.5 months (CXCR5 +) versus 30.8 months (CXCR5 -), 20.3 months (MMP-13 +) versus 24.6 months; overall survival, 26.5 months (CXCR5 +) versus 47.5 months (CXCR5 -), 22.7 months (MMP-13 +) versus 29.3 months. The expression of CXCR5 and MMP-13 could promote the pathogenesis, development, metastasis, and relapse of colorectal cancer. It could also serve as a valuable indicator for the prediction of metastasis and relapse of colorectal cancer. PMID- 25726158 TI - Individuals with isolated patellofemoral joint osteoarthritis exhibit higher mechanical loading at the knee during the second half of the stance phase. AB - BACKGROUND: Patellofemoral joint osteoarthritis is a highly prevalent disease and an important source of pain and disability. Nonetheless, biomechanical risk factors associated with this disease remain unclear. The purpose of this study was to compare biomechanical factors that are associated with patellofemoral joint loading during walking between individuals with isolated patellofemoral joint osteoarthritis and no osteoarthritis. METHODS: MR images of the knee were obtained using a 3D fast-spin echo sequence to identify patellofemoral joint cartilage lesions. Thirty-five subjects with isolated patellofemoral joint osteoarthritis (29 females) and 35 control subjects (21 females) walked at a self selected speed and as fast as possible. Peak knee flexion moment, flexion moment impulse and peak patellofemoral joint stress during the first and second halves of the stance phase were compared between groups. FINDINGS: When compared to the controls, individuals with patellofemoral joint osteoarthritis demonstrated significantly higher peak knee flexion moment (P=.03, Eta(2)=.07), higher knee flexion moment impulse (P=.03, Eta(2)=.07) and higher peak patellofemoral joint stress (P=.01, Eta(2)=.10) during the second half of the stance phase. No significant group difference was observed during the first half of the stance phase. INTERPRETATION: Findings of this study suggest that increased mechanical loading (i.e. knee flexion moment, impulse and patellofemoral joint stress) during the second half of the stance phase is associated with patellofemoral joint osteoarthritis. Prevention and rehabilitation programs for patellofemoral joint osteoarthritis may focus on reducing the loading on the patellofemoral joint, specifically during late stance. PMID- 25726159 TI - Graft position and fusion rate following arthroscopic Latarjet. AB - PURPOSE: The arthroscopic Latarjet procedure is recently becoming an increasingly popular technique. Nevertheless, position and fusion of the autograft had not been well studied yet. The purpose of this study was to assess the positioning of the coracoid graft and the fusion rate on CT scan in the arthroscopic Latarjet procedure. METHODS: The study design was a prospective series of 19 consecutive patients who received arthroscopic Latarjet procedure. Radiological assessment on CT scan performed 3 months post-operatively included an analysis of the fusion and the position of the coracoid bone graft using a validated method. 02:30-04:20 was considered an ideal positioning in the sagittal view. In the axial view, the positioning was considered as flush, congruent, medial, too medial, or lateral. RESULTS: The median age of patients was 27.6 (+/-6.9). Mean operative time was of 161 min +/-34.8. The fusion rate was of 78 %. Coracoid grafts were positioned 01:52 h (56 degrees +/- 14 degrees ) to 4:04 h (122 degrees +/- 12.5 degrees ). In the axial view, 32 % of the grafts positioning were considered as flush, 38 % as congruent, 30 % as medial, and 6 % too medial. No lateral position was noted. Two complications occurred, one graft fracture during screwing requiring opening conversion and an early case of osteolysis in a medial-positioned graft. CONCLUSION: The arthroscopic Latarjet procedure is a technically challenging technique that provides satisfactory fusion rate and graft positioning with a low complication rate. The clinical importance of this study lies in the observation that it is the first study to evaluate the position of the coracoid bone graft in arthroscopic Latarjet according to a detailed and validated method. LEVEL OF EVIDENCE: IV. PMID- 25726161 TI - Reply to Sala: "Post-meal affective states". PMID- 25726160 TI - Effect of fixation angle and graft tension in double-bundle anterior cruciate ligament reconstruction on knee biomechanics. AB - PURPOSE: To compare the effect of graft fixation angle and tension in double bundle anterior cruciate ligament (ACL) reconstruction on knee biomechanics. METHODS: Fourteen cadaver knees were tested using a robotic system under two loadings: (1) an 89-N anterior tibial load (ATL) at full extension (FE), 15 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees , and (2) combined 7 N m valgus and 5 N m internal tibial torques (simulated pivot-shift test) at FE, 15 degrees and 30 degrees . Four graft fixation angles and tensions were used for the anteromedial (AM) and posterolateral (PL) bundles, respectively: (Recon 1) 30 degrees /20N and FE/20N, (Recon 2) 30 degrees /30N and FE/10N, (Recon 3) 45 degrees /20N and 15 degrees /20N, and (Recon 4) 45 degrees /30N and 15 degrees /10N. RESULTS: All fixation protocols closely restored the intact knee kinematics under ATL and simulated pivot-shift loading. For the AM bundle under ATL, the in situ force (ISF) with Recon 3 at the FE was significantly lower than that of the intact knee. For the PL bundle under ATL, the ISF with Recon 3 at the FE, 15 degrees and 30 degrees was significantly higher than that of the intact knee. In PL bundle under simulated pivot-shift loading, the ISF with Recon 1 and Recon 2 at FE was lower and the ISF of the PL bundle with Recon 3 at the 15 degrees was higher than that of the intact knee. CONCLUSION: The AM-45 degrees /30N and PL-15 degrees /10N fixation most closely matched intact knee kinematics; however, stabilizing the knee during anterior tibial translation may risk an imbalance of the AM and the PL bundle loading. The results indicate that ACL bundle forces may not be restored even if the clinical assessment shows good results with the Lachman test and pivot-shift test. This may alter the loading on other structures of the knee. PMID- 25726162 TI - Agonist binding by the beta2-adrenergic receptor: an effect of receptor conformation on ligand association-dissociation characteristics. AB - The beta2-adrenergic receptor (beta2-AR), a G protein-coupled receptor (GPCR), is a physiologically important transmembrane protein that is a target for drugs used for treatment of asthma and cardiovascular diseases. Study of the first steps of ligand recognition and the molecular basis of ligand binding to the orthosteric site is essential for understanding the pharmacological properties of the receptor. In this work we investigated the characteristic features of the agonist association-dissociation process to and from the different conformational forms of beta2-AR by use of advanced molecular modeling techniques. The investigation was focused on estimating the free energy profiles (FEPs) corresponding to the process of a full agonist ((R,R)-fenoterol) and an inverse agonist (carazolol) binding and unbinding to and from beta2-AR. The two different conformational forms of beta2-AR, i.e. active beta2-AR-PDB: 3P0G and inactive beta2-AR-PDB: 2RH1 were included in this stage of the study. We revealed several significant qualitative differences between FEPs characteristic of both conformational forms. Both FEPs suggest the existence of three transient binding sites in the extracellular domain of beta2-AR. Comparison of the residues surrounding these transient binding sites in both beta2-AR states revealed the importance of the aromatic residues F194, H93(2.64), H296(6.58), and H178 (extracellular part of beta2-AR) in the early stages of the binding process. In addition, slightly different exit and entry paths are preferred by the ligand molecule in the extracellular part of beta2-AR, depending on the conformation of the receptor. PMID- 25726163 TI - Epilepsy in a boy with a developmental venous anomaly--case-based update. AB - BACKGROUND: Developmental venous anomalies (DVAs) are the most common intracranial vascular malformations of the brain. They are most commonly asymptomatic and often diagnosed incidentally. ILLUSTRATIVE CASE: We present a rare case of a 9-year-old boy with seizures caused by a subcortically located DVA posterior to the postcentral gyrus of the left brain hemisphere. MRI also showed an enlarged, microcystically altered pineal gland and an extracranial cavernous hemangioma. EEG showed left fronto-centro-parietal spikes that corresponded with the location of the DVA. The spikes were occasionally secondary generalized. The boy responded well to oxcarbazepine treatment, and no surgical intervention was required. Control MRI scans showed no progression of the DVA. CONCLUSION: Epilepsy may be caused by DVA. The treatment starts with anticonvulsants. The surgical treatment is the therapeutic choice only if seizures are resistant to conservative therapy because surgery might result in serious ischemic or hemorrhagic complications because DVAs are considered to be variations of normal transmedullary veins that are necessary for the drainage of white and gray matter. PMID- 25726164 TI - Differential clinical outcomes following encephaloduroarteriosynangiosis in pediatric moyamoya disease presenting with epilepsy or ischemia. AB - PURPOSE: The purpose of this study was to compare clinical outcomes and surgical results after encephaloduroarteriosynangiosis (EDAS) in pediatric patients with Moyamoya disease that manifested as either ischemia or epileptic seizures. METHODS: We treated 23 children who underwent EDAS; we divided the patients into either ischemic or epileptic groups according to the individuals' clinical presentation. Group Ia included those who mainly presented with cerebral ischemia in the form of preoperative transient ischemic attacks (TIA), while Group Ib presented with ischemia in the form of irreversible neurologic deficits or proven cerebral infarcts. Group II included those who presented with epileptic seizures rather than cerebral ischemia. We compared the clinical outcomes and surgical results following EDAS in the three groups. RESULTS: We grouped the patients into three groups according to their main preoperative clinical symptoms (Group Ia n = 10, Group Ib n = 6, and Group II n = 7). Group II, the epileptic manifestation group, tended to show more favorable clinical outcomes compared to the ischemic manifestation group, especially the severe ischemic group. However, there were no significant differences in postoperative neuroimaging and hemodynamic assessments between the groups. CONCLUSIONS: EDAS is a safe and effective surgical technique that prevents epileptic seizures and shows more favorable clinical outcomes when used in patients with Moyamoya disease presenting with epileptic seizures compared to cerebral ischemia. PMID- 25726165 TI - Long-term psychiatric outcomes in pediatric brain tumor survivors. AB - PURPOSE: The increased efficacy of cancer treatments has led to a greater survival rate of patients with pediatric brain cancers. Therefore, it is imperative to explore the long-term consequences of therapies employed to treat pediatric brain tumors. The goal of this study was to provide a review of literature regarding the downstream psychological and psychiatric consequences experienced by adult survivors of pediatric brain cancer as a result of treatment, tumor type, or tumor location. METHODS: A PubMed MeSH search and additional online database searches were conducted to include pertinent studies that discussed psychological deficits in childhood brain cancer survivors. The studies included were subjected to data extraction to quantify relevant information for further analysis. RESULTS: A total of 17 papers with 5320 pediatric brain tumor patients were incorporated in our review. Mean age at diagnosis (8.13 +/- 0.77 years), mean follow-up time (9.98 +/- 3.05 years), and male-to-female ratios (1.08:1) were compiled from studies reporting this information. Incidences of depression (19 %), anxiety (20 %), suicidal ideation (10.9 %), schizophrenia and its related psychoses (9.8 %), and behavioral problem (28.7 %) were higher among pediatric brain cancer survivors than in the normal population. Craniospinal radiotherapy and/or surgery corresponded to an increased likelihood of developing adverse deficits. Astrocytomas or other glial tumors were linked to poorer outcomes. CONCLUSION: Physicians treating pediatric brain tumor patients should be aware of the possible consequences associated with treatment. Psychiatric monitoring is warranted in survivors of pediatric brain tumors, but further investigation is needed to elucidate late outcomes regarding tumor type and location. PMID- 25726166 TI - Expression of magnesium transporter genes in head and neck cancer patients underwent neoadjuvant cisplatin-based chemotherapy. AB - We aimed to investigate expression of magnesium transporter genes in patients with head and neck cancer who underwent cisplatin-based neoadjuvant chemotherapy and their association with serum magnesium level. Head and neck cancer patients scheduled to undergo neoadjuvant cisplatin-based chemotherapy were eligible for enrollment. Blood samples were obtained at three time points: prior to, during, and after completion of chemotherapy. Expression levels of magnesium transporter genes were determined by quantitative real-time PCR. A total of 23 patients were included in the final analysis. The average serum magnesium levels dropped 6.98 and 5.20% during and after completion of chemotherapy. There were neither significant associations between serum magnesium level and demographic variables nor tumor-related variables. SLC41A1 expression level was positively correlated with serum magnesium whereas TRPM6 expression level was negatively correlated with serum magnesium. Serum magnesium level decreased during cisplatin-based chemotherapy in head and neck cancer patients. Further studies are warranted to investigate optimal magnesium measurement and substitution protocol. PMID- 25726167 TI - A 16-year experience in treating thyroglossal duct cysts with a "conservative" Sistrunk approach. AB - Although Sistrunk operation is the standard method to treat thyroglossal duct cyst, the reported recurrence rates after a "classic" or "modified" Sistrunk procedure still varied from 0 to 15.8 %, indicating the existence of some technical uncertainties. While simple cystectomy has been recognized as the most important prognostic factor predicting thyroglossal duct cyst recurrence, whether other clinico-pathological parameters also affect disease recurrence has not been well studied. We retrospectively reviewed the medical records of all patients who underwent thyroglossal duct cyst surgery between June 1998 and June 2014 at our institution. Among the 180 primary patients, 160 patients received a "conservative" Sistrunk operation, while the remaining 20 patients received simple cystectomy only. Five patients (2.8 %, 5/180) had recurrence. Four of them received simple cystectomy while 1 had "conservative" Sistrunk operation. In univariable analysis, age (p = 0.02), history of previous infection (p = 0.004) and the type of resection (p = 0.001) were significantly correlated with disease recurrence. In multivariable analysis, the type of resection turned out to be the most important factor (p = 0.03) related to recurrence. In the most parsimonious model selected by backward elimination, both history of infection (p = 0.048) and the type of resection (p = 0.02) were important predictors of postoperative recurrence. Our results demonstrated that a "conservative" Sistrunk approach could provide a comparably low recurrence rate (0.6 %, 1/160) in dealing with primary thyroglossal dust cysts. Routine dissection of suprahyoid tissue may not be imperative. Overall, the type of resection and history of infection are the most important predictors of recurrence for thyroglossal duct cyst. PMID- 25726168 TI - Prognostic factors for local control in patients receiving radiation therapy for early glottic cancer: anterior commissure involvement and effect of chemoradiotherapy. AB - To assess the prognostic factors for local control in patients with early glottic cancer, we retrospectively analyzed the data of 130 consecutive patients who were treated by definitive radiation therapy (RT) or concurrent chemoradiotherapy (CRT) for early glottic squamous cell carcinoma (UICC sixth edition T1N0M0 and T2N0M0) at Kanagawa cancer center between 1999 and 2011. There were 63 patients with T1 cancer and 67 patients with T2 cancer. Twenty-one patients with T2 tumors were treated by chemoradiotherapy (CRT). The median follow-up period was 73 months (range, 22-165 months). The 5-year local control (LC) rate in all patients was 81 %. The 5-year LC rates in the patients with T1 and T2 cancer were 89 and 74 %, respectively. Univariate analysis showed that a higher T stage (T2) (p = 0.0301), anterior commissure involvement (p < 0.000001), and habitual drinking (p = 0.054) were correlated with decreased local control rate. Multivariate analysis identified only anterior commissure involvement as a significant prognostic factor for local control (LC rate 91 vs. 51 %, risk ratio 5.3, 95 % CI 2.3-12, p < 0.001). In the patients with T2 cancer, there was no statistically significant difference in the LC rate between patients who received RT alone and those who received CRT (RT alone 76 % vs. CRT 67 %; p = 0.832). The findings of this study suggest that anterior commissure involvement is a significant factor influencing the prospect of local control. CRT was not found to be effective for T2 patients in this study. PMID- 25726169 TI - The antimalarial agent artesunate causes sperm DNA damage and hepatic antioxidant defense in mice. AB - Artesunate is an artemisinin derivative effective against multidrug resistant malaria. We analyzed the effects of artesunate 40 mg/kg b.w. as a single dose (ART1) or 13.3mg/kg b.w. for 3 days at 24h intervals (ART2) on mice spermatozoa at morphological and molecular level, and hepatic antioxidant status following 24h and 35 days following exposures in vivo. Artesunate significantly reduced epididymal sperm count and increased the frequency of sperms with abnormal head morphology following 24h of exposure. Comet assay analysis revealed significant increase in DNA strand breaks in spermatozoa evidenced by about 3-fold increase in comet tail DNA and up to 10-fold increase in Olive tail moment following 35 days of artesunate treatment. The damage index was significantly higher in the treated groups (40.27 +/- 6.62 and 37.07 +/- 5.35 for ART1 and ART2 respectively) as compared to the control group (16.13 +/- 3.21) indicating the genotoxic effect of artesunate. The significant reduction in GSH, SOD and increase in lipid peroxidation indicate involvement of oxidative mechanisms in artesunate induced toxicity in mice. The present study suggests that artesunate has the potential to breach the testis-blood barrier and cause toxicity to male germ cells which may have implications in male reproductive toxicity. PMID- 25726170 TI - Histone markers identify the mode of action for compounds positive in the TK6 micronucleus assay. AB - The in vitro micronucleus assay with TK6 cells is frequently used as part of the genotoxicity testing battery for pharmaceuticals. Consequently, follow-up testing strategies are needed for positive compounds to determine their mode of action, which would then allow for deployment of appropriate in vivo follow-up strategies. We have chosen 3 micronucleus positive compounds, the clastogen etoposide, the aneugen noscapine and the cytotoxicant tunicamycin to evaluate different approaches to determine their aneugenic or clastogenic properties. Each of the three compounds were evaluated following 4 and 24h of continuous treatment by flow cytometry for micronucleus induction, the aneugenicity markers phosphorylated-histone 3 (p-H3) and polyploidy, the clastogenicity marker gammaH2AX and the apoptosis marker cleaved caspase 3. They were further evaluated by Western blot for mono-ubiquitinated and gammaH2AX. Results show that the clastogen etoposide produced a dose related increase in gammaH2AX and mono ubiquitinated H2AX and a dose related decrease in p-H3 positive mitotic cells. Conversely, the aneugen produced increases in p-H3 and polyploidy with no significant increases seen in mono-ubiquitinated H2AX or gammaH2AX. Lastly, the cytotoxicant tunicamycin induced neither an increase in p-H3 nor gammaH2AX. All three compounds produced dose-related increases in cleaved caspase 3. The results from this study provide evidence that adding clastogenicity and aneugenicity markers to the in vitro micronucleus assay in TK6 cells could help to identify the mode of action of positive compounds. The combination of endpoints suggested here needs to be further evaluated by a broader set of test compounds. PMID- 25726171 TI - Investigations into the genotoxic potential of olive extracts. AB - The phenolic anti-oxidant 3-hydroxytyrosol (HT) is a major constituent of olives and olive oil. Published data showed it was negative in the Ames test at concentrations up to 5 MUL per plate, but did induce chromosomal aberrations in human lymphocytes. HIDROX, an olive extract containing approximately 2.4% HT, was reported as both positive and equivocal in an Ames test in different papers from the same laboratory. Negative results for micronucleus induction in vivo in both an acute study and as part of a 90-day rat toxicity study were also reported for HIDROX. Given the widespread use and consumption of olives, olive oil and olive extracts, it was important to obtain more data. Here we confirm that pure HT, and an olive extract containing 15% HT, both induced micronuclei in cultured cells in vitro, but show that these responses were either due to high levels of cytotoxicity or to reaction of HT with culture medium components to produce hydrogen peroxide. Another extract (H40) containing 40% HT also induced micronuclei in vitro, probably via the same mechanism. However, both extracts were negative in robust Ames tests. The 15% HT formulated extract did not induce micronuclei in rat bone marrow after 4 weeks of dosing up to 561 mg HT/kg/day. H40 produced increased rat bone marrow micronucleus frequencies at 250 and 500 mg HT/kg/day in a 90-day toxicity study, but the results were questionable for various reasons. However, when two different batches of this extract were tested in acute micronucleus studies at doses up to 2000 mg HT/kg, giving plasma exposures that exceeded those in the 90-day study, negative results were obtained. Based on weight of evidence it is concluded that the olive extracts tested are not genotoxic at high doses in vivo, and any genotoxic risks for human consumers are negligible. PMID- 25726172 TI - Forskolin: genotoxicity assessment in Allium cepa. AB - Forskolin, a diterpene, 7beta-acetoxy-8,13-epoxy-1alpha,6beta,9alpha-trihydroxy labd-14-en-11-one (C22H34O7) isolated from Coleus forskohlii, exerts multiple physiological effects by stimulating the enzyme adenylate cyclase and increasing cyclic adenosine monophosphate (cAMP) concentrations. Forskolin is used in the treatment of hypertension, congestive heart failure, eczema, and other diseases. A cytogenetic assay was performed in Allium cepa to assess possible genotoxic effects of forskolin. Forskolin was tested at concentrations 5-100 MUM for exposure periods of 24 or 48 h. Treated samples showed significant reductions in mitotic index (p < 0.05) and increases in the frequency of chromosome aberrations (p < 0.01) at both exposure times. The treated meristems showed chromosome aberrations including sticky metaphases, sticky anaphases, laggard, anaphase bridges, micronuclei, polyploidy, fragments, breaks, and C-mitosis. Forskolin may cause genotoxic effects and further toxicological evaluations should be conducted to ensure its safety. PMID- 25726174 TI - Genotoxic and cytostatic effects of 6-pentadecyl salicylic anacardic acid in transformed cell lines and peripheral blood mononuclear cells. AB - In Mexico, as in many other countries, traditional medicine is used for the treatment of several diseases. In particular, Amphipterygium adstringens infusion is used for gastritis, gastric ulcers, and gastric cancer. Extracts from this tree have microbicidal effects against Helicobacter pylori, an important risk factor for gastric cancer development. Anacardic acids are constituents of A. adstringens, and 6-pentadecyl salicylic acid (6-PSA) is the most abundant. However, there is a lack of information regarding the effects of 6-PSA on cancer cells. Therefore, we investigated whether 6-PSA has differential effects on the induction of genotoxicity, cytostaticity, and apoptosis in normal human peripheral blood mononucleated cells (PBMCs), bone marrow polychromatic erythrocytes of Balb/c mice, and human transformed cell lines derived from both gastric cancer (AGS cells) and leukaemia (K562 cells). Treatment with 6-PSA (30 150 MUM) reduced the viability of AGS and K562 cells together with a moderate, but significant, increase in the frequency of micronucleated cells and the induction of DNA breakage (Comet Assay). Moreover, 6-PSA increased the apoptosis rate in both the AGS and K562 cell lines in a caspase 8-dependent manner. In contrast, neither cytotoxicity nor genotoxicity were observed in PBMCs or bone marrow polychromatic erythrocytes of Balb/c mice after treatment with low doses of 6-PSA (0.2-2.0 mg/Kg). Instead, 6-PSA treatment resulted in the inhibition of PBMC proliferation, which was reversible after the compound was removed. Additionally, 6-PSA treatments (2-20 mg/Kg) increased the frequency of mature polychromatic erythrocytes in the bone marrow, suggesting a possible effect on the differentiation process of immune cells. The present results indicate that 6 PSA induces cytotoxicity and moderate genotoxicity, together with an increase in the apoptosis rate, in a caspase 8-dependent manner in gastric cancer cells. In contrast, a low toxicity was observed when PBMCs were exposed to 6-PSA. PMID- 25726173 TI - Comparative mutagenicity and genotoxicity of particles and aerosols emitted by the combustion of standard vs. rapeseed methyl ester supplemented bio-diesel fuels: impact of after treatment devices: oxidation catalyst and particulate filter. AB - Diesel exhausts are partly responsible for the deleterious effects on human health associated with urban pollution, including cardiovascular diseases, asthma, COPD, and possibly lung cancer. Particulate fraction has been incriminated and thus largely investigated for its genotoxic properties, based on exposure conditions that are, however, not relevant for human risk assessment. In this paper, original and more realistic protocols were used to investigate the hazards induced by exhausts emitted by the combustion of standard (DF0) vs. bio diesel fuels (DF7 and DF30) and to assess the impact of exhaust treatment devices (DOC and DPF). Mutagenicity and genotoxicity were evaluated for (1) resuspended particles ("off line" exposure that takes into account the bioavailability of adsorbed chemicals) and for (2) the whole aerosols (particles+gas phase components) under continuous flow exposure ("on line" exposure). Native particles displayed mutagenic properties associated with nitroaromatic profiles (YG1041), whereas PAHs did not seem to be involved. After DOC treatment, the mutagenicity of particles was fully abolished. In contrast, the level of particle deposition was low under continuous flow exposure, and the observed mutagenicity in TA98 and TA102 was thus attributable to the gas phase. A bactericidal effect was also observed in TA102 after DOC treatment, and a weak but significant mutagenicity persisted after DPF treatment for bio-diesel fuels. No formation of bulky DNA adducts was observed on A549 cells exposed to diesel exhaust, even in very drastic conditions (organic extracts corresponding to 500 MUg equivalent particule/mL, 48 h exposure). Taken together, these data indicate that the exhausts issued from the bio-diesel fuels supplemented with rapseed methyl ester (RME), and generated by current diesel engines equipped with after treatment devices are less mutagenic than older ones. The residual mutagenicity is linked to the gas phase and could be due to pro-oxydants, mainly for RME-supplemented fuels. PMID- 25726175 TI - The cosmetic dye quinoline yellow causes DNA damage in vitro. AB - Quinoline yellow (QY) is a chinophthalon derivative used in cosmetic compositions for application to the skin, lips, and/or body surface. However, regulatory data about the genotoxicity and/or mutagenicity of this compound are still controversial. Therefore, this work evaluated the genotoxicity of QY using the comet assay and the cytokinesis-block micronucleus cytome assay (CBMN-Cyt) in the metabolically competent cell line HepG2, which closely mimics phase I metabolism. This research also identified the products formed after electrochemical oxidation of the QY dye, which simulates hepatic biotransformation. The primary products generated after the oxidation process were analyzed by High Performance Liquid Chromatography coupled with a Diode Array Detector (HPLC/DAD), which detected the production of 4,4'-diaminodiphenylmethane, 2-methoxy-5-methylaniline and 4,4' oxydianiline. The results demonstrated that low (from 0.5 to 20 MUg mL(-1)) QY concentrations were genotoxic in HepG2 cells on both assays and those harmful compounds were detected after the oxidation process. Our findings suggest that this colorant could cause harmful effects to humans if it is metabolized or absorbed through the skin. PMID- 25726176 TI - Genotoxicity assessment of melamine in the in vivo Pig-a mutation assay and in a standard battery of assays. AB - The genotoxicity of melamine was evaluated with the combined Pig-a mutation/micronucleus assay, the bacterial reverse mutation assay, and the in vitro cytokinesis-block micronucleus assay (CBMN). Five groups of six- to eight week-old male Sprague-Dawley (SD) rats were given three daily doses of vehicle control (100% pure sesame oil), melamine (500, 1000, and 2000 mg/kg) or positive control (N-ethyl-N-nitrosourea, ENU, 20 mg/kg) by oral gavage. Peripheral blood was sampled pre-dose (day -1) and at time points up to day 60. Pig-a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as RBC(CD59-) and RET(CD59-) frequencies, on days -1, 15, 29 and 60, and micronucleus frequencies were measured in RETs on day 4. No significant increases in RBC(CD59-) or RET(CD59-) frequencies were observed for the melamine-treated group at any of the time points studied, but the positive control, ENU, induced statistically significant increases compared with the vehicle control. Similar results were obtained in the micronucleus assay. Melamine did not induce statistically significant increases in %MN-RET. In the bacterial reverse mutation assay, melamine was tested from 62.5 to 1000 MUg/plate in tester strains TA97a, TA98, TA100, TA102, and TA1535, with and without metabolic activation, and no evidence of toxicity or mutagenicity was observed at any dose tested. In the in vitro CBMN assay, in Chinese hamster ovary (CHO) cells, melamine was tested (75, 150, and 300 MUg/mL) in the presence and absence of S9 mix, and no positive increases in the number of cells containing micronuclei were seen. These results suggest that melamine does not exhibit significant genotoxic potential. These data could be valuable for risk assessment purposes and also for further characterizing the new in vivoPig-a gene mutation assay. PMID- 25726177 TI - Ames positive boronic acids are not all eukaryotic genotoxins. AB - Boronic acids and their derivatives have been exploited for their pharmacological activity and their utility as intermediates in the synthesis of novel non-boron containing compounds. A recent study reported that boronic acids are bacterial mutagens. Here, results are reported from the testing of nine boronic acids using the pan-mechanistic eukaryotic GADD45a genotoxicity assays, BlueScreen HC and GreenScreen HC. Positive results were produced for one compound in GreenScreen and four compounds in BlueScreen. Only negative results were produced when tested with S9 metabolic activation. These data suggest that there is not a general genotoxic liability in eukaryotes, within this chemical domain. Furthermore, they are not potent eukaryotic genotoxins: positive results were produced only at concentrations between 1mM and 10mM. Their presence as low concentration contaminants or impurities would be unlikely to produce misleading positive results for a test material. PMID- 25726178 TI - Isolation rearing reveals latent antisnake behavior in California ground squirrels (Otospermophilus becheeyi) searching for predatory threats. AB - This study of California ground squirrels (Otospermophilus beecheyi) investigated the long-term effects of isolation rearing on alarm-call recognition. Six wild caught squirrels, trapped as yearlings, and six laboratory-reared squirrels were maintained in solitary cages for approximately 3 years prior to the study. Visual searching and olfactory searching were measured as squirrels emerged from their burrow-like nest box into a laboratory room after hearing repetitive playbacks of alarm calls or control sounds consisting of pulses of white-noise or ambient laboratory sounds. Before exiting completely after hearing alarm calls, both groups exhibited similar levels of visual searching that was reliably higher than after hearing the other sounds. After exiting completely, the laboratory-reared squirrels exhibited a reliably greater amount of olfactory investigation than the wild-caught squirrels. Five laboratory-reared squirrels turned around after exiting and inspected their dark nest-box opening, three of which tail flagged repeatedly and one threw substrate into the opening. Since pups recognize snakes and engage in this behavior, this latent expression of antisnake behavior illustrates its robust organizational properties in the appropriate burrow-like context irrespective of the presumed retardation of neural development known to occur in other species of rodent subjected to similar isolation rearing. PMID- 25726179 TI - Continuous noninvasive arterial pressure measurement using the volume clamp method: an evaluation of the CNAP device in intensive care unit patients. AB - The CNAP system allows continuous noninvasive arterial pressure measurement based on the volume clamp method using a finger cuff. We aimed to evaluate the agreement between arterial pressure measurements noninvasively obtained using the CNAP device and arterial catheter-derived arterial pressure measurements in intensive care unit patients. In 55 intensive care unit patients, we simultaneously recorded arterial pressure values obtained by an arterial catheter placed in the abdominal aorta through the femoral artery (criterion standard) and arterial pressure values determined noninvasively using CNAP. We performed Bland Altman analysis and calculated the percentage error. The mean difference (+/ standard deviation, 95% limits of agreement, percentage error) between noninvasive (CNAP) and invasively assessed arterial pressure was for mean arterial pressure +1 mmHg (+/-9 mmHg, -16 to +19 mmHg, 22%), for systolic arterial pressure -10 mmHg (+/-16 mmHg, -42 to +21 mmHg, 27%), and for diastolic arterial pressure +7 mmHg (+/-9 mmHg, -10 to +24 mmHg, 28%). Our results indicate a reasonable accuracy and precision for the determination of mean and diastolic arterial pressure by noninvasive continuous arterial pressure measurements using the volume clamp method compared with the criterion standard (invasive arterial catheter). Systolic arterial pressure is determined less accurately and precisely. PMID- 25726181 TI - Effect of electrolyte valency, alginate concentration and pH on engineered TiO2 nanoparticle stability in aqueous solution. AB - Agglomeration and disagglomeration processes are expected to play a key role on the fate of engineered nanoparticles in natural aquatic systems. These processes are investigated here in detail by studying first the stability of TiO2 nanoparticles in the presence of monovalent and divalent electrolytes at different pHs (below and above the point of zero charge of TiO2) and discussing the importance of specific divalent cation adsorption with the help of the DLVO theory as well as the importance of the nature of the counterions. Then the impact of one polysaccharide (alginate) on the stability of agglomerates formed under pH and water hardness representative of Lake Geneva environmental conditions is investigated. In these conditions the large TiO2 agglomerates (diameter>1MUm) are positively charged due to Ca(2+) and Mg(2+) specific adsorption and alginate, which is negatively charged, adsorbs onto the agglomerate surface. Our results indicate that the presence of alginate at typical natural organic matter concentration (1-10 mg L(-1)) strongly modifies the TiO2 agglomerate (50 mg L(-1)) stability by inducing their partial and rapid disagglomeration. The importance of disagglomeration is found dependent on the alginate concentration with maximum of disagglomeration obtained for alginate concentration >=8 mg L(-1) and leading to 400 nm fragments. From an environmental point of view partial restabilization of TiO2 agglomerates in the presence of alginate constitutes an important outcome. Disagglomeration will enhance their transport and residence time in aquatic systems which is an important step in the current knowledge on risk assessment associated to engineered nanoparticles. PMID- 25726180 TI - Contribution of apoptosis in myocardial reperfusion injury and loss of cardioprotection in diabetes mellitus. AB - Ischemic heart disease is one of the major causes of death worldwide. Ischemia is a condition in which blood flow of the myocardium declines, leading to cardiomyocyte death. However, reperfusion of ischemic regions decreases the rate of mortality, but it can also cause later complications. In a clinical setting, ischemic heart disease is always coincident with other co-morbidities such as diabetes. The risk of heart disease increases 2-3 times in diabetic patients. Apoptosis is considered to be one of the main pathophysiological mechanisms of myocardial ischemia-reperfusion injury. Diabetes can disrupt the anti-apoptotic intracellular signaling cascades involved in myocardial protection. Therefore, targeting these changes may be an effective cardioprotective approach in the diabetic myocardium against ischemia-reperfusion injury. In this article, we review the interaction of diabetes with the pathophysiology of myocardial ischemia-reperfusion injury, focusing on the contribution of apoptosis in this context, and then discuss the alterations of pro-apoptotic or anti-apoptotic pathways probably responsible for the loss of cardioprotection in diabetes. PMID- 25726182 TI - A French Nationwide Survey on Anesthesiologist-Perceived Barriers to the Use of Epidural and Paravertebral Block in Thoracic Surgery. AB - OBJECTIVES: To explore the barriers to the use of epidural block (EDB) or paravertebral block (PVB) for thoracotomy or thoracoscopy. DESIGN: Cross sectional ancillary study. SETTING: French nationwide practice survey. PARTICIPANTS: Lead anesthesiologists at centers practicing thoracic surgery completed an online questionnaire. INTERVENTIONS: A 9-item electronic questionnaire regarding perceived barriers to the use of EDB and PVB was developed, including technical factors, nursing factors (training and supervision), and reluctance of non-anesthesiologist colleagues (eg, surgeons, nurses and hospital managers). Descriptive and factorial analyses were conducted, including the current use of the techniques in the model. MEASUREMENTS AND MAIN RESULTS: The questionnaire was answered by 84 of 103 (82%) centers. For both techniques, the most frequently cited barriers were the 4 technical ones and lack of nursing supervision. There was a high rate of do not know/no opinion responses regarding barriers to paravertebral block. The type of center did not influence the responses, but paravertebral block was used more often in university hospitals. Colleague reluctance and time consumption (for both techniques), nursing barriers (for epidural block), and perception of risk and complexity (for paravertebral block), were correlated inversely with actual use. Perception of cost had no influence on practice. CONCLUSIONS: This survey suggested that the use of epidural or paravertebral block to provide analgesia for thoracic surgery might be increased by multimodal actions focused on improved communication with surgical and managerial teams. Paravertebral block, as an emerging technique, still is insufficiently recognized in France. PMID- 25726183 TI - Expression of podoplanin in the invasion front of oral squamous cell carcinoma is not prognostic for survival. AB - Podoplanin is involved in actin remodeling of the cytoskeleton of tumor cells and may promote tumor cell invasion by increasing cell motility and formation of filopodia-like membrane protrusions. Podoplanin is expressed in a variety of tumors, but its role in head and neck cancer, particularly in oral squamous cell carcinoma, remains unclear. We studied podoplanin expression by immunohistochemistry in 92 oral squamous cell carcinomas (OSCC) using a monoclonal antibody against an epitope of podoplanin (D2-40). In terms of the number of stained cells, 34 OSCC (38 %) had low podoplanin expression (less than 33 % of cells), 33 (36 %) showed moderate expression (between 34 and 66 % of cells), and 21 (22 %) showed high expression. The intensity of immunostaining was strong in 26 (28 %) cases, moderate in 36 (40 %), and weak or negative in the remaining 30 tumors (32 %). Immunohistochemical expression of podoplanin was associated with a tumor histological grade. A diffuse pattern of podoplanin expression significantly decreased in moderately differentiated (37 %) and poorly differentiated (20 %) carcinomas compared to well-differentiated (43 %) carcinomas. In addition, the focal expression of podoplanin in the invasion front of the tumor, without expression in the tumor center, was observed in 72 % of well-differentiated tumors, 27 % of moderate tumors, and 0 % of poorly differentiated tumors. Moreover, a trend was found toward an association of diffuse podoplanin staining with the development of second primary carcinomas (13 %), in contrast to its expression in the invasion front (3 %). No association was observed between podoplanin expression and nodal metastasis. PMID- 25726184 TI - HtrA1 may regulate the osteogenic differentiation of human periodontal ligament cells by TGF-beta1. AB - Periodontal ligament cells (PDLCs) in periodontal ligament (PDL) can differentiate into osteoblasts, while physiologically PDL remains non-mineralized space although located two hard tissues. But the exact mechanism of which is still unclear. High-temperature requirement protein A1 (HtrA1) is a key mineralization regulator and could inhibit the osteogenesis by transforming growth factor-beta (TGF-beta) signaling. However, the role of HtrA1 in PDLCs osteogenic differentiation has yet to be clarified. We assume HtrA1 may play an important role in maintaining the balance of PDL mineralization, and may regulate human periodontal ligament cells (hPDLCs) osteogenic differentiation by TGF beta1. Firstly we confirmed the mRNA expression of HtrA1 and TGF-beta1 in hPDLCs by RT-PCR, then QDs-based immunofluorescence demonstrated the co-localization of them in the cytoplasm, and co-immunoprecipitation further confirmed the interaction between them. Lentivirus-mediated HtrA1 overexpression enhanced the osteogenic differentiation of hPDLCs, as well as up-regulation of TGF-beta1. In contrast, knockdown of HtrA1 suppressed the osteogenic differentiation with down regulation of TGF-beta1. These findings suggested that HtrA1 plays a positive role in hPDLCs osteogenic differentiation and may regulate this process by TGF beta1. PMID- 25726185 TI - NIA's Intervention Testing Program at 10 years of age. AB - The previous 20 years of basic research on aging has identified a large number of genes and gene products whose expression can be manipulated in a variety of ways to increase the healthy life span of animal models such as yeast, nematodes, fruit flies, and mice. In an overt attempt to capitalize on this information, the National Institute on Aging (NIA) began a program in 2003 to identify nutritional and pharmaceutical interventions that could be safely employed to extend the healthy life span of mice. This program is called the Intervention Testing Program (ITP), and this article briefly describes the development of this initiative and some of the early success achieved during its first 10 years (2004 2014) of operation. PMID- 25726186 TI - Intuitive eating: an emerging approach to eating behavior. AB - INTRODUCTION: In an effort to treat obesity, health care professionals pursue, by means of dieting and exercise interventions, weight loss as a primary goal of treatment. Although in few cases these interventions induce shortterm moderate weight loss, in the long-term, the efficacy of these treatments is at least questionable. Weight-loss interventions based on restrictive diets may be associated to adverse health and well-being. In this regard, some researchers have considered shifting the focus of obesity treatment into a health-centered paradigm. Among the models derived from this new paradigm, Health at Every Size (HAES) is one of the most referenced. HAES has enhanced intuitive eating as a core component of the paradigm, which refers to the reliance on biological mechanisms to regulate food intake (i.e., internal hunger and satiety cues). Recently, intuitive eating has been winning recognition since it have been associated with numerous indices of physical and psychological well-being, and noteworthy, it have not been related to any adverse effects. OBJECTIVE: The present paper reviews the concept of intuitive eating, as well as the existing evidence that upholds this emerging approach. Also, it discusses the implication of shifting the focus of dietetic interventions into a health-centered paradigm. DESIGN: Narrative Review. CONCLUSIONS: Although it is certain there is a need to extend current research on health-centered interventions, this approach may be a more promising and realistic alternative to address overweight and obesity than the conventional weight-loss treatments. PMID- 25726187 TI - [Protocol for peripheral parenteral nutrition management ready to use in surgical patients]. AB - INTRODUCTION: Patients undergoing elective surgery, require a comprehensive clinical treatment that tends to maintain or prevent deterioration of nutritional status and promote clinical outcomes, and in turn improve the safety of parenteral nutrition therapy through optimization of technology, as a option aimed at minimizing risk and lower operating costs in institutions providing health services. AIM: To review the literature in order to study the requirements and recommendations of peripheral parenteral nutritional support and / or complementary ready to use in people undergoing surgery. METHODS: Data synthesis after reviewing the relevant literature, to allow the protocol design. The search was conducted in the following databases: PubMed, Medline, Embase and ScienceDirect. CONCLUSIONS: Peripheral parenteral nutrition is a ready to use alternative nutritional support that improves the contribution Protein-Energy and demonstrate improvements in patient safety, decrease costs and increase patient satisfaction. PMID- 25726188 TI - Mediterranean diet adherence and prostate cancer risk. AB - BACKGROUND: Countries following the traditional Mediterranean Diet, particularly Southern European countries, have lower prostate cancer incidence and mortality compared to other European regions. The beneficial effect has been attributed to a specific eating pattern. OBJECTIVE: The purpose of this review is to examine the evidence to date on the effects of adherence to a Mediterranean Diet on prostate cancer risk; and to identify which elements of the Mediterranean diet are likely to protect against prostate cancer. METHODS: The search for articles came from extensive research in the following databases: PubMed, Scopus and Web of Science. We used the search terms "Mediterranean diet", "adherence", "fruit and vegetable", "olive oil", "fish" "legume", "cereal" "alcohol" "milk", "dairy product","prostate cancer", and combinations, such as "Mediterranean diet and prostate cancer" or "Olive oil and prostate cancer". RESULTS: There is strong evidence supporting associations between foods that are typical of a Mediterranean eating pattern and reduced prostate cancer risk. However, there are few studies that have assessed the effect of the Mediterranean diet on cancer prostate incidence. Recent data do not support associations to adherence to a Mediterranean Diet and risk of prostate cancer or disease progression. However, Mediterranean eating pattern after diagnosis of nonmetastatatic cancer was associated with lower overall mortality. CONCLUSION: Further large-scale studies are required to clarify the effect of Mediterranean diet on prostate health, in order to establish the role of this diet in the prevention of prostate cancer. PMID- 25726189 TI - [Proposal of new trace elements classification to be used in nutrition, oligotherapy and other therapeutics strategies]. AB - OBJECTIVES: 1) to propose a new classification of the trace elements based on a study of the recently reported research; 2) to offer detailed and actualized information about trace elements. RESULTS: the analysis of the research results recently reported reveals that the advances of the molecular analysis techniques point out the importance of certain trace elements in human health. A detailed analysis of the catalytic function related to several elements not considered essential o probably essentials up to now is also offered. To perform the integral analysis of the enzymes containing trace elements informatics tools have been used. Actualized information about physiological role, kinetics, metabolism, dietetic sources and factors promoting trace elements scarcity or toxicity is also presented. RESULTS: Oligotherapy uses catalytic active trace elements with therapeutic proposals. The new trace element classification here presented will be of high interest for different professional sectors: doctors and other professions related to medicine; nutritionist, pharmaceutics, etc. Using this new classification and approaches, new therapeutic strategies could be designed to mitigate symptomatology related to several pathologies, particularly carential and metabolic diseases. PMID- 25726190 TI - Somatotype tendency in Chilean adolescents from Valparaiso: review from 1979 to 2011. AB - INTRODUCTION: A good tool to determine the biotype of growing and developing subjects that has been observed is the somatotype (ST). Objetive: This research study aims to describe the ST tendency in Chilean adolescents along the years. METHODS: The bibliographic review was carried out using data from Medline, ISI Web of Knowledge, and SciELO. The key words used for the search were: somatotype, somatotyping, adolescent (in English and Spanish). The selected articles must describe ST in Chilean adolescents between 15 and 18 years of age. The graphic representation was made through a somato-chart and the series ST. To analyze the trajectory of the ST, the moving average method was used (SM), and the tendency line (lineal; TL), which expresses the data direction and projection. RESULTS: Eight articles complied with the inclusion criteria. Samples of students between 1979 and 2011 from the Regions of Valparaiso, Araucania, and the Metropolitan region of Chile were reported. All studies correspond to transversal samples. The authors cite and/or describe the Heath-Carter anthropometric methods to assess the ST. The results showed positive TL for the endomorph component in all ages and genders. The mesomorph component maintained in male, unlike the female's component, which was negative except for the one at 18 years old. SM trajectory describes a regularity of the mesomorphic endomorph profile in female, yet with an increase in the endomorphy. In male, a change was observed from an ectomorphic mesomorph to endomorphic mesomorph. CONCLUSIONS: This progressive rise of the adipose component in both genders increases the risk of suffering non communicable diseases. PMID- 25726191 TI - [Association between feeding behavior, and genetic polymorphism of leptin and its receptor in obese Chilean children]. AB - INTRODUCTION: Leptin (LEP) is mainly produced in adipose tissue and acts in the hypothalamus to regulate energy intake. Mutations in the LEP gene or its receptor (LEPR) that produce monogenic obesity are infrequent. However, LEP and LEPR polymorphisms have been associated with obesity multifactorial, due to the association found with body weight and eating behavior. AIM: Measure the association between LEP and LEPR polymorphisms with childhood obesity and eating behavior. METHODS: 221 Chilean obese children (BMI above the 95th percentile) were recruited. Parents of 134 of these children were also recruited to determine the association between LEP and LEPR polymorphisms with obesity in a case study parent trio. Eating behavior was measured through the questionnaire of three factors progenitors' version (TFEQ-P19) and eating behavior in children (CEBQ). RESULTS: No significant difference between the studied polymorphisms and childhood obesity, after correction for multiple comparisons, was observed. The dimensions; "Slow eating", "emotional eating", "enjoyment of food" and "uncontrolling eating" were significant associated with certain polymorphisms of LEP and LEPR. CONCLUSIONS: There would be an association between polymorphisms of the LEP and LEPR genes with eating behavior in Chilean obese children. PMID- 25726192 TI - Are subjects with criteria for adult attention-deficit/ hyperactivity disorder doing worse after bariatric surgery? A case-control study. AB - INTRODUCTION: There is an increasing awareness of the strong associations between obesity and adult attention- deficit/hyperactivity disorder (ADHD), with high rates of ADHD (26-61%) in patients seeking weight loss. AIMS: To determine the frequency of ADHD in a bariatric surgery (BS) sample and investigate whether there were any differences among clinical, analytical and psychological parameters in individuals with criteria for ADHD. METHODS: Sixty patients (78.3% female, age 46.3+/-9.8, months since BS 46.28+/-18.1) who underwent BS, with a minimum follow-up of 18 months, were evaluated cross-sectionally. Initial and current BMI, eating patterns, comorbidity, socio-demographic and biochemical parameters were recorded. For the screening of ADHD, ADHD self rating scale-v1.1 was administered. RESULTS: Nineteen individuals (31.6%) had a positive screening for ADHD. This group had higher levels of HDL-cholesterol (62.8+/-17.3 mg/dl vs 53.5+/-9.9 mg/dl; p=0.011) and Apo-A (177.7+/-28.4 mg/dl vs 154.9+/-34.7 mg/ dl; p=0.015), and an increased consumption of lipids (42.2+/-7.1% vs 36.7+/-8.3%; p=0.019). Subjects with ADHD symptoms had more difficulties in following visits after BS (52.6% vs 24.3%; p= 0.011).We could not find any differences in achieved BMI, depressive symptoms or quality of life. CONCLUSIONS: Patients who met criteria for ADHD face significant difficulties with compliance in follow-up, but we could not find differences in major clinical outcomes. Surprisingly, these patients could have a protective lipid profile. PMID- 25726193 TI - Biomarkers of the prothrombotic state in abdominal obesity. AB - INTRODUCTION: Central obesity is specifically associated with cardiovascular disease. Nevertheless, the molecular events that promote these conditions remain incompletely defined and risk stratifying patients for cardiovascular disease continues a challenge. OBJECTIVE: The aim of this study was to assess some cost efficient haemostatic markers, and its association with central obesity and traditional cardiovascular risk factors, in a cohort of middle aged subjects, without clinical cardiovascular disease, as basis for an improved prevention and intervention. METHODS: We studied 307 men, aged 45+/-7 years, which underwent medical history, physical examination, anthropometric measurements, plasmatic biochemical parameters, plasma concentrations of fibrinogen, prothrombin activity, activated partial thromboplastin time, platelet count and mean platelet volume. RESULTS: Prothrombin activity values were significantly higher in patients with central obesity (103 +/- 16 % vs 111 +/- 17 %, p<0.001). Across tertiles of fibrinogen (low and high), there was an increase in cholesterol, adjusted for age and body mass index (4.9+/-0.9 mmol/L vs 5.4+/-1.1 mmol/L, p< 0.01). High tertile of prothrombin activity showed higher levels of cholesterol (4.8+/-1.0 mmol/L vs 5.4+/-0.9 mmol/L , p< 0.05), triglycerides (1.07+/-0.6 mmol/L vs 1.32+/-0.9 mmol/L, p< 0.05), and waist circumference (92.8+/-8.3 cm vs 96.5+/-8.8 cm, p= ns) . Mean values of cholesterol were higher in low-activated partial thromboplastin time tertile (5.3+/-0.9 mmol/L vs 4.9+/-1.1 mmol/L, p<0.01). Participants in the high-mean platelet volume tertile showed higher levels of glycemia (5.7+/-0.6 mmol/L vs 5.99+/-0.7 mmol/L, p<0.05). Significant positive correlations were observed between fibrinogen and cholesterol (r=0.198, p<0.001) and triglycerides (r=0.116, p<0.05). Prothrombin activity was positively correlated with waist circumference (r=0.156, p<0.05), glucose (r=0.227, p<0.001), cholesterol (r=0.270, p=0.001), triglycerides (r=0.187, p=0.001) and mean platelet volume (r=0.130, p=0.05). Activated partial thromboplastin time was inversely related cholesterol (r=-0.172, p<0.01) concentrations. Mean platelet volume rose with increasing glucose concentrations (r=0.170, p<0.01). CONCLUSIONS: Haemostatic markers studied have shown association with abdominal adiposity and established cardiovascular risk factors. These markers are widely available, relatively inexpensive, and might allow risk stratifying patients for cardiovascular disease and the identification of hypercoagulable state in patients who might deserve preventive measures and are potential tools for assessing the impact of these measures. PMID- 25726194 TI - Influence of age and religious fasting on the body composition of Muslim women living in a westernized context. AB - INTRODUCTION: Currently there is some controversy to whether Ramadan fasting leads to changes in the nutritional status and body composition of females who observe this practice. Furthermore, recent research suggest that age may be an important factor that affects anthropometric values and body composition just before and at the end of Ramadan. The aim of our study was to analyze the effects of Ramadan fasting, as modulated by age, on the nutritional status and body composition of a group of Muslim female subjects living in a westernized context. MATERIAL AND METHODS: A longitudinal study was carried out of 62 Berber Muslim females of ages ranging from 18 to 61 in the North African city of Melilla (Spain). The nutritional status was evaluated by anthropometry and their body composition studied by means of bioimpedance scales. These evaluations were performed before fasting began and again in the last week of Ramadan. RESULTS: The intermittent fasting produced important changes in the nutritional status and body composition of the female subjects. More specifically, there was a significant reduction (p=0.000) in total body weight values, BMI, body fat percentage measured by bioimpedance, and hip circumference (p=0.008). Significant differences were found (p=0.000) in anthropometric values and body composition before and at the end of Ramadan, depending on age. CONCLUSIONS: All the subjects experienced significant changes in nutritional status and body composition at the end of Ramada. These changes were more pronounced in the group of women over thirty years of age. . PMID- 25726195 TI - [Childhood obesity is associated to the interaction between firmicutes and high energy food consumption]. AB - INTRODUCTION: Obesity is a serious public health problem in Mexico, the National Health and Nutrition Survey (ENSANUT 2012) reported a 34.4% prevalence of overweight, and obesity in children aged 5-11. Recent research has suggested that the gut microbiota may be a risk factor of obesity through its influence on human metabolism. AIM OF THE STUDY: To evaluate association between the intestinal microbiota profile and obesity among children and whether this association is modified depending on the feeding pattern of a sample of schoolchildren from Mexico City. METODOLOGY AND RESULTS: Cross-sectional study on 1042 children aged 6-14 years; physical activity questionnaire, personal medical history and heredofamilial of obesity and type 2 diabetes were administered to all the children. Eating patterns was performed by principal component analysis (PCA). The association between intestinal microbiota and overweight / obesity depending on diet was assessed with logistic regression models. CONCLUSION: Our results shows that the interaction between the intestinal microbiota and diet, particularly high in fats and simple carbohydrates increases the chance of developing obesity. PMID- 25726196 TI - [Body image satisfaction in Mexican adolescents and adults and its relation with body selfperception and real body mass index]. AB - INTRODUCTION: Body Image (BI) perception could determine the nutritional care search, even though there is not always concordance between the real BMI and the self-perceived one. OBJETIVE: To determine the correlation between self-perceived and real BMI, and their relation with body image (BI) satisfaction in a sample of Mexican adolescents and adults. SUBJECTS AND METHODS: An cross-sectional and analytical study, conformed by 556 participants; of which 330 were adolescents and 217 were adults with anthropometric, self-perception and BI satisfaction assessment. RESULTS: The BMI was higher 23+/-6 vs 29.3+/-5 p<0.001 in adults, which doubled the level of overweight and obesity present in the adolescents 79% vs 43%. About 50% of participants had concordance between their real BMI and their perceived one (p<0.001). Of all adults with overweight and obesity 68% had satisfaction with their BI, whereas the prevalence of satisfaction with the BI in adolescents was 80%. The predictive variables of BI insatisfaction were being an adult, being a woman and having overweight/obesity (p=0.013). Those ones who referred a positive judgment about their BI, they also reported being satisfied with their BI and presented a real normal or overweight BMI. CONCLUSIONS: Half of the participants had concordance of their perceived BI with their real BMI. The satisfaction with BI was more frequent between the lower real and perceived BMI, but subjects with overweight and obesity also reported satisfaction with their BI even though it is considered a risk condition. PMID- 25726197 TI - Prevalence of underweight, overweight and obesity in university students from the region of Anhui (China). AB - BACKGROUND: Overweight and obesity are epidemic worldwide. Our previous study found that the prevalence of overweight and obesity in primary students is high. OBJECTIVE: we sought to estimate whether the prevalence of overweight and obesity among university students is still high in China. METHODS: A cross-sectional study was designed to collect the routine health screening data for university students in 2013. The height and weight of students were measured, and BMI was calculated with height and weight, we estimated the underweight and obesity prevalence of university students using by two references [Working Group on Obesity references in China (2004) and World Health Organization (WHO) criteria (2000)]. RESULTS: Depending on the China references used, the overall prevalence of underweight, overweight (including obesity) and obesity in male university students were 14.2%, 14.7% and 4.2%, respectively; in female university students were 27.5%, 4.4% and 0.6%, respectively. Depending on the WHO references used, the overall prevalence of underweight, overweight (including obesity) and obesity in male university students were 14.2%, 11.5% and 2.5%, respectively, in female university students were 27.5%, 2.4% and 0.3%, respectively. An interesting observation made was that the underweight prevalence of university students has an increasing trend, especially in female. CONCLUSION: The study showed that the prevalence of underweight in university students, especially in female students has become a critical health issue. Related department of school and government should pay more attention to student's physical health. PMID- 25726198 TI - Prevalence of obesity among secondary school students from 2009 to 2014 in China: a meta-analysis. AB - BACKGROUND: In recent years, obesity was a major public health problem in many countries. It was estimated that 8% of their children are obese. However, little is known about the overall prevalence of obesity among secondary students in China, the aim of this study was to evaluate the overall obesity prevalence of student from Chinese secondary school. METHODS: Publications from 2009 to 2014 on the obesity prevalence among secondary school students in China were retrieved from PubMed, online Chinese periodical full-text databases of VIP, CNKI and Wan fang. Meta Analyst was used analyze the total rates of obesity for Chinese secondary school. RESULTS: After evaluation of the quality of the articles, 32 papers were finally included in our study, and the total sample sizes on the obesity investigation were 218317 (107631 male and 110686 female), in which 27455(14865 male and 12590 female) were obesity. Meta-analyst findings showed that the pooled prevalence of obesity in secondary school students are 8.4 %( 95% CI: 6.2%- 11.3%) and 4.8 %( 95% CI: 3.2%-7.2%) for boy and girl respectively. CONCLUSION: Our results suggest that school and government related department should pay more attention to the obesity among secondary school students in China, and take some properly measures should to curve the trend growth of obesity. PMID- 25726199 TI - Levels of eicosapentaenoic acid in obese schoolchildren with and without insulin resistance. AB - BACKGROUND: Obesity in children is now an increasing health risk worldwide in which the insulin-resistance can be present. Studies have linked a diet rich in n 3 fatty acids with a lower prevalence of insulin-resistance. OBJECTIVE: To compare the levels of eicosapentaenoic acid among obese children with and without insulin-resistance. MATERIALS AND METHODS: In 56 randomly school-age children with obesity, insulin-resistance was determined by the homeostasis model assessment for insulin-resistance index and the serum levels of eicosapentaenoic acid were determined by gas chromatography. Insulin-resistance was established when the index was >6.0, non- insulin- resistance when that index was within the range of 1.4-5.9. The serum levels of eicosapentaenoic acid were compared with the Kruskal-Wallis and Mann-Whitney U tests, as needed. RESULTS: No differences in age or sex were identified among the groups studied. The anthropometric parameters were significantly higher in the group of children with insulin resistance than in the other two groups. The children with insulin- resistance had significantly lower levels of eicosapentaenoic acid than the non- insulin resistance group [12.4% area under the curve vs. 37.4%, p = 0.031], respectively. CONCLUSION: Obese primary school-aged children with insulin-resistance had lower plasma levels of eicosapentaenoic acid. PMID- 25726200 TI - [Short bowel syndrome and failure intestinal features in our community]. AB - INTRODUCTION: Intestinal failure is being an entity with higher prevalence in the pediatric age, especially due to bowel resections causing the appearance of a short bowel syndrome. OBJECTIVES: To determine the prevalence and etiology of cases of short bowel syndrome (SIC) and Intestinal Failure (FI) existing in Andalusia. Analyze factors involved in evolution, the number of transplant patients and to know the time required to achieve enteral autonomy, studying whether there are differences in management between different participants. METHODS: Multicenter retrospective descriptive observational study in which are collected data of patients diagnosed with short bowel syndrome or intestinal failure in 6 hospitals in Andalusia in the period from 1 January 2008 to 31 January 2014. RESULTS: 25 patients. Average age at diagnosis 7.4 months. Average length of remnant intestine: 113.8 cm; 64% of patients with <75 cm length remaining intestine. We show that: the early introduction of enteral nutrition is a factor favoring the suspension of the NP (p = 0'033); and that the prevention of liver disease associated with parenteral nutrition (EHANP) is favored by: the use of fewer lipid Parenteral Nutrition (p = 0'008), a greater length of remaining intestine (p = 0'049 ), the early introduction of enteral nutrition (p = 0'009) and a lower gestational age (p = 0'006). PMID- 25726201 TI - Reorganization of nutritional therapy can markedly reduce the rate of catheter related blood stream infections in pediatric patients receiving parenteral nutrition - a 7-year prospective follow-up study. AB - BACKGROUND: Implementation of hygienic measures and simple changes in the structure of medical team may considerably reduce the rate of catheter-related bloodstream infections (CRBSIs) in parenterally nourished patients. AIM: To analyze the effects of organizational changes in parenteral nutrition services on the CRBSI rates in pediatric patients. METHODS: We compared the CRBSI rates documented prior to, during and after the implementation of the organizational changes (introduction of a nutritional support team and related procedures, medical staff training). FINDINGS: A total of 260 courses of parenteral nutrition were offered to 141 pediatric patients during the analyzed period. Thirty CRBSIs were documented during this period. The most frequent etiological factors were staphylococci (21/30), followed by Klebsiella pneumoniae, Escherichia coli and Candida albicans (2/30 each). The reorganization was reflected by more than 8 fold reduction of the CRBSI incidence rate: from the initial value of 10.14 to 6.89 per 1000 catheter days and 1.17 per 1000 catheter days during and after the reorganization, respectively. CONCLUSION: Introduction of a nutritional support team, accompanied by extensive training of medical staff, can result in a marked reduction of CRBSI rate in pediatric patients nourished parenterally in a hospital setting. PMID- 25726202 TI - Prevalence of factors related to the bone mass formation of children from a cohort in Southern Brazil. AB - INTRODUCTION: The amount of bone mass acquired in the early stages of life is an important determinant of its peak and future risk of osteoporosis and fractures. OBJECTIVE: To describe the prevalence of factors that contributes to the formation of bone mass in children of a Southern Brazil cohort. METHODS: A retrospective cohort study with hospital screening of all births (2741) occurred from September/ 2002 to May/2003 and monitoring of a random sample of 30.0% of these (one, three and six months and eight years old). During the eight years old visit, a questionnaire containing questions related to food and physical activity was applied. Results e Discussion: Of the 616 children studied, 51.3% were male, 70.3% Caucasian, about half belonged to economic class C, 20.5% were overweight, 16.9% were obese and 71.2% were sedentary. As for food intake low consumption of fruits, vegetables, dairy products, meat, cereals and tubers was noticed. Vitamin D administration in the first six months of life was followed by 14.1% of premature, 16.1% of infants with low birth weight, 24.2% of weaned in the first month and only 16.4% at three months. CONCLUSION: The evaluated children have low nutrients consumption, including calcium, inappropriate vitamin D administration in the first semester of life, little regular physical activity and high prevalence of overweight and obesity are factors that can impair the formation of bone mass. PMID- 25726203 TI - Glycemic control and oxidative stress markers and their relationship with the thioredoxin interacting protein (TXNIP) gene in type 2 diabetic patients. AB - OBJECTIVE: To investigate the relationship between oxidative stress and biochemical parameters and the expression of TXNIP, IL-6, IL-1beta and TNF-alpha in peripheral mononuclear cells (PMCs) from type-2 diabetic patients. METHODS: We studied 60 males: 20 normal-weight type- 2 diabetic patients (NW), 20 obese diabetic patients (OB) and 20 controls (C). Biochemical and oxidative stress parameters were evaluated. PMCs were isolated and total RNA was extracted in order to determine the expression of TXNIP, IL-6, IL-1beta and TNF-alpha by qRT PCR. RESULTS: OB had higher weight, BMI and abdominal circumference (One way ANOVA, p<0.0001). NW had higher fasting glycemia (One way ANOVA, p=0.0034) however OB had higher HbA1c (One way ANOVA, p<0.0001). OB also had higher hsCRP (One way ANOVA, p=0.0158). TBARS and AGES were elevated in both NW and OB (One way ANOVA, p<0.0001 and p=0.0008, respectively). Compared to OB and C participants, the expression of TXNIP was significantly higher in NW (Kruskal Wallis, p=0.0074); IL-1beta, IL-6 and TNF-alpha transcripts were higher in NW and OB (Kruskal Wallis, p<0.0001, for all). In NW patients, the expression of TXNIP was positively correlated with fasting glycemia and AGES and negatively correlated with HOMA-beta (r=0.72; r=0.59; r=-0.44, respectively, for all p<0.05), in OB there was correlation only with 8-Isoprostanes (r=0.42, p=0.046). CONCLUSIONS: Our results suggest that fasting glycemic control, independent of adiposity and nutritional status, represents a risk factor for beta-cell dysfunction, increases oxidative stress markers and it is related with an elevation of TXNIP expression. PMID- 25726204 TI - Central obesity and not age increases skeletal muscle lipids, without influencing lean body mass and strength. AB - BACKGROUND/AIMS: To measure skeletal muscle lipid infiltration, its association with insulin resistance (IR) lean mass and function, in Chilean men differing in age and body composition. Our hypothesis was that muscle lipid accumulation would be higher among older and heavier individuals and this would deteriorate insulin sensitivity (IS) and decrease muscle mass and function, both features of the ageing process. METHODS: Healthy men (38 < 55 and 18 > 65 years), underwent anthropometric measurements, body composition assessment through radiologic densitometry, Nuclear Magnetic Resonance spectroscopy at the tibialis anterioris muscle to measure intra (IMCL) and extramyocellular lipids (EMCL), quadriceps and handgrip strength, 12 minute walking distance and serum biochemistry (haemoglobin, lipoproteins, creatinine, ultrasensitive C Reactive Protein, fasting and post glucose insulin and glucose concentrations, to assess IS). Physical activity was estimated by actigraphy. RESULTS: 23 men were eutrophic, 26 were overweight and 7 were obese and mostly sedentary, independent of age. Both IMCL and EMCL were higher in overweight/ obese men. Abdominal fat was negatively associated with IS and positively correlated with muscle lipid accretion (both IMCL and EMCL), but not with age. As expected, older individuals had lower muscle mass and strength, but not more adipose tissue nor intramyocellular lipids, yet were more glucose intolerant. CONCLUSIONS: central obesity was associated with IMCL and EMCL infiltration and IR. This type of lipid accretion was not related with ageing nor age-related sarcopenia. Older individuals were more glucose intolerant, which was explained by a decrease of insulin secretion more than adiposity-related IR. PMID- 25726205 TI - [Longitudinal study of the metabolic syndrome after kidney transplantation]. AB - BACKGROUND: The occurence of the metabolic syndrome (MS) between the renal receptors is one of the major complications after transplantation and is associated with an increased risk of graft failure and high rates of obesity and diabetes new appearance. AIMS: This study aims to investigate the prevalence and risk factors associated with the development of the MS and to evaluate the association between the same with the allograft dysfunction. METHODS: The samples consisted of 138 renal transplant patients, 83 men and 55 women, kidney transplant, which was attended by over five years for the transplant consultation. Were analyzed as potential risk factors for MS: age, sex, body mass index (BMI), weight, hypertension, diabetes, LDL, HDL, triglycerides in serum and immunosuppressive therapy (cyclosporine, tacrolimus, mycophenolate mofetil), was also assessed the prevalence of acute rejection episodes and renal function. RESULTS: The prevalence of MS was 39.85 %. As statistically significant risk factors were obtained the BMI, overweight, HDL cholesterol levels, triglycerides and LDL as well as hypertension and diabetes. There were high rates of acute rejection and differences in story to the glomerular filtration rate. CONCLUSIONS: There is a high prevalence of the MS that severely compromised renal function and graft survival in renal transplant patients, it is very important the control and strict monitoring of all risk factors identified. PMID- 25726206 TI - Nutritional adequacy in subjects with metabolic syndrome. AB - INTRODUCTION: The nutritional approach in the treatment of metabolic syndrome is a fundamental factor. It is important to raise awareness to patients about the benefits of following the treatments when you want to promote changes in lifestyle. OBJECTIVE: The aim of this study was to assess nutritional adequacy in subjects with metabolic syndrome according to the dietary recommendations prescribed. METHODS: Quasi-experimental research with 72 subjects with metabolic syndrome, held in southern Brazil. A nutritional orientation was conducted, related or not with physical exercise for three months. A 24-hour recall and two day food record, were the reference method of dietary intake assessment. Nutritional adequacy was determined by the energy and nutrient intakes as defined by the Brazilian Food Guide Pyramid groups. RESULTS: Volunteers reached on average 80% of the energy consumption recommended. Protein and lipid intake was higher, and carbohydrate consumption was lower than recommended levels. There was a low intake of cereals, vegetables, dairy product and beans (p<0.001) as compared with the recommended servings. A high consumption of meat (p<0.001) and an adequate intake of fruit (p=0.149) were observed. CONCLUSION: The dietary intake was insufficient to meet the recommendation of energy, although the goal for weight loss was achieved. Still, the results show the need for a balance in food intake and quality of the diet to achieve nutritional adequacy. PMID- 25726207 TI - [Serum vitamin D and metabolic risk factors in a group of Spanish schoolchildren]. AB - OBJECTIVE: To analyze the vitamin D status and its relationship with metabolic syndrome (MS) risk factors in a group of Spanish schoolchildren. MATERIAL AND METHODS: A group of 314 Spanish schoolchildren (8-13 years old) from A Coruna, Barcelona, Madrid, Seville and Valencia were studied. Anthropometric data on weight, height, waist and hip circumferences, and triceps skinfold, as well as blood pressure data were collected. Serum levels of glucose, triglycerides, HDL-c and 25-hydroxycholecalciferol (25 (OH) D) were assessed. Following Cook criterion, the following MS risk factors were defined: glucose >=100 mg/dL; >=P90 waist circumference; triglycerides> P90, HDL <=P10; and sistolic and/or diastolic blood pressure > P90. RESULTS: Mean serum 25(OH)D were 23.0?+/-8.6 ng/mL. Forty seven percent of children had hypovitaminosis (20- 30 ng/mL) and 35% had vitamin deficiency (<20 ng/mL). Compared to the first tertile, children in the second tertile have a lower risk of elevated triglycerides (OR = 0.50 [CI = 0.25 to 0.99]; those in the the third tertile had lower risk of high blood pressure and triglycerides (0.60 [CI = 0.42-0.86] and 0.50 [CI = 0.32 to 0.79], respectively). CONCLUSION: The prevalence of vitamin D deficiency is high in this group of Spanish schoolchildren. Low serum levels of vitamin D are associated with an increased risk of elevated triglycerides and blood pressure. PMID- 25726208 TI - Antioxidant capacity of leaf extracts from two Stevia rebaudiana Bertoni varieties adapted to cultivation in Mexico. AB - The recent introduction of the cultivation of Stevia rebaudiana Bertoni in Mexico has gained interest for its potential use as a non-caloric sweetener, but some other properties of this plant require studies. Extracts from two varieties of S. rebaudiana Bertoni adapted to cultivation in Mexico were screened for their content of some phytochemicals and antioxidant properties. Total pigments, total phenolic and flavonoids contents of the extracts ranged between 17.7-24.3 mg/g, 28.7-28.4 mg/g, and 39.3-36.7 mg/g, respectively. The variety "Criolla" exhibited higher contents of pigments and flavonoids. Trolox equivalent antioxidant capacity ranged between 618.5-623.7 mM/mg and DPPH decolorization assay ranged between 86.4-84.3%, no significant differences were observed between varieties. Inhibition of beta-carotene bleaching ranged between 62.3-77.9%, with higher activity in the variety "Criolla". Reducing power ranged between 85.2-86% and the chelating activity ranged between 57.3-59.4% for Cu2+ and between 52.2-54.4% for Fe2+, no significant differences were observed between varieties. In conclusion, the results of this study showed that polar compounds obtained during the extraction like chlorophylls, carotenoids, phenolic compounds and flavonoids contribute to the antioxidative activity measured. The leaves of S. rebaudiana Bertoni could be used not only as a source of non-caloric sweeteners but also naturally occurring antioxidants. PMID- 25726209 TI - The Mediterranean diet and micronutrient levels in depressive patients. AB - INTRODUCTION: An inverse association between depression and some serum micronutrient levels (selenium, zinc, iron, magnesium, vitamin B and folic acid) has been reported. In addition, other studies reported that this micronutrient supplementation may improve depressed mood. The Mediterranean diet contains a sufficient amount of the micronutrients mentioned, although no study has reported an association between diet prescription and increased levels of them in depressive patients. OBJECTIVE: To examine the impact of dietary patterns recommendations on micronutrient levels in depressive patients. METHODS: 77 outpatients were randomly assigned either to the active (hygienic-dietary recommendations on diet, exercise, sleep, and sun exposure) or control group. Outcome measures were assessed before and after the six month intervention period. RESULTS: Serum selenium and zinc levels were slightly low at basal point and serum selenium was inversely correlated with severity of depression (r= 0.233; p=0.041). A better outcome of depressive symptoms was found in the active group. Nevertheless, no significant differences in micronutrient levels were observed after the Mediterranean diet pattern prescription, probably due to an insufficient adherence. CONCLUSION: Selenium, zinc, iron, magnesium, vitamin B12 and folic acid serum levels didn't increase in depressed patients after six months of the Mediterranean diet pattern prescription. PMID- 25726210 TI - Chia induces clinically discrete weight loss and improves lipid profile only in altered previous values. AB - INTRODUCTION: chia (Salvia hispanica L.) has an elevated concentration of dietary fiber, it has been used to weight loss and enhance blood glucose and lipid profile. However, data in human are still scarce or do not exist, according to the analyzed variable. AIM: to evaluate the effect of chia supplementation in body composition, lipid profile and blood glucose in overweight or obese individuals. METHODS: men and women were randomly allocated in groups that ingested 35 g of chia flour/day (CHIA; n=19; 48.8+/-1.8 years) or placebo (PLA; n=7; 51.4+/-3.1 years) for 12 weeks. Body composition and food intake were evaluated in each four weeks. Lipid profile and blood glucose were measured in the beginning and in the end of the study. RESULTS: Chia induced significant intragroup reduction in body weight (-1.1+/-0.4 kg; p<0.05), with a greater reduction among obese than overweighed individuals (-1.6+/-0.4 kg; p<0.00), but without difference when compared to PLA. Waist circumference reduced 1.9+/-0.6 cm in CHIA group (p <0.05), but only intragroup. It was observed a reduction in total cholesterol (p=0.04) and VLDL-c (p=0.03), and an increase in HDL-c (p=0.01) but only in the groups that ingested chia flour and presented abnormal initial values. Triglycerides, blood glucose and LDL-C showed no changes for either group. CONCLUSION: consumption of chia for 12 weeks promotes significant but discrete reduction in weight and waist circumference, and enhances lipid profile dependent of initial values. PMID- 25726211 TI - Effect of computer radiation on weight and oxidant-antioxidant status of mice. AB - OBJECTIVES: To explore the effects of computer radiation on weight and oxidant antioxidant status of mice, and further to confirm that whether vitamin C has protective effects on computer radiation. METHODS: Sixty Male adult ICR mice were randomly divided into six groups. each group give different treatment as follows: group A was control, group B given vitamin C intake, group C given 8 h/day computer radiation exposure, group D given vitamin C intake and 8 h/day computer radiation group E given 16 h/day computer radiation exposure, group F given vitamin C intake plus exposure to 16 h/day computer radiation. After seven weeks, mice was executed to collect the blood samples, for detecting total antioxidant capacity (T-AOC) and alkaline phosphatases (ALP)content in serum or liver tissue were determined by ELISA. RESULTS: No difference was found for the change of weight among six groups at different week. In the group C, D and F, the liver tissue T-AOC level were higher than the group A. In the group B, C and E, the serum ALP level were lower than the group A (P<0.05). CONCLUSIONS: The study indicate that computer radiation may have an adverse effect on T-AOC and ALP level of mice, and vitamin C have protective effect against computer radiation. PMID- 25726212 TI - [Validation of cut points of skeletal muscle mass index for identifying sarcopenia in Chilean older people]. AB - OBJECTIVES: To estimate and validate cut-off points of skeletal muscle mass index (SMI) in Chilean population, for using in an algorithm for a diagnosis of sarcopenia developed by European Working Group on Sarcopenia in Older People (EWGSOP). METHODS: Secondary analysis of Cross-sectional data in 440 Chilean older subjects to estimate cut-off points of SMI determined by DEXA and predicted by an anthropometric equation. Afterward a cross-sectional validation in a sample of 164 older people was performed. Anthropometric measures, self-reported health status, physical performance tests and DEXA were carried out. Decreased muscle strength was defined as handgrip strength <15 kg in women and <27 kg in male. Cut off points of SMI were defined as values under 20th percentile for DEXA measures and estimated through ROC curves for the anthropometric model. Biological validity of the algorithm was tested by contrasting the diagnosis with physical performance tests and functionality. RESULTS: Cut-off points of SMI obtained by DEXA were 7.19 kg/m2 in men and 5.77 kg/m2 in women and 7.45 kg/ m2 and 5.88 kg/m2, respectively for the predicted by the model. Sensibility and specificity of estimations vs DEXA measures were 80% and 92% in men and 77% and 89% in women. CONCLUSIONS: We obtained cut-off points of SMI for DEXA and for a prediction equation for older adults Chilean, with good sensibility and specificity for the measurement by DEXA. It will allow to apply the EWGSOP algorithm to the early diagnosis of sarcopenia and to develop programs for prevention, delay or reversion this syndrome. PMID- 25726213 TI - Nutritional status of institutionalized elderly Brazilians: a study with the Mini Nutritional Assessment. AB - OBJECTIVE: To assess the nutritional status of elderly living in nursing homes in the city of Salvador, Brazil and associated factors. METHODS: Cross-sectional study performed with 359 individuals of both sexes, ages equal or over 60 years old, located in Nursing Homes in the urban area of the city of Salvador, Bahia, Brazil. RESULTS: Regarding nutritional status according to Mini Nutritional Assessment (MNA), 66.3% of the evaluated elderly were malnourished and at risk of malnutrition. When comparing sexes, it has been observed that among men the prevalence of this condition (76.6%) was higher than in women (62.4%). It has been observed, as a result of the multivariate analysis, that only the variable functional capacity for Activities of Daily Living (ADL) was statistically significant. There was moderate correlation between MNA and Mini-Mental State Examination (r=0.454; p<0.0001), as well as between MNA and the ADL scale (r=0.569; p<0.0001). There was weak negative correlation between MNA total score and age (r=0.159; p=0.002). CONCLUSION: Malnutrition and malnutrition risk were conditions of remarkable importance, with almost two-thirds of the elderly in this situation. ADL functional capacity must be monitored given their close relationship with the nutritional status of the elderly. An interdisciplinary approach in the context of institutionalization is needed due to the association between nutritional status and variables of different dimensions. PMID- 25726214 TI - [Prevalence of malnutrition in Spanish institutionalized older people: a multicentric nationwide analysis]. AB - INTRODUCTION: Deficient nutritional status has important implications on vulnerable people's health status, such as those with chronic diseases or older people in situation of dependency. OBJECTIVE: To examine SARquavitae centers users' nutritional status at admission. MATERIAL AND METHODS: Health, cognitive and functional status of people admitted to any company centers during 2012 was studied. Nutritional status was assessed using the short version of the Mini Nutritional Assessment. Finally, an analysis was performed to identify the most influential variables on the sample's nutritional status. RESULTS: Clinical records of 4,297 admissions were analyzed. The average age was 82.08 years and 66.1% were women with high comorbidity. At admission, 30.4% of the sample was in malnutrition and 49.4% at risk of malnutrition. A higher prevalence of malnutrition is found in women, in those coming from an acute care hospital or its outpatient clinics, with worse functional and cognitive status and those with chronic conditions such as dementia, cerebrovascular disease or dysphagia. CONCLUSIONS: As demonstrated by the study results, people admitted to SARquavitae nursing homes present a high clinical complexity. Comprehensive assessments are needed that allow establishing specific care plans for people with complex care needs in nursing homes. PMID- 25726215 TI - [Impact of exercise on the body composition and aerobic capacity of elderly with obesity through three models of intervention]. AB - OBJECTIVE: The objective of this study was to analyze the influence of aerobic exercise on body composition and aerobic capacity of a sample of older, sedentary adults with obesity rates by three different models of intervention (recommendation, prescription at home and monitoring). MATERIAL AND METHODS: A total of 76 older adults with a mean age 67.1+/-1.2 years, sedentary, with a BMI> 30 kg/ m2 were randomized in to four groups: Control (CON) recommendation (REC), prescription home (PRES) and monitoring in a sports center (MON). The same program of aerobic exercise for groups of home and sports center for 24 weeks, 3 days a week was developed. It was determined before and after the intervention BMI, Waist- Hip-index (ICC), the% fat ( Sigma folds) and aerobic capacity (T6M) throughout the sample. RESULTS: MON and PRES groups showed significant improvements in the ICC, Sigma folds and T 6M variables, not the case in BMI. However the MON group presented significant differences from group PRES between group analysis (p <0.001). The recommendation did not get positive effects. CONCLUSION: Monitoring is the most effective exercise programs in adults with obesity methodology. However the exercise prescription at home since early intervention is an important approach for people with physical and/ or psychological reasons such as obesity cannot access the sports centers to participate in activities led by a monitor. Unknowns of aerobic exercise are cleared in the home that are of great impact for social policies regarding the health of the elderly population. PMID- 25726216 TI - [Influence of sport practice and physical exercise on anthropometric indicators and weight satisfaction in men university students: a pilot study]. AB - INTRODUCTION: University students generally have low levels of physical activity, which could affect the body weight and composition and the knowledge and acceptance of their own body. OBJECTIVE: To assess weight status and body composition, as well as self-perception and satisfaction with body weight in university students, and to analyze the influence of sport practice and physical exercise on these variables. METHODS: A sample of 62 male students with a mean age of 20.7+/-1.7 years was evaluated. Sport practice and physical exercise in leisure time were analyzed by questionnaire. Weight status and body composition were assessed by anthropometry. Data about self-reported and desired weight and self-reported height were also registered. Measurements of actual, self-reported and desired weight were used to estimate self- perception and satisfaction with weight. Statistical analysis was performed using SPSS version 22.0. RESULTS: Overall 17.7% of participants had overweight and 6.5% underweight. The energy consumption due to sport practice and/or physical exercise was <= 3,000 kcal/ week in the 45.2% of the students and > 3,000 kcal/week in the 32.3%. Self perception and satisfaction with weight was better in the group who practiced sport and/or physical exercise at the rate of <= 3.000 kcal/week than in those who did not practice any sport or exercise (P < 0.05). CONCLUSION: Regular practice of sport or physical exercise is associated with a better self perception and satisfaction with body weight compared with a sedentary lifestyle. The university studies period should be used to promote sport practice and physical exercise, using the resources or assets of the University. PMID- 25726217 TI - [Physical activity habits in schoolchildren: influential factors and relationships with physical fitness]. AB - INTRODUCTION: Current lifestyles have led to an increase in sedentary activities and a decrease in physical activity, which can lead to a worsening of the present and future health of children. AIMS: This study sought to describe the lifestyle and physical activity habits of schoolchildren in a city in northern Spain and to analyse the relationships between these habits and body composition, physical fitness and certain socio-demographic factors. METHODS: The study was conducted on a representative sample of 329 sixth grade elementary school students (aged 11 12) from 31 schools in Logrono (La Rioja). Socio- demographic data, anthropometric data, blood pressure, development level, physical fitness and lifestyle habits and physical activity were recorded. RESULTS: The male students who performed extracurricular sports activities and those at earlier stages of development reported higher levels of physical activity. Direct correlations between physical exercise and fitness were detected, especially with respect to aerobic capacity (r = 0.38), and inverse correlations with hours in front of a screen (r = -0.18), but not with body composition. CONCLUSIONS: Given the relationships between levels of physical activity and fitness, strategies to promote physical exercise should be encouraged in order to improve the health of young people. Interventions should focus on promoting access to extracurricular sports activities, reducing sedentary habits and increasing the level of physical exercise in girls. PMID- 25726218 TI - [Effects of diet and aerobic or anaerobic exercises on eating disorders]. AB - INTRODUCTION: Endurance exercises have a direct influence on aerobic capacity. To improve this quality is necessary develop an extensive and continuous training sessions. However anaerobic exercise requires low volume of training and high intensity to sport performance. In aerobic or anaerobic exercise is obvious to state that weight reduction must be performed from the body fat component, furthermore is an important point of view from the last years. Therefore, it is of vital importance to control the strategies used by the athletes in order to obtain the correct weight and avoid eating disorders. OBJECTIVE: identify differences comparing for groups that develop aerobic or anaerobic exercises, and concerns related to eating disorders, dietetic habits and physical activity. METHOD: 206 trained men were examined and participated in the study, that can be screened using the validated EAT-26 questionnaire, Predimed fat-free diet questionnaire and Spanish short version of the Minessota Leisure Time Physical Activity questionnaire. RESULTS: Athletes who practice aerobic physical activity showed higher values at majority of EAT-26 scales and total score. When this population increased their training sessions presented higher scores of Oral Control. The effects of consuming supplementation increases EAT-26 scores and eating disorder predisposition. In addition, high-structured training session increases EAT-26 scores and eating disorder predisposition too. DISCUSSION: Practice aerobic physical activities seem to show a greater predisposition to the presence of TCA in athletes. PMID- 25726219 TI - [Spanish version of Adonis Complex Questionnaire. A questionnaire to test the muscle dimorphism and vigorexy]. AB - AIM: To validate the Spanish version of Adonis Complex Questionnaire in bodybuilders. METHOD: Participants included 99 bodybuilders who train regularly (age: 25.45+/-5.19 y; BMI=24.53+/-1.89). In order to test the discriminant and concurrent validity the Exercise Dependence Scale-Revised (EDS-R) and the Eating Attitudes Test (EAT-26) were used. The scale's psychometric properties were obtained through a concurrent validity process, factorial analysis of principal components, internal consistency, and test-retest reliability. RESULTS: The internal consistency of this questionnaire was high (Cronbach's Alpha= 0.880) in total scale. The intraclass correlation coefficient (ICC) to test the temporal consistency of the questionnaire was 0.707 (95% IC=0.336- 0.871). The questionnaire obtained concurrent validity with the EDS-R (r=0.613, p<0.001), and EAT-26 (r=0.422, p<0.001). The results have shown a three-factor structure Factor 1: psychosocial effect of physical appearance, Factor 2: control of physical appearance, Factor 3: concern about physical appearance which explain 65.29% of variance. CONCLUSION: The Adonis Complex Questionnaire shows a proper psychometric properties and it is a valid and reliable measure of vigorexy and muscle dimorphism in bodybuilders. PMID- 25726220 TI - [A better self-perception of physical fitness is associated with lower prevalence of metabolic syndrome and its components among university students]. AB - OBJECTIVE: To evaluate whether more positive self-perception of physical fitness is associated with lower prevalence of metabolic syndrome (MetS) and its components in university students in Bogota, Colombia Method: A total of 493 men (mean age 28.5+/-11.5 years old) without cardiovascular disease university students completed the self-report fitness tool, namely "The International FItness Scale" (IFIS). The overall prevalence of MetS and its components according to "International Diabetes Federation" (IDF) criteria and the "National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood, Cholesterol in Adults" (NCEP: ATP-III) were measured. Body Fat Mass (BFM), Body Fat Percentage (BF %), Fat-Free Mass (FFM) and Fat-Free Mass Index (FFMI), were estimated using segmental bioelectrical impedance equipment. RESULTS: Twenty three percent of participants had met the criteria of MetS. Central obesity (33%) was the most prevalent factor, followed by low HDL cholesterol level (31%). The other factors associated with the presence of MetS were hypercholesterolemia (60%), high LDL cholesterol level (32%) and hypertriglyceridemia (19%). Participants reporting to have a "good/very good" in the self-reported (cardiorespiratory and muscle fitness specific components), shown a healthy range in blood pressure, FFM, FFMI and triglycerides level (p <0.05). After adjustment for age and BMI, participants reporting to have a "good/very good" had lower prevalence in the components central obesity, blood pressure, triglycerides and HDL cholesterol level than those grouped in "acceptable" and/or "very poor/poor" (p <0.05). CONCLUSION: Participants with a lower self-perception of physical fitness have an increased prevalence of MetS and its components. This study suggests that the self-report tool used in this study, the IFIS tool, is a useful method to be used in large scale surveys and epidemiological studies in which, because of time, equipment, or qualified personnel limitations, fitness cannot be directly measured. PMID- 25726221 TI - [Effect of precipitation and seasonal period on the patterns of commuting to school in children and adolescents from Granada]. AB - BACKGROUND: Active commuting (walking or cycling) to school contributes to increase physical activity levels in young people. Meteorological conditions might have a remarkable influence on this behaviour. OBJECTIVE: The aim is to study the impact of the rainfall and seasonality on the mode of commuting to primary school or secondary school in children and adolescents from Granada. METHODS: A total of 384 students (166 children and 218 adolescents) between 8-18 years from 2 different schools (primary and secondary schools) of Granada took part in the research. Participants filled a questionnaire about their weekly pattern on the mode of commuting to school in the three seasons of the academic year. Data about the rainfall in those three weeks was obtained from the National Agency of Meteorology. The association between rainfall and seasonality with mode of commuting to school was studied by McNemar test. RESULTS: No significant associations were spotted between the rainfall and the seasonality with mode of commuting in children and adolescents (p>0.05) except for: a) a positive effect of rainfall in the percentage of children who usually walked to school between a rainy day and a non-rainy day in spring (p=0.031) and b) a weak effect of the seasonality on the percentage of children and adolescents who usually walk between autumn and winter (45.8% and 37.5% walk to school) and between autumn and spring (59.7% and 56%) respectively (p=0.07). CONCLUSIONS: The meteorological conditions do not seem to influence the mode of commuting to school in children and adolescents from Granada, which might indicate that this behavior keeps a constant pattern throughout the whole academic year. PMID- 25726222 TI - Hydration status after exercise affect resting metabolic rate and heart rate variability. AB - INTRODUCTION: Heart rate variability and resting metabolic rate are commonly to assess athlete's physiological status and energy requirements. Exercise-induced dehydration can reach up to 5% of body mass per hour. Consequently, dehydration may have a profound physiological effect on human's homeostasis. OBJECTIVES: To compare the effects of dehydration and rehydration after exercise on heart rate variability and resting metabolic rate in college athletes. METHODS: 14 college athletes were divided into a dehydration group (n=7) and a rehydration group (n=7), both submitted to basal (T1) heart rate variability and resting metabolic rate measurements. After basal measurements both groups were actively dehydrated (-3.4 +/- 0.4% of body mass for both groups). Afterwards, dehydration group rested, while rehydration group receive a fluid intake (during a 3 h period) equivalent to 150% of body mass loss achieved during active dehydration. Four hours after active dehydration heart rate variability and resting metabolic rate were re-assessed (T2). RESULTS: At T2 both rehydration group (+13%) and dehydration group (+30%) achieve a significant (p<0.05) increase in resting metabolic rate, however, only dehydration group ..showed a significant reduction in heart rate variability. More so, the change in resting metabolic rate was significantly higher in dehydration group compared to rehydration group. DISCUSSION: Hydric homeostasis after exercise affects resting metabolic rate and heart rate variability, highlighting the necessity to control hydration state before resting metabolic rate and heart rate variability assessment. PMID- 25726223 TI - [Phase angle as an indicator of nutritional status and prognosis in critically ill patients]. AB - INTRODUCTION: The phase angle (PA) has been considered a sensitive tool to assess nutritional status and effectiveness of interventions dietetics. OBJECTIVE: To evaluate the PA as an indicator of nutritional status and prognosis in critically ill patients. METHODS: Prospective observational study of patients admitted to the Coronary Intensive Care Unit between May and October 2013. The PA was determined by bioelectrical impedance analysis, PA was considered low below 5o values for men and 4.6o for women. The values obtained were related to other evaluation parameters of nutritional status: anthropometric (arm circumference - AC , triceps skinfold thickness - TST , corrected arm muscle area - AMAc and calf circumference - CC) and biochemical (total lymphocyte count, hemoglobin, hematocrit), in addition to clinical prognostic APACHE II (Acute Physiology and Chronic Health Disease Classification System II) and serum albumin. The tabulation and analysis were performed using SPSS version 13.0. RESULTS: The sample consisted of 110 patients, in which an association was found between low AF and renal failure on dialysis (p < 0.001), % adequacy AC (p = 0.028), % adequacy of TST (p = 0.043), albumin level (p = 0.042), anemia (p = 0.040) and APACHE II (p = 0.012) scores. The AF was positively correlated with CC (p= 0.043) and inversely with the length of hospitalization (p = 0.006). CONCLUSIONS: PA in the ICU may be useful to identify early and malnourished patients as a prognostic indicator. PMID- 25726224 TI - Late referral for chronic kidney disease patients: nutritional point of view. AB - The prevalence of late referral of patients with chronic kidney disease (CKD) is high and has been associated with a worse CKD prognosis, however few studies have been conducted from a nutritional perspective. OBJECTIVE: Characterize the nutritional status of patients with CKD at first attendance in a nephrology service, with early (ER) and late referral (LR). METHODOLOGY: It was a cross sectional study with patients older than 18 years referred to the Nephrology service of a University Hospital. The referral groups were classified according to estimated glomerular filtration rate (eGFR) as: LR (eGFR15 ml/min/1.73m2) based on the Kidney Disease Outcomes Quality Initiative. Nutritional evaluation included subjective global assessment (SGA), anthropometric, laboratory and bioelectrical impedance data. The SAS software was used for statistical analysis. RESULTS: Seventy-five patients were evaluated, 29% of them belonging to the LR group. This group showed a greater previous weight loss (-7.0 +/- 3.5 versus -2.8 +/- 7.0 Kg) and lower values for all anthropometric and body composition variables. In general, the laboratory results of the LR group also were worse. According to the SGA, all LR patients had some degree of malnutrition (50% with severe malnutrition against 28.8% in ER), showing significantly lower results for GFR (21.4 + 12.2 ml/ min/1.73 m2), albumin (3.9 + 0.3 g/dL), serum bicarbonate (22.8 + 5.1 mmol/L) and phase angle (5.3+ 0.6 theta). Renal function was positively correlated with percent adequacy of arm circumference (r=0,40; p<0,01) and albumin (r=0,45; p<0,01). CONCLUSION: The LR group showed a worse nutritional status showing that, for the nutritional point of view, the delayed referral brings substantial losses that can make difference in future treatment, thus demonstrating the importance of early nutritional monitoring for this population. PMID- 25726225 TI - Body composition assessment of paddle and tennis adult male players. AB - INTRODUCTION: Racket sports require athletes to constantly improve and progress in their physical qualities in order to maintain competitive standards. This includes achieving and maintaining an optimal body composition. However, few studies have been published addressing this topic. OBJECTIVE: This study tries to provide a complete anthropometric profile, including somatotype and body composition, of paddle and tennis male adult players. METHODS: Anthropometric parameters including weight, height, skinfolds, girths and breadths were measured in 21 paddle and 26 tennis players, and the results were compared between the two groups as well as a control group, who did not play racket-based sports. RESULTS: No significant differences in any body composition variable were found comparing tennis vs paddle players, with both groups showing a meso-endomorphic somatotype. The athletes presented lower muscle mass, and therefore less mesomorphic component, compared to the control group. CONCLUSION: Since body composition is a major determinant in racket sport performance, it is instrumental to control fat and muscle body mass by using adequate dietetic and nutritional tools as well as optimal training programs. PMID- 25726226 TI - [Nutritional content of foods offered and consumed in a Spanish university canteen]. AB - OBJECTIVE: The prime objective of our work was to study the eating habits at lunchtime of staff and students at a University of "hidden due to confidentiality"of Spain. The second one was to attempt to reduce the energy consumption of cholesterol and fat in the diet of those groups. SETTING: The study was made between 2010 and 2012 in the main canteen serving food at this university, focusing on food intake at lunch, the main meal of the day, containing between 35 and 40% of the total calories ingested throughout the day. SUBJECTS: A total of 9530 observations were made, each one corresponding to the nutritional valuation of food eaten (a complete lunch) per person, by students, teachers and service personnel. DESIGN: The study was carried out in 5 intervention stages and a previous non-intervention one to establish the habitual food intake of these groups. In each stage the nutritional information supplied to canteen users was increased to that in the final stage a modification of the price of the menus served was made. ANALYSIS: The food choices freely made by the groups were converted into the amount of nutrients by means of a prior nutritional evaluation of the dishes offered via their calculation using the database Nutriplato. This permitted the evaluation of 29 nutrients which, taking the user data observed, were converted into % of contribution to the RDA (per each population group), which produced a standardization of the data, permitting a subsequent statistical study by the GLM (SPSS v15) procedure to assess the effect of the different factors contemplated. MAIN OUTCOME MEASURE(S): The following were taken into account as classification factors (independent variables): sex, age group and level of body fat, as well as the intervention stage. The dependent variables were: energy, protein, lipid, carbohydrate, fiber, Ca, Mg, P, Na, K, Fe, Cu, Zn, Mn, I, Se, vitamins: B1, B2, B3, B5, B6, B8, B9, B12, C, A, D, E and cholesterol. RESULT: The mean energy and cholesterol intake was significantly reduced in the individuals investigated in the last two intervention stages. Moreover, those last two stages were statistically differentiated, the last one being that which presented the lowest intake of those nutrients. As positive collateral effects, although this was not a priority objective in the study, a greater statistically significant intake of vitamin D, B9, dietetic fiber, and calcium and a lower intake of sodium with respect to the initial stages were noted. CONCLUSIONS AND IMPLICATIONS: Our conclusions go in two directions: the positive effect of the nutritional information and the need to complement that information with economic measures that encourage still further food changes in population groups whose purchasing power is not very great. PMID- 25726227 TI - [Nutritional characteristics of school lunch menus in Biscay (Basque Country, Spain) in 2012/2013]. AB - INTRODUCTION: One of the areas of intervention of the Spanish strategy for nutrition, physical activity and prevention of obesity (NAOS) is school nutrition. OBJECTIVES: To evaluate, taking as reference the minimum set of indicators and recommendations of NAOS Strategy, a sample of school lunch menus distributed in several school dining rooms of Biscay. METHODS: A descriptive cross sectional study was conducted, based on the theoretical information of the basal menus distributed by seven catering enterprises to 324 schools (80,969 pupils). Weekly frequency of several types of food groups was determined and evaluated; reference documents were "Evaluation and Monitoring of NAOS Strategy: set of indicators" and recommendations of the "Consensus document of feeding in school". RESULTS AND DISCUSSION: The 100 per cent of the school dining rooms meets minimums concerning legumes, fish and pre-cooked meals and with the recommendations of meat and meat products. However, although being close to guidelines, none meets the minimum of fruit, vegetables or of additional nutritional information. Differences among NAOS Strategy recommendations and requirements of the Department of Education have been found, and also difficulties in the quantification and classification of several foodstuffs. CONCLUSIONS: It is recommended to increase the content of fruits, vegetables, eggs and oily fish in school menus as well as offering more detailed description of menus to families. PMID- 25726228 TI - [Study of serum albumin and BMI as nutritional markers in hemodialysis patients]. AB - BACKGROUND: Protein calorie malnutrition as well as systemic inflammation and metabolic disorders are common among patients with chronic renal failure undergoing renal replacement therapy (haemodialysis), which contributes to its morbidity and mortality. AIMS: The aims of this work was to evaluate the nutritional status of patients in a hemodialysis treatment through the assessment of biochemical parameters nutritional as albumin, and anthropometric parameters of body mass index during ten years of follow up. METHODS: In this work has been followed 90 patients of both sexes with chronic kidney disease who were treated with hemodialysis regularly on our unit for ten years. All patients were conducted quarterly measurements of plasma albumin (Alb), and other biochemical determinations, and anthropometric measurements of height, weight and body mass index calculated by the formula weight/height2, grouped n BMI < 23 kg/m2 and albumin levels <3.8 g/dl according to the consensus of the panel of experts of the International Society for renal Nutrition and metabolism. RESULTS: During the 10 years all patients showed a significant decline in the biochemical parameters and the albumin, change in BMI does not presented significant changes in relation to malnutrition. CONCLUSIONS: Malnutrition in patients on dialysis is a fact patent, BMI does not correspond with the biochemical parameters were observed, for what nutritional impairment in these patients is mainly expressed by serum albumin. PMID- 25726229 TI - Design and development of a nutritional assessment application for smartphones and tablets with Android OS. AB - BACKGROUND & AIMS: To design and develop a nutritional application for smartphones and tablets with Android operating system for using to in- and outpatients that need a nutritional assessment. To check the validity of the results of such software. METHODS: The application was compiled for version 2.1 of the Android operating system from Google. A cohort of 30 patients was included for evaluating the reliability of the application. The calculations were performed by staff of the Nutrition Unit of the Complexo Hospitalario Universitario de Vigo, manually and through e-Nutrimet software on a smartphone and a tablet. RESULTS: Concordance was absolute between results of different methods obtained using e-Nutrimet on a smartphone and a tablet (Fleiss index kappa= 1). The same level of concordance was obtained by comparing handmade and e Nutrimet made results. CONCLUSIONS: The degree of correlation is good, and it would be extended to all healthcare staff who wants to determine whether a patient has malnutrition, or not. The nutritional assessment software e-Nutrimet does not replace healthcare staff in any case, but could be an important aid in assessing patients who may be in risk of malnutrition, saving time of evaluation. PMID- 25726230 TI - Clinical-nutritional evolution of older women submitted to Roux-en-Y gastric bypass. AB - The aim of the present study was to describe the clinical- nutritional evolution of older women submitted to Roux-en-Y gastric bypass surgery. A concurrent, retrospective study was conducted involving a sample of 16 older women with morbid obesity submitted to Rouxen- Y gastric bypass surgery between 1997 and 2010. Weight, body mass index (BMI), percentage of weight loss (%WL) and percentage of excess weight loss (%EWL) were evaluated three, six and 12 months after surgery. Preoperative comorbidities, postoperative clinical-nutritional manifestations and peri-operative mortality were also investigated. Mean age was 62.02 +/- 2.02 years. A progressive reduction was found in mean body weight (116.04 +/- 22.99 to 80.96 +/- 21.43 Kg) and BMI (47.13 +/- 8.19 to 33.42 +/- 9.31 Kg/m2), with a consequent %WL of 28.60 +/- 8.59% and %EWL of 64.79 +/- 3.99% throughout the one-year follow-up period (p < 0.05). All patients has diseases associated with obesity, the most frequent of which were arterial hypertension (n = 16), arthropathy (n = 11), dyslipidemia (n = 9) and diabetes (n = 7). The following clinical-nutritional symptoms were reported: alopecia (n = 9), nausea/vomiting (n = 7), constipation (n = 5) and food intolerance (n = 4). One patient was diagnosed with malnutrition one year after surgery. No deaths occurred within 30 days after surgery. At the one-year evaluation, surgical success was evidenced by the significant reductions in mean weight and BMI and the more than 50% loss of excess weight. PMID- 25726231 TI - [Normal values of bioimpedance vector in Spanish population]. AB - BACKGROUND AND OBJECTIVE: The bioelectrical impedance vector analysis is useful for the determination of body composition in patients with altered hydration status. The original tolerance ellipses were made in Italian healthy individuals. Due to differences in body composition between populations, the aim of the study was to establish specific tolerance ellipses for the Spanish population and compare them with those ellipses made in the original reference population. METHODS: We studied 311 Spanish healthy subjects of both sexes, between 18 and 80 years old, with a BMI between 18 and 31 Kg/m2, who underwent measurements of weight, height and bioelectrical impedance. The values of resistance and reactance standardized by height (R/H and Xc/H) derived from the impedance measurement, were used to determine the body composition and construct the specific tolerance ellipses for this population. RESULTS: The characteristics of body composition were different between sex and age groups. We plotted values of R/H and Xc/H of the Spanish population on the Italian tolerance ellipses finding that vectors were placed in left quadrants, indicating different body composition. We therefore built specific tolerance ellipses for Spanish population based on values of R/H and Xc/H. Spanish tolerance ellipses were statistically different from the Italian. CONCLUSIONS: The vectors of the Spanish population were different from those of the Italian, hence the importance of having a self-reference pattern. PMID- 25726232 TI - Can we improve the birth weight prediction? The effect of normal BMI using a multivariate model. AB - OBJECTIVE: The construction of a predictive model that improves the estimation of the fetal weight (EFW). STUDY DESIGN: a comparative, descriptive study. One hundred forty pregnant women were recruited at two-stage sample in health department in Spain. They were classified in four groups depending on the pre gestational BMI. Fetal weight at term was estimated by ultrasound at 33-35 weeks (EFW40w) by one gynecologist. A regression model was created with the variables that reacted to the newborn's weight, symphysis-fundal height (SFH), EFW40w, gestational age (GA), ferritin level and cigarettes smoked. RESULTS: A multivariate model was created for the NW group to estimate the fetal weight (EFWme), resulting in R2=0.727 (p<0.001). The differences of the averages obtained between EFW40w and EFWme, with the newborn's weight were significant (p<0.001). EFWme underestimates birth weight by 0.07 g (mean error 0.53%), and EFW40w overestimates it by 300.89 g (mean error 10.12%). In order to evaluate the predictive model and verify the predictions we used the Bland-Altman analysis. The average error in estimating the birth weight with EFWme was 1.94% underestimating the result, whereas the ultrasound error overestimated the result 10.93%. CONCLUSION: The multivariate model created for the NW group improves the accuracy of the ultrasound. PMID- 25726233 TI - Assessment of the reliability and consistency of the "malnutrition inflammation score" (MIS) in Mexican adults with chronic kidney disease for diagnosis of protein-energy wasting syndrome (PEW). AB - BACKGROUND: The protein-energy wasting syndrome (PEW) is a condition of malnutrition, inflammation, anorexia and wasting of body reserves resulting from inflammatory and non-inflammatory conditions in patients with chronic kidney disease (CKD).One way of assessing PEW, extensively described in the literature, is using the Malnutrition Inflammation Score (MIS). OBJECTIVE: To assess the reliability and consistency of MIS for diagnosis of PEW in Mexican adults with CKD on hemodialysis (HD). METHODS: Study of diagnostic tests. A sample of 45 adults with CKD on HD were analyzed during the period June-July 2014.The instrument was applied on 2 occasions; the test-retest reliability was calculated using the Intraclass Correlation Coefficient (ICC); the internal consistency of the questionnaire was analyzed using Cronbach's alphacoefficient. A weighted Kappa test was used to estimate the validity of the instrument; the result was subsequently compared with the Bilbrey nutritional index (BNI). RESULTS: The reliability of the questionnaires, evaluated in the patient sample, was ICC=0.829.The agreement between MIS observations was considered adequate, k= 0.585 (p <0.001); when comparing it with BNI, a value of k = 0.114 was obtained (p <0.001).In order to estimate the tendency, a correlation test was performed. The r2 correlation coefficient was 0.488 (P <0.001). CONCLUSION: MIS has adequate reliability and validity for diagnosing PEW in the population with chronic kidney disease on HD. PMID- 25726234 TI - Cross-sectional study to evaluate the associated factors with differences between city and districts secondary school students of the southeast of Spain (Murcia) for their adherence to the Mediterranean diet. AB - INTRODUCTION: The "Mediterranean diet" is recognized as one of the healthiest dietary patterns but, even in Mediterranean countries it is gradually being lost. Adolescence is a crucial period for changes in dietary patterns. OBJECTIVES: The purpose of this study was to evaluate the Adherence to Mediterranean diet (AMD) of secondary school students and evaluate possible variations between those residents in the city or in the districts. METHODS: A cross-sectional study was designed with 379 secondary school students. To assess the AMD a self administered questionnaire KIDMED was used. They were classified according to sex and residence (city or districts). RESULTS: The body mass index (BMI) for the whole sample was 22.34 in boys and 20.79 in girls (p<0.05). Students from the city resulted more physically active than those from the districts (p<0.05). The average AMD score was 5.8, with 20.3% of students showing good adherence. In general, there was a low consumption of fruits, vegetables and pasta or rice, all foods included in the bottom of the dietary pyramid and the consumption of olive oil and legumes was very positive. Around 25% of students skip breakfast regularly. CONCLUSIONS: Although BMI was in general in the range of normality, AMD of secondary school students is lower than expected attending to previous studies. Consume of fruits and vegetables several times per day, having breakfast daily and regular physical activity should be promoted. Educational and informative activities should be designed for adolescents and also for their parents since in these stages menus at home are usually established by them. PMID- 25726235 TI - [Nutritional knowledge and perception on dialysis: influence on adhesion and transgression; initial study]. AB - BACKGROUND: The dialysis patients have problems in maintaining proper conduct and adherence to the diet prescribed in liquid nephrology consultation. Indicate the interdialytic weight gain, serum potassium and phosphorus along with self-report instruments, markers that have been used as indicators of non-adherence to the diet. Most of the time is not counted in dialysis units with dietitians nutritionists. Nephrologists and nurses lack the time and / or sufficient to establish and monitor adherence to an individualized diet knowledge. OBJECTIVES: The main objective is to determine adherence to dietary guidelines and hemodialysis fluids by DDFQ questionnaire and establish its relationship with the dietary habits of the patients, assessed by test dietary habits and cooking procedures. Secondary objectives are to measure adherence by DDFQ and relate the results to biochemical markers of intake and interdialytic weight gain (GID). Linking monitoring liquid diet and reported by the patient, biochemical markers of intake, interdialytic weight gain and the outcome of DDFQ. Determine membership based on sex, time on hemodialysis, have diabetes or have been transplanted once. And linking dietary habits reported by patients in the test of dietary habits and cooking procedures with patients' knowledge of the guidelines prescribed by nephrologists in consultation. METHODOLOGY: Cross-sectional pilot study. Sociodemographic variables: age and sex. Clinical variables: diabetic transplant patient ever, time on dialysis, dry weight and GID. Biochemical markers: serum potassium and phosphorus. Variables adherence to diet questionnaire measures DDFQ. STATISTICAL ANALYSIS: SPSS 20 Descriptive, Spearman correlation test, Student t test, Mann-Whitney U test and contingency table. RESULTS: 42 patients; 59.5% male, 40.5% female. Age 63.64 +/- 16.17 years. Diabetics 11.9%. GID 1.96 +/- 0.70 kg. Potassium 5.08 +/- 0.86 meq / l phosphorus 4.71 +/- 1.63 mg / dl. DDFQ Measured with 50% of patients not adhering to the diet in 2 days 14 days and 50% have no adherence to liquid in 1 day 14 days. There are correlations between adherence to diet and phosphorus (rho= 0.304) and adherence to fluid and GID (rho= 0.413). CONCLUSIONS: There is a lack of adherence to dietary guidelines in dialysis patients, in contrast to the accession referred by them. The review of dietary and fluid patterns is necessary in patients with CKD on dialysis. Hence the importance of training and support for nurses using simple tools to detect breaches and act with greater dietary education. PMID- 25726236 TI - [Adherence to oral nutrition supplements in hospitalized patients with clinical pathology-surgical]. AB - INTRODUCTION: Studies about the use of nutritional supplements suggest that acceptance is good, so that it is widely recognized and used by professionals. However, in clinical daily practice it seems to be not as much accepted as I seems. The aim of our study is to know the level of adherence to oral nutritional supplements and the main reasons for non-adherence in patients admitted for medical or surgical pathologies. METHODS: An observational, prospective and single-center study was designed. Consecutive patients admitted to a high complexity hospital between August 2012 and May 2013 and with subjective global assessment category B were included. A daily supplement was indicated, the adherence was evaluated and the reasons for non-adherence were determined. Adherent patient was considered when >=75% of the supplements was consumed. RESULTS: Of a total of 807 patients with subjective global assessment, 73 patients were prescribed oral nutritional supplements. The median age was 52 years (IQR 35-62), 58.9% was male, the median body mass index was 24.5 (IQR 22.5 to 27.3). A total of 489 supplements were indicated and a total of 371 were consumed. The median days of indication for the supplements per patient were 5 days (IQR 4-10) and the median consumed was 4 days per patient (IQR 1- 8). The adherence was 58.9% (43 patients). The reasons for non-adherence were: patients own digestive reasons in 5 patients (16.7%), intolerance to oral nutritional supplement in 18 patients (60%) and unjustified patient's refusal in 7 patients (23.3%). CONCLUSIONS: In patients admitted for clinical or surgical pathologies with subjective global assessment B, adherence to oral nutritional supplements was insufficient. Intolerance to supplements was the most frequent reason of non adherence. PMID- 25726237 TI - [Implementation of respiratory rehabilitation in the municipalities of Valparaiso, Vina del Mar, Quilpue and Villa Alemana in 2013]. AB - INTRODUCTION: Pulmonary rehabilitation is a keystone in the treatment of patients with Chronic Obstructive Pulmonary Disease. Significantly reduces the costs to the health system, the use of health resources by reducing hospital stay and consultations to emergency services. OBJECTIVE: Describe the current condition of respiratory rehabilitation in primary care centers located in the region of Valparaiso. METHOD: A closed survey in the respiratory centers of primary health care was applied. The sample consisted of 32 health centers corresponding to the communes of Valparaiso, Vina del Mar, Quilpue and Villa Alemana. RESULTS: 9 centers (28%) of the total sample performed pulmonary rehabilitation and the same number have a structured rehabilitation program. In 15 (47%) of the centers there is a Nutritionist in the health team. In 100% of hospitals patients assessed by spirometry and dyspnea scales. Most centers (89%) training upper and lower extremities. Among the factors that limit the performance of respiratory rehabilitation, 20 (63%) report that the schedule are one of the most limiting factors, while 23 (72%) report that centers do not have adequate space and 22 (69%) centers relate not have the minimum equipment necessary. DISCUSSION: Our findings suggest that most respiratory rehabilitation center did not performed as part of the treatment of patients with chronic obstructive pulmonary disease, mainly due to problems of human, material and infrastructure. PMID- 25726238 TI - Are fat acids of human milk impacted by pasteurization and freezing? AB - The Human Milk Bank undergo human milk to pasteurization, followed by storage in a freezer at -18 degrees C for up to six months to thus keep available the stocks of this product in maternal and infant hospitals. The objective of this study was to evaluate the effects of processing on the lipid fraction of human milk. A sample of human milk was obtained from a donor and was subdivided into ten sub-samples that was subjected to the following treatments: LC = raw milk; T0 = milk after pasteurization; T30 = milk after pasteurization and freezing for 30 days; T60 = milk after pasteurization and freeze for 60 days, and so on every 30 days until T240 = milk after pasteurization and freezing for 240 days, with 3 repetitions for each treatment. Lipids were extracted, methylated and fatty acid profiles determined by gas chromatography. The fatty acids were characterized by nuclear magnetic resonance and functional groups were identified by infrared spectroscopy. There were variations in the concentration of fatty acids. For unsaturated fatty acids there was increasing trend in their concentrations. The IR and NMR analyze characterized and identified functional groups presents in fatty acids. PMID- 25726239 TI - [Contents, positioning and quality analysis in Spanish websites related to nutrition and eating behavior disorders]. AB - INTRODUCTION: Eating disorders are serious psychological disorders with an increased incidence in last years. One of the factors that determine the high prevalence of eating disorders in our society is the lack of knowledge about nutrition. One of the reasons of this lack of knowledge could be the presence of online resources without scientific validity. OBJECTIVE AND SCOPE: The aim of this study was to analyze the scientific quality and positioning of websites in Spanish that have information on nutrition, eating disorders and obesity. MATERIALS AND METHODS: For this purpose, a web search was conducted in the Google Chrome browser using the key words: diet, anorexia, bulimia, obesity and nutrition, and selecting the first 20 results of each search at the rates offered by SeoQuake positioning (Page Rank, Alexa Rank y SEMrush Rank). The variables used for the analysis were: information related to eating habits and diets, information on healthy eating, information about eating disorders and their diagnostics, and formative information about general health topics with professional criteria. RESULTS: Only the 50% of the webpages accomplished the inclusion criteria for this study. Most of them did not follow the guidelines established by e- Europe assessment for quality. The median of the Webpage's PageRank was 2, except those associated with health institutions. CONCLUSIONS: Given the scarcity of healthcare websites with scientific rigor is essential to review the existing one and to create new online spaces whose supervision must be carried out by specialists in health and nutrition. PMID- 25726240 TI - Predictors of adherence to the Mediterranean diet from the first to the second trimester of pregnancy. AB - BACKGROUND: Although changes in eating patterns may occur during gestation, predictors of these changes have not been explored. This study aimed to identify predictors of adherence to the Mediterranean diet (MD) from the first to second trimester of pregnancy. METHODS: A prospective study was conducted with 102 pregnant women aged 18-40, from the city of Porto, Portugal. Socio-demographic and lifestyle characteristics were assessed through a questionnaire. Food consumption was assessed with a three-day food diary completed during the first and second trimesters. Participants were categorized according to their change in adherence to the MD into the negative change group (i.e., women who had low adherence in each trimester or had high adherence in the first trimester and then low adherence in the second) and the positive change group (i.e., women who had high adherence in both trimesters or had low adherence in the first trimester and then high adherence in the second). Conditional stepwise logistic regression models were performed to assess the potential predictors of negative MD change. RESULTS: Among the 102 women, 39.2% had negative change from the first to the second trimester. The logistic model's results show that being married (OR=0.26, 95%CI: 0.10, 0.76) and having a higher intake of vegetables in the first trimester (OR=0.17, 95%CI: 0.10, 0.43) were associated with lower odds of having a negative change in adherence to the MD from the first to second trimester. CONCLUSION: Marital status and vegetable consumption seem to be associated with a lower occurrence of negative change in adherence to the MD from early to middle pregnancy. PMID- 25726241 TI - Heightened sensitivity to somatosensory stimuli in anorexia nervosa: an exploratory study with the SASTCA scale. AB - OBJECTIVES: To analyse the presence of heightened sensory sensitivity in patients with anorexia nervosa, which seems similar but not identical to that described in patients with unexplained somatic symptoms or body dysmorphic disorder. METHODS: We developed a sensory sensitivity scale in eating disorders (SASTCA), which measures the intensity of the response to specific somatosensory stimuli. The scale was completed by 48 patients with anorexia and a control group of 31 participants matched in age, sex and social and educational level. The results were compared with those obtained with the Barsky Somatosensory Amplification Scale (SSAS). RESULTS: The reliability (Cronbach's/alpha, 0.946; Guttman/ split half, 0.936) and validity (ROC, 0.933) of the SASTCA scale are indicative of its high sensitivity and specificity. The anorexia group had a significantly higher mean score on the SASTCA scale than the control group (p<.001). Similarly, the patients with anorexia had a significantly higher mean value on the SSAS than the participants in the control group (p<.01), although the difference was less extreme. The 2 scales correlated positively (r=.634). DISCUSSION: These preliminary results suggest the presence in Anorexia of heightened sensory sensitivity which differs from the sensitivity of the control group. This sensitivity has a significant relationship with that described in patients with somatic complaints about health (SSD) or appearance (BDD). Could this heightened sensory sensitivity help us to explain the process of forming the distorted body self-concept (I'm fat, sick, ugly) in all these patients? Once its presence has been confirmed in other patients with anorexia, their relatives and other patients with somatic disorders this heightened sensitivity could constitute the somatic endophenotype of anorexia? PMID- 25726242 TI - [Satisfaction with body image in a universitary population of the Comunidad de Madrid]. AB - OBJECTIVE: To evaluate anthropometric characteristics and satisfaction with self body image in a group of university students. MATERIAL AND METHODS: 64 university students from 21 to 25 years old, 36 females and 28 males, were studied. Body composition was evaluated by anthropometric data and bioimpedance. Satisfaction with body image was self evaluated by a score from 0 to 10. RESULTS: Mean BMI was 21.95 and fat mass 12.15 +/- 5.27 Kg, greater in women. Satisfaction level was high, with a mean score of 7.15 + 1.15, only 3 participants rated themselves below 5 points. There were no differences between sexes and there was not correlation between self evaluation and anthropometric data in the whole group but, in women, an inverse correlation (r=-0.52) between self evaluation and BMI was observed. This correlation was lesser (r=-0.30) between self evaluation and fat mass percent. CONCLUSIONS: Anthropometric characteristics in the study population were appropriate, as reflected by the high level of satisfaction with their body images. Nevertheless, there is a trend towards a lower self evaluation at greater BMI in women. This trend is not so strong with greater fat mass percent, despite this parameter would represent more exactly the real body image. PMID- 25726243 TI - Polyphenols benefits of olive leaf (Olea europaea L) to human health. AB - INTRODUCTION: The phenolic compounds present in olive leaves (Olea europaea L.) confer benefits to the human health. OBJECTIVES: To review the scientific literature about the benefits of the polyphenols of olive leaves to human health. METHOD: Literature review in the LILACS-BIREME, SciELO and MEDLINE databases for publications in English, Portuguese and Spanish with the descriptors "Olea europaea", "olive leaves", "olive leaf", "olive leaves extracts", "olive leaf extracts", "phenolic compounds", "polyphenols", "oleuropein", "chemical composition", and "health". There were identified 92 articles, but only 38 related to the objectives of the study and 9 articles cited in the works were included due to their relevance. RESULTS AND DISCUSSION: The phenolic compounds present in olive leaves, especially the oleuropein, are associated to antioxidant, antihypertensive, hypoglycemic, hypocholesterolemic and cardioprotective activity. Furthermore, studies associate the oleuropein to an anti-inflammatory effect in trauma of the bone marrow and as a support in the treatment of obesity. PMID- 25726244 TI - Effect of zinc supplementation on superoxide dismutase activity in patients with ulcerative rectocolitis. AB - INTRODUCTION: Ulcerative rectocolitis is characterized by diffuse mucosal inflammation and oxidative stress. Thus, the organism activates the antioxidant defence system in an attempt to reduce the excessive production of reactive oxygen species or neutralize them. OBJECTIVE: This study evaluated the effect of zinc supplementation on the activity of the enzyme superoxide dismutase (SOD) in patients with ulcerative rectocolitis. METHODS: The study included 24 patients, aged between 20 and 59 years and diagnosed with ulcerative rectocolitis, in the remission stage of the disease, who were divided into two groups: experimental - deficient in zinc (n=12) and control - normal or high zinc (n=12). Only the first group underwent supplement intervention, in the form of zinc gluconate (30 mg Zn/day), taken daily in the morning, fasted for 60 days. Plasma and erythrocyte zinc concentrations were determined by flame atomic absorption spectrophotometer. The erythrocyte SOD activity was determined in vitro according to the methodology recommended by the manufacturer Randox. RESULTS AND DISCUSSION: Zinc supplementation caused a significant increase in the plasma concentrations of the mineral, and showed a significant reduction in erythrocyte zinc, remaining within normal limits. The SOD activity was high in patients of both the experimental and control groups, with no difference after supplementation. CONCLUSION: This study demonstrates that zinc supplementation improves the homeostatic condition of the mineral, with no change in SOD activity, as a marker of oxidative stress in patients with ulcerative rectocolitis. PMID- 25726245 TI - Availability of food stores and consumption of fruit, legumes and vegetables in a Brazilian urban area. AB - BACKGROUND: The food environment can have an important influence on the availability of and access to food, which plays a significant role in the health of individuals. The goal of this study was to compare the consumption of fruits, legumes and vegetables (FLV) by adults and the availability of food stores in the context of socioeconomic and geographic space connected to basic health units in a Brazilian capital city. METHODS: The study was developed from information obtained through the Risk Factors Surveillance for Non-Communicable Diseases Prevention by Telephone Survey (VIGITEL), using samples from Belo Horizonte from the years 2008 to 2010. A total of 5611 records were geocoded based on the postal code. A score was created based on the weekly and daily frequency of FLV intake of individuals. The coverage area of basic health units was used as a neighborhood unit. Georeferenced data on food stores in the city and neighborhood income were used. RESULTS: As neighborhood income increased, there was an increase in the distribution of food establishments for all of the studied categories. The highest FLV intake scores were observed in areas with higher income levels. CONCLUSION: The highest concentration of food stores, regardless of supply quality, was observed in geographic areas with higher purchasing power and in those where there was a greater concentration of other types of businesses and services, a different pattern from that found in other countries. PMID- 25726246 TI - [Improvement of clinical parameters in a patient with metabolic syndrome through intervention in nutrition education and improvement of lifestyle]. AB - OBJECTIVE: The main objective is the reduction of early morbidity and mortality associated with metabolic syndrome (MS). METHODS: 24h intakes count for 3 days and clinical-nutritional history. Follow-up of 19 visits to monitor the evolution. RESULTS: Following weight loss, the measurement of capillary blood glucose was 59 mg/dl, discontinuing then treatment with metformin; after 7 days without metformin treatment the value was 64 mg/dl. CONCLUSIONS: Intervention in nutritional education and lifestyle contributed to almost a 10% reduction of body weight; the patient moved from the obesity BMI range to overweight. Peripheral insulin resistance was also enhanced and the GP in charge decided to discontinue the dosing of metformin as a result. PMID- 25726247 TI - [Metabolic encephalopathy secondary to vitamin D intoxication]. AB - The association between vitamin D deficiency and increased risk of, among others, cardiovascular and autoimmune diseases has lead in the last years to an enhanced interest in the usage of supplements to achieve the normalization of plasmatic values at 25(OH) D. Apparently this search for normalization is resulting in an higher incidence on vitamin D intoxication. We present the case of an 81 years old woman with metabolic encephalopathy and renal failure secondary to iatrogenic vitamin D intoxication. Calcium and vitamin D oral supplements were prescribed after an osteoporotic vertebral fracture. The patient improved clinically as well as analytically after receiving treatment with diuretics and hydration. We emphasize the importance of discarding hypercalcemia as a cause of metabolic encephalopathy; moreover we highly recommend keeping vitamin D intoxication in mind as an uncommon although always possible etiology of reversible hypercalcemia and renal failure. PMID- 25726248 TI - Hydrokinesitherapy program using the Halliwick method on strength endurance and flexibility in a person with poliomyelitis sequelae. AB - This case study attempts to determine the effect of a hydrokinesitherapy program by means of the Halliwick method on physical fitness in a female aged 35 years with poliomyelitis sequelae. The intervention followed sixteen weeks of hydrokinesitherapy during 70 minutes, five times a week, where we carried out exercises from the Halliwick method. There was an assessment both before and after the application. Strength endurance and flexibility were determined according to a senior fitness test protocol. The results showed positive improvements when carrying out the exercises from the Halliwick method and the percentage change (Delta%) of strength endurance increase 361.5% in the right arm and 300% in the left arm. Flexibility increased 2 cm in the right shoulder and 10 cm in the left shoulder. In conclusion the subject was able to improve the performance of Halliwick exercises while showing an increase in strength endurance and flexibility. PMID- 25726249 TI - [Outstanding features of training in public health - Response]. PMID- 25726250 TI - [Epidemiology of Lyme disease in a healthcare area in north-west Spain]. AB - OBJECTIVE: To evaluate the influence of some risk factors on the incidence rate of Lyme disease and the main clinical manifestations. METHODS: A retrospective study of Lyme disease (2006-2013) was performed in north-west Spain; we included only patients who fulfilled the epidemiological surveillance criteria defined by the Centers for Disease Control and Prevention. RESULTS: The incidence rate varied between 2.64 and 11.61/100,000 inhabitants/year. Significant differences were found in relation to habitat, age and area of residence. Patients showed neurological (67.59%), dermatological (47.22%), rheumatological (15.74%) and cardiac (13.88%) manifestations, alone or combined. CONCLUSIONS: Due to the increase of the disease in north-west Spain and the differences observed between the different areas, epidemiological studies are needed that increase the index of diagnostic suspicion and lead to the implementation of effective prevention measures. PMID- 25726251 TI - Severe hypocalcemia due to lenalidomide. PMID- 25726252 TI - [Serious adverse side effects after pupillary dilation in preterm infants]. AB - PURPOSE: This study aimed at investigating serious side effects of the pupillary dilation protocol used in Caen University Hospital for the screening of retinopathy of prematurity. This protocol includes one drop of phenylephrine 5% and two drops of tropicamide 0.5% instilled at a 5-minute interval. PATIENTS AND METHODS: This retrospective study included all premature infants with a birth weight less than or equal to 1500 g and/or a gestational age less than or equal to 30 gestational weeks, hospitalized in the neonatal intensive care unit of Caen University Medical Center, having ocular fundus examinations for retinopathy of prematurity screening between 2009 and 2014. The medical records of patients who died or developed necrotizing enterocolitis were reviewed to analyze the imputability of the two eye drops used for pupil dilation. RESULTS: Five-hundred and twelve infants were included, corresponding to 1033 ocular fundus examinations. No case of death could be ascribed to the use of eye drops. Two cases of necrotizing enterocolitis could be ascribed to the use of tropicamide with a doubtful and plausible intrinsic imputability according to French imputability criteria. CONCLUSION: The pupillary dilation protocol used in Caen University Hospital for screening of retinopathy of prematurity might be implicated in two cases of necrotizing enterocolitis with an uncertain imputability of tropicamide 0.5% eye drops. No serious side effect could be ascribed to the use of phenylephrine 5% eye drops in this study. PMID- 25726253 TI - [Adverse effects of calcium channels blockers used as tocolytic treatment]. AB - OBJECTIVE: Tocolysis with calcium channel blockers is widespread in France. However, these molecules are off label use for this indication. The objective of this work is to give an update on all the side effects of calcium channel blockers published or reported to the National Bank of Pharmacovigilance. MATERIALS AND METHODS: We conducted a literature review incorporating the animal experimental data on calcium channel blockers, retrospective and prospective studies (randomized or not) comparing different tocolytics, and the published clinical case reports. Finally we inquired the National Bank of Pharmacovigilance for reported cases of adverse effects after use of calcium channel blockers as tocolytics. RESULTS: Adverse effects are found in 2% to 6% of patients after use of nifedipine, of which 0.9% to 1.9% are severe. These are mainly headache, flushes and arterial hypotension. Data on Nicardipine are more limited. For the latter, adverse effects specifically related to the route of administration (induced phlebitis) are described but it seems that other adverse effects reported are not more frequent. Several meta-analyses have demonstrated a decrease in maternal side effects when using calcium channel blockers compared to beta-agonists. Comparison of calcium channel blockers to Atosiban is less documented. More rare serious side effects are reported as clinical cases, consisting almost exclusively of cardiovascular complications (dyspnea, pulmonary edema, myocardial infarction, arterial hypotension). They are more common with Nicardipine than Nifedipine. Similar observations are found by querying the National Bank of Pharmacovigilance. CONCLUSION: The prescription of calcium channel blockers as tocolysis exposes patients to maternal side effects, which are not serious most of the time, and less frequent than with the beta-agonist. Severe maternal complications were nonetheless reported more frequently with Nicardipine than Nifedipine, which justifies avoiding Nicardipine in tocolysis. Nifedipine is the most studied molecule. It is not possible to define a maximum posology from literature data. It seems unreasonable to associate different tocolytics and necessary to closely monitor maternal blood pressure, the occurrence of a skin reaction or hypersensitivity, dyspnea or chest pain during treatment. PMID- 25726254 TI - [Chart for estimation of fetal weight 2014 by the French College of Fetal Sonography (CFEF)]. AB - OBJECTIVE: To establish a reference chart for estimated fetal weight (EFW) using the Hadlock formula based on recent biometric data (2012-2013). MATERIAL AND METHODS: A prospective multicentric longitudinal study was carried out. Biometric parameters as the head circumference (HC), abdominal circumference (AC) and the femur length were measured in multiple areas of France from January 2012 until December 2013. EFW was calculated using the predictive formula of Hadlock using three parameters. The accurate gestational age was the main inclusion criteria calculated in weeks of gestation (WG). A polynomial regression approach was used to calculate the mean and standard deviation for every WG adjusted to raw data. Centiles of EFW were calculated from the z score that corresponds to the -1.88, 1.28, 0, +1.28, +1.88 respectively for the 3rd, 10th, 50th, 90th, et 97th percentile in order to establish a new chart of EFW. RESULTS: Measurements were obtained for 33,143 fetus between 17 et 38 WG. Reference charts with the 3rd, 10th, 50th, 90th et 97th percentiles were presented. CONCLUSION: The reference Chart 2014 is an in utero chart for EFW based on ultrasound measurements data reliable and homogenous from a sample of 33,143 fetus of a general population. It offers a tool to use in routine ultrasound examination for the survey of the fetal growth and to diagnose fetus that are small for gestational age or presenting a restriction in growth. PMID- 25726255 TI - Identification of circulating miR-101, miR-375 and miR-802 as biomarkers for type 2 diabetes. AB - PURPOSE: The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice. BASIC PROCEDURES: We selected four miRNAs, miR-101, miR-335, miR 375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT). MAIN FINDINGS: The serum concentrations of miRNAs, log(10)miR 101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41+/-2.01 v.s. -0.57+/-1.05 (P=1.36*10( 5)), 0.20+/-0.58 v.s. 0.038+/-1.00 (P=3.06*10(-6)), and 2.45+/-1.27 v.s. 0.97+/ 0.98 (P=0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08+/-1.35 v.s. -0.38+/ 1.21 (P=0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants. PRINCIPAL CONCLUSIONS: The present findings demonstrated that the circulating miR-101, miR 375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes. PMID- 25726256 TI - Pneumatosis intestinalis in a corticosteroid-dependent child. PMID- 25726257 TI - Statistical process control: separating signal from noise in emergency department operations. AB - BACKGROUND: Statistical process control (SPC) is a visually appealing and statistically rigorous methodology very suitable to the analysis of emergency department (ED) operations. OBJECTIVE: We demonstrate that the control chart is the primary tool of SPC; it is constructed by plotting data measuring the key quality indicators of operational processes in rationally ordered subgroups such as units of time. Control limits are calculated using formulas reflecting the variation in the data points from one another and from the mean. SPC allows managers to determine whether operational processes are controlled and predictable. We review why the moving range chart is most appropriate for use in the complex ED milieu, how to apply SPC to ED operations, and how to determine when performance improvement is needed. DISCUSSION: SPC is an excellent tool for operational analysis and quality improvement for these reasons: 1) control charts make large data sets intuitively coherent by integrating statistical and visual descriptions; 2) SPC provides analysis of process stability and capability rather than simple comparison with a benchmark; 3) SPC allows distinction between special cause variation (signal), indicating an unstable process requiring action, and common cause variation (noise), reflecting a stable process; and 4) SPC keeps the focus of quality improvement on process rather than individual performance. CONCLUSION: Because data have no meaning apart from their context, and every process generates information that can be used to improve it, we contend that SPC should be seriously considered for driving quality improvement in emergency medicine. PMID- 25726258 TI - A Common Source Outbreak of Severe Delirium Associated with Exposure to the Novel Synthetic Cannabinoid ADB-PINACA. AB - BACKGROUND: Since 2009, synthetic cannabinoid (SC) use has emerged as a growing public health threat in the United States (US). Several outbreaks of unexpected, severe toxicity linked to SC use have been reported since 2012. Reports of varied and significant morbidity after SC use are expected to increase because newer compounds enter the marketplace more frequently as manufacturers attempt to circumvent regulatory efforts. CASE REPORT: We report a cluster of 7 patients who experienced a spectrum of anxiety, delirium, psychosis, and aggressive behaviors after smoking the same SC-containing product at a party. An 8th patient with the same exposure source presented with delayed onset seizures. Biologic samples were analyzed for novel, newly identified SCs belonging to the FUBINACA family of compounds. A previously unknown SC, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1 pentyl-1H-indazole-3-carboxamide (ADB-PINACA) was identified in biologic samples from 7 of the individuals. ADB-PINACA was identified in the SC-containing product ("Crazy Clown") seized by law enforcement and identified as the product smoked by the 8 patients in the reported cluster. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The information compiled using this cluster of cases, and a similar reported outbreak of altered mental status in Colorado, implicating the same SC (ADB-PINACA) and brands of SC-containing products, aided the US Drug Enforcement Administration in its temporary scheduling of ADB-PINACA and three other SCs. In this outbreak, close cooperation between public health and law enforcement allowed for a rapid intervention, which halted the outbreak by interrupting the common source and accelerated regulatory efforts to prevent further morbidity and mortality. PMID- 25726259 TI - Validation of the Italian translation of the Revised Temperament and Character Inventory--TCI-140--in adult participants and in participants with medical diseases. AB - INTRODUCTION: This study aimed at assessing the reliability and construct validity of the TCI-140. METHODOLOGY: SAMPLE: 428 Italian participants. EXCLUSION CRITERIA: psychiatric disorders. 100 subjects - longitudinal retest study. RESULTS: The results of descriptive statistics of internal consistency reliabilities (Cronbach coefficient) of TCI-R dimensions showed: a strong internal consistence of the scales: HA (alpha = 0.84); RD (alpha = 0.70); SD (alpha = 0.86); C (alpha = 0.75); ST (alpha = 0.83); a low level in NS (alpha = 0.60). In relation to facets, internal consistency reliabilities (Cronbach coefficient) ranged from 0.14 C3 to 0.79 C4 (from 3rd to 4th facet of C scale). Correlations: highest inverse correlation between HA and SD (r = -0.56); moderate inverse correlations for: HA and PS (r = -0.37); C and RD(r = 0.32); C and SD (r = 0.44). P, SD, C and ST showed good inter class correlations (ICC) >= 70 maintaining a good stability of the measures over the time. Four factors accounted for 56.3% of the variance for temperament subscale. Subscales of: PS4, PS3 PS2, PS1, NS3 for factor 1; HA2, HA1, HA4, HA3 for factor 2; RD1, RD2 and RD3 for factor 3; NS4, NS1 and NS2 for factor 4. Three factors that were identified accounted for 58.3% of the variance for character subscales of: SD3, SD5, SD1, SD2 for factor 1; C4, C1, C5, SD4, C3 for factor 2; ST2, ST1, ST3, C2 for factor 3. CONCLUSION: The reliability coefficients were significantly good for some dimensions of TCI-140 and showed a good correlation after time, while some dimensions as NS have low reliability. In the principal components analysis does not saturate all dimensions in its theoretical factor. Moreover TCI-140 is a useful inventory for the evaluation of the principal dimensions of temperament and character. PMID- 25726260 TI - Auditory pathways: anatomy and physiology. AB - This chapter outlines the anatomy and physiology of the auditory pathways. After a brief analysis of the external, middle ears, and cochlea, the responses of auditory nerve fibers are described. The central nervous system is analyzed in more detail. A scheme is provided to help understand the complex and multiple auditory pathways running through the brainstem. The multiple pathways are based on the need to preserve accurate timing while extracting complex spectral patterns in the auditory input. The auditory nerve fibers branch to give two pathways, a ventral sound-localizing stream, and a dorsal mainly pattern recognition stream, which innervate the different divisions of the cochlear nucleus. The outputs of the two streams, with their two types of analysis, are progressively combined in the inferior colliculus and onwards, to produce the representation of what can be called the "auditory objects" in the external world. The progressive extraction of critical features in the auditory stimulus in the different levels of the central auditory system, from cochlear nucleus to auditory cortex, is described. In addition, the auditory centrifugal system, running from cortex in multiple stages to the organ of Corti of the cochlea, is described. PMID- 25726261 TI - Anatomic organization of the auditory cortex. AB - The auditory cortex is a network of areas in the part of the brain that receives inputs from the subcortical auditory pathways in the brainstem and thalamus. Through an elaborate network of intrinsic and extrinsic connections, the auditory cortex is thought to bring about the conscious perception of sound and provide a basis for the comprehension and production of meaningful utterances. In this chapter, the organization of auditory cortex is described with an emphasis on its anatomic features and the flow of information within the network. These features are then used to introduce key neurophysiologic concepts that are being intensively studied in humans and animal models. The discussion is presented in the context of our working model of the primate auditory cortex and extensions to humans. The material is presented in the context of six underlying principles, which reflect distinct, but related, aspects of anatomic and physiologic organization: (1) the division of auditory cortex into regions; (2) the subdivision of regions into areas; (3) tonotopic organization of areas; (4) thalamocortical connections; (5) serial and parallel organization of connections; and (6) topographic relationships between auditory and auditory-related areas. Although the functional roles of the various components of this network remain poorly defined, a more complete understanding is emerging from ongoing studies that link auditory behavior to its anatomic and physiologic substrates. PMID- 25726263 TI - Representation of loudness in the auditory cortex. AB - Changes in stimulus intensity are reflected in changes in the fundamental perceptual attribute of loudness. Stimulus intensity changes also profoundly impact the evoked neural responses throughout the auditory system. A fundamental question is how measurements of neural activity, from the single-neuron level to mass-activity metrics such as functional magnetic resonance imaging or magnetoencephalography, reflect the physical properties of stimulus intensity as opposed to perceived loudness. In this chapter we discuss findings from psychophysics and animal neurophysiology as well as human brain activity measurements to clarify our current understanding of the neural mechanisms that contribute to the perceptual correlate of stimulus intensity. PMID- 25726262 TI - Development of the auditory system. AB - Auditory development involves changes in the peripheral and central nervous system along the auditory pathways, and these occur naturally, and in response to stimulation. Human development occurs along a trajectory that can last decades, and is studied using behavioral psychophysics, as well as physiologic measurements with neural imaging. The auditory system constructs a perceptual space that takes information from objects and groups, segregates sounds, and provides meaning and access to communication tools such as language. Auditory signals are processed in a series of analysis stages, from peripheral to central. Coding of information has been studied for features of sound, including frequency, intensity, loudness, and location, in quiet and in the presence of maskers. In the latter case, the ability of the auditory system to perform an analysis of the scene becomes highly relevant. While some basic abilities are well developed at birth, there is a clear prolonged maturation of auditory development well into the teenage years. Maturation involves auditory pathways. However, non-auditory changes (attention, memory, cognition) play an important role in auditory development. The ability of the auditory system to adapt in response to novel stimuli is a key feature of development throughout the nervous system, known as neural plasticity. PMID- 25726264 TI - Temporal coding in the auditory cortex. AB - Speech is a complex acoustic signal showing a quasiperiodic structure at several timescales. Integrated neural signals recorded in the cortex also show periodicity at different timescales. In this chapter we outline the neural mechanisms that potentially allow the auditory cortex to segment and encode continuous speech. This chapter focuses on how the human auditory cortex uses the temporal structure of the acoustic signal to extract phonemes and syllables, the two major constituents of connected speech. We argue that the quasiperiodic structure of collective neural activity in auditory cortex represents the ideal mechanical infrastructure to fractionate continuous speech into linguistic constituents of variable sizes. PMID- 25726265 TI - Sound localization. AB - The auditory system derives locations of sound sources from spatial cues provided by the interaction of sound with the head and external ears. Those cues are analyzed in specific brainstem pathways and then integrated as cortical representation of locations. The principal cues for horizontal localization are interaural time differences (ITDs) and interaural differences in sound level (ILDs). Vertical and front/back localization rely on spectral-shape cues derived from direction-dependent filtering properties of the external ears. The likely first sites of analysis of these cues are the medial superior olive (MSO) for ITDs, lateral superior olive (LSO) for ILDs, and dorsal cochlear nucleus (DCN) for spectral-shape cues. Localization in distance is much less accurate than that in horizontal and vertical dimensions, and interpretation of the basic cues is influenced by additional factors, including acoustics of the surroundings and familiarity of source spectra and levels. Listeners are quite sensitive to sound motion, but it remains unclear whether that reflects specific motion detection mechanisms or simply detection of changes in static location. Intact auditory cortex is essential for normal sound localization. Cortical representation of sound locations is highly distributed, with no evidence for point-to-point topography. Spatial representation is strictly contralateral in laboratory animals that have been studied, whereas humans show a prominent right-hemisphere dominance. PMID- 25726266 TI - New perspectives on the auditory cortex: learning and memory. AB - Primary ("early") sensory cortices have been viewed as stimulus analyzers devoid of function in learning, memory, and cognition. However, studies combining sensory neurophysiology and learning protocols have revealed that associative learning systematically modifies the encoding of stimulus dimensions in the primary auditory cortex (A1) to accentuate behaviorally important sounds. This "representational plasticity" (RP) is manifest at different levels. The sensitivity and selectivity of signal tones increase near threshold, tuning above threshold shifts toward the frequency of acoustic signals, and their area of representation can increase within the tonotopic map of A1. The magnitude of area gain encodes the level of behavioral stimulus importance and serves as a substrate of memory strength. RP has the same characteristics as behavioral memory: it is associative, specific, develops rapidly, consolidates, and can last indefinitely. Pairing tone with stimulation of the cholinergic nucleus basalis induces RP and implants specific behavioral memory, while directly increasing the representational area of a tone in A1 produces matching behavioral memory. Thus, RP satisfies key criteria for serving as a substrate of auditory memory. The findings suggest a basis for posttraumatic stress disorder in abnormally augmented cortical representations and emphasize the need for a new model of the cerebral cortex. PMID- 25726267 TI - Neural basis of speech perception. AB - The functional neuroanatomy of speech processing has been difficult to characterize. One major impediment to progress has been the failure to consider task effects when mapping speech-related processing systems. We summarize a dual stream model of speech processing that addresses this situation. In this model, a ventral stream processes speech signals for comprehension, and a dorsal stream maps acoustic speech signals to parietal and frontal-lobe articulatory networks. The model assumes that the ventral stream is largely bilaterally organized, although there are important computational differences between the left- and right-hemisphere systems, whereas the dorsal stream is strongly left-hemisphere dominant. PMID- 25726268 TI - Role of the auditory system in speech production. AB - This chapter reviews evidence regarding the role of auditory perception in shaping speech output. Evidence indicates that speech movements are planned to follow auditory trajectories. This in turn is followed by a description of the Directions Into Velocities of Articulators (DIVA) model, which provides a detailed account of the role of auditory feedback in speech motor development and control. A brief description of the higher-order brain areas involved in speech sequencing (including the pre-supplementary motor area and inferior frontal sulcus) is then provided, followed by a description of the Hierarchical State Feedback Control (HSFC) model, which posits internal error detection and correction processes that can detect and correct speech production errors prior to articulation. The chapter closes with a treatment of promising future directions of research into auditory-motor interactions in speech, including the use of intracranial recording techniques such as electrocorticography in humans, the investigation of the potential roles of various large-scale brain rhythms in speech perception and production, and the development of brain-computer interfaces that use auditory feedback to allow profoundly paralyzed users to learn to produce speech using a speech synthesizer. PMID- 25726269 TI - White-matter pathways for speech and language processing. AB - The language-relevant brain regions, Brodmann's area in the inferior frontal cortex and Wernicke's area in the superior temporal cortex, are connected via long-range fiber bundles, which are located dorsally and ventrally to the sylvian fissure. These dorsal and ventral pathways consist of a number of partly parallel running fiber tracts, which can be differentiated by their termination regions and by the particular language functions of these termination regions. Dorsally, there are two major fiber tracts connecting the posterior temporal cortex with the frontal cortex: one terminating in the premotor cortex that subserves sensory to-motor mapping and one terminating in posterior Broca's area, the pars opercularis, that supports the processing of complex syntactic structures. Ventrally, two language-related fiber tracts are discussed: one connects the inferior frontal cortex, i.e., the pars triangularis and orbitalis, with Wernicke's area and supports semantic processes and another one connects the most ventral portions of the inferior frontal cortex, including the frontal operculum, with the anterior temporal cortex. This latter ventral tract is suggested to subserve elementary combinatorial processes in language. Together these fiber tracts guarantee the transmission of information between different brain regions within the neural language network. PMID- 25726270 TI - Neural basis of music perception. AB - Music is a multifaceted psychologic phenomenon, and separating the perceptual aspects of musical experiences from other aspects of those experiences is difficult, given music's propensity to trigger memories, movements, and emotions. Given that music is primarily an auditory phenomenon, it is reasonable to assume that the auditory cortex will play a major role in the representation of musical auditory scenes. The primary objective of this chapter was to survey the literature and perform a meta-analysis of the neuroimaging literature in order to determine whether a delineation of the lateral temporal lobes emerges in terms of the processing of tonal, temporal, and timbral aspects of musical information. The meta-analysis revealed both overlapping and non-overlapping areas of auditory cortex, with a tendency for melodic and harmonic manipulations to activate areas outside the primary auditory cortex. Regions of the superior temporal gyrus and superior temporal sulcus rostral and ventral to the auditory cortex appear to play an important role in the perception of melodic intervals and patterns, and harmonies, but may not play a direct role in maintaining or evaluating higher order tonal relationships that govern key membership or relationships between major and minor keys. PMID- 25726271 TI - Music and language: relations and disconnections. AB - Music and language provide an important context in which to understand the human auditory system. While they perform distinct and complementary communicative functions, music and language are both rooted in the human desire to connect with others. Since sensory function is ultimately shaped by what is biologically important to the organism, the human urge to communicate has been a powerful driving force in both the evolution of auditory function and the ways in which it can be changed by experience within an individual lifetime. This chapter emphasizes the highly interactive nature of the auditory system as well as the depth of its integration with other sensory and cognitive systems. From the origins of music and language to the effects of auditory expertise on the neural encoding of sound, we consider key themes in auditory processing, learning, and plasticity. We emphasize the unique role of the auditory system as the temporal processing "expert" in the brain, and explore relationships between communication and cognition. We demonstrate how experience with music and language can have a significant impact on underlying neural function, and that auditory expertise strengthens some of the very same aspects of sound encoding that are deficient in impaired populations. PMID- 25726272 TI - Invasive recordings in the human auditory cortex. AB - This chapter provides an overview of current invasive recording methodology and experimental paradigms used in the studies of human auditory cortex. Invasive recordings can be obtained from neurosurgical patients undergoing clinical electrophysiologic evaluation for medically refractory epilepsy or brain tumors. This provides a unique research opportunity to study the human auditory cortex with high resolution both in time (milliseconds) and space (millimeters) and to generate valuable information about its organization and function. A historic overview presents the development of the experimental approaches from the pioneering works of Wilder Penfield to modern day. Practical issues regarding research subject population, stimulus presentation, data collection, and analysis are discussed for acute (intraoperative) and chronic experiments. Illustrative examples are provided from experimental paradigms, including studies of spectrotemporal processing, functional connectivity, and functional lesioning in human auditory cortex. PMID- 25726273 TI - Electromagnetic recording of the auditory system. AB - Auditory processing is remarkably fast and sensitive to the precise temporal structure of acoustic signals over a range of scales, from submillisecond phenomena such as localization to the construction of elementary auditory attributes at tens of milliseconds to basic properties of speech and music at hundreds of milliseconds. In light of the rapid (and often transitory) nature of auditory phenomena, in order to investigate the neurocomputational basis of auditory perception and cognition, a technique with high temporal resolution is appropriate. Here we briefly outline the utility of magnetoencephalography (MEG) for the study of the neural basis of audition. The basics of MEG are outlined in brief, and some of the most-used neural responses are described. We discuss the classic transient evoked fields (e.g., M100), responses elicited by change in a stimulus (e.g., pitch-onset response), the auditory steady-state response, and neural oscillations (e.g., theta-phase tracking). Because of the high temporal resolution and the good spatial resolution of MEG, paired with the convenient location of human auditory cortex for MEG-based recording, electromagnetic recording of this type is well suited to investigate various aspects from audition, from crafted laboratory experiments on pitch perception or scene analysis to naturalistic speech and music tasks. PMID- 25726274 TI - Hemodynamic imaging of the auditory cortex. AB - Over the past 20 years or so, functional magnetic resonance imaging (fMRI) has proven to be an influential tool for measuring perceptual and cognitive processing non-invasively in the human brain. This article provides a brief yet comprehensive overview of this dominant method for human auditory neuroscience, providing the reader with knowledge about the practicalities of using this technique to assess central auditory coding. Key learning objectives include developing an understanding of the basic MR physics underpinning the technique, the advantage of auditory fMRI over other current neuroimaging alternatives, and highlighting some of the practical considerations involved in setting up, running, and analyzing an auditory fMRI experiment. The future utility of fMRI and anticipated technical developments is also briefly evaluated. Throughout the review, key concepts are illustrated using specific author examples, with particular emphasis on fMRI findings that address questions pertaining to basic sound coding (such as frequency and pitch). PMID- 25726275 TI - Imaging white-matter pathways of the auditory system with diffusion imaging tractography. AB - The recent advent of diffusion imaging tractography has opened a new window into the in vivo white-matter anatomy of the human brain. This is of particular importance for the connections of the auditory system, which may have undergone substantial development in humans in relation to language. However, tractography of the human auditory pathways has proved to be challenging due to current methodologic limitations and the intrinsic anatomic features of the subcortical connections that carry acoustic information in the brainstem. More reliable findings are forthcoming from tractography studies of corticocortical connections associated with language processing. In this chapter we introduce the reader to basic principles of diffusion imaging and tractography. A selected review of the tractography studies of the auditory pathways will be presented, with particular attention given to the cerebral association pathways of the temporal lobe. Finally, new diffusion methods based on advanced model for mapping fiber crossing will be discussed in the context of the auditory and language networks. PMID- 25726276 TI - Electrophysiologic auditory tests. AB - Auditory stimulation elicits a complex series of electric signals in the ear and nervous system which can be used for hearing assessment, audiologic and neurologic diagnosis, intraoperative monitoring, and neurophysiologic research. The earliest components comprise the electrocochleogram. The cochlear microphonic arises from receptor potentials from cochlear hair cells, and is used to assess hair cell function in patients with auditory neuropathy. The summating potential becomes larger in Meniere's disease. The eighth-nerve compound action potential is useful for objective audiometry. Brainstem auditory evoked potentials, a series of components generated in the eighth nerve and the brainstem auditory pathways, can be used for diagnostic assessment and intraoperative monitoring of the ears and of the auditory pathways up through the mesencephalon. They are relatively easy to record, highly consistent in normal subjects, and little unaffected by surgical anesthesia. Middle-latency and long-latency auditory evoked potentials are generated in multiple areas of cerebral cortex that are activated by auditory stimulation. Anesthetic effects limit their utility for intraoperative monitoring, and substantial intersubject variability limits their utility as a diagnostic test in individual patients, but they are important research tools for the study of memory processes and the way in which the brain analyzes auditory stimuli. PMID- 25726277 TI - Psychophysical and behavioral peripheral and central auditory tests. AB - Diagnostic batteries to assess the integrity of the central auditory nervous system (CANS) include behavioral (i.e., psychophysical) tests, electrophysiologic procedures, and to some degree, electroacoustic procedures. In this chapter, we focus on behavioral tests used to identify lesions (including diffuse lesions), abnormalities, or dysfunction of the CANS, as well as identify associated functional deficits (e.g., listening in noise deficits). Following a brief review of several tests considered more peripheral in their application (e.g., pure-tone thresholds, otoacoustic emissions, acoustic reflex), we provide some historic context and a review of tests currently in use which are sensitized by design to measure central auditory function, as well as others which have not been adopted clinically and new tests and procedures which hold promise for clinical diagnosis. Tests reviewed include those of dichotic listening, temporal processing (e.g., temporal resolution and temporal patterning), binaural interaction (e.g., masking level differences), monaural low-redundancy measures (e.g., speech in noise or competition, filtered speech, time-compressed speech), and new paradigms which measure auditory evoked potentials in response to test stimuli typically used in behavioral tests. PMID- 25726278 TI - Neurocognitive development in congenitally deaf children. AB - This chapter presents an overview of neurocognitive development in children with hearing loss across the spectrum of hearing disorders. It begins with information about the characteristics of pediatric hearing loss and its consequences in terms of neurophysiologic effects on the developing auditory system and functional effects on spoken language acquisition. The importance of early learning experiences on the developing brain is elaborated and the role of parents is discussed. The chapter briefly describes recent advances in early hearing loss identification and intervention, including the impact of cochlear implant technology, and discusses how these have substantially changed and continue to change developmental outcomes for children with hearing loss. Multiple factors that affect early and later development are outlined. Findings from current literature that provide useful information on developmental outcomes in children with hearing loss of all levels of severity are presented. The chapter also considers information that has accumulated about cognitive processes, particularly related to speech and language acquisition in children with hearing loss. PMID- 25726279 TI - Aging of the auditory system. AB - Presbycusis or age-related hearing loss (ARHL) affects most elderly people. It is characterized by reduced hearing thresholds and speech understanding with the well-known negative consequences for communication and quality of social life. The hearing loss is connected to age-related histologic changes, as described and classified by Schuknecht. Aging itself is a multifactorial, genetically driven process that is influenced by oxidative stress that gradually leads to reduced endocochlear potential and cell loss of key players in sound transmission and supporting structures. Oxidative stress is caused by damaging factors like noise, infection, and other systemic factors. All reparative mechanisms in acute and chronic cochlear damage attempt to reduce oxidative stress and to balance inner ear homeostasis. Accurate clinical assessment of ARHL starts with the differentiation between peripheral and central components. Treatment of the peripheral hearing loss often involves hearing aids, whereas auditory and psychologic training seems to be important in central auditory disturbance. PMID- 25726280 TI - Decreased sound tolerance: hyperacusis, misophonia, diplacousis, and polyacousis. AB - Definitions, potential mechanisms, and treatments for decreased sound tolerance, hyperacusis, misophonia, and diplacousis are presented with an emphasis on the associated physiologic and neurophysiological processes and principles. A distinction is made between subjects who experience these conditions versus patients who suffer from them. The role of the limbic and autonomic nervous systems and other brain systems involved in cases of bothersome decreased sound tolerance is stressed. The neurophysiological model of tinnitus is outlined with respect to how it may contribute to our understanding of these phenomena and their treatment. PMID- 25726281 TI - Auditory synesthesias. AB - Synesthesia is experienced when sensory stimulation of one sensory modality (the inducer) elicits an involuntary or automatic sensation in another sensory modality or different aspect of the same sensory modality (the concurrent). Auditory synesthesias (AS) occur when auditory stimuli trigger a variety of concurrents, or when non-auditory sensory stimulations trigger auditory synesthetic perception. The AS are divided into three types: developmental, acquired, and induced. Developmental AS are not a neurologic disorder but a different way of experiencing one's environment. They are involuntary and highly consistent experiences throughout one's life. Acquired AS have been reported in association with neurologic diseases that cause deafferentation of anterior optic pathways, with pathologic lesions affecting the central nervous system (CNS) outside of the optic pathways, as well as non-lesional cases associated with migraine, and epilepsy. It also has been reported with mood disorders as well as a single idiopathic case. Induced AS has been reported in experimental and postsurgical blindfolding, as well as intake of hallucinogenics or psychedelics. In this chapter the three different types of synesthesia, their characteristics, and phenomologic differences, as well as their possible neural mechanisms are discussed. PMID- 25726282 TI - Tinnitus. AB - Tinnitus, the perception of sound in the absence of an external sound, usually results from a disorder of: (1) the auditory system (usually peripheral, rarely central); (2) the somatosensory system (head and neck); or (3) a combination of the two. Its cause can be determined through its characteristics. The history must include the tinnitus': (1) quality (including whether it can ever be pulsatile or have a clicking component); (2) location; (3) variability; (4) predominant pitch (low or high); and (5) whether the patient can do something to modulate the percept. In addition to the standard neuro-otologic examination, the exam should include inspection of the teeth for evidence of wear, listening around the ear and neck for sounds similar to the tinnitus, palpation of the craniocervical musculature for trigger points, and probing whether the tinnitus percept can be modulated with "somatic testing." All subjects should have a recent audiogram. Presently the most compelling tinnitus theory is the dorsal cochlear nucleus (DCN) hypothesis: both the auditory and somatosensory systems converge upon and interact within the DCN. If the activity of the DCN's somatosensory-interacting fusiform cells exceeds an individual's tinnitus threshold, then tinnitus results. PMID- 25726283 TI - Auditory hallucinations. AB - Auditory hallucinations constitute a phenomenologically rich group of endogenously mediated percepts which are associated with psychiatric, neurologic, otologic, and other medical conditions, but which are also experienced by 10-15% of all healthy individuals in the general population. The group of phenomena is probably best known for its verbal auditory subtype, but it also includes musical hallucinations, echo of reading, exploding-head syndrome, and many other types. The subgroup of verbal auditory hallucinations has been studied extensively with the aid of neuroimaging techniques, and from those studies emerges an outline of a functional as well as a structural network of widely distributed brain areas involved in their mediation. The present chapter provides an overview of the various types of auditory hallucination described in the literature, summarizes our current knowledge of the auditory networks involved in their mediation, and draws on ideas from the philosophy of science and network science to reconceptualize the auditory hallucinatory experience, and point out directions for future research into its neurobiologic substrates. In addition, it provides an overview of known associations with various clinical conditions and of the existing evidence for pharmacologic and non-pharmacologic treatments. PMID- 25726284 TI - Palinacousis. AB - Palinacousis is derived from the Greek words palin, which means again or anew, and acousis, meaning hearing. It was first described by Jacobs et al. (1971), who defined the phenomenon as "an auditory illusion of perseveration or persistence of sound impressions for seconds, minutes, or hours after the cessation of auditory stimulation." The auditory perseveration does not occur spontaneously but is triggered by something in the environment. A limited number of cases have been described in the literature. This chapter describes the anatomic abnormalities that may cause this phenomenon, the clinical characteristics that define palinacousis, differential diagnosis and potential etiologies. PMID- 25726285 TI - Musicogenic epilepsy. AB - Musicogenic epilepsy, which is a form of reflex epilepsy, is characterized by the triggering of epileptic seizures by specific music experiences. Individuals with musicogenic epilepsy differ in the music trigger, but may have similar seizures. Typically, these seizures are focal dyscognitive and have a temporal-lobe origin with a limbic system distribution. As such, the music trigger is likely related to either an emotional or memory aspect of music perception. Investigations into musicogenic epilepsy may lead to a better understanding of seizure propagation within the brain and of neurologic aspects of the music experience. Successful treatment of medication-resistant musicogenic epilepsy has been achieved with anterior temporal-lobe resection. PMID- 25726286 TI - Deafness in cochlear and auditory nerve disorders. AB - Sensorineural hearing loss is the most common type of hearing impairment worldwide. It arises as a consequence of damage to the cochlea or auditory nerve, and several structures are often affected simultaneously. There are many causes, including genetic mutations affecting the structures of the inner ear, and environmental insults such as noise, ototoxic substances, and hypoxia. The prevalence increases dramatically with age. Clinical diagnosis is most commonly accomplished by measuring detection thresholds and comparing these to normative values to determine the degree of hearing loss. In addition to causing insensitivity to weak sounds, sensorineural hearing loss has a number of adverse perceptual consequences, including loudness recruitment, poor perception of pitch and auditory space, and difficulty understanding speech, particularly in the presence of background noise. The condition is usually incurable; treatment focuses on restoring the audibility of sounds made inaudible by hearing loss using either hearing aids or cochlear implants. PMID- 25726287 TI - Auditory neuropathy. AB - Neural disorders of the auditory nerve are associated with particular disorders of auditory perceptions dependent on processing of acoustic temporal cues. These include: (1) speech perception; (2) localizing a sound's origin in space; and (3) identifying sounds in background noise. Auditory neuropathy (AN) is a consequence of: (1) presynaptic disorders affecting inner hair cell ribbon synapses; (2) postsynaptic disorders of auditory nerve dendrites; and (3) postsynaptic disorders of auditory nerve axons. The etiologies of these disorders are diverse, similar to other cranial or peripheral neuropathies. The pathologies cause attenuated and dyssynchronous auditory nerve discharges. Therapies and management of patients with AN are reviewed. PMID- 25726288 TI - Hearing disorders in brainstem lesions. AB - Auditory processing can be disrupted by brainstem lesions. It is estimated that approximately 57% of brainstem lesions are associated with auditory disorders. However diseases of the brainstem usually involve many structures, producing a plethora of other neurologic deficits, often relegating "auditory symptoms in the background." Lesions below or within the cochlear nuclei result in ipsilateral auditory-processing abnormalities detected in routine testing; disorders rostral to the cochlear nuclei may result in bilateral abnormalities or may be silent. Lesions in the superior olivary complex and trapezoid body show a mixture of ipsilateral, contralateral, and bilateral abnormalities, whereas lesions of the lateral lemniscus, inferior colliculus, and medial geniculate body do not affect peripheral auditory processing and result in predominantly subtle contralateral abnormalities that may be missed by routine auditory testing. In these cases psychophysical methods developed for the evaluation of central auditory function should be employed (e.g., dichotic listening, interaural time perception, sound localization). The extensive connections of the auditory brainstem nuclei not only are responsible for binaural interaction but also assure redundancy in the system. This redundancy may explain why small brainstem lesions are sometimes clinically silent. Any disorder of the brainstem (e.g., neoplasms, vascular disorders, infections, trauma, demyelinating disorders, neurodegenerative diseases, malformations) that involves the auditory pathways and/or centers may produce hearing abnormalities. PMID- 25726289 TI - Central auditory processing disorders in children and adults. AB - Central auditory processing disorders (CAPD) can affect children and adults of all ages due to a wide variety of causes. CAPD is a neurobiologic deficit in the central auditory nervous system (CANS) that affects those mechanisms that underlie fundamental auditory perception, including localization and lateralization; discrimination of speech and non-speech sounds; auditory pattern recognition; temporal aspects of audition, including integration, resolution, ordering, and masking; and auditory performance with competing and/or degraded acoustic signals (American Speech-Language-Hearing Association, 2005a, b). Although it is recognized that central auditory dysfunction may coexist with other disorders, CAPD is conceptualized as a sensory-based auditory disorder. Administration of behavioral and/or electrophysiologic audiologic tests that have been shown to be sensitive and specific to dysfunction of the CANS is critical for a proper diagnosis of CAPD, in addition to assessments and collaboration with a multidisciplinary team. Intervention recommendations for CAPD diagnosis are based on the demonstrated auditory processing deficits and related listening and related complaints. This chapter provides an overview of current definitions and conceptualizations, methods of diagnosis of, and intervention for, CAPD. The chapter culminates with a case study illustrating pre- and posttreatment behavioral and electrophysiologic diagnostic findings. PMID- 25726290 TI - Auditory neglect and related disorders. AB - Neglect is a neurologic disorder, typically associated with lesions of the right hemisphere, in which patients are biased towards their ipsilesional - usually right - side of space while awareness for their contralesional - usually left - side is reduced or absent. Neglect is a multimodal disorder that often includes deficits in the auditory domain. Classically, auditory extinction, in which left sided sounds that are correctly perceived in isolation are not detected in the presence of synchronous right-sided stimulation, has been considered the primary sign of auditory neglect. However, auditory extinction can also be observed after unilateral auditory cortex lesions and is thus not specific for neglect. Recent research has shown that patients with neglect are also impaired in maintaining sustained attention, on both sides, a fact that is reflected by an impairment of auditory target detection in continuous stimulation conditions. Perhaps the most impressive auditory symptom in full-blown neglect is alloacusis, in which patients mislocalize left-sided sound sources to their right, although even patients with less severe neglect still often show disturbance of auditory spatial perception, most commonly a lateralization bias towards the right. We discuss how these various disorders may be explained by a single model of neglect and review emerging interventions for patient rehabilitation. PMID- 25726291 TI - Auditory agnosia. AB - Auditory agnosia refers to impairments in sound perception and identification despite intact hearing, cognitive functioning, and language abilities (reading, writing, and speaking). Auditory agnosia can be general, affecting all types of sound perception, or can be (relatively) specific to a particular domain. Verbal auditory agnosia (also known as (pure) word deafness) refers to deficits specific to speech processing, environmental sound agnosia refers to difficulties confined to non-speech environmental sounds, and amusia refers to deficits confined to music. These deficits can be apperceptive, affecting basic perceptual processes, or associative, affecting the relation of a perceived auditory object to its meaning. This chapter discusses what is known about the behavioral symptoms and lesion correlates of these different types of auditory agnosia (focusing especially on verbal auditory agnosia), evidence for the role of a rapid temporal processing deficit in some aspects of auditory agnosia, and the few attempts to treat the perceptual deficits associated with auditory agnosia. A clear picture of auditory agnosia has been slow to emerge, hampered by the considerable heterogeneity in behavioral deficits, associated brain damage, and variable assessments across cases. Despite this lack of clarity, these striking deficits in complex sound processing continue to inform our understanding of auditory perception and cognition. PMID- 25726292 TI - Congenital amusias. AB - In contrast to the sophisticated music processing reported in the general population, individuals with congenital amusia show deficits in music perception and production. Congenital amusia occurs without brain damage, sensory or cognitive deficits, and has been suggested as a lifelong deficit with genetic origin. Even though recognized for a long time, this disorder has been systematically studied only relatively recently for its behavioral and neural correlates. The currently most investigated hypothesis about the underlying deficits concerns the pitch dimension, notably with impaired pitch discrimination and memory. Anatomic and functional investigations of pitch processing revealed that the amusic brain presents abnormalities in the auditory and inferior frontal cortices, associated with decreased connectivity between these structures. The deficit also impairs processing of pitch in speech material and processing of the time dimension in music for some of the amusic individuals, but does not seem to affect spatial processing. Some studies suggest at least partial dissociation in the disorder between perception and production. Recent studies revealed spared implicit pitch perception in congenital amusia, supporting the power of implicit cognition in the music domain. Current challenges consist in defining different subtypes of congenital amusia as well as developing rehabilitation programs for this "musical handicap." PMID- 25726293 TI - Acquired amusia. AB - Recent developments in the cognitive neuroscience of music suggest that a further review of the topic of amusia is timely. In this chapter, we first consider previous taxonomies of amusia and propose a fresh framework for understanding the amusias, essentially as disorders of cognitive information processing. We critically review current cognitive and neuroanatomic findings in the published literature on amusia. We assess the extent to which the clinical and neuropsychologic evidence in amusia can be reconciled; both with the information processing framework we propose, and with the picture of the brain organization of music and language processing emerging from cognitive neuroscience and functional neuroimaging studies. The balance of evidence suggests that the amusias can be understood as disorders of musical object cognition targeting separable levels of an information-processing hierarchy and underpinned by specific brain network dysfunction. The neuroanatomic associations of the amusias show substantial overlap with brain networks that process speech; however, this convergence leaves scope for separable brain mechanisms based on altered connectivity and dynamics across culprit networks. The study of the amusias contributes to an increasingly complex picture of the musical brain that transcends any simple dichotomy between music and speech or other complex sounds. PMID- 25726294 TI - Hearing disorders in stroke. AB - Stroke may affect all levels of the auditory pathway and lead to hearing reception and/or perception deficits. Sudden-onset hearing loss after stroke of the vertebrobasilar territory and/or low brainstem is one of the less frequent neurologic impairments, while cortical or central deafness is even rarer. However, studies of populations with stroke indicate that hearing loss is very common, while in the general population, a past history of stroke increases the likelihood of having hearing loss. Auditory-processing deficits after stroke are less well studied than hearing loss and possibly underdocumented. Auditory dysfunction may impact on patient communication and may even predict long-term patient outcome after stroke. Despite this, clinical guidelines for auditory assessments after stroke are rudimentary. This chapter reviews the available information of auditory function in patients with stroke. On the basis of the information available, it is suggested that screening the patient's hearing before the patient leaves the stroke ward with a short test and a minimum set of hearing-related questions and subsequently screening the patient's hearing needs with targeted questions at the chronic stage of stroke may be a cost-effective bare-minimum assessment approach to addressing the hearing needs of this complex population. PMID- 25726295 TI - Hearing disorders in multiple sclerosis. AB - Multiple sclerosis (MS) is a disease that is both a focal inflammatory and a chronic neurodegenerative disease. The focal inflammatory component is characterized by destruction of central nervous system myelin, including the spinal cord; as such it can impair any central neural system, including the auditory system. While on the one hand auditory complaints in MS patients are rare compared to other senses, such as vision and proprioception, on the other hand auditory tests of precise neural timing are never "silent." Whenever focal MS lesions are detected involving the pontine auditory pathway, auditory tests requiring precise neural timing are always abnormal, while auditory functions not requiring such precise timing are often normal. Azimuth sound localization is accomplished by comparing the timing and loudness of the sound at the two ears. Hence tests of azimuth sound localization must obligatorily involve the central nervous system and particularly the brainstem. Whenever a focal lesion was localized to the pontine auditory pathway, timing tests were always abnormal, but loudness tests were not. Moreover, a timing test that included only high frequency sounds was very often abnormal, even when there was no detectable focal MS lesion involving the pontine auditory pathway. This test may be a marker for the chronic neurodegenerative aspect of MS, and, as such could be used to complement the magnetic resonance imaging scan in monitoring the neurodegenerative aspect of MS. Studies of MS brainstem lesion location and auditory function have led to advances in understanding how the human brain processes sound. The brain processes binaural sounds independently for time and level in a two-stage process. The first stage is at the level of the superior olivary complex (SOC) and the second at a level rostral to the SOC. PMID- 25726297 TI - Future advances. AB - Future advances in the auditory systems are difficult to predict, and only educated guesses are possible. It is expected that innovative technologies in the field of neuroscience will be applied to the auditory system. Optogenetics, Brainbow, and CLARITY will improve our knowledge of the working of neural auditory networks and the relationship between sound and language, providing a dynamic picture of the brain in action. CLARITY makes brain tissue transparent and offers a three-dimensional view of neural networks, which, combined with genetically labeling neurons with multiple, distinct colors (Optogenetics), will provide detailed information of the complex brain system. Molecular functional magnetic resonance imaging (MRI) will allow the study of neurotransmitters detectable by MRI and their function in the auditory pathways. The Human Connectome project will study the patterns of distributed brain activity that underlie virtually all aspects of cognition and behavior and determine if abnormalities in the distributed patterns of activity may result in hearing and behavior disorders. Similarly, the programs of Big Brain and ENIGMA will improve our understanding of auditory disorders. New stem-cell therapy and gene therapies therapy may bring about a partial restoration of hearing for impaired patients by inducing regeneration of cochlear hair cells. PMID- 25726298 TI - The first historical document that reported impaired hearing is found in a set of tablets excavated in Epidaurus. Introduction. PMID- 25726296 TI - Hearing and music in dementia. AB - Music is a complex acoustic signal that relies on a number of different brain and cognitive processes to create the sensation of hearing. Changes in hearing function are generally not a major focus of concern for persons with a majority of neurodegenerative diseases associated with dementia, such as Alzheimer disease (AD). However, changes in the processing of sounds may be an early, and possibly preclinical, feature of AD and other neurodegenerative diseases. The aim of this chapter is to review the current state of knowledge concerning hearing and music perception in persons who have a dementia as a result of a neurodegenerative disease. The review focuses on both peripheral and central auditory processing in common neurodegenerative diseases, with a particular focus on the processing of music and other non-verbal sounds. The chapter also reviews music interventions used for persons with neurodegenerative diseases. PMID- 25726299 TI - It is curious how little attention most neurologists direct at hearing. Introduction. PMID- 25726300 TI - Developmental origins of chronic inflammation: a review of the relationship between birth weight and C-reactive protein. AB - PURPOSE: The developmental origins of adult disease hypothesis suggests that the intrauterine environment may program postnatal health outcomes through mechanisms such as chronic inflammation. The purpose of this article was to review the literature on the association between infant birth weight and C-reactive protein (CRP), markers of the fetal environment and inflammation, respectively. METHODS: We used PubMed, Google Scholar, Web of Science, ScienceDirect, the citation lists of the reviewed literature, and recommendations from experts in the field to identify potential articles. Inclusion criteria for the studies, regardless of study design, included human subjects, documented or self-reported infant birth weight, and a minimum of one measurement of CRP (during childhood, adolescence, or adulthood). RESULTS: Several studies demonstrated a statistically significant inverse association between birth weight and CRP in adulthood, although in many cases only after controlling for markers of current adiposity. No studies significantly linked birth weight to CRP in childhood or adolescence. CONCLUSIONS: Longitudinal studies, including multigenerational studies, are needed to further understand whether adult CRP has origins in the fetal environment. PMID- 25726301 TI - Superoxide dismutase of Streptococcus suis serotype 2 plays a role in anti autophagic response by scavenging reactive oxygen species in infected macrophages. AB - Streptococcus suis serotype 2 (SS2) causes septic shock and meningitis. However, its pathogenesis is still not well-understood. We have recently shown that superoxide dismutase sodA of SS2 is a virulence factor probably by increasing resistance to oxidative stresses. Reactive oxygen species (ROS) are products of the respiratory burst of phagocytic cells and have been shown to activate autophagy. We wanted to know if and how SS2 explores its sodA to interfere with cell autophagic responses. A sodA deletion mutant (Deltasod) was compared with its parent and complemented strain in autophagic response in the murine macrophage cell line RAW264.7. We found that the Deltasod mutant induced significant autophagic responses in infected cells, shown as increased LC3 lipidation (LC3-II) and EGFP-LC3 punctae, than those infected by its parent or complemented strain at 1 or 2h post-infection. Co-localization of the autophagosomal EGFP-LC3 vesicles with lysosomes was seen in cells infected with Deltasod mutant and its parent strain, indicating that SS2 infection induced complete autophagic responses. Reduced autophagic responses of cells infected with the wild-type strain might be related to decreased ROS by the scavenging effect of its sodA, as shown by increased superoxide anion or ROS level in cells infected with the Deltasod mutant and in the cell free xanthine oxidase hypoxanthine ROS-generating system, as compared with its parent or complemented strain. Taken together, SS2 makes use of its sodA for survival not only by scavenging ROS but also by alleviating the host autophagic responses due to ROS stimulation. PMID- 25726302 TI - Outbreak investigation identifies a single Listeria monocytogenes strain in sheep with different clinical manifestations, soil and water. AB - Listeria (L.) monocytogenes causes orally acquired infections and is of major importance in ruminants. Little is known about L. monocytogenes transmission between farm environment and ruminants. In order to determine potential sources of infection, we investigated the distribution of L. monocytogenes genetic subtypes in a sheep farm during a listeriosis outbreak by applying four subtyping methods (MALDI-TOF-MS, MLST, MLVA and PFGE). L. monocytogenes was isolated from a lamb with septicemia and from the brainstem of three sheep with encephalitis. Samples from the farm environment were screened for the presence of L. monocytogenes during the listeriosis outbreak, four weeks and eight months after. L. monocytogenes was found only in soil and water tank swabs during the outbreak. Four weeks later, following thorough cleaning of the barn, as well as eight months later, L. monocytogenes was absent in environmental samples. All environmental and clinical L. monocytogenes isolates were found to be the same strain. Our results show that the outbreak involving two different clinical syndromes was caused by a single L. monocytogenes strain and that soil and water tanks were potential infection sources during this outbreak. However, silage cannot be completely ruled out as the bales fed prior to the outbreak were not available for analysis. Faeces samples were negative, suggesting that sheep did not act as amplification hosts contributing to environmental contamination. In conclusion, farm management appears to be a crucial factor for the limitation of a listeriosis outbreak. PMID- 25726303 TI - [Hereditary angioedema]. PMID- 25726304 TI - [Invasive listeriosis in Pontevedra province, Spain: Target of epidemiological surveillance?]. PMID- 25726305 TI - [Large vessels vasculopathy in systemic sclerosis]. AB - Vasculopathy in systemic sclerosis is a severe, in many cases irreversible, manifestation that can lead to amputation. While the classical clinical manifestations of the disease have to do with the involvement of microcirculation, proximal vessels of upper and lower limbs can also be affected. This involvement of large vessels may be related to systemic sclerosis, vasculitis or atherosclerotic, and the differential diagnosis is not easy. To conduct a proper and early diagnosis, it is essential to start prompt appropriate treatment. In this review, we examine the involvement of large vessels in scleroderma, an understudied manifestation with important prognostic and therapeutic implications. PMID- 25726306 TI - [IgG4-related disease]. AB - IgG4-related disease is a recently described clinicopathological entity showing a wide spectrum of clinical manifestations that share a common pathology. Its most characteristic feature is the formation of inflammatory tumors in different organs, which makes differentiation mainly with neoplastic diseases fundamental. The inflammatory process is typically comprised of IgG4 lymphoplasmacytic cells. The pathophysiological role of the immunoglobulin is not clear. The treatment of choice is corticosteroids. This article aims to summarize the main features of the disease. PMID- 25726307 TI - [Painful generalized erythematous patches: A very rare cutaneous adverse effect of pemetrexed]. PMID- 25726308 TI - [Multidisciplinary approach in the diagnosis and therapy of patients with endocrine tumors]. PMID- 25726310 TI - [Podoconiosis, a society and medical community neglected disease]. AB - Podoconiosis, mossy foot or endemic non-filarial elephantiasis, is a geochemical disease that causes lower limb lymphedema; it is directly related to walking barefoot over soils of volcanic origin, in areas with a high pluviometric annual index. It has a specific geographical distribution, affecting around 5% population in areas where it is endemic. It is debilitating and disfiguring disease, which frequently leads to social margination. Podoconiosis is totally preventable and, once a diagnosis is established, it may improve with simple therapeutic measures. PMID- 25726309 TI - [Prognostic factors of early breast cancer]. AB - Decision about the administration of adjuvant therapy for early breast cancer depends on the evaluation of prognostic factors. Lymph node status, tumor size and grade of differentiation are classical variables in this regard, and can be complemented by hormonal receptor status and HER2 expression. These factors can be combined into prognostic indexes to better estimate the risk of relapse or death. Other factors are less important. Gene profiles have emerged in recent years to identify low-risk patients who can forgo adjuvant chemotherapy. A number of profiles are available and can be used in selected cases. In the future, gene profiling will be used to select patients for treatment with new targeted therapies. PMID- 25726311 TI - [Is the recruitment of researchers economically profitable for institutions of the National Health System? The case of the Miguel Servet Programme]. PMID- 25726312 TI - [Prevalence of benign and malignant tumors in acromegalic patients]. PMID- 25726313 TI - Altered left ventricular twist is associated with clinical severity in adults and adolescents with homozygous sickle cell anemia. AB - BACKGROUND: Sickle cell anemia (SCA) is associated with cardiac abnormalities and premature death. The aims of this study were to identify early markers of cardiac dysfunction through ventricular strain and ventricular twist and determine the relationships between these measures and other markers of cardiovascular risk. METHODS: Forty patients with SCA (mean age, 23.5 +/- 9.3 years; 24 male patients) and 40 age- and sex-matched healthy individuals were compared. All subjects participated in structured interviews, and blood samples were collected. Standard echocardiography with subsequent offline evaluations using left ventricular (LV) and right ventricular systolic strain and rotational analyses of the left ventricle using two-dimensional speckle-tracking echocardiography were performed. RESULTS: There were no differences in LV ejection fraction, global LV strain (longitudinal, circumferential, and radial), and global right ventricular longitudinal strain between patients and controls; however, LV twist was significantly lower in the patient group (mean, 7.4 +/- 1.2 degrees vs 10.7 +/- 1.8 degrees ; P < .0001). Several variables were strongly related to LV twist, including the clinical severity index (rho = -0.97, Z score = -6.05, P < .0001), E/e' ratio (r = 0.78, P < .0001), LV end-diastolic volume index (r = 0.81, P < .0001), and pulmonary artery systolic pressure (r = 0.72, P < .0001). CONCLUSIONS: LV twist is altered in patients with SCA. There were strong correlations between left ventricular twist and clinical severity index, E/e' ratio, LV end-diastolic volume index, and pulmonary artery systolic pressure. These data suggest that decreased LV twist may indicate a subgroup of patients with SCA at greater cardiac risk. PMID- 25726315 TI - Two-year results of intermittent electrical stimulation of the lower esophageal sphincter treatment of gastroesophageal reflux disease. AB - BACKGROUND: Lower esophageal sphincter (LES) electrical stimulation therapy (EST) has been shown to improve outcome in gastroesophageal reflux disease (GERD) patients at 1 year. The aim of this open-label extension trial (NCT01578642) was to study the 2-year safety and efficacy of LES-EST in GERD patients. METHODS: GERD patients responsive partially to proton pump inhibitors (PPI) with off-PPI GERD health-related quality of life (HRQL) of >=20, 24-hour esophageal pH <=4.0 for >5% of the time, hiatal hernia <=3 cm, and esophagitis LA grade C or lower participated in this trial. Bipolar stitch electrodes and a pulse generator (EndoStim BV, The Hague, The Netherlands) were implanted laparoscopically. LES EST at 20 Hz, 215 MUs, 3-8 mAmp was delivered over 30-minute sessions, 6-12 sessions per day, starting on day 1 after implantation. Patients were evaluated using GERD-HRQL, symptom diaries, Short Form-12, and esophageal pH testing at regular intervals. Stimulation sessions were optimized based on residual symptoms and esophageal pH at follow-up. RESULTS: Twenty-five patients (mean age [SD] = 52 [12] years; 14 men) were implanted successfully; 23 patients participated in the 2-year extension trial, and 21 completed their 2-year evaluation. At 2 years, there was improvement in their median GERD-HRQL on LES-EST compared with both their on-PPI (9 vs 0; P = .001) and off-PPI (23.5 vs. 0; P < .001) baseline scores. Median 24-hour distal esophageal acid exposure improved from 10% at baseline to 4% (per-protocol analysis; P < .001) at 2 years with 71% demonstrating either normalization or a >=50% decrease in their distal esophageal acid exposure. All except 5 patients (16/21) reported complete cessation of PPI use; only 2 patients were using a PPI regularly (>=50% of days). There was significant improvement in sleep quality and daily symptoms of heartburn and regurgitation on LES-EST. At baseline, 92% of the subjects (22/24) reported that they were "unsatisfied" with their condition off-PPI and 71% (17/24) on-PPI compared with 0% (0/21) "unsatisfied" at the 24-month visits on LES-EST. There were no device- or therapy-related serious adverse events and no untoward sensation or dysphagia reported with LES-EST. CONCLUSION: LES-EST is safe and effective for treating patients with GERD over a period of 2 years. LES-EST resulted in a significant and sustained improvement in GERD symptoms, and esophageal acid exposure and eliminated PPI use in majority of patients (16 of 21). Further, LES-EST was not associated with any gastrointestinal side effects or adverse events. PMID- 25726316 TI - Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Although marked improvements have been made in surgical technique and chemoradiotherapy, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) and its downstream signaling, p70 ribosomal S6 protein kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), seem to play central roles in the regulation of cancer cell proliferation and survival. The significance of mTOR and its downstream targets, p70S6K and 4E-BP1, on the prognosis of ESCC remains uncertain, but this pathway is of particular concern because effective inhibitors are already available. METHODS: Immunohistochemistry performed to evaluate the expression of phosphorylated mTOR (p-mTOR), phosphorylated p70S6K (p-p70S6K), phosphorylated 4E-binding protein 1 (p-4E-BP1), and Ki-67 using 105 surgically resected ESCC correlated with treatment outcome. The effect of the mTOR signaling pathway inhibitor everolimus on ESCC cell lines were investigated in vitro by the 3-(4.5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay and in vivo by a nude mouse xenograft model. RESULTS: Univariate analysis showed that p-mTOR overexpression (P = .022), p-p70S6K overexpression (P = .002), and Ki-67 labeling index >50% (P = .045) were associated with inferior overall survival (OS). In a multivariate comparison, p p70S6K overexpression (P = .001; hazard ratio, 2.247) remained independently associated with worse OS. In cell lines and the xenograft model, everolimus significantly inhibited ESCC growth. CONCLUSION: Overexpression of p-p70S6K is associated independently with a poor prognosis among patients with ESCC. The mTOR signaling pathway inhibitor everolimus can inhibit ESCC growth in vitro and in vivo. Our findings suggest that inhibition of mTOR signaling pathway may be a promising novel target for ESCC. PMID- 25726317 TI - Combined intraoperative administration of a histone deacetylase inhibitor and a neurokinin-1 receptor antagonist synergistically reduces intra-abdominal adhesion formation in a rat model. AB - BACKGROUND: Intra-abdominal adhesions are the most frequent postoperative complication after abdominopelvic surgery. Our laboratory has previously shown that an intraoperative peritoneal lavage containing either the histone deacetylase inhibitor valproic acid (VPA) or a neurokinin-1 receptor antagonist (NK-1RA) reduced adhesions by approximately 50% in a rat model. The objective of this study was to determine whether the combination of these 2 drugs was more effective in reducing adhesions than either alone. METHODS: Rats underwent laparotomy with creation of peritoneal ischemic buttons to induce adhesions. A single dose of VPA (25 mg/kg), NK-1RA (50 mg/kg), a combination of both, or 0.9% saline was lavaged intraperitoneally just before wound closure. On postoperative day 7, adhesions were quantified. To investigate early mechanisms of adhesiogenesis, adhesions were created as described and adhesive button tissue was harvested at 30 minutes and 3 hours postoperatively and fibrinogen and vascular endothelial growth factor (VEGF) protein levels, both indices of peritoneal extravasations, were determined by Western blot analysis. Peritoneal fluid was collected in similar experiments at 30 minutes, and 3 and 6 hours to measure fibrinolytic activity, an index of the ability of the peritoneum to degrade fibrinous adhesions. RESULTS: The coadministration of VPA plus NK-1RA reduces adhesions by 72.6% relative to saline (P < .001); this reduction was greater than either compound alone (P < .001). Peritoneal fibrinolytic activity was significantly increased at 3 and 6 hours postoperatively in animals administered the combination therapy versus saline (P = .01). VPA plus NK-1RA significantly decreased fibrinogen and VEGF protein levels at 3 and 6 hours compared with saline controls. CONCLUSION: These results suggest that a combined pharmacologic approach targeting multiple adhesiogenic pathways provides optimal adhesion prevention. PMID- 25726319 TI - Expedited Biliopancreatic Juice Flow to the Distal Gut Benefits the Diabetes Control After Duodenal-Jejunal Bypass. AB - BACKGROUND: Serum bile acids (BAs) are elevated after metabolic surgeries including Roux-en-Y gastric bypass (RYGB), ileal transposition (IT), and duodenal jejunal bypass (DJB). Recently, BAs have emerged as a kind of signaling molecules, which can not only promote glucagon-like peptide-1 (GLP-1) secretion but can also regulate multiple enzymes involved in glucose metabolism. The aim of this study was to investigate whether expedited biliopancreatic juice flow to the distal gut contributes to the increased serum GLP-1 and BAs and benefits the diabetes control after DJB. METHODS: DJB, long alimentary limb DJB (LDJB), duodenal-jejunal anastomosis (DJA), and sham operation were performed in diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ). Body weight, food intake, oral glucose tolerance, insulin tolerance, glucose stimulated insulin and GLP-1 secretion, fasting serum total bile acids (TBAs), and lipid profiles were measured at indicated time points. RESULTS: Compared with sham operation, DJA, DJB, and LDJB all achieved rapid and dramatic improvements in glucose tolerance and insulin sensitivity independently of food restriction and weight loss. DJB and LDJB-operated rats exhibited even better glucose tolerance, higher fasting serum TBAs, and higher glucose-stimulated GLP-1 secretion than the DJA group postoperatively. No difference was detected in insulin sensitivity and glucose-stimulated insulin secretion between DJA, DJB, and LDJB groups. CONCLUSIONS: Expedited biliopancreatic juice flow to the distal gut was associated with augmented GLP-1 secretion and increased fasting serum TBA concentration, which may partly explain the metabolic benefits of DJB. PMID- 25726318 TI - Inequity to the utilization of bariatric surgery: a systematic review and meta analysis. AB - This systematic review explores the sociodemographic factors associated with the utilization of bariatric surgery among eligible patients. Electronic databases were searched for population-based studies that explored the relationship between sociodemographic characteristics of patients eligible for bariatric surgery to those who actually received the procedure. Twelve retrospective cohort studies were retrieved, of which the results of 9 studies were pooled using a random effects model. Patients who received bariatric surgery were significantly more likely to be white versus non-white (OR 1.54; 95% CI 1.08, 2.19), female versus male (OR 2.80; 95% CI 2.46, 3.22), and have private versus government or public insurance (OR 2.51; 95% CI 1.04, 6.05). Prospective cohort studies are warranted to further determine the relative effect of these factors, adjusting for confounding factors. PMID- 25726320 TI - Controversies in perioperative anesthetic management of the morbidly obese: I am a surgeon, why should I care? AB - Over the last four decades, as the rates of obesity have increased, so have the challenges associated with its anesthetic management. In the present review, we discuss perioperative anesthesia management issues that are modifiable by the early involvement of the surgical team. We sum up available evidence or expert opinion on issues like patient positioning, postoperative analgesia, and the effect of continuous positive airway pressure (CPAP) ventilation on surgical anastomosis. We also address established predictors of higher perioperative risk and suggest possible management strategies and concerns of obese patients undergoing same day procedures. Finally, a generalized pharmacological model relevant to altered pharmacokinetics in these patients is presented. PMID- 25726321 TI - Changes in Glucose Metabolism in Vertical Sleeve Gastrectomy. AB - BACKGROUND: We evaluated metabolic changes after vertical sleeve gastrectomy (VSG) surgery in a rat model using proteomics and metabolomic profiling in liver and serum. METHODS: Rats were randomly divided into two groups: sham (n = 10) and VSG (n = 12). Food intake, body weight, blood glucose, insulin, and thyroid hormone levels were measured. Two-dimensional electrophoresis, nuclear resonance spectroscopy, mass spectroscopy, immunofluorescence, and immunoblot analyses were used to determine and validate changes in metabolites and proteins in liver tissue and serum samples. RESULTS: Food intake and body weight decreased after VSG group (p < 0.05 and p < 0.05, respectively). Random blood glucose (sham, 183.3 +/- 5.6 mg/dL; VSG, 138.5 +/- 3.7 mg/dL) decreased while random insulin (sham, 0.45 +/- 0.16 MUg/L; VSG, 1.05 +/- 0.18 MUg/L) increased after VSG (p < 0.05 and p < 0.01, respectively). We found that expressions of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase-1 and glucose-6-phosphatase) and concentrations of pyruvate and malate decreased while lactate, NADH, NADPH, glucose, and AMP/ATP ratio increased after VSG. Thyroid hormones, triiodothyronine (T3) and free thyroxine (fT4), decreased after VSG. CONCLUSION: This study proves that VSG suppresses hepatic glucose production. PMID- 25726322 TI - Skin pentosidine and telomere length do not covary with age in a long-lived seabird. AB - The questions about why and how senescence occurs in the wild are among the most pertinent ones in evolutionary ecology. Telomere length is a commonly used marker for aging, while other biomarkers of aging have received considerably less attention. Here we studied how another potent indicator of aging-skin pentosidine concentration-relates to age and blood telomere length in a long-lived seabird with well-documented reproductive senescence. We found no associations between telomere length, skin pentosidine and chronological age in male common gulls (Larus canus), aging from 2 to 30 years. However, the variance in telomere length was 4.6 times higher among the birds older than 13 years, which hints at relaxed selection on telomere length among the birds that have passed their prime age of reproduction. These results suggest that physiological and chronological ages may be largely uncoupled in our study system. Furthermore, our findings do not support a hypothesis about the presence of a common physiological factor (e.g., such as oxidative stress) that would cause covariation between two independent markers of aging. PMID- 25726323 TI - Decision-making in child protective services: Influences at multiple levels of the social ecology. AB - Decision-making in the child protection system is influenced by multiple factors; agency and geographic contexts, caseworker attributes, and families' unique circumstances all likely play a role. In this study, we use the second cohort of the National Survey of Child and Adolescent Well-Being to explore how these factors are associated with two key case decisions-substantiation and removal to out-of-home care. Analyses are conducted using weighted hierarchical linear models. We find that substantiation is strongly influenced by agency factors, particularly constraints on service accessibility. Substantiation is less likely when agencies can provide services to unsubstantiated cases and when collaboration with other social institutions is high. This supports the concept that substantiation may be a gateway to services in some communities. Agency factors contributed less to the probability of removal among substantiated cases, though time resources and constraints on decision-making had some influence. For both substantiation and removal risks, county, caseworker, and child characteristics were less influential than agency characteristics and family risk factors. PMID- 25726325 TI - Interleukin-1 receptor antagonist: friend or foe to the heart? PMID- 25726326 TI - Biochemical, cytological, and immunological mechanisms of rhododendrol-induced leukoderma. AB - Recently, an unexpected outbreak of patients with leukoderma occurred in Japan with the use of brightening/lightening cosmetics containing rhododendrol (RD). Patients developed leukoderma mostly on the skin sites repeatedly applied with RD, but some patients also had vitiligo-like lesions on the non-applied sites. RD is a tyrosinase-competitive inhibiting substance, thereby serving as an inhibitor of melanin synthesis. Upon inhibition of tyrosinase, RD is converted to new products such as tyrosinase-catalyzed hydroxyl-metabolite, which damage melanocytes. The melanocyte cell lysates seem to induce T-cell response. The frequencies of CD8+ T cells in both lesional skin and peripheral blood are significantly higher in the RD leukoderma as well as non-segmental vitiligo patients than in normal controls. In HLA-A*02:01 positive cases, circulating Melan-A-specific cytotoxic T cells can be detected at a high frequency. It is thus suggested that RD-induced leukoderma is induced by not only cytolysis of melanocytes but also subsequent immune reactions toward melanocytes. PMID- 25726327 TI - Ichthyosis and Kallmann syndrome: not always a contiguous gene syndrome. PMID- 25726328 TI - N-acylated sulfonamide congeners of fosmidomycin lack any inhibitory activity against DXR. AB - The antibiotic fosmidomycin (3a) is an inhibitor of the non-mevalonate pathway for isoprenoid biosynthesis. Four analogues in which an acylated sulfonamide group is substituting for its phosphonate moiety have been synthesized in a fruitless effort to preserve one negative charge in order to increase the accompanying affinity for 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the fosmidomycin target enzyme. PMID- 25726324 TI - Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis. AB - BACKGROUND: To investigate potential cardiovascular and other effects of long term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. METHODS: We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1alpha and IL-1beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants). FINDINGS: For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p = 9.3 * 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; 1.7%; p = 3.5 * 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p = 7.7 * 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 * 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p = 3.9 * 10(-10)). Per allele odds ratios were 0.97 (0.95-0.99; p = 9.9 * 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p = 0.47) for type 2 diabetes, 1.00 (0.98-1.02; p = 0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p = 1.8 * 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. INTERPRETATION: Human genetic data suggest that long-term dual IL-1alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. PMID- 25726329 TI - Effect of the tyrosinase inhibitor (S)-N-trans-feruloyloctopamine from garlic skin on tyrosinase gene expression and melanine accumulation in melanoma cells. AB - In our searching for novel tyrosinase inhibitors from natural sources, (S)-N trans-feruloyloctopamine isolated from garlic skin was found to be a potential mushroom tyrosinase inhibitor. Here, we examined the effects of the potential tyrosinase inhibitor in B16F10 cells on intracellular melanin contents, cytotoxicity, and the signaling mechanism involved in the expression of tyrosinase. The results showed the inhibitor displayed little or no cytotoxicity at all concentrations examined and decreased the relative melanin contents in a dose-dependent manner in the alpha-MSH-stimulated B16F10 cells. Real-time PCR and Western blot analysis showed that it inhibits melanogenesis signaling by down regulates mRNA and protein expression levels of tyrosinase, which leads to a lower melanin contents. These results suggested that (S)-N-trans feruloyloctopamine was an ideal tyrosinase inhibitor, and could be used in food and medical industry. PMID- 25726330 TI - Synthesis, solution and crystal structure of the coenzyme B(12) analogue Co(beta) 2'-fluoro-2',5'-dideoxyadenosylcobalamin. AB - Crystal structure analyses have helped to decipher the mode of binding of coenzyme B12 (AdoCbl) in the active site of AdoCbl-dependent enzymes. However, the question of how such enzymes perform their radical reactions is still incompletely answered. A pioneering study by Gruber and Kratky of AdoCbl dependent glutamate mutase (GLM) laid out a path for the movement of the catalytically active 5'-deoxyadenosyl radical, in which H-bonds between the protein and the 2'- and 3'-OH groups of the protein bound AdoCbl would play a decisive role. Studies with correspondingly modified coenzyme B12-analogues are of interest to gain insights into cofactor binding and enzyme mechanism. Here we report the preparation of Cobeta-2'-fluoro-2',5'-dideoxyadenosylcobalamin (2'FAdoCbl), which lacks the 2'-OH group critical for the interaction in enzymes. 2'FAdoCbl was prepared by alkylation of cob(I)alamin, obtained from the electrochemical reduction of aquocobalamin. Spectroscopic data and a single crystal X-ray analysis of 2'FAdoCbl established its structure, which was very similar to that one of coenzyme B12. 2'FAdoCbl is a (19)F NMR active mimic of coenzyme B12 that may help to gain insights into binding interactions of coenzyme B12 with AdoCbl-dependent enzymes, proteins of B12 transport and of AdoCbl biosynthesis, as well as with B12-riboswitches. PMID- 25726331 TI - The role of stem cells and tissue engineering in orthopaedic sports medicine: current evidence and future directions. AB - The use of stem cell therapies for the treatment of orthopaedic injuries continues to advance. The purpose of this review was to provide an update of the current role and future directions of stem cell strategies in sports medicine. The application of cell-based treatments in the sports medicine arena has expanded in recent years. Promising preclinical results have led to translation of these novel therapies into the clinical setting. Early well-designed comparative clinical studies have also shown positive outcomes. Despite significant advances in this arena, there remains a need for additional high powered and well-designed clinical trials to confirm the safety and efficacy of treatment. PMID- 25726332 TI - Exosomal protein interactors as emerging therapeutic targets in urothelial bladder cancer. AB - BACKGROUND: Exosomes are rich sources of biological material (proteins and nucleic acids) secreted by both tumor and normal cells, and found in urine of urinary bladder cancer patients. OBJECTIVE: The objective of the study was to identify interacting exosomal proteins in bladder cancer for future use in targeted therapy. METHODS: The Exocarta database (www.exocarta.org) was mined for urinary bladder cancer specific exosomal proteins. The urinary bladder cancer specific exosomal proteins (n=248) were analyzed to identify enriched pathways by Onto-tool Pathway Express (http://vortex.cs.wayne.edu/ontoexpress). RESULTS: Enriched pathways included cellular architecture, motility, cell to cell adhesion, tumorigenesis and metastasis. Proteins in the 9 top-ranked pathways included CTNNA1 (alpha-catenin), CTNNB1 (beta-catenin), VSAP, ITGA4, PAK1, DDR1, CDC42, RHOA, NRAS, RHO, PIK3AR1, MLC1, MMRN1, and CTTNBP2 and network analysis revealed 10 important hub proteins and identified inferred interactor NF2. CONCLUSIONS: The importance of identifying interactors is that that they can be used as targets for therapy, for example, using Bevacizumab (avastin--an angiogenesis inhibitor) against NF2 to inhibit protein-protein interactions will inhibit tumor growth and progression by hindering the exosome biogenesis. PMID- 25726333 TI - Glycemic control according to glomerular filtration rate in patients with type 2 diabetes and overt nephropathy: a prospective observational study. AB - BACKGROUND AND OBJECTIVE: Type 2 diabetes (T2D) and chronic kidney disease (CKD) are closely linked. This study aimed to describe and analyze the relations between renal function and glycemic control in T2D patients with overt nephropathy. PATIENTS AND METHODS: Data were collected from a French observational prospective multicenter study. Patients included were adults with T2D, clinical proteinuria and an estimated glomerular filtration rate (eGFR) over 15 mL/min/1.73 m(2). Baseline data and glycemic control after a one-year follow up are presented here. RESULTS: Data from 986 adult patients were analyzed. Mean age was 70 years. Mean eGFR was 42 mL/min/1.73 m(2), 66% of patients had proteinuria above 1g/day. HbA1c was higher in patients with lower eGFR in a model adjusted to age, gender, body mass index, hemoglobin level and erythropoietin use. Statistical significance was lost when stepwise multivariate analysis took into account the type of pharmacological treatment used to treat hyperglycemia.The type of antidiabetic agents differed across eGFR strata. Below 60 mL/min/1.73 m(2), the use of metformin declined while the use of insulin increased.After one year of follow up, 35% of patients had persistently poor or worsened glycemic control (HbA1c>8%). The only covariate independently associated with this characteristic was the duration of insulin therapy. CONCLUSION: In patients with T2D and overt nephropathy, the observed correlation of low eGFR with high HbA1c was not predicted by eGFR. Our data rather underscore a different use of antidiabetic treatments in patients with advanced renal dysfunction, and the difficulty to improve glycemic control in patients with long standing insulin therapy. PMID- 25726334 TI - The ankle brachial index is associated with prognosis in patients with diabetic kidney disease. AB - AIMS: Peripheral arterial disease (PAD) could be an additional risk factor for the clinical outcomes in different populations. The purpose of this study was to evaluate the influence of PAD on patients with diabetic kidney disease. METHODS: 362 persons with type 2 diabetes were followed-up for a mean 4.8 years grouped by ankle brachial index (ABI) (<0.9 vs. ?0.9) and albuminuria (with or without). Primary and secondary outcomes were composite events (all-cause mortality, hospitalization for coronary artery disease, stroke, re-vascularization, amputation, and diabetic foot) and all-cause mortality. RESULTS: Inter-group differences in duration of diabetes, glycated hemoglobin, creatinine, and estimated glomerular filtration rate were significant. During the follow-up period, 53 composite events were recorded (14.7%) and 13 (3.5%) individuals died. Subjects with albuminuria plus ABI<0.9 had higher risk of composite events than those with albuminuria but normal ABI (p<0.05). The only trend difference between the two groups was in all-cause mortality. Albuminuria plus ABI <0.9 was associated with risk of composite events (hazard ratio [HR] 4.20, 95% confidence interval [CI] 1.77-9.92, p=0.001) and all-cause mortality (HR 17.77, 95% CI 1.93 162.20, p=0.011). CONCLUSIONS: PAD might be an additional risk factor for adverse outcomes in patients with diabetic kidney disease. Further prospective data are required to validate this conclusion. PMID- 25726336 TI - Preventing tooth loss with biannual dental visits and genetic testing: does it work? PMID- 25726335 TI - Marker of lipid peroxidation related to diabetic nephropathy in Indonesian type 2 diabetes mellitus patients. AB - OBJECTIVE: Even though diabetes patients exhibit an increased oxidative stress, its correlation with diabetic nephropathy is not fully understood. The purpose of this study was to determine whether lipid peroxidation marker correlates well with eGFR and UACR in type 2 diabetes mellitus patients. METHODS: We collected urine and serum samples of Indonesian type 2 diabetes mellitus outpatients with normo- and microalbuminuria at a Local Government Clinic (from ages: 39-74 years). Urinary 8-iso-PGF2alpha was measured by ELISA, the serum malondialdehyde by TBARS assay, and urinary albumin by BCG albumin assay. eGFR was calculated using the corrected-Cockcroft-Gault (CG), MDRD, and CKD-EPI equation. Other necessary data were obtained through questionnaires. RESULTS: The results showed that the increasing level of malondialdehyde was mildly correlated with the decline in eGFR (MDRD). In contrary, there was a significant positive correlation between 8-iso-PGF2alpha concentration and eGFR based on the corrected-CG, MDRD study, and CKD-EPI equation (r=0.457, p<0.001; r=0.424, p<0.001; r=0.443, p<0.001). This relationship still persisted in the normoalbuminuric subjects (n=43) (r=0.491, p=0.001; r=0.461, p=0.002; r=0.455, p=0.002). The multivariate analysis showed that 8-iso-PGF2alpha together with fasting plasma glucose was the most predictive factor for the high 2-quantile eGFR (adjusted OR 1.001, (95% CI, 1.000-1.001)). However, there was no significant correlation between UACR with malondialdehyde (r=0.268, p=0.050) and 8-iso-PGF2alpha(r=-0.030, p=0.808). UACR itself was inversely correlated with eGFR based on the corrected-CG, the MDRD, and CKD-EPI (r=-0.232, p<0.05; r=-0.228, p<0.05; r=-0.232, p<0.05). CONCLUSIONS: Increased 8-iso-PGF2alpha and malondialdehyde in type 2 diabetes mellitus patients may play a role in the pathophysiologic significance of diabetic nephropathy, even while considering the effect of potential confounders. PMID- 25726337 TI - Ethical characteristics. PMID- 25726338 TI - Authors' response. PMID- 25726339 TI - Melanoma and TMD. PMID- 25726340 TI - Author's response. PMID- 25726341 TI - Antibiotics and implants. PMID- 25726342 TI - Effectiveness of systemic antimicrobial therapy in combination with scaling and root planing in the treatment of periodontitis: a systematic review. AB - BACKGROUND: The use of systemic antibiotics in conjunction with scaling and root planing (SRP) may improve the clinical outcome and even could be essential for a successful treatment of periodontitis. However, the effectiveness and clinical safety of this combination of therapy remain unclear. The authors of this study reviewed the available literature related to this hypothesis, evaluating the effectiveness of the use of systemic antimicrobials in combination with SRP versus SRP alone in the treatment of chronic periodontitis (CP) or aggressive periodontitis (AgP). METHODS: The authors used 3 electronic databases and hand searched articles published from April 2001 through October 2013 in selected journals. The authors selected clinical trials with a minimum of 6 months follow up during which patients with either CP or AgP had been treated with systemic antibiotics plus SRP in comparison with SRP alone or with placebo. The authors analyzed the gain in clinical attachment level (CAL), reduction in probing pocket depth (PPD), reduction in bleeding on probing (BOP), and patient-related variables (that is, adverse effects). RESULTS: After the selection process, the authors included 23 clinical trials in this review. Assessment of the quality of the studies revealed the risk of bias as a common finding. Overall, there was a tendency toward improvement of the measured outcomes, CAL, PPD, and BOP in studies for which systemic antibiotics were used as adjunctive therapy with SRP. CONCLUSION: Owing to the high level of heterogeneity of the studies included in this review, the authors could not establish definitive conclusions and guidelines regarding the use of adjunctive systemic antibiotics. However, within the limitations of this review, the use of systemic antibiotics with SRP may be beneficial for specific populations. Standardized clinical disease diagnostic criteria and additional randomized controlled clinical trials are necessary to verify the effectiveness of the use of adjunctive systemic antimicrobials with SRP. PRACTICAL IMPLICATIONS: Owing to methodological differences and biases among clinical trials evaluating systemic antibiotics adjunctive to SRP, clinicians should base their decisions to prescribe on the results of weighing both benefits and risks for each patient. PMID- 25726343 TI - Interleukin 1 genetic tests provide no support for reduction of preventive dental care. AB - BACKGROUND: It has been proposed that the PST and PerioPredict genetic tests that are based on polymorphisms in interleukin 1 (IL-1) genes identify a subset of patients who experience fewer tooth extractions if provided with 2 annual preventive visits. Economic analyses indicate rationing preventive care to only "high-risk" genotypes, smokers, patients with diabetes, or combinations of these risk factors would reduce the cost of dental care by $4.8 billion annually in the United States. METHODS: Data presented in the study that claimed clinical utility for the PST and PerioPredict tests were obtained for reanalysis using logistic regression to assess whether the PST genetic test, smoking, diabetes, or number of preventive visits were risk factors for tooth extraction during a span of 16 years. Consistency of risk classification by the PST (version 1) and PerioPredict (version 2) genetic tests was evaluated in different ethnic groups from the 1000 Genomes database. RESULTS: Multivariate analyses revealed association of tooth extraction with diabetes (P < .0001), smoking (P < .0001), and number of preventive visits (P = .004), but no support for the PST genetic test (P = .96) nor indication that the benefit of 2 preventive visits was affected by this genetic test (P = .58). Classification of risk was highly inconsistent between the PST (version 1) and PerioPredict (version 2) genetic tests. CONCLUSIONS: Two annual preventive visits were supported as beneficial for all patients, and there was no evidence that the IL-1 PST genetic test has any effect on tooth extraction risk or influences the benefits of 2 annual preventive visits. PRACTICAL IMPLICATIONS: Neither IL-1 PST nor PerioPredict genetic tests are useful for rationing preventive dental care. Further research is needed to identify genetic biomarkers with robust clinical validity and clinical utility to effectively personalize the practice of dentistry. PMID- 25726344 TI - Counterpoint: Risk factors, including genetic information, add value in stratifying patients for optimal preventive dental care. AB - BACKGROUND: There is disagreement as to whether patient stratification by a combination of diabetes, smoking, and genetic test results is useful for informing the frequency of dental prophylaxes. METHODS: The authors appeal to basic tenets of clinical study design and statistical analysis of clinical investigations, and highlight how secondary ad hoc analyses, such as those of Diehl and colleagues, are frequently underpowered and inconclusive. They also provide evidence from numerous studies supporting the use of genetics to identify risk. RESULTS: The authors believe the conclusions reached from their original analyses are valid and the analyses of Diehl and colleagues serve to simply reinforce the authors' specific intent of avoiding such underpowered analyses altogether with the Michigan Personalized Prevention Study. CONCLUSIONS: Until full genome sequencing in many people with highly specified disease phenotypes is feasible, experimental approaches based on biological findings and hypothesis testing should not be summarily discounted. PRACTICAL IMPLICATIONS: Stratification of patients to provide "personalized" treatment remains an important, yet elusive, goal. The current debate serves to highlight the need for large, clinical utility studies that can adequately determine how phenotypic and genotypic data can be best used to improve oral health in the US population. PMID- 25726345 TI - Hospitalizations for dental infections: optimally versus nonoptimally fluoridated areas in Israel. AB - BACKGROUND: Odontogenic infections may result in local, systemic, and even potentially life-threatening complications. The authors investigated whether water fluoridation was associated with reduction in rates of hospitalizations due to odontogenic infections. METHODS: The authors included cities in Israel that had fluoride concentrations of either 0.7 milligrams per liter or more (optimally fluoridated) or 0.5 mg/L or less (nonoptimally fluoridated) and that had a public water fluoride concentration consistent for the last decade. The authors compared hospitalization rates (per 10,000 children) for odontogenic infections in children younger than 18 years in each socioeconomic group between optimally and nonoptimally fluoridated cities. RESULTS: The authors included 1,413 hospitalizations between January 2005 and December 2011 of children residing in the 38 studied municipalities. The cities with the higher fluoride concentration reported a lower hospitalization rate (2.0 versus 4.3 for cities with a lower fluoride concentration; relative risk [RR]: 2.16; P < .001). When the authors divided cities into 3 socioeconomic groups, a large difference in hospitalization rates was seen in the lowest socioeconomic group (10.1 versus 2.6; RR: 3.79; P < .001) and the middle socioeconomic group (3.6 versus 1.9; RR: 2.35; P < .001) in optimally and nonoptimally fluoridated cities, respectively. No significant difference in hospitalization rates was apparent between the 2 fluoridation groups in the higher socioeconomic level. CONCLUSIONS: These results clearly indicate that there is an association between adequacy of water fluoridation and hospitalization due to dental infections among children and adolescents. This effect is more prominent in populations of lower socioeconomic status. PRACTICAL IMPLICATIONS: Water fluoridation is associated with reduction in dental health disparity. PMID- 25726346 TI - A practical approach to evidence-based dentistry: V: how to appraise and use an article about diagnosis. AB - BACKGROUND AND OVERVIEW: Questions regarding diagnosis are common in dental practice. Studies in which investigators apply a diagnostic test and a reference standard to all patients and compare their results represent the best type of design to answer these questions. The critical appraisal of these studies includes an assessment of the risk of bias, results, and applicability of the study. The authors provide the concepts and guidelines that dentists can apply to most effectively use articles regarding diagnosis to guide their clinical practice. PRACTICAL IMPLICATIONS: Dentists who wish to inform their clinical decisions regarding questions related to diagnostic test properties can use these guidelines to decide what type of studies to search, define the specific question of interest to search efficiently for these studies, and critically appraise studies addressing diagnosis. PMID- 25726347 TI - Unilateral ear fullness and temporary hearing loss diagnosed and successfully managed as a temporomandibular disorder: a case report. AB - BACKGROUND AND OVERVIEW: A 73-year-old woman had a 4-month history of debilitating left-sided otic fullness, hearing loss, and a watery sensation in her ear without obvious cause. She had consulted with an otolaryngologist who cleared the ear of all middle ear pathology and then placed ventilation tubes in the tympanic membrane to relieve her symptoms of ear fullness. The ventilation tubes did not produce long-lasting relief so she was referred to the dental clinic. CASE DESCRIPTION: The patient did not have substantial symptoms of jaw dysfunction or jaw pain and was clearly bothered more by her ear symptoms; she exhibited the following signs and symptoms: limited mandibular range of motion (37 millimeters), crepitation in the left temporomandibular joint (TMJ), active trigger points in the left superficial masseter, and severe pain on palpation in the left TMJ (lateral and dorsal). A panoramic radiograph and maxillary computed tomography scan revealed moderate degenerative changes observed bilaterally in the TMJs. A diagnosis of localized osteoarthritis (OA) of the TMJ (TMJ-OA) and masticatory myofascial pain was given. The authors provided 3 months of treatment that included self-applied physical therapy (stretch and thermal packs), full arch stabilization splint, trigger point injection, and a TMJ injection using triamcinolone acetonide (20 milligrams). RESULTS: The patient reported a 90% improvement in her TMJ and ear-related symptoms as a result of the treatments. The authors speculated that TMJ-OA and myofascial muscle disorders are potentially contributory to a tensor tympani muscle dysfunction, which could explain her ear fullness and hypoacusis. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Diagnosis and management of TMJ dysfunction (pain on palpation, OA, and limitation of motion) should be considered when patients have symptoms of unexplained ear fullness and have been cleared for ear infection or other ear related pathology. PMID- 25726348 TI - Nodular lesion in the buccal mucosa. PMID- 25726349 TI - Complex regional pain syndrome. PMID- 25726350 TI - Orthodontic miniscrew implants usually are clinically effective to minimize undesirable tooth movements. PMID- 25726351 TI - Of lawyers, lattes, and dentists. PMID- 25726352 TI - How clear communication can improve practice performance. PMID- 25726353 TI - How to appropriately use dental auxiliaries. PMID- 25726354 TI - Imaging memory and predicting postoperative memory decline in temporal lobe epilepsy: Insights from functional imaging. AB - After medial temporal lobe epilepsy (MTLE) surgery, there is considerable individual variation in the extent, nature and direction of postoperative memory change. Before surgery, epileptic patients who are surgery candidates need precise information about the potential cognitive after effects, and particularly in temporal lobe epilepsy, postoperative memory changes. Clinical and neuropsychological data may bring useful information to predict the postoperative memory outcome, but, these data are not always sufficient to replace the Wada test, considered for a long time, as the gold standard to predict postoperative decline following surgery. In any case, numerous studies demonstrate that the Wada procedure can be nowadays reliably replaced by functional MRI (fMRI) activation studies. A vast majority of fMRI studies suggest that it is the functional adequacy of the resected hippocampus rather than the functional reserve of the contralateral hippocampus that determines the extent of postoperative memory decline. In addition, new functional neuroimaging procedures that explore more widespread network disruptions commonly found in MTLE such as diffusion-tensor imaging (DTI) or connectivity studies could in the future constitute a reliable approach combined with fMRI activation studies to significantly improve the prediction of postsurgical memory decline. PMID- 25726355 TI - H.M. never again! An analysis of H.M.'s epilepsy and treatment. AB - On August 25, 1953, the patient H.M., aged 27, underwent a bilateral surgical destruction of the inner aspect of his temporal lobes performed by William Beecher Scoville with the aim to control H.M.'s drug refractory epileptic seizures and alleviate their impact on his quality of life. Postoperatively, H.M. presented for 55 years a "striking and totally unexpected grave loss of recent memories". This paper reports what we know about H.M.'s epilepsy before and after surgery and puts forward arguments supporting the syndromic classification of his epilepsy. We attempted to elucidate what could have been the rationale, in 1953, of Scoville's decision to carry out a bilateral ablation of H.M.'s medial temporal lobe structures, and we examined whether there was any convincing argument published before 1953 suggesting that bilateral hippocampal ablation could result in a permanent and severe amnesia. Our a posteriori analysis of H.M.'s medical history suggested that he was most probably suffering from idiopathic generalized epilepsy with absences and generalized convulsive seizures worsened by high dosage phenytoin treatment, or less probably from cryptogenic frontal lobe epilepsy. Importantly, he did not have temporal lobe epilepsy. Scoville based his proposal of bilateral mesial temporal lobe ablation on his experience as a psychosurgeon and on the assumption that the threshold of generalized epileptic activity could be lowered by some kind of hippocampal dysfunction potentially epileptic in nature. Given the scanty information on the link between amnesia and medial temporal lobe lesions that was available in humans in 1953, one can understand why Scoville was so surprised by the "striking and totally unexpected" memory loss he observed in H.M. after the bilateral ablation of his mesial temporal lobe structures. PMID- 25726356 TI - Reprint of: The prostate cancer genome: Perspectives and potential. AB - OBJECTIVES: Prostate cancer has a variable clinical course, and molecular characterization has revealed striking mutational heterogeneity that may underlie the unpredictable clinical behavior of the disease. Advances in technology have resulted in a rapid expansion of our understanding of the genomic events responsible for the development and progression of prostate cancer. In this review, we discuss the genomic alterations underlying prostate cancer, and potential to utilize this knowledge for diagnostic and prognostic benefit. METHODS AND MATERIALS: We reviewed the relevant literature, with a focus on recent studies on somatic alterations in prostate cancer. RESULTS: Pathways known to affect tumorigenesis across a wide spectrum of tissues are dysregulated, such as the PI3K pathway, cell cycle control, and chromatin regulation. Lesions more specific to prostate cancer include alterations in androgen signaling, gene fusions of ETS transcription factors, and mutations in SPOP. Accumulating data suggests that prostate cancer can be subdivided based on a molecular profile of these genetic alterations. CONCLUSIONS: These findings raise the possibility that prostate cancer could transition from a poorly understood, heterogeneous disease with a variable clinical course to a collection of homogenous subtypes, identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies. PMID- 25726357 TI - Using value-based analysis to influence outcomes in complex surgical systems. AB - BACKGROUND: Value-based analysis (VBA) is a management strategy used to determine changes in value (quality/cost) when a usual practice (UP) is replaced by a best practice (BP). Previously validated in clinical initiatives, its usefulness in complex systems is unknown. To answer this question, we used VBA to correct deficiencies in cardiac surgery at Memorial Healthcare System. STUDY DESIGN: Cardiac surgery is a complex surgical system that lends itself to VBA because outcomes metrics provided by the Society of Thoracic Surgeons provide an estimate of quality; cost is available from Centers for Medicare and Medicaid Services and other contemporary sources; the UP can be determined; and the best practice can be established. RESULTS: Analysis of the UP at Memorial Healthcare System revealed considerable deficiencies in selection of patients for surgery; the surgery itself, including choice of procedure and outcomes; after care; follow up; and control of expenditures. To correct these deficiencies, each UP was replaced with a BP. Changes included replacement of most of the cardiac surgeons; conversion to an employed physician model; restructuring of a heart surgery unit; recruitment of cardiac anesthesiologists; introduction of an interactive educational program; eliminating unsafe practices; and reducing cost. CONCLUSIONS: There was a significant (p < 0.01) reduction in readmissions, complications, and mortality between 2009 and 2013. Memorial Healthcare System was only 1 of 17 (1.7%) database participants (n = 1,009) to achieve a Society of Thoracic Surgeons 3-star rating in all 3 measured categories. Despite substantial improvements in quality, the cost per case and the length of stay declined. These changes created a savings opportunity of $14 million, with actual savings of $10.4 million. These findings suggest that VBA can be a powerful tool to enhance value (quality/cost) in a complex surgical system. PMID- 25726358 TI - Childhood cancer in El Salvador: A preliminary exploration of parental concerns in the abandonment of treatment. AB - PURPOSE: In El Salvador, children under 12 diagnosed with cancer have access to free treatment at a specialized national facility. Until recently, 13 percent of patients annually abandoned therapy--a serious loss of lives and scarce resources. This qualitative study explores how some parents perceived their child's cancer and treatment, and what led them to stop bringing their child for chemotherapy. METHOD: In in-depth interviews, parents of six children who abandoned their child's cancer treatment discussed sickness and life circumstances during the course of treatment. RESULTS: Poverty, effects of treatment, mistrust, emotions and religious convictions all figured in the parents' explanation of their actions. However, each family weighed these concerns differently. It was the interaction of the concerns, and not the concern per se, that represented the explanatory frameworks the families used to explain stopping their child's treatment. This finding illustrates the parents' navigation among a collection of variable concerns, rather than exposing one fixed cause for their behavior. For example, poverty affects a parent's worldview as well as concrete living conditions, and therefore has a complex relationship with abandonment of treatment. Thus, it follows that strategies to reduce treatment abandonment (and increase a child's chance for survival) must be multidimensional. CONCLUSIONS: Qualitative studies of how families perceive childhood cancer and treatment can illuminate the processes and relationships involved in abandonment of treatment. This approach can also show how families' living circumstances frame their perceptions and inform strategies to improve how medical services are provided, thus reducing abandonment of treatment. PMID- 25726359 TI - Formative research in the development of a care transition intervention in breast cancer survivors. AB - PURPOSE: The purpose of this qualitative study was to evaluate breast cancer survivors' (BCS) responses to a self-management survivorship care transition intervention in the formative development of such an intervention. The experience of BCS is marked by uncertainty and anxiety about subsequent care, and a desire for more information about future care needs and late effects of treatment. Self management strategies have demonstrated improved outcomes in chronic illness, and may address the unmet needs of breast cancer survivors. METHODS AND SAMPLE: Five focus and discussion groups each were conducted at a single site in the Southeastern United States with a total of twenty breast cancer survivors. BCS were presented with a description of a survivorship transition intervention that encouraged self-management. Groups were led by a trained moderator using a semi structured guide with 7 open-ended questions about their care transition experience and response to the proposed intervention. A theoretically-derived, concept-guided coding strategy was developed after review of transcripts. Iterative constant comparative methods were used to ensure that transcripts were reviewed exhaustively for emerging codes and relationships. KEY RESULTS: Three dominant themes emerged around readiness for self-management: 1) the breast cancer experience as a catalyst for self-management; 2) fear of recurrence as a catalyst for self-management; and 3) the impact of the meaning of breast cancer on individual readiness for self-management. CONCLUSIONS: These findings contribute to further development of a conceptual model and interventions built on BCS self-management to improve the survivorship experience. PMID- 25726360 TI - Rare structural genetic variation in human prion diseases. AB - Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high risk mutation. PMID- 25726361 TI - Decreased mitochondrial bioenergetics and calcium buffering capacity in the basal ganglia correlates with motor deficits in a nonhuman primate model of aging. AB - Altered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman primate model of human aging. Six young (6-8 years old) and 6 aged (20-25 years old) female Rhesus monkeys (Macaca mulatta) were behaviorally characterized from standardized video records. Additionally, we measured mitochondrial bioenergetics along with calcium buffering capacity in the substantia nigra and putamen (PUT) from both age groups. Our results demonstrate that the aged animals had significantly reduced locomotor activity and movement speed compared with younger animals. Moreover, aged monkeys had significantly reduced ATP synthesis capacity (in substantia nigra and PUT), reduced pyruvate dehydrogenase activity (in PUT), and reduced calcium buffering capacity (in PUT) compared with younger animals. Furthermore, this age-related decline in mitochondrial function in the basal ganglia correlated with decline in motor function. Overall, our results suggest that drug therapies designed to enhance altered mitochondrial function may help improve motor deficits in the elderly. PMID- 25726363 TI - Hypofractionated stereotactic body radiotherapy in spinal metastasis - with or without epidural extension. AB - AIMS: To evaluate clinical outcome and the effect of malignant epidural compression (MEC) in the treatment of spine metastasis with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Seventy-six lesions in 52 patients with spinal metastasis received SBRT during the period July 2010 to December 2012. MEC was detected in 20 patients (38.4%) and was separately contoured. The median dose prescribed to involved vertebra (planning target volume) was 24 Gy (range 24-27 Gy) in a median of three fractions (range 1-3). Uninvolved elements were prescribed 21 Gy in three fractions. In 59 lesions (77.6%), the entire vertebra was treated and in 17 lesions (22.4%) only the anterior elements were treated. All patients were treated with volumetric modulated arc therapy with image guidance on a Novalis Tx linear accelerator with the ExacTrac system. Dosimetric and clinical outcomes were compared in patients with or without MEC. RESULTS: At a median follow-up of 8.48 months (range 3-40 months), 1 year local control and overall survival was 94 and 68%, respectively. In patients with or without epidural extension, the median dose to the gross tumour volume (GTV; 95%) was 23.48 Gy (range 13.70-25.75) and 22.99 Gy (range 13.55-26.84), the median spinal cord Dmax was 17.36 Gy (range 8.47-21.63) and 15.71 Gy (range 8.39-23.33). The median GTV epidural (D95%) was 21.16 Gy (range 15.43-23.92). Complete pain relief was seen in 90% of patients with MEC and 93.75% without MEC (P=NS) and neurological improvement was seen in 60% of patients in both groups of patients. CONCLUSION: It is feasible to deliver a high dose of radiation (~90% of the prescription dose) to the epidural component with volumetric modulated arc therapy SBRT and image guidance. It yielded high rates of pain control and local control in patients with spine metastases with or without MEC. PMID- 25726362 TI - CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. AB - Mutations in CHCHD10 have recently been described as a cause of frontotemporal dementia (FTD) comorbid with amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the frequency and clinical characteristics of CHCHD10 mutations in Italian patients diagnosed with familial (n = 64) and apparently sporadic ALS (n = 224). Three apparently sporadic patients were found to carry c.100C>T (p.Pro34Ser) heterozygous variant in the exon 2 of CHCHD10. This mutation had been previously described in 2 unrelated French patients with FTD ALS. However, our patients had a typical ALS, without evidence of FTD, cerebellar or extrapyramidal signs, or sensorineural deficits. We confirm that CHCHD10 mutations account for ~ 1% of Italian ALS patients and are a cause of disease in subjects without dementia or other atypical clinical signs. PMID- 25726364 TI - Tuberculosis origin: The Neolithic scenario. AB - This paper follows the dramatic changes in scientific research during the last 20 years regarding the relationship between the Mycobacterium tuberculosis complex and its hosts - bovids and/or humans. Once the M. tuberculosis and Mycobacterium bovis genomes were sequenced, it became obvious that the old story of M. bovis evolving into the human pathogen should be reversed, as M. tuberculosis is more ancestral than M. bovis. Nevertheless, the timescale and geographical origin remained an enigma. In the current study human and cattle bone samples were examined for evidence of tuberculosis from the site of Atlit-Yam in the Eastern Mediterranean, dating from 9250 to 8160 (calibrated) years ago. Strict precautions were used to prevent contamination in the DNA analysis, and independent centers used to confirm authenticity of findings. DNA from five M. tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex. These, together with pathological changes detected in some of the bones, confirm the presence of the disease in the Levantine populations during the Pre-pottery Neolithic C period, more than 8000 years ago. PMID- 25726365 TI - Feelings of the future. AB - Affective forecasting refers to the capacity to predict future feelings. Humans have been found to exhibit systematic affective forecasting biases that involve overestimation of the intensity and duration of future feelings. Although recent research has elucidated the proximate mechanisms underlying our ability to predict future feelings, explanations concerning the potential adaptive significance of these biases have attracted little attention. Here we consider the function of affective forecasts as signals of biological value, drivers of goal pursuit, and tools for eliciting collaboration. Although affective forecasting biases can have significant costs, for instance in terms of one's pursuit of happiness, they may ultimately serve adaptive functions. PMID- 25726366 TI - Revision and reversal after biliopancreatic diversion for excessive side effects or ineffective weight loss: a review of the current literature on indications and procedures. AB - BACKGROUND: Biliopancreatic diversion is a powerful bariatric procedure that relies on gastric restriction combined with a large malabsorptive component. This can lead to excessive side effects and/or weight loss. Despite this, long-term weight regain can also occur. OBJECTIVES: To determine the rate of and options for revision in patients who experience excessive side effects and weight loss. To explore the revisional procedures available to overcome weight regain. METHODS: A PubMed search was conducted of all reports published between 1979 and August 31, 2014. Series and case reports on revision or reversal after biliopancreatic diversion with duodenal switch (BPD/DS) or without (BPD) were included. RESULTS: Revision rates for excessive malabsorption ranges from .5% 4.9% and 3%-18.5% after BPD/DS and BPD respectively. Revisions increase common channel by up to 150 cm. Reversal is necessary in .2%-7% of cases, with an increased risk when the common channel is <= 50 cm. In most instances, reversal (of the malabsorptive component only) is indicated after the revision failure. A proximal, side-to-side anastomosis between the biliopancreatic and alimentary limbs is the preferred option. Most reoperations are performed within 2 years of the initial procedure and for protein malnutrition in about half of the cases. Revision for insufficient weight loss is reported in .5%-2.78% of cases. Except inadequate channel lengths, little is to be gained by common channel shortening. Additional gastric restriction, which results in an average 9-14 kg weight loss, is another option. CONCLUSIONS: Biliopancreatic diversion can be relatively easily revised to control excessive side effects and protein malnutrition. Early diagnosis is essential and warrants a close nutritional monitoring. In case of weight regain, limited results can be obtained by reducing the gastric volume provided the lengths of the small bowel channels are adequate. PMID- 25726367 TI - [Current status of continuous subcutaneous insulin infusion and continuous glucose monitoring systems in the Community of Madrid]. AB - OBJECTIVE: To analyze the available information about continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems in the public health care system of the Community of Madrid. MATERIAL AND METHODS: A survey consisting of 31 items was sent to the 28 endocrinology department of the Madrid public hospitals. Items focused on CSII and CGM and included patients' registrations, as well as data regarding healthcare, administrative, and logistic aspects. Responses from a total of 20 hospitals where these procedures are used were received from March 2013 to May 2014. Data about pediatric patients were obtained from adult endocrinology departments, except for two hospitals which directly reported the information. RESULTS: A total of 1256 CSII pumps were recorded in the Madrid region, of which 1089 were used by adults, and the remaining 167 by pediatric patients. During 2013, 151 new CSII systems were implanted (12% of the total), while 14 pumps were withdrawn. Availability of human resources (medical assistance) and the number of staff practitioners experienced in management of these systems widely varied between hospitals. Eighty-five percent of hospitals used retrospective CGM systems, and 40% routinely placed them before starting an insulin pump. Thirteen hospitals (65%) used long-term, real-time CGM systems in selected cases (a total of 67 patients). CONCLUSIONS: Use of these technologies in diabetes is unequal between public health care hospitals in Madrid, and is still significantly lower as compared to other countries with similar incomes. However, there appears to be a trend to an increase in their use. PMID- 25726368 TI - [Cardiovascular risk parameters, metabolic syndrome and alcohol consumption by workers]. AB - INTRODUCTION: Prevalence of alcohol consumption is high in the general population and generates specific problems at the workplace. OBJECTIVE: To establish benchmarks between levels of alcohol consumption and cardiovascular risk variables and metabolic syndrome. METHODS: A cross-sectional study of 7,644 workers of Spanish companies (2,828 females and 4,816 males). Alcohol consumption and its relation to cardiovascular risk was assessed using Framingham calibrated for the Spanish population (REGICOR) and SCORE, and metabolic syndrome was assessed using modified ATPIII and IDF criteria and Castelli and atherogenic index and triglycerides/HDL ratio. A multivariate analysis was performed using logistic regression and odds ratios were estimated. RESULTS: Statistically significant differences were seen in the mean values of the different parameters studied in prevalence of metabolic syndrome, for both sexes and with modified ATPIII, IDF and REGICOR and SCORE. The sex, age, alcohol, and smoking variables were associated to cardiovascular risk parameters and metabolic syndrome. Physical exercise and stress are only associated to with some of them. CONCLUSIONS: The alcohol consumption affects all cardiovascular risk parameters and metabolic syndrome, being more negative the result in high level drinkers. PMID- 25726369 TI - [Relationship between vitamin D deficiency and metabolic syndrome in adult population of the Community of Madrid]. AB - BACKGROUNDS AND OBJECTIVE: Previous studies have suggested an association between MS and vitamin D deficiency, but data are not conclusive. This study was intended to find out if metabolic syndrome, according to the 2009 IDF/AHA/NHLBI, is associated to the presence of vitamin D deficiency. MATERIAL AND METHODS: A cross sectional study was conducted on a sample of 326 subjects aged 18 years or older, recruited from a health center in Alcala de Henares. Participants underwent an interview and a standardized clinical examination. In a second visit, blood tests were performed in 255 subjects to quantify serum levels of 25-hydroxyvitamin D (25 OH-VitD) and different laboratory parameters associated to MS. The association between vitamin D deficiency and metabolic syndrome (and each of its components) was examined. RESULTS: In the study population, MS prevalence was 36.1% and prevalence of vitamin D deficiency (25 OH-Vit D<20 ng/mL) was 56.3%. MS was more common in the group of patients with vitamin D deficiency (43.4%) than in the group with no deficiency (26.8%, P=.006), with an estimated prevalence ratio of 1.62 (95% CI: 1.13-2.31). Adjustment for age, sex, and body mass index did not change such association. CONCLUSIONS: There is a significant association between vitamin D deficiency and MS. Both conditions are highly prevalent in our population. PMID- 25726370 TI - 18F-DOPA vs. 18F-FDG PET/CT in the ectopic ACTH syndrome due to pulmonary carcinoid tumor. PMID- 25726371 TI - Effect of neonatal or adult heat acclimation on testicular and epididymal morphometry and sperm production in rats. AB - The accessory gland weight, testicular and epididymal morphometry and sperm production were analyzed in four groups of rats housed at 20 or 34 degrees C: (1) control rats (CR) kept at 20 degrees C from birth to day 90; (2) adult heat acclimated rats (AHA) kept at 20 degrees C from birth to day 45 followed by 34 degrees C to day 90; (3) neonatal heat-acclimated rats (NHA) kept at 34 degrees C from birth to day 90 and (4) de-acclimated rats (DA) kept at 34 degrees C from birth to day 45 followed by 20 degrees C to day 90. In NHA and DA rats, accessory gland weight was higher than in controls. Despite the lack of differences in testicular and epididymal morphometry, curvilinear velocity of spermatozoa was lower in the NHA group compared to controls. Areas of seminiferous tubules were lower in the DA than in CR and NHA groups, however, sperm concentration and motility were not affected by the treatment in this group. In AHA rats, epithelium of approximately 20% of seminiferous tubules was degenerated and Sertoli cell number was lower in the remaining tubules. In contrast to sperm motility, epididymal duct area, area of the duct occupied by spermatozoa and cauda epididymis sperm concentration were lower in AHA rats than in the other groups. In conclusion, neonatal heat acclimation did not affect the testicular morphometry and epididymal sperm concentration, suggesting adjustment to high ambient temperature. On the contrary, adult heat acclimation of rats affected the examined parameters, leading to decreased sperm concentration. PMID- 25726372 TI - A critical assessment of the effect of serine protease inhibitors on porcine fertilization and quality parameters of porcine spermatozoa in vitro. AB - Proteases play an important role during mammalian fertilization. Their function is frequently investigated using specific inhibitors. We analyzed four serine protease inhibitors [4-(2-aminoethyl) benzene sulfonyl fluoride hydrochloride (AEBSF), soybean trypsin inhibitor from glycine max (STI), Nalpha-tosyl-L-lysine chloromethyl ketone hydrochloride (TLCK) and N(p)-tosyl-L-phenylalanine chloromethyl ketone (TPCK)] for their in vitro effect on fertilization and sperm quality in pigs. Inhibitor concentrations were chosen based on the reduction of fertilization rate during preliminary dose-response experiments with cryopreserved epididymal spermatozoa. The inhibitor effects on in vitro fertilization (IVF) and sperm parameters (membrane and acrosomal integrity, motility and mitochondrial membrane potential - MMP) were evaluated using diluted fresh semen. AEBSF (100 MUM), TLCK (100 MUM) and TPCK (100 MUM) decreased total fertilization and polyspermy rates by at least 50%. STI (5 MUM) lowered total fertilization rates but not the level of polyspermy. AEBSF and TPCK reduced fertilization parameters to a similar degree using cryopreserved epididymal spermatozoa (dose-response experiment) or diluted fresh semen. Inhibition by STI was more pronounced using cryopreserved epididymal spermatozoa, whereas TLCK inhibited IVF only with diluted fresh semen. AEBSF and STI had no effect on sperm parameters, and TLCK significantly reduced motility. TPCK diminished MMP and motility and affected membrane and acrosomal integrity in a negative way. In summary, serine protease inhibitors differed in the way they reduce the fertilization rate. These results emphasize the necessity of inhibitor testing before they can be applied in fertilization studies. AEBSF and STI can be used in the future IVF studies without compromising sperm quality. PMID- 25726373 TI - Caffeine stimulates in vitro pituitary LH secretion in lipopolysaccharide-treated ewes. AB - The study was designed to determine the effects of caffeine on luteinizing hormone (LH) secretion and gene expression of caffeine-associated receptors in anterior pituitary (AP) explants obtained from saline- and lipopolysaccharide (LPS)-treated ewes. Animals had been treated with LPS or saline daily for seven days. Three hours after the last injection of LPS/saline, the AP were collected and divided into four explants. The explants were incubated with: 1/medium-199 (control explants), 2/gonadotropin-releasing hormone (GnRH; 100 pmol/mL; a positive control), 3/caffeine (10 mmol/L), or 4/GnRH+caffeine. Caffeine stimulated (p<0.05) LH release by explants from both saline (19.7 vs. control 12.6 ng/mg) and LPS (28.3 vs. control 13.9 ng/mg) treated animals. The effect of caffeine on LH secretion was stronger in the LPS-treated group than in saline treated group, and the observed LH release was similar to that induced by GnRH alone (27.2 ng/mg). Caffeine increased (p<0.05) LHbeta gene expression only in explants from LPS-treated animals. In conclusion, the results of the present study demonstrated a stimulatory in vitro effect of caffeine on LH secretion by ovine pituitary explants. The potency of the caffeine-induced LH secretion was affected by in vivo treatment of the animals with endotoxin. PMID- 25726374 TI - Nitric oxide and thyroid hormone receptor alpha 1 contribute to ovarian follicular development in immature hyper- and hypo-thyroid rats. AB - Thyroid dysfunction can cause ovarian cycle and ovulatory disturbances, however, the molecular link(s) between these two disorders remains largely unknown. In the current study, we examined the roles of nitric oxide synthase (NOS) and thyroid hormone receptor alpha 1 (TRalpha1) in these disorders using immature hyper thyroid (hyper-T) and hypo-thyroid (hypo-T) rats. In comparison to controls, hyper-T rats had higher serum concentrations of triiodothyronine (T3) and thyroxine (T4), whereas hypo-T rats had lower serum T3 and T4. Serum estradiol (E2) level was decreased in both hyper-T and hypo-T animals and serum E2 in hyper T rats were lower than in hypo-T rats. We found that neuronal NOS (nNOS) and TRalpha1 were present in oocytes, granulosa cells and theca cells of all examined rat groups. Ovarian nitric oxide (NO) content and the constitutive NOS (cNOS) activity in hyper-T rats were significantly decreased compared with control or hypo-T rats. Moreover, the number of large antral follicles was reduced in hyper T rats, and number of primordial follicles was decreased in hypo-T rats compared with control rats. In conclusion, we observed an association between thyroid hormone and NO signaling pathways during the process of ovarian follicular development in immature rats. In hyperthyroidism, thyroid hormones induced an estrogen deficiency that inhibited the function of nNOS, resulting in the inhibition of NO synthesis and suppressed development of large antral follicles, while in hypothyroidism only development of primordial follicles was inhibited. PMID- 25726375 TI - Intracytoplasmic sperm injection affects embryo developmental potential and gene expression in cattle. AB - Some reports have linked intracytoplasmic sperm injection (ICSI) with chromosomal abnormalities, low developmental potential and altered gene expression in embryos. ICSI has also been linked with obesity, early aging and increased incidence of tumors in offspring. Other reports have demonstrated that some of these complications disappeared within a few weeks of life or even showed a lack of such associations. The aim of this study was to evaluate and compare embryo development, quality and gene expression in bovine embryos generated by ICSI and by conventional in vitro fertilization (IVF) insemination. The results showed differences in cleavage (88.5% in IVF and 64.1% in ICSI) and blastocyst formation rates (36.1% in IVF and 22.3% in ICSI). The proportion of ICM cells to total cell count was higher in ICSI (39.2%) than in IVF embryos (29.5%). However, no differences were observed in the total embryonic cell numbers (159.3+/-28.5 and 161.2+/-56.2 for IVF and ICSI, respectively) or in the proportion of apoptotic nuclei to the total embryonic cell numbers (2.12 and 2.64% for IVF and ICSI, respectively). Gene expression analysis showed a down-regulation of insulin-like growth factor 2 (IGF2) and overexpression of bcl-2-like protein 4 (BAX), octamer binding transcription factor four (OCT4), interferon-tau (IFNt), Mn-superoxide dismutase in the mitochondria (SOD2), and catalase (CAT) in embryos generated by ICSI. In conclusion, our study demonstrated differences in the morphological development of bovine embryos as well as in the expression of genes involved in early development between ICSI and IVF embryos. The results may indicate lower developmental potential of ICSI embryos compared with that of IVF. PMID- 25726376 TI - Functional consequences of knocking down porcine prostaglandin synthases in SK-6 swine kidney cell line. AB - We hypothesized that in vitro knock-down of the previously cloned genes of prostaglandin synthases will result in a reduction of synthesis, and thus secretion of their respective products, i.e., prostaglandin (PG) E2 or PGF2alpha. For this purpose, we designed short hairpin RNA (shRNA)-encoding constructs to knock down porcine mPGES-1 and PGFS (also named as AKR1CL1 in GenBank) and used them to transfect swine kidney SK-6 cells. Knocking down PGFS or mPGES-1 transcripts resulted in at least 50% inhibition of protein expression of each respective enzyme, as well as a reduction in the production of their respective prostaglandin, PGF(2alpha) or PGE(2). These results confirmed the identities of PGFS and mPGES-1. Moreover, they illustrate a unique opportunity to use the gene knock-down constructs in primary endometrial cells in order to study their biological roles in the porcine endometrium, particularly during the establishment of pregnancy. PMID- 25726377 TI - IGF1 regulation of BOULE and CDC25A transcripts via a testosterone-independent pathway in spermatogenesis of adult mice. AB - The Deleted in AZoospermia (DAZ) gene family plays an essential role in spermatogenesis and fertility in mammals. This gene family contains two autosomal genes, BOULE and DAZL (DAZ-Like), and the DAZ gene cluster in the Y chromosome. CDC25A (a cell cycle regulator) has been proposed as a putative substrate for the RNA-binding proteins of DAZ family. However, mechanisms regulating DAZ gene expression have been poorly investigated. We analyzed immunohistochemical localization of DAZL, BOULE and CDC25A, as well as the involvement of testosterone (T) and insulin-like growth factor 1 (IGF1) in the modulation of mRNA expression for DAZL, BOULE and CDC25A in the adult mouse testes. It was found that DAZL was mostly immunolocalized in spermatogonia, while BOULE and CDC25A were detected in spermatocytes and round spermatids. Three-color immunofluorescence showed that DAZL-positive cells also expressed proliferating cell nuclear antigen (PCNA). In vitro incubation of the testes showed that neither T nor IGF1 affected DAZL mRNA expression. However, either T or IGF1 increased BOULE mRNA expression. Antiandrogen flutamide abolished the T-induced increase in BOULE mRNA, but had no effect on the IGF1 induced increase in the mouse testes. Extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor, U0126, prevented IGF1-induction of BOULE mRNA. It was found that IGF1 increased CDC25A mRNA expression and that U0126 - but not flutamide - abolished the IGF1 induced CDC25A mRNA expression. These results showed that IGF1 regulated the expression of BOULE and CDC25A mRNAs via ERK1/2 signaling and in T-independent pathway during spermatogenesis in the adult mouse testes. PMID- 25726378 TI - The effects of superoxide dismutase addition to the transport medium on cumulus oocyte complex apoptosis and IVF outcome in cats (Felis catus). AB - The aim of the present study was to examine the effects of superoxide dismutase (SOD) addition to the ovary transport medium (4 degrees C, 3-72 h) on ovarian cell viability and apoptosis and in vitro embryo production (IVEP) in domestic cats. The ovaries collected from 76 mixed-breed domestic queens were randomly assigned to the control or SOD-treated groups and incubated for 3, 24, 48 or 72 h. The ovaries were then subjected to the following: (1) fixed in formalin to assess the incidence of apoptosis (fragmented DNA in situ detection kit), (2) stored at -196 degrees C in liquid nitrogen to evaluate the expression of the pro apoptotic Bax gene and the anti-apoptotic Bcl-2 gene (RT-PCR), and (3) used to obtain the cumulus-oocyte complexes (COCs) in order to test the cell viability (carboxyfluorescein or trypan blue staining) and IVEP. The incidence of apoptosis appeared to be higher in the control compared with the SOD-treated ovaries. The ovarian expression of Bax was lower and the Bcl-2 expression was higher in the SOD-treated group compared with the control group. The presence of SOD in the transport medium increased the viability of COCs and IVEP compared with the control medium. In summary, the supplementation of the ovary transport medium with SOD reduced cellular apoptosis and enhanced COC survival and IVEP in domestic cats. PMID- 25726379 TI - Luteal phase defect is associated with impaired VEGF mRNA expression in the secretory phase endometrium. AB - Endometrial morphology and expression of vascular endothelial growth factor (VEGF) was examined in the endometria of women with history of recurrent miscarriage (RM group) and of fertile women without history of gynecological diseases (control group). Luteal phase defect (LPD) was diagnosed in 42% cases in the RM group vs. 13% in controls. Endometrial VEGF mRNA expression was lower in LPD endometria compared to mature endometria. In conclusion, LPD in non-pregnant endometrium is associated with angiogenic abnormalities and may cause pregnancy complications. PMID- 25726380 TI - Age-related effects of smoking on coronary artery disease assessed by gray scale and virtual histology intravascular ultrasound. AB - Although smoking is a risk factor for coronary atherosclerosis, the age-related impact on lesion morphology has not been studied. The aim of this study was to assess the age-related impact of smoking on the extent of atherosclerosis and arterial remodeling. In Providing Regional Observations to Study Predictors of Events in the Coronary Tree, 687 patients with acute coronary syndrome underwent 3-vessel gray scale and virtual histology intravascular ultrasound imaging of 3,185 nonculprit lesions. In 207 patients <=65 years, current (smoking within 1 month) and former (no smoking for >1 month) smokers showed significantly smaller normalized volumes of external elastic membrane (EEM), lumen, and P + M (plaque + media) compared with nonsmokers. At the minimal lumen area site, current and former smokers had significantly smaller EEM, lumen, and P + M areas than nonsmokers. Conversely, in 480 patients >65 years, current smokers had greater normalized P + M volumes than nonsmokers with no difference in normalized EEM or lumen volumes. Finally, in patients >65 years (but not in patients <=65 years), current smokers showed more plaque ruptures (4.7% vs 1.8%, p = 0.05) and echolucent plaques (8.3% vs 3.9%, p = 0.05) compared with nonsmokers. On multivariable analysis, a history of smoking (combining current and former smoking) predicted smaller normalized EEM volumes compared with nonsmokers <=65 years. In conclusion, in patients <=65 years, but not in patients >65 years, smoking had a vascular constrictive effect that contributed to severe luminal stenosis. Conversely, smokers >65 years had more plaque with greater plaque instability. PMID- 25726382 TI - The 50% coronary stenosis. PMID- 25726381 TI - Antithrombotic strategies and outcomes in acute coronary syndrome with atrial fibrillation. AB - Atrial fibrillation (AF) frequently occurs with acute coronary syndromes (ACS) and adds complexity to the selection of an appropriate antithrombotic strategy. We determined whether associations of antithrombotic treatment with bleeding, stroke, and death differ between patients with ACS with and without AF. Residents of Olmsted County, Minnesota, hospitalized with incident ACS during 2005 to 2010 were classified according to the presence or absence of AF either before or during the index ACS hospitalization. Antithrombotic strategy at discharge was categorized as double/triple agents versus no/single agent. Patients were followed through 2012, and propensity scores were used to estimate associations of treatment with bleeding, ischemic stroke, and mortality. Of 1,159 patients with incident ACS, 252 (21.7%) had concomitant AF (ACS + AF). Over a median follow-up of 4.3 years, 312 bleeds, 67 ischemic strokes, and 268 deaths occurred. The overall risks of bleeding, stroke, and death were similar between treatment strategies. Although limited by the small number of events, a suggestion of a lower risk of ischemic stroke for patients with ACS + AF on double/triple therapy was observed; the hazard ratios for stroke with double/triple versus no/single therapy were 0.30 (0.07 to 1.26) and 1.10 (0.52 to 2.33) in those with and without AF, respectively (p value for interaction = 0.10). In conclusion, the choice of antithrombotic strategy is not associated with the risk of ischemic stroke, bleeding, or death in patients with ACS overall. Patients with ACS + AF on double/triple therapy may experience reduced risks of stroke, although future studies are needed to confirm this finding. PMID- 25726383 TI - Feasibility and safety of early discharge after transfemoral transcatheter aortic valve implantation with the Edwards SAPIEN-XT prosthesis. AB - There is currently no consensus on the duration of hospitalization required after transfemoral transcatheter aortic valve implantation (TAVI). We report the feasibility and safety of early discharge after TAVI with the Edwards SAPIEN-XT prosthesis. From 2009 to 2013, 337 patients underwent transfemoral TAVI with the Edwards SAPIEN-XT prosthesis using local anesthesia and were discharged home either early (<=3 days, Early Discharge group, n = 121) or after 3 days (Late Discharge group, n = 216). The primary end point of the study combined death and rehospitalization from discharge to 30-day follow-up. Patients in the Early Discharge group were less symptomatic (New York Heart Association class >=III: 64.5% vs 75.5%, p = 0.01) and had less renal failure (creatinine: 102.1 +/- 41.0 vs 113.3 +/- 58.9 MUmol/L, p = 0.04), atrial fibrillation (33.1% vs 46.3%, p = 0.02), and previous balloon aortic valvuloplasty (11.6% vs 23.1%, p = 0.01) and were more likely to have a pacemaker before TAVI (16.5% vs 8.3%, p = 0.02). Pre existing pacemaker (p = 0.05) and the absence of acute kidney injury (p = 0.02) were independent predictors of an early discharge, whereas previous balloon aortic valvuloplasty (p = 0.03) and post-TAVI blood transfusions (p = 0.002) were independent predictors of late discharge. The primary end point occurred in 4 patients (3.3%) in the Early Discharge group and in 11 patients (5.1%) in the Late Discharge group (p = 0.58). In conclusion, the results of our study suggest that early discharge after transfemoral TAVI using the Edwards SAPIEN-XT prosthesis is feasible and safe in selected patients. PMID- 25726385 TI - Evaluating the effects of different dental devices on implantable cardioverter defibrillators. AB - INTRODUCTION: The implantable cardioverter defibrillator (ICD) is an electronic device that emits electrical signals to the heart via lead wires and electrodes. It is used for cardiac rhythm monitoring and treatment. Because electronic dental devices have been shown to produce electromagnetic fields, we hypothesize that they may interfere with ICD function. METHODS: Nine dental devices (heat carrier, electronic apex locator, electric pulp tester, unipolar electrosurgery unit, electric motor, curing light, and 3 gutta-percha guns) were tested in this study for their ability to interfere with the function of 4 ICDs (2 single-chambered and 2 dual-chambered ICDs). ICD activity was monitored for 30 seconds using an ICD programmer (Medtronic 2090; Minneapolis, MN) and evaluated through an electrogram test strip printout. RESULTS: Electromagnetic interference was detected with the electric motor, curing light, electric pulp tester, and electrosurgery unit although no electromagnetic disturbances were detected with these devices. No electromagnetic interferences were observed for the gutta percha guns, heat carrier, and apex locator. However, the electrosurgery unit affected the dual-chambered ICD (Consulta CRT-D, Medtronic) and delivered therapies for fibrillation when no ventricular fibrillation was present. CONCLUSIONS: Our results suggest that the electrosurgery unit produces electromagnetic disturbances with unwanted therapy delivery shock and potentially clinically significant outcomes. PMID- 25726386 TI - Challenges faced by journal editors. PMID- 25726387 TI - Was the destiny of orthodontics written in the stars? PMID- 25726384 TI - Biliverdin reductase isozymes in metabolism. AB - The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets. PMID- 25726388 TI - Physics and clinical orthodontics: 100 years ago and today. PMID- 25726389 TI - Orthodontic radiography guidelines. PMID- 25726390 TI - From misinformation to overtreatment. PMID- 25726391 TI - Does the Frankel function regulator III affect maxillary growth over the short term? PMID- 25726392 TI - Author's response. PMID- 25726393 TI - Authors' response. PMID- 25726394 TI - In memoriam: Harvey Carlyle Pollock, 1884-1970. PMID- 25726395 TI - The salient skill. PMID- 25726397 TI - Curve of Spee and its relationship to vertical eruption of teeth among different malocclusion groups. AB - INTRODUCTION: Our objectives were to assess the depth of the curve of Spee (COS) in different malocclusion groups, to relate this to the eruption of anterior or posterior teeth quantitatively, and to determine whether the depth of the COS is affected by the vertical eruption of anterior or posterior teeth. METHODS: Two hundred conventional lateral cephalograms and 3-dimensional models of untreated patients (70 boys, mean age: 16.4 +/- 1.4 years; 130 young women, mean age: 18.1 +/- 1.8 years) were included and assigned to 4 malocclusion groups as Class I, Class II Division 1, Class II Division 2, and Class III. The depth of the COS, overjet, and overbite were measured on 3-dimensional models. The perpendicular distance between the incisal tip of the mandibular central incisor (L1-MP), the deepest point of the COS (S-MP), and the distobuccal cusp tip of the mandibular second molar (L7-MP) to the mandibular plane were calculated and proportioned with each other. The Pearson correlation coefficient was calculated, and multiple linear regression analysis was carried out. Also, multivariate analysis of variance was performed at the P <0.05 level. RESULTS: The mesiobuccal cusp of the first molar was the deepest part of the COS in all groups, with a maximum depth of 2.44 +/- 0.73 mm in the Class II Division 1 subjects and a minimum depth of 1.76 +/- 0.94 in the Class III subjects. The depth of the COS changed as follows: Class II Division 1 > Class II Division 2 > Class I > Class III malocclusion groups. Statistically significant positive correlations were found between the depth of the COS and L1-MP/S-MP (r = 0.541) and L7-MP/S-MP (r = 0.269) in the Class I and Class III subjects, and between the depth of the COS and overjet (r = 0.483) and L7-MP/S-MP (r = 0.289) in the Class II Division 1 subjects. All variables except overjet had positive correlations with the depth of the COS in Class II Division 2 subjects. The multivariate analysis of variance showed statistically significant differences in overjet, overbite, L1-MP/S-MP, L7-MP/S MP, and the depth of the COS (P <0.001) among the groups. CONCLUSIONS: Although the overjet differed, vertical eruption of the anterior teeth did not differ among the different malocclusion groups and had a significant contribution to the depth of the COS in subjects with Class I and Class III malocclusions. PMID- 25726398 TI - Accuracy of cone-beam computed tomography in detecting alveolar bone dehiscences and fenestrations. AB - INTRODUCTION: The purposes of this study were to evaluate the accuracy of cone beam computed tomography (CBCT) for detecting naturally occurring alveolar bone dehiscences and fenestrations and to find a better method to diagnose them. METHODS: The sample consisted of 122 anterior teeth in 14 patients with Class III malocclusion who accepted accelerated osteogenic orthodontic surgery in the anterior tooth region. Dehiscences and fenestrations were measured both directly, with a gauge during surgery, and indirectly, by CBCT scans collected before treatment. A Bland-Altman plot for calculating agreement between the 2 methods was used. Direct data were regarded as the gold standard, and indirect data were analyzed to evaluate the accuracy of CBCT for detecting dehiscences and fenestrations by sensitivity, specificity, positive predictive value, negative predictive value, Youden index, positive likelihood ratio, and negative likelihood ratio. Receiver operator characteristic curves were also used to determine the area under curve and the best critical points of CBCT for detecting dehiscences and fenestrations. RESULTS: Both the sensitivity and specificity of CBCT for dehiscences and fenestrations were over 0.7. The negative predictive values were high (dehiscence, 0.82; fenestration, 0.98), whereas the positive predictive values were relatively low (dehiscence, 0.75; fenestration, 0.16). Areas under the curve were 0.873 for dehiscences and 0.766 for fenestrations. The best critical points for detecting both dehiscences and fenestrations were 2.2 mm. CONCLUSIONS: Our study showed that the CBCT method has some diagnostic value for detecting naturally occurring alveolar bone dehiscences and fenestrations. However, this method might overestimate the actual measurements. PMID- 25726399 TI - In-vivo evaluation of the surface roughness and morphology of enamel after bracket removal and polishing by different techniques. AB - INTRODUCTION: The aim of this study was to evaluate the surface roughness and morphology of enamel with a surface roughness tester and scanning electron microscopy after the removal of metal brackets and polishing. METHODS: Ten orthodontic patients were selected for the study. At the conclusion of orthodontic treatment, their metal brackets were removed. For each patient, teeth on one side of the mouth were randomly chosen for finishing and polishing with aluminum oxide discs (n = 10). Teeth on the other side were finished with multilaminated carbide burs (n = 10). Dental replicas (before and after tooth polishing) were obtained with epoxy resin. Three surface roughness measurements were made in different directions with an angle of 120 degrees among them, and a mean for each dental replica was calculated. The roughness data were statistically evaluated by repeated-measurements analysis of variance. Three specimens from each group were also used for scanning electron microscopy analysis. RESULTS: After resin removal, the average roughness in the carbide bur group (0.31 MUm) was significantly greater than that in the aluminum oxide disc group (0.25 MUm). CONCLUSIONS: The aluminum oxide disc polishing system resulted in less enamel roughness than did the multilaminated carbide bur system. PMID- 25726400 TI - Efficacy of the Nance appliance as an anchorage-reinforcement method. AB - INTRODUCTION: The Nance appliance is widely considered to be an efficient method of anchorage reinforcement; however, much of the perceived advantage is based on clinical judgment. The aim of this study was to assess the amounts of anchorage loss and desired tooth movement associated with the Nance appliance. METHODS: The mandibular arches of 7 beagle dogs were used. The first and third premolars were extracted. Reference miniscrews were placed at the first premolar sites as stable references to measure the amounts of anchorage loss and desired tooth movement. Four beagles were fitted with custom-made Nance appliances on the fourth premolars and orthodontic bands on the second premolars (Nance group). Three beagles were fitted with orthodontic bands on the second and fourth premolars with no anchorage reinforcement (control group). The second premolars were retracted over 15 weeks in both groups. The amounts of second premolar movement (desired tooth movement) and fourth premolar movement (anchorage loss) were recorded at 5, 10, and 15 weeks. The percentages of desired tooth movement and anchorage loss to the total space closure were calculated. RESULTS: The mean desired tooth movement was significantly more in the Nance group than in the control group at 10 weeks (P <0.05) but was not significantly different at 5 and 15 weeks. The mean percentages of anchorage loss to the total space closure at 15 weeks were 45.7% in the control group and 28.8% in the Nance group. The Nance group had 16.9% less anchorage loss and 16.6% more desired tooth movement than did the control group at 15 weeks (P <0.05). Most of the anchorage loss (80%) in the Nance group occurred during the first 10 weeks. CONCLUSIONS: The Nance appliance did not provide absolute anchorage, but there was significantly less anchorage loss with it than in the control group. The majority of anchorage loss occurred during the first 10 weeks in the Nance group. PMID- 25726401 TI - Diagnostic accuracy of 2 cone-beam computed tomography protocols for detecting arthritic changes in temporomandibular joints. AB - INTRODUCTION: The temporomandibular joint (TMJ) is a complex joint that often develops degenerative joint disease. Clinical examination alone cannot usually diagnose this accurately, and a radiographic examination complements and aids in diagnosis and treatment. The osseous components of the TMJ complex are best imaged using computed tomography. The evolution of cone-beam computed tomography (CBCT) offers a low radiation dose and a high spatial resolution alternative and is becoming the imaging modality of choice for the TMJ. To further reduce the dose and yet not compromise the diagnostic task at hand, some alternative rotation acquisition protocols are available but have not been adequately evaluated. The aim of this study was to evaluate the diagnostic efficacy of 2 CBCT acquisition protocols to detect degenerative changes associated with the TMJ complex. METHODS: Thirty-four TMJs, from 17 dry human skulls, were obtained from the anatomy department at the School of Dental Medicine of the University of Connecticut. The sample consisted of complete dentate and partially dentate skulls with no identifiable markers such as age, sex, or ethnicity. Small and large lesions simulating early and established arthritic changes were created on the mandibular condyle. Each defect was randomly created on the medial pole, articulating surface, or lateral pole. After simulating the articular disc with rubber dam material, the condyle and the glenoid fossa were articulated and positioned in place by a rubber band. The skulls were scanned by using an Accuitomo CBCT scanner (J. Morita Corp, Kyoto, Japan) with 180 degrees and 360 degrees rotation protocols. Two operators scored the lesions and compared the results to the gold standard, which was the master list of where the lesions were made on the condyles. RESULTS: On the 102 randomly selected sites, 39 large and 33 small lesions were made, and the rest of the sites had no lesions. The detection rates for areas with large lesions and areas with no lesions were 100% between the examiners. However, of the 33 small lesions, each examiner was able to identify 32 of them with the 360 degrees scans: a 97.4% detection rate when compared with the gold standard. With the 180 degrees scan, 94.9% of the small lesions were detected when compared with the gold standard, and 96.9% were detected with the 360 degrees scan. The overall interexaminer reliability was over 90% for both imaging protocols (Cronbach's alpha, 92.4% for 180 degrees and 97% for 360 degrees ). CONCLUSIONS: Based on the results of this study, the 180 degrees CBCT acquisition protocol can detect small and large arthritic lesions with high reliability and is comparable with the 360 degrees spin acquisition. PMID- 25726402 TI - Radiographic predictors for maxillary canine impaction. AB - INTRODUCTION: The aims of this study were to compare 3-dimensional cone-beam computed tomography (CBCT) images of patients with unilaterally impacted canines and to determine the possible radiographic factors for prediction of maxillary canine impactions. METHODS: The sample consisted of 65 patients ranging in age from 9.6 to 13.8 years. The patients comprised 43 girls and 22 boys, with a mean age of 12.1 years and a median age of 12.2 years (+/-SD 1.23 years). Of the impacted maxillary canines, 32 were located on the right side and 33 on the left side. CBCT radiography was available for all patients. The diagnosis of a unilaterally impacted canine was determined from the patients' dental records as a unilateral failure of the canine to erupt at its appropriate site in the dental arch in contrast to normal eruption of the contralateral side. Radiographic follow-up assessment to identify unilateral impaction was performed for 1 year. The radiographic variables generated and the specific features investigated were collected with 3-dimensional CBCT imaging and compared between the impacted and the contralateral maxillary canines. RESULTS: Statistically significant differences were found between the impacted and nonimpacted canines. Based on these results, clinical relevance and correlations among the variables-canine rotation, canine crown position, canine cusp tip to the midline and to the occlusal plane, canine angle to the midline, and canine angle to the lateral incisor-were considered as variables in a multivariable prediction model. A prediction model using CBCT for canine impaction was established (area under the curve, 0.965; 95% confidence interval, 0.936 to 0.995). Canine crown position, canine cusp tip to the occlusal plane, and canine angulation to the lateral incisor were the relevant predictors in this model. CONCLUSIONS: Prediction of canine impaction based on CBCT was excellent. The probability of canine impaction obtained from the prediction model can help orthodontists to define the optimal intervention method. PMID- 25726403 TI - Impacted central incisors: factors affecting prognosis and treatment duration. AB - INTRODUCTION: In this study, we aimed to assess the patient and treatment factors that influence the success rate and the duration of the orthodontic-surgical modality for impacted central incisors. METHODS: The records of 60 consecutively treated patients (64 impacted incisors) were retrospectively evaluated. The success rate and the duration of each stage of treatment were examined in relation to age, sex, etiology of impaction, location of the impacted tooth, and type of surgical exposure performed. Logistic regression analyses were applied. RESULTS: The group consisted of 26 male and 34 female subjects, 7.0 to 21.9 years old; 27 patients had impactions because of root dilaceration, 29 had impactions because of obstruction, and 4 had impactions with unknown causes. The overall success rate was 90.0%. Five of the 6 failures were dilacerated incisors. The average duration of treatment was 21.6 +/- 8.7 months. The only factor that significantly increased the duration was the height of the impacted tooth. Dilaceration was related to a longer stage of traction and, in older patients (late mixed and full permanent dentition), to a longer finishing stage. CONCLUSIONS: The orthodontic-surgical treatment of impacted incisors is generally successful, but relatively long. Patients and parents should be warned of the risk of failure and the increased treatment duration, especially for dilacerated incisors impacted high in the alveolus. PMID- 25726404 TI - Orthodontic informed consent considering information load and serial position effect. AB - INTRODUCTION: Previous research has demonstrated that current methods of informed consent are relatively ineffective as shown by poor recall and comprehension by adolescent patients and their parents. The purpose of this study was to determine whether adding a short videotape presentation reiterating the issues related to informed consent to a modified informed consent document that emphasizes a limited number of core and patient-specific custom "chunks" at the beginning of an informed consent presentation improved the recall and comprehension of the risks, benefits, and alternatives of orthodontic treatment. A second objective was to evaluate the current related data for recommendable practices. METHODS: Seventy patient-parent pairs were randomly divided into 2 groups. The intervention group (group A) patients and parents together reviewed a customized slide show and a short videotape presentation describing the key risks of orthodontic treatment. Group B followed the same protocol without viewing the videotape. All patients and parents were interviewed independently by research assistants using an established measurement tool with open-ended questions. Interviews were transcribed and scored for the appropriateness of responses using a previously established codebook. Lastly, the patients and parents were given 2 reading literacy tests, 1 related to health and 1 with general content followed by the self-administered demographic and psychological state questionnaires. RESULTS: There were no significant differences between the groups for sociodemographic variables. There were no significant differences between the groups for overall recall and comprehension; recall and comprehension for the domains of treatment, risk, and responsibility; and recall and comprehension for core, general, and custom items. The positional effects were limited in impact. When compared with previous studies, these data further demonstrate the benefit of improved readability and audiovisual supplementation with the addition of "chunking." CONCLUSIONS: There is no benefit to adding a short video to the previously established improved readability and audiovisual supplementation. There is a significant benefit of improved readability and audiovisual slide supplementation with the addition of "chunking" over traditional informed consent methods in terms of patient improvement in overall comprehension, treatment recall, and treatment comprehension. The treatment domain is the most affected. PMID- 25726405 TI - Influence of standardization on the precision (reproducibility) of dental cast analysis with virtual 3-dimensional models. AB - INTRODUCTION: Virtual 3-dimensional (3D) models obtained by scanning of physical casts have become an alternative to conventional dental cast analysis in orthodontic treatment. If the precision (reproducibility) of virtual 3D model analysis can be further improved, digital orthodontics could be even more widely accepted. The purpose of this study was to clarify the influence of "standardization" of the target points for dental cast analysis using virtual 3D models. Physical plaster models were also measured to obtain additional information. METHODS: Five sets of dental casts were used. The dental casts were scanned with R700 (3Shape, Copenhagen, Denmark) and REXCAN DS2 3D (Solutionix, Seoul, Korea) scanners. In this study, 3 system and software packages were used: SureSmile (OraMetrix, Richardson, Tex), Rapidform (Inus, Seoul, Korea), and I DEAS (SDRC, Milford, Conn). RESULTS: Without standardization, the maximum differences were observed between the SureSmile software and the Rapidform software (0.39 mm +/- 0.07). With standardization, the maximum differences were observed between the SureSmile software and measurements with a digital caliper (0.099 mm +/- 0.01), and this difference was significantly greater (P <0.05) than the 2 other mean difference values. Furthermore, the results of this study showed that the mean differences "WITH" standardization were significantly lower than those "WITHOUT" standardization for all systems, software packages, or methods. CONCLUSIONS: The results showed that elimination of the influence of usability or habituation is important for improving the reproducibility of dental cast analysis. PMID- 25726406 TI - Distraction osteogenesis and orthognathic surgery for a patient with unilateral cleft lip and palate. AB - Maxillary deficiency is a common feature in patients with repaired cleft lip and palate. Orthognathic surgery has been the conventional approach for the management of cleft-related maxillary hypoplasia. However, for patients with a severe maxillary deficiency, orthognathic surgery alone has many disadvantages, such as high relapse rates of 25% to 40%, instability, limited amount of advancement, and a highly invasive surgical technique. As an alternative treatment method, distraction osteogenesis has been used successfully in the distraction of the mandible, the maxilla, the entire midface, and the orbits as well as the cranial bones, with stable outcomes. The type of distraction device, either external or internal, can be chosen based on the surgical goals set for the patient. In this study, we report on the use of a rigid external distraction device for maxillary advancement in a 22-year-old woman with a repaired unilateral cleft lip and palate and severe maxillary hypoplasia. After the distraction osteogenesis, 2-jaw surgery was performed to correct the maxillary yaw deviation and the mandibular prognathism. PMID- 25726407 TI - Premolar transplantation to replace a missing central incisor. AB - During childhood, the anterior maxilla is susceptible to injury, and the loss of incisors is one of the most serious injuries. In many cases, autotransplantation is the best alternative for children who lose an incisor during the growth phase. This case report describes the treatment of a boy who had a traumatic injury when he was 8 years old that resulted in avulsion of the maxillary right central incisor. When he sought treatment at age 10, the space was lost as was bone in the incisor region. Because he lacked space in the mandibular arch for proper tooth alignment, extractions were planned. One extracted premolar was transplanted into the space of the missing maxillary incisor area. The posttreatment results were good, and follow-up records 7 and 9 years after treatment showed healthy periodontal support and cortical bone gain in the transplanted tooth's buccal area. PMID- 25726408 TI - Litigation and legislation: how much is too much? PMID- 25726409 TI - Statistics for orthodontists. PMID- 25726410 TI - Bone metastases of unknown origin: epidemiology and principles of management. AB - Metastases are the most common malignancies involving bone; breast, prostate, lung and thyroid are the main sites of primary cancer. However, up to 30 % of patients present with bone metastases of unknown origin, where the site of the primary neoplasm cannot be identified at the time of diagnosis despite a thorough history, physical examination, appropriate laboratory testing and modern imaging technology (CT, MRI, PET). Sometimes only extensive histopathological investigations on bone specimens from biopsy can suggest the primary malignancy. At other times, a bone lesion can have such a highly undifferentiated histological appearance that a precise pathological classification on routine hematoxylin-eosin-stained section is not possible. The authors reviewed the relevant literature in an attempt to investigate the epidemiology of the histological primaries finally identified in patients with bone metastases from occult cancer, and a strategy of management and treatment of bone metastases from occult carcinomas is suggested. Lung, liver, pancreas and gastrointestinal tract are common sites for primary occult tumors. Adenocarcinoma is the main histological type, accounting for 70 % of all cases, while undifferentiated cancer accounts for 20 %. Over the past 30 years, lung cancer is the main causative occult primary for bone metastases and has a poor prognosis with an average survival of 4-8 months. Most relevant literature focuses on the need for standardized diagnostic workup, as surgery for bone lesions should be aggressive only when they are solitary and/or the occult primaries have a good prognosis; in these cases, identification of the primary tumor may be important and warrants special diagnostic efforts. However, in most cases, the primary site remains unknown, even after autopsy. Thus, orthopedic surgery has a mainly palliative role in preventing or stabilizing pathological fractures, relieving pain and facilitating the care of the patient in an attempt to provide the most appropriate therapy for the primary tumor as soon as possible. LEVEL OF EVIDENCE: 5. PMID- 25726411 TI - A randomized, multicenter, multivendor study of myocardial perfusion imaging with regadenoson CT perfusion vs single photon emission CT. AB - BACKGROUND: Myocardial CT perfusion (CTP) is a promising tool for the detection of myocardial ischemia. We hypothesize that regadenoson CTP is noninferior to regadenoson single photon emission CT (SPECT) for detecting or excluding myocardial ischemia. METHODS: Patients (men >= 45 years; women >= 50 years) with known or suspected coronary artery disease (n = 124) were randomized to 1 of 2 diagnostic sequences: rest and regadenoson SPECT on day 1, then regadenoson CTP and rest CTP (and coronary CT angiography [CTA]) (CTA; same acquisition) on day 2 or regadenoson CTP and rest CTP (and CTA) on Day 1, then rest and regadenoson SPECT on day 2. Scanning platforms included 64-, 128-, 256-, and 320-slice systems. The primary analysis examined the agreement rate between CTP and SPECT for detecting or excluding reversible ischemia in >= 2 myocardial segments as assessed by independent, blinded readers. RESULTS: Complete and interpretable CTP and SPECT scans were obtained for 110 patients. Regadenoson CTP was noninferior to SPECT for detecting or excluding reversible ischemia with an agreement rate of 0.87 (95% confidence interval [CI], 0.77-0.97) and sensitivity and specificity of 0.90 (95% CI, 0.71-1.00) and 0.84 (95% CI, 0.77-0.91), respectively. The agreement rate for detecting or excluding >= 1 fixed defects by regadenoson CTP and SPECT was 0.86 (95% CI, 0.74-0.98). With SPECT as the reference standard, the diagnostic accuracies for detecting or excluding ischemia by regadenoson CTP and CTA alone were 0.85 (95% CI, 0.78-0.91) and 0.69 (95% CI, 0.60-0.77), respectively. CONCLUSIONS: This study establishes the noninferiority of regadenoson CTP to SPECT for detecting or excluding myocardial ischemia. PMID- 25726412 TI - Arrhythmogenic biventricular cardiomyopathy: emerging findings on cardiac CT performed in the emergency department to evaluate chest pain. AB - We present multimodality imaging findings demonstrating arrhythmogenic biventricular cardiomyopathy initially observed on cardiac CT in a patient who presented to the emergency department with nonanginal chest pain. As the volume of patients referred for coronary CT angiography increases, structural pathology may emerge in previously unencountered diagnostic sequences. The high spatial resolution and volumetric coverage afforded by multidetector CT imaging remind us that cardiac pathology encompasses far more than atherosclerosis. PMID- 25726413 TI - Imaging of Sarcoidosis. AB - The diagnostic imaging contributes significantly to the diagnosis and management of sarcoidosis. Imaging techniques are widely employed in the assessment of thoracic and extra-thoracic involvement from sarcoidosis. For the diagnosis of sarcoidosis, chest radiograph has been the cornerstone of sarcoidosis since 1961, when Scadding proposed a standardized staging system. Currently, computed tomography (CT) represents the reference standard for the assessment of both mediastinal lymph nodes and pulmonary findings. In particular, high-resolution computed tomography (HRCT) is more accurate compared to chest radiography for the detection of subtle parenchymal involvement, and provides comprehensive overview of anatomical detail and abnormalities of lung structures. Notably, HRCT allows for accurate differentiation between reversible and irreversible lung disease, which is cornerstone of prognostication. Radionuclide imaging (gallium-67 and (18)F-fluorodeoxyglucose) provides information about activity of the disease and is also useful for diagnostic workup of patients with unexplained persistent disabling symptoms. Magnetic resonance is sensitive for the detection of sarcoidosis granulomata within myocardium, thus providing detailed roadmap for biopsy. For the management of sarcoidosis, CT is of paramount importance in the detection and differential of most common complications, such as vascular disease and suspicious nodular lesions. Conversely, the role of CT in the follow-up of asymptomatic subjects is still under debate. This review focuses on the role of diagnostic imaging in the diagnosis and follow-up of sarcoidosis. PMID- 25726414 TI - Enhanced NADPH oxidases and reactive oxygen species in the mechanism of methanol initiated protein oxidation and embryopathies in vivo and in embryo culture. AB - Methanol (MeOH) teratogenicity in rodents may be mediated in part by reactive oxygen species (ROS), the source of which is unknown. To determine if MeOH enhances embryonic ROS-producing NADPH oxidases (NOXs), p22phox mRNA and protein and oxidatively damaged protein were measured in gestational day 12 MeOH-exposed CD-1 mouse embryos with or without pretreatment with the free radical spin trap phenylbutylnitrone (PBN) or the NOX inhibitor diphenyleneiodonium chloride (DPI). MeOH exposure upregulated p22phox mRNA and protein expression, and enhanced protein oxidation, within 3-6 h. Compared to embryos exposed to MeOH alone, PBN and DPI pretreatment decreased MeOH-enhanced p22phox mRNA expression, DPI but not PBN blocked p22phox protein expression, and both blocked protein oxidation. To assess developmental relevance, mouse embryos were exposed in culture for 24 h to MeOH or vehicle with or without pretreatment with PBN, DPI, or the prostaglandin H synthase (PHS) inhibitor eicosatetraynoic acid (ETYA), and evaluated for abnormalities. ETYA did not prevent MeOH embryopathies, despite blocking phenytoin embryopathies (ROS-initiating positive control), precluding bioactivation of MeOH or its metabolites by PHS. Concentration-dependent MeOH embryopathies were blocked by both DPI and PBN pretreatment, suggesting that enhanced embryonic NOX-catalyzed ROS formation and oxidative stress may contribute to the mechanism of MeOH embryopathies. PMID- 25726415 TI - Oxidative stress-induced apoptotic insults to rat osteoblasts are attenuated by nitric oxide pretreatment via GATA-5-involved regulation of Bcl-X L gene expression and protein translocation. AB - Nitric oxide (NO) has biphasic effects on regulating osteoblast survival and death. This study was aimed to evaluate the effects of NO pretreatment on hydrogen peroxide (HP)-induced insults of rat osteoblasts and the possible mechanisms. Exposure of osteoblasts prepared from rat calvarias to HP significantly increased intracellular reactive oxygen species levels, decreased alkaline phosphatase activity and cell survival, and ultimately induced cell apoptosis. However, NO pretreatment lowered HP-induced oxidative stress and apoptotic insults. In parallel, HP increased Bax levels and its translocation from the cytoplasm to mitochondria. NO pretreatment caused significant attenuations in HP-induced modulations in Bax synthesis and translocation. In contrast, pretreatment with NO enhanced levels and translocation of antiapoptotic Bcl-XL protein in rat osteoblasts. RNA analyses further revealed that HP inhibited Bcl-XL mRNA expression without affecting Bax mRNA levels. In comparison, NO induced Bcl-XL mRNA production and alleviated HP-caused inhibition of this mRNA expression. As to the mechanism, HP suppressed RNA and protein levels of transcription factor GATA-5 in rat osteoblasts. Pretreatment with NO induced GATA-5 mRNA and protein expressions and simultaneously attenuated HP induced inhibition of this gene's expression. Consequently, GATA-5 knockdown using RNA interference inhibited Bcl-XL mRNA expression and concurrently lowered NO's protection against HP-induced apoptotic insults. Therefore, this study showed that NO can protect rat osteoblasts from HP-induced apoptotic insults. The protective mechanisms are mediated by GATA-5-mediated transcriptional induction of Bcl-X L gene, and translocational modulation of Bcl-XL and Bax proteins. PMID- 25726416 TI - Long-term outcome of physiologic VDD pacing versus non-physiologic VVI pacing in dogs with high-grade atrioventricular block. AB - OBJECTIVE: To compare the long-term outcome associated with physiologic VDD and non-physiologic VVI or VVIR pacing in dogs with high-grade atrioventricular block. ANIMALS: Forty-nine paced dogs with high-grade atrioventricular block were included. METHODS: Retrospective review of medical records, thoracic radiographs and echocardiograms for all dogs. Patient owners and referring veterinarians were contacted for survival times and a satisfaction questionnaire was submitted to the owners. Survival times, complication rates, resolution of clinical signs, and owner satisfaction were compared between the pacing modalities. RESULTS: A single lead VDD pacemaker was implanted in 19 dogs (39%) whereas 30 dogs (61%) were treated with VVI pacing. The median survival time for all dogs post-pacemaker implantation was 24.5 months. Survival time was significantly decreased in dogs that were older at the time of presentation or that presented with ventricular tachycardia or reduced left ventricular fractional shortening. Median survival times after implantation were not significantly different between pacing modalities (P = 0.29). Major complication rates were 11% within the VDD group and 20% within the VVI group and were not significantly different (P = 0.46). Minor complications were significantly higher within the VDD group than within the VVI group (47% versus 7% respectively; P < 0.01) due to a higher number of dogs in the VDD group experiencing transient ventricular premature contractions in the immediate post-implantation time period. Resolution of clinical signs, owner satisfaction, and quality of life perception were considered excellent in both groups. CONCLUSIONS: No long-term clinical benefit of VDD over VVI pacing could be identified in the present study. PMID- 25726417 TI - Osteoporosis prevalence and characteristics of treated and untreated nursing home residents with osteoporosis. AB - OBJECTIVES: Our primary objective was to describe the prevalence of osteoporosis (OP) diagnosis in nursing home residents (NHRs). Secondary objectives included assessment of pharmacologic therapies and risk of fracture in NHRs with OP, as well as differentiating clinical characteristics of treated versus untreated male and female NHR with OP. Finally, we sought to evaluate persistence and compliance rates in NHRs treated with OP and determine the prevalence of severe renal impairment in NHRs with OP treated with a bisphosphonate. DESIGN: Retrospective cohort analysis. SETTING: US NH. PARTICIPANTS: NHRs with a Minimum Data Set (MDS) 3.0 record in the Omnicare Senior Health Outcomes (OSHO) data repository during the time period of October 1, 2011, to September 30, 2012. MEASUREMENTS: A patient was considered to have an OP diagnosis if MDS item I3800 indicated the NHR had OP or if the MDS record contained ICD-9-CM codes 733.0x. An expanded definition of OP diagnosis was explored, in which an NHR with a previous fracture (MDS items I3900, I4000, J1700C=1) was also considered to have OP. OP pharmacologic therapies were extracted from the pharmacy claims data and included alendronate, calcitonin salmon, denosumab, ibandronate, raloxifene, risedronate, and teriparatide. Using MDS items, cognitive impairment (Brief Instrument for Mental Status, Cognitive Performance Scale) and functional impairment (composite activities of daily living) were assessed. Using MDS and prescription claims data, high risk of fracture (at least 2 of the following: age >=75 years, female gender, previous fracture, history of falls, and use of a bisphosphonate) was assessed. Persistence was indicated by continuous use of therapy without a gap of more than 60 days, compliance was calculated using the medication possession ratio, and creatinine clearance (Clcr) was calculated using a modified Cockcroft Gault equation. RESULTS: The prevalence of OP in NHRs was 13.5%. Using the expanded OP definition, the prevalence of OP increased to 24.2%. Among NHRs with OP (n = 23,666), the mean age was 82.5 and 85.1% were female; 36.8% had gastroesophageal reflux disease or ulcer. Per the definition of high risk for fracture based on older age, female gender, prior fracture, fall history, and use of bisphosphonates, 89.0% of NHRs with OP met the criteria. Additionally, 10.8% had hip fracture, and 15.8% had other fracture. Overall, few NHRs with OP received active treatment: one-third received pharmacologic therapy, of which 73.5% received an oral bisphosphonate. Those with a history of hip fracture had similar treatment rates (31.7%) to those without (32.0%) (P = .804), whereas those with a history of other fracture were more likely to be treated (35.9%) than those without (31.2%) (P = .001). Two-thirds of residents with OP had moderate/severe cognitive impairment, and these residents were less likely to receive OP therapy than those without (P = .001). Persistence with pharmacologic therapy in NHR with a full year of pharmacy data (n = 1399) was higher for raloxifene (82.9%), with calcitonin salmon and bisphosphonates being similar, and the few NHRs who received teriparatide and denosumab were lower. Of the NHRs who received bisphosphonates for whom there was creatinine clearance data, 57% had a Clcr lower than 35 mL/min. CONCLUSION: The recognized prevalence of OP in NHRs using MDS records was low, but consistent with previous reports. Among those with a documented diagnosis of OP, approximately 89% of NHRs with OP were at high risk of fracture and only one-third were treated with active pharmacologic therapy. For those treated, persistence and compliance was suboptimal, but higher with oral therapies. More than half of NHRs with OP treated with bisphosphonates had Clcr of less than 35 mL/min, suggesting alternative forms of therapy should be considered. For all of these reasons, the opportunity exists to improve the care and medication use of residents with OP who are at high risk of fracture. PMID- 25726418 TI - Comparison of Conventional Microwave and Focused Microwave-assisted Extraction to Enhance the Efficiency of the Extraction of Antioxidant Flavonols from Jocote Pomace (Spondias purpurea L.). AB - Jocote (Spondias purpurea L.) is rich in phenolic compounds which have antioxidant properties. The focused microwave-assisted extraction (FMAE) was compared with the conventional microwave-assisted extraction (MAE) to obtain flavonols from jocote pomace. The effects of parameters such as the extraction time, the temperature and the composition of the solvent mixture (i.e., the ethanol to water ration) were evaluated and optimized using a statistical experimental design approach. Response surface methodology (RSM) was applied to determine the important effects and interactions of these independent variables on the extractive yield and quantification of some flavonoids. In addition, the antioxidant activity was analyzed. The total phenolic and flavonoid content was determined according to the Folin-Ciocalteu and aluminum chloride methods, respectively. The free radical scavenging activity of the extract was evaluated according to the DPPH assay. The results showed that the optimum extracting parameters used FMAE with extraction time of 20 min, temperature of 68 degrees C and ethanol composition of 80% in water. Under these conditions, a yield of 3.42% was obtained. Rutin and quercetin were quantified (0.19 mg/mL and 0.024 mg/mL, respectively) through HPLC-DAD. The total phenol and flavonoid contents were found to be 0.897 g GAE/g and 1.271 g QE/g, respectively. In the DPPH scavenging assay, the IC50 value of the extract occurred at 43.10 MUg/mL. This study shows that FMAE is suitable as an efficient extraction procedure for the extraction of flavonols from jocote pomace. PMID- 25726419 TI - Influence of Extraction Methods on the Yield of Steviol Glycosides and Antioxidants in Stevia rebaudiana Extracts. AB - This study evaluated the application of ultrasound techniques and microwave energy, compared to conventional extraction methods (high temperatures at atmospheric pressure), for the solid-liquid extraction of steviol glycosides (sweeteners) and antioxidants (total phenols, flavonoids and antioxidant capacity) from dehydrated Stevia leaves. Different temperatures (from 50 to 100 degrees C), times (from 1 to 40 min) and microwave powers (1.98 and 3.30 W/g extract) were used. There was a great difference in the resulting yields according to the treatments applied. Steviol glycosides and antioxidants were negatively correlated; therefore, there is no single treatment suitable for obtaining the highest yield in both groups of compounds simultaneously. The greatest yield of steviol glycosides was obtained with microwave energy (3.30 W/g extract, 2 min), whereas, the conventional method (90 degrees C, 1 min) was the most suitable for antioxidant extraction. Consequently, the best process depends on the subsequent use (sweetener or antioxidant) of the aqueous extract of Stevia leaves. PMID- 25726420 TI - Dobutamine stress cardiac MRI for assessment of coronary artery disease prior to kidney transplantation. PMID- 25726421 TI - A review of parent participation engagement in child and family mental health treatment. AB - Engagement in child and family mental health treatment has critically important clinical, implementation, and policy implications for efforts to improve the quality and effectiveness of care. This article describes a review of the existing literature on one understudied element of engagement, parent participation. Twenty-three published articles were identified. Questions asked of the literature include what terms are used to represent parent participation engagement, how parent participation engagement is measured, what are the rates of parent participation engagement reported in studies of child and family mental health treatment, whether parent participation engagement has been found to overlap with attendance engagement, what factors have been identified as associated with parent participation engagement, whether parent participation engagement is associated with improved outcomes, and what strategies have been designed to improve PPE and whether such strategies are associated with improved outcomes. Results indicate varied terms and measures of parent participation engagement, moderate overall rates, and high overlap with measures of attendance engagement. The extant literature on factors associated with parent participation engagement was somewhat limited and focused primarily on parent-/family-level factors. Evidence of links between parent participation engagement and outcome improvements was found across some outcome domains, and strategies designed to target parent participation engagement were found to be effective overall. A framework for organizing efforts to examine the different elements of engagement is described, and findings are discussed in terms of suggestions for consistent terminology, clinical implications, and areas for the future research. PMID- 25726422 TI - Flavobacterium shanxiense sp. nov., isolated from soil. AB - Strain YF-2(T), a Gram-staining-negative, non-motile, non-spore-forming, light yellow-pigmented bacterium, was isolated from soil samples collected in the city of Yuncheng, Shanxi province of China. Strain YF-2(T) grew over a temperature range of 25-37 degrees C, at pH 5.0-8.0 and with 0-5 % (w/v) NaCl. Phylogenetic analysis based on sequence of the 16S rRNA gene showed that strain YF-2(T) was closely related to strains Flavobacterium akiainvivens CIP 110358(T) and Flavobacterium hauense KCTC 32147(T) with 95.99 and 95.92 % sequence similarity, respectively. The dominant fatty acids of strain YF-2(T) were Summed Feature 3 (comprising C16:1 omega7c and/or C16:1 omega6c) (21.97 %), iso-C15:0 (18.65 %), iso-C17:0 3OH (11.41 %), C16:0 (9.92 %), and anteiso-C15:0 (6.21 %). It contained phosphatidylethanolamine and menaquinone MK-6 as major polar lipid and respiratory quinone, respectively. Strain YF-2(T) differs from other Flavobacterium species in many characteristics and represents a novel species, for which the name Flavobacterium shanxiense sp. nov. is proposed. The type strain is strain YF-2(T) (=CCTCC AB 2014079(T) = JCM 30153(T)). PMID- 25726423 TI - Ribosomal protein L3 mutations are associated with cfr-mediated linezolid resistance in clinical isolates of Staphylococcus cohnii. AB - From June, 2012 to November, 2013 five linezolid-resistant Staphylococcus cohnii isolates were identified in our hospital in Beijing, China. The investigation of the resistance mechanisms confirmed that the cfr-carrying plasmids were the main cause of linezolid resistance in those clinical isolates. Moreover, all the five isolates had ribosomal protein L3 mutations, which had different coordinate effect on cfr-mediated linezolid resistance directly through the substitution of serine 158 by phenylalanine or tyrosine in L3 protein. In this study, two types of plasmids (p432, p438) (Accession No. KM114207) were found, which share high sequence identity with previously reported cfr-carrying pRM01 and pMHZ plasmids originated from northern and southern China, showing wide regional dissemination in China. The stability of linezolid resistance was studied by passaging single colonies serially on antibiotic-free blood medium, which showed that the susceptible derivatives emerged until the passages 39-42 with the elimination of cfr-carrying plasmid. Thus the high stability of this plasmid may pose a risk for the transmission among patients or even cause an outbreak in clinical settings. PMID- 25726424 TI - Association between multiple geriatric syndromes and life satisfaction in community-dwelling older adults: A nationwide study in Taiwan. AB - OBJECTIVE: Although previous studies have investigated the association between a single geriatric syndrome and life satisfaction in the older adults, the accumulated effects of multiple geriatric syndromes on life satisfaction remain unclear. METHODS: We conducted a nationwide study by using data from the Taiwan Longitudinal Study on Aging database. A total of 2415 older adults were enrolled. Life satisfaction was evaluated according to the Life Satisfaction Index, and the geriatric syndromes included a depressive disorder, cognitive impairment, functional impairment, urine incontinence, pain, a fall, and polypharmacy. Other characteristics were age, sex, marital status, education level, self-rated health, and chronic diseases. RESULTS: Univariate analysis revealed that the older adults, who were illiterate, did not live with a partner, yet other issues such as stroke, malignancy, osteoarthritis, poor self-rated health, a depressive disorder, functional impairment, urine incontinence, or pain were associated with lower life satisfaction. In the multivariate regression model, the older adults who were male, illiterate, lived without a partner, had poor self-rated health, or had a depressive disorder were more likely to have lower life satisfaction. In addition, life satisfaction was unaffected in the older adults with only 1 geriatric syndrome, but among those with >=2 geriatric syndromes, an increased number of geriatric syndromes were associated with lower life satisfaction. CONCLUSION: In addition to socio-demographic factors, cumulative effects of multiple geriatric syndromes might affect life satisfaction in the older adults. Further study of interventions for reducing geriatric syndromes to maintain life satisfaction is required. PMID- 25726425 TI - Silica microspheres are superior to polystyrene for microvesicle analysis by flow cytometry. AB - BACKGROUND: Cell-derived microvesicles (MVs) in biological fluids are studied for their potential role in pathological conditions. Flow cytometry is used to characterize MVs. Polystyrene microspheres are often used in flow cytometry to distinguish MV from cells by setting a 1-MUm MV gate in a side-scatter (SSC) vs. forward-scatter (FSC) dot plot. Polystyrene microspheres, however, exhibit higher FSC and SSC than MVs of equal size. Consequently, some platelets are included within the MV gate, which incorrectly increases the reported percentage of platelet-derived MVs. Silica microspheres exhibit FSC that is closer to that of cellular vesicles and, therefore, should permit more accurate discrimination of MV from platelets. OBJECTIVE: Compare silica with polystyrene microspheres to calibrate flow cytometers for definition of MV population and estimation of MV sizes. METHODS: Silica and polystyrene microspheres of various sizes were used in flow cytometry assays to define MV populations and determine platelet and MV sizes in human plasma samples. Sizes determined by flow cytometry were compared to sizes determined by resistive pulse sensing (RPS) method. RESULTS/CONCLUSION: Use of 1.0-MUm polystyrene microspheres to define the upper MV gate produced a median platelet contamination of 16.53% (8.24, 20.98) of the MV population; whereas, use of 1.0-MUm silica microspheres excluded platelet events completely. Calibration with silica microspheres resulted in significantly better estimation of MV diameter than calibration with polystyrene microspheres. We conclude that silica microspheres are superior to polystyrene microspheres as standards to define MV populations without platelet contamination and to determine MV sizes by flow cytometry for a given cytometer. PMID- 25726426 TI - Patterns, risk factors and treatment associated with PICC-DVT in hospitalized adults: A nested case-control study. AB - BACKGROUND: Peripherally inserted central catheters (PICCs) are associated with upper extremity-deep vein thrombosis (DVT). However, patterns, risk factors and treatment associated with this event remain poorly defined. OBJECTIVE: To determine patterns, risk factors and treatment related to PICC-DVT in hospitalized patients. DESIGN, SETTING & PATIENTS: Between 2012-2013, consecutive cases of ultrasound-confirmed, symptomatic PICC-DVT were identified. For each case, at least two contemporaneous controls were identified and matched by age and gender. Patient- and device-specific data were obtained through electronic medical records. Using variables selected a priori, multivariable logistic regression models were fit to the outcome of PICC-DVT, comparing cases to controls. RESULTS: 909 adult hospitalized patients (268 cases, 641 controls) were included in the study. Indications for PICC placement included long-term intravenous antibiotic therapy (n=447; 49.1%), in-hospital venous access for blood draws or infusion of medications (n=342; 44.2%), and total parenteral nutrition (n=120; 6.7%). Patients with PICC-DVT were more likely to have a history of venous thromboembolism (OR 1.70, 95% CI=1.02-2.82) or have undergone surgery while the PICC was in situ (OR 2.17, 95%CI=1.17-4.01 for surgeries longer than two hours). Treatment for PICC-DVT varied and included heparin bridging, low molecular weight heparin only and device removal only; the average duration of treatment also varied across these groups. Compared to 4-Fr PICCs, 5- and 6-Fr PICCs were associated with greater risk of DVT (OR 2.74, 95%CI=0.75-10.09 and OR 7.40 95%CI=1.94-28.16, respectively). Patients who received both aspirin and statins were less likely to develop PICC-DVT than those that received neither treatment (OR 0.31, 95%CI=0.16-0.61). Receipt of pharmacological DVT prophylaxis during hospitalization showed a non-significant trend towards reduction in risk of PICC-DVT (OR=0.72, 95%CI=0.48-1.08). CONCLUSION: Several factors appear associated with PICC-DVT. While some of these characteristics may be non modifiable, future studies that target potentially modifiable variables to prevent this adverse outcome would be welcomed. PMID- 25726427 TI - Blood pressure and stroke risk in left ventricular assist devices. PMID- 25726428 TI - Changes in body composition in heart failure patients after a resistance exercise program and branched chain amino acid supplementation. AB - BACKGROUND & AIMS: Heart Failure (HF) is a complex syndrome, which can include the physiological, neural hormonal and metabolic complications known as "Cardiac Cachexia" (CC). In the development of CC there is a release of catabolic cytokines (Tumor Necrosis Factor-alpha, interleukins 1 and 6) that cause a decrease of fat free mass and fat mass. These changes in body composition might be reversed with a therapeutic combination of resistance exercise and branched chain amino acid supplementation (BCAA). AIM: Evaluate changes in body composition after a resistance exercise program and BCAA supplementation in patients with HF. METHODS: In a randomized clinical trial with 3 month of follow up anthropometric body composition analysis and stress tests were evaluated at the beginning and in the end of the study. Patients were divided into two groups; the experimental group performed the resistance exercise program and received 10 g/day BCAA supplementation, and the control group only performed the resistance exercise program. Both groups were provided with individualized diets and conventional medical treatment. RESULTS: Changes were found in hip circumference between the groups (p = 0.02), and muscle strength was increased in the experimental group (8%) and the control group (11.4%) with no difference between them. METS and VO2Max also increased in experimental and control groups (16.6% and 50.1% respectively). Regarding changes in symptoms, improvements in fatigue (45.4%), decubitus intolerance (21.8%) and dyspnea (25.4%) were observed in the overall sample. CONCLUSION: Improvements in physical and functional capacities are attributed to resistance exercise program but not to the BCAA supplementation. CLINICAL TRIALS IDENTIFIER: NCT02240511. PMID- 25726429 TI - Older, in hospital and confused - the value of nursing care in preventing falls in older people with cognitive impairment. PMID- 25726430 TI - Eligibility criteria in systematic reviews: A methodological review. AB - BACKGROUND: Systematic reviews of literature are increasingly important in healthcare. While reviewers are expected to follow reporting guidelines, inconsistencies may be observed in presentation of reviews, potentially detracting from the credibility of findings. Predetermined eligibility criteria are fundamental to the systematic process of reviewing, and should be given primacy in authors' reports. METHOD: This methodological review assessed the specification and application of eligibility criteria in systematic reviews in three leading generic nursing journals. RESULTS: While reporting guidelines were generally followed, major anomalies were revealed by this review. Over three quarters of review papers placed eligibility criteria after description of the search strategy. Unjustified time restrictions were common, and many flowcharts omitted vital information. CONCLUSION: Greater scrutiny of systematic reviews submitted to nursing journals would enhance the quality of reports and contribute to more robust evidence-based practice. PMID- 25726431 TI - Case vignettes to evaluate the accuracy of identifying healthcare-associated infections by surveillance persons. AB - BACKGROUND: National surveillance systems depend on accurate and reproducible diagnosis of infections. AIM: To investigate the effect of accuracy of diagnosing healthcare-associated infections (HCAIs) on HCAI rates in a national healthcare associated surveillance system. METHODS: Data from the validation process from the intensive care unit (ICU) surveillance component of the German Krankenhaus Infektions Surveillance System (KISS; Hospital Infection Surveillance System) were used to calculate the accuracy of diagnosing HCAI for each individual surveillance person (SP) responsible for surveillance of HCAI in the ICU of his or her hospital. Multivariate analyses were performed to identify factors that were attributed to surveillance accuracy. FINDINGS: A total of 189 SPs responsible for surveillance in 218 ICUs assessed 30 case vignettes. The chance of belonging to the group of SPs with high accuracy was increased by being a physician (odds ratio: 3.14; P = 0.02) and by being an external SP (odds ratio: 4.69; P <= 0.01). ICU HCAI rates depend on the sensitivity of the ICU's SP [incidence rate ratio (IRR): 1.28 (1.07, 1.53); P <= 0.01]. High sensitivity increases healthcare-associated urinary tract infection rates [IRR: 1.33 (1.02, 1.75); P = 0.03] and bloodstream infection rates [IRR: 1.33 (1.06, 1.68); P = 0.01]. High specificity was not a significant factor. CONCLUSION: In light of the link between sensitivity of diagnosing HCAI by case vignettes and the ICU HCAI rates, this validation method can be recommended for validation of other surveillance systems. PMID- 25726432 TI - Substantive effect of chlorhexidine. PMID- 25726434 TI - Case study on the orientation of phaco hand pieces during steam sterilization processes. AB - BACKGROUND: Steam sterilization is an essential part of infection prevention. The literature shows that sterilization of medical instruments containing channels is not trivial. Phaco hand pieces have a simple configuration: a device contains a channel with a constant radius. No literature was found indicating whether the sterilization conditions on the inner surface of a phaco hand piece are influenced by the orientation of the hand piece. AIM: To determine whether the orientation of a phaco hand piece influences the results of a sterilization process of this device. METHODS: A qualitative case study, including experiments, is performed with a protocolled combination of steam sterilizer, process, phaco hand piece, orientation of the phaco hand piece, and wrapping. FINDINGS: In this specific case, the orientation of the hand piece influenced the result of the steam sterilization process; in vertically (upright) oriented phaco hand pieces with free water drainage, sterilization conditions are reproducibly established. In the same process, in horizontally oriented or vertically oriented hand pieces without free drainage, these conditions are not established in a reproducible way. CONCLUSION: In the investigated combination of sterilizer, process, load, loading pattern and wrapping, phaco hand pieces have to be oriented vertically (upright) with free water drainage to obtain steam sterilization conditions on the inner surface. It is likely that instruments with comparable configuration and dimensions will yield comparable results. It is therefore recommended that this issue is considered during the development of medical instruments and during performance qualifications of such instruments. PMID- 25726435 TI - Impact of organizations on healthcare-associated infections. AB - Resolving the challenges presented by healthcare-associated infections requires a 'whole healthcare economy' perspective encompassing the interactions between biological, therapeutic, and structural factors. The importance and influence of organizational characteristics is receiving increasing attention. This article reviews some keys features that can facilitate the success of patient safety initiatives related to healthcare-associated infections, and highlights areas for further consideration and research. The impact of guidelines and indicators is discussed, together with some challenges resulting from the need to maintain and sustain clinicians' commitment to desired behaviour. Novel technology solutions such as electronic healthcare games and engagement with social media platforms may serve to support and reinforce traditional patient safety improvement initiatives. Recently published essential structural components and indicators of infection prevention and control programmes stress the need for comprehensive approaches that integrate multimodal and multidisciplinary solutions and strive to reinforce an organizational culture of patient safety. PMID- 25726433 TI - Burden of norovirus in healthcare facilities and strategies for outbreak control. AB - Norovirus is the most frequently occurring cause of community-acquired acute gastroenteritis in people of all ages. It is also one of the most frequent causes of outbreaks in healthcare settings, affecting both long-term care facilities and acute care hospitals. Whereas norovirus gastroenteritis is typically mild and resolves without medical attention, healthcare-associated infections often affect vulnerable populations, resulting in severe infections and disruption of healthcare services. Globally, most norovirus outbreaks in hospitals and residential care institutions are associated with genogroup II type 4 (GII.4) strains. Recent data demonstrate that excess mortality occurs during outbreak periods in healthcare facilities. Nosocomial outbreaks can result in large economic and societal costs. Current control measures for norovirus are largely based on general infection control principles, and treatment is mainly supportive and non-specific. While neither vaccines nor antiviral agents are currently available, both are being developed with encouraging results. PMID- 25726436 TI - Development of a teicoplanin loading regimen that rapidly achieves target serum concentrations in critically ill patients with severe infections. AB - We performed high-dose loading (12 mg/kg every 12 h for 48 h; 4 doses total) of teicoplanin (TEIC) in patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections, with the goal of achieving target serum concentration (TEICc) >= 15 mg/l within 48 h of starting administration. The safety and effectiveness of the fixed, early-stage administration method were evaluated across a range of kidney dysfunction severity levels. TEIC high-dose loading was administered to 106 patients with MRSA infection from February 2010 to February 2013. After high-dose loading, maintenance doses based on therapeutic drug monitoring (TDM) of TEICc were administered via 30-min intravenous drips, every 24 h. Subjects were divided into 4 groups based on kidney function and renal replacement therapy (RRT) status for safety and effectiveness evaluation: group 1 (G1) did not undergo RRT and exhibited creatinine clearance (Ccr; ml/min/m(2)) >50, group 2 (G2) exhibited Ccr <= 50, group 3 (G3) underwent continuous RRT (CRRT), and group 4 (G4) underwent intermittent RRT (IRRT). TEICc was measured after 24, 48, 72, and 144 h, immediately before TEIC administration. Target TEICc was reached in all groups, and bacteriological effectiveness and utility were high in G1, G2, and G3. The maximum TEICc (>= 28.0 mg/l) and serum albumin (<= 1.84 g/dl) were associated with organ toxicity. Fixed high-dose loading of TEIC achieved the target therapeutic range (>= 15 mg/l) within 48 h of the start of administration regardless of kidney dysfunction, and exhibited sufficient utility. PMID- 25726437 TI - Understanding the evolving role of the Personal Health Record. PMID- 25726438 TI - Maternal control of oocyte quality in cattle "a review". AB - The oocyte is a central regulator of multiple aspects of female fertility, including ovarian follicular development and early embryogenesis. During its prolonged diplotene arrest, the oocyte is subjected to endogenous (i.e., reactive oxygen species from metabolism) and exogenous (i.e., heat stress, malnutrition) sources of damage-inducing factors, which may lead to a progressive deterioration of oocyte quality. A deficit in oocyte competence can lead not only to a failure of fertilization but also to a lower developmental rate after fertilization. Thus, an appropriate environment for growth and maturation of the oocyte, in vivo and in vitro, is critical to ensure optimal oocyte quality. The objectives of the current review are to give an overview of some maternal key factors that influence oocyte quality in cattle and describe some of the findings to date in the hope of obtaining competent oocytes that could be used for clinical and applied purposes. PMID- 25726439 TI - Toxic effects of cadmium on testis of birds and mammals: a review. AB - In humans and other mammals, cadmium (Cd) causes various damages to different organs and tissues of the body. This review presents a comprehensive overview on the effect of Cd on the structure of seminiferous tubules, Leydig cells and blood vessels in the testis. The main observation of the effect of Cd is destruction of the seminiferous tubules with severe necrotic areas. Damage is to all stages of developing germ cells by inducing their structural changes and the apoptotic cell death. Sertoli supporting cells are considered the most vulnerable cells. Their damage results in cytoplasmic rearrangement and disruption of inter-Sertoli tight junctions resulting in increased permeability of the blood-testis barrier, structural changes in the Leydig cells and decreased testosterone secretion. After long time of Cd exposure an increase of the amount of interstitial connective tissue occurs. In blood vessels Cd exposure causes various morphological and physiological changes in vascular endothelial cells and smooth muscle cells. In humans and other mammals, the range of effect depends on the dose, route, ways, and duration of exposure. After necrosis of the sensitive cells Cd produced lesions in surrounding tissue and activate free cells. Atrophy of the seminiferous tubules is followed by Leydig cell regeneration and interstitial revascularization. In birds, spermatogenic cells underwent irreversible degeneration or atrophy of seminiferous tubules in the absence of significant vascular lesions. PMID- 25726440 TI - Influence of 4-hydroxylated polychlorinated biphenyls on the secretory function of bovine ovarian cells: role of the steroidogenic factor-1 receptor. AB - The hydroxy-derivatives (OHPCBs) of polychlorinated biphenyls (PCBs) can accumulate in the tissues of the reproductive tract in animals and humans and may still have estrogen-like properties. Moreover, the "orphan" nuclear receptor Steroidogenic Factor-1 (SF-1) can be the target of PCBs. The aim of the present study was to determine the effect 4OH4CB and 4OH3CB on the secretion of estradiol (E2), progesterone (P4), and oxytocin (OT) from granulosa cells of follicles <1cm and >1cm in diameter and from luteal cells collected at four stages of the estrous cycle of cows. Furthermore, the possibility that 4OHPCBs have an effect on OT synthesis and secretion via the SF receptor was studied using receptor blocker (F0160). Used OHPCBs increased the secretion of P4 from the granulosa cells of follicles of both sizes and increased the secretion of OT from follicles with a diameter of >1cm. These increases were inhibited by an SF-1 receptor blocker. In luteal cells, 4OH3CB increased the secretion of P4 and OT from luteal cells at all phases of the estrous cycle, while 4OH4CB increased OT secretion during the first half of the estrous cycle. Concomitant with the increase in OT secretion from the cells, an increase in the expression of OT precursor mRNA (NP I/OT) was observed. This effect was inhibited by SF-1 receptor blocker. These results indicate that 4OHPCBs impair the secretory function of ovarian steroidogenic cells by disrupting steroidogenesis and increasing OT secretion, and the receptor SF-1 appears to be essentially involved in these processes. PMID- 25726441 TI - Quality of life in patients with different constipation subtypes based on the Rome III criteria. AB - BACKGROUND: Functional constipation and irritable bowel syndrome with constipation are highly prevalent and affect the quality of life of those who suffer from them. AIMS: To evaluate quality of life in patients with functional constipation and irritable bowel disease in accordance with the Rome III criteria, using the PAC-QOL and SF-36 questionnaires. MATERIALS AND METHODS: A cross-sectional study was conducted using self-administered questionnaires. The PAC-QOL, SF-36, and Rome III constipation module questionnaires were applied to patients that complained of constipation at the outpatient clinic of a tertiary care hospital. The constipation subtypes were: functional constipation (no pain), irritable bowel syndrome with constipation (pain and/or discomfort >=3 days/month), and unclassifiable constipation (pain <=2 days/month). Data were summarized in proportions, and group comparisons were made between the scores of each of the areas of the PAC-QOL and SF-36 questionnaires using parametric tests (Student's t test and ANOVA). RESULTS: A total of 43 PAC-QOL surveys were analyzed, resulting in cases of irritable bowel syndrome with constipation (14%), functional constipation (37%), and unclassifiable constipation (49%). There were statistically significant differences (P<.05) in Physical discomfort (irritable bowel syndrome with constipation vs. functional constipation and unclassifiable constipation vs. irritable bowel syndrome with constipation), Worries and concerns (irritable bowel syndrome with constipation vs. functional constipation), and Treatment satisfaction (irritable bowel syndrome with constipation vs. functional constipation and unclassifiable constipation vs. irritable bowel syndrome with constipation). A total of 93 SF-36 questionnaires were analyzed, describing cases of irritable bowel syndrome with constipation (23%), functional constipation (27%), and unclassifiable constipation (51%). Lower physical energy was found in relation to irritable bowel syndrome with constipation vs. functional constipation (P<.0221) and unclassifiable constipation (P<.0086), respectively, and there was greater physical pain in the cases of irritable bowel syndrome with constipation vs. unclassifiable constipation (P<.0362). CONCLUSIONS: Differences in quality of life of patients presenting with constipation subtypes were identified using the PAC-QOL and SF-36 questionnaires. The patients that had the irritable bowel syndrome with constipation subtype experienced poorer quality of life in all the evaluated domains. PMID- 25726442 TI - Antibiotic susceptibility profiles of Prevotella species in The Netherlands. PMID- 25726443 TI - Presence of infection influences the epithelial lining fluid penetration of oral levofloxacin in adult patients. AB - Although epithelial lining fluid (ELF) is the presumed site for pulmonary infections, most antibiotic penetration studies are conducted in uninfected patients or healthy volunteers. Levofloxacin concentrations in plasma and ELF were collected from two previous studies involving 18 infected patients with acute exacerbations of chronic bronchitis and 15 uninfected elderly patients undergoing diagnostic bronchoscopy. Concentration data were population modelled using the BigNPAG algorithm, and a 5000-patient Monte Carlo simulation was conducted to simulate ELF exposure for a dosing regimen 750mg every 24h for five doses in plasma and ELF of infected versus uninfected patients. Mean+/-S.D. model parameters for plasma in infected patients were similar to uninfected patients (volume of central compartment, 68.4+/-36.3 vs. 50.2+/-17.3L; clearance, 6.0+/ 2.5 vs. 6.8+/-3.3L/h; and absorption rate, 5.4+/-2.5 vs. 4.7+/-2.7h(-1)), resulting in similar simulated AUC in plasma (infected, 140.5+/-54.8 vs. uninfected, 133.7+/-61.6MUgh/mL). The volume of ELF was 57.2+/-25.0 and 14.8+/ 9.0L in infected and uninfected patients, respectively, resulting in a lower simulated AUCELF exposure for infected patients (189.1+/-210.5 vs. 461.0+/ 558.7MUgh/mL). Penetration ratios for infected and uninfected patients were, respectively, 1.4+/-1.8 and 3.5+/-3.7, with median values of 0.9 and 2.4. ELF penetration in infected patients was approximately one-half that of uninfected adults. These data highlight the importance of confirming exposure in infected patients to further support dosage regimen selection. PMID- 25726444 TI - Transgenic omega-3 PUFA enrichment alters morphology and gene expression profile in adipose tissue of obese mice: Potential role for protectins. AB - OBJECTIVE: Dietary administration of omega-3 polyunsaturated fatty acids (PUFA) is often associated with altered adipose tissue (AT) morphology and/or function in obese mice. Yet, it is unclear whether this is an indirect consequence of reduced weight gain or results from direct actions of omega-3 PUFA. Here we studied the AT of high fat (HF)-fed fat-1 transgenic mice that convert endogenous omega-6 to omega-3 PUFA while maintaining equivalent fat accretion as their wild type (WT) counterparts. MATERIALS AND METHODS: Adipocyte size profiling, Affymetrix microarray pathway analysis, qPCR and protectin identification and analysis were performed in epididymal AT from hemizygous fat-1(+/-) mice and their wild type littermates that had been fed a HF diet for 8weeks from 6weeks of age. RESULTS: Despite equivalent fat pad mass, we found that epididymal AT from HF-fed transgenic animals possesses fewer large and very large but more mid-size adipocytes compared to WT mice. In order to better understand the underlying mechanisms contributing to the observed alteration in adipocyte size we performed an Affymetrix microarray. Pathway analysis of these data highlighted adipogenesis, cholesterol biosynthesis, insulin signaling, prostaglandin synthesis/regulation and small ligand GPCRs as points where differentially expressed genes were significantly overrepresented. Observed changes were confirmed for four candidate genes: Cnr1, Cnr2, Faah and Pparg by qPCR. Finally we demonstrated that protectin DX is present in AT and that protectin DX and protectin D1 promote comparable PPARgamma transcriptional activity. CONCLUSIONS: These data provide unprecedented evidence that omega-3 PUFA coordinately regulate AT gene expression programs in a manner that is independent of restriction of weight gain or fat accrual and highlight an important influence of omega-3 PUFA on adipogenesis. Furthermore we provide primary evidence suggesting that protectins likely contribute to these effects via their influence on PPARgamma. PMID- 25726445 TI - The effect of chronic kidney disease on the urine proteome in the domestic cat (Felis catus). AB - Chronic kidney disease (CKD) is a major cause of mortality in cats, but sensitive and specific biomarkers for early prediction and monitoring of CKD are currently lacking. The present study aimed to apply proteomic techniques to map the urine proteome of the healthy cat and compare it with the proteome of cats with CKD. Urine samples were collected by cystocentesis from 23 healthy young cats and 17 cats with CKD. One-dimensional sodium-dodecyl-sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) was conducted on 4-12% gels. Two-dimensional electrophoresis (2DE) was applied to pooled urine samples from healthy cats (n = 4) and cats with CKD (n = 4), respectively. Sixteen protein bands and 36 spots were cut, trypsin-digested and identified by mass spectrometry. 1D-SDS-PAGE yielded an overall view of the protein profile and the separation of 32 +/- 6 protein bands in the urine of healthy cats, while CKD cats showed significantly fewer bands (P < 0.01). 2-DE was essential in fractionation of the complex urine proteome, producing a reference map that included 20 proteins. Cauxin was the most abundant protein in urine of healthy cats. Several protease inhibitors and transport proteins that derive from plasma were also identified, including alpha 2-macroglobulin, albumin, transferrin, haemopexin and haptoglobin. There was differential expression of 27 spots between healthy and CKD samples (P < 0.05) and 13 proteins were unambiguously identified. In particular, increased expression of retinol-binding protein, cystatin M and apolipoprotein-H associated with decreased expression of uromodulin and cauxin confirmed tubular damage in CKD cats suggesting that these proteins are candidate biomarkers. PMID- 25726446 TI - Seizing the potential of scientific advance. PMID- 25726447 TI - The glory of the garden...mostly. PMID- 25726448 TI - Tackling the present, shaping the future. PMID- 25726449 TI - Building the field of improvement science. PMID- 25726450 TI - What you need to know to make the most of big data in biology. PMID- 25726451 TI - Work-life balance in academic medicine. PMID- 25726452 TI - Bioscience industry: opportunities for early career researchers. PMID- 25726453 TI - [Neurosurgical peculiarity based on the medical and economic analysis of its activities at a university hospital]. PMID- 25726454 TI - External validation is only needed when prediction models are worth it (Letter commenting on: J Clin Epidemiol. 2015;68:25-34). PMID- 25726455 TI - Editorial overview: cardiovascular and renal: blood pressure regulation and hypertension-hunt for new treatment targets in the kidneys. PMID- 25726456 TI - Immune checkpoint inhibitors in the treatment of metastatic melanoma. PMID- 25726457 TI - The impact of 2-dose routine measles, mumps, rubella, and varicella vaccination in France on the epidemiology of varicella and zoster using a dynamic model with an empirical contact matrix. AB - PURPOSE: Varicella has a high incidence affecting the vast majority of the population in France and can lead to severe complications. Almost every individual infected by varicella becomes susceptible to herpes zoster later in life due to reactivation of the latent virus. Zoster is characterized by pain that can be long-lasting in some cases and has no satisfactory treatment. Routine varicella vaccination can prevent varicella. The vaccination strategy of replacing both doses of measles, mumps, and rubella (MMR) with a combined MMR and varicella (MMRV) vaccine is a means of reaching high vaccination coverage for varicella immunization. The objective of this analysis was to assess the impact of routine varicella vaccination, with MMRV in place of MMR, on the incidence of varicella and zoster diseases in France and to assess the impact of exogenous boosting of zoster incidence, age shift in varicella cases, and other possible indirect effects. METHODS: A dynamic transmission population-based model was developed using epidemiological data for France to determine the force of infection, as well as an empirically derived contact matrix to reduce assumptions underlying these key drivers of dynamic models. Scenario analyses tested assumptions regarding exogenous boosting, vaccine waning, vaccination coverage, risk of complications, and contact matrices. FINDINGS: The model provides a good estimate of the incidence before varicella vaccination implementation in France. When routine varicella vaccination is introduced with French current coverage levels, varicella incidence is predicted to decrease by 57%, and related complications are expected to decrease by 76% over time. After vaccination, it is observed that exogenous boosting is the main driver of change in zoster incidence. When exogenous boosting is assumed, there is a temporary increase in zoster incidence before it gradually decreases, whereas without exogenous boosting, varicella vaccination leads to a gradual decrease in zoster incidence. Changing vaccine efficacy waning levels and coverage assumptions are still predicted to result in overall benefits with varicella vaccination. IMPLICATIONS: In conclusion, the model predicted that MMRV vaccination can significantly reduce varicella incidence. With suboptimal coverage, a limited age shift of varicella cases is predicted to occur post-vaccination with MMRV. However, it does not result in an increase in the number of complications. GSK study identifier: HO-12 6924. PMID- 25726458 TI - Increased premotor cortex activation in high functioning autism during action observation. AB - The mirror neuron (MN) hypothesis of autism has received considerable attention, but to date has produced inconsistent findings. Using functional MRI, participants with high functioning autism or Asperger's syndrome were compared to typically developing individuals (n=12 in each group). Participants passively observed hand gestures that included waving, pointing, and grasping. Concerning the MN network, both groups activated similar regions including prefrontal, inferior parietal and superior temporal regions, with the autism group demonstrating significantly greater activation in the dorsal premotor cortex. Concerning other regions, participants with autism demonstrated increased activity in the anterior cingulate and medial frontal gyrus, and reduced activation in calcarine, cuneus, and middle temporal gyrus. These results suggest that during observation of hand gestures, frontal cortex activation is affected in autism, which we suggest may be linked to abnormal functioning of the MN system. PMID- 25726459 TI - Automated 3D RNA structure prediction using the RNAComposer method for riboswitches. AB - Understanding the numerous functions of RNAs depends critically on the knowledge of their three-dimensional (3D) structure. In contrast to the protein field, a much smaller number of RNA 3D structures have been assessed using X-ray crystallography, NMR spectroscopy, and cryomicroscopy. This has led to a great demand to obtain the RNA 3D structures using prediction methods. The 3D structure prediction, especially of large RNAs, still remains a significant challenge and there is still a great demand for high-resolution structure prediction methods. In this chapter, we describe RNAComposer, a method and server for the automated prediction of RNA 3D structures based on the knowledge of secondary structure. Its applications are supported by other automated servers: RNA FRABASE and RNApdbee, developed to search and analyze secondary and 3D structures. Another method, RNAlyzer, offers new way to analyze and visualize quality of RNA 3D models. Scope and limitations of RNAComposer in application for an automated prediction of riboswitches' 3D structure will be presented and discussed. Analysis of the cyclic di-GMP-II riboswitch from Clostridium acetobutylicum (PDB ID 3Q3Z) as an example allows for 3D structure prediction of related riboswitches from Clostridium difficile 4, Bacillus halodurans 1, and Thermus aquaticus Y5.1 of yet unknown structures. PMID- 25726460 TI - Modeling complex RNA tertiary folds with Rosetta. AB - Reliable modeling of RNA tertiary structures is key to both understanding these structures' roles in complex biological machines and to eventually facilitating their design for molecular computing and robotics. In recent years, a concerted effort to improve computational prediction of RNA structure through the RNA Puzzles blind prediction trials has accelerated advances in the field. Among other approaches, the versatile and expanding Rosetta molecular modeling software now permits modeling of RNAs in the 100-300 nucleotide size range at consistent subhelical (~1 nm) resolution. Our laboratory's current state-of-the-art methods for RNAs in this size range involve Fragment Assembly of RNA with Full-Atom Refinement (FARFAR), which optimizes RNA conformations in the context of a physically realistic energy function, as well as hybrid techniques that leverage experimental data to inform computational modeling. In this chapter, we give a practical guide to our current workflow for modeling RNA three-dimensional structures using FARFAR, including strategies for using data from multidimensional chemical mapping experiments to focus sampling and select accurate conformations. PMID- 25726461 TI - Computational methods toward accurate RNA structure prediction using coarse grained and all-atom models. AB - Computational methods can provide significant insights into RNA structure and dynamics, bridging the gap in our understanding of the relationship between structure and biological function. Simulations enrich and enhance our understanding of data derived on the bench, as well as provide feasible alternatives to costly or technically challenging experiments. Coarse-grained computational models of RNA are especially important in this regard, as they allow analysis of events occurring in timescales relevant to RNA biological function, which are inaccessible through experimental methods alone. We have developed a three-bead coarse-grained model of RNA for discrete molecular dynamics simulations. This model is efficient in de novo prediction of short RNA tertiary structure, starting from RNA primary sequences of less than 50 nucleotides. To complement this model, we have incorporated additional base pairing constraints and have developed a bias potential reliant on data obtained from hydroxyl probing experiments that guide RNA folding to its correct state. By introducing experimentally derived constraints to our computer simulations, we are able to make reliable predictions of RNA tertiary structures up to a few hundred nucleotides. Our refined model exemplifies a valuable benefit achieved through integration of computation and experimental methods. PMID- 25726462 TI - Improving RNA secondary structure prediction with structure mapping data. AB - Methods to probe RNA secondary structure, such as small molecule modifying agents, secondary structure-specific nucleases, inline probing, and SHAPE chemistry, are widely used to study the structure of functional RNA. Computational secondary structure prediction programs can incorporate probing data to predict structure with high accuracy. In this chapter, an overview of current methods for probing RNA secondary structure is provided, including modern high-throughput methods. Methods for guiding secondary structure prediction algorithms using these data are explained, and best practices for using these data are provided. This chapter concludes by listing a number of open questions about how to best use probing data, and what these data can provide. PMID- 25726463 TI - Computational prediction of riboswitch tertiary structures including pseudoknots by RAGTOP: a hierarchical graph sampling approach. AB - The modular organization of RNA structure has been exploited in various computational and theoretical approaches to identify RNA tertiary (3D) motifs and assemble RNA structures. Riboswitches exemplify this modularity in terms of both structural and functional adaptability of RNA components. Here, we extend our computational approach based on tree graph sampling to the prediction of riboswitch topologies by defining additional edges to mimick pseudoknots. Starting from a secondary (2D) structure, we construct an initial graph deduced from predicted junction topologies by our data-mining algorithm RNAJAG trained on known RNAs; we sample these graphs in 3D space guided by knowledge-based statistical potentials derived from bending and torsion measures of internal loops as well as radii of gyration for known RNAs. We present graph sampling results for 10 representative riboswitches, 6 of them with pseudoknots, and compare our predictions to solved structures based on global and local RMSD measures. Our results indicate that the helical arrangements in riboswitches can be approximated using our combination of modified 3D tree graph representations for pseudoknots, junction prediction, graph moves, and scoring functions. Future challenges in the field of riboswitch prediction and design are also discussed. PMID- 25726464 TI - Using reweighted pulling simulations to characterize conformational changes in riboswitches. AB - Riboswitches are RNA sequences located in noncoding portions of mRNA that can sense specific ligands and subsequently control gene expression. The ligand binding event induces conformational changes in the riboswitch that are then transmitted to the gene expression apparatus. Probing the mechanisms of such a fine regulation at atomic resolution is very difficult experimentally and molecular dynamics (MD) could be used to quantify the ligand-dependent behavior of a riboswitch. However, since the accessible time scale of fully atomistic simulations is limited, this can only be done using enhanced sampling techniques. Here, we discuss the application of steered MD to the characterization of the ligand-dependent stability of the aptamer terminal helix in the add adenine sensing riboswitch. The employed techniques are discussed in detail and sample input files are provided. We show that with a limited computational effort it is possible to quantify, in terms of free energy, the stacking interaction between the ligand and the terminal helix, obtaining results in agreement with thermodynamic experiments. PMID- 25726465 TI - Force field dependence of riboswitch dynamics. AB - Riboswitches are noncoding regulatory elements that control gene expression in response to the presence of metabolites, which bind to the aptamer domain. Metabolite binding appears to occur through a combination of conformational selection and induced fit mechanism. This demands to characterize the structural dynamics of the apo state of aptamer domains. In principle, molecular dynamics (MD) simulations can give insights at the atomistic level into the dynamics of the aptamer domain. However, it is unclear to what extent contemporary force fields can bias such insights. Here, we show that the Amber force field ff99 yields the best agreement with detailed experimental observations on differences in the structural dynamics of wild type and mutant aptamer domains of the guanine sensing riboswitch (Gsw), including a pronounced influence of Mg2+. In contrast, applying ff99 with parmbsc0 and parmchiOL modifications (denoted ff10) results in strongly damped motions and overly stable tertiary loop-loop interactions. These results are based on 58 MD simulations with an aggregate simulation time>11 MUs, careful modeling of Mg2+ ions, and thorough statistical testing. Our results suggest that the moderate stabilization of the chi-anti region in ff10 can have an unwanted damping effect on functionally relevant structural dynamics of marginally stable RNA systems. This suggestion is supported by crystal structure analyses of Gsw aptamer domains that reveal chi torsions with high-anti values in the most mobile regions. We expect that future RNA force field development will benefit from considering marginally stable RNA systems and optimization toward good representations of dynamics in addition to structural characteristics. PMID- 25726466 TI - Thermodynamic and kinetic folding of riboswitches. AB - Riboswitches are structured RNA regulatory elements located in the 5'-UTRs of mRNAs. Ligand-binding induces a structural rearrangement in these RNA elements, effecting events in downstream located coding sequences. Since they do not require proteins for their functions, they are ideally suited for computational analysis using the toolbox of RNA structure prediction methods. By their very definition riboswitch function depends on structural change. Methods that consider only the thermodynamic equilibrium of an RNA are therefore of limited use. Instead, one needs to employ computationally more expensive methods that consider the energy landscape and the folding dynamics on that landscape. Moreover, for the important class of kinetic riboswitches, the mechanism of riboswitch function can only be understood in the context of co-transcriptional folding. We present a computational approach to simulate the dynamic behavior of riboswitches during co-transcriptional folding in the presence and absence of a ligand. Our investigations show that the abstraction level of RNA secondary structure in combination with a dynamic folding landscape approach is expressive enough to understand how riboswitches perform their function. We apply our approach to a experimentally validated theophylline-binding riboswitch. PMID- 25726467 TI - Integrating molecular dynamics simulations with chemical probing experiments using SHAPE-FIT. AB - Integration and calibration of molecular dynamics simulations with experimental data remain a challenging endeavor. We have developed a novel method to integrate chemical probing experiments with molecular simulations of RNA molecules by using a native structure-based model. Selective 2'-hydroxyl acylation by primer extension (SHAPE) characterizes the mobility of each residue in the RNA. Our method, SHAPE-FIT, automatically optimizes the potential parameters of the force field according to measured reactivities from SHAPE. The optimized parameter set allows simulations of dynamics highly consistent with SHAPE probing experiments. Such atomistic simulations, thoroughly grounded in experiment, can open a new window on RNA structure-function relations. PMID- 25726468 TI - Using simulations and kinetic network models to reveal the dynamics and functions of riboswitches. AB - Riboswitches, RNA elements found in the untranslated region, regulate gene expression by binding to target metaboloites with exquisite specificity. Binding of metabolites to the conserved aptamer domain allosterically alters the conformation in the downstream expression platform. The fate of gene expression is determined by the changes in the downstream RNA sequence. As the metabolite dependent cotranscriptional folding and unfolding dynamics of riboswitches are the key determinant of gene expression, it is important to investigate both the thermodynamics and kinetics of riboswitches both in the presence and absence of metabolite. Single molecule force experiments that decipher the free energy landscape of riboswitches from their mechanical responses, theoretical and computational studies have recently shed light on the distinct mechanism of folding dynamics in different classes of riboswitches. Here, we first discuss the dynamics of water around riboswitch, highlighting that water dynamics can enhance the fluctuation of nucleic acid structure. To go beyond native state fluctuations, we used the Self-Organized Polymer model to predict the dynamics of add adenine riboswitch under mechanical forces. In addition to quantitatively predicting the folding landscape of add-riboswitch, our simulations also explain the difference in the dynamics between pbuE adenine- and add adenine riboswitches. In order to probe the function in vivo, we use the folding landscape to propose a system level kinetic network model to quantitatively predict how gene expression is regulated for riboswitches that are under kinetic control. PMID- 25726469 TI - Computational methods for prediction of RNA interactions with metal ions and small organic ligands. AB - In the recent years, it has become clear that a wide range of regulatory functions in bacteria are performed by riboswitches--regions of mRNA that change their structure upon external stimuli. Riboswitches are therefore attractive targets for drug design, molecular engineering, and fundamental research on regulatory circuitry of living cells. Several mechanisms are known for riboswitches controlling gene expression, but most of them perform their roles by ligand binding. As with other macromolecules, knowledge of the 3D structure of riboswitches is crucial for the understanding of their function. The development of experimental methods allowed for investigation of RNA structure and its complexes with ligands (which are either riboswitches' substrates or inhibitors) and metal cations (which stabilize the structure and are also known to be riboswitches' inhibitors). The experimental probing of different states of riboswitches is however time consuming, costly, and difficult to resolve without theoretical support. The natural consequence is the use of computational methods at least for initial research, such as the prediction of putative binding sites of ligands or metal ions. Here, we present a review on such methods, with a special focus on knowledge-based methods developed in our laboratory: LigandRNA- a scoring function for the prediction of RNA-small molecule interactions and MetalionRNA--a predictor of metal ions-binding sites in RNA structures. Both programs are available free of charge as a Web servers, LigandRNA at http://ligandrna.genesilico.pl and MetalionRNA at http://metalionrna.genesilico.pl/. PMID- 25726470 TI - Computational prediction of riboswitches. AB - Riboswitches present a ubiquitous genetic regulatory mechanism for prokaryotes and have been found in HIV1, fungi, plants, and even H. sapiens. We present an overview of approaches to predict riboswitch aptamers and, more generally, RNA conformational switches. PMID- 25726471 TI - Computational and experimental studies of reassociating RNA/DNA hybrids containing split functionalities. AB - Recently, we developed a novel technique based on RNA/DNA hybrid reassociation that allows conditional activation of different split functionalities inside diseased cells and in vivo. We further expanded this idea to permit simultaneous activation of multiple different functions in a fully controllable fashion. In this chapter, we discuss some novel computational approaches and experimental techniques aimed at the characterization, design, and production of reassociating RNA/DNA hybrids containing split functionalities. We also briefly describe several experimental techniques that can be used to test these hybrids in vitro and in vivo. PMID- 25726473 TI - Preface. PMID- 25726474 TI - Aspects of competition in word production: reply to Mahon and Navarrete. PMID- 25726475 TI - Parameterization of electron beam output factor. AB - Electron beam dose distribution is dependent on the beam energy and complicated trajectory of particles. Recent treatment planning systems using Monte Carlo calculation algorithm provide accurate dose calculation. However, double check of monitor units (MUs) based on an independent algorithm is still required. In this study, we have demonstrated single equation that reproduces the measured relative output factor (ROF) that can be used for MU calculation for electron radiotherapy. Electron beams generated by an iX (Varian Medical Systems) and a PRIMUS (Siemens) accelerator were investigated. For various energies of electron beams, the ROF at respective dmax were measured using diode detector in a water phantom at SSD of 100 cm. Curve fitting was performed with an exponential generalized equation ROF = alpha(beta - e(-gammaR)) including three variables (alpha, beta, gamma) as a function of field radius and electron energy. The correlation coefficients between the ROF measured and that calculated by the equation were greater than 0.998. For ROF of Varian electron beams, the average values of all fitting formulas were applied for two of the constants; alpha and beta. The parameter gamma showed good agreement with the quadratic approximation as a function of mean energy at surface (E0). The differences between measured and calculated ROF values were within +/- 3% for beams with cutout radius of >= 1.5 cm for electron beams with energies from 6 MeV to 15 MeV. The proposed formula will be helpful for double-check of MUs, as it requires minimal efforts for MU calculation. PMID- 25726472 TI - Multiscale methods for computational RNA enzymology. AB - RNA catalysis is of fundamental importance to biology and yet remains ill understood due to its complex nature. The multidimensional "problem space" of RNA catalysis includes both local and global conformational rearrangements, changes in the ion atmosphere around nucleic acids and metal ion binding, dependence on potentially correlated protonation states of key residues, and bond breaking/forming in the chemical steps of the reaction. The goal of this chapter is to summarize and apply multiscale modeling methods in an effort to target the different parts of the RNA catalysis problem space while also addressing the limitations and pitfalls of these methods. Classical molecular dynamics simulations, reference interaction site model calculations, constant pH molecular dynamics (CpHMD) simulations, Hamiltonian replica exchange molecular dynamics, and quantum mechanical/molecular mechanical simulations will be discussed in the context of the study of RNA backbone cleavage transesterification. This reaction is catalyzed by both RNA and protein enzymes, and here we examine the different mechanistic strategies taken by the hepatitis delta virus ribozyme and RNase A. PMID- 25726476 TI - Bone calcium/phosphorus ratio determination using dual energy X-ray method. AB - Non-invasive dual energy methods have been used extensively on osteoporosis diagnosis estimating parameters, such as, Bone Mineral Density (BMD) and Bone Mineral Content (BMC). In this study, an X-ray dual energy method (XRDE) was developed for the estimation of the bone Calcium-to-Phosphorous (Ca/P) mass ratio, as a bone quality index. The optimized irradiation parameters were assessed by performing analytical model simulations. X-ray tube output, filter material and thickness were used as input parameters. A single exposure technique, combined with K-edge filtering, was applied. The optimal X-ray spectra were selected according to the resulted precision and accuracy values. Experimental evaluation was performed on an XRDE system incorporating a Cadmium Telluride (CdTe) photon counting detector and three bone phantoms with different nominal mass Ca/P ratios. Additionally, the phantoms' mass Ca/P ratios were validated with energy-dispersive X-ray spectroscopy (EDX). Simulation results showed that the optimum filter atomic number (Z) ranges between 57 and 70. The optimum spectrum was obtained at 100 kVp, filtered with Cerium (Ce), with a surface density of 0.88 g/cm(2). All Ca/P ratio measurements were found to be accurate to within 1.6% of the nominal values, while the precision ranged between 0.91 and 1.37%. The accuracy and precision values of the proposed non-invasive method contributes to the assessment of the bone quality state through the mass Ca/P ratio determination. PMID- 25726477 TI - In vivo quantification of renal function in mice using clinical gamma cameras. AB - INTRODUCTION: In preclinical research, the growing number of transgenic models has led to the need for renal-function studies in mice. Many efforts have been made to develop dedicated SPECT systems for rodents, but their availability is limited due to high capital costs. The aim of this work is to demonstrate the feasibility of mouse renal imaging by using an inexpensive alternative based on clinical gamma-cameras. METHODS: A healthy mouse was scanned 3 h after injection of 6 mCi of Dimercaptosuccinic acid (DMSA) labeled with 99mTc by using a single head gamma-camera in conjunction with a dedicated pinhole collimator. List-mode data were binned to emulate multiple injections of 1 mCi, 0.1 mCi and 0.01 mCi of 99mTc-DMSA and 6-min ventral and dorsal planar images were acquired and SPECT imaging (60 projection images acquired over 60 min) was performed. An optimization of the protocols in terms of injected activity, time scan, renal cortex uniformity and cortex-to-pelvis contrast was carried out. RESULTS: The appropriate protocols were an injected activity of 0.6 mCi, combined with duration of scanning of 1 min for planar and 60 min for SPECT imaging. Our results were validated through the relative quantification of renal function, which showed that both kidneys contributed equally to the total function. They showed that functional structures of the mouse kidneys can be visually distinguished as easily as in human studies. CONCLUSIONS: Our findings showed the feasibility of conducting quantitative DMSA SPECT studies of anesthetized mice on clinical gamma cameras. PMID- 25726478 TI - Time series prediction of lung cancer patients' breathing pattern based on nonlinear dynamics. AB - This study focuses on predicting breathing pattern, which is crucial to deal with system latency in the treatments of moving lung tumors. Predicting respiratory motion in real-time is challenging, due to the inherent chaotic nature of breathing patterns, i.e. sensitive dependence on initial conditions. In this work, nonlinear prediction methods are used to predict the short-term evolution of the respiratory system for 62 patients, whose breathing time series was acquired using respiratory position management (RPM) system. Single step and N point multi step prediction are performed for sampling rates of 5 Hz and 10 Hz. We compare the employed non-linear prediction methods with respect to prediction accuracy to Adaptive Infinite Impulse Response (IIR) prediction filters. A Local Average Model (LAM) and local linear models (LLMs) combined with a set of linear regularization techniques to solve ill-posed regression problems are implemented. For all sampling frequencies both single step and N-point multi step prediction results obtained using LAM and LLM with regularization methods perform better than IIR prediction filters for the selected sample patients. Moreover, since the simple LAM model performs as well as the more complicated LLM models in our patient sample, its use for non-linear prediction is recommended. PMID- 25726479 TI - Posterior tibial tendoscopy. AB - The posterior tibial tendon (PTT) helps the triceps surae to work more efficiently during ambulation. Disorders of the PTT include tenosynovitis, acute rupture, degenerative tears, dislocation, instability, enthesopathies, and chronic tendinopathy with dysfunction and flat foot deformity. Open surgery of the PTT has been the conventional approach to deal with these disorders. However, tendoscopy has become a useful technique to diagnose and treat PTT disorders. This article focuses on PTT tendoscopy and tries to provide an understanding of the pathomechanics of the tendon, indications for surgery, surgical technique, advantages, complications, and limitations of this procedure. PMID- 25726480 TI - Peroneal tendoscopy. AB - Peroneal tendoscopy is indicated for peroneal tenosynovitis, subluxation or dislocation, snapping, partial tears requiring debridement, and postoperative adhesions and scarring. Peroneal tendoscopy was also found to be valuable as a diagnostic tool in some instances. It is generally reported to have good to excellent outcomes in most patients with a relatively low occurrence of complications. PMID- 25726481 TI - Achilles tendoscopy. AB - Endoscopic surgery provides a minimally invasive approach to visualize and treat several pathologic conditions of the Achilles tendon. Open surgery on the Achilles tendon is notorious for wound complications, whereas endoscopic procedures have been recognized for less scaring, less perioperative pain, fewer wound complications, and faster recovery. This article reviews various endoscopic techniques for the treatment of equinus contracture, Achilles rupture, Haglund's deformity, and noninsertional Achilles tendinopathy. PMID- 25726482 TI - Anterior ankle arthroscopy: indications, pitfalls, and complications. AB - Anterior ankle arthroscopy is a useful, minimally invasive technique for diagnosing and treating ankle conditions. Arthroscopic treatment offers the benefit of decreased surgical morbidity, less postoperative pain, and earlier return to activities. Indications for anterior ankle arthroscopy continue to expand, including ankle instability, impingement, management of osteochondritis dissecans, synovectomy, and loose body removal. Anterior ankle arthroscopy has its own set of inherent risks and complications. Surgeons can decrease the risk of complications through mastery of ankle anatomy and biomechanics, and by careful preoperative planning and meticulous surgical technique. PMID- 25726483 TI - Ankle instability and arthroscopic lateral ligament repair. AB - Over the last 50 years, the surgical management of chronic lateral ankle ligament insufficiency has focused on 2 main categories: local soft-tissue reconstruction and tendon grafts/transfer procedures. There is an increasing interest in the arthroscopic solutions for chronic instability of the ankle. Recent biomechanical studies suggest the at least one of the arthroscopic techniques can provide equivalent results to current open local soft-tissue reconstruction (such as the modified Brostrom technique). Arthroscopic lateral ankle ligament reconstruction is becoming an increasingly acceptable method for the surgical management of chronic lateral ankle instability. PMID- 25726484 TI - Arthroscopic ankle arthrodesis. AB - Arthroscopic ankle arthrodesis is a good option for the treatment of end-stage ankle arthritis. The surgical technique involving the use of a standard 4.5-mm arthroscope is described. Standard anteromedial and anterolateral portals are used. Joint surfaces except the lateral gutter are prepared to point bleeding with motorized burr, abraider, and curettes. Rigid fixation is achieved with cannulated screws. The postoperative regime includes 12 weeks protection, staged from non-weight bearing through partial to full weight bearing. Advantages compared with the open procedure include shorter hospital stay and shorter time to union with similar or better union rates. PMID- 25726485 TI - Endoscopic coalition resection. AB - Excision of symptomatic tarsal coalitions, after failure of attempted conservative treatment, is a widely accepted surgical procedure, when the surrounding joints are not degenerated. Historically, the literature has supported open resection. Recently, arthroscopic/endoscopic resection has been described for both calcaneonavicular (CNC) and talocalcaneal (TCC) coalitions. This article describes indications, preoperative planning, surgical techniques, and results of arthroscopic/endoscopic CNC and TCC resection. PMID- 25726486 TI - Subtalar arthroscopy: indications, technique and results. AB - The emergence of subtalar arthroscopy has improved the understanding and accuracy of diagnosing several hindfoot pathologic conditions, in particular, sinus tarsi syndrome. Subtalar arthroscopy has evolved into a useful diagnostic and therapeutic tool. The surgeon's experience is still essential to achieve good results. This article reviews the clinical indications, surgical techniques, and outcomes of subtalar arthroscopy. PMID- 25726487 TI - Hallux metatarsophalangeal arthroscopy: indications and techniques. AB - With mounting attention focused on decreasing postsurgical pain and dysfunction, emphasis has been placed on approaching disorders using minimally invasive techniques. Surgical procedures of the hallux, such as hallux valgus correction, have earned the reputation for high postsurgical pain and prolonged recovery. Arthroscopic hallux procedures have the advantages of minimizing pain, swelling, and disability. Certain conditions, such as synovitis, loose bodies, and early grade hallux rigidus, are better addressed arthroscopically. With the correct indications, hallux metatarsophalangeal arthroscopy can be a valuable tool for the foot and ankle surgeon. PMID- 25726488 TI - Small joint arthroscopy in foot and ankle. AB - The clinical application of small joint arthroscopies (metatarsophalangeal joint, Lisfranc joint, Chopart joint, and interphlangeal joint) in the foot has seen significant advancements in the past decades. This article reviews the clinical indications, technical details, outcomes, and potential complications of small joint arthroscopies of the foot. PMID- 25726489 TI - Hindfoot endoscopy for posterior ankle impingement syndrome and flexor hallucis longus tendon disorders. AB - Hindfoot endoscopic surgery is an alternative to conventional open surgery for treatment of posterior ankle pain. This procedure can be applied not only for accurate diagnosis under direct visualization but also for low-invasive therapy. Common indications for hindfoot endoscopy are posterior ankle impingement syndrome and damaged soft tissue. Several studies have reported good clinical outcomes of hindfoot endoscopy with lower complication rates than in the conventional open procedure. Nerve injury remains a common complication. To avoid such injury, make a posterolateral portal just lateral to the Achilles tendon and perform the hindfoot endoscopic procedure in the region lateral to the flexor hallucis longus tendon. PMID- 25726490 TI - Endoscopic calcaneoplasty. AB - Opinions differ regarding the surgical treatment of posterior calcaneal exostosis. After failure of conservative treatment, open surgical bursectomy and resection of the calcaneal prominence is indicated by many investigators. Clinical studies have shown high rates of unsatisfactory results and complications. Endoscopic calcaneoplasty (ECP) is a minimally invasive surgical option that can avoid some of these obstacles. ECP is an effective procedure for the treatment of patients with posterior calcaneal exostosis. The endoscopic exposure is superior to the open technique and has less morbidity, less operating time, fewer complications, and the disorders can be better differentiated. PMID- 25726491 TI - Current techniques and future direction. PMID- 25726492 TI - Soft tissue tumor pathology: New diagnostic immunohistochemical markers. AB - Recent insights into the pathogenesis of various soft tissue tumors, along with the identification of recurrent molecular alterations characteristic of specific tumor types, have resulted in the development of many diagnostically useful immunohistochemical markers. In some cases, expression of these markers is significantly associated with distinctive clinical and histologic features, which may impart prognostic or predictive information. This review outlines new diagnostic immunohistochemical markers in soft tissue tumor pathology, emphasizing their utility in clinical practice and potential pitfalls, molecular correlates and clinical associations. PMID- 25726493 TI - [Facial edema caused by multifocal myiasis of Cordylobia rodhaini in Yaounde - Cameroon]. PMID- 25726494 TI - [A rare giant abdomino-pelvic tumor]. PMID- 25726495 TI - Prevalence and structure of multiple chronic conditions in Lithuanian population and the distribution of the associated healthcare resources. AB - BACKGROUND: Chronic multiple conditions have become a major threat to the world's healthcare systems within the last years. OBJECTIVE: To estimate the prevalence and structure of chronic conditions in Lithuania and to analyse the utilisation of healthcare resources striving to manage patients with multimorbidity. METHODS: It was based on the National Health Insurance Fund (NHIF) database, that covered the period from January, 2012 to June, 2014 and included 452,769 subjects. The prevalence of multimorbidity in Lithuania, the structure of chronic diseases within the age and gender groups as well as the association between multimorbidity and facilities usage were analysed. RESULTS: The prevalence of chronic diseases in adult Lithuanian population was 17.2%, where 94.6% (N=428 430) of the chronically diseased subjects had >1 chronic condition. The number of chronic conditions increased with the age, especially at the age of 45-54 years, and male gender (p<0.001). 10% of patients had at least 2 chronic diseases at the age of 45 and over. Multimorbidity accounted for 258,761 additional bed days per year nationally and 61% increase in the 30-day readmission rate. Primary care and outpatient visits per 1000 population were 2.1 times more prevalent and home visits were 9.6 times more frequent in multimorbid patients compared to a single chronic disease. CONCLUSIONS: Multimorbidity and its increasing prevalence among the younger patients will put additional strain on healthcare resources at an earlier stage by increasing admission, readmission rates and vastly increasing primary care contacts. PMID- 25726496 TI - Decreased glial cell line-derived neurotrophic factor levels in patients with depression: a meta-analytic study. AB - Glial cell-line derived neurotrophic factor (GDNF) has been shown to promote development, differentiation, and protection of CNS neurons and was thought to play an important role in various neuropsychiatric disorders. Several studies have examined the GDNF levels in patients with depression but shown inconsistent results. In this study, we compared blood GDNF levels between depressive patients and control subjects through meta-analytic method. The effect sizes (ESs) from all eligible studies were synthesized by using a random effect model. In this meta-analysis, we included 526 patients and 502 control subjects from 12 original articles. Compared to control subjects, blood GDNF levels are significantly decreased in patients with depression (ES = -0.62, p = 0.0011). However, significant heterogeneity was found among included studies. Through subgroup analysis, we found that GDNF was still decreased in studies with major depressive disorder (ES = -0.73, p = 0.0001); in studies with non-old-age depression (ES = 1.25, p = 0.0001), but not with old-age depression; and in studies using serum samples (ES = -0.86, p < 0.0001), but not in studies using plasma sample. Meta regression did not show moderating effects of mean age of subjects, gender distribution, and age of onset of depression. Our findings support blood GDNF levels as a biomarker of depression as a whole, but the results were modulated by psychiatric diagnosis, age of included subjects, and sampling sources. With these results, future studies are required to examine whether effective antidepressant treatment is associated with an increase in serum GDNF levels. PMID- 25726497 TI - A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. AB - BACKGROUND: Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published. METHODS: Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery-Asberg Depression Rating Scale from baseline. RESULTS: There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Asberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively. CONCLUSION: The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed. PMID- 25726498 TI - Prostate-specific antigen kinetic profiles during androgen deprivation therapy as prognostic factors in castration-resistant prostate cancer. AB - OBJECTIVE: To identify pretreatment prognostic factors for patients with castration-resistant prostate cancer (CRPC) undergoing docetaxel (DCT) chemotherapy. MATERIALS AND METHODS: We retrospectively analyzed 102 patients with CRPC who underwent DCT chemotherapy (dosage: 60-75 mg/m(2)) from December 2001 to August 2013. The parameters evaluated as prognostic factors were as follows: age, body mass index, Gleason score, clinical TNM stage, prior radical prostatectomy, prior radiation therapy, performance status, presence of pain, laboratory results at the start of DCT, and prostate-specific antigen (PSA) kinetics during prior androgen deprivation therapy (ADT), including PSA level at the start of ADT (PSA-ADT), PSA half-time (PSAT1/2), time to nadir, PSA level at nadir (PSA-Nadir), duration of nadir, PSA doubling time (PSADT), and PSA level at the start of DCT (PSA-DCT). Univariate and multivariate analyses were performed to identify independent prognostic factors. RESULTS: Median cancer-specific survival (CSS) duration following CRPC diagnosis was 28.0 months. In univariate analyses, performance status, serum albumin, serum creatinine, PSAT1/2, time to nadir, PSA-Nadir, duration of nadir, PSADT, and PSA-DCT showed a potential association with prognosis (P<0.001-0.077). Multivariate analyses of these parameters showed that performance status (hazard ratio [HR] = 0.046; P = 0.046), serum creatinine (HR = 3.028; P = 0.036), PSAT1/2 (HR = 0.172; P = 0.007), PSA Nadir (HR = 4.884; P = 0.033), PSADT (HR = 0.148; P<0.001), and PSA-DCT (HR = 5.222; P = 0.004) remained independent predictors of CSS in CRPC. CONCLUSIONS: PSA kinetic parameters measured during prior ADT are significant surrogate markers predicting CSS in patients undergoing DCT chemotherapy for CRPC. PMID- 25726499 TI - All-trans retinoic acid-induced, life-threatening complete atrioventricular block. AB - We report a case of complete atrioventricular block (CAVB) with ventricular asystole and recurrent AVBs due to all-trans retinoic acid (ATRA). A 57-year-old man with acute promyelocytic leukemia was undergoing induction therapy with ATRA and developed episodic seizures with altered consciousness on the 14(th) day and then CAVB followed by cardiac arrest on the 15(th) day. Although he initially recovered after resuscitation, he suffered from recurrent CAVB, which persisted for 3 days despite immediate ATRA discontinuation. He then received ATRA retreatment with reduction of dosage, but a high-degree AVB recurred on the 5(th) day. After discontinuation of ATRA therapy, the patient recovered 3 days later without any cardiovascular event during follow-up. The serial electrocardiogram changes suggested an infra-Hisian block with possible ATRA dose-response relationship. To our knowledge, this is the first established case of ATRA induced CAVB in the literature. We suggest clinical alertness for this life threatening complication. PMID- 25726500 TI - Ontogenetic changes in the expression of estrogen receptor beta in mouse duodenal epithelium. AB - Estrogen is considered to be involved in duodenal function; however, the details of its receptor expression are largely unknown. The purpose of this study was to determine the expression and localization of estrogen receptors (ERs) in mouse duodenum. Male and female C57BL/6J mouse intestinal tissues were used to investigate the expression of ERalpha and ERbeta by RT-PCR, western blotting, immunohistochemistry, and Southwestern histochemistry. ERbeta, but not ERalpha, was expressed in proximal duodenal epithelium, but not in jejunum and ileum. The expression of ERbeta mRNA and protein were confirmed by RT-PCR and western blotting, respectively. At postnatal day 20, the transit period of suckling to weaning, the distribution of ERbeta-positive cells was changed in the crypt villus axis, and cytoplasm/nuclear staining changed to only nuclear staining. Moreover, Southwestern histochemistry was used to detect estrogen response element (ERE)-binding proteins, and their expression pattern was highly similar to that of ERbeta. These results suggested that ERbeta is the predominant ER type in mouse small intestine, and the highly similar co-localization of ERE-binding proteins reveals that ERbeta is functionally active in mouse duodenum. The ERbeta expression changes during postnatal development indicate that ERbeta may be involved in the differentiation of duodenal epithelium. PMID- 25726501 TI - Hypoxia preconditioning induced HIF-1alpha promotes glucose metabolism and protects mitochondria in liver I/R injury. AB - BACKGROUND: Ischemia and reperfusion (I/R) injury is one of the main lesions after liver transplantation. This study aims to detect hypoxia-induced HIF-1alpha protects transplanted liver against I/R injury by promoting glucose metabolism to decrease mitochondrial injury and apoptosis on rat model. METHODS: The rats were given a treatment of 90 min non-lethal hypoxic preconditioning to induce and increase the HIF-1alpha expression. The autologous orthotopic liver transplantation model was used to imitate liver I/R injury. RESULTS: Hypoxic induced HIF-1alpha was detected to increase in liver tissue after 90-minute hypoxic environment (HP vs. Ctrl, *P<0.001). After operation, the expression of HIF-1alpha in liver tissue was also stayed at a high level. At 24h after operation, several genes were promoted, such as the levels of HK-2 (HP vs. AT, 24h, *P=0.004), Lactate dehydrogenase (LDHA) (HP vs. AT, 24h, *P=0.003), pyruvate dehydrogenase kinase (PDK-1) (HP vs. AT, 24h, *P=0.007), even the NF-kappaB and Erk pathways. From the TUNEL assay, the apoptosis in hypoxic preconditioning liver tissue was decreased compared with non-HP operative group at 12h after operation. The expressions of cleaved-caspase 3 (HP vs. AT, *P=0.0119) and PARP (HP vs. AT, *P=0.0134) in HP group were also significantly lower than AT group. CONCLUSION: The hypoxia-induced HIF-1alpha could promote glucose metabolism to protect hepatocellular mitochondria from damage. It could be a useful way to protect liver against I/R injuries and inflammatory injury, and particularly promote the recovery of graft function. PMID- 25726502 TI - Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. AB - BACKGROUND: In most countries, alteplase given within 4.5 h of onset is the only approved medical treatment for acute ischaemic stroke. The newer thrombolytic drug tenecteplase has been investigated in one randomised trial up to 3 h after stroke and in another trial up to 6 h after stroke in patients selected by advanced neuroimaging. In the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST), we aimed to assess the efficacy and safety of tenecteplase versus alteplase within 4.5 h of stroke onset in a population not selected on the basis of advanced neuroimaging, and to use imaging biomarkers to inform the design of a definitive phase 3 clinical trial. METHODS: In this single-centre, phase 2, prospective, randomised, open-label, blinded end-point evaluation study, adults with supratentorial ischaemic stroke eligible for intravenous thrombolysis within 4.5 h of onset were recruited from The Institute of Neurological Sciences, Glasgow, Scotland. Patients were randomly assigned (1:1) to receive tenecteplase 0.25 mg/kg (maximum 25 mg) or alteplase 0.9 mg/kg (maximum 90 mg). Treatment allocation used a mixed randomisation and minimisation algorithm including age and National Institutes of Health Stroke Scale score, generated by an independent statistician. Patients were not informed of treatment allocation; treating clinicians were aware of allocation but those assessing the primary outcome were not. Imaging comprised baseline CT, CT perfusion, and CT angiography; and CT plus CT angiography at 24-48 h. The primary endpoint was percentage of penumbra salvaged (CT perfusion-defined penumbra volume at baseline minus CT infarct volume at 24-48 h). Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT01472926. FINDINGS: Between Jan 1, 2012, and Sept 7, 2013, 355 patients were screened, of whom 157 were eligible for intravenous thrombolysis, and 104 patients were enrolled. 52 were assigned to the alteplase group and 52 to tenecteplase. Of 71 patients (35 assigned tenecteplase and 36 assigned alteplase) contributing to the primary endpoint, no significant differences were noted for percentage of penumbral salvaged (68% [SD 28] for the tenecteplase group vs 68% [23] for the alteplase group; mean difference 1.3% [95% CI -9.6 to 12.1]; p=0.81). Neither incidence of symptomatic intracerebral haemorrhage (by SITS-MOST definition, 1/52 [2%] tenecteplase vs 2/51 [4%] alteplase, p=0.55; by ECASS II definition, 3/52 [6%] vs 4/51 [8%], p=0.59) nor total intracerebral haemorrhage events (8/52 [15%] vs 14/51 [29%], p=0.091) differed significantly. The incidence of serious adverse events did not differ between groups (32 in the tenecteplase group, three considered probably or definitely related to drug treatment; 16 in the alteplase group, five were considered drug-related). INTERPRETATION: Neurological and radiological outcomes did not differ between the tenecteplase and alteplase groups. Evaluation of tenecteplase in larger trials of patients with acute stroke seems warranted. FUNDING: The Stroke Association. PMID- 25726503 TI - Breaking up is hard to do: tenecteplase in acute stroke. PMID- 25726504 TI - Long-term outcomes after monocular corneal inlay implantation for the surgical compensation of presbyopia. AB - PURPOSE: To evaluate long-term outcomes of small-aperture corneal inlay implantation for the surgical compensation of presbyopia. SETTING: Paracelsus Medical University, Salzburg, Austria. DESIGN: Prospective interventional cohort study. METHODS: Monocular implantation of a Kamra small-aperture inlay (model ACI7000) (1.6 mm central aperture) was performed in emmetropic presbyopic eyes. The preoperative and postoperative parameters included monocular and binocular uncorrected (UDVA) and corrected (CDVA) distance visual acuities, uncorrected intermediate visual acuity (UIVA), and uncorrected (UNVA) and corrected (CNVA) near visual acuities; refraction; patient satisfaction; and complications. RESULTS: From September 4, 2006, to May 21, 2007, a small-aperture inlay (1.6 mm central aperture) was implanted in 32 emmetropic presbyopic eyes. The mean binocular uncorrected visual acuities improved as follows: UNVA from Jaeger (J) 6 +/- 1.2 lines (~20/50) to J2 +/- 1.8 lines (~20/25) (P < .001) and UIVA from 0.2 logMAR +/- 1.3 lines (~20/32) to 0.1 logMAR +/- 1.3 lines (~20/25) (P = .04). The UDVA decreased from -0.2 logMAR +/- 0.2 lines (~20/12.5) to -0.1 logMAR +/- 0.6 lines (~20/16) (P < .001). At 60 months, 74.2% of patients had a UNVA of J3 (~20/32) or better, 87.1% had a UIVA of 0.2 logMAR (~20/32) or better, and 93.5% had a UDVA of 0.0 logMAR (~20/20) or better. One inlay was removed after 36 months because of patient dissatisfaction with vision after a hyperopic shift in the surgical eye, with no loss of CDVA or CNVA 2 years after removal. CONCLUSION: Long-term results of monocular corneal inlay implantation indicate increased UNVA and UIVA and slightly compromised UDVA in emmetropic presbyopic eyes. FINANCIAL DISCLOSURE: Dr. Grabner was reimbursed for travel expenses from Acufocus. Dr. Riha is a consultant to Acufocus. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25726505 TI - Clinical Outcomes of Metastatic Poor Prognosis Germ Cell Tumors: Current Perspective From a Referral Center. AB - BACKGROUND: Survival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. PATIENTS AND METHODS: A retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. RESULTS: Between 1982 and 2013, 168 patients were identified. The median age was 27 years (interquartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; chi(2)P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). CONCLUSION: In this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality. PMID- 25726506 TI - Influencing weight bias: The impact of biased questionnaire anchors on stereotype beliefs and judgments. AB - OBJECTIVES: In this investigation, biased questionnaire response anchors were designed to indirectly manipulate respondents' estimates of their peers' stereotypic beliefs or the estimates of scientific research findings about individuals with obesity. The current study tested the hypothesis that biased response anchors could influence personal beliefs about obesity. METHODS: Two hundred adults participated in the study. A simple manipulation of questionnaire items (i.e., asking respondents to estimate peers' beliefs or scientific research findings) using biased response scale anchors was designed to subtly relay information about certain personality traits of individuals with obesity. RESULTS: The anchor manipulation significantly influenced participants' immediate and follow-up weight biased beliefs as well as participants' evaluation of an obese job applicant's potential for employment. CONCLUSION: Social judgments about obese individuals may be susceptible to subtle manipulation of response anchors and may be impacted by the source of comparison information (e.g., peers; scientific research). PMID- 25726507 TI - Luis Sanchez Granjel (1920-2014) and his contribution to the history of Spanish urology. PMID- 25726508 TI - Cardiovascular mortality in patients with prostate cancer exposed to androgen deprivation therapy. AB - INTRODUCTION: A relationship between the administration of GnRH agonists and the risk of acute myocardial infarction (AMC) in patients with prostate cancer has been showed in the third observational study published in April 2014. The association AMC-orchiectomy was not found in any of these studies. OBJECTIVE: Define risk factors for cardiovascular disease in patients treated with GnRH agonist. Their probable underlying pathogenic mechanism in the myocardium and peripheral vascular tree was also analyzed. EVIDENCE ACQUISITION: English articles cited in PubMed were reviewed. No time period is specified. The last search date was 11/30/14. EVIDENCE SYNTHESIS: In patients with coronary history of AMC or congestive heart failure, hormonal neoadjuvant therapy increased cardiovascular mortality rates (HR: 1.96, IC 95%: 1.04-3.71; P=.04) as well as cardiovascular-specific mortality rates (AHR: 3.28; IC 95%: 1.01-10.64; P=.048). Two possible mechanisms can be involved: a) direct mechanism through myocardial receptor for GnRH/PKA along with atherogenic plaques; and b) indirect mechanism related with metabolic disturbances. CONCLUSIONS: Patients with AMC or congestive heart failure history could present a higher risk of death related to the use of GnRH agonists. In these cases, should carefully consider appropriateness of such treatment. These effects can explained by a direct mechanism on myocardium and peripheral vascular tree and indirect ones related with modified metabolic syndrome. PMID- 25726509 TI - Disparities in Overall Survival for Male Breast Cancer Patients in the State of Florida (1996-2007). AB - BACKGROUND: Little is known regarding population-based disparities in male breast cancer (MBC). We analyzed this for Florida using data from 1996 to 2007. MATERIALS AND METHODS: Data from the Florida Cancer Data System, the Agency for Health Care Administration, and the US Census were linked for MBC patients (n = 1589). Survival time was our primary end point, with adjustments for sociodemographic status, neighborhood-based poverty measures, clinical and hospital characteristics, and comorbidity measures based on linkage with in- and outpatient treatment records. Survival time was modeled using univariate and multivariate Cox regression models. RESULTS: Five-year overall survival was 65.7%. Overall mean survival time in years was 7.7, but shorter in black (5.9) than white (7.8) individuals, in non-Hispanic (7.7) than Hispanic (8.5) individuals, and in the lowest socioeconomic status (SES) group (5.9) than in the highest (8.2) SES group. Patients with low SES also presented at a more advanced stage with only 75/175 [42.9%] of low SES patients who presented with localized disease compared with 311/621 [50.1%] for middle-high SES and 162/334 [48.5%] for the highest SES. Univariate hazard regressions found only the highest (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.46-0.85) and middle-high (HR, 0.71; 95% CI, 0.54-0.94) SES were at improved survival compared with lowest SES but this advantage did not remain significant in the fully adjusted model. Marital status, age, smoking status, stage, treatments, and comorbidities were also predictors of survival. CONCLUSION: Survival disparities among SES groups were most apparent in our study. Improved access to screening and health care utilization might attenuate these differences. Understanding other survival disparities can aid in public health and clinical care choices. PMID- 25726510 TI - Objective analysis of contact lens fit. AB - PURPOSE: To assess the validity and repeatability of objective compared to subjective contact lens fit analysis. METHODS: Thirty-five subjects (aged 22.0+/ 3.0 years) wore two different soft contact lens designs. Four lens fit variables: centration, horizontal lag, post-blink movement in up-gaze and push-up recovery speed were assessed subjectively (four observers) and objectively from slit-lamp biomicroscopy captured images and video. The analysis was repeated a week later. RESULTS: The average of the four experienced observers was compared to objective measures, but centration, movement on blink, lag and push-up recovery speed all varied significantly between them (p<0.001). Horizontal lens centration was on average close to central as assessed both objectively and subjectively (p>0.05). The 95% confidence interval of subjective repeatability was better than objective assessment (+/-0.128 mm versus +/-0.168 mm, p=0.417), but utilised only 78% of the objective range. Vertical centration assessed objectively showed a slight inferior decentration (0.371+/-0.381 mm) with good inter- and intrasession repeatability (p>0.05). Movement-on-blink was lower estimated subjectively than measured objectively (0.269+/-0.179 mm versus 0.352+/-0.355 mm; p=0.035), but had better repeatability (+/-0.124 mm versus +/-0.314 mm 95% confidence interval) unless correcting for the smaller range (47%). Horizontal lag was lower estimated subjectively (0.562+/-0.259 mm) than measured objectively (0.708+/-0.374 mm, p<0.001), had poorer repeatability (+/-0.132 mm versus +/-0.089 mm 95% confidence interval) and had a smaller range (63%). Subjective categorisation of push-up speed of recovery showed reasonable differentiation relative to objective measurement (p<0.001). CONCLUSIONS: The objective image analysis allows an accurate, reliable and repeatable assessment of soft contact lens fit characteristics, being a useful tool for research and optimisation of lens fit in clinical practice. PMID- 25726511 TI - ACTH: The forgotten therapy. AB - Although anti-inflammatory drugs are among the most common class of marketed drugs, chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis or inflammatory bowel disease still represent unmet needs. New first-in class drugs might be discovered in the future but the repurpose and further development of old drugs also offers promise for these conditions. This is the case of the melanocortin adrenocorticotropin hormone, ACTH, used in patients since 1952 but regarded as the last therapeutic option when other medications, such as glucocorticoids, cannot be used. Better understanding on its physiological and pharmacological mechanisms of actions and new insights on melanocortin receptors biology have revived the interest on rescuing this old and effective drug. ACTH does not only induce cortisol production, as previously assumed, but it also exerts anti-inflammatory actions by targeting melanocortin receptors present on immune cells. The endogenous agonists for these receptors (ACTH, alpha-, beta-, and gamma-melanocyte stimulating hormones), are also produced locally by immune cells, indicating the existence of an endogenous anti inflammatory tissue-protective circuit involving the melanocortin system. These findings suggested that new ACTH-like melanocortin drugs devoid of steroidogenic actions, and hence side effects, could be developed. This review summarizes the actions of ACTH and melanocortin drugs, their role as endogenous pro-resolving mediators, their current clinical use and provides an overview on how recent advances on GPCR functioning may lead to a novel class of drugs. PMID- 25726512 TI - Epigenetic and transcriptional regulation of gammadelta T cell differentiation: Programming cells for responses in time and space. AB - gammadelta T cells are major providers of the pro-inflammatory cytokines interferon-gamma (IFNgamma) and interleukin-17 (IL-17) in protective or pathogenic immune responses. Notably, murine gammadelta T cells commit to either IFNgamma or IL-17 production during development in the thymus, before any subsequent activation in the periphery. Here we discuss the molecular networks that underlie thymic gammadelta T cell differentiation, as well as the mechanisms that sustain or modify their functional properties in the periphery. We concentrate on recent findings on lymphoid and tissue-resident gammadelta T cell subpopulations, with an emphasis on genome-wide studies and their added value to elucidate the regulation of gammadelta T cell differentiation at the transcriptional and epigenetic (chromatin) levels. PMID- 25726514 TI - Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown. We aimed to assess ADHD-related mortality in a large cohort of Danish individuals. METHODS: By use of the Danish national registers, we followed up 1.92 million individuals, including 32,061 with ADHD, from their first birthday through to 2013. We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, family history of psychiatric disorders, maternal and paternal age, and parental educational and employment status, by Poisson regression, to compare individuals with and without ADHD. FINDINGS: During follow-up (24.9 million person-years), 5580 cohort members died. The mortality rate per 10,000 person-years was 5.85 among individuals with ADHD compared with 2.21 in those without (corresponding to a fully adjusted MRR of 2.07, 95% CI 1.70-2.50; p<0.0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1.86 (95% CI 0.93-3.27), and it was 1.58 (1.21-2.03) for those aged 6-17 years, and 4.25 (3.05-5.78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1.50, 1.11-1.98), and was higher in girls and women (2.85, 1.56-4.71) than in boys and men (1.27, 0.89-1.76). INTERPRETATION: ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents. FUNDING: This study was supported by a grant from the Lundbeck Foundation. PMID- 25726516 TI - On the alert for outcome improvement in acute kidney injury. PMID- 25726517 TI - Attention deficit hyperactivity disorder and premature death. PMID- 25726515 TI - Automated, electronic alerts for acute kidney injury: a single-blind, parallel group, randomised controlled trial. AB - BACKGROUND: Acute kidney injury often goes unrecognised in its early stages when effective treatment options might be available. We aimed to determine whether an automated electronic alert for acute kidney injury would reduce the severity of such injury and improve clinical outcomes in patients in hospital. METHODS: In this investigator-masked, parallel-group, randomised controlled trial, patients were recruited from the hospital of the University of Pennsylvania in Philadelphia, PA, USA. Eligible participants were adults aged 18 years or older who were in hospital with stage 1 or greater acute kidney injury as defined by Kidney Disease Improving Global Outcomes creatinine-based criteria. Exclusion criteria were initial hospital creatinine 4.0 mg/dL (to convert to MUmol/L, multiply by 88.4) or greater, fewer than two creatinine values measured, inability to determine the covering provider, admission to hospice or the observation unit, previous randomisation, or end-stage renal disease. Patients were randomly assigned (1:1) via a computer-generated sequence to receive an acute kidney injury alert (a text-based alert sent to the covering provider and unit pharmacist indicating new acute kidney injury) or usual care, stratified by medical versus surgical admission and intensive care unit versus non-intensive care unit location in blocks of 4-8 participants. The primary outcome was a composite of relative maximum change in creatinine, dialysis, and death at 7 days after randomisation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01862419. FINDINGS: Between Sept 17, 2013, and April 14, 2014, 23,664 patients were screened. 1201 eligible participants were assigned to the acute kidney injury alert group and 1192 were assigned to the usual care group. Composite relative maximum change in creatinine, dialysis, and death at 7 days did not differ between the alert group and the usual care group (p=0.88), or within any of the four randomisation strata (all p>0.05). At 7 days after randomisation, median maximum relative change in creatinine concentrations was 0.0% (IQR 0.0-18.4) in the alert group and 0.6% (0.0-17.5) in the usual care group (p=0.81); 87 (7.2%) patients in the alert group and 70 (5.9%) patients in usual care group had received dialysis (odds ratio 1.25 [95% CI 0.90-1.74]; p=0.18); and 71 (5.9%) patients in the alert group and 61 (5.1%) patients in the usual care group had died (1.16 [0.81-1.68]; p=0.40). INTERPRETATION: An electronic alert system for acute kidney injury did not improve clinical outcomes among patients in hospital. FUNDING: Penn Center for Healthcare Improvement and Patient Safety. PMID- 25726518 TI - Characterization of gastrointestinal disorders in patients with parkinsonian syndromes. AB - OBJECTIVES: This study was aimed to investigate gastrointestinal (GI) dysfunction in patients with Parkinson's disease (PD) compared with those in patients with other parkinsonian disorders, and to characterize parkinsonian motor and non motor correlates for GI dysfunction. METHODS: Consecutive patients with PD, atypical parkinsonism (P-plus) and vascular parkinsonism (VP) were enrolled in this multicenter systematic survey. Data for weight loss, appetite loss, sialorrhea, dysphagia, gastroesophageal reflux disease (GERD) and constipation were simultaneously collected using symptom-specific, structured questionnaires. For the PD group, information for onset age, PD duration, anti-parkinsonian drug dosages, unified PD rating scale, and Hoehn & Yahr stage were collected at the time of the interview. RESULTS: Enrolled in the study were 329 PD, 82 P-plus, and 62 VP patients. GI symptom frequencies were similar in PD and other parkinsonian groups. Among the PD patients, constipation was the most common symptom, followed by appetite loss, weight loss, dysphagia, sialorrhea, and GERD (64.9%, 45.4%, 35.7%, 19.4%, 15.0%, and 9.6%, respectively). Dysphagia, sialorrhea, and constipation became more frequent with more advanced PD stages. Cognition, sleep and mood disturbances were significantly associated with weight loss, appetite loss, and dysphagia, whereas bradykinesia, axial and postural instability with gait disturbance were associated with dysphagia. CONCLUSIONS: GI disturbance is common in patients with non-PD parkinsonism as well as in those with PD. GI symptoms correlated with distinct parkinsonian motor and nonmotor features in PD. Further studies are warranted to reveal the pathophysiological mechanisms and prognostic features of GI disturbances in parkinsonian disorders. PMID- 25726519 TI - Does midtrimester cervical length aid in predicting vaginal birth after cesarean? AB - OBJECTIVE: A longer midtrimester cervical length (CL) is associated with an increased chance of cesarean delivery, but CL has not been used to predict the chance of successful trial of labor after cesarean delivery (TOLAC). The objective of this study was to identify whether midtrimester CL improves the prediction of vaginal birth after cesarean delivery (VBAC) among women undergoing a TOLAC. STUDY DESIGN: Women with 1 prior cesarean and a singleton gestation in the vertex position who had a routine CL assessment between 18 and 24 weeks and chose to undergo a TOLAC were identified. Midtrimester CL and characteristics identifiable in early prenatal care that have been used in a validated predictive model for VBAC (ie, age, body mass index, race/ethnicity, prior vaginal delivery, prior VBAC, and indication for prior cesarean delivery) were abstracted from the medical record. Multivariable regressions with VBAC as the dependent variable, with and without CL, were created and their predictive capacity compared using receiver-operating characteristic curves and reclassification tables. RESULTS: Of the 678 women who met inclusion criteria, 517 (76.3%) experienced a VBAC. Mean midtrimester CL was lower in women who achieved a VBAC compared with those who required a cesarean delivery in labor (4.3 +/- 0.8 cm vs 4.7 +/- 0.8 cm, P < .001). In a multivariable logistic regression, midtrimester CL (centimeters) was significantly associated with a reduced chance of VBAC (adjusted odds ratio [aOR], 0.60; 95% confidence interval [CI], 0.47-0.76). Although the addition of CL improved the area under the receiver-operating characteristic curve (aOR, 0.695 [95% CI, 0.648-0.743] vs aOR, 0.727 [95% CI, 0.681-0.773]; P = .03), it did not significantly enhance the clinical value of the model, as quantified by net reclassification improvement (P = .11). CONCLUSION: Shorter midtrimester CL is associated with a greater chance of vaginal birth after a TOLAC. However, midtrimester CL does not significantly improve the clinical value of a previously developed VBAC prediction model. PMID- 25726520 TI - Recalibrating the spirit level: An analysis of the interaction of income inequality and poverty and its effect on health. AB - The publication of The Spirit Level (Wilkinson and Pickett, 2009) marked a paramount moment in the analysis of health and inequality, quickly attracting a remarkable degree of attention, both positive and negative, both in academic and in public discourse. Following at least 20 years of research, the book proposes a simple and powerful argument: inequality per se, more specifically income inequality, is harmful to every aspect of social life. In order to confirm this idea, the authors present a series of bivariate, cross-sectional associations showing comparisons across countries and within the United States. Despite the methodological limitations of this approach, the authors advance causal claims concerning the detrimental effects of income inequality. They also rule out poverty as a plausible alternative explanation, without directly measuring it. Meanwhile, over the last decade stratification scholars have demonstrated the nonlinear effect of economic factors, especially income, on health. The results suggest that a relative approach is best for analyzing dynamics at the top of the income distribution, whereas an absolute approach seems most appropriate for studying the bottom of the distribution. Consistent with this perspective, here I reanalyze data from The Spirit Level, adding a measure of poverty, in order to control the effect of inequality and explore its interaction with poverty. The findings show that inequality and poverty-which I contend are two interdependent but nonetheless distinct phenomena-interact across countries, such that the detrimental effects of inequality are present or stronger in countries with high poverty, and absent or weaker in countries with low poverty; poverty replaces inequality as the favored explanation of health and social ills across states. The new evidence suggests that income distributions are characterized by a complex interplay between inequality and poverty, whose interaction deserves further analysis. PMID- 25726521 TI - Transferability/generalizability deserves more attention in 'retest' studies in Diagnosis and Prognosis. PMID- 25726522 TI - Relative risk reduction is useful metric to standardize effect size for public heath interventions for translational research. AB - OBJECTIVES: Heterogeneity of effect measures in intervention studies undermines the use of evidence to inform policy. Our objective was to develop a comprehensive algorithm to convert all types of effect measures to one standard metric, relative risk reduction (RRR). STUDY DESIGN AND SETTING: This work was conducted to facilitate synthesis of published intervention effects for our epidemic modeling of the health impact of human immunodeficiency virus [HIV testing and counseling (HTC)]. We designed and implemented an algorithm to transform varied effect measures to RRR, representing the proportionate reduction in undesirable outcomes. RESULTS: Our extraction of 55 HTC studies identified 473 effect measures representing unique combinations of intervention-outcome population characteristics, using five outcome metrics: pre-post proportion (70.6%), odds ratio (14.0%), mean difference (10.2%), risk ratio (4.4%), and RRR (0.9%). Outcomes were expressed as both desirable (29.5%, eg, consistent condom use) and undesirable (70.5%, eg, inconsistent condom use). Using four examples, we demonstrate our algorithm for converting varied effect measures to RRR and provide the conceptual basis for advantages of RRR over other metrics. CONCLUSION: Our review of the literature suggests that RRR, an easily understood and useful metric to convey risk reduction associated with an intervention, is underused by original and review studies. PMID- 25726523 TI - GATA1 induces epithelial-mesenchymal transition in breast cancer cells through PAK5 oncogenic signaling. AB - Epithelial-mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell-cell junctions, resulting in the acquisition of migratory and invasive properties. E-cadherin is a major component of intercellular junctions and the reduction or loss of its expression is a hallmark of EMT. Transcription factor GATA1 has a critical anti-apoptotic role in breast cancer, but its function for metastasis has not been investigated. Here, we found that GATA1, as a novel E-cadherin repressor, promotes EMT in breast cancer cells. GATA1 binds to E-cadherin promoter, down-regulates E cadherin expression, disrupts intercellular junction and promotes metastasis of breast cancer cell in vivo. Moreover, GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. Our findings provide insights into the novel function of GATA1, contributing to a better understanding of the EMT, indicating that GATA1 and its phosphorylation may play an important role in the metastasis of breast cancer. PMID- 25726524 TI - PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects. AB - The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease. PMID- 25726525 TI - IL-32theta inhibits monocytic differentiation of leukemia cells by attenuating expression of transcription factor PU.1. AB - PU.1 is a key transcription factor regulating the myeloid differentiation. PU.1 induced monocytic differentiation into macrophage is also important for blood cancer development. Therefore, we chose THP-1 monocytic leukemia cells to investigate the function of a recently discovered IL-32theta. Genetic analyses identified differences in the sequences of IL-32theta and IL-32beta. Using previously established cell lines that stably express IL-32theta and IL-32beta and cell lines transiently expressing IL-32theta, we observed that expression of IL-32theta inhibited phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation in both THP-1 and HL-60 cells. IL-32theta also suppressed expression of the macrophage cell surface markers, CD11b, CD18, and CD36. Interestingly, expression of IL-32beta or IL-32theta had no effect on the expression levels of cell cycle related factors. As a result, we concluded that these isoforms did not contribute to PMA-induced cell cycle arrest. IL-32theta was found to modulate expression of PU.1, a transcription factor necessary for myeloid lineage commitment. Transient expression of PU.1 in THP-1/IL-32theta cells rescued the observed differentiation defect. Additionally, transient expression of both CCAAT-enhancer-binding protein alpha (C/EBPalpha) and PU.1 in THP-1/IL-32theta cells exhibited synergistic effects in rescuing the differentiation defect. These observations indicate that intracellular IL-32theta inhibits the differentiation of monocytes into macrophages by attenuating PU.1 expression. PMID- 25726526 TI - Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas. AB - Nuclear-encoded cytochrome c oxidase subunit 4 (COX4) is a key regulatory subunit of mammalian cytochrome c oxidase, and recent studies have demonstrated that COX4 isoform 1 (COX4-1) could have a role in glioma chemoresistance. The Polycomb complex protein BMI1 is a stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including glioma. This study sought to determine if COX4 regulates BMI1 and modulates tumor cell proliferation. Using The Cancer Genome Atlas database and a retrospective data set from patients with glioblastoma multiforme, we found that BMI1 expression levels positively correlated with COX4-1 expression and overall survival. Whereas COX4-1 promoted cell growth by increasing BMI1 expression, COX4-2 inhibited cell growth even in cells overexpressing BMI1. We also demonstrate that COX4-1 attenuates mitochondrial reactive oxygen species (ROS) production, which is required for COX4-1-mediated effects on BMI1 expression and cell proliferation. Notably, mice bearing COX4-1-expressing glioma cell xenografts quickly developed invasive tumors characterized by the presence of multiple lesions positive for Ki-67, BMI1, and COX4-1, whereas mice bearing COX4-2-expressing xenografts rarely developed tumors by this point. COX4-1 also promoted the self-renewal of glioma stem-like cells, consistent with the reported role of BMI1 in stem cell growth. Taken together, these findings identify a novel COX4-1-mitochondrial ROS axis, in which differential expression of COX4 isoforms regulates mitochondrial ROS production and controls BMI1 expression. PMID- 25726527 TI - HIF-2alpha mediates hypoxia-induced LIF expression in human colorectal cancer cells. AB - Leukemia inhibitory factor (LIF), a multi-functional cytokine, has a complex role in cancer. While LIF induces the differentiation of several myeloid leukemia cells and inhibits their growth, it also promotes tumor progression, metastasis and chemoresistance in many solid tumors. LIF is frequently overexpressed in a variety of human tumors and its overexpression is often associated with poor prognosis of patients. Currently, the mechanism for LIF overexpression in tumor cells is not well-understood. Here, we report that hypoxia, a hallmark of solid tumors, induced LIF mRNA expression in human colorectal cancer cells. Analysis of LIF promoter revealed several hypoxia-responsive elements (HREs) that can specifically interact with and be transactivated by HIF-2alpha but not HIF 1alpha. Consistently, ectopic expression of HIF-2alpha but not HIF-1alpha transcriptionally induced LIF expression levels in cells. Knockdown of endogenous HIF-2alpha but not HIF-1alpha by siRNA largely abolished the induction of LIF by hypoxia in cells. Furthermore, there is a strong association of HIF-2alpha overexpression with LIF overexpression in human colorectal cancer specimens. In summary, results from this study demonstrate that hypoxia induces LIF expression in human cancer cells mainly through HIF-2alpha, which could be an important underlying mechanism for LIF overexpression in human cancers. PMID- 25726528 TI - Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells. AB - c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G2/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non apoptotic mechanism of cell death. PMID- 25726530 TI - Untreatable tuberculosis: is surgery the answer? PMID- 25726531 TI - Tobacco and tuberculosis: could we improve tuberculosis outcomes by helping patients to stop smoking? PMID- 25726529 TI - The microRNA feedback regulation of p63 in cancer progression. AB - The transcription factor p63 is a member of the p53 gene family that plays a complex role in cancer due to its involvement in epithelial differentiation, cell cycle arrest and apoptosis. MicroRNAs are a class of small, non-coding RNAs with an important regulatory role in various cellular processes, as well as in the development and progression of cancer. A number of microRNAs have been shown to function as transcriptional targets of p63. Conversely, microRNAs also can modulate the expression and activity of p63. However, the p63-microRNA regulatory circuit has not been addressed in depth so far. Here, computational genomic analysis was performed using miRtarBase, Targetscan, microRNA.ORG, DIANA-MICROT, RNA22-HSA and miRDB to analyze miRNA binding to the 3'UTR of p63. JASPAR (profile score threshold 80%) and TFSEARCH datasets were used to search transcriptional start sites for p53/p63 response elements. Remarkably, these data revealed 63 microRNAs that targeted p63. Furthermore, there were 39 microRNAs targeting p63 that were predicted to be regulated by p63. These analyses suggest a crosstalk between p63 and microRNAs. Here, we discuss the crosstalk between p63 and the microRNA network, and the role of their interactions in cancer. PMID- 25726532 TI - Smoking, asthma, chronic airflow obstruction and COPD. PMID- 25726533 TI - It is not time to lower the guard! PMID- 25726534 TI - A conservative approach for subsolid lung nodules: is it safe enough? PMID- 25726535 TI - Bed-sharing and childhood asthma: from associations to causal modelling. PMID- 25726536 TI - A bleeding problem in lung cancer patients. PMID- 25726537 TI - Stressing the stepchild: assessing right ventricular contractile reserve in pulmonary arterial hypertension. PMID- 25726538 TI - Keeping health on the political agenda. PMID- 25726539 TI - What's the (end) point? PMID- 25726540 TI - What's the (end) point? PMID- 25726541 TI - Low socioeconomic status and lung function. PMID- 25726542 TI - Low socioeconomic status and lung function. PMID- 25726543 TI - Electronic nicotine delivery systems. PMID- 25726544 TI - Electronic nicotine delivery systems. PMID- 25726545 TI - Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium. PMID- 25726546 TI - "Clean air in Europe: beyond the horizon?" Bert Brunekreef, Nino Kunzli, Juha Pekkanen, Isabella Annesi-Maesano, Bertil Forsberg, Torben Sigsgaard, Menno Keuken, Francesco Forastiere, Maeve Barry, Xavier Querol and Roy M. Harrison. Eur Respir J 2015; 45: 7-10. PMID- 25726547 TI - "Electronic nicotine delivery systems (ENDS): the beginning of the end or the end of the beginning?" Francesco Blasi and Brian Ward. Eur Respir J 2014; 44: 585 588. PMID- 25726549 TI - Rheumatoid arthritis-associated lung disease. PMID- 25726550 TI - Nutritional advances in patients with respiratory diseases. AB - Nutritional issues are increasingly recognised in the course of respiratory diseases, from primary prevention to advanced disease care. During the 2014 ERS International Congress in Munich, Germany, the topic was addressed in a Clinical Year in Review session. This review highlights new insights in generic and disease-specific nutritional issues from recently published peer-reviewed articles. The clinical relevance of obesity was highlighted in primary and secondary prevention across all respiratory diseases. Radiographic imaging was explored for characterisation of metabolic phenotypes as an integrated part of diagnostic work-up. Muscle regenerative defects and the autophagy-lysosome pathway were identified as new leads for combatting muscle wasting. PMID- 25726551 TI - Advances in target therapy in lung cancer. AB - Herein, we have reviewed and analysed recent literature, published in 2013 and early 2014, in the context of pre-existing data. Considered target therapies were tyrosine kinase inhibitors of active epidermal growth factor receptor mutations (e.g. erlotinib, gefinitib and afatinib), anaplastic lymphoma kinase rearrangements (e.g. crizotinib) or angiogenesis (drugs under development), or monoclonal antibodies against vascular endothelial growth factor (e.g. bevacizumab) or epidermal growth factor receptors (e.g. cetuximab). The therapeutic project has to consider tyrosine kinase inhibitors in the case of nonsmall cell lung cancer with active epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangement. However, these drugs should not be used in the absence of the targeted genetic abnormalities. PMID- 25726552 TI - Advances in asthma pathophysiology: stepping forward from the Maurizio Vignola experience. AB - Maurizio Vignola was a superb and innovative researcher, who wrote seminal papers on the biology of airway epithelium in asthma. Inflammation and remodelling were the main topics of his research, mostly conducted in biopsy specimens from patients with asthma of variable severity, encompassing the entire spectrum of the disease from mild to severe asthma. His observations contributed to define the biology of asthma as we know it today, and opened the way to the personalised treatment of asthma. His group has successfully continued to investigate the biology and clinical aspects of bronchial asthma, with major interest in the clinical use of biomarkers to monitor disease activity, and in the development of new therapeutic perspectives. This review summarises the latest work on these topics proudly conducted by Maurizio's closest collaborators. The results indicate significant progress in our understanding of asthma in the last 10 years, in particular increased knowledge of the complex interaction between inflammatory and remodelling pathways, improved recognition of biological and clinical asthma phenotypes, and development of new treatment strategies, especially for patients with severe corticosteroid-resistant asthma. PMID- 25726553 TI - Targeted screening programmes in COPD: how to identify individuals with alpha1 antitrypsin deficiency. AB - alpha1-antitrypsin deficiency (AATD) is a significantly under-recognised autosomal genetic disorder with <10% of affected individuals being clinically diagnosed. Moreover, rigorous genetic epidemiological data regarding AATD are lacking. The majority of findings come from the USA and Western Europe, and no information is available for many countries. To address this concern, an alpha1 antitrypsin (AAT) laboratory was set up in 2009 at the National Institute of Tuberculosis and Lung Diseases (Warsaw, Poland). In 2010, an AATD screening programme targeting patients with respiratory disorders was initiated in Poland. This targeted survey has provided valuable information regarding AAT-deficient genotypes, clinical disease and levels of expertise at the physician level. After 4 years, almost 2500 patients with chronic obstructive pulmonary disorders have been screened and, in this cohort, ~13% had AATD alleles. In these patients, the detection frequency for S and Z alleles was four times greater, and the frequency of homozygous PI*ZZ was 16 times greater than that of the general population. These results highlight the need to build awareness in the medical community, and the project is currently being extended to cover central Eastern Europe, with the creation of the Central Eastern European Alpha-1 Antitrypsin Network. PMID- 25726554 TI - Long-term experience in the treatment of alpha1-antitrypsin deficiency: 25 years of augmentation therapy. AB - Although it is often under-recognised, alpha1-antitrypsin deficiency (AATD) represents one of the most common genetic respiratory disorders worldwide. Since the publication of studies in the late 1980s, which demonstrated that plasma derived augmentation therapy with intravenous alpha1-antitrypsin (AAT) can reverse the biochemical deficiencies in serum and lung fluid that characterise emphysema, augmentation therapy has become the cornerstone of patient management. This article, with a focus on experience gained in clinical practice in Germany, provides an overview of some of the research highlights and clinical experience gained in the use of augmentation therapy for AATD during the past 25 years, and briefly discusses the potential role of AAT augmentation therapy in lung transplant recipients. Additionally, the goals of AAT augmentation therapy will be discussed, namely to delay the progression of emphysema, reduce the frequency of exacerbations and improve health-related quality of life. Beyond pulmonary disease, there is recent growing evidence to indicate that AATD could also play a role in rare disorders such as panniculitis, granulomatosis with polyangiitis and ulcerative colitis. PMID- 25726555 TI - Diagnosing alpha1-antitrypsin deficiency: how to improve the current algorithm. AB - Over the past 10-15 years, the diagnosis of alpha1-antitrypsin deficiency (AATD) has markedly improved as a result of increasing awareness and the publication of diagnostic recommendations by the American Thoracic Society (ATS)/European Respiratory Society (ERS). Nevertheless, the condition remains substantially underdiagnosed. Furthermore, when AATD is diagnosed there is a delay before treatment is introduced. This may help explain why AATD is the fourth most common cause of lung transplantation. Clearly we need to do better. The ATS/ERS recommend testing high-risk groups, such as: all chronic obstructive pulmonary disease patients; all nonresponsive asthmatic adults/adolescents; all cases of cryptogenic cirrhosis/liver disease; subjects with granulomatosis with polyangitis; bronchiectasis of unknown aetiology; panniculitis and first-degree relatives of patients with AATD. In terms of laboratory diagnosis, measurement of alpha1-antitrypsin levels will identify patients with protein deficiency, but cannot differentiate between the various genetic subtypes of AATD. Phenotyping is the current gold standard for detecting rare variants of AATD (except null variants), while advances in molecular diagnostics are making genotyping more effective. An accurate diagnosis facilitates the physician's ability to actively intervene with measures such as smoking cessation and perhaps augmentation therapy, and it will also help provide a better understanding of the natural history of the disease. PMID- 25726556 TI - Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, progressively destructive lung disease that culminates in respiratory failure and death. Randomised controlled trials have demonstrated that treatment of IPF patients with pirfenidone reduces lung function decline, improves progression-free survival and significantly reduces the risk of all-cause mortality at 1 year. Pirfenidone has been shown to have a favourable safety profile and was generally well tolerated over the long term in clinical trials and real-world experience. However, side-effect management is critical to help some patients remain on treatment over the long term. The primary treatment-related adverse events associated with pirfenidone therapy are gastrointestinal upset, rash and photosensitivity. Gastrointestinal events may be mitigated by ensuring that pirfenidone is taken with food, while skin symptoms may be reduced by avoiding sun exposure and frequent use of sunblock. Educating patients about the potential for these adverse events to occur and providing instructions prior to treatment to avoid adverse drug reactions are an important means of ensuring patients may derive the important benefits provided by long-term treatment with pirfenidone. PMID- 25726557 TI - The changing treatment landscape in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible fibrotic disease of the lung that has greatly frustrated clinicians for a long time. The prognosis of IPF (median survival 2-5 years following diagnosis) is poorer than that of some cancers and for many years no significant advances were made in its management. However, between 2011 and 2014 a number of pivotal developments were made that have improved the outlook for patients with IPF. Herein, we review this rapidly changing landscape, discussing key events whilst still acknowledging that IPF remains a challenging disease to diagnose and manage. PMID- 25726558 TI - The multidisciplinary approach in the diagnosis of idiopathic pulmonary fibrosis: a patient case-based review. AB - Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressively fibrosing interstitial pneumonia that is associated with a significantly worse prognosis than other forms of chronic interstitial pneumonia. An early and accurate diagnosis of IPF is important to enable the initiation of disease specific therapies, which have the potential to reduce disease progression, and the avoidance of inappropriate and potentially harmful drugs. Establishing an accurate diagnosis of IPF can be challenging. Recent studies and international guidelines advocate the importance of a multidisciplinary team (MDT) in the initial diagnostic assessment of patients with suspected IPF. Typical MDT members include a pulmonologist, a radiologist and a pathologist, with further input from a thoracic surgeon, a rheumatologist, a specialist nurse and an occupational physician where appropriate. Multidisciplinary diagnosis is considered the gold standard because it can improve the accuracy of diagnosis of IPF, avoid unnecessary testing (e.g. lung biopsy), and optimise patient management. Here we highlight the strengths and limitations of the multidisciplinary approach to IPF diagnosis through MDT discussion of two patient cases. PMID- 25726559 TI - Host-microbe interactions in distal airways: relevance to chronic airway diseases. AB - This article is the summary of a workshop, which took place in November 2013, on the roles of microorganisms in chronic respiratory diseases. Until recently, it was assumed that lower airways were sterile in healthy individuals. However, it has long been acknowledged that microorganisms could be identified in distal airway secretions from patients with various respiratory diseases, including cystic fibrosis (CF) and non-CF bronchiectasis, chronic obstructive pulmonary disease, asthma and other chronic airway diseases (e.g. post-transplantation bronchiolitis obliterans). These microorganisms were sometimes considered as infectious agents that triggered host immune responses and contributed to disease onset and/or progression; alternatively, microorganisms were often considered as colonisers, which were considered unlikely to play roles in disease pathophysiology. These concepts were developed at a time when the identification of microorganisms relied on culture-based methods. Importantly, the majority of microorganisms cannot be cultured using conventional methods, and the use of novel culture-independent methods that rely on the identification of microorganism genomes has revealed that healthy distal airways display a complex flora called the airway microbiota. The present article reviews some aspects of current literature on host-microbe (mostly bacteria and viruses) interactions in healthy and diseased airways, with a special focus on distal airways. PMID- 25726560 TI - Volatile organic compounds and risk of asthma and allergy: a systematic review. AB - Volatile organic compounds (VOCs) are ubiquitous domestic pollutants. Their role in asthma/allergy development and exacerbations is uncertain. This systematic review investigated whether domestic VOC exposure increases the risk of developing and/or exacerbating asthma and allergic disorders. We systematically searched 11 databases and three trial repositories, and contacted an international panel of experts to identify published and unpublished experimental and epidemiological studies. 8455 potentially relevant studies were identified; 852 papers were removed after de-duplication, leaving 7603 unique papers that were screened. Of these, 278 were reviewed in detail and 53 satisfied the inclusion criteria. Critical appraisal of the included studies indicated an overall lack of high-quality evidence and substantial risk of bias in this body of knowledge. Aromatics (i.e. benzenes, toluenes and xylenes) and formaldehyde were the main VOC classes studied, both in relation to the development and exacerbations of asthma and allergy. Approximately equal numbers of studies reported that exposure increased risks and that exposure was not associated with any detrimental effects. The available evidence implicating domestic VOC exposure in the risk of developing and/or exacerbating asthma and allergy is of poor quality and inconsistent. Prospective, preferably experimental studies, investigating the impact of reducing/eliminating exposure to VOC, are now needed in order to generate a more definitive evidence base to inform policy and clinical deliberations in relation to the management of the now substantial sections of the population who are either at risk of developing asthma/allergy or living with established disease. PMID- 25726561 TI - Cellular interactions in the pathogenesis of interstitial lung diseases. AB - Interstitial lung disease (ILD) encompasses a large and diverse group of pathological conditions that share similar clinical, radiological and pathological manifestations, despite potentially having quite different aetiologies and comorbidities. Idiopathic pulmonary fibrosis (IPF) represents probably the most aggressive form of ILD and systemic sclerosis is a multiorgan fibrotic disease frequently associated with ILD. Although the aetiology of these disorders remains unknown, in this review we analyse the pathogenic mechanisms by cell of interest (fibroblast, fibrocyte, myofibroblast, endothelial and alveolar epithelial cells and immune competent cells). New insights into the complex cellular contributions and interactions will be provided, comparing the role of cell subsets in the pathogenesis of IPF and systemic sclerosis. PMID- 25726562 TI - Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic. AB - Asbestos is the term for a family of naturally occurring minerals that have been used on a small scale since ancient times. Industrialisation demanded increased mining and refining in the 20th century, and in 1960, Wagner, Sleggs and Marchand from South Africa linked asbestos to mesothelioma, paving the way to the current knowledge of the aetiology, epidemiology and biology of malignant pleural mesothelioma. Pleural mesothelioma is one of the most lethal cancers, with increasing incidence worldwide. This review will give some snapshots of the history of pleural mesothelioma discovery, and the body of epidemiological and biological research, including some of the controversies and unresolved questions. Translational research is currently unravelling novel circulating biomarkers for earlier diagnosis and novel treatment targets. Current breakthrough discoveries of clinically promising noninvasive biomarkers, such as the 13-protein signature, microRNAs and the BAP1 mesothelioma/cancer syndrome, are highlighted. The asbestos history is a lesson to not be repeated, but here we also review recent in vivo and in vitro studies showing that manmade carbon nanofibres could pose a similar danger to human health. This should be taken seriously by regulatory bodies to ensure thorough testing of novel materials before release in the society. PMID- 25726563 TI - Recent advances in mechanical ventilation in patients with acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is characterised by different degrees of severity and different stages. Understanding these differences can help to better adapt the ventilatory settings to protect the lung from ventilator-induced lung injury by reducing hyperinflation or keeping the lung open when it is possible. The same therapies may be useful and beneficial in certain forms of ARDS, and risky or harmful at other stages: this includes high positive end expiratory pressure, allowance of spontaneous breathing activity or use of noninvasive ventilation. The severity of the disease is the primary indicator to individualise treatment. Monitoring tools such as oesophageal pressure or lung volume measurements may also help to set the ventilator. At an earlier stage, an adequate lung protective strategy may also help to prevent the development of ARDS. PMID- 25726564 TI - Innate immunity is a key factor for the resolution of inflammation in asthma. AB - The resolution of inflammation is an integral and natural part of the physiological response to tissue injury, infection and allergens or other noxious stimuli. Resolution is now recognised as an active process with highly regulated cellular and biochemical events. Recent discoveries have highlighted that innate inflammatory cells have bimodal effector functions during the inflammatory response, including active roles during the resolution process. Several mediators displaying potent pro-resolving actions have recently been uncovered. Lipoxin A4, the lead member of this new class of pro-resolving mediators, has anti inflammatory actions on type 2 innate lymphoid cells and pro-resolving actions through natural killer cells in asthma immunobiology. Eosinophils are also able to control crucial aspects of resolution through the generation of pro-resolving mediators. Uncontrolled asthma has been associated with a defect in the generation of specialised pro-resolving mediators, including lipoxin A4 and protectin D1. Thus, bioactive stable analogue mimetics of these mediators that can harness endogenous resolution mechanisms for inflammation may offer new therapeutic strategies for asthma and airway inflammation associated diseases. PMID- 25726565 TI - Pneumonectomy subjects with acute respiratory distress syndrome: what to do. PMID- 25726566 TI - Near-fatal haemoptysis as presentation of a giant intralobar pulmonary sequestration. PMID- 25726567 TI - Medical student awareness of and interest in clinical informatics. AB - OBJECTIVE: We aimed to investigate medical students' attitudes about Clinical Informatics (CI) training and careers. MATERIALS AND METHODS: We distributed a web-based survey to students at four US allopathic medical schools. RESULTS: Five hundred and fifty-seven medical students responded. Interest in CI training opportunities (medical school electives, residency electives, or academic fellowships) surpassed respondents' prior awareness of these opportunities. Thirty percent of student respondents expressed at least some interest in a CI related career, but they were no more aware of training opportunities than their peers who did not express such an interest. DISCUSSION: Almost one third of medical students who responded to our survey expressed an interest in a CI related career, but they were generally unaware of CI training and mentoring opportunities available to them. Early outreach to such medical students, through elective classes, professional society incentives, or expert partnerships, may positively influence the size and skill set of the future CI workforce. CONCLUSION: We should work as a field to increase the quantity, quality, and publicity of CI learning opportunities for interested medical students. PMID- 25726568 TI - Technology-mediated interventions for enhancing medication adherence. AB - BACKGROUND: Despite effective therapies for many conditions, patients find it difficult to adhere to prescribed treatments. Technology-mediated interventions (TMIs) are increasingly being used with the hope of improving adherence. OBJECTIVE: To assess the effects of TMI, intended to enhance patient adherence to prescribed medications, on both medication adherence and clinical outcomes. METHODS: A secondary in-depth analysis was conducted of the subset of studies that utilized technology in at least one component of the intervention from an updated Cochrane review on all interventions for enhancing medication adherence. We included studies that clearly described an information and communication technology or medical device as the sole or major component of the adherence intervention. RESULTS: Thirty-eight studies were eligible for in-depth review. Only seven had a low risk of bias for study design features, primary adherence, and clinical outcomes. Eighteen studies used a TMI for education and/or counseling, 11 studies used a TMI for self-monitoring and/or feedback, and nine studies used electronic reminders. Studies used a variety of TMIs, with telephone the most common technology in use. Studies targeted a wide distribution of diseases and used a variety of adherence and clinical outcome measures. A minority targeted children and adolescents. Fourteen studies reported significant effects in both adherence and clinical outcome measures. CONCLUSIONS: This review provides evidence for the inconsistent effectiveness of TMI for medication adherence and clinical outcomes. These results must be interpreted with caution due to a lack of high-quality studies. PMID- 25726570 TI - Unusual erythrocyte split chimerism in pregnancy after allogeneic stem cell transplantation. PMID- 25726571 TI - Factors determining non-compliance to mass drug administration for lymphatic filariasis elimination in endemic districts of Nepal. AB - BACKGROUND: Mass drug administration (MDA) has been implemented in Nepal since 2003 for elimination of Lymphatic Filariasis (LF). The objective of this study was to explore the factors that determine the non-compliance to MDA for Lymphatic Filariasis elimination in endemic districts of Nepal. METHODS: A cross-sectional descriptive study was carried out in three endemic districts namely Dhading, Kapilvastu and Kailali. A total of 900 people were interviewed with structured questionnaire. RESULTS: The result shows that the respondents who knew the DEC contains Albendazole (84.9% vs 42.5%, P<0.001, Adjusted OR=2.89(1.946-4.29) at 95% CI), who were aware of MDA campaign (78.2% vs 33.8% P<0.001, Adjusted OR=2.87(1.73-4.74) at 95% CI), who were visited by health workers at their home during MDA campaign (75.9% vs 24.1% P<0.001, Adjusted OR=4.85(2.448-9.594) at 95% CI) had significantly higher compliance. The respondents who had knowledge of side effects during MDA campaign had lower prevalence of non-compliance as compared who did not have (9.4% vs 33.2%, P<0.001). CONCLUSIONS: Advanced age, primary or below education, ever married, inadequate knowledge on drug, inadequate awareness on MDA, no home visit by health workers during MDA, no belief on MDA drugs were significantly associated with higher non-compliance to MDA. In future, MDA program should focus on awareness campaigns related to composition of drugs, side effects of drugs and compulsory home visit during the campaign. PMID- 25726569 TI - Development of data representation standards by the human proteome organization proteomics standards initiative. AB - OBJECTIVE: To describe the goals of the Proteomics Standards Initiative (PSI) of the Human Proteome Organization, the methods that the PSI has employed to create data standards, the resulting output of the PSI, lessons learned from the PSI's evolution, and future directions and synergies for the group. MATERIALS AND METHODS: The PSI has 5 categories of deliverables that have guided the group. These are minimum information guidelines, data formats, controlled vocabularies, resources and software tools, and dissemination activities. These deliverables are produced via the leadership and working group organization of the initiative, driven by frequent workshops and ongoing communication within the working groups. Official standards are subjected to a rigorous document process that includes several levels of peer review prior to release. RESULTS: We have produced and published minimum information guidelines describing what information should be provided when making data public, either via public repositories or other means. The PSI has produced a series of standard formats covering mass spectrometer input, mass spectrometer output, results of informatics analysis (both qualitative and quantitative analyses), reports of molecular interaction data, and gel electrophoresis analyses. We have produced controlled vocabularies that ensure that concepts are uniformly annotated in the formats and engaged in extensive software development and dissemination efforts so that the standards can efficiently be used by the community.Conclusion In its first dozen years of operation, the PSI has produced many standards that have accelerated the field of proteomics by facilitating data exchange and deposition to data repositories. We look to the future to continue developing standards for new proteomics technologies and workflows and mechanisms for integration with other omics data types. Our products facilitate the translation of genomics and proteomics findings to clinical and biological phenotypes. The PSI website can be accessed at http://www.psidev.info. PMID- 25726572 TI - [C1-INH]. PMID- 25726573 TI - Japanese Encephalitis Vaccines: WHO position paper - February 2015. PMID- 25726574 TI - [Cell-free protein synthetic system: progress and applications in biopharmaceutical engineering]. AB - Cell-free protein synthesis (CFPS) systems based on crude cell extracts have been used in protein expression in vitro. With the researchers' endeavor for decades, the CFPS system has been developed as an important research tool in many frontiers of fundamental and applied biology because of its clear genetic background and simplicity to control the reaction. The yield of CFPS systems derived from prokaryote or eukaryote has increased to several grams per liter with constantly decreasing cost. Nowadays grams of protein could be prepared using a large-scale cell-free system. Recently, the advantages on the expression of complicated, toxic and membrane proteins have shown the great potential of the CFPS systems. The rapid progress of this technology made us to believe that it will take an important place in biopharmaceutical industries undoubtedly. PMID- 25726575 TI - [Modification and decoration of transposase: a review]. AB - Transposons are the mobile and autonomic replication DNA fragments in genomes. With more understanding of the structure and function of transposons, numerous transposons have been developed to the genetics tool for gene function analysis, gene transformation and gene therapy. The low transpositional activity of the natural transposons is the main obstacles to the utilization of transposons. Recently, with the progress in bioinformatics and protein engineering methods, researchers have reconstructed and optimized natural transposases to create hyperactive transposases that catalyze the transposition with high efficiency. The resulted hyperactive transposons have been applied to gene-modification and gene-tagging. Meanwhile, transposase chimeras were created by protein fusion technology. The insertion characteristic of transposons were artificially regulated which could be utilized in gene therapy. PMID- 25726576 TI - [Progress in dedifferentiated fat cells]. AB - When mature adipocytes are subjected to an in vitro dedifferentiation strategy referred to as ceiling culture, these mature adipocytes can revert to dedifferentiated fat (DFAT) cells. DFAT cells have many advantages compared with adipose-derived stem cells (ASCs) and bone marrow mesenchymal stem cells (BMSCs). For example, DFAT cells are homogeneous and could be obtained from donors regardless of their age. Furthermore, DFAT cells also have the same multi-lineage potentials and low immunogenicity as ASCs. As an excellent source of seed cells for tissue engineering and stem cell transplantation, DFAT cells have better prospects in the treatment of many clinical diseases, such as bone defects, neurological diseases, ischemic heart disease and kidney disease. It is necessary to make more intensive studies of DFAT cells. This article summarizes progresses in the immunological characteristics, differentiation ability and potential clinical applications of DFAT cells. PMID- 25726577 TI - [Effect of different transfection reagents and injection methods in mice testicular injection on the expression of exogenous gene]. AB - The purpose of this study was to study the effect of three different transfection reagents (LipofectamineTM LTX & PLUSTM, Lipofectamine 2000 and Nano-PAMAM-D) and three different testicular injection methods (rete testicular injection, seminiferous tubules injection and testicular interstitial injection) on the efficiency of production transgenic mice. After the mixtures of plasmid DNA (pEFP C1) and transfection reagent were injected with different testicular injection methods, the sperm density, vitality, positive sperm rates and PCR positive transgenic mice rate were examined 30 days after injection. The results showed that the damage degree from slight to serious of three transfection reagents was LipofectamineTM LTX & PLUSTM, Lipofectamine 2000, and PAMAM-D. The sperm positive rates with green fluorescence of these three groups were 35.65%+/-0.69%, 12.86%+/ 0.35% and 10.04%+/-0.20%, respectively. The PCR positive rates of transgenic newborn mice were 29.17%, 13.70% and 5.88%, respectively. Among the groups of different testicular injection methods, the damage degree from slight to serious was rete testicular injection, seminiferous tubules injection, and testicular interstitial injection, whereas the sperm positive rates with green fluorescence were 35.13%, 15.13%, and 0%, respectively. The PCR positive rates of transgenic newborn mice among different testicular injection groups were 33.3%, 12.5%, and 0.0%. The combination of rete testicular injection and LipofectamineTM LTX & PLUSTM had the lowest toxicity and highest transgenic efficiency in the production of transgenic mice. PMID- 25726578 TI - [BAMBI inhibits porcine preadipocyte differentiation by facilitating ERK1/2 phosphorylation]. AB - To study the role of BAMBI in adipogenesis, we constructed lentivirus interfering vector targeting on porcine BAMBI, packaged and infected the porcine preadipocyte. The differentiation state of preadipocyte was detected by Oil Red O staining and Oil Red O extraction assay and the expression levels of adipogenic marker genes were detected by Real-time qPCR and Werstern bloting. Results show that BAMBI expression was significant decreased after lentivirus infection, which was repressed more than 60% by shRNA2. Moreover, knockdown BAMBI increased the lipid accumulation of porcine preadipocyte and improved the expression of PPARgamma (peroxisome proliferator-activated receptorgamma) and ap2 (adipocyte protein 2). In summary, these data indicated that BAMBI inhibited adipocyte differentiation by facilitating the phosphorylation of ERK1/2. PMID- 25726579 TI - [Expression and biological activity of porcine interleukin-18 in recombinant Lactococcus lactis]. AB - To obtain active protein of pIL-18 expression in Lactococcus lactis, and to observe its biological activity, the total RNA was extracted as template from peripheral blood mononuclear cells. Porcine interleukin 18 (pIL-18) was amplified by RT-PCR. The resulting fragment was cloned into pAMJ399 L. lactis vector, and then transformed to L. lactis MG1363 cells by electroporation. Expression of pIL 18 protein was detected by SDS-PAGE and Western-blotting. Bioactivity of the product was tested by pig spleen lymphocyte proliferation test and cytopathogenic effect inhibition assay. The result of Western blotting and bioactivity test shows that the molecular weight of pIL-18 protein was 19 kDa. The react line was observed in both supernatant and precipitated of the recombinant bacteria pAMJ399 pIL18/MG1363. The expressed pIL-18 can promote the proliferation of pig spleen lymphocyte, and significantly inhibit virus multiplication. As conclusion, porcine interleukin-18 was successfully expressed in L. lactis, and the product was biologically active. PMID- 25726580 TI - [Improving 3-dehydroshikimate production by metabolically engineered Escherichia coli]. AB - In the aromatic amino acid biosynthetic pathway 3-dehydroshikimate (DHS) is a key intermediate. As a potent antioxidant and important feedstock for producing a variety of important industrial chemicals, such as adipate and vanillin, DHS is of great commercial value. Here, in this study, we investigated the effect of the co-expression of aroFFBR (3-deoxy-D-arabino-heptulosonate 7-phosphate synthase mutant with tyrosine feedback-inhibition resistance) and tktA (Transketolase A) at different copy number on the production of DHS. The increased copy number of aroFFBR and tktA would enhance the production of DHS by the fold of 2.93. In order to further improve the production of DHS, we disrupted the key genes in by product pathways of the parent strain Escherichia coli AB2834. The triple knockout strain of ldhA, ackA-pta and adhE would further increase the production of DHS. The titer of DHS in shake flask reached 1.83 g/L, 5.7-fold higher than that of the parent strain E. coli AB2834. In 5-L fed-batch fermentation, the metabolically engineered strain produced 25.48 g/L DHS after 62 h. Metabolically engineered E. coli has the potential to further improve the production of DHS. PMID- 25726581 TI - [Transformation of phosphotransferase system in Escherichia coli]. AB - We constructed several recombinant Escherichia coli strains to transform phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS system) and compared the characteristics of growth and metabolism of the mutants. We knocked out the key genes ptsI and ptsG in PTS system by using Red homologous recombination in E. coli and meanwhile we also knocked-in the glucose facilitator gene glf from Zymomonas mobilis in the E. coli chromosome. Recombinant E. coli strains were constructed and the effects of cell growth, glucose consumption and acetic acid accumulation were also evaluated in all recombinant strains. The deletion of gene ptsG and ptsI inactivated some PTS system functions and inhibited the growth ability of the cell. Expressing the gene glf can help recombinant E. coli strains re-absorb the glucose through Glf-Glk (glucose facilitator-glucokinase) pathway as it can use ATP to phosphorylate glucose and transport into cell. This pathway can improve the availability of glucose and also reduce the accumulation of acetic acid; it can also broaden the carbon flux in the metabolism pathway. PMID- 25726582 TI - [Effects of 6-benzylaminopurine and alpha-naphthaleneacetic acid on growth and isoflavone contents of Pueraria phaseoloides hairy roots]. AB - In order to study the effect of phytohormone on growth and isoflavones contents of Pueraria phaseoloides hairy roots, we cultured the hairy roots with different concentrations of 6-benzylaminopurine (6-BA) alone or in combination with alpha naphthaleneacetic acid (NAA). Then we determined the effects of 6-BA alone or in combination with NAA on the growth and the contents of isoflavones compounds and levels of antioxidase activities of hairy roots by spectrophotometry. The results show that 6-BA inhibited the growth, and decreased biomass and total isoflavones compounds of P. phaseoloides hairy roots. Furthermore, the inhibition was increased with the concentrations of 6-BA. Compared with the controls, different concentrations of 6-BA in combination with NAA 2.0 mg/L could inhibit the growth of hairy roots and decrease the content of total isoflavone compounds, and also significantly enhanced the contents of soluble protein and levels of peroxidase (POD) activities, but decreased the activities of superoxide dismutase (SOD). DNA ladders detected by agarose gel electrophoresis can be observed after hairy roots of P. phaseoloides were cultured with 6-BA alone for 30 days, but can appear on the 20th day after culture with 6-BA in combination with NAA 2.0 mg/L. This result indicates that 6-BA or 6-BA in combination with NAA can both stimulate appearance of programmed cell death (PCD), and NAA may play a synergistic role on PCD. PMID- 25726583 TI - [Construction and characterization of a novel recombinant retroviral vector expressing mouse T-bet]. AB - In order to study T-bet function in mouse cells, a novel retroviral vector expressing mouse T-bet and reporter gene Thy1.1 was constructed. Retrovirus particles were then produced by transfection of the recombinant retroviral plasmid into a packaging cell line Platinum-E. The recombinant retrovirus played considerable infection ability. T-bet expression was then identified by FACS after infection of CD4+ primary T cells from T-bet knockout mouse with recombinant retrovirus. To determine if exogenous expressing T-bet has normal function, we checked the expression level of T-bet target gene, Ifng. IFN-y expression was upregulated in the T-bet knockout T cells infected with recombinant retrovirus. In conclusion, we successfully constructed an effective mouse T-bet recombinant retroviral vector. PMID- 25726584 TI - [Expression of limulus Factor C in silkworm larvae by Bac-to-Bac/BmNPV baculovirus expression system]. AB - Limulus Factor C, a serine protease zymogen from the amoebocytes of the limulus, has high affinity for endotoxin. When Factor C is activated by endotoxin, it hydrolyses artificial tripeptide substrate and measurable products are released, so it can be used as an alternative reagent for endotoxin analysis. Factor C gene of Tachypleus tridentatus was obtained through RT-PCR and the recombinant protein was expressed by Bac-to-Bac/BmNPV baculovirus expression system in silkworm larvae. The activity of Factor C was detected with diluted serum of silkworm larvae, and the sensitivity of endotoxin detected was 0.2 EU/mL when the serum was diluted at 1:500. The silkworm larvae expressed limulus Factor C could be used to develop a new low-cost endotoxin test reagent. PMID- 25726585 TI - [Feeding mouse with stable isotope labelled with amino acid]. AB - The stable isotope labeling by amino acids in culture (SILAC) based quantitative proteomics serves as a gold standard because of the high accuracy and throughput for protein identifications and quantification. In this study, we discussed the application of SILAC technology in mammal model, and developed quantitative internal standard for comparative proteomics of disease model. The C57BL/6J mice fed by special diet containing the 13C6-Lysine and bred F2 generation. We identified and analyzed total proteins of 9 mice tissues of F2 generation, including brain, lung, heart, stomach, intestine, liver, spleen, kidney, and muscle. Quantitative analysis information could evaluate the mice and different tissues' labeling efficiency. Liver was the most efficient, brain the least, and the labeling efficiency were 96.34%+/-0.90% and 92.62%+/-1.98% respectively. The average of the labeling efficiency of F2 generation was 95.80%+/-0.64%, which met the international standard (>= 95%) for SILAC quantitative proteomics effective study. SILAC technology was successfully extended to mammalian model system, which will provide powerful tools for the mechanism study of the pathophysiology process with mouse model. PMID- 25726586 TI - [Preparation and vitality detection of protoplast in Salvia miltiorrhiza Bunge]. AB - We prepared protoplasts from Salvia miltiorrhiza Bunge suspension culture cells. Then, the protoplasts' vitality and functions were tested by fluorescein diacetate staining method and Fluo-3/AM flourescent probe. The optimal condition of protoplast isolation was Cellulase R-10 1.5%, Pectinase Y-23 0.3%, Macerozyme R-10 0.5%, 40 r/min 12 h, 600 r/min 5 min, and the protoplasts yield was 1.1x10(6) cells/g FW, the vitality was more than 95% by using fluorescein diacetate staining method. It has been confirmed that calcium fluorescent probe Fluo-3/AM can be successfully loaded into protoplasts. PMID- 25726587 TI - [Comparison of stilbene synthase from different plant sources for resveratrol biosynthesis]. AB - Resveratrol is a natural phytoalexin with special pharmacological and health functions. Stilbene synthase (STS) is a key and rate-limiting enzyme in the biosynthesis of resveratrol that is present only in a limited number of plants. The content of resveratrol from Polygonum cuspidatum is more than 1000 times higher than grapes and peanuts. We speculate that the catalytic ability of different STS may be one of the reasons causing differences in the content of resveratrol. To verify the above speculation, Vitis vinifera stilbene synthase gene (VvSTS) was amplified according to overlap PCR protocol with genomic DNA as template. VvSTS and PcSTS (PcPKS5) were analyzed through heterologous expression in Escherichia coli. The expression products were purified with Ni-NTA sepharose affinity chromatography and desalted through PD-10 column. The molecular weight of the two fusion proteins was about 43 kDa. Enzyme reaction and product analysis showed that the two products were resveratrol. The enzyme kinetic analysis showed that the catalyze efficiency (Kcat/Km) of PcPKS5 was 2.4 times of the VvSTS. Our findings confirms that STS from certain plants has much higher catalytic capability. PMID- 25726588 TI - [Purification of recombinant human antithrombin III expressed in a goat mammary bioreactor]. AB - Antithrombin III (AT III) is the most important anti-clotting substance. Recombinant human antithrombin III (rhAT III) expressed in transgenic goat milk attracts more and more attention. Develop an effective purification route for rhAT III is vital to its industrial production. An efficient purification method was developed for the rapid purification of rhAT III by isoelectric precipitation and heparin affinity chromatography. First, casein was effectively removed by isoelectric precipitation. rhAT III was further purified by heparin affinity chromatography. In the process of heparin affinity chromatography, the effects of pH and temperature on the stability of rhAT III were studied, and the effects of operating conditions, elution gradient, flow rate and sample loaded, on the purification efficiency were also studied. Under the optimized conditions, the protein recovery of rhAT III was about 90% with purity over 99%, while its activity recovery was about 50%. Such a purification process is very simple and effective, and it would provide a valuable reference for the further scaling-up of industrial production. PMID- 25726589 TI - [Optimization of photoautotrophic lipid production of Chlorella ellipsoidea seeded with heterotrophic cells]. AB - Photoautotrophic cultivation with heterotrophic cells as seeds (heterotrophic cells/photoautotrophic cultivation) is an effective way for the development of microalgal biofuel, but its development potential from the point of process optimization has not been investigated in literatures. To evaluate this, the optimizations of medium and culture conditions for Chlorella ellipsoidea were studied. In the heterotrophic stage, the biomass concentration reached 11.04 g/L with the optimized medium in flask, which were 28.0% higher than that with the original medium, and the biomass concentration reached 73.89 g/L in 5-L fermenter. In the photoautotrophic stage, the culture medium and conditions were studied in a 2-L column photobioreactor. The maximum biomass concentration, lipid content and lipid productivity reached 1.62 g/L, 36.34% and 6.1 mg/(L.h) under the optimal photoautotrophic conditions. The lipids were mainly composed of C16 C18 fatty acids, which were raw material suitable for biodiesel. After optimization, heterotrophic cells/photoautotrophic cultivation can significantly improve the capacity of biofuel production by Chlorella ellipsoidea, this method is also expected to be an efficient way for the cultivation of other microalgae that can grow heterotrophically. PMID- 25726590 TI - [Molecular cloning and localization of Leishmania donovani expression site associated genes-like protein]. AB - OBJECTIVE: To clone the novel gene that specifically expressed in the amastigotes of Leishmania donovani, and observe subcellular localization of the gene encoding protein. METHODS: mRNA from promastigotes and amastigotes of L. donovani were prepared. The novel expressed sequence tag of amastigotes was selected by suppression subtractive hybridization. The expression of the novel gene in different stages of L. donovani was detected by Northern hybridization and semi quantitative RT-PCR. The subcellular localization of the novel gene encoding protein was observed. RESULTS: The subtractive library of the specifically expressed sequence tag of amastigotes was constructed, and a novel gene designated as expression site associated genes-like protein (ESAGLP) gene was cloned. The full length of ESAGLP cDNA was 2,258 bp. The open-reading frame encoded a polypeptide of 620 amino acid residues. ESAGLP gene expressed only in amastigotes, the encoding protein was localized in the mitochondria. CONCLUSION: The ESAGLP gene is identified as a novel gene which specifically expressed in Leishmania donovani amastigotes, and its encoding protein is localized in the mitochondria. PMID- 25726591 TI - [Dipylidium caninum infection in a toddler]. PMID- 25726592 TI - [Retrospective analysis of echinococcosis surgerical cases in Xinjiang from 2005 to 2013]. AB - [Abstract] OBJECTIVE: To analyze the situation of echinococcosis surgerical cases in Xinjiang Uygur Autonomous Region from 2005 to 2013. METHODS: The surgery cases of echinococcosis in Xinjiang from 2005 to 2013 were collected, and analyzed with SPSS 17.0 and Epi Info 3.5.3 software. RESULTS: A total of 8 639 hydatid disease cases were reported during 2005-2013 from 94 counties (cities and districts) of 14 prefectures (municipalities) in the Region. The average number of annual operation cases were 960 cases (8,639/9 years), and the annual incidence was 4.40/100,000 (960/21.81 million). 82.8% (7,152/8,639) of report cases came from northern Xinjiang area with an incidence of 7.59/100,000, and 17.2% (1,487/8,639) distributed in southern Xinjiang area with an incidence of 1.58/100,000. There were 373 cases (4.4%, 373/8,639) reported in 2005, and increased to 1434 cases (16.5% 1,434/8,639) in 2013 (P<0.05). The cases mainly distributed in Yili Kazak Autonomous Prefecture (2,028 cases), Tarbagatai Prefecture (1,218 cases), Changji Hui Autonomous Prefecture (1,179 cases), and Urumqi City (1,128 cases) of the northern Xinjiang area. There were 4,557 male (52.8%, 4,557/8,639) and 4 082 famale patients (47.3%, 4,082/8,639)(P<0.05). The age distribution showed a single-peak curve, and more patients concentrated in the age group of 31-40 years, accounting for 26.2% (2,265/8,639). Among 8,639 cases, farmers accounted for 47.9% (4 134/8 639). CONCLUSION: The nunber of surgical cases of echinococcosis increases every year in Xinjiang since 2005, and the distribution of the disease shows a trend from the agricultural and pastoral areas to the towns. PMID- 25726593 TI - [Construction and immunogenicity analysis of the attenuated recombinant Salmonella typhimurium strains expressing Echinococcus granulosus Eg95 antigen]. AB - OBJECTIVE: To study the feasibility of using attenuated Salmonella typhimurium as carrier for oral immunization of Eg95 antigen of Echinococcus granulosus. METHODS: The recombinant plasmid pYA3341-Eg95 was constructed by inserting the Eg95 gene into expression vector pYA3341, and identified by the methods of PCR and enzyme digestion. The recombinant plasmid pYA3341-Eg95 was electro transformed into attenuated S. typhimurium strains X3730 and X4550 one by one to construct the recombinant strain St-Eg95. The expression of recombinant Eg95 protein in the recombinant strains St-Eg95 was analyzed by Western blotting. The strains of St-Eg95 were passaged 10 times in vitro and the recombinant plasmids were extracted at one generation interval. The genetic stability of recombinant plasmids was identified by PCR. BALB/c mice were randomly divided into six groups (five mice per group) and inoculated orally with St-Eg95, 100 ul/mouse, at dosage of 1 x 10(9), 1 x 10(10), 1 x 10(11), and 1 x 10(12) cfu/ml, wild-type S. typhimurium strain(l x l0(7)cfu/ml), and PBS, respectively. The survival rate was monitored daily for 30 days. Another 15 mice were divided into three groups and inoculated orally with St-Eg95(5 x 10(5) cfu/ml), X4550(pYA3341)(5 x 10(5) cfu/ml), and PBS, respectively, for 2 times, 0.5 ml/mouse/time, at biweekly intervals. On weeks 0, 2, 4, and 6 after the second immunization, sera were collected and tested for the presence of Eg95 antibody titers using commercially Eg antibody detection ELISA kit. The splenic lymphocyte proliferation was detected by MTT assay at 6 weeks after the second immunization. RESULTS: The constructed recombinant plasmid pYA3341-Eg95 was identified by enzyme digestion and PCR identification. The Eg95 protein (M, 18000) was expressed in the recombinant strains St-Eg95. After the recombinant strains St-Eg95 were passaged 10 times, the Eg95 gene (about 486 bp) was still amplified from St-Eg95. Safety results showed that mice inoculated orally with the St-Eg95 or PBS were all survival on the 30th day after immunization. However, all mice taking wild virulent S. typhimurium strain diedr within 4 days. The Eg95-specific antibodies examined by indirect ELISA were significantly higher in mice immunized with St Eg95 than that of mice immunized with X4550 (pYA3341) or PBS at 2 weeks after the second immunization (P<0.05). The average Eg95-specific antibody titers reached up to the highest value of 1:1700 in mice immunized with St-Eg95 at 4 weeks after the second immunization. The lymphocyte proliferation test showed that the stimulation index value was significantly higher(P<0.05) in mice immunized with the St-Eg95(reached up to 1.94+/-0.15) than that in mice immunized with X4550 (pYA3341) or PBS at 6 weeks after the second immunization. CONCLUSION: The recombinant oral attenuated S. typhimurium St-Eg95 was successfully constructed, and has a good safety and immunogenicity profile in mouse. PMID- 25726594 TI - [A case of Taenia solium infection]. PMID- 25726595 TI - [Genetic polymorphism of the gene encoding the apical membrane antigen-1 of Plasmodium falciparum]. AB - OBJECTIVE: To study the genetic diversity of apical membrane antigen-1 gene from Plasmodium falciparum (PfAMA-1). METHODS: Filter paper blood samples were collected from 23 imported P. falciparum malaria patients who returned to Fujian Province from 2006 to 2012. Nested PCR were used to amplify the PfAMA-1 gene. The umplified fragments were sequenced, and analyzed by bioinformatic software. RESULTS: All 23 samples were amplified a 505 bp band. Thirty-two nucleotides were found to be variable, resulting in 18 haplotypes. Eight of these 18 halotypes were being reported here for the first time. The parasites collected from Africa showed the higher level of variability [haplotypes diversity (Hd)= 0.0985, nucleotide diversity (pi)=0.0258] as compared to the isolates from Asia (Hd=0.909, pi=0.0221). The average difference of dN-dS for all 23 PfAMA-1 sequences was 0.031+/-0.006. Sequence-based neutrality tests were not significant in Africa and Asia (P>0.05). The minimum number of recombination events (Rm) was 10, and the linkage disequilibrium index (R2) evidently declined with the increase of nucleotide distance. A molecular phylogenetic tree constructed using the neighbor-joining method showed that the 23 isolates were assigned to three clades (G1, G2 and G3). Most samples from Africa formed G1, and G3 contained most of Asian isolates. CONCLUSION: Plasmodium falciparum isolates from Africa show a higher genetic diversity than the isolates from Asia for PfAMA-1 gene. PMID- 25726596 TI - [Change of the Valpha24 NKT cells in peripheral blood of the patients with advanced schistosomiasis and its relation to the degree of hepatic fibrosis]. AB - OBJECTIVE: To investigate the change of Valpha24 NKT cells number in peripheral blood and its correlation with the degree of hepatic fibrosis in patients with advanced schistosomiasis. METHODS: Thirty-two advanced schistosomiasis patients and 23 healthy persons were included in the study. The percentage of peripheral blood Valpha24 NKT cells was determined by flow cytometry. The relevant indicators of liver function were detected by enzyme cycling method. Type-B ultrasound was used to examine the degree of hepatic fibrosis. RESULTS: Flow cytometry showed that the percentage of Valpha24 NKT cells in advanced schistosomiasis patients [(0.23+/-0.09)%] was significantly lower than that of healthy persons [(1.44+/-0.62)%] (P<0.01). Liver function test showed that the alanine aminotransferase (ALT) [(44.78+/- 33.42) U/L], gamma-glutamyl transpeptidase(gamma-GT) [(68.75+/-57.95) U/L] and total bilirubin (Tbil)[(20.16+/-11.20) umol/L] in the patients were significantly higher than those of healthy persons[(18.77+/-14.19) U/L, (20.20+/-13.82) U/L, and (11.65alpha 5.09) umol/L], respectively (P<0.01, P<0.01, P<0.05). The percentage of Valpha24 NKT cells was positively correlated with y-GT (r=0.365, P<0.05), but not significantly correlated with ALT, aspartate transaminase, direct bilirubin, alkaline phosphatase, albumin, albumin-globulin ratio (P>0.05). The percentage of Valpha24 NKT cells in patients with grades I (5 cases), II (11 cases), and III (16 cases) fibrosis was (0.37+/-0.02)%, (0.28+/-0.04)%, (0.15+/-0.03)%, respectively (P< 0.01). The percentage of Valpha24 NKT cells showed a significant negative correlation with the degree of liver fibrosis (r=-0.91, P<0.01). CONCLUSION: The percentage of Valpha24 NKT cells in peripheral blood decreases with the aggravation of hepatic fibrosis in patients with advanced schistosomiasis. PMID- 25726597 TI - [An imported case of visceral leishmaniasis in Hubei Province]. PMID- 25726598 TI - [Interaction between Toxoplasma GRA7 dense granule protein and the protein from host macrophages]. AB - OBJECTIVE: To identify the protein from host macrophages which interacted with GRA7 dense granule protein of Toxoplasma gondii, and reveal the relationship between protein interaction and infection process. METHODS: The recombinant GRA7 protein with N-terminal GST tag were used as a bait in in vitro GST Pull-down experiment, the proteins of THP-1 monocytic macrophage cell line were captured and identified by LC-MS/MS proteomics method. The in vivo protein interaction was verified by Co-IP experiment The overexpression of the target host protein by pcDNA3.1 (+) vector in THP-1 macrophage was further used to analyze the relationship between protein interaction and infection process. RESULTS: The captured THP-1 cell protein was about Mr 29000, which was identified as human carbonic anhydrase 1 (hCA1). The significant in vivo protein-protein interaction between GRA7 and hCA1 was verified by Co-IP assay. The overexpression of hCA1 gene in THP-1 macrophage induced a higher propagation speed of Tgondii and the formation of the parasitophorous vacuole, but did nmt influence the number of the parasite. CONCLUSION: There is a significant protein interaction between Toxoplasma GRA7 dense granule protein and hCA1 enzyme from host macrophages, which is positively related with the propagation speed of T. gondii. PMID- 25726599 TI - [Cloning, expression and antigenic analysis of merozoite surface protein MSPDBL2 DBL2 domain from Plasmodium falciparum]. AB - OBJECTIVE: To clone and express the DBL domain of Plasmodium falciparum merozoite surface protein MSPDBL2(DBL2), and investigate its antigenicity. METHODS: The DBL2 fragment was amplified by PCR and cloned into pET28a vector. The recombinant pET28a-DBL2 plasmid was transformed into E. coli BL21 (DE3) and protein expression was induced by IPTG. The expressed product was purified by Ni-NTA affinity chromatography, and analyzed by SDS-PAGE and Western blotting. RESULTS: DBL2 gene fragment of Plasmodium falciparum merozoite surface protein MSPDBL2 (950 bp) was obtained by PCR. The recombinant pET28a-DBL2 plasmid was identified by PCR, double enzyme digestion, and DNA sequencing. The recombinant DBL2 protein was expressed in an inclusion body form with Mr 340,000 after being induced with IPTG. Moreover, the purified recombinant DBL2 protein was recognized by sera from patients with falciparum malaria. CONCLUSION: The recombinant pET28a-DBL2 plasmid has been constructed. The purified rDBL2 protein shows adequate antigenicity. PMID- 25726600 TI - [Iditification of five imported cases of Plasmodium ovale wallikeri infection in Zhejiang Province]. AB - OBJECTIVE: To identify and analyze Plasmodium ovale wallikeri in 5 imported malaria cases, who were detected positive by microscopy and negative by conventional PCR. METHODS: Epidemiological information and blood samples were collected from the five patients. The detection was conducted by microscopy, Rapid Diagnostic Test (RDT) and nested PCR with Plasmodium genus-specific, species-specific and Plasmodium ovale wallikeri-specific primers. The amplified products were sequenced and Blast analysis was performed on line in NCBI. RESULTS: The five patients returned from Africa, and all had a history of malaria. They were microscopically positive for Plasmodium sp., and two cases showed Pan positive RDT result. All blood samples were negative for four Plasmodium spp. by conventional nested PCR, but positive by nested PCR with Plasmodium ovale wallikeri-specific primers. Blast analysis showed that the amplified sequences of the five cases had complete homology with P. ovale wallikeri clone RSH10 18S ribosomal RNA gene (Accession No. KF219561.1). CONCLUSION: The five cases which classified as positive by microscopy while negative by conventional PCR have been confirmed as Plasmodium ovale wallikeri infection by nested PCR with P. ovale wallikeri-specific primers. PMID- 25726601 TI - [Seroprevalance of Toxoplasma gondii infection and genotyping of the isolates from cancer patients in Anhui, eastern China]. AB - OBJECTIVE: To investigate the seroprevalence of Toxoplasma gondii infection and identify the genotypes of T. gondii isolates from cancer patients in Anhui Province. METHODS: Three hundred and fifty-six blood samples were collected from outpatients and hospitalized cancer patients in Hefei, Anhui Province. IgG and gM antibodies specific to T gondii were determined by ELISA. The ELISA positive samples were subjected to detection of Toxoplasma DNA with PCR targeting a 529-bp repeat element of T. gondii. Genotyping of T. gondii isolates was performed using multilocus PCR-RFLP and 10 genetic markers, including 9 nuclear loci, sagl, sag2, sag3, btub, gra6, L358, pkl, c22-8, c29-2, and apico. RESULTS: Among 356 cancer patients, 21 (5.9%) cases were found to be IgG-positive and 8 (2.3%) were IgM positive, and five of them were found to have both IgG and IgM antibodies. The total seroprevalence of Toxoplasma infection was 6.8%. Six PCR-positive samples were genotyped at 10 loci and two of them obtained all genetic markers and identified as the genotype of Chinese 1 (ToxoDB#9). CONCLUSION: In this study, latent and active toxoplasmosis exist in the patients with malignant tumors, and two isolates are genotyped as the type of Chinese 1 (ToxoDB#9) in Anhui, China. PMID- 25726602 TI - [Malaria situation in Henan Province in 2013]. AB - In 2013, 197 cases were reported in Henan Province and all of them were imported cases. Among them, 154 (78.2%) were Plasmodium falciparum cases, 18 (9.1%) were P. vivax cases, 2 (1.0%) were P. malariae cases, and 23(11.7%) were P. ovale cases. The ratio of males to females was 97.5 : 1. The average age was (37.8+/ 9.9) years old. 183(92.9%) patients were returned from Africa. Most of the cases were peasants, export labours and workers. Cases were reported every month with 28 cases in May. The median interval from symptom appearing to diagnosis was 4 d, only 17 patients (8.6%) were diagnosed within 24 h. 61 cases (31.0%) were reported by provincial medical institutions. 60 cases (30.5%) were reported by county CDCs. A total of 193 cases recovered with chemotherapy and 4 cases died. PMID- 25726603 TI - [Polymorphism analysis of Plasmodium falciparum histidine-rich protein II and III]. AB - OBJECTIVE: To analyze the polymorphism of Plasmodium falciparum histidine-rich protein (PfHRP) II and III. METHODS: Genomic DNA was isolated from blood samples of 20 patients infected with Plasmodium falciparum in Yunnan Province. Blood samples were tested by microscopy and RDTs. The Pfhrp2 and Pfhrp3 gene fragments were amplified by PCR and sequenced. The sequencing results were analyzed and compared using the bioinformatics software. RESULTS: 20 patients infected with Plasmodium falciparum tested by microscopy and RDTs. PCR showed that the Pfhrp2 gene was with 389~986 bp, and Pfhrp3 gene with 329-640 bp. All PfH-IRP II sequences started with type 1 repeat (AHHAHHVAD) and ended with the type 12 repeat (AHHAAAHHEAATH). The number of type 7 (AHHAAD), type 2 (AHHAHHAAD) and type 6 (AHHATD) within PfHRP II was more than the other types of repeats, as well as type 16 (AHHAAN) and type 17 (AHHDG) for PfHRP III. Type 11 repeat (AHN) was not found from the PfHRP II and PfHRP III sequences. CONCLUSION: There is an extensive diversity in Pfhrp2 and Pfhrp3 fragments in the individuals infected with P. falciparum in Yunnan. Some types of repeats are shared by PfHRP II and PfHRP III. PMID- 25726604 TI - [Progress on parasiticidal activity of anitimicrobial peptides]. AB - Antimicrobial peptides are a kind of gene encoded, ribosome synthesized, small molecular polypeptides that have high efficiency, wide antibacterial spectrum, and low immunogenicity. Many studies have indicated that antimicrobial peptides can inhibit the growth of parasites or even kill them. This paper reviews the research progress on parasiticidal activity of the antimicrobial peptides in recent years, and presents the problems in the research. PMID- 25726605 TI - [Artemisinin resistance in Plasmodium falciparum: global status and basic research]. AB - Artemisinin-resistant Plasmodium falciparum has been identified by WHO in the Greater Mekong subregion. While there is no report on artemisinin resistance in Africa and South America by now, related surveillance measures have been taken place. The genes related artemisinin-resistance has been identified and the molecular markers will be used for large-scale surveillance efforts to contain artemisinin resistance. The emergence and spread of artemisinin resistance worldwide is a present danger and needs more attention. This article reviews the progress of artemisininresistance malaria parasites and artemisinin-based combination therapies. PMID- 25726606 TI - [An overview on the physiological and ecological adaptation mechanisms of the overwinter ticks]. AB - The current paper introduces the recent research and development on the cryobiology of ticks, based on their overwinter behavior strategy and biochemical and physiological adaptation mechanisms, and provides detail information on the cold hardiness, biochemical and physiological mechanisms, the relationship between cold hardiness and diapause, which will give theoretical clues for subsequent research on the molecular regulation of cold hardiness of ticks. PMID- 25726607 TI - [Research progress on mitochondrial genome structure in the phylum apicomplexa]. AB - Mitochondria are ubiquitous organelles in all eukaryotic cells which are essential for a series of cellular processes and signal transduction. The phylum Apicomplexa includes series of unicellular eukaryotes and some of them are clinically or economically important parasites. Recent studies have demonstrated that apicomplexan parasites' mitochondrial genomes exhibit remarkably diverse structures and they are ideal biological models to comprehend the evolution of mitochondrial genomes. This paper summarizes the mitochondrial genome structure of some representative apicomplexan, highlights their structure characteristics along with evolution process, and briefly describes their nuclear mitochondrial DNA and nuclear plastid DNA. PMID- 25726608 TI - [Design and implementation of command system for emergency events of parasitic diseases]. AB - Based on the requirement analysis and functional design of the command system for parasitic disease outbreaks, the system was constructed by workflow technique, function modules and technical architecture. The command system was a multi platform system, could achieve multiple functions, such as monitoring and early warning of parasitic diseases, emergency video communication, emergency dispatcher, and emergency management. The system can meet the needs in emergency events of parasitic diseases, and increase preparedness level. PMID- 25726609 TI - [Development and application of information system for epidemiological investigation on parasitic diseases]. AB - An information system for epidemiological investigation on parasitic diseases was developed. The foreground of this system was realized by using C# programming language, and the ACCESS database was used to implement the data management. The system was improved by continuous field application, and has been updated from version 1.0 to 3.0. The average treatment time, logic error rate, rate of sample loss, and post-processing error rate have now been reduced by 88.0%, 100%, 98.1%, and 100%, respectively (P<0.01). This system can reduce the human error and change the field investigation into effective and high-quality pattern. PMID- 25726610 TI - [Prevalence and molecular characterization of Giardia lamblia isolates from goats in Anhui Province]. AB - Five hundred and six fresh fecal samples were collected from Lu'an, Fuyang, Suzhou, Chizhou, Wuhu, Chuzhou and Bozhou in Anhui Province, and detected firstly by direct smear microscopy. The microscopy-positive samples were amplified by nested PCR targeting the triosephosphate isomerase (TPI) and glutamate dehydrogenase(GDH) genes. The positive PCR products were sequenced in both directions. The sequences were analyzed by ClustalX 1.81 for sequence alignment and the neighbor-joining trees were constructed by Mega 5.05. Thirty-two out of 506 fecal specimens were diagnosed as Giardia-positive by microscopy with an infection rate of 6.3%. 23 and 16 of the samples were typed as assemblage E by the TPI (530 bp) and GDH (450 bp) genes, respectively. These findings indicated that there was a different distribution of subtypes of assemblage E in different areas. The zoonosis genotypes such as assemblage A or B was not found in the present study. PMID- 25726611 TI - [Seroepidemiological survey of Toxoplasma gondii in dogs in Urumqi]. AB - From 2011 to 2012 in Urumqi, blood samples of 308 household dogs and of 110 stray dogs were collected from three pet hospitals and a stray dog shelter, respectively. Serum anti-Toxoplasma gondii IgG was detected by ELISA. The results showed that the overall seropositive rate was 31.8% (133/418). The rate in household dogs and stray dogs was 29.9% (92/308) and 37.3% (41/110), respectively (P>0.05). Among 308 household dogs, the positive rate in males and females was 27.0% (41/152) and 32.7% (51/156), respectively (P>0.05). The seropositive rate in dogs <1 years old, 1-2 years old, and more than 2 years old was 27.1% (32/118), 30.2% (29/96), and 33.3% (31/94), respectively (P>0.05). The results revealed a high seroprevalence of T. gondii infection in dogs in Urumqi. PMID- 25726612 TI - [The development of Clonorchis sinensis in mice]. AB - Freshwater fish were caught from Nenjiang River in Qiqihaer City, and examined for metacercariae of Clonorchis sinensis by the artificial digestion (pepsin-HCl) method. The metacercariae (35-40) were given orally into stomach to each Kunming mouse of infection group (50 mice). The mice in control group were given the same amount of normal saline. The mice were sacrificed on the 5th, 10th, 15th, 20th, 25th, and 30th day after infection. Worms were collected, fixed and stained with carmine acetate, and observed under microscope. The egg-laying capacity of C. sinensis was observed in mice. 96%(48/50) mice were infected with metacercariae of C. sinensis. The recovery rate of adult worms on the 5th, 10th, 15th, 20th, 25th, and 30th day post-infection was 42.1%, 52.6%, 63.2%, 62.2%, 63.3%, and 63.2%, respectively. The first appearance of eggs in utero and feces was on the 15th and 20th day after infection, respectively. The branch of testis in worms was observed after 20 days of infection. PMID- 25726613 TI - DRE has vital role in early detection of prostate cancer. PMID- 25726615 TI - Professor Haslam replies. PMID- 25726614 TI - Education is not the filling of a pail but the lighting of a fire. PMID- 25726616 TI - Establishing the cause of memory loss in older people. AB - Common causes of memory loss in older people are mild cognitive impairment, the various types of dementia, and psychiatric illness, mainly depression. Around 10% of patients with mild cognitive impairment progress to dementia each year. Alzheimer's disease accounts for 60-80% of cases. Other common types of dementia are vascular, fronto-temporal, Lewy body, Parkinson's, and mixed type dementia. There is evidence to suggest that dementia pathology is established before the onset of symptoms, and thus mild cognitive impairment can be considered as a predementia stage. NICE guidance suggests examination of: attention, concentration, short- and long-term memory, praxis, language and executive function. Particular attention should be paid to any signs of neglect, state of dress, agitation or poor attention. Dysphasia and difficulty in naming objects is often present. Mood symptoms (including suicidal ideation) may be primary or comorbid. Abnormal thoughts and perceptions should be probed for, as psychotic symptoms are common. Primary care options for cognitive testing include the General Practitioner Assessment of Cognition or the Abbreviated Mental Test Score. Physical examination should include observation of gait, inspection for tremor; examination for rigidity, bradykinesia, frontal release signs, upper motor neurone lesions, pulse and BP. Structural brain imaging can improve diagnostic accuracy, exclude other pathologies and act as a prognostic marker of dementia progression but the overlap in structural changes between the dementias makes imaging alone insufficient for diagnostic purposes. NICE guidelines recommend referral to a memory clinic for patients with mild cognitive impairment, those at high risk of dementia, such as patients with learning disabilities, Parkinson's disease, or patients who have had several strokes. PMID- 25726617 TI - Diagnosis and management of postherpetic neuralgia. AB - Risk factors for postherpetic neuralgia (PHN) include: increasing age; a prodrome of pain before rash onset; the degree of spread of the rash, particularly if it extends beyond a single dermatome; and severity of pain during the acute attack. Forty per cent of patients over 50 and 75% of those over 75 develop PHN following resolution of the rash. Patients develop persistent pain classified as PHN 120 days following rash onset. It can be either constant or paroxysmal and is commonly described as burning, stabbing or itching and located in the same dermatomal distribution as the shingles rash. Pain can lead to sleep disturbance, anorexia, reduced socialisation and reactive depression. Paracetamol should be tried initially for mild to moderate pain, either alone or in combination with codeine but there is no evidence to support the use of NSAIDs. Compared with other antidepressants, tricyclic antidepressants are the most likely to confer benefit in neuropathic pain. In frail elderly patients nortriptyline appears to be tolerated best. Both gabapentin and pregabalin can reduce pain and improve sleep patterns in patients with PHN. Patients with severe pain or those whose condition is affecting their daily activities and function should be referred to a specialist in pain management. PMID- 25726618 TI - Managing patients with type 2 diabetes and obesity. AB - Diabetes risk increases exponentially with increasing BMI particularly if fat accumulates centrally and/or in the skeletal muscle, liver and other organs such as the pancreas. Those with diabetes and co-existing obesity, particularly if it is severe, are also at risk of other obesity-related conditions, such as cardiovascular disease, obstructive sleep apnoea, joint pain, many cancers and depression. In people with impaired glucose tolerance, modest weight loss can reduce the development of overt diabetes by 50% or more over four years. Once diabetes has developed weight loss can also be of benefit. Supporting patients to lose weight should be considered a key goal of diabetes care for all overweight and obese patients with type 2 diabetes. Increased physical activity improves insulin sensitivity and can help weight loss maintenance. Metformin is the first line therapy and is generally considered weight neutral. Of the oral therapies available second line, DPP-IV inhibitors are weight neutral and the newer SGLT2 inhibitors can produce 2-3 kg of weight loss on average. Insulin often causes weight gain and patients should be counselled about this. Adjunctive treatment with metformin, SGLT2 inhibitors, DPP-IV inhibitors and GLP-1 analogues can help keep insulin doses lower and limit weight gain. Currently in the UK, obesity pharmacotherapy in type 2 diabetes is limited to orlistat which has been shown to improve glucose control. NICE recommends bariatric surgery as a clinically and cost effective option for obese patients with type 2 diabetes, particularly those with severe obesity. It typically results in 20-30% of body weight loss. PMID- 25726619 TI - Scalp conditions. PMID- 25726620 TI - Electro-therapeutics in war. 1915. PMID- 25726621 TI - Do you always reveal what you do for a living? PMID- 25726622 TI - Current therapies in hepatorenal syndrome. AB - Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with critically poor prognosis. The pathophysiologic hallmark is severe renal vasoconstriction, resulting from complex changes in splanchnic and general circulations as well as systemic and renal vasoconstrictors and vasodilators. Rapid diagnosis and management are important, since recent treatment modalities including vasoconstrictor therapy can improve short-term outcome and buy time for liver transplantation, which can result in complete recovery. PMID- 25726623 TI - Fabry disease--a primer for cardiologists. AB - Fabry disease is an X-linked lysosomal storage disorder caused by alpha galactosidase A deficiency. It is a systemic disease mostly affecting the kidneys, the heart and the brain. Cardiac involvement often presents as concentric nonobstructive left ventricular hypertrophy and is a differential to be taken into account by cardiologists. This review describes the most important systemic features, but mostly highlights the cardiac involvement. Patients with known Fabry disease should be screened early for cardiac involvement, as treatment benefit may not be seen once cardiac fibrosis has developed. Screening for Fabry can be effective among individuals with end-stage renal disease, unexplained cardiac hypertrophy or strokes in young people with no apparent predisposing factors. Enzyme replacement therapy reverses metabolic and various pathologic abnormalities and should be initiated in all patients with symptomatic Fabry disease. PMID- 25726624 TI - Cancer biomarkers in clinical practice. AB - Cancer is the second cause of mortality worldwide, after cardiovascular diseases. Increased prevalence of cancer but also the fact that, most often, the diagnosis is established at a moment when therapeutic resources are already limited, constituted the premise for researching and developing indicators of disease or evolution. With the present article we aim to perform a brief review of the biomarkers currently in use in clinical practice for the diagnosis, prognosis and therapy of neoplasms, as well as those that are under evaluation. PMID- 25726625 TI - A new pharmacologic agent, possible to be used in reducing insulin resistance. AB - Insulin resistance is the cornerstone of multiple diseases such as metabolic syndrome, diabetes mellitus, arterial hypertension, dyslipidemia, acute coronary syndrome, etc. There are some medications and changes in lifestyle that can reduce insulin resistance. Not all are suitable for all patients. We discovered another pharmacologic agent that can be successfully added to the old methods already in use. PMID- 25726626 TI - A review of morphological aspects in dermatofibrosarcoma protuberans with clinicopathological correlations. AB - Dermatofibrosarcoma protuberans represents a rare malignant neoplasm involving the skin affecting all ages, frequently young adults. It is characterized by high rates of local recurrences after surgery and rare distant metastasis. Clinically it may present as a non-protuberant or a protuberant lesion, having a relative non-specific aspect mimicking a scar, morphea, a benign cyst or other skin tumor. Several clinicopathologic subtypes of dermatofibrosarcoma protuberans have been described: fibrosarcomatous, pigmented, juvenile, myxoid, atrophic, sclerosing and myoid. Among these, the fibrosarcomatous variant stands out as the most aggressive subtype with higher risk of local recurrences and metastasis. All clinicopathologic variants have in common a characteristic microscopic pattern of infiltration into subcutaneous fat. However, this may be present on small areas or unavailable for examination on biopsy fragments. For this reason, the awareness of this variable morphology is essential for establishing a correct diagnosis and performing an optimal treatment. PMID- 25726627 TI - Clinical characteristics of obese patients with hypertension and chronic ischemic heart disease. AB - Obesity is a risk factor for arterial hypertension, type 2 diabetes and cardiovascular diseases. Some studies reported an obesity paradox: obese patients with cardiovascular diseases have better prognosis than patients with body mass index BMI <25 kg/m2. The objective of the study was to identify the differences between the clinical characteristics of obese hypertensive patients with chronic ischemic heart disease in comparison with lean hypertensive patients with chronic ischemic heart disease. MATERIALS AND METHOD: The study included 219 patients with hypertension and chronic ischemic heart disease, consecutively hospitalized in the Internal Medicine Clinic of the Clinical Emergency Hospital of Bucharest, Romania. We analyzed data from the hospital record database. RESULTS: 73 from the 219 patients were obese (33.33%). Of the 219 patients, 15.98% had a BMI 20-24.9 kg/m2, 50.68% BMI 25-29.9 kg/m2, 22.37% BMI 30-34.9 kg/m2, 6.84% BMI 35-39.9 kg/m2, 4.10% BMI > 40 kg/m2. The majority of obese patients were women: 67.12% women and 32.87% men. Obese patients (BMI > 30 kg/m2) had a higher prevalence of diabetes, dyslipidemia, left ventricle hypertrophy and heart failure than those with normal weight (BMI 20-24.9 kg/m2). Blood pressure control was achieved in 51.52% of normally weight patients, as compared to 34.69% of obese patients (BMI > 30 kg/m2). Diabetes was controlled in 42.85% of normally weight patients, as compared to 18.36% of obese patients. CONCLUSIONS: In conclusion, in patients with hypertension and chronic ischemic heart disease, the clinical profile worsens as BMI increases. Also, there is an inverse relationship between control rates of arterial hypertension and diabetes and BMI. Blood pressure was uncontrolled in a high percentage of obese hypertensive patients with ischemic heart disease. PMID- 25726628 TI - Evaluation of histologic features with potential prognostic value in ulcerative colitis. AB - Inflammatory bowel diseases (IBD) are a complex, heterogeneous, idiopathic, inflammatory, chronic entity with common clinical, endoscopical and histological features including some well-defined diseases (UC and CD), but also a group of indeterminate colitis. Ulcerative colitis is the most frequent and prominent member of IBD. The current study is trying to evaluate the impact of various histologic features on UC's evolution and outcome--an issue that has generated considerable interest in the academical environment. We gathered a cohort of 20 consecutive patients with positive clinical, endoscopical, histologic and imagistic diagnosis of UC who were prospectively enrolled for close clinical, biochemical, endoscopic and histologic surveillance. Every patient underwent an ileo-colonoscopy and multiple biopsies were taken from inflamed and normal areas of the mucosa. All these procedures were repeated after a year (12 months) of follow-up. This study is presenting the correlation between Mayo score for assessment of ulcerative colitis activity and several histologic features: Geboes histologic score for ulcerative colitis, basal plasmacytosis and vascular lesions using Pearson correlation test. The most promising prognosis value has basal plasmacytosis, confirming previous studies. These data emphasize the need of a more complex, clinical, endoscopic and histologic system of semi-quantitative assessment of UC lesions in order to stratify patients according to their risk to relapse. PMID- 25726629 TI - Pathologic features of renal biopsies based on H & E, immunofluorescence and electron microscopy. AB - Kidneys are complex organs with multiple vital functions. They are an essential part of the urinary system and also are necessary for regulation of body homeostasis like electrolytes, acid base balance and blood pressure. Diagnosis of renal injuries is based on clinical and histopathologic features. In a descriptive cross-sectional study conducted in Shahid Sadoughi Hospital, Yazd, Iran, pathology reports of all renal biopsies, by light microscopic examination, immunofluorecence and electron microscopy (EM) were perused. Data were registered in a questionnaire with questions on patients' demographic information such as age, sex and also questions on clinical signs and symptoms and pathologic findings such as H & E, Immunofluorescence (IF) and electron microscopy. All data were analyzed by SPSS-15 software with descriptive analysis. A total of 80 patients were included in this study, 42 men (52.5%) and 38 women (47.5%), aged 19-73 years (mean: 40.59 +/- 16.36). Based on H & E, IF and electron microscopic findings, it seems that in 26.4% of cases the IFM was necessary and in 67.6% was helpful and in 6% was unnecessary for diagnosis. Between 42 patients, EM was necessary in 12% of patients, while in 71.5% was helpful and in 16.5% was unnecessary. Based on IFM the most common renal disease was FSGS (focal segmental glomerulosclerosis) with mean age of 41.3 years. IFM was necessary in RPGN, chronic glomerulonephritis, mesangial hypercellularity, minimal change disease, IgA nephropathy, and was helpful in FSGS, MPGN, tubulointerstitial nephritis, diffuse sclerosing glomerulonephritis and membranous glomerulopathy but was unnecessary in lupus nephritis. EM was necessary in mesangial hypercellularity, chronic glomerulonephritis and diffuse sclerosing glomerulopathy and was helpful in FSGS, MPGN, lupus nephritis and membranous glomerulopathy while it was unnecessary in minimal change disease and IgA nephropathy. PMID- 25726630 TI - Lyme disease. AB - Lyme disease (Borreliosis), also called the "disease of 1000 faces", is produced by a bacterium called Borrelia burgdorferi, transmitted by the Ixodes tick. The clinical picture is non-specific and polymorph, with multisystemic involvement. Diagnosis is most often one of exclusion, and certain diagnosis is based on the presence of Borellia antibodies. The treatment is done differently depending on the stage of the disease and the severity of injuries, being used antibiotics like Doxycycline, Amoxicillin, Erythromycin or Penicillin. Under treatment the disease quickly heals without sequel, in the early stages, but advanced stages are usually resistant to treatment and chronic injuries can occur. Symptoms get worse without treatment and become chronic. We present the case of a woman of 66 year-old with a complex history of disease, which began one year prior to admission, through multiple and nonspecific symptoms; she presented herself in numerous medical services (gastroenterology, rheumatology--where an immunosuppressive treatment was initiated, hematology) without determining a final diagnosis. She was admitted in our service with altered general state and worsening symptoms, predominantly fever, muscle pain, joint pain, the patient being immobilized in bed. After multiple investigations and the problem of differential diagnosis with multiple pathologies, we finally established the diagnosis of Lyme disease. The peculiarities of the case are represented by the severity of the clinical manifestations and fulminant disease evolution under the unjustified administration of immunosuppressive treatment, and atypical joint involvement regarding localization and evolution that raised the issue of differential diagnosis with osteosarcoma or bone tuberculosis. PMID- 25726631 TI - Rheumatoid arthritis and ischemic strokes in a young woman. Are these conditions interrelated? AB - Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is associated with an increased risk of cardio and cerebrovascular pathology. A 48 year old Caucasian female was admitted for diffuse arthralgias. She was diagnosed eight years before with seropositive RA and she received Methotrexate, Prednisone and anti-inflammatory drugs. A week after the admission the patient presented sudden onset of left hemiplegia. Cerebral CT scan was suggestive for acute infarction in the right middle cerebral artery area and an old sequelar infarction in the left posterior artery area. Laboratory tests revealed: erythrocyte sedimentation rate of 40 mm/hour, fibrinogen 656 mg/dL, C-reactive protein of 20 mg/dL, rheumatoid factor 66.83 U/mL, anti CCP3 IgG 213.54 U/mL, ANA 128.126 U/mL. Also, she had high LDL-cholesterol serum concentration (190 mg/dL). The ECG revealed sinus rhythm, QRS axis-45 degrees, antero-lateral ischemia. Ultrasound examination of cervico-cerebral arteries emphasized occlusion of the left internal carotid artery, large atheromas in both carotid and vertebral arteries. A treatment with anti-aggregant and statin was started, and the former treatment for RA was continued with a raised Prednisone dose. The outcome was favorable, the patient's motor deficit improved (3/5 BMRC at the upper limb and 4/5 at the inferior limb) and she was able to walk with a cane support. She also presented an alleviation in the laboratory test status. Ischemic stroke is a possible complication of RA, presenting as principal risk factor precocious atherosclerosis. A better control of inflammation by new anti-rheumatic treatments will protect the RA patients of deleterious effects of ischemic stroke. PMID- 25726632 TI - Diagnostic difficulties in acute myeloid leukemia. AB - We present the case of a patient who presented cells with different morphologic appearance, lymphoblasts on peripheral blood smear, lymphoblasts on bone marrow aspirate and myloblasts on bone marrow biopsy, and immunophenotyping, leading to different stage diagnosis. The final diagnosis was that of acute myeloid leukemia (LAM0). PMID- 25726633 TI - The human microbiome in autoimmune diseases. AB - The human microbiome is the collection of all of the genes in all of the microbes in and on our bodies. Recently, the more appropriate term is "microbiota". There are numerous and complex relationships between the microbiome and our immune system. It is also becoming clear that if there is a disruption or disorganization in the microbiome community an inflammatory disease can occur. PMID- 25726634 TI - [Cryoablation for renal cell carcinoma - minimally invasive therapy under image guidance]. PMID- 25726635 TI - [Current advances in mammalian germ cell research]. PMID- 25726636 TI - [Optimization of submerged culture conditions for Xylaria striata mycelium]. AB - OBJECTIVE: To establish the optimum submerged culture condition of Xylaria striata mycelium. METHODS: One-factor-at-a-time method and orthogonal experiment design were applied and the dry weight of mycelium was tested for evaluation the biomass of the growth of Xylaria striata mycelium. RESULTS: The results from one factor-at-a-time experiments showed that maltose, glucose or corn powder could be used as the best carbon source and the optimum nitrogen source was soybean powder. The best ratio of carbon source to nitrogen source was 5:1. In addition, the higher dry weight of mycelium was found at pH 6 when 2 mycelial discs were inoculated and fermented for 7 days. Otherwise, the growth of mycelium was observed to be promoted significantly by addition with K,Mg,P and VB1. The consequence of orthogonal experiment showed that the optimum carbon source and nitrogen source were maltose 4% and soybean powder 0.8%, respectively,and the highest mycelium biomass could be obtained at pH 7 and 25 degrees C shaking for 13 days. CONCLUSION: A large amount of mycelium will be obtained under the optimum condition of liquid culture for Xylaria striata. PMID- 25726637 TI - [Study on physiological characteristics and effects of salt stress in Andrographis paniculata]. AB - OBJECTIVE: To study the physiological characteristics and effects of salt stress in Andrographis paniculata. METHODS: Andrographis paniculata was treated with NaCl of different concentration. The photosynthetic characteristics and transpiration rate were an- alyzed by LI-6400 Portable Photosynthesis System. The activities of enzymes were studied with kits. RESULTS: The net photosynthetic rate (Pn) and stomatal conductance (Gs) showed a diurnal variation of bimodal curve, the transpiration rate (Tr) and stomatal limitation (Ls) both had a single peak diurnal variation, while the intercellular CO2 concentration (Ci) and the water use efficiency (WUE) presented a single valley type of diurnal variation. With salt concentration rising, Pn, Tr, Ci, Ca and WUE decreased but L, increased, the activities of SOD, CAT and POD increased firstly and then decreased, while the MDA and proline content showed a rising trend. CONCLUSION: Andrographis paniculata is a type of sun plant. The net photosynthetic rate of Andrographis paniculata leaves has an obvious "midday depression" phenomenon. The results also indicate that Andrographis paniculata has a resistance to salt stress and appropriate shade is good for the quality improvement. PMID- 25726639 TI - [Analysis of genetic diversity of cultivated Eucommia ulmoides from Guizhou Province by phenotypic traits and SCoT markers]. AB - OBJECTIVE: To explore the phenotypic characteristics and the genetic diversity of cultivated Eucommia ulmoides from Guizhou Province. METHODS: The genetic diversity of cultivated Eucommia ulmoides in Guizhou Province was analyzed by phenotypic traits and start condon targeted polymorphism(SCoT)markers. RESULTS: The phenotypic diversity index of the number of buds on neonatal branch was the highest, which was 2.0638, and the number of blades on neonatal branch was the lowest,which was 1.7084. By data obtained, 40 cultivated samples of Eucommia ulmoides in Guizhou Province could be divided into 4 groups. A total of 76 bands were produced by 10 primers, among which 50 bands were polymorphic bands, and the percentage of polymorphic bands was 65.79%. The average value of Nei's genetic diversity index (H) was 0.1937, Shannon's information index (I) was 0.2832, Genetic differentiation coefficient (Gst) was 0.1733, and the gene flow (Nm) among populations was 2.3848. Cluster analysis based on genetic identity indicated that 4 populations could be divided into 2 groups. CONCLUSION: Genetic diversity of cultivated populations of Eucommia ulmoides in Guizhou Province had little differences. The genetic differentiation within populations was bigger than that among the populations. The high level of gene flow among populations was beneficial to extension of Eucommia ulmoides. The phenotypic cluster was similar to the SCoT cluster, the two classification results were significantly correlated with geographic position,which can providing a good foundation for the identification of Eucommia ulmoides germplasms. PMID- 25726638 TI - [Quantitative analysis of phenolic acids in ainsliaea fragrans from different habitats]. AB - OBJECTIVE: The contents of major phenolic acids in Ainsliaea fragrans from different habitats were determined,in order to improve quality standards of Ainsliaea fragrans and provide reference for optimization its daodi habitat. METHODS: Separation and determination of two kinds of phenolic acids, caffeoylquinic acids (CQA)and dicaffeoylquinic acid (DCQA), in Ainsliaea fragrans were carried out by RP-HPLC with Cosmosil RP-C18 column (250 mm x 4.6 mm, 5 MUm), acetonitrile-0.1% formic acid solution as mobile phase at the flow rate of 1.0 mL/min, detection wavelength at 328 nm and column temperature at 35 degrees C. RESULTS: CQA and DCQA were uneven in Ainsliaea fragrans from different habitats. In the sample from Wuyuan, Jiujiang and Shangrao in Jiangxi, the contents of phenolic acids were higher than those from other habitats significantly. The sample from Guangxi habitat had the lowest phenolic acids content. And the chlorogenic acid and 3,5-DCQAs' percentage were higher than other phenolic acids. CONCLUSION: This method is accurate and easy with good repeatability, which can be used in determination of eight phenolic acids in Ainsliaea fragrans from different habitats. Ainsliaea fragrans in Jiangxi Province has good qulity. PMID- 25726640 TI - [Study on microwave processing technology of achyranthis bidentatae radix by orthogonal design]. AB - OBJECTIVE: To study the microwave processing method of Achyranthis Bidentatae Radix processed with wine. METHODS: The content of total saponins, oleanolic acid and beta-ecdysterone were determined as the indices to get the optimal microwave processing technology by orthogonal design. RESULTS: The best technology of Achyranthis Bidentatae Radix processed with wine were:the amount of vinegar was 20%, moistening time was 60 min, with 60% microwave heating for 3 min. CONCLUSION: This method is simple, practical, scientific and easy to control. PMID- 25726641 TI - [Study on antibacterial and anti-inflammatory effects of different processed products of Rosa laevigata root and stem]. AB - OBJECTIVE: To study the anti-inflammatory and antibacterial effects of different processed products of Rosa laevigata root and stem. METHODS: Different processed products were obtained from Rosa laevigata root and stem by frying with vinegar,salt,honey and black bean juice. Their antibacterial effect was observed on bacteria such as Bacillus subtilis, Staphylococcus aureus and Escherichia coli; The mice auricle swelling method was used in anti-inflammatory experiment by using xylene. The mice cotton granuloma method was used to observe the chronic inflammatory effect. RESULTS: The antibacterial effects of processed products of Rosa laevigata root were better than that of the stem, especially the honey processed root. All processed products had no obvious effect on mouse auricular swelling. The raw root,salt processed stem, honey processed stem and honey processed root of Rosa laevigata had an inhibitory effect on cotton-pellet inducing mouse granuloma. CONCLUSION: The honey processed root of Rosa laevigata have significant antibacteral effect and anti-inflammatory effect on chronic infammation. PMID- 25726642 TI - [Identification of Panax notoginseng base on solid three-dimensional fluorescence fingerprint spectra technology]. AB - OBJECTIVE: To establish the solid three-dimensional fluorescence fingerprint spectra for the main root and branch root of Panax notoginseng. METHODS: With the Xuesaitong power as a control, the solid three-dimensional fluorescence technique was employed to establish the fingerprint spectra. RESULTS: The fluorescence peaks of Xuesaitong power were at 230 nm/330 nm,280 nm/660 nm,300 nm/340 nm, 370 nm/590 nm, 440 nm/550 nm, and 490 nm/610 nm. Among of them, the 300 nm/340 nm peak was the strongest. The fluorescence peaks of Panax notoginseng main root power were at 230 nm/340 nm,290 nm/340 nm,370 nm/480 nm,and 430 nm/540 nm. Among of them, the peak at 290 nm/340 nm was the strongest. The branch root of Panax notoginseng was at 280 nm/450 nm,290 nm/350 nm and 350 nm/440 nm,and the peak at 350 nm/440 nm was the strongest. All of them had the peak at 290-300 nm/340-350 nm, this peak was the strongest in Xuesaitong and Panax notoginseng main root power, but 350 nm/440 nm was the strongest in the branch root of Panax notoginseng. Only the peak at 230 nm/330-340 nm was not detected in the branch root of Panax notoginseng. CONCLUSION: The solid three-dimensional fluorescence fingerprints spectra are established. Using peaks at 290-300 nm/340-350 nm and 230 nm/330-340 nm as characteristics of the fluorescence peak can efficiently identify main root and branch root of Panax notoginseng. PMID- 25726643 TI - [Identification of Smilax glabra and its related species based on psbA-trnH sequence]. AB - OBJECTIVE: To identify Smilax glabra and its related species using DNA barcoding technique and psbA-trnH sequence. METHODS: Total genomic DNA was isolated as template and the chloroplast gene psbA-trnH region was amplified by PCR technology and sequenced bidirectionally. The sequences and the related data were analyzed using the software CodonCode Aligner and MEGA 6.0; The intra- and inter specific Kimura-2-Parameter(K2P) distances were calculated and the phylogenetic tree was constructed using the Neighbor-joining method. RESULTS: The maximum K2P genetic distance of the plants of Smilax glabra was lower than the minimum K2P genetic distance of its related species. In the cluster dendrogram, the plants of Smilax glabra from various sources showed the monophyletic and simultaneously distinguished from the closely relative species. CONCLUSION: psbA-trnH barcoding could be used to distinguish Smilax glabra and its related species effectively, and provide important molecular evidence for identification of original plant of Smilacis Glabrae Rhizoma and clinic safety in medicinal use. PMID- 25726644 TI - [Chemical constituents from leaf of Rhododendron przewalskii]. AB - OBJECTIVE: To study the chemical constituents from the leaf of Rhododendron przewalskii. METHODS: Isolate and purify compounds by chromatographic methods, and identify structures by spectroscopic methods. RESULTS: Six compounds were isolated and identified as hyperin (1), avicularin (2), gossypetin-3-O-beta-D galactoside (3), quercetin (4), betuloside (5) and beta-sitosterol (6). CONCLUSION: Compounds 1-4 and 6 are isolated from Rhododendron przewalskii for the frist time. PMID- 25726645 TI - [Chemical constituents from flower of Lonicera fragrantissima]. AB - OBJECTIVE: To study the chemical constituents from the flower of Lonicera fragrantissima. METHODS: The chemical constituents were isolated and purified by means of several chromatographic techniques, and their structures were elucidated by spectroscopic methods. RESULTS: Nine compounds were isolated and identified as chlorogenic acid (1), caffeic acid (2), secologanoside (3), secoxyloganin(4), loganin (5), sucrose (6), myo-inositol (7), rutin (8), and chrysoeriol-7-O-beta-D glucoside (9). CONCLUSION: Compounds 2-9 are obtained from this plant for the first time. PMID- 25726646 TI - [Chemical constituents of Mallotus paniculatus]. AB - OBJECTIVE: To study the chemical constituents of Mallotus paniculatus. METHODS: Column chromatography were used for the isolation and purification. Spectroscopic methods including 1H-NMR, 13C-NMR and MS were used for the identification of structures. RESULTS: Six compounds were isolated from the CHCl3 extract of 75% alcohol extract of the whole plant and identified to be quercetin( 1), kaempherol(2), hesperetin (3), 7,3'-O-dimethylluteolin (4), p-sitosterol (5) and syringaresinol (6). CONCLUSION: All the compounds above were isolated from this plant for the first time. PMID- 25726647 TI - [Chemical constituents from fruit of Panax ginseng]. AB - OBJECTIVE: To investigate chemical constituents from the ripe fruit of Panax ginseng. METHODS: The compounds were isolated and purified by chromatographic methods such as macroporous resin, sephadex LH-20, Bio-gel P-2, ODS and silica gel. Their structures were identified by their physical and spectral data(ESI-MS, 1H-NMR and 13C-NMR). RESULTS: Eleven compounds were isola- ted and identified as arginyl-fructose (1), arginyl-fructosyl-glucose (2), L-pyroglutamic acid (3), p hydroxybenzoic acid (4), 5-hydroxy-methylfuraldehyde (5), ginsenosides Rb1 (6), Re (7), Rg1 (8), Rb2 (9), Rc (10) and daucosterol (11). CONCLUSION: Compounds 1-5 were obtained from the fruit of Panax ginseng for the first time. PMID- 25726648 TI - [Chemical constituents from aerial part of Aconitum brachypodum]. AB - OBJECTIVE: To study the chemical constituents from the aerial part of Aconitum brachypodum. METHODS: The constituents were isolated and purified by silica gel, activated alumina and Sephadex LH-20 column chromatography. their structures were elucidated on the basis of spectral data and physiochemical evidence. RESULTS: Eleven compounds were isolated from 80% ethanol extract and identified as secokaraconitine (1), brachyaconitines A (2), C (3), talatisamine (4), hypaconitine (5), songrine (6), bullatine A (7), 7-carbony sitosterone (8), lupeol (9), beta-sitosterol (10) and daucosterol (11). CONCLUSION: All compounds are isolated from the aerial part of Aconitum brachypodum for the first time. PMID- 25726649 TI - [Study on monosaccharide composition of intracellular polysacchride and contents of cordycepin and cordyceps polysacchride produced by Cordyceps militaris induced by blue light]. AB - OBJECTIVE: To study effects of blue light irradiation on monosaccharide composition of intracellular polysacchride and contents of cordycepin and cordyceps polysacchride of mycelium and sporocarp in Cordyceps militaris. METHODS: The monosaccharide composition of intracellular polysacchride of mycelium and sporocarp in Cordyceps militaris as materials were determined by gas chromatography after 144 h blue light irradiation. The contents of cordycepin and cordyceps polysacchride of mycelium and sporocarp in Cordyceps militaris were detected at different blue light irradiation periods. At the same time, the growth of mycelium and sporocarp in Cordyceps militaris were observed during blue light irradiation. RESULTS: Mycelium polysaccharide in Cordyceps militaris was a kind of heteropolysaccharide containing four kinds of monosaccharide and fruiting body polysaccharide was a kind of heteropolysaccharide containing five kinds of monosaccharide. Whether blue light irradiation or dark culture, the content changes of cordyceps polysacchride in two groups showed similar patterns in the test of mycelium polysaccharides. The content changes of cordyceps polysacchride in two groups were basically the same in the detection of sporocarp polysacchride. Cordycepin content in the two set of experiments of blue light irradiation all showed a clear upward trend in the detection of mycelium and sporocarp in Cordyceps militaris. CONCLUSION: The blue light irradiation has certain effect on the species and quantity of monosaccharide in intracellular polysaccharide. The content increase of cordycepin and cordyceps polysacchride in Cordyceps militaris are promoted by blue light irradiation. Blue light can help the morphogenesis and promote the differentiation and growth of sporocarp in Cordyceps militaris. This study is the first report about the effect of blue light on the type and quantity of the monosaccharide composition in polysaccharide of Cordyceps militaris, which will lay the foundation for further study on the metabolism of active substance in Cordyceps militaris by blue light irradiation. PMID- 25726650 TI - [Comparative study on substituting hedyseri radix for astragali radix in serum containing yiqiyangxue prescription on aged mice spleen lymphocyte proliferation and anti-oxidant effect]. AB - OBJECTIVE: By substituting Hedyseri Radix for Astragali Radix in Yiqiyangxue prescription, to compare the effects of both serum containing medicine on aged mice spleen lymphocyte proliferation and anti-oxidant effect. METHOD: After using the same dose of Hedyseri Radix to replace Astragali Radix in Yiqiyangxue prescription, the best concentration of serum containing medicine,the best incubation time and the effects of ConA-induced spleen lymphocyte proliferation were determined by MTY method. Use reagent kits to detect the activity of SOD, MDA and ROS levels in aged mice spleen lymphocytes and IL-2 level in culture supernatant fluid of spleen lymphocytes. RESULTS: Both serum containing medicine can enhance the proliferation of aged mice spleen lymphocytes. The best concentration of serum containing medicine was 40% and the incubation time was 72 h. The serum containing Yiqiyangxue of Hedyseri Radix prescription acted more effective than that of Astragali Radix on the enhancement of proliferation. Both serum containing medicine showed similar effects on increasing SOD activity, IL-2 level and decreasing MDA and ROS level. Moreover,serum of Hedyseri Radix was superior in the enhancement of proliferation, IL-2 and the reduction of ROS level. CONCLUSION: Both serum containing medicine of Hedyseri Radix and Astragali Radix generate the same effect of anti-aging and enhancement of proliferation. PMID- 25726651 TI - [Therapeutic effects of ethanol extracts of Angelica sinensis and Astragalus mongholicus in diabetic gastroparesis rats]. AB - OBJECTIVE: To observe therapeutic effects of the ethanol extract of Angelica sinensis and Astragalus mongholicus (1:2) in diabetic gastroparesis (DG) rats. METHODS: Diabetic rats were induced by intraperitoneal injection of alloxan (200 mg/kg). DG was based on gastrointestinal motility index and the character of stool in diabetic rats. The metformin and cisapride mixed solution (containing met-formin 175 mg/kg and cisapride 3.5 mg/kg)was intragastric administrated in the positive control group, the ethanol extract of Angelica sinensis and Astragalus mongholicus was intragastric treated in the high dose (10. 5 g/kg) and low dose(5. 2 g/kg) group rats, 1/d for 42 consecutive days. The body weight, fasting blood glucose (FBG) value and 24 h intake and drinking amount were detected at interval of 14 days. The gastrointestinal propulsion index, motilin (MOT), glucagon (GLG) and gastrin (GAS) contents in the blood were detected after the last administration. And then the gastric antrum smooth muscle cells and interstitial cells of Cajal were observed in microscope. RESULTS: The general state and stool had been improved,and the body weight and 24 h intake were significantly increased, and 24 h drinking in the high and low dose groups at 28 d of administration were reduced. At the 42th day,the body weight and 24 h in- take were increased, 24 h drinking water and FBG were reduced, and the MOT, GAS and GLG contents were decreased in the high dose group. Gastric mucosa and gastric smooth muscle tissue morphology were significantly improved. CONCLUSION: The therapeutic effect of ethanol extracts of Angelica sinensis and Astragalus mongholicus was obvious in DG rats. Its mechanism of action was associated with FBG, MOT and GAS levels decreasing. PMID- 25726652 TI - [Study on protective effect of Panax notoginseng total saponins on H9c2 cells senescence against D-galactose]. AB - OBJECTIVE: To investigate the protective effect of Panax notoginseng Total Saponins (PNTS) on D-galactose-induced H9c2 cell senescence and the underlying mechanism. METHODS: D-galactose was used to cause H9c2 cells senescence. Different concentrations of PNTS (5,25 and 50 MUg/mL) were added into medium to protect H9c2 cells. Cell senescence was identified by senescence associated beta galactosidase. Level of reactive oxgen species (ROS) was observed according to the effect of DCFH-DA detection. The activity of superoxide dicmutase (SOD) and the content of malondialdehyde (MDA) in cells were measured by biochemical assay kits. The apoptosis of cells was tested by Hochest. RESULTS: Compared with the control group, the number of beta-galactosidase positive cells and the fluorescence intensity of ROS in the model group were markedly increased. Meanwhile, the activity of SOD was decreased whereas the content of MDA was increased. The apoptosis level assessed by the Hochest dyeing was significantly increased with chromatin concentration and condensation. Compared with the model group, the quantity of beta-galactosidase in different PNTS treatment group was obviously decreased, the activity of SOD was increased and the content of MDA was reduced. The apoptosis rate in the cells treated with PNTS was improved. CONCLUSION: PNTS improved D-galactose-induced H9c2 cell senescence through upregulation of antioxidative ability and attenuation of cell apoptosis. PMID- 25726653 TI - [Study on material basis of essential oil from Yin Teng Gu Bi Kang prescription on activating blood circulation]. AB - OBJECTIVE: To explore the component difference of the serum containing essential oil from Yin Teng Gu Bi Kang prescription in pathologic and physiologic rat models, and to reveal the material basis of its efficacy of activating blood circulation. METHODS: The essential oils were obtained by CO2 supercritical fluid extraction and the ingredients of the essential oils in vitro and in vivo (under physiological and pathological status) were analyzed by GC-MS to compare differences of the essential oil under physiological and pathological status in rats. RESULTS: 32 components were identified with the main components of Z ligustilide (39.23%) and d-limonene (21.7%) in the essential oil. In vivo analysis on the essential oil indicated that 16 components were identified, 7 existed originally in essential oil and 9 were metabolites under physiological status; while 22 components were identified, 10 existed originally in essential oil and 12 were metabolites under pathological status (acute blood stasis). There were 7 common prototypes and 8 common metabolites under different physiological status. CONCLUSION: The absorption and metabolism of essential oils were affected by blood stasis and the compounds migrating to blood may be the effective substance in activating blood circulation. PMID- 25726654 TI - [Protective effect of total glycosides of Ranunculus japonicus on myocardial ischemic-reperfusion injury in isolated rat hearts]. AB - OBJECTIVES: To study the protective effect of total glycosides of Ranunculus japonicus (TGRJ) on myocardial ischemic-reperfusion injury in isolated rat hearts. METHODS: The SD rats were randomly divided into normal control group, ischemia-reperfusion group, and TGRJ in 0.05, 0.10 and 0.20 mg/mL groups. The ischemia-reperfusion injury model was built using Langendroff isolated rats hearts perfusion system. The indexes of heart function such as heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular systolic pressure maximum rate of rise (+ dp/dt(max)), left ventricular diastolic pressure maximum rate of descent (-dp/dt(max)) and coronary flow (CF) before ischemia and later at 1, 5, 10, 20, 30 and 40 min after reperfusion were recorded. The activity of Lactate dehydrogenase (LDH) and creatine kinase (CK) at 20 and 40 min after reperfusion were determined. The myocardial tissues were stained with Triphenyltetrazolium chloride (TTC) and the percentage of myocardial infarction area was calculated. RESULTS: HR, LVDP, +dp/dt(max) and CF of the I/R group were significantly decreased after reperfusion, LDH and CK levels were increased and the area of myocardial infraction was 58.78%. TGRJ had improving effect on all above indexes. CONCLUSION: TGRJ has protective effet on the myo- cardial ischemic reperfusion injury. PMID- 25726655 TI - [Identification of major components of Xingsusan decoction by HPLC-HR-TOF/MS]. AB - OBJECTIVE: The major components of Xingsusan decoction were studied by HPLC-HR TOF-MS. METHODS: A Welchrom- C18 column (4.6 mm x 250 mm, 5 MUm) was used at a flow rate of 1.0 mL/min. The HPLC gradient was acetonitrile-formic acid (99.9: 0.1, V/V) (B) and water-formic acid (99.9:0.1, V/V) (A). HR-MS/MS analysis were carried out using a Micro/TOF-Q II Focus mass spectrometer fitted with an ESI source operating in Auto-MSn mode to obtain fragment ions. TIC chemical profiles of the extract were established in both positive and negative modes. The structures of the known components in Xingsusan decoction were identified by comparing their retention times, molecular weight and CID fragmentation patterns with their corresponding compounds reported in the literature. RESULTS: A total of 52 components were simultaneously detected in Q-TOF/MS. CONCLUSION: This method can be used as reference for other Chinese Medicine formulas study. PMID- 25726656 TI - [Study on UPLC fingerprint of Xiasangju Granules]. AB - OBJECTIVE: To establish a UPLC fingerprint method of Xiasangju Granules. METHODS: UPLC analysis was performed on a Waters ACQUITY UPLC H-Class system and carried out at 30 degrees C on a Waters Column ACQUITY UPLC BEH C18 (2.1 mm x 50 mm, 1.7 MUm). A binary gradient elution system was composed of acetonitrile (phase A)and 0.5% acetic acid solution (phase B). Detection was performed at the wavelength of 320 nm,the mobile flow rate was at 0.4 mL/min. A matrix including 16 variations (characteristic peaks area)and 12 samples was constructed for similarity evaluation, cluster analysis and principle component analysis. RESULTS: The results showed that the collected samples had a good similarity. A specificity fingerprint was produced and 16 characteristic peaks were designated. 12 samples were divided into 6 groups. CONCLUSION: It is a reliable, available and quick method for quality control of Xiasangju Granules. PMID- 25726657 TI - [Preparation of solid dispersion of triterpenoid acids from Eriobotrya japonica leaf and study on their dissolution in vitro]. AB - To prepare the solid dispersion of Eriobotrya japonica leaf triterpenoid acids(EJA) in order to enhance their dissolution characteristics in vitro. METHODS: Taking ursolic acid and oleanolic acid in vitro dissolution as an indicator, the influence of factors including different water-soluble carriers (PEG 6000, PVPk30 and P188) and the drug/carrier weight ratio for the preparation of solid dispersion were examined using single factor experiment. Differential scanning calorimetry (DSC) and X-ray diffraction (X-RD) were used to describe the characterization of solid dispersion. RESULTS: P188 was used as appropriate carrier for the preparation of solid dispersion and the drug/carrier weight ratio was 1:5. The X-RD and DSC showed EJA existed in the solid dispersion as the way of amorphous. The dissolution rate of EJA solid dispersion was significantly higher than physical mixture and EJA. CONCLUSION: The solid dispersion prepared with P188 can significantly increase the solubility and dissolution of EJA in vitro. This study provides the scientific evidence for further preparation of solid dispersion tablet. PMID- 25726658 TI - [Clinical effect of modified Xuefuzhuyutang on senile chronic subdural hematoma after operation]. AB - OBJECTIVE: To investigate the curative effect of modified Xuefuzhuyutang on chronic subdural hematoma (CSDH)after burr holes irrigation and drainage. METHODS: From January 2010 to April 2013,137 CSDH patients were randomly divided into two groups: 65 cases of control group and 72 cases of medicine group (modified Xuefuzhuyutang). RESULTS: Compared with the control group, the cases of total absorption of hematoma in medicine group increased significantly (P < 0.05). The cases of 50%-99%, 30%-49% and 0%-29% absorption in above two groups had no significant differences (P > 0.05). There were no significant side effects were observed in the two groups. Compared with the control group, the marked effective cases and total effective cases in medicine group were higher (P < 0.05). CONCLUSION: Modified Xuefuzhuyutang is effective in reducing the postoperative residual volume and recurrent CS-DH. PMID- 25726659 TI - [External auditory canal cholesteatoma with chronic renal failure or hemodialysis]. AB - BACKGROUND: External auditory canal cholesteatoma (EACC) is a rare otologic disease, characterized by focal osteonecrosis, sequestration and overlying epithelial loss of the bony external auditory canal (EAC). The etiology and pathogenesis of EACC remain controversial. There are only 2 reports on the association between EACC and chronic renal failure (CRF)/hemodialysis (HD). METHOD & RESULT: (1) This study reviewed seven EACC cases with CRF. The mean age was 68.4 years (range: 56 -81 years), and the male-female ratio was 5:2. There were 12 ears with EACC (5 cases were bilateral and 2 cases were unilateral). The EACCs were found in the inferior or posterior inferior part of the EAC in 11 ears. The number of the ears in stage III or IV was 6. Five cases were on HD. (2) Seventy-six cases with CRF on HD were examined for EACC, and 2 out of those 70 cases were diagnosed as having EACC. (3) A comparative study of the 7 EACC cases on HD and 68 non-EACC cases on HD revealed no significant differences in the sex, age, period on CRF/HD, complications (diabetes mellitus or skin disease), smoking, ear cleaning and the use of an earphone or a hearing aid. CONCLUSION & DISCUSSION: Six out of all 9 EACC cases with CRF developed bilaterally, and in the inferior or posterior inferior part of the EAC, which implies a common pathological condition that contributes to the development of EACC. The mean age of 9 patients with EACC was relatively older (66.7 years), therefore age-related changes in the EAC are suspected in the cases with CRF on HD. The patients with CRF on HD have a high incidence of EACC. This strongly suggests the association between EACC and CRF/HD, but the mechanism of this pathogenesis has not been revealed. PMID- 25726660 TI - [A retrospective study on parotid carcinoma]. AB - We retrospectively analyzed the clinicopathological factors affecting survival in patients with previously untreated parotid carcinoma. The subjects were 50 patients treated in our department from 1987 through 2011. The T stage was T1, T2, T3, and T4 in 4 patients, 11 patients, 9 patients, and 26 patients, respectively. The N stage was N0, N1, and N2 in 36 patients, 3 patients, and 11 patients, respectively. The clinical stage was I, II, III, and IV in 4 patients, 10 patients, 7 patients, and 29 patients, respectively. Histopathologically, eleven tumor types were observed; mucoepidermoid carcinoma was the most common. The overall 5-year survival rate was 72.1%, and the disease-specific 5-year survival rate was 74.0% in 42 patients who received radical surgery. Twelve patients relapsed; the site of relapse was the primary site alone in 2, in the neck alone in 3 patients, in the neck with distant metastases in 2 patients, and in distant metastatic site (s) alone in 5 patients. Univariate analysis showed that significant prognostic factors for overall survival rates were the T stage, cervical lymph node metastasis, clinical stage, grade, facial nerve palsy, and tumor size. We concluded that patients at high risk of recurrence should receive adjuvant therapy to improve the therapeutic outcomes. PMID- 25726661 TI - [A case of idiopathic neck bleeding from a parathyroid cyst]. AB - Bleeding from parathyroid cysts is rare. The retropharyngeal space has a very soft structure and if bleeding spreads to this space, airway obstruction can easily occur. We report on a 50-year-old female case with idiopathic neck bleeding from a left parathyroid cyst without any episode of injury. The patient complained of neck swelling after exercise and went to a nearby hospital. At the hospital, the doctor thought this swelling was caused by retropharyngeal bleeding from a tumor behind the left thyroid gland. Embolization of the left thyroid artery was performed. However, the next day, airway obstruction.was occurred and she was brought to our hospital. An emergency operation was performed to open the left neck swelling region. The operation findings and pathological examination showed that the bleeding was caused by a parathyroid cyst and airway obstruction had occurred because of retropharyngeal edema. In this case, the bleeding may have been caused by torsion of the neck when the patient exercised. The retropharyngeal edema probably resulted from the delay of delivery of the lymphatic and venous return and the arterial embolization. 1 year after the operation, the patient is very well and there has been no recurrence. PMID- 25726662 TI - [The age at which the grade of Special Child Dependent's Allowance Act can be judged in the case of deaf children]. AB - The spread of neonatal hearing screening has made the identification of hearing loss in early childhood possible, and most of the children with hearing loss are diagnosed and provided with early intervention within several months after their birth. However, they have to wait to receive the Special Child Dependent's Allowance until their hearing levels are evaluated with audiometers. Under the Special Child Dependent's Allowance Act now in force, a delay of several years occurs for those children before they can receive the allowance after diagnosis. We retrospectively reviewed hearing test results of children who had not reacted at 90dBnHL bilaterally in ABR within 12 months after birth, and examined when those results were certain enough to determine their allowance eligibility. We found that the eligibility in children with hearing loss alone could be determined at 1 year of age; as for children who had other disorders, since it was mostly difficult to test them with an audiometer, the diagnosis of hearing loss must always be made carefully but it was also possible to determine the eligibility for the allowance at 1 year of age. PMID- 25726663 TI - [Glycopolymers of microorganisms: achievements and future research (review)]. AB - This review presents the current literature data on the structure of peptidoglycans, lipopolysaccharides, teichoic acids, the mechanism of biological action of lipopolysaccharides, and the possibility of uising oligosaccharides for creation of glycoconjugate vaccines, as well as promising areas for further research of glycopolymers of microorganisms. PMID- 25726664 TI - [Degradation of polyribonucleotides: biocatalysis and the monitoring of products]. AB - Macroporous monolithic material containing covalently linked ribonuclease A was used to create high-performance flow heterogeneous biocatalysts (bioreactors). The kinetic parameters of the degradation of polycytidylic acid were identified, and the properties of the obtained systems were compared. A HPLC method has been developed for monitoring products of biocatalytic degradation of RNA, and the possibility of using biocatalytic and HPLC columns in RNA degradation processes in a multicomponent mixture of biological molecules was shown. PMID- 25726665 TI - [Bioanode for a microbial fuel cell based on Gluconobacter oxydans inummobilized into a polymer matrix]. AB - Acetic acid bacteria Gluconobacter oxydans subsp. industrius RKM V-1280 were immobilized into a synthetic matrix based on polyvinyl alcohol modified with N vinylpyrrolidone and used as biocatalysts for the development ofbioanodes for microbial fuel cells. The immobilization method did not significantly affect bacterial substrate specificity. Bioanodes based on immobilized bacteria functioned stably for 7 days. The maximum voltage (fuel cell signal) was reached when 100-130 uM of an electron transport mediator, 2,6-dichlorophenolindophenol, was added into the anode compartment. The fuel cell signals reached a maximum at a glucose concentration higher than 6 mM. The power output of the laboratory model of a fuel cell based on the developed bioanode reached 7 mW/m2 with the use of fermentation industry wastes as fuel. PMID- 25726666 TI - [Isolation and physiological and biochemical characterization of the Chlamydomonas reinhardtii C-41 mutant, a superproducer of xi-carotene]. AB - The composition of the carotenes and xanthophylls of Chlamydomonas reinhardtii Dang. C-41, a mutant of a unicellular green alga and a superproducer of xi carotene, was studied. The light-harvesting complexes and a complex of the PS-II reaction center were established to be disrupted in the C-41 mutant. However, the mutant retained a high (up to 46%) photosynthetic activity and the capacity to accumulate chlorophylls and carotenoids (up to 50%). The composition of carotenes was studied, and it was shown that, in contrast to wild-type K(+) cells, which accumulate up to 95% of beta13-carotene and 5% alpha-carotene, cells of the C-41 mutant contained 43% beta13-carotene, 19% beta3-zeacarotene, and 38% xi-carotene. The high level of C-41 mutant biomass accumulation made it possible to recommend the mutant as a superproducer of xi-carotene in phytobiotechnology. PMID- 25726667 TI - [Influence of calcium and rhizobial infections (Rhizobium leguminosarum) on the dynamics of nitric oxide (NO) content in roots of etiolated pea (Pisum sativum L.) seedlings]. AB - The effect of exogenous calcium (Ca2+) and rhizobial infections (Rhizobium leguminosarum bv viceae) on the dynamics of the level of nitric oxide (NO) was studied in cross cuts of roots of two-day-old etiolated pea seedlings (Pisum sativum L.) using a DAF-2DA fluorescent probe. Fluctuations of the NO level, indicating the presence of a rhythm in the generation of NO in roots, were observed during the incubation of seedlings in water, a CaCl2 solution, and with rhizobial infections. Exogenous factors (Ca2+ and two rhizobial stamms) change the time dynamics of the NO level in comparison with the control (water). PMID- 25726668 TI - [The role of reactive oxygen species and calcium ions in the implementation of the stress-protective effect of brassinosteroids on plant cells]. AB - The effect of the brassinosteroids (BS) 24-epibrassiniolide and 24 epicastasterone on the thermoresistance of wheat coleoptile (Triticum aestivum L.) and their generation of the superoxide anion radical and antioxidant enzymes activity were investigated. The treatment of coleoptiles with 10 nM solutions of BS caused a transient increase in O2.- generation and a subsequent increase in the activity of superoxide dismutase and catalase and an improvement in heat resistance. Pretreatment of coleoptiles with the NADPH oxidase inhibitor imidazole leveled the increase in production of the superoxide anion radical and prevented an increase in the activity of antioxidant enzymes and the development of cell thermostability. The investigated effects of BS were also depressed by the pretreatment of coleoptile segments with extracellular calcium chelator EGTA and inhibitor of ADP-ribosyl cyclase nicotinamide. A conclusion was made about the participation of calcium ions and reactive oxygen species generated by the action of NADPH oxidase in the implementation of the stress-protective effect of the BS in the cells of wheat coleoptile. PMID- 25726669 TI - [Comparison of the transcriptional activity of protective protein genes in different wheat cultivars infected with Septoria nodorum Berk]. AB - A comparison was performed with respect to the transcriptional activity of protective protein genes (peroxidase TC 151917, oxalate oxidase AJ556991.1, and proteinase inhibitor EU 293132.1) in five wheat cultivars (Omskaya 35 and 36, Simbirka, Bashkirskaya 26, and Kazakhstanskaya 10) infected with Septoria nodorum Berk, which causes septoria disease. The intensity of parasite development on leaves was assessed based on the areas of infectious sites in plant tissues. This value was minimal in cultivars Omskaya 35 and 36 and maximal in cultivars Simbirka and Kazakhstanskaya 10; cultivar Bashkirskaya 26 was at an intermediate position. Resistant cultivars had a higher degree of transcriptional activity of genes of anionic peroxidase, oxalate oxidase, and proteinase inhibitor during infection than sensitive cultivars. Our data demonstrate the prospects of using expression levels of the AJ556991. 1, TC 151917, and EU 293132.1 genes as markers for the selection of resistant wheat cultivars. PMID- 25726670 TI - [cis and trans conformational changes of bacterial fatty acids in comparison with analogs of animal and vegetable origin]. AB - The conditions of the formations of trans isomers of fatty acids, depending on the method of processing and storage of the raw material of microbial, plant and animal origin, were investigated. In the composition of lipids, except for the main trans-isomer elaidic acid, nonsignificant amounts of trans-2-hexen-4-ynal, trans-2-formlcyclopro-panecarboxylate, methyl octadeca-9-yn-l1-trans-enoate, trans-2, 2-dimethyl-3-(2-propenyl)-ethyl ester, trans-9-octadecenoic acid, and trans-1,5-heptadiene, and mixed isomers of methyl-octadeca-9-yn-1-trans-enoate, methyl-9-cis, 11-trans-octadecadienoate, 1-[trans-4-(2-iodo-ethyl) cyclohexyl] trans-4-pentylcyclo-hexane and cis-9, and trans 11-octadecenoic acid. The major trans elaidic acid component was detected in natural objects of different origin in quantities not exceeding 0.05-0.11%. The combination of thermal processing with other parameters, especially enzymatic treatment, led to an increased proportion of trans isomers. The content of trans isomers is usually proportional to the time of storage of materials. PMID- 25726671 TI - [Application of diagnosticum based on functionalized carbon nanoparticles for monitoring of affine immunoglobulin purification]. AB - A diagnostic reagent application based on carbon nanoparticles covalently functionalized by streptococcus G-protein was investigated in order to construct a system for the monitoring and optimization of the affinity purification technology of rabbit polyclonal antibodies to alpha-fetoprotein. The developed system allows semiquantitative assessment ofthe immunoglobulin content (IgG) of most higher animals and human beings in blood serum samples and eluate in a short time (45 min). IgG detection sensitivity using the carbon-G-protein diagnosticum was 80 ng/mL. Approaches to stabilizing the components of the analysis system, which ensures the preservation of their functional properties during long storage, were developed. The storage life of the diagnosticum was more than 20 years, and that of immunosorbents was more than year and a half. A technique of long-term immunosorbent storage, used in the analysis, was developed. Application of the test-system is possible without the presence of registration equipment. PMID- 25726672 TI - [Obesity and diabetes mellitus]. AB - New literature data and the results of own researches concerning the role of excessive body weight and the development of type 2 diabetes mellitus in humans are presented in the analytical review. Inaccordance with current insights, obesity and type 2 diabetes are considered diseases of inflammatory nature, characterized by systemic chronic low-grade inflammation, where different kinds of cytokines are cardinally involved. Unfavourable life style, i.e. excessive, high-energy, and irrational nutrition--an excessive consumption of animal fats and foods containing the high amount of glucose and starch with an insufficient use of high fiber vegetables, fish and vitamin D, and also sedentary, inactive life style leads to adipocyte hypertrophy and migration of M1 macrophages into the adipose tissue (AT). As a result, there is a low-grade inflammation accompanied by an increased production of proinflammatory cytokines (IL-1, IL-6, TNF-alpha, etc.), adipokines (leptin, resistin, visfatin etc.) and chemokines (CCL2, CCL5, CCL26 and CX3C). Under the influence of these cytokines, on the one hand, IR "is emerged", and on the other--there is apoptosis of the beta-cells, that should be followed by the occurrence of clinically diagnosed type 2 diabetes. However, there is also the opposite system in humans, protecting the organism from the development of type 2 diabetes, and including an increase in the formation of M2 macrophages and the increased formation of secretion of antidiabetic cytokines (IL-4, IL-10, IL-13, etc.) and adiponectin. PMID- 25726673 TI - [Recombinant alpha-2 interferon in preventing the progression of melanoma]. AB - A brief history of interferon application in the treatment of cutaneous melanoma is represented. PMID- 25726674 TI - [Morphological verification problems of Chernobyl factor influence on the prostate of coalminers of Donbas--liquidators of Chernobyl accident]. AB - Problem of a diagnostic of Chernobyl factor influences on different organs and systems of Chernobyl accident liquidators are remain actually until now. Though morbidly background which development at unfavorable work conditions in underground coalminers prevents from objective identification features of Chernobyl factor influences. The qualitative and quantitative histological and immunohistochemical law of morphogenesis changes in prostate of Donbas's coalminer-non-liquidators Chernobyl accident in comparison with the group of Donbas's coalminers-liquidators Chernobyl accident which we were stationed non determined problem. This reason stipulates to development and practical use of mathematical model of morphogenesis of a prostatic gland changes. PMID- 25726675 TI - [Pathogenic mechanisms of proatherogenic changes in pregnant women with concomitant obesity]. AB - The concentration of insulin, high sensitivity C-reactive protein (CRP) and indices of lipid metabolism (concentrations of triacylglycerols, total cholesterol, cholesterol of low density lipoproteins and cholesterol of very low density lipoproteins) in women with concomitant obesity in the second trimester of pregnancy were studied. Changes of the lipid profile in the pregnant women with concomitant obesity indicate development of type IV hyperlipoproteinemia. Concentrations of insulin and CRP in the blood serum of the pregnant women with obesity were respectively 92.1% and 62.5% higher than in the control group. On the basis of literature data and our own research it was concluded that the complex of the metabolic changes (insulin resistance, dislipidemia, endothelial dysfunction, systemic inflammation) in pregnant women with obesity promotes development of proatherogenic changes. PMID- 25726676 TI - [Exhaled air analysis and its application for diagnosis of the gas exchange abnormalities in COPD patients]. AB - 165 participants (100 chronic obstructive lung disease patients (COPD), 30 bronchial asthma patients (BA), and 35 healthy subjects) were examined. This study has aim to investigate possibilities of diagnosis gas exchange abnormalities in COPD patients with the use of capnometry. Capnometry allows to assess such ventilation and gas exchange abnormalities in stage III and IV COPD patients: decrease carbon dioxide production and its elimination impairment; decrease oxygen consumption, increase rest minute lung volume ventilation; tachypnoe and total duration of the respiratory cycle reduction; increase the "dead" space volume and its fraction in the tidal volume. PMID- 25726677 TI - [Treatment of drug resistant destructive pulmonary tuberculosis: gemifloxacin and other fluoroquinolones clinical efficiency and tolerance at the end of initial phase of treatment]. AB - Gemifloxacin efficiency and tolerance in comparison to the ofloxacin, levofloxacin and gatifloxacin during the intensive phase of the antituberculosis therapy for drug resistant cases was evaluated. 156 drug resistant TB patients were examined in the open, prospective, randomized research, being divided into 2 groups with similar drug resistance profile. The 1st group received gemifloxacin, the 2nd--other fluoroquinolones. Gemifloxacin efficiency in the treatment regimen for the drug resistant TB patients did not differ from the efficiency of the use of other fluoroquinolones of the 4th generation and was significantly higher in comparison to ofloxacin. At the same time the identical level of side effects was registered in the course of treatment with mentioned drugs. Gemifloxacin is effective and safe at treatment of tuberculosis in comparison to other fluoroquinolones that allows considering it as the drug of choice among fluoroquinolones for treatment of drug resistant TB, including multidrug resistant TB. PMID- 25726678 TI - [Functional state of the sympathoadrenal system in patients with the tuberculosis associated with HIV infection]. AB - The results of study of adrenaline and noradrenaline concentration in urine in patients with pulmonary tuberculosis associated with HIV-infection are represented in the article. In patients with the tuberculosis/HIV by comparison to HIV-negative patients there is more high activity of the sympathoadrenal system. Revealed dependency of the functional condition of the sympathoadrenal system from volume pulmonary process. Such is a functional condition of the system can aggravate metabolic breaches and promote development to reduction of the mass of the body in patients with pulmonary tuberculosis associated with HIV infection. PMID- 25726679 TI - [Epidemiological characteristics of menstrual cycle disorders and perimenopause in women as risk factors of breast cancer development (C.50) (according to data of sociological research)]. AB - Risk factors of arising and development of breast cancer (C.50) are established among 400 women (P < 0,05) with breast cancer (C.50) in the epidemiological research of disturbances of menstrual cycle and perimenopause and verified by results of multifactor analysis. PMID- 25726680 TI - [New possibilities of Doppler flowmetric ultrasound diagnosis of portal hypertension complicated with varicose veins of the esophagus and bleeding prediction]. AB - Liver cirrhosis as a stage in chronic diffuse liver diseases development manifests itself in structural remodeling of parenchyma and appearance of the main syndrome--portal hypertension. In turn it leads to hemorrhage in 54,3% with death rate of 30-50%. In the article research of hemodynamics in abdominal vessels by the means of modified sonographic Doppler flowmetry and prognosis of high risk esophageal varices are described. On the basis of statistical dependency between degree of esophageal varices, cirrhotic gastropathy and results of modified protocol close correlation is shown, which allow to recommend them as alternative in non-invasive diagnosis of liver cirrhosis complications. PMID- 25726681 TI - [Possibilities of arthroscopy in the diagnosis and treatment of rheumatoid arthritis]. AB - Arthroscopy is a technique that can be used in rheumatoid arthritis, regarding for indications with diagnostic purposes--synovial membrane macroscore and biopsy with following histological examination. Changes in the synovium in rheumatoid arthritis are localized in the lateral and anterior parts of the knee, where hyperemia, rheumatoid pannus growth, hypertrophic clavate villus are often seen. It also can be used for therapeutic purposes--synovectomy in combination with flushing of the knee. After the arthroscopy with debridment in patients with rheumatoid arthritis, pain syndrome, swelling and the amount of effusion in the joint is significantly reduced or eliminated, amplitude of movements increases, functional activity of the limbs restores. PMID- 25726682 TI - [Multidisciplinary approach to the treatment of patients with diabetic foot]. AB - Diabetic foot (DF) is considered now the main cause of amputations of lower limbs. The analysis of the results of 266 percutaneous endovascular interventions (EV) performed during 2008-2012 in 245 patients with ischemic and neuroishemic DF was carried out. 76% of the patients underwent percutaneous balloon angioplasty (PBA), 24%--PBA + stenting. 91% of EV were technically successful. In 95% of the patients who achieved recovery of the main flow in the occluded arterial segment, clinical improvement was observed in the form of disappearance of the pain and start of the healing of ulcer-necrotic lesions of the foot. The main causes of technical failure (9%) were impossibility to pass through long calcified occlusions of infrainguinal arteries. The complication rate was 10.5%, major amputation--5.2%, mortality--0.8%. Long-term results were shown by the combined rate of amputation-free survival after 1, 3 and 5 years follow-up which made up respectively, 86%, 70% and 43%. EV is an effective treatment for patients with DF and an integrated multidisciplinary approach to achieve high limb salvage rates in the long-term period. PMID- 25726683 TI - [Clinical course and causes of death in patients with HIV/AIDS-associated tuberculosis]. AB - It was determined that most of the patients with HIV/AIDS-associated tuberculosis were antisocial way of life. There were more causes of newly diagnosed tuberculosis and drug resistance tuberculosis among the dead cases of HIV/AIDS associated tuberculosis. Tuberculosis more often had started after HIV-infection. In patients who died of co-infection disseminated and infiltrative forms of pulmonary tuberculosis were determined more often. Death came more often from progression of disseminated pulmonary tuberculosis. Most patients had no commitment to a specific anti-TB and antiretroviral treatment. PMID- 25726684 TI - [Characteristics of medical use of Korvazan(r) for restorative treatment of patients with myocardial infarction, counting the risk factors]. AB - The largest contribution to mortality from cardiovascular diseases belongs risk factors for cardiovascular events. In order to determine the effectiveness of rehabilitation patients undergoing examined 240 patients with myocardial infarction with concomitant risk factors. The study found that the inclusion in the standard therapy of beta-blocker carvedilol in individually selected dose and depending on the risk factor of cardiovascular events helps increase myocardial functional reserves and increasing tolerance to physical exertion. PMID- 25726685 TI - [Clinical application of Potentilla alba for prevention and treatment of thyroid gland pathologies]. AB - Available data on the effect of various trace elements on iodine metabolism and function of thyroid gland (TG) were systematized in this article. Subsequently, promising possibilities of herbal therapy in treatment and prevention of TG diseases were considered. Systemic analyis of the results of 3 independent open label clinical studies performed in accordance with requirements of evidence based medicine that involved herbal medicinal product Alba(r) (root extract of white cinquefoil) was carried out. Therapeutic options of Alba(r) use in various TG pathologies were presented. PMID- 25726686 TI - [Corrective action of bacillary probiotic on the immune system of animals in experimential dysbacteriosis]. AB - Is established that at intestinal dysbacteriosis in the organism of experimental animals develop reactions of inflammatory type (early and late), leading to an accumulation in the blood serum of humoral immunity factors, blocking reactions mediated by lymphocytes ormacrophages, while maintaining their cytotoxic activity. Introduction of animals of tne probiotic endosporin promotes restoration of quantitative and qualitative indicators of intestinal microbiocenosis and the normalization of the immune system. PMID- 25726687 TI - [The influence of leadership experience on the style of resolving management decisions by executives of healthcare institutions]. AB - The aim of our study was to examine the influence of age and management experience of executives in healthcare institutions at the style of decision making. The psychological study of 144 executives was conducted. We found out that the age of executives in healthcare institutions does not affect the style of managerial decision making, while experience in leadership position does. Also it was established that the more experienced leader is, the more often he will make decision in authoritative, autonomous, marginal style and the less management experience is, the more likely is the usage of indulgent and situational style. Moreover, the authoritarian style is typical for younger executives, marginal and autonomous is typical for elder executives. PMID- 25726688 TI - [Scientific medical forum as important source of scientific-information provision for innovation processes in the healthcare sector of Ukraine]. AB - The article made a retrospective analysis of the scientific medical forums (congresses, symposia and scientific conferences) in the healthcare sector of Ukraine in 2008-2012, planned by higher medical schools and post-graduate medical education schools, scientific institutions of Ministry of Healthcare of Ukraine, National Academy of Medical Science of Ukraine, medical associations and scientific and medical societies. Quantitative and qualitative assessment was carried out of the effectiveness of their implementation, provided suggestions for improving the planning and conducting of medical research forums. PMID- 25726689 TI - [Standardization and archiving of clinical reviews: search for optimal solutions]. AB - The article refers to the necessity of the optimization processes for standardization and archiving of clinical examinations at the different stages of care, including also outpatient care. The compromise solution to the problem has been offered in the article. PMID- 25726690 TI - [Analysis of morbidity and state of diagnostics of malignant neoplasms of maxillofacial localization (based on materials from Poltava region)]. AB - In the article information is resulted about morbidity by malignant new formations of maxillofacial localization in region of Poltava for 20 years of supervisions, which diminished from 4 to 2,5% to 2011 year, but increased to 3,3% in the structure of general oncologic morbidity in 2012; about the change of structure and grade places of oncostomatology's morbidity; about establishment of reasons of late diagnostics. It is suggested to continue the study of monitoring of malignant new formations of maxillofacial localization of population and level of motivation of providing of the specialized help a population with the obligatory analysis of information; to count the indexes of timely diagnostics of shrine one of basic criteria of estimation of activity of stomatological service; to oblige doctors--necessarily to pass stomatologies courses of the in-plant training on oncology 1 time in 5 years. PMID- 25726691 TI - Short-wavelength enrichment of polychromatic light enhances human melatonin suppression potency. AB - The basic goal of this research is to determine the best combination of light wavelengths for use as a lighting countermeasure for circadian and sleep disruption during space exploration, as well as for individuals living on Earth. Action spectra employing monochromatic light and selected monochromatic wavelength comparisons have shown that short-wavelength visible light in the blue appearing portion of the spectrum is most potent for neuroendocrine, circadian, and neurobehavioral regulation. The studies presented here tested the hypothesis that broad spectrum, polychromatic fluorescent light enriched in the short wavelength portion of the visible spectrum is more potent for pineal melatonin suppression in healthy men and women. A total of 24 subjects were tested across three separate experiments. Each experiment used a within-subjects study design that tested eight volunteers to establish the full-range fluence-response relationship between corneal light irradiance and nocturnal plasma melatonin suppression. Each experiment tested one of the three types of fluorescent lamps that differed in their relative emission of light in the short-wavelength end of the visible spectrum between 400 and 500 nm. A hazard analysis, based on national and international eye safety criteria, determined that all light exposures used in this study were safe. Each fluence-response curve demonstrated that increasing corneal irradiances of light evoked progressively increasing suppression of nocturnal melatonin. Comparison of these fluence-response curves supports the hypothesis that polychromatic fluorescent light is more potent for melatonin regulation when enriched in the short-wavelength spectrum. PMID- 25726692 TI - The scent of mixtures: rules of odour processing in ants. AB - Natural odours are complex blends of numerous components. Understanding how animals perceive odour mixtures is central to multiple disciplines. Here we focused on carpenter ants, which rely on odours in various behavioural contexts. We studied overshadowing, a phenomenon that occurs when animals having learnt a binary mixture respond less to one component than to the other, and less than when this component was learnt alone. Ants were trained individually with alcohols and aldehydes varying in carbon-chain length, either as single odours or binary mixtures. They were then tested with the mixture and the components. Overshadowing resulted from the interaction between chain length and functional group: alcohols overshadowed aldehydes, and longer chain lengths overshadowed shorter ones; yet, combinations of these factors could cancel each other and suppress overshadowing. Our results show how ants treat binary olfactory mixtures and set the basis for predictive analyses of odour perception in insects. PMID- 25726693 TI - [Laparoscopic cystectomy and ileal conduit urinary diversion for neurogenic bladders and related conditions. Morbidity and better quality of life]. AB - OBJECTIVES: To assess morbidity and functional consequences of laparoscopic cystectomy with ileal conduit urinary diversion: in neurologic patients. MATERIALS: We reviewed the records of forty-two patients (ten men and thirty-two women) who underwent surgery between August 2007 and October 2013. The median age of the patient was 54 years old (range between 21-79 years). A laparoscopic cystectomy was performed followed by a short laparotomy to perform the ileal conduit urinary diversion. Records were reviewed to retrieve the indications and describe the postoperative and functional course. Patients and GPs were interviewed during phone calls to appreciate the quality of life by the PGII scale in order to assess the functional outcome. RESULTS: The operation was performed on 42 patients, of whom 18 had multiple sclerosis, nine a post traumatic neurogenic bladder. Among the total population, 10 patients (23.81%) required a transfusion of at least one packed red blood cells (1-7). The overall rate of early complications was 35.71%. Belated complications were seen in 52.38% of the population. The median duration of hospital stay was 16 days (range between 9-70 days). The median follow up was 34 months (range between 1-76 months). For patients, the PGII scale rating had a median value of 6 (2-7). All referring physicians described a better functional status. CONCLUSION: The laparoscopic cystectomy can make postoperative course smoother for the neurological patients. However, the surgeon must weigh individually the benefit of performing the operation. PMID- 25726694 TI - [Emerging uropathogens: Point for urologists and biologists]. AB - INTRODUCTION: Technological advances during the last years in bacterial identification by molecular biology and mass spectrometry, or Matrix Assisted Laser Desorption Ionisation-Time of Flight (MALDI-TOF) have allowed identifying new bacteria involved in urinary tract infections. The purpose of this review is to familiarize clinicians with these bacteria so that they can look at a particular target population and help biologists to suspect and identify them. METHOD: A bibliographic research was performed using the Medline database concerning the keywords Aerococcus, Actinobaculum, Alloscardovia, Trueperella. RESULTS: If Aerococcus sp. is now well known, Actinobaculum sp., Alloscardovia sp. and Trueperella sp. remain rarely isolated and unknown from clinicians. Importance of these germs could be underestimated because of the identifying and isolation difficulties which existed beforehand. They are particularly found in a population of elderly people with underlying conditions or urological risk factors of urinary tract infection. Actinobaculum schaalii is also found more frequently in young children. CONCLUSION: Aerococcus sp. et A. schaalii are true uropathogens not to be underestimated. Further studies are still needed to confirm the specific involvement of Trueperella and Alloscardovia in urinary diseases. PMID- 25726695 TI - Redirecting the thrust to put "therapeutic" back into therapeutic exercise. PMID- 25726696 TI - 2014 JOSPT Awards focus on 2 contemporary topics: dry needling and knee articular cartilage defects. PMID- 25726697 TI - Cervical myelopathy in a special operations soldier. AB - The patient was a 31-year-old man who was currently serving in a military special operations combat unit. He was evaluated by a physical therapist for a chief complaint of upper extremity weakness and decreased hand dexterity bilaterally. Due to strong suspicion of spinal cord involvement, the physical therapist ordered magnetic resonance imaging, which revealed advanced degenerative changes of the cervical spine and a large disc extrusion at C5-C6. PMID- 25726699 TI - Gender-dimorphic regulation of DJ1 and its interactions with metabolic proteins in streptozotocin-induced diabetic rats. AB - Regulation of DJ1 is associated with a number of human diseases. To determine the involvement of DJ1 in progression of diabetes in a gender-dependent manner, we investigated its tissue-specific expression in streptozotocin (STZ)-induced diabetic male and female rats in this study. In animal experiments, females showed greater susceptibility towards developing diabetes because of lower insulin secretion and higher blood glucose levels as compared to male diabetic rats upon exposure to STZ. Immunoblotting confirmed sexually dimorphic regulation of DJ1 in various metabolic tissues such as the liver, pancreas and skeletal muscle. Immunofluorescence analysis revealed the location as well as reinforced the gender-dependent expression of DJ1 in hepatic tissue. Co-immunoprecipitation assay identified several interacting proteins with DJ1 whose functions were shown to be involved in various metabolic pathways viz. antioxidative and stress defence system, protein and methionine metabolism, nitrogen metabolism, urea metabolism, etc. Using GeneMANIA, a predictive web interface for gene functions, we showed for the first time that DJ1 may regulate T1DM via the JNK1 pathway, suggesting DJ1 interacts with other proteins from various metabolic pathways. We anticipate that the current data will provide insights into the aetiology of T1DM. PMID- 25726701 TI - Introduction: on-label and off-label drug use in reproductive medicine. AB - This Views and Reviews article examines FDA-approved uses of prescription drugs, as well as common off-label uses of drugs for several disorders that are frequently seen in reproductive medicine. Off-label drug use is ubiquitous in reproductive medicine, a fact that may be related to the disincentives to formally study these drugs in a potentially vulnerable population (i.e., pregnant women). It behooves clinicians to discuss with patients the risk-benefit ratio of treatment, and whether a treatment is FDA-approved for that condition. Researchers, seeking better data on effects of these drugs, may find fodder for future clinical studies in these articles. PMID- 25726700 TI - Dynamics of equilibrium folding and unfolding transitions of titin immunoglobulin domain under constant forces. AB - The mechanical stability of force-bearing proteins is crucial for their functions. However, slow transition rates of complex protein domains have made it challenging to investigate their equilibrium force-dependent structural transitions. Using ultra stable magnetic tweezers, we report the first equilibrium single-molecule force manipulation study of the classic titin I27 immunoglobulin domain. We found that individual I27 in a tandem repeat unfold/fold independently. We obtained the force-dependent free energy difference between unfolded and folded I27 and determined the critical force (~5.4 pN) at which unfolding and folding have equal probability. We also determined the force dependent free energy landscape of unfolding/folding transitions based on measurement of the free energy cost of unfolding. In addition to providing insights into the force-dependent structural transitions of titin I27, our results suggest that the conformations of titin immunoglobulin domains can be significantly altered during low force, long duration muscle stretching. PMID- 25726702 TI - Off-label drug use in the treatment of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a complex lifelong disorder with an etiology and pathophysiology that is not yet entirely understood. Women with PCOS have clinical presentations that may vary from adolescence to menopause, including menstrual irregularity/anovulation and symptoms of hyperandrogenism, such as acne and hirsutism. Over a lifetime, treatment needs and requirements can change. Unfortunately, there are no Food and Drug Administration-approved medications that are approved solely for the purpose of PCOS, but the symptoms and presentation of PCOS are often amenable to several approved agents, such as oral contraceptives for the indication of acne and clomiphene citrate for the indication of induction of ovulation. However, to meet the needs of women with PCOS, off-label use of medications has flourished. This review explores the data for those agents that do not carry an indication for PCOS but have been used for treating the signs and symptoms of PCOS. PMID- 25726703 TI - Autonomy, futility, and good business in reproductive medicine: is the slope getting more slippery? PMID- 25726704 TI - Performance of embryo transfer in fellowship training. PMID- 25726705 TI - Appropriate use of fluoroquinolones in children. AB - With the increasing resistance to antibiotics among common bacterial pathogens, challenges associated with the use of fluoroquinolones (FQs) in paediatrics have emerged. The majority of FQs have favourable pharmacokinetic properties, although these properties can differ in children compared with adults. Moreover, all FQs have broad antimicrobial activity both against Gram-positive and Gram-negative bacteria. However, only some FQs for which adequate studies are available have been approved for use in children in a limited number of clinical situations owing to the supposed risk of development of severe musculoskeletal disorders, as demonstrated in juvenile animals. Recent short- and long-term evaluations appear to indicate that, at least for levofloxacin, this risk, if present at all, is marginal. This marginal risk could lead to more frequent use of FQs in children, even to treat diseases for which several other drugs with documented efficacy, safety and tolerability are considered the first-line antibiotics. However, for most of the FQs, adequate long-term studies of safety are not available. This indicates that the use of FQs should be limited to selected respiratory infections (including tuberculosis), exacerbation of lung disease in cystic fibrosis, central nervous system infections, enteric infections, febrile neutropenia, as well as serious infections attributable to FQ-susceptible pathogen(s) in children with life-threatening allergies to alternative agents. When considering diseases that could benefit from the use of FQs, particular attention must be paid to the choice of drug and its dosage, considering that not all of the FQs have been evaluated in different diseases. PMID- 25726706 TI - Childhood Pre-B acute lymphoblastic leukemia and glutathione S-transferase omega 1 and 2 polymorphisms. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy among children and makes up 23% of total childhood cancers worldwide. Pre-B ALL is one of the most common ALLs, comprising about 80% of childhood cases. A variety of genes are involved in metabolizing carcinogens. These gene polymorphisms can result in less efficient or overly-down metabolic pathways, which may contribute to the susceptibility to develop cancer. Glutathione S transferase omega (GSTO) is a new known class among GSTs superfamily. GSTO1 and GSTO2 polymorphisms have been reported to be related to several types of disease. We assessed the association between GSTO1 and GSTO2 polymorphisms and childhood pre-B ALL risk in Iran. METHODS: This case-control study analyzed GSTO1 A140D (rs. 4925) and GSTO2 N142D (rs. 156697) gene polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism method, in 100 patients and 120 healthy controls. RESULTS: The genotype frequencies were not significantly different between patients and healthy controls. Odds ratio (95% confidence intervals) for mutant homozygotes were 1.54 (0.628-3.778) and 0.791 (0.349-1.793) for GSTO1 A140D and GSTO2 N142D, respectively. CONCLUSION: This study found no significant association between Pre-B ALL and GSTO1 A140D and GSTO2 N142D polymorphisms. PMID- 25726707 TI - Nosocomial bloodstream infections in a nationwide study: comparison between solid organ transplant patients and the general population. AB - BACKGROUND: The incidence of bloodstream infection (BSI) varies according to the transplanted organ. Mortality can be as high as 24%, with a significant impact on graft survival. Transplantation is a risk factor for multidrug-resistant (MDR) organisms, but comparison with a non-transplanted population in a single large cohort has not been described. METHODS: This is a prospective nationwide study (16 centers) reporting data on 2364 monomicrobial nosocomial BSIs, comparing 83 episodes in solid organ transplant patients with 2447 BSIs occurring in the general hospital population. RESULTS: The prevalence of groups of infecting organisms (gram-positive, gram-negative, and fungi) was similar between transplant patients and the general population and a similar crude mortality rate was observed (34.9% in transplant vs. 43.3% in non-transplant patients). Staphylococcus aureus was the single most frequently isolated organism in both groups, and Acinetobacter species was more frequently isolated in the general population. Regarding MDR organisms, Klebsiella species, and Enterobacter species resistant to cefepime, as well as Acinetobacter species resistant to meropenem, were significantly more frequent in transplant patients. CONCLUSION: Antimicrobial resistance is higher, particularly among gram-negative bacteria in the transplant population, although the overall mortality rate between transplant and non-transplant patients with nosocomial BSI is similar. PMID- 25726708 TI - Effect of acute kidney injury on mortality and hospital stay in patient with severe acute pancreatitis. AB - AIM: Severe acute pancreatitis (SAP) is believed to be a major risk factor leading to acute kidney injury (AKI) among critically ill patients, but little is known about SAP-induced AKI. We study the incidence of AKI defined by the Acute Kidney Injury Network (AKIN) criteria and the risk factors associated with outcomes among SAP-induced AKI patients. METHOD: We conducted a multicenter retrospective study of critically ill SAP-induced AKI patients during the period August 2009 to June 2013. Data on enrolled patients were retrieved from electronic records. Univariate and multiple regression analyses were performed. RESULTS: Among a total of 414 SAP patients admitted to intensive care units(ICU), 287 (69.3%) developed AKI during their ICU stay, with 16.7%, 18.4%, and 34.3% classified as AKI stage I,II, and III, respectively. SAP-induced AKI patients experienced a significantly higher ICU mortality than those without AKI. The risk factors associated with ICU mortality among SAP-induced AKI patients included ACS (odds ratio (OR) 10.58), RRT (OR 3.31), sepsis (OR 2.46), CTSI (OR 3.01), APACHE II score (OR 1.82), AKI III (OR 1.38), ICU-length-of-stay (OR 1.04), and multi organ failure. CONCLUSIONS: The paper represents the first attempt to investigate the etiology and epidemiology of AKI following SAP under the AKIN criteria among critically ill patients. Several independent risk factors were found to be associated with ICU mortality for AKI patients. The findings may pinpoint crucial therapeutic measures for preventing AKI among a vulnerable population and for more effective management of SAP-induced AKI to improve the quality of intensive care. PMID- 25726709 TI - Dynamic light scattering study and DLVO analysis of physicochemical interactions in colloidal suspensions of charged disks. AB - The interparticle interactions in colloidal suspensions of charged disks of Laponite clay in water were investigated using dynamic light scattering (DLS) and Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. We studied the effects of clay concentration (C(L)), the concentration of externally added salt (C(S)), and temperature (T) on the microscopic dynamics of the clay suspensions. The fast (tau1) and mean slow relaxation times (?tau(ww)?) of Laponite suspensions were extracted from intensity autocorrelation functions measured at different waiting times (t(w)) after sample preparation. Comprehensive Laponite concentration-salt concentration-temperature-time superpositions of both the microscopic diffusive time scales and the stretching exponent corresponding to the slow relaxation process highlight the self-similar nature of the energy landscapes of the Laponite suspensions. The evolution of the sodium ion concentration in the aging suspension with tw, measured for several values of CL, CS, and T, was used in a DLVO analysis of the free energy of the suspension for two charged disks parallely approaching one another. This analysis confirms that, in addition to repulsive interparticle interactions, attractive interactions also play a pivotal role in the microscopic dynamics of spontaneously evolving Laponite suspensions. PMID- 25726710 TI - Frequency of P2RX7 A1513C and TLR2 -196 to -174 ins/del in healthy Polish individuals. AB - Polymorphisms within genes coding innate immune response proteins are involved in genetic susceptibility to various conditions. We investigated the frequency of P2RX7 A1513C and TLR2 -196 to -174 ins/del polymorphisms in healthy Polish population. Frequency of minor alleles was relatively similar to the pattern presented by Caucasian populations while it differed significantly when compared to non-European populations, which could be a result of variable selection pressure put upon studied alleles or hindered gene flow between populations. PMID- 25726711 TI - Self-esteem, body-esteem, emotional intelligence, and social anxiety in a college sample: the moderating role of weight. AB - To examine the relationships between self-esteem, body-esteem, emotional intelligence, and social anxiety, as well as to examine the moderating role of weight between exogenous variables and social anxiety, 520 university students completed the self-report measures. Structural equation modeling revealed that individuals with low self-esteem, body-esteem, and emotional intelligence were more likely to report social anxiety. The findings indicated that obese and overweight individuals with low body-esteem, emotional intelligence, and self esteem had higher social anxiety than others. Our results highlight the roles of body-esteem, self-esteem, and emotional intelligence as influencing factors for reducing social anxiety. PMID- 25726712 TI - PDK1 is a potential therapeutic target against angiosarcoma cells. AB - BACKGROUND: Angiosarcoma is a rare and aggressive malignant neoplasm of endothelial cells. Recent studies have shown that the mTOR pathway is also aberrantly activated in cutaneous angiosarcoma. New therapeutic strategies are required because the prognosis of this disease is still poor. OBJECTIVE: The aim of the present study was to determine the driver gene of angiosarcoma useful for the screening of small molecule inhibitors. METHODS: We investigated the sensitivity of inhibitors for the PI3K/AKT/mTOR pathway in ISOS-1 and ISO-HAS cutaneous angiosarcoma cell lines. Flow cytometric analysis was conducted to evaluate cell-cycle progression and apoptosis. Western blot analyses were performed to elucidate the possible underlying mechanisms of growth inhibition. The colony formation assay was conducted to evaluate the clonogenic potential. We used the siRNA for PDK1 to examine the role of PDK1 on the growth of angiosarcoma cells. RESULTS: The PI3K inhibitor and mTOR inhibitor inhibited the growth of both cell lines in a dose-dependent manner. The PI3K inhibitor more effectively induced cell-cycle arrest at the G1 phase with the downregulated expression of cyclin D in ISOS-1 cells than the mTOR inhibitor. The PI3K inhibitor and mTOR inhibitor weakly but significantly induced G1 cell cycle arrest at the same degree in ISO-HAS cells. The expression of cyclin D was downregulated by the treatment with siRNA for PDK1, but not by the AKT inhibitor in ISOS-1 and ISO-HAS cells. The knock down of PDK1 with siRNA was more effective at reducing colony numbers than the mTOR inhibitor in ISOS-1 cells. CONCLUSION: These data showed that PDK1 played a pivotal role in the growth of angiosarcoma cells. Therefore, inhibition of PDK1, but not AKT, may be a more appropriate strategy than that of mTORC1 for the treatment of cutaneous angiosarcoma; the PDK1 inhibitor is promising as a therapeutic agent. PMID- 25726713 TI - Hedgehog inhibitors: a patent review (2013 - present). AB - INTRODUCTION: The hedgehog (Hh) signaling pathway is an important signaling pathway, playing a critical role in regulation of cell growth, development, metastasis and angiogenesis. Aberrant activation of this pathway has been linked to the development of several human tumor types, which makes it an attractive target for cancer treatment. Now many efforts in both industry and academia have been made to explore small molecular Hh inhibitors as anticancer agents. AREAS COVERED: This review aims to provide an overview of recent patents (2013- present) in the discovery, research and development of Hh inhibitors. EXPERT OPINION: Hh signaling pathway inhibitors attract much interest for their therapeutic potential in the treatment of a variety of human cancers. In 2012, vismodegib was approved by the FDA as a smoothened inhibitor for locally advanced or metastatic basal cell carcinoma treatment, and presently, it is ongoing clinical trials for validating its use in other tumor types. It is clear that Hh inhibitors may provide a promising clinical benefit in treating tumors involving active Hh signaling pathway with a mutation-driven mechanism. However, the efficacy of Hh inhibitors on other human tumor types is still needed to further identify. PMID- 25726714 TI - Case of familial Michelin tire baby syndrome. PMID- 25726715 TI - Is oxidative stress related to cadmium accumulation in the Mollusc Crassostrea angulata? AB - The kinetics of cadmium (Cd) accumulation in the gills and digestive gland of Crassotrea angulata at three concentrations of cadmium (0.088 MUM, 0.44 MUM and 2.22 MUM) was monitored for 28 days. The relationship between accumulation and toxicity was studied using metallothionein-like protein (MTLP) concentration and reduced glutathione levels (GSH) as biochemical endpoints. The activity of enzymes which form part of the antioxidant defense system, in particular glutathione reductase (GR), total glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), as enzymatic endpoints, was also assessed. A first order kinetic model demonstrated that the accumulation process does not take place linearly, as the Cd concentration in gills and digestive gland tended toward a stationary state. Metallothionein-like protein is clearly induced by Cd accumulation; however, at high Cd concentrations the detoxification mechanism of this protein is affected. High Cd concentrations (2.22 MUM) lead to a decrease in GSH levels, and also inhibit antioxidant enzyme activities, demonstrating the adverse effect of this metal on the antioxidant balance system. PMID- 25726716 TI - Antibiotic resistance as collateral damage: the tragedy of the commons in a two disease setting. AB - We propose a simple two-disease epidemic model where one disease exhibits only a drug-sensitive strain, while the other exhibits both drug-sensitive and drug resistant strains. Treatment for the first disease may select for resistance in the other. We model antibiotic use as a mathematical game through the study of individual incentives and community welfare. The basic reproduction number is derived and the existence and local stability of the model equilibria are analyzed. When the force of infection of each disease is unaffected by the presence of the other, we find that there is a conflict of interest between individual and community, known as a tragedy of the commons, under targeted treatment toward persons infected by the single strain disease, but there is no conflict under mass treatment. However, we numerically show that individual and social incentive to use antibiotics may show disaccord under mass treatment if the restriction on the transmission ability of the dually infected people is removed, or drug resistant infection is worse than drug sensitive infection, or the uninfected state has a comparative disutility over the infected states. PMID- 25726717 TI - An international road map to improve pain assessment in people with impaired cognition: the development of the Pain Assessment in Impaired Cognition (PAIC) meta-tool. AB - BACKGROUND: Pain is common in people with dementia, yet identification is challenging. A number of pain assessment tools exist, utilizing observation of pain-related behaviours, vocalizations and facial expressions. Whilst they have been developed robustly, these often lack sufficient evidence of psychometric properties, like reliability, face and construct validity, responsiveness and usability, and are not internationally implemented. The EU-COST initiative "Pain in impaired cognition, especially dementia" aims to combine the expertise of clinicians and researchers to address this important issue by building on previous research in the area, identifying existing pain assessment tools for dementia, and developing consensus for items for a new universal meta-tool for use in research and clinical settings. This paper reports on the initial phase of this collaboration task. METHODS: All existing observational pain behaviour tools were identified and elements categorised using a three-step reduction process. Selection and refinement of items for the draft Pain Assessment in Impaired Cognition (PAIC) meta-tool was achieved through scrutiny of the evidence, consensus of expert opinion, frequency of use and alignment with the American Geriatric Society guidelines. The main aim of this process was to identify key items with potential empirical, rather than theoretical value to take forward for testing. RESULTS: 12 eligible assessment tools were identified, and pain items categorised according to behaviour, facial expression and vocalisation according to the AGS guidelines (Domains 1 - 3). This has been refined to create the PAIC meta-tool for validation and further refinement. A decision was made to create a supporting comprehensive toolkit to support the core assessment tool to provide additional resources for the assessment of overlapping symptoms in dementia, including AGS domains four to six, identification of specific types of pain and assessment of duration and location of pain. CONCLUSIONS: This multidisciplinary, cross-cultural initiative has created a draft meta-tool for capturing pain behaviour to be used across languages and culture, based on the most promising items used in existing tools. The draft PAIC meta-tool will now be taken forward for evaluation according to COSMIN guidelines and the EU-COST protocol in order to exclude invalid items, refine included items and optimise the meta-tool. PMID- 25726718 TI - Clinicopathologic findings in (anti-FcepsilonR1alpha) autoimmune-related chronic urticaria. AB - BACKGROUND: One cause of chronic urticaria is autoreactivity which is diagnosed by detecting autoantibodies against the IgE receptor alpha subunit (anti-Fc R1alpha). OBJECTIVE: To compare the histopathologic features of chronic urticaria patients testing positive for anti-IgE receptor antibody (Ab) to those testing negative. METHODS: Totally, 438 patients with a clinical presentation of chronic urticaria (2011-2013) had anti-IgE receptor Ab tested and 37 of those patients had skin biopsy. We evaluated microscopic features including: spongiosis, dermal edema, presence of mast cells, density of lymphocytic infiltration, predomination of eosinophils/neutrophils; intravascular neutrophils and presence of vasculitis. The aforementioned features were compared between negative and positive anti-IgE receptor Ab groups. RESULTS: Of 37 patients , 69% were women and 31% were men. 49% had positive anti-IgE receptor Ab and 51% had negative anti-IgE receptor Ab. In the positive anti-IgE receptor Ab group, 83% showed intravascular neutrophils. Eosinophil predominance was identified in 72% and neutrophil predominance was identified in 28%. In the negative anti-IgE receptor Ab group, 89% showed intravascular neutrophils. Eosinophil predominance was identified in 53% and neutrophil predominance was identified in 47%. There was no evidence of vasculitis in either group. CONCLUSION: There were no significant histopathologic differences between the anti-IgE receptor Ab positive and negative cases. Therefore, serum testing for anti-IgE receptor Ab is required to identify this subgroup of chronic urticaria patients. PMID- 25726719 TI - Action of anti-M3muscarinic acetylcholine receptor IgG of primary Sjogren's syndrome on the enzymatic antioxidant system in rat submandibular gland. AB - BACKGROUND: We demonstrate that serum immunoglobulin G (IgG) directed against glandular M3 muscarinic acetylcholine receptors (M3mAChR) and pilocarpine triggers the increment of superoxide dismutase (SOD) and catalase (CAT) and the production of nitric oxide (NO) and prostaglandin E2(PGE2). METHODS: Enzyme linked immunosorbent assay (ELISA) was performed in the presence of the human M2mAChR synthetic peptide as antigen to detect in serum of pSS patients the autoantibodies. Further, SOD and CAT specific activity and NO were determined chemically in the presence of anti-M3mAChR IgG and pilocarpine. The level of PGE2generation in the presence of autoantibody and pilocarpine was determined by ELISA. RESULTS: An association between anti-M2mAChR autoantibodies and pilocarpine given the increment of the specific activity of SOD and CAT in the serum of pSS patients and in the rat submandibular gland was observed. As a result of this action, M3synthetic peptide and atropine abrogated the stimulatory action. The L-type calcium channel, calcium/calmodulin complex and COX-2 inhibitors selectively blocked the increment of the specific activity of SOD and CAT in the rat submandibular gland. An increased production of NO and PGE2by the cholinergic autoantibody and pilocarpine was also detected. CONCLUSION: On the basis of these results, the increment of the specific activity of SOD and CAT in pSS patients as compared to control healthy individuals may be seen as a defensive reaction to the increment of the amount of ROS, which becoming uncontrollable, leads to irreversible cellular and tissue damage. PMID- 25726720 TI - Biomarkers for Bisphosphonate-Related Osteonecrosis of the Jaw. AB - PURPOSE: The aim of this study was to investigate a possible biomarker for bisphosphonate-related osteonecrosis of the jaw (BRONJ) in an animal model. MATERIALS AND METHODS: Forty-eight Sprague-Dawley rats were randomly divided into the bisphosphonate group (n = 36), who were injected once a week with zoledronic acid, and the control group (n = 12), who were injected once a week with saline. After 6 weeks, surgical intervention was performed, and injections were continued up to 8 weeks. Rats in the bisphosphonate group were then further classified to the ONJ group, and the non-ONJ group, and biomarkers, including CTx, Glu-OC, TRACP 5b, RANKL, and OPG, were assessed at baseline (T0), at surgical intervention (T1), and at sacrifice (T2). Histomorphometric analysis for quantification of osteoclasts was performed. RESULTS: Repeated measures analysis of variance revealed that TRACP 5b levels and the RANKL/OPG ratio were significantly decreased over time in the ONJ group compared with the non-ONJ group (p < .05). At T2, the area under the curve was 0.807 for TRACP 5b (sensitivity: 88.9%, specificity 66.7% at cutoff) and 0.765 for the RANKL/OPG ratio (sensitivity: 77.8%, specificity 62.9% at cutoff). TRACP 5b showed a lower least significant change (29.6%) with lower intra-assay coefficient of variability (CV; 6.32%) and interassay CV (11.20%) compared with those of the RANKL/OPG ratio (39.27%) and showed a higher signal-to-noise ratio (2.76) than that of the RANKL/OPG ratio (1.62). N.Oc/T.Ar and N.Oc/B.Ar demonstrated significantly decreased number of osteoclasts in ONJ group versus non-ONJ group. CONCLUSIONS: These results show that serum TRACP 5b and the RANKL/OPG ratio were possible biomarkers for BRONJ. These data may provide useful additional information for future ONJ research. Further studies are needed to validate these results in humans with ONJ. PMID- 25726721 TI - Infrequent dream recall associated with low performance but high overnight improvement on mirror-tracing. AB - Although sleep facilitates learning and memory, the roles of dreaming and habitual levels of recalling dreams remain unknown. This study examined if performance and overnight improvement on a rapid eye movement sleep-sensitive visuomotor task is associated differentially with habitually high or low dream recall frequency. As a relation between dream production and visuospatial skills has been demonstrated previously, one possibility is that frequency of dream recall will be linked to performance on visuomotor tasks such as the Mirror Tracing Task. We expected that habitually low dream recallers would perform more poorly on the Mirror Tracing Task than would high recallers and would show less task improvement following a night of sleep. Fifteen low and 20 high dream recallers slept one night each in the laboratory and performed the Mirror Tracing Task before and after sleep. Low recallers had overall worse baseline performance but a greater evening-to-morning improvement than did high recallers. Greater improvements in completion time in low recallers were associated with Stage 2 rather than rapid eye movement sleep. Findings support the separate notions that dreaming is related to visuomotor processes and that different levels of visuomotor skill engage different sleep- and dream-related consolidation mechanisms. PMID- 25726722 TI - Preoperative computed tomography assessment of skeletal muscle mass is valuable in predicting outcomes following hepatectomy for perihilar cholangiocarcinoma. AB - BACKGROUND: Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with high rates of morbidity and mortality. OBJECTIVES: This study investigated the impact of low skeletal muscle mass on short- and longterm outcomes following hepatectomy for PHC. METHODS: Patients included underwent liver surgery for PHC between 1998 and 2013. Total skeletal muscle mass was measured at the level of the third lumbar vertebra using available preoperative computed tomography images. Sex-specific cut-offs for low skeletal muscle mass were determined by optimal stratification. RESULTS: In 100 patients, low skeletal muscle mass was present in 42 (42.0%) subjects. The rate of postoperative complications (Clavien Dindo Grade III and higher) was greater in patients with low skeletal muscle mass (66.7% versus 48.3%; multivariable adjusted P = 0.070). Incidences of sepsis (28.6% versus 5.2%) and liver failure (35.7% versus 15.5%) were increased in patients with low skeletal muscle mass. In addition, 90-day mortality was associated with low skeletal muscle mass in univariate analysis (28.6% versus 8.6%; P = 0.009). Median overall survival was shorter in patients with low muscle mass (22.8 months versus 47.5 months; P = 0.014). On multivariable analysis, low skeletal muscle mass remained a significant prognostic factor (hazard ratio 2.02; P = 0.020). CONCLUSIONS: Low skeletal muscle mass has a negative impact on postoperative mortality and overall survival following resection of PHC and should therefore be considered in preoperative risk assessment. PMID- 25726724 TI - In situ measurements of radiofrequency exposure levels in Greece from 2008 to 2013: a multi-parametric annual analysis. AB - From 2008 through 2013, more than 6,000 in situ frequency selective audits, in the proximity of base stations, were conducted throughout Greece by the Greek Atomic Energy Commission (EEAE), in order to verify exposure limit compliance. EEAE is the competent national authority for protection of the general public against artificially produced non-ionizing radiation. This paper presents the first post processing and multi-parametric year statistical analysis of in situ measurement data corresponding to 4,705 audits in the whole country, compared to general public exposure levels, according to Greek legislation. The aim is to derive nationwide conclusions for the characterization of general public exposure to radiofrequency electromagnetic fields, during the last 6 years. The results' presentation includes electric field exposure ratios referring to broadband and frequency selective measurements at the highest exposure measurement point. Statistical analysis is applied to assist the data presentation and evaluation, based on selected criteria and classification parameters, including: (i) year (2008-2013); (ii) environment (urban/suburban/rural); (iii) frequency bands of selected common telecommunication services (e.g., TV, FM, GSM, DCS, UMTS); and (iv) number of service providers installed at the same site. In general, measurement results revealed that the vast majority of exposure values were below reference levels for general public exposure, as defined by Greek legislation. Data are constantly updated with the latest measurements, including emerging wireless technologies. PMID- 25726723 TI - Intrathecal gadodiamide for identifying subarachnoid and ventricular neurocysticercosis. AB - OBJECTIVE: Some neurocysticercosis cysts may remain hidden despite novel MRI sequences. This study evaluates the diagnostic value of gadodiamide (GDD) contrasted MRI cisternography in selected cases of neurocysticercosis. METHODS: We included patients aged 18-65 years with a probable diagnosis of subarachnoid cysticercosis in whom previous neuroimaging studies failed to demonstrate the presence of cysts. One millilitre of GDD was administered intrathecally as a contrast agent with subsequent performance of MRI. RESULTS: Fourteen patients were included. Optimal contrast diffusion was achieved in nine patients, and partial diffusion was achieved in 4. Intracranial vesicles were identified in 10 patients, with the presence of more than 60 basal subarachnoid vesicles being revealed in all, with five cysts in the fourth ventricle in four patients and a floating cyst in the lateral ventricle in one. In one case, intrathecal GDD demonstrated spinal cysticercosis. No adverse events were reported after intrathecal GDD administration. CONCLUSIONS: Intrathecal GDD administration is useful for the diagnosis of subarachnoid and intraventricular neurocysticercosis and can be used to improve diagnostic accuracy in selected cases. PMID- 25726725 TI - Association of carotenoids with risk of gastric cancer: A meta-analysis. AB - BACKGROUND & AIMS: Prior studies on carotenoids and gastric cancer risk have generated inconsistent results. We performed a meta-analysis of observational studies to summarize the evidence regarding the relation of carotenoids and gastric cancer risk. METHODS: A comprehensive search was performed to identify all observational studies providing quantitative estimates between gastric cancer risk and carotenoids. The fixed or random effect model was selected based on the homogeneity test among studies in the highest vs. lowest categorical analyses. RESULTS: 13 published case-control studies with 14 results including 3919 cases and 7400 controls, and 8 cohort studies involving 1972 cases of gastric cancer and 96,691 participants, met the inclusion criteria. For case-control studies, only intake of beta-carotene and alpha-carotene were significantly associated with a reduced gastric cancer risk. The summary OR(95%CI) for beta-carotene, alpha-carotene, lycopene and lutein were 0.52(0.46-0.59), 0.59(0.37-0.92), 0.88(0.55-1.41) and 0.85(0.56-1.30) respectively. In contrast, the summary RR(95%CI) for beta-carotene, alpha-carotene, lycopene and lutein were 0.72(0.50 1.03), 0.79(0.58-1.07), 0.80(0.60-1.07) and 0.95(0.77-1.18), respectively. CONCLUSION: Although data from case-control studies suggested that beta-carotene, alpha-carotene were inversely associated with risk of gastric cancer, there was no conclusive evidence on this association because of inconsistencies between case-control and cohort studies. PMID- 25726726 TI - Analysis of splice variants for the C. elegans orthologue of human neuroligin reveals a developmentally regulated transcript. AB - Neuroligins are synaptic adhesion molecules and important determinants of synaptic function. They are expressed at postsynaptic sites and involved in synaptic organization through key extracellular and intracellular protein interactions. They undergo trans-synaptic interaction with presynaptic neurexins. Distinct neuroligins use differences in their intracellular domains to selectively recruit synaptic scaffolds and this plays an important role in how they encode specialization of synaptic function. Several levels of regulation including gene expression, splicing, protein translation and processing regulate the expression of neuroligin function. We have used in silico and cDNA analyses to investigate the mRNA splicing of the Caenorhabditis elegans orthologue nlg-1. Transcript analysis highlights the potential for gene regulation with respect to both temporal expression and splicing. We found nlg-1 splice variants with all the predicted exons are a minor species relative to major splice variants lacking exons 13 and 14, or 14 alone. These major alternatively spliced variants change the intracellular domain of the gene product NLG-1. Interestingly, exon 14 encodes a cassette with two distinct potential functional domains. One is a polyproline SH3 binding domain and the other has homology to a region encoding the binding site for the scaffolding protein gephyrin in mammalian neuroligins. This suggests differential splicing impacts on NLG-1 competence to recruit intracellular binding partners. This may have developmental relevance as nlg-1 exon 14 containing transcripts are selectively expressed in L2-L3 larvae. These results highlight a developmental regulation of C. elegans nlg-1 that could play a key role in the assembly of synaptic protein complexes during the early stages of nervous system development. PMID- 25726727 TI - The paradoxical role of thioredoxin on oxidative stress and aging. AB - In spite of intensive study, there is still controversy about the free radical or oxidative stress theory of aging, particularly in mammals. Our laboratory has conducted the first detailed studies on the role of thioredoxin (Trx) in the cytosol (Trx1) and in mitochondria (Trx2) on oxidative stress and aging using unique mouse models either overexpressing or down-regulating Trx1 or Trx2. The results generated from our lab and others indicate that: (1) oxidative stress and subsequent changes in signaling pathways could have different pathophysiological impacts at different stages of life; (2) changes in redox-sensitive signaling controlled by levels of oxidative stress and redox state could play more important roles in pathophysiology than accumulation of oxidative damage; (3) changes in oxidative stress and redox state in different cellular compartments (cytosol, mitochondria, or nucleus) could play different roles in pathophysiology during aging, and their combined effects show more impact on aging than changes in either oxidative stress or redox state alone; and (4) the roles of oxidative stress and redox state could have different pathophysiological consequences in different organs/tissues/cells or pathophysiological conditions. To critically test the role of oxidative stress on aging and investigate changes in redox sensitive signaling pathways, further study is required. PMID- 25726729 TI - Continence outcomes of robot-assisted radical prostatectomy in patients with adverse urinary continence risk factors. AB - OBJECTIVE: To analyse the continence outcomes of robot-assisted radical prostatectomy (RARP) in suboptimal patients that have challenging continence recovery factors such as enlarged prostates, elderly patients, higher body mass index (BMI), salvage prostatectomy, and bladder neck procedures before RARP. PATIENTS AND METHODS: From January 2008 through November 2012, 4,023 patients underwent RARP by a single surgeon at our institution. Retrospective analysis of prospectively collected data identified 3,362 men who had minimum of 1-year follow-up. This cohort of patients was stratified into six groups: Group I, aged >=70 years (451 patients); Group II, BMI >=35 kg/m(2) (197); Group III, prior bladder neck procedures (103); Group IV, prostate weight >=80 g (280); and Group V, salvage prostatectomy (41). Group VI consisted of patients (2 447) with none of these risk factors. Continence outcomes at follow-up were analysed for all groups. RESULTS: The continence rate at 1 year and mean (sd) time to continence in different groups were: for patients aged >=70 years, 85.6% and 3.2 (4.5) months; BMI of >=35 kg/m(2) , 87.8% and 3.1 (4.5) months; prior bladder neck treatment, 82.4% and 3.4 (4.7) months; prostate weight of >=80 g, 85.8% and 3.3 (4.4) months; salvage procedures, 51.3% and 6.6 (8.3) months; and in Group VI (none of the risk factors), 95.1% and 2.4 (3.2) months. The continence rate was significantly higher in group VI compared with the salvage group (group V) at the different follow-up intervals (P < 0.001). When compared with the other groups (I IV), the continence rate, although higher, was not statistically significant at the different intervals in group VI (no risk). The mean time to continence was significantly lower in group VI compared with the other groups (I-V; P < 0.001). CONCLUSIONS: This study has shown that selected risk factors adversely affect the time to return of continence after RARP, yet aside from salvage patients, there was no statistically significant difference demonstrated between the adverse-risk groups included. Patients undergoing salvage RP had significantly lower continence rates at the various intervals compared with the other groups. Patients with the risk factors identified should be counselled concerning expectations for achieving urinary continence. PMID- 25726728 TI - Phosphorylation of Ser283 enhances the stiffness of the tropomyosin head-to-tail overlap domain. AB - The ends of coiled-coil tropomyosin molecules are joined together by nine to ten residue-long head-to-tail "overlapping domains". These short four-chained interconnections ensure formation of continuous tropomyosin cables that wrap around actin filaments. Molecular Dynamics simulations indicate that the curvature and bending flexibility at the overlap is 10-20% greater than over the rest of the molecule, which might affect head-to-tail filament assembly on F actin. Since the penultimate residue of striated muscle tropomyosin, Ser283, is a natural target of phosphorylating enzymes, we have assessed here if phosphorylation adjusts the mechanical properties of the tropomyosin overlap domain. MD simulations show that phosphorylation straightens the overlap to match the curvature of the remainder of tropomyosin while stiffening it to equal or exceed the rigidity of canonical coiled-coil regions. Corresponding EM data on phosphomimetic tropomyosin S283D corroborate these findings. The phosphorylation induced change in mechanical properties of tropomyosin likely results from electrostatic interactions between C-terminal phosphoSer283 and N-terminal Lys12 in the four-chain overlap bundle, while promoting stronger interactions among surrounding residues and thus facilitating tropomyosin cable assembly. The stiffening effect of D283-tropomyosin noted correlates with previously observed enhanced actin-tropomyosin activation of myosin S1-ATPase, suggesting a role for the tropomyosin phosphorylation in potentiating muscle contraction. PMID- 25726731 TI - Styloid/C1 transverse process juxtaposition as a cause of Eagle's syndrome. AB - BACKGROUND: The purpose of this case report was to characterize styloid/C1 transverse process juxtaposition as a cause for Eagle's syndrome. METHODS AND RESULTS: A case series was conducted with a chart review of 5 patients with radiographic evidence of jugular vein compression who underwent styloid process excision between 2010 and 2013. There were 4 men and 1 woman, aged 35 to 62 years (mean, 46 years). Cervicalgia (4 of 5 patients) and otalgia (4 of 5 patients) were the most commonly reported symptoms. Styloid process length ranged from 2.4 to 8.5 cm. The distance between the styloid process and the transverse process of C1 ranged from 0.05 to 0.46 cm. All patients underwent a transcervical approach for the excision of the styloid process with immediate postoperative resolution of symptoms and good cosmetic results. CONCLUSIONS: Styloid/C1 transverse process juxtaposition can produce symptoms of cervicalgia and otalgia even in the setting of a normal length styloid process. The transcervical approach is safe and effective for excision of the styloid process and has good functional and cosmetic results. PMID- 25726730 TI - Interstitial lung abnormalities in treatment-naive advanced non-small-cell lung cancer patients are associated with shorter survival. AB - OBJECTIVE: Interstitial lung diseases are associated with increased risk of lung cancer. The prevalence of ILA at diagnosis of advanced non-small-cell lung cancer (NSCLC) and its impact on overall survival (OS) remain to be investigated. MATERIALS AND METHOD: The study included 120 treatment-naive stage IV NSCLC patients (53 males, 67 females). ILA was scored on CT prior to any systemic therapy using a 4-point scale [0=no evidence of ILA, 1=equivocal for ILA, 2=suspicious for ILA, 3=ILA] by a sequential reading method previously reported. ILA scores of 2 or 3 indicated the presence of ILA. RESULTS: ILA was present in 17 patients (14%) with advanced NSCLC prior to any treatment (score3: n=2, score2: n=15). These 17 patients were significantly older (median age: 69 vs. 63, p=0.04) and had a heavier smoking history (median: 40 vs. 15.5 pack-year, p=0.003) than those with ILA score 0 or 1. Higher ILA scores were associated with shorter OS (p=0.001). Median OS of the 17 patients with ILA was 7.2 months [95%CI: 2.9-9.4] compared to 14.8 months [95%CI: 11.1-18.4] in patients with ILA score 0 or 1 (p=0.002). In a multivariate model, the presence of ILA remained significant for increased risk for death (HR=2.09, p=0.028) after adjusting for first-line systemic therapy (chemotherapy, p<0.001; TKI, p<0.001; each compared to no therapy) and pack years of smoking (p=0.40). CONCLUSION: Radiographic ILA was present in 14% of treatment-naive advanced NSCLC patients. Higher ILA scores were associated with shorter OS, indicating that ILA could be a marker of shorter survival in advanced NSCLC. PMID- 25726732 TI - Association of onabotulinum toxin A treatment with salivary pH and dental caries of neurologically impaired children with sialorrhea. AB - BACKGROUND: Sialorrhea is a common manifestation of several neurological disorders. The use of intraglandular onabotulinum toxin A (OBTXA) injection has been recognized to effectively treat sialorrhea. As OBTXA injection reduces salivary flow rate and alters salivary quality, its use may have a detrimental effect on oral health. AIM: To examine the effect of OBTXA injection on caries experience and salivary pH of neurologically impaired children with sialorrhea. DESIGN: Twenty-five children receiving OBTXA treatment and 25 control children were enrolled in the study. Whole saliva was collected to determine salivary pH. All participants underwent an interview on their dietary habits. Dental clinical examinations were carried out to evaluate caries experience and oral hygiene level. RESULTS: Overall, mean salivary pH value was significantly lower in the OBTXA group (6.92 +/- 0.77) compared with the control group (7.36 +/- 0.70). Caries activity was significantly higher in the OBTXA group (P = 0.01). The regression analyses showed a significant association between OBTXA treatment and salivary pH value (P = 0.03). Results from the logistic regression show that dental caries was significantly associated with OBTXA treatment (OR = 1.73, CI = 1.14-27.3). CONCLUSIONS: The study showed an intricate relationship between OBTXA treatment and oral findings. Hence, special dental care should be given to children receiving OBTXA treatment. PMID- 25726733 TI - Importance of T1-MRI enhanced pyramidal tracts in differential diagnosis as to paraneoplastic encephalomyelitis. PMID- 25726734 TI - Epigenetic heredity: RNA-mediated modes of phenotypic variation. AB - In addition to the Mendelian mutations, several instances of heritable phenotypic variation have been reported. We have observed, in mice, a role for sperm RNAs in the induction of such stable phenotypic variation. When experimentally transferred by RNA microinjection into fertilized mouse eggs, the noncoding RNAs homologous in sequence to the target locus are efficient inducers of variation at the transcriptional level. Transmission of the phenotypic variation to progeny is highly efficient and independent of gender. Here, we have summarized these finding and how they relate to other reports of epigenetic variation. PMID- 25726735 TI - Molecular, Neurochemical, and Behavioral Hallmarks of Reserpine as a Model for Parkinson's Disease: New Perspectives to a Long-Standing Model. AB - The administration of reserpine to rodents was one of the first models used to investigate the pathophysiology and screening for potential treatments of Parkinson's disease (PD). The reserpine model was critical to the understanding of the role of monoamine system in the regulation of motor and affective disorders, as well as the efficacy of current PD treatments, such as L-DOPA and dopamine agonists. Nevertheless, with the introduction of toxin-induced and genetic models of PD, reserpine became underused. The main rationale to this drawback was the supposed absence of reserpine construct validity with PD. Here, we highlight classical and recent experimental findings that support the face, pharmacological, and construct validity of reserpine PD model and reason against the current rationale for its underuse. We also aim to shed a new perspective upon the model by discussing the main challenges and potentials for the reserpine model of PD. PMID- 25726736 TI - Is obeticholic Acid the solution to nonalcoholic steatohepatitis? PMID- 25726737 TI - Endoscopic Retrograde Cholangiopancreatography After Roux-en-Y Gastric Bypass: Challenges and Cautions. PMID- 25726738 TI - Preventing diverticulitis: mesalamine may still be indicated in the decision. PMID- 25726739 TI - Reply: To PMID 25160979. PMID- 25726740 TI - Reply: To PMID 25167986. PMID- 25726741 TI - Esophageal tumor after radical surgery for gastric cancer. PMID- 25726742 TI - Are levels of alkaline phosphatases and bilirubin surrogate markers of outcomes of patients with primary biliary cirrhosis? PMID- 25726743 TI - A liver mass found after subtotal gastrectomy. PMID- 25726744 TI - Reply: To PMID 24975458. PMID- 25726745 TI - Recurrent regurgitation of a spongy mass into the mouth. PMID- 25726746 TI - The challenges of endoscopic retrograde cholangiopancreatography in gastric bypass patients: the game is not yet over. PMID- 25726748 TI - The dual roles of immunity in ALS: injury overrides protection. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease affecting motor neurons. Disease progression is accompanied by a multi phased immune response, and recent studies indicate that the immune system is not simply a bystander during disease, but plays an active role in shaping ALS pathology. The role of the immune system during ALS progression is highly complex, however, as it has been found to have a role in both enhancing neurodegeneration as well as protecting the central nervous system. Previous reports have established that the immune response can therefore be separated into two distinct phases: a protective Type 2 response followed by a neurotoxic Type 1 response. This review will address the two phases of the immune response in ALS and describe their roles during disease progression. More importantly, it will also examine the likely sources of immune polarization that are responsible for shifting immunity from the protective T2 phase to the neurotoxic T1 phase. PMID- 25726747 TI - Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. AB - Nerve injury can lead to axonal regeneration, axonal degeneration, and/or neuronal cell death. Remarkably, the MAP3K dual leucine zipper kinase, DLK, promotes each of these responses, suggesting that DLK is a sensor of axon injury. In Drosophila, mutations in proteins that stabilize the actin and microtubule cytoskeletons activate the DLK pathway, suggesting that DLK may be activated by cytoskeletal disruption. Here we test this model in mammalian sensory neurons. We find that pharmacological agents designed to disrupt either the actin or microtubule cytoskeleton activate the DLK pathway, and that activation is independent of calcium influx or induction of the axon degeneration program. Moreover, activation of the DLK pathway by targeting the cytoskeleton induces a pro-regenerative state, enhancing axon regeneration in response to a subsequent injury in a process akin to preconditioning. This highlights the potential utility of activating the DLK pathway as a method to improve axon regeneration. Moreover, DLK is required for these responses to cytoskeletal perturbations, suggesting that DLK functions as a key neuronal sensor of cytoskeletal damage. PMID- 25726749 TI - Ranibizumab in the treatment of choroidal neovascularization associated with morning glory syndrome. PMID- 25726750 TI - Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats. AB - The present study explores the role of simvastatin in vincristine-induced neuropathic pain, which was induced by administering vincristine (100 ug/kg i.p.) for 10 days (two 5 day cycles with 2 days pause). Pain was assessed by determining mechanical hyperalgesia, mechanical dynamic allodynia, heat hyperalgesia and cold allodynia. Biochemically, myeloperoxidase (MPO) activity was measured along with serum cholesterol levels. Simvastatin (7.5, 15 and 30 mg/kg) was administered for 14 days after administration of vincristine. Simvastatin (7.5 and 15 mg/kg) reversed vincristine-induced neuropathic pain and attenuated vincristine-induced increase in MPO, without altering cholesterol levels. Simvastatin at higher dose (30 mg/kg) did not alter neuropathic pain despite decreasing MPO levels. Furthermore, administration of simvastatin (30 mg/kg i.p.) in vincristine treated rats as well as it's per se administration in normal rats reduced cholesterol levels. Per se administration of simvastatin in normal rats produced neuropathic pain. It is concluded that simvastatin attenuates neuropathic pain only at lower doses with no reduction in cholesterol levels and anti-inflammatory effects may possibly reverse neuropathic pain. However, despite reducing inflammation, simvastatin did not confer beneficial effects at higher doses at which there is reduction in cholesterol levels, suggesting the critical role of cholesterol in neuropathic pain induction. PMID- 25726752 TI - Speculum versus Bimanual Lid Retraction during Intravitreal Injection. PMID- 25726751 TI - The regulation of T follicular helper responses during infection. AB - Following infection, naive CD4 T cells can differentiate into various functionally distinct effector and memory subsets, including T follicular helper (TFH) cells that orchestrate germinal center (GC) reactions necessary for high affinity, pathogen-specific antibody responses. The origins and function of this cell type have been extensively examined in response to subunit immunization with model antigens. More recently, we are beginning to also appreciate the extent to which microbial infections shape the generation, function and maintenance of TFH cells. Here, we review recent advances and highlight additional knowledge gaps in our understanding of how microbial infections influence priming, differentiation, localization and activity of TFH cells following acute and chronic infections. PMID- 25726753 TI - The transcription-coupled repair protein ERCC6/CSB also protects against repeat expansion in a mouse model of the fragile X premutation. AB - The fragile X-related disorders (FXDs) are members of the group of diseases known as the repeat expansion diseases. The FXDs result from expansion of an unstable CGG/CCG repeat tract in the 5' UTR of the FMR1 gene. Contractions are also seen, albeit at lower frequency. We have previously shown that ERCC6/CSB plays an auxiliary role in promoting germ line and somatic expansions in a mouse model of the FXDs. However, work in model systems of other repeat expansion diseases has suggested that CSB may protect against expansions by promoting contractions. Since FXD mice normally have such a high expansion frequency, it is possible that such a protective effect would have been masked. We thus examined the effect of the loss of CSB in an Msh2(+/-) background where the germ line expansion frequency is reduced and in an Msh2(-/-) background where expansions do not occur, but contractions do. Our data show that in addition to promoting repeat expansion, CSB does in fact protect the genome from germ line expansions in the FXD mouse model. However, it likely does so not by promoting contractions but by promoting an error-free process that preserves the parental allele. PMID- 25726754 TI - Effect of oil overlay on inhibition potential of roscovitine in sheep cumulus oocyte complexes. AB - Inhibitors of cyclin-dependent kinases, as roscovitine, have been used to prevent the spontaneous resumption of meiosis in vitro and to improve the oocyte developmental competence. In this study, the interference of oil overlay on the reversible arrest capacity of roscovitine in sheep oocytes as well as its effects on cumulus expansion was evaluated. For this, cumulus-oocyte complexes (COCs) were cultured for 20 h in TCM 199 with 10% foetal bovine serum (Control) containing 75 MUm roscovitine (Rosco). Subsequently, they were in vitro matured (IVM) for further 18 h in inhibitor-free medium with LH and FSH. The culture was performed in Petri dishes under mineral oil (+) or in 96 well plates without oil overlay (-) at 38.5 degrees C and 5% CO2 . At 20 and 38 h, the cumulus expansion and nuclear maturation were evaluated under stereomicroscope and by Hoechst 33342 staining, respectively. No group presented cumulus expansion at 20 h. After additional culture with gonadotrophins, a significant rate of COCs from both Control groups (+/-) exhibited total expansion while in both Rosco groups (+/-) the partial expansion prevailed. Among the oocytes treated with roscovitine, 65.2% were kept at GV in the absence of oil overlay while 40.6% of them reached MII under oil cover (p < 0.05). This meiotic arrest was reversible, and proper meiosis progression also occurred in the Control groups (+/-). So, the culture system without oil overlay improved the meiotic inhibition promoted by roscovitine without affecting the cumulus expansion rate or the subsequent meiosis progression. PMID- 25726755 TI - Sutureless scleral fixation of intraocular lenses. PMID- 25726756 TI - A family of [Mn(III)6Ln(III)2] rod-like clusters. AB - Employment of H3L (= 2-(beta-naphthalideneamino)-2-hydroxymethyl-1-propanol) in mixed-metal manganese-lanthanide cluster chemistry has led to the isolation of five new octametallic heteronuclear isostructural [Mn(III)6Ln(III)2] complexes. More specifically, the reaction of Mn(ClO4)2.6H2O with H3L and the corresponding lanthanide nitrate in MeCN in the presence of a base, NEt3, yielded four complexes with the general formula [Mn(III)6Ln(III)2O2(OH)2(H2O)2(HL)6(NO3)6].6MeCN.0.5H2O (Ln: Gd, 1.6MeCN.0.5H2O; Tb, 2.6MeCN.0.5H2O; Dy, 3.6MeCN.0.5H2O; Er, 4.6MeCN.0.5H2O). Furthermore, the Y(III) analogue, [Mn(III)6Y(III)2O2(OH)2(H2O)2(HL)6(NO3)6].6MeCN.0.5H2O (5.6MeCN.0.5H2O), was also synthesized in the same manner. All five clusters describe a central rod-like topology consisting of four face-sharing defective cubane metallic units, forming a planar hexametallic [Mn(III)4Ln(III)2] core, which is further capped by two Mn(III) ions. Dc magnetic susceptibility studies in the 5-300 K range for complexes 1-5 reveal the presence of dominant antiferromagnetic exchange interactions within the metallic clusters, while ac magnetic susceptibility measurements show temperature and frequency dependent out of-phase signals for the Dy(III) analogue (3.6MeCN.0.5H2O), suggesting potential single molecule magnetism character. Furthermore, the Y(III) analogue yielded a diamagnetic ground-state for the [Mn(III)6] core, thus proving that the SMM character displayed by 3.6MeCN.0.5H2O is due to the presence of the Dy(III) centres. PMID- 25726757 TI - TCR sequences and tissue distribution discriminate the subsets of naive and activated/memory Treg cells in mice. AB - Analyses of the regulatory T (Treg) cell TCR repertoire should help elucidate the nature and diversity of their cognate antigens and thus how Treg cells protect us from autoimmune diseases. We earlier identified CD44(hi) CD62L(low) activated/memory (am) Treg cells as a Treg-cell subset with a high turnover and possible self-specificity. We now report that amTreg cells are predominantly distributed in lymph nodes (LNs) draining deep tissues. Multivariate analyses of CDR3 spectratyping first revealed that amTreg TCR repertoire is different from that of naive Treg cells (nTreg cells) and effector T (Teff) cells. Furthermore, in deep- versus superficial LNs, TCR-beta deep sequencing further revealed diversified nTreg-cell and amTreg-cell repertoires, although twofold less diverse than that of Teff cells, and with repertoire richness significantly lower in deep LN versus superficial-LN Treg cells. Importantly, expanded clonotypes were mostly detected in deep-LN amTreg cells, some accounting for 20% of the repertoire. Strikingly, these clonotypes were absent from nTreg cells, but found at low frequency in Teff cells. Our results, obtained in nonmanipulated mice, indicate different antigenic targets for naive and amTreg cells and that amTreg cells are self-specific. The data we present are consistent with an instructive component in Treg-cell differentiation. PMID- 25726758 TI - Eumycetoma and actinomycetoma--an update on causative agents, epidemiology, pathogenesis, diagnostics and therapy. AB - Mycetoma is a chronic putrid infection of the cutaneous and subcutaneous tissue concerning predominantly the feet, and more rarely other body parts. Mycetoma can be caused by both fungi (eumycetoma) and bacteria (actinomycetoma). Mode of infection is an inoculation of the causative microorganism via small injuries of the skin. The clinical correlate of both forms of mycetoma is tumescence with abscesses, painless nodules, sinuses and discharge. The latter is commonly serous purulent and contains grains (filamentous granules) which can be expressed for diagnostic purposes. Distinctive for both eumycetoma and actinomycetoma, are the formation of grains. Grains represent microcolonies of the microorganism in vivo in the vital tissue. The most successful treatment option for eumycetomas offers itraconazole in a dosage of 200 mg twice daily. This triazole antifungal is considered as 'gold standard' for eumycetomas. Alternatively, the cheaper ketoconazole was widely used, however, it was currently stopped by the FDA. Actinomycetomas should be treated by the combination of trimethoprim sulphamethoxazole (co-trimoxazole 80/400 to 160/800 mg per day) and amikacin 15 mg/kg body weight per day. Mycetomas are neglected infections of the poor. They are more than a medical challenge. In rural areas of Africa, Asia and South America mycetomas lead to socio-economic consequences involving the affected patients, their families and the society in general. PMID- 25726759 TI - Dynamic association of PfEMP1 and KAHRP in knobs mediates cytoadherence during Plasmodium invasion. AB - Plasmodium falciparum infected erythrocytes display membrane knobs that are essential for their adherence to vascular endothelia and for prevention of clearance by the spleen. The knob associated histidine rich protein (KAHRP) is indispensable to knob formation and has been implicated in the recruitment and tethering of P. falciparum erythrocyte membrane protein-1 (PfEMP1) by binding to its cytoplasmic domain termed VARC. However, the precise mechanism of interaction between KAHRP and VARC is not very well understood. Here we report that both the proteins co-localize to membrane knobs of P. falciparum infected erythrocytes and have identified four positively charged linear sequence motifs of high intrinsic mobility on KAHRP that interact electrostatically with VARC in solution to form a fuzzy complex. The current study provides molecular insight into interaction between KAHRP and VARC in solution that takes place at membrane knobs. PMID- 25726760 TI - Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing. AB - INTRODUCTION: The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for (11)C-labeling of AZD3241 was developed. METHODS: AZD3241 was labeled in the thio-carbonyl position starting from [(11)C]potassium cyanide in a 4-step procedure using microwave assisted heating. In the first step [(11)C]potassium cyanide was converted to [(11)C]potassium thiocyanate followed by reaction with benzoyl chloride to yield benzoyl [(11)C]isothiocyanate. The benzoyl [(11)C]isothiocyanate was subsequently reacted with the precursor ethyl 3-(2 isopropoxyethylamino)-1H-pyrrole-2-carboxylate and the formed intermediate underwent a base catalyzed cyclization to obtain [(11)C]AZD3241 in the final step. To assess [(11)C]AZD3241 brain exposure PET measurements were performed in three cynomolgus monkeys. RESULTS: [(11)C]AZD3241 was produced in good and reproducible radiochemical yield 710 +/- 294 MBq (mean +/- SD, n = 7). Total time of synthesis was 60 min from end of bombardment. The specific radioactivity was 9 +/- 4GBq/MUmol and the radiochemical purity was >98%. Following iv administration of [(11)C]AZD3241 there was a rapid presence of radioactivity in brain in each of the three monkeys. The distribution of [(11)C]AZD3241 to brain was fast and a Cmax of 1.9 to 2.6% of the injected radioactivity was observed within 1.5 min. [(11)C]AZD3241 was homogeneously distributed in brain. CONCLUSION: The MPO inhibitor AZD3241 was successfully labeled with carbon-11 in a challenging 4-step procedure in good radiochemical yield allowing PET microdosing studies in cynomolgus monkey. [(11)C]AZD3241 rapidly entered brain and confirmed adequate brain exposure to support translation of AZD3241 to phase 2a studies in patients. PMID- 25726761 TI - Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma. AB - Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion. These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior. PMID- 25726762 TI - Selective retinol production by modulating the composition of retinoids from metabolically engineered E. coli. AB - Retinoids can be produced from E. coli when introduced with the beta-carotene biosynthesis pathway and the BCMO gene. E. coli has no inherent metabolic pathways related to retinoids, therefore only retinal should be produced from the cleavage of beta-carotene by BCMO. However, retinol and retinyl acetate were also produced in significant amounts, by the non-specific activity of inherent promiscuous enzymes or the antibiotic resistance marker of the retinal-producing plasmids. Retinol was produced by the ybbO gene of E. coli which encodes oxidoreductase and retinyl acetate was produced by the chloramphenicol resistance gene, called cat gene which encodes chloramphenicol acetyltransferase, present within the pS-NA plasmid that also contains the mevalonate pathway. The composition of retinoids could be modulated by manipulating the relevant genes. The composition of retinol, a commercially important retinoid, was significantly increased by the overexpression of ybbO gene and the removal of cat gene in the recombinant E. coli, which suggests the possibility of selective retinoid production in the future. PMID- 25726763 TI - Fingerprinting 2,3,7,8-tetrachlorodibenzodioxin contamination within the lower Passaic River. AB - The lower Passaic River is an operable unit of the Diamond Alkali Superfund site at 80 and 120 Lister Avenue in Newark, New Jersey, USA. Between 1948 and 1969, the Diamond Shamrock Chemicals Company and its predecessors manufactured chemicals such as pesticides and phenoxy herbicides, including 2,4,5 trichlorophenol, which is a precursor to 2,4,5-trichlorophenoxyacetic acid, one of the primary components used to make the military defoliant Agent Orange. A by product of this manufacturing process was 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TCDD), and the site is considered the dominant source of 2,3,7,8-TCDD to the lower Passaic River and its environs. Several investigators have identified the ratio of 2,3,7,8-TCDD to total TCDD as a fingerprint for the site source. The present study presents data that establish polychlorinated dibenzodioxin/polychlorinated dibenzofuran (collectively, PCDD/F) congener and homolog fingerprints of soil and sump samples from the site. It then compares those fingerprints to the PCDD/F congener and homolog patterns in lower Passaic River sediments. The similarity of the patterns in lower Passaic River sediments to the site fingerprint indicates the site is the dominant source of the 2,3,7,8 TCDD in sediments within approximately the lower 14 miles of the lower Passaic River, excluding, for the purposes of the present discussion, Newark Bay. In addition, PCDD/F congener data indicate that the ratio of 1,3,7,8-TCDD to 2,3,7,8 TCDD is another marker of the site and corroborates the findings from the other fingerprints. PMID- 25726764 TI - Anticholinergic medications and risk of community-acquired pneumonia in elderly adults: a population-based case-control study. AB - OBJECTIVES: To determine whether use of anticholinergics is associated with risk of community-acquired pneumonia in older adults. DESIGN: Population-based case control study. SETTING: An integrated healthcare delivery system in Washington State. PARTICIPANTS: Data from a nested case-control study of community-dwelling immunocompetent adults aged 65 to 94 were analyzed. Pneumonia cases (n=1,039) were ascertained according to International Classification of Diseases, Ninth Revision, codes from 2000 to 2003 and validated using chart review. Controls (n=2,022) were matched 2:1 to cases according to age, sex, and year. MEASUREMENTS: Anticholinergic medication exposure was ascertained using prescription data; acute use was defined as one or more prescription fills 90 days or less before the index date (date of pneumonia diagnosis), past use was defined as one or more prescription fills within the prior year but none within 90 days, and chronic use was defined as three or more prescription fills within the prior year. The reference group was those with no fills in the prior year. Conditional logistic regression was used to analyze the association between anticholinergic use and pneumonia, adjusted for comorbidities. RESULTS: Acute use of anticholinergics was observed in 59% of cases and 35% of controls (adjusted odds ratio (aOR)=2.55, 95% confidence interval (CI)=2.08-3.13) and past use in 17% of cases and 23% of controls (aOR=1.19, 95% CI=0.92-1.53). Chronic use of anticholinergics was observed in 53% of cases and 36% of controls (aOR 2.07, 95% CI=1.68-2.54). Results were not different for high- and low-potency anticholinergic medications. CONCLUSION: In older adults, anticholinergic medication use is associated with pneumonia risk, adding to substantial evidence suggesting that these medications are high risk. PMID- 25726765 TI - "Plug and play" full-dimensional ab initio potential energy and dipole moment surfaces and anharmonic vibrational analysis for CH4-H2O. AB - The potential energy surface of the methane-water dimer is represented as the sum of a new intrinsic two-body potential energy surface and pre-existing intramolecular potentials for the monomers. Different fits of the CH4-H2O intrinsic two-body energy are reported. All these fits are based on 30 467 ab initio interaction energies computed at CCSD(T)-F12b/haTZ (aug-cc-pVTZ for C and O, cc-pVTZ for H) level of theory. The benchmark fit is a full-dimensional, permutationally-invariant analytical representation with root-mean-square (rms) fitting error of 3.5 cm(-1). Two other computationally more efficient two-body potentials are also reported, albeit with larger rms fitting errors. Of these a compact permutationally invariant fit is shown to be the best one in combining precision and speed of evaluation. An intrinsic two-body dipole moment surface is also obtained, based on MP2/haTZ expectation values, with an rms fitting error of 0.002 au. As with the potential, this dipole moment surface is combined with existing monomer ones to obtain the full surface. The vibrational ground state of the dimer and dissociation energy, D0, are determined by diffusion Monte Carlo calculations, and MULTIMODE calculations are performed for the IR spectrum of the intramolecular modes. The relative accuracy of the different intrinsic two-body potentials is analyzed by comparing the energetics and the harmonic frequencies of the global minimum well, and the maximum impact parameter employed in a sample methane-water scattering calculation. PMID- 25726766 TI - [Healthcare aspects of domestic abuse]. AB - The paper reviews the forms of domestic abuse, its causes, prevalence and possible consequences. British and Hungarian Law, guidelines and the roles and responsibilities of healthcare professionals in relation to dealing with domestic abuse in their practice is also addressed within the paper. PMID- 25726767 TI - [Acatalasemia and type 2 diabetes mellitus]. AB - The catalase enzyme decomposes the toxic concentrations of hydrogen peroxide into oxygen and water. Hydrogen peroxide is a highly reactive small molecule and its excessive concentration may cause significant damages to proteins, deoxyribonucleic acid, ribonucleic acid and lipids. Acatalasemia refers to inherited deficiency of the catalase enzyme. In this review the authors discuss the possible role of the human catalase enzyme, the metabolism of hydrogen peroxide, and the phenomenon of hydrogen peroxide paradox. In addition, they review data obtained from Hungarian acatalasemic patients indicating an increased frequency of type 2 diabetes mellitus, especially in female patients, and an early onset of type 2 diabetes in these patients. There are 10 catalase gene variants which appear to be responsible for decreased blood catalase activity in acatalasemic patients with type 2 diabetes. It is assumed that low levels of blood catalase may cause an increased concentration of hydrogen peroxide which may contribute to the pathogenesis of type 2 diabetes mellitus. PMID- 25726768 TI - [Soft tissue-cutting law, i.e. the career concept of an autopsy assistant]. AB - Practical experience shows that the autopsy assistant society is fairly divided. There are some people who would have needed a thorough basic training, and there are those who - due to their diligence and the close cooperation with physician colleagues - would deserve an opportunity for further progress due to their extensive knowlegde. As regards the autopsy assistant profession the training, and the training system as well has changed significantly, and it requires further changes. Examining the issue in a wide spectrum, the aim of the authors is, as much as possible, to promote the formation of an "Autopsy assistant career," in which they want to create a predictable way for the members of the profession from the phase of becoming a student (competency, training, exams, vocational training, single note) to obtaining the master's degree. The authors would like to provide a summary about their experience and plans regarding this issue. PMID- 25726770 TI - [Dr. Gyorgy Forrai (1930-2014)]. PMID- 25726769 TI - [Changes in the outcome for infants, with birth weight under 500 grams, at our department (First Department of Obstetrics and Gynecology, Semmelweis University, Budapest)]. AB - INTRODUCTION: The mortality and morbidity of extremely low birth weight infants (birth weight below 1000 grams) are different from low birth weight and term infants. The Centers for Disease Control statistics from the year 2009 shows that the mortality of preterm infants with a birth weight less than 500 grams is 83.4% in the United States. In many cases, serious complications can be expected in survivals. AIM: The aim of this retrospective study was to find prognostic factors which may improve the survival of the group of extremely low birth weight infants (<500 grams). METHOD: Data of extremely low birth weight infants with less than 500 grams born at the 1st Department of Obstetrics and Gynecology, Semmelweis University between January 1, 2006 and June 1, 2012 were analysed, and mortality and morbidity of infants between January 1, 2006 and December 31, 2008 (period I) were compared those found between January 1, 2009 and June 1, 2012 (period II). Statistical analysis was performed with probe-t, -F and -Chi-square. RESULTS: Survival rate of extremely low birth weight infants less than 500 grams in period 1 and II was 26.31% and 55.17%, respectively (p = 0.048), whereas the prevalence of complications were not significantly different between the period examined. The mean gestational age of survived infants (25.57 weeks) was higher than the gestational age of infants who did not survive (24.18 weeks) and the difference was statistically significant (p = 0.0045). CONCLUSIONS: Education of the team of the Neonatal Intensive Care Unit, professional routine and technical conditions may improve the survival chance of preterm infants. The use of treatment protocols, conditions of the Neonatal Intensive Care Unit and steroid prophylaxis may improve the survival rate of extremely low birth weight infants. PMID- 25726771 TI - [Significance of balneo- and mechanotherapy in the treatment of cardiac diseases in the second part of the 19th and the first part of the 20th century]. PMID- 25726773 TI - Rh(III)-catalyzed and alcohol-involved carbenoid C-H insertion into N phenoxyacetamides using alpha-diazomalonates. AB - Here we report a new and mild Rh(III)-catalyzed and alcohol-involved carbenoid C H insertion into N-phenoxyacetamides using alpha-diazomalonates. This reaction provided a straightforward way for installing both an alpha-quaternary carbon center and a free-OH moiety into the phenyl ring, thus giving access to useful 2 (2-hydroxyphenyl)-2-alkoxymalonates with good substrate/functional group tolerance. PMID- 25726774 TI - [Controversial problems of clinical psychiatry]. AB - Current existing problems of clinical psychiatry are considered in the aspect of most urgent and unresolved issues in the field of schizophrenia. Special attention is drawn to the differences in existing approaches to the classification of schizophrenia. In this connection, the author emphasizes the importance of the classification developed by A.V. Snezhnevsky and his school for theoretical and practical psychiatry. In view of this classification, the problem of clinical heterogeneity of schizophrenia related with the conception of different disease forms is considered. Difficulties of diagnosis of some forms and psychopathological evaluation of psychotic attacks developed in the continuous course of schizophrenia well as insufficient understanding of the problem of negative (deficit) symptoms and remission classification are discussed. PMID- 25726775 TI - [Stress-induced dissociation in the trajectory of schizotypal personality disorder (on the model of nosogenias in oncologic patients)]. AB - OBJECTIVE: Stress-induced dissociative disorders (DD) have high prevalence in psychiatry and general medicine but the psychopathological differentiation of DD and contribution of personality disorders in their development is less studied. Authors conducted a clinical analysis of stress-induced persistent DD and underlying constitutional abnormalities. MATERIAL AND METHODS: It was examined 20 patients with DD induced by the stress caused by a cancer diagnosis, including 10 patients of detachment-dissociation group (denial of the disease, non-compliance) and 10 patients with compartment-dissociation (complete or partial detachment of stress response components (emotional, cognitive), adequate compliancy). The groups were matched for demographic and cancer characteristics. Clinical and psychological methods were used. RESULTS AND CONCLUSION: DD are secondary psychopathological phenomena. Detachment-dissociation develops in the frames of schizophrenic nosogenic reactions based on overvalued ideas of somatic well-being (or complete recovery from cancer) and has some similarities to schizotypal personality disorder. Compartment-dissociation develops within the limits of neurotic nosogenic reactions on the basis of binary psychogenic complexes - pathology of the imagination ("the beautiful indifference") concomitant to anxiety about the real illness and is similar to hysterical personality spectrum. PMID- 25726776 TI - [Schizophrenia: age at disease onset]. AB - OBJECTIVE: Until now the problem of the typical age of schizophrenia onset has been actively discussing in the world literature. Though there are more and more publications, which mention the growth in the number of cases with late-onset and very-late-onset of the disease, a conviction that schizophrenia is the illness of teenagers or young people is still exists. Author aimed to determine a preferable age of the onset of schizophrenia. MATERIAL AND METHODS: Data obtained in multi year epidemiological research in Mental Health Research Center (Moscow) were analized. The total number of patients with schizophrenia and spectrum disorders was 5486. A subgroup of the patients with the diagnosis that met the current diagnostic criteria of schizophrenia included 1108 people. The study was based on clinical-epidemiological and statistical methods. RESULTS: Most of patients had early onset schizophrenia (16-20 years old maximum). However, it mostly depended on demographic factors, because more than half of patients were young or middle aged at the moment of the examination. The examination of the group aged over 60 years and those who conditionally belonged to this generation (if 100% would have lived to that age) showed that the maximum number of patients had onset between 30-40 years old. CONCLUSION: This research demonstrates the essential predominance of cases with onset of the disease in adolescent and young age that may be rather related with demographic characteristics than pathogenetic mechanisms of schizophrenia. The latter determine predominantly middle age of disease onset (30-40 years). Cases both with early and late onset of the disease are not rare and are random deviations from the mean valuation. PMID- 25726777 TI - [Some variants of premanifesting disorders in attack-like schizophrenia]. AB - OBJECTIVE: To investigate a spectrum of disorders preceding the development of manifesting psychosis in the aspect of their topology and possible prognostic value. MATERIAL AND METHODS: Authors examined 60 outpatients, 21 women and 39 men, aged from 22 to 34 years. All patients were diagnosed with attack-like progressive schizophrenia. The retrospective evaluation of disease history and determination of the psychopathological structure and dynamics of manifesting episode and premanifesting symptom clustering were carried out. RESULTS AND CONCLUSION: It was identified 4 variants of premanifesting disorders: affective (n=15), affective with neurotic-like symptoms (n=17), affective with hallucinatory/paranoid symptoms (n=21) and affective with deficit symptoms (n=7). These disorders determine not only the transparent symptomatics but project in the manifesting episode structure and has a prognostic value thus reflecting a trend towards the continuous course of schizophrenia already at the premanifesting stage. PMID- 25726778 TI - [The typology of oneiroid-catatonic states in schizophrenia]. AB - OBJECTIVE: To determine the types of oneiroid-catatonic states characteristic of corresponding schizophrenia attacks and their treatment-related changes. MATERIAL AND METHODS: We examined 68 outpatients, 25 men and 43 women, aged from 18 to 54 years, using psychopathological and follow-up methods. Results and conclusion. Two groups of oneiroid states were described. Oneiroid-catatonic states with the predominance of visual (optical) component derangement of consciousness were characteristic of the first group and oneiroid states with the prevalence of sensory component of derangement of consciousness were described in the second group. The second group was divided into two subgroups by the severity of the visual component (minimal and mixed). The types of oneiroid-catatonic states determined the dynamics of the attack in whole and were related to treatment (drug-induced pathomorphosis). These results are significant for differential diagnosis, treatment, and prognosis of the disease. PMID- 25726779 TI - [Variants of cognitive development in children and adolescents with different forms of schizophrenia]. AB - OBJECTIVE: To explore cognitive disorders in children and adolescents with schizophrenia from the perspective of cognitive dysontogenesis concept, assess severity and specificity of cognitive deficits and identify variants of the dynamics and types of cognitive development. MATERIAL AND METHODS: Three diagnostic groups of patients were studied: 1) childhood onset schizophrenia, 2) schizotypal disorder, and 3) other types of schizophrenia. RESULTS AND SONCLUSION: There was a predomination of cognitive development types, named cognitive dysontogenesis, which structure was determined by a combination of the dynamics of cognitive development and severity of cognitive deficits. Severity and type of the dynamics of cognitive deficits were associated with the diagnosis and cognitive process. PMID- 25726780 TI - [Test scores as indicators of treatment efficacy in dementia caused by Alzheimer's disease in clinical practice]. AB - OBJECTIVE: To analyze the possibility of using MMSE and CGIS as well as the Clock drawing test for the objectification of treatment efficacy in Alzheimer's disease (AD). MATERIAL AND METHODS: Authors examined 765 patients with mild and moderate dementia treated with donepezil during 3 months. The efficacy was assessed using the MMSE and CGIS. RESULTS AND CONCLUSION: The methods demonstrated the reproducibility compared to those used in earlier clinical trials and efficacy of donepezile in the treatment of mild and moderate AD, the Clock drawing test can be recommended as an additional technique for assessment of treatment efficacy in relation to opticospatial function. PMID- 25726781 TI - [EEG-correlates of frontal dysfunction as predictors of relative pharmacoresistance in treatment of endogenous affective disorders]. AB - OBJECTIVE: To analyze background EEG parameters correlated with frontal lobe dysfunction, that might be considered, prospectively, as individual predictors of relative pharmacoresistance (or relatively lower treatment efficacy) in different forms of endogenous affective disorders. MATERIAL AND METHODS: An analysis of a set of several EEG parameters and quantitative clinical assessments has been carried out during the treatment in patients with endogenous depression (group 1), depressive-delusional conditions in the frames of attack-like schizophrenia (group 2), and manic-delusional conditions in the frames of attack-like schizophrenia (group 3). RESULTS AND CONCLUSION: Statistically significant correlations have been revealed between initial (before treatment course) values of narrow-band EEG spectral power (mainly of beta activity reflected the frontal lobe dysfunction and hyper-activation of brain stem structures) and quantitative clinical assessments of patient's conditions at remission stage. The data obtained allow to justify the basic considerations on the brain mechanisms of different affective disorders, and to reveal possible neurophysiologic predictors of relative pharmacoresistance (or relatively lower treatment efficacy) in patients with endogenous affective disorders. PMID- 25726782 TI - [Inflammatory markers in schizophrenia in aged]. AB - OBJECTIVE: To identify inflammatory markers in schizophrenia in aged. MATERIAL AND METHODS: The main group included 29 patients with schizophrenia, mean age 72.1 +/- 6.9 years. A comparison group comprised 34 patients with Alzheimer's disease, mean age 73.4 +/- 7.9 years. Seven plasma inflammatory indicators were determined. RESULTS: There was a significant increase in the activity/content of acute inflammation stage proteins: alpha1-proteinase inhibitor and C-reactive protein as well as anti-inflammatory interleukin-10 compared to the controls while the activity of other inflammatory molecules (leukocyte elastase, tumor necrosis factor alpha, interleukin-1 receptor antagonist) was not changed. No correlations between immunological parameters and clinical presentations were found. CONCLUSION: The results suggest that inflammation does not play a significant role in the remote stages of schizophrenia, in contrast to earlier stages of the disease, and the activity of the pathological process decreased in the late stages. These characteristics can reflect the body reactivity in elderly patients. PMID- 25726783 TI - [Reactivity of perineuronal astrocytes in the prefrontal cortex in schizophrenia: an ultrastructural morphometric study]. AB - OBJECTIVE: Previously the ultrastructural alterations of astrocytes have been reported in schizophrenia. Reduced dendritic arborization of the neurons in layer 5 of the prefrontal cortex has been found in schizophrenia. Authors hypothesized that the abnormalities in perineuronal astrocytes (PA) might contribute to these neuronal changes. It was aimed to study the ultrastructure of PA in the prefrontal cortex in schizophrenia. MATERIAL AND METHODS: Postmortem electron microscopic morphometric study of PA was performed in layer 5, area 10 of the prefrontal cortex in 39 cases of schizophrenia and 37 controls. RESULTS: No significant group differences were found in areas of cell, nucleus, cytoplasm, volume fraction (Vv) of lipofuscin granules and areal density of PA. However, in the subgroup of women with schizophrenia, the areal density of PA was significantly lower and the area of PA was significantly higher as compared to the subgroup of healthy women (-52%, p<0,01; +32%, p<0.05 respectively) and to the subgroup of men with schizophrenia (-56%, p<0,01; +23%, p<0,05 respectively). The area of PA nucleus was negatively correlated with the duration of disease (r= -0.37, p=0.02) and positively with the age of disease onset (ADO) (r=0,47, p<0,01). Areas of PA and of PA nucleus were significantly lower in early ADO (<21 y.o.) as compared to the adult ADO (>21 y.o.) (-24%, p<0.05). Vv of lypofuscin granules was correlated with the age in control group (r=0.52, p=0.001), but not in schizophrenia group (r=0.13, p=0.4). CONCLUSION: Significant differences in PA reactivity in the prefrontal cortex in the schizophrenia are associated with gender and age at onset of the disease. PMID- 25726784 TI - [The use of cereton in patients with chronic brain ischemia and moderate cognitive impairment]. AB - OBJECTIVE: To study the efficacy and safety of cereton in the treatment of patients with chronic brain ischemia and moderate cognitive impairment. MATERIAL AND METHODS: The study included 25 patients, 16 women and 9 men, mean age 53,8 +/ 1,3 years. Moderate cognitive impairment measured with MMSE and HADS was found in all patients. Quality of life was assessed with SF-36. Somatic and neurological studies as well as brain MRI were carried out. Inpatients received cereton in dose 1000 mg in 200 ml of physiological solution during 15 days, after the discharge from the hospital patients received 1 capsule three times a day during 3 months. RESULTS AND SONCLUSION: Cereton had a significant positive effect on patient's condition including cognitive function. Subjective effect was recorded after 5-6 days of treatment, more evident and stable effect was seen from the 15th day. In the end of treatment, clinicians recorded "moderate" effect in 11 patients and "marked" effect in 8 patients (according to patients' reports, those effects were noted in 9 and 12 cases, respectively). The drug was well tolerated and had a positive effect on quality of life of the patients. PMID- 25726785 TI - [Aspects of encephalopathy in oncologic patients after chemotherapy]. AB - OBJECTIVE: To study clinical presentations and neuroimaging results in post chemotherapy encephalopathy. MATERIAL AND METHODS: We examined 27 patients with cancer after chemotherapy (n=16) or chemoradiation (n=11). RESULTS AND CONCLUSION: All patients complained of memory impairment, sluggish mentality, moderate headache, fatigue, sleep disorder, irritability. Their neurologic status included different organic symptoms. Post chemotherapy encephalopathy is characterized by the combination of severe cerebral asthenia and different organic neurologic symptoms with moderate cephalgic syndrome. MRT showed single and multiple loci of gliosis in the white matter. PMID- 25726786 TI - [Mild cognitive impairment in patients with coronary artery disease: clinical demographyc and EEG-correlates]. AB - OBJECTIVE: The clinical and demographic factors associated with mild cognitive impairment (MCI) and the topographical features of electroencephalogram (EEG) spectral power in patients with coronary artery disease (CAD) depending on the presence or absence of MCI were studied. MATERIAL AND METHODS: Seventy-five male patients with CAD were assigned to the groups with (n=31) and without MCI (n=44). The control group included 15 healthy people (the mean age 60.0 +/- 4.39 years). The MMSE, the Frontal Assessment battery, the Trail-Making Test, Khanin Speilberger and Beck depression scales were used. RESULTS: A lower level of education, more severe coronary lesions and lower cardiac contractility, as well as higher spectral power (Theta-rhythm) of parietooccipital theta activity have been found in CAD patients with MCI compared to patients without MCI. The latter parameter in MCI patients also differed from controls. CONCLUSION: Education is an important factor to preserve cognitive abilities in patients with CAD. In addition, the severity of coronary artery lesions and low cardiac contractility affect the degree of cerebral ischemia and neuronal dysfunction detected by spectral EEG power. The efficacy of quantitative EEG analysis methods for early detection and prevention of cognitive disorders in CAD patients was confirmed. PMID- 25726787 TI - [Tactics of management of preschool children with different variants of speech delay]. AB - OBJECTIVE: To study the efficacy of neurometabolic treatment in dependence of different variants of speech delay (SD), general underdevelopment of speech (GUDS) type, in preschool children. MATERIAL AND METHODS: The study included 130 children, aged 4-6 years, with SD, GUDS type, Most of children were boys (74%). Clinical and psychological characteristics and efficacy of neurorehabilitation were studied in 3 parallel groups. RESULTS AND SONCLUSION: The results demonstrate the heterogeneity of disorders of speech development depending on the clinical and neurological SD variant. Authors have identified characteristics that allow to determine the amount of corrective actions for children with associated pathology and improve rehabilitation actions. PMID- 25726788 TI - [Asthenic disorders in children and their differentiated treatment]. AB - OBJECTIVE: To study clinical/psychological characteristics of neurasthenia and residual asthenia and to assess the efficacy of noofen and adaptol in the treatment of these disorders. MATERIAL AND METHODS: Authors examined 30 adolescents with neurasthenia and 30 with residual asthenia. The Multidimensional Fatigue Inventory (MFI-20), A.M. Vein questionnaire, Spilberger-Khanin questionnaire, The Test of Variables of Attention (TOVA) were used. Patients were divided into two equal groups (n=30), each included 15 patients with residual asthenia and neurasthenia. Patients of the first group received adaptol in dosage 1000 mg daily and patients of the second group received noofen in dosage 500 mg daily. The duration of the study was 30 days. RESULTS AND CONCLUSION: The significantly higher levels of fatigue, inattention and exhaustibility were identified in patients with residual asthenia. Adolescents with neurasthenia were characterized by higher anxiety. The higher efficacy of adaptol in treatment of neurasthenia (80% in adolescents with neurasthenia and 60% of patients with residual asthenia) was shown. Noofen was more effective in treatment of residual asthenia (66.7% of adolescents with neurasthenia and 86.7% with residual asthenia. PMID- 25726789 TI - [Treatment of asthenic syndrome in patients with chronic brain ischemia: results of the non-interventional observational program TRIUMPH]. AB - OBJECTIVE: To assess the severity of asthenic syndrome (AS) in chronic brain ischemia (CBI) in primary health care settings. MATERIAL AND METHODS: The study included 1170 patients with brain ischemia, aged 45-65 years, treated with phenotropil in dose 100 mg during 2 and 3 months. Clinical examination and MFI-20 subscales were administered. RESULTS AND SONCLUSION: The high incidence of asthenic syndrome was observed across all MFI-20 subscales. The decrease in asthenic syndrome severity was significant already in the end of the first month of treatment with phenotropil. Such dynamics maintained to the end of the second and third month of treatment. More than 2-fold decrease in the severity of asthenia symptoms was achieved in all subgroups 3 months after treatment. More rapid and apparent decrease in asthenic syndrome was observed in younger patients. PMID- 25726790 TI - [The primary screening of patients with autonomic disorders in outpatient clinics in Russia (START1) using the Russian version of The Four-Dimensional Symptom Questionnaire (4DSQ)]. AB - OBJECTIVE: To develop an effective diagnostic algorithm for detection of a mental component in the state of patients diagnosed with autonomic nervous system disorder. MATERIAL AND METHODS: In the frames of START1 epidemiological study, we examined 6633 patients with autonomic nervous system disorders (ICD-10 G.90.8 and G90.9) and somatoform disorders (F45) including 18,8% patients who got a referral to a psychiatrist. A linguistically validated Russian version of The Dutch Four Dimensional Symptoms Questionnaire (4DSQ) was tested in domain subpopulations. RESULTS: In subpopulations of anxiety and depression, more than 26% of the patients got a referral to a psychiatrist that indirectly supported the assumption on the conformity of 4DSQ to the purposes of primary screening of four dimensional disorders in the general population of patients with autonomic nervous system disorders. CONCLUSION: The linguistically validated Russian version of 4DSQ enabled to formalize the description of clinical profile of these patients. Cluster analysis of the results allowed to single out two superdomains by the pairwise combination somatization with distress (SDis) and anxiety with depression (ADep). The detection of superdomain SDis appears to be a population specific characteristic of autonomic nervous system disorders in the Russian Federation. PMID- 25726791 TI - [The effect of 3-oxypyridine and succinic acid derivatives on the resistance to acute cerebral ischemia]. AB - OBJECTIVE: The effect of original domestic derivatives of 3-oxypiridine and succinic acid (emoxipine, reamberin and mexidol) on the resistance to acute brain ischemia was studied in an experimental mouse models. MATERIAL AND METHODS: We used 260 adult outbred mice. The drugs were introduced intraperitoneally 30 min before the modeling of acute brain ischemia. Each drug was used in 3 three doses: 1/2 of the calculated equivalent of mean treatment dose (EMTD), EMTD and double EMTD. A strangulation model with the assessment of mouse mortality latency and decapitation model with the assessment of agonal respiration (gasping) were used. The efficacy of the drugs was determined by comparison against alpha-lipoic acid that was used as a reference substance in previous studies of antihypoxic activity of emoxipine, reamberin and mexidol. RESULTS AND CONCLUSION: It was established that the derivatives of 3-oxipiridine and succinic acid protected against subtotal ischemia of rostral brain segments (of cerebral hemispheres) as evidenced by the increase in longevity. Emoxipine demonstrated the maximal effect thereby surpassing reamberin and mexidol in the intensity of antiischemic activity. Antiischemic effect of alpha-lipoic acid was comparable to emoxipine. In the model of total brain ischemia, the derivatives of 3-oxipiridine and succinic acid caused the opposite (proischemic) action on the bulbar respiratory center as evidenced by the reduction in duration of gasping. Alpha-lipoic acid did not affect the duration of gasping. PMID- 25726792 TI - [Cerebrovascular disease incidence in workers occupationally exposed to radiation over prolonged time periods]. AB - OBJECTIVE: To estimate incidence rates for cerebrovascular diseases (CVD) in a cohort of workers occupationally exposed to radiation over prolonged time periods. MATERIAL AND METHODS: CVD incidence was estimated in a cohort of 22.377 workers of the nuclear facility "Mayak" Production Association over the follow-up period 1948-2008. Non standardized and standardized incidence rates were estimated. An indirect method of standardization was used for the estimates. RESULTS: As of 31/12/2008, 8.717 CVD cases (5.802 men and 2.915 women) were registered in the study cohort of workers. CVD incidence in the cohort was significantly associated with sex, age, smoking, alcohol consumption (in men) and arterial hypertension. CVD incidence was increased in workers exposed to external gamma-rays at total dose above 0.5 Gy and/or to internal alpha-radiation due to incorporated plutonium at total absorbed liver dose above 0.025 Gy. CONCLUSION: CVD incidence in the cohort of workers occupationally exposed to radiation over prolonged time periods was associated both with non-radiation and radiation factors. PMID- 25726793 TI - [Sleep disorders in the structure of cerebrovascular diseases]. AB - The literature on the place and role of insomnia in cerebral blood circulation disturbances is reviewed. It is emphasized that insomnia is a modifying risk factor of cerebrovascular pathology. The syndrome of obstructive sleep apnea may be a cause of arterial hypertension. The diagnostic relevance of the complex examination of patients with sleep pathology, including polysomnographic technology, and its role in the choice of corrective measures and treatment of insomnia in whole are shown. PMID- 25726794 TI - [Stroke and neuroplasticity]. AB - Characteristics of stroke development and processes of restoration of brain function in post stroke period are considered. The dynamics of neuroplasticity and ambiguity of the involvement of the opposite brain hemisphere in the restoration is highlighted. Special attention is drawn to the time from stroke onset and activation of different brain regions in post stroke period. The importance of neurorehabilitation in these patients is emphasized. PMID- 25726795 TI - [Moyamoya disease]. AB - Moyamoya syndrome is a rare chronic progressive disease of brain vessels in which certain arteries in the brain are constricted. During the disease a collateral circulation develops around the blocked vessels to compensate for the blockage, and on angiography these collateral vessels have the appearance of a "puff of smoke". Moyamoya syndrome is extremely rare disease, especially outside of Japan We describe a clinical case of a 27-year-old patient from Tomsk with Moyamoya disease. The clinical features are an acute stroke in the right middle cerebral artery with dysarthria and paralysis of VII and XII cranial nerves. The diagnosis of moyamoya is suggested by MRI-angiogram results in accordance to the diagnostic criteria. PMID- 25726796 TI - [Multimodal imaging protocols and their predictive role in acute stroke functional outcome]. AB - Brain imaging plays a central role in the assessment of patients with acute ischemic stroke. Within a few minutes, modern multimodal imaging protocols can provide one with comprehensive information about prognosis, management, and outcome of the disease, and may detect changes in the intracranial structures reflecting severity of the ischemic injury depicted by four Ps: parenchyma (of the brain), pipes (i.e., the cerebral blood vessels), penumbra, and permeability (of the blood brain barrier). In this article, we have reviewed neuroradiological predictors of stroke functional outcome in the light of the aforementioned four Ps. PMID- 25726797 TI - [Posttraumatic stress disorder in patients after stroke]. AB - Objective. To assess the frequency of main symptoms of posttraumatic stress disorder (PTSD) in post stroke patients. Material and methods. Forty-eight patients took part in the study. We used the Impact of Events Scale (IES) and other scales to assess the severity of posttraumatic stress. Results and conclusion. Thirty three percent of patients experienced posttraumatic stress, 12.5% suffered from PTSD. We found an association between the severity of posttraumatic stress after stroke and the level of anxiety, sleep disturbances and decrease of quality of life. Symptoms of posttraumatic stress are often observed after stroke, this needs to be taken into account during planning of rehabilitation programs. PMID- 25726798 TI - [Post stroke delirium]. AB - This review considers the issues of clinical typology of delirium (mental confusion), its etiology and pathogenesis. Based on these data, the peculiarities of treatment, prevention and rehabilitation of delirium are discussed. Attention is drawn to the risk factors of this disorder (potentially modifiable or non modifiable), which are most important in treatment and prevention of delirium. The questions of rehabilitation measures are regarded. Section "Treatment" presents pharmacological and non-pharmacological approaches to treatment of delirium. PMID- 25726799 TI - [The analysis of functional brain asymmetry in patients with ischemic stroke: a neuropsychological research]. AB - Objective. To study neuropsychological status based on functional asymmetry of patients after ischemic stroke (II). Material and methods. We examined 92 patients after II of different pathogenetic types (atherothrombotic, cardioembolic, lacunar). Results. The first-ever description of patient's neuropsychological status of II patients based on the functional asymmetry of the brain is presented. In case of left-hemisphere lesion, parameters of expressive speech and count function were systemic factors in right-handed patients and expressive speech and praxis in left-handed patients. In right-hemisphere lesion, basic factors were reading function in right-handed patients and praxis and count functions in left-handed patients. CONCLUSION: The results can be used for development of rehabilitation programs in post stroke patients. PMID- 25726800 TI - [Some features of morphometric characteristics of the brain in patients with lacunar stroke]. AB - Objective. To determine the structural-morphometric peculiarities of the brain in patients with lacunar ischemic stroke and their influence on cognitive functions. Material and methods. A morphometric analysis of brain CT was performed in 48 patients in the acute period of lacunar stroke. The width of subarachnoid spaces at the pole of the frontal lobes and the lateral sulcus was measured in axial sections, the ventricular system was assessed be several parameters. To adjust for the total head size, the data were evaluated as ratios. Mean populations values adjusted for age were used as normal values. Cognitive functions were measured with the MoCA scale. Results. It was determined that 71% of the patients had lacunar stroke as a result of the atrophic process in the brain. Atrophic process of the brain was often diagnosed in the age group of 61-70 years, multiple lacunar lesions were diagnosed in the group of 51-60 years. Cognitive functions were impaired in 91% of the patients in the acute period of lacunar stroke. Conclusion. Correlations between the level of cognitive functions and morphometric markers of subcortical atrophy demonstrate the leading role of the subcortical atrophy in the development and progression of cognitive deficit. PMID- 25726801 TI - [The active neuroprotective therapy of acute carotid ischemic stroke of moderate severity]. AB - Objective. To evaluate the efficacy of neuroprotective therapy in carotid ischemic stroke. Material and methods. An open comparative study of combined neuroprotective therapy in comparison with standard treatment has been carried out in 25 patients with carotid ischemic stroke of moderate severity in the acute period of disease. Patients received cytoflavin, gliatilin and actovegin, along with basic therapy, during 15 days. Patient's state was assessed every 5 days using the NIHSS. The Barthel index was estimated in the 21st day. Results and conclusion. By the end of treatment, the degree of neurological deficit was significantly lower in patients treated with the combination of the neuroprotectors. The better functional rehabilitation to the 21st day and the positive dynamics of inflammation indices and free-radical processes were shown in patients of the main group. PMID- 25726802 TI - [Efficacy of serebrolysin in acute ischemic stroke]. AB - Objective. To study the effect of cerebrolysin used in dose 30 ml daily during 10 days on rehabilitation measures in patients with acute ischemic stroke. Material and methods. The 1st group consisited of 23 patients who received standard treatment and cerebrolysin, the 2nd group included 89 patients who received standard treatment only. The severity of neurological deficits (NIHSS) and the level of disability (mRS) were assessed. Results and conclusion. A significantly earlier recovery (p<0,05) and decrease in disability were identified. A more pronounced effect was seen in young patinets and when treatment started early. PMID- 25726803 TI - [Cerebral revascularization for the treatment of patients with acute ischemic stroke]. AB - The effectiveness of surgical prevention of ischemic stroke has been demonstrated in several international randomized studies. Issues about the surgery time, patient selection criteria, surgery techniques remained unresolved. We have reviewed 46 publications in this field. The current vast arsenal of surgical techniques allows to conduct revascularization surgery procedures in patients with acute ischemic stroke and lesions of extra- and intracranial arteries. The benefits of early carotid endarterectomy in patients with mild stroke and transitory ischemic attacks (TIA) are undeniable fact. Necessity of urgent endarterectomy and thrombintimectomy in patients with stroke, TIA, acute inner carotid artery occlusion is a subject of current discussions. The experience in performance of these interventions has been accumulated but randomized studies are needed to verify their effectiveness. Microsurgical techniques have made it possible to perform bypass surgery and open embolectomy in situations earlier considered as incurable. PMID- 25726804 TI - [The relations between quality of life, morbidity of chronic non-infectious diseases and use of medications in stroke patients]. AB - Objective. To determine relations between quality of life, morbidity of chronic non-infectious diseases and use of pharmaceuticals by stroke patients. Material and methods. The case group consisted of 508 Kaunas citizens, aged 25-84 years, who survived the stroke. The control group consisted of randomly chosen 508 sex- and age-matched Kaunas citizens without stroke. SF-12 questionnaire on the quality of life was used. Quality of life was analysed in physical and mental health domains taking into consideration morbidity of chronic non-infectious diseases and use of pharmaceuticals. The percentage of those who had more than one chronic non-infectious disease was 38.6 in the case group and 17.2 in the control group (p<0.001). With respect to the use of antihypertensive (66.5% in the case group and 67.3% in the control group), antithrombotic (21.5% and 24.6%) and antidepressant (100% and 100%) medication, case and control groups were similar. Results and conclusion. Compared to people without arterial hypertension, scores in physical health domain were lower in people with arterial hypertension (p=0.018) and the control group (p=0,0005). In the main group, people without atrial fibrillation scored lower (p=0.0005) in physical health domain compared to those with atrial fibrillation. Scores in mental health domain were lower in the control group (p=0.048). Compared to people with diabetes mellitus (DM), those with DM scored lower in the case group (p=0.0005). The use of antihypertensive or antithrombotic medication before stroke did not predict quality of life in patients with chronic non-infectious diseases. Meanwhile, in the control group the use of antithrombotic medication improved (p<0.05) the quality of life in physical health domain. PMID- 25726805 TI - [Increase in patient vertical stability in acute period of ischemic stroke]. AB - OBJECTIVES: To develop a technique of physical rehabilitation of stroke based on the gradual increase of motor/cognitive loading using biofeedback to supporting reaction based on stabilometry with a focus on the changes in peripheral afferentation with the help of an axial loading suit and simple non-apparatus vestibular and respiratory exercises. The efficacy of standard scheme of restorative treatment and a new technique of optimized complex rehabilitative treatment of acute ischemic stroke in the vertebral-basilar system was compared. MATERIAL AND METHODS: We examined 28 patients with acute stroke in the vertebrobasilar area manifesting with dizziness, disturbances of equilibrium and stability. The patients were randomized into two equal groups (n=14). In the main group, a new technique was added to standard treatment. In the control group, traditional pharmacological and physical treatment was used. We administered clinical scales and instrumental stabilometric assessment as well. RESULTS: A significant improvement of the vertical stability assessed with clinical scales (Bohannon, Perry, Stolyarova, Berg Balance Scale) and stabilometric parameters (the Romberg's test) was shown in the main group compared to the control one. CONCLUSION: The new technique expands the potentials of rehabilitation in the acute stage of stroke and allows to prepare the patient to independent gait. PMID- 25726806 TI - [Rehabilitation of post stroke patients using a bioengineering system "brain computer interface + exoskeleton"]. AB - Objective. To investigate the possibility of using a bioengineering system, which includes an electroencephalograph and a personal computer with a software for synchronous data transmission, recognition and classification of EEG signals, development of directions for intended actions in real time in the combination with the hand exoskeleton (the bioengineering system "brain-computer interface + exoskeleton"), in motor rehabilitation of post stroke patients with paresis of the upper extremity. Material and methods. Brain-computer interface is a promising field of neurorehabilitation. Rehabilitation treatment, including 8-10 sessions, was conducted in 5 patients with paresis of the upper extremity. All patients had large MRI lesions in cortical/subcortical areas. Results. Positive changes in neurological status measured with the NIHSS, a significant increase in the volume and power of movements in the paretic hand, improvement of coordination and slight decrease in the level of spasticity were found after the treatment. There was an increase in daily activities measured with the Barthel index, mostly due to the improvement of fine motor skills. The level of disability assessed by the modified Rankin scale was changed significantly. Conclusion. The use of "brain-computer interface + exoskeleton" in the rehabilitation of post stroke patients with hand paresis provided positive results that would need to be verified in further studies. PMID- 25726807 TI - [Modern methods of rehabilitation for poststroke patients]. AB - The article reviews the problem of complex post stroke rehabilitation. Special attention is drawn to neurorehabilitation aspect of patient's state, restorative treatment in the acute stage of stroke, peculiarities of working up individualized rehabilitation programs, innovations and medicament support of rehabilitation process. PMID- 25726808 TI - Morphology versus DNA barcoding: two sides of the same coin. A case study of Ceutorhynchus erysimi and C. contractus identification. AB - Genotyping of 2 well-known weevil species from the genus Ceutorhynchus (Coleoptera: Curculionidae) distributed in west Palearctic, C. erysimi and C. contractus, revealed phenotype versus genotype inconsistencies in a set of 56 specimens (25 C. erysimi and 31 C. contractus) collected from 25 locations in Serbia and Montenegro. An analysis of the mitochondrial cytochrome oxidase subunit I gene (COI), widely used as a barcoding region, and a nuclear gene, elongation factor-1alpha (EF-1alpha), revealed stable genetic divergence among these species. The average uncorrected pairwise distances for the COI and EF 1alpha genes were 3.8%, and 1.3%, respectively, indicating 2 genetically well segregated species. However, the genetic data were not congruent with the phenotypic characteristics of the studied specimens. In the first place, C. erysimi genotypes were attached to specimens with phenotypic characteristics of C. contractus. Species-specific PCR-RFLP assays for the barcoding gene COI were applied for the molecular identification of 101 additional specimens of both morphospecies (33 C. erysimi and 68 C. contractus) and were found to confirm this incongruity. The discrepancy between the genetic and morphological data raises the question of the accuracy of using a barcoding approach, as it may result in misleading conclusions about the taxonomic position of the studied organism. Additionally, the typological species concept shows considerable weakness when genetic data are not supported with phenotypic characteristics as in case of asymmetric introgression, which may cause certain problems, especially in applied studies such as biological control programs in which the biological properties of the studied organisms are the main focus. PMID- 25726809 TI - Revision of fleas of the genus Plocopsylla belonging to the 'angusticeps-lewisi' complex in the Andean biogeographic region, with the description of a new species. AB - In Argentina, the Andean biogeographic region accommodates the most diverse population of fleas in the country. The Craneopsyllinae (Siphonaptera: Stephanocircidae) represent one of the most commonly found subfamilies in this region and show some endemism and high diversity. Plocopsylla is the most diverse genus of Craneopsyllinae; it includes 10 species mainly distributed in the Patagonian subregion, which parasitize sigmodontine rodents (Rodentia: Cricetidae). We describe and illustrate the morphology of the aedeagus in species of Plocopsylla that belong to the 'angusticeps-lewisi' complex. This character is of diagnostic value in differentiating among species. A new species of this complex, Plocopsylla (Plocopsylla) linardii sp. n., is described and identified by the shape and chaetotaxy of the distal arm of sternite IX, as well as by the shape of the median dorsal lobe of the aedeagus. New host associations for this complex and range extensions for most of its species are reported. Plocopsylla (P.) silewi is recorded for the first time in Argentina. The southern limits of the distributions of Plocopsylla (P.) lewisi and Plocopsylla (P.) wilesi are extended to Santa Cruz Province. The angusticeps-lewisi complex is found for the first time in San Juan Province. The information may be useful in epidemiological studies of flea-borne diseases. PMID- 25726810 TI - Myoglobin structure and function: A multiweek biochemistry laboratory project. AB - We have developed a multiweek laboratory project in which students isolate myoglobin and characterize its structure, function, and redox state. The important laboratory techniques covered in this project include size-exclusion chromatography, electrophoresis, spectrophotometric titration, and FTIR spectroscopy. Regarding protein structure, students work with computer modeling and visualization of myoglobin and its homologues, after which they spectroscopically characterize its thermal denaturation. Students also study protein function (ligand binding equilibrium) and are instructed on topics in data analysis (calibration curves, nonlinear vs. linear regression). This upper division biochemistry laboratory project is a challenging and rewarding one that not only exposes students to a wide variety of important biochemical laboratory techniques but also ties those techniques together to work with a single readily available and easily characterized protein, myoglobin. PMID- 25726811 TI - Epitope mapping by solution NMR spectroscopy. AB - Antibodies play an ever more prominent role in basic research as well as in the biotechnology and pharmaceutical sectors. Characterizing their epitopes, that is, the region that they recognize on their target molecule, is useful for purposes ranging from molecular biology research to vaccine design and intellectual property protection. Solution NMR spectroscopy is ideally suited to the atomic level characterization of intermolecular interfaces and, as a consequence, to epitope discovery. Here, we illustrate how NMR epitope mapping can be used to rapidly and accurately determine protein antigen epitopes. The basic concept is that differences in the NMR signal of an antigen free or bound by an antibody will identify epitope residues. NMR epitope mapping provides more detailed information than mutagenesis or peptide mapping and can be much more rapid than X ray crystallography. Advantages and drawbacks of this technique are discussed together with practical considerations. PMID- 25726812 TI - [The paradigm of the neurodevelopmental disorders]. PMID- 25726813 TI - [Attention deficit hyperactivity disorder and adoption]. AB - INTRODUCTION: The term adoption or adoptive filiation is understood as referring to the legal act by which family ties are created between two persons such that a relationship of fatherhood or motherhood is established between them. AIMS. The purpose of this study is to outline the problems derived from prenatal exposure to alcohol and other risk factors, from hypostimulation during the 'critical period' in institutionalised patients (especially those adopted from eastern European countries) and their relation with attention deficit hyperactivity disorder (ADHD). This work also seeks to take a deeper look into the diagnosis, prevention and treatment of these problems. DEVELOPMENT: These children have problems in terms of psychosocial relationships, behavioural problems, delayed language or reading development and, above all, ADHD. In practice it is extremely difficult to separate the two factors during the assessment of children adopted from eastern European countries in neuropaediatric consultations. Exactly how all these factors are interrelated is not well understood. CONCLUSIONS: There is a close relationship between prenatal exposure to alcohol and the consequences of adoption. There is a need for placebo-controlled randomised studies, with larger population samples, that test the benefits and profile of side effects, both with psychostimulants and with atomoxetine in this group of patients. PMID- 25726814 TI - [Is attention deficit hyperactivity disorder associated with other prevalent pathologies of early childhood?]. AB - AIM: To determine whether attention deficit hyperactivity disorder (ADHD) is associated with other prevalent medical pathologies of the paediatric age. DEVELOPMENT: Several paediatric pathologies were selected with the aim of reviewing their association with ADHD: in paediatric pulmonology, asthma and other allergic processes; in paediatric neurology, headache and febrile seizures; in paediatric gastroenterology, diarrhoea, constipation, abdominal pain, gastroesophageal reflux and infection by Helicobacter pylori; in paediatric nephrology, enuresis; in paediatric cardiology, bruits and congenital heart disease; in paediatric endocrinology, thyroid disorders and obesity; and in paediatric ophthalmology, ametropia and strabismus. CONCLUSIONS: Several studies were found that related ADHD with allergic processes, overweight/obesity, peripheral resistance to thyroid hormone, enuresis, febrile seizures, headache, congenital heart disease, ophthalmic disorders and tooth decay, with some controversial issues and details still to be defined. It can be concluded that further interdisciplinary studies are needed to clarify the associations and underlying mechanisms involved, so as to be able to gain a deeper understanding of the complex entity of ADHD and to suggest preventive, diagnostic and therapeutic interventions with regard to its comorbidities. PMID- 25726815 TI - [Cognitive-behavioural guidance interventions in adolescents with attention deficit hyperactivity disorder]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that may become manifest at any time in life. In 50 70% of children diagnosed with the disorder it presents in adolescence. Young people with ADHD have high rates of comorbidity with other psychiatric disorders and a high degree of functional compromise. AIMS: To review the literature on cognitive-behavioural interventions that have been applied to the treatment of ADHD in adolescence. DEVELOPMENT: The studies that have been conducted on psychological treatment to date were reviewed, and the interventions were classified into: psychosocial treatments, mindfulness therapy and cognitive behavioural treatment (individual and in groups). The only study on cognitive behavioural therapy for adolescents with ADHD is also reviewed, as well as a new intervention protocol for application to groups designed at the Hospital Universitari Vall d'Hebron. CONCLUSIONS: Although there has been a recent increase in the number of publications dealing with the psychological treatment of ADHD in adolescents, there is a need for a greater development of intervention protocols and studies on their efficacy/effectiveness. PMID- 25726817 TI - [Change in the therapeutic strategy when faced with an inadequate response to the pharmacological treatment of attention deficit hyperactivity disorder]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a disorder of a biological origin affecting the neurodevelopment of the brain. It is estimated that 3-7% of school-age children present ADHD. The most commonly used pharmacological treatments are amphetamines and methylphenidate (MPH). Although response rates to MPH are high, full remission rates reach only 56%. The 25% of patients who do not respond to MPH would show a response to other stimulants and vice-versa. AIMS. To clinically evaluate patients by detecting inadequate responses and the efficacy of a change to lisdexamfetamine dimesylate (LDX). PATIENTS AND METHODS: The study was prospective and observation-based. Inadequate responses were considered to be those that presented non-coverage or no effect. The Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) and Clinical Global Impression-Severity (CGI-S) assessment scales were used for the clinical assessment, together with the Weiss Functional Impairment Rating Scale (WFIRS) and the Child Health and Illness Profile (CHIP-AE). Data regarding adverse side effects were also collected. RESULTS: Forty-one patients met criteria for inadequate response to treatment: 13.6 +/- 3.4 years, 54.6 +/- 13.2 kg, 158.5 +/- 17.2 cm and body mass index of 20.9 +/- 3.5 kg/m2. Reasons for change (non-exclusive): non-coverage (76%), lack of intensity of effect (68%) and presence of adverse side effects with the previous medication (16%). The mean score both at baseline and at nine months, on the ADHD-RS, was 24.54 +/- 6.3 versus 12.01 +/- 3.2 (p < 0.01), respectively, and for the CGI-S values were 5.09 +/- 0.5 versus 2.91 +/- 0.8 (p < 0.01), respectively. The safety profile coincided with that of other stimulant-based treatments for ADHD. CONCLUSIONS: When the response to MPH presents non-coverage or lack of effect, changing to LDX has proved to be effective, with an improvement in 86.7% of cases, which is similar to that of other studies. It is therefore a good therapeutic option in these patients. PMID- 25726818 TI - [The role of the prefrontal cortex in the sensory problems of children with autism spectrum disorder and its involvement in social aspects]. AB - INTRODUCTION: In persons with autism spectrum disorders (ASD), aberrant sensory perceptions could be as characteristic and disruptive as the presence of anomalies in social communication and interaction or restricted and repetitive interests. Most of them present sensory modulation disorders (hyper- or hypo responsiveness) in several sensory channels. Furthermore, there is a deficit in the integration of the information from a number of sensory systems (for example, auditory and visual). All this would worsen the core symptoms related with communication and increase the appearance of behavioural problems. AIMS: This study aims to review the experimental evidence that addresses the role played by the prefrontal cortex in unusual sensory experiences in ASD and its involvement in social aspects. There is evidence of hypoactivation and dysfunction of the neural networks, which include the prefrontal cortex and participate in social cognition, such as the default mode and the mirror neuron system in children with ASD. CONCLUSIONS: Sensory-motor problems at an early age correspond to a disruption in the organisation and regulation not only of perception and action but also language, thought, emotion and even memory. PMID- 25726819 TI - [From early detection to early care: intervention strategies based on prospective screening]. AB - INTRODUCTION. The challenge of early detection can be tackled from an evolutionary perspective. Early intervention treatments have shown themselves to be effective provided that they are applied systematically as part of the strategic planning of the treatment. AIMS. The aim of this study is to provide an updated review in response to the criticism targeted towards early detection and to offer some considerations on the intervention strategy. Our research is based on a review of the early care techniques that are commonly used within the field of autism and it intends to reflect the most significant aspects that can be deduced from the experiments and studies carried out to date. CONCLUSIONS. From the findings of the review it can be concluded that early detection may be more efficient if carried out within the framework of developmental surveillance, which also offers the opportunity to provide guidance on the child's development. Early care is an effective resource for attending to the needs of children with autism. Professionals have the duty to assess the work they do on available treatments with a reflexive, judicious attitude, taking into account the values and preferences of the families. Programmes must focus on the core symptoms and apply the active ingredients of the treatment. PMID- 25726820 TI - Reducing age of autism diagnosis: developmental social neuroscience meets public health challenge. AB - Autism spectrum disorder (autism) is a highly prevalent and heterogeneous family of neurodevelopmental disorders of genetic origins with potentially devastating implications for child, family, health and educational systems. Despite advances in paper-and-pencil screening and in standardization of diagnostic procedures, diagnosis of autism in the US still hovers around the ages of four or five years, later still in disadvantaged communities, and several years after the age of two to three years when the condition can be reliably diagnosed by expert clinicians. As early detection and treatment are two of the most important factors optimizing outcome, and given that diagnosis is typically a necessary condition for families to have access to early treatment, reducing age of diagnosis has become one of the greatest priorities of the field. Recent advances in developmental social neuroscience promise the advent of cost-effective and community-viable, performance-based procedures, and suggest a complementary method for promoting universal screening and much greater access to the diagnosis process. Small but critical studies have already reported on experiments that differentiate groups of children at risk for autism from controls, and at least one study so far could predict diagnostic classification and level of disability on the basis of a brief experiment. Although the road to translating such procedures into effective devices for screening and diagnosis is still a long one, and premature claims should be avoided, this effort could be critical in addressing this worldwide public health challenge. PMID- 25726821 TI - [Early development of language in small children with autism spectrum disorder using alternative systems]. AB - INTRODUCTION: The latest research findings show the importance of early intervention in children with autism spectrum disorder (ASD) in all areas of development, including language. The use of augmentative and alternative communication systems (AACS) favors linguistic and communicative development. AIM: To show the effectiveness of AACS to develop oral language in non-verbal toddlers diagnosed with ASD. PATIENTS AND METHODS: Thirty children (25 males and 5 females) diagnosed with ASD when they were between 18 and 30 months of age, through the instruments ADOS and ADIR. None of them displayed oral language development at the time of assessment. An intervention program in the area of language was designed based on the use of total communication by the therapist and training the child in the Picture Exchange Communication System (PECS). One year later, the formal aspects of language were assessed with the PLON-R because oral language had been developed. RESULTS: All the children had developed oral language to some extent over a one-year period. CONCLUSIONS: Early intervention and the use of AACS with visual props favor the development of oral language in children with ASD in the first years of life. PMID- 25726822 TI - [Comorbidity of autism spectrum disorder and attention deficit with hyperactivity. A review study]. AB - INTRODUCTION: The high presence of attention deficit hyperactivity disorder (ADHD) in autism spectrum disorder (ASD) has been acknowledged in the Diagnostic and statistical manual of mental disorders, fifth edition, thus allowing the diagnosis of both disorders. AIMS: The purpose of this study is to review the research published between 2010 and 2014 on the cognitive and social characteristics of the concurrence of ASD and ADHD. DEVELOPMENT: A review of the 33 studies that were identified showed evidence that the prevalence of symptoms of ADHD in children with ASD was 33-37%. The comorbid condition presents a greater deficit in inhibitory control, attention and working memory. Likewise, in social cognition, the clinical features of ADHD increase the difficulties in cases of ASD. Moreover, the clinical profile of ASD + ADHD is seen to be more severe than that of pure ADHD or ASD, and delayed language development and the intensity/frequency of tantrums are symptoms that are a valuable aid in identification at early ages. CONCLUSIONS: Findings suggest an 'additive' overlapping and ASD + ADHD shares some of the deficits from both disorders, which has implications for the evaluation and design of effective treatments. PMID- 25726823 TI - [Therapeutic approaches in autism spectrum disorders]. AB - Autistic spectrum disorders affect one out of every 68 persons, with a 4:1 dominance in males. Since they are dysfunctions rather than irreversible injuries to the central nervous system, which can be attributed to deficits in the neuronal networks and synaptogenesis and are modifiable thanks to the plasticity of the brain, starting therapy as early as possible is essential for more favourable progress. Very few treatments are backed by solid scientific evidence. We will analyse the therapeutic approaches oriented towards improving autism spectrum disorders which showed a clinical improvement that can be related to neurophysiological or functional changes in the central nervous system. We will classify the behavioural educational treatments and those in the research phase into a hierarchy, highlighting the neurogenetic entities with a high prevalence of autism, in which their pathophysiology and molecular base are known, that attempt to modify the consequences of those alterations by means of pharmacological agents. These entities include fragile X syndrome (GABAergic and metabotropic glutamate receptor inhibitors), tuberous sclerosis (mTOR inhibitors), Phelan-McDermid syndrome and Rett syndrome (insulin-like growth factor 1 inhibitors). Oxytocin, which has been shown to improve social cognition in persons with autism spectrum disorders, is analysed separately. PMID- 25726824 TI - [Relationships between language disorders and socio-emotional competence]. AB - INTRODUCTION: The rate of comorbidity between language disorders and behavioural, emotional and social problems is high. AIM: To review the literature on the social and emotional difficulties of children with specific language impairment from a developmental perspective. DEVELOPMENT: In early childhood, findings concerning this kind of difficulties in children with delayed language development are not conclusive. Yet, as of the period of preschool education, research points to a greater occurrence of difficulties in the social and emotional area. The longitudinal studies that have made it possible to determine the psychosocial adjustment of teenagers suggest a greater risk of presenting experiences involving victimisation and bullying or of developing anxiety and depression in the long term, although some studies offer a more promising scenario. CONCLUSIONS: Disorders involving comprehension and the pragmatic component of language are an important predictor in the manifestation of socio emotional alterations. In mixed comprehension-expression disorders, general difficulty in processing could at least partially account for this association. In turn, these limitations in the development of social cognition are likely to help explain, at least up to a point, the difficulties experienced by persons with pragmatic disorders, although the research conducted to date is not consistent in this sense. PMID- 25726825 TI - [Cerebellum and language: speech therapy intervention to treat their disorders]. AB - INTRODUCTION: Advances in neuroimaging techniques have sparked a growing interest in the study of the cerebellum and its role in the cognitive processes. It is becoming increasingly clear that there is a relationship between this organ and linguistic production, and between pathologies of the cerebellum and some language disorders, such as cerebellar dysarthria. AIMS: To review the contribution made by the cerebellum to the linguistic functions, to analyse the language disorders that derive from cerebellar diseases and to propose the use of speech therapy intervention in conditions of this kind. DEVELOPMENT: An analysis is performed to determine the role of the cerebellum as a modulator in language, of cerebellar dysarthria, of the aetiological factors and of the clinical manifestations that can be observed in verbal production. Procedures for functional assessment and the contents of speech therapy treatment are proposed. CONCLUSIONS: The acquisition of language in early childhood is conditioned by, among other things, the anatomical shaping and neurophysiological activity of the cerebellum. Alterations affecting the development of the structure of the cerebellum, as well as the pathologies and neurophysiological dysfunctions affecting it, can lead to language disorders. The speech therapist's diagnosis must be used to start treatment as early as possible, which will affect the perceptive organisation, motor skills, cognitive profile and linguistic competencies. The work programme will be drawn up in a global and interdisciplinary manner. The intervention of family members and their participation in the therapeutic process will make an invaluable contribution to have positive recovery environments. PMID- 25726826 TI - [School failure and pediatric epilepsy]. AB - INTRODUCTION: School failure, learning and behavioral problems are more common in children with epilepsy than the general population. The aim of this study is to examine the different factors which can affect the school performance of children with epilepsy. DEVELOPMENT: Various psychosocial, medication-related, and epilepsy-related factors may be associated with learning disorders in epilepsy. The age of onset of epilepsy, the type of syndrome, its aetiology, and the response to treatment are some of the most important epilepsy-related factors. All of the established antiepileptic drugs can produce cognitive side effects, which are increased with polypharmacy and with increasing dosage and anticonvulsant blood levels. CONCLUSIONS: Judicious management of all related factors is essential for an optimal outcome. Recent onset of educational problems in a child with epilepsy deserves immediate and exhaustive evaluation and management. PMID- 25726827 TI - [Emotional self-regulation in infantile attention deficit hyperactivity disorder and P300 evoked potentials]. AB - INTRODUCTION: The difficulties that patients with attention deficit hyperactivity disorder (ADHD) have when it comes to emotional regulation have aroused a great deal of interest in recent years and there is a line of research working on the identification of the neurophysiological correlates. AIMS: To analyse measures of emotional functioning and their correlation with the P300 component in a sample of children with ADHD with and without treatment. PATIENTS AND METHODS: The sample was made up of 71 children with ADHD, almost half of whom were taking some form of medication. The auditory potential P300 was analysed. The parents filled in a scale to assess executive behaviour at home, the Behavior Rating Inventory of Executive Function (BRIEF), which the emotional self-regulation index and the emotional expression scale were taken from. RESULTS: Significant correlations were found between the amplitude of the P300 and the emotional self-regulation index from the version of the BRIEF for preschoolers, and a relation was observed between P300 latency and the severity of the symptoms. CONCLUSIONS: The results highlight the usefulness of evoked potentials for the study of executive correlates and associated conditions in the day-to-day functioning of children with ADHD. PMID- 25726828 TI - [Neurofunctional differences in the P300 frequency for multi-sensory stimulation in kids with attention deficit hyperactivity disorder]. AB - INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, motor hyperactivity, impulsivity, or a combination of all. The P300 is a non-invasive neurophysiological that has shown its effectiveness to detect differences between subjects with ADHD but results are not yet conclusive. AIM: To assess brain information processing by the P300 component, auditory, visual and tactile modality in children with ADHD. SUBJECTS AND METHODS: The P300 components auditory, visual and tactile 17 children with ADHD (11 combined and 7 in-attentive) and 15 control children aged between 7 and 10 years were recorded. RESULTS: In response reaction times found a more pronounced trend in the auditory and visual time but not statistically significant in any of the three responses. In the error rate increased in children with ADHD compared to the control group. Children with ADHD have a significant increase in latency of visual P300 wave while there is no significant decrease in tactile and auditory P300. We found increased cortical areas in the P300 component in children with ADHD during visual and auditory test, but not touch. CONCLUSIONS: Our results support the hypothesis of the existence of increased brain areas during auditory and visual sensory processing in ADHD group, except for tactile stimulation happens otherwise. PMID- 25726829 TI - [Executive functioning and motivation in preschool children at risk for learning difficulties in mathematics]. AB - INTRODUCTION: Early identification of the factors involved in the development of learning difficulties in mathematics is essential to be able to understand their origin and implement successful interventions. This study analyses the capacity of executive functioning and of variables from the motivational belief system to differentiate and classify preschool children with and without risk of having difficulties in mathematics. SUBJECTS AND METHODS: A total of 146 subjects from the third year of preschool education took part in the study, divided into risk/no risk according to the score obtained on the operations subtest of the TEDI-MATH test. Working memory (verbal and visuospatial) and inhibition (with auditory and visual stimuli) neuropsychological tasks were applied. Teachers filled in a questionnaire on the children's motivation with regard to learning. RESULTS AND CONCLUSIONS: Significant differences were found between the two groups on the working memory and inhibition-auditory factors, as well as on all the motivation variables. The results also show a similar power of classification, with percentages above 80%, for both groups of variables. The implications of these findings for educational practice are discussed. PMID- 25726830 TI - [Educational intervention for the expression of cognitive excellence]. AB - The aim of the study is a reflection on the current standing of giftedness research and the effectiveness of gifted education in order to facilitate its optimal developmental trajectory from potential to eminence. The necessity of rethinking high intellectual ability as a developmental process is exposed from a new paradigm sustained by research results that could lead us to a better understanding of its nature and functioning as the product of the inter-relation of predictor factors and psychosocial modulators across the development, and the participation of executive functions on cognitive management. Rethinking giftedness education is needed, too, in order to prepare young people for outstanding achievement or eminence. Finally, one of the actual effective models of intervention for gifted learners to excellence is exposed and exemplified: the integrated curriculum model. PMID- 25726831 TI - [Unresolved issues in the DSM-5]. AB - This paper analyses the criticism prompted by the publication of the Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), which was already foreseen to a certain extent during the final stages of its drafting. Part of the criticism has focused on the changes in the diagnostic criteria for certain disorders and the incorporation of new entities into the DSM. Another line of criticism, however, is aimed at the lack of diagnostic validity of the DSM, which has led to its efficiency in the research field being questioned. The basic underlying flaw in the DSM is the incoherence of a model based on a wide range of definitions of categorical entities, all of which have a high element of comorbidity. As a proposal to overcome the blockage generated in research and the scarcity of therapeutic advances, the US National Institute of Mental Health has put forward a research strategy based on identifying and studying the fundamental dimensions of the dysfunctions that present transversally in mental disorders. PMID- 25726833 TI - From forest to cropland and pasture systems: a critical review of soil organic carbon stocks changes in Amazonia. AB - The impact of deforestation on soil organic carbon (SOC) stocks is important in the context of climate change and agricultural soil use. Trends of SOC stock changes after agroecosystem establishment vary according to the spatial scale considered, and factors explaining these trends may differ sometimes according to meta-analyses. We have reviewed the knowledge about changes in SOC stocks in Amazonia after the establishment of pasture or cropland, sought relationships between observed changes and soil, climatic variables and management practices, and synthesized the delta13 C measured in pastures. Our dataset consisted of 21 studies mostly synchronic, across 52 sites (Brazil, Colombia, French Guiana, Suriname), totalling 70 forest-agroecosystem comparisons. We found that pastures (n = 52, mean age = 17.6 years) had slightly higher SOC stocks than forest (+6.8 +/- 3.1 %), whereas croplands (n = 18, mean age = 8.7 years) had lower SOC stocks than forest (-8.5 +/- 2.9 %). Annual precipitation and SOC stocks under forest had no effect on the SOC changes in the agroecosystems. For croplands, we found a lower SOC loss than other meta-analyses, but the short time period after deforestation here could have reduced this loss. There was no clear effect of tillage on the SOC response. Management of pastures, whether they were degraded/nominal/improved, had no significant effect on SOC response. delta13 C measurements on 16 pasture chronosequences showed that decay of forest-derived SOC was variable, whereas pasture-derived SOC was less so and was characterized by an accumulation plateau of 20 Mg SOC ha-1 after 20 years. The large uncertainties in SOC response observed could be derived from the chronosequence approach, sensitive to natural soil variability and to human management practices. This study emphasizes the need for diachronic and long-term studies, associated with better knowledge of agroecosystem management. PMID- 25726832 TI - Salivary proline-rich proteins and gluten: Do structural similarities suggest a role in celiac disease? AB - PURPOSE: Gluten proteins, the culprits in celiac disease (CD), show striking similarities in primary structure with human salivary proline-rich proteins (PRPs). Both are enriched in proline and glutamine residues that often occur consecutively in their sequences. We investigated potential differences in the spectrum of salivary PRPs in health and CD. EXPERIMENTAL DESIGN: Stimulated salivary secretions were collected from CD patients, patients with refractory CD, patients with gastrointestinal complaints but no CD, and healthy controls. PRP isoforms/peptides were characterized by anionic and SDS-PAGE, PCR, and LC-ESI-MS. RESULTS: The gene frequencies of the acidic PRP isoforms PIF, Db, Pa, PRP1, and PRP2 did not differ between groups. At the protein level, PRPs peptides showed minor group differences, but these could not differentiate the CD and/or refractory CDs groups from the controls. CONCLUSIONS AND CLINICAL RELEVANCE: This extensive study established that salivary PRPs, despite similarity to gluten proteins, show no apparent correlation with CD and thus will not serve as diagnostic markers for the disease. The structural basis for the tolerance to the gluten-like PRP proteins in CD is worthy of further exploration and may lead to the development of gluten-like analogs lacking immunogenicity that could be used therapeutically. PMID- 25726834 TI - Charge separation in graphene-decorated multimodular tris(pyrene) subphthalocyanine-fullerene donor-acceptor hybrids. AB - A new approach to probe the effect of graphene on photochemical charge separation in donor-acceptor conjugates is devised. For this, multimodular donor-acceptor conjugates, composed of three molecules of pyrene, a subphthalocyanine, and a fullerene C60 ((Pyr)3 SubPc-C60 ), have been synthesized and characterized. These systems were hybridized on few-layer graphene through pi-pi stacking interactions of the three pyrene moieties. The hybrids were characterized using Raman, HRTEM, and spectroscopic and electrochemical techniques. The energy levels of the donor acceptor conjugates were fine-tuned upon interaction with graphene and photoinduced charge separation in the absence and presence of graphene was studied by femtosecond transient absorption spectroscopy. Accelerated charge separation and recombination was detected in these graphene-decorated conjugates suggesting that they could be used as materials for fast-responding optoelectronic devices and in light energy harvesting applications. PMID- 25726835 TI - Enzymatic basis of "hybridity" in thiomarinol biosynthesis. AB - Thiomarinol is a naturally occurring double-headed antibiotic that is highly potent against methicillin-resistant Staphylococcus aureus. Its structure comprises two antimicrobial subcomponents, pseudomonic acid analogue and holothin, linked by an amide bond. TmlU was thought to be the sole enzyme responsible for this amide-bond formation. In contrast to this idea, we show that TmlU acts as a CoA ligase that activates pseudomonic acid as a thioester that is processed by the acetyltransferase HolE to catalyze the amidation. TmlU prefers complex acyl acids as substrates, whereas HolE is relatively promiscuous, accepting a range of acyl-CoA and amine substrates. Our results provide detailed biochemical information on thiomarinol biosynthesis, and evolutionary insight regarding how the pseudomonic acid and holothin pathways converge to generate this potent hybrid antibiotic. This work also demonstrates the potential of TmlU/HolE enzymes as engineering tools to generate new "hybrid" molecules. PMID- 25726836 TI - Prevention of mother-to-child transmission of HIV in rural Uganda: modelling effectiveness and impact of scaling-up PMTCT services. AB - BACKGROUND: The reported coverage of any antiretroviral (ARV) prophylaxis for prevention of mother-to-child transmission (PMTCT) has increased in sub-Saharan Africa in recent years, but was still only 60% in 2010. However, the coverage estimate is subject to overestimations since it only considers enrolment and not completion of the PMTCT programme. The PMTCT programme is complex as it builds on a cascade of sequential interventions that should take place to reduce mother-to child transmission (MTCT) of HIV: starting with antenatal care (ANC), HIV testing, and ARVs for the woman and the baby. OBJECTIVE: The objective was to estimate the number of children infected with HIV in a district population, using empirical data on uptake of PMTCT components combined with data on MTCT rates. DESIGN: This study is based on a population-based cohort of pregnant women recruited in the Iganga-Mayuge Health and Demographic Surveillance Site in rural Uganda 2008-2010. We later modelled different scenarios assuming increased uptake of specific PMTCT components to estimate the impact on MTCT for each scenario. RESULTS: In this setting, HIV infections in children could be reduced by 28% by increasing HIV testing capacity at health facilities to ensure 100% testing among women seeking ANC. Providing ART to all women who received ARV prophylaxis would give an 18% MTCT reduction. CONCLUSIONS: Our results highlight the urgency in scaling-up universal access to HIV testing at all ANC facilities, and the potential gains of early enrolment of all pregnant women on antiretroviral treatment for PMTCT. Further, to determine the effectiveness of PMTCT programmes in different settings, it is crucial to analyse at what stages of the PMTCT cascade that dropouts occur to target interventions accordingly. PMID- 25726837 TI - Three dimensional culture of HepG2 liver cells on a rat decellularized liver matrix for pharmacological studies. AB - Three-dimensional in vitro tumor models are needed to obtain more information about drug behavior in tumors. The aim of this study is to establish a new model for hepatocellular carcinoma (HCC) using decellularized rat livers. After generating the rat liver scaffolds, HepG2 liver cancer cells were perfused via the portal vein and placed in a bioreactor for 10 days. Histology was performed to analyze cell distribution within the scaffolds. Function and tumor-related gene expression were examined by polymerase chain reaction (PCR). We evaluated the function of HepG2 cells grown on scaffolds in the presence of a well-known anti-cancer drug to investigate the potential application of our system for drug screening. The scaffolds were devoid of cellular materials and preserved extracellular matrix components. HepG2 cells grew well on the scaffolds. The PCR results showed that the cells maintained function and invasion ability at significantly higher levels than cells grown on two-dimensional (2-D) dishes or spheroids on Matrigel. Unlike the 2-D cultures, albumin secretion and alpha fetoprotein expression in three-dimensional cultures were less susceptible to lower concentrations of the drug. Cells grown in scaffolds seemed to respond to the drug in an analogous manner to its known activity in vivo. These findings strengthen the potential use of rat liver scaffolds for screening HCC drugs. PMID- 25726838 TI - Transcatheter interventions across fresh suture lines in infants and children: an 8-year experience. AB - OBJECTIVES: The purpose of this study was to examine the outcomes of catheter dilation interventions in general upon surgical anastomotic sites in the immediate postoperative period. BACKGROUND: Early postoperative cardiac catheter intervention is regarded as high-risk, particularly when a dilation intervention across a fresh suture line is performed. METHODS: All catheter dilation interventions performed upon a fresh suture line within 30 days of congenital heart surgery between August 2005 and December 2013 were reviewed. Values are reported as median and interquartile range (IQR). Primary endpoint was procedural success, which was defined as an increase in vessel diameter of >75% of the adjacent normal vessel or 50% increase over pre-dilation diameter. Secondary endpoints included procedural complications and survival to hospital discharge. RESULTS: Forty-five patients, median age 0.15 years (0.03-0.51 years), weight 4.1 kg (3.1-6.4 kg), underwent 62 interventional procedures on median postoperative day 7 (3-13 days). Among the 62 dilation interventions at surgical anastomotic areas, were 30 stent and 32 balloon angioplasty procedures. There were two major complications including: arterial dissection during stent placement and a procedural mortality due to pulmonary artery avulsion during angioplasty. There were 12 deaths (27%) prior to hospital discharge. The median ratio of maximum stent diameter to stenosis diameter was 2.62 (2.27-3.73). The median ratio of maximum balloon diameter to stenosis diameter was 2.27 (1.84-2.94). Stent placement was more likely to result in procedural success (OR 2.1; 95% confidence interval 1.6-2.8). CONCLUSION: Though caution is paramount, early postoperative catheter dilation intervention across fresh suture lines can be performed safely in small, critically ill children. PMID- 25726839 TI - The effect of mesenchymal stem cells and sildenafil on flap viability in perforator-based flaps for ischemia/reperfusion injury: An experimental study. AB - PURPOSE: In this study, we evaluated the individual and combined effects of mesenchymal stem cells (MSCs) and sildenafil citrate (SC) on the viability of pedicled perforator flaps in which ischemia/reperfusion injury developed after induction of primary ischemia. MATERIALS AND METHODS: Seven Sprague-Dawley rats were used as donors of cells. Rectangular flaps (7 * 7 cm2 ) were created featuring the right second epigastric musculocutaneous perforator in 63 male Sprague-Dawley rats. The animals were randomly divided into two experimental groups (based on the ischemia time of 4 or 8 hours) and a control group. Each of the experimental group was further divided into four subgroups with no treatment, subcutaneous administration of MSCs after termination of ischemia, intraperitoneal administration of SC after termination of ischemia, and combined MSCs and SC treatments at the end of the period of ischemia (n = 7 for each subgroup). A sham group with no-ischemia to flap was used as the control (n = 7). On day 7, viable areas on the flaps were calculated from photographs. The levels of the antioxidative enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), were analyzed in tissue samples obtained from the most distal regions of the flap prior to ischemia and on day 7 after induction of ischemia. RESULTS: No difference was detected between the no ischemia group and 4-hours SC-treated subgroup, 4-hours combined MSC and SC treated subgroup, 8-hours MSC-treated subgroup, or 8-hours SC-treated subgroup (P > 0.05). In 4-hours ischemia group, the viable flap area of combined MSC and SC treated subgroup was significantly greater than that of the ischemia subgroup (17.17 +/- 12.56 cm2 vs. 7.24 +/- 7.17 cm2 ; P = 0.015). However, in 8-hours ischemia group, the viable flap area of MSC- treated subgroup was significantly greater than that of the ischemia subgroup (2.69 +/- 3.71 cm2 vs. 14.52 +/- 8.57 cm2 ; P = 0.004). There were no significant differences in SOD, CAT, and GPX levels detected between no-ischemia group and any of the treated subgroups in 4- and 8-hours ischemia groups (P > 0.05). However, SOD, CAT, and GPX levels in the no-ischemia group were lower than that in 4-hours ischemia control subgroup or 8 hours ischemia control subgroup (P < 0.05). CONCLUSION: In this rat pedicled perforator based abdominal flap, we found that after primary ischemia, application of MSCs and SC, either individually or in combined form, significantly enhanced antioxidant enzyme levels compared with those in the control group, and provided protection against ischemia/reperfusion injury. The two treatments acted synergistically to protect against damage after 4 hours of ischemia, but either treatment alone more effectively enhanced viable flap area after 8 hours of ischemia, although some flap damage was apparent. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:402-409, 2016. PMID- 25726840 TI - The study of surface states in a semi-infinite crystal. AB - An infinite three dimensional (3D) crystal can be constructed by an infinite number of parallel 2D (hkl) crystal planes (CPs) coupled to each other. Based on lattice model Hamiltonian with the hopping between the nearest neighbor (1NN) CPs and all possible neighbor hoppings within each CP, we analytically prove that a (hkl) cut crystal will not accommodate any surface states if the original infinite crystal has the reflection symmetry which results in the forward transfer matrix F to be equal to the backward one B, named as F-B dynamical symmetry. We also study the effect of the longer range couplings among the nNN (n > 1) CPs and surface relaxation on our conclusion and find that the small perturbation from both factors has no effect on our conclusion based on the perturbation theory. Thus our model may have the potential for studying surface states in some cut crystals with low-index surfaces. Our result may be helpful to visually predict which cutting direction in some non-topological crystals is unfavorable to generate surface states. PMID- 25726842 TI - The occurrence of acanthocephalans in teleost fish from the Bizerte lagoon, Tunisia. AB - Seven species of acanthocephalans were identified for the first time in teleost fish from the Bizerte lagoon, Tunisia, including Neoechinorhynchus (Hebesoma) agilis (Rudolphi, 1819) Van Cleave, 1916; N. (Neoechinorhynchus) rutili Muller, 1780 (Neoechinorhynchidae); Acanthocephaloide propinquus (Dujardin, 1845) Meyer, 1932; A. incrassatus (Molin, 1858) Meyer, 1932 (Arhythmacanthidae); Longicollum pagrosomi Yamaguti, 1935 (Pomphorhynchidae); Rhadinorhynchus cadenati (Golvan et Houin, 1964) Golvan, 1969 (Rhadinorhynchidae); and Telosentis exiguus (von Linstow, 1901) Van Cleave, 1923 (Illiosentidae). Acanthocephaloide propinquus, N. (N.) rutili, L. pagrosomi and R. cadenati were restricted to the rectum and the posterior intestine, whereas the other species (A. incrassatus, T. exiguus and N. (H.) agilis) colonized two or three parts of the intestine. The most diverse acanthocephalan fauna was recorded in Lithognathus mormyrus, with three species; two species were reported from Trachurus trachurus; and a single species was recorded in Liza aurata and in Atherina boyeri. Neoechinorhynchus (N.) rutili, L. pagrosomi and R. cadenati attained the lowest prevalences of less than 6% and were considered as to be rare species. Acanthocephaloide incrassatus, A. propinquus, T. exiguus and N. (H.) agilis were satellite species. The diversity of the acanthocephalan fauna in the fish from the Bizerte lagoon is compared with previous studies from other localities. The report of A. incrassatus, A. propinquus and N. (N.) rutili in L. mormyrus presents new host records in Mediterranean waters. PMID- 25726841 TI - Rare variants in gamma-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. AB - OBJECTIVE: To test whether mutations in gamma-aminobutyric acid type A receptor (GABAA -R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). METHODS: We performed exome sequencing to compare the frequency of variants in 18 GABAA -R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function. RESULTS: Of 18 screened GABAA -R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio = 18.07, 95% confidence interval = 2.01-855.07, p = 0.0024, pcorr = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant gamma2 subunit. INTERPRETATION: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants. PMID- 25726843 TI - Macular arteritis associated with concurrent HIV and hepatitis B infections: a case report and evidence for a disease spectrum association with cutaneous polyarteritis nodosa. AB - We report the first case of macular arteritis in a 33-year-old Black, African female with concurrent human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. Of particular interest in macular arteritis is the striking discordance between the clinical presentation and the histopathological findings, a fact that both dermatologists and dermatopathologists should be aware. Histopathologically, the case showed typical findings of macular arteritis with a perivascular, predominantly lymphocytic, infiltrate and intraluminal thrombosis. Both HIV and HBV have been reported as viral inducers of cutaneous polyarteritis nodosa (PAN). Their association with macular arteritis in this case supports existing evidence that macular arteritis and cutaneous PAN represent a single disease spectrum of vasculitides, with macular arteritis representing the chronic, lymphocytic and indolent stage, and cutaneous PAN the neutrophilic, acute stage with a risk for systemic progression. Lymphocytic thrombophilic arteritis (LTA), a third, uncommon disease would be in between macular arteritis and cutaneous PAN on a spectrum. Features of this case and other published cases provide strong evidence that there is a single, mild-to-severe disease spectrum of macular arteritis-LTA-cutaneous PAN. PMID- 25726844 TI - Does Bruxism Contribute to Dental Implant Failure? A Systematic Review and Meta Analysis. AB - BACKGROUND: Bruxism was usually considered as a contraindication for oral implanting. The causal relationship between bruxism and dental implant failure was remained controversial in existing literatures. PURPOSE: This meta-analysis was performed to investigate the relationship between them. MATERIALS AND METHODS: This review conducted an electronic systematic literature search in MEDLINE (PubMed) and EmBase in November 2013 without time and language restrictions. Meanwhile, a hand searching for all the relevant references of included studies was also conducted. Study information extraction and methodological quality assessments were accomplished by two reviewers independently. A discussion ensued if any disagreement occurred, and unresolved issues were solved by consulting a third reviewer. Methodological quality was assessed by using the Newcastle-Ottawa Scale tool. Odds ratio (OR) with 95% confidence interval (CI) was pooled to estimate the relative effect of bruxism on dental implant failures. Fixed effects model was used initially; if the heterogeneity was high, random effects model was chosen for meta-analysis. Statistical analyses were carried out by using Review Manager 5.1. RESULTS: In this meta-analysis review, extracted data were classified into two groups based on different units. Units were based on the number of prostheses (group A) and the number of patients (group B). In group A, the total pooled OR of bruxers versus nonbruxers for all subgroups was 4.72 (95% CI: 2.66-8.36, p = .07). In group B, the total pooled OR of bruxers versus nonbruxers for all subgroups was 3.83 (95% CI: 2.12-6.94, p = .22). CONCLUSIONS: This meta-analysis was performed to evaluate the relationship between bruxism and dental implant failure. In contrast to nonbruxers, prostheses in bruxers had a higher failure rate. It suggests that bruxism is a contributing factor of causing the occurrence of dental implant technical/biological complications and plays a role in dental implant failure. PMID- 25726845 TI - Primary IgA nephropathy in elderly patients. AB - AIM: Data on clinicopathological features, treatment and outcomes of IgA nephropathy (IgAN) in elderly patients are limited. METHODS: Native kidney biopsies with a pathological diagnosis of IgAN (n = 1084) from Mayo Clinic Rochester in the years 1994-2013 were examined. After exclusion of the secondary IgAN, 45 elderly IgAN patients (age >=65 years) were identified. One hundred sixty-two younger adults (age 18-64 years) with IgAN were randomly selected for comparison. RESULTS: Compared with younger adults, elderly patients showed a higher rate of chronic hypertension (62.2 vs 27.2%), higher pulse pressures (65 +/- 17 vs 51 +/- 15 mmHg), requiring greater number of antihypertensive medications (2.5 +/- 1.2 vs 1.7 +/- 0.7) and lower blood haemoglobin (11.1 +/- 2.3 vs 12.7 +/- 2.1 g/dL) at time of kidney biopsy, all P < 0.001. Pathologically, elderly kidneys showed a higher degree of tubulointerstitial fibrosis (P = 0.04) and vascular sclerosis (P < 0.001). Treatments (including the use of angiotensin-converting enzyme inhibitor (ACEI) inhibitor, angiotensin II receptor blocker (ARB) and immunosuppressants) were similar in the two cohorts. Elderly patients had more end-stage renal disease at 6 months (HR 5.51; 95% CI 1.46-22.3, P = 0.01) and higher 6-month and 5-year mortality (HR 2.31; 95% CI 1.04-5.17, P = 0.04) after adjusting the age and comorbidities. CONCLUSION: IgAN diagnosed at age >65 years tends to have a faster renal disease progression and higher patient mortality. PMID- 25726846 TI - High-mobility group box-1 induces vascular remodelling processes via c-Jun activation. AB - Extracellular high-mobility group box-1 (HMGB1) acts as a signalling molecule during inflammation, cell differentiation and angiogenesis. Increased abundance of HMGB1 is associated with several pathological disorders such as cancer, asthma and chronic obstructive pulmonary disease (COPD). In this study, we investigated the relevance of HMGB1 in the pathological remodelling present in patients with idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension (PH) associated with COPD. Remodelled vessels present in COPD with PH and IPAH lung samples were often surrounded by HMGB1-positive cells. Increased HMGB1 serum levels were detected in both patient populations compared to control samples. The effects of physiological HMGB1 concentrations were then examined on cellular responses in vitro. HMGB1 enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and primary human arterial endothelial cells (PAEC). HMGB1 stimulated p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation. Furthermore, activation of the downstream AP-1 complex proteins c-Fos and c-Jun was observed. Silencing of c-Jun ablated the HMGB1-induced proliferation in PASMC. Thus, an inflammatory component such as HMGB1 can contribute to PASMC and PAEC proliferation and therefore potentially to vascular remodelling and PH pathogenesis. PMID- 25726847 TI - Elevated Lin28B expression is correlated with lymph node metastasis in oral squamous cell carcinomas. AB - BACKGROUND: Lymph node (LN) metastasis is the most common cause of oral squamous cell carcinoma (OSCC)-related death. Searching the detailed molecular mechanisms involved LN metastasis in OSCC is still an open question. METHODS: Paired tissue samples from tumor (T) and adjacent non-cancerous matched tissues (NCMT) parts, as well as LN metastatic lesions in patient with OSCC tissues were subjected to quantitative real-time PCR analysis for the expression levels of Lin28B. Arecoline, a major areca nut alkaloid, was to explore whether expression of Lin28B could be changed dose dependent in oral epithelial cells. Control and Lin28B-knockdown arecoline-stimulated oral epithelial cells were subjected to migration/invasion/anchorage-independent growth assay. RESULTS: Compared with NCMT samples from the same OSCC patient, the expression of Lin28B was increased in all of the tumor samples. A similar upregulation of Lin28B was also observed in LN metastatic when compared with local tumors. Arecoline treatment dose dependently induced Lin28B expression in SG and FaDu cells. Lentiviral-mediated silencing Lin28B expression significantly attenuated arecoline-induced oncogenicity including proliferation, migration, invasiveness, and anchorage independent growth in SG and FaDu cells. CONCLUSIONS: Lin28B may be a useful biomarker and novel molecular target for LN metastasis OSCC patients' treatment. PMID- 25726848 TI - Emergence of carbapenem non-susceptible multidrug resistant Acinetobacter baumannii strains of clonal complexes 103(B) and 92(B) harboring OXA-type carbapenemases and metallo-beta-lactamases in Southern India. AB - The molecular epidemiology and carbapenem resistance mechanisms of clinical isolates of Acinetobacter baumannii obtained from a south Indian tertiary care hospital were investigated by repetitive extragenic palindromic sequence PCR (REP PCR) and multi-locus sequence typing (MLST). Analysis of resistant determinants was achieved by PCR screening for the presence of genes encoding OXA carbapenemases, metallo-beta-lactamases (MBLs) and efflux pumps. REP-PCR generated around eight clusters of high heterogeneity; of these, two major clusters (I and V) appeared to be clonal in origin. Analysis of representative isolates from different clusters by MLST revealed that most of the isolates belonged to sequence type 103 of CC103(B) . Second most prevalent ST belonged to clonal complex (CC) 92(B) which is also referred to as international clone II. Most of the isolates were multi-drug resistant, being susceptible only to polymyxin-B and newer quinolones. Class D beta-lactamases such as blaOXA-51-like (100%), blaOXA-23-like (56.8%) and blaOXA-24-like (14.8%) were found to be predominant, followed by a class B beta-lactamase, namely blaIMP-1 (40.7%); none of the isolates had blaOXA-58 like, blaNDM-1 or blaSIM-1 . Genes of efflux-pump adeABC were predominant, most of isolates being biofilm producers that were PCR positive for autoinducer synthase gene (>94%). Carbapenem non-susceptible isolates were highly diverse and present throughout the hospital irrespective of type of ward or intensive care unit. Although previous reports have documented diverse resistant mechanisms in A. baumannii, production of MBL and OXA-type of carbapenamases were found to be the predominant mechanism(s) of carbapenem resistance identified in strains isolated from Southern India. PMID- 25726849 TI - Coping and the stages of psychosis: an investigation into the coping styles in people at risk of psychosis, in people with first-episode and multiple-episode psychoses. AB - AIM: The concept of coping is central to recent models of psychosis. The aim of the present paper is to explore whether specific coping styles relate to certain stages of the disorder. METHODS: Thirty-nine clients at clinical high risk (CHR) of first-episode psychosis, 19 clients with first-episode psychosis and 52 clients with multiple-episode psychosis completed a Stress Coping Questionnaire. This questionnaire consists of 114 items defining one overall positive coping scale (with three subscales) and one negative coping scale. Analyses of variance with group as between-subject factor and coping behaviour as within-subject factor were used to identify different coping patterns. RESULTS: On the level of subscales no group differences could be detected, but analysis of variance revealed slightly different patterns: CHR clients used significantly more negative than positive coping styles (P = 0.001), followed by patients with multiple-episode psychosis (P = 0.074). First-episode patients were most likely to use negative as well as positive coping (P = 0.960). Across all stages of illness, stress control was significantly preferred compared to the other positive coping styles distraction and devaluation. Again, this pattern was especially pronounced for at-risk clients and patients with multiple-episode psychosis, whereas patients with first-episode psychosis were most likely to use devaluation as well as distraction. CONCLUSIONS: The overall coping styles were similar across the different stages of psychosis. However, at-risk persons presented especially pronounced negative coping and a small range of strategies, indicating a specific need for psychosocial support in this stage of the disorder. PMID- 25726850 TI - Yeast contribution to melatonin, melatonin isomers and tryptophan ethyl ester during alcoholic fermentation of grape musts. AB - Melatonin (MEL) has been found in some medicinal and food plants, including grapevine, a commodity of particular interest for the production of wine, a beverage of economic relevance. It has also been suggested that MEL in wine may, at least in part, contribute to the health-promoting properties attributed to this beverage and, possibly, to other traditional Mediterranean foodstuffs. After a preliminary screening of 9 yeast strains in laboratory medium, three selected strains (Saccharomyces cerevisiae EC1118, Torulaspora delbrueckii CBS1146(T) and Zygosaccharomyces bailii ATCC36947(T) ) were inoculated in experimental musts obtained from 2 white (Moscato and Chardonnay) and 2 red (Croatina and Merlot) grape varieties. The production of MEL, melatonin isomers (MIs) and tryptophan ethyl ester (TEE) was monitored during the alcoholic fermentation. The screening showed that the three investigated strains produced the highest concentrations of MEL and two MIs in optimal growth conditions. However, MEL and MIs were not produced in oenological conditions, but the three strains synthesized high concentrations of a new MI and TEE in musts. PMID- 25726851 TI - Photosensitizing Activity of Endogenous Eye Lens Chromophores: An Attempt to Unravel Their Contributions to Photo-Aging and Cataract Disease. AB - UVA-visible light has been proposed as a risk factor in the photo-aging of the human eye lens, as well as in the etiology of cataract disease. There is accumulating evidence indicating that photosensitizing reactions mediated by endogenous chromophores, which are generated during human eye lens aging, can play an important role in the generation of these processes. These reactions can lead to protein impairment by inducing non-enzymatic post-translational modifications such as protein oxidation and crosslinking. Although numerous chromophores have been characterized as both bound to human eye lens proteins and as unbound low-molecular-mass compounds, their contribution to eye lens photoaging and cataract disease is not completely understood. In this article we discuss the photochemical contribution of UV-filters derived from tryptophan catabolism and advanced glycation end products (AGEs) to human eye lens aging and cataract disease. We also discuss the recently described photosensitizing capacity of chromophores derived from newly discovered glucose and ascorbate degradation as a parallel pathway to their role in AGEs generation. PMID- 25726852 TI - Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder. AB - OBJECTIVES: Huntington's disease is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms that are caused by huntingtin gene (HTT) CAG trinucleotide repeat alleles of 36 or more units. A greater than expected prevalence of incompletely penetrant HTT CAG repeat alleles observed among individuals diagnosed with major depressive disorder raises the possibility that another mood disorder, bipolar disorder, could likewise be associated with Huntington's disease. METHODS: We assessed the distribution of HTT CAG repeat alleles in a cohort of individuals with bipolar disorder. HTT CAG allele sizes from 2,229 Caucasian individuals diagnosed with DSM-IV bipolar disorder were compared to allele sizes in 1,828 control individuals from multiple cohorts. RESULTS: We found that HTT CAG repeat alleles > 35 units were observed in only one of 4,458 chromosomes from individuals with bipolar disorder, compared to three of 3,656 chromosomes from control subjects. CONCLUSIONS: These findings do not support an association between bipolar disorder and Huntington's disease. PMID- 25726853 TI - Women's perceptions of the quality of emergency obstetric care in a referral hospital in rural Tanzania. AB - OBJECTIVES: To assess perceptions of the quality of obstetric care of women who delivered in a rural Tanzanian referral hospital. METHODS: A descriptive exploratory qualitative study, using semistructured in-depth interviews and participatory observation. Nineteen recently delivered women and 3 health workers were interviewed. RESULTS: Although most women held positive views about the care they received in hospital, several participants expressed major concerns about negative attitudes of healthcare workers. Lack of medical communication given by care providers constituted a major complaint. CONCLUSIONS: A more positive attitude by health workers and the provision of adequate medical information may promote a more positive hospital experience of women in need of obstetric care and enhance attendance. PMID- 25726854 TI - Tumour growth after portal vein embolization with pre-procedural chemotherapy for colorectal liver metastases. AB - BACKGROUND: For resection of colorectal cancer (CRC) liver metastases, pre operative portal vein embolization (PVE) is used to increase the size of the future liver remnant (FLR) prior to advanced liver resection when indicated. PVE is speculated to cause tumour progression, but only a limited number of studies have analysed tumour growth after PVE in the context of pre-procedural chemotherapy, which was the aim of this retrospective study. METHODS: Patients treated with stabilizing chemotherapy and PVE before liver resection for CRC metastases were included. Tumour progression according to RECIST guidelines and a change in tumour volume was analysed on computed tomography (CT) scans prior to chemotherapy, before PVE and after PVE, respectively. RESULTS: Thirty-four patients were included, of whom 23 had bilobar disease. Of tumours in the embolized lobe, 3/34 showed progression after PVE as compared with 3/23 in the non-embolized lobe (P = 0.677). A decrease in tumour volume of 16% and 11% was noted in the embolized and non-embolized lobe, respectively (P = 0.368). Patients were off chemotherapy in a median of 16 days before PVE. There was a linear correlation between the growth of tumours and time between the end of chemotherapy and PVE (r = 0.25, P = 0.0005). CONCLUSION: The rate of progression of CRC liver metastases after PVE and pre-procedural chemotherapy was lower in the present study as compared with previous reports. This applies to tumours in both the embolized and non-embolized lobes and is associated with keeping the time between the end of chemotherapy and PVE short. PMID- 25726855 TI - Proteomic and gene expression analysis of zebrafish brain undergoing continuous light/dark stress. AB - Several organisms irrespective of their complexity in structure and function have an inbuilt circadian rhythm. Zebrafish could be used as an alternate model animal in sleep research as it exhibits similar sleep-wake dynamics as mammals and Drosophila. In this study, we have analysed the adult zebrafish brain for its differential proteome and gene expression during perturbed light/dark cycle. A total of 53 and 25 proteins including sncb, peroxiredoxins and TCR alpha were identified based on two-dimensional gel electrophoresis Fourier transform mass spectrometer/ion trap tandem mass spectrometer and differential in-gel electrophoresis MALDI TOF MS/MS analysis, respectively, with at least 1.5-fold changes between the control and experimental brains. Real time-polymerase chain reaction revealed that many circadian pathway-associated genes, such as per1b, bmal1b, cry1b, bmal2 and nr1d2, were differentially regulated during continuous light/dark exposures. It is hypothesized that the differential regulation of these genes might lead to the discovery of potential diagnostic markers for gaining insight into the light/dark-associated stress in humans. PMID- 25726856 TI - Sampling of the anterior apical region results in increased cancer detection and upgrading in transrectal repeat saturation biopsy of the prostate. AB - OBJECTIVE: To evaluate whether biopsy cores taken via a transrectal approach from the anterior apical region of the prostate in a repeat-biopsy population can result in an increased overall cancer detection rate and in more accurate assessment of the Gleason score. PATIENTS AND METHODS: The study was a prospective, randomised (end-fire vs side-fire ultrasound probe) evaluation of 288 men by repeat transrectal saturation biopsy with 28 cores taken from the transition zone, base, mid-lobar, anterior and the anterior apical region located ventro-laterally to the urethra of the peripheral zone. RESULTS: The overall prostate cancer detection rate was 44.4%. Improvement of the overall detection rate by 7.8% could be achieved with additional biopsies of the anterior apical region. Two tumours featuring a Gleason score 7 could only be detected in the anterior apical region. In three cases (2.34%) Gleason score upgrading was achieved by separate analysis of each positive core of the anterior apical region. A five-fold higher cancer detection rate in the anterior apical region compared with the transition zone could be shown. CONCLUSION: Sampling of the anterior apical region results in higher overall cancer detection rate in repeat transrectal saturation biopsies of the prostate. Specimens from this region can detect clinically significant cancer, improve accuracy of the Gleason Scoring and therefore may alter therapy. PMID- 25726857 TI - Trends in the prevalence of erosive tooth wear in Brazilian preschool children. AB - OBJECTIVES: To report trends in the prevalence of ETW in Brazilian preschool children. METHODS: Three cross-sectional surveys were carried out on boys and girls aged 3-4 years living in Diadema, in the years 2008, 2010 and 2012 following the same criteria and methodology. A total of 2801 children were systematically examined during a National Day of Children's vaccination. Examiners were trained and calibrated to diagnose ETW using a modified version of the O'Brien index. RESULTS: The prevalence of ETW was 51.6% (95% CI 48.4-55.0) in 2008, 53.9% (95% CI 50.7-57.0) in 2010 and 51.3% (95% CI 47.8-54.7) in 2012. There was no significant association between prevalence of ETW from 2008 to 2012 (chi(2) for trend: P = 0.92). There was no significant association in the severity of ETW during this study's period. Most lesions were confined to enamel in all three studies. CONCLUSIONS: A high prevalence of ETW was found in this sample of preschool children in 2008, 2010 and 2012. No trends of increase or decrease in the prevalence and severity of ETW during this study's period. PMID- 25726858 TI - New one-step thiol functionalization procedure for Ni by self-assembled monolayers. AB - This article reports on a facile and fast strategy for the self-assembled monolayer (SAM) functionalization of nickel surfaces, employing cyclic voltammetry (CV) cycling of a suitable tailored solution containing the species to be adsorbed. Results are presented for ultrathin films formed on Ni by 1 hexadecanethiol (C16), L-cysteine (L-cys), and the poly{methyl (2R)-3-(2,2' bithiophen-4-ylsulfanyl)-2-[(tert-butoxycarbonyl)amino]propanoate} (PCT-L) thiophene-based chiral polymer. The effective formation of high-quality ultrathin organic films on the nickel was verified both electrochemically and by exploiting typical surface characterization techniques such as contact angle, ellipsometry, atomic force microscopy (AFM), polarization modulation-infrared reflection absorption spectroscopy (PM-IRRAS), and X-ray photoelectron spectroscopy (XPS). PMID- 25726859 TI - Pessimistic back beliefs and lack of exercise: a longitudinal risk study in relation to shoulder, neck, and back pain. AB - This cross-lagged-panel study tested the validity of the German version of the back beliefs questionnaire (BBQ) in predicting pain in the shoulders, neck, and back. A random sample of 2860 individuals participated at baseline, and 73% responded at one-year follow-up. Structural equation modeling was used to carry out a model comparison to evaluate whether paths differed between individuals with and without initial back pain and between those who exercised at baseline and those who did not. Factor analysis showed eight of the nine original items loaded on the expected common factor. High BBQ scores at baseline significantly predicted an increase in shoulder, neck, and back pain in individuals with current back pain (beta = .11, p < .05), but not in other respondents (beta = .02, p = .259). Similarly, baseline BBQ scores predicted the increase in shoulder, neck, and back pain among those who did not exercise (beta = .15, p < .05), but not in those who did (beta = .04, ns). The risk of negative back beliefs preceding an increase in shoulder, neck, and back pain was greatest for those with current back pain who did not exercise (beta = .29, p < .05). The findings confirmed the validity of the German BBQ. Cognitive behavioral interventions should address pessimistic back beliefs in high-risk groups. PMID- 25726860 TI - Leptin signaling as a therapeutic target of obesity. AB - INTRODUCTION: Leptin is a hormone with a key role in food intake and body weight homeostasis. Congenital leptin deficiency (CLD) is a rare disease that causes hyperphagia and early severe obesity. However, common obesity conditions are associated with hyperleptinemia and leptin resistance. AREAS COVERED: The main signaling pathways activated by leptin as well as the mechanisms underlying the regulatory actions of leptin on food intake and on lipid and glucose metabolism are reviewed. The potential mechanisms involving leptin resistance and the main regulatory hormonal and nutritional factors controlling leptin production/functions are also analyzed. The pathophysiology of leptin in human obesity, and especially the trials analyzing effects of leptin replacement therapy in patients with CLD or in subjects with common obesity and in post-obese weight-reduced subjects are also summarized. EXPERT OPINION: The use of drugs or specific bioactive food components with anti-inflammatory properties to reduce the inflammatory state associated with obesity, especially at the hypothalamus, may help to overcome leptin resistance. Research should also be focused on investigating dietary strategies, food supplements or drugs capable of avoiding or reversing the leptin fall during weight management, in order to promote sustained body weight lowering and weight loss maintenance. PMID- 25726861 TI - Fabrication of Microscale Hydrogels with Tailored Microstructures based on Liquid Bridge Phenomenon. AB - Microscale hydrogels (microgels) find widespread applications in various fields, such as drug delivery, tissue engineering, and biosensing. The shape of the microgels is a critical parameter that can significantly influence their function in these applications. Although various methods have been developed (e.g., micromolding, photolithography, microfluidics, and mechanical deformation method), it is still technically challenging to fabricate microgels with tailored microstructures. In this study, we have developed a simple and versatile method for preparing microgels by stretching hydrogel precursor droplets between two substrates to form a liquid bridge. Microgels with tailored microstructures (e.g., barrel-like, dumbbell-like, or funnel-like shapes) have been achieved through adjusting the distance between and the hydrophobicity of the two substrates. The developed method holds great potential to impact multiple fields, such as drug delivery, tissue engineering, and biosensing. PMID- 25726862 TI - Mal de debarquement syndrome: new insights. AB - Mal de Debarquement Syndrome (MdDS) is an enigmatic neurotological disorder with high morbidity, psychosocial burden, and few treatment options. Fortunately, there has been recent growth in scientific interest in understanding the biological basis of and in treating MdDS. Recent studies using functional neuroimaging have shown increased glucose metabolism in the left entorhinal cortex (EC) and amygdala in the setting of decreased prefrontal and temporal cortex metabolism in subjects with persistent MdDS. The EC is a key player in processing and gating spatial information to be stored in the hippocampus and is a major driver of brain oscillations. A limbic focus may also be key to spontaneous MdDS-like symptoms occurring in individuals with a history of anxiety or chronic stress. Treatment with repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex can decrease the rocking dizziness of MdDS, with successful responses associated with decreases in the coherence between brain networks with nodes in the parietal and occipital lobes. A new theory of MdDS is proposed as pathology secondary to entrainment of intrinsic brain networks driven by oscillatory motion exposure coupled with an inability to subsequently desynchronize the activity of these nodes. Future treatment strategies may be directed toward unyoking these networks. PMID- 25726864 TI - Engineering the phase front of light with phase-change material based planar lenses. AB - A novel hybrid planar lens is proposed to engineer the far-field focusing patterns. It consists of an array of slits which are filled with phase-change material Ge2Sb2Te5 (GST). By varying the crystallization level of GST from 0% to 90%, the Fabry-Perot resonance supported inside each slit can be spectrally shifted across the working wavelength at 1.55 um, which results in a transmitted electromagnetic phase modulation as large as 0.56pi. Based on this geometrically fixed platform, different phase fronts can be constructed spatially on the lens plane by assigning the designed GST crystallization levels to the corresponding slits, achieving various far-field focusing patterns. The present work offers a promising route to realize tunable nanophotonic components, which can be used in optical circuits and imaging applications. PMID- 25726865 TI - Macular thickness assessed with spectral domain OCT in a population-based study of children: normative data, repeatability and reproducibility and comparison with time domain OCT. AB - PURPOSE: To collect data on macular thickness assessed with Cirrus OCT in healthy children in a population-based study, to examine the repeatability and reproducibility, and to compare the values with Stratus OCT. METHODS: Fifty-eight 6- to 15-year-old children, born at term, were examined. Best-corrected visual acuity and refraction were assessed. One examiner performed three OCT assessments, and the repeatability was calculated. Thereafter, a second examiner repeated the examinations to calculate the reproducibility. One eye was randomized to be included in the normal material. Finally, the second examiner assessed the macular thickness with the Stratus OCT. RESULTS: The mean value (+/ SD) of central macular thickness was 255 +/- 17 MUm, and the total macular volume was 10.3 +/- 0.5 mm(3) . No correlations were found between macular thickness and age, gender or refraction. The coefficients of variance (CoVs) for both repeatability and reproducibility were <1.21%, and the intraclass correlations (ICCs) were over 0.86. The Cirrus OCT showed a 29% thicker central macular thickness than the Stratus OCT. CONCLUSION: Normal values for macular thickness assessed with Cirrus OCT in healthy full-term children in a population-based study were reported. The assessments showed high repeatability and reproducibility. The values of Cirrus and Stratus OCT differed and the techniques were not interchangeable. PMID- 25726866 TI - Determining chemically and spatially resolved atomic profile of low contrast interface structure with high resolution. AB - We present precise measurements of atomic distributions of low electron density contrast at a buried interface using soft x-ray resonant scattering. This approach allows one to construct chemically and spatially highly resolved atomic distribution profile upto several tens of nanometer in a non-destructive and quantitative manner. We demonstrate that the method is sensitive enough to resolve compositional differences of few atomic percent in nano-scaled layered structures of elements with poor electron density differences (0.05%). The present study near the edge of potential impurities in soft x-ray range for low-Z system will stimulate the activity in that field. PMID- 25726867 TI - Doxepin-induced bullous pemphigoid-like drug eruption. PMID- 25726871 TI - Rapid deployment aortic valves and minimally invasive aortic valve replacement: a perfect marriage of technology and technique? PMID- 25726869 TI - Complement 5a receptor-mediated neutrophil dysfunction is associated with a poor outcome in sepsis. AB - Complement 5a (C5a) has been implicated in the pathogenesis of sepsis by inducing the functional impairment of neutrophils; however, the utility of C5a receptors (C5aRs; C5aR and C5L2) as biomarkers for the management of sepsis is uncertain. This study investigated the dynamic expression of C5aR and C5L2 on neutrophils and their effects on neutrophil function. We found that sepsis patients displayed low expression levels of C5aR and C5L2 on neutrophils compared to healthy and systemic inflammatory response syndrome (SIRS) subjects, and this expression pattern was correlated with disease severity. Additionally, the expression levels of C5aR and C5L2 were associated with the survival of sepsis patients. In vitro, the addition of C5a significantly reduced C5aR and C5L2 expression levels and IL 8 production in neutrophils from sepsis patients. Those findings suggest that the reduced expression of C5aRs was associated with the functional impairment of neutrophils and a poor prognosis for sepsis patients. Overall, these findings may help establish C5aRs expression levels as early markers to predict the severity of sepsis. PMID- 25726868 TI - Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. AB - Recent genome-wide cDNA microarray analysis of gene expression profiles in comprehensive tumor types coupled with isolation of cancer tissues by laser microbeam microdissection have revealed ideal tumor-associated antigens (TAAs) that are frequently overexpressed in various cancers including head and neck squamous cell cancer (HNSCC) and lung cancer, but not in most normal tissues except for testis, placenta, and fetal organs. Preclinical studies using HLA transgenic mice and human T cells in vitro showed that TAA-derived CTL-epitope short peptides (SPs) are highly immunogenic and induce HLA-A2 or -A24-restricted CTLs. Based on the accumulated evidence, we carried out a phase II clinical trial of the TAA-SP vaccine in advanced 37 HNSCC patients. This study showed a significant induction of TAA-specific CTLs in the majority of patients without serious adverse effects. Importantly, clinical responses including a complete response were observed in this study. Another phase II clinical trial of therapeutic TAA-SP vaccine, designed to evaluate the ability of prevention of recurrence, is ongoing in HNSCC patients who have received curative operations. Further studies in human preclinical studies and in vivo studies using HLA class I transgenic mice showed TAA-derived long peptides (TAA-LPs) have the capacity to induce not only promiscuous HLA class II-restricted CD4(+) T helper type 1 cells but also tumor-specific CTLs through a cross-presentation mechanism. Moreover, we observed an augmentation of TAA-LP-specific T helper type 1 cell responses and tumor antigen-spreading in HNSCC patients vaccinated with TAA-SPs. This accumulated evidence suggests that therapeutic TAA-SPs and LPs vaccines may provide a promising cancer immunotherapy. PMID- 25726872 TI - Coronary revascularization in the setting of surgical aortic valve replacement: do we need extra icing on the cake? PMID- 25726873 TI - Transient systolic anterior motion after mitral valve repair: does it affect long term outcomes? PMID- 25726874 TI - Composite vein grafting: is it a "Y's" decision? PMID- 25726875 TI - National Aeronautics and Space Administration "threat and error" model applied to pediatric cardiac surgery: error cycles precede ~85% of patient deaths. AB - BACKGROUND: We hypothesized that the National Aeronautics and Space Administration "threat and error" model (which is derived from analyzing >30,000 commercial flights, and explains >90% of crashes) is directly applicable to pediatric cardiac surgery. METHODS: We implemented a unit-wide performance initiative, whereby every surgical admission constitutes a "flight" and is tracked in real time, with the aim of identifying errors. The first 500 consecutive patients (524 flights) were analyzed, with an emphasis on the relationship between error cycles and permanent harmful outcomes. RESULTS: Among 524 patient flights (risk adjustment for congenital heart surgery category: 1-6; median: 2) 68 (13%) involved residual hemodynamic lesions, 13 (2.5%) permanent end-organ injuries, and 7 deaths (1.3%). Preoperatively, 763 threats were identified in 379 (72%) flights. Only 51% of patient flights (267) were error free. In the remaining 257 flights, 430 errors occurred, most commonly related to proficiency (280; 65%) or judgment (69, 16%). In most flights with errors (173 of 257; 67%), an unintended clinical state resulted, ie, the error was consequential. In 60% of consequential errors (n = 110; 21% of total), subsequent cycles of additional error/unintended states occurred. Cycles, particularly those containing multiple errors, were very significantly associated with permanent harmful end-states, including residual hemodynamic lesions (P < .0001), end-organ injury (P < .0001), and death (P < .0001). Deaths were almost always preceded by cycles (6 of 7; P < .0001). CONCLUSIONS: Human error, if not mitigated, often leads to cycles of error and unintended patient states, which are dangerous and precede the majority of harmful outcomes. Efforts to manage threats and error cycles (through crew resource management techniques) are likely to yield large increases in patient safety. PMID- 25726878 TI - Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. AB - OBJECTIVES: We evaluated the long-term results of pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, prophylactic chest wall radiotherapy (21 Gy), and systemic chemotherapy in patients with malignant pleural mesothelioma. METHODS: A cohort of patients having surgery between January 2004 and December 2013 were retrospectively studied. All patients received prophylactic radiotherapy postoperatively and all were supposed to receive systemic chemotherapy, either preoperatively or as adjuvant therapy. Patients were reviewed at 30 days, then followed up 6-monthly. (18)F-FDG-PET-CT was used routinely to diagnose disease recurrence. Second-line therapies were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: One hundred two patients had P/D followed by prophylactic radiotherapy and were referred for adjuvant chemotherapy. Median age at operation was 64 years. Eighty one patients (79.4%) were male; 57 patients (55.9%) had complete macroscopic resection. Thirty-day mortality was nil and 30 patients (29.4%) experienced postoperative complications. Seventy-three patients had epithelioid mesothelioma (71.5%). Sixty-eight patients (66.6%) had N0 disease. Ninety-six patients (94.1%) received the planned 4 to 6 chemotherapy cycles. At last follow-up, 49 patients were alive. Univariate analysis showed no significant difference when sex, age >70 years, nodal status, or prior chemotherapy were considered. The overall median survival was 32 months and 5-year survival rate was 23.1%. Median survival and 5-year survival rates were 35.0 months and 30.7% for epithelioid mesothelioma and 15 months and 7% for nonepithelioid mesothelioma, respectively (P = .0001). Median survival was 45.0 months for R0-R1 resection versus 17.4 months for R2 resection (P = .0001). CONCLUSIONS: P/D, hyperthermic pleural lavage with povidone-iodine, prophylactic chest wall radiotherapy, and systemic chemotherapy is a safe and well-tolerated multimodality therapy. PMID- 25726880 TI - Prehabilitation: Prevention is better than cure. PMID- 25726882 TI - Reprint of: Continuous renal replacement therapy and mild hypothermia for acute left heart failure after cardiovascular surgery. PMID- 25726883 TI - Innovative strategy for severe left ventricular failure without use of a left ventricular assist device. PMID- 25726884 TI - Double the jeopardy: balancing maternal and fetal risk during cardiac surgery. PMID- 25726885 TI - del Nido cardioplegia: ready for prime time in adult cardiac surgery? PMID- 25726886 TI - Valve-in-valve: estimating the risk of ostium obstruction in Sorin stentless valves. PMID- 25726887 TI - The vats advantage: seeing is believing ... and vice versa. PMID- 25726888 TI - Does video-assisted thoracoscopic surgical (VATS) lobectomy really result in fewer complications than thoracotomy? The biases are clear, the role of video assisted thoracoscopic surgery less so. PMID- 25726889 TI - Clinical challenges in the treatment of patients with tracheostomy in a hyperbaric chamber. PMID- 25726890 TI - Reply to the editor. PMID- 25726891 TI - Factors to be considered in aortic repair. PMID- 25726892 TI - Measures of circadian preference in childhood and adolescence: A review. AB - PURPOSE: To review the psychometric properties of the questionnaires commonly filled in by children and adolescents to measure circadian preference. METHODS: We examined the Morningness-Eveningness Questionnaire for Children and Adolescents (MEQ-CA), the Morningness-Eveningness Scale for Children (MESC) and the Composite Scale of Morningness (CSM). We critically analyzed the reliability, in term of internal consistency (through the Cronbach's alpha) and test-retest reliability (through the correlation coefficient), and the type of validation against external criteria (objective assessment of the sleep/wake cycle, body temperature, hormones and other questionnaires). Fifty studies that reported these data were included in the review: 7 studies used the MEQ-CA, 28 used the MESC and 15 used the CSM. RESULTS: The percentage of studies reporting at least acceptable levels of internal consistency was high and similar between the three questionnaires. Evidence for test-retest reliability was scant, since only 3 studies were available; it was at least acceptable for the MESC (two studies with a time interval of 1 month), not acceptable for the MEQ-CA (one study with a time interval of 6 months), while no information was available for the CSM. As regards the validation evidence, the MEQ-CA has been validated by the highest number of external criteria (actigraphy, oral body temperature and other questionnaires), followed by the CSM (cortisol sampling and other questionnaires). The MESC has been validated only against self-report measures. CONCLUSIONS: The present state of the art would suggest the use of the MEQ-CA to assess circadian preference in children and adolescents. PMID- 25726894 TI - Soak and smear: an effective treatment for eczematous dermatoses. AB - Eczematous dermatoses are common inflammatory skin diseases that can be difficult to treat and have a major impact on patients' quality of life and psychological status. Soak and smear is an effective treatment that can eliminate the need for oral steroids and, in chronic situations, other systemic immunosuppressives. PMID- 25726893 TI - Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder. AB - Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders. PMID- 25726895 TI - On neuraminidase inhibitors and evidence-based medicine. AB - The quest initiated by the Cochrane authors to obtain the best available evidence on the efficacy of neuraminidase inhibitors is nearing completion, with complete divulging of individual patient data of the original randomized controlled trials. We will remain with the deficiencies of the original trials relating to the population studied, poor recording of clinically-significant complications and the data that were not kept. This experience should serve to improve the design of future trials, their documentation and preservation of patient data for future analyses. PMID- 25726896 TI - Delta opioid agonists: a concise update on potential therapeutic applications. AB - WHAT IS KNOWN AND OBJECTIVE: The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators - thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes (PNOC, PENK, PDYN and POMC) are the pentapeptides Met enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor (DOR). We present a concise update on the status of progress and opportunities of this approach. METHODS: A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from www.clinicaltrials.com. RESULTS AND DISCUSSION: DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. WHAT IS NEW AND CONCLUSION: Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. PMID- 25726897 TI - Rapid feedback processing in human nucleus accumbens and motor thalamus. AB - The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structures are the NAcc and the ventral anterior and ventro-lateral nuclei (VA/VL) of the thalamus, for OCD and TS, respectively. The feedback related negativity (FRN) is an event related potential associated with feedback processing reflecting posterior medial frontal cortex (pMFC) activity. Here we report on three cases where we recorded scalp EEG and local field potentials (LFP) from externalized electrodes located in the NAcc or thalamus (VA/VL) while patients engaged in a modified time estimation task, known to engage feedback processing and elicit the FRN. Additionally, scalp EEG were recorded from 29 healthy participants (HP) engaged in the same task. The signal in all structures (pMFC, NAcc, and thalamus) was differently modulated by positive and negative feedback. LFP activity in the NAcc showed a biphasic time course after positive feedback during the FRN time interval. Negative feedback elicited a much weaker and later response. In the thalamus a monophasic modulation was recorded during the FRN time interval. Again, this modulation was more pronounced after positive performance feedback compared to negative feedback. In channels outside the target area no modulation was observed. The surface-FRN was reliably elicited on a group level in HP and showed no significant difference following negative feedback between patients and HP. German Clinical Trial Register: Neurocognitive specification of dysfunctions within basal ganglia-cortex loops and their therapeutic modulation by deep brain stimulation in patients with obsessive compulsive disorder and Tourette syndrome, http://www.drks.de/DRKS00005316. PMID- 25726899 TI - Molecular dynamics of the Diels-Alder reactions of tetrazines with alkenes and N2 extrusions from adducts. AB - The cycloadditions of tetrazines with cyclopropenes and other strained alkenes have become among the most valuable bioorthogonal reactions. These reactions lead to bicyclic Diels-Alder adducts that spontaneously lose N2. We report quantum mechanical (QM) and quasiclassical trajectory simulations on a number of these reactions, with special attention to stereoelectronic and dynamic effects on spontaneous N2 loss from these adducts. QM calculations show that the barrier to N2 loss is low, and molecular dynamics calculations show that the intermediate is frequently bypassed dynamically. There is a large preference for N2 loss anti to the cyclopropane moiety rather than syn from adducts formed from reactions with cyclopropenes. This is explained by the interactions of the Walsh orbitals of the cyclopropane group with the breaking C-N bonds in N2 loss. Dynamical effects opposing the QM preferences have also been discovered involving the coupling of vibrations associated with the formation of the new C-C bonds in the cycloaddition step, and those of the breaking C-N bonds during subsequent N2 loss. This dynamic matching leads to pronounced nonstatistical effects on the lifetimes of Diels-Alder intermediates. An unusual oscillatory behavior of the intermediate decay rate has been identified and attributed to specific vibrational coupling. PMID- 25726898 TI - Conceptual control across modalities: graded specialisation for pictures and words in inferior frontal and posterior temporal cortex. AB - Controlled semantic retrieval to words elicits co-activation of inferior frontal (IFG) and left posterior temporal cortex (pMTG), but research has not yet established (i) the distinct contributions of these regions or (ii) whether the same processes are recruited for non-verbal stimuli. Words have relatively flexible meanings - as a consequence, identifying the context that links two specific words is relatively demanding. In contrast, pictures are richer stimuli and their precise meaning is better specified by their visible features - however, not all of these features will be relevant to uncovering a given association, tapping selection/inhibition processes. To explore potential differences across modalities, we took a commonly-used manipulation of controlled retrieval demands, namely the identification of weak vs. strong associations, and compared word and picture versions. There were 4 key findings: (1) Regions of interest (ROIs) in posterior IFG (BA44) showed graded effects of modality (e.g., words>pictures in left BA44; pictures>words in right BA44). (2) An equivalent response was observed in left mid-IFG (BA45) across modalities, consistent with the multimodal semantic control deficits that typically follow LIFG lesions. (3) The anterior IFG (BA47) ROI showed a stronger response to verbal than pictorial associations, potentially reflecting a role for this region in establishing a meaningful context that can be used to direct semantic retrieval. (4) The left pMTG ROI also responded to difficulty across modalities yet showed a stronger response overall to verbal stimuli, helping to reconcile two distinct literatures that have implicated this site in semantic control and lexical-semantic access respectively. We propose that left anterior IFG and pMTG work together to maintain a meaningful context that shapes ongoing semantic processing, and that this process is more strongly taxed by word than picture associations. PMID- 25726900 TI - Spread of a common blaNDM-1-carrying plasmid among diverse Acinetobacter species. PMID- 25726901 TI - Is 25-hydroxycholesterol the interplay of statins and inflammation? PMID- 25726902 TI - Renal sympathetic denervation might be an adjunctive treatment approach for managing ventricular arrhythmia. PMID- 25726903 TI - Prognostic implications of pericardial effusion in acute heart failure: Does size matter? PMID- 25726904 TI - The Nrf-2/ARE-HO-1 axis: An important therapeutic approach for attenuating myocardial ischemia and reperfusion injury-induced cardiac remodeling. PMID- 25726905 TI - Re: On the quest of unravelling the pathophysiology of takotsubo syndrome. PMID- 25726906 TI - AMPs and OMPs: Is the folding and bilayer insertion of beta-stranded outer membrane proteins governed by the same biophysical principles as for alpha helical antimicrobial peptides? AB - The folding and function of membrane proteins is controlled not only by specific but also by unspecific interactions with the constituent lipids. In this review, we focus on the influence of the spontaneous lipid curvature on the folding and insertion of peptides and proteins in membranes. Amphiphilic alpha-helical peptides, as represented by various antimicrobial sequences, are compared with beta-barrel proteins, which are found in the outer membrane of Gram-negative bacteria. It has been shown that cationic amphiphilic peptides are always surface bound in lipids with a negative spontaneous curvature like POPC, i.e. they are oriented parallel to the membrane plane. On the other hand, in lipids like DMPC with a positive curvature, these peptides can get tilted or completely inserted in a transmembrane state. Remarkably, the folding and spontaneous membrane insertion of beta-barrel outer membrane proteins also proceeds more easily in lipids with a positive intrinsic curvature, while it is hampered by negative curvature. We therefore propose that a positive spontaneous curvature of the lipids promotes the ability of a surface-bound molecule to insert more deeply into the bilayer core, irrespective of the conformation, size, or shape of the peptide, protein, or folding intermediate. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25726907 TI - Antimony bioavailability: knowledge and research perspectives for sustainable agricultures. AB - The increasing interest in urban agriculture highlights the crucial question of crop quality. The main objectives for environmental sustainability are a decrease in chemical inputs, a reduction in the level of pollutants, and an improvement in the soil's biological activity. Among inorganic pollutants emitted by vehicle traffic and some industrial processes in urban areas, antimony (Sb) is observed on a global scale. While this metalloid is known to be potentially toxic, it can transfer from the soil or the atmosphere to plants, and accumulate in their edible parts. Urban agriculture is developing worldwide, and could therefore increasingly expose populations to Sb. The objective of this review was in consequences to gather and interpret actual knowledge of Sb uptake and bioaccumulation by crops, to reveal investigative fields on which to focus. While there is still no legal maximal value for Sb in plants and soils, light has to be shed on its accumulation and the factors affecting it. A relative absence of data exists about the role of soil flora and fauna in the transfer, speciation and compartmentation of Sb in vegetables. Moreover, little information exists on Sb ecotoxicity for terrestrial ecosystems. A human risk assessment has finally been reviewed, with particular focus on Sb bioaccessibility. PMID- 25726908 TI - Extending the cross-linking/mass spectrometry strategy: Facile incorporation of photo-activatable amino acids into the model protein calmodulin in Escherichia coli cells. AB - Photo-induced cross-linking is a highly promising technique to investigate protein conformations and protein-protein interactions in their natural cellular environment. One strategy relies on the non-directed incorporation of diazirine containing photo-activatable amino acids into proteins and a subsequent cross link formation induced by UV-A irradiation. The advantage of this photo-cross linking strategy is that it is not restricted to lysine residues and that hydrophobic regions in proteins can also be targeted, which is advantageous for investigating membrane proteins. Here, we present a simplified protocol that relies on the use of mineral salts medium without any special requirements for the incorporation of photo-methionines into proteins in Escherichia coli cells. The possibility to perform these experiments in E. coli is especially valuable as it is the major system for recombinant protein production. The method is exemplified for the Ca(2+) regulating protein calmodulin containing nine methionines, which were found to be replaced by their photo-activatable analogues. Our protocol allows the facile and stochastic incorporation of photo methionines as the basis for conducting photo-cross-linking experiments in E. coli in an efficient manner. PMID- 25726909 TI - Mass spectrometric characterization of limited proteolysis activity in human plasma samples under mild acidic conditions. AB - We developed a limited proteolysis assay for estimating dynamics in plasma-borne protease activities using MALDI ToF MS analysis as readout. A highly specific limited proteolysis activity was elicited in human plasma by shifting the pH to 6. Mass spectrometry showed that two singly charged ion signals at m/z 2753.44 and m/z 2937.56 significantly increased in abundance under mild acidic conditions as a function of incubation time. For proving that a provoked proteolytic activity in mild acidic solution caused the appearance of the observed peptides, control measurements were performed (i) with pepstatin as protease inhibitor, (ii) with heat-denatured samples, (iii) at pH 1.7, and (iv) at pH 7.5. Mass spectrometric fragmentation analysis showed that the observed peptides encompass the amino acid sequences 1-24 and 1-26 from the N-terminus of human serum albumin. Investigations on peptidase specificities suggest that the two best candidates for the observed serum albumin cleavages are cathepsin D and E. Reproducibility, robustness, and sensitivity prove the potential of the developed limited proteolysis assay to become of clinical importance for estimating dynamics of plasma-borne proteases with respect to associated pathophysiological tissue conditions. PMID- 25726910 TI - Structural analysis of the interleukin-8/glycosaminoglycan interactions by amide hydrogen/deuterium exchange mass spectrometry. AB - The recruitment of different chemokines and growth factors by glycosaminoglycans (GAGs) such as chondroitin sulfate or hyaluronan plays a critical role in wound healing processes. Thus, there is a special interest in the design of artificial extracellular matrices with improved properties concerning GAG interaction with common regulating proteins. In this study, amide hydrogen/deuterium (H/D) exchange mass spectrometry (HDX MS) combined with molecular modeling and docking experiments was used to obtain structural models of proinflammatory chemokine interleukin-8 (IL-8) in complex with hexameric chondroitin sulfate. Experiments on the intact protein showed a difference in deuterium labeling of IL-8 due to chondroitin sulfate binding. The extent of deuteration was reduced from 24% to 13% after 2 min exchange time, which corresponds to a reduced exchange of approximately 10 backbone amides. By local HDX MS experiments, H/D exchange information on the complete sequence of IL-8 could be obtained. A significantly reduced H/D exchange, especially of the C-terminal alpha-helical region comprising amino acids 70-77 and to the loop comprising amino acids 27-29 was observed in the presence of chondroitin sulfate. HDX MS data were used to model the IL-8/chondroitin sulfate complex. The binding interface of IL-8 and chondroitin sulfate determined this way correlated excellently with the corresponding NMR based atomistic model previously published. Our results demonstrate that HDX-MS in combination with molecular modeling is a valuable approach for the analysis of protein/GAG complexes at physiological pH, temperature, and salt concentration. The fact that HDX-MS requires only micrograms of protein and GAGs makes it a very promising technique to address protein-GAG interactions. PMID- 25726911 TI - Small targeted cytotoxics from DNA-encoded chemical libraries. AB - Conventional chemotherapeutic drugs do not selectively localize to tumors, causing undesired toxicities to healthy organs, and precluding the escalation to therapeutically active regimens. The selective delivery at sites of disease of potent effector molecules represents a promising strategy for the treatment of cancer and other diseases. High affinity antibodies towards disease-associated antigens are currently the vehicles of choice for the targeted delivery of payloads. Low molecular weight ligands have the potential to overcome some of the intrinsic limitations associated with antibodies, and have recently been proposed for the development of a novel class of targeted therapeutics. However, the identification of binding molecules, which display high affinity properties and exquisite specificity against protein of therapeutic interest, remains a great challenge. DNA-encoded chemical library technology relies on small molecule libraries of unprecedented size to identify high affinity ligands towards specific target proteins, and could help in the development of next generation targeted cytotoxics. PMID- 25726912 TI - Transcriptional regulation of the apolipoprotein F (ApoF) gene by ETS and C/EBPalpha in hepatoma cells. AB - Apolipoprotein F (ApoF) inhibits cholesteryl ester transfer protein (CETP) activity and plays an important role in lipid metabolism. In the present study, the full-length human ApoF promoter was cloned, and the molecular mechanism of the regulation of ApoF was investigated. The ApoF promoter displayed higher activities in hepatoma cell lines, and the -198 nt to +79 nt promoter region contained the maximum promoter activity. In the promoter region of -198 nt to -2 nt there were four putative binding sites for transcription factors ETS-1/ETS-2 (named EBS-1 to EBS-4) and one for C/EBP. Mutation of EBS-2, EBS4 and the C/EBP binding site abolished the promoter activity, and ETS-1/ETS-2 and C/EBPalpha could interact with corresponding binding sites. In addition, overexpression of ETS-1/2 or C/EBPalpha enhanced, while dominant-negative mutants of ETS-1/2 and knockdown of C/EBPalpha decreased, ApoF promoter activities. ETS-1 and C/EBPalpha associated physically, and acted synergistically to activate ApoF transcription. These results demonstrated combined activation of the ApoF promoter by liver enriched and ubiquitous transcription factors. Direct interactions between C/EBPalpha and ETS-1 were important for high liver-specific expression of ApoF. PMID- 25726913 TI - Lewis y enhances CAM-DR in ovarian cancer cells by activating the FAK signaling pathway and upregulating Bcl-2/Bcl-XL expression. AB - Oligosaccharides on the surface of adhesion molecules may contribute to the process of CAM-DR. To investigate the role of the Lewis y antigen in this process, we established a cell adhesion model mediated by the integrin alpha5beta1-FN interaction in the ovarian cancer cell line, RMG-1-hFUT, which highly expresses Lewis y by transfection with alpha1,2-fucosyltransferase into RMG-1 cells. Our results indicate that the rates of carboplatin-induced apoptosis and necrosis are reduced in FN-adhered tumor cells, and carboplatin resistance is significantly decreased in the presence of anti-Lewis y antibody. CAM-DR in tumor cells has been correlated with elevated expression of the nuclear anti-apoptotic proteins Bcl-2 and Bcl-XL. Lewis y promotes the expression of the Bcl-2 and Bcl XL genes by activating the focal adhesion kinase signaling pathway and accelerating their transcription. Thus, Lewis y leads to inhibition of apoptosis and enhancement of CAM-DR by activation of the FAK signaling pathway and upregulation of Bcl-2/Bcl-XL expression in ovarian cancer cell lines. PMID- 25726914 TI - MicroRNA regulation of stem cell differentiation and diseases of the bone and adipose tissue: Perspectives on miRNA biogenesis and cellular transcriptome. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through targeting and suppression of mRNAs. miRNAs have been under investigation for the past twenty years and there is a large breadth of information on miRNAs in diseases such as cancer and immunology. Only more recently have miRNAs shown promise as a mechanism for intervention with respect to diseases of the bone and adipose tissue. In mesenchymal stem cell (MSC) differentiation, alterations in miRNA expression patterns can differentially promote an osteogenic, adipogenic, or myogenic phenotype. This manuscript reviews the current literature with respect to miRNAs in the context of MSC function with a particular focus on novel avenues for the examination of miRNA associated with bone and adipose tissue biology and disease. Specifically we highlight the need for a greater depth of investigation on MSCs with respect to miRNA biogenesis, processing, strand selection, and heterogeneity. We discuss how these mechanisms facilitate both altered miRNA expression and function. PMID- 25726915 TI - Vasotocin--A new player in the control of oocyte maturation and ovulation in fish. AB - In this article, the physiological role of ovarian vasotocin (VT) on fish final oocyte maturation (FOM) and ovulation is reviewed based on the studies mainly available in the catfish Heteropneustes fossilis. The VT system is characterized in the follicular layer of the oocytes by both immunocytochemical and in situ hybridization techniques. The distribution was confirmed in isolated follicular layer preparations by HPLC characterization and quantification. Three VT receptor subtype genes are identified: V1a1 and V1a2 subtypes are distributed in the follicular layer and V2 subtype is present along the granulosa-oocyte membrane junction. The expression of peptide, VT precursor gene and VT receptor genes shows seasonal and periovulatory changes in the ovary. VT secretion is modulated by E2 differentially in a season-specific manner, and by progestin steroids positively. VT modulates E2 in a biphasic manner in early recrudescent phase and induces a steroidogenic shift inhibiting E2 and stimulating progestin steroid (P4, 17P4 and 17,20beta-DP) pathways in the late recrudescent phase. VT stimulates prostaglandin secretion, germinal vesicle breakdown (GVBD), oocyte hydration and ovulation. VT acts through different receptors to stimulate these processes. It uses the V1 type receptor to stimulate GVBD and ovulation, and the V2 type to stimulate oocyte hydration. VT acts as an important link in the cascade of gonadotropin control of FOM and ovulation. More research is required in other species. PMID- 25726916 TI - Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. AB - Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases. PMID- 25726917 TI - Determination of epigenetic inheritance, genetic inheritance, and estimation of genome DNA methylation in a full-sib family of Cupressus sempervirens L. AB - Genetic inheritance and epigenetic inheritance are significant determinants of plant evolution, adaptation and plasticity. We studied inheritance of restriction site polymorphisms by the f-AFLP method and epigenetic DNA cytosine methylation inheritance by the f-MSAP technique. The study involved parents and 190 progeny of a Cupressus sempervirens L. full-sib family. Results from AFLP genetic data revealed that 71.8% of the fragments studied are under Mendelian genetic control, whereas faithful Mendelian inheritance for the MSAP fragments was low (4.29%). Further, MSAP fragment analysis showed that total methylation presented a mean of 28.2%, which was higher than the midparent value, while maternal inheritance was higher (5.65%) than paternal (3.01%). Interestingly de novo methylation in the progeny was high (19.65%) compared to parental methylation. Genetic and epigenetic distances for parents and offspring were not correlated (R(2)=0.0005). Furthermore, we studied correlation of total relative methylation and CG methylation with growth (height, diameter). We found CG/CNG methylation (N: A, C, T) to be positively correlated with height and diameter, while total relative methylation and CG methylation were positively correlated with height. Results are discussed in light of further research needed and of their potential application in breeding. PMID- 25726918 TI - Fractures of the mandibular condyle--Open versus closed--A treatment dilemma. AB - PURPOSE: The aim of this prospective randomized controlled study was to evaluate the superiority of open method of treatment of mandibular condylar fracture over closed method of treatment by comparing them. METHODS AND PATIENTS: Out of a total of 50 randomized patients fractures of the mandibular condylar process completed the study and were evaluated. All fractures were displaced, being either angulated between 10 degrees and 45 degrees . The follow-up examinations 1st day, 2nd day, 1st week, 2nd week, 6th week, and 6 months following treatment included clinical evaluation of functional and subjective parameters including visual analogue scale for pain and the interincisal mouth opening, malocclusion, deviation of mouth, range of motion, radiographic measurements were done. RESULTS: No significant difference was found between the two groups in the maximal interincisal opening, range of movements and TMJ pain. However statistically significant difference was seen in the anatomic reduction of condyle, shortening of ascending ramus, occlusal status and deviation on mouth opening on immediate postoperative phase. CONCLUSION: Both treatment options for condylar fractures of the mandible yielded acceptable results. However, a statistically significant difference was seen in the anatomic reduction of the condyle and there was no deviation on maximum mouth opening in patients treated with open reduction and internal fixation which suggests its superiority over closed method. PMID- 25726919 TI - Beyond single-level accounts: the role of cognitive architectures in cognitive scientific explanation. AB - We consider approaches to explanation within the cognitive sciences that begin with Marr's computational level (e.g., purely Bayesian accounts of cognitive phenomena) or Marr's implementational level (e.g., reductionist accounts of cognitive phenomena based only on neural-level evidence) and argue that each is subject to fundamental limitations which impair their ability to provide adequate explanations of cognitive phenomena. For this reason, it is argued, explanation cannot proceed at either level without tight coupling to the algorithmic and representation level. Even at this level, however, we argue that additional constraints relating to the decomposition of the cognitive system into a set of interacting subfunctions (i.e., a cognitive architecture) are required. Integrated cognitive architectures that permit abstract specification of the functions of components and that make contact with the neural level provide a powerful bridge for linking the algorithmic and representational level to both the computational level and the implementational level. PMID- 25726920 TI - Motivational interviewing for smoking cessation. AB - BACKGROUND: Motivational Interviewing (MI) is a directive patient-centred style of counselling, designed to help people to explore and resolve ambivalence about behaviour change. It was developed as a treatment for alcohol abuse, but may help people to a make a successful attempt to quit smoking. OBJECTIVES: To determine whether or not motivational interviewing (MI) promotes smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register for studies using the term motivat* NEAR2 (interview* OR enhanc* OR session* OR counsel* OR practi* OR behav*) in the title or abstract, or motivation* as a keyword. Date of the most recent search: August 2014. SELECTION CRITERIA: Randomized controlled trials in which motivational interviewing or its variants were offered to tobacco users to assist cessation. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. The main outcome measure was abstinence from smoking after at least six months follow-up. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. We counted participants lost to follow-up as continuing smoking or relapsed. We performed meta-analysis using a fixed-effect Mantel-Haenszel model. MAIN RESULTS: We identified 28 studies published between 1997 and 2014, involving over 16,000 participants. MI was conducted in one to six sessions, with the duration of each session ranging from 10 to 60 minutes. Interventions were delivered by primary care physicians, hospital clinicians, nurses or counsellors. Our meta-analysis of MI versus brief advice or usual care yielded a modest but significant increase in quitting (risk ratio (RR) 1.26; 95% confidence interval (CI) 1.16 to 1.36; 28 studies; N = 16,803). Subgroup analyses found that MI delivered by primary care physicians resulted in an RR of 3.49 (95% CI 1.53 to 7.94; 2 trials; N = 736). When delivered by counsellors the RR was smaller (1.25; 95% CI 1.15 to 1.63; 22 trials; N = 13,593) but MI still resulted in higher quit rates than brief advice or usual care. When we compared MI interventions conducted through shorter sessions (less than 20 minutes per session) to controls, this resulted in an RR of 1.69 (95% CI 1.34 to 2.12; 9 trials; N = 3651). Single-session treatments might increase the likelihood of quitting over multiple sessions, but both regimens produced positive outcomes. Evidence is unclear at present on the optimal number of follow-up calls.There was variation across the trials in treatment fidelity. All trials used some variant of motivational interviewing. Critical details in how it was modified for the particular study population, the training of therapists and the content of the counselling were sometimes lacking from trial reports. AUTHORS' CONCLUSIONS: Motivational interviewing may assist people to quit smoking. However, the results should be interpreted with caution, due to variations in study quality, treatment fidelity, between-study heterogeneity and the possibility of publication or selective reporting bias. PMID- 25726921 TI - Pediatric Professionals' Attitudes about Secondary Findings in Genomic Sequencing of Children. AB - OBJECTIVES: To evaluate the attitudes of pediatric professionals towards the March 2013 statement of the American College of Medical Genetics and Genomics that whenever genomic sequencing is ordered, the laboratory must look for 56 genes known to be highly penetrant in high-risk groups, and these results must be reported to the clinician regardless of patient age or consent. STUDY DESIGN: E mail and postal survey sent to 332 members of the American Academy of Pediatrics (AAP) Section on Bioethics (SOB) (n=183), Section on Genetics and Birth Defects (n=148), and 1 member of both groups regarding the mandatory search and reporting of secondary findings from genomic sequencing performed on children. RESULTS: Of 332 potential participants, 12 asked to be excluded and 181 partially or completely responded (181/320, or 56.6%). Two were subsequently excluded (179). More than 80% believed that patients and parents (guardians) should have the right to refuse to be informed of secondary findings. Only 34.7% of AAP SOB members supported the American College of Medical Genetics and Genomics proposed mandatory search policy in contrast with 70.8% of Section of Genetics and Birth Defects members (P<.01). Approximately 30% of both groups thought that parents should not have access to information about adult-onset conditions in their children. AAP SOB members were less likely to support testing a child for parental benefit (34.5% vs 79.7%, P<.01). CONCLUSIONS: There is broad consensus that parents should have the right to opt out of receiving secondary findings. There is no consensus about the ethics of justifying disclosure on the basis of parental benefit. PMID- 25726922 TI - Curious discoveries in antiviral drug development: the role of serendipity. AB - Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2 phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses. PMID- 25726923 TI - Comparative study on acid-soluble and pepsin-soluble collagens from skin and swim bladder of grass carp (Ctenopharyngodon idella). AB - BACKGROUND: Collagen has a wide range of applications in food, biomedical and pharmaceutical products. RESULTS: The collagens in grass carp (Ctenopharyngodon idella) skin and swim bladder were extracted using acetic acid and pepsin. Higher yield of pepsin-soluble collagen (PSC) was obtained from skin (178 g kg(-1)) than from swim bladder (114 g kg(-1)). Not surprisingly, yields of PSC from skin and swim bladder were also higher than those of acid-soluble collagen (ASC) from the same organs (89 and 51 g kg(-1)). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) profiles showed that ASC and PSC were type I collagens, with PSC containing a higher proportion of alpha components than ASC. Fourier transform infrared spectra revealed that ASC and PSC were very similar in their protein secondary structures. Scanning electron micrographs showed that the collagens had a spongy structure, with more pores being obtained in swim bladder than in skin collagens. The collagens showed high solubility in the acidic pH range. However, their solubility decreased in the presence of NaCl at concentrations above 20 g kg(-1). CONCLUSION: Collagens were successfully extracted from the skin and swim bladder of grass carp. These fish by-products could serve as an alternative source of collagens for a wide variety of applications in the food and nutraceutical industries. PMID- 25726924 TI - Transformation optics with Fabry-Perot resonances. AB - Transformation optics is a powerful tool to design various novel devices, such as invisibility cloak. Fantastic effects from this technique are usually accompanied with singular mappings, resulting in challenging implementations and narrow bands of working frequencies. Here in this article, Fabry-Perot resonances in materials of extreme anisotropy are used to design various transformation optical devices that are not only easy to realize but also work well for a set of resonant frequencies (multiple frequencies). As an example, a prototype of a cylindrical concentrator is fabricated for microwaves. PMID- 25726925 TI - Palladium-coated stainless-steel wire as a solid-phase microextraction fiber. AB - A novel palladium solid-phase microextraction coating was fabricated on a stainless-steel wire by a simple in situ oxidation-reduction process. The palladium coating exhibited a rough microscaled surface and its thickness was about 2 MUm. Preparation conditions (reaction time and concentration of palladium chloride and hydrochloric acid) were optimized in detail to achieve sufficient extraction efficiency. Extraction properties of the fiber were investigated by direct immersion solid-phase microextraction of several polycyclic aromatic hydrocarbons and phthalate esters in aqueous samples. The extracted analytes were transferred into a gas chromatography system by thermal desorption. The effect of extraction and desorption conditions on extraction efficiency were investigated. Under the optimum conditions, good linearity was obtained and correlation coefficients between 0.9908 and 0.9990 were obtained. Limits of detection were 0.05-0.10 MUg/L for polycyclic aromatic hydrocarbons and 0.3 MUg/L for phthalate esters. Their recoveries for real aqueous samples were in the range from 97.1 to 121% and from 89.1 to 108%, respectively. The intra- and interday tests were also investigated with three different addition levels, and satisfactory results were also obtained. PMID- 25726927 TI - Single nucleotide polymorphism array profiling identifies distinct chromosomal aberration patterns across colorectal adenomas and carcinomas. AB - The progression of benign colorectal adenomas into cancer is associated with the accumulation of chromosomal aberrations. Even though patterns and frequencies of chromosomal aberrations have been well established in colorectal carcinomas, corresponding patterns of aberrations in adenomas are less well documented. The aim of this study was to profile chromosomal aberrations across colorectal adenomas and carcinomas to provide a better insight into key changes during tumor initiation and progression. Single nucleotide polymorphism array analysis was performed on 216 colorectal tumor/normal matched pairs, comprising 60 adenomas and 156 carcinomas. While many chromosomal aberrations were specific to carcinomas, those with the highest frequency in carcinomas (amplification of chromosome 7, 13q, and 20q; deletion of 17p and chromosome 18; LOH of 1p, chromosome 4, 5q, 8p, 17p, chromosome 18, and 20p) were also identified in adenomas. Hierarchical clustering using chromosomal aberrations revealed three distinct subtypes. Interestingly, these subtypes were only partially dependent on tumor staging. A cluster of colorectal cancer patients with frequent chromosomal deletions had the least favorable prognosis, and a number of adenomas (n = 9) were also present in the cluster suggesting that, at least in some tumors, the chromosomal aberration pattern is determined at a very early stage of tumor formation. Finally, analysis of LOH events revealed that copy-neutral/gain LOH (CN/G-LOH) is frequent (>10%) in carcinomas at 5q, 11q, 15q, 17p, chromosome 18, 20p, and 22q. Deletion of the corresponding region is sometimes present in adenomas, suggesting that LOH at these loci may play an important role in tumor initiation. PMID- 25726926 TI - Robust kinetics of an RNA virus: Transcription rates are set by genome levels. AB - In order to persist in nature, RNA viruses have evolved strategies to grow in diverse host environments. To better understand how such strategies might work, we used qRT-PCR to measure viral RNA species during cellular infections by a model RNA virus, vesicular stomatitis virus (VSV). Absolute levels of the VSV major transcript and genome were measured for infections in BHK and PC3 cells, across different multiplicities of infection (MOI 1, 10, 100), in the absence or presence of protein synthesis, as well as in cells in an interferon-activated anti-viral state. While viral genome replication was delayed in more resistant host cells, kinetic modeling of these data revealed a simple linear relationship between the mRNA production rate and genome levels under all tested conditions. These results indicate that while viral transcription and genome replication both depend on the availability of the viral RNA-dependent RNA polymerase and host cellular resources, transcription proceeds without apparent limits on these resources. PMID- 25726928 TI - Update and Mutational Analysis of SLC20A2: A Major Cause of Primary Familial Brain Calcification. AB - Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis. PMID- 25726930 TI - Preparation and rebinding properties of protein-imprinted polysiloxane using mesoporous calcium silicate grafted non-woven polypropylene as matrix. AB - Calcium silicate particle containing mesoporous SiO2 (CaSiO3@SiO2) was grafted on the surface of non-woven polypropylene. The PP non-woven grafted calcium silicate containing mesoporous SiO2 (PP-g-CaSiO3@SiO2) was used as the matrix to prepare bovine serum albumin (BSA) molecularly imprinted polysiloxane (MIP) by using silanes as the functional monomers and BSA as the template. PP non-woven grafted BSA-imprinted polysiloxane (PP-g-CaSiO3@SiO2 MIP) was characterized by scanning electron microscope (SEM), Fourier transform infrared spectometry (FTIR) and drilling string compensator (DSC). Influence factors on the rebinding capacity of the MIP were investigated, such as grafting degree, the pH in treating CaSiO3 and the type and proportion of silanes. The rebinding properties of BSA on PP-g CaSiO3@SiO2 and MIP were investigated under different conditions. The results indicated that the rebinding capacity of MIP for BSA reached 56.32 mg/g, which was 2.65 times of NIP. The non-woven polypropylene grafted BSA-imprinted polysiloxane could recognize the template protein and the selectivity factor (beta) was above 2.4 when using ovalbumin, hemoglobin and gamma-globulin as control proteins. The PP-g-CaSiO3@SiO2 MIP has favorable reusability. PMID- 25726929 TI - Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade. AB - Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy. PMID- 25726931 TI - Spatial and topographic trends in forest expansion and biomass change, from regional to local scales. AB - Natural forest growth and expansion are important carbon sequestration processes globally. Climate change is likely to increase forest growth in some regions via CO2 fertilization, increased temperatures, and altered precipitation; however, altered disturbance regimes and climate stress (e.g. drought) will act to reduce carbon stocks in forests as well. Observations of asynchrony in forest change is useful in determining current trends in forest carbon stocks, both in terms of forest density (e.g. Mg ha(-1) ) and spatially (extent and location). Monitoring change in natural (unmanaged) areas is particularly useful, as while afforestation and recovery from historic land use are currently large carbon sinks, the long-term viability of those sinks depends on climate change and disturbance dynamics at their particular location. We utilize a large, unmanaged biome (>135 000 km(2) ) which spans a broad latitudinal gradient to explore how variation in location affects forest density and spatial patterning: the forests of the North American temperate rainforests in Alaska, which store >2.8 Pg C in biomass and soil, equivalent to >8% of the C in contiguous US forests. We demonstrate that the regional biome is shifting; gains exceed losses and are located in different spatio-topographic contexts. Forest gains are concentrated on northerly aspects, lower elevations, and higher latitudes, especially in sheltered areas, whereas loss is skewed toward southerly aspects and lower latitudes. Repeat plot-scale biomass data (n = 759) indicate that within-forest biomass gains outpace losses (live trees >12.7 cm diameter, 986 Gg yr(-1) ) on gentler slopes and in higher latitudes. This work demonstrates that while temperate rainforest dynamics occur at fine spatial scales (<1000 m(2) ), the net result of thousands of individual events is regionally patterned change. Correlations between the disturbance/establishment imbalance and biomass accumulation suggest the potential for relatively rapid biome shifts and biomass changes. PMID- 25726932 TI - Using HeLa cell stress response to introduce first year students to the scientific method, laboratory techniques, primary literature, and scientific writing. AB - Incorporating scientific literacy into inquiry driven research is one of the most effective mechanisms for developing an undergraduate student's strength in writing. Additionally, discovery-based laboratories help develop students who approach science as critical thinkers. Thus, a three-week laboratory module for an introductory cell and molecular biology course that couples inquiry-based experimental design with extensive scientific writing was designed at Westminster College to expose first year students to these concepts early in their undergraduate career. In the module students used scientific literature to design and then implement an experiment on the effect of cellular stress on protein expression in HeLa cells. In parallel the students developed a research paper in the style of the undergraduate journal BIOS to report their results. HeLa cells were used to integrate the research experience with the Westminster College "Next Chapter" first year program, in which the students explored the historical relevance of HeLa cells from a sociological perspective through reading The Immortal Life of Henrietta Lacks by Rebecca Skloot. In this report I detail the design, delivery, student learning outcomes, and assessment of this module, and while this exercise was designed for an introductory course at a small primarily undergraduate institution, suggestions for modifications at larger universities or for upper division courses are included. Finally, based on student outcomes suggestions are provided for improving the module to enhance the link between teaching students skills in experimental design and execution with developing student skills in information literacy and writing. PMID- 25726933 TI - Desorption electrospray ionization-based imaging of interaction between vascular graft and human body. AB - The desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) is known as a fast and convenient MS-based method for lipid imaging in various biological materials. Here, we applied this technique to visualize lipid distribution in a vascular graft removed from a patient's body. This is a good example of the DESI system capabilities toward imaging of interaction between artificial material and living tissues. Detailed analysis allowed for visualization of the spatial distribution of selected lipids in this implanted, artificial material. Not only DESI-MSI allowed visualization of lipid distribution in the investigated material but also enabled identification of the detected molecular species using MS/MS. Here, this technique was successfully used to evaluate the saturation and spatial distribution of endogenous lipids in the artificial vascular graft. Unambiguous identification of the lipids was done with the aid of fragmentation procedure. We also showed that various lipids localize preferably in graft material or internal plaque existing inside the graft. PMID- 25726934 TI - Model predictive filtering MR thermometry: Effects of model inaccuracies, k-space reduction factor, and temperature increase rate. AB - PURPOSE: Evaluate effects of model parameter inaccuracies (thermal conductivity, k, and ultrasound power deposition density, Q), k-space reduction factor (R), and rate of temperature increase ( T) in a thermal model-based reconstruction for MR thermometry during focused-ultrasound heating. METHODS: Simulations and ex vivo experiments were performed to investigate the accuracy of the thermal model and the model predictive filtering (MPF) algorithm for varying R and T, and their sensitivity to errors in k and Q. Ex vivo data was acquired with a segmented EPI pulse sequence to achieve large field-of-view (192 * 162 * 96 mm) four dimensional temperature maps with high spatiotemporal resolution (1.5 * 1.5 * 2.0 mm, 1.7 s). RESULTS: In the simulations, 50% errors in k and Q resulted in maximum temperature root mean square errors (RMSE) of 6 degrees C for model only and 3 degrees C for MPF. Using recently developed methods, estimates of k and Q were accurate to within 3%. The RMSE between MPF and true temperature increased with R and T. In the ex vivo study the RMSE remained below 0.7 degrees C for R ranging from 4 to 12 and T of 0.28-0.75 degrees C/s. CONCLUSION: Errors in MPF temperatures occur due to errors in k and Q. These MPF temperature errors increase with increase in R and T, but are smaller than those obtained using the thermal model alone. PMID- 25726935 TI - Superaerophobic electrodes for direct hydrazine fuel cells. AB - Direct liquid-feed fuel cells possess high energy and power densities, but suffer from severe adhesion of gas products. Here, a "superaerophobic" surface that enables a small release size and fast evolution behavior of the gas product is introduced, thereby, maximizing and stabilizing the working area. Consequently, the "superaerophobic" nanostructured Cu electrodes exhibit excellent performance as anodes in a direct hydrazine fuel cell. PMID- 25726936 TI - Traumatic brain injury in later life increases risk for Parkinson disease. AB - OBJECTIVE: Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson disease (PD), but results are conflicting. Many studies do not account for confounding or reverse causation. We sought to address these concerns by quantifying risk of PD after TBI compared to non-TBI trauma (NTT; defined as fractures). METHODS: Using inpatient/emergency department (ED) International Classification of Disease, Ninth Revision code data for California hospitals from 2005-2006, we identified patients aged >=55 years with TBI (n = 52,393) or NTT (n = 113,406) and without baseline PD or dementia who survived hospitalization. Using Kaplan-Meier estimates and Cox proportional hazards models (adjusted for age, sex, race/ethnicity, income, comorbidities, health care use, and trauma severity), we estimated risk of PD after TBI during follow-up ending in 2011. We also assessed interaction with mechanism of injury (fall vs nonfall) and effect of TBI severity (mild vs moderate/severe) and TBI frequency (1 TBI vs >1 TBI). RESULTS: TBI patients were significantly more likely to be diagnosed with PD compared to NTT patients (1.7% vs 1.1%, p < 0.001, adjusted hazard ratio [HR] = 1.44, 95% confidence interval [CI] = 1.31-1.58). Risk of PD was similar for TBI sustained via falls versus nonfalls (interaction p = 0.6). Assessment by TBI severity (mild TBI: HR = 1.24, 95% CI = 1.04-1.48; moderate/severe TBI: HR = 1.50, 95% CI = 1.35-1.66) and TBI frequency (1 TBI: HR = 1.45, 95% CI = 1.30 1.60; >1 TBI: HR = 1.87, 95% CI = 1.58-2.21) revealed a dose response. INTERPRETATION: Among patients aged >=55 years presenting to inpatient/ED settings with trauma, TBI is associated with a 44% increased risk of developing PD over 5 to 7 years that is unlikely to be due to confounding or reverse causation. PMID- 25726937 TI - Well-defined CuC2F5 complexes and pentafluoroethylation of acid chlorides. AB - Four new well-defined Cu(I) complexes bearing a C2 F5 ligand have been prepared and fully characterized: [(Ph3 P)2 CuC2 F5 ] (2), [(bpy)CuC2 F5 ] (3), [(Ph3 P)Cu(phen)C2 F5 ] (4), and [(IPr*)CuC2 F5 ] (5). X-ray structures of all four have been determined, showing that the C2 F5 -ligated Cu atom can be di- (5), tri (2 and 3), and tetracoordinate (4). The mixed phen-PPh3 complex 4 is a highly efficient fluoroalkylating agent for a broad variety of acid chlorides. This high yielding transformation represents the first general method for the synthesis of RCOC2 F5 from the corresponding RCOCl. PMID- 25726938 TI - C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies. AB - AIMS: Acute antibody-mediated rejection can occur in absence of circulating donor specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. METHODS: We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. RESULTS: All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. CONCLUSIONS: These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre emptive treatment with angiotensin receptor blockers. PMID- 25726939 TI - Melan-A positive dermal cells in malignant melanoma in situ. AB - The presence of Melan-A positive dermal cells in excisions for melanoma in situ represents a frequent conundrum for pathologists. These cells may represent superficially invasive melanoma, benign, incidental, dermal nevi or non-specific staining of dermal melanophages. Occasionally, rare, Melan-A positive dermal cells are present which do not clearly correspond to the above three categories. Our objective was to further characterize these Melan-A positive dermal cells. To do this, immunoperoxidase staining for Melan-A and SOX-10 was performed on 188 cutaneous excisions, including examples of melanoma in situ, atypical junctional melanocytic hyperplasia and non-melanocytic tumors. These were evaluated for the presence of Melan-A and SOX-10 positive dermal cells. Dermal cells, positive for both markers, were identified in 17% of the excisions. The cells were present in 10% of cases from the melanocytic group and 31% of the cases from the non melanocytic group. These cells did not exhibit cytologic atypia and resembled neither the co-existing neoplasm nor melanophages. We conclude that positivity of these rare Melan-A positive cells for SOX-10 argues that they represent true melanocytes and not non-specific staining. The absence of cytologic atypia in these cells and their presence in excisions of non-melanocytic neoplasms argues that they are benign, reactive, dermal melanocytes. PMID- 25726940 TI - Biological and molecular profile of fracture non-union tissue: current insights. AB - Delayed bone healing and non-union occur in approximately 10% of long bone fractures. Despite intense investigations and progress in understanding the processes governing bone healing, the specific pathophysiological characteristics of the local microenvironment leading to non-union remain obscure. The clinical findings and radiographic features remain the two important landmarks of diagnosing non-unions and even when the diagnosis is established there is debate on the ideal timing and mode of intervention. In an attempt to understand better the pathophysiological processes involved in the development of fracture non union, a number of studies have endeavoured to investigate the biological profile of tissue obtained from the non-union site and analyse any differences or similarities of tissue obtained from different types of non-unions. In the herein study, we present the existing evidence of the biological and molecular profile of fracture non-union tissue. PMID- 25726941 TI - A Comparison of Zirconia and Titanium Abutments for Microleakage. AB - BACKGROUND: Microleakage through the interface has been documented in implant systems with titanium (Ti) abutments. There is a current increase in the use of zirconia (Zi) abutments especially in esthetic zone in where higher risk of visible metal color through the peri-implant tissues exists. PURPOSE: The aim of the present in vitro study is to evaluate the leakage at the implant fixture abutment interface with two different screw-retained abutment systems at different torque values in a nonloading condition. MATERIALS AND METHODS: In vitro study design included four groups (Ti and Zi torqued at 25 and 15 Ncm [N = 8/group]). Microcomputed tomography (micro-CT) was chosen to detect microgap. Microleakage from the implant chamber to the external milieu was evaluated using limulus amebocyte lysate (LAL) test, while microleakage from external milieu to the implant chamber was evaluated using toluidine blue dye (TBD) and colorimeter. RESULTS: Micro-CT images did not reveal any microgap. LAL test showed that there is a time-, abutment-, and torque-dependent increase in microleakage (p = .001) with Zi torqued at 15 Ncm having higher leakage with time compared with Ti torqued at 15 Ncm (p = .002), as well as Zi torqued at 15 Ncm having higher leakage with time compared with Zi torqued at 25 Ncm (p = .01). TBD test showed a nonsignificant increase in microleakage with higher leakage related to titanium abutment groups (p > .05). Repeated torque/antitorque handling differentially affected microleakage (p = .01). CONCLUSIONS: Within the limits of this study, there is a statistically significant difference in bidirectional microleakage with time, abutment type, and torque values being major players for leakage from internal implant chamber to external milieu, while the abutment type and time but not the torque value being important factors for leakage from external milieu into implant chamber in nonloading condition. Future studies are needed to determine peri-implant health around Zi abutments. PMID- 25726942 TI - Cost implications of intraprocedural thrombotic events during PCI. AB - OBJECTIVES: We sought to estimate the direct costs (in-hospital and 30-day) associated with an intraprocedural thrombotic event (IPTE) among patients with non-ST-segment elevation acute coronary syndromes (NSTEACS) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Patients with IPTE have higher rates of in-hospital and 30-day major adverse cardiac events than patients without IPTE. The extent to which IPTE also add to medical costs is unknown. METHODS: Hospital costs for patients in the ACUITY Trial were compared between patients with and without IPTE. Adjusted comparisons were performed using generalized linear models (GLMs). All costs are reported in 2012 US dollars. RESULTS: A total of 1,307 patients with both core laboratory-based angiographic assessment and detailed economic data were included in the final study population. IPTE occurred in 52 patients (4.0%). Median in-hospital costs were higher in patients with IPTE than in those without IPTE ($23,719 vs. $18,419, P = 0.01). Thirty-day median costs were also higher for IPTE patients ($23,719 vs. $19,556, P = 0.05). After adjusting for baseline differences, IPTE was associated with 19.5% (95% CI: [2.8-38.8%], P = 0.02) and 18.9% (95% CI: [1.2-39.7%], P = 0.04) increases in in-hospital and 30-day costs, respectively. These relative differences represent median increases of $3,592 in initial hospital costs and $3,696 in 30-day costs. CONCLUSIONS: The occurrence of IPTE during the index PCI in patients with NSTEACS is associated with substantial increases in-hospital and 30-day costs. These findings suggest that strategies to prevent IPTE may be associated with important cost offsets as well as improved clinical outcomes. PMID- 25726943 TI - Superprotonic conductivity of a UiO-66 framework functionalized with sulfonic acid groups by facile postsynthetic oxidation. AB - Facile postsynthetic oxidation of the thiol-laced UiO-66-type framework UiO 66(SH)2 enabled the generation of UiO-66(SO3 H)2 with sulfonic acid groups covalently linked to the backbone of the system. The oxidized material exhibited a superprotonic conductivity of 8.4*10(-2) S cm(-1) at 80 degrees C and 90 % relative humidity, and long-term stability of the conductivity was observed. This level of conductivity exceeds that of any proton-conducting MOF reported to date and is equivalent to the conductivity of the most effective known electrolyte, Nafion. PMID- 25726944 TI - Cardioprotective role of growth/differentiation factor 1 in post-infarction left ventricular remodelling and dysfunction. AB - Growth/differentiation factor 1 (GDF1) is a secreted glycoprotein of the transforming growth factor-beta (TGF-beta) superfamily that mediates cell differentiation events during embryonic development. GDF1 is expressed in several tissues, including the heart. However, the functional role of GDF1 in myocardial infarction (MI)-induced cardiac remodelling and dysfunction is not known. Here, we performed gain-of-function and loss-of-function studies using cardiac-specific GDF1 transgenic (TG) and knockout (KO) mice to determine the role of GDF1 in the pathogenesis of functional and architectural cardiac remodelling after MI, which was induced by surgical left anterior descending coronary artery ligation. Our results demonstrate that overexpression of GDF1 in the heart causes a significant decrease in MI-derived mortality post-MI and leads to attenuated infarct size expansion, left ventricular (LV) dilatation, and cardiac dysfunction at 1 week and 4 weeks after MI injury. Compared with control animals, cardiomyocyte apoptosis, inflammation, hypertrophy, and interstitial fibrosis were all remarkably reduced in the GDF1-TG mice following MI. In contrast, GDF1 deficiency greatly exacerbated the pathological cardiac remodelling response after infarction. Further analysis of the in vitro and in vivo signalling events indicated that the beneficial role of GDF1 in MI-induced cardiac dysfunction and LV remodelling was associated with the inhibition of non-canonical (MEK-ERK1/2) and canonical (Smad) signalling cascades. Overall, our data reveal that GDF1 in the heart is a novel mediator that protects against the development of post infarction cardiac remodelling via negative regulation of the MEK-ERK1/2 and Smad signalling pathways. Thus, GDF1 may serve as a valuable therapeutic target for the treatment of MI. PMID- 25726945 TI - Intentional replantation of adhesively reattached vertically fractured maxillary single-rooted teeth. AB - AIM: To evaluate the clinical outcomes of intentionally replanted maxillary single-rooted teeth with vertical root fractures (VRFs) after being repaired extraorally using 4-methacryloxyethyl trimellitate anhydride/methacrylate-tri-n butyl borane (4-META/MMA-TBB) resin cement. METHODOLOGY: Twenty-one root filled maxillary single-rooted teeth with VRFs were evaluated. After atraumatic extraction, fractured fragments were adhesively cemented. The teeth were then replanted and splinted to the neighbouring teeth for 2 weeks. Plaque index (PI), gingival index (GI), probing depth (PD) and clinical attachment level (CAL) were assessed at baseline, 6 and 12 months, and radiographic evaluations were made using PAI scores at baseline and 12 months. Mobility was evaluated using periotest values (PTV) at baseline, 1, 3, 6 and 12 months. Replanted teeth, contralateral teeth (control teeth) and adjacent teeth were analysed statistically using repeated measures one-way anova, unpaired t-tests and Wilcoxon matched-pairs signed-rank tests. RESULTS: Two teeth were extracted in the first month after surgery. PI, GI, CAL and PD scores of the replanted teeth were significantly lower at 6 month (P < 0.0001 for all) and 12 month (P < 0.0001 for all) postoperatively when compared to baseline, but the values were not significantly different from those of the control and adjacent teeth. PTV of the test teeth increased significantly (P < 0.0001) after the intervention and decreased to baseline levels by month 12. PTVs were significantly higher (P < 0.05) at baseline, 1, 3 and 6 months in the test teeth when compared with the control teeth, but were not significantly different at month 12. PAI scores of teeth with VRF were significantly lower (P < 0.05) at 12 months compared with baseline. CONCLUSIONS: Adhesive cementation and intentional replantation were an effective treatment modality for this group of vertically fractured maxillary single-rooted teeth. The clinical periodontal parameters decrease by month 6, and the mobility returned to the physiological limits of natural teeth 12 months after replantation. PMID- 25726946 TI - Microemulsion flame pyrolysis for hopcalite nanoparticle synthesis: a new concept for catalyst preparation. AB - A new route to highly active hopcalite catalysts via flame spray pyrolysis of an inverse microemulsion precursor is reported. The nitrate derived nanoparticles are around 15 nm in diameter and show excellent conversion of CO under ambient conditions, outperforming commercial reference hopcalite materials produced by co precipitation. PMID- 25726948 TI - Effect of increased adiposity on insulin sensitivity and adipokine concentrations in horses and ponies fed a high fat diet, with or without a once daily high glycaemic meal. AB - REASONS FOR PERFORMING STUDY: The relative influences of obesity and adaptation to high glycaemic diets on the development of insulin dysregulation in equids are unclear. OBJECTIVES: To determine whether increased adiposity per se is responsible for the decreased insulin sensitivity often observed in obese horses or whether a dietary glycaemic response is critically important. STUDY DESIGN: Randomised controlled trial. METHODS: Eighteen horses and ponies were studied over a 20-week period. They received ad libitum hay plus either a high fat (low glycaemic) diet (FAT; n = 6) or a similar (isocaloric) diet containing 1.5 g/kg bwt once daily glucose (GLU; n = 6) to induce obesity. A third group received a control ration (CON; n = 6). Adiposity was monitored using body condition score (BCS) and total body fat mass percentage (TBFM) determined using a deuterium oxide dilution technique. Insulin sensitivity was assessed using a frequently sampled i.v. glucose tolerance test. Plasma concentrations of glucose, insulin, leptin, adiponectin, tumour necrosis factor-alpha (TNF-alpha) and serum amyloid A (SAA) were measured. RESULTS: The FAT and GLU groups became obese (BCS >=7) whereas the CON group maintained moderate condition (BCS <=6). Total body fat mass and leptin concentrations were increased in the FAT and GLU groups than in the CON group (P<0.001 and P = 0.003, respectively). Values for both insulin dependent (SI) and insulin-independent (Sg) glucose disposal were higher in the GLU group compared with the FAT and CON groups (P = 0.006 and P = 0.03, respectively). There were no differences in adiponectin, TNF-alpha or SAA between groups (all P>=0.4). CONCLUSIONS: Increased adiposity did not reduce insulin sensitivity in either the FAT or the GLU diet groups, suggesting that obesity per se might not be responsible for the lower SI values reported in previous studies. Contrary to expectations, once daily glucose appeared to increase insulin sensitivity. Further work is required into the dietary causes of insulin resistance in equids. PMID- 25726949 TI - Negative and paranoid symptoms are associated with negative performance beliefs and social cognition in 22q11.2 deletion syndrome. AB - AIMS: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic condition associated with an increased risk of developing schizophrenia. Previous studies have shown that negative symptoms represent the most specific clinical characteristic of psychosis in 22q11.2DS and are strongly associated with outcome. However, the psychological mechanisms associated with these symptoms in this population are poorly understood. In accordance with recent conceptualizations in the field of schizophrenia, the present study aims at investigating whether negative symptoms are associated with the presence of negative performance beliefs and cognitive deficits. METHODS: Thirty-five participants with 22q11.2DS and 24 typically developing individuals aged between 11 and 24 years were included in the study. Self-reported schizotypal symptoms (cognitive-perceptual, paranoid, negative and disorganization symptoms) and dysfunctional beliefs (negative performance beliefs and need for approval) were assessed. Measures of processing speed, verbal memory, working memory, executive functioning and face recognition were also extracted from a broad cognitive evaluation protocol. RESULTS: Adolescents with 22q11.2DS reported significantly higher score on the negative dimension of the Schizotypal Personality Questionnaire than controls, even when controlling for the influence of anxiety/depression and intellectual functioning. Negative and paranoid symptoms were associated with the severity of negative performance beliefs and lower face recognition abilities. Mediation analyses revealed that negative performance beliefs significantly mediated the association between face recognition and negative/paranoid symptoms. CONCLUSIONS: These findings suggest that negative performance beliefs and basic social cognitive mechanisms are associated with negative and paranoid symptoms in individuals with 22q11.2DS. Implications for intervention are discussed in this article. PMID- 25726950 TI - Trends in the use of pre-operative radiation for adenocarcinoma of the pancreas in the United States. AB - BACKGROUND: The benefit and timing of radiation therapy (RT) for patients undergoing a resection for pancreatic adenocarcinoma remains unclear. This study identifies trends in the use of radiation over a 10-year period and factors associated with the use of pre-operative radiation, in particular. METHODS: The Surveillance, Epidemiology and End Results registry was used to identify patients aged >=18 years with pancreatic adenocarcinoma who underwent a surgical resection between 2000 and 2010. Logistic regression was used to identify time trends and factors associated with the use of pre-operative radiation. RESULTS: The overall use of radiation decreased with time among the 8474 patients who met the inclusion criteria. However, the use of pre-operative radiation increased from 1.8% to 3.9% (P <= 0.05). Factors significantly associated with receipt of pre operative radiation were younger age, treatment in more recent years and having an advanced T-stage tumour. The 5-year hazard of death was significantly less for those who received pre-operative radiation versus surgery alone [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.55-0.74] and for those who received post-operative radiation versus surgery alone (HR 0.69, 95% CI 0.65-0.73). DISCUSSION: The use of pre-operative radiation significantly increased during the study period. However, the overall use of pre-operative radiation therapy remains low in spite of the potential benefits. PMID- 25726951 TI - Five-year outcome of bipolar I and II disorders: findings of the Jorvi Bipolar Study. AB - OBJECTIVES: The long-term outcome of bipolar disorder (BD) has been extensively investigated. However, previous studies may be biased towards hospitalized patients with bipolar I disorder (BD-I), and generalizability to the current treatment era remains uncertain. In this naturalistic study, we followed a secondary-care cohort of patients with BD. METHODS: In the Jorvi Bipolar Study, 191 patients with BD-I and bipolar II disorder (BD-II) were followed using a life chart method. Interviews were conducted at six months, 18 months, and five years. Time to full remission, time to first recurrence, total time ill, their predictors, and BD-I versus BD-II differences were investigated among the 151 patients remaining in follow-up. RESULTS: Nearly all subjects recovered from the index episode, but almost all (90%) had a recurrence, and most had multiple recurrences. The patients spent about one-third of their time in illness episodes and 15% of their time with subthreshold symptoms; half of the time they were euthymic. After controlling for confounders, no difference in time spent in depressive states between patients with BD-I and BD-II persisted. Among patients with a depressive index phase, cluster C personality disorders [hazard ratio (HR) = 0.452, p = 0.040] and higher 17-item Hamilton Depression Scale score (HR = 0.951, p = 0.022) predicted longer time to remission, whereas lifetime psychotic symptoms (HR = 2.162, p = 0.016) predicted shorter time to first recurrence. CONCLUSIONS: Among patients with BD, chronicity as uninterrupted persistence of illness was rare, but multiple recurrences were the norm. Patients with BD spent only half of their time euthymic. Patients with BD-I and BD-II may differ little in proneness to depressive states. Severity of depression, cluster C personality disorders, and psychotic symptoms predicted outcome. PMID- 25726952 TI - Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain. AB - The involvement of melatonin in mammalian brain pathophysiology has received growing interest, but information about the anatomical distribution of its two G protein-coupled receptors, MT1 and MT2 , remains elusive. In this study, using specific antibodies, we examined the precise distribution of both melatonin receptors immunoreactivity across the adult rat brain using light, confocal, and electron microscopy. Our results demonstrate a selective MT1 and MT2 localization on neuronal cell bodies and dendrites in numerous regions of the rat telencephalon, diencephalon, and mesencephalon. Confocal and ultrastructural examination confirmed the somatodendritic nature of MT1 and MT2 receptors, both being localized on neuronal membranes. Overall, striking differences were observed in the anatomical distribution pattern of MT1 and MT2 proteins, and the labeling often appeared complementary in regions displaying both receptors. Somadendrites labeled for MT1 were observed for instance in the retrosplenial cortex, the dentate gyrus of the hippocampus, the islands of Calleja, the medial habenula, the suprachiasmatic nucleus, the superior colliculus, the substantia nigra pars compacta, the dorsal raphe nucleus, and the pars tuberalis of the pituitary gland. Somadendrites endowed with MT2 receptors were mostly observed in the CA3 field of the hippocampus, the reticular thalamic nucleus, the supraoptic nucleus, the inferior colliculus, the substantia nigra pars reticulata, and the ventrolateral periaqueductal gray. Together, these data provide the first detailed neurocytological mapping of melatonin receptors in the adult rat brain, an essential prerequisite for a better understanding of melatonin distinct receptor function and neurophysiology. PMID- 25726953 TI - Social cognition dysfunction in adolescents with 22q11.2 deletion syndrome (velo cardio-facial syndrome): relationship with executive functioning and social competence/functioning. AB - BACKGROUND: Social difficulties are often noted among people with intellectual disabilities. Children and adults with 22q.11.2 deletion syndrome (22q11DS) often have poorer social competence as well as poorer performance on measures of executive and social-cognitive skills compared with typically developing young people. However, the relationship between social functioning and more basic processes of social cognition and executive functioning are not well understood in 22q11DS. The present study examined the relationship between social-cognitive measures of emotion attribution and theory of mind with executive functioning and their contribution to social competence in 22q11DS. METHOD: The present cross sectional study measured social cognition and executive performance of 24 adolescents with 22q11DS compared with 27 age-matched typically developing controls. Social cognition was tested using the emotion attribution task (EAT) and a picture sequencing task (PST), which tested mentalising (false-belief), sequencing, cause and effect, and inhibition. Executive functioning was assessed using computerised versions of the Tower of London task and working memory measures of spatial and non-spatial ability. Social competence was also assessed using the parent-reported Strengths and Difficulties Questionnaire. RESULTS: Adolescents with 22q11DS showed impaired false-belief, emotion attribution and executive functioning compared with typically developing control participants. Poorer performance was reported on all story types in the PST, although, patterns of errors and response times across story types were similar in both groups. General sequencing ability was the strongest predictor of false-belief, and performance on the false-belief task predicted emotion attribution accuracy. Intellectual functioning, rather than theory of mind or executive functioning, predicted social competence in 22q11DS. CONCLUSIONS: Performance on social cognitive tasks of theory of mind indicate evidence of a general underlying dysfunction in 22q11DS that includes executive ability to understand cause and effect, to logically reason about social scenarios and also to inhibit responses to salient, but misleading cues. However, general intellectual ability is closely related to actual social competence suggesting that a generalised intellectual deficit coupled with more specific executive impairments may best explain poor social cognition in 22q11DS. PMID- 25726954 TI - Elevated lymphocyte count at time of acute myeloid leukemia diagnosis is associated with shorter remission. AB - In solid tumors, decreased absolute lymphocyte count (ALC) at diagnosis was found to be associated with poorer outcome, but there is only limited data on the impact of ALC in acute myeloid leukemia (AML). In this study we evaluated the prognostic value of ALC on outcome in 259 adult patients with AML who responded to induction therapy. Higher than normal ALC at diagnosis was associated with shorter remission (HR 4.06; p < 0.001), and decreased relapse free and overall survival (HR 3.47; p < 0.001 and HR 3.85; p < 0.001 respectively). Flow cytometry showed low frequency of natural killer (NK) cells and high frequency of CD4+ T cells (which includes the subset of T regulatory cells) in the high ALC group. Low frequency of NK cells and potentially high frequency of inhibitory T regulatory cells may result in weaker immune responses against residual leukemia and may explain the poorer outcome of the high ALC group. PMID- 25726955 TI - Management of adverse events associated with idelalisib treatment: expert panel opinion. AB - Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade >= 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy. PMID- 25726956 TI - Multifunctional cyanate ester nanocomposites reinforced by hexagonal boron nitride after noncovalent biomimetic functionalization. AB - Boron nitride (BN) reinforced polymer nanocomposites have attracted a growing research interest in the microelectronic industry for their uniquely thermal conductive but electrical insulating properties. To overcome the challenges in surface functionalization, in this study, hexagonal boron nitride (h-BN) nanoparticles were noncovalently modified with polydopamine in a solvent-free aqueous condition. The strong pi-pi interaction between the hexagonal structural BN and aromatic dopamine molecules facilitated 15 wt % polydopamine encapsulating the nanoparticles. High-performance bisphenol E cyanate ester (BECy) was incorporated by homogeneously dispersed h-BN at different loadings and functionalities to investigate their effects on thermo-mechanical, dynamic mechanical, and dielectric properties, as well as thermal conductivity. Different theoretical and empirical models were successfully applied to predict thermal and dielectric properties of h-BN/BECy nanocomposites. Overall, the prepared h BN/BECy nanocomposites exhibited outstanding performance in dimensional stability, dynamic-mechanical properties, and thermal conductivity, together with the controllable dielectric property and preserved thermal stability for high temperature applications. PMID- 25726957 TI - Structure evolution in "114" oxides CaBaZn2Ga(2-x)Al(x)O7 (x = 0, 1, 2) and layered cationic ordering in tetrahedral sites for CaBaZn2Al2O7. AB - Rietveld refinements were performed on CaBaZn2Ga(2-x)Al(x)O7 (x = 0, 1, 2) to investigate the site preference of cations in tetrahedral cavities. Tri-valent Ga(3+)/Al(3+) preferred the tetrahedral sites (T1-sites) within the triangular layers. Moreover, a layered type cationic ordering was observed in CaBaZn2Al2O7, where all the T1-sites were occupied by Al(3+). This represents the first example of a cationic ordering in "114" compounds. By substituting Al(3+) into CaBaZn2Ga2O7, the major change in the structure was the shrinkage of the T1O4 tetrahedrons, especially the shortening of the T1-O2 bond distance along the c axis, which led to an anisotropic shrinkage of the unit cell. In the literature, such an anisotropic change of unit cell would induce a structure distortion, as well as a decrease in the symmetry from P63mc to Pbn21. All the title compounds crystallized in P63mc, which is unexpected. A comparison with the selected "114" magnetic oxides help us to confirm that the strong antiferromagnetic interactions of magnetic lattices would also be beneficial for symmetry lowering. Overall, the factors affecting cationic ordering on T1-sites and symmetry lowering are discussed for the title compounds, which may also be applicable to other "114" oxides. PMID- 25726958 TI - Cost of neurocysticercosis patients treated in two referral hospitals in Mexico City, Mexico. AB - OBJECTIVES: To estimate annual costs related to the diagnosis, treatment and productivity losses among patients with neurocysticercosis (NCC) receiving treatment at two referral hospitals, the Instituto Nacional de Neurologia y Neurocirugia (INNN) and the Hospital de Especialidades of the Instituto Mexicano del Seguro Social (HE-IMSS), in Mexico City from July 2007 to August 2008. METHODS: Information on presenting clinical manifestations, diagnostic tests, hospitalisations, surgical procedures and other treatments received by NCC outpatients was collected from medical charts, and supplemented by an individual questionnaire regarding productivity losses and out-of-pocket expenses related to NCC. RESULTS: The annual average per-patient direct costs were US$ 503 (95% CI: 414-592) and US$ 438 (95% CI: 322-571) for patients without a history of hospitalisation and/or surgery seen at the INNN and the HE-IMSS, respectively. These costs increased to US$ 2506 (95% CI: 1797-3215) and US$ 2170 (95% CI: 1303 3037), respectively, for patients with a history of hospitalisation and/or surgery. The average annual per-patient indirect costs were US$ 246 (95% CI: 165 324) and US$ 114 (95% CI: 51-178), respectively, using minimum salary wages for individuals not officially employed. CONCLUSIONS: The total annual cost for patients who had and had not been hospitalised and/or undergone a surgical procedure for the diagnosis or treatment of NCC corresponded to 212% and 41% of an annual minimum wage salary, respectively. The disease tends to affect rural socioeconomically disadvantaged populations and creates health disparities and significant economic losses in Mexico. PMID- 25726959 TI - Accelerated dynamics in active media: from Turing patterns to sparkling waves. AB - We report the destabilization of stationary Turing patterns and the subsequent emergence of fast spatiotemporal dynamics due to reactant consumption. The localized hexagonal Turing spots switch from a stationary regime to a dynamics state by exhibiting spatial oscillations with two characteristic wavelengths and one representative temporal period. These oscillatory Turing spots are not temporally stable and evolve into traveling spiral tips that, in addition to the unexpected birth of spots, rapidly transform into target patterns and originate multiple collisions and wave breakups due to their proximity, degenerating into a chaotic scenario. PMID- 25726960 TI - Water-bath assisted convective assembly of aligned silver nanowire films for transparent electrodes. AB - Manipulating Ag nanowire (AgNW) assembly to tailor the opto-electrical properties and surface morphology could improve the performance of next-generation transparent conductive electrodes. In this paper, we demonstrated a water-bath assisted convective assembly process at the temporary water/alcohol interface for fabricating hierarchical aligned AgNW electrodes. The convection flow plays an important role during the assembly process. The assembled AgNW film fabricated via three times orthogonal dip-coating at a water-bath temperature of 80 degrees C has a sheet resistance of 11.4 Omega sq(-1) with 89.9% transmittance at 550 nm. Moreover, the root mean square (RMS) of this assembled AgNW film was only 15.6 nm which is much lower than the spin-coated random AgNW film (37.6 nm) with a similar sheet resistance. This facile assembly route provides a new way for manufacturing and tailoring ordered nanowire-based devices. PMID- 25726961 TI - Exploring the association between oral health problems and oral health-related quality of life in Peruvian 11- to 14-year-old children. AB - BACKGROUND: This is the first study that tested a Spanish version of the Child Perceptions Questionnaire (CPQ11-14 ) in a population-based sample. AIM: To assess the impact of oral health problems on OHRQoL in 11- to 14-year-old children. DESIGN: Data from 473 11- to 14-year-old children were analysed. They were interviewed using the CPQ11-14. Examinations included dental caries, malocclusion, and traumatic dental injuries. Adjusted Poisson regression was used to associate different clinical conditions to the outcome. RESULTS: Overall, 100% of children reported oral impacts (total CPQ11-14 score >= 1). Children aged 12- to 14 years old experienced a negative impact on all domains and total CPQ11-14 scores (P < 0.05); the increase in DMFT index showed a negative impact on the oral symptoms domain (RR = 1.01; P = 0.05, whereas Class III malocclusion showed a positive impact on the emotional well-being domain (RR = 0.71; P < 0.01). TDI (RR = 1.11; P = 0.01) and crown discoloration (RR = 1.23; P < 0.01) showed a negative impact on the emotional social well-being domain. CONCLUSION: Children aged 12- to 14 years old had a negative impact on all domains and total CPQ11-14 scores compared with those who are 11 years old. The increase in dental caries experience, presences of TDI and crown discoloration have a negative impact on some aspects of the children's OHRQoL. Class III malocclusion showed a positive impact on the emotional well-being domain. PMID- 25726962 TI - Detection of serum cytokines before and after pharmacological and surgical treatment in patients with cystic echinococcosis. AB - Human cystic echinococcosis (CE), caused by Echinococcus granulosus, is one of the most important and widespread parasitic zoonoses. One of the problems that can be encountered after treating CE patients is the risk of post-surgical relapses or treatment failure, thus a long-term clinical and serological follow up is required to evaluate the success or failure of therapy. In the present study immunological markers have been identified to indicate the effectiveness of pharmacological and surgical treatments. The relationship between serum cytokine levels and the outcome of chemotherapy and surgery was evaluated in 50 patients with CE. Serum interleukin (IL)-4, IL-10 and interferon-gamma (IFN-gamma) concentrations were determined by enzyme-linked immunosorbent assay (ELISA) before and after pharmacological and surgical treatment. Serum cytokine levels of IL-4, IL-10 and IFN-gamma were elevated in a significant proportion of patients during the active stage of disease. IL-4, IL-10 and IFN-gamma were measurable in 41 (82%), 37 (74%) and 25 (50%) patients before the treatment. Clinical and radiological assessment of patients 2 years after pharmacological treatment has shown that 48 of 50 patients responded to treatment. IL-4 and IL-10 levels were decreased significantly (P< 0.05) in these patients. Conversely, patients who did not respond showed high levels of IL-4 and IL-10 and undetectable levels of IFN gamma. Hence these results suggest that serum IL-4 and IL-10 detection may be useful in the follow-up of patients with CE. PMID- 25726963 TI - Pouched mitral isthmus is associated with incomplete linear block in atrial fibrillation patients with mechanical mitral valve replacement. AB - BACKGROUND: Previous studies have described the impact of mitral isthmus (MI) anatomy on the likelihood of achieving MI linear block in patients with native mitral valves (NMV) who underwent atrial fibrillation (AF) ablation. However, none have investigated that issue in AF patients with mechanical mitral valve replacements (MMVR). METHODS AND RESULTS: Twenty-nine consecutive patients who developed symptomatic persistent AF post-MMVR and referred for ablation were enrolled. Twenty-nine patients with NMV who underwent ablation of persistent AF during the same period were matched. With preprocedural cardiac computed tomographic imaging, MI anatomical features of all the participants were analyzed. Pouched MI was observed in 19 (65.5%) MMVR patients versus to 6 (20.7%) controls (P = 0.001). Bidirectional linear block across MI was achieved in 21 (72.4%) MMVR patients and 22 (75.9%) in the controls (P = 0.764). In the multivariable analysis, pouched MI was an independent predictor of incomplete MI block. CONCLUSIONS: Pouched MI accounts for the majority of AF patients with MMVR and may be associated with incomplete bidirectional linear block of MI. PMID- 25726964 TI - Intravital microscopic interrogation of peripheral taste sensation. AB - Intravital microscopy is a powerful tool in neuroscience but has not been adapted to the taste sensory organ due to anatomical constraint. Here we developed an imaging window to facilitate microscopic access to the murine tongue in vivo. Real-time two-photon microscopy allowed the visualization of three-dimensional microanatomy of the intact tongue mucosa and functional activity of taste cells in response to topically administered tastants in live mice. Video microscopy also showed the calcium activity of taste cells elicited by small-sized tastants in the blood circulation. Molecular kinetic analysis suggested that intravascular taste sensation takes place at the microvilli on the apical side of taste cells after diffusion of the molecules through the pericellular capillaries and tight junctions in the taste bud. Our results demonstrate the capabilities and utilities of the new tool for taste research in vivo. PMID- 25726965 TI - Hypertonic saline for the management of raised intracranial pressure after severe traumatic brain injury. AB - Hyperosmolar agents are commonly used as an initial treatment for the management of raised intracranial pressure (ICP) after severe traumatic brain injury (TBI). They have an excellent adverse-effect profile compared to other therapies, such as hyperventilation and barbiturates, which carry the risk of reducing cerebral perfusion. The hyperosmolar agent mannitol has been used for several decades to reduce raised ICP, and there is accumulating evidence from pilot studies suggesting beneficial effects of hypertonic saline (HTS) for similar purposes. An ideal therapeutic agent for ICP reduction should reduce ICP while maintaining cerebral perfusion (pressure). While mannitol can cause dehydration over time, HTS helps maintain normovolemia and cerebral perfusion, a finding that has led to a large amount of pilot data being published on the benefits of HTS, albeit in small cohorts. Prophylactic therapy is not recommended with mannitol, although it may be beneficial with HTS. To date, no large clinical trial has been performed to directly compare the two agents. The best current evidence suggests that mannitol is effective in reducing ICP in the management of traumatic intracranial hypertension and carries mortality benefit compared to barbiturates. Current evidence regarding the use of HTS in severe TBI is limited to smaller studies, which illustrate a benefit in ICP reduction and perhaps mortality. PMID- 25726966 TI - Parental Cultural Socialization of Mexican-American Adolescents' Family Obligation Values and Behaviors. AB - The current study examined how parents' cultural socialization efforts contribute to adolescents' family obligation values and behaviors and how these processes may depend upon the relational climate at home. Utilizing survey and daily diary methodologies, 428 Mexican-American adolescents (50% males; Mage = 15 years) and their parents (83% mothers; Mage = 42 years) participated in the study. Adolescents reported on their family obligation values and engagement in family assistance tasks across 14 days. Parents reported on their cultural socialization practices. Results indicated that parental cultural socialization was associated with adolescents' family obligation values and behaviors when parent-child relationships were low in conflict and high in support. Findings suggest that the transmission of cultural values and practices is best facilitated through positive parent-child relationships. PMID- 25726967 TI - Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear. AB - Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term. PMID- 25726968 TI - TNF-alpha gene polymorphisms can help to predict response to etanercept in psoriatic patients. AB - BACKGROUND: Genetic factors might have a role for lack of therapeutic response to anti-TNF-alpha agents, as previously suggested in patients with rheumatoid arthritis and inflammatory bowel disease. OBJECTIVES: We evaluated the role of the main TNF-alpha polymorphisms (-238G>A, -308G>A, -857C>T) in predicting the response to etanercept, an anti-TNF-alpha fusion protein. MATERIAL AND METHODS: Genomic DNA was extracted from buccal epithelial cells in a series of 97 psoriatic patients who received etanercept for at least 3 months. Patients were classified as responders, if they achieved a PASI improvement >= 75% after 12 weeks of etanercept treatment, and non-responders, if PASI improvement was <75%. Single-nucleotide polymorphisms (SNPs) in TNF-alpha gene (-238G>A, -308G>A, 857C>T) were genotyped by PCR restriction fragment length polymorphism (RFLP) assays. RESULTS: We found that patients heterozygous (GA) for the -238G>A polymorphism were more likely not responsive to therapy compared to the GG genotype. In fact, the GA genotype was found in 5/59 (8.5%) responders and in 14/38 (36.8%) non-responders (P = 0.001). A significant relationship with therapy was also observed for the -308G>A polymorphisms. In fact, the GG, GA and AA genotypes were detected in 48 (81.4%), 9 (15.3%) and 2 (3.4%) of the 59 responders and in 22 (57.9%), 11 (28.9%) and 5 (13.2%) of the 38 non-responder patients (P = 0.03). No association with therapy was observed for the -857C>T polymorphisms. CONCLUSION: Our study supports the role of TNF-alpha polymorphisms in predicting the response to anti-TNF-alpha agents. In particular, we found that the presence of -238G>A and -308G>A polymorphisms is associated with poor response to a 3-month therapy with etanercept. However, our data have yet to be validated in larger cohorts. PMID- 25726969 TI - Chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 7 in angle closure glaucoma. AB - PURPOSE: To compare the concentrations of chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) ligand 7 (CCL7) in aqueous humour of eyes with acute primary angle-closure (APAC), primary angle-closure glaucoma (PACG) or with age related cataract. METHODS: The prospective investigation included a study group of 56 patients (24 patients with APAC; 32 patients with PACG) undergoing glaucoma surgery and a control group of 21 patients undergoing routine cataract surgery. The interval between glaucoma attack and trabeculectomy was 19.4 +/- 9.8 days. RESULTS: The concentrations of CCL2 (3037 +/- 501 versus 1127 +/- 141 pg/ml; p = 0.003) and CCL7 (10.5 +/- 2.4 versus 2.8 +/- 0.4 pg/ml; p < 0.001) were significantly higher in the APAC group than in the PACG group, while the concentrations of both cytokines did not differ significantly between the PACG group and the control group (CCL2: 1190 +/- 98 pg/ml; p = 0.10; CCL7: 2.0 +/- 0.6; p = 0.18). The concentrations of both cytokines were significantly and inversely correlated with the interval between the acute angle-closure attack and surgery (CCL2: p = 0.02; rho = -0.48; CCL7: p = 0.04; rho = -0.42). Higher CCL2 concentrations were associated with higher prevalence of surgical failure (28.6% versus 7.1%; p = 0.036). CONCLUSIONS: Concentrations of CCL2 and CCL7 as major inflammatory cytokines with potential influence on the risk of filtering surgery failure were significantly elevated after an acute glaucoma attack and decreased with longer interval to the attack. Trabeculectomy may have a lower risk of failure if performed later than earlier after an acute glaucoma attack, with lower CCL2 concentrations associated with better surgical outcome. PMID- 25726970 TI - Throbbing headache associated with enoxaparin administration: a case report, a review of pharmacovigilance databases for similar cases and possible mechanisms. AB - WHAT IS KNOWN AND OBJECTIVES: To date, no case of headache has been reported with enoxaparin. We present the case of a 60-years-old man, who developed enoxaparin induced throbbing headache and discuss the possible pharmacological mechanisms. We provide an analysis of enoxaparin-induced headache in three international databases. CASE SUMMARY: A few hours after the subcutaneous administration of this drug at therapeutic dose, the patient experienced throbbing headache. Rechallenge on two other separate occasions separated by several days produced the same effect although with reduced intensity when the dose was lowered. The Naranjo Algorithm indicated a 'certain' relationship. WHAT IS NEW AND CONCLUSION: We report a case of throbbing headache associated with the use of enoxaparin; with the increasing use of enoxaparin, physicians who prescribe this drug should be aware of this potential ADR. We suggest that it is a heparin class-effect, and therefore, a more general caution is also appropriate. PMID- 25726971 TI - Widespread distribution and structural diversity of Type IV IRESs in members of Picornaviridae. AB - Picornavirus genomes contain internal ribosomal entry sites (IRESs) that promote end-independent translation initiation. Five structural classes of picornavirus IRES have been identified, but numerous IRESs remain unclassified. Here, previously unrecognized Type IV IRESs were identified in members of three proposed picornavirus genera (Limnipivirus, Pasivirus, Rafivirus) and four recognized genera (Kobuvirus, Megrivirus, Sapelovirus, Parechovirus). These IRESs are ~230-420 nucleotides long, reflecting heterogeneity outside a common structural core. Closer analysis yielded insights into evolutionary processes that have shaped contemporary IRESs. The presence of related IRESs in diverse genera supports the hypothesis that they are heritable genetic elements that spread by horizontal gene transfer. Recombination likely also accounts for the exchange of some peripheral subdomains, suggesting that IRES evolution involves incremental addition of elements to a pre-existing core. Nucleotide conservation is concentrated in ribosome-binding sites, and at the junction of helical domains, likely to ensure orientation of subdomains in an active conformation. PMID- 25726972 TI - Coronavirus envelope (E) protein remains at the site of assembly. AB - Coronaviruses (CoVs) assemble at endoplasmic reticulum Golgi intermediate compartment (ERGIC) membranes and egress from cells in cargo vesicles. Only a few molecules of the envelope (E) protein are assembled into virions. The role of E in morphogenesis is not fully understood. The cellular localization and dynamics of mouse hepatitis CoV A59 (MHV) E protein were investigated to further understanding of its role during infection. E protein localized in the ERGIC and Golgi with the amino and carboxy termini in the lumen and cytoplasm, respectively. E protein does not traffic to the cell surface. MHV was genetically engineered with a tetracysteine tag at the carboxy end of E. Fluorescence recovery after photobleaching (FRAP) showed that E is mobile in ERGIC/Golgi membranes. Correlative light electron microscopy (CLEM) confirmed the presence of E in Golgi cisternae. The results provide strong support that E proteins carry out their function(s) at the site of budding/assembly. PMID- 25726973 TI - N-glycosylation profiling of porcine reproductive and respiratory syndrome virus envelope glycoprotein 5. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a positive-sense ssRNA virus whose envelope contains four glycoproteins and three nonglycosylated proteins. Glycans of major envelope glycoprotein 5 (GP5) are proposed as important for virus assembly and entry into permissive cells. Structural characterization of GP5 glycans would facilitate the mechanistic understanding of these processes. Thus, we purified the PRRSV type 2 prototype strain, VR2332, and analyzed the virion-associated glycans by both biochemical and mass spectrometric methods. Endoglycosidase digestion showed that GP5 was the primary protein substrate, and that the carbohydrate moieties were primarily complex-type N glycans. Mass spectrometric analysis (HPLC-ESI-MS/MS) of GP5 N-glycans revealed an abundance of N-acetylglucosamine (GlcNAc) and N-acetyllactosamine (LacNAc) oligomers in addition to sialic acids. GlcNAc and LacNAc accessibility to ligands was confirmed by lectin co-precipitation. Our findings help to explain PRRSV infection of cells lacking sialoadhesin and provide a glycan database to facilitate molecular structural studies of PRRSV. PMID- 25726974 TI - An observational study of pharmacological treatment in primary care of children with ADHD in the United kingdom. AB - OBJECTIVE: The study described initial pharmacological treatment of children in the United Kingdom diagnosed as having ADHD and assessed predictors of medication persistence. METHODS: U.K. children ages 3-16 diagnosed as having ADHD between 1994 and 2006 were identified from primary care practice data. Child characteristics, prescription patterns, and initial medication prescribed were described over the study period. The associations of child and clinical factors with medication persistence (defined as initial treatment length greater than six months) were estimated by using binomial regression. RESULTS: Of 2,878 children with an ADHD diagnosis, 46% (N=1,314) received at least one prescription for ADHD medication within two years of diagnosis. The mean initial treatment length was 10.7+/-.5 months. Only 35% (N=464) of pharmacologically treated children had a treatment length greater than six months after initial medication prescription when the analysis used a 30-day grace period; 57% were persistent in treatment when a less stringent 60-day grace period was used. Children who were initially prescribed long-acting methylphenidate were more likely to persist in treatment than those prescribed standard methylphenidate (risk ratio=1.2, 95% confidence interval=1.1-1.4). CONCLUSIONS: A large proportion of children who received medication for ADHD in primary care did not continue in initial treatment for more than six months. Few child or clinical factors were associated with treatment persistence. Epidemiological research about the effects of long-term ADHD medication use should account for the observed limited persistence in medication treatment. PMID- 25726975 TI - Use of quality measures for Medicaid behavioral health services by state agencies: implications for health care reform. AB - OBJECTIVE: The structure-process-outcome quality framework espoused by Donabedian provides a conceptual way to examine and prioritize behavioral health quality measures used by states. This report presents an environmental scan of the quality measures and satisfaction surveys that state Medicaid managed care and behavioral health agencies used prior to Medicaid expansion in 2014. METHODS: Data were collected by reviewing online documents related to Medicaid managed care contracts for behavioral health, quality strategies, quality improvement plans, quality and performance indicators data, annual outcomes reports, performance measure specification manuals, legislative reports, and Medicaid waiver requests for proposals. RESULTS: Information was publicly available for 29 states. Most states relied on process measures, along with some structure and outcome measures. Although all states reported on at least one process measure of behavioral health quality, 52% of states did not use any outcomes measures and 48% of states had no structure measures. A majority of the states (69%) used behavioral health measures from the National Committee for Quality Assurance's Healthcare Effectiveness Data and Information Set, and all but one state in the sample (97%) used consumer experience-of-care surveys. Many states supplemented these data with locally developed behavioral health indicators that rely on administrative and nonadministrative data. CONCLUSIONS: State Medicaid agencies are using nationally recognized as well as local measures to assess quality of behavioral health care. Findings indicate a need for additional nationally endorsed measures in the area of substance use disorders and treatment outcomes. PMID- 25726976 TI - Prevalence of neurodevelopmental disorders among low-income African Americans at a clinic on Chicago's south side. AB - OBJECTIVE: This study examined the point prevalence of neurodevelopmental disorders among predominantly low-income, African-American psychiatric patients at Jackson Park Hospital's Family Medicine Clinic on Chicago's South Side. METHODS: Using active case ascertainment methodology, the authors assessed the records of 611 psychiatric patients visiting the clinic between May 23, 2013, and January 14, 2014, to identify those with DSM-5 neurodevelopmental disorders. RESULTS: A total of 297 patients (49%) met criteria for a neurodevelopmental disorder during childhood. Moreover, 237 (39%) had clinical profiles consistent with neurobehavioral disorder associated with prenatal alcohol exposure, and 53 (9%) had other neurodevelopmental disorders. The authors disagreed on the specific type of neurodevelopmental disorder of seven (1% of 611) of the 297 patients with neurodevelopmental disorders. CONCLUSIONS: A high prevalence of neurodevelopmental disorders was found among low-income predominantly African American psychiatric patients on Chicago's South Side. If replicated, these findings should bring about substantial changes in medical practice with African American patients. PMID- 25726977 TI - Metabolic monitoring for youths initiating use of second-generation antipsychotics, 2003-2011. AB - OBJECTIVE: In 2004, the American Diabetes Association (ADA) released treatment guidelines recommending metabolic screening for children and adolescents before and after initiation of second-generation antipsychotics. Prior studies showed that the guidelines coincided with a small increase in glucose testing of children and adults but had limited follow-up. This study sought to evaluate changes in metabolic screening of children initiating second-generation antipsychotics around the time of the 2004 guidelines and in the following eight years. METHODS: Study patients (N=52,407) were identified in a large nationwide commercial insurance claims database for the period January 1, 2003, through December 31, 2011. The study population was a cohort of nondiabetic new users of second-generation antipsychotics who were ages 5-18. Glucose and HbA1c tests completed before and after second-generation antipsychotic initiation were identified with Current Procedural Terminology-4 codes. Metabolic screening was also examined by second-generation antipsychotic agent prescribed and psychiatric diagnosis. RESULTS: The proportion of patients receiving a glucose test preinitiation increased from 17.9% in 2003 to 18.9% in 2004, and testing postinitiation increased from 14.7% to 16.6% in the same period. The slight increase in glucose testing was not sustained; the proportion tested dropped in the following years before rising again in 2008. Glucose screening was most common for patients taking aripiprazole. Patients with a diagnosis of hyperkinetic disorder were less likely to be tested. HbA1c testing was less frequent but had a similar usage pattern. CONCLUSIONS: The small improvement in metabolic screening immediately after the 2004 ADA guidelines were issued was not sustained. Overall, metabolic screening rates remained suboptimal throughout the study period. PMID- 25726978 TI - Change in emergency department providers' beliefs and practices after use of new protocols for suicidal patients. AB - OBJECTIVE: The study examined changes in self-reported attitudes and practices related to suicide risk assessment among providers at emergency departments (EDs) during a three-phase quasi-experimental trial involving implementation of ED protocols for suicidal patients. METHODS: A total of 1,289 of 1,828 (71% response rate) eligible providers at eight EDs completed a voluntary, anonymous survey at baseline, after introduction of universal suicide screening, and after introduction of suicide prevention resources (nurses) and a secondary risk assessment tool (physicians). RESULTS: Among participants, the median age was 40 years old, 64% were female, and there were no demographic differences across study phases; 68% were nurses, and 32% were attending physicians. Between phase 1 and phase 3, increasing proportions of nurses reported screening for suicide (36% and 95%, respectively, p<.001) and increasing proportions of physicians reported further assessment of suicide risk (63% and 80%, respectively, p<.01). Although increasing proportions of providers said universal screening would result in more psychiatric consultations, decreasing proportions said it would slow down clinical care. Increasing proportions of nurses reported often or almost always asking suicidal patients about firearm access (18%-69%, depending on the case), although these numbers remained low relative to ideal practice. Between 35% and 87% of physicians asked about firearms, depending on the case, and these percentages did not change significantly over the study phases. CONCLUSIONS: These findings support the feasibility of implementing universal screening for suicide in EDs, assuming adequate resources, but providers should be educated to ask suicidal patients about firearm access. PMID- 25726979 TI - VA Disability Compensation and Money Spent on Substance Use Among Homeless Veterans: A Controversial Association. AB - OBJECTIVE: There has long been concern that public support payments are used to support addictive behaviors. This study examined the amount of money homeless veterans spend on alcohol and drugs and the association between public support income, including VA disability compensation, and expenditures on alcohol and drugs. METHODS: Data were from 1,160 veterans from 19 sites on entry into the Housing and Urban Development-Veterans Affairs Supportive Housing program. Descriptive statistics and nonparametric analyses were conducted. RESULTS: About 33% of veterans reported spending money on alcohol and 22% reported spending money on drugs in the past month. No significant association was found between public support income, VA disability compensation, and money spent on alcohol and drugs. CONCLUSIONS: A substantial proportion of homeless veterans spend some income on alcohol and drugs, but disability income, including VA compensation, does not seem to be related to substance use or money spent on addictive substances. PMID- 25726980 TI - Insurance status, use of mental health services, and unmet need for mental health care in the United States. AB - OBJECTIVE: The purpose of this study was to provide updated national estimates and correlates of service use, unmet need, and barriers to mental health treatment among adults with mental disorders. METHODS: The sample included 36,647 adults ages 18-64 (9,723 with any mental illness and 2,608 with serious mental illness) from the 2011 National Survey on Drug Use and Health. Logistic regression models were used to examine predictors of mental health treatment and perceived unmet need. RESULTS: Substantial numbers of adults with mental illness did not receive treatment (any mental illness, 62%; serious mental illness, 41%) and perceived an unmet need for treatment (any mental illness, 21%; serious mental illness, 41%). Having health insurance was a strong correlate of mental health treatment use (any mental illness: private insurance, adjusted odds ratio [AOR]=1.63, 95% confidence interval [CI]=1.29-2.06; Medicaid, AOR=2.66, CI=2.04 3.46; serious mental illness: private insurance, AOR=1.65, CI=1.12-2.45; Medicaid, AOR=3.37, CI=2.02-5.61) and of lower odds of perceived unmet need (any mental illness: private insurance, AOR=.78, CI=.65-.95; Medicaid, AOR=.70, CI=.54 .92). Among adults with any mental illness and perceived unmet need, 72% reported at least one structural barrier and 47% reported at least one attitudinal barrier. Compared with respondents with insurance, uninsured individuals reported significantly more structural barriers and fewer attitudinal barriers. CONCLUSIONS: Low rates of treatment and high unmet need persist among adults with mental illness. Strategies to reduce both structural barriers, such as cost and insurance coverage, and attitudinal barriers are needed. PMID- 25726981 TI - Trends in parent-reported emotional and behavioral problems among children using special education services. AB - OBJECTIVE: This report describes trends in health conditions reported by parents as the limitations leading to special education services for their children. METHODS: Data are reported for children ages 6-17 (N=182,998) surveyed in households in the 2001-2012 National Health Interview Survey. RESULTS: Between 2001 and 2012, the overall percentage of U.S. children ages 6-17 who were receiving special education services increased from 7.2% to 8.7%. Between 2001 and 2012, the leading causes of activity limitations among children receiving special education services included emotional or behavioral problems, which increased from 36% to 43%; speech problems, which increased from 16% to 22%; and learning disability, which decreased from 41% to 27%. There were no significant trends in any of the other conditions considered as possible sources of activity limitations. CONCLUSIONS: Emotional and behavioral problems have become the most frequently reported source of activity limitations among children receiving special education services. PMID- 25726982 TI - Impact of the 2nd story peer respite program on use of inpatient and emergency services. AB - OBJECTIVE: By providing a safe and supportive space for individuals experiencing or at risk of experiencing a mental health crisis, a peer respite may reduce the need for traditional crisis interventions. This study examined the relationship between peer respite and use of inpatient and emergency services among adults receiving publicly funded behavioral health services. METHODS: This analysis used propensity score matching to create matched pairs of 139 users of peer respite and 139 nonusers of respite with similar histories of behavioral health service use and clinical and demographic characteristics. A two-stage regression model first predicted the likelihood of inpatient or emergency service use after peer respite start date and then predicted hours of inpatient and emergency service use among 89 individuals who used any inpatient or emergency services. RESULTS: After the authors controlled for relevant covariates, the odds of using any inpatient or emergency services after the program start date were approximately 70% lower among respite users than nonrespite users, although the odds increased with each additional respite day. Among individuals who used any inpatient or emergency services, a longer stay in respite was associated with fewer hours of inpatient and emergency service use. However, the association was one of diminishing returns, with negligible decreases predicted beyond 14 respite days. CONCLUSIONS: By reducing the need for inpatient and emergency services for some individuals, peer respites may increase meaningful choices for recovery and decrease the behavioral health system's reliance on costly, coercive, and less person-centered modes of service delivery. PMID- 25726983 TI - Geographic variations in use of Medicaid mental health services. AB - An extensive literature documents geographic variations in patterns of health services use and spending but virtually ignores mental health services. The authors assessed geographic variations in use of and spending on mental health services among adult disabled Medicaid recipients with mental illness. Data were derived from 2008 Medicaid claims in 35 states. Per capita annual inpatient days, ambulatory visits, psychotropic medication fills, and spending on psychiatric services varied widely across regions. The proportion of total variation explained by interstate differences ranged from 43% (inpatient days) to 71% (ambulatory visits). Understanding these variations more thoroughly may help improve the effectiveness and efficiency of mental health services delivered under Medicaid. PMID- 25726984 TI - A randomized clinical trial of a telephone depression intervention to reduce employee presenteeism and absenteeism. AB - OBJECTIVES: The study tested an intervention aimed at improving work functioning among middle-aged and older adults with depression and work limitations. METHODS: A randomized clinical trial allocated an initial sample of 431 eligible employed adults (age >=45) to a work-focused intervention (WFI) or usual care. Inclusion criteria were depression as measured by the Patient Health Questionnaire-9 (PHQ 9) and at-work limitations indicated by a productivity loss score >=5% on the Work Limitations Questionnaire (WLQ). Study sites included 19 employers and five related organizations. Telephone-based counseling provided three integrated modalities: care coordination, cognitive-behavioral therapy strategy development, and work coaching and modification. Effectiveness (change in productivity loss scores from preintervention to four months postintervention) was tested with mixed models adjusted for confounders. Secondary outcomes included change in WLQ work performance scales, self-reported absences, and depression. RESULTS: Of 1,227 eligible employees (7% of screened), 431 (35%) enrolled and 380 completed the study (12% attrition). At-work productivity loss improved 44% in the WFI group versus 13% in usual care (difference in change, p<.001). WFI group scores on the four WLQ scales improved 44% to 47%, significantly better than in usual care (p<.001 for each scale). Absence days declined by 53% in the WFI group versus 13% in usual care (difference in change, p<.001). Mean PHQ-9 depression symptom severity scores declined 51% for WFI versus 26% for usual care (difference in change, p<.001). CONCLUSIONS: The WFI was more effective than usual care at four-month follow-up. Given increasing efforts to provide more patient-centered, value-based care, the WFI could be an important resource. PMID- 25726985 TI - Peer respites: a research and practice agenda. AB - Peer respites are voluntary, short-term residential programs designed to support individuals experiencing or at risk of a psychiatric crisis. These programs posit that for many mental health services users, traditional psychiatric emergency department and inpatient hospital services are undesirable and avoidable when less coercive or intrusive community-based supports are available. Intended to provide a safe and homelike environment, peer respites are usually situated in residential neighborhoods. These programs are starting to spread across the United States, yet there is very little rigorous research on whether they are being implemented consistently across sites and which processes and outcomes may lead to benefits for persons experiencing psychiatric crises and for overburdened mental health systems. This Open Forum outlines implementation and research issues that peer respites face. PMID- 25726986 TI - A tale of two states: do consumers see mental health insurance parity when shopping on state exchanges? AB - All insurance products sold on the health insurance exchanges established by the Affordable Care Act are required to offer mental health and substance use disorder benefits in compliance with requirements of the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA). This column identifies two dimensions of parity compliance that consumers observe while shopping for insurance products offered on two state-run exchanges. The authors discuss a number of apparent discrepancies with the requirements of MHPAEA in these observable dimensions, emphasizing the potential impact of these factors on consumers' decisions about plan enrollment. The analysis reveals a nuanced picture of how insurance issuers are presenting behavioral health benefits to potential enrollees and illustrates broader concerns about parity compliance and the potential for selection on the exchanges. Four specific discrepancies are highlighted as areas for further evaluation. PMID- 25726987 TI - Rhodium(I)-catalyzed asymmetric carbene insertion into B-H bonds: highly enantioselective access to functionalized organoboranes. AB - A unique rhodium(I)-catalyzed asymmetric B-H insertion of alpha-diazo carbonyl compounds with easily available amine-borane adducts was achieved using a newly developed C1-symmetric chiral diene as ligand. This first Rh(I)-carbene-directed B-H insertion example represents an attractive and promising approach for synthesis of highly enantioenriched organoboron compounds, allowing for the efficient construction of alpha-boryl esters and ketones with excellent enantioselectivities (up to 99% ee) under exceptionally mild conditions. PMID- 25726988 TI - Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder. AB - INTRODUCTION: Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. AREAS COVERED: This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. EXPERT OPINION: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development. PMID- 25726989 TI - Ultrasound microbubble-carried PNA targeting to c-myc mRNA inhibits the proliferation of rabbit iliac arterious smooth muscle cells and intimal hyperplasia. AB - OBJECTIVE: To elucidate the transfected effect of albumin ultrasound microbubbles carrying peptide nucleic acids (PNAs) against c-myc gene to the vascular walls and their effect on the intimal proliferation induced by vascular denudation. METHODS: A rabbit iliac artery intimal proliferation model was constructed and PNA against c-myc mRNA was designed and synthesized and was added to albumin solution before ultrasound microbubbles were prepared and encapsulated in matrix of albumin. The ultrasound microbubbles carrying PNA were transfected to intima under ultrasound exposure. The transfected effect was identified by a histochemical method and the expression of c-myc was detected by in situ hybridization. The proliferation of intimal smooth muscle cells was estimated by the expression of proliferative cell nuclear antigen (PCNA) of them. The intimal area and thickness were judged morphologically for intimal hyperplasia. RESULTS: The ultrasound microbubbles with PNA were successfully prepared and c-myc PNA was transfected to vascular intimal cells. The expression of c-myc and PCNA by intimal vascular smooth muscle cells (vSMCs) was inhibited significantly and the intimal thickness and area were reduced remarkably. CONCLUSION: Transfection of c myc PNA could inhibit proliferartion of vSMCs and intima in the rabbit iliac artery intimal proliferation model and the targeted transfection of albumin ultrasound microbubbles carrying PNA offers a feasible way to facilitate its access to specific cells in vivo and produce bioavailability. PMID- 25726990 TI - Transdermal delivery of vancomycin hydrochloride using combination of nano ethosomes and iontophoresis: in vitro and in vivo study. AB - This study aimed to evaluate transdermal delivery of vancomycin hydrochloride using the combination of ethosomes as an encapsulating vesicle and iontophoresis. Ethosomes were prepared and evaluated in terms of electrochemical stability. Cathodal iontophoresis of negatively charged ethosomes and anodal iontophoresis of free drug solution and positively charged vesicles were conducted. The effect of current mode, density, concentration of drug and ionic strength was studied. In vivo study was performed by inducing mediastinitis in Sprague-Dawley rats using methicillin-resistant Staphylococcus aureus as infected pathogen, the mean bacterial count was compared between groups of rats, one of the treated groups received drug intramuscularly while the other group received vancomycin using iontophoretic delivery of optimized ethosomal formula. Ethosomes showed efficient electrochemical stability, cathodal iontophoresis of negatively charged vesicle (F2) showed maximum transdermal flux (550 ug/cm(2)/h) compared to free drug solution and other ethosomal formulae, transdermal flux was reduced by altering current mode from continuous to ON/OFF mode, reducing current density and by using normal saline as drug solvent; on the other hand, flux was potentiated by increasing drug concentration from 25 to 75 mg/ml. In vivo study revealed that there was a significant difference in terms of bacterial count between untreated and treated groups, while there was no statistically significant difference between the I.M. vancomycin treatment and treatment conducted by iontophoretic delivery of vancomycin encapsulated in ethosomal formula. Combination between ethosomes and iontophoresis had succeeded in delivering vancomycin transdermally. PMID- 25726991 TI - Improving blood transfusion practice by educational emphasis of the Blood Utilization Committee: experience of one hospital. AB - AIM: The aim of this study was to reduce crossmatch to transfusion ratio through development of a new Blood Utilization Committee. BACKGROUND: Blood utilization hinges on the cooperation between transfusion services, medical staff, nursing and administration. Transfusion committees have attempted to bring about better oversight and bridge the gap between departments but in our institution this did not work until we had a catalyst to drive the effort. The unabashed desire and enthusiasm of one of our cardiac surgeons for self-improvement led to the formation of a new Blood Utilization Committee in October of 2012. STUDY DESIGN AND METHODS: Crossmatch and transfusion data were gathered from our blood bank information system starting with the 4th quarter of 2011 through the 1st quarter of 2013. The crossmatch to transfusion ratio (C:T) was calculated and comparisons were made between the results from before and after the initiation of the committee. RESULTS: At the commencement of the committee the initial C:T for the cardiac team was 2.48. We calculated a decrease of the C:T to 1.5 four months after the November 2012 formation of the new committee. The P-value calculated (P<0.0005) proved that the decrease was statistically significant. CONCLUSION: The initial impulse generated by the cardiothoracic surgery team is now spreading to other DRG groups in our hospital and we are seeing a drop in their C:T as well. Better blood utilization is attainable when the physicians who perform most transfusions lead the charge. PMID- 25726992 TI - Imaging coronary artery disease and the myocardial ischemic cascade: clinical principles and scope. AB - On a subcellular level, atherogenesis is characterized by the translocation of proatherogenic lipoproteins into the arterial wall. An inflammatory response involving complex repair mechanisms subsequently causes maladaptive vascular changes resulting in coronary stenosis or occlusion. The chronology of the underlying processes occurring from atherosclerosis to myocardial ischemia affect the selection and interpretation of diagnostic testing. An understanding of the ischemic cascade, atherosclerosis, coronary remodeling, plaque morphology, and their relationship to clinical syndromes is essential in determining which diagnostic modalities are useful in clinical practice. PMID- 25726993 TI - Computed tomographic assessment of coronary artery disease: state-of-the-art imaging techniques. AB - While coronary computed tomography (CT) angiography and more refined imaging of the coronary anatomy have driven technical innovation in cardiac CT for the last 10 years, there is now an increasing focus on functional applications of cardiac CT, such as evaluation of the myocardial blood supply or assessment of dynamic myocardial perfusion. Novel techniques show promising results. This article focuses on state-of-the-art CT imaging techniques to visualize the coronary anatomy, describes aspects of radiation dose reduction, and briefly touches on recent approaches to obtain functional information from a CT scan of the heart, in particular dual-energy CT. PMID- 25726994 TI - Coronary computed tomographic angiography in clinical practice: state of the art. AB - In patients with stable chest pain, coronary CT angiography (CCTA) has demonstrated high accuracy in excluding coronary artery disease and CCTA findings carry prognostic significance for the occurrence of future cardiovascular events. Increasingly, CCTA has been adopted as a triage tool in patients with acute chest pain. In specific clinical scenarios, CCTA further represents a useful tool to exclude an ischemic etiology in patients with cardiac arrhythmias or newly diagnosed heart failure. Several novel techniques are currently being investigated which may extend the ability of CCTA to characterize and quantify coronary artery plaque and assess the hemodynamic significance of stenosis. PMID- 25726995 TI - Cardiac computed tomography for the evaluation of the acute chest pain syndrome: state of the art. AB - Coronary computed tomography angiography (CCTA) is recommended for the triage of acute chest pain in patients with a low-to-intermediate likelihood for acute coronary syndrome. Absence of coronary artery disease (CAD) confirmed by CCTA allows rapid emergency department discharge. This article shows that CCTA-based triage is as safe as traditional triage, reduces the hospital length of stay, and may provide cost-effective or even cost-saving care. PMID- 25726996 TI - Computed tomography imaging of coronary artery plaque: characterization and prognosis. AB - The exact definition and prognostication of vulnerable plaque remain elusive, and multiple imaging modalities aim to identify these plaques. As a noninvasive technique for the diagnosis of coronary artery disease, coronary computed tomography angiography has become increasingly utilized, primarily in patients with an elevated cardiovascular risk profile. Recent advances in technical methods have allowed for improved visualization of the vessel wall and surrounding tissue, allowing for improved characterization of vulnerable plaques by identifying features such as low-density plaques, positive remodeling, and spotty calcification. Quantification and qualification of these plaques may enhance the ability to predict future cardiovascular events. PMID- 25726997 TI - Beyond stenosis detection: computed tomography approaches for determining the functional relevance of coronary artery disease. AB - Coronary computed tomography angiography (CCTA) is an established imaging technique for the noninvasive assessment of coronary arteries. However, CCTA remains a morphologic technique with the same limitations as invasive coronary angiography in evaluating the hemodynamic significance of coronary stenosis. Different computed tomography (CT) techniques for the functional analysis of coronary lesions have recently emerged, including static and dynamic CT myocardial perfusion imaging and CT-based fractional flow reserve and transluminal attenuation gradient methods. These techniques hold promise for achieving a comprehensive appraisal of anatomic and functional aspects of coronary heart disease with a single modality. PMID- 25726998 TI - Current state of the art cardiovascular MR imaging techniques for assessment of ischemic heart disease. AB - Cardiac magnetic resonance (CMR) imaging is increasingly being used to evaluate patients with known or suspected ischemic heart disease, because of its ability to acquire images in any orientation and the wide variety of sequences available to characterize normal and abnormal structure and function. Substantial improvements have been made in the hardware and software used to perform CMR, resulting in better and more consistent image quality. There has been a greater emphasis recently in developing and validating quantitative CMR techniques. This article reviews advances in CMR techniques for assessing cardiac function, myocardial perfusion, late gadolinium enhancement, and tissue characterization with T1 and T2 mapping sequences. PMID- 25726999 TI - MR imaging of the coronary vasculature: imaging the lumen, wall, and beyond. AB - The characteristics of coronary artery disease are gradual thickening of the coronary walls and narrowing of the vascular lumen by the buildup of atherosclerosis plaques. These morphologic changes can be noninvasively detected by coronary magnetic resonance (MR) imaging/MR angiography (MRA). In addition, functional changes, such as coronary wall distensibility and flow changes, may also be evaluated with MR imaging. However, the application of current MR imaging/MRA techniques is limited in clinical practice because of several adverse technical and physiologic factors, such as cardiac and respiratory motion. Many technical innovations have been adopted to address these problems from multiple aspects. PMID- 25727000 TI - Stress cardiac MR imaging: the role of stress functional assessment and perfusion imaging in the evaluation of ischemic heart disease. AB - Stress cardiac magnetic resonance imaging can provide valuable information for the diagnosis and management of ischemic heart disease (IHD). It plays an important role in the initial diagnosis in patients with acute chest pain, in the diagnosis of complications post myocardial infarction (MI), in the assessment of the right ventricle after an acute MI, to detect complications due to or after interventions, in prediction of myocardial recovery, to detect inducible ischemia in patients with known IHD, in differentiating ischemic from non-ischemic dilated cardiomyopathy, and in risk stratification. PMID- 25727001 TI - Global and regional functional assessment of ischemic heart disease with cardiac MR imaging. AB - Cardiac MR imaging (CMR) combines assessment of myocardial function and tissue characterization, and is therefore ideally suited to evaluating patients with ischemic heart disease (IHD). This article discusses evaluation of left ventricular global function at CMR, reviewing the literature supporting global parameters in risk stratification and assessment of treatment response in IHD. Techniques for assessment of regional myocardial function are reviewed, and normal myocardial motion and fiber arrangement discussed. Despite barriers to clinical adoption, integration of this assessment into clinical routine should improve the ability to detect functional consequences of early myocardial structural alterations in patients with IHD. PMID- 25727002 TI - Late gadolinium enhancement imaging in assessment of myocardial viability: techniques and clinical applications. AB - Assessment of myocardial viability is of ever-evolving interest in cardiovascular imaging, with major societies having incorporated viability imaging as class I or class IIa indications in their guidelines to better guide patient management. As with late gadolinium enhancement cardiac magnetic resonance (MR), assessment of residual myocardial viability or the extent of myocardial infarction is straightforward and this technique may easily be combined with other cardiac MR modules. In clinical routine functional assessment and myocardial perfusion imaging if often used in conjunction allowing for a comprehensive assessment of ischemic heart disease. PMID- 25727003 TI - Tissue characterization of the myocardium: state of the art characterization by magnetic resonance and computed tomography imaging. AB - Late gadolinium enhancement (LGE) is a simple, robust, well-validated method for assessing scar in acute and chronic myocardial infarction. LGE is useful for distinguishing between ischemic and nonischemic cardiomyopathy. Specific LGE patterns are seen in nonischemic cardiomyopathy. Patient studies using T1 mapping have varied in study, design, and acquisition sequences. Despite the differences in technique, a clear pattern that has been seen is that in cardiac disease postcontrast T1 times are shorter. Extracellular volume fraction measured with cardiac computed tomography represents a new approach to the clinical assessment of diffuse myocardial fibrosis by evaluating the distribution of iodinated contrast. PMID- 25727004 TI - Coronary artery disease and the myocardial ischemic cascade: state-of-the-art computed tomography and MR imaging. PMID- 25727005 TI - TSC1 activates TGF-beta-Smad2/3 signaling in growth arrest and epithelial-to mesenchymal transition. AB - The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling. They suppress cell growth and proliferation by acting in a heteromeric complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1). In this study, we identify TSC1 as a component of the transforming growth factor beta (TGF-beta)-Smad2/3 pathway. Here, TSC1 functions independently of TSC2. TSC1 interacts with the TGF-beta receptor complex and Smad2/3 and is required for their association with one another. TSC1 regulates TGF-beta-induced Smad2/3 phosphorylation and target gene expression and controls TGF-beta-induced growth arrest and epithelial-to-mesenchymal transition (EMT). Hyperactive Akt specifically activates TSC1-dependent cytostatic Smad signaling to induce growth arrest. Thus, TSC1 couples Akt activity to TGF-beta-Smad2/3 signaling. This has implications for cancer treatments targeting phosphoinositide 3-kinases and Akt because they may impair tumor-suppressive cytostatic TGF-beta signaling by inhibiting Akt- and TSC1-dependent Smad activation. PMID- 25727007 TI - The gut microbiome restores intrinsic and extrinsic nerve function in germ-free mice accompanied by changes in calbindin. AB - BACKGROUND: The microbiome is essential for normal myenteric intrinsic primary afferent neuron (IPAN) excitability. These neurons control gut motility and modulate gut-brain signaling by exciting extrinsic afferent fibers innervating the enteric nervous system via an IPAN to extrinsic fiber sensory synapse. We investigated effects of germ-free (GF) status and conventionalization on extrinsic sensory fiber discharge in the mesenteric nerve bundle and IPAN electrophysiology, and compared these findings with those from specific pathogen free (SPF) mice. As we have previously shown that the IPAN calcium-dependent slow afterhyperpolarization (sAHP) is enhanced in GF mice, we also examined the expression of the calcium-binding protein calbindin in these neurons in these different animal groups. METHODS: IPAN sAHP and mesenteric nerve multiunit discharge were recorded using ex vivo jejunal gut segments from SPF, GF, or conventionalized (CONV) mice. IPANs were excited by adding 5 MUM TRAM-34 to the serosal superfusate. We probed for calbindin expression using immunohistochemical techniques. KEY RESULTS: SPF mice had a 21% increase in mesenteric nerve multiunit firing rate and CONV mice a 41% increase when IPANs were excited by TRAM-34. For GF mice, this increase was barely detectable (2%). TRAM-34 changed sAHP area under the curve by -77 for SPF, +3 for GF, or -54% for CONV animals. Calbindin-immunopositive neurons per myenteric ganglion were 36% in SPF, 24% in GF, and 52% in CONV animals. CONCLUSIONS & INFERENCES: The intact microbiome is essential for normal intrinsic and extrinsic nerve function and gut-brain signaling. PMID- 25727008 TI - Healthy hand-ups; an editor's enabling epilogue. PMID- 25727009 TI - The relationship between the Patient-rated Ulnar Nerve Evaluation and the common impairment measures of grip strength, pinch strength, and sensation. AB - STUDY DESIGN: Prospective cohort study. INTRODUCTION: Grip strength, pinch strength, and sensory threshold are common evaluations used on a daily basis. Identifying how these variables relate to function for patients allows these assessments to be used for screening to identify who may benefit from surgical intervention, and provides valuable information about what impairments patients think are important with respect to functional use of their upper extremity. Therapists can use this information to focus rehabilitation programs on the most important impairments. PURPOSE: To evaluate the relationship between the Patient rated Ulnar Nerve Evaluation (PRUNE) and impairment measures of grip strength, pinch strength, and one-point sensory threshold. METHODS: Data was prospectively collected from 77 patients before surgery and during regular time points for 2 years following surgery. Patients completed the PRUNE, grip and pinch strength measures, and a one-point sensory threshold evaluation. Correlations between these variables were calculated at baseline, 2 years after surgery, and for change scores during the 2-year follow up. A multiple regression analysis was used to determine the contribution of the impairment variables for determining functional change. RESULTS: Grip strength showed moderate, statistically significant correlation with PRUNE scores at both baseline (r = -0.38) and at two years (r = -0.29). There was also a statistically significant correlation between one point sensory threshold for the small finger at two years (r = 0.36), but not at baseline. Change in grip strength (r = -0.28) and pinch strength (r = -0.30) both demonstrated significant correlations with PRUNE change scores. Overall, changes in grip strength, pinch strength, and sensation accounted for 20% of the variance in PRUNE changes. CONCLUSION: Since grip strength was most highly correlated with PRUNE scores at baseline and at two years, rehabilitation programs that target grip strengthening is supported. While neither grip nor pinch strength were significant contributors to the regression when used together, each showed significant contributions to PRUNE variability when used in the model independently. Therefore, a combination of grip and pinch strengthening may be important during rehabilitation for improving functional results in patients that undergo surgical intervention for cubital tunnel syndrome. LEVEL OF EVIDENCE: 2b. PMID- 25727006 TI - CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere. AB - CENP-A is a centromere-specific histone H3 variant that epigenetically determines centromere identity to ensure kinetochore assembly and proper chromosome segregation, but the precise mechanism of its specific localization within centromeric heterochromatin remains obscure. We have discovered that CUL4A-RBX1 COPS8 E3 ligase activity is required for CENP-A ubiquitylation on lysine 124 (K124) and CENP-A centromere localization. A mutation of CENP-A, K124R, reduces interaction with HJURP (a CENP-A-specific histone chaperone) and abrogates localization of CENP-A to the centromere. Addition of monoubiquitin is sufficient to restore CENP-A K124R to centromeres and the interaction with HJURP, indicating that "signaling" ubiquitylation is required for CENP-A loading at centromeres. The CUL4A-RBX1 complex is required for loading newly synthesized CENP-A and maintaining preassembled CENP-A at centromeres. Thus, CENP-A K124R ubiquitylation, mediated by the CUL4A-RBX1-COPS8 complex, is essential for CENP-A deposition at the centromere. PMID- 25727010 TI - Linking of the Patient Rated Elbow Evaluation (PREE) and the American Shoulder and Elbow Surgeons - Elbow questionnaire (pASES-e) to the International Classification of Functioning Disability and Health (ICF) and Hand Core Sets. AB - STUDY DESIGN: Content analysis-ICF linking. INTRODUCTION: The Patient Rated Elbow Evaluation (PREE) and the self-report section of the American Shoulder and Elbow Surgeons society - Elbow form (ASES-e) are the two commonly used elbow pain and disability self-report measures (PROs). The content of these questions have never been analyzed in light of the International Classification of Functioning Disability and Health (ICF) which is the current standard to describe health and health-related states. PURPOSE: The purposes of this study were to analyze the conceptual basis of the PREE and the ASES-e by linking the meaningful concepts in these PROs to the ICF using standardized linking rules and to determine the extent to which the ICF core set for hand conditions cover the content of elbow questionnaires using summary ICF linkage indicators. METHODS: Two raters linked the two PROs to the ICF using the linking rules proposed by Cieza and colleagues. Percentage agreement was calculated between the raters. Summary linkage indicators proposed by MacDermid were used to estimate the extent to which the ICF core set for hand conditions cover the content of the elbow questionnaires. RESULTS: All the items of the PREE (Measure to ICF linkage - 100%) and all but one item of the pASES-e (Measure to ICF linkage - 95%) were linked to the ICF. The satisfaction item on the ASES-e was not-covered by the ICF. Percentage agreement on linking between the raters was 96% and 95% for the PREE and the pASES-e respectively. The unique linkage of the PREE and the pASES-e to the unique codes on the brief and comprehensive core set were lower than absolute linkage to the core set for hand conditions. The PROs represented less than 20% of the comprehensive core set and more than 70% of the brief core set. While for the unique core set disability representation the 2 PROMs represented 100% brief core set unique disability codes and less than 35% of the comprehensive core set unique disability codes. CONCLUSION: The PREE and the ASES-e are aligned with the ICF framework and the core sets for hand conditions. The ICF Core Set devised for hand conditions may also be useful for elbow conditions. LEVEL OF EVIDENCE: 1b. PMID- 25727011 TI - Interleukin-18 enhances breast cancer cell migration via down-regulation of claudin-12 and induction of the p38 MAPK pathway. AB - Interleukin-18 (IL-18) was recently reported to have a pro-tumor effect in various cancers. Increased IL-18 levels in the serum of cancer patients correlated with malignancy, and IL-18 acts a crucial factor for cell migration in gastric cancer and melanoma. Claudins, which are the most important tight junction proteins, are also linked with cancer progression and metastasis. However, the relationship between claudins and IL-18 is not well-understood. Here, we show that the migratory ability of MCF-7 cells was reduced when endogenous IL-18 expression was inhibited with IL-18 siRNA. Moreover, exogenous IL-18 enhanced breast cancer cell migration and suppressed the expression of the tight junction proteins claudin-1, claudin-3, claudin-4, and claudin-12 in MCF-7 cells. Knockdown of claudin-3, claudin-4, and claudin-12, but not claudin-1, increased breast cancer migration with maximal effects observed in claudin-12 siRNA-transfected cells. To investigate whether the mitogen-activated protein kinase (MAPK) signaling pathway is involved in IL-18-induced cell migration and claudin-12 expression, cells were pretreated with SB203580 (an inhibitor of p38 MAPK) or PD98059 (an inhibitor of ERK1/2) prior to the addition of IL-18. Although pretreatment of MCF-7 cells with SB203580 blocked both the enhanced cell migration and the decreased claudin-12 expression, PD98059 only blocked cell migration and did not affect claudin-12 expression. In addition, exogenous IL-18 induced rapid phosphorylation of p38 MAPK. These results suggest that IL-18 is an important factor inducing breast cancer cell migration through down-regulation of claudin-12 and activation of the p38 MAPK pathway. PMID- 25727012 TI - Endoplasmic reticulum stress induces up-regulation of hepatic beta-Klotho expression through ATF4 signaling pathway. AB - Fibroblast growth factor 21 (FGF21) plays critical roles in regulating glucose and lipid metabolism. beta-Klotho is the co-receptor for mediating FGF21 signaling, and the mRNA levels of this receptor are increased in the liver of human subjects with obesity. However, the molecular mechanisms underlying the regulation of beta-klotho expression remain poorly defined. Here, we report that elevation of beta-klotho protein expression in diet-induced obese mice and human patients is associated with increased endoplasmic reticulum (ER) stress. In vivo study indicates that administration of the ER stressor tunicamycin in mice led to increased expression of beta-klotho in the liver. In addition, we show that ER stress is sufficient to potentiate FGF21 signaling in HepG2 cell and ATF4 signaling pathway is essential for mediating the effect of ER stress on beta klotho expression. These findings demonstrate a link of ER stress with up regulation of hepatic beta-klotho expression and the molecular mechanism underlying ER stress-regulated FGF21 signaling. PMID- 25727013 TI - Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling. AB - Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-alpha receptor (IFNAR) was higher in Panc-PAUF cells than in Panc Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN alpha signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. PMID- 25727014 TI - Oct3/4 directly regulates expression of E2F3a in mouse embryonic stem cells. AB - Embryonic stem (ES) cells, derived from the inner cell mass of blastocysts, have a characteristic cell cycle with truncated G1 and G2 phases. Recent findings that suppression of Oct3/4 expression results in a reduced proliferation rate of ES cells suggest the involvement of Oct3/4 in the regulation of ES cell growth, although the underlying molecular mechanism remains unclear. In the present study, we identified E2F3a as a direct target gene of Oct3/4 in ES cells. Oct3/4 directly bound to the promoter region of the E2F3a gene and positively regulated expression of E2F3a in mouse ES cells. Suppression of E2F3a activity by E2F6 overexpression led to the reduced proliferation in ES cells, which was relieved by co-expression of E2F3a. Furthermore, cell growth retardation caused by loss of Oct3/4 was rescued by E2F3a expression. These results suggest that Oct3/4 upregulates E2F3a expression to promote ES cell growth. PMID- 25727015 TI - Inwardly rectifying Kir2.1 currents in human beta-cells control electrical activity: characterisation and mathematical modelling. AB - Pancreatic beta-cells fire action potentials as do cardiac cells and neurons, and electrical activity plays a central role in glucose-stimulated insulin secretion, which is disturbed in diabetes. The inwardly rectifying Kir2.1 potassium channels (KCNJ2 gene) control cardiac electrical activity by stabilising the interspike interval. Loss-of-function abnormalities in cardiac Kir2.1 currents can lead to the long QT syndrome and alterations of cardiac excitability, and patients with some forms of long QT syndrome suffer from over-secretion of insulin, hyperinsulinemia and symptomatic hypoglycemia. The KCNJ2 gene is also expressed in human pancreatic islets, and we show that functional Kir2.1 currents are present in human beta-cells. We characterised the human Kir2.1 beta-cell current, and included it in a recent mathematical model of electrical activity in human beta-cells. Based on our simulations we propose that Kir2.1 currents control the interspike interval, and predict that blocking Kir2.1 channels increases the action potential frequency, which should augment the rate of insulin secretion. Vice versa, the model suggests that hyperactive Kir2.1 channels may lead to reduced insulin secretion. Our findings provide a putative link between increased insulin secretion and the long QT syndrome, and give novel insight into normal and disturbed beta-cell function. PMID- 25727016 TI - MicroRNA-301a modulates doxorubicin resistance in osteosarcoma cells by targeting AMP-activated protein kinase alpha 1. AB - MicroRNAs have been implicated in drug resistance of osteosarcoma (OS). MicroRNA 301a (miR-301a) is up-regulated and functions as an oncogene in various cancers. However, little is known about the role of miR-301a in drug resistance of OS cells. In this study, we found that doxorubicin induced time-dependent expression of miR-301a in OS cells. Meantime, doxorubicin promoted HMGCR expression and inhibited AMPKalpha1 expression, which was further facilitated by miR-301a overexpression. Luciferase reporter assay identified AMPKalpha1 as direct target gene of miR-301a. Notably, miR-301a reduced doxorubicin-induced cell apoptosis whereas anti-miR-301a enhanced apoptosis in OS cells, suggesting that up regulation of miR-301a contributed to chemoresistance of OS cells. Consistently, our data showed that miR-301a and HMGCR were up-regulated in chemotherapy resistant OS compared to those in control OS. Our findings suggested that miR 301a might be a potential biomarker for chemotherapy-resistant OS and a promising therapeutic target for overcoming drug resistance of OS. PMID- 25727017 TI - A hairpin within YAP mRNA 3'UTR functions in regulation at post-transcription level. AB - The central dogma of gene expression is that DNA is transcribed into messenger RNAs, which in turn serve as the template for protein synthesis. Recently, it has been reported that mRNAs display regulatory roles that rely on their ability to compete for microRNA binding, independent of their protein-coding function. However, the regulatory mechanism of mRNAs remains poorly understood. Here, we report that a hairpin within YAP mRNA 3'untranslated region (3'UTR) functions in regulation at post-transcription level through generating endogenous siRNAs (esiRNAs). Bioinformatics analysis for secondary structure showed that YAP mRNA displayed a hairpin structure (termed standard hairpin, S-hairpin) within its 3'UTR. Surprisingly, we observed that the overexpression of S-hairpin derived from YAP 3'UTR (YAP-sh) increased the luciferase reporter activities of transcriptional factor NF-kappaB and AP-1 in 293T cells. Moreover, we identified that a fragment from YAP-sh, an esiRNA, was able to target mRNA 3'UTR of NF2 (a member of Hippo-signaling pathway) and YAP mRNA 3'UTR itself in hepatoma cells. Thus, we conclude that the YAP-sh within YAP mRNA 3'UTR may serve as a novel regulatory element, which functions in regulation at post-transcription level. Our finding provides new insights into the mechanism of mRNAs in regulatory function. PMID- 25727018 TI - Interaction of pituitary hormones and expression of clock genes modulated by bone morphogenetic protein-4 and melatonin. AB - Functional interaction of clock genes and pituitary hormones was investigated by focusing on bone morphogenetic protein (BMP)-4 and melatonin actions in anterior pituitary cells. A significant correlation between the mRNA expression of proopiomelanocortin (POMC) and Per2 was revealed in serial cultures of corticotrope AtT20 cells. Knockdown of Per2 expression by siRNA in AtT20 cells resulted in a significant reduction of POMC mRNA level with or without corticotropin-releasing hormone (CRH) stimulation. Treatments with BMP-4 and melatonin, both of which suppress POMC expression, reduced Per2 mRNA as well as protein levels in AtT20 cells. On the other hand, in lactosomatotrope GH3 cells, an expressional correlation was found between prolactin (PRL) and Clock mRNA levels, which was attenuated in the presence of forskolin treatment. The siRNA mediated knockdown of Clock expression, but not that of Bmal1, significantly reduced PRL mRNA levels in GH3 cells. Interestingly, Clock mRNA and protein levels did not fluctuate with melatonin, BMP-4 or forskolin treatment, although Bmal1 expression was significantly increased by forskolin treatment. Collectively, a significant correlation between the expression of POMC and Per2 and that between PRL and Clock were uncovered in corticotrope and lactosomatotrope cells, respectively. Per2 expression was inhibited by POMC modulators including melatonin and BMP-4, while Clock expression was steadily maintained. Thus, the effects of melatonin and BMP-4 on clock gene expression may imply differential stability of circadian rhythms of adrenocorticotropin (ACTH) and PRL secreted from the anterior pituitary. PMID- 25727019 TI - Structural insights into domain movement and cofactor specificity of glutamate dehydrogenase from Corynebacterium glutamicum. AB - Glutamate dehydrogenase (GDH) is an enzyme involved in the synthesis of amino acids by converting glutamate to alpha-ketoglutarate, and vice versa. To investigate the molecular mechanism of GDH, we determined a crystal structure of the Corynebacterium glutamicum-derived GDH (CgGDH) in complex with its NADP cofactor and alpha-ketoglutarate substrate. CgGDH functions as a hexamer, and each CgGDH monomer comprises 2 separate domains; a Rossmann fold cofactor-binding domain and a substrate-binding domain. The structural comparison between the apo- and cofactor/substrate-binding forms revealed that the CgGDH enzyme undergoes a domain movement during catalysis. In the apo-form, CgGDH exists as an open state, and upon binding of the substrate and cofactor the protein undergoes a conformation change to a closed state. Our structural study also revealed that CgGDH has cofactor specificity for NADP, but not NAD, and this was confirmed by GDH activity measurements. Residues involved in the stabilization of the NADP cofactor and the alpha-ketoglutarate substrate were identified, and their roles in substrate/cofactor binding were confirmed by site-directed mutagenesis experiments. PMID- 25727020 TI - Omega-3 free fatty acids inhibit tamoxifen-induced cell apoptosis. AB - Fish oil, which contains omega-3 fatty acids mainly in the form of triglycerides, has benefits for reducing breast cancer risk, similar to tamoxifen action. However, it remains to be elucidated whether the combination of omega-3 free fatty acid (omega-3FFA) with tamoxifen leads to improved treatment in breast cancer. In this study, we observed that omega-3FFA induces MCF-7 cell apoptosis to suppress cell growth. The treatment of breast cancer cells with omega-3FFA attenuated tamoxifen-induced cell apoptosis. omega-3FFA and tamoxifen significantly increased Erk1/2 and Akt phosphorylation levels in a dose and time dependent manner. Compared to omega-3FFA alone, the combination of tamoxifen with omega-3FFA significantly increased Erk1/2 and Akt phosphorylation levels. Because Erk1/2 and Akt activation has been linked to tamoxifen-related anti-estrogen resistance in breast cancer patients, these results indicate that omega-3FFA may interfere with the effects of tamoxifen in the prevention of breast cancer risk. PMID- 25727021 TI - Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus. AB - Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-kappaB and MAPK signaling pathways because either overexpression of a super-repressor form of IkappaBalpha or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-kappaB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs. PMID- 25727022 TI - Association of depression with coronary artery disease and QTc interval prolongation in women with chest pain: data from the KoRean wOmen'S chest pain rEgistry (KoROSE) study. AB - The presence of depression is reportedly related with cardiovascular diseases, including coronary artery disease (CAD), but little is known concerning the association between depressive symptoms reflecting the cultural constructions of female patients with chest pain as well as coronary artery stenosis, coronary vasospasm, and the corrected QT (QTc) interval. In a multicenter prospective cross-sectional survey of 163 Korean women with chest pain, the presence of depression was evaluated using the Beck Depression Inventory (BDI) and Lee and Rhee Depression (LRD) scales. The differences in the QTc interval and the presence of CAD (defined as >= 50% coronary artery stenosis on coronary angiography) and coronary vasospasm were compared between depressed and non depressed women. Significant CAD was present in 83 of 163 female patients (mean age, 61 years), and coronary vasospasm was present in 11 of 80 patients. The mean BDI and LRD scores were significantly higher in patients with significant CAD (BDI: 13.4 +/- 9.6 vs. 6.9 +/- 5.6, p < 0.001; LRD: 46.9 +/- 21.4 vs. 39.8 +/- 15.2, p = 0.027) and coronary vasospasm (BDI: 12.3 +/- 6.4 vs. 4.6 +/- 2.8; and LRD: 49.8 +/- 12.3 vs. 30.5 +/- 13.9; both p < 0.05). On multivariate analysis, BDI scores were important risk factors for the presence of CAD (odds ratio [OR] = 1.138; 95% confidence interval [CI] = 1.071-1.210; p=0.021) and coronary vasospasm (OR = 2.534; 95% CI = 1.161-2.028; p = 0.003), with similar findings obtained for LRD scores (CAD: OR = 1.034; 95% CI = 1.013-1.056; p = 0.001; coronary vasospasm: OR = 1.125; 95% CI = 1.050-1.206; p = 0.001). The mean QTc interval was also significantly higher in the depressed group than in the non depressed group (440.1 +/- 32.0 ms vs. 408.2 +/- 26.4ms; p < 0.001). The QTc interval displayed significant positive with the BDI (r = 0.595; p < 0.001) and LRD scores (r = 0.467; p< 0.001). This study demonstrated that depression is associated with a prolonged QTc interval, CAD, and coronary vasospasm in female patients with chest pain, suggesting a possible mechanism by which depressive mood may be linked with coronary endothelial dysfunction and atherosclerosis. PMID- 25727023 TI - Reduced cerebral and cardiovascular hemodynamics during sustained affective stimulation in young women with chronic low blood pressure. AB - Although low blood pressure has been associated with lower affect and higher depressive symptoms in the elderly, the presence of possible impairment in emotional reactivity in chronic hypotensive individuals in early adulthood remains largely unexplored. Using a combination of transcranial Doppler sonography, beat-to-beat blood pressure recording and impedance cardiography we assessed central and peripheral hemodynamic changes in 15 undergraduate women with chronic hypotension (Age: 23.9 +/- 2.7 years) and 15 normotensive controls (Age: 23.7 +/- 3.1 years) during sustained exposure to pleasant, unpleasant and neutral pictures. Overall, systolic blood pressure (SBP) increased in normotensives and decreased in hypotensives during picture viewing as compared to baseline. Also, compared to normotensives, in hypotensives mean cerebral blood flow velocity increased to a lesser extent during the viewing of pleasant pictures and the magnitude of this increase was negatively associated with subjective emotional arousal. In addition, in hypotensives screening SBP was positively associated with valence rating of pleasant contents. These findings indicate a close association between chronic low blood pressure and reduced processing of pleasant stimuli in young adulthood. PMID- 25727024 TI - Influence of flow velocity on motor behavior of sea cucumber Apostichopus japonicus. AB - The influence of flow velocity on the motor behavior of the sea cucumber, Apostichopus japonicus was investigated in the laboratory. Cameras were used to record sea cucumber movements and behavior analysis software was used to measure the distance traveled, time spent, upstream or downstream of the start position and the speed of movements. In general, the mean velocity of A. japonicus was below 0.7mms(-1). The maximum velocity recorded for all the sea cucumbers tested was for a large individual (89.25+/-17.11g), at a flow rate of 4.6+/-0.5cms(-1). Medium sized (19.68+/-5.53g) and large individuals moved significantly faster than small individuals (2.65+/-1.24g) at the same flow rate. A. japonicus moved significantly faster when there was a moderate current (4.6+/-0.5cms(-1) and 14.7+/-0.3cms(-1)), compared with the fast flow rate (29.3+/-3.7cms(-1)) and when there was no flow (0cms(-1)). Sea cucumbers did not show positive rheotaxis in general, but did move in a downstream direction at faster current speeds. Large, medium and small sized individuals moved downstream at the fastest current speed tested, 29.3+/-3.7cms(-1). When there was no water flow, sea cucumbers tended to move in an irregular pattern. The movement patterns show that the sea cucumber, A. japonicus can move across the direction of flow, and can move both upstream and downstream along the direction of flow. PMID- 25727025 TI - Association of neopterin as a marker of immune system activation and juvenile rheumatoid arthritis activity. AB - OBJECTIVE: To evaluate neopterin plasma concentrations in patients with active juvenile idiopathic arthritis (JIA) and correlate them with disease activity. METHODS: Sixty patients diagnosed as active JIA, as well as another 60 apparently healthy age- and gender-matched children as controls, were recruited from the Pediatrics Allergy and Immunology Clinic, Ain Shams University. Disease activity was assessed by the Juvenile Arthritis Disease Activity Score 27 (JADAS-27). Laboratory investigations were performed for all patients, including determination of hemoglobin concentration (Hgb), erythrocyte sedimentation rate (ESR), and C-reactive protein. Serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP 1), and neopterin were measured. RESULTS: Significant differences were found between JIA patients and controls with regard to the mean levels of Hgb, ESR, TNF alpha, IL-6, and MCP-1 (p<0.05). A statistically significant higher mean level serum neopterin concentration (p<0.05) was found in JIA patients (20.43+/-8.73 nmol/L) than in controls (6.88+/-2.87 nmol/L) (p<0.05). Positive significant correlations were detected between serum neopterin and ESR, TNF-alpha, IL-6, MCP 1, and JADAS-27 (p<0.05). No correlation was found between serum neopterin and CRP (p>0.05). Multiple linear regression analysis showed that JADAS- 27 and ESR were the main variables associated with serum neopterin in JIA patients (p<0.05). CONCLUSION: The elevation of plasma neopterin concentrations in early JIA patients may indicate stimulation of immune response. Serum neopterin can be used as a sensitive marker for assaying background inflammation and disease activity score in JIA patients. PMID- 25727026 TI - Parental tobacco consumption and child development. AB - OBJECTIVE: To analyze the association between parental tobacco consumption and the prevalence of psychomotor development disorders in children between 6 and 22 months of age. METHOD: One hundred and nine mothers, fathers, and their babies participated in the study. The sociodemographic and clinical conditions were assessed using questionnaires. Tobacco consumption was assessed using the Fagerstrom Test for Nicotine Dependence (FTND). Child development was evaluated using the Scale of Psychomotor Development in Early Childhood. RESULTS: There was a significant negative correlation between the father's morning smoking (FTND) and the child's language development quotient; r=-0.41, p=0.005, r(2)=0.15. The children of mothers without nicotine dependence had a higher mean language development quotient than children of mothers with nicotine dependence; F(1, 107)=5.51, p=0.021, etap(2)=0.05. CONCLUSION: Parental smoking appears to have a detrimental effect on child development. PMID- 25727028 TI - Is His54 a gating residue for the ferritin ferroxidase site? AB - Ferritin is a ubiquitous iron concentrating nanocage protein that functions through the enzymatic oxidation of ferrous iron and the reversible synthesis of a caged ferric-oxo biomineral. Among vertebrate ferritins, the bullfrog M homopolymer ferritin is a frequent model for analyzing the role of specific amino acids in the enzymatic reaction and translocation of iron species within the protein cage. X-ray crystal structures of ferritin in the presence of metal ions have revealed His54 binding to iron(II) and other divalent cations, with its imidazole ring proposed as "gate" that influences iron movement to/from the active site. To investigate its role, His54 was mutated to Ala. The H54A ferritin variant was expressed and its reactivity studied via UV-vis stopped-flow kinetics. The H54A variant exhibited a 20% increase in the initial reaction rate of formation of ferric products with 2 or 4 Fe2+/subunit and higher than 200% with 20 Fe2+/subunit. The possible meaning of the increased efficiency of the ferritin reaction induced by this mutation is proposed taking advantage of the comparative sequence analysis of other ferritins. The data here reported are consistent with a role for His54 as a metal ion trap that maintains the correct levels of access of iron to the active site. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications. PMID- 25727027 TI - Health promoting behaviors in adolescence: validation of the Portuguese version of the Adolescent Lifestyle Profile. AB - OBJECTIVE: Reliable and valid instruments are essential for understanding health promoting behaviors in adolescents. This study analyzed the psychometric properties of the Portuguese version of the Adolescent Lifestyle Profile (ALP). METHODS: A linguistic and cultural translation of the ALP was conducted with 236 adolescents from two different settings: a community (n=141) and a clinical setting (n=95). Internal consistency reliability and confirmatory factor analysis were performed. RESULTS: Results showed an adequate fit to data, yielding a 36 item, seven-factor structure (CMIN/DF=1.667, CFI=0.807, GFI=0.822, RMR=0.051, RMSEA=0.053, PNFI=0.575, PCFI=0.731). The ALP presented a high internal consistency (alpha=0.866), with the subscales presenting moderate reliability values (from 0.492 to 0.747). The highest values were in Interpersonal Relations (3.059+/-0.523) and Positive Life Perspective (2.985+/-0.588). Some gender differences were found. Findings showed that adolescents from the clinic reported an overall healthier lifestyle than those from the community setting (2.598+/ 0.379 vs. 2.504+/-0.346; t=1.976, p=0.049). CONCLUSION: The ALP Portuguese version is a psychometrically reliable, valid, and useful measurement instrument for assessing health-promoting lifestyles in adolescence. The ALP is cross culturally validated and can decisively contribute to a better understanding of adolescent health promotion needs. Additional research is needed to evaluate the instrument's predictive validity, as well as its clinical relevance for practice and research. PMID- 25727029 TI - Rates and product identification for trenbolone acetate metabolite biotransformation under aerobic conditions. AB - Trenbolone acetate metabolites are endocrine-active contaminants discharged into the aquatic environment in runoff from agricultural fields, rangelands, and concentrated animal feeding operations. To investigate the environmental fate of these compounds and their biotransformation mechanisms, the authors used inocula from a variety of different water sources and dosed biologically active microcosms with approximately 1400 ng/L of trenbolone acetate metabolites, including 17beta-trenbolone, trendione, and 17alpha-trenbolone. To investigate aerobic biotransformation rates and interconversions between known trenbolone acetate metabolites, gas chromatography-tandem mass spectrometry was used to measure concentrations and assess product distributions as a function of time. High-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to characterize novel transformation products and potential transformation pathways. Kinetic analysis yields observed half-lives of approximately 0.9 d, 1.3 d, and 2.2 d for 17beta-trenbolone, trendione, and 17alpha-trenbolone, respectively, at 20 degrees C, although colder conditions increased half-lives to 8.5 d and biphasic transformation was observed. Relative to reported faster attenuation rates in soils, trenbolone acetate metabolites are likely more persistent in aqueous systems. Product distributions indicate an enzymatic preference for biotransformation between trendione and 17beta-trenbolone. The LC MS/MS characterization indicates dehydrogenation products as the major detectable products and demonstrates that major structural elements responsible for bioactivity in steroids are likely retained during biotransformation. PMID- 25727030 TI - Do maximum waiting times guarantees change clinical priorities for elective treatment? Evidence from Scotland. AB - The level and distribution of patient waiting times for elective treatment are a major concern in publicly funded health care systems. Strict targets, which have specified maximum waiting times, have been introduced in the NHS over the last decade and have been criticised for distorting existing clinical priorities in scheduling hospital treatment. We demonstrate the usefulness of conditional density estimation (CDE) in the evaluation of the reform using data for Scotland for 2002 and 2007. We develop a modified goodness of fit test to discriminate between models with different numbers of bins. We document a change in prioritisation between different patient groups with longer waiting patients benefiting at the expense of those who previously waited less. Our results contribute to understanding the response of publicly funded health systems to enforced targets for maximum waiting times. PMID- 25727031 TI - Optimal health insurance for multiple goods and time periods. AB - We examine the efficiency-based arguments for second-best optimal health insurance with multiple treatment goods and multiple time periods. Correlated shocks across health care goods and over time interact with complementarity and substitutability to affect optimal cost sharing. Health care goods that are substitutes or have positively correlated demand shocks should have lower optimal patient cost sharing. Positive serial correlations of demand shocks and uncompensated losses that are positively correlated with covered health services also reduce optimal cost sharing. Our results rationalize covering pharmaceuticals and outpatient spending more fully than is implied by static, one good, or one period models. PMID- 25727032 TI - BSA as additive: A simple strategy for practical applications of PNA in bioanalysis. AB - Application of peptide nucleic acid (PNA) in bioanalysis has been limited due to its nonspecific adsorption onto hydrophobic surface in spite of favorable properties such as higher chemical/biological stability, specificity and binding affinity towards target nucleic acids compared to natural nucleic acid probes. Herein, we employed BSA in PNA application to enhance the stability of PNA in hydrophobic containers and improve the sensing performance of the DNA sensor based on graphene oxide (GO) and PNA. Addition of 0.01% BSA in a PNA solution effectively prevented the adsorption of PNA on hydrophobic surface and increased the portion of the effective PNA strands for target binding without interfering duplex formation with a complementary target sequence. In the GO based biosensor using PNA, BSA interrupted the unfavorable adsorption of PNA/DNA duplex on GO surface, while allowing the adsorption of ssPNA, resulting in improvement of the performance of the DNA sensor system by reducing the detection limit by 90-folds. PMID- 25727033 TI - Highly sensitive colorimetric sensor for Hg(2+) detection based on cationic polymer/DNA interaction. AB - The detection of ultralow concentrations of mercury is a currently significant challenge. Here, a novel strategy is proposed: the colorimetric detection of Hg(2+) based on the aggregation of gold nanoparticles (AuNPs) driven by a cationic polymer. In this three-component system, DNA combines electrostatically with phthalic diglycol diacrylate (PDDA) in a solution of AuNPs. In the presence of Hg(2+), thymine (T)-Hg(2+)-T induced hairpin turns are formed in the DNA strands, which then do not interact with PDDA, enabling the freed PDDA to subsequently facilitate aggregation of the AuNPs. Thus, according to the change in color from wine-red to blue-purple upon AuNPs aggregation, a colorimetric sensor is established to detect Hg(2+). Under optimal conditions, the color change is clearly seen with the naked eye. A linear range of 0.25-500nM was obtained by absorption spectroscopy with a detection limit of approximately 0.15nM. Additionally, the proposed method shows high selectivity toward Hg(2+) in the presence of other heavy metal ions. Real sample analysis was evaluated with the use of lake water and the results suggest good potential for practical application. PMID- 25727034 TI - Highly sensitive cell imaging "Off-On" fluorescent probe for mitochondria and ATP. AB - A smart Off-On molecular scaffold/fluorescent probe 1 has been designed and synthesized. The probe has shown considerable photostability, cell permeability, organelle specificity and selectivity for ATP. The multicolor live cell imaging experiments in HeLa cells showed high selectivity of probe 1 for mitochondria with fluorescence "turn-on" response. As a proof of concept and promising prospects for application in biological sciences probe 1 has been utilized to detect ATP sensitively in a partial aqueous medium and intracellularly in HeLa cells. The favorable interaction between triphosphate unit of ATP and piperazine N atoms of probe 1 is attributed to synergistic effects of H-bonding and electrostatic interactions that encouraged the CH-pi and pi->pi stacking between anthracene and purine rings. Consequently, the observed enhanced "turn-on" emission and a naked-eye sensitive blue-green color in the medium is attributable to arrest in photoinduced electron transfer (PET) process. PMID- 25727035 TI - Oblique lip-alveolar banding in patients with cleft lip and palate. AB - We report an oblique lip-alveolar band, a rare banding of soft tissue that involves the lip and alveolus, which we have found in five patients with cleft lip and palate (0.2%), compared with an incidence of the Simonartz lip-lip band of 5.7%). To our knowledge this has not been reported previously. In two patients the bands affected the cleft lip and alveolus bilaterally, with or without the palatal cleft, and in three the bands were unilateral cleft lip and alveolus with or without the palatal cleft. PMID- 25727036 TI - The founding of Zagreb's Institute for the Culture of Health: an important step toward a new medical paradigm. PMID- 25727037 TI - Ginkgolide B increases hydrogen sulfide and protects against endothelial dysfunction in diabetic rats. AB - AIM: To evaluate the effect of ginkgolide B treatment on vascular endothelial function in diabetic rats. METHODS: The study included four groups with 15 male Sprague-Dawley rats: control group; control group treated with ginkgolide B; diabetic group; and diabetic treated with ginkgolide B. The activity of superoxide dismutase (SOD), malondialdehyde content, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, and glutathione peroxidase 1 (GPX1) protein expression were determined in aortic tissues. Vasoconstriction to phenylephrine (PHE) and vasorelaxation to acetylcholine (Ach) and sodium nitroprusside (SNP) were assessed in aortic rings. Nitric oxide (NO) and hydrogen sulfide (H2S) were measured, as well as cystathionine gamma lyase (CSE) and cystathionine beta synthetase (CBS) protein expression, and endothelial nitric oxide synthase (eNOS) activity. RESULTS: Diabetes significantly impaired PHE induced vasoconstriction and Ach-induced vasorelaxation (P<0.001), reduced NO bioavailability and H2S production (P<0.001), SOD activity, and GPX1 protein expression (P<0.001), and increased malondialdehyde content and NADPH oxidase subunits, and CSE and CBS protein expression (P<0.001). Ginkgolide B treatment improved PHE vasoconstriction and Ach vasorelaxation (P<0.001), restored SOD (P=0.005) and eNOS (P<0.001) activities, H2S production (P=0.044) and decreased malondialdehyde content (P=0.014). Vasorelaxation to SNP was not significantly different in control and diabetic rats with or without ginkgolide B treatment. Besides, ginkgolide B increased GPX1 protein expression and reduced NADPH oxidase subunits, CBS and CSE protein expression. CONCLUSION: Ginkgolide B alleviates endothelial dysfunction by reducing oxidative stress and elevating NO bioavailability and H2S production in diabetic rats. PMID- 25727038 TI - Comparison of four international cardiovascular disease prediction models and the prevalence of eligibility for lipid lowering therapy in HIV infected patients on antiretroviral therapy. AB - AIM: To compare four cardiovascular disease (CVD) risk models and to assess the prevalence of eligibility for lipid lowering therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European AIDS Clinical Society Guidelines (EACS), and European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS) guidelines for CVD prevention in HIV infected patients on antiretroviral therapy. METHODS: We performed a cross-sectional analysis of 254 consecutive HIV infected patients aged 40 to 79 years who received antiretroviral therapy for at least 12 months. The patients were examined at the HIV-treatment centers in Belgrade and Zagreb in the period February-April 2011. We compared the following four CVD risk models: the Framingham risk score (FRS), European Systematic Coronary Risk Evaluation Score (SCORE), the Data Collection on Adverse Effects of Anti-HIV Drugs study (DAD), and the Pooled Cohort Atherosclerotic CVD risk (ASCVD) equations. RESULTS: The prevalence of current smoking was 42.9%, hypertension 31.5%, and hypercholesterolemia (>6.2 mmol/L) 35.4%; 33.1% persons were overweight, 11.8% were obese, and 30.3% had metabolic syndrome. A high 5-year DAD CVD risk score (>5%) had substantial agreement with the elevated (>=7.5%) 10-year ASCVD risk equation score (kappa=0.63). 21.3% persons were eligible for statin therapy according to EACS (95% confidence intervals [CI], 16.3% to 27.4%), 25.6% according to ESC/EAS (95% CI, 20.2% to 31.9%), and 37.9% according to ACC/AHA guidelines (95% CI, 31.6 to 44.6%). CONCLUSION: In our sample, agreement between the high DAD CVD risk score and other CVD high risk scores was not very good. The ACC/AHA guidelines would recommend statins more often than ESC/EAS and EACS guidelines. Current recommendations on treatment of dyslipidemia should be applied with caution in the HIV infected population. PMID- 25727039 TI - Long-term angiographic outcome of stent-assisted coiling compared to non-assisted coiling of intracranial saccular aneurysms. AB - AIM: To compare angiographic result at long-term follow-up, and rates of progressive occlusion, recurrence, and retreatment of stent-assisted coiled (SAC) and non-assisted coiled (NAC) intracranial saccular aneurysms. METHODS: Retrospective evaluation of department records identified 260 patients with 283 saccular intracranial aneurysms who had long-term angiographic follow-up (more than 12 months) and were successfully treated with SAC (89 aneurysms) or NAC (194 aneurysms) at the University Hospital Center Zagreb from June 2005 to July 2012. Initial and control angiographic results in both groups were graded using Roy/Raymond scale, converted to descriptive terms, and the differences between them were evaluated for statistical significance. A multivariate analysis was performed to identify factors related to progression of aneurysm occlusion and recurrence at follow-up, and those related to aneurysm retreatment. RESULTS: There were more progressively occluded aneurysms in SAC group (38 of 89 aneurysms, 42.7%) than in NAC group (46 of 194, 23.7%) (P=0.002), but there were no significant differences in the rates of recanalization, regrowth, and stable result. Multivariate logistic regression identified the use of stent as the most important factor associated with progressive occlusion (P=0.015, odds ratio 2.22, 95% confidence interval 1.17-4.21), and large aneurysm size and posterior circulation location as most predictive of aneurysm recurrence and retreatment. CONCLUSION: The use of stent is associated with delayed occlusion of initially incompletely coiled aneurysms during follow-up, but does not reduce the rate of recurrence and retreatment compared to coiling alone. Long-term angiographic follow-up is needed for both SAC and NAC aneurysms. PMID- 25727041 TI - Contribution of Slovenian community pharmacist counseling to patients' knowledge about their prescription medicines: a cross-sectional study. AB - AIM: To assess patients' knowledge about prescription medicines they are taking and their view on how much community pharmacist counseling contributed to their knowledge. METHODS: An observational study was designed to obtain information about patients' knowledge, their view on pharmacist counseling, and physicians'/pharmacists' provision of information. This study used a specifically designed questionnaire, which served as an interview guide. 400 patients picking up a prescription medicine were structurally interviewed upon leaving one of the 20 randomly chosen Slovenian pharmacies. The interviews took place in November and December 2013. RESULTS: Patients were familiar with general information about the medicines and their application (93%-100% of patients). Knowledge about considerations (16% of patients) and adverse effects (20% of patients) was limited. Factors associated with patient knowledge were physicians'/pharmacists' adequate provision of information (beta=0.259), patient's age (beta=- 0.149), patient's education (beta=0.100), and prescription type (beta=-0.104). Patients' responses were mostly consistent with the Summaries of Product Characteristics (72%-96% of responses). However, 42% of responses to the question about taking medicine with meals were incorrect. Pharmacists routinely informed the patients about medication purpose, dose, application rate, and timing of medication (in 72%, 89%, 89%, and 77% of cases, respectively). Other information was rarely offered. Patients with new prescriptions received significantly more counseling (pharmacist counseling score 5.9, 5.2, and 4.7 of maximum 10 for new, regular, and refill prescriptions, respectively, P=0.001) and obtained adequate labeling (69%, 26%, and 17% of patients for new, regular and refill prescriptions, respectively, P<0.001) than patients with regular or refill prescriptions. CONCLUSION: Patients were familiar with basic information about administration of their prescription medicines, but lacked knowledge about medication safety. This could be attributed to pharmacist counseling, which primarily focused on medicine use instructions. PMID- 25727040 TI - Practical aspects of genetic identification of hallucinogenic and other poisonous mushrooms for clinical and forensic purposes. AB - AIM: To assess the usefulness of a DNA-based method for identifying mushroom species for application in forensic laboratory practice. METHODS: Two hundred twenty-one samples of clinical forensic material (dried mushrooms, food remains, stomach contents, feces, etc) were analyzed. ITS2 region of nuclear ribosomal DNA (nrDNA) was sequenced and the sequen-ces were compared with reference sequences collected from the National Center for Biotechnology Information gene bank (GenBank). Sporological identification of mushrooms was also performed for 57 samples of clinical material. RESULTS: Of 221 samples, positive sequencing results were obtained for 152 (69%). The highest percentage of positive results was obtained for samples of dried mushrooms (96%) and food remains (91%). Comparison with GenBank sequences enabled identification of all samples at least at the genus level. Most samples (90%) were identified at the level of species or a group of closely related species. Sporological and molecular identification were consistent at the level of species or genus for 30% of analyzed samples. CONCLUSION: Molecular analysis identified a larger number of species than sporological method. It proved to be suitable for analysis of evidential material (dried hallucinogenic mushrooms) in forensic genetic laboratories as well as to complement classical methods in the analysis of clinical material. PMID- 25727042 TI - Reliability and validity of the Croatian version of Consultation and Relational Empathy (CARE) Measure in primary care setting. AB - AIM: To translate the Consultation and Relational Empathy (CARE) Measure into Croatian and validate the Croatian version of the questionnaire. METHODS: A cross sectional study was conducted in July 2011 in 8 general practices (GP) in Croatia. Following two stages of translation, back-translation, and pilot testing, the Croatian version of the CARE was tested on 568 consecutive patients. RESULTS: Face validity was high, the number of missing values was low (9%), and the internal consistency (Cronbach's alpha) was 0.77. A principal component analysis of 10 CARE Measure items extracted two components with eigenvalues >1. These two components explained 43.6% of the total instrument variance. CONCLUSION: The Croatian version of the CARE Measure had acceptable reliability and face validity, but its intended component structure was not reproduced and further research is needed to understand its dimensionality. PMID- 25727043 TI - Peroneal tendoscopy--more than just a solitary procedure: case-series. AB - This study presents a series of 13 patients who underwent peroneal tendoscopy as a solitary or accessory procedure at our department in 2013. Patients were clinically diagnosed with peroneal tendons disorders and underwent an additional radiological assessment. Peroneal tendoscopy was carried out in a standard manner before any other arthroscopic or open procedure. Postoperative management depended on the type of pathology. We found 3 peroneus brevis tendon partial tears, 4 cases of a low-lying peroneus brevis muscle belly, 5 cases of tenosynovitis, and 1 case of an intrasheath peroneal tendon subluxation. In 5 patients peroneal tendoscopy was performed as a solitary procedure and in 8 patients as an accessory procedure--together with anterior or posterior ankle arthroscopy, combined posterior and anterior ankle arthroscopy, or open surgery. Both as a solitary and accessory procedure, peroneal tendoscopy was safe and successful, ie, all patients were without any symptoms at one-year follow-up. Our series of patients showed that peroneal tendoscopy can be used both as an independent procedure as well as a valuable accessory procedure. PMID- 25727044 TI - Novel patched 1 mutations in patients with nevoid basal cell carcinoma syndrome- case report. AB - Nevoid basal cell carcinoma syndrome (Gorlin syndrome) is a rare autosomal dominant disorder characterized by numerous basal cell carcinomas, keratocystic odontogenic tumors of the jaws, and diverse developmental defects. This disorder is associated with mutations in tumor suppressor gene Patched 1 (PTCH1). We present two patients with Gorlin syndrome, one sporadic and one familial. Clinical examination, radiological and CT imaging, and mutation screening of PTCH1 gene were performed. Family members, as well as eleven healthy controls were included in the study. Both patients fulfilled the specific criteria for diagnosis of Gorlin syndrome. Molecular analysis of the first patient showed a novel frameshift mutation in exon 6 of PTCH1gene (c.903delT). Additionally, a somatic frameshift mutation in exon 21 (c.3524delT) along with germline mutation in exon 6 was detected in tumor-derived tissue sample of this patient. Analysis of the second patient, as well as two affected family members, revealed a novel nonsense germline mutation in exon 8 (c.1148 C>A). PMID- 25727045 TI - A neuroscience perspective on incidental imaging findings and diagnostic and therapeutic silos. PMID- 25727046 TI - Myc mouse and anti-ageing therapy. AB - Reduction in the expression and activity of a well-known proto-oncogene, Myc, has a beneficial effect on mouse health and survival to old age, in part independently of cancer impact, a recent study reveals. Is this new anti-ageing intervention pointing a way towards new treatments for age-related diseases? PMID- 25727047 TI - Expression, purification and characterization of the receptor-binding domain of botulinum neurotoxin serotype B as a vaccine candidate. AB - The receptor-binding domain of botulinum neurotoxins (the HC fragment) is a promising vaccine candidate. Among the HC fragments of the seven BoNT serotypes, the expression of HC/B in Escherichia coli is considered especially challenging due to its accumulation as a non-soluble protein aggregate. In this study, the effects of different parameters on the expression of soluble HC/B were evaluated using a screening assay that included growing the bacterium at a small scale, a chemical cell lysis step, and a specific ELISA. The highest soluble HC/B expression levels were obtained when the bacterium E. coli BL21(DE3)+pET-9a-HC/B was grown in terrific broth media at 18 degrees C without induction. Under these conditions, the yield was an order of magnitude higher than previously reported. Standard purification of the protein using a nickel column resulted in a low purity of HC/B. However, the addition of an acidic wash step prior to protein elution released a major protein contaminant and significantly increased the purity level. Mass spectrometry analysis identified the contaminant as ArnA, an E. coli protein that often contaminates recombinant His-tagged protein preparations. The purified HC/B was highly immunogenic, protecting mice from a 10(6) LD50 challenge after a single vaccination and generating a neutralizing titer of 50IU/ml after three immunizations. Moreover, the functionality of the protein was preserved, as it inhibited BoNT/B intoxication in vivo, presumably due to blockade of the neurotoxin protein receptor synaptotagmin. PMID- 25727048 TI - Overproduction of recombinant human transforming growth factor beta 3 in Chinese hamster ovary cells. AB - Transforming growth factor beta 3 (TGFbeta3) is an important cytokine, functioning in cell proliferation and differentiation, and has been considered to have therapeutic potential for treating various diseases and for scar reduction in adult wound healing. In the current study, a Chinese hamster ovary (CHO) cell line overexpressing recombinant human TGFbeta3 (rhTGFbeta3) was established. Through a 15-day fed-batch culture process in a 7.5-l bioreactor (5-l working volume) using chemically defined medium, the established cells could produce over 133mg/l of rhTGFbeta3 protein. The rhTGFbeta3 was purified to homogeneity from the culture supernatant using a two-step chromatographic procedure, resulting in a recovery rate of approximately 65%, with protein purity greater than 97%. The N terminal amino acid sequences of the purified rhTGFbeta3 were confirmed by N terminal sequencing analysis. The purified rhTGFbeta3 was further demonstrated to be functionally active by measuring the inhibition of growth of HT-2 cells, revealing a half-maximal effective concentration of 42.11pg/ml and specific activity of 1.84*10(7)U/mg. PMID- 25727049 TI - Kinetics effects and modeling of mRNA turnover. AB - Broader comprehension of gene expression regulatory mechanisms can be gained from a global analysis of how transcription and degradation are coordinated to orchestrate complex cell responses. The role of messenger RNA (mRNA) turnover modulation in gene expression levels has become increasingly recognized. From such perspective, in this review we briefly illustrate how a simple but effective mathematical model of mRNA turnover and some experimental findings, may together shed light on the molecular mechanisms underpinning the major role of mRNA decay rates in shaping the kinetics of gene activation and repression. PMID- 25727050 TI - Cooperative genetic changes in pediatric B-cell precursor acute lymphoblastic leukemia with deletions or mutations of IKZF1. AB - In contrast to IKZF1 deletions (DeltaIKZF1), IKZF1 sequence mutations (mutIKZF1) have been reported to be rare in B-cell precursor acute lymphoblastic leukemia and their clinical implications are unknown. We performed targeted deep sequencing of all exons of IKZF1 in 140 pediatric cases, eight (5.7%) of which harbored a mutIKZF1. The probabilities of relapse (pRel) and event-free survival (pEFS) did not differ between cases with or without mutIKZF1, whereas pEFS was decreased and pRel increased in DeltaIKZF1-positive case. Coexisting microdeletions, mutations (FLT3, JAK2, SH2B3, and SPRED1), and rearrangements (ABL1, CRLF2, JAK2, and PDGFRB) in 35 DeltaIKZF1 and/or mutIKZF1-positive cases were ascertained using fluorescence in situ hybridization, single nucleotide polymorphism array, Sanger, and targeted deep sequencing analyses. The overall frequencies of copy number alterations did not differ between cases with our without DeltaIKZF1/mutIKZF1. Deletions of HIST1, SH2B3, and the pseudoautosomal region (PAR1), associated with deregulation of CRLF2, were more common in DeltaIKZF1-positive cases, whereas PAR1 deletions and JAK2 mutations were overrepresented in the combined DeltaIKZF1/mutIKZF1 group. There was no significant impact on pRel of the deletions in DeltaIKZF1-positive cases or of JAK2 mutations in cases with DeltaIKZF1/mutIKZF1. In contrast, the pRel was higher (P = 0.005) in DeltaIKZF1/mutIKZF1-positive cases with PAR1 deletions. PMID- 25727051 TI - Depression and pain: an appraisal of cost effectiveness and cost utility of antidepressants. AB - BACKGROUND: Although depression and chronic pain frequently co-occur, there is a lack of clarity in the literature regarding the cost-effectiveness and cost utility of antidepressants in the presence of these two conditions. From the perspective of healthcare provider, the current study aims to compare the cost effectiveness and cost-utility of antidepressants in a national cohort of depressed patients with and without comorbid pain conditions. METHODS: Adult patients prescribed with antidepressants for depression were identified from the National Health Insurance Research Database in Taiwan (n=96,501). By using remission as effectiveness measure and quality-adjusted life years (QALYs) as utility measure, the cost-effectiveness and cost-utility were compared across selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), as well as by the presence of comorbid painful physical symptoms (PPS). RESULTS: SSRIs dominated SNRIs in both the cost-effectiveness and cost-utility regardless of comorbid PPS. In comparison with TCAs, SSRIs were likely to be the cost-effective option for patients without PPS. In patients with PPS, the cost-utility advantage for SSRIs over TCAs varied with threshold willingness-to-pay levels. Comorbid PPS may be considered an effect modifier of the cost-utility comparisons between SSRIs and TCAs. CONCLUSIONS: For depressed patients without PPS, SSRIs are likely to be cost-effective in improving remission rates and QALYs compared to TCAs and SNRIs. However, to improve cost-utility in those with comorbid PPS, people need to choose between SSRIs and TCAs according to threshold willingness-to-pay levels. Future research is warranted to clarify the impacts of different pain conditions on the economic evaluations of pharmacological treatments in patients with depression. PMID- 25727053 TI - Enhanced tolerance and accumulation of heavy metal ions by engineered Escherichia coli expressing Pyrus calleryana phytochelatin synthase. AB - Contamination by heavy metals is a major environmental problem worldwide and microbial bioremediation is an efficient method for removing this type of pollution. The plant enzymephytochelatin synthase (PCS, also known as glutathione g-glutamylcysteinyltransferase, EC2.3.2.15) involved in the synthesis of phytochelatins (PCs), which are metal-binding cysteine-rich peptides, has a major role in the detoxification of heavy metals in plants. Expression of the PcPCS1 gene from the bean pear (Pyrus calleryana Dcne.) was induced after cadmium and copper treatments. However, functional analysis of this gene in vivo has not been reported. And it is or not suitable for bioremediation also needs to be assessed. In this study, we found Escherichia coli with over-expressed PcPCS1 had enhanced tolerance to cadmium, copper, sodium, and mercury. E. colicells transformed with pPcPCS1 was found to survive in solid M9 medium containing 2.0 mM Cd(2+), 4.0 mM Cu(2+). 4.5% (w/v) Na+, or 200 MU MHg(2+). Moreover, the growth curve showed 1.5 mM Cd(2+), 2.5 mM Cu(2+), 3.5% (w/v) Nap, and 100 MU MHg(2+) had no effect on the growth of the E. coli cells transformed with pPcPCS1. Also, we found the contents of PCs and the accumulation of cadmium,copper, sodium, and mercury ions were enhanced in the recombinant E. coli strain Rosetta(TM) (DE3).These results suggested the PcPCS1 gene might be a candidate for heavy metal bioremediation via recombinant bacteria. PMID- 25727054 TI - Identification of functional residues essential for dehalogenation by the non stereospecific alpha-haloalkanoic acid dehalogenase from Rhizobium sp. RC1. AB - The non-stereospecific alpha-haloalkanoic acid dehalogenase DehE from Rhizobium sp. RC1 catalyzes the removal of the halide from alpha-haloalkanoic acid D,L stereoisomers and, by doing so, converts them into hydroxyalkanoic acid L,D stereoisomers, respectively. DehE has been extensively studied to determine its potential to act as a bioremediation agent, but its structure/function relationship has not been characterized. For this study, we explored the functional relevance of several putative active-site amino acids by site-specific mutagenesis. Ten active-site residues were mutated individually, and the dehalogenase activity of each of the 10 resulting mutants in soluble cell lysates against D- and L-2-chloropropionic acid was assessed. Interestingly, the mutants W34->A,F37->A, and S188->A had diminished activity, suggesting that these residues are functionally relevant. Notably, the D189->N mutant had no activity, which strongly implies that it is a catalytically important residue. Given our data, we propose a dehalogenation mechanism for DehE, which is the same as that suggested for other non-stereospecific alpha-haloalkanoic acid dehalogenases. To the best of our knowledge, this is the first report detailing a functional aspect for DehE, and our results could help pave the way for the bioengineering of haloalkanoic acid dehalogenases with improved catalytic properties. PMID- 25727055 TI - Interpersonal Subtypes and Therapy Response in Patients Treated for Posttraumatic Stress Disorder. AB - Interpersonal traits may influence psychotherapy success. One way of conceptualizing such traits is the interpersonal circumplex model. In this study, we analyse interpersonal circumplex data, assessed with the Inventory of Interpersonal Problems (Horowitz, Straubeta, & Kordy, 1994) from a randomized study with 138 patients suffering from posttraumatic stress disorder after trauma in adulthood. The study compared cognitive processing therapy and dialogical exposure therapy, a Gestalt-based intervention. We divided the interpersonally heterogeneous sample according to the quadrants of the interpersonal circumplex. The division into quadrants yielded subgroups that did not differ in their general psychological distress, but the cold-submissive quadrant tended to exhibit higher posttraumatic stress disorder symptom severity and interpersonal distress than the other three. There was also a trend for patients in different quadrants to be affected differently by the treatments. Correlation analyses supported these results: in cognitive processing therapy, more dominant patients had more successful therapies, while in dialogical exposure therapy, success was not correlated with interpersonal style. Results indicate that especially patients with cold interpersonal styles profited differentially from the two treatments offered. Dividing samples according to the interpersonal circumplex quadrants seems promising. KEY PRACTITIONER MESSAGE: Interpersonal traits may contribute to psychotherapy outcome. Dividing the sample according to the quadrants of the interpersonal circumplex, as opposed to cluster analysis, yielded promising results. Patients higher in dominance fared better with cognitive processing therapy, while interpersonal style had no correlations with therapy success in dialogical exposure therapy. PMID- 25727056 TI - Analysis of therapeutic proteins and peptides using multiangle light scattering coupled to ultra high performance liquid chromatography. AB - Analysis of the physical properties of biotherapeutic proteins is crucial throughout all the stages of their lifecycle. Herein, we used size-exclusion ultra high performance liquid chromatography coupled to multiangle light scattering and refractive index detection systems to determine the molar mass, mass-average molar mass, molar-mass dispersity and hydrodynamic radius of two monoclonal antibodies (rituximab and trastuzumab), a fusion protein (etanercept), and a synthetic copolymer (glatiramer acetate) employed as models. A customized instrument configuration was set to diminish band-broadening effects and enhance sensitivity throughout detectors. The customized configuration showed a performance improvement with respect to the high-performance liquid chromatography standard configuration, as observed by a 3 h column conditioning and a higher resolution analysis in 20 min. Analysis of the two monoclonal antibodies showed averaged values of 148.0 kDa for mass-average molar mass and 5.4 nm for hydrodynamic radius, whereas for etanercept these values were 124.2 kDa and 6.9 nm, respectively. Molar-mass dispersity was 1.000 on average for these proteins. Regarding glatiramer acetate, a molar mass range from 3 to 45 kDa and a molar-mass dispersity of 1.304 were consistent with its intrinsic peptide diversity, and its mass-average molar mass was 10.4 kDa. Overall, this method demonstrated an accurate determination of molar mass, overcoming the difficulties of size-exclusion chromatography. PMID- 25727057 TI - Visual assessment of CPR quality during pediatric cardiac arrest: does point of view matter? AB - AIM: In many clinical settings, providers rely on visual assessment when delivering feedback on CPR quality. Little is known about the accuracy of visual assessment of CPR quality. We aimed to determine how accurate pediatric providers are in their visual assessment of CPR quality and to identify the optimal position relative to the patient for accurate CPR assessment. METHODS: We videotaped high-quality CPR (based on 2010 American Heart Association guidelines) and 3 variations of poor quality CPR in a simulated resuscitation, filmed from the foot, head and the side of the manikin. Participants watched 12 videos and completed a questionnaire to assess CPR quality. RESULTS: One hundred and twenty five participants were recruited. The overall accuracy of visual assessment of CPR quality was 65.6%. Accuracy was better from the side (70.8%) and foot (68.8%) of the bed when compared to the head of the bed (57.2%; p<0.001). The side was the best position for assessing depth (p<0.001). Rate assessment was equivalent between positions (p=0.58). The side and foot of the bed were superior to the head when assessing chest recoil (p<0.001). Factors associated with increased accuracy in visual assessment of CPR quality included recent CPR course completion (p=0.034) and involvement in more cardiac arrests as a team member (p=0.003). CONCLUSION: Healthcare providers struggle to accurately assess the quality of CPR using visual assessment. If visual assessment is being used, providers should stand at the side of the bed. PMID- 25727058 TI - Fluid and cell behaviors along a 3D printed alginate/gelatin/fibrin channel. AB - Three-dimensional (3D) cell manipulation is available with the integration of microfluidic technology and rapid prototyping techniques. High-Fidelity (Hi-Fi) constructs hold enormous therapeutic potential for organ manufacturing and regenerative medicine. In the present paper we introduced a quasi-three dimensional (Q3D) model with parallel biocompatible alginate/gelatin/fibrin hurdles. The behaviors of fluids and cells along the microfluidic channels with various widths were studied. Cells inside the newly designed microfluidic channels attached and grew well. Morphological changes of adipose-derived stem cells (ADSCs) in both two-dimensional (2D) and 3D milieu were found on the printed constructs. Endothelialization occurred with the co-cultures of ADSCs and hepatocytes. This study provides insights into the interactions among fluids, cells and biomaterials, the behaviors of fluids and cells along the microfluidic channels, and the applications of Q3D techniques. PMID- 25727059 TI - SNIPER peptide-mediated degradation of endogenous proteins. AB - Rapid and reversible methods for altering the function of endogenous proteins are not only indispensable tools for probing complex biological systems, but may potentially drive the development of new therapeutics for the treatment of human diseases. Genetic approaches have provided insights into protein function, but are limited in speed, reversibility and spatiotemporal control. To overcome these limitations, we have developed a peptide-based method (SNIPER: Selective Native Protein Eradication) to degrade any given endogenous protein at the post translational level by harnessing chaperone-mediated autophagy, a major intracellular protein degradation pathway. This unit presents a typical strategy in the design and validation of a protein-knockdown peptide. PMID- 25727060 TI - Universal non-antibody detection of protein phosphorylation using pIMAGO. AB - This article describes methods for a new, non-antibody phosphorylation detection reagent, termed pIMAGO (phospho-imaging). This novel reagent takes advantage not only of the unique properties of the soluble nanoparticles, but also of the multiple functionalities of the molecule, allowing for highly selective, sensitive, and quantitative assessment of protein phosphorylation without using radioactive isotopes or phospho-specific antibodies. The methods allow for multiplexed detection of phosphorylation and total protein amount simultaneously. The straightforward and routine detection and quantitation of general phosphorylation on any site of any protein can be performed in western blot and ELISA formats. PMID- 25727061 TI - Diffraction-unlimited fluorescence microscopy of living biological samples using pcSOFI. AB - The complex microscopic nature of many live biological processes is often obscured by the diffraction limit of light, requiring diffraction-unlimited fluorescence microscopy to resolve them. Because of the vast range of different processes that can be studied, sub-diffraction imaging should work efficiently under many different conditions. Photochromic stochastic optical fluctuation imaging (pcSOFI) is a recent addition to the field of diffraction-unlimited fluorescence microscopy. This robust and versatile method employs a statistical analysis of random fluctuations in the emission of single labels, in this case reversibly switchable fluorescent proteins (RSFPs), to retrieve super-resolution information. Added to the resolution enhancement, pcSOFI also offers contrast enhancement and background reduction in a practical and convenient way. Here, we describe the necessary steps to obtain diffraction-unlimited images, including multicolor and three-dimensional imaging, and highlight the advantages of pcSOFI together with the circumstances under which pcSOFI can be favorably applied. PMID- 25727062 TI - Preparation and separation of DNA-wrapped carbon nanotubes. AB - Purification of single-chirality single-wall carbon nanotubes (SWCNTs) from their synthetic mixture is a prerequisite for many applications. DNA-controlled carbon nanotube (CNT) purification has evolved over a decade along with other separation techniques utilizing different types of dispersing agents such as surfactants and polymers. The size of single-stranded DNA (ssDNA) libraries affords practically unlimited ways of coating SWCNTs. Recent developments in separating surfactant dispersed SWCNTs by polymer aqueous two-phase (ATP) extraction has enabled rapid and efficient SWCNT separation on a larger volume scale. Applying the ATP separation method to DNA-SWCNT hybrids opens a new route for effective sorting of nanotubes into each and every single-chirality species. Here, we report protocols for purifying as many as 15 single-chirality nanotube species from a synthetic mixture based on the separation of DNA-SWCNTs by the aqueous two-phase (ATP) method. PMID- 25727063 TI - Techno-functional characterization of salad dressing emulsions supplemented with pea, lentil and chickpea flours. AB - BACKGROUND: Salad dressings supplemented with pulse flours are novel products. A three-factor face-centered central composite design (CCD) was used to determine the effect of pulse flour concentration (3.5%, 7%, 10.5% w/w), egg yolk concentration (3%, 5%, 7% w/w) and oil concentration (20%, 35%, 50% w/w) on the rheological and color characteristics of salad dressings supplemented with pulse flours. RESULTS: The consistency coefficient m, plateau modulus G(N)(0), recoverable strain Q(t) and color values were all affected by the concentrations of pulse flours used. Scanning electron microscopy showed that dressings with lower oil and egg yolk contents had a less densely packed network compared with dressings with higher oil and egg yolk contents. Sensory results were most promising for salad dressings supplemented with the whole green lentil, yellow pea with low flour content, and chickpea with high oil content. CONCLUSION: This study should be useful for designing novel types of salad dressings to meet market requirements as well as helping to increase pulse consumption. PMID- 25727064 TI - Determination of key flavonoid aglycones by means of nano-LC for the analysis of dietary supplements and food matrices. AB - A method for the analysis of flavonoids (myricetin, quercetin, naringenin, hesperitin, and kaempferol), with interesting bioactivity, has been developed and validated utilizing nano-LC technique. In order to find optimal conditions, capillary columns (75 MUm id * 10 cm) packed with different types of stationary phases, Kinetex(r) C18 core-shell (2.6 MUm particle size), Hydride-based RP-C18 (sub-2 MUm particle size), and LiChrospher(r) 100 RP-18 endcapped (5 MUm particle size) were evaluated. The method was validated using Hydride-based RP-C18 stationary phase, with sub-2 MUm particle size. A good chromatographic performance, expressed in terms of repeatability (RSD, in the range 1.63-4.68% for peak area), column-to-column reproducibility (RSD not higher than 8.01% for peak area), good linearity and sensitivity was obtained. In particular limit of detection values between 0.07 and 0.31 MUg/mL were achieved with on column focusing technique. The method was applied to the determination of studied flavonoids in dietary supplements as well as in food matrices. The amount of quercetin found in the first analyzed dietary supplement, was in agreement to the labeled content. In the other samples, where the content of flavonoids was not labeled, most of the studied flavonoids were determined in amounts somewhere comparable to those reported in literature. PMID- 25727065 TI - Recruitment of striatonigral disinhibitory and nigrotectal inhibitory GABAergic pathways during the organization of defensive behavior by mice in a dangerous environment with the venomous snake Bothrops alternatus (Reptilia, Viperidae). AB - The neuropsychopharmacological basis of fear- or panic-related behavior has been the focus of several studies. Some mesencephalic tectum (MT) structures, such as the superior colliculus (SC) and dorsal periaqueductal gray matter (dPAG), are considered to be responsible for the control of defensive responses evoked during threatening situations. Furthermore, the pars reticulata of the substantia nigra (SNpr) sends inputs to the SC that can work as a sensory channel to MT neurons fundamental for the elaboration of defensive responses. The purpose of the present study was to investigate the role of striato-nigral GABAergic inputs in the activity of nigro-tectal outputs during the elaboration of defensive behavior using a GABA(A) receptor selective blockade in the MT of mice confronted pre treated with Bothrops alternatus. Mice with injections of physiological saline into the SNpr and treated with a GABA(A) receptor selective antagonist in the MT displayed an increase in panic-related behavior, expressed by an increase in the duration of freezing, frequency of nonoriented escape and frequency of total escape responses during the confrontation with the snake. However, intra-SNpr injections of cobalt chloride followed by MT injections of bicuculline caused a significant decrease in the duration of freezing and total escape responses. In addition, intra-SNpr injections of lidocaine followed by MT injections of bicuculline caused an increase in panic-related behavior. The results highlight the involvement of SNpr and MT structures in the organization of defensive behaviors and suggest an inhibitory control of striatonigral-nigrotectal pathways during the elaboration of fear- and panic-related behavior. PMID- 25727066 TI - Introducing ethics to chemistry students in a "Research Experiences for Undergraduates" (REU) program. AB - A three-day ethics seminar introduced ethics to undergraduate environmental chemistry students in the Research Experiences for Undergraduates (REU) program. The seminar helped students become sensitive to and understand the ethical and values dimensions of their work as researchers. It utilized a variety of resources to supplement lectures and class discussion on a variety of issues. Students learned about the relevance of ethics to research, skills in moral reasoning, and the array of ethical issues facing various aspects of scientific research. PMID- 25727068 TI - Focal cartilage defect compromises fluid-pressure dependent load support in the knee joint. AB - A focal cartilage defect involves tissue loss or rupture. Altered mechanics in the affected joint may play an essential role in the onset and progression of osteoarthritis. The objective of the present study was to determine the compromised load support in the human knee joint during defect progression from the cartilage surface to the cartilage-bone interface. Ten normal and defect cases were simulated with a previously tested 3D finite element model of the knee. The focal defects were considered in both condyles within high load-bearing regions. Fluid pressurization, anisotropic fibril-reinforcement, and depth dependent mechanical properties were considered for the articular cartilages and menisci. The results showed that a small cartilage defect could cause 25% reduction in the load support of the knee joint due to a reduced capacity of fluid pressurization in the defect cartilage. A partial-thickness defect could cause a fluid pressure decrease or increase in the remaining underlying cartilage depending on the defect depth. A cartilage defect also increased the shear strain at the cartilage-bone interface, which was more significant with a full-thickness defect. The effect of cartilage defect on the fluid pressurization also depended on the defect sites and contact conditions. In conclusion, a focal cartilage defect causes a fluid-pressure dependent load reallocation and a compromised load support in the joint, which depend on the defect depth, site, and contact condition. PMID- 25727067 TI - Novel bayes factors that capture expert uncertainty in prior density specification in genetic association studies. AB - Bayes factors (BFs) are becoming increasingly important tools in genetic association studies, partly because they provide a natural framework for including prior information. The Wakefield BF (WBF) approximation is easy to calculate and assumes a normal prior on the log odds ratio (logOR) with a mean of zero. However, the prior variance (W) must be specified. Because of the potentially high sensitivity of the WBF to the choice of W, we propose several new BF approximations with logOR ~N(0,W), but allow W to take a probability distribution rather than a fixed value. We provide several prior distributions for W which lead to BFs that can be calculated easily in freely available software packages. These priors allow a wide range of densities for W and provide considerable flexibility. We examine some properties of the priors and BFs and show how to determine the most appropriate prior based on elicited quantiles of the prior odds ratio (OR). We show by simulation that our novel BFs have superior true-positive rates at low false-positive rates compared to those from both P value and WBF analyses across a range of sample sizes and ORs. We give an example of utilizing our BFs to fine-map the CASP8 region using genotype data on approximately 46,000 breast cancer case and 43,000 healthy control samples from the Collaborative Oncological Gene-environment Study (COGS) Consortium, and compare the single-nucleotide polymorphism ranks to those obtained using WBFs and P-values from univariate logistic regression. PMID- 25727070 TI - Triboelectric-pyroelectric-piezoelectric hybrid cell for high-efficiency energy harvesting and self-powered sensing. AB - A triboelectric-pyroelectric-piezoelectric hybrid cell, consisting of a triboelectric nanogenerator and a pyroelectric-piezoelectric nanogenerator, is developed for highly efficient mechanical energy harvesting through multiple mechanisms. The excellent performance of the hybrid cell enhances the energy harvesting efficiency significantly (by 26.2% at 1 kOmega load resistance), and enables self-powered sensing, which will lead to a variety of advanced applications. PMID- 25727069 TI - CD28/CTLA-4/B7 costimulatory pathway blockade affects regulatory T-cell function in autoimmunity. AB - Naive T cells require B7/CD28 costimulation in order to be fully activated. Attempts to block this pathway have been effective in preventing unwanted immune reactions. As B7 blockade might also affect Treg cells and interfere with negative signaling through membrane CTLA-4 on effector T (Teff) cells, its immune modulatory effects are potentially more complex. Here, we used the mouse model of multiple sclerosis (MS), EAE, to study the effect of B7 blockade. An effective therapy for MS patients has to interfere with ongoing inflammation, and therefore we injected CTLA-4Ig at day 7 and 9 after immunization, when myelin-reactive T cells have been primed and start migrating toward the CNS. Surprisingly, B7 blockade exacerbated disease signs and resulted in more severe CNS inflammation and demyelination, and was associated with an enhanced production of the inflammatory cytokines IL-17 and IFN-gamma. Importantly, CTLA-4Ig treatment resulted in a transient reduction of Ki67 and CTLA-4 expression and function of peripheral Treg cells. Taken together, B7 blockade at a particular stage of the autoimmune response can result in the suppression of Treg cells, leading to a more severe disease. PMID- 25727071 TI - Fe-Au and Fe-Ag composites as candidates for biodegradable stent materials. AB - In this study, Fe-Ag and Fe-Au composites were fabricated by powder metallurgy using spark plasma sintering. Their microstructures, mechanical properties, and biocorrosion behavior were investigated by using optical microscopy, X-ray diffraction, environment scanning electronic microscopy, compressive test, electrochemical measurements, and immersion tests. Microstructure characterization indicated that the as-sintered iron-based materials obtained much finer grains than that of as-cast pure iron. Phase analysis showed that the Fe-Ag composites were composed of alpha-Fe and pure Ag phases, and Fe-Au composites consisted of alpha-Fe and Au phases. Compressive test showed that the improved mechanical strengths were obtained in as-sintered iron-based materials, among which the Fe-5 wt %Ag exhibited the best mechanical properties. The electrochemical and immersion tests revealed that the addition of Ag and Au could increase the corrosion rate of the iron matrix and change the corrosion mode into more uniform one. Based on the results of cytotoxicity evaluation, it was found that all the experimental material extracts performed no significant toxicity on the L-929 cells and EA. hy-926 cells, whereas a considerable inhibition on the proliferation of vascular smooth muscle cells was observed. The hemocompatibility tests showed that the hemolysis of all the experimental materials was within the range of 5%, which is the criteria value of biomaterials with good hemocomaptibility. The amount of platelet adhered on the surface of as-sintered iron-based materials was lower than that of as-cast pure iron, and the morphology of platelets kept smoothly spherical on the surface of all the experimental materials. PMID- 25727072 TI - Toward the measurement of multiple fluorescence lifetimes in flow cytometry: maximizing multi-harmonic content from cells and microspheres. AB - Flow cytometry is a powerful means for in vitro cellular analyses where multi fluorescence and multi-angle light scattering can indicate unique biochemical or morphological features of single cells. Yet, to date, flow cytometry systems have lacked the ability to capture complex fluorescence dynamics due to the transient nature of flowing cells. In this contribution we introduce a simple approach for measuring multiple fluorescence lifetimes from a single cytometric event. We leverage square wave modulation, Fourier analysis, and high frequency digitization and show the ability to resolve more than one fluorescence lifetime from fluorescently-labelled cells and microspheres. Illustration of a flow cytometer capable of capturing multiple fluorescence lifetime measurements; creating potential for multi-parametric, time-resolved signals to be captured for every color channel. PMID- 25727074 TI - Copper/palladium synergistic catalysis for the syn- and anti-selective carboboration of alkenes. AB - A method for the diastereoselective carboboration of 1,2-disubstituted styrenes with aryl/vinyl bromides and (Bpin)2 is reported. High diastereoselectivities and yields are observed for the formation of either diastereomer of the product from a single alkene isomer. These reactions provide access to a diverse range of structures from simple starting materials. PMID- 25727075 TI - Sebaceous induction in dermatofibroma: a common feature of dermatofibromas on the shoulder. AB - BACKGROUND: Dermatofibroma (DF) has multiple histopathological variants and overlying acanthosis, hyperkeratosis and hyperpigmentation are often present. We have frequently observed sebaceous induction in DFs on the shoulder and wanted to assess if this is a site-specific finding. METHODS: We prospectively collected 100 DFs and assessed for sebaceous induction, the histopathologic pattern of the DF and any associated-epidermal changes. We retrospectively searched for DFs with sebaceous induction to assess the anatomic site of the biopsy. RESULTS: In the 100 prospectively collected DFs, 49% occurred on the lower extremities, 39% on the upper extremities, 10% on the trunk and 2% on the head. Sebaceous induction was present in 16 DFs, 81% of which occurred on or near the shoulder. The most common variant was fibrocollagenous DF (64%), including in DFs with sebaceous induction. The retrospective search for DFs with sebaceous induction found 19 cases in which 95% occurred on the shoulder area. Sclerotic pattern DFs were most common in this retrospective cohort (47%), and seborrheic keratosis-like hyperplasia occurred in 100% of these cases. CONCLUSION: DFs occurring on the shoulder have a high incidence of sebaceous induction with seborrheic keratosis like epidermal hyperplasia and a fibrocollagenous or sclerotic pattern. PMID- 25727073 TI - Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection. AB - The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling. PMID- 25727076 TI - The Effectiveness of a Customized Titanium Mesh for Ridge Preservation with Immediate Implantation in Dogs. AB - PURPOSE: The purpose of this study was to determine the effect of a newly designed titanium mesh (TM) for preserving the buccal bone around an immediately placed implant following tooth extraction in dogs. MATERIALS AND METHODS: Immediate implant placements were performed bilaterally in the mesial socket of the fourth premolar in five dogs. In one site, the TM was affixed to the fixture using its own stabilization components (TM group), and the contralateral site was left untreated (control group). All surgical sites were intended to be submerged with primary flap closure. Histologic and histomorphometric analyses were performed 16 weeks postoperatively. RESULTS: All implants were histologically osseointegrated, and buccal bone resorption was evident in both groups with the high rate of TM exposure (4/5). The most coronal level of bone-implant contact and the bone crest were not statistically different between the TM and the control group. A dense connective tissue layer consistently predominated under the TM, where mineralized tissue was not observed, and the vascularity and cellularity were minimal. CONCLUSIONS: It can be conjectured that preservation of buccal plate by using the TM in immediate implantation was not predictable due to vulnerability to wound dehiscence and substantial pseudoperiosteum formation beneath the TM. PMID- 25727077 TI - Second-derivative synchronous spectrofluorimetric determination of nebivolol hydrochloride and amlodipine besylate in their combined dosage form. AB - A rapid, simple, accurate and highly sensitive spectrofluorimetric method was developed for the simultaneous analysis of nebivolol hydrochloride (NEB) and amlodipine besylate (AML). The method was based on measuring the synchronous fluorescence intensity of the drugs at Deltalambda = 40 nm in methanol. Various experimental parameters affecting the synchronous fluorescence of the studied drugs were carefully studied and optimized. The calibration plots were rectilinear over concentration ranges of 0.05-1.5 ug/mL and 0.5-10 ug/mL for NEB and AML with limits of detection (LOD) of 0.010 and 0.051 ug/mL and limits of quantitation (LOQ) of 0.031 and 0.156, respectively. The peak amplitudes ((2) D) of the second derivative synchronous fluorimetry (SDSF) were estimated at 282 nm for NEB and at 393 nm for AML. Good linearity was obtained over the concentration ranges. The proposed method was successfully applied to the determination of the studied compounds in laboratory-prepared mixtures, commercial single and laboratory-prepared tablets. The results were in good agreement with those obtained using the comparison method. The mean percent recoveries were found to be 100.12 +/- 0.77 and 99.91 +/- 0.77 for NEB and AML, respectively. PMID- 25727078 TI - A concise flow synthesis of efavirenz. AB - Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45%. This streamlined proof-of principle synthesis relies on the efficient copper-catalyzed formation of an aryl isocyanate and a subsequent intramolecular cyclization to install the carbamate core of Efavirenz in one step. The three-step method represents the shortest synthesis of this life-saving drug to date. PMID- 25727079 TI - Relationship between serum low-density lipoprotein cholesterol and in-hospital mortality following acute myocardial infarction (the lipid paradox). AB - Lipoprotein levels are currently recognized as independent risk factors for long term cardiovascular events after acute myocardial infarction (AMI). During the acute-phase reaction after AMI, previous studies have reported trends of decreased low-density lipoprotein cholesterol (LDL-C), increased triglycerides, and variable high-density lipoprotein cholesterol (HDL-C) levels. However, the association between LDL-C and HDL-C levels and in-hospital mortality has not been well established following AMI. The relationship between lipid levels and in hospital all-cause mortality in 115,492 patients hospitalized for AMI (July 2002 to December 2006), registered in the National Registry of Myocardial Infarction (NRMI) 4b-5, was evaluated using multivariable-adjusted logistic regression models. Mean LDL-C was 104 +/- 38, HDL-C was 41 +/- 14, and triglycerides 143 +/- 83 mg/dl. Compared with the lowest quartile of LDL-C (<77 mg/dl), the risk of in hospital mortality in the second to fourth quartiles was decreased (adjusted odds ratio 0.79, 0.80, and 0.85, respectively). For HDL-C, only those in the lowest quartile (<31 mg/dl) had higher risk of in-hospital mortality (odds ratio 1.20) compared with the highest quartile (>=47 mg/dl). Results from NRMI 4b-5 suggest a lipid paradox, with lower LDL-C levels associated with increased risk of in hospital mortality, contrary to findings outside the acute setting. Consistent with previous analyses, lowest HDL-C levels were associated with increased in hospital mortality. In conclusion, further explorations of the relationship between very low levels of LDL-C, myocardial necrosis, and subsequent adverse cardiovascular events are warranted. PMID- 25727080 TI - A home-based walking program improves erectile dysfunction in men with an acute myocardial infarction. AB - The purpose of this study was to evaluate the influence of a home-based walking program on erectile function and the relation between functional capacity and erectile dysfunction (ED) in patients with recent myocardial infarctions. Patients with acute myocardial infarctions deemed to be at low cardiovascular risk were randomized into 2 groups: (1) a home-based walking group (n = 41), instructed to participate in a progressive outdoor walking program, and (2) a control group (n = 45), receiving usual care. Functional capacity was determined by the 6-minute walk test and evaluation of sexual function by the International Index of Erectile Function questionnaire; the 2 tests were performed at hospital discharge and 30 days later. In the overall cohort, 84% of patients reported previous ED at hospital discharge. After 30 days, ED had increased by 9% in the control group in relation to baseline (p = 0.08). However, the home-based walking group had a significant decrease of 71% in reported ED (p <0.0001). The 6-minute walk distance was statistically significant higher in the home-based walking group compared with the control group (p = 0.01). There was a significant negative correlation between 6-minute walk distance and ED 30 days after hospital discharge (r = -0.71, p <0.01). In conclusion, an unsupervised home-based progressive walking program led to significant improvements in functional capacity in men at low cardiovascular risk after recent acute myocardial infarctions. In addition, this intervention demonstrated a link between functional capacity and exercise training and erectile function improvement. PMID- 25727081 TI - Coronary computed tomography angiography alone versus confirmatory functional testing for guiding treatment strategy for patients with intermediate coronary artery stenosis. AB - Intermediate coronary artery stenosis (>=50% and <90%) on coronary computed tomography angiography (CTA) is usually considered as a significant lesion. However, anatomical diagnosis is not well correlated with the functional significance of myocardial ischemia. We investigated whether functional testing in addition to coronary CTA improves outcomes of patients with intermediate stenosis, compared with the 1-step CTA-alone-based strategy. From 2006 to 2011, we consecutively enrolled 335 patients with chest pain with intermediate stenosis detected by an initially performed coronary CTA. Of these, 159 patients followed the 1-step strategy, whereas 176 followed the 2-step strategy with confirmatory functional tests. One-year follow-up data were obtained for all patients. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, and repeated or delayed revascularization (major adverse cardiac event) within a year. Baseline clinical parameters were comparable between patients of the 2 different strategies. The rate of invasive catheterization or percutaneous intervention was 75.5% in the 1-step group and 35.2% in the 2-step group (p <0.001). Consequently, more patients in the 2-step group were medically treated without unnecessary revascularization compared with patients in the 1 step group (71.0% vs 40.9%, p <0.001). Only 2.5% of the patients who received medical treatment in the 2-step group finally received delayed revascularization, whereas 14% in the 1-step group did. Overall, the primary end point occurred in 11.3% in the 1-step group and 4.0% in the 2-step group (p = 0.011). In conclusion, confirmatory functional testing reduces invasive catheterization and coronary intervention and improves clinical outcomes in patients with intermediate stenosis on coronary CTA. PMID- 25727082 TI - Meta-analysis of the association between whole grain intake and coronary heart disease risk. AB - Epidemiologic studies evaluating the association of whole-grain intake with risk for coronary heart disease (CHD) have produced inconsistent results. The aim of this meta-analysis was to summarize the evidence from observed studies regarding the association between whole-grain intake and risk for CHD. Pertinent studies were identified by searching the Web of Knowledge and PubMed up to July 2014. A random-effects model was used to combine the results. Publication bias was estimated using Begg's funnel plot and Egger's regression asymmetry test. Ultimately, fourteen reports of 18 studies (15 cohort studies and 3 case-control studies) involving 14,427 patients with CHD and 400,492 participants were used in this meta-analysis. Pooled results suggested that highest whole-grain intake amount compared with the lowest amount was significantly associated with reduced risk for CHD (summary relative risk 0.787, 95% confidence interval 0.743 to 0.833), with no between-study heterogeneity observed (I(2) = 0%, p = 0.537). The association was significant in cohort studies but not in case-control studies. Inverse associations were also found in the United States and Europe. No publication bias was found. In conclusion, this meta-analysis indicates that higher whole-grain intake has a protective effect against CHD. PMID- 25727083 TI - Risk stratification and stroke prevention therapy care gaps in Canadian atrial fibrillation patients (from the Co-ordinated National Network to Engage Physicians in the Care and Treatment of Patients With Atrial Fibrillation chart audit). AB - The objectives of this national chart audit (January to June 2013) of 6,346 patients with atrial fibrillation (AF; >=18 years without a significant heart valve disorder) from 647 primary care physicians were to (1) describe the frequency of stroke and bleed risk assessments in patients with nonvalvular AF by primary care physicians, including the accuracy of these assessments relative to established predictive indexes; (2) outline contemporary methods of anticoagulation used; and (3) report the time in the therapeutic range among patients prescribed warfarin. An annual stroke risk assessment was not undertaken in 15% and estimated without a formal risk tool in 33%; agreement with CHADS2 score estimation was seen in 87% of patients. Major bleeding risk assessment was not undertaken in 25% and estimated without a formal risk tool in 47%; agreement with HAS-BLED score estimation was observed in 64% with physician overestimation in 26% of patients. Antithrombotic therapy included warfarin (58%), dabigatran (22%), rivaroxaban (14%), and apixaban (<1%). Among warfarin-treated patients, the median international normalized ratio was 2.4 and time in therapeutic range (TTR) was 73%; however, the TTR was <50% in 845 (25%), 50% to 69% in 674 (20%), and >=70% in 1,827 (55%) patients. In conclusion, we describe a contemporary real world elderly population with AF at important risk for stroke. There is apparent overestimation of bleeding risk in many patients. Warfarin was the dominant stroke prevention treatment; however, the suggested TTR target was achieved in only 55% of these patients. PMID- 25727084 TI - Relation of biventricular strain and dyssynchrony in repaired tetralogy of fallot measured by cardiac magnetic resonance to death and sustained ventricular tachycardia. AB - Ventricular strain and dyssynchrony can be measured in patients with repaired tetralogy of Fallot (TOF), but their effect on clinical outcomes is poorly understood. The purpose of this study was to investigate if ventricular strain and dyssynchrony measured by cardiac magnetic resonance feature tracking are associated with death and sustained ventricular tachycardia. Patients with TOF who died or had ventricular tachycardia (TOF case, n = 16) were compared with age matched patients with TOF with no adverse outcome (TOF control, n = 32). For each patient, midventricular short-axis and 4-chamber cine steady-state free precession images were analyzed using cardiac magnetic resonance feature-tracking software. Peak left ventricular (LV) and right ventricular (RV) global circumferential and longitudinal strain and indexes of dyssynchrony were compared between groups. Compared with the TOF control group, median strain values were significantly lower for the TOF case group for both the LV (circumferential: 17% vs 23%, p = 0.003; longitudinal: 13% vs 18%, p <0.001) and the RV (circumferential: 10% vs 16%, p = 0.001; longitudinal: 11% vs 18%, p <0.001). In a multivariate model including strain and dyssynchrony parameters, RV and LV longitudinal strain were strongly associated with the adverse outcome (p = 0.003 and 0.04, respectively; area under the curve = 0.92). No differences in ventricular dyssynchrony were identified between the groups. In conclusion, patients with TOF in this cohort who experienced adverse outcomes had lower values of all strain parameters than those who did not, and impaired longitudinal strain of both ventricles was strongly associated with adverse clinical outcomes. PMID- 25727085 TI - Palliative care in the cardiac intensive care unit. AB - Patients admitted to today's cardiac intensive care units (CICUs) have increasingly complex medical conditions; consequently, palliative care is becoming an integral component of their care. Although there is a robust body of literature emanating from other intensive care unit settings, there has been less discussion about the role of palliative care in the CICU. This study examined all admissions to the Mount Sinai Hospital CICU from January 1 through December 31, 2012. Of the 1,368 patients admitted, there were 117 CICU patient deaths. End-of life discussions were carried out in 85 patients (72.6%) who died during that hospital admission; the primary CICU team led these discussions and helped with decision making in >1/2 of them. For the 85 patients who had goals of care (GOC) discussions, there was a higher rate of redirected GOC toward comfort care or no escalation of care (38.8% vs 3.1%, p <0.001) and withdrawal of life-sustaining treatments, such as mechanical ventilation and vasopressors (23.5% vs 6.3%, p = 0.02) compared with patients for whom no GOC discussions were held. Among patients who had GOC discussions, there was no statistically significant difference for patients who had their mechanical circulatory support, defibrillator, or pacing therapies turned off compared with patients who were not involved in GOC discussions. With the exception of discontinuation of mechanical circulatory support which took place for 6 of the 7 patients in the CICU, end-of life interventions were split evenly between the palliative care unit and the CICU. There was no difference in CICU length of stay or days to mortality from the time of CICU admission between the 2 groups. In conclusion, our study demonstrates the effect of palliative care and end-of-life decision making in the CICU. As such, we advocate for increased palliative care education and training among clinicians who are involved in cardiac critical care. PMID- 25727086 TI - Clinical and morphologic features of acute, subacute and chronic cor pulmonale (pulmonary heart disease). AB - Described are certain clinical and morphologic features of one patient with acute, another with subacute, and one with chronic cor pulmonale. All 3 had evidence of severe pulmonary hypertension. The patient with acute cor pulmonale 4 days after coronary bypass for unstable angina pectoris suddenly developed severe breathlessness with cyanosis and had fatal cardiac arrest and necropsy disclosed massive pulmonary embolism. The patient with subacute cor pulmonale had severe right-sided heart failure for 5 weeks and necropsy disclosed microscopic-sized neoplastic pulmonary emboli from a gastric carcinoma without parenchymal pulmonary metastases. The patient with chronic cor pulmonale had evidence of right-sided heart failure for years, the result of primary or idiopathic pulmonary hypertension almost certainly present from birth because the pattern of elastic fibers in the pulmonary trunk was that seen in newborns where the pressure in the pulmonary trunk and ascending aorta are similar. The patient with chronic cor pulmonale had plexiform pulmonary lesions indicative of irreversible pulmonary hypertension. Neither the acute nor the subacute patient had chronic pulmonary vascular changes. All 3 patients had dilated right ventricular cavities and non-dilated left ventricular cavities and only the patient with chronic cor pulmonale had right ventricular hypertrophy. PMID- 25727087 TI - Excellent electrochemical performance of NiV3O8/natural graphite anodes via novel in situ electrochemical reconstruction. AB - A novel in situ electrochemical reconstruction occurs in NiV3O8/natural graphite electrodes, which results in excellent electrochemical performance. After repeated rate performance from 0.16 to 3.1 A g(-1) over 320 cycles, the specific capacity can restore well and shows no obvious attenuation in the subsequent 360 cycles. PMID- 25727088 TI - N-terminal processing of affinity-tagged recombinant proteins purified by IMAC procedures. AB - The ability of a new class of metal binding tags to facilitate the purification of recombinant proteins, exemplified by the tagged glutathione S-transferase and human growth hormone, from Escherichia coli fermentation broths and lysates has been further investigated. These histidine-containing tags exhibit high affinity for borderline metal ions chelated to the immobilised ligand, 1,4,7 triazacyclononane (tacn). The use of this tag-tacn immobilised metal ion affinity chromatography (IMAC) system engenders high selectivity with regard to host cell protein removal and permits facile tag removal from the E. coli-expressed recombinant protein. In particular, these tags were specifically designed to enable their efficient removal by the dipeptidyl aminopeptidase 1 (DAP-1), thus capturing the advantages of high substrate specificity and rates of cleavage. MALDI-TOF MS analysis of the cleaved products from the DAP-1 digestion of the recombinant N-terminally tagged proteins confirmed the complete removal of the tag within 4-12 h under mild experimental conditions. Overall, this study demonstrates that the use of tags specifically designed to target tacn-based IMAC resins offers a comprehensive and flexible approach for the purification of E. coli-expressed recombinant proteins, where complete removal of the tag is an essential prerequisite for subsequent application of the purified native proteins in studies aimed at delineating the molecular and cellular basis of specific biological processes. PMID- 25727089 TI - The Scylla and Charybdis of glucose control in childhood type 1 diabetes? AB - Glucose control in childhood type 1 diabetes is difficult and often characterized by significant glucose variability, including periods of prolonged hyperglycemia and intermittent episodes of hypoglycemia that can be severe. The brain of the developing child is thought to be more susceptible to metabolic insults because of its relatively high demand for glucose to fuel neuronal growth and differentiation. In this review we consider the impact of glucose variability, especially when associated with recurrent hypoglycemia, on long-term cognitive function in childhood type 1 diabetes. At present, this indicates a subtle effect of type 1 diabetes per se on a number of cognitive modalities. Within the population of children with type 1 diabetes, a history of severe hypoglycemia also appears to have an additional negative effect on cognitive function. However, interpretation of the literature is difficult in that the human studies draw largely from cross-sectional observational epidemiology while more basic work has used models that do not translate well into human disease. Moreover, it is likely to be many years before we will be able to clearly document the effects of recurrent hypoglycemia or chronic hyperglycemia on cognitive function. In the meantime, it seems appropriate to advocate that minimizing glucose variability when achieving glycemic targets should be the therapeutic goal of clinicians involved in the management of childhood type 1 diabetes. PMID- 25727090 TI - Subcutaneous Panniculitis-Like T-Cell Lymphoma in Children: A Review of the Literature. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a type of skin lymphoma. Pleomorphic T-cells infiltrate the subcutaneous tissue and mimic lobular panniculitis. We report a case occurring in a 12-year-old Chinese boy who presented with multiple indolent erythematous subcutaneous nodules on both extremities without systemic symptoms. He had a protracted course of multiple erythematous subcutaneous nodules for 1 year and underwent biopsy of lesional skin for histology and T-cell receptor (TCR) gene analysis. Histopathology showed infiltration of medium to large atypical pleomorphic cells involving the subcutis with characteristic rimming of fat spaces. TCR gene rearrangement shows monoclonal rearrangements of the TCR beta and gamma chains. Immunophenotypic studies showed that CD3, CD4, and CD8 were strongly and diffusely positive in lesional cells and that CD56 was focally positive. In contrast, these cells were negative for CD20, CD30, and CD68. The combined morphology, characteristic histologic features, and positive T-CR gene rearrangement supported a diagnosis of SPTCL. He is being treated with combination chemotherapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone. PMID- 25727092 TI - Two thiadiazole compounds promote rice defence against Xanthomonas oryzae pv. oryzae by suppressing the bacterium's production of extracellular polysaccharides. AB - Thiazole, isothiazole, thiadiazole, and their derivatives are used to control various human, animal and plant diseases. In addition to having direct anti microbial and anti-fungal properties, these compounds are thought to induce host defences, but the mechanism of defence induction remains poorly understood. This article reports that the thiadiazoles of zinc thiazole and bismerthiazol induce H2 O2 accumulation, up-regulation of defence-related genes, callose deposition and hypersensitive response-like cell death in rice leaves infected with Xanthomonas oryaze pv. oryzae (Xoo) strain ZJ173, but not in non-infected leaves. These defence responses in Xoo-infected leaves were suppressed by the exogenous application of catalase, which reduces H2 O2 accumulation. The application of extracellular polysaccharides (EPSs) extracted from strain ZJ173 significantly compromised rice defence against ZJ173 with or without thiadiazole treatment. The EPS-deficient Xoo mutant ?gumH triggered a stronger defence than its parent strain ZJ173. The thiadiazole treatments reduced EPS production by strain ZJ173, but not by the thiadiazole-resistant strain 2-1-1, which is thiadiazole resistant in vivo, but not in vitro; moreover, enhanced defence was not detected in thiadiazole-treated rice inoculated with 2-1-1. Based on these data, we infer that zinc thiazole and bismerthiazol promote rice defence against Xoo by inhibiting the production of bacterial EPS. PMID- 25727091 TI - Minimally invasive versus the conventional open surgical approach of a radical cholecystectomy for gallbladder cancer: a retrospective comparative study. AB - BACKGROUND: Laparoscopic surgery has traditionally been contraindicated for the management of gall bladder cancer (GBC). This study was undertaken to determine the safety and feasibility of a laparoscopic radical cholecystectomy (LRC) for GBC and compare it with an open radical cholecystectomy (ORC). METHODS: Retrospective analysis of primary GBC patients (with limited liver infiltration) and incidental GBC (IGBC) patients (detected after a laparoscopic cholecystectomy) who underwent LRC between June 2011 and October 2013. Patients who fulfilled the study criteria and underwent ORC during the same period formed the control group. RESULTS: During the study period, 147 patients with GBC underwent a radical cholecystectomy. Of these, 24 patients (primary GBC- 20, IGBC - 4) who underwent a LRC formed the study group (Group A). Of the remaining 123 patients who underwent ORC, 46 matched patients formed the control group (Group B). The median operating time was higher in Group A (270 versus 240 mins, P = 0.021) and the median blood loss (ml) was lower (200 versus 275 ml, P = 0.034). The post-operative morbidity and mortality were similar (P = 1.0). The pathological stage of the tumour in Group A was T1b (n = 1), T2 (n = 11) and T3 (n = 8), respectively. The median lymph node yield was 10 (4-31) and was comparable between the two groups (P = 0.642). During a median follow-up of 18 (6 34) months, 1 patient in Group A and 3 in Group B developed recurrence. No patient developed a recurrence at a port site. CONCLUSION: LRC is safe and feasible in selected patients with GBC, and the results were comparable to ORC in this retrospective comparison. PMID- 25727093 TI - Anti Mullerian hormone levels before and after uterine artery embolization: A preliminary report. AB - OBJECTIVE: To determine the effects of uterine artery embolization on Anti Mullerian hormone levels for women under 40 years of age. MATERIAL AND METHODS: Non-randomized, observational study of women under 40 years of age and who received UAE. Twenty-seven women under the age of 40 who underwent UAE were included in the study. Hormone levels were measured prior to UAE, and at least six months post UAE. RESULTS: Statistical analysis from a paired t-test showed that the AMH levels pre- and post-embolization of these women fell within the normal range. The average AMH level prior to embolization was 2.54 +/- 3.99 ng/mL. The mean AMH concentration after embolization was 2.33 +/- 2.70 ng/mL. The average change in AMH levels between pre-and post-embolization was -0.21 +/- 1.08 ng/mL. There is no statistically significant difference between the pre- and post UAE AMH levels (95% CI -0.64 to 0.22, p=0.32). CONCLUSION: UAE does not affect ovarian reserve in women under 40 as evidenced by no significant change in AMH levels before and after embolization. Women who are of reproductive age and have fibroids can consider UAE without concern for adverse effects on their fertility. PMID- 25727094 TI - Joint attention behaviours and vocabulary development in children with Down syndrome. AB - BACKGROUND: Because of their difficulties in language development, various studies have focussed on the precursors of linguistic skills in children with Down syndrome. However, data on the predictive role of joint attention on language development in this population are inconsistent. The present study aimed to analyse attention behaviours in a group of children with Down syndrome. The existence of both concurrent and longitudinal relationships between joint attention and vocabulary development was investigated. METHOD: The participants were 18, 24-month-old, Italian children with Down syndrome. The children's attention skills were assessed during semi-structured free-play sessions in interaction with their mothers. A nominal exhaustive scheme was applied to code the children's behaviour. Moreover, the children's vocabulary development (both receptive and expressive) was assessed with the Italian version of the MacArthur Bates Communicative Development Inventory at both 24 and 30 months. RESULTS: Data analyses showed that children with Down syndrome spent a large part of the interactive play session in joint attention situations. Moreover, the children's behaviour of proposing a joint attention focus to their communicative partners appeared to be a significant predictor of the children's vocabulary comprehension skills as assessed 6 months later. CONCLUSIONS: These results support the hypothesis of continuity between preverbal precursors and vocabulary development in a population with atypical development. PMID- 25727095 TI - Predictive value of family history of allergy and cord blood IgE level for allergic diseases up to adulthood. PMID- 25727096 TI - Pre-operative Functional Parameters of Patients Undergoing Total Knee Arthroplasty. AB - BACKGROUND AND PURPOSE: Total knee arthroplasty (TKA) has become the gold standard to manage pain and disability associated with knee osteoarthritis (KOA). There are no clear criteria on to determine when or who should undergo TKA. The creation of a pre-operative profile that includes physical functional data may aid in the clinical decision-making for the timing of TKA. Aim 1: to observe the pre-operative functional profile of subjects with advanced KOA and to depict it according to gender. Aim 2: to assess the association between pain, self-reported and performance-based physical function outcomes. MATERIALS AND METHODS: STUDY DESIGN: retrospective study. Physical functional data from 122 persons (89 women and 33 men) with end-stage KOA were obtained through a database. Data consisted of height, weight, 6-minute walk test (6MWT) and the deficit when compared with normative values, self-visual analogue scale (VAS) after 6MWT and Western Ontario and McMaster Universities Index (WOMAC). Descriptive statistics were used to report the observed data; student t-test and Mann-Whitney were used to compare gender groups. Spearman correlation was used to asses the association with the 6MWT, WOMAC and VAS. RESULTS: The mean (standard deviation) values of our sample for the WOMAC, 6MWT deficit and VAS were calculated. There was a significant difference between gender in the WOMAC score and pain intensity (VAS) after the 6MWT (p = 0.002; p = 0.01). Moderate to weak correlations between WOMAC score, VAS and 6MWT were found. Correlation values ranged from r = 0.23 to 0.48. CONCLUSION: The current study suggests a functional profile for subjects who are scheduled to undergo TKA. Our results show that the correlations of self-report and performance-based measures of function and reported pain are poor. This enhances the idea of using all of these types of measures to establish the functional profile a sample of subjects with advanced KOA. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25727097 TI - Ghrelin's Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction. AB - Understanding the intricate pathways that modulate appetite and subsequent food intake is of particular importance considering the rise in the incidence of obesity across the globe. The serotonergic system, specifically the 5-HT2C receptor, has been shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor that is well known for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signaling is not due to coupling to GalphaS, as no increase in cAMP signaling is observed. Next, flow cytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5 HT2C receptor. In addition, we demonstrate colocalized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signaling is blocked ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5 HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into a biologically significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management. PMID- 25727098 TI - Population origin of Atlantic sturgeon Acipenser oxyrinchus oxyrinchus by-catch in U.S. Atlantic coast fisheries. AB - Microsatellite DNA and mitochondrial DNA control-region sequence analyses were used to determine the population and distinct population segment (DPS) origin of 173 Atlantic sturgeon Acipenser oxyrinchus oxyrinchus encountered from the Gulf of Maine to Cape Hatteras, North Carolina, in NOAA's Northeast Fisheries Observer Program. It was found that the Hudson River was by far the greatest contributor to this coastal by-catch, with 42.2-46.3% of specimens originating there. Generally, specimens represented the geographic province of the river in which they were spawned, but some specimens, particularly those originating in the South Atlantic DPS, moved to great distances. Genetic mixed-stock analyses provide an accurate approach to determine the DPS and population origin of A. o. oxyrinchus by-catch in coastal waters, but most informative management requires that these results be partitioned by locale, season, target fishery and gear type. PMID- 25727099 TI - Prognostic value of circulating CD133(+) cells in patients with gastric cancer. AB - OBJECTIVES: Gastric cancer is an important cause of cancer-related mortality worldwide (1). There is increasing evidence that the existence of cancer stem cells (CSC) is responsible for tumour formation and maintenance. MATERIALS AND METHODS: The present study was designed to recognise circulating CSCs from blood samples of patients with gastric cancer, using CD133 and ABCG2 as potential markers. CD133(-) , CD133(+) ABCG2(-) and CD133(+) ABCG2(+) cells lines were analysed by flow cytometry, immunofluorescence staining, western blotting and real-time PCR. Furthermore, functional assays (clonogenic assay in vitro and tumourigenic assay in vivo) were also performed using these cell lines. RESULTS: Higher percentages of CD133(+) cells were identified in blood samples from gastric cancer patients compared to normal controls. In addition, we found by using Kaplan-Meier analysis, that numbers of CD133(+) cells correlated with poor prognosis gastric cancer patients. Finally, tumourigenic properties of CD133(+) ABCG2(+) cells were determined in vitro and in vivo. CONCLUSIONS: Our in vitro and in vivo experiments demonstrated that CD133(+) ABCG2(+) cells exhibited well known CSC characteristics; thus when circulating they could be used as a prognostic marker for gastric cancer. PMID- 25727100 TI - Selective spatial attention modulates bottom-up informational masking of speech. AB - To hear out a conversation against other talkers listeners overcome energetic and informational masking. Largely attributed to top-down processes, information masking has also been demonstrated using unintelligible speech and amplitude modulated maskers suggesting bottom-up processes. We examined the role of speech like amplitude modulations in information masking using a spatial masking release paradigm. Separating a target talker from two masker talkers produced a 20 dB improvement in speech reception threshold; 40% of which was attributed to a release from informational masking. When across frequency temporal modulations in the masker talkers are decorrelated the speech is unintelligible, although the within frequency modulation characteristics remains identical. Used as a masker as above, the information masking accounted for 37% of the spatial unmasking seen with this masker. This unintelligible and highly differentiable masker is unlikely to involve top-down processes. These data provides strong evidence of bottom-up masking involving speech-like, within-frequency modulations and that this, presumably low level process, can be modulated by selective spatial attention. PMID- 25727101 TI - Early amplitude-integrated EEG monitoring 6 h after birth predicts long-term neurodevelopment of asphyxiated late preterm infants. AB - The present study aimed to assess the prognostic value of early amplitude integrated electroencephalogram (aEEG) in late preterm infants who were born at a gestational age between 34 0/7 and 36 6/7 weeks for the prediction of neurobehavioral development. Late preterm infants (n = 170) with normal, mild, and severe asphyxia underwent continuous recording of aEEG for 4-6 h starting 6-8 h after delivery. The recordings were analyzed for background pattern, sleep-wake cycle (SWC), and seizures. Survivors were assessed at 18 months by neurological examination and Bayley Scales of Infant Development II. The incidence of adverse neurological outcome in the asphyxia group was significantly higher than in the normal group. For late preterm infants in the asphyxia group, abnormal aEEG pattern had a predictive potential of neurological outcomes with sensitivity of 78.57% (specificity, 87.80%; positive predictive value [PPV], 68.75%; negative predictive value [NPV], 92.31%; power, 85.45%). Non-SWC and intermediate SWC significantly were increased (25.45 and 52.73%, respectively) in the asphyxia group vs. the normal group. SWC pattern had neurological prognosis value in the asphyxia group with sensitivity of 64.29% (specificity, 87.80%; PPV, 64.29%; NPV, 87.80%; power, 81.82%). CONCLUSION: Early aEEG patterns are important determinants of long-term prognosis of neurodevelopmental outcome in asphyxiated late preterm infants. PMID- 25727102 TI - Toward hyperuniform disordered plasmonic nanostructures for reproducible surface enhanced Raman spectroscopy. AB - We report on the self-assembling of clusters of gold-nanoparticles (Au-NPs) directed by the phase separation of poly(styrene)-b-poly(methylmethacrylate) (PS b-PMMA) block-copolymer (BCP) on indium tin oxide coated glass, which induces the onset of vertical lamellar domains. After thermal evaporation of gold on BCP, Au NPs of 4 nm are selectively included into PS-nanodomains by thermal annealing, and then clustered with large density of hot spots (> 10(4) MUm(2)) in a random two-dimensional pattern. The resulting nanostructure exhibits near-hyperuniform long-range correlations. The consequent large degree of homogeneity of this isotropic plasmonic pattern gives rise to a highly reproducible Surface-Enhanced Raman Scattering (SERS) enhancement factor over the centimeter scale (std. dev. ~ 10% over 0.25 cm(2)). We also discuss the application of a static electric field for modulating the BCP host morphology. The electric field induces an alignment of Au-NP clusters into ordered linear chains, exhibiting a stronger SERS activity, but reduced SERS spatial reproducibility. PMID- 25727103 TI - Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. AB - The discovery of ketamine's rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. Ketamine has been generally well tolerated across patient groups, with transient mild-to-moderate adverse effects during infusion. However, the optimal dosing and route of administration and the safety of chronic treatment are not fully known. This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action, which may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that may continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders. PMID- 25727104 TI - Evaluation of the tolerability and safety of a 0.015% ingenol mebutate gel compared to 5% 5-fluorouracil cream for the treatment of facial actinic keratosis: a prospective randomized trial. AB - BACKGROUND: Five per cent 5-fluorouracil (5-FU) cream is a well-established treatment for actinic keratosis (AK), and ingenol mebutate gel (IMB) is a novel topical field-directed therapy. OBJECTIVE: To compare the tolerability and safety of IMB with that of 5-FU for the treatment of facial AK. METHODS: An open-label, prospective, randomized, controlled clinical trial with 100 patients with AKs within a 25-cm(2) contiguous field on the face was conducted. IMB was applied daily for three consecutive days. 5-FU was applied twice a day for 4 weeks. The treatment effect and the adverse events were evaluated at baseline and on days 2, 3, 4, 8, 15, 22, 29, 36 and 43 for intent-to-treat populations. RESULTS: The mean (+/- SD) maximum local skin reactions (LSR) for patients treated with IMB was 10.85 (+/- 3.12), compared with 10.86 (+/- 3.55) for those who received 5-FU. Patients in the IMB group presented LSR that peaked at day 4 and almost completely regressed after 15 days. Differently, in the 5-FU group, the LSR peaked at day 29 and lasted until visit 36. Additionally, the area under the curve (LSR * visit) was significantly smaller for IMB. No differences between the treatments for pruritus, pain, tearing, conjunctival hyperaemia or headaches were noted, but the eyelid oedema rate was higher for IMB group. No significant difference in the proportion of dropouts was observed between groups. Both treatments demonstrated a suitable safety profile. CONCLUSION: For treating AKs, the local skin reactions in the IMB group were more short-lived compared with those of 5-FU, but both treatments seemed to be safe and tolerable. PMID- 25727105 TI - Diameter-dependent release of a cisplatin pro-drug from small and large functionalized carbon nanotubes. AB - The use of platinum-based chemotherapeutic drugs in cancer therapy still suffers from severe disadvantages, such as lack of appropriate selectivity for tumor tissues and insurgence of multi-drug resistance. Moreover, drug efficacy can be attenuated by several mechanisms such as premature drug inactivation, reduced drug uptake inside cells and increased drug efflux once internalized. The use of functionalized carbon nanotubes (CNTs) as chemotherapeutic drug delivery systems is a promising strategy to overcome such limitations due to their ability to enhance cellular internalization of poorly permeable drugs and thus increase the drug bioavailability at the diseased site, compared to the free drug. Furthermore, the possibility to encapsulate agents in the nanotubes' inner cavity can protect the drug from early inactivation and their external functionalizable surface is useful for selective targeting. In this study, a hydrophobic platinum(IV) complex was encapsulated within the inner space of two different diameter functionalized multi-walled CNTs (Pt(IV)@CNTs). The behavior of the complexes, compared to the free drug, was investigated on both HeLa human cancer cells and RAW 264.7 murine macrophages. Both CNT samples efficiently induced cell death in HeLa cancer cells 72 hours after the end of exposure to CNTs. Although the larger diameter CNTs were more cytotoxic on HeLa cells compared to both the free drug and the smaller diameter nanotubes, the latter allowed a prolonged release of the encapsulated drug, thus increasing its anticancer efficacy. In contrast, both Pt(IV)@CNT constructs were poorly cytotoxic on macrophages and induced negligible cell activation and no pro-inflammatory cytokine production. Both CNT samples were efficiently internalized by the two types of cells, as demonstrated by transmission electron microscopy observations and flow cytometry analysis. Finally, the platinum levels found in the cells after Pt(IV)@CNT exposure demonstrate that they can promote drug accumulation inside cells in comparison with treatment with the free complex. To conclude, our study shows that CNTs are promising nanocarriers to improve the accumulation of a chemotherapeutic drug and its slow release inside tumor cells, by tuning the CNT diameter, without inducing a high inflammatory response. PMID- 25727107 TI - Is prognosis of schizophrenia worsening in non-Western countries? PMID- 25727109 TI - Employee assistance programs in private health plans: what do they offer? PMID- 25727106 TI - MRI Assessment of Ablation-Induced Scarring in Atrial Fibrillation: Analysis from the DECAAF Study. AB - BACKGROUND: There is limited knowledge on the extent and location of scarring that results from catheter ablation and its role in suppressing atrial fibrillation (AF). We examined the effect of atrial fibrosis and ablation-induced scarring on catheter ablation outcomes in AF. METHODS: We conducted a prospective multicenter study that enrolled 329 AF patients presenting for catheter ablation. Delayed enhancement magnetic resonance imaging (DE-MRI) of the left atrium was obtained preablation. Scarring was evaluated in 177 patients with a DE-MRI scan obtained 90 days postablation. We evaluated residual fibrosis, defined as preablation atrial fibrosis not covered by ablation scar. The primary outcome was freedom from recurrent atrial arrhythmia. RESULTS: In the analysis cohort of 177 patients, preablation fibrosis was 18.7 +/- 8.7% of the atrial wall. Ablation aimed at pulmonary vein (PV) isolation was performed in 163 patients (92.1%). Ablation-induced scar averaged 10.6 +/- 4.4% of the atrial wall. Scarring completely encircled all 4 PVs only in 12 patients (7.3%). Residual fibrosis was calculated at 15.8 +/- 8.0%. At 325 days follow-up, 35% of patients experienced recurrent arrhythmia. Multivariable Cox proportional hazards models demonstrated that baseline atrial fibrosis (HR and 95% CIs) (1.09 [1.06-1.12], P < 0.001) and residual fibrosis (1.09 [1.05-1.13], P < 0.001) were associated with atrial arrhythmia recurrence, while PV encirclement and overall scar were not. CONCLUSIONS: Catheter ablation of AF targeting PVs rarely achieves permanent encircling scar in the intended areas. Overall atrial fibrosis present at baseline and residual fibrosis uncovered by ablation scar are associated with recurrent arrhythmia. PMID- 25727110 TI - Using feedback from patient-reported outcome measures in mental health services: a scoping study and typology. AB - OBJECTIVE: Routine evaluation of mental health services has become widespread, and the use of patient-reported outcome measures (PROMs) as clinical aids or discussion tools has been receiving increasing attention. The purpose of this scoping study was to provide a typology of the diverse ways in which studies reporting on PROM use in mental health services have utilized PROMs. METHODS: Iterative scoping searches of the literature identified articles reporting on the use of PROM feedback in mental health settings, which were then categorized to develop a typology along a dimension of intensity of use of PROM feedback, ranging from no feedback to patient and clinician to clinician-patient discussion that followed a formalized structure. RESULTS: Of the 172 studies that were identified, 27 were grouped into five categories, ranging from studies in which there was no PROM feedback to clinician or patient to studies in which a formalized structure was available by which PROM feedback could be discussed between clinician and patient. Of the 11 studies in the category with formalized feedback, nine reported some significant effects of feedback compared with a control condition, and two reported partial significant effects. CONCLUSIONS: The proposed procedural typology helps explain the diversity of results from studies reporting on the effects of PROM feedback, by highlighting that PROM feedback appears to be more effective when integrated in a formalized and structured manner. Future work is required to isolate these effects from common procedural correlates, such as monitoring of the therapeutic alliance. PMID- 25727111 TI - Disparities in receipt of specialty services among children with mental health need enrolled in the CMHI. AB - OBJECTIVE: The study assessed racial-ethnic differences in receipt of mental health services among children enrolled in systems of care under the Children's Mental Health Initiative (CMHI). METHODS: Survey data for 3,920 CMHI enrollees were used to estimate the association between race-ethnicity and the number of days in the 12 months postenrollment during which the child received individual psychotherapy, family and group psychotherapy, medication monitoring, assessment and evaluation, case management, residential treatment, and inpatient care. Two part regressions with fixed site effects were estimated to adjust for geography and baseline population differences, including child and caregiver characteristics. RESULTS: Compared with white non-Latino children, African Americans had lower odds of using any individual psychotherapy (odds ratio [OR]=.73, p=.019), family and group psychotherapy (OR=.79, p=.043), and medication monitoring (OR=.51, p<.001); among users of each service, African Americans had lower utilization of individual psychotherapy (incidence rate ratio [IRR]=.79, p<.001), family and group psychotherapy (IRR=.86, p=.011), and inpatient care (IRR=.75, p=.026). Latino children had lower odds of receiving medication monitoring (OR=.70, p=.007) and assessment and evaluation services (OR=.75, p=.027); among users, Latinos had lower utilization of individual (IRR=.91, p=.044) and family and group (IRR=.88, p=.044) psychotherapy. Pacific Islanders who received medication monitoring used services at a lower rate (IRR=.60, p=.009) than white children. No other associations with race-ethnicity were significant. CONCLUSIONS: Racial-ethnic disparities in children's mental health treatment persist within systems of care. Further work is necessary to understand the role of individual program components, their interactions with community characteristics, and how they might affect mental health services use. PMID- 25727112 TI - Schizophrenia-related disability in China: prevalence, gender, and geographic location. AB - OBJECTIVE: This study estimated the prevalence of schizophrenia-related disability in the Chinese population and explored factors that may contribute to differences in prevalence rates between women and men and across geographic regions. METHODS: Data for 1,909,205 noninstitutionalized adults (age 18 and older) from a representative national sample were obtained from the Second China National Sample Survey on Disabilities in 2006 (participation rate of 99.8%). The sample was first screened for disability (activities of daily living and social participation adversely affected by the disorder) via in-person household interviews. Trained clinical psychiatrists then administered the ICD-10 Symptom Checklist for Mental Disorders and the World Health Organization Disability Assessment Schedule Version II to all individuals who screened positive for a psychiatric disability. RESULTS: The prevalence of schizophrenia disability was .41% in China. It was higher in rural areas (.45%) than in urban areas (.32%). In rural areas, the prevalence was higher among women than among men (.51% versus .38%), but in urban areas, the rates were similar for women and men (.30% versus .35%). The results of logistic regression analysis showed that after adjustment for variables related to socioeconomic status, the likelihood of having schizophrenia disability was slightly lower among rural residents than among urban residents (odds ratio [OR]=.92, 95% confidence interval [CI]=.86-.98), although the disparity between rural women and rural men remained (OR=1.9, CI=1.78-2.02). CONCLUSIONS: Socially disadvantaged rural women were disproportionately affected by schizophrenia-related disability. Limited access to health services may have contributed to the increased disease burden among rural women. PMID- 25727113 TI - Intersection of race-ethnicity and gender in depression care: screening, access, and minimally adequate treatment. AB - OBJECTIVES: This study examined the interaction of race-ethnicity and gender in depression screening, receipt of any mental health care, and receipt of adequate care. METHODS: Data from electronic health records (2010-2012) of adult primary care patients from a New England urban health care system were used (N=65,079). Multivariate logit regression models were estimated to assess associations between race-ethnicity, gender, and other covariates and depression screening, any depression care among those with a positive screen, and adequate depression care. To measure disparities in utilization, we controlled for need variables but not for non-need variables, including insurance, marital status, and socioeconomic status. RESULTS: Among males and females, blacks and Asians were less likely and Latinos were more likely to be screened for depression compared with whites. Among those with moderate or severe depression, black males and females, Latino males, and Asian males and females were less likely than whites to receive any mental health care. The disparity in screening between blacks and whites was greater among females compared with males. The disparity between Latinos and whites in receipt of any mental health care and of adequate care was greater among males than females. CONCLUSIONS: This approach underscored the importance of identifying disparities at each step of depression care by both race-ethnicity and gender. Targeting certain groups in specific stages of care, for example, screening of black females or providing any mental health care and adequate care for Latino males, would be more effective than a blanket approach to disparities reduction. PMID- 25727114 TI - The role of gender in moderating treatment outcome in collaborative care for anxiety. AB - OBJECTIVE: The aim of this study was to test whether gender moderates intervention effects in the Coordinated Anxiety Learning and Management (CALM) intervention, a 12-month, randomized controlled trial of a collaborative care intervention for anxiety disorders (panic disorder, generalized anxiety disorder, posttraumatic stress disorder, and social anxiety disorder) in 17 primary care clinics in California, Washington, and Arkansas. METHODS: Participants (N=1,004) completed measures of symptoms (Brief Symptom Inventory [BSI]) and functioning (mental and physical health components of the 12-Item Short Form [MCS and PCS] and Healthy Days, Restricted Activity Days Scale) at baseline, six, 12, and 18 months. Data on dose, engagement, and beliefs about psychotherapy were collected for patients in the collaborative care group. RESULTS: Gender moderated the relationship between treatment and its outcome on the BSI, MCS, and Healthy Days measures but not on the PCS. Women who received collaborative care showed clinical improvements on the BSI, MHC, and Healthy Days that were significantly different from outcomes for women in usual care. There were no differences for men in collaborative care compared with usual care on any measures. In the intervention group, women compared with men attended more sessions of psychotherapy, completed more modules of therapy, expressed more commitment, and viewed psychotherapy as more helpful. CONCLUSIONS: These findings contribute to the broader literature on treatment heterogeneity, in particular the influence of gender, and may inform personalized care for people seeking anxiety treatment in primary care settings. PMID- 25727115 TI - Reduction of patient-reported antidepressant side effects, by type of collaborative care. AB - OBJECTIVE: Antidepressants are effective for treating depression, and collaborative care increases initiation of and adherence to antidepressants. Side effects of antidepressants are common and can adversely affect quality of life. Care managers address antidepressant side effects directly, but the impact of collaborative care on adverse effects is unknown. This secondary data analysis tested the hypothesis that patient-reported antidepressant side effects were lower for depressed patients receiving high-intensity, telemedicine-based collaborative care (TBCC) than for patients receiving low-intensity, practice based collaborative care (PBCC). METHODS: This analysis used data from 190 patients enrolled in a pragmatic, multisite, comparative-effectiveness trial from 2007 to 2009 and followed for 18 months. Most patients were female (83%) and Caucasian (80%). The mean age was 50. Patients randomly assigned to PBCC received 12 months of evidence-based care from an on-site primary care provider and nurse care manager. Patients in TBCC received evidence-based care from an on-site primary care provider supported by a nurse care manager available off site by telephone, as well as by a telepharmacist, telepsychologist, and telepsychiatrist. Telephone interviews completed at baseline, six, 12, and 18 months included assessments of sociodemographic characteristics, beliefs about antidepressant treatment, depression severity, psychiatric comorbidity, medications, adherence, and side effects. RESULTS: With controls for baseline case mix and time-variant medication characteristics, the TBCC group reported significantly fewer side effects at six and 12 months (p=.008 and .002, respectively). The number of antidepressants prescribed increased risk of side effects (p=.02). CONCLUSIONS: Patients in the TBCC group reported fewer antidepressant-related side effects, which may have contributed to improved quality of life. PMID- 25727116 TI - Ambiguity in determining financial capability of SSI and SSDI beneficiaries with psychiatric disabilities. AB - OBJECTIVE: The liberty of individuals who receive Social Security disability payments is constrained if they are judged incapable of managing their payments and are assigned a payee or conservator to manage benefit payments on their behalf. Conversely, beneficiaries' well-being may be compromised if they misspend money that they need to survive. Several studies have shown that determinations of financial capability are made inconsistently and that capability guidelines appear to be applied inconsistently. This article describes ambiguities that remained for individuals even after a comprehensive assessment of financial capability was conducted by independent assessors. METHODS: Trained, experienced assessors rated the financial capability of 118 individuals in intensive outpatient or inpatient psychiatric facilities who received Social Security Disability Insurance or Supplemental Security Income. RESULTS: Ten individuals' cases were determined to be difficult to judge. Six sources of ambiguity were identified by case review: distinguishing incapability from the challenges of navigating poverty, the amount of nonessential spending that indicates incapability, the amount of spending on harmful things that indicates incapability, how to consider intermittent periods of capability and incapability, the relative weighting of past behavior and future plans to change, and discrepancies between different sources of information. CONCLUSIONS: The cases raise fundamental questions about how to define and identify financial incapability, but they also illustrate how detailed consideration of beneficiaries' living situations and decision making can inform the difficult dichotomous decision about capability. PMID- 25727118 TI - Implementation of smoking cessation treatment in VHA substance use disorder residential treatment programs. AB - OBJECTIVES: Although the prevalence of tobacco use among individuals with substance use disorders remains high, smoking cessation (SC) has not been a focus of addiction treatment programs. Veterans Health Administration (VHA) policy requires tobacco use screening and the availability of evidence-based SC treatment in specialty care settings, including substance use disorder programs. As part of a larger quality improvement effort, this qualitative study examined how SC treatment is delivered in VHA substance use disorder residential treatment programs (SRTPs) and the barriers and opportunities for growth that exist within these settings. METHODS: Twenty-five staff were interviewed across a sample of 15 SRTPs. Participants were asked to describe their knowledge and attitudes about SC treatment as well as organizational barriers and facilitators related to implementation of SC treatment in their programs. Content analysis was used to extract responses within and across programs. RESULTS: Participants endorsed SC as a general goal and reported that SRTPs responded to patients who requested help. However, many programs did not emphasize SC as an important part of recovery from substance use disorders and did not document, reevaluate, or consistently address tobacco use. CONCLUSIONS: The results identified critical gaps in the provision of SC treatment in VHA SRTPs. These findings suggest actionable opportunities to improve SC treatment in SRTPs, including providing training opportunities, developing or enforcing policies that support SC, implementing systems to track and report tobacco-related diagnoses and treatment, and obtaining leadership support for building a culture that encourages SC. PMID- 25727117 TI - Comorbid depression and substance abuse among safety-net clients in Los Angeles: a community participatory study. AB - OBJECTIVE: Depression and substance abuse are common among low-income adults from racial-ethnic minority groups who receive services in safety-net settings, although little is known about how clients differ by service setting. This study examined characteristics and service use among depressed, low-income persons from minority groups in underresourced communities who did and did not have a substance abuse history. METHODS: The study used cross-sectional baseline client data (N=957) from Community Partners in Care, an initiative to improve depression services in Los Angeles County. Clients with probable depression (eight-item Patient Health Questionnaire) from substance abuse programs were compared with depressed clients with and without a history of substance abuse from primary care, mental health, and social and community programs. Sociodemographic, health status, and services utilization variables were examined. RESULTS: Of the 957 depressed clients, 217 (23%) were from substance abuse programs; 269 (28%) clients from other sectors had a substance abuse history, and 471 (49%) did not. Most clients from substance abuse programs or with a substance abuse history were unemployed and impoverished, lacked health insurance, and had high rates of arrests and homelessness. They were also more likely than clients without a substance abuse history to have depression or anxiety disorders, psychosis, and mania and to use emergency rooms. CONCLUSIONS: Clients with depression and a substance abuse history had significant psychosocial stressors and high rates of service use, which suggests that communitywide approaches may be needed to address both depression and substance abuse in this safety-net population. PMID- 25727119 TI - Correlation between reduction of seclusion and restraint and assaults by patients in Pennsylvania's state hospitals. AB - OBJECTIVE: This prospective study assessed the use of seclusion and restraint in the Pennsylvania state hospital system from 2001 through 2010. It also examined the correlation between declining use of containment procedures and assaults by patients on other patients and staff. METHODS: The 12,900 anonymized records involving the 1,801 unique, civilly committed individuals who were physically or mechanically restrained and secluded in the nine civil hospitals during this study period were entered into a database. The data set included demographic and diagnostic information about the patients and the cause and effect of the procedures. These data were compared with rates of patient-to-patient and patient to-staff assaults to determine any correlation between changes in use of containment and assaults. RESULTS: From 2001 to 2010, the use of mechanical restraint significantly declined from .37 to .08 episodes per 1,000 days (p<.018), and the use of seclusion significantly declined from .21 to .01 episodes per 1,000 days (p<.001). Persons with an axis I diagnosis of psychotic disorder accounted for 44% of containment procedures used during this study. Patient-to-patient assaults declined slightly, and patient-to-staff assaults were unaffected. CONCLUSIONS: Decreasing the use of containment procedures did not increase assaults. Better leadership, data transparency, use of clinical alerts, workforce development, policy changes, enhanced use of response teams, implementation of dialectical behavior therapy, and discontinuation of the psychiatric use of PRN orders contributed to the change in use of containment procedures. A philosophical change to a recovery model of psychiatric care and services was the driving force behind this transformation. PMID- 25727120 TI - The Affordable Care Act: an opportunity for improving care for substance use disorders? AB - The Patient Protection and Affordable Care Act (ACA) will greatly increase coverage for treatment of substance use disorders. To realize the benefits of this opportunity, it is critical to develop reliable, valid, and feasible measures of quality to ensure that treatment is accessible and of high quality. The authors review the availability of current quality measures for substance use disorder treatment and conclude there is a pressing need for development, validation, and use of quality measures. They provide recommendations for research and policy changes to increase the likelihood that patients, families, and society benefit from the increased coverage provided by the ACA. PMID- 25727121 TI - Comparing the impact on Latinos of a depression brochure and an entertainment education depression fotonovela. AB - OBJECTIVE: The purpose was to evaluate the impact of a depression fotonovela in increasing knowledge of depression symptoms and treatments and reducing stigma among Latinos. METHODS: Data were from a randomized controlled trial in which Latinos from adult schools (N=132) were assigned to receive the fotonovela or a depression brochure and were assessed on knowledge and stigma measures before and after reading the material and one month later. Random-effects linear and logistic regression models assessed changes within and between groups. RESULTS: No significant differences were found between groups in symptom knowledge, social distance, and perceptions of dangerousness. Gains in depression treatment knowledge were significantly greater for the fotonovela than for the depression brochure group. CONCLUSIONS: Findings suggest that a depression fotonovela informed by an entertainment-education approach is a useful tool for improving depression treatment knowledge among Latinos but is limited in improving symptom knowledge and reducing stigma related to social distance and perceptions of dangerousness. PMID- 25727122 TI - Disparities in housing status among veterans with general medical, cognitive, and behavioral health conditions. AB - OBJECTIVE: The study explored disparities in housing status among veterans with general medical, cognitive, and behavioral health conditions. METHODS: Multinomial mixed-effects models estimated the relationship between medical, cognitive, and behavioral health comorbidities and housing instability among veterans enrolled in the Veterans Health Administration (VHA) (N=1,582,125) who responded to the Homelessness Screening Clinical Reminder for homelessness and risk during a three-month period. RESULTS: Veterans were two or more times as likely to screen positive for homelessness or risk if they had a diagnosis of a cognitive or behavioral health conditions in the study. Findings related to general medical conditions were inconsistent. CONCLUSIONS: The study found disparities in housing instability among VHA outpatients with cognitive and behavioral health conditions, suggesting the need to identify veterans with these conditions experiencing housing instability and the need to develop appropriate interventions to mitigate homelessness or risk. PMID- 25727123 TI - When "need plus supply" does not equal demand: challenges in uptake of depression treatment in HIV clinical care. AB - OBJECTIVE: Depression is common among patients in HIV care and is associated with worse HIV-related health behaviors and outcomes. Effective depression treatment is available, yet depression remains widely underdiagnosed and undertreated in HIV care. METHODS: As part of a multisite, randomized trial of depression treatment in HIV clinical care, the proportion of positive depression screens that resulted in study enrollment and reasons for nonenrollment were examined. RESULTS: Over 33 months, patients completed 9,765 depression screens; 19% were positive for depression, and of these 88% were assessed for study eligibility. Of assessed positive screens, 11% resulted in study enrollment. Nonenrollment after a positive screen was sometimes dictated by the study eligibility criteria, but it was often related to potentially modifiable provider- or patient-level barriers. CONCLUSIONS: Addressing patient- and provider-level barriers to engaging in depression treatment will be critical to maximize the reach of depression treatment services for HIV patients. PMID- 25727124 TI - State mandates regarding postpartum depression. AB - OBJECTIVE: Postpartum depression continues to be undertreated. This project identified state policies that have been enacted regarding peripartum mental health and assessed how effective they might be. METHODS: A systematic search strategy was used to detect state-level legislative initiatives. Legislative tracking resources were used to determine which were enacted. Policies were sorted into categories. Related evidence was reviewed to gauge the impact of each category. RESULTS: Thirteen states have enacted one or more state-level peripartum mental health policies. Categories include patient education mandates, depression screening mandates, mandated task force, and public awareness campaigns. Those mandating screening include Illinois, Massachusetts, New Jersey, and West Virginia. Related outcomes evidence suggests a very limited impact. CONCLUSIONS: Several states have enacted policies addressing peripartum mental health, but these are probably not influencing clinical outcomes. Home visits with a mental health component are effective for postpartum depression; state policies could support home visits. PMID- 25727125 TI - Coming home: self-guided dialogues to facilitate soldiers' readjustment. PMID- 25727126 TI - Exploring the use of digital picture frames on schizophrenia inpatient wards. PMID- 25727127 TI - Why is there a link between smoking and suicide? PMID- 25727128 TI - Why is there a link between smoking and suicide? In reply. PMID- 25727129 TI - Medications for maltreated children: wrong conclusions? PMID- 25727130 TI - Medications for maltreated children: wrong conclusions? In reply. PMID- 25727131 TI - Delineating responsibility: primary care provider perspective. PMID- 25727133 TI - Subjective ratings of neurocognitive functioning in depressed young people undergoing treatment: utility of a brief screening tool. AB - AIMS: To determine how young people with depression rate their neurocognitive functioning during treatment, and whether these ratings are affected by depression severity, age, suicidal ideation and antidepressant status. METHODS: Fifty young people (12-25 years) engaged in psychological therapy completed the Neuropsychological Symptoms Self-Report rating their neurocognitive functioning in a range of domains. RESULTS: In two domains, working memory/multitasking and motivation, more than 40% of the sample rated their functioning as improved, since commencing treatment. Ratings of neurocognitive functioning were affected by depression severity and suicidal ideation, particularly in the areas of wakefulness, attention and concentration, working memory/multitasking, and motivation. However, there were few differences related to age or antidepressant status. CONCLUSIONS: The Neuropsychological Symptoms Self-Report - a rapid measure of subjective neurocognitive functioning - can provide a snapshot of subjective changes in neurocognitive functioning during treatment for depression. This information may guide treatment approaches. PMID- 25727134 TI - Sequential cobalt magnetization collapse in ErCo2: beyond the limits of itinerant electron metamagnetism. AB - The itinerant electron metamagnetism (IEM) is an essential physical concept, describing magnetic properties of rare earth - transition metal (R-TM) intermetallics, demonstrating technologically important giant magnetoresistance and magnetocaloric effects. It considers an appearance of TM magnetization induced by spontaneous magnetization of surrounding R atoms, which provides significant response of the magnetic and transport properties on variation of external parameters (temperature, pressure, magnetic field) due to strong coupling between magnetic sublattices. The RCo2 compounds were generally considered as model systems for understanding of basic properties of IEM intermetallics. However, microscopic nature of magnetic properties still remains unclear. In our experimental and theoretical study of ErCo2 in a wide range of thermodynamic parameters a sequential collapse of cobalt sublattice magnetization in the background of nearly unchanged Er sublattice magnetization was revealed. The uncoupled magnetizations behavior challenges the IEM concept applicability and evidences more complex nature of magnetism in ErCo2 and related RCo2 systems. PMID- 25727135 TI - Creation of high-density and low-defect single-layer film of magnetic nanoparticles by the method of interfacial molecular films. AB - A technique to solubilize fine magnetic inorganic particles in general organic solvents is proposed via surfaces modification by long-chain carboxylic acids. This organic modification should overcome the relatively weak van der Waals interactions between the nanoparticles, allowing the formation of ordered arrangements of the modified Fe3O4 and CoFe2O4 materials. Using nanodispersions of these organo-modified magnetic nanoparticles as "spreading solutions", Langmuir monolayers of these particles were formed. Multiparticle layered structures were constructed by the Langmuir-Blodgett (LB) technique. The fabrication of single- and multiparticle layers of organo-modified magnetic nanoparticles was investigated using surface pressure-area (pi-A) isotherms, out of-plane X-ray diffraction (XRD), in-plane XRD, and atomic force microscopy (AFM). The out-of-plane XRD profile of a single-particle layer of organo-modified Fe3O4 clearly showed a sharp peak which was attributed to the distance between Fe3O4 layers along the c-axis. The AFM image of single-particle layer of organo modified CoFe2O4 revealed integrated particle organization with a uniform height; these aggregated particles formed large two-dimensional crystals. For both nanoparticle species, regular periodic structures along the c-axis and high density single-particle layers were produced via the Langmuir and LB techniques. PMID- 25727136 TI - Need for sedation and analgesia in patients with a history of substance misuse admitted to an intensive care unit. AB - BACKGROUND: Patients with a history of substance misuse may develop tolerance to analgesics and psychotropic drugs which alter the need for sedation and analgesia after ICU admittance. AIMS: The objective was to qualify and quantify the needs for sedation and analgesia in critically ill patients with and without a history of substance misuse admitted to an intensive care unit (ICU). DESIGN: A 2-year prospective, observational study. METHODS: Patients admitted to an ICU who required sedation and analgesia for >=72 h were included and were classified as substance misusers and non-substance misusers. We analysed demographic data and the consumption of alcohol and other substances. Comparisons between groups were made using the non-parametric Mann-Whitney test for quantitative variables and Fisher's exact test for qualitative variables. The analysis was made using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows. Statistical significance was established as p < 0.05. RESULTS: We included 44 patients, of whom 31 (70.3%) were users of >=1 substance. The median age was 47 years, 8 (18.2%) patients were female. The most-consumed substances were tobacco (56.8%), alcohol (54.5%), cannabis (13.6%), amphetamines (11.4%) and cocaine (9.1%). Toxicological samples were positive for alcohol (65.2%, mean blood alcohol level 1.38 +/- 1.05 g/L). There were no significant differences in the need for sedation between substance misusers and non-substance misusers (p > 0.05). CONCLUSIONS: The prevalence of substance misuse in this population was high. We found no greater need for sedation in patients with a history of substance misuse although these patients often require three or more drugs to achieve optimal sedation. RELEVANCE TO CLINICAL PRACTICE: Physicians and nurses should be aware of substance misuse in order to provide adequate care by optimizing drug administration and dosages in the ICU. PMID- 25727137 TI - Hematologic and biochemical reference intervals for adult Friesian horses from North America. AB - BACKGROUND: Established breed-specific reference intervals (RI) are an important tool for monitoring the health of horses. There is a lack of published work on breed-specific RI for Friesian horses. OBJECTIVES: The goal of this project was to determine hematologic and biochemical RI for Friesian horses residing in North America. METHODS: Strict inclusion and exclusion criteria were established for selection of reference subjects and for blood specimen collection and handling. Blood samples from 123 healthy, adult (range 3-18 years, median 8 years) Friesian horses of both sexes (70 mares, 45 geldings, and 8 stallions) were used to determine RI. Complete blood counts (CBC) and biochemistry profiles were performed on the Sysmex XT-2000iV hematology and Olympus AU400 biochemistry analyzers, respectively, at IDEXX Laboratories Inc. (Columbus, OH, USA). Results were analyzed using Reference Value Advisor. According to the guidelines of the ASVCP, nonparametric RI with 90% confidence intervals were determined. RESULTS: IDEXX equine RI are transferrable to Friesian horses for 30 of 36 analytes. Friesian-specific RI (medians) are recommended for the following variables: RBC 5.02-8.74 * 10(6) /MUL (6.66), HCT 27-42% (34), HGB 9.0-14.3 g/dL (11.4), lactate dehydrogenase 299-866 U/L (493), direct bilirubin 0.3-0.7 mg/dL (0.5), and anion gap 7-18 mEq/L (12). CONCLUSIONS: The RI established in this study provide a useful baseline for the assessment of hematologic and biochemical data in Friesian horses residing in North America. PMID- 25727138 TI - A stable-isotope dilution GC-MS approach for the analysis of DFRC (derivatization followed by reductive cleavage) monomers from low-lignin plant materials. AB - The derivatization followed by reductive cleavage (DFRC) method is a well established tool to characterize the lignin composition of plant materials. However, the application of the original procedure, especially the chromatographic determination of the DFRC monomers, is problematic for low-lignin foods. To overcome these problems a modified sample cleanup and a stable-isotope dilution approach were developed and validated. To quantitate the diacetylated DFRC monomers, their corresponding hexadeuterated analogs were synthesized and used as internal standards. By using the selected-ion monitoring mode, matrix associated interferences can be minimized resulting in higher selectivity and sensitivity. The modified method was applied to four low-lignin samples. Lignin from carrot fibers was classified as guaiacyl-rich whereas the lignins from radish, pear, and asparagus fibers where classified as balanced lignins (guaiacyl/syringyl ratio=1-2). PMID- 25727139 TI - Electrical stimulation enhances sensory recovery: a randomized controlled trial. AB - OBJECTIVE: Brief postsurgical electrical stimulation (ES) has been shown to enhance peripheral nerve regeneration in animal models following axotomy and crush injury. However, whether this treatment is beneficial in humans with sensory nerve injury has not been tested. The goal of this study was to test the hypothesis that ES would enhance sensory nerve regeneration following digital nerve transection compared to surgery alone. METHODS: Patients with complete digital nerve transection underwent epineurial nerve repair. After coaptation of the severed nerve ends, fine wire electrodes were implanted before skin closure. Postoperatively, patients were randomized to receiving either 1 hour of 20Hz continuous ES or sham stimulation in a double-blinded manner. Patients were followed monthly for 6 months by a blinded evaluator to monitor physiological recovery of spatial discrimination, pressure threshold, and quantitative small fiber sensory testing. Functional disability was measured using the Disability of Arm, Shoulder, and Hand questionnaire. RESULTS: A total of 36 patients were recruited, with 18 in each group. Those in the ES group showed consistently greater improvements in all sensory modalities by 5 to 6 months postoperatively compared to the controls. Although there was a trend of greater functional improvements in the ES group, it was not statistically significant (p > 0.01). INTERPRETATION: Postsurgical ES enhanced sensory reinnervation in patients who sustained complete digital nerve transection. The conferred benefits apply to a wide range of sensory functions. PMID- 25727140 TI - Approaches targeting the type III secretion system to treat or prevent bacterial infections. AB - INTRODUCTION: The type III secretion system (T3SS) injectisome is an essential virulence mechanism used by many bacterial pathogens to inject host cells with effector proteins. Bacteria harboring T3SSs can cause significant disease in humans. As bacterial antibiotic resistance is a major concern, alternative prophylaxis and therapeutics are needed and T3SSs are a target for anti-virulence drugs. AREAS COVERED: In this article, the authors review whole-cell-based high throughput screens (HTSs), which have been the main approach used to identify small molecules inhibiting T3SSs. The authors review this in the context of particular characteristics of T3SSs. Furthermore, they also describe the follow up approaches used to study the inhibitors found. The authors also highlight target-based approaches to find inhibitors of specific T3SS components. Finally, the authors briefly review strategies used to find inhibitors of effectors or of effector-activated host cell pathways, and approaches based on T3SSs for active or passive immunization and rational vaccine design. EXPERT OPINION: Future efforts targeting T3SS to prevent or treat bacterial infections should focus on deciphering the mode of action of inhibitors and on target-based approaches. The aim should not only be to find anti-T3SS drugs but also to develop novel or improved vaccines. Continuous efforts to understand many remaining fundamental questions about the structure and function of T3SSs will also be needed. PMID- 25727141 TI - Slaughterhouse survey of cystic echinococcosis in cattle and sheep from the Republic of Moldova. AB - The Echinococcus granulosus tapeworm is responsible for cystic echinococcosis (CE), a zoonotic disease with worldwide distribution. The life cycle of the parasite is mainly domestic and takes place between dogs and livestock species. A slaughterhouse survey was conducted in 2012 in the Republic of Moldova in order to estimate the prevalence of CE. A total of 1525 cattle, 5580 sheep and 12,700 pigs were surveyed. No CE infection was observed in pigs, while prevalence was estimated at 59.3% in cattle and 61.9% in sheep. Infection was significantly higher in animals raised in private households than in those from collective farms. The frequency of infection increased with age in both species. In cattle and in sheep, infection of both the liver and lungs was the most common, while infection in the lungs only was much less frequent. Farm type appears to be an important factor in CE infection in Moldova, due to the extensive farming and the home-slaughtering undertaken in the majority private sector, despite a high prevalence of CE also recorded in the public sector. The low fertility of cysts in cattle (1.1%) compared to sheep (47.6%) confirmed the maintenance of E. granulosus sensu stricto in a dog-sheep life cycle which excludes cattle. Further studies are needed to obtain a complete overview of the parasite's epidemiology in its intermediate and definitive hosts, in order to implement control and preventive measures, with specific attention given to farms in the private sector. PMID- 25727143 TI - Machine learning in medical imaging. PMID- 25727142 TI - PATIENTS' AND RELATIVES' EXPERIENCES OF PERITONITIS WHEN USING PERITONEAL DIALYSIS. AB - BACKGROUND: Internationally, increasing numbers of patients are requiring treatment for end-stage kidney disease and greater use of peritoneal dialysis is thus being promoted. However, peritonitis can be a significant problem in this population. It is the leading cause of technique failure in patients using peritoneal dialysis and results in considerable morbidity and mortality. There is a dearth of research exploring patients' and their families' experiences of peritonitis. OBJECTIVES: The aim of this paper is to explore patients' and their families' perspectives and experiences of peritonitis. DESIGN: An ethnographic study was conducted in 2011 in the United Kingdom. PARTICIPANTS: Sixteen patients and nine of their relatives were recruited through purposive and convenience sampling. APPROACH: In-depth interviews were undertaken with patients and their families, who were also observed using peritoneal dialysis in their homes. The data were analysed thematically using Wolcott's (1994) three-stage approach. RESULTS: This article describes four themes: learning about the risk of peritonitis; measures taken to prevent the infection; how participants monitored continuously for signs and symptoms of the infection; how they then identified and intervened once peritonitis was suspected. Overall, peritonitis was associated with fear and uncertainty, pain and learning from episodes of the infection. CONCLUSIONS: Overall, peritonitis was a distressing experience that participants sought to prevent. However, there was some confusion amongst participants about the signs and symptoms of the infection and further education for patients and their families is thus crucial. PMID- 25727144 TI - Glycosylation and cancer: moving glycomics to the forefront. AB - There is a long research history of studying the function of glycosylation in relation to the development and progression of different types of cancer. The technological advances of the "omic" have in the last decade have afforded many new opportunities and approaches for studying the cancer glycome. A collection of research articles has been assembled that collectively summarize the progress in this area for each type of major O-linked and N-linked glycan species and other classes of glycans, as well as what is known about specific glycans associated with individual types of cancer (brain, breast, colon, liver, lung, ovarian, pancreatic, prostate). These chapters also include descriptions of the latest cutting-edge technologies that have been developed recently for cancer glycomic studies. An introduction to these topics and highlights of emerging areas of research opportunity for cancer glycomics are presented. This includes the development of new glycomics-based cancer biomarkers and therapeutic targets, as well as different integrated cancer "omics" strategies. PMID- 25727145 TI - Glycans and cancer: role of N-glycans in cancer biomarker, progression and metastasis, and therapeutics. AB - Glycosylation is catalyzed by various glycosyltransferase enzymes which are mostly located in the Golgi apparatus in cells. These enzymes glycosylate various complex carbohydrates such as glycoproteins, glycolipids, and proteoglycans. The enzyme activity of glycosyltransferases and their gene expression are altered in various pathophysiological situations including cancer. Furthermore, the activity of glycosyltransferases is controlled by various factors such as the levels of nucleotide sugars, acceptor substrates, nucleotide sugar transporters, chaperons, and endogenous lectin in cancer cells. The glycosylation results in various functional changes of glycoproteins including cell surface receptors and adhesion molecules such as E-cadherin and integrins. These changes confer the unique characteristic phenotypes associated with cancer cells. Therefore, glycans play key roles in cancer progression and treatment. This review focuses on glycan structures, their biosynthetic glycosyltransferases, and their genes in relation to their biological significance and involvement in cancer, especially cancer biomarkers, epithelial-mesenchymal transition, cancer progression and metastasis, and therapeutics. Major N-glycan branching structures which are directly related to cancer are beta1,6-GlcNAc branching, bisecting GlcNAc, and core fucose. These structures are enzymatic products of glycosyltransferases, GnT-V, GnT-III, and Fut8, respectively. The genes encoding these enzymes are designated as MGAT5 (Mgat5), MGAT3 (Mgat3), and FUT8 (Fut8) in humans (mice in parenthesis), respectively. GnT-V is highly associated with cancer metastasis, whereas GnT-III is associated with cancer suppression. Fut8 is involved in expression of cancer biomarker as well as in the treatment of cancer. In addition to these enzymes, GnT-IV and GnT-IX (GnT-Vb) will be also discussed in relation to cancer. PMID- 25727147 TI - Intracellular protein O-GlcNAc modification integrates nutrient status with transcriptional and metabolic regulation. AB - The inducible, nutrient-sensitive posttranslational modification of protein Ser/Thr residues with O-linked beta-N-acetylglucosamine (O-GlcNAc) occurs on histones, transcriptional regulators, metabolic enzymes, oncogenes, tumor suppressors, and many critical intermediates of growth factor signaling. Cycling of O-GlcNAc modification on and off of protein substrates is catalyzed by the actions of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. To date, there are less than 150 publications addressing the role of O-GlcNAc modification in cancer and over half were published in the last 2 years. These studies have clearly established that increased expression of OGT and hyper-O GlcNAcylation is common to human cancers of breast, prostate, colon, lung, and pancreas. Furthermore, attenuating OGT activity reduces tumor growth in vitro and metastasis in vivo. This chapter discusses the structure and function of the O GlcNAc cycling enzymes, mechanisms by which protein O-GlcNAc modification sense changes in nutrient status, the influence of O-GlcNAc cycling enzymes on glucose metabolism, and provides an overview of recent observations regarding the role of O-GlcNAcylation in cancer. PMID- 25727146 TI - Simple sugars to complex disease--mucin-type O-glycans in cancer. AB - Mucin-type O-glycans are a class of glycans initiated with N-acetylgalactosamine (GalNAc) alpha-linked primarily to Ser/Thr residues within glycoproteins and often extended or branched by sugars or saccharides. Most secretory and membrane bound proteins receive this modification, which is important in regulating many biological processes. Alterations in mucin-type O-glycans have been described across tumor types and include expression of relatively small-sized, truncated O glycans and altered terminal structures, both of which are associated with patient prognosis. New discoveries in the identity and expression of tumor associated O-glycans are providing new avenues for tumor detection and treatment. This chapter describes mucin-type O-glycan biosynthesis, altered mucin-type O glycans in primary tumors, including mechanisms for structural changes and contributions to the tumor phenotype, and clinical approaches to detect and target altered O-glycans for cancer treatment and management. PMID- 25727148 TI - The detection and discovery of glycan motifs in biological samples using lectins and antibodies: new methods and opportunities. AB - Recent research has uncovered unexpected ways that glycans contribute to biology, as well as new strategies for combatting disease using approaches involving glycans. To make full use of glycans for clinical applications, we need more detailed information on the location, nature, and dynamics of glycan expression in vivo. Such studies require the use of specimens acquired directly from patients. Effective studies of clinical specimens require low-volume assays, high precision measurements, and the ability to process many samples. Assays using affinity reagents-lectins and glycan-binding antibodies-can meet these requirements, but further developments are needed to make the methods routine and effective. Recent advances in the use of glycan-binding proteins involve improved determination of specificity using glycan arrays; the availability of databases for mining and analyzing glycan array data; lectin engineering methods; and the ability to quantitatively interpret lectin measurements. Here, we describe many of the challenges and opportunities involved in the application of these new approaches to the study of biological samples. The new tools hold promise for developing methods to improve the outcomes of patients afflicted with diseases characterized by aberrant glycan expression. PMID- 25727149 TI - Glycosylation characteristics of colorectal cancer. AB - Glycans on proteins and lipids are known to alter with malignant transformation. The study of these may contribute to the discovery of biomarkers and treatment targets as well as understanding of cancer biology. We here describe the change of glycosylation specifically defining colorectal cancer with view on N-glycans, O-glycans, and glycosphingolipid glycans in colorectal cancer cells and tissues as well as patient sera. Glycan alterations observed in colon cancer include increased beta1,6-branching and correlating higher abundance of (poly-)N acetyllactosamine extensions of N-glycans as well as an increase in (truncated) high-mannose type glycans, while bisected structures decrease. Colorectal cancer associated O-glycan changes are predominated by reduced expression of core 3 and 4 glycans, whereas higher levels of core 1 glycans, (sialyl) T-antigen, (sialyl) Tn-antigen, and a generally higher density of O-glycans are observed. Specific changes for glycosphingolipid glycans are lower abundances of disialylated structures as well as globo-type glycosphingolipid glycans with exception of Gb3. In general, alterations affecting all discussed glycan types are increased sialylation, fucosylation as well as (sialyl) Lewis-type antigens and type-2 chain glycans. As a consequence, interactions with glycan-binding proteins can be affected and the biological function and cellular consequences of the altered glycosylation with regard to tumorigenesis, metastasis, modulation of immunity, and resistance to antitumor therapy will be discussed. Finally, analytical approaches aiding in the field of glycomics will be reviewed with focus on binding assays and mass spectrometry. PMID- 25727151 TI - Functional impact of tumor-specific N-linked glycan changes in breast and ovarian cancers. AB - Changes in glycosylation have been implicated in various human diseases, including cancer. Research over the past few decades has produced significant findings that illustrate the importance of cancer-specific alterations in glycosylation in the regulation of tumor formation and metastasis. The identification of glycan-based biomarkers and strategies targeting specific glycan epitopes on the tumor cell surface has become one of the widely pursued research areas. In this chapter, we will summarize and provide perspective on available knowledge about the functional roles that glycan structures play in the development and progression of the gynecological cancers, breast and ovarian, with a specific focus on N-linked glycans. A better understanding of the functional roles for glycans in cancer will drive future innovations for diagnostics and therapeutics. PMID- 25727150 TI - Glycosylation and liver cancer. AB - Liver cancer is the fifth most common cancer, but the second leading cause of cancer death, in the world, with more than 700,000 fatalities annually. The major etiology of liver cancer is infection with an hepatotropic virus such as hepatitis B virus or hepatitis C virus infection. While chronic viral infection remains the main cause of liver disease and risk of hepatocellular carcinoma (HCC), rates of nonviral-associated HCC are occurring at an alarmingly increasing rate. Like many cancers, survival rates are closely associated with time of detection. If HCC is caught early, survival rates can be as high as 50%. Regrettably, most cases of HCC are caught late where survival rates can be as low as 2-7%. Thus, there has been great interest in discovering serum biomarkers that could be used to identify those with HCC. To this end, many groups have examined the N-linked glycans to identify changes that occur with HCC. As the liver secretes the vast majority of proteins into the serum, this has often been a starting point for study. In serum, alterations in core fucosylation, outer-arm fucosylation, increased sialylation, and glycan branching have been observed in patients with HCC. Similar findings have been found directly in HCC tissue suggesting that these glycan changes may play a role in tumor formation and development. PMID- 25727153 TI - Altered glycosylation in prostate cancer. AB - Prostate cancer is annually the most common newly diagnosed cancer in men. The prostate functions as a major secretory gland for the production of glycoproteins critical to sperm activation and reproduction. Prostate-specific antigen (PSA), produced by the prostate, is one of the most commonly assayed glycoproteins in blood, serving as a biomarker for early detection and progression of prostate cancer. The single site of N-glycosylation on PSA has been the target of multiple glycan characterization studies. In this review, the extensive number of studies that have characterized the changes in O-linked and N-linked glycosylations associated with prostate cancer development and progression will be summarized. This includes analysis of the glycosylation of PSA, and other prostate glycoproteins, in tissues, clinical biofluids, and cell line models. Other studies are summarized in the context of understanding the complexities of these glycan changes in order to address the many confounding questions associated with prostate cancer, as well as efforts to improve prostate cancer biomarker assays using targeted glycomic-based strategies. PMID- 25727154 TI - Unique to this volume is the subsequent focus of individual chapters on what is known about glycosylation in relation to specific organ sites of cancer. Preface. PMID- 25727155 TI - Effects of nitrate dosing on sulfidogenic and methanogenic activities in sewer sediment. AB - Nitrate dosing is widely used to control sulfide and methane formation in sewers. The impact of nitrate on sulfide and methane production by sewer biofilms in rising mains has been elucidated recently. However, little is known about the effect of nitrate on biologically active sewer sediment, which is substantially thicker than rising main biofilms (centimeters vs. hundreds of micrometers, respectively). In this study, we investigated the effect of nitrate addition to sewer sediment cultivated in lab-scale sewer sediment reactors. Batch test results showed that nitrate addition does not suppress sulfide production in sewer sediment, but it reduces sulfide accumulation through anoxic sulfide oxidation in the sediment and hence, also reduces sulfide accumulation in the bulk water. Microsensor measurement of sediment sulfide revealed the presence of sulfide oxidation and sulfide production zones with the interface dynamically regulated by the depth of nitrate penetration. In contrast, the methane production activity of sewer sediment was substantially reduced, likely due to the long-term inhibitory effects of nitrate on methanogens. Pore water measurements showed that methane production activity in the sediment zone with frequent nitrate exposure was completely suppressed, and consequently, the methane production zone re-established deeper in the sediment where nitrate penetration was infrequent. PMID- 25727152 TI - Glycosylation alterations in lung and brain cancer. AB - Alterations in glycosylation are common in cancer and are thought to contribute to disease. Lung cancer and primary malignant brain cancer, most commonly glioblastoma, are genetically heterogeneous diseases with extremely poor prognoses. In this review, we summarize the data demonstrating that glycosylation is altered in lung and brain cancer. We then use specific examples to highlight the diverse roles of glycosylation in these two deadly diseases and illustrate shared mechanisms of oncogenesis. In addition to alterations in glycoconjugate biosynthesis, we also discuss mechanisms of postsynthetic glycan modification in cancer. We suggest that alterations in glycosylation in lung and brain cancer provide novel tumor biomarkers and therapeutic targets. PMID- 25727156 TI - Environmental sustainability of an energy self-sufficient sewage treatment plant: improvements through DEMON and co-digestion. AB - It is still not proven that treatment of sewage in a wastewater treatment plant (WWTP) is (in every case) environmentally friendly. To address this matter, we have applied a state-of-the-art life cycle assessment (LCA) to an energy self sufficient WWTP in Strass (Austria), its supply chain and the valorization of its 'products': produced electricity out of biogas from sludge digestion and the associated stabilized digestate, applied as agricultural fertilizer. Prominent aspects of our study are: a holistic environmental impact assessment, measurement of greenhouse gas emissions (including N2O), and accounting for infrastructure, replacement of conventional fertilizers and toxicity of metals present in the stabilized digestate. Additionally, the environmental sustainability improvement by implementing one-stage partial nitritation/anammox (e.g. DEMON((r))) and co digestion was also assessed. DEMON on the digesters reject water leads to a considerable saving of natural resources compared to nitritiation/denitritation (about 33% of the life cycle resource input), this through the lowering of sludge consumption for N-removal, and thus increasing electricity production via a higher sludge excess. However, its N2O emission could be restrained through further optimization as it represents a large share (30-66%) of the plants' damaging effect on human health, this through climate change. The co-substrate addition to the digester resulted in no significant improvement of the digestion process but induced net electricity generation. If respective amounts of conventional fertilizers are replaced, the land application of the stabilized digestate is environmentally friendly through prevention of natural resource consumption and diversity loss, but possibly not regarding human health impact due the presence of toxic heavy metals, mainly Zn, in the digestate. The outcomes show that the complete life cycle results in a prevention of resource extraction from nature and a potential mitigation of diversity loss (though for some impact categories no quantification of associated diversity loss is possible) but it also leads to a damaging effect on human health, mainly via climate change and heavy metal toxicity. Since it is for now impossible to aggregate the impact to these different aspects in a sound manner, it is not yet possible to consider in this case the studied system as environmentally friendly. Generally, the field of LCA needs further development to present a better and single outcome. PMID- 25727157 TI - PIC microcontroller based external fast analog to digital converter to acquire wide-lined solid NMR spectra by BRUKER DRX and Avance-I spectrometers. AB - Concerning many former liquid or hybrid liquid/solid NMR consoles, the built in Analog-to-Digital Converters (ADCs) are incapable of digitizing the fids at sampling rates in the MHz range. Regarding both strong anisotropic interactions in the solid state and wide chemical shift dispersion nuclei in solution phase such as (195)Pt, (119)Sn, (207)Pb etc., the spectrum range of interest might be in the MHz range. As determining the informative tensor components of anisotropic NMR interactions requires nonlinear fitting over the whole spectrum including the asymptotic baseline, it is prohibited by low sampling rates of the ADCs. Wide spectrum width is also useful in solution NMR, since windowing of wide chemical shift ranges is avoidable. We built an external analog to digital converter with 10 MHz maximal sampling rate, which can work simultaneously with the built in ADC of the spectrometer. The ADC was tested on both Bruker DRX and Avance-I NMR consoles. In addition to the analog channels it only requires three external digital lines of the NMR console. The ADC sends data to PC via USB. The whole process is controlled by software written in JAVA which is implemented under TopSpin. PMID- 25727161 TI - 'HepConomics': cost-effective, indeed, but how can we pay for it? PMID- 25727162 TI - [Fetomaternal transfusion and diagnosis of gestational choriocarcinoma]. AB - Choriocarcinoma is a rare but agressive malignant trophoblastic neoplasm. Fetomaternal transfusion can be the first sign of choriocarcinoma. We describe two cases of gestational choriocarinoma whose first manifestation was a fetomaternal transfusion. Fetomaternal transfusion is a rare demonstration of choriocarcinoma but its diagnosis must lead to a placenta examination with specific research of choriocarcinoma. The more the therapeutic care is precise, the better is the forecast. PMID- 25727163 TI - [Migraine and contraception]. AB - Migraine is a common pathology in women. Migraine disease is well defined by the International Headache Society and has to be distinguished from others types of headaches. The occurrence of migraine attacks is frequently linked to the menstrual cycle. Many studies have related a connexion with hormonal fluctuations and migraine event. Migraine with aura is currently identified as a stroke risk factor and this risk dramatically increases in case of oestroprogestative pill intake and smoking. The World Health Organization established guidelines about oestroprogestative intake in case of migraine while strictly contraindicating oestroprogestative intake in patients with migraine with aura. This review explains the influence of different contraceptive intake, oral contraceptive regimens, and type of oestrogen in oestroprogestative contraceptive on migraine occurrence. PMID- 25727164 TI - [Ultrasonographic score for predicting vaginal delivery within 24h of induction: a pilot study]. AB - OBJECTIVE: Evaluate if a score based on ultrasound measurements (cervical length, perineal-fetal presentation distance, fetal occiput position) before the induction of labour is a good predictive test of vaginal delivery within 24h and compare it to Bishop score. METHODS: From January to April 2014, we included in a monocentric prospective study 45 patients who underwent a labour induction in the department of obstetrics and gynecology at Croix-Rousse Hospital. Ultrasound measurements of the distance between the perineum and the foetal presentation (with transperineal ultrasound), of the cervical length (with transvaginal ultrasound) and of the position of the occiput were collected before induction. Bishop score was also calculated for these patients, without receiving ultrasound data (and vice versa), in order to determine the mode of induction. Receiver Operating Characteristics (ROC) curves were used to evaluate performance of the ultrasonographic score and the Bishop score for predicting vaginal delivery within 24h. RESULTS: The area under the ROC curve for ultrasonographic score was 84.5% (IC95% 64,6-100%). The area under the ROC curve for Bishop score was 73.2% (IC95% 64,2-82,2%). The comparison of these areas under the curve has shown a difference of 11.3% with a P-value of 0.055 in a two-tailed test. CONCLUSION: Ultrasonographic score made with a combination of these ultrasound measurements appears to be an effective test to predict the chances of vaginal delivery within 24h of induction. PMID- 25727165 TI - Acute pulmonary embolism masquerading as inferior myocardial infarction. PMID- 25727166 TI - Hemorrhagic transformation of a plunging ranula: an unusual cause of a rapidly enlarging neck mass. PMID- 25727167 TI - Comparison of quantitative EEG to current clinical decision rules for head CT use in acute mild traumatic brain injury in the ED. AB - STUDY OBJECTIVE: We compared the performance of a handheld quantitative electroencephalogram (QEEG) acquisition device to New Orleans Criteria (NOC), Canadian CT Head Rule (CCHR), and National Emergency X-Radiography Utilization Study II (NEXUS II) Rule in predicting intracranial lesions on head computed tomography (CT) in acute mild traumatic brain injury in the emergency department (ED). METHODS: Patients between 18 and 80 years of age who presented to the ED with acute blunt head trauma were enrolled in this prospective observational study at 2 urban academic EDs in Detroit, MI. Data were collected for 10 minutes from frontal leads to determine a QEEG discriminant score that could maximally classify intracranial lesions on head CT. RESULTS: One hundred fifty-two patients were enrolled from July 2012 to February 2013. A total 17.1% had acute traumatic intracranial lesions on head CT. Quantitative electroencephalogram discriminant score of greater than or equal to 31 was found to be a good cutoff (area under receiver operating characteristic curve = 0.84; 95% confidence interval [CI], 0.76-0.93) to classify patients with positive head CT. The sensitivity of QEEG discriminant score was 92.3 (95% CI, 73.4-98.6), whereas the specificity was 57.1 (95% CI, 48.0-65.8). The sensitivity and specificity of the decision rules were as follows: NOC 96.1 (95% CI, 78.4-99.7) and 15.8 (95% CI, 10.1-23.6); CCHR 46.1 (95% CI, 27.1-66.2) and 86.5 (95% CI, 78.9-91.7); NEXUS II 96.1 (95% CI, 78.4 99.7) and 31.7 (95% CI, 23.9-40.7). CONCLUSION: At a sensitivity of greater than 90%, QEEG discriminant score had better specificity than NOC and NEXUS II. Only CCHR had better specificity than QEEG discriminant score but at the cost of low (<50%) sensitivity. PMID- 25727168 TI - Successful treatment of epidural anesthesia-induced severe pneumocephalus by hyperbaric oxygen therapy. PMID- 25727169 TI - A comparison of routine, opt-out HIV screening with the expected yield from physician-directed HIV testing in the ED. AB - OBJECTIVES: The Centers for Disease Control and Prevention recommends routine opt out HIV screening in health care settings. Our goal was to evaluate the feasibility and yield of this strategy in the emergency department (ED) and to compare it to the expected yield of physician-directed testing. METHODS: This is a cross-sectional study in an urban ED during random shifts over 1 year. Patients were ineligible for screening if they were younger than 18 years or older than 64, a prisoner, a victim of sexual assault, in an ED resuscitation room, or had altered mental status. Research associates administered rapid HIV tests and conducted standardized interviews. The patients' ED physician, blinded to the HIV result, was asked if they would have ordered a rapid HIV test if it had been available. RESULTS: Of 7756 ED patients, 3957 (51%) were eligible for HIV screening, and 2811 (71%) of those did not opt out. Routine testing yielded 9 new HIV cases (0.32% of those tested; 95% confidence interval, 0.16%-0.63%). Physician-directed testing would have missed most of these infections: 2 of the 785 patients identified by physicians for testing would have been newly diagnosed with HIV (0.25%; 95% confidence interval, 0.04%-1.0%). Of the 9 new HIV cases, 5 established HIV care, and their median CD4 count was 201 cells/MUL (range, 71-429 cells/MUL). CONCLUSIONS: Routine opt-out HIV screening was feasible and accepted by a majority of ED patients. The yield of this strategy only modestly exceeded what may have been observed with physician-directed testing. PMID- 25727170 TI - Effects of lead and cadmium co-exposure on hemoglobin in a Chinese population. AB - Cadmium (Cd) and lead (Pb) show adverse effects on hemoglobin. But most studies are focussed on one single agent. In this study, we observed the main and interactive effects of Cd and Pb on the hemoglobin level in a Chinese population. A total of 308 persons (202 women and 106 men), living in controlled and polluted areas, were included in this study. Blood and urine were collected to determine the levels of hemoglobin (Hb), Cd, Pb, and urinary N-acetyl-beta-D glucosaminidase (UNAG). The Cd and Pb level of subjects living in the polluted area were significantly higher compared to those living in the control area (p<0.05). The level of hemoglobin was declined with the increasing BPb (p<0.05) and BCd in women. The Hb of women and men with the highest level of BCd and BPb were decreased by 8.3g/L and 10.7 g/L compared to those with the lowest level of BCd and BPb, respectively. The Hb level of those women and men with the highest level of UNAG decreased by 4.2g/L and 17.2g/L compared with those with low level of UNAG, respectively. Hb was negatively associated with BPb, BCd, and UNAG. This study evidenced that Cd and Pb can influence Hb level. In addition, our study shows that Cd and Pb may have interactive effects on Hb and Hb level was correlated with tubular dysfunction caused by Cd and Pb exposure. PMID- 25727171 TI - Gallic acid isolated from Spirogyra sp. improves cardiovascular disease through a vasorelaxant and antihypertensive effect. AB - In this study, we investigated the vasorelaxant and antihypertensive effects of gallic acid (GA), a polyphenol isolated from the green alga Spirogyra sp., to assess its suitability as a therapeutic for cardiovascular diseases (CVDs). We examined the effect of GA on endothelium-dependent vasorelaxation in human umbilical vein endothelial cells (HUVECs). GA increased nitric oxide (NO) levels by increasing phosphorylation of endothelial nitric oxide synthase (eNOS), and its effect on NO production was attenuated by pretreatment with the eNOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). We also investigated its antihypertensive effect by examining GA-mediated inhibition of angiotensin-I converting enzyme (ACE). GA inhibited ACE with a half-maximal inhibitory concentration (IC50) value of 37.38 +/- 0.39 MUg/ml. In silico simulations revealed that GA binds to the active site of ACE (PDB: 1O86) with a binding energy of -270.487 kcal/mol. Furthermore, GA clearly reduced blood pressure in spontaneously hypertensive rats (SHR) to an extent comparable to captopril. These results suggest that GA isolated from Spirogyra sp. exerts multiple therapeutic effects and has potential as a CVD treatment. PMID- 25727172 TI - Biocompatibility of electrospun human albumin: a pilot study. AB - Albumin is rarely used for electrospinning because it does not form fibres in its native globular form. This paper presents a novel method for electrospinning human albumin from a solution containing pharmaceutical grade protein and 25% polyethylene oxide (PEO) used as the fibre-forming agent. After spontaneous cross linking at body temperature, with no further chemicals added, the fibres become insoluble and the excess PEO can be washed out. Albumin deposited along the fibres retains its native characteristics, such as its non-adhesiveness to cells and its susceptibility for degradation by macrophages. To demonstrate this we evaluated the mechanical properties, biocompatibility and biodegradability of this novel product. After subcutaneous implantation in mice, albumin mats were completely resorbable within six days and elicited only a limited local inflammatory response. In vitro, the mats suppressed cell attachment and migration. As this product is inexpensive, produced from human pharmaceutical grade albumin without chemical modifications, retains its native protein properties and fulfils the specific requirements for anti-adhesive dressings, its clinical use can be expedited. We believe that it could specifically be used when treating paediatric patients with epidermolysis bullosa, in whom non-healing wounds occur after minor hand injuries which lead to rapid adhesions and devastating contractures. PMID- 25727173 TI - Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats. AB - The naturally occurring polyphenol phytoalexin resveratrol (RSV) regulates neuronal inflammation in various disease models and protects the brain against ischemic injury. Cell surface glutamate transporters on perisynaptic astrocytes are important regulators of extracellular glutamate levels and synaptic activation. Following cerebral ischemia, reduced astroglial type-1 glutamate transporter (GLT-1) expression in the CA1 pyramidal layers of the hippocampus contribute to neurotoxic glutamate levels. The current study examined the effects of 21-day RSV pretreatment (1 or 10mg/kg dose; i.p.) on microglia and astrocyte activation and characterized GLT-1 expression in the dentate gyrus (DG), CA1 and CA3 layers of the hippocampus 7 days following 10min global ischemia. Male Wistar rats were divided into five groups; sham/saline, ischemia/saline, ischemia/1mg/kg RSV, ischemia/10mg/kg RSV and sham/10mg/kg RSV. Immunohistochemical detection of GLT-1, CD11b/c, glial fibrillary acidic protein (GFAP) assessed type 1 glutamate transporter expression and microglial/glial cell activation following sham surgery or global ischemia. Our findings demonstrate prevention by RSV of ischemia-induced reduction of GLT-1 expression in the vulnerable CA1 layer 7 days following global ischemia, which was accompanied by the polyphenol's inhibition of post ischemic increase in CD11b/c and GFAP expression. RSV also conferred significant CA1 neuronal protection positively correlated with attenuation of glutamate transporter activation. These findings support beneficial effects of RSV in modulation of the excitotoxic cascade postischemia, which are congruent with anti-inflammatory effects observed in various pathological models. PMID- 25727174 TI - Trio gene is required for mouse learning ability. AB - Trio is a guanine nucleotide exchange factor with multiple guanine nucleotide exchange factor domains. Trio regulates cytoskeleton dynamics and actin remodeling and is involved in cell migration and axonal guidance in neuronal development. The null allele of the Trio gene led to embryonic lethality, and Trio null embryos displayed aberrant organization in several regions of the brain at E18.5, including hippocampus. Nestin-Trio-/- mice, in which the Trio gene was deleted specifically in the neuronal system by the Nestin-Cre system, displayed severe phenotypes, including low survival rate, ataxia and multiple developmental defects of the cerebellum. All Nestin-Trio-/- mice died before reaching adulthood, which hinders research on Trio gene function in adult mice. Thus, we generated EMX1-Trio-/- mice by crossing Trio-floxed mice with EMX1-Cre mice in which Cre is expressed in the brain cortex and hippocampus. EMX1-Trio-/- mice can survive to adulthood. Trio gene deletion results in smaller brains, an abnormal hippocampus and disordered granule cells in the dentate gyrus (DG) and cornu ammonis (CA). Behavior tests showed that Trio deletion interfered with the hippocampal-dependent spatial learning in the mice, suggesting that Trio plays critical roles in the learning ability of adult mice. We conclude that the Trio gene regulates the neuronal development of the hippocampus and that it affects the intelligence of adult mice. PMID- 25727175 TI - What is ischemia and how should this be defined based on modern imaging? AB - How do we define myocardial ischemia? This is an important question for clinicians and one that, while conceptually straight forward, can be practically difficult to assess. In this article we describe the various imaging methods available in cardiology to quantify myocardial ischemia. Anatomic assessments of ischemia such as angiography, while the "gold standard", have limitations. While some of these limitations can be mitigated with invasively measurements of fractional flow reserve or intravascular ultrasound, these tools have their own weaknesses. Non-invasive metabolic assessment, such as measuring glucose and fatty acid metabolism, are reliable in identifying ischemic, hibernating, or stunned myocardium but can be difficult to use clinically. Non-invasive physiologic assessment with myocardial perfusion agents with single photon emission tomography imaging and positron emission tomography (PET) with measurement of absolute myocardial flow additionally have their own strengths and weaknesses. In this article we review the data behind the various cardiac modalities used in defining myocardial assessments along with their strengths, practical use, and limitations. We conclude by discussing an integrative approach of relative uptake and absolute myocardial flow using cardiac PET imaging that allows for a more accurate assessment of ischemia along with cases demonstrating various scenarios available in cardiac PET imaging. PMID- 25727176 TI - Technical advances and clinical applications of quantitative myocardial blood flow imaging with cardiac MRI. AB - The recent FAME 2 study highlights the importance of myocardial ischemia assessment, particularly in the post-COURAGE trial era of managing patients with stable coronary artery disease. Qualitative assessment of myocardial ischemia by stress cardiovascular magnetic resonance imaging (CMR) has gained widespread clinical acceptance and utility. Despite the high diagnostic and prognostic performance of qualitative stress CMR, the ability to quantitatively assess myocardial perfusion reserve and absolute myocardial blood flow remains an important and ambitious goal for non-invasive imagers. Quantitative perfusion by stress CMR remains a research technique that has yielded progressively more encouraging results in more recent years. The ability to safely, rapidly, and precisely procure quantitative myocardial perfusion data would provide clinicians with a powerful tool that may substantially alter clinical practice and improve downstream patient outcomes and the cost effectiveness of healthcare delivery. This may also provide a surrogate endpoint for clinical trials, reducing study population sizes and costs through increased power. This review will cover emerging quantitative CMR techniques for myocardial perfusion assessment by CMR, including novel methods, such as 3-dimensional quantitative myocardial perfusion, and some of the challenges that remain before more widespread clinical adoption of these techniques may take place. PMID- 25727178 TI - Salvage low-dose-rate permanent seed brachytherapy for locally recurrent prostate cancer: Association between dose and late toxicity. AB - PURPOSE: Rates of late toxicity are higher for salvage treatment of local recurrence after prior radiotherapy. We present our experience with salvage prostate brachytherapy (BT) for local recurrence after definitive external beam radiotherapy with attention to the relationship between dose and late toxicity. METHODS AND MATERIALS: From 2005 to 2012, 18 patients with biopsy proven locally recurrent prostate cancer and negative staging received low-dose-rate BT with a prescribed dose of 130-144 Gy. Toxicities were graded using Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Median followup is 31.5 months (range, 12-104). International Prostate Symptom Scores peaked at 3 months (median, 21/35), returning to baseline by 24 months. Urinary catheterization rate was 33% (median duration, 14 days; range, 1-90 days). Late Grade 3/4 genitourinary toxicity occurred in 1 patient each, one of whom also had Grade 3 late gastrointestinal toxicity; urethral strictures developed in three others. These 5 patients with late toxicity had higher dose to the prostate (isodose enclosing 90% [D90] median, 151 Gy; range, 135-185 Gy) compared with those without late complications (median, 134 Gy; range, 105-165; p < 0.04). Acute gastrointestinal toxicity Grade <3 occurred in 44%. Four patients (22%) experienced biochemical failure. CONCLUSION: Salvage low-dose-rate prostate BT can provide durable biochemical control. Care should be taken to select patients with higher likelihood of organ-confined disease. The goal of planning should be to treat the recurrent disease to an adequate dose with careful attention to maintain a conservative D90. PMID- 25727179 TI - Juvenile hormone (JH) esterase activity but not JH epoxide hydrolase activity is downregulated in larval Adoxophyes honmai following nucleopolyhedroviruses infection. AB - Juvenile hormones (JHs) and ecdysteroids are critical insect developmental hormones. JH esterase (JHE) and JH epoxide hydrolase (JHEH) are JH-selective enzymes that metabolize JH and thus regulate the titer of JH. Baculoviruses are known to alter host endocrine regulation. The nucleopolyhedroviruses, AdhoNPV and AdorNPV, are known to have slow and fast killing activity against Adoxophyes honmai (Lepidoptera: Tortricidae), respectively. Here we found that when penultimate (4th) instar A. honmai are inoculated with AdhoNPV or AdorNPV, the mean survival time is 9.7 and 8.2 days, respectively. The larvae molted once but did not pupate. The AdhoNPV- or AdorNPV-infected larvae did not show a dramatic increase in JHE activity as was found in mock-infected larvae, instead they showed a marked decrease in JHE activity. In contrast, both viral infections had no effect on JHEH activity. In order to further characterize the JHE activity, the JHE-coding sequence of A. honmai (ahjhe) was cloned and confirmed to encode a biologically active JHE. Quantitative real-time PCR analysis of ahjhe expression in 4th and 5th instar A. honmai revealed that AdhoNPV and AdorNPV are able to reduce ahjhe expression levels. PMID- 25727177 TI - Diagnostic Biomarkers for Posttraumatic Stress Disorder: Promising Horizons from Translational Neuroscience Research. AB - Posttraumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). Although its diagnostic features have been recently reclassified with the emergence of the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition, the disorder remains characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the etiology and maintenance of PTSD. Translational research spanning the past few decades has revealed several potential avenues for the identification of diagnostic biomarkers for PTSD. These include, but are not limited to, monoaminergic transmitter systems, the hypothalamic-pituitary-adrenal axis, metabolic hormonal pathways, inflammatory mechanisms, psychophysiological reactivity, and neural circuits. The current review provides an update to the literature with regard to the most promising putative PTSD biomarkers, with specific emphasis on the interaction between neurobiological influences on disease risk and symptom progression. Such biomarkers will most likely be identified by multi-dimensional models derived from comprehensive descriptions of molecular, neurobiological, behavioral, and clinical phenotypes. PMID- 25727180 TI - Therapeutic plasma exchange in antisynthetase syndrome with severe interstitial lung disease. AB - Antisynthetase syndrome (ASS) is a rare condition characterized by interstitial lung disease (ILD), inflammatory myositis, fever, Raynaud phenomenon, mechanic's hand, and inflammatory polyarthritis in the setting of antibodies to amino acyl transfer RNA synthetases, with anti-Jo-1 antibody being the most common. Prognosis is very poor especially when there is associated ILD. To date, there is no standardized treatment for ILD associated ASS. Therapy is based on the use of steroids alone or in combination with other immunosuppressive agents, especially in severe or refractory cases. The role of therapeutic plasma exchange (TPE) in the management of this rare condition has not been established. Here, we report a case of severe ILD associated ASS in a 41-year-old woman who did not show clinical or laboratory response after six doses of high dose steroids and a dose of IV cyclophosphamide. Because of the aggressive nature of her disease and poor prognostic indices present, a decision was made to add TPE to her treatment. She underwent five sessions of TPE. At the end of the 5th session, the anti-Jo-1 antibody levels dropped to 3.6 AI (antibody index) and her creatinine kinase (CK) level from 875 to 399 U L(-1) (Units per liter) with overall improvement in her respiratory status. This case suggests TPE may be a promising treatment option in patients with ILD associated ASS refractory to steroids and other immunosuppressive therapy, particularly those with severe disease. PMID- 25727181 TI - Novel monoclonal antibody against alphaX subunit from horse CD11c/CD18 integrin. AB - The alphaX I-domain of the horse integrin CD11c was successfully expressed in Escherichia coli, purified, biochemically characterized and used as immunogen to generate murine monoclonal antibodies against horse CD11c, which are not yet commercially available. One monoclonal antibody mAb-1C4 against the alphaX I domain, is an IgG2a able to interact with the recombinant I-domain, showing an EC50=2.4ng according to ELISA assays. By western blot with horse PBMCs lysates the mAb-1C4 recognized a protein of 150kDa which corresponds well with the CD11c molecule. Using immunohistochemistry in horse lymph node tissue sections, mAb-1C4 marked cells in situ, some with apparent dendritic morphology. Thus the mAb generated to a recombinant epitope from horse CD11c identified the molecule in intact cells within horse lymphoid tissue. By the labelling intensity, the histological location (paracortical and interfollicular areas) and the apparent morphology of the marked cells, we can say that these are putative horse dendritic cells (DCs). The development of a mAb to horse CD11c provides a new tool to better study the horse DC biology and opens other biotechnological avenues, such as DC targeting-based vaccines. PMID- 25727182 TI - The stress-induced heat shock protein 70.3 expression is regulated by a dual component mechanism involving alternative polyadenylation and HuR. AB - Heat shock protein 70.3 (Hsp70.3) expression increases in response to cellular stress and plays a cytoprotective role. We have previously shown that Hsp70.3 expression is controlled through coordinated post-transcriptional regulation by miRNAs and alternative polyadenylation (APA), and APA-mediated shortening of the Hsp70.3 3'-UTR facilitates increased protein expression. A stress-induced increase in Hsp70.3 mRNA and protein expression is accompanied by alternative polyadenylation (APA)-mediated truncation of the 3'UTR of the Hsp70.3 mRNA transcript. However, the role that APA plays in stress-induced expression of Hsp70.3 remains unclear. Our results show that APA-mediated truncation of the Hsp70.3 3'UTR increases protein expression through enhanced polyribosome loading. Additionally, we demonstrate that the RNA binding protein HuR, which has been previously shown to play a role in mediating APA, is necessary for heat shock mediated increase in Hsp70.3 mRNA and protein. However, it is somewhat surprising to note that HuR does not play a role in APA of the Hsp70.3 mRNA, and these two regulatory events appear to be mutually exclusive regulators of Hsp70.3 expression. These results not only provide important insight to the regulation of stress response genes following heat shock, but also contribute an enhanced understanding of how alternative polyadenylation contributes to gene regulation. PMID- 25727183 TI - Biological management of Sclerotinia sclerotiorum in pea using plant growth promoting microbial consortium. AB - The beneficial plant-microbe interactions play crucial roles in protection against large number of plant pathogens causing disease. The present study aims to investigate the growth promoting traits induced by beneficial microbes namely Pseudomonas aeruginosa PJHU15, Trichoderma harzianum TNHU27, and Bacillus subtilis BHHU100 treated singly and in combinations under greenhouse and field conditions to control Sclerotinia sclerotiorum. Plants treated with three microbe consortium enhanced plant growth maximally both in the presence and absence of the pathogen. Increase in plant length, total biomass, number of leaves, nodules and secondary roots, total chlorophyll and carotenoid content, and yield were recorded in plants treated with microbial consortia. Also, a decrease in plant mortality was observed in plants treated with microbial consortia in comparison to untreated control plants challenged with S. sclerotiorum. Furthermore, the decrease in disease of all the treatments can be associated with differential improvement of growth induced in pea. PMID- 25727184 TI - Each cell counts: Hematopoiesis and immunity research in the era of single cell genomics. AB - Hematopoiesis and immunity are mediated through complex interactions between multiple cell types and states. This complexity is currently addressed following a reductionist approach of characterizing cell types by a small number of cell surface molecular features and gross functions. While the introduction of global transcriptional profiling technologies enabled a more comprehensive view, heterogeneity within sampled populations remained unaddressed, obscuring the true picture of hematopoiesis and immune system function. A critical mass of technological advances in molecular biology and genomics has enabled genome-wide measurements of single cells - the fundamental unit of immunity. These new advances are expected to boost detection of less frequent cell types and fuzzy intermediate cell states, greatly expanding the resolution of current available classifications. This new era of single-cell genomics in immunology research holds great promise for further understanding of the mechanisms and circuits regulating hematopoiesis and immunity in both health and disease. In the near future, the accuracy of single-cell genomics will ultimately enable precise diagnostics and treatment of multiple hematopoietic and immune related diseases. PMID- 25727185 TI - Structural basis for carbohydrate binding properties of a plant chitinase-like agglutinin with conserved catalytic machinery. AB - A new chitinase-like agglutinin, RobpsCRA, related to family GH18 chitinases, has previously been identified in black locust (Robinia pseudoacacia) bark. The crystal structure of RobpsCRA at 1.85A resolution reveals unusual molecular determinants responsible for the lack of its ancestral chitinase activity. Unlike other chitinase-like proteins, which lack chitinase catalytic residues, RobpsCRA has conserved its catalytic machinery. However, concerted rearrangements of loop regions coupled to non-conservative substitutions of aromatic residues central to the chitin-binding groove explain the lack of hydrolytic activity against chitin and the switch toward recognition of high-mannose type N-glycans. Identification of close homologs in flowering plants with conservation of sequence motifs associated to the structural adaptations seen in RobpsCRA defines an emerging class of agglutinins, as emphasized by a phylogenetic analysis, that are likely to share a similar carbohydrate binding specificity for high-mannose type N glycans. This study illustrates the recent evolution and molecular adaptation of a versatile TIM-barrel scaffold within the ancestral GH18 family. PMID- 25727186 TI - Influence of food matrix on outgrowth heterogeneity of heat damaged Bacillus cereus spores. AB - Spoilage of heat treated foods can be caused by the presence of surviving spore formers. It is virtually impossible to prevent contamination at the primary production level as spores are ubiquitous present in the environment and can contaminate raw products. As a result spore inactivation treatments are widely used by food producing industries to reduce the microbial spore loads. However consumers prefer mildly processed products that have less impact on its quality and this trend steers industry towards milder preservation treatments. Such treatments may result in damaged instead of inactivated spores, and these spores may germinate, repair, and grow out, possibly leading to quality and safety issues. The ability to repair and grow out is influenced by the properties of the food matrix. In the current communication we studied the outgrowth from heat damaged Bacillus cereus ATCC 14579 spores on Anopore membrane, which allowed following outgrowth heterogeneity of individual spores on broccoli and rice-based media as well as standard and mildly acidified (pH 5.5) meat-based BHI. Rice, broccoli and BHI pH 5.5 media resulted in delayed outgrowth from untreated spores, and increased heterogeneity compared to BHI pH 7.4, with the most pronounced effect in rice media. Exposure to wet heat for 1 min at 95 degrees C caused 2 log inactivation and approximately 95% of the spores in the surviving fraction were damaged resulting in substantial delay in outgrowth based on the time required to reach a maximum microcolony size of 256 cells. The delay was most pronounced for heat-treated spores on broccoli medium followed by spores on rice media (both untreated and treated). Interestingly, the increase in outgrowth heterogeneity of heat treated spores on BHI pH 7.4 was more pronounced than on rice, broccoli and BHI pH 5.5 conceivably reflecting that conditions in BHI pH 7.4 better support spore damage repair. This study compares the effects of three main factors, namely heat treatment, pH of BHI and the effect of food matrix highlighting the impact of different (model) food recovery media on outgrowth efficiency and heterogeneity of non-heat-treated and heat-damaged B. cereus spores. PMID- 25727187 TI - Development of a new suturing technique for tendon graft preparation: an animal cadaver study. AB - BACKGROUND: This study should analyze ten different suturing techniques for tendon graft preparation to allow the development of an entirely new suturing technique. METHODS: Extensor tendon grafts of fattening bulls' forelegs were sutured with Ethibond Excel size three (six metric) fibers (Ethicon, Somerville, New York, USA). The tendon/suture complexes were biomechanically tested with a hydraulic testing machine applying traction according to a standardized protocol. The testing was observed to find out why the failure at the maximum traction load occurred. The mean values for the maximum tension and extension stiffness were recorded for each suturing technique. FINDINGS: An entirely new suturing technique was developed based on the observations and biomechanical results. The newly developed suture was also tested and provided a higher traction stability than the other ten techniques that had been evaluated. Compared to the other ten techniques the new technique was ranked 3rd in terms of extension stiffness and reached 10.3 N/mm. INTERPRETATION: The new technique evolved in the course of this study provided promising results. Therefore this study provides initial evidence that this technique could be useful in clinical routine. PMID- 25727188 TI - Halophilic microbial communities and their environments. AB - Use of culture-independent studies have greatly increased our understanding of the microbiology of hypersaline lakes (the Dead Sea, Great Salt Lake) and saltern ponds in recent years. Exciting new information has become available on the microbial processes in Antarctic lakes and in deep-sea brines. These studies led to the recognition of many new lineages of microorganisms not yet available for study in culture, and their cultivation in the laboratory is now a major challenge. Studies of the metabolic potentials of different halophilic microorganisms, Archaea as well as Bacteria, shed light on the possibilities and the limitations of life at high salt concentrations, and also show their potential for applications in bioremediation. PMID- 25727190 TI - Separation and concentration of sulfonylurea herbicides in milk by ionic-liquid based foam flotation solid-phase extraction. AB - The ultrasound-assisted ionic liquid foam flotation solid-phase extraction of sulfonylurea herbicides in milk was developed and validated. The proteins and lipids were isolated from the sample matrix by adding salt and adjusting the pH value. The target analytes eluted from the solid-phase extraction cartridge were determined by high-performance liquid chromatography. Some experimental parameters, including the pH value of sample solution, amount of NaCl, ionic liquid type, extraction time, flow rate of carrier gas, flotation time, and solid phase extraction cartridge type were investigated and optimized. Under the optimized experimental conditions, the limits of detection for metsulfuron, pyrazosulfuron, chlorimuron-ethyl, and nicosulfuron were 1.3, 0.6, 0.7, and 1.1 MUg/L, respectively. When the present method was applied to the analysis of milk samples the recoveries of the analytes ranged from 84.3 to 105.2% and relative standard deviations were >5.7%. PMID- 25727191 TI - In response to A systematic review of the quality of randomized controlled trials in head and neck oncology surgery. PMID- 25727192 TI - Integrating responsible conduct of research education into undergraduate biochemistry and molecular biology laboratory curricula. AB - Recently, a requirement for directed responsible conduct in research (RCR) education has become a priority in the United States and elsewhere. In the US, both the National Institutes of Health and the National Science Foundation require RCR education for all students who are financially supported by federal awards. The guidelines produced by these agencies offer useful templates for the introduction of RCR materials into courses worldwide. Many academic programs already offer courses or workshops in RCR for their graduate students and for undergraduate science majors and/or researchers. Introducing RCR into undergraduate biochemistry and molecular biology laboratory curricula is another, highly practical way that students can be exposed to these important topics. In fact, a strong argument can be made for integrating RCR into laboratory courses because these classes often introduce students to a scientific environment like that they might encounter in their careers after graduation. This article focuses on general strategies for incorporating explicit RCR education into biochemistry and molecular biology laboratory coursework using the topics suggested by NIH as a starting point. PMID- 25727193 TI - Cortistatin protects myocardium from endoplasmic reticulum stress induced apoptosis during sepsis. AB - Sepsis and septic shock are common entities encountered in intensive care units. Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis, and myocardial apoptosis is a key step for this progression, which may contribute to cardiac contractile dysfunction. Increasing evidence suggested the anti-inflammatory role of cortistatin (CST) during lethal endotoxemia. However, the direct protective effect of CST on myocardial is still not clear. Here, we aimed to study whether CST can directly protect myocardial from apoptosis. To test that, we used cecal ligation and puncture (CLP) induced sepsis rat model. CST (175 ug/kg, intraperitoneal administration) was injected every 24 h before the model induction for 3 days. Electron microscopy, TUNEL staining, caspase-3 expression, and the Bcl-2/Bax ratio were used to measure myocardial apoptosis. In addition, the protein levels of endoplasmic reticulum stress (ERS) markers were overexpressed in sepsis. To further test whether CST can directly protect myocardial apoptosis from ERS, we compared dithiothreitol (DTT) induced cardiomyocyte (CM) ERS with or without CST in vitro. We found that CST strongly attenuated lipopolysaccharide (LPS) and DTT induced CM ERS. Blocking GHS-R1a, one of CST's receptors expressed by CMs, completely abrogated CST's protective effect. Finally, CST's protective effect was associated with the decrease of ERS both in vivo and in vitro. In conclusion, our results for the first time showed the previously unexpected role of CST to directly protect myocardial from apoptosis through inhibiting ERS and partly through GHS-R1a. PMID- 25727194 TI - High throughput screening of particle conditioning operations: II. Evaluation of scale-up heuristics with prokaryotically expressed polysaccharide vaccines. AB - Multivalent polysaccharide conjugate vaccines are typically comprised of several different polysaccharides produced with distinct and complex production processes. Particle conditioning steps, such as precipitation and flocculation, may be used to aid the recovery and purification of such microbial vaccine products. An ultra scale-down approach to purify vaccine polysaccharides at the micro-scale would greatly enhance productivity, robustness, and speed the development of novel conjugate vaccines. In part one of this series, we described a modular and high throughput approach to develop particle conditioning processes (HTPC) for biologicals that combines flocculation, solids removal, and streamlined analytics. In this second part of the series, we applied HTPC to industrially relevant feedstreams comprised of capsular polysaccharides (CPS) from several bacterial species. The scalability of HTPC was evaluated between 0.8 mL and 13 L scales, with several different scaling methodologies examined. Clarification, polysaccharide yield, impurity clearance, and product quality achieved with HTPC were reproducible and comparable with larger scales. Particle sizing was the response with greatest sensitivity to differences in processing scale and enabled the identification of useful scaling rules. Scaling with constant impeller tip speed or power per volume in the impeller swept zone offered the most accurate scale up, with evidence that time integration of these values provided the optimal basis for scaling. The capability to develop a process at the micro-scale combined with evidence-based scaling metrics provide a significant advance for purification process development of vaccine processes. The USD system offers similar opportunities for HTPC of proteins and other complex biological molecules. PMID- 25727195 TI - An ab initio study of nuclear volume effects for isotope fractionations using two component relativistic methods. AB - We investigate the accuracy of two-component Douglas-Kroll-Hess (DKH) methods in calculations of the nuclear volume term (= lnK(nv)) in the isotope fractionation coefficient. lnK(nv) is a main term in the chemical equilibrium constant for isotope exchange reactions in heavy element. Previous work based on the four component method reasonably reproduced experimental lnK(nv) values of uranium isotope exchange. In this work, we compared uranium reaction lnK(nv) values obtained from the two-component and four-component methods. We find that both higher-order relativistic interactions and spin-orbit interactions are essential for quantitative description of lnK(nv). The best alternative is the infinite order Douglas-Kroll-Hess method with infinite-order spin-orbit interactions for the one-electron term and atomic-mean-field spin-same-orbit interaction for the two-electron term (IODKH-IOSO-MFSO). This approach provides almost equivalent results for the four-component method, while being 30 times faster. The IODKH IOSO-MFSO methodology should pave the way toward computing larger and more general molecules beyond the four-component method limits. PMID- 25727196 TI - Modern Art as Public Care: Alzheimer's and the Aesthetics of Universal Personhood. AB - This article is based on ethnographic research of the New York Museum of Modern Art's influential Alzheimer's access program, Meet Me at MoMA. The program belongs to an increasingly popular model of psychosocial treatment that promotes art as potentially therapeutic or beneficial to people experiencing symptoms of dementia as well as to their caregivers. Participant observation of the sessions and a series of interviews with museum staff and educators reveal broader assumptions about the relationship between modern art, dementia, and personhood. These assumptions indicate a museological investment in the capacity and perceived interiority of all participants. Ultimately, the program authorizes a narrative of universal personhood that harmonizes with the museum's longstanding focus on temporal and aesthetic modernism. PMID- 25727197 TI - Quantitative proteomic approaches in mouse: stable isotope incorporation by metabolic (SILAC) or chemical labeling (reductive dimethylation) combined with high-resolution mass spectrometry. AB - Mass spectrometry-based quantitative proteomics is a powerful method for in-depth exploration of protein expression, allowing researchers to probe its regulation and study signal-transduction networks, protein turnover, secretion, and spatial distribution, as well as post-translational modification and protein-protein interaction, on a large scale. Precise protein quantitation may be achieved by incorporation of stable isotopes, which introduce a mass shift detectable by mass spectrometry, allowing multiplexing of several samples and therefore relative quantification. Stable isotope incorporation into proteins or peptides can be attained either by metabolic labeling (e.g., SILAC) or by chemical labeling (e.g., reductive dimethylation). Both labeling approaches are presented here. They are straightforward and robust and can be applied to murine samples. While both SILAC and reductive dimethylation offer similar multiplexing capabilities and quantitative accuracy, reductive dimethylation is more versatile and can be used with any sample type. PMID- 25727198 TI - Overview of biological mechanisms and applications of three murine models of bone repair: closed fracture with intramedullary fixation, distraction osteogenesis, and marrow ablation by reaming. AB - Fractures are one of the most common large-organ, traumatic injuries in humans, and osteoporosis-related fractures are the fastest growing health care problem of aging. Elective orthopedic surgeries of the bones and joints also represent some of most common forms of elective surgeries performed. Optimal repair of skeletal tissues is necessary for successful outcomes of these many different orthopedic surgical treatments. Research focused on post-natal skeletal repair is therefore of immense clinical importance and of particular relevance in situations in which bone tissue healing is compromised due to the extent of tissue trauma or specific medical co-morbidities. Three commonly used murine surgical models of bone healing, closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming, are presented. The biological aspects of these models are contrasted and the types of research questions that may be addressed with these models are presented. PMID- 25727199 TI - Mouse models of bone healing: fracture, marrow ablation, and distraction osteogenesis. AB - Three commonly used murine surgical models of bone healing [closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming] are presented. Detailed surgical protocols for each model are outlined. The nature of the regenerative processes and the types of research questions that may be addressed with these models are briefly outlined. The relative strengths and weaknesses of these models are compared to a number of other surgical models that are used to address similar research questions. PMID- 25727200 TI - Mouse anesthesia and analgesia. AB - Providing anesthesia and analgesia for mouse subjects is a common and critical practice in the laboratory setting. These practices are necessary for performing invasive procedures, achieving prolonged immobility for sensitive imaging modalities (magnetic resonance imaging for instance), and providing intra- and post-procedural pain relief. In addition to facilitating the procedures performed by the investigator, the provision of anesthesia and analgesia is crucial for the preservation of animal welfare and for humane treatment of animals used in research. Furthermore, anesthesia and analgesia are important components of animal use protocols reviewed by Institutional Animal Care and Use Committees, requiring careful consideration and planning for the particular animal model. In this article, we provide technical outlines for the investigator covering the provision of anesthesia by two routes (injectable and inhalant), guidelines for monitoring anesthesia, current techniques for recognition of pain, and considerations for administering preventative analgesia. PMID- 25727201 TI - Glucose tolerance tests for systematic screening of glucose homeostasis in mice. AB - This article presents a detailed description of intraperitoneal and oral glucose tolerance tests in mice. The former is widely used in initial high-throughput phenotyping of mutant mice to assess a diabetic phenotype and alterations in glucose homeostasis. Each protocol provides a comprehensive description of each step in the workflow, including variation of the standard protocol under particular circumstances (e.g., sensitivity to food deprivation, excessive deviations in body composition, or need for extra blood samples for additional analyses). We also describe how reduction of body mass and body temperature can be used as additional readouts to monitor metabolic function in response to food deprivation. PMID- 25727202 TI - Ludwig von Bertalanffy's organismic view on the theory of evolution. AB - Ludwig von Bertalanffy was a key figure in the advancement of theoretical biology. His early considerations already led him to recognize the necessity of considering the organism as a system, as an organization of parts and processes. He termed the resulting research program organismic biology, which he extended to all basic questions of biology and almost all areas of biology, hence also to the theory of evolution. This article begins by outlining the rather unknown (because often written in German) research of Bertalanffy in the field of theoretical biology. The basics of the organismic approach are then described. This is followed by Bertalanffy's considerations on the theory of evolution, in which he used methods from theoretical biology and then introduced his own, organismic, view on evolution, leading to the demand for finding laws of evolution. Finally, his view on the concept of homology is presented. PMID- 25727203 TI - Oxidative addition of carbon-carbon bonds to gold. AB - The oxidative addition of strained C?C bonds (biphenylene, benzocyclobutenone) to DPCb (diphosphino-carborane) gold(I) complexes is reported. The resulting cationic organogold(III) complexes have been isolated and fully characterized. Experimental conditions can be adjusted to obtain selectively acyl gold(III) complexes resulting from oxidative addition of either the C(aryl)?C(O) or C(alkyl)?C(O) bond of benzocyclobutenone. DFT calculations provide mechanistic insight into this unprecedented transformation. PMID- 25727208 TI - Role of crushed skeletal muscle extract in hemostasis. AB - BACKGROUND: Use of muscle grafts for hemostasis during surgery has re-emerged; recent animal model studies have shown effective bleeding control with their use. However, the mechanism of action is unknown. The aim of this study is to evaluate the action of muscle extracts on the coagulation pathways and platelet aggregation. METHODS: Muscle extracts were prepared by dissolving crushed snap frozen muscle tissue (0.04 to 0.8 mg) in 1 mL saline. Saline was used as control. Prothrombin time, activated partial thromboplastin time (APTT), thrombin time, and platelet aggregation studies were performed on both muscle extract and saline. Prothrombin time and APTT were repeated using factor VII-deficient plasma, factor X-deficient plasma, lupus plasma, and contact pathway-inhibited plasma. Mean readings in the muscle group and control group were compared using nonparametric Mann-Whitney U test (Wilcoxon rank sum test with continuity correction). RESULTS: Among the various coagulation parameters, there was no significant difference between saline and muscle (p > 0.05), except in the APTT using factor X-deficient plasma (mean APTT 133.89 seconds and 185.10 seconds for muscle and saline, respectively; p < 0.0001). Higher concentrations of the muscle extract (>0.5 mg/mL) increased platelet aggregation from 23.9% to 85.5% (p = 0.0001). CONCLUSION: Platelet aggregation plays a role in the hemostatic efficacy of muscle grafts. Even though action on the coagulation pathway via APTT is statistically significant, clinical significance may be low. PMID- 25727209 TI - Pathogenic functions of B cells in autoimmune diseases: IFN-gamma production joins the criminal gang. AB - B-cell depletion therapy has emerged as a powerful strategy to intercept the progression of T-cell-mediated autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, or relapsing remitting multiple sclerosis. However, its mode of action remains incompletely defined, reflecting our incomplete understanding of the pathogenic functions of B cells in such pathologies. B cells can contribute to immune responses through the production of antibodies, presentation of antigen to T cells, and production of cytokines. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2015. 45: 988-998], Olalekan et al. demonstrate that IFN-gamma production by B cells is essential for the development of arthritis in mice. Lack of IFN-gamma expression in B cells results in reduced autoimmune T cell responses and autoantibody levels, impacting the arthritogenic reaction akin to that in B-cell depletion therapy. Together with other reports, the article by Olalekan et al. emphasizes the importance of cytokine-producing B cells in the pathogenesis of autoimmune diseases. In this commentary, I discuss how these findings shed new light on the roles of B cells as drivers of autoimmune pathogenesis, and how they more generally contribute to our understanding of the role of B cells in immunity. PMID- 25727210 TI - Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma. AB - BACKGROUND: Histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. As a result, more sophisticated and objective methods have been sought. The goal of this study was to identify a gene expression signature that reliably differentiated benign and malignant melanocytic lesions and evaluate its potential clinical applicability. Herein, we describe the development of a gene expression signature and its clinical validation using multiple independent cohorts of melanocytic lesions representing a broad spectrum of histopathologic subtypes. METHODS: Using quantitative reverse-transcription polymerase chain reaction (PCR) on a selected set of 23 differentially expressed genes, and by applying a threshold value and weighting algorithm, we developed a gene expression signature that produced a score that differentiated benign nevi from malignant melanomas. RESULTS: The gene expression signature classified melanocytic lesions as benign or malignant with a sensitivity of 89% and a specificity of 93% in a training cohort of 464 samples. The signature was validated in an independent clinical cohort of 437 samples, with a sensitivity of 90% and specificity of 91%. CONCLUSIONS: The performance, objectivity, reliability and minimal tissue requirements of this test suggest that it could have clinical application as an adjunct to histopathology in the diagnosis of melanocytic neoplasms. PMID- 25727212 TI - Label-free, zeptomole cancer biomarker detection by surface-enhanced fluorescence on nanoporous gold disk plasmonic nanoparticles. AB - We experimentally demonstrate a label-free biosensor for the ERBB2 cancer gene DNA target based on the distance-dependent detection of surface-enhanced fluorescence (SEF) on nanoporous gold disk (NPGD) plasmonic nanoparticles. We achieve detection of 2.4 zeptomole of DNA target on the NPGD substrate with an upper concentration detection limit of 1 nM. Without the use of molecular spacers, the NPGD substrate as an SEF platform was shown to provide higher net fluorescence for visible and NIR fluorophores compared to glass and non-porous gold substrates. The enhanced fluorescence signals in patterned nanoporous gold nanoparticles make NPGD a viable material for further reducing detection limits for biomolecular targets used in clinical assays. With patterned nanoporous gold disk (NPGD) plasmonic nanoparticles, a label-free biosensor that makes use of distance-dependent detection of surface-enhanced fluorescence (SEF) is constructed and tested for zeptomole detection of ERBB2 cancer gene DNA targets. PMID- 25727211 TI - Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains. AB - Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. PMID- 25727213 TI - Study on the interaction between ginsenoside Rh2 and calf thymus DNA by spectroscopic techniques. AB - The interaction between ginsenoside Rh2 (G-Rh2) and calf thymus DNA (ctDNA) was investigated by spectroscopic methods including UV-vis absorption, fluorescence and circular dichroism (CD) spectroscopy, coupled with DNA melting techniques and viscosity measurements. Stern-Volmer plots at different temperatures proved that the quenching mechanism was a static quenching procedure. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS) were calculated to be -22.83 KJ . mol(-1) and 15.11 J . mol(-1) . K(-1) by van 't Hoff equation, suggesting that hydrophobic force might play a major role in the binding of G-Rh2 to ctDNA. Moreover, the fluorescence quenching study with potassium iodide as quencher indicated that the KSV (Stern-Volmer quenching constant) value for the bound G-Rh2 with ctDNA was lower than the free G-Rh2. The relative viscosity of ctDNA increased with the addition of G-Rh2 and also the ctDNA melting temperature increased in the presence of G-Rh2. Denatured DNA studies showed that quenching by single-stranded DNA was less than that by double-stranded DNA. The observed changes in CD spectra also demonstrated that the intensities of the positive and negative bands decreased with the addition of G-Rh2. The experimental results suggest that G-Rh2 molecules bind to ctDNA via an intercalative binding mode. PMID- 25727214 TI - Esthetic Evaluation of Implant Crowns and Peri-Implant Soft Tissue in the Anterior Maxilla: Comparison and Reproducibility of Three Different Indices. AB - BACKGROUND: A successful implant reconstruction with optimal esthetics consists of a visually pleasing prosthesis and complete and healthy surrounding soft tissue. In the current literature, numerous indices used to qualitatively assess esthetics have been described. However, studies comparing the indices and their reproducibility are scarce. PURPOSE: The aim of this study was to compare three different esthetic indices for the evaluation of single implant-supported crowns. MATERIALS AND METHODS: A total of 10 prosthodontists (P), 10 orthodontists (O), 10 general dentists (G), and 10 lay people (L) independently performed the same assessment using 30 photographs and corresponding casts with three different esthetic indices (Peri-Implant and Crown Index [PICI], Implant Crown Aesthetic Index [ICAI], "Pink Esthetic Score/White Esthetic Score [PES/WES]) and repeated the evaluations 4 weeks later. RESULTS: The PES/WES and the PICI showed significantly higher esthetic scores (pink, white, total) and clinical acceptance compared with the ICAI in all four groups and in both assessments. The highest intraobserver agreement was achieved using the PES/WES and the least with the ICAI. The mean Kappa per group ranged from 0.18 (group L with ICAI) to 0.63 (group G with PICI). CONCLUSION: In comparison with the ICAI, the PES/WES and PICI were more reproducible. Therefore, PES/WES and PICI seem to be more suitable as esthetic indices for single implant crowns. PMID- 25727215 TI - Enantioselective desymmetrization of prochiral cyclohexanones by organocatalytic intramolecular Michael additions to alpha,beta-unsaturated esters. AB - A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. Employing a cyclohexanediamine-derived primary amine organocatalyst, a range of prochiral cyclohexanone derivatives possessing an alpha,beta-unsaturated ester moiety linked to the 4-position afforded the bicyclic products, which possess three stereogenic centers, as single diastereoisomers in high enantioselectivity (83-99% ee) and in good yields (60-90%). Calculations revealed that stepwise C-C bond formation and proton transfer via a chair-shaped transition state dictate the exclusive endo selectivity and enabled the development of a highly enantioselective primary amine catalyst. PMID- 25727218 TI - Introduction. Neurooncology: update on therapeutic options. PMID- 25727216 TI - Methylation-induced loss of miR-484 in microsatellite-unstable colorectal cancer promotes both viability and IL-8 production via CD137L. AB - Colorectal cancer (CRC) exhibiting MSI (microsatellite instability) represents a well-defined subtype characterized by a deficient mismatch repair pathway and typical clinico-pathological features. Our objective was to identify the entire miRNome and its molecular pathological roles in MSI CRCs. We profiled miRNA expression in MSI CRCs and compared it with MSS counterparts. Microarray and qRT PCR analysis identified eight miRNAs that could distinguish the MSI status of CRCs. MiR-484 was the most significantly decreased miRNA in MSI CRCs, primarily mediated by the CpG island methylator phenotype. MiR-484 functions as a tumour suppressor to inhibit MSI CRC cell viability in vitro and in vivo. Moreover, miR 484 repressed CD137L expression and thereby attenuated IL-8 production by MSI CRC cells. Our results contribute to a better understanding of the roles of dysregulated miRNAs in the distinct phenotypic features of MSI CRCs and indicate an option for early diagnosis and gene therapy for these patients. PMID- 25727219 TI - Novel delivery methods bypassing the blood-brain and blood-tumor barriers. AB - Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications. PMID- 25727220 TI - Aggressive repeat surgery for focally recurrent primary glioblastoma: outcomes and theoretical framework. AB - OBJECT The relative benefit of repeat surgery for recurrent glioblastoma is unclear, in part due to the very heterogeneous nature of the patient population and the effect of clinician philosophy on the duration and aggressiveness of treatment. The authors sought to investigate the role of time to last recurrence on patient outcomes following aggressive repeat surgery for recurrent glioblastoma. METHODS The authors present outcomes in 104 patients undergoing repeat surgery for focally recurrent glioblastoma with at least 95% resection and adjuvant treatment at most recent prior surgery. In addition to common variables, they provide data regarding the period of progression-free survival (PFS) following an aggressive lesionectomy for focally recurrent primary glioblastoma (T2) and the time the tumor took to recur since the previous surgery (T1). They term the ratio T1/T2 the relative aggressivity index (RAI). RESULTS The median PFS was 7.8 months, 6.0 months, and 4.8 months following the second, third, and fourth-sixth craniotomies, respectively. Importantly, there was a wide range of outcomes, with time to postoperative recurrence ranging from 1 to 24 months in this group. Analysis showed no meaningful relationship between T1 and T2, meaning that previous PFS is entirely unable to predict the PFS that another surgery will provide the patient. CONCLUSIONS Repeat surgery for glioblastoma is beneficial in many cases, however this is hard to predict preoperatively. Often, surgery can provide the patient with a good period of disease freedom, but this is variable and in general it is not possible to reliably predict who these patients are. PMID- 25727221 TI - Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors. AB - OBJECT: Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells. METHODS: Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress-induced cell death, autophagy, and cell death. RESULTS: All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis. CONCLUSIONS: Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas. PMID- 25727222 TI - Renaissance of laser interstitial thermal ablation. AB - Laser interstitial thermal therapy (LITT) is a minimally invasive technique for treating intracranial tumors, originally introduced in 1983. Its use in neurosurgical procedures was historically limited by early technical difficulties related to the monitoring and control of the extent of thermal damage. The development of magnetic resonance thermography and its application to LITT have allowed for real-time thermal imaging and feedback control during laser energy delivery, allowing for precise and accurate provision of tissue hyperthermia. Improvements in laser probe design, surgical stereotactic targeting hardware, and computer monitoring software have accelerated acceptance and clinical utilization of LITT as a neurosurgical treatment alternative. Current commercially available LITT systems have been used for the treatment of neurosurgical soft-tissue lesions, including difficult to access brain tumors, malignant gliomas, and radiosurgery-resistant metastases, as well as for the ablation of such lesions as epileptogenic foci and radiation necrosis. In this review, the authors aim to critically analyze the literature to describe the advent of LITT as a neurosurgical, laser excision tool, including its development, use, indications, and efficacy as it relates to neurosurgical applications. PMID- 25727223 TI - The effects of alternating electric fields in glioblastoma: current evidence on therapeutic mechanisms and clinical outcomes. AB - Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields-also known as tumor-treating fields (TTFs)-represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue. PMID- 25727224 TI - Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas. AB - The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies. PMID- 25727225 TI - An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas. AB - The management of WHO Grade II "atypical" meningiomas (AMs) and Grade III "malignant" meningiomas (MMs) remains controversial and under-investigated in prospective studies. The roles of surgery, radiation therapy, radiosurgery, and chemotherapy have been incompletely delineated. This has left physicians to decipher how they should treat patients on a case-by-case basis. In this study, the authors review the English-language literature on the management and clinical outcomes associated with AMs and MMs diagnosed using the WHO 2000/2007 grading criteria. Twenty-two studies for AMs and 7 studies for MMs were examined in detail. The authors examined clinical decision points using the literature and concepts from evidence-based medicine. Acknowledging the retrospective nature of the studies concerning AM and MM, the authors did find evidence for the following clinical strategies: 1) maximal safe resection of AM and MM; 2) active surveillance after gross-total resection of AM; 3) adjuvant radiation therapy after subtotal resection of AM, especially in the absence of putative radioresistant features; and 4) adjuvant radiation therapy after resection of MM. PMID- 25727226 TI - A practical review of prognostic correlations of molecular biomarkers in glioblastoma. AB - Despite extensive efforts in research and therapeutics, achieving longer survival for patients with glioblastoma (GBM) remains a formidable challenge. Furthermore, because of rapid advances in the scientific understanding of GBM, communication with patients regarding the explanations and implications of genetic and molecular markers can be difficult. Understanding the important biomarkers that play a role in GBM pathogenesis may also help clinicians in educating patients about prognosis, potential clinical trials, and monitoring response to treatments. This article aims to provide an up-to-date review that can be discussed with patients regarding common molecular markers, namely O-6 methylguanine-DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q. The importance of the distinction between a prognostic and a predictive biomarker as well as clinical trials regarding these markers and their relevance to clinical practice are discussed. PMID- 25727227 TI - Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case series. AB - OBJECT In patients with large or symptomatic brain lesions from metastatic melanoma, the value of resection of metastases to facilitate administration of systemic ipilimumab therapy has not yet been described. The authors undertook this study to investigate whether craniotomy creates the opportunity for patients to receive and benefit from ipilimumab who would otherwise succumb to brain metastasis prior to the onset of regression. METHODS All patients with metastatic melanoma who received ipilimumab and underwent craniotomy for metastasis resection between 2008 and 2014 at the Massachusetts General Hospital were identified through retrospective chart review. The final analysis included cases involving patients who underwent craniotomy within 3 months prior to initiation of therapy or up to 6 months after cessation of ipilimumab administration. RESULTS Twelve patients met the inclusion criteria based on timing of therapy (median age 59.2). The median number of metastases at the time of craniotomy was 2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of ipilimumab were stopped for disease progression, and 1 was stopped for treatment induced colitis. Eight of 12 patients had improvement in their performance status following craniotomy. Of the 6 patients requiring corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction after surgery. Ten of 12 patients had died by the time of data collection, with 1 patient lost to follow up. The median survival after the start of ipilimumab treatment was 7 months. CONCLUSIONS In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment. PMID- 25727228 TI - Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma. AB - The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanoma's elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity. PMID- 25727229 TI - Preoperative endovascular embolization of meningiomas: update on therapeutic options. AB - In this review paper the authors analyze new therapeutic options for the embolization of meningiomas, as well as the future of meningioma treatment through recent relevant cohorts and articles. They investigate various embolic materials, types of meningiomas amenable to embolization, imaging techniques, and potential imaging biomarkers that could aid in the delivery of embolic materials. They also analyze perfusion status, complications, and new technical aspects of endovascular preoperative embolization of meningiomas. A literature search was performed in PubMed using the terms "meningioma" and "embolization" to investigate recent therapeutic options involving embolization in the treatment of meningioma. The authors looked at various cohorts, complications, materials, and timings of meningioma treatment. Liquid embolic materials are preferable to particle agents because particle embolization carries a higher risk of hemorrhage. Liquid agents maximize the effect of devascularization because of deeper penetration into the trunk and distal tumor vessels. The 3 main imaging techniques, MRI, CT, and angiography, can all be used in a complementary fashion to aid in analyzing and treating meningiomas. Intraarterial perfusion MRI and a new imaging modality for identifying biomarkers, susceptibility-weighted principles of echo shifting with a train of observations (SW-PRESTO), can relay information about perfusion status and degrees of ischemia in embolized meningiomas, and they could be very useful in the realm of therapeutics with embolic material delivery. Direct puncture is yet another therapeutic technique that would allow for more accurate embolization and less blood loss during resection. PMID- 25727230 TI - Effects of convection-enhanced delivery of bevacizumab on survival of glioma bearing animals. AB - OBJECT Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution. METHODS Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels. RESULTS The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice. CONCLUSIONS The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas. PMID- 25727231 TI - Therapeutic strategies to improve drug delivery across the blood-brain barrier. AB - Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it. PMID- 25727232 TI - Ionic liquid-mediated synthesis of meso-scale porous lanthanum-transition-metal perovskites with high CO oxidation performance. AB - Lanthanum-transition-metal perovskites with robust meso-scale porous frameworks (meso-LaMO3) are synthesized through the use of ionic liquids. The resultant samples demonstrate a rather high activity for CO oxidation, by taking advantage of unique nanostructure-derived benefits. This synthesis strategy opens up a new opportunity for preparing functional mesoporous complex oxides of various compositions. PMID- 25727233 TI - Proteome-wide B and T cell epitope repertoires in outer membrane proteins of Mycobacterium avium subsp. paratuberculosis have vaccine and diagnostic relevance: a holistic approach. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is an etiological agent of chronic inflammation of the intestine among ruminants and humans. Currently, there are no effective vaccines and sensitive diagnostic tests available for its control and detection. For this, it is of paramount importance to identify the MAP antigens, which may be immunologically recognized by the host immune system. To address this challenge, we performed identification of the immunogenic epitopes in the MAP outer membrane proteins (OMPs). We have previously identified 57 MAP proteins as OMPs [Rana A, Rub A, Akhter Y. 2014. Molecular BioSystems, 10:2329-2337] and have evaluated them for the epitope selection and analysis employing a computational approach. Thirty-five MAP OMPs are reported with nine mer peptides showing high binding affinity to major histocompatibility complex (MHC) class I molecules and 28 MAP OMPs with 15-mer peptides of high binding affinity for MHC class II molecules. The presence of MHC binding epitopes indicates the potential cell-mediated immune response inducing capacity of these MAP OMPs in infected host. To further investigate the humoral response inducing properties of OMPs of MAP, we report potential B cell epitopes based on the sequences of peptide antigens and their molecular structures. We also report 10 proteins having epitopes for both B and T cells representing potential candidates which may invoke both humoral and cellular immune responses in the host. These findings will greatly accelerate and expedite the formulation of effective and cost-efficient vaccines and diagnostic tests against MAP infection. PMID- 25727234 TI - Obituary. Prof Dr Dr h.c. Andre E. Lauchli. PMID- 25727235 TI - A Review and Proposed Approach to the Neutrophilic Dermatoses of Childhood. AB - Neutrophilic dermatoses (NDs) are inflammatory skin conditions that are not associated with infection. The classification and clinical approach to these conditions in children is poorly described. This review classifies these conditions into five nosological subtypes: Sweet's syndrome, pyoderma gangrenosum, aseptic pustules, neutrophilic urticarial dermatoses, and Marshall's syndrome. In addition, we review the various secondary diseases that need to be excluded in the clinical management of the NDs of childhood, with a focus on the autoinflammatory conditions that the reader may not be familiar with. We propose a practical clinical approach to these disorders. PMID- 25727236 TI - Outcomes of treatment targeting syntax production in people with Broca's-type aphasia: evidence from psycholinguistic assessment tasks and everyday conversation. AB - BACKGROUND: Capturing evidence of the effects of therapy within everyday communication is the holy grail of aphasia treatment design and evaluation. Whilst impaired sentence production is a predominant symptom of Broca's-type aphasia, the effects of sentence production therapy on everyday conversation have not been investigated. Given the context-sensitive nature of spoken production by people with aphasia, it is difficult to extrapolate implications for everyday conversation based on results from task-based assessment (such as picture description, story retell or interview). Thus, there are strong theoretical and clinical motivations to investigate generalization from sentence production treatment to everyday conversation. AIMS: To evaluate a theoretically driven treatment focused on the language production skills of participants with post stroke Broca's aphasia and to track outcomes from psycholinguistic assessment tasks to everyday conversation. METHODS & PROCEDURES: A case series design was utilized with pragmatic selection of participants with chronic aphasia undergoing the same assessment and treatment procedures. Nine participants with Broca's aphasia and their main conversation partners took part in the study. Treatment was implemented once weekly over 8 weeks and targeted production of basic syntax two, three and four constituent constructions-through principles of mapping and reduced syntax treatment. Use of different possible exemplars for nouns, particularly pronouns, was trained together with use of both light and heavy verbs. Participants had the opportunity to 'top-up' therapy practise by completely a homework task that mirrored the therapy task. OUTCOMES & RESULTS: Syntactic well-formedness was assessed in samples of constrained sentence production, narrative retell and naturally occurring conversations at baseline, 1 week post-treatment, and 1 month post-treatment. Treatment showed strong direct effects in trained and untrained sentence construction tasks, with some generalization to narrative retell tasks. There was little evidence of change in everyday conversation. CONCLUSIONS & IMPLICATIONS: Improvement in language production in constrained assessment tasks may not impact on everyday conversations. Implications for further research are discussed, e.g. the need for bridging interventions between constrained and unconstrained contexts of language production. Clinical implications include the potential to streamline therapy planning and delivery by making use of rich, hybrid therapies to treat individuals with similar symptom profiles but with a range of underlying deficits. PMID- 25727237 TI - The APSES transcription factor LmStuA is required for sporulation, pathogenic development and effector gene expression in Leptosphaeria maculans. AB - Leptosphaeria maculans causes stem canker of oilseed rape (Brassica napus). The APSES transcription factor StuA is a key developmental regulator of fungi, involved in morphogenesis, conidia production and also more recently described as required for secondary metabolite production and for effector gene expression in phytopathogenic fungi. We investigated the involvement of the orthologue of StuA in L. maculans, LmStuA, in morphogenesis, pathogenicity and effector gene expression. LmStuA is induced during mycelial growth and at 14 days after infection, corresponding to the development of pycnidia on oilseed rape leaves, consistent with the function of StuA described so far. We set up the functional characterization of LmStuA using an RNA interference approach. Silenced LmStuA transformants showed typical phenotypic defects of StuA mutants with altered growth in axenic culture and impaired conidia production and perithecia formation. Silencing of LmStuA abolished the pathogenicity of L. maculans on oilseed rape leaves and also resulted in a drastic decrease in expression of at least three effector genes during in planta infection, suggesting either that LmStuA regulates, directly or indirectly, the expression of several effector genes in L. maculans or that the infection stage in which effectors are expressed is not reached when LmStuA expression is silenced. PMID- 25727239 TI - An Exploratory Investigation of the Role of Parenting Stress in Relationship Focused Intervention. AB - BACKGROUND: Mothers of young children with Pervasive Developmental Disorders (PDD) and other disabilities (DD) have been reported to experience high levels of stress. This investigation examined the effects of parental stress on mothers' participation in a Relationship Focused intervention (RFI). METHODS: Mothers and young children who had either PDD (n = 18) or DD (n = 26) received weekly RF intervention for one year. RESULTS: Pre-post comparisons indicated significant increases in mothers' responsiveness and children's development and social emotional functioning. Intervention effects were greater for mothers of children with PDD than for mothers of children with DD. There were three findings related to the role parenting stress. First, high levels of parenting stress did not interfere with mothers' ability to learn RFI strategies; second, there were non significant decreases in parenting stress during intervention; third, parenting stress enhanced the effects of mothers' responsiveness on children. CONCLUSION: High levels of parenting stress does not appear to interfere with parent participation in RFI. PMID- 25727238 TI - Financial incentives for smoking cessation in pregnancy: a single-arm intervention study assessing cessation and gaming. AB - AIMS: Financial incentives were the single most effective intervention for smoking cessation in pregnancy in a recent Cochrane Review, but based on a few small trials in the United States using only 7-day point prevalence measures of cessation. This study estimates (a) prolonged cessation in an unselected population of English pregnant smokers who are offered financial incentives for quitting and (b) 'gaming', i.e. false reporting of smoking status to enter the scheme or gain an incentive. DESIGN: Single-arm intervention study SETTING: Antenatal clinic and community PARTICIPANTS: A total of 239 pregnant smokers enrolled into the financial incentive scheme, attending for maternity care at one hospital in an area of high deprivation in England over a 42-week period. MEASUREMENTS: Smoking cessation at delivery and 6 months postpartum, assessed using salivary cotinine; gaming assessed using urinary and salivary cotinine at enrolment, 28 and 36 weeks gestation, and 2 days and 6 months postpartum. FINDINGS: Thirty-nine per cent (239 of 615) of smokers were enrolled into the scheme, 60% (143 of 239) of whom made a quit attempt. Of those enrolled, 20% [48 of 239; 95% confidence interval (CI) = 14.9%, 25.1%] were quit at delivery and 10% (25 of 239; 95% CI = 6.2%, 13.8%) at 6 months postpartum. There was no evidence that women gamed to enter the scheme, but evidence that 4% (10 of 239) of those enrolled gamed on one or more occasions to gain vouchers. CONCLUSIONS: Enrolment on an incentive scheme in an unselected English cohort of pregnant smokers was associated with prolonged cessation rates comparable to those reported in US trials. Rates of gaming were arguably insufficiently high to invalidate the use of such schemes. PMID- 25727240 TI - Angina and mental stress-induced myocardial ischemia. AB - OBJECTIVE: Mental stress-induced myocardial ischemia is a common phenomenon in patients with coronary artery disease (CAD) and an emerging prognostic factor. Mental stress ischemia is correlated with ambulatory ischemia. However, whether it is related to angina symptoms during daily life has not been examined. METHODS: We assessed angina frequency (past month) in 98 post-myocardial infarction (MI) subjects (age 18-60 years) using the Seattle Angina Questionnaire. Patients underwent [(99m)Tc]sestamibi SPECT perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed difference score (SDS), the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. RESULTS: The mean age was 50 years, 50% were female and 60% were non-white. After adjustment for age, sex, smoking, CAD severity, depressive, anger, and anxiety symptoms, each 1-point increase in mental stress-SDS was associated with 1.73 unit increase in the angina frequency score (95% CI: 0.09-3.37) and 17% higher odds of being in a higher angina frequency category (OR: 1.17, 95% CI: 1.00 1.38). Depressive symptoms were associated with 12% higher odds of being in a higher angina frequency category (OR: 1.12, 95% CI: 1.03-1.21). In contrast, exercise/pharmacological stress-induced SDS was not associated with angina frequency. CONCLUSION: Among young and middle-aged post-MI patients, myocardial ischemia induced by mental stress in the lab, but not by exercise/pharmacological stress, is associated with higher frequency of retrospectively reported angina during the day. Psychosocial stressors related to mental stress ischemia may be important contributory factor to daily angina. PMID- 25727241 TI - Evaluation of sleep disorders in cancer patients based on Pittsburgh Sleep Quality Index. AB - Insomnia, poor sleep quality and short sleep durations are the most common problems seen in cancer patients. More studies are needed about sleep disorders in cancer patients. In our study, we aimed to investigate the prevalence of sleep disorders and the impact of these problems on the quality of life in cancer patients. Pittsburgh Sleep Quality Index (PSQI) was given to a total of 314 patients. The psychometric evaluation of the Turkish version of PSQI in cancer patients revealed that 127 (40.4%) patients had global PSQI scores >5, indicating poor sleep quality. There was no statistically significant relationship between PSQI scores and sexuality, marital status, cancer stage and chemotherapy type (P > 0.05); while the patients with bone and visceral metastasis had much lower PSQI scores (P = 0.006). Patients with Eastern Cooperative Oncology Group performance scores of 3 or more had also significantly lower PSQI scores (P = 0.02). In conclusion, PSQI questionnaire may be used to evaluate the sleep disorders in cancer patients. Consistent use of multi-item measures such as PSQI with established reliability and validity would improve our understanding of difficulties experienced by cancer patients with chronic insomnia. PMID- 25727242 TI - High-throughput preparation methods of crude extract for robust cell-free protein synthesis. AB - Crude extract based cell-free protein synthesis (CFPS) has emerged as a powerful technology platform for high-throughput protein production and genetic part characterization. Unfortunately, robust preparation of highly active extracts generally requires specialized and costly equipment and can be labor and time intensive. Moreover, cell lysis procedures can be hard to standardize, leading to different extract performance across laboratories. These challenges limit new entrants to the field and new applications, such as comprehensive genome engineering programs to improve extract performance. To address these challenges, we developed a generalizable and easily accessible high-throughput crude extract preparation method for CFPS based on sonication. To validate our approach, we investigated two Escherichia coli strains: BL21 StarTM (DE3) and a K12 MG1655 variant, achieving similar productivity (defined as CFPS yield in g/L) by varying only a few parameters. In addition, we observed identical productivity of cell extracts generated from culture volumes spanning three orders of magnitude (10 mL culture tubes to 10 L fermentation). We anticipate that our rapid and robust extract preparation method will speed-up screening of genomically engineered strains for CFPS applications, make possible highly active extracts from non model organisms, and promote a more general use of CFPS in synthetic biology and biotechnology. PMID- 25727243 TI - Reversibility after inhaling salbutamol in different body postures in asthmatic children: a pilot study. AB - RATIONALE: Pulmonary medication is mostly delivered in the form of medical aerosols to minimize systemic side effects. A major drawback of inhaled medication is that the majority of inhaled particles impacts in the oropharynx at the sharp bend of the airway. Stretching the airway by a forward leaning body posture with the neck extended ("sniffing position") may improve pulmonary deposition and clinical effects. METHODS: 41 asthmatic children who were planned for standard reversibility testing at the pulmonary function lab, alternately inhaled 200 MUgr salbutamol with an Autohaler((r)) in the standard or in the forward leaning body posture. Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), Peak Expiratory Flow (PEF), Mean Expiratory Flow at 25% of vital capacity (MEF25) and Mean Expiratory Flow at 75% of vital capacity (MEF75) were analysed. RESULTS: The children in the forward leaning body posture group showed a significantly higher mean FEV1 reversibility than the control group after inhalation of 200 MUgr salbutamol (10.2% versus 4.1%, p = 0.019). Additionally, mean MEF75 was significantly more reversible in the forward leaning body posture group versus the standard body posture group (32.2% resp. 8.9%, p = 0.013). CONCLUSION: This pilot study showed a higher reversibility of FEV1 and MEF75 after inhaling salbutamol in a forward leaning body posture compared to the standard body posture in asthmatic children. This suggests that pulmonary effects of salbutamol can be improved by inhaling in a forward leaning body posture with the neck extended. This effect is possibly due to a higher pulmonary deposition of salbutamol and should be confirmed in a randomized controlled trial. PMID- 25727244 TI - SCF/c-kit signaling is required in 12-O-tetradecanoylphorbol-13-acetate-induced migration and differentiation of hair follicle melanocytes for epidermal pigmentation. AB - Hair follicle melanocyte stem cells (McSCs) are responsible for hair pigmentation and also function as a major melanocyte reservoir for epidermal pigmentation. However, the molecular mechanism promoting McSCs for epidermal pigmentation remains elusive. 12-O-tetradecanoylphorbol-13-acetate (TPA) mimics key signaling involved in melanocyte growth, migration and differentiation. We therefore investigated the molecular basis for the contribution of hair follicle McSCs to epidermal pigmentation using the TPA induction model. We found that repetitive TPA treatment of female C57BL/6 mouse dorsal skin induced epidermal pigmentation by increasing the number of epidermal melanocytes. Particularly, TPA treatment induced McSCs to initiate proliferation, exit the stem cell niche and differentiate. We also demonstrated that TPA promotes melanoblast migration and differentiation in vitro. At the molecular level, TPA treatment induced robust expression of stem cell factor (SCF) in keratinocytes and c-kit in melanoblasts and melanocytes. Administration of ACK2, a neutralizing antibody against the Kit receptor, suppressed mouse epidermal pigmentation, decreased the number of epidermal melanocytes, and inhibited melanoblast migration. Taken together, our data demonstrate that TPA promotes the expansion, migration and differentiation of hair follicle McSCs for mouse epidermal pigmentation. SCF/c-kit signaling was required for TPA-induced migration and differentiation of hair follicle melanocytes. Our findings may provide an excellent model to investigate the signaling mechanisms regulating epidermal pigmentation from mouse hair follicle McSCs, and a potential therapeutic option for skin pigmentation disorders. PMID- 25727245 TI - Cofilin reduces the mechanical properties of actin filaments: approach with coarse-grained methods. AB - An actin filament is an essential cytoskeleton protein in a cell. Various proteins bind to actin for cell functions such as migration, division, and shape control. ADF/cofilin is a protein that severs actin filaments and is related to their dynamics. Actin is known to have excellent mechanical properties. Binding cofilin reduces its mechanical properties, and is related to the severing process. In this research, we applied a coarse-grained molecular dynamics simulation (CGMD) method to obtain actin filaments and cofilin-bound actin (cofilactin) filaments. Using these two obtained models, we constructed an elastic network model-based structure and conducted a normal mode analysis. Based on the low-frequency normal modes of the filament structure, we applied the continuum beam theory to calculate the mechanical properties of the actin and cofilactin filaments. The CGMD method provided structurally accurate actin and cofilactin filaments in relation to the mechanical properties, which showed good agreement with the established experimental results. PMID- 25727247 TI - Frey's syndrome and botulinum toxin type A: duration of efficacy and patient satisfaction. PMID- 25727246 TI - Splicing regulation in spinal muscular atrophy by an RNA structure formed by long distance interactions. AB - Humans carry two copies of the survival motor neuron gene: SMN1 and SMN2. Loss of SMN1 coupled with skipping of SMN2 exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS-N1) is a promising target, currently in a phase III clinical trial, for an antisense oligonucleotide-mediated splicing correction in SMA. We have recently shown that the first residue of ISS-N1 is locked in a unique RNA structure that we term ISTL1 (internal stem through long distance interaction-1). Complementary strands of ISTL1 are separated from each other by 279 nucleotides. Using site-specific mutations and chemical structure probing, we confirmed the formation and functional significance of ISTL1. Located in the middle of intron 7, the 3' strand of ISTL1 falls within an inhibitory region that we term ISS-N2. We demonstrate that an antisense oligonucleotide mediated sequestration of ISS-N2 fully corrects SMN2 exon 7 splicing and restores high levels of SMN in SMA patient cells. These results underscore the therapeutic potential of the regulatory information present in a secondary and high-order RNA structure of a human intron. PMID- 25727248 TI - Age, atrial fibrillation, and structural heart disease are the main determinants of left atrial fibrosis detected by delayed-enhanced magnetic resonance imaging in a general cardiology population. AB - INTRODUCTION: We studied the extent and distribution of left atrial (LA) fibrosis on delayed-enhanced (DE) MRI in a general cardiology population. METHODS AND RESULTS: One hundred ninety consecutive patients referred for cardiac MRI underwent DE imaging using a free breathing method. The population comprised 60 AF patients and 130 patients without AF, including 75 with structural heart disease (SHD). DE was quantified using histogram thresholding, expressed in % of the wall. Regression analysis was performed to identify predictors of DE. Additionally, DE was registered on a template to study its distribution in subpopulations. In the total population, age, AF, and SHD were independently associated with DE. DE was increasingly observed from 11.1 +/- 4.7% in patients with no SHD nor AF, 18.8 +/- 7.8% in SHD and no AF history, 22.9 +/- 7.8% in paroxysmal AF, to 27.8 +/- 7.7% in persistent AF. Among non-AF patients, age and SHD were independently associated with DE. Among AF patients, female gender and AF persistence were independently associated with DE. DE was variably distributed but more frequently detected in the posterior wall. CONCLUSION: Age, history of AF, and SHD are the most powerful predictors of atrial fibrosis, as detected by MRI, in a general cardiology population. Atrial fibrosis predominates in the posterior LA wall. PMID- 25727249 TI - In situ nanomechanical characterization of the early stages of swelling and degradation of a biodegradable polymer. AB - The interactions of a biodegradable scaffold with cells or living tissues depend on the time-evolution of the nanoscale properties of the scaffold. We present an in situ quantitative study on the early-stage swelling and degradation of poly(lactic-co-glycolic acid) (PLGA). A novel metrology scheme based on force microscopy measurements of the patterns of PLGA nanostructures is developed to characterize the evolution of topography, volume and nanomechanical properties. The volume and nanoscale roughness show an oscillating behaviour during the first eight days of immersion; at a later stage, we observe a continuous decrease of the volume. The effective Young's modulus exhibits a monotonic decrease from an initial value of about 2.4 GPa down to 9 MPa at day 14. The oscillating behaviour of the volume before the onset of full degradation is explained by a coupled diffusion-swelling mechanism. The appearance of a second maximum in the volume evolution results from the competition between swelling and degradation. PMID- 25727250 TI - Perceptions and knowledge of voluntary medical male circumcision for HIV prevention in traditionally non-circumcising communities in South Africa. AB - Voluntary medical male circumcision (VMMC) has been recommended for the prevention of HIV transmission, particularly in sub-Saharan Africa. Uptake of the campaign has been relatively poor, particularly in traditionally non-circumcising regions. This study evaluates the knowledge, attitudes and practices of medical male circumcision (MC) of 104 community members exposed to promotional campaigns for VMMC for five years. Results show that 93% of participants have heard of circumcision and 72% have heard of some health benefit from the practice. However, detailed knowledge of the relationship with HIV infection is lacking: 12.2% mistakenly believed you could not get HIV after being circumcised, while 75.5% believe that a circumcised man is still susceptible and another 12.2% do not know of any relationship between HIV and MC. There are significant barriers to the uptake of the practice, including misperceptions and fear of complications commonly attributed to traditional, non-medical circumcision. However, 88.8% of participants believe circumcision is an acceptable practice, and community specific promotional campaigns may increase uptake of the service. PMID- 25727251 TI - Scalable quantum memory in the ultrastrong coupling regime. AB - Circuit quantum electrodynamics, consisting of superconducting artificial atoms coupled to on-chip resonators, represents a prime candidate to implement the scalable quantum computing architecture because of the presence of good tunability and controllability. Furthermore, recent advances have pushed the technology towards the ultrastrong coupling regime of light-matter interaction, where the qubit-resonator coupling strength reaches a considerable fraction of the resonator frequency. Here, we propose a qubit-resonator system operating in that regime, as a quantum memory device and study the storage and retrieval of quantum information in and from the Z2 parity-protected quantum memory, within experimentally feasible schemes. We are also convinced that our proposal might pave a way to realize a scalable quantum random-access memory due to its fast storage and readout performances. PMID- 25727252 TI - The role and scope of retrieval nurse practitioners in the UK. AB - BACKGROUND: The first independent paediatric retrieval nurse practitioners (RNP) in the UK and Europe were appointed in 2006 in one hospital Trust. Since then, many have been appointed around the UK but the range of responsibility and scope of the role is unknown as well as possible geographical variability. AIM: The aim of this paper is to explore the role and scope of paediatric retrieval nurse practitioners in the United Kingdom (UK). METHOD: A two part questionnaire was sent to all RNPs identified by the regional retrieval/transport centres. Information was sought about the role and scope of RNPs and how the role may have changed since appointment. RNPs were asked to self-assess their own ability in a variety of technical and leadership skills. CONCLUSION: The majority of respondents felt their role had expanded since appointment. RNPs reported that they would now lead the team for any critically ill infant or child where previously they were retrieving stable or high dependency patients. Other expansions of their role included being on a middle grade tier of the medical rota, asked to undertake aeromedical transfers, providing the withdrawal of care at referring centres and non-medical independent prescribing. RELEVANCE TO PRACTICE: This survey has revealed the changing role and scope of RNPs in the UK but most importantly, the increased responsibility of the roles. Over 80% of RNPs rated their leadership skills between proficient and expert on Benner's Novice to Expert Continuum (Benner, 1984). PMID- 25727253 TI - How sotolon can impart a Madeira off-flavor to aged beers. AB - 4,5-Dimethyl-3-hydroxy-2(5H)-furanone or sotolon is known to impart powerful Madeira-oxidized-curry-walnut notes to various alcoholic beverages. It has been much studied in oxidized Jura flor-sherry wines, aged Roussillon sweet wines, and old Port wines, in which it contributes to the characteristic "Madeira-oxidized" aroma of these beverages. No scientific paper describes how sotolon might be involved in the Madeira off-flavor found in aged beers. The specific extraction procedure applied here allowed us to quantify this lactone in 7 special beers, at levels sometimes well above its threshold (from 5 to 42 MUg/L after 6, 12, 18, and 24 months of natural aging, while unquantifiable in fresh beer). Investigation of spiked beers led us to highlight the key role of pro-oxidants and acetaldehyde. Addition of ascorbic acid without sulfites should be avoided by brewers, as the former would intensify sotolon synthesis. Acetoin, a beer fermentation byproduct, also emerged as possible precursor in beer when combined with serine. PMID- 25727254 TI - Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus. AB - OBJECTIVE: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, leading to memory impairment in up to 65% of patients. Memory dysfunction in MS has been associated with loss of synapses in the hippocampus, but its molecular basis is unknown. Accumulating evidence suggests that components of the complement system, C1q and C3, can mediate elimination of synapses. METHODS: To investigate the involvement of complement in synaptic changes in MS, gene and protein expression and localization of C1q and C3 were analyzed in relation to neuropathological changes in myelinated and demyelinated hippocampi from postmortem MS brains. Findings were compared to hippocampi of Alzheimer disease (AD) and non-neurological controls. RESULTS: C1q expression and C3 activation were increased in myelinated and demyelinated MS hippocampi, mainly in the CA3/2 and CA1 subfields, which also showed a marked decrease in synaptic density and increased neuronal staining for the mitochondrial heat shock protein 70 (mtHSP70) stress marker. Neurons were the major source of C1q mRNA. C1q protein and activated C3 localized at synapses within human leukocyte antigen positive cell processes and lysosomes, suggesting engulfment of complement-tagged synapses by microglia. A significant association (p < 0.0001) between the density of C1q and synaptophysin-positive synapses or mtHSP70 was seen in myelinated MS hippocampi, further pointing toward a link between the complement pathway and synaptic changes. In contrast to AD, MS hippocampi were consistently negative for the terminal complement activation complex C5b9. INTERPRETATION: These data support a role for the C1q-C3 complement axis in synaptic alterations in the MS hippocampus. PMID- 25727255 TI - Combining label-free cell phenotypic profiling with computational approaches for novel drug discovery. AB - INTRODUCTION: Drug discovery is a long and costly process. Innovations and paradigm shifts are essential for continuous improvement in the productivity of pharmaceutical R&D. AREAS COVERED: The author reviews the progress of label-free cell phenotypic and computational approaches in early drug discovery since 2004 and proposes a novel paradigm, which combines both approaches. EXPERT OPINION: Label-free cell phenotypic profiling techniques offer an unprecedented and integrated approach to comprehend drug-target interactions in their native environments. However, these approaches have disadvantages associated with the lack of molecular details. Computational approaches, including ligand-, structure and phenotype-based virtual screens, have become versatile tools in the early drug discovery process. However, these approaches mostly predict the binding of drug molecules to targets of interest and are limited to targets that are either well annotated for ligands or that are structurally resolved. Thus, combining label-free cell phenotypic profiling with computational approaches can provide a potential paradigm to accelerate novel drug discovery by taking advantages of the best of both approaches. PMID- 25727257 TI - State of the art science addressing injecting drug use, HIV and harm reduction. PMID- 25727256 TI - Regulation of plasmid-encoded isoprene metabolism in Rhodococcus, a representative of an important link in the global isoprene cycle. AB - Emissions of biogenic volatile organic compounds (VOCs) form an important part of the global carbon cycle, comprising a significant proportion of net ecosystem productivity. They impact atmospheric chemistry and contribute directly and indirectly to greenhouse gases. Isoprene, emitted largely from plants, comprises one third of total VOCs, yet in contrast to methane, which is released in similar quantities, we know little of its biodegradation. Here, we report the genome of an isoprene degrading isolate, Rhodococcus sp. AD45, and, using mutagenesis shows that a plasmid-encoded soluble di-iron centre isoprene monooxygenase (IsoMO) is essential for isoprene metabolism. Using RNA sequencing (RNAseq) to analyse cells exposed to isoprene or epoxyisoprene in a substrate-switch time-course experiment, we show that transcripts from 22 contiguous genes, including those encoding IsoMO, were highly upregulated, becoming among the most abundant in the cell and comprising over 25% of the entire transcriptome. Analysis of gene transcription in the wild type and an IsoMO-disrupted mutant strain showed that epoxyisoprene, or a subsequent product of isoprene metabolism, rather than isoprene itself, was the inducing molecule. We provide a foundation of molecular data for future research on the environmental biological consumption of this important, climate-active compound. PMID- 25727258 TI - People who inject drugs in prison: HIV prevalence, transmission and prevention. AB - In 2011, over 10.1 million people were held in prisons around the world. HIV prevalence is elevated in prison and this is due to the over representation of people who inject drugs (PWID). Yet HIV prevention programs for PWID are scarce in the prison setting. With a high proportion of drug users and few prevention programs, HIV transmission occurs and sometimes at an alarming rate. This commentary focuses primarily on drug users in prison; their risk behaviours and levels of infection. It also comments on the transmission of HIV including outbreaks and the efforts to prevent transmission within the prison setting. The spread of HIV in prison has substantial public health implications as virtually all prisoners return to the community. HIV prevention and treatment strategies known to be effective in community settings, such as methadone maintenance treatment, needle and syringe programs, condoms and antiretroviral therapy should be provided to prisoners as a matter of urgency. PMID- 25727259 TI - Compulsory drug detention centers in East and Southeast Asia. AB - Over the last three decades in response to a rise in substance use in the region, many countries in East and Southeast Asia responded by establishing laws and policies that allowed for compulsory detention in the name of treatment for people who use drugs. These centers have recently come under international scrutiny with a call for their closure in a Joint Statement from United Nations entities in March 2012. The UN's response was a result of concern for human rights violations, including the lack of consent for treatment and due process protections for compulsory detention, the lack of general healthcare and evidence based drug dependency treatment and in some centers, of forced labor and physical and sexual abuse (United Nations, 2012). A few countries have responded to this call with evidence of an evolving response for community-based voluntary treatment; however progress is likely going to be hampered by existing laws and policies, the lack of skilled human resource and infrastructure to rapidly establish evidence based community treatment centers in place of these detention centers, pervasive stigmatization of people who use drugs and the ongoing tensions between the abstinence-based model of treatment as compared to harm reduction approaches in many of these affected countries. PMID- 25727260 TI - The cost-effectiveness of harm reduction. AB - HIV prevalence worldwide among people who inject drugs (PWID) is around 19%. Harm reduction for PWID includes needle-syringe programs (NSPs) and opioid substitution therapy (OST) but often coupled with antiretroviral therapy (ART) for people living with HIV. Numerous studies have examined the effectiveness of each harm reduction strategy. This commentary discusses the evidence of effectiveness of the packages of harm reduction services and their cost effectiveness with respect to HIV-related outcomes as well as estimate resources required to meet global and regional coverage targets. NSPs have been shown to be safe and very effective in reducing HIV transmission in diverse settings; there are many historical and very recent examples in diverse settings where the absence of, or reduction in, NSPs have resulted in exploding HIV epidemics compared to controlled epidemics with NSP implementation. NSPs are relatively inexpensive to implement and highly cost-effective according to commonly used willingness-to-pay thresholds. There is strong evidence that substitution therapy is effective, reducing the risk of HIV acquisition by 54% on average among PWID. OST is relatively expensive to implement when only HIV outcomes are considered; other societal benefits substantially improve the cost-effectiveness ratios to be highly favourable. Many studies have shown that ART is cost-effective for keeping people alive but there is only weak supportive, but growing evidence, of the additional effectiveness and cost-effectiveness of ART as prevention among PWID. Packages of combined harm reduction approaches are highly likely to be more effective and cost-effective than partial approaches. The coverage of harm reduction programs remains extremely low across the world. The total annual costs of scaling up each of the harm reduction strategies from current coverage levels, by region, to meet WHO guideline coverage targets are high with ART greatest, followed by OST and then NSPs. But scale-up of all three approaches is essential. These interventions can be cost-effective by most thresholds in the short-term and cost-saving in the long-term. PMID- 25727261 TI - Bile duct adenoma should not be designated as a reactive process. PMID- 25727262 TI - Diagnostics for resource-limited settings in the era of interferon-free HCV therapy. AB - The field of hepatitis C (HCV) therapy is moving inexorably towards a time when interferon is no longer part of routine HCV treatment. 2015 will see at least two interferon-free directly acting antiviral (DAA) treatments licensed in Europe and the USA. For those parts of the world that can afford it, this will mean the potential for treatment of those who have either failed interferon-based therapy or have been unable to tolerate the side-effects that commonly accompany treatment. PMID- 25727263 TI - 3D-QSAR and molecular modeling studies on 2,3-dideoxy hexenopyranosid-4-uloses as anti-tubercular agents targeting alpha-mannosidase. AB - Ligand-based and structure-based methods were applied in combination to exploit the physicochemical properties of 2,3-dideoxy hex-2-enopyranosid-4-uloses against Mycobacterium tuberculosis H37Rv. Statistically valid 3D-QSAR models with good correlation and predictive power were obtained with CoMFA steric and electrostatic fields (r(2) = 0.797, q(2) = 0.589) and CoMSIA with combined steric, electrostatic, hydrophobic and hydrogen bond acceptor fields (r(2) = 0.867, q(2) = 0.570) based on training set of 33 molecules with predictive r(2) of 0.808 and 0.890 for CoMFA and CoMSIA respectively. The results illustrate the requirement of optimal alkyl chain length at C-1 position and acceptor groups along hydroxy methyl substituent of C-6 to enhance the anti-tubercular activity of the 2,3-dideoxy hex-2-enopyranosid-4-uloses while any substitution at C-3 position exert diminishing effect on anti-tubercular activity of these enulosides. Further, homology modeling of M. tuberculosis alpha-mannosidase followed by molecular docking and molecular dynamics simulations on co-complexed models were performed to gain insight into the rationale for binding affinity of selected inhibitors with the target of interest. The comprehensive information obtained from this study will help to better understand the structural basis of biological activity of this class of molecules and guide further design of more potent analogues as anti-tubercular agents. PMID- 25727264 TI - 2,4-dihydroxy benzaldehyde derived Schiff bases as small molecule Hsp90 inhibitors: rational identification of a new anticancer lead. AB - Hsp90 is a molecular chaperone that heals diverse array of biomolecules ranging from multiple oncogenic proteins to the ones responsible for development of resistance to chemotherapeutic agents. Moreover they are over-expressed in cancer cells as a complex with co-chaperones and under-expressed in normal cells as a single free entity. Hence inhibitors of Hsp90 will be more effective and selective in destroying cancer cells with minimum chances of acquiring resistance to them. In continuation of our goal to rationally develop effective small molecule azomethines against Hsp90, we designed few more compounds belonging to the class of 2,4-dihydroxy benzaldehyde derived imines (1-13) with our validated docking protocol. The molecules exhibiting good docking score were synthesized and their structures were confirmed by IR, (1)H NMR and mass spectral analysis. Subsequently, they were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The antiproliferative effect of the molecules were examined on PC3 prostate cancer cell lines by adopting 3-(4,5-dimethythiazol 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay methodology. Finally, schiff base 13 emerged as the lead molecule for future design and development of Hsp90 inhibitors as anticancer agents. PMID- 25727265 TI - Emissions and ambient air monitoring trends of lower olefins across Texas from 2002 to 2012. AB - Texas has the largest ambient air monitoring network in the country with approximately 83 monitoring sites that measure ambient air concentrations of volatile organic compounds (VOCs). The lower olefins, including 1,3-butadiene, ethylene, isoprene, and propylene, are a group of VOCs that can be measured in both 24h/every sixth-day canister samples and continuous 1-h Automated Gas Chromatography (AutoGC) samples. Based on 2012 Toxics Release Inventory data, the total reported industrial air emissions in Texas for these olefins, as compared to total national reported air emissions, were 79% for 1,3-butadiene, 62% for ethylene, 76% for isoprene, and 54% for propylene, illustrating that Texas industries are some of the major emitters for these olefins. The purpose of this study was to look at the patterns of annual average air monitoring data from 2002 to 2012 using Texas Commission on Environmental Quality (TCEQ) data for these four lower olefins. It should be emphasized that monitors may not be located close to or downwind of the highest emitters of these lower olefins. In addition, air monitors only provide a snapshot in time of air concentrations for their respective locations, and may not be able to discriminate emissions between specific sources. In 2012, the highest annual average air concentration for 1,3 butadiene was 1.28 ppb by volume (ppbv), which was measured at the Port Neches monitoring site in Region 10-Beaumont. For ethylene, the highest 2012 annual average air concentration was 5.77 ppbv, which was measured at the Dona Park monitoring site in TCEQ Region 14-Corpus Christi. Although reported industrial emissions of isoprene are predominantly from the Houston and Beaumont regions, trees are natural emitters of isoprene, and the highest ambient air concentrations tend to be from regions with large areas of coniferous and hardwood forests. This was observed with TCEQ Region 5-Tyler, which had the two highest isoprene annual average air concentrations for 2012: 0.56 ppbv at the Karnack monitoring site and 0.47 ppbv at the Longview monitoring site. For propylene, the highest 2012 annual average air concentration was recorded at the HRM 7 monitoring site in TCEQ Region 12-Houston, which was 7.9 ppbv. A significant portion of the total 2012 industrial propylene emissions were also reported in TCEQ Region 12-Houston. Although some individual monitors showed increased annual averages from 2002 to 2012, there was a general decreasing trend present across the state for all four lower olefins examined. The annual average air concentrations of the four lower olefins were well below their respective Air Monitoring Comparison Values (AMCVs) and are not expected to cause long-term or chronic adverse health effects. PMID- 25727266 TI - High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation. AB - 1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1 (N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl) 1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-L-cystein-S-yl)-1,2,3 trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high throughput HPLC-ESI(-)-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 MUl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI(-) MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA+DHBMA+THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers. PMID- 25727267 TI - Health- and vegetative-based effect screening values for ethylene. AB - Ethylene (ET) is ubiquitous in the environment and is produced both naturally and due to anthropogenic sources. Interestingly, the majority of ambient ET contribution is from natural sources and anthropogenic sources contribute only a minor portion. While microbes and plants naturally produce a large amount of ET, mammals are reported to produce only a small amount of ET endogenously. Anthropogenic sources of ET include the combustion of gas, fuel, coal and biomass. ET is also widely used as an intermediate to make other chemicals and products and is also used for controlled ripening of fruits and vegetables. Although, a review of human and laboratory animal studies indicate ET to be relatively non-toxic, there is concern about the potential toxicity of ET because ET is metabolically converted to ethylene oxide (EtO). EtO has been classified to be carcinogenic to human by the inhalation route by the International Agency for Research on Cancer (IARC) cancer. ET, however, has been classified as a Group 3 chemical which indicates it is not classified as a human carcinogen by IARC. Several studies have reported ET to cause adverse effects to plant species (vegetation effects) at concentrations that are not adverse to humans. Therefore, the Texas Commission of Environmental Quality (TCEQ) conducted detailed health and welfare (odor and vegetation) based assessments of ET to develop both health and vegetative based toxicity factors in 2008 in accordance with TCEQ guidelines. The health assessment based on well-conducted animal toxicity studies resulted in identification of higher points of departures and subsequently higher effect screening levels (ESLs) that were more than a magnitude higher than the threshold adverse effect level for vegetative effects for ET. Further, based on a weight-of evidence evaluation of potential mutagenic and carcinogenic mode-of-actions for ET it appears the metabolic conversion of ET to EtO is of insufficient magnitude to cause concern of potential cancer risk. Therefore, the short-term ESL for air permit reviews and air monitoring evaluations is the vegetation-based ESL of 1200 ppb as it is more than a magnitude lower than the health-based acute ESL of 150,000 ppb. Similar to the acute derivation, the chronic evaluation resulted in the derivation of a chronic vegetation based ESL of 30 ppb that was much lower than the chronic ESL of 1600 ppb. In summary, the TCEQ's acute and chronic ESLs for vegetation will protect the general public from short-term and long-term adverse health and welfare effects. The general public includes children, the elderly, pregnant women, and people with pre-existing health conditions. PMID- 25727268 TI - Finding our optimal scope of practice. PMID- 25727270 TI - Inhaled nitric oxide to improve oxygenation for safe critical care transport of adults with severe hypoxemia. AB - BACKGROUND: Inhaled nitric oxide (iNO) is a rescue treatment for severe hypoxemia in the intensive care unit setting. OBJECTIVE: To evaluate the effectiveness and safety of iNO in adult patients with severe hypoxemia before and during transport to a tertiary care center. METHODS: Prospective data were examined in a retrospective cohort study. Patients with severe hypoxemia and cardiopulmonary failure (n=139) at referring hospitals in whom conventional therapy was unsuccessful were treated with iNO in the intensive care units in anticipation of transfer to a tertiary center. Treatment wih iNO was initiated by the critical care transport team in 114 patients and continued in 25 patients. Arterial blood gas analysis was done before and after iNO treatment. RESULTS: Patients treated with iNO had significant improvement in oxygenation: mean (SD) for PaO2 increased from 60.7 (20.2) to 72.3 (40.6) mm Hg (P=.008), and mean (SD) for ratio of PaO2 to fraction of inspired oxygen (P:F) increased from 62.4 (26.1) to 73.1 (42.6) (P= .03). Use of iNO was continued through transport in 102 patients, all of whom were transported without complication. The P:F continued to improve, with a mean (SD) of 109.7 (73.8) from 6 to 8 hours after arrival at the tertiary center (P< .001 relative to values both before and after treatment). Among patients treated with iNO, 60.2% survived to discharge. In 35 nonresponders, iNO was discontinued, and 15 patients could not be transferred owing to life-threatening hypoxemia; 2 were later transferred on extracorporeal membrane oxygenation. Of 18 patients transported without iNO, 9 (50%) survived. CONCLUSIONS: Use of iNO significantly improves oxygenation of patients with severe hypoxemia and allows safe transfer to a tertiary care center. PMID- 25727272 TI - Safe weaning from mechanical ventilation. PMID- 25727271 TI - Heart rate variability as a predictor of cardiac dysrhythmias during weaning from mechanical ventilation. AB - BACKGROUND: Weaning from mechanical ventilation to spontaneous breathing is associated with changes in the hemodynamic and autonomic nervous systems that are reflected by heart rate variability. Although cardiac dysrhythmias are an important manifestation of hemodynamic alterations, the impact of heart rate variability on the occurrence of dysrhythmias during weaning has not been specifically studied. OBJECTIVES: To describe differences in heart rate variability spectral power and occurrence of cardiac dysrhythmias at baseline and during the initial trial of weaning from mechanical ventilation and to evaluate the impact of heart rate variability during weaning on occurrence of dysrhythmias. METHOD: Continuous 3-lead electrocardiographic recordings were collected from 35 patients receiving mechanical ventilation for 24 hours at baseline and during the initial weaning trial. Heart rate variability was evaluated by using spectral power analysis. RESULTS: Low-frequency power increased (P = .04) and high-frequency and very-low-frequency power did not change during weaning. The mean number of supraventricular ectopic beats per hour during weaning was higher than the mean at baseline (P < .001); the mean of ventricular ectopic beats did not change. Low-frequency power was a predictor of ventricular and supraventricular ectopic beats during weaning (P < .001). High frequency power was predictive of ventricular and supraventricular (P = .02) ectopic beats during weaning. Very-low-frequency power was predictive of ventricular ectopic beats (P < .001) only. CONCLUSION: Heart rate variability power spectra during weaning were predictive of dysrhythmias. PMID- 25727273 TI - Hemodynamic changes with manual and automated lateral turning in patients receiving mechanical ventilation. AB - BACKGROUND: Lateral turning of critical care patients receiving mechanical ventilation can adversely affect hemodynamic status. OBJECTIVE: To study hemodynamic responses to lateral turning. METHOD: A time-series design with automated signal processing and ensemble averaging was used to evaluate changes in heart rate, mean arterial pressure, and pulse pressure due to lateral turning in 13 adult medical-surgical critical care patients receiving mechanical ventilation. Patients were randomly assigned to the manual-turn or the automated turn protocol for up to 7 consecutive days. Heart rate and arterial pressure were measured every 6 seconds for more than 24 hours, and pulse pressure was computed. RESULTS: A total of 6 manual-turn patients and 7 automated-turn patients completed the study. Statistically significant changes in heart rate, mean arterial pressure, and pulse pressure occurred with the manual turn. Return of the hemodynamic variables to baseline values required up to 45 minutes in the manual-turn patients (expected recovery time <= 5 minutes). However, clinically important changes dissipated within 15 minutes of the lateral turn. The steady state heart rate response on the right side was slightly greater (3 beats per minute) than that on the back (P = .003). Automated turning resulted in no clinically important changes in any of the 3 variables. CONCLUSIONS: In medical surgical critical care patients receiving mechanical ventilation, manual lateral turning was associated with changes in heart rate, mean arterial pressure, and pulse pressure that persisted up to 45 minutes. PMID- 25727274 TI - Heat retention head wrap for rewarming infants undergoing cardiopulmonary bypass surgery. AB - BACKGROUND: A major postoperative problem for infants undergoing cardiopulmonary bypass surgery is hypothermia. OBJECTIVE: To determine the safety and feasibility of a newly designed Heat Retention Head Wrap on infants during the rewarming period of cardiopulmonary bypass surgery. METHODS: A sample of 10 infants was recruited into this descriptive pilot study. The health care providers completed ease-of-use questionnaires to describe the feasibility of the head wrap. Interval body temperatures were recorded to characterize temperature progression from onset of rewarming to arrival in the cardiac intensive care unit (ICU) and were compared with the temperature progression of a similar group of nonparticipants. Adverse events were recorded on the basis of perioperative body temperatures and skin assessments. RESULTS: The head wrap was easily applied to the infant's head and was removed without difficulty. A steady increase in median body temperature from (1) the onset of rewarming (28 degrees C), to (2) removal of bypass cannulas (28.9 degrees C), to (3) removal of the rectal temperature probe before transfer from the operating room to the cardiac ICU (34.5 degrees C), and (4) upon arrival in the cardiac ICU (36.0 degrees C) was observed. No skin lesions or temperature related adverse events were observed. CONCLUSIONS: The newly designed Heat Retention Head Wrap was associated with a gradual normalization of temperature during rewarming and did not interfere with routine perioperative care of infants undergoing bypass surgery. This pilot study indicates that the head wrap is both safe and feasible for use in infants undergoing cardiopulmonary bypass surgery. PMID- 25727275 TI - A computer-based education intervention to enhance surrogates' informed consent for genomics research. AB - BACKGROUND: Many research studies conducted today in critical care have a genomics component. Patients' surrogates asked to authorize participation in genomics research for a loved one in the intensive care unit may not be prepared to make informed decisions about a patient's participation in the research. OBJECTIVES: To examine the effectiveness of a new, computer-based education module on surrogates' understanding of the process of informed consent for genomics research. METHODS: A pilot study was conducted with visitors in the waiting rooms of 2 intensive care units in a Midwestern tertiary care medical center. Visitors were randomly assigned to the experimental (education module plus a sample genomics consent form; n = 65) or the control (sample genomics consent form only; n = 69) group. Participants later completed a test on informed genomics consent. RESULTS: Understanding the process of informed consent was greater (P = .001) in the experimental group than in the control group. Specifically, compared with the control group, the experimental group had a greater understanding of 8 of 13 elements of informed consent: intended benefits of research (P = .02), definition of surrogate consenter (P= .001), withdrawal from the study (P = .001), explanation of risk (P = .002), purpose of the institutional review board (P = .001), definition of substituted judgment (P = .03), compensation for harm (P = .001), and alternative treatments (P = .004). CONCLUSIONS: Computer-based education modules may be an important addition to conventional approaches for obtaining informed consent in the intensive care unit. Preparing patients' family members who may consider serving as surrogate consenters is critical to facilitating genomics research in critical care. PMID- 25727276 TI - Outcomes associated with postoperative delirium after cardiac surgery. AB - BACKGROUND: Delirium after surgery is a common condition that leads to poor outcomes. Few studies have examined the effect of postoperative delirium on outcomes after cardiac surgery. OBJECTIVES: To assess the relationship between delirium after cardiac surgery and the following outcomes: length of stay after surgery, prevalence of falls, discharge to a nursing facility, discharge to home with home health services, and use of inpatient physical therapy. METHODS: Electronic medical records of 656 cardiac surgery patients were reviewed retrospectively. RESULTS: Postoperative delirium occurred in 161 patients (24.5%). Patients with postoperative delirium had significantly longer stays (P < .001) and greater prevalence of falls (P < .001) than did patients without delirium. Patients with delirium also had a significantly greater likelihood for discharge to a nursing facility (P < .001) and need for home health services if discharged to home (P < .001) and a significantly higher need for inpatient physical therapy (P < .001). Compared with patients without postoperative delirium, patients who had this complication were more likely to have received zolpidem and benzodiazepines postoperatively and to have a history of arrhythmias, renal disease, and congestive heart failure. CONCLUSIONS: Patients who have delirium after cardiac surgery have poorer outcomes than do similar patients without this complication. Development and implementation of an extensive care plan to address postoperative delirium is necessary for cardiac surgery patients who are at risk for or have delirium after the surgery. PMID- 25727277 TI - Preoperative education on postoperative delirium, anxiety, and knowledge in pulmonary thromboendarterectomy patients. AB - BACKGROUND: Delirium is the most common postoperative psychiatric condition in intensive care settings and can lead to increased complications and costs. OBJECTIVES: To evaluate the impact of multifaceted preoperative patient education on postoperative delirium, anxiety, and knowledge and to explore predictors of postoperative delirium, days of mechanical ventilation, and days in the intensive care unit (ICU) in patients undergoing pulmonary thromboendarterectomy. METHOD: A prospective, randomized controlled trial was conducted on consented patients from October 2011 to April 2013. Patients were randomized in a 1 to 1 ratio to receive either an individualized 45-minute multifaceted preoperative education (experimental group, n = 63) or standard education (control group, n = 66). Participants completed the State-Trait Anxiety Inventory and Knowledge Test before and after the education. Data on incidence of delirium, days of mechanical ventilation, ICU days, and cardiopulmonary parameters were collected. RESULTS: The experimental group had significantly more knowledge about postoperative care (P< .001) and fewer days of mechanical ventilation (P = .04) than the control group. The 2 groups did not differ significantly in anxiety, incidence of delirium, or ICU days. In exploratory multivariate analyses, hearing impairment was a positive predictor for days of delirium (P = .009), days of mechanical ventilation (P< .001), and ICU days (P= .049), whereas the posttest knowledge was a negative predictor for days of mechanical ventilation (P = .02). CONCLUSION: The patient education appeared to be effective in improving knowledge and reducing days of mechanical ventilation. Hearing impairment was an unexpected predictor of adverse outcomes for patients but may be amenable to nursing intervention. PMID- 25727278 TI - Pleth variability index and fluid responsiveness of hemodynamically stable patients after cardiothoracic surgery. AB - BACKGROUND: Fluid responsiveness is a measure of preload dependence and is defined as an increase in cardiac output due to volume expansion. Recent publications have suggested that variation in amplitude of the pulse oximetry waveform may be predictive of fluid responsiveness. The pleth variability index (PVI) was developed as a noninvasive bedside measurement of this variation in the pulse oximetry waveform. OBJECTIVES: To measure the discriminatory value of PVI for predicting fluid responsiveness as measured by pulmonary artery catheter thermodilution in patients after cardiothoracic surgery. METHODS: A prospective observational study of hemodynamically stable postoperative cardiac surgery patients with pulmonary artery catheters. A fingertip sensor was used to measure PVI. Vital signs, PVI, and cardiac index were measured before, during, and after passive leg raise. Fluid responsiveness was defined by increase in cardiac index of greater than 15% during passive leg raise. The discriminatory value of PVI was assessed by using the Wilcoxon method to measure the area under the receiver operating curve. RESULTS: In 13 months, 47 patients (24 receiving mechanical ventilation, 23 spontaneously breathing) were enrolled. Fluid responsiveness was noted in 42% of intubated patients and 48% of spontaneously breathing patients. PVI was not adequate to discriminate fluid responsiveness in intubated patients (area under curve, 0.63; P = .16) or spontaneously breathing patients (area under curve, 0.41; P = .75). CONCLUSIONS: Among postoperative cardiac surgery patients, PVI is not reliable for predicting fluid responsiveness as measured by pulmonary artery catheter thermodilution, regardless of ventilatory status. PMID- 25727279 TI - East meets west: effects of massage on the experience of cardiac surgery patients. PMID- 25727280 TI - Prehospital 12-lead ECGs and delivery of care. PMID- 25727281 TI - Fever in trauma patients: evaluation of risk factors, including traumatic brain injury. AB - BACKGROUND: The role of fever in trauma patients remains unclear. Fever occurs as a response to release of cytokines and prostaglandins by white blood cells. Many factors, including trauma, can trigger release of these factors. OBJECTIVES: To determine whether (1) fever in the first 48 hours is related to a favorable outcome in trauma patients and (2) fever is more common in patients with head trauma. METHOD: Retrospective study of trauma patients admitted to the intensive care unit for at least 2 days. Data were analyzed by using multivariate analysis. RESULTS: Of 162 patients studied, 40% had fever during the first 48 hours. Febrile patients had higher mortality rates than did afebrile patients. When adjusted for severity of injuries, fever did not correlate with mortality. Neither the incidence of fever in the first 48 hours after admission to the intensive care unit nor the number of days febrile in the unit differed between patients with and patients without head trauma (traumatic brain injury). About 70% of febrile patients did not have a source found for their fever. Febrile patients without an identified source of infection had lower peak white blood cell counts, lower maximum body temperature, and higher minimum platelet counts than did febrile patients who had an infectious source identified. The most common infection was pneumonia. CONCLUSIONS: No relationship was found between the presence of fever during the first 48 hours and mortality. Patients with traumatic brain injury did not have a higher incidence of fever than did patients without traumatic brain injury. About 30% of febrile patients had an identifiable source of infection. Further studies are needed to understand the origin and role of fever in trauma patients. PMID- 25727282 TI - Computer-assisted interventions to improve QTc documentation in patients receiving QT-prolonging drugs. AB - BACKGROUND: Many medications commonly used in hospitals can cause prolonged corrected QT interval (QTc), putting patients at risk for torsade de pointes (TdP), a potentially fatal arrhythmia. However, documentation of QTc for hospitalized patients receiving QT-prolonging medications is often not consistent with American Heart Association standards. OBJECTIVE: To examine effects of education and computerized documentation enhancements on QTc documentation. METHODS: A quasi-experimental multisite study among 4011 cardiac-monitored patients receiving QTc-prolonging medications within a 10-hospital health care system was conducted to compare QTc documentation before (n=1517), 3 months after (n = 1301), and 4 to 6 months after (n = 1193) an intervention. The intervention included (1) online education for 3232 nurses, (2) electronic notifications to alert nurses when a patient received at least 2 doses of a QT-prolonging medication, and (3) computerized calculation of QTc in electronic health records after nurses had documented heart rate and QT interval. RESULTS: QTc documentation for inpatients receiving QTc-prolonging drugs increased significantly from baseline (17.3%) to 3 months after the intervention (58.2%; P < .001) within the 10 hospitals and had increased further 4 to 6 months after the intervention (62.1%, P = .75). Patients at larger hospitals were significantly more likely to have their QTc documented (46.4%) than were patients at smaller hospitals (26.2%; P < .001). CONCLUSION: A 3-step system-wide intervention was associated with an increase in QTc documentation for patients at risk for drug induced TdP, and improvements persisted over time. Further study is needed to assess whether increased QTc documentation decreases occurrence of drug-induced TdP. (American Journal of Critical Care. 2015;24:e6-e15). PMID- 25727283 TI - Building skills, knowledge and confidence in eating and exercise behavior change: brief motivational interviewing training for healthcare providers. AB - OBJECTIVE: Obesity related health problems affect individuals, families, communities and the broader health care system, however few healthcare providers (e.g., doctors, nurses, social workers, psychologists, counselors) receive formal training in obesity prevention interventions. We examined the effectiveness of training healthcare providers in brief motivational interviewing (brief MI) targeting eating and exercise behavior change. METHODS: 163 healthcare providers participated. 128 participants completed a one-day experiential brief MI training workshop followed by electronic peer-support and a further 35 matched controls did not receive the training. RESULTS: Participant's knowledge of brief MI and confidence in their ability to counsel patients using brief MI significantly improved following training (p<0.05) and remained at 3 and 6-month follow-up (p<0.05). Brief MI skills assessed during the simulated patient interactions indicated a significant improvement across two practical training blocks (p<0.05). CONCLUSION: Healthcare providers can learn brief MI skills and knowledge quickly and confidence in their counseling abilities improves and is sustained. PRACTICE IMPLICATIONS: Healthcare providers may consider brief MI as an obesity prevention intervention. PMID- 25727284 TI - Development and practical implications of the Exercise Resourcefulness Inventory. AB - OBJECTIVE: To determine the validity and reliability of the Exercise Resourcefulness Inventory (ERI) designed to assess the self-regulatory strategies used to promote regular exercise. METHODS: In Study 1, the inventory's relationship with other established scales in the exercise behavior change field was examined. In Study 2, the test-retest reliability and predictive validity of the ERI was established by having participants from Study 1 complete the inventory a second time. RESULTS: Internal consistency, and convergent, discriminant, and concurrent validity were supported in both studies. The test retest correlation of the ERI was .80. As well, participants scoring higher on the ERI in Study 1 were more likely to be at a higher stage of change in Study 2, and greater increases in exercise resourcefulness over time were predictive of advancement to higher stages of change. CONCLUSIONS: ERI is a reliable and valid measure to assess the self-regulatory strategies used to promote regular exercise. PRACTICAL IMPLICATIONS: Facilitators may want to tailor exercise programs for individuals scoring lower in resourcefulness to prevent them from relapsing. PMID- 25727285 TI - Midwives' perceptions of communication during videotaped counseling for prenatal anomaly tests: how do they relate to clients' perceptions and independent observations? AB - OBJECTIVE: This study aimed to provide insight into Dutch midwives' self evaluation of prenatal counseling for anomaly screening in real life practice and, the degree of congruence of midwives' self-assessments with clients' perceptions and with observed performance. METHODS: Counseling sessions were videotaped. We used the QUOTE(prenatal) questionnaire to have each midwife (N = 20) and her client (N = 240) rate the prenatal counseling that they had together. We used an adapted version of the RIAS video-coding system to assess actual counseling during videotaped prenatal counseling (N = 240). RESULTS: Midwives perceived the following functions of counseling performed well: 100% of Client Counselor relation (CCR); 80% of Health Education (HE); and 17% Decision-Making Support (DMS). Congruence on HE of midwives with observers and with clients was >= 75%; congruence on DMS was higher between midwives and observers (80%) compared to midwives and clients (62%). CONCLUSION: Midwives perceive that during prenatal counseling the CCR and HE functions of counseling were performed well, whereas DMS was not. Furthermore, this study shows incongruence between midwives and clients about the discussion during DMS, indicating DMS is more difficult to assess than HE. PRACTICE IMPLICATIONS: The best way to measure prenatal counseling practice might be by using assessments of different sources within one study. PMID- 25727287 TI - NOD.H-2h4 mice: an important and underutilized animal model of autoimmune thyroiditis and Sjogren's syndrome. AB - NOD.H-2h4 mice express the K haplotype on the NOD genetic background. They spontaneously develop thyroiditis and Sjogren's syndrome, but they do not develop diabetes. Although autoimmune thyroid diseases and Sjogren's syndrome are highly prevalent autoimmune diseases in humans, there has been relatively little emphasis on the use of animal models of these diseases for understanding basic mechanisms involved in development and therapy of chronic organ-specific autoimmune diseases. The goal of this review is to highlight some of the advantages of NOD.H-2h4 mice for studying basic mechanisms involved in development of autoimmunity. NOD.H-2h4 mice are one of relatively few animal models that develop organ-specific autoimmune diseases spontaneously, i.e., without a requirement for immunization with antigen and adjuvant, and in both sexes in a relatively short period of time. Thyroiditis and Sjogren's syndrome in NOD.H-2h4 mice are chronic autoimmune diseases that develop relatively early in life and persist for the life of the animal. Because the animals do not become clinically ill, the NOD.H-2h4 mouse provides an excellent model to test therapeutic protocols over a long period of time. The availability of several mutant mice on this background provides a means to address the impact of particular cells and molecules on the autoimmune diseases. Moreover, to our knowledge, this is the only animal model in which the presence or absence of a single cytokine, IFN-gamma, is sufficient to completely inhibit one autoimmune thyroid disease, with a completely distinct autoimmune thyroid disease developing when it is absent. PMID- 25727286 TI - The second nationwide surveillance of the antimicrobial susceptibility of Neisseria gonorrhoeae from male urethritis in Japan, 2012-2013. AB - Worldwide, the most important concern in the treatment of sexually transmitted infections is the increase in antimicrobial resistant Neisseria gonorrhoeae strains including resistance to cephalosporins, penicillins, fluoroquinolones or macrolides. To investigate the trends of antimicrobial susceptibility among N. gonorrhoeae strains isolated from male patients with urethritis, a Japanese surveillance committee conducted the second nationwide surveillance study. Urethral discharge was collected from male patients with urethritis at 26 medical facilities from March 2012 to January 2013. Of the 151 specimens, 103 N. gonorrhoeae strains were tested for susceptibility to 20 antimicrobial agents. None of the strains was resistant to ceftriaxone, but the minimum inhibitory concentration (MIC) 90% of ceftriaxone increased to 0.125 MUg/ml, and 11 (10.7%) strains were considered less susceptible with an MIC of 0.125 MUg/ml. There were 11 strains resistant to cefixime, and the MICs of these strains were 0.5 MUg/ml. The distributions of the MICs of fluoroquinolones, such as ciprofloxacin, levofloxacin and tosufloxacin, were bimodal. Sitafloxacin, a fluoroquinolone, showed strong activity against all strains, including strains resistant to other three fluoroquinolones, such as ciprofloxacin, levofloxacin and tosufloxacin. The azithromycin MICs in 2 strains were 1 MUg/ml. PMID- 25727289 TI - Epithelial cell contributions to intestinal immunity. AB - The epithelial surfaces of the mammalian intestine interface directly with the external environment and thus continuously encounter pathogenic bacteria, fungi, viruses, and parasites. The intestinal epithelium is also closely associated with complex communities of symbiotic microorganisms. Intestinal epithelial cells are thus faced with the unique challenge of directly interacting with enormous numbers of microbes that include both pathogens and symbionts. As a result, gut epithelia have evolved an array of strategies that contribute to host immunity. This chapter considers the various mechanisms used by epithelial cells to limit microbial invasion of host tissues, shape the composition of indigenous microbial communities, and coordinate the adaptive immune response to microorganisms. Study of intestinal epithelial cells has contributed fundamental insights into intestinal immune homeostasis and has revealed how impaired epithelial cell function can contribute to inflammatory disease. PMID- 25727292 TI - MIR and NIR group spectra of n-alkanes and 1-chloroalkanes. AB - Numerous attempts were undertaken to resolve the absorption originating from different parts of alkanes. The separation of the contributions from the terminal and midchain methylene units was observed only in the spectra of solid alkanes at low temperatures. On the other hand, for liquid alkanes this effect was not reported as yet. In this study, ATR-IR, Raman and NIR spectra of eight n-alkanes and seven 1-chloroalkanes in the liquid phase were measured from 1000 to 12,000cm(-1). The spectra were analyzed by using two-dimensional (2D) correlation approach and chemometrics methods. It was shown that in 2D asynchronous contour plots, constructed from the spectra of n-alkanes and 1-chloroalkanes, the methylene band was resolved into two components. These two components were assigned to the terminal and midchain methylene groups. For the first time, the contributions from these two molecular fragments were resolved in the spectra of liquid n-alkanes and 1-chloroalkanes. MCR-ALS resolved these spectra into two components that were assigned to the ethyl and midchain methylene groups. These components represent the group spectra that can be used for assignment, spectral analysis and prediction of unknown spectra. The spectral prediction based on the group spectra provides very good results for n-alkanes, especially in the first and second overtone regions. PMID- 25727291 TI - AML1/ETO cooperates with HIF1alpha to promote leukemogenesis through DNMT3a transactivation. AB - The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and hypoxia-inducible factor 1alpha (HIF1alpha) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1alpha is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1alpha in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1alpha form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1alpha loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1alpha expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia. PMID- 25727293 TI - Electrochemical and fluorescence properties of SnO2 thin films and its antibacterial activity. AB - Nanocrystalline SnO2 thin films were deposited by a simple and inexpensive sol gel spin coating technique and the films were annealed at two different temperatures (350 degrees C and 450 degrees C). Structural, vibrational, optical and electrochemical properties of the films were analyzed using XRD, FTIR, UV Visible, fluorescence and cyclic voltammetry techniques respectively and their results are discussed in detail. The antimicrobial properties of SnO2 thin films were investigated by agar agar method and the results confirm the antibacterial activity of SnO2 against Escherichiacoli and Bacillus. PMID- 25727290 TI - Innate memory T cells. AB - Memory T cells are usually considered to be a feature of a successful immune response against a foreign antigen, and such cells can mediate potent immunity. However, in mice, alternative pathways have been described, through which naive T cells can acquire the characteristics and functions of memory T cells without encountering specific foreign antigen or the typical signals required for conventional T cell differentiation. Such cells reflect a response to the internal rather the external environment, and hence such cells are called innate memory T cells. In this review, we describe how innate memory subsets were identified, the signals that induce their generation and their functional properties and potential role in the normal immune response. The existence of innate memory T cells in mice raises questions about whether parallel populations exist in humans, and we discuss the evidence for such populations during human T cell development and differentiation. PMID- 25727288 TI - Approaches for analyzing the roles of mast cells and their proteases in vivo. AB - The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such "controversial" results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified. PMID- 25727294 TI - Optical behavior and sensor activity of Pb ions incorporated ZnO nanocrystals. AB - We present the synthesis and characterization of nanocrystalline ZnO doped with Pb in different concentrations. The structural and chemical compositions of the products are characterized by XRD, XPS, EDS and FT-IR spectroscopy. The observed results suggest that Pb ions (Pb(2+) and Pb(4+)) are successfully incorporated into the lattice position of Zn(2+) ions in ZnO. The optical properties of the products are studied by UV-Vis and room temperature PL measurements. The PL emission spectra of ZnO:Pb, show the intensity quenching for both the UV and visible emissions. The influence of Pb on controlling the size and morphology of ZnO is studied by FESEM and confirmed by HRTEM. Amperometric response shows that ZnO incorporated with 0.075M of Pb ions has enhanced sensor activity for H2O2 than the undoped product. PMID- 25727295 TI - Spectrophotometric quantification of the thermodynamic constants of the complexes formed by dopamine and Cu(II) in aqueous media. AB - The thermodynamic constants of the complex Cu(II)-dopamine in aqueous solution were evaluated from spectrophotometric data using the software SQUAD. It was found that there exist Cu(II):DA complexes with 1:1 and 1:2 stoichiometries and that their predominance depends on both the solution pH and the [Cu(II)]/[DA] ratio. Moreover, it is shown that the solubility of Cu(OH)2(s) increases drastically when these complexes are thermodynamically stable. PMID- 25727296 TI - Growth, structure, spectral and optical properties of semiorganic crystal: Pyridine-1-ium-2-carboxylatehydrogenbromide. AB - Pyridine-1-ium-2-carboxylatehydrogenbromide (PHBr) crystal was grown from aqueous solution by slow evaporation method. The calculated lattice parameters of single crystal X-ray diffraction have shown the triclinic crystal system with centrosymmetric space group of Pi. The interaction of functional groups and their importance in their application was identified by FTIR spectral analysis. The material is optically transparent and the grown crystal is having lower cut off wavelength as 294nm, thereby confirming the enhancement of non-linear optical (NLO) property and optical band gap of the PHBr have been determined as 2.49eV by UV-Vis-NIR studies. The (1)H NMR spectrum confirms the molecular structure and the presence of different kinds of protons. PMID- 25727297 TI - Thermal, dielectric characteristics and conduction mechanism of azodyes derived from quinoline and their copper complexes. AB - A novel series of (5-(4'-derivatives phenyl azo)-8-hydroxy-7 quinolinecarboxaldehyde) (AQLn) (n=1, p-OCH3; n=2, R=H; and n=3; p-NO2) and their complexes [Cu(AQLn)2].5H2O are synthesized and investigated. The optimized bond lengths, bond angles and the calculated quantum chemical parameters for AQLn are investigated. HOMO-LUMO energy gap, absolute electronegativities, chemical potentials, and absolute hardness are also calculated. The thermal properties, dielectric properties, alternating current conductivity (sigmaac) and conduction mechanism are investigated in the frequency range 0.1-100kHz and temperature range 293-568K for AQL1-3 and 318-693K for [Cu(AQL1-3)2].5H2O complexes. The thermal properties are of ligands (AQLn) and their Cu(II) complexes investigated by thermogravimetric analysis (TGA). The temperature and frequency dependence of the real and the imaginary part of the dielectric constant are studied. The values of the thermal activation energy of conduction mechanism for AQLn and their complexes [Cu(AQLn)2].5H2O under investigation are calculated at different test frequencies. The values of thermal activation energies DeltaE1 and DeltaE2 for AQLn and [Cu(AQLn)2].5H2O decrease with increasing the values of frequency. The ac conductivity is found to be depending on the chemical structure of the compounds. Different conduction mechanisms have been proposed to explain the obtained experimental data. The small polaron tunneling (SPT) is the dominant conduction mechanism for AQL1 and its complex [Cu(AQL1)2].5H2O. The quantum mechanical tunneling (QMT) is the dominant conduction mechanism for AQL2 and its complex [Cu(AQL2)2].5H2O. The correlated barrier hopping (CBH) is the dominant conduction mechanism for AQL3 and its complex [Cu(AQL3)2].5H2O, and the values of the maximum barrier height (Wm) are calculated. PMID- 25727298 TI - Maskless fabrication of cell-laden microfluidic chips with localized surface functionalization for the co-culture of cancer cells. AB - The utilization of the microfabrication technique to fabricate advanced computing chips has exponentially increased in the last few decades. Needless to say, this fabrication technique offers some unique advantages to develop micro-systems. Though many conventional microfabrication techniques today uses very harsh chemicals, the authors believe that the manipulation of system components and fabrication methods may aid in the utilization of the microfabrication techniques used in fabricating computer chips to develop advanced biological microfluidic systems. Presented in this paper is a fabrication approach in which popular fabrication methods and techniques are coupled together to develop an integrated system that aids in the fabrication of cell-laden microfluidic systems. This system aims to reduce the uses of harsh chemicals and decreases the lengthy fabrication time. Additionally, this integrated system will enable the printing of cells as the microfluidic chip is being fabricated. To demonstrate the unique capabilities of the integrated system, an advanced microfluidic chip is being fabricated and investigated. The advanced chip will feature the investigation of cancer cells in a co-cultured microfluidic environment. The investigations presented demonstrate co-cultures in a microfluidic chip, advanced cell printing with localized surface enhancement, cell integration, and full additive fabrication of a microfluidic chip. PMID- 25727299 TI - Initial institutional experience of uncooled single-antenna microwave ablation for large hepatocellular carcinoma. AB - AIM: To evaluate the safety, efficacy, and feasibility of a novel microwave generator, designed to deliver automatically adjusted energy by tissue permittivity feedback control into the tumour via an uncooled antenna, in patients with larger hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Fourteen patients with HCC >5 cm in diameter received surgical or percutaneous microwave ablation with more than 12 months of follow-up. Microwave ablation was performed using a 902-928 MHz generator at 28 W; a single 14 G antenna without water-cooled system was used. The patients were followed up with contrast enhanced CT and serum alpha-foetoprotein to monitor for tumour recurrence at 1 month and then every 3 months after tumour ablation. RESULTS: The follow-up duration for the 11 male and three female patients (mean tumour size 5.77 cm, range 5-7 cm; mean age 63.8 years) was 15.8 months. The mean ablation time was 2025 s (range 900-3600 s), and the mean ablation session was 2.5 (range 1-4). The complete ablation rate was 85% (17 of 20). Local recurrence rate was 5.8% (1 of 17). All patients survived and the morbidity and mortality rate was 21.4% and 0%, respectively. CONCLUSIONS: Microwave tissue ablation using this novel system with tissue permittivity feedback control and a single uncooled antenna has a high complete ablation rate and lower morbidity. It proved to be a fast, easy, and effective option for ablation of large (>5 cm) tumours. PMID- 25727300 TI - Substance use in individuals at clinical high risk of psychosis. AB - BACKGROUND: A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed. METHOD: At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models. RESULTS: CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment. CONCLUSIONS: In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone. PMID- 25727301 TI - The role of intravesical prostatic protrusion (IPP) in the evaluation and treatment of bladder outlet obstruction (BOO). AB - AIMS: Intravesical prostatic protrusion (IPP) may be an underutilized modality for the assessment of bladder outlet obstruction (BOO). Pressure flow studies or urodynamics have long been the gold standard for the evaluation of lower urinary tract symptoms (LUTS) in men but are invasive, time-consuming and costly. Potentially, IPP may be a useful adjunct prior to performing urodynamics. METHODS: Measurement of IPP is taken in the sagittal view, using the transabdominal ultrasound. It is the vertical height from the tip of the protrusion to the base of the prostate. This technique was previously described. We reviewed previous publications that studied the accuracy, positive predictive value and clinical use of IPP. In addition, we noted the comments regarding the challenges of using this technique. RESULTS: IPP has been shown to have a positive predictive value of 72% for BOO. It has been calculated to have an area under curve (AUC) value of 0.71 and 0.84 in some stuies. Clinically, it may be used to predict the outcome of a trial without catheter following acute retention of urine. Patients with higher IPP grade were noted to have a higher risk of clinical progression. Studies have also shown that men with higher IPP are poorer responders to medical treatment such as alpha-blockers. CONCLUSIONS: Compared to other modalities, the advantage of IPP in assessing BOO may be its easy applicability and non-invasive nature. Therefore, there is a consideration for a larger role of IPP in bedside assessment and management of BOO in daily practice. Neurourol. Urodynam. 35:535-537, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25727302 TI - Spontaneous Hemorrhage from Central Nervous System Hemangioblastomas. AB - OBJECTIVE: Hemagioblastomas are highly vascular tumors that rarely present with hemorrhage. To date, the only factor reported to possibly influence the propensity of a tumor to bleed has been its size (>1.5 cm). Here, we present our series of hemorrhagic hemangioblastomas, which includes 2 very small tumors (<1.5 cm). We propose that other factors apart from size may predispose tumors to hemorrhage. METHODS: We conducted a retrospective analysis of 55 cases of central nervous system hemangioblastomas operated on at Harborview Medical Hospital and the University of Washington between 2004 and 2014. Demographical and clinical data were collected and analyzed to determine factors that may predispose these tumors to hemorrhage. RESULTS: Of 55 cases, only 3 patients presented with hemorrhage (5.5%). None of the patients were von Hippel-Lindau positive. Two of the hemorrhagic tumors were less than 1.5 cm, countering previous studies in which authors proposed that hemangioblastomas that are less than 1.5 cm have essentially no risk of hemorrhage. One tumor also rebled after preoperative embolization. CONCLUSIONS: Our series suggests that small hemangioblastomas may represent a hemorrhagic risk. We speculate that other factors, such as genetic predisposition caused by single-nucleotide polymorphisms, may play a role in hemangiobalstomas that present with rupture. PMID- 25727303 TI - Intrasellar Symptomatic Salivary Gland Rest with Inflammations. AB - BACKGROUND: Instances of ectopic salivary gland tissue within the pituitary gland are rare, they are mostly asymptomatic, and the underlying pathophysiology of symptomatic cases is unclear. We report a case of intrasellar salivary gland rest that presented clinical symptoms and clearly related to inflammatory changes. CASE DESCRIPTION: In the present case, headache, bitemporal hemianopia, and hormone abnormality led to the detection of ectopic salivary gland tissue within the pituitary gland of a 24-year-old man. Imaging revealed a well-circumscribed intrasellar cystic lesion having a diameter of major axis of 16 mm, for which tumorectomy was performed using the nasal approach. The tumor was cystic with stringy content. Pathologic findings revealed that the lesion was composed principally of secretions lacking cell components, whereas the salivary gland tissue was found in the cyst wall. Dilated ducts due to the leakage of secretions were also observed. Acute and chronic inflammation was present around the salivary gland. CONCLUSIONS: Not only are instances of symptomatic ectopic salivary glands rare, but this was also the first case detected to be caused by the pathophysiology involving the leakage of secretions from an ectopic salivary gland and associated inflammation. We report this case to help elucidate the pathophysiology of the condition. PMID- 25727304 TI - Effects of Perioperative Acetyl Salicylic Acid on Clinical Outcomes in Patients Undergoing Craniotomy for Brain Tumor. AB - OBJECTIVE: To evaluate the safety of continuing acetyl salicylic acid (ASA) in patients undergoing brain tumor resection. Many patients are on antiplatelet agents that are withheld before elective neurosurgical procedures to reduce bleeding risk. Cessation of ASA in patients with cardiovascular disease is associated with a known increased risk of thrombotic events, especially in patients with coronary stents. METHODS: The medical records of patients who underwent surgical resection of a brain tumor at the University of Florida from 2010 to 2014 were evaluated. The patients were separated into groups based on preoperative ASA use and whether or not it was stopped before surgery. Patients were evaluated for thrombotic complications, postoperative hemorrhage, estimated blood loss, length of hospital stay, and discharge disposition. RESULTS: Of the 452 patients analyzed, 368 patients were not on chronic ASA therapy, 55 patients had their ASA discontinued before surgery, and 28 patients were continued on ASA perioperatively. The patients on preoperative ASA were comparable on all collected demographic variables. There were no statistical differences detected between the groups for outcomes including bleeding complications, need for reoperation, or thrombotic complications. CONCLUSIONS: In this analysis, perioperative low dose ASA use was not associated with increased risk of perioperative complications. PMID- 25727305 TI - The Safe Area in the Parieto-Occipital Lobe in the Human Brain: Diffusion Tensor Tractography. AB - OBJECTIVE: A recent study reported on the relatively safe area in the frontal lobe for performance of neurological interventions; however, no study on the posterior safe area has been reported. In this study, using diffusion tensor tractography, we attempted to identify the safe area in the parieto-occipital lobe in healthy subjects. METHODS: A total of 47 healthy subjects were recruited for this study. Eleven neural tracts were reconstructed in and around the parieto occipital area of the brain using diffusion tensor tractography. The safe area, which is free from any trajectory of 10 neural tracts, was measured anteriorly and medially from the line of the most posterior and lateral margin of the brain at 5 axial levels (from the cerebral cortex to the corona radiata). RESULTS: The anterior boundaries of the safe area in the upper cerebral cortex, lower cerebral cortex, centrum semiovale, upper corona radiata, and lower corona radiata levels were located at 31.0, 32.6, 32.7, 35.1, and 35.2 mm anteriorly from the line of the most posterior margin of the brain, respectively, and the medial boundaries were located at an average of 34.7, 38.1, 39.2, 36.1, and 33.6 mm medially from the line of the most lateral margin of the brain, respectively. CONCLUSIONS: According to our findings, the safe area was located in the posterolateral portion of the parieto-occipital lobe in the shape of a triangle. However, we found no safe area in the deep white matter around the lateral ventricle. PMID- 25727306 TI - A Concept Car or an All-road Car To Drive All Along Glioma Resection? PMID- 25727307 TI - Outcomes after adenotonsillectomy using a fixed anesthesia protocol in children with obstructive sleep apnea. AB - OBJECTIVE: To document the effects of a fixed anesthesia protocol on peri operative events in children undergoing adenotonsillectomy for obstructive sleep apnea (OSA). METHODS: A non-randomized prospective study was conducted during the years 2011-2013 within a setting of a tertiary-level university hospital. Sixty five children with polysomnographically proven OSA undergoing adenotonsillectomy were enrolled in the study and stratified into three groups based on severity. The relationship between severity of OSA as determined by apnea-hypopnea index (AHI) and oxygen saturation (SpO2) nadir were compared with time taken to (i) extubation following emergence and (ii) discharge from the post-anesthesia care unit. Adjustments were made in the dosages of premedication (midazolam) and opioid analgesic administered following induction (hydromorphone) depending on the severity of OSA. A non-validated but fixed anesthesia protocol tailored to the severity of OSA was used in all patients. In addition, all adverse events were also monitored. RESULTS: A paradoxical, yet significant reduction in emergence time was observed among patients with severe OSA following surgery (ANOVA, Tukey-Kramer post hoc tests, P<0.001). There were also fewer adverse events in this group. CONCLUSIONS: Emergence from anesthesia after adenotonsillectomy may be positively influenced by an anesthetic technique titrated according to the severity of OSA. Adverse respiratory events due to the severity of sleep apnea and attendant hypoxemia may be minimized and outcomes improved with similarly tailored protocols. PMID- 25727308 TI - Editorial: Probiotics. PMID- 25727309 TI - Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria. AB - OBJECTIVE: To characterize the mechanism of action of thiazolidinedione (TZD) induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. METHODS: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50MUM) for 48h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p<0.05. RESULTS: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. CONCLUSION: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. PMID- 25727310 TI - The imperatorin derivative OW1, a new vasoactive compound, inhibits VSMC proliferation and extracellular matrix hyperplasia. AB - Chronic hypertension induces vascular remodeling. The most important factor for hypertension treatment is reducing the risk of cardiovascular disease. OW1 is a novel imperatorin derivative that exhibits vasodilative activity and antihypertensive effects in two-kidney one-clip (2K1C) renovascular hypertensive rats. It also inhibited vascular remodeling of the thoracic aorta in a previous study. Here, the inhibitory effects and mechanisms of OW1 on arterial vascular remodeling were investigated in vitro and in 2K1C hypertensive rats in vivo. OW1 (20MUM, 10MUM, 5MUM) inhibited Ang II-induced vascular smooth muscle cells (VSMCs) proliferation and ROS generation in vitro. OW1 also reversed the Ang II mediated inhibition of alpha-SMA levels and stimulation of OPN levels. Histology results showed that treatment of 2K1C hypertensive rats with OW1 (20, 40, and 80mg/kg per day, respectively for 5weeks) in vivo significantly decreased the number of VSMCs, the aortic cross-sectional area (CSA), the media to lumen (M/L) ratio, and the content of collagen I and III in the mesenteric artery. Western blot results also revealed that OW1 stimulated the expression of alpha-SMA and inhibited the expression of collagen I and III on the thoracic aorta of 2K1C hypertensive rats. In mechanistic studies, OW1 acted as an ACE inhibitor and affected calcium channels. The suppression of MMP expression and the MAPK pathway may account for the effects of OW1 on vascular remodeling. OW1 attenuated vascular remodeling in vitro and in vivo. It could be a novel candidate for hypertension intervention. PMID- 25727311 TI - Purification and characterization of a novel cold-adapted phytase from Rhodotorula mucilaginosa strain JMUY14 isolated from Antarctic. AB - A yeast producing a cold-adapted phytase was isolated from Antarctic deep-sea sediment and identified as a Rhodotorula mucilaginosa strain JMUY14 of basidiomycetous yeasts. It was cultured in fermentation optimized by a response surface methodology based on the Box-Behnken design. The maximum activity of phytase reached 205.447 U ml(-1), which was close to the predicted value of 201.948 U ml(-1) and approximately 3.4 times higher than its initial activity. The extracellular phytase was purified by 15.2-fold to homogeneity with a specific activity of 31,635 U mg(-1) by (NH4 )2 SO4 precipitation, and a combination of DEAE Sepharose Fast Flow, SP Sepharose Fast Flow, and Sephadex G 100. The molecular weight of the purified enzyme was estimated to be 63 kDa and its pI was 4.33. Its optimal temperature and pH were 50 degrees C and 5.0, respectively. Its activity was 85% at 37 degrees C, and showed good stability at pH 3.0 ~ 7.0. When compared with mesophilic counterparts, the phytase not only exhibited a higher activity during 20 ~ 30 degrees C but also had a low Km (247 uM) and high kcat (1394 s(-1)). The phytase activity was slightly stimulated in the presence of Mg(2+), Fe(2+), Fe(3+), K(+), Na(+), Ca(2+), EDTA, and EGTA and moderately inhibited by Cu(2+), Zn(2+), Mn(2+), Ag(+), PMSF, SDS, and phenylgloxal hydrate. It was resistant to both pepsin and trypsin. Since the phytase produced by the R. mucilaginosa JMUY14 showed a high specific activity, good pH stability, strong protease resistance, and high activity at low temperature, it has great potential for feed applications, especially in aquaculture. PMID- 25727312 TI - Comparison of indicators measuring the proportion of human immunodeficiency virus infected persons with a suppressed viral load. AB - PURPOSE: The Centers for Disease Control and Prevention uses the last viral load to estimate the proportion of human immunodeficiency virus (HIV)-infected persons with a suppressed viral load. Several recent studies report that it may overestimate viral suppression in the population and have suggested using sustained viral suppression. The objective of this analysis is to compare these indicators. METHODS: Using New York City HIV surveillance data, two indicators were compared with a new one, weighted viral suppression, which accounts for both the status and duration of viral suppression. RESULTS: Among 72,315 HIV-infected persons with at least one viral load measurement in New York City in 2013, 62,829 had at least one suppressed viral load, 58,041 had a suppressed last viral load, and 47,948 had sustained viral suppression. Compared with the weighted proportion (77.5%), the proportion based on last viral load suppression (80.3%) was slightly higher, and the proportion based on sustained viral suppression (66.3%) was substantially lower. CONCLUSIONS: The indicator based on last viral load suppression is the most straightforward to calculate and understand and also approximates the weighted indicator, which measures viral suppression for the entire analysis period. Therefore, we support using the indicator based on last viral load suppression to monitor the National HIV/AIDS Strategy. PMID- 25727313 TI - Apolipoprotein E isoforms 3/3 and 3/4 differentially interact with circulating stearic, palmitic, and oleic fatty acids and lipid levels in Alaskan Natives. AB - Lifestyle changes in Alaskan Natives have been related to the increase of cardiovascular disease and metabolic syndrome in the last decades. Variation of the apolipoprotein E (Apo E) genotype may contribute to the diverse response to diet in lipid metabolism and influence the association between fatty acids in plasma and risk factors for cardiovascular disease. The aim of this investigation was to analyze the interaction between Apo E isoforms and plasma fatty acids, influencing phenotypes related to metabolic diseases in Alaskan Natives. A sample of 427 adult Siberian Yupik Alaskan Natives was included. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, Apo A1, and Apo B plasma concentrations were measured using reference methods. Concentrations of 13 fatty acids in fasting plasma were analyzed by gas chromatography, and Apo E variants were identified. Analyses of covariance were conducted to identify Apo E isoform and fatty acid main effects and multiplicative interactions. The means for body mass index and age were 26 +/ 5.2 and 47 +/- 1.5, respectively. Significant main effects were observed for variation in Apo E and different fatty acids influencing Apo B levels, triglycerides, and total cholesterol. Significant interactions were found between Apo E isoform and selected fatty acids influencing total cholesterol, triglycerides, and Apo B concentrations. In summary, Apo E3/3 and 3/4 isoforms had significant interactions with circulating levels of stearic, palmitic, oleic fatty acids, and phenotypes of lipid metabolism in Alaskan Natives. PMID- 25727314 TI - Seagrass biofilm communities at a naturally CO2 -rich vent. AB - Seagrass meadows are a crucial component of tropical marine reef ecosystems. Seagrass plants are colonized by a multitude of epiphytic organisms that contribute to broadening the ecological role of seagrasses. To better understand how environmental changes like ocean acidification might affect epiphytic assemblages, the microbial community composition of the epiphytic biofilm of Enhalus acroides was investigated at a natural CO2 vent in Papua New Guinea using molecular fingerprinting and next-generation sequencing of 16S and 18S rRNA genes. Both bacterial and eukaryotic epiphytes formed distinct communities at the CO2 -impacted site compared with the control site. This site-related CO2 effect was also visible in the succession pattern of microbial epiphytes. We further found an increased relative sequence abundance of bacterial types associated with coral diseases at the CO2 -impacted site (Fusobacteria, Thalassomonas), whereas eukaryotes such as certain crustose coralline algae commonly related to healthy reefs were less diverse. These trends in the epiphytic community of E. acroides suggest a potential role of seagrasses as vectors of coral pathogens and may support previous predictions of a decrease in reef health and prevalence of diseases under future ocean acidification scenarios. PMID- 25727315 TI - From candidate gene studies to GWAS and post-GWAS analyses in breast cancer. AB - There are now more than 90 established breast cancer risk loci, with 57 new ones, revealed through genome-wide-association studies (GWAS) during the last two years. Established high, moderate and low penetrance genetic variants currently explain ~49% of familial breast cancer risk. GWAS-discovered variants account for 14%, and it is estimated that another 1000 yet-to-be-discovered loci could contribute an additional ~14% of familial risk. Polygenic risk scores can already be used to stratify breast cancer risk in the female population and could improve the targeting of mammographic screening programmes, which are at present largely based on age-specific risks. Fine-scale mapping and functional analyses are revealing candidate causal variants and the molecular mechanisms by which GWAS hits may act. Better-powered GWAS and genome-wide sequencing projects are likely to continue identifying new breast cancer causal variants. PMID- 25727316 TI - Turning off of GluN2B subunits and turning on of CICR in hippocampal LTD induction after developmental GluN2 subunit switch. AB - NMDA receptors (NMDARs) are essential for the induction of synaptic plasticity that mediates activity-dependent refinement of neural circuits during development. GluN2B subunits of NMDARs are abundant at synapses in the immature hippocampus and begin to be replaced by GluN2A subunits with the help of casein kinase 2 activity in the second postnatal week, the critical period for the GluN2 subunit switch (Sanz-Clemente et al. (2000) Neuron 67:984-996). However, the physiological role of GluN2B subunits in the hippocampus during this critical period has not been elucidated. Here, we report that GluN2B subunits mediate the induction of long-term depression (LTD) in the CA1 region of the hippocampus only until this period. Ifenprodil and Ro25-6981, selective inhibitors of NMDARs containing GluN2B subunits, blocked LTD in postnatal Day 11-14 (P11-14) rat hippocampal slices but not in P18-22 hippocampus. Just a few days after P14, synaptic NMDAR currents became narrower than those at P11-14, and calcium influx through NMDARs must be reduced. We found that calcium-induced calcium release (CICR) through ryanodine receptors starts to support the induction of NMDAR dependent LTD at P18-22. Intracellular application of thapsigargin and ryanodine, inhibitors of Ca2+ -ATP pumps on internal stores and ryanodine receptors, respectively, did not at all affect LTD in the hippocampus at P11-14 but completely blocked LTD in the P18-22 hippocampus. Therefore, calcium influx through NMDAR with GluN2B subunits is sufficient to induce LTD at P11-14, after which CICR compensates for the decrease in calcium influx during LTD induction. PMID- 25727317 TI - Cyclodextrin-functionalized reduced graphene oxide as a fiber coating material for the solid-phase microextraction of some volatile aromatic compounds. AB - A novel solid phase microextraction fiber was prepared for the first time by using a sol-gel technique with hydroxypropyl-beta-cyclodextrin-functionalized reduced graphene oxide as the fiber coating material. The results verified that the beta-cyclodextrin was successfully grafted onto the surface of reduced graphene oxide and the coating possessed a uniform folded and wrinkled structure. The performance of the solid phase microextraction fiber was evaluated by using it to extract nine volatile aromatic compounds from water samples before determination with gas chromatography and flame ionization detection. Some important experimental parameters that could affect the extraction efficiency such as the extraction time, extraction temperature, desorption temperature, desorption time, the volume of water sample solution, stirring rate, as well as ionic strength were optimized. The new method was validated to be effective for the trace analysis of some volatile aromatic compounds, with the limits of detection ranging from 2.0 to 8.0 ng/L. Single fiber repeatability and fiber-to fiber reproducibility were in the range of 2.5-9.4 and 5.4-12.9%, respectively. The developed method was successfully applied to the analysis of three different water samples, and the recoveries of the method were in the range from 77.9 to 113.6% at spiking levels of 10, 100, and 1000 ng/L, respectively. PMID- 25727318 TI - Peripheral and central glucose utilizations modulated by mitochondrial DNA 10398A in bipolar disorder. AB - Bipolar disorder (BD) is highly heritable and associated with dysregulation of brain glucose utilizations (GU). The mitochondrial DNA (mtDNA) 10398A polymorphism, as a reported BD risk factor, leads to deficient glycolytic energy production by affecting mitochondrial matrix pH and intracellular calcium levels. However, whether mtDNA-10398A has functional effects on the brain and how our body responds remain elusive. We compared peripheral and central glucose utilizing patterns between mtDNA A10398G polymorphisms in BD and their unaffected siblings (BDsib). Since siblings carry identical mtDNA, we hypothesized that certain characteristics co-segregate in BD families. We recruited twenty-seven pairs of non-diabetic BD patients and their BDsib and 30 well-matched healthy control subjects (HC). The following were investigated: mtDNA, fasting plasma glucose/insulin, cognitive functions including Montreal Cognitive Assessment (MoCA), and brain GU at rest. Insulin resistance was rechecked in sixty-one subjects (19-BD, 18-BDsibib, and 24-HC) six months later. We found that BD-pairs (BD+BDsib) carried more mtDNA-10398A and had higher fasting glucose, even after controlling for many covariates. BD-pairs had abnormally lower dorso-prefrontal GU and higher cerebellar-GU, but only BD demonstrated lower medio-prefrontal-GU and MoCA. Subjects carrying mtDNA-10398A had significantly lower prefrontal-GU (FWE-corrected p<0.05). An abnormal inverse pattern of insulin-GU and insulin MoCA correlation was found in BD-pairs. The insulin-MoCA correlation was particularly prominent in those carrying mtDNA-10398A. mtDNA-10398A predicted insulin resistance 6 months later. In conclusion, mtDNA-10398A was associated with impaired prefrontal-GU. An up-regulation of glucose utilizations was found in BD-pairs, probably compensating for mtDNA-10398A-related energy loss. PMID- 25727319 TI - Role of runt-related transcription factor 2 in signal network of tumors as an inter-mediator. AB - Runt-related transcription factor 2 (RUNX2) is a member of the polyomavirus enhancer-binding protein 2/core-binding factor superfamily. RUNX2 is known for its contribution to osteoblast phenotype and bone formation. In recent years, increasing attention has been focused on the relationship of Runx2 with tumorigenesis. In different types of tumor cells, RUNX2 cooperates with its co activators or co-inhibitors, and mediates the responses of cells to various signaling pathways that are hyperactive in tumors. Thus, several downstream target genes of RUNX2 are activated when RUNX2 interacts with its co-factors, leading to a variety of effects on tumor cells (epithelial-mesenchymal transition, metastasis, proliferation, and osteolytic lesion). This review focuses on the involvement of RUNX2 in tumor cells in the crosstalk of diverse signaling pathways and its multiple functions to develop optimal and feasible approaches for clinical treatment based on the functions of RUNX2. PMID- 25727320 TI - Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-kappaB signaling pathway for gastric cancer metastasis. AB - Heparanase (HPA) is an endoglucuronidase that can promote the shedding of associated cytokines in several types of tumors. However, little is known about what controls the expression of HPA or its role in gastric cancer. In this study, we report for the first time that HGF regulates HPA expression to promote gastric cancer metastasis. In this study, HGF and HPA were found to be significantly expressed in 58 gastric cancer patients. High expression of both HGF and HPA was positively associated with TNM stage, invasion depth and poor prognosis. In MKN74 cells, exogenous HGF significantly increased HPA expression at both the mRNA and protein levels. Further study revealed that HGF first activated PI3K/Akt signaling. NF-kappaB signaling was activated downstream of PI3K/Akt and promoted HPA expression. However, when c-met, PI3K/Akt or NF-kappaB signal inhibitors were used, HPA expression was significantly decreased. All of these results indicate that HGF regulates HPA expression by PI3K/Akt and downstream NF-kappaB signaling. Using bioinformatics and the ChIP assay, p65 was observed to bind to the HPA promoter. Furthermore, HGF significantly induced tumor cell migration, whereas treatment with an NF-kappaB inhibitor decreased migration. Moreover, when HPA was overexpressed in MKN74 cells, migration was significantly enhanced, and the HGF concentration was increased. However, when HPA was down-regulated in MKN45 cells, migration and HGF levels decreased. Together, these results demonstrate that HGF/c-met can activate PI3K/Akt and downstream NF-kappaB signaling to promote HPA expression and subsequent tumor metastasis. PMID- 25727321 TI - Hi-Fi SELEX: A High-Fidelity Digital-PCR Based Therapeutic Aptamer Discovery Platform. AB - Current technologies for aptamer discovery typically leverage the systematic evolution of ligands by exponential enrichment (SELEX) concept by recursively panning semi-combinatorial ssDNA or RNA libraries against a molecular target. The expectation is that this iterative selection process will be sufficiently stringent to identify a candidate pool of specific high-affinity aptamers. However, failure of this process to yield promising aptamers is common, due in part to (i) limitations in library designs, (ii) retention of non-specific aptamers during screening rounds, (iii) excessive accumulation of amplification artifacts, and (iv) the use of screening criteria (binding affinity) that does not reflect therapeutic activity. We report a new selection platform, High Fidelity (Hi-Fi) SELEX, that introduces fixed-region blocking elements to safeguard the functional diversity of the library. The chemistry of the target display surface and the composition of the equilibration solvent are engineered to strongly inhibit non-specific retention of aptamers. Partition efficiencies approaching 10(6) are thereby realized. Retained members are amplified in Hi-Fi SELEX by digital PCR in a manner that ensures both elimination of amplification artifacts and stoichiometric conversion of amplicons into the single-stranded library required for the next selection round. Improvements to aptamer selections are first demonstrated using human alpha-thrombin as the target. Three clinical targets (human factors IXa, X, and D) are then subjected to Hi-Fi SELEX. For each, rapid enrichment of ssDNA aptamers offering an order-nM mean equilibrium dissociation constant (Kd) is achieved within three selection rounds, as quantified by a new label-free qPCR assay reported here. Therapeutic candidates against factor D are identified. PMID- 25727322 TI - Theoretical investigation of the halogen bonded complexes between carbonyl bases and molecular chlorine. AB - The halogen bonded complexes between six carbonyl bases and molecular chlorine are investigated theoretically. The interaction energies calculated at the CCSD(T)/aug-cc-pVTZ level range between -1.61 and -3.50 kcal mol(-1). These energies are related to the ionization potential, proton affinity, and also to the most negative values (V(s,min)) on the electrostatic potential surface of the carbonyl bases. A symmetry adapted perturbation theory decomposition of the energies has been performed. The interaction results in an elongation of the Cl Cl bond and a contraction of the CF and CH bonds accompanied by a blue shift of the nu(CH) vibrations. The properties of the Cl2 molecules are discussed as a function of the sigma*(Cl-Cl) occupation, the hybridization, and the occupation of the Rydberg orbitals of the two chlorine atoms. Our calculations predict a large enhancement of the infrared and Raman intensities of the nu(Cl-Cl) vibration on going from isolated to complexed Cl2. PMID- 25727323 TI - Recreating Virginity in Iran: Hymenoplasty as a Form of Resistance. AB - Hymenoplasty is a controversial surgery in Iran, where a woman's failure to present herself as virginal for marriage may result in severe social repercussions. Critical literature surrounding this clandestine surgery is sparse. During ethnographic fieldwork in Tehran, I interviewed women who have and have not undergone hymenoplasty and physicians who perform it. Using a Foucauldian framework, I argue that the medicalization of virginity is a form of female social control in Iran. The resulting narratives and discourses suggest that hymenoplasty is a covert form of resistance against socioculturally prescribed sexual inegalitarianism that restricts women to the social sphere of premarital chastity. By manipulating the medicalization of virginity, women inadvertently resist dichotomous gendered classifications that constrain them as either the deviant woman who has premarital sex or the normal woman who remains virginal until marriage. These women deviate from a fixed notion of gender embodiment, eroding socioculturally constituted categorical boundary markers regarding femininity. PMID- 25727324 TI - Perceptions of the living dead: An assessment of knowledge and opinions about whole body donation, its process, and willingness to become cadaveric donors in Pennsylvania. AB - Despite the many important uses for human cadavers, there is a relative shortage of bodies donated to the scientific community in the United States of America. The purpose of this study was to determine the community's perceptions regarding whole body donation and their willingness to become donors. Moreover, we aimed to investigate people's understanding of the process of whole body donation, and examine their opinions regarding its importance. Individuals in Erie, Pennsylvania were surveyed. Data were collected via a questionnaire, which was offered to friends and family members of patients in the waiting area of the UPMC Hamot Surgery Center. All participants were residents of Erie County. The questionnaire was designed to evaluate knowledge and opinions about whole body donation. A total of 123 people completed the survey. We found people were willing to become whole body donors and understood the importance of this giving act, but lacked understanding about the registration process and the use of donated bodies. Participants revealed the belief that they have the right to decide what is to be done with their bodies after death, but did not indicate specific negative repercussions of becoming whole body donors. In conclusion, our findings indicate that the shortage of cadaveric donors could be due to lack of understanding about whole body donation and the registration process. PMID- 25727325 TI - Quercetin and isorhamnetin aglycones are the main metabolites of dietary quercetin in cerebrospinal fluid. AB - SCOPE: Reports on the protective effect of certain foods on brain functions are numerous; however, the permeability of the brain barriers by food components is still hardly recognised. There have been in vitro studies aimed at demonstrating this possibility, but not much is known about this phenomenon in in vivo systems. The objective of the study was to determine the metabolites of dietary quercetin (Q) in urine, blood plasma and cerebrospinal fluid (CSF) after intra-rumen administration of Q rich onion dry skin in an animal model. METHODS AND RESULTS: Eleven sheep had permanently implanted cannulas in the third ventricle of the brain as the means for CSF collection. The animals were administered Q at the dose of 10 mg/kg bwt. For 12 h the concentration of Q metabolites was measured in urine, blood plasma, and CSF. It was demonstrated that while in blood plasma Q and isorhamnetin mono-glucuronides or mono-sulphates were the main metabolites (80%), in CSF their aglycones were the dominating ones (88%). CONCLUSION: Q and IR aglycones are the main Q metabolites present in CSF after dietary Q intake. Their passive transport through blood-CSF barrier or a de-conjugating mechanism within that barrier may be involved. PMID- 25727326 TI - Cerium(IV)-driven water oxidation catalyzed by a manganese(V)-nitrido complex. AB - The study of manganese complexes as water-oxidation catalysts (WOCs) is of great interest because they can serve as models for the oxygen-evolving complex of photosystem II. In most of the reported Mn-based WOCs, manganese exists in the oxidation states III or IV, and the catalysts generally give low turnovers, especially with one-electron oxidants such as Ce(IV) . Now, a different class of Mn-based catalysts, namely manganese(V)-nitrido complexes, were explored. The complex [Mn(V) (N)(CN)4 ](2-) turned out to be an active homogeneous WOC using (NH4 )2 [Ce(NO3 )6 ] as the terminal oxidant, with a turnover number of higher than 180 and a maximum turnover frequency of 6 min(-1) . The study suggests that active WOCs may be constructed based on the Mn(V) (N) platform. PMID- 25727327 TI - Basic techniques in mammalian cell tissue culture. AB - Cultured mammalian cells are used extensively in cell biology studies. It requires a number of special skills in order to be able to preserve the structure, function, behavior, and biology of the cells in culture. This unit describes the basic skills required to maintain and preserve cell cultures: maintaining aseptic technique, preparing media with the appropriate characteristics, passaging, freezing and storage, recovering frozen stocks, and counting viable cells. PMID- 25727328 TI - Isolation and culture of spinal cord motor neurons. AB - Isolated spinal motoneurons are a powerful tool for studying basic mechanisms of neurite growth and survival. Since motoneurons are a minor population of developing spinal cord cells, they need to be purified and enriched to separate them from non-neuronal cells. Therefore, the particular feature of embryonic motoneurons to express the low affinity neurotrophin receptor p75(NTR) is used to separate the motoneurons from other contaminating cells. Two ways are described to isolate embryonic motoneurons: the basic protocol taking advantage of the ability of p75(NTR) to bind lectin, and an alternative method using an antibody against p75(NTR) for a panning procedure. These protocols comprise suggestions for the cultivation of the isolated motoneurons for experiments regarding neural outgrowth and survival as well as instruction for the preparation of proteins of the cells. PMID- 25727329 TI - Adhesive micropatterns to study intermediate filament function in nuclear positioning. AB - The nucleus is generally found near the cell center; however its position can vary in response to extracellular or intracellular signals, leading to a polarized intracellular organization. Nuclear movement is mediated by the cytoskeleton and its associated motors. While the role of actin and microtubule cytoskeletons in nuclear positioning has been assessed in various systems, the contribution of intermediate filaments is less established due in part to the lack of tools to study intermediate filament functions. The methods described here use micropatterned substrates to impose reproducible cell shape and nucleus position. Intermediate filament organization can be perturbed using gene downregulation or upregulation; intermediate filaments can also be visualized using fluorescent intermediate filament proteins. This protocol is valuable for characterizing the role of intermediate filaments in a variety of live or fixed adherent cells. PMID- 25727330 TI - Reconstitution of a bioengineered salivary gland using a three-dimensional cell manipulation method. AB - One concept in regenerative therapy is the replacement of a lost or damaged organ with a regenerated, fully functional organ. Three-dimensional cell manipulation techniques, designated "organ germ methods," enable the normal development of a bioengineered organ germ in several types of ectodermal organs, such as teeth, hair follicles, and secretory glands. This method is useful for both organ regeneration technology and developmental biology, including cell kinetic analysis and the elucidation of gene regulation during organogenesis. Here, we describe a protocol for salivary gland reconstitution using the organ germ method to transplant a bioengineered salivary gland germ. PMID- 25727331 TI - Isolation of integrin-based adhesion complexes. AB - The integration of cells with their extracellular environment is facilitated by cell surface adhesion receptors, such as integrins, which play important roles in both normal development and the onset of pathologies. Engagement of integrins with their ligands in the extracellular matrix, or counter-receptors on other cells, initiates the intracellular assembly of a wide variety of proteins into adhesion complexes such as focal contacts, focal adhesions, and fibrillar adhesions. The proteins recruited to these complexes mediate bidirectional signaling across the plasma membrane, and, as such, help to coordinate and/or modulate the multitude of physical and chemical signals to which the cell is subjected. The protocols in this unit describe two approaches for the isolation or enrichment of proteins contained within integrin-associated adhesion complexes, together with their local plasma membrane/cytosolic environments, from cells in culture. In the first protocol, integrin-associated adhesion structures are affinity isolated using microbeads coated with extracellular ligands or antibodies. The second protocol describes the isolation of ventral membrane preparations that are enriched for adhesion complex structures. The protocols permit the determination of adhesion complex components via subsequent downstream analysis by western blotting or mass spectrometry. PMID- 25727332 TI - Sinonasal neuroendocrine carcinoma: a population-based analysis of incidence and survival. AB - BACKGROUND: Sinonasal neuroendocrine carcinoma (SNEC) is a rare, aggressive tumor usually associated with a poor prognosis. This study analyzes the clinicopathological characteristics and survival outcomes of SNEC using population-based data. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2011) was queried for SNEC cases. Data analyzed included patient demographics, incidence, treatment modality, and survival. RESULTS: A total of 201 cases of SNEC were identified. Mean age at diagnosis was 55.8 +/- 15.7 years. Overall 5-year disease-specific survival (DSS) rate for SNEC was 50.8%. Five-year survival analysis for SNEC by site revealed DSS of 80.7%, 59.2%, 34.5%, and 33.0% for the sphenoid sinus, nasal cavity, maxillary sinus, and ethmoid sinus, respectively (p = 0.0014). Cox proportional hazard analysis revealed greater hazard of death for the maxillary (hazard ratio [HR] 2.14; 95% confidence interval [CI], 1.21 to 3.71; p = 0.0094) and ethmoid sinuses (HR 1.83; 95% CI, 1.05 to 3.16; p = 0.0345) when compared to the nasal cavity. Advanced stage disease (stages III to IV, 5-year DSS 40.5%, p = 0.0008) was associated with poor survival outcomes. Survival was better among those treated with surgery (with [59.4%] or without [69.0%] radiotherapy) than those treated with primary radiotherapy alone (39.9%) (p < 0.0001). CONCLUSION: SNEC commonly presents at an advanced-stage with poor survival outcomes. Negative prognostic factors include primary tumor site and advanced stage disease. SNEC is a highly aggressive tumor necessitating surgery and/or surgery with adjuvant radiotherapy as the treatment of choice. PMID- 25727333 TI - (E)-,(Z)-parallel preparative methods for stereodefined beta,beta-diaryl- and alpha,beta-diaryl-alpha,beta-unsaturated esters: application to the stereocomplementary concise synthesis of zimelidine. AB - Parallel and practical methods for the preparation of both (E)- and (Z)-beta aryl(1)-beta-aryl(2)-alpha,beta-unsaturated esters 1 and (E)- and (Z)-alpha aryl(1)-beta-aryl(2)-alpha,beta-unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N-methylimidazole (NMI)-mediated enol tosylations (14 examples, 70-99% yield), as well as stereoretentive Suzuki Miyaura cross-couplings (36 examples, 64-99% yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)- and (Z)-pure products 1 and 2 by utilizing sequential enol tosylations and cross-coupling reactions. An expeditious and parallel synthesis of (E)- and (Z)-zimelidine (3), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods. PMID- 25727334 TI - Detecting concentrations of milk components by an iterative optical technique. AB - This paper introduces a theoretical and practical model for reconstructing the scattering properties of a participating media. Our theory is based on a robust generalization of the Gerchberg-Saxton (G-S) algorithm. At the end of this algorithm the reduced scattering coefficient MU's of a given substance, can be estimated from the standard deviation (STD) of the retrieved phase of the remitted light. We use the theory to compute the phase's STD that directly correlated to the optical properties for different types of milk components, and we derive a novel appearance model for milk parameterized by the lactose and protein contents. Our results show that we are able to detect the possibility of lactose and milk proteins' quantitative signature by the G-S optical tool, en route to the design of a novel milk-content-monitoring tool. Sketch of the experimental setup for light intensity measurements and reduced scattering coefficient reconstruction. The samples were prepared from various milk components: whey protein, sodium casienate and lactose, at different concentrations. PMID- 25727335 TI - Comparative effect of a new mouthrinse containing chlorhexidine, triclosan and zinc on volatile sulphur compounds: a randomized, crossover, double-blind study. AB - AIM: The aims of this study were to compare the volatile sulphur compounds (VSC) reducing effect of two commercial mouthrinses using a morning bad breath model and to assess the role of mechanical plaque control (MPC) when performed previously to mouthrinse use. PATIENTS AND METHODS: Eleven volunteers with good oral health were enrolled in a double-blind, randomized, six-step crossover design study with a 7-day washout period. Two commercial mouthrinses were tested using a saline solution (NaCl 0.9%) as a negative control: one mouthrinse contained 0.05% chlorhexidine, 0.05% cetylpyridinium chloride and 0.14% zinc lactate (CHX-CPC-Zn), while the other contained 0.05% chlorhexidine, 0.15% triclosan and 0.18% zinc pidolate (CHX-triclosan-Zn). A portable sulphide monitor (Halimeter((r)) ) was used for VSC quantification. Measurements were made at baseline, and 1, 3 and 5 h after rinsing. Significant differences were detected by analysis of variance. RESULTS: No significant differences between groups were detected at baseline. We were unable to demonstrate a significant influence of mechanical plaque control on the reduction of VSC levels when performed before mouthrinse use (P = 0.631). Both mouthrinses effectively lowered VSC levels in all test intervals (P < 0.05). No statistically significant differences were found between mouthrinses in any of the test intervals (P = 0.629, 0.069 and 0.598 at 1, 3 and 5 h). CONCLUSION: This study demonstrated that CHX-CPC-Zn and CHX-triclosan-Zn have significant and similar effects in reducing VSC levels, which persist for at least 5 h. Such effects were independent of previous MPC, which failed to improve on the results of mouthrinse use alone. PMID- 25727336 TI - Invasive onychocytic carcinoma. AB - Neoplasms originating from nail matrix keratinocytes are very rare. Onychomatricoma and onychocytic matricoma are benign tumors arising from nail matrix keratinocytes. Only one case of onychocytic carcinoma, the malignant counterpart of onychocytic matricoma, has been reported in the literature. Herein, we describe a case of invasive onychocytic carcinoma. Two biopsy specimens of the tumor, obtained at early and invasive stages, were examined histopathologically. The first biopsy specimen showed a retiform proliferation of eosinophilic and basophilic cells in the nail matrix. The second biopsy specimen showed a retiform basophilic cell proliferation with focal keratinization. Similar to normal nail matrix keratinocytes, the proliferating basophilic cells failed to express cytokeratin (CK)1, CK6 and CK10. Focal expression of hair specific keratins, including K31, K85 and K86, was observed. On the basis of these findings, the tumor was identified as an invasive malignant tumor originating from nail matrix keratinocytes. PMID- 25727337 TI - Sequential Healing at Calcium- versus Calcium Phosphate-Modified Titanium Implant Surfaces: An Experimental Study in Dogs. AB - PURPOSE: The aim of this paper was to study the sequential healing of bone tissues at implants with different configuration and different modified surfaces. MATERIALS AND METHODS: Twelve Beagle dogs were used. Extractions of all teeth from the second premolar to the first molar were performed in both sides of the mandible. After 3 months, full-thickness flaps were elevated and two implants of different systems and with different surfaces were randomly installed in the premolar region in one side of the mandible. One surface was acid etched and further modified with calcium ions (BTI unicCa(r)), the other was sandblasted and acid etched plus a nanometer calcium phosphate deposition (3i T3(r)). The flaps were sutured to allow a fully submerged healing. The surgery on the other side of the mandible and the sacrifices were planned in such a way to obtain biopsies representing the healing after 1, 2, 4, and 8 weeks (n = 6 per period). RESULTS: After 1 and 2 weeks of healing, the mean values of new bone apposition on the implant surfaces were 5.9 +/- 3.3% and 29.8 +/- 16.0% at BTI unicCa and 4.6 +/- 3.3% and 12.4 +/- 5.6% at 3i T3, respectively. After 4 and 8 weeks, the percentage increased, being 49.4 +/- 8.1% and 63.6 +/- 7.3% at BTI unicCa and 40.3 +/- 10.0% and 47.3 +/- 20.2 at 3i T3, respectively. Differences statistically significant between the two surfaces were found only at the 2- and 4-week observation periods. Concomitantly, the old bone was resorbed at both surfaces from about 15-17% after 1 week to about 4-6% after 8 weeks of healing. CONCLUSION: Moderately rough surfaces modified with calcium ions or discrete calcium phosphate nanocrystalline deposition showed similar patterns of sequential healing. Higher new bone percentages were found at BTI unicCa compared with the 3i T3 implants, the difference being statistically significant at 2 and 4 weeks observation. PMID- 25727338 TI - Cyclization of a 1,4-diborabutadiene ligand with both atoms of CO. AB - A 1,4-dibora-1,3-butadiene iron complex was successfully synthesized through the stoichiometric reaction of an iron bis(borylene) complex with diphenylacetylene. This complex was treated with CO and PMe3 , which led to the formation of an unusual six-membered B2 C3 O ylidic ring bound to both the PMe3 group and zerovalent iron center. The reaction is a very rare example of the incorporation of both atoms of CO into a ring system. PMID- 25727339 TI - Synthesis and Anti-Inflammatory Evaluation of Novel C66 Analogs for the Treatment of LPS-Induced Acute Lung Injury. AB - We previously reported a symmetric monocarbonyl analog of curcumin (MACs), C66, which demonstrated potential anti-inflammatory activity and low toxicity. In continuation of our ongoing research, we designed and synthesized 34 asymmetric MACs based on C66 as a lead molecule. A majority of the C66 analogs effectively inhibited LPS induction of TNF-alpha and IL-6 expression. Additionally, a preliminary SAR was conducted. Furthermore, active compounds 4a11 and 4a16 were found to effectively reduce the W/D ratio in the lungs and the protein concentration in the bronchoalveolar lavage fluid (BALF). Meanwhile, a histopathological examination indicated that these two analogs significantly attenuate tissue injury in the lungs with LPS-induced ALI rats. 4a11 and 4a16 also inhibited mRNA expression of several inflammatory cytokines, including TNF alpha, IL-6, IL-1beta, COX-2, ICAM-1 and VCAM-1, in the Beas-2B cells after LPS challenge. Altogether, the data exhibit a series of new C66 analogs as promising anti-inflammatory agents for the treatment of LPS-induced ALI. PMID- 25727341 TI - Effective separation of the actinides Am(III) and Cm(III) by electronic modulation of bis-(1,2,4-triazin-3-yl)phenanthrolines. AB - It has been shown that modification of the phenanthroline backbone of CyMe4 BTPhen leads to subtle electronic modulation, permitting differential ligation of Am(III) and Cm(III) resulting in separation factors up to 7. PMID- 25727340 TI - Feeding cancer's sweet tooth: specialized tumour vasculature shuttles glucose in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal neoplasm characterized by a 'fortress' of thick collagen fibres, abundant myofibroblasts, and paradoxically reduced vascularization compared to normal pancreas. Despite these features, PDAC shows no reduction in the uptake of glucose that fuels tumour cell survival. In new work published in The Journal of Pathology, Saiyin and colleagues have identified a novel adaptation of PDAC tumour endothelium; namely, 'hairy-like' basal microvilli that increase the total vascular surface area and correlate with regions of highest glucose uptake. Since basal microvilli are not present on normal pancreatic blood vessels, their presence may add diagnostic value and blocking their function is a potential new treatment strategy for PDAC. This novel finding of basal microvilli on PDAC endothelium is a striking example of how phenotypic plasticity in tumour blood vessels contributes to tumour growth and progression, independent of conventional modes of angiogenesis. PMID- 25727342 TI - Estimation of interaction between oriented immobilized green fluorescent protein and its antibody by high performance affinity chromatography and molecular docking. AB - Although green fluorescence protein (GFP) and its antibody are widely used to track a protein or a cell in life sciences, the binding behavior between them remains unclear. In this work, diazo coupling method that synthesized a new stationary GFP was oriented immobilized on the surface of macro-porous silica gel by a phase. The stationary phase was utilized to confirm the validation of injection amount-dependent analysis in exploring protein-protein interaction that use GFP antibody as a probe. GFP antibody was proved to have one type of binding site on immobilized GFP. The number of binding site and association constant were calculated to be (6.41 +/- 0.76) * 10(-10) M and (1.39 +/- 0.12) * 10(9) M(-1). Further analysis by molecular docking showed that the binding of GFP to its antibody is mainly driven by hydrogen bonds and salt bridges. These results indicated that injection amount-dependent analysis is capable of exploring the protein-protein interactions with the advantages of ligand and time saving. It is a valuable methodology for the ligands, which are expensive or difficult to obtain. PMID- 25727343 TI - Suicide attempts and stressful life events among female victims of intimate partner violence living in poverty in Nicaragua. AB - This article describes a study of 136 female intimate partner violence victims living in poverty in Nicaragua. The paper aimed to analyze the relationship between experiencing stressful life events (SLE) and perceived social support with suicide attempts, and to evaluate the differences in the SLE experienced by female suicide attempters versus non-attempters. The results showed the existence of a high level of SLE among the interviewees, and that women who have attempted suicide have experienced substantially more of these events. Experiences of violence and less social support were especially related to suicide attempts among the interviewees. PMID- 25727344 TI - Changes in southern Piedmont grassland community structure and nutritive quality with future climate scenarios of elevated tropospheric ozone and altered rainfall patterns. AB - Forage species common to the southern USA Piedmont region, Lolium arundinacea, Paspalum dilatatum, Cynodon dactylon and Trifolium repens, were established in a model pasture system to test the future climate change scenario of increasing ozone exposure in combination with varying rainfall amounts on community structure and nutritive quality. Forages were exposed to two levels of ozone [ambient (non-filtered; NF) and twice ambient (2*) concentrations] with three levels of precipitation (average or +/-20% of average) in modified open-top chambers (OTCs) from June to September 2009. Dry matter (DM) yield did not differ over the growing season between forage types, except in primary growth grasses where DM yield was higher in 2* than NF treatment. Primary growth clover decreased in nutritive quality in 2* ozone because of increased concentrations of neutral detergent fibre (NDF), acid detergent fibre (ADF) and acid detergent lignin (ADL). Re-growth clover exhibited the largest decrease in nutritive quality, whereas grasses were not adversely affected in 2* ozone. Re-growth grasses responded positively to 2* ozone exposure, as indicated in increased relative food value (RFV) and percentage crude protein (CP) than NF-exposed re growth grasses. Effects of precipitation were not significant over the growing season for primary or re-growth forage, except in primary growth grasses where DM yield was higher in chambers with above average (+20%) precipitation. Total canopy cover was significantly higher over the growing season in chambers receiving above average precipitation, but no significant effects were observed with ozone. Results indicate shifts in plant community structure and functioning related to mammalian herbivore herbivory in future climate change scenarios. PMID- 25727345 TI - Cyclosporin treatment improves skin findings in omenn syndrome. AB - Omenn syndrome is a combined immunodeficiency characterized by a generalized erythematous skin rash, enlarged lymph nodes, hepatosplenomegaly, severe susceptibility to infections, eosinophilia, and hyperimmunoglobulinemia E. A 3 month-old girl was admitted to our hospital with a history of recurrent sepsis. Physical examination revealed severe erythroderma, hepatosplenomegaly, lymphadenopathy, and failure to thrive. Laboratory findings revealed leukocytosis, lymphocytosis with high CD3 T-cells, a high CD4:CD8 ratio, absence of CD19 B-cells, high eosinophil count, and low immunoglobulin levels. A heterozygote RAG1 gene mutation was found. She had itchy, scaling, ichthyosiform erythroderma and protracted diarrhea. Cyclosporin treatment up to 10 mg/kg effectively resolved erythroderma and lowered total eosinophil counts, and she gained weight during treatment. Since extensive erythroderma with generalized itching causes patient discomfort in Omenn syndrome, cyclosporin treatment can be considered while waiting for treatment with hematopoietic stem cell transplantation. PMID- 25727346 TI - Temporal information processing as a basis for auditory comprehension: clinical evidence from aphasic patients. AB - BACKGROUND: Temporal information processing (TIP) underlies many aspects of cognitive functions like language, motor control, learning, memory, attention, etc. Millisecond timing may be assessed by sequencing abilities, e.g. the perception of event order. It may be measured with auditory temporal-order threshold (TOT), i.e. a minimum time gap separating two successive stimuli necessary for a subject to report their temporal order correctly, thus the relation 'before-after'. Neuropsychological evidence has indicated elevated TOT values (corresponding to deteriorated time perception) in different clinical groups, such as aphasic patients, dyslexic subjects or children with specific language impairment. AIMS: To test relationships between elevated TOT and declined cognitive functions in brain-injured patients suffering from post-stroke aphasia. METHODS & PROCEDURES: We tested 30 aphasic patients (13 male, 17 female), aged between 50 and 81 years. TIP comprised assessment of TOT. Auditory comprehension was assessed with the selected language tests, i.e. Token Test, Phoneme Discrimination Test (PDT) and Voice-Onset-Time Test (VOT), while two aspects of attentional resources (i.e. alertness and vigilance) were measured using the Test of Attentional Performance (TAP) battery. OUTCOMES & RESULTS: Significant correlations were indicated between elevated values of TOT and deteriorated performance on all applied language tests. Moreover, significant correlations were evidenced between elevated TOT and alertness. Finally, positive correlations were found between particular language tests, i.e. (1) Token Test and PDT; (2) Token Test and VOT Test; and (3) PDT and VOT Test, as well as between PDT and both attentional tasks. CONCLUSIONS & IMPLICATIONS: These results provide further clinical evidence supporting the thesis that TIP constitutes the core process incorporated in both language and attentional resources. The novel value of the present study is the indication for the first time in Slavic language users a clear coexistence of the 'timing-auditory comprehension attention' relationships. PMID- 25727347 TI - Degradation of the benzoxazolinone class of phytoalexins is important for virulence of Fusarium pseudograminearum towards wheat. AB - Wheat, maize, rye and certain other agriculturally important species in the Poaceae family produce the benzoxazolinone class of phytoalexins on pest and pathogen attack. Benzoxazolinones can inhibit the growth of pathogens. However, certain fungi can actively detoxify these compounds. Despite this, a clear link between the ability to detoxify benzoxazolinones and pathogen virulence has not been shown. Here, through comparative genome analysis of several Fusarium species, we have identified a conserved genomic region around the FDB2 gene encoding an N-malonyltransferase enzyme known to be involved in benzoxazolinone degradation in the maize pathogen Fusarium verticillioides. Expression analyses demonstrated that a cluster of nine genes was responsive to exogenous benzoxazolinone in the important wheat pathogen Fusarium pseudograminearum. The analysis of independent F. pseudograminearum FDB2 knockouts and complementation of the knockout with FDB2 homologues from F. graminearum and F. verticillioides confirmed that the N-malonyltransferase enzyme encoded by this gene is central to the detoxification of benzoxazolinones, and that Fdb2 contributes quantitatively to virulence towards wheat in head blight inoculation assays. This contrasts with previous observations in F. verticillioides, where no effect of FDB2 mutations on pathogen virulence towards maize was observed. Overall, our results demonstrate that the detoxification of benzoxazolinones is a strategy adopted by wheat infecting F. pseudograminearum to overcome host-derived chemical defences. PMID- 25727348 TI - Self-reported health and comfort in 'modern' office buildings: first results from the European OFFICAIR study. AB - In the European research project OFFICAIR, a procedure was developed to determine associations between characteristics of European offices and health and comfort of office workers, through a checklist and a self-administered questionnaire including environmental, physiological, psychological, and social aspects. This procedure was applied in 167 office buildings in eight European countries (Portugal, Spain, Italy, Greece, France, Hungary, the Netherlands, and Finland) during the winter of 2011-2012. About 26 735 survey invitation e-mails were sent, and 7441 office workers were included in the survey. Among respondents who rated an overall comfort less than 4 (23%), 'noise (other than from building systems)', air 'too dry', and temperature 'too variable' were the main complaints selected. An increase of perceived control over indoor climate was positively associated with the perceived indoor environment quality. Almost one-third of office workers suffered from dry eyes and headache in the last 4 weeks. Physical building characteristics were associated with occupants' overall satisfaction (acoustical solutions, mold growth, complaints procedure, cleaning activities) and health (number of occupants, lack of operable windows, presence of carpet and cleaning activities). OFFICAIR project provides a useful database to identify stressors related to indoor environmental quality and office worker's health. PMID- 25727349 TI - Elderly Mothers of Adult Children with Intellectual Disability: An Exploration of a Stress Process Model for Caregiving Satisfaction. AB - BACKGROUND: This study examines the utility of Pearlin's caregiving stress model for understanding the caregiving satisfaction of elderly mothers of adult children with intellectual disability. METHODS: Mothers living in Seoul, Kyonggi, and Incheon who were 55 years of age or older and providing care for adult children with intellectual disability aged 18 or above were selected purposively from community rehabilitation centre users. A total of 392 participants responded to the survey. The structural equation modelling method was used to evaluate the suitability of the stress process model and to test the hypotheses. RESULTS: The stress model proved to be a good fit to the data. The results showed that a mediating variable - a problem-centred coping strategy - transmitted the effect of stress variables such as recognition of ageing, establishment of permanency planning, and worries about the future on caregiving satisfaction. The relationship of adult children with intellectual disability also transmitted the effect of establishment of permanency planning on caregiving satisfaction. However, an indirect effect of an emotion-centred coping strategy was not shown. CONCLUSIONS: The findings of this study shed light on the development of intervention strategies for elderly mothers who provide care permanently to adult children with intellectual disabilities. PMID- 25727350 TI - Analysis of the treatment of neuromyelitis optica. AB - BACKGROUND: Treatment options for neuromyelitis optica (NMO) are currently based on small retrospective case series and open label studies, ranging from 10 to 103 patients. OBJECTIVE: To compare the efficacy and tolerability of azathioprine, cyclophosphamide, mycophenolate, and rituximab in patients with neuromyelitis optica. METHODS: This is a retrospective chart review and telephone follow-up study of 71 patients with NMO or NMO spectrum disorder, 54 of whom were treated with the study drugs. We compared adverse events, annualized relapse rates and expanded disability status scales before and after treatment. RESULTS: The median ARR decreased from 1.17 to 0.25 on rituximab (P<0.01), 0.92 to 0.56 on azathioprine (P=0.475), 1.06 to 0.39 on mycophenolate (P<0.05) and 1.30 to 0.92 on cyclophosphamide (P=0.746). When compared directly to azathioprine, rituximab significantly reduced relapse rates (P=0.021). The median EDSS decreased from 7 to 5 on rituximab (P<0.01) and 7 to 6 on azathioprine (P<0.01), and did not change significantly on mycophenolate (4 to 5; P=0.463) or cyclophosphamide (6.5 to 6.5; P=0.881). Twenty-five percent of patients noted adverse events on rituximab, 36% on azathioprine, 36% on mycophenolate, and 80% on cyclophosphamide. CONCLUSION: Rituximab significantly reduces relapse rates and improves disability while maintaining comparable tolerability to other immunosuppressive treatments for NMO. PMID- 25727351 TI - Simultaneous assessment of cognitive and affective functions in multiple system atrophy and cortical cerebellar atrophy in relation to computerized touch-panel screening tests. AB - Cognitive impairment and affective dysfunction of multiple system atrophy (MSA) and cortical cerebellar atrophy (CCA) have not been simultaneously examined comparing standard test batteries and a sensitive tool to detect subtle cognitive decline in patients. In the present study, we simultaneously examined cognitive and affective ability in MSA with predominant cerebellar ataxia (MSA-C, n=25), MSA with predominant parkinsonism (MSA-P, n=8), and CCA (n=14) patients using computerized touch panel screening tests. Mini-mental state examination (MMSE), Hasegawa dementia scale-revised (HDS-R), frontal assessment battery (FAB), and Montreal cognitive assessment (MoCA) scores were significantly lower in MSA-C patients than in age-and gender-matched normal controls. One MSA-C patient showed a decrease in the regional cerebral blood flow (rCBF) of the frontal lobe. MSA-P patients showed no such cognitive decline. Only FAB and MoCA scores were significantly lower in the CCA patients. MSA and CCA patients also showed a mild to moderate depressive state. Touch-panel screening tests demonstrated a significant decline of beating devils game in all three disease groups including MSA-P patients, and a significant extension of the flipping cards game only in MSA-C patients. The present study demonstrated different cognitive and affective functions among MSA-C, MSA-P, and CCA patients, and a sensitive screening method for cognitive assessment using touch-panel tests. PMID- 25727352 TI - Taking the guesswork out of supplying multicompartment compliance aids: do pharmacists require further guidance on medication stability? AB - OBJECTIVE: The purpose of this article is to identify information that is currently available to pharmacists concerning the stability of medications repackaged into multicompartment compliance aids (MCAs). This article explores the potential risks associated with repackaging medications into MCAs for pharmacists who supply and patients who use them. KEY FINDINGS: There is a paucity of information currently available to pharmacists concerning the stability of medications repackaged into MCAs as it is not routinely provided by pharmaceutical manufacturers. However, some studies have identified the potential for adverse effects on safety, bioavailability and stability that may have a clinical impact. There are also professional and legal implications of removing medications from their original packaging for storage in MCAs. CONCLUSION: There is a growing need for further information concerning the stability of medications repackaged into MCAs to guide pharmacists who are supplying these compliance aids to primary and secondary care. Pharmaceutical manufacturers and researchers should be advised to conduct stability testing in MCAs for orally administered medications. This information should be readily available, and pharmacists should be made aware of it via their pharmaceutical bodies. As a result, decisions regarding MCA preparation can be more informed, and pharmacist and patient risks associated with repackaging potentially unstable medications can be minimised. PMID- 25727353 TI - Bioavailability of iron from plant and animal ferritins. AB - Iron deficiency is a major public health problem in the world. Ferritin is being explored as a novel and natural strategy for iron supplementation. The objective of this study was to evaluate iron bioavailability from ferritin isolated from plant and animal sources. The stability of plant ferritin and animal ferritin was studied by in vitro and in vivo digestion to determine whether these ferritins can pass through the gastrointestinal tract in intact form. Results from sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot indicate that both plant ferritin and animal ferritin can resist digestion (both under acidic and moderately acidic conditions). Furthermore, ferritin was labeled with (59)Fe, and bioavailability of iron from ferritin was assessed by uptake into Caco-2 cells. Our results indicate that iron is taken up from the ferritins and that iron bioavailability from soybean ferritin (rH-1:rH-2=1:1) is the highest. These results may be explained by the binding of ferritin to Caco-2 cells, which can be attributed to the interaction between ferritin and its putative receptor(s) at the surface of Caco-2 cells. In conclusion, ferritin from plant and animal sources may be developed as an iron source. PMID- 25727354 TI - Mirror neuron therapy for hemispatial neglect patients. AB - Mirror neuron system(MNS) based therapy has been employed to treat stroke induced movement disorders. However, its potential effects on patients with hemispatial neglect were uninvestigated. The present study set out to test the therapeutic efficiency of video watching of series of hand actions/movements (protocol A) in two patients with left hemispatial neglect, due to the right hemisphere stroke. The video containing dynamic landscape of natural scene or cities but not human/animals was used as the protocol B. The "ABA" training procedure for 3 weeks therefore allows us to internally control the individual differences. Before and after each week of training, the Chinese behavioral inattention test- Hongkong version (CBIT-HK) was implemented to evaluate the hemispatial neglect severity. Functional magnetic resonance imaging (fMRI) experiment was implemented in two health subjects to reveal the difference of brain activation between protocol A and B. The results showed that protocol A rather than protocol B significantly improved the CBIT-HK scores at first and third weeks, respectively. Protocol A induced more bilateral activations including right inferior parietal lobe (supramarginal gyrus), which belongs to MNS and is also critical region resulting to hemineglect. CONCLUSION: MNS activation can provide a novel therapy for hemispatial neglect patients. PMID- 25727356 TI - Computational psychological study of the Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP) for patients with chronic low back pain: verification of responsiveness. AB - BACKGROUND: We developed the Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP, physician and patient versions) and have previously shown that the BS-POP is reliable and has construct validity, criterion validity, and reproducibility. The present study aimed to proactively verify the responsiveness of the BS-POP with regard to chronic low back pain (LBP) patients. METHODS: The study subjects included 193 chronic LBP patients (81 males, 112 females; mean age 62 years) who had suffered from persistent LBP for >=3 months. During the first test (before the treatment), the BS-POP, the Minnesota Multiphasic Personality Inventory (MMPI), the Profile of Mood States (POMS), the 36-item Short-form Health Survey version 2 (SF-36 v2), and the Roland-Morris Disability Questionnaire (RDQ) were conducted. The BS-POP, POMS, SF-36 v2, and RDQ for the third test were conducted (4-6 weeks after treatment) on all patients who had participated in the first test to determine the responsiveness of the BS-POP. The responsiveness of the BS-POP was investigated statistically. RESULTS: The total crude BS-POP scores were significantly lower for both physician and patient versions in the third test than in the first test. Moreover, the crude RDQ scores and SF-36 v2 items, physical functioning (PF), bodily pain (BP), MH, VT, and GH, and POMS items, tension-anxiety (T-A), D, F, and confusion (C) improved significantly, confirming responsiveness to treatment. DISCUSSION: The present findings indicate that the BS-POP possesses sufficient responsiveness from a computational psychology perspective. The BS-POP constitutes a tool enabling orthopaedists to easily identify psychiatric problems in orthopaedic patients. PMID- 25727355 TI - Evolution of double-stranded DNA viruses of eukaryotes: from bacteriophages to transposons to giant viruses. AB - Diverse eukaryotes including animals and protists are hosts to a broad variety of viruses with double-stranded (ds) DNA genomes, from the largest known viruses, such as pandoraviruses and mimiviruses, to tiny polyomaviruses. Recent comparative genomic analyses have revealed many evolutionary connections between dsDNA viruses of eukaryotes, bacteriophages, transposable elements, and linear DNA plasmids. These findings provide an evolutionary scenario that derives several major groups of eukaryotic dsDNA viruses, including the proposed order "Megavirales," adenoviruses, and virophages from a group of large virus-like transposons known as Polintons (Mavericks). The Polintons have been recently shown to encode two capsid proteins, suggesting that these elements lead a dual lifestyle with both a transposon and a viral phase and should perhaps more appropriately be named polintoviruses. Here, we describe the recently identified evolutionary relationships between bacteriophages of the family Tectiviridae, polintoviruses, adenoviruses, virophages, large and giant DNA viruses of eukaryotes of the proposed order "Megavirales," and linear mitochondrial and cytoplasmic plasmids. We outline an evolutionary scenario under which the polintoviruses were the first group of eukaryotic dsDNA viruses that evolved from bacteriophages and became the ancestors of most large DNA viruses of eukaryotes and a variety of other selfish elements. Distinct lines of origin are detectable only for herpesviruses (from a different bacteriophage root) and polyoma/papillomaviruses (from single-stranded DNA viruses and ultimately from plasmids). Phylogenomic analysis of giant viruses provides compelling evidence of their independent origins from smaller members of the putative order "Megavirales," refuting the speculations on the evolution of these viruses from an extinct fourth domain of cellular life. PMID- 25727357 TI - Organic field-effect transistor-based gas sensors. AB - Organic field-effect transistors (OFETs) are one of the key components of modern organic electronics. While the past several decades have witnessed huge successes in high-performance OFETs, their sophisticated functionalization with regard to the responses towards external stimulations has also aroused increasing attention and become an important field of general concern. This is promoted by the inherent merits of organic semiconductors, including considerable variety in molecular design, low cost, light weight, mechanical flexibility, and solution processability, as well as by the intrinsic advantages of OFETs including multiparameter accessibility and ease of large-scale manufacturing, which provide OFETs with great potential as portable yet reliable sensors offering high sensitivity, selectivity, and expeditious responses. With special emphases on the works achieved since 2009, this tutorial review focuses on OFET-based gas sensors. The working principles of this type of gas sensors are discussed in detail, the state-of-the-art protocols developed for high-performance gas sensing are highlighted, and the advanced gas discrimination systems in terms of sensory arrays of OFETs are also introduced. This tutorial review intends to provide readers with a deep understanding for the future design of high-quality OFET gas sensors for potential uses. PMID- 25727358 TI - Droplet-droplet interactions investigated using a combination of electrochemical and dynamic light scattering techniques. The case of water/BHDC/benzene:n-heptane system. AB - In this contribution the electrochemistry of [Fe(CN)6](4-/3-) as the probe molecule was investigated in benzyl-n-hexadecyldimethylammonium chloride (BHDC) reverse micelles (RMs) varying the composition of the external solvent (benzene:n heptane mixtures) and the surfactant concentration, at a fixed water content and probe concentration. The electrochemical and dynamic light scattering results show that in water/BHDC/benzene:n-heptane systems the aggregate sizes increase on increasing BHDC concentration. This behavior was unexpected since it is known that for water/BHDC/benzene RM systems keeping the water content constant and the surfactant concentration below 0.2 M, the droplet sizes are independent of the concentration of the surfactant. We explain the results considering that on changing the external solvent to benzene:n-heptane mixtures, RMs tend to associate in clusters and equilibrium between free RMs and droplet clusters is established. A model is presented which, using electrochemical and dynamic light scattering data, allows calculating the aggregation number of the RMs, the number of RMs that form the droplet clusters and the standard electron transfer heterogeneous rate constant. PMID- 25727359 TI - Newborn cord care practices in Haiti. AB - Newborn cord infections commonly lead to neonatal sepsis and death, particularly in low-resource countries where newborns may receive unhygienic cord care. Topical application of chlorhexidine to the newborn's cord has been shown to prevent infection. Such benefits may be particularly important in Haiti. We explored current cord care practices by conducting a qualitative study using five focus groups among key community stakeholders (mothers of newborns/children under age two years, pregnant women, traditional birth attendants, community health workers, traditional healers) in Petit-Goave, Haiti. Data collection was guided by the Health Belief Model. Results suggest community stakeholders recognise that infants are susceptible to cord infection and that cord infection is a serious threat to newborns. Long-held traditional cord care practices are potential barriers to adopting a new cord care intervention. However, all groups acknowledged that traditional practices could be harmful to the newborn while expressing a willingness to adopt practices that would protect the newborn. Results demonstrate potential acceptability for altering traditional cord care practices among neonatal caretakers in Haiti. An informational campaign designed to educate local health workers and new mothers to eliminate unhygienic cord applications while promoting chlorhexidine application may be a strong approach for preventing neonatal cord infections. PMID- 25727360 TI - A retrospective analysis of allele frequency changes of major genes during 20 years of selection in the Italian Large White pig breed. AB - In this study, we investigated whether a selection programme based on boar genetic evaluation obtained with a classical BLUP animal model can change allele frequencies in a pig population. All Italian Large White boars born from 1992 to 2012 with estimated breeding value reliability >0.85 (n = 200) were selected among all boars of this breed. Boars were genotyped with markers in major genes (IGF2 intron3-g.3072G>A, MC4R p.D298N, VRTN PRE1 insertion, PRKAG3 p.I199V and FTO g.276T>G). Genotyping data were analysed grouping boars in eight classes according to their year of birth. To evaluate the influence of time on allele frequencies of the genotyped markers, multinomial logistic regression models were computed. Four of five polymorphic sites (IGF2, MC4R, VRTN and FTO) showed significant (p < 0.01) changes in allele frequencies over time due to a progressive and continuous increase of one allele (associated with higher lean meat content, higher average daily gain and favourable feed: gain ratio) and, consequently, decrease of the other one, following the directional selection of the selection programme of this pig breed. The retrospective analysis that was carried out in Italian Large White boars suggests that selection based on methodologies assuming the infinitesimal model is able to modify in a quite short period of time allele frequencies in major genes, increasing the frequency of alleles explaining a relevant (non-infinitesimal) fraction of the overall genetic variability for production traits. PMID- 25727361 TI - Blood Pressure and Atrial Fibrillation: A Combined AF-CHF and AFFIRM Analysis. AB - BACKGROUND: Hypertension is an established risk factor for new-onset atrial fibrillation (AF). However, the relationship between blood pressure and recurrent AF is less well understood. METHODS AND RESULTS: A pooled analysis of patient level data from AFFIRM and AF-CHF trials was conducted on all 2,715 patients with paroxysmal or persistent AF, 68 +/- 8 years, 66% male, randomized to rhythm control and followed for 40.6 +/- 16.5 months. We assessed the impact of a baseline systolic blood pressure (SBP; <120 mmHg [N = 1,008], 120-140 mmHg [N = 930], >140 mmHg [N = 777]) on recurrent AF and proportion of time spent in AF. In patients with LVEF >40% (N = 1,719), SBP was not associated with recurrent AF in multivariate regression analyses (P = 0.752). In contrast, in patients with LVEF <=40% (N = 996), the AF recurrence rate was higher in those with an SBP >140 mmHg compared to 120-140 mmHg (hazard ratio 1.47; 95% CI [1.12-1.93], P = 0.005). The rate of recurrent AF was similar in patients with SBP <120 mmHg compared to 120 140 mmHg (hazard ratio 1.15; 95% CI [0.92-1.43], P = 0.225). Consistently, the proportion of time spent in AF was not influenced by SBP in patients with LVEF >40% (P = 0.645). However, in patients with LVEF <=40%, the adjusted mean proportion of time spent in AF was 17.2% if SBP was <120 mmHg, 15.4% for SBP 120 140 mmHg, and 24.0% for SBP >140 mmHg (P = 0.025). CONCLUSION: Systolic blood pressure is an important determinant of recurrent AF and overall AF burden in patients with left ventricular dysfunction (LVEF<=40%) but not in those with preserved ventricular function. PMID- 25727362 TI - Biodegradable hydrophilic polyurethane PEGU25 loading antimicrobial peptide Bmap 28: a sustained-release membrane able to inhibit bacterial biofilm formation in vitro. AB - Catheter-related infection makes up a large part of hospital infection and contributes 80% to all nosocomial urological infection, costing hundreds of millions dollar per year for treatment. Biodegradable hydrophilic material incorporating antibiotic substance is a promising way to prevent catheter-related infection. And antimicrobial peptide seems an optimal drug for its desirable antibiotic effect. In the current research, we produced a new kind of antibiotic material by incorporating antimicrobial peptide Bmap-28 with polyurethane PEGU25 and tested its effect on Proteus mirabilis in vitro. Compared with the control group, PEGU25 membrane incorporating Bmap-28 had a significant lower bacteria load after co-cultured with the Proteus mirabilis. And its antibiotic effect could be observed throughout the whole 7-day test. Also the Bmap-28 membrane could delay catheter obstruction caused by encrustation. Our findings reveal that PEGU25 incorporating Bmap-28 can well inhibit bacterial biofilm formation of common pathogens for catheter-related urinary tract infection in vitro, which makes it a promising antibiotic material for medical tubes for urology. PMID- 25727363 TI - Transferring critically ill patients home to die: developing a clinical guidance document. AB - BACKGROUND: With preferred place of care at the time of death a key consideration in end of life care, it is important that transfer home be considered for critically ill patients who want this as part of their end of life care. However, there is limited guidance available to inform the transfer of critically ill patients home to die. AIMS AND OBJECTIVES: To develop clinical guidance on the practice of transferring patients home to die for doctors and nurses in critical care. DESIGN: Consensus methodology. METHODS: At a one-day national event, stakeholders from cross-community and hospital settings engaged in group work wherein 'virtual clinical teams' mapped out, and agreed on, the processes involved in transferring critically ill patients home to die. Using two clinical cases and nominal group technique, factors were identified that promoted and inhibited transfer home and areas in need of development. Findings from the day informed development of a clinical guidance document. RESULTS: Eighty-five stakeholders attended the event from across England. The majority of stakeholders strongly agreed that transfer of critically ill patients home to die was a good idea in principle. Stakeholders identified 'access to care in the community' (n = 22, 31.4%) and 'unclear responsibility for care of patient' (n = 17, 24.3%) as the most important barriers. Consensus was reached on the processes and decision making required for transfer home and was used to inform content of a clinical practice guidance document. This underwent further refinement following review by 14 clinicians. A final document in the form of a flow chart was developed. CONCLUSIONS: Transferring critically ill patients home to die is a complex, multifactorial process involving health care agencies across the primary and secondary care interface. The guidance developed from this consensus event will enable staff to actively consider the practice of transferring home to die in appropriate patients. PMID- 25727364 TI - Quality evaluation of terpinen-4-ol-type Australian tea tree oils and commercial products: an integrated approach using conventional and chiral GC/MS combined with chemometrics. AB - GC/MS, chiral GC/MS, and chemometric techniques were used to evaluate a large set (n=104) of tea tree oils (TTO) and commercial products purported to contain TTO. Twenty terpenoids were determined in each sample and compared with the standards specified by ISO-4730-2004. Several of the oil samples that were ISO compliant when distilled did not meet the ISO standards in this study primarily due to the presence of excessive p-cymene and/or depletion of terpinenes. Forty-nine percent of the commercial products did not meet the ISO specifications. Four terpenes, viz., alpha-pinene, limonene, terpinen-4-ol, and alpha-terpineol, present in TTOs with the (+)-isomer predominant were measured by chiral GC/MS. The results clearly indicated that 28 commercial products contained excessive (+)-isomer or contained the (+)-isomer in concentrations below the norm. Of the 28 outliers, 7 met the ISO standards. There was a substantial subset of commercial products that met ISO standards but displayed unusual enantiomeric+/-ratios. A class predictive model based on the oils that met ISO standards was constructed. The outliers identified by the class predictive model coincided with the samples that displayed an abnormal chiral ratio. Thus, chiral and chemometric analyses could be used to confirm the identification of abnormal commercial products including those that met all of the ISO standards. PMID- 25727365 TI - The Neutrophil Nucleus and Its Role in Neutrophilic Function. AB - The cell nucleus plays a key role in differentiation processes in eukaryotic cells. It is not the nucleus in particular, but the organization of the genes and their remodeling that provides the data for the adjustments to be made according to the medium. The neutrophil nucleus has a different morphology. It is a multi lobed nucleus where some researchers argue no longer function. However, studies indicate that it is very probable the occurrence of chromatin remodeling during activation steps. It may be that the human neutrophil nucleus also contributes to the mobility of neutrophils through thin tissue spaces. Questions like these will be discussed in this small review. The topics include morphology of human neutrophil nucleus, maturation process and modifications of the neutrophil nucleus, neutrophil activation and chromatin modifications, causes and consequences of multi-lobulated segmented morphology, and importance of the nucleus in the formation of neutrophil extracellular traps (NETs). PMID- 25727366 TI - Tolerance of the newborn to antiretroviral drug exposure in utero. AB - INTRODUCTION: The prevention of mother-to-child HIV-1 transmission by antiretroviral drug treatment is remarkably effective. The risk of transmission to the child is now almost zero for women optimally treated during pregnancy. The rapid expansion of this prophylactic treatment has led the World Health Organization to aspire to the virtual elimination of mother-to-child transmission and pediatric AIDS over the next few years. In 2014, more than 900,000 women worldwide were treated with antiretroviral drugs during pregnancy. The issue of fetal and neonatal antiretroviral drug tolerance is therefore extremely important. AREAS COVERED: This review focuses on the possible impact of in utero exposure to antiretroviral drug on newborn health. To restrict analysis to this period is justified by the specificities of transplacental drug exposure and fetal vulnerability. Relevant data are available from trials and observational cohorts. The significance of various bio-markers detectable at birth is still unresolved, but merits a careful evaluation. Long-term assessment is associated with various logistical difficulties. EXPERT OPINION: The health of 'exposed but not infected' children poses no major problem in the immense majority of cases, but a series of biological, clinical and imaging-based warning signs have emerged indicating the need for careful attention to be paid to this issue. Some effects that are straightforward to manage in industrialized countries may have more severe consequences in countries in which access to effective healthcare is limited. Nucleoside/nucleotide analogs are potentially genotoxic to mitochondrial and nuclear DNA, and the principal question to be addressed concerns their potential long-term effects. PMID- 25727367 TI - Metagenomic analysis of a high carbon dioxide subsurface microbial community populated by chemolithoautotrophs and bacteria and archaea from candidate phyla. AB - Research on geologic carbon sequestration raises questions about potential impacts of subsurface microbiota on carbon cycling and biogeochemistry. Subsurface, high-CO2 systems are poorly biologically characterized, partly because of difficulty accessing high-volume, uncontaminated samples. CO2 -driven Crystal Geyser (CG, Utah, USA), an established geologic carbon sequestration analogue, provides high volumes of deep (~ 200-500 m) subsurface fluids. We explored microbial diversity and metabolic potential in this high-CO2 environment by assembly and analysis of metagenomes recovered from geyser water filtrate. The system is dominated by neutrophilic, iron-oxidizing bacteria, including 'marine' Mariprofundus (Zetaproteobacteria) and 'freshwater' Gallionellales, sulfur oxidizing Thiomicrospira crunogena and Thiobacillus-like Hydrogenophilales. Near complete genomes were reconstructed for these bacteria. CG is notably populated by a wide diversity of bacteria and archaea from phyla lacking isolated representatives (candidate phyla) and from as-yet undefined lineages. Many bacteria affiliate with OD1, OP3, OP9, PER, ACD58, WWE3, BD1-5, OP11, TM7 and ZB2. The recovery of nearly 100 genes encoding ribulose-1,5 bisphosphate carboxylase-oxygenase subunit proteins of the Calvin cycle and AMP salvage pathways suggests a strong biological role in high-CO2 subsurface carbon cycling. Overall, we predict microbial impacts on subsurface biogeochemistry via iron, sulfur, and complex carbon oxidation, carbon and nitrogen fixation, fermentation, hydrogen metabolism, and aerobic and anaerobic respiration. PMID- 25727368 TI - G-cell hyperplasia of the stomach induces ECL-cell proliferation in the pyloric glands in a paracrinal manner. AB - An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G cell density. Somatostatin immunoreactive cells (D-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands. PMID- 25727369 TI - Stroke after cyst fenestration in a patient with autosomal dominant polycystic kidney disease and polycystic liver disease: Not necessarily aneurysm-related. PMID- 25727370 TI - Comparison of the contributions of polychlorinated dibenzo-p-dioxins and dibenzofurans and other unintentionally produced persistent organic pollutants to the total toxic equivalents in air of steel plant areas. AB - The concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and the "dioxin-like" (dl) compounds polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), polybrominated dibenzo-p dioxins (PBDDs), and dibenzofurans (PBDFs), were determined in the air samples collected from six steel plants. The toxic equivalent (TEQ) concentrations of the PCDDs, PCDFs, dl-PCBs, dl-PCNs, PBDDs, and PBDFs in the air were 0.01-0.19 pg WHO TEQ Nm(-3), 0.01-0.69 pg WHO-TEQN m(-3), 0.001-0.089 pg WHO-TEQ Nm(-3), 0.002 0.011 pg TEQ Nm(-3), 0.004-0.02 pg TEQ Nm(-3), and 0.02-0.12 pg TEQ Nm(-3), respectively. The PCNs were the most abundant compounds (by mass concentration), contributing about 87% of the total mass concentrations of the analytes that were found in the air of the steel plant areas. The PCDFs contributed about 47% of the total TEQs, following by the PBDFs (28%) and the PCDDs (18%). The dioxin-like compounds together contributed up to 40% of the total TEQs, so their contributions to the toxic effects that could be caused by exposure to the air of the steel plant areas were significant. The congener profiles in the air were similar to the congener profiles that were found in stack gas emissions, indicating that the steelmaking plants were possible sources of the PCDDs, PCDFs, and dioxin-like compounds that were found in the air of the steel plant areas. PMID- 25727371 TI - Cardiolipin linoleic acid content and mitochondrial cytochrome c oxidase activity are associated in rat skeletal muscle. AB - Cardiolipin (CL) is an inner-mitochondrial membrane phospholipid that is important for optimal mitochondrial function. Specifically, CL and CL linoleic (18:2omega6) content are known to be positively associated with cytochrome c oxidase (COX) activity. However, this association has not been examined in skeletal muscle. In this study, rats were fed high-fat diets with a naturally occurring gradient in linoleic acid (coconut oil [CO], 5.8%; flaxseed oil [FO], 13.2%; safflower oil [SO], 75.1%) in an attempt to alter both mitochondrial CL fatty acyl composition and COX activity in rat mixed hind-limb muscle. In general, mitochondrial membrane lipid composition was fairly resistant to dietary treatments as only modest changes in fatty acyl composition were detected in CL and other major mitochondrial phospholipids such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE). As a result of this resistance, CL 18:2omega6 content was not different between the dietary groups. Consistent with the lack of changes in CL 18:2omega6 content, mitochondrial COX activity was also not different between the dietary groups. However, correlational analysis using data obtained from rats across the dietary groups showed a significant relationship (p = 0.009, R(2) = 0.21). Specifically, our results suggest that CL 18:2omega6 content may positively influence mitochondrial COX activity thereby making this lipid molecule a potential factor related to mitochondrial health and function in skeletal muscle. PMID- 25727372 TI - Treatment patterns of elderly breast cancer patients at two Canadian cancer centres. AB - BACKGROUND: Treatment of breast cancer in elderly women is limited by declining functional status and life expectancy. The impact of providing less aggressive treatment remains controversial. This study assessed the treatment patterns of elderly breast cancer patients. METHODS: Retrospective chart review of women >=70 y with breast cancer treated between 2004 and 2011 at two large Canadian cancer centres. Tumour and treatment characteristics were collected across three subgroups: 70-74 y (n = 314), 75-79 y (n = 233), and >=80 y (n = 219). Comparisons were made using Chi-squared test, Fisher-Freeman-Halton exact test, or ANOVA. Disease free (DFS) and overall (OS) survival were estimated by Kaplan Meier analysis and compared by log-rank test. RESULTS: Women >=80 y had larger tumours that were better differentiated, hormone receptor-positive, HER2 negative, and lymph node (LN)-positive relative to younger women (p < 0.05). Women >=80 y more frequently underwent mastectomy than breast conserving surgery and lacked LN staging (p < 0.05). Chemotherapy was provided in few patients, especially >=80 y. Radiation therapy was provided less often in women >=80 y despite indications. Hormone therapy was more frequently provided in women >=80 y. Women >=80 y had a significantly lower DFS (17.5 m) relative to women 70-74 y (31 m, p = 0.02) and 75-79 y (35 m, p = 0.006). Women >=80 y had the lowest median OS (53 m) relative to 70-74 y (79 m, p = 0.001) and 75-79 y (75 m, p = 0.003) women. CONCLUSIONS: Women >=80 y received less aggressive treatment than younger women and had less favourable DFS and OS. Until age-specific recommendations are available physicians must use clinical judgement and assess the tumour biology with the patient's comorbidties to make the best choice. PMID- 25727373 TI - Quantitative T1rho mapping links the cerebellum and lithium use in bipolar disorder. PMID- 25727374 TI - Microfluidically supported biochip design for culture of endothelial cell layers with improved perfusion conditions. AB - Hemodynamic forces generated by the blood flow are of central importance for the function of endothelial cells (ECs), which form a biologically active cellular monolayer in blood vessels and serve as a selective barrier for macromolecular permeability. Mechanical stimulation of the endothelial monolayer induces morphological remodeling in its cytoskeleton. For in vitro studies on EC biology culture devices are desirable that simulate conditions of flow in blood vessels and allow flow-based adhesion/permeability assays under optimal perfusion conditions. With this aim we designed a biochip comprising a perfusable membrane that serves as cell culture platform multi-organ-tissue-flow (MOTiF biochip). This biochip allows an effective supply with nutrition medium, discharge of catabolic cell metabolites and defined application of shear stress to ECs under laminar flow conditions. To characterize EC layers cultured in the MOTiF biochip we investigated cell viability, expression of EC marker proteins and cell adhesion molecules of ECs dynamically cultured under low and high shear stress, and compared them with an endothelial culture in established two-dimensionally perfused flow chambers and under static conditions. We show that ECs cultured in the MOTiF biochip form a tight EC monolayer with increased cellular density, enhanced cell layer thickness, presumably as the result of a rapid and effective adaption to shear stress by remodeling of the cytoskeleton. Moreover, endothelial layers in the MOTiF biochip express higher amounts of EC marker proteins von Willebrand-factor and PECAM-1. EC layers were highly responsive to stimulation with TNFalpha as detected at the level of ICAM-1, VCAM-1 and E-selectin expression and modulation of endothelial permeability in response to TNFalpha/IFNgamma treatment under flow conditions. Compared to static and two dimensionally perfused cell culture condition we consider MOTiF biochips as a valuable tool for studying EC biology in vitro under advanced culture conditions more closely resembling the in vivo situation. PMID- 25727376 TI - Urodynamic changes in mice with experimental autoimmune encephalomyelitis correlate with neurological impairment. AB - AIMS: Neurogenic bladder dysfunction is a major issue in Multiple Sclerosis (MS). High intravesical pressure should be treated early. Available therapies are insufficient and there is need for drug development and investigation of pathogenesis. Experimental Autoimmune Encephalomyelitis (EAE) in rodents is a well validated model to study MS. Previous research has shown that these animals develop urinary symptoms. However, from clinical studies, we know that symptoms do not necessarily reflect changes in bladder pressure. This paper aims to provide a complete overview of urodynamic changes in a model for detrusor overactivity in MS. METHODS: Female C57Bl/6J mice, injected with MOG35-55 and control mice, injected with vehicle (Complete Freund's adjuvant), were monitored daily for neurologic symptoms. Within 1 month after symptom development, mice were used for cystometry or histology of the bladder. RESULTS: Increasing disease score correlated with increased micturition frequency, basal pressure, and average pressure, and with a decrease in functional bladder capacity, voiding amplitude, and maximum pressure. CONCLUSIONS: This paper provides a detailed description of bladder function in C57Bl/6J mice with Myelin Oligodendrocyte Glycoprotein peptide (MOG35-55 ) induced EAE. This EAE model induces detrusor overactivity in close relationship to neurological impairment. EAE in mice is a suitable model to study detrusor overactivity in MS. Neurourol. Urodynam. 35:450 456, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25727375 TI - A computational analysis of flanker interference in depression. AB - BACKGROUND: Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study. METHOD: One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials). RESULTS: Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007). CONCLUSIONS: Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression. PMID- 25727377 TI - The relative effectiveness of testers during field surveillance for bovine tuberculosis in unrestricted low-risk herds in Ireland. AB - In Ireland, new bovine tuberculosis (bTB) cases are detected using both field and abattoir surveillance. Field surveillance is conducted on all cattle annually using the single intradermal comparative tuberculin test (SICTT). Testing is reliant on the skills and experience of the tester and a broad range of factors may adversely affect test accuracy. There is considerable emphasis on quality control (QC) within the national programme and field inspection of testers has been conducted in Ireland for many years. Since 2008, inspection has been supplemented with quantitative performance reports, enabling testers to be evaluated and ranked using a range of performance indicators. The objectives of this study were first, to quantify the relative effectiveness of testers during field surveillance and, second, to assess whether there has been any change in the performance of testers between 2008 and 2011. Mixed logistic regression was used to assess the relative effectiveness of testers. The study population included all testers who carried out at least ten eligible tests in Ireland during 2008 or 2011. The outcome measure was a herd restriction at the eligible test. Results from the mixed model indicated that the variation by tester had significantly (p=0.039) decreased from 0.589 in 2008 to 0.426 in 2011, indicating an increase in consistency of testing, after accounting for other known risk factors. This study provides objective data on the variation in tester performance over time and the relative performance of testers during field surveillance in Ireland. PMID- 25727378 TI - Response to the letter to the editor by Prof. Viroj Wiwanitkit. PMID- 25727379 TI - Relaxation-compensated CEST-MRI of the human brain at 7T: Unbiased insight into NOE and amide signal changes in human glioblastoma. AB - Endogenous chemical exchange saturation transfer (CEST) effects of protons resonating near to water protons are always diluted by competing effects such as direct water saturation and semi-solid magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that contaminate the observed CEST signal. Furthermore, all CEST effects appear to be scaled by the T1 relaxation time of the mediating water pool. As MT, T1 and T2 are also altered in tumor regions, a recently published correction algorithm yielding the apparent exchange dependent relaxation AREX, is used to evaluate in vivo CEST effects. This study focuses on CEST effects of amides (3.5ppm) and Nuclear-Overhauser-mediated saturation transfer (NOE, -3.5ppm) that can be properly isolated at 7T. These were obtained in 10 glioblastoma patients, and this is the first comprehensive study where AREX is applied in human brain as well as in human glioblastoma. The correction of CEST effects alters the contrast significantly: after correction, the CEST effect of amides does not show significant contrast between contrast enhancing tumor regions and normal tissue, whereas NOE drops significantly in the tumor area. In addition, new features in the AREX contrasts are visible. This suggests that previous CEST approaches might not have shown pure CEST effects, but rather water relaxation shine-through effects. Our insights help to improve understanding of the CEST effect changes in tumors and correlations on a cellular and molecular level. PMID- 25727380 TI - The transcriptomic and proteomic basis for the evolution of a novel venom phenotype within the Timber Rattlesnake (Crotalus horridus). AB - The genetics underlying adaptive trait evolution describes the intersection between the probability that particular types of mutation are beneficial and the rates they arise. Snake venoms can vary in a directly meaningful manner through coding mutations and regulatory mutations. The amounts of different components determine venom efficacy, but point mutations in coding sequences can also change efficacy and function. The Timber Rattlesnake (Crotalus horridus) has populations that have evolved neurotoxic venom from the typical hemorrhagic rattlesnake venom present throughout most of its range. We identified only a handful of nonsynonymous differences in just five loci between animals with each venom type, and these differences affected lower-abundance toxins. Expression of at least 18 loci encoding hemorrhagic toxins was severely reduced in the production of neurotoxic venom. The entire phospholipase A2 toxin family was completely replaced in the neurotoxic venom, possibly through intergeneric hybridization. Venom paedomorphosis could, at best, explain only some of the loss of expression of hemorrhagic toxins. The number of potential mechanisms for altering venom composition and the patterns observed for C. horridus suggest that rapid venom evolution should occur primarily through changes in venom composition, rather than point mutations affecting coding sequences. PMID- 25727381 TI - Efficacy of parenteral administration of bee venom in experimental arthritis in the rat: a comparison with methotrexate. AB - The use of bee venom (BV) to treat inflammation and pain in arthritis has become increasingly common. This study aimed to compare the effects of BV and methotrexate (MTX), the most used disease-modifying anti-rheumatic drug, in arthritic rats. Edema, erythema, cyanosis, hyperalgesia, reduction of the body mass gain, high circulating tumor necrosis factor alpha (TNF-alpha) and anti-type II collagen antibodies (AACII), and altered activity of basic (APB) and neutral (APN) aminopeptidases and dipeptidyl peptidase IV (DPPIV) are present in arthritic rats. MTX and/or BV do not affect AACII in healthy or arthritic individuals, but restores TNF-alpha to normal levels in arthritic rats. BV restores body mass gain to normal levels and MTX ameliorates body mass gain. BV contains DPPIV. BV restores APN in synovial fluid (SF) and in soluble fraction (S) from synovial tissue (ST), and DPPIV in solubilized membrane-bound fraction (M) from peripheral blood mononuclear cells (PBMCs). MTX restores APN of SF, as well as ameliorates APB of S-PBMCs, APN of S-ST and DPPIV of M-PBMCs. The combination therapy does not overcome the effects of BV or MTX alone on the peptidase activities. Edema is ameliorated by MTX or BV alone. MTX, but not BV, is effective in reducing hyperalgesia. Data show that anti-arthritic effects of BV at non-acupoints are not negligible when compared with MTX. PMID- 25727382 TI - Inflammation and oxidative stress in viper bite: an insight within and beyond. AB - Though systemic and local manifestations of snakebite are considered serious, the relevance of oxidative stress in viper bite pathology is largely denied. However, over the past decade, studies have provided substantial evidence for the presence of persistent oxidative stress in viper bite victims. This review aims at highlighting the disturbances in redox homeostasis soon after viper envenomation and its implications in the pathomechanism of secondary/long term complications including thrombocytopenia, hypopituitarism, infertility, renal abnormalities and persistent local tissue degradation. Both enzymatic and non-enzymatic components of viper venom play a pivotal role in bringing redox turbulence in victims. Venom induced hemorrhage and necrosis with subsequent release of damage associated molecular pattern (DAMPs) molecules also contribute to sustained oxidative stress and inflammation. Studies have demonstrated that along with anti-venom therapy an antioxidant treatment during the early stages of viper bite and also long term treatment could help to reduce the occurrence of secondary/long term complications. Further, proper knowledge regarding the pathophysiology will allow for exploration of new avenues in the treatment of viper bite. PMID- 25727383 TI - Distribution and biomarkers of carbon-14-labeled fullerene C60 ([(14) C(U)]C60 ) in female rats and mice for up to 30 days after intravenous exposure. AB - A comprehensive distribution study was conducted in female rats and mice exposed to a suspension of uniformly carbon-14-labeled C60 ([(14) C(U)]C60 ). Rodents were administered [(14) C(U)]C60 (~0.9 mg kg(-1) body weight) or 5% polyvinylpyrrolidone-saline vehicle alone via a single tail vein injection. Tissues were collected at 1 h and 1, 7, 14 and 30 days after administration. A separate group of rodents received five daily injections of suspensions of either [(14) C(U)]C60 or vehicle with tissue collection 14 days post exposure. Radioactivity was detected in over 20 tissues at all time points. The highest concentration of radioactivity in rodents at each time point was in liver, lungs and spleen. Elimination of [(14) C(U)]C60 was < 2% in urine and feces at any 24 h time points. [(14) C(U)]C60 and [(14) C(U)]C60 -retinol were detected in liver of rats and together accounted for ~99% and ~56% of the total recovered at 1 and 30 days postexposure, respectively. The blood radioactivity at 1 h after [(14) C(U)]C60 exposure was fourfold higher in rats than in mice; blood radioactivity was still in circulation at 30 days post [(14) C(U)]C60 exposure in both species (<1%). Levels of oxidative stress markers increased by 5 days after exposure and remained elevated, while levels of inflammation markers initially increased and then returned to control values. The level of cardiovascular marker von Willebrand factor, increased in rats, but remained at control levels in mice. This study demonstrates that [(14) C(U)]C60 is retained in female rodents with little elimination by 30 days after i.v. exposure, and leads to systemic oxidative stress. PMID- 25727385 TI - Comparative genomics of three Methanocellales strains reveal novel taxonomic and metabolic features. AB - Methanocellales represents a new order of methanogens, which is widespread in environments and plays specifically the important role in methane emissions from paddy fields. To gain more insights into Methanocellales, comparative genomic studies were performed among three Methanocellales strains through the same annotation pipeline. Genetic relationships among strains revealed by genome alignment, pan-genome reconstruction and comparison of amino average identity suggest that they should be classified in different genera. In addition, multiple copies of cell cycle regulator proteins were identified for the first time in Archaea. Core metabolisms were reconstructed, predicting certain unique and novel features for Methanocellales, including a set of methanogenesis genes potentially organized toward specialization in utilizing low concentrations of H2, a new route of disulfide reduction catalysed by a disulfide-reducing hydrogenase (Drh) complex phylogenetically related to sulfate-reducing prokaryotes, an oxidative tricarboxylic acid (TCA) cycle, a sophisticated nitrogen uptake and regulation system as well as a versatile sulfur utilization system. These core metabolisms are largely conserved among the three strains, but differences in gene copy number and metabolic diversity are evident. The present study thus adds new dimensions to the unique ecophysiology of Methanocellales and offers a road map for further experimental characterization of this methanogen lineage. PMID- 25727384 TI - Cardiorenal Syndrome and the Role of the Bone-Mineral Axis and Anemia. AB - The association between chronic kidney disease (CKD) and cardiovascular disease (CVD) is well established, and there is mounting evidence of interorgan cross talk that may accelerate pathologic processes and the progression of organ dysfunction in both systems. This process, termed cardiorenal syndrome (CRS) by the Acute Dialysis Quality Initiative, is considered a major health problem: patients with CKD and CVD are at much higher risk of mortality than patients with either condition alone. To date, the majority of CRS research has focused on neurohormonal mechanisms and hemodynamic alterations. However, mounting evidence suggests that abnormalities in the normal pathophysiology of the bone-mineral axis, iron, and erythropoietin play a role in accelerating CKD and CVD. The goal of this article is to review the role and interrelated effects of the bone mineral axis and anemia in the pathogenesis of chronic CRS. PMID- 25727387 TI - Themes and variations in cell type patterning in the plant epidermis. AB - It has recently become evident that plant development, like animal development, has molecular patterning modules that are reused again and again to create different cell type patterns. Here we focus on three of these plant modules: (1) the MYB-bHLH-WD40 protein complex, (2) the transmembrane calpain protease DEFECTIVE KERNEL1 (DEK1), and (3) homeodomain leucine zipper (HD-ZIP) class IV transcription factors acting in concert with SIAMESE-related cyclin-dependent kinase inhibitors. These three modules initiate the patterning of multiple cell types in the plant epidermis: the regular spacing of trichomes (leaf hairs), the stripes of root hairs, diverse pigmentation patterns in petals, the scattering of giant cells, and the files of bulliform cells. Varied combinations of players and additional regulatory inputs partially account for the diversity of patterns that are generated by reusing the same molecular mechanisms. PMID- 25727386 TI - Bringing memory fMRI to the clinic: comparison of seven memory fMRI protocols in temporal lobe epilepsy. AB - fMRI is increasingly implemented in the clinic to assess memory function. There are multiple approaches to memory fMRI, but limited data on advantages and reliability of different methods. Here, we compared effect size, activation lateralisation, and between-sessions reliability of seven memory fMRI protocols: Hometown Walking (block design), Scene encoding (block design and event-related design), Picture encoding (block and event-related), and Word encoding (block and event-related). All protocols were performed on three occasions in 16 patients with temporal lobe epilepsy (TLE). Group T-maps showed activity bilaterally in medial temporal lobe for all protocols. Using ANOVA, there was an interaction between hemisphere and seizure-onset lateralisation (P = 0.009) and between hemisphere, protocol and seizure-onset lateralisation (P = 0.002), showing that the distribution of memory-related activity between left and right temporal lobes differed between protocols and between patients with left-onset and right-onset seizures. Using voxelwise intraclass Correlation Coefficient, between-sessions reliability was best for Hometown and Scenes (block and event). The between sessions spatial overlap of activated voxels was also greatest for Hometown and Scenes. Lateralisation of activity between hemispheres was most reliable for Scenes (block and event) and Words (event). Using receiver operating characteristic analysis to explore the ability of each fMRI protocol to classify patients as left-onset or right-onset TLE, only the Words (event) protocol achieved a significantly above-chance classification of patients at all three sessions. We conclude that Words (event) protocol shows the best combination of between-sessions reliability of the distribution of activity between hemispheres and reliable ability to distinguish between left-onset and right-onset patients. PMID- 25727388 TI - Hippocampal long-term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta adrenoreceptors and the locus coeruleus. AB - The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus-based learning, and facilitates synaptic plasticity in the form of long-term depression (LTD) and long-term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the beta-adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires beta adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on beta-adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant-path (pp) stimulation in vivo or that is facilitated by spatial learning depends on beta-adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. beta-adrenoreceptor-antagonism also prevented spatial learning. Strikingly, activation of the LC before high frequency stimulation (HFS) of the pp prevented short-term potentiation but not LTP, and LC stimulation after pp-HFS-induced depotentiation of LTP. This depotentiation was prevented by beta-adrenoreceptor-antagonism. These data suggest that beta-adrenoreceptor-activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. PMID- 25727389 TI - Selective separation and characterization of the stress degradation products of ondansetron hydrochloride by liquid chromatography with quadrupole time-of-flight mass spectrometry. AB - Ondansetron hydrochloride was subjected to forced degradation studies under various conditions of hydrolysis (acidic, basic, and neutral), oxidation, photolysis, and thermal as prescribed by International Conference on Harmonisation guideline Q1A (R2). A simple, selective, precise, and accurate high performance liquid chromatography method was developed on a Waters Xterra C18 (150 * 4.6 mm id, 3.5 MUm) column using 10 mM ammonium formate (pH 3.0)/methanol as a mobile phase in gradient elution mode at a flow rate of 0.6 mL/min. The method was extended to liquid chromatography quadrupole time-of-flight tandem mass spectrometry for identification and structural characterization of stress degradation products of ondansetron. The drug showed significant degradation in base hydrolytic and photolytic stress conditions in the liquid state, while it was found to be stable in neutral, acidic, thermal, and oxidative stress conditions. A total of five degradation products were characterized and most probable mechanisms for the formation of degradation products have been proposed on the basis of a comparison of the fragmentation of the [M + H](+) ions of the drug and its degradation products. Finally, the developed method was validated in terms of specificity, linearity, accuracy, precision, and robustness as per International Conference on Harmonisation guideline Q2 (R1). PMID- 25727390 TI - Local delivery of COMP-angiopoietin 1 accelerates new bone formation in rat calvarial defects. AB - Recombinant COMP-Ang1, a chimera of angiopoietin-1 (Ang1) and a short coiled-coil domain of cartilage oligomeric matrix protein (COMP), is under consideration as a therapeutic agent in bone reconstruction. However, the potential of COMP-Ang1 to regenerate impaired bone and induce new bone formation has not been completely explored. In this study, male Sprague-Dawley rats underwent calvarial defect surgery and divided into two groups: scaffold treatment alone (control group) and COMP-Ang1-impregnated scaffold (COMP-Ang1 group). According to live micro-CT and histological analyses, the COMP-Ang1 group showed greater new bone formation and maturation than did the control both four and eight weeks after surgery. The values of bone volume, bone mineral density, and bone surface were also higher in the COMP-Ang1 group than in the control at the same weeks after surgery. In addition, the delivery of COMP-Ang1 facilitated significantly the expression of osteoblast-specific markers such as runt-related transcription factor 2 (p < 0.001), osterix (p < 0.001), bone morphogenetic protein-2 (p < 0.001), alkaline phosphatase (p < 0.01), osteocalcin (p < 0.001), and type I collagen (p < 0.05) in newly formed bone, compared with the control. Immunohistochemistric assay supported the COMP-Ang1-facilitated induction of bone-specific markers. Furthermore, COMP-Ang1 augmented the mRNA expression of angiogenic factors, especially of platelet endothelial cell adhesion molecule 1, stromal cell-derived factor 1, and Tie-2 in the defect site. Our current findings demonstrate for the first time that a local delivery of recombinant COMP-Ang1 promotes bone formation in calvarial defects, which is coupled with enhanced angiogenesis and chemoattraction. PMID- 25727392 TI - Phenprobamate dependence: a case report. AB - Phenprobamate (3-phenylpropylcarbamate) is a centrally acting muscle relaxant with mild sedative and anticonvulsant effects. Muscle relaxants can enhance and prolong the effect of narcotic drugs and enable to obtain same effect with a smaller amount of alcohol or illicit substance. Almost all of the centrally acting muscle relaxants have varying sedative effects on which their abuse potential mainly depends. Data related to abuse of carisoprodol, meprobamate, baclofen takes place in the literature. However, to our knowledge this is the first case report about abuse of and tolerance to phenprobamate. We aimed to attract attention to important points of prescribing drugs that have abuse potential like in our case who was using up to 16000 mg/day phenprobamate. PMID- 25727393 TI - Perceived smoking availability differentially affects mood and reaction time. AB - INTRODUCTION: This between subjects study explored the relationship between smoking availability and smoking motivation and is the first study to include three smoking availability time points. This allowed for an examination of an extended period of smoking unavailability, and a test of the linearity of the relationships between smoking availability and smoking motivation measures. METHODS: Ninety 3-hour abstinent smokers (mean ~15 cigarettes per day) were randomly assigned to one of three availability manipulations while being exposed to smoking stimuli (i.e., pack of cigarettes): smoke in 20 min, smoke in 3 h, or smoke in 24 h. Participants completed pre- and post-manipulation measures of urge, positive affect and negative affect, and simple reaction time. RESULTS: The belief that smoking would next be available in 24 h resulted in a significant decrease in positive affect and increase in negative affect relative to the 3 h and 20 min conditions. A Lack of Fit test suggested a linear relationship between smoking availability and affect. A quadratic model appeared to be a better fit for the relationship between smoking availability and simple reaction time with participants in the 24 h and 20 min conditions showing a greater slowing of reaction time relative to the 3 h condition. There were no effects of the manipulations on self-reported urge, but baseline ceiling effects were noted. CONCLUSIONS: Future investigations that manipulate three or more periods of time before smoking is available will help to better elucidate the nature of the relationship between smoking availability and smoking motivation. PMID- 25727394 TI - Sensation seeking and smoking behaviors among adolescents in the Republic of Korea. AB - OBJECTIVE: This study aimed to explore the relationship between the four components of sensation seeking (i.e., disinhibition, thrill and adventure seeking, experience seeking, and boredom susceptibility) and three types of smoking behavior (i.e., non-smoking, experimental smoking, and current smoking) among high school students in the Republic of Korea. METHODS: Multivariate multinomial logistic regression analysis was performed using two models. In Model 1, the four subscales of sensation seeking were used as covariates, and in Model 2, other control factors (i.e., characteristics related to demographics, individuals, family, school, and friends) were added to Model 1 in order to adjust for their effects. RESULTS: In Model 1, the impact of disinhibition on experimental smoking and current smoking was statistically significant. In Model 2, the influence of disinhibition on both of these smoking behaviors remained statistically significant after controlling for all the other covariates. Also, the effect of thrill and adventure seeking on experimental smoking was statistically significant. The two statistically significant subscales of sensation seeking were positively associated with the risk of smoking behaviors. CONCLUSIONS: According to extant literature and current research, sensation seeking, particularly disinhibition, is strongly associated with smoking among youth. Therefore, sensation seeking should be measured among adolescents to identify those who are at greater risk of smoking and to develop more effective intervention strategies in order to curb the smoking epidemic among youth. PMID- 25727395 TI - Expansion, harvest and cryopreservation of human mesenchymal stem cells in a serum-free microcarrier process. AB - Human mesenchymal stem cell (hMSC) therapies are currently progressing through clinical development, driving the need for consistent, and cost effective manufacturing processes to meet the lot-sizes required for commercial production. The use of animal-derived serum is common in hMSC culture but has many drawbacks such as limited supply, lot-to-lot variability, increased regulatory burden, possibility of pathogen transmission, and reduced scope for process optimization. These constraints may impact the development of a consistent large-scale process and therefore must be addressed. The aim of this work was therefore to run a pilot study in the systematic development of serum-free hMSC manufacturing process. Human bone-marrow derived hMSCs were expanded on fibronectin-coated, non porous plastic microcarriers in 100 mL stirred spinner flasks at a density of 3 * 10(5) cells.mL(-1) in serum-free medium. The hMSCs were successfully harvested by our recently-developed technique using animal-free enzymatic cell detachment accompanied by agitation followed by filtration to separate the hMSCs from microcarriers, with a post-harvest viability of 99.63 +/- 0.03%. The hMSCs were found to be in accordance with the ISCT characterization criteria and maintained hMSC outgrowth and colony-forming potential. The hMSCs were held in suspension post-harvest to simulate a typical pooling time for a scaled expansion process and cryopreserved in a serum-free vehicle solution using a controlled-rate freezing process. Post-thaw viability was 75.8 +/- 1.4% with a similar 3 h attachment efficiency also observed, indicating successful hMSC recovery, and attachment. This approach therefore demonstrates that once an hMSC line and appropriate medium have been selected for production, multiple unit operations can be integrated to generate an animal component-free hMSC production process from expansion through to cryopreservation. PMID- 25727398 TI - CRISPR craze conquers the RNA world: precise manipulation of DNA and RNA based on a bacterial defense system. PMID- 25727397 TI - Deoxynivalenol inhibits the expression by goblet cells of intestinal mucins through a PKR and MAP kinase dependent repression of the resistin-like molecule beta. AB - SCOPE: The food-associated mycotoxin deoxynivalenol (DON) is known to affect intestinal functions. However, its effect on intestinal mucus is poorly characterized. METHODS AND RESULTS: We analyzed the effects of DON on human goblet cells (HT29-16E cells) and porcine intestinal explants. Results showed that subtoxic doses of DON (as low as 1 MUM) decreased mucin (MUC) production. qPCR analysis demonstrated that this inhibition was due to a specific decrease in the level of mRNA encoding for the intestinal membrane-associated (MUC1) and the secreted MUCs (MUC2, MUC3). Mechanistic studies demonstrated that DON effect relied on the activation of the protein kinase R and the mitogen-activated protein kinase p38 ultimately leading to the inhibition of the expression of resistin-like molecule beta, a known positive regulator of MUC expression. CONCLUSION: Taken together, our results show that at low doses found in food and feed, DON is able to affect the expression and production of MUCs by human and animal goblet cells. Due to the important role of MUCs in the barrier function and in the interaction of commensal bacteria with the host, such effect could explain the observed modifications in the microbial diversity and the increased susceptibility to enteric infection following exposure to DON. PMID- 25727396 TI - Environmental physical cues determine the lineage specification of mesenchymal stem cells. AB - BACKGROUND: Physical cues of cellular environment affect cell fate and differentiation. For example, an environment with high stiffness drives mesenchymal stem cells (MSCs) to undergo osteogenic differentiation, while low stiffness leads to lipogenic differentiation. Such effects could be independent of chemical/biochemical inducers. SCOPE OF REVIEW: Stiffness and/or topography of cellular environment can control MSC differentiation and fate determination. In addition, physical factors such as tension, which resulted from profound cytoskeleton reorganization during MSC differentiation, affect the gene expression essential for the differentiation. Although physical cues control MSC lineage specification probably by reorganizing and tuning cytoskeleton, the full mechanism is largely unclear. It also remains elusive how physical signals are sensed by cells and transformed into biochemical and biological signals. More importantly, it becomes pivotal to define explicitly the physical cue(s) essential for cell differentiation and fate decision. With a focus on MSC, we present herein current understanding of the interplay between i) physical cue and factors and ii) MSC differentiation and fate determination. MAJOR CONCLUSIONS: Biophysical cues can initiate or strengthen the biochemical signaling for MSC fate determination and differentiation. Physical properties of cellular environment direct the structural adaptation and functional coupling of the cells to their environment. GENERAL SIGNIFICANCE: These observations not only open a simple avenue to engineer cell fate in vitro, but also start to reveal the physical elements that regulate and determine cell fate. PMID- 25727399 TI - Comparing apples and oranges-the influence of food mechanical properties on ingestive bite sizes in lemurs. AB - Previously we found that Maximum Ingested Bite Size (Vb )-the largest piece of food that an animal will ingest whole without biting first-scales isometrically with body size in 17 species of strepsirrhines at the Duke Lemur Center (DLC). However, because this earlier study focused on only three food types (two with similar mechanical properties), it did not yield results that were easily applied to describing the broad diets of these taxa. Expressing Vb in terms of food mechanical properties allows us to compare data across food types, including foods of wild lemurs, to better understand dietary adaptations in lemurs. To this end, we quantified Vb in five species of lemurs at the DLC representing large and small frugivores and folivores using ten types of food that vary widely in stiffness and toughness to determine how these properties relate to bite sizes. We found that although most species take smaller bites of stiffer foods, this negative relationship was not statistically significant across the whole sample. However, there is a significant relationship between bite size and toughness. All three of the more frugivorous taxa in our sample take significantly smaller bites of tougher foods. However, the two more folivorous lemurs do not. They take small bites for all foods. This suggests that the species most adapted to the consumption of tough foods do not modulate their ingestive sizes to accommodate larger pieces of weak foods. PMID- 25727401 TI - Fluoro- and perfluoralkylsulfonylpentafluoroanilides: synthesis and characterization of NH acids for weakly coordinating anions and their gas-phase and solution acidities. AB - Fluoro- and perfluoralkylsulfonyl pentafluoroanilides [HN(C6F5)(SO2X); X = F, CF3, C4F9, C8F17] are a class of imides with two different strongly electron withdrawing substituents attached to a nitrogen atom. They are NH acids, the unsymmetrical hybrids of the well-known symmetrical bissulfonylimides and bispentafluorophenylamine. The syntheses, the structures of these perfluoroanilides, their solvates, and some selected lithium salts give rise to a structural variety beyond the symmetrical parent compounds. The acidities of representative subsets of these novel NH acids have been investigated experimentally and quantum-chemically and their gas-phase acidities (GAs) are reported, as well as the pKa values of these compounds in acetonitrile (MeCN) and DMSO solution. In quantum chemical investigations with the vertical and relaxed COSMO cluster-continuum models (vCCC/rCCC), the unusual situation is encountered that the DMSO-solvated acid Me2SO-H-N(SO2CF3)2, optimized in the gas phase (vCCC model), dissociates to Me2SO-H(+)-N(SO2CF3)2(-) during structural relaxation and full optimization with the solvation model turned on (rCCC model). This proton transfer underlines the extremely high acidity of HN(SO2CF3)2. The importance of this effect is studied computationally in DMSO and MeCN solution. Usually this effect is less pronounced in MeCN and is of higher importance in the more basic solvent DMSO. Nevertheless, the neglect of the structural relaxation upon solvation causes typical changes in the computational pKa values of 1 to 4 orders of magnitude (4-20 kJ mol(-1)). The results provide evidence that the published experimental DMSO pKa value of HN(SO2CF3)2 should rather be interpreted as the pKa of a Me2SO-H(+)-N(SO2CF3)2(-) contact ion pair. PMID- 25727400 TI - Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK. AB - Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor involved in both solid and hematological tumors. About 80% of ALK-positive anaplastic large-cell lymphoma (ALCL) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (NPM)-ALK, whereas 5% of non-small-cell lung cancer (NSCLC) patients carry the inv(2)(p21;p23) rearrangement, encoding for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion. The ALK/c-MET/ROS inhibitor crizotinib successfully improved the treatment of ALK-driven diseases. However, several cases of resistance appeared in NSCLC patients, and ALK amino acid substitutions were identified as a leading cause of resistance to crizotinib. Second-generation ALK inhibitors have been developed in order to overcome crizotinib resistance. In this work, we profiled in vitro the activity of crizotinib, AP26113, ASP3026, alectinib, and ceritinib against six mutated forms of ALK associated with clinical resistance to crizotinib (C1156Y, L1196M, L1152R, G1202R, G1269A, and S1206Y) and provide a classification of mutants according to their level of sensitivity/resistance to the drugs. Since the biological activity of ALK mutations extends beyond the specific type of fusion, both NPM-ALK- and EML4-ALK-positive cellular models were used. Our data revealed that most mutants may be targeted by using different inhibitors. One relevant exception is represented by the G1202R substitution, which was highly resistant to all drugs (>10-fold increased IC50 compared to wild type) and may represent the most challenging mutation to overcome. These results provide a prediction of cross-resistance of known crizotinib-resistant mutations against all second-generation tyrosine kinase inhibitors (TKIs) clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib-resistance cases. PMID- 25727402 TI - High-throughput screening of thin-film semiconductor material libraries I: system development and case study for Ti-W-O. AB - An automated optical scanning droplet cell (OSDC) enables high-throughput quantitative characterization of thin-film semiconductor material libraries. Photoelectrochemical data on small selected measurement areas are recorded including intensity-dependent photopotentials and -currents, potentiodynamic and potentiostatic photocurrents, as well as photocurrent (action) spectra. The OSDC contains integrated counter and double-junction reference electrodes and is fixed on a precise positioning system. A Xe lamp with a monochromator is coupled to the cell through a thin poly(methyl methacrylate) (PMMA) optical fiber. A specifically designed polytetrafluoroethylene (PTFE) capillary tip is pressed on the sample surface and defines through its diameter the homogeneously illuminated measurement area. The overall and wavelength-resolved irradiation intensities and the cell surface area are precisely determined and calibrated. System development and its performance are demonstrated by means of screening of a Ti?W?O thin film. PMID- 25727403 TI - Efficacy of glycine powder air polishing in comparison with sodium bicarbonate air polishing and ultrasonic scaling - a double-blind clinico-histopathologic study. AB - BACKGROUND: Subgingival biofilm removal using glycine powder air polishing (GPAP) has antecedently been shown to be safe. The hypothesis that GPAP is efficacious during periodontal maintenance therapy and results in less gingival erosion than sodium bicarbonate air polishing (SBAP) or ultrasonic scaling was assessed. METHODS: Initial periodontal therapy was performed in each of the 22 chronic periodontitis patients having residual 5 mm probing depth in each quadrant and were randomly assigned to one of the following interventions: GPAP (test), SBAP (positive control), ultrasonic scaling (positive control) or no treatment. Clinical parameters were assessed, and gingival biopsies were taken immediately after instrumentation and sent for histological quantification. RESULTS: Significant improvement in plaque and gingival index scores were noted in glycine powder air-polishing and ultrasonic group. GPAP resulted in minor erosion of the gingival epithelium (score 1 & 2), whereas positive control specimens displayed moderate to severe erosions (score 3 & 4). Difference between GPAP and positive control was significant. (P < 0.05). CONCLUSION: GPAP results in clinically significant improvement in plaque and gingival index scores and histologically causes less gingival erosion than SBAP or ultrasonic instrumentation, further supporting the safety of this debridement technique in periodontal maintenance therapy. PMID- 25727404 TI - Panniculitis with crystals induced by etanercept subcutaneous injection. AB - Panniculitis with lipid crystallization within adipocytes may be seen in several disorders, including crystal-storing histiocytosis, gouty panniculitis, subcutaneous fat necrosis of the newborn, post-steroid panniculitis, sclerema neonatorum, oxalosis and subcutaneous fungal infections by mucormycosis, zygomycosis or aspergillosis. Panniculitis at the sites of subcutaneous injection of drugs are frequent, but to our knowledge no crystals have been described in the drug-induced panniculitis at the sites of subcutaneous injections. We report on a patient who developed a panniculitis with lipid crystallization at the site of etanercept injection. PMID- 25727405 TI - Serum Cystatin C as an Early Marker of Neutrophil Gelatinase-associated Lipocalin positive Acute Kidney Injury Resulting from Cardiopulmonary Bypass in Infants with Congenital Heart Disease. AB - OBJECTIVE: Acute kidney injury (AKI) is a common complication resulting from cardiopulmonary bypass in infants. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a sensitive and specific marker of such injury. In this study, we compared the performance of serum cystatin C (Cys C) and serum creatinine (Cr) as early markers of renal dysfunction in infants undergoing cardiac surgery under bypass. STUDY DESIGN, SETTING, AND PATIENTS: The study was designed as a prospective observational study. The study was conducted in the cardiac intensive care unit (ICU) of a tertiary, academic children's hospital in the United States. Infants (age <1 year) undergoing cardiac surgery under cardiopulmonary bypass were included in the study. OUTCOME MEASURE: Acute kidney injury was defined based on postoperative urinary NGAL. RESULTS: A total of 17 infants were included in the study, and five of them developed AKI. Serum Cys C and Cr levels were measured postoperatively on days 1, 2, and 3, and compared with baseline levels. On postoperative day 2, infants with AKI showed significant change from baseline in serum Cys C levels compared with non-AKI infants (28% vs. -9%, P = .03). The two groups did not show significant differences with respect to rise in serum Cr on any of the 3 postoperative days. Serum Cr on days 1 and 2 showed nonspecific increases in both AKI and non-AKI groups. The area under the receiver operating characteristic curve for day 2 Cys C was 0.87 (95% CI 0.67 1.00) in recognizing NGAL-positive AKI. CONCLUSIONS: Postoperative serum Cys C appears to be a more specific and sensitive biomarker for NGAL-positive AKI resulting from cardiopulmonary bypass surgery in infants undergoing cardiac surgery. PMID- 25727406 TI - Discrimination between 8-oxo-2'-deoxyguanosine and 2'-deoxyguanosine in DNA by the single nucleotide primer extension reaction with adap triphosphate. AB - The adenosine derivative of 2-oxo-1,3-diazaphenoxazine (Adap) exhibits a superb ability to recognize and form base pairs with 8-oxo-2'-deoxyguanosine (8-oxo-dG) in duplex DNA. In this study, the triphosphate of Adap (dAdapTP) was synthesized and tested for single nucleotide incorporation into primer strands using the Klenow Fragment. The efficiency of dAdapTP incorporation into 8-oxo-dG-containing templates was more than 36-fold higher than with dG-containing templates, and provides better discrimination than does the incorporation of natural 2' deoxyadenosine triphosphate (dATP). The selective incorporation of dAdapTP into 8 oxo-dG templates was therefore applied to the detection of 8-oxo-dG in human telomeric DNA sequences extracted from H2 O2 -treated HeLa cells. The enzymatic incorporation of dAdapTP into 8-oxo-dG-containing templates may provide a novel basis for sequencing oxidative DNA damage in the genome. PMID- 25727408 TI - Surface confined synthesis of porphyrin containing two-dimensional polymers: the effect of rigidity and preferential adsorption of building blocks. AB - We have designed and synthesized two porphyrin containing two-dimensional (2D) polymers based on the imine linkage. Both the 2D polymers are revealed to be 2D organic semiconductors with band gaps of around 1 eV. STM characterization reveals that the rigidity and affinity of building blocks to the surface has essential effects on the topology of the 2D polymers. PMID- 25727409 TI - Effective epitope identification employing phylogenetic, mutational variability, sequence entropy, and correlated mutation analysis targeting NS5B protein of hepatitis C virus: from bioinformatics to therapeutics. AB - Hepatitis C virus (HCV) is considered as a foremost cause affecting numerous human liver-related disorders. An effective immuno-prophylactic measure (like stable vaccine) is still unavailable for HCV. We perform an in silico analysis of nonstructural protein 5B (NS5B) based CD4 and CD8 epitopes that might be implicated in improvement of treatment strategies for efficient vaccine development programs against HCV. Here, we report on effective utilization of knowledge obtained from multiple sequence alignment and phylogenetic analysis for investigation and evaluation of candidate epitopes that have enormous potential to be used in formulating proficient vaccine, embracing multiple strains prevalent among major geographical locations. Mutational variability data discussed herein focus on discriminating the region under active evolutionary pressure from those having lower mutational potential in existing experimentally verified epitopes, thus, providing a concrete framework for designing an effective peptide-based vaccine against HCV. Additionally, we measured entropy distribution in NS5B residues and pinpoint the positions in epitopes that are more susceptible to mutations and, thus, account for virus strategy to evade the host immune system. Findings from this study are expected to add more details on the sequence and structural aspects of NS5B protein, ultimately facilitating our understanding about the pathophysiology of HCV and assisting advance studies on the function of NS5B antigen on the epitope level. We also report on the mutational crosstalk between functionally important coevolving residues, using correlated mutation analysis, and identify networks of coupled mutations that represent pathways of allosteric communication inside and among NS5B thumb, finger, and palm domains. PMID- 25727407 TI - NF-kappaB1, NF-kappaB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice. AB - NF-kappaB signalling is an important factor in the development of inflammation associated cancers. Mouse models of Helicobacter-induced gastric cancer and colitis-associated colorectal cancer have demonstrated that classical NF-kappaB signalling is an important regulator of these processes. In the stomach, it has also been demonstrated that signalling involving specific NF-kappaB proteins, including NF-kappaB1/p50, NF-kappaB2/p52, and c-Rel, differentially regulate the development of gastric pre-neoplasia. To investigate the effect of NF-kappaB subunit loss on colitis-associated carcinogenesis, we administered azoxymethane followed by pulsed dextran sodium sulphate to C57BL/6, Nfkb1(-/-), Nfkb2(-/-), and c-Rel(-/-) mice. Animals lacking the c-Rel subunit were more susceptible to colitis-associated cancer than wild-type mice, developing 3.5 times more colonic polyps per animal than wild-type mice. Nfkb2(-/-) mice were resistant to colitis associated cancer, developing fewer polyps per colon than wild-type mice (median 1 compared to 4). To investigate the mechanisms underlying these trends, azoxymethane and dextran sodium sulphate were administered separately to mice of each genotype. Nfkb2(-/-) mice developed fewer clinical signs of colitis and exhibited less severe colitis and an attenuated cytokine response compared with all other groups following DSS administration. Azoxymethane administration did not fully suppress colonic epithelial mitosis in c-Rel(-/-) mice and less colonic epithelial apoptosis was also observed in this genotype compared to wild-type counterparts. These observations demonstrate different functions of specific NF kappaB subunits in this model of colitis-associated carcinogenesis. NF kappaB2/p52 is necessary for the development of colitis, whilst c-Rel-mediated signalling regulates colonic epithelial cell turnover following DNA damage. PMID- 25727410 TI - NAP (davunetide) protects primary hippocampus culture by modulating expression profile of antioxidant genes during limiting oxygen conditions. AB - Hypoxia is a well-known threat to neuronal cells and triggers the pathophysiological syndromes in extreme environments such as high altitudes and traumatic conditions such as stroke. Among several prophylactic molecules proven suitable for ameliorating free radical damage, NAP (an octapeptide with initial amino acids: asparagine/N, alanine/A, and proline/P) can be considered superlative, primarily due to its high permeability into brain through blood brain barrier and observed activity at femtomolar concentrations. Several mechanisms of action of NAP have been hypothesized for its protective role during hypoxia, yet any distinct mechanism is unknown. Oxidative stress is advocated as the leading event in hypoxia; we, therefore, investigated the regulation of key antioxidant genes to understand the regulatory role of NAP in providing neuroprotection. Primary neuronal culture of rat was subjected to cellular hypoxia by limiting the oxygen concentration to 0.5% for 72 h and observing the prophylactic efficacies of 15fM NAP by conventional cell death assays using flow cytometry. We performed real-time quantitative polymerase chain reaction to comprehend the regulatory mechanism. Further, we validated the significantly regulated candidates by enzyme assays and immunoblotting. In the present study, we report that NAP regulates a major clad of cellular antioxidants and there is an involvement of more than one route of action in neuroprotection during hypoxia. PMID- 25727411 TI - Perioperative blood product administration and thromboembolic events in patients with treated polycythemia vera: a case-control study. AB - BACKGROUND: Patients with polycythemia vera (PV) have historically been considered to be at high risk for perioperative hemorrhagic and thromboembolic complications. However, no recent studies have compared these outcomes between treated PV patients and patients without PV undergoing similar procedures. STUDY DESIGN AND METHODS: Patients with PV who underwent surgery with anesthesia from June 1, 2006, to May 31, 2011, were randomly matched (sex, age, type of surgical procedure, surgical year) at a ratio of 1:4 with control patients without PV. Conditional logistic regression analysis adjusting for surgical duration, preoperative hemoglobin, platelet count, and cardiovascular disease was used to assess the association between PV and blood product transfusions, thromboembolism, and other major cardiovascular and pulmonary complications. RESULTS: Fifty-six PV patients who underwent 79 surgeries were matched with 312 controls. During hospitalization, 35 (44.3%) and 82 (25.9%) PV and control patients, respectively, were transfused with blood products. PV patients were at increased risk for transfusion intraoperatively (odds ratio [OR], 4.35; 95% confidence interval [CI], 1.79-10.57; p = 0.001) and during hospitalization (OR, 4.35; 95% CI, 1.84-10.31; p < 0.001). The likelihood of thromboembolic complications and/or other major complications did not differ between the two study groups (thromboembolic-OR 1.53, 95% CI 0.39-6.02, p = 0.540; other major complications-OR 2.15, 95% CI 0.93-4.96, p = 0.073). CONCLUSIONS: Medically managed PV patients had an increased likelihood of receiving blood products perioperatively. Given the low number of observed thromboembolic events, we cannot make definitive conclusions regarding the association between PV and thromboembolism. PMID- 25727412 TI - Surgical Site Infection After Skin Excisions in Children: Is Field Sterility Sufficient? AB - Skin excisions are common procedures in children. They may be performed in the clinic using field sterility or the operating room with strict sterile technique. We compared the effect of these locations and the use of antibiotics on the incidence of surgical site infection (SSI) after skin excisions. Patients ages 0 18 years presenting to our department for the excision of lesions from 2006 to 2010 with complete medical records were included in our study. Records were reviewed for demographic characteristics, presentation, perioperative conditions, and postoperative SSI and other wound complications. Analyses were performed to estimate the costs associated with sterility technique and perioperative antibiotic use. We identified 700 patients with a mean age of 9.1 years. Of 872 lesions excised, 0.3% resulted in SSI and 1.8% had other wound complications. The incidence of SSI did not vary according to sterility technique, antibiotic usage, surgeon, age, or lesion size, type, or location. The equipment costs to excise a lesion in the operating room were 200% greater than in the clinic. The incidence of SSI after excision of benign lesions in children did not differ between those performed using clinic field sterility and those using the standard aseptic sterile technique in the operating room. A considerable cost savings could be realized by adopting field sterility for simple excisions performed in the operating room and avoiding routine perioperative antibiotics in pediatric skin excisions. PMID- 25727413 TI - Effector discovery in the fungal wheat pathogen Zymoseptoria tritici. AB - Fungal plant pathogens, such as Zymoseptoria tritici (formerly known as Mycosphaerella graminicola), secrete repertoires of effectors to facilitate infection or trigger host defence mechanisms. The discovery and functional characterization of effectors provides valuable knowledge that can contribute to the design of new and effective disease management strategies. Here, we combined bioinformatics approaches with expression profiling during pathogenesis to identify candidate effectors of Z. tritici. In addition, a genetic approach was conducted to map quantitative trait loci (QTLs) carrying putative effectors, enabling the validation of both complementary strategies for effector discovery. In planta expression profiling revealed that candidate effectors were up regulated in successive waves corresponding to consecutive stages of pathogenesis, contrary to candidates identified by QTL mapping that were, overall, expressed at low levels. Functional analyses of two top candidate effectors (SSP15 and SSP18) showed their dispensability for Z. tritici pathogenesis. These analyses reveal that generally adopted criteria, such as protein size, cysteine residues and expression during pathogenesis, may preclude an unbiased effector discovery. Indeed, genetic mapping of genomic regions involved in specificity render alternative effector candidates that do not match the aforementioned criteria, but should nevertheless be considered as promising new leads for effectors that are crucial for the Z. tritici-wheat pathosystem. PMID- 25727414 TI - Welcome to RCNi. PMID- 25727416 TI - Liverpool Care Pathway still being used. PMID- 25727418 TI - Special day urges staff to become 'the change they want to be'. PMID- 25727419 TI - College aims to end culture of working beyond shifts. PMID- 25727420 TI - NMC revised code unveils 25 standards for good practice. PMID- 25727421 TI - Talking point: decor designed to calm younger patients. PMID- 25727422 TI - New law demands the reporting of female genital mutilation. PMID- 25727423 TI - Report states that NHS reforms have led to fractured leadership. PMID- 25727424 TI - Service providers say plans to cut tariff will jeopardise 'safe care'. PMID- 25727425 TI - Time to move on. PMID- 25727427 TI - International outlook--Why not learn some lessons from the past? PMID- 25727430 TI - Vantage point--We must stop female genital mutilation. PMID- 25727439 TI - A framework to support the revalidation process. AB - In January 2016, all registered nurses and midwives will be required to revalidate their practice every three years. This will have implications for individual registrants and line managers. In May 2014 the chief nursing officer for Wales launched a new governance framework for post-registration nurse education in Wales. This article describes the framework, how it underpins a continuous cycle of improvement in care delivery, and how it could be used to support nurses and nurse managers to meet the requirements of the revalidation process. PMID- 25727440 TI - Effects of advanced practitioners' learning in one hospital. AB - A master of science degree course in advanced practice (health and social care) was launched at the University of Salford in 2005 to prepare students for advanced practice roles as part of a workforce modernisation strategy for the north west of England. The development needs of qualified advanced practitioners (APs) and the effects of their roles on service outcomes are difficult to capture; therefore, a study was undertaken to evaluate the longer term effects of the programme and address some of these gaps in knowledge. This article reports the results of the study, which focused on the effects of education in the workplace and found that APs apply their learning in the workplace and can demonstrate its impact on services. Results also suggest that APs are more effective when they have supportive managers with a clear vision for the role in a service area and who develop the roles based on skill and service need. PMID- 25727441 TI - Hospital nurses' working conditions in relation to motivation and patient safety. AB - There is a lack of empirical knowledge about nurses' perceptions of their workplace characteristics and conditions, such as level of autonomy and decision authority, work climate, teamwork, skill exploitation and learning opportunities, and their work motivation in relation to practice outputs such as patient safety. Such knowledge is needed particularly in countries, such as Estonia, where hospital systems for preventing errors and improving patient safety are in the early stages of development. This article reports the findings from a cross sectional survey of hospital nurses in Estonia that was aimed at determining their perceptions of workplace characteristics, working conditions, work motivation and patient safety, and at exploring the relationship between these. Results suggest that perceptions of personal control over their work can affect nurses' motivation, and that perceptions of work satisfaction might be relevant to patient safety improvement work. PMID- 25727442 TI - An exploratory short-term double-blind randomized trial of varenicline versus nicotine patch for smoking cessation in women. AB - AIMS: Within a parent study examining ovarian hormone effects on smoking cessation in women, we conducted an exploratory short-term trial of varenicline versus transdermal nicotine patch. DESIGN: Double-blind double-dummy randomized trial. SETTING: Single-site out-patient research clinic in the United States. PARTICIPANTS: Female smokers, ages 18-45 years and averaging >=10 cigarettes per day for at least 6 months (n=140). INTERVENTIONS: Participants were randomized to receive a 4-week course of (a) varenicline tablets and placebo patches (n = 67) or (b) placebo tablets and nicotine patches (n=73). Two brief cessation counseling sessions were provided for all participants. MEASUREMENTS: The outcome of primary clinical interest was 2-week end-of-treatment abstinence. Secondary outcomes included 1- and 4-week end-of treatment abstinence and abstinence at a post-treatment follow-up visit occurring 4 weeks after treatment conclusion. Breath carbon monoxide (<= 10 parts per million) was used to confirm biochemically self-reported abstinence. FINDINGS: Two-week end-of-treatment abstinence was achieved by 37.3% (25 of 67) of varenicline participants and by 17.8% (13 of 73) of nicotine patch participants [odds ratio (OR) = 2.7, 95% confidence interval (CI)=1.3-6.0, P=0.011]. One-week (44.8 versus 20.6%, OR=3.1, 95% CI=1.5-6.6, P=0.003) and 4-week (22.4 versus 9.6%, OR=2.7, 95% CI=1.0-7.2, P=0.043) end-of-treatment abstinence similarly favored varenicline, although post treatment follow-up Russell Standard abstinence was not significantly different between groups (23.9 versus 13.7%, OR=2.0, 95% CI=0.8-4.7, P=0.126). CONCLUSION: In an exploratory 4-week head-to-head trial in female smokers, varenicline, compared with nicotine patch, more than doubled the odds of end-of-treatment abstinence, although this diminished somewhat at post-treatment follow-up. PMID- 25727443 TI - Volumetric analysis of remodelling pattern after ridge preservation comparing use of two types of xenografts. A multicentre randomized clinical trial. AB - OBJECTIVES: The aim of this randomized clinical trial was to analyse and compare the volumetric changes after ridge preservation procedures using two different biomaterials and to evaluate associations between outcome variables and pristine three-dimensional aspects of the ridges. MATERIALS AND METHODS: Twenty-eight patients subjected to single-tooth alveolar ridge preservation were enrolled in the present multicentre, single-blind, prospective and randomized clinical trial. Fourteen sites were randomly allocated to each experimental group. The experimental sites were grafted with pre-hydrated collagenated cortico-cancellous porcine bone (coll group) or with a cortical porcine bone (cort group) and a collagen membrane; a secondary soft tissue healing was obtained for all experimental sites. Plaster casts were scanned (preoperative, at 1 and 3 months postoperative). Analysis of volumes and areas was performed, and all measured variables were statistically compared. RESULTS: Intragroup analyses at 3 months revealed that when examining changes related to three-dimensional features of remodelling patterns (volume, surfaces, height and shape), the two biomaterials showed similar behaviours with a minor loss in volume and ridge surface. Intergroup analysis at 3-month survey revealed that volume resorption of the coll group (244 mm3 ) was significantly lower (P = 0.0140) than that of the cort group (349 mm3 ). The reduction for basal surface appeared significantly different between the two groups at 1-month survey only (P = 0.0137), while the final basal surface reduction was 4.9 and 12.2 mm2 for coll and cort group, respectively. The superior surface reduction was 40.8 mm2 for coll and 50.7 mm2 for cort group, with no significant difference between the two groups. CONCLUSION: At the 3rd month analysis, coll group showed a significantly lower reduction of ridge volume and a significantly smaller shrinkage of the basal area when compared to the cort group; moreover, the coll group experienced a smaller superior surface shrinkage when compared to the cort group, even though no significance was evaluated. PMID- 25727444 TI - Histopathological findings of a 1-month-old Ologen implant. PMID- 25727445 TI - Sign-Supported English: is it effective at teaching vocabulary to young children with English as an Additional Language? AB - BACKGROUND: Children who are learning English as an Additional Language (EAL) may start school with smaller vocabularies than their monolingual peers. Given the links between vocabulary and academic achievement, it is important to evaluate interventions that are designed to support vocabulary learning in this group of children. AIMS: To evaluate an intervention, namely Sign-Supported English (SSE), which uses conventionalized manual gestures alongside spoken words to support the learning of English vocabulary by children with EAL. Specifically, the paper investigates whether SSE has a positive impact on Reception class children's vocabulary development over and above English-only input, as measured over a 6 month period. METHODS & PROCEDURES: A total of 104 children aged 4-5 years were recruited from two neighbouring schools in a borough of Outer London. A subset of 66 had EAL. In one school, the teachers used SSE, and in the other school they did not. Pupils in each school were tested at two time points (the beginning of terms 1 and 3) using three different assessments of vocabulary. Classroom-based observations of the teachers' and pupils' manual communication were also carried out. OUTCOMES & RESULTS: Results of the vocabulary assessments revealed that using SSE had no effect on how well children with EAL learnt English vocabulary: EAL pupils from the SSE school did not learn more words than EAL pupils at the comparison school. SSE was used in almost half of the teachers' observations in the SSE school, while spontaneous gestures were used with similar frequency by teachers in the comparison school. CONCLUSIONS & IMPLICATIONS: There are alternative explanations for the results. The first is that the use of signs alongside spoken English does not help EAL children of this age to learn words. Alternatively, SSE does have an effect, but we were unable to detect it because (1) teachers in the comparison school used very rich natural gesture and/or (2) teachers in the SSE school did not know enough BSL and this inhibited their use of spontaneous gesture. Explanations (1) and (2) might mean that the potential benefits of spontaneous gesture in the input to the children in the comparison school matched any potential benefits of SSE. We suggest that studying early years professionals' spontaneous use of gesture, and how their gesture supports the language learning of all children in their class, would be fruitful areas of research for the future. PMID- 25727447 TI - Apply a large magnet to prevent inappropriate therapy: using cardiac magnetic resonance to optimize atrial fibrillation ablation. PMID- 25727448 TI - Numerical analysis of particulate organic waste diffusion in an aquaculture area of Gokasho Bay, Japan. AB - Particulate organic waste, originating from fish cultured in cages, often brings about negative effects on the structure of bottom sediments. These effects result in deterioration of the aquatic environment. In the present study, a three dimensional numerical model was coupled with developed submodels of fish cage drag and aquaculture waste diffusion to simulate the hydrodynamic environment and distribution of particulate organic waste. Numerical simulation results showed that fish cages exerted an influence on both the velocity and direction of water current; the reduction of water current velocity was a maximum of approximately 38%. The contribution of fish fecal matter was dominant during winter (ca. 80%), whereas waste fish feed was the main source in other seasons. The distribution of organic waste near the sea bottom indicated that organic waste not only loaded mainly on the sea floor just beneath the fish cages but also diffused towards the coastlines. PMID- 25727446 TI - Enhancing the imaging and biosafety of upconversion nanoparticles through phosphonate coating. AB - Upconversion nanoparticles (UCNPs), which are generated by doping with rare earth (RE) metals, are increasingly used for bioimaging because of the advantages they hold over conventional fluorophores. However, because pristine RE nanoparticles (NPs) are unstable in acidic physiological fluids (e.g., lysosomes), leading to intracellular phosphate complexation with the possibility of lysosomal injury, it is important to ensure that UCNPs are safely designed. In this study, we used commercially available NaYF4:Er/Yb UCNPs to study their stability in lysosomes and simulated lysosomal fluid. We demonstrate that phosphate complexation leads to REPO4 deposition on the particle surfaces and morphological transformation. This leads to a decline in upconversion fluorescence efficiency as well as inducing pro-inflammatory effects at the cellular level and in the intact lung. In order to preserve the imaging properties of the UCNPs as well as improve their safety, we experimented with a series of phosphonate chemical moieties to passivate particle surfaces through the strong coordination of the organophosphates with RE atoms. Particle screening and physicochemical characterization revealed that ethylenediamine tetra(methylenephosphonic acid) (EDTMP) surface coating provides the most stable UCNPs, which maintain their imaging intensity and do not induce pro-inflammatory effects in vitro and in vivo. In summary, phosphonate coating presents a safer design method that preserves and improves the bioimaging properties of UCNPs, thereby enhancing their biological use. PMID- 25727449 TI - Efficient Vocational Skills Training for People with Cognitive Disabilities: An Exploratory Study Comparing Computer-Assisted Instruction to One-on-One Tutoring. AB - BACKGROUND: This study compared the effectiveness of computer-assisted instruction to that of one-on-one tutoring for teaching people with mild and moderate cognitive disabilities when both training methods are designed to take account of the specific mental deficits most commonly found in cognitive disability populations. METHOD: Fifteen participants (age 22-71) received either computer-assisted instruction or one-on-one tutoring in three content domains that were of functional and daily relevance to them: behavioural limits, rights and responsibilities (two modules) and alphabetical sorting. Learning was assessed by means of a series of pretests and four learning cycle post-tests. Both instructional conditions maintained time-on-task and teaching material equivalence, and both incorporated a set of best-practices and empirically supported teaching techniques designed to address attentional deficits, stimulus processing inefficiencies and cognitive load limitations. RESULTS: Strong evidence of learning was found in both instructional method conditions. Moreover, in all content domains the two methods yielded approximately equivalent rates of learning and learning attainment. CONCLUSIONS: These findings offer tentative evidence that a repetitive, computer-assisted training program can produce learning outcomes in people with mild and moderate cognitive disabilities that are comparable to those achieved by high-quality one-on-one tutoring. PMID- 25727450 TI - Important biological information uncovered in previously unaligned reads from chromatin immunoprecipitation experiments (ChIP-Seq). AB - Establishing the architecture of gene regulatory networks (GRNs) relies on chromatin immunoprecipitation followed by massively parallel sequencing (ChIP Seq) methods that provide genome-wide transcription factor binding sites (TFBSs). ChIP-Seq furnishes millions of short reads that, after alignment, describe the genome-wide binding sites of a particular TF. However, in all organisms investigated an average of 40% of reads fail to align to the corresponding genome, with some datasets having as much as 80% of reads failing to align. We describe here the provenance of previously unaligned reads in ChIP-Seq experiments from animals and plants. We show that a substantial portion corresponds to sequences of bacterial and metazoan origin, irrespective of the ChIP-Seq chromatin source. Unforeseen was the finding that 30%-40% of unaligned reads were actually alignable. To validate these observations, we investigated the characteristics of the previously unaligned reads corresponding to TAL1, a human TF involved in lineage specification of hemopoietic cells. We show that, while unmapped ChIP-Seq read datasets contain foreign DNA sequences, additional TFBSs can be identified from the previously unaligned ChIP-Seq reads. Our results indicate that the re-evaluation of previously unaligned reads from ChIP-Seq experiments will significantly contribute to TF target identification and determination of emerging properties of GRNs. PMID- 25727451 TI - Harm reduction in U.S. tobacco control: Constructions in textual news media. AB - BACKGROUND: U.S. tobacco control has long emphasized abstinence, yet quitting smoking is hard and cessation rates low. Tobacco harm reduction alternatives espouse substituting cigarettes with safer nicotine and tobacco products. Policy shifts embracing tobacco harm reduction have increased media attention, yet it remains controversial. Discourse theory posits language as fluid, and socially constructed meaning as neither absolute nor neutral, elevating certain views over others while depicting "discursive struggle" between them. While an abstinence based framework dominates tobacco policy, discourse theory suggests constructions of nicotine and tobacco use can change, for example by positioning tobacco harm reduction more favorably. METHODS: Textual discourse analysis was used to explore constructions of tobacco harm reduction in 478 (308 original) U.S. textual news media articles spanning 1996-2014. Using keyword database sampling, retrieved articles were analyzed first as discrete recording units and then to identify emergent thematic content. RESULTS: Constructions of tobacco harm reduction shifted over this time, revealing tension among industry and policy interests through competing definitions of tobacco harm reduction, depictions of its underlying science, and accounts of regulatory matters including tobacco industry support for harm reduction and desired marketing and taxation legislation. CONCLUSIONS: Heightened salience surrounding tobacco harm reduction and electronic cigarettes suggests their greater acceptance in U.S. tobacco control. Various media depictions construct harm reduction as a temporary means to cessation, and conflict with other constructions of it that place no subjective value on continued "safer" tobacco/nicotine use. Constructions of science largely obscure claims of the veracity of tobacco harm reduction, with conflict surrounding appropriate public health benchmarks for tobacco policy and health risks of nicotine use. Taxation policies and e-cigarette pricing relative to cigarettes are key for wider adoption, while concerns are raised for whether their availability will increase initiation. PMID- 25727452 TI - The effect of links on the interparticle dipolar correlations in supramolecular magnetic filaments. AB - We present a combined computational and analytical study of supramolecular magnetic filaments, i.e., permanently linked chains of ferromagnetic nanocolloids. We put forward two different models for the interparticle connectivity within the chain. In the first model, the magnetic dipoles of the particles are free to rotate independently from the permanent links. The second model penalises the misalignment of the dipoles by coupling their orientations to the chain backbone. We show that the effect of the long-range magnetic dipolar interactions on the zero field net magnetic moment of the chain becomes less significant in the second case. However, the overall magnetic response in the model of freely rotating dipoles is much weaker. PMID- 25727453 TI - Understanding the influence of all nodes in a network. AB - Centrality measures such as the degree, k-shell, or eigenvalue centrality can identify a network's most influential nodes, but are rarely usefully accurate in quantifying the spreading power of the vast majority of nodes which are not highly influential. The spreading power of all network nodes is better explained by considering, from a continuous-time epidemiological perspective, the distribution of the force of infection each node generates. The resulting metric, the expected force, accurately quantifies node spreading power under all primary epidemiological models across a wide range of archetypical human contact networks. When node power is low, influence is a function of neighbor degree. As power increases, a node's own degree becomes more important. The strength of this relationship is modulated by network structure, being more pronounced in narrow, dense networks typical of social networking and weakening in broader, looser association networks such as the Internet. The expected force can be computed independently for individual nodes, making it applicable for networks whose adjacency matrix is dynamic, not well specified, or overwhelmingly large. PMID- 25727454 TI - Inflammatory and redox reactions in colorectal carcinogenesis. AB - It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment. PMID- 25727455 TI - Towards a gender perspective in qualitative research on voluntary medical male circumcision in east and southern Africa. AB - The World Health Organization endorsed voluntary medical male circumcision (VMMC) in 2007 as an effective method to provide partial protection against heterosexual female-to-male transmission of HIV in regions with high rates of such transmission, and where uptake of VMMC is low. Qualitative research conducted in east and southern Africa has focused on assessing acceptability, barriers to uptake of VMMC and the likelihood of VMMC increasing men's adoption of risky sexual behaviours. Less researched, however, have been the perceptions of women and sexual minorities towards VMMC, even though they are more vulnerable to HIV/AIDS transmission than are heterosexual men. The purpose of this paper is to identify core areas in which a gendered perspective in qualitative research might improve the understanding and framing of VMMC in east and southern Africa. Issues explored in this analysis are risk compensation, the post-circumcision appearance of the penis, inclusion of men who have sex with men as study respondents and the antagonistic relation between VMMC and female genital cutting. If biomedical and social science researchers explore these issues in future qualitative inquiry utilising a gendered perspective, a more thorough understanding of VMMC can be achieved, which could ultimately inform policy and implementation. PMID- 25727456 TI - Assessment of bagging GBLUP for whole-genome prediction of broiler chicken traits. AB - Bootstrap aggregation (bagging) is a resampling method known to produce more accurate predictions when predictors are unstable or when the number of markers is much larger than sample size, because of variance reduction capabilities. The purpose of this study was to compare genomic best linear unbiased prediction (GBLUP) with bootstrap aggregated sampling GBLUP (Bagged GBLUP, or BGBLUP) in terms of prediction accuracy. We used a 600 K Affymetrix platform with 1351 birds genotyped and phenotyped for three traits in broiler chickens; body weight, ultrasound measurement of breast muscle and hen house egg production. The predictive performance of GBLUP versus BGBLUP was evaluated in different scenarios consisting of including or excluding the TOP 20 markers from a standard genome-wide association study (GWAS) as fixed effects in the GBLUP model, and varying training sample sizes and allelic frequency bins. Predictive performance was assessed via five replications of a threefold cross-validation using the correlation between observed and predicted values, and prediction mean-squared error. GBLUP overfitted the training set data, and BGBLUP delivered a better predictive ability in testing sets. Treating the TOP 20 markers from the GWAS into the model as fixed effects improved prediction accuracy and added advantages to BGBLUP over GBLUP. The performance of GBLUP and BGBLUP at different allele frequency bins and training sample sizes was similar. In general, results of this study confirm that BGBLUP can be valuable for enhancing genome-enabled prediction of complex traits. PMID- 25727457 TI - The effects of systematic educational interventions about nasogastric tube feeding on caregivers' knowledge and skills and the incidence of feeding complications. AB - AIMS AND OBJECTIVES: To compare the influence of a systematic nursing intervention on primary caregivers' knowledge and skills about nasogastric tube feeding and the number of nasogastric tube-related complications with that of routine nursing instructions BACKGROUND: To ensure the quality of care and reduce the incidence of complications, it is crucial that primary caregivers receive comprehensive health education about nasogastric tube feeding before hospital discharge. DESIGN: A quasi-experimental research with pretest/post-test evaluations. METHODS: The control group included 127 inpatients whose caregivers received routine education about nasogastric tube feeding, while the experimental group included 106 inpatients whose caregivers received systematic nursing intervention including comprehensive educational pamphlets and video education. The evaluation questionnaire included demographic variables, a nasogastric tube care knowledge scale, and a nasogastric tube skills assessment scale. The post test was administered after the caregiver performed nasogastric tube feeding for the first time, and complications were noted at follow-up within three months of discharge. RESULTS: In terms of post-test knowledge and skills, the experimental group scored significantly higher than the control group, despite no difference in the pretests. In addition, the incidence rates for constipation, diarrhoea and abdominal distention were lower in the experimental group. CONCLUSIONS: Systematic nursing intervention, including comprehensive educational pamphlets and video education, significantly improved the knowledge and skills of primary caregivers for nasogastric tube feeding. The increased ability of caregivers may have contributed to less incidence of complication. RELEVANCE TO CLINICAL PRACTICE: The results of this study underlined the importance of developing nasogastric tube-related nursing interventions and educational strategies for clinical nurses, home care nurses and caregivers. The research tool used here may serve as a reference for assessing the technical operations of healthcare professionals and the knowledge and skills of caregivers. PMID- 25727459 TI - Mono-, di- and tetra-zinc complexes derived from an amino-benzotriazole phenolate ligand containing a bulkier N-alkyl pendant arm: synthesis, structure and catalysis for ring-opening polymerization of cyclic esters. AB - Zinc complexes constructed from the amino-modified benzotriazole phenol pro ligand, 2-(2H-benzotriazol-2-yl)-6-((diisopropylamino)methyl)-4-(2,4,4 trimethylpentan-2-yl)phenol ((C8DIA)BTP-H, 1), were synthesized stepwise and structurally characterized. The reaction of (C8DIA)BTP-H (1) with one equivalent of diethyl zinc (ZnEt2) generates a dimeric and four-coordinated zinc complex, [(MU-(C8DIA)BTP)ZnEt]2 (2), which is doubly bridged by two phenolate groups of C8DIABTP ligands. Further reaction of 2 with benzyl alcohol (BnOH) in stoichiometric proportions affords a tetranuclear zinc benzylalkoxide complex [(MU-OBn)((C8DIA)BTP)Zn]4 (3) that possesses a saddle-shaped core with four MU2 bridging benzylalkoxy groups upon four Zn centres. Interestingly, the di-nuclear Zn alkoxide [(MU-OBn)((C8DIA)BTP)Zn(DMAP)]2 (4) could be prepared by treatment of 3 with a stoichiometric amount of 4-(dimethylamino)pyridine (DMAP). ZnEt2 reacts with two equivalents of 1 in the presence of DMAP (1.0 mol equiv.) to yield a five-coordinated mononuclear zinc complex, [((C8DIA)BTP)2Zn(DMAP)] (5). All complexes adopt an N,O-bidentate coordination mode from the phenoxy oxygen atom and benzotriazole nitrogen atom, in which the nitrogen atom of the pendent arm substituent is not coordinated to the zinc centre. Ring-opening polymerization of epsilon-caprolactone and beta-butyrolactone catalysed by 2 and 3 was investigated. PMID- 25727458 TI - Peripheral nerve tumours: 30-year experience in the surgical treatment. AB - Peripheral nerve tumours are relatively rare type of soft tissue tumours. The aim of this work is to present our experience with surgical treatment of this type of lesions. Clinical material consists of 94 patients (56 females, 38 males), in whom 101 tumours deriving from peripheral nervous system were removed. The patients underwent surgical treatment between 1983 and 2012. Tumours occurred mainly in the upper extremity (72 tumours), less often in the lower extremity (25 tumours). Lesions developed in major peripheral nerves (51 tumours) and small nerve branches (50 tumours). The most common symptoms reported before surgery included presence of tumour mass (100 %), positive Hoffmann-Tinel sign (95.6 %) and paraesthesia (93.4 %). Less often sensory deficit (89.1 %) and pain (71.7 %) were observed. Motor deficit was the least common manifestation (41.3 %). Benign tumours prevailed in presented material (94 tumours). In 7 cases, malignant peripheral nerve sheath tumour (MPNST) was identified. As a result of surgical treatment in the group of tumours deriving from major peripheral nerves, in 87.8 % of the patients, pain relief was achieved; in 84 %, Hoffmann-Tinel sign was negative; and in 79 %, paraesthesia resolved. Sensory function improvement was observed in 51.2 % of the patients while motor function improved in 26.3 % of the patients. None of the patients experienced tumour relapse. In the group of tumours deriving from small nerve branches, 47 patients had no signs of tumour recurrence. One female patient diagnosed with MPNST suffered a relapse. Obtaining satisfactory results of peripheral nerve tumour treatment requires both careful differential diagnosis and well thought-out strategy at every stage of therapeutic management. PMID- 25727460 TI - Circularly polarized near-field optical mapping of spin-resolved quantum Hall chiral edge states. AB - We have successfully developed a circularly polarized near-field scanning optical microscope (NSOM) that enables us to irradiate circularly polarized light with spatial resolution below the diffraction limit. As a demonstration, we perform real-space mapping of the quantum Hall chiral edge states near the edge of a Hall bar structure by injecting spin polarized electrons optically at low temperature. The obtained real-space mappings show that spin-polarized electrons are injected optically to the two-dimensional electron layer. Our general method to locally inject spins using a circularly polarized NSOM should be broadly applicable to characterize a variety of nanomaterials and nanostructures. PMID- 25727461 TI - Comparison and characterization of soybean and sunflower lecithins used for chocolate production by high-performance thin-layer chromatography with fluorescence detection and electrospray mass spectrometry. AB - The scarce availability of nongenetically modified soybeans on the world market represents a growing problem for food manufacturers. Hence, in this study the effects of substituting soybean with sunflower lecithin were investigated with regard to chocolate production. The glycerophospholipid pattern of the different lecithin samples was investigated by high-performance thin-layer chromatography fluorescence detection (HPTLC-FLD) and by HPTLC-positive ion electrospray ionization mass spectrometry (ESI(+)-MS) via the TLC-MS Interface and by scanning HPTLC-matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOFMS). Especially, the contents of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were of interest due to the influencing effects of these two glycerophospholipids on the rheological parameters of chocolate production. The lecithin substitution led to only slight differences in the rheological parameters of milk and dark chocolate. Limits of detection (LODs) and limits of quantification (LOQs) of seven glycerophospholipids were studied for three detection modes. Mean LODs ranged from 8 to 40 mg/kg for HPTLC-FLD and, using a single-quadrupole MS, from 10 to 280 mg/kg for HPTLC-ESI(+)-MS as well as from 15 to 310 mg/kg for HPTLC-FLD-ESI(+)-MS recorded after derivatization with the primuline reagent. PMID- 25727462 TI - Mobile Health: empowering patients and driving change. AB - Diabetes is a global epidemic, with insufficient medical management capacity. It is becoming increasingly relevant to develop sustainable methods of self management and collaboration between clinical personnel and those living with diabetes. While there have been favorable advances in mobile self-management tools for the disease, few have been validated and acknowledged. Health policies are not being established as quickly as these tools are becoming available, and the public has taken action into their own hands. PMID- 25727463 TI - The 2014 Claude Bernard Distinguished Lecture: the social contract of learning. AB - The shift to competency-based education expands the role of the teacher from that of a provider of information and into a shaper of knowledge, skills, and attitudes. These roles are facilitated by establishing a social contract between the instructor and learner, a contract that clearly defines the rights and duties of each. Adopting greater responsibility for the development of competencies in our learners allows faculty members to truly have an impact by shaping the behaviors of learners. PMID- 25727464 TI - Is Wikipedia a reliable learning resource for medical students? Evaluating respiratory topics. AB - The aim of the present study was to critically evaluate the accuracy and readability of English Wikipedia articles on the respiratory system and its disorders and whether they can be a suitable resource for medical students. On April 27, 2014, English Wikipedia was searched for articles on respiratory topics. Using a modified DISCERN instrument, articles were independently scored by three assessors. The scoring targeted content accuracy, frequency of updating, and quality of references. The readability of articles was measured using two other instruments. The mean DISCERN score for the 40 articles identified was 26.4+/-6.3. Most articles covered causes, signs and symptoms, prevention, and treatment. However, several knowledge deficiencies in the pathogenesis of diseases, investigations needed, and treatment were observed. The total number of references for the 40 articles was 1,654, and the references varied from 0 to 168 references, but several problems were identified in the list of references and citations made. The readability of articles was in the range of 9.4+/-1.8 to 22.6+/-10.7 using the Flesch-Kincaid Grade Level instrument and 10.0+/-2.6 to 19.6+/-8.3 using the Readability Coleman-Liau index. A strong correlation was found between the two instruments (r2=0.744, P<0.001). The agreement between the assessors had mean kappa scores in the range of 0.712-0.857. In conclusion, despite the effort placed in creating Wikipedia respiratory articles by anonymous volunteers (wikipedians), most articles had knowledge deficiencies, were not accurate, and were not suitable for medical students as learning resources. PMID- 25727465 TI - Understanding the electrical behavior of the action potential in terms of elementary electrical sources. AB - A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However, this model is unsuitably complex for teaching purposes. In addition, the Hodgkin and Huxley approach describes the shape of the action potential only in terms of ionic currents, i.e., it is unable to explain the electrical significance of the action potential or describe the electrical field arising from this source using basic concepts of electromagnetic theory. The goal of the present report was to propose a new model to describe the electrical behaviour of the action potential in terms of elementary electrical sources (in particular, dipoles). The efficacy of this model was tested through a closed-book written exam. The proposed model increased the ability of students to appreciate the distributed character of the action potential and also to recognize that this source spreads out along the fiber as function of space. In addition, the new approach allowed students to realize that the amplitude and sign of the extracellular electrical potential arising from the action potential are determined by the spatial derivative of this intracellular source. The proposed model, which incorporates intuitive graphical representations, has improved students' understanding of the electrical potentials generated by bioelectrical sources and has heightened their interest in bioelectricity. PMID- 25727466 TI - A puzzle used to teach the cardiac cycle. AB - The aim of the present article is to describe a puzzle developed for use in teaching cardiac physiology classes. The puzzle presents figures of phases of the cardiac cycle and a table with five columns: phases of cardiac cycle, atrial state, ventricular state, state of atrioventricular valves, and pulmonary and aortic valves. Chips are provided for use to complete the table. Students are requested to discuss which is the correct sequence of figures indicating the phases of cardiac cycle. Afterward, they should complete the table with the chips. Students of biology, dentistry, medicine, pharmacy, and nursing graduation courses from seven institutions performed the puzzle evaluation. They were invited to indicate whether the puzzle had been useful for learning about the subject by filling one of four alternatives. Of the students, 4.6% answered that it was not necessary but helped them to confirm what they had learned, 64.5% reported that although they had previously understood the cardiac cycle, the puzzle helped them to solve doubts and promoted a better understanding of it, and 30.9% said that they needed the puzzle to understand the cardiac cycle, without differences among courses, institutions, and course semesters. The results of the present study suggest that a simple and inexpensive puzzle may be useful as an active learning methodology applied after the theoretical lecture, as a complementary tool for studying cardiac cycle physiology. PMID- 25727467 TI - Research-oriented series: a portal into the culture of biomedical research for junior medical students at Alfaisal University in Saudi Arabia. AB - Student contributions to research have been shown to effectively reflect on their communication and critical thinking skills. Short-term research courses offer opportunities for medical students to advance their research experience in subsequent high-demanding long-term research opportunities. The purpose of the present study was to describe the development, implementation, and evaluation of a research-oriented series (ROS) on undergraduate students at Alfaisal University in Saudi Arabia. The ROS was designed to comprise eight sessions. Each session addressed core principles and the practice of research concepts and was based on theoretical morning sessions supplemented by afternoon practical sessions delivered by experienced senior medical students and faculty members. Students were assessed comprehensively by the end of the ROS. The series was conducted twice, and 35 students were involved each time. A total of 70 enrolled students (35 men and 35 women) with grade point averages of >3.5 and <3.5 were asked to fill out an anonymous, online, self-administered questionnaire assessing their perception of knowledge, skills, and confidence after attending the ROS and evaluating their senior peers. Ninety percent of the medical students responded to the online survey and rated the ROS highly in improving their research knowledge, skills, and confidence. Male students reported significant gains compared with their female peers (P<0.05). Grade point averages did not play a role in student gains after attending the ROS. Qualitative responses were in support of three recurring themes favoring the unique learning environment in the ROS. In conclusion, the ROS offers a short-term systematic approach to fundamental steps and concepts of biomedical research. PMID- 25727468 TI - Development of a manipulative for nephron physiology education. PMID- 25727469 TI - The Thermus thermophilus comEA/comEC operon is associated with DNA binding and regulation of the DNA translocator and type IV pili. AB - Natural transformation systems and type IV pili are linked in many naturally competent bacteria. In the Gram-negative bacterium Thermus thermophilus, a leading model organism for studies of DNA transporters in thermophilic bacteria, seven competence proteins play a dual role in both systems, whereas two competence genes, comEA and comEC, are suggested to represent unique DNA translocator proteins. Here we show that the T. thermophilus ComEA protein binds dsDNA and is anchored in the inner membrane. comEA is co-transcribed with the flanking comEC gene, and transcription of this operon is upregulated by nutrient limitation and low temperature. To our surprise, a comEC mutant was impaired in piliation. We followed this observation and uncovered that the impaired piliation of the comEC mutant is due to a transcriptional downregulation of pilA4 and the pilN both playing a dual role in piliation and natural competence. Moreover, the comEC mutation resulted in a dramatic decrease in mRNA levels of the pseudopilin gene pilA1, which is unique for the DNA transporter. We conclude that ComEC modulates transcriptional regulation of type IV pili and DNA translocator components thereby mediating a response to extracellular parameters. PMID- 25727470 TI - [AFSSAPS 2005 recommendations have not modified the way parents take care of children's fever]. AB - INTRODUCTION: Fever in children is frequent. Often mild, initial care is the parents' responsibility: medicinal treatments and medical consultations. Unfortunately, the efficiency of parental care is poor. Therefore, in 2005 the AFSSAPS updated its recommendations. One and 6 years after publication of the guidelines, this study rates their impact by describing and comparing parents' knowledge and behavior when faced with fever in their children. MATERIAL AND METHODS: This survey was conducted in families whose children were attending preschool in and near Metz (France) in 2006 and 2012. The same questionnaire was given to assess the knowledge, care, and symptoms of serious fever. The results were processed based on the number of children in the family and the family's socioeconomic category. RESULTS: In 2006, 1038 questionnaires were distributed and 1273 in 2012. The fever threshold was not better known in 2012. Bathing and uncovering children remained the predominant physical methods used. Treatment was based on the use of ibuprofen and alternating treatments. However, the conditions of administering medication were well known to parents. The causes and motives for consultation were not better understood in 2012 however. The main source of information was physicians. DISCUSSION: The message disseminated since 2005 has not been efficient. Its complexity has not eradicated old beliefs and inappropriate parental practices. A campaign based on a brief, simple message has to be organized, providing better chances of being assimilated by the public. Medical practices should be standardized. PMID- 25727471 TI - [Drugs news]. PMID- 25727472 TI - [Acute viral bronchiolitis: a national study in pediatric emergency departments]. AB - The 2000 French guidelines for acute viral bronchiolitis management underlined clinical criteria for hospitalization. We aimed to assess the impact of these guidelines on admission rates in pediatric emergency departments. METHODS: A prospective multicentric observational study was conducted over 24h in 66 pediatric emergency departments. Questions were asked about the structure, the course of care, clinical data, resource utilization, and hospitalization or discharge of every patient under 2 years of age with acute viral bronchiolitis. An open-ended question allowed clinicians to explain the reason for hospitalization. Multivariable logistic regression analyses were performed to identify independent risk factors for severe disease to assess potential clinical factors associated with hospitalization. Responses were compared using the Student t-test and the Chi(2) test. RESULTS: Of 338 patients enrolled, 145 (45.1%) were admitted. Clinical criteria were associated with hospitalization: clinical deterioration (OR: 3 [95% CI: 1.0-8.5], p=0.04), respiratory rate more than 60/min (OR: 3.4 [95% CI: 1.3-8.8], p=0.02), age under 6 weeks (OR: 29.8 [95% CI: 7.0-125.4], p<0.001), oxygen saturation less than 94% (OR: 15.8 [95% CI: 4.2 60.1], p<0.001), food intake less than 50% of the usual intake (OR: 4.9 [95% CI: 2.2-10.9], p<0.001), and age between 6 weeks and 3 months (OR: 3.2 [95% CI: 1.4 7.2], p=0.007). CONCLUSION: The clinical criteria of the 2000 French guidelines influence hospitalization for acute viral bronchiolitis in pediatric emergency departments. However, other criteria are cited in about one-third of the patients. PMID- 25727473 TI - [Adolescent pathological gambling]. AB - BACKGROUND: Although experts have long thought that the problems of gambling involved only adults, recent studies tend to show that teenagers are also affected. OBJECTIVE: The objective of this paper is to show the characteristics of pathological gambling in adolescents. This review focuses on the clinical features, prevalence, psychopathology, prevention and treatment of this disorder. METHODS: A review of the medical literature was conducted, using PubMed, using the following keywords alone or combined: pathological gambling, dependence, addiction and adolescents. We selected 12 English articles from 1997 to 2014. RESULTS: Recent work estimate that between 4 and 8% of adolescents suffer from problem gambling, and the prevalence of pathological gambling is 2-4 times higher in adolescents than in adults. The term adolescent pathological gambler starts early around the age of 10-12 years, with a quick change of status from casual to that of problem gambler and player. Complications appear quickly and comorbidities are common. There is no curative pharmacological treatment approved by health authorities. CONCLUSION: Pathological gambling among adolescents has grown significantly in recent years and should be promptly taken care of. Further studies must be performed to improve our understanding of this problem among adolescents. PMID- 25727474 TI - [Neonatal hyperthyroidism and maternal Graves disease]. AB - The onset of Graves disease during pregnancy exposes the neonate to the risk of hyperthyroidism. The newborn must be monitored and treatment modalities known to ensure early treatment of the newborn. We report on the case of an infant born at term of a mother with Graves disease discovered during pregnancy. He was asymptomatic during the first days of life, before declaring the disease. Neonatal hyperthyroidism was confirmed by hormonal assays. Hyperthyroidism was treated with antithyroid drugs and propranolol with a satisfactory clinical and biological course. Neonatal hyperthyroidism should be systematically sought in infants born to a mother with Graves disease. The absence of clinical signs during the first days of life does not exclude the diagnosis. The duration of monitoring should be decided according to the results of the first hormonal balance tests. PMID- 25727475 TI - [Pitfalls in hemoglobin oxygen saturation measurement: a case of chronic desaturation]. AB - The measurement of oxygen saturation by pulse oximetry (SpO2) is simple and fast. This non-invasive and widespread technique gives an indication of the oxygen level in arterial blood. While the method is reliable, there are limitations that can compromise the diagnostic procedure. The objective of the present paper is to list these limitations and discuss the precautions to be taken to optimize the interpretation of the results. Based on the case of a 3-year-old patient who presented with chronic hemoglobin oxygen desaturation, we discuss a decision making algorithm in order to avoid unnecessary, expensive, and stressful investigations. PMID- 25727476 TI - [A difficult transition from childhood to adult healthcare: the case of epilepsy]. AB - OBJECTIVE: The purpose of this study was to analyze modalities of the transition from pediatric to adult epilepsy care and patients' acquisition of autonomy. METHOD: This study was conducted using semidirected interviews composed of three major parts: the patient's criteria of transition toward adult healthcare (factors taken into account, anticipation, the patient's opinion, etc.), conditions (teamwork with the neurologists, transmission of the medical record, continuity of health care, etc.), and the role played by social workers and psychologists. We interviewed 10 doctors belonging to six major Parisian hospital units involved in the monitoring of children and adolescents with epilepsy and working in Pediatric Neurology Departments of the Ile-de-France region. RESULTS: For most of the doctors, reaching 18 years of age was the major argument taken into account to consider transition to adult care. According to the doctors interviewed, parents are generally worried when their child has to find another doctor (7/10). According to eight out of 10 doctors, the neurologist is selected to take over. The doctors recognize the importance of psychologists and social workers even if they are not always included. The process by which the patient gains autonomy depends a great deal on the role played by the pediatricians and parents, although some parents are very protective. This behavior weakens the patient's capacity for autonomy and it varies according to the degree of his or her physical and/or neurological disabilities. Furthermore, developing autonomy requires interdisciplinary work that is not yet fully in place. CONCLUSION: The lack of structures well-adapted to the uniqueness of each patient and the lack of coordination between the various institutions do not favor the acquisition of autonomy. A network that could efficiently respond to the needs of epileptic patients as well as medical care tailored to adolescents would be the answer to this dilemma. PMID- 25727477 TI - A case of cord capillary hemangioma of the spleen: a recently proven true neoplasm. AB - Cord capillary hemangioma (CCH) of the spleen is an extremely rare lesion. Once classified under splenic hamartoma, CCH is now differentiated from hamartoma, as its clonality has recently been proven. Herein, we present the case of an incidentally found CCH, measuring 6 * 5.5 * 5 cm, in a 45-year-old man. He underwent splenectomy and has been recurrence-free for 8 years. Macroscopically, the cut surface of the mass showed a central stellate scar with peripheral interspersed reddish areas of variable sizes and intervening fibrous bands. Microscopically, the mass was well demarcated from the splenic tissue. The macroscopic reddish areas were found to correspond to nodules of various sizes, which were predominantly composed of CD34-expressing capillaries without the presence of CD8-expressing sinuses. The relative proportion of these two types of vessels distinguishes CCH from sclerosing angiomatoid nodular transformation (SANT), as SANT shows the apparent presence of CD8-expressing sinuses. In longstanding cases of SANT, sinuses might become ambiguous and the differences between CCH and SANT might become subtle. Nonetheless, immunohistochemistry should be performed when these conditions are suspected, since accurate distinction is usually achieved as a result. PMID- 25727478 TI - The failure of anxiolytic therapies in early clinical trials: what needs to be done. AB - INTRODUCTION: Anxiety spectrum disorders (ASDs) are highly prevalent psychiatric illnesses that affect millions of people worldwide. Strongly associated with stress, common ASDs include generalized anxiety disorder, panic, social anxiety, phobias and drug-abuse-related anxiety. In addition to ASDs, several other prevalent psychiatric illnesses represent trauma/stressor-related disorders, such as post-traumatic stress disorder and acute stress disorder. Anxiolytic drugs, commonly prescribed to treat ASDs and trauma/stressor-related disorders, form a highly heterogenous group, modulating multiple neurotransmitters and physiological mechanisms. However, overt individual differences in efficacy and the potential for serious side-effects (including addiction and drug interaction) indicate a need for further drug development. Yet, over the past 50 years, there has been relatively little progress in the development of novel anxiolytic medications, especially when promising candidate drugs often fail in early clinical trials. AREAS COVERED: Herein, the authors present recommendations of the Task Force on Anxiolytic Drugs of the International Stress and Behavior Society on how to improve anxiolytic drug discovery. These recommendations cover a wide spectrum of aspects, ranging from methodological improvements to conceptual insights and innovation. EXPERT OPINION: In order to improve the success of anxiolytic drugs in early clinical trials, the goals of preclinical trials may need to be adjusted from a clinical perspective and better synchronized with those of clinical studies. Indeed, it is important to realize that the strategic goals and approaches must be similar if we want to have a smoother transition between phases. PMID- 25727479 TI - The role of Ca(2+) activated Cl(-) channels in blood pressure control. AB - Ca(2+)-activated Cl(-) channels (CaCCs) have numerous functions in the body and are potential players in the control of blood pressure. The CaCCs represent a heterologous group including at least two protein families; TMEM16 and bestrophins. CaCCs expression has been shown in the kidney, the heart and blood vessels. Agonist-stimulated Ca(2+)-activated Cl(-) current is important for secretion in kidney epithelia, generation of a repolarizing current in the heart and amplification of excitation-contraction coupling in vascular smooth muscle cells. Changes in CaCC expression are shown in association with hypertension, kidney cysts, sudden cardiac death and arrhythmias. This review discusses recent advances in studies concerning the role of CaCC for blood pressure control with focus on the kidney, the heart and blood vessels. PMID- 25727480 TI - Cell therapies for treatment of human immunodeficiency virus infection. AB - After the serendipitous discovery of HIV eradication in the "Berlin patient", interest has grown in curing HIV infection by replacing the patient's replication competent blood cells with infection-resistant ones. At the same time, induced pluripotent stem cell technologies and genetic engineering have boosted cell therapy transfer into the clinic. Currently available cell therapy approaches to attempt to cure HIV infection include the following: (1) Transplantation of autologous or allogeneic cells spontaneously resistant or edited to resist HIV infection; (2) Transplantation of autologous T-lymphocytes spontaneously targeting or redirected against HIV; and (3) Transplantation of autologous cells engineered to work as anti-HIV antibody factories. We review here the preliminary results and potential for future applications of these approaches. PMID- 25727481 TI - SMAD3 and SP1/SP3 Transcription Factors Collaborate to Regulate Connective Tissue Growth Factor Gene Expression in Myoblasts in Response to Transforming Growth Factor beta. AB - Fibrotic disorders are characterized by an increase in extracellular matrix protein expression and deposition, Duchene Muscular Dystrophy being one of them. Among the factors that induce fibrosis are Transforming Growth Factor type beta (TGF-beta) and the matricellular protein Connective Tissue Growth Factor (CTGF/CCN2), the latter being a target of the TGF-beta/SMAD signaling pathway and is the responsible for the profibrotic effects of TGF-beta. Both CTGF and TGF are increased in tissues affected by fibrosis but little is known about the regulation of the expression of CTGF mediated by TGF-beta in muscle cells. By using luciferase reporter assays, site directed mutagenesis and specific inhibitors in C2C12 cells; we described a novel SMAD Binding Element (SBE) located in the 5' UTR region of the CTGF gene important for the TGF-beta-mediated expression of CTGF in myoblasts. In addition, our results suggest that additional transcription factor binding sites (TFBS) present in the 5' UTR of the CTGF gene are important for this expression and that SP1/SP3 factors are involved in TGF beta-mediated CTGF expression. PMID- 25727482 TI - In vitro metabolism and stability of the actinide chelating agent 3,4,3-LI(1,2 HOPO). AB - The hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco 2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 min, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of coadministered drugs metabolized by these enzymes. Plasma protein-binding assays revealed that the compound is protein bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37 degrees C in mouse, rat, dog, and human plasma samples. Finally, a bidirectional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies. PMID- 25727483 TI - High-throughput screening of thin-film semiconductor material libraries II: characterization of Fe-W-O libraries. AB - Metal oxides are promising materials for solar water splitting. To identify suitable materials within the ternary system Fe?W?O, thin-film material libraries with combined thickness and compositional gradients were synthesized by combinatorial reactive magnetron sputtering. These libraries (>1000 different samples) were investigated by means of structural and functional high-throughput characterization techniques to establish correlations between composition, crystallinity, morphology, thickness, and photocurrent density in the compositional range between (Fe6 W94 )Ox and (Fe61 W39 )Ox . In addition to the well-known phase WO3 , the binary phase W5 O14 and the ternary phase Fe2 O6 W show enhanced photoelectrochemical activity. The highest photocurrent density of 65 MUA cm(-2) was achieved for the composition (Fe15 W85 )Ox , which contains the W5 O14 phase and has a thickness of 1060 nm. PMID- 25727484 TI - Effects of water content and chain length of n-alkane on the interaction enthalpy between the droplets in water/sodium bis(2-ethylhexyl)-sulfosuccinate/n-alkane microemulsions. AB - The concentration-dependent enthalpies of mixing for water/sodium bis(2 ethylhexyl)-sulfosuccinate (AOT)/n-alkane microemulsions with different water contents omega0 and chain lengths n of n-alkane were determined by isothermal titration microcalorimetry (ITC) and flow-mixing microcalorimetry at 298.15 K and used to calculate the interaction enthalpies (-DeltaH(C)) between the droplets. It was found that -DeltaH(C) increased with omega0, and changed from negative to positive at about omega0 = 10. The investigation of the dependence of -DeltaH(C) on n revealed that the values of -DeltaH(C) were negative and had a minimum for omega0 = 5; while they were positive and had a maximum for omega0 = 15. These phenomena were discussed based on the competition of the overlapping contribution of the surfactant tails between two neighbouring droplets and the penetration contribution of the solvent molecules into the surfactant tails. These results indicated the important role of entropy in the stability of the microemulsion systems. PMID- 25727485 TI - Joining forces: motor control meets mirror neurons: comment on "Grasping synergies: a motor-control approach to the mirror neuron mechanism" by D'Ausilio, Bartoli, and Maffongelli. PMID- 25727486 TI - Identifying biomarker patterns and predictors of inflammation and myocardial stress. AB - BACKGROUND: Regular exercise is recommended to improve outcomes in patients with heart failure. Exercise is known to decrease inflammation and thought to decrease myocardial stress; however, studies of exercise in heart failure have had mixed results on levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hsCRP). A multimarker analysis may help to identify distinct subgroups of patients who respond to exercise. Our primary study objective was to identify common and distinct patterns of change in hsCRP and NT-proBNP and to quantify the influence of exercise therapy on the observed patterns of change. METHODS AND RESULTS: NT-proBNP and hsCRP were assessed in a random sample of 320 participants from the biomarker substudy of HF-ACTION, a randomized clinical trial of exercise training versus usual care in patients with stable and chronic heart failure. Growth mixture modeling was used to identify unique biomarker patterns over 12 months. Three statistically independent and clinically meaningful biomarker patterns of NT-proBNP and hsCRP were identified. Two patterns were combined and compared with the "low/stable" pattern, which was characterized by the lowest levels of NT-proBNP and hsCRP over time. Participants who were taking a loop diuretic and had hypertension or ischemic etiology were ~2 times as likely to be in the "elevated/worsening" biomarker pattern. Participants randomized to the exercise intervention were less likely to be in the elevated/worsening pattern of NT-proBNP and hsCRP (relative risk ratio 0.56, 95% confidence interval 0.32-0.98; P = .04). CONCLUSIONS: Exercise therapy was protective for reducing the frequency of membership in the elevated/worsening biomarker pattern, indicating that exercise may be helpful in delaying the progression of heart failure. PMID- 25727487 TI - Preventive care delivered within Public Dental Service after caries risk assessment of young adults. AB - OBJECTIVES: To study preventive care provided to young adults in relation to their estimated risk category over a 3-year period. METHODS: The amount and type of preventive treatment during 3 years was extracted from the digital dental records of 982 patients attending eight public dental clinics. The baseline caries risk assessment was carried out by the patient's regular team in four classes according to a predetermined model, and the team was responsible for all treatment decisions. Based on the variables 'oral health information', 'additional fluoride' and 'professional tooth cleaning', a cumulative score was constructed and dichotomized to 'basic prevention' and 'additional prevention'. RESULTS: More additional preventive care was provided to the patients in the 'low risk' and 'some risk' categories than to those classified as 'high' or 'very high' risk (OR = 2.0, 95% CI 1.4-3.0; P < 0.05). Professional tooth cleaning and additional fluorides were most frequently employed in the 'low-risk' and 'some risk' categories, respectively. Around 15% of the patients in the high-risk categories did not receive additional preventive measures over the 3-year period. There was an insignificant tendency that patients with additional prevention developed less caries than those that received basic prevention in all risk categories except for the 'very high-risk' group. CONCLUSION: The caries risk assessment process was not accompanied by a corresponding targeted individual preventive care in a cohort of young adults attending public dental service. Further research is needed how to reach those with the greatest need of primary and secondary prevention. PMID- 25727488 TI - Temporal distributions and environmental adaptations of two types of multicellular magnetotactic prokaryote in the sediments of Lake Yuehu, China. AB - Two morphotypes (spherical and ellipsoidal) of multicellular magnetotactic prokaryotes (MMPs) have been reported from the sediments of Lake Yuehu, China. Here, their temporal distributions and their relationships with biogeochemical parameters are studied. Samples were collected at approximately 2-week intervals from two sites (A and B) during the period September 2012 to December 2013. The abundance of MMPs was high in summer and autumn, but low in winter and spring. Furthermore, the peaks in the numbers of the two types of MMPs were sequential, with the highest concentration of the spherical MMPs occurring prior to that of the ellipsoidal MMPs. This may be related to different optimal growth temperatures for the two types. Although the two types of MMP coexisted at both sites, their numbers were different; at most times, spherical MMPs dominated at site A, whereas ellipsoidal MMPs dominated at site B. Geochemical analysis revealed that the environmental conditions at site A varied more than at site B. Compared with the widely distributed spherical MMPs, ellipsoidal MMPs seemed to prefer more stable habitats. This is the first report of the temporal distribution of ellipsoidal MMPs in sediments, suggesting that their environmental adaptations differ from those of spherical MMPs. PMID- 25727489 TI - Validity and reliability of the T-Scan((r)) III for measuring force under laboratory conditions. AB - Although measuring bite force is an important indicator of the health of the masticatory system, few commercially available transducers have been validated for routine clinical use. T-Scan((r)) III Occlusal Analysis System allows to record the bite force distribution, indicating its relative intensity and occlusal timing. Nevertheless, even fewer studies have evaluated the validity and reliability of the latest generation of the T-Scan((r)) occlusal analysis system. To determine the validity and reliability of the T-Scan((r)) III system when measuring total absolute bite force under laboratory conditions. Known forces were applied to 18 T-Scan((r)) III sensors, which were classified into two groups differentiated by their production series. Both Lin's concordance correlation coefficient (CCC) and the intra-class correlation coefficient (ICC) were used to assess the system's reliability and validity. Considering all the sensors studied, a substantial level (Lin's CCC 0.969) and a very good level of reliability (CCI 0.994) were obtained. When evaluating the validity of the system, a poor (Lin's CCC 0.530) and moderate (ICC 0.693) agreement were also obtained. The main factor that negatively influenced the validity of the T Scan((r)) III under these study conditions was the significant difference in the behaviour of the two sensor groups. The T-Scan((r)) III showed a high degree of reliability when used to perform consecutive measurements. However, the system showed an insufficient degree of validity for measuring absolute force when estimating total occlusal force under laboratory conditions. PMID- 25727490 TI - From Profusion to Confusion: The Saga of Managing Hypertension in Chronic Kidney Disease! PMID- 25727491 TI - The shape of the face template: geometric distortions of faces and their detection in natural scenes. AB - Human face detection might be driven by skin-coloured face-shaped templates. To explore this idea, this study compared the detection of faces for which the natural height-to-width ratios were preserved with distorted faces that were stretched vertically or horizontally. The impact of stretching on detection performance was not obvious when faces were equated to their unstretched counterparts in terms of their height or width dimension (Experiment 1). However, stretching impaired detection when the original and distorted faces were matched for their surface area (Experiment 2), and this was found with both vertically and horizontally stretched faces (Experiment 3). This effect was evident in accuracy, response times, and also observers' eye movements to faces. These findings demonstrate that height-to-width ratios are an important component of the cognitive template for face detection. The results also highlight important differences between face detection and face recognition. PMID- 25727492 TI - Effective alignment of RNA pseudoknot structures using partition function posterior log-odds scores. AB - BACKGROUND: RNA pseudoknots play important roles in many biological processes. Previous methods for comparative pseudoknot analysis mainly focus on simultaneous folding and alignment of RNA sequences. Little work has been done to align two known RNA secondary structures with pseudoknots taking into account both sequence and structure information of the two RNAs. RESULTS: In this article we present a novel method for aligning two known RNA secondary structures with pseudoknots. We adopt the partition function methodology to calculate the posterior log-odds scores of the alignments between bases or base pairs of the two RNAs with a dynamic programming algorithm. The posterior log-odds scores are then used to calculate the expected accuracy of an alignment between the RNAs. The goal is to find an optimal alignment with the maximum expected accuracy. We present a heuristic to achieve this goal. The performance of our method is investigated and compared with existing tools for RNA structure alignment. An extension of the method to multiple alignment of pseudoknot structures is also discussed. CONCLUSIONS: The method described here has been implemented in a tool named RKalign, which is freely accessible on the Internet. As more and more pseudoknots are revealed, collected and stored in public databases, we anticipate a tool like RKalign will play a significant role in data comparison, annotation, analysis, and retrieval in these databases. PMID- 25727493 TI - Functional Outcome and Graft Retention in Patients With Septic Arthritis After Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - PURPOSE: To provide a comprehensive review of clinical and functional outcomes after treatment for septic arthritis after anterior cruciate ligament reconstruction. METHODS: A systematic review of the literature was performed. Two reviewers assessed and confirmed the methodologic quality of each study. Studies that met the inclusion criteria were assessed for pertinent data, and when available, similar outcomes were combined to generate frequency-weighted means. RESULTS: Nineteen studies met the inclusion and exclusion criteria for this review, reporting on a total of 203 infected knees. The mean age was 27.5 years and the mean length of follow-up was 44.2 months, with male patients comprising 88% of the population. Hamstring and bone-patellar tendon-bone autografts were used in 63% and 33% of patients, respectively, with 78% of patients retaining their grafts. The studies reported mean flexion and extension deficits of 5.8 degrees and 1.0 degrees , respectively, and laxity testing showed a mean difference of 1.9 mm. The studies reported mean Lysholm, International Knee Documentation Committee, and Tegner scores of 82.1, 68.2, and 5.6, respectively. Of the patients, 83% reported an ability to return to activities of daily living whereas 67% reported a return to their preinjury level of athletics. Evidence of new degenerative changes was seen in 22% of patients. CONCLUSIONS: Septic arthritis after anterior cruciate ligament reconstruction remains a very infrequent event, affecting 0.5% of patients. On average, outcomes in these patients are comparable with those in patients in whom infection does not develop, including postoperative range of motion, residual instability, Lysholm scores, and return to preinjury level of activity. These patients do exhibit decreased International Knee Documentation Committee scores compared with patients without septic arthritis, however. The impact of this differential is not clear, but this scoring difference suggests that septic arthritis may be associated with more severe symptoms and reduced functional outcomes. In addition, there is limited evidence suggesting that septic arthritis leads to early degenerative changes found on imaging. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 25727494 TI - Intervention frameworks for offender populations. PMID- 25727496 TI - Multiple conformational states of riboswitches fine-tune gene regulation. AB - Riboswitches are structured regions of mRNAs that modulate gene expression in response to specific binding of low molecular-weight ligands. They function by induced transitions between different functional conformations. The standard model assumed that the two functional states, the ligand-bound and ligand-free state, populated only two stable conformations. Recent discoveries of multiple conformations for the apo-state and holo-state of riboswitches challenge this model. Moreover, it becomes evident that detected conformational heterogeneity- mostly in the apo-state--provides sensitivity to multiple environmental inputs for riboswitch-based gene-regulation. PMID- 25727497 TI - Anatomy of the clitoris and the female sexual response. AB - The clitoris may be the most pivotal structure for female sexual pleasure. While its significance has been reported for hundreds of years, no complete anatomical description was available until recently. Most of the components of the clitoris are buried under the skin and connective tissues of the vulva. It comprises an external glans and hood, and an internal body, root, crura, and bulbs; its overall size is 9-11 cm. Clitoral somatic innervation is via the dorsal nerve of the clitoris, a branch of the pudendal nerve, while other neuronal networks within the structure are complex. The clitoris is the center for orgasmic response and is embryologically homologous to the male penis. While the source of vaginal eroticism might or might not be exclusively clitoral stimulation, it is necessary to understand the intricate anatomy of the organ to assess the data in this regard. Ultimately, sexual enjoyment entails a balance of physical and emotional factors and should be encouraged. PMID- 25727495 TI - Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. AB - Lysosomal phospholipase A2 (LPLA2) and lecithin:cholesterol acyltransferase (LCAT) belong to a structurally uncharacterized family of key lipid-metabolizing enzymes responsible for lung surfactant catabolism and for reverse cholesterol transport, respectively. Whereas LPLA2 is predicted to underlie the development of drug-induced phospholipidosis, somatic mutations in LCAT cause fish eye disease and familial LCAT deficiency. Here we describe several high-resolution crystal structures of human LPLA2 and a low-resolution structure of LCAT that confirms its close structural relationship to LPLA2. Insertions in the alpha/beta hydrolase core of LPLA2 form domains that are responsible for membrane interaction and binding the acyl chains and head groups of phospholipid substrates. The LCAT structure suggests the molecular basis underlying human disease for most of the known LCAT missense mutations, and paves the way for rational development of new therapeutics to treat LCAT deficiency, atherosclerosis and acute coronary syndrome. PMID- 25727498 TI - Evaluation of an intact, an ACL-deficient, and a reconstructed human knee joint finite element model. AB - The human knee joint has a three-dimensional geometry with multiple body articulations that produce complex mechanical responses under loads that occur in everyday life and sports activities. Understanding the complex mechanical interactions of these load-bearing structures is of use when the treatment of relevant diseases is evaluated and assisting devices are designed. The anterior cruciate ligament (ACL) in the knee is one of four main ligaments that connects the femur to the tibia and is often torn during sudden twisting motions, resulting in knee instability. The objective of this work is to study the mechanical behavior of the human knee joint and evaluate the differences in its response for three different states, i.e., intact, ACL-deficient, and surgically treated (reconstructed) knee. The finite element models corresponding to these states were developed. For the reconstructed model, a novel repair device was developed and patented by the author in previous work. Static load cases were applied, as have already been presented in a previous work, in order to compare the calculated results produced by the two models the ACL-deficient and the surgically reconstructed knee joint, under the exact same loading conditions. Displacements were calculated in different directions for the load cases studied and were found to be very close to those from previous modeling work and were in good agreement with experimental data presented in literature. The developed finite element model for both the intact and the ACL-deficient human knee joint is a reliable tool to study the kinematics of the human knee, as results of this study show. In addition, the reconstructed human knee joint model had kinematic behavior similar to the intact knee joint, showing that such reconstruction devices can restore human knee stability to an adequate extent. PMID- 25727499 TI - Orientational preference of long, multicenter bonds in radical anion dimers: a case study of pi-[TCNB]2 (2-) and pi-[TCNP]2 (2.). AB - The similar shape and electronic structure of the radical anions of 1,2,4,5 tetracyanopyrazine (TCNP) and 1,2,4,5-tetracyanobenzene (TCNB) suggest a similar relative orientation for their long, multicenter carbon-carbon bond in pi-[TCNP]2 (2-) and in pi-[TCNB]2 (2-) , in good accord with the Maximin Principle predictions. Instead, the two known structures of pi-[TCNP]2 (2-) have a D2h (theta=0 degrees ) and a C2 (theta=30 degrees ) orientation (theta being the dihedral angle that determines the rotation of one radical anion relative to the other along the axis that passes through center of the two six-membered rings). The only known pi-[TCNB]2 (2-) structure has a C2 (theta=60 degrees ) orientation. The origin of these preferences was investigated for both dimers by computing (at the RASPT2/RASSCF(30,28) level) the variation with theta of the interaction energy (Eint ) and the variation of the Eint components. It was found that: 1) a long, multicenter bond exists for all orientations; 2) the Eint (theta) angular dependence is similar in both dimers; 3) for all orientations the electrostatic component dominates the value of Eint (theta), although the dispersion and bonding components also play a relevant role; and 4) the Maximin Principle curve reproduces well the shape of the Eint (theta) curve for isolated dimers, although none of them reproduce the experimental preferences. Only after the (radical anion)(.-) ???cation(+) interactions are also included in the model aggregate are the experimental data reproduced computationally. PMID- 25727500 TI - Pharmaceuticals and society: power, promises and prospects. PMID- 25727501 TI - Abstracts of the 49th Annual Scientific Meeting of the Vascular Society of Great Britain and Ireland, November 26-28, 2015. PMID- 25727502 TI - Dissociative experiences in epilepsy: effects of epilepsy-related factors on pathological dissociation. AB - Psychogenic nonepileptic seizures (PNESs) in patients with epilepsy can be categorized as dissociative disorders. The prevalence of PNESs in patients with epilepsy appears to be much higher than that of dissociative experiences in nonclinical subjects. In order to clarify as to whether epilepsy-related factors were associated with pathological dissociation, we conducted a controlled study with 225 patients with epilepsy and 334 nonclinically matched individuals. All participants completed the Japanese version of the Dissociative Experiences Scale (DES). There was no significant difference in the DES score (DES-S) between the group with epilepsy and the control group. The group with epilepsy showed a significantly higher DES taxon (DES-T; a subset of DES-S and an index of pathological dissociation) than the control group. Thirty-one out of the 225 patients with epilepsy (13.8%) had PNESs. Because of its strong association with the DES-S and DES-T, PNESs can be regarded as a symptom of dissociation. With multiple regression analysis, the patients with a shorter duration of epilepsy, higher seizure frequency, or shorter period in education tend to suffer from pathological dissociation. These findings demonstrate that patients with epilepsy are more prone to experiencing pathological dissociation when having certain clinical factors. PMID- 25727503 TI - Decoupled distance-decay patterns between dsrA and 16S rRNA genes among salt marsh sulfate-reducing bacteria. AB - In many habitats, microorganisms exhibit significant distance-decay patterns as determined by analysis of the 16S rRNA gene and various other genetic elements. However, there have been few studies that examine how the similarities of both taxonomic and functional genes co-vary over geographic distance within a group of ecologically related microbes. Here, we determined the biogeographic patterns of the functional dissimilatory sulfite reductase gene (dsrA) and the 16S rRNA gene in sulfate-reducing bacterial communities of US East Coast salt marsh sediments. Distance-decay, ordination and statistical analyses revealed that the distribution of 16S rRNA genes is strongly influenced by geographic distance and environmental factors, whereas the dsrA gene is not. Together, our results indicate that 16S rRNA genes are likely dispersal limited and under environmental selection, whereas dsrA genes appear randomly distributed and not selected for by any expected environmental variables. Selection, drift, dispersal and mutation are all factors that may help explain the decoupled biogeographic patterns for the two genes. These data suggest that both the taxonomic and functional elements of microbial communities should be considered in future studies of microbial biogeography to aid in our understanding of the diversity, distribution and function of microorganisms in the environment. PMID- 25727504 TI - Pediatric neurocritical care. Introduction. PMID- 25727505 TI - Interdisciplinary approach to neurocritical care in the intensive care nursery. AB - Neurocritical care is a multidisciplinary subspecialty that combines expertise in critical care medicine, neurology, and neurosurgery, and has led to improved outcomes in adults who have critical illnesses. Advances in resuscitation and critical care have led to high rates of survival among neonates with life threatening conditions such as perinatal asphyxia, extreme prematurity, and congenital malformations. The sequelae of neurologic conditions arising in the neonatal period include lifelong disabilities such as cerebral palsy and epilepsy, as well as intellectual and behavioral disabilities. Centers of excellence have adapted the principles of neurocritical care to reflect the needs of the developing newborn brain, including early involvement of a neurologist for recognition and treatment of neurologic conditions, attention to physiology to help prevent secondary brain injury, a protocol-driven approach for common conditions like seizures and hypoxic-ischemic encephalopathy, and education of specialized teams that use brain monitoring and imaging to evaluate the effect of critical illness on brain function and development. PMID- 25727506 TI - Building a pediatric neurocritical care program: a multidisciplinary approach to clinical practice and education from the intensive care unit to the outpatient clinic. AB - We describe our 10-year experience developing the Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program at Northwestern University Feinberg School of Medicine. The neurocritical care team includes intensivists, neurologists, and an advanced practice nurse who have expertise in critical care neurology and who continue care in long-term follow-up of intensive care unit patients in a dedicated neurocritical care outpatient clinic. Brain-directed critical care requires collaboration between intensivists and neurologists with specific expertise in neurocritical care, using protocol-directed consistent care, and physiological measures to protect brain function. The heterogeneity of neurologic disorders in the pediatric intensive care unit requires a background in the relevant basic science and pathophysiology that is beyond the scope of standard neurology or critical care fellowships. To address this need, we also created a fellowship in neurocritical care for intensivists, neurologists, and advanced practice nurses. Last, we discuss the implications for pediatric neurocritical care from the experience of management of pediatric stroke and the development of stroke centers. PMID- 25727507 TI - Intracranial pressure and cerebrovascular autoregulation in pediatric critical illness. AB - Protecting the brain in vulnerable infants and children with critical illness involving the brain is a central aspect of pediatric intensive care and neurocritical care. Collectively, illness-induced derangements in intracranial pressure, circulatory homeostasis, and pressure autoregulation are all fundamental in informing bedside management. Therefore, this review provides an understanding of these entities and a physiological approach to bedside care and monitoring. PMID- 25727509 TI - Evidence-based assessment of severe pediatric traumatic brain injury and emergent neurocritical care. AB - Pediatric traumatic brain injury accounts for approximately 474,000 emergency department visits, 37,000 hospitalizations, and 3,000 deaths in children 14 years and younger annually in the United States. Acute neurocritical care in children has advanced with specialized pediatric trauma centers and emergency medical services. This article reviews pediatric-specific diagnosis, management, and medical decision making related to the neurocritical care of severe traumatic brain injury. PMID- 25727510 TI - Evaluation and treatment of autoimmune neurologic disorders in the pediatric intensive care unit. AB - Autoimmunity is being increasingly recognized as a cause of neurologic presentations both inside and outside the intensive care unit (ICU) setting. Pediatric autoimmune neurologic diseases likely to be seen in the ICU include autoimmune encephalitidies such as N-Methyl-D-aspartate (NMDA) receptor encephalitis, central nervous system vasculitis, demyelinating disorders, and neurologic involvement of systemic autoimmune disorders. In addition, there are conditions of suspected autoimmune etiology such as febrile infection-related epilepsy syndrome (FIRES) and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) syndrome that are rare, but when they do present, it is often to the ICU. Refractory seizures, altered mental status, and disordered breathing are the most common indications for intensive care for these patients. PMID- 25727511 TI - Multimodal monitoring in the pediatric intensive care unit: new modalities and informatics challenges. AB - We review several newer modalities to monitor the brain in children with acute neurologic disease in the pediatric intensive care unit, such as partial brain tissue oxygen tension (PbtO2), jugular venous oxygen saturation (SjvO2), near infrared spectroscopy (NIRS), thermal diffusion measurement of cerebral blood flow, cerebral microdialysis, and EEG. We then discuss the informatics challenges to acquire, consolidate, analyze, and display the data. Acquisition includes multiple data types: discrete, waveform, and continuous. Consolidation requires device interoperability and time synchronization. Analysis could include pressure reactivity index and quantitative EEG. Displays should communicate the patient's current status, longitudinal and trend information, and critical alarms. PMID- 25727508 TI - Status epilepticus and refractory status epilepticus management. AB - Status epilepticus (SE) describes persistent or recurring seizures without a return to baseline mental status and is a common neurologic emergency. SE can occur in the context of epilepsy or may be symptomatic of a wide range of underlying etiologies. The clinician's aim is to rapidly institute care that simultaneously stabilizes the patient medically, identifies and manages any precipitant conditions, and terminates seizures. Seizure management involves "emergent" treatment with benzodiazepines followed by "urgent" therapy with other antiseizure medications. If seizures persist, then refractory SE is diagnosed and management options include additional antiseizure medications or infusions of midazolam or pentobarbital. This article reviews the management of pediatric SE and refractory SE. PMID- 25727512 TI - The practice of pediatric neurocritical care by the child neurologist. AB - Pediatric neurocritical care (NCC) has emerged as a defined subspecialty in child neurology and requires a collaborative effort among child neurologists, pediatric critical care medicine specialists, and pediatric neurosurgeons. Pediatric NCC has evolved differently in children than in adults, and its delivery depends on the local resources available for pediatric care. This article reviews the current practice of pediatric NCC by child neurologists: where it is practiced, how it is practiced, the disorders encountered (that differ from adult NCC), the training required to care for these disorders, and what is needed for the future of pediatric NCC. PMID- 25727513 TI - Development of an enzymatic assay to measure lactate in perchloric acid precipitated whole blood. AB - BACKGROUND: The lactate to pyruvate (L:P) ratio is used to identify the cause of a lactic acidosis. Because tests for whole blood lactate and pyruvate require different sample types, the accuracy of the L:P ratio may be compromised by preanalytical errors. The measurement of lactate in the sample required for pyruvate is desirable. METHODS: Whole blood was added to 8% perchloric acid to obtain a protein-free supernatant. Lactate was measured by its oxidation to pyruvate and hydrogen peroxide by lactate oxidase. Assay accuracy, imprecision, analytical sensitivity, linearity, analyte stability, and a reference interval were determined. RESULTS: Deming regression of lactate results from paired plasma and supernatant produced a slope of 0.95 and y-intercept of -0.37 mmol/l (R(2)=0.95). Recovery of lactate added to supernatant ranged from 103.4 to 112.7%. Within-laboratory CVs were 6.1% and 1.1% at 1.58 and 10.89 mmol/l, respectively and between-day CVs were 2.3% and 0.9%, respectively. The limit-of detection was 0.18 mmol/l and the assay was linear to 13.15 mmol/l. Lactate in the supernatant was stable for a minimum of 8h, 21 days, or 6 months at room temperature, 4-8 degrees C, and -20 degrees C, respectively. The lactate reference interval was 0.31-2.00 mmol/l from 116 healthy adults. CONCLUSIONS: Lactate can be quantified in the same protein-free supernatant used for the measurement of pyruvate allowing the calculation of the L:P ratio from a single specimen. PMID- 25727514 TI - Proton nuclear magnetic resonance spectroscopy of urine samples in preterm asphyctic newborn: a metabolomic approach. AB - In order to highlight differences in the metabolic profile of healthy (control) compared with asphyxiated newborns, by using untargeted metabolomic approach coupled with (1)H NMR spectroscopy, we evaluated the effects of asphyxia on newborn urine metabolites. Our results showed that lactate, glucose and TMAO, together with threonine plus 3-hydroxyisovalerate are the metabolites more characterizing the asphyxiated group; lower contribute to discrimination is related to other metabolites such as dimethylglycine, dimethylamine, creatine, succinate, formate, urea and aconitate. After 24-48h from resuscitation preterm asphyctic neonates showed their recovery pattern that still can be differentiated by the controls. PMID- 25727515 TI - A rapid and accurate closed-tube Methylation-Sensitive High Resolution Melting Analysis assay for the semi-quantitative determination of SOX17 promoter methylation in clinical samples. AB - INTRODUCTION: SOX17 promoter methylation can provide important prognostic information in cancer. We developed a novel semi-quantitative MS-HRMA assay for SOX17 promoter methylation. METHODS: The assay was optimized by using synthetic control samples and validated by analyzing 165 clinical samples: a) 107 formalin fixed paraffin embedded (FFPEs) samples of patients with early breast cancer, b) 27 FFPE samples of patients with metastatic breast cancer, c) 15 reduction mammoplasty specimens obtained from healthy women and d) 16 genomic DNA samples isolated from healthy blood donors. Comparison with real time MSP was also performed. RESULTS: The assay is highly specific and sensitive and provides a semi-quantitative estimation of SOX17 promoter methylation. SOX17 promoter was found methylated in 96/134 (71.6%) breast cancer samples, while none of the 31 non-cancerous samples tested was positive (0%). SOX17 promoter methylation levels varied significantly among samples. When 165 clinical samples were analyzed both by MS-HRMA and real time MSP results were significantly comparable (concordance: 146/165, 88.5%). CONCLUSIONS: This novel MS-HRMA assay for SOX17 promoter methylation is closed-tube, highly sensitive, specific, cost-effective, rapid and easy-to-perform. It gives comparable results to Real-Time MSP in less time, while it offers the advantage of additionally providing an estimation of SOX17 promoter methylation levels. PMID- 25727516 TI - Absolute quantitative PCR for detection of molecular biomarkers in melanoma patients: a preliminary report. AB - BACKGROUND: Malignant melanoma is the most malignant tumours of skin and mucous membranes mainly due to its aggressive biological behaviour and tendency to generate early metastases. Unfortunately, the mechanisms underlying the development, progression and the expression of an aggressive melanoma phenotype still remain largely unknown. OBJECTIVES: The purpose of this study was to determine whether a multi-panel of molecular transcripts can be predictive for risk of recurrent disease in malignant melanoma patients. RESULTS: Peripheral blood was collected from 31 malignant melanoma patients in follow-up for melanoma and from 30 healthy volunteers randomly selected. Each specimen was examined by qRT-PCR analysis for the expression of six markers: PAX3d, TYR, MITFm, MCAM, TGFbeta2 and ABCB5. Malignant melanoma patients expressed an important number of markers, with a median value of four markers. Only PAX3d displayed a trend in terms of differences when the levels of gene expression were made in function of Breslow index. Furthermore, PAX3d showed the best diagnostic capacity among the remaining residual markers or in combination with TGFbeta2 and MTIF. CONCLUSIONS: We demonstrated the usefulness of multimarker qRT-PCR to detect circulating melanoma cells in blood and to potentially assessing patient disease status or progression, especially when PAX3d was used in combination with MTIFm and TGFbeta2. PMID- 25727517 TI - Spatial analysis of environment and population at risk of natural gas fracking in the state of Pennsylvania, USA. AB - Hydraulic fracturing, also known as fracking, has been increasing exponentially across the United States, which holds the largest known shale gas reserves in the world. Studies have found that the high-volume horizontal hydraulic fracturing process (HVHFP) threatens water resources, harms air quality, changes landscapes, and damages ecosystems. However, there is minimal research focusing on the spatial study of environmental and human risks of HVHFP, which is necessary for state and federal governments to administer, regulate, and assess fracking. Integrating GIS and spatial kernel functions, we study the presently operating fracking wells across the state of Pennsylvania (PA), which is the main part of the current hottest Marcellus Shale in US. We geographically process the location data of hydraulic fracturing wells, 2010 census block data, urbanized region data, railway data, local road data, open water data, river data, and wetland data for the state of PA. From this we develop a distance based risk assessment in order to understand the environmental and urban risks. We generate the surface data of fracking well intensity and population intensity by integrating spatial dependence, semivariogram modeling, and a quadratic kernel function. The surface data of population risk generated by the division of fracking well intensity and population intensity provide a novel insight into the local and regional regulation of hydraulic fracturing activities in terms of environmental and health related risks due to the proximity of fracking wells. PMID- 25727518 TI - Oxidative stress biomarkers in long-term participants in clean-up work after the Hebei Spirit oil spill. AB - BACKGROUND: The oil tanker Hebei Spirit spilled 12,547kL of oil near the western coastline of Korea on December 7, 2007. We aimed to investigate the relationship between oil spill exposure and oxidative stress in residents living near the affected area. METHODS: Study subjects were 671 residents who participated in a health examination between February and September 2009. As surrogates for oil spill exposure, we used the total duration of clean-up work and levels of urinary metabolites of polycyclic aromatic hydrocarbons (PAHs), 1-hydroxypyrene (1-OHP) and 2-naphthol (2-NAPH). Oxidative stress was measured using urinary levels of malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), indicators of lipid peroxidation and oxidative DNA damage, respectively. RESULTS: Levels of oxidative stress biomarkers were significantly increased with longer involvement in clean-up work over one year after the Hebei Spirit oil spill (MDA, p trend<0.0001; 8-OHdG, p-trend<0.0001). As more time elapsed since the last involvement in clean-up, the total duration of clean-up work participation and levels of PAH metabolites (1-OHP and 2-NAPH), as well as levels of the oxidative stress biomarkers (MDA and 8-OHdG) decreased further. The level of 1-OHP had a significant positive correlation with the total duration of clean-up work involvement, with a higher level found in those who participated in clean-up for >100 days. Increasing levels of 1-OHP were significantly associated with increased MDA and 8-OHdG after adjusting for covariates, while the strength of association weakened as time passed since the last participation in clean-up work. The significance of the association was maintained for up to 12 months after the last clean-up work. CONCLUSIONS: The results suggested that oil exposure from prolonged clean-up activity likely induced oxidative stress in clean-up participants up to at least one year after the last exposure. PMID- 25727519 TI - Fibular taping does not alter lower extremity spinal reflex excitability in individuals with chronic ankle instability. AB - OBJECTIVE: To determine changes in spinal reflex excitability of the soleus and fibularis longus muscles before and after fibular taping intervention. METHODS: Twenty-one individuals (age = 23.4 +/- 2.7 y, height = 171.0 +/- 12.8 cm, mass = 69.7 +/- 11.8 kg) with chronic ankle instability (CAI) and at least 5 degrees ankle dorsiflexion asymmetry volunteered for this randomised crossover design study. Each participant received a fibular taping with tension or fibular taping without tension during separate sessions. Spinal reflex excitability of the soleus and fibularis longus was determined by obtaining maximum values for H reflex (Hoffmann reflex) and maximum compound muscle action potential (Mmax), which was expressed as a ratio (H/M ratio). Measures were obtained immediately before and after a fibular taping intervention. RESULTS: The application of tape to the fibula, regardless of tension, did not produce a change in spinal reflex excitability for the soleus (F1,39 = .01, P = .91) or fibularis longus (F1,39 = .001, P = .99). CONCLUSIONS: Fibular taping with and without tension did not result in an immediate change in spinal reflex excitability of the soleus or fibularis longus in individuals with CAI. Although fibular taping has been shown to reduce recurrent ankle sprains in individuals with CAI, the mechanism of effectiveness may not involve an immediate increase in spinal reflex excitability. PMID- 25727521 TI - A meta-analysis of criterion effects for the Implicit Relational Assessment Procedure (IRAP) in the clinical domain. AB - BACKGROUND AND OBJECTIVES: The Implicit Relational Assessment Procedure (IRAP) is a technique that is attracting a substantial body of research literature, particularly within the clinical domain. METHOD: In response, the present paper outlines a meta-analysis of clinically-focused IRAP effects (N = 494) to provide the first estimate of how well such effects validate against their respective criterion variables in general. RESULTS: The meta-analysis incorporated clinically-focused IRAP effects from 15 studies yielding a large effect size, r- = .45, with a desirably narrow 95% credibility interval (.23, .67). The funnel plot and subsequent sensitivity analyses indicated that this meta-effect was not subject to publication bias. LIMITATIONS: The present meta-effect is an estimate based upon an IRAP literature that is still evolving rapidly in the clinical domain, and so as per its accompanying credibility interval, all conclusions that follow are necessarily provisional even if bounded. Apart from the fact that the current meta-effect might be subject to inadvertent under- and/or over estimations of the current literature, the present meta-effect might strengthen with further refinements of the IRAP. CONCLUSIONS: The current meta-effect provides the means to calculate what sample size would be required to achieve a statistical power of .80 when testing the criterion validity of clinically focused IRAP effects using a given parametric statistic. For example, first-order Pearson correlations would hypothetically require an N of 29-37 for such purposes depending upon how conservatively over-estimation of the present meta-effect is controlled for. Overall, the IRAP compares favourably with alternative implicit measures in clinical psychology. PMID- 25727520 TI - GSK3 inhibitors CHIR99021 and 6-bromoindirubin-3'-oxime inhibit microRNA maturation in mouse embryonic stem cells. AB - Wnt/beta-catenin signalling plays a prominent role in maintaining self-renewal and pluripotency of mouse embryonic stem cells (mESCs). microRNAs (miRNAs) have critical roles in maintaining pluripotency and directing reprogramming. To investigate the effect of GSK3 inhibitors on miRNA expression, we analysed the miRNA expression profile of J1 mESCs in the absence or presence of CHIR99021 (CHIR) or 6-bromoindirubin-3'-oxime (BIO) by small RNA deep-sequencing. The results demonstrate that CHIR and BIO decrease mature miRNAs of most miRNA species, 90.4% and 98.1% of the differentially expressed miRNAs in BIO and CHIR treated cells were downregulated respectively. CHIR and BIO treatment leads to a slight upregulation of the primary transcripts of the miR-302-367 cluster and miR 181 family of miRNAs, these miRNAs are activated by Wnt/beta-catenin signalling. However, the precursor and mature form of the miR-302-367 cluster and miR-181 family of miRNAs are downregulated by CHIR, suggesting CHIR inhibits maturation of primary miRNA. Western blot analysis shows that BIO and CHIR treatment leads to a reduction of the RNase III enzyme Drosha in the nucleus. These data suggest that BIO and CHIR inhibit miRNA maturation by disturbing nuclear localisation of Drosha. Results also show that BIO and CHIR induce miR-211 expression in J1 mESCs. PMID- 25727522 TI - Lifestyle intervention and one-year prognosis of patients following open heart surgery: a randomised clinical trial. AB - AIMS AND OBJECTIVES: To evaluate the one-year prognosis of a lifestyle counselling intervention (diet, smoking cessation and exercise) among patients who had open heart surgery. BACKGROUND: Cardiovascular disease is the leading cause of morbidity worldwide in both developing and developed countries. Lifestyle modification plays an important role for patients who are at a high risk of developing cardiovascular disease and for those with an established cardiovascular disease. DESIGN: Randomised, nonblind and lifestyle counselling intervention study with a one-year follow-up. METHODS: A randomised, nonblind intervention study was performed on 500 patients who had open heart surgery. After hospital discharge, 250 patients (intervention group) were randomly allocated lifestyle counselling according to the recent guidelines provided by the European Society of Cardiology (European Journal Preventive Cardiology, 19, 2012, 585). The remaining 250 patients (control group) received the regular instructions. Primary end-point was the development of a cardiovascular disease (nonfatal event) during the first year; secondary end-points included fatal events, smoking abstinence, dietary habits and a physical activity evaluation. RESULTS: According to the primary end-point, the odds of having a nonfatal cardiovascular disease event are 0.56-times (95%CI 0.28, 0.96, p = 0.03) lower for the intervention group compared to the control group. One-year after surgery, it was found that participants in the intervention group were 1.96-times (95%CI 1.31, 2.93, p < 0.001) more likely to achieve dietary recommendations, 3.32-times (95%CI 2.24, 4.91, p < 0.001) more likely to achieve physical activity recommendations and 1.34-times (95%CI 1.15, 1.56, p < 0.001) more likely to return to work. CONCLUSION: Lifestyle counselling intervention following open heart surgery can improve health outcomes and reduce the risk of a new cardiac event. Health care services must recommend and organise well-structured cardiac rehabilitation programmes adjusted to the patient's needs. RELEVANCE TO CLINICAL PRACTICE: A well-structured cardiac rehabilitation programme adjusted to the patient's profile is a safe and cost-effective way to improve patients' outcome. PMID- 25727524 TI - Differences in pelvic floor morphology between continent, stress urinary incontinent, and mixed urinary incontinent elderly women: An MRI study. AB - AIMS: To compare magnetic resonance imaging (MRI) of the pelvic floor musculature (PFM), bladder neck and urethral sphincter morphology under three conditions (rest, PFM maximal voluntary contraction (MVC), and straining) in older women with symptoms of stress (SUI) or mixed urinary incontinence (MUI) or without incontinence. METHODS: This 2008-2012 exploratory observational cohort study was conducted with community-dwelling women aged 60 and over. Sixty six women (22 per group), mean age of 67.7 +/- 5.2 years, participated in the study. A 3 T MRI examination was conducted under three conditions: rest, PFM MVC, and straining. ANOVA or Kruskal-Wallis tests (data not normally distributed) were conducted, with Bonferroni correction, to compare anatomical measurements between groups. RESULTS: Women with MUI symptoms had a lower PFM resting position (M-Line P = 0.010 and PC/H-line angle P = 0.026) and lower pelvic organ support (urethrovesical junction height P = 0.013) than both continent and SUI women. Women with SUI symptoms were more likely to exhibit bladder neck funneling and a larger posterior urethrovesical angle at rest than both continent and MUI women (P = 0.026 and P = 0.008, respectively). There were no significant differences between groups on PFM MVC or straining. CONCLUSIONS: Women with SUI and MUI symptoms present different morphological defects at rest. These observations emphasize the need to tailor UI interventions to specific pelvic floor defects and UI type in older women. PATIENT SUMMARY: Older women with UI demonstrate different problems with their pelvic organ support structures depending on the type of UI. These new findings should be taken into consideration for future research into developing new treatment strategies for UI in older women. Neurourol. Urodynam. 35:515-521, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25727523 TI - Metabolic and vascular origins of the BOLD effect: Implications for imaging pathology and resting-state brain function. AB - The blood oxygenation level-dependent (BOLD) phenomenon has profoundly revolutionized neuroscience, with applications ranging from normal brain development and aging, to brain disorders and diseases. While the BOLD effect represents an invaluable tool to map brain function, it does not measure neural activity directly; rather, it reflects changes in blood oxygenation resulting from the relative balance between cerebral oxygen metabolism (through neural activity) and oxygen supply (through cerebral blood flow and volume). As such, there are cases in which BOLD signals might be dissociated from neural activity, leading to misleading results. The emphasis of this review is to develop a critical perspective for interpreting BOLD results, through a comprehensive consideration of BOLD's metabolic and vascular underpinnings. We demonstrate that such an understanding is especially important under disease or resting conditions. We also describe state-of-the-art acquisition and analytical techniques to reveal physiological information on the mechanisms underlying measured BOLD signals. With these goals in mind, this review is structured to provide a fundamental understanding of: 1) the physiological and physical sources of the BOLD contrast; 2) the extraction of information regarding oxidative metabolism and cerebrovascular reactivity from the BOLD signal, critical to investigating neuropathology; and 3) the fundamental importance of metabolic and vascular mechanisms for interpreting resting-state BOLD measurements. PMID- 25727525 TI - Discharge performance of solid-state oxygen shuttle metal-air battery using Ca stabilized ZrO2 electrolyte. AB - The effects of metal choice on the electrochemical performance of oxygen-shuttle metal-air batteries with Ca-stabilized ZrO2 (CSZ) as the electrolyte and various metals as the anodes were studied at 1073 K. The equilibrium oxygen partial pressure (P O 2) in the anode chamber was governed by the metal used in the anode chamber. A lower-P O 2 environment in the anode decreased the polarization resistance of the anode. The oxidation of oxide ions to oxygen in the anode is drastically enhanced by the n-type conduction generated in the CSZ electrolyte when it is exposed to a reducing atmosphere. A high discharge potential and high capacity can be achieved in an oxygen-shuttle battery with a Li or Mg anode because of the fast anode reaction compared to that of cells with a Zn, Fe, or Sn anode. However, only the mildly reducing metals (Zn, Si, Fe, and Sn) can potentially be used in rechargeable metal-air batteries because the transport number of the CSZ electrolyte must be unity during charge and discharge. Oxygen shuttle rechargeable batteries with Fe, and Sn electrodes are demonstrated. PMID- 25727526 TI - [Prostate cancer]. AB - The Vall d'Hebron multidisciplinary prostate cancer (PC) team reviews recent advances in the management of this neoplasm. Screening studies with long follow up show a reduction in mortality, whereas active surveillance is emerging as a therapeutic approach of non-aggressive cancers. New markers increase the specificity of PSA and also allow targeting suspected aggressive cancers. Multiparametric magnetic resonance (mMRI) has emerged as the most effective method in the selection of patients for biopsy and also for local tumor staging. The paradigm of random prostatic biopsy is changing through the fusion techniques that allow guiding ultrasonography-driven biopsy of suspicious areas detected in mMRI. Radical prostatectomy (RP) and radiotherapy (RT) are curative treatments of localized PC and both have experienced significant technological improvements. RP is highly effective and the incorporation of robotic surgery is reducing morbidity. Modern RT allows the possibility of high tumor dose with minimal adjacent dose reducing its toxicity. Androgen deprivation therapy with LHRH analogues remains the treatment of choice for advanced PC, but should be limited to this indication. The loss of bone mass and adverse metabolic effects increases the frequency of fractures and cardiovascular morbimortality. After castration resistance in metastatic disease, new hormone-based drugs have demonstrated efficacy even after chemotherapy resistance. PMID- 25727527 TI - Synthesis and Structural Evolution of Nickel-Cobalt Nanoparticles Under H2 and CO2. AB - Bimetallic nanoparticle (NP) catalysts are interesting for the development of selective catalysts in reactions such as the reduction of CO2 by H2 to form hydrocarbons. Here the synthesis of Ni-Co NPs is studied, and the morphological and structural changes resulting from their activation (via oxidation/reduction cycles), and from their operation under reaction conditions, are presented. Using ambient-pressure X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and transmission electron microscopy, it is found that the initial core-shell structure evolves to form a surface alloy due to nickel migration from the core. Interestingly, the core consists of a Ni-rich single crystal and a void with sharp interfaces. Residual phosphorous species, coming from the ligands used for synthesis, are found initially concentrated in the NP core, which later diffuse to the surface. PMID- 25727528 TI - The effect of Fe2O3 and ZnO nanoparticles on cytotoxicity and glucose metabolism in lung epithelial cells. AB - Metallic nanoparticles (NPs) have potential applications in industry and medicine, but they also have the potential to cause many chronic pulmonary diseases. Mechanisms for their cytotoxicity, glucose and energy metabolism responses need to be fully explained in lung epithelial cells after treatment with metallic nanoparticles. In our study, two different metallic nanoparticles (Fe2 O3 and ZnO) and two cell-based assays (BEAS-2B and A549 cell lines) were used. Our findings demonstrate that ZnO nanoparticles, but not Fe2 O3 nanoparticles, induce cell cycle arrest, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial dysfunction and glucose metabolism perturbation, which are responsible for cytotoxicity. These results also suggest that the glucose metabolism and bioenergetics had a great potential in evaluating the cytotoxicity and thus were very helpful in understanding their underlying molecular mechanisms. PMID- 25727529 TI - Medications for first-episode psychosis: making a good start. PMID- 25727530 TI - Genetic investigation of autism-related social communication deficits. PMID- 25727531 TI - Amygdala reactivity as mental health risk endophenotype: a tale of many trajectories. PMID- 25727532 TI - Failure modes of the will: from goals to habits to compulsions? PMID- 25727533 TI - Improvement in psychotic symptoms after a gluten-free diet in a boy with complex autoimmune illness. PMID- 25727534 TI - Psychiatric treatment of a health care worker after infection with Ebola virus in Lagos, Nigeria. PMID- 25727535 TI - The artist, depression, and the mood landscape. PMID- 25727536 TI - Prescription practices in the treatment of first-episode schizophrenia spectrum disorders: data from the national RAISE-ETP study. AB - OBJECTIVE: Treatment guidelines suggest distinctive medication strategies for first-episode and multiepisode patients with schizophrenia. To assess the extent to which community clinicians adjust their usual treatment regimens for first episode patients, the authors examined prescription patterns and factors associated with prescription choice in a national cohort of early-phase patients. METHOD: Prescription data at study entry were obtained from 404 participants in the Recovery After an Initial Schizophrenia Episode Project's Early Treatment Program (RAISE-ETP), a nationwide multisite effectiveness study for patients with first-episode schizophrenia spectrum disorders. Treatment with antipsychotics did not exceed 6 months at study entry. RESULTS: The authors identified 159 patients (39.4% of the sample) who might benefit from changes in their psychotropic prescriptions. Of these, 8.8% received prescriptions for recommended antipsychotics at higher than recommended dosages; 32.1% received prescriptions for olanzapine (often at high dosages), 23.3% for more than one antipsychotic, 36.5% for an antipsychotic and also an antidepressant without a clear indication, 10.1% for psychotropic medications without an antipsychotic, and 1.2% for stimulants. Multivariate analysis showed evidence for sex, age, and insurance status effects on prescription practices. Racial and ethnic effects consistent with effects reported in previous studies of multiepisode patients were found in univariate analyses. Despite some regional variations in prescription practices, no region consistently had different practices from the others. Diagnosis had limited and inconsistent effects. CONCLUSIONS: Besides prescriber education, policy makers may need to consider not only patient factors but also service delivery factors in efforts to improve prescription practices for first-episode schizophrenia patients. PMID- 25727537 TI - Outcomes of nontransitioned cases in a sample at ultra-high risk for psychosis. AB - OBJECTIVE: Two-thirds of individuals identified as at ultra-high risk for psychosis do not develop psychotic disorder over the medium term. The authors examined outcomes in a group of such patients. METHOD: Participants were help seeking individuals identified as being at ultra-high risk for psychosis 2-14 years previously. The 226 participants (125 female, 101 male) completed a follow up assessment and had not developed psychosis. Their mean age at follow-up was 25.5 years (SD=4.8). RESULTS: At follow-up, 28% of the participants reported attenuated psychotic symptoms. Over the follow-up period, 68% experienced nonpsychotic disorders: mood disorder in 49%, anxiety disorder in 35%, and substance use disorder in 29%. For the majority (90%), nonpsychotic disorder was present at baseline, and it persisted for 52% of them. During follow-up, 26% of the cohort had remission of a disorder, but 38% developed a new disorder. Only 7% did not experience any disorder at baseline or during follow up. The incidence of nonpsychotic disorder was associated with more negative symptoms at baseline. Female participants experienced higher rates of persistent or recurrent disorder. Meeting criteria for brief limited intermittent psychotic symptoms at intake was associated with lower risk for persistent or recurrent disorder. CONCLUSIONS: Individuals at ultra-high risk for psychosis who do not transition to psychosis are at significant risk for continued attenuated psychotic symptoms, persistent or recurrent disorders, and incident disorders. Findings have implications for ongoing clinical care. PMID- 25727538 TI - IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk. AB - OBJECTIVE: The authors sought to clarify the relationship between IQ and subsequent risk for schizophrenia. METHOD: IQ was assessed at ages 18-20 in 1,204,983 Swedish males born between 1951 and 1975. Schizophrenia was assessed by hospital diagnosis through 2010. Cox proportional hazards models were used to investigate future risk for schizophrenia in individuals as a function of their IQ score, and then stratified models using pairs of relatives were used to adjust for familial cluster. Finally, regression models were used to examine the interaction between IQ and genetic liability on risk for schizophrenia. RESULTS: IQ had a monotonic relationship with schizophrenia risk across the IQ range, with a mean increase in risk of 3.8% per 1-point decrease in IQ; this association was stronger in the lower than the higher IQ range. Co-relative control analyses showed a similar association between IQ and schizophrenia in the general population and in cousin, half-sibling, and full-sibling pairs. A robust interaction was seen between genetic liability to schizophrenia and IQ in predicting schizophrenia risk. Genetic susceptibility for schizophrenia had a much stronger impact on risk of illness for those with low than high intelligence. The IQ-genetic liability interaction arose largely from IQ differences between close relatives. CONCLUSIONS: IQ assessed in late adolescence is a robust risk factor for subsequent onset of schizophrenia. This association is not the result of a declining IQ associated with insidious onset. In this large, representative sample, we found no evidence for a link between genius and schizophrenia. Co-relative control analyses showed that the association between lower IQ and schizophrenia is not the result of shared familial risk factors and may be causal. The strongest effect was seen with IQ differences within families. High intelligence substantially attenuates the impact of genetic liability on the risk for schizophrenia. PMID- 25727539 TI - Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8. AB - OBJECTIVE: Autism spectrum disorder is characterized by deficits in social function and the presence of repetitive and restrictive behaviors. Following a previous test of principle, the authors adopted a quantitative approach to discovering genes contributing to the broader autism phenotype by using social responsiveness as an endophenotype for autism spectrum disorder. METHOD: Linkage analyses using scores from the Social Responsiveness Scale were performed in 590 families from the Autism Genetic Resource Exchange, a largely multiplex autism spectrum disorder cohort. Regional and genomewide association analyses were performed to search for common variants contributing to social responsiveness. RESULTS: Social Responsiveness Scale scores were unimodally distributed in male offspring from multiplex autism families, in contrast with a bimodal distribution observed in female offspring. In correlated analyses differing by Social Responsiveness Scale respondent, genomewide significant linkage for social responsiveness was identified at chr8p21.3 (multipoint LOD=4.11; teacher/parent scores) and chr8q24.22 (multipoint LOD=4.54; parent-only scores), respectively. Genomewide or linkage-directed association analyses did not detect common variants contributing to social responsiveness. CONCLUSIONS: The sex-differential distributions of Social Responsiveness Scale scores in multiplex autism families likely reflect mechanisms contributing to the sex ratio for autism observed in the general population and form a quantitative signature of reduced penetrance of inherited liability to autism spectrum disorder among females. The identification of two strong loci for social responsiveness validates the endophenotype approach for the identification of genetic variants contributing to complex traits such as autism spectrum disorder. While causal mutations have yet to be identified, these findings are consistent with segregation of rare genetic variants influencing social responsiveness and underscore the increasingly recognized role of rare inherited variants in the genetic architecture of autism spectrum disorder. PMID- 25727540 TI - Differential effectiveness of right unilateral versus bilateral electroconvulsive therapy in resistant bipolar depression. PMID- 25727541 TI - Response to Kotzalidis et al. PMID- 25727542 TI - Electroconvulsive therapy versus pharmacotherapy for bipolar depression. PMID- 25727543 TI - Response to Kellner and Fink. PMID- 25727547 TI - The multiform motor cortical output: Kinematic, predictive and response coding. AB - Observing actions performed by others entails a subliminal activation of primary motor cortex reflecting the components encoded in the observed action. One of the most debated issues concerns the role of this output: Is it a mere replica of the incoming flow of information (kinematic coding), is it oriented to anticipate the forthcoming events (predictive coding) or is it aimed at responding in a suitable fashion to the actions of others (response coding)? The aim of the present study was to disentangle the relative contribution of these three levels and unify them into an integrated view of cortical motor coding. We combined transcranial magnetic stimulation (TMS) and electromyography recordings at different timings to probe the excitability of corticospinal projections to upper and lower limb muscles of participants observing a soccer player performing: (i) a penalty kick straight in their direction and then coming to a full stop, (ii) a penalty kick straight in their direction and then continuing to run, (iii) a penalty kick to the side and then continuing to run. The results show a modulation of the observer's corticospinal excitability in different effectors at different times reflecting a multiplicity of motor coding. The internal replica of the observed action, the predictive activation, and the adaptive integration of congruent and non-congruent responses to the actions of others can coexist in a not mutually exclusive way. Such a view offers reconciliation among different (and apparently divergent) frameworks in action observation literature, and will promote a more complete and integrated understanding of recent findings on motor simulation, motor resonance and automatic imitation. PMID- 25727548 TI - Asymmetrical white matter networks for attending to global versus local features. AB - The ability to draw objects is a complex process depending on an array of cognitive mechanisms including routines for spatial coding, attention and the processing of both local and global features. Previous studies using both neuropsychological and neuroimaging data have reported hemispheric asymmetries in attending to local versus global features linked to a variety of cortical loci. However, it has not been examined to date whether such asymmetries exist at the level of white matter pathways sub-serving global/local attention. The current study provides a comprehensive analysis of brain-behaviour relationships in the processing of local versus global features based on data from a large cohort of sub-acute stroke patients (n = 248) and behavioural measures from a complex figure copy task. The data analysis used newly developed methods for automated delineation of stroke lesions combined with track-wise lesion deficits procedures. We found (i) that reproduction of local features in figure copying was supported by a neural network confined to the left hemisphere, consisting of cortical loci within parietal, occipital and insular lobes and interconnected by the inferior-fronto-occipital fasciculus (IFOF), and (ii) that global feature processing was associated with a right hemisphere network interconnected by the third branch of the superior longitudinal fasciculus and the long segment of the perisylvian network. The data support the argument that asymmetrical white matter disconnections within long-range association pathways predict poor complex figure drawing resulting from deficits in hierarchical representation. We conclude that hemispheric asymmetries in attending to local versus global features exist on the level of both cortical loci and the supporting white matter pathways. PMID- 25727549 TI - Relative efficacy of nucleic acid amplification testing and serologic screening in preventing hepatitis C virus transmission risk in seven international regions. AB - BACKGROUND: The relative contribution of serologic screening and nucleic acid testing (NAT) to prevent hepatitis C virus (HCV) transmission has not been rigorously addressed. STUDY DESIGN AND METHODS: Twenty-one blood organizations in seven geographical regions performing individual-donation (ID)-NAT in parallel with anti-HCV screening provided data from 10,897,105 donations to establish HCV infection rates in first-time, lapsed, and repeat donations. Screening efficacy was modeled for: anti-HCV alone, HCV antigen/antibody (combo), minipool (MP)-NAT in pools of 8 and 16 with anti-HCV, ID-NAT and anti-HCV, and ID-NAT alone. Probabilities of infectivity for red blood cell transfusions were estimated as 100% from window period (WP) and concordant HCV RNA/antibody-positive (concordantly positive [CP]) donations and 0.028% from anti-HCV-positive and RNA negative probable resolved (PR) donations. RESULTS: There were 5146 confirmed infections (30 WP, 3827 CP, and 1289 PR). Infection rates and transmission risks varied substantially across regions and by donation status. Residual risk with ID NAT and serology screening was estimated at one in 250,000 in Egypt and at one in 10,000,000 in other regions combined; risk would increase to one in 7300 and one in 312,000, respectively, if NAT had not been performed. ID-NAT with or without anti-HCV testing showed higher efficacy than either MP-NAT or combo assays, particularly in lapsed or repeat donors in whom 99.2, 98.5, and 93.2% of infectious donations were estimated to be interdicted by these respective testing strategies. CONCLUSIONS: The incremental efficacy of anti-HCV testing when ID- NAT screening is performed was minimal, particularly for screening lapsed and repeat donations. PMID- 25727551 TI - Special issue in dermatology and plastic surgery of Lasers in Surgery and Medicine. PMID- 25727552 TI - The effect of 595 nm pulsed dye laser on connective tissue growth factor (CTGF) expression in cultured keloid fibroblasts. AB - OBJECTIVE: To investigate the effect of pulsed dye laser (PDL 595 nm) on the proliferation and expression of connective tissue growth factor (CTGF) in cultured keloid fibroblasts. MATERIALS AND METHODS: Cultured keloid fibroblasts were exposed to pulsed dye laser irradiation at fluences of 6, 8, and 10 J/cm(2) , with pulse durations of 1.5, 3, and 10 ms. The viability of keloid fibroblasts was measured with CCK-8 at 72, 24, and 12 hours prior to irradiation. Subsequently, viability was measured at 12, 24, and 72 hours post-irradiation. Additionally, the fibroblast cell cycle and apoptosis rate were measured by flow cytometry. Finally, keloid fibroblasts underwent real-time polymerase chain reaction (PCR) and Western blot to investigate the CTGF mRNA and protein expression after PDL irradiation. The untreated cultured keloid fibroblasts served as controls. RESULTS: The proliferation of keloid fibroblasts was significantly inhibited after PDL irradiation. Both CTGF mRNA and protein expression were significantly down-regulated in 1.5, 3, and 10 ms pulse duration groups, in a dose dependent manner (P < 0.05). However, there was no statistically significant difference between groups of different pulse duration in 6, 8, and 10 J/cm(2) fluence ranges (P > 0.05). CONCLUSIONS: Within certain fluence ranges, pulsed dye laser can effectively suppress the growth of keloids and significantly down-regulate CTGF mRNA and CTGF expression. PMID- 25727550 TI - OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice. AB - Osteonecrosis of the jaws (ONJ) is a significant complication of antiresorptive medications, such as bisphosphonates and denosumab. Antiresorptive discontinuation to promote healing of ONJ lesions remains highly controversial and understudied. Here, we investigated whether antiresorptive discontinuation alters ONJ features in mice, employing the potent bisphosphonate zoledronic acid (ZA) or the receptor activator of NF-kappaB ligand (RANKL) inhibitor OPG-Fc, utilizing previously published ONJ animal models. Mice were treated with vehicle (veh), ZA, or OPG-Fc for 11 weeks to induce ONJ, and antiresorptives were discontinued for 6 or 10 weeks. Maxillae and mandibles were examined by MUCT imaging and histologically. ONJ features in ZA and OPG-Fc groups included periosteal bone deposition, empty osteocyte lacunae, osteonecrotic areas, and bone exposure, each of which substantially resolved 10 weeks after discontinuing OPG-Fc but not ZA. Full recovery of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclast numbers occurred after discontinuing OPG-Fc but not ZA. Our data provide the first experimental evidence demonstrating that discontinuation of a RANKL inhibitor, but not a bisphosphonate, reverses features of osteonecrosis in mice. It remains unclear whether antiresorptive discontinuation increases the risk of skeletal-related events in patients with bone metastases or fracture risk in osteoporosis patients, but these preclinical data may nonetheless help to inform discussions on the rationale for a "drug holiday" in managing the ONJ patient. PMID- 25727554 TI - Influence of neoadjuvant chemotherapy on radiotherapy for breast cancer. AB - Neoadjuvant chemotherapy is a standard treatment option for patients with locally advanced operable breast cancer and is increasingly used in early breast cancer. Initial randomized trials of neoadjuvant chemotherapy established equivalency to adjuvant chemotherapy in terms of survival, but they also demonstrated improved rates of breast conservation and the ability to modify the risk of locoregional recurrence after a favorable response to chemotherapy. High-quality nonrandomized data have helped to tailor radiotherapy treatment recommendations after neoadjuvant chemotherapy and breast-conserving surgery or mastectomy. Results from an ongoing phase 3 randomized trial (NSABP B-51/RTOG 1304) will help to clarify the value of locoregional radiotherapy for patients with clinical N1 disease that becomes node negative after neoadjuvant chemotherapy. PMID- 25727555 TI - Role of imaging in neoadjuvant therapy for breast cancer. AB - Neoadjuvant chemotherapy (NAC) involves administration of chemotherapeutic agents to patients with newly diagnosed breast cancer prior to definitive surgical treatment. Assessment of disease response to chemotherapeutic agents in vivo prior to any surgical intervention is necessary as medical oncologists are commonly tailoring or changing therapy during NAC based on response. It can also maximize the pathologic complete response (pCR) rate, resulting in more women undergoing breast conservation rather than mastectomy. Although some studies show a pCR to NAC in only 13-26 % of women, recent studies have shown higher pCR rates, especially for HER2-positive disease treated with targeted anti-HER2 therapy. Thus, accurate imaging tools for quantifying disease response are critical in the evaluation and management of patients undergoing NAC. There is currently no standard imaging method for monitoring response to therapy. Response to therapy tends to vary by tumor subtype and can be accurately assessed on imaging. We review the role of imaging before and after neoadjuvant therapy and discuss the advantages and limitations of currently available modalities, including mammography, ultrasonography, magnetic resonance imaging, and nuclear imaging. PMID- 25727556 TI - Pathological complete response in neoadjuvant treatment of breast cancer. AB - BACKGROUND: There has been recent interest in using pathological complete response (pCR) as a potential surrogate endpoint for long-term outcomes in the neoadjuvant treatment of high-risk, early-stage breast cancer. METHODS: We review the clinical trials that have contributed to our understanding of the association between pCR and long-term outcomes, describe the various definitions of pCR, describe patient populations in which pCR may predict long-term benefit, and discuss the implications of pCR on drug development and accelerated approval for neoadjuvant treatment of breast cancer. RESULTS: Varying definitions of pCR across clinical trials conducted in heterogeneous patient populations make understanding the association of pCR with long-term outcomes challenging. The US Food and Drug Administration established the Collaborative Trials in Neoadjuvant Breast Cancer group to evaluate the potential use of pCR as a regulatory endpoint. The group demonstrated that pCR defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0) provided a better association with improved outcomes compared to eradication of invasive tumor from the breast alone (ypT0/is). CONCLUSION: Even though pCR was not validated as a surrogate endpoint for long term outcomes, the promising data regarding the strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer supported the opening of an accelerated approval pathway for patients with high-risk, early-stage breast cancer. PMID- 25727558 TI - Impact of neoadjuvant chemotherapy on locoregional surgical treatment of breast cancer. AB - Preoperative (neoadjuvant) chemotherapy (NC) has become the standard of care for patients with locally advanced breast cancer and is being increasingly used in those with large operable disease. Its main clinical advantages from a surgical therapy standpoint include the potential for conversion of patients requiring mastectomy to breast-conservation candidates, the potential for improving the cosmetic outcome following lumpectomy by decreasing the size of the primary breast tumor even if the patient is a lumpectomy candidate at presentation, and the potential for converting patients who present with positive axillary nodes and who would initially require axillary lymph node dissection to candidates for sentinel lymph node biopsy alone. Important steps are required from the time of diagnosis until the time of surgical resection to ensure successful locoregional therapy outcomes in patients treated with NC. They include accurate assessment of the location and extent of the primary breast tumor and determination of axillary nodal status before and after NC. This information is critical for successful execution of the surgical plan and to optimize the use of adjuvant radiotherapy following NC. In the future, development of more active neoadjuvant chemotherapy regimens and novel molecular and imaging techniques will undoubtedly lead to further individualization of breast cancer surgical management following NC, including the possibility of avoiding surgical resection in cases with a high likelihood of achieving a pathological complete response. PMID- 25727557 TI - Landscape of neoadjuvant therapy for breast cancer. AB - Neoadjuvant chemotherapy provides clinical outcomes equivalent to those achieved when the same regimen is provided in the adjuvant setting. The therapeutic response to neoadjuvant treatment may include a reduction in tumor burden that alleviates the morbidity associated with locoregional therapy. Important prognostic information can be gained based on the response to treatment and knowing the quantity and biology of the residual disease. The evaluation of investigational agents in the neoadjuvant setting is of particular value for accelerating drug development. This review highlights landmark trials and contemporary perspectives on neoadjuvant chemotherapy and hormonal therapy, treatment response as a prognostic biomarker, use of the neoadjuvant paradigm for new drug development, and clinical advances in neoadjuvant therapy by molecular subtype of breast cancer. PMID- 25727559 TI - Spotlight on neoadjuvant therapy for breast cancer. PMID- 25727560 TI - In-clinic diagnosis of canine anaplasmosis based on haematological abnormalities and evaluation of a stained blood smear. AB - OBJECTIVE: Haematological changes, evaluation of a blood smear and seasonal variations may assist in an in-clinic diagnosis of acute anaplasmosis. MATERIAL AND METHODS: Blood samples from 57 dogs were evaluated. The diagnosis of canine anaplasmosis was confirmed by detection of the microorganism by microscopic examination of a stained blood smear. RESULTS: Thrombocytopenia was present in 56 dogs (98.2%). Red blood cell count, packed cell volume and haemoglobin values were below the reference interval in 38.6%, 24.5% and 26.3% of affected dogs respectively. Based on reticulocyte counts, a non-regenerative anaemia was present in 78.6% of A. phagocytophilum-positive dogs. Leukopenia, lymphopenia, neutropenia, monocytosis and eosinophilia were present in 35.1%, 66.7%, 10.9%, 5.7% and 15.4% of the dogs respectively. CONCLUSION: The results demonstrate that together with clinical signs, a tentative diagnosis of canine anaplasmosis can be made based on typical haematological changes. The most common haematological abnormalities in dogs affected by canine anaplasmosis were a thrombocytopenia and a lymphopenia; most cases of anaemia were non-regenerative. PMID- 25727561 TI - Vitamin D and insulin resistance. AB - Vitamin D is a steroid hormone, which in active form binds to the vitamin D receptor. Expression of the vitamin D receptor in diverse cell types (pancreatic islet cells, myocytes, hepatocytes and adipocytes) raises the suspicion that vitamin D may be involved in multiple cellular processes, including the response to insulin. Insulin resistance is a characteristic feature of type 2 DM, and its attenuation may reduce the incidence of type 2 DM and cardiovascular disease. In observational studies, low serum 25-hydroxyvitamin D (25-OHD) concentrations are associated with an increased risk of type 2 DM. It has been suggested that increasing serum 25-OHD concentrations may have beneficial effects on glucose and insulin homeostasis. However, cross-sectional and interventional studies of vitamin D supplementation provide conflicting results and demonstrate no clear beneficial effect of vitamin D on insulin resistance. These studies are complicated by inclusion of different patient cohorts, different 25-OHD assays and different doses and preparations of vitamin D. Any possible association may be confounded by alterations in PTH, 1,25-dihydroxyvitamin D or tissue vitamin D concentrations. We identified 39 studies via MEDLINE and PUBMED. We review the evidence from 10 studies (seven observational and three interventional) examining vitamin D and type 2 DM incidence, and 29 studies (one prospective observational, 12 cross-sectional and 16 interventional trials) examining vitamin D and insulin resistance. Based on this data, it is not possible to state that vitamin D supplementation has any effect on type 2 DM incidence or on insulin resistance. Data from the multiple ongoing randomized controlled trials of vitamin D supplementation due to report over the next few years should help to clarify this area. PMID- 25727562 TI - Removal of thiol ligands from surface-confined nanoparticles without particle growth or desorption. AB - Size-dependent properties of surface-confined inorganic nanostructures are of interest for applications ranging from sensing to catalysis and energy production. Ligand-stabilized nanoparticles are attractive precursors for producing such nanostructures because the stabilizing ligands may be used to direct assembly of thoroughly characterized nanoparticles on the surface. Upon assembly; however, the ligands block the active surface of the nanoparticle. Methods used to remove these ligands typically result in release of nanoparticles from the surface or cause undesired growth of the nanoparticle core. Here, we demonstrate that mild chemical oxidation (50 ppm of ozone in nitrogen) oxidizes the thiolate headgroups, lowering the ligand's affinity for the gold nanoparticle surface and permitting the removal of the ligands at room temperature by rinsing with water. XPS and TEM measurements, performed using a custom planar analysis platform that permits detailed imaging and chemical analysis, provide insight into the mechanism of ligand removal and show that the particles retain their core size and remain tethered on the surface core during treatment. By varying the ozone exposure time, it is possible to control the amount of ligand removed. Catalytic carbon monoxide oxidation was used as a functional assay to demonstrate ligand removal from the gold surface for nanoparticles assembled on a high surface area support (fumed silica). PMID- 25727563 TI - Robot-assisted radical adrenalectomy with clamping of the vena cava for excision of a metastatic adrenal vein thrombus: a case report. AB - BACKGROUND: Renal or adrenal neoplastic vein thrombi are relative contra indications for laparoscopic treatment. To the best of our knowledge, we present the first robot-assisted radical adrenalectomy (RARA) with the presence of a thrombus in the adrenal vein. METHODS: A 54 year-old male with a history of laparoscopic left radical nephrectomy for clear cell carcinoma was referred to our department with a diagnosed right adrenal tumour extending into the adrenal vein. A RARA was planned through a trans-peritoneal approach, and an en bloc resection of the adrenal and its vein with clamping of the vena cava was performed. RESULTS: Console time was 94 min and the estimated blood loss was 44 ml. The pathology report confirmed clear cell carcinoma with negative surgical margins. Convalescence was uneventful. CONCLUSION: RARA with thrombectomy and vascular reconstruction can be safe, effective and feasible in experienced hands, using robotic bulldogs. PMID- 25727564 TI - On Zn(II) 2,2'-bisdipyrrin circular helicates. AB - Coordination of two 2,2'-bisdipyrrin ligands, bearing methyl ester or methylthioether peripheral groups, with Zn(II) cations leads not only to the formation of the expected linear helicates but also concomitantly to novel tri- and tetra-nuclear circular species that have been isolated and fully characterized in solution and by X-ray diffraction. PMID- 25727565 TI - Hierarchical cupric oxide nanostructures on copper substrate for cold cathode emission: an experimental venture with theoretical correlation. AB - In this paper we report a facile route for the synthesis of controlled CuO nanoarchitectures directly grown on a copper substrate by a one-step simple chemical route with varying concentration of non-ionic surfactant PEG-6K. The phase purity and degree of crystallinity of the as-developed nanostructures were systemically investigated by X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy (HRTEM). A detailed analysis by field emission scanning electron microscopy confirmed the uniformity of the prepared nanostructures on the substrates. These architectures displayed substantial improvement of field emission properties with respect to other structures of CuO reported so far. A particular nanostructure (needle) among them showed a down shift of the turn-on field to 2.2 V MUm(-1) coupled with a good enhancement factor (beta) ~516, which are deemed as sufficient for electron emission based applications such as field emission displays and vacuum nanoelectronic devices. The origin of this efficient field emission from CuO nanoarchitectures, were probed computationally by investigating the local electric field distribution through finite element based simulation method using the ANSYS Maxwell simulation package. PMID- 25727566 TI - Findings on Advance Care Plans among Cognitively Impaired Older Adults. AB - Cognitively impaired and cognitively intact older adults seemingly differ regarding engagement in aspects of advance care plans (ACPs). Through informant reports in the Canadian Study on Health and Aging, we examined differences between deceased cognitively impaired and intact older adults in components of ACPs: (1) discussions/arrangements for end-of-life care; (2) creation of legal documents; and in ACP outcomes, (3) location of death; and (4) dying in accordance with wishes. Cognitively impaired older adults were more likely to have made arrangements for a substitute decision-maker (OR = 1.90) and to have created legal documents (OR = 2.64 for health care preferences, OR = 2.00 for naming a decision-maker). They were less likely to have discussed preferences for end-of-life care (OR = 0.62). These findings suggest that ACPs differ for cognitively impaired persons, indicating a need for further investigation. This is a step towards understanding this complex process in a particularly vulnerable population. PMID- 25727567 TI - A novel fabrication method to create a thick collagen bundle composed of uniaxially aligned fibrils: an essential technology for the development of artificial tendon/ligament matrices. AB - In this study, we developed a fabrication method for thick collagen gel bundles comprising uniaxially aligned fibrils of sufficient size for filling defects in ligament tissues. The fabrication involved rotary shearing to dense collagen sols using a rheometer and then warming them from 23 degrees C to 37 degrees C to trigger gelation upon rotation. Gelation due to collagen fibril formation was accelerated by increased concentrations of neutral phosphate buffer, and fibril alignment occurred within 20 s during the early stage of rapid gelation. Fabrication of gels was completed with slippage between gels and the movable upper plate, and well-aligned fibrils along the rotation direction were observed in the marginal regions of disc-shaped gels. Gel thickness could be increased from 1 to 3 mm with homogeneous alignment of fibrils in the entire sample. The alignment of fibrils improved mechanical properties against tensile loads that were placed parallel to the alignment axis. Elongation of cultured fibroblast along the alignment was observed on the gels. The present method will enable the bottom-up fabrication of an artificial tendon for ligament reconstruction and repair. PMID- 25727568 TI - Cooperative bond activation and catalytic reduction of carbon dioxide at a group 13 metal center. AB - A single-component ambiphilic system capable of the cooperative activation of protic, hydridic and apolar H?X bonds across a Group 13 metal/activated beta diketiminato (Nacnac) ligand framework is reported. The hydride complex derived from the activation of H2 is shown to be a competent catalyst for the highly selective reduction of CO2 to a methanol derivative. To our knowledge, this process represents the first example of a reduction process of this type catalyzed by a molecular gallium complex. PMID- 25727569 TI - Multicentric reticulohistiocytosis: a case report of an atypical presentation in a 2-year-old. AB - Multicentric reticulohistiocytosis (MRH) is a rare systemic inflammatory granulomatous disease marked by severe and often rapidly progressive polyarticular arthritis and cutaneous papulonodules. Initial clinical diagnosis may be difficult. We describe a 2-year-old girl presenting with pink dermal papules on the forehead, thighs, elbows, knees, and palms of the hands. Based on clinical findings and skin biopsy results, she was initially diagnosed with granuloma annulare. At 5 years of age, she developed arthritis, fatigue, and more widespread skin papules leading to the diagnosis of MRH. To our knowledge, this is the youngest individual with MRH yet described. We outline the timeline and unique features of her case and review the literature pertaining to MRH in children. Although rare, MRH can be permanently debilitating, making prompt diagnosis critical. A standardized approach to investigation and management needs to be developed. PMID- 25727570 TI - Breastfeeding and maternal sensitivity predict early infant temperament. AB - AIM: Research findings are inconclusive when it comes to whether breastfeeding is associated with the mother-infant relationship or infant temperament. We examined the association between breastfeeding at three months postpartum and infant temperament at 18 months postpartum and whether this link was affected by the mothers' anxiety and mediated by her sensitivity. METHODS: We assessed 170 mothers for breastfeeding and anxiety using the Spielberger State-Trait Anxiety Inventory (STAI) at three months postpartum, maternal sensitivity using the Ainsworth Sensitivity Scale at six months postpartum and infant temperament using the Early Childhood Behaviour Questionnaire at 18 months postpartum. RESULTS: Mothers who breastfed at three months postpartum were more sensitive in their interactions with their infants at six months postpartum, and elevated sensitivity, in turn, predicted reduced levels of negative affectivity in infant temperament at 18 months postpartum. This indirect mediation persisted after controlling for confounders (effect ab = -0.0312 [0.0208], 95% CI = -0.0884 to 0.0031). A subsequent analysis showed that the mediation through sensitivity only occurred in women experiencing higher anxiety, with a STAI score >=33.56 at three months (ab = -0.0250 [0.0179], 95% CI = -0.0759 to -0.0013). CONCLUSION: Our results suggest that breastfeeding and maternal sensitivity may have a positive impact on the early development of infant temperament. PMID- 25727571 TI - Interactions of Salmonella enterica subspecies enterica serovar Typhimurium with gut bacteria. AB - The aim of this study was to evaluate the impact of the gut microbiota on the growth and survival of S. Typhimurium. This was tested in two-species co-cultures and in mixed cultures with a simplified gut model microbiota. Subsequently, interactions between S. Typhimurium and human faecal bacteria were quantified in both batch and continuous culture systems simulating the human colon. The exponential growth of S. Typhimurium was halted when the population of Escherichia coli reached the maximum population density in a two-compartment co culture system where the two species were separated by a 0.45 MUm pore membrane. Furthermore, the growth of some gut bacteria such as Lactobacillus gasseri and Bifidobacterium bifidum was inhibited by the presence of S. Typhimurium in the other compartment. The survival of S. Typhimurium was severely affected in mixed batch cultures with human faecal samples; a reduction of 10(3)-10(4) cfu/ml in the concentration of S. Typhimurium was observed in these cultures. However, no effect on S. Typhimurium survival was observed in mixed batch cultures with a simplified gut model microbiota under the same conditions. The effect of human faecal samples on S. Typhimurium in a three-stage continuous culture was different to that obtained in batch cultures; its growth rather than survival was affected under these conditions. S. Typhimurium growth was inhibited, and the bacterium was therefore eliminated by the continuous flow of the medium. Depending upon culturing conditions, the gut microbiota caused either growth inhibition, inactivation or did not affect S. Typhimurium. PMID- 25727572 TI - Differences in acid tolerance between Bifidobacterium breve BB8 and its acid resistant derivative B. breve BB8dpH, revealed by RNA-sequencing and physiological analysis. AB - Bifidobacteria are common inhabitants of the human gastrointestinal tract, and their application has increased dramatically in recent years due to their health promoting effects. The ability of bifidobacteria to tolerate acidic environments is particularly important for their function as probiotics because they encounter such environments in food products and during passage through the gastrointestinal tract. In this study, we generated a derivative, Bifidobacterium breve BB8dpH, which displayed a stable, acid-resistant phenotype. To investigate the possible reasons for the higher acid tolerance of B. breve BB8dpH, as compared with its parental strain B. breve BB8, a combined transcriptome and physiological approach was used to characterize differences between the two strains. An analysis of the transcriptome by RNA-sequencing indicated that the expression of 121 genes was increased by more than 2-fold, while the expression of 146 genes was reduced more than 2-fold, in B. breve BB8dpH. Validation of the RNA-sequencing data using real-time quantitative PCR analysis demonstrated that the RNA-sequencing results were highly reliable. The comparison analysis, based on differentially expressed genes, suggested that the acid tolerance of B. breve BB8dpH was enhanced by regulating the expression of genes involved in carbohydrate transport and metabolism, energy production, synthesis of cell envelope components (peptidoglycan and exopolysaccharide), synthesis and transport of glutamate and glutamine, and histidine synthesis. Furthermore, an analysis of physiological data showed that B. breve BB8dpH displayed higher production of exopolysaccharide and lower H(+)-ATPase activity than B. breve BB8. The results presented here will improve our understanding of acid tolerance in bifidobacteria, and they will lead to the development of new strategies to enhance the acid tolerance of bifidobacterial strains. PMID- 25727573 TI - Skeletal evidence of tuberculosis in a modern identified human skeletal collection (Certosa cemetery, Bologna, Italy). AB - The diagnosis of tuberculosis (TB) in osteoarcheological series relies on the identification of osseous lesions caused by the disease. The study of identified skeletal collections provides the opportunity to investigate the distribution of skeletal lesions in relation to this disease. The aim of this study was to examine the skeletal evidence for TB in late adolescent and adult individuals from the identified human collection of the Certosa cemetery of Bologna (Italy, 19th-20th c.). The sample group consists of 244 individuals (138 males, 106 females) ranging from 17 to 88 years of age. The sample was divided into three groups on the basis of the recorded cause of death: TB (N = 64), pulmonary non-TB (N = 29), and other diseases (N = 151). Skeletal lesions reported to be related to TB were analyzed. The vertebral lesions were classified into three types: enlarged foramina (EnF, vascular foramina with diameter of 3-5 mm), erosions (ER), and other foramina (OtF, cavities of various shapes > 3 mm). A CT scan analysis was also performed on vertebral bodies. Some lesions were seldom present in our sample (e.g., tuberculous arthritis). OtF (23.7%) and subperiosteal new bone formation on ribs (54.2%) are significantly more frequent in the TB group with respect to the other groups. The CT scan analysis showed that the vertebrae of individuals who have died of TB may have internal cavities in the absence of external lesions. These traits represent useful elements in the paleopathological diagnosis of TB. PMID- 25727574 TI - Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years. AB - Previous studies have suggested that heroin addiction is associated with structural and functional brain abnormalities. However, it is largely unknown whether these characteristics of brain abnormalities would be persistent or restored after long periods of abstinence. Considering the very high rates of relapse, we hypothesized that there may exist some latent neural vulnerabilities in abstinent heroin users. In this study, structural and resting-state functional magnetic resonance imaging data were collected from 30 former heroin-dependent (FHD) subjects who were drug free for more than 3 years and 30 non-addicted control (CN) volunteers. Voxel-based morphometry was used to identify possible gray matter volume differences between the FHD and CN groups. Alterations in resting-state functional connectivity in FHD were examined using brain areas with gray matter deficits as seed regions. Significantly reduced gray matter volume was observed in FHD in an area surrounding the parieto-occipital sulcus, which included the precuneus and cuneus. Functional connectivity analyses revealed that the FHD subjects showed reduced positive correlation within the default mode network and visual network and decreased negative correlation between the default mode network, visual network and task positive network. Moreover, the altered functional connectivity was correlated with self-reported impulsivity scores in the FHD subjects. Our findings suggest that disruption of large-scale brain systems is present in former heroin users even after multi-year abstinence, which could serve as system-level neural underpinnings for behavioral dysfunctions associated with addiction. PMID- 25727575 TI - Narrative synthesis of equine-assisted psychotherapy literature: Current knowledge and future research directions. AB - Equine-assisted psychotherapy (EAP) is an innovative emerging approach to mental health treatment. This narrative synthesis explores the current state of knowledge and areas for future research in EAP. Specifically reviewed are qualitative and quantitative empirical studies, including both articles published in peer-reviewed journals and research presented in theses and dissertations. We selected 24 studies for final inclusion in this study, dating between 2005 and 2013, and including the first EAP empirical research completed in 2005. Four of these studies are peer-reviewed journal articles, while 20 are master's theses or doctoral dissertations. The reviewed qualitative research provides initial evidence for the value of EAP for enhancing adolescents' communication and relationship skills. The reviewed experimental and quasi-experimental research provides initial evidence for the value of EAP for enhancing children's and adolescents' emotional, social and behavioural functioning. Yet, conclusions about the effectiveness of EAP must still be considered preliminary due to various methodological limitations in the reviewed research. The narrative review describes these methodological limitations and concludes with recommendations for future research. PMID- 25727576 TI - Treatment of amblyopia: the "eye pad," or the iPad? PMID- 25727577 TI - Description and validation of a structured simulation curriculum for strabismus surgery. AB - PURPOSE: To describe and validate a Web-based structured simulation curriculum of strabismus surgery for residents in training using noncadaveric eye models. METHODS: A pre- and posttest of cognitive skills, objective wet laboratory structured assessment of technique, and summative global evaluation form were implemented as part of a systematic ophthalmology wet lab (OWL) curriculum. Strabismus techniques were taught using a structured simulation method on noncadaveric models of eyes. Likert scale questionnaires were administered to assess the comfort level with strabismus surgery of residents before and after participation in the wet laboratory. Statistical analysis was performed using the paired t test. RESULTS: Seven residents participated in the curriculum. Average test scores improved from 65% to 91% (P = 0.0002). Resident comfort level improved from an average score (assessed by Likert scale of 1-5) with standard deviation of 2.6 +/- 1.0 to 4.3 +/- 0.5 for passing scleral sutures (P = 0.0008), of 2.6 +/- 0.5 to 4.3 +/- 0.5 for isolating and suturing muscles (P = 0.00004), and of 2.7 +/- 1.0 to 4.6 +/- 0.5 for comfort with naming instruments (P = 0.0007). CONCLUSIONS: In this study of 7 residents, knowledge and comfort level with strabismus surgery statistically improved with a structured simulation curriculum. PMID- 25727578 TI - Binocular iPad treatment for amblyopia in preschool children. AB - BACKGROUND: Recent experimental evidence supports a role for binocular visual experience in the treatment of amblyopia. The purpose of this study was to determine whether repeated binocular visual experience with dichoptic iPad games could effectively treat amblyopia in preschool children. METHODS: A total of 50 consecutive amblyopic preschool children 3-6.9 years of age were assigned to play sham iPad games (first 5 children) or binocular iPad games (n = 45) for at least 4 hours per week for 4 weeks. Thirty (67%) children in the binocular iPad group and 4 (80%) in the sham iPad group were also treated with patching at a different time of day. Visual acuity and stereoacuity were assessed at baseline, at 4 weeks, and at 3 months after the cessation of game play. RESULTS: The sham iPad group had no significant improvement in visual acuity (t4 = 0.34, P = 0.75). In the binocular iPad group, mean visual acuity (plus or minus standard error) improved from 0.43 +/- 0.03 at baseline to 0.34 +/- 0.03 logMAR at 4 weeks (n = 45; paired t44 = 4.93; P < 0.0001). Stereoacuity did not significantly improve (t44 = 1.35, P = 0.18). Children who played the binocular iPad games for >=8 hours (>=50% compliance) had significantly more visual acuity improvement than children who played 0-4 hours (t43 = 4.21, P = 0.0001). CONCLUSIONS: Repeated binocular experience, provided by dichoptic iPad game play, was more effective than sham iPad game play as a treatment for amblyopia in preschool children. PMID- 25727579 TI - Incidence of retinopathy of prematurity in the middle Black Sea region of Turkey over a 10-year period. AB - PURPOSE: To report the incidence of retinopathy of prematurity (ROP) in babies with a birth weight of <=1750 g over a 10-year period in the north of Turkey. METHODS: The medical records of 2,365 preterm babies who had been referred for ophthalmological examination were retrospectively reviewed, and children with a birth weight of <=1750 g were included. The incidence of ROP was compared between two successive 5-year periods: 2004-2008 and 2009-2013. RESULTS: A total of 1,565 babies were included: 624 in the first period and 941 in the second. The incidence of ROP significantly increased during the second period compared to the first (35.3% vs 48.2% [P < 0.001]). The number of patients who required treatment was 11.9% in the first period and 11.4% in the second (P = 0.768). CONCLUSIONS: Although the incidence of ROP increased during the latter period of study (2009 2013), the numbers of treatment-requiring cases were similar in both periods. PMID- 25727580 TI - Objective vision screening in 3-year-old children at a multispecialty practice. AB - BACKGROUND: Vision screening is rarely effectively accomplished for 3-year-olds as part of pediatric well-child examinations. We investigate changes in screening rates and positive predictive values of referrals for 3-year-olds after introducing a photoscreener to a multispecialty group practice. METHODS: The vision screening results of 3-year-old children undergoing routine well-child examinations between 2007 and 2013 were retrospectively reviewed. From 2007 to 2009, the only method available for vision screening was the Kindergarten Eye Test Chart. From 2010 to 2013 a PlusOptix photoscreener was also available. Rates of vision screening before and after PlusOptix adoption were compared. All children who failed screening were referred to a single pediatric ophthalmologist. Referral rates, follow-up rates, and positive predictive values were determined for PlusOptix photoscreening. Cases were defined by cycloplegic retinoscopy using the 2013 American Association for Pediatric Ophthalmology and Strabismus (AAPOS) vision screening recommendations for amblyopia risk factors. RESULTS: Of 593 children seen for their 3-year well-child examination between 2007-2009, before introduction of a photoscreener, 59 (10%) received vision screening. The screening rate increased to 766 of 958 (80%) between 2010 and 2013, after introduction of the PlusOptix (P < 0.001). Only 49% of children had a reliable first screening with PlusOptix, and the average number of screenings to obtain a reliable result was 2.39. The positive predictive value of PlusOptix referrals was 51% for amblyopia risk factors and 41% for potential amblyopia. CONCLUSIONS: Availability of a photoscreener can increase the rate of vision screening for 3-year-old children in a multispecialty practice. PMID- 25727581 TI - Relationship of inferior oblique overaction to macular and subfoveal choroidal thickness. AB - PURPOSE: To evaluate the macular and subfoveal choroidal thickness of eyes with inferior oblique muscle overaction (IOOA) using enhanced depth imaging spectral domain optical coherence tomography (EDI SD-OCT). METHODS: The measurements of macular and subfoveal choroidal thickness obtained by EDI SD-OCT of patients with IOOA (24 patients) were compared with those of age- and sex-matched controls (25 subjects). RESULTS: There were no morphological abnormalities of the macula in patients with IOOA or in control subjects. There were no statistically significant differences in macular and subfoveal choroidal thickness between the eyes with IOOA and the eyes of the control subjects (P > 0.05). When the patients with IOOA were assigned to two distinct groups according to the degree of IOOA, the macular thickness did not differ between groups (P = 0.66), whereas subfoveal choroidal thickness measures were significantly lower in eyes with severe IOOA compared to eyes of the controls (P = 0.01). CONCLUSIONS: IOOA has no effect on the morphology and the thickness of the macula. Severe IOOA seems to be related to thinning of subfoveal choroid due to possible external mechanical effect. PMID- 25727582 TI - Cataract surgery in children with congenital keratolenticular adhesion (Peters anomaly type 2). AB - PURPOSE: To report the visual and surgical outcomes after cataract surgery in children with keratolenticular adhesion (Peters anomaly type 2). METHODS: The medical records of consecutive patients with keratolenticular adhesion (KLA) with partial (iris defects)/complete aniridia were retrospectively reviewed. Cataract surgery (in-the-bag irrigation and aspiration) with or without intraocular lens implantation and with or without broad iridectomy was performed. The main outcome measures were postoperative visual acuity, complications, and progression of corneal opacity. RESULTS: The study included 4 eyes of 3 patients ranging in age from 3 months to 7 years. The mean age at cataract surgery was 37 months; the median, 24 months (range, 3-84 months). The mean follow-up was 3.3 years and median was 2 years (range, 2-6 years). Preoperative visual acuity ranged from fixing and following objects to 20/200. Only 1 patient had PAX6 mutation confirmed aniridia. The other 2 patients had partial iris defects. All eyes improved in visual acuity ranging from counting fingers at 3 feet to 20/60. There was no progression of corneal opacity. There were no postoperative complications. CONCLUSIONS: Children with KLA with complete or partial iris defects with localized corneal opacity and cataract can achieve satisfactory visual outcomes by undergoing meticulous lensectomy with or without iridectomy. PMID- 25727583 TI - Validity of a layperson-administered Web-based vision screening test. AB - PURPOSE: To determine the sensitivity and specificity of the Web-based vision screening test (WBT) VisionForKids.org when administered by an untrained layperson in a controlled environment. METHODS: Visual acuities were obtained by an untrained layperson using the WBT under observation and by an ophthalmic professional using the Electronic Visual Acuity (EVA) Tester. Subjects were randomized to which method was used first. Subjects were considered to have failed by the following criteria: in children <48 months, 20/50 vision; in children between 48 and 59 months, 20/40 or worse; in children >=60 months, 20/30 or worse. The results of the vision examinations by the WBT and the EVA Tester were compared; sensitivity and specificity of the WBT and the correlation coefficient to detect normal and abnormal vision compared to EVA testing were determined. RESULTS: Visual acuities were obtained on 203 children between ages 3 and 12 years (average age, 7.4 years). Sensitivity of the WBT was 78.7% (95% CI, 66.0%-87.7%), specificity was 89.4% (95% CI, 82.9%-93.8%). The correlation coefficient of EVA testing with the WBT was 0.89 (P < 0.001). CONCLUSIONS: This layperson-administered WBT, VisionForKids.org, is valid for identifying amblyopia in a controlled environment, making it possible for cost-effective and easily accessible vision screening to be performed by laypersons. PMID- 25727584 TI - Quantifying variability in the measurement of control in intermittent exotropia. AB - PURPOSE: To evaluate the performance of a series of summary measures of control and to assess reliability in quantifying exodeviation control in intermittent exotropia. METHODS: A large, simulated dataset of control scores for 10,000 hypothetical patients with intermittent exotropia was created using Monte Carlo simulations. These data were based on children with intermittent exotropia in whom control was assessed twice during one clinical examination, using the office control score (0-5). Each simulated patient had a baseline and 11 subsequent control scores. The repeatability of a series of summary measures of control (the mean of 2 vs the mean of 3 up to the mean of 6), was calculated using 95% limits of agreement (LOA). RESULTS: A total of 322 examinations in 152 patients were used to provide representative distributions of control scores. From the resultant Monte Carlo simulations, the 95% LOAs were 2.60 for 1 distance control score measure, 1.76 for the average of 3, and 1.28 for the average of 6. Therefore using the average of 3 scores, a change of <1.76 would be consistent with short-term variability, whereas a change of >1.76 would suggest a real change in control. CONCLUSIONS: The large dataset of simulated control scores allowed us to assess the variability of specific summary measures of control. We recommend the average of 3 scores (a triple control score) as a new standard for assessing control, providing improved reliability over a single measure, while remaining implementable in clinical practice. PMID- 25727585 TI - Head oscillations in infantile nystagmus syndrome. AB - PURPOSE: To quantitatively characterize eye and head oscillations in patients with infantile nystagmus syndrome (INS). METHODS: Vertical and horizontal eye and head position in INS patients were measured simultaneously at a sampling frequency of 500 Hz. Eye and head movements were measured continuously for 180 seconds. The data was calibrated and converted to angular vectors, which were further analyzed with custom software. RESULTS: A total of 10 patients with INS were included: 3 with pseudo-jerk, 3 with pure-jerk, 2 with pseudo-pendular with foveating saccade form of jerk, 1 with bidirectional jerk, and 1 with asymmetric pendular nystagmus waveforms. None of the patients had periodic, aperiodic, or a superimposed latent nystagmus component. Two types of head oscillations were observed: one with a frequency of 1-3 Hz, present in all patients; and another with a frequency range of 5-8 Hz, present in only 7 patients. High-frequency oscillations were episodic, whereas low-frequency oscillations were constantly present. Peak velocity of the high-frequency head oscillations and eye velocity of nystagmus were not correlated, suggesting that these oscillations did not influence foveation. CONCLUSIONS: Two types of head oscillations were found in INS patients: a constant, low-frequency and an episodic, high-frequency. Lack of correlation between the foveation period of nystagmus and peak head velocity during high-frequency oscillations suggests a coexisting pathological phenomenon rather than a compensatory mechanism used to improve the visual acuity. PMID- 25727587 TI - Periocular skin hyperpigmentation in children treated with prostaglandin analogues. AB - PURPOSE: To report periocular skin hyperpigmentation related to prostaglandin analogue (PGA) use in children with glaucoma. METHODS: This cross-sectional study examined children treated with PGA for at least 6 months between June 2013 and December 2013. The pigmentation scores of the upper eyelids, lower eyelids and cheek were recorded with a chromameter. Hyperpigmentation was defined as a positive difference in scores between the cheek and the upper/lower eyelid. The influence of age, baseline skin pigmentation, duration of PGA, type of PGA and mono- or multitherapy on hyperpigmentation were evaluated. Subjective grading of pigmentation on standardized face photographs and the parent's perception of hyperpigmentation were also recorded. A P value of <0.05 was considered significant. RESULT: A total of 55 patients were included. Hyperpigmentation of the upper and lower eyelids occurred in all eyes. Subjectively, 26 (47%) eyes had mild and 14 (26%) moderate hyperpigmentation. The upper eyelid showed significantly greater hyperpigmentation than the lower eyelid (P = 0.00004). Chromameter measurements overlapped with pigmentation grading on photographs. The type of and duration of PGA use, PGA mono- or multidrug therapy or baseline skin pigmentation had no effect on the grade of hyperpigmentation. CONCLUSIONS: PGA use for more than 6 months was associated with periocular skin hyperpigmentation that was greater in the upper eyelid versus lower eyelid. All variables examined failed to show a relationship with the grade of hyperpigmentation. PMID- 25727588 TI - Effect of combining oblique muscle weakening procedures with bimedial rectus recessions on the surgical correction of esotropia. AB - PURPOSE: To evaluate the effects of oblique muscle weakening when combined with medial rectus muscle recession on the primary position horizontal alignment after surgery to correct esotropia. METHODS: The medical records of patients who underwent bilateral medial rectus recessions with or without simultaneous oblique muscle surgery between 2004 and 2013 at two Brazilian hospitals were retrospectively reviewed. Patients who had undergone previous strabismus surgery and those with incomplete data were excluded. The amount of correction for every millimeter of medial rectus recession was analyzed for patients undergoing an isolated procedure (group A), those undergoing additional inferior oblique muscle weakening (group B), and those undergoing additional superior oblique muscle weakening, or tenectomy (group C). RESULTS: A total of 160 patients (71 females) met inclusion criteria. The magnitudes of preoperative esotropia and the times of postoperative evaluation did not differ between groups. The amounts of correction did not differ when patients younger and older than 7 years were compared in every group. The amounts of correction for every millimeter of medial rectus recession were 3.0(Delta) in group A, 3.1(Delta) in group B, and 2.6(Delta) in group C. The reduction for group C was significant (P = 0.0036). CONCLUSIONS: Pateints undergoing superior oblique weakening surgery in combination with bimedial rectus recessions may require larger medial rectus recessions to correct the primary position esodeviation. The authors suggest that a 10%-15% increase of the planned recession should be considered. PMID- 25727590 TI - Surgical management of strabismus in Duane retraction syndrome. AB - SUMMARY: While Duane retraction syndrome (DRS) is relatively common, surgical management of the associated strabismus can be challenging because of the lack of abduction/adduction, the variable severity of muscle contracture, and the variety of clinical presentations. In this workshop a panel of experienced surgeons provide their perspective and practical tips on the management of strabismus in patients with DRS. PMID- 25727589 TI - Macular optical coherence tomography in patients with unilateral optic nerve hypoplasia. AB - PURPOSE: To characterize the extent and location of macular thinning in patients with unilateral optic nerve hypoplasia (ONH) as compared to the contralateral normal eye. METHODS: The medical records of patients with unilateral ONH who underwent spectral domain optical coherence tomography (SD-OCT) of the macula were retrospectively reviewed. SD-OCT scans were manually segmented by 3 observers in 3 macular regions (superior, central, inferior). Boundaries identified included the inner limiting membrane, the junction between the inner nuclear layer and outer plexiform layer, and the neural retina-retinal pigment epithelium interface. Using custom MATLAB software, inner and outer retinal thickness profiles were quantified. A paired t test was used to compare the retinal thickness between the ONH eye and the contralateral normal eyes. RESULTS: Inner retinal thickness of the ONH eye was decreased in all areas of the macula (superior, central, and inferior) compared to the contralateral normal eye (P < 0.05). Outer retinal thicknesses were also decreased in the central and inferior sections compared with the normal eye (P < 0.05). CONCLUSIONS: Optic nerve hypoplasia is a congenital disease known to result in thinning of the nerve fiber and ganglion cell layer. Our small cohort demonstrated thinning of the inner retinal layers as well as the outer retinal layers in the ONH eye compared with the contralateral normal eye. PMID- 25727586 TI - A randomized trial of adding a plano lens to atropine for amblyopia. AB - BACKGROUND: Some children have residual amblyopia after treatment with atropine eyedrops for amblyopia due to strabismus and/or anisometropia. We conducted a randomized clinical trial to evaluate the effectiveness of augmenting the effect of atropine by changing the lens over the fellow eye to plano in children with residual amblyopia. METHODS: A total of 73 children 3 to <8 years of age (mean, 5.8 years) with stable residual amblyopia (range, 20/32 to 20/160, mean 20/63(+1)) were enrolled after at least 12 weeks of atropine treatment of the fellow eye. Participants were randomly assigned to continuing weekend atropine alone or wearing a plano lens over the fellow eye (while continuing atropine). The primary outcome was assessed at 10 weeks, and participants were followed until improvement ceased. RESULTS: At the 10-week primary outcome visit, amblyopic-eye visual acuity had improved an average of 1.1 lines with the plano lens and 0.6 lines with atropine only (difference adjusted for baseline visual acuity = + 0.5 line; 95% CI, -0.1 to +1.2). At the primary outcome or later visit when the best-measured visual acuity was observed, the mean amblyopic-eye improvement from baseline was 1.9 lines with the plano lens and 0.8 lines with atropine only. CONCLUSIONS: When amblyopic-eye visual acuity stops improving with atropine treatment, there may be a small benefit to augmenting atropine therapy with a plano lens over the fellow eye. However, the effect was not statistically significant, and the large confidence interval raises the possibility of no benefit or a benefit larger than we observed. A larger study would be necessary to get a more precise estimate of the treatment effect. PMID- 25727591 TI - Ophthalmic manifestations of cherubism. AB - Cherubism is a rare craniofacial disorder characterized by progressive replacement of mandibular and maxillary bone with multicystic fibro-osseous tissue, potentially resulting in significant deformity and morbidity. The severity of the disorder is variable; more advanced disease may affect the orbit and impact vision. We detail the ophthalmological findings in 2 patients, 7 and 8 years of age, with cherubism. PMID- 25727592 TI - Superselective intra-arterial chemotherapy for advanced retinoblastoma complicated by metastatic disease. AB - We present a case of a child with unilateral group E retinoblastoma (according to the International Classification of Retinoblastoma) who received superselective intra-arterial chemotherapy as primary therapy. Although the tumor showed signs of regression, the patient developed orbital metastases requiring surgical excision and chemotherapy. Eventually the affected eye progressed to total retinal detachment and required enucleation. PMID- 25727593 TI - A case of frosted branch angiitis in an immunocompromised child. AB - Frosted branch angiitis is a rare vascular reaction believed to be a nonspecific immune response to an infective, neoplastic, or idiopathic insult. The clinical presentation is characteristic and typically affects children and younger adults, and the prognosis is good. We report a case of frosted branch angiitis during immune recovery in a 2-year-old boy with Langerhans cell histiocytosis on systemic immunosuppressive therapy. PMID- 25727594 TI - A technique for standardizing disk foveal angle measurement. AB - Ocular torsion can been measured by perimetry, double Maddox rod, Bagolini glasses, indirect ophthalmoscopy lens, slit-lamp biomicroscopy, synoptophore, and fundus photography. Wide variations have been reported in the measurement of the disk foveal angle (DFA) using fundus photography. We describe a technique for measuring the DFA, formed by a horizontal line extending from the center of the optic disk and a line from the center of disk to the fovea, using Microsoft PowerPoint and ImageJ software. PMID- 25727595 TI - Total clinical regression of an orbital macrocystic lymphatic malformation following intralesional sodium tetradecyl sulphate injection. AB - Lymphatic malformations are usually managed by observation, although significant cosmetic abnormalities, compressive optic neuropathy, risk of amblyopia, exposure keratopathy, or elevated intraocular pressure mandate treatment. We report the case of a 10-year-old boy with a deep orbital macrocystic lymphatic malformation that was successfully treated with intralesional injection of sodium tetradecyl sulphate, a sclerozing agent mainly used in the treatment of small varicose veins in the lower extremity. PMID- 25727596 TI - Fundus autofluorescence and optical coherence tomography findings in glutathione synthetase deficiency. AB - We report the autofluorescence pattern and optical coherence tomography (OCT) characteristics in a 6-year-old boy with glutathione synthetase deficiency. The patient underwent complete ophthalmological examination, including full-field electroretinography, visual evoked potentials, fundus autofluorescence, and OCT imaging. Electrophysiological studies showed time-delay and subnormal responses. Fundus autofluorescence imaging revealed increased parafoveal autofluorescence compared to normal, and OCT showed alteration of photoreceptor and retinal pigment epithelium layers in the parafoveal region. PMID- 25727597 TI - Sector iris hemangioma in association with diffuse choroidal hemangioma. AB - Two patients referred for iris lesions were found to have sector hemangioma of the iris stroma in contiguity with diffuse choroidal hemangioma. Neither patient had other manifestations of Sturge-Weber syndrome. PMID- 25727598 TI - Hypersensitivity to sub-Tenon's topotecan in fibrin adhesive in patients with retinoblastoma. AB - Sub-Tenon's space delivery of topotecan in a fibrin sealant was used as an adjunct to laser therapy for small retinoblastoma tumors in 25 children (77 injections). We report serious hypersensitivity reactions in 2 children on their third sub-Tenon's injection of topotecan in fibrin sealant. One child subsequently had topotecan in an autologous blood clot with no allergic reaction. Although allergic reaction to topotecan has been reported in the literature, fibrin glue reactions are more common and are likely due to aprotinin hypersensitivity. PMID- 25727599 TI - Malaria retinopathy and cerebellitis in a 9-year-old boy in the United States. AB - Malarial retinopathy is characterized by retinal whitening, vessel change, and hemorrhages usually associated with a white center. We present the case of a 9 year-old boy who presented with a systemic Plasmodium falciparum infection, hemorrhagic cerebellitis and malarial retinopathy characterized by "fire flare" hemorrhages (scleral icterus with subconjunctival hemorrhages), Roth spot-like hemorrhages, and subhyaloid hemorrhage. To our knowledge, this is the first reported case of hemorrhagic cerebellitis secondary to P. falciparum infection in the United States. PMID- 25727600 TI - Zone 3 ruptured globe from a dog bite. AB - Periocular injuries from dog bites are relatively common in school-age children, but intraocular trauma is exceedingly rare. We present a 7-year-old boy who sustained a zone 3 ruptured globe injury after attack by a Perro de Presa Canario. At presentation, visual acuity in the injured eye was counting fingers. Surgical exploration revealed an inferotemporal corneoscleral laceration extending 15 mm posterior to the limbus, with protrusion of uveal tissue, which was repaired. Visual acuity improved to 20/40 by the first postoperative month. PMID- 25727601 TI - Photographic simulation of off-axis blurring due to chromatic aberration in spectacle lenses. AB - Spectacle lens materials of high refractive index (nd) tend to have high chromatic dispersion (low Abbe number [V]), which may contribute to visual blurring with oblique viewing. A patient who noted off-axis blurring with new high-refractive-index spectacle lenses prompted us to do a photographic simulation of the off-axis aberrations in 3 readily available spectacle lens materials, CR-39 (nd = 1.50), polyurethane (nd = 1.60), and polycarbonate (nd = 1.59). Both chromatic and monochromatic aberrations were found to cause off-axis image degradation. Chromatic aberration was more prominent in the higher-index materials (especially polycarbonate), whereas the lower-index CR-39 had more astigmatism of oblique incidence. It is important to consider off-axis aberrations when a patient complains of otherwise unexplained blurred vision with a new pair of spectacle lenses, especially given the increasing promotion of high refractive-index materials with high chromatic dispersion. PMID- 25727602 TI - Reply: To PMID 24568986. PMID- 25727603 TI - Hyperopic corneal refractive surgery in patients with accommodative esotropia and amblyopia: comment. PMID- 25727604 TI - Reply: To PMID 25087646. PMID- 25727605 TI - Brittle cornea syndrome: a case report and comparison with Ehlers Danlos syndrome. PMID- 25727606 TI - Reply: To PMID 25266838. PMID- 25727607 TI - Characteristics and surgical results in patients with age-related divergence insufficiency esotropia. PMID- 25727608 TI - Reply: To PMID 25173902. PMID- 25727609 TI - Corneal injuries from liquid detergent pods. PMID- 25727610 TI - Reply: To PMID 25280925. PMID- 25727611 TI - For your information... RCNi. PMID- 25727612 TI - Task force funded to tackle delayed discharges in Scotland. PMID- 25727613 TI - Scheme trials emergency care at home to reduce hospital admissions. PMID- 25727614 TI - Nurses urged to use RCN's manifesto in run up to general election. PMID- 25727616 TI - When the beautiful game becomes a walk in the park. PMID- 25727617 TI - Code of conduct for professional standards revised. PMID- 25727618 TI - All patients with dementia should have pain relief. PMID- 25727619 TI - Pilot extended as integrated care produces good results. PMID- 25727624 TI - Creating experts. PMID- 25727625 TI - A place to call home? PMID- 25727632 TI - Practice question. Patient safety. PMID- 25727633 TI - Redesigning a home oxygen assessment and review service. AB - The Sheffield home oxygen assessment and review service was developed as a nurse led, protocol-driven service, offering high standards of care to a limited number of patients. In line with national changes to oxygen provision in 2011, the service team was approached to address inconsistencies and inequalities in the existing care pathway, with a view to becoming a fully commissioned service. This required a complete redesign of the service, using a collaborative approach to include relevant interested parties in planning and decision making. Additional support was gained through participation in the NHS Improvement lung national improvement project. This article outlines the process of service redesign, including some of the major challenges as well as the main learning points. It has led to the provision of an equitable and efficient service for all oxygen patients across the city, offering more community clinics and robust cost controls, while maintaining quality of care. PMID- 25727634 TI - Improving patients' and staff's experiences of acute care. AB - The aim of this audit was to assess the effect of the Quality Mark programme on the quality of acute care received by older patients by comparing the experiences of staff and older adults before and after the programme. Data from 31 wards in 12 acute hospitals were collected over two stages. Patients and staff completed questionnaires on the perceived quality of care on the ward. Patients rated improved experiences of nutrition, staff availability and dignity. Staff received an increase in training and reported better access to support, increased time and skill to deliver care and improved morale, leadership and teamwork. Problems remained with ward comfort and mealtimes. Overall, results indicated an improvement in ratings of care quality in most domains during Quality Mark data collection. Further audits need to explore ways of improving ward comfort and mealtime experience. PMID- 25727635 TI - Using the Newcastle Model to understand people whose behaviour challenges in dementia care. AB - National guidance for working with people whose behaviour challenges in dementia care suggests that a psychosocial approach should be the first-line intervention. However, there is little guidance for nurses about how to assess and manage behaviour that challenges in people with dementia. Nurses across specialties who work with older people might be asked to contribute to an assessment or provide advice to care home staff or families. This article presents one psychosocial model--the Newcastle Model--that provides a framework and process in which to understand behaviour that challenges in terms of needs which are unmet, and suggests a structure in which to develop effective interventions that keep people with dementia central to their care. PMID- 25727636 TI - Confidence builder. PMID- 25727637 TI - Lysophosphatidylcholine increases the neurotoxicity of Alzheimer's amyloid beta1 42 peptide: role of oligomer formation. AB - Oligomer formation is considered as a critical process for the neurotoxic effects of Alzheimer's amyloid beta (Abeta) peptide. Previously we have demonstrated that lysophosphatidylcholine (LPC) increases the oligomer formation of Abeta1-42, the major Abeta peptide found Alzheimer's disease (AD) lesions. In this study, we have investigated whether LPC affects the neurotoxic effects of Abeta1-42 in a neuronal cell line (A1) culture. Dimethyl thiazolyl diphenyl tetrazolium (MTT) assay revealed that up to 10MUM concentration, LPC did not affect A1 cell viability. Abeta1-42 decreased the cell viability, and such effect was dose dependently enhanced by LPC. However, neither LPC nor Abeta1-42, alone or in combination increased lactate dehydrogenase (LDH) release from A1 cells after 24 h treatment. Terminal deoxynucleotidyl transferase dUTP-biotin nick-end-labeling (TUNEL) assay showed that LPC increased Abeta1-42-induced apoptotic cell number. To determine the underlying mechanisms, the proteins implicated in apoptosis pathways including Bcl-2- and caspase-family were analyzed by Western blotting. The results demonstrated that Abeta1-42 decreased Bcl-2 in A1 cells at 24h, whereas LPC had no effect at any time point. Both LPC and Abeta1-42 increased Bax level at 24h, and their combined stimulation showed a synergistic effect. Similar synergistic effect of LPC and Abeta1-42 on caspase9 activation was observed. Dot blot immunoassay and Western blotting showed that LPC augmented Abeta1-42 oligomer formation in cell culture medium. Removing LPC-induced early-formed Abeta1-42 oligomer from the culture medium by immunoprecipitation decreased active caspase9 level and neurotoxicity, as revealed by Western blotting and MTT assay. Furthermore, dihydroethidium (DHE) assay showed that Abeta1-42 increased reactive oxygen species level in A1 cells, such effect was further enhanced by LPC. Thus, our results demonstrated that LPC increased the oligomer formation process of Abeta1-42 peptide in culture condition, and consequently increased apoptotic neuronal death. Such process might be important for the pathogenesis of AD, and inhibition of LPC generation could be a therapeutic target for the disease. PMID- 25727638 TI - Astrocytic vesicles and gliotransmitters: Slowness of vesicular release and synaptobrevin2-laden vesicle nanoarchitecture. AB - Neurotransmitters released at synapses activate neighboring astrocytes, which in turn, modulate neuronal activity by the release of diverse neuroactive substances that include classical neurotransmitters such as glutamate, GABA or ATP. Neuroactive substances are released from astrocytes through several distinct molecular mechanisms, for example, by diffusion through membrane channels, by translocation via plasmalemmal transporters or by vesicular exocytosis. Vesicular release regulated by a stimulus-mediated increase in cytosolic calcium involves soluble N-ethyl maleimide-sensitive fusion protein attachment protein receptor (SNARE)-dependent merger of the vesicle membrane with the plasmalemma. Up to 25 molecules of synaptobrevin 2 (Sb2), a SNARE complex protein, reside at a single astroglial vesicle; an individual neuronal, i.e. synaptic, vesicle contains ~70 Sb2 molecules. It is proposed that this paucity of Sb2 molecules in astrocytic vesicles may determine the slow secretion. In the present essay we shall overview multiple aspects of vesicular architecture and types of vesicles based on their cargo and dynamics in astroglial cells. PMID- 25727640 TI - Time-dependent bidirectional effects of chronic caffeine on functional recovery of the dorsal light reflex after hemilabyrinthectomy in the goldfish Carassius auratus. AB - Caffeine works through a variety of complex mechanisms to exert an often bidirectional set of functional and structural neurological changes in vertebrates. We investigated the effects of chronic caffeine exposure on functional recovery of the dorsal light reflex (DLR) in hemilabyrinthectomized common goldfish, Carassius auratus. In this lesion model, the unilateral removal of the vestibular organs results in a temporary loss of gravitationally modulated postural control which is quantifiable via the DLR. We compared the functional recovery over 24 days of post-surgery goldfish continuously held in a caffeine solution of 2.5mg/L (n=10), 5.0mg/L (n=10), 10.0mg/L (n=11), or 0.0mg/L control (n=9). Comparison to a sham surgery group (n=11) indicated statistically significant changes in the DLR of all hemilabyrinthectomized fish on day 1. The control group recovered over the study period and approached, but did not reach sham surgery DLR. Although the caffeine-treated fishes appeared to initiate some postural recovery within the first 2 weeks, beginning on day 10, all caffeine groups diverged from the control group with a deterioration of postural control. All three caffeine groups were significantly deficient in comparison with the control on days 10-24. These results suggest that caffeine exposure can at first be benign, but that high dosage or prolonged exposure hinders functional recovery. PMID- 25727639 TI - Adolescent intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat. AB - The brain continues to develop through adolescence when excessive alcohol consumption is prevalent in humans. We hypothesized that binge drinking doses of ethanol during adolescence will cause changes in brain ethanol responses that persist into adulthood. To test this hypothesis Wistar rats were treated with an adolescent intermittent ethanol (AIE; 5 g/kg, i.g. 2 days on-2 days off; P25-P54) model of underage drinking followed by 25 days of abstinence during maturation to young adulthood (P80). Using markers of neuronal activation c-Fos, EGR1, and phophorylated extracellar signal regulated kinase (pERK1/2), adult responses to a moderate and binge drinking ethanol challenge, e.g., 2 or 4 g/kg, were determined. Adult rats showed dose dependent increases in neuronal activation markers in multiple brain regions during ethanol challenge. Brain regional responses correlated are consistent with anatomical connections. AIE led to marked decreases in adult ethanol PFC (prefrontal cortex) and blunted responses in the amygdala. Binge drinking doses led to the nucleus accumbens (NAc) activation that correlated with the ventral tegmental area (VTA) activation. In contrast to other brain regions, AIE enhanced the adult NAc response to binge drinking doses. These studies suggest that adolescent alcohol exposure causes long-lasting changes in brain responses to alcohol that persist into adulthood. PMID- 25727641 TI - Periorbital contact dermatitis caused by octylisothiazolinone in a floor-cleaning agent. PMID- 25727642 TI - Random regression test day models to estimate genetic parameters for milk yield and milk components in Philippine dairy buffaloes. AB - Heritabilities and genetic correlations for milk production traits were estimated from first-parity test day records on 1022 Philippine dairy buffalo cows. Traits analysed included milk (MY), fat (FY) and protein (PY) yields, and fat (Fat%) and protein (Prot%) concentrations. Varying orders of Legendre polynomials (Leg(m)) as well as the Wilmink function (Wil) were used in random regression models. These various models were compared based on log likelihood, Akaike's information criterion, Bayesian information criterion and genetic variance estimates. Six residual variance classes were sufficient for MY, FY, PY and Fat%, while seven residual classes for Prot%. Multivariate analysis gave higher estimates of genetic variance and heritability compared with univariate analysis for all traits. Heritability estimates ranged from 0.25 to 0.44, 0.13 to 0.31 and 0.21 to 0.36 for MY, FY and PY, respectively. Wilmink's function was the better fitting function for additive genetic effects for all traits. It was also the preferred function for permanent environment effects for Fat% and Prot%, but for MY, FY and PY, the Legm was the appropriate function. Genetic correlations of MY with FY and PY were high and they were moderately negative with Fat% and Prot%. To prevent deterioration in Fat% and Prot% and improve milk quality, more weight should be applied to milk component traits. PMID- 25727643 TI - A combination of neostigmine and anisodamine protects against ischemic stroke by activating alpha7nAChR. AB - BACKGROUND: Increasing endogenous acetylcholine by neostigmine decreased the ischemic cerebral injury. The off-target action on muscarinic receptor produced a variety of adverse effects and limited the clinical application on stroke. AIM: We combined neostigmine with anisodamine and investigated the neuroprotection and mechanism. METHODS: Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neuroprotective action of neostigmine in combination with anisodamine at varying ratios was examined to determine the optimal combination as well as ideal therapeutic window. Potential involvement of alpha7 nicotinic acetylcholine receptor was examined by measuring the infarct size, the expression of proinflammatory cytokines, and the biomarkers of apoptosis in alpha7 nicotinic acetylcholine receptor knockout mice. A set of in vitro experiments was conducted in RAW264.7 cells to probe into potential molecular mechanisms. RESULTS: The neostigmine/anisodamine combination conferred neuroprotection. The protection was most potent at a ratio of 1:500. At such a ratio, the combination increased the binding of acetylcholine to alpha7 nicotinic acetylcholine receptor and reduced proinflammatory cytokines. The neuroprotection was evident only in wild-type and not in alpha7 nicotinic acetylcholine receptor knockout mice. The combination significantly decreased the expression of Bad and Bax, and increased Bcl-2 and Bcl-xl in alpha7 nicotinic acetylcholine receptor wild-type mice but not in knockout mice. The combination did not affect caspase-8, cleaved caspase-8, or caspase-12. CONCLUSIONS: Current study identified the optimal combination of neostigmine and anisodamine against ischemic stroke, and indicated that the acetylcholine-alpha7 nicotinic acetylcholine receptor is involved in the protective effects. PMID- 25727644 TI - Evaluation of androgen receptor and GATA binding protein 3 as immunohistochemical markers in the diagnosis of metastatic breast carcinoma to the lung. AB - Differentiating metastatic breast carcinoma in the lungs from primary lung tumors and mesotheliomas is important for determining prognosis and treatment. We evaluated novel breast specific markers, androgen receptor (AR) and GATA binding protein 3 (GATA3) immunohistostaining, for this differential, and compare to other traditional markers. The specimens comprised 33 metastatic breast carcinomas to the lung, 566 primary lung tumors (170 adenocarcinomas, 157 squamous cell carcinomas, 31 pleomorphic carcinomas, 115 large cell neuroendocrine carcinomas, 43 small cell carcinomas, and 49 typical carcinoids) and 42 malignant mesotheliomas. They were analyzed by immunohistochemistry using antibodies to AR, GATA3, estrogen receptor (ER), progesterone receptor (PgR), mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15). Of the metastatic breast carcinomas, immunohistostaining of AR, GATA3, ER, PgR, mammaglobin, GCDFP 15 were positive in 27 cases (81.8%), 24 cases (72.7%), 26 cases (78.8%), 13 cases (39.4%), 12 cases (36.4%), 9 cases (27.3%), respectively. Of primary lung tumors and mesotheliomas, staining of AR, GATA3, ER, PgR, mammaglobin, GCDFP-15 were positive in 18 cases (3%), 3 cases (0.5%), 4 cases (0.7%), 2 cases (0.3%), 0 case (0%), 2 cases (0.3%), respectively. Immunohistochemistry of AR and GATA3 are reliable for differentiating metastatic breast carcinoma from primary lung tumors and mesotheliomas. PMID- 25727645 TI - The Royal College of Radiologists' audit of prostate brachytherapy in the year 2012. AB - AIMS: This audit provides a comprehensive overview of UK prostate brachytherapy practice in the year 2012, measured against existing standards, immediately before the introduction of new Royal College of Radiologists (RCR) guidelines. This audit allows comparison with European and North American brachytherapy practice and for the impact of the RCR 2012 guidelines to be assessed in the future. MATERIALS AND METHODS: A web-based data collection tool was developed by the RCR Clinical Audit Committee and sent to audit leads at all cancer centres in the UK. Standards were developed based on available guidelines in use at the start of 2012 covering case mix and dosimetry. Further questions were included to reflect areas of anticipated change with the implementation of the 2012 guidelines. Audit findings were compared with similar audits of practice in Europe, the USA and Latin America. RESULTS: Forty-nine of 59 cancer centres submitted data. Twenty-nine centres reported carrying out prostate brachytherapy; of these, 25 (86%) provided data regarding the number of implants, staffing, dosimetry, medication and anaesthesia and follow-up. Audit standards achieved excellent compliance in most areas, although were low in post-implant dosimetry and in post-implant scanning at 30 days. CONCLUSION: This audit provides a comprehensive picture of prostate brachytherapy in the UK in 2012. Patterns of care of prostate brachytherapy are similar to practice in the USA and Europe. The number of prostate brachytherapy implants carried out in the UK has grown significantly since a previous RCR audit in 2005 and it is important that centres maintain minimum numbers of cases to ensure that experience can be maintained and compliance to guidelines achieved. PMID- 25727646 TI - Evaluating competing and emerging technologies for stereotactic body radiotherapy and other advanced radiotherapy techniques. AB - Stereotactic body radiotherapy (SBRT) refers to the precise irradiation of an image-defined extracranial lesion, using a high total radiation dose delivered in a small number of fractions. A significant proportion of SBRT treatment has been successfully delivered using conventional gantry-based linear accelerators with appropriate image guidance and motion management techniques, although a number of specialist systems are also available. Evaluating the competing SBRT technologies is difficult due to frequent refinements to all major platforms. Comparison of geometric accuracy or treatment planning performance can be hard to interpret and may not provide much useful information. Nevertheless, a general specification overview can provide information that may help radiotherapy providers decide on an appropriate system for their centre. A number of UK randomised controlled trials (RCTs) have shown that better radiotherapy techniques yield better results. RCTs should play an important part in the future evaluation of SBRT, especially where there is a smaller volume of existing data, and where outcomes from conventional radiotherapy are very good. RCT comparison of SBRT with surgery is more difficult due to the radically different treatment arms, although successful recruitment can be possible if the lessons from previous failed trials are learned. The evaluation of new technology poses a number of challenges to the conventional RCT methodology, and there may be situations where it is genuinely not possible, with careful observational studies or decision modelling being more appropriate. Further development in trial design may have an important role in providing clinical evidence in a more timely manner. PMID- 25727647 TI - Pelvic Intensity-modulated Radiotherapy: Can we Better Quantify the Late Side effects? PMID- 25727648 TI - Measuring vascular reactivity with breath-holds after stroke: a method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies. AB - Blood oxygenation level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath-hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task-related BOLD signal changes. Three methods of analyzing the breath-hold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue and the peri-infarct tissue, both sub-acutely (~2 weeks) and chronically (~4 months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared with the controls may be confounded by a reduced CVR, longitudinal group-level BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath-hold-based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity. PMID- 25727649 TI - At the centre of neuronal, synaptic and axonal pathology in murine prion disease: degeneration of neuroanatomically linked thalamic and brainstem nuclei. AB - AIMS: The processes by which neurons degenerate in chronic neurodegenerative diseases remain unclear. Synaptic loss and axonal pathology frequently precede neuronal loss and protein aggregation demonstrably spreads along neuroanatomical pathways in many neurodegenerative diseases. The spread of neuronal pathology is less studied. METHODS: We previously demonstrated severe neurodegeneration in the posterior thalamus of multiple prion disease strains. Here we used the ME7 model of prion disease to examine the nature of this degeneration in the posterior thalamus and the major brainstem projections into this region. RESULTS: We objectively quantified neurological decline between 16 and 18 weeks post inoculation and observed thalamic subregion-selective neuronal, synaptic and axonal pathology while demonstrating relatively uniform protease-resistant prion protein (PrP) aggregation and microgliosis across the posterior thalamus. Novel amyloid precursor protein (APP) pathology was particularly prominent in the thalamic posterior (PO) and ventroposterior lateral (VPL) nuclei. The brainstem nuclei forming the major projections to these thalamic nuclei were examined. Massive neuronal loss in the PO was not matched by significant neuronal loss in the interpolaris (Sp5I), while massive synaptic loss in the ventral posteromedial nucleus (VPM) did correspond with significant neuronal loss in the principal trigeminal nucleus. Likewise, significant VPL synaptic loss was matched by significant neuronal loss in the gracile and cuneate nuclei. CONCLUSION: These findings demonstrate significant spread of neuronal pathology from the thalamus to the brainstem in prion disease. The divergent neuropathological features in adjacent neuronal populations demonstrates that there are discrete pathways to neurodegeneration in different neuronal populations. PMID- 25727650 TI - Severe Angioedema Associated With Angiotensin-Converting Enzyme Inhibitor Therapy in Two Patients With Pollen-Food Allergy Syndrome. PMID- 25727651 TI - Cellular immunotherapy in ovarian cancer: Targeting the stem of recurrence. AB - Ovarian cancer is a devastating disease with a high relapse rate. Due to a mostly asymptomatic early stage and lack of early diagnostic tools, the disease is usually diagnosed in a late stage. Surgery and chemotherapy with taxanes and platinum compounds are very effective in reducing tumor burden. However, relapses occur frequently and there is a lack of credible second-line options. Therefore, new treatment modalities are eagerly awaited. The presence and influx of immune cells in the ovarian cancer tumor microenvironment are correlated with survival. High numbers of infiltrating T cells correlate with improved progression free and overall survival, while the presence of regulatory T cells and expression of T cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy, especially cell-based immunotherapy could be a promising novel addition to the treatment of ovarian cancer. Here, we review the available data on the immune contexture surrounding ovarian cancer and discuss novel strategies and targets for immunotherapy in ovarian cancer. In the end the addition of immunotherapy to existing therapeutic options could lead to a great improvement in the outcome of ovarian cancer, especially when targeting cancer stem cells. PMID- 25727652 TI - Contribution of lymphoscintigraphy to intraoperative sentinel lymph node detection in early cervical cancer: Analysis of the prospective multicenter SENTICOL cohort. AB - PURPOSE: To evaluate the contribution of preoperative lymphoscintigraphy to intraoperative lymphatic mapping (ILM) in early cervical cancer METHODS: We conducted an ancillary analysis of the multicenter prospective SENTICOL study in early cervical cancer. Radiocolloid was injected intracervically on the day before (long protocol) or morning of (short protocol) surgery, lymphoscintigraphy was performed, and the results of a centralized image review were communicated to the surgeons. ILM was performed on combined radioactivity/patent blue detection. Sentinel lymph nodes (SLNs) were electively sampled before routine bilateral pelvic lymphadenectomy by laparoscopy. RESULTS: Of 139 patients in the modified intention-to-diagnose analysis, 114 had centrally reviewed lymphoscintigrams, which showed 352 SLNs in 100 patients. Lymphoscintigraphy and ILM detection rates were 87.8% and 97.8%, respectively. Agreement between lymphoscintigraphy and ILM was low for the number of SLNs (kappa=0.23; -0.04; 0.49) and bilateral SLNs (kappa=0.36; 0.2; 0.52). No patient without SLNs by ILM had SLNs by lymphoscintigraphy. Lymphoscintigraphy identified substantial proportions of unusual drainage pathways. No patients with metastatic nodes had SLNs by lymphoscintigraphy but not by ILM in the relevant territory. In 1 of the 2 patients with false-negative SLN results, SLNs were bilateral by lymphoscintigraphy and unilateral by ILM. CONCLUSION: Although the detection rate was lower by lymphoscintigraphy than by ILM, the substantial proportions of SLNs in unusual territories provided valuable guidance for the surgical exploration. Awareness of the limited agreement between lymphoscintigraphic and surgical detection might help surgeons decrease the false-negative rate. PMID- 25727653 TI - [Indications of lung transplantation: Patients selection, timing of listing, and choice of procedure]. AB - Lung transplantation (LT) is now considered as an excellent treatment option for selected patients with end-stage pulmonary diseases, such as COPD, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension. The 2 goals of LT are to provide a survival benefit and to improve quality of life. The 3-step decision process leading to LT is discussed in this review. The first step is the selection of candidates, which requires a careful examination in order to check absolute and relative contraindications. The second step is the timing of listing for LT; it requires the knowledge of disease-specific prognostic factors available in international guidelines, and discussed in this paper. The third step is the choice of procedure: indications of heart-lung, single-lung, and bilateral-lung transplantation are described. In conclusion, this document provides guidelines to help pulmonologists in the referral and selection processes of candidates for transplantation in order to optimize the outcome of LT. PMID- 25727654 TI - [A rare tumor of the chest wall: the synovialosarcoma]. PMID- 25727655 TI - [Extensively drug resistant tuberculosis in Ivory Coast]. AB - INTRODUCTION: The emergence of tuberculosis with ultraresistant bacilli (TB-UR or XDR-TB) came to increase the threat concerning the progress realized in tuberculosis control. This observation establishes the only case of XDR-TB documented and published since the beginning of pharmacoresistant tuberculosis management in Ivory Coast from 2000 till 2010. This case was diagnosed in 2005 at a HIV-negative 32-year-old woman, initially declared MDR-TB. Looking forward to a treatment of category IV, she was treated by therapeutic truncated protocols recombining antituberculous molecules to which the patient was still sensitive. This treatment (PAS, cycloserin, ciprofoxacin, ethionamid, ethambutol and kanamycin) was introduced after 9 months of waiting and was completely led in ambulatory under the supervision of a member of the family. The diagnosis of XDR TB concerned new tests of sensibility spread to second line antituberculous drugs in front of the absence of spits negativation at the end of 14 months of a second line treatment marked by frequent stock shortages. The death arose at M19 of treatment by chronic heart pulmonary. CONCLUSION: XDR-TB remains dark prognosis and is almost synonymic of "death sentence" in our countries with limited resources. The application of the international recommendations for tuberculosis management and better accessibility to antituberculous second line drugs would allow to prevent the appearance of such forms of tuberculosis. PMID- 25727656 TI - [Life threatening haemoptysis associated with partial abnormal pulmonary venous return and pulmonary arterial hypertension]. AB - A 73-year-old man with chronic respiratory insufficiency was referred to the intensive care unit because of life threatening haemoptysis and hypoxemia. The patient was in respiratory failure with pulmonary arterial hypertension. The bleeding was issuing from the left inferior lobe. A small arterio-venous fistula was suspected on tomodensitometry. Arterial embolization was contraindicated because of diffuse vascular disease. A left inferior lobectomy was performed. The left superior pulmonary vein was draining into the brachiocephalic vein forming a partial anomalous pulmonary venous return. An anatomic restoration of the venous return to the left atrium was performed. The postoperative course was uneventful. No recurrence of haemoptysis was observed, after 9-month follow-up the vascular anastomosis was patent. Despite the pulmonary vascular bed reduction following lobectomy, echocardiography showed a globally mild improvement of cardiac status that might be attributed to right heart preload amelioration. PMID- 25727657 TI - [Severe pulmonary tuberculosis in the ICU, diagnosis and treatment]. AB - INTRODUCTION: Pulmonary tuberculosis can rarely lead to acute respiratory distress syndrome and anti-tuberculous therapy initiation depends on this difficult diagnosis in ICU. CASE REPORT: A 50-year-old man presented a septic shock and acute respiratory distress syndrome with bilateral infiltrates mainly in the upper lobes on chest radiography. Diagnosis of pulmonary tuberculosis was made 10days after admission on examination of cavitary and diffuse infiltrates on a second CT scan, in addition to presence of acid-fast bacilli on smear examination of bronchial aspirates. Amikacin, with four first-line anti tuberculous drugs, was started in the case of a resistant strain and seriousness of the illness. After 14weeks, he left on rifampicin and isoniazid treatment. CONCLUSIONS: There are no specific recommendations concerning pulmonary tuberculosis in ICU but a delay in initiation of anti-tuberculous therapy is a factor of poor prognosis. Using a second-line anti-tuberculous drug, like amikacin or/and fluoroquinolones, within initial treatment may accelerate improvement of sepsis and immediately treat resistant strains, when genomic methods for detection of resistance are not available in routine. PMID- 25727658 TI - [Consequences of tobacco smoking on lung cancer treatments]. AB - In France, in 2010, tobacco induced 81% of deaths by lung cancer corresponding to about 28,000 deaths. Continued smoking after diagnosis has a significant impact on treatment. In patients with lung cancer, the benefits of smoking cessation are present at any stage of disease. For early stages, smoking cessation decreases postoperative morbidity, reduces the risk of second cancer and improves survival. Previous to surgery, smoking cessation of at least six to eight weeks or as soon as possible is recommended in order to reduce the risk of infectious complications. Tobacco could alter the metabolism of certain chemotherapies and targeted therapies, such as tyrosine kinase inhibitors of the EGF receptor, through an interaction with P450 cytochrome. Toxicity of radiations could be lower in patients with lung cancer who did not quit smoking before treatment. For patients treated by radio-chemotherapy, overall survival seems to be better in former smokers but no difference is observed in terms of recurrence-free survival. For advanced stages, smoking cessation enhances patients' quality of life. Smoking cessation should be considered as full part of lung cancer treatment whatever the stage of disease. PMID- 25727659 TI - [Patient's course requiring NIPPV in Centre Hospitalier Lyon-Sud]. AB - Non-invasive positive pressure ventilation (NIPPV) has become a major therapeutic of acute respiratory failure. Thanks to technical progress, its use has become widespread in intensive care units and now in emergency and pneumology departments, for indications recognized and validated as decompensation of chronic obstructive pulmonary disease and acute cardiogenic pulmonary edema. Patients with this conditions transit in the hospital, from the emergency or pulmonology departments, sometimes through intensive care units. Knowledge of the NIPPV, its indications, contraindications, terms of use and surveillance requires trained teams. This training covers not only the technical but also the hardware, multiple ventilation modes, and interfaces. Other indications being evaluated, such as ventilation in the perioperative period, also require coordination between different actors. The establishment of a specific group of thinking and working around the NIPPV is clearly needed, allowing teams of hospital (emergency department, intensive care unit, pulmonology, anesthesia) to work together. This work deals with different areas: training, equipment, condition of receiving patients in the different services within the constraints of personnel and equipment. In this article, we trace the point of view of each of the professionals in this group and some of the actions implemented. PMID- 25727661 TI - [Therapeutic advances in cystic fibrosis in 2014]. AB - Twenty-five years after the cystic fibrosis (CF) gene identification, this discovery actually begins to benefit to patients. Increasing our knowledge on CFTR biology, as well as technical progress made in order to screen for new drugs have made therapeutic strategies move an important step forward. It is likely that in the forthcoming years, the panel of molecules available for CF patients will be larger, with new activators and potentiators. The disease by itself may consequently change in its natural history. CF is an example of the so-called personalized medicine, aiming to fit treatment according to patient's genetic background. Ongoing clinical trials may enlarge the actually limited eligible number of CF patients for new drugs such as ivacaftor. Beyond this exciting and promising new therapeutic approach, one may not push symptomatic treatments on the side. Improvements have been made for inhaled antibiotics administration, aiming to simplify patient's life; clinical trials using new molecules able to liquefy mucus or with anti-inflammatory properties are actually underway. One important next step in the care for CF will be to design and conduct early intervention trials in CF infants. Newborn screening program have been widely implanted around the word, and cohorts studies have shown that both functional and structural abnormalities occurred very early, making the therapeutic window of opportunity tight. PMID- 25727660 TI - [Management of spontaneous pneumothorax during pregnancy: a case report and review of literature]. PMID- 25727663 TI - [Infectious pleurisy as first sign of multiple myeloma in a young 28 years old]. AB - Multiple myeloma is a malignant proliferation of plasma cells, mainly affecting the bone marrow. It rarely occurs in young patients. The medical observation study reveals multiple myeloma discovered through a purulent pleurisy in a 28 year-old subject. This patient was admitted to the pneumology service of the Mohamed V military hospital in Rabat for a fever and dyspnea evolving into a context of poor general condition. Clinical examination found a right pleural fluid effusion syndrome. The pleural puncture reveals a germ-free exudative purulent fluid without plasma cells. The myeloma diagnosis was suspected due to the combination of an aplastic normochromic normocytic anemia at 4.5g/dL of hemoglobin, an accelerated erythrocyte sedimentation rate, hypercalcemia, renal failure and osteolytic lesions located mainly in the skull and pelvis area, oriented by electrophoresis and serum protein immunosubstraction revealing a narrow peak in monoclonal beta-2 globulin at 70.56g/L with a lambda monoclonal gammopathy with immunoglobulin G, and confirmed by the myelogram showing a 74% rate of bone marrow plasma cells. The occurrence of myeloma at a young age is rare and the purulent pleurisy without plasma cells is a rare form of presentation and represents a poor prognosis. PMID- 25727662 TI - [Results of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer: importance of the lymph node involvement prevalence]. AB - OBJECTIVE: We studied the non-surgical invasive staging by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and we detailed the differences of our series, in order to understand the criteria allowing to achieve a better performance. METHODS: Retrospective observational study conducted between 2007 and 2011, including all patients with proven NSCLC who underwent EBUS-TBNA. RESULTS: For the 92 EBUS-TBNA performed, we found a sensitivity of 78%, a specificity of 93%, a positive predictive value (PPV) of 98%, a negative predictive value (NPV) of 45%, an accuracy of 80% and a prevalence of lymph node involvement at 84%. A learning curve has been demonstrated and a significant difference was found based on the number of punctures by procedure (P=0.02) or on histological type (P=0.02). By analyzing the data of the literature, we have been able to demonstrate that the accuracy and the negative predictive value are correlated with the prevalence. If we take into account this correlation, we can consider the results of our study close to those of the literature. CONCLUSION: We highlighted a number of criteria that will influence the diagnostic yield of EBUS-TBNA. While some have already been described, other criteria such as histological type or patient selection criteria are less discussed. The key point is the correlation between the prevalence and EBUS-TBNA results. Results of the assessment of lymph node involvement techniques should be interpreted according to the prevalence of lymph node involvement. PMID- 25727664 TI - [Acute asthma in emergency room. Primum non nocere!]. PMID- 25727665 TI - Real-time NMR monitoring of biological activities in complex physiological environments. AB - Biological reactions occur in a highly organized spatiotemporal context and with kinetics that are modulated by multiple environmental factors. To integrate these variables in our experimental investigations of 'native' biological activities, we require quantitative tools for time-resolved in situ analyses in physiologically relevant settings. Here, we outline the use of high-resolution NMR spectroscopy to directly observe biological reactions in complex environments and in real-time. Specifically, we discuss how real-time NMR (RT-NMR) methods have delineated insights into metabolic processes, post-translational protein modifications, activities of cellular GTPases and their regulators, as well as of protein folding events. PMID- 25727669 TI - A surface plasmon resonance assay for measurement of neuraminidase inhibition, sensitivity of wild-type influenza neuraminidase and its H274Y mutant to the antiviral drugs zanamivir and oseltamivir. AB - Antiviral resistance is currently monitored by a labelled enzymatic assay, which can give inconsistent results because of the short half-life of the labelled product, and variations in assay conditions. In this paper, we describe a competitive surface plasmon resonance (SPR) inhibition assay for measuring the sensitivities of wild-type neuraminidase (WT NA) and the H274Y (histidine 274 tyrosine) NA mutant to antiviral drugs. The two NA isoforms were expressed in High-fiveTM (Trichoplusia ni) insect cells. A spacer molecule (1,6-hexanediamine (HDA)) was conjugated to the 7-hydroxyl group of zanamivir, and the construct (HDA-zanamivir) was immobilized onto a SPR sensor chip to obtain a final immobilization response of 431 response units. The immobilized HDA-zanamivir comprised a bio-specific ligand for the WT and mutant proteins. The effects of the natural substrate (sialic acid) and two inhibitors (zanamivir and oseltamivir) on NA binding to the immobilized ligand were studied. The processed SPR data was analysed to determine 50% inhibitory concentrations (IC50-spr ), using a log dose-response curve fit. Although both NA isoforms had almost identical IC50-spr values for sialic acid (WT = 5.5 nM; H274Y mutant = 3.25 nM) and zanamivir (WT = 2.16 nM; H274Y mutant = 2.42 nM), there were significant differences between the IC50-spr values obtained for the WT (7.7 nM) and H274Y mutant (256 nM) NA in the presence of oseltamivir, indicating that oseltamivir has a reduced affinity for the H274Y mutant. The SPR inhibition assay strategy presented in this work could be applied for the rapid screening of newly emerging variants of NA for their sensitivity to antiviral drugs. PMID- 25727667 TI - The effects of atorvastatin treatment on the mean platelet volume and red cell distribution width in patients with dyslipoproteinemia and comparison with plasma atherogenicity indicators--A pilot study. AB - OBJECTIVES: The mean platelet volume (MPV) and red cell distribution width (RDW) have recently arisen interest because of their association with an increased cardiovascular risk. The aim of our study was, therefore, to determine whether an association exists between MPV, RDW and lipoprotein sub-fractions, and to show the impact of statin therapy on these new possible biomarkers of atherosclerotic risk. DESIGN AND METHODS: A cohort of 40 patients with hypercholesterolaemia (29 females, mean age 62.9+/-9 years), without previous hypolipidaemic treatment were enrolled. The patients were treated with atorvastatin 40 mg/day for 12 weeks. Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density cholesterol (HDL-C), triglycerides (TG), LDL-C sub-fractions [large LDL-C 1-2 and small dense (sd)-LDL-C 3-7], apolipoproteins (apoA1, apoB), apoB/apoA1 ratio, atherogenic index of plasma (AIP), haematological parameters (including MPV, RDW) and safety parameters (renal, hepatic) were measured before and after 12 weeks of atorvastatin treatment. RESULTS: At baseline, a strong correlation between HDL-C, TG, sd-LDL-C, apoB, apoB/apoA1, and AIP with MPV (r=-0.55, p<0.001; r=0.57, p<0.001; r=0.73, p<0.001; r=0.41, p<0.05; r=0.52, p<0.001; r=0.61, p<0.001, respectively) and RDW (r=-0.49, p<0.001; r=0.62, p<0.001; r=0.67, p<0.001; r=0.41, p<0.05; r=0.43, p<0.05; r=0.65, p<0.001, respectively) was found. After 12 weeks of treatment with atorvastatin, MPV and RDW values underwent significant modification only in those patients displaying the strongest lipid-lowering effect. CONCLUSIONS: Values of MPV and RDW seem to reflect a pro-atherogenic lipoprotein profile mainly represented by the presence of sd-LDL-C. PMID- 25727668 TI - Functional distinctness in the exoproteomes of marine Synechococcus. AB - The exported protein fraction of an organism may reflect its life strategy and, ultimately, the way it is perceived by the outside world. Bioinformatic prediction of the exported pan-proteome of Prochlorococcus and Synechococcus lineages demonstrated that (i) this fraction of the encoded proteome had a much higher incidence of lineage-specific proteins than the cytosolic fraction (57% and 73% homologue incidence respectively) and (ii) exported proteins are largely uncharacterized to date (54%) compared with proteins from the cytosolic fraction (35%). This suggests that the genomic and functional diversity of these organisms lies largely in the diverse pool of novel functions these organisms export to/through their membranes playing a key role in community diversification, e.g. for niche partitioning or evading predation. Experimental exoproteome analysis of marine Synechococcus showed transport systems for inorganic nutrients, an interesting array of strain-specific exoproteins involved in mutualistic or hostile interactions (i.e. hemolysins, pilins, adhesins), and exoenzymes with a potential mixotrophic goal (i.e. exoproteases and chitinases). We also show how these organisms can remodel their exoproteome, i.e. by increasing the repertoire of interaction proteins when grown in the presence of a heterotroph or decrease exposure to prey when grown in the dark. Finally, our data indicate that heterotrophic bacteria can feed on the exoproteome of Synechococcus. PMID- 25727670 TI - Phase II anti-inflammatory and immune-modulating drugs for acute ischaemic stroke. AB - INTRODUCTION: Stroke is the second leading cause of death worldwide and the leading cause of adult neurological disability. Despite advances in stroke unit care, and increasing use of thrombolysis, there remains an urgent need for safe and effective treatments for acute ischaemic stroke. However, this is against a backdrop of multiple failures in translational drug development. Cerebral ischaemia initiates a complex cascade of immune and inflammatory pathways in the brain microvasculature and periphery, which contribute to the evolution of cerebral injury, resolution and repair. Targeting specific inflammatory or immune pathways, therefore, represents an attractive treatment strategy in acute ischaemic stroke. Although anti-inflammatory drugs have already failed in clinical trial development, several are currently at the Phase II developmental stage. AREAS COVERED: The authors highlight several candidate drugs, which modulate a range of inflammatory and immune pathways, and have been investigated in pre-clinical and Phase II studies to date. EXPERT OPINION: Drugs targeting inflammatory and immune pathways offer theoretical advantages including potentially longer therapeutic time windows and effects complementary to thrombolysis (ameliorating reperfusion injury). Fundamental changes in the approach to pre-clinical and clinical drug development are required to facilitate successful translation of promising candidate drugs into clinical practice. PMID- 25727671 TI - Quality of referrals and guideline compliance for time to consultation at an acute neurovascular clinic. AB - BACKGROUND: The Age, Blood pressure, Clinical features, Duration of symptoms, Diabetes (ABCD2) score can be used to predict early recurrent stroke risk following Transient ischemic attack (TIA). Given that recurrent stroke risk can be as high as 20% in the first week, international guidelines recommend "high risk" TIAs (ABCD2 >3) be seen by specialist services such as dedicated acute neurovascular clinics within 24 hours. The goal of this study was to examine the associations of both quality of referrals to a specialist acute clinic and of "guideline congruence" of time-to-clinic consultation after TIA/minor stroke. We hypothesized high-quality referrals containing key clinical elements would be associated with greater guideline congruence. METHODS: A retrospective analysis of referrals to an acute neurovascular clinic within a tertiary care hospital of consecutive patients with TIA/minor stroke. Quality of general practitioner and emergency department referrals was defined on the basis of information content enabling ABCD2-based risk stratification by the clinic triage service. Time-to clinic consultation was used to define "guideline congruence." RESULTS: Referrals of 148 consecutive eligible patients were reviewed. Sixty-six percent of cases were subsequently neurologist-diagnosed as TIA or minor stroke. Seventy-nine percent were referred by general practitioners. Fifty-three percent of referrals were of high quality, but quality was not associated with guideline congruence. Of the high-risk patients, only 3.6% were seen at the clinic within 24 hours of index event and 31.3% within 24 hours of referral. CONCLUSIONS: Current guidelines are pathophysiologically logical and evidence based, but are difficult to implement. Improving quality of primary-secondary communication by improved referral quality is unlikely to improve guideline compliance. Alternative strategies are needed to reduce recurrent stroke risk after TIA/minor stroke. PMID- 25727672 TI - Next generation sequencing for systematic assessment of genetics of small-vessel disease and lacunar stroke. AB - BACKGROUND: The pathogenesis of cerebral small-vessel disease (SVD) is still incompletely understood, although evidence from family and twin studies supports the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge on SVD pathogenesis. SVE-LA (Small Vessel and Lacunar) project is a multicenter prospective Lombardia region study aimed at applying innovative genetic technologies and accurate patient phenotyping to discover the genetic basis of SVD. METHODS: A continuous series of subjects (aged 15-80 years) with a clinically and radiologically defined lacunar stroke referring to the participating Lombardia region stroke centers and an adequate number of age- and sex-matched controls are being included into the study. For each patient, clinical, demographic, instrumental, and familial data are collected applying standardized forms. After informed consent, a DNA sample for genetic analysis from patients and controls has been collected. The next generation sequencing (NGS) technology was applied to systematically screen patients for the most important genetic factors both monogenic and polygenic associated with SVD. The study includes also a centralized quantitative and qualitative analysis of neuroimaging studies. RESULTS: Between March 2011 and October 2013, 212 lacunar stroke patients and 78 controls have been collected. Mean age of cases was 65.8 +/- 11.1 years and 67% were men. CONCLUSIONS: This is the first study applying systematically NGS technology on a wide series of lacunar stroke patients. A translational approach combining a systematic genetic screening with a detailed phenotyping may facilitate the discovery of genetic basis and improve our knowledge in the pathogenesis of SVD. PMID- 25727673 TI - A study of the hourly variability of the urban heat island effect in the Greater Athens Area during summer. AB - Measurements of air temperature and humidity in the urban canopy layer during July 2009 in 26 sites in Athens, Greece, allowed for the mapping of the hourly spatiotemporal evolution of the urban heat island (UHI) effect. City districts neighboring to the mountains to the east were the hottest during the afternoon, while being among the coolest during the early morning hours. While during the early morning some coastal sites were the hottest, the warm air plume slowly moved to the densely urbanized center of the city until 14:00-15:00, moving then further west, to the Elefsis industrial area in the afternoon. Results from the UrbClim model agree fairly well with the observations. Satellite-derived land surface temperature (LST) data from AATSR, ASTER, AVHRR and MODIS, for pixels corresponding to ground stations measuring Tair, showed that LST can be up to 5K lower than the respective Tair during nighttime, while it can be up to 15K higher during the rest of the day. Generally, LST during late afternoon as acquired from AATSR is very near to Tair for all stations and all days, i.e., the AATSR LST afternoon retrieval can be used as a very good approximation of Tair. The hourly evolution of the spatial Tair distribution was almost the same during days with NE Etesian flow as in days with sea breeze circulation, indicating that the mean wind flow was not the main factor controlling the diurnal UHI evolution, although it influenced the temperatures attained. No unambiguous observation of the urban moisture excess (UME) phenomenon could be made. PMID- 25727674 TI - Porewater dynamics of silver, lead and copper in coastal sediments and implications for benthic metal fluxes. AB - To determine the conditions that lead to a diffusive release of dissolved metals from coastal sediments, porewater profiles of Ag, Cu, and Pb have been collected over seven years at two contrasting coastal sites in Massachusetts, USA. The Hingham Bay (HB) site is a contaminated location in Boston Harbor, while the Massachusetts Bay (MB) site is 11 km offshore and less impacted. At both sites, the biogeochemical cycles include scavenging by Fe-oxyhydroxides and release of dissolved metals when Fe-oxyhydroxides are reduced. Important differences in the metal cycles at the two sites, however, result from different redox conditions. Porewater sulfide and seasonal variation in redox zone depth is observed at HB, but not at MB. In summer, as the conditions become more reducing at HB, trace metals are precipitated as sulfides and are no longer associated with Fe oxyhydroxides. Sulfide precipitation close to the sediment-water interface limits the trace metal flux in summer and autumn at HB, while in winter, oxidation of the sulfide phases drives high benthic fluxes of Cu and Ag, as oxic conditions return. The annual diffusive flux of Cu at HB is found to be significant and contributes to the higher than expected water column Cu concentrations observed in Boston Harbor. At MB, due to the lower sulfide concentrations, the association of trace metals with Fe-oxyhydroxides occurs throughout the year, leading to more stable fluxes. A surface enrichment of solid phase trace metals was found at MB and is attributed to the persistent scavenging by Fe-oxyhydroxides. This process is important, particularly at sites that are less reducing, because it maintains elevated metal concentrations at the surface despite the effects of bioturbation and sediment accumulation, and because it may increase the persistence of metal contamination in surface sediments. PMID- 25727675 TI - Endocrine disrupting alkylphenolic chemicals and other contaminants in wastewater treatment plant effluents, urban streams, and fish in the Great Lakes and Upper Mississippi River Regions. AB - Urban streams are an integral part of the municipal water cycle and provide a point of discharge for wastewater treatment plant (WWTP) effluents, allowing additional attenuation through dilution and transformation processes, as well as a conduit for transporting contaminants to downstream water supplies. Domestic and commercial activities dispose of wastes down-the-drain, resulting in wastewater containing complex chemical mixtures that are only partially removed during treatment. A key issue associated with WWTP effluent discharge into streams is the potential to cause endocrine disruption in fish. This study provides a long-term (1999-2009) evaluation of the occurrence of alkylphenolic endocrine disrupting chemicals (EDCs) and other contaminants discharged from WWTPs into streams in the Great Lakes and Upper Mississippi River Regions (Indiana, Illinois, Michigan, Minnesota, and Ohio). The Greater Metropolitan Chicago Area Waterways, Illinois, were evaluated to determine contaminant concentrations in the major WWTP effluents and receiving streams, and assess the behavior of EDCs from their sources within the sewer collection system, through the major treatment unit processes at a WWTP, to their persistence and transport in the receiving stream. Water samples were analyzed for alkylphenolic EDCs and other contaminants, including 4-nonylphenol (NP), 4-nonylphenolpolyethoxylates (NPEO), 4-nonylphenolethoxycarboxylic acids (NPEC), 4-tert-octylphenol (OP), 4 tert-octylphenolpolyethoxylates (OPEO), bisphenol A, triclosan, ethylenediaminetetraacetic acid (EDTA), and trace elements. All of the compounds were detected in all of the WWTP effluents, with EDTA and NPEC having the greatest concentrations. The compounds also were detected in the WWTP effluent dominated rivers. Multiple fish species were collected from river and lake sites and analyzed for NP, NPEO, NPEC, OP, and OPEO. Whole-body fish tissue analysis indicated widespread occurrence of alkylphenolic compounds, with the highest concentrations occurring in streams with the greatest WWTP effluent content. Biomarkers of endocrine disruption in the fish indicated long-term exposure to estrogenic chemicals in the wastewater impacted urban waterways. PMID- 25727676 TI - Quantification and characterization of glyphosate use and loss in a residential area. AB - Urban runoff can be a significant source of pesticides in urban streams. However, quantification of this source has been difficult because pesticide use by urban residents (e.g., on pavements or in gardens) is often unknown, particularly at the scale of a residential catchment. Proper quantification and characterization of pesticide loss via urban runoff require sound information on the use and occurrence of pesticides at hydrologically-relevant spatial scales, involving various hydrological conditions. We conducted a monitoring study in a residential area (9.5 ha, Flanders, Belgium) to investigate the use and loss of a widely-used herbicide (glyphosate) and its major degradation product (aminomethylphosphonic acid, AMPA). The study covered 13 rainfall events over 67 days. Overall, less than 0.5% of glyphosate applied was recovered from the storm drain outflow in the catchment. Maximum detected concentrations were 6.1 MUg/L and 5.8 MUg/L for glyphosate and AMPA, respectively, both of which are below the predicted no effect concentration for surface water proposed by the Flemish environmental agency (10 MUg/L), but are above the EU drinking water standard (0.1 MUg/L). The measured concentrations and percentage loss rates can be attributed partially to the strong sorption capacity of glyphosate and low runoff potential in the study area. However, glyphosate loss varied considerably among rainfall events and event load of glyphosate mass was mainly controlled by rainfall amount, according to further statistical analyses. To obtain urban pesticide management insights, robust tools are required to investigate the loss and occurrence of pesticides influenced by various factors, particularly the hydrological and spatial factors. PMID- 25727678 TI - Computerised therapies for anxiety and depression in children and young people: a systematic review and meta-analysis. AB - One quarter of children and young people (CYP) experience anxiety and/or depression before adulthood, but treatment is sometimes unavailable or inadequate. Self-help interventions may have a role in augmenting treatment and this work aimed to systematically review the evidence for computerised anxiety and depression interventions in CYP aged 5-25 years old. Databases were searched for randomised controlled trials and 27 studies were identified. For young people (12-25 years) with risk of diagnosed anxiety disorders or depression, computerised CBT (cCBT) had positive effects for symptoms of anxiety (SMD -0.77, 95% CI -1.45 to -0.09, k = 6, N = 220) and depression (SMD -0.62, 95% CI -1.13 to -0.11, k = 7, N = 279). In a general population study of young people, there were small positive effects for anxiety (SMD -0.15, 95% CI -0.26 to -0.03; N = 1273) and depression (SMD -0.15, 95% CI -0.26 to -0.03; N = 1280). There was uncertainty around the effectiveness of cCBT in children (5-11 years). Evidence for other computerised interventions was sparse and inconclusive. Computerised CBT has potential for treating and preventing anxiety and depression in clinical and general populations of young people. Further program development and research is required to extend its use and establish its benefit in children. PMID- 25727679 TI - Behavioral treatment of social phobia in youth: does parent education training improve the outcome? AB - Social phobia is one of the most common anxiety disorders in children and adolescents, and it runs a fairly chronic course if left untreated. The goals of the present study were to evaluate if a parent education course would improve the outcome for children with a primary diagnosis of social phobia and if comorbidity at the start of treatment would impair the outcome of the social phobia. A total of 55 children, 8-14 years old, were randomly assigned to one of three conditions: 1) Child is treated, 2) Child is treated and parent participates in the course, or 3) A wait-list for 12 weeks. The treatment consisted of individual exposure and group social skills training based on the Beidel, Turner, and Morris (2000) SET-C. Children and parents were assessed pre-, post-, and at one year follow-up with independent assessor ratings and self-report measures. Results showed that there was no significant difference between the two active treatments and both were better than the wait-list. The treatment effects were maintained or furthered at the follow-up. Comorbidity did not lead to worse outcome of social phobia. Comorbid disorders improved significantly from pre-to post-treatment and from post-to follow-up assessment without being targeted in therapy. PMID- 25727677 TI - Using visual lateralization to model learning and memory in zebrafish larvae. AB - Impaired learning and memory are common symptoms of neurodegenerative and neuropsychiatric diseases. Present, there are several behavioural test employed to assess cognitive functions in animal models, including the frequently used novel object recognition (NOR) test. However, although atypical functional brain lateralization has been associated with neuropsychiatric conditions, spanning from schizophrenia to autism, few animal models are available to study this phenomenon in learning and memory deficits. Here we present a visual lateralization NOR model (VLNOR) in zebrafish larvae as an assay that combines brain lateralization and NOR. In zebrafish larvae, learning and memory are generally assessed by habituation, sensitization, or conditioning paradigms, which are all representatives of nondeclarative memory. The VLNOR is the first model for zebrafish larvae that studies a memory similar to the declarative memory described for mammals. We demonstrate that VLNOR can be used to study memory formation, storage, and recall of novel objects, both short and long term, in 10-day-old zebrafish. Furthermore we show that the VLNOR model can be used to study chemical modulation of memory formation and maintenance using dizocilpine (MK-801), a frequently used non-competitive antagonist of the NMDA receptor, used to test putative antipsychotics in animal models. PMID- 25727680 TI - Anxiety sensitivity, catastrophic misinterpretations and panic self-efficacy in the prediction of panic disorder severity: towards a tripartite cognitive model of panic disorder. AB - The present study examined the contribution of three main cognitive factors (i.e., anxiety sensitivity, catastrophic misinterpretations of bodily symptoms, and panic self-efficacy) in predicting panic disorder (PD) severity in a sample of patients with a principal diagnosis of panic disorder. It was hypothesized that anxiety sensitivity (AS), catastrophic misinterpretation of bodily sensations, and panic self-efficacy are uniquely related to panic disorder severity. One hundred and sixty-eight participants completed measures of AS, catastrophic misinterpretations of panic-like sensations, and panic self-efficacy prior to receiving treatment. Results of multiple linear regression analyses indicated that AS, catastrophic misinterpretations and panic self-efficacy independently predicted panic disorder severity. Results of path analyses indicated that AS was direct and indirectly (mediated by catastrophic misinterpretations) related with panic severity. Results provide evidence for a tripartite cognitive account of panic disorder. PMID- 25727681 TI - The research versus clinical service role of medical physics. PMID- 25727682 TI - Pharmacokinetics: the view from Clinical Therapeutics. PMID- 25727683 TI - CNS drugs: the needs are great, the advances, incremental. PMID- 25727684 TI - Improving self-perception and self-efficacy in patients with spinal cord injury: the efficacy of DVD-based instructions. AB - AIMS AND OBJECTIVES: We assessed the effects of a spinal cord injury home rehabilitation DVD on patients with spinal cord injury. BACKGROUND: Multimedia have been used widely in health care in the digital age. The provision of rehabilitation instructions is a major responsibility of the rehabilitation staff. DESIGN: This study adopted a quasi-experimental pretest-posttest control group design. METHODS: We collected data from a rehabilitation nursing ward at a medical centre between October 2011-April 2012. The participants were recruited before being discharged from the hospital. The experimental group (n = 28) received multimedia DVD instructions for three months, in addition to teaching sessions conducted by the researcher, whereas the control group (n = 31) received instructions without a DVD. Both groups completed the self-perception and self efficacy scales used in this study before and after the intervention. RESULTS: The results indicated that, after the multimedia DVD intervention, the experimental group exhibited a considerably greater improvement in self perception than did the control group. Although we recorded increased scores for both self-perception and self-efficacy for both groups, no marked differences emerged between the control and the intervention groups by using a generalised estimating equation. CONCLUSION: These results suggest that the home rehabilitation DVD is an effective instrument for improving self-perception and self-efficacy in patients with spinal cord injury. However, monitoring these patients over the long term is necessary. RELEVANCE TO CLINICAL PRACTICE: Our study results confirmed that the spinal cord injury home rehabilitation DVD is a practical health education tool. We plan to use the proposed DVD intervention with a larger number of hospitalised patients, and to continuously monitor their improvement. PMID- 25727685 TI - Olive fruits infested with olive fly larvae respond with an ethylene burst and the emission of specific volatiles. AB - Olive fly (Bactrocera oleae R.) is the most harmful insect pest of olive (Olea europaea L.) which strongly affects fruits and oil production. Despite the expanding economic importance of olive cultivation, up to now, only limited information on plant responses to B. oleae is available. Here, we demonstrate that olive fruits respond to B. oleae attack by producing changes in an array of different defensive compounds including phytohormones, volatile organic compounds (VOCs), and defense proteins. Bactrocera oleae-infested fruits induced a strong ethylene burst and transcript levels of several putative ethylene-responsive transcription factors became significantly upregulated. Moreover, infested fruits induced significant changes in the levels of 12-oxo-phytodienoic acid and C12 derivatives of the hydroperoxide lyase. The emission of VOCs was also changed quantitatively and qualitatively in insect-damaged fruits, indicating that B. oleae larval feeding can specifically affect the volatile blend of fruits. Finally, we show that larval infestation maintained high levels of trypsin protease inhibitors in ripe fruits, probably by affecting post-transcriptional mechanisms. Our results provide novel and important information to understand the response of the olive fruit to B. oleae attack; information that can shed light onto potential new strategies to combat this pest. PMID- 25727686 TI - Efficient method for analyzing MR real-time cines: Toward accurate quantification of left ventricular function. AB - BACKGROUND: To develop and assess an efficient method to identify end-expiratory end-diastolic (ED) and end-systolic (ES) images for accurate quantification of left ventricular (LV) function in real-time cine imaging. METHODS: ECG-free free breathing real-time cine imaging was performed on short-axis slices of thirteen healthy volunteers at 3 Tesla. K-means cluster segmentation was applied to delineate the endocardial contour, from which the LV centroid and cavity area were determined in each cine image. LV centroid displacement along the superior inferior direction was filtered to extract respiratory motion in each slice. End expiratory ED and ES images were then identified and used for LV function quantification. Accuracy was evaluated with that measured from the slice-matched standard ECG-gated breathhold segmented cines using two-tail paired Student's t tests, linear regression analyses and Bland-Altman plots. Intra- and interobserver variability was calculated for each imaging technique. RESULTS: Qualitatively, end-expiratory ED and ES images identified with the proposed method agreed with those determined by frame-by-frame visual inspection in 97.5% of cases (P > 0.05). Quantitatively, good agreement of LV function indices between the real-time cine and the standard segmented cine was observed with averaged differences of 0.1 +/- 0.9 g for myocardium mass, -0.3 +/- 1.0 mL for ED volume, 0.2 +/- 1.2 mL for ES volume, -0.2 +/- 1.3 mL for stroke volume, and -0.3 +/- 0.8% for ejection fraction. Paired LV function values exhibited strong correlation (r >= 0.96) and no significant difference (P > 0.05). The real-time cine and the standard segmented cine showed similar intra- (1.2-3.3% and 1.1 2.8%, respectively) and interobserver variability (2.6-6.9% and 1.8-4.8%, respectively) with all P-values > 0.05. All the variability was comparable with published results. CONCLUSION: Compared with the laborious frame-by-frame visual inspection, as conventionally adopted, the proposed method is efficient in analyzing real-time cines for the accurate quantification of LV function without excessively manual interactions. PMID- 25727687 TI - Production of dihydroxylated betalains and dopamine in cell suspension cultures of Celosia argentea var. plumosa. AB - Betalains are plant pigments of hydrophilic nature with demonstrated chemopreventive potential in cancer cell lines and animal models. Among the betalains, those containing an aromatic moiety with two free hydroxyl groups possess the strongest antioxidant and free radical scavenging activities. The betaxanthins dopaxanthin and miraxanthin V and the betacyanins betanidin and decarboxy-betanidin are the only natural betalains with catecholic substructures. These four pigments have been produced in cell cultures established from hypocotyls of the plant Celosia argentea. Two stable and differentially colored cell lines, yellow and red, were maintained on Murashige and Skoog medium supplemented with the plant growth regulators 6-benzylaminopurine (6.66 MUM) and 2,4-dichlorophenoxyacetic acid (6.79 MUM). Derived suspension cultures showed increased production of dihydroxylated betalains in the cells and secreted to the medium with a maximum reached after 8 days of culture. In addition, precursor molecules betalamic acid and dopamine, with content up to 42.08 mg/g dry weight, were also obtained. The joint presence of the bioactive betalains together with the production of dopamine and betalamic acid show the ability of cell cultures of C. argentea to become a stable source of valuable phytochemicals. PMID- 25727688 TI - Uranium transport in a crushed granodiorite: experiments and reactive transport modeling. AB - The primary objective of this study was to develop and demonstrate an experimental method to refine and better parameterize process models for reactive contaminant transport in aqueous subsurface environments and to reduce conservatism in such models without attempting to fully describe the geochemical system. Uranium was used as an example of a moderately adsorbing contaminant because of its relevance in geologic disposal of spent nuclear fuel. A fractured granodiorite from the Grimsel Test Site (GTS) in Switzerland was selected because this system has been studied extensively and field experiments have been conducted with radionuclides including uranium. We evaluated the role of pH, porous media size fraction, and flow interruptions on uranium transport. Rock cores drilled from the GTS were shipped to Los Alamos National Laboratory, characterized by x-ray diffraction and optical microscopy, and used in uranium batch sorption and column breakthrough experiments. A synthetic water was prepared that represented the porewater that would be present after groundwater interacts with bentonite backfill material near a nuclear waste package. Uranium was conservatively transported at pH8.8. Significant adsorption and subsequent desorption was observed at pH ~7, with long desorption tails resulting after switching the column injection solution to uranium-free groundwater. Our experiments were designed to better interrogate this slow desorption behavior. A three-site model predicted sorption rate constants for a pH7.2 solution with a 75 150 MUm granodiorite fraction to be 3.5, 0.012, and 0.012 mL/g-h for the forward reactions and 0.49, 0.0025, and 0.001 h(-1) for the reverse reactions. Surface site densities were 1.3, 0.042, and 0.042 MUmol/g for the first, second, and third sites, respectively. 10-year simulations show that including a slow binding site increases the arrival time of a uranium pulse by ~70%. PMID- 25727689 TI - Response to authors; Re: Rosier PFWM, Kirschner-Hermanns R, Svihra J, Homma Y, Wein AJ. ICS teaching module: Analysis of voiding, pressure flow analysis (basic module) Neurourol Urodyn. 2014 Sep 11. doi: 10.1002/nau.22660. PMID- 25727690 TI - The synthetic cationic lipid diC14 activates a sector of the Arabidopsis defence network requiring endogenous signalling components. AB - Natural and synthetic elicitors have contributed significantly to the study of plant immunity. Pathogen-derived proteins and carbohydrates that bind to immune receptors, allow the fine dissection of certain defence pathways. Lipids of a different nature that act as defence elicitors, have also been studied, but their specific effects have been less well characterized, and their receptors have not been identified. In animal cells, nanoliposomes of the synthetic cationic lipid 3 tetradecylamino-tert-butyl-N-tetradecylpropionamidine (diC14) activate the TLR4 dependent immune cascade. Here, we have investigated whether this lipid induces Arabidopsis defence responses. At the local level, diC14 activated early and late defence gene markers (FRK1, WRKY29, ICS1 and PR1), acting in a dose-dependent manner. This lipid induced the salicylic acid (SA)-dependent, but not jasmonic acid (JA)-dependent, pathway and protected plants against Pseudomonas syringae pv. tomato (Pst), but not Botrytis cinerea. diC14 was not toxic to plant or pathogen, and potentiated pathogen-induced callose deposition. At the systemic level, diC14 induced PR1 expression and conferred resistance against Pst. diC14 induced defence responses required the signalling protein EDS1, but not NDR1. Curiously, the lipid-induced defence gene expression was lower in the fls2/efr/cerk1 triple mutant, but still unchanged in the single mutants. The amidine headgroup and chain length were important for its activity. Given the robustness of the responses triggered by diC14, its specific action on a defence pathway and the requirement for well-known defence components, this synthetic lipid is emerging as a useful tool to investigate the initial events involved in plant innate immunity. PMID- 25727691 TI - Highly efficient binuclear ruthenium catalyst for water oxidation. AB - Water splitting is one of the key steps in the conversion of sunlight into a usable renewable energy carrier such as dihydrogen or more complex chemical fuels. Developing rugged and highly efficient catalysts for the oxidative part of water splitting, the water oxidation reaction generating dioxygen, is a major challenge in the field. Herein, we introduce a new, and rationally designed, pyrazolate-based diruthenium complex with the highest activity in water oxidation catalysis for binuclear systems reported to date. Single-crystal X-ray diffraction showed favorable preorganization of the metal ions, well suited for binding two water molecules at a distance adequate for O?O bond formation; redox titrations as well as spectroelectrochemistry allowed characterization of the system in several oxidation states. Low oxidation potentials reflect the trianionic character of the elaborate compartmental pyrazolate ligand furnished with peripheral carboxylate groups. Water oxidation has been mediated both by a chemical oxidant (Ce(IV) )-by means of manometry and a Clark electrode for monitoring the dioxygen production-and electrochemically with impressive activities. PMID- 25727692 TI - Risk factors for lower extremity injuries among half marathon and marathon runners of the Lage Landen Marathon Eindhoven 2012: A prospective cohort study in the Netherlands. AB - To determine risk factors for running injuries during the Lage Landen Marathon Eindhoven 2012. Prospective cohort study. Population-based study. This study included 943 runners. Running injuries after the Lage Landen Marathon. Sociodemographic and training-related factors as well as lifestyle factors were considered as potential risk factors and assessed in a questionnaire 1 month before the running event. The association between potential risk factors and injuries was determined, per running distance separately, using univariate and multivariate logistic regression analysis. In total, 154 respondents sustained a running injury. Among the marathon runners, in the univariate model, body mass index >= 26 kg/m(2), <= 5 years of running experience, and often performing interval training, were significantly associated with running injuries, whereas in the multivariate model only <= 5 years of running experience and not performing interval training on a regular basis were significantly associated with running injuries. Among marathon runners, no multivariate model could be created because of the low number of injuries and participants. This study indicates that interval training on a regular basis may be recommended to marathon runners to reduce the risk of injury. PMID- 25727693 TI - Bacterial biofilms associated with ocular prostheses. PMID- 25727694 TI - A Roadmap for Controlled Production of Topological Insulator Nanostructures and Thin Films. AB - The group V-VI chalcogenide semiconductors (Bi2 Se3 , Bi2 Te3 , and Sb2 Te3 ) have long been known as thermoelectric materials. Recently, they have been once more generating interest because Bi2 Se3 , Bi2 Te3 and Sb2 Te3 have been crowned as 3D topological insulators (TIs), which have insulating bulk gaps and metallic Dirac surface states. One big challenge in the study of TIs is the lack of high quality materials with few defects and insulating bulk states. To manifest the topological surface states, it is critical to suppress the contribution from the bulk carriers. Controlled production of TI nanostructures that have a large surface-to-volume ratio is an efficient way to reduce the bulk conductance and to significantly enhance the topological surface conduction. In this review article, the recent progress on the preparation of TI nanostructures is highlighted. Basic production methods for TI nanostructures are introduced in detail. Furthermore, several specific production approaches to reduce the residual bulk carriers from defects are summarized. Finally, the progress and the prospects of the production of TI-based heterostructures, which hold promise in both fundamental study and novel applications are discussed. PMID- 25727695 TI - Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity. AB - The pe/ppe genes represent one of the most intriguing aspects of the Mycobacterium tuberculosis genome. These genes are especially abundant in pathogenic mycobacteria, with more than 160 members in M. tuberculosis. Despite being discovered over 15 years ago, their function remains unclear, although various lines of evidence implicate selected family members in mycobacterial virulence. In this review, we use PE/PPE phylogeny as a framework within which we examine the diversity and putative functions of these proteins. We report on the evolution and diversity of the respective gene families, as well as the implications thereof for function and host immune recognition. We summarize recent findings on pe/ppe gene regulation, also placing this in the context of PE/PPE phylogeny. We collate data from several large proteomics datasets, providing an overview of PE/PPE localization, and discuss the implications this may have for host responses. Assessment of the current knowledge of PE/PPE diversity suggests that these proteins are not variable antigens as has been so widely speculated; however, they do clearly play important roles in virulence. Viewing the growing body of pe/ppe literature through the lens of phylogeny reveals trends in features and function that may be associated with the evolution of mycobacterial pathogenicity. PMID- 25727696 TI - Non-clinical safety and biodistribution of AS03-adjuvanted inactivated pandemic influenza vaccines. AB - Pandemic-influenza vaccines containing split-inactivated-virus antigen have been formulated with the immunostimulatory Adjuvant System AS03 to enhance the antigen immunogenicity and reduce antigen content per dose. AS03 is an oil-in-water emulsion containing alpha-tocopherol, squalene and polysorbate 80. To support the clinical development of AS03-adjuvanted pandemic-influenza vaccines, the local and systemic toxicity of test articles containing split-influenza A(H5N1) and/or AS03 were evaluated after 3-4 intramuscular (i.m.) injections in rabbits. Treatment-related effects were restricted to mild inflammatory responses and were induced primarily by the test articles containing AS03. The injection-site inflammation was mild at 3 days, and minimal at 4 weeks after the last injection; and was reflected by signs of activation in the draining lymph nodes and by systemic effects in the blood including a transient increase of neutrophils. In addition, a study in mice explored the biodistribution of A(H5N1) vaccines or AS03 through radiolabelling the antigen or constituents of AS03 prior to injection. In this evaluation, 57-73% of AS03's principal constituents had cleared from the injection site 3 days after injection, and their different clearance kinetics were suggestive of AS03's dissociation. All these AS03 constituents entered into the draining lymph nodes within 30 min after injection. In conclusion, the administration of repeated doses of the H5N1/AS03 vaccine was well tolerated in the rabbit, and was primarily associated with transient mild inflammation at the injection site and draining lymph nodes. The biodistribution kinetics of AS03 constituents in the mouse were consistent with AS03 inducing this pattern of inflammation. PMID- 25727698 TI - The intracellular domain of L1CAM binds to casein kinase 2alpha and is neuroprotective via inhibition of the tumor suppressors PTEN and p53. AB - Cell adhesion molecule L1 promotes neuritogenesis and neuronal survival through triggering MAPK pathways. Based on the findings that L1 is associated with casein kinase 2 (CK2), and that deficiency in PTEN promotes neuritogenesis in vitro and regeneration after trauma, we examined the functional relationship between L1 and PTEN. In parallel, we investigated the tumor suppressor p53, which also regulates neuritogenesis. Here, we report that the intracellular domain of L1 binds to the subunit CK2alpha, and that knockdown of L1 leads to CK2 dephosphorylation and an increase in PTEN and p53 levels. Overexpression of L1, but not the L1 mutants L1 (S1181N, E1184V), which reduced binding between L1 and CK2, reduced expression levels of PTEN and p53 proteins, and enhanced levels of phosphorylated CK2alpha and mammalian target of rapamycin, which is a downstream effector of PTEN and p53. Treatment of neurons with a CK2 inhibitor or transfection with CK2alpha siRNA increased levels of PTEN and p53, and inhibited neuritogenesis. The combined observations indicate that L1 downregulates expression of PTEN and p53 via direct binding to CK2alpha. We suggest that L1 stimulates neuritogenesis by activating CK2alpha leading to decreased levels of PTEN and p53 via a novel, L1 triggered and CK2alpha-mediated signal transduction pathway. L1CAM (L1 cell adhesion molecule) is implicated in neural functions through the cognate src/MAP kinase signaling pathway. We now describe a novel signaling platform operating via the alpha subunit of casein kinase 2 which binds to the intracellular domain of L1. Knockdown of L1CAM leads to increased levels of tumor suppressor PTEN (phosphatase and tensin homolog) and p53, known to inhibit neuritogenesis in vitro and recovery from trauma in vivo. By activating this enzyme, L1CAM adds to its beneficial functions by decreasing the levels of PTEN and p53. PMID- 25727697 TI - Zero-Fluoroscopy Ablation of Accessory Pathways in Children and Adolescents: CARTO3 Electroanatomic Mapping Combined with RF and Cryoenergy. AB - BACKGROUND: Fluoroscopic catheter ablation of cardiac arrhythmias in pediatric patients exposes the patients to the potential risk of radiation considering the sensitivity of this population and its longer life expectancy. We evaluated the feasibility, safety, and efficacy of accessory pathway (AP) ablation guided by CARTO3 electroanatomic mapping (EAM) system with both cryoenergy and radiofrequency (RF) energy in order to avoid x-ray exposure in pediatric patients. METHODS: We included 44 patients (mean age: 13.1 +/- 3.3 years); nine of 44 presented concealed AP. An electrophysiological study with a three dimensional EAM reconstruction was performed in every patient with a venous transfemoral direct right atrium approach or an arterial transfemoral retrograde approach to reach the mitral annulus. In two patients with left-sided AP, the ablation was performed via a patent foramen ovale. RESULTS: A total of 47 APs were present, left sided in 45% (21/47) of cases (15 lateral, one anterior, three posteroseptal, and two posterolateral) and right sided in 55% (26/47; one anterior, three anterolateral, one posterolateral, three lateral, five para Hisian, 12 posteroseptal, and one anteroseptal). Ablation without the use of fluoroscopy was successfully performed in every patient (33 with RF and in 11 with cryoenergy). No complication occurred. At a mean follow-up of 16.0 +/- 11.7 months, we observed seven recurrences, three of them successfully re-ablated without fluoroscopy. In one case cryoablation of a para-Hisian AP was ineffective in the long term. CONCLUSIONS: Three-dimensional EAM allowed a safe and effective fluoroless AP ablation procedure in a pediatric population both with RF and cryoenergy. PMID- 25727699 TI - Basic substances: an opportunity for approval of low-concern substances under EU pesticide regulation. AB - Plant extracts and byproducts furnish various alternative products for crop protection and are traditionally used by farmers. However, the cost and timeframe for their registration as active substances are prohibitive for small companies and farmers' associations with the new Plant Protection Products (PPP) Regulation (EC) No. 1107/2009. However, there is now a possibility of registering light compounds as 'basic substances', a new category described in Article 23 and in 'Whereas/Recital 18'. We developed a regulatory expertise on the approval of such products within the framework of the PPP regulation. A Draft Assessment Report in one volume was established, later transformed by EC Directorate into a Basic Substance Application Template, and subsequently used by the EC as a matrix for the corresponding Guidelines for applicants (SANCO 10363/2012 rev. 9). Here we provide further tools, consisting of methodological, linguistic and strategic recommendations in order to constitute a Basic Substance Application (BSA) and proceed to its registration. While the use of alternative agents for crop protection is increasing both in organic and conventional agriculture, these usages are still considered as 'minor uses'. Our approach and tools are valuable to non-PPP specialised applicants for simplifying and facilitating their submission of the BSA. PMID- 25727700 TI - Comparison of Automated Brain Volume Measures obtained with NeuroQuant and FreeSurfer. AB - PURPOSE: To examine intermethod reliabilities and differences between FreeSurfer and the FDA-cleared congener, NeuroQuant, both fully automated methods for structural brain MRI measurements. MATERIALS AND METHODS: MRI scans from 20 normal control subjects, 20 Alzheimer's disease patients, and 20 mild traumatically brain-injured patients were analyzed with NeuroQuant and with FreeSurfer. Intermethod reliability was evaluated. RESULTS: Pairwise correlation coefficients, intraclass correlation coefficients, and effect size differences were computed. NeuroQuant versus FreeSurfer measures showed excellent to good intermethod reliability for the 21 regions evaluated (r: .63 to .99/ICC: .62 to .99/ES: -.33 to 2.08) except for the pallidum (r/ICC/ES = .31/.29/-2.2) and cerebellar white matter (r/ICC/ES = .31/.31/.08). Volumes reported by NeuroQuant were generally larger than those reported by FreeSurfer with the whole brain parenchyma volume reported by NeuroQuant 6.50% larger than the volume reported by FreeSurfer. There was no systematic difference in results between the 3 subgroups. CONCLUSION: NeuroQuant and FreeSurfer showed good to excellent intermethod reliability in volumetric measurements for all brain regions examined with the only exceptions being the pallidum and cerebellar white matter. This finding was robust for normal individuals, patients with Alzheimer's disease, and patients with mild traumatic brain injury. PMID- 25727702 TI - Recent advances in cancer therapeutics. AB - In the past 20 years, cancer therapeutics has undergone a paradigm shift away from the traditional cytotoxic drugs towards the targeting of proteins intimately involved in driving the cancer phenotype. The poster child for this alternative approach to the treatment of cancer is imatinib, a small-molecule kinase inhibitor designed to target chronic myeloid leukaemia driven by the BCR-ABL translocation in a defined patient population. The improvement in survival achieved by treatment of this patient cohort with imatinib is impressive. Thus, the aim is to provide efficacy but with low toxicity. The role of the medicinal chemist in oncology drug discovery is now closely aligned with the role in most other therapeutic areas with high-throughput and/or fragment-based screening, structure-based design, selectivity, pharmacokinetic optimisation and pharmacodynamic biomarker modulation, all playing a familiar part in the process. In this chapter, we selected four areas in which compounds are either approved drugs or in clinical trials. These are chaperone inhibitors, kinase inhibitors, histone deacetylase inhibitors and inhibitors of protein-protein interactions. Even within these areas, we have been selective, particularly for kinase inhibitors, and our aim has been to exemplify newer approaches and novel aspects of medicinal chemistry. PMID- 25727701 TI - Application of lemongrass oil in vapour phase for the effective control of anthracnose of 'Sekaki' papaya. AB - AIMS: To evaluate the potential use of lemongrass essential oil vapour as an alternative for synthetic fungicides in controlling anthracnose of papaya. METHODS AND RESULTS: Lemongrass oil used in the study was characterized using gas chromatography-flame ionization detection (GC-FID) before it was tested against anthracnose of papaya in vitro and in vivo. The GC-FID analysis showed that geranial (45.6%) and neral (34.3%) were the major components in lemongrass oil. In vitro study revealed that lemongrass oil vapour at all concentrations tested (33, 66, 132, 264 and 528 MUl l(-1) ) suppressed the mycelial growth and conidial germination of Colletotrichum gloeosporioides. For the in vivo study, 'Sekaki' papaya were exposed to lemongrass oil fumigation (0, 7, 14, 28 MUl l(-1) ) for 18 h and at room temperature for 9 days. Lemongrass oil vapour at the concentration of 28 MUl l(-1) was most effective against anthracnose of artificially inoculated papaya fruit while quality parameters of papaya were not significantly altered. CONCLUSIONS: This suggests that lemongrass oil vapour can control anthracnose disease development on papaya without affecting its natural ripening process. SIGNIFICANCE AND IMPACT OF THE STUDY: The potential practical application of this technology can reduce reliance on synthetic fungicides for the control of postharvest diseases in papaya. PMID- 25727703 TI - Fluorine in medicinal chemistry. AB - Since its first use in the steroid field in the late 1950s, the use of fluorine in medicinal chemistry has become commonplace, with the small electronegative fluorine atom being a key part of the medicinal chemist's repertoire of substitutions used to modulate all aspects of molecular properties including potency, physical chemistry and pharmacokinetics. This review will highlight the special nature of fluorine, drawing from a survey of marketed fluorinated pharmaceuticals and the medicinal chemistry literature, to illustrate key concepts exploited by medicinal chemists in their attempts to optimize drug molecules. Some of the potential pitfalls in the use of fluorine will also be highlighted. PMID- 25727704 TI - A perspective on the next generation of antibacterial agents derived by manipulation of natural products. AB - Natural products have been a major source of anti-infective drugs for many decades. With urgent need for new antibacterial agents to combat drug-resistant bacteria, the investigation of both new and existing classes of natural products has once again become an important focus. In this review, we highlight how a medicinal chemistry/semi-synthetic approach to natural product manipulation continues to offer a valuable strategy to overcome limitations in current therapy. Approaches to address toxicity and to improve the solubility, bioavailability and the spectrum of activity are demonstrated. Examples are drawn from aminoglycosides, glycopeptides, tetracyclines, macrolides, thiazolyl peptides, pleuromutilins and polymyxins and are taken from the current literature, patents and abstracts of symposia. In many cases, this approach has led to drug candidates currently in late stages of clinical development. PMID- 25727705 TI - A new era for chagas disease drug discovery? AB - Recent clinical trials investigating treatment of chronic indeterminate Chagas disease with two re-purposed azole anti-fungal drugs, posaconazole and ravuconazole, revealed their inferiority to the current standard-of-care benznidazole and highlighted the inadequacy of the existing pre-clinical testing paradigm for this disease. A very limited number of controlled clinical trials for Chagas disease have been conducted to date. The selection of these compounds for clinical evaluation relied heavily on pre-clinical data obtained from in vitro screens and animal studies. This chapter reviews the evolution of CYP51 as a target for Trypanosoma cruzi growth inhibition and also explores the impact of clinical trial data on contemporary Chagas disease drug discovery. Advances in pre-clinical profiling assays, the current compound landscape and progress towards the identification of new drug targets to re-invigorate research are reviewed. PMID- 25727706 TI - Imaging in drug development. AB - Imaging has played an important part in the diagnosis of disease and development of the understanding of the underlying disease mechanisms and is now poised to make an impact in the development of new pharmaceuticals. This chapter discusses the underlying technologies that make the field ready for this challenge. In particular, the potentials of magnetic resonance imaging and functional magnetic resonance imaging are outlined, including the new methods developed to provide additional information from the scans carried out. The field of nuclear medicine has seen a rapid increase in interest as advances in radiochemistry have enabled a wide range of new radiotracers to be synthesised. PMID- 25727707 TI - Preface. PMID- 25727708 TI - Controlling the direction of rectification in a molecular diode. AB - A challenge in molecular electronics is to control the strength of the molecule electrode coupling to optimize device performance. Here we show that non-covalent contacts between the active molecular component (in this case, ferrocenyl of a ferrocenyl-alkanethiol self-assembled monolayer (SAM)) and the electrodes allow for robust coupling with minimal energy broadening of the molecular level, precisely what is required to maximize the rectification ratio of a molecular diode. In contrast, strong chemisorbed contacts through the ferrocenyl result in large energy broadening, leakage currents and poor device performance. By gradually shifting the ferrocenyl from the top to the bottom of the SAM, we map the shape of the electrostatic potential profile across the molecules and we are able to control the direction of rectification by tuning the ferrocenyl-electrode coupling parameters. Our demonstrated control of the molecule-electrode coupling is important for rational design of materials that rely on charge transport across organic-inorganic interfaces. PMID- 25727709 TI - Does defective bone lead to defective muscle? PMID- 25727710 TI - Magnetic nanoparticles: Applications in gene delivery and gene therapy. AB - Gene therapy is defined as the direct transfer of genetic material to tissues or cells for the treatment of inherited disorders and acquired diseases. For gene delivery, magnetic nanoparticles (MNPs) are typically combined with a delivery platform to encapsulate the gene, and promote cell uptake. Delivery technologies that have been used with MNPs contain polymeric, viral, as well as non-viral platforms. In this review, we focus on targeted gene delivery using MNPs. PMID- 25727711 TI - Removal of iron by chelation with molecularly imprinted supermacroporous cryogel. AB - Iron chelation therapy can be used for the selective removal of Fe(3+) ions from spiked human plasma by ion imprinting. N-Methacryloyl-(L)-glutamic acid (MAGA) was chosen as the chelating monomer. In the first step, MAGA was complexed with the Fe(3+) ions to prepare the precomplex, and then the ion-imprinted poly(hydroxyethyl methacrylate-N-methacryloyl-(L)-glutamic acid) [PHEMAGA-Fe(3+)] cryogel column was prepared by cryo-polymerization under a semi-frozen temperature of - 12 degrees C for 24 h. Subsequently, the template, of Fe(3+) ions was removed from the matrix by using 0.1 M EDTA solution. The values for the specific surface area of the imprinted PHEMAGA-Fe(3+) and non-imprinted PHEMAGA cryogel were 45.74 and 7.52 m(2)/g respectively, with a pore size in the range of 50-200 MUm in diameter. The maximum Fe(3+) adsorption capacity was 19.8 MUmol Fe(3+)/g cryogel from aqueous solutions and 12.28 MUmol Fe(3+)/g cryogel from spiked human plasma. The relative selectivity coefficients of ion-imprinted cryogel for Fe(3+)/Ni(2+) and Fe(3+)/Cd(2+) were 1.6 and 4.2-fold greater than the non-imprinted matrix, respectively. It means that the PHEMAGA-Fe(3+) cryogel possesses high selectivity to Fe(3+) ions, and could be used many times without significantly decreasing the adsorption capacity. PMID- 25727712 TI - Snow et al.'s response to Richard Armstrong's Letter to the Editor. PMID- 25727713 TI - A randomized noninferiority crossover trial of corrected count increments and bleeding in thrombocytopenic hematology patients receiving 2- to 5- versus 6- or 7-day-stored platelets. AB - BACKGROUND: Bacterial screening offers the possibility of extending platelet (PLT) storage to Day 7. We conducted a noninferiority, crossover trial comparing PLTs stored for 6 or 7 days versus 2 to 5 days. STUDY DESIGN AND METHODS: Stable hematology patients were allocated to receive blocks of 2- to 5- and 6- or 7-day PLTs in random order. The primary outcome was the proportion of successful transfusions during the first block, defined as a corrected count increment (CCI) of more than 4.5 at 8 to 24 hours posttransfusion. RESULTS: Of 122 patients with an evaluable first block, 87 (71%) and 84 (69%) had successful transfusions after 2- to 5- and 6- or 7-day PLTs of mean (SD) ages of 3.8 (1.0) and 6.4 (0.5) days, respectively. Six- or 7-day PLTs were declared noninferior to 2- to 5-day PLTs since the upper confidence interval (CI) limit was less than the predefined noninferiority margin of 10% (95% CI, -14.0% to 9.1%; p = 0.766). Logistic regression analysis gave an adjusted odds ratio of 0.86 (95% CI, 0.47-1.58; p = 0.625). Mean (SD) 8- to 24-hour CCIs were 9.4 (7.9) and 7.7 (7.1) after transfusion with 2- to 5- or 6- or 7-day PLTs (95% CI, -3.31 to 0.03; p = 0.054). The proportions of days with bleeding scores of WHO Grade 2 or higher were 13% (38/297 days) and 11% (32/296 days; 95% CI, -3.2 to 7.2; p = 0.454). Median interval to next PLT transfusion (2 days) was unaffected (95% CI, -10.5 to 5.4; p = 0.531). CONCLUSION: In hematology patients, there was no evidence that 6- or 7 day PLTs were inferior to 2- to 5-day PLTs, as measured by proportion of patients with successful transfusions, bleeding events, or interval to next transfusion. PMID- 25727714 TI - Genome size evolution in Ontario ferns (Polypodiidae): evolutionary correlations with cell size, spore size, and habitat type and an absence of genome downsizing. AB - Genome size is known to correlate with a number of traits in angiosperms, but less is known about the phenotypic correlates of genome size in ferns. We explored genome size variation in relation to a suite of morphological and ecological traits in ferns. Thirty-six fern taxa were collected from wild populations in Ontario, Canada. 2C DNA content was measured using flow cytometry. We tested for genome downsizing following polyploidy using a phylogenetic comparative analysis to explore the correlation between 1Cx DNA content and ploidy. There was no compelling evidence for the occurrence of widespread genome downsizing during the evolution of Ontario ferns. The relationship between genome size and 11 morphological and ecological traits was explored using a phylogenetic principal component regression analysis. Genome size was found to be significantly associated with cell size, spore size, spore type, and habitat type. These results are timely as past and recent studies have found conflicting support for the association between ploidy/genome size and spore size in fern polyploid complexes; this study represents the first comparative analysis of the trend across a broad taxonomic group of ferns. PMID- 25727715 TI - Functional neuroanatomy of human cortex cerebri in relation to wanting sex and having it. AB - Neuroanatomical textbooks typically restrict the central nervous system control of sexual responsiveness to the hypothalamus, brainstem and spinal cord. However, for all its primitive functions human sex is surprisingly complex and versatile. This review aims to extend the neuroanatomy of sexual responsiveness by providing a comprehensive overview of the empirical evidence for cerebral cortical involvement. To this end I will structure relevant human brain research data to fit the sexual pleasure cycle template-wanting sex, having sex, inhibiting sex arguing that going through these sexual response phases requires adequate shifting between functional cortical networks. The relevance of this notion for understanding certain sexual dysfunctions is discussed. PMID- 25727716 TI - Affective Differences Between Psychopathy Variants and Genders in Adjudicated Youth. AB - The present study used Model-Based Cluster analysis to identify primary and secondary psychopathy variants in a mixed-gender sample of 150 adjudicated adolescents (60 % male; M = 15.2 years old). Distinct primary and secondary psychopathy groups emerged and were entered into a structural equation path model for the purpose of predicting group differences in emotional experiences reported between youth assigned to each variant. Youth characterized by secondary psychopathy reported experiencing significantly more frequent and more intense negative affect than their primary psychopathy counterparts. Frequency and intensity of affect also mediated the association between psychopathy variants and symptoms of depression, in which the secondary psychopathy group endorsed significantly more symptoms of major depression than the primary psychopathy group. Overall, these results suggest that different causal processes and affective experiences may underlie distinct trajectories to primary and secondary psychopathy variants in adjudicated adolescents. As such, youths comprising the secondary subtype of psychopathy may be more aptly considered "callous and emotional," compared with the primary subtype who present as prototypically callous and unemotional. PMID- 25727717 TI - MH4P6N12 (M = Mg, Ca): new imidonitridophosphates with an unprecedented layered network structure type. AB - Isotypic imidonitridophosphates MH4P6N12 (M = Mg, Ca) have been synthesized by high-pressure/high-temperature reactions at 8 GPa and 1000 degrees C starting from stoichiometric amounts of the respective alkaline-earth metal nitrides, P3N5, and amorphous HPN2. Both compounds form colorless transparent platelet crystals. The crystal structures have been solved and refined from single-crystal X-ray diffraction data. Rietveld refinement confirmed the accuracy of the structure determination. In order to quantify the amounts of H atoms in the respective compounds, quantitative solid-state (1)H NMR measurements were carried out. EDX spectroscopy confirmed the chemical compositions. FTIR spectra confirmed the presence of NH groups in both structures. The crystal structures reveal an unprecedented layered tetrahedral arrangement, built up from all-side vertex sharing PN4 tetrahedra with condensed dreier and sechser rings. The resulting layers are separated by metal atoms. PMID- 25727718 TI - Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer. AB - BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2.7(2.5) versus 5.9(4.8) per cent respectively; P = 0.006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com). PMID- 25727719 TI - Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism. AB - OBJECTIVES: Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) >=4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut off of <4 without sufficient evidence for its diagnostic accuracy. AIM: The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS. DESIGN AND PATIENTS: A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia. RESULTS: The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0.2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0.004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0.01). CONCLUSIONS: In patients with PA, where the LI is <4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management. PMID- 25727720 TI - Fractal nanoparticle plasmonics: the Cayley tree. AB - There has been strong, ongoing interest over the past decade in developing strategies to design and engineer materials with tailored optical properties. Fractal-like nanoparticles and films have long been known to possess a remarkably broad-band optical response and are potential nanoscale components for realizing spectrum-spanning optical effects. Here we examine the role of self-similarity in a fractal geometry for the design of plasmon line shapes. By computing and fabricating simple Cayley tree nanostructures of increasing fractal order N, we are able to identify the principle behind how the multimodal plasmon spectrum of this system develops as the fractal order is increased. With increasing N, the fractal structure acquires an increasing number of modes with certain degeneracies: these modes correspond to plasmon oscillations on the different length scales inside a fractal. As a result, fractals with large N exhibit broad, multipeaked spectra from plasmons with large degeneracy numbers. The Cayley tree serves as an example of a more general, fractal-based route for the design of structures and media with highly complex optical line shapes. PMID- 25727721 TI - Unilateral robotic hybrid mini-maze: a novel experimental approach. AB - BACKGROUND: A complete Cox maze IV procedure is difficult to accomplish using current endoscopic and minimally invasive techniques. These techniques are hampered by inability to adequately dissect the posterior structures of the heart and place all necessary lesions. We present a novel approach, using robotic technology, that achieves placement of all the lesions of the complete maze procedure. METHODS: In three cadaveric human models, the technical feasibility of using robotic instruments through the right chest to dissect the posterior structures of the heart and place all Cox maze lesions was performed. RESULTS: The entire posterior aspect of the heart was dissected in the cadaveric model facilitating successful placement of all Cox maze IV lesions with robotic assistance through minimally invasive incisions. CONCLUSION: The robotic Cox maze IV procedure through the novel right thoracic approach is feasible. This obviates the need for sternotomy and avoids the associated morbidity of the conventional Cox-maze procedure. PMID- 25727723 TI - Detection of Mycobacterium abscessus from deep pharyngeal swabs in cystic fibrosis. PMID- 25727722 TI - Two novel octamolybdate nanoclusters as catalysts for dye degradation by air under room conditions. AB - Two novel inorganic-organic hybrid materials, namely, (NH4)2CuMo8O26(C10H8N2)2 (1) and Mo8O26(C10H10N2)2(C10H8N2).2(H2O) (2) have been synthesized based on beta octamolybdate cluster and 4,4'-bipyridine (4,4'-bpy) ligand under solvothermal conditions. Their structures have been determined by single-crystal X-ray diffraction analyses and characterized by FT-IR, atomic absorption spectroscopy, powder X-ray diffraction (PXRD) and thermogravimetric analysis (TGA). In addition, microcrystals of 1 were used to synthesize its nanocrystals via an ultrasound-assisted top-down method. The nanocrystals were characterized by scanning electron microscopy (SEM), PXRD and FT-IR analyses. The prepared hybrid materials have been proved to be active heterogeneous catalysts for catalytic wet air oxidation (CWAO) of some dyes under mild conditions. Leaching experiments showed that the catalysts had good stability under the reaction conditions and could be easily recycled and reused after a simple treatment. PMID- 25727724 TI - Copper-catalyzed oxidative C(sp(3))-H/N-H coupling of sulfoximines and amides with simple alkanes via a radical process. AB - A copper-catalyzed oxidative C(sp(3))-H/N-H coupling of sulfoximines with simple alkanes was developed. This protocol involved C(sp(3))-N bond formation via a radical pathway and tolerated a series of functional groups, such as chloro, methyl and aryl, on the phenyl rings. Apart from sulfoximines, amides, saccharin and aniline also worked well to give the corresponding N-alkylated products. PMID- 25727725 TI - [Options for the reduction of magnetic susceptibility artifacts caused by implanted microchips in 0.5 Tesla magnetic resonance imaging]. AB - OBJECTIVE: Microchips contain ferromagnetic materials, which lead to severe focal image interferences when performing magnetic resonance imaging (MRI). Very small animals are particularly prone to these susceptibility artifacts, which may hinder analysis of the neck-region MRI image. We investigated the impact of sequence type on the artifact's size and determined the optimal imaging parameters to minimize these artifacts. Furthermore, the minimum distance between the microchip and the spinal canal required to assess the spinal structures should be determined. MATERIAL AND METHODS: Investigations were performed on the cadavers of 26 cats and two dogs using a low-field MRI System (field strength 0.5 Tesla). To quantify susceptibility artifacts, several sequence types (spin echo, turbo-spin echo (TSE), gradient echo) and imaging parameters (echo time (TE), voxel volume, frequency direction) were systematically varied. Additionally, computed tomography imaging was performed to determine the distance between the microchip and the spinal canal. RESULTS: The size of the artifact was smallest with T1-weighted TSE sequences. A short TE (10 ms) and a small voxel size (acquisition matrix 256 x 256 pixels, field of view 160 mm, slice thickness 2 mm) significantly reduced artifact size. Furthermore, it could be shown that by changing the frequency- and phase-encoding direction, the shape and orientation of the maximum dimension of the artifact could be influenced. Even when using an optimized T1-weighted TSE sequence, it was impossible to evaluate the spinal cord when the distance between the microchip and the center of the spinal canal was < 19 mm. CONCLUSION AND CLINICAL RELEVANCE: In MR studies of the cervical spine of small dogs and cats, microchips can cause severe susceptibility artifacts. Because of the small distance between the microchip and the spinal structures, spinal evaluation may be limited or impossible. The investigations demonstrated that the adjustment of sequence parameters helps to significantly minimize artifact size and shape. The greatest reduction in artifact size was achieved by using a T1-weighted TSE sequence. PMID- 25727726 TI - Synthesis and in vitro evaluation of melatonin entrapped PLA nanoparticles: an oxidative stress and T-cell response using golden hamster. AB - This study was carried out to evaluate the effects of melatonin entrapped PLA nanoparticles (Mel-NPs) and pure Mel on impact of reactive oxygen species (ROS), blastogenic responses (%SR) in terms of proliferation of splenocytes. ROS have been proposed to play an important role in balancing the pro- and antioxidant homeostasis during different physiological condition of organism. Melatonin has been suggested as an effective free radical scavenger that may have an important role during this process. Mel-NPs were prepared by using emulsification (o/w) nanoprecipitation method and their physicochemical characterizations were studied for evaluation of particle size and encapsulation efficiency by using SEM, TEM, particle size analyzer, DSC and FTIR. The TEM micrograph showed excellent findings regarding size, shape, encapsulation efficiency and difference between pure PLA nanoparticles and Mel-NPs. The SEM micrographs of Mel-NPs showed spherical shape, smooth surfaces and the homogeneous particle size distribution. In TEM micrograph, the average diameter of Mel-NPs was found to be 36 +/- 8 nm with ~78% (w/w) of entrapment efficiency. The size of pure PLA nanoparticles was found to be larger as compared to Mel-NPs which confirm that the drug supports the reduction of the size of Mel-NPs. In in vitro study, we observed that Mel-NPs significantly reduce the level of ROS in splenocytes and increased the level %SR at 96 h of splenocytes culture as compared to the culture with pure Mel. Thus our results propose high clinical value for improvement of depressed immunity by Mel NPs. PMID- 25727727 TI - Interrupted chalcogenide-based zeolite-analogue semiconductor: atomically precise doping for tunable electro-/photoelectrochemical properties. AB - Incorporation of semiconductor property into zeolite materials is a plausible approach to graft oxide zeolites with multifunctionality in which both electronic/optoelectronic functions and high porosity are integrated. However, creating such semiconductor zeolites, especially the ones with controllable function regulation still remains as a great synthetic challenge over the years. Hereby, we reported the first case of an interrupted chalcogenide-based zeolite analog semiconductor with an entirely new boracite-related framework and specific sites at the interrupted section. The semiconducting nature and band structure of this open-framework n-type semiconductor material were characterized with solid state UV/Vis diffuse reflectance spectroscopy and Mott-Schottky measurements. More importantly, the In-Se chalcogenide zeolite analog was for the first time explored as an effective electrocatalyst for the oxygen reduction reaction (ORR). The specific indium sites served as active centers and proved to be responsible for a superior ORR activity. Meanwhile, these specific sites could be precisely replaced by bismuth(III) ions, leading to facile manipulation in their electro /photoelectrochemical properties. Such atomically precise doping successfully implemented at the semiconductor zeolite material with specifically interrupted sites presents a very promising route for accurately regulating electronic structure and photoelectrical properties of other open-framework semiconductor materials. PMID- 25727728 TI - Lentigines in resolving psoriatic plaques: rarely reported sequelae in pediatric cases. AB - Lentigo formation has been described in adults after the resolution of psoriatic plaques treated with various standard psoriasis treatments. We describe three cases of lentigines developing in areas of resolving psoriatic plaques: two in patients treated with etanercept and one before starting etanercept. A possible pathomechanism is proposed. PMID- 25727729 TI - Chorioretinal scars and visual deprivation are common in children with cochlear implants after congenital cytomegalovirus infection. AB - AIM: The aim of this study was to compare visual function and ocular characteristics in children with cochlear implants, due to severe hearing impairment caused by the congenital cytomegalovirus (CMV) infection, with control children fitted with cochlear implants due to connexin 26 mutations (Cx26), a genetic cause of hearing impairment. METHODS: We carried out ophthalmological assessments, including visual acuity, ocular alignment, Ocular Motor Score, biomicroscopy and fundus photography, on 26 children with congenital CMV (median age 8.3 years, range 1.4-16.7) and 13 Cx26 controls (median age 5.6 years, range 1.7-12.5). RESULTS: We found unilateral chorioretinal macular scars that reduced best-corrected visual acuity <=0.3 in five (19%) of the children with congenital CMV, but in none of the children with Cx26 (p = 0.15). Ocular motility problems were more common among children with congenital CMV, but the difference was not significant (p = 0.20). The vestibulo-ocular reflex was more frequently pathological in children with congenital CMV (p = 0.011). CONCLUSION: Ocular complications with central chorioretinal scars and ocular motility disturbances were common in children treated with cochlear implants due to severe hearing impairment caused by the congenital CMV infection. Ophthalmological assessments are advisable in such children for early identification, intervention and follow up. PMID- 25727731 TI - Childhood trauma: Methods for the identification of physeal fractures in nonadult skeletal remains. AB - OBJECTIVES: Today, fractures at the growth plate (or physis) are common injuries in children, but provide challenges of identification in skeletonized remains. Clinical studies provide detailed information on the mechanisms, locations, age of occurrence, and complications associated with physeal fractures, enabling the development of new criteria for identifying this injury in nonadults. To test these criteria, skeletal remains from five rural and urban medieval cemeteries were examined. METHODS: The sample consisted of 961 skeletons (0-17 years) with open epiphyses. Macroscopic observation looked for any irregularities of the metaphysis or epiphysis, which was consistent with the clinical appearance of physeal fractures or resulting complications. Radiographic examination was applied to identify fracture lines or early growth arrest. RESULTS: This study revealed 12 cases of physeal trauma (1.2%). Physeal fractures occurred predominantly at the distal end (75%), and while they were identified in all age categories, they were most frequent in those aged 12-17 years (0.2% TPR). The humerus was the most commonly affected location (3/12 or 25%). CONCLUSIONS: This study highlights the potential for recognizing physeal fractures in children of all ages, enhancing our understanding of nonadult trauma, and enabling us to assign a more precise age of the injury to build up a picture of their activities in the past. PMID- 25727730 TI - Skeletal muscle as an endogenous nitrate reservoir. AB - The nitric oxide synthase (NOS) family of enzymes form nitric oxide (NO) from arginine in the presence of oxygen. At reduced oxygen availability NO is also generated from nitrate in a two step process by bacterial and mammalian molybdopterin proteins, and also directly from nitrite by a variety of five coordinated ferrous hemoproteins. The mammalian NO cycle also involves direct oxidation of NO to nitrite, and both NO and nitrite to nitrate by oxy-ferrous hemoproteins. The liver and blood are considered the sites of active mammalian NO metabolism and nitrite and nitrate concentrations in the liver and blood of several mammalian species, including human, have been determined. However, the large tissue mass of skeletal muscle had not been generally considered in the analysis of the NO cycle, in spite of its long-known presence of significant levels of active neuronal NOS (nNOS or NOS1). We hypothesized that skeletal muscle participates in the NO cycle and, due to its NO oxidizing heme protein, oxymyoglobin has high concentrations of nitrate ions. We measured nitrite and nitrate concentrations in rat and mouse leg skeletal muscle and found unusually high concentrations of nitrate but similar levels of nitrite, when compared to the liver. The nitrate reservoir in muscle is easily accessible via the bloodstream and therefore nitrate is available for transport to internal organs where it can be reduced to nitrite and NO. Nitrate levels in skeletal muscle and blood in nNOS(-/-) mice were dramatically lower when compared with controls, which support further our hypothesis. Although the nitrate reductase activity of xanthine oxidoreductase in muscle is less than that of liver, the residual activity in muscle could be very important in view of its total mass and the high basal level of nitrate. We suggest that skeletal muscle participates in overall NO metabolism, serving as a nitrate reservoir, for direct formation of nitrite and NO, and for determining levels of nitrate in other organs. PMID- 25727732 TI - Care arrangements for community-dwelling people with dementia in Germany as perceived by informal carers - a cross-sectional pilot survey in a provincial rural setting. AB - The majority of people with dementia live at home, and informal carers assume the role of key care providers, often supported by formal services. The purpose of this pilot study was to assess home-based care arrangements, to illustrate utilisation of formal services over time and to identify factors associated with perceived stability of the care situation from the informal carer's perspective. A self-administered questionnaire (D-IVA 'Instrument for Assessing Home-Based Care Arrangements for People with Dementia') was developed and distributed in a provincial-rural setting in Germany as a cross-sectional survey. Data analysis used descriptive statistics, unbiased conditional inference trees and thematic analysis for open-ended questions. In total, 84 care arrangements were assessed. The majority of participants were direct relatives of the care-dependent person [mostly adult children (48.8%) or spouses (27.4%)]. Formal services were already sought in the first year after onset of memory problems. The most frequently used formal services were home care nursing services (53.0%), day care (49.4%) and respite care (29.6%), whereas 15.5% did not use any type of formal support. Companion home visit, home care nursing service and day care were used over the longest periods of time. The recruitment strategy used in this study may have recruited persons who were relatively more dependent on their informal carers. In this small sample, carers' perceived stability of the care situation was high, and this was associated with the country of origin and sex of the person with dementia (P = 0.004 and 0.023 respectively). Most care arrangements consisted of a mix of informal and formal services. However, informal carers assumed prime responsibility. The questionnaire D-IVA proved to be suitable. It remains a challenge to further examine factors associated with perceived stability and to explain the phenomenon in its whole complexity. Further research using the D-IVA should consider applying complementing quantitative measures as well as qualitative methods. PMID- 25727733 TI - Moving forward in plant food safety and security through NanoBioSensors: Adopt or adapt biomedical technologies? AB - Plant-based foods are integral part of our day-to-day diet. Increasing world population has put forth an ever increasing demand for plant-based foods, and food security remains a major concern. Similarly, biological, chemical, and physical threats to our food and increasing regulatory demands to control the presence of foreign species in food products have made food safety a growing issue. Nanotechnology has already established its roots in diverse disciplines. However, the food industry is yet to harness the full potential of the unique capabilities offered by this next-generation technology. While there might be safety concerns in regards to integration of nanoproducts with our food products, an aspect of nanotechnology that can make remarkable contribution to different elements of the food chain is the use of nanobiosensors and diagnostic platforms for monitoring food traceability, quality, safety, and nutritional value. This brings us to an important question that whether existing diagnostic platforms that have already been well developed for biomedical and clinical application are suitable for food industry or whether the demands of the food industry are altogether different that may not allow adoption/adaptation of the existing technology. This review is an effort to raise this important "uncomfortable" yet "timely" question. PMID- 25727734 TI - Antibacterial activity of berry juices, an in vitro study. AB - OBJECTIVE: The aim of the present study was to evaluate in vitro antibacterial activities of blackcurrant and sea buckthorn juices on bacteria associated with gingival inflammation. MATERIALS AND METHODS: The growth of selected bacteria (Streptococcus mitis, Streptococcus mutans, Streptococcus sanguinis, Streptococcus gordonii, Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa) was studied in vitro on agar plates. The content of phenols in the different extracts was measured with HPLC-ESI-MS. RESULTS: The spectrometric analysis identified that the highest level of the single phenols studied was found for ferulic acid (113 MUg/ml) in blackcurrant juice. Sea buckthorn contained low levels of selected phenols. Total bacterial inhibition for all bacterial species studied was found at 20% berry juice concentration with pH varying between 4.1-5.4. CONCLUSIONS: The present study identified that in vitro bacterial growth on agar plates was inhibited by blackcurrant and sea buckthorn juices and that low juice pH explains bacterial in vitro growth. This may have clinical implications in biofilm development, reducing the risks for both tooth decay and gingivitis. PMID- 25727735 TI - Four new cytotoxic xanthones from Garcinia nujiangensis. AB - Bioassay-guided fractionation of the acetone extract of the twigs of Garcinia nujiangensis resulted in the isolation of four new prenylated xanthones, nujiangexanthones C-F (1-4), and ten known related analogues. The structures of compounds 1-4 were elucidated by interpretation of their spectroscopic data. The compounds isolated were evaluated for their cytotoxic effects against three cancer cell lines, the test substances demonstrated selectivity toward the cancer cells. PMID- 25727736 TI - Estimates of genetic variance and variance of predicted genetic merits using pedigree or genomic relationship matrices in six Brown Swiss cattle populations for different traits. AB - The amount of variance captured in genetic estimations may depend on whether a pedigree-based or genomic relationship matrix is used. The purpose of this study was to investigate the genetic variance as well as the variance of predicted genetic merits (PGM) using pedigree-based or genomic relationship matrices in Brown Swiss cattle. We examined a range of traits in six populations amounting to 173 population-trait combinations. A main aim was to determine how using different relationship matrices affect variance estimation. We calculated ratios between different types of estimates and analysed the impact of trait heritability and population size. The genetic variances estimated by REML using a genomic relationship matrix were always smaller than the variances that were similarly estimated using a pedigree-based relationship matrix. The variances from the genomic relationship matrix became closer to estimates from a pedigree relationship matrix as heritability and population size increased. In contrast, variances of predicted genetic merits obtained using a genomic relationship matrix were mostly larger than variances of genetic merit predicted using pedigree-based relationship matrix. The ratio of the genomic to pedigree-based PGM variances decreased as heritability and population size rose. The increased variance among predicted genetic merits is important for animal breeding because this is one of the factors influencing genetic progress. PMID- 25727738 TI - Cultural safety, diversity and the servicer user and carer movement in mental health research. AB - This study will be of interest to anyone concerned with a critical appraisal of mental health service users' and carers' participation in research collaboration and with the potential of the postcolonial paradigm of cultural safety to contribute to the service user research (SUR) movement. The history and nature of the mental health field and its relationship to colonial processes provokes a consideration of whether cultural safety could focus attention on diversity, power imbalance, cultural dominance and structural inequality, identified as barriers and tensions in SUR. We consider these issues in the context of state driven approaches towards SUR in planning and evaluation and the concurrent rise of the SUR movement in the UK and Australia, societies with an intimate involvement in processes of colonisation. We consider the principles and motivations underlying cultural safety and SUR in the context of the policy agenda informing SUR. We conclude that while both cultural safety and SUR are underpinned by social constructionism constituting similarities in principles and intent, cultural safety has additional dimensions. Hence, we call on researchers to use the explicitly political and self-reflective process of cultural safety to think about and address issues of diversity, power and social justice in research collaboration. PMID- 25727737 TI - Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. AB - Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke. PMID- 25727739 TI - Elemental diet induces the proliferation of sialomucin goblet cells in the rat duodenum and jejunum. AB - We histologically examined the effects of elemental diet (ED) on the goblet cell profile in the rat small intestine. The sulfomucin goblet cells were predominant throughout the small intestine in the control group, while sialomucin goblet cells were manifest in the duodenum and jejunum in the ED group. Next, we investigated the possible relevance of luminal osmolality to the goblet cell profile. Gastric osmolality in the ED group was within the physiological range. Meanwhile, ingestion of high glucose diet elevated gastric osmolality and increased the number of sialomucin goblet cells in the duodenum and jejunum. Further, it turned out that the lower sulfur contents in ED was not related to the unique goblet cell profile by ED ingestion. It is inductively suggested that the influx of high concentrations of low molecular nutrients into the small intestine could be associated with the goblet cell alteration, but the alteration was not necessarily due to the changes in the gastric osmolality by ED ingestion. PMID- 25727741 TI - Fundamental movement skills in preschoolers: a randomized controlled trial targeting object control proficiency. AB - BACKGROUND: Adequately developed fundamental movement skills, particularly object control dimensions, are considered essential to learn more complex movement patterns and to increase the likelihood to successfully participate in organized and non-organized sports during later years. Thus, the present randomized controlled trial aimed at improving object control dimensions at an early state in a kindergarten setting. METHODS: Catching, throwing, kicking, rolling and stationary dribbling were assessed via gross motor development 2 (TGMD-2) testing in 41 normally developed preschoolers. On a cluster-randomized basis [strata: age, sex and body mass index (BMI)], three kindergartens were randomly assigned to an intervention group (n = 22, INT, age: 4.6 +/- 1.0 years; BMI: 16.2 +/- 1.1 kg/m(2) ) and three to a control group (n = 19, CON: age: 4.5 +/- 1.2 years; BMI: 16.8 +/- 1.2 kg/m(2) ). Twelve structured training sessions were given within 6 weeks (12 sessions). The total training volume was 330 min. RESULTS: Moderate time * group interaction were observed for the total sum score (Delta+22%, P = 0.05) and dribbling (Delta+41%, P = 0.002). Adjusting for baseline differences analyses of covariance did not affect these results. Interestingly, likely to most likely practically worthwhile effects were detected for the total sum score, catching and dribbling. CONCLUSION: Object control dimensions such as dribbling and catching that apparently rely on rhythmical movement patterns and anticipatory eye-hand coordination seem to benefit from short-term object control training. These skills are considered important for successful team-sport participation and appropriate sportive motor development. PMID- 25727740 TI - The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults. AB - In functional magnetic resonance imaging (fMRI) research one is typically interested in neural activity. However, the blood-oxygenation level-dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting-state fluctuation amplitude (RSFA) in the fMRI signal (rsfMRI) has been proposed as an index of vascular reactivity. The RSFA compares favourably with other techniques such as breath-hold and hypercapnia, but the latter are more difficult to perform in some populations, such as older adults. The RSFA is therefore a candidate for use in adjusting for age-related changes in vascular reactivity in fMRI studies. The use of RSFA is predicated on its sensitivity to vascular rather than neural factors; however, the extent to which each of these factors contributes to RSFA remains to be characterized. The present work addressed these issues by comparing RSFA (i.e., rsfMRI variability) to proxy measures of (i) cardiovascular function in terms of heart rate (HR) and heart rate variability (HRV) and (ii) neural activity in terms of resting state magnetoencephalography (rsMEG). We derived summary scores of RSFA, a sensorimotor task BOLD activation, cardiovascular function and rsMEG variability for 335 healthy older adults in the population-based Cambridge Centre for Ageing and Neuroscience cohort (Cam-CAN; www.cam-can.com). Mediation analysis revealed that the effects of ageing on RSFA were significantly mediated by vascular factors, but importantly not by the variability in neuronal activity. Furthermore, the converse effects of ageing on the rsMEG variability were not mediated by vascular factors. We then examined the effect of RSFA scaling of task-based BOLD in the sensorimotor task. The scaling analysis revealed that much of the effects of age on task-based activation studies with fMRI do not survive correction for changes in vascular reactivity, and are likely to have been overestimated in previous fMRI studies of ageing. The results from the mediation analysis demonstrate that RSFA is modulated by measures of vascular function and is not driven solely by changes in the variance of neural activity. Based on these findings we propose that the RSFA scaling method is articularly useful in large scale and longitudinal neuroimaging studies of ageing, or with frail participants, where alternative measures of vascular reactivity are impractical. PMID- 25727743 TI - Hypertension Prevention and Control in Latin America and the Caribbean. PMID- 25727742 TI - Metabolism of 20-hydroxyvitamin D3 and 20,23-dihydroxyvitamin D3 by rat and human CYP24A1. AB - CYP11A1 hydroxylates vitamin D3 producing 20S-hydroxyvitamin D3 [20(OH)D3] and 20S,23-dihydroxyvitamin D3 [20,23(OH)2D3] as the major and most characterized metabolites. Both display immuno-regulatory and anti-cancer properties while being non-calcemic. A previous study indicated 20(OH)D3 can be metabolized by rat CYP24A1 to products including 20S,24-dihydroxyvitamin D3 [20,24(OH)2D3] and 20S,25-dihydroxyvitamin D3, with both producing greater inhibition of melanoma colony formation than 20(OH)D3. The aim of this study was to characterize the ability of rat and human CYP24A1 to metabolize 20(OH)D3 and 20,23(OH)2D3. Both isoforms metabolized 20(OH)D3 to the same dihydroxyvitamin D species with no secondary metabolites being observed. Hydroxylation at C24 produced both enantiomers of 20,24(OH)2D3. For rat CYP24A1 the preferred initial site of hydroxylation was at C24 whereas the human enzyme preferred C25. 20,23(OH)2D3 was initially metabolized to 20S,23,24-trihydroxyvitamin D3 and 20S,23,25 trihydroxyvitamin D3 by rat and human CYP24A1 as determined by NMR, with both isoforms showing a preference for initial hydroxylation at C25. CYP24A1 was able to further oxidize these metabolites in a series of reactions which included the cleavage of C23-C24 bond, as indicated by high resolution mass spectrometry of the products, analogous to the catabolism of 1,25(OH)2D3 via the C24-oxidation pathway. Similar catalytic efficiencies were observed for the metabolism of 20(OH)D3 and 20,23(OH)2D3 by human CYP24A1 and were lower than for the metabolism of 1,25(OH)2D3. We conclude that rat and human CYP24A1 metabolizes 20(OH)D3 producing only dihydroxyvitamin D3 species as products which retain biological activity, whereas 20,23(OH)2D3 undergoes multiple oxidations which include cleavage of the side chain. PMID- 25727744 TI - Quality of Diagnosis and Treatment Plans After Using the 'Diagnostic Guideline for Anxiety and Challenging Behaviours' in People with Intellectual Disabilities: A Comparative Multiple Case Study Design. AB - BACKGROUND: People with intellectual disabilities often have a multitude of concurrent problems due to the combination of cognitive impairments, psychiatric disorders (particularly anxiety) and related challenging behaviours. Diagnoses in people with intellectual disabilities are complicated. This study evaluates the quality of the diagnoses and treatment plans after using a guideline that was developed to support professionals in their diagnostic tasks. MATERIALS AND METHODS: A comparative multiple case study with an experimental and control condition, applying deductive analyses of diagnoses and treatment plans. RESULTS: The analyses revealed that the number of diagnostic statements and planned treatment actions in the experimental group was significantly larger and more differentiated than in the control condition. In the control group, consequential harm and protective factors were hardly mentioned in diagnoses and treatment plans. CONCLUSIONS: Working with the 'Diagnostic Guideline for Anxiety and CB' leads to improved diagnoses and treatment plans compared with care as usual. PMID- 25727745 TI - Dissolution and regeneration of hide powder/cellulose composite in Gemini imidazolium ionic liquid. AB - Gemini imidazolium ionic liquid, 3,3'-[1,2-ethanediylbis (oxy-2,1-ethanediyl)] bis[1-methyl-imidazolium]-dibromide ([C6O2(mim)2][Br]2), was used for the dissolution and regeneration of white hide powder (from pigskin), and blend white hide powder with cellulose for the easy production of white hide powder/cellulose composite. Dissolution performance of white hide powder in [C6O2(mim)2][Br]2 was studied. The native white hide powder and [C6O2(mim)2][Br]2 regenerated white hide powder were characterized by FT-IR, XRD, DSC-TG and FE-SEM. The results showed that [C6O2(mim)2][Br]2 was a good solvent to white hide powder. The dissolution time was 55 min when the white hide powder was 8% at 120 degrees C. The dissolution time of [C6O2(mim)2][Br]2 for white hide powder was shorter than those of common ionic liquids. The triple helical structure of white hide powder was partly destroyed during [C6O2(mim)2][Br]2 dissolution. The possible mechanism of white hide powder dissolution in [C6O2(mim)2][Br]2 and the regeneration of white hide powder in methanol had been proposed. White hide powder/cellulose composites were successfully dissolved in [C6O2(mim)2][Br]2. The performance of white hide powder/cellulose film was measured by FT-IR and TG. The tensile strength, and elongation at break of white hide powder/cellulose composite films were tested. This work demonstrated that the white hide powder/cellulose composite exhibited some potential in collagen-based tissue engineering. PMID- 25727747 TI - Determination of the origin of dissolved inorganic carbon in groundwater around a reclaimed landfill in Otwock using stable carbon isotopes. AB - Chemical and isotopic analyses of groundwater from piezometers located around a reclaimed landfill in Otwock (Poland) were performed in order to trace the origin of dissolved inorganic carbon (DIC) in the groundwater. Due to differences in the isotopic composition of carbon from different sources, an analysis of stable carbon isotopes in the groundwater, together with the Keeling plot approach and a two-component mixing model allow us to evaluate the relative contributions of carbon from these sources in the groundwater. In the natural (background) groundwater, DIC concentrations and the isotopic composition of DIC (delta(13)CDIC) comes from two sources: decomposition of organic matter and carbonate dissolution within the aquifer sediments, whereas in the leachate contaminated groundwater, DIC concentrations and delta(13)CDIC values depend on the degradation of organic matter within the aquifer sediments and biodegradation of organic matter stored in the landfill. From the mixing model, about 4-54% of the DIC pool is derived from organic matter degradation and 96-46% from carbonate dissolution in natural conditions. In the leachate-contaminated groundwater, about 20-53% of the DIC is derived from organic matter degradation of natural origin and 80-47% from biodegradation of organic matter stored in the landfill. Partial pressure of CO2 (P CO2) was generally above the atmospheric, hence atmospheric CO2 as a source of carbon in DIC pool was negligible in the aquifer. P CO2 values in the aquifer in Otwock were always one to two orders of magnitude above the atmospheric P CO2, and thus CO2 escaped directly into the vadose zone. PMID- 25727746 TI - Alternative plasticizers for the production of thermo-compressed agar films. AB - Agar films were produced by thermo-compression using choline chloride (ChCl) as a plasticizer with urea. The three solid components were mixed together with the salt and urea (minor components) added to agar (main component) according to a fixed mass ratio of, respectively, 1.16:1:5. A central composite rotatable design (CCRD) with three parameters, 2(3), was used to evaluate the effects of temperature (X1; degrees C), time (X2; min) and applied load (X3; kN) of heat pressing on the maximum tensile strength (TS) of the films (Y; MPa). Mixtures of urea and agar prepared at a mass ratio of 1:5 did not form homogeneous films suggesting the important plasticizing role of the salt. Heat-pressing the mixtures at more draconian conditions led to much darker and opaque films, with better mechanical resistance (higher values of TS). The most resistant film (~ 15 MPa) was obtained at 140 degrees C, 20 min and 176 kN. Selected films, including the optimal, showed similar water sorption profiles and close values of water vapor permeability (~ 2.5-3.7 * 10(-9)gm(-1)s(-1)Pa(-1)). The fracture behavior and mechanical properties of the films were greatly affected by additional water plasticization when the films were stored at different conditions of relative humidity. PMID- 25727748 TI - Systematic review of cost-effectiveness analyses of novel oral anticoagulants for stroke prevention in atrial fibrillation. AB - INTRODUCTION AND OBJECTIVES: Novel oral anticoagulants are emerging options for the prevention and treatment of thromboembolic diseases. They are increasingly used in clinical practice due to their simplicity of use and clinical benefits, but an important step is to evaluate their cost-effectiveness. The aim of the AFFORD study (A Review of Cost EFFectiveness of Novel ORal Anticoagulant Drugs) was to perform a systematic review of cost-effectiveness studies of novel oral anticoagulants for stroke prevention in non-valvular atrial fibrillation (AF). METHODS: A systematic review of the literature was conducted by searching the PubMed, Embase, Scopus, Cochrane and Web of Knowledge databases to identify all cost-effectiveness studies of novel oral anticoagulants for stroke prevention in AF. RESULTS: The search identified 27 studies, 18 with dabigatran, three with apixaban, two with rivaroxaban and four with at least two of these drugs. The incremental cost-effectiveness ratios were 30 405 +/- 16 101 euros per quality adjusted life-year (QALY) for dabigatran 110 mg, 17 566 +/- 16 902 euros/QALY for dabigatran 150 mg, 8102 +/- 3252 euros/QALY for age-adjusted dabigatran, 11 897 +/- 3341 euros/QALY for apixaban and 17 960 +/- 12 005 euros/QALY for rivaroxaban. CONCLUSION: The present systematic review demonstrates that novel oral anticoagulants are cost-effective for stroke prevention in AF. PMID- 25727749 TI - Impact of syncope on quality of life: validation of a measure in patients undergoing tilt testing. AB - INTRODUCTION AND OBJECTIVES: Recurrent syncope has a significant impact on quality of life. The development of measurement scales to assess this impact that are easy to use in clinical settings is crucial. The objective of the present study is a preliminary validation of the Impact of Syncope on Quality of Life questionnaire for the Portuguese population. METHODS: The instrument underwent a process of translation, validation, analysis of cultural appropriateness and cognitive debriefing. A population of 39 patients with a history of recurrent syncope (>1 year) who underwent tilt testing, aged 52.1 +/- 16.4 years (21-83), 43.5% male, most in active employment (n=18) or retired (n=13), constituted a convenience sample. The resulting Portuguese version is similar to the original, with 12 items in a single aggregate score, and underwent statistical validation, with assessment of reliability, validity and stability over time. RESULTS: With regard to reliability, the internal consistency of the scale is 0.9. Assessment of convergent and discriminant validity showed statistically significant results (p<0.01). Regarding stability over time, a test-retest of this instrument at six months after tilt testing with 22 patients of the sample who had not undergone any clinical intervention found no statistically significant changes in quality of life. CONCLUSIONS: The results indicate that this instrument is of value for assessing quality of life in patients with recurrent syncope in Portugal. PMID- 25727750 TI - Cardiac calcification: an incidental finding. PMID- 25727751 TI - Takayasu arteritis revisited. AB - Takayasu arteritis is a large vessel vasculitis with various clinical presentations depending on the territories affected. We report the case of a 47 year-old woman who was diagnosed with Takayasu arteritis following rapid progression of coronary disease. The condition evolved rapidly under corticosteroid therapy, with formation of new arterial stenoses within the carotid and splanchnic circulations. Disease remission was achieved with cyclophosphamide pulses and percutaneous angioplasty of the affected vessels was performed. PMID- 25727752 TI - Percutaneous patent foramen ovale closure: the Paradoxical Cerebral Embolism Prevention Registry. AB - INTRODUCTION: The natural history and therapeutic interventions for secondary prevention after a cerebrovascular event in patients with patent foramen ovale (PFO) are not yet established. This study aims to assess the safety and efficacy of percutaneous PFO closure in a population of patients with ischemic cerebrovascular disease of unknown etiology. METHODS: This prospective observational study included patients with a history of cryptogenic transient ischemic attack (TIA) or stroke who underwent percutaneous PFO closure. The effectiveness of the device for the secondary prevention of TIA or stroke was assessed by comparing observed events in the sample with expected events for this clinical setting. RESULTS: The sample included 193 cases of percutaneous PFO closure (age 46.4 +/- 13.1 years, 62.2% female) with a mean follow-up of 4.3 +/- 2.2 years, corresponding to a total exposure to ischemic events of 542 patient years. The high-risk characteristics of the PFO were assessed prior to device implantation. There were seven primary endpoint events during follow-up (1.3 per 100 patient-years), corresponding to a relative risk reduction of 68.2% in recurrent TIA or stroke compared to medical therapy alone. The procedure was associated with a low rate of device- or intervention-related complications (1.5%). CONCLUSIONS: In this long-term registry, percutaneous PFO closure was shown to be a safe and effective therapy for the secondary prevention of cryptogenic stroke or TIA. PMID- 25727753 TI - Patent foramen ovale: seeing through the mist. PMID- 25727754 TI - Snare system for left ventricular lead placement in cardiac resynchronization therapy. PMID- 25727755 TI - Iron Regulatory Protein 1 Suppresses Hypoxia-Induced Iron Uptake Proteins Expression and Decreases Iron Levels in HepG2 Cells. AB - Transferrin receptor (TfR1) and divalent metal transporter 1 (DMT1) are important proteins for cellular iron uptake, and both are regulated transcriptionally through the binding of hypoxia-inducible factor 1 (HIF-1) to hypoxia-responsive elements (HREs) under hypoxic conditions. These proteins are also regulated post transcriptionally through the binding of iron regulatory protein 1 (IRP1) to iron responsive elements (IREs) located in the mRNA untranslated region (UTR) to control cellular iron homeostasis. In iron-deficient cells, IRP1-IRE interactions stabilize TfR1 and DMT1 mRNAs, enhancing iron uptake. However, little is known about the impact of IRP1 on the regulation of cellular iron homeostasis under hypoxia. Thus, to investigate the role of IRP1 in hypoxic condition, overexpression and knockdown assays were performed using HepG2 cells. The overexpression of IRP1 suppressed the hypoxia-induced increase in TfR1 and DMT1 (+IRE) expression and reduced the stability of TfR1 and DMT1 (+IRE) mRNAs under hypoxia, whereas IRP1 knockdown further increased the hypoxia-induced expression of both proteins, preventing the decrease in IRE-dependent luciferase activity induced by hypoxia. Under hypoxic conditions, ferrous iron uptake, the labile iron pool (LIP), and total intracellular iron reduced when IRP1 was overexpressed and further increased when IRP1 was knocked down. IRP1 expression declined and TfR1/DMT1 (+IRE) expression increased with the time of hypoxia prolonged, whereas the binding of IRP1 to the IRE of TfR1/DMT1 mRNA maintained. In summary, IRP1 suppressed TfR1/DMT1 (+IRE) expression, limited the cellular iron content and decreased lactate dehydrogenase (LDH) release induced by hypoxia. PMID- 25727757 TI - The design of dual emitting cores for green thermally activated delayed fluorescent materials. AB - Dual emitting cores for thermally activated delayed fluorescent (TADF) emitters were developed. Relative to the corresponding TADF emitter with a single emitting core the TADF emitter with a dual emitting core, 3,3',5,5'-tetra(carbazol-9-yl) [1,1'-biphenyl]-2,2',6,6'-tetracarbonitrile, showed enhanced light absorption accompanied by a high photoluminescence quantum yield. The quantum and power efficiencies of the TADF devices were enhanced by the dual emitting cores. PMID- 25727756 TI - Association of dose escalation of octreotide long-acting release on clinical symptoms and tumor markers and response among patients with neuroendocrine tumors. AB - Patients with nonresectable metastatic neuroendocrine tumors (NETs) experience symptoms of hormone hypersecretion including diarrhea, flushing, and bronchoconstriction, which can interfere with quality of life [Anthony and Vinik (2011) Pancreas, 40:987]. Treatment with a long-acting release formulation of octreotide, a somatostatin analog, can help to alleviate these symptoms. Although high doses of octreotide are often required for adequate symptom control, the relationship between octreotide dose escalation and symptom control in the NET context is not well quantified in the literature. A retrospective chart review was conducted of nonresectable metastatic NET patients who received a dose greater than 30 mg intramuscular octreotide long-acting formulation (O-LAR) at any time between January 2005 and December 2011 at the British Columbia Cancer Agency (BCCA). The association between dose escalation of O-LAR, chromogranin A (CGA), 24-h urine 5-hydoxyindoacetate (5-HIAA), symptom control, and radiological progression was explored. Dose escalation of O-LAR was associated with improved symptom control in NET patients who were refractory to the standard dose levels. Reduction of serum CGA & 5-HIAA levels by at least 10% was observed in 31% and 23% respectively. Retrospective review of imaging did not document any reductions in tumor volume. Higher doses of O-LAR are associated with improved symptom control in NET patients. The variability in tumor marker levels in response to O LAR dose escalation may indicate that tumor marker levels may not be an accurate assessment of therapeutic efficacy. PMID- 25727758 TI - Comparative biochemical methane potential of paragrass using an unacclimated and an acclimated microbial consortium. AB - The effect of inoculum sources on the anaerobic digestion of paragrass was investigated. Two types of sludge were used as the inoculums: an anaerobic sludge obtained from a domestic wastewater treatment plant (OS) and a sludge acclimated to fibrous substrates in raw palm oil mill effluent (AMC). Microbial activity assays showed that the AMC had hydrolytic and acetogenic activities two times greater than the activities of the OS. In addition, the production of methane from acetate by the AMC occurred without a lag phase, while it took 8 days for the OS to start producing methane from the same substrate. The biochemical methane potential after 80 days digestion was 316 ml STP/g VS(added) using the AMC, and 277 ml STP/g VS(added) using the OS. The methane potential of the paragrass was estimated to be 3337 Nm(3) CH4/ha a. PMID- 25727759 TI - Potential use of feedlot cattle manure for bioethanol production. AB - This paper reports on processing options for the conversion of feedlot cattle manures into composite sugars for ethanol fermentation. Small-scale anaerobic digestion trials revealed that the process significantly reduces the content of glucan and xylan (ca. 70%) without effecting lignin. Moreover, anaerobic digestate (AD) fibres were poor substrates for cellulase (Cellic(r) CTec 2) saccharification, generating a maximum combined sugar yield of ca. 12% per original dry weight. Dilute acid pretreatment and enzyme saccharification of raw manures significantly improved total sugar recoveries, totalling 264 mg/g (79% theoretical). This was attained when manures were pretreated with 2.5% H2SO4 for 90 min at 121 degrees C and saccharified with 50 FPU CTec 2/g glucan. Saccharomyces cerevisiae efficiently fermented crude hydrolysates within 6 h, yielding 7.3 g/L ethanol, representing glucose to ethanol conversion rate of 70%. With further developments (i.e., fermentation of xylose), this process could deliver greater yields, reinforcing its potential as a biofuel feedstock. PMID- 25727760 TI - Study of moving bed biofilm reactor in diethyl phthalate and diallyl phthalate removal from synthetic wastewater. AB - Phthalic acid esters have received significant attention over the last few years since they are considered as priority pollutants. In this study, effects of different operation conditions including hydraulic retention time, phthalates loading rates and aeration rate on process performance of moving bed biofilm reactor (MBBR) for removing diethyl phthalate (DEP) and diallyl phthalate (DAP) from synthetic wastewater was evaluated. In optimum conditions, 94.96% and 93.85% removal efficiency were achieved for DEP and DAP, respectively. Moreover, MBBR achieved to remove more than 92% of COD for both phthalates. The results showed that DEP had a higher biodegradation rate compared to DAP, according to the selected parameters such as half saturation constant, overall reaction rate and maximum specific growth rate. The Grau second order model found as the best model for predicting MBBR performance due to its high correlation coefficients and more conformity of its kinetic coefficients to the results. PMID- 25727761 TI - Magnesium carbonate precipitate strengthened aerobic granules. AB - Aerobic granules were precipitated internally with magnesium carbonate to enhance their structural stability under shear. The strengthened granules were tested in continuous-flow reactors for 220 days at organic loadings of 6-39 kg/m(3)/day, hydraulic retention times of 0.44-19 h, and temperatures of 10 or 28 degrees C. The carbonate salt had markedly improved the granule strength without significant changes in granule morphology or microbial communities (with persistent strains Streptomyces sp., Rhizobium sp., Brevundimonas sp., and Nitratireductor sp.), or sacrifice in biological activity for organic degradation. MgCO3 precipitated granules could be used in continuous-flow reactor for wastewater treatment at low cost and with easy processing efforts. PMID- 25727762 TI - Techno-economic assessment of integrating methanol or Fischer-Tropsch synthesis in a South African sugar mill. AB - This study considered an average-sized sugar mill in South Africa that crushes 300 wet tonnes per hour of cane, as a host for integrating methanol and Fischer Tropsch synthesis, through gasification of a combined flow of sugarcane trash and bagasse. Initially, it was shown that the conversion of biomass to syngas is preferably done by catalytic allothermal gasification instead of catalytic autothermal gasification. Thereafter, conventional and advanced synthesis routes for both Methanol and Fischer-Tropsch products were simulated with Aspen Plus(r) software and compared by technical and economic feasibility. Advanced FT synthesis satisfied the overall energy demands, but was not economically viable for a private investment. Advanced methanol synthesis is also not viable for private investment since the internal rate of return was 21.1%, because it could not provide the steam that the sugar mill required. The conventional synthesis routes had less viability than the corresponding advanced synthesis routes. PMID- 25727763 TI - Understanding diversity patterns in bacterioplankton communities from a sub Antarctic peatland. AB - Bacterioplankton communities inhabiting peatlands have the potential to influence local ecosystem functions. However, most microbial ecology research in such wetlands has been done in ecosystems (mostly peat soils) of the Northern Hemisphere, and very little is known of the factors that drive bacterial community assembly in other regions of the world. In this study, we used high throughput sequencing to analyse the structure of the bacterial communities in five pools located in a sub-Antarctic peat bog (Tierra del Fuego, Argentina), and tested for relationships between bacterial communities and environmental conditions. Bacterioplankton communities in peat bog pools were diverse and dominated by members of the Proteobacteria, Actinobacteria, Bacteroidetes and Verrucomicrobia. Community structure was largely explained by differences in hydrological connectivity, pH and nutrient status (ombrotrophic versus minerotrophic pools). Bacterioplankton communities in ombrotrophic pools showed phylogenetic clustering, suggesting a dominant role of deterministic processes in shaping these assemblages. These correlations between habitat characteristics and bacterial diversity patterns provide new insights into the factors regulating microbial populations in peatland ecosystems. PMID- 25727765 TI - Physiological and genetic analyses reveal a mechanistic insight into the multifaceted lifestyles of Pseudoalteromonas sp. SM9913 adapted to the deep-sea sediment. AB - Although bacteriobenthos play a major role in the degradation of particulate organic matter in marine sediment, knowledge of the sediment-adapted lifestyles of bacteriobenthos is still scarce. Here, the particle-associated, swimming and swarming lifestyles of the benthonic bacterium Pseudoalteromonas sp. SM9913 (SM9913) were illustrated. SM9913 had a clay particle-associated lifestyle, and its exopolysaccharide played an important role in this lifestyle. SM9913 also had swimming and swarming motilities, indicating that it may have swimming and swarming lifestyles in the sediment. The lateral flagella were responsible for the swarming motility, and the polar flagella were responsible for the swimming motility. Iron limitation was an indispensable inductive signal of the swarming motility. An analysis of the motilities of SM9913 and its mutants in clay demonstrated that SM9913 moved in clay by both swimming and swarming motilities. Genomic analysis suggests that having two flagella systems is most likely a common adaptation of some bacteriobenthos to the sediment environment. Our results reveal the lifestyles of benthonic SM9913, providing a better understanding of the environmental adaptation of benthonic bacteria. PMID- 25727764 TI - How does religious affiliation affect women's attitudes toward reproductive health policy? Implications for the Affordable Care Act. AB - BACKGROUND: Supreme Court cases challenging the Affordable Care Act (ACA) mandate for employer-provided reproductive health care have focused on religiously based opposition to coverage. Little is known about women's perspectives on such reproductive health policies. STUDY DESIGN: Data were drawn from the Women's Health Care Experiences and Preferences survey, a randomly selected, nationally representative sample of 1078 US women aged 18-55 years. We examined associations between religious affiliation and attitudes toward employer-provided insurance coverage of contraception and abortion services as well as the exclusion of religious institutions from this coverage. We used chi-square and multivariable logistic regression for analysis. RESULTS: Respondents self-identified as Baptist (18%), Protestant (Other Mainline, 17%), Catholic (17%), Other Christian (20%), Religious, Non-Christian (7%) or No Affiliation (21%). Religious affiliation was associated with proportions of agreement for contraception (p=.03), abortion (p<.01) and religious exclusion (p<.01) policies. In multivariable models, differences in the odds of agreement varied across religious affiliations and frequency of service attendance. For example, compared to non-affiliated women, Baptists and Other Nondenominational Christians (but not Catholics) had lower odds of agreement with employer coverage of contraception (OR 0.63, 95% CI 0.4 0.1 and OR 0.57, CI 0.4-0.9, respectively); women who attended services weekly or more than weekly had lower odds of agreement (OR 0.53, 95% CI 0.3-0.8 and OR 0.33, CI 0.2-0.6, respectively), compared to less frequent attenders. CONCLUSIONS: Recent religiously motivated legal challenges to employer-provided reproductive health care coverage may not represent the attitudes of many religious women. IMPLICATIONS: Recent challenges to the ACA contraceptive mandate appear to equate religious belief with opposition to employer-sponsored reproductive health coverage, but women's views are more complex. PMID- 25727766 TI - The use of agomelatine in OCD: effects on the motivational aspects and dysregulated circadian rhythms. AB - INTRODUCTION: A considerable proportion of subjects with obsessive-compulsive disorder (OCD) have shown resistance or an incomplete response to the standard first-line treatment of serotonin reuptake inhibitors. In particular, patients often continue to show disrupted circadian rhythms with related sleep disturbances and comorbidity with bipolar spectrum disorders. AREAS COVERED: This paper discusses the possible role of agomelatine in the treatment of motivational aspects and dysregulated circadian rhythms of OCD. In particular, the article highlights the pharmacokinetics and pharmacodynamics of agomelatine. Additionally, the article highlights its clinical efficacy, safety and tolerability and provides perspectives on its future development as a potential therapy for the treatment of OCD. EXPERT OPINION: Agomelatine offers the effective resynchronization of circadian rhythm with an improvement in patients' reward mechanism, incentive motivation and general OCD symptoms. Indeed, the authors believe that agomelatine could be a valid alternative drug in treatment resistant OCD patients, particularly those suffering with bipolar spectrum comorbidity and related sleep disturbances. PMID- 25727767 TI - Functionalised Mn(VI)-nanoparticles: an advanced high-valent magnetic catalyst. AB - We discover Mn(VI)-nanoparticles (NPs) bearing functional groups, high oxidation state, strong electron affinity, unique redox and paramagnetic nature, which opens up a new avenue to catalysis, magnetism and material application. However, its synthesis is challenging and remains unexplored because of associated serious difficulties. A simple benign synthetic strategy is devised to fabricate the high valent NPs using mild reducing agent bromide, which transformed Mn(VII) to valuable Mn(VI)-species. The EELS-imaging of individual elements, ESI-MS, XPS and other techniques established its composition as Br(Me3SiO)Mn(VI)O2. It revealed significantly improved magnetic moment (SQUID) with isotropic hyperfine splitting of six line spectrum (EPR). The high-oxidation state and incorporated-ligands of the metals present on the active surface of the NPs led to development of a general catalytic process for oxidative heterodifunctionalisation to C-C triple bond towards formation of a new O-C/N-C/S-C and C-C coupling cum cyclisation to biologically important flavones and their aza- and marcapto-analogues, and valuable enaloxy synthons. PMID- 25727768 TI - Time to cool off on a hot topic? Let's not forget about evidence when discussing heat-induced pump thrombogenesis. PMID- 25727769 TI - Risk models for mechanical circulatory support in children. PMID- 25727770 TI - Ironman triathlon performance pre- and post-heart transplant. PMID- 25727771 TI - HLA molecular epitope mismatching and long-term graft loss in pediatric heart transplant recipients. AB - BACKGROUND: Although evidence links HLA allele mismatching to worse outcomes in pediatric heart transplantation, no studies to our knowledge have applied the quantification of structural HLA differences between donor and recipient to risk evaluation. We examine the association between molecular-level HLA mismatching and long-term graft loss in pediatric recipients of heart transplants. METHODS: HLA Matchmaker was used to quantify the number of mismatched class-specific HLA eplets among 4,851 heart transplant recipients <=18 years of age in the Scientific Registry of Transplant Recipients (1987-2012). Survival analysis was used to compare long-term probabilities of graft loss by number of eplet mismatches and allele mismatches stratified by eplet mismatches. RESULTS: Recipients with 10 to 20 or >20 class I (HLA-A and HLA-B) eplet mismatches experienced increased long-term graft loss compared with recipients with <10 class I eplet mismatches (adjusted hazard ratio = 1.23 [95% confidence interval = 1.06-1.42], adjusted hazard ratio = 1.27 [95% confidence interval = 1.08-1.50], respectively). Recipients with 2 to 4 class I allele mismatches had increased long-term graft loss compared with recipients with 0 to 1 class I allele mismatches. Neither class II (HLA-DR) eplet mismatching nor class II allele mismatching was associated with graft loss. On stratification by allele and structural eplet mismatching, only recipients with 2 to 4 class I allele mismatches and >=10 class I eplet mismatches had an increased probability of graft loss compared with recipients with 0 to 1 class I allele mismatches (adjusted hazard ratio = 1.42 [95% confidence interval = 1.09-1.57]). CONCLUSIONS: Molecular-level HLA mismatching may aid in identifying recipients at increased risk of long-term graft loss who could benefit from intensified post transplant surveillance and management. PMID- 25727772 TI - What we expected all along: Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplantation! PMID- 25727773 TI - Detection of Mycobacterium tuberculosis DNA on the oral mucosa of tuberculosis patients. AB - Diagnosis of pulmonary tuberculosis (TB) usually includes laboratory analysis of sputum, a viscous material derived from deep in the airways of patients with active disease. As a diagnostic sample matrix, sputum can be difficult to collect and analyze by microbiological and molecular techniques. An alternative, less invasive sample matrix could greatly simplify TB diagnosis. We hypothesized that Mycobacterium tuberculosis cells or DNA accumulate on the oral epithelia of pulmonary TB patients, and can be collected and detected by using oral (buccal) swabs. To test this hypothesis, 3 swabs each were collected from 20 subjects with active pulmonary TB and from 20 healthy controls. Samples were tested by using a polymerase chain reaction (PCR) specific to the M. tuberculosis IS6110 insertion element. Eighteen out of 20 confirmed case subjects (90%) yielded at least 2 positive swabs. Healthy control samples were 100% negative. This case-control study supports past reports of M. tuberculosis DNA detection in oral swabs. Oral swab samples are non-invasive, non-viscous, and easy to collect with or without active TB symptoms. These characteristics may enable simpler and more active TB case finding strategies. PMID- 25727774 TI - Failed drug discovery in psychiatry: time for human genome-guided solutions. AB - Our knowledge about the molecular and neural mechanisms of emotional and cognitive processes has increased exponentially in the past decades. Unfortunately, there has been no translation of this knowledge into the development of novel and improved pharmacological treatments for psychiatric disorders. We comment on some of the reasons for failed drug discovery in psychiatry, particularly on the use of ill-suited disease models and on the use of diagnostic constructs unrelated to the underlying biological mechanisms. Furthermore, we argue that the use of human genetic findings together with biologically informed phenotypes and advanced data-mining methodology will catalyze the identification of promising drug targets and, finally, will lead to improved therapeutic outcomes. PMID- 25727775 TI - Neuroradiology of acute stroke, where are we today? PMID- 25727776 TI - Comparison of stretched-Exponential and monoexponential model diffusion-Weighted imaging in prostate cancer and normal tissues. AB - BACKGROUND: To compare stretched-exponential and monoexponential model diffusion weighted imaging (DWI) in prostate cancer and normal tissues. METHODS: Twenty seven patients with prostate cancer underwent DWI exam using b-values of 0, 500, 1000, and 2000 s/mm(2) . The distributed diffusion coefficients (DDC) and alpha values of prostate cancer and normal tissues were obtained with stretched exponential model and apparent diffusion coefficient (ADC) values using monoexponential model. The ADC, DDC (both in 10(-3) mm(2)/s), and alpha values (range, 0-1) were compared among different prostate tissues. The ADC and DDC were also compared and correlated in each tissue, and the standardized differences between DDC and ADC were compared among different tissues. RESULTS: Data were obtained for 31 cancers, 36 normal peripheral zone (PZ) and 26 normal central gland (CG) tissues. The ADC (0.71 +/- 0.12), DDC (0.60 +/- 0.18), and alpha value (0.64 +/- 0.05) of tumor were all significantly lower than those of the normal PZ (1.41 +/- 0.22, 1.47 +/- 0.20, and 0.85 +/- 0.09) and CG (1.25 +/- 0.14, 1.32 +/- 0.13, and 0.82 +/- 0.06) (all P < 0.05). ADC was significantly higher than DDC in cancer, but lower than DDC in the PZ and CG (all P < 0.05). The ADC and DDC were strongly correlated (R(2) = 0.99, 0.98, 0.99, respectively, all P < 0.05) in all the tissue, and standardized difference between ADC and DDC of cancer was slight but significantly higher than that in normal tissue. CONCLUSION: The stretched exponential model DWI provides more parameters for distinguishing prostate cancer and normal tissue and reveals slight differences between DDC and ADC values. PMID- 25727777 TI - An observational study of older patients' participation in hospital admission and discharge--exploring patient and next of kin perspectives. AB - AIMS AND OBJECTIVES: To explore older patients' participation during hospital admission and discharge. BACKGROUND: Patient participation is suggested as a means to improve the quality of transitional healthcare. Older people with chronic diseases, physical disabilities and cognitive impairments often need to transfer from primary to hospital healthcare and vice versa. DESIGN: This study adopts a participant observational research design. METHODS: Participant observations of 41 older patients (over 75 years of age) during hospital admission and discharge were conducted in two hospitals in Norway (in 2012). The observations included short conversations with the patient and their next of kin to capture their participation experiences. Systematic text condensation was used to analyse the data material from the field notes. RESULTS: Varying degrees of information exchange between healthcare professionals and patients, and a lack of involvement of the patient in decision-making (in admission and discharge) were observed and experienced by patients and their next of kin. The next of kin appeared to be important advocates for the patients in admission and provided practical support both during admission and discharge. Data suggest that patient participation in admission and discharge is influenced by time constraints and the heavy workloads of healthcare professionals. Patients' health conditions and preferences also influence participation. CONCLUSIONS: Several issues influence the participation of the older patients during hospital admission and discharge. Participation of the older patients needs continuous support from healthcare professionals that acknowledges both the individual patient's preferences and their capacity to participate. RELEVANCE TO CLINICAL PRACTICE: Study findings report discrepancies in the involvement of older people and their next of kin. There is a need to increase and support older patients' participation in hospital admission and discharge. PMID- 25727779 TI - Cosmetic procedures and the distortion of beauty. PMID- 25727778 TI - Complex formation of blueberry (Vaccinium angustifolium) anthocyanins during freeze-drying and its influence on their biological activity. AB - Biological activity of polyphenols is influenced by their uptake and is highly influenced by their interactions with the food matrix. This study evaluated the complex formation of blueberry polyphenols with fruit matrixes such as pectin and cellulose and their effect on the biological and antiproliferative properties of human colon cell lines HT-29 and CRL 1790. Free or complexed polyphenols were isolated by dialyzing aqueous or methanolic blueberry homogenates. Seven phenolic compounds and thirteen anthocyanins were identified in blueberry extracts. Blueberry extracts showed varying degrees of antioxidant and antiproliferative activities, as well as alpha-glucosidase activity. Fruit matrix containing cellulose and pectin, or purified polygalacturonic acid and cellulose, did not retain polyphenols and showed very low antioxidant or antiproliferative activities. These findings suggest that interactions between polyphenols and the food matrix may be more complex than a simple association and may play an important role in the bioefficacy of blueberry polyphenols. PMID- 25727780 TI - Hydrogen sulfide acts as a downstream signal molecule in salicylic acid-induced heat tolerance in maize (Zea mays L.) seedlings. AB - Salicylic acid (SA), 2-hydroxy benzoic acid, is a small phenolic compound with multifunction that is involved in plant growth, development, and the acquisition of stress tolerance. In recent years, hydrogen sulfide (H2S) has been found to have similar functions, but cross talk between SA and H2S in the acquisition of heat tolerance is not clear. In this study, pretreatment of maize seedlings with SA improved the survival percentage of seedlings under heat stress, indicating that SA pretreatment could improve the heat tolerance of maize seedlings. In addition, treatment with SA enhanced the activity of L-cysteine desulfhydrase (L DES), a key enzyme in H2S biosynthesis, which in turn induced accumulation of endogenous H2S. Interestingly, SA-induced heat tolerance was enhanced by addition of NaHS, a H2S donor, but weakened by specific inhibitors of H2S biosynthesis DL propargylglycine (PAG) and its scavenger hydroxylamine (HT). Furthermore, pretreatment with paclobutrazol (PAC) and 2-aminoindan-2-phosphonic acid (AIP), inhibitors of SA biosynthesis, had no significant effect on NaHS-induced heat tolerance of maize seedlings. Similarly, significant change in the activities of phenylalanine ammonia lyase (PAL) and benzoic-acid-2-hydroxylase (BA2H), the key enzymes in SA biosynthesis, and the content of endogenous SA, was not observed in maize seedlings by NaHS treatment. All of the above-mentioned results suggest that SA pretreatment could improve the heat tolerance of maize seedlings, and H2S might be a novel downstream signal molecule in SA-induced heat tolerance. PMID- 25727781 TI - Pattern of activation of pelvic floor muscles in men differs with verbal instructions. AB - AIMS: To investigate the effect of instruction on activation of pelvic floor muscles (PFM) in men as quantified by transperineal ultrasound imaging (US) and to validate these measures with invasive EMG recordings. METHODS: Displacement of pelvic floor landmarks on transperineal US, intra-abdominal pressure (IAP) recorded with a nasogastric transducer, and surface EMG of the abdominal muscles and anal sphincter were recorded in 15 healthy men during sub-maximal PFM contractions in response to different verbal instructions: "tighten around the anus," "elevate the bladder," "shorten the penis," and "stop the flow of urine." In three men, fine-wire EMG recordings were made from puborectalis and bulbocavernosus, and trans-urethral EMG recordings from the striated urethral sphincter (SUS). Displacement data were validated by analysis of relationship with invasive EMG. Displacement, IAP, and abdominal/anal EMG were compared between instructions. RESULTS: Displacement of pelvic landmarks correlated with the EMG of the muscles predicted anatomically to affect their locations. Greatest dorsal displacement of the mid-urethra and SUS activity was achieved with the instruction "shorten the penis." Instruction to "elevate the bladder" induced the greatest increase in abdominal EMG and IAP. "Tighten around the anus" induced greatest anal sphincter activity. CONCLUSIONS: The pattern of urethral movement measured from transperineal US is influenced by the instructions used to teach activation of the pelvic floor muscles in men. Efficacy of PFM training may depend on the instructions used to train activation. Instructions that optimize activation of muscles with a potential to increase urethral pressure without increasing abdominal EMG/IAP are likely ideal. Neurourol. Urodynam. 35:457-463, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25727782 TI - Facile synthesis and enhanced visible-light photocatalysis of graphitic carbon nitride composite semiconductors. AB - The semiconductor heterojunction has been an effective architecture to enhance photocatalytic activity by promoting photogenerated charge separation. Here, graphitic carbon nitride (CN) and B-modified graphitic carbon nitride (CNB) composite semiconductors were fabricated by a facile calcination process using cheap, sustainable, and easily available sodium tetraphenylboron and urea as precursors. The synthetic CN-CNB-25 semiconductor with a suitable CNB content showed the highest visible-light activity. Its degradation ratio for methyl orange and phenol was more than twice that of CN and CNB and its H2 evolution rate was ~3.4 and ~1.8 times higher than that of CN and CNB, respectively. It also displayed excellent stability and reusability. The enhanced activity of CN CNB-25 was attributed predominantly to the efficient separation of photoinduced electrons and holes. This paper describes a visible-light-responsive CN composite semiconductor with great potential in environmental and energy applications. PMID- 25727783 TI - Butyrate prevents muscle atrophy after sciatic nerve crush. AB - INTRODUCTION: Histone deacetylases (HDACs) have been implicated in neurogenic muscle atrophy, but the mechanisms by which HDAC inhibitors might have beneficial effects are not defined. METHODS: We used sciatic nerve crush to determine the effect of butyrate on denervation-induced gene expression and oxidative stress. RESULTS: Butyrate treatment initiated 3 weeks before injury and continued 1 week after injury increases histone acetylation and reduces muscle atrophy after nerve crush. Butyrate delivered only after nerve crush similarly prevented muscle atrophy. Butyrate had no effect on the increase in histone deacetylase 4 (HDAC4) protein levels following nerve crush but prevented the increase in expression of myogenin, MuRF1, and atrogin-1. Butyrate did not affect mitochondrial reactive oxygen species production, but it increased antioxidant enzyme activity, reduced proteasome activity, and reduced oxidative damage following nerve injury. CONCLUSIONS: These data suggest that HDAC inhibitors are promising pharmacological agents for treating neurogenic muscle atrophy. Muscle Nerve 52: 859-868, 2015. PMID- 25727784 TI - [Radiology in the 21(st) century: strengths, weaknesses, opportunities, and threats]. PMID- 25727785 TI - Dual stator dynamics in the Shewanella oneidensis MR-1 flagellar motor. AB - The bacterial flagellar motor is an intricate nanomachine which converts ion gradients into rotational movement. Torque is created by ion-dependent stator complexes which surround the rotor in a ring. Shewanella oneidensis MR-1 expresses two distinct types of stator units: the Na(+)-dependent PomA4 B2 and the H(+)-dependent MotA4 B2. Here, we have explored the stator unit dynamics in the MR-1 flagellar system by using mCherry-labeled PomAB and MotAB units. We observed a total of between 7 and 11 stator units in each flagellar motor. Both types of stator units exchanged between motors and a pool of stator complexes in the membrane, and the exchange rate of MotAB, but not of PomAB, units was dependent on the environmental Na(+)-levels. In 200 mM Na(+), the numbers of PomAB and MotAB units in wild-type motors was determined to be about 7:2 (PomAB:MotAB), shifting to about 6:5 without Na(+). Significantly, the average swimming speed of MR-1 cells at low Na(+) conditions was increased in the presence of MotAB. These data strongly indicate that the S. oneidensis flagellar motors simultaneously use H(+) and Na(+) driven stators in a configuration governed by MotAB incorporation efficiency in response to environmental Na(+) levels. PMID- 25727786 TI - Photosynthetic Proteins in Supported Lipid Bilayers: Towards a Biokleptic Approach for Energy Capture. AB - In nature, plants and some bacteria have evolved an ability to convert solar energy into chemical energy usable by the organism. This process involves several proteins and the creation of a chemical gradient across the cell membrane. To transfer this process to a laboratory environment, several conditions have to be met: i) proteins need to be reconstituted into a lipid membrane, ii) the proteins need to be correctly oriented and functional and, finally, iii) the lipid membrane should be capable of maintaining chemical and electrical gradients. Investigating the processes of photosynthesis and energy generation in vivo is a difficult task due to the complexity of the membrane and its associated proteins. Solid, supported lipid bilayers provide a good model system for the systematic investigation of the different components involved in the photosynthetic pathway. In this review, the progress made to date in the development of supported lipid bilayer systems suitable for the investigation of membrane proteins is described; in particular, there is a focus on those used for the reconstitution of proteins involved in light capture. PMID- 25727787 TI - Brain area-specific diurnal and photic regulation of val-opsinA and val-opsinB genes in the zebrafish. AB - Zebrafish possess two isoforms of vertebrate ancient long (VAL)-opsin, val-opsinA (valopa) and val-opsinB (valopb), which probably mediate non-visual responses to light. To understand the diurnal and light-sensitive regulation of the valop genes in different cell groups, the current study used real-time quantitative PCR to examine the diurnal changes of valopa and b mRNA levels in different brain areas of adult male zebrafish. Furthermore, effects of the extended exposure to light or dark condition, luminous levels and the treatment with a melatonin receptor agonist or antagonist on valop transcription were examined. In the thalamus, valop mRNA levels showed significant diurnal changes; valopa peaked in the evening, while valopb peaked in the morning. The diurnal change of valopa mRNA levels occurred independent of light conditions, whereas that of valopb mRNA levels were regulated by light. A melatonin receptor agonist or antagonist did not affect the changes of valop mRNA levels. In contrast, the midbrain and hindbrain showed arrhythmic valop mRNA levels under light and dark cycles. The differential diurnal regulation of the valopa and b genes in the thalamus and the arrhythmic expression in the midbrain and hindbrain suggest involvement of deep brain VAL-opsin in time- and light-dependent physiology. We show diurnal expression changes of vertebrate ancient long (VAL) opsin genes (valopa and valopb), depending on brain area, time of day and light condition, in the adult male zebrafish. Differential regulation of the valop genes in the thalamus and arrhythmic expression in the midbrain and hindbrain suggest their involvement in time- and light-dependent physiology to adjust to environmental changes. PMID- 25727788 TI - Neutrophil CD64 level as a rapid and promising diagnostic tool for infectious diseases in elderly patients. AB - AIM: We examined the utility of the neutrophil CD64 level as a rapid and sensitive diagnostic marker for infections in febrile aged patients. METHODS: The expression level of CD64 per neutrophil was quantitatively measured with flow cytometry using a QuantiBrite kit in samples from febrile (aged >65 years) patients. Information about the presence or absence of infectious disease was retrospectively obtained from each patient's medical record in which attending physicians were obliged to write down a tentative diagnosis after resolution of manifestations. RESULTS: With receiver operating characteristic curve evaluation using the results, a CD64 level >2000 molecules per neutrophil was sensitive and specific for detecting infection. Among 102 patients suspected of having infection, 72 patients were diagnosed with infectious diseases, and 30 patients had non-infectious diseases. The sensitivity and specificity of determination of the neutrophil CD64 level were 88% and 63%, respectively. However, considering the high frequency of infections in elderly patients (71% in the present study), the post-test probability reached as high as 93%. The positive likelihood ratio was 2.4, and the negative likelihood ratio was 0.2. CONCLUSIONS: Considering the frequency of infectious diseases in elderly patients, determination of the neutrophil CD64 level helps detect infectious diseases. PMID- 25727789 TI - Toxicity induced by Basic Violet 14, Direct Red 28 and Acid Red 26 in zebrafish larvae. AB - Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC50 value at 60.63 and 476.84 ug ml( 1) , respectively, whereas the LC50 of Acid Red 26 was between 2500 and 2800 ug ml(-1) . Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 ug ml(-1) . Basic Violet 14 also caused significant up-regulation of GCLC gene expression in a dose-dependent manner whereas Acid Red 26 induced significant up-regulation of NKX2.5 and down regulation of GATA4 at a high concentration in a dose-dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ-specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26. PMID- 25727790 TI - Improvement in Bilateral Carpal Valgus Deviation in 9 Foals After Unilateral Distolateral Radial Periosteal Transection and Elevation. AB - OBJECTIVES: To evaluate the effect of periosteal transection and elevation in foals with naturally occurring carpal valgus deviation. STUDY DESIGN: Prospective clinical study. ANIMALS: Foals (n = 9) with bilateral carpal valgus. METHODS: Foals with bilateral carpal valgus had distolateral radial periosteal transection and elevation (PE) including distal ulnar transection on 1 limb. Foals were stall confined until the skin incisions healed, and then allowed free exercise in a small paddock or round pen. Dorsopalmar carpal radiographs were obtained at 14 day intervals to determine the carpal valgus angle (CVA) until it was <5 degrees . RESULTS: All limbs had a reduction in CVA and there was no significant difference in total carpal valgus angular correction or the rate at which the correction occurred between the surgical and control limb. CONCLUSIONS: Unilateral distolateral radial PE had no effect on carpal angulation in 9 foals with naturally occurring bilateral carpal valgus deviation when performed between 19 and 43 days. PMID- 25727791 TI - Risk factors for acute and overuse sport injuries in Swedish children 11 to 15 years old: What about resistance training with weights? AB - To determine the 1-year self-reported incidence of overuse and traumatic sport injuries and risk factors for injuries in children participating in a summer sports camp representing seven different sports. 4363 children, 11 to 15 years old participating in a summer camp in seven different sports answered a questionnaire. Injury in this cross-sectional study was defined as a sport related trauma or overload leading to pain and dysfunction preventing the person from participation in training or competition for at least 1 week. A number of risk factors for injury were investigated such as sex, age, number of hours spent on training in general, and on resistance training with weights. Nearly half [49%, 95% confidence interval (CI) 48-51%] of the participants had been injured as a result of participation in a sport during the preceding year, significantly more boys than girls (53%, 95% CI 50-55% vs 46%, 95% CI 43-48%; P < 0.001). Three factors contributed to increased incidence of sport injuries: age, sex, and resistance training with weights. Time spent on resistance training with weights was significantly associated with sport injuries in a logistic regression analysis. In children age 11 to 15 years, the risk of having a sport-related injury increased with age and occurred more often in boys than in girls. Weight training was the only modifiable risk factor that contributed to a significant increase in the incidence of sport injuries. PMID- 25727795 TI - Potential and actual uses of zeolites in crop protection. AB - In this review, it is demonstrated that zeolites have a potential to be used as crop protection agents. Similarly to kaolin, zeolites can be applied as particle films against pests and diseases. Their honeycomb framework, together with their carbon dioxide sorption capacity and their heat stress reduction capacity, makes them suitable as a leaf coating product. Furthermore, their water sorption capacity and their smaller particle sizes make them effective against fungal diseases and insect pests. Finally, these properties also ensure that zeolites can act as carriers of different active substances, which makes it possible to use zeolites for slow-release applications. Based on the literature, a general overview is provided of the different basic properties of zeolites as promising products in crop protection. PMID- 25727794 TI - Rapid quantification of viable Legionella in nuclear cooling tower waters using filter cultivation, fluorescent in situ hybridization and solid-phase cytometry. AB - AIMS: To develop a rapid and sensitive method to quantify viable Legionella spp. in cooling tower water samples. METHODS AND RESULTS: A rapid, culture-based method capable of quantifying as few as 600 Legionella microcolonies per litre within 2 days in industrial waters was developed. The method combines a short cultivation step of microcolonies on GVPC agar plate, specific detection of Legionella cells by a fluorescent in situ hybridization (FISH) approach, and a sensitive enumeration using a solid-phase cytometer. Following optimization of the cultivation conditions, the qualitative and quantitative performance of the method was assessed and the method was applied to 262 nuclear power plant cooling water samples. CONCLUSIONS: The performance of this method was in accordance with the culture method (NF-T 90-431) for Legionella enumeration. SIGNIFICANCE AND IMPACT OF THE STUDY: The rapid detection of viable Legionella in water is a major concern to the effective monitoring of this pathogenic bacterium in the main water sources involved in the transmission of legionellosis infection (Legionnaires' disease). The new method proposed here appears to be a robust, efficient and innovative means for rapidly quantifying cultivable Legionella in cooling tower water samples within 48 h. PMID- 25727796 TI - Development and evaluation of a latex agglutination test for the rapid serodiagnosis of tularemia. AB - A latex agglutination test (LAT) was developed for a rapid detection of antibodies against Francisella tularensis. The assay is performed by mixing serum with antigen-coated latex beads and read within 5 min. Developed LAT has been proved to be a specific, sensitive, fast, easy-to-perform and cost-efficient tool for the routine diagnosis of tularemia. PMID- 25727797 TI - Self-biased reconfigurable graphene stacks for terahertz plasmonics. AB - The gate-controllable complex conductivity of graphene offers unprecedented opportunities for reconfigurable plasmonics at terahertz and mid-infrared frequencies. However, the requirement of a gating electrode close to graphene and the single 'control knob' that this approach offers limits the practical implementation and performance of these devices. Here we report on graphene stacks composed of two or more graphene monolayers separated by electrically thin dielectrics and present a simple and rigorous theoretical framework for their characterization. In a first implementation, two graphene layers gate each other, thereby behaving as a controllable single equivalent layer but without any additional gating structure. Second, we show that adding an additional gate allows independent control of the complex conductivity of each layer within the stack and provides enhanced control on the stack equivalent complex conductivity. These results are very promising for the development of THz and mid-infrared plasmonic devices with enhanced performance and reconfiguration capabilities. PMID- 25727799 TI - Conflicts of interest: a matter of transparency. PMID- 25727798 TI - Home visits by commissioned welfare volunteers and psychological distress: a population-based study of 11,312 community-dwelling older people in Japan. AB - OBJECTIVE: Novel countermeasures to increase healthcare expenditures should be explored in rapidly aging societies, including Japan. Social support is a resource for the older people that effectively reduces psychological distress, with or without specialized health service provision. This cross-sectional study was conducted to determine whether home visits by commissioned welfare volunteers (organizations of community residents assigned by national or local governments) are associated with a lower risk of psychological distress among the older people. METHODS: Questionnaires were sent in August 2010 to all residents aged >=65 years in three municipalities (n = 21,232) in Okayama Prefecture in Japan; 13,929 were returned (response rate = 65.6%). The final sample size for the analysis was 11,312 participants. Home visits, psychological distress (Kessler Psychological Distress Scale: K6 > 5), and severe psychological distress (K6 > 13) were measured by the questionnaire. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for psychological distress, adjusting for age, gender, education, marital status, and qualification for long-term care insurance. RESULTS: The prevalence was 41.4% for psychological distress and 6.5% for severe psychological distress among all participants. Home visits were significantly associated with a lower risk of psychological distress after adjusting for the covariates (OR: 0.71, 95% CI: 0.65-0.77). These associations were comparable for men and women. The association was clearer for severe psychological distress (OR: 0.51, 95% CI: 0.43-0.61). CONCLUSIONS: Home visits by commissioned welfare volunteers are significantly associated with a lower risk of psychological distress among older people. PMID- 25727800 TI - Venous thromboembolism and problems related to its continuous medical surveillance. PMID- 25727801 TI - Addressing conflict of interest in non-pharmacological research. PMID- 25727802 TI - Treatment for metastatic melanoma: a new and evolving era. PMID- 25727803 TI - Clarifying the costs of conflicts of interest. PMID- 25727804 TI - Response to clarifying the costs of conflicts of interest. PMID- 25727805 TI - Cryopreservation of cord blood CD34+ cells before or after thrombopoietin expansion differentially affects early platelet recovery in NOD SCID mice. AB - BACKGROUND: Expansion of human cord blood (CB) CD34+ cells with thrombopoietin (TPO) can accelerate delayed platelet (PLT) recovery after transplantation into immunodeficient mice. Clinical implementation, however, will depend on practical and effective protocols. The best timing of TPO expansion in relation to cryopreservation in this respect is unknown. STUDY DESIGN AND METHODS: In this study, we evaluated whether the order of cryopreservation and TPO expansion affected the expansion rate and numbers of clonogenic hematopoietic progenitor cells in vitro or PLT and longer-term hematopoietic repopulation in NOD SCID mice in vivo. RESULTS: Our results demonstrate higher expansion rates and the generation of higher numbers of multilineage and megakaryocytic progenitors (granulocyte, erythrocyte, monocyte, megakaryocyte colony-forming units and megakaryocyte colony-forming units) in vitro when freshly isolated CB CD34+ cells are first cultured with TPO and then cryopreserved and thawed as compared to TPO expansion after CD34+ cell cryopreservation. In contrast, the cells produced with the latter strategy showed higher expression of CD62L and a superior stromal cell derived factor-1alpha-mediated migration. This might play a role in an also observed superior early PLT recovery after transplantation of these cells into NOD SCID mice. The hematopoietic engraftment in the marrow 6 weeks after transplantation was not different between the two strategies. CONCLUSION: Although TPO expansion before cryopreservation would yield higher nucleated cell and clonogenic myeloid and megakaryocyte cell numbers and enable earlier availability, CB TPO expansion after cryopreservation is likely to be clinically more effective, despite the lower number of cells obtained after expansion. Moreover, the latter strategy is logistically more feasible. PMID- 25727806 TI - Differential hemodynamic effects during the provision of active and passive support in the laboratory. AB - OBJECTIVE: Recent research has pointed to the cardiovascular benefits of providing social support to others in times of stress; however, little is known about what factors influence such benefits. DESIGN AND MEASURES: In a between groups design, we investigated the possible interaction between intimacy (friend vs. stranger) and support type (active vs. passive) in determining the cardiovascular responses of support providers. Eighty participants had their blood pressure and heart rate monitored while providing either active or passive social support to a friend or a stranger who completed a stress task. RESULTS: Although there was no interaction effect, a significant main effect showed that those who provided passive support showed larger decreases relative to those in the active support condition. There was no effect of intimacy. Further, these effects withstood adjustment for a number of potential confounds (e.g. sex and body mass index). CONCLUSION: It appears that the greatest physiological benefit for social support providers may come from providing passive, rather than active support, regardless of whether the support receiver is a friend or a stranger. PMID- 25727807 TI - Chiral resolution and absolute configuration of the enantiomers of the psychoactive "designer drug" 3,4-methylenedioxypyrovalerone. AB - Illicit rac-MDPV (3,4-methylenedioxypyrovalerone), manufactured in clandestine labs, has become widely abused for its cocaine-like stimulant properties. It has recently been found as one of the toxic materials in the so-called "bath salts," producing, among other effects, psychosis and tachycardia in humans when introduced by any of the several routes of administration (e.g., intravenous, oral, etc.). The considerable toxicity of this "designer drug" probably resides in one of the enantiomers of the racemate. In order to obtain a sufficient amount of the enantiomers of rac-MDPV to determine their activity, we improved the known synthesis of rac-MDPV and found chemical resolving agents, (+)- and (-)-2' bromotetranilic acid, that gave the MDPV enantiomers in >96% enantiomeric excess as determined by (1) H nuclear magnetic resonance and chiral high-performance liquid chromatography. The absolute stereochemistry of these enantiomers was determined by single-crystal X-ray diffraction studies. PMID- 25727809 TI - Structural transformation and hysteretic sorption of light hydrocarbons in a flexible Zn-pyrazole-adenine framework. AB - A three-dimensional metal-organic framework (MOF) was synthesized by combining 4 pyrazolecarboxylic acid and adenine. This MOF exhibits reversible flexibility and breathing adsorption behaviors in response to light hydrocarbons, with high capacity. The flexibility of the structural transitions was studied on the molecular scale by obtaining the crystal structures at 303, 353 and 373 K. The bridging nitrogen atoms of the pyrazolate rings act as a "kneecap" around the M???M axis, which causes the rotation of ligands around the M???M axis in response to external stimulus, thus giving rise to the deformation of the framework structure. PMID- 25727808 TI - Interplay between order-parameter and system parameter dynamics: considerations on perceptual-cognitive-behavioral mode-mode transitions exhibiting positive and negative hysteresis and on response times. AB - A mathematical model is presented for the emergence of perceptual-cognitive behavioral modes in psychophysical experiments in which participants are confronted with two alternatives. The model is based on the theory of self organization and, in particular, the order parameter concept such that the emergence of a mode is conceptualized as an instability leading to the emergence of an appropriately defined order parameter. The order parameter model is merged with a second model that describes adaptation in terms of a system parameter dynamics. It is shown that the two-component model predicts hysteretic mode-mode transitions when control parameters are increased or decreased beyond critical values. The two-component model can account for both positive and negative hysteresis effects due to the interaction between order parameter and system parameter dynamics. Moreover, the model-based analysis reveals that response time curves look rather flat when response times are relatively decoupled from the mode-mode transition phenomenon. In general, response time curves exhibit a peaked close to the mode-mode transition point. In this context, the possibility is discussed that such peaked response time curves belong to the class of critical phenomena of self-organizing systems. In order to illustrate the relevance of peaked response time curves for future research and research reported in the past, results from a perceptual judgment experiment are reported, in which participants judged their ability to stand on a tilted slope for various angles of inclination. Response time curves were found that exhibited a peak around the mode-mode-transition points between "yes" and "no" responses. PMID- 25727810 TI - Maternal vitamin D supplementation during pregnancy prevents vitamin D deficiency in the newborn: an open-label randomized controlled trial. AB - OBJECTIVE: To determine whether maternal vitamin D supplementation, in the vitamin D deficient mother, prevents neonatal vitamin D deficiency. DESIGN: Open label randomized controlled trial. SETTING: Metropolitan Melbourne, Australia, tertiary hospital routine antenatal outpatient clinic. PARTICIPANTS: Seventy eight women with singleton pregnancies with vitamin D deficiency/insufficiency (serum 25-OH Vit D < 75 nmol/l) at their first antenatal appointment at 12-16 week gestation were recruited. INTERVENTION: Participants were randomized to vitamin D supplementation (2000-4000 IU cholecalciferol) orally daily until delivery or no supplementation. MAIN OUTCOME MEASURES: The primary outcome was neonatal serum 25-OH vit D concentration at delivery. The secondary outcome was maternal serum 25-OH vit D concentration at delivery. RESULTS: Baseline mean maternal serum 25-OH vit D concentrations were similar (P = 0.9) between treatment (32 nmol/l, 95% confidence interval 26-39 nmol/l) and control groups (33 nmol/l, 95% CI 26-39 nmol/l). Umbilical cord serum 25-OH vit D concentrations at delivery were higher (P < 0.0001) in neonates of treatment group mothers (81 nmol/l, 95% CI; 70-91 nmol/l) compared with neonates of control group mothers (42 nmol/l, 95% CI; 34-50 nmol/l) with a strongly positive correlation between maternal serum 25-OH Vit D and umbilical cord serum 25-OH vit D concentrations at delivery (Spearman rank correlation coefficient 0.88; P < 0.0001). Mean maternal serum 25-OH Vit D concentrations at delivery were higher (P < 0.0001) in the treatment group (71 nmol/l, 95% CI; 62-81 nmol/l) compared with the control group (36 nmol/l, 95% CI; 29-42 nmol/l). CONCLUSION: Vitamin D supplementation of vitamin D deficient pregnant women prevents neonatal vitamin D deficiency. PMID- 25727811 TI - Risk stratification by the Appendicitis Inflammatory Response score to guide decision-making in patients with suspected appendicitis. AB - BACKGROUND: Current management of suspected appendicitis is hampered by the overadmission of patients with non-specific abdominal pain and a significant negative exploration rate. The potential benefits of risk stratification by the Appendicitis Inflammatory Response (AIR) score to guide clinical decision-making were assessed. METHODS: During this 50-week prospective observational study at one institution, the AIR score was calculated for all patients admitted with suspected appendicitis. Appendicitis was diagnosed by histological examination, and patients were classified as having non-appendicitis pain if histological findings were negative or surgery was not performed. The diagnostic performance of the AIR score and the potential for risk stratification to reduce admissions, optimize imaging and prevent unnecessary explorations were quantified. RESULTS: A total of 464 patients were included, of whom 210 (63.3 per cent) with non appendicitis pain were correctly classified as low risk. However, 13 low-risk patients had appendicitis. Low-risk patients accounted for 48.1 per cent of admissions (223 of 464), 57 per cent of negative explorations (48 of 84) and 50.7 per cent of imaging requests (149 of 294). An AIR score of 5 or more (intermediate and high risk) had high sensitivity for all severities of appendicitis (90 per cent) and also for advanced appendicitis (98 per cent). An AIR score of 9 or more (high risk) was very specific (97 per cent) for appendicitis, and the majority of patients with appendicitis in the high-risk group (21 of 30, 70 per cent) had perforation or gangrene. Ultrasound imaging could not exclude appendicitis in low-risk patients (negative likelihood ratio (LR) 1.0) but could rule-in the diagnosis in intermediate-risk patients (positive LR 10.2). CT could exclude appendicitis in low-risk patients (negative LR 0.0) and rule-in appendicitis in the intermediate group (positive LR 10.9). CONCLUSION: Risk stratification of patients with suspected appendicitis by the AIR score could guide decision-making to reduce admissions, optimize utility of diagnostic imaging and prevent negative explorations. PMID- 25727813 TI - Luminescent [Cu4I4] aggregates and [Cu3I3]-cyclic coordination polymers supported by quinolyl-triazoles. AB - Quinolyl-1,2,3-triazole ligand supported [Cu4I4] stair-step aggregates [Cu4I4(L1)2] (1), [Cu4I4(L2)2] (2), [Cu4I4(L3)2] (3), [Cu4I4(L4)2] (4), [Cu4I4(L5)2] (5), and six-membered [Cu3I3] metallacycle based coordination polymers [Cu2I2(L6)]n (6) and [Cu2I2(L7)]n (7) (ligands are 2-((1H-1,2,3-triazol 1-yl)methyl)quinoline (L1), 2-((4-alkyl-1H-1,2,3-triazol-1-yl)methyl)quinoline (propyl, butyl and isobutyl for L2, L3 and L4, respectively) and 2-(1-((quinolin 2-yl)methyl)-1H-1,2,3-triazol-4-yl)alcohol (methanol, ethanol and propanol for L5, L6 and L7, respectively)) have been prepared and characterized by single crystal X-ray diffraction (XRD), powder XRD, photoluminescence spectroscopy and thermogravimetric analysis. Complexes 1-5 are stair-step [Cu4I4] aggregate structures supported by two quinolyl-triazole hybrid ligands. Complexes 6 and 7 are rare cyclic [Cu3I3] aggregate-based 1-D coordination polymers. All ligands adopt a common tridentate-bridging coordination mode. These complexes are strongly luminescent with a yellow emission (500-700 nm) in the solid state. PMID- 25727812 TI - Deep sea minerals prolong life span of streptozotocin-induced diabetic rats by compensatory augmentation of the IGF-I-survival signaling and inhibition of apoptosis. AB - Consumption of deep sea minerals (DSM), such as magnesium, calcium, and potassium, is known to reduce hypercholesterolemia-induced myocardial hypertrophy and cardiac-apoptosis and provide protection against cardiovascular diseases. Heart diseases develop as a lethal complication among diabetic patients usually due to hyperglycemia-induced cardiac-apoptosis that causes severe cardiac damages, heart failure, and reduced life expectancy. In this study, we investigated the potential of DSM and its related cardio-protection to increase the life expectancy in diabetic rats. In this study, a heart failure rat model was developed by using streptozotocin (65 mg kg(-1) ) IP injection. Different doses of DSM-1* (37 mg kg(-1) day(-1) ), 2* (74 mg kg(-1) day(-1) ) and 3* (111 mg kg(-1) day(-1) ), were administered to the rats through gavages for 4 weeks. The positive effects of DSM on the survival rate of diabetes rats were determined with respect to the corresponding effects of MgSO4 . Further, to understand the mechanism by which DSM enhances the survival of diabetic rats, their potential to regulate cardiac-apoptosis and control cardiac-dysfunction were examined. Echocardiogram, tissue staining, TUNEL assay, and Western blotting assay were used to investigate modulations in the myocardial contractile function and related signaling protein expression. The results showed that DSM regulate apoptosis and complement the cardiomyocyte proliferation by enhancing survival mechanisms. Moreover DSM significantly reduced the mortality rate and enhanced the survival rate of diabetic rats. Experimental results show that DSM administration can be an effective strategy to improve the life expectancy of diabetic subjects by improving cardiac-cell proliferation and by controlling cardiac-apoptosis and associated cardiac-dysfunction. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 769-781, 2016. PMID- 25727814 TI - Beliefs about antidepressants among persons aged 70 years and older in treatment after a suicide attempt. AB - BACKGROUND: The use of antidepressants is associated with decreased suicide risk in late life, and these drugs are often prescribed after a suicide attempt. Yet little is known about attitudes to antidepressants in older persons with suicidal behavior. The aim of this study was to assess beliefs about antidepressant medicines in older persons in treatment one year after a suicide attempt. METHODS: Forty-four individuals aged 70 years and older, who were treated in emergency wards at five hospitals in western Sweden in connection with a suicide attempt, were interviewed at index attempt and one year later. Beliefs about medicines questionnaire (BMQ) specific for antidepressants were analyzed one year after index attempt, in relation to sociodemographic variables, medication use, psychiatric evaluation, and personality traits. RESULTS: The majority of participants perceived the necessity of their antidepressant medicine to outweigh their concerns. Lower perceived necessity of antidepressants was observed in those who were not on antidepressants at the time of the attempt as well as those with no prior history of suicide attempt before the index attempt. Individuals reporting hopelessness at follow-up had a higher perceived concern about using medication. CONCLUSIONS: Beliefs about antidepressants tended to be more positive than negative in older persons taking these drugs in the aftermath of a suicide attempt. Further studies are called for, and should include objective measures of medication adherence. PMID- 25727815 TI - Catalytic one-electron reduction of uranyl(VI) to Group 1 uranyl(V) complexes via Al(III) coordination. AB - Reactions between the uranyl(VI) Pacman complex [(UO2)(py)(H2L)] of the Schiff base polypyrrolic macrocycle L and Tebbe's reagent or DIBAL result in the first selective reductive functionalisation of the uranyl oxo by Al to form [(py)(R2AlOUO)(py)(H2L)] (R = Me or (i)Bu). The clean displacement of the oxo coordinated Al(III) by Group 1 cations has enabled the development of a one-pot, DIBAL-catalysed reduction of the U(VI) uranyl complexes to a series of new, mono oxo alkali-metal-functionalised uranyl(V) complexes [(py)3(MOUO)(py)(H2L)] (M = Li, Na, K). PMID- 25727816 TI - Assessment of the level of damage to the genetic material of children exposed to pesticides in the province of Cordoba. AB - INTRODUCTION: In the past decades, several authors have investigated the genotoxicity caused by exposure to chemicals, but there are no reports on studies analyzing such effects on children in Argentina. The objective of this study was to establish the micronucleus frequency in exfoliated buccal mucosa cells in children from urban areas with environmental exposure (through inhalation) and to compare it with the micronucleus frequency in children from urban regions far from areas subjected to spraying. POPULATION AND METHODS: Fifty children living in the town of Marcos Juarez (Cordoba) at different distances from pesticide spraying areas and twenty-five children from the city of Rio Cuarto (Cordoba), who are considered not exposed to pesticides, were studied; the micronucleus assay in buccal mucosa cells was used. RESULTS: A significant difference was observed between exposed children living less than 500 m from areas subjected to spraying and those who were not exposed. Forty percent of exposed children suffer some type of persistent condition, which may be associated with chronic exposure to pesticides. CONCLUSIONS: Results indicate that genotoxicity is present in a group of children compared to the other one, and highlight the importance of the micronucleus assay in buccal mucosa cells for genetic biomonitoring and public health surveillance. This assay is capable of detecting a level of damage that can be reversible. PMID- 25727817 TI - Archivos Argentinos de Pediatria turns 85 years old. PMID- 25727818 TI - Scientific publication: How to handle rejection? PMID- 25727819 TI - Art as an instrument to develop empathy. PMID- 25727820 TI - Weaknesses of assisted electronic prescription in hospitalized pediatric inpatients. PMID- 25727821 TI - Writing a scientific paper abstract. PMID- 25727822 TI - Tobacco use during adolescence may predict smoking during adulthood: simulation based research. AB - INTRODUCTION: There is little information about the age of onset of smoking among adolescents and its continuation into adulthood. The objective of this study was to assess the influence of tobacco use during adolescence to predict the prevalence of adult smoking using simulation models. MATERIAL AND METHODS: Five models were examined based on initiation and tobacco use rates among 421 adolescents. After simulating different scenarios, expected adult tobacco use rates were obtained and compared to those observed in a validation sample made up of 1218 adults. RESULTS: Models adequately predicted adult smoking rates by comparing them to data obtained using the validation sample (Markov: 37.6% versus 34.5%, p=0.109; dynamic simulation: 32.0% versus 34.5%, p=0.197). The simulation demonstrated that smoking, at least, one cigarette per month during adolescence sufficed to predict adult tobacco use rates. Eliminating tobacco use during adolescence may reduce the rate of tobacco use among adults by 12.2-16.2%. CONCLUSIONS: Adolescent tobacco use models adequately predicted the proportion of smokers among adults. Scenarios of restriction regarding the age of onset of tobacco use showed the expected reductions in the rates of tobacco use among adults. Although it was not evaluated in this study, restricting tobacco use among adolescents may help to protect their health and would probably have an impact on the reduction of tobacco-associated mortality among adults. PMID- 25727823 TI - Transcultural adaptation and validation of the CRAFFT as a screening test for problematic alcohol and substance use, abuse and dependence in a group of Argentine adolescents. AB - INTRODUCTION: Substance use and abuse and their consequences are a major problem among adolescents. The screening for problematic alcohol and substance use, abuse and dependence should be part of the case-taking process for adolescents. The Problem Oriented Screening Instrument for Teenagers (POSIT) and the Car, Relax, Alone, Forget, Family/Friends, Trouble questionnaire (CRAFFT) are used to this end. POSIT: 17 items corresponding to substance use and abuse (POSITsua); it has been validated in Spanish. CRAFFT: six questions; it has not been validated in Argentina. OBJECTIVE: To assess the validity of a version of the CRAFFT screening test adapted to Spanish in a group of Argentine adolescents using the POSITsua test as reference. POPULATION AND METHODS: The CRAFFTa and the POSITsua tests were administered to 14-20 year-old adolescents. An affirmative answer was scored as 1, and a negative answer, as 0. An individual was considered to have an increased risk of problematic use, abuse and dependence if he/she scored >2 in the CRAFFTa and POSITsua tests. RESULTS: Two hundred and eighty-six adolescents were included; 52% were female; mean age: 16.6 years old. The CRAFFTa score was >2 for 29%, while the POSIT score was >2 for 37%. CRAFFTa sensitivity: 59%; specificity: 88%. CRAFFTa positive predictive value: 0.74; negative predictive value: 0.78. The area under the curve was 0.73. In the linear regression, the R for the six CRAFFT questions was 0.60. Gender and age did not modify results. Cronbach's alpha was 0.64. CONCLUSION: CRAFFTa sensitivity was 59%, and its specificity was 88%, compared to the POSITsua test as a screening tool for problematic alcohol and substance use, abuse and dependence among Argentine adolescents. PMID- 25727824 TI - Assessment of cardiometabolic risk factors among adolescent survivors of childhood cancer. AB - INTRODUCTION: Survivors of childhood cancer have an increased risk of developing cardiovascular and metabolic disease as adults, secondary to cancer treatment. During adolescence, habits are developed which have a negative impact on the development of these conditions. OBJECTIVES: To estimate the prevalence of cardiometabolic risk factors among adolescent survivors of childhood cancer (ASCC) and compare them to healthy adolescents. POPULATION AND METHODS: Cross sectional, analytical study. LOCATION: Department of Adolescence, Hospital Elizalde, Buenos Aires. Subjects included were 61 ASCC and 138 healthy adolescents. Age: 15+/-3 years old, range: 1021 years old. The level of physical activity in the past 30 days, adding salt to foods, weekly consumption of fruit and vegetables, tobacco use, alcohol use, body mass index, and waist circumference were analyzed. RESULTS: ASCC were significantly more obese (19.7% versus 7.2%, p=0.019, odds ratio 3.01) and had a larger waist circumference (19.7% versus 8%, p=0.017, odds ratio 2.82) than healthy adolescents. In addition, they did not eat vegetables more frequently (26.2% versus 13%, p=0.017). No statistically significant differences were found in terms of prevalence for the other risk factors: usually adding salt to foods (55.7%), lack of fruit consumption (32.8%), low level of physical activity (60.7%), tobacco use (4.9%), and alcohol use (39%). CONCLUSIONS: ASCC had a higher risk for obesity and a larger waist circumference; in addition, they ate less vegetables than adolescents without a history of cancer. The prevalence of the remaining factors for cardiometabolic risk was similar. PMID- 25727825 TI - High frequency of E148Q sequence variation in children with familial Mediterranean fever in southeast Turkey. AB - OBJECTIVE: The aim of this study was to investigate the spectrum of Mediterranean fever (MEFV) gene mutations and genotype-phenotype correlation in children with familial Mediterranean fever (FMF) in southeast Turkey. METHODS: A total of 507 children (274 females) with FMF and MEFV gene mutation(s) were included. A 15 year retrospective evaluation was conducted; parameters analyzed were: age, sex, age at symptoms onset, age at FMF diagnosis, delay between symptoms onset and diagnosis, FMF attack symptoms, and response to colchicine. Disease severity scores were calculated and MEFV mutation analysis was performed via real-time PCR for the 6 most frequent mutations. Children with comorbid diseases or tested negative for MEFV gene mutations were excluded to provide homogeneity. RESULTS: A family history of FMF was found in 60.2% (n=305) of patients. The most common symptoms reported for FMF attacks were abdominal pain (98.0%), fever (93.9%) and arthralgia (47.3%); 75.0% of patients (n=380) were heterozygous, 14.2% were homozygous (n=72) and 10.8% were compound heterozygous (n=55).The following MEFV gene mutation alleles were identified: E148Q (40.1%), M694V (25.9%), V726A (15.8%), R761H (7.4%), M680I (6.8%), and P369S (4.1%). The M694V subgroup had the lowest mean age of disease onset and the highest mean disease severity score, whereas the E148Q group had later mean disease onset and the lowest mean disease severity score (p<0.05). CONCLUSION: The highest E148Q mutation frequency and milder disease in the course of FMF in our study population may be due to geographic and ethnic background dissimilarities of southeast Turkey. PMID- 25727826 TI - Clinical comparison between patients with selective immunoglobulin A deficiency and other primary immunodeficiencies. AB - Primary immunodeficiencies (PID) are low-prevalence diseases. There are warning signs that may raise clinical suspicion. The objectives of this study were to describe the clinical characteristics and warning signs of patients with PID and to compare the clinical differences between selective immunoglobulin A (IgA) deficiency and other PIDs. Eighty-nine patients were studied; their median age at the time of diagnosis was 6 years old (4.08-11.67). Fifty-three (59.5%) patients were male. Fifty-four (60.7%) patients had selective IgA deficiency, and 35 (39.3%) had other PIDs. The main clinical manifestations were rhinopharyngitis in 65 (73.03%) patients and atopy in 39 (43.82%). Twenty- four (26.97%) patients showed warning signs, and none had selective IgA deficiency. Patients with other PIDs had a higher incidence of lower respiratory tract infection, sepsis, skin infections, mucocutaneous candidiasis, dental alterations, cardiovascular malformations, angioedema, hospitalizations and death. Ten (28.57%) patients received intravenous gammaglobulin, 15 (42.85%) antibiotic prophylaxis, and 2 (2.24%) antifungal prophylaxis. PMID- 25727827 TI - [Market-based medicine or patient-based medicine?]. AB - The health care has evolved over the centuries from a theocentric model to a model centered on man, environment and society. The process of neoliberal globalization has changed the relationship between the components of the health system and population. The active participation of organizations such as the World Trade Organization, the International Monetary Fund and the World Bank by the techno-medical industrial complex tends to make the health care in a model focused on economy. This, impacts negatively on all components in the process of health care and have an adverse effect on the humanized care. The analysis of each sector in particular and their interactions shows the effects of this change. Alternatives are proposed for each sector to contribute to a model of care focused on the patient, their family and the social environment. PMID- 25727828 TI - Crowdfunding. A new option for funding health projects. PMID- 25727829 TI - Type 1 diabetes mellitus: psychosocial factors and adjustment of pediatric patient and his/her family. Review. AB - Type 1 diabetes mellitus is the most common chronic endocrine disease in children, with a very low incidence in the first months of life and reaching its peak during puberty (10-15 years old is the age group with the highest incidence at the time of onset). Based on the review of the scientific literature, our objective is to study the main psychosocial factors associated with the adjustment of these pediatric patients and their families. Research underscore the following risk factors: situational (stressful life events), personal (additional physical diseases, low self-esteem, emotional disturbances), and interpersonal (family breakdown and conflicts), and also protection factors (coping strategies, social support, fluent communication). There is a pressing need to deal with the disturbances that affect these diabetic patients and their families, by implementing effective health care psychological interventions that take into account psychosocial factors associated with the course of type 1 diabetes mellitus. PMID- 25727830 TI - [Hereditary spherocytosis. Review. Part II. Symptomatology, outcome, complications, and treatment]. AB - Hereditary spherocytosis must always be suspected in children with anemia, hyperbilirubinemia, splenomegaly or cholelithiasis, in the asymptomatic individual with an affected relative, and in the neonate with hyperbilirubinemia with no blood group incompatibility; its early detection is key to avoid kernicterus. Follow-up of these patients is based on periodical control and supply of information on the adequate management of hemolytic or aplastic crisis, and early detection of cholelithiasis. The decision to perform splenectomy is usually associated with quality of life rather than life-threatening risk, and it should result from a consensus between patient, parents and physicians. The postsplenectomy follow-up is based on control of compliance with the prophylactic antibiotic therapy and the early diagnosis of infectious disorders. PMID- 25727831 TI - [Consensus on management of dyslipidemia in pediatrics]. AB - This document is intended for pediatricians, family, nutritionists and others. It aimed to convey the guidelines for early diagnosis and treatment of dyslipidemia in children and sensitize the pediatrician to the prevention of cardiovascular disease in adults. Atherosclerosis is a gradual process that begins in childhood and dyslipidemia belongs to the group of risk factors that accelerate their evolution. Universal screening for dyslipidemia at 6 years and 17 years is proposed; selective screening after 2 years is recommended if there are risk factors or predisposing disease. Assay of total cholesterol, LDL, HDL and triglycerides is recommended, prior fasting. Treatment of dyslipidemia in children aims to reduce the risk of premature cardiovascular events in the case of hypercholesterolemia, and decreasing the risk of pancreatitis in the case of severe hypertriglyceridemia. The pediatrician should address screening, diagnosis and implementation of lipid-lowering measures. Patients with higher levels should be referred to specialists with expertise in drug therapy. PMID- 25727832 TI - [Nutritional requirements of hospitalized children are not covered]. PMID- 25727834 TI - [Flexible Fiberoptic Bronchoscopy in children with persistent atelectasis: a case series report]. AB - Most patients with pulmonary atelectasis have complete resolution with medical therapy. In patients with persistent atelectasis, endoscopic treatment has proven to be an effective therapy. OBJECTIVE: To describe our experience using flexible fiberoptic bronchoscopy in children with persistent atelectasis. This is a case series report of children treated with flexible bronchoscopy between January 2005 and December 2013, at the Pediatric Pulmonology Section of the Hospital Italiano de Buenos Aires. RESULTS: From a total of 106 bronchoscopies performed, 32 of the patients had a diagnosis of persistent atelectasis. Mean age, 5 years. Laryngeal mask airway was the most common route for flexible bronchoscopy. In 28/32 patients, the procedure was therapeutically useful (complete or partial re expansion). The procedure was well tolerated and presented only mild complications. CONCLUSIONS: Flexible bronchoscopy proved to be a safe and effective tool for the treatment of children with persistent atelectasis. PMID- 25727833 TI - Congenital tuberculosis: presentation of a rare case. AB - Congenital tuberculosis is a rare disease with a high mortality rate. Congenital tuberculosis is considered the result of mother-to-child transmission from the placenta to the fetus, through the ingestion of the amniotic fluid, or via transplacental transmission through the umbilical vein. Given the non-specific clinical signs of tuberculosis, it is usually difficult to diagnose it. The case of a 48-day-old male infant hospitalized due to weight loss, fever, cough, hemoptysis, and respiratory distress for the past 20 days, is presented. In this period, he had received broad spectrum antibiotics but with no improvement. A chest x-ray showed the presence of consolidation and a cavitary lesion in the upper and middle left lung fields. Mycobacterium tuberculosis was detected by polymerase chain reaction in a bronchoalveolar lavage specimen. Congenital tuberculosis was diagnosed based on this finding; hence, a tuberculostatic regimen was started accordingly. The patient died 13 days after treatment initiation. Congenital tuberculosis should be considered in infants with weight loss, fever, cough, hemoptysis and respiratory distress. PMID- 25727835 TI - [Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses]. AB - Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses. PMID- 25727836 TI - [Malignant hyperthermia syndrome: case report]. AB - Malignant hyperthermia syndrome is a family myopathy of pharmacogenetic nature, which appears as a skeletal muscle hypercatabolic syndrome linked to anesthesia. The incidence in pediatrics is 1 event per 10 000 surgeries. The clinical picture may have a rapid onset associated with succinylcholine, or a late onset related to inhalation agents. The clinical picture includes tachycardia, hyperthermia, hypercapnia, acidosis, muscle rigidity, hyperkalemia, renal failure and arrhythmia. Mortality without specific treatment is of 80% and drops to 7% with the use of dantrolene sodium. We report an 8-year-old patient admitted for phimosis surgery; having tachycardia, hypercapnia and muscle rigidity, he started treatment with dantrolene sodium in the operating room, which was maintained for 72 hours. He evolved the first 12 hours with low cardiac output and creatine phosphokinase maximum of 155,147 U/L. He remained with mechanical ventilation for 48 hours. Discharge was given on the sixth day without sequelae. PMID- 25727837 TI - [Operational tolerance in a pediatric liver transplant recipient. Case report]. AB - Operational tolerance (absence of allograft rejection and good outcome without immunosuppression) has been object of intense research in pediatric liver transplant in the last years. The morbidity and mortality related to long-term immunosuppressive treatment of these patients are well known. We report a case of operational tolerance of our unit in a pediatric liver transplant recipient who is immunosuppressant-free since 16 month after transplant after progressive withdrawal related to asymptomatic Epstein-Barr virus first infection. He has good histological, clinical and serological outcome after 22 month of follow-up. To our knowledge, this is the first operational tolerance reported case in our country after liver transplant in a pediatric recipient and we believe that the study of these patients is important in order to detect characteristics that allow to identify a potentially tolerant group in which it is possible to withdraw immunosuppressive drugs. PMID- 25727838 TI - [Septic arthritis caused by Kingella kingae in children]. AB - INTRODUCTION: Approximately 50% of cases of bacterial arthritis occur in childhood. Currently Kingella kingae is considered as an emerging pathogen. CLINICAL CASE: A ten month old male patient presented joint immobility in right knee. Arthrocentesis was performed.Kingella kingae was identified. He received treatment with ampiciline for 14 days. DISCUSSION: This pathogen colonizes the posterior pharynx.Isolation in solid culture media may be difficult. CONCLUSION: It is essential to consider this pathogen when septic arthritis is suspected, and to routinely use blood culture bottles for processing samples of synovial fluid. PMID- 25727839 TI - [Gluten sensitivity: presentation of three cases]. AB - In the last few years, the existence of a clinical profile similar to celiac disease has become important; this disease does not adapt to the traditional diagnosis canons. It is related to a number of patients who are diagnosed as having the celiac disease but present normal serology and small bowel's biopsy. Since the 80's, medical literature reports the existence of a syndrome that connects gluten diet with a toxic effect that produces gastrointestinal symptoms even though the mucosa remains normal. This disease is called the Cooper-Cook syndrome. Over the last few years, there have been lots of publications about this disease under the name "gluten sensitivity". In the following article, three clinical cases that refer to this condition are presented. PMID- 25727840 TI - [Acute abdomen at onset of incomplete and atypical Kawasaki disease: case report]. AB - Kawasaki disease is one of the most common systemic vasculitis in children and the most common cause of acquired heart disease in developed countries. Diagnosis relies on clinical findings and there is no specific test. Diagnosis and treatment decisions are very difficult in incomplete or atypical cases and questions inevitably arise during the care of these patients. In children with atypical or incomplete disease, the option in favor of therapy with gamma globulin seems currently to be the most suitable one. A patient with acute abdomen is presented as the initial symptom of Kawasaki disease. PMID- 25727841 TI - [Ornithine carbamoyltransferase deficiency. A clinical case]. AB - Disorders of urea cycle account for up to 60% of severe neonatal hyperamoniemias. The base of this cycle disorders results in a deficit of its enzymes. Deficiency of the enzyme ornithine transcarbamylase is the most frequently detected. The prognosis depends on the degree of enzyme deficiency, age, early diagnosis and initiation of treatment. We report the case of a teenager who was treated with prednisone because of a peripheral facial palsy. He showed a progressive worsening and died a few days later. The high levels of ammonia made suspect a congenital disorder of urea cycle. The postmortem genetic study confirmed it. We studied the family and advised carriers. We reflect about the importance of the neonatal screening programs and their applicability for detection of inborn errors of metabolism. PMID- 25727842 TI - Supraventricular tachycardia after nebulized salbutamol therapy in a neonate: case report. AB - Supraventricular tachycardia (SVT) is the most common sustained arrhythmia in neonates and infants. Presentation of SVT in the neonate is usually subtle and frequently complicated by congestive heart failure. Despite the widespread use of beta2-agonists, their safety has been questioned. Several studies have reported an increased incidence of cardiac arrhythmias in patients treated with these agents, and other studies have found increased rates of cardiovascular death associated with the use of oral and nebulized beta2-agonists such as salbutamol, which is used to treat bronchospasm in newborns with several diseases. Herein, we report a case of SVT following administration of nebulized salbutamol in a neonate. PMID- 25727843 TI - Enhanced engraftment and repairing ability of human adipose-derived stem cells, conveyed by pharmacologically active microcarriers continuously releasing HGF and IGF-1, in healing myocardial infarction in rats. AB - One of the main cause of ineffective cell therapy in repairing the damaged heart is the poor yield of grafted cells. To overcome this drawback, rats with 4-week old myocardial infarction (MI) were injected in the border zone with human adipose-derived stem cells (ADSCs) conveyed by poly(lactic-co-glycolic acid) microcarriers (PAMs) releasing hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) (GFsPAMs). According to treatments, animals were subdivided into different groups: MI_ADSC, MI_ADSC/PAM, MI_GFsPAM, MI_ADSC/GFsPAM, and untreated MI_V. Two weeks after injection, a 31% increase in ADSC engraftment was observed in MI_ADSC/PAM compared with MI_ADSC (p < 0.05). A further ADSC retention was obtained in MI_ADSC/GFsPAM with respect to MI_ADSC (106%, p < 0.05) and MI_ADSC/PAM (57%, p < 0.05). A 130% higher density of blood vessels of medium size was present in MI_ADSC/GFsPAM compared with MI_ADSC (p < 0.01). MI_ADSC/GFsPAM also improved, albeit slightly, left ventricular remodeling and hemodynamics with respect to the other groups. Notably, ADSCs and/or PAMs, with or without HGF/IGF-1, trended to induce arrhythmias in electrically driven, Langendorff-perfused, hearts of all groups. Thus, PAMs releasing HGF/IGF-1 markedly increase ADSC engraftment 2 weeks after injection and stimulate healing in chronically infarcted myocardium, but attention should be paid to potentially negative electrophysiological consequences. PMID- 25727845 TI - Successful treatment of severe psoriasis in an adolescent with ustekinumab. AB - Psoriasis is a chronic, inflammatory, immune-mediated disease. Approximately 30% of patients have disease onset before age 18 years. Psoriasis in children and adolescents may be difficult to control, with subsequent poor quality of life and psychosocial consequences. We describe the case of a 12-year-old boy with severe, refractory, chronic plaque psoriasis for 6 years. Various therapeutic regimens including different topical corticosteroids, topical vitamin D analogs, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin, and combination therapies showed only partial or transient responses with frequent relapses. Because anti-interleukin-12/23 agents have been successfully used in adults with psoriasis, ustekinumab was initiated and our patient showed a rapid, excellent, sustained response. No recurrence or flares have been observed after 33 months of follow-up. This case illustrates that ustekinumab may be an effective and safe therapeutic option in adolescents with psoriasis. PMID- 25727846 TI - Assessing the clinical value of fast onset and sustained duration of action of long-acting bronchodilators for COPD. AB - The long-acting inhaled bronchodilators available for use in chronic obstructive pulmonary disease (COPD) vary in their pharmacological class (beta2-adrenergic agonist or antimuscarinic/anticholinergic, alone or combined), durations of action and speed of onset of bronchodilator effect. In the early stages of development of a maintenance bronchodilator, the goals are to identify a molecule with the theoretically 'ideal' profile of fast onset and prolonged duration of action in comparison with existing agents, while minimizing non-specific activity at organs outside the lungs. The move towards increasing duration of bronchodilator action is generally paralleled by improved effects on clinical outcomes, and the advent of more potent agents seems likely to provide an opportunity to reduce overreliance on the use of inhaled corticosteroids in treating COPD. In terms of onset of action, an immediately perceived benefit in reducing dyspnea, although not definitively demonstrated, might prove useful in increasing adherence, which is very poor among patients with COPD. Once-daily administration may also be helpful in this respect. Shared decision-making between patient and physician in the choice of treatment is important in optimizing adherence and, thus, treatment effectiveness. PMID- 25727847 TI - Increased mRNA expression of glucocorticoid receptor-P in placenta is associated with a decreased risk of allergen sensitisation in the child. PMID- 25727848 TI - Preferential gene expression and epigenetic memory of induced pluripotent stem cells derived from mouse pancreas. AB - Induced pluripotent stem cells (iPSCs) have been established from various somatic cell types. Accumulating evidence suggests that iPSCs from different cell sources have distinct molecular and functional properties. Here, we establish iPSC derived from mouse pancreas (Panc-iPSC) and compared their properties with those of iPSC derived from tail-tip fibroblast (TTF-iPSC). The metabolic profile differs between Panc-iPSC and TTF-iPSC, indicating distinct cell properties in these iPSCs. Expression of Pdx1, a marker of pancreas differentiation, is increased through formation of embryoid body (EB) in Panc-iPSC, but the level is similar to that in TTF-iPSC. In contrast, EBs derived from Panc-iPSC express liver-specific albumin (Alb) and alpha-fetoprotein (Afp) genes much more strongly than those from TTF-iPSC. Epigenetic analysis shows a different histone modification pattern between Panc-iPSC and TTF-iPSC. Promoter regions of Alb and Afp genes in Panc-iPSC are suggested to have a more open chromatin structure than those in TTF-iPSC, which also is seen in primary cultured pancreatic cells. Our data suggest that Panc-iPSC possesses distinct differentiation capacity from that of TTF-PSC, which may be influenced by epigenetic memory. PMID- 25727849 TI - Impacts of care-giving and sources of support: a comparison of end-of-life and non-end-of-life caregivers in Canada. AB - This is the second in a series of papers that deal with care-giving in Canada, as based on data available from the Canadian General Social Survey (2007). Building on the first paper, which reviewed the differences between short-term, long-term and end-of-life (EOL) caregivers, this paper uniquely examines the caregiver supports employed by EOL caregivers when compared to non-EOL caregivers (short term and long-term caregivers combined). Both papers employ data from Statistics Canada's General Social Survey (GSS Cycle 21: 2007). The GSS includes three modules, where respondents were asked questions about the unpaid home care assistance that they had provided in the last 12 months to someone at EOL or with either a long-term health condition or a physical limitation. The objective of this research paper was to investigate the link between the impact of the care giving experience and the caregiver supports received, while also examining the differences in these across EOL and non-EOL caregivers. By way of factor analysis and regression modelling, we examine differences between two types of caregivers: (i) EOL and (ii) non-EOL caregivers. The study revealed that with respect to socio-demographic characteristics, health outcomes and caregiver supports, EOL caregivers were consistently worse off. This suggests that although all non-EOL caregivers are experiencing negative impacts from their care-giving role, comparatively greater supports are needed for EOL caregivers. PMID- 25727850 TI - Combining native MS approaches to decipher archaeal box H/ACA ribonucleoprotein particle structure and activity. AB - Site-specific isomerization of uridines into pseudouridines in RNAs is catalyzed either by stand-alone enzymes or by box H/ACA ribonucleoprotein particles (sno/sRNPs). The archaeal box H/ACA sRNPs are five-component complexes that consist of a guide RNA and the aCBF5, aNOP10, L7Ae, and aGAR1 proteins. In this study, we performed pairwise incubations of individual constituents of archaeal box H/ACA sRNPs and analyzed their interactions by native MS to build a 2D connectivity map of direct binders. We describe the use of native MS in combination with ion mobility-MS to monitor the in vitro assembly of the active H/ACA sRNP particle. Real-time native MS was used to monitor how box H/ACA particle functions in multiple-turnover conditions. Native MS also unambiguously revealed that a substrate RNA containing 5-fluorouridine (f(5) U) was hydrolyzed into 5-fluoro-6-hydroxy-pseudouridine (f(5) ho(6) Psi). In terms of enzymatic mechanism, box H/ACA sRNP was shown to catalyze the pseudouridylation of a first RNA substrate, then to release the RNA product (S22 f(5) ho(6) psi) from the RNP enzyme and reload a new substrate RNA molecule. Altogether, our native MS-based approaches provide relevant new information about the potential assembly process and catalytic mechanism of box H/ACA RNPs. PMID- 25727851 TI - Airway responsiveness to mannitol 24 h after allergen challenge in atopic asthmatics. AB - BACKGROUND: Airway responsiveness to indirect stimuli correlates positively with airway inflammation. In atopic asthmatics, allergen inhalation is associated with an influx of inflammatory cells and increased responsiveness to the direct-acting stimuli methacholine at 3 and 24 h after exposure. We have shown mannitol responsiveness decreases 3 h after allergen inhalation. The current investigation assessed mannitol responsiveness 24 h after allergen challenge. METHODS: Eleven mild atopic asthmatics completed allergen challenges on two separate occasions. In random order, methacholine or mannitol challenges were performed 24 h pre- and post-allergen challenge. Levels of fractional exhaled nitric oxide were also measured. RESULTS: Allergen challenge increased airway responsiveness to methacholine 24 h postchallenge; the geometric mean (95% CI) methacholine PC20 decreased from 5.9 mg/ml (1.8-19.4) to 2.2 mg/ml (0.81-5.89); P = 0.01. This coincided with a significant increase (P = 0.02) in FeNO levels. Conversely, allergen challenge decreased airway responsiveness to mannitol; geometric mean (95% CI) dose-response ratio was significantly higher after allergen exposure (57 mg/% FEV1 fall [27-121] to 147 mg/% FEV1 fall [57-379]; P = 0.03), and FeNO levels were not significantly increased (P = 0.054). CONCLUSION: Allergen-induced changes in airway responsiveness to direct and indirect stimuli are markedly different. The loss in responsiveness to mannitol is likely not explainable by a refractory state. The effect(s) of allergen exposure on airway responsiveness to indirect-acting stimuli require further investigation. PMID- 25727852 TI - p130Cas/BCAR1 scaffold protein in tissue homeostasis and pathogenesis. AB - BCAR1 (also known as p130Cas/BCAR1) is an adaptor protein that belongs to the CAS family of scaffold proteins. In the past years, increasing evidence has demonstrated the ability of p130Cas/BCAR1 to activate signaling originating from mechanical stimuli, cell-extracellular matrix (ECM) adhesion and growth factor stimulation cascades during normal development and disease in various biological models. In this review we will specifically discuss the more recent data on the contribution of p130Cas/BCAR1 in the regulation of tissue homeostasis and its potential implications in pathological conditions. PMID- 25727853 TI - In vitro antifungal susceptibilities of isolates of Candida spp. and Aspergillus spp. from China to nine systemically active antifungal agents: data from the SENTRY antifungal surveillance program, 2010 through 2012. AB - We report the in vitro activity of nine systemically active antifungal agents against 237 contemporary clinical isolates of yeast and moulds obtained from 13 laboratories in China during 2010 through 2012. Susceptibility testing was performed using CLSI methods. Sequencing of fks hot spots was performed for echinocandin non-wild-type (WT) strains. Isolates included 220 from eight species of Candida, 15 from four species of Aspergillus and one isolate each of Rhodotorula mucilaginosa and Trichosporon asahii. Resistance to amphotericin B (0.0%), flucytosine (0.0-1.7%) and the echinocandins (0.0-3.4%) was distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. pelliculosa. Three C. albicans isolates showed resistance to echinocandins and one harboured a mutation in HS1 of fks1. Resistance to the azoles was much more common with resistance to fluconazole, voriconazole and posaconazole detected among isolates of C. glabrata and C. tropicalis. Both C. parapsilosis and C. pelliculosa exhibited decreased susceptibility to fluconazole. Amphotericin B, the mould-active azoles and the echinocandins were all quite active against isolates of A. fumigatus and A. flavus. Consistent with previous studies from China, resistance to fluconazole is prominent among Candida spp. isolates in this country. PMID- 25727854 TI - Effective immobilization of glucose oxidase on chitosan submicron particles from gladius of Todarodes pacificus for glucose sensing. AB - An effective enzymatic glucose biosensor was developed by immobilizing glucose oxidase on chitosan submicron particles synthesized from the gladius of Todarodes pacificus (GCSP). The chemically synthesized chitosan from gladius was pulverized to submicron particles by ball milling technique, which was further characterized and compared with the standard chitosan (SCS). The degree of deacetylation of GCSP was determined using FTIR spectroscopy which was comparable to the value of standard chitosan. The glucose oxidase (GOx) was immobilized over GCSP on porous zinc oxide/platinum nanoparticle (ZnO/Pt) based electrode. The morphological and structural properties of the electrodes were analyzed using scanning electron microscopy and X-ray diffraction analysis. The glucose sensing behavior of electrode was estimated using electrochemical analysis and showed an excellent analytical performance. The electrode ZnO/Pt/GCSP conjugated with GOx displayed high sensitivity (88.76 MUA mM(-1) cm(-2)) with low detection limit in short response time. In addition, the very low value of Michaelis-Menten constant for GCSP based electrode contributes a better affinity of the electrode surface towards glucose oxidase. PMID- 25727855 TI - Validity of the Japanese version of the REM Sleep Behavior Disorder (RBD) Screening Questionnaire for detecting probable RBD in the general population. AB - AIMS: In order to evaluate the validity of the REM Sleep Behavior Disorder (RBD) Screening Questionnaire (RBDSQ) as a screening tool for RBD in a general population setting, we conducted a validation study using residents of a rural community. METHODS: We sent questionnaires that included the RBDSQ to 2631 eligible adult residents in the town of Daisen, Japan. RESULTS: Of those residents, 1572 participants (59.7%) gave complete answers to the RBDSQ. Among them, 179 participants (11.4%) scored >=5 points on the questionnaire; an additional 149 participants scoring <=4 points were randomly selected for further telephone interview. Based on obtained results, nine participants (0.57%) were judged as having probable RBD. Receiver-operator curve analysis revealed that a total score of 6 points on the RBDSQ represented the best cut-off value for detecting probable RBD (sensitivity: 100%; specificity: 73.0%). Analysis based on the item response theory revealed that items 1, 4, 6-1, 7, and 8 had lower difficulty than the remaining items, suggesting that these items are more essential in the screening for probable RBD. CONCLUSIONS: The present study revealed that a score of 6 points on the RBDSQ could be used as a cut-off value for the screening of probable RBD in the general population. Evaluation of the distribution of positive items might be helpful for identifying the intensity of a person's RBD symptoms. PMID- 25727856 TI - Natural history of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a parenchymal lung disease characterized by progressive interstitial fibrosis. IPF has a poor prognosis, with a median survival time of 2-3 years from diagnosis, but varying from a few months to a decade. The natural history of IPF is highly variable and the course of disease in an individual patient is difficult to predict. Some patients with IPF experience rapid decline, others progress much more slowly, and some patients show periods of relative stability interspersed with acute deteriorations in respiratory function. Many clinical, radiographic, serologic, and histopathologic variables have been shown to predict mortality in IPF. However, the accuracy of these predictors varies due to the retrospective nature of some of the studies and variations in study design. The ability to identify clinical characteristics that predict disease progression and survival would be useful for counseling patients, treatment decision-making, and prompt consideration for lung transplantation. A number of indices for predicting mortality in patients with IPF are available, but they require further validation. As high-resolution computed tomography scans become more widely available and patients with IPF are diagnosed earlier, survival times following diagnosis will improve. Early referral to interstitial lung disease specialty centers is important for accurate diagnosis and may be associated with improved outcomes. The goal of this review is to examine the natural history of IPF, discuss predictors of mortality, and highlight the importance of prompt diagnosis and referral for patients with IPF. PMID- 25727857 TI - SPARTA clinical trial design: exploring the efficacy and safety of two dose regimens of alpha1-proteinase inhibitor augmentation therapy in alpha1 antitrypsin deficiency. AB - BACKGROUND: Alpha1-antitrypsin deficiency (AATD) is an underdiagnosed genetic disorder that results in early-onset emphysema due to low serum levels of alpha1 proteinase inhibitor (alpha1-PI), leading to increased activity of tissue damaging neutrophil elastase. Clinical outcomes of AATD may be improved by administering alpha1-PI augmentation therapy. Here, we describe the design of the ongoing Study of ProlAstin-c Randomized Therapy with Alpha-1 augmentation (SPARTA), a phase 3 trial designed to evaluate progression of lung tissue loss in patients with severe AATD receiving human alpha1-PI (Prolastin((r))-C) versus placebo, using whole-lung computed tomography (CT) densitometry. STUDY DESIGN: SPARTA is a randomized, placebo-controlled trial assessing the efficacy and safety of two separate doses of Prolastin-C (60 and 120 mg/kg) administered weekly over 3 years in patients aged 18-70 years with a diagnosis of AATD and clinical evidence of pulmonary emphysema. The primary measure of efficacy (change from baseline whole-lung 15th percentile lung density [PD15]) will be determined by CT lung densitometry measured at total lung capacity. Secondary efficacy variables will be the evaluation of severe chronic obstructive pulmonary disease exacerbations, as defined by American Thoracic Society/European Respiratory Society criteria, and PD15 of the basal lung region using CT densitometry. Adverse events will be collected and documented. CONCLUSIONS: The SPARTA trial is designed to evaluate the long-term (3-year) efficacy of 2 separate doses of Prolastin-C for the treatment of emphysema in patients with AATD. Protocol number: GTi1201. CLINICAL TRIALS IDENTIFIER: NCT01983241. PMID- 25727859 TI - Relative and absolute structure of phomolide C. AB - Phomolide C (1) was isolated from a fungus Diaporthe sp. being found at Shirakami mountainous area. Although only the planar structure of 1 has been known, our detailed NMR spectroscopic analysis and ECD studies revealed its both relative and absolute configuration. PMID- 25727861 TI - The revival of the Bravais lattice. PMID- 25727860 TI - Sildenafil improves renal function in patients with pulmonary arterial hypertension. AB - AIM: Elevated serum creatinine (sCr) and low estimated glomerular filtration rate (eGFR) are associated with poor outcomes in patients with pulmonary arterial hypertension (PAH) whereas sildenafil treatment improves PAH outcomes. This post hoc analysis assessed the effect of sildenafil on kidney function and links with clinical outcomes including 6-min walk distance, functional class, time to clinical worsening and survival. METHODS: Patients with PAH received placebo or sildenafil 20, 40 or 80 mg three times daily in the SUPER-1 study and open-label sildenafil titrated to 80 mg three times daily (as tolerated) in the extension study. RESULTS: Baseline characteristics were similar among groups (n = 277). PAH was mostly idiopathic (63%) and functional class II (39%) or III (58%). From baseline to week 12, kidney function improved (increased eGFR, decreased sCr) with sildenafil and worsened with placebo. In univariate logistic regression, improved kidney function was associated with significantly improved exercise and functional class (odds ratios 1.17 [95% CI 1.01, 1.36] and 1.21 [95% CI 1.03, 1.41], respectively, for sCr and 0.97 [95% CI 0.94, 0.99] and 0.97 [95% CI 0.94, 0.99] for eGFR, all P < 0.05). In patients who maintained or improved kidney function, time to worsening was significantly delayed (P < 0.02 for both kidney parameters). Observed trends towards improved survival were not significant. Patients with eGFR <60 (vs. >=60) ml min(-1) 1.73 m(-2) appeared to have worse survival. CONCLUSIONS: Sildenafil treatment was associated with improved kidney function in patients with PAH, which was in turn associated with improved exercise capacity and functional class, a reduced risk of clinical worsening, and a trend towards reduced mortality. PMID- 25727858 TI - Multicenter mapping of structural network alterations in autism. AB - Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions primarily characterized by abnormalities in social cognition. Abundant previous functional MRI studies have shown atypical activity in networks encompassing medial prefrontal cortex (mPFC) and medial parietal regions corresponding to posterior cingulate cortex and precuneus (PCC/PCU). Conversely, studies assessing structural brain anomalies in ASD have been rather inconsistent. The current work evaluated whether structural changes in ASD can be reliability detected in a large multicenter dataset. Our comprehensive structural MRI framework encompassed cortical thickness mapping and structural covariance analysis based on three independent samples comprising individuals with ASD and controls (n = 220), selected from the Autism Brain Imaging Data Exchange open-access database. Surface-based analysis revealed increased cortical thickness in ASD relative to controls in mPFC and lateral prefrontal cortex. Clusters encompassing mPFC were embedded in altered inter-regional covariance networks, showing decreased covariance in ASD relative to controls primarily to PCC/PCU and inferior parietal regions. Cortical thickness increases and covariance reductions in ASD were consistent, yet of variable effect size, across the different sites evaluated and measurable both in children and adults. Our multisite study shows regional and network-level structural alterations in mPFC in ASD that, possibly, relate to atypical socio-cognitive functions in this condition. PMID- 25727862 TI - Partial order among the 14 Bravais types of lattices: basics and applications. AB - Neither International Tables for Crystallography (ITC) nor available crystallography textbooks state explicitly which of the 14 Bravais types of lattices are special cases of others, although ITC contains the information necessary to derive the result in two ways, considering either the symmetry or metric properties of the lattices. The first approach is presented here for the first time, the second has been given by Michael Klemm in 1982. Metric relations between conventional bases of special and general lattice types are tabulated and applied to continuous equi-translation phase transitions. PMID- 25727863 TI - The affine and Euclidean normalizers of the subperiodic groups. AB - The affine and Euclidean normalizers of the subperiodic groups, the frieze groups, the rod groups and the layer groups, are derived and listed. For the layer groups, the special metrics used for plane-group Euclidean normalizers have been considered. PMID- 25727864 TI - Generalized Penrose tiling as a quasilattice for decagonal quasicrystal structure analysis. AB - The generalized Penrose tiling is, in fact, an infinite set of decagonal tilings. It is constructed with the same rhombs (thick and thin) as the conventional Penrose tiling, but its long-range order depends on the so-called shift parameter (s ? <0; 1)). The structure factor is derived for the arbitrarily decorated generalized Penrose tiling within the average unit cell approach. The final formula works in physical space only and is directly dependent on the s parameter. It allows one to straightforwardly change the long-range order of the refined structure just by changing the s parameter and keeping the tile decoration unchanged. This gives a great advantage over the higher-dimensional method, where every change of the tiling (change in the s parameter) requires the structure model to be built from scratch, i.e. the fine division of the atomic surfaces has to be redone. PMID- 25727865 TI - A simple approach to estimate isotropic displacement parameters for hydrogen atoms. AB - A simple combination of riding motion and an additive term is sufficient to estimate the temperature-dependent isotropic displacement parameters of hydrogen atoms, for use in X-ray structure refinements. The approach is validated against neutron diffraction data, and gives reasonable estimates in a very large temperature range (10-300 K). The model can be readily implemented in common structure refinement programs without auxiliary software. PMID- 25727866 TI - Group-theoretical analysis of aperiodic tilings from projections of higher dimensional lattices Bn. AB - A group-theoretical discussion on the hypercubic lattice described by the affine Coxeter-Weyl group W(a)(B(n)) is presented. When the lattice is projected onto the Coxeter plane it is noted that the maximal dihedral subgroup D(h) of W(B(n)) with h = 2n representing the Coxeter number describes the h-fold symmetric aperiodic tilings. Higher-dimensional cubic lattices are explicitly constructed for n = 4, 5, 6. Their rank-3 Coxeter subgroups and maximal dihedral subgroups are identified. It is explicitly shown that when their Voronoi cells are decomposed under the respective rank-3 subgroups W(A(3)), W(H(2)) * W(A(1)) and W(H(3)) one obtains the rhombic dodecahedron, rhombic icosahedron and rhombic triacontahedron, respectively. Projection of the lattice B(4) onto the Coxeter plane represents a model for quasicrystal structure with eightfold symmetry. The B(5) lattice is used to describe both fivefold and tenfold symmetries. The lattice B(6) can describe aperiodic tilings with 12-fold symmetry as well as a three-dimensional icosahedral symmetry depending on the choice of subspace of projections. The novel structures from the projected sets of lattice points are compatible with the available experimental data. PMID- 25727867 TI - Mathematical aspects of molecular replacement. III. Properties of space groups preferred by proteins in the Protein Data Bank. AB - The main goal of molecular replacement in macromolecular crystallography is to find the appropriate rigid-body transformations that situate identical copies of model proteins in the crystallographic unit cell. The search for such transformations can be thought of as taking place in the coset space Gamma?G where Gamma is the Sohncke group of the macromolecular crystal and G is the continuous group of rigid-body motions in Euclidean space. This paper, the third in a series, is concerned with viewing nonsymmorphic Gamma in a new way. These space groups, rather than symmorphic ones, are the most common ones for protein crystals. Moreover, their properties impact the structure of the space Gamma?G. In particular, nonsymmorphic space groups contain both Bieberbach subgroups and symmorphic subgroups. A number of new theorems focusing on these subgroups are proven, and it is shown that these concepts are related to the preferences that proteins have for crystallizing in different space groups, as observed in the Protein Data Bank. PMID- 25727868 TI - Twinning of aragonite - the crystallographic orbit and sectional layer group approach. AB - The occurrence frequency of the {110} twin in aragonite is explained by the existence of an important substructure (60% of the atoms) which crosses the composition surface with only minor perturbation (about 0.2 A) and constitutes a common atomic network facilitating the formation of the twin. The existence of such a common substructure is shown by the C2/c pseudo-eigensymmetry of the crystallographic orbits, which contains restoration operations whose linear part coincides with the twin operation. Furthermore, the local analysis of the composition surface in the aragonite structure shows that the structure is built from slices which are fixed by the twin operation, confirming and reinforcing the crystallographic orbit analysis of the structural continuity across the composition surface. PMID- 25727869 TI - Statistical tests against systematic errors in data sets based on the equality of residual means and variances from control samples: theory and applications. AB - Statistical tests are applied for the detection of systematic errors in data sets from least-squares refinements or other residual-based reconstruction processes. Samples of the residuals of the data are tested against the hypothesis that they belong to the same distribution. For this it is necessary that they show the same mean values and variances within the limits given by statistical fluctuations. When the samples differ significantly from each other, they are not from the same distribution within the limits set by the significance level. Therefore they cannot originate from a single Gaussian function in this case. It is shown that a significance cutoff results in exactly this case. Significance cutoffs are still frequently used in charge-density studies. The tests are applied to artificial data with and without systematic errors and to experimental data from the literature. PMID- 25727870 TI - On the number of k-faces of primitive parallelohedra. AB - Dehn-Sommerville relations for simple (simplicial) polytopes are applied to primitive parallelohedra. New restrictions on numbers of k-faces of non-principal primitive parallelohedra are explicitly formulated for five-, six- and seven dimensional parallelohedra. PMID- 25727871 TI - Color groups arising from index-n subgroups of symmetry groups. AB - One of the main goals in the study of color symmetry is to classify colorings of symmetrical objects through their color groups. The term color group is taken to mean the subgroup of the symmetry group of the uncolored symmetrical object which induces a permutation of colors in the coloring. This work looks for methods of determining the color group of a colored symmetric object. It begins with an index n subgroup H of the symmetry group G of the uncolored object. It then considers H-invariant colorings of the object, so that the color group H(*) will be a subgroup of G containing H. In other words, H <= H(*) <= G. It proceeds to give necessary and sufficient conditions for the equality of H(*) and G. If H(*) ? G and n is prime, then H(*) = H. On the other hand, if H(*) ? G and n is not prime, methods are discussed to determine whether H(*) is G, H or some intermediate subgroup between H and G. PMID- 25727872 TI - Computational analysis of thermal-motion effects on the topological properties of the electron density. AB - The distributions of bond topological properties (BTPs) of the electron density upon thermal vibrations of the nuclei are computationally examined to estimate different statistical figures, especially uncertainties, of these properties. The statistical analysis is based on a large ensemble of BTPs of the electron densities for thermally perturbed nuclear geometries of the formamide molecule. Each bond critical point (BCP) is found to follow a normal distribution whose covariance correlates with the displacement amplitudes of the nuclei involved in the bond. The BTPs are found to be markedly affected not only by normal modes of the significant bond-stretching component but also by modes that involve mainly hydrogen-atom displacements. Their probability distribution function can be decently described by Gumbel-type functions of positive (negative) skewness for the bonds formed by non-hydrogen (hydrogen) atoms. PMID- 25727873 TI - Structure refinement using precession electron diffraction tomography and dynamical diffraction: theory and implementation. AB - Accurate structure refinement from electron-diffraction data is not possible without taking the dynamical-diffraction effects into account. A complete three dimensional model of the structure can be obtained only from a sufficiently complete three-dimensional data set. In this work a method is presented for crystal structure refinement from the data obtained by electron diffraction tomography, possibly combined with precession electron diffraction. The principle of the method is identical to that used in X-ray crystallography: data are collected in a series of small tilt steps around a rotation axis, then intensities are integrated and the structure is optimized by least-squares refinement against the integrated intensities. In the dynamical theory of diffraction, the reflection intensities exhibit a complicated relationship to the orientation and thickness of the crystal as well as to structure factors of other reflections. This complication requires the introduction of several special parameters in the procedure. The method was implemented in the freely available crystallographic computing system Jana2006. PMID- 25727874 TI - Density- and wavefunction-normalized Cartesian spherical harmonics for l <= 20. AB - The widely used pseudoatom formalism [Stewart (1976). Acta Cryst. A32, 565-574; Hansen & Coppens (1978). Acta Cryst. A34, 909-921] in experimental X-ray charge density studies makes use of real spherical harmonics when describing the angular component of aspherical deformations of the atomic electron density in molecules and crystals. The analytical form of the density-normalized Cartesian spherical harmonic functions for up to l <= 7 and the corresponding normalization coefficients were reported previously by Paturle & Coppens [Acta Cryst. (1988), A44, 6-7]. It was shown that the analytical form for normalization coefficients is available primarily for l <= 4 [Hansen & Coppens, 1978; Paturle & Coppens, 1988; Coppens (1992). International Tables for Crystallography, Vol. B, Reciprocal space, 1st ed., edited by U. Shmueli, ch. 1.2. Dordrecht: Kluwer Academic Publishers; Coppens (1997). X-ray Charge Densities and Chemical Bonding. New York: Oxford University Press]. Only in very special cases it is possible to derive an analytical representation of the normalization coefficients for 4 < l <= 7 (Paturle & Coppens, 1988). In most cases for l > 4 the density normalization coefficients were calculated numerically to within seven significant figures. In this study we review the literature on the density-normalized spherical harmonics, clarify the existing notations, use the Paturle-Coppens (Paturle & Coppens, 1988) method in the Wolfram Mathematica software to derive the Cartesian spherical harmonics for l <= 20 and determine the density normalization coefficients to 35 significant figures, and computer-generate a Fortran90 code. The article primarily targets researchers who work in the field of experimental X ray electron density, but may be of some use to all who are interested in Cartesian spherical harmonics. PMID- 25727876 TI - Hans Wondratschek (1925-2014). PMID- 25727877 TI - An analysis of multidisciplinary staffing levels and clinical activity in Australian tertiary persistent pain services. AB - OBJECTIVE: To document staffing (medical, nursing, allied health [AH], administrative) in Australian multidisciplinary persistent pain services and relate them to clinical activity levels. METHODS: Of the 68 adult outpatient persistent pain services approached (Dec'08-Jan'10), 45 agreed to participate, received over 100 referrals/year, and met the contemporaneous International Association for the Study of Pain criteria for Level 1 or 2 multidisciplinary services. Structured interviews with Clinical Directors collected quantitative data regarding staff resources (disciplines, amount), services provided, funding models, and activity levels. RESULTS: Compared with Level 2 clinics, Level 1 centers reported higher annual demand (referrals), clinical activity (patient numbers) and absolute numbers of medical, nursing and administrative staff, but comparable numbers of AH staff. When staffing was assessed against activity levels, medical and nursing resources were consistent across services, but Level 1 clinics had relatively fewer AH and administrative staff. Metropolitan and rural services reported comparable activity levels and discipline-specific staff ratios (except occupational therapy). The mean annual AH staffing for pain management group programs was 0.03 full-time equivalent staff per patient. CONCLUSIONS: Reasonable consistency was demonstrated in the range and mix of most disciplines employed, suggesting they represented workable clinical structures. The greater number of medical and nursing staff within Level 1 clinics may indicate a lower multidisciplinary focus, but this needs further exploration. As the first multidisciplinary staffing data for persistent pain clinics, this provides critical information for designing and implementing clinical services. Mapping against clinical outcomes to demonstrate the impact of staffing patterns on safe and efficacious treatment delivery is required. PMID- 25727878 TI - Moral foundations and political attitudes: The moderating role of political sophistication. AB - Political attitudes can be associated with moral concerns. This research investigated whether people's level of political sophistication moderates this association. Based on the Moral Foundations Theory, this article examined whether political sophistication moderates the extent to which reliance on moral foundations, as categories of moral concerns, predicts judgements about policy positions. With this aim, two studies examined four policy positions shown by previous research to be best predicted by the endorsement of Sanctity, that is, the category of moral concerns focused on the preservation of physical and spiritual purity. The results showed that reliance on Sanctity predicted political sophisticates' judgements, as opposed to those of unsophisticates, on policy positions dealing with equal rights for same-sex and unmarried couples and with euthanasia. Political sophistication also interacted with Fairness endorsement, which includes moral concerns for equal treatment of everybody and reciprocity, in predicting judgements about equal rights for unmarried couples, and interacted with reliance on Authority, which includes moral concerns for obedience and respect for traditional authorities, in predicting opposition to stem cell research. Those findings suggest that, at least for these particular issues, endorsement of moral foundations can be associated with political attitudes more strongly among sophisticates than unsophisticates. PMID- 25727879 TI - Nurse-coordinated collaborative disease management improves the quality of guideline-recommended heart failure therapy, patient-reported outcomes, and left ventricular remodelling. AB - BACKGROUND: Heart failure (HF) pharmacotherapy is often not prescribed according to guidelines. This longitudinal study investigated prescription rates and dosages of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta-blockers, and mineralocorticoid receptor antagonists (MRA), and concomitant changes of symptoms, echocardiographic parameters of left ventricular (LV) function and morphology and results of the Short Form-36 (SF-36) Health Survey in participants of the Interdisciplinary Network Heart Failure (INH) programme. METHODS AND RESULTS: The INH study evaluated a nurse-coordinated management, HeartNetCare-HF(TM) (HNC), against Usual Care (UC) in patients hospitalized for decompensated HF [LV ejection fraction (LVEF) <=40% before discharge). A total of 706 subjects surviving >18 months (363 UC, 343 HNC) were examined 6-monthly. At baseline, 92% received ACEi/ARB, (HNC/UC 91/93%, P = 0.28), 86% received beta-blockers (86/86%, P = 0.83), and 44% received MRA (42/47%, P = 0.07). After 18 months, beta-blocker use had increased only in HNC (+7.6%, P < 0.001). Guideline-recommended target doses were achieved more frequently in HNC for ACEi/ARB (HNC/UC: 50/25%, P < 0.001) and beta-blockers (39/15%, P < 0.001). The following variables were more improved and/or better in subjects undergoing HNC compared with UC: LVEF (47 +/- 12 vs. 44 +/- 12%, P = 0.004, change +17/+14%, P = 0.010), LV end-diastolic diameter (59 +/- 9 vs. 61 +/ 9.6 mm, P = 0.024, change -2.3/-1.4 mm, P = 0.13), New York Heart Association class (1.9 +/- 0.7 vs. 2.1 +/- 0.7, P = 0.001, change -0.44/-0.25, P = 0.002) and SF-36 physical component summary score (41.6 +/- 11.2 vs. 38.5 +/- 11.8, P = 0.004, change +3.3 vs. +1.1 score points, P < 0.02). CONCLUSIONS: Prescription rates and dosages of ACEi/ARB and beta-blockers improved more in HNC than UC patients. Concomitantly, participation in HNC was associated with significantly better clinical outcomes and more favourable echocardiographic changes after 18 months. PMID- 25727880 TI - Molecular cloning and characterization of autophagy-related gene TmATG8 in Listeria-invaded hemocytes of Tenebrio molitor. AB - Macroautophagy (hereinafter called autophagy) is a highly regulated process used by eukaryotic cells to digest portions of the cytoplasm that remodels and recycles nutrients and disposes of unwanted cytoplasmic constituents. Currently 36 autophagy-related genes (ATG) and their homologs have been characterized in yeast and higher eukaryotes, including insects. In the present study, we identified and functionally characterized the immune function of an ATG8 homolog in a coleopteran insect, Tenebrio molitor (TmATG8). The cDNA of TmATG8 comprises of an ORF of 363 bp that encodes a protein of 120 amino acid residues. TmATG8 transcripts are detected in all the developmental stages analyzed. TmAtg8 protein contains a highly conserved C-terminal glycine residue (Gly116) and shows high amino acid sequence identity (98%) to its Tribolium castaneum homolog, TcAtg8. Loss of function of TmATG8 by RNAi led to a significant increase in the mortality rates of T. molitor larvae against Listeria monocytogenes. Unlike dsEGFP-treated control larvae, TmATG8-silenced larvae failed to turn-on autophagy in hemocytes after injection with L. monocytogenes. These data suggest that TmATG8 play a role in mediating autophagy-based clearance of Listeria in T. molitor. PMID- 25727881 TI - The risk of prostate cancer for men on aspirin, statin or antidiabetic medications. AB - BACKGROUND: A decreased risk of prostate cancer (PCa) has been suggested in men taking aspirin, statins and metformin, although the evidence has been conflicting. We estimated the association between prescribed medications, prostate specific antigen (PSA) levels and the risk of either any PCa or high grade PCa. METHODS: This population-based cohort study included 185,667 men having a first recorded PSA test and 18,574 men having a first prostate biopsy in Stockholm County, Sweden for the period 2007-2012. Detailed clinical information including PSA levels, biopsy results, comorbidities and educational level were obtained from population-based registers. High-grade prostate cancer was defined as a Gleason score of seven or higher. Differences in PSA levels by medication status were estimated using linear regression on log PSA values. PCa risk was estimated using multivariate logistic regression. RESULTS: Compared with men who were not on medication, the PSA level at the first PSA test was lower among men using 75 mg/dose aspirin (-3.9% change in PSA concentration; 95% confidence interval (CI): -5.8 to -2.1), statin (-4.6%; 95% CI: -6.2 to -2.9), metformin ( 14%; 95% CI: -17 to -12) and insulin (-16%; 95% CI: -18 to -14). Men using any statins had an increased risk of both high-grade PCa (odds ratio (OR) 1.25; 95% CI: 1.10-1.42) and PCa of any grade (OR 1.16; 95% CI 1.04-1.29). There were no significant associations between aspirin or any antidiabetic medication and the risk of PCa. CONCLUSION: We found no protective effect of aspirin, statins or antidiabetics in terms of risk for any PCa or high-grade PCa. Use of any statins was associated with an elevated risk of being diagnosed with high-grade prostate cancer. PMID- 25727884 TI - RE1-Silencing Transcription Factor (Rest) is a Novel Regulator of Osteoblast Differentiation. AB - RE1-silencing transcription factor (Rest) has been identified as a master negative regulator of neuronal differentiation. Nothing is known about Rest function in bone cells. In this study, we examined the Rest expression levels and role during osteoblast differentiation. We found that Rest is abundantly expressed in bone marrow stromal cells, calvarial osteoblasts, and MC3T3-E1 osteoblasts. Treatment of primary osteoblasts with ascorbic acid (AA) down regulated Rest mRNA expression at an early stage, but not in later stages of differentiation. Consistent with treatment of primary cultures, AA treatment of MC3T3-E1 cells significantly reduced Rest protein expression at day 3 and at day 8 after initiation of osteoblast differentiation. Treatment of bone marrow stromal cells with BMP-2 and dexamethasone, but not IGF-I for 3 days greatly decreased Rest mRNA expression. To test the function of Rest during osteoblast differentiation, Rest expression was knocked down in MC3T3-E1 cell subclones segregated on the basis of ALP activity (differentiation status) using lentivirus expressing shRNA against Rest. An 80% knockdown of Rest expression decreased Osterix (Osx) expression by 52-57% and as a result, increased both basal and AA induced ALP expression and activity in the subclone that expresses low basal level of ALP (undifferentiated). By contrast, a 98% knockdown of Rest expression in cells that express high basal levels of ALP (differentiated cells) caused a significant reduction in Osx expression, basal and AA induced ALP expression and activity. These data suggest that Rest regulates early osteoblast differentiation via modulating Rest expression that is independent of Osx expression. PMID- 25727882 TI - Trabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of the French Sarcoma Group. AB - AIM: The French Sarcoma Group performed this retrospective analysis of the 'RetrospectYon' database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with trabectedin 1.5 mg/m(2) as a 24-h infusion every three weeks. METHODS: Patients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression. RESULTS: Overall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1-28). The objective response rate was 17% (six complete/127 partial responses) and 50% (n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P<0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively. CONCLUSION: The results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS. PMID- 25727885 TI - Sleep quality, sleep duration and physical activity in obese adolescents: effects of exercise training. AB - BACKGROUND: Decreased sleep duration and altered sleep quality are risk factors for obesity in youth. Structured exercise training has been shown to increase sleep duration and improve sleep quality. OBJECTIVES: This study aimed at evaluating the impact of exercise training for improving sleep duration, sleep quality and physical activity in obese adolescents (OB). METHODS: Twenty OB (age: 14.5 +/- 1.5 years; body mass index: 34.0 +/- 4.7 kg m(-2) ) and 20 healthy weight adolescents (HW) completed an overnight polysomnography and wore an accelerometer (SenseWear Bodymedia) for 7 days. OB participated in a 12-week supervised exercise-training programme consisting of 180 min of exercise weekly. Exercise training was a combination of aerobic exercise and resistance training. RESULTS: Sleep duration was greater in HW compared with OB (P < 0.05). OB presented higher apnoea-hypopnoea index than HW (P < 0.05). Physical activity (average daily metabolic equivalent of tasks [METs]) by accelerometer was lower in OB (P < 0.05). After exercise training, obese adolescents increased their sleep duration (+64.4 min; effect size: 0.88; P = 0.025) and sleep efficiency (+7.6%; effect size: 0.76; P = 0.028). Physical activity levels were increased in OB as evidenced by increased steps per day and average daily METs (P < 0.05). Improved sleep duration was associated with improved average daily METs (r = 0.48, P = 0.04). CONCLUSION: The present study confirms altered sleep duration and quality in OB. Exercise training improves sleep duration, sleep quality and physical activity. PMID- 25727886 TI - Active targeting of tumors through conformational epitope imprinting. AB - Inspired by the knowledge that most antibodies recognize a conformational epitope because of the epitope's specific three-dimensional shape rather than its linear structure, we combined scaffold-based peptide design and surface molecular imprinting to fabricate a novel nanocarrier harboring stable binding sites that captures a membrane protein. In this study, a disulfide-linked alpha-helix containing peptide, apamin, was used to mimic the extracellular, structured N terminal part of the protein p32 and then serve as an imprinting template for generating a sub-40 nm-sized polymeric nanoparticle that potently binds to the target protein, recognizes p32-positive tumor cells, and successfully mediates targeted photodynamic therapy in vivo. This could provide a promising alternative for currently used peptide-modified nanocarriers and may have a broad impact on the development of polymeric nanoparticle-based therapies for a wide range of human diseases. PMID- 25727887 TI - Protective effect of Lactobacillus plantarum 21, a probiotic on trinitrobenzenesulfonic acid-induced ulcerative colitis in rats. AB - Inflammatory mediators play a crucial role in ulcerative colitis (UC). The present study was aimed to evaluate the effects of Lactobacillus plantarum 21 (LAB 21) on inflammatory mediators in trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. The inflammatory response was assessed by changes in colon morphology, histopathology, and measurement of reduced glutathione (GSH), lipid peroxidation (TBARS), nitric oxide (NO), interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interleukin 10 (IL-10) mRNA and protein levels by ELISA. Besides, protein expressions of IL-1beta and IL-10 were also evaluated by western blot. Treatment with LAB 21 (1*10(10)CFU/rat/day) and sulfasalazine (500mgkg(-1) body weight) for 14days after induction of colitis, significantly decreased TBARS, NO and increased GSH concentration. The protein and mRNA expressions of IL-1beta and TNFalpha were down-regulated, whereas, protein and mRNA expression of IL-10 was up-regulated in LAB 21-treated rats. Moreover, LAB 21 attenuated the macroscopic colonic damage, histopathological changes induced by TNBS. These results suggest that LAB 21 may be effective in the treatment of UC by immunomodulatory and antioxidant properties. PMID- 25727888 TI - Leonurine ameliorates kidney fibrosis via suppressing TGF-beta and NF-kappaB signaling pathway in UUO mice. AB - Fibrosis is one of the characteristic features of chronic kidney disease (CKD). Inflammatory reactions and oxidative stress are implicated in the pathogenesis of fibrosis of CKD. Leonurine (LEO) is one of the active compounds from Herba leonuri. In this study, we further evaluated its renoprotective effect in a mouse unilateral urethral obstruction (UUO), featuring the renal tubulointerstitial fibrosis and inflammation. In this model, pretreat of LEO before ureteral obstruction abolished the expression of fibronectin, suppressed the expression of alpha-SMA and type I/III collagen and down-regulated vimentin. LEO also modified the cytokine expression of TGF-beta, TNF-alpha, IL-6 and IL-1beta and suppressed the phosphorylation of Smad3. Moreover, LEO blocked phosphorylation of NF-kappaB, and inactivated the signaling pathways associated with the progression of kidney inflammatory response. Our data support that LEO is a candidate renoprotective compound for renal fibrosis through targeting the TGF-beta/Smad3 and NF-kappaB pathway. PMID- 25727890 TI - Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall. AB - Midline defects account for approximately 5% of congenital abnormalities observed at birth. However, the molecular mechanisms underlying the formation of the ventral body wall are not well understood. Recent studies linked mutations in Porcupine-an O-acetyl transferase mediating Wnt ligand acylation-with defects in the thoracic body wall. We hypothesized that anomalous Wnt signaling is involved in the pathogenesis of defective closure of the thoracic body wall. We generated a mouse model wherein Wntless (Wls), which encodes a cargo receptor mediating secretion of Wnt ligands, was conditionally deleted from the developing mesenchyme using Dermo1Cre mice. Wls(f/f);Dermo1(Cre/+) embryos died during mid gestation. At E13.5, skeletal defects were observed in the forelimbs, jaw, and rib cage. At E14.5, midline defects in the thoracic body wall began to emerge: the sternum failed to fuse and the heart protruded through the body wall at the midline (ectopia cordis). To determine the molecular mechanism underlying the phenotype observed in Wls(f/f);Dermo1(Cre/+) embryos, we tested whether Wnt/beta catenin signaling was operative in developing the embryonic ventral body wall using Axin2(LacZ) and BatGal reporter mice. While Wnt/beta-catenin signaling activity was observed at the midline of the ventral body wall before sternal fusion, this pattern of activity was altered and scattered throughout the body wall after mesenchymal deletion of Wls. Mesenchymal cell migration was disrupted in Wls(f/f);Dermo1(Cre/+) thoracic body wall partially due to anomalous beta catenin independent Wnt signaling as determined by in vitro assays. Deletion of Lrp5 and Lrp6 receptors, which mediate Wnt/beta-catenin signaling in the mesenchyme, partially recapitulated the phenotype observed in the chest midline of Wls(f/f);Dermo1(Cre/+) embryos supporting a role for Wnt/beta-catenin signaling activity in the normal formation of the ventral body wall mesenchyme. We conclude that Wls-mediated secretion of Wnt ligands from the developing ventral body wall mesenchyme plays a critical role in fusion of the sternum and closure of the secondary body wall. Thus, impaired Wls activity in the ventral body wall mesenchyme is a mechanism underlying ectopia cordis and unfused sternum. PMID- 25727891 TI - Disturbance opens recruitment sites for bacterial colonization in activated sludge. AB - Little is known about the role of immigration in shaping bacterial communities or the factors that may dictate success or failure of colonization by bacteria from regional species pools. To address these knowledge gaps, the influence of bacterial colonization into an ecosystem (activated sludge bioreactor) was measured through a disturbance gradient (successive decreases in the parameter solids retention time) relative to stable operational conditions. Through a DNA sequencing approach, we show that the most abundant bacteria within the immigrant community have a greater probability of colonizing the receiving ecosystem, but mostly as low abundance community members. Only during the disturbance do some of these bacterial populations significantly increase in abundance beyond background levels and in few cases become dominant community members post-disturbance. Two mechanisms facilitate the enhanced enrichment of immigrant populations during disturbance: (i) the availability of resources left unconsumed by established species and (ii) the increased availability of niche space for colonizers to establish and displace resident populations. Thus, as a disturbance decreases local diversity, recruitment sites become available to promote colonization. This work advances our understanding of microbial resource management and diversity maintenance in complex ecosystems. PMID- 25727889 TI - The initial establishment and epithelial morphogenesis of the esophagus: a new model of tracheal-esophageal separation and transition of simple columnar into stratified squamous epithelium in the developing esophagus. AB - The esophagus and trachea are tubular organs that initially share a single common lumen in the anterior foregut. Several models have been proposed to explain how this single-lumen developmental intermediate generates two tubular organs. However, new evidence suggests that these models are not comprehensive. I will first briefly review these models and then propose a novel 'splitting and extension' model based on our in vitro modeling of the foregut separation process. Signaling molecules (e.g., SHHs, WNTs, BMPs) and transcription factors (e.g., NKX2.1 and SOX2) are critical for the separation of the foregut. Intriguingly, some of these molecules continue to play essential roles during the transition of simple columnar into stratified squamous epithelium in the developing esophagus, and they are also closely involved in epithelial maintenance in the adults. Alterations in the levels of these molecules have been associated with the initiation and progression of several esophageal diseases and cancer in adults. PMID- 25727892 TI - The effect of metabolic alkalosis on central and peripheral mechanisms associated with exercise-induced muscle fatigue in humans. AB - NEW FINDINGS: What is the central question of this study? Does metabolic alkalosis affect central and peripheral mechanisms associated with exercise induced muscle fatigue in humans? What is the main finding and its importance? Inducing metabolic alkalosis before exercise preserved voluntary activation, but not muscle excitation, after a 2 min maximal voluntary contraction (MVC) followed by ischaemia. An effect of pH was also observed in maximal rates of torque development, where alkalosis mitigated the reduction in maximal rates of torque development after the initial 2 min MVC. For the first time, these results demonstrate a differential effect of pH on voluntary activation as well as maximal rates of torque development after sustained, maximal voluntary knee extension in humans. The increased concentration of protons during fatiguing exercise may contribute to increased activation of group III and IV afferents and subsequently reduced central drive, but this has yet to be confirmed in exercising humans. Here, we determined whether inducing metabolic alkalosis differentially affects descending central drive after fatiguing exercise and whether this effect may, in part, be explained by attenuating group III and IV afferent firing. Eleven men performed a maximal 2 min voluntary knee extension (MVC) followed by a 2 min rest and subsequent 1 min MVC with an occlusive cuff either in placebo [PLA; 0.3 g (kg body weight)(-1) calcium carbonate] or alkalosis conditions [ALK; 0.3 g (kg body weight)(-1) sodium bicarbonate]. Femoral nerve stimulation was applied before exercise, after the 2 min MVC and at 40-60 s intervals throughout the remainder of the protocol to explore central and peripheral mechanisms associated with reductions in maximal force and rate of torque development. Although voluntary activation declined to a similar extent after the 2 min MVC, during the ischaemic period voluntary activation was higher during ALK (PLA, 57 +/- 8%; ALK, 76 +/- 5%). Maximal voluntary torque declined at similar rates during the task (203 +/- 19 N m), but maximal rate of torque development was significantly higher in the ALK conditions after the 2 min MVC (mean difference of 177 +/- 60 N m s(-1) ). These results demonstrate the effect of pH on voluntary activation as well as maximal rates of torque development after sustained, maximal voluntary knee extension in humans. PMID- 25727894 TI - Electrolytic reduction of liquid metal oxides and its application to reconfigurable structured devices. AB - Structured metallic patterns are routinely used for a wide variety of applications, ranging from electronic circuits to plasmonics and metamaterials. Numerous techniques have been developed for the fabrication of these devices, in which the metal patterns are typically formed using conventional metals. While this approach has proven very successful, it does generally limit the ability to reconfigure the geometry of the overall device. Here, we demonstrate the ability to create artificially structured metallic devices using liquid metals, in which the configuration can be altered via the electrolysis of saline solutions or deionized water. We accomplish this using an elastomeric mold with two different sets of embedded microfluidic channels that are patterned and injected with EGaIn and water, respectively. The electrochemical reaction is then used to etch the thin oxide layer that forms on eutectic gallium indium (EGaIn) in a controlled reproducible manner. Once the oxide layer is dissolved locally, the underlying liquid metal retracts away from the original position to a position where a new stable oxide layer can reform, which is equivalent to erasing a section of the liquid metal. To allow for full reconfigurability, the entire device can be reset by refilling all of the microchannels with EGaIn. PMID- 25727893 TI - Investigational agents for treatment of traumatic brain injury. AB - INTRODUCTION: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. To date, there are no pharmacologic agents proven to improve outcomes from TBI because all the Phase III clinical trials in TBI have failed. Thus, there is a compelling need to develop treatments for TBI. AREAS COVERED: The following article provides an overview of select cell-based and pharmacological therapies under early development for the treatment of TBI. These therapies seek to enhance cognitive and neurological functional recovery through neuroprotective and neurorestorative strategies. EXPERT OPINION: TBI elicits both complex degenerative and regenerative tissue responses in the brain. TBI can lead to cognitive, behavioral, and motor deficits. Although numerous promising neuroprotective treatment options have emerged from preclinical studies that mainly target the lesion, translation of preclinical effective neuroprotective drugs to clinical trials has proven challenging. Accumulating evidence indicates that the mammalian brain has a significant, albeit limited, capacity for both structural and functional plasticity, as well as regeneration essential for spontaneous functional recovery after injury. A new therapeutic approach is to stimulate neurovascular remodeling by enhancing angiogenesis, neurogenesis, oligodendrogenesis, and axonal sprouting, which in concert, may improve neurological functional recovery after TBI. PMID- 25727896 TI - Prenatal tolbutamide treatment alters plasma glucose and insulin concentrations and negatively affects the postnatal performance of chickens. AB - To examine the relationship of insulin and glucose, broiler embryos were subjected to acute or prolonged hypoglycemia during the late embryonic phase by, respectively, injecting once (at embryonic day [ED] 16 or 17) or on 3 consecutive days (ED 16, 17, and 18) with tolbutamide (80 MUg/g embryo weight), a substance that stimulates insulin secretion from the pancreas. After 1 tolbutamide injection, a prolonged (32 h) decrease of plasma glucose and a profound acute increase in plasma insulin were observed. The 3 consecutive tolbutamide injections induced hypoglycemia for 4 days (from ED 16 to ED 19). The postnatal performance after 3 consecutive tolbutamide injections in broiler embryos was also investigated. Body weight was lower in tolbutamide-treated chickens from hatch to 42 d compared with sham (P = 0.001) and control (P < 0.001) chickens. Feed intake was lower in the tolbutamide group from hatch to 42 d as compared with sham (P = 0.007) and control (P = 0.017) animals. In addition, at 42 d, plasma glucose concentrations, after an insulin injection challenge (50 MUg/kg body weight), were higher in tolbutamide-treated chickens compared with the sham and the control group as were their basal glucose levels (P value of group effect <0.001). In conclusion, tolbutamide treatment during the late embryonic development in broilers resulted in prolonged hypoglycemia in this period and negatively influenced the posthatch performance. PMID- 25727897 TI - Human short-term spatial memory: precision predicts capacity. AB - Here, we aimed to determine the capacity of human short-term memory for allocentric spatial information in a real-world setting. Young adults were tested on their ability to learn, on a trial-unique basis, and remember over a 1-min interval the location(s) of 1, 3, 5, or 7 illuminating pads, among 23 pads distributed in a 4m*4m arena surrounded by curtains on three sides. Participants had to walk to and touch the pads with their foot to illuminate the goal locations. In contrast to the predictions from classical slot models of working memory capacity limited to a fixed number of items, i.e., Miller's magical number 7 or Cowan's magical number 4, we found that the number of visited locations to find the goals was consistently about 1.6 times the number of goals, whereas the number of correct choices before erring and the number of errorless trials varied with memory load even when memory load was below the hypothetical memory capacity. In contrast to resource models of visual working memory, we found no evidence that memory resources were evenly distributed among unlimited numbers of items to be remembered. Instead, we found that memory for even one individual location was imprecise, and that memory performance for one location could be used to predict memory performance for multiple locations. Our findings are consistent with a theoretical model suggesting that the precision of the memory for individual locations might determine the capacity of human short-term memory for spatial information. PMID- 25727898 TI - On-nerve needle nerve conduction study in the sural nerve: A new technique for evaluation of peripheral neuropathy. AB - OBJECTIVE: The objective of this study was to compare the nerve conduction study (NCS) data by the surface electrode (SE)-NCS versus the on-nerve needle (ONN)-NCS and to assess their clinical usefulness in the diagnosis of peripheral neuropathy. METHODS: Sensory compound nerve action potentials (CNAPs) were obtained by the ONN-NCS with needle electrodes placed on the exposed sural nerve during biopsy in 94 patients with peripheral neuropathy. RESULTS: The ONN-NCS is possible in 95% of cases. The ONN-NCS was able to record sensory CNAP in 15% of cases when it was unobtainable in the SE-NCS. The ONN-NCS showed higher amplitude and longer duration of the CNAP but a slower maximum nerve conduction velocity (NCV) than the SE-NCS. The ONN-NCS showed a significantly better concordance with the nerve biopsy findings, especially in demyelinating neuropathy. CONCLUSION: The ONN-NCS is a better electrophysiological test for the histopathological correlation with nerve biopsy. SIGNIFICANCE: The ONN-NCS was able to record sensory CNAP in 15% of cases when it was unobtainable in the SE-NCS. PMID- 25727895 TI - Ultrasmall glutathione-protected gold nanoclusters as next generation radiotherapy sensitizers with high tumor uptake and high renal clearance. AB - Radiotherapy is often the most straightforward first line cancer treatment for solid tumors. While it is highly effective against tumors, there is also collateral damage to healthy proximal tissues especially with high doses. The use of radiosensitizers is an effective way to boost the killing efficacy of radiotherapy against the tumor while drastically limiting the received dose and reducing the possible damage to normal tissues. Here, we report the design and application of a good radiosensitizer by using ultrasmall Au(29-43)(SG)(27-37) nanoclusters (<2 nm) with a naturally-occurring peptide (e.g., glutathione or GSH) as the protecting shell. The GSH-coated Au(29-43)(SG)(27-37) nanoclusters can escape the RES absorption, leading to a good tumor uptake (~8.1% ID/g at 24 h post injection). As a result, the as-designed Au nanoclusters led to a strong enhancement for radiotherapy, as well as a negligible damage to normal tissues. After the treatment, the ultrasmall Au(29-43)(SG)(27-37) nanoclusters can be efficiently cleared by the kidney, thereby avoiding potential long-term side effects caused by the accumulation of gold atoms in the body. Our data suggest that the ultrasmall peptide-protected Au nanoclusters are a promising radiosensitizer for cancer radiotherapy. PMID- 25727899 TI - Signal features of surface electromyography in advanced Parkinson's disease during different settings of deep brain stimulation. AB - OBJECTIVE: Electromyography (EMG) and acceleration (ACC) measurements are potential methods for quantifying efficacy of deep brain stimulation (DBS) treatment in Parkinson's disease (PD). The treatment efficacy depends on the settings of DBS parameters (pulse amplitude, frequency and width). This study quantified, if EMG and ACC signal features differ between different DBS settings and if DBS effect is unequal between different muscles. METHODS: EMGs were measured from biceps brachii (BB) and tibialis anterior (TA) muscles of 13 PD patients. ACCs were measured from wrists. Measurements were performed during seven different settings of DBS and analyzed using methods based on spectral analysis, signal morphology and nonlinear dynamics. RESULTS: The results showed significant within-subject differences in the EMG signal kurtosis, correlation dimension, recurrence rate and EMG-ACC coherence between different DBS settings for BB but not for TA muscles. Correlations between EMG feature values and clinical rest tremor and rigidity scores were weak but significant. CONCLUSIONS: Surface EMG features differed between different DBS settings and DBS effect was unequal between upper and lower limb muscles. SIGNIFICANCE: EMG changes pointed to previously defined optimal settings in most of patients, which should be quantified even more deeply in the upcoming studies. PMID- 25727900 TI - Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis? AB - There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy. PMID- 25727901 TI - Increased motor unit potential shape variability across consecutive motor unit discharges in the tibialis anterior and vastus medialis muscles of healthy older subjects. AB - OBJECTIVE: To study the potential utility of using near fiber (NF) jiggle as an assessment of neuromuscular transmission stability in healthy older subjects using decomposition-based quantitative electromyography (DQEMG). METHODS: The tibialis anterior (TA) and vastus medialis (VM) muscles were tested in 9 older men (77 +/- 5 years) and 9 young male control subjects (23 +/- 0.3 years). Simultaneous surface and needle-detected electromyographic (EMG) signals were collected during voluntary contractions, and then analyzed using DQEMG. Motor unit potential (MUP) and NF MUP parameters were analyzed. RESULTS: NF jiggle was significantly increased for both the TA and VM in the old age group relative to the younger controls (P<0.05). NF jiggle was significantly higher in the TA compared to VM (P<0.05). For TA, NF jiggle was negatively correlated with MUNE, and positively correlated with S-MUP amplitude, NF count, MUP duration, MUP peak to-peak voltage, and MUP area (P<0.05). For VM, NF jiggle was positively correlated with NF count and MUP area (P<0.05), and no significant correlations were found between NF jiggle and S-MUP amplitude, MUP duration, or MUP peak-to peak voltage (MUNE was not calculated for VM, so no correlation could be made). CONCLUSIONS: Healthy aging is associated with neuromuscular transmission instability (increased NF jiggle) and MU remodeling, which can be measured using DQEMG. SIGNIFICANCE: NF jiggle derived from DQEMG can be a useful method of identifying neuromuscular dysfunction at various stages of MU remodeling and aging. PMID- 25727902 TI - A review of nurses' knowledge, attitudes, and ability to communicate the risks and benefits of complementary and alternative medicine. AB - AIMS AND OBJECTIVES: This study reviewed existing literature to investigate how frequently nurses include complementary and alternative forms of medicine in their clinical practice. In so doing, we investigated nurses' knowledge of and attitudes towards complementary and alternative medicine as well as their ability to communicate the risks and benefits of these therapies with patients. BACKGROUND: Little information is available concerning nurses' knowledge and attitudes towards complementary and alternative medicine or how they incorporate these therapies into their practice. In addition, little is known about the ability of nurses to communicate the risks and benefits of complementary and alternative medicine to their patients. STUDY DESIGN: This study used a scoping review method to map and synthesise existing literature. DATA SOURCES: Both electronic and manual searches were used to identify relevant studies published between January 2007 and January 2014. REVIEW METHODS: The review was conducted in five stages: (1) identification of research question(s), (2) locate studies, (3) selection of studies, (4) charting of data, and (5) collating, summarising, and reporting of results. RESULTS: Fifteen papers met the inclusion criteria for this review, among which 53.7% referenced how frequently nurses include complementary and alternative medicine in their practice. We found that 66.4% of nurses had positive attitudes towards complementary and alternative medicine; however, 77.4% did not possess a comprehensive understanding of the associated risks and benefits. In addition, nearly half of the respondents (47.3-67.7%) reported feeling uncomfortable discussing complementary and alternative medicine therapies with their patients. CONCLUSION: The lack of knowledge about complementary and alternative medicine among nurses is a cause for concern, particularly in light of its widespread application. RELEVANCE TO CLINICAL PRACTICE: Findings from this study suggest that health care professionals need to promote evidence informed decision-making in complementary and alternative medicine practice and be knowledgeable enough to discuss complementary and alternative medicine therapies. Without involvement of complementary and alternative medicine communication on the part of our profession, we may put our patients at risk of uninformed and without medical guidance. PMID- 25727903 TI - Metabolomics investigation to shed light on cheese as a possible piece in the French paradox puzzle. AB - An NMR-based metabolomics approach was used to investigate the differentiation between subjects consuming cheese or milk and to elucidate the potential link to an effect on blood cholesterol level. Fifteen healthy young men participated in a full crossover study during which they consumed three isocaloric diets with similar fat contents that were either (i) high in milk, (ii) high in cheese with equal amounts of dairy calcium, or (iii) a control diet for 14 days. Urine and feces samples were collected and analyzed by NMR-based metabolomics. Cheese and milk consumption decreased urinary choline and TMAO levels and increased fecal excretion of acetate, propionate, and lipid. Compared with milk intake, cheese consumption significantly reduced urinary citrate, creatine, and creatinine levels and significantly increased the microbiota-related metabolites butyrate, hippurate, and malonate. Correlation analyses indicated that microbial and lipid metabolism could be involved in the dairy-induced effects on blood cholesterol level. PMID- 25727905 TI - Re: Rosier PFWM, Kirschner-Hermanns R, Svihra J, Homma Y, Wein AJ. ICS teaching module: Analysis of voiding, pressure flow analysis (basic module). Neurourol Urodyn. 2014 Sep 11. doi: 10.1002/nau.22660. PMID- 25727904 TI - In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells. AB - In aged mice, new B-cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B-cell precursors with higher levels of the surrogate light chain (SLC) proteins (lambda5/VpreB) and (ii) lambda5(low) B-cell precursors generate new B cells which show increased reactivity to the self-antigen/bacterial antigen phosphorylcholine (PC). Pro-B cells in old bone marrow as well as pro-B cells from young adult lambda5-deficient mice are resistant to cytokine-induced apoptosis (TNFalpha; TGFbeta), indicating that low lambda5 expression in pro-B cells is sufficient to cause increased survival. Transfer of TNFalpha-producing 'age-associated B cells' (ABC; CD21/35(-) CD23(-)) or follicular (FO) B cells from aged mice into RAG-2 KO recipients led to preferential loss of lambda5(high) pro-B cells, but retention of lambda5(low), apoptosis-resistant pro-B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of lambda5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNFalpha producing B cells, results in preferential loss of SLC(high) pro-B cells within the bone marrow. Further B-cell development then occurs via an 'SLC(low)' pathway that not only impairs B-cell generation, but promotes autoreactivity within the naive antibody repertoires in the bone marrow and periphery. PMID- 25727906 TI - Postural vital capacity difference with aging in duchenne muscular dystrophy. AB - INTRODUCTION: A change in vital capacity (VC) from standing to supine can be an index of diaphragm paralysis if it exceeds 25%. We aimed to verify whether the postural VC difference increases with age and reflects diaphragm weakness in DMD. METHODS: VCs were measured in DMD. Postural VC difference and percentage were calculated from the VC data. Maximal inspiratory pressure (MIP) and MIP percentage were measured as an indirect index of diaphragm weakness. RESULTS: A total of 220 patients and 544 measurements were collected. MIP and MIP percentage decreased significantly with age (P < 0.001 for both). Estimated postural VC difference and percentage also decreased (P < 0.001, P = 0.006, respectively). Age group comparisons showed a significant decrease in younger, but not older subjects. CONCLUSIONS: This study shows that the postural VC difference tended to decrease with age and might not reflect diaphragmatic weakness in DMD; however, this should be interpreted cautiously. PMID- 25727907 TI - MTLE with hippocampal sclerosis in adult as a syndrome. AB - Mesial temporal lobe epilepsy with hippocampal sclerosis, (MTLE-HS) is a well characterized disorder which associates electroclinical features suggestive of seizure onset in the mesial or limbic structures of the temporal lobe, and hippocampal sclerosis. This underlying pathology differentiates MTLE-HS from MTLE due to other pathological substrates. Typically, when MTLE-HS is diagnosed, a typical course of the disease can be retrospectively recognized, including early prolonged febrile seizures, a latent period, onset in mid-to-late childhood, auras that may initially occur in isolation, periods of seizure remission during adolescence or early adulthood. Then the condition progresses, associating elaborated seizures, progressive drug-resistance and cognitive, mainly memory, disorders of variable intensity. The seizures have a relatively gradual onset/offset, developing over 1-2minutes, with partial awareness at the onset, and lasting for 2 to 10minutes. Auras are common, with visceral, autonomic, psycho-affective, experiential components, presenting less frequently diverse sensory or sensorial symptoms. Awareness is generally preserved at onset, but then loss of consciousness occurs, with initial motionless stare, and automatisms, which typically are oro-alimentary, vocal or gestural, accompanied by motor signs such as contralateral dystonic posturing. A dysphasia is frequent when the focus is in the dominant hemisphere, often prolonged by a post-ictal dysphasia and confusion. Interictal EEG shows anterior or mid-temporal spikes/sharp ipsilaterally to the focus, in combination with non-epileptiform regional slowing. These changes may be bilateral but usually predominates ipsilaterally. Ictal EEG changes are marked by rhythmic temporal alpha or theta activity within 30seconds of clinical onset. The hallmark is the presence of hippocampal sclerosis, demonstrable on coronal MRI sequences by unilateral (or asymmetrical) decrease in hippocampal volume and increase in signal on T2 weighted sequences. The diagnosis of MTLE is crucial because of its frequent poor prognosis under antiepileptic drugs, and of the possibility of excellent results after resective surgery. PET scanning shows a typical antero-mesial hypometabolism extending to the pole and lateral aspects of the temporal lobe. Presurgical investigations may also include depth-electrode recordings in case of doubt about more extensive or bilateral onsets. They demonstrate and lateralize the amygdalo-hippocampal discharges, some of them remaining apparently asymptomatic in the absence of extrahippocampal spreading. These interactions between hippocampal and extrahippocampal networks confer its specificity to MTLE HS, together with its remarkable natural course. This entity is diagnostically essential, whether it should be regarded as an epileptic syndrome, disease or a distinctive constellation. PMID- 25727908 TI - Acinetobacter strains carry two functional oligosaccharyltransferases, one devoted exclusively to type IV pilin, and the other one dedicated to O glycosylation of multiple proteins. AB - Multiple species within the Acinetobacter genus are nosocomial opportunistic pathogens of increasing relevance worldwide. Among the virulence factors utilized by these bacteria are the type IV pili and a protein O-glycosylation system. Glycosylation is mediated by O-oligosaccharyltransferases (O-OTases), enzymes that transfer the glycan from a lipid carrier to target proteins. O oligosaccharyltransferases are difficult to identify due to similarities with the WaaL ligases that catalyze the last step in lipopolysaccharide synthesis. A bioinformatics analysis revealed the presence of two genes encoding putative O OTases or WaaL ligases in most of the strains within the genus Acinetobacter. Employing A. nosocomialis M2 and A. baylyi ADP1 as model systems, we show that these genes encode two O-OTases, one devoted uniquely to type IV pilin, and the other one responsible for glycosylation of multiple proteins. With the exception of ADP1, the pilin-specific OTases in Acinetobacter resemble the TfpO/PilO O OTase from Pseudomonas aeruginosa. In ADP1 instead, the two O-OTases are closely related to PglL, the general O-OTase first discovered in Neisseria. However, one of them is exclusively dedicated to the glycosylation of the pilin-like protein ComP. Our data reveal an intricate and remarkable evolutionary pathway for bacterial O-OTases and provide novel tools for glycoengineering. PMID- 25727909 TI - Moisture Barrier Composites Made of Non-Oxidized Graphene Flakes. AB - Graphene flakes (GFs) with minimized defects and oxidation ratios are incorporated into polyethylene (PE) to enhance the moisture barrier. GFs produced involving solvothermal intercalation show extremely low oxidation rates (3.17%), and are noncovalently functionalized in situ, inducing strong hydrophobicity. The fabricated composite possesses the best moisture barrier performance reported for a polymer-graphene composite. PMID- 25727910 TI - Estrogen-related receptor gamma regulates dopaminergic neuronal phenotype by activating GSK3beta/NFAT signaling in SH-SY5Y cells. AB - The orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is highly expressed in the nervous system during embryogenesis and in adult brains, but its physiological role in neuronal development remains unknown. In this study, we evaluated the relevance of ERRgamma in regulating dopaminergic (DAergic) phenotype and the corresponding signaling pathway. We used retinoic acid (RA) to differentiate human neuroblastoma SH-SY5Y cells. RA induced neurite outgrowth of SH-SY5Y cells with an increase in DAergic neuron-like properties, including up regulation of tyrosine hydroxylase, dopamine transporter, and vesicular monoamine transporter 2. ERRgamma, but not ERRalpha, was up-regulated by RA, and participated in RA effect on SH-SY5Y cells. ERRgamma over-expression enhanced mature DAergic neuronal phenotype with neurite outgrowth as with RA treatment; and RA-induced increase in DAergic phenotype was attenuated by silencing ERRgamma expression. ERRgamma appears to have a crucial role in morphological and functional regulation of cells that is selective for DAergic neurons. Polo-like kinase 2 was up-regulated in ERRgamma-over-expressing SH-SY5Y cells, which was involved in phosphorylation of glycogen synthase kinase 3beta and resulting downstream activation of nuclear factor of activated T cells. The likely involvement of ERRgamma in regulating the DAergic neuronal phenotype makes this orphan nuclear receptor a novel target for understanding DAergic neuronal differentiation. We propose the relevance of estrogen-related receptor gamma (ERRgamma) in regulating dopaminergic neuronal phenotype: ERRgamma is up regulated by retinoic acid in SH-SY5Y cells, and enhances dopaminergic phenotypes and induces neurite outgrowth; Polo-like kinase 2 (PLK2) and glycogen synthase kinase 3 beta/nuclear factor of activated T cells (GSK3beta/NFAT) signaling are responsible for the ERRgamma effect. Our findings provide the first insights into the role of ERRgamma in the brain, as a novel approach toward understanding dopaminergic differentiation. PMID- 25727911 TI - Downregulation of miR-146a, cyclooxygenase-2 and advanced glycation end-products in simvastatin-treated older patients with hyperlipidemia. AB - AIM: Hyperlipidemia is a disease with abnormally elevated levels of lipids/lipoproteins in the blood, and it is regarded as an important risk factor for cardiovascular and cerebrovascular diseases. Statins have been found to prevent vascular diseases by reducing low-density lipoprotein cholesterol and regulation of immune responses. Here, we aim to study the expression change of immune-related microRNA and genes in older patients with hyperlipidemia after treatment with simvastatin. METHODS: A total of 25 older male patients with hyperlipidemia were included in the study and received simvastatin treatment (20 mg/day). Clinical characteristics of these patients were examined, including lipoprotein cholesterol, high-sensitivity C-reactive protein, blood routine and biochemical characters. We tested miR-146a, interleukin-1-receptor-associated kinase 1, tumor necrosis factor-receptor-associated factor 6 and cyclooxygenase-2 level by real-time polymerase chain reaction, and expressions of advanced glycation end-products, p53 and p21 were analyzed by enzyme-linked immunosorbent assay. RESULTS: Simvastatin treatment effectively reduced total cholesterol and low-density lipoprotein cholesterol, but had little effect on high-density lipoprotein cholesterol. High-sensitivity C-reactive protein was slightly reduced. Expression of cyclooxygenase-2 and advanced glycation end-products were significantly reduced. Furthermore, simvastatin effectively reduced the expression of p53 and p21. Significantly downregulated miR-146a, and an obvious reduction of interleukin-1-receptor-associated kinase 1 were also detected, whereas tumor necrosis factor-receptor-associated factor 6 remained unchanged. Besides, there was a significant reduction of alanine transaminase, aspertate aminotransferase, alkaline phosphatase and lactate dehydrogenase. CONCLUSION: Simvastatin treatment could inhibit inflammation and senescence-associated genes in older patients with hyperlipidemia, suggesting its application in inflammatory and age-related diseases. PMID- 25727912 TI - Inhibitory effects of indole alpha-lipoic acid derivatives on nitric oxide production in LPS/IFNgamma activated RAW 264.7 macrophages. AB - Alpha-lipoic acid (alpha-lipoic acid) is a potent antioxidant compound that has been shown to possess anti-inflammatory effects. RAW 264.7 macrophages produce various inflammatory mediators such as nitric oxide, IL-1beta, IL-6 and TNF-alpha upon activation with LPS (Lipopolysaccharide) and IFNgamma (interferon gamma). In this study, the effect of 12 synthetic indole alpha-lipoic acid derivatives on nitric oxide production and iNOS (inducible nitric oxide synthase) protein expression in LPS/IFNgamma activated RAW 264.7 macrophages was determined. Cell proliferation, nitric oxide levels and iNOS protein expression were examined with thiazolyl blue tetrazolium blue test, griess assay and western blot, respectively. Our results showed that all of the indole alpha-lipoic acid derivatives showed significant inhibitory effects on nitric oxide production and iNOS protein levels (p < 0.05). The most active compounds were identified as compound I-4b, I-4e and II-3b. In conclusion, these indole alpha-lipoic acid derivatives may have the potential for treatment of inflammatory conditions related with high nitric oxide production. PMID- 25727913 TI - Comparison of Veterinary Student Ability to Learn 1-Handed and 2-Handed Techniques for Surgical Knot Tying. AB - OBJECTIVE: To determine which type of surgical hand-tie trainee surgeons learn most readily in a laboratory setting, using a combination of audiovisual demonstration and one-on-one teaching. STUDY DESIGN: Randomized controlled learning trial. SAMPLE POPULATION: Year 4 veterinary students in their 1st year of clinical training (n = 58). METHODS: Veterinary students entering clinical rotations were randomly allocated to 2 learning groups: 1-handed (28 students) or 2-handed (30 students) surgical ties. Knot tying technique was taught followed by three 15-minute practice sessions with student progress recorded by filming each student tying a square knot (2 throws). All 3 knot tying attempts were scored for technique and knot formation. Data on potential confounding factors between groups, including age and gender, were recorded. RESULTS: There were no significant differences between group scores for each attempt (1st attempt P = .5; 2nd P = .2; 3rd P = .19). Initially, scores indicated more rapid learning in the 1-handed group but fewer individuals achieved a perfect technique and knot after 60 minutes of learning (29/30 for 2-handed; 24/28 for 1-handed group). The 1-handed group was the most error-prone (after 45 minutes P < .01; after 60 min P < .01). CONCLUSIONS: Over 95% of students in the 2-handed group performed the technique and knot perfectly after 60 minutes learning time; were significantly less error-prone and fewer students continued to make corrected errors after 60 minutes. This evidence indicates that the 2-handed technique allows students to achieve success in a manageable teaching time. PMID- 25727914 TI - Influence of 4 weeks of bovine colostrum supplementation on neutrophil and mucosal immune responses to prolonged cycling. AB - Bovine colostrum (COL) has been advocated as a nutritional countermeasure to exercise-induced immune dysfunction. The aims of this study were to identify the effects of 4 weeks of COL supplementation on neutrophil responses and mucosal immunity following prolonged exercise. In a randomized double-blind, parallel group design, participants [age 28 +/- 8 years; body mass 79 +/- 7 kg; height 182 +/- 6 cm; maximal oxygen uptake (VO2max) 55 +/- 9 mL/kg/min] were assigned to 20 g per day of COL (n = 10) or an isoenergetic/isomacronutrient placebo (PLA; n = 10) for 4 weeks. Venous blood and unstimulated saliva samples were obtained before and after 2.5 h of cycling at 15% Delta (~55-60% VO2max). A significantly greater formyl-methionyl-leucyl phenylalanine-stimulated oxidative burst was observed in the COL group compared with PLA group (P < 0.05) and a trend toward a time * group interaction (P = 0.06). However, there was no effect of COL on leukocyte trafficking, phorbol-12-myristate-13-acetate-stimulated oxidative burst, bacterial-stimulated neutrophil degranulation, salivary secretory IgA, lactoferrin or lysozyme (P > 0.05). These findings provide further evidence of the beneficial effects of COL on receptor-mediated stimulation of neutrophil oxidative burst in a model of exercise-induced immune dysfunction. PMID- 25727915 TI - Corrigendum to "Identification of biosecurity measures and spatial variables as potential risk factors for Aleutian disease in Danish mink farms" [Prev. Vet. Med. 107 (2012) 134-141]. PMID- 25727916 TI - Exploration of a haloarchaeon, Halostagnicola larsenii, isolated from rock pit sea water, West Coast of Maharashtra, India, for the production of bacteriorhodopsin. AB - AIMS: The aim of the present investigation was to isolate haloarchaea from rock pit sea water, West Coast of India and to explore their potential in the production of bacteriorhodopsin (BR) which converts light energy into electrical energy. METHODS AND RESULTS: Haloarchaeal strains were isolated from rock pit sea water samples collected from Rock garden, Malvan, West Coast of India. Based on morphological, physiological and biochemical characteristics, and 16S rRNA gene sequencing, all the 11 strains were identified as Halostagnicola larsenii. All the strains require at least 1.5 mol l(-1) NaCl for growth; grow optimally in the range of 3.5-5.2 mol l(-1) NaCl. BR was detected in all the strains ranging from 0.035 to 0.258 g l(-1) . All 11 strains showed conversion of light energy into electrical energy in the range of 0.7-44.2 mV, when exposed to sunlight. CONCLUSIONS: A haloarchaeon, Hst. larsenii is isolated from rock pit sea water and demonstrated to have BR that converted light energy into electrical energy. SIGNIFICANCE AND IMPACT OF THE STUDY: The present investigation is presumably the first report of the isolation of Hst. larsenii from low salinity environment and its potential in production of BR. The haloarchaeon could be explored for the generation of electrical energy. PMID- 25727917 TI - Successful liver transplantation in a child with acute-on-chronic liver failure and acquired thrombotic thrombocytopenic purpura. PMID- 25727918 TI - Measurement of internal diameter changes and pulse wave velocity in fetal descending aorta using the ultrasonic phased-tracking method in normal and growth restricted fetuses. AB - Phased tracking (PT) is an ultrasound-based technique that enables precise measurement of a target velocity. The aims of this study were to use PT to evaluate arterial pulse waveform, pulse wave velocity and fetal pulse pressure in normal and growth-restricted fetuses. One hundred fetuses with normal development and 15 fetuses with growth restriction were analyzed. Ultrasonic raw radiofrequency signals were captured from a direction perpendicular to the vascular axis at the fetal diaphragmatic level for the difference in internal dimensions (DID), or simultaneously from different directions for the pulse wave velocity. Pulsatile movement of the proximal and distal intima of the vessels was analyzed using PT. The fetal DID exhibited no significant changes in growth restricted fetuses. Pulse wave velocity (3.8 +/- 0.32 m/s vs. 2.2 +/- 0.069 m/s, p < 0.001) and estimated pulse pressure (6.9 +/- 0.90 kPa vs. 2.5 +/- 0.18 kPa, p < 0.001) were significantly elevated in growth-restricted fetuses. Assessment of DID and pulse wave velocity of the descending aorta using PT is a feasible, non invasive approach to evaluation of fetal hemodynamics. PMID- 25727919 TI - Wavelet entropy of Doppler ultrasound blood velocity flow waveforms distinguishes nitric oxide-modulated states. AB - Wavelet entropy assesses the degree of order or disorder in signals and presents this complex information in a simple metric. Relative wavelet entropy assesses the similarity between the spectral distributions of two signals, again in a simple metric. Wavelet entropy is therefore potentially a very attractive tool for waveform analysis. The ability of this method to track the effects of pharmacologic modulation of vascular function on Doppler blood velocity waveforms was assessed. Waveforms were captured from ophthalmic arteries of 10 healthy subjects at baseline, after the administration of glyceryl trinitrate (GTN) and after two doses of N(G)-nitro-L-arginine-methyl ester (L-NAME) to produce vasodilation and vasoconstriction, respectively. Wavelet entropy had a tendency to decrease from baseline in response to GTN, but significantly increased after the administration of L-NAME (mean: 1.60 +/- 0.07 after 0.25 mg/kg and 1.72 +/- 0.13 after 0.5 mg/kg vs. 1.50 +/- 0.10 at baseline, p < 0.05). Relative wavelet entropy had a spectral distribution from increasing doses of L-NAME comparable to baseline, 0.07 +/- 0.04 and 0.08 +/- 0.03, respectively, whereas GTN had the most dissimilar spectral distribution compared with baseline (0.17 +/- 0.08, p = 0.002). Wavelet entropy can detect subtle changes in Doppler blood velocity waveform structure in response to nitric-oxide-mediated changes in arteriolar smooth muscle tone. PMID- 25727921 TI - Namibia's transition from whole blood-derived pooled platelets to single-donor apheresis platelet collections. AB - BACKGROUND: Few African countries separate blood donations into components; however, demand for platelets (PLTs) is increasing as regional capacity to treat causes of thrombocytopenia, including chemotherapy, increases. Namibia introduced single-donor apheresis PLT collections in 2007 to increase PLT availability while reducing exposure to multiple donors via pooling. This study describes the impact this transition had on PLT availability and safety in Namibia. STUDY DESIGN AND METHODS: Annual national blood collections and PLT units issued data were extracted from a database maintained by the Blood Transfusion Service of Namibia (NAMBTS). Production costs and unit prices were analyzed. RESULTS: In 2006, NAMBTS issued 771 single and pooled PLT doses from 3054 whole blood (WB) donations (drawn from 18,422 WB donations). In 2007, NAMBTS issued 486 single and pooled PLT doses from 1477 WB donations (drawn from 18,309 WB donations) and 131 single-donor PLT doses. By 2011, NAMBTS issued 837 single-donor PLT doses per year, 99.1% of all PLT units. Of 5761 WB donations from which PLTs were made in 2006 to 2011, a total of 20 (0.35%) were from donors with confirmed test results for human immunodeficiency virus or other transfusion-transmissible infections (TTIs). Of 2315 single-donor apheresis donations between 2007 and 2011, none of the 663 donors had a confirmed positive result for any pathogen. As apheresis replaced WB-derived PLTs, apheresis production costs dropped by a mean of 8.2% per year, while pooled PLT costs increased by an annual mean of 21.5%. Unit prices paid for apheresis- and WB-derived PLTs increased by 9 and 7.4% per year on average, respectively. CONCLUSION: Namibia's PLT transition shows that collections from repeat apheresis donors can reduce TTI risk and production costs. PMID- 25727920 TI - Visualizing the non-equilibrium dynamics of photoinduced intramolecular electron transfer with femtosecond X-ray pulses. AB - Ultrafast photoinduced electron transfer preceding energy equilibration still poses many experimental and conceptual challenges to the optimization of photoconversion since an atomic-scale description has so far been beyond reach. Here we combine femtosecond transient optical absorption spectroscopy with ultrafast X-ray emission spectroscopy and diffuse X-ray scattering at the SACLA facility to track the non-equilibrated electronic and structural dynamics within a bimetallic donor-acceptor complex that contains an optically dark centre. Exploiting the 100-fold increase in temporal resolution as compared with storage ring facilities, these measurements constitute the first X-ray-based visualization of a non-equilibrated intramolecular electron transfer process over large interatomic distances. Experimental and theoretical results establish that mediation through electronically excited molecular states is a key mechanistic feature. The present study demonstrates the extensive potential of femtosecond X ray techniques as diagnostics of non-adiabatic electron transfer processes in synthetic and biological systems, and some directions for future studies, are outlined. PMID- 25727923 TI - Calcium-catalyzed carboarylation of alkynes. AB - The first transition-metal-free carboarylation of alkynes with commercial and readily available alcohols as alkylating agents was realized in the presence of an environmentally benign calcium catalyst. Thereby, a novel protocol for the one step synthesis of highly congested, all-carbon tetrasubstituted alkenes, as incorporated in potentially bioactive, complex dihydronaphthalene, chromene and dihydroquinoline structures, is provided. The reaction features an unprecedented, particularly wide substrate scope, good functional-group tolerance and simple experimental operation under mild reaction conditions. PMID- 25727922 TI - Genetic Counseling in Portugal: Education, Practice and a Developing Profession. AB - Portugal is one of the European countries where genetic counseling is emerging as an independent clinical and scientific field, paralleling the international expansion of this profession. Important steps have been consistently made towards establishing safe and ethical genetic counseling, delivered by adequately trained professionals. In 1998, Clinical Genetics was recognized in Portugal as a medical specialty. Eleven years later, the first generation of Portuguese (non MD) genetic counselors started a master level training programme at the University of Porto. PMID- 25727924 TI - 'It's hard but you've just gotta get on with it'--The experiences of growing-up with a liver transplant. AB - The successful evolution of paediatric liver transplantation means that increasing numbers of young people survive into adulthood. Non-adherence to medication regimens leading to liver dysfunction, graft loss and patient death are prevalent in this vulnerable group. Insight into young people's experiences of living with a liver transplant (LTx) is vital to improve outcomes and guide future work in this area. Through semi-structured interviews, this study explored the experiences of living with a LTx for 13 young people transplanted as children and adolescents. Interviews were analysed using interpretative phenomenological analysis, revealing that young people felt different from their peers as a result of their LTx. Young people's perceptions of their scar, experiences of illness symptoms and taking medications acted as triggers of differences. This led to an ongoing struggle to be normal when faced with typical activities for young people and to attempts to take back control. Findings support the implementation of routine psychosocial screening to identify additional support needs and the development of a peer mentoring programme to allow young people to gain social support, thus reducing feelings of being different. It is hoped that such initiatives will have positive consequences for quality of life, self-management and adherence to medications. PMID- 25727925 TI - Chiral discrimination by ionic liquids: impact of ionic solutes. AB - Chiral ionic liquids hold promise in many asymmetric applications. This study explores the impact of ionic solutes on the chiral discrimination of five amino acid methyl ester-based ionic liquids, including L- and D-alanine methyl ester, L proline methyl ester, L-leucine methyl ester, and L-valine methyl ester cations combined with bis(trifluoromethanesulfonimide) anion. Circularly polarized luminescence spectroscopy was used to study the chiral discrimination by measuring the racemization equilibrium of a dissymmetric europium complex, Eu(dpa)3(3-) (where dpa = 2,6-pyridinedicarboxylate). The chiral discrimination measured was dependent on the concentration of Eu(dpa)3(3-) and this concentration-dependence was different in each of the ionic liquids. Ionic liquids with L-leucine methyl ester and L-valine methyl ester even switched enantiomeric preference based on the solute concentration. Changing the cation of the Eu(dpa)3(3-) salt from tetrabutylammonium to tetramethylammonium ion also affected the chiral discrimination demonstrated by the ionic liquids. PMID- 25727926 TI - Incidence of haemoglobinopathies in Sicily: the impact of screening and prenatal diagnosis. AB - BACKGROUND: Haemoglobinopathies are a major public health problem in Sicily: it was estimated a frequency of 1/245 couples are at risk of haemoglobinopathies. This paper reviews legislative actions, prevention activities, carrier screening, genetic counselling, foetal sampling and laboratory methodology analysis evolution reporting the results of 30 years of prevention actions to assess the efficiency of our preventative programme in the control of haemoglobinopathies in Sicily. METHODS: This programme consisted principally of five phases: legislative actions, public awareness campaign, carrier screening, genetic counselling and prenatal diagnosis. RESULTS: These programmes have been very effective, which we can see from a greater public awareness of thalassaemia and its prevention in the target population furthermore by a marked decline in the incidence of thalassaemia major and sickle cell anaemia from 1 in 245 live births in the absence of prevention to 1 in 2000, with a reduction in about 85%. The residual cases were because of a conscious choice by expecting parents in relation to improved life expectancy as well as improved quality of life of the affected patients. CONCLUSION: The study suggests that public health authorities should act and invest in a similar programme for prevention of thalassaemia, as well as in relation to the increased survival of patients and the consequent organ complications. PMID- 25727927 TI - An analysis of different therapeutic options in patients with Cushing's syndrome due to bilateral macronodular adrenal hyperplasia: a single-centre experience. AB - CONTEXT: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of Cushing's syndrome (CS). A variety of in vivo tests to identify aberrant receptor expression have been proposed to guide medical treatment. Unilateral adrenalectomy (UA) may be effective in selected patients, but little is known about recurrence during follow-up. OBJECTIVE: To describe a series of patients with BMAH and CS treated by different approaches, with a particular focus on the benefit of UA. DESIGN AND PATIENTS: We retrospectively assessed 16 patients with BMAH and CS (11 females, five males), analysing the in vivo cortisol response to different provocative tests. Twelve of the 16 patients underwent UA and were monitored over the long term. RESULTS: Based on in vivo test results, octreotide LAR or propranolol was administered in one case of food-dependent CS and two patients with a positive postural test. A significant improvement in biochemical values was seen in all patients but with limited clinical response. UA was performed in 12 patients, producing long-term remission in three (106 +/- 28 months; range: 80-135), recurrence in eight (after 54 +/- 56 months; range 12 180) and persistence in one other. Four patients subsequently underwent contralateral adrenalectomy for overt CS, one received ketoconazole, and four other patients remain under observation for subclinical CS. CONCLUSIONS: Medical treatment based on cortisol response to provocative tests had a limited role in our patients, whereas UA was useful in some of them. Although recurrence is likely, the timing of onset is variable and close follow-up is mandatory to identify it. PMID- 25727928 TI - Protective effects of Sesamum indicum extract against oxidative stress induced by vanadium on isolated rat hepatocytes. AB - Vanadium toxicity is a challenging problem to human and animal health with no entirely understanding cytotoxic mechanisms. Previous studies in vanadium toxicity showed involvement of oxidative stress in isolated liver hepatocytes and mitochondria via increasing of ROS formation, release of cytochrome c and ATP depletion after incubation with different concentrations (25-200 uM). Therefore, we aimed to investigate the protective effects of Sesamum indicum seed extract (100-300 MUg/mL) against oxidative stress induced by vanadium on isolated rat hepatocytes. Our results showed that quite similar to Alpha-tocopherol (100 uM), different concentrations of extract (100-300 MUg/mL) protected the isolated hepatocyte against all oxidative stress/cytotoxicity markers induced by vanadium in including cell lysis, ROS generation, mitochondrial membrane potential decrease and lysosomal membrane damage. Besides, vanadium induced mitochondrial/lysosomal toxic interaction and vanadium reductive activation mediated by glutathione in vanadium toxicity was significantly (P < 0.05) ameliorated by Sesamum indicum extracts. These findings suggested a hepato protective role for extracts against liver injury resulted from vanadium toxicity. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 979-985, 2016. PMID- 25727929 TI - Electrochemical functionalization of N-methyl-2-pyrrolidone-exfoliated graphene nanosheets as highly sensitive analytical platform for phenols. AB - Graphene nanosheets (GS) were easily prepared from graphite via a one-step ultrasonic exfoliation approach using N-methyl-2-pyrrolidone (NMP) as the solvent. Compared with the widely used graphene oxide (GO) obtained by multistep chemical oxidation, the NMP-exfoliated GS exhibited apparently better electrochemical activity toward the oxidation of a series of phenols like hydroquinone, catechol, 4-chlorophenol, and 4-nitrophenol. Interestingly, the electrochemical activity of GS toward these phenols can be further enhanced by simply anodizing at 1.8 V for 2 min (denoted as EGS), reflected by the apparently enlarged oxidation peak currents in voltammograms and the obviously reduced charge transfer resistance in electrochemical impedance spectra (EIS). Characterizations by techniques like X-ray photoelectron spectra (XPS), Raman spectra, and atomic force microscopy (AFM) demonstrated that the introduction of new oxygen-containing groups or edge-plane defects and the enhanced surface roughness were responsible for the enhanced activity of EGS. Thereafter, a simple electrochemical method for the highly sensitive detection of phenols was established and the detection limits were 0.012 MUM, 0.015 MUM, 0.01 MUM, and 0.04 MUM for hydroquinone, catechol, 4-chlorophenol, and 4-nitrophenol, respectively. The facile synthesis of EGS, together with its high electrochemical activity, thus created a novel platform for developing highly sensitive electrochemical sensing systems. PMID- 25727930 TI - Perceived cognitive difficulties and cognitive test performance as predictors of employment outcomes in people with multiple sclerosis. AB - Perceived cognitive difficulties and cognitive impairment are important determinants of employment in people with multiple sclerosis (pwMS). However, it is not clear how they are related to adverse work outcomes and whether the relationship is influenced by depressive symptoms. Thus, this study examined perceived and actual general cognitive and prospective memory function, and cognitive appraisal accuracy, in relation to adverse work outcomes. The possible mediating and/or moderating role of depression was also examined. A cross sectional community-based sample of 111 participants (33 males, 78 females) completed the Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ), Beck Depression Inventory - Fast Screen (BDI-FS), and questions related to their current or past employment. They then underwent cognitive testing using the Screening Examination for Cognitive Impairment, Auditory Consonant Trigrams test, Zoo Map Test, and Cambridge Prospective Memory Test. Perceived general cognitive and prospective memory difficulties in the workplace and performance on the respective cognitive tests were found to predict unemployment and reduced work hours since MS diagnosis due to MS. Depression was also related to reduced work hours, but it did not explain the relationship between perceived cognitive difficulties and the work outcomes. Nor was it related to cognitive test performance. The results highlight a need to address the perceptions of cognitive difficulties together with cognitive impairment and levels of depression in vocational rehabilitation programs in pwMS. PMID- 25727931 TI - Boosting of activity enhancement of K(+)-responsive quadruplex hammerhead ribozyme. AB - Two second-generation quadruplex hammerhead ribozymes, whose activity enhances in response to K(+)via quadruplex formation of embedded r(GGA)3GG, were developed. Different strategies were applied to suppress basal activity when K(+) is absent. As a result, the activity enhancement upon the addition of K(+) has reached as high as 21-fold. PMID- 25727932 TI - Processing of dielectric oxynitride perovskites for powders, ceramics, compacts and thin films. AB - Oxynitride perovskites, having oxide and nitride anions together in a compound, are a new class of dielectric material. The shaping process in either bulk ceramics or thin films is an essential factor for investigating and utilizing the dielectric properties of these materials. In this perspective, recent studies on the shaping of dielectric oxynitride perovskites are reviewed with a consideration of the powder preparation and thermal stability for sintering, several sintering methods, ultra-high pressure compaction, and thin-film formation. PMID- 25727933 TI - Randomized clinical trial of skin closure by subcuticular suture or skin stapling after elective colorectal cancer surgery. AB - BACKGROUND: The best suture method to prevent incisional surgical-site infection (SSI) after clean-contaminated surgery has not been clarified. METHODS: Patients undergoing elective colorectal cancer surgery at one of 16 centres were randomized to receive either subcuticular sutures or skin stapling for skin closure. The primary endpoint was the rate of incisional SSI. Secondary endpoints of interest included time required for wound closure, incidence of wound problems, postoperative length of stay, wound aesthetics and patient satisfaction. RESULTS: A total of 1264 patients were enrolled. The cumulative incidence of incisional SSI by day 30 after surgery was similar after subcuticular sutures and stapled closure (8.7 versus 9.8 per cent respectively; P = 0.576). Comparison of cumulative incidence curves revealed that SSI occurred later in the subcuticular suture group (P = 0.019) (hazard ratio 0.66, 95 per cent c.i. 0.45 to 0.97). Wound problems (P = 0.484), wound aesthetics (P = 0.182) and postoperative duration of hospital stay (P = 0.510) did not differ between the groups; subcuticular sutures took 5 min longer than staples (P < 0.001). Patients in the subcuticular suture group were significantly more satisfied with their wound (52.4 per cent versus 42.7 per cent in the staple group; P = 0.002). CONCLUSION: Compared with skin stapling, subcuticular sutures did not reduce the risk of incisional SSI after colorectal surgery. REGISTRATION NUMBER: UMIN000004001 (http://www.umin.ac.jp/ctr). PMID- 25727934 TI - Electrospinning, mechanical properties, and cell behavior study of chitosan/PVA nanofibers. AB - Electrospinning process has been widely used to produce nanofibers from polymer blends. Poly(vinyl alcohol) (PVA) and chitosan (CS) have numerous biomedical applications such as wound healing and tissue engineering. Nanofibers of CS/PVA have been prepared by many works, however, a complete physicochemical and mechanical characterization as well as cell behavior has not been reported. In this study, PVA and CS/PVA blend solutions in acetic acid 70% with different volume ratios (30/70, 50/50, and 70/30) were electrospun in constant electrospinning process parameters. The structure and morphology of nanofibrous mats were characterized by SEM, FTIR, and XRD methods. The best nanofibrous mat was achieved from the CS/PVA 30/70 blend solution regarding the electrospinning throughput. The dynamic mechanical thermal analysis (DMTA) of PVA and CS/PVA 30/70 nanofibrous mats were measured which were not considered in the previous studies. DMTA results in accordance to the DSC analysis approved the partial compatibility between the two polymers, while a single glass transition temperature was not observed for the blend. The tensile strength of PVA and CS/PVA nanofibers were also reported. Results of cell behavior study indicated that the heat stabilized nanofibrous mat CS/PVA 30/70 was able to support the attachment and proliferation of the fibroblast cells. PMID- 25727935 TI - Quantifying normal geometric variation in human pulmonary lobar geometry from high resolution computed tomography. AB - Previous studies of the ex vivo lung have suggested significant intersubject variability in lung lobe geometry. A quantitative description of normal lung lobe shape would therefore have value in improving the discrimination between normal population variability in shape and pathology. To quantify normal human lobe shape variability, a principal component analysis (PCA) was performed on high resolution computed tomography (HRCT) imaging of the lung at full inspiration. Volumetric imaging from 22 never-smoking subjects (10 female and 12 male) with normal lung function was included in the analysis. For each subject, an initial finite element mesh geometry was generated from a group of manually selected nodes that were placed at distinct anatomical locations on the lung surface. Each mesh used cubic shape functions to describe the surface curvilinearity, and the mesh was fitted to surface data for each lobe. A PCA was performed on the surface meshes for each lobe. Nine principal components (PCs) were sufficient to capture >90% of the normal variation in each of the five lobes. The analysis shows that lobe size can explain between 20% and 50% of intersubject variability, depending on the lobe considered. Diaphragm shape was the next most significant intersubject difference. When the influence of lung size difference is removed, the angle of the fissures becomes the most significant shape difference, and the variability in relative lobe size becomes important. We also show how a lobe from an independent subject can be projected onto the study population's PCs, demonstrating potential for abnormalities in lobar geometry to be defined in a quantitative manner. PMID- 25727936 TI - Biologic response modifiers and pediatric psoriasis. AB - The efficacy and safety of biologic response modifiers such as etanercept, adalimumab, infliximab, and ustekinumab have been demonstrated in the treatment of psoriasis in adults, but none are currently approved for the treatment of psoriasis in children in the United States, and only etanercept is approved for the treatment of psoriasis in children in the European Union. Through case reports, case series, and a large clinical trial of the use of etanercept, the literature supports the use of these agents to treat psoriasis in children. Data on the use of the tumor necrosis factor-alpha antagonists etanercept, adalimumab, and infliximab in the treatment of other inflammatory diseases in children-namely Crohn's disease, juvenile arthritis, and uveitis--support their safety profile in children. PMID- 25727937 TI - Bioinspired therapeutic dendrimers as efficient peptide drugs based on supramolecular interactions for tumor inhibition. AB - Bioinspired tryptophan-rich peptide dendrimers (TRPDs) are designed as a new type of dendritic peptide drugs for efficient tumor therapy. The TRPDs feature a precise molecular structure and excellent water solubility and are obtained in a facile process. Based on the unique features of peptide dendrimers, including highly branched structures, abundant terminal groups, and globular-protein-like architectures, the therapeutic dendrimers show significant supramolecular interactions with DNA through the tryptophan residues (indole rings and amino groups). Further experimental results indicate that TRPDs are efficient antitumor agents both in vitro and in vivo. PMID- 25727938 TI - Physiological and ecological performance differs in four coral taxa at a volcanic carbon dioxide seep. AB - Around volcanic carbon dioxide (CO2) seeps in Papua New Guinea, partial pressures of CO2 (pCO2) approximate those as predicted for the end of this century, and coral communities have low diversity and low structural complexity. To assess the mechanisms for such community shifts in response to ocean acidification, we examined the physiological performance of two hard corals that occur with increased or unaltered abundance at a seep site (mean pHTotal=7.8, pCO2=862 MUatm) compared to a control site (mean pHTotal=8.1, pCO2=323 MUatm), namely massive Porites spp. and Pocillopora damicornis, and two species with reduced abundance, Acropora millepora and Seriatopora hystrix. Oxygen fluxes, calcification, and skeletal densities were analyzed in corals originating from the seep and control site. Net photosynthesis rates increased considerably in Porites spp. and A. millepora and slightly in P. damicornis at increased pCO2, but remained unaltered in S. hystrix. Dark respiration rates remained constant in all corals investigated from both sites. Rates of light calcification declined in S. hystrix at high pCO2, but were unaffected by pCO2 in the other three coral taxa. Dark and net calcification rates remained unchanged in massive Porites and P. damicornis, but were drastically reduced at high pCO2 in A. millepora and S. hystrix. However, skeletal densities were similar at both seep and control sites in all coral taxa investigated. Our data suggest that the pCO2-tolerant corals were characterized by an increased ability to acclimatize to ocean acidification, e.g. by maintaining net calcification. Thus, robust corals, such as Porites spp. and P. damicornis, are more likely to persist for longer in a future high pCO2 world than those unable to acclimatize. PMID- 25727939 TI - Is national health spending on an unaffordable trajectory? PMID- 25727941 TI - Corn silk aqueous extracts and intraocular pressure of systemic and non-systemic hypertensive subjects. AB - BACKGROUND: Hypotensive properties have been attributed to the stigma/style of Zea mays L (corn silk). Although the effect of corn silk extract on blood pressure has been documented in animal studies, we are not aware of any study on its effect on human blood pressure and intraocular pressure. METHODS: A randomised study was carried out on the effect of water only, masked doses of corn silk aqueous extract (60, 130, 192.5 and 260 mg/kg body weight) on intraocular pressure and blood pressure of 20 systemic and 20 non-systemic hypertensive subjects. Intraocular pressure and blood pressure were measured at baseline and every hour for eight hours after administering water or a masked dose of corn silk aqueous extract. Each dose was administered at two-week intervals to each subject in the two study groups. RESULTS: The results showed that the last three doses of corn silk aqueous extract gave a statistically significant reduction (p < 0.001) in mean intraocular pressure and blood pressure within eight hours of administration. The peak effect on intraocular pressure was observed after four hours and this was preceded by the peak effect on blood pressure, which occurred after three hours of administration. The hypotensive effect was dose-dependent in the two groups. CONCLUSION: Corn silk aqueous extract has a lowering effect on intraocular pressure in systemic and non systemic hypertensive subjects. This may have resulted from the fall in blood pressure that is due to potassium-induced natriuresis and diuresis caused by the high potassium content in the high doses of the corn silk extract. PMID- 25727940 TI - Stretch-dependent changes in surface profiles of the human crystalline lens during accommodation: a finite element study. AB - BACKGROUND: A non-linear isotropic finite element (FE) model of a 29-year-old human crystalline lens was constructed to study the effects of various geometrical parameters on lens accommodation. METHODS: The model simulates dis accommodation by stretching of the lens and predicts the change in surface profiles of the lens capsule, cortex and nucleus at select states of stretching/accommodation. Multiple regression analysis (MRA) is used to develop a stretch-dependent mathematical model relating the lens sagittal height to the radial position of the lens surface as a function of dis-accommodative stretch. A load analysis is performed to compare the finite element results to empirical results from lens stretcher studies. Using the predicted geometrical changes, the optical response of the whole eye during accommodation was analysed by ray tracing. RESULTS: Aspects of lens shape change relative to stretch were evaluated, including change in diameter, central thickness and accommodation. Maximum accommodation achieved was 10.29 D. From the multiple regression analysis, the stretch-dependent mathematical model of the lens shape related lens curvatures as a function of lens ciliary stretch well (maximum mean-square residual error 2.5 * 10(-3 ) MUm, p < 0.001). The results are compared with those from in vitro studies. CONCLUSIONS: The finite element and ray-tracing predictions are consistent with Ex Vivo Accommodation Simulator (EVAS) studies in terms of load and power change versus change in thickness. The mathematical stretch-dependent model of accommodation presented may have utility in investigating lens behaviour at states other than the relaxed or fully accommodated states. PMID- 25727942 TI - Paradoxical response to anti-tuberculous therapy presenting as choroiditis. PMID- 25727943 TI - Re.: Is screening for congenital colour vision deficiency in school students worthwhile? PMID- 25727944 TI - Don Noack: (1933-2012): a profile of a contact lens innovator and pioneer. PMID- 25727947 TI - rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1. AB - Previous genomewide association studies identified prostate stem cell antigen (PSCA) as a gastric cancer (GC) susceptibility gene and showed an association between GC and the T allele of the single nucleotide polymorphism rs2294008 (C/T) in this gene. The protein product of this gene inhibits cell growth, and the T allele significantly suppresses the transcriptional activity of the -3.2 kb PSCA upstream region. However, the mechanism remains unknown. In this study, we conducted reporter assays using the PSCA upstream region containing the C allele and identified the region from -200 to +38 bp of the transcription initiation site of the gene as a critical region of the -3.2 kb PSCA upstream region. We found that introducing the T allele at rs2294008 generated a consensus binding sequence for the Polycomb group transcription factor Yin Yang 1 (YY1) and that disruption of the consensus sequence restored the transcriptional activity to the -3.2 kb PSCA upstream region. These findings imply that the T allele significantly suppresses PSCA expression in vivo by recruiting YY1 to its promoter, which eventually predisposes gastric epithelial cells to GC development. PMID- 25727948 TI - 'We are always in some form of contact': friendships among homeless drug and alcohol users living in hostels. AB - Homeless drug and alcohol users are one of the most marginalised groups in society. They frequently have complex needs and limited social support. In this paper, we explore the role of friendship in the lives of homeless drug and alcohol users living in hostels, using the concepts of 'social capital' and 'recovery capital' to frame the analyses. The study was undertaken in three hostels, each in a different English city, during 2013-2014. Audio recorded semi structured interviews were conducted with 30 residents (9 females; 21 males) who self-reported drink and/or drug problems; follow-up interviews were completed 4-6 weeks later with 22 participants (6 females; 16 males). Data were transcribed verbatim, coded using the software package MAXQDA, and analysed using Framework. Only 21 participants reported current friends at interview 1, and friendship networks were small and changeable. Despite this, participants desired friendships that were culturally normative. Eight categories of friend emerged from the data: family-like friends; using friends; homeless friends; childhood friends; online-only friends; drug treatment friends; work friends; and mutual interest friends. Routine and regular contact was highly valued, with family-like friends appearing to offer the most constant practical and emotional support. The use of information and communication technologies (ICTs) was central to many participants' friendships, keeping them connected to social support and recovery capital outside homelessness and substance-using worlds. We conclude that those working with homeless drug and alcohol users - and potentially other marginalised populations - could beneficially encourage their clients to identify and build upon their most positive and reliable relationships. Additionally, they might explore ways of promoting the use of ICTs to combat loneliness and isolation. Texting, emailing, online mutual aid meetings, chatrooms, Internet penpals, skyping and other social media all offer potentially valuable opportunities for building friendships that can bolster otherwise limited social and recovery capital. PMID- 25727949 TI - The Kaiser Permanente shoulder arthroplasty registry: results from 6,336 primary shoulder arthroplasties. AB - BACKGROUND AND PURPOSE: Shoulder arthroplasty is being performed in the United States with increasing frequency. We describe the medium-term findings from a large integrated healthcare system shoulder arthroplasty registry. PATIENTS AND METHODS: Shoulder arthroplasty cases registered between January 2005 and June 2013 were included for analysis. The registry included patient characteristics, surgical information, implant data, attrition, and patient outcomes such as surgical site infections, venous thromboembolism, and revision procedures. RESULTS: During the study period, 6,336 primary cases were registered. Median follow-up time for all primaries was 3.3 years; 461 cases were lost to follow-up by ending of health plan membership. Primary cases were predominantly female (56%) and white (81%), with an average age of 70 years. The most common reason for surgery was osteoarthritis in 60% of cases, followed by acute fracture (17%) and rotator cuff tear arthropathy (15%). In elective shoulder arthroplasty procedures, 200 all-cause revisions (4%) were reported, with glenoid wear being the most common reason. INTERPRETATION: Most arthroplasties were elective procedures: over half performed for osteoarthritis. Glenoid wear was the most common reason for revision of primary shoulder arthroplasty in elective cases. PMID- 25727950 TI - Human herpes virus reactivations and dynamic cytokine profiles in patients with cutaneous adverse drug reactions --a prospective comparative study. AB - BACKGROUND: Sequential human herpes virus (HHV) reactivation is well known in drug reaction with eosinophilia and systemic symptom (DRESS), but such a phenomenon has seldom studied in other types of cutaneous adverse drug reactions (cADRs). Moreover, the association between viral reactivations and cytokine or chemokine changes is largely unknown. We aimed to evaluate the viral reactivation rates of HHV-6, HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in different cADRs and their impacts on clinical prognosis. Cytokine and chemokine changes with viral reactivations were also examined. METHODS: A prospective study was conducted to monitor the viral statuses of patients with different cADRs by polymerase chain reaction and serum-specific antibody titers. Changes in plasma cytokine and chemokine levels were also evaluated by sequential blood samples. RESULTS: Among the various cADRs, HHV-6 reactivation was only observed in DRESS, but EBV and CMV could be detected in other cADRs. Many proinflammatory cytokines and chemokines, including interleukin (IL)-1beta, IL-2, IL-6, interferon-gamma, tumor necrosis factor-alpha, were significantly lower in DRESS patients with HHV 6 reactivation when compared to those without HHV-6 reactivation. In addition, these mediators were significantly lower before and during HHV-6 reactivation, compared to cytokine levels after HHV-6 reactivation in the same patient. CONCLUSION: HHV-6 reactivation was only observed in DRESS patients, not in any other cADR. In DRESS patients, some proinflammatory cytokines were significantly lower before or during HHV-6 reactivation. PMID- 25727952 TI - Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease. AB - Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders. PMID- 25727951 TI - Exposing the subunit diversity and modularity of protein complexes by structural mass spectrometry approaches. AB - Although the number of protein-encoding genes in the human genome is only about 20 000 not far from the amount found in the nematode worm genome, the number of proteins that are translated from these sequences is larger by several orders of magnitude. A number of mechanisms have evolved to enable this diversity. For example, genes can be alternatively spliced to create multiple transcripts; they may also be translated from different alternative initiation sites. After translation, hundreds of chemical modifications can be introduced in proteins, altering their chemical properties, folding, stability, and activity. The complexity is then further enhanced by the various combinations that are generated from the assembly of different subunit variants into protein complexes. This, in turn, confers structural and functional flexibility, and endows the cell with the ability to adapt to various environmental conditions. Therefore, exposing the variability of protein complexes is an important step toward understanding their biological functions. Revealing this enormous diversity, however, is not a simple task. In this review, we will focus on the array of MS based strategies that are capable of performing this mission. We will also discuss the challenges that lie ahead, and the future directions toward which the field might be heading. PMID- 25727953 TI - Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia. AB - The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 +/- 1.35 l and 23.19 +/- 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 MUg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR >= 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem. PMID- 25727954 TI - Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus. AB - A hybrid pharmacokinetic/pharmacodynamic (PK/PD) model with extended-release (ER) process and target mediated drug disposition (TMDD) was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R)-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM) were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PK profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol. PMID- 25727955 TI - Myeloid HIF-1 attenuates the progression of renal fibrosis in murine obstructive nephropathy. AB - Hypoxia-inducible factors (HIFs) play an important role in the pathogenesis of renal fibrosis. Although the role of macrophage infiltration in the progression of renal fibrosis is well known, the role of macrophage HIF-1 remains to be revealed. To address this question, myeloid specific conditional HIF-1 knock out mice were subjected to unilateral ureteral obstruction (UUO). Renal interstitial deposition of collagen III and mRNA expressions of collagen I and collagen III were markedly increased at 7 days after UUO and myeloid HIF-1 depletion significantly accelerated these increases. Immunohistochemistry and flow cytometric analysis revealed that renal infiltrating macrophages were increased with duration of UUO but myeloid HIF-1 depletion did not affect these changes. Myeloid HIF-1 depletion did not affect M1 and M2 macrophage phenotype polarization in obstructed kidneys. Renal connective tissue growth factor (CTGF) expression was markedly increased and myeloid HIF-1 depletion further enhanced this increase. Immunomagnetic separation of renal cells revealed that renal CTGF was expressed predominantly in renal cells other than macrophages. It is suggested that myeloid HIF-1 attenuates the progression of renal fibrosis in murine obstructive kidney. Alteration of CTGF expression in renal cells other than macrophages is one of possible mechanisms by which myeloid HIF-1 protected renal fibrosis. PMID- 25727956 TI - Interaction of rocuronium with human liver cytochromes P450. AB - Rocuronium is a neuromuscular blocking agent acting as a competitive antagonist of acetylcholine. Results of an inhibition of eight individual liver microsomal cytochromes P450 (CYP) are presented. As the patients are routinely premedicated with diazepam, possible interaction of diazepam with rocuronium has been also studied. Results indicated that rocuronium interacts with human liver microsomal CYPs by binding to the substrate site. Next, concentration dependent inhibition of liver microsomal CYP3A4 down to 42% (at rocuronium concentration 189 MUM) was found. This effect has been confirmed with two CYP3A4 substrates, testosterone (formation of 6beta-hydroxytestosterone) and diazepam (temazepam formation). CYP2C9 and CYP2C19 activities were inhibited down to 75-80% (at the same rocuronium concentration). Activities of other microsomal CYPs have not been inhibited by rocuronium. To prove the possibility of rocuronium interaction with other drugs (diazepam), the effect of rocuronium on formation of main diazepam metabolites, temazepam (by CYP3A4) and desmethyldiazepam, (also known as nordiazepam; formed by CYP2C19) in primary culture of human hepatocytes has been examined. Rocuronium has caused inhibition of both reactions by 20 and 15%, respectively. The results open a possibility that interactions of rocuronium with drugs metabolized by CYP3A4 (and possibly also CYP2C19) may be observed. PMID- 25727957 TI - Salinomycin causes dedifferentiation via the extracellular signal-regulated kinase (ERK) pathway in rabbit articular chondrocytes. AB - Salinomycin (SAL), a monocarboxylic polyether antibiotic isolated from Streptomyces albus, modulates various cellular responses, including proliferation, apoptosis, and inflammation. However, the effect of SAL on the dedifferentiation of chondrocytes remains unclear. Thus, we investigated the effects and regulatory mechanisms of SAL on the dedifferentiation of rabbit articular chondrocytes. Our results indicate that SAL-induced a loss of type II collagen and decreased sulfated proteoglycan levels in a dose- and time-dependent manner, as assessed by western blot analysis and alcian blue staining. Consistent with dedifferentiation, we found that type II collagen expression was decreased and type I collagen and SOX-9 expression was increased using RT-PCR. Immunohistochemical and immunofluorescence staining also indicated dedifferentiation of chondrocytes. SAL treatment activated the mitogen-activated protein (MAP) kinase signaling pathway. Among the MAP kinases, extracellular signal-regulated kinase (ERK) was phosphorylated and translocated into the nucleus from the cytosol following SAL treatment. Inhibition of ERK with PD98059 (PD) rescued the SAL-induced decrease in type II collagen, increase in type I collagen, and reduction in sulfated proteoglycan. Our findings suggest that SAL induces dedifferentiation via the ERK pathway in rabbit articular chondrocytes. PMID- 25727959 TI - Impaired retinal vasodilator response to acetylcholine in a rat model of NMDA induced retinal degeneration. AB - Previous studies have shown that degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity, but it is unclear whether vasodilatory mechanisms are altered in retinal blood vessels. The purpose of the present study was to determine whether retinal vasodilator responses are affected in a rat model of NMDA-induced retinal damage. At 14 days after a single intravitreal injection of NMDA (200 nmol), retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in fundus images. Acetylcholine-induced vasodilation of retinal arterioles was significantly reduced in NMDA-treated retinas, whereas retinal vasodilatory effects of the nitric oxide (NO) donor NOR3, the beta2-adrenoceptor agonist salbutamol, and the beta3-adrenoceptor agonist CL316243 were unaltered. The vasodilator response to acetylcholine observed under the combined blockade of NO synthase and cyclooxygenase with N(G)-nitro-L-arginine methyl ester (30 mg/kg, i.v.) plus indomethacin (5 mg/kg, i.v.), possibly an endothelium-derived hyperpolarizing factor-mediated response, was also reduced. These results suggest that endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired in the rat model of NMDA-induced retinal degeneration. Glutamate-induced neurotoxicity is implicated in several retinal diseases; therefore, abnormal retinal circulation would contribute to the progression of the diseases. PMID- 25727958 TI - Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways. AB - Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury. PMID- 25727960 TI - Effect of caffeine contained in a cup of coffee on microvascular function in healthy subjects. AB - Recent epidemiological studies have demonstrated that coffee drinking is associated with reduced mortality of cardiovascular disease. However, its precise mechanisms remain to be clarified. In this study, we examined whether single ingestion of caffeine contained in a cup of coffee improves microvascular function in healthy subjects. A double-blind, placebo-controlled, crossover study was performed in 27 healthy volunteers. A cup of either caffeinated or decaffeinated coffee was drunk by the subjects, and reactive hyperemia of finger blood flow was assessed by laser Doppler flowmetry. In an interval of more than 2 days, the same experimental protocol was repeated with another coffee in a crossover manner. Caffeinated coffee intake slightly but significantly elevated blood pressure and decreased finger blood flow as compared with decaffeinated coffee intake. There was no significant difference in heart rate between caffeinated and decaffeinated coffee intake. Importantly, caffeinated coffee intake significantly enhanced post-occlusive reactive hyperemia of finger blood flow, an index of microvascular endothelial function, compared with decaffeinated coffee intake. These results provide the first evidence that caffeine contained in a cup of coffee enhances microvascular function in healthy individuals. PMID- 25727961 TI - Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice. AB - Cav3.2 T-type Ca(2+) channels targeted by H2S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Cav3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc-l-carnosine), a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-gamma-lyase, an H2S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30-100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc. PMID- 25727962 TI - Effects of L-tryptophan on gastric emptying evaluated by breath test in relation to gastric accommodation evaluated by Barostat in rats. AB - Gastric emptying has been known to correlate the pyloric sphincter contractile function and distention-induced gastric relaxation (gastric accommodation). In the present study, the effects of L-tryptophan on the gastric emptying and accommodation were evaluated by breath test using [1-(13)C]acetic acid and Barostat study, respectively, in rats. L-Tryptophan significantly decreased Cmax and AUC120min and delayed Tmax, indicating the inhibition of gastric emptying. L Tryptophan significantly enhanced the gastric accommodation. These findings show that L-tryptophan may inhibit the gastric emptying through the enhanced gastric accommodation. Therefore, L-tryptophan may be useful for the therapy of postprandial dyspepsia, especially for early satiety. PMID- 25727963 TI - Role of the 5-HT1A autoreceptor in the enhancement of fluvoxamine-induced increases in prefrontal dopamine release by adrenalectomy/castration in mice. AB - We have found that fluvoxamine-induced increases in prefrontal dopamine release are enhanced by adrenalectomy/castration and 5-HT1A receptors are involved in the enhancement. This study examined which 5-HT1A autoreceptors or postsynaptic receptor play a key role in the enhancement in mice. Adrenalectomy/castration induced enhancement of fluvoxamine-induced increase in the dopamine release was not blocked by local perfusion with the 5-HT1A receptor antagonist WAY100635 (10 MUM), while it was blocked by systemic administration of WAY100635 at low dose (0.1 mg/kg) which blocked preferentially autoreceptor-mediated responses. These finding suggests that 5-HT1A autoreceptors play a key role in the enhancement of prefrontal dopamine release. PMID- 25727964 TI - Protective effect of Euphorbia hirta and its components against snake venom induced lethality. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Despite the use of snake anti-venom therapy, herbal medicine is still in practice to treat snakebites. Euphorbia hirta is traditionally used as antidote for snakebites and also for numerous other ailments. However, the scientific evidence for its anti-snake venom property is still lacking. MATERIALS AND METHODS: Methanolic extract of E. hirta was evaluated for anti-venom activity under in vitro and ex vivo conditions. Histopathological changes in the vital organs of the mice were also monitored. UHPLC-SRM/MS was used to estimate the phenolic constituents whereas GC-MS analysis was performed to analyze the volatile metabolites present. The major compound was further evaluated for its contribution to the overall inhibitory potential of the extract. RESULTS: Methanolic extract of E. hirta completely inhibited the venom enzymes under in vitro and reduced the edema ratio. The extract increased the survival time (>24h) of mice which was further evidenced by histopathological analysis of vital organs. Phytochemical analysis revealed higher content of phenolic (144 mg/g extract) compounds in the extract. UHPLC SRM/MS demonstrated that ellagic acid, gallic acid and quinic acid are the major phenolics whereas GC-MS analysis revealed pyrogallol as the major constituent (60.07%) among the volatile components of the extract. It was also shown that pyrogallol has the ability to differentially inhibit venom protease but not phospholipase A2. CONCLUSION: The present study confirmed that E. hirta methanolic extract was able to completely inhibit Naja naja venom induced toxicity under in vitro as well as ex vivo conditions, thus providing scientific evidence to its traditional use. PMID- 25727965 TI - Molecular typing of Sporothrix schenckii isolates from cats in Malaysia. AB - Epidemiological data on the aetiologic agents of feline sporotrichosis in Malaysia have not been reported, though human sporotrichosis in Malaysia is reported to be transmitted primarily via cat scratch. To the best of our knowledge, the present report is the first study of the molecular epidemiology of Sporothrix schenckii isolates from cats with sporotrichosis in Malaysia. In the present work, we characterised 18 clinical isolates from cats in Malaysia based on molecular properties, including sequence analyses of the calmodulin gene and the rDNA ITS region and selective PCR of mating type (MAT) loci. In this study, isolates from feline sporotrichosis were identified as a S. schenckii sensu stricto by sequence analyses of the calmodulin gene and the internal transcribed spacer (ITS) region. Notably, phylogenetic analysis of the ITS confirmed assignment to clinical clade D (and not C) of S. schenckii sensu stricto. Therefore, clinical clade D of S. schenckii sensu stricto appeared to be the prevailing source of feline sporotrichosis in Malaysia. The ratio of MAT1-1 1:MAT1-2-1 in these Malaysian isolates was found to be 1 : 0. This result suggested that a clonal strain of S. schenckii is the prevailing causative agent of feline sporotrichosis in Malaysia. PMID- 25727966 TI - Dietary unsaturated fatty acids differently affect catecholamine handling by adrenal chromaffin cells. AB - Catecholamines (CA) play an important role in cardiovascular (CDV) disease risk. Namely, noradrenaline (NA) levels positively correlate whereas adrenaline (AD) levels negatively correlate with obesity and/or CDV disease. Western diets, which are tipically rich in Omega-6 fatty acids (FAs) and deficient in Omega-3 FAs, may contribute to the development of obesity, type 2 diabetes and/or coronary artery disease. Taking this into consideration and the fact that our group has already described that saturated FAs affect catecholamine handling by adrenal chromaffin cells, this work aimed to investigate the effect of unsaturated FAs upon catecholamine handling in the same model. Our results showed that chronic exposure to unsaturated FAs differently modulated CA cellular content and release, regardless of both FA series and number of carbon atoms. Namely, the Omega-6 arachidonic and linoleic acids, based on their effect on CA release and cellular content, seemed to impair NA and AD vesicular transport, whereas gamma linolenic acid selectively impaired AD synthesis and release. Within the Omega-9 FAs, oleic acid was devoid of effect, and elaidic acid behaved similarly to gamma linolenic acid. Eicosapentaenoic and docosahexaenoic acids (Omega-3 series) impaired the synthesis and release of both NA and AD. These results deserve attention and future development, namely, in what concerns the mechanisms involved and correlative effects in vivo. PMID- 25727967 TI - Do all patients with idiopathic pulmonary fibrosis warrant a trial of therapeutic intervention? A pro-con perspective. AB - Idiopathic pulmonary fibrosis (IPF) is an incurable condition that is characterized by progressive pulmonary fibrosis, architectural distortion of the lung and loss of gas exchange units. Until recently, there was no effective treatment for this condition. However, there were two landmark trials published earlier this year, which have changed the management of this condition. Pirfenidone (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis trial) and nintedanib (Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis-1 and -2 trials) have both demonstrated positive outcomes in patients with IPF. In this perspective, we critically discuss the role of these agents in IPF and in the broader pulmonary fibrosis population. PMID- 25727969 TI - Mitogen-activated protein kinases MpkA and MpkB independently affect micafungin sensitivity in Aspergillus nidulans. AB - The transcriptional regulation of the MAPK mpkA and cell wall-related genes in Aspergillus nidulans differs from that of their counterparts in Saccharomyces cerevisiae. The A. nidulans MAPK MpkB is putatively orthologous to the yeast MAPKs Kss1p and Fus3p. To investigate MpkB and its contribution to cell wall integrity in A. nidulans, we constructed mpkB-disruptant (mpkB?) strains. We previously showed that mpkA? strains exhibited reduced colony growth and increased sensitivity to the beta-1,3-glucan synthase inhibitor micafungin. Like mpkA? strains, mpkB? strains exhibited slight growth retardation and increased sensitivity to micafungin. Although MpkB-dependent signaling modulated the transcription of some cell wall-related genes, the sugar composition of cell wall fractions was similar among wild-type, mpkA?, and mpkB? strains. To elucidate the relationship between MpkA and MpkB pathways, we compared conditional mutants of mpkB with those with mpkA deletion. Sensitivity testing suggested that MpkA and MpkB additively contribute to micafungin activity in A. nidulans. PMID- 25727968 TI - TAF4b is required for mouse spermatogonial stem cell development. AB - Long-term mammalian spermatogenesis requires proper development of spermatogonial stem cells (SSCs) that replenish the testis with germ cell progenitors during adult life. TAF4b is a gonadal-enriched component of the general transcription factor complex, TFIID, which is required for the maintenance of spermatogenesis in the mouse. Successful germ cell transplantation assays into adult TAF4b deficient host testes suggested that TAF4b performs an essential germ cell autonomous function in SSC establishment and/or maintenance. To elucidate the SSC function of TAF4b, we characterized the initial gonocyte pool and rounds of spermatogenic differentiation in the context of the Taf4b-deficient mouse testis. Here, we demonstrate a significant reduction in the late embryonic gonocyte pool and a deficient expansion of this pool soon after birth. Resulting from this reduction of germ cell progenitors is a developmental delay in meiosis initiation, as compared to age-matched controls. While GFRalpha1+ spermatogonia are appropriately present as Asingle and Apaired in wild-type testes, TAF4b deficient testes display an increased proportion of long and clustered chains of GFRalpha1+ cells. In the absence of TAF4b, seminiferous tubules in the adult testis either lack germ cells altogether or are found to have missing generations of spermatogenic progenitor cells. Together these data indicate that TAF4b deficient spermatogenic progenitor cells display a tendency for differentiation at the expense of self-renewal and a renewing pool of SSCs fail to establish during the critical window of SSC development. PMID- 25727974 TI - Assessing research activity and capacity of community-based organizations: development and pilot testing of an instrument. AB - BACKGROUND: Although awareness of the importance of the research capacity of community-based organizations (CBOs) is growing, a uniform framework of the research capacity domains within CBOs has not yet been developed. OBJECTIVES: To develop a framework and instrument (the Community REsearch Activity assessment Tool [CREAT]) for assessing the research activity and capacity of CBOs that incorporates awareness of the different data collection and analysis priorities of CBOs. METHODS: We conducted a review of existing tools for assessing research capacity to identify key capacity domains. Instrument items were developed through an iterative process with CBO representatives and community researchers. The CREAT was then pilot tested with 30 CBOs. RESULTS: The four primary domains of the CREAT framework include 1) organizational support for research, 2) generalizable experiences, 3) research specific experiences, and 4) funding. Organizations reported a high prevalence of activities in the research-specific experiences domain, including conducting literature reviews (70%), use of research terminology (83%), and primary data collection (100%). Respondents see research findings as important to improve program and service delivery, and to seek funds for new programs and services. Funders, board members, and policymakers are the most important dissemination audiences. CONCLUSION: The work reported herein advances the field of CBO research capacity by developing a systematic framework for assessing research activity and capacity relevant to the work of CBOs, and by developing and piloting an instrument to assess activity in these domains. PMID- 25727975 TI - Community health screenings can complement public health outreach to minority immigrant communities. AB - OBJECTIVES: We sought to provide culturally competent, community-based respiratory health screening and education in minority communities with high concentrations of Latino immigrants on Long Island and to assess the impact of this intervention on their decision to seek medical care. METHODS: Seven health care screenings were performed in communities with high concentrations of immigrants from Latin America. A subgroup of participants who identified themselves as Hispanic/Latino were analyzed. After completion of a respiratory health questionnaire and spirometry, screening scores were calculated, education provided, and recommendations were made for medical evaluation in those who screened positive. A positive screen was defined as abnormal respiratory symptoms, abnormal spirometry, or both. Follow-up contacts were made at 1, 6, and 12 months to assess compliance with the recommendation to seek care in those who screened positive. RESULTS: High positive screening rates for both men (64%) and women (61%) were found. Of the participants who screened positive and were advised to seek medical care, 52% did so. Compliance with the recommendation to seek care was associated with the presence of an identified medical provider at baseline. Of those who screened positive and who did not comply with team's recommendation, 75% were unable to identify a health care provider. CONCLUSIONS: A significant number of participants who screened positive could not identify a health care provider and did not follow-up with the recommendation to seek medical evaluation. Community-based screenings provide an opportunity to access at-risk immigrant populations for health screening and education, and to facilitate referral and access to medical services. PMID- 25727977 TI - Using community-based participatory research to assess the asthma needs of Vietnamese American children. AB - BACKGROUND: Very little is known about the burden of asthma in Vietnamese American children. Prior data have suggested that the burden of childhood asthma is significant for this population, although they seem to underutilize Western healthcare for unclear reasons. OBJECTIVES: To gain insight into the perceptions of the burden, health needs, and traditional health beliefs regarding childhood asthma in the Vietnamese American community in Orange County, CA. Additionally, to foster and build sustainable relationships with the community and to ensure that our research process is mutually rewarding for all stakeholders. METHODS: Using a community-based participatory research (CBPR) approach, we initiated the formation of the Vietnamese Children's Asthma Project (VCAP) and used focus groups of various community stakeholders as a platform to gather information, give basic asthma education, and build relationships. RESULTS: A total of 66 people participated in the focus groups: 26 parents, 20 Vietnamese American physicians, 12 school nurses, and 8 school-community liaisons (SCLs). Overall, all participants believe that asthma is a significant problem and that language is a barrier to healthcare access for the Vietnamese community. We learned that academic achievement is a high priority for Vietnamese parents and associating better asthma control with improved academic performance may be a way to improve asthma education and adherence with therapy. We also found that although healthcare providers believe that parental traditional beliefs contribute to non adherence to Western therapies, Vietnamese American parents report that they prefer to use Western medications to treat their children's asthma. CONCLUSIONS: Through the use of CBPR and the development of VCAP, we successfully conducted focus groups to assess the Vietnamese American perception of the burden of childhood asthma in their community and to gauge their receptivity to participate in further studies about childhood asthma and receptivity to subsequent interventions. PMID- 25727976 TI - Perceived sources of stress and resilience in men in an African American community. AB - BACKGROUND: Little is known about the perceived causes of stress and what strategies African American men use to promote resiliency. Participatory research approaches are recommended as an approach to engage minority communities. A key goal of participatory research is to shift the locus of control to community partners. OBJECTIVE: To understand perceived sources of stress and tools used to promote resiliency in African American men in South Los Angeles. METHODS: Our study utilized a community-partnered participatory research approach to collect and analyze open-ended responses from 295 African American men recruited at a local, cultural festival in Los Angeles using thematic analysis and the Levels of Racism framework. RESULTS: Almost all men (93.2%) reported stress. Of those reporting stress, 60.8% reported finances and money and 43.2% reported racism as a specific cause. More than 60% (63.4%) reported that they perceived available sources of help to deal with stress. Of those noting a specific source of help for stress (n = 76), 42.1% identified religious faith. Almost all of participants (92.1%) mentioned specific sources of resiliency such as religion and family. CONCLUSIONS: Stress owing to psychosocial factors such as finances and racism are common among African American men. But, at the same time, most men found support for resiliency to ameliorate stress in religion and family. Future work to engage African American men around alleviating stress and supporting resiliency should both take into account the perceived causes of stress and incorporate culturally appropriate sources of resiliency support. PMID- 25727978 TI - Working through bound liberation: a community engagement framework for health partnerships. AB - BACKGROUND: A community-academic partnership was developed to implement a community-based participatory research project within Chicago's Englewood community. OBJECTIVES: We explain how Mental Health Impact Assessment (MHIA) ensures that mental health and health inequities are considered in decision making by using a systematic process that engages populations most likely to be impacted by those decisions. METHODS: We report on the process of developing an MHIA by engaging community partners to evaluate and predict potential mental health outcomes of an employment policy. LESSONS LEARNED: We describe the principle of working through bound liberation, resulting in a bidirectional engagement between academics and community partners. We highlight lessons and challenges of our engagement process. CONCLUSIONS: Effectively joining in solidarity with community partners was critical for project success, but community capacity needs to be increased to support future projects. PMID- 25727979 TI - A community partnered-participatory research approach to reduce cancer disparities in South Los Angeles. AB - BACKGROUND: Community-academic partnerships may offer opportunities to improve population health in communities that suffer from cancer-related health disparities. OBJECTIVES: This project describes a community partnered effort to promote cancer research and reduce local cancer-related disparities. METHODS: We used a community-partnered participatory research (CPPR) model and modified Delphi method approach to bring together community and academic stakeholders from South Los Angeles around reducing cancer disparities. RESULTS: The 36-member Community-Academic Council consisted of cancer survivors, academics, and representatives of local community-based organizations and churches. Forty-nine unique cancer-related community priorities were collaboratively used to develop shared products. Early CPPR products included convening of a community conference, a collaboratively developed survey instrument, and new partnerships resulting in externally funded projects. CONCLUSIONS: Our approach demonstrates the feasibility of the use of a replicable model of community and academic engagement that has resulted in products developed through collaborative efforts. PMID- 25727980 TI - Storytelling in community intervention research: lessons learned from the walk your heart to health intervention. AB - BACKGROUND: Contextually and culturally congruent interventions are urgently needed to reduce racial, ethnic, and socioeconomic inequities in physical activity and cardiovascular disease. OBJECTIVES: To examine a community-based participatory research (CBPR) process that incorporated storytelling into a physical activity intervention, and consider implications for reducing health inequities. METHODS: We used a CBPR process to incorporate storytelling in an existing walking group intervention. Stories conveyed social support and problem solving intervention themes designed to maintain increases in physical activity over time, and were adapted to the walking group context, group dynamics, challenges, and traditions. LESSONS LEARNED: After describing of the CBPR process used to adapt stories to walking group sites, we discuss challenges and lessons learned regarding the adaptation and implementation of stories to convey key intervention themes. CONCLUSIONS: A CBPR approach to incorporating storytelling to convey intervention themes offers an innovative and flexible strategy to promote health toward the elimination of health inequities. PMID- 25727982 TI - Building research capacity on the rez: an interinstitution collaborative effort. AB - BACKGROUND: The Little Priest Tribal College (LPTC) and the College of Public Health at University of Nebraska Medical Center (COPH-UNMC) partnered to develop a 3-credit hour course, "Indigenous Research METHODS." OBJECTIVES: The objectives were to increase LPTC students' understanding of research methods, awareness of urban and tribal health issues affecting American Indian communities, and create a pipeline program to increase diversity of the health-related workforce by expanding health career options for tribal college students. METHODS: The course was co-led by an LPTC and a COPHUNMC instructor with guest lectures by COPH-UNMC faculty using distance education and on-site presentations. RESULTS: Eight out of 10 students completed the course that was well received by both institutions. This mode information transfer and pedagogical exchange between minority serving institutions and an academic health center, geared toward enhancement of undergraduate curriculum, can be replicated in other contexts. PMID- 25727983 TI - A campus-community partnership for farmworkers' health: interventions for tomato workers in Tennessee. AB - BACKGROUND: Migrant farm workers are exposed to job hazards in Tennessee, which is among the top five tomato-producing states. OBJECTIVES: This project sought to cultivate and evaluate a partnership to marshal greater resources to address migrants' concerns and to better prepare future health professionals to address occupational issues. METHODS: In the spring of 2008, an interprofessional student faculty team at a regional university catalyzed a partnership with a clinic for migrants and a national network caring for the itinerant underserved. RESULTS: Several community-based participatory research (CBPR) activities are underway. The partnership has resulted in the following projects: Use of the Rapid Entire Body Assessment (REBA) method to identify job tasks likely to be injurious, development and use of a health screening questionnaire to capture more information about occupational health, and continuing education seminars for providers and a case-based curriculum module for third-year medical students. CONCLUSIONS: Interprofessional service learning about migrant occupational health issues may have its greatest impact as participating students enter the regional workforce, caring for patients employed in slow-to-change agricultural operations. PMID- 25727985 TI - Engaging the for-profit sector in community-based participatory research: lessons from the ground. AB - BACKGROUND: Principles of community engagement articulated by leading governmental public health and research organizations are widely accepted. Academics seeking to partner effectively with communities have a variety of guidelines to access, and resources to assist community-based organizations (CBOs) exist. However, experiences related to inclusion of nontraditional partners from the for-profit private industry sector, utilizing participatory approaches, are not documented. OBJECTIVES: This paper describes the perspective of community and academic participants on partnership development with a for profit environmental engineering firm. Challenges related to building a transdisciplinary, crosssector partnership are highlighted. METHODS: Results are reported using the National Institute for Environmental Health Sciences Partnerships for Environmental Public Health (PEPH) evaluation manual. Five activities pursued in early phases of research are described. CONCLUSIONS: Community members and scholars recognize that complex public health problems warrant transdisciplinary and cross-sector effort. Efforts to build CBPR partnerships with for-profit industry may benefit from a stepwise approach. PMID- 25727984 TI - Curriculum development to increase minority research literacy for HIV prevention research: a CBPR approach. AB - BACKGROUND: Minority engagement in HIV prevention research can improve the process and products of research. Using community-based participatory research (CBPR) to develop capacity-building tools can promote community awareness of HIV prevention, clinical research, and community roles in research. OBJECTIVES: We sought to describe a CBPR approach to curriculum development to increase HIV prevention research literacy among Blacks ages 18 to 30. METHODS: Community members and researchers documented the iterative and participatory nature of curriculum development and lessons learned.Results/Lessons Learned: We used specific strategies to support and verify multi-stakeholder engagement, team building, capacity building, and shared decision making. Objective or formal assessments of baseline capacity, ongoing stakeholder engagement, and reinforcing the value of multiple perspectives can promote further equity in curriculum development between researchers and community members. CONCLUSIONS: The iterative process of shared discussion, development, and consensus building strengthened collaboration between stakeholder groups and produced a stronger, more culturally appropriate curriculum to promote HIV prevention research engagement among young Blacks. PMID- 25727986 TI - A community partnership to respond to an outbreak: a model that can be replicated for future events. AB - THE PROBLEM: Nassau County Department of Health (NCDOH) found itself in the midst of the initial U.S. outbreak of the H1N1 influenza global pandemic. A coordinated, collaborative approach to address the outbreak was needed. Yet, a description of a multisector community partnership during an influenza pandemic has not been described in the literature. PURPOSE: This article reports the efforts taken by a local health department to partner with the community utilizing a three-phase model to communicate, plan, and implement a strategy to ease the fear that existed and to minimize the illness in the region. This article describes in detail critical components of the community wide partnership. Lessons learned from this event are highlighted which have implications for future public health policy. KEY POINTS: The key points to the article are that there are three critical phases to successful community partnership during an influenza outbreak: Communication, planning, and implementation. The learning points include that communication is paramount, creation of partnerships is vital to a successful implementation phase, and public health funds are leveraged more effectively by collaborating with community partners. CONCLUSION: The NCDOH's multisector partnership with hospitals, physicians, and community organizations to address the H1N1influenza pandemic was nontraditional and allowed for leveraging of public health resources. The three-phase model can be replicated for future infectious disease outbreaks. PMID- 25727987 TI - The National Cambodian American Town Hall Meeting: a community dialogue on "eat, walk, sleep" for health. AB - BACKGROUND: The 2009 National Cambodian American Town Hall Meeting was a public private partnership convened to address long-term health issues related the Cambodian holocaust. Goals for participants were to dispel myths about diabetes; goals for the partnership were to build research capacity and to strengthen relationships. METHODS: Partners collaborated on all aspects of the meeting which was held in Khmer by bridged videoconferencing in 10 sites and webinar at 5 sites across the United States over a 3-hour period. EAT, WALK, SLEEP for Health (EWS), the National Cambodian American Diabetes Project program, provided the framework for the meeting. RESULTS: Pre and post surveys were completed by 323 participants. Modest improvements were seen in participants' belief that they could improve their own and their community's health, although significant barriers remained. Participants and community partners evaluated the meeting positively. CONCLUSIONS: The meeting is a model for other populations, and results inform future work. PMID- 25727988 TI - Community engagement in health status instrument development: experience with the HIV disability questionnaire. AB - BACKGROUND: People with HIV face a variety of health-related challenges from HIV, concurrent health conditions, and side effects of treatment. These health-related challenges may be termed disability. Community involvement in conceptualizing and understanding disability is essential to developing appropriate measurement tools. OBJECTIVE: To describe a community-academic partnership in the development of a new self-administered health status instrument, the HIV Disability Questionnaire (HDQ), using a community-engaged approach. METHODS: With a Community Advisory Committee, we used categories from the Episodic Disability Framework, a conceptual framework developed in an earlier stage of research, as a foundation for item generation. RESULTS: The purpose of the 70-item HDQ is to characterize the presence, severity, and episodic nature of disability experienced by adults with HIV. The Community Advisory Committee suggested items beyond those in the Episodic Disability Framework, refined item phrasing, order, response options, and questionnaire instructions to enhance feasibility and relevance of the HDQ to adults with HIV, advised on how to structure the questionnaire to capture the episodic nature of disability, and suggested next steps for testing and implementation. CONCLUSIONS: The HDQ is the first HIV specific questionnaire to describe disability experienced by adults with HIV. Engaging community research partners in the development of the HDQ enhanced the questionnaire's relevance, feasibility, and face and content validities. This approach may be considered by others interested in health status instrument development. PMID- 25727989 TI - A method for achieving reciprocity of funding in community-based participatory research. AB - BACKGROUND: The St. Louis Komen Project was conceived to address disparities in breast cancer treatment and outcomes between African-American and White women in St. Louis, Missouri. Our goal was to apportion tasks and funding through a process to which all researcher partners had input and to which all could agree, thus eliminating institutionalized inequalities. METHODS: This paper describes the collaborative process and resulting division of responsibilities, determination of costs, and ultimate allocation of funds and resources, as well as the documentation employed to achieve funding reciprocity and equal accountability. RESULTS: Both communication and documentation are critical. Although the Memoranda of Understanding employed are not a panacea, they codify roles and expectations and promote trust. The process of developing financial transparency set the tone for subsequent steps in the research process. CONCLUSIONS: The exhaustive planning process and project-specific procedures developed by its partners have helped the project foster reciprocity, facilitate participation, and equitably distribute resources. PMID- 25727990 TI - Application of Antidromic Conduction Monitoring in Ganglion Radiofrequency Thermocoagulation for Locating Trigeminal Branches in Trigeminal Neuralgia. AB - OBJECTIVE: The aim of this study was to investigate whether antidromic conduction monitoring (ACM) can be utilized to map the trigeminal system under sedation as a potential substitute for subjective paresthesia description (SPD) during percutaneous ganglion radiofrequency thermocoagulation (PGRT). METHODS: Eighty two patients with 152 pain divisions of trigeminal neuralgia (TN) were treated by computed tomography (CT)-guided PGRT. After the puncture needle entered the foramen ovale (FO), sensory and motor stimulation were applied to locate the pain division. And the corresponding voltage values were recorded by patients' SPD. In the following, the proper location was certified by ACM. The corresponding earliest waves and voltage values in the identified trigeminal branch were also recorded to outline a comparison between two methods. RESULTS: The correlation of ACM and patients' SPD with voltage at <= 0.5 V was statistically significant (P < 0.05, r = 0.159; Spearman's rank correlation analysis). Although ACM and SPD showed weak correlation, as their interclass correlation coefficient was significant (F = 1.868, P < 0.01) with coefficient of internal consistency. Moreover, the two methods had consistency. Kruskal-Wallis test showed that ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions had significant differences for test sensitivity (H = 15.945, P < 0.01). For comparison of sensitivities with ACM, V3 was most sensitive followed by V2 and then V1. CONCLUSION: ACM could potentially substitute for SPD of the paresthesias intra operatively, enabling greater specificity and eliminating the need to interrupt the administration of anesthetic. These improvements would increase patient satisfaction and practitioner efficiency and accuracy. PMID- 25727991 TI - Silencing Angiopoietin-Like Protein 4 (ANGPTL4) Protects Against Lipopolysaccharide-Induced Acute Lung Injury Via Regulating SIRT1 /NF-kB Pathway. AB - Lung inflammation and alveolar epithelial cell death are critical events in the development and progression of acute lung injury (ALI). Although angiopoietin like protein 4 (ANGPTL4) participates in inflammation, whether it plays important roles in ALI and alveolar epithelial cell inflammatory injury remains unclear. We therefore investigated the role of angptl4 in lipopolysaccharide (LPS)-induced ALI and the associated mechanisms. Lentivirus-mediated short interfering RNA targeted to the mouse angptl4 gene (AngsiRNA) and a negative control lentivirus (NCsiRNA) were intranasally administered to mice. Lung inflammatory injury and the underlying mechanisms for regulation of angptl4 on the LPS-induced ALI were subsequently determined. We reported that angptl4 levels were increased both in human alveolar epithelial A549 cells and lung tissues obtained from a mouse model of LPS-induced ALI. Angptl4 expression was induced by LPS in alveolar epithelial cells, whereas LPS-induced lung inflammation (neutrophils infiltration in the lung tissues, tumor necrosis factor alpha, interleukin 6), lung permeability (lung wet/dry weight ratio and bronchoalveolar lavage fluid (BALF) protein concentration), tissue damage (caspase3 activation), and mortality rates were attenuated in AngsiRNA-treated mice. The inflammatory reaction (tumor necrosis factor alpha, interleukin 6) and apoptosis rates were reduced in AngsiRNA(h) treated A549 cells. Moreover, angptl4 promoted NF-kBp65 expression and suppressed SIRT1 expression both in mouse lungs and A549 cells. Additionally, SIRT1 antagonist nicotinamide (NAM) attenuated the inhibitory effects of AngsiRNA both on LPS-induced NF-kBp65 expression and IL6 expression. These findings suggest that silencing angptl4 protects against LPS-induced ALI via regulating SIRT1/NF kB signaling pathway. PMID- 25727992 TI - Heart failure in patients with atrial fibrillation in Europe: a report from the EURObservational Research Programme Pilot survey on Atrial Fibrillation. AB - AIMS: The purpose of this study was too describe the associated baseline features of AF patients with heart failure (HF) with reduced and preserved ejection fraction (HFrEF and HFpEF). Secondly, we assessed symptomatic status and their clinical correlates. Finally, we examined independent predictors for 'heart failure' at the 1-year follow-up period. METHODS AND RESULTS: A survey of European cardiologists from nine countries, participating in the EURObservational Research Programme Pilot survey on Atrial Fibrillation (EORP-AF Pilot), was carried out. Of the whole cohort of 2972 patients, 1411 (47.5%) had a diagnosis of HF. Of the AF patients with HF, oral anticoagulants were prescribed to 82.1% and antiarrhythmic drugs in 36.7%. Independent predictors of HFpEF were high body mass index, high heart rate, high systolic blood pressure, low diastolic blood pressure, high CHA2DS2-VASc score, and absence of chronic kidney disease, sleep apnoea, or ischaemic cardiomyopathy. On multivariate stepwise regression analysis, independent predictors of the development of HF were mode of AF presentation, diuretic use, prior HF, COPD, and valvular disease. At 1 year, HF was associated with a greater risk of all-cause mortality (log-rank test, P < 0.001). When HFrEF was compared with HFpEF at 1 year, crude rates were significant for the composite endpoint of 'stroke/thrombo-embolism/transient ischaemic attack and death' (15.9% vs. 11.1%, P = 0.043). CONCLUSION: We provide insights into the clinical characteristics and outcomes in AF patients with HF, who were managed by European cardiologists. Despite a high prevalence of oral anticoagulant use, 1-year mortality and morbidity remained high in AF patients with HF, whether HFrEF or HFpEF. Such patients require a holistic approach to cardiovascular risk management. PMID- 25727993 TI - The management of non-tuberculous cervicofacial lymphadenitis in children: A systematic review and meta-analysis. AB - OBJECTIVES: Cervicofacial lymphadenitis is the most common manifestation of infection with non-tuberculous mycobacteria (NTM) in immunocompetent children. Although complete excision is considered standard management, the optimal treatment remains controversial. This study reviews the evidence for different management options for NTM lymphadenitis. METHODS: A systematic literature review and meta-analysis were performed including 1951 children from sixty publications. Generalised linear mixed model regressions were used to compare treatment modalities. RESULTS: The adjusted mean cure rate was 98% (95% CI 97.0-99.5%) for complete excision, 73.1% (95% CI 49.6-88.3%) for anti-mycobacterial antibiotics, and 70.4% (95% CI 49.6-88.3%) for 'no intervention'. Compared to 'no intervention', only complete excision was significantly associated with cure (OR 33.1; 95% CI 10.8-102.9; p < 0.001). Complete excision was associated with a 10% risk of facial nerve palsy (2% permanent). 'No intervention' was associated with delayed resolution. CONCLUSIONS: Complete excision is associated with the highest cure rate in NTM cervicofacial lymphadenitis, but also had the highest risk of facial nerve palsy. In the absence of large, well-designed RCTs, the choice between surgical excision, anti-mycobacterial antibiotics and 'no intervention' should be based on the location and extent of the disease, and acceptability of prolonged time to resolution. PMID- 25727994 TI - Hepatitis E virus in hematopoietic stem cell donors: Towards a systematic HEV screening of donors? PMID- 25727995 TI - Severe ulcerative penile leishmaniasis--Importance of PCR-based diagnostics. PMID- 25727996 TI - Lipid mediators of inflammation as novel plasma biomarkers to identify patients with bacteremia. AB - OBJECTIVES: Rapid diagnostic tests for bacteremia are important for early treatment to improve clinical outcome. We sought to identify plasma biomarkers that can identify patients with bacteremia using an untargeted global metabolomic analysis. METHODS: Plasma metabolomic profiles were analyzed for 145 adult patients with (cases) and without (controls) bacteremia using ultra-high performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). All metabolites were compared between cases and controls using a 2-tier filtering approach, and each metabolite underwent receiver operating characteristic (ROC) curve analysis. Individual metabolites that distinguish between cases and controls were characterized. Subgroup analysis was performed to identify metabolites with prognostic significance. RESULTS: After 2-tier filtering, 128 molecular features were identified to be potential biomarkers that could distinguish cases from controls. Five metabolites had an area under the ROC curve (AUC) of >0.8 in ROC curve analysis, including a sphingolipid, an acylcarnitine, a fatty acid ester, and 2 glycerophosphocholines. These metabolites could distinguish cases from controls in the unsupervised hierarchical clustering analysis. Subgroup analysis of bacteremic patients showed that the level of trans-2,3,4-trimethoxycinnamate was lower in fatal than non fatal cases. CONCLUSIONS: Plasma lipid mediators of inflammation can distinguish bacteremia cases from non-bacteremia controls. These biomarkers may be used as targets for rapid test in clinical practice. PMID- 25727997 TI - Characterizing compositional changes of Napier grass at different stages of growth for biofuel and biobased products potential. AB - Napier grass, Pennisetum purpureum, is a high yielding, perennial feedstock that can be harvested year-round in (sub)tropical geographies of the world. Because of its high moisture content (~ 80%w/w), Napier grass presents a unique opportunity for fractionation into solid and liquid streams, where the extruded cellulosic fibers can serve as a substrate for biofuel production, and the nutrient-rich juice can serve as a substrate for co-product generation. The aim of this study evaluated the effects of biomass age on constituents relevant to biofuel and biobased product generation. Although obvious morphological changes can be observed in the field due to natural senescence, the results obtained in this work suggested that the cellulose content does not change significantly with respect to age. Data surrounding the hemicellulose and lignin contents, however, were inconclusive as their degree of significance varied with the statistics applied to analyze the raw data. PMID- 25727999 TI - Medicare Reimbursement Attributable to Periprosthetic Joint Infection Following Primary Hip and Knee Arthroplasty. AB - This study estimated Medicare reimbursement attributable to periprosthetic joint infection (PJI) across the continuum of covered services four years following hip or knee arthroplasty. Using 2001-2008 Medicare claims data, total and annual attributable reimbursements were assessed using generalized linear regression, adjusting for potential confounders. Within one year following arthroplasty, 109 (1.04%) of 10,418 beneficiaries were diagnosed with PJI. Cumulative Medicare reimbursement in the PJI arm was 2.2-fold (1.9-2.6, P<.0001) or $53,470 ($39,575 $68,221) higher than that of the non-PJI arm. The largest difference in reimbursement occurred the first year (3.2-fold); differences persisted the second (2.3-fold) and third (1.9-fold) follow up years. PJI following hip or knee arthroplasty appears costly to Medicare, with cost traversing several years and health care service areas. PMID- 25727998 TI - Comparative metagenomics demonstrating different degradative capacity of activated biomass treating hydrocarbon contaminated wastewater. AB - This study demonstrates the diverse degradative capacity of activated biomass, when exposed to different levels of total dissolved solids (TDS) using a comparative metagenomics approach. The biomass was collected at two time points to examine seasonal variations. Four metagenomes were sequenced on Illumina Miseq platform and analysed using MG-RAST. STAMP tool was used to analyse statistically significant differences amongst different attributes of metagenomes. Metabolic pathways related to degradation of aromatics via the central and peripheral pathways were found to be dominant in low TDS metagenome, while pathways corresponding to central carbohydrate metabolism, nitrogen, organic acids were predominant in high TDS sample. Seasonal variation was seen to affect catabolic gene abundance as well as diversity of the microbial community. Degradation of model compounds using activated sludge demonstrated efficient utilisation of single aromatic ring compounds in both samples but cyclic compounds were not efficiently utilised by biomass exposed to high TDS. PMID- 25727666 TI - Early-life establishment of the swine gut microbiome and impact on host phenotypes. AB - Early bacterial colonization and succession within the gastrointestinal tract has been suggested to be crucial in the establishment of specific microbiota composition and the shaping of host phenotype. Here, the composition and dynamics of faecal microbiomes were studied for 31 healthy piglets across five age strata (days 14, 36, 48, 60 and 70 after birth) together with their mothers. Faecal microbiome composition was assessed by 16S rRNA gene 454-pyrosequencing. Bacteroidetes and Firmicutes were the predominant phyla present at each age. For all piglets, luminal secretory IgA concentration was measured at day 70, and body weight was recorded until day 70. The microbiota of suckling piglets was mainly represented by Bacteroides, Oscillibacter, Escherichia/Shigella, Lactobacillus and unclassified Ruminococcaceae genera. This pattern contrasted with that of Acetivibrio, Dialister, Oribacterium, Succinivibrio and Prevotella genera, which appeared increased after weaning. Lactobacillus fermentum might be vertically transferred via breast milk or faeces. The microbiota composition coevolved with their hosts towards two different clusters after weaning, primarily distinguished by unclassified Ruminococcaceae and Prevotella abundances. Prevotella was positively correlated with luminal secretory IgA concentrations, and body weight. Our study opens up new possibilities for health and feed efficiency manipulation via genetic selection and nutrition in the agricultural domain. PMID- 25728000 TI - Dietary fibre linked to decreased inflammation in overweight minority youth. AB - OBJECTIVE: The objective of this study was to examine the relationship between diet and inflammation, and adiposity in minority youth. DESIGN AND METHODS: The study was designed as a cross-sectional analysis of 142 overweight (>=85th body mass index percentile) Hispanic and African-American adolescents (14-18 years) with the following measures: anthropometrics, adiposity via magnetic resonance imaging, dietary intake via 24-h dietary recalls, and inflammation markers from fasting blood draws utilizing a multiplex panel. Partial correlations were estimated and analysis of covariance (ancova) models fit to examine the relationship among dietary variables, inflammation markers and adiposity measures with the following a priori covariates: Tanner stage, ethnicity, sex, total energy intake, total body fat and total lean mass. RESULTS: Inference based on ancova models showed that the highest tertile of fibre intake (mean intake of 21.3 +/- 6.1 g d(-1) ) vs. the lowest tertile of fibre intake (mean intake of 7.4 +/- 1.8 g d(-1) ) was associated with 36% lower plasminogen activator inhibitor-1 (P = 0.02) and 43% lower resistin (P = 0.02), independent of covariates. Similar results were seen for insoluble fibre. No other dietary variables included in this study were associated with inflammation markers. CONCLUSIONS: These results suggest that increases in dietary fibre could play an important role in lowering inflammation and therefore metabolic disease risk in high-risk minority youth. PMID- 25728001 TI - A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). AB - PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 =31+/ 2 nM, KD =53+/-2 nM) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease. PMID- 25728003 TI - Visible to infrared low temperature luminescence of Er(3+), Nd(3+) and Sm(3+) in CaSnO3 phosphors. AB - Novel stannate phosphor, orthorhombic CaSnO3 phosphors doped with Er(3+), Nd(3+) and Sm(3+) have been synthesized by a conventional solid-state method under N2+H2 gas flow. Visible and near-infrared photoluminescence (PL) properties were investigated as function of laser power and temperature. It was observed that all dopant ions are well incorporated in CaSnO3 and are responsible for the optical emission in the temperature range of 10-300K. PL peaks at 490, 546, 656, 696, 894, 1065, and 1344nm were observed for the CaSnO3:Nd(3+) phosphor and associated to f-f transition of Nd(3+) ion. Emissions at 564, 600-607, 646-656 and 714nm were detected for the CaSnO3:Sm(3+). The strongest one, observed at 600nm, was associated to (4)G5/2->(6)H7/2 of Sm(3). Emission lines at 528, 548, 662 at 852nm were also seen for CaSnO3:Er(3+) and correspond to Er(3+) intra-4f(n) shell transitions. In addition, at low temperatures, a stark splitting of the 4f electron energy levels of the Er(3+) ions were observed in infrared region (1520 1558nm) and assigned to the transition between the (4)I13/2 state and the (4)I15/2 state. Finally, our results show that the rare earth doped CaSnO3 has remarkable potential for applications as optical material since it exhibits efficient and sharp emissions due to rare earth ions. PMID- 25728005 TI - (65)Cu isomeric cross sections for (n,alpha) reaction using approximately 14MeV neutrons. AB - In this paper, activation cross-section measurements for the (65)Cu(n,alpha)(62m)Co (T1/2=13.86min.) reaction at six different neutron energies ranging from 13.6 and 14.9MeV are presented. The fast neutrons were produced via (3)H(d, n)(4)He reactions from an SAMES T-400 neutron generator. An activation technique was used to measure induced gamma activities. A high resolution gamma-ray spectrometer with a high-purity germanium (HpGe) detector was used to acquire the data. The measured cross section data were corrected for gamma-ray attenuations, pulse pile-up effects, dead time, variations in neutron flux, and contributions from scattered low-energy neutrons. The measured cross sections were compared with statistical model calculations (TALYS 1.6 code), the experimental data available in the literature and the data obtained from TENDL. PMID- 25728004 TI - Dicentric assay: inter-laboratory comparison in Indian laboratories for routine and triage applications. AB - An Inter-Laboratory Comparison (ILC) study on Dicentric Chromosome Assay (DCA) was carried out between two Indian biodosimetry labs. Human peripheral blood samples exposed to 10 different doses of X-rays up to 5Gy were shared between the labs to generate calibration data. Validation of calibration curves was done by dose estimation of coded samples exposed to X- or gamma radiation. Reliability of the DCA data for triage application was evaluated by scoring 20, 50 and 100 metaphases in the dose range of 0.5-3.0Gy. No significant difference was observed between labs regarding the established calibration data as well as the DCA triage dose assessments. Scoring of 20 metaphases (MP) was adequate to detect radiation exposure of >2Gy whereas 50 MP were sufficient to determine exposures of 0.5Gy. Both labs performed the DCA in a reliable manner and made the first step in setting up a biodosimetry network in India. PMID- 25728006 TI - Identification and characterization of novel serum microRNAs in unstable angina pectoris and subclinical atherosclerotic patients. AB - BACKGROUND: MicroRNAs (miRNAs) are involved in cardiac developmental and pathological processes, and serum profile is useful for identifying novel miRNAs. METHODS AND RESULTS: Serum samples were collected from unstable angina pectoris (UAP) and subclinical atherosclerotic (AS) patients. Solexa sequencing was used to predict novel miRNAs in 15 control individuals, 15 AS patients and 15 UAP patients. After bioinformatics analysis and filtering out in the newest version of miRbase (version 20.0), three novel miRNAs were validated in 80 control individuals, 80 AS patients and 80 UAP patients by quantitative reverse transcriptase polymerase chain reaction. Two of the three novel microRNAs (N1 and N3) were expressed at the highest levels in the AS group. N1 had an area under curve (AUC) of 0.811 (95% confidence interval 0.743-0.880) for AS. N3 showed a moderate separation with an area under curve (AUC) of 0.748 (95% confidence interval 0.664-0.833) for AS. Combined the two novel microRNAs can significantly distinguish AS from control. CONCLUSIONS: Three novel miRNAs were identified by Solexa sequencing and two of them may be new potential predictors for arthrosclerosis. PMID- 25728002 TI - Specification of the somatic musculature in Drosophila. AB - The somatic muscle system formed during Drosophila embryogenesis is required for larvae to hatch, feed, and crawl. This system is replaced in the pupa by a new adult muscle set, responsible for activities such as feeding, walking, and flight. Both the larval and adult muscle systems are comprised of distinct muscle fibers to serve these specific motor functions. In this way, the Drosophila musculature is a valuable model for patterning within a single tissue: while all muscle cells share properties such as the contractile apparatus, properties such as size, position, and number of nuclei are unique for a particular muscle. In the embryo, diversification of muscle fibers relies first on signaling cascades that pattern the mesoderm. Subsequently, the combinatorial expression of specific transcription factors leads muscle fibers to adopt particular sizes, shapes, and orientations. Adult muscle precursors (AMPs), set aside during embryonic development, proliferate during the larval phases and seed the formation of the abdominal, leg, and flight muscles in the adult fly. Adult muscle fibers may either be formed de novo from the fusion of the AMPs, or are created by the binding of AMPs to an existing larval muscle. While less is known about adult muscle specification compared to the larva, expression of specific transcription factors is also important for its diversification. Increasingly, the mechanisms required for the diversification of fly muscle have found parallels in vertebrate systems and mark Drosophila as a robust model system to examine questions about how diverse cell types are generated within an organism. PMID- 25728007 TI - A yeast model of the Parkinson's disease-associated protein Parkin. AB - Mutations in Parkin, an E3 ubiquitin ligase, are associated to autosomal recessive Parkinson's disease (PD). Parkin has been mainly implicated, along with Pink1, in mitochondrial autophagy in response to stress. In this study, a yeast model was developed to analyse the biological function of human Parkin. We observed that Parkin increases yeast chronological lifespan and oxidative stress resistance, through a mitochondrial-dependent pathway. Moreover, in response to H2O2, Parkin translocate to mitochondria, leading to a higher mitochondrial degradation. Parkin-induced H2O2 resistance is dependent on the autophagic pathway and on the mitochondrial protein Por1p. Although expression of Pink1 induces an H2O2 resistance phenotype similar to Parkin, co-expression of both proteins does not result in a synergistic effect. Concerning H2O2 resistance, this may indicate that these two proteins independently affect the same pathway. Altogether, this work establishes a yeast model for Parkin, which may provide new insights on Parkin function and potential mechanisms of pathogenicity. PMID- 25728008 TI - Effects, but no interactions, of ubiquitous pesticide and parasite stressors on honey bee (Apis mellifera) lifespan and behaviour in a colony environment. AB - Interactions between pesticides and parasites are believed to be responsible for increased mortality of honey bee (Apis mellifera) colonies in the northern hemisphere. Previous efforts have employed experimental approaches using small groups under laboratory conditions to investigate influence of these stressors on honey bee physiology and behaviour, although both the colony level and field conditions play a key role for eusocial honey bees. Here, we challenged honey bee workers under in vivo colony conditions with sublethal doses of the neonicotinoid thiacloprid, the miticide tau-fluvalinate and the endoparasite Nosema ceranae, to investigate potential effects on longevity and behaviour using observation hives. In contrast to previous laboratory studies, our results do not suggest interactions among stressors, but rather lone effects of pesticides and the parasite on mortality and behaviour, respectively. These effects appear to be weak due to different outcomes at the two study sites, thereby suggesting that the role of thiacloprid, tau-fluvalinate and N. ceranae and interactions among them may have been overemphasized. In the future, investigations into the effects of honey bee stressors should prioritize the use of colonies maintained under a variety of environmental conditions in order to obtain more biologically relevant data. PMID- 25728009 TI - Promising therapies for the treatment of chronic lymphocytic leukemia. AB - INTRODUCTION: The combination schedule of fludarabine, cyclophosphamide and rituximab is the gold standard of therapy for younger, physically fit chronic lymphocytic leukemia (CLL) patients; it allows achieving high and durable complete response rates. Although treatment outcome has considerably improved with chemo-immunotherapy, most patients eventually relapse and CLL is still incurable. Thus, newer and more rationally developed drugs are needed to improve CLL therapy, particularly in cases of relapsed/refractory disease. AREAS COVERED: The authors review preclinical and clinical data regarding newer CLL agents, currently undergoing examination, such as: signal transduction and cyclin dependent kinase inhibitors, immunomodulatory agents, B-cell lymphoma 2 inhibitors, next generation mAbs, heat shock protein 90 and histone deacetylase inhibitors, and chimeric antigen receptor T-cell therapy. EXPERT OPINION: Newer compounds with different mechanisms of action, such as B-cell receptor signal transduction inhibitors, lenalidomide, next generation mAbs and several pro apoptotic molecules, have shown efficacy in relapsed or refractory CLL patients. Several studies are under way to investigate the efficacy of combinations of these novel drugs. Hopefully, the combined use of these molecules in risk-adapted treatment strategies will change the therapeutic approach in the near future and will pave the way for a long-term control of CLL. PMID- 25728010 TI - Identification of hybrid node and link communities in complex networks. AB - Identifying communities in complex networks is an effective means for analyzing complex systems, with applications in diverse areas such as social science, engineering, biology and medicine. Finding communities of nodes and finding communities of links are two popular schemes for network analysis. These schemes, however, have inherent drawbacks and are inadequate to capture complex organizational structures in real networks. We introduce a new scheme and an effective approach for identifying complex mixture structures of node and link communities, called hybrid node-link communities. A central piece of our approach is a probabilistic model that accommodates node, link and hybrid node-link communities. Our extensive experiments on various real-world networks, including a large protein-protein interaction network and a large network of semantically associated words, illustrated that the scheme for hybrid communities is superior in revealing network characteristics. Moreover, the new approach outperformed the existing methods for finding node or link communities separately. PMID- 25728011 TI - New DSM-V neurocognitive disorders criteria and their impact on diagnostic classifications of mild cognitive impairment and dementia in a memory clinic setting. AB - OBJECTIVE: To examine diagnostic agreement between Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Neurocognitive Disorders (NCDs) criteria and DSM, Fourth Edition (DSM-IV) criteria for dementia and International Working Group (IWG) criteria for mild cognitive impairment (MCI) and DSM-V's impact on diagnostic classifications of NCDs. The authors further examined clinical factors for discrepancy in diagnostic classifications between the different operational definitions. METHODS: Using a cross-sectional study in tertiary memory clinic, the authors studied consecutive new patients aged 55 years or older who presented with cognitive symptoms. Dementia severity was scored based on the Clinical Dementia Rating scale (CDR). All patients completed neuropsychological evaluation. Agreement in diagnostic classifications between DSM-IV/IWG and DSM-V was examined using the kappa test and AC1 statistic, with multinomial logistic regression for factors contributing to MCI reclassification as major NCDs as opposed to diagnostically concordant MCI and dementia groups. RESULTS: Of 234 patients studied, 166 patients achieved concordant diagnostic classifications, with overall kappa of 0.41. Eighty-six patients (36.7%) were diagnosed with MCI and 131 (56.0%) with DSM-IV-defined dementia. With DSM-V, 40 patients (17.1%) were classified as mild NCDs and 183 (78.2%) as major NCDs, representing a 39.7% increase in frequency of dementia diagnoses. CDR sum-of boxes score contributed independently to differentiation of MCI patients reclassified as mild versus major NCDs (OR: 0.01; 95% CI: 0-0.09). CDR sum-of boxes score (OR: 5.18; 95% CI: 2.04-13.15), performance in amnestic (OR: 0.14; 95% CI: 0.06-0.34) and language (Boston naming: OR: 0.52; 95% CI: 0.29-0.94) tests, were independent determinants of diagnostically concordant dementia diagnosis. CONCLUSION: The authors observed moderate agreement between the different operational definitions and a 40% increase in dementia diagnoses with operationalization of the DSM-V criteria. PMID- 25728012 TI - Neural correlates of single word reading in bilingual children and adults. AB - The present study compared the neural correlates of language processing in children and adult Spanish-English bilinguals. Participants were asked to perform a visual lexical processing task in both Spanish and English while being scanned with fMRI. Both children and adults recruited a similar network of left hemisphere "language" areas and showed similar proficiency profiles in Spanish. In terms of behavior, adults showed better language proficiency in English relative to children. Furthermore, neural activity in adults was observed in the bilateral MTG. Age-related differences were observed in Spanish in the right MTG. The current results confirm the presence of neural activity in a set of left hemisphere areas in both adult and child bilinguals when reading words in each language. They also reveal that differences in neural activity are not entirely driven by changes in language proficiency during visual word processing. This indicates that both skill development and age can play a role in brain activity seen across development. PMID- 25728013 TI - Reduced fractional anisotropy in the anterior corpus callosum is associated with reduced speech fluency in persistent developmental stuttering. AB - Developmental stuttering is a speech disorder that severely limits one's ability to communicate. White matter anomalies were reported in stuttering, but their functional significance is unclear. We analyzed the relation between white matter properties and speech fluency in adults who stutter (AWS). We used diffusion tensor imaging with tract-based spatial statistics, and examined group differences as well as correlations with behavioral fluency measures. We detected a region in the anterior corpus callosum with significantly lower fractional anisotropy in AWS relative to controls. Within the AWS group, reduced anisotropy in that region is associated with reduced fluency. A statistically significant interaction was found between group and age in two additional regions: the left Rolandic operculum and the left posterior corpus callosum. Our findings suggest that anterior callosal anomaly in stuttering may represent a maladaptive reduction in interhemispheric inhibition, possibly leading to a disadvantageous recruitment of right frontal cortex in speech production. PMID- 25728014 TI - Cocaine exposure impairs multilineage hematopoiesis of human hematopoietic progenitor cells mediated by the sigma-1 receptor [corrected]. AB - Prenatal exposure to cocaine is a significant source of fetal and neonatal developmental defects. While cocaine associated neurological and cardiac pathologies are well-documented, it is apparent that cocaine use has far more diverse physiological effects. It is known that in some cell types, the sigma-1 receptor mediates many of cocaine's cellular effects. Here we present a novel and concise investigation into the mechanism that underlies cocaine associated hematopoietic pathology. Indeed, this is the first examination of the effects of cocaine on hematopoiesis. We show that cocaine impairs multilineage hematopoiesis from human progenitors from multiple donors and tissue types. We go on to present the first demonstration of the expression of the sigma-1 receptor in human CD34 + human hematopoietic stem/progenitor cells. Furthermore, we demonstrate that these cocaine-induced hematopoietic defects can be reversed through sigma-1 receptor blockade. PMID- 25728015 TI - The vasovagal response during confrontation with blood-injury-injection stimuli: the role of perceived control. AB - The vasovagal response (VVR) is a common medical problem, complicating and deterring people from various procedures. It is an unusual stress response given the widespread decreases in physiological activity. Nevertheless, VVR involves processes similar to those observed during episodes of strong emotions and pain. We hypothesized that heightened perceived control would reduce symptoms of VVR. Eighty-two young adults were randomly assigned to perceived control or no perceived control conditions during exposure to a stimulus video of a mitral valve surgery, known to trigger VVR in non-medical personnel. Perceived control was manipulated by allowing some participants to specify a break time, though all received equivalent breaks. Outcomes included subjective symptoms of VVR, anxiety, blood pressure, heart rate, and other measures derived from impedance cardiography. Compared to participants with perceived control, participants with no perceived control reported significantly more vasovagal symptoms and anxiety, and experienced lower stroke volume, cardiac output, and diastolic blood pressure. Participants who were more fearful of blood were more likely to benefit from perceived control in several measures. Perceived control appears to reduce vasovagal symptoms. Results are discussed in terms of cognition and emotion in VVR. PMID- 25728016 TI - Developing scales measuring disorder-specific intolerance of uncertainty (DSIU): a new perspective on transdiagnostic. AB - Intolerance of uncertainty (IU) is a construct of growing prominence in literature on anxiety disorders and major depressive disorder. Existing measures of IU do not define the uncertainty that respondents perceive as distressing. To address this limitation, we developed eight scales measuring disorder-specific intolerance of uncertainty (DSIU) relating to various anxiety disorders and major depressive disorder. We used exploratory factor analysis and item characteristic curves in two large undergraduate samples (Ns=627 and 628) to derive eight three item DSIU scales (24 items total) that exhibited excellent psychometric properties. Confirmatory factor analysis supported the factor structures of the scales and the transdiagnostic nature of IU. Each scale predicted unique variance in its respective symptom measure beyond a traditional measure of IU. DSIU represents a theoretically proximal and causal intermediary between known vulnerability factors and disorder symptomatology. The DSIU scales can be used to advance theories of psychopathology and inform case conceptualization and treatment planning. PMID- 25728017 TI - Effects of genetic polymorphisms on antioxidant status and concentrations of the metals in the blood of riverside Amazonian communities co-exposed to Hg and Pb. AB - There have been reports of genetic effects affecting the metabolism of Hg and Pb individually, and thus modulating their toxicities. However, there is still a knowledge gap with respect to how genetics may influence the toxicities of these toxic metals during a co-exposure scenario. This present study is therefore aimed at investigating the effects of polymorphisms in genes (GSTM1, GSTT1, GSTP1, GCLM, GCLC, GPx1, ALAD, VDR and MDR1) that have been implicated in Hg and Pb metabolisms affects the kinetics of these metals, as well as various blood antioxidant status parameters: MDA and GSH, and the activities of CAT, GPx and ALAD among populations that have been co-exposed to both Hg and Pb. Study subjects (207 men; 188 women) were from an Amazonian population in Brazil, exposed to Hg and Pb from diet. The blood levels of Hg and Pb were determined by ICP-MS while genotyping were performed by PCR assays. The median values of Hg and Pb in blood were 39.8ug/L and 11.0ug/dL, respectively. GSTM1, ALAD and VDR polymorphisms influenced Hg in blood (beta=0.17; 0.37 and 0.17; respectively, p<0.050) while variations on GCLM, GSTT1 and MDR1 (TT) modulated the concentrations of Pb among the subjects (beta=-0.14; 0.13 and -0.22; re spectively, p<0.050). GSTT1 and GCLM polymorphisms also are associated to changes of MDA concentrations. Persons with null GSTM1 genotype had higher activity of the antioxidant enzyme CAT than carries of the allele. Individuals with deletion of both GSTM1 and GSTT1 had a decreased expression of GPx compared to those that expressed at least, one of the enzymes. ALAD 1/2 subjects had lower ALAD activity than individuals with the non-variant genotype. Our findings give further support that polymorphisms related to Hg and Pb metabolism may modulate Hg and Pb body burden and, consequently metals-induced toxicity. PMID- 25728018 TI - HIV and STI testing in older adults: an integrative review. AB - AIMS AND OBJECTIVES: To examine the frequency of human immunodeficiency virus testing and sexually transmitted infection testing among older adults (50 years and older), present factors related to human immunodeficiency virus and sexually transmitted infection testing among older adults, and summarise the perspectives and practices of older adults and health care providers related to sexual health communication. BACKGROUND: Reported cases of sexually transmitted infections and human immunodeficiency virus among older adults have increased, therefore refuting the stereotype of the sexually inactive older adult. DESIGN: Integrative review. METHODS: Database searches in PubMed, EMBASE, CINAHL, and Web of Science; manual reference list searches; and database searches for articles that cited previously identified articles. RESULTS: There is limited research on this topic and considerable diversity in the populations studied and outcomes measured. The search process yielded 20 articles meeting the eligibility criteria. Human immunodeficiency virus and sexually transmitted infection testing of older adults are infrequent. Human immunodeficiency virus testing among older adults is associated with perceived risk of contracting human immunodeficiency virus and influenced by encouragement from health care providers. Sexually transmitted infection testing due to genital symptoms is more likely than asymptomatic screening. Few providers collect routine sexual histories from older adult patients, although older adults are receptive to sexual history taking. CONCLUSIONS: There are missed opportunities to identify sexually transmitted infections and human immunodeficiency virus in older adults. Stereotypes and assumptions have hindered providers from identifying and testing older adults at risk for human immunodeficiency virus and sexually transmitted infections. RELEVANCE TO CLINICAL PRACTICE: Sexual health assessment is essential to comprehensive health care. A sexual history provides information that may indicate human immunodeficiency virus and sexually transmitted infection testing. Detection and treatment of human immunodeficiency virus and sexually transmitted infections will break the chain of infection and improve quality of life. PMID- 25728019 TI - Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure. AB - The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2). PMID- 25728020 TI - Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. AB - Aging leads to dysregulation of multiple components of the immune system that results in increased susceptibility to infections and poor response to vaccines in the aging population. The dysfunctions of adaptive B and T cells are well documented, but the effect of aging on innate immunity remains incompletely understood. Using a heterogeneous population of peripheral blood mononuclear cells (PBMCs), we first undertook transcriptional profiling and found that PBMCs isolated from old individuals (>= 65 years) exhibited a delayed and altered response to stimulation with TLR4, TLR7/8, and RIG-I agonists compared to cells obtained from adults (<= 40 years). This delayed response to innate immune agonists resulted in the reduced production of pro-inflammatory and antiviral cytokines and chemokines including TNFalpha, IL-6, IL-1beta, IFNalpha, IFNgamma, CCL2, and CCL7. While the major monocyte and dendritic cell subsets did not change numerically with aging, activation of specific cell types was altered. PBMCs from old subjects also had a lower frequency of CD40+ monocytes, impaired up-regulation of PD-L1 on monocytes and T cells, and increased expression of PD L2 and B7-H4 on B cells. The defective immune response to innate agonists adversely affected adaptive immunity as TLR-stimulated PBMCs (minus CD3 T cells) from old subjects elicited significantly lower levels of adult T-cell proliferation than those from adult subjects in an allogeneic mixed lymphocyte reaction (MLR). Collectively, these age-associated changes in cytokine, chemokine and interferon production, as well as co-stimulatory protein expression could contribute to the blunted memory B- and T-cell immune responses to vaccines and infections. PMID- 25728021 TI - Follow-up nerve conduction studies in CIDP after treatment with IGIV-C: Comparison of patients with and without subsequent relapse. AB - INTRODUCTION: Electrodiagnostic studies (EDX) are not performed routinely before treatment suspension in CIDP, and no data exist regarding their value in predicting clinical relapse. METHODS: Serial EDX (baseline and after IGIV-C therapy) were analyzed from subjects in the ICE clinical trial who responded to IGIV-C treatment and were subsequently re-randomized to placebo in an extension phase. Comparisons were made between subjects who relapsed and those who did not. RESULTS: A total of 55% (6/11) of the Relapse group had an increase in total number of demyelinating findings (DF) versus 8% (1/13) in the No Relapse group (P = 0.023). In the Relapse group, 100% had >= 1 new DF and 73% (8/11) had >= 4 new DF versus 60% (8/13) and 8% (1/13), respectively, in the No Relapse group. CONCLUSIONS: An increased total number of DF or the occurrence of >= 4 new DF may indicate a higher risk of clinical relapse after treatment cessation in IGIV-C responsive patients. PMID- 25728022 TI - Purine-benzimidazole hybrids: synthesis, single crystal determination and in vitro evaluation of antitumor activities. AB - In an effort to identify novel compounds for the treatment of cancer, a diverse array of potential bioactive hybrid, purine-benzimidazole was synthesized in good yields through nucleophilic substitution at C6 position of purine ring with versatile cyclic amines at C2 position. The structures of newly prepared compounds were confirmed by IR, (1)H, (13)C NMR, mass spectroscopy and, in case of 19, by single crystal X-ray diffraction analysis. The newly synthesized compounds were evaluated against 60 human tumour cell lines at one dose concentration level. Compound 6 exhibited significant growth inhibition and was evaluated as 60 cell panel at five dose concentration levels. Compound 6 proved to be 1.25 fold more active than the positive control 5-FU, with GI50 value of 18.12 MUM (MG-MID). Interaction of the compounds with Aurora-A enzyme involved in the process of propagation of cancer, has also been investigated. Compound 6 showed selectivity towards Aurora-A kinase inhibition with IC50 value of 0.0l MUM. Molecular docking studies in the active binding site provided theoretical support for the experimental biological data acquired. PMID- 25728023 TI - Fluoroalkane thioheterocyclic derivatives and their antitumor activity. AB - Two series of novel trifluorobutenyl derivatives of heterocyclic with convenient and efficient synthesis methods and their antitumor activity on three cell lines have been reported for the first time. The derivatives were synthesized by the nucleophilic substitution between 4-bromo-1,1,2-trifluorobutene-1-ene and commercially available nitrogen-containing heterocycles with sulfydryl or monosubstituted malononitrile. The twenty-four new compounds were characterized by (1)HNMR, (13)CNMR and HR-MS. Totally, thirty-seven compounds were evaluated for the antitumor activity on three cancer cell lines (SH-SY5Y, MCF-7 and HepG2) using conventional MTT assay. The pharmacological results indicated that the compounds 3c, 3h, 4c, 8, 9, 10 and 11 showed potent to moderate antitumor activity against three cancer cell lines, with IC50 values ranging between 0.4 MUM and 41.5 MUM. Even though they had less active than the reference compound taxol against MCF-7 and HepG2 lines, but they were better than the reference compound noscapine against SH-SY5Y cells, especially the compound 3h with a IC50 value of 0.4 MUM. PMID- 25728024 TI - Structure-activity relationships of 3-O-beta-chacotriosyl ursolic acid derivatives as novel H5N1 entry inhibitors. AB - A series of methyl ursolate 3-O-beta-chacotrioside analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 3 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 3 indicated that both the type of pentacyclic triterpene and the subtle modification of ursolic acid as an aglycon had key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of ursolic acid or alteration of the C-3 configuration of ursolic acid from 3beta-to 3alpha-forms was helpful to significantly improve the selective index while keeping their antiviral activities. PMID- 25728025 TI - Antioxidant activity and inhibition of alpha-glucosidase by hydroxyl functionalized 2-arylbenzo[b]furans. AB - This study synthesized a series of hydroxyl-functionalized 2-arylbenzo[b]furans based on the structure of tournefolic acid A and evaluated them for antioxidant and alpha-glucosidase inhibitory activities. Compounds 5a, 5e, and 5n showed remarkable inhibition of alpha-glucosidase (IC50 values of 1.9-3.0 MUM), and they appear to be even more potent than quercetin. A kinetic binding study indicated that compounds 5a and 5n used a mechanism of mixed-competition to inhibit alpha glucosidase. This study also revealed that compounds 5a and 5n bind to either the alpha-glucosidase or alpha-glucosidase-4-NPGP complex. Using the crystal structure of the Saccharomyces cerevisiae alpha-glucosidase, the molecular docking study has predicted the binding of compounds 5a and 5n to the active site of alpha-glucosidase through both hydrophobic and hydrogen interactions. A DPPH radical scavenging assay further showed that most hydroxyl-functionalized 2 arylbenzo[b]furans possess antioxidant activity. The exception was compound 5p, which has only one hydroxyl group on the 2-phenyl ring of 2-arylbenzo[b]furan. Our results indicate that hydroxyl-functionalized 2-arylbenzo[b]furans possess both antidiabetic as well as antioxidant properties. PMID- 25728026 TI - (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2 one derivatives as dual inhibitors of HIV-1 reverse transcriptase. AB - The HIV-1 Reverse Transcriptase (RT) is a validated and deeply explored biological target for the treatment of AIDS. However, only drugs targeting the RT associated DNA polymerase (DP) function have been approved for clinical use. We designed and synthesised a new generation of HIV-1 RT inhibitors, based on the (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2 one scaffold. These compounds are active towards both RT-associated functions, DNA polymerase and ribonuclease H. The structure, biological activity and mode of action of the new derivatives have been investigated. In particular, the nature of the aromatic group in the position 4 of the thiazole ring plays a key role in the modulation of the activity towards the two RT-associated functions. PMID- 25728027 TI - Synthesis and assessment of the antioxidant and antitumor properties of asymmetric curcumin analogues. AB - In this study, 12 asymmetric curcumin (CUR) analogues and 5 symmetric curcumin derivatives were synthesized, the antioxidant activity of these derivatives were evaluated by radicals 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay, 2,2-azino bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assay, ROO (TRAP) assay and O(2 ) (NET) assay and anti-proliferative activities of these analogues were assessed against the human hepatoma cell line (SMMC-7721), the human breast cancer cell line (MCF-7) and the human prostate cancer cell lines (PC-3). Most of the asymmetric compounds showed stronger antioxidant activities than Vitamin C (Vc). Curcumin analogues reducing free radicals contain two reaction mechanisms: H-atom and electron transfer mechanisms. Compound 14 showed the most significant antioxidant activity compared with curcumin and other derivatives. Shorted the carbon chain of 14 can reduce the O-H bond dissociation enthalpy (BED) to improve the antioxidant activity. The antioxidant activity of 25 was similar to curcumin. All of the compounds performed better in an anti-proliferate assay than curcumin, especially compound 25, which exhibited the preferential cytotoxic activity against MCF-7 cells(25, IC50 = 9.11 MUM, curcumin, IC50 = 70.2 MUM). Considering these data, future studies should be performed to assess the therapeutic values of these asymmetric curcumin analogues. PMID- 25728028 TI - Identification of fused 16beta,17beta-oxazinone-estradiol derivatives as a new family of non-estrogenic 17beta-hydroxysteroid dehydrogenase type 1 inhibitors. AB - A new family of cyclic carbamate-estradiol derivatives has been designed to remove the intrinsic estrogenic activity of a parent acyclic compound reported as a potent inhibitor of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1). The synthesis of two series of fused 16beta,17beta-oxazinone-estradiol derivatives, saturated compounds 7a-d and unsaturated compounds 10a-d, led to the identification of 10b, a 17beta-HSD1 inhibitor (IC50 = 1.4 MUM) without estrogenic activity in estrogen-sensitive T-47D cells. Interestingly, this compound was found selective over 17beta-HSD2 and 17beta-HSD12. A computational analysis of inhibitors into 17beta-HSD1 by molecular docking also revealed interesting structure-activity relationships that could be helpful in the design of new generation of 16beta,17beta-oxazinone-estradiol analogs. PMID- 25728030 TI - Genome-wide identification of target genes of a mating-type alpha-domain transcription factor reveals functions beyond sexual development. AB - Penicillium chrysogenum is the main industrial producer of the beta-lactam antibiotic penicillin, the most commonly used drug in the treatment of bacterial infections. Recently, a functional MAT1-1 locus encoding the alpha-box transcription factor MAT1-1-1 was discovered to control sexual development in P. chrysogenum. As only little was known from any organism about the regulatory functions mediated by MAT1-1-1, we applied chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) to gain new insights into the factors that influence MAT1-1-1 functions on a molecular level and its role in genome wide transcriptional regulatory networks. Most importantly, our data provide evidence for mating-type transcription factor functions that reach far beyond their previously understood role in sexual development. These new roles include regulation of hyphal morphology, asexual development, as well as amino acid, iron, and secondary metabolism. Furthermore, in vitro DNA-protein binding studies and downstream analysis in yeast and P. chrysogenum enabled the identification of a MAT1-1-1 DNA-binding motif, which is highly conserved among euascomycetes. Our studies pave the way to a more general understanding of these master switches for development and metabolism in all fungi, and open up new options for optimization of fungal high production strains. PMID- 25728031 TI - Systematic review of the use of pre-operative simulation and navigation for hepatectomy: current status and future perspectives. AB - Pre-operative simulation using three-dimensional (3D) reconstructions have been suggested to enhance surgical planning of hepatectomy. Evidence on its benefits for hepatectomy patients remains limited. This systematic review examined the use and impact of pre-operative simulation and intraoperative navigation on hepatectomy outcomes. A systematical searched electronic databases for studies reporting on the use and results of simulation and navigation for hepatectomy was performed. The primary outcome was change in operative plan based on simulation. Secondary outcomes included operating time (min), estimated blood loss, surgical margins, 30-day postoperative morbidity and mortality, and study-specific outcomes. From 222 citations, we included 11 studies including 497 patients. All were observational cohort studies. No study compared hepatectomy with and without simulation. All studies performed 3D reconstruction and segmentation, most commonly with volumetrics measurements. In six studies reporting intraoperative navigation, five relied on ultrasound, and one on a resection map. Of two studies reporting on it, the resection line was changed intraoperatively in one third of patients, based on simulation. Virtually predicted liver volumes (Pearson correlation r = 0.917 to 0.995) and surgical margins (r = 0.84 to 0.967) correlated highly with actual ones in eight studies. Heterogeneity of the included studies precluded meta-analysis. Pre-operative simulation seems accurate in measuring volumetrics and surgical margins. Current studies lack intraoperative transposition of simulation for direct navigation. Simulation appears useful planning of hepatectomies, but further work is warranted focusing on the development of improved tools and appraisal of their clinical impact compared to traditional resection. PMID- 25728032 TI - The Little Six Personality Dimensions From Early Childhood to Early Adulthood: Mean-Level Age and Gender Differences in Parents' Reports. AB - The present research pursues three major goals. First, we develop scales to measure the Little Six youth personality dimensions: Extraversion, Agreeableness, Conscientiousness, Neuroticism, Openness to Experience, and Activity. Second, we examine mean-level age and gender differences in the Little Six from early childhood into early adulthood. Third, we examine the development of more specific nuance traits. We analyze parent reports, made using the common-language California Child Q-Set (CCQ), for a cross-sectional sample of 16,000 target children ranging from 3 to 20 years old. We construct CCQ-Little Six scales that reliably measure each Little Six dimension. Using these scales, we find (a) curvilinear, U-shaped age trends for Agreeableness, Conscientiousness, and Openness, with declines followed by subsequent inclines; (b) monotonic, negative age trends for Extraversion and Activity; (c) higher levels of Conscientiousness and Agreeableness among girls than boys, as well as higher levels of Activity among boys than girls; and (d) gender-specific age trends for Neuroticism, with girls scoring higher than boys by mid-adolescence. Finally, we find that several nuance traits show distinctive developmental trends that differ from their superordinate Little Six dimension. These results highlight childhood and adolescence as key periods of personality development. PMID- 25728033 TI - Mitochondrial replacement therapy: Cautiously replace the master manipulator. PMID- 25728034 TI - Marriage and Family Therapy Trainees' Reports of Explicit Weight Bias. AB - Discrimination based on an individual's weight has been observed in health care, education, retail, and other public sectors (Puhl & Huer, Obesity, 17, 941, 2007). Such inequity, known as "weight bias," generates negative short-term and long-term consequences for the individuals that experience it (Puhl & Brownell, Weight bias in health care settings, 2007). Past research has shown that healthcare trainees exhibit weight bias (Phelan et al., Obesity, 22, 1201, 2014; Wigton & McGaghie, Journal of General Internal Medicine, 16, 262, 2001), yet little focus is given to weight bias in marriage and family therapy (MFT) education. The purpose of this study was to survey MFT students (N = 162) to explore weight bias and how contextual factors associate with weight bias. Participants in MFT programs reported explicit weight bias, with specific contextual factors associating with more bias. Female participants reported more fear of gaining weight, and individuals who identified as overweight had higher rates of explicit weight bias. Contextual differences and implications for training programs are discussed. PMID- 25728035 TI - Anterior cruciate ligament injury about 20 years post-treatment: A kinematic analysis of one-leg hop. AB - Reduced dynamic knee stability, often evaluated with one-leg hops (OLHs), is reported after anterior cruciate ligament (ACL) injury. This may lead to long standing altered movement patterns, which are less investigated. 3D kinematics during OLH were explored in 70 persons 23 +/- 2 years after ACL injury; 33 were treated with physiotherapy in combination with ACL reconstruction (ACL(R)) and 37 with physiotherapy alone (ACL(PT)). Comparisons were made to 33 matched controls. We analyzed (a) maximal knee joint angles and range of motion (flexion, abduction, rotation); (b) medio-lateral position of the center of mass (COM) in relation to knee and ankle joint centers, during take-off and landing phases. Unlike controls, ACL-injured displayed leg asymmetries: less knee flexion and less internal rotation at take-off and landing and more lateral COM related to knee and ankle joint of the injured leg at landing. Compared to controls, ACL(R) had larger external rotation of the injured leg at landing. ACL(PT) showed less knee flexion and larger external rotation at take-off and landing, and larger knee abduction at Landing. COM was more medial in relation to the knee at take off and less laterally placed relative to the ankle at landing. ACL injury results in long-term kinematic alterations during OLH, which are less evident for ACL(R). PMID- 25728036 TI - Cardiac autonomic neuropathy: The hidden cardiovascular comorbidity in elderly patients with chronic obstructive pulmonary disease attending primary care settings. AB - AIM: To quantify the prevalence of chronic comorbidities including cardiac autonomic neuropathy among elderly patients with chronic obstructive pulmonary disease (COPD). METHODS: A cross-sectional study was carried out on 175 elderly male patients with COPD attending Ain Shams University Hospital, Cairo, Egypt. The comorbidities that might alter cardiac autonomic function in patients with COPD were identified. The patients without reported comorbidities underwent arterial blood gas analysis, pulmonary function tests and autonomic function assessment using cardiovascular reflexes. RESULTS: A total of 69.14% of the participants presented with comorbidities (group 1), whereas 30.85% of the participants reported no comorbidity (group 2). Among the participants, the most prevalent comorbid diseases were hypertension (34.20%), cor pulmonale (31.42%), ischemic heart disease (20.00%), diabetes (18.28%) and congestive heart failure (13.70%). In group 2, 29.60% and 22.20% of the patients had early and definite cardiac autonomic neuropathy (CAN) respectively. CAN occurred early in the course of the disease with 40.90% of mild COPD cases being affected. The patients with definite CAN had the highest resting heart rate. The presence of CAN was related to hypercapnia, but not hypoxemia or COPD severity. CONCLUSION: COPD has a complex spectrum of comorbidities. Cardiac autonomic neuropathy in elderly male patients with COPD correlated with hypercapnia, but not hypoxemia or the disease severity. PMID- 25728037 TI - Yeast strain affects phenolic concentration in Pinot noir wines made by microwave maceration with early pressing. AB - AIMS: This study examined the effects of yeast strains in a novel winemaking process that had been designed to optimize phenolic extraction and improve production efficiency for Pinot noir winemaking. METHODS AND RESULTS: Microwave maceration with early pressing and co-inoculation of yeast and malolactic bacteria for simultaneous alcoholic and malolactic fermentation was investigated. Yeast treatments (Saccharomyces cerevisiae RC212 and EC1118, and Saccharomyces bayanus AWRI1176) were co-inoculated with Oenococcus oeni PN4 immediately after must microwave maceration. Alcoholic and malolactic fermentation were complete 17 days postinoculation for all three yeast treatments. At 16-month bottle age, the AWRI1176-treated wines had approximately twice the nonbleachable pigment and colour density of wines fermented by EC1118 and RC212. CONCLUSIONS: The novel winemaking process produced Pinot noir wine that was stable 37 days after fruit had been harvested and yeast strain choice significantly impacted the stability and phenolic character of wine. SIGNIFICANCE AND IMPACT OF STUDY: Successful simultaneous alcoholic and malolactic fermentation in 17 days, and a demonstrated lack of inhibition between the yeast strains and malolactic strain applied in this study, provide proof of concept for very rapid red winemaking using the novel winemaking approach described herein. Further investigation would be required to assess strain effects on wine aroma, mouth feel and taste, however, this novel winemaking approach may offer significant industry efficiencies. PMID- 25728038 TI - Cyclophilin D disruption attenuates lipopolysaccharide-induced inflammatory response in primary mouse macrophages. AB - According to recent results, various mitochondrial processes can actively regulate the immune response. In the present report, we studied whether mitochondrial permeability transition (mPT) has such a role. To this end, we compared bacterial lipopolysaccharide (LPS)-induced inflammatory response in cyclophilin D (CypD) knock-out and wild-type mouse resident peritoneal macrophages. CypD is a regulator of mPT; therefore, mPT is damaged in CypD(-/-) cells. We chose this genetic modification-based model because the mPT inhibitor cyclosporine A regulates inflammatory processes by several pathways unrelated to the mitochondria. The LPS increased mitochondrial depolarisation, cellular and mitochondrial reactive oxygen species production, nuclear factor-kappaB activation, and nitrite- and tumour necrosis factor alpha accumulation in wild type cells, but these changes were diminished or absent in the CypD-deficient macrophages. Additionally, LPS enhanced Akt phosphorylation/activation as well as FOXO1 and FOXO3a phosphorylation/inactivation both in wild-type and CypD(-/-) cells. However, Akt and FOXO phosphorylation was significantly more pronounced in CypD-deficient compared to wild-type macrophages. These results provide the first pieces of experimental evidence for the functional regulatory role of mPT in the LPS-induced early inflammatory response of macrophages. PMID- 25728039 TI - Characterization of CD22 expression in acute lymphoblastic leukemia. AB - BACKGROUND: CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). PROCEDURE: Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. RESULTS: CD22 expression was demonstrated in all subjects (n = 163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349-19,653, n = 160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349 3,624, n = 20 versus 3,853 sites/cell, range 451-19,653, n = 140; P = <0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22%-82% CD22 +). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. CONCLUSIONS: These characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population. PMID- 25728040 TI - Bitten by a bug or a bag? Transfusion-transmitted dengue: a rare complication in the bleeding surgical patient. AB - BACKGROUND: Blood-borne infections remain a risk of blood transfusions. While routine screening of donated blood products has greatly reduced the risk of human immunodeficiency virus, hepatitis B, and hepatitis C transmission, arboviruses such as dengue, chikungunya, and the West Nile virus remain significant risks especially during outbreaks. CASE REPORT: We report a rare case of dengue documented to be acquired through a blood transfusion, which resulted in severe thrombocytopenia prolonging admission in hospital in a neurosurgical patient. RESULTS: The donor of one of the units of red blood cells presented with dengue fever 2 days after donating. Sanger sequencing confirmed DENV-2 (dengue virus, Serotype 2) in both the donor and the patient samples and showed 100% nucleotide sequence identity between the two viruses, confirming transfusion-transmitted dengue infection. CONCLUSION: This case highlights the importance of arboviral screening of donor blood, especially for populations in endemic areas during outbreaks. PMID- 25728041 TI - IL-10 inhibits neuraminidase-activated TGF-beta and facilitates Th1 phenotype during early phase of infection. AB - Th1 cells control their activity by producing regulatory IL-10. Here we report that Th1 cell-derived IL-10 facilitates their expansion and, in addition, augments Th1 cell production of IFN-gamma, TNF-alpha and IL-2 during the early phase of influenza. In our antigen-specific mouse experimental system, influenza haemagglutinin-specific CD4(+) T cells respond to infection with the induction of T-bet, and produce both IFN-gamma and IL-10. In the early phase of infection, an abundance of viral neuraminidase causes TGF-beta activation of haemagglutinin specific CD4(+) T cells. CD4(+) T-cell-derived IL-10 inhibits neuraminidase driven TGF-beta activation and counteracts the virus-mediated immune suppression. As the host eradicates the virus, neuraminidase activity wanes and IL-10 receptors are upregulated on CD4(+) T cells in the late phase of infection. IL-10 then suppresses immune activation and aids in recovery from infection and inflammation. These results reveal a previously unrecognized function of Th1 cell derived IL-10 in vivo. PMID- 25728043 TI - Randomizing the unfolded state of peptides (and proteins) by nearest neighbor interactions between unlike residues. AB - To explore the influence of nearest neighbors on conformational biases in unfolded peptides, we combined vibrational and 2D NMR spectroscopy to obtain the conformational distributions of selected "GxyG" host-guest peptides in aqueous solution: GDyG, GSyG, GxLG, GxVG, where x/y=A, K, L, V. Large changes of conformational propensities were observed due to nearest-neighbor interactions, at variance with the isolated pair hypothesis. We found that protonated aspartic acid and serine lose their above-the-average preference for turn-like structures in favor of polyproline II (pPII) populations in the presence of neighbors with bulky side chains. Such residues also decrease the above-the-average pPII preference of alanine. These observations suggest that the underlying mechanism involves a disruption of the hydration shell. Thermodynamic analysis of (3) J(H(N) ,H(alpha) ) (T) data for each x,y residue reveals that modest changes in the conformational ensemble masks larger changes of enthalpy and entropy governing the pPII<->beta equilibrium indicating a significant residue dependent temperature dependence of the peptides' conformational ensembles. These results suggest that nearest-neighbor interactions between unlike residues act as conformational randomizers close to the enthalpy-entropy compensation temperature, eliminating intrinsic biases in favor of largely balanced pPII/beta dominated ensembles at physiological temperatures. PMID- 25728044 TI - A longitudinal case-control study on goals in adolescents with cancer. AB - OBJECTIVE: This study examined whether: (1) the goals of adolescents with cancer at 3 months post-diagnosis (T1) and healthy peers differed in terms of content, valuation, and abstraction level, (2) the content, valuation and abstraction level of the goals of the adolescents with cancer differed between 3 and 12 months post-diagnosis (T2). METHODS: Thirty-three adolescents with cancer and 66 matched controls completed the Personal Project Analysis Inventory. After nine months, the adolescents with cancer completed the measure again. RESULTS: Compared to controls, adolescents with cancer at 3 months post-diagnosis (T1) reported more intrinsic than extrinsic goals, appraised intrinsic goals as more important than extrinsic goals and reported more concrete goals. Within the adolescents with cancer, the content, valuation and abstraction level of the goals did not differ between T1 and T2. CONCLUSIONS: Adolescents recently diagnosed with cancer set different types of goals than healthy peers and continue to set these types of goals until one year post-diagnosis. Future research can help determine how the personal goals of adolescents with cancer develop in the long term and to what extent personal goal setting during cancer influences the attainment of age-graded developmental tasks and well-being. PMID- 25728042 TI - The efficacy of a standalone protective behavioral strategies intervention for students accessing mental health services. AB - Students with poor mental health are at increased risk for problematic alcohol use. These students also tend to underutilize alcohol-related protective behavioral strategies (PBS). Cross-sectional studies indicate that PBS use may be particularly useful for students with mental health challenges; however, it is unclear whether training these students to use PBS is an effective approach for reducing alcohol use and consequences. The current study evaluated the efficacy of a standalone PBS skills training and personalized feedback (PBS-STPF) intervention among students accessing mental health services. Participants (N = 251) were randomly assigned to either an individual facilitator-led PBS-STPF intervention or a health-related control condition. Participants completed online follow-up surveys 1 and 6 months post-intervention which included measures of alcohol use, negative consequences, and a composite measure of PBS use. Relative to control participants, students in the PBS-STPF condition reported significantly greater PBS use but no differences in alcohol use or consequences. Participants in both conditions reported decreases in drinking outcomes over time. Tests of mediation indicated that the intervention indirectly led to reduction in drinking outcomes at 6 months through increased PBS use. Although the intervention resulted in changes in PBS use that were maintained for up to 6 months post-intervention, the effects of the intervention on drinking and consequences were limited. A brief standalone PBS training may need augmentation in order to promote effective use of PBS for substantial decreases in alcohol consequences. PMID- 25728045 TI - Correction: 9,9'-Anthryl-anthroxyl radicals: strategic stabilization of highly reactive phenoxyl radicals. PMID- 25728046 TI - Influence of gravity on transport and retention of representative engineered nanoparticles in quartz sand. AB - Four types of NPs: carbon nanotubes and graphene oxide (carbon-based NPs), titanium dioxide and zinc oxide metal-oxide NPs, were utilized to systematically determine the influence of gravity on the transport of NPs in porous media. Packed column experiments for two types of carbon-based NPs were performed under unfavorable conditions in both up-flow (gravity-negative) and down-flow (gravity positive) orientations, while for two types of metal-oxide NPs, experiments were performed under both unfavorable and favorable conditions in both up-flow and down-flow orientations. Both breakthrough curves and retained profiles of two types of carbon-based NPs in up-flow orientation were equivalent to those in down flow orientation, indicating that gravity had negligible effect on the transport and retention of carbon-based NPs under unfavorable conditions. In contrast, under both unfavorable and favorable conditions, the breakthrough curves for two types of metal-oxide NPs in down-flow orientation were lower relative to those in up-flow orientation, indicating that gravity could decrease the transport of metal-oxide NPs in porous media. The distinct effect of gravity on the transport and retention of carbon-based and metal-oxide NPs was mainly attributed to the contribution of gravity to the force balance on the NPs in quartz sand. The contribution of gravity was determined by the interplay of the density and sizes of NP aggregates under examined solution conditions. PMID- 25728047 TI - Value of resting echocardiographic findings and dobutamine stress echocardiography for diagnosing myocardial ischemia in patients with suspected angina pectoris. AB - BACKGROUND: We evaluated the diagnostic value of resting echocardiographic findings including total heart calcification (THC) score in combination with dobutamine stress echocardiography (DSE) for detection of myocardial ischemia. METHODS: Altogether, 110 patients with suspected angina pectoris underwent resting echocardiography and DSE. On the basis of resting echocardiography, we determined the THC score, left anterior descending artery diastole-to-systole velocity ratio (LAD-DSVR), and positive myocardial velocity during isovolumic relaxation phase (VIVR ) detected by color-coded tissue Doppler imaging. Myocardial ischemia was diagnosed by a 25% or greater reduction in the internal diameter of major coronary vessels with impaired fractional flow reserve (FFR <=0.80). RESULTS: DSE had excellent specificity (89%) but modest sensitivity (52%) for wall-motion abnormality (WMA) analysis. Multivariate analysis showed that THC score >=2 (odds ratio and 95% confidence interval: 4.49 [2.29-10.6]; P = 0.018), LAD-DSVR <=1.5 (6.43 [1.39-20.3], P = 0.019), and duration of positive VIVR >=71 msec (7.93 [3.72-12.1]; P < 0.001) were independent predictors of ischemia. The combination of inducible WMA and THC score yielded significantly higher sensitivity for ischemia detection than the inducible WMA alone (80% vs. 52%, P = 0.0008). Using receiver operating characteristics analyses, adding all three resting echocardiographic findings to clinical variables plus inducible WMA further improved prediction of ischemia (P = 0.028). CONCLUSIONS: Integration of DSE and resting echocardiographic findings describing degree of heart calcification, impaired LAD flow, and extent of delayed ejection motion of the myocardium improves detection of coronary angiogram-based FFR-guided ischemia. PMID- 25728048 TI - Membrane electrospray ionization for direct ultrasensitive biomarker quantitation in biofluids using mass spectrometry. AB - The ability of rapid biomarker quantitation in raw biological samples would expand the application of mass spectrometry in clinical diagnosis. Up until now, the conventional chromatography-mass spectrometry method is time-consuming in both sample preparation and chromatography separation processes, while ambient ionization methods normally suffer from sensitivity. The membrane electrospray ionization (MESI) introduced in this study could not only achieve sensitive biomolecule quantitation, but also minimize the sample handling process. As a unique feature of MESI, both vertical and horizontal chemical separations could be achieved in real-time. With the capability of mass-selectively minimizing matrix effects from salts, small molecules, and macromolecules, ultrasensitive detection of cytochrome C (>500-fold sensitivity improvement) in raw urine samples was demonstrated in less than 20 min. PMID- 25728049 TI - Effects of Wiskott-Aldrich Syndrome Protein Deficiency on IL-10-Producing Regulatory B Cells in Humans and Mice. AB - The Wiskott-Aldrich syndrome protein (WASp) is an important regulator of the actin cytoskeleton and is required for immune cell function. WASp deficiency causes a marked reduction in major mature peripheral B cell subsets, particularly marginal zone (MZ) B cells. We hypothesized that WASp deficiency may also lead to a reduction of regulatory B cells (known as B10 cells) belonging to a novel subset of B cells. And in consideration of the key role of B10 cells play in maintaining peripheral tolerance, we conjectured that a deficit of these cells could contribute to the autoimmunity in patients with Wiskott-Aldrich syndrome (WAS). The effects of WASp deficiency on B10 cells have been reported by only one group, which used an antigen-induced arthritis model. To add more information, we measured the percentage of B10 cells, regulatory T cells (Tregs) and Th1 cells in WASp knockout (WASp KO) mice. We also measured the percentage of B10 cells in patients with WAS by flow cytometry. Importantly, we used the non-induced autoimmune WASp KO mouse model to investigate the association between B10 cell frequency and the Treg/Th1 balance. We found that the percentage of B10 cells was reduced in both mice (steady state and inflammatory state) and in humans and that the lower B10 population correlated with an imbalance in the Treg/Th1 ratio in old WASp KO mice with autoimmune colitis. These findings suggest that WASp plays a crucial role in B10 cell development and that WASp-deficient B10 cells may contribute to autoimmunity in WAS. PMID- 25728050 TI - Theoretical Modeling of Surface Confined Chiral Nanoporous Networks: Cruciform Molecules as Versatile Building Blocks. AB - Patterning of solid surfaces with functional organic molecules has been a convenient route to fabricate two-dimensional materials with programmed architecture and activities. One example is the chiral nanoporous networks that can be created via controlled self-assembly of star-shaped molecules under 2D confinement. In this contribution we use computer modeling to predict the formation of molecular networks in adsorbed overlayers comprising cruciform molecular building blocks equipped with discrete interaction centers. To that end, we employ the Monte Carlo simulation method combined with a coarse-grained representation of the adsorbed molecules which are treated as collections of interconnected segments. The interaction centers within the molecules are represented by active segments whose number and distribution are adjusted. Our particular focus is on those distributions that produce prochiral molecules able to occur in adsorbed configurations being mirror images of each other (surface enantiomers). We demonstrate that, depending on size, aspect ratio, and intramolecular distribution of active sites, the surface enantiomers can co crystallize or segregate into extended homochiral domains with largely diversified nanosized cavities. The insights from our theoretical studies can be helpful in designing 2D chiral porous networks with potential applications in enantioselective adsorption and asymmetric heterogeneous catalysis. PMID- 25728051 TI - Recurrent pneumonia due to olive aspiration in a healthy adult: a case report. PMID- 25728052 TI - Comparative assessment of HIF-1alpha and Akt responses in human lung and skin cells exposed to benzo[alpha]pyrene: Effect of conditioned medium from pre exposed primary fibroblasts. AB - Exposure to atmospheric pollutants has been accused for many adverse health effects. Benzo[alpha]pyrene (Beta[alpha]Rho) in particular, the most extensively studied member of pollutants, is implicated in both cancer initiation and promotion. In the present study, we compared the effects of noncytotoxic doses of Beta[alpha]Rho, between human skin and lung epithelial cells A431 and A549, respectively, focusing on Akt kinase and HIF-1alpha, as it is well known that these proteins are upregulated in various human cancers promoting survival, angiogenesis and metastasis of tumor cells. Also, taking into consideration that fibroblasts are involved in cancer progression, we tested the possible modulation of epithelial cell response by paracrine factors secreted by Beta[alpha]Rho treated fibroblasts. Low doses of Beta[alpha]Rho were found to enhance epithelial cell proliferation and upregulate both Akt kinase and HIF-1alpha, with A549 cells exhibiting a more sustained profile of upregulation. It is to notice that, the response of HIF-1alpha was remarkably early, acting as a sensitive marker in response to airborne pollutants. Also, HIF-1alpha was induced by Beta[alpha]Rho in both lung and skin fibroblasts indicating that this effect may be conserved throughout different cell types and tissues. Interestingly however, the response of both proteins was differentially modified upon treatment with conditioned medium from Beta[alpha]Rho-exposed fibroblasts. This is particularly evident in A459 cells and confirms the critical role of intercellular and paracrine factors in the modulation of the final response to an extracellular signal. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1103-1112, 2016. PMID- 25728053 TI - A meta-analysis of published studies of endothelial dysfunction does not support its routine clinical use. AB - BACKGROUND: Endothelial dysfunction is a marker of future cardiovascular disease (CVD) risk, yet epidemiological studies have yielded inconsistent results. We therefore studied the association between endothelial dysfunction and CVD under diverse circumstances. METHODS AND RESULTS: Literature-based meta-analysis of prospective observational studies with >= 12 months of follow-up published in Medline and having information on endothelial function and CVD outcomes. Tabular data on participant characteristics, endothelial function assessments and incident CVD outcomes were abstracted from individual studies. Random-effects meta-analysis was used to quantify pooled associations, and I(2) statistic to evaluate between-study heterogeneity. Potential sources of heterogeneity were explored by subgroup analyses and meta-regression. Thirty five studies involving 17,206 participants met the inclusion criteria. During more than 80,000 person years of observation, up to 2755 CVD events were accrued, yielding a pooled relative risk (RR) of 1.25 (95% confidence interval 1.15-1.35) for CVD comparing top (i.e. more severe) vs. bottom (less severe) third of endothelial dysfunction. There was significant between-study heterogeneity and evidence of publication bias. RRs varied importantly according to the method used to ascertain endothelial function, and were higher among older individuals and among participants with risk factors for CVD or established CVD at baseline. CONCLUSIONS: Although endothelial dysfunction is an important determinant of cardiovascular outcomes in people with pre-existing CVD, current evidence base does not support its use as a potentially useful measurement for risk stratification in people at lower risk of CVD. PMID- 25728054 TI - Phenanthriporphyrin: an antiaromatic aceneporphyrinoid as a ligand for a hypervalent organophosphorus(V) moiety. AB - The incorporation of a phenanthrene moiety into a porphyrin framework results in the formation of a hybrid macrocycle-phenanthriporphyrin-merging the structural features of polycyclic aromatic hydrocarbons and porphyrins. An antiaromatic aceneporphyrinoid, adopting the trianionic {CCNN} core, is suitable for the incorporation of a phosphorus(V) center to form a hypervalent organophosphorus(V) derivative. PMID- 25728056 TI - Solvent-controlled three families of Zn(II) coordination compounds: synthesis, crystal structure, solvent-induced structural transformation, supramolecular isomerism and photoluminescence. AB - This work reports the assembly, topological structure, supramolecular isomerism and luminescence of three solvent-controlled families of coordination compounds, [Zn(bpz)2(H2O)3.2Hpta] (1), [Zn(bpz)(pta)]n (2), [Zn(bpz)(tpa)(H2O)]n (3), [Zn(bpz)(tpa).4H2O]n (4), and [Zn(bpz)(npa).H2O]n (5 and 6) (bpz = 3,3',5,5' tetramethyl-4,4'-bipyrazole, H2pta = phthalic acid, H2tpa = terephthalic acid, H2npa = 4-nitrophthalic acid). The six transition metal compounds reported in this study were definitely characterized by X-ray crystallography to reveal how networks with different topologies are constructed around the same four-connected metal centers. Compound 1 is a 0D discrete molecule, in which Zn(II) is in a trigonal bipyramidal coordination geometry, whereas the guest Hpta(-) as counteranion is hydrogen-bonded with the [Zn(bpz)2(H2O)3]. In compound 2, the Zn(II) center is linked by two bpz and two pta; thus, a 4-connected dia network with the point symbol {6(6)} is formed. In 3, the Zn(II) center is six coordinated, but in fact it is also a 4-connected node in the whole network due to the terminal aqua ligand and bidentate chelating carboxylate group thus, the resultant network has a 4-connected cds topology with the point symbol {6(5).8}. Compound 4 exhibits a chiral two-fold interpenetrated 4-connected qtz network with the point symbol {6(4).8(2)}. Compounds 5 and 6 are a pair of genuine supramolecular isomers with identical 4-connected dia topology. The three families of compounds, namely, 1/2, 3/4, and 5/6, are structurally controlled by the solvent systems H2O/CH3OH-H2O, H2O/DMF-CH3OH, and CH3OH-H2O/CH3CN-H2O, respectively. Except for the discrete molecule 1, the other five compounds have the same 4-connected coordination networks, but with different topologies ranging from dia (2, 5, 6), cds (3) to qtz (4), suggesting the important influences that the linkage orientations of the ligand and different geometries of the 4 connected node exert in self-assembly. Interestingly, discrete 1 can be irreversibly transformed from a 0D discrete molecule to an infinite 3D structure (2) by heating it in CH3OH-H2O solvent, indicating a solvent-induced structural transformation. In addition, results about thermal stabilities and photoluminescence spectra are also discussed in detail. PMID- 25728055 TI - Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion. AB - Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype. PMID- 25728057 TI - Treatment-related toxicities in older adults with head and neck cancer: A population-based analysis. AB - BACKGROUND: Despite advantages in terms of cancer control and organ preservation, the benefits of chemotherapy and radiation therapy (CTRT) may be offset by potentially severe treatment-related toxicities, particularly in older patients. The objectives of this study were to assess the types and frequencies of toxicities in older adults with locally or regionally advanced head and neck squamous cell carcinoma (HNSCC) who were receiving either primary CTRT or radiation therapy (RT) alone. METHODS: With Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims, patients who were 66 years old or older with locally advanced HNSCC, were diagnosed from 2001 to 2009, and received CTRT or RT alone were identified. Differences in the frequency of toxicity-related hospital admissions and emergency room visits as well as feeding tube use were examined, and controlling for demographic and disease characteristics, this study estimated the impact of chemotherapy on the likelihood of toxicity. RESULTS: Among patients who received CTRT (n = 1502), 62% had a treatment-related toxicity, whereas 46% of patients who received RT alone (n = 775) did. When the study controlled for demographic and disease characteristics, CTRT patients were twice as likely to experience an acute toxicity in comparison with their RT-only peers. Fifty-five percent of CTRT patients had a feeding tube placed during or after treatment, whereas 28% of the RT-only group did. CONCLUSIONS: In this population-based cohort of older adults with HNSCC, the rates of acute toxicities and feeding tube use in patients receiving CTRT were considerable. It is possible that for certain older patients, the potential benefit of adding chemotherapy to RT does not outweigh the harms of this combined-modality therapy. PMID- 25728058 TI - Sputum and BAL Clara cell secretory protein and surfactant protein D levels in asthma. AB - Clara cell secretory protein (CC16) is associated with Th2 modulation. Surfactant protein D (SPD) plays an important role in surfactant homeostasis and eosinophil chemotaxis. We measured CC16 and SPD in sputum supernatants of 84 asthmatic patients and 12 healthy controls. In 22 asthmatics, we additionally measured CC16 and SPD levels in BAL and assessed smooth muscle area (SMA), reticular basement membrane (RBM) thickness, and epithelial detachment (ED) in bronchial biopsies. Induced sputum CC16 and SPD were significantly higher in patients with severe asthma (SRA) compared to mild-moderate and healthy controls. BAL CC16 and SPD levels were also higher in SRA compared to mild-moderate asthma. CC16 BAL levels correlated with ED, while SPD BAL levels correlated with SMA and RBM. Severity represented a significant covariate for these associations. CC16 and SPD levels are upregulated in SRA and correlate with remodeling indices, suggesting a possible role of these biomarkers in the remodeling process. PMID- 25728059 TI - Trends of the HIV/AIDS epidemic in Lyon University Hospitals from 1985 to 2011: continuous decrease since the introduction of HAART. PMID- 25728060 TI - Factors affecting fruit and vegetable school lunch waste in Wisconsin elementary schools participating in Farm to School programmes. AB - OBJECTIVE: To examine characteristics potentially associated with school lunch fruit and vegetable waste, both overall and pre/post implementation of the Healthy, Hunger-Free Kids Act. DESIGN: Multi-year (2010-2013) cross-sectional study using pre- and post-meal digital photographs of students' school lunch trays to estimate fruit and vegetable availability and consumption. Fruit and vegetable items were categorized for factors suspected to impact waste: prior farm to school years, placement (main menu, salad bar), procurement (local, conventional), preparation (cooked, raw) and meal component (entree, side, topping). Analyses to assess within-category differences in waste volume were performed using a Tobit model. SETTING: Wisconsin elementary schools participating in farm to school programmes, USA. SUBJECTS: Children in third to fifth grade. RESULTS: Many within-factor differences were detected overall and/or across time. Cooked fruits were wasted less than raw, while cooked vegetables were wasted more than raw. Where identified, locally sourced items were wasted more than conventionally sourced (+0.1 cups, P<0.0001) and salad bar items more than main menu items (+0.01 cups, P<0.0001). Increasing prior farm to school years decreased waste (-0.02 cups, P<0.0001). Items previously tried were wasted at the same volume whether reported as liked or not. New school lunch meal pattern requirement implementation did not uniformly impact fruit and vegetable waste across all categories and there was no change in waste for seven of fifteen assessed categories. CONCLUSIONS: Many factors impact elementary students' school lunch waste. These factors may be helpful for school food-service authorities to consider when planning school menus. PMID- 25728061 TI - Dynamic transition of transcription and chromatin landscape during fission yeast adaptation to glucose starvation. AB - Shortage of glucose, the primary energy source for all organisms, is one of the most critical stresses influencing cell viability. Glucose starvation promptly induces changes in mRNA and noncoding RNA (ncRNA) transcription. We previously reported that glucose starvation induces long ncRNA (lncRNA) transcription in the 5' segment of a fission yeast gluconeogenesis gene (fbp1+), which leads to stepwise chromatin alteration around the fbp1+ promoter and to subsequent robust gene activation. Here, we analyzed genomewide transcription by strand-specific RNA sequencing, together with chromatin landscape by immunoprecipitation sequencing (ChIP-seq). Clustering analysis showed that distinct mRNAs and ncRNAs are induced at the early, middle and later stages of cellular response to glucose starvation. The starvation-induced transcription depends substantially on the stress-responsive transcription factor Atf1. Using a new computer program that examines dynamic changes in expression patterns, we identified ncRNAs with similar behavior to the fbp1+ lncRNA. We confirmed that there are continuous lncRNAs associated with local reduction of histone density. Overlapping with the regions for transcription of these lncRNAs, antisense RNAs are antagonistically transcribed under glucose-rich conditions. These results suggest that Atf1 dependent integrated networks of mRNA and lncRNA govern drastic changes in cell physiology in response to glucose starvation. PMID- 25728062 TI - Response of Corynebacterium glutamicum exposed to oscillating cultivation conditions in a two- and a novel three-compartment scale-down bioreactor. AB - The oscillatory conditions in substrate and oxygen supply that typically occur on a large (industrial) scale are usually simulated in two-compartment scale-down reactors. In this study, the performance of nutrient-limited fed-batch cultivations of Corynebacterium glutamicum in a standard two-compartment reactor (two-CR) is compared to the performance in a novel three-compartment reactor (three-CR). The three-CR is designed to mimic three distinct zones of an industrial scale bioreactor that occur if the feed addition is installed at the bottom of the fluid phase. Our findings show that lactate and succinate appear in concentrations two-fold higher in the three-CR cultivation than in the two-CR cultivation. Similar results are revealed for the amino acids glycine, threonine, glutamate, and glutamine. In contrast to the two-CR cultivation, no intracellular accumulation of pyruvate is observed in the three-CR cultivation, since the carbon fluxes are directed toward lactate. As previously reported, the expression of lactate dehydrogenase (LDH) is increased in the context of oxygen deprivation. Thus, C. glutamicum adapts to the oscillating environment in the three-CR. This successful adaptation is revealed by a flow cytometric analysis of BOX-stained cells and a series of electrooptical at line measurements of cell polarisability. Both methods indicate a higher polarisability of cells in the three-CR cultivation. PI-staining does not indicate any membrane damage or accelerated cell death in either system. However, although the strain shows robustness, the product yield of lysine is reduced in scale-down cultivations as compared to cultivations at homogeneous conditions, which underlines the relevance of process optimization. PMID- 25728063 TI - Performance-based contracting in home-care work in The Netherlands: professionalism under pressure? AB - Our aim was to improve the understanding of the relationships between performance based contracting, management supportiveness and professionalism in home care. Using path analysis, this article explores the relationships between home-care workers' perceptions of management support, implementation of performance-based contracting (i.e. use of strict time registration rules and cost-efficiency measures) and autonomy and intrinsic job satisfaction. We hypothesised that: use of strict time registration rules and cost-efficiency measures relates to lower levels of autonomy and intrinsic job satisfaction (H1); there is an indirect relationship between use of strict time registration rules and use of cost efficiency measures and intrinsic job satisfaction via autonomy (H2); higher levels of management support relate to the use of looser time registration rules and less use of cost-efficiency measures (H3); and higher levels of management support relate to higher levels of autonomy and intrinsic job satisfaction (H4). We used data from a cross-sectional survey conducted in 2010 of a sample of Dutch home-care workers (N = 156, response rate = 34%). Overall, our study suggests that the consequences of performance-based contracting for professionalism are ambiguous. More specifically, using strict time registration rules is related to lower levels of autonomy, whereas using cost-efficiency measures does not seem to affect autonomy (H1). Performance-based contracting has no consequences for the level of fulfilment home-care workers find in their job, as neither of the two contracting dimensions measured was directly or indirectly related to intrinsic job satisfaction (H1, H2). The role of managers must be taken into account when studying performance-based contracting, because perceived higher management support is related to managers' less frequent use of both strict time registration rules and of cost-efficiency measures (H3). The insight we gained into the importance of supportive managers for both autonomy and job satisfaction (H4) can help home-care organisations improve the attractiveness of home-care work. PMID- 25728064 TI - A presentation of iridoschisis with plateau iris: an imaging study. PMID- 25728065 TI - Polymer-based nanoparticles for oral insulin delivery: Revisited approaches. AB - Diabetes mellitus is a high prevalence and one of the most severe and lethal diseases in the world. Insulin is commonly used to treat diabetes in order to give patients a better life condition. However, due to bioavailability problems, the most common route of insulin administration is the subcutaneous route, which may present patients compliance problems to treatment. The oral administration is thus considered the most convenient alternative to deliver insulin, but it faces important challenges. The low stability of insulin in the gastrointestinal tract and low intestinal permeation, are problems to overcome. Therefore, the encapsulation of insulin into polymer-based nanoparticles is presented as a good strategy to improve insulin oral bioavailability. In the last years, different strategies and polymers have been used to encapsulate insulin and deliver it orally. Polymers with distinct properties from natural or synthetic sources have been used to achieve this aim, and among them may be found chitosan, dextran, alginate, poly(gamma-glutamic acid), hyaluronic acid, poly(lactic acid), poly(lactide-co-glycolic acid), polycaprolactone (PCL), acrylic polymers and polyallylamine. Promising studies have been developed and positive results were obtained, but there is not a polymeric-based nanoparticle system to deliver insulin orally available in the market yet. There is also a lack of long term toxicity studies about the safety of the developed carriers. Thus, the aims of this review are first to provide a deep understanding on the oral delivery of insulin and the possible routes for its uptake, and then to overview the evolution of this field in the last years of research of insulin-loaded polymer based nanoparticles in the academic and industrial fields. Toxicity concerns of the discussed nanocarriers are also addressed. PMID- 25728066 TI - Novel approaches of producing bioenergies from microalgae: A recent review. AB - Microalgae have caught the world's attention for its potential to solve one of the world's most pressing issues-sustainable green energy. Compared to biofuels supplied by oil palm, rapeseed, soybean and sugar cane, microalgae alone can be manipulated to generate larger amounts of biodiesel, bioethanol, biohydrogen and biomass in a shorter time. Apart from higher productivity, microalgae can also grow using brackish water on non-arable land, greatly reducing the competition with food and cash crops. Hence, numerous efforts have been put into the commercialisation of microalgae-derived biofuel by both the government and private bodies. This paper serves to review conventional and novel methods for microalgae culture and biomass harvest, as well as recent developments in techniques for microalgal biofuel production. PMID- 25728067 TI - Impact of synthetic biology and metabolic engineering on industrial production of fine chemicals. AB - Industrial bio-processes for fine chemical production are increasingly relying on cell factories developed through metabolic engineering and synthetic biology. The use of high throughput techniques and automation for the design of cell factories, and especially platform strains, has played an important role in the transition from laboratory research to industrial production. Model organisms such as Saccharomyces cerevisiae and Escherichia coli remain widely used host strains for industrial production due to their robust and desirable traits. This review describes some of the bio-based fine chemicals that have reached the market, key metabolic engineering tools that have allowed this to happen and some of the companies that are currently utilizing these technologies for developing industrial production processes. PMID- 25728068 TI - Quantitative proteomic analysis of Giardia duodenalis assemblage A: A baseline for host, assemblage, and isolate variation. AB - Giardia duodenalis is a gastrointestinal protozoan parasite of vertebrates and is a species complex comprised of eight assemblages, with the zoonotic assemblage A one of two subtypes infective for humans. With increasing genomic and transcriptomic data publicly available through the centralized giardiaDB.org, we have quantitatively analyzed the proteomes of eight G. duodenalis assemblage A strains (seven A1 and one A2) to provide a proteomic baseline to complement the available data. A nonredundant total of 1197 subassemblage A1 proteins and 719 subassemblage A2 proteins were identified with an average of 770 proteins in each strain. The eight strains were also searched against both assemblage A genome sequences (subassemblage A1 and A2 genomes) and demonstrated subassemblage specific differences in protein identifications, especially for variable gene families. Substantial differences were observed in the numbers and abundance in the variable surface protein family, and two different variable surface protein expression profiles that were independent of host origin, subassemblage, or geographic origin. We hypothesize that this variation in surface antigen switching events may be related to karotype and chromosomal variation, which would indicate an assemblage-independent mechanism of diversity generation in G. duodenalis. All MS data have been deposited in the ProteomeXchange with identifier PXD001272 (http://proteomecentral.proteomexchange.org/dataset/PXD001272). PMID- 25728069 TI - Proven and probable invasive fungal infections in children with acute lymphoblastic leukaemia: results from an university hospital, 2005-2013. AB - Despite improvements in diagnosis and treatment, invasive fungal infections (IFIs) are still a major cause of morbidity and mortality in immunocompromised patients. The data on IFI among children with acute lymphoblastic leukaemia (ALL) are still scarce, and our aim was to estimate the risk, aetiology and outcome of proven and probable IFIs in children with ALL who did not receive primary prophylaxis over an 8-year period. Between January 2005 and February 2013, 125 children who were treated for ALL at the Pediatric Hematology Department of the Medical School of Ege University were retrospectively reviewed. Proven and probable IFIs were defined according to revised definitions of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. The proven and probable IFI incidence was 30/125 (24%). Profound neutropenia was detected in 18 (60%) patients, and prolonged neutropenia was detected in 16 (53.3%) of the patients. The most isolated agents were non albicans Candida spp. The crude and attributable mortality was 20% and 13.3% respectively. Profound neutropenia was associated with mortality (P < 0.05). The younger patients were especially at risk for proven IFI. Prolonged neutropenia, to be in the induction phase of chemotherapy, and profound neutropenia were found to be the most common predisposing factors for IFI episodes. PMID- 25728070 TI - Role of rhinovirus load in the upper respiratory tract and severity of symptoms in lung transplant recipients. AB - BACKGROUND: Rhinovirus is the most common cause of respiratory viral infections and leads to frequent respiratory symptoms in lung transplant recipients. However, it remains unknown whether the rhinovirus load correlates with the severity of symptoms. OBJECTIVES: This study aimed to better characterize the pathogenesis of rhinoviral infection and the way in which viral load correlates with symptoms. STUDY DESIGN: We assessed rhinovirus load in positive upper respiratory specimens of patients enrolled prospectively in a cohort of 116 lung transplant recipients. Rhinovirus load was quantified according to a validated in house, real-time, reverse transcription polymerase chain reaction in pooled nasopharyngeal and pharyngeal swabs. Symptoms were recorded in a standardised case report form completed at each screening/routine follow-up visit, or during any emergency visit occurring during the 3-year study. RESULTS: Rhinovirus infections were very frequent, including in asymptomatic patients not seeking a specific medical consultation. Rhinovirus load ranged between 4.1 and 8.3 log copies/ml according to the type of visit and clinical presentation. Patients with highest symptom scores tended to have higher viral loads, particularly those presenting systemic symptoms. When considering symptoms individually, rhinovirus load was significantly higher in the presence of symptoms such as sore throat, fever, sputum production, cough, and fatigue. There was no association between tacrolimus levels and rhinovirus load. CONCLUSIONS: Rhinovirus infections are very frequent in lung transplant recipients and rhinoviral load in the upper respiratory tract is relatively high even in asymptomatic patients. Patients with the highest symptom scores tend to have a higher rhinovirus load. PMID- 25728071 TI - Molecular epidemiology of newly acquired hepatitis C infections in England 2008 2011: genotype, phylogeny and mutation analysis. AB - BACKGROUND: Analysis of laboratory testing data collected through the Sentinel Surveillance programme has provided a method for identifying individuals who have recently acquired their hepatitis C virus (HCV) infection. Access to samples from these individuals provided a rare opportunity to undertake molecular characterization studies. OBJECTIVES: To describe the epidemiology and genetic diversity of hepatitis C in recent seroconverter infections and to predict how this will impact on HCV treatment and control. STUDY DESIGN: One hundred and forty seven samples were available from individuals, identified to have recently acquired their HCV infection. Genotype determination with additional phylogenetic analysis was carried out on NS5B sequences. Analysis across the NS3 region investigated the presence of antiviral resistance mutations. Where possible, molecular data was linked to demographic and risk/behavioural factor information. RESULTS: The majority of new infections occurred in males with a mean age of 37 years. The most commonly observed genotypes were 1a (49%) and 3a (42%) and injecting drug use (58%) was the most common risk factor. Genotype distribution differed between persons who inject drugs and those with other risk factors suggesting two possible epidemics. Phylogenetic analysis indicated possible transmission networks within specific risk groups. Amino acid changes associated with antiviral resistance were noted in the NS3 region in some samples. CONCLUSIONS: Continued surveillance of linked molecular, virological, demographic and epidemiological information on recently acquired infections will contribute to understanding the on-going HCV epidemic in England. PMID- 25728072 TI - Dolutegravir for the treatment of HIV-2 infection. AB - BACKGROUND: Therapeutic options are limited for HIV-2 infected persons, largely in part due to the lack of susceptibility to HIV-1 non-nucleoside reverse transcriptase inhibitors and poor susceptibility to some HIV-1 protease inhibitors. This is particularly worrisome for HIV-2 patients with prior antiretroviral failure. OBJECTIVES: Report the virological response to dolutegravir in HIV-2-infected individuals. STUDY DESIGN: Retrospective observational assessment of all HIV-2 individuals treated with dolutegravir in Spain. RESULTS: From 297 HIV-2-infected individuals recorded at the Spanish national registry, 26% received antiretroviral therapy. Six out of 8 failing on raltegravir selected for integrase resistance mutations N155H (4), Y143G (1) and Q148R (1). Two patients bearing N155H subsequently received dolutegravir. Both experienced initially more than 1.5 log drop in plasma HIV-2 RNA and significant CD4 gains. Whereas one kept on undetectable viremia 6 months later, the other experienced viral rebound. CONCLUSION: Dolutegravir may be a good therapeutic option for patients with HIV-2 infection, including those that previously failed other integrase inhibitors. PMID- 25728073 TI - West Nile virus lineage 2 infection in a blood donor from Vienna, Austria, August 2014. AB - Eastern Austria is neighbouring regions with ongoing West Nile virus (WNV) transmissions. Three human WNV infections had been diagnosed during the past decade in Austria. The Austrian Red Cross Blood Service (ARC-BS) started a first voluntary screening for WNV in blood donors from Eastern Austria by Nucleic Acid Testing (NAT) in June 2014. This is also the most extensive WNV surveillance programme in humans in Austria so far. In August 2014, one autochthonous WNV infection was detected in a blood donor from Vienna. By now, one in 67,800 whole blood donations was found to be positive for WNV RNA. PMID- 25728074 TI - Evaluation of the Elecsys((r)) Anti-HCV II assay for routine hepatitis C virus screening of different Asian Pacific populations and detection of early infection. AB - BACKGROUND: Early diagnosis of hepatitis C virus (HCV) infection is essential to allow appropriate treatment and prevent transmission. OBJECTIVES: To evaluate the Elecsys((r)) Anti-HCV II assay as a routine screening assay in Asia using a large number of samples from different Asian Pacific populations and compare its performance with other HCV assays routinely used in the region. STUDY DESIGN: The sensitivity and specificity of the Elecsys((r)) Anti-HCV II assay were determined using routine hospital samples and compared with at least one of the following comparator assays at nine independent centers: ARCHITECTTM Anti-HCV; Serodia((r)) HCV Particle Agglutination; Vitros((r)) ECi Anti-HCV; Elecsys((r)) Anti-HCV; ADVIA Centaur((r)) HCV; InTec((r)) HCV EIA; or Livzon((r)) Anti-HCV. Commercially available seroconversion panels were used to assess sensitivity for early detection of infection. RESULTS: The Elecsys((r)) Anti-HCV II assay was more sensitive in recognizing early infection and detected acute HCV infection earlier on average than the comparator assays for all six panels tested. 7,726 routine samples were tested and 322 identified as HCV positive. Elecsys((r)) Anti-HCV II had a sensitivity of 100% and a specificity of 99.66%, both of which were comparable or superior to the results obtained for competitor assays, which ranged from 87.5-100% and 98.98-100%, respectively. CONCLUSIONS: The Elecsys((r)) Anti-HCV II assay has the sensitivity and specificity to support its use as a routine screening method in the Asia Pacific region. Furthermore, this assay shortens the diagnostic window between infection and the detection of antibodies compared with established methods. PMID- 25728075 TI - WU and KI polyomaviruses in respiratory, blood and urine samples from renal transplant patients. AB - BACKGROUND: It is suggested that immunosuppression due to transplantation might be a risk for human polyomavirus KI (KIPyV) and WU (WUPyV) infection. Most of the publications report data about stem cell transplant patients, little is known about these virus infections in renal transplant patients. OBJECTIVES: To study the presence of KIPyV and WUPyV in upper respiratory, plasma and urine samples from renal transplant patients. To analyse clinical and personal data. STUDY DESIGN: 532 respiratory, 503 plasma and 464 urine samples were collected from 77 renal transplant patients. KIPyV and WUPyV were detected by nested and quantitative real-time PCR. Patient and clinical data from medical records were analyzed. RESULTS: KIPyV was detected in respiratory, plasma and urine samples from 14.3%, 3.9% and 4.1% of renal transplant patients. WUPyV was found in respiratory and plasma specimens from 9.1% and 5.3% of the patients. Significant association was revealed between the detection of KIPyV and WUPyV and the time of samples collection and the age of the patients. KIPyV was presented in respiratory and plasma sample at the same time. KIPyV was detected in plasma samples from two patients and in urine samples of three other patients providing also KIPyV positive respiratory samples at the same time. No clinical consequences of KIPyV or WUPyV infection were found. CONCLUSION: Although no clinical consequences of KIPyV and WUPyV infections were found in renal transplant patients, it is suggested that renal transplantation might result in higher susceptibility or reactivation of these infection. PMID- 25728076 TI - Measles elimination in Italy: data from laboratory activity, 2011-2013. AB - BACKGROUND: The European Regional Office of the World Health Organization developed a strategic approach to halt the indigenous transmission of measles in its 53 Member States by 2015, World Health Organization [1]. Many European countries, including Italy began the implementation of national programs to reach this goal. OBJECTIVES: To describe and discuss the results of laboratory activity in measles surveillance, performed from January 2011 to December 2013 by the Italian National Reference Laboratory for Measles and Rubella. STUDY DESIGN: Samples of suspected measles cases were collected from different Italian regions to confirm clinical diagnosis. Anti-measles IgM antibodies detection by Enzyme Linked Immunosorbent Assay and/or molecular detection by Reverse Transcriptase Polymerase Chain Reaction assay were performed. Positive samples were sequenced for viral characterization. RESULTS AND CONCLUSIONS: According to results from the National Reference Laboratory's activity urine and blood seem to be the best specimens for measles laboratory surveillance. Phylogenetic analysis revealed a co-circulation of the genotypes D4 and D8 during the reviewed period, a cluster of B3 and sporadic cases of D9 and H1. PMID- 25728077 TI - Conjunctival geographic ulcer: an overlooked sign of herpes simplex virus infection. AB - Herpes simplex virus (HSV) ocular infection causes significant visual burden worldwide. Despite the fact that dendritic or geographic corneal ulcers are typical findings in HSV epithelial keratitis, conjunctival ulcer as a sign of HSV infection has rarely been reported. Although easily overlooked, this important sign could be enhanced by fluorescein staining. We report two cases of conjunctival geographic ulcers proven to be HSV infection by viral isolation and polymerase chain reaction (PCR). One patient had bilateral disease and blepharitis, and the other had unilateral involvement without skin lesions. With timely diagnosis and proper management, excellent visual outcome can be expected. PMID- 25728078 TI - Primary human cytomegalovirus infections: kinetics of ELISA-IgG and neutralizing antibody in pauci/asymptomatic pregnant women vs symptomatic non-pregnant subjects. AB - BACKGROUND: Human cytomegalovirus infections are mostly asymptomatic in infants and young children, while they are often associated with overt clinical symptoms in adults. OBJECTIVES: To verify whether the antibody response to HCMV is more potent in symptomatic non-pregnant adults as compared to asymptomatic/paucisymptomatic pregnant women. STUDY DESIGN: Overall, 36 consecutive pregnant women with primary HCMV infection were compared with 10 consecutive symptomatic non-pregnant subjects with primary HCMV infection and overt clinical symptoms. Levels of IgG antibody responses to HCMV-infected cell lysate and the pentamer gH/gL/pUL128L, gH/gL and gB HCMV glycoprotein complexes as well as neutralizing antibodies preventing infection of epithelial cells (ARPE 19) and human embryonic lung fibroblast (HELF) cells were compared at intervals of 1-30, 31-60, 61-90, 91-180 and 181-360 days after onset of infection. In parallel, viral load was quantified by real-time PCR. RESULTS: In symptomatic non pregnant subjects, the IgG responses to HCMV lysate as well as to gH/gL and ARPE 19 neutralizing antibodies were significantly higher from 31 to 60 through 180 days after infection onset. In the same patients, the IgG antibody responses to the pentamer and HELF-neutralizing antibody were significantly higher starting 90 days post-infection. CONCLUSIONS: The presence of overt clinical symptoms is associated with a significantly higher antibody response (concomitantly with a higher viral load) in non-pregnant subjects with symptomatic primary HCMV infection as compared to pregnant women with paucisymptomatic/ asymptomatic primary infection (and lower viral load). PMID- 25728079 TI - Pregnant women infected with pandemic influenza A(H1N1)pdm09 virus showed differential immune response correlated with disease severity. AB - BACKGROUND: During pregnancy, immunological and hormonal alterations place women at increased risk for influenza-related severe illnesses including hospitalization and death. Although A(H1N1) pdm09 infection resulted in increased disease severity in pregnant women, the precise mechanisms responsible for this risk have yet to be established. OBJECTIVES: The present study was aimed to investigate the role of host chemokines and cytokine profiles in A(H1N1) pdm09 infection regarding disease severity in pregnant women. STUDY DESIGN: This retrospective survey examined 41 pregnant women with confirmed A(H1N1) pdm09 infection. Of them, 12 died (D), 29 survived (S), and 17 remained uninfected and served as controls (C). Antiviral response was evaluated for IFN-beta expression and gene expression profiles of cytokines (TNF-alpha, IL-6, IL-12, TGF-beta) and chemokines (IL-8, RANTES, MCP-1, IP-10), and the viral Matrix (M1) gene was quantified and normalized using the housekeeping gene product beta-actin mRNA. RESULTS: Higher IL-8 and TNF-alpha mRNA expression were found in D and S compared with C, while IL-6 showed higher expression in D. Interestingly, these results were associated with a decrease in the anti-inflammatory response of TGF-beta mRNA and IFN-beta. These alterations would lead to an imbalance in the immune response of those patients. CONCLUSIONS: Pregnancy-related reductions in IFN-beta and TGF-beta expression levels and elevated levels of pro-inflammatory cytokines could explain the increased severity of infection and death of pregnant women. These findings may help improve the understanding of the high susceptibility and disease severity to influenza virus infection during pregnancy. PMID- 25728080 TI - Detection of respiratory viruses in gargle specimens of healthy children. AB - BACKGROUND: Respiratory tract viral infection is one of the most common and important diseases in children. Polymerase chain reaction (PCR) tests are often used to detect viruses in samples, it is difficult to interpret the clinical significance of PCR positivity, which may reflect a past, imminent or active asymptomatic infection due to their high sensitivity. Although single respiratory viruses have been detected in samples from children with symptoms, other respiratory viruses can also be detected simultaneously. However, the clinical importance of these findings for the symptoms is not known. OBJECTIVES: To investigate the prevalence of respiratory viruses among children without any symptoms such as acute respiratory illness and/or fever. STUDY DESIGN: From week twenty-five 2013 to week twenty-six 2014, gargle samples were collected from children once a week and these samples were subjected to real-time PCR to detect respiratory viruses. On each sampling day, we asked the parents about their children's health condition. RESULTS: Among the 286 samples collected, 200 were from asymptomatic children. In the asymptomatic condition, human parechovirus, adenovirus, enterovirus, rhinovirus, coronavirus 229E and HKU1 were observed in 45 episodes. In samples from symptomatic children, parainfluenza viruses, respiratory syncytial virus and coronavirus OC43 were detected in addition to those mentioned above. CONCLUSIONS: Various viruses of different species were detected in the specimens from the children regardless of their health status. It might be speculated that host factors such as the function of the immune system influence the clinical outcome of the infection. However, this needs to be studied further. PMID- 25728081 TI - Clinical implications of hepatitis B viral infection in Epstein-Barr virus associated nasopharyngeal carcinoma. AB - BACKGROUND: Little is known about the clinical implication of hepatitis B virus (HBV) infection in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). OBJECTIVE: This study aimed to investigate the clinical characteristics and prognostic factors in patients with newly-diagnosed NPC with HBV infection. STUDY DESIGN: A total of 722 patients with pathologically-diagnosed NPC who received comprehensive treatment at First People's Hospital of Foshan between June 2006 and December 2011 were enrolled in this retrospective study; 79 and 643 patients were HBsAg(+) and HBsAg(-), respectively. The correlations between HBV (HBsAg status and HBV DNA load) and EBV DNA were analyzed, further long-term survival and prognostic factors also were explored. RESULTS: We reported NPC patients with HBsAg(+) represented worse outcome, and distant-failure especially liver metastasis was more common in these patients. HBV infection was more frequent in younger patients and male patients. No correlation was observed between the pre-treatment plasma EBV DNA load (cutoff, 1500 copies/ml) and HBsAg status (positive or negative; r=-0.036, P=0.392), or the pre-treatment plasma EBV DNA load and HBV DNA load (r = 0.042, P = 0823). CONCLUSIONS: Both HBV and EBV infection is an independent negative prognostic factor for long-term survival, distant metastasis, especially liver metastasis, was more common in NPC patients with HBsAg(+), and it seemed no link between EBV DNA load and HBsAg status in NPC. PMID- 25728082 TI - Absence of HTLV-1/2 infection among HCV-infected patients with no HIV-1/2 infection in Spain. PMID- 25728084 TI - Reliable typing of MERS-CoV variants with a small genome fragment. AB - BACKGROUND: Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging pathogen that causes lower respiratory tract infection in humans. Camels are the likely animal source for zoonotic infection, although exact transmission modes remain to be determined. Human-to-human transmission occurs sporadically. The wide geographic distribution of MERS-CoV among dromedary camels and ongoing transmissions to humans provides concern for the evolution of a MERS-CoV variant with efficient human-to-human transmission capabilities. Phylogenetic analysis of MERS-CoV has occurred by analysis of full-length genomes or multiple concatenated genome fragments, which is time-consuming, costly and limited to high viral load samples. OBJECTIVE: To develop a simple, reliable MERS-CoV variant typing assay to facilitate monitoring of MERS-CoV diversity in animals and humans. STUDY DESIGN: Phylogenetic analysis of presently known full-length MERS-CoV genomes was performed to identify genomic regions with sufficient phylogenetic content to allow reliable MERS-CoV variant typing. RT-PCR assays targeting these regions were designed and optimized. RESULTS: A reverse-transcription PCR assay for MERS CoV targeting a 615 bp spike fragment provides a phylogenetic clustering of MERS CoV variants comparable to that of full-length genomes. The detection limit corresponds to a cycle treshold value of ~ 35 with standard upE real time PCR assays on RNA isolated from MERS-CoV EMC. Nasal swabs from RT-PCR positive camels (Ct values 12.9-32.2) yielded reliable sequence information in 14 samples. CONCLUSIONS: We developed a simple, reliable MERS-CoV variant typing assay which is crucial in monitoring MERS-CoV circulation in real time with relatively little investment on location. PMID- 25728083 TI - Epidemiologic, clinical, and virologic characteristics of human rhinovirus infection among otherwise healthy children and adults: rhinovirus among adults and children. AB - BACKGROUND: human rhinovirus (HRV) is a major cause of influenza-like illness (ILI) in adults and children. Differences in disease severity by HRV species have been described among hospitalized patients with underlying illness. Less is known about the clinical and virologic characteristics of HRV infection among otherwise healthy populations, particularly adults. OBJECTIVES: to characterize molecular epidemiology of HRV and association between HRV species and clinical presentation and viral shedding. STUDY DESIGN: observational, prospective, facility-based study of ILI was conducted from February 2010 to April 2012. Collection of nasopharyngeal specimens, patient symptoms, and clinical information occurred on days 0, 3, 7, and 28. Patients recorded symptom severity daily for the first 7 days of illness in a symptom diary. HRV was identified by RT-PCR and genotyped for species determination. Cases who were co-infected with other viral respiratory pathogens were excluded from the analysis. We evaluated the associations between HRV species, clinical severity, and patterns of viral shedding. RESULTS: eighty-four HRV cases were identified and their isolates genotyped. Of these, 62 (74%) were >18 years. Fifty-four were HRV-A, 11HRV-B, and 19HRV-C. HRV-C infection was more common among children than adults (59% vs. 10%, P<0.001). Among adults, HRV-A was associated with higher severity of upper respiratory symptoms compared to HRV-B (P=0.02), but no such association was found in children. In addition, adults shed HRV-A significantly longer than HRV-C (P trend=0.01). CONCLUSIONS: among otherwise healthy adults with HRV infection, we observed species-specific differences in respiratory symptom severity and duration of viral shedding. PMID- 25728085 TI - Evaluation of human papillomavirus DNA detection in samples obtained for routine Chlamydia trachomatis screening. AB - BACKGROUND: The costs and logistics involved in obtaining samples is a bottleneck in large-scale studies of the circulation of human papillomavirus (HPV), which are useful for monitoring and optimisation of HPV-vaccination programs. Residual samples obtained after screening for Chlamydia trachomatis could constitute a convenient, low-cost solution. OBJECTIVES: We evaluated HPV DNA detection and typing using (i) the residual samples routinely taken for C. trachomatis screening or (ii) the sample types used in large-scale phase III HPV vaccination trials (cervical, vulvar, labial, perineal, perianal, scrotal and penile shaft samples). STUDY DESIGN: Samples from 127 men and 110 women attending two sexual health clinics were analysed using PCR for HPV DNA, with typing using mass spectrometry. RESULTS: The HPV DNA prevalence was 7.1% in male urine samples, but 57.3% in female urine/vaginal samples, which was even higher than the HPV prevalence found in cervical samples (54.1%). The sensitivity for HPV DNA detection in the urine/vaginal samples was 7.9% (95% CI 3.0-16.4) for men and 78.9% (95% CI 67.6-87.7) for women, using detection in any one of the reference samples as reference. With cervical samples as reference, the sensitivity was 89.3 % (95% CI 78.1-95.9). CONCLUSIONS: Among men, low sensitivity of urine for HPV detection suggests limited usefulness. Among women, the high sensitivity of urine/vaginal samples for HPV detection suggests a useful low-cost solution for the study of HPV epidemiology. PMID- 25728086 TI - Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration. AB - BACKGROUND: The benefits of intravenous immunoglobulin (IVIG) therapy for severe neonatal enterovirus infections are still controversial. OBJECT: To evaluate whether timing of IVIG administration might affect clinical outcomes of neonates with severe enteroviral infections. STUDY DESIGNS: We retrospectively analyzed 67 neonates with culture-confirmed severe enteroviral infection, defined as hepatitis with coagulopathy and thrombocytopenia. Clinical features, outcomes and the usage of IVIG therapy were collected and analyzed. IVIG administered within 3 days of illness onset was classified as early IVIG therapy. RESULTS: Of the 67 cases, 38 (57%) were male, 27 (40%) were premature, 57 (85%) had disease onset within 7 days of life and all but 2 cases were caused by coxsackievirus B group. Ten infants (15%) had clinically evident myocarditis. 41 infants (61%) received IVIG therapy and 29 were early IVIG therapy. Fifteen infants (22%) eventually died, without IVIG therapy for 7 infants. The deceased had a significantly higher peak serum aspartate aminotransferase (AST) level than the survivors (3539 vs. 866 IU/L, p<0.01). The timing of IVIG therapy was highly correlated with the timing of peak AST level in patients with early IVIG therapy. Multiple logistic regression analysis showed that a higher nadir hemoglobin level (adjusted odds ratio 2.8, 95% confidence interval: 1.4-5.4), no concurrent myocarditis (42.6 [3.4-5289]) and early IVIG therapy (14.7 [1.3-163]) were independently associated with a favorable prognosis. CONCLUSIONS: In defined severe neonatal enterovirus infections, serum AST level correlated with the disease severity. Early IVIG therapy, if needed, may be beneficial for survival. PMID- 25728088 TI - Similarities and differences between Arabidopsis PCNA1 and PCNA2 in complementing the yeast DNA damage tolerance defect. AB - Proliferating cell nuclear antigen (PCNA) forms a homotrimer that functions as a sliding clamp essential for genomic DNA replication. It is also directly involved in the regulation of cellular response to DNA damage, which is typically achieved through its covalent modifications. The Arabidopsis genome encodes two PCNAs with only nine amino acid variations, yet two recent reports indicate that AtPCNA2 plays a more critical role in DNA damage response than AtPCNA1. In this study, it was found that both AtPCNAs were able to functionally complement the essential roles of yeast POL30 (PCNA), but failed to rescue the DNA damage tolerance defect of pol30. Surprisingly, the AtPCNA1-K164R mutation rendered cells more tolerant to DNA damage, which appears to be dependent on PCNA sumoylation but not ubiquitination. Two critical residues proximal in structure to K164 were identified in AtPCNAs that contribute to their differences in DNA damage tolerance, since their amino acid substitutions alter the level of DNA damage tolerance. Collectively, it is concluded that the two AtPCNAs differ in their efficiency for ubiquitination and sumoylation, leading to their differential responses to DNA damage in yeast cells. PMID- 25728087 TI - Molecular classification of outcomes from dengue virus -3 infections. AB - OBJECTIVES: Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub clinical disease to intermediate syndrome of vascular complications called dengue fever complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology. STUDY DESIGN: We integrated a proteomics discovery pipeline with a heuristics approach to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome. RESULTS: 121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a random forest classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF. CONCLUSIONS: Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions. PMID- 25728089 TI - Day and night variations in the repair of ionizing-radiation-induced DNA damage in mouse splenocytes. AB - In mammals, biological rhythms synchronize physiological and behavioral processes to the 24-h light-dark (LD) cycle. At the molecular level, self-sustaining processes, such as oscillations of transcription-translation feedback loops, control the circadian clock, which in turn regulates a wide variety of cellular processes, including gene expression and cell cycle progression. Furthermore, previous studies reported circadian oscillations in the repair capacity of DNA lesions specifically repaired by nucleotide excision repair (NER). However, it is so far only poorly understood if DNA repair pathways other than NER are under circadian control, in particular base excision and DNA strand break repair. In the present study, we analyzed potential day and night variations in the repair of DNA lesions induced by ionizing radiation (i.e., mainly oxidative damage and DNA strand breaks) in living mouse splenocytes using a modified protocol of the automated FADU assay. Our results reveal that splenocytes isolated from mice during the light phase (ZT06) displayed higher DNA repair activity than those of the dark phase (ZT18). As analyzed by highly sensitive and accurate qPCR arrays, these alterations were accompanied by significant differences in expression profiles of genes involved in the circadian clock and DNA repair. Notably, the majority of the DNA repair genes were expressed at higher levels during the light phase (ZT06). This included genes of all major DNA repair pathways with the strongest differences observed for genes of base excision and DNA double strand break repair. In conclusion, here we provide novel evidence that mouse splenocytes exhibit significant differences in the repair of IR-induced DNA damage during the LD cycle, both on a functional and on a gene expression level. It will be interesting to test if these findings could be exploited for therapeutic purposes, e.g. time-of-the-day-specific application of DNA-damaging treatments used against blood malignancies. PMID- 25728090 TI - Vermicomposting as manure management strategy for urban small-holder animal farms - Kampala case study. AB - Inadequate organic waste management can contribute to the spread of diseases and have negative impacts on the environment. Vermicomposting organic waste could have dual beneficial effects by generating an economically viable animal feed protein in the form of worm biomass, while alleviating the negative effects of poor organic waste management. In this study, a low-maintenance vermicomposting system was evaluated as manure and food waste management system for small-holder farmers. A vermicomposting system using the earthworm species Eudrilus eugeniae and treating cow manure and food waste was set up in Kampala, Uganda, and monitored for 172days. The material degradation and protein production rates were evaluated after 63days and at the end of the experiment. The material reduction was 45.9% and the waste-to-biomass conversion rate was 3.5% in the vermicomposting process on a total solids basis. A possible increase in the conversion rate could be achieved by increasing the frequency of worm harvesting. Vermicomposting was found to be a viable manure management method in small-scale urban animal agriculture; the return of investment was calculated to be 280% for treating the manure of a 450kg cow. The vermicompost was not sanitised, although hygiene quality could be improved by introducing a post-stabilisation step in which no fresh material is added. The value of the animal feed protein generated in the process can act as an incentive to improve current manure management strategies. PMID- 25728091 TI - Respiration and enzymatic activities as indicators of stabilization of sewage sludge composting. AB - The objective of this work was to study the evolution of physico-chemical and microbial parameters in the composting process of sewage sludge (SS) with pruning wastes (PW) in order to compare these parameters with respect to their applicability in the evaluation of organic matter (OM) stabilization. To evaluate the composting process and organic matter stability, different microbial activities were compared during composting of anaerobically digested SS with two volumetric ratios, 1:1 and 3:1 of PW:SS and two aeration techniques including aerated static piles (ASP) and turned windrows (TW). Dehydrogenase activity, fluorescein diacetate hydrolysis, and specific oxygen uptake rate (SOUR) were used as microbial activity indices. These indices were compared with traditional parameters, including temperature, pH, moisture content, organic matter, and C/N ratio. The results showed that the TW method and 3:1 (PW:SS) proportion was superior to the ASP method and 1:1 proportion, since the former accelerate the composting process by catalyzing the OM stabilization. Enzymatic activities and SOUR, which reflect microbial activity, correlated well with temperature fluctuations. Based on these results it appears that SOUR and the enzymatic activities are useful parameters to monitor the stabilization of SS compost. PMID- 25728092 TI - Chemical recycling of cell phone Li-ion batteries: Application in environmental remediation. AB - This paper presents, for the first time, the recycling and use of spent Li-ion battery cathode tape as a catalyst in the degradation of an organic dye. In our proposal, two major environmental problems can be solved: the secure disposal of cell phone batteries and the treatment of effluents with potentially toxic organic dyes. The spent Li-ion battery cathode investigated in this paper corresponds to 29% of the mass of Li-ion batteries and is made up of 83% LiCoO2, 14.5% C and less than 2.5% Al, Al2O3 and Co3O4. The use of spent Li-ion battery cathode tape increased the degradation velocity constant of methylene blue in the absence of light by about 200 times in relation to pure H2O2. This increase can be explained by a reduction in the activation energy from 83 kJ mol(-1) to 26 kJ mol(-1). The mechanism of degradation promoted by LiCoO2 is probably related to the generation of superoxide radical (O2(-)). The rupture of the aromatic rings of methylene blue was analyzed by ESI-MS. PMID- 25728093 TI - Concise review: reactive astrocytes and stem cells in spinal cord injury: good guys or bad guys? AB - Spinal cord injury (SCI) usually results in long lasting locomotor and sensory neuron degeneration below the injury. Astrocytes normally play a decisive role in mechanical and metabolic support of neurons, but in the spinal cord they cause injury, exerting well-known detrimental effects that contribute to glial scar formation and inhibition of axon outgrowth. Cell transplantation is considered a promising approach for replacing damaged cells and promoting neuroprotective and neuroregenerative repair, but the effects of the grafted cells on local tissue and the regenerative properties of endogenous neural stem cells in the injured spinal cord are largely unknown. During the last 2 decades cumulative evidence from diverse animal models has indicated that reactive astrocytes in synergy with transplanted cells could be beneficial for injury in multiple ways, including neuroprotection and axonal growth. In this review, we specifically focus on the dual opposing roles of reactive astrocytes in SCI and how they contribute to the creation of a permissive environment when combined with transplanted cells as the influential components for a local regenerative niche. Modulation of reactive astrocyte function might represent an extremely attractive new therapy to enhance the functional outcomes in patients. PMID- 25728094 TI - High incidence of Epstein-Barr virus (EBV)-positive Hodgkin lymphoma and Hodgkin lymphoma-like B-cell lymphoproliferations with EBV latency profile 2 in children with interleukin-2-inducible T-cell kinase deficiency. AB - AIMS: Interleukin-2-inducible T-cell kinase (ITK) deficiency is an inherited T cell deficiency characterized by the development of Epstein-Barr virus (EBV) associated lymphoproliferations. We aimed to describe the histopathological features of lymphoproliferative processes arising in ITK deficiency, and to compare them with lymphoproliferations in otherwise immunocompromised patients. METHODS AND RESULTS: We revised the histopathological diagnoses of 12 biopsies of lymphoproliferations from seven ITK-deficient children according to the World Health Organization criteria, and determined the EBV latency types and lytic activity by staining for EBV-encoded small RNA, latent membrane protein 1, EBV nuclear antigen 2, and ZEBRA. We found polymorphic and borderline polymorphic to monomorphic B-cell lymphoproliferations with variable contents in large cells (five cases), a Hodgkin-like B-cell proliferation (one case), and classic mixed cellularity Hodgkin lymphoma (six cases). All cases (12/12) were EBV-positive. The Hodgkin lymphoma-like and Hodgkin lymphoma, and all but one polymorphic B cell lymphoproliferation, showed EBV latency type 2, as observed in classic EBV positive Hodgkin lymphoma. CONCLUSIONS: The 100% EBV association, the high percentage of EBV-positive classic Hodgkin lymphoma and Hodgkin-like B-cell proliferations and the predominance of EBV latency type 2 even in polymorphic lesions are the main features of lymphoproliferations in patients with ITK deficiency, and suggest a unique pathomechanism of lymphomagenesis in this T-cell immunodeficiency. PMID- 25728095 TI - Tissue engineering: novel opportunities that encourage lateral thinking, outside the box. PMID- 25728096 TI - Author copyright forms modifications. PMID- 25728097 TI - Evaluation of linear dimensional accuracy of hard chairside and laboratory heat cure reline resins at different time intervals after processing. AB - CONTEXT: Relining with heat cure denture base resin is time-consuming and the patient has to remain without dentures within this period. Recently, some autopolymerizing resins marketed as hard chairside reline systems with low exothermic heat allow the dentists to reline prosthesis directly in the mouth. However, the decision to use these materials must be based on physical properties such as dimensional accuracy that directly influences the accuracy of fit of the denture base. AIM: The aim was to compare the linear dimensional changes of two hard chairside reline resins with two laboratory heat cure resins at 3 times intervals after processing. SETTINGS AND DESIGN: A stainless steel split mold (International Organization for Standardization 1567) was used for sample fabrication. Five measurements of the reference dimensions (AB and CD) were measured directly from the mold and the samples with a profile projector, and mean difference were calculated. SUBJECTS AND METHODS: Forty samples were fabricated by incorporating the split mold into first pour of denture flasks and packing each of the chairside reline resins ("Kooliner" and "Ufi Gel Hard") and laboratory heat cure resins ("Dental Products of India Heat Cure" and "Trevalon"). The mean difference in dimensional change at 3 times intervals (0 h, 4 days and 2 months) were calculated and subjected to statistical analysis. STATISTICAL ANALYSIS USED: One-way ANOVA, RMANOVA and post hoc Tukey's tests. RESULTS: All resins showed different levels of significant shrinkage (P<0.001) after processing (T0) ranging from -0.128 to -0.310 mm. After 4 days (T1), there was significant shrinkage (P<0.001) ranging from -0.168 to -0.296 mm. After 2 months (T2), there was again significant shrinkage (P<0.001) ranging from -0.018 to -0.216 mm. Chairside reline resins showed less dimensional shrinkage at each time interval than the laboratory heat cure resins. CONCLUSIONS: Hard chairside resins are dimensionally accurate than the laboratory heat cure resins. PMID- 25728098 TI - Comparison of physical and mechanical properties of mineral trioxide aggregate and Biodentine. AB - BACKGROUND: Mineral trioxide aggregate (MTA) fulfills many of the ideal properties of the root-end filling material. However, its low cohesive property often makes it difficult to handle. Biodentine, new calcium-silicate-based cement has been developed to improve some MTA drawbacks such as its difficult handling property and long-setting time. AIM: The objective of this study was to compare at different times the microleakage of roots filled with Biodentine and white MTA (WMTA)-Angelus and to investigate their setting time, handling properties and compressive strength. MATERIALS AND METHODS: Root canals of single-rooted teeth were instrumented, filled with either Biodentine or WMTA-Angelus (n=15 each) with two positive and two negative control roots and stored at 37 degrees C. Sealing was assessed at 4, 24 h, 1, 2, 4, 8, and 12 weeks by a fluid filtration method. The initial setting time, handling properties, and compressive strength of the test groups were investigated by a vicat needle, questionnaire of operational hand feel, and universal instron machine, respectively. RESULTS: Significant differences in microleakage were found between two groups at 4-h and 24 h (P<0.05) and no difference at 1, 2, 4, 8, and 12 weeks. No significant difference was seen in the setting time of MTA-Angelus and Biodentine, though latter was found to have better handling consistency. Compressive strength of Biodentine was significantly higher than MTA-Angelus. CONCLUSIONS: The results suggest that the new calcium-silicate-based endodontic cement provides improvement in sealing ability as well as clinical manageability of dental filling materials. PMID- 25728099 TI - Micro-computed tomography and bond strength analysis of different root canal filling techniques. AB - INTRODUCTION: The aim of this study was to evaluate the quality and bond strength of three root filling techniques (lateral compaction, continuous wave of condensation and Tagger's Hybrid technique [THT]) using micro-computed tomography (CT) images and push-out tests, respectively. MATERIALS AND METHODS: Thirty mandibular incisors were prepared using the same protocol and randomly divided into three groups (n=10): Lateral condensation technique (LCT), continuous wave of condensation technique (CWCT), and THT. All specimens were filled with Gutta percha (GP) cones and AH Plus sealer. Five specimens of each group were randomly chosen for micro-CT analysis and all of them were sectioned into 1 mm slices and subjected to push-out tests. RESULTS: Micro-CT analysis revealed less empty spaces when GP was heated within the root canals in CWCT and THT when compared to LCT. Push-out tests showed that LCT and THT had a significantly higher displacement resistance (P<0.05) when compared to the CWCT. Bond strength was lower in apical and middle thirds than in the coronal thirds. CONCLUSIONS: It can be concluded that LCT and THT were associated with higher bond strengths to intraradicular dentine than CWCT. However, LCT was associated with more empty voids than the other techniques. PMID- 25728100 TI - In vitro performance of a pen-type laser fluorescence device and bitewing radiographs for approximal caries detection in permanent and primary teeth. AB - AIM: To evaluate the performance of a pen-type laser fluorescence device (DIAGNOdent 2190; LFpen, KaVo, Germany) and bitewing radiographs (BW) for approximal caries detection in permanent and primary teeth. MATERIALS AND METHODS: A total of 246 anterior approximal surfaces (102 permanent and 144 primary) were selected. Contact points were simulated using sound teeth. Two examiners assessed all approximal surfaces using LFpen and BW. The teeth were histologically assessed for the reference standard. Optimal cut-off limits were calculated for LFpen for primary and permanent teeth. Sensitivity, specificity, accuracy and area under the receiver operating characteristic curve (Az) were calculated for D1 (enamel and dentin lesions) and D3 (dentin lesions) thresholds. The reproducibility was assessed by intraclass correlation coefficient (ICC) and Cohen's weighted kappa values. RESULTS: For permanent teeth, the LFpen cut-off were 0-27 (sound), 28-33 (enamel caries) and >33 (dentin caries). For primary teeth, the LFpen cut-off were 0-7 (sound), 8- 32 (enamelcaries) and >32 (dentin caries). The LFpen presented higher sensitivity values than BW for primary teeth (0.58 vs. 0.32 at D1 and 0.80 vs. 0.47 at D3) and permanent teeth (0.80 vs. 0.57 at D1 and 0.94 vs. 0.51 at D3). Specificity did not show a significant difference between the methods. Rank correlations with histology were 0.59 and 0.83 (LFpen) and 0.36 and 0.70 (BW) for primary and permanent teeth, respectively, considering all lesions. ICC values for LFpen were 0.71 (inter) and 0.86 (intra) for permanent teeth and 0.94 (inter) and 0.90/0.99 for primary teeth. Kappa values for BW were 0.69 (inter) and 0.68/0.90 (intra) for permanent teeth and 0.64 (inter) and 0.89/0.89 for primary teeth. CONCLUSION: LFpen presented better reproducibility for primary and permanent teeth and higher accuracy in detecting caries lesions at D1 threshold than BW for permanent teeth. LFpen should be used as an adjunct method for approximal caries detection. PMID- 25728101 TI - Comparing the effects of cryotherapy with nitrous oxide gas versus topical corticosteroids in the treatment of oral lichen planus. AB - BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa with treatment challenges for clinicians. AIMS: The objective of this study is to compare the effects of cryotherapy as a new modality with topical corticosteroids as a conventional therapy in the treatment of OLP. MATERIALS AND METHODS: Thirty patients with bilateral OLP lesions were selected. From each patient a lesion on one side was chosen randomly for a single session of cryotherapy with nitrous oxide gas and the lesion on the other side received triamcinolone acetonide 0.1% ointment in orabase. Treatment outcome was measured by means of an appearance score, pain score (visual analogue scale), and severity of lesions before treatment and after 2, 4 and 6 weeks of treatment. STATISTICAL ANALYSIS USED: Paired samples t-test and Wilcoxon test. RESULTS: In both methods of treatment sign score, pain score and severity of lesions was significantly reduced in all follow-up sessions (P<0.05). But the treatment outcome and relapse was not significantly different between the two treatment methods (P>0.05). CONCLUSION: Cryotherapy with nitrous oxide gas is as effective as topical triamcinolone acetonide in the treatment of OLP with no systemic side effects and needs less patient compliance. It can be considered as an alternative or adjuvant therapy in OLP patients to reduce the use of treatments with adverse effects. PMID- 25728102 TI - Effect of prostaglandin E1 versus corticotomy on orthodontic tooth movement: an in vivo study. AB - BACKGROUND AND AIM: The aim of the present study is to compare the effect of corticotomy versus prostaglandin E1 injection in human subjects on rate of tooth movement, anchorage loss and their effect on crest bone height and root length. SETTINGS AND DESIGN: Clinical interventional study. Split mouth design was used. MATERIALS AND METHODS: Study was done on 32 regular orthodontic patients. A volume of 100 mcg of prostaglandin E1 was injected on the right side once in 2 weeks and on the left side corticotomy was performed, and canine retraction was started on both sides simultaneously. The rate of space closure and anchorage loss was assessed with casts. The root length and crestal bone height changes were assed with IOPAs. The comparison of rate of tooth movement, anchorage loss, crestal bone height and root length changes between the sides were statistically analyzed using paired t-test. RESULTS: The average rate of space closure on right side was 0.36 mm/week with a standard deviation of 0.05 mm/week and on the left side average rate of space closure was 0.40 mm/week with a standard deviation of 0.04 mm/week. The difference between the rate of closure between the right side and left where found to be statistically significant (P=0.003). The anchorage loss, the crestal bone height changes and root length changes were not statistically significant. CONCLUSION: The rate of tooth movement was significantly more with corticotomies when compared with given dose of prostaglandin injection. PMID- 25728103 TI - Co-relation of body mass index, dental caries and periodontal status with fluorosis in different high fluoridated areas of Haryana state, India. AB - BACKGROUND AND AIM: The aim of the present study is to compare the effect of corticotomy versus prostaglandin E1 injection in human subjects on rate of tooth movement, anchorage loss and their effect on crest bone height and root length. SETTINGS AND DESIGN: Clinical interventional study. Split mouth design was used. MATERIALS AND METHODS: Study was done on 32 regular orthodontic patients. A volume of 100 mcg of prostaglandin E1 was injected on the right side once in 2 weeks and on the left side corticotomy was performed, and canine retraction was started on both sides simultaneously. The rate of space closure and anchorage loss was assessed with casts. The root length and crestal bone height changes were assed with IOPAs. The comparison of rate of tooth movement, anchorage loss, crestal bone height and root length changes between the sides were statistically analyzed using paired t-test. RESULTS: The average rate of space closure on right side was 0.36 mm/week with a standard deviation of 0.05 mm/week and on the left side average rate of space closure was 0.40 mm/week with a standard deviation of 0.04 mm/week. The difference between the rate of closure between the right side and left where found to be statistically significant (P=0.003). The anchorage loss, the crestal bone height changes and root length changes were not statistically significant. CONCLUSION: The rate of tooth movement was significantly more with corticotomies when compared with given dose of prostaglandin injection. PMID- 25728104 TI - A comparative evaluation of endodontic practice trends in India: "the Mumbai study". AB - INTRODUCTION: Multiple treatment protocols are available to the Indian endodontist. Hence a survey is required to recognize the common trends in endodontics and set a basic standard of treatment. AIMS AND OBJECTIVES: The aim of this article is to present practice trends among Indian endodontists and compare the same with established practice trends internationally through various surveys that have been conducted respectively. MATERIALS AND METHODS: Questionnaires were mailed to 1085 endodontists in dental schools and private practice in India. A response rate of 42% was observed. The data was analyzed and compared with other studies. RESULTS: Most of the endodontists in India follow the basic protocols and techniques in their practices. 40% of the Endodontists preferred digital radiography technique. 2.5% NaOCl is the most preferred irrigant of choice for primary root canal treatment and 2% chlorhexidine in retreatment cases. Calcium hydroxide was the most preferred intracanal medicament in all clinical situations. Lateral compaction (70.8%) was the most widely used method. AH Plus was the most preferred root canal sealer (46.6%). CONCLUSION: Indian endodontists are following the basic protocol but when compared to other studies there were concepts like, the use of rubber dam and microscope which need to be improved and raised to a level that ensures international standards in clinical practice. PMID- 25728105 TI - The effect of Propolis and Xylitol chewing gums on salivary Streptococcus mutans count: a clinical trial. AB - BACKGROUND: Streptococcus mutans is one of the most common cariogenic microorganisms. Use of natural anticariogenic agents, such as Xylitol has been well-established in the literature. On the other hand, there is a scarcity of studies that have reported the antimicrobial potential of Propolis as an anticariogenic chewing agent; hence, the present study was designed. AIMS: To evaluate and compare the anticariogenic action of two commercial chewing gums Propolis and Xylitol on the salivary S. mutans count in a group of children from Bengaluru city. SETTINGS AND DESIGN: Clinical setting and experimental design. MATERIALS AND METHODS: Thirty healthy children aged 8-11 years with decayed, missing, and filled teeth (dmft)/DMFT index score>=3 were included in the study. Before the test, unstimulated saliva was collected. Children divided into Group I and II were given Propolis and Xylitol chewing gums respectively; to chew for 15 min. Saliva samples were then collected at 15 min (just after spitting) and after 1 h. The amount of S. mutans in saliva was evaluated using a selective media (MSAB). In addition, compliance of the two chewing gums among the children was tested with a questionnaire. STATISTICAL ANALYSIS USED: Student's t-test. RESULTS: Six samples out of 30 were excluded due to no growth. The total number of bacterial colonies was significantly reduced when compared to baseline in both the groups. Propolis gum showed statistically significant reduction in the number of colonies as compared to Xylitol. Xylitol gum was more preferred than Propolis gum by the children. CONCLUSIONS: Propolis chewing gum can be used as an anticariogenic agent in children. PMID- 25728106 TI - Maternal periodontal disease as a significant risk factor for low birth weight in pregnant women attending a secondary care hospital in South India: a case-control study. AB - CONTEXT: Periodontal disease (PD) is a common infection in the community; however, its relationship with low birth weight (LBW) has not been well established. AIMS: The aim was to determine the association between maternal PD and LBW. SETTINGS AND DESIGN: A case-control (1:1) study. MATERIALS AND METHODS: The study population comprised of women who delivered at the hospital during the study period (September 2011 to February 2012).Women between 18 and 35 years of age, who delivered singleton, live infants during study period with at least 18 teeth were enrolled. Those with pregnancy induced hypertension, gestational diabetes, blood-borne viral infections, periodontal treatment within the past 6 months and valvular heart disease were excluded. Control population was parity matched to the cases. STATISTICAL ANALYSIS USED: Chi-square test, t-test and univariant and multivariant logistic regression were used to analyze various study findings, and level of significance was set at 5% (P<0.05). RESULTS: PD was independently associated with LBW (odds ratio: 4.94, 95% confidence interval: 1.03-23.65, P=0.045). Additionally, conventional risk factors such as maternal height (P=0.029), secondary schooling (<8 years of schooling) (P=0.001), socio economic status (P=0.046), type of family (joint) (P=0.008), number of ante-natal visits (P=0.028) and gestational age at birth (<37 weeks) (P=0.045) showed significant association with LBW. CONCLUSIONS: There seems to be an association between PD and LBW independent of conventional risk factors. Women who had PD were 5 times more likely to deliver LBW infants. PMID- 25728107 TI - Corticotomy-assisted retraction: an outcome assessment. AB - BACKGROUND: To assess the efficiency and treatment outcome of patients treated with corticotomy-assisted en-masse orthodontic retraction as compared with the en masse retraction without corticotomy. MATERIALS AND METHODS: Forty adult patients with bimaxillary protrusion requiring correction of bidental proclination constituted the sample. The study group consisted of 22 patients (male 11, female 11) willing to undergo surgery to reduce the duration of their orthodontic treatment and 18 patients (male 9, female 9) desirous of undergoing conventional orthodontic treatment without surgical intervention constituted the control group. Comparison of rate of retraction and anchor loss between the study and the control group was assessed. RESULTS: Average rate of space closure of 1.8 mm/month in the maxilla and 1.57 mm/month in the mandible was observed in the study group compared to 1.02 mm/month in the maxilla and 0.87 mm/month in the mandible in the control group. The rate of retraction accelerated during the first 2 months of retraction. Molar anchor loss of approximately 0.6 mm occurred in the study group, and 1.8 mm occurred in the control group during the 4 months. CONCLUSION: The rate of retraction with study group was twice as faster when compared to the control group, accelerating during the first 2 months of retraction. There was better anchorage control with the undecorticated molar segment during the retraction period but was found to increase as time advanced. PMID- 25728109 TI - Scanning electron microscopic observations of fibrous structure of cemento dentinal junction in healthy teeth. AB - INTRODUCTION: The cemento-dentinal junction (CDJ) is a structural and biologic link between cementum and dentin present in the roots of teeth. Conflicting reports about the origin, structure and composition of this layer are present in literature. The width of this junctional tissue is reported to be about 2-4 MUm with adhesion of cementum and dentin by proteoglycans and by collagen fiber intermingling. AIM AND OBJECTIVE: The objective of this study is to observe and report the fibrous architecture of the CDJ of healthy tooth roots. MATERIALS AND METHODS: A total of 15 healthy teeth samples were collected, sectioned into halves, demineralized in 5% ethylenediaminetetraacetic acid, processed using NaOH maceration technique and observed under a scanning electron microscope. RESULTS: The CDJ appeared to be a fibril poor groove with a width of 2-4 um. Few areas of collagen fiber intermingling could be appreciated. A detailed observation of these tissues has been presented. PMID- 25728108 TI - Analysis of stresses during the polymerization shrinkage of self-curing resin cement in indirect restorations: a finite-element study. AB - BACKGROUND: Adhesive cementation is essential for the longevity of indirect esthetic restorations. However, polymerization shrinkage of resin cement generates stress, which may cause failures in the tooth-restoration interface. So, understanding of the biomechanics of resin cement is important for predicting the clinical behavior of an esthetic indirect restoration. AIMS: To analyze the stresses generated during polymerization shrinkage of self-curing resin cement in ceramic and in indirect resin (IR) restorations, using the finite-element method (FEM). SETTINGS AND DESIGN: Numerical study using the finite-element analysis. MATERIALS AND METHODS: A three-dimensional (3D) model of a second molar restored with ceramic or IR onlay restoration was designed. The polymerization shrinkage of self-curing resin cement was simulated in FEM software using an analogy between the thermal stress and the resulting contraction of the resin cement. The localization and values of tensile stresses in the dental structure, cement, and adhesive layer were identified. RESULTS: The location and value of the tensile stresses were similar for the two restorative materials. High tensile stresses were identified in the axiopulpal wall and angles of the tooth preparation, with the major stresses found in the cement located in the axiopulpal wall. CONCLUSIONS: The high stresses values and their concentration in the angles of the prepared tooth emphasize the importance of round angles and the use of cements with lower rates of shrinkage. PMID- 25728110 TI - Immunohistochemical study of polycystin-1 in dentigerous cysts. AB - BACKGROUND: The alterations involved in step-wise transformation of a dental follicle to dentigerous cyst (DC) is not clearly known. Primary cilium and its protein have been hypothesized to be associated with DC. Mutation of a ciliary protein, polycystin-1 (PC1) is associated with autosomal dominant polycystic kidney disease. This study was performed to assess the immunohistochemical expression of PC1 between DC and postfunctional follicular tissue (PFFT). MATERIALS AND METHODS: Thirty-one consecutive PFFT and 15 DC formed the study group. The PFFT and DC tissues were stained with antibody against PC1. Statistical Package for Social Service was used to analyze data. Descriptive statistics and Student's Chi-square test were appropriately used. P<=0.05 was taken as significant. RESULTS: Fifteen DC (100%) and 7 (22.58%) PFFT were positive for PC1. The difference was statistically significant (P=0.000). PC1 expression was observed in the cytoplasm with varying intensity. DISCUSSION AND CONCLUSION: All PC1 positive epithelial cells' cytoplasm stained diffusely. Abnormal cytoplasmic expression of PC1 in all positive epithelial lining indicates that the PC1 probably is associated with cystic transformation. PMID- 25728111 TI - Ergonomic risk factors and their association with musculoskeletal disorders among Indian dentist: a preliminary study using Rapid Upper Limb Assessment. AB - CONTEXT: Ergonomics is the scientific study of people and their work. The manufacturers typically do not design to accommodate the dimensions of the individual user. Work-related musculoskeletal disorders (MSDs) have emerged as major health problem among workers in both industrialized and industrially developing countries. Rapid Upper Limb Assessment (RULA) was developed to investigate the exposure of the individual workers to risk factors associated with work-related upper limb disorders. AIMS: The assessment of the posture using RULA, which is quick reliable tool to determine the posture, has not been done in the Indian dentist population, indicating the need for the same. SETTINGS AND DESIGN: A total of 104 subjects were included from New Delhi/NCR. SUBJECTS AND METHODS: The procedure was explained, and the questionnaire was distributed and assessment was done using RULA. The MSDs can be recorded using the standard Nordic questionnaire. STATISTICAL ANALYSIS USED: The data were collected from 104 subjects out of the 192 evaluated and was statistically analyzed using SPSS software. RESULTS: The study sample included 70 male and 34 female dentists. The posture of the subjects and the MSDs are not associated with a significant difference as according to Pearson's Chi-square test (0.231). CONCLUSIONS: RULA can be used as a screening tool for postural risks following a short training session regardless of the assessor's experience in postural risk assessments. PMID- 25728112 TI - A study of sister chromatid exchange in patients with dental amalgam restorations. AB - STUDY BACKGROUND: Dental amalgam is still widely used as a restorative material in developing countries due to its low cost and ease of manipulation. The health risks associated with the components of this restorative material has always been a matter of concern. Our study was designed to address this question regarding dental amalgam. OBJECTIVE: To study sister chromatid exchange (SCE) as an indicator of systemic genotoxicity, due to the exposure from the components of amalgam restorations during its placement and chronic use. MATERIALS AND METHODS: Systemic genotoxicity in subjects exposed to amalgam during its placement (Group II; n=5) and subjects with chronic exposure to amalgam (Group III; n=5) were compared with controls (Group I; n=5) by SCE assay in cultured peripheral blood lymphocytes. RESULT: Subjects exposed to amalgam during its placement and subjects having chronic exposure to amalgam showed an increase in the frequency of SCE, but the change was not statistically significant (P=0.84, P=0.123 respectively). CONCLUSION: Systemic genotoxicity was not observed due to the components of amalgam restorations released during its placement and chronic use. The findings of this study can be considered as preliminary information on the systemic toxicity due to the components of amalgam restorations. PMID- 25728113 TI - Remineralizing efficacy of Calcarea Fluorica tablets on the artificial carious enamel lesions using scanning electron microscope and surface microhardness testing: in vivo study. AB - CONTEXT: Remineralization is defined as the process whereby calcium and phosphate ions are supplied from a source external to tooth to promote ion deposition into crystal voids in demineralized enamel to produce net mineral gain. The remineralization produced by saliva is less and also a slow process, therefore remineralizing agents are required. AIMS: The study was planned to evaluate the effectiveness of homeopathic Calcarea Fluorica (calc-f) tablets as remineralizing agents on artificial carious lesions using scanning electron microscope (SEM) and surface microhardness (SMH) testing. SUBJECTS AND METHODS: A total of 24 patients needing removable orthodontic treatment were included in the study. They were divided into two groups of 12 patients each. The Group I consisted of patients in whom no tablets were given while Group II consisted of patients in whom calc-f tablets were given in a dosage of 4 tablets twice a day. Four enamel samples with the artificial carious lesions were then embedded in the removable appliance for a period of 6 weeks. After 6 weeks, the enamel samples were retrieved and evaluated by SEM and SMH. STATISTICAL ANALYSIS USED: One-sample Kolmogorov Smirnov test and Student's t-test were applied to analyze the difference in the Vickers microhardness number (VHN) values of remineralized enamel obtained from control and experimental group. RESULTS: The signs of remineralization such as reduction in depth prismatic holes or decrease in porosity, variable sized uneven distribution of deposits and amorphous deposits were seen in enamel samples of both the groups. The mean SMH of remineralized enamel sample of Group I and Group II were 270.48 and 302.06, respectively, and the difference was statistically significant. CONCLUSIONS: (1) Remineralization occurred in both the groups as indicated by SEM and the increase in surface hardness values in both the groups. (2) Remineralization of enamel samples in the control group as indicated by SEM and also by increase in VHN values indicated that the saliva has a tendency of remineralizing the early carious lesions. Conclusions drawn from the study are that the calc-f tablets can be used as safe and cost effective remineralizing agent. PMID- 25728114 TI - Evaluation of two-dimensional and three-dimensional radiography with direct surgical assessment of periodontal osseous defects: a clinical study. AB - AIM: To compare the diagnostic values of radiovisiograph (RVG) and computed tomography (CT) images in comparison with direct surgical measurements for the determination of periodontal bone loss. MATERIALS AND METHODS: Thirty-one vertical defects were included for direct measurements during surgery with a periodontal probe. RVG and CT images were taken prior to the surgery. Similar measurements were done on their images and compared with the direct surgical values. RESULTS: Mean difference (in mm) of RVG and CT scan in vertical defects, and intrabony component was 0.814, 0.474 and 0.073, 0.066 respectively. Intra class correlation of CT scan (0.997 and 0.990) was highest with the smallest length of 95% confidence interval. CT scan furthermore depicted maximum agreement with the surgical value. CT scan overestimated in the maximum percentage of sites in vertical defects. CT scan outscored over RVG in evaluation of the osseous defects. CONCLUSIONS: CT scan demonstrated more precise and clinically useful images of the osseous defects closer to the gold standard. PMID- 25728115 TI - Golden proportions as predictors of attractiveness and malocclusion. AB - OBJECTIVE: In recent years, the golden proportions have been evaluated by various researchers in the general population and orthodontic patients to establish their correlation with facial attractiveness and esthetics, but with conflicting results. The present study aimed to analyze the frontal facial golden proportions for three groups of young adult females, an attractive group, and two malocclusion groups. Our null hypothesis stated that the golden proportions of attractive females were analogous with or closer to the golden number than those with an established malocclusion. MATERIALS AND METHODS: Frontal facial photographs of 80 female dental students were scored for facial attractiveness by 10 dental specialists. Thirty females with scores greater than the median score of 48 formed the attractive group. Thirteen females with Class I malocclusion and 15 females with Class II division 1 malocclusion formed the two malocclusion groups. Ten landmarks and 19 golden proportions were calculated for all subjects. One-way ANOVA and unpaired Student's t-test was used to analyze the differences in golden proportions between the attractive and malocclusion groups. RESULTS: Significant differences were observed for 10 proportions (P<0.04 to <0.0001). Five vertical proportions showed significant differences in both subgroups; Attractive versus Class I and Attractive versus Class II division 1; while one vertical and all transverse proportions showed significant differences only in Attractive versus Class II division 1 subgroup. The average values of these proportions varied both toward and away from the golden number for both attractive and malocclusion groups. CONCLUSION: Facial proportions of the attractive females were significantly different from those with malocclusion, but did not show a constant trend of being closer to the golden number. Furthermore, the golden proportions were not analogous with the facial esthetics of the attractive females. PMID- 25728116 TI - Estimation of salivary neopterin in chronic periodontitis. AB - BACKGROUND: Periodontal diseases are the most common bacterial infection predominantly associated with Gram-negative microorganisms that exist in the subgingival biofilm. Analysis of saliva provides a noninvasive means of evaluating the role of the host response in periodontal disease. Though salivary enzymes can be used as the biomarkers, neopterin has been recently used as one of the important diagnostic tools in the field of periodontics. Hence, we aimed to identify the neopterin levels in unsimulated saliva from the chronic periodontitis patients and compare them with the periodontally healthy subjects. MATERIALS AND METHODS: Twenty subjects participated in the study and were categorized as the experimental group (chronic periodontitis patients) and control groups (healthy subjects). Unstimulated saliva samples were collected from both the groups for neopterin estimation. Neopterin in saliva was estimated using Shimadzu High Performance Liquid Chromatography with LC-20AD pump system, equipped with RF-10 AXL fluorescence detector. STATISTICAL ANALYSIS USED: Data were expressed as mean+/-SD and analyzed using GraphPad Prism version 6.0 (California, USA). Statistical analysis was done by Student's t-test. RESULTS: The neopterin level in unstimulated saliva was found to be higher in the experimental group than the control group with P<=0.05. CONCLUSIONS: The chronic periodontitis patients showed higher neopterin level in unstimulated saliva as compared to control. Hence, neopterin can be used as a potential biomarker for identification of the periodontal disease in its initial stage can help in preventing the disease progression. PMID- 25728117 TI - Promoter hypermethylation patterns of P16, DAPK and MGMT in oral squamous cell carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common cancer world-wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic mechanism that leads to gene silencing in tumors and could be a useful biomarker in OSCC. The prevalence of P16, death-associated protein kinase (DAPK) and O6-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation in OSCC has been evaluated for several years while the results remain controversial. OBJECTIVE: The aim of this systematic review is to critically analyze and perform a meta-analysis on the various studies in the literature that have reported the promoter hypermethylation of P16, DAPK and MGMT genes in OSCC. SEARCH STRATEGY: Articles were searched and selected through PubMed. Hand search from the relevant journals was also performed. Articles were reviewed and analyzed. RESULTS: The estimated prevalence of P16 methylation was 43%, DAPK methylation was 39.7% and MGMT methylation was 39.8%. Heterogeneity in methylation prevalences and correlations with the clinical outcomes of the disease prevailed in various studies. CONCLUSION: We can conclude from our systematic review that a higher prevalence of methylation of P16, DAPK and MGMT occur in OSCC. Further studies are required to substantiate the role of methylation of P16, DAPK and MGMT as a marker in OSCC. PMID- 25728118 TI - Congenital epulides: a rare case report. AB - Congenital epulis (CE) or "Granular cell epulis" also previously termed as "Neumann's tumor" is a benign growth arising from the mucosa of the gingiva, typically seen as a mass protruding from the infant's mouth, often interfering with respiration and feeding. These tumors generally present as a single mass arising from the upper alveolus. We report a rare case of two congenital epulides arising from the maxillary and mandibular alveolus in a day old female infant, which was surgically excised, allowing for early initiation of breast feeding. The tumor cells stained negative for S100 protein hence differentiating from other granular cell tumors. The clinical presentation, differential diagnosis in regard to the various neonatal oral swellings and the management of CE has been discussed. PMID- 25728119 TI - One-step apexification using platelet rich fibrin matrix and mineral trioxide aggregate apical barrier. AB - The absence of a natural apical constriction in a nonvital young permanent tooth makes endodontic treatment a challenge. There is a need to induce or create an apical barrier against, which the obturating material can be condensed. Traditionally, calcium hydroxide is the material of choice to induce apexification. Due to certain drawbacks such as prolonged treatment duration and unpredictable apical barrier formation, it is being replaced by materials, which have a more predictable outcome like mineral trioxide aggregate (MTA). One-step apexification with MTA reduces the treatment time when compared with traditional calcium hydroxide apexification, which requires an average time of 12-19 months. In one-step apexification using MTA, the technical problem encountered is controlling the overfill or underfill of MTA. The use of a matrix material helps to overcome this shortcoming. Platelet rich fibrin (PRF) is an immune platelet concentrate, which can be used as a matrix, it also promotes wound healing and repair. This case report presents a case of one step apexification using MTA as an apical barrier and autologous PRF as an internal matrix. PMID- 25728120 TI - Intramuscular cavernous hemangioma: a rare entity in the buccinator muscle. AB - Intramuscular hemangiomas are rare benign neoplasms accounting for <1% of all hemangiomas and <20% are found in head and neck area. The muscle most frequently involved is the masseter muscle and very few cases have been reported for the occurrence of these hemangiomas in the buccinator muscle. Here, we are presenting a case report of intramuscular hemangioma occurring in the buccinator muscle in a 22-year-old girl. PMID- 25728121 TI - Treatment of multiple gingival recessions adopting modified tunnel subepithelial connective tissue graft technique. AB - Gingival recession related to periodontal disease or developmental problems can result in root sensitivity, root caries, and esthetically unacceptable root exposures. In the past, multiple surgical procedures have been proposed to obtain root coverage on exposed buccal root surfaces. There has been great interest in the treatment of gingival recession defects, especially with subepithelial connective-tissue grafting (SCTG). Recent advances have focused on SCTG by the tunnel technique. This article highlights the esthetic results obtained by adopting a modification of the tunnel technique using a single vertical incision along with autologous SCTG in the management of multiple adjacent Miller Class-II gingival recessions. A single vertical incision was used along with tunnel preparation for the facile placement of SCTG into the prepared tunnel. After 6 months of follow-up, the clinical condition was stable with satisfactory root coverage outcome. An excellent esthetical outcome was achieved and the patient was satisfied with the result. PMID- 25728122 TI - Continuing professional development of dentists through distant learning: an Indira Gandhi National Open University-Dental Council of India experiment a report. AB - To keep themselves updated with all the advancements in the field of dentistry, dentists should involve themselves in some kind of professional development. Distance learning is the most appropriate way to serve the growing demand due to technological advancements. Indira Gandhi National Open University in collaboration with Dental Council of India (DCI) developed and launched two continuing professional development programs in Endodontics (postgraduate certificate in endodontics) and postgraduate certificate in oral implantology and has trained over 400 and 280 BDS dentists respectively till date. The program package consists of self-instructional material, assignments, videos and practical training. The training is conducted in premiere dental colleges and institutions recognized by DCI. The certificate is awarded after a term end examination, both in theory and practical. The pass percentages of the theory courses ranged from around 63% to 98%, and 90% of the candidates cleared the practical exam. PMID- 25728123 TI - Fronto-temporal cerebriform connective tissue nevus in Proteus syndrome. AB - Proteus syndrome is one of the very rare syndromes with occurrence of cerebriform connective tissue nevus. The aim of the present manuscript was to present a case of Proteus syndrome in an unusual facial location, which to the best of our knowledge, is being reported for the first time. The unusual occurrence further strengthens the mosaical basis of its etiopathogenesis. PMID- 25728124 TI - Dentin dysplasia type 1d: a rare case. AB - Dentin dysplasia is a rare hereditary disturbance of dentin formation characterized by a defective dentin development with clinically normal-appearing crowns, severe hypermobility of teeth and spontaneous dental abscesses or cysts. Radiographic analysis shows obliteration of all pulp chambers by pulp stones, short, blunted and malformed or absent roots, peri-apical radiolucencies of noncarious teeth. We present a case of dentin dysplasia type 1d in a 19-year-old boy along with the clinical, radiographic findings of this condition and treatment. There are still many inconclusive issues in the diagnosis and management of patients with dentin dysplasia. The diagnostic features of this rare disturbance will remain incompletely defined until additional cases have been described. PMID- 25728125 TI - Unsuccessful pulsed radiofrequency of the sphenopalatine ganglion in patients with chronic cluster headache and subsequent successful thermocoagulation. AB - We present the results of pulsed and continuous radiofrequency (CRF) of the sphenopalatine ganglion in a case series of 3 patients with chronic cluster headache (CCH). Three patients were referred to our neurosurgical department because of CCH, which was refractory to pharmacological treatment. They underwent pulsed radiofrequency of the sphenopalatine ganglion (PRF-SPG), and the procedure was performed through an infrazygomatic approach. In the PRF procedures, we applied 2 cycles of PRF at 42 degrees C and 45 V for 120 seconds, with a pulse frequency of 2 Hz and a pulse width of 20 ms. In those procedures where thermocoagulation was carried out, 2 CRF lesions at 80 degrees C for 90 seconds each were performed. Following corticosteroid and local anesthetic (40 mg of methylprednisolone and 1 mL of 1% lidocaine) injection, 2 patients had no pain relief at all, whereas the third one experienced a partial response, which lasted only 1 month and his pain then returned to its baseline level. Thus, this outcome was assessed as a nonsustained partial response. Therefore, all of them underwent a CRF lesioning of the SPG, and after this procedure, they achieved complete pain relief until the end of the follow-up period. Furthermore, the associated autonomic manifestations disappeared. The 3 patients presented in this case series failed to achieve adequate pain relief after PRF-SPG. However, these same patients subsequently underwent a successful CRF of the SPG. PMID- 25728126 TI - Transplanted Adipose-Derived Stem Cells Ameliorate Testicular Dysfunction In A D Galactose-Induced Aging Rat Model. AB - Glycation product accumulation during aging of slowly renewing tissues may be an important mechanism underlying aging of the testis. Adipose-derived stem cells (ADSCs) have shown promise in a novel tissue regenerative technique and may have utility in treating sexual dysfunction. ADSCs have also been found to be effective in antiaging therapy, although the mechanism underlying their effects remains unknown. This study was designed to investigate the anti-aging effect of ADSCs in a D-galactose (D-gal)-induced aging animal model and to clarify the underlying mechanism. Randomly selected 6-week-old male Sprague-Dawley rats were subcutaneously injected with D-gal daily for 8 weeks. Two weeks after completion of treatment, D-gal-induced aging rats were randomized to receive caudal vein injections of 3 * 10(6) 5-bromo 2'deoxy-uridine-labeled ADSCs or an equal volume of phosphate-buffered saline. Serum testosterone level, steroidogenic enzymes (3 beta-hydroxysteroid dehydrogenase), and superoxide dismutase (SOD) activity decreased significantly in aging rats compared with the control group; serum lipid peroxidation, spermatogenic cell apoptosis, and methane dicarboxylic aldehyde (MDA) expression increased significantly. ADSCs increased the SOD level and reduced the MDA level in the aging animal model and restored levels of serum testosterone, steroidogenic enzymes, and spermatogenic cell apoptosis. These results demonstrate that ADSCs can contribute to testicular regeneration during aging. ADSCs also provide functional benefits through glycation suppression and antioxidant effects in a rat model of aging. Although some ADSCs differentiated into Leydig cells, the paracrine pathway seems to play a main role in this process, resulting in the reduction of apoptosis. PMID- 25728127 TI - A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle-specific genes. AB - AIMS: Despite considerable progress being made in genetic diagnostics for dilated cardiomyopathy (DCM) using panels of the most prevalent genes, the cause remains unsolved in a substantial percentage of patients. We hypothesize that several previously described DCM genes with low or unknown prevalence have been neglected, which, if catalogued, could increase the yield of diagnostic DCM testing. The aim of this study is to catalogue all genetic evidence on DCM comprehensively. METHODS AND RESULTS: We have conducted a systematic literature search on PubMed, Embase, and OMIM to find genes implicated in syndromic and non syndromic DCM and peripartum cardiomyopathy (PPCM). Our search yielded 110 nuclear protein-coding genes and 24 mitochondrial DNA genes. For nuclear genes, in addition to 42 genes sufficiently reviewed previously (group A), we provide a comprehensive annotation of the level of genetic evidence for the remaining 68 genes (group B). Next, we investigated the tissue specificity of the collected genes using public RNA sequencing data. We show that genes primarily expressed in heart and skeletal muscle are more likely to result in DCM with possible skeletal myopathies, while genes expressed ubiquitously cause DCM with extramuscular manifestations. CONCLUSION: This comprehensive analysis of DCM-associated genes revealed a much higher number of genes than currently screened in diagnostics. Since most genes in group B have only been found mutated in single DCM patients or families, their importance for DCM genetic diagnostics needs to be validated in large cohorts. Targeted sequencing of validated DCM-implicated protein-coding genes and mitochondrial DNA, together with consideration of the tissue specificity of mutated genes, may facilitate further genotype-phenotype studies in DCM. PMID- 25728128 TI - Flipping the molecular switch for innate protection and repair of tissues: Long lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. AB - Many disease processes activate a cellular stress response that initiates a cascade of inflammation and damage. However, this process also triggers a tissue protection and repair system mediated by locally-produced hyposialated erythropoietin (hsEPO). Although recombinant EPO is used widely for treating anemia, potential use of recombinant EPO for tissue-protection is limited by rises in hematocrit, platelet activation, and selectin expression resulting in a high risk of thrombosis. Importantly, the erythropoietic and tissue-protective effects of EPO are mediated by different receptors. Whereas EPO stimulates red cell progenitors by binding to an EPO receptor (EPOR) homodimer, a heterodimer receptor complex composed of EPOR and beta common receptor (betacR) subunits, termed the innate repair receptor (IRR), activates tissue protection and repair. The IRR is typically not expressed by normal tissues, but instead is rapidly induced by injury or inflammation. Based on this understanding, EPO derivatives have been developed which selectively activate the IRR without interacting with the EPOR homodimer. The latest generation of specific ligands of the IRR includes an 11 amino acid peptide modeled from the three dimensional structure of the EPO in the region of helix B called pyroglutamate helix B surface peptide (pHBSP; ARA 290). Despite a short plasma half-life (~2min), pHBSP activates a molecular switch that triggers sustained biological effects that have been observed in a number of experimental animal models of disease and in clinical trials. This review summarizes pharmacokinetic and pharmacodynamic data and discusses the molecular mechanisms underlying the long-lasting effects of this short-lived peptide. PMID- 25728129 TI - Novel neurotrophic phenylbutenoids from Indonesian ginger Bangle, Zingiber purpureum. AB - Two new curcuminoids 1 and 2, and a new phenylbutenoid dimer 3, were isolated from Bangle (Zingiber purpureum). Their structures were determined on the basis of comprehensive spectroscopic data and their biogenetic pathway. Compounds 1 and 2 are the first example of curcumin coupled with phenylbutenoid. Compounds 1 and 2 promoted neurite outgrowth of NGF-mediated PC12 cells at concentrations ranging from 1 to 10 MUM. In addition, compound 1 was found to accelerate the prevention of Abeta42 aggregation. PMID- 25728130 TI - Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. AB - Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4 chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs. PMID- 25728131 TI - Visual outcomes and patient satisfaction with a rotational asymmetric refractive intraocular lens for emmetropic presbyopia. AB - PURPOSE: To evaluate the efficacy, safety, predictability, and patient satisfaction after refractive lens exchange with a zonal refractive intraocular lens (IOL) with an inferior reading addition in emmetropic patients. SETTING: Optical Express, London, United Kingdom. DESIGN: Retrospective case series. METHODS: Emmetropic presbyopic patients who had implantation of a Lentis Mplus LS 313 MF30 IOL were evaluated. Inclusion criteria were sphere between -0.50 diopter (D) and +1.00 D with no more than 0.75 D of refractive cylinder and an uncorrected distance visual acuity (UDVA) of 6/6 or better in each eye. The main outcome measures were monocular and binocular UDVA, uncorrected near visual acuity (UNVA), corrected distance visual acuity (CDVA), and patient satisfaction. Three months data are presented. RESULTS: Four hundred forty eyes of 220 patients were evaluated. The mean monocular UDVA changed from -0.04 logMAR +/- 0.06 (SD) preoperatively to -0.04 +/- 0.11 logMAR postoperatively (P = .39). The mean CDVA was -0.10 +/- 0.05 logMAR preoperatively and -0.09 +/- 0.06 logMAR postoperatively (P = .06). At 3 months, 99.7% of eyes were within +/-1.00 D of emmetropia. The mean UNVA was 0.13 +/- 0.14 logMAR monocularly and 0.10 +/- 0.12 logMAR binocularly. On the patient satisfaction questionnaire, 91.9% of patients said the refractive procedure improved their lives and 93.5% were willing to recommend it to friends and family. Three patients requested IOL exchange because of severe night-vision phenomena or unsatisfactory quality of vision. CONCLUSION: Refractive lens exchange with this zonal refractive IOL was safe in emmetropic presbyopic patients. FINANCIAL DISCLOSURE: Dr. Schallhorn is a consultant to Abbott Medical Optics. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25728132 TI - Ten-year beverage intake trends among US preschool children: rapid declines between 2003 and 2010 but stagnancy in recent years. AB - BACKGROUND: It has been previously reported that total energy intake among US preschool children (ages 2-5 years) decreased between 2003-2004 and 2009-2010. However, little is known about how intakes of beverages among US preschoolers (ages 2-5 years) changed from 2003-2004 to 2011-2012. OBJECTIVES: This paper examines changes in intakes of key beverages during this period, as well as how eating location (at home or away from home) and source (store vs. others) may have contributed to these changes. METHODS: Cross-sectional day one dietary data among children ages 2-5 years from the National Health and Nutrition Examination Survey 2003-2004, 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were used. Survey weighted mean intakes by survey year, eating location and source were computed for total sugar-sweetened beverages (SSBs), milks, 100% juice, low/no-calorie beverages, 10 key beverages, total beverages and total foods. Means were compared using two-tailed z-tests with Bonferroni corrections (alpha < 0.05). RESULTS: Between 2003-2004 and 2011-2012, among 2-5 year olds, total caloric intake fell by 132 kcal d(-1) , with intakes of beverages falling by 55 kcal d(-1) . Decreases in intakes of total SSBs (-57 kcal d(-1) ), fruit-flavoured or juice drinks containing <100% juice (juice drinks) (-37 kcal d(-1) ), caloric soft drinks (-13 kcal d(-1) ) and >1% fat, low-sugar milk (-42 kcal d(-1) ) were among the major changes. By eating location, total beverage intake at home fell by 73 kcal d(-1) . By source, total beverage intake from stores fell by 106 kcal d(-1) . Changes in intakes occurred primarily between 2003-2004 and 2009-2010, as there were no significant differences in beverage intakes between 2009-2010 and 2011 2012. Intakes of total calories (+49 kcal d(-1) ) and calories from foods (+53 kcal d(-1) ) trended upward between 2009-2010 and 2011-2012, but changes were not significant. CONCLUSIONS: These findings suggest improvements in the diets of preschoolers between 2003-2004 and 2009-2010, of which stores were a major contributor. PMID- 25728133 TI - Highly isoselective coordination polymerization of ortho-methoxystyrene with beta diketiminato rare-earth-metal precursors. AB - Stereoselective coordination/insertion polymerization of the polar ortho methoxystyrene has been achieved for the first time by using the cationic beta diketiminato rare-earth-metal species. High activity and excellent isoselectivity (mmmm>99 %) were acheived. The unmasked Lewis-basic methoxy group does not poison the Lewis-acidic metal center, but instead activates the polymerization through sigma-pi chelation to the active species together with the vinyl group, thus lower the coordination and activation energies as compared with those of styrene derivatives lacking the methoxy group. PMID- 25728134 TI - Emerging influenza viruses and the prospect of a universal influenza virus vaccine. AB - Influenza viruses cause annual seasonal epidemics and pandemics at irregular intervals. Several cases of human infections with avian and swine influenza viruses have been detected recently, warranting enhanced surveillance and the development of more effective countermeasures to address the pandemic potential of these viruses. The most effective countermeasure against influenza virus infection is the use of prophylactic vaccines. However, vaccines that are currently in use for seasonal influenza viruses have to be re-formulated and re administered in a cumbersome process every year due to the antigenic drift of the virus. Furthermore, current seasonal vaccines are ineffective against novel pandemic strains. This paper reviews zoonotic influenza viruses with pandemic potential and technological advances towards better vaccines that induce broad and long lasting protection from influenza virus infection. Recent efforts have focused on the development of broadly protective/universal influenza virus vaccines that can provide immunity against drifted seasonal influenza virus strains but also against potential pandemic viruses. PMID- 25728135 TI - BdVIL4 regulates flowering time and branching through repressing miR156 in ambient temperature dependent way in Brachypodium distachyon. AB - Responsing to environmental signals, Vernalization Insensitive 3 (VIN3) family proteins are involved in plant development control by repressing the target genes epigenecticly together with Polycomb Repressive Complex 2 (PRC2) complex. BdVIL4 is a VIN3 like gene in Brachypodium distachyon, preferentially expressed in young tissues spatially. The RNAi plants were constructed to study the function of BdVIL4 on the development process. The plants with BdVIL4 RNA interferenced (BdVIL4 RNAi plants) had no obvious difference from the wild at 23 degrees C, but flowered significantly later and had more branches than the control at l6 degrees C. In BdVIL4 RNAi plants the expression of miR156 were upregulated, and much more at low temperature (l6 degrees C). Coincidentally, similar to the BdVIL4 RNAi plants, the miR156 overexpressors also showed late flowering and more branches, and the late flowering phynotype just only performanced at lower temperature. The results suggested that BdVIL4 are involved in the regulation of branching and flowering responsing to the ambient temperature by repressing the expression of miR156. PMID- 25728136 TI - Structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion in rats. AB - Recent studies have shown retinal blood vessel damage in experimental models of retinal degeneration. The present study aimed to provide a detailed description of the structural and functional changes in retinal vasculature induced by retinal ischemia-reperfusion (I/R) in rats. Retinal ischemia was induced for 60 min by raising the intraocular pressure to 130 mmHg. Morphological changes in vascular components (endothelial cells, pericytes, and basement membranes), the patency and perfusion of blood vessels, and expression of vascular endothelial growth factor (VEGF) were assessed in the retinas at 2, 7, and 14 days after I/R. Significant reductions in vascular densities were observed at 7 and 14 days after I/R. Pericyte loss occurred after the appearance of endothelial cell degeneration, whereas the vascular basement membranes remained unchanged. Some vessels showed no perfusion in damaged retina. A decrease in the immunoreactivity of VEGF in the region extending from the ganglion cell layer to the outer plexiform layer was evident 2 days after I/R. In retinal I/R model, retinal ganglion cells are rapidly (<2 day) damaged following reperfusion, therefore, the current results suggest that neuronal cell damage precedes capillary degeneration, and neuronal cells may play an important role in maintaining vascular structure and function through the production and release of endothelial cell survival factors, including VEGF. Neuronal cell damage could be an additional cause of progression of ischemic retinal damage by reducing blood supply to the retinal neurons due to the destruction of the blood vessel network. PMID- 25728137 TI - Acclimation to environmentally relevant Mn concentrations rescues a cyanobacterium from the detrimental effects of iron limitation. AB - The functions of micronutrient transition metals in photosynthetic organisms are interconnected. So are the effects of their limitation. Here we present evidence for the effects of Mn limitation on Fe limitation responses in the cyanobacterium Synechocystis sp. PCC 6803. Low Mn acclimated cells were able to detect and respond to iron insufficiency by inducing specific Fe transporters. However, they did not bleach, lose additional photosystem I activity and did not induce isiA transcription. Induction of the isiAB operon is a hallmark of iron limitation, and the isiA protein is considered to be central to the acclimation of the photosynthetic apparatus. Our results suggest that acclimation to environmentally relevant Mn concentrations that much lower than those used in laboratory experiments reduces the detrimental effects of iron limitation and modifies iron stress responses. PMID- 25728138 TI - The lncRNA NRON modulates HIV-1 replication in a NFAT-dependent manner and is differentially regulated by early and late viral proteins. AB - A majority of the human genome is transcribed into noncoding RNAs, of which the functions of long noncoding RNAs (lncRNAs) are poorly understood. Many host proteins and RNAs have been characterized for their roles in HIV/AIDS pathogenesis, but there is only one lncRNA, NEAT1, which is shown to affect the HIV-1 life cycle. We profiled 90 disease-related lncRNAs and found NRON (noncoding repressor of Nuclear Factor of Activated T cells [NFAT]) to be one of several lncRNAs whose expression was significantly altered following HIV-1 infection. The regulation of NRON expression during the HIV-1 life cycle was complex; its levels were reduced by the early viral accessory protein Nef and increased by the late protein Vpu. Consequently, Nef and Vpu also modulated activity of the transcription factor NFAT. The knockdown of NRON enhanced HIV-1 replication through increased activity of NFAT and the viral LTR. Using siRNA mediated NFAT knockdown, we show the effects of NRON on HIV-1 replication to be mediated by NFAT, and the viral Nef and Vpu proteins to modulate NFAT activity through their effects on NRON. These findings add the lncRNA, NRON to the vast repertoire of host factors utilized by HIV for infection and persistence. PMID- 25728139 TI - Prediction of small-for-gestational-age neonates: screening by fetal biometry at 35-37 weeks. AB - OBJECTIVE: To investigate the value of fetal biometry at 35-37 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in singleton pregnancies at 35-37 weeks' gestation, comprising 278 that delivered SGA neonates with a birth weight < 5th percentile and 5237 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors and Z-scores of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) or estimated fetal weight (EFW) had a significant contribution to the prediction of SGA neonates. RESULTS: Multivariable logistic regression analysis demonstrated that the likelihood of delivering a SGA neonate with a birth weight < 5th percentile decreased with maternal weight and height, and in parous women the risk increased with a longer interpregnancy interval. The risk was higher in women of Afro-Caribbean and South Asian racial origins, in cigarette smokers, nulliparous women and in those with history of SGA, with or without prior PE. Combined screening by maternal characteristics and history with EFW Z-scores at 35-37 weeks predicted 89% of SGA neonates with birth weight < 5th percentile delivering < 2 weeks following assessment, at a 10% false-positive rate (FPR). The respective detection rate for the prediction of SGA neonates delivering >= 37 weeks' gestation was 70%. The performance of screening by a combination of Z scores of fetal HC, AC and FL was similar to that achieved by the EFW Z-score. CONCLUSION: Combined testing by maternal characteristics and fetal biometry at 35 37 weeks could identify, at a 10% FPR, about 90% of pregnancies that subsequently deliver SGA neonates within 2 weeks of assessment and 70% of those that deliver >= 37 weeks. PMID- 25728140 TI - How slow is too slow? Correlation of operative time to complications: an analysis from the Tennessee Surgical Quality Collaborative. AB - BACKGROUND: The Tennessee Surgical Quality Collaborative analyzes NSQIP data from 21 participating hospitals. The Tennessee Surgical Quality Collaborative has reduced surgical complications, but causative factors are unclear. We sought to correlate surgical duration with complications to reveal mitigating strategies. STUDY DESIGN: Risk-adjusted Tennessee Surgical Quality Collaborative data on 104,632 general and vascular cases had a standard duration for 35 procedures (eg, breast, colectomy) calculated and NSQIP outcomes complication rates recorded. We derived a marginal time risk for each extra hour of operative time and reported per 1,000 cases. RESULTS: Procedures taking <95% upper confidence standard time limit (n = 99,741) were deemed "not long" and had significantly fewer urinary tract infections, organ-space surgical site infection, sepsis/septic shock, prolonged intubation, and pneumonia. "Long" cases had increased rates of these complications and also deep venous thrombosis, deep incisional infection, and wound disruption. Per 1,000 cases, there were 116 occurrences per operating room hour. Surgical site infections occurred in 14.4/1,000 cases per hour; risk started at 42 minutes of operative time. Death, pneumonia, and prolonged intubation saw their risks begin before the operation. The highest marginal time risk was for sepsis, occurring 16.6 times per additional hour of operative time over standard. Studying only the 25,146 clean procedures, a significant correlation (p < 0.001) to operation duration persisted, despite an occurrence incidence of 4.5%. CONCLUSIONS: Duration of operation correlates with complications and time longer than a statewide established standard carries higher risk. To reduce risk of complications, these data support expeditious surgical technique and preoperative pulmonary training, and offer accurate outcomes assessment for patient counseling based on case duration. These data can be used directly to counsel individual surgeons to improve outcomes. PMID- 25728141 TI - How are select chronic pancreatitis patients selected for total pancreatectomy with islet autotransplantation? Are there psychometric predictors? AB - BACKGROUND: Selected patients with chronic pancreatitis can benefit from total pancreatectomy with islet autotransplantation. Patient selection is challenging and outcomes assessment is essential. STUDY DESIGN: A prospective database of total pancreatectomy with islet autotransplantation patients was reviewed. Attention was given to psychometric assessments, including Short Form-12 Quality of Life Survey (SF-12), Center for Epidemiologic Studies 10-Item Depression scale, and Current Opioid Misuse Measure in the preoperative period, and SF-12 in the postoperative period. RESULTS: One hundred and twenty-seven patients (76% women, mean age 40.5 years) underwent total pancreatectomy with islet autotransplantation. Preoperatively, the mean SF-12 physical quality of life score (physQOL) was 27.24 (SD 9.9) and the mean psychological QOL score (psychQOL) was 38.5 (SD 12.8), with a score of 50 representing the mean of a healthy population. Mean improvements in physQOL relative to baseline at 1 year, 2 years, and 3 years post surgery were 7.1, 5.8, and 7.8, respectively, which represented significant change (all p < 0.001). Mean improvements in psychQOL relative to baseline at 1 year, 2 years, and 3 years post surgery were 3.9, 4.9, and 6.6, which also represented significant improvement (all p < 0.001). The percentages of patients evidencing at least a 3-point improvement in physQOL at 1 year, 2 years, and 3 years post surgery were 65%, 60%, and 61%, respectively. The percentages of patients evidencing at least a 3-point improvement in psychQOL at 1 year, 2 years, and 3 years post surgery were 49%, 58%, and 66%, respectively. Exploratory regression analyses of SF-12, Current Opioid Misuse Measure, and Center for Epidemiologic Studies 10-Item Depression scale data revealed limited baseline predictability of surgical response; however, higher opioid misuse scores at baseline were significantly and positively related to physQOL improvement at 2 years (r[54] = 0.33, p = 0.02). CONCLUSIONS: Total pancreatectomy with islet autotransplantation improves QOL for selected patients with chronic pancreatitis. The physQOL improves quickly after surgery, and psychQOL improvements are more gradual. Opioid misuse can predict physQOL improvement. PMID- 25728142 TI - Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified? AB - BACKGROUND: The incidence of hepatocellular cancer (HCC) is increasing dramatically worldwide. Optimal management remains undefined, especially for well compensated cirrhosis and HCC. STUDY DESIGN: This retrospective analysis included 5 US liver cancer centers. Patients with surgically treated HCC between 1990 and 2011 were analyzed; demographics, tumor characteristics, and survival rates were included. RESULTS: There were 1,765 patients who underwent resection (n = 884, 50.1%) or transplantation (n = 881, 49.9%). Overall, 248 (28.1%) resected patients were transplant eligible (1 tumor <5 cm or 2 to 3 tumors all <3 cm, no major vascular invasion); these were compared with 496 transplant patients, matched based on year of transplantation and tumor status. Overall survivals at 5 and 10 years were significantly improved for transplantation patients (74.3% vs 52.8% and 53.7% vs 21.7% respectively, p < 0.001), with greater differences in disease-free survival (71.8% vs 30.1% at 5 years and 53.4% vs 11.7% at 10 years, p < 0.001). Ninety-seven of the 884 (11%) resected patients were within Milan criteria and had cirrhosis; these were compared with the 496 transplantation patients, with similar results to the overall group. On multivariate analysis, type of surgery was an independent variable affecting all survival outcomes. CONCLUSIONS: The increasing incidence of HCC stresses limited resources. Although transplantation results in better long-term survival, limited donor availability precludes widespread application. Hepatic resection will likely remain a standard therapy in selected patients with HCC. In this large series, only about 10% of patients with cirrhosis were transplant-eligible based on tumor status. Although liver transplantation results are significantly improved compared with resection, transplantation is available only for a minority of patients with HCC. PMID- 25728143 TI - Putting the value framework to work in surgery. AB - BACKGROUND: Health policy experts have proposed a framework defining value as outcomes achieved per dollar spent on health care. However, few institutions quantify their delivery of care along these dimensions. Our objective was to measure the value of our surgical services over time. STUDY DESIGN: We reviewed the data of patients undergoing general and vascular surgery from 2002 through 2012 at a tertiary care university hospital as abstracted by the American College of Surgeons NSQIP. Morbidity and mortality data from the American College of Surgeons NSQIP database were risk adjusted to calculate observed-to-expected ratios, which were then inverted into a numerator as a surrogate for quality. Costs, the denominator of the value equation, were determined for each patient's hospitalization. The ratio was then transformed by a constant and analyzed with linear regression to analyze and compare values from 2002 through 2012. RESULTS: A total of 25,453 patients met criteria for inclusion. Overall, the value of surgical services increased from 2002 through 2012. The observed increase in value was greater in general surgery than in vascular surgery, and value actually decreased in vascular procedures. Although there was a similar increase in outcomes in vascular surgery compared with general surgery, costs rose significantly higher ($474/year vs -$302/year; p < 0.001). These increased costs were mostly observed from 2006 through 2010 with the adoption of endovascular technology. CONCLUSIONS: Despite the challenges posed by current information systems, calculating risk-adjusted value in surgical services represents a critical first step for providers seeking to improve outcomes, avoid ill-advised cost containment, and determine the costs of innovation. PMID- 25728144 TI - Extraordinary sensitivity enhancement by metasurfaces in terahertz detection of antibiotics. AB - We have detected trace amounts of molecules of antibiotics (kanamycin sulfate) dispersed on metasurfaces with terahertz (THz) spectroscopy. Utilizing the extraordinary optical transmission resonance of an array of square-shaped slits on a silicon substrate at ~0.3 THz, we were able to monitor varying concentrations of kanamycin sulfate as low as ~100 picogram/L. In contrast, the lowest detectable concentration of kanamycin sulfate on silicon without any metallic structure was ~1 gram/L. This dramatic ~10(10) times enhancement of sensitivity is due to the near-field enhancement of THz electric fields by the metamaterial structure. This result thus demonstrates the power and usefulness of metamaterial-assisted THz spectroscopy in trace molecular detection for biological and chemical sensing as well as for food product quality and safety inspection and control. PMID- 25728145 TI - Microstructural parameter-based modeling for transport properties of collagen matrices. AB - Recent advances in modulating collagen building blocks enable the design and control of the microstructure and functional properties of collagen matrices for tissue engineering and regenerative medicine. However, this is typically achieved by iterative experimentations and that process can be substantially shortened by computational predictions. Computational efforts to correlate the microstructure of fibrous and/or nonfibrous scaffolds to their functionality such as mechanical or transport properties have been reported, but the predictability is still significantly limited due to the intrinsic complexity of fibrous/nonfibrous networks. In this study, a new computational method is developed to predict two transport properties, permeability and diffusivity, based on a microstructural parameter, the specific number of interfibril branching points (or branching points). This method consists of the reconstruction of a three-dimensional (3D) fibrous matrix structure based on branching points and the computation of fluid velocity and solute displacement to predict permeability and diffusivity. The computational results are compared with experimental measurements of collagen gels. The computed permeability was slightly lower than the measured experimental values, but diffusivity agreed well. The results are further discussed by comparing them with empirical correlations in the literature for the implication for predictive engineering of collagen matrices for tissue engineering applications. PMID- 25728146 TI - Systemic inflammatory response syndrome between 24 and 48 h after ERCP predicts prolonged length of stay in patients with post-ERCP pancreatitis: a retrospective study. AB - BACKGROUND: Early systemic inflammatory response syndrome (SIRS) has been associated with severe non-iatrogenic acute pancreatitis. The aims of this study were to determine whether early SIRS could be used to predict severe post-ERCP pancreatitis (PEP) and to determine the effect of prophylactic-pancreatic stenting (PS) on SIRS and severe PEP. METHODS: Between 1/2000 and 6/2012, all patients admitted for PEP after an outpatient ERCP and who had >=1 abdominal CT scan during hospitalization were retrospectively evaluated. The presence of SIRS was assessed between 0 and 24 h and 24 and 48 h after the time of ERCP completion. SIRS was evaluated as a predictor of severe PEP using area under receiver operating characteristic (AUROC) curve analysis. RESULTS: There were 113 patients with PEP of whom 22 (19.5%) had severe PEP. SIRS was present in 44 (38.9%) and 33 (29.2%) patients between 0 and 24 h and 24 and 48 h, respectively. SIRS between 24 and 48 h had a higher predictive accuracy for severe PEP compared to SIRS between 0 and 24 h (AUROC = 0.7 vs. 0.5, p = 0.002). The prevalence of SIRS between 24 and 48 h was significantly less among the 19 patients who underwent PS (11% vs. 37%, p = 0.03). There was no difference between the prophylactic stenting and no stenting groups with regards to acute fluid collection(s), pancreatic necrosis, organ failure or mortality during hospitalization. CONCLUSIONS: SIRS between 24 and 48 h after ERCP is an accurate, easy to obtain, and inexpensive predictor of severe PEP. PS is associated with a decreased prevalence of SIRS between 24 and 48 h after ERCP. PMID- 25728148 TI - Employee influenza vaccination in a large cancer center with high baseline compliance rates: comparison of carrot versus stick approaches. AB - BACKGROUND: Influenza is a major complication in patients with cancer and hematopoietic cell transplant recipients. We set out to maximize influenza vaccination rates in health care personnel at our large ambulatory cancer center with high baseline compliance and to assess alternatives to mandatory policies. METHODS: Baseline influenza vaccine compliance rates at our center were >85%. During 2011 an incentive-based "carrot" campaign was implemented, and in 2012 a penalty-based "stick" approach to declining staff was required. Yearly approaches were compared using Kaplan-Meier survival estimates. RESULTS: Both the incentive and penalty approaches significantly improved the baseline rates of vaccination (2010 vs 2011 P = .0001 and 2010 vs 2012 P < .0001), and 2012 significantly improved over 2011 (P < .0001). Staff with direct patient contact had significantly higher rates of vaccination compared with those with indirect and minimal contact in every campaign year, except in the penalty-driven campaign from 2012 (P < .001, P < .001, and P = .24 and P < .001, P < .001, and P = .17, respectively). CONCLUSIONS: A multifaceted staff vaccination program that included education, training, and active declination was more effective than a program offering incentives. Improvements in vaccination rates in the penalty driven campaign were driven by staff without direct care responsibilities. High compliance with systemwide influenza vaccination was achieved without requiring mandatory vaccination. PMID- 25728149 TI - Understanding the current state of infection prevention to prevent Clostridium difficile infection: a human factors and systems engineering approach. AB - BACKGROUND: Achieving and sustaining high levels of health care worker (HCW) compliance with contact isolation precautions is challenging. The aim of this study was to determine HCW work system barriers to and facilitators of adherence to contact isolation for patients with suspected or confirmed Clostridium difficile infection (CDI) using a human factors and systems engineering approach. METHODS: This prospective cohort study took place between September 2013 and November 2013 at a large academic medical center (hospital A) and an affiliated Veterans Administration hospital (hospital B). A human factors engineering (HFE) model for patient safety, the Systems Engineering Initiative for Patient Safety model, was used to guide work system analysis and direct observation data collection. There were 288 observations conducted. HCWs and visitors were assessed for compliance with all components of contact isolation precautions (hand hygiene, gowning, and gloving) before and after patient contact. Time required to complete contact isolation precautions was measured, and adequacy of contact isolation supplies was assessed. RESULTS: Full compliance with contact isolation precautions was low at both hospitals A (7%) and B (22%). Lack of appropriate hand hygiene prior to room entry (compliance for hospital A: 18%; compliance for hospital B: 29%) was the most common reason for lack of full compliance. More time was required for full compliance compared with compliance with no components of contact isolation precautions before patient room entry, inside patient room, and after patient room exit (59.9 vs 3.2 seconds, P < .001; 507.3 vs 149.7 seconds, P = .006; 15.2 vs 1.3 seconds, P < .001, respectively). Compliance was lower when contact isolation supplies were inadequate (4% vs 16%, P = .005). CONCLUSIONS: Adherence to contact isolation precautions for CDI is a complex, time-consuming process. HFE analysis indicates that multiple work system components serve as barriers and facilitators to full compliance with contact isolation precautions and should be addressed further to prevent CDI. PMID- 25728150 TI - Predictors of asymptomatic Clostridium difficile colonization on hospital admission. AB - BACKGROUND: Clostridium difficile (CD) is the leading cause of health care associated diarrhea and can result in asymptomatic carriage. Rates of asymptomatic CD colonization on hospital admission range from 1.4%-21%. The objective of this study was to evaluate host and bacterial factors associated with colonization on admission. METHODS: The Consortium de recherche quebecois sur le Clostridium difficile study provided data for analysis, including demographic information, known risk factors, and potential confounding factors, prospectively collected for 5,232 patients from 6 hospitals in Quebec and Ontario over 15 months from 2006-2007. Stool or rectal swabs were obtained for culture on admission. Pulsed-field gel electrophoresis was performed on the isolates. The presence of antibody against CD toxins A and B was measured. RESULTS: There were 212 (4.05%) patients colonized with CD on admission, and 5,020 patients were not colonized with CD. Multivariate logistic regression analysis showed that hospitalization within the last 12 months, use of corticosteroids, prior CD infection, and presence of antibody against toxin B were associated with colonization on admission. Of patients colonized on admission, 79.4% had non NAP1, non-NAP2 strains. CONCLUSION: There are identifiable risk factors among asymptomatic CD carriers that could serve in their detection and provide a basis for targeted screening. PMID- 25728151 TI - Introducing the No Preventable Harms campaign: creating the safest health care system in the world, starting with catheter-associated urinary tract infection prevention. AB - BACKGROUND: Endemic health care-associated safety problems, including health care associated infection, account for substantial morbidity and mortality. We outline a regional No Preventable Harms campaign to reduce these safety problems and describe the initial results from the first initiative focusing on catheter associated urinary tract infection (CAUTI) prevention. METHODS: We formed a think tank composed of multidisciplinary experts from within a 7-hospital Midwestern Veterans Affairs network to identify hospital-acquired conditions that had strong evidence on how to prevent the harm and outcome data that could be easily collected to evaluate improvement efforts. The first initiative of this campaign focused on CAUTI prevention. Quantitative data on CAUTI rates and qualitative data from site visit interviews were used to evaluate the initiative. RESULTS: Quantitative data showed a significant reduction in CAUTI rates per 1,000 catheter days for nonintensive care units across the region (2.4 preinitiative and 0.8 postinitiative; P = .001), but no improvement in the intensive care unit rate (1.4 preinitiative and 2.1 postinitiative; P = .16). Themes that emerged from our qualitative data highlight the need for considering local context and the importance of communication when developing and implementing regional initiatives. CONCLUSIONS: A regional collaborative can be a valuable strategy for addressing important endemic patient safety problems. PMID- 25728153 TI - Systematic qualitative literature review of health care workers' compliance with hand hygiene guidelines. AB - BACKGROUND: Acquisition of a health care-associated infection is a substantial risk to patient safety. When health care workers comply with hand hygiene guidelines, it reduces this risk. Despite a growing body of qualitative research in this area, a review of the qualitative literature has not been published. METHODS: A systematic review of the qualitative literature. RESULTS: The results were themed by the factors that health care workers identified as contributing to their compliance with hand hygiene guidelines. Contributing factors were conceptualized using a theoretical background. This review of the qualitative literature enabled the researchers to take an inductive approach allowing for all factors affecting the phenomenon of interest to be explored. Two core concepts seem to influence health care workers' compliance with hand hygiene guidelines. These are motivational factors and perceptions of the work environment. Motivational factors are grounded in behaviorism, and the way in which employees perceive their work environment relates to structural empowerment. CONCLUSION: Noncompliance with hand hygiene guidelines remains a collective challenge that requires researchers to adopt a consistent and standardized approach. Theoretical models should be used intentionally to better explain the complexities of hand hygiene. PMID- 25728152 TI - Safety and efficacy of a novel silver-impregnated urinary catheter system for preventing catheter-associated bacteriuria: a pilot randomized clinical trial. AB - BACKGROUND: The purpose of this study was to evaluate the safety of a novel silver-impregnated Foley catheter system designed to prevent catheter-associated bacteriuria and funguria, assess recruitment feasibility for a future pivotal trial, and preliminarily assess efficacy. METHODS: This single-center, randomized controlled trial at a university hospital involved adult neurosurgical patients expected to have a urinary catheter for >=24 hours. Subjects were randomized to a novel silver-impregnated (test) Foley catheter system or a control system. They were followed for 30 days (or until discharge) while catheterized and for up to 48 hours after catheter removal, with daily bacteriuria testing and assessment for symptoms of infection and catheter intolerance. RESULTS: Ninety-five subjects were randomized (intention-to-treat [ITT] population). Of these, 61 subjects (64%) had a catheter for >=24 hours without perioperative antibiotics beyond 24 hours (evaluable population). In the ITT population, 11 of 95 (12%) subjects had an asymptomatic bacteriuria (ABU) event. Compared with controls, test system recipients had a trend toward longer time to ABU in the ITT population (P = .08, log-rank test) and a longer time to ABU in the evaluable population (P = .03). All 6 ABU events caused by gram-negative bacilli occurred in the control group. CONCLUSION: In this pilot randomized trial the test system was well tolerated and seemingly effective in preventing catheter-associated bacteriuria, especially with gram-negative bacilli. A pivotal study is warranted. PMID- 25728154 TI - Successful reduction in central line-associated bloodstream infections in a Chinese neonatal intensive care unit. AB - BACKGROUND: Few data are available on central-line associated bloodstream infections (CLABSIs) in Chinese neonatal intensive care units (NICUs). The aims of this study were to characterize CLABSIs among neonates in a Chinese NICU and evaluate the impact of a multifaceted evidence-based practice for improving quality program to decrease CLABSI. METHODS: We conducted a prospective before after intervention study with a 1-year follow-up among patients with central lines at the NICU of the Children's Hospital of Fudan University between January 2008 and December 2010. The study was conducted in 3 phases: before, during, and after the intervention. A multifaceted infection control program was introduced in phase 2 with successive surveillance. CLABSIs were prospectively monitored and compared. RESULTS: A total of 171 patients with central lines (CLs) were observed; 29 of them developed CLABSI corresponding to 7.35 per 1,000 catheter days, with a CL utilization ratio of 37.9%. Overall CLABSI rate decreased gradually from 16.7 per 1,000 CL days in phase 1 to 7.6 per 1,000 CL days in phase 2 (P = .08) to 5.2 per 1,000 CL days in phase 3 (P < .01). Gram-negative bacterium (54.5%) was the predominant pathogen in CLABSIs. CONCLUSION: A multifaceted infection control program is effective in reducing the CLABSI rate among neonates. Such interventions could be extended to other resource-limited countries. PMID- 25728155 TI - Assessment of an innovative antimicrobial surface disinfectant in the operating room environment using adenosine triphosphate bioluminescence assay. AB - Terminal cleaning in the operating room is a critical step in preventing the transmission of health care-associated pathogens. The persistent disinfectant activity of a novel isopropyl alcohol/organofunctional silane solution (ISO) was evaluated in 4 operating rooms after terminal cleaning. Adenosine triphosphate bioluminescence documented a significant difference (P < .048) in surface bioburden on IOS-treated surfaces versus controls. RODAC plate cultures revealed a significant (P < .001) reduction in microbial contamination on IOS-treated surfaces compared with controls. Further studies are warranted to validate the persistent disinfectant activity of ISO within selective health care settings. PMID- 25728156 TI - Keyboard cleanliness: a controlled study of the residual effect of chlorhexidine gluconate. AB - A controlled trial of once daily cleaning of computer keyboards in an intensive care unit was performed comparing 2% chlorhexidine gluconate-70% isopropyl alcohol (CHG) and a chlorine dioxide-based product used as a standard in our hospital. A study before and after the introduction of once daily keyboard cleaning with CHG in the wider hospital was also completed. Cleaning with CHG showed a sustained and significant reduction in bacterial colony forming units compared with the chlorine dioxide-based product, demonstrating its unique advantage of maintaining continuous keyboard cleanliness over time. PMID- 25728157 TI - Impact of the first hand sanitizing relay world record on compliance with hand hygiene in a hospital. AB - Staff of a large hospital in Hong Kong attempted and set the first Guinness World Record for the most participants in a hand sanitizing relay in May 2014. After this event, average compliance with hand hygiene increased from 72% (95% CI, 70% 74%) in 2013 to 85% (95% CI, 83%-87%) in June-July 2014, and the conceptual understanding of good hand hygiene practices improved. PMID- 25728158 TI - Knowledge, beliefs, and confidence regarding infections and antimicrobial stewardship: a survey of Veterans Affairs providers who care for older adults. AB - We conducted an anonymous survey of providers who care for older adults from 10 Veterans Affairs long-term-care facilities to assess their knowledge, beliefs, and confidence toward treating infections and antimicrobial stewardship. The average score on 5 questions assessing knowledge was 3.6 out of 5.0 (95% confidence interval, 3.3-3.9), which supports a need for education regarding the care of older adults with infections. PMID- 25728159 TI - Oral hygiene protocols in intensive care units in a large Brazilian city. AB - This study investigated oral hygiene protocols for patients in intensive care units (ICUs) in 25 of 30 hospitals in Belo Horizonte, Brazil, using a questionnaire. Although all hospital representatives said there was a protocol for the maintenance of patients' oral hygiene, it was observed that there was no standardization. Only 2 hospitals had dentists on the ICU staff. Cetylpyridinium chloride was the most frequently used antiseptic, even in patients under mechanical ventilation. PMID- 25728160 TI - Fluid dispersal from safety cannulas: an in vitro comparative test. AB - We report a comparative laboratory study between 2 peripheral intravenous catheters equipped with a passive fully automatic safety mechanism to assess generation of blood droplets during withdrawal. One presented no fluid droplets, whereas the other presented droplets in 48% and 60% for the best and worst case, with analysis of variance showing positive effects on the number of droplets generated (P < .001). Safety devices can introduce hazards if health care workers are at risk from blood splatter. PMID- 25728161 TI - Health care workers use disposable microfiber cloths for cleaning clinical equipment. PMID- 25728162 TI - Effectiveness of a chlorine dioxide-based coating on environmental contamination in long-term-care facilities. PMID- 25728163 TI - Nurses' and personal care assistants' role in improving the relocation of older people into nursing homes. AB - AIMS AND OBJECTIVES: This article presents findings from a study that explored nurses' and personal care assistants' role in improving the relocation of older people into a nursing home. BACKGROUND: Suggestions for improving the relocation process for older people moving into a nursing home have been the outcomes of studies that have interviewed residents and their families. However, the views of nurses and personal care assistants working in nursing homes have not been previously explored. DESIGN: An exploratory, descriptive qualitative research design. METHODS: Individual interviews were conducted with 20 care staff (seven registered nurses, five enrolled nurses and eight personal care assistants) employed at four nursing homes. FINDINGS: Using thematic analysis, two key themes were identified: 'What it's like for them' - highlighted staffs' awareness of the advantages, disadvantages and meaning of relocation, and focused on staffing and nursing care; other services provided and the environment. The second theme - 'We can make it better', revealed suggestions for improving the relocation process, and included spending time with new residents and the importance of a person centred approach to care. CONCLUSION: Care staff have an important role in improving the relocation process of older people into a nursing home, as well as contributing to the discussion on this important clinical topic. RELEVANCE TO CLINICAL PRACTICE: Challenging care staff to acknowledge the importance of their role in helping older people settle into a nursing home is a key requirement of nursing practice in aged care. Nursing practice guidelines, with a focus on person-centred care, on how to manage the relocation process for an older person and their family are required for this aspect of nursing home care. Education of staff on relocation policies and procedures is essential to ensure that residents and their families are supported through this process. PMID- 25728165 TI - Register-based indicators for potentially inappropriate medication in high-cost patients with excessive polypharmacy. AB - BACKGROUND: Excessive polypharmacy is often associated with inappropriate drug use. Because drug expenditures are heavily skewed and a considerable share of patients in the top 5% of the cost distribution have excessive polypharmacy, the appropriateness of their drug use should be reviewed. OBJECTIVES: The aim of this study was to review the quality of drug use in patients with extremely high costs and excessive polypharmacy and to compare them with all drug users. RESEARCH DESIGN: This is a nationwide register study. SUBJECTS: The subjects of this study were all drug users in Finland over 15 years of age, n = 3,303,813. MEASURES: The measures used were annual total costs, average costs, and number of patients. The background characteristics used included gender, age, morbidity, number of prescribers, active substances, and indicators of potentially inappropriate drug use, for example, Beers criteria. RESULTS: The patients with high costs and excessive polypharmacy accounted for 22% of the total pharmaceutical expenditures but only 3% of drug users. One-third of them were elderly, compared with 11.3% of all drug users (p < 0.001). Almost all of them, 93.6%, had chronic disease compared with 34.0% of all the drug users (p < 0.001). The high-cost polypharmacy patients used more potentially inappropriate (28.0% vs 19.9%, p < 0.001) and anticholinergic drugs (26.7% vs. 9.6%, p < 0.001) and psychotropics more often simultaneously (20.4% vs. 3.8%, p < 0.001) than all drug users. CONCLUSIONS: Excessive polypharmacy with inappropriate medication use should be prevented using all the methods. The patients with excessive polypharmacy and high-drug costs provide a most interesting group for containing pharmaceutical costs via medication reviews. PMID- 25728164 TI - Modifications in stromal extracellular matrix of aged corneas can be induced by ultraviolet A irradiation. AB - With age, structural and functional changes can be observed in human cornea. Some studies have shown a loss of corneal transparency and an increase in turbidity associated with aging. These changes are caused by modifications in the composition and arrangement of extracellular matrix in the corneal stroma. In human skin, it is well documented that exposure to solar radiation, and mainly to the UVA wavelengths, leads to phenotypes of photoaging characterized by alteration in extracellular matrix of the dermis. Although the cornea is also exposed to solar radiation, the extracellular matrix modifications observed in aging corneas have been mainly attributed to chronological aging and not to solar exposure. To ascertain the real implication of UVA exposure in extracellular matrix changes observed with age in human cornea, we have developed a model of photoaging by chronically exposing corneal stroma keratocytes with a precise UVA irradiation protocol. Using this model, we have analyzed UVA-induced transcriptomic and proteomic changes in corneal stroma. Our results show that cumulative UVA exposure causes changes in extracellular matrix that are found in corneal stromas of aged individuals, suggesting that solar exposure catalyzes corneal aging. Indeed, we observe a downregulation of collagen and proteoglycan gene expression and a reduction in proteoglycan production and secretion in response to cumulative UVA exposure. This study provides the first evidence that chronic ocular exposure to sunlight affects extracellular matrix composition and thus plays a role in corneal changes observed with age. PMID- 25728166 TI - EMG spectral differences among the quadriceps femoris during the stretch reflex. AB - INTRODUCTION: The purpose of this study was to examine the electromyographic (EMG) spectral characteristics of the quadriceps femoris muscles during tendon tap stretch reflexes. METHODS: Sixteen healthy subjects (mean +/- SD age = 21.2 +/- 2.8 years) performed tendon tap reflexes of the leg extensors as surface EMG signals were detected from the vastus lateralis (VL), rectus femoris (RF), and vastus medialis (VM) muscles of the dominant thigh. All EMG signals were processed with a wavelet analysis, and the resulting spectra were decomposed with nonparametric spectral decomposition. RESULTS: The results showed that the spectra for the VL had significantly more high-frequency power than those for the RF and VM, with similar spectral shapes for the RF and VM. CONCLUSIONS: These findings could be due to differences in the width of the innervation zone, or the fiber type composition of the muscles, although the latter seems to be more likely. PMID- 25728167 TI - Connecting phenotype and chemotype: high-content discovery strategies for natural products research. AB - In recent years, the field of natural products has seen an explosion in the breadth, resolution, and accuracy of profiling platforms for compound discovery, including many new chemical and biological annotation methods. With these new tools come opportunities to examine extract libraries using systematized profiling approaches that were not previously available to the field and which offer new approaches for the detailed characterization of the chemical and biological attributes of complex natural products mixtures. This review will present a summary of some of these untargeted profiling methods and provide perspective on the future opportunities offered by integrating these tools for novel natural products discovery. PMID- 25728168 TI - A validated sensitive HPLC-MS/MS method for quantification of a potential hypnotic drug MT502 and its application to a pharmacokinetic study in rat. AB - A rapid, sensitive HPLC-MS/MS method was established and validated to assay the concentration and pharmacokinetic profile of MT502, a promising hypnotic drug. The plasma sample was treated by a liquid-liquid extraction and separated on a kromasil C18 column at an isocratic flow rate of 0.3 mL/min using methanol and 0.1% formic acid in water (75:25, v/v) as mobile phase. The mass spectrometric detection was carried out using a triple-quadrupole system via positive electrospray ionization. Multiple reaction monitoring was used for quantitation of m/z transitions from 261 to 188 for MT502 and from 247 to 188 for MT501 (internal standard). Good linearity was achieved over the concentration range of 1-1000 ng/mL and 10-5000 ng/mL with lower limit of quantification of 0.30 and 0.80 ng/mL. The intra- and inter-day precisions, accuracy, recovery and stability were satisfactory for the concentration test. The above method can be used for a pharmacokinetic study at doses of 1, 5 and 20 mg/kg. Results indicated that MT502 had rapid absorption, rapid elimination and linear pharmacokinetic properties within the range of the tested intragastric dose. This developed HPLC-MS/MS method was successfully applied to a pharmacokinetic study of MT502 for the first time and was demonstrated to be simple and sensitive. PMID- 25728169 TI - Omission bias and perceived intention in children and adults. AB - Omission bias refers to the tendency to judge acts of commission as morally worse than equivalent acts of omission. Children aged 7-8 and 11-12 years, as well as adults, made moral judgements about acts of commission and omission in two conditions in which the protagonist obtained a self-directed benefit. In the antisocial condition, the other person was harmed; in the selfish condition, the other person was not harmed. The results showed that adults and both age groups of children judged that the agent who did something (act of commission) was morally worse than the agent who did nothing (omission) for both antisocial and selfish conditions, although this judgement tendency was clearer in the selfish condition than in the antisocial condition. Agent intention was held constant across commission and omission, but most participants rated the intention of the agent who did something as stronger than that of the agent who did nothing. These results suggest that omission bias occurs regardless of differences in age and situation. In addition, perceived intention appears to change in conjunction with omission bias. PMID- 25728170 TI - Demographic differences in sport performers' experiences of organizational stressors. AB - Organizational stressors are particularly prevalent across sport performers' experiences and can influence their performance, health, and well-being. Research has been conducted to identify which organizational stressors are encountered by sport performers, but little is known about how these experiences vary from athlete to athlete. The purpose of this study was to examine if the frequency, intensity, and duration of the organizational stressors that sport performers encounter vary as a function of gender, sport type, and performance level. Participants (n = 1277) completed the Organizational Stressor Indicator for Sport Performers (OSI-SP; Arnold et al., 2013), and the resultant data were analyzed using multivariate analyses of covariance. The findings show that demographic differences are apparent in the dimensions of the goals and development, logistics and operations, team and culture, coaching, and selection organizational stressors that sport performers encounter. More specifically, significant differences were found between males and females, between team and individual-based performers, and between performers competing at national or international, regional or university, and county or club levels. These findings have important implications for theory and research on organizational stress, and for the development of stress management interventions with sport performers. PMID- 25728171 TI - Authors' response: Re: Rosier PFWM, Kirschner-Hermanns R, Svihra J, Homma Y, Wein AJ. ICS teaching module: Analysis of voiding, pressure flow analysis (basic module). Neurourol Urodyn. 2014 Sep 11. doi: 10.1002/nau.22660. PMID- 25728172 TI - Auditory cortex 2014 - towards a synthesis of human and animal research. PMID- 25728173 TI - Bat auditory cortex - model for general mammalian auditory computation or special design solution for active time perception? AB - Audition in bats serves passive orientation, alerting functions and communication as it does in other vertebrates. In addition, bats have evolved echolocation for orientation and prey detection and capture. This put a selective pressure on the auditory system in regard to echolocation-relevant temporal computation and frequency analysis. The present review attempts to evaluate in which respect the processing modules of bat auditory cortex (AC) are a model for typical mammalian AC function or are designed for echolocation-unique purposes. We conclude that, while cortical area arrangement and cortical frequency processing does not deviate greatly from that of other mammals, the echo delay time-sensitive dorsal cortex regions contain special designs for very powerful time perception. Different bat species have either a unique chronotopic cortex topography or a distributed salt-and-pepper representation of echo delay. The two designs seem to enable similar behavioural performance. PMID- 25728174 TI - Aural localization of silent objects by active human biosonar: neural representations of virtual echo-acoustic space. AB - Some blind humans have developed the remarkable ability to detect and localize objects through the auditory analysis of self-generated tongue clicks. These echolocation experts show a corresponding increase in 'visual' cortex activity when listening to echo-acoustic sounds. Echolocation in real-life settings involves multiple reflections as well as active sound production, neither of which has been systematically addressed. We developed a virtualization technique that allows participants to actively perform such biosonar tasks in virtual echo acoustic space during magnetic resonance imaging (MRI). Tongue clicks, emitted in the MRI scanner, are picked up by a microphone, convolved in real time with the binaural impulse responses of a virtual space, and presented via headphones as virtual echoes. In this manner, we investigated the brain activity during active echo-acoustic localization tasks. Our data show that, in blind echolocation experts, activations in the calcarine cortex are dramatically enhanced when a single reflector is introduced into otherwise anechoic virtual space. A pattern classification analysis revealed that, in the blind, calcarine cortex activation patterns could discriminate left-side from right-side reflectors. This was found in both blind experts, but the effect was significant for only one of them. In sighted controls, 'visual' cortex activations were insignificant, but activation patterns in the planum temporale were sufficient to discriminate left-side from right-side reflectors. Our data suggest that blind and echolocation-trained, sighted subjects may recruit different neural substrates for the same active echolocation task. PMID- 25728175 TI - Meaning in the avian auditory cortex: neural representation of communication calls. AB - Understanding how the brain extracts the behavioral meaning carried by specific vocalization types that can be emitted by various vocalizers and in different conditions is a central question in auditory research. This semantic categorization is a fundamental process required for acoustic communication, and presupposes discriminative and invariance properties of the auditory system for conspecific vocalizations. Songbirds have been used extensively to study vocal learning, but the communicative function of all their vocalizations and their neural representation has yet to be examined. In this study, we first generated a library containing almost the entire zebra finch vocal repertoire, and organised communication calls along nine different categories according to their behavioral meaning. We then investigated the neural representations of these semantic categories in the primary and secondary auditory areas of six anesthetised zebra finches. To analyse how single units encode these call categories, we described neural responses in terms of their discrimination, selectivity and invariance properties. Quantitative measures for these neural properties were obtained with an optimal decoder using both spike counts and spike patterns. Information theoretic metrics show that almost half of the single units encode semantic information. Neurons achieve higher discrimination of these semantic categories by being more selective and more invariant. These results demonstrate that computations necessary for semantic categorization of meaningful vocalizations are already present in the auditory cortex, and emphasise the value of a neuro ethological approach to understand vocal communication. PMID- 25728176 TI - Mixed-complexity artificial grammar learning in humans and macaque monkeys: evaluating learning strategies. AB - Artificial grammars (AG) can be used to generate rule-based sequences of stimuli. Some of these can be used to investigate sequence-processing computations in non human animals that might be related to, but not unique to, human language. Previous AG learning studies in non-human animals have used different AGs to separately test for specific sequence-processing abilities. However, given that natural language and certain animal communication systems (in particular, song) have multiple levels of complexity, mixed-complexity AGs are needed to simultaneously evaluate sensitivity to the different features of the AG. Here, we tested humans and Rhesus macaques using a mixed-complexity auditory AG, containing both adjacent (local) and non-adjacent (longer-distance) relationships. Following exposure to exemplary sequences generated by the AG, humans and macaques were individually tested with sequences that were either consistent with the AG or violated specific adjacent or non-adjacent relationships. We observed a considerable level of cross-species correspondence in the sensitivity of both humans and macaques to the adjacent AG relationships and to the statistical properties of the sequences. We found no significant sensitivity to the non-adjacent AG relationships in the macaques. A subset of humans was sensitive to this non-adjacent relationship, revealing interesting between- and within-species differences in AG learning strategies. The results suggest that humans and macaques are largely comparably sensitive to the adjacent AG relationships and their statistical properties. However, in the presence of multiple cues to grammaticality, the non-adjacent relationships are less salient to the macaques and many of the humans. PMID- 25728177 TI - Auditory and visual cortex of primates: a comparison of two sensory systems. AB - A comparative view of the brain, comparing related functions across species and sensory systems, offers a number of advantages. In particular, it allows separation of the formal purpose of a model structure from its implementation in specific brains. Models of auditory cortical processing can be conceived by analogy to the visual cortex, incorporating neural mechanisms that are found in both the visual and auditory systems. Examples of such canonical features at the columnar level are direction selectivity, size/bandwidth selectivity, and receptive fields with segregated vs. overlapping ON and OFF subregions. On a larger scale, parallel processing pathways have been envisioned that represent the two main facets of sensory perception: (i) identification of objects; and (ii) processing of space. Expanding this model in terms of sensorimotor integration and control offers an overarching view of cortical function independently of sensory modality. PMID- 25728178 TI - Sensorimotor neural dynamics during isochronous tapping in the medial premotor cortex of the macaque. AB - We determined the response properties of neurons in the primate medial premotor cortex that were classified as sensory or motor during isochronous tapping to a visual or auditory metronome, using different target intervals and three sequential elements in the task. The cell classification was based on a warping transformation, which determined whether the cell activity was statistically aligned to sensory or motor events, finding a large proportion of cells classified as sensory or motor. Two distinctive clusters of sensory cells were observed, i.e. one cell population with short response-onset latencies to the previous stimulus, and another that was probably predicting the occurrence of the next stimuli. These cells were called sensory-driven and stimulus-predicting neurons, respectively. Sensory-driven neurons showed a clear bias towards the visual modality and were more responsive to the first stimulus, with a decrease in activity for the following sequential elements of the metronome. In contrast, stimulus-predicting neurons were bimodal and showed similar response profiles across serial-order elements. Motor cells showed a consecutive activity onset across discrete neural ensembles, generating a rapid succession of activation patterns between the two taps defining a produced interval. The cyclical configuration in activation profiles engaged more motor cells as the serial-order elements progressed across the task, and the rate of cell recruitment over time decreased as a function of the target interval. Our findings support the idea that motor cells were responsible for the rhythmic progression of taps in the task, gaining more importance as the trial advanced, while, simultaneously, the sensory-driven cells lost their functional impact. PMID- 25728179 TI - Neuronal activity in primate auditory cortex during the performance of audiovisual tasks. AB - This study aimed at a deeper understanding of which cognitive and motivational aspects of tasks affect auditory cortical activity. To this end we trained two macaque monkeys to perform two different tasks on the same audiovisual stimulus and to do this with two different sizes of water rewards. The monkeys had to touch a bar after a tone had been turned on together with an LED, and to hold the bar until either the tone (auditory task) or the LED (visual task) was turned off. In 399 multiunits recorded from core fields of auditory cortex we confirmed that during task engagement neurons responded to auditory and non-auditory stimuli that were task-relevant, such as light and water. We also confirmed that firing rates slowly increased or decreased for several seconds during various phases of the tasks. Responses to non-auditory stimuli and slow firing changes were observed during both the auditory and the visual task, with some differences between them. There was also a weak task-dependent modulation of the responses to auditory stimuli. In contrast to these cognitive aspects, motivational aspects of the tasks were not reflected in the firing, except during delivery of the water reward. In conclusion, the present study supports our previous proposal that there are two response types in the auditory cortex that represent the timing and the type of auditory and non-auditory elements of a auditory tasks as well the association between elements. PMID- 25728180 TI - Computational modelling suggests that temporal integration results from synaptic adaptation in auditory cortex. AB - Incoming sounds are represented in the context of preceding events, and this requires a memory mechanism that integrates information over time. Here, it was demonstrated that response adaptation, the suppression of neural responses due to stimulus repetition, might reflect a computational solution that auditory cortex uses for temporal integration. Adaptation is observed in single-unit measurements as two-tone forward masking effects and as stimulus-specific adaptation (SSA). In non-invasive observations, the amplitude of the auditory N1m response adapts strongly with stimulus repetition, and it is followed by response recovery (the so-called mismatch response) to rare deviant events. The current computational simulations described the serial core-belt-parabelt structure of auditory cortex, and included synaptic adaptation, the short-term, activity-dependent depression of excitatory corticocortical connections. It was found that synaptic adaptation is sufficient for columns to respond selectively to tone pairs and complex tone sequences. These responses were defined as combination sensitive, thus reflecting temporal integration, when a strong response to a stimulus sequence was coupled with weaker responses both to the time-reversed sequence and to the isolated sequence elements. The temporal complexity of the stimulus seemed to be reflected in the proportion of combination-sensitive columns across the different regions of the model. Our results suggest that while synaptic adaptation produces facilitation and suppression effects, including SSA and the modulation of the N1m response, its functional significance may actually be in its contribution to temporal integration. This integration seems to benefit from the serial structure of auditory cortex. PMID- 25728181 TI - Averaging auditory evoked magnetoencephalographic and electroencephalographic responses: a critical discussion. AB - In the analysis of data from magnetoencephalography (MEG) and electroencephalography (EEG), it is common practice to arithmetically average event-related magnetic fields (ERFs) or event-related electric potentials (ERPs) across single trials and subsequently across subjects to obtain the so-called grand mean. Comparisons of grand means, e.g. between conditions, are then often performed by subtraction. These operations, and their statistical evaluation with parametric tests such as ANOVA, tacitly rely on the assumption that the data follow the additive model, have a normal distribution, and have a homogeneous variance. This may be true for single trials, but these conditions are rarely met when ERFs/ERPs are compared between subjects, meaning that the additive model is seldom the correct model for computing grand mean waveforms. Here, we summarize some of our recent work and present new evidence, from auditory-evoked MEG and EEG results, that the non-normal distributions and the heteroscedasticity observed instead result because ERFs/ERPs follow a mixed model with additive and multiplicative components. For peak amplitudes, such as the auditory M100 and N100, the multiplicative component dominates. These findings emphasize that the common practice of simply subtracting arithmetic means of auditory-evoked ERFs or ERPs is problematic without prior adequate transformation of the data. Application of the area sinus hyperbolicus (asinh) transform to data following the mixed model transforms them into the requested additive model with its normal distribution and homogeneous variance. We therefore advise checking the data for compliance with the additive model and using the asinh transform if required. PMID- 25728183 TI - The auditory cortex and tinnitus - a review of animal and human studies. AB - Tinnitus is the sound heard in the absence of physical sound sources external or internal to the body. Tinnitus never occurs in isolation; it typically develops after hearing loss, and not infrequently for losses at the higher frequencies not tested in clinical audiology. Furthermore, tinnitus is often accompanied by hyperacusis, i.e. increased loudness sensitivity, which may reflect the central gain change in the auditory system that occurs after hearing loss. I will first review the electrophysiological findings in the thalamus and cortex pertaining to animal research into tinnitus. This will comprise the changes in tonotopic maps, spontaneous firing rates and changes in pairwise neural cross-correlation induced by tinnitus-inducing agents that are commonly used in animal experiments. These are systemic application of sodium salicylate, and noise exposure at levels ranging from those that do not cause a hearing loss, to those that only cause a temporary threshold shift, to those that cause a permanent hearing loss. Following this, I will review neuroimaging and electrophysiological findings in the auditory cortex in humans with tinnitus. The neural substrates of tinnitus derived from animal data do not apply universally, as neither hearing loss nor hyperacusis appear to be necessary conditions for tinnitus to occur in humans. Finally, I will relate the findings in humans to the predictions from animal models of tinnitus. These comparisons indicate that neural correlates of tinnitus can be studied successfully both at the level of animal models and in humans. PMID- 25728184 TI - Increased audiovisual integration in cochlear-implanted deaf patients: independent components analysis of longitudinal positron emission tomography data. AB - It has been demonstrated in earlier studies that patients with a cochlear implant have increased abilities for audio-visual integration because the crude information transmitted by the cochlear implant requires the persistent use of the complementary speech information from the visual channel. The brain network for these abilities needs to be clarified. We used an independent components analysis (ICA) of the activation (H2(15)O) positron emission tomography data to explore occipito-temporal brain activity in post-lingually deaf patients with unilaterally implanted cochlear implants at several months post-implantation (T1), shortly after implantation (T0) and in normal hearing controls. In between group analysis, patients at T1 had greater blood flow in the left middle temporal cortex as compared with T0 and normal hearing controls. In within-group analysis, patients at T0 had a task-related ICA component in the visual cortex, and patients at T1 had one task-related ICA component in the left middle temporal cortex and the other in the visual cortex. The time courses of temporal and visual activities during the positron emission tomography examination at T1 were highly correlated, meaning that synchronized integrative activity occurred. The greater involvement of the visual cortex and its close coupling with the temporal cortex at T1 confirm the importance of audio-visual integration in more experienced cochlear implant subjects at the cortical level. PMID- 25728182 TI - Attention and prediction in human audition: a lesson from cognitive psychophysiology. AB - Attention is a hypothetical mechanism in the service of perception that facilitates the processing of relevant information and inhibits the processing of irrelevant information. Prediction is a hypothetical mechanism in the service of perception that considers prior information when interpreting the sensorial input. Although both (attention and prediction) aid perception, they are rarely considered together. Auditory attention typically yields enhanced brain activity, whereas auditory prediction often results in attenuated brain responses. However, when strongly predicted sounds are omitted, brain responses to silence resemble those elicited by sounds. Studies jointly investigating attention and prediction revealed that these different mechanisms may interact, e.g. attention may magnify the processing differences between predicted and unpredicted sounds. Following the predictive coding theory, we suggest that prediction relates to predictions sent down from predictive models housed in higher levels of the processing hierarchy to lower levels and attention refers to gain modulation of the prediction error signal sent up to the higher level. As predictions encode contents and confidence in the sensory data, and as gain can be modulated by the intention of the listener and by the predictability of the input, various possibilities for interactions between attention and prediction can be unfolded. From this perspective, the traditional distinction between bottom-up/exogenous and top-down/endogenous driven attention can be revisited and the classic concepts of attentional gain and attentional trace can be integrated. PMID- 25728186 TI - The role of auditory cortices in the retrieval of single-trial auditory-visual object memories. AB - Single-trial encounters with multisensory stimuli affect both memory performance and early-latency brain responses to visual stimuli. Whether and how auditory cortices support memory processes based on single-trial multisensory learning is unknown and may differ qualitatively and quantitatively from comparable processes within visual cortices due to purported differences in memory capacities across the senses. We recorded event-related potentials (ERPs) as healthy adults (n = 18) performed a continuous recognition task in the auditory modality, discriminating initial (new) from repeated (old) sounds of environmental objects. Initial presentations were either unisensory or multisensory; the latter entailed synchronous presentation of a semantically congruent or a meaningless image. Repeated presentations were exclusively auditory, thus differing only according to the context in which the sound was initially encountered. Discrimination abilities (indexed by d') were increased for repeated sounds that were initially encountered with a semantically congruent image versus sounds initially encountered with either a meaningless or no image. Analyses of ERPs within an electrical neuroimaging framework revealed that early stages of auditory processing of repeated sounds were affected by prior single-trial multisensory contexts. These effects followed from significantly reduced activity within a distributed network, including the right superior temporal cortex, suggesting an inverse relationship between brain activity and behavioural outcome on this task. The present findings demonstrate how auditory cortices contribute to long-term effects of multisensory experiences on auditory object discrimination. We propose a new framework for the efficacy of multisensory processes to impact both current multisensory stimulus processing and unisensory discrimination abilities later in time. PMID- 25728185 TI - Single-unit analysis of somatosensory processing in the core auditory cortex of hearing ferrets. AB - The recent findings in several species that the primary auditory cortex processes non-auditory information have largely overlooked the possibility of somatosensory effects. Therefore, the present investigation examined the core auditory cortices (anterior auditory field and primary auditory cortex) for tactile responsivity. Multiple single-unit recordings from anesthetised ferret cortex yielded histologically verified neurons (n = 311) tested with electronically controlled auditory, visual and tactile stimuli, and their combinations. Of the auditory neurons tested, a small proportion (17%) was influenced by visual cues, but a somewhat larger number (23%) was affected by tactile stimulation. Tactile effects rarely occurred alone and spiking responses were observed in bimodal auditory tactile neurons. However, the broadest tactile effect that was observed, which occurred in all neuron types, was that of suppression of the response to a concurrent auditory cue. The presence of tactile effects in the core auditory cortices was supported by a substantial anatomical projection from the rostral suprasylvian sulcal somatosensory area. Collectively, these results demonstrate that crossmodal effects in the auditory cortex are not exclusively visual and that somatosensation plays a significant role in modulation of acoustic processing, and indicate that crossmodal plasticity following deafness may unmask these existing non-auditory functions. PMID- 25728187 TI - Musical expertise is related to neuroplastic changes of multisensory nature within the auditory cortex. AB - Recent neuroscientific evidence indicates that multisensory integration does not only occur in higher level association areas of the cortex as the hierarchical models of sensory perception assumed, but also in regions traditionally thought of as unisensory, such as the auditory cortex. Nevertheless, it is not known whether expertise-induced neuroplasticity can alter the multisensory processing that occurs in these low-level regions. The present study used magnetoencephalography to investigate whether musical training may induce neuroplastic changes of multisensory processing within the human auditory cortex. Magnetoencephalography data of four different experiments were used to demonstrate the effect of long-term and short-term musical training on the integration of auditory, somatosensory and visual stimuli in the auditory cortex. The cross-sectional design of three of the experiments allowed us to infer that long-term musical training is related to a significantly different way of processing multisensory information within the auditory cortex, whereas the short term training design of the fourth experiment allowed us to causally infer that multisensory music reading training affects the multimodal processing within the auditory cortex. PMID- 25728188 TI - Perceptual learning in the developing auditory cortex. AB - A hallmark of the developing auditory cortex is the heightened plasticity in the critical period, during which acoustic inputs can indelibly alter cortical function. However, not all sounds in the natural acoustic environment are ethologically relevant. How does the auditory system resolve relevant sounds from the acoustic environment in such an early developmental stage when most associative learning mechanisms are not yet fully functional? What can the auditory system learn from one of the most important classes of sounds, animal vocalizations? How does naturalistic acoustic experience shape cortical sound representation and perception? To answer these questions, we need to consider an unusual strategy, statistical learning, where what the system needs to learn is embedded in the sensory input. Here, I will review recent findings on how certain statistical structures of natural animal vocalizations shape auditory cortical acoustic representations, and how cortical plasticity may underlie learned categorical sound perception. These results will be discussed in the context of human speech perception. PMID- 25728189 TI - Subthreshold membrane responses underlying sparse spiking to natural vocal signals in auditory cortex. AB - Natural acoustic communication signals, such as speech, are typically high dimensional with a wide range of co-varying spectro-temporal features at multiple timescales. The synaptic and network mechanisms for encoding these complex signals are largely unknown. We are investigating these mechanisms in high-level sensory regions of the songbird auditory forebrain, where single neurons show sparse, object-selective spiking responses to conspecific songs. Using whole-cell in vivo patch clamp techniques in the caudal mesopallium and the caudal nidopallium of starlings, we examine song-driven subthreshold and spiking activity. We find that both the subthreshold and the spiking activity are reliable (i.e. the same song drives a similar response each time it is presented) and specific (i.e. responses to different songs are distinct). Surprisingly, however, the reliability and specificity of the subthreshold response was uniformly high regardless of when the cell spiked, even for song stimuli that drove no spikes. We conclude that despite a selective and sparse spiking response, high-level auditory cortical neurons are under continuous, non selective, stimulus-specific synaptic control. To investigate the role of local network inhibition in this synaptic control, we then recorded extracellularly while pharmacologically blocking local GABAergic transmission. This manipulation modulated the strength and the reliability of stimulus-driven spiking, consistent with a role for local inhibition in regulating the reliability of network activity and the stimulus specificity of the subthreshold response in single cells. We discuss these results in the context of underlying computations that could generate sparse, stimulus-selective spiking responses, and models for hierarchical pooling. PMID- 25728190 TI - The associations between maternal factors during pregnancy and the risk of childhood acute lymphoblastic leukemia: A meta-analysis. AB - BACKGROUND: Although genetic and environmental factors are considered to be the main causes of acute lymphoblastic leukemia, the associations between maternal factors during pregnancy and the childhood ALL is still unclear. PROCEDURE: In this study, meta-analysis was used. Medline, PubMed, and Web of Science were searched. The result was assessed based on pooled odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The pooled ORs showed that there were associations between childhood ALL and the birth order (The first vs others, OR = 1.08, 95%CI = 1.00-1.16), the education of pregnant woman (>high school vs <= high school, OR = 0.82, 95%CI = 0.77-0.86), smoking (Ever vs never, OR = 1.10, 95%CI = 1.02-1.19). CONCLUSIONS: Our meta-analysis showed that there were important associations between childhood ALL and the birth order, the education of pregnant woman, smoking. PMID- 25728191 TI - Appendiceal tuberculosis. PMID- 25728192 TI - Sex Differences in Judgments of Social Desirability. AB - This study evaluates sex differences in the perceived desirability of personality behaviors and beliefs. Men and women (N = 149, Mage = 18.7) judged the social desirability scale values (SDSVs) of 150 personality statements as applied either to a male target or a female target. For comparison, some estimated SDSVs with no target sex specified. A separate sample of 537 respondents endorsed the 150 items via self-report. Raters showed a high consensus in their SDSV judgments within conditions (alpha = .86 to .90) and no sex-of-rater effects across conditions. Substantial sex-of-target effects (p < .001), however, revealed many behaviors that were viewed as desirable for one sex but not for the other. The behaviors seen as more (less) desirable when applied to men rather than to women were endorsed more (less) by men than by women in the respondent sample. Similar results were found when no target sex was specified for the SDSV ratings, presumably because judges evaluated the behaviors as applied to a target of their own sex. The present results have important implications for the measurement and reporting of SDSVs, the evaluation of substance versus style in self-reports, and the construction of desirability-reduced personality inventories. PMID- 25728193 TI - Ultrastructural immunolocalization of nestin in the regenerating tail of lizards shows its presence during cytoskeletal modifications in the epidermis, muscles and nerves. AB - Nestin has been considered a neural stem cell marker, and represents an intermediate filament protein likely involved in restructuring the cytoskeleton in different cell types. The present ultrastructural study has immunodetected nestin especially in the wound epidermis, regenerating myotubes and in the growing nerves of the regenerating tail of lizards. In keratinocytes of the stratified wound epidermis nestin is present in the irregular electron-paler meshwork located along the cell perimeter and among keratin bundles converging into desmosomes. In the regenerating muscles nestin-immunoreactivity remains confined to some external regions along the myotubes and in the cytoplasmic ends of the myotubes not occupied by myofibrils. A diffuse nestin immunolabeling is also present among the neurofilaments of growing axons, in Schwann cells and in ependymal cells of the regenerating spinal cord of the tail. The localization of nestin in sites of cytoskeletal remodeling in keratinocytes, myotubes, ependymal cells and axons, suggests that this protein is associated to the reassembling of keratin tonofilaments in moving keratinocytes, assembling of contractile proteins in myotubes, and in the organization of neurofilaments during the growth and myelination of axons within the regenerating lizard tail. PMID- 25728194 TI - Development of criteria used to establish a background environmental monitoring station. AB - It is generally considered necessary to measure concentrations of contaminants-of concern at a background location when conducting atmospheric environmental surveillance. This is because it is recognized that measurements of background concentrations can enhance interpretation of environmental monitoring data. Despite the recognized need for background measurements, there is little published guidance available that describes how to identify an appropriate atmospheric background monitoring location. This paper develops generic criteria that can guide the decision making process for identifying suitable locations for background atmospheric monitoring station. Detailed methods for evaluating some of these criteria are also provided and a case study for establishment of an atmospheric background surveillance station as part of an environmental surveillance program is described. While the case study focuses on monitoring for radionuclides, the approach is equally valid for any airborne constituent being monitored. The case study shows that implementation of the developed criteria can result in a good, defensible choice for a background atmospheric monitoring location. PMID- 25728195 TI - HR007: a family of biomaterials based on glycosaminoglycans for tissue repair. AB - Most new advances in tissue engineering (TE) focus on the creation of adequate microenvironments that may accelerate the repair processes of damaged tissues. Extracellular matrix (ECM) of Wharton's jelly (WJ) from umbilical cords is very rich in sulphated GAGs (sGAGs) and hyaluronic acid (HA), components which have special properties that could positively influence the regeneration of several types of tissue. Previously, we described the methodology for the extraction and purification of GAGs from WJ and, importantly, the separation of sGAGs and HA to develop various scaffolds for regenerative medicine. In this new study we hypothesized that the biomaterials obtained, called HR007s, would be excellent candidates for two different applications, chondral and dermal repair. First, we have confirmed that the GAGs obtained are biocompatible, as they do not cause cytotoxicity, haemolysis or an inflammatory response. Second, we have developed three-dimensional (3D) structures through the combination of different ratios of GAGs and their subsequent stabilization, which can be properly adapted to target tissues, cartilage or skin. Finally, we have combined these scaffolds with adipose mesenchymal stem cells (ASCs) or fibroblasts for application to chondral or dermal defects, respectively, with the goal of promoting fast reparative processes. The results show that HR007 scaffolds induce cell proliferation, enhance the expression of specific gene markers, increase the production of tissue ECM proteins and have chemotactic effects over the studied cells. In summary, the bioactive properties of HR007 scaffolds make them promising candidates for use in regenerative medicine, at least for chondral and dermal repair. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25728196 TI - Identification and characterization of novel Staphylococcus aureus pathogenicity islands encoding staphylococcal enterotoxins originating from staphylococcal food poisoning isolates. AB - AIMS: Horizontal transfer of Staphylococcus aureus pathogenicity islands (SaPIs) plays an important role in acquiring pathogenicity. This study aimed to identify novel SaPIs encoding staphylococcal enterotoxins (SEs) and to characterize their SE productivity and replication process. METHODS AND RESULTS: Four novel SaPIs (SaPITokyo12413, SaPITokyo11212, SaPITokyo12571 and SaPITokyo12381) were determined using the SaPI scanning method. These SaPIs were composed of mosaic structures containing reported sequences. Four strains harbouring novel SaPIs produced significant amounts of SEs to cause staphylococcal food poisoning (SFP). With focus on the interaction between the replication initiator protein (Rep) and the replication origin (ori sites) that are proposed to be important for the replication of SaPIs, each Rep was prepared and their two functions were confirmed: binding activity to ori sites and helicase activity. These activities were present in the Reps of SaPITokyo11212, SaPITokyo12571 and SaPITokyo12381, but were both absent in the Rep of SaPITokyo12413. CONCLUSIONS: All four novel SaPIs could give sufficient toxicity to Staph. aureus to cause SFP. However, SaPITokyo12413 may be restricted in its replication capacity, suggesting that it lacks transfer ability unlike the other SaPIs. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report to identify four novel SE-encoding SaPIs and to examine their toxicity and replication capacity. Because SaPIs deeply participate in SE acquisition, it is important to elucidate their characteristics for understanding Staph. aureus virulence and speculating regarding its evolution as a pathogen. PMID- 25728197 TI - Simultaneous observation of the quantization and the interference pattern of a plasmonic near-field. AB - Surface plasmon polaritons can confine electromagnetic fields in subwavelength spaces and are of interest for photonics, optical data storage devices and biosensing applications. In analogy to photons, they exhibit wave-particle duality, whose different aspects have recently been observed in separate tailored experiments. Here we demonstrate the ability of ultrafast transmission electron microscopy to simultaneously image both the spatial interference and the quantization of such confined plasmonic fields. Our experiments are accomplished by spatiotemporally overlapping electron and light pulses on a single nanowire suspended on a graphene film. The resulting energy exchange between single electrons and the quanta of the photoinduced near-field is imaged synchronously with its spatial interference pattern. This methodology enables the control and visualization of plasmonic fields at the nanoscale, providing a promising tool for understanding the fundamental properties of confined electromagnetic fields and the development of advanced photonic circuits. PMID- 25728199 TI - Phytoextraction of metals by Erigeron canadensis L. from fly ash landfill of power plant "Kolubara". AB - The objectives of this study were to determine the concentrations of Pb, Cd, As, Cr, Cu, Co, Ni, Zn, Ba, Fe, Al and Ag in Erigeron canadensis L. growing on fly ash landfill of power plant "Kolubara", Serbia. The content of each element was determined in every part of plant separately (root, stalk and inflorescence) and correlated with the content of elements in each phase of sequential extraction of fly ash. In order to ambiguously select the factors that are able to decidedly characterize the particular part of plant, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were performed. The bioconcentration factors and translocation factors for each metal were calculated in order to determine the feasibility of the use of plant E. canadensis L. for phytoremediation purpose. There were strong positive correlations between metals in every part of plant samples, and metals from pseudo total form of sequential extraction indicate that the bioavailability of elements in fly ash is similarly correlated with total form. Retained Al, Fe, Cr and Co in the root indicate its suitability for phytostabilization. This plant takes up Cd and Zn from the soil (bioconcentration factors (BCFs) greater than 1), transporting them through the stalk into the inflorescence (translocation factors (TFs) higher than 1). Regarding its dominance in vegetation cover and abundance, E. canadensis L. can be considered adequate for phytoextraction of Cd and Zn from coal ash landfills at Kolubara. PMID- 25728198 TI - Comparison of adsorption behavior of PCDD/Fs on carbon nanotubes and activated carbons in a bench-scale dioxin generating system. AB - Porous carbon-based materials are commonly used to remove various organic and inorganic pollutants from gaseous and liquid effluents and products. In this study, the adsorption of dioxins on both activated carbons and multi-walled carbon nanotube was internally compared, via series of bench scale experiments. A laboratory-scale dioxin generator was applied to generate PCDD/Fs with constant concentration (8.3 ng I-TEQ/Nm(3)). The results confirm that high-chlorinated congeners are more easily adsorbed on both activated carbons and carbon nanotubes than low-chlorinated congeners. Carbon nanotubes also achieved higher adsorption efficiency than activated carbons even though they have smaller BET-surface. Carbon nanotubes reached the total removal efficiency over 86.8 % to be compared with removal efficiencies of only 70.0 and 54.2 % for the two other activated carbons tested. In addition, because of different adsorption mechanisms, the removal efficiencies of carbon nanotubes dropped more slowly with time than was the case for activated carbons. It could be attributed to the abundant mesopores distributed in the surface of carbon nanotubes. They enhanced the pore filled process of dioxin molecules during adsorption. In addition, strong interactions between the two benzene rings of dioxin molecules and the hexagonal arrays of carbon atoms in the surface make carbon nanotubes have bigger adsorption capacity. PMID- 25728200 TI - Immobilization of high concentrations of soluble Mn(II) from electrolytic manganese solid waste using inorganic chemicals. AB - Electrolytic manganese solid waste (EMSW) is a by-product of electrolytic manganese production and generally contains a high concentration of soluble Mn(II) (2000-3000 mg/L). Millions of tons of EMSW are stored in China, and the environmental pollution caused by manganese in this waste product is concerning. Unfortunately, little attention has been paid to the immobilization of manganese from industrial solid waste because manganese is absent from toxicological identification standards, and there is a lack of relevant quality standards in China. The objectives of this study were to immobilize soluble Mn(II) using chemical reagents, to analyze the immobilization mechanism, and to identify the most economical reagents. We investigated the immobilization degrees of soluble Mn(II) achieved by the reagents quicklime (CaO), carbonates (NaHCO3 and Na2CO3), phosphates (Na3PO4, Na2HPO4, NH4H2PO4, and Ca10(PO4)6(OH)2), and caustic magnesia (MgO) both individually and in combination. Our results showed that the use of 9% CaO+ 5% NaHCO3, 9% CaO+ 5% Na3PO4, 10% MgO alone, or with 1-5% NaHCO3 or 1-5% Na2CO3 can reduce the amount of Mn(II) leached to 100 mg/kg when the eluate pH was in the range of 6-9. The most economical reagent treatments were determined using K-means cluster analysis. Analysis of the immobilization mechanism showed that CaO + NaHCO3 may be favorable for immobilizing soluble Mn(II) as precipitation and oxidation products because the addition of NaHCO3 releases OH( ) and buffers the system. PMID- 25728201 TI - RM-DEMATEL: a new methodology to identify the key factors in PM2.5. AB - Weather system is a relative complex dynamic system, the factors of the system are mutually influenced PM2.5 concentration. In this paper, a new method is proposed to quantify the influence on PM2.5 by other factors in the weather system and identify the most important factors for PM2.5 with limited resources. The relation map (RM) is used to figure out the direct relation matrix of 14 factors in PM2.5. The decision making trial and evaluation laboratory(DEMATEL) is applied to calculate the causal relationship and extent to a mutual influence of 14 factors in PM2.5. According to the ranking results of our proposed method, the most important key factors is sulfur dioxide (SO2) and nitrogen oxides (NO(X)). In addition, the other factors, the ambient maximum temperature (T(max)), concentration of PM10, and wind direction (W(dir)), are important factors for PM2.5. The proposed method can also be applied to other environment management systems to identify key factors. PMID- 25728202 TI - Long-term nickel exposure altered the bacterial community composition but not diversity in two contrasting agricultural soils. AB - Nickel pollution imposes deleterious effects on soil ecosystem. The responses of soil microorganisms to long-term nickel pollution under field conditions remain largely unknown. Here, we used high-throughput sequencing to elucidate the impacts of long-term nickel pollution on soil bacterial communities in two contrasting agricultural soils. Our results found that the soil microbial biomass carbon consistently decreased along the nickel gradients in both soils. Nickel pollution selectively favored or impeded the prevalence of several dominant bacterial guilds, in particular, Actinobacteria showed tolerance, while Acidobacteria and Planctomycetes displayed sensitivity. Despite the apparent shifts in the bacterial community composition, no clear tendency in the bacterial diversity and abundance was identified along the nickel gradients in either soil. Collectively, we provide evidence that long-term nickel pollution shifted the soil bacterial communities, resulting in the decrease of microbial biomass although the bacterial diversity was not significantly changed. PMID- 25728203 TI - Experimental study of wind-induced sediment suspension and nutrient release in Meiliang Bay of Lake Taihu, China. AB - Wind-induced sediment suspension and nutrient release is an important source for shallow eutrophic lakes. This work studies the quantitative relationship between wind speed and sediment release rate in Meiliang Bay of Lake Taihu, China, using field observations and indoor simulations. Natural wind, water flow, and water quality conditions were synchronously monitored to establish the relationship between wind speed and sediment release rate. Sediment suspension processes under different wind speeds were also simulated in a specially designed reactor. We then established the relationship between natural wind speed and indoor-simulated sediment release rate through hydrodynamic conditions (expressed using water shear stress). The indoor experiment was a supplement to the field observations. The results showed that (1) the critical wind speeds at which sediment became suspended and demonstrated maximum suspension were approximately 3-4 and 8 m s( 1), respectively; (2) the relationship between wind speed and suspended sediment (SS), total nitrogen (TN), and total phosphorous (TP) release rate could be expressed by exponential functions (SS release rate: y = 1.287e(0.177x) , R (2) = 0.981; TN release rate: y = 7.55e(0.363x), R (2) = 0.981; TP release rate: y = 0.381e(0.186x), R (2) = 0.945); and (3) the critical (wind speed, 8 m s(-1)) release rates of SS, TN, and TP were 1000, 5.8, and 2.2 g m(-2) day(-1), while the maximum (wind speed, 16 m s(-1)) rates were 5000, 24.7, and 5.4 g m(-2) day( 1), respectively. PMID- 25728204 TI - The spatial distribution of dissolved and particulate heavy metals and their response to land-based inputs and tides in a semi-enclosed industrial embayment: Jiaozhou Bay, China. AB - In order to evaluate heavy metal contamination in surface waters in the Jiaozhou Bay (JZB), a typical semi-enclosed bay in the north of China, and to identify the response of heavy metal distribution to terrigenous sources and tides, the land based discharge flux of dissolved Cu, Pb, Zn and Cd and their particulates, as well as their concentrations, were synchronously surveyed in JZB in flood season and normal season respectively. The survey results showed that the amount of dissolved Cu clearly increased from the estuaries to the offshore waters during the flood season, especially from the Dagu estuary to the mouth of JZB. The same trend was observed for Pb. The isopleths of dissolved Zn during the flood season presented a different pattern in which a clear decrease was observed from the Lianwan, Moshui and Dagu estuaries to the offshore waters. However, the particulate Cu isopleths during the flood season, which had the same pattern as those of particulate Pb, Zn and Cd, showed a clear decrease from the Dagu estuary to the mouth of JZB. The isopleths for dissolved and particulate Cu during the normal season showed a clear decrease from the northeast to the entrance of JZB, and the same trend was observed for Pb, Zn and Cd. Observations based on synchronous investigations of the fluvial fluxes of the selected metals and their average concentrations in JZB showed that these patterns were controlled by the strong external fluvial inputs, especially from the Dagu River. The diurnal change in the Cu, Pb, Zn and Cd concentrations showed a periodicity with a cycle length of approximately 12 h in JZB, which indicates the noticeable impact of the semi-diurnal tide. The weighed average concentration from freshwater inputs calculated for dissolved Cu, Pb, Zn and Cd were higher than their average concentrations in JZB. This indicated that JZB had been contaminated with these metals, whose concentrations were also higher than those found in uncontaminated waters. PMID- 25728205 TI - Asymmetric Suzuki-Miyaura cross-coupling for the synthesis of chiral biaryl compounds as potential monophosphine ligands. AB - Efficient asymmetric Suzuki-Miyaura coupling reactions have been employed for the first time to synthesize chiral biaryl compounds with phosphinate groups as chiral auxiliaries. A series of functionalized chiral biaryls are thereby synthesized in excellent yields and good diastereoselectivities (up to >95:5 d.r.) and axially chiral monophosphorus ligands are obtained through further functionalizations. PMID- 25728206 TI - Postexposure management of healthcare personnel to infectious diseases. AB - Healthcare personnel (HCP) are at risk of exposure to various pathogens through their daily tasks and may serve as a reservoir for ongoing disease transmission in the healthcare setting. Management of HCP exposed to infectious agents can be disruptive to patient care, time-consuming, and costly. Exposure of HCP to an infectious source should be considered an urgent medical concern to ensure timely management and administration of postexposure prophylaxis, if available and indicated. Infection control and occupational health departments should be notified for management of exposed HCP, identification of all contacts of the index case, and application of immediate infection control measures for the index case and exposed HCP, if indicated. This article reviews the main principles of postexposure management of HCP to infectious diseases, in general, and to certain common infections, in particular, categorized by their route of transmission, in addition to primary prevention of these infections. PMID- 25728207 TI - Photocarrier recombination dynamics in ternary chalcogenide CuInS2 quantum dots. AB - Photocarrier recombination dynamics in ternary chalcogenide CuInS2 quantum dots (CIS QDs) was studied by means of femtosecond transient-absorption (TA) and nanosecond time-resolved photoluminescence (PL) spectroscopy. Under strong excitation, the TA dynamics in CIS QDs is well described by a simple rate equation including single-carrier trapping, free-to-bound recombination, and trap assisted Auger recombination. Under weak excitation, on the other hand, the PL decays of the QDs are composed of a short-lived component caused by surface trapping and a long-lived one caused by free-to-bound recombination. It is found that the surface trapping accelerates markedly with decreasing QD size while the free-to-bound radiative recombination hardly depends on the QD size. Besides this, we observed both a decrease in the PL lifetimes and a dynamic spectral redshift, which are attributed to the surface trapping and the coexistent inhomogeneous broadening in CIS QDs. The spectral redshift becomes less pronounced in CIS/ZnS core/shell QDs because of the suppression of the fast nonradiative recombination caused by the passivation of the surface traps. These results give clear evidence that the free-to-bound model is appropriate for interpreting the optical properties of CIS QDs. PMID- 25728209 TI - Recognition of resting heart calcification as a means to an end: an eye-opener in the application of dobutamine stress echocardiography in subjects with chest pain. PMID- 25728208 TI - Reduction in Clostridium difficile environmental contamination by hospitalized patients treated with fidaxomicin. AB - Fidaxomicin is sporicidal and may be associated with a reduced time to resolution of diarrhoea when used to treat patients with Clostridium difficile infection (CDI). This study investigated whether fidaxomicin for treatment of all patients with CDI reduced C. difficile environmental contamination. Surfaces in the rooms of 66 hospitalized patients treated with metronidazole and/or vancomycin and 68 hospitalized patients treated with fidaxomicin were sampled. Patients treated with fidaxomicin were less likely to contaminate their environment (25/68, 36.8%) than patients treated with metronidazole and/or vancomycin (38/66 57.6%) (P = 0.02). Treatment with fidaxomicin was associated with reduced environmental contamination with C. difficile. PMID- 25728210 TI - Genetic analysis of the human Insulin-like 3 gene: absence of mutations in a Greek paediatric cohort with testicular maldescent. AB - This study investigated the hypothesis that genetic alterations of the human insulin-like 3 (INSL3) gene are associated with testicular maldescent (TMD). Genomic DNA was extracted and amplified from peripheral blood samples of 170 unrelated children with all possible phenotypical expressions of TMD and 50 volunteers with normal external genitalia from the general paediatric population (controls). PCR-single strand conformation polymorphism analysis was used to screen INSL3 gene for genetic variants. For rapid screening of a detected nonsilent genetic alteration, restriction assay using endonuclease Eag I was further employed. Products were analysed on 2% agarose gel and restriction patterns were visualised by ethidium bromide. Differences in genotype and allelic distributions of nonsilent genetic alterations were evaluated between (i) patients-controls, (ii) familial-sporadic, (iii) bilateral-unilateral and (iv) intra-abdominal-inguinal cases of TMD. No mutations were detected. Three common INSL3 gene polymorphisms (27G>A, 126G>A, 178G>A) unrelated to any particular phenotype of TMD were detected both in patients and controls. These results indicate that INSL3 gene mutations are not a common cause of TMD in the human. PMID- 25728211 TI - Audit of radiation dose delivered in time-resolved four-dimensional computed tomography in a radiotherapy department. AB - INTRODUCTION: To review the dose delivered to patients in time-resolved computed tomography (4D CT) used for radiotherapy treatment planning. METHODS: 4D CT is used at Peter MacCallum Cancer Centre since July 2007 for radiotherapy treatment planning using a Philips Brilliance Wide Bore CT scanner (16 slice, helical 4D CT acquisition). All scans are performed at 140 kVp and reconstructed in 10 datasets for different phases of the breathing cycle. Dose records were analysed retrospectively for 387 patients who underwent 4D CT procedures between 2007 and 2013. RESULTS: A total of 444 4D CT scans were acquired with the majority of them (342) being for lung cancer radiotherapy. Volume CT dose index (CTDIvol) as recorded over this period was fairly constant at approximately 20 mGy for adults. The CTDI for 4D CT for lung cancers of 19.6 +/- 9.3 mGy (n = 168, mean +/- 1SD) was found to be 63% higher than CTDIs for conventional CT scans for lung patients that were acquired in the same period (CTDIvol 12 +/- 4 mGy, sample of n = 25). CTDI and dose length product (DLP) increased with increasing field of view; however, no significant difference between DLPs for different indications (breast, kidney, liver and lung) could be found. Breathing parameters such as breathing rate or pattern did not affect dose. CONCLUSION: 4D CT scans can be acquired for radiotherapy treatment planning with a dose less than twice the one required for conventional CT scanning. PMID- 25728212 TI - Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma. AB - Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-beta (TGF-beta) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-beta signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-beta receptor (TGFBR3) through TGF-beta-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor suppressive GDF10 in OSCC. PMID- 25728213 TI - Mapping monoclonal antibody structure by 2D 13C NMR at natural abundance. AB - Monoclonal antibodies (mAbs) represent an important and rapidly growing class of biotherapeutics. Correct folding of a mAb is critical for drug efficacy, while misfolding can impact safety by eliciting unwanted immune or other off-target responses. Robust methods are therefore needed for the precise measurement of mAb structure for drug quality assessment and comparability. To date, the perception in the field has been that NMR could not be applied practically to mAbs due to the size (~150 kDa) and complexity of these molecules, as well as the insensitivity of the method. The feasibility of applying NMR methods to stable isotope-labeled, protease-cleaved, mAb domains (Fab and Fc) has been demonstrated from both E. coli and Chinese hamster ovaries (CHO) cell expression platforms; however, isotopic labeling is not typically available when analyzing drug products. Here, we address the issue of feasibility of NMR-based mapping of mAb structure by demonstrating for the first time the application of a 2D (13)C NMR methyl fingerprint method for structural mapping of an intact mAb at natural isotopic abundance. Further, we show that 2D (13)C NMR spectra of protease cleaved Fc and Fab fragments can provide accurate reporters on the domain structures that can be mapped directly to the intact mAb. Through combined use of rapid acquisition and nonuniform sampling techniques, we show that these Fab and Fc fingerprint spectra can be rapidly acquired in as short as approximately 30 min. PMID- 25728214 TI - Healthcare provider targeted interventions to improve medication adherence: systematic review and meta-analysis. AB - OBJECTIVE: This systematic review applied meta-analytic procedures to synthesise medication adherence (also termed compliance) interventions that focus on healthcare providers. DESIGN: Comprehensive searching located studies testing interventions that targeted healthcare providers and reported patient medication adherence behaviour outcomes. Search strategies included 13 computerised databases, hand searches of 57 journals, and both author and ancestry searches. Study sample, intervention characteristics, design and outcomes were reliably coded. Standardised mean difference effect sizes were calculated using random effects models. Heterogeneity was examined with Q and I(2) statistics. Exploratory moderator analyses used meta-analytic analogue of ANOVA and regression. RESULTS: Codable data were extracted from 218 reports of 151,182 subjects. The mean difference effect size was 0.233. Effect sizes for individual interventions varied from 0.088 to 0.301. Interventions were more effective when they included multiple strategies. Risk of bias assessment documented larger effect sizes in studies with larger samples, studies that used true control groups (as compared with attention control), and studies without intention-to treat analyses. CONCLUSION: Overall, this meta-analysis documented that interventions targeted to healthcare providers significantly improved patient medication adherence. The modest overall effect size suggests that interventions addressing multiple levels of influence on medication adherence may be necessary to achieve therapeutic outcomes. PMID- 25728215 TI - Environmentally relevant concentration of arsenic trioxide and humic acid promoted tumor progression of human cervical cancer cells: In vivo and in vitro studies. AB - In a previous study, treatment at higher concentrations of arsenic trioxide or co exposure to arsenic trioxide and humic acid was found to be inhibited cell growth of cervical cancer cells (SiHa cells) by reactive oxygen species generation. However, treatment at lower concentrations slightly increased cell viability. Here, we investigate the enhancement of progression effects of environmentally relevant concentration of humic acid and arsenic trioxide in SiHa cell lines in vitro and in vivo by measuring cell proliferation, migration, invasion, and the carcinogenesis-related protein (MMP-2, MMP-9, and VEGF-A) expressions. SiHa cells treated with low concentrations of humic acid and arsenic trioxide alone or in co exposure significantly increased reactive oxygen species, glutathione levels, cell proliferation, scratch wound-healing activities, migration abilities, and MMP-2 expression as compared to the untreated control. In vivo the tumor volume of either single drug (humic acid or arsenic trioxide) or combined drug-treated group was significantly larger than that of the control for an additional 45 days after tumor cell injection on the back of NOD/SCID mice. Levels of MMP-2, MMP-9, and VEGF-A, also significantly increased compared to the control. Histopathologic effects of all tumor cells appeared round in cell shape with high mitosis, focal hyperkeratosis and epidermal hyperplasia in the skin, and some tumor growth in the muscle were observed. Our results may indicate that exposure to low concentrations of arsenic trioxide and humic acid is associated with the progression of cervical cancer. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1121-1132, 2016. PMID- 25728216 TI - Aromatic amide-derived non-biaryl atropisomers as highly efficient ligands in silver-catalyzed asymmetric cycloaddition reactions. AB - The synthesis of a series of aromatic amide-derived non-biaryl atropisomers with a phosphine group and multiple stereogenic centers is reported. The novel phosphine ligands exhibit high diastereo- and enantioselectivities (up to >99:1 d.r., 95-99 % ee) as well as yields in the silver-catalyzed asymmetric [3+2] cycloaddition of aldiminoesters with nitroalkenes, which provides a highly enantioselective strategy for the synthesis of optically pure nitro-substituted pyrrolidines. In addition, the experimental results with regard to the carbon stereogenic center as well as the amide stereochemistry confirmed the potential of hemilabile atropisomers as chiral ligand in catalytic asymmetric [3+2] cycloaddition reaction. PMID- 25728217 TI - Light emission in nonlocal plasmonic metamaterials. AB - We present analytical and computational studies of light emission in nonlocal metamaterials formed by arrays of aligned plasmonic nanowires. We demonstrate that the emission lifetime in these composites is a complex function of geometrical and material parameters of the system that cannot be reduced to the "trivial" hyperbolic or elliptical dispersion topology of a homogenised metamaterial. In particular, our studies suggest that the Purcell factor can often be maximized when the composite operates in the elliptic regime, with strong radiation coupling to an additional TM-polarized mode supported by the nonlocal composite, in contrast to the accepted "hyperbolicity related" enhancement. PMID- 25728218 TI - First report of ovarian epidermoid cyst in a teleost. PMID- 25728220 TI - Bispecific antibodies. AB - Bispecific antibodies (bsAbs) combine specificities of two antibodies and simultaneously address different antigens or epitopes. BsAbs with 'two-target' functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or inflammatory processes. BsAbs can also place targets into close proximity, either to support protein complex formation on one cell, or to trigger contacts between cells. Examples of 'forced-connection' functionalities are bsAbs that support protein complexation in the clotting cascade, or tumor-targeted immune cell recruiters and/or activators. Following years of research and development (R&D), the first bsAb was approved in 2009. Another bsAb entered the market in December 2014 and several more are in clinical trials. Here, we describe the potentials of bsAbs to become the next wave of antibody-based therapies, focusing on molecules in clinical development. PMID- 25728219 TI - Physical activity in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Physical activity is an important parameter in patients with chronic obstructive pulmonary disease, but has not been studied in detail in patients with interstitial lung disease. This study aimed to evaluate physical activity in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Physical activity was monitored in 31 stable IPF patients using an accelerometer for 1 month. The following factors reflecting physical activity were measured: the number of steps, walking distance, the time spent at magnitude of movement (MM) 1 6, physical activity-related energy expenditure (PAEE) and total energy expenditure. We also measured the following clinical parameters: the modified Medical Research Council (MRC) scale, Krebs von den Lungen-6 (KL-6), pulmonary function parameters, 6-min walk test (6MWT) results and high-resolution computed tomography (HRCT) findings of the chest. We determined the relationship between these parameters and physical activity. RESULTS: We recorded 24 days of physical activity data. The time spent at MM < 1 was more than 10 h per day, whereas that at MM > 1 was approximately 1 h per day. The modified MRC scale, serum KL-6 levels, 6MWT distance, and the extent of honeycomb and reticular abnormality on HRCT were associated with several facets of physical activity. In particular, lower KL-6 levels were correlated with higher physical activity based on the number of steps, walking distance, the time spent at MM 1-4 and PAEE. CONCLUSIONS: The modified MRC scale, 6MWT distance, extent of fibrosis on HRCT and serum KL-6 levels are strongly associated with physical activity. PMID- 25728222 TI - Understanding of altered N-glycosylation-related gene expression in recombinant Chinese hamster ovary cells subjected to elevated ammonium concentration by digital mRNA counting. AB - To understand the effects of ammonium on N-glycosylation, recombinant Chinese hamster ovary (rCHO) cells that produce the Fc-fusion protein were cultivated in serum-free suspension cultures with 10 mM ammonium addition. The addition of ammonium to the cultures reduced the relative proportion of acidic isoforms and sialic acid content of an Fc-fusion protein. Fifty two N-glycosylation-related gene expressions were assessed by the NanoString nCounter system, which provides a digital readout using custom-designed color-coded probes. Among these queried genes, thirteen genes (gale, nans, gpi, man2a1, b4galt5, b4galt7, st3gal2, st3gal5, glb1, hexa, hexb, neu1, and neu3) were up-regulated over 1.5 times in the culture with ammonium addition after 5 days of culture; however, none of the 54 genes were significantly different after 3 days of culture. In particular, the expression level of neu1 (sialidase-1) and neu3 (sialidase-3), which play a role in reduction of sialylation, increased over 2 times. Likewise, the protein expression levels of sialidase-1 and sialidase-3 determined by Western blot analysis were also increased significantly in the culture with ammonium addition. Transient transfection of neu-1 or neu3-targeted siRNAs significantly improved the sialic acid content of the Fc-fusion protein in the culture with ammonium addition, indicating that the decreased sialic acid content was in part due to the increased expression level of sialidase. Taken together, the results obtained in this study provide a better understanding of the detrimental effect of ammonium on N-glycosylation, especially sialylation, in rCHO cells. PMID- 25728221 TI - Validity of anthropometric measurements for characterizing obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort Study. AB - BACKGROUND: Childhood cancer survivors (CCSs) are at risk for obesity. The purpose of this project was to determine which clinical measures of body composition are most accurate among CCSs in comparison with dual-energy x-ray absorptiometry (DXA). METHODS: The agreement between the body mass index (BMI), skinfold percent body fat, and waist-to-height ratio (WHtR) and DXA was evaluated among 1361 CCSs (mean age, 32.4 +/- 7.7 years) 10 or more years after the diagnosis. The sensitivity and specificity of BMI, skinfold, and WHtR obesity classifications were calculated with respect to DXA. Log-binomial regression, stratified by sex, was used to evaluate treatment-related factors for misclassification as nonobese by BMI, skinfolds, and WHtR. RESULTS: The mean body fat values were 23.3% +/- 7.7% (males) and 32.3% +/- 8.1% (females) for skinfolds and 26.9% +/- 7.4% (males) and 38.4% +/- 7.7% (females) for DXA. Pearson correlations between skinfolds and DXA were high (R = 0.83 for males, R = 0.84 for females). Skinfolds incorrectly classified 34.5% of obese males and 27.3% of obese females. BMI measures were the least sensitive with false-negative rates of 46.4% (males) and 53.1% (females). Males exposed to abdominal/pelvic radiation were at increased risk for misclassification as nonobese by BMI (relative risk, 1.57; 95% confidence interval, 1.25-1.95). The percentages classified as obese were highest with DXA (males, 63.1%; females, 84.8%) and lowest with BMI (males, 35.7%; females, 39.7%). Although skinfolds and WHtR underestimated the percentage classified as obese in comparison with DXA, the differences were not as large. CONCLUSIONS: Findings suggest that skinfolds and WHtR are better than BMI for obesity classification in CCSs. Clinicians should be aware of the high risk of misclassifying obese CCSs as nonobese. PMID- 25728223 TI - Demographics and treatment of adolescent posttraumatic headache in a regional concussion clinic. AB - OBJECTIVE: Mild traumatic brain injury affects over one million pediatric patients annually. Minimal data and no guidelines exist regarding treatment of posttraumatic headache (PTH). The current study investigated treatment and outcomes in patients with posttraumatic headache. METHODS: Medical records of all patients (age 13-18 years of age) seen at a regional concussion program from 2006 to 2011 were reviewed. Statistical analysis using SAS 9.2 was conducted to determine the effectiveness of treatment as well as the association of gender, concussion history, and football participation on the duration of posttraumatic headache. RESULTS: Four hundred subjects met the inclusion criteria. Females were more likely to report posttraumatic headache than males (90% vs. 79%, P = 0.004), more likely to be prescribed amitriptyline (24% vs. 13%, P = 0.004), and had a significantly longer recovery time (median, 80 days versus 34 days, P < 0.001). Seventeen percent of subjects were prescribed amitriptyline for treatment of posttraumatic headache, of which 82% reported a beneficial effect. There was no difference in the percentage of posttraumatic headache or recovery time in football players versus other male athletes from other sport mechanisms. CONCLUSION: Females are more likely to report posttraumatic headache than males and also take longer to recover. Amitriptyline appears to be well-tolerated and an effective treatment strategy for patients with posttraumatic headache. Among pediatric patients evaluated in a concussion clinic, there is no difference in the proportion of football players reporting headaches compared with male players of other sports. PMID- 25728224 TI - Social interactions at the onset of rheumatoid arthritis and their influence on help-seeking behaviour: A qualitative exploration. AB - OBJECTIVES: To explore how social interactions at the onset of rheumatoid arthritis (RA) influence help-seeking behaviour from the perspectives of those with RA and their significant others (family and friends). METHODS: Nineteen semi structured qualitative interviews were undertaken with people recently diagnosed with RA and their significant others. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Significant others' initial appraisals of symptoms led them to provide practical support with daily activities rather than advice to seek help. People with RA described difficulties in communicating the severity of their symptoms and often attempted to hide their symptoms from others. Significant others also reacted negatively, expressing disbelief and dismissing symptoms. On occasion, early symptoms were even described as the catalyst for the breakdown of relationships. On reflection, significant others expressed guilt about their initial reactions and wished that they had recognized the need for intervention earlier. When symptoms had advanced and were more obvious, significant others often strongly advised that help should be sought and, in some cases, physically escorted the patient to their medical appointment. In many instances, people with RA described significant others as the catalyst for eventually seeking help. CONCLUSIONS: Significant others play an important role in influencing help-seeking behaviour; this has implications for theoretical models of help-seeking and the development of help-seeking interventions. A negative consequence of social interactions resulted from a lack of understanding and knowledge about RA among significant others, highlighting the need for greater public awareness about the early symptoms of RA. PMID- 25728225 TI - Photocatalytic destruction of Escherichia coli in water by V2O5 /TiO2. AB - Vanadia modified titania (V2O5/TiO2) photo-catalysts are prepared by incipient wet impregnation method using aqueous ammonium metavanadate and anatase (Aldrich) titania. Titania with various loading concentrations of vanadia from 0 to 10 wt.% have been prepared and characterized by X-ray diffraction (XRD), Thermogravimetry (TGA), Laser Raman Spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), X-ray Photoelectron Spectroscopy (XPS), UV-Visible Spectrophotometry and Transmission Electron Microscopy (TEM). XRD study reveals that vanadia loading on titania does not bring any phase change of titania, however, diffuse (UV-Vis) reflectance spectra show that absorption edge of titania shifted from UV to visible region. TEM confirms that titania and vanadia modified titania have the particle size below 50 nm. XPS shows alteration of 2p3/2 peak of V(V) in the V2O5/TiO2 samples whereas no such change is noticed in pure V2O5 indicating the interaction between vanadia and titania support. Antibacterial activity of each sample has been investigated against Escherichia coli present in the water under both UV-Visible irradiation and UV alone. V2O5/TiO2 catalysts exhibit better photocatalytic effect than the unmodified titania and pure V2O5. It is observed that with increasing loading concentrations of V2O5 from 0 to 10 wt.% on titania support, the photocatalytic annihilation of E.coli is also increased and found to be little higher under UV alone than the UV-Visible irradiation. PMID- 25728226 TI - Evaluation of photodegradation, phototoxicity and photogenotoxicity of ofloxacin in ointments with sunscreens and in solutions. AB - Fluoroquinolones are widely used anti-bacterial agents that are known to exhibit moderate to severe phototoxicity. Furthermore some of them reveal photogenotoxicity under UV irradiation. Incidence of side effects due to light exposure may be augmented, if the medicament is used topically. The main goal of this work was to compare the extent of photodegradation of ofloxacin in ointments with various excipients: hydrated or non-hydrated base and the addition of sunscreens: bisoctrizole (Tinosorb M) and bemotrizinol (Tinosorb S). The next goal of present work was the analysis of phototoxicity and photogenotoxicity of ofloxacin photodegradation products in tested ointments and in solutions with the umu-test, the test of mitotic gene conversion with Saccharomyces cerevisiae D7 and the micronucleus assay with V79 Chinese hamster cell line. At the same time an attempt was made to determinate the photodegradation products of ofloxacin in different unguents variants. We observed a significant photoprotective effect in ointment with Tinosorb M. We did not evaluated relevant differences regarding the genotoxicity and toxicity of unguents. However, the pre-irradiated ofloxacin solutions in comparison to samples stored in the dark were significantly more genotoxic to bacteria, slightly increased the number of micronuclei in V79 cell line and were toxic to the yeast strain. PMID- 25728227 TI - Gastroprotective effect of kefir on ulcer induced in irradiated rats. AB - The current study was designed to investigate the protective effect of kefir milk on ethanol-induced gastric ulcers in gamma-irradiated rats. The results of the present study revealed that treatment with gamma-irradiation and/or ethanol showed a significant increase in ulcers number, total acidity, peptic, H(+)K(+)ATPase, MMP-2 and MMP-9 activities and MDA level, which were accompanied by a significant decrease in the mucus content, the stomach GSH level, the GSH-Px activity and DNA damage. Pre-treatment with kefir milk exert significant improvement in all the tested parameters. Kefir milk exerts comparable effect to that of the antiulcer drug ranitidine. In conclusion, the present study revealed that oral administration of kefir milk prevents ethanol-induced gastric ulcer in gamma-irradiated rats that could attribute to its antioxidant, anti-apoptotic and radio-protective activities. PMID- 25728228 TI - Protective Effects of Human iPS-Derived Retinal Pigmented Epithelial Cells in Comparison with Human Mesenchymal Stromal Cells and Human Neural Stem Cells on the Degenerating Retina in rd1 mice. AB - Retinitis pigmentosa (RP) is a group of visual impairments characterized by progressive rod photoreceptor cell loss due to a genetic background. Pigment epithelium-derived factor (PEDF) predominantly secreted by the retinal pigmented epithelium (RPE) has been reported to protect photoreceptors in retinal degeneration models, including rd1. In addition, clinical trials are currently underway outside Japan using human mesenchymal stromal cells and human neural stem cells to protect photoreceptors in RP and dry age-related macular degeneration, respectively. Thus, this study aimed to investigate the rescue effects of induced pluripotent stem (iPS)-RPE cells in comparison with those types of cells used in clinical trials on photoreceptor degeneration in rd1 mice. Cells were injected into the subretinal space of immune-suppressed 2-week-old rd1 mice. The results demonstrated that human iPS-RPE cells significantly attenuated photoreceptor degeneration on postoperative days (PODs) 14 and 21 and survived longer up to at least 12 weeks after operation than the other two types of graft cells with less immune responses and apoptosis. The mean PEDF concentration in the intraocular fluid in RPE-transplanted eyes was more than 1 ug/ml at PODs 14 and 21, and this may have contributed to the protective effect of RPE transplantation. Our findings suggest that iPS-RPE cells serve as a competent source to delay photoreceptor degeneration through stable survival in degenerating ocular environment and by releasing neuroprotective factors such as PEDF. PMID- 25728229 TI - The effect of perceived organisational support on burnout among community health nurses in China: the mediating role of professional self-concept. AB - AIM: To examine the mediating effect of professional self-concept on the association between perceived organisational support and burnout among community health nurses in Chengdu, China. BACKGROUND: Burnout is a common phenomenon among nurses and previous studies have focused on work environmental factors contributing to burnout. Limited studies have examined the effects of perceived organisational support and professional self-concept on burnout among community health nurses. METHODS: This was a cross-sectional study with 551 community health nurses in Chengdu, China, which included a two-stage sampling method. Structural equation modelling was used to examine the relationships among perceived organisational support, professional self-concept and burnout. RESULTS: The final sample included 456 nurses (82.7%). Perceived organisational support was a significant positive direct predictor for professional self-concept and a significant negative direct predictor for burnout. Professional self-concept was a significant negative direct contributor to burnout. Professional self-concept had a mediating effect on the relationship between perceived organisational support and burnout. CONCLUSIONS: Perceived organisational support may result in reduced burnout by facilitating the development of positive professional self concept. IMPLICATIONS FOR NURSING MANAGEMENT: Strategies such as establishing a supportive work environment and professional competence training may be effective methods for burnout prevention and management among community health nurses. PMID- 25728230 TI - Acaricidal effects of fluazuron (2.5 mg/kg) and a combination of fluazuron (1.6 mg/kg) + ivermectin (0.63 mg/kg), administered at different routes, against Rhipicephalus (Boophilus) microplus parasitizing cattle. AB - The present study aimed to evaluate the acaricidal efficacy of fluazuron (2.5 mg/kg), administered as a pour-on, in comparison to an injectable formulation containing fluazuron (1.6 mg/kg) + ivermectin (0.63 mg/kg), against Rhipicephalus (Boophilus) microplus in naturally and experimentally infested cattle. Two studies were conducted with different tick strains, one with artificial infestations (Stall Test, using leight animals per group) and one with natural infestations (utilizing ten animals per group). In both studies, the animals were randomized, according to average tick counts performed on days -3, -2 and -1, into four groups: T01, negative control (saline solution); T02, pour-on fluazuron (2.5 mg/kg); T03: subcutaneous fluazuron (1.6 mg/kg) + ivermectin (0.63 mg/kg); and T04 subcutaneous ivermectin (0.63 mg/kg). Based on obtained results, and considering the utilized tick strains, it was possible to conclude that the pour on fluazuron (2.5 mg/kg) formulation demonstrated high acaricidal efficacy, with protection periods ranging from 49 to 77 days against Rhipicephalus (Boophilus) microplus. On the other hand, for the injectable fluazuron (1.6 mg/kg) + ivermectin (0.63 mg/kg) formulation, it was not possible to observe elevated anti R. (B.) microplus effect on both artificial and experimental infestation studies. Results observed for this combination were similar or inferior to those obtained by subcutaneous ivermectin (0.63 mg/kg). Future studies with this formulation containing fluazuron (1.6 mg/kg) + ivermectin (0.63 mg/kg), regarding pharmacokinetic and/or bioavailability profiles, or even studies analyzing both this active principles separately, are needed, seeking to better understand the effects of such combination against Rhipicephalus (Boophilus) microplus parasitizing cattle. PMID- 25728231 TI - Suppression of OVA-alum induced allergy by Heligmosomoides polygyrus products is MyD88-, TRIF-, regulatory T- and B cell-independent, but is associated with reduced innate lymphoid cell activation. AB - The murine intestinal nematode Heligmosomoides polygyrus exerts multiple immunomodulatory effects in the host, including the suppression of allergic inflammation in mice sensitized to allergen presented with alum adjuvant. Similar suppression is attained by co-administration of H. polygyrus excretory/secretory products (HES) with the sensitizing dose of ovalbumin (OVA) in alum. We investigated the mechanism of suppression by HES in this model, and found it was maintained in MyD88xTRIF-deficient mice, implying no role for helminth- or host derived TLR ligands, or IL-1 family cytokines that signal in a MyD88- or TRIF dependent manner. We also found suppression was unchanged in uMT mice, which lack B2 B cells, and that suppression was not abrogated when regulatory T cells were depleted in Foxp3.LuciDTR-4 mice. However, reduced IL-5 production was seen in the first 12 h after injection of OVA-alum when HES was co-administered, associated with reduced activation of IL-5(+) and IL-13(+) group 2 innate lymphoid cells. Thus, the suppressive effects of HES on alum-mediated OVA sensitization are reflected in the very earliest innate response to allergen exposure in vivo. PMID- 25728232 TI - Isolation and characterization of Heat Shock Protein 100-Batu1 from Toxoplasma gondii RH strain. AB - Toxoplasma gondii is an intracellular parasitic protozoon which infects human and most warm-blooded animals. Almost one-third of the world's population is affected by life-threatening infection of T. gondii tachyzoites form. Slow growing, transmissible and encysted bradyzoites forms are composed after tachyzoites stage. Cellular and environmental stresses induce conversion of tachyzoites from bradyzoites and this condition is associated with Heat Shock Protein (Hsps) family. Hsp100 is a member of this protein family, and coordinates to disassemble protein aggregates with Hsp70 and Hsp40 in an ATP dependent manner. Several proteins are involved during this stage differentiation and Hsp100 may help them to be in their native soluble form to perform their function as observed in other organisms. For this purpose, Hsp100-Batu1 was isolated from T. gondii RH strain to characterize its biochemical properties in this current study. Hsp100 proteins play a role in survival and virulence of pathogens as shown in the literature. Therefore, manipulation of protein-protein interaction may perturb T. gondii infection and impair conversion to tachyzoites by inhibiting Hsp100 function. Therefore, results of this work present a potential route for vaccination or immunotherapy. PMID- 25728233 TI - The role of transcriptome resilience in resistance of corals to bleaching. AB - Wild populations increasingly experience extreme conditions as climate change amplifies environmental variability. How individuals respond to environmental extremes determines the impact of climate change overall. The variability of response from individual to individual can represent the opportunity for natural selection to occur as a result of extreme conditions. Here, we experimentally replicated the natural exposure to extreme temperatures of the reef lagoon at Ofu Island (American Samoa), where corals can experience severe heat stress during midday low tide. We investigated the bleaching and transcriptome response of 20 Acropora hyacinthus colonies 5 and 20 h after exposure to control (29 degrees C) or heated (35 degrees C) conditions. We found a highly dynamic transcriptome response: 27% of the coral transcriptome was significantly regulated 1 h postheat exposure. Yet 15 h later, when heat-induced coral bleaching became apparent, only 12% of the transcriptome was differentially regulated. A large proportion of responsive genes at the first time point returned to control levels, others remained differentially expressed over time, while an entirely different subset of genes was successively regulated at the second time point. However, a noteworthy variability in gene expression was observed among individual coral colonies. Among the genes of which expression lingered over time, fast return to normal levels was associated with low bleaching. Colonies that maintained higher expression levels of these genes bleached severely. Return to normal levels of gene expression after stress has been termed transcriptome resilience, and in the case of some specific genes may signal the physiological health and response ability of individuals to environmental stress. PMID- 25728235 TI - Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery. AB - Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest-activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest-activity rhythm, cancer specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-beta; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1beta, TNF-alpha, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-gamma; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest-activity rhythms had higher Factor 1 scores (R(2)=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R(2)=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression. PMID- 25728234 TI - Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala. AB - Precise regulation of the epigenome during perinatal development is critical to the formation of species-typical behavior later in life. Recent data suggests that Gadd45b facilitates active DNA demethylation by recruiting proteins involved in base excision repair (BER), which will catalyze substitution of 5-methyl cytosine (5mC) for an unmodified cytosine. While a role for Gadd45b has been implicated in both hippocampal and amygdalar learning tasks, to the best of our knowledge, no study has been done investigating the involvement of Gadd45b in neurodevelopmental programming of social behavior. To address this, we used a targeted siRNA delivery approach to transiently knock down Gadd45b expression in the neonatal rat amygdala. We chose to examine social behavior in the juvenile period, as social deficits associated with neurodevelopmental disorders tend to emerge in humans at an equivalent age. We find that neonatal Gadd45b knock-down results in altered juvenile social behavior and reduced expression of several genes implicated in psychiatric disorders, including methyl-CpG-binding protein 2 (MeCP2), Reelin, and brain derived neurotrophic factor (BDNF). We furthermore report a novel role for Gadd45b in the programmed expression of alpha2 adrenoceptor (Adra2a). Consistent with Gadd45b's role in the periphery, we also observed changes in the expression of pro-inflammatory cytokines interleukin-6 (Il-6) and interleukin-1beta (Il-1beta) in the amygdala, which could potentially mediate or exacerbate effects of Gadd45b knockdown on the organization of social behavior. These data suggest a prominent role for Gadd45b in the epigenetic programming of complex juvenile social interactions, and may provide insight into the etiology of juvenile behavioral disorders such as ADHD, autism, and/or schizophrenia. PMID- 25728236 TI - A schizophrenia-associated HLA locus affects thalamus volume and asymmetry. AB - Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analysed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia. PMID- 25728237 TI - Biosynthesis of the carbamoylated D-gulosamine moiety of streptothricins: involvement of a guanidino-N-glycosyltransferase and an N-acetyl-D-gulosamine deacetylase. AB - Streptothricins (STNs) are atypical aminoglycosides containing a rare carbamoylated D-gulosamine (D-GulN) moiety, and the antimicrobial activity of STNs has been exploited for crop protection. Herein, the biosynthetic pathway of the carbamoylated D-GulN moiety was delineated. An N-acetyl-D-galactosamine is first attached to the streptolidine lactam by the glycosyltransferse StnG and then epimerized to N-acetyl-D-gulosamine by the putative epimerase StnJ. After carbamoylation by the carbamoyltransferase StnQ, N-acetyl-D-GulN is deacetylated by StnI to furnish the carbamoylated D-GulN moiety. In vitro studies characterized two novel enzymes: StnG is an unprecedented GT-A fold N glycosyltransferase that glycosylates the imine nitrogen atom of guanidine, and StnI is the first reported N-acetyl-D-GulN deacetylase. PMID- 25728239 TI - Comparative proteomic analysis of biofilm and planktonic cells of Lactobacillus plantarum DB200. AB - This study investigated the relative abundance of extracellular and cell wall associated proteins (exoproteome), cytoplasmic proteins (proteome), and related phenotypic traits of Lactobacillus plantarum grown under planktonic and biofilm conditions. Lactobacillus plantarum DB200 was preliminarily selected due to its ability to form biofilms and to adhere to Caco2 cells. As shown by fluorescence microscope analysis, biofilm cells became longer and autoaggregated at higher levels than planktonic cells. The molar ratio between glucose consumed and lactate synthesised was markedly decreased under biofilm compared to planktonic conditions. DIGE analysis showed a differential exoproteome (115 protein spots) and proteome (44) between planktonic and biofilm L. plantarum DB200 cells. Proteins up- or downregulated by at least twofold (p < 0.05) were found to belong mainly to the following functional categories: cell wall and catabolic process, cell cycle and adhesion, transport, glycolysis and carbohydrate metabolism, exopolysaccharide metabolism, amino acid and protein metabolisms, fatty acid and lipid biosynthesis, purine and nucleotide metabolism, stress response, oxidation/reduction process, and energy metabolism. Many of the above proteins showed moonlighting behavior. In accordance with the high expression levels of stress proteins (e.g., DnaK, GroEL, ClpP, GroES, and catalase), biofilm cells demonstrated enhanced survival under conditions of environmental stress. PMID- 25728238 TI - Familial and individual predictors of obesity and insulin resistance in urban Hispanic children. AB - BACKGROUND: High intake of sugar-sweetened beverages (SSB) has been suggested to contribute to the pediatric obesity epidemic, however, how the home food environment influence children's intake of SSB among Hispanic families is still poorly understood. OBJECTIVES: To evaluate the relationships between the home food environment and Hispanic children's diet in relation to weight status and insulin resistance (IR). METHODS: A food frequency questionnaire was administered to 187 Hispanic children (ages 10 to 14 years) and anthropometrics were measured. IR was estimated from fasting insulin and glucose levels using the homeostasis model assessment of insulin resistance (HOMAIR ). Parents reported on family demographics and the home food environment. A structural equation modelling approach was applied to examine the hypothesized relationships among variables. RESULTS: The prevalence of childhood overweight and obesity was 52.8% and it was positively associated with HOMAIR (beta = 0.687, P < .0001). Children's SSB consumption was positively associated with children's body mass index z-score (beta = 0.151, P < 0.05) and subsequently to HOMAIR . Children's SSB consumption was predicted by home availability (beta = 0.191) and parental intake of SSB (beta = 0.419) (P < 0.05). The model fit indices [chi(2) = 45.821 (d.f. = 30, P > 0.01 and < 0.05), chi(2) /d.f. = 1.53, root mean square error of approximation = 0.053 (90% confidence interval = 0.016, 0.082), comparative fit index = 0.904] suggested a satisfactory goodness-of-fit. CONCLUSIONS: The home food environment and parental diet seem to play an important role in the children's access to and intake of SSB, which in turn predicted children's weight status. PMID- 25728240 TI - Current resources for evidence-based practice, March/April 2015. PMID- 25728241 TI - Transvaginal sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis: association with symptoms. AB - OBJECTIVES: To investigate whether there are sonographic features of diffuse adenomyosis in 18-30-year-old nulligravid women without endometriosis and to examine their association with symptoms of dysmenorrhea and abnormal uterine bleeding. METHODS: This was a prospective observational study including women referred from a gynecology outpatient center to our university hospital for ultrasound examination. Inclusion criteria were age between 18 and 30 years, regular menstrual cycle and nulligravid status. Exclusion criteria were a past or current history of endometriosis, fibroids, ovarian cysts or lesions, endometrial pathology, current use of hormonal treatments or medications that would affect the menstrual cycle, previous uterine surgery and history of infertility. Women underwent a detailed clinical assessment and a two- (2D) and three-dimensional (3D) transvaginal ultrasound (TVS) examination. 2D-TVS features associated with diffuse adenomyosis were predefined as: (1) heterogeneous myometrium; (2) hypoechoic striation in the myometrium; (3) myometrial anechoic lacunae or cysts; (4) asymmetrical myometrial thickening of the uterine walls with the presence of straight vessels, extending into the hypertrophic myometrium, on power Doppler examination. On 3D-TVS, endomyometrial junctional zone (JZ) was measured as the distance from the basal endometrium to the internal layer of the outer myometrium on coronal section at any level of the uterus, and the smallest (JZmin) and largest (JZmax) JZ thicknesses and their difference (JZdiff) were recorded. 3D TVS evaluation was considered suggestive for adenomyosis when JZmax >= 8 mm and/or JZdiff >= 4 mm. The presence of associated symptomatology represented our main outcome: the amount of menstrual loss was assessed by a pictorial blood loss analysis chart (PBAC) and painful symptoms were evaluated using a visual analog scale (VAS). RESULTS: During the observation period, 205 women (median age, 24 (interquartile range, 23-27) years) were enrolled into the study and 156 met the inclusion criteria. According to the 2D-TVS criteria, diffuse adenomyosis was found in 53 (34.0%) women and asymmetrical myometrial thickening of the uterine walls was the most common sonographic feature observed. ANOVA showed a significant relationship between the number of 2D-TVS features of diffuse adenomyosis and VAS score for dysmenorrhea (P = 0.005) as well as PBAC score for menstrual loss (P = 0.03). 3D-TVS showed that women with 2D-TVS features of diffuse adenomyosis had a significantly higher value of JZmax (6.38 +/- 2.30 mm, P < 0.001), JZmin (2.07 +/- 0.43 mm, P = 0.002) and JZdiff (4.33 +/- 1.99 mm, P < 0.001) than did women without these features. Women with sonographic features of diffuse adenomyosis were symptomatic in 83% of cases, reported dysmenorrhea in 79.2% and showed a higher incidence of heavy bleeding than did those without these features (18.9% vs 2.9%; P = 0.001). CONCLUSIONS: Sonographic features suggestive of diffuse adenomyosis may develop earlier in reproductive life than previously thought, and may occur in association with dysmenorrhea and abnormal uterine bleeding in nulligravid women. Their observation in these women should therefore warrant further gynecological investigation. PMID- 25728243 TI - Evidence for a link between tail biting and central monoamine metabolism in pigs (Sus scrofa domestica). AB - Tail biting in pigs is a major welfare problem within the swine industry. Even though there is plenty of information on housing and management-related risk factors, the biological bases of this behavioral problem are poorly understood. The aim of this study was to investigate a possible link between tail biting, based on behavioral recordings of pigs during an ongoing outbreak, and certain neurotransmitters in different brain regions of these pigs. We used a total of 33 pigs at a farm with a long-standing problem of tail biting. Three equally big behavioral phenotypic groups, balanced for gender and age were selected, the data thus consisting of 11 trios of pigs. Two of the pigs in each trio originated from the same pen: one tail biter (TB) and one tail biting victim (V). A control (C) pig was selected from a pen without significant tail biting in the same farm room. We found an effect of tail biting behavioral phenotype on the metabolism of serotonin and dopamine, with a tendency for a higher 5-HIAA level in the prefrontal cortex (PFC) of TB compared to the other groups, while V pigs showed changes in both serotonin and dopamine metabolism in the striatum (ST) and limbic cortex (LC). Trp:BCAA and Trp:LNAA correlated positively with serotonin and 5 HIAA in the PFC, but only in TB pigs. Furthermore, in both ST and LC, several of the neurotransmitters and their metabolites correlated positively with the frequency of bites received by the pig. This is the first study indicating a link between brain neurotransmission and tail biting behavior in pigs with TB pigs showing a tendency for increased PFC serotonin metabolism and V pigs showing several changes in central dopamine and serotonin metabolism in their ST and LC, possibly due to the acute stress caused by being bitten. PMID- 25728242 TI - Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice. AB - KEY POINTS: Potential roles of endogenous leptin and endocannabinoids in sweet taste were examined by using pharmacological antagonists and mouse models including leptin receptor deficient (db/db) and diet-induced obese (DIO) mice. Chorda tympani (CT) nerve responses of lean mice to sweet compounds were increased after administration of leptin antagonist (LA) but not affected by administration of cannabinoid receptor antagonist (AM251). db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid levels in the taste organ, and enhanced expression of a biosynthesizing enzyme of endocannabinoids in taste cells. The effect of LA was gradually decreased and that of AM251 was increased during the course of obesity in DIO mice. These findings suggest that circulating leptin, but not local endocannabinoids, is a dominant modulator for sweet taste in lean mice and endocannabinoids become more effective modulators of sweet taste under conditions of deficient leptin signalling. ABSTRACT: Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1 : AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA administration, while they showed no significant changes in CT responses after AM251. In contrast, db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid (2-arachidonoyl-sn glycerol (2-AG)) levels in the taste organ, and enhanced expression of a biosynthesizing enzyme (diacylglycerol lipase alpha (DAGLalpha)) of 2-AG in taste cells. In DIO mice, the LA effect was gradually decreased and the AM251 effect was increased during the course of obesity. Taken together, our results suggest that circulating leptin, but not local endocannabinoids, may be a dominant modulator for sweet taste in lean mice; however, endocannabinoids may become more effective modulators of sweet taste under conditions of deficient leptin signalling, possibly due to increased production of endocannabinoids in taste tissue. PMID- 25728244 TI - Balancing research interests and patient interests: a qualitative study into the intertwinement of care and research in paediatric oncology. AB - BACKGROUND: Traditionally, in ethical guidelines and in research ethics literature, care and research are clearly separated based on their different objectives. In contrast, in paediatric oncology, research and care are closely combined. Currently, it is unknown how relevant actors in paediatric oncology perceive this combination of research and care. We conducted a qualitative study into the experiences of those involved in Dutch paediatric oncology with the intertwinement of research and care and the dual role of paediatric oncologists as researchers and treating physicians. PROCEDURE: A qualitative study approach, using two focus groups and 19 semi-structured, in-depth interviews with paediatric oncologists, research coordinators, parents of children with cancer, and adolescents with cancer. RESULTS: Four themes characterize how actors experience the intertwinement of research and care in paediatric oncology. First, research is considered of major importance, and paediatric oncology professionals convey this message to patients and their parents. Second, there is ambiguity about categorization of studies into cancer therapy as either research or treatment. Third, role conflicts appear within the work of the paediatric oncologists. Finally, the various benefits of combining treatment with research are emphasized. CONCLUSIONS: Research is regarded as a fundamental and indispensable characteristic of paediatric oncology practice. Paediatric oncology professionals, parents, and patients have a very positive outlook on combining research and care, but they may not be sufficiently critical with respect to potential conflicts. Increased reflection on how to optimally combine research and care could serve as an important protection of the interests of children with cancer and their parents. PMID- 25728245 TI - The first case of onychomycosis due to Aspergillus uvarum (section Nigri). PMID- 25728246 TI - Sociotechnical approaches to workplace safety: Research needs and opportunities. AB - The sociotechnical systems perspective offers intriguing and potentially valuable insights into problems associated with workplace safety. While formal sociotechnical systems thinking originated in the 1950s, its application to the analysis and design of sustainable, safe working environments has not been fully developed. To that end, a Hopkinton Conference was organised to review and summarise the state of knowledge in the area and to identify research priorities. A group of 26 international experts produced collaborative articles for this special issue of Ergonomics, and each focused on examining a key conceptual, methodological and/or theoretical issue associated with sociotechnical systems and safety. In this concluding paper, we describe the major conference themes and recommendations. These are organised into six topic areas: (1) Concepts, definitions and frameworks, (2) defining research methodologies, (3) modelling and simulation, (4) communications and decision-making, (5) sociotechnical attributes of safe and unsafe systems and (6) potential future research directions for sociotechnical systems research. PRACTITIONER SUMMARY: Sociotechnical complexity, a characteristic of many contemporary work environments, presents potential safety risks that traditional approaches to workplace safety may not adequately address. In this paper, we summarise the investigations of a group of international researchers into questions associated with the application of sociotechnical systems thinking to improve worker safety. PMID- 25728247 TI - p16(INK4A) inhibits the pro-metastatic potentials of osteosarcoma cells through targeting the ERK pathway and TGF-beta1. AB - Extracellular signal-regulated kinase (ERK) is a downstream component of the evolutionarily conserved mitogen-activated protein kinase-signaling pathway, which controls the expression of a plethora of genes implicated in various physiological processes. This pathway is often hyper-activated by mutations or abnormal extracellular signaling in different types of human cancer, including the most common primary malignant bone tumor osteosarcomas. p16(INK4A) is an important tumor suppressor gene frequently lost in osteosarcomas, and is associated with the progression of these malignancies. We have shown, here, that the ERK1/2 protein kinase is also activated by p16(INK4A) down-regulation in osteosarcoma cells and normal human as well as mouse cells. This inhibitory effect is associated with the suppression of the upstream kinase MEK1/2, and is mediated via the repression of miR-21-5p and the consequent up-regulation of the MEK/ERK antagonist SPRY2 in osteosarcoma cells. Furthermore, we have shown that p16(INK4) inhibits the migration/invasion abilities of these cells through miR-21 5p-dependent inhibition of ERK1/2. In addition, we present clear evidence that p16(INK4) represses the paracrine pro-migratory effect of osteosarcoma cells on stromal fibroblasts through the inhibition of the TGF-beta1 expression/secretion. This effect is also ERK1/2-dependent, indicating that in addition to their cell autonomous actions, p16(INK4) and ERK1/2 have also non-cell-autonomous cancer related functions. Together, these results indicate that the tumor suppressor p16(INK4) protein represses the carcinogenic process of osteosarcoma cells not only as a cell cycle regulator, but also as a negative regulator of pro carcinogenic/-metastatic pathways. This indicates that targeting the ERK pathway is of utmost therapeutic value. PMID- 25728248 TI - The interactive association of dietary diversity scores and breast-feeding status with weight and length in Filipino infants aged 6-24 months. AB - OBJECTIVE: To assess how breast-feeding and dietary diversity relate to infant length-for-age Z-score (LAZ) and weight-for-age Z-score (WAZ). DESIGN: Breast feeding, dietary and anthropometric data from the Cebu Longitudinal Health and Nutrition Survey were analysed using sex-stratified fixed-effects longitudinal regression models. A dietary diversity score (DDS) based on seven food groups was classified as low (<4) or high (>= 4). The complementary feeding patterns were: (i) non-breast-fed with low DDS (referent); (ii) breast-fed with low DDS; (iii) non-breast-fed with high DDS; and (iv) breast-fed with high DDS (optimal). Interactions between age, energy intake and complementary feeding patterns were included. SETTING: Philippines. SUBJECTS: Infants (n 2822) measured bimonthly from 6 to 24 months. RESULTS: Breast-feeding (regardless of DDS) was significantly associated with higher LAZ (until 24 months) and WAZ (until 20 months). For example, at 6 months, breast-fed boys with low DDS were 0.246 (95% CI 0.191, 0.302) sd longer and 0.523 (95% CI 0.451, 0.594) sd heavier than the referent group. There was no significant difference in size between breast-fed infants with high v. low DDS. Similarly, high DDS conferred no advantage in LAZ or WAZ among non-breast-fed infants. There were modest correlations between the 7 point DDS and nutrient intakes but these correlations were substantially attenuated after energy adjustment. We elucidated several interactions between sex, age, energy intake and complementary feeding patterns. CONCLUSIONS: These results demonstrate the importance of prolonged breast-feeding up to 24 months. The DDS provided qualitative information on infant diets but did not confer a significant advantage in LAZ or WAZ. PMID- 25728250 TI - Spatial relationships among the cellular tapetum, visual streak and rod density in dogs. AB - The dog visual system is well suited to dim light conditions due to rod-dominated retina and the reflective tapetum. The topographical distributions of rods and thickness of the tapetum of the dog were quantified in retinal whole mounts stained with thionine, and spatial relationships among the tapetum, rod density and visual streak of high ganglion cell density were elucidated. The relationship between the retina and tapetum was analyzed in parasagittal sections stained with thionine or hematoxylin-eosin. The tapetum was thick in its center, and the thickest part consisted of 9 to 12 tapetal cell layers. Rod density ranged from 200,000 to 540,000/mm(2). Maximum rod density was found in the area dorsal to the visual streak, and the density in that area was significantly higher than the rod density in the visual streak and accorded spatially with the thickest part of the tapetum. The horizontal visual streak was found over the horizontal line through the optic disc in the temporal half and extended slightly into the nasal half. The central area of the highest density of ganglion cells was approximately located midway between the nasal and temporal ends of the visual streak. The visual streak was located within the tapetal area, but ventrally to the thick part of the tapetum. PMID- 25728249 TI - Pantethine Alters Lipid Composition and Cholesterol Content of Membrane Rafts, With Down-Regulation of CXCL12-Induced T Cell Migration. AB - Pantethine, a natural low-molecular-weight thiol, shows a broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We have recently shown that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study, we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to a chronic inflammation. We found that pantethine-treated cells showed a significant change in raft fatty acid composition and cholesterol content, with ultimate downregulation of cell adhesion, CXCL12-driven chemotaxis, and transendothelial migration of various T cell types, including human Jurkat cell line and circulating effector T cells. The mechanisms involved include the alteration of the following: (i) CXCL12 binding to its target cells; (ii) membrane dynamics of CXCR4 and CXCR7, the two CXCL12 receptors; and (iii) cell redox status, a crucial determinant in the regulation of the chemokine system. In addition, we considered the linker for activation of T cells molecule to show that pantethine effects were associated with the displacement from the rafts of the acylated signaling molecules which had their palmitoylation level reduced.. In conclusion, the results presented here, together with previously published findings, indicate that due to its pleiotropic action, pantethine can downregulate the multifaceted process leading to pathogenic T cell activation and migration. PMID- 25728251 TI - Usefulness of CT imaging for segmental lung lobe torsion without typical radiographic imaging in a Pomeranian. AB - A 3-year-old, intact female Pomeranian presented with a 1-month history of coughing. Thoracic radiography showed focal infiltration of the left cranial lung lobe and widening of the cranial mediastinum. Subsequent computed tomography revealed torsion of the caudal segment of the left cranial lung lobe, which was confirmed by exploratory thoracotomy. There was no apparent underlying etiology for the condition. To the authors' knowledge, this is the first report of lung lobe torsion in this breed and the first detailed CT imaging report for segmental lung lobe torsion. PMID- 25728252 TI - Food allergens inducing a lymphocyte-mediated immunological reaction in canine atopic-like dermatitis. AB - Canine atopic-like dermatitis (ALD) is suspected to be associated with food allergies, particularly those mediated by lymphocytes. In this study, 54 cases were included as ALD dogs, based on the negative IgE test results. In the dogs, the percentage of activated cells in helper-T lymphocytes was measured by flow cytometry using cultured peripheral lymphocytes under food allergen stimulation. We observed that 49 of the 54 ALD dogs (90.7%) had positive lymphocyte reactions against one or more food allergens. The most common food allergen was soybean, showing positive results in 21 dogs (42.9%), while the allergen to cause the lowest number of reactions was catfish (only 5 dogs, 10.2%). These results may be useful in considering elimination diets for ALD dogs. PMID- 25728253 TI - Regulation of the p19(Arf)/p53 pathway by histone acetylation underlies neural stem cell behavior in senescence-prone SAMP8 mice. AB - Brain aging is associated with increased neurodegeneration and reduced neurogenesis. B1/neural stem cells (B1-NSCs) of the mouse subependymal zone (SEZ) support the ongoing production of olfactory bulb interneurons, but their neurogenic potential is progressively reduced as mice age. Although age-related changes in B1-NSCs may result from increased expression of tumor suppressor proteins, accumulation of DNA damage, metabolic alterations, and microenvironmental or systemic changes, the ultimate causes remain unclear. Senescence-accelerated-prone mice (SAMP8) relative to senescence-accelerated resistant mice (SAMR1) exhibit signs of hastened senescence and can be used as a model for the study of aging. We have found that the B1-NSC compartment is transiently expanded in young SAMP8 relative to SAMR1 mice, resulting in disturbed cytoarchitecture of the SEZ, B1-NSC hyperproliferation, and higher yields of primary neurospheres. These unusual features are, however, accompanied by premature loss of B1-NSCs. Moreover, SAMP8 neurospheres lack self-renewal and enter p53-dependent senescence after only two passages. Interestingly, in vitro senescence of SAMP8 cells could be prevented by inhibition of histone acetyltransferases and mimicked in SAMR1 cells by inhibition of histone deacetylases (HDAC). Our data indicate that expression of the tumor suppressor p19, but not of p16, is increased in SAMP8 neurospheres, as well as in SAMR1 neurospheres upon HDAC inhibition, and suggest that the SAMP8 phenotype may, at least in part, be due to changes in chromatin status. Interestingly, acute HDAC inhibition in vivo resulted in changes in the SEZ of SAMR1 mice that resembled those found in young SAMP8 mice. PMID- 25728254 TI - Ethnic disparities in utilisation of maternal health care services in Ghana: evidence from the 2007 Ghana Maternal Health Survey. AB - OBJECTIVE: Disparities in utilisation of maternal health care remain a challenge to attainment of the maternal health-related Millennium Development Goals. The objective of this descriptive study was to examine disparities in utilisation of maternal health care among ethnic groups in Ghana. DESIGN: Data from the 2007 Ghana Maternal Health Survey were analysed for disparities in antenatal care (ANC) visit, utilisation of tetanus toxoid immunisation and iron tablets/syrup intake during pregnancy, place of delivery, skilled birth attendance, caesarean section (CS) and post-natal care (PNC) among different ethnic groups. RESULTS: Findings show that the proportion of women who received any form of skilled antenatal, delivery and PNC in the five years (2003-2007) preceding the survey was 96%, 55% and 55%, respectively. Despite the incremental progress Ghana made in improving access to skilled maternal health care services, large gradients of disparities exist. The ethnic difference in utilisation of institutional prenatal care was small; however, fewer births to women from majority ethnic groups such as the Akan (21%) took place at home compared with births to women from minority ethnic groups such as the Ewe (58.8%), Guan (42.7%), Grusi (53.4%), Mole-Dagbani (74.7%) and Gruma (58.8%). The rate of consultation of a skilled health care provider for delivery among the different ethnic groups also ranged from a low of 27% for births to Mole-Dagbani women to a high of 68.8% among births to Akan women. CONCLUSION: Minority ethnic groups reported lower utilisation levels for most of the components of skilled maternity care in Ghana. However, ethnic disparities in utilisation of all the components of ANC in Ghana were less compared to delivery in health facilities, skilled attendance at birth, use of CS and PNC. Therefore, efforts to promote universal access to skilled maternity care not only should target those sub-populations with significantly low utilisation levels but also must focus on those components of maternal health care such as skilled attendance at delivery that demonstrate the greatest disparities. There is also the need to further explore who continues to remain excluded from receiving needed care, and how to encourage such women, especially minority women, to seek skilled care. PMID- 25728255 TI - Rapid development of osteoarthritis following arthroscopic resection of an "os acetabuli" in a mildly dysplastic hip: a case report. PMID- 25728256 TI - The revolution continues: energiewende 2.0. PMID- 25728257 TI - Influence of censoring on conclusions of trials for women with metastatic breast cancer. AB - Progression-free survival and time-to-progression (PFS/TTP) are used commonly as primary end-points in trials evaluating treatments for metastatic breast cancer (MBC). We reviewed the impact of censoring on interpretation of these end-points. A systematic review identified phase 3 trials in MBC published between 2001 and 2012 that reported hazard ratios (HRs) for PFS/TTP and Kaplan-Meier curves indicating numbers at risk. We calculated HRs for time-to-treatment-failure (TTF) where discontinuation of treatment for any reason is considered an event. Mean HRs for PFS/TTP, TTF, and overall survival (OS) were 0.79, 0.89 and 0.91, respectively. Unbalanced censoring of patients prior to progression was prevalent, usually with more patients censored in the experimental arms. There was moderate-to-poor correlation of HRs of PFS/TTP and TTF with HRs for OS. We suggest that TTF should be reported as supportive analysis in registration trials and extent of missing data due to censoring be considered in decisions made by regulatory agencies. PMID- 25728258 TI - Phosphohistone H3 outperforms Ki67 as a marker of outcome for breast cancer patients. AB - AIMS: The proliferation marker Ki67 has been extensively investigated as a prognostic factor in breast cancer, but has not gained widespread clinical acceptance. Phosphohistone H3 is a new immunohistochemical marker for quantifying mitoses; however, there is limited information on its prognostic value in breast cancer. In this study, we performed a head-to-head comparison of Ki67 and phosphohistone H3 to establish the marker with the greatest prognostic value. METHODS AND RESULTS: Tissue microarrays from 108 breast cancer patients were immunohistochemically stained for Ki67 and phosphohistone H3. Our results showed that phosphohistone H3 had a greater prognostic value than Ki67 in a multivariable model that adjusted for traditional prognostic variables in breast cancer. Phosphohistone H3 staining was a stronger predictor of survival at 5 years after diagnosis [hazard ratio (HR) 4.35, P < 10(-5) ] than Ki67 (HR 2.44, P = 0.004), and better separated the risk of death in patients aged >45 years. Importantly, phosphohistone H3 consistently showed strong unequivocal staining, in contrast to the variable staining intensities associated with Ki67. CONCLUSIONS: Our study suggests that phosphohistone H3 staining is a stronger and more robust prognostic indicator than Ki67 staining in breast cancer patients, and has the potential for use in routine diagnostic laboratories. PMID- 25728259 TI - Hypertension: a systemic key to understanding local keloid severity. AB - This study assessed whether hypertension, a circulating factor, influences local keloid severity. This retrospective cross-sectional study involved 304 consecutive patients (13-78 years old) with keloids who were surgically treated in our hospital between January 2011 and August 2013. Their blood pressure (BP), age and gender, and the size and number of their keloids before surgery were recorded. Ordinal logistic regression analyses showed that BP associated significantly with both keloid size and number (all p < 0.0001). Age also associated with keloid size (p < 0.0001). However, a Goodness-of-fit chi-square test showed that the prevalence of hypertension was not higher among keloid patients than in the general Japanese population. This study provides epidemiological evidence for the possibility that primary hypertension may aggravate keloids. We propose that the skin, along with the heart and liver, is a target organ of hypertension. The observations of this study, which require validation with large-scale prospective interventional trials, suggest that keloid patients should be screened for hypertension and that antihypertensive treatments may be of prophylactic and therapeutic value for skin fibrosis. PMID- 25728260 TI - Ocular nerve growth factor administration counteracts the impairment of neural precursor cell viability and differentiation in the brain subventricular area of rats with streptozotocin-induced diabetes. AB - The ocular administration of nerve growth factor (NGF) as eye drops (oNGF) has been shown to exert protective effects in forebrain-injured animal models, including adult diabetes induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). This type 1 diabetes model was used in this study to investigate whether oNGF might extend its actions on neuronal precursors localised in the subventricular zone (SVZ). NGF or saline was administrated as eye drops twice daily for 2 weeks in rats with STZ-induced diabetes and healthy control rats. The expression of mature and precursor NGF and the NGF receptors, tropomyosin-related kinase A and neurotrophin receptor p75, and the levels of DNA fragmentation were analysed by ELISA and western blotting. Incorporation of bromodeoxyuridine was used to trace newly formed cells. Nestin, polysialylated neuronal cell adhesion molecule (PSA-NCAM), doublecortin (DCX) and glial fibrillary acidic protein antibodies were used to identify the SVZ cells by confocal microscopy. It was found that oNGF counteracts the STZ-induced cell death and the alteration of mature/pro-NGF expression in the SVZ. It also affects the survival and differentiation of SVZ progenitors. In particular, oNGF counteracts the reduction in the number of cells expressing PSA-NCAM/DCX (neuroblast type A cells) and the related reductions in the number and distribution of nestin/DCX-positive cells (C-type cells), or glia-committed cells (type B cells), observed in the SVZ of diabetic rats. These findings show that oNGF treatment counteracts the effect of type 1 diabetes on neuronal precursors in the SVZ, and further support the neuroprotective and reparative role of oNGF in the brain. PMID- 25728261 TI - Both piston-like and rotational motions are present in bacterial chemoreceptor signaling. AB - Bacterial chemotaxis signaling is triggered by binding of chemo-effectors to the membrane-bound chemoreceptor dimers. Though much is known about the structure of the chemoreceptors, details of the receptor dynamics and their effects on signaling are still unclear. Here, by using molecular dynamics simulations and principle component analysis, we study the dynamics of the periplasmic domain of aspartate chemoreceptor Tar dimer and its conformational changes when binding to different ligands (attractant, antagonist, and two attractant molecules). We found two dominant components (modes) in the receptor dynamics: a relative rotation of the two Tar monomers and a piston-like up-and-down sliding movement of the alpha4 helix. These two modes are highly correlated. Binding of one attractant molecule to the Tar dimer induced both significant piston-like downward movements of the alpha4 helix and strong relative rotations of the two Tar monomers, while binding of an antagonist or the symmetric binding of two attractant molecules to a Tar dimer suppresses both modes. The anti-symmetric effects of the relative rotation mode also explained the negative cooperativity between the two binding pockets. Our results suggest a mechanism of coupled rotation and piston-like motion for bacterial chemoreceptor signaling. PMID- 25728262 TI - Supplementing factual information with patient narratives in the cancer screening context: a qualitative study of acceptability and preferences. AB - OBJECTIVE: To explore people's responses to narrative information in the context of colorectal cancer screening. DESIGN: Nineteen in-depth interviews were conducted with men and women (aged 45-59). Participants were given two types of colorectal screening information to read: factual and narrative. Participants gave their views on both types of information. Data were analysed using Framework Analysis. RESULTS: The most frequent responses to the narrative information were that they were reassuring, made colorectal screening more vivid, participants could relate to the people in the stories and they liked the range of narratives presented. Despite the narrative information being seen as more persuasive by some, this was not regarded as manipulative or negative. Both types of information were seen as equally credible. Participants felt a combination of facts and narratives would be useful when considering an offer of colorectal cancer screening. CONCLUSION: Overall, participants were positive about the addition of narrative information to the currently provided factual information about colorectal cancer screening. Supplementing existing factual information with narrative information may provide participants with a more complete understanding of participation in colorectal cancer screening when considering an offer to be screened. PMID- 25728263 TI - Isolated ventriculomegaly on prenatal ultrasound: what does fetal MRI add? AB - INTRODUCTION: Cerebral ventriculomegaly is one of the most commonly detected fetal anomalies at the midtrimester ultrasound. Current evidence suggests that magnetic resonance imaging (MRI) is indicated when the isolated ventriculomegaly (IVM) on ultrasound is severe (>15 mm), but there is less agreement when IVM is mild or moderate (10-15 mm). The current study aimed to determine the frequency and nature of additional findings on MRI in IVM and their relationship to the severity of VM and gestational age. METHODS: Data were gathered prospectively from all pregnant women with ultrasound-diagnosed IVM referred for MRI between November 2006 and February 2013. Cases with IVM and no other suspected cranial abnormality on a tertiary ultrasound performed at our institution, at or after 20 weeks gestation, were included. RESULTS: Of the 59 fetuses with unilateral or bilateral IVM, additional findings were seen on MRI in 10 cases (17%) and half of these findings were identified in fetuses with mild IVM. Five of 40 (12.5%) fetuses with mild IVM had additional findings and 3/5 (60%) were potentially clinically significant. No additional abnormalities were identified in fetuses less than or equal to 24 weeks gestation with mild or moderate IVM. There was no statistically significant relationship between gestational age and additional findings on MRI in mild IVM. Callosal and septum pellucidum lesions, periventricular abnormalities and malformations of cortical development accounted for all of the significant additional findings. CONCLUSION: This study helps to inform referral of pregnant women with a fetus who has IVM for prenatal MRI. PMID- 25728264 TI - Auger ionization beats photo-oxidation of semiconductor quantum dots: extended stability of single-molecule photoluminescence. AB - Despite the bright and tuneable photoluminescence (PL) of semiconductor quantum dots (QDs), the PL instability induced by Auger recombination and oxidation poses a major challenge in single-molecule applications of QDs. The incomplete information about Auger recombination and oxidation is an obstacle in the resolution of this challenge. Here, we report for the first time that Auger ionized QDs beat self-sensitized oxidation and the non-digitized PL intensity loss. Although high-intensity photoactivation insistently induces PL blinking, the transient escape of QDs into the ultrafast Auger recombination cycle prevents generation of singlet oxygen ((1) O2 ) and preserves the PL intensity. By the detection of the NIR phosphorescence of (1) O2 and evaluation of the photostability of single QDs in aerobic, anaerobic, and (1) O2 scavenger-enriched environments, we disclose relations of Auger ionization and (1) O2 -mediated oxidation to the PL stability of single QDs, which will be useful during the formulation of QD-based single-molecule imaging tools and single-photon devices. PMID- 25728265 TI - Association between pneumococcal pneumonia and venous thromboembolism in hospitalized patients: A nationwide population-based study. AB - BACKGROUND AND OBJECTIVES: This was a nationwide population-based retrospective cohort study to investigate the risk of developing deep-vein thrombosis (DVT) and pulmonary embolism (PE) in patients with a pneumococcal pneumonia. METHODS: We analysed data from 1998 to 2010 from the Taiwan National Health Insurance Database. The follow-up period was extended to the end of 2011. We identified patients with pneumococcal pneumonia and selected a comparison cohort matched for age, sex and diagnosis year at a ratio of one pneumococcal pneumonia patient to four control patients. We analysed the risks of DVT and PE by using Cox proportional hazards regression models, including gender, age and comorbidities. RESULTS: In total, 18,928 pneumococcal pneumonia patients and 75,712 controls were included in the study. The risks of developing DVT and PE were 1.78-fold (95% CI: 1.39-2.28) and 1.97-fold (95% CI: 1.43-2.72), respectively, in patients with pneumococcal pneumonia compared to the control cohort after adjusting for age, gender and comorbidities. The increased risks of DVT and PE were significant in patients who exhibited any comorbidity. The incidences of DVT and PE were highest in the first 4 weeks after pneumonia and remained slightly elevated from 13 weeks to 2 years after acute infection. CONCLUSION: Pneumococcal pneumonia should be considered a risk factor for DVT and PE, even after the patient has recovered from the acute infection. PMID- 25728266 TI - [Commitment of primary care to gender violence. Have we met the challenge?]. PMID- 25728267 TI - A mass spectrometry platform for a streamlined investigation of proteasome integrity, posttranslational modifications, and inhibitor binding. AB - The proteasome is responsible for the majority of protein degradation within eukaryotic cells and proteasome inhibitors have gained blockbuster status as anticancer drugs. Here, we introduce an analytical platform comprising reverse phase chromatography, intact protein mass spectrometry, and customized data analysis that allows a streamlined investigation of proteasome integrity and posttranslational modifications. We report the complete mass spectrometric assignment of all subunits of the yeast core particle, as well as of the human constitutive 20S proteasome and the human immunoproteasome, including phosphorylated isoforms of alpha7. Importantly, we found several batches of commercially available immunoproteasome to also contain constitutive catalytic subunits. Moreover, we applied the method to study the binding mechanisms of proteasome inhibitors, both validating the approach and providing a direct readout of subunit preferences complementary to biochemical methods. Collectively, our platform facilitates an easy, reliable and comprehensive detection of different types of covalent modifications on multisubunit protein complexes with high accuracy. PMID- 25728268 TI - Converting a Staphylococcus aureus toxin into effective cyclic pseudopeptide antibiotics. AB - Staphylococcus aureus produces peptide toxins that it uses to respond to environmental cues. We previously characterized PepA1, a peptide toxin from S. aureus, that induces lytic cell death of both bacterial and host cells. That led us to suggest that PepA1 has an antibacterial activity. Here, we demonstrate that exogenously provided PepA1 has activity against both Gram-positive and Gram negative bacteria. We also see that PepA1 is significantly hemolytic, thus limiting its use as an antibacterial agent. To overcome these limitations, we converted PepA1 into nonhemolytic derivatives. Our most promising derivative is a cyclic heptapseudopeptide with inconsequential toxicity to human cells, enhanced stability in human sera, and sharp antibacterial activity. Mechanistically, linear and helical PepA1 derivatives form pores at the bacterial and erythrocyte surfaces, while the cyclic peptide induces bacterial envelope reorganization, with insignificant action on the erythrocytes. Our work demonstrates that bacterial toxins might be an attractive starting point for antibacterial drug development. PMID- 25728269 TI - Global analysis of protein N-myristoylation and exploration of N myristoyltransferase as a drug target in the neglected human pathogen Leishmania donovani. AB - N-Myristoyltransferase (NMT) modulates protein function through the attachment of the lipid myristate to the N terminus of target proteins, and is a promising drug target in eukaryotic parasites such as Leishmania donovani. Only a small number of NMT substrates have been characterized in Leishmania, and a global picture of N-myristoylation is lacking. Here, we use metabolic tagging with an alkyne functionalized myristic acid mimetic in live parasites followed by downstream click chemistry and analysis to identify lipidated proteins in both the promastigote (extracellular) and amastigote (intracellular) life stages. Quantitative chemical proteomics is used to profile target engagement by NMT inhibitors, and to define the complement of N-myristoylated proteins. Our results provide new insight into the multiple pathways modulated by NMT and the pleiotropic effects of NMT inhibition. This work constitutes the first global experimental analysis of protein lipidation in Leishmania, and reveals the extent of NMT-related biology yet to be explored for this neglected human pathogen. PMID- 25728270 TI - Recent Y chromosome divergence despite ancient origin of dioecy in poplars (Populus). AB - All species of the genus Populus (poplar, aspen) are dioecious, suggesting an ancient origin of this trait. Despite some empirical counter examples, theory suggests that nonrecombining sex-linked regions should quickly spread, eventually becoming heteromorphic chromosomes. In contrast, we show using whole-genome scans that the sex-associated region in Populus trichocarpa is small and much younger than the age of the genus. This indicates that sex determination is highly labile in poplar, consistent with recent evidence of 'turnover' of sex-determination regions in animals. We performed whole-genome resequencing of 52 P. trichocarpa (black cottonwood) and 34 Populus balsamifera (balsam poplar) individuals of known sex. Genomewide association studies in these unstructured populations identified 650 SNPs significantly associated with sex. We estimate the size of the sex-linked region to be ~100 kbp. All SNPs significantly associated with sex were in strong linkage disequilibrium despite the fact that they were mapped to six different chromosomes (plus 3 unmapped scaffolds) in version 2.2 of the reference genome. We show that this is likely due to genome misassembly. The segregation pattern of sex-associated SNPs revealed this to be an XY sex determining system. Estimated divergence times of X and Y haplotype sequences (6 7 Ma) are much more recent than the divergence of P. trichocarpa (poplar) and Populus tremuloides (aspen). Consistent with this, in P. tremuloides, we found no XY haplotype divergence within the P. trichocarpa sex-determining region. These two species therefore have a different genomic architecture of sex, suggestive of at least one turnover event in the recent past. PMID- 25728271 TI - CHF5074 (CSP-1103) stabilizes human transthyretin in mice humanized at the transthyretin and retinol-binding protein loci. AB - Familial amyloidotic polyneuropathy is one type of protein misfolding disease. Transthyretin (TTR) tetramer dissociation is the limiting step for amyloid fibril formation. CHF5074 (CSP-1103) stabilizes TTR tetramer in vitro by binding to the T4 binding site. Here, we used three strains of double humanized mice (mTtr(hTTRVal30/hTTRVal30), mTtr(hTTRVal30/hTTRMet30), and mTtr(hTTRMet30/hTTRMet30)) to assess whether CHF5074 stabilizes TTR tetramers in vivo. Treatment of mice with CHF5074 increased serum TTR levels by stabilizing TTR tetramers. Although the binding affinities of CHF5074 and diflunisal with TTRMet30 were similar, CHF5074 bound TTRVal30 more strongly than did diflunisal, suggesting the potent TTR-stabilizing activity of CHF5074. PMID- 25728272 TI - Mutational analyses of YqjA, a Tvp38/DedA protein of E. coli. AB - Membrane proteins of the DedA/Tvp38 protein family are involved in membrane integrity and virulence of pathogenic organisms. However, the structure and exact function of any member of this large protein family are still unclear. In the present study we analyzed the functional and structural properties of a DedA homolog. Purified YqjA variants from Escherichia coli are detectable in different oligomeric states and specific homo-interaction of YqjA monomers in the membrane were confirmed by formation of a disulfide bond in the C-terminal transmembrane helix. Moreover, alanine scanning mutagenesis exhibited different interaction sites crucial for YqjA activity vs. dimer formation. PMID- 25728273 TI - MicroRNA-575 targets BLID to promote growth and invasion of non-small cell lung cancer cells. AB - This study was designed to detect miR-575 expression and function in non-small cell lung cancer (NSCLC). A higher expression of miR-575 in NSCLC tissues was observed compared with adjacent non-neoplastic tissues. Furthermore, re introduction of miR-575 significantly promoted cell proliferation, migration, and invasion in the NSCLC line. Moreover, we showed that BLID is negatively regulated by miR-575 at the posttranscriptional level, via a specific target site within the 3'UTR. Overexpression of BLID counteracted miR-575-induced proliferation and invasion in NSCLC cells. The expression of BLID is frequently downregulated in NSCLC tumors and cell lines and inversely correlates with miR-575 expression. The findings of this study contribute to the current understanding of the functions of miR-575 in NSCLC. PMID- 25728274 TI - Structural elements responsible for the glucosidic linkage-selectivity of a glycoside hydrolase family 13 exo-glucosidase. AB - Glycoside hydrolase family 13 contains exo-glucosidases specific for alpha-(1->4) and alpha-(1->6)-linkages including alpha-glucosidase, oligo-1,6-glucosidase, and dextran glucosidase. The alpha-(1->6)-linkage selectivity of Streptococcus mutans dextran glucosidase was altered to alpha-(1->4)-linkage selectivity through site-directed mutations at Val195, Lys275, and Glu371. V195A showed 1300 fold higher kcat/Km for maltose than wild-type, but its kcat/Km for isomaltose remained 2-fold higher than for maltose. K275A and E371A combined with V195A mutation only decreased isomaltase activity. V195A/K275A, V195A/E371A, and V195A/K275A/E371A showed 27-, 26-, and 73-fold higher kcat/Km for maltose than for isomaltose, respectively. Consequently, the three residues are structural elements for recognition of the alpha-(1->6)-glucosidic linkage. PMID- 25728275 TI - The histone deacetylase Rpd3/Sin3/Ume6 complex represses an acetate-inducible isoform of VTH2 in fermenting budding yeast cells. AB - The tripartite Rpd3/Sin3/Ume6 complex represses meiotic isoforms during mitosis. We asked if it also controls starvation-induced isoforms. We report that VTH1/VTH2 encode acetate-inducible isoforms with extended 5'-regions overlapping antisense long non-coding RNAs. Rpd3 and Ume6 repress the long isoform of VTH2 during fermentation. Cells metabolising glucose contain Vth2, while the protein is undetectable in acetate and during sporulation. VTH2 is a useful model locus to study mechanisms implicating promoter directionality, lncRNA transcription and post-transcriptional control of gene expression via 5'-UTRs. Since mammalian genes encode transcript isoforms and Rpd3 is conserved, our findings are relevant for gene expression in higher eukaryotes. PMID- 25728276 TI - Phosphorylation of Serine422 increases the stability and transactivation activities of human Osterix. AB - Osterix (Osx) is an essential regulator for osteoblast differentiation and bone formation. Although phosphorylation has been reported to be involved in the regulation of Osx activity, the precise underlying mechanisms remain to be elucidated. Here we identified S422 as a novel phosphorylation site of Osx and demonstrated that GSK-3beta interacted and co-localized with Osx. GSK-3beta increased the stability and transactivation activity of Osx through phosphorylation of the newly identified site. These findings expanded our understanding of the mechanisms of posttranslational regulation of Osx and the role of GSK-3beta in the control of Osx transactivation activity. PMID- 25728277 TI - Transmembrane protein 173 inhibits RANKL-induced osteoclast differentiation. AB - Tmem173 was identified as a growth inhibitor associated with major histocompatibility complex (MHC) class II and a potential stimulator for IFN beta, an innate immune inducer and a negative feedback controller for RANKL induced osteoclast differentiation of monocytic macrophage cells. In this study, we confirmed that transmembrane protein 173 (Tmem173) overexpression inhibited the expression of osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, and matrix metalloproteinase-9 (MMP-9), as well as bone resorption pit formation in RANKL-treated RAW 264.7 cells. Activation of osteoclast-specific transcription factors, c-Fos and nuclear factor of activated T cells cytoplasmic-1 (NFATc1), and RANKL-induced activation of ERK were also down-regulated by Tmem173 overexpression. Collectively, these results suggest that Tmem173 plays a regulatory role in RANKL-RANK-mediated signaling in osteoclastogenesis. PMID- 25728278 TI - MiR-193b regulates early chondrogenesis by inhibiting the TGF-beta2 signaling pathway. AB - Cartilage generation and degradation are regulated by miRNAs. Our previous study has shown altered expression of miR-193b in chondrogenic human adipose-derived mesenchymal stem cells (hADSCs). In the current study, we investigated the role of miR-193b in chondrogenesis and cartilage degradation. Luciferase reporter assays showed that miR-193b targeted seed sequences of the TGFB2 and TGFBR3 3' UTRs. MiR-193b suppressed the expression of early chondrogenic markers in chondrogenic ATDC5 cells, and TNF-alpha expression in IL-1b-induced PMCs. In conclusion, MiR-193b may inhibit early chondrogenesis by targeting TGFB2 and TGFBR3, and may regulate inflammation by repressing TNF-alpha expression in inflamed chondrocytes. PMID- 25728279 TI - A cell-based screening system for anti-influenza A virus agents. AB - Emerging of drug resistant influenza A virus (IAV) has been a big challenge for anti-IAV therapy. In this study, we describe a relatively easy and safe cell based screening system for anti-IAV replication inhibitors using a non replicative strain of IAV. A nickel (II) complex of polyhydroxybenzaldehyde N4 thiosemicarbazone (NiPT5) was recently found to exhibit anti-inflammatory activity in vivo and in vitro. NiPT5 impedes the signaling cascades that lead to the activation of NF-kappaB in response to different stimuli, such as LPS and TNFalpha. Using our cell-based screening system, we report that pretreating cells with NiPT5 protects cells from influenza A virus (IAV) and vesicular stomatitis virus (VSV) infection. Furthermore, NiPT5 inhibits replication of IAV by inhibiting transcription and translation of vRNAs of IAV. Additionally, NiPT5 reduces IAV-induced type I interferon response and cytokines production. Moreover, NiPT5 prevents activation of NF-kappaB, and IRF3 in response to IAV infection. These results demonstrate that NiPT5 is a potent antiviral agent that inhibits the early phase of IAV replication. PMID- 25728280 TI - Disruption of photoautotrophic intertidal mats by filamentous fungi. AB - Ring-like structures, 2.0-4.8 cm in diameter, observed in photosynthetic microbial mats on the Wadden Sea island Schiermonnikoog (the Netherlands) showed to be the result of the fungus Emericellopsis sp. degrading the photoautotrophic top layer of the mat. The mats were predominantly composed of cyanobacteria and diatoms, with large densities of bacteria and viruses both in the top photosynthetic layer and in the underlying sediment. The fungal attack cleared the photosynthetic layer; however, no significant effect of the fungal lysis on the bacterial and viral abundances could be detected. Fungal-mediated degradation of the major photoautotrophs could be reproduced by inoculation of non-infected mat with isolated Emericellopsis sp., and with an infected ring sector. Diatoms were the first re-colonizers followed closely by cyanobacteria that after about 5 days dominated the space. The study demonstrated that the fungus Emericellopsis sp. efficiently degraded a photoautotrophic microbial mat, with potential implications for mat community composition, spatial structure and productivity. PMID- 25728281 TI - Probing the effect of an inhibitor of an ATPase domain of Hsc70 on clathrin mediated endocytosis. AB - Hsc70 is known to be involved in clathrin-mediated endocytosis (CME) by which cells take up various extracellular materials. More specifically, this protein promotes the disassembly of clathrin-coated vesicles (CCVs) by directly binding to clathrin during CME. As the ATPase activity of Hsc70 is required for its association with clathrin, we have investigated the effect of an inhibitor (apoptozole, Az) of an ATPase domain of Hsc70 on CME. The results of biochemical studies show that Az binds to Hsc70 and Hsp70 without binding to other types of heat shock proteins. Structure-activity relationship studies provide information on the structural features responsible for the inhibition of the ATPase activity of Hsc70. The results obtained from cell experiments reveal that Az disrupts the interaction of Hsc70 with clathrin in cells, thereby leading to the accumulation of transferrin in CCVs and suppression of release of free Fe(3+) from CCVs during transferrin receptor-mediated endocytosis. PMID- 25728282 TI - Overall survival according to type of surgery in young (<=40 years) early breast cancer patients: A systematic meta-analysis comparing breast-conserving surgery versus mastectomy. AB - OBJECTIVES: Young age is an independent risk factor for local recurrence after breast conserving surgery (BCS) and whole breast radiotherapy (WBRT) for breast cancer. The aim of this study was to carry out a systematic meta-analysis to address the issue as to whether type of surgery might have an impact on overall survival (OS) of young patients with early breast cancer. MATERIAL AND METHODS: We summarized six studies comparing OS between BCS + WBRT vs. mastectomy in young patients (<=40 years) with T1-T2 N0-N + M0 breast cancer. Primary endpoint was OS or distant metastasis free survival (DMFS). Only studies with fully adjusted Hazard Ratios (HR) were analyzed. Summary HRs were calculated through random effects models. We investigated publication bias and heterogeneity by means of sensitivity analyses and meta-regression models. RESULTS: Five population-based studies and a pooled study of two clinical trials, for a total of 22598 patients 40 years old or younger, were considered: 10898 patients underwent BCS and 11700 underwent mastectomy. After all the adjustments, including nodal status and tumor size, no difference in risk of death was found between the two groups (10% not significant risk reduction in patients who underwent BCS compared to mastectomy; summary HR = 0.90; 95%CI: 0.81 to 1.00). Between-study heterogeneity was not statistically significant (I(2) = 34% and Chi-square P = 0.15). Heterogeneity investigation did not find any variable influencing results. No indication for publication bias was found (P-value = 0.37). Excluding the only study presenting DMFS the results did not change (HR = 0.88; 95%CI: 0.78 to 1.01). CONCLUSION: Considering all the limitations, from the present meta-analysis carried out on 22598 patients it appears unlikely that mastectomy provides better OS compared to BCS + WBRT in early breast cancer patients aged 40 years or younger. PMID- 25728283 TI - Prevalence and clinical outcomes of young breast cancer (YBC) patients according to intrinsic breast cancer subtypes: Single institutional experience in Korea. AB - The purpose of our study was to investigate and identify comprehensively the clinicopathological features and long-term outcome of young breast cancer (YBC) according to intrinsic subtype. We analyzed clinical and pathological characteristics of 2844 women who were diagnosed with invasive breast cancer from 2000 to 2007 and the treatment outcomes by age at diagnosis. The median age of the patients was 46 years (range, 21-83 years), and we divided them into three age group: <=35 years (Group 1), 36-50 years (Group 2), and >50 years (Group 3). During a median follow-up of 100 months, the 5-year recurrence-free survival rate (RFSR) and overall survival rate (OSR) were 90.8% and 94.6%, respectively. The 10 year estimated RFSR and OSR were 81.9% and 86.9%, respectively. The prognosis of TN subtype appeared not to be worse than that of other subtypes in Group 1. In Group 1 alone (<=35 years), subtype was not identified as an independent risk factor for distant recurrence-free survival (DRFS) in a Cox-regression multivariate model (hazard ratio, 0.85; 95% CI, 0.68-1.06; p = 0.148). This analysis revealed a very high prevalence of YBC in this cohort. The poor outcomes of YBC patients might result from an increased frequency of triple negative (TN)/HER2 subtypes and the more aggressive clinical behavior of ER-positive tumors compared with older patients. Further research to elucidate the biologic difference of the ER+ tumors of YBC patients is warranted. PMID- 25728284 TI - CDK2 phosphorylation regulates the protein stability of KLF10 by interfering with binding of the E3 ligase SIAH1. AB - Downregulation of multiple cell cycle-regulatory molecules is a dominant event in TGF-beta1-mediated growth inhibition of human carcinoma cells. It is known that KLF10 mimics the anti-proliferative and apoptotic effects that TGF-beta1 has on epithelial cell growth and the growth of various tumor cells; based on these findings it is considered as a tumor suppressor. KLF10 protein expression is tightly associated with cell cycle-dependent events. However, the regulatory mechanism and its biological meaning have not been identified. In this study, we have demonstrated that KLF10 is a substrate of CDK2/cyclin E and can be phosphorylated. We also have shown that KLF10 efficiently binds to CDK2, while binding much less to CDK4, and displaying no binding to Cdk6. Using mass spectrometry, site direct mutagenesis, in vitro kinase assays and depletion assays, we have established that CDK2 phosphorylates Ser206, which subsequently affects the steady state level of KLF10 in cells. Our studies have also proved that CDK2 up-regulates the protein level of KLF10 through reducing its association with SIAH1, a KLF10 E3-ubiqutin ligase involved in proteasomal degradation. Taken all together, these findings indicate that CDK2-dependent phosphorylation regulates KLF10 stability and that this affects the role of KLF10 in cell. PMID- 25728285 TI - Copayments and Emergency Department Use Among Adult Medicaid Enrollees. AB - A number of state Medicaid programs have recently proposed or implemented new or increased copayments for nonemergent emergency department (ED) visits. Evidence suggests that copayments generally reduce the level of healthcare utilization, although there is little specific evidence regarding the effectiveness of copayments in reducing nonurgent ED use among Medicaid enrollees or other low income populations. Encouraging efficient and appropriate use of healthcare services will be of particular importance for Medicaid programs as they expand under the Patient Protection and Affordable Care Act. This analysis uses national data from 2001 to 2009 to examine the effect of copayments on nonurgent ED utilization among nonelderly adult enrollees. We find that visits among Medicaid enrollees in state-years where a copayment is in place are significantly less likely to be for nonurgent reasons. Our findings suggest that copayments may be an effective tool for reducing use of the ED for nonurgent care. PMID- 25728287 TI - The visual cliff's forgotten menagerie: rats, goats, babies, and myth-making in the history of psychology. AB - Eleanor Gibson and Richard Walk's famous visual cliff experiment is one of psychology's classic studies, included in most introductory textbooks. Yet the famous version which centers on babies is actually a simplification, the result of disciplinary myth-making. In fact the visual cliff's first subjects were rats, and a wide range of animals were tested on the cliff, including chicks, turtles, lambs, kid goats, pigs, kittens, dogs, and monkeys. The visual cliff experiment was more accurately a series of experiments, employing varying methods and a changing apparatus, modified to test different species. This paper focuses on the initial, nonhuman subjects of the visual cliff, resituating the study in its original experimental logic, connecting it to the history of comparative psychology, Gibson's interest in comparative psychology, as well as gender-based discrimination. Recovering the visual cliff's forgotten menagerie helps to counter the romanticization of experimentation by focusing on the role of extrascientific factors, chance, complexity, and uncertainty in the experimental process. PMID- 25728288 TI - X-ray visible and uniform alginate microspheres loaded with in situ synthesized BaSO4 nanoparticles for in vivo transcatheter arterial embolization. AB - The lack of noninvasive tracking and mapping the fate of embolic agents has restricted the development and further applications of the transcatheter arterial embolization (TAE) therapy. In this work, inherent radiopaque embolic material, barium alginate (ALG) microspheres loaded with in situ synthesized BaSO4 (denoted as BaSO4/ALG microspheres), have been synthesized by a one-step droplet microfluidic technique. One of the advantages of our microfluidic approach is that radiopaque BaSO4 is in the form of nanoparticles and well dispersed inside ALG microspheres, thereby greatly enhancing the imaging quality. The crystal structure of in situ synthesized BaSO4 nanoparticles in ALG microspheres is confirmed by X-ray diffraction analysis. Results of in vitro and in vivo assays from digital subtraction angiography and computed tomography scans demonstrate that BaSO4/ALG microspheres possess excellent visibility under X-ray. Histopathological analysis verifies that the embolic efficacy of BaSO4/ALG microspheres is similar to that of commercially available alginate microsphere embolic agents. Furthermore, the visibility of radiopaque BaSO4/ALG microspheres under X-ray promises the direct detection of the embolic efficiency and position of embolic microspheres after embolism, which offers great promises in direct real-time in vivo investigations for TAE. PMID- 25728286 TI - Identification of geographic clustering and regions spared by cutaneous T-cell lymphoma in Texas using 2 distinct cancer registries. AB - BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) (mycosis fungoides and its leukemic variant, Sezary syndrome) are rare malignancies. Reports of the occurrence of mycosis fungoides in married couples and families raise the possibility of an environmental trigger for this cancer. Although it has been suggested that CTCL arises from inappropriate T-cell stimulation, to the authors' knowledge no preventable trigger has been identified to date. METHODS: Using region, zip code, age, sex, and ethnicity, the authors analyzed the demographic data of 1047 patients from Texas who were seen in a CTCL clinic at The University of Texas MD Anderson Cancer Center during 2000 through 2012 (the MDACC database) and 1990 patients who were recorded in the population-based Texas Cancer Registry between 1996 and 2010. Subsequently, data from both databases were cross-analyzed and compared. RESULTS: The current study findings, based on the MDACC database, documented geographic clustering of patients in 3 communities within the Houston metropolitan area, in which CTCL incidence rates were 5 to 20 times higher than the expected population rate. Analysis of the Texas Cancer Registry database defined the CTCL population rate for the state to be 5.8 cases per million individuals per year (95% confidence interval, 5.5-6.0 per million individuals per year), thus confirming the observations from the MDACC database and further highlighting additional areas of geographic clustering and regions spared from CTCL in Texas. CONCLUSIONS: The current study documented geographic clustering of CTCL cases in Texas and argued for the existence of yet unknown external causes/triggers for this rare malignancy. PMID- 25728289 TI - Comparison between Ki-67 index and mitotic index for predicting outcome in canine mast cell tumours. AB - OBJECTIVES: To assess correlation between Ki67 index and mitotic index and determine which more accurately predicts survival in canine mast cell tumours. METHODS: Retrospective analysis of cases from three UK referral hospitals. Correlation between Ki67 index and mitotic index was assessed and survival analysis performed. RESULTS: A total of 162 dogs were included: 57 dogs died with 37 due to mast cell tumour. Correlation between Ki67 index and mitotic index was moderate, while the agreement was poor. A high Ki67 index was considered sensitive (86 . 5%) at predicting mast cell tumour-related death, but poorly specific (57 . 9%). Mitotic index(>5) was poorly sensitive (32 . 4%), but highly specific (96%). A mitotic index of e2 had a 75 . 7% sensitivity and an 80 . 0% specificity. Ki67 index showed a statistically significant survival difference within the mitotic index <2 (P = 0 . 009) group. Ki67 index did not predict survival rate in tumours with mitotic index of e2. CLINICAL RELEVANCE: Correlation between Ki67 and mitotic index is moderate. High mitotic index accurately predicted death, but many dogs with low mitotic index also died. Low Ki67 accurately predicted survival, but high Ki67 should not be considered a poor prognostic indicator. A three-tier mitotic index assessment may more accurately predict death due to mast cell tumour. PMID- 25728290 TI - Paul of Aegina's surgical instruments: a complete surgical instrumentarium in the seventh century AD. AB - BACKGROUND: Although current progress in surgical instruments is oriented towards stapler devices, minimally invasive instrumentation and advanced cautery tools, it definitely seems intriguing to determine what instruments were used in antiquity and to appraise their use. Most adequate information can be retrieved from manuscripts of early medical authors, of whom Paul of Aegina (AD 625-690), also being a most important surgeon, is the most recent. The aim of this study is to present surgical instruments used in his practice. METHODS: Surgical instruments mentioned in the original Greek text of his monumental work named Epitome of Medicine were sought using computer software. Further, similar research was performed on other significant manuscripts of earlier Greek medical writers to determine whether some of the instruments were exclusively mentioned by Paul of Aegina. RESULTS: In total, 121 different surgical instruments were identified and described in detail in the Epitome of Medicine. Thirty-three instruments (27%) were exclusively reported by Paul of Aegina. CONCLUSIONS: In antiquity a large number of surgical instruments were already being used. Paul of Aegina described in detail a large variety of fine, as well as a substantial number of, original surgical instruments, which he himself used in a wide spectrum of surgical operations. PMID- 25728291 TI - Detection of functional hydrogen-bonded water molecules with protonated/deprotonated key carboxyl side chains in the respiratory enzyme ba3 oxidoreductase. AB - The protonation/deprotonation of active carboxyl side chains by water networks forming the proton loading and exit sites in proteins are important steps in protein catalysis. An excellent system to study such basic principles is the heme copper ba3 from T. thermophilus because it utilizes one proton input channel and it delivers protons to the active site for both O2 chemistry and proton pumping. We report the interaction of the heme a3 Fe propionate-A and the Asp372-His376 pair which forms the valve for the exit pathway for the protons with internal water molecules in ba3 oxidoreductase by light minus dark FTIR spectroscopy in conjunction with H2O/H2(18)O/D2O exchange. The proton loading site consists of several water molecules including w941/w946 which are H-bonded to propionate-A H(+), acting as the Zundel cation. The detection of two H2(18)O sensitive bands at 3640 and 3634 cm(-1) shows the existence of weakly H-bonded water molecules. PMID- 25728292 TI - Cangrelor for the treatment of arterial thrombosis: pharmacokinetics/pharmacodynamics and clinical data. AB - INTRODUCTION: Dual antiplatelet therapy is the standard of care for patients with acute coronary syndromes or with recent coronary stents implantation. P2Y12 receptor antagonists have shown to reduce the risk of recurrent ischemic events among these patients, at the expense of an increased risk of bleeding. Cangrelor is a novel, intravenous, short-acting, reversible platelet P2Y12 inhibitor, which has been evaluated for the treatment of arterial thrombosis. AREAS COVERED: Studies on the pharmacological characteristics of cangrelor and clinical trials were retrieved by a PubMed literature search. EXPERT OPINION: Cangrelor has been tested in patients with coronary artery diseases undergoing percutaneous coronary intervention and as bridging therapy for patients undergoing coronary artery bypass graft. The rapid peak of action allows a fast and complete inhibition of platelet aggregation; the rapid offset is advantageous in case of bleeding complications; and finally, the intravenous administration also makes this drug suitable for patients unable to consume oral medications. Unfortunately, the large clinical trials evaluating cangrelor in percutaneous coronary intervention did not show superiority to the standard antiplatelet therapy, and its future use in this setting still needs to be better assessed. Conversely, when used as bridging therapy to coronary artery bypass graft, cangrelor showed promising results. PMID- 25728293 TI - Ultrathin platinum nanowires grown on single-layered nickel hydroxide with high hydrogen evolution activity. AB - Design and synthesis of effective electrocatalysts for hydrogen evolution reaction in alkaline environments is critical to reduce energy losses in alkaline water electrolysis. Here we report a hybrid nanomaterial comprising of one dimensional ultrathin platinum nanowires grown on two-dimensional single-layered nickel hydroxide. Judicious surface chemistry to generate the fully exfoliated nickel hydroxide single layers is explored to be the key for controllable growth of ultrathin platinum nanowires with diameters of about 1.8 nm. Impressively, this hybrid nanomaterial exhibits superior electrocatalytic activity for hydrogen evolution reaction in alkaline solution, which outperforms currently reported catalysts, and the obviously improved catalytic stability. We believe that this work may lead towards the development of single-layered metal hydroxide-based hybrid materials for applications in catalysis and energy conversion. PMID- 25728294 TI - A simple iridicycle catalyst for efficient transfer hydrogenation of N heterocycles in water. AB - A cyclometalated iridium complex is shown to catalyse the transfer hydrogenation of various nitrogen heterocycles, including but not limited to quinolines, isoquinolines, indoles and pyridinium salts, in an aqueous solution of HCO2H/HCO2Na under mild conditions. The catalyst shows excellent functional-group compatibility and high turnover number (up to 7500), with catalyst loadings as low as 0.01 mol % being feasible. Mechanistic investigation of the quinoline reduction suggests that the transfer hydrogenation proceeds via both 1,2- and 1,4 addition pathways, with the catalytic turnover being limited by the step of hydride transfer. PMID- 25728295 TI - Observation of lens aberrations for high resolution electron microscopy II: simple expressions for optimal estimates. AB - This paper lists simple closed-form expressions estimating aberration coefficients (defocus, astigmatism, three-fold astigmatism, coma / misalignment, spherical aberration) on the basis of image shift or diffractogram shape measurements as a function of injected beam tilt. Simple estimators are given for a large number of injected tilt configurations, optimal in the sense of least squares fitting of all the measurements, and so better than most reported previously. Standard errors are given for most, allowing different approaches to be compared. Special attention is given to the measurement of the spherical aberration, for which several simple procedures are given, and the effect of foreknowledge of this on other aberration estimates is noted. Details and optimal expressions are also given for a new and simple method of analysis, requiring measurements of the diffractogram mirror axis direction only, which are simpler to make than the focus and astigmatism measurements otherwise required. PMID- 25728296 TI - Probing buried magnetic interface structure with the quantum size effect in spin dependent electron reflectivity. AB - The quantum size effect (QSE) in electron reflectivity from Fe thin films grown on a W(110) surface precovered with a two monolayer Cu film has been investigated using spin polarized low energy electron microscopy. Spin-dependent QSE-induced oscillations in the reflected intensity occur with energy and film thickness. The series of intensity peaks that is observed identifies spin-dependent quantum well resonances in the Fe film that are sensitive to electronic band structure and details of the buried interface. Information about the spin-dependent unoccupied bands of the Fe film in the GammaNu direction normal to the film plane is obtained by analyzing the observed quantum well resonance conditions. The spin split bands that are determined are uniformly shifted downward by 1.7 eV compared to bulk-like bands determined previously in Fe films on a bare W(110) substrate by the same method. Evidence is also obtained that the buried interface that defines the thin film quantum well boundary is located one layer above the W(110) surface. These results suggest that the Cu layer in direct contact with the substrate remains largely intact, but the weakly-bound second Cu layer mixes or segregates freely. PMID- 25728297 TI - Phytoplankton production systems in a shellfish hatchery: variations of the bacterial load and diversity of vibrios. AB - AIMS: Outbreaks of disease caused by some Vibrio species represent the main production bottleneck in shellfish hatcheries. Although the phytoplankton used as food is one of the main sources of bacteria, studies of the associated bacterial populations, specifically vibrios, are scarce. The aim of the study was the microbiological monitoring of the microalgae as the first step in assessing the risk disease for bivalve cultures. METHODS AND RESULTS: Two phytoplankton production systems were sampled weekly throughout 1-year period in a bivalve hatchery. Quantitative analysis revealed high levels of marine heterotrophic bacteria in both systems throughout the study. Presumptive vibrios were detected occasionally and at low concentrations. In most of the cases, they belonged to the Splendidus and Harveyi clades. CONCLUSIONS: The early detection of vibrios in the microalgae may be the key for a successful bivalve culture. Their abundance and diversity were affected by factors related to the hatchery environment. SIGNIFICANCE AND IMPACT OF THE STUDY: This work represents the first long study where the presence of vibrios was evaluated rigorously in phytoplankton production systems and provides a suitable microbiological protocol to control and guarantee the quality of the algal cultures to avoid the risk of transferring potential pathogens to shellfish larvae and/or broodstock. PMID- 25728298 TI - Old, new, and widely true: The bacteriophage T4 DNA packaging mechanism. AB - DNA packaging into empty viral procapsids by ATP-driven motor proteins applies widely among viruses. Recent fluorescence studies of phage T4 reveal: 1) the small terminase subunit (TerS) synapses pac homologs by a twin ring mechanism to gauge DNA maturation and allow packaging by the large terminase subunit (TerL); 2) translocation of linear DNA is efficient by TerL acting alone; expansion of the procapsid is controlled by the portal-terminase assembly; 3) both ends of the packaged DNA are held at the portal, showing a loop of DNA is packaged; 4) transient spring-like compression of B form to A form-like DNA accompanies translocation; 5) the C-terminal domain of TerL is docked to the portal and moves toward it when stalled; 6) a portal bound resolvase can release stalled Y-DNA compression and allow translocation in vitro; and 7) ATP powered translocation on A form dsDNA is supported by recent hexameric helicase studies. PMID- 25728300 TI - DNA virus uncoating. AB - Virus genomes are condensed and packaged inside stable proteinaceous capsids that serve to protect them during transit from one cell or host organism, to the next. During virus entry, capsid shells are primed and disassembled in a complex, tightly-regulated, multi-step process termed uncoating. Here we compare the uncoating-programs of DNA viruses of the pox-, herpes-, adeno-, polyoma-, and papillomavirus families. Highlighting the chemical and mechanical cues virus capsids respond to, we review the conformational changes that occur during stepwise disassembly of virus capsids and how these culminate in the release of viral genomes at the right time and cellular location to assure successful replication. PMID- 25728299 TI - Poxvirus membrane biogenesis. AB - Poxviruses differ from most DNA viruses by replicating entirely within the cytoplasm. The first discernible viral structures are crescents and spherical immature virions containing a single lipoprotein membrane bilayer with an external honeycomb lattice. Because this viral membrane displays no obvious continuity with a cellular organelle, a de novo origin was suggested. Nevertheless, transient connections between viral and cellular membranes could be difficult to resolve. Despite the absence of direct evidence, the intermediate compartment (ERGIC) between the endoplasmic reticulum (ER) and Golgi apparatus and the ER itself were considered possible sources of crescent membranes. A break through in understanding poxvirus membrane biogenesis has come from recent studies of the abortive replication of several vaccinia virus null mutants. Novel images showing continuity between viral crescents and the ER and the accumulation of immature virions in the expanded ER lumen provide the first direct evidence for a cellular origin of this poxvirus membrane. PMID- 25728301 TI - Toxaphene in the aquatic environment of Greenland. AB - The octa- and nonachlorinated bornanes (toxaphene) CHBs 26, 40, 41, 44, 50 and 62 were analysed in Arctic char (Salvelinus alpinus), shorthorn sculpin (Myoxocephalus scorpius), ringed seal (Pusa hispida) and black guillemot eggs (Cepphus grylle) from Greenland. Despite their high trophic level, ringed seals had the lowest concentrations of these species, with a Sigma6Toxaphene median concentration of 13-20 ng/g lipid weight (lw), suggesting metabolisation. The congener composition also suggests transformation of nona- to octachlorinated congeners. Black guillemot eggs had the highest concentrations (Sigma6Toxaphene median concentration of 971 ng/g lw). Although concentrations were higher in East than in West Greenland differences were smaller than for other persistent organic pollutants. In a circumpolar context, toxaphene had the highest concentrations in the Canadian Arctic. Time trend analyses showed significant decreases for black guillemot eggs and juvenile ringed seals, with annual rates of -5 to -7% for Sigma6Toxaphene. The decreases were generally steepest for CHBs 40, 41 and 44. PMID- 25728302 TI - Daily negative affect and smoking after a self-set quit attempt: The role of dyadic invisible social support in a daily diary study. AB - OBJECTIVES: Social support receipt from one's partner is assumed to be beneficial for successful smoking cessation. However, support receipt can have costs. Recent research suggests that the most effective support is unnoticed by the receiver (i.e., invisible). Therefore, this study examined the association between everyday levels of dyadic invisible emotional and instrumental support, daily negative affect, and daily smoking after a self-set quit attempt in smoker-non smoker couples. METHODS: Overall, 100 smokers (72.0% men, mean age M = 40.48, SD = 9.82) and their non-smoking partners completed electronic diaries from a self set quit date on for 22 consecutive days, reporting daily invisible emotional and instrumental social support, daily negative affect, and daily smoking. RESULTS: Same-day multilevel analyses showed that at the between-person level, higher individual mean levels of invisible emotional and instrumental support were associated with less daily negative affect. In contrast to our assumption, more receipt of invisible emotional and instrumental support was related to more daily cigarettes smoked. CONCLUSIONS: The findings are in line with previous results, indicating invisible support to have beneficial relations with affect. However, results emphasize the need for further prospective daily diary approaches for understanding the dynamics of invisible support on smoking cessation. Statement of contribution What is already known on this subject? Social support receipt from a close other has proven to have emotional costs. According to current studies, the most effective social support is unnoticed by the receiver (i.e., invisible). There is empirical evidence for beneficial effects of invisible social support on affective well-being. What does this study add? Confirming benefits of invisible social support for negative affect in a health behaviour change setting Providing first evidence for detrimental effects of invisible social support on smoking. PMID- 25728303 TI - The relationship between mean platelet volume and varicocele. PMID- 25728304 TI - Relevance of serum nitric oxide levels and the efficacy of selective serotonin reuptake inhibitors treatment on premature ejaculation: decreased nitric oxide is associated with premature ejaculation. PMID- 25728305 TI - Pomphorhynchus laevis (Acanthocephala) from the Sava River basin: New insights into strain formation, mtDNA-like sequences and dynamics of infection. AB - Here we report the genetic variability and presence of mtDNA-like sequences of Pomphorhynchus laevis from the chub, Squalius cephalus, caught at the sampling sites along the Sava River and its tributary the Sutla River in Croatia. Sequences of the cytochrome c oxidase subunit 1 (COI) gene of the recovered P. laevis specimens were used for haplotype network construction and phylogenetic analysis. These analyses showed that some specimens contained mitochondrial-like sequences, and they uncovered the existence of a Sava River basin strain different from known strains of P. laevis. This is the first time that P. laevis has been shown to contain mtDNA-like sequences, suggesting the need to exercise caution during COI analyses of P. laevis using universal primers. Highly conserved sequences of two nuclear markers, the ITS region and 18S rRNA, were not helpful for understanding genetic variability or differentiating strains. Furthermore, analysis of the dynamics of P. laevis infections in S. cephalus from the Sava and Sutla Rivers showed decreased prevalence and abundance at sites with inferior water quality, positive association of parasite abundance with fish size, and no clear association of parasite abundance with fish condition index or sex. PMID- 25728306 TI - Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1). AB - Chromosomal translocation of 2q37.1 just distal to the NPPC gene coding for C type natriuretic peptide (CNP) and subsequent overproduction of CNP have been reported to cause a skeletal overgrowth syndrome. Loeys-Dietz syndrome (LDS) is one of marfanoid overgrowth syndromes, of which subtype IV is caused by haploinsufficiency of transforming growth factor beta 2 (TGFB2). We report on a girl with clinical phenotypes of overgrowth syndrome, including long and slim body habitus, macrodactyly of the big toe, scoliosis, ankle valgus deformity, coxa valga, slipped capital femoral epiphysis, and aortic root dilatation. Karyotyping revealed a balanced chromosomal translocation between 1q41 and 2q37.1, and the breakpoints could be mapped by targeted resequencing analysis. On chromosome 2q37.1, the translocation took place 200,365 bp downstream of NPPC, and serum level of the amino terminal of CNP was elevated. The contralateral site of translocation on chromosome 1q41 disrupted TGFB2 gene, presumed to cause its haploinsufficiency. This case supports the concept that NPPC is overexpressed because of the loss of a specific negative regulatory control in the normal chromosomal location, and demonstrates the effectiveness of targeted resequencing in the mapping of breakpoints. PMID- 25728307 TI - Task complexity modulates pilot electroencephalographic activity during real flights. AB - Most research connecting task performance and neural activity to date has been conducted in laboratory conditions. Thus, field studies remain scarce, especially in extreme conditions such as during real flights. Here, we investigated the effects of flight procedures of varied complexity on the in-flight EEG activity of military helicopter pilots. Flight procedural complexity modulated the EEG power spectrum: highly demanding procedures (i.e., takeoff and landing) were associated with higher EEG power in the higher frequency bands, whereas less demanding procedures (i.e., flight exercises) were associated with lower EEG power over the same frequency bands. These results suggest that EEG recordings may help to evaluate an operator's cognitive performance in challenging real-life scenarios, and thus could aid in the prevention of catastrophic events. PMID- 25728308 TI - Acute Lyme Neuroborreliosis With Transient Hemiparesis and Aphasia. AB - Nervous system involvement in Lyme disease often mimics other conditions and thus represents a diagnostic challenge, especially in an emergency department setting. We report a case of a female teenager presenting with sudden-onset aphasia and transient right-sided faciobrachial hemiplegia, along with headache and agitation. Ischemia, vasculitis, or another structural lesion was excluded by brain imaging. Toxicologic evaluation results were negative. Cerebral perfusion computed tomography and electroencephalography showed left parietotemporal brain dysfunction. Lumbar puncture result, although atypical, suggested bacterial infection and intravenous ceftriaxone was initiated. Finally, microbiological cerebrospinal fluid analysis revealed Lyme neuroborreliosis, showing specific intrathecal antibody production and high level of C-X-C motif chemokine 13. The patient rapidly recovered. To our knowledge, this report for the first time illustrates that acute-onset language and motor symptoms may be directly related to Lyme neuroborreliosis. Neuroborreliosis may mimic other acute neurologic events such as stroke and should be taken into diagnostic consideration even in the absence of classic symptoms and evolution. PMID- 25728309 TI - Defective interfering viruses and their impact on vaccines and viral vectors. AB - Defective interfering particles (DIPs) have been found for many important viral pathogens and it is believed that most viruses generate DIPs. This article reviews the current knowledge of the generation and amplification of DIPs, which possess deletions in the viral genome but retain the ability to replicate in the presence of a complete helper virus. In addition, mechanisms are discussed by which DIPs interfere with the replication of their helper virus leading to the production of mainly progeny DIPs by coinfected cells. Even though DIPs cannot replicate on their own, they are biologically active and it is well known that they have a huge impact on virus replication, evolution, and pathogenesis. Moreover, defective genomes are potent inducers of the innate immune response. Yet, little attention has been paid to DIPs in recent years and their impact on biotechnological products such as vaccines and viral vectors remains elusive in most cases. With a focus on influenza virus, this review demonstrates that DIPs are important for basic research on viruses and for the production of viral vaccines and vectors. Reducing the generation and/or amplification of DIPs ensures reproducible results as well as high yields and consistent product quality in virus production. PMID- 25728310 TI - NIR-triggered drug delivery by collagen-mediated second harmonic generation. AB - Second harmonic generation is a process through which nonlinear materials such as collagen can absorb two photons and scatter one with twice the energy. Collagen upconverts 730 nm (near-IR) to 365 nm (UV) through second harmonic generation, which cleaves a molecule bound to collagen via a UV-sensitive linker. PMID- 25728311 TI - Structural and functional evolution of chitinase-like proteins from plants. AB - The plant genome contains a large number of sequences that encode catalytically inactive chitinases referred to as chitinase-like proteins (CLPs). Although CLPs share high sequence and structural homology with chitinases of glycosyl hydrolase 18 (TIM barrel domain) and 19 families, they may lack the binding/catalytic activity. Molecular genetic analysis revealed that gene duplication events followed by mutation in the existing chitinase gene have resulted in the loss of activity. The evidences show that adaptive functional diversification of the CLPs has been achieved through alterations in the flexible regions than in the rigid structural elements. The CLPs plays an important role in the defense response against pathogenic attack, biotic and abiotic stress. They are also involved in the growth and developmental processes of plants. Since the physiological roles of CLPs are similar to chitinase, such mutations have led to plurifunctional enzymes. The biochemical and structural characterization of the CLPs is essential for understanding their roles and to develop potential utility in biotechnological industries. This review sheds light on the structure-function evolution of CLPs from chitinases. PMID- 25728312 TI - Red yeast rice for the treatment of dyslipidemia. AB - Red yeast rice (RYR) is a Chinese herbal supplement produced by fermenting white rice with the yeast, Monascus purpureus. The Chinese have used RYR to flavor, color, and preserve foods and as a traditional medicine for many years. In the USA, RYR has been used as an alternative to statin therapy in treating patients with mild to moderate hypercholesterolemia. RYR contains a variety of monacolins, which inhibit hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase, the rate limiting step in cholesterol synthesis. Consumption of RYR has increased recently especially among patients who might be intolerant to standardized therapy due to statin-associated myalgia (SAM). Several clinical trials have shown RYR to be safe, effective, and well tolerated; however, the studies are small and of short duration. The US Food and Drug Administration has prohibited the sale of all RYR products containing monacolin K, which is chemically identical to lovastatin, because it is considered an unapproved drug. However, many RYR supplements continue to remain on the market and lack standardization and quality control. PMID- 25728313 TI - miR-181a/b control the assembly of visual circuitry by regulating retinal axon specification and growth. AB - Connectivity and function of neuronal circuitry require the correct specification and growth of axons and dendrites. Here, we identify the microRNAs miR-181a and miR-181b as key regulators of retinal axon specification and growth. Loss of miR 181a/b in medaka fish (Oryzias latipes) failed to consolidate amacrine cell processes into axons and delayed the growth of retinal ganglion cell (RGC) axons. These alterations were accompanied by defects in visual connectivity and function. We demonstrated that miR-181a/b exert these actions through negative modulation of MAPK/ERK signaling that in turn leads to RhoA reduction and proper neuritogenesis in both amacrine cells and RGCs via local cytoskeletal rearrangement. Our results identify a new pathway for axon specification and growth unraveling a crucial role of miR-181a/b in the proper establishment of visual system connectivity and function. PMID- 25728314 TI - Expression of intercellular adhesion molecule-1 by myofibers in mdx mice. AB - INTRODUCTION: We investigated the extent to which intercellular adhesion molecule 1 (ICAM-1), a critical protein of the inflammatory response, is expressed in skeletal muscles of mdx mice (a murine model of Duchenne muscular dystrophy). METHODS: Muscles were collected from control and mdx mice at 2-24 weeks of age and analyzed for ICAM-1 expression by means of Western blot and immunofluorescence. RESULTS: Western blot revealed higher expression of ICAM-1 in mdx compared with control muscles through 24 weeks of age. In contrast to control muscles, ICAM-1 was expressed on the membrane of damaged, regenerating, and normal myofibers of mdx mice. CD11b+ myeloid cells also expressed ICAM-1 in mdx muscles, and CD11b+ cells were closely associated with the membrane of myofibers expressing ICAM-1. CONCLUSIONS: These findings support a paradigm in which ICAM-1 and its localization to myofibers in muscles of mdx mice contributes to the dystrophic pathology. PMID- 25728315 TI - Pandemic influenza A vaccination and incidence of Guillain-Barre syndrome in Korea. AB - BACKGROUND: Many studies have investigated the association between Guillain-Barre syndrome (GBS) and vaccinations during the influenza A H1N1 pandemic of 2009 (pH1N1). Based on a nationally representative sample, we estimated the incidence of GBS during the pandemic period in Korea. MATERIALS AND METHODS: All medical records of GBS cases were reviewed in 28 randomly selected hospitals during 2008 2010, and the number of GBS cases at the national level was extrapolated using emergency care utilization data. The GBS rate per 100,000 person-years was estimated in the reference and pandemic periods. RESULTS: The incidence of GBS was 0.63 (95% CI: 0.37-0.89) per 100,000 person-years in the reference period and 0.87 (0.49-1.26) in the pandemic period. During the vaccination season, the pandemic period GBS incidence rate was not significantly higher than the reference period incidence rate (rate ratio: 1.52; 0.99-2.32), but difference was observed among persons aged 20-34 years. Rate of GBS increased after pH1N1 vaccination compared to the reference period (1.46, 1.26-1.68). DISCUSSION: The incidence of GBS increased slightly but not significantly during the pandemic period, although pH1N1 vaccination increased the GBS rate. Therefore, mass influenza vaccination programs should not be precluded on the basis of GBS. PMID- 25728316 TI - Five year follow-up after primary vaccination against tick-borne encephalitis in children. AB - BACKGROUND: A first tick-borne encephalitis (TBE) vaccine booster in children is currently suggested 3 years after completing either a conventional (doses on Days 0, 28 and 300) or accelerated conventional (doses on Days 0, 14 and 300) TBE immunization schedule. This recommendation, however, may not be appropriate in cases where different TBE vaccines have been used interchangeably during the primary immunization series. METHODS: To provide robust data to better inform such recommendations, TBE antibody persistence was evaluated after 3-5 years in four groups of children (aged 5-15 years): two groups previously primed with three doses of Encepur((r)) Children (conventional/accelerated conventional schedule); and two groups previously primed with two doses of FSME-IMMUN((r)) followed by a third dose of Encepur((r)) Children (conventional/accelerated conventional schedule). Immunogenicity was evaluated using neutralization (NT) assays based on both vaccine antigens as well as on the Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: In the two Encepur((r)) Children groups (full series), protective NT titers of >=10 were detected in 98-100% of children up to 5 years after their last primary vaccination, irrespective of schedule. In contrast, only 65-70% subjects in the FSME-IMMUN((r)) Junior groups (mixed series) displayed NT titers >=10 after 3 years. Thus, due to lower probability of achieving/maintaining long-term protective antibody levels (recently defined by the World Health Organization as an NT titer >=10) after this time point, both FSME-IMMUN Junior groups were discontinued. CONCLUSION: A strong antibody response persists for at least 5 years after full primary vaccination with Encepur((r)) Children. The study thus provides support for extending the time interval for a first booster dose after primary vaccination (conventional/accelerated conventional schedule) with Encepur((r)) Children from 3 to 5 years. PMID- 25728317 TI - Novel vaccination approach for dengue infection based on recombinant immune complex universal platform. AB - Dengue infection is on the rise in many endemic areas of the tropics. Vaccination remains the most realistic strategy for prevention of this potentially fatal viral disease but there is currently no effective vaccine that could protect against all four known serotypes of the dengue virus. This study describes the generation and testing of a novel vaccination approach against dengue based on recombinant immune complexes (RIC). We modelled the dengue RIC on the existing Ebola RIC (Phoolcharoen, et al. Proc Natl Acad Sci USA 2011;108(Dec (51)):20695) but with a key modification that allowed formation of a universal RIC platform that can be easily adapted for use for other pathogens. This was achieved by retaining only the binding epitope of the 6D8 ant-Ebola mAb, which was then fused to the consensus dengue E3 domain (cEDIII), resulting in a hybrid dengue-Ebola RIC (DERIC). We expressed human and mouse versions of these molecules in tobacco plants using a geminivirus-based expression system. Following purification from the plant extracts by protein G affinity chromatography, DERIC bound to C1q component of complement, thus confirming functionality. Importantly, following immunization of mice, DERIC induced a potent, virus-neutralizing anti-cEDIII humoral immune response without exogenous adjuvants. We conclude that these self adjuvanting immunogens have the potential to be developed as a novel vaccine candidate for dengue infection, and provide the basis for a universal RIC platform for use with other antigens. PMID- 25728318 TI - A Plasmodium falciparum 48/45 single epitope R0.6C subunit protein elicits high levels of transmission blocking antibodies. AB - The sexual stage Pfs48/45 antigen is a well-established lead candidate for a transmission blocking (TB) vaccine because of its critical role in parasite fertilization. We have recently produced the carboxy-terminal 10C-fragment of Pfs48/45 containing three known epitopes for TB antibodies as a chimera with the N-terminal region of GLURP (R0). The resulting fusion protein elicited high titer TB antibodies in rodents. To increase the relatively low yield of correctly folded Pfs48/45 we have generated a series of novel chimera truncating the 10C fragments to 6 cysteine residues containing sub-units (6C). All constructs harbor the major epitope I for TB antibodies. One of these sub-units (R0.6Cc), produced high yields of correctly folded conformers, which could be purified by a simple 2 step procedure. Purified R0.6Cc was stable and elicits high titer TB antibodies in rats. The yield, purity and stability of R0.6Cc allows for further clinical development. PMID- 25728319 TI - Conjugation of beta-glucan markedly increase the immunogencity of meningococcal group Y polysaccharide conjugate vaccine. AB - Meningococcal disease is a fatal illness of sudden onset caused by Neisseria meningitides. Meningococcal capsular polysaccharide (CPS) is a major virulence factor that generally does not induce immunological memory. Conjugation with a carrier protein can significantly increase the immunogenicity of CPS and induce immunological memory. However, it is highly desired to optimize the CPS-specific immunogenicity of the conjugate vaccine. Although adjuvant has been widely used to improve the immunogenicity of antigens, co-administration and conjugation of adjuvant with the conjugate vaccine has rarely been investigated. As a stimulator of humoral and cellular immunity, beta-glucan can activate macrophages and trigger intracellular processes to secrete cytokines initiating inflammatory reactions. In the present study, a conjugate vaccine (CPS-TT) was generated by conjugation of tetanus toxoid (TT) with meningococcal group Y CPS. CPS-TT was further conjugated with beta-glucan to generate CPS-TT-G. Immunization with CPS TT-G led to an 8.2-fold increase in the CPS-specific IgG titers as compared with CPS-TT. Presumably, conjugation of beta-glucan ensured the two components to simultaneously reach the antigen presenting cells and stimulate the immune response. In contrast, co-administration of beta-glucan suppressed the CPS specific immunogenicity of CPS-TT. Thus, conjugation of beta-glucan is an effective strategy to markedly improve the CPS-specific immunogenicity of the conjugate vaccine. PMID- 25728320 TI - Low uptake of influenza vaccine among university students: evaluating predictors beyond cost and safety concerns. AB - INTRODUCTION: Annual influenza vaccine coverage for young adults (including college students) remains low, despite a 2011 US recommendation for annual immunization of all people 6 months and older. College students are at high risk for influenza morbidity given close living and social spaces and extended travel during semester breaks when influenza circulation typically increases. We evaluated influenza vaccine uptake following an on-campus vaccine campaign at a large, public New York State university. METHODS: Consecutive students visiting the University Health Center were recruited for a self-administered, anonymous, written survey. Students were asked about recent influenza vaccination, barriers to influenza vaccination, and willingness to get vaccinated to protect other vulnerable individuals they may encounter. Frequencies and proportions were evaluated. RESULTS: Of 653 students approached, 600 completed surveys (92% response proportion); respondents were primarily female (61%) and non-Hispanic white (59%). Influenza vaccine coverage was low (28%). Compared to coverage among non-Hispanic white students (30%), coverage was similar among Hispanic (30%) and other race/ethnicity students (28%) and lowest among non-Hispanic black students (17%). Among the unvaccinated, the most commonly selected vaccination barriers were "Too lazy to get the vaccine" (32%) and "Don't need the vaccine because I'm healthy" (29%); 6% of unvaccinated students cited cost as a barrier. After being informed that influenza vaccination of young, healthy people can protect other vulnerable individuals (e.g., infants, elderly), 71% of unvaccinated students indicated this would increase their willingness to get vaccinated. CONCLUSIONS: Influenza vaccine uptake among college students is very low. While making vaccine easily obtained may increase vaccine uptake, college students need to be motivated to get vaccinated. Typically healthy students may not perceive a need for influenza vaccine. Education about vaccinating healthy individuals to prevent the spread of influenza to close contacts, such as vulnerable family members, may provide this motivation to get vaccinated. PMID- 25728321 TI - Uptake of a government-funded pertussis-containing booster vaccination program for parents of new babies in Victoria, Australia. AB - INTRODUCTION: An epidemic of Bordetella pertussis in Victoria, Australia, led to the implementation of a Government-funded vaccination program for parents of new babies. The rationale was to protect unimmunised infants from infection by vaccinating parents with a pertussis-containing vaccine. This is known as cocooning. AIM: To estimate uptake of the vaccine among parents of new babies, two-and-a-half years after the program was implemented. METHODS: A state-wide cross-sectional survey of parents was conducted to ascertain vaccine uptake, and to identify where and when the vaccination took place. Surveys were administered between 15 February and 14 March 2012, inclusive. RESULTS: Of 6308 surveys distributed, 2510 completed surveys were returned (response rate 40%). Ninety five surveys completed outside the study period were excluded, leaving 2415 available for analysis. Overall, 1937 (80%) mothers and 1385 (70%) fathers were vaccinated in relation to the birth of their most recent child. A majority of mothers were vaccinated in hospital (62%). Most fathers were vaccinated by a general practitioner (72%). The most common point at which mothers were vaccinated was before their child turned two weeks of age (65%). Fathers' vaccination time-point varied more widely: during pregnancy (25%); before their child turned two weeks of age (29%); and when their child was between two and eight weeks of age (28%). CONCLUSION: Results of this survey indicated excellent uptake of the vaccine among both mothers and fathers under the Government-funded cocooning program. The findings are suggestive of an effective communications program designed to raise awareness of the risks of pertussis, and to promote availability of the funded vaccination program. The results may contribute to policy implementation of adult immunisation programs such as cocooning. PMID- 25728322 TI - Pertussis in infants under one year old: risk markers and vaccination status--a case-control study. AB - BACKGROUND: Pertussis is a contagious bacterial disease causing substantial health burden. Pertussis-related morbidity and mortality are highest in young infants. We investigated risk markers for pertussis and vaccination status in infants. METHODS: Reported pertussis cases under one year old during 1998-2011 in the Jerusalem district were matched to controls by birthdate and residence. Data sources included epidemiological investigations, health records and vaccination records (number and dates of DTP?DTaP doses scheduled at 2, 4, 6 months). Vaccine effectiveness was calculated by number of vaccine doses stratified by age group. Timeliness of vaccine doses was also evaluated. RESULTS: The study population included 1268 infants under 1 year: 317 pertussis cases and 951 age-matched controls (mean age 3.95+/-3, median 2.9 months). Low birthweight (<2500g, 12.3% in cases vs. 6.3% in controls) and high birth order (4th and above) were found to be independent risk markers. Male gender and low socio-economic status were more frequent among cases. Some 40% of the cases (127/317) were hospitalized, most of them (111/127, 87.4%) were under 4 months (mean age 2.42+/-2.05, median 1.8 months). The distribution of the number of pertussis vaccine doses 0, 1, 2 and 3 differed considerably being 42.2%, 32.7%, 15.6%, 9.5% vs. 13.7%, 41.9%, 22.9%, 21.5% among cases and controls (>=2m), respectively. The overall vaccine effectiveness found was 72.9%, 76.1% and 84.4%, for the 1st, 2nd and 3rd doses of a pertussis vaccine. The infant's age at the first dose of pertussis vaccine was recorded with follow-up until age 18 months. Delay was more common among cases with a lower proportion vaccinated-78.9% at 18 months vs. 99% in controls. CONCLUSIONS: Specific risk markers for pertussis in young infants were identified. Reported pertussis cases over age 2 months were significantly more likely to be unvaccinated and have delayed vaccinations. The vaccine effectiveness increased with the number of vaccine doses. PMID- 25728324 TI - A Case Report of Double-Chambered Right Ventricle Associated with Subaterial Ventricular Septal Defect and Rupture of Right Coronary Sinus Aneurysm. AB - Double-chambered right ventricle (DCRV) is a rare congenital heart disease in which the right ventricle (RV) is divided into two chambers by anomalous muscle bundles. Here, we report a case of DCRV associated with subarterial ventricular septal defect (VSD) and rupture of right coronary sinus aneurysm (RCSA); the patient was diagnosed by echocardiography and later confirmed by surgical operation. PMID- 25728325 TI - High selectivity for ethylene from carbon dioxide reduction over copper nanocube electrocatalysts. AB - Nanostructured surfaces have been shown to greatly enhance the activity and selectivity of many different catalysts. Here we report a nanostructured copper surface that gives high selectivity for ethylene formation from electrocatalytic CO2 reduction. The nanostructured copper is easily formed in situ during the CO2 reduction reaction, and scanning electron microscopy (SEM) shows the surface to be dominated by cubic structures. Using online electrochemical mass spectrometry (OLEMS), the onset potentials and relative selectivity toward the volatile products (ethylene and methane) were measured for several different copper surfaces and single crystals, relating the cubic shape of the copper surface to the greatly enhanced ethylene selectivity. The ability of the cubic nanostructure to so strongly favor multicarbon product formation from CO2 reduction, and in particular ethylene over methane, is unique to this surface and is an important step toward developing a catalyst that has exclusive selectivity for multicarbon products. PMID- 25728323 TI - Frequencies of Gag-restricted T-cell escape "footprints" differ across HIV-1 clades A1 and D chronically infected Ugandans irrespective of host HLA B alleles. AB - OBJECTIVE(S): We evaluated relationships between critical Gag T-cell escape mutations and concomitant T-cell responses to determine whether HLA-restricted Gag mutations that confer protection, occur at similar rates in a population infected with mixed HIV-1 clades A1 and D viruses. METHODS: Assessment of Gag selective pressure, and adaptive T-cell functions to KAFSPEVIPMF (KF11), ISPRTLNAW (ISW9) and TSTLQEQIGW (TW10) Gag epitopes were combined with host HLA to assess correlations with rates of critical epitope escape mutations in clades A1- (n=23) and D- (n=21) infected, untreated subjects. Infecting clades and selection pressure were determined from the gag sequences. RESULTS: Overall, Gag escape mutations A163X in KF11 were detected in 61% (14/23) A1- infected compared to 5% (1/21) in D-infected subjects (p=0.00015). Gag mutations I147X in the ISW9 epitope were seen in 43%: (10/23) clade A compared to 5%: (1/21) clade D infected subjects, p=0.007, Fisher's Exact test. Both mutations were more frequent in clade A1 infection. Frequencies of the measured epitope-specific T-cell responses were comparable across clades. Peptide binding affinities for the restricting HLA alleles did not differ across clades. Overall, selection pressure on the Gag protein was significantly greater in clade A than in clade D sequences. CONCLUSIONS: These findings imply that HIV-1 vaccine strategies designed to target structurally constrained T-cell epitopes may be further challenged by clade-driven outcomes in specific HLA-restricted Gag epitopes. Equally, the data are line with slower HIV-1 disease progression in clade A infection; and raise hope that increased selective pressure on Gag may be protective irrespective of host HLA alleles. PMID- 25728326 TI - Simultaneous determination of camptothecin and 10-hydroxycamptothecine in the Camptotheca acuminate, its medicinal preparation and in rat plasma by liquid chromatography with fluorescence detection. AB - Camptotheca acuminata Decne is an important medicinal plant that contains various cytotoxic alkaloids, such as camptothecine (CPT) and 10-hydroxycamptothecine (HCPT). A rapid and sensitive liquid chromatography with fluorescence detection (LC-FLD) method for the quantification of CPT and HCPT is described. The separation was carried out on a DL-Cl8 column (4.6 * 150 mm, 5 um), with the mobile phase of acetonitrile-sodium dihydrogen phosphate buffer (10 mm) using an gradient elution at the flow rate of 0.6 mL/min. The LC-FLD method was validated for linearity, sensitivity, accuracy and precision, and then used to determine the content of the above components. The lower detection limits of CPT and HCPT were 0.4 and 0.1 ng/mL, respectively. The precision was <1.58% and the mean recovery of the analytes was 96.0-98.6%. The LC-FLD method was successfully applied to determine CPT and HCPT in real samples including C. acuminate, HCPT injection and rat plasma. PMID- 25728327 TI - Food for thought: ego-dystonicity and fear of self in eating disorders. AB - Degree of ego-dystonicity in obsessions is clinically relevant to the conceptualization and treatment of eating disorders (EDs). Obsessive-compulsive disorder research has suggested that the transformation of intrusive thoughts into obsessions is linked to the degree to which intrusive thoughts threaten core perceptions of the self. This study aims to explore the relationship between the ego-dystonic nature of obsessions in ED patients and a fear of self, the link between ED symptom severity and ego-dystonicity in obsessions, and differences between non-clinical and individuals with EDs in the presence of ego-dystonic thoughts and a fear of self. Ego-dystonicity (Ego-dystonicity Questionnaire (EDQ)) and feared self (Fear of Self Questionnaire (FSQ)) degrees were measured in a clinical sample (n = 57 with EDs) and a non-clinical sample (n = 45). EDQ and FSQ scores were highly correlated in both samples. EDQ scores were not significantly correlated to ED symptom severity with the exception of the EDQ Irrationality subscale, which was strongly related to compulsion severity. Participants with an ED had significantly higher EDQ and FSQ scores compared with controls. PMID- 25728328 TI - Transverse septum lingual view on two-dimensional ultrasound for prenatal detection of cleft palate. PMID- 25728329 TI - Initial single-center experience with the Ovation stent-graft system in the treatment of abdominal aortic aneurysms: application to challenging iliac access anatomies. AB - BACKGROUND: To present our preliminary results with the Ovation(TM) abdominal stent-graft system in abdominal aortic aneurysms (AAA) with narrow (<=7 mm) or angulated iliac vessels. METHODS: From April 2012 to January 2014, 42 patients (97% men; mean age, 71 years; range, 55-89 years) with AAAs of 55.5 mm (50-79 mm) were treated with the Ovation device. Primary end points included technical success and freedom from early secondary interventions, any type of endoleak, and aneurysm-related death. Limb occlusion was studied with respect to iliac access diameter and angulation. Iliac angulation between 90 degrees and 120 degrees or <90 degrees was considered moderate or severe, respectively. RESULTS: The postoperative follow-up was 7.8 +/- 4.6 months (mean +/- standard deviation). Infrarenal neck angulation was 26 degrees +/- 26 degrees . AAA neck length and diameter were 27.3 +/- 10.5 and 24.1 +/- 3.2 mm, respectively. Forty-five percent of patients had at least 1 vessel of <=7-mm diameter, and almost half of patients (24 of 44) had at least 1 iliac artery of moderate or severe angulation. Technical and treatment success were 100% and 95%, respectively. No stent-graft migration or type I, III, or IV endoleaks occurred. Type II endoleaks were identified in 5 patients, leading to sac enlargement in 2 and necessitating an embolization attempt that was unsuccessful in 1 case. No limb occlusion occurred, irrespective of the iliac diameter or angulation. CONCLUSIONS: Our 1-year results of the Ovation stent-graft system demonstrate excellent safety and effectiveness. The easy navigation through highly angulated and stenosed iliac vessels ensures high technical success in cases of challenging iliac anatomy. Follow-up is ongoing. PMID- 25728330 TI - Aneurysm sac shrinkage after endovascular repair: predictive factors and long term follow-up. AB - BACKGROUND: The aim of this study was to determine the predictive factors of reduction in diameter >=10 mm of the aneurysm sac after endovascular treatment and analyze evolution in these patients. METHODS: Between December 1997 and December 2008, all patients electively treated at our center for an infrarenal abdominal aortic aneurysm (AAA) were included in a prospective registry. We did a retrospective study between patients whose aneurysm was reduced by at least 10 mm in diameter on computed tomography scan during follow-up (Group 1) and the other patients who did not (Group 2). A univariate and multivariate statistical analysis was performed. RESULTS: The files of 197 patients (mean age 74.8 years) with a mean follow-up of 54.8 months were reviewed. One hundred two patients (51.8%) had a reduction of >=10 mm of AAA diameter (Group 1); this reduction was achieved after an average follow-up of 23.6 months. The delay to obtain at least a 10-mm diameter reduction was not influenced by any preoperative characteristics of patients or characteristics of the AAA. Patients in Group 1 were younger (74 vs. 76 years, P = 0.039), with a longer (31 vs. 27.7 mm, P = 0.038) and narrower upper neck (23.1 vs. 24.0 mm, P = 0.02) compared with Group 2. After multivariate analysis, these 3 variables were independently predictive of reduction in AAA diameter. In Group 1, secondary procedures were performed in 13 patients after a diameter reduction of >=10 mm, including 3 type 1 endoleaks treated after 36 months (1 case) and after 123 months (2 cases) and 1 type 3 endoleak treated after 78 months. In Group 2, secondary procedures were performed in 28 patients, including 9 type 1 endoleaks treated after a median time of 26 months and no type 3 endoleak. Secondary procedures were significantly more frequent in Group 2 than in Group 1 (29.4% vs. 12.7%, respectively; P = 0.005). Freedom from secondary procedure at 5 years was 87.9% in Group 1 and 65.4% in Group 2 (P = 0.003). Freedom from AAA rupture at 8 years was significantly superior in Group 1 than in Group 2 (100% vs. 83.5%, P = 0.008). CONCLUSIONS: Sac shrinkage after endovascular aortic aneurysm repair is more likely observed in younger patients with long and small proximal neck anatomy and is associated with better long-term outcomes. However, late failures do occur even in those with significant sac shrinkage; therefore, follow-up should continue lifelong. PMID- 25728331 TI - Total Aortic Arch Revascularization with Extra-anatomic Bypass for Takayasu Arteritis. AB - Total arch replacement with median sternotomy and hypothermic circulatory arrest is described for Takayasu arteritis (TA) with aortic arch and supra-aortic trunk involvement.(1,2) We report aortic arch revascularization using extra-anatomic bypass through partial sternotomy, without cardiopulmonary bypass, in a TA patient. Avoidance of cardiopulmonary bypass may enhance outcomes and represent an attractive approach to arch revascularization in TA. PMID- 25728332 TI - Midterm results of type B intramural hematoma endovascular treatment. AB - BACKGROUND: Recently, intramural hematoma (IMH) has been characterized as a rare variant of aortic dissection, falling within the acute aortic syndromes (AAS). Although aortic endovascular treatment seems to provide good results, no consensus has been established regarding the optimal management of IMH affecting the descending thoracic aorta (IMH B). The aim of this study was to assess long term clinical and morphological results of IMH B treated with a stent graft. METHODS: Between 2002 and 2013, 15 of the 423 (3.5%) consecutive patients with AAS were found to have IMH B. During follow-up, complications related to IMH B were observed in 10 patients, including 5 during the acute period (<14 days). Surgical indications were ulcerations, refractory pain, aneurysm evolution, aortic rupture, and pleural effusion. An endovascular approach was taken for all forms with suitable anatomy. RESULTS: Technical success rate was 100%, with complete exclusion of lesions of the descending thoracic aorta in all cases treated with a stent graft. No neurological complications or deaths occurred within the first 30 postoperative days, nor at the end of the mean follow-up of 46 months (1-137 months). After the aortic stent graft, partial or complete regression of the hematoma was observed in all cases. CONCLUSIONS: IMH B is most often a progressive disease requiring long-term monitoring. In case of complications, stent-graft treatment of the descending thoracic aorta can be performed successfully in most cases. This procedure appears to be a safe technique that provides very good long-term results, with favorable remodeling of the aorta. PMID- 25728333 TI - Risk factors for deep vein thrombosis after orthopedic surgery and the diagnostic value of D-dimer. AB - BACKGROUND: This study was prospectively designed to determine the risk factors of deep vein thrombosis (DVT) in patients who underwent different surgeries, and to evaluate the efficacy and accuracy of plasma D-dimer level as a screening test. METHODS: From June 2013 to June 2014, 360 consecutive patients undergoing orthopedic surgery were evaluated. All patients underwent ultrasonography preoperatively and on postoperative day 7. Plasma D-dimer levels were estimated by latex immunoturbidimetry on the day of surgery and on postoperative days 1, 3, and 7. RESULTS: Of the 360 patients in this study, 339 patients completed the analysis. Among them, DVT was confirmed in 28 (8.26%) patients based on ultrasonographic findings. Multivariate logistic analysis revealed that body mass index was an independent risk factor for developing DVT (P = 0.018) and D-dimer levels on postoperative days 1 and 7 were independently correlated with the development of DVT (P = 0.019 and P < 0.001, respectively). The receiver operating characteristic curve analysis determined that the area under the curve was largest (0.752) when using D-dimer level on postoperative day 7 as diagnostic index, and the sensitivity and specificity were 71.4% and 81.7% at the cut-off value of 6.17 MUg/mL, respectively. The elevated D-dimer levels followed the same tendency toward a double-peaked distribution with peaks at days 1 and 7 postoperatively. CONCLUSION: D-dimer level was a useful screening test to exclude DVT, and the cut-off values of D-dimer determined in this study will provide a reference for the absence of DVT to a certain extent. PMID- 25728334 TI - Factors influencing maturation time of native arteriovenous fistulas. AB - BACKGROUND: To determine the factors influencing the maturation time of native arteriovenous fistulas. METHODS: A retrospective review was performed of hemodialysis patients from a single university-associated dialysis center from 2004 to 2009. Demographics, comorbidities, and insurance status were recorded. Maturation time was defined as the time from access creation until the access was able to be used regularly for hemodialysis for a period of 2 weeks. RESULTS: A total of 249 patients were identified during the study period who had an arteriovenous fistula created that successfully matured; 104 (42%) patients were women and 145 (58%) were men. Most of the patients were Hispanic (82%). Ninety seven (39%) of the patients had Medicaid-type insurance and 133 (53%) had Medicare. The mean age was 51 years, and 190 (76%) of the patients had diabetes. The overall mean maturation time was 79 days. Women had a significantly longer time to fistula maturation than males (91.9 days vs. 70.5 days, P = 0.0028). Diabetics also had a significantly longer maturation time than nondiabetics (92.5 days vs. 75.4 days, P = 0.0004). Age did not have an effect on maturation time. On multivariable analysis, sex remained significant (P = 0.007), however, diabetes lost its significance. CONCLUSIONS: In this predominantly Hispanic hemodialysis population, women require longer fistula maturation times than men. The exact reasons for this are unknown based on this data. More study is required to determine the etiology of this gender discrepancy. PMID- 25728335 TI - Combined frozen elephant trunk and endovascular repair for extensive thoracic aortic aneurysms. AB - BACKGROUND: We describe a 1-step treatment of extensive arch and descending aortic aneurysm by combination of frozen elephant trunk (FET) (hybrid endoprosthesis) and of conventional endoprosthesis deployment. METHODS: In a single-center, prospective, treatment-only study, the clinical data of 4 patients receiving combined FET and distal endoprosthesis deployment in the descending aorta were prospectively collected. Thoracic endoprostheses were deployed either retrogradely (off-pump from the femoral arterial access) or antegradely (from the aortic arch during hypothermic arrest). A distal-first approach was used ("trombone" mechanism). Spinal cord protection was achieved by transposition of the left subclavian artery to the left common carotid artery and selective antegrade cerebral perfusion. Preoperative computed tomography scan was performed to identify the collateral circulation. Preoperative planning was assisted by a sizing software (Endosize, Therenva Inc.). RESULTS: The aortic coverage was extended down to the orifice of the celiac trunk in one case and to the T8 level in the remainders. There was no operative mortality, 1 transient paraparesis, and 1 case of renal insufficiency. Follow-up results were satisfying (no device migration, no endoleak, no endotension, and no late neurologic complications). CONCLUSIONS: The present strategy may abolish the risks connected with the waiting time between the surgical first step and the later completion (aortic related adverse events and drop-out) and deserves further investigations to determine its safety and feasibility profile. PMID- 25728336 TI - Genetic and antigenic analysis of Chlamydia pecorum strains isolated from calves with diarrhea. AB - Chlamydia pecorum (designated 22-58) was isolated in 2010 in HmLu-1 cells from the jejunum of a calf which died of necrotizing enterocolitis in Yamaguchi Prefecture, Japan. Immunohistochemical staining identified C. pecorum positive reactions in the jejunal villi. C. pecorum, designated 24-100, was isolated from the feces of a calf with diarrhea in another farm in Yamaguchi Prefecture in 2012. A significant increase in neutralizing antibody titers against C. pecorum was confirmed in paired sera. Nucleotide sequence identities of omp1 genes of the 2 isolates were 100%. The isolates were genetically and antigenically more closely related to C. pecorum Bo/Yokohama strain isolated from cattle with enteritis in Japan than to the other prototype strains, Bo/Maeda isolated from cattle with pneumonia and Ov/IPA isolated from sheep with polyarthritis. These results indicate that C. pecorum strains similar to 22-58 and 24-100 might be endemic in Yamaguchi Prefecture and cause enteric disease in cattle. PMID- 25728337 TI - A New Medical Device Rigeneracons Allows to Obtain Viable Micro-Grafts From Mechanical Disaggregation of Human Tissues. AB - Autologous graft is considered the gold standard of graft materials; however, this approach is still limited due to both small amount of tissue that can be collected and to reduced cell viability of cells that can be obtained. The aim of this preliminary study was to demonstrate the efficacy of an innovative medical device called Rigeneracons(r) (CE certified Class I) to provide autologous micro grafts immediately available to be used in the clinical practice. Moreover, Rigeneracons(r) is an instrument able to create micro-grafts enriched of progenitors cells which maintain their regenerative and differentiation potential. We reported preliminary data about viability cell of samples derived from different kind of human tissues, such as periosteum, cardiac atrial appendage biopsy, and lateral rectus muscle of eyeball and disaggregated by Rigeneracons(r). In all cases we observed that micro-grafts obtained by Rigeneracons(r) displayed high cell viability. Furthermore, by cell characterization of periosteum samples, we also evidenced an high positivity to mesenchymal cell markers, suggesting an optimal regenerative potential. PMID- 25728338 TI - Sodium arsenite inhibited genomic estrogen signaling but induced pERalpha (Ser118) via MAPK pathway in breast cancer cells. AB - Arsenic (As) is considered a major environmental health threat worldwide due to its widespread contamination in drinking water. Recent studies reported that arsenic is a potential xenoestrogen as it interfered with the action of estrogen (E2) and estrogen receptor (ER) signaling. The present study investigated the effects of sodium arsenite (NaAsO2 ) on estrogen signaling in human breast cancer cells. The results demonstrated that NaAsO2 dose-dependently increased viability of hormone-dependent breast cancer MCF-7 and T47D cells expressing both ERalpha and ERbeta but not hormone-independent MDA-MB-231 cells expressing ERbeta. These suggested ERalpha contribution to NaAsO2 -stimulated breast cancer cells growth. NaAsO2 induced down-regulation of ERalpha but up-regulation of ERbeta protein expressions in T47D cells. Moreover, NaAsO2 dose-dependently inhibited E2-induced ER transcriptional activity as it decreased E2-mediated ERE-luciferase transcription activation and PgR mRNA transcription but increased pS2 mRNA transcription. However, NaAsO2 induced both rapid and sustained activation of ERK1/2 and increased in phosphorylation of ERalpha at serine 118 residue, c-fos and c-myc protein expressions. These results indicated that NaAsO2 interferes the genomic estrogen-signaling pathway but induces activation of a rapid nongenomic signal transduction through ERK1/2 pathway which may contribute to its proliferative effect on hormone-dependent breast cancer cells. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1133-1146, 2016. PMID- 25728339 TI - Increasing girls' physical activity during a short-term organized youth sport basketball program: A randomized controlled trial. AB - OBJECTIVES: To evaluate the short-term efficacy of coach education on basketball players' physical activity (PA) intensity during practices. Intervention effects on players' motivation were also investigated. DESIGN: Randomized controlled trial. METHODS: This study took place over the course of a 5-day organized youth sport (OYS) basketball program in 2 sports centres in Greater Western Sydney, Australia (September, 2013). A convenience sample of 76 players and 8 coaches were recruited. Players were girls aged 9 to 12 years. Following the first 2 days of the basketball program, coaches allocated into the intervention condition attended 2 coach education sessions where strategies to increase moderate-to vigorous physical activity (MVPA) and decrease inactivity were discussed. Each coach education session lasted approximately 2h. RESULTS: Compared to the control group, players in the intervention group spent a significantly higher proportion of practice time in MVPA (mean difference [MD]=14.6%; standard error [SE]=2.2%), vigorous PA (VPA; MD=12.6%; SE=1.9%), moderate PA (MD=2.0%; SE=0.5%) and a significantly lower proportion of practice time inactive (MD=-14.5%; SE=2.3%) from baseline to follow-up. There were no significant changes in motivation from baseline to follow-up in either group. CONCLUSIONS: Brief coach education sessions can increase MVPA and decrease inactivity without deleterious effects on players' motivation. Also, substantial increases in VPA were found, which is an important finding because VPA has been associated with health benefits, over and above benefits accrued from lower-intensity activity. PMID- 25728340 TI - Effect of a Vietnamese Cinnamomum cassia essential oil and its major component trans-cinnamaldehyde on the cell viability, membrane integrity, membrane fluidity, and proton motive force of Listeria innocua. AB - The antibacterial mechanism of a Cinnamomum cassia essential oil from Vietnam and of its main component (trans-cinnamaldehyde, 90% (m/m) of C. cassia essential oil) against a Listeria innocua strain was investigated to estimate their potential for food preservation. In the presence of C. cassia essential oil or trans-cinnamaldehyde at their minimal bactericidal concentration (2700 MUg.mL( 1)), L. innocua cells fluoresced green after staining with Syto9(r) and propidium iodide, as observed by epifluorescence microscopy, suggesting that the perturbation of membrane did not cause large pore formation and cell lysis but may have introduced the presence of viable but nonculturable bacteria. Moreover, the fluidity, potential, and intracellular pH of the cytoplasmic membrane were perturbed in the presence of the essential oil or trans-cinnamaldehyde. However, these membrane perturbations were less severe in the presence of trans cinnamaldehyde than in the presence of multicomponent C. cassia essential oil. This indicates that in addition to trans-cinnamaldehyde, other minor C. cassia essential oil components play a major role in its antibacterial activity against L. innocua cells. PMID- 25728341 TI - Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH. PMID- 25728342 TI - Structural characterisation of pretreated solids from flow-through liquid hot water treatment of sugarcane bagasse in a fixed-bed reactor. AB - Untreated sugarcane bagasse and sugarcane bagasse pretreated with flow-through liquid hot water (LHW) treatment (170-207 degrees C and 204-250 ml/min) in a fixed-bed reactor have been structurally characterised. Field emission gun scanning electron microscopy (FEG-SEM) and transmission electron microscopy (TEM) were used to investigate changes in the residues, in particular due to the fate of lignin. FEG-SEM results show that the LHW treatment modified the surface morphology of the pretreated bagasse with lignin droplets being observed on the fibre surface. TEM showed an increase in the plant cell wall porosity and lignin migration across the plant cell wall. Increases in pretreatment temperature were observed to increase the average size and density of lignin droplets on the fibre surface. The results provide evidence that for LHW flow-through treatment, just as for batch treatment, lignin repolymerisation and deposition on the surface of pretreated sugarcane bagasse is an important consideration. PMID- 25728343 TI - Biodegradation and utilization of dimethylformamide by biofilm forming Paracoccus sp. strains MKU1 and MKU2. AB - Two bacterial strains capable of degrading N,N-dimethylformamide (DMF) were isolated from the effluent and sludge samples of textile and tyre industries. The 16S rRNA gene analysis revealed that bacterial strains belonged to the genera Paracoccus and named as Paracoccus sp. MKU1 and Paracoccus sp. MKU2. The DMF degradation experiments conducted at a DMF concentration of 1% v/v and HPLC analysis revealed that MKU1 and MKU2 degraded 55% and 46% of DMF after 120 h of growth. Biofilm quantification by microtiter plate assay revealed that both the bacterial isolates can form efficient biofilm on during DMF utilization. The presence of secondary carbon sources influenced the DMF degradation and biofilm formation where highest biofilm formation was observed in the presence of acetate and enhanced the DMF degradation to a maximum of 86.59% with MKU1 whereas glucose and acetate enhanced DMF degradation by MKU2 to a maximum of 82.7% and 80% respectively. PMID- 25728344 TI - Beneficial synergetic effect on gas production during co-pyrolysis of sewage sludge and biomass in a vacuum reactor. AB - A vacuum fixed bed reactor was used to pyrolyze sewage sludge, biomass (rice husk) and their blend under high temperature (900 degrees C). Pyrolytic products were kept in the vacuum reactor during the whole pyrolysis process, guaranteeing a long contact time (more than 2h) for their interactions. Remarkable synergetic effect on gas production was observed. Gas yield of blend fuel was evidently higher than that of both parent fuels. The syngas (CO and H2) content and gas lower heating value (LHV) were obviously improved as well. It was highly possible that sewage sludge provided more CO2 and H2O during co-pyrolysis, promoting intense CO2-char and H2O-char gasification, which benefited the increase of gas yield and lower heating value. The beneficial synergetic effect, as a result, made this method a feasible one for gas production. PMID- 25728345 TI - Reproductive and parental behavior in Taveta golden weavers (Ploceus castaneiceps). AB - Taveta golden weavers are popular in zoos, but little has been published on their reproduction, social behavior, or other aspects of their management. At Disney's Animal Kingdom(r) , we have had great success with our breeding program and house a large flock in our mixed-species walk-through Africa aviary and smaller groups in the off-exhibit Avian Research Center. We conducted observations on both groups in order to document behavioral differences between the groups living under differing management conditions. Data on which individuals were inside, on or near focal nests were collected using a 30-s scan samples. Scan data were analyzed using a two-factor ANOVA, with aviary location and nest contents as the factors. We found that, in both aviary locations, females spent more time inside and on the nests than males did. As expected, females spent more time inside the nests containing eggs and more time on the nests containing chicks, likely due to incubation and chick-feeding demands, respectively. Interestingly, we found that females spent significantly more time inside their nests and males spent more time near their nests in the Africa aviary than in ARC. Despite Africa aviary's higher nest attendance, a higher proportion of nests fledged chicks in ARC (72% vs. 41%). These data are consistent with findings in wild sociable weavers [Spottiswoode, 2007. Oecologia 154: 589-600]. Future work with zoo-housed populations of weavers could help shed light on this phenomenon, which is not yet well understood. A better understanding of the consequences of different group sizes and housing conditions could have important implications for how Taveta weavers are managed. PMID- 25728346 TI - Intraventricular CNS lesions: A pictorial essay. AB - Intraventricular lesions of the central nervous system (CNS) can present a diagnostic challenge due to a range of differential diagnoses and radiological appearances. Both CT and MRI imaging findings, in combination with location and patient's age, can help limit the differentials. This pictorial essay presents the salient radiological features, location and demographics of the more common intraventricular lesions of the brain. PMID- 25728348 TI - Tragedy in sport. PMID- 25728349 TI - Microtubule-based nanomaterials: Exploiting nature's dynamic biopolymers. AB - For more than a decade now, biomolecular systems have served as an inspiration for the development of synthetic nanomaterials and systems that are capable of reproducing many of unique and emergent behaviors of living systems. One intriguing element of such systems may be found in a specialized class of proteins known as biomolecular motors that are capable of performing useful work across multiple length scales through the efficient conversion of chemical energy. Microtubule (MT) filaments may be considered within this context as their dynamic assembly and disassembly dissipate energy, and perform work within the cell. MTs are one of three cytoskeletal filaments in eukaryotic cells, and play critical roles in a range of cellular processes including mitosis and vesicular trafficking. Based on their function, physical attributes, and unique dynamics, MTs also serve as a powerful archetype of a supramolecular filament that underlies and drives multiscale emergent behaviors. In this review, we briefly summarize recent efforts to generate hybrid and composite nanomaterials using MTs as biomolecular scaffolds, as well as computational and synthetic approaches to develop synthetic one-dimensional nanostructures that display the enviable attributes of the natural filaments. PMID- 25728347 TI - Propranolol induces regression of hemangioma cells via the down-regulation of the PI3K/Akt/eNOS/VEGF pathway. AB - BACKGROUND: Infantile hemangioma (IH) is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes in infants. Propranolol, a non-selective beta-adrenergic blocker, has recently emerged as an effective therapy for IH, causing regression. However, its potential therapeutic mechanism remains largely unknown. PROCEDURE: An XPTS-1 cell line was established by isolating hemangioma-derived endothelial cells (HemECs) from a specimen of human proliferating IH. Flow cytometer assay was performed to assess the effect of propranolol on cell cycle distribution. Western blot was employed to determine changes of protein expression. Matrigel invasion and tube formation assays were used to measure invasion ability and tube formation ability, respectively. Commercial kits were employed to quantify NO and VEGF levels. RESULTS: Propranolol blocked norepinephrine-induced HemECs cell cycle progression as well as the expression of cyclin A2 and cyclin D2; whereas p21 and p27 proteins were altered conversely. Propranolol inhibited norepinephrine-induced cell invasion by reducing the expression of MMP-9, VEGF, and p-cofilin. NO and VEGF release induced by norepinephrine was decreased by propranolol pretreatment, coincident with alterations in the phosphorylation of Akt, eNOS, and VEGFR-2. Tube formation ability and subsequent levels of NO and VEGF elevated by norepinephrine were distinctively counteracted in HemECs. CONCLUSIONS: The current study demonstrated the antiangiogenic properties of propranolol in vitro and that the drug was able to induce the regression of hemangioma cells via the inhibition of cell cycle progression, invasion, and tube formation, concomitantly with decreased NO and VEGF levels through the down-regulation of the PI3K/Akt/eNOS/VEGF pathway. PMID- 25728350 TI - Synthesis of D- and L-phenylalanine derivatives by phenylalanine ammonia lyases: a multienzymatic cascade process. AB - The synthesis of substituted D-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). A simple high-throughput solid-phase screening method has also been developed to identify PALs with higher rates of formation of non natural D-phenylalanines. The best variants were exploited in the chemoenzymatic cascade, thus increasing the yield and ee value of the D-configured product. Furthermore, the system was extended to the preparation of those L-phenylalanines which are obtained with a low ee value using PAL amination. PMID- 25728351 TI - The reproducibility and absolute values of echocardiographic measurements of left ventricular size and function in children are algorithm dependent. AB - BACKGROUND: Several quantification algorithms for measuring left ventricular (LV) size and function are used in clinical and research settings. The aims of this study were to investigate the effects of measurement algorithm and beat averaging on the reproducibility of measurements of the left ventricle and to assess the magnitude of agreement among the algorithms in children with dilated cardiomyopathy. METHODS: Echocardiograms were obtained in 169 children from eight clinical centers. Inter- and intrareader reproducibility was assessed on measurements of LV volumes using the biplane Simpson, modified Simpson, and 5/6 * area * length (5/6AL) algorithms. Percentage error was calculated as inter- or intrareader difference/mean * 100. Single-beat measurements and the three-beat average (3BA) were compared. Intraclass correlation coefficients were calculated to assess agreement. RESULTS: Single-beat interreader reproducibility was lowest (percentage error was highest) using biplane Simpson; 5/6AL and modified Simpson were similar but significantly better than biplane Simpson (P < .05). Single-beat intrareader reproducibility was highest using 5/6AL (P < .05). The 3BA improved reproducibility for almost all measures (P < .05). Reproducibility in both single beat and 3BA values fell with greater LV dilation and systolic dysfunction (P < .05). Intraclass correlation coefficients were >0.95 across measures, although absolute volume and mass values were systematically lower for biplane Simpson compared with modified Simpson and 5/6AL. CONCLUSIONS: The reproducibility of LV size and functional measurements in children with dilated cardiomyopathy is highest using the 5/6AL algorithm and can be further improved by using the 3BA. However, values derived from different algorithms are not interchangeable. PMID- 25728353 TI - Development of a computerized Digit Vigilance Test and validation in patients with stroke. AB - OBJECTIVES: To develop a computerized Digit Vigilance Test (C-DVT) with lower random measurement error than that of the DVT and to examine the concurrent validity, ecological validity, and test-retest reliability of the C-DVT in patients with stroke. DESIGN: A cross-sectional study. PATIENTS: Forty-four patients with stroke. METHODS: We developed and tested the C-DVT. To examine the psychometric properties, the participants completed both the C-DVT and DVT twice with a 14-day interval. RESULTS: We developed the C-DVT on the basis of expert input and examinee feedback. C-DVT scores were highly correlated with DVT scores (rho = 0.75), supporting the concurrent validity. The C-DVT scores were moderately correlated with the scores of the Barthel Index and the Activities of Daily Living Computerized Adaptive Testing system (rho = -0.60~-0.57), supporting the ecological validity. The test-retest agreement of the C-DVT was excellent (intra-class correlation coefficient = 0.92). The random measurement error of the C-DVT (minimal detectable change percent change (MDC%) = 15.4%) was acceptable and lower than that of the DVT (33.0%). The practice effects of the C-DVT were statistically significant, but the effect size d was small (0.15). CONCLUSION: A C-DVT with a limited amount of random measurement error was developed. These preliminary findings show that the C-DVT demonstrates satisfactory concurrent validity, ecological validity, and test-retest reliability in patients with stroke. PMID- 25728352 TI - Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer. AB - Activation of the sonic hedgehog (Shh) signaling pathway controls tumorigenesis in a variety of cancers. Here, we show a role for Shh signaling in the promotion of epithelial-to-mesenchymal transition (EMT), tumorigenicity, and stemness in the bladder cancer. EMT induction was assessed by the decreased expression of E cadherin and ZO-1 and increased expression of N-cadherin. The induced EMT was associated with increased cell motility, invasiveness, and clonogenicity. These progression relevant behaviors were attenuated by treatment with Hh inhibitors cyclopamine and GDC-0449, and after knockdown by Shh-siRNA, and led to reversal of the EMT phenotype. The results with HTB-9 were confirmed using a second bladder cancer cell line, BFTC905 (DM). In a xenograft mouse model TGF-beta1 treated HTB-9 cells exhibited enhanced tumor growth. Although normal bladder epithelial cells could also undergo EMT and upregulate Shh with TGF-beta1 they did not exhibit tumorigenicity. The TGF-beta1 treated HTB-9 xenografts showed strong evidence for a switch to a more stem cell like phenotype, with functional activation of CD133, Sox2, Nanog, and Oct4. The bladder cancer specific stem cell markers CK5 and CK14 were upregulated in the TGF-beta1 treated xenograft tumor samples, while CD44 remained unchanged in both treated and untreated tumors. Immunohistochemical analysis of 22 primary human bladder tumors indicated that Shh expression was positively correlated with tumor grade and stage. Elevated expression of Ki-67, Shh, Gli2, and N-cadherin were observed in the high grade and stage human bladder tumor samples, and conversely, the downregulation of these genes were observed in the low grade and stage tumor samples. Collectively, this study indicates that TGF-beta1-induced Shh may regulate EMT and tumorigenicity in bladder cancer. Our studies reveal that the TGF-beta1 induction of EMT and Shh is cell type context dependent. Thus, targeting the Shh pathway could be clinically beneficial in the ability to reverse the EMT phenotype of tumor cells and potentially inhibit bladder cancer progression and metastasis. PMID- 25728354 TI - Radiostereometric analysis of sacroiliac joint movement and outcomes of pelvic joint fusion. PMID- 25728355 TI - Nurse management of the NICU environment is critical to optimal infant development. PMID- 25728357 TI - Quantitative structure-activity relationship (QSAR) prediction of (eco)toxicity of short aliphatic protic ionic liquids. AB - Ionic liquids (ILs) are considered as a group of very promising compounds due to their excellent properties (practical non-volatility, high thermal stability and very good and diverse solving capacity). The ILs have a good prospect of replacing traditional organic solvents in vast variety of applications. However, the complete information on their environmental impact is still not available. There is also an enormous number of possible combinations of anions and cations which can form ILs, the fact that requires a method allowing the prediction of toxicity of existing and potential ILs. In this study, a group contribution QSAR model has been used in order to predict the (eco)toxicity of protic and aprotic ILs for five tests (Microtox(r), Pseudokirchneriella subcapitata and Lemna minor growth inhibition test, and Acetylcholinestherase inhibition and Cell viability assay with IPC-81 cells). The predicted and experimental toxicity are well correlated. A prediction of EC50 for these (eco)toxicity tests has also been made for eight representatives of the new family of short aliphatic protic ILs, whose toxicity has not been determined experimentally to date. The QSAR model applied in this study can allow the selection of potentially less toxic ILs amongst the existing ones (e.g. in the case of aprotic ILs), but it can also be very helpful in directing the synthesis efforts toward developing new "greener" ILs respectful with the environment (e.g. short aliphatic protic ILs). PMID- 25728356 TI - Race and sex disparities in prehospital recognition of acute stroke. AB - OBJECTIVES: The objective of this study was to examine prehospital provider recognition of stroke by race and sex. METHODS: Diagnoses at emergency department (ED) and hospital discharge from a statewide database in California were linked to prehospital diagnoses from an electronic database from two counties in Northern California from January 2005 to December 2007 using probabilistic linkage. All patients 18 years and older, transported by ambulances (n = 309,866) within the two counties, and patients with hospital-based discharge diagnoses of stroke (n = 10,719) were included in the study. Logistic regression was used to analyze the independent association of race and sex with the correct prehospital diagnosis of stroke. RESULTS: There were 10,719 patients discharged with primary diagnoses of stroke. Of those, 3,787 (35%) were transported by emergency medical services providers. Overall, 32% of patients ultimately diagnosed with stroke were identified in the prehospital setting. Correct prehospital recognition of stroke was lower among Hispanic patients (odds ratio [OR] = 0.77, 95% confidence interval [CI] 0.61 to 0.96), Asians (OR = 0.66, 95% CI 0.55 to 0.80), and others (OR = 0.71, 95% CI = 0.53 to 0.94), when compared with non-Hispanic whites, and in women compared with men (OR = 0.82, 95% CI = 0.71 to 0.94). Specificity for recognizing stroke was lower in females than males (OR = 0.84, 95% CI = 0.78 to 0.90). CONCLUSIONS: Significant disparities exist in prehospital stroke recognition. PMID- 25728358 TI - Assessment of the toxic effect exerted by fluorescent pseudomonads on embryos and larvae of the sea urchin Strongylocentrotus nudus. AB - Strains of bacteria capable of growing on artificial culture media were isolated from the fouling of brass plates submerged in Nha Trang Bay, South China Sea, and from tissues of the seastar Distolasterias nipon, caught in Peter the Great Bay, Sea of Japan. According to the complex of data of genetic and physiological/biochemical analyzes, two strains of cultivated bacteria were identified by us as the species Pseudomonas aeruginosa, two strains as Pseudomonas fluorescens, and one strain as Ruegeria sp. It was shown that the cultivated strains of P. aeruginosa released exotoxins, particularly phenazine pigments, into the environment. Production of the toxins did not depend on presence of a target organism in the system and was aimed at regulation of interactions in the microbial community. The toxicity of the studied natural isolates of fluorescent pseudomonads was analyzed by using embryos and larvae of the sea urchin Strongylocentrotus nudus, which are the sensitive and dynamic toxicological sea-urchin embryo test (SET) system. As was established, exotoxins produced by the strains of P. aeruginosa inhibit activity of cilia in sea urchin larvae, as well as disturb processes of cell differentiation in embryos and larvae. Their toxic influence is accompanied by disturbances of protein synthesis and the disruptions of cytoskeleton in the course of zygote cleavage and larval development. Unlike P. aeruginosa, the strains of P. fluorescens and Ruegeria sp. did not exert the toxic effect on SET. The obtained data allow considering objects of the environment as the natural reservoir of opportunistic microorganisms posing a potential threat to human, whereas the use of SET for determination of toxicity of isolated bacteria provides an opportunity to study the mechanisms of their interactions with organisms in marine ecosystems. PMID- 25728359 TI - Effects of Bacillus thuringiensis israelensis and spinosad on adult emergence of the non-biting midges Polypedilum nubifer (Skuse) and Tanytarsus curticornis Kieffer (Diptera: Chironomidae) in coastal wetlands. AB - To optimize their efficacy, some insecticides used for mosquito control are introduced into aquatic ecosystems where mosquito larvae develop (marshes, ponds, sanitation devices) and cannot escape from the treated water. However, this raises the question of possible effects of mosquito larvicides on non-target aquatic species. Bacillus thuringiensis var. israelensis (Bti), which is well known for its selectivity for Nematocera dipterans, is widely used for mosquito control all over the world. Spinosad, a mixture of spinosyns A and D known as fermentation products of a soil actinomycete (Saccharopolyspora spinosa), is a biological neurotoxic insecticide with a broader action spectrum. It is a candidate larvicide for mosquito control, but some studies showed that it may be toxic to beneficial or non-target species, including non-biting midges. The present study was therefore undertaken to assess the impact of Bti and spinosad on natural populations of Polypedilum nubifer (Skuse) and Tanytarsus curticornis Kieffer (Diptera: Chironomidae) in field enclosures implemented in Mediterranean coastal wetlands. Unlike Bti, spinosad had a strong lethal effect on P. nubifer and seems to affect T. curticornis at presumed recommended rates for field application. Differences in the sensitivity of these two species to spinosad confirm that population dynamics need to be known for a proper assessment of the risk encountered by chironomids in wetlands where larvicide-based mosquito control occurs. PMID- 25728360 TI - Regional variations in percutaneous absorption of methimazole: an in vitro study on cat skin. AB - The use of transdermal gel medications in cats has become popular in veterinary medicine due to the ease of administration compared to oral medication. The research to support systemic absorption of drugs after transdermal gel administration and the preferred skin region to apply these drugs in cats is limited. The aim of this study was to characterize the effect of different skin regions on the percutaneous absorption pharmacokinetics of a commercially available transdermal methimazole after a finite dose was applied to feline skin in vitro. A commercial formulation of methimazole (10 mg) was applied to four skin regions (the inner stratum corneum of the ear, groin, neck, and thorax regions) from six cats. The receptor medium was sampled up to 36 h postapplication, and methimazole concentrations were measured using high performance liquid chromatography. Methimazole was absorbed more completely across the pinnal skin, compared to the groin, neck, and thorax (P < 0.001), which justifies application to the pinna to maximize efficacy and also to minimize the effects of grooming. PMID- 25728361 TI - Quantitative CT evaluation in patients with combined pulmonary fibrosis and emphysema: correlation with pulmonary function. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate the correlations between objective quantitative computed tomography (CT) measurements of the extent of emphysematous and fibrotic lesions and the results of pulmonary function tests (PFTs) in patients with combined pulmonary fibrosis and emphysema (CPFE). MATERIALS AND METHODS: This study involved 43 CPFE patients who underwent CT and PFTs. The extent of emphysematous lesions was obtained by calculating the percentage of low attenuation area (%LAA) values lower than -950 Hounsfield units (HU). Fibrotic lesions were defined as high attenuation area (HAA) using thresholds with pixels between 0 and -700 HU, and the extent of fibrosis was obtained by calculating the percentage of HAA (%HAA). The correlations of %LAA and %HAA with PFTs were evaluated by the Spearman rank correlation coefficients and multiple linear regression analysis. RESULTS: A significant negative correlation was found between %HAA and diffusing capacity of the lung for carbon monoxide (DLco) %predicted (rho = -0.747; P < .001), whereas no significant correlation was found between %LAA and DLco %predicted. On multiple linear regression analysis, although the %HAA and %LAA were independent contributors to DLco %predicted, the predictive power of %HAA was superior to that of %LAA. CONCLUSIONS: In CPFE, the extent of fibrosis has a more significant impact on DLco than emphysema. PMID- 25728362 TI - CD39+ regulatory T cells attenuate allergic airway inflammation. AB - BACKGROUND: The suppressive mechanism of regulatory T cells (Tregs) has remained incompletely clarified. Recent studies found that CD39 expressed by Tregs may participate in the immunoregulatory role of Tregs. CD39-induced ATP hydrolysis and/or adenosine generation contribute to the suppressive mechanism of Tregs. Previous studies suggested that ATP is involved in allergic airway inflammation by acting on type 2 purinergic (P2) receptors, but the role of CD39 and CD39(+) Tregs in allergic airway inflammation has not been elaborated. OBJECTIVE: To investigate the role and underlying mechanism of CD39 expression by Tregs in allergic airway inflammation. METHODS: A model of allergic asthma was developed with ovalbumin-alum in female Cd39 wild type (Cd39(+/+) ) and deficient (Cd39(-/ ) ) C57BL/6 mice. Foxp3-GFP knock-in Cd39(+/+) and Cd39(-/-) mice were used to sort CD4(+) GFP(+) cells (Tregs) for exploring the role of CD39 expression by Tregs in allergic asthma. The effects of modulating CD39 activity with ARL67156 (inhibitor) or apyrase were also observed. RESULTS: ARL67156 greatly worsened airway inflammation including increased lung inflammatory cells infiltration, goblet cell hyperplasia, and higher levels of Th2 and Th17 cytokines in bronchoalveolar lavage fluid (BALF), accompanied by an increment in transcription factor (GATA-3 and RORgammat) and P2R (P2Y2, P2Y4 and P2Y6) mRNA expression in lungs. This potentiating effect was rescued by intratracheal injection of apyrase. Airway inflammation was markedly increased in Cd39(-/-) mice compared to Cd39(+/+) mice. In contrast to CD39(-) Tregs, CD39(+) Tregs showed stronger suppressive effects on airway inflammation. In vitro suppression assay suggested that CD39(+) Tregs have more potent suppressive effect on cytokines secretion from CD4(+) CD25(-) responder T cells and the inhibitory effects were reduced by addition of adenosine A2A receptor antagonist. CONCLUSION: CD39 expressed on Tregs participates in the regulation of limiting allergic airway inflammation by regulating extracellular ATP and/or adenosine. CD39 may represent a new therapeutic target for asthma. PMID- 25728363 TI - Release of anti-inflammatory peptides from thermosensitive nanoparticles with degradable cross-links suppresses pro-inflammatory cytokine production. AB - Pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) are mediators in the development of many inflammatory diseases. To demonstrate that macrophages take up and respond to thermosensitive nanoparticle drug carriers, we synthesized PEGylated poly(N-isopropylacrylamide-2 acrylamido-2-methyl-1-propanesulfonate) particles cross-linked with degradable disulfide (N,N'-bis(acryloyl)cystamine) (NGPEGSS). An anti-inflammatory peptide (KAFAK) was loaded and released from the thermosensitive nanoparticles and shown to suppress levels of TNF-alpha and IL-6 production in macrophages. Cellular uptake of fluorescent, thermosensitive, and degradable nanoparticles and therapeutic efficacy of free KAFAK peptide compared to that of KAFAK loaded in PEGylated degradable thermosensitive nanoparticles were examined. The data suggests that the degradable, thermosensitive nanoparticles loaded with KAFAK may be an effective tool to treat inflammatory diseases. PMID- 25728364 TI - Reversible redox modifications in the microglial proteome challenged by beta amyloid. AB - Microglia are resident macrophages in the central nervous system, whose participation against exogenous injuries and infections is mainly marked by an immediate release of inflammatory cytokines along with a toxic efflux of superoxide radicals. Indeed, many lines of evidence indicate that persistent activation of these cells turns their neuroprotective phenotype into a neurotoxic one, which contributes to destroy neuronal activity and induces neuronal loss in several neurodegeneration processes, such as Alzheimer's disease. In this study we attempted to fill-in the gap in our knowledge about redox regulation of amyloid activated microglia. With this aim, we carried out a robust and comprehensive characterization of the reversibly redox modified proteome both at the level of resting and amyloid-activated BV2 cells, an immortalised cell line of murine microglia. The approach we used combined the selective enrichment of reversible redox modified proteins through a biotin bait with nanoscale liquid chromatography tandem mass spectrometry of their proteolytic peptides. By this reliable approach, we identified 60 proteins changing the redox status of their selective cysteine residues upon treatment with the amyloidogenic Abeta25-35 peptide. These results assessed that in microglia stimulated by amyloids, redox modifications of the proteome specifically target proteins involved in crucial cell processes, i.e. those involved in the protein synthesis. In particular, for peroxiredoxin-6 (Prdx6) and Ras-related C3 botulinum toxin substrate 1 (Rac1) we suggest mechanisms through which reversible redox modifications could affect the peculiar role of microglia in amyloidogenic injury, which at the same time reinforce the oxidative burst and resist toward it. Moreover, the redox modulation we observed on chloride intracellular channel protein 1 (CLIC1) strengthens the structural and functional relationship between the oxidative stress and the metamorphic transition of this protein from a soluble form to an integral membrane form. The redox signatures we determined might also provide neurologists with more specific and reliable biomarkers to distinguish the diverse microglia status in neurodegeneration and then to drive targeted drug design. PMID- 25728365 TI - Lung function following very preterm birth in the era of 'new' bronchopulmonary dysplasia. AB - One of the most significant complications of preterm birth is bronchopulmonary dysplasia (BPD). The pathophysiology of BPD has changed in recent years as advances in neonatal care have led to increased survival of smaller, more preterm, infants who display alterations to alveolar and pulmonary microvascular development. It is becoming clear that infants with 'new' BPD experience lung disease that persists into later childhood, however, the oldest of these children are just now entering young adulthood and therefore the longer term pulmonary implications remain unknown. The role of lung function testing in the identification and subsequent management of patients with lung disease resulting from a neonatal classification of BPD is reviewed based on the underlying pathophysiology of the disease. PMID- 25728366 TI - Inflammation-induced activation of the indoleamine 2,3-dioxygenase pathway: Relevance to cancer-related fatigue. AB - Cancer-related fatigue (CRF) is a common complication of cancer and its treatment that can significantly impair quality of life. Although the specific mechanisms remain poorly understood, inflammation is now considered to be a distinct component of CRF in addition to effects of depression, anxiety, insomnia, and other factors. One key biological pathway that may link inflammation and CRF is indoleamine 2,3-dioxygenase (IDO). Induced by inflammatory stimuli, IDO catabolizes tryptophan to kynurenine (KYN), which is subsequently converted into neuroactive metabolites. Here we summarize current knowledge concerning the relevance of the IDO pathway to CRF, including activation of the IDO pathway in cancer patients and, as a consequence, accumulation of neurotoxic KYN metabolites and depletion of serotonin in the brain. Because IDO inhibitors are already being evaluated as therapeutic agents in cancer, the elucidation of the relationship between IDO activation and CRF in cancer patients may lead to novel diagnostic and clinical approaches to managing CRF and its debilitating consequences. PMID- 25728367 TI - Filamentous fungal infections of the cornea: a global overview of epidemiology and drug sensitivity. AB - Fungal keratitis is a serious suppurative, usually ulcerative corneal infection which may result in blindness or reduced vision. Epidemiological studies indicate that the occurrence of fungal keratitis is higher in warm, humid regions with agricultural economy. The most frequent filamentous fungal genera among the causal agents are Fusarium, Aspergillus and Curvularia. A more successful therapy of fungal keratitis relies on precise identification of the pathogen to the species level using molecular tools. As the sequence analysis of the internal transcribed spacer (ITS) region of the ribosomal RNA gene cluster (rDNA) is not discriminative enough to reveal a species-level diagnosis for several filamentous fungal species highly relevant in keratitis infections, analysis of other loci is also required for an exact diagnosis. Molecular identifications may also reveal the involvement of fungal species which were not previously reported from corneal infections. The routinely applied chemotherapy of fungal keratitis is based on the topical and systemic administration of polyenes and azole compounds. Antifungal susceptibility testing of the causal agents is of special importance due to the emergence and spread of resistance. Testing the applicability of further available antifungals and screening for new, potential compounds for the therapy of fungal keratitis are of highlighted interest. PMID- 25728368 TI - Direct detection of Mycobacterium tuberculosis in sputum using combined solid phase extraction-gas chromatography-mass spectrometry. AB - Recently, thermally-assisted hydrolysis and methylation followed by gas chromatography-mass spectrometry (THM-GC-MS) in combination with chemometrics has been used to develop a 20-compound model for fast differentiation of Mycobacterium tuberculosis (MTB) from Non-tuberculous mycobacteria (NTM) in bacterial cultures. This model provided better than 95% accuracy. In our current work a hexane/methanol/water extraction followed by a solid phase extraction (SPE) clean-up procedure was developed for use before THM-GC-MS, to make the test suitable for the identification of mycobacteria in sputum. The 20 biomarker model had to be adapted since many compounds were also found in the sputum of non tuberculosis patients. An algorithm was established based on tuberculostearic acid, hexacosanoic acid and mycoserosates. The detection limit of the method was approximately 1*10(4) bacteria/mL sputum. Sputum specimens from 32 patients from South Africa who were suspected of having tuberculosis were blindly tested using the new method. Eight of the nine culture-positive sputum specimens were detected by the new SPE-THM-GC-MS method, resulting in a sensitivity of 89%. The specimen that was missed by the new method was also microscopy negative. The specificity of the test was 100%; all 23 microscopy- and culture-negative specimens were correctly identified as negative by SPE-THM-GC-MS. PMID- 25728369 TI - HPLC separation and ultrasensitive optical quantification of ceramide species applying 7-(diethylamino)coumarin-3-carbonyl azide derivatisation. AB - Ceramides are derivatised using 7-(diethylamino)coumarin-3-carbonyl azide; subsequent gradient HPLC separation allows sensitive optical quantification of individual cellular ceramides. Compared to 9-anthracenecarbonyl cyanide (9 anthroyl nitrile) as derivatisation agent, the limit of detection could be improved 415-fold, respectively 10,000-fold (detection limit 0.6 pmol labelled ceramide/sample) when compared to benzoyl chloride-labelling. Acidic or alkaline catalysts are not required, enabling drying and storing of the labelled samples and a free choice of solvents for subsequent HPLC-separation. The quantitative method is characterised by high sensitivity, linearity and robustness in the pico to nanomolar concentration range and does not require mass-spectrometry for quantification of cellular ceramides. PMID- 25728370 TI - Determination of zolpidem in human plasma by liquid chromatography-tandem mass spectrometry for clinical application. AB - Zolpidem (ZPD) is widely described for the short-term treatment of insomnia. We have developed and validated a simple and rapid liquid chromatography analytical method using tandem mass spectrometry (LC-MS/MS) for the quantification of ZPD in human plasma. Using dibucaine as an internal standard (IS), the analyte was extracted with methyl t-butyl ether (MTBE). Chromatographic separation of ZPD was performed on a reversed-phase Luna C18 column (50 mm * 2.0 mm i.d., 5 MUm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.0)-methanol (15:85, v/v) at a flow rate of 250 MUm/min. The total run-time was 2.5 min and the retention times of ZPD and IS were 0.66 and 0.74 min, respectively. The mass to-charge transition monitored for quantification of ZPD and IS was 308.2->235.2 and 344.0->271.0, respectively. The lower limit of quantification (LLOQ) using 100 MUL of human plasma was 0.05 ng/mL and the calibration curves were linear over a range of 0.05-200 ng/mL (r(2)>0.9964). The mean accuracy and precision for intra- and inter-run validation of ZPD were within acceptable limits. In the present LC-MS/MS method, we showed improved sensitivity for quantification of the ZPD in human plasma using lower volume of plasma compared with previously described analytical methods for ZPD. This validated method was successfully applied to a pharmacokinetic study in humans. PMID- 25728371 TI - Development of sample clean up methods for the analysis of Mycobacterium tuberculosis methyl mycocerosate biomarkers in sputum extracts by gas chromatography-mass spectrometry. AB - A proof of principle gas chromatography-mass spectrometry method is presented, in combination with clean up assays, aiming to improve the analysis of methyl mycocerosate tuberculosis biomarkers from sputum. Methyl mycocerosates are generated from the transesterification of phthiocerol dimycocerosates (PDIMs), extracted in petroleum ether from sputum of tuberculosis suspect patients. When a high matrix background is present in the sputum extracts, the identification of the chromatographic peaks corresponding to the methyl derivatives of PDIMs analytes may be hindered by the closely eluting methyl ether of cholesterol, usually an abundant matrix constituent frequently present in sputum samples. The purification procedures involving solid phase extraction (SPE) based methods with both commercial Isolute-Florisil cartridges, and purpose designed molecularly imprinted polymeric materials (MIPs), resulted in cleaner chromatograms, while the mycocerosates are still present. The clean-up performed on solutions of PDIMs and cholesterol standards in petroleum ether show that, depending on the solvent mix and on the type of SPE used, the recovery of PDIMs is between 64 and 70%, whilst most of the cholesterol is removed from the system. When applied to petroleum ether extracts from representative sputum samples, the clean-up procedures resulted in recoveries of 36-68% for PDIMs, allowing some superior detection of the target analytes. PMID- 25728372 TI - Homogeneous self-aligned liquid crystals on wrinkled-wall poly(dimethylsiloxane) via localised ion-beam irradiation. AB - We demonstrate self-aligned liquid crystals (LCs) using a wrinkled-wall polydimethylsiloxane (PDMS) wrinkle structure, which is a key factor to obtain a stable homogeneous alignment state with positive LCs. We constructed the wrinkled walls via localised surface exposure to IB radiation, which passed through a long length localised pattern mask. The creation of the wrinkled wall helped to align the LC molecules homogeneously because the wrinkled wall acted as a guide for the arrangement of positive LC molecules. In addition, we confirmed the stability of the alignment state as the width of the wrinkled wall was changed. Although this wrinkled-wall method is a non-contact method, LC alignment is achieved via an anisotropic topographical guide, which provides the LC molecules with stable homogeneous alignment. PMID- 25728373 TI - A systematic review of ovarian cancer and fear of recurrence. AB - OBJECTIVE: To assess demographic, medical, and psychological factors that are associated with fear of recurrence (FCR) in ovarian cancer patients. METHOD: We searched PubMed, EMBASE, Cochrane, CINAHL, and PsycINFO. For PubMed, a search using Medical Subject Headings (MeSH) was run, as well as a text-word search from 1990 to July of 2014. The search terms used consisted of ovarian terms, fear terms, and recurrence/progression themes. Title and abstract reviews were conducted by two independent reviewers to determine eligibility, and discrepancies were decided by a third reviewer. Full-text reviews of potentially eligible articles were conducted by the review team, which met regularly to ensure the reliability of eligibility ratings across all articles. RESULTS: A total of 15 articles met our inclusion criteria. Nine were quantitative studies that utilized a cross-sectional design, and the other six included three qualitative studies, two small intervention studies, and one study that utilized content analysis to explore written correspondence among ovarian cancer patients. FCR was reported as a significant concern for both older and younger women at both early and advanced stages. Women were distressed about recurrence at various times during their treatment and posttreatment. FCR was noted to be prevalent around cancer follow-up examinations. Many women reported not receiving adequate support for recurrence. FCR was also shown to be linked in some way to hopelessness, faith/spirituality, and posttraumatic stress disorder (PTSD). FCR was also linked to patients' anxiety about death and dying and uncertainty about the future of their medical health. SIGNIFICANCE OF RESULTS: This review demonstrates that FCR is prevalent in the ovarian cancer population. Moreover, cancer recurrence fears are not adequately assessed or treated. More information is needed on the factors that may be related to women's fears about recurrence of ovarian cancer. In addition, a validated measure of FCR among ovarian cancer patients as well as a treatment intervention are needed. PMID- 25728374 TI - Structural basis for substrate-specific acetylation of Nalpha-acetyltransferase Ard1 from Sulfolobus solfataricus. AB - Nalpha-acetyltransferases (Nats) possess a wide range of important biological functions. Their structures can vary according to the first two residues of their substrate. However, the mechanisms of substrate recognition and catalysis of Nats are elusive. Here, we present two structure of Sulfolobus solfataricus Ard1 (SsArd1), a member of the NatA family, at 2.13 and 1.84 A. Both structures contain coenzyme A, while the latter also contains a substrate-derived peptide. Sequential structure-based mutagenesis revealed that mutations of critical residues for CoA binding decreased the binding affinity of SsArd1 by 3 ~ 7-fold. Superimposition of SsArd1 (NatA) with human Naa50p (NatE) showed significant differences in key residues of enzymes near the first amino-acid position of the substrate peptide (Glu35 for SsArd1 and Val29 for Naa50p). Further enzyme activity assays revealed that the substrate specificity of SsArd1 could be altered from SSGTPT to MEEKVG by a range of Glu35 mutants. These studies provide not only a molecular elucidation of substrate recognition and specificity for the NatA family, but also insight into how members of the NAT family distinguish between amino acids at the substrate N-terminus from the ancient monomeric archaeal Ard1. PMID- 25728375 TI - First case of Neisseria meningitidis capsule null locus infection in China. AB - Invasive meningococcal diseases are rarely caused by capsule null locus (cnl) strains, which are unencapsulated owing to an absence of capsule synthesis genes. Only a few cases of cnl meningococcemia in severely immunocompromised patients have been reported. Here, we describe and discuss the first case of invasive disease in an immunocompetent patient due to a cnl strain of Neisseria meningitidis in China. We characterize this strain and discuss the special ST-198 complex of cnl. PMID- 25728376 TI - Heterozygote advantage at MHC DRB may influence response to infectious disease epizootics. AB - The effect of MHC polymorphism on individual fitness variation in the wild remains equivocal; however, much evidence suggests that heterozygote advantage is a major determinant. To understand the contribution of MHC polymorphism to individual disease resistance or susceptibility in natural populations, we investigated two MHC class II B loci, DQB and DRB, in the New Zealand sea lion (NZSL, Phocarctos hookeri). The NZSL is a threatened species which is unusually susceptible to death by bacterial infection at an early age; it has suffered three bacterial induced epizootics resulting in high mortality levels of young pups since 1997. The MHC DQB and DRB haplotypes of dead NZSL pups with known cause of death (bacteria, enteritis or trauma) were sequenced and reconstructed, compared to pups that survived beyond 2 months of age, and distinct MHC DRB allele frequency and genotype differences were identified. Two findings were striking: (i) one DRB allele was present only in dead pups, and (ii) one heterozygous DRB genotype, common in live pups, was absent from dead pups. These results are consistent with some functional relationship with these variants and suggest heterozygote advantage is operating at DRB. We found no association between heterozygosity and fitness at 17 microsatellite loci, indicating that general heterozygosity is not responsible for the effect on fitness detected here. This result may be a consequence of recurrent selection by multiple pathogen assault over recent years and highlights the importance of heterozygote advantage at MHC as a potential mechanism for fitness differences in wild populations. PMID- 25728377 TI - 150 years of BASF. PMID- 25728378 TI - Methane hydrate formation in confined nanospace can surpass nature. AB - Natural methane hydrates are believed to be the largest source of hydrocarbons on Earth. These structures are formed in specific locations such as deep-sea sediments and the permafrost based on demanding conditions of high pressure and low temperature. Here we report that, by taking advantage of the confinement effects on nanopore space, synthetic methane hydrates grow under mild conditions (3.5 MPa and 2 degrees C), with faster kinetics (within minutes) than nature, fully reversibly and with a nominal stoichiometry that mimics nature. The formation of the hydrate structures in nanospace and their similarity to natural hydrates is confirmed using inelastic neutron scattering experiments and synchrotron X-ray powder diffraction. These findings may be a step towards the application of a smart synthesis of methane hydrates in energy-demanding applications (for example, transportation). PMID- 25728379 TI - Supramolecular capsules from bilayer membrane scission driven by corannulene. AB - Self-assembly of polyaromatic systems has proved to be a powerful technique to construct nanoscale optoelectronic materials. However, attempts to develop self assembled nanomaterials guided by pristine polyaromatic molecules have been limited. Here the construction of photoactive nanocapsules through the scission of an aromatic bilayer membrane driven by curved corannulene intercalation is reported. The framework of the capsule consists of the lateral array of corannulene, a buckyball fragment. The supramolecular capsules exhibit photocatalytic activity to degrade encapsulated fluorescein dye molecules under sunlight irradiation. PMID- 25728380 TI - Plexogenic pulmonary arteriopathy in a cat with non-restrictive ventricular septal defect and chronic pulmonary hypertension. AB - A 10-week-old, male, domestic long-hair cat was medically managed for congenital heart disease over a period of 8 years. Regular clinical examinations, including sequential echocardiography, documented a non-restrictive paramembranous ventricular septal defect, secundum-type atrial septal defect and aortic dextroposition. Pulmonary arterial hypertension was diagnosed by the presence of high-velocity tricuspid regurgitation, bidirectional low velocity flow across the ventricular septal defect, pulmonary arterial dilation and severe right ventricular hypertrophy without evidence of pulmonary outflow tract obstruction. The cat remained clinically stable until it died suddenly at 8 years of age. Histopathology of the lungs found evidence of plexogenic pulmonary arteriopathy. Despite severe pulmonary vascular lesions, other post-mortem evidence of right heart failure was lacking and death was attributed to a fatal cardiac arrhythmia. In this case report of a cat with chronic pulmonary hypertension over 8 years, plexogenic lesions were found on histopathology. The microscopic findings resemble those previously reported in dogs. PMID- 25728382 TI - Pharmacokinetic evaluation of fluvoxamine for the treatment of anxiety disorders. AB - INTRODUCTION: Fluvoxamine is one of the most widely prescribed antidepressants and presents data from 30 years of clinical experience. AREAS COVERED: The present review article describes the pharmacokinetic properties of fluvoxamine and their implications for the treatment of anxiety disorders (AD). A search in the main database sources (Medline, Isi Web of Knowledge and Medscape) has been performed in order to obtain a comprehensive and balanced evaluation of fluvoxamine about the implications of its pharmacokinetic properties for the treatment of AD. The word 'fluvoxamine' has been associated with 'pharmacokinetics', 'interactions', 'generalized anxiety disorder', 'social anxiety disorder', 'social phobia', 'panic disorder', 'anxiety' and 'tolerability'. No restriction criteria were established in relation to methodology or year of publication. Only English-language articles have been selected. EXPERT OPINION: Fluvoxamine presents high tolerability and safety so that it can be considered as a therapeutic option in case of panic disorder and social anxiety disorder. In contrast, its weakness is in extended interaction with CYP450 enzymatic system that may limit its use in elderly or patients with medical comorbidities. Finally, data of efficacy about generalized anxiety disorder are very limited and preliminary so that it is not possible to draw any sound conclusions. PMID- 25728381 TI - Contribution of B-1a cells to systemic lupus erythematosus in the NZM2410 mouse model. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease of complex etiology in which B cells play a central role. An expanded number of B-1a cells have been consistently associated with murine lupus, and more recently with human SLE. We have identified Cdkn2c, a gene that controls cell cycle progression, as a key regulator of B-1a cell numbers and have associated Cdkn2c deficiency with autoimmune pathology, including the production of autoantibodies and the skewing of CD4(+) T cells toward inflammatory effector functions. We review the genetic studies that have led to these findings, as well as the possible mechanisms by which B-1a cell expansion and Cdkn2c deficiency are related to SLE pathogenesis. PMID- 25728383 TI - Tibial tuberosity fracture with a proximal triplane extension--a case report. PMID- 25728386 TI - The role of Sn in enhancing the visible-light photocatalytic activity of hollow hierarchical microspheres of the Bi/BiOBr heterojunction. AB - Hollow hierarchical microspheres of Bi/BiOBr (SBB) with oxygen vacancies were prepared using a one step solvothermal method. It was found that the stannous chloride dihydrate played key roles in the formation of Bi, defects and the stacking mode of hierarchical construction units. Positron annihilation lifetime spectroscopy (PALS) was used to demonstrate the oxygen vacancies in Bi/BiOBr samples. The density of states (DOS) of the valence band of BiOBr can be modulated by the introduction of oxygen vacancies according to the valence band XPS and Density Functional Theory (DFT) calculations. Analyses of photoluminescence and BET demonstrated that SBB hollow hierarchical microspheres with higher specific surface area have a lower recombination rate of photo generated electrons and holes. The photocatalytic and adsorptive performances showed that the samples exhibited stronger adsorption capacity toward rhodamine B (RhB) and highly efficient photocatalytic activity in the degradation of RhB, which were attributed to the higher adsorption ability and synergistic effect of oxygen vacancies and construction of the heterojunction structure (Bi/BiOBr). PMID- 25728387 TI - Surgical outcomes of facial nerve hemangiomas in temporal bones. AB - OBJECTIVE: To report surgical outcomes of 15 cases who had facial nerve hemangiomas. METHODS: All cases underwent complete removal of hemangiomas, and preservation of nerve integrity was attempted. The postoperative outcomes of facial nerve was assessed. RESULTS: Nerve integrity was successfully preserved in 10 cases, all of which maintained or recovered to Grade I or Grade II, and facial nerve was sacrificed in 5 cases, who recovered to Grade III or Grade IV. CONCLUSIONS: When possible, facial nerve preservation should be attempted, which was critical to yield better outcomes of facial nerve. PMID- 25728388 TI - The association of plasma vitamin A and E levels with coronary collateral circulation. AB - OBJECTIVE: To investigate if plasma levels of vitamin A and E have an association with coronary collateral development. METHODS: A total of 189 patients who underwent coronary angiography and had total occlusion in at least one major epicardial coronary artery were enrolled in the study. To classify coronary collateral circulation (CCC), the Rentrop scoring system was used. Patients were classified as having poor CCC (Rentrop grades 0-1) or good CCC (Rentrop grades 2 3), and all patients were also screened for hypertension, hypercholesterolemia, diabetes, and smoking history. RESULTS: There were no differences in plasma vitamin A and E levels between the two groups (vitamin A: 2.37 +/- 0.65 vs. 2.35 +/- 0.78, p = 0.253; vitamin E: 47.1 +/- 12.8 vs. 44.6 +/- 15.1, p = 0.082), and plasma vitamin A and E levels were not associated with CCC. Serum high sensitivity C-reactive protein (hs-CRP) levels were significantly higher in patients with poor CCC (4.68 +/- 2.52 vs. 3.89 +/- 1.78, p = 0.001). The higher frequency of diabetes and higher serum hs-CRP levels were found to be an independent predictor for poor CCC (odds ratio = 2.44, p = 0.006; odds ratio = 1.24, p = 0.007, respectively). And a higher frequency of total occluded RCA was found to be a positive predictor for good CCC (odds ratio = 2.36, p = 0.06) in a multivariate logistic regression analysis. CONCLUSIONS: We found that serum hs CRP levels, presence of diabetes, and total occlusion of RCA have an effect on coronary collateral development. We found no correlation between plasma vitamin A and E levels and CCC. PMID- 25728389 TI - Coxiella burnetii: turning hostility into a home. AB - Coxiella burnetii, the causative agent of the human disease Q fever, is a unique intracellular bacterial pathogen. Coxiella replicates to high numbers within a pathogen-derived lysosome-like vacuole, thriving within a low pH, highly proteolytic and oxidative environment. In 2009, researchers developed means to axenically culture Coxiella paving the way for the development of tools to genetically manipulate the organism. These advances have revolutionized our capacity to examine the pathogenesis of Coxiella. In recent years, targeted and random mutant strains have been used to demonstrate that the Dot/Icm type IV secretion system is essential for intracellular replication of Coxiella. Current research is focused towards understanding the unique cohort of over 130 effector proteins that are translocated into the host cell. Mutagenesis screens have been employed to identify effectors that play important roles for the biogenesis of the Coxiella-containing vacuole and intracellular replication of Coxiella. A surprisingly high number of effector mutants demonstrate significant intracellular growth defects, and future studies on the molecular function of these effectors will provide great insight into the pathogenesis of Coxiella. Already, this expanse of new data implicates many eukaryotic processes that are targeted by the arsenal of Coxiella effectors including autophagy, apoptosis and vesicular trafficking. PMID- 25728390 TI - Distinct invasion strategies operating within a natural annual plant system. AB - Alien plant species are known to have a wide range of impacts on recipient communities, from resident species' exclusions to coexistence with resident species. It remains unclear; however, if this variety of impacts is due to different invader strategies, features of recipient communities or both. To test this, we examined multiple plant invasions of a single ecosystem in southwestern Australia. We used extensive community data to calculate pairwise segregation between target alien species and many co-occurring species. We related segregation to species' positions along community trait hierarchies and identified at least two distinct invasion strategies: 'exploiters' which occupy high positions along key trait hierarchies and reduce local native species diversity (particularly in nutrient-enriched situations), and 'coexisters' who occupy intermediate trait positions and have no discernable impact on native diversity. We conclude that trait hierarchies, linked to measures of competition, can provide valuable insights about the processes driving different invasion outcomes. PMID- 25728391 TI - A Note on the Comparative Statics of Pay-for-Performance in Health Care. AB - Pay-for-performance (P4P) is a widely implemented quality improvement strategy in health care that has generated much enthusiasm, but only limited empirical evidence to support its effectiveness. Researchers have speculated that flawed program designs or weak financial incentives may be to blame, but the reason for P4P's limited success may be more fundamental. When P4P rewards multiple services, it creates a special case of the well-known multitasking problem, where incentives to increase some rewarded activities are blunted by countervailing incentives to focus on other rewarded activities: these incentives may cancel each other out with little net effect on quality. This paper analyzes the comparative statics of a P4P model to show that when P4P rewards multiple services in a setting of multitasking and joint production, the change in both rewarded and unrewarded services is generally ambiguous. This result contrasts with the commonly held intuition that P4P should increase rewarded activities. PMID- 25728392 TI - PIP4K and the role of nuclear phosphoinositides in tumour suppression. AB - Phosphatidylinositol-5-phosphate (PtdIns5P)-4-kinases (PIP4Ks) are stress regulated lipid kinases that phosphorylate PtdIns5P to generate PtdIns(4,5)P2. There are three isoforms of PIP4Ks: PIP4K2A, 2B and 2C, which localise to different subcellular compartments with the PIP4K2B isoform being localised predominantly in the nucleus. Suppression of PIP4K expression selectively prevents tumour cell growth in vitro and prevents tumour development in mice that have lost the tumour suppressor p53. p53 is lost or mutated in over 70% of all human tumours. These studies suggest that inhibition of PIP4K signalling constitutes a novel anti-cancer therapeutic target. In this review we will discuss the role of PIP4K in tumour suppression and speculate on how PIP4K modulates nuclear phosphoinositides (PPIns) and how this might impact on nuclear functions to regulate cell growth. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25728393 TI - Fluoro amino acids: a rarity in nature, yet a prospect for protein engineering. AB - Fluoro amino acids are highly valuable compounds constantly gaining relevance in diverse fields of the biosciences as well as in the pharmaceutical industry. The value of these compounds can be attributed to the properties of the extremely electronegative fluorine atom. This atom forms a highly polarized bond of extraordinary strength with carbon. The formation of the fluorine-carbon bond is challenging: its chemical synthesis demands harsh reaction conditions and to date only one class of enzyme has been found capable of introducing the fluoride ion into an organic compound. Most of these fluorinating enzymes participate in the biosynthesis of 4-fluoro-L-threonine, the only fluoro amino acid of natural origin discovered so far. Despite their scarcity in nature, fluoro amino acids are valuable tools to fluorinate proteins. The fluoro protein variants often show improved stability and folding as well as altered activity and fluorescence characteristics. This review details the biosynthesis of 4-fluoro-L-threonine with a special focus on the fluorinating enzymes. Moreover, we elaborate on the application of fluoro amino acids as building blocks for fluorinated protein variants. Insight into different techniques to incorporate fluoro amino acids into proteins is also provided. We highlight prospects and the current relevance of fluoro amino acids as a tool to engineer proteins with novel traits. PMID- 25728394 TI - Comparative proteomics of a tor inducible Aspergillus fumigatus mutant reveals involvement of the Tor kinase in iron regulation. AB - The Tor (target of rapamycin) kinase is one of the major regulatory nodes in eukaryotes. Here, we analyzed the Tor kinase in Aspergillus fumigatus, which is the most important airborne fungal pathogen of humans. Because deletion of the single tor gene was apparently lethal, we generated a conditional lethal tor mutant by replacing the endogenous tor gene by the inducible xylp-tor gene cassette. By both 2DE and gel-free LC-MS/MS, we found that Tor controls a variety of proteins involved in nutrient sensing, stress response, cell cycle progression, protein biosynthesis and degradation, but also processes in mitochondria, such as respiration and ornithine metabolism, which is required for siderophore formation. qRT-PCR analyses indicated that mRNA levels of ornithine biosynthesis genes were increased under iron limitation. When tor was repressed, iron regulation was lost. In a deletion mutant of the iron regulator HapX also carrying the xylp-tor cassette, the regulation upon iron deprivation was similar to that of the single tor inducible mutant strain. In line, hapX expression was significantly reduced when tor was repressed. Thus, Tor acts either upstream of HapX or independently of HapX as a repressor of the ornithine biosynthesis genes and thereby regulates the production of siderophores. PMID- 25728395 TI - Influences of use activities and waste management on environmental releases of engineered nanomaterials. AB - Engineered nanomaterials (ENM) offer enhanced or new functionalities and properties that are used in various products. This also entails potential environmental risks in terms of hazard and exposure. However, hazard and exposure assessment for ENM still suffer from insufficient knowledge particularly for product-related releases and environmental fate and behavior. This study therefore analyzes the multiple impacts of the product use, the properties of the matrix material, and the related waste management system (WMS) on the predicted environmental concentration (PEC) by applying nine prospective life cycle release scenarios based on reasonable assumptions. The products studied here are clothing textiles treated with silver nanoparticles (AgNPs), since they constitute a controversial application. Surprisingly, the results show counter-intuitive increases by a factor of 2.6 in PEC values for the air compartment in minimal AgNP release scenarios. Also, air releases can shift from washing to wearing activity; their associated release points may shift accordingly, potentially altering release hot spots. Additionally, at end-of-life, the fraction of AgNP residues contained on exported textiles can be increased by 350% when assuming short product lifespans and globalized WMS. It becomes evident that certain combinations of use activities, matrix material characteristics, and WMS can influence the regional PEC by several orders of magnitude. Thus, in the light of the findings and expected ENM market potential, future assessments should consider these aspects to derive precautionary design alternatives and to enable prospective global and regional risk assessments. PMID- 25728396 TI - The experience of sleep in chronic fatigue syndrome: A qualitative interview study with patients. AB - OBJECTIVES: Sleep disturbances are common in chronic fatigue syndrome (CFS), and one of the key symptom complaints, yet it has been neglected by previous qualitative research. The aim was to explore the specific role of sleep in patients' experience of their illness. DESIGN: A qualitative semi-structured interview format facilitated a detailed and open exploration of sleep, and the extent to which its management and problems were linked to the lived experience of CFS. METHODS: Eleven semi-structured interviews were conducted with individuals with CFS. Data were transcribed verbatim and analysed thematically, to explore and describe patients' experience of their sleep, and its impact on their condition. RESULTS: Sleep emerged as a key aspect of the illness experience, and its management and effect on daytime functioning was a central pre-occupation for all 11 participants; all of them saw sleep as playing a critical role in their illness through either maintaining or exacerbating existing symptoms. Exploration of individual experiences presented three overarching themes: (1) sleep pattern variability over illness course and from day to day; (2) effect of sleep on daytime functioning; and (3) attempts at coping and sleep management. CONCLUSIONS: Each patient with CFS has a unique experience of sleep. Despite the differing narratives regarding the role of sleep in CFS, all participants held the belief that sleep is a vital process for health and well-being which has had a direct bearing on the course and progression of their CFS. Also, every participant regarded their sleep as in some way 'broken' and in need of management/repair. Patients' insights demonstrate sleep-specific influences on their CFS, and the impact of disturbed sleep should be a consideration for clinical and research work. STATEMENT OF CONTRIBUTION: What is already known on this subject? Sleep disturbances are common in CFS, and one of the key symptom complaints, yet it has been neglected by previous qualitative research. Ontology of CFS is a matter of dispute, with models ranging from the biological to the psychological competing to explain symptomatology in this illness. A qualitative study has the potential to add some clarity to the debate by making the patients' lived experience of the condition, and their own understanding of it, the focus of research. What this study adds? Coping and attempts at managing sleep problems in CFS adds to the 'illness burden' experienced by patients. Disturbed sleep is universally seen by patients with CFS as impacting on other daytime symptoms. Broken sleep may contribute to a biopsychosocial cycle that serves to maintain this illness. PMID- 25728397 TI - Sonographic characteristics of the facial nerve in healthy volunteers. AB - INTRODUCTION: Peripheral nerve ultrasound has become an effective imaging technique. However, imaging of cranial nerves, especially in healthy volunteers, has received minimal attention. The objectives of this study were to describe the sonographic characteristics of the facial nerve and to establish average values of its diameter. METHODS: The extra-cranial part of the facial nerve was scanned bilaterally along its longitudinal axis inside the parotid gland using a 13-MHz probe in 50 healthy adults. The diameter was measured at the nerve's thickest region. RESULTS: The facial nerve appeared as a thin, tubular, hypoechoic structure inside the parotid gland. The mean facial nerve diameter was 0.5 +/- 0.1 mm, and the mean side-to-side difference in diameter was 0.1 +/- 0.1 mm. CONCLUSIONS: The average facial nerve diameter values may provide help with identification of nerve abnormalities using ultrasound. PMID- 25728398 TI - Elf5 inhibits TGF-beta-driven epithelial-mesenchymal transition in prostate cancer by repressing SMAD3 activation. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of migration, invasiveness, and metastasis traits. During tumor progression, EMT can be induced by transforming growth factor-beta (TGF-beta) signal that epithelial cells receive from their microenvironment. However, the master regulatory controls on TGF-beta-EMT axis are not understood. METHODS: The protein expression in human specimens was measured by immunohistochemical staining. E74-like factor 5 (Elf5) was silenced by short interfering RNAs in LNCaP cells and stably overexpressed by HA-tagged Elf5 cDNAs in 22Rv1 cells. These cells were used to study migration and anchorage-independent growth. RESULTS: Our data reveal that Elf5 results in the failure of mesenchymal morphogenesis, upregulation of EMT markers, spheres formation, and migration in the presence of TGF-beta. Furthermore, Elf5 blocks TGF-beta signaling, through decreasing drosophila mothers against decapentaplegic protein (SMAD3) activation by binding to it, one of the major effector of TGF-beta-induced EMT. Moreover, Elf5 can serve as a prognostic marker of metastasis-free survival in patients with TGF-beta-positive prostate cancer. CONCLUSIONS: Elf5 expression is inversely correlated with EMT. Elf5 inhibits TGF-beta-driven EMT via repressing SMAD3 phosphorylation in prostate cancer cells. In addition, Elf5 can be used as a biomarker of metastasis-free survival in patients with TGF-beta-positive prostate cancer. PMID- 25728399 TI - A single dose of S-ketamine induces long-term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation. AB - Ketamine, an antagonist of N-methyl-d-aspartate receptors, has produced rapid antidepressant effects in patients with depression, as well as in animal models. However, the extent and duration of the antidepressant effect over longer periods of time has not been considered. This study evaluated the effects of single dose of ketamine on behavior and oxidative stress, which is related to depression, in the brains of adult rats subjected to maternal deprivation. Deprived and nondeprived Wistar rats were divided into four groups nondeprived+saline; nondeprived+S-ketamine (15 mg/kg); deprived+saline; deprived+S-ketamine (15 mg/kg). A single dose of ketamine or saline was administrated during the adult phase, and 14 days later depressive-like behavior was assessed. In addition, lipid damage, protein damage, and antioxidant enzyme activities were evaluated in the rat brain. Maternal deprivation induces a depressive-like behavior, as verified by an increase in immobility and anhedonic behavior. However, a single dose of ketamine was able to reverse these alterations, showing long-term antidepressant effects. The brains of maternally deprived rats had an increase in protein oxidative damage and lipid peroxidation, but administration of a single dose of ketamine reversed this damage. The activities of antioxidant enzymes superoxide dismutase and catalase were reduced in the deprived rat brains. However, ketamine was also able to reverse these changes. In conclusion, these findings indicate that a single dose of ketamine is able to induce long-term antidepressant effects and protect against neural damage caused by oxidative stress in adulthood rats following maternal deprivation. PMID- 25728400 TI - Chromosome 1p36.22p36.21 duplications/triplication causes Setleis syndrome (focal facial dermal dysplasia type III). AB - Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype. PMID- 25728401 TI - Tricuspid Annular Plane Systolic Excursion and Its Association with Mortality in Critically Ill Patients. AB - BACKGROUND: Transient left ventricular dysfunction can occur under conditions of extreme emotional or physiological stress. There is little data on right ventricular function in such situations. METHODS: One hundred twenty patients admitted to an ICU with a noncardiac illness were studied. Those with documented coronary disease, ejection fraction <40%, sepsis, or intracranial hemorrhage were excluded. Echocardiograms were performed within 24 hours of admission. Tricuspid annular plane systolic excursion (TAPSE) was measured to assess right ventricular systolic function. Plasma catecholamines (norepinephrine, epinephrine, dopamine) were measured on admission. Clinical and demographic data were collected, along with data on ICU length of stay (LOS), hospital LOS, and in-hospital and long term mortality. TAPSE was tested for correlation with adverse outcomes and length of stay. RESULTS: Mean TAPSE for the group was 2.05 +/- 0.66 cm. Based on area under the ROC curve analysis, TAPSE <2.4 cm was the best cutoff for predicting in hospital and long-term mortality. There were 13 in-hospital deaths, 12 in the group with TAPSE <2.4 cm and one among those with TAPSE >=2.4 cm. On multivariate analysis, TAPSE <2.4 cm was a significant predictor of in-hospital mortality (chi(2) = 4.6, P = 0.03). When tested against hospital LOS, an inverse correlation was found (P = 0.04). No association was found between TAPSE and catecholamine levels. CONCLUSIONS: Right ventricular systolic function, as assessed by TAPSE, has important prognostic value in critically ill patients. Mean values were lower in patients who died in-hospital versus those who survived to discharge. In addition, patients with TAPSE <2.4 cm had a longer hospital length of stay. PMID- 25728402 TI - Microneedle biosensor for real-time electrical detection of nitric oxide for in situ cancer diagnosis during endomicroscopy. AB - A dual-diagnostic system of endom-icroscope and microneedle sensor is developed to demonstrate high-resolution imaging combined with electrical real-time detection of NO released from cancer tissues. The dual-diagnostic system can be a new platform for facile, precise, rapid, and accurate detection of cancers in various biomedical applications. PMID- 25728404 TI - Association of fetal biparietal diameter with mode of delivery and perinatal outcome. AB - OBJECTIVE: To determine the association between sonographic assessment of fetal biparietal diameter (BPD) and pregnancy outcome. METHODS: This was a retrospective cohort study of pregnancies at 37-42 weeks of gestation which had antepartum sonographic measurement of BPD within 7 days before delivery. Eligibility was limited to singleton pregnancies with neither known structural or chromosomal abnormalities nor prelabor Cesarean delivery (CD). The association of BPD with outcome was analyzed using multivariate logistic regression, receiver operating characteristics curves and stratification according to BPD quartiles. RESULTS: In total, 3229 women were eligible for analysis, of whom 2483 (76.9%) had a spontaneous vaginal delivery (SVD), 418 (12.9%) underwent operative vaginal delivery (OVD) and 328 (10.2%) underwent CD. The mean BPD in the obstetric intervention groups (OVD and CD) was significantly higher than that in the SVD group (P < 0.001). After adjusting for confounders, increased BPD was an independent risk factor such that higher values of BPD were associated with progressively higher risk of obstetric intervention (adjusted odds ratio, 1.05 for each 1-mm increase in BPD (95% CI, 1.02-1.09)), but no clear cut-off value for obstetric intervention was found. The fourth quartile group (BPD >= 97 mm) was associated with a significantly lower SVD rate (P < 0.001) and higher OVD rate (P = 0.04), relative to the first (BPD 88-90 mm) and second (BPD 91-93 mm) quartile groups, with no apparent adverse impact on immediate neonatal outcome. CONCLUSIONS: Increased BPD within the week prior to delivery is an independent risk factor such that higher values of BPD are associated with progressively higher risk of obstetric intervention; however, in our experience, no adverse neonatal outcome resulted from such intervention. Thus, increased BPD should not discourage a trial of vaginal delivery. PMID- 25728403 TI - Diabetes and epilepsy in children and adolescents. AB - Over the last years, there has been an increasing interest in the potential association between type 1 diabetes (T1D) and epilepsy. Both T1D and epilepsy are common conditions in children and adolescents, and therefore, their association might represent simply a coincidence or be related to common underlying mechanisms with a potential causal relationship. Few epidemiological studies have been performed in the pediatric population, and they have reached discordant conclusions, with some studies reporting an increased prevalence of epilepsy in children and adolescents with T1D, whereas others have not confirmed this finding. Several mechanisms could explain the occurrence of epilepsy in young people with T1D, such as metabolic abnormalities (hypo/hyperglycemia) and autoantibodies, along with a genetic predisposition and the presence of brain lesions/damage. Further studies are required to better define whether there is a causal relationship between the two conditions and to understand the underlying mechanisms. PMID- 25728405 TI - Surface-induced selection during in situ photoswitching at the solid/liquid interface. AB - Here we report for the first time a submolecularly resolved scanning tunneling microscopy (STM) study at the solid/liquid interface of the in situ reversible interconversion between two isomers of a diarylethene photoswitch, that is, open and closed form, self-assembled on a graphite surface. Prolonged irradiation with UV light led to the in situ irreversible formation of another isomer as by product of the reaction, which due to its preferential physisorption accumulates at the surface. By making use of a simple yet powerful thermodynamic model we provide a quantitative description for the observed surface-induced selection of one isomeric form. PMID- 25728406 TI - Identification of FAK substrate peptides via colorimetric screening of a one-bead one-peptide combinatorial library. AB - Focal adhesion kinase (FAK) is a protein tyrosine kinase that is associated with regulating cellular functions such as cell adhesion and migration and has emerged as an important target for cancer research. Short peptide substrates that are selectively and efficiently phosphorylated by FAK have not been previously identified and tested. Here we report the synthesis and screening of a one-bead one-peptide combinatorial library to identify novel substrates for FAK. Using a solid-phase colorimetric antibody tagging detection platform, the peptide beads phosphorylated by FAK were sequenced via Edman degradation and then validated through radioisotope kinetic studies with [gamma-(32)P] ATP to derive Michaelis Menton constants. The combination of results gathered from both colorimetric and radioisotope kinase assays led to the rational design of a second generation of FAK peptide substrates. Out of all the potential peptide substrates evaluated, the most active was GDYVEFKKK with a K(M) = 92 MUM and a Vmax = 1920 nmol/min/mg. Peptide substrates discovered within this study may be useful diagnostic tools for future kinase investigations and may lead to novel therapeutic agents. PMID- 25728408 TI - Contribution of Lidia cattle breed historical castes to the paternal genetic stock of Spain. AB - The main objective of this work was to determine whether the five founding castes defined in the Lidia cattle breed actually have an important contribution to the Spanish paternal genetic stock as well as to the paternal genetic origin support. A total of 1300 Bos taurus male individuals were genotyped for five microsatellites (INRA189, UMN0103, UMN0307, BM861 and BYM1) and one indel (ZFY10). Microsatellite and indel alleles were combined into haplotypes, identifying a total of 38 haplotypes, 11 of them belonging to haplogroup Y1 and 27 to haplogroup Y2. Ten different haplotypes were found in the Lidia cattle breed, with five being exclusive to this breed. Our results agree with different male genetic stocks in the Lidia breed: one hypothetically representing the ancient Iberian bovine genetic stock (Gallardo, Navarra and Cabrera castes and some encastes from Vistahermosa) and a second one that is the result of the more recent breeding strategy of choosing the most aggressive individuals from traditional herds (including some Vistahermosa encastes and the Vazquena caste). In terms of conservation, it would be better to not consider this breed as a unit but to consider the caste, or even better the encaste, as the target of putative conservation efforts. PMID- 25728407 TI - Safety evaluation of the human-identical milk monosaccharide, l-fucose. AB - l-Fucose is a natural monosaccharide present in mammals where it is found predominantly as an O-glycosidically linked component of glycoproteins, glycolipids, and oligosaccharides. It is also present in its free form in human breast milk (human milk monosaccharide). l-Fucose plays important roles in the development of the immune and nervous systems and is involved in cognitive function and memory formation. The human-identical milk monosaccharide l-fucose is therefore proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of l fucose, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. l-Fucose was without maternal toxicity or compound-related adverse effects on female reproduction and general growth and development of offspring at a maternal dietary level up to 1%, equivalent to a dose of 1655 mg/kg body weight (bw)/day. During the subchronic phase, no compound related adverse effects were observed in first generation rats at dietary levels of up to 1% (highest level tested), corresponding to doses of 516 and 665 mg/kg bw/day in males and females, respectively. l-Fucose was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of l-fucose in infant formula and as a food ingredient at levels equivalent to those present in human breast milk. PMID- 25728409 TI - Risk scores for hepatocellular carcinoma in chronic hepatitis B. PMID- 25728410 TI - Medications as a source of paraben exposure. AB - BACKGROUND: Parabens are used as antimicrobial excipients in some pharmaceuticals. Parabens may adversely affect reproduction. OBJECTIVES: Determine whether paraben-containing medication contributes to high urinary paraben concentrations. METHODS: Individuals at a fertility clinic provided multiple urine samples during evaluation/treatment and reported 24-h use of medications and personal care products (PCP). Repeated measures models compared specific gravity-adjusted urinary methyl, propyl, and butyl paraben concentrations between samples "exposed" and "unexposed" to paraben-containing medication. RESULTS: Eleven participants contributed 12 exposed and 45 unexposed samples, among which paraben concentrations did not differ. Use within 7h was associated with 8.7-fold and 7.5-fold increases in mean methyl (P=0.11) and propyl (P=0.10) paraben concentrations, respectively, after adjusting for PCP use. However, these associations decreased to 1.3-fold (P=0.76) and 2.6-fold (P=0.34), respectively, after removal of one influential individual. CONCLUSION: Paraben-containing medications contributed to higher urinary paraben concentrations within hours of use. PMID- 25728411 TI - Use of quantitative real-time RT-PCR to investigate the correlation between viremia and viral shedding of canine distemper virus, and infection outcomes in experimentally infected dogs. AB - We used real-time RT-PCR and virus titration to examine canine distemper virus (CDV) kinetics in peripheral blood and rectal and nasal secretions from 12 experimentally infected dogs. Real-time RT-PCR proved extremely sensitive, and the correlation between the two methods for rectal and nasal (r=0.78, 0.80) samples on the peak day of viral RNA was good. Although the dogs showed diverse symptoms, viral RNA kinetics were similar; the peak of viral RNA in the symptomatic dogs was consistent with the onset of symptoms. These results indicate that real-time RT-PCR is sufficiently sensitive to monitor CDV replication in experimentally infected dogs regardless of the degree of clinical manifestation and suggest that the peak of viral RNA reflects active CDV replication. PMID- 25728412 TI - In vivo sodium tungstate treatment prevents E-cadherin loss induced by diabetic serum in HK-2 cell line. AB - Diabetic nephropathy (DN) is characterized by interstitial inflammation and fibrosis, which is the result of chronic accumulation of extracellular matrix produced by activated fibroblasts in the renal tubulointerstitium. Renal proximal tubular epithelial cells (PTECs), through the process of epithelial-to mesenchymal transition (EMT), are the source of fibroblasts within the interstitial space, and loss of E-cadherin has shown to be one of the earliest steps in this event. Here, we studied the effect of the anti-diabetic agent sodium tungstate (NaW) in the loss of E-cadherin induced by transforming growth factor (TGF) beta-1, the best-characterized in vitro EMT promoter, and serum from untreated or NaW-treated diabetic rats in HK-2 cell line, a model of human kidney PTEC. Our results showed that both TGFbeta-1 and serum from diabetic rat induced a similar reduction in E-cadherin expression. However, E-cadherin loss induced by TGFbeta-1 was not reversed by NaW, whereas sera from NaW-treated rats were able to protect HK-2 cells. Searching for soluble mediators of NaW effect, we compared secretion of TGFbeta isoforms and vascular endothelial growth factor (VEGF)-A, which have opposite actions on EMT. One millimolar NaW alone reduced secretion of both TGFbeta-1 and -2, and stimulated secretion of VEGF-A after 48 h. However, these patterns of secretion were not observed after diabetic rat serum treatment, suggesting that protection from E-cadherin loss by serum from NaW-treated diabetic rats originates from an indirect rather than a direct effect of this salt on HK-2 cells, via a mechanism independent of TGFbeta and VEGF-A functions. PMID- 25728414 TI - Critical elements in the development of cell therapy potency assays for ischemic conditions. AB - A successful potency assay for a cell therapy product (CTP) used in the treatment of ischemic conditions should quantitatively measure relevant biological properties that predict therapeutic activity. This is especially challenging because of numerous degrees of complexity stemming from factors that include a multifactorial complex mechanism of action, cell source, inherent cell characteristics, culture method, administration mode and the in vivo conditions to which the cells are exposed. The expected biological function of a CTP encompasses complex interactions that range from a biochemical, metabolic or immunological activity to structural replacement of damaged tissue or organ. Therefore, the requirements for full characterization of the active substance with respect to biological function could be taxing. Moreover, the specific mechanism of action is often difficult to pinpoint to a specific molecular entity; rather, it is more dependent on the functionality of the cellular components acting in a in a multifactorial fashion. In the case of ischemic conditions, the cell therapy mechanism of action can vary from angiogenesis, vasculogenesis and arteriogenesis that may activate different pathways and clinical outcomes. The CTP cellular attributes with relation to the suggested mechanism of action can be used for the development of quantitative and reproducible analytical potency assays. CTPs selected and released on the basis of such potency assays should have the highest probability of providing meaningful clinical benefit for patients. This White Paper will discuss and give examples for key elements in the development of a potency assay for treatment of ischemic disorders treated by the use of CTPs. PMID- 25728413 TI - Gestational and lactational exposition to Di-N-butyl-phthalate (DBP) increases inflammation and preneoplastic lesions in prostate of wistar rats after carcinogenic N-methyl-N-nitrosourea (MNU) plus testosterone protocol. AB - In the present study, it was evaluated the susceptibility of prostatic lesions in male adult rats exposed to Di-N-butyl-phthalate during fetal and lactational periods and submitted to MNU plus testosterone carcinogenesis protocol. Pregnant females were distributed into four experimental groups: CN (negative control); CMNU (MNU control); TDBP100 (100 mg/kg of DBP); TDBP500 (500 mg/kg of DBP). Females from the TDBP groups received DBP, by gavage, from gestation day 15 (GD15) to postnatal day 21 (DPN21), while C animals received the vehicle (corn oil). CMNU, TDBP100, and TDBP500 groups received a single intraperitoneal injection of MNU (50 mg/kg) on the sixth postnatal week. After that, testosterone cypionate was administered subcutaneously two times a week (2 mg/kg) for 24 weeks. The animals were euthanized on PND220. Distal segment fragments of the ventral (VP) and dorsolateral prostate (DLP) were fixed and processed for histopathological analysis. Protein extracts from ventral prostate were obtained, and western blotting was performed to AR, ERalpha, MAPK (ERK1/2), and pan-AKT. Stereological analysis showed an increase in the epithelial compartment in TDBP100 and TDBP500 compared to CN. In general, there was increase in the incidence of inflammation and metaplasia/dysplasia in the DBP-treated groups, mainly in DLP, compared to CN and CMNU. Proliferation index was significant higher in TDBP500 and PIN (prostatic intraepithelial neoplasia) was more frequent in this group compared to CMNU. Western blot assays showed an increase in the expressions of AR and MAPK (ERK1/2) in the TDBP100 compared to CN, and ERalpha and AKT expressions were higher in the TDBP500 group compared do CN. These results showed that different doses of DBP during prostate organogenesis in Wistar rats could increase the incidence of premalignant lesions in initiated rats inducing distinct biological responses in the adulthood. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1185-1195, 2016. PMID- 25728415 TI - Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance. AB - BACKGROUND: von Willebrand factor (VWF) is cleared in a shear stress- and macrophage-dependent manner by LRP1. von Willebrand disease (VWD)-type 2B mutants are endocytosed more efficiently than wild-type (wt)-VWF by macrophages. OBJECTIVE: To investigate if VWD-type 2B mutations in the VWF A1-domain affect LRP1 binding and LRP1-dependent clearance. METHODS: Recombinant Fc-tagged A1 domain (A1-Fc, A2-Fc, A3-Fc) and full-length VWF (wt or mutants thereof) were tested for binding to LRP1 or a recombinant fragment thereof in a static immunosorbent assay. Mutant and wt-VWF were also compared for clearance in mice lacking macrophage LRP1 (macLRP1(-) ) and control mice (macLRP1(+) ). RESULTS: We found that A1-Fc but not A2-Fc or A3-Fc binds dose-dependently to LRP1. Binding of A1-Fc to LRP1 was markedly enhanced by the VWD-type 2B mutation p.V1316M. As expected, full-length wt-VWF was unable to bind LRP1 under static conditions unless ristocetin was added. In contrast, the presence of the p.V1316M or p.R1306Q mutation induced spontaneous binding to LRP1 without the need for ristocetin or shear stress. Both mutants were cleared more rapidly than wt-VWF in control macLRP1(+) mice. Surprisingly, deletion of macrophage LRP1 abrogated the increased clearance of the VWF/p.R1306Q and VWF/p.V1316M mutant. CONCLUSION: The VWF A1-domain contains a binding site for LRP1. Certain VWD-type 2B mutations relieve the need for shear stress to induce LRP1 binding. Enhanced LRP1 binding coincides with a reduced survival of VWF/p.R1306Q and VWF/p.V1316M. Our data provide a rationale for reduced VWF levels in at least some VWD-type 2B patients. PMID- 25728417 TI - The Concept of Identification in Threat Assessment. AB - Identification is one of eight warning behaviors--superordinate patterns of accelerating risk--that are theorized to correlate with targeted violence, and have some empirical validation. It is characterized by one or more of five characteristics: pseudo-commando behavior, evidence of a warrior mentality, a close association with weapons or other military or law enforcement paraphernalia, wanting to imitate and often surmount previous attackers or assassins, or believing oneself to be an agent to advance a particular cause or belief system. The authors briefly explore the history of the psychology of identification, its current usage, and its application to threat assessment. Four cases are used to illustrate identification as both a process and a product, and a likely motive for targeted violence in some subjects. Its operational relevance for threat assessment is suggested. PMID- 25728416 TI - Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors. AB - The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor. PMID- 25728418 TI - Preventive antibiotics in pediatric patients with acute myeloid leukemia (AML). AB - BACKGROUND: Treatment of acute myeloid leukemia (AML) comes with a significant risk of life-threatening infection during periods of prolonged severe neutropenia. We studied the impact of preventive intravenous (IV) antibiotic administration at onset of absolute neutropenia on the incidence and outcome of life-threatening infections during treatment of childhood AML. PROCEDURES: This is a retrospective study on pediatric patients (aged 0-18 years) consecutively diagnosed with de novo AML and treated at a single institution from April 2005 through February 2013. Patients were treated on the Children's Oncology Group (COG) AAML0531 protocol or with a modified United Kingdom Medical Research Council (UK MRC) AML 10 regimen. Pertinent data were extracted from hard copy or electronic chart review. RESULTS: A total of 76 chemotherapy phases were analyzed from 29 patients. In each phase reported, preventive antibiotics were initiated when the daily absolute neutrophil count was <500 cells/mcl, before onset of fever. Seven episodes of bacteremia were documented with predominantly coagulase negative staphylococci and viridans group streptococci. One infection-related death occurred, attributed to progressive respiratory failure occurring months after documented candidal pneumonia. CONCLUSIONS: Initiation of preventive antibiotics at the onset of absolute neutropenia was associated with no mortality from bacteremia. This preventive approach appears feasible and safe. PMID- 25728419 TI - Foreword to common childhood viral infections. PMID- 25728420 TI - Commentary: common childhood viral infections. PMID- 25728421 TI - Development of an in vivo glucosylation platform by coupling production to growth: Production of phenolic glucosides by a glycosyltransferase of Vitis vinifera. AB - Glycosylation of small molecules can significantly alter their properties such as solubility, stability, and/or bioactivity, making glycosides attractive and highly demanded compounds. Consequently, many biotechnological glycosylation approaches have been developed, with enzymatic synthesis and whole-cell biocatalysis as the most prominent techniques. However, most processes still suffer from low yields, production rates and inefficient UDP-sugar formation. To this end, a novel metabolic engineering strategy is presented for the in vivo glucosylation of small molecules in Escherichia coli W. This strategy focuses on the introduction of an alternative sucrose metabolism using sucrose phosphorylase for the direct and efficient generation of glucose 1-phosphate as precursor for UDP-glucose formation and fructose, which serves as a carbon source for growth. By targeted gene deletions, a split metabolism is created whereby glucose 1 phosphate is rerouted from the glycolysis to product formation (i.e., glucosylation). Further, the production pathway was enhanced by increasing and preserving the intracellular UDP-glucose pool. Expression of a versatile glucosyltransferase from Vitis vinifera (VvGT2) enabled the strain to efficiently produce 14 glucose esters of various hydroxycinnamates and hydroxybenzoates with conversion yields up to 100%. To our knowledge, this fast growing (and simultaneously producing) E. coli mutant is the first versatile host described for the glucosylation of phenolic acids in a fermentative way using only sucrose as a cheap and sustainable carbon source. PMID- 25728430 TI - Online accesses to medical research articles on publication predicted citations up to 15 years later. AB - OBJECTIVES: To examine whether the number of early online accesses to medical research articles predicts citations in the scientific literature over time. STUDY DESIGN AND SETTING: Cohort study of research articles published in the BMJ between January and June 1999. The number of online assesses within 1 week of publication was examined in relation to citation counts in 1999-2004, 2004-2009, and 2009-2014. RESULTS: The 148 included articles were accessed on average 691 times up publication, and each was cited on average 33 times in 1999-2004, 32 times in 2004-2009, and 26 times in 2009-2014. The logarithm of accesses predicted the logarithm of citations for all three subsequent periods, but the association weakened over time (correlation with citations in 1999-2004: 0.54, 2004-2009: 0.49, 2009-2014: 0.39; all P < 0.001). In addition to online accesses, the presence of an abstract also predicted more citations for all periods. CONCLUSION: Early interest in a medical research article, reflected by online accesses within a week of publication, predicts citations up to 15 years later. This strengthens the validity of online usage as a measure of the scientific merit of publications. PMID- 25728431 TI - Teaming up to tackle neurodegenerative diseases. PMID- 25728432 TI - A new gene for Parkinson's disease: should we care? PMID- 25728433 TI - Type 2 diabetes and cognitive function: many questions, few answers. PMID- 25728434 TI - Building bridges between neuroscientific evidence and policy. PMID- 25728435 TI - Anxious wait for patients and big pharma. PMID- 25728436 TI - David Burke: unravelling motor control and axonal excitability. PMID- 25728437 TI - Orexin or hypocretin? PMID- 25728438 TI - Lara Jehi. PMID- 25728441 TI - Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. AB - The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA DQB1*06:02 allele and then with the T-cell receptor alpha locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems. PMID- 25728442 TI - Cognitive function in patients with diabetes mellitus: guidance for daily care. AB - Diabetes mellitus is associated with an increase in the risk of dementia and the proportion of patients who convert from mild cognitive impairment (MCI) to dementia. In addition to MCI and dementia, the stages of diabetes-associated cognitive dysfunction include subtle cognitive changes that are unlikely to affect activities of daily life or diabetes self-management. These diabetes associated cognitive decrements have structural brain correlates detectable with brain MRI, but usually show little progression over time. Although cognitive decrements do not generally represent a pre-dementia stage in patients below the age of 60-65 years, in older individuals these subtle cognitive changes might represent the earliest stages of a dementia process. Acknowledgment of diabetes associated cognitive decrements can help to improve understanding of patients' symptoms and guide management. Future challenges are to establish the importance of screening for cognitive impairment in people with diabetes, to identify those at increased risk of accelerated cognitive decline at an early stage, and to develop effective treatments. PMID- 25728443 TI - Fe degrees enhanced acetification of propionate and granulation of sludge in acidogenic reactor. AB - Acidogenic reactors commonly operated at short hydraulic retention times (HRT) are liable to cause low chemical oxygen demand (COD) removal and acidogenic efficiency especially under fluctuating feed. Granular sludge as an efficient form for anaerobic microbial community to resist shocks in methanogenic reactors has been widely investigated, which however was less focused in acidogenic reactors. Adding Fe(0) in an acidogenic reactor with propionate as the substrate operated at HRT of 2 h was found to enhance the propionate decomposition and sludge granulation in this study. When increasing the organic load and decreasing pH in the feed, the propionate conversion and COD removal in the reactor with Fe(0) were higher than those in the control reactor. The sludge granulation was well developed in this reactor. Fe(0) advanced the growth of homoacetogenic bacteria that consumed the hydrogen produced in acetification of propionate. The propionate-oxidizing bacteria and homoacetogenic bacteria grew together in the sludge to accelerate hydrogen transfer, which was an important reason for the enhanced propionate decomposition and sludge granulation in the acidogenesis. PMID- 25728444 TI - Trichloroethylene removal and bacterial variations in the up-flow anaerobic sludge blanket reactor in response to temperature shifts. AB - Trichloroethylene (TCE) degradation and the variations of bacteria composition and structure in the up-flow anaerobic sludge blanket (UASB) reactor were investigated by increasing the operating temperature from 20 to 40 degrees C. The influent was supplemented with 36.5 mg/L of TCE. There was a rise in the chemical oxygen demand (COD) removal efficiency from 20 to 35 degrees C and a decline when temperature enhanced to 40 degrees C. It reached maximum at 35 degrees C. In addition, TCE removal efficiency increased with temperature varying from 20 to 35 degrees C, and it dropped dramatically to 78.38 % at 40 degrees C, which presumably because the genus of Dehalobacter, a kind of bacteria with the ability to dechlorinate TCE to the corresponding chlorinated products, was not detected at 40 degrees C according to sequencing results. The Illumina MiSeq platform was adopted to explore the bacteria composition and structure in response to temperature shifts. The results indicated that temperature impacted greatly on the dominance and presence of specific populations at different taxonomic levels. Importantly, the class Dehalococcoidia was detected from 25 to 40 degrees C, in which there were many well-known Dehalococcoides sp. strains that were capable of complete dechlorination of TCE to ethene. It also suggested the potential function of the dominant genera (non-dechlorinating bacteria and dechlorinating bacteria) in the reactor. PMID- 25728445 TI - EC300: a phage-based, bacteriolysin-like protein with enhanced antibacterial activity against Enterococcus faecalis. AB - Bacteriophage lytic enzymes, either endolysins or virion-associated lysins, have been receiving considerable attention as potential antibacterial agents, particularly for the combat of antibiotic-resistant Gram-positive pathogens. A conclusion that easily emerges from the careful analysis of a great number of reports on the field is that the activity of phage lytic enzymes is rarely studied in conditions that support robust growth of the target bacteria. Here, we report the construction and study of a chimerical lysin, EC300, which was designed to target and kill Enterococcus faecalis in conditions supporting vigorous bacterial growth. EC300 resulted from the fusion of a predicted M23 endopeptidase domain of a virion-associated lysin to the putative cell wall binding domain of a previously characterized amidase endolysin, both produced by the E. faecalis phage F170/08. This bacteriolysin-like protein exhibited a clear enhanced lytic activity over the parental endolysin when both were assayed in a rich bacterial growth medium. We demonstrate the killing efficacy of EC300 against growing cells of a panel of typed E. faecalis clinical strains with high level of antibiotic resistance. The possible reasons for the marked difference between the lytic performance of EC300 and that of the amidase are discussed. PMID- 25728446 TI - Improving biohydrogen production using Clostridium beijerinckii immobilized with magnetite nanoparticles. AB - In order to supplement the need for alternative energy resources within the near future, enhancing the production of biohydrogen with immobilized Clostridium beijerinckii NCIMB8052 was investigated. Magnetite nanoparticles were functionalized, with chitosan and alginic acid polyelectrolytes using a layer-by layer method, to promote bacterial attachment. Cultivating C. beijerinckii with these nanoparticles resulted in a shorter lag growth phase and increased total biohydrogen production within 100-ml, 250-ml and 3.6-L reactors compared with freely suspended organisms. The greatest hydrogen yield was obtained in the 250 ml reactor with a value of 2.1 +/- 0.7 mol H2/mol glucose, corresponding to substrate conversion and energy conversion efficiencies of 52 +/- 18 and 10 +/- 3 %, respectively. The hydrogen yields obtained using the immobilized bacteria are comparable to values found in literature. However, to make this process viable, further improvements are required to increase the substrate and energy conversion efficiencies. PMID- 25728450 TI - Aortic valve rupture during isometric muscle contraction. AB - Aortic valve rupture has been previously reported in association with blunt chest trauma as well as spontaneously in the setting of abnormal valves. We present a case of a patient who required emergent aortic valve replacement following rupture of his aortic valve during an isometric muscle contraction. PMID- 25728447 TI - Peri-operative risk factors for delayed gastric emptying after a pancreaticoduodenectomy. AB - BACKGROUND: Delayed gastric emptying (DGE) is a frequent cause of morbidity, prolonged hospital stay and readmission after a pancreaticoduodenectomy (PD). We sought to evaluate predictive peri-operative factors for DGE after a PD. METHODS: Four hundred and sixteen consecutive patients who underwent a PD at our tertiary referral centre were identified. Univariate and multivariate (MV) logistic regression models were used to assess peri-operative factors associated with the development of clinically significant DGE and a post-operative pancreatic fistula (POPF). RESULTS: DGE occurred in 24% of patients (n = 98) with Grades B and C occurring at 13.5% (n = 55) and 10.5% (n = 43), respectively. Using MV regression, a body mass index (BMI) >=35 [odds ratio (OR) = 3.19], operating room (OR) length >5.5 h (OR = 2.72) and prophylactic octreotide use (OR = 2.04) were independently associated with an increased risk of DGE. DGE patients had a significantly longer median hospital stay (12 versus 7 days), higher 90-day readmission rates (32% versus 18%) and an increased incidence of a pancreatic fistula (59% versus 27%). When controlling for POPF, only OR length >5.5 h (OR 2.73) remained significantly associated with DGE. CONCLUSIONS: DGE remains a significant cause of morbidity, increased hospital stay and readmission after PD. Our findings suggest patients with a BMI >=35 or longer OR times have a higher risk of DGE either independently or through the development of POPF. These patients should be considered for possible enteral feeding tube placement along with limited octreotide use to decrease the potential risk and consequences of DGE. PMID- 25728451 TI - Time to antivenom administration is not associated with total antivenom dose administered in a copperhead-predominant snakebite population. AB - OBJECTIVES: To prevent unnecessary antivenom administration in crotaline snakebite, observation for progression is recommended for the patient with minor envenomation whose condition is stable and not progressing. The objective of this study was to determine the association between the time from bite to initial antivenom administration (Time(AV)) and the total amount of antivenom administered (Total(AV)) and to determine what proportion of patients did not have progression of the envenomation syndrome and did not receive antivenom. METHODS: This was a retrospective chart review of patients presenting with crotaline snakebite within 24 hours from 2009 through 2012. Blinded dual-chart abstraction and strict data point definitions were used. Spearman correlation was used to determine the association between Time(AV) and Total(AV). A general linear model was used to examine this association using Time(AV) categorized to early and late administration, adjusted for likely confounders. Confounders included age, extremity involved, initial severity, and year of envenomation. RESULTS: Ninety-five eligible patients were analyzed with 45 (47%) males and a mean (+/-SD) age of 36.5 (+/-21.1) years. Eighty-five (89%) received antivenom, with a median Time(AV) of 3.3 hours (interquartile range [IQR] = 2.5 to 5.2 hours). The median Total(AV) was 10 vials (IQR = 6 to 14 vials). The univariate analysis showed a small but statistically significant decrease in Total(AV) given to patients treated greater than 6 hours from bite (r = -0.26, p = 0.015). The multivariate analysis resulted in no significant relation between early or late Time(AV) and Total(AV) (p = 0.10) after adjustment for confounders. Most minimal envenomation syndromes (80%, or 41 of 51) progressed to moderate grade envenomations. CONCLUSIONS: Time(AV) was not associated with Total(AV) when adjusted for likely confounders and supports current recommendations to observe for progression in minor envenomation. The majority of envenomations progressed, resulting in only a small proportion of patients not eventually receiving antivenom. The authors recommend observation in an environment where the patient can be adequately reassessed for progression of the envenomation. PMID- 25728452 TI - Perfluorooctane sulfonate: a review of human exposure, biomonitoring and the environmental forensics utility of its chirality and isomer distribution. AB - Perfluorooctane sulfonate (PFOS) found extensive use for over 60 years up until its restriction in the early 2000s, culminating in its listing under the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2009. Efforts to minimise human body burdens are hindered by uncertainty over their precise origins. While diet appears the principal source for the majority of western populations (with other pathways like dust ingestion, drinking water and inhalation also important contributors); the role played by exposure to PFOS precursor compounds followed by in vivo metabolism to PFOS as the ultimate highly stable end-product is unclear. Such PFOS-precursor compounds include perfluorooctane sulfonamide derivates, e.g., perfluorooctane sulfonamides (FOSAs) and sulfonamidoethanols (FOSEs). Understanding the indirect contribution of such precursors to human body burdens of PFOS is important as a significant contribution from this pathway would render the margin of safety between the current exposure limits and estimates of external exposure to PFOS alone, narrower than hitherto appreciated. Estimates derived from mathematical modelling studies, put the contribution of so-called "precursor exposure" at between 10% and 40% of total PFOS body burdens. However, there are substantial uncertainties associated with such approaches. This paper reviews current understanding of human exposure to PFOS, with particular reference to recent research highlighting the potential of environmental forensics approaches based on the relative abundance and chiral signatures of branched chain PFOS isomers to provide definitive insights into the role played by "precursor exposure". PMID- 25728453 TI - Low copulatory activity in selectively bred Sardinian alcohol-nonpreferring (sNP) relative to alcohol-preferring (sP) rats. AB - BACKGROUND: There is a growing consensus that similar neural mechanisms are involved in the reinforcing properties of natural rewards, like food and sex, and drugs of abuse. Rat lines selectively bred for high and low oral alcohol intake and preference have been useful for understanding factors contributing to excessive alcohol intake and may constitute proper animal models for investigating the neurobiological basis of natural rewarding stimuli. METHODS: The present study evaluated copulatory behavior in alcohol and sexually naive Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats in three consecutive copulatory behavior tests. RESULTS: The main finding was that, under the conditions used in this study, sNP rats were sexually inactive relative to sP rats. To gain more information about the sexual behavior in sP rats, Wistar rats were included as an external reference strain. Only minor differences between sP and Wistar rats were revealed. CONCLUSIONS: The reason behind the low copulatory activity of sNP rats remains to be elucidated, but may in part be mediated by innate differences in brain transmitter systems. The comparison between sP and Wistar rats may also suggest that the inherent proclivity to excessive alcohol drinking in sP rats may mainly be dependent on its anxiolytic properties, as previously proposed, and not changes in the reward system. PMID- 25728454 TI - Plasma kinetics, excretion in milk of eprinomectin, and its efficacy against Hypoderma spp. following topical administration in yaks. AB - The plasma pharmacokinetics and mammary excretion of eprinomectin were determined in dairy yaks following topical administration at a dose of 0.5 mg/kg. The kinetics of plasma and milk concentrations were analyzed using a noncompartmental model. Plasma and milk concentrations of eprinomectin increased to reach maximal concentrations of 5.45 +/- 2.84 and 2.29 +/- 0.90 ng/mL at a Tmax of 1.79 +/- 0.57 and 2.00 +/- 0.82 days, respectively. The concentration of eprinomectin in plasma was remained >0.5 ng/mL for more than 30 days after administration. The mean residence times of eprinomectin in plasma and milk were 14.73 +/- 6.22 and 9.37 +/- 2.81 days, respectively. The AUC value in plasma (55.89 +/- 18.16 ng day/mL) was threefold greater than that in milk (18.02 +/- 6.48 ng day/mL). The AUC milk/plasma ratio was 0.33 +/- 0.08. The systemic availability of eprinomectin in yaks was lower than that observed value in other domestic bovines. The low level of eprinomectin excretion in milk suggests that eprinomectin can be used in yaks with zero milk-withdrawal time. The efficacy of eprinomectin against naturally acquired larvae of Hypoderma spp. was also determined in yaks. Topically administrated eprinomectin at a dose of 0.5 mg/kg was 100% efficacious against larvae of Hypoderma bovis, H. lineatum, and H. sinense. PMID- 25728455 TI - Chronic mesenteric ischemia: 20 year experience of open surgical treatment. AB - OBJECTIVES: Both open surgery (OS) and endovascular surgery (ES) have been proposed for the treatment of symptomatic chronic mesenteric ischaemia (CMI). OS was considered the gold standard but ES is increasingly proposed as the first option. The aim was to report long-term outcomes associated with OS in patients suffering CMI in the modern era in order to help in choose between the two techniques. MATERIALS AND METHODS: A retrospective single centre analysis of all consecutive digestive artery revascularizations performed for CMI between January 2003 and December 2012 was carried out. Primary outcomes were 30 day mortality and morbidity, and secondary outcomes were survival, primary patency (PP), secondary patency (SP), and freedom from digestive symptoms, depending on the completeness of the revascularization performed. RESULTS: Eighty-six revascularizations were performed. Median follow up was 6.9 years (range 0.3 20.0). The 30 day mortality and morbidity rates were respectively 3.5% and 13.9%. Ten year survival was 88% for complete revascularization (CR) and 76% for incomplete revascularization (IR) (p = .54). The PP was 84% at 10 years for CR and 87% respectively for IR (p = .51). The 10 year SP was 92% for CR and 93% for IR (p = .63). Freedom from digestive symptoms was influenced by the completeness of revascularization: 79% for CR versus 65% for IR at 10 years (p = .04). CONCLUSIONS: OS for CMI, especially complete revascularization, provides lasting results despite high morbidity. PMID- 25728456 TI - Endotension after bypass for popliteal aneurysm. PMID- 25728457 TI - Toward structured macroporous hydrogel composites: electron beam-initiated polymerization of layered cryogels. AB - The ability to tailor mechanical properties and architecture is crucial in creating macroporous hydrogel scaffolds for tissue engineering. In the present work, a technique for the modification of the pore size and stiffness of acrylamide-based cryogels is demonstrated via the regulation of an electron beam irradiation dose. The samples were characterized by equilibrium swelling measurements, light and scanning electron microscopy, mercury porosimetry, Brunauer-Emmett-Teller surface area analysis, and stiffness measurements. Their properties were compared to cryogels prepared by a standard redox-initiated radical polymerization. A (125)I radiolabeled azidopentanoyl-GGGRGDSGGGY-NH2 peptide was bound to the surface to determine the concentration of the adhesive sites available for biomimetic modification. The functionality of the prepared substrates was evaluated by in vitro cultivation of adipose-derived stem cells. Moreover, the feasibility of preparing layered cryogels was demonstrated. This may be the key to the future preparation of complex hydrogel-based scaffolds to mimic the extracellular microenvironment in a wide range of applications. PMID- 25728458 TI - Lessons from the synthetic chemist nature. AB - This conceptual review examines the ideal multistep synthesis from the perspective of nature. We suggest that besides step- and redox economies, one other key to efficiency is steady state processing with intermediates that are immediately transformed to the next intermediate when formed. We discuss four of nature's strategies (multicatalysis, domino reactions, iteration and compartmentation) that commonly proceed via short-lived intermediates and show that these strategies are also part of the chemist's portfolio. We particularly focus on compartmentation which in nature is found microscopically within cells (organelles) and between cells and on a molecular level on multiprotein scaffolds (e.g. in polyketide synthases) and demonstrate how compartmentation is manifested in modern multistep flow synthesis. PMID- 25728461 TI - Evidence suggesting superiority of visual (verbal) vs. auditory test presentation modality in the P300-based, Complex Trial Protocol for concealed autobiographical memory detection. AB - One group of participants received a series of city name stimuli presented on trials of the Complex Trial Protocol (CTP) version of a P300-based, concealed information test (CIT). Stimuli were presented on alternating trials in either auditory or visual presentation modality. In 1/7 of the trials the participant's home town (probe) repeatedly appeared in a series of 6 other (irrelevant) repeated city names. In both modalities, probe stimuli produced larger P300s than irrelevant stimuli. Visual stimuli produced shorter behavioral reaction times and P300 latencies, as well as larger P300 probe amplitudes, probe-irrelevant amplitude differences, and individual diagnostic accuracies than the same stimuli presented in the auditory modality. Possible reasons for these effects are discussed, and subject to discussed limitations, the applied conclusion reached is that in all CITs, visual presentation of stimuli, if feasible, should be preferentially used. PMID- 25728460 TI - Accuracy of digital mRNA profiling of oesophageal biopsies as a novel diagnostic approach to eosinophilic oesophagitis. AB - BACKGROUND: Quantification of tissue eosinophils remains the golden standard in diagnosing eosinophilic oesophagitis (EoE), but this approach suffers from poor specificity. It has been recognized that histopathological changes that occur in patients with EoE are associated with a disease-specific tissue transcriptome. OBJECTIVE: We hypothesized that digital mRNA profiling targeted at a set of EoE specific and Th2 inflammatory genes in oesophageal biopsies could help differentiate patients with EoE from those with reflux oesophagitis (RE) or normal tissue histology (NH). METHODS: The mRNA expression levels of 79 target genes were defined in both proximal and distal biopsies of 196 patients with nCounter(r) (Nanostring) technology. According to clinicopathological diagnosis, these patients were grouped in a training set (35 EoE, 30 RE, 30 NH) for building of a three-class prediction model using the random forest method, and a blinded predictive set (n = 47) for model validation. RESULTS: A diagnostic model built on ten differentially expressed genes was able to differentiate with 100% sensitivity and specificity between conditions in the training set. In a blinded predictive set, this model was able to correctly predict EoE in 14 of 18 patients in distal (sensitivity 78%, 95% CI 52-93%) and 16 of 18 patients in proximal biopsies (sensitivity 89%, 95% CI 64-98%), without false-positive diagnosis of EoE in RE or NH patients (specificity 100%, 95% CI 85-100%). Sensitivity was increased to 94% (95% CI 71-100%) when either the best predictive distal or proximal biopsy was used. CONCLUSION AND CLINICAL RELEVANCE: We conclude that mRNA profiling of oesophageal tissue is an accurate diagnostic strategy in detecting EoE. PMID- 25728462 TI - Effectiveness of professional training in bereavement care: Survey of Japanese pediatricians supporting families who have lost a child. AB - BACKGROUND: The aim of this study was to assess the effectiveness of professional training in bereavement care. METHOD: We mailed a questionnaire to 554 Japanese pediatricians. It asked about demographic characteristics, personal support experiences, professional training, psychological distress, recognition of high risk after a child's death, and eight items relating to awareness in bereavement care. We divided the subjects into two groups based on the presence or absence of professional training and compared them on the basis of each item (chi(2) test), and conducted logistic regression analysis. RESULTS: Of the 239 respondents, 193 (80.8%) had performed bereavement care. The final number included in the analysis was 175, after excluding responses with missing data. A total of 46 respondents (26.3%) had attended bereavement care training. The subjects who had had training were more likely to recognize those at high risk for poor psychological recovery, have information about support groups, have a desire to study bereavement care, and understand the necessity of cooperation with mental health specialists. CONCLUSION: Many pediatricians had personally provided support for the bereaved. On logistic analysis, it was considered that four factors (recognition of high risk for poor recovery, information about support, desire to study, and cooperation with professionals) were significantly associated with the professional training. There were no significant differences, however, in psychological distress, helplessness, and fatigue. Training programs related to stress management must be improved for pediatricians who feel high levels of psychological distress. PMID- 25728459 TI - A review of low-intensity ultrasound for cancer therapy. AB - The literature describing the use of low-intensity ultrasound in four major areas of cancer therapy-sonodynamic therapy, ultrasound-mediated chemotherapy, ultrasound-mediated gene delivery and anti-vascular ultrasound therapy-was reviewed. Each technique consistently resulted in the death of cancer cells, and the bio-effects of ultrasound were attributed primarily to thermal actions and inertial cavitation. In each therapeutic modality, theranostic contrast agents composed of microbubbles played a role in both therapy and vascular imaging. The development of these agents is important as it establishes a therapeutic diagnostic platform that can monitor the success of anti-cancer therapy. Little attention, however, has been given either to the direct assessment of the mechanisms underlying the observed bio-effects or to the viability of these therapies in naturally occurring cancers in larger mammals; if such investigations provided encouraging data, there could be prompt application of a therapy technique in the treatment of cancer patients. PMID- 25728463 TI - Osteochondroma in long-term survivors of high-risk neuroblastoma. AB - BACKGROUND: Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high-risk neuroblastoma includes dose-intensive chemotherapy, local RT, an anti-GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging. METHODS: The authors examined osteochondromas in 362 patients who were aged <10 years when diagnosed with neuroblastoma, had received a MoAb plus isotretinoin since 2000, and had survived >24 months from the time of the first dose of the MoAb. The incidence rate of osteochondroma was determined using the competing risks approach, in which the primary event was osteochondroma calculated from the date of neuroblastoma diagnosis and the competing event was death without osteochondroma. RESULTS: A total of 21 osteochondroma cases were found among 14 patients who were aged 5.7 to 15.3 years (median, 10.4 years) and 3.1 to 11.2 years (median, 8.2 years) from the time of neuroblastoma diagnosis. The cumulative incidence rate was 0.6% at 5 years and 4.9% at 10 years from the neuroblastoma diagnosis. Nine osteochondromas were revealed incidentally during assessments of neuroblastoma disease status or bone age. Thirteen osteochondromas were detected outside RT portals and had characteristics of spontaneous forms. Complications were limited to pain necessitating surgical resection in 3 patients, but follow-up was short at 0.3 to 7.7 years (median, 3.5 years). CONCLUSIONS: Osteochondromas in long-term survivors of neuroblastoma should be expected because these benign growths can be related to RT and these patients undergo radiologic studies over years, are monitored for late toxicities through and beyond adolescence, and receive special attention (because of concerns about disease recurrence) if they develop a bony protuberance. A pathogenic role for chemotherapy, anti-GD2 MoAbs, or isotretinoin remains speculative. PMID- 25728464 TI - Phenotypic and molecular identification of Fonsecaea pedrosoi strains isolated from chromoblastomycosis patients in Mexico and Venezuela. AB - Chromoblastomycosis is a chronic granulomatous disease caused frequently by fungi of the Fonsecaea genus. The objective of this study was the phenotypic and molecular identification of F. pedrosoi strains isolated from chromoblastomycosis patients in Mexico and Venezuela. Ten strains were included in this study. For phenotypic identification, we used macroscopic and microscopic morphologies, carbohydrate assimilation test, urea hydrolysis, cixcloheximide tolerance, proteolitic activity and the thermotolerance test. The antifungal activity of five drugs was evaluated against the isolates. Molecular identification was performed by sequencing the internal transcribed spacer (ITS) ribosomal DNA regions of the isolated strains. The physiological analysis and morphological features were variable and the precise identification was not possible. All isolates were susceptible to itraconazole, terbinafine, voriconazole and posaconazole. Amphotericin B was the least effective drug. The alignment of the 559-nucleotide ITS sequences from our strains compared with sequences of GenBank revealed high homology with F. pedrosoi (EU285266.1). In this study, all patients were from rural areas, six from Mexico and four from Venezuela. Ten isolates were identified by phenotypic and molecular analysis, using ITS sequence and demonstrated that nine isolates from Mexico and Venezuela were 100% homologous and one isolate showed a small genetic distance. PMID- 25728465 TI - Bullous prurigo pigmentosa in a pregnant woman with hyperemesis gravidarum. PMID- 25728467 TI - Incentivising improvements in health care delivery. AB - This Special Section of Health Economics, Policy and Law begins with an article on the different ways in which one might incentivise improved performance among health care providers. I asked five experts on performance management, Gwyn Bevan, Tim Doran, Peter Smith, Sandra Tanenbaum and Karsten Vrangbaek, to write brief reactions to the article and to the notion of performance management in health care in general. The commentators were given an open remit to be as critical as they wished to be, and their reactions can be found in the pages that follow. I would like to thank Albert Weale for reviewing all of the articles, and Katie Brennan for serving as the catalyst for this collection. PMID- 25728468 TI - Acceleration of genetic gain in cattle by reduction of generation interval. AB - Genomic selection (GS) approaches, in combination with reproductive technologies, are revolutionizing the design and implementation of breeding programs in livestock species, particularly in cattle. GS leverages genomic readouts to provide estimates of breeding value early in the life of animals. However, the capacity of these approaches for improving genetic gain in breeding programs is limited by generation interval, the average age of an animal when replacement progeny are born. Here, we present a cost-effective approach that combines GS with reproductive technologies to reduce generation interval by rapidly producing high genetic merit calves. PMID- 25728466 TI - Complete genome sequence of hypervirulent and outbreak-associated Acinetobacter baumannii strain LAC-4: epidemiology, resistance genetic determinants and potential virulence factors. AB - Acinetobacter baumannii is an important human pathogen due to its multi-drug resistance. In this study, the genome of an ST10 outbreak A. baumannii isolate LAC-4 was completely sequenced to better understand its epidemiology, antibiotic resistance genetic determinants and potential virulence factors. Compared with 20 other complete genomes of A. baumannii, LAC-4 genome harbors at least 12 copies of five distinct insertion sequences. It contains 12 and 14 copies of two novel IS elements, ISAba25 and ISAba26, respectively. Additionally, three novel composite transposons were identified: Tn6250, Tn6251 and Tn6252, two of which contain resistance genes. The antibiotic resistance genetic determinants on the LAC-4 genome correlate well with observed antimicrobial susceptibility patterns. Moreover, twelve genomic islands (GI) were identified in LAC-4 genome. Among them, the 33.4-kb GI12 contains a large number of genes which constitute the K (capsule) locus. LAC-4 harbors several unique putative virulence factor loci. Furthermore, LAC-4 and all 19 other outbreak isolates were found to harbor a heme oxygenase gene (hemO)-containing gene cluster. The sequencing of the first complete genome of an ST10 A. baumannii clinical strain should accelerate our understanding of the epidemiology, mechanisms of resistance and virulence of A. baumannii. PMID- 25728469 TI - Diagnosis of mild Alzheimer disease through the analysis of eye movements during reading. AB - Reading requires the integration of several central cognitive subsystems, ranging from attention and oculomotor control to word identification and language comprehension. Reading saccades and fixations contain information that can be correlated with word properties. When reading a sentence, the brain must decide where to direct the next saccade according to what has been read up to the actual fixation. In this process, the retrieval memory brings information about the current word features and attributes into working memory. According to this information, the prefrontal cortex predicts and triggers the next saccade. The frequency and cloze predictability of the fixated word, the preceding words and the upcoming ones affect when and where the eyes will move next. In this paper we present a diagnostic technique for early stage cognitive impairment detection by analyzing eye movements during reading proverbs. We performed a case-control study involving 20 patients with probable Alzheimer's disease and 40 age-matched, healthy control patients. The measurements were analyzed using linear mixed effects models, revealing that eye movement behavior while reading can provide valuable information about whether a person is cognitively impaired. To the best of our knowledge, this is the first study using word-based properties, proverbs and linear mixed-effect models for identifying cognitive abnormalities. PMID- 25728471 TI - Evidence for the formation of an enamine species during aldol and Michael-type addition reactions promiscuously catalyzed by 4-oxalocrotonate tautomerase. AB - The enzyme 4-oxalocrotonate tautomerase (4-OT), which has a catalytic N-terminal proline residue (Pro1), can promiscuously catalyze various carbon-carbon bond forming reactions, including aldol condensation of acetaldehyde with benzaldehyde to yield cinnamaldehyde, and Michael-type addition of acetaldehyde to a wide variety of nitroalkenes to yield valuable gamma-nitroaldehydes. To gain insight into how 4-OT catalyzes these unnatural reactions, we carried out exchange studies in D2 O, and X-ray crystallography studies. The former established that H D exchange within acetaldehyde is catalyzed by 4-OT and that the Pro1 residue is crucial for this activity. The latter showed that Pro1 of 4-OT had reacted with acetaldehyde to give an enamine species. These results provide evidence of the mechanism of the 4-OT-catalyzed aldol and Michael-type addition reactions in which acetaldehyde is activated for nucleophilic addition by Pro1-dependent formation of an enamine intermediate. PMID- 25728473 TI - New exponential synchronization criteria for time-varying delayed neural networks with discontinuous activations. AB - This paper investigates the problem of exponential synchronization of time varying delayed neural networks with discontinuous neuron activations. Under the extended Filippov differential inclusion framework, by designing discontinuous state-feedback controller and using some analytic techniques, new testable algebraic criteria are obtained to realize two different kinds of global exponential synchronization of the drive-response system. Moreover, we give the estimated rate of exponential synchronization which depends on the delays and system parameters. The obtained results extend some previous works on synchronization of delayed neural networks not only with continuous activations but also with discontinuous activations. Finally, numerical examples are provided to show the correctness of our analysis via computer simulations. Our method and theoretical results have a leading significance in the design of synchronized neural network circuits involving discontinuous factors and time-varying delays. PMID- 25728472 TI - GABA Deficits Enhance the Psychotomimetic Effects of Delta9-THC. PMID- 25728474 TI - Development and characterization of a free therapeutic ligand binding assay with assistance from kinetics modeling. AB - Bioanalytical data from early human studies conducted in normal volunteers are often used for building pharmacokinetic/pharmacodynamic models that can predict outcomes of future studies in diseased patients. Thus, it is important to develop and validate reliable and accurate bioanalytical assays that instill confidence that the intended therapeutic species (total or free) are being measured. Assays quantifying the free therapeutic species, the partially bound (for multivalent therapeutics) and unbound species, require much more characterization than assays that quantify the total therapeutic species. We have developed an immunoassay to measure free BMS-962476, an Adnectin protein therapeutic against soluble proprotein convertase subtilisin kexin (PCSK)-9, and performed an in-depth characterization of the accuracy of this assay with the assistance of modeling. The experimental data correlates with modeled data within 15% at all clinically relevant levels of PCSK9 in normal and diseased populations. PMID- 25728475 TI - Control over excited state intramolecular proton transfer and photoinduced tautomerization: influence of the hydrogen-bond geometry. AB - The influence of H-bond geometry on the dynamics of excited state intramolecular proton transfer (ESIPT) and photoinduced tautomerization in a series of phenol quinoline compounds is investigated. Control over the proton donor-acceptor distance (dDA ) and dihedral angle between the proton donor-acceptor subunits is achieved by introducing methylene backbone straps of increasing lengths to link the phenol and quinoline. We demonstrate that a long dDA correlates with a higher barrier for ESIPT, while a large dihedral angle opens highly efficient deactivation channels after ESIPT, preventing the formation of the fully relaxed tautomer photoproduct. PMID- 25728470 TI - Different ornaments signal male health and MHC variation in two populations of a warbler. AB - Male traits that signal health and vigour are used by females to choose better quality mates, but in some cases the male trait selected by females differs among populations. Multiple male traits can be maintained through female mate choice if both traits are equally honest indicators of male quality, but tests of this prediction are rare. By choosing males based on such traits, females could gain direct benefits from males (assistance with parental care), but when females choose extra-pair mates based on these traits, females gain only male sperm, and potentially indirect genetic benefits for their offspring. In common yellowthroats (Geothylpis trichas), female choice of extra-pair mates targets two different plumage ornaments: the black mask in a Wisconsin population and the yellow bib in a New York population. Previously, we found that the black mask in Wisconsin is related to greater major histocompatibility complex (MHC) class II variation, which in turn signals better survival and disease resistance. In this study, we examined the signalling function of the yellow bib in New York to test whether it signals the same aspects of male quality as the black mask in Wisconsin. As predicted, we found that the yellow bib in New York is most closely associated with MHC variation, which also signals survival and resistance to blood parasites. Thus, the ornament preferred by females differs between the two populations, but the different ornaments signal similar aspects of male health and genetic quality, specifically information regarding MHC variation and potential indirect genetic benefits to females. PMID- 25728476 TI - Assembly and operation of bacterial tripartite multidrug efflux pumps. AB - Microorganisms encode several classes of transmembrane pumps that can expel an enormous range of toxic substances, thereby improving their fitness in harsh environments and contributing to resistance against antimicrobial agents. In Gram negative bacteria these pumps can take the form of tripartite assemblies that actively efflux drugs and other harmful compounds across the cell envelope. We describe recent structural and functional data that have provided insights into the transport mechanisms of these intricate molecular machines. PMID- 25728477 TI - Common questions in veterinary toxicology. AB - Toxicology is a vast subject. Animals are exposed to numerous drugs, household products, plants, chemicals, pesticides and venomous animals. In addition to the individual toxicity of the various potential poisons, there is also the question of individual response and, more importantly, of species differences in toxicity. This review serves to address some of the common questions asked when dealing with animals with possible poisoning, providing evidence where available. The role of emetics, activated charcoal and lipid infusion in the management of poisoning in animals, the toxic dose of chocolate, grapes and dried fruit in dogs, the use of antidotes in paracetamol poisoning, timing of antidotal therapy in ethylene glycol toxicosis and whether lilies are toxic to dogs are discussed. PMID- 25728478 TI - Making personalized medicine more affordable. AB - Precision medicine holds promise to solve the conundrums of clinical care. Foremost is the well-known but vexing problem of heterogeneity and the tyranny of the mean. Who will respond to a treatment? How can patients avoid the harms of treatments that will not work for them? And if we know who to treat, will that make care more efficient and less costly? But the converse can also be true: treatments become more expensive as the costs of development must be distributed across smaller populations. Next-generation sequencing is making genetic testing radically cheaper. But the costs of medical tests also include false-positive results, incidental findings, and the cascade of follow-up. The affordability of precision medicine is intertwined with the broader issue of affordability of our healthcare system, and will require all stakeholders to assume stewardship for access and sustainability. PMID- 25728479 TI - Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity. AB - INTRODUCTION: Fluorine's unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. AREAS COVERED: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the physicochemical characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biological systems for fluorinated drug production is discussed. EXPERT OPINION: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technology for the manufacturing scale and new reagents and methods are required to meet the demands for the preparation of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to determine the nature of transformation products that may cause ecological damage. PMID- 25728480 TI - Contraceptive practice after surgical repair of obstetric fistula in southeast Nigeria. AB - OBJECTIVE: To determine the contraceptive practices of women after surgical repair of obstetric fistula and to assess determinants of uptake and the pregnancy rate in the first year. METHODS: A prospective cohort study enrolled women who had a successful surgical repair of obstetric fistula at a center in Nigeria between 2011 and 2013. Patients were followed up for 1year. Data were obtained through record review and completion of a semi-structured questionnaire. RESULTS: Among 188 participants, 180 (95.7%) were aware of contraception, but only 70 (37.2%) used contraceptive methods after surgery. The most commonly used methods were the male condom (50 [71.4%] of 70) and hormonal injections (14 [20.0%]). The main reasons for non-use were fear of adverse effects (48 [40.7%] of 118 women), future desire for more children (35 [29.7%]), religious prohibition (26 [22.0%]), cultural beliefs (29 [24.6%]), and partner disapproval (42 [35.6%]). The risk of unplanned pregnancy in the first year was significantly lower among women who used contraceptives than among those who did not (relative risk 0.14, 95% confidence interval 0.02-1.06; P=0.03). CONCLUSION: Contraceptive uptake for birth control after fistula repair surgery was low because of socioeconomic reasons, religious and cultural beliefs, and myths, resulting in unplanned pregnancies. PMID- 25728482 TI - Self-oriented beta-crystalline phase in the polyvinylidene fluoride ferroelectric and piezo-sensitive ultrathin Langmuir-Schaefer film. AB - We report on the direct observation of ferroelectric switching and piezoelectric behaviour in ultrathin polyvinylidene fluoride (PVDF) films prepared by horizontal Langmuir-Schaefer (LS) technique. We have prepared pure beta-phase by just increasing the number of LS layers without using additional non ferroelectric assisting agents. Edge-on oriented CH2-CF2 units of PVDF at the air water interface enable self-orientation of ferroelectric dipoles by means of the hydrogen bonding network. Such restricted conformation of PVDF at the air-water interface results in an increased net dipole moment with the number of LS layers. The film's ferroelectric switching and piezoelectric sensitivity are demonstrated by hysteretic polarization switching loops and butterfly-loops, respectively. Successful circular domain writing on ultrathin LS film, down to 5 monolayers of PVDF, is demonstrated. The achievement of pure beta-phase of PVDF at room temperature without using any assisting agents may be promising for non-volatile memory and piezoelectric-based, ultrathin smart sensor devices. PMID- 25728481 TI - Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/beta4GalNT2 genes. AB - BACKGROUND: Simultaneous inactivation of pig GGTA1 and CMAH genes eliminates carbohydrate xenoantigens recognized by human antibodies. The beta4GalNT2 glycosyltransferase may also synthesize xenoantigens. To further characterize glycan-based species incompatibilities, we examined human and non-human primate antibody binding to cells derived from genetically modified pigs lacking these carbohydrate-modifying genes. METHODS: The Cas9 endonuclease and gRNA were used to create pigs lacking GGTA1, GGTA1/CMAH, or GGTA1/CMAH/beta4GalNT2 genes. Peripheral blood mononuclear cells were isolated from these animals and examined for binding to IgM and IgG from humans, rhesus macaques, and baboons. RESULTS: Cells from GGTA1/CMAH/beta4GalNT2 deficient pigs exhibited reduced human IgM and IgG binding compared to cells lacking both GGTA1 and CMAH. Non-human primate antibody reactivity with cells from the various pigs exhibited a slightly different pattern of reactivity than that seen in humans. Simultaneous inactivation of the GGTA1 and CMAH genes increased non-human primate antibody binding compared to cells lacking either GGTA1 only or to those deficient in GGTA1/CMAH/beta4GalNT2. CONCLUSIONS: Inactivation of the beta4GalNT2 gene reduces human and non-human primate antibody binding resulting in diminished porcine xenoantigenicity. The increased humoral immunity of non-human primates toward GGTA1-/CMAH-deficient cells compared to pigs lacking either GGTA1 or GGTA1/CMAH/beta4GalNT2 highlights the complexities of carbohydrate xenoantigens and suggests potential limitations of the non-human primate model for examining some genetic modifications. The progressive reduction of swine xenoantigens recognized by human immunoglobulin through inactivation of pig GGTA1/CMAH/beta4GalNT2 genes demonstrates that the antibody barrier to xenotransplantation can be minimized by genetic engineering. PMID- 25728483 TI - The impact of diminished housing wealth on health in the United States: evidence from the Great Recession. AB - The sharp decline in home values in many industrialized and developing countries was one of the most evident facets of the global economic recession of 2008. Using data from the Panel Study of Income Dynamics (PSID) for 2007-2011, this study examines how the decline in housing wealth affected the psychological and physical health and health-related behaviors of 4007 U.S. households who were homeowners in 2007. We focus on two mechanisms that could account for how the drop in housing wealth affects health: increase in stress and negative changes in health-related behaviors. Controlling for the changes in non-housing wealth and employment status during the recession, the decline in housing wealth is associated with a small but statistically significant increase in psychological distress. Psychological health deteriorates more as the housing wealth relative to total wealth decreases. Finally, homeowners who have difficulties with mortgage payments report substantial increases in psychological distress and have higher rates of depression. These findings, combined with limited evidence of the change in health-related behaviors, suggest that the increase in stress is the main cause of the adverse health outcomes. PMID- 25728484 TI - Civil Society Organizations and medicines policy change: a case study of registration, procurement, distribution and use of misoprostol in Uganda. AB - Misoprostol use for postpartum haemorrhage (PPH) has been promoted by Civil Society Organizations (CSOs) since the early 2000s. Yet, CSOs' role in improving access to misoprostol and shaping health policy at global and national levels is not well understood. We document the introduction of misoprostol in Uganda in 2008 from its registration, addition to treatment guidelines and national Essential Medicines List (EML), to its distribution and use. We then analyse the contribution of CSOs to this health policy change and service provision. Policy documents, procurement data and 82 key informant interviews with government officials, healthcare providers, and CSOs in four Ugandan districts of Kampala, Mbarara, Apac, Bundibugyo were collected between 2010 and 2013. Five key CSOs promoted and accelerated the rollout of misoprostol in Uganda. They supported the registration of misoprostol with the National Drug Authority, the development of clinical guidelines, and the piloting and training of health care providers. CSOs and National Medical Stores were procuring and distributing misoprostol country wide to health centres two years before it was added to the clinical guidelines and EML of Uganda and in the absence of good evidence. The evidence suggests an increasing trend of misoprostol procurement and availability over the medicine of choice, oxytocin. This shift in national priorities has serious ramifications for maternal health care that need urgent evaluation. The absence of clinical guidelines in health centres and the lack of training preclude rational use of misoprostol. CSOs shifted their focus from the public to the private sector, where some of them continue to promote its use for off-label indications including induction of labour and abortion. There is an urgent need to build capacity to improve the robustness of the national and local institutions in assessing the safety and effectiveness of all medicines and their indications in Uganda. PMID- 25728485 TI - Challenges and strategies of medication adherence in Parkinson's disease: A qualitative study. AB - Little is known about strategies used by people with Parkinson's disease (PD) to facilitate medication adherence in the U.S. The purpose of this study was to describe challenges in adherence to medication regimens and to identify strategies used to facilitate adherence to medication regimens. A qualitative research design was used to interview sixteen community-dwelling people with PD and five caregivers. Data analysis was performed using content analysis. The majority of the participants (81.3%) reported decreased adherence to medication regimens. Seven themes emerged from the data. The main challenges of medication adherence included medication responses, cost of medications, and forgetfulness. Strategies used to facilitate adherence to medication regimens included seeking knowledge about antiparkinsonian medications, seeking advice from family and friends, use of devices, and use of reminders. These findings may be important in formulating interventions to improve adherence to medication regimens for people living with PD. PMID- 25728486 TI - Deposition of zwitterionic polymer brushes in a dense gas medium. AB - Poly(sulfobetaine methacrylate) (PSBMA) films known for their resistance to nonspecific protein adsorption, cell/bacterial adhesion and biofilm formation were produced by surface initiated polymerization on a silicon surface via a batch reaction system in CO2 expanded liquid (CO2-EL) medium. Atom transfer radical polymerization (ATRP) was carried out using 2,2'-bipyridyl as ligand and CuBr as a catalyst in water/methanol mixture with trichloro[4 (chloromethyl)phenyl]silane (CMPS) used as the initiating species. The films were grown in the CO2-EL environment at a range of conditions and thickness up to 10nm. In contrast to films produced by conventional solvent systems at atmospheric pressure, the polymer films grown by the CO2-EL process showed uniform thickness and pin-hole free topography. Most importantly, the CO2-EL processed PSBMA films showed no trace of copper (used as the catalyst), thus obviating the need for post-deposition processing and avoiding adverse effects of the metal leaching during service. Finally, PSBMA films from both the conventional and CO2-EL processes were exposed to Human mesenchymal stem cells (hMSCs) and the results showed that, while in both the cases the cell proliferation rate was inhibited by the charged polymeric brush surface, the CO2 EL-processed brush exhibited inhibition to a larger extent due to the reduced occurrence of pinholes. The process can be easily exploited effectively when carrying out surface initiated polymerization on non-flat topographies, such as in trenches and nanostructured features with high aspect ratios. PMID- 25728487 TI - Transcriptional silencing and activation of paternal DNA during Plasmodium berghei zygotic development and transformation to oocyst. AB - The malaria parasite develops sexually in the mosquito midgut upon entry with the ingested blood meal before it can invade the midgut epithelium and embark on sporogony. Recent data have identified a number of distinct transcriptional programmes operating during this critical phase of the parasite life cycle. We aimed at characterizing the parental contribution to these transcriptional programmes and establish the genetic framework that would guide further studies of Plasmodium zygotic development and ookinete-to-oocyst transition. To achieve this we used in vitro and in vivo cross-fertilization experiments of various parasite lines expressing fluorescent reporters under the control of constitutive and stage-specific promoters. The results revealed that the zygote/ookinete stage exhibits a maternal phenotype with respect to constitutively expressed reporters, which is derived from either maternal mRNA inheritance or transcription of the maternal allele. The respective paternal alleles are silenced in the zygote/ookinete but reactivated after midgut invasion and transformation to oocyst. Transcripts specifically produced in the zygote/ookinete are synthesized de novo by both parental alleles. These findings highlight a putative role of epigenetic regulation of Plasmodium zygotic development and add substantially to the emerging picture of the molecular mechanisms regulating this important stage of malaria transmission. PMID- 25728488 TI - The community ecology of pathogens: coinfection, coexistence and community composition. AB - Disease and community ecology share conceptual and theoretical lineages, and there has been a resurgence of interest in strengthening links between these fields. Building on recent syntheses focused on the effects of host community composition on single pathogen systems, we examine pathogen (microparasite) communities using a stochastic metacommunity model as a starting point to bridge community and disease ecology perspectives. Such models incorporate the effects of core community processes, such as ecological drift, selection and dispersal, but have not been extended to incorporate host-pathogen interactions, such as immunosuppression or synergistic mortality, that are central to disease ecology. We use a two-pathogen susceptible-infected (SI) model to fill these gaps in the metacommunity approach; however, SI models can be intractable for examining species-diverse, spatially structured systems. By placing disease into a framework developed for community ecology, our synthesis highlights areas ripe for progress, including a theoretical framework that incorporates host dynamics, spatial structuring and evolutionary processes, as well as the data needed to test the predictions of such a model. Our synthesis points the way for this framework and demonstrates that a deeper understanding of pathogen community dynamics will emerge from approaches working at the interface of disease and community ecology. PMID- 25728489 TI - Pilot of a theoretically grounded psychologist-delivered intervention for fear of cancer recurrence (Conquer Fear). PMID- 25728490 TI - Regulatory T-cell subsets in response to specific Mycobacterium tuberculosis antigens in vitro distinguish among individuals with different QTF and TST reactivity. AB - Regulatory T cells (Tregs), a subset of CD4+ T cells related with immune regulation, have been associated with active and latent tuberculosis infection (LTBI). Treg frequencies were evaluated by multicolor flow cytometry (FC) in peripheral blood mononuclear cells (PBMCs) stimulated with mycobacterial antigens ESAT-6, CFP-10, and TB7.7 to assess their capacity to distinguish subjects with different reactivity to the QuantiFERON-TB(r) Gold In-Tube (QFT-IT) test and the tuberculin skin test (TST). Increased frequencies of CD4+CD25highCD39+ cells were found for the [TST+, QTF+] compared with the [TST+, QTF-] group. Also, higher frequencies were observed for the [TST+, QTF+] compared with the [TST+, QTF-] and [TST-, QTF-] groups in CD4+CD25highFoxp3+ and CD4+CD25highCD39+Foxp3+ populations. Receiver operating characteristics (ROC curve) analysis confirmed these discriminating results. QFT-IT and TST quantitative values correlated with several Treg population frequencies. PMID- 25728491 TI - Ex vivo peptide-MHC II tetramer analysis reveals distinct end-differentiation patterns of human pertussis-specific CD4(+) T cells following clinical infection. AB - Pertussis is occurring in highly vaccinated populations, suggesting insufficient protective memory CD4(+) T cells to Bordetella (B.) pertussis. P.69 Pertactin (P.69 Prn) is an important virulence factor of B. pertussis, and P.69 Prn7-24 is an immunodominant CD4(+) T cell epitope in mice and broadly recognized in humans. P.69 Prn7-24 peptide-MHC II tetramers (DRB4*0101/IVKT) were designed to ex vivo interrogate the presence and differentiation state of P.69 Prn7-24 specific CD4(+) T cells in six symptomatic pertussis cases. Cases with relatively more CD45RA(-)CCR7(+) central memory CD4(+)DRB4*0101/IVKT(+) T cells secreted Th1 cytokines, while cases with more CD45RA(-)CCR7(-) effector memory CD4(+)DRB4*0101/IVKT(+) T cells secreted both Th1 and Th2 cytokines upon peptide stimulation. CD45RA(+)CCR7(-) terminal differentiation pattern was associated with low or non-functionality based on cytokine secretion. This study provides proof of principle for further peptide-MHC II tetramer guided approaches in the elucidation of limited immunological memory to B. pertussis and the resurgence of pertussis. PMID- 25728492 TI - Cyr61 participates in the pathogenesis of rheumatoid arthritis by promoting proIL 1beta production by fibroblast-like synoviocytes through an AKT-dependent NF kappaB signaling pathway. AB - IL-1beta plays a major role in the development of rheumatoid arthritis (RA). We previously showed that Cyr61 participates in RA pathogenesis as a proinflammatory factor. Here, we found that the levels of IL-1beta and Cyr61 were higher in RA SF than in osteoarthritis (OA) SF. IL-1beta mRNA and proIL-1beta protein levels were remarkably increased in Cyr61-stimulated FLS; however, IL-1beta was hardly detectable in the supernatant. We also found that the level of adenosine triphosphate (ATP) in SF and ST was significantly increased in RA patients and that the level of IL-1beta in supernatants from Cyr61-activated FLS increased significantly when we added exogenous ATP to the culture. Mechanistically, Cyr61 induced proIL-1beta production in FLS via the AKT-dependent NF-kappaB signaling pathway, and ATP caused Cyr61-induced proIL-1beta to generate IL-1beta in a caspase-1-dependent manner. Our results reveal a novel role of Cyr61 in RA that involves the promotion of proIL-1beta production in FLS. PMID- 25728493 TI - Vagaries of the ELISpot assay: specific detection of antigen responsive cells requires purified CD8(+) T cells and MHC class I expressing antigen presenting cell lines. AB - Quantification of antigen-specific CD8(+) T cells is important for monitoring infection, vaccination, and response to therapy in cancer and immune-mediated diseases. Cytokine enzyme-linked-immunospot (ELISpot) assays are often used for this purpose. We found that substantial spot formation in IFNgamma ELISpot assays occurred independently of CD8(+) T cells even when classical MHC class I restricted peptides are used for stimulation. Using fractionated cells and intracellular cytokine staining, the non-CD8(+) T cell IFNgamma production was attributed to the CD4(+) T cell fraction. We therefore refined a cell line-based ELISpot assay combining HLA-A*0201 expressing K562 cells for antigen presentation with purified CD8(+) T cells and demonstrated that it specifically detected CD8(+) T cell responses with detection limits comparable to traditional ELISpot assays and dextramer-based quantification. The assay was further adapted to whole antigen responses with antigen (pre-proinsulin)-expressing HLA-A*0201K562 cells. Thus, we revealed and corrected a weak spot of the CD8(+) ELISpot assay. PMID- 25728494 TI - Direct allylation of quinones with allylboronates. AB - Allylboronates undergo C-H allylation of unsubstituted or monosubstituted benzoquinone and naphthoquinone substrates. In the case of 2,5- or 2,6 disubstituted quinones addition involving the substituted carbon takes place. Allylation with stereodefined allylboronates occurs with retention of the configuration. PMID- 25728495 TI - Structure of full-length p53 tumor suppressor probed by chemical cross-linking and mass spectrometry. AB - The tumor suppressor p53 presents a great challenge for 3D structural analysis due to its inherent flexibility. In this work, we gained insight into the structure of full-length wild-type human p53 in solution by chemical cross linking/MS. This approach allowed us obtaining structural information of free wild-type p53 in solution without making use of the ultrastable quadruple p53 variant. The cross-links within one p53 monomer are in good agreement with the small-angle X-ray scattering based model of full-length p53. Our cross-linking data between different p53 molecules in the tetramer however indicate a large degree of flexibility in the C-terminal regulatory domain of full-length p53 in the absence of DNA. The cross-links suggest that the C-terminal regulatory domains are much closer to each other, resulting in a more compact arrangement of the p53 tetramer than perceived by the small-angle X-ray scattering model. PMID- 25728496 TI - Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: A meta analysis of 6 randomized clinical trials. AB - OBJECTIVE: A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and safety of direct factor Xa inhibitors (rivaroxaban and apixaban) with enoxaparin for the prevention of venous thromboembolism (VTE) after total knee replacement. METHODS: A systematic literature search in Medline, EMBASE, EBSCO, Springer, Ovid and Cochrane library databases was performed to identify RCTs comparing rivaroxaban/apixaban with enoxaparin for the prevention of VTE after total knee replacement. The outcomes including deep vein thrombosis (DVT), pulmonary embolism (PE) and major bleeding were pooled using risk ratios (RRs) with their 95% confidence intervals (95% CIs) as statistic. RESULTS: A total of 6 RCTs with 13,790 patients were included in this meta-analysis. Overall, the incidence of DVT was significantly decreased with the use of direct Xa inhibitors (both twice daily [b.i.d] and once daily [q.d.] regimes) comparing with the enoxaparin treatment (P<0.01); however, there was no significant influencing difference between direct Xa inhibitors (b.i.d. regime) and enoxaparin on the incidence of PE (P=0.06), while significantly lower rate was found for q.d. regime of direct Xa inhibitors (P=0.02). With respect to major bleeding, the pooled analysis did not demonstrate a significant difference between direct Xa inhibitors (b.i.d. and q.d. regimes) and enoxaparin (30mg and 40mg b.i.d.). CONCLUSION: In conclusion, our results confirmed that direct Xa inhibitors (rivaroxaban and apixaban) were more effective for prevention of VTE after total knee replacement as compared with enoxaparin, without increasing major bleeding risk. PMID- 25728497 TI - Factors associated with the platelet count in patients with chronic hepatitis C. AB - BACKGROUND: There are many potential causes of thrombocytopenia in patients with chronic hepatitis C (CHC). AIMS: We sought to determine the association between thrombopoietin (TPO) level, immature platelet fraction (IPF), immunoglobulin G (IgG) level, spleen size, and the platelet count in CHC. METHODS: We studied a consecutive sample of patients enrolled in an observational study at a referral based research center, excluding subjects based on eligibility criteria. TPO, glycocalicin, and von Willebrand Factor (vWF) levels were determined using stored sera. Hepatic fibrosis was assessed via transient elastography (TE) when available, and clinical laboratory values and radiologic data were obtained from the medical record. We performed analyses of the relationships between independent variables and the platelet count. RESULTS: On univariate analysis, the following variables were significantly associated with the platelet count: age, alanine aminotransferase (ALT), direct bilirubin, total bilirubin, IPF, international normalized ratio (INR), spleen size, vWF, glycocalicin, fibrosis stage on liver biopsy, and TE (P-values all <0.05). A multivariable model determined that imputed TE score, TPO, IPF, and spleen size were independently associated with the platelet count (P-values all<0.05). CONCLUSIONS: The platelet count in CHC is significantly associated with fibrosis, TPO level, IPF, and spleen size. Our findings challenge the proposed mechanism of decreased TPO levels or decreased bone marrow production of platelets as a cause of thrombocytopenia in CHC. Future studies focusing on the effects of fibrosis and splenomegaly on platelets may shed more light on the pathophysiology of thrombocytopenia in patients with CHC. PMID- 25728498 TI - Birth order and risk of hepatocellular carcinoma in chronic carriers of hepatitis B virus: a case-control study in The Gambia. AB - BACKGROUND & AIMS: Early age at infection with Hepatitis B virus (HBV) increases the risk of chronic infection. Moreover, early HBV infection may further independently increase the risk of hepatocellular carcinoma (HCC) beyond its effect on chronicity. METHODS: The distribution of birth order, a proxy for mode and timing of HBV transmission, was compared in The Gambia between hepatitis B surface antigen (HBsAg)-positive HCC cases recruited from hospitals (n = 72) and two HBsAg-positive control groups without HCC: population-based controls from a community HBV screening (n = 392) and hospital-based controls (n = 63). RESULTS: HCC risk decreased with increasing birth order in the population-based case control analysis. Using first birth order as the reference, the odds ratios were 0.52 (95% CI: 0.20-1.36), 0.52 (0.17-1.56), 0.57 (0.16-2.05) and 0.14 (0.03-0.64) for second, third, fourth and greater than fourth birth order respectively (P = 0.01). A similar inverse association was observed in the hospital-based case control comparison (P = 0.04). CONCLUSIONS: Compared to controls, HCC cases had earlier birth order, a proxy for young maternal age and maternal HBV viraemia at birth. This finding suggests that in chronic HBV carriers perinatal mother-to infant transmission may increase HCC risk more than horizontal transmission. Providing HBV vaccine within 24 h of birth to interrupt perinatal transmission might reduce the incidence of HCC in The Gambia. PMID- 25728499 TI - Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases. AB - Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >>>CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-kappaB, KLF2), (x) T cells produce dopamine (Tregs>>>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs expression and/or responses to dopamine or production of dopamine, (xiii) drugs that affect the dopaminergic system have potent effects on T cells (e.g. dopamine=Intropin, L-dopa, bromocriptine, haloperidol, quinpirole, reserpine, pergolide, ecopipam, pimozide, amantadine, tetrabenazine, nomifensine, butaclamol). Dopamine-induced activation of resting Teffs and suppression of Tregs seem beneficial for health and may also be used for immunotherapy of cancer and infectious diseases. Independently, suppression of DRs in autoimmune and pro inflammatory T cells, and also in cancerous T cells, may be advantageous. The review is relevant to Immunologists, Neurologists, Neuroimmunologists, Hematologists, Psychiatrists, Psychologists and Pharmacologists. PMID- 25728500 TI - Genetic screens and functional genomics using CRISPR/Cas9 technology. AB - Functional genomics attempts to understand the genome by perturbing the flow of information from DNA to RNA to protein, in order to learn how gene dysfunction leads to disease. CRISPR/Cas9 technology is the newest tool in the geneticist's toolbox, allowing researchers to edit DNA with unprecedented ease, speed and accuracy, and representing a novel means to perform genome-wide genetic screens to discover gene function. In this review, we first summarize the discovery and characterization of CRISPR/Cas9, and then compare it to other genome engineering technologies. We discuss its initial use in screening applications, with a focus on optimizing on-target activity and minimizing off-target effects. Finally, we comment on future challenges and opportunities afforded by this technology. PMID- 25728501 TI - Hermansky-Pudlak syndrome: high-resolution computed tomography findings and literature review. AB - Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by platelet dysfunction, oculocutaneous albinism, and life threatening pulmonary fibrosis. There are 7 HPS genotypes, with type 1 being the most severe. Pulmonary involvement usually begins during the third or fourth decades of life, with fibrosis being the most common cause of death. We present imaging and histopathologic findings of a 16-year-old Saudi adolescent girl with HPS-related pulmonary fibrosis, emphasizing on the role of imaging in assessment of disease severity and prognosis. PMID- 25728502 TI - Assessment effects in educational and psychosocial intervention trials: an important but often-overlooked problem. AB - Baseline assessments and repeated measures are an essential part of educational and psychosocial intervention trials, but merely measuring an outcome of interest can modify that outcome, either by the measurement process alone or by interacting with the intervention to strengthen or weaken the intervention effects. Assessment effects can result in biased estimates of intervention effects and may not be controlled by the usual two-group randomized controlled trial design. In this paper, we review the concept of assessment effects and other related phenomena, briefly describe study designs that estimate assessment effects separately from intervention effects and discuss their strengths and limitations, review evidence regarding the strength of assessment effects in intervention trials targeting behavior change, and discuss implications for intervention research. PMID- 25728504 TI - Accuracy of Echocardiographic Cardiac Index Assessment in Subjects with Preserved Left Ventricular Ejection Fraction. AB - INTRODUCTION: We aimed to determine the accuracy of the echocardiographic assessment of cardiac index (CI) in subjects with preserved left ventricular ejection fraction (LVEF). METHODS: Thirty-three subjects with LVEF >50%, normal sinus rhythm, and a broad spectrum of hemodynamic profiles underwent echocardiography immediately followed by right heart catheterization. As gold standards, CI was assessed using thermodilution [CI (TD)] and the Fick method [CI (F)]. Echocardiographic CI was assessed by four methods: from the left ventricular outflow tract (LVOT) velocity time integral and the LVOT diameter as measured [CI (LVOTm)] as well as estimated from body surface area [CI (LVOTe)], and from stroke volume indices assessed using the biplane [CI (BP)] and monoplane [CI (MP)] methods. RESULTS: The mean CI (TD), CI (F), CI (LVOTm), CI (LVOTe), CI (BP), and CI (MP) were 3.0 +/- 0.9, 3.1 +/- 0.7, 2.8 +/- 0.6, 3.3 +/- 0.6, 2.0 +/ 0.6, and 2.2 +/- 0.7 L/min/m(2) . There were modest correlations between CI (TD) and CI (F) and all four noninvasive measures of CI with r(2) values ranging from 0.09 to 0.30. CI (LVOTm) underestimated CI (TD) and CI (F) by 0.3 and 0.3 L/min/m(2) , CI (LVOTe) overestimated CI (TD) and CI (F) by 0.3 and 0.2 L/min/m(2) , and CI (BP) and CI (MP) underestimated CI (TD) and CI (F) by 1.1 and 1.1 L/min/m(2) and 0.9 and 0.9 L/min/m(2) , respectively, with large limits of agreement for all comparisons. CONCLUSIONS: In subjects with nondilated left ventricles with preserved LVEF, flow- or volume-based measures of CI by 2D echocardiography may not accurately reflect CI (TD) and CI (F). Further larger studies are required to verify our findings and to evaluate the accuracy of contrast and 3D echocardiography in this setting. PMID- 25728503 TI - Genetic causes of intellectual disability in a birth cohort: a population-based study. AB - Intellectual disability affects approximately 1-3% of the population and can be caused by genetic and environmental factors. Although many studies have investigated the etiology of intellectual disability in different populations, few studies have been performed in middle-income countries. The present study estimated the prevalence of genetic causes related to intellectual disability in a cohort of children from a city in south Brazil who were followed from birth. Children who showed poor performance in development and intelligence tests at the ages of 2 and 4 were included. Out of 4,231 liveborns enrolled in the cohort, 214 children fulfilled the inclusion criteria. A diagnosis was established in approximately 90% of the children evaluated. Genetic causes were determined in 31 of the children and 19 cases remained unexplained even after extensive investigation. The overall prevalence of intellectual disability in this cohort due to genetic causes was 0.82%. Because this study was nested in a cohort, there were a large number of variables related to early childhood and the likelihood of information bias was minimized by collecting information with a short recall time. This study was not influenced by selection bias, allowing identification of intellectual disability and estimation of the prevalence of genetic causes in this population, thereby increasing the possibility of providing appropriate management and/or genetic counseling. PMID- 25728509 TI - Dynamic nano-interfaces enable harvesting of functional 3D-engineered tissues. AB - Functional 3D-engineered tissues are successfully harvested from a substrate using stimuli-responsive hydrogel films with dynamic nano-interface. The dynamic wettability control at the interfaces allows cellular detachment, leading to tissue harvesting without serious damage and remaining polymers. This method can be applied to various types of organs and used for tissue transplantation in regenerative medicine. PMID- 25728510 TI - Effects of Local Administration of Boric Acid on Posterolateral Spinal Fusion with Autogenous Bone Grafting in a Rodent Model. AB - Spinal fusion is among the most frequently applied spinal surgical procedures. The goal of the present study was to evaluate whether the local administration of boric acid (BA) improves spinal fusion in an experimental spinal fusion model in rats. Currently, there is no published data that evaluates the possible positive effects if the local administration of BA on posterolateral spinal fusion. Thirty two rats were randomly divided into four independent groups: no material was added at the fusion area for group 1; an autogenous morselized corticocancellous bone graft was used for group 2; an autogenous morselized corticocancellous bone graft with boric acid (8.7 mg/kg) for group 3; and only boric acid was placed into the fusion area for group 4. The L4-L6 spinal segments were collected at week 6, and the assessments included radiography, manual palpation, and histomorphometry. A statistically significant difference was determined between the groups with regard to the mean histopathological scores (p = 0.002), and a paired comparison was made with the Mann-Whitney U test to detect the group/groups from which the difference originated. It was determined that only the graft + BA practice increased the histopathological score significantly with regard to the control group (p = 0.002). Whereas, there was no statistically significant difference between the groups in terms of the manual assessment of fusion and radiographic analysis (respectively p = 0.328 and p = 0.196). This preliminary study suggests that BA may clearly be useful as a therapeutic agent in spinal fusion. However, further research is required to show the most effective dosage of BA on spinal fusion, and should indicate whether BA effects spinal fusion in the human body. PMID- 25728511 TI - Interleukin-1 receptor associated kinase inhibitors: potential therapeutic agents for inflammatory- and immune-related disorders. AB - The various cells of innate immune system quickly counter-attack invading pathogens, and mount up "first line" defense through their trans-membrane receptors including Toll-like receptors (TLRs) and interleukin receptors (IL-Rs) that result in the secretion of pro-inflammatory cytokines. Albeit such inflammatory responses are beneficial in pathological conditions, their overstimulation may cause severe inflammatory damage; thus, make this defense system a "double edged sword". IRAK-4 has been evaluated as an indispensable element of IL-Rs and TLR pathways that can regulate the abnormal levels of cytokines, and therefore could be employed to manage immune- and inflammation related disorders. Historically, the identification of selective and potent inhibitors has been challenging; thus, a limited number of small molecule IRAK-4 inhibitors are available in literature. Recently, IRAK-4 achieved great attention, when Ligand(r) pharmaceutical and Nimbus Discovery(r) reported the beneficial potentials of IRAK-4 inhibitors in the pre-clinical evaluation for various inflammatory- and immune-related disorders, but not limited to, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, gout, asthma and cancer. PMID- 25728512 TI - Rap2a is a novel target gene of p53 and regulates cancer cell migration and invasion. AB - The p53 transcription factor is a critical regulator of the cell cycle, DNA repair, and apoptosis. Recent evidences suggest that p53 may contribute to the regulation of cell invasion and migration. Rap2a, a member of the small GTPase superfamily, mediates diverse cellular events such as cell adhesion, migration and proliferation through various signaling pathways. In this study, we identify that Rap2a is a novel target of p53 and is induced upon DNA damage in a p53 dependent manner. Upon DNA damage, p53 directly binds to the promoter of Rap2a and activates its transcription. We show that Rap2a is significantly upregulated in many types of tumors. In addition, the ectopic expression of Rap2a enhances the migration and invasive ability of cancer cells and increases activities of matrix metalloproteinase MMP2 and MMP9. In contrast, the inactivation of Rap2a inhibits cell invasion and activities of MMP2 and MMP9. We also show that Rap2a regulates the phosphorylation level of Akt. Collectively, our results show that ectopic expression of Rap2a has a key role in enhancing migration, invasion and metastasis by upregulating p-Akt. PMID- 25728515 TI - Microbiotica in women. AB - The perception that certain body cavities and spaces that are heavily inhabited by micro-organisms should be regarded as 'external' to the body function is no longer valid. Extensive research during recent years has demonstrated the importance of those microbes to normal physiology, which means that the human body and those tiny organisms are actually symbiotic. The major point of interaction between the human body and the microbiome is the gut. There are also gender-specific aspects for this symbiosis: bacterial vaginosis has serious implications for female morbidity, including reports of pelvic inflammatory disease, adverse pregnancy outcomes, increased susceptibility to sexually transmitted infections and infertility. Re-establishing a normal flora might be beneficial and therefore the use of probiotics and re-colonization by 'healthy' bacteria have become very popular. Probiotics may serve as an adjunct for treating recurrences of urogenital infections and vaginal atrophy. Some animal studies have pointed at potential beneficial effects of Lactobacilli species on bone health. PMID- 25728513 TI - Participation of proteasome-ubiquitin protein degradation in autophagy and the activation of AMP-activated protein kinase. AB - Although activation of the AMP-activated protein kinase (AMPK) as well as of ubiquitin/proteasome degradative pathways play an essential role in the preservation of metabolic homeostasis, little is known concerning interactions between protein turnover and AMPK activity. In the present studies, we found that inhibition of the 26S proteasome resulted in rapid activation of AMPK in macrophages, epithelial and endothelial cells. This was associated with increased levels of non-degraded Ub-protein conjugates, in both cytosolic and mitochondrial fractions. Selective inhibitors of ubiquitination or siRNA-dependent knockdown of Ub-ligase E1 diminished AMPK activation in cells treated with MG132, a 26S proteasome inhibitor. In addition to inhibition of AMPK activation by Ub-ligase E1 inhibitors, deficiency in Park2 mitochondria-associated Ub-ligase E3 also reduced AMPK activation upon dissipation of mitochondrial membrane potential (Deltapsim). Accumulation of Ub-proteins was correlated with decreases in cellular bioenergetics, including mitochondria oxidative phosphorylation, and an increase in ROS formation. Antioxidants, such as N-acetyl-L-cysteine or mitochondria-targeted MitoTEMPO, effectively diminished MG132-induced AMPK activation. Glucose-dependent regulation of AMPK or AMPK-mediated autophagy was modulated by alterations in intracellular levels of Ub-protein conjugates. Our results indicate that accumulation of ubiquitinated proteins alter cellular bioenergetics and redox status, leading to AMPK activation. PMID- 25728514 TI - A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth. AB - SMYD3 is a histone lysine methyltransferase that plays an important role in transcriptional activation as a member of an RNA polymerase complex, and its oncogenic role has been described in different cancer types. We studied the expression and activity of SMYD3 in a preclinical model of colorectal cancer (CRC) and found that it is strongly upregulated throughout tumorigenesis both at the mRNA and protein level. Our results also showed that RNAi-mediated SMYD3 ablation impairs CRC cell proliferation indicating that SMYD3 is required for proper cancer cell growth. These data, together with the importance of lysine methyltransferases as a target for drug discovery, prompted us to carry out a virtual screening to identify new SMYD3 inhibitors by testing several candidate small molecules. Here we report that one of these compounds (BCI-121) induces a significant reduction in SMYD3 activity both in vitro and in CRC cells, as suggested by the analysis of global H3K4me2/3 and H4K5me levels. Of note, the extent of cell growth inhibition by BCI-121 was similar to that observed upon SMYD3 genetic ablation. Most of the results described above were obtained in CRC; however, when we extended our observations to tumor cell lines of different origin, we found that SMYD3 inhibitors are also effective in other cancer types, such as lung, pancreatic, prostate, and ovarian. These results represent the proof of principle that SMYD3 is a druggable target and suggest that new compounds capable of inhibiting its activity may prove useful as novel therapeutic agents in cancer treatment. PMID- 25728516 TI - Role of endocrine dysfunction in frequently unexplained disorders. PMID- 25728518 TI - 207th ENMC Workshop on chronic respiratory insufficiency in myotonic dystrophies: management and implications for research, 27-29 June 2014, Naarden, The Netherlands. PMID- 25728519 TI - BAG3 myofibrillar myopathy presenting with cardiomyopathy. AB - Myofibrillar myopathies (MFMs) are a heterogeneous group of neuromuscular disorders distinguished by the pathological hallmark of myofibrillar dissolution. Most patients present in adulthood, but mutations in several genes including BCL2 associated athanogene 3 (BAG3) cause predominantly childhood-onset disease. BAG3 related MFM is particularly severe, featuring weakness, cardiomyopathy, neuropathy, and early lethality. While prior cases reported either neuromuscular weakness or concurrent weakness and cardiomyopathy at onset, we describe the first case in which cardiomyopathy and cardiac transplantation (age eight) preceded neuromuscular weakness by several years (age 12). The phenotype comprised distal weakness and severe sensorimotor neuropathy. Nerve biopsy was primarily axonal with secondary demyelinating/remyelinating changes without "giant axons." Muscle biopsy showed extensive neuropathic changes that made myopathic changes difficult to interpret. Similar to previous cases, a p.Pro209Leu mutation in exon 3 of BAG3 was found. This case underlines the importance of evaluating for MFMs in patients with combined neuromuscular weakness and cardiomyopathy. PMID- 25728520 TI - Adult polyglucosan body disease: clinical and histological heterogeneity of a large Italian family. AB - Adult Polyglucosan Body Disease (APBD) is a rare inherited leukodystrophy associated with axonal polyneuropathy, mainly reported in persons of Ashkenazi Jewish descent. We describe three Italian siblings at disease onset, presenting in their fifties with a combination of pyramidal and ataxic signs, mild demyelinating neuropathy on neurophysiological investigation (1/3 cases) and transient symptoms (1/3). A leucoencephalopathy with infratentorial lesions without enhancement and medullary/spine atrophy was demonstrated on brain/spine MRI (3/3). Muscle biopsy was normal in 2/3; both muscle and nerve biopsy showed polyglucosan bodies in the sibling with polyneuropathy. This indicated a need for GBE1 sequencing, which revealed a novel missense mutation (c.1064G>A; p.Arg355His) and one previously described (c.1604A>G; p.Tyr535Cys) in all siblings. We highlight that peripheral neuropathy, deemed as disease hallmark, may be missing and that transient symptoms are confirmed as early disease manifestations. The pattern of damage at neuro-imaging described recurs irrespective of clinical presentation, constituting a unifying diagnostic clue. PMID- 25728521 TI - Fast and simple preparation of iron-based thin films as highly efficient water oxidation catalysts in neutral aqueous solution. AB - Water oxidation is the key step in natural and artificial photosynthesis for solar-energy conversion. As this process is thermodynamically unfavorable and is challenging from a kinetic point of view, the development of highly efficient catalysts with low energy cost is a subject of fundamental significance. Herein, we report on iron-based films as highly efficient water-oxidation catalysts. The films can be quickly deposited onto electrodes from Fe(II) ions in acetate buffer at pH 7.0 by simple cyclic voltammetry. The extremely low iron loading on the electrodes is critical for improved atom efficiency for catalysis. Our results showed that this film could catalyze water oxidation in neutral phosphate solution with a turnover frequency (TOF) of 756 h(-1) at an applied overpotential of 530 mV. The significance of this approach includes the use of earth-abundant iron, the fast and simple method for catalyst preparation, the low catalyst loading, and the large TOF for O2 evolution in neutral aqueous media. PMID- 25728522 TI - Oregon's Gun Relief Program for Adjudicated Mentally Ill Persons: The Psychiatric Security Review Board. AB - This article describes the State of Oregon's implementation of two programs designed to comply with federal gun laws regarding reporting individuals who have received mental health adjudications in criminal and civil courts. One mandate requires that states submit names of adjudicated individuals to the National Instant Criminal Background Check System (NICS) while the second requires that the state establish a qualifying gun restoration program for those disqualified from gun ownership. In 2009, Oregon's Legislature developed an administrative approach to gun restoration and assigned the responsibility for conducting these hearing to the Oregon Psychiatric Security Review Board (PSRB). The PSRB is a state administrative board that has existed since 1977 and has been primarily focused on the supervision and treatment of adult and juvenile insanity acquittees. The gun restoration program began in 2010, but to date has only received three completed petitions requesting restoration of firearm rights. The article concludes with a discussion that surmises why very few of the Oregonians who are listed in NICS have submitted petitions for relief. PMID- 25728523 TI - Hospital-acquired anemia: the contribution of diagnostic blood loss. PMID- 25728524 TI - Possible link between hepatitis B infection and gastric cancer. PMID- 25728525 TI - Long-lasting opioids and unintentional overdose. PMID- 25728526 TI - Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. AB - BACKGROUND: Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours. METHODS: We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421. FINDINGS: By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9-32) of 49 women with breast cancer, ten (21%, 10-35) of 48 participants with small-cell lung cancer, one (4%, 0-22) of 23 patients with non-small-cell lung cancer, four (9%, 2-21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2-20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3-4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients. INTERPRETATION: These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer. FUNDING: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. PMID- 25728529 TI - The Quantification of Representative Sequences pipeline for amplicon sequencing: case study on within-population ITS1 sequence variation in a microparasite infecting Daphnia. AB - Next generation sequencing (NGS) platforms are replacing traditional molecular biology protocols like cloning and Sanger sequencing. However, accuracy of NGS platforms has rarely been measured when quantifying relative frequencies of genotypes or taxa within populations. Here we developed a new bioinformatic pipeline (QRS) that pools similar sequence variants and estimates their frequencies in NGS data sets from populations or communities. We tested whether the estimated frequency of representative sequences, generated by 454 amplicon sequencing, differs significantly from that obtained by Sanger sequencing of cloned PCR products. This was performed by analysing sequence variation of the highly variable first internal transcribed spacer (ITS1) of the ichthyosporean Caullerya mesnili, a microparasite of cladocerans of the genus Daphnia. This analysis also serves as a case example of the usage of this pipeline to study within-population variation. Additionally, a public Illumina data set was used to validate the pipeline on community-level data. Overall, there was a good correspondence in absolute frequencies of C. mesnili ITS1 sequences obtained from Sanger and 454 platforms. Furthermore, analyses of molecular variance (amova) revealed that population structure of C. mesnili differs across lakes and years independently of the sequencing platform. Our results support not only the usefulness of amplicon sequencing data for studies of within-population structure but also the successful application of the QRS pipeline on Illumina-generated data. The QRS pipeline is freely available together with its documentation under GNU Public Licence version 3 at http://code.google.com/p/quantification representative-sequences. PMID- 25728528 TI - Nephrotoxic effects of lead nitrate exposure in diabetic and nondiabetic rats: Involvement of oxidative stress and the protective role of sodium selenite. AB - Heavy metals are known to be toxic to organisms. The present study was undertaken to evaluate the protective effect of sodium selenite against lead nitrate (LN) induced nephrotoxicity in diabetic and nondiabetic rats. Animals were divided into eight groups where the first was served as a control, whereas the remaining groups were treated with sodium selenite (1 mg/kg b.w.), LN (22.5 mg/kg b.w.) and a combination of LN and sodium selenite and diabetic forms of these groups. Changes in antioxidant enzyme activities, malondialdehide levels, serum urea, uric acid, creatinine levels, body, and kidney weights and histopathological changes were determined after 28 days. LN caused severe histopathological changes, increment in urea, uric acid, creatinine, and MDA levels, also decreasing in antioxidant enzyme activities, body, and kidney weights. In sodium selenite + LN group, we observed the protective effect of sodium selenite on examining parameters. Also diabetes caused alterations on these parameters compared with nondiabetic animals. We found that sodium selenite did not show protective effect on diabetes caused damages. As a result, LN caused nephrotoxicity and sodium selenite alleviated this toxicity but sodium selenite did not protect kidneys against diabetes mediated toxicity. Also, LN caused more harmfull effects in diabetic groups compared with nondiabetic groups. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1229-1240, 2016. PMID- 25728527 TI - A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: a Children's Oncology Group Phase I Consortium report. AB - BACKGROUND: Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities, and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide. PROCEDURES: Reolysin was administered intravenously for 5 consecutive days, every 28 days. Using a 3 + 3 design, the following dose levels were evaluated: 3 * 10(8) Tissue Culture Inhibitory Dose 50% (TCID50 )/kg; 5 * 10(8) TCID50 /kg (maximum dose was 3 * 10(10) TCID50 ); and 5 * 10(8) TCID50 /kg plus oral cyclophosphamide (50 mg/m(2) /day * 21 days). RESULTS: Twenty-nine patients were enrolled; 28 were eligible and 24 were evaluable for toxicity and response. There were no hematologic dose-limiting toxicities. Grade 5 respiratory failure and a Grade 5 thromboembolic event were reported, both in the setting of progressive disease. The median time to clear the reovirus viremia was 6.5 days. Eight of 24 patients were viremic beyond the 5 days of therapy, all were negative by day 17. No patient had detectable viral RNA in saliva or stool. There were no objective responses. CONCLUSIONS: Reolysin at a dose of 5 * 10(8) TCID50 /kg daily for 5 days was well tolerated in children alone and in combination with oral cyclophosphamide. Virus was cleared rapidly from the serum and shedding in stool and saliva was not detectable. PMID- 25728530 TI - A non-chromatographic method for the removal of endotoxins from bacteriophages. AB - The Ff filamentous bacteriophages show potential as a new class of therapeutics, displaying utility in materials science as well as pharmaceutical applications. These phages are produced by the infection of E. coli, a Gram-negative bacterium which unavoidably sheds endotoxins into the extracellular space during growth. Since endotoxin molecules are highly immunoreactive, separation from the phage product is of critical importance, particularly those developed for human therapeutic use. The properties of M13, one of the Ff group, present a purification challenge chiefly because the standard scalable method for endotoxin removal from proteins-anion exchange chromatography-is not applicable due to pI similarity between the particles. This article examines the potential of polyethylene glycol (PEG)-NaCl precipitation as a scalable method for the separation of endotoxins from phage M13. Precipitation of M13 by 2% (w/v) PEG 6 000, 500 mM NaCl reduced endotoxin contamination of the phage product by 88%, but additional precipitation rounds did not maintain this proportional decrease. Dynamic light scattering was subsequently used to determine the effectiveness of a detergent to disassociate endotoxin molecules from M13. As a result, PEG-NaCl precipitation was supplemented with up to 2% (v/v) Triton X-100 to improve separation. A 5.7 log10 reduction in endotoxin concentration was achieved over three rounds of precipitation whilst retaining over 97% of the phage. This method compares favorably with the well-known ATPS (Triton X-114) technique for endotoxin removal from protein solutions. PMID- 25728531 TI - Special Issue for selected papers from Bioelectrics 2013--10th International Symposium on Bioelectrics: co-organized by COST TD1104 "EP4Bio2Med". PMID- 25728533 TI - Mechanically sintered gallium-indium nanoparticles. AB - Liquid metal nanoparticles that are mechanically sintered at and below room temperature are introduced. This material can be sintered globally on large areas of entire deposits or locally to create liquid traces within deposits. The metallic nanoparticles are fabricated by dispersing a liquid metal in a carrier solvent via sonication. The resulting dispersion is compatible with inkjet printing, a process not applicable to the bulk liquid metal in air. PMID- 25728532 TI - The TMPRSS2:ERG fusion and response to androgen deprivation therapy for prostate cancer. AB - BACKGROUND: In the United States, half of men with prostate cancer harbor the androgen-regulated gene fusion TMPRSS2:ERG. We hypothesized that men with TMPRSS2:ERG positive tumors are more responsive to androgen deprivation therapy (ADT). METHODS: We studied a cohort of 239 men with prostate cancer from the Physicians' Health Study and Health Professionals Follow-up Study who received ADT during their disease course. Fusion status was assessed on available tumor tissue by immunohistochemistry for ERG protein expression. We used Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for assessment of prostate cancer-specific mortality after ADT initiation. RESULTS: Roughly half of the men had stage T3 or higher tumors at diagnosis and 39% had Gleason 8-10 tumors. During an average follow up of 10.2 years, 42 men died from prostate cancer. There was a non-significant inverse association between positive fusion status and time to death from prostate cancer after ADT (multivariable HR: 0.76; 95% CI: 0.40-1.45). Harboring the TMPRSS2:ERG fusion was associated with a statistically significant lower risk of prostate cancer mortality among men who were treated with orchiectomy (multivariable HR: 0.13; 95% CI: 0.03-0.62), based on 15 events. CONCLUSIONS: Our results, combined with those from earlier studies, provide suggestive evidence that men with TMPRSS2:ERG positive tumors may have longer prostate cancer survival after ADT. Larger cohorts are needed for more robust results and to assess whether men with tumors harboring the fusion benefit from treatment with ADT in the (neo) adjuvant or metastatic setting specifically. PMID- 25728535 TI - Pulmonary artery dissection. AB - Pulmonary artery dissection is a rare and life-threatening event, usually a complication of chronic pulmonary hypertension leading to pulmonary artery aneurysm. We review the literature on this subject. PMID- 25728534 TI - Acetabular fractures in elderly patients: a comparative study of low-energy versus high-energy injuries. AB - PURPOSE: The goal of this study is to compare the characteristics, clinical course, and mortality rates of acetabular fractures in the elderly population with respect to two types of injury. METHODS: We reviewed 183 consecutive patients with acetabular fractures aged 60 years old and older. One hundred eighty-three patients (129 men and 54 women) were included in the study with an average age of 70.2 years. There were 186 fractures, which included three cases of bilateral fractures. Patients were divided into two groups: low-energy injuries (group I), 56, and high-energy injuries (group II), 130. Patient characteristics and fracture pattern, as well as in-hospital mortality rates were compared between the low-energy and high-energy groups. RESULTS: Patient demographics and comorbidities were significantly different between the groups. In group I, the average age was 74.9 years, versus 68.2 years in group II (p < 0.001). The percent of females in each group was 39.3 % and 24.6 %, respectively (p = 0.043), and the average body mass index (BMI) was 25.6 and 28.4, respectively (p = 0.001). The Charlson comorbidity index was higher in group I (1.98 vs 0.95 in group II, p < 0.001). However, the American Society of Anesthesiologists physical status (ASA) was similar between groups (2.56 vs 2.53, respectively, p = 0.808). The proportion of surgical treatment was 44.6 % in group I and 61.6 % in group II (p = 0.019). Group II had a longer hospital stay (10.4 days vs 14.5 days, p = 0.025), but in-hospital death was not significantly different (5.3 % vs 7.9 %, respectively, p = 0.567). CONCLUSION: Patients with acetabular fractures resulting from low-energy injuries were older and had lower BMI with more comorbidities. This study may highlight characteristics of fragility fractures of the acetabulum. PMID- 25728537 TI - Rhodium-catalyzed [(3+2)+2] carbocyclization of alkynylidenecyclopropanes with substituted allenes: stereoselective construction of tri- and tetrasubstituted exocyclic olefins. AB - The development of the stereoselective rhodium-catalyzed [(3+2)+2] carbocyclization of alkynylidenecyclopropanes (ACPs) with substituted allenes is described. This work demonstrates that activated and unactivated allenes preferentially undergo carbometalation at the distal terminus to generate tri- and tetrasubstituted exocyclic olefins with a neutral rhodium catalyst. In addition, this method provides a strategy for the total synthesis of the guaiane family of sesquiterpenes, which are not directly accessible using alkynes as exogenous pi-components. Finally, the preparation of the bicyclo[5.4.0]undecane ring system using a homologated ACP tether serves to further illustrate the versatility of this approach. PMID- 25728536 TI - Action-effect congruence during observational learning leads to faster action sequence learning. AB - Common coding theory suggests that any action (pressing a piano key) is intimately linked with its resultant sensory effect (an auditory musical tone). We conducted two experiments to explore the effect of varying auditory action effect patterns during complex action learning. In Experiment 1, participants were assigned to 1 of 4 groups, watched a silent video of a hand playing a sequence on a piano keyboard with no auditory action effect (observation) and were asked to practise and perform the sequence on an identical keyboard with varying action effects (reproduction). During reproduction, Group 1 heard no auditory tones (identical to observed video), Group 2 heard typical scale ascending piano tones with each key press, Group 3 heard fixed but out-of sequence piano tones with each key press, and Group 4 heard random piano tones with each key press. In Experiment two, new participants were assigned to 1 of 2 groups and watched an identical video; however, the video in this experiment contained typical, scale-ascending piano sounds. During reproduction, Group 1 heard no auditory tones while Group 2 heard typical, scale-ascending piano tones with each key press (identical to observed video). Our results showed that participants whose action-effect patterns during reproduction matched those in the observed video learned the action sequence faster than participants whose action-effect patterns during reproduction differed from those in the observed video. Additionally, our results suggest that adding an effect during reproduction (when one is absent during observation) is somewhat more detrimental to action sequence learning than removing an effect during reproduction (when one is present during observation). PMID- 25728538 TI - Review: Innate immunity, lipid metabolism and nutrition in canine atopic dermatitis. AB - BACKGROUND: The pathogenesis of canine atopic dermatitis (AD) involves dysfunction of the adaptive immune system. Recent evidence suggests that nonantigen-specific inflammatory elements may play a role in the development and perpetuation of canine AD. OBJECTIVES: The objective of this review is to provide an update on recent advances in the understanding of the role of innate immune cells, keratinocytes, lipid metabolism and nutrition in the pathogenesis of AD in dogs. METHODS: Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 are reviewed in this update. Where necessary, older articles are included for background information. RESULTS: Members of the innate immune system (including dendritic cells, Langerhans cells and mast cells) and keratinocytes interact with each other and with environmental antigens during both induction and effector phases of atopic inflammation. The responses of these cells and associated noncellular factors (such as complement and protease-activated receptors) to environmental stimuli influence the entire future course of the immune response to a given agent. Abnormalities in lipid metabolism may also influence the pathogenesis of canine AD via the production of inflammatory mediators and by alteration of epidermal barrier function and antigen presentation. However, a lack of fully controlled studies precludes definitive interpretation of these data. CONCLUSIONS AND CLINICAL IMPORTANCE: Evidence indicates that the cells and noncellular components of the innate immune system and the epidermis may play critical roles during both the sensitization and the effector phases of canine AD. Derangements in lipid metabolism may be involved in the pathogenesis of AD in dogs, but additional controlled studies are required in this area. PMID- 25728539 TI - Use of posaconazole delayed-release tablets for treatment of invasive aspergillosis. AB - A 65-year-old man developed Aspergillus brain abscesses following surgical resection of a sinus aspergilloma. He was treated with voriconazole for 1 year but infection recurred. We elected to treat with posaconazole delayed-release tablets, currently only indicated as antifungal prophylaxis in high-risk patients. A maintenance dose of 300 mg Q24 h resulted in a therapeutic serum concentration and appears safe and clinically effective thus far. This is the first report of successful use of posaconazole tablets for treatment of invasive aspergillosis. PMID- 25728541 TI - Vestibular migraine. AB - Vestibular migraine is now considered a distinct diagnostic entity by both the Barany Society and the International Headache Society. The recognition of vestibular migraine as a diagnostic entity required decades and was presaged by several reports indicating that a large proportion of patients with migraine headaches have vestibular symptoms and that a large proportion of patients with undiagnosed episodic vestibular symptoms have migraine headache. Despite the availability of diagnostic criteria for vestibular migraine, challenges to diagnosis include variability in terms of the character of dizziness, the presence or absence of clearly defined attacks, the duration of attacks, and the temporal association between headache or other migrainous features and vestibular symptoms. Also, symptoms of vestibular migraine often overlap with symptoms of other causes of dizziness, especially Meniere's disease and benign paroxysmal positional vertigo (BPPV). This article will discuss the demographics, epidemiology, clinical manifestations, physical examination findings, laboratory testing, comorbidities, treatment options, and pathophysiology of vestibular migraine. Future research in the field of vestibular migraine should include both clinical and basic science efforts to better understand the pathophysiology of this condition. Controlled treatment trials for vestibular migraine are desperately needed. PMID- 25728542 TI - Necessity of human milk banking in Japan: Questionnaire survey of neonatologists. AB - BACKGROUND: If their own mother's milk (OMM) is not available, another mother's milk may be used for extremely low-birthweight (ELBW) infants. Human milk is a bodily fluid, however, therefore we have assumed that other mother's milk is currently seldom given to infants despite its superiority to formula. Although the World Health Organization and the American Academy of Pediatrics have recommended using donor human milk (DHM) from a human milk bank (HMB) in the case that OMM is not available, there is no HMB in Japan. To assess whether other mother's milk is used for ELBW infants and whether an HMB is necessary in Japan, we surveyed neonatal intensive care units (NICU) via questionnaire. METHODS: The questionnaire was sent by email to members of the Japanese Neonatologist Association who are responsible for NICU. RESULTS: In total, 126 completed questionnaires (70.7%) were returned and analyzed. One-fourth of NICU give other mother's milk to ELBW infants. The first choice of nutrition is OMM, but other mother's milk or formula is given to infants at 19% of NICU if OMM is unavailable. Approximately three-fourths of NICU would like an HMB. CONCLUSION: Although human milk contains contagious agents and authorities do not recommend giving other mother's milk as a substitute for OMM, other mother's milk is still a choice in NICU in Japan. Many neonatologists, however, would prefer a safer alternative, that is, DHM obtained from an accredited HMB. A well-regulated HMB should be established and safe DHM should be available for all preterm infants if necessary. PMID- 25728540 TI - Helicobacter pylori Eradication in Patients with Immune Thrombocytopenic Purpura: A Review and the Role of Biogeography. AB - Idiopathic thrombocytopenic purpura (ITP) is typically a diagnosis of exclusion, assigned by clinicians after ruling out other identifiable etiologies. Since a report by Gasbarrini et al. in 1998, an accumulating body of evidence has proposed a pathophysiological link between ITP and chronic Helicobacter pylori (H. pylori) infection. Clinical reports have described a spontaneous resolution of ITP symptoms in about 50% of chronic ITP patients following empirical treatment of H. pylori infection, but response appears to be geography dependent. Studies have also documented that ITP patients in East Asian countries are more likely to express positive antibody titers against H. pylori-specific cytotoxic associated gene A (CagA), a virulence factor that is associated with an increased risk for gastric diseases including carcinoma. While a definitive mechanism by which H. pylori may induce thrombocytopenia remains elusive, proposed pathways include molecular mimicry of CagA by host autoantibodies against platelet surface glycoproteins, as well as perturbations in the phagocytic activity of monocytes. Traditional treatments of ITP have been largely empirical, involving the use of immunosuppressive agents and immunoglobulin therapy. However, based on the findings of clinical reports emerging over the past 20 years, health organizations around the world increasingly suggest the detection and eradication of H. pylori as a treatment for ITP. Elucidating the exact molecular mechanisms of platelet activation in H. pylori-positive ITP patients, while considering biogeographical differences in response rates, could offer insight into how best to use clinical H. pylori eradication to treat ITP, but will require well designed studies to confirm the suggested causative relationship between bacterial infection and an autoimmune disease state. PMID- 25728543 TI - Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis. AB - BACKGROUND: The clinical perspective on hepatic growth is limited. The goal of the present study was to compare hepatic hypertrophy and the kinetic growth rate(KGR) in patients after the ALPPS (Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy) procedure, portal vein embolization (PVE) and living donor liver transplantation. METHODS: Volumetry and KGR of the future liver remnant (FLR) were compared from (15) patients undergoing ALPPS, (53) patients undergoing PVE, (90) recipients of living donor liver grafts and (93) donors of living donor liver grafts. RESULTS: The degree of hypertrophy was significantly greater after ALPPS (84.3 +/- 7.8%) than after PVE (36.0 +/- 27.2%) (P < 0.001). The KGR was also significantly greater for ALPPS [32.7 +/- 13.6 cubic centimetres (cc)/day] (10.8 +/- 4.5%/day) compared with PVE (4.4 +/- 3.2 cc/day) (0.98 +/- 0.75%/day) (P < 0.001). The FLR of living donor donors had the greatest degree of hypertrophy (107.5 +/- 39.2%) and was greater than after ALPPS (P = 0.02), PVE (P < 0.001) and in living donor-recipient grafts (P < 0.001). KGR (cc/day) was greater in FLR of living donor donors compared with both ALPPS (P < 0.001) and PVE (P < 0.001). The KGR in patients undergoing ALPPS and living donor liver transplantation had a linear relationship with the size of FLR. CONCLUSION: FLR hypertrophy and KGR were greater after ALPPS than PVE. However, the degree of hypertrophy after ALPPS is not unprecedented, as KGR in the FLR from living donor donors is equal to or greater than after ALPPS. The KGR of the FLR in patients after ALPPS and living donor donors correlates directly with the size of the FLR. PMID- 25728544 TI - Suspected natural lysosomal storage disease from ingestion of pink morning glory (Ipomoea carnea) in goats in northern Argentina. AB - This study describes an occurrence of pink morning glory (Ipomoea carnea) intoxication in goats in northern Argentina. The clinical signs displayed by the affected animals were ataxia, lethargy, emaciation, hypertonia of the neck muscles, spastic paresis in the hind legs, abnormal postural reactions and death. The clinico-pathologic examination revealed that the affected animals were anemic and their serum level of aspartate aminotransferase was significantly increased. Cytoplasmic vacuolation in the Purkinje cells and pancreatic acinar cells was observed by histological examination. The neuronal lectin binding pattern showed a strong positive reaction to WGA (Triticum vulgaris), sWGA (succinylated T. vulgaris) and LCA (Lens culinaris). Although I. carnea is common in tropical regions, this is the first report of spontaneous poisoning in goats in Argentina. PMID- 25728545 TI - Xenotransplantation-theological-ethical considerations in an interdisciplinary symposium. AB - BACKGROUND: Unlike allotransplantation, reflections on xenotransplantation are infrequent in theological literature. However, xenotransplantation poses questions specifically concerning ethical and theological aspects that are imperative to address, such as personal identity between the poles of body, soul, and mind, the relationship between humans and animals, as well as challenges regarding specific issues of medical and social ethics. METHOD: This study summarizes the lectures of the symposium on "Xenotransplantation-a challenge to theological ethics," which took place in Munich from September 30 until October 2, 2013, and analyses the implications of xenotransplantation from the perspectives of Christian theological ethics, biblical theology, and systematic theology. Furthermore, the issue of xenotransplantation is addressed from the perspectives of Judaism and Islam. Beyond these theological deliberations, the metaphorical and religious meaning of the human heart, which may have an impact on the societal acceptability of xenotransplantation, as well as the Christian notion of compassion regarding animals, is analyzed from the perspective of historical sciences. RESULTS AND CONCLUSION: According to the perspectives of Christianity, Judaism, and Islam, there are no specifically religious fundamental and generally binding reasons to prohibit xenotransplantation as a means of treating grave and life-threatening organ insufficiencies. PMID- 25728546 TI - Pharmacokinetic characteristics of fentanyl iontophoretic trandermal system over a range of applied current. AB - OBJECTIVE: To evaluate the pharmacokinetic (PK) characteristics of a modified fentanyl iontophoretic transdermal system (ITS). RESEARCH DESIGN AND METHODS: This was a prospective, open-label, single-center, randomized, 3-period, 5 treatment, 6-sequence study. Each subject was randomly assigned to receive three treatments in a sequence consisting of intravenous fentanyl citrate, fentanyl ITS at 170 MUA, and then one of three other fentanyl ITS treatments at 140, 200 or 230 MUA. MAIN OUTCOME MEASURES: The following PK parameters were determined: Cmax, tmax, t1/2, AUC23 - 25 and amount of fentanyl absorbed into systemic circulation (i.e., Dose Absorbed). RESULTS: Fifty-two subjects received at least one fentanyl treatment. Serum exposure (Cmax and AUC23 - 25) and Dose Absorbed increased with increasing current. The median tmax ranged from 23.0 to 23.2 h across the 4 ITS groups. Mean t1/2 values ranged from 11.0 to 13.0 h. The Dose Absorbed from the fentanyl ITS at 170 MUA met bioequivalence criteria when compared to data from an earlier version of the fentanyl ITS. CONCLUSIONS: Exposure of fentanyl and the amount of fentanyl absorbed increased with the magnitude of applied current with the ITS. The fentanyl ITS at 170 MUA is bioequivalent to an earlier version of the system. PMID- 25728547 TI - Refractory Kasabach-Merritt phenomenon successfully treated with sirolimus, and a mini-review of the published work. AB - Kasabach-Merritt phenomenon (KMP) is a rare and life-threatening disease involving a vascular tumor combined with severe consumptive coagulopathy. We present for the first time a case of KMP with the vascular tumor involving two anatomical sites; the patient failed to respond to steroids and vincristine. Following sirolimus therapy at a dose of 0.8 mg/m(2) twice daily, the lesions shrank and the platelet count improved and remained normal 4 months after initial therapy. Current treatments for KMP are not particularly effective. Sirolimus at 0.8 mg/m(2) per dose, administrated twice daily, appears to be a safe and effective management option. It appears to be an interesting therapeutic option in refractory KMP, but the time to response is variable. PMID- 25728548 TI - ELF cut-off points: aetiology is also a relevant factor. PMID- 25728549 TI - Large-scale topographical screen for investigation of physical neural-guidance cues. AB - A combinatorial approach was used to present primary neurons with a large library of topographical features in the form of micropatterned substrate for high throughput screening of physical neural-guidance cues that can effectively promote different aspects of neuronal development, including axon and dendritic outgrowth. Notably, the neuronal-guidance capability of specific features was automatically identified using a customized image processing software, thus significantly increasing the screening throughput with minimal subjective bias. Our results indicate that the anisotropic topographies promote axonal and in some cases dendritic extension relative to the isotropic topographies, while dendritic branching showed preference to plain substrates over the microscale features. The results from this work can be readily applied towards engineering novel biomaterials with precise surface topography that can serve as guidance conduits for neuro-regenerative applications. This novel topographical screening strategy combined with the automated processing capability can also be used for high throughput screening of chemical or genetic regulatory factors in primary neurons. PMID- 25728550 TI - Side-chain cysteine-functionalized poly(2-oxazoline)s for multiple peptide conjugation by native chemical ligation. AB - We prepared statistical copolymers composed of 2-methyl-2-oxazoline (MeOx) in combination with 2-butenyl-2-oxazoline (BuOx) or 2-decenyl-2-oxazoline (DecOx) as a basis for polymer analogous introduction of 1,2-aminothiol moieties at the side chain. MeOx provides hydrophilicity as well as cyto- and hemocompatibility, whereas the alkene groups of BuOx and DecOx serve for functionalization with a thiofunctional thiazolidine by UV-mediated thiol-ene reaction. After deprotection the cysteine content in functionalized poly(2-oxazoline) (POx) is quantified by NMR and a modified trinitrobenzenesulfonic acid assay. The luminescent cell viability assay shows no negative influence of cysteine-functionalized POx (cys POx) concerning cell viability and cell number. cys-POx was used for multiple chemically orthogonal couplings with thioester-terminated peptides through native chemical ligation (NCL), which was performed and confirmed by NMR and MALDI-ToF measurements. PMID- 25728551 TI - Acceleration of cyanobacterial dominance in north temperate-subarctic lakes during the Anthropocene. AB - Increases in atmospheric temperature and nutrients from land are thought to be promoting the expansion of harmful cyanobacteria in lakes worldwide, yet to date there has been no quantitative synthesis of long-term trends. To test whether cyanobacteria have increased in abundance over the past ~ 200 years and evaluate the relative influence of potential causal mechanisms, we synthesised 108 highly resolved sedimentary time series and 18 decadal-scale monitoring records from north temperate-subarctic lakes. We demonstrate that: (1) cyanobacteria have increased significantly since c. 1800 ce, (2) they have increased disproportionately relative to other phytoplankton, and (3) cyanobacteria increased more rapidly post c. 1945 ce. Variation among lakes in the rates of increase was explained best by nutrient concentration (phosphorus and nitrogen), and temperature was of secondary importance. Although cyanobacterial biomass has declined in some managed lakes with reduced nutrient influx, the larger spatio temporal scale of sedimentary records show continued increases in cyanobacteria throughout the north temperate-subarctic regions. PMID- 25728552 TI - Anterior lumbar spine surgery: a systematic review and meta-analysis of associated complications. AB - BACKGROUND CONTEXT: The anterior approach to the lumbar spine is increasingly used to accomplish various surgical procedures. However, the incidence and risk factors for complications associated with anterior lumbar spine surgery (ALS) have not been fully elucidated. PURPOSE: To identify and document types of complications and complication rates associated with ALS, determine risk factors for these events, and evaluate the effect of measures used to decrease complication rates. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of the English-language literature was conducted for articles published between January 1992 and December 2013. A MEDLINE search was conducted to identify articles reporting complications associated with ALS. For each complication, the data were combined using a generalized linear mixed model with a binomial probability distribution and a random effect based on the study. Predictors used were the type of procedure (open, minimally invasive, or laparoscopic), the approach used (transperitoneal vs. retroperitoneal), use of recombinant bone morphogenetic protein-2, use of preoperative computed tomography angiography (CTA), and the utilization of an access surgeon. Open surgery was used as a reference category. RESULTS: Seventy-six articles met final inclusion criteria and reported complication rates in 11,410 patients who underwent arthrodesis and/or arthroplasty via laparoscopic, mini-open, and open techniques. The overall complication rate was 14.1%, with intraoperative and postoperative complication rates of 9.1% and 5.2%, respectively. Only 3% of patients required reoperation or revision procedures. The most common complications reported were venous injury (3.2%), retrograde ejaculation (2.7%), neurologic injury (2%), prosthesis related (2%), postoperative ileus (1.4%), superficial infection (1%), and others (1.3%). Laparoscopic and transperitoneal procedures were associated with higher complication rates, whereas lower complication rates were observed in patients receiving mini-open techniques. Our analysis indicated that the use of recombinant bone morphogenetic protein-2 was associated with increased rates of retrograde ejaculation; however, there may be limitations in interpreting these data. Data regarding the use of preoperative CTA and an access surgeon were limited and demonstrated mixed benefit. CONCLUSIONS: Overall complication rates with ALS are relatively low, with the most common complications occurring at a rate of 1% to 3%. Complication rates are related to surgical technique, approach, and implant characteristics. Further randomized controlled trials are needed to validate the use of preventative measures including CTA and the use of an access surgeon. PMID- 25728553 TI - The comparison of pedicle screw and cortical screw in posterior lumbar interbody fusion: a prospective randomized noninferiority trial. AB - BACKGROUND CONTEXT: Pedicle screws (PS) offer great benefits in posterior lumbar interbody fusion (PLIF), but several drawbacks of PS, including the risk of superior facet joint violation and muscle injury, have also pointed out. Recently, cortical screws (CS) were invented, which can be placed without the drawbacks associated with PS. However, whether CS in PLIF can provide similar or greater clinical and radiologic outcomes compared to those of PS has not been fully evaluated in clinical research studies. PURPOSE: To evaluate whether the CS provides similar results to the PS in PLIF, in terms of fusion rate, clinical and surgical outcomes, and complications. STUDY DESIGN: This is a prospective, randomized, noninferiority trial. PATIENT SAMPLE: Seventy-nine eligible patients were randomly assigned to either Group A (39 patients), for which PS was used, or Group B (40 patients), for which CS was used. OUTCOME MEASURES: The primary study end point was to measure fusion rate using dynamic radiographs and computed tomography scans. Secondary end points included intensity of low back pain and pain radiating to the leg using visual analog scales, and also, functional status using the Oswestry Disability Index, surgical morbidity, and additional outcomes such as pedicle fracture and mechanical failure. METHODS: We compared baseline data in both groups. To evaluate the efficacy of CS in PLIF compared to PS, we compared fusion rates, clinical outcomes, and complications after surgery in both groups. RESULTS: At the 6- and 12-month follow-up points, similar fusion rates were observed in both groups (p=.81 and 0.61, respectively). According to the clinical outcome, CS provided similar improvements in pain amelioration and functional status compared to PS, with no significant differences. Additionally, CS resulted in significantly less surgical morbidity, including shorter incision length, quicker operative time, and less blood loss, compared to PS. CONCLUSIONS: CS in PLIF provides similar clinical and radiologic outcomes compared to PS in PLIF. On the basis of the present study, we suggest CS to be a reasonable alternative to PS in PLIF. PMID- 25728554 TI - Electronic structure and partial charge distribution of Doxorubicin in different molecular environments. AB - The electronic structure and partial charge of doxorubicin (DOX) in three different molecular environments-isolated, solvated, and intercalated in a DNA complex-are studied by first-principles density functional methods. It is shown that the addition of solvating water molecules to DOX, together with the proximity to and interaction with DNA, has a significant impact on the electronic structure as well as on the partial charge distribution. Significant improvement in estimating the DOX-DNA interaction energy is achieved. The results are further elucidated by resolving the total density of states and surface charge density into different functional groups. It is concluded that the presence of the solvent and the details of the interaction geometry matter greatly in determining the stability of DOX complexation. Ab initio calculations on realistic models are an important step toward a more accurate description of the long-range interactions in biomolecular systems. PMID- 25728555 TI - Interleukin-10 and tumour necrosis factor-alpha serum levels in chronic Chagas disease patients. AB - In Chagas disease, chronically infected individuals may be asymptomatic or may present cardiac or digestive complications, and it is well known that the human immune response is related to different clinical manifestations. Different patterns of cytokine levels have been previously described in different clinical forms of this disease, but contradictory results are reported. Our aim was to evaluate the serum levels of interleukin-10 and tumour necrosis factor-alpha in patients with asymptomatic and cardiac Chagas disease. The serum interleukin-10 levels in patients with cardiomyopathy were higher than those in asymptomatic patients, mainly in those without heart enlargement. Although no significant difference was observed in serum tumour necrosis factor-alpha levels among the patients, we found that cardiac patients also present high levels of this cytokine, largely those with heart dilatation. Therefore, these cytokines play an important role in chronic Chagas disease cardiomyopathy. Follow-up investigations of these and other cytokines in patients with chronic Chagas disease need to be conducted to improve the understanding of the immunopathology of this disease. PMID- 25728558 TI - Medical education on cannabis and cannabinoids: Perspectives, challenges, and opportunities. AB - The global regulatory landscape regarding the medical use of cannabis and cannabinoids is changing rapidly. This has considerable impact on health care professionals who currently receive little or no education on issues regarding medical cannabis. We propose a 'cannabis curriculum' that covers the spectrum of historical, botanical, physiological, clinical and legal issues to allow health care professionals to engage in meaningful discussions with their patients and colleagues around this stigmatized and controversial subject. PMID- 25728557 TI - An investigation of anatomical competence in junior medical doctors. AB - Because of a decrease of the time available for anatomy education, decisions need to be made to reduce the relevant content of the anatomy curriculum. Several expert consensus initiatives resulted in lists of structures, lacking analysis of anatomical competence. This study aims to explore the use of anatomical knowledge by medical doctors in an attempt to delineate the nature of anatomical competence. The research question is: what kind of anatomical knowledge do junior medical doctors use during a consultation with a patient presenting with a shoulder complaint? Ten junior medical doctors participated in this stimulated recall study. Each of them was videotaped while performing a consultation with a standardized patient with a complex shoulder complaint. The recording was viewed immediately after. Participants were videotaped again while verbalizing the thoughts they remembered having during the consultation. Verbatim transcriptions were coded by two coders using the qualitative data analysis ATLAS.ti software. Results were that these junior medical doctors used anatomical knowledge in all phases of the consultation, especially during physical examination. The use of anatomical terms was strongly associated with clinical reasoning and it was apparent that every subject visualized relevant anatomical information. Conclusion is that young medical doctors actively use their anatomical knowledge and it seems that the relevant anatomy consists largely of adequate visual representations in memory. Anatomy teachers should focus the students' learning activity on building an adequate visual representation of anatomical structures. This should be supported by assessments that test the quality of the students' visual representations. PMID- 25728559 TI - An investigation of ultramarathon-associated visual impairment. AB - OBJECTIVE: The purpose of this study was to investigate the characteristics under which ultramarathon-associated visual impairment occurs and to seek to identify its physiological basis and risk factors. METHODS: Through an online questionnaire, distributed worldwide, we obtained information from 173 self identified ultramarathon runners who had experienced visual impairment during an ultramarathon. We attempted to characterize this vision impairment-its symptoms, duration, and the conditions under which it occurs. Select characteristics were compared with a reference group of 412 registrants of the 161-km Western States Endurance Run. RESULTS: Ultramarathon-associated visual impairment was typically characterized as painless clouding of vision that resolved either during (13.5%) or after racing within a median of 3.5 hours (range 0 to 48 hours) upon cessation of running. The mean (+/-SD) distance at which vision impairment occurred was 73+/-40 km, and the 161-km distance was the most frequent race distance (46.8%) in which visual impairment occurred. Visual impairment was often recurrent, with respondents reporting having it develop during a median of 2 races. Respondents with a history of refractive surgery had more episodes than those without such history (median 3.5 vs 2 episodes, P=.010). Compared with the reference group, runners with visual impairment were nearly twice as likely (23.7% vs 12.1%, P<.001) to have had refractive surgery. CONCLUSIONS: Ultramarathon-associated visual impairment typically presents as a painless clouding of vision that is self-limited but tends to recur in certain runners. Risk appears higher among those with a history of refractive surgery, which is relevant for ultramarathon runners who are considering, or who have a history of, refractive surgery. PMID- 25728560 TI - Merging advanced technologies with classical methods to uncover dendritic spine dynamics: A hot spot of synaptic plasticity. AB - The structure of dendritic spines determines synaptic efficacy, a plastic process that mediates information processing in the vertebrate nervous system. Aberrant spine morphology, including alterations in shape, size, and number, are common in different brain diseases. Because of this, accurate and unbiased characterization of dendritic spine structure is vital to our ability to explore and understand their involvement in neuronal development, synaptic plasticity, and synaptic failure in neurological diseases. Investigators have attempted to elucidate the precise structure and function of dendritic spines for more than a hundred years, but their fundamental role in synaptic plasticity and neurological diseases remains elusive. Limitations and ambiguities in imaging techniques have exacerbated the challenges of acquiring accurate information about spines and spine features. However, recent advancements in molecular biology, protein engineering, immuno-labeling techniques, and the use of super-resolution nano microscopy along with powerful image analysis software have provided a better understanding of dendritic spine architecture. Here we describe the pros and cons of the classical staining techniques used to study spine morphology, and the alteration of dendritic spines in various neuropathological conditions. Finally, we highlight recent advances in super-resolved nanoscale microscopy, and their potentials and pitfalls when used to explore dendritic spine dynamics. PMID- 25728562 TI - High Curie temperature and coercivity performance of Fe3-xCrxSe4 nanostructures. AB - Monoclinic Fe3-xCrxSe4 nanostructures (0<=x<=2.5) were synthesized using a high temperature solution chemical method. With increasing the Cr doping, the peak positions in the X-ray diffraction (XRD) patterns of Fe3-xCrxSe4 nanostructures slightly shifted to lower 2theta values due to the changes in lattice parameters. Expansions in the unit cell volumes of Fe3-xCrxSe4 nanostructures (x>0.3) may have been responsible for enhancing the ferromagnetic (FM) interaction between magnetic ions, which resulted in a significant increase in the Curie temperature (TC) from 331 K for Fe3Se4 to 429 K for FeCr2Se4, distinctly differing from the magnetic properties of the corresponding bulk materials. A room-temperature coercivity (HC) analysis showed an obvious increase from 3.2 kOe for Fe3Se4 to 12 kOe for Fe2.3Cr0.7Se4 nanostructure, but gradually decreased upon further increasing the Cr content. PMID- 25728561 TI - 'Towards a unified approach for the determination of the bioaccessibility of organic pollutants'. AB - Bioaccessibility studies have been widely used as a research tool to determine the potential human exposure to ingested contaminants. More recently they have been practically applied for soil borne toxic elements. This paper reviews the application of bioaccessibility tests across a range of organic pollutants and contaminated matrices. Important factors are reported to be: the physiological relevance of the test, the components in the gut media, the size fraction chosen for the test and whether it contains a sorptive sink. The bioaccessibility is also a function of the composition of the matrix (e.g. organic carbon content of soils) and the physico-chemical characteristics of the pollutant under test. Despite the widespread use of these tests, there are a large number of formats used and very few validation studies with animal models. We propose a unified format for a bioaccessibility test for organic pollutants. The robustness of this test should first be confirmed through inter laboratory comparison, then tested in-vivo. PMID- 25728563 TI - Gender-related mortality and in-hospital complications following ST-segment elevation myocardial infarction: data from a primary percutaneous coronary intervention cohort. AB - BACKGROUND: The increased mortality related to female gender in ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI) has been reported from various patient cohorts and treatment strategies with controversial results. In the present work, we evaluated the impact of female gender on mortality and in-hospital complications among a specific subset of consecutive STEMI patients managed solely by PPCI. HYPOTHESIS: Female gender is not an independent predicor for mortality among STEMI patients. METHODS: We performed a retrospective, single center observational study that included 1346 consecutive STEMI patients undergoing PPCI, of which 1075 (80%) were male. Patient's records were evaluated for 30-day mortality, in-hospital complications, and long-term mortality over a mean period of 2.7 +/- 1.6 years. RESULTS: Compared with males, females were older (69 +/- 13 vs 60 +/- 13 years, P < 0.001), had a significantly higher rate of baseline risk factors, and had prolonged symptom duration (460 +/- 815 minutes vs 367 +/- 596 minutes, P = 0.03). Females suffered from more in-hospital complications and had higher 30-day mortality (5% vs 2%, P = 0.008) as well as higher overall mortality (12.5% vs 6%, P < 0.001). In spite of the significant mortality risk in unadjusted models, a multivariate adjusted Cox regression model did not demonstrate that female gender was an independent predictor for mortality among STEMI patients. CONCLUSIONS: Among patients with STEMI treated by PPCI, female gender is associated with a higher 30-day mortality and complications rates compared to males. Following multivariate analysis, female gender was not a significant predictor of long-term death following STEMI. PMID- 25728564 TI - Phototherapy in atopic dermatitis: a systematic review of the literature. AB - BACKGROUND: Phototherapy is a treatment option for atopic dermatitis recommended by several guidelines. OBJECTIVE: To perform a systematic review of the efficacy of different modalities of phototherapy and photochemotherapy in moderate to severe atopic dermatitis. MATERIAL AND METHODS: We considered all randomized clinical trials (RCTs) performed in patients with atopic dermatitis, and accepted all outcome measures. Articles were identified via an online search of the MEDLINE (via Ovid) and Embase databases and the Cochrane Central Register of Controlled Trials. We also searched for clinical trials registered in Current Controlled Trials and in the World Health Organization's International Clinical Trials Registry Platform. RESULTS: Twenty-one RCTs (961 patients) were included in the qualitative analysis. Two of the trials included children and adolescents (32 patients). The efficacy of narrow-band UV-B and UV-A1 phototherapy was similar for the different outcome measures contemplated. Two RCTs assessed the efficacy of psoralen plus UV-A therapy (PUVA). No serious adverse events were described. In general, the publications reviewed were characterized by a high risk of bias and poor reporting of methodology and results. CONCLUSIONS: There is evidence for the use of narrow-band UV-B and UV-A1 phototherapy in moderate to severe atopic dermatitis. Evidence supporting the use of PUVA in atopic dermatitis is scarce and there is little information on the use of phototherapy in childhood. For the purpose of future studies, it would be advisable to use comparable criteria and scales for the evaluation of disease severity and patients, to standardize radiation methods, and to establish a minimum follow-up time. PMID- 25728565 TI - Necrobiosis lipoidica: a descriptive study of 35 cases. AB - INTRODUCTION AND OBJECTIVES: Necrobiosis lipoidica (NL) is a chronic idiopathic granulomatous disease considered to occur in association with diabetes mellitus. Data on the frequency of this association, however, are inconsistent. Our aim was to retrospectively analyze the clinical characteristics of patients diagnosed with NL at our hospital and to investigate the association with diabetes mellitus and other diseases. MATERIAL AND METHODS: We performed a chart review of all patients with a clinical and histologic diagnosis of NL treated and followed in the dermatology department of Hospital de Bellvitge in Barcelona, Spain between 1987 and 2013. RESULTS: Thirty-five patients (6 men and 29 women with a mean age of 47.20 years) were diagnosed with NL in the study period. At the time of diagnosis, 31 patients had pretibial lesions. Thirteen patients (37%) had a single lesion at diagnosis, and the mean number of lesions was 3.37. Twenty-three patients (65.71%) had diabetes mellitus (type 1 in 10 cases and type 2 in 13). In 20 patients, onset of diabetes preceded that of NL by a mean of 135.70 months. The 2 conditions were diagnosed simultaneously in 3 patients. None of the 35 patients developed diabetes mellitus during follow-up. Six patients had hypothyroidism, and 4 of these also had type 1 diabetes. CONCLUSIONS: NL is frequently associated with type 1 and 2 diabetes. Although diabetes tends to develop before NL, it can occur simultaneously. PMID- 25728566 TI - Cobalt-catalyzed C-H arylations with weakly-coordinating amides and tetrazoles: expedient route to angiotensin-II-receptor blockers. AB - Cobalt-catalyzed C-H arylations enabled the synthesis of biaryl tetrazoles, which are key structural motifs in antihypertensive angiotensin-II-receptor blockers. Thus, weakly-coordinating benzamides were employed for step-economical C-H arylations with ample scope. Further, a low-valent NHC complex enabled first cobalt-catalyzed C-H functionalization by tetrazole assistance. PMID- 25728567 TI - Neutrophil vacuolation in acetaminophen-induced acute liver failure. PMID- 25728568 TI - How accurate are orthopedic surgeons in diagnosing periprosthetic joint infection after total knee arthroplasty?: A multicenter study. AB - BACKGROUND: The lack of standardized diagnostic criteria for periprosthetic joint infection (PJI) poses a challenge to accurate diagnosis of PJI. Recently, the Musculoskeletal Infection Society (MSIS) proposed diagnostic criteria for PJI. However, it is not known how well these proposed criteria accommodate real clinical scenarios. We determined what proportion of patients satisfied the MSIS criteria, and if MSIS criteria were not met, what other rationales were used to diagnose PJI. METHODS: We retrospectively reviewed the records of 303 patients who underwent two-stage exchange arthroplasty for treatment of PJI of the knee at 17 institutions. The rationale for making the diagnosis of PJI was also recorded, if the case did not meet the MSIS criteria. In addition, detailed information about isolated microorganisms were gathered. RESULTS: Among the 303 patients, 198 met the diagnostic criteria proposed by MSIS. Among the 105 patients who did not meet the MSIS criteria, 88% met two or three minor criteria; however joint fluid analysis or histologic analysis was not performed in 85% of these 105 patients. The most common rationale for the diagnosis of PJI was the presence of abnormal physical findings. Microorganisms were identified in only 52% of all patients; the most common organism was coagulase-negative Staphylococcus. CONCLUSIONS: The diagnosis of PJI was based on clinical suspicion in approximately one-third of cases. In this series, joint aspiration or histological analysis was not performed in a large number of patients. Thus, surgeons should perform joint fluid and histologic analysis to assure the accuracy of PJI diagnosis. PMID- 25728569 TI - G-protein-coupled receptor controls steroid hormone signaling in cell membrane. AB - G-protein-coupled receptors (GPCRs) are involved in animal steroid hormone signaling, but their mechanism is unclear. In this research, we report that a GPCR called ErGPCR-2 controls steroid hormone 20-hydroxyecdysone (20E) signaling in the cell membrane of the lepidopteran insect Helicoverpa armigera. ErGPCR-2 was highly expressed during molting and metamorphosis. 20E, via ErGPCR-2, regulated rapid intracellular calcium increase, protein phosphorylation, gene transcription, and insect metamorphosis. ErGPCR-2 was located in the cell surface and was internalized by 20E induction. GPCR kinase 2 participated in 20E-induced ErGPCR-2 phosphorylation and internalization. The internalized ErGPCR-2 was degraded by proteases to desensitize 20E signaling. ErGPCR-2 knockdown suppressed the entrance of 20E analog [(3)H] ponasterone A ([(3)H]Pon A) into the cells. ErGPCR-2 overexpression or blocking of ErGPCR-2 internalization increased the entrance of [(3)H]Pon A into the cells. However, ErGPCR-2 did not bind to [(3)H]Pon A. Results suggest that ErGPCR-2 transmits steroid hormone 20E signaling and controls 20E entrance into cells in the cell membrane. PMID- 25728570 TI - Control of inhibitory synaptic outputs by low excitability of axon terminals revealed by direct recording. AB - An axon is thought to faithfully conduct action potentials to its terminals. However, many features of the axon and axon terminals, especially at inhibitory synapses, remain unknown. By directly recording from the axon and terminal of a cultured cerebellar Purkinje cell (PC), we demonstrate that low membrane excitability of axon terminals shapes synaptic output. Simultaneous measurements of presynaptic capacitance and evoked IPSCs revealed PC axon terminals contained large readily releasable synaptic vesicles that exhibited a low release probability. Nevertheless, IPSCs evoked by stimulating a PC soma underwent frequency-dependent depression. Direct axonal recordings showed that high frequency action potentials were faithfully conducted over axonal bifurcations but were attenuated around terminals. Sparse Na(+) channels relative to enriched voltage-gated K(+) channels in terminals caused short-term depression of IPSCs by reducing Ca(2+) influx. Together with confirmation in slice recordings, our findings reveal a presynaptic mechanism that shapes short-term synaptic depression without depleting releasable vesicles. PMID- 25728571 TI - Natural grouping of neural responses reveals spatially segregated clusters in prearcuate cortex. AB - A fundamental challenge in studying the frontal lobe is to parcellate this cortex into "natural" functional modules despite the absence of topographic maps, which are so helpful in primary sensory areas. Here we show that unsupervised clustering algorithms, applied to 96-channel array recordings from prearcuate gyrus, reveal spatially segregated subnetworks that remain stable across behavioral contexts. Looking for natural groupings of neurons based on response similarities, we discovered that the recorded area includes at least two spatially segregated subnetworks that differentially represent behavioral choice and reaction time. Importantly, these subnetworks are detectable during different behavioral states and, surprisingly, are defined better by "common noise" than task-evoked responses. Our parcellation process works well on "spontaneous" neural activity, and thus bears strong resemblance to the identification of "resting-state" networks in fMRI data sets. Our results demonstrate a powerful new tool for identifying cortical subnetworks by objective classification of simultaneously recorded electrophysiological activity. PMID- 25728573 TI - A physiological, rather than a superovulated, post-implantation environment can attenuate the compromising effect of assisted reproductive techniques on gene expression in developing mice embryos. AB - Assisted reproductive techniques (ARTs) may perturb the pre-/peri-conception microenvironments, which subsequently threaten the health of offspring. This study aimed to investigate the effects of superovulation, vitrification, in vitro culture, and embryo transfer on the expression of epigenetic modulators, imprinted genes, and pluripotency markers in expanded blastocysts and Day-9.5 (D9.5) concepti. Results revealed that 53.4% (8/15) and 86.7% (13/15) of genes in the fetus and placenta, respectively, have similar patterns of transcription in all D9.5 concepti, despite the perturbed mRNA expression observed at the blastocyst stage for each embryo-production technique. These observations indicate a counterbalancing of the abnormal expression pattern analyzed at the blastocyst stage during post-implantation development, particularly when the uterus of a naturally synchronized foster mother is employed. Superovulation resulted in the most abnormal expression patterns compared to other treatment groups, although these same blastocysts were able to develop in a synchronized uterus. Thus, superovulation creates a hormonal environment that negatively affected gene expression and impairs fetal growth more adversely during post implantation development than other ART protocols, such as in vitro culture, vitrification, or embryo transfer-although each did contribute negatively to the implantation and development process. Together, these results may have implications for treating infertility in humans. PMID- 25728572 TI - Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects. AB - Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue compared to pH 7.6, a value close to the pH in healthy brain tissue. This should maximize neuroprotection in ischemic tissue while minimizing on-target side effects associated with NMDAR blockade in noninjured brain regions. We have determined the mechanism underlying pH-dependent inhibition and demonstrate the utility of this approach in vivo. We also identify dicarboxylate dimers as a novel proton sensor in proteins. These results provide insight into the molecular basis of pH dependent neuroprotective NMDAR block, which could be beneficial in a wide range of neurological insults associated with tissue acidification. PMID- 25728575 TI - Stochastic modelling of shifts in allele frequencies reveals a strongly polygynous mating system in the re-introduced Asiatic wild ass. AB - Small populations are prone to loss of genetic variation and hence to a reduction in their evolutionary potential. Therefore, studying the mating system of small populations and its potential effects on genetic drift and genetic diversity is of high importance for their viability assessments. The traditional method for studying genetic mating systems is paternity analysis. Yet, as small populations are often rare and elusive, the genetic data required for paternity analysis are frequently unavailable. The endangered Asiatic wild ass (Equus hemionus), like all equids, displays a behaviourally polygynous mating system; however, the level of polygyny has never been measured genetically in wild equids. Combining noninvasive genetic data with stochastic modelling of shifts in allele frequencies, we developed an alternative approach to paternity analysis for studying the genetic mating system of the re-introduced Asiatic wild ass in the Negev Desert, Israel. We compared the shifts in allele frequencies (as a measure of genetic drift) that have occurred in the wild ass population since re introduction onset to simulated scenarios under different proportions of mating males. We revealed a strongly polygynous mating system in which less than 25% of all males participate in the mating process each generation. This strongly polygynous mating system and its potential effect on the re-introduced population's genetic diversity could have significant consequences for the long term persistence of the population in the Negev. The stochastic modelling approach and the use of allele-frequency shifts can be further applied to systems that are affected by genetic drift and for which genetic data are limited. PMID- 25728574 TI - Roles of p38alpha mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer. AB - The p38alpha mitogen-activated protein kinase pathway not only regulates the production of inflammatory mediators, but also controls processes related to tissue homeostasis, such as cell proliferation, differentiation and survival, which are often disrupted during malignant transformation. The versatility of this signaling pathway allows for the regulation of many specific functions depending on the cell type and context. Here, we discuss mouse models that have been used to identify in vivo functions of p38alpha signaling in the pathogenesis of inflammatory diseases and cancer. Experiments using genetically modified mice and pharmacological inhibitors support that targeting the p38alpha pathway could be therapeutically useful for some inflammatory diseases and tumor types. PMID- 25728576 TI - Dietary protein:carbohydrate balance is a critical modulator of lifespan and reproduction in Drosophila melanogaster: a test using a chemically defined diet. AB - Macronutrient balance is an important determinant of fitness in many animals, including insects. Previous studies have shown that altering the concentrations of yeast and sugar in the semi-synthetic media has a profound impact on lifespan in Drosophila melanogaster, suggesting that dietary protein:carbohydrate (P:C) balance is the main driver of lifespan and ageing processes. However, since yeast is rich in multiple nutrients other than proteins, this lifespan-determining role of dietary P:C balance needs to be further substantiated through trials using a chemically-defined, synthetic diet. In the present study, the effects of dietary P:C balance on lifespan and fecundity were investigated in female D. melanogaster flies fed on one of eight isocaloric synthetic diets differing in P:C ratio (0:1, 1:16, 1:8, 1:4, 1:2, 1:1, 2:1 or 4:1). Lifespan and dietary P:C ratio were related in a convex manner, with lifespan increasing to a peak at the two intermediate P:C ratios (1:2 and 1:4) and falling at the imbalanced ratios (0:1 and 4:1). Ingesting nutritionally imbalanced diets not only caused an earlier onset of senescence but also accelerated the age-dependent increase in mortality. Egg production was suppressed when flies were fed on a protein-deficient food (0:1), but increased with increasing dietary P:C ratio. Long-lived flies at the intermediate P:C ratios (1:2 and 1:4) stored a greater amount of lipids than those short-lived ones at the two imbalanced ratios (0:1 and 4:1). These findings provide a strong support to the notion that adequate dietary P:C balance is crucial for extending lifespan in D. melanogaster and offer new insights into how dietary P:C balance affects lifespan and ageing through its impacts on body composition. PMID- 25728577 TI - A novel chemical footprinting approach identifies critical lysine residues involved in the binding of receptor-associated protein to cluster II of LDL receptor-related protein. AB - Tandem mass tags (TMTs) were utilized in a novel chemical footprinting approach to identify lysine residues that mediate the interaction of receptor-associated protein (RAP) with cluster II of LDL (low-density lipoprotein) receptor (LDLR) related protein (LRP). The isolated RAP D3 domain was modified with TMT-126 and the D3 domain-cluster II complex with TMT-127. Nano-LC-MS analysis revealed reduced modification with TMT-127 of peptides including Lys(256), Lys(270) and Lys(305)-Lys(306) suggesting that these residues contribute to cluster II binding. This agrees with previous findings that Lys(256) and Lys(270) are critical for binding cluster II sub-domains [Fisher, Beglova and Blacklow (2006) Mol. Cell 22, 277-283]. Cluster II-binding studies utilizing D3 domain variants K(256)A, K(305)A and K(306)A now showed that Lys(306) contributes to cluster II binding as well. For full-length RAP, we observed that peptides including Lys(60), Lys(191), Lys(256), Lys(270) and Lys(305)-Lys(306) exhibited reduced modification with TMT in the RAP-cluster II complex. Notably, Lys(60) has previously been implicated to mediate D1 domain interaction with cluster II. Our results suggest that also Lys(191) of the D2 domain contributes to cluster II binding. Binding studies employing the RAP variants K(191)A, K(256)A, K(305)A and K(306)A, however, revealed a modest reduction in cluster II binding for the K(256)A variant only. This suggests that the other lysine residues can compensate for the absence of a single lysine residue for effective complex assembly. Collectively, novel insight has been obtained into the contribution of lysine residues of RAP to cluster II binding. In addition, we propose that TMTs can be utilized to identify lysine residues critical for protein complex formation. PMID- 25728578 TI - iTRAQ proteomic analysis of N-acetylmuramic acid mediated anti-inflammatory capacity in LPS-induced RAW 264.7 cells. AB - Lactobacillus acidophilus probiotic bacteria have lasting beneficial health effects in the gastrointestinal tract, including protecting against pathogens, improving immunomodulation, and producing beneficial bacteria-derived molecules. In lipopolysaccharide (LPS) induced RAW 264.7 cells treated with peptidoglycan or N-acetylmuramic acid (NAM) from L. acidophilus, 390 differentially expressed proteins (8.76%) were identified by iTRAQ analysis, 257 (5.77%) of which were upregulated and 133 (2.99%) were downregulated under LPS-induced conditions. Most of these proteins were grouped into the following inflammation-related cellular signaling: lysosome pathway, calcium signaling pathway, and Toll-like receptor (TLR) signaling pathway. Among them, clathrin, SERCA, and interleukin 1 receptor antagonist were differentially expressed to a significant degree in peptidoglycan or NAM pretreated RAW 264.7 cells. Bioinformatics analysis indicated that NAM may mediate an anti-inflammatory process via a Ca(2+) -dependent NF-kappaB pathway. These observations reveal new insights into the molecular mechanisms involved in the suppression of LPS-induced macrophage inflammation by L. acidophilus. PMID- 25728579 TI - Client-therapist alliance discrepancies and outcome in cognitive-behavioral therapy for youth anxiety. AB - BACKGROUND: Studies exploring the association between alliance and outcome in youth cognitive-behavioral therapy (CBT) have yielded inconsistent results based upon whose perspective is measured. OBJECTIVE: The current study explored the degree to which youth with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, anxiety disorders and their therapists agree in their ratings of the alliance at multiple assessment points and evaluated whether inter-rater discrepancies predicted treatment outcome. METHOD: Youth (N = 62; Mage = 12.43, SD = .76) received empirically supported CBT. Paired samples t tests assessed for significant disagreement between youth- and therapist-rated alliance at sessions 4, 8, and 12. Regression analyses were conducted to evaluate whether discrepancies between raters at each time point predicted posttreatment anxiety symptom scores. RESULTS: Overall, alliance was positive for both child (aged 7-12 years) and adolescent (aged 13-16 years) clients. Discrepancies between youth and therapist ratings of alliance were statistically significant at session 4 for children and session 8 for adolescents, with youth rating the relationship more favorably than therapists. However, rating discrepancies did not predict youth- or parent-reported treatment outcome. CONCLUSIONS: Considerable variability may exist between youth and therapist perspectives on the therapeutic alliance, indicating potential attunement problems, particularly during earlier phases of treatment. However, these discrepancies did not negatively affect treatment response. Implications for alliance research and clinical practice are discussed. PMID- 25728580 TI - Center of pressure control for balance maintenance during lateral waist-pull perturbations in older adults. AB - When balance is disturbed, location of the center of pressure (COP) contributes to a person's ability to recover from a perturbation. This study investigated COP control prior to first step lift-off (FSLO) during lateral perturbations in older non-fallers and fallers. 38 non-fallers and 16 fallers received lateral waist pulls at 5 different intensities. Crossover stepping responses at the intensity level where the largest number of subjects responded with crossover steps were analyzed. Whole-body center of mass (COM) and COP positions in the medio-lateral (ML) direction with respect to the base of support (BOS), and COP velocity were calculated. An inverted pendulum model was used to define the BOS stability boundary at FSLO, which was also adjusted using the COP position at FSLO (functional boundary). No significant differences were found in the COP velocities between fallers and non-fallers (p>.093). However, the COP positions for fallers were located significantly more medial at FSLO (p<=.01), resulting in a significantly reduced functional boundary. Although the stability margins, measures of stability based on the BOS, were significantly larger than zero for fallers (p<=.004), they were not significantly different from zero for the functional boundary, i.e., reaching the functional stability limit. Fallers had reduced functional limits of stability in the ML direction, which would predispose them to more precarious stability conditions than non-fallers. This could be a cause for taking more steps than non-fallers for balance recovery as we observed. The functional boundary estimation may be a more sensitive marker of balance instability than the BOS boundary. PMID- 25728581 TI - Running with a load increases leg stiffness. AB - Spring-mass models have been used to characterize running mechanics and leg stiffness in a variety of conditions, yet it remains unknown how running while carrying a load affects running mechanics and leg stiffness. The purpose of this study was to test the hypothesis that running with a load increases leg stiffness. Twenty-seven subjects ran at a constant speed on a force-measuring treadmill while carrying no load, and while wearing weight vests loaded with 10%, 20%, and 30% of body weight. We measured lower extremity motion and created a scaled musculoskeletal model of each subject, which we used to estimate lower extremity joint angles and leg length. We estimated dimensionless leg stiffness as the ratio of the peak vertical ground reaction force (normalized to body weight) and the change in stance phase leg length (normalized to leg length at initial foot contact). Leg length was calculated as the distance from the center of the pelvis to the center-of-pressure under the foot. We found that dimensionless leg stiffness increased when running with load (p=0.001); this resulted from an increase in the peak vertical ground reaction force (p<0.001) and a smaller change in stance phase leg length (p=0.025). When running with load, subjects had longer ground contact times (p<0.020), greater hip (p<0.001) and knee flexion (p=0.048) at the time of initial foot contact, and greater peak stance phase hip, knee, and ankle flexion (p<0.05). Our results reveal that subjects run in a more crouched posture and with higher leg stiffness to accommodate an added load. PMID- 25728583 TI - Deciphering the impact of parameters influencing transgene expression kinetics after repeated cell transduction with integration-deficient retroviral vectors. AB - Lentiviral and gammaretroviral vectors are state-of-the-art tools for transgene expression within target cells. The integration of these vectors can be deliberately suppressed to derive a transient gene expression system based on extrachromosomal circular episomes with intact coding regions. These episomes can be used to deliver DNA templates and to express RNA or protein. Importantly, transient gene transfer avoids the genotoxic side effects of integrating vectors. Restricting their applicability, episomes are rapidly lost upon dilution in dividing target cells. Addressing this limitation, we could establish comparably stable percentages of transgene-positive cells over prolonged time periods in proliferating cells by repeated transductions. Flow cytometry was applied for kinetic analyses to decipher the impact of individual parameters on the kinetics of fluoroprotein expression after episomal retransduction and to visualize sequential and simultaneous transfer of heterologous fluoroproteins. Expression windows could be exactly timed by the number of transduction steps. The kinetics of signal loss was affected by the cell proliferation rate. The transfer of genes encoding fluoroproteins with different half-lives revealed a major impact of protein stability on temporal signal distribution and accumulation, determining optimal retransduction intervals. In addition, sequential transductions proved broad applicability in different cell types and using different envelope pseudotypes without receptor overload. Stable percentages of cells coexpressing multiple transgenes could be generated upon repeated coadministration of different episomal vectors. Alternatively, defined patterns of transgene expression could be recapitulated by sequential transductions. Altogether, we established a methodology to control and adjust a temporally defined window of transgene expression using retroviral episomal vectors. Combined with the highly efficient cell entry of these vectors while avoiding integration, the developed technology is of great significance for a broad panel of applications, including transcription-factor-based induced cell fate conversion and controlled transfer of genetically encoded RNA- or protein-based drugs. PMID- 25728582 TI - Influence of heat treatment on bond strength and corrosion resistance of sol-gel derived bioglass-ceramic coatings on magnesium alloy. AB - In this study, bioglass-ceramic coatings were prepared on magnesium alloy substrates through sol-gel dip-coating route followed by heat treatment at the temperature range of 350-500 degrees C. Structure evolution, bond strength and corrosion resistance of samples were studied. It was shown that increasing heat treatment temperature resulted in denser coating structure as well as increased interfacial residual stress. A failure mode transition from cohesive to adhesive combined with a maximum on the measured bond strength together suggested that heat treatment enhanced the cohesion strength of coating on the one hand, while deteriorated the adhesion strength of coating/substrate on the other, thus leading to the highest bond strength of 27.0MPa for the sample heat-treated at 450 degrees C. This sample also exhibited the best corrosion resistance. Electrochemical tests revealed that relative dense coating matrix and good interfacial adhesion can effectively retard the penetration of simulated body fluid through the coating, thus providing excellent protection for the underlying magnesium alloy. PMID- 25728584 TI - Antimicrobial efficacy of an innovative emulsion of medium chain triglycerides against canine and feline periodontopathogens. AB - OBJECTIVES: To test the in vitro antimicrobial efficacy of a non-toxic emulsion of free fatty acids against clinically relevant canine and feline periodontopathogens METHODS: Antimicrobial kill kinetics were established utilising an alamarBlue((r)) viability assay against 10 species of canine and feline periodontopathogens in the biofilm mode of growth at a concentration of 0.125% v/v medium chain triglyceride (ML:8) emulsion. The results were compared with 0.12% v/v chlorhexidine digluconate and a xylitol-containing dental formulation. Mammalian cellular cytotoxicity was also investigated for both the ML:8 emulsion and chlorhexidine digluconate (0.25 to 0.0625% v/v) using in vitro tissue culture techniques. RESULTS: No statistically significant difference was observed in the antimicrobial activity of the ML:8 emulsion and chlorhexidine digluconate; a high percentage kill rate (>70%) was achieved within 5 minutes of exposure and was maintained at subsequent time points. A statistically significant improvement in antibiofilm activity was observed with the ML:8 emulsion compared with the xylitol-containing formulation. The ML:8 emulsion possessed a significantly lower (P < 0.001) toxicity profile compared with the chlorhexidine digluconate in mammalian cellular cytotoxicity assays. CLINICAL SIGNIFICANCE: The ML:8 emulsion exhibited significant potential as a putative effective antimicrobial alternative to chlorhexidine- and xylitol- based products for the reduction of canine and feline periodontopathogens. PMID- 25728585 TI - On the role of the electronic structure of the heteronuclear oxide cluster [Ga2Mg2O5 ](.+) in the thermal activation of methane and ethane: an unusual doping effect. AB - The reactivity of the heteronuclear oxide cluster [Ga2 Mg2 O5 ](.+) , bearing an unpaired electron at a bridging oxygen atom (Ob (.-) ), towards methane and ethane has been studied using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). Hydrogen-atom transfer (HAT) from both methane and ethane to the cluster ion is identified experimentally. The reaction mechanisms of these reactions are elucidated by state-of-the-art quantum chemical calculations. The roles of spin density and charge distributions in HAT processes, as revealed by theory, not only deepen our mechanistic understanding of C?H bond activation but also provide important guidance for the rational design of catalysts by pointing to the particular role of doping effects. PMID- 25728586 TI - Why do patients regret their prostate cancer treatment? A systematic review of regret after treatment for localized prostate cancer. AB - OBJECTIVE: The aim of this study was to review regret following treatment for localized prostate cancer, including factors associated with higher levels of regret, regret after specific treatments and the use of interventions to modify the likelihood of regret. METHODS: Online databases including Medline, CINAHL, EMBASE, EBSCO and PsycINFO were searched in June 2014, using the terms 'prostate' and 'regret' for publications written in English and appearing in print since the year 1997. RESULTS: Of 422 articles identified by the search criteria, 28 contained analyzable data regarding 8118 patients. The most commonly identified factors associated with regret after prostate cancer treatment were treatment toxicity factors, especially sexual and urinary function. Other factors included older age and longer time since treatment. The levels of regret were generally higher after radical prostatectomy than external beam radiotherapy or brachytherapy. Decision-making aids were the most commonly used method for reducing the likelihood of regret and were effective. CONCLUSIONS: This is the first systematic review of regret following treatment for localized prostate cancer. Suggestions for the future study of regret in this setting can be made. These include the use of a standardized scale; recognizing levels of regret as low, medium or high; and separately identifying the decision made when patients have combinations of treatments such as surgery followed by radiotherapy. PMID- 25728587 TI - Randomised clinical trial: deep remission in biologic and immunomodulator naive patients with Crohn's disease - a SONIC post hoc analysis. AB - BACKGROUND: As treatment goals in Crohn's disease (CD) evolve, targets now include clinical remission (CR), mucosal healing (MH) and biological remission [C reactive protein normalisation (CRPnorm )]. AIMS: To evaluate the association of baseline factors and treatment with the achievement of different composite remission parameters at week 26. METHODS: This post hoc analysis of the SONIC trial evaluated different composite remission measures at week 26 in a subgroup of patients with Crohn's disease activity index (CDAI) scores, CRP, and endoscopic data available at baseline and week 26 (N = 188). Assessed composite remission measures were: CR (CDAI < 150) and MH (absence of any mucosal ulcerations), previously referred to as 'deep remission;' and alternative composite endpoints: CR + CRPnorm (CRP < 0.8 mg/dL); CRPnorm + MH; and CR + CRPnorm + MH. RESULTS: Among analysed patients, 136/188 (72.3%) achieved CR and 90/188 (47.9%) achieved MH at week 26. All composite outcomes were significantly greater (Bonferroni significance level, P <= 0.016) with combination therapy (i.e. infliximab and azathioprine; 52.3-63.6%) vs. azathioprine monotherapy (12.9 29.0%; p <= 0.005 for all comparisons). Composite remission rates including MH were significantly greater with combination therapy (52.3-56.9%) vs. infliximab (25.6-32.3%; P <= 0.015 for all comparisons except CRPnorm + MH, P = 0.017) and vs. azathioprine monotherapy (12.9-20.4%; P <= 0.002 for all comparisons). Median serum trough infliximab concentrations among patients who achieved MH or CR + MH were greater when compared with those among patients who did not achieve MH (P = 0.018) or CR + MH (P = 0.053). Among the subgroup of patients with early Crohn's disease, MH alone or in combination with composite remission criteria significantly improved clinical outcomes of patients who received combination therapy. CONCLUSIONS: Combination therapy was more effective in achieving various composite remission measures vs. azathioprine or infliximab monotherapy. These data illustrate that 'deep remission' is achievable with combination therapy in a high percentage of patients with early Crohn's disease. ClinicalTrials.gov number: NCT00094458. PMID- 25728589 TI - Cutaneous immunopathology of long-standing complex regional pain syndrome. AB - BACKGROUND: Both increased mast cells numbers and raised immune mediator concentrations indicate immune activation in the affected skin of patients with early complex regional pain syndrome (CRPS), but little is known about regional immune cell involvement in late-stage CRPS. The aim of the current study was to determine skin immune cell populations in long-standing CRPS. METHODS: Using 6-mm skin punch biopsies from CRPS-affected and non-affected tissues, and a combination of chemical and immunofluorescence staining, we examined the density and function of key cell populations including mast cells, epidermal Langerhans cells (LCs) and tissue resident T-cells. RESULTS: We found no significant differences in either overall immune cell infiltrates, or mast cell density between CRPS-affected and non-affected sub-epidermal tissue sections, contrasting recent findings in early CRPS by other groups. However, CD1a(+) LC densities in the epidermal layer were significantly decreased in affected compared to non affected CRPS limbs (p < 0.01). T-cell clones isolated from CRPS-affected sub epidermal tissues displayed a trend towards increased IL-13 production in ELISPOT assays when compared to T-cells isolated from non-affected areas, suggesting a Th2 bias. CONCLUSIONS: Immune cell abnormalities are maintained in late-stage CRPS disease as manifest by changes in epidermal LC density and tissue resident T cell phenotype. PMID- 25728588 TI - Shared genetic and environmental influences on early temperament and preschool psychiatric disorders in Hispanic twins. AB - OBJECTIVE: Despite an increasing recognition that psychiatric disorders can be diagnosed as early as preschool, little is known how early genetic and environmental risk factors contribute to the development of psychiatric disorders during this very early period of development. METHOD: We assessed infant temperament at age 1, and attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and separation anxiety disorder (SAD) at ages 3 through 5 years in a sample of Hispanic twins. Genetic, shared, and non shared environmental effects were estimated for each temperamental construct and psychiatric disorder using the statistical program MX. Multivariate genetic models were fitted to determine whether the same or different sets of genes and environments account for the co-occurrence between early temperament and preschool psychiatric disorders. RESULTS: Additive genetic factors accounted for 61% of the variance in ADHD, 21% in ODD, and 28% in SAD. Shared environmental factors accounted for 34% of the variance in ODD and 15% of SAD. The genetic influence on difficult temperament was significantly associated with preschool ADHD, SAD, and ODD. The association between ODD and SAD was due to both genetic and family environmental factors. The temperamental trait of resistance to control was entirely accounted for by the shared family environment. CONCLUSIONS: There are different genetic and family environmental pathways between infant temperament and psychiatric diagnoses in this sample of Puerto Rican preschool age children. PMID- 25728590 TI - Minimally Invasive Single Implant Treatment (M.I.S.I.T.) based on ridge preservation and contour augmentation in patients with a high aesthetic risk profile: one-year results. AB - AIM: To evaluate the 1-year outcome of Minimally Invasive Single Implant Treatment (M.I.S.I.T.) based on ridge preservation and contour augmentation in patients with a high aesthetic risk profile. MATERIALS AND METHODS: Periodontally healthy non-smoking patients with a failing tooth in the anterior maxilla (15-25) were selected. All were in need of a single implant and demonstrated high risk for aesthetic complications given mid-facial recession at the failing tooth and/or a buccal bone dehiscence and/or a thin-scalloped gingival biotype. Patients without mid-facial recession (NRG) received flapless tooth extraction and ridge preservation using a collagen-enriched bovine-derived xenograft, flapless installation of a bone condensing implant with variable-thread design (4 6 months later), a provisional screw-retained crown and connective tissue graft (CTG) inserted in the buccal mucosa (3 months later) and a permanent crown (3 months later). Patients with mid-facial recession (RG) were treated similarly, yet they received a CTG at the time of ridge preservation. All patients were treated by an experienced periodontist using a microsurgical approach. Primary outcome variables included papillary and mid-facial recession. Clinical parameters, pink (PES) and white aesthetic score (WES) were considered secondary outcome variables. RESULTS: Fifty patients (25 females, 25 males; mean age 39, range 19-81; 42 in NRG and 8 in RG) met the selection criteria and consented to the treatment. Forty-seven could be examined at 12 months and all implants survived. Mean bone loss amounted to 0.48 mm (range 0.00-1.80) at 12 months. Papillary recession was minimal in both groups at 12 months (mean <= 0.3 mm), as was mid-facial recession in the NRG (mean 0.1 mm). Twelve patients in the NRG even demonstrated coronal migration of the mucosal margin following CTG and needed adaptation of the provisional crown to induce soft tissue retraction. Due to CTG at the time of ridge preservation in the RG, mid-facial soft tissue gain amounted to 0.9 mm at 12 months, hereby eliminating 2/3rd of the initial recession. PES and WES were favourable pointing to 10.9/14 and 8.2/10 respectively. CONCLUSION: This short-term prospective study offers a proof of principle of M.I.S.I.T. in patients with a high aesthetic risk profile. PMID- 25728591 TI - Other factors related to the completion of treatment after breast cancer. PMID- 25728592 TI - Application of a fluorescence resonance energy transfer (FRET)-based biosensor for detection of drug-induced apoptosis in a 3D breast tumor model. AB - Two-dimensional (2D) cultures are commonly used for testing drug effects largely because of their easy maintenance. But they do not represent the spatial interactions of the cells within a tumor. Three-dimensional (3D) cultures can overcome those limitations thus mimicking the architecture of solid tumor. However, it is not easy to evaluate drug effects in 3D culture for a long time. This necessitates the development of a real-time and longitudinal analysis of 3D platforms. In this study, we transfected the plasmid DNA encoding the fluorescence resonance energy transfer (FRET)-based biosensor into human breast cancer cells and generated two cell lines of MCF7-C3 and MDA-MB-231-C3 (231-C3) cells. We used them to determine the activation of caspase-3, whereby healthy cells appear green and apoptotic cells appear blue by FRET imaging. As the caspase sensors can be constantly produced within the cells and quickly respond to caspase activation, we hypothesized that these sensor cells will allow longitudinal detection of apoptosis. MCF7-C3 and 231-C3 spheroids were generated and subjected to histological examination, gene expression studies, drug treatment, and FRET analyses. Our results demonstrated that MCF7-C3 cells formed tight 3D spheroids, and mimicked in vivo tumor architecture. The mRNA level of tumorigenic markers such as MMP-9, SOX2, and OCT4A were much higher in cells cultured in 3D than in 2D. Finally, upon treatment with paclitaxel, the FRET effect was reduced at the rim of MCF7-C3 spheroids in a dose and time-dependent manner demonstrating these sensor cells can be used to determine drug-induced apoptosis in a 3D set up. This study supports the possibility of developing a biosensor-based in vitro 3D breast tumor model for determination of anti-cancer drug penetration over a long course of time in a non-invasive manner. PMID- 25728593 TI - Self-fertilization and inbreeding limit the scope for sexually antagonistic polymorphism. AB - Sexual antagonism occurs when there is a positive intersexual genetic correlation in trait expression but opposite fitness effects of the trait(s) in males and females. As such, it constrains the evolution of sexual dimorphism and may therefore have implications for adaptive evolution. There is currently considerable evidence for the existence of sexually antagonistic genetic variation in laboratory and natural populations, but how sexual antagonism interacts with other evolutionary phenomena is still poorly understood in many cases. Here, we explore how self-fertilization and inbreeding affect the maintenance of polymorphism for sexually antagonistic loci. We expected a priori that selfing should reduce the region of polymorphism, as inbreeding reduces the frequency of heterozygotes and speeds fixation. This expectation was supported, but although previous results suggest that the more an allele that is deleterious to one sex is dominant in that sex, the smaller the region of parameter space that will admit polymorphism, we found that this effect is weakened by self fertilization. However, the effect of inbreeding is not strong enough to completely cancel out the effect of dominance: For a given frequency of inbreeding, it will still be the case that the more dominant the alleles are in their deleterious context, the smaller the region of parameter space in which they can exist at polymorphism. PMID- 25728594 TI - Energy metabolism and the brain: a bidirectional relationship. PMID- 25728595 TI - Iterative mesh transformation for 3D segmentation of livers with cancers in CT images. AB - Segmentation of diseased liver remains a challenging task in clinical applications due to the high inter-patient variability in liver shapes, sizes and pathologies caused by cancers or other liver diseases. In this paper, we present a multi-resolution mesh segmentation algorithm for 3D segmentation of livers, called iterative mesh transformation that deforms the mesh of a region-of interest (ROI) in a progressive manner by iterations between mesh transformation and contour optimization. Mesh transformation deforms the 3D mesh based on the deformation transfer model that searches the optimal mesh based on the affine transformation subjected to a set of constraints of targeting vertices. Besides, contour optimization searches the optimal transversal contours of the ROI by applying the dynamic-programming algorithm to the intersection polylines of the 3D mesh on 2D transversal image planes. The initial constraint set for mesh transformation can be defined by a very small number of targeting vertices, namely landmarks, and progressively updated by adding the targeting vertices selected from the optimal transversal contours calculated in contour optimization. This iterative 3D mesh transformation constrained by 2D optimal transversal contours provides an efficient solution to a progressive approximation of the mesh of the targeting ROI. Based on this iterative mesh transformation algorithm, we developed a semi-automated scheme for segmentation of diseased livers with cancers using as little as five user-identified landmarks. The evaluation study demonstrates that this semi-automated liver segmentation scheme can achieve accurate and reliable segmentation results with significant reduction of interaction time and efforts when dealing with diseased liver cases. PMID- 25728596 TI - Belowground environmental effects of transgenic crops: a soil microbial perspective. AB - Experimental studies investigated the effects of transgenic crops on the structure, function and diversity of soil and rhizosphere microbial communities playing key roles in belowground environments. Here we review available data on direct, indirect and pleiotropic effects of engineered plants on soil microbiota, considering both the technology and the genetic construct utilized. Plants modified to express phytopathogen/phytoparasite resistance, or traits beneficial to food industries and consumers, differentially affected soil microorganisms depending on transformation events, experimental conditions and taxa analyzed. Future studies should address the development of harmonized methodologies by taking into account the complex interactions governing soil life. PMID- 25728597 TI - Synthesis of nano-TaO(x) oxygen reduction reaction catalysts on multi-walled carbon nanotubes connected via a decomposition of oxy-tantalum phthalocyanine. AB - Nano-TaOx particles were supported on multi-walled carbon nanotubes via the thermal decomposition of oxy-tantalum phthalocyanine. The phthalocyanine-derived carbon connected TaOx particles with the nanotube-support to provide a conductive path. The oxygen reduction reaction activity, which solely originated from TaOx, was above 0.9 V with larger currents than conventional TaOx particles in acidic media. PMID- 25728599 TI - Androgens and innate immunity in rehabilitated semi-captive orangutans (Pongo pygmaeus morio) from Malaysian Borneo. AB - Despite the implications for the development of life-history traits, endocrine immune trade-offs in apes are not well studied. This is due, in part, to difficulty in sampling wild primates, and lack of methods available for immune measures using samples collected noninvasively. Evidence for androgen-mediated immune trade-offs in orangutans is virtually absent, and very little is known regarding their pattern of adrenal development and production of adrenal androgens. To remedy both of these deficiencies, sera were collected from orangutans (Pongo pygmaeus morio) (N = 38) at the Sepilok Orangutan Rehabilitation Centre, Sabah, Malaysia, during routine health screenings. Testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-sulfate (DHEA-S) were assayed, along with two measures of functional innate immunity. DHEA-S concentrations, but not DHEA, increased with age in this sample of 1-18 year old animals. DHEA concentrations were higher in animals with higher levels of serum bacteria killing ability, while DHEA-S and testosterone concentrations were higher in animals with reduced complement protein activity. Patterns of DHEA S concentration in this sample are consistent with patterns of adrenarche observed in other apes. Results from this study suggest that in addition to testosterone, DHEA and DHEA-S may have potent effects on immunological activity in this species. PMID- 25728598 TI - Towards a universal barcode of oomycetes--a comparison of the cox1 and cox2 loci. AB - Oomycetes are a diverse group of eukaryotes in terrestrial, limnic and marine habitats worldwide and include several devastating plant pathogens, for example Phytophthora infestans (potato late blight). The cytochrome c oxidase subunit 2 gene (cox2) has been widely used for identification, taxonomy and phylogeny of various oomycete groups. However, recently the cox1 gene was proposed as a DNA barcode marker instead, together with ITS rDNA. The cox1 locus has been used in some studies of Pythium and Phytophthora, but has rarely been used for other oomycetes, as amplification success of cox1 varies with different lineages and sample ages. To determine which out of cox1 or cox2 is best suited as a universal oomycete barcode, we compared these two genes in terms of (i) PCR efficiency for 31 representative genera, as well as for historic herbarium specimens, and (ii) sequence polymorphism, intra- and interspecific divergence. The primer sets for cox2 successfully amplified all oomycete genera tested, while cox1 failed to amplify three genera. In addition, cox2 exhibited higher PCR efficiency for historic herbarium specimens, providing easier access to barcoding-type material. Sequence data for several historic type specimens exist for cox2, but there are none for cox1. In addition, cox2 yielded higher species identification success, with higher interspecific and lower intraspecific divergences than cox1. Therefore, cox2 is suggested as a partner DNA barcode along with ITS rDNA instead of cox1. The cox2-1 spacer could be a useful marker below species level. Improved protocols and universal primers are presented for all genes to facilitate future barcoding efforts. PMID- 25728600 TI - Pituitary size and response of growth hormone deficient children to growth hormone therapy. PMID- 25728601 TI - Tunable quantum confinement in ultrathin, optically active semiconductor nanowires via reverse-reaction growth. AB - A unique growth scheme is demonstrated to realize ultrathin GaAs nanowires on Si with sizes down to the sub-10 nm regime. While this scheme preserves the bulk like crystal properties, correlated optical experiments reveal huge blueshifted photo-luminescence (up to ~100 meV) with decreasing nanowire cross-section, demonstrating very strong quantum confinement effects. PMID- 25728603 TI - Comparing the genotoxicity of a potentially carcinogenic and a noncarcinogenic PAH, singly, and in binary combination, on peripheral blood cells of the European sea bass. AB - Research on the toxicological mechanisms of polycyclic aromatic hydrocarbons (PAHs) deemed carcinogenic and noncarcinogenic has mostly been developed for individual compounds even though, in the environment, PAHs invariably occur in mixtures. The present work aimed at understanding the interaction effects of two model PAHs, the potentially carcinogenic benzo[b]fluoranthene (B[b]F) and the noncarcinogenic phenanthrene (Phe) to a marine fish (the sea bass Dicentrarchus labrax). The study endeavoured an ecologically-relevant scenario with respect to concentrations and contaminant matrix, sediments, which are the main reservoirs of these substances in the environment, due to their hydrophobic nature. For the purpose, 28-day laboratorial bioassays with spiked sediments (with individual and combined PAHs at equitoxic concentrations) were conducted. Genotoxicity was determined in peripheral blood through the "Comet" assay and by scoring erythrocytic nuclear abnormalities (ENA). The results showed that exposure to either PAHs induced similar levels of DNA strand breaks, although without a clear dose- or time-response, likely due to the low concentrations of exposure and potential shits in PAH bioavailability during the assays. However, clastogenic/aneugenic lesions were only observed in fish exposed to B[b]F-spiked sediments. Conversely, the combination assays revealed a supra-additive effect especially at chromosome level, linked to concentrations of PAHs in water. A decrease in DNA-strand breakage was observed over time during all assays, revealing some ability of fish to cope with this DNA lesion. Overall, the findings show that low-moderate concentrations of sediment-bound mixed PAHs may significantly increase the hazard of mutagenesis even when the individual concentrations indicate low risk, especially considering that chromosome-level damage is unlikely to be repaired, leading to the fixation of DNA lesions upon prolonged exposures. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1307 1318, 2016. PMID- 25728604 TI - Integrating oral health into pediatric nursing practice: Caring for kids where they live. AB - PURPOSE: The purpose was to identify the factors influencing pediatric oral health and describe the Caring for Kids Where They Live program. CONCLUSIONS: In North America, the burden of pediatric oral disease is significant. Despite evidence to this effect, oral health is an often-neglected aspect of pediatric nursing care. The Caring for Kids Where They Live program has successfully integrated oral health into pediatric nursing care as evidenced by increased accessibility of health care, pathways for care, and disease prevention. PRACTICE IMPLICATIONS: Pediatric nurses can address oral health disparities by integrating an oral health assessment tool as well as interprofessional follow-up and referral processes in practice. PMID- 25728605 TI - Repeat blood cultures in children with persistent fever and neutropenia: Diagnostic and clinical implications. AB - BACKGROUND: Repeat blood cultures are frequently obtained in children with persistent fever and neutropenia (FN), but their clinical impact is uncertain. METHODS: We identified children with persistent FN in the context of hematologic malignancy or hematopoietic stem cell transplantation from July 2006 to June 2012. For each episode, we reviewed blood cultures to determine the yield of true positive and false positive results. We then examined episode-level and culture level predictors to determine factors associated with new bloodstream infections (BSI). RESULTS: Among 135 children who met inclusion criteria, there were 184 persistent FN episodes, during which 17 new BSI were diagnosed after the first 24 hr of fever (9.2%; 95% CI 5.4-15.3%). After the first 24 hr, the incidence of new BSI was 1.5% (95% CI 1.0-2.4%) per day and the incidence of blood culture contamination was 1.1% (95% CI 0.6-2.1%) per day. Of 17 new BSI identified, 14 (82%) required changes in therapy, while all 12 contaminant blood cultures were followed by additional antibiotic therapy. Increased odds of new BSI were associated with a history of BSI within 30 days of the episode (OR 5.18; 95% CI 1.29-20.8) and increasing time between recurrent fevers (OR 1.29; 95% CI 1.06 1.57). CONCLUSIONS: Repeat blood cultures have an important role in diagnosing new BSI and directing therapy in children with persistent FN. The current strategy could be improved by reducing the frequency of blood cultures after the first 24 hr, and targeting repeat cultures by risk. PMID- 25728606 TI - Sectional anatomy of the abducens nerve: according to 3D-SPACE magnetic resonance sequences correlated with cryosectional specimens. AB - PURPOSE: To identify and justify the best section to reveal each segment of the abducens nerve according to 3D-SPACE magnetic resonance sequences and correlate with cryosectional specimens. METHODS: Thirty-four healthy adults were recruited for MRI using a 3D-SPACE sequence. Eighteen adult head specimens were cut into serial transverse, sagittal and coronal section using an electric band saw after the specimens were frozen. The MRI characteristics and the anatomical features of the abducens nerve were analyzed by correlation with the cryosection. RESULTS: We divided the abducens nerve into five segments, the cisternal segment, Dorello canal (DC) segment, cavernous sinus (CS) segment, superior orbital fissure (SOF) segment and intraorbital segment. In the transverse sections, the detection rates for the cisternal and Dorello canal segments of the abducens nerve were 97.06 and 94.12 %, respectively, on 3D-SPACE MR images. In the sagittal section of the frozen specimens, only the cisternal segment of the abducens nerve could be observed, and its detection rate was 51.50 %. In the coronal section, the CS segment of the abducens nerve was located inferior lateral to the ICA as well as, inferior to the oculomotor and trochlear nerves, and the detection rate of the CS segment was 42.60 % on 3D-SPACE MR images. CONCLUSION: 3D-SPACE sequence MR scanning was a useful method for observing the cisternal and DC segment of the abducens nerve in a transverse section, observing the cisternal segment in a sagittal section and observing the CS segment in a coronal section. PMID- 25728607 TI - When circles become triangular: how transsaccadic predictions shape the perception of shape. AB - Human vision is characterized by a consistent pattern of saccadic eye movements. With each saccade, internal object representations change their retinal position and spatial resolution. This raises the question as to how peripheral perception is affected by imminent saccadic eye movements. Here, we suggest that saccades are accompanied by a prediction of their perceptual consequences (i.e., the foveation of the target object). Accordingly, peripheral perception should be biased toward previously associated foveal input. In this study, we first exposed participants to an altered visual stimulation where one object systematically changed its shape during saccades. Subsequently, participants had to judge the shape of briefly presented peripheral saccade targets. The results showed that targets were perceived as less curved for objects that previously changed from more circular in the periphery to more triangular in the fovea. Similarly, shapes were perceived as more curved for objects that previously changed from triangular to circular. Thus, peripheral perception seems to depend not solely on the current input but also on memorized experiences, enabling predictions about the perceptual consequences of saccadic eye movements. PMID- 25728609 TI - What are the Consequences of Volume Expansion in Chronic Dialysis Patients?: Intra-dialytic Hypotension in Conventional Hemodialysis: Unavoidable in Some, but Preventable in Most. PMID- 25728608 TI - SLUG is a direct transcriptional repressor of PTEN tumor suppressor. AB - BACKGROUND: PTEN/AKT signaling plays a key role in prostate cancer development and maintenance of prostate cancer stem cells. How other oncogenes or tumor suppressors interact with this pathway remain to be elucidated. SLUG is an zinc finger transcription factor of the Snail superfamily, and it promotes cancer metastasis and determines the mammary stem cell state. METHODS: SLUG was overexpressed in cells by retroviral vector and knockdown of SLUG and PTEN was mediated by shRNAs-expressing lentiviruses. Expression level of SLUG and PTEN was examined by Western blot, RT-PCR, and qPCR analyses. PTEN promoter activity was measured by luciferase reporter assay. ChIP assay was used to measure the binding between SLUG and the PTEN promoter in vivo. RESULT: We showed that overexpression of SLUG decreased expression of PTEN tumor repressor in prostate cancer cell lines 22RV1 and DU145; conversely, knockdown of SLUG expression elevated PTEN expresson at both protein and RNA level in these cells. We demonstrated that SLUG overexpression inhibits PTEN promoter activity through the proximal promoter region in prostate cancer cells. By ChIP assay, we confirmed that SLUG directly binds to the PTEN promoter region covering the E-box sites. We also showed that Slug deficiency leads to an increased expression of PTEN in mouse embryo fibroblasts and prostate tissues. Importantly, we found that overexpression of SLUG increases drug resistance of DU145 prostate cancer cell line and knockdown of SLUG by shRNA sensitizes DU145 cell line to chemotherapeutic drugs. We further demonstrated that PTEN knockdown converts drug sensitivity of DU145 cells expressing SLUG shRNA to anticancer drugs. CONCLUSION: We provide compelling evidence showing that PTEN is a direct functional target of SLUG. Our findings offer new insight in the regulation of the PTEN/AKT pathway and provide a molecular basis for potential targeted therapies of prostate cancer Prostate 75:907-916, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25728610 TI - Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models. AB - New pyridopyrimidine derivatives were defined using a novel HTS in silico docking method (FRIGATE). The target protein was a dUTPase enzyme (EC 3.6.1.23; Rv2697) which plays a key role in nucleotide biosynthesis of Mycobacterium tuberculosis (Mtb). Top hit molecules were assayed in vitro for their antimycobacterial effect on Mtb H37Rv culture. In order to enhance the cellular uptake rate, the TB820 compound was conjugated to a peptid-based carrier and a nanoparticle type delivery system (polylactide-co-glycolide, PLGA) was applied. The conjugate had relevance to in vitro antitubercular activity with low in vitro and in vivo toxicity. In a Mtb H37Rv infected guinea pig model the in vivo efficacy of orally administrated PLGA encapsulated compound was proven: animals maintained a constant weight gain and no external clinical signs of tuberculosis were observed. All tissue homogenates from lung, liver and kidney were found negative for Mtb, and diagnostic autopsy showed that no significant malformations on the tissues occurred. PMID- 25728611 TI - Review: The role of antibodies, autoantigens and food allergens in canine atopic dermatitis. AB - BACKGROUND: Canine atopic dermatitis (AD) is considered to be an immunoglobulin E (IgE)-mediated hypersensitivity response to environmental allergens. The role of other antibody isotypes and nonenvironmental allergens in disease pathogenesis remains unclear. OBJECTIVES: The objective of this review is to provide an update on advances in the understanding of the relevance of specific antibody isotypes, autoallergens and nonenvironmental allergens in the pathogenesis of canine AD. METHODS: Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed. Where necessary, older articles were included for background information. RESULTS: Neither total nor allergen-specific IgE necessarily correlates with clinical disease in canine AD. Some dogs exhibit clinical signs that are indistinguishable from AD but have no demonstrable allergen-specific IgE (atopic-like dermatitis). Allergen-specific immunoglobulin G may be demonstrated in canine AD, but there is no evidence that this isotype plays a role in disease development. Although humans with AD may develop serum IgE against autoallergens, this finding has not been substantiated in the dog. In contrast, adverse food reactions are frequently co-associated with AD in the dog. Ingestion of food and environmental allergens may trigger exacerbations of AD. CONCLUSIONS AND CLINICAL IMPORTANCE: Determination of the role of IgE in the pathogenesis of canine AD still requires clarification. Clinical trials and research studies must distinguish atopic dogs with allergen specific IgE or skin test reactivity from those without. There is no convincing evidence demonstrating a pathogenic role for either allergen-specific immunoglobulin G or autoallergens in canine AD, but food items may be triggers for disease flares in certain individuals. PMID- 25728612 TI - Efficacy, safety and tolerability of aleglitazar in patients with type 2 diabetes: pooled findings from three randomized phase III trials. AB - AIMS: To evaluate the potential efficacy, safety and tolerability of aleglitazar as monotherapy or add-on therapy to metformin or to a sulphonylurea (either alone or in combination with metformin). METHODS: We conducted a pooled analysis of data from three randomized phase III clinical trials of aleglitazar in patients with type 2 diabetes (n = 591). The three studies focused on: (i) aleglitazar alone; (ii) aleglitazar and metformin; and (iii) aleglitazar and sulphonylurea with or without metformin. Patients were randomized to 26 weeks' treatment with aleglitazar 150 ug/day or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) concentration from baseline to week 26. Secondary endpoints included changes in lipids, fasting plasma glucose and homeostatic model assessment of insulin resistance (HOMA-IR) at week 26. RESULTS: Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. Aleglitazar treatment was associated with more beneficial changes in lipid profiles and HOMA-IR values than was placebo. Aleglitazar was generally well tolerated, with no reports of congestive heart failure. The incidence of peripheral oedema was similar in both groups. Change in body weight was +1.37 kg with aleglitazar and -0.53 kg with placebo. Hypoglycaemia was more frequently reported with aleglitazar (7.8%) than with placebo (1.7%), a result probably driven by the type of background medication. CONCLUSIONS: Development of aleglitazar was halted because of a lack of cardiovascular efficacy and peroxisome proliferator-activated receptor-related side effects in patients with type 2 diabetes post-acute coronary syndrome; however, in the present studies, aleglitazar was well tolerated and effective in improving HbA1c, insulin resistance and lipid variables. PMID- 25728613 TI - Massive intra-alveolar hemorrhage caused by Leptospira serovar Djasiman in a traveler returning from Laos. AB - Leptospirosis is one of the most common pathogens responsible for life threatening tropical disease in travelers. We report a case of massive intra alveolar hemorrhage caused by Leptospira serovar Djasiman in a 38-year-old man returning from Laos, who was cured with antibiotics and salvage treatment with extra-corporeal membrane oxygenation. PMID- 25728614 TI - Mild deoxygenation of aromatic ketones and aldehydes over Pd/C using polymethylhydrosiloxane as the reducing agent. AB - Herein, a practical and mild method for the deoxygenation of a wide range of benzylic aldehydes and ketones is described, which utilizes heterogeneous Pd/C as the catalyst together with the green hydride source, polymethylhydrosiloxane. The developed catalytic protocol is scalable and robust, as exemplified by the deoxygenation of ethyl vanillin, which was performed on a 30 mmol scale in an open-to-air setup using only 0.085 mol % Pd/C catalyst to furnish the corresponding deoxygenated product in 93 % yield within 3 hours at room temperature. Furthermore, the Pd/C catalyst was shown to be recyclable up to 6 times without any observable decrease in efficiency and it exhibited low metal leaching under the reaction conditions. PMID- 25728616 TI - [Nasogastric feeding tube with distal tip in right pleural cavity]. PMID- 25728615 TI - Parenteral nutrition-associated liver disease in extremely low-birthweight infants with intestinal disease. AB - BACKGROUND: The aim of this study was to investigate factors associated with the development of parenteral nutrition-associated liver disease (PNALD) and to examine the clinicopathological relationship of PNALD in extremely low birthweight infants (ELBWI). METHODS: The subjects were 13 ELBWI who had received PN because of intestinal perforation or functional ileus between 2000 and 2013. We measured the serum levels of biochemical parameters, including aspartate aminotransferase, alanine aminotransferase, and direct bilirubin. Liver histopathology was examined in relation to outcome. The subjects were categorized into two groups on liver histopathology: F(+), development of hepatic fibrosis and necrosis with/without cholestasis; and F(-), no hepatic fibrosis. RESULTS: Of 13 ELBWI, five died of hepatic failure, five died of sepsis, and the other three were alive at the time of the study. Of the five infants who died of hepatic failure, two developed fulminant hepatitis without cholestasis, and the other three developed chronic cholestasis and finally hepatic failure. Postmortem histopathology in F(+) indicated not only massive hepatic necrosis, but also massive hepatic fibrosis. These histopathological findings explained the clinical presentation of portal hypertension. There were significant differences in the fasting period after intestinal disease onset between the two groups. CONCLUSION: The prolonged fasting with PN is responsible for severe hepatocellular necrosis with fibrosis and consequent lethal portal hypertension. PMID- 25728617 TI - Reduced human platelet uptake by pig livers deficient in the asialoglycoprotein receptor 1 protein. AB - BACKGROUND: The lethal thrombocytopenia that accompanies liver xenotransplantation is a barrier to clinical application. Human platelets are bound by the asialoglycoprotein receptor (ASGR) on pig sinusoidal endothelial cells and phagocytosed. Inactivation of the ASGR1 gene in donor pigs may prevent xenotransplantation-induced thrombocytopenia. METHODS: Transcription activator like effector nucleases (TALENs) were targeted to the ASGR1 gene in pig liver derived cells. ASGR1 deficient pig cells were used for somatic cell nuclear transfer (SCNT). ASGR1 knock out (ASGR1-/-) fetal fibroblasts were used to produce healthy ASGR1 knock out piglets. Human platelet uptake was measured in ASGR1+/+ and ASGR1-/- livers. RESULTS: Targeted disruption of the ASGR1 gene with TALENs eliminated expression of the receptor. ASGR1-/- livers phagocytosed fewer human platelets than domestic porcine livers during perfusion. CONCLUSIONS: The use of TALENs in liver-derived cells followed by SCNT enabled the production of healthy homozygous ASGR1 knock out pigs. Livers from ASGR1-/- pigs exhibit decreased human platelet uptake. Deletion of the ASGR1 gene is a viable strategy to diminish platelet destruction in pig-to-human xenotransplantation. PMID- 25728618 TI - Oestrogen hormone receptors in focal nodular hyperplasia. AB - BACKGROUND: The role of hormones in focal nodular hyperplasia (FNH) has been investigated with conflicting results. OBJECTIVE: The aim of this study was to evaluate oestrogen and progesterone receptor immunohistochemical expression in FNH and surrounding normal liver (control material). METHODS: Biopsy materials from FNH and control tissue were investigated using an immunostainer. Receptor expression was graded as the proportion score (percentage of nuclear staining) and oestrogen receptor intensity score. RESULTS: Study material included tissue from 11 resected FNH lesions and two core biopsies in 13 patients (two male). Twelve samples showed oestrogen receptor expression. The percentage of nuclear oestrogen receptor staining was <33% in eight FNH biopsies, 34-66% in two FNH biopsies, and >67% in both core biopsies. The better staining in core biopsies relates to limitations of the staining technique imposed by the fibrous nature of larger resected FNH. Control samples from surrounding tissue were available for nine of the resected specimens and all showed oestrogen receptor expression. Progesterone receptor expression was negligible in FNH and control samples. CONCLUSIONS: By contrast with previous studies, the majority of FNH and surrounding liver in this cohort demonstrated oestrogen receptor nuclear staining. The implications of this for continued oral contraceptive use in women of reproductive age with FNH remain uncertain given the lack of consistent reported growth response to oestrogen stimulation or withdrawal. PMID- 25728620 TI - Association between diabetes and increased prevalence of paranasal sinus disease: a cross-sectional study in Japanese adults. AB - BACKGROUND: The association between diabetes and paranasal sinus disease has not been thoroughly investigated. METHODS: We cross-sectionally investigated the association between diabetes and the presence of paranasal sinus disease, which was confirmed by a head MRI scan in 1350 adults who underwent a health screening program focusing on brain diseases and metabolic syndrome. Logistic regression, which was adjusted for age, sex, body mass index, waist-to-hip ratio, hypertension, smoking status, alcohol intake, and white blood cell count, was performed to calculate the odds ratio (OR) of having paranasal sinus disease among adults with diabetes in relation to those without. The dose-response relationship between hemoglobin A1c (HbA1c) levels and the presence of paranasal sinus disease was also investigated. RESULTS: Of the 1350 participants (mean age, 61.6 +/- 10.0 years; 71.6% men), 220 diabetes cases were identified. Paranasal sinus disease was diagnosed in 151 adults. The adjusted OR of having paranasal sinus disease was 1.74 (95% confidence interval [CI], 1.12-2.71) in those with diabetes. The odds of having paranasal sinus disease increased with HbA1c levels. Compared to those with HbA1c of <=5.4%, those with HbA1c of 5.5%-6.4%, 6.5%-7.9%, and >=8.0% were more likely to have paranasal sinus disease, with adjusted ORs of 1.32 (95% CI, 0.88-1.98), 1.63 (95% CI, 0.86-3.09) and 2.71 (95% CI, 1.12-6.61), respectively (P for trend = 0.019). CONCLUSIONS: Diabetes may be significantly associated with higher prevalence of paranasal sinus disease in Japanese adults. We should keep this increased risk in mind when a diabetic patient is suspected of having paranasal sinus disease. PMID- 25728619 TI - Association between serum long-chain n-3 and n-6 polyunsaturated fatty acid profiles and glomerular filtration rate assessed by serum creatinine and cystatin C levels in Japanese community-dwellers. AB - BACKGROUND: Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n 3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived long-chain n-3 PUFA intake. METHODS: A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFRcre and eGFRcys). Using multivariate adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. RESULTS: In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had non significantly higher eGFRcre and significantly higher eGFRcys (P = 0.016). In addition, eGFRcys in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFRcys, T1: 87 ml/min/1.73 m(2), T2+T3: 91 ml/min/1.73 m(2); P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFRcys. CONCLUSIONS: Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFRcys in Japanese community-dwellers. PMID- 25728621 TI - Perspectives of fixed daily dose of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C. AB - The fixed dose combination of sofosbuvir and ledipasvir (SOF/LDV) has marked a new era for patients with chronic HCV because it is the first drug to be approved by the FDA that does not include peginterferon or ribavirin. The results of three clinical studies show that SOF/LDV has sustained virologic response of approximately 96% when given as once a day pill for 3 months to both treatment naive and treatment-experienced HCV-1 patients with the exception of prior null responder patients with cirrhosis. Moreover, emerging data in special populations (patients with decompensated cirrhosis, with post-transplant recurrence, with prior SOF-based therapy failure, and with HIV co-infection) show a good tolerance and high sustained virological profile. Many other emerging therapies are now available. Actually, the recommendations of the international guidelines are applicable only for selected patients followed-up by dedicated specialists, including hepatologists and infectologists, and are specifically individualized for patients with advanced fibrosis. We will expect that the landscape for management of HCV will include direct-acting antivirals for treatment of patients with different genotypes and low-grade fibrosis in order to interrupt the progression to late stage of disease and the complications of the infection, including renal disease, thyroid dysfunction, and some cancers. PMID- 25728622 TI - Sex hormones in male psoriasis patients and their correlation with the Psoriasis Area and Severity Index. AB - Modulation of psoriasis severity by estradiol during pregnancy, menstruation and menopause has been investigated previously. The correlation between sex hormones and Psoriasis Area Severity Index (PASI) has not been studied in male psoriasis patients. We investigated serum sex hormones in male psoriasis patients compared with healthy controls and correlated these findings with PASI. Estradiol, testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured in 47 male patients with psoriasis and 20 healthy controls. Patients with psoriasis showed higher body mass index and higher serum levels of FSH and LH relative to healthy controls, although this difference was not statistically significant. However, serum levels of testosterone and estradiol were significantly different between patients with psoriasis and healthy controls. Testosterone was significantly increased in control patients and estradiol was significantly increased among psoriatic patients. A significant inverse correlation was found between estradiol and PASI. Although the role of sex hormones in the pathogenesis of psoriasis has not been demonstrated, this is the first report of an inverse correlation between estradiol and PASI in male patients. PMID- 25728623 TI - Effect of toothbrushing on color changes of esthetic restorative materials. AB - PURPOSE: The aim of this study was to evaluate the effects of various drinks and toothbrushing on the color changes of esthetic restorative materials used in pediatric dentistry. MATERIALS AND METHODS: Forty specimens were prepared from each of three restorative materials (compomer [Dyract AP], glass ionomer cement [Ionofil Molar AC, Voco], composite resin [Filtek Z 250]). Specimens were divided into four groups for immersion in three different staining solutions (cherry juice, cola, chocolate milk) and distilled water. Each group was subdivided into brushing and non-brushing groups. The specimens in the brushing subgroups were brushed with toothpaste once a day using an electric toothbrush. Color was measured using a colorimeter, and color changes were calculated between baseline and 1, 7, 30, 60 days. Data was analyzed using Kruskal-Wallis, Mann-Whitney U, Wilcoxon, and Wilcoxon Signed Rank tests. RESULTS: All the solutions evaluated yielded color changes, and these changes were significantly greater for composite resin than for glass ionomer cement or compomer (p < 0.006). Brushing significantly decreased the color changes of restorative materials (p < 0.004). CONCLUSION: Brushing significantly influenced the color stability of esthetic restorative materials. The results of this study also showed that glass ionomer cements and compomers had higher color stability than composite resins. CLINICAL SIGNIFICANCE: The color stability values after brushing may better reflect the discoloration of the esthetic restorative materials. Any color stability study model should consider the effects of toothbrushing that can remove the adsorbed colorants. The results of this study also showed that glass ionomer cements and compomers can be used in anterior restorations of children with their higher color stability than composite resins. PMID- 25728624 TI - The role of seedling recruitment from juvenile populations of Carex brevicuspis (Cyperaceae) at the Dongting Lake wetlands, China. AB - Seedlings and vegetative ramets may contribute differentially to the recruitment of clonal populations in different growth phases, but this has rarely been investigated. In this study, we quantified the number and survivorship of seedlings and vegetative ramets monthly in juvenile and mature populations of Carex brevicuspis. During the first growing season after flooding (from October to January), 9 seedlings m(-2) (13% of all established shoots) were found in juvenile populations, while no seedlings were found in mature populations. During the second growing season before flooding (from February to May), no new seedling recruits were found either in juvenile or in mature populations. All shoots of seedlings were withered during the dormant season (January and February), but 62.5% seedlings could produce vegetative ramets in the following growing season. During the dormant season, all the early emerging ramets (sprouted in October) withered, but the later emerging ones (sprouted in November and December) survived in both mature and juvenile populations. These results indicated that seedling recruitment was only apparent in juvenile populations of C. brevicuspis. The genetic diversity in mature C. brevicuspis populations may be established in juvenile populations by seedling recruitment, and sustained in mature populations by vegetative reproduction. PMID- 25728626 TI - Gender differences in detoxification metabolism of polycyclic aromatic hydrocarbon (chrysene) in scallop Chlamys farreri during the reproduction period. AB - This study aims to investigate the effects of chrysene (CHR) on biotransformation and detoxification responses of mature scallop Chlamys farreri during the reproduction period. Scallops were exposed to 0.2, 0.8 and 3.2 MUg/L CHR for 21 days; at day 10 scallops were induced to spawn. At days 1, 3, 6, 10, 11, 15 and 21, enzymatic activities of 7-ethoxyresorufin O-deethylase (EROD) and glutathione s-transferase (GST), related mRNA expression levels of CYP1A1, GST-pi and P glycoprotein (P-gp) in digestive glands and CHR bioaccumulation in tissues were examined by separately analyzing male and female scallops. During the pre-spawn period, CHR concentrations of the treated groups in tissues except the hemolymph increased rapidly. Levels of enzymatic activities and related gene expressions were all induced by the exposure to CHR for females and males. GST activity and GST-pi mRNA expression showed a good time- and dose-dependent relationship only in males, and P-gp mRNA expression exhibited a dose-dependent manner in both sexes. During the post-spawn period, spawning caused significant reductions of bioaccumulation in tissues but the gill and hemolymph. Enzymatic activities and related gene expressions were for females significantly depressed at day 21 at 0.8 or 3.2 MUg/L CHR. Overall, females accumulated more CHR than males, while males were more sensitive than females to CHR exposure in gene expressions and enzyme activities. P-gp mRNA expression seemed to be a potential biomarker for PAH exposure. These results will offer the information on CHR biotransformation in this species, and ensure the influence of gender and reproductive status on PAH detoxification metabolism. PMID- 25728628 TI - Expanding the conceptual toolkit of organ gifting. AB - In jurisdictions where the sale of body tissue and organs is illegal, organ transplantation is often spoken of as a gift of life. In the social sciences and bioethics this concept has been subject to critique over the course of the last two decades for failing to reflect the complexities of organ and tissue exchange. I suggest that a new ethical model of organ donation and transplantation is needed to capture the range of experiences in this domain. The proposed model is both analytical and empirically oriented, and draws on research findings linking a series of qualitative sociological studies undertaken in New Zealand between 2007 and 2013. The studies were based on document analysis, field notes and 127 semi-structured in-depth interviews with people from different cultural and constituent groups directly involved in organ transfer processes. The aim of the article is to contribute to sociological knowledge about organ exchange and to expand the conceptual toolkit of organ donation to include the unconditional gift, the gift relation, gift exchange, body project, and body work. The rationale for the proposed model is to provide an explanatory framework for organ donors and transplant recipients and to assist the development of ethical guidelines and health policy discourse. PMID- 25728627 TI - Effect of the pi Bridge and Acceptor on Intramolecular Charge Transfer in Push Pull Cationic Chromophores: An Ultrafast Spectroscopic and TD-DFT Computational Study. AB - Three (donor-pi-acceptor)(+) systems with a methyl pyridinium or quinolinium as the electron-deficient group, a dimethyl amino as the electron-donor group, and an ethylene or butadiene group as the spacer have been investigated in a joint spectroscopic and TD-DFT computational study. A negative solvatochromism has been revealed in the absorption spectra, which implies a solution color change, and interpreted by considering the variation in the permanent dipole moment modulus and orientation upon photoexcitation. The fluorescence efficiency decreases upon increasing solvent polarity, in agreement with the excited-state optimized geometries (planar in low-polarity media and twisted in high-polarity media). Femtosecond transient absorption has revealed the occurrence of a fast photoinduced intramolecular charge transfer (ICT) and the molecular factors that determine an efficient ICT. Considering the crucial role of the ICT in tuning the nonlinear optical (NLO) properties, these compounds can be considered promising NLO materials. PMID- 25728629 TI - A comparison of systemic inflammatory responses between immunocompetent and immunocompromised patients presenting with otorrhea due to chronic suppurative middle ear disease. AB - OBJECTIVES: To study the occurrence of fever and the behaviours of inflammatory blood markers (C-reactive protein - CRP and procalcitonin - PCT) during episodes of otorrhea due to uncomplicated chronic otitis media in immunocompetent and immunocompromised patients. DESIGN: Prospective study of patients presenting with otorrhea over a 36-month period. SETTING: All patients were treated at Bonsucesso General Hospital, a tertiary referral hospital in Rio de Janeiro, Brazil. PARTICIPANTS: A total of 84 participants, of which 50 were immunocompetent and 34 were immunocompromised. Immunocompetent patients had a total of 106 episodes of otorrhea, and immunocompromised patients had 117 episodes of otorrhea. MAIN OUTCOME MEASURES: Occurrence of fever (axillary temperature over 38( degrees ) C) and elevation of C-reactive protein and procalcitonin levels above the normal ranges. RESULTS: In the immunocompetent group, the levels of procalcitonin were elevated in five of 106 episodes of otorrhea. The C-reactive protein levels were above the normal range in nine of 106 episodes, the same number of episodes in which fever was observed. In the immunocompromised group, procalcitonin was elevated in 38 of 117 episodes of otorrhea, C-reactive protein levels were abnormal in 40 episodes, and fever was detected in 37 episodes. Cases of otorrhea with systemic inflammatory response were significantly more common in immunocompromised patients with associated rhinosinusitis. CONCLUSIONS: Otorrhea due to uncomplicated chronic otitis media rarely causes a systemic inflammatory response in immunocompetent patients. Its occurrence in immunocompromised patients seems to be more related to concurrent rhinosinusitis than to the chronic middle ear inflammation itself. PMID- 25728630 TI - Pitt-Hopkins Mouse Model has Altered Particular Gastrointestinal Transits In Vivo. AB - Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder, classified as an autism spectrum disorder that is caused by the haploinsufficiency of Transcription Factor 4 (TCF4). The most common non-neurological symptoms in PTHS patients are gastrointestinal (GI) disturbances, mainly gastroesophageal reflux and severe constipation (in about 30 and 75% of PTHS patients, respectively). We hypothesized that the recently recognized mouse model of PTHS will exhibit problems with their gut function. We conducted series of in vivo tests on 15- to 19- week old male mice, heterozygous for the TCF4 functional deletion, mimicking the TCF4 haploinsufficiency in PTHS patients, and their wild type littermates. Data collection and initial analysis were performed blindly, that is, the genotyping key was received after the mean values were calculated for each individual animal, and then mean/median of each group was subsequently calculated. Body weight, fecal pellet output, and fluid content were similar between the groups, indicating normal gross growth of PTHS mice and their overall physiological GI motility and intestinal secretion/absorption. There were no significant differences in gut length and gross appearance pointing out that PTHS mice have normal gut in gross anatomical terms. However, the assessment of gut transit indicates that, while whole-gut transit velocity was similar between the groups, the upper GI and distal colon transit velocities were significantly reduced in the PTHS mice. This is the first evidence of specific gut related problems in the PTHS mice. Our study also validates the TCF4 functional knockout mice as an animal model to study PTHS-associated GI disturbances. PMID- 25728631 TI - Spatial analysis of under-5 mortality and potential risk factors in the Basse Health and Demographic Surveillance System, the Gambia. AB - OBJECTIVES: To describe the spatial pattern in under-5 mortality rates in the Basse Health and Demographic Surveillance System (BHDSS) and to test for associations between under-5 deaths and biodemographic and socio-economic risk factors. METHODS: Using data on child survival from 2007 to 2011 in the BHDSS, we mapped under-5 mortality by km(2) . We tested for spatial clustering of high or low death rates using Kulldorff's spatial scan statistic. Associations between child death and a variety of biodemographic and socio-economic factors were assessed with Cox proportional hazards models, and deviance residuals from the best-fitting model were tested for spatial clustering. RESULTS: The overall death rate among children under 5 was 0.0195 deaths per child-year. We found two spatial clusters of high death rates and one spatial cluster of low death rates; children in the two high clusters died at a rate of 0.0264 and 0.0292 deaths per child-year, while in the low cluster, the rate was 0.0144 deaths per child-year. We also found that children born to Fula mothers experienced, on average, a higher hazard of death, whereas children born in the households in the upper two quintiles of asset ownership experienced, on average, a lower hazard of death. After accounting for the spatial distribution of biodemographic and socio economic characteristics, we found no residual spatial pattern in child mortality risk. CONCLUSION: This study demonstrates that significant inequality in under-5 death rates can occur within a relatively small area (1100 km(2) ). Risks of under-5 mortality were associated with mother's ethnicity and household wealth. If high mortality clusters persist, then equity concerns may require additional public health efforts in those areas. PMID- 25728632 TI - Drop-by-drop chemical reaction and sample introduction for capillary electrophoresis. AB - In this paper, we report a novel sample introduction and chemical reaction strategy by drop-by-drop inkjet injection for an electrophoretically mediated microanalysis (EMMA). This method makes it possible to achieve an on-line introduction of reactant solutions by alternately ejecting small plugs, with an overlapping region of the plugs for mixing the reactants by electrophoresis, supporting chemical reactions, followed by electrophoretic separation of the final compounds. As a proof-of-concept of the method, the EMMA of an inkjetted mixture of 4-fluoro-7-nitrobenzofurazan (NBD-F) and amino acids was carried out as a model chemical reaction. The product NBD-amino acids were quantified by detection with laser induced fluorescence. The optimal conditions for the procedure were: inkjet driving voltage: +40-44 V; pulse width: 20-24 MUs; drop-by drop injection of reactant solutions: alternately 2 drops * 25 times for the amino acid solution and the NBD-F solution; zone overlapping voltage and time: 3 kV and 2 s; incubation time after overlapping: 5 min; separation voltage: 18 kV. Under the optimized conditions, a significant enhancement in sensitivity and a sensitive quantitative analysis were realized. The results obtained were comparable with those using the off-line labeling method. This method is rapid, cost-effective, and readily automated for EMMA. PMID- 25728633 TI - Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate, and comprehensive approach. AB - OBJECTIVE: Accurate prenatal diagnosis of genetic conditions can be challenging and usually requires invasive testing. Here, we demonstrate the potential of next generation sequencing (NGS) for the analysis of cell-free DNA in maternal blood to transform prenatal diagnosis of monogenic disorders. METHODS: Analysis of cell free DNA using a PCR and restriction enzyme digest (PCR-RED) was compared with a novel NGS assay in pregnancies at risk of achondroplasia and thanatophoric dysplasia. RESULTS: PCR-RED was performed in 72 cases and was correct in 88.6%, inconclusive in 7% with one false negative. NGS was performed in 47 cases and was accurate in 96.2% with no inconclusives. Both approaches were used in 27 cases, with NGS giving the correct result in the two cases inconclusive with PCR-RED. CONCLUSION: NGS provides an accurate, flexible approach to non-invasive prenatal diagnosis of de novo and paternally inherited mutations. It is more sensitive than PCR-RED and is ideal when screening a gene with multiple potential pathogenic mutations. These findings highlight the value of NGS in the development of non-invasive prenatal diagnosis for other monogenic disorders. PMID- 25728634 TI - Association between serum level of ubiquinol and NT-proBNP, a marker for chronic heart failure, in healthy elderly subjects. AB - Ubiquinone and ubiquinol represent the oxidized and reduced forms of Coenzyme Q10 (CoQ10). CoQ10 is present in membranes of almost all human tissues and organs, with highest concentration in the heart. In patients with heart failure, serum levels of the N-terminal pro-brain natriuretic peptide (NT-proBNP) are an indicator of disease severity. Here, we investigated the relationship between serum levels of CoQ10 and NT-proBNP in healthy volunteers of an elderly study population (mean age 52 years, n = 871). We found a negative association between serum levels of ubiquinol and NT-proBNP (P < 0.001). Accordingly, the CoQ10 redox state (% oxidized form of CoQ10) is positively associated with serum NT-proBNP level (P < 0.001). Compared to patients who survived a myocardial infarction (n = 21), healthy subjects have lower NT-proBNP level (500.39 +/- 631.28 pg/ml vs. 76.90 +/- 120.27 pg/ml, P < 0.001), higher ubiquinol serum level (0.43 +/- 0.19 umol/L vs. 0.71 +/- 0.32 umol/L; P < 0.001), and a lower CoQ10 redox state (27.6 +/- 13.8% vs. 17.6 +/- 10.1%; P < 0.001). Interestingly, ubiquinol supplementation (150 mg/day; 14 day; n = 53) slightly reduces the expression of CLCN6, a gene related to NT-proBNP level. In summary, higher serum levels of ubiquinol are associated with lower serum NT-proBNP levels in healthy elderly subjects. However, to what extent a high serum level of ubiquinol is a protective factor for heart failure remains to be elucidated in prospective studies. PMID- 25728635 TI - Nrf2 sensitizes prostate cancer cells to radiation via decreasing basal ROS levels. AB - Androgen deprivation therapy (ADT) was reported to lower basal ROS level in prostate cancer (PCa) and to sensitize PCa to radiation. We aimed to seek for the underlying molecular mechanism and to develop novel additive treatments to ADT in this regard. We simulated human androgen milieu in vitro and tested the ROS level in PCa cells undergoing ADT. We also tested the Nrf2 level in PCa cells with or without ADT. Genetic and pharmaceutical upregulation of Nrf2 was applied in vitro and in vivo in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with or without castration to investigate whether Nrf2 overexpression supplemented the effect of ADT in PCa. We first discovered that androgen deprivation increased basal ROS level in PCa cells with AR expression. We then found that genetic Nrf2 upregulation lowered basal ROS similar to ADT. Also, SFN sensitized PCa cell to radiation via upregulation of Nrf2. We then found that Nrf2 level in control TRAMP groups was lower than castration or SFN groups. The SFN treated TRAMP mice showed similar level of Nrf2 to castration. Genetic and pharmaceutical upregulation of Nrf2 lowered the ROS in PCa cells and sensitized PCa cells to radiation similar to ADT, implicating possible administration of SFN in place of ADT for PCa patients requiring radiotherapy. PMID- 25728636 TI - Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin. AB - Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin, was isolated from the dried calices of Hibiscus sabdariffa L, which has been used for folk beverages and herbal medicine although the molecular mechanisms are poorly defined. Based on the properties of Dp3-Sam and the information of inflammatory processes, we investigated the anti-inflammatory activity and molecular mechanisms in both cell and animal models in the present study. In the cell model, Dp3-Sam and Delphinidin (Dp) reduced the levels of inflammatory mediators including iNOS, NO, IL-6, MCP-1, and TNF-alpha induced by LPS. Cellular signaling analysis revealed that Dp3-Sam and Dp downregulated NF-kappaB pathway and MEK1/2 ERK1/2 signaling. In animal model, Dp3-Sam and Dp reduced the production of IL-6, MCP-1 and TNF-alpha and attenuated mouse paw edema induced by LPS. Our in vitro and in vivo data demonstrated that Hibiscus Dp3-Sam possessed potential anti inflammatory properties. PMID- 25728638 TI - Reply to: "Coagulation and fibrosis: A potential non-negligible target of statins in chronic hepatitis". PMID- 25728639 TI - Long-term, long-distance recording of a living migrating neuron by scanning ion conductance microscopy. AB - Bias-free, three-dimensional imaging of entire living cellular specimen is required for investigating shape and volume changes that occur during cellular growth or migration. Here we present fifty consecutive recordings of a living cultured neuron from a mouse dorsal root ganglion obtained by Scanning ion conductance microscopy (SICM). We observed a saltatory migration of the neuron with a mean velocity of approximately 20 MUm/h. These results demonstrate the non invasiveness of SICM, which makes it unique among the scanning probe microscopes. In contrast to SICM, most scanning probe techniques require a usually denaturating preparation of the cells, or they exert a non-negligible force on the cellular membrane, impeding passive observation. Moreover, the present series of recordings demonstrates the potential use of SICM for the detailed investigation of cellular migration and membrane surface dynamics even of such delicate samples as living neurons. PMID- 25728640 TI - Mapping and characterization of antigenic epitopes of arginine kinase of Scylla paramamosain. AB - Arginine kinase (AK) is a panallergen present in crustaceans, which can induce an immunoglobulin (Ig) E-mediated immune response in humans. The aim of this work was to map and characterize the antigenic epitopes of Scylla paramamosain AK. Specific-protein-A-enriched IgG raised in rabbits against purified S. paramamosain AK was used to screen a phage display random peptide library. Five AK mimotope clones were identified among 20 random clones after biopanning. Four conformational epitopes D3A4K43M1A5T49T44I7, L31K33V35T32E11E18F14S34D37, V177G172M173D176Q178T174L181K175L187, and R202L170Y203E190P205W204L187T206Y145 were identified with the program LocaPep, and mapped to S. paramamosain AK. The key amino acids of these conformational epitopes were D3, K33, T174, and W204, respectively. On the basis of biopanning, six IgE-specific peptides were mapped with synthetic overlapping peptides using the sera from crab-allergic patients, and four seropositive peptides (amino acids 113-127, 127-141, 141-155, and 204 218) were confirmed as linear epitopes in a degranulation assay in RBL-2H3 cells. Stability experiments showed that the structural integrity of AK is essential for its allergenicity, and the intramolecular disulfide bond at Cys201-Cys271 is essential for its structural stability. PMID- 25728641 TI - MicroRNA 26a modulates regulatory T cells expansion and attenuates renal ischemia reperfusion injury. AB - Ischemia-reperfusion injury (IRI) was one of the main causes of acute kidney injury. Mir-26a has been reported to play functions in cellular differentiation, cell growth, cell apoptosis and metastasis. Furthermore, the renal vein levels of Mir-26a were demonstrated to be lower in the poststenotic kidney. However, the effect of Mir-26a on the renal IRI has never been investigated. In our current study, Mir-26a overexpression results in attenuated renal IRI and promoted tregs expansion. The promoted renal function after IRI induced by Mir-26a overexpression was abrogated by depletion of tregs with anti-CD25 antibodies. Mir 26a also significantly suppressed IL-6 expression. And IL-6 overexpression led to significant suppression of the Mir-26a-induced upregulation of Foxp3. Next, we performed additional experiments to determine the therapeutic potential of Mir 26a during the recovery phase after renal IRI. Results showed that Mir-26a treatment after IRI also induced significant expansion of Foxp3(+)CD4(+) Tregs in both spleen and renal on day 10 after IRI. Taken together, our data indicate an important role for Mir-26a in promoting tregs expansion in renal IRI that involving repression of IL-6 expression. PMID- 25728642 TI - Legacies of past exploitation and climate affect mammalian sexes differently on the roof of the world - the case of wild yaks. AB - In polar environments, a lack of empirical knowledge about biodiversity prompts reliance on species distribution models to predict future change, yet these ignore the role of biotic interactions including the role of long past human exploitation. To explore how mammals of extreme elevation respond to glacial recession and past harvest, we combined our fieldwork with remote sensing and used analyses of ~60 expeditions from 1850-1925 to represent baseline conditions for wildlife before heavy exploitation on the Tibetan Plateau. Focusing on endangered wild yaks (Bos mutus), we document female changes in habitat use across time whereupon they increasingly relied on steeper post-glacial terrain, and currently have a 20x greater dependence on winter snow patches than males. Our twin findings-that the sexes of a cold-adapted species respond differently to modern climate forcing and long-past exploitation-indicate that effective conservation planning will require knowledge of the interplay between past and future if we will assure persistence of the region's biodiversity. PMID- 25728643 TI - Usefulness of the integrated scoring model of treadmill tests to predict myocardial ischemia and silent myocardial ischemia in community-dwelling adults (from the Rancho Bernardo study). AB - To investigate the association between analyses of submaximal treadmill exercise test (TMT) and long-term myocardial ischemia (Mis) and silent Mis in community dwelling older adults, 898 Rancho Bernardo Study participants (mean age 55 years) without coronary heart disease underwent TMT and were followed up to 27 years. The main outcome measures are incidence of Mis and silent Mis. During follow-up, 97 Mis and 103 silent Mis events occurred. We measured ST change, inability to achieve target heart rate, abnormal heart rate recovery (HRR), and chronotropic incompetence (ChI). Each parameter was a significant predictor for Mis and silent Mis. An integrated scoring model was based on these 4 parameters and defined as sum of numbers of abnormal parameters. After multiple adjustments, an integrated scoring model independently predicted Mis and silent Mis. The incidence rates of abnormalities of parameters are 36.5% for 1 abnormality, 9.1% for 2 abnormalities, and 2.0% for 3 or 4 abnormalities. Compared with those with normal results, participants with 1 or 2 abnormalities had significantly increased risk for Mis (hazard ratio [HR] 1.79 or 2.34, respectively) and silent Mis (HR 1.80 or 2.64, respectively). Participants with 3 or more positive findings showed an even greater risk for Mis (HR 7.96 [3.02 to 21.00]) and silent Mis (HR 3.22 [0.76 to 13.60]). In conclusion, ST change, ChI, abnormal HRR, inability to achieve target heart rate, and integrated scoring model of TMT were independent predictors of long-term Mis and silent Mis in an asymptomatic middle-aged population. Management of ChI or abnormal HRR in an asymptomatic population may prevent future ischemic heart disease and thus improve the quality of life. PMID- 25728644 TI - Prognostic impact of clopidogrel pretreatment in patients with acute coronary syndrome managed invasively. AB - Pretreatment with antiP2Y12 agents before angiography in acute coronary syndrome (ACS) is associated with a reduction in thrombotic events. However, recent evidences have questioned the benefits of upstream antiP2Y12, reporting a higher incidence of bleeding. We analyzed the prognostic impact of clopidogrel pretreatment in a large cohort of invasively managed patients with ACS. In hospital, safety and efficacy of clopidogrel pretreatment were retrospectively analyzed in patients included in the ARIAM-Andalucia Registry (Analysis of Delay in Acute Myocardial Infarction). Propensity score and inverse probability of treatment weighting analysis were performed to control treatment selection bias. Results were stratified by ACS type. Sensitivity analyses were used to explore stability of the overall treatment effect. Of 9,621 patients managed invasively, 69% received clopidogrel before coronary angiography. In the ST-elevation myocardial infarction group, pretreatment was associated with a significant reduction in reinfarction (odds ratio 0.53, 95% confidence interval [CI] 0.27 to 0.96; p = 0.027), stent thrombosis (odds ratio 0.15, 95% CI 0.06 to 0.38; p <0.0001), and mortality (odds ratio 0.67, 95% CI 0.48 to 0.94; p = 0.020), with an increase in minor bleeding but remained as a net clinical benefit strategy. Those benefits were not present in patients without ST elevation (non-ST elevation ACS). The weighting and propensity analysis confirmed the same results. An interaction between pretreatment duration and bleeding was observed. In conclusion, pretreatment with clopidogrel reduced the occurrence of death and thrombotic outcomes at the cost of minor bleeding. Those benefits exclusively affected ST-elevation myocardial infarction cases. The potential benefit of routine upstream pretreatment in patients with non-ST-elevation ACS should be reappraised at the present. PMID- 25728645 TI - Safety and efficacy of using the Viabahn endoprosthesis for percutaneous treatment of vascular access complications after transfemoral aortic valve implantation. AB - Vascular access complications (VACs) remain one of the biggest challenges when performing transcatheter aortic valve implantation (TAVI). This study aimed to investigate the short- and medium-term safety and efficacy of the Viabahn endoprosthesis (Gore, Flagstaff, AZ) when used to treat TAVI-induced vascular injury. Over a 40-month period, 354 patients underwent true percutaneous transfemoral (TF)-TAVI using a CoreValve and Prostar-XL closure system; this was our study population. A VAC leading to acute intervention occurred in 72 patients (20.3%) - of these, 18 were managed by balloon angioplasty, 48 were treated by Viabahn stenting (technical success rate 98%), and 6 needed surgical intervention. Overall, this approach resulted in a major VAC rate of 3.1% (n = 11) in our study cohort. Length of hospitalization and 30-day mortality rates were comparable in patients with a VAC treated by Viabahn stenting versus patients without vascular complications. Two patients (4.5%) presented with new onset claudication; one of them had the stent implanted covering the deep femoral artery (DFA). At medium-term follow-up (median 372 days; range 55 to 978 days) duplex ultrasound showed 100% patency of the Viabahn endoprostheses with no signs of stent fracture or in-stent stenosis/occlusion. In conclusion, the use of self expanding covered stents is safe and effective in case of TF-TAVI-induced vascular injury, with good short- and medium-term outcomes. Importantly, coverage of the DFA should be avoided. If confirmed by long-term (>5 years) follow-up studies, this strategy for treating TAVI-induced VAC may be used routinely in high-risk patients. PMID- 25728646 TI - Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding cangrelor. AB - Landmark clinical trials have established the benefit of P2Y12 inhibitors in the setting of acute coronary syndrome and percutaneous coronary intervention. On February 12, 2014, the Medicines Company (Sponsor) presented efficacy and safety data regarding cangrelor to the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee. The Sponsor sought approval for 2 indications: (1) in the setting of percutaneous coronary intervention for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with coronary artery disease and (2) in the setting of bridging therapy in patients with acute coronary syndrome or with stents who are at increased risk for thrombotic events (such as stent thrombosis) when oral P2Y12 therapy is interrupted because of surgery. The following is a summary of the data presented to the FDA by the Sponsor, the FDA's clinical review of cangrelor. PMID- 25728648 TI - An overview of conditioning regimens for haploidentical stem cell transplantation with post-transplantation cyclophosphamide. AB - Haploidentical related donors are an attractive alternative source of stem cells for allogeneic stem cell transplantation due to widespread availability and ease of stem cell procurement. Historically, haploidentical stem cell transplantation (HaploSCT) with extensive T-cell depletion has been associated with high rates of infectious complications and nonrelapse mortality (NRM). Post-transplantation cyclophosphamide (PTCy) has been shown to induce immune tolerance, effectively control graft-versus-host-disease (GVHD), and is associated with lower NRM, making it a preferred option for patients undergoing HaploSCT. Over the last decade, several groups investigated PTCy for GVHD prevention in HaploSCT; it is now successfully utilized with both myeloablative and nonmyeloablative conditioning regimens with survival comparable to HLA-matched transplantation. Future directions will focus on optimizing conditioning regimens by diagnosis, improving donor selection, and enhancing graft-versus-leukemia effect. PMID- 25728647 TI - Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency. AB - Cytochrome P450 oxidoreductase (POR) is a 2-flavin protein that transfers electrons from NADPH via its FAD and FMN moieties to all microsomal cytochrome P450 enzymes, including steroidogenic and drug-metabolizing P450s. Defects in the POR gene can cause POR deficiency (PORD), manifested clinically by disordered steroidogenesis, genital anomalies and skeletal malformations. We examined the POR mutant A287P, which is the most frequent cause of PORD in patients of European ancestry and partially disrupts most P450 activities in vitro. Flavin content analysis showed that A287P is deficient in FAD and FMN binding, although the mutation site is distant from the binding sites of both flavins. Externally added flavin partially restored the cytochrome c reductase activity of A287P, suggesting that flavin therapy may be useful for this frequent form of PORD. Transient kinetic dissection of the reaction of POR with NADPH and the reduction in cytochrome c by POR using stopped-flow techniques revealed defects in individual electron transfer steps mediated by A287P. A287P had impaired ability to accept electrons from NADPH, but was capable of a fast FMN -> cytochrome c electron donation reaction. Thus the reduced rates of P450 activities with A287P may be due to deficient flavin and impaired electron transfer from NADPH. PMID- 25728649 TI - [Evaluation of optic nerve perfusion in optic neuropathies and neurodegenerative diseases]. PMID- 25728650 TI - "You produce while I clean up", a strategy revealed by exoproteomics during Synechococcus-Roseobacter interactions. AB - Most of the energy that is introduced into the oceans by photosynthetic primary producers is in the form of organic matter that then sustains the rest of the food web, from micro to macro-organisms. However, it is the interactions between phototrophs and heterotrophs that are vital to maintaining the nutrient balance of marine microbiomes that ultimately feed these higher trophic levels. The primary produced organic matter is mostly remineralized by heterotrophic microorganisms but, because most of the oceanic dissolved organic matter is in the form of biopolymers, and microbial membrane transport systems operate with molecules <0.6 kDa, it must be hydrolyzed outside the cell before a microorganism can acquire it. As a simili of the marine microbiome, we analyzed, using state-of the-art proteomics, the exoproteomes obtained from synthetic communities combining specific Roseobacter (Ruegeria pomeroyi DSS-3, Roseobacter denitrificans OCh114, and Dinoroseobacter shibae DFL-12) and Synechococcus strains (WH7803 and WH8102). This approach identified the repertoire of hydrolytic enzymes secreted by Roseobacter, opening up the black box of heterotrophic transformation/remineralization of biopolymers generated by marine phytoplankton. As well as highlighting interesting exoenzymes this strategy also allowed us to infer clues on the molecular basis of niche partitioning. PMID- 25728652 TI - Exon Skipping Is Correlated with Exon Circularization. AB - Circular RNAs are found in a wide range of organisms and it has been proposed that they perform disparate functions. However, how RNA circularization is connected to alternative splicing remains largely unexplored. Here, we stimulated primary human endothelial cells with tumor necrosis factor alpha or tumor growth factor beta, purified RNA, generated >2.4 billion RNA-seq reads, and used a custom pipeline to characterize circular RNAs derived from coding exons. We find that circularization of exons is widespread and correlates with exon skipping, a feature that adds considerably to the regulatory complexity of the human transcriptome. PMID- 25728653 TI - Relevance of two-dimensional gas chromatography and high resolution olfactometry for the parallel determination of heat-induced toxicants and odorants in cooked food. AB - The assessment of the dual impact of heating treatments on food safety and aroma is a major issue for the food sector. The aim of the present study was to demonstrate the relevance of multidimensional GC techniques, olfactometry and mass spectrometry for the parallel determination of process-induced toxicants and odorants in food starting with cooked meat as a food model. PAHs were analyzed by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry after extraction by accelerated solvent extraction (ASE-GC * GC-TOF/MS). Odour active compounds were determined by dynamic headspace-GC hyphenated with eight booth olfactometry and mass spectrometry (DH-GC-MS/8O) and DH-heart-cutting multidimensional GC hyphenated with olfactometry and mass spectrometry (DH-GC-GC MS/O). For PAH determination, the GC * GC conditions consisted of a combination of a primary non-polar BPX-5 column and a secondary polar BPX-50 column, and a modulation period of 5s. In terms of linearity (R(2) ranging from 0.985 to 0.997), recovery rate (84-111%) and limit of detection (5-65 ng/kg of cooked meat), the ASE-GC * GC-TOF/MS method was found consistent with the multiresidue determination of 16 PAHs including benzo[a]pyrene in cooked meat. For aroma compounds, DH-GC-MS/8O and DH-GC-MS/O revealed 53 major meat odour-active compounds. A customized heart-cutting GC-GC-MS/O enabled the coeluting odour zones with high odour-activity to be resolved and revealed 15 additional odour active compounds. Finally, these developments of multidimensional approaches were used to investigate the balance between 16 PAHs and 68 odour-active compounds generated with different cooking techniques. PMID- 25728651 TI - A proteomics perspective on viral DNA sensors in host defense and viral immune evasion mechanisms. AB - The sensing of viral DNA is an essential step of cellular immune response to infections with DNA viruses. These human pathogens are spread worldwide, triggering a wide range of virus-induced diseases, and are associated with high levels of morbidity and mortality. Despite similarities between DNA molecules, mammalian cells have the remarkable ability to distinguish viral DNA from their own DNA. This detection is carried out by specialized antiviral proteins, called DNA sensors. These sensors bind to foreign DNA to activate downstream immune signaling pathways and alert neighboring cells by eliciting the expression of antiviral cytokines. The sensing of viral DNA was shown to occur both in the cytoplasm and in the nucleus of infected cells, disproving the notion that sensing occurred by simple spatial separation of viral and host DNA. A number of omic approaches, in particular, mass-spectrometry-based proteomic methods, have significantly contributed to the constantly evolving field of viral DNA sensing. Here, we review the impact of omic methods on the identification of viral DNA sensors, as well as on the characterization of mechanisms involved in host defense or viral immune evasion. PMID- 25728654 TI - Accurate analysis of ginkgolides and their hydrolyzed metabolites by analytical supercritical fluid chromatography hybrid tandem mass spectrometry. AB - Hydrolysis plays an important role in the metabolic transformations of lactones. Analysis of lactones and their hydrolyzed metabolites in biological samples is challenging, because unexpected hydrolysis or reversed dehydration may occur depending on the test environments. In this work, a supercritical fluid chromatography hybrid triple-quadrupole mass spectrometry (SFC-QQQ MS) method has been proposed for simultaneous analysis of ginkgolides and hydrolyzed metabolites. The SFC utilizes carbon dioxide as the mobile phase, avoiding hydrolysis of ginkgolides that always happens during reversed phase liquid chromatographic detection. Compared with normal phase liquid chromatography, the SFC provides good resolutions especially for ginkgolide with similar structures. This SFC-QQQ MS method was validated in linearity, precision, accuracy, and stability for ginkgolides and metabolites. Then this method was successfully applied to pharmacokinetic study of 3 ginkgolides and their 6 hydrolyzed metabolites after intravenous administration of total ginkgolide extract. Ginkgolides and metabolites showed different clear rates and excluded in 2-4h. The developed SFC-QQQ MS method allows accurate determination of ginkgolides and metabolites with high resolutions, and can be extended to analysis of other water unstable compounds. PMID- 25728655 TI - Polydopamine-based immobilization of zeolitic imidazolate framework-8 for in-tube solid-phase microextraction. AB - Zeolitic imidazolate frameworks (ZIFs), a subfamily of metal-organic frameworks (MOFs), have received considerable attention as a novel porous material for sample preparation due to their fascinating structures and unique properties. Here, we developed a novel bio-inspired polydopamine (PDA) method to immobilize ZIFs inside the chemical resistance poly(ether ether ketone) (PEEK) tube for online solid-phase microextraction (SPME). Firstly, PDA layer was assembled inside the PEEK tube. Secondly, attributing to its noncovalent adsorption and covalent reaction ability, PDA could attract and anchor ZIF-8 nutrients onto the inner surface of PEEK tube to promote the nucleation and growth of ZIF-8. The morphology and surface properties of the prepared ZIF-8-PDA-PEEK tube were characterized by scanning electron microscopy and energy dispersive X-ray spectrometry. The ZIF-8-PDA-PEEK tube exhibits excellent extraction efficiency toward six polycyclic aromatic hydrocarbons (PAHs), with enrichment factor from 550 to 734. The developed online SPME-HPLC method shows good linearity (10 5000pg/mL) and low detection limits (0.5-5 pg/mL) for six PAHs. It also has been used to determine PAHs in environmental samples, with recoveries in the range of 82.5-98.6%. PMID- 25728656 TI - Investigation of bi-enzymatic reactor based on hybrid monolith with nanoparticles embedded and its proteolytic characteristics. AB - The bottom-up strategy of proteomic profiling study based on mass spectrometer (MS) has drawn high attention. However, conventional solution-based digestion could not satisfy the demands of highly efficient and complete high throughput proteolysis of complex samples. We proposed a novel bi-enzymatic reactor by immobilizing two different enzymes (trypsin/chymotrypsin) onto a mixed support of hybrid organic-inorganic monolith with SBA-15 nanoparticles embedded. Typsin and chymotrypsin were crossly immobilized onto the mixed support by covalent bonding onto the monolith with glutaraldehyde as bridge reagent and chelation via copper ion onto the nanoparticles, respectively. Compared with single enzymatic reactors, the bi-enzymatic reactor improved the overall functional analysis of membrane proteins of rat liver by doubling the number of identified peptides (from 1184/1010 with trypsin/chymotrypsin enzymatic reactors to 2891 with bi enzymatic reactor), which led to more proteins identified with deep coverage (from 452/336 to 620); the efficiency of the bi-enzymatic reactor is also better than that of solution-based tandem digestion, greatly shorting the digestion time from 24h to 50s. Moreover, more transmembrane proteins were identified by bi enzymatic reactor (106) compared with solution-based tandem digestion (95) with the same two enzymes and enzymatic reactors with single enzyme immobilized (75 with trypsin and 66 with chymotrypsin). The proteolytic characteristics of the bi enzymatic reactors were evaluated by applying them to digestion of rat liver proteins. The reactors showed good digestion capability for proteins with different hydrophobicity and molecular weight. PMID- 25728657 TI - Selective and sentivive method based on capillary liquid chromatography with in tube solid phase microextraction for determination of monochloramine in water. AB - Due to the difficulties of working with chloramines, a critical examination of monochloramine standard preparation has been performed in order to select the best synthesis conditions. The analyte has been determined by in-tube solid phase extraction coupled to capillary liquid chromatography with UV detection (IT-SPME Capillary LC DAD). Potential factors affecting the response of monochloramine such as the pH of mobile phase and the volume of sample processed by IT-SPME Capillary LC DAD have been investigated and optimized. According to the results of the study, 0.1 mL or 4.0 mL of sample at neutral pH were loaded in the chromatographic system. A sensitive and selective method has been developed for the determination of monochloramine in water. Validation of the method has been performed. The linear range was 0.09-5mg/L with linear regression coefficients (R(2)) greater than 0.995. Method reproducibility expressed as relative standard deviation (RSD, %), was lower than 15%. The limits of detection (LODs) were 0.029 and 0.01 mg/L by processing 0.100mL or 4 mL of the samples, respectively, being below the maximum residues levels allowed for this compound. The sensitivity achieved by the developed method was better than that obtained by the reference method. The developed method was applied to water samples (tap and swimming pool water). PMID- 25728658 TI - Isolation of beta-carotene, alpha-carotene and lutein from carrots by countercurrent chromatography with the solvent system modifier benzotrifluoride. AB - A carotenoid purification method with dual-mode countercurrent chromatography (CCC) for beta-carotene, alpha-carotene and lutein from a fresh carrot extract was developed. The fluorinated liquid benzotrifluoride (IUPAC name: (trifluoromethyl)benzene) was used as a novel modifier in the non-aqueous ternary solvent system n-hexane/benzotrifluoride/acetonitrile. The ternary phase diagram of the type I solvent system was used to select two-phase solvent mixtures which enabled an efficient preparative separation of alpha-carotene, beta-carotene and lutein from concomitant pigments in crude carrot extract. By means of the modifier, high separation factors (alpha >= 1.2) were obtained, allowing baseline resolution between alpha-carotene and beta-carotene due to specific chemical interactions such as pi-pi molecular interactions. After optimizing the injection step with a pseudo-ternary phase diagram, 51 mg of beta-carotene, 32 mg of alpha carotene and 4 mg of lutein could be isolated from 100.2mg crude carrot extract in a short time and with high purities of 95% and 99% by using dual-mode CCC, respectively. Temperatures > 22 degrees C had a negative impact on the separation of alpha-carotene and beta-carotene. PMID- 25728659 TI - Contact solid-phase microextraction with uncoated glass and polydimethylsiloxane coated fibers versus solvent sampling for the determination of hydrocarbons in adhesion secretions of Madagascar hissing cockroaches Gromphadorrhina portentosa (Blattodea) by gas chromatography-mass spectrometry. AB - Molecular profiles of adhesion secretions of Gromphadorrhina portentosa (Madagascar hissing cockroach, Blattodea) were investigated by gas chromatography mass spectrometry with particular focus on a comprehensive analysis of linear and branched hydrocarbons. For this purpose, secretions from the tarsi (feet), possibly contributing to adhesion on smooth surfaces, and control samples taken from the tibiae (lower legs), which contain general cuticular hydrocarbons that are supposed to be not involved in the biological adhesion function, were analyzed and their molecular fingerprints compared. A major analytical difficulty in such a study constitutes the representative, spatially controlled, precise and reproducible sampling from a living insect as well as the minute quantities of insect secretions on both tarsi and tibiae. Thus, three different in vivo sampling methods were compared in terms of sampling reproducibility and extraction efficiency by replicate measurement of samples from tarsi and tibiae. While contact solid-phase microextraction (SPME) with a polydimethylsiloxane (PDMS) fiber showed higher peak intensities, a self-made uncoated glass fiber had the best repeatability in contact-SPME sampling. Chromatographic profiles of these two contact-SPME sampling methods were statistically not significantly different. Inter-individual variances were larger than potentially existing minor differences in molecular patterns of distinct sampling methods. Sampling by solvent extraction was time consuming, showed lower sensitivities and was less reproducible. In general, sampling by contact-SPME with a cheap glass fiber turned out to be a viable alternative to PDMS-SPME sampling. Hydrocarbon patterns of the tarsal adhesion secretions were qualitatively similar to those of epicuticular hydrocarbon profiles of the tibiae. However, hydrocarbons were in general less abundant in tarsal secretions than secretions from tibiae. PMID- 25728660 TI - Preparation of anionic polyelectrolyte modified magnetic nanoparticles for rapid and efficient separation of lysozyme from egg white. AB - Poly(sodium 4-styrenesulfonate) modified magnetic nanoparticles (PSS-MNPs) were successfully synthesized and characterized by transmission electron microscopy, scanning electron microscopy, zeta potential, vibrating sample magnetometry, and Fourier-transform infrared spectrometry. The PSS-MNPs were found to enable effective separation of lysozyme from egg white. The impacts of solution pH, ionic strength, and contact time on the adsorption process were investigated. The adsorption kinetic data were well fitted using a pseudo-second-order kinetic model and the adsorption equilibrium can be reached in 3 min. The adsorption isotherm data could be well described by the Langmuir equation. The maximum adsorption capacity of PSS-MNPs for lysozyme was calculated to be 476.2 mg g(-1) according to the Langmuir adsorption isotherm. The fast and efficient adsorption of lysozyme by PSS-MNPs was mainly based on electrostatic interactions between them. The adsorbed lysozyme can be eluted using 20mM phosphate buffer (pH 7.0) containing 1.0M NaCl with a recovery of 96%. The extracted lysozyme from egg white demonstrated high purity, retaining about 90.7% of total lysozyme activity. PMID- 25728661 TI - Identification of aroma-active volatiles in banana Terra spirit using multidimensional gas chromatography with simultaneous mass spectrometry and olfactometry detection. AB - Fruit spirits have been produced and consumed throughout the world for centuries. However, the aroma composition of banana spirits is still poorly characterised. We have investigated the aroma-impact compounds of the banana Terra spirit for the first time, using multidimensional gas chromatography (MDGC and GC * GC) in a multi-hyphenated system - i.e., coupled to flame ionisation detection (FID), mass spectrometry (MS), and olfactometry (O). Solid-phase microextraction (SPME) was used to isolate the headspace aroma compounds of the banana spirit. The detection frequency (DF) technique was applied and aroma regions, detected in the first column separation at >60% Nasal Impact Frequency (NIF), were screened as target potent odour regions in the sample. Using a polar/non-polar phase column set, the potent odour regions were further subjected to MDGC separation with simultaneous O and MS detection for correlation of the aroma perception with MS data for individual resolved aroma-impact compounds. GC-O analysis enabled 18 aroma-impact regions to be located as providing volatiles of interest for further study; for example, those comprising perceptions of flower, whisky, green, amongst others. Compounds were tentatively identified through MS data matching and retention indices in both first and second dimensions. The principal volatile compounds identified in this work, which are responsible for the characteristic aroma of the banana spirit, are 3-methylbutan-1-ol, 3-methylbutan-1-ol acetate, 2 phenylethyl acetate and phenylethyl alcohol. This is the first such study to reveal the major aroma compounds that contribute to banana spirit aroma. PMID- 25728662 TI - Dissolved carbon dioxide flotation: an effective way for phase separation in emulsification microextraction method. AB - Dissolved carbon dioxide flotation after emulsification microextraction (DCF-EME) technique coupled with gas chromatography-electron capture detection (GC-ECD) was introduced for preconcentration and determination of six organochlorine pesticides (OCPs) in seawater samples. DCF-EME method is based on the rapid and simple phase separation of low density organic solvent from the aqueous phase via introducing of a saturated NaHCO3 solution (9.6% w/v) into the acidified sample solution (0.1M of HCl) containing analytes. Thanks to the in situ generation of carbon dioxide (CO2) bobbles intensified by ultrasound radiation, the dispersed extraction solvent was collected to the surface of the aqueous sample and then was narrowed to the capillary part of a special home-made extraction cell for facile retrieving. Under the optimal conditions, the limits of detection were at the range of 2.6-9.2 ng L(-1) and preconcentration factors were varied between 271 and 307 for different OCPs. The applicability of the developed method was evaluated by the extraction and determination of the target analytes from Caspian seawater samples. PMID- 25728663 TI - Nucleophilic substitution in preparation and surface modification of hypercrosslinked stationary phases. AB - Four linear diaminoalkanes (1,2-diaminoethane, 1,4-diaminobutane, 1,6 diaminohexane, and 1,8-diaminooctane) have been used to hypercrosslink poly(styrene-co-vinylbenzyl chloride-co-divinylbenzene) monolithic stationary phases by nucleophilic substitution reaction. The column efficiency of polymer monoliths improved with longer diaminoalkane with 1,8-diaminoctane providing the highest efficiency. The concentration of 1,8-diaminoctane, together with hypercrosslinking time and temperature has been optimized. To improve the permeability of prepared columns, the hypercrosslinking modification has been combined with an early termination of polymerization reaction and decrease in polymerization temperature. The optimal column has been prepared by a polymerization reaction for 2h at 65 degrees C and hypercrosslinked in the presence of 3% 1,8-diaminooctane for 2h at 95 degrees C. The repeatability study of the presented protocol provided relative standard deviation for nine columns prepared independently out of three individual polymerization mixtures in between 2.0-12.0% for retention factors and 1.5-6.5% for plate heights, respectively. Further, we have modified residual chloromethyl groups with 2-aminoethanesulfonic acid (taurine) to prepare monolithic columns suitable for separation of small polar molecules in hydrophilic interaction chromatography. The highest retention of polar thiourea showed the column modified at 70 degrees C for 20 h. Taurine modified hypercrosslinked column showed the minimum of van Deemter curve of 20 MUm. The prepared column provided dual-retention mechanism, including hydrophilic interaction and reversed-phase liquid chromatography that can be controlled by the composition of the mobile phase. The prepared column has been successfully used for an isocratic separation of low-molecular phenolic acids. PMID- 25728664 TI - Assessment of vacuum-assisted closure therapy on the wound healing process in cardiac surgery. AB - Postoperative deep sternal wound infection (DSWI) is a serious complication in cardiac surgery (1-5% of patients) with high mortality and morbidity rates. Vacuum-assisted closure (VAC) therapy has shown promising results in terms of wound healing process, postoperative hospital length of stay and lower in hospital costs. The aim of our retrospective study is to report the outcome of patients with DSWI treated with VAC therapy and to assess the effect of contributory risk factors. Data of 52 patients who have been treated with VAC therapy in a single institution (study period: September 2003-March 2012) were collected electronically through PAtient Tracking System PATS and statistically analysed using SPSS version 20. Of the 52 patients (35 M: 17 F), 88.5% (n = 46) were solely treated with VAC therapy and 11.5% (n = 6) had additional plastic surgical intervention. Follow-up was complete (mean 33.8 months) with an overall mortality rate of 26.9% (n = 14) of whom 50% (n = 7) died in hospital. No death was related to VAC complications. Patient outcomes were affected by pre operative, intra-operative and postoperative risk factors. Logistic EUROscore, postoperative hospital length of stay, advanced age, chronic obstructive pulmonary disease (COPD) and long-term corticosteroid treatment appear to be significant contributing factors in the long-term survival of patients treated with VAC therapy. PMID- 25728665 TI - Genetic isolation between two recently diverged populations of a symbiotic fungus. AB - Fungi are an omnipresent and highly diverse group of organisms, making up a significant part of eukaryotic diversity. Little is currently known about the drivers of fungal population differentiation and subsequent divergence of species, particularly in symbiotic, mycorrhizal fungi. Here, we investigate the population structure and environmental adaptation in Suillus brevipes (Peck) Kuntze, a wind-dispersed soil fungus that is symbiotic with pine trees. We assembled and annotated the reference genome for Su. brevipes and resequenced the whole genomes of 28 individuals from coastal and montane sites in California. We detected two clearly delineated coast and mountain populations with very low divergence. Genomic divergence was restricted to few regions, including a region of extreme divergence containing a gene encoding for a membrane Na(+) /H(+) exchanger known for enhancing salt tolerance in plants and yeast. Our results are consistent with a very recent split between the montane and coastal Su. brevipes populations, with few small genomic regions under positive selection and a pattern of dispersal and/or establishment limitation. Furthermore, we identify a putatively adaptive gene that motivates further functional analyses to link genotypes and phenotypes and shed light on the genetic basis of adaptive traits. PMID- 25728666 TI - COLD1 confers chilling tolerance in rice. AB - Rice is sensitive to cold and can be grown only in certain climate zones. Human selection of japonica rice has extended its growth zone to regions with lower temperature, while the molecular basis of this adaptation remains unknown. Here, we identify the quantitative trait locus COLD1 that confers chilling tolerance in japonica rice. Overexpression of COLD1(jap) significantly enhances chilling tolerance, whereas rice lines with deficiency or downregulation of COLD1(jap) are sensitive to cold. COLD1 encodes a regulator of G-protein signaling that localizes on plasma membrane and endoplasmic reticulum (ER). It interacts with the G-protein alpha subunit to activate the Ca(2+) channel for sensing low temperature and to accelerate G-protein GTPase activity. We further identify that a SNP in COLD1, SNP2, originated from Chinese Oryza rufipogon, is responsible for the ability of COLD(jap/ind) to confer chilling tolerance, supporting the importance of COLD1 in plant adaptation. PMID- 25728667 TI - Neuronal prediction of opponent's behavior during cooperative social interchange in primates. AB - A cornerstone of successful social interchange is the ability to anticipate each other's intentions or actions. While generating these internal predictions is essential for constructive social behavior, their single neuronal basis and causal underpinnings are unknown. Here, we discover specific neurons in the primate dorsal anterior cingulate that selectively predict an opponent's yet unknown decision to invest in their common good or defect and distinct neurons that encode the monkey's own current decision based on prior outcomes. Mixed population predictions of the other was remarkably near optimal compared to behavioral decoders. Moreover, disrupting cingulate activity selectively biased mutually beneficial interactions between the monkeys but, surprisingly, had no influence on their decisions when no net-positive outcome was possible. These findings identify a group of other-predictive neurons in the primate anterior cingulate essential for enacting cooperative interactions and may pave a way toward the targeted treatment of social behavioral disorders. PMID- 25728668 TI - TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. AB - Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment beta-amyloid (Abeta) accumulation due to a dysfunctional response of microglia, which fail to cluster around Abeta plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Abeta in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Abeta accumulation. PMID- 25728670 TI - Volvulus complicating jejunal diverticulosis: A case report. AB - INTRODUCTION: Diverticular disease is uncommon among Africans though increasing number of cases is now being reported, mainly of colonic diverticulosis. This condition afflicts all parts of the gastrointestinal tract but commonly the colon. Jejunal diverticula are rare, usually asymptomatic but may lead to an acute abdomen. CASE PRESENTATION: A 68 year old female trader, who was referred from a peripheral center with insidious onset of severe colicky, generalized abdominal pain, repeated vomiting of recently ingested meal, no hematemesis. There was constipation and abdominal distension. The working diagnosis was dynamic intestinal obstruction of small bowel origin. She had emergency exploratory laparotomy following resuscitation. The findings were: volvulus of the jejunum and multiple jejunal diverticula. A resection of 80cm of the jejunum with most of the diverticula involved in the torsion was done with an end-to-end anastomosis of the jejunum. Her out-patient follow-up has been uneventful. DISCUSSION: Jejunal diverticular disease is rare in Africa. Our patient presented with small bowel obstruction due to volvulus. Other complications are discussed. CONCLUSION: Intestinal obstruction from diverticular disease is not always of colonic origin. It can occur in the jejunum. PMID- 25728671 TI - Rare tumors of the gallbladder: Clear cell carcinoma. AB - INTRODUCTION: Gallbladder cancer is a rare tumor in the gastrointestinal tract has poor prognosis, low survival and is difficult to diagnose. The most common type of gallbladder cancer is adenocarcinoma, and the incidence of clear cell carcinoma is low. Mostly, it is difficult to determine whether the isolated tumor is a primary tumor in the gallbladder or a metastatic tumor from another region. Before accepting a clear cell carcinoma as a primary gallbladder tumor, the kidneys and other possible secondary focuses are clinically considered in terms of metastases. PRESENTATION OF CASE: Here, we present a rarely seen case of gallbladder clear cell carcinoma, which was diagnosed by pathological examination after the surgery. DISCUSSION: Prior to establishing that clear cell carcinoma is a primary gallbladder cancer, it is appropriate to clinically investigate possible secondary focuses, in particular the kidneys in terms of metastasis. CONCLUSION: Our goal in presenting this case was to emphasize the importance of taking an accurate medical history in patients with clear cell carcinoma, a rarely seen gallbladder cancer. PMID- 25728669 TI - Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. AB - Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems. PMID- 25728672 TI - The tip of the iceberg: Post caesarean wound dehiscence presenting as abdominal wound sepsis. AB - INTRODUCTION: Uterine scar dehiscence can complicate caesarean section with complications like post partum hemorrhage, endomyometritis, localized/generalized peritonitis, and sepsis. PRESENTATION OF CASE: Our patient had abdominal wound infection after LSCS surgery and features of sepsis. The wound infection was actually the presentation of a uterine scar dehiscence and localized peritonitis. DISCUSSION: Incidence of uterine scar dehiscence is around 0.6%. Presentation can be post partum hemorrhage, endomyometritis, and generalized/localized peritonitis. Peritonitis caused by uterine incisional necrosis must be dealt surgically. A high index of suspicion with appropriate investigations can highlight such problems for early treatment and cure with least morbidity especially related to further pregnancies. CONCLUSION: Uterine scar dehiscence with infection requires high index of suspicion as rare cause for post partum localized/generalized peritonitis with sepsis. Severe abdominal wound infection after caesarean section may be associated with uterine wound dehiscence, which poses a grave risk to the mother in a future pregnancy. PMID- 25728673 TI - HSPB1 as a novel regulator of ferroptotic cancer cell death. AB - Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1-HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. Our findings reveal an essential role for HSPB1 in iron metabolism with important effects on ferroptosis mediated cancer therapy. PMID- 25728675 TI - TRIM25 has a dual function in the p53/Mdm2 circuit. AB - P53 is an important tumor suppressor that, upon activation, induces growth arrest and cell death. Control of p53 is thus of prime importance for proliferating cells, but also for cancer therapy, where p53 activity contributes to the eradication of tumors. Mdm2 functionally inhibits p53 and targets the tumor suppressor protein for degradation. In a genetic screen, we identified TRIM25 as a novel regulator of p53 and Mdm2. TRIM25 increased p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26 S proteasomes. TRIM25 co precipitated with p53 and Mdm2 and interfered with the association of p300 and Mdm2, a critical step for p53 polyubiquitination. Despite the increase in p53 levels, p53 activity was inhibited in the presence of TRIM25. Downregulation of TRIM25 resulted in an increased acetylation of p53 and p53-dependent cell death in HCT116 cells. Upon genotoxic insults, TRIM25 dampened the p53-dependent DNA damage response. The downregulation of TRIM25 furthermore resulted in massive apoptosis during early embryogenesis of medaka, which was rescued by the concomitant downregulation of p53, demonstrating the functional relevance of the regulation of p53 by TRIM25 in an organismal context. PMID- 25728674 TI - p53, a translational regulator: contribution to its tumour-suppressor activity. AB - A growing body of evidences indicate that deregulation of translation contributes to tumourigenesis. In tumours, alterations of translational control of specific mRNAs encoding oncogenes or tumour suppressors have been extensively reported. Moreover, restricting the rate of protein synthesis has been shown to delays tumourigenesis in C-Myc overexpressing or PTEN deleted mice models. Finally, the specific inhibition of RNA polymerase I (RNA pol I) has been shown to kill cancer cells without affecting normal cells. It thus emerges that a tight coordination between the rate of global protein synthesis and a defined translational program is required to prevent tumour development. In this review, we expose the evidences supporting that p53 acts as a translational regulator. In addition, this review discusses the notion that the ability to maintain both a selective translational program and a low level of protein synthesis could directly contribute to the p53 tumour-suppressor activity. PMID- 25728676 TI - Transcriptional repression of IFNbeta1 by ATF2 confers melanoma resistance to therapy. AB - The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-E (PKCE)- and ATF2 mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-beta1 (IFNbeta1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKCE with chemotherapies relieves ATF2 mediated transcriptional repression of IFNbeta1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKCE. Notably, nuclear ATF2 and low expression of IFNbeta1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN alpha2a. Conversely, cytosolic ATF2 and induction of IFNbeta1 coincides with therapeutic responsiveness. Collectively, we identify an IFNbeta1-dependent, cell autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCE-ATF2 regulatory axis. PMID- 25728677 TI - SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer. AB - The long noncoding RNA TINCR shows aberrant expression in human squamous carcinomas. However, its expression and function in gastric cancer remain unclear. We report that TINCR is strongly upregulated in human gastric carcinoma (GC), where it was found to contribute to oncogenesis and cancer progression. We also revealed that TINCR overexpression is induced by nuclear transcription factor SP1. Silencing TINCR expression inhibited cell proliferation, colony formation, tumorigenicity and apoptosis promotion, whereas TINCR overexpression promoted cell growth, as documented in the SGC7901 and BGC823 cell lines. Mechanistic analyses indicated that TINCR could bind to STAU1 (staufen1) protein, and influence KLF2 mRNA stability and expression, then KLF2 regulated cyclin dependent kinase genes CDKN1A/P21 and CDKN2B/P15 transcription and expression, thereby affecting the proliferation and apoptosis of GC cells. Together, our findings suggest that TINCR contributes to the oncogenic potential of GC and may constitute a potential therapeutic target in this disease. PMID- 25728678 TI - CUB-domain-containing protein 1 overexpression in solid cancers promotes cancer cell growth by activating Src family kinases. AB - The transmembrane glycoprotein, CUB (complement C1r/C1s, Uegf, Bmp1) domain containing protein 1 (CDCP1) is overexpressed in several cancer types and is a predictor of poor prognosis for patients on standard of care therapies. Phosphorylation of CDCP1 tyrosine sites is induced upon loss of cell adhesion and is thought to be linked to metastatic potential of tumor cells. Using a tyrosine phosphoproteomics screening approach, we characterized the phosphorylation state of CDCP1 across a panel of breast cancer cell lines. We focused on two phospho tyrosine pTyr peptides of CDCP1, containing Tyr707 and Tyr806, which were identified in all six lines, with the human epidermal growth factor 2-positive HCC1954 cells showing a particularly high phosphorylation level. Pharmacological modulation of tyrosine phosphorylation indicated that, the Src family kinases (SFKs) were found to phosphorylate CDCP1 at Tyr707 and Tyr806 and play a critical role in CDCP1 activity. We demonstrated that CDCP1 overexpression in HEK293 cells increases global phosphotyrosine content, promotes anchorage-independent cell growth and activates several SFK members. Conversely, CDCP1 downregulation in multiple solid cancer cell lines decreased both cell growth and SFK activation. Analysis of primary human tumor samples demonstrated a correlation between CDCP1 expression, SFK and protein kinase C (PKC) activity. Taken together, our results suggest that CDCP1 overexpression could be an interesting therapeutic target in multiple solid cancers and a good biomarker to stratify patients who could benefit from an anti-SFK-targeted therapy. Our data also show that multiple tyrosine phosphorylation sites of CDCP1 are important for the functional regulation of SFKs in several tumor types. PMID- 25728679 TI - Wnt7a is a novel inducer of beta-catenin-independent tumor-suppressive cellular senescence in lung cancer. AB - Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of beta-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer. PMID- 25728680 TI - Regulation of MET receptor tyrosine kinase signaling by suppressor of cytokine signaling 1 in hepatocellular carcinoma. AB - Suppressor of cytokine signaling 1 (SOCS1) is considered as a tumor suppressor protein in hepatocellular carcinoma (HCC), but the underlying mechanisms remain unclear. Previously, we have shown that SOCS1-deficient hepatocytes displayed increased responsiveness to hepatocyte growth factor (HGF) due to enhanced signaling via the MET receptor tyrosine kinase. As aberrant MET activation occurs in many tumors including HCC, here we elucidated the mechanisms of SOCS1-mediated regulation. SOCS1 attenuated HGF-induced proliferation of human and mouse HCC cell lines and their growth as tumors in NOD.scid.gamma mice. Tumors formed by SOCS1 expressing HCC cells showed significantly reduced MET expression, indicating that SOCS1 not only attenuates MET signaling but also regulates MET expression. Mechanistically, SOCS1 interacted with MET via the Src homology 2 domain and this interaction was promoted by MET tyrosine kinase activity. The SOCS1-mediated reduction in MET expression does not require the juxtamembrane Y1003 residue implicated in Cbl-mediated downmodulation. Moreover, the proteasome inhibitor MG-132, but not the inhibitors of lysosomal degradation bafilomycin and chloroquine, reversed the SOCS1-mediated reduction in MET expression, indicating that this process is distinct from Cbl-mediated downmodulation. Accordingly, SOCS1 promoted polyubiquitination of MET via K48-dependent but not K63-mediated ubiquitin chain elongation. Furthermore, siRNA-mediated downmodulation of Cbl did not abolish SOCS1-mediated reduction in MET expression in HCC cells. SOCS1 dependent ubiquitination of endogenous MET receptor occurred rapidly following HGF stimulation in HCC cells, leading to proteasomal degradation of phosphorylated MET receptor. These findings indicate that SOCS1 mediates its tumor suppressor functions, at least partly, by binding to MET and interfering with downstream signaling pathways as well as by promoting the turnover of the activated MET receptor. We propose that loss of this control mechanism due to epigenetic repression of SOCS1 could contribute to oncogenic MET signaling in HCC and other cancers, and that MET inhibitors might be useful in treating these patients. PMID- 25728681 TI - The membrane protein melanoma cell adhesion molecule (MCAM) is a novel tumor marker that stimulates tumorigenesis in hepatocellular carcinoma. AB - Yes-associated protein (YAP) is overexpressed and has an oncogenic role in hepatocellular carcinoma (HCC). However, whether membrane protein can serve not only as a tumor marker that reflects YAP function but also as a therapeutic target that stimulates tumorigenesis in HCC remains unknown. Here we report that the membrane protein melanoma cell adhesion molecule (MCAM) was under positive regulation by YAP and was highly elevated in HCC cells. Within the MCAM promoter, we found the presence of a cAMP Response Element (CRE; -32 to -25 nt), which is conserved among species and is essential for YAP- and CREB-dependent regulation. Moreover, the interaction between CREB and YAP at the CRE site was dependent on PTPIY-WW domain interactions. However, MCAM expression was low and could not be regulated by YAP in breast and colon cancer cells because of the low levels of the acetyltransferase p300. In HCC cells, high levels of p300 facilitated the binding of YAP to the MCAM promoter, which in turn enhanced histone acetylation and polymerase II recruitment through the dissociation of the deacetylase Sirt1. These results suggest that MCAM is an HCC-specific target of YAP. In clinical serum samples, we found that the serum levels of MCAM were highly elevated in patients with HCC compared with healthy controls and with patients with cirrhosis, hepatitis, colon cancer and breast cancer. MCAM levels were shown to be a slightly better indicator than serum alpha-fetoprotein for predicting HCC. We further demonstrated that MCAM is essential for the survival and transformation of HCC. Mechanistically, MCAM induced translation initiation and the transcriptional activities of c-Jun/c-Fos. In addition, AKT activation had an essential role in the MCAM-promoted binding of eukaryotic initiation factor 4E to c-Jun/c-Fos mRNA. In conclusion, we demonstrated that MCAM may be a potential tumor marker and therapeutic target for the diagnosis and treatment of HCC. PMID- 25728683 TI - Potential and limitations of X-Ray micro-computed tomography in arthropod neuroanatomy: a methodological and comparative survey. AB - Classical histology or immunohistochemistry combined with fluorescence or confocal laser scanning microscopy are common techniques in arthropod neuroanatomy, and these methods often require time-consuming and difficult dissections and sample preparations. Moreover, these methods are prone to artifacts due to compression and distortion of tissues, which often result in information loss and especially affect the spatial relationships of the examined parts of the nervous system in their natural anatomical context. Noninvasive approaches such as X-ray micro-computed tomography (micro-CT) can overcome such limitations and have been shown to be a valuable tool for understanding and visualizing internal anatomy and structural complexity. Nevertheless, knowledge about the potential of this method for analyzing the anatomy and organization of nervous systems, especially of taxa with smaller body size (e.g., many arthropods), is limited. This study set out to analyze the brains of selected arthropods with micro-CT, and to compare these results with available histological and immunohistochemical data. Specifically, we explored the influence of different sample preparation procedures. Our study shows that micro CT is highly suitable for analyzing arthropod neuroarchitecture in situ and allows specific neuropils to be distinguished within the brain to extract quantitative data such as neuropil volumes. Moreover, data acquisition is considerably faster compared with many classical histological techniques. Thus, we conclude that micro-CT is highly suitable for targeting neuroanatomy, as it reduces the risk of artifacts and is faster than classical techniques. PMID- 25728682 TI - SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. AB - Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase delta hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair. PMID- 25728685 TI - Quantifying autophagosomes and autolysosomes in cells using imaging flow cytometry. AB - Autophagy dysregulation has been implicated in numerous diseases and many therapeutic agents are known to modulate this pathway. Therefore, the ability to accurately monitor autophagy is critical to understanding its role in the pathogenesis and treatment of many diseases. Recently an imaging flow cytometry method measuring colocalization of microtubule associated protein 1B light chain 3 (LC3) and lysosomal signals via Bright Detail Similarity (BDS) was proposed which enabled evaluation of autophagic processing. However, since BDS only evaluates colocalization of LC3 and lysosomal signals, the number of autophagy organelles was not taken into account. We found that in cells classified as having Low BDS, there was a large degree of variability in accumulation of autophagosomes. Therefore, we developed a new approach wherein BDS was combined with number of LC3+ puncta, which enabled us to distinguish between cells having very few autophagy organelles versus cells with accumulation of autophagosomes or autolysosomes. Using this method, we were able to distinguish and quantify autophagosomes and autolysosomes in breast cancer cells cultured under basal conditions, with inhibition of autophagy using chloroquine, and with induction of autophagy using amino acid starvation. This technique yields additional insight into autophagy processing making it a useful supplement to current techniques. PMID- 25728684 TI - Behaviors of cavefish offer insight into developmental evolution. AB - Many developmental processes have evolved through natural selection, yet in only a few cases do we understand if and how a change of developmental process produces a benefit. For example, many studies in evolutionary biology have investigated the developmental mechanisms that lead to novel structures in an animal, but only a few have addressed if these structures actually benefit the animal at the behavioral level of prey hunting and mating. As such, this review discusses an animal's behavior as the integrated functional output of its evolved morphological and physiological traits. Specifically, we focus on recent findings about the blind Mexican cavefish, Astyanax mexicanus, for which clear relationships exist between its physical traits and ecosystem. This species includes two morphotypes: an eyed surface dweller versus many conspecific types of blind cave dwellers, some of which evolved independently; all of the blind subtypes derived from eyed surface dwellers. The blind cavefish evolved under clear selection pressures: food is sparse and darkness is perpetual. Simulating the major aspects of a cave ecosystem in the laboratory is relatively easy, so we can use this species to begin resolving the relationships between evolved traits and selection pressures-relationships which are more complex for other animals models. This review discusses the recent advances in cavefish research that have helped us establish some key relationships between morphological evolution and environmental shifts. PMID- 25728686 TI - Blue-light dependent reactive oxygen species formation by Arabidopsis cryptochrome may define a novel evolutionarily conserved signaling mechanism. AB - Cryptochromes are widespread blue-light absorbing flavoproteins with important signaling roles. In plants they mediate de-etiolation, developmental and stress responses resulting from interaction with downstream signaling partners such as transcription factors and components of the proteasome. Recently, it has been shown that Arabidopsis cry1 activation by blue light also results in direct enzymatic conversion of molecular oxygen (O2 ) to reactive oxygen species (ROS) and hydrogen peroxide (H2 O2 ) in vitro. Here we explored whether direct enzymatic synthesis of ROS by Arabidopsis cry1 can play a physiological role in vivo. ROS formation resulting from cry1 expression was measured by fluorescence assay in insect cell cultures and in Arabidopsis protoplasts from cryptochrome mutant seedlings. Cell death was determined by colorimetric assay. We found that ROS formation results from cry1 activation and induces cell death in insect cell cultures. In plant protoplasts, cryptochrome activation results in rapid increase in ROS formation and cell death. We conclude that ROS formation by cryptochromes may indeed be of physiological relevance and could represent a novel paradigm for cryptochrome signaling. PMID- 25728687 TI - Skin cancer screening in the medically underserved population: A unique opportunity for APNs to make a difference. AB - PURPOSE: To implement and evaluate the feasibility of an annual skin cancer screening program for the medically underserved at a free clinic in Marion, Indiana. DATA SOURCES: Clinical initiative with descriptive analysis of results. IRB approval was obtained and the project was found to be exempted. CONCLUSIONS: The participation rate of 65% supported the feasibility of the skin screening program in a free clinic. The skin screening program allowed for detection of 17 worrisome lesions and all of these patients were referred to either the small procedure clinic, general surgeon, or dermatologist for definitive treatment. IMPLICATIONS FOR PRACTICE: The project affirmed that clients in this setting are interested in total body skin exams and will participate in the screening program. Furthermore, there were a significant number of worrisome lesions discovered, which underscores the importance of this screening exam and the need for healthcare providers to either perform or refer patients for skin cancer screening on a regular basis. This area of screening is a unique opportunity for advanced practice nurses to make a difference in the medically underserved population who often lack skin cancer screening. PMID- 25728688 TI - Internet-based guided self-help for parents of children on cancer treatment: a randomized controlled trial. AB - OBJECTIVE: The aim of the study was to investigate the feasibility and preliminary efficacy of an Internet-based guided self-help intervention for posttraumatic stress symptoms (PTSS) and related symptoms in parents of children on cancer treatment. METHODS: Parents of children on cancer treatment, who fulfilled the modified symptom criteria on the PTSD Checklist, were randomly allocated to the intervention or to a wait-list control condition. The intervention group accessed a 10-week guided self-help program via the Internet based on principles from cognitve behavior therapy. The primary outcome PTSS and the secondary outcomes depression and anxiety were assessed by self-report preintervention and postintervention. RESULTS: Seven hundred forty-seven parents were approached and informed about the study, 92 were assessed for eligibility, and 58 were included and randomized to the intervention (n = 31) or wait list (n = 27). Eightteen participants completed the intervention. Intention-to-treat analyses indicated a significant effect of the intervention on PTSS with a large between-group effect size at postassessment (Cohen's d = 0.88). The intervention group reported reductions in PTSS with a large within-group effect size (d = 1.62) compared with a minimal reduction in the wait-list group (d = 0.09). There was a significant intervention effect on depression and anxiety and reductions in the intervention group with large within-group effect sizes (d = 0.85-1.09). CONCLUSIONS: Findings indicate a low enrollment rate and considerable attrition but also that Internet-based guided self-help shows promise for parents of children on cancer treatment who report a high level of PTSS and would like to take part in an Internet-based intervention. PMID- 25728689 TI - Does breastfeeding behavior run in families? Evidence from twins, their sisters and their mothers in the Netherlands. AB - The aim of the present article was to study the prevalence and the heritability of the initiation of breastfeeding in the Netherlands. The study was carried out in 5,581 participants from the Netherlands Twin Register, and included female twins, their sisters and mothers. All of the participants were born between 1911 and 1991. Breastfeeding was self-reported by the participants, and its prevalence was estimated conditional on birth cohort (born before 1955, 1955-1964, 1965 1974, 1975, or later). To estimate the heritability, we conducted extended twin family modeling using the SEM package OpenMx in R. Mothers of twins had lower prevalence to initiate breastfeeding and the prevalence of initiation of breastfeeding increased with birth cohort: among mothers of twins 66% in the oldest (pre-1955) to 74% in the youngest (post-1974) and among mothers, who were twins themselves or sisters of twins, 79% in the oldest (pre-1955) to 85% in the youngest (post-1974). When accounting for prevalence differences between mothers of twins and other women, heritability of initiation of breastfeeding was 70%. However, the familial resemblance for sister and mother-daughter pairs was clearly lower than for DZ twin pairs, but as the number of non-twin sisters was relatively low, this observation did not lead to a significant contribution of a special shared twin environment. PMID- 25728690 TI - Mechanochromic photonic-crystal fibers based on continuous sheets of aligned carbon nanotubes. AB - A new family of mechanochromic photonic-crystal fibers exhibits tunable structural colors under stretching. This novel mechanochromic fiber is prepared by depositing polymer microspheres onto a continuous aligned-carbon-nanotube sheet that has been wound on an elastic poly(dimethylsiloxane) fiber, followed by further embedding in poly(dimethylsiloxane). The color of the fiber can be tuned by varying the size and the center-to-center distance of the polymer spheres. It further experiences reversible and rapid multicolor changes during the stretch and release processes, for example, between red, green, and blue. Both the high sensitivity and stability were maintained after 1000 deformation cycles. These elastic photonic-crystal fibers were woven into patterns and smart fabrics for various display and sensing applications. PMID- 25728691 TI - Neocortical somatostatin neurons reversibly silence excitatory transmission via GABAb receptors. AB - BACKGROUND: Understanding the dynamic range for excitatory transmission is a critical component of building a functional circuit diagram for the mammalian brain. Excitatory synaptic transmission is typically studied under optimized conditions, when background activity in the network is low. The range of synaptic function in the presence of inhibitory and excitatory activity within the neocortical circuit is unknown. RESULTS: Paired-cell recordings from pyramidal neurons in acute brain slices of mouse somatosensory cortex show that excitatory synaptic transmission is markedly suppressed during spontaneous network activity: EPSP amplitudes are 2-fold smaller and failure rates are greater than 50%. This suppression is mediated by tonic activation of presynaptic GABAb receptors gated by the spontaneous activity of somatostatin-expressing (Sst) interneurons. Optogenetic suppression of Sst neuron firing was sufficient to enhance EPSP amplitude and reduce failure rates, effects that were fully reversible and occluded by GABAb antagonists. CONCLUSIONS: These data indicate that Sst interneurons can rapidly and reversibly silence excitatory synaptic connections through the regulation of presynaptic release. This is an unanticipated role for Sst interneurons, which have been assigned a role only in fast GABAa-mediated inhibition. Because Sst interneuron activity has been shown to be regulated by sensory and motor input, these results suggest a mechanism by which functional connectivity and synaptic plasticity could be gated in a state-dependent manner. PMID- 25728692 TI - Merging of long-term memories in an insect. AB - Research on comparative cognition has largely focused on successes and failures of animals to solve certain cognitive tasks, but in humans, memory errors can be more complex than simple failures to retrieve information [1, 2]. The existence of various types of "false memories," in which individuals remember events that they have never actually encountered, are now well established in humans [3, 4]. We hypothesize that such systematic memory errors may be widespread in animals whose natural lifestyle involves the processing and recollection of memories for multiple stimuli [5]. We predict that memory traces for various stimuli may "merge," such that features acquired in distinct bouts of training are combined in an animal's mind, so that stimuli that have never been viewed before, but are a combination of the features presented in training, may be chosen during recall. We tested this using bumblebees, Bombus terrestris. When individuals were first trained to a solid single-colored stimulus followed by a black and white (b/w) patterned stimulus, a subsequent preference for the last entrained stimulus was found in both short-term- and long-term-memory tests. However, when bees were first trained to b/w-patterned stimuli followed by solid single-colored stimuli and were tested in long-term-memory tests 1 or 3 days later, they only initially preferred the most recently rewarded stimulus, and then switched their preference to stimuli that combined features from the previous color and pattern stimuli. The observed merging of long-term memories is thus similar to the memory conjunction error found in humans [6]. PMID- 25728693 TI - Insight reconfigures hippocampal-prefrontal memories. AB - Our memories are remarkably dynamic and allow us to reinterpret the past once new information comes to light. Gaining novel insights can lead to mental reorganization of previously unrelated events, thus linking them into narratives. The hippocampus and medial prefrontal cortex (mPFC) support integration of partially overlapping events, but the neural mechanisms underlying the reorganization of memories for the formation of coherent narratives remain elusive. Here, we combine fMRI with The Sims 3 videos of life-like animated events, which could either be integrated into narratives or not. We show that insight triggers the emergence of de novo mnemonic representations of the narratives and is associated with increased neural similarity between linked event representations in the posterior hippocampus, mPFC, and autobiographical memory network. Simultaneously, events irrelevant to the newly established memory of the narrative were pruned out. This process was accompanied by increased neural dissimilarity between non-linked event representations in the posterior hippocampus and mPFC and was additionally signaled by a mismatch response in the anterior hippocampus. Our results demonstrate that insight leads to neural reconfiguration of representational networks within a memory space and have implications for knowledge acquisition in educational settings. PMID- 25728695 TI - Spatiotemporal neural pattern similarity supports episodic memory. AB - Formal computational models of human memory posit a central role of feature representations in episodic memory encoding and retrieval [1-4]. Correspondingly, fMRI studies have found that, in addition to activity level [5, 6], the neural activation pattern similarity across repetitions (i.e., self-similarity) was greater for subsequently remembered than forgotten items [7-9]. This self similarity has been suggested to reflect pattern reinstatement due to study-phase retrieval [7, 10, 11]. However, the low temporal resolution of fMRI measures could determine neither the temporal precision of study-phase reinstatement nor the processing stage at which the reinstatement supported subsequent memory [12]. Meanwhile, although self-similarity has been shown to correlate with the activity level in the left lateral prefrontal cortex (LPFC) [10, 13], a causal link between left LPFC function and pattern similarity remains to be established. Combining transcranial direct current stimulation (tDCS) and EEG, we found that greater spatiotemporal pattern similarity (STPS) across repetitions of the same item (i.e., self-STPS) during encoding predicted better subsequent memory. The self-STPS located in the right frontal electrodes occurred approximately 500 ms after stimulus onset, reflected item-specific encoding, and contributed to memory above and beyond the effects of ERP amplitude and global pattern similarity (i.e., similarity to all other items in memory space). Anodal stimulation over the left LPFC specifically enhanced memory performance and item-specific STPS in the right frontal electrodes. These results support a causal role of LPFC in enhancing STPS and memory and contribute to a mechanistic understanding of memory formation. PMID- 25728694 TI - Sweet taste and nutrient value subdivide rewarding dopaminergic neurons in Drosophila. AB - Dopaminergic neurons provide reward learning signals in mammals and insects [1 4]. Recent work in Drosophila has demonstrated that water-reinforcing dopaminergic neurons are different to those for nutritious sugars [5]. Here, we tested whether the sweet taste and nutrient properties of sugar reinforcement further subdivide the fly reward system. We found that dopaminergic neurons expressing the OAMB octopamine receptor [6] specifically convey the short-term reinforcing effects of sweet taste [4]. These dopaminergic neurons project to the beta'2 and gamma4 regions of the mushroom body lobes. In contrast, nutrient dependent long-term memory requires different dopaminergic neurons that project to the gamma5b regions, and it can be artificially reinforced by those projecting to the beta lobe and adjacent alpha1 region. Surprisingly, whereas artificial implantation and expression of short-term memory occur in satiated flies, formation and expression of artificial long-term memory require flies to be hungry. These studies suggest that short-term and long-term sugar memories have different physiological constraints. They also demonstrate further functional heterogeneity within the rewarding dopaminergic neuron population. PMID- 25728696 TI - Zyxin antagonizes the FERM protein expanded to couple F-actin and Yorkie dependent organ growth. AB - BACKGROUND: Coordinated multicellular growth during development is achieved by the sensing of spatial and nutritional boundaries. The conserved Hippo (Hpo) signaling pathway has been proposed to restrict tissue growth by perceiving mechanical constraints through actin cytoskeleton networks. The actin-associated LIM proteins Zyxin (Zyx) and Ajuba (Jub) have been linked to the control of tissue growth via regulation of Hpo signaling, but the study of Zyx has been hampered by a lack of genetic tools. RESULTS: We generated a zyx mutant in Drosophila using TALEN endonucleases and used this to show that Zyx antagonizes the FERM-domain protein Expanded (Ex) to control tissue growth, eye differentiation, and F-actin accumulation. Zyx membrane targeting promotes the interaction between the transcriptional co-activator Yorkie (Yki) and the transcription factor Scalloped (Sd), leading to activation of Yki target gene expression and promoting tissue growth. Finally, we show that Zyx's growth promoting function is dependent on its interaction with the actin-associated protein Enabled (Ena) via a conserved LPPPP motif and is antagonized by Capping Protein (CP). CONCLUSIONS: Our results show that Zyx is a functional antagonist of Ex in growth control and establish a link between actin filament polymerization and Yki activity. PMID- 25728697 TI - Functional gastrointestinal disorders in 35,447 adults and their association with body mass index. AB - BACKGROUND: Functional gastrointestinal disorders' (FGIDs) associations with body mass index (BMI) have not been thoroughly investigated in the general population. AIM: To investigate the overlap between functional dyspepsia (FDy), irritable bowel syndrome (IBS), functional constipation (FC) and functional diarrhoea (FDh) and the relationship between BMI and those diagnoses in a large French adult population. METHODS: Subjects participating in the Nutrinet-Sante cohort study completed a questionnaire based on Rome III criteria. Anthropometrics, socio demographical and lifestyle data were collected via self-administered questionnaires. Associations between BMI and FGIDs were investigated with multivariate logistic regression. RESULTS: A total of 35 447 subjects were included in the analysis. Among subjects with FGIDs, 10.4% presented more than one disorder. [FDy coexisted with IBS (23.6%) and FC (15.1%)]. Associations between BMI and FDy differed according to sex. In females, higher odds were observed for underweight and obesity subgroups (OR = 1.26 (95% CI: 0.99-1.59), OR = 1.35 (1.08-1.69), OR = 1.20 (0.81-1.77), OR = 1.47 (0.89-2.42) for underweight, class I, II and III obesity respectively compared with normal BMI), forming a U shaped relationship confirmed with nonlinear model (P < 0.001). In females, FDh was associated with BMI [OR = 1.05 (1.03-1.07), P < 0.001]. In males, a negative association between BMI and IBS was observed [OR = 0.97 (0.94-0.99), P=0.04]. Other associations were not significant. CONCLUSIONS: Our study showed an important overlap in FGIDs, supporting the contention of common pathophysiological mechanisms. Relationships between BMI and FGIDs appeared to be sex-dependent. Interaction by sex in the association between BMI and FGIDs should therefore be further explored. PMID- 25728698 TI - Direct and indirect healthcare resource utilization and costs associated with ulcerative colitis in a privately-insured employed population in the US. AB - OBJECTIVE: To assess direct and indirect healthcare resource utilization and costs of privately insured US employees with ulcerative colitis (UC) from a societal perspective. RESEARCH DESIGN AND METHODS: Employees aged 18-64 with >= 2 UC diagnoses and no more than one diagnosis of Crohn's disease (CD) were identified from a large, de-identified, private insurance US claims database from January 1, 2005 through March 31, 2013. Patients with UC were matched 1:1 to non IBD controls based on demographics and index date (a randomly selected UC diagnosis). All patients were required to have continuous eligibility for >= 1 year before (baseline period) and after (study period) the index date. Descriptive analyses compared baseline characteristics and study period outcomes. Multivariate cost analysis adjusted for baseline comorbidities. Sub-group analyses compared patients with moderate-to-severe UC with matched controls. MAIN OUTCOME MEASURES: Costs (2013 US dollars) were measured from a societal perspective, which included direct (patient and payer costs) and indirect (lost wages because of time away from work) costs. RESULTS: Patients with UC (n = 4314; mean age = 45.1 years, 63.6% male) had significantly higher baseline comorbidity rates compared with controls. In the study period, significantly more patients with UC (p < 0.0001) had higher hospitalization rates (16.9% vs 6.2%), emergency department visits (31.1% vs 22.0%), prescription drug use (95.3% vs 72.0%), and work loss (100% vs 81.4%). Patients with UC also had significantly higher adjusted total direct ($15,548 vs $4812) and indirect costs ($4125 vs $1961). Patients with moderate-to-severe UC (n = 1728) had significantly (p < 0.0001) higher hospitalization rates (26.5% vs 6.2%) and adjusted total direct ($23,085 vs $4932) and indirect costs ($5666 vs $1960). CONCLUSIONS: Patients with UC had higher resource utilization and direct and indirect costs compared with matched controls. The excess burden was greatest in patients with moderate-to-severe UC. PMID- 25728699 TI - The impact of structured plaque control for patients with gingival manifestations of oral lichen planus: a randomized controlled study. AB - AIM: To evaluate the impact of a structured plaque control intervention on clinical and patient-centred outcomes for patients with gingival manifestations of oral lichen planus. MATERIALS AND METHODS: Eighty-two patients were recruited into a 20-week randomized controlled trial. The intervention was structured plaque control comprising powered tooth brushing and inter-dental cleaning advice. Control subjects continued with their normal dental plaque control regimen. The primary outcome measure was the oral health impact profile (OHIP) with secondary outcomes of pain, plaque index, mucosal disease score and cost effectiveness. RESULTS: Overall, the intervention patients showed statistically significant improvements in OHIP sum ordinal and OHIP dichotomous scores compared with control. There were improvements in the functional limitation, psychological discomfort and physical disability domains at 4- and 20-weeks and in the psychological disability domain at 20-weeks. The intervention was successful in reducing plaque compared to control (p < 0.001) and improvements were observed using the mucosal disease indices at the 4- and 20-week follow-ups (p < 0.001). CONCLUSION: A structured plaque control intervention was effective in improving the oral health-related quality of life and clinically observed gingival lesions. This study provides evidence to include intensive plaque control within patients' initial and on-going management. PMID- 25728701 TI - Triterpene hydrocarbon production engineered into a metabolically versatile host- Rhodobacter capsulatus. AB - Triterpene hydrocarbon biosynthesis of the ancient algae Botryococcus braunii was installed into Rhodobacter capsulatus to explore the production of C30 hydrocarbon in a host capable of diverse growth habits-utilizing carbohydrate, sunlight or hydrogen (with CO2 fixation) as alternative energy feedstocks. Engineering an enhanced MEP pathway was also used to augment triterpene accumulation. Despite dramatically different sources of carbon and reducing power, nearly the same level of botryococcene or squalene (~5 mg oil/g-dry-weight [gDW]) was achieved in small-scale aerobic heterotrophic, anaerobic photoheterotrophic, and aerobic chemoautotrophic growth conditions. A glucose fed batch bioreactor reached 40 mg botryococcene/L (~12 mg/gDW), while autotrophic bioreactor performance with CO2 , H2 , and O2 reached 110 mg/L (16.7 mg/gDW) during batch and 60 mg/L (23 mg/gDW) during continuous operation at a dilution rate corresponding to about 10% of MU(max). Batch and continuous autotrophic specific productivity was found to reach 0.5 and 0.32 mg triterpene/g DW/h, comparable to prior reports for terpene production driven by heterotrophic growth conditions. This demonstrates the feasibility of alternative feedstocks and trophic modes to provide comparable routes to biochemicals that do not rely on sugar. PMID- 25728702 TI - Expression of CD105 and CD34 receptors controls BMP-induced in vitro mineralization of mouse adipose-derived stem cells but does not predict their in vivo bone-forming potential. AB - Adipose-derived stem cells (ADSCs) can be excellent alternative to bone marrow derived stem cells for enhancing fracture repair since ADSCs can be isolated comparatively in large numbers from discarded lipoaspirates. However, osteogenic potential of ADSCs in vivo is very controversial. We hypothesized that adipose derived stem cells (ADSCs) that respond maximally to bone morphogenetic proteins (BMPs) in vitro would possess maximum bone-forming potential. Four purified populations of mouse ADSCs: CD105(+) CD34(+), CD105(-) CD34(-), CD105(+) CD34(-) and CD105(-) CD34(+) were obtained using fluorescence-activated cell sorting (FACS) and their BMP-responsiveness was determined in vitro. CD105(+) CD34(-) population showed the strongest response to BMPs in terms of robust increase in mineralization. Expression of CD105 correlated with high BMP-responsive phenotype and larger cell size while expression of CD34 correlated with low BMP-responsive phenotype and smaller cell size. CD105(+) CD34(-) population displayed higher gene expression of Alk1 or Alk6 receptors in comparison with other populations. However, CD105(+) CD34(-) ADSCs failed to induce ectopic bone formation in vivo after they were transplanted into syngeneic mice, indicating that in vitro BMP responsiveness is not a good indicator to predict in vivo bone forming potential of ADSCs. Therefore greater precautions should be executed during selection of competent ADSCs for bone repair. PMID- 25728703 TI - The relevance of intestinal dysbiosis in liver transplant candidates. AB - BACKGROUND: The gut microbial ecosystem plays an important role in the pathogenesis of liver diseases. However, the association of microbial community structure with the severity of liver dysfunction is not completely understood. METHODS: Fecal microflora was assessed in 40 patients with liver cirrhosis listed for primary liver transplantation (LT). Independent associations between fecal microbial counts and serum bilirubin, serum creatinine, international normalized ratio (INR), and the Model for End-stage Liver Disease (MELD) score were established in multiple linear regression models. RESULTS: Bifidobacterium (standardized regression coefficient [sbeta] = -0.549; P < 0.001), Enterococcus (sbeta = 0.369; P = 0.004), and yeast (sbeta = 0.315; P = 0.018) numbers were independently associated with serum bilirubin, while Escherichia coli counts (sbeta = 0.318; P = 0.046) correlated with INR, and Bifidobacterium counts (sbeta = 0.410; P = 0.009) with serum creatinine. Only Bifidobacterium (sbeta = -0.468; P = 0.003) and Enterococcus (sbeta = 0.331; P = 0.029) counts were independent predictors of the MELD score. Bifidobacterium/Enterococcus ratio, proposed as a measure of pre-LT gut dysbiosis, was significantly related to the MELD score following the adjustment for the absolute Bifidobacterium (sbeta = -0.333; P = 0.029) and Enterococcus (sbeta = -0.966; P = 0.003) numbers. This pre-transplant dysbiosis ratio (PTDR) was significantly correlated with Enterococcus (R = 0.897; P < 0.001) but not with Bifidobacterium (R = 0.098; P = 0.546) counts. Among the other components of gut microflora, only hydrogen peroxide (H2 O2 ) producing Lactobacillus strains significantly influenced Enterococcus counts (sbeta = 0.349; P = 0.028) and PTDR (sbeta = -0.318; P = 0.046). CONCLUSION: While the abundance of both Bifidobacterium and Enterococcus is related to liver dysfunction, the size of the Enterococcus population seems to be the most important determinant of pre-LT gut dysbiosis in cirrhotic patients. The H2 O2 producing Lactobacillus strains potentially ameliorate this dysbiotic state. PMID- 25728704 TI - Continued progression of lumbar disc degeneration in postmenopausal women. PMID- 25728705 TI - Apps and eating disorders: A systematic clinical appraisal. AB - OBJECTIVE: Smartphone applications (apps) are proliferating and health-related apps are particularly popular. The aim of this study was to identify, characterize, and evaluate the clinical utility of apps designed either for people with eating disorders or for eating disorder professionals. METHOD: A search of the major app stores identified 805 potentially relevant apps, of which 39 were primarily designed for people with eating disorders and five for professionals. RESULTS: The apps for people with eating disorders had four main functions. Most common was the provision of advice, the quality of which ranged from sound to potentially harmful. Five apps included self-assessment tools but only two used methods that would generally be viewed as reliable. Four apps had the self-monitoring of eating habits as a major feature. Entering information into these apps could be accomplished with varying degrees of ease, but viewing it was more difficult. One app allowed the transfer of information between patients and clinicians. DISCUSSION: The enthusiasm for apps outstrips the evidence supporting their use. Given their popularity, it is suggested that clinicians evaluate app use as part of routine assessment. The clinical utility of the existing apps is not clear. Some are capable of tracking key features over time, but none has the functions required for analytic self-monitoring as in cognitive behavioral treatments. The full potential of apps has yet to be realized. Specialized apps could be designed to augment various forms of treatment, and there is the possibility that they could deliver an entire personalized intervention. PMID- 25728706 TI - PPARbeta/delta ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation. AB - We studied whether PPARbeta/delta deficiency modifies the effects of high fructose intake (30% fructose in drinking water) on glucose tolerance and adipose tissue dysfunction, focusing on the CD36-dependent pathway that enhances adipose tissue inflammation and impairs insulin signaling. Fructose intake for 8 weeks significantly increased body and liver weight, and hepatic triglyceride accumulation in PPARbeta/delta-deficient mice but not in wild-type mice. Feeding PPARbeta/delta-deficient mice with fructose exacerbated glucose intolerance and led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the JNK pathway in white adipose tissue compared to those of water-fed PPARbeta/delta-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPARbeta/delta activator GW501516. Interestingly, the levels of the nuclear factor E2-related factor 2 (Nrf2), a transcription factor reported to up-regulate Cd36 expression and to impair insulin signaling, were increased in fructose-exposed adipocytes whereas co-incubation with GW501516 abolished this increase. In agreement with Nrf2 playing a role in the fructose-induced CD36 protein level increases, the Nrf2 inhibitor trigonelline prevented the increase and the reduction in insulin-stimulated AKT phosphorylation caused by fructose in adipocytes. Protein levels of the well-known Nrf2 target gene NAD(P)H: quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPARbeta/delta-null mice, suggesting that PPARbeta/delta deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPARbeta/delta-deficient mice. These findings indicate that the combination of high fructose intake and PPARbeta/delta deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue. PMID- 25728707 TI - SNP rs1049430 in the 3'-UTR of SH3GL2 regulates its expression: Clinical and prognostic implications in head and neck squamous cell carcinoma. AB - Single nucleotide polymorphisms (SNPs) in the 3'-UTR region are emerging cis regulatory factors associated with the occurrences of several human diseases. SH3GL2, which is located at chromosome 9p21-22, is associated with hyperplastic/mildly dysplastic lesions of the head and neck and has a long 3'-UTR with multiple SNPs. The aim of the present study was to determine the susceptible allele(s) in the 3'-UTR SNPs of SH3GL2 in head and neck squamous cell carcinoma (HNSCC). First, we screened the genotypes of all SNPs located in the 3'-UTR of SH3GL2 in 110 controls and 147 cases in Indian populations by sequencing. A SNP (rs1049430:>G/T) that showed only heterozygosity was further confirmed by genotyping with an Illumina GoldenGate platform in 530 controls and 764 cases. Genotype-specific survival analysis of the HNSCC patients was performed. In addition, genotype-specific mRNA stability, isoform expression and protein expression were analyzed. SNP rs1049430 was not associated with disease occurrence, but it was associated with poor patient outcome. The G allele was associated with decreased SH3GL2 mRNA stability, differential splicing and low protein expression. Thus, our data demonstrate that the presence of the susceptible G allele in SNP rs1049430 is associated with the inactivation of SH3GL2 and could be used as a prognostic marker of HNSCC. PMID- 25728708 TI - Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK. AB - No effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma. PMID- 25728709 TI - The role of MoS2 as an interfacial layer in graphene/silicon solar cells. AB - The role of MoS2 as an effective interfacial layer in graphene/silicon solar cells is systematically investigated by varying MoS2 film annealing temperature and thickness. It is found that the power conversion efficiency (PCE) is increased by ~100% from ~2.3% to ~4.4% with 80 degrees C annealed MoS2 film whereas it drops significantly to ~0.6% with 200 degrees C annealed MoS2 film. The results are well explained based on the device energy band diagram. That is, the incorporation of MoS2(80) films leads to the formation of type II structure, facilitating hole transport; while valence band mismatch is formed with MoS2(200) films due to the increase in the work function of MoS2. Besides, the PCE increases gradually with decreasing MoS2 film thickness, and "saturates" at about 2 nm. The PCE can be further enhanced to ~6.6% with the aid of silicon surface passivation. Our work demonstrates that MoS2 is an excellent interfacial layer to improve the PCE with low-temperature annealing (80 degrees C in air), which may be helpful in developing efficient and low-cost G/Si solar cells. PMID- 25728710 TI - Somatic thrombopoietin (THPO) gene mutations in childhood myeloid leukemias. AB - We report, for the first time, a non-syndromic infant with a reversible myeloproliferative disease that harbors a germline hereditary thrombopoietin (THPO) gene mutation, a condition that is known to induce familial thrombocytosis at increasing age. In order to investigate whether somatic THPO gene mutations play a role in sporadic pediatric myeloproliferative diseases, we performed a mutation screening of a large representative cohort of pediatric acute myeloid leukemia, myeloid leukemia of Down syndrome, and juvenile myelomonocytic leukemia samples and show that gain-of-function THPO mutations are extremely rare in sporadic pediatric myeloproliferative diseases. PMID- 25728711 TI - Interfacing materials science and biology for drug carrier design. AB - Over the last ten years, there has been considerable research interest in the development of polymeric carriers for biomedicine. Such delivery systems have the potential to significantly reduce side effects and increase the bioavailability of poorly soluble therapeutics. The design of carriers has relied on harnessing specific variations in biological conditions, such as pH or redox potential, and more recently, by incorporating specific peptide cleavage sites for enzymatic hydrolysis. Although much progress has been made in this field, the specificity of polymeric carriers is still limited when compared with their biological counterparts. To synthesize the next generation of carriers, it is important to consider the biological rationale for materials design. This requires a detailed understanding of the cellular microenvironments and how these can be harnessed for specific applications. In this review, several important physiological cues in the cellular microenvironments are outlined, with a focus on changes in pH, redox potential, and the types of enzymes present in specific regions. Furthermore, recent studies that use such biologically inspired triggers to design polymeric carriers are highlighted, focusing on applications in the field of therapeutic delivery. PMID- 25728712 TI - Mutagenicity of cigarette butt waste in the bacterial reverse mutation assay: The protective effects of beta-caryophyllene and beta-caryophyllene oxide. AB - Cigarette filters pose a serious litter and toxic waste disposal problem, because of their not biodegradability and to the leaching of toxins in the environment. Therefore, cigarette butts need to be manipulated as special waste, with potential risks to human health and environment. In the present study, the genotoxic potential of a methanol extract from commonly discharged cigarette butts (CBE) was evaluated in the bacterial reverse mutation assay on Salmonella typhimurium TA98 and TA100 and Escherichia coli WP2uvrA strains, both in the absence and presence of the S9 exogenous metabolic activator. Furthermore, the ability of the natural sesquiterpenes beta-caryophyllene (CRY) and beta caryophyllene oxide (CRYO) to inhibit the mutagenicity of CBE was studied as a possible preventive strategy. In order to identify the potential antimutagenic mechanisms, three different protocols (pretreatment, cotreatment, and posttreatment) were applied. CBE showed to increase the number of revertant colonies in all the strains tested in presence of S9, so resulting mutagenic. In the antimutagenicity assay, both CRY and CRYO significantly reduced the revertant colonies induced by CBE, although with different potency and specificity. For both sesquiterpenes, the antimutagenicity was strong in all experimental conditions, except for the cotreatment of CRY with CBE in WP2uvrA, which produced a moderate inhibition. Both desmutagenic and bioantimutagenic mechanisms seem to be involved in the antimutagenicity of the test substances. Taking into account the potential genotoxicity of cigarette butts, CRY and CRYO appear as possible further candidates as environmental decontaminants against this hazardous waste. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1319-1328, 2016. PMID- 25728713 TI - Remission of CVB3-induced myocarditis with Astragaloside IV treatment requires A20 (TNFAIP3) up-regulation. AB - Viral myocarditis (VMC) most prevalently caused by coxsackievirus B3 (CVB3) infection is characterized by severe cardiac inflammation. Therapeutic options for the disease are still limited. Astragaloside IV (AST-IV), a purified small molecular saponin (C41 H68 O14 , MW 784), is the main active component of Chinese medical herb Astragalus which has been empirically prescribed for the treatment of heart dysfunction for centuries. In this study, we investigated the effect of AST-IV on CVB3-induced myocarditis and explored its possible mechanism involved. The results showed that AST-IV administration alleviated the severity of myocarditis and attenuated cardiac inflammation, which was mediated by inhibition of nuclear factor-kappaB (NF-kappaB) signalling. Importantly, we further identified that the inhibitory effect of AST-IV on NF-kappaB signalling was through increasing A20 (TNFAIP3) expression. Moreover, we validated that A20 was critical for the therapeutic efficacy of AST-IV on CVB3-induced myocarditis. Finally, we revealed that AST-IV enhanced A20 expression at post-transcriptional level by stabilization of mRNA. Our findings uncover a previously unknown mechanism for AST-IV in the treatment of VMC because of modulating inflammatory response via increasing A20 expression, which provide a potential target for screening new drugs and are helpful for optimization of the therapeutic strategies for VMC. PMID- 25728714 TI - Suggestion of response evaluation criteria in patients with ocular adnexal mucosa associated lymphoid tissue lymphoma (OAML). AB - Ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) has been recognized as most common primary orbital malignancy. However, little was known about the response criteria for OAML. Our aim was to suggest response criteria for nonconjunctival OAML; the response evaluation of which using the conventional response criteria is inappropriate. A retrospective chart review of 34 eyes from 30 patients diagnosed with nonconjunctival OAML was conducted, focusing on the change in tumor size based on linear bi-dimensional and three-dimensional methods in magnetic resonance imaging (MRI) of the orbit. The maximum tumor response period of each case was investigated, and the expected optimal response period was calculated using regression analysis. In 30 evaluable patients, the median time taken for the maximum tumor response was 6 months (range, 3-18). More than 75 % of patients attained maximal tumor response in 6 months after initial therapy for follow-up period, the median value of which was 30 months (range, 15 77). Based on the regression analysis, it took 4.7 months for the maximum diameter (2r) of tumor to decrease by 50 % of initial lesion size. We cautiously suggest that optimal response could be defined as 50 % reduction of the maximum diameter in 6 months since the treatment was initiated, and that only observation without additional therapy is enough for nonconjunctival OAML, if optimal response is achieved. PMID- 25728715 TI - Persistent vertigo and dizziness after mild traumatic brain injury. AB - Vertigo, dizziness, and disequilibrium are common symptoms following concussion or mild traumatic brain injury (mTBI). Dizziness and vertigo may be the result of trauma to the peripheral vestibular system or the central nervous system, or, in some cases, may be due to anxiety, depression, or posttraumatic stress disorder; these mechanisms are not mutually exclusive. While most peripheral vestibular disorders can be identified by testing and examination, those without inner-ear causes that have persisting complaints of dizziness and motion sickness are more difficult to understand and to manage. Some of these patients exhibit features compatible with vestibular migraine and may be treated successfully with migraine preventative medications. This paper reviews the nonotogenic causes of persisting dizziness, the possible mechanisms, and the pathophysiology, as a framework for patient management and for future research. PMID- 25728716 TI - Using the GORE(r) Septal Occluder (GSO) in challenging patent foramen ovale (PFO) anatomies. AB - OBJECTIVES: We assessed efficacy and safety of the Gore((r)) Septal Occluder (GSO) for patent foramen ovale (PFO) closure focusing on patients with challenging septal anatomies. BACKGROUND: In times of controversial discussion whether percutaneous PFO closure is superior to medical therapy for the prevention of recurrent embolic events after cryptogenic stroke, patient selection should mainly focus on individuals with an increased likelihood that the ischaemic event is related to the PFO. In this context, specific septal anatomies-such as the presence of an atrial septal aneurysm as well as long PFO tunnel anatomy-have been associated with a higher rate of cerebrovascular accidents. METHODS: The GSO was used for PFO closure in 41 patients presenting with either atrial septal aneurysm (ASA; 27/41; 65.9%) or long PFO tunnel (> 10 mm; 32/41; 78%). Seven of these patients even presented with a tunnel length >= 20 mm (7/41; 17.1%). Eighteen patients had both, long-tunnel anatomy and ASA (18/41; 43.9%). RESULTS: The GSO was successfully implanted in all cases. No procedural complications occurred and all patients were discharged the day after the procedure. Short-term follow-up, including TEE examination, in all patients was performed 37.6 +/- 9.0 days after the procedure. Mid-term follow-up was performed after 192.7 +/- 45.3 days. Later complications occurred in 7.3% (2 new onset atrial fibrillation, 1 device thrombus). Only 3 patients (7.3%) had more than trace residual shunts at 6-weeks follow-up. At 6-months follow-up, the complete closure rate was 95.1% (39/41). CONCLUSIONS: The Gore((r)) Septal Occluder is an efficient device for patent foramen ovale closure in challenging anatomies, including long-tunnel PFOs and atrial septal aneurysms. PMID- 25728717 TI - Latent prostate cancer in Japanese men who die unnatural deaths: A forensic autopsy study. AB - BACKGROUND: An accurate natural history of prostate cancer (PC) can be obtained from forensic autopsies of individuals who had performed their normal daily activities immediately before death and had not undergone long-term medical interventions. A retrospective analysis of such individuals was performed to understand the features of latent PC in Japan. METHODS: The findings of forensic autopsies performed at Dokkyo Medical University from August 2002 to July 2005 on men without severely destroyed or severely decomposed tissues were collected. Two cross sections, at the base and apex of the prostate, were examined histopathologically. Data collected included basic history, cause of death, location of PC, and Gleason score. RESULTS: Of 196 forensically autopsied males aged 0-90 years, 24 (12.7%) had latent PC. When analyzed by age group, PC was most prevalent among individuals in their eighties (33.3%). The prevalence of PC was similar in males who died of disease and of external causes. Most PCs were located at the base of the prostate, but were present on both the anterior and posterior sides. Nine of the 24 autopsied individuals also had other diseases, with three having cancers other than PC. CONCLUSIONS: This is the first report of the features of latent PC in Asian men who died of unnatural causes. Forensic autopsies can clarify the natural history of PC and may help fill knowledge gaps regarding latent PC. PMID- 25728718 TI - Platelet-rich plasma as treatment for persistent ocular epithelial defects. AB - Platelet- rich plasma (PRP) exhibits regenerative proprieties in wound healing but the biochemical mechanisms are unclear. In this study, autologous PRP with a mean value of 338 * 10(3) platelets/uL was used to treat corneal lesions of different aetiology, while homologous PRP with 1 * 10(6) platelets/uL was used to treat cornel lesions induced by a graft versus host disease. The impact of platelet count on the levels of PDGF AA and BB, VEGF, and EGF in the two PRPs was evaluated after a cycle of freezing/thawing. Treated corneal lesions healed or improved. The levels of PDGF AA and BB, VEGF, and EGF in the autologous PRP raised from 296 +/- 61; 201.8 +/- 24; 53 +/- 14 and 8.9 +/- 2 to 1017 +/- 253; 924.7 +/- 222; 101 +/- 46.5 and 174 +/- 15.5 pg/mL, while in the homologous PRP were 3.4, 4.5, 3.2 and 2 folds higher, respectively. High level of platelet counts seems not required to treat corneal lesions. PMID- 25728719 TI - Improving cardiovascular clinical trials conduct in the United States: recommendation from clinicians, researchers, sponsors, and regulators. AB - Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States. PMID- 25728720 TI - The periprocedural management of novel oral anticoagulants in patients with nonvalvular atrial fibrillation: rationale and a summary of the available evidence from phase 3 clinical trials. AB - The novel oral anticoagulants (NOACs) have rapidly emerged as an alternative therapy to warfarin. Several recent phase 3 randomized control trials have demonstrated the efficacy and safety of the NOACs in the treatment for patients with nonvalvular atrial fibrillation. As the NOACs are incorporated in clinical practice, questions have begun to arise concerning their optimal use in commonly encountered situations. In this review, we provide a summary of the available evidence from the phase 3 randomized control trials specifically with regard to 1 such scenario, the periprocedural management of NOACs, with a goal of providing guidance for practicing clinicians. PMID- 25728721 TI - A reappraisal of loop diuretic choice in heart failure patients. AB - The health and economic burden of heart failure is significant and continues to grow each year. Loop diuretics are an integral part of symptom management in heart failure. Furosemide is used disproportionately compared with other loop diuretics, and there is currently no guidance for physicians regarding which agent to choose. However, there exist pharmacologic differences as well as other mechanistic differences that appear to favor torsemide use over furosemide. Compared with furosemide, torsemide improves surrogate markers of heart failure severity such as left ventricular function, plasma brain natriuretic peptide levels, and New York Heart Association functional class and may also reduce hospitalizations, readmissions, and mortality. Data suggest that these benefits could be mediated through torsemide's ability to positively affect the renin angiotensin-aldosterone system. Specifically, torsemide has been shown to inhibit aldosterone secretion, synthesis, and receptor binding in vitro, as well as decrease transcardiac extraction of aldosterone, myocardial collagen production, and cardiac fibrosis in patients with heart failure. We identified pertinent literature using keyword MEDLINE searches and cross-referencing prior bibliographies. We summarize the available data suggesting potential benefits with torsemide over furosemide, and call attention to the need for a reappraisal of diuretic use in heart failure patients and also for a well-powered, randomized control trial assessing torsemide versus furosemide use. PMID- 25728722 TI - A randomized trial of continuous versus interrupted chest compressions in out-of hospital cardiac arrest: rationale for and design of the Resuscitation Outcomes Consortium Continuous Chest Compressions Trial. AB - The Resuscitation Outcomes Consortium is conducting a randomized trial comparing survival with hospital discharge after continuous chest compressions without interruption for ventilation versus currently recommended American Heart Association cardiopulmonary resuscitation with interrupted chest compressions in adult patients with out-of-hospital cardiac arrest without obvious trauma or respiratory cause. Emergency medical services perform study cardiopulmonary resuscitation for 3 intervals of manual chest compressions (each ~2 minutes) or until restoration of spontaneous circulation. Patients randomized to the continuous chest compression intervention receive 200 chest compressions with positive pressure ventilations at a rate of 10/min without interruption in compressions. Those randomized to the interrupted chest compression study arm receive chest compressions interrupted for positive pressure ventilations at a compression:ventilation ratio of 30:2. In either group, each interval of compressions is followed by rhythm analysis and defibrillation as required. Insertion of an advanced airway is deferred for the first >=6 minutes to reduce interruptions in either study arm. The study uses a cluster randomized design with every-6-month crossovers. The primary outcome is survival to hospital discharge. Secondary outcomes are neurologically intact survival and adverse events. A maximum of 23,600 patients (11,800 per group) enrolled during the post run-in phase of the study will provide >=90% power to detect a relative change of 16% in the rate of survival to discharge, 8.1% to 9.4% with overall significance level of 0.05. If this trial demonstrates improved survival with either strategy, >3,000 premature deaths from cardiac arrest would be averted annually. PMID- 25728723 TI - Evaluating the safety and efficacy of sodium-restricted/Dietary Approaches to Stop Hypertension diet after acute decompensated heart failure hospitalization: design and rationale for the Geriatric OUt of hospital Randomized MEal Trial in Heart Failure (GOURMET-HF). AB - BACKGROUND: Heart failure (HF) is a major public health problem affecting predominantly older adults. Nonadherence to diet remains a significant contributor to acute decompensated HF (ADHF). The sodium-restricted Dietary Approaches to Stop Hypertension (DASH/SRD) eating plan reduces cardiovascular dysfunction that can lead to ADHF and is consistent with current HF guidelines. We propose that an intervention that promotes adherence to the DASH/SRD by home delivering meals will be safe and improve health-related quality of life (QOL) in older adults after hospitalization for ADHF. METHODS/DESIGN: This is a 3-center, randomized, single-blind, controlled trial of 12-week duration designed to determine the safety and efficacy of home-delivered DASH/SRD-compliant meals in older adults after discharge from ADHF hospitalization. Sixty-six subjects will be randomized in a 1:1 stratified fashion by gender and left ventricular ejection fraction (<50% vs >=50%). Study subjects will receive either preprepared, home delivered DASH/SRD-compliant meals or usual dietary advice for 4weeks after hospital discharge. Investigators will be blinded to group assignment, food diaries, and urinary electrolyte measurements until study completion. The primary efficacy end point is the change in the Kansas City Cardiomyopathy Questionnaire summary scores for health-related QOL from study enrollment to 4weeks postdischarge. Safety evaluation will focus on hypotension, renal insufficiency, and hyperkalemia. Exploratory end points include echocardiography, noninvasive vascular testing, markers of oxidative stress, and salt taste sensitivity. CONCLUSION: This randomized controlled trial will test the efficacy, feasibility, and safety of 4weeks of DASH/SRD after ADHF hospitalization. By testing a novel dietary intervention supported by multiple levels of evidence including preliminary data in outpatients with stable HF, we will address a critical evidence gap in the care of older patients with ADHF. If effective and safe, this intervention could be scaled to assess effects on readmission and healthcare costs in older adults after ADHF. PMID- 25728724 TI - Rational and design of a stepped-wedge cluster randomized trial evaluating quality improvement initiative for reducing cardiovascular events among patients with acute coronary syndromes in resource-constrained hospitals in China. AB - BACKGROUND: Acute coronary syndromes (ACSs) are a major cause of morbidity and mortality, yet effective ACS treatments are frequently underused in clinical practice. Randomized trials including the CPACS-2 study suggest that quality improvement initiatives can increase the use of effective treatments, but whether such programs can impact hard clinical outcomes has never been demonstrated in a well-powered randomized controlled trial. DESIGN: The CPACS-3 study is a stepped wedge cluster-randomized trial conducted in 104 remote level 2 hospitals without PCI facilities in China. All hospitalized ACS patients will be recruited consecutively over a 30-month period to an anticipated total study population of more than 25,000 patients. After a 6-month baseline period, hospitals will be randomized to 1 of 4 groups, and a 6-component quality improvement intervention will be implemented sequentially in each group every 6months. These components include the following: establishment of a quality improvement team, implementation of a clinical pathway, training of physicians and nurses, hospital performance audit and feedback, online technical support, and patient education. All patients will be followed up for 6months postdischarge. The primary outcome will be the incidence of in-hospital major adverse cardiovascular events comprising all-cause mortality, myocardial infarction or reinfarction, and nonfatal stroke. CONCLUSIONS: The CPACS-3 study will be the first large randomized trial with sufficient power to assess the effects of a multifaceted quality of care improvement initiative on hard clinical outcomes, in patients with ACS. PMID- 25728725 TI - The impact of smoking on long-term outcome of patients with premature (<=35years) ST-segment elevation acute myocardial infarction. AB - BACKGROUND: There are few data regarding the long-term prognosis of young survivors of acute myocardial infarction (AMI). We explored the long-term outcome in individuals who had sustained a premature ST-segment elevation AMI. METHODS: We recruited 257 consecutive patients who had survived their first AMI <=35years of age. Patients were followed up for up to 18years. Clinical end points included all major adverse coronary events (MACE): cardiac death, readmission for acute coronary syndrome, arrhythmias, or coronary revascularization due to clinical deterioration. RESULTS: The most prevalent risk factor at presentation was smoking (93.7%). Follow-up data were obtained from 237 patients (32.2+/-3.7years old). The median follow-up period was 9.1years. During follow-up, 139 (58.6%) patients reported continuation of smoking. Ninety-one (38.4%) patients had recurrent MACE (13 deaths, 59 acute coronary syndromes, 2 arrhythmias, and 17 revascularizations). Multivariable Cox regression analysis showed that persistence of smoking, left ventricular ejection fraction (LVEF), and reperfusion therapy (fibrinolysis or primary coronary angioplasty) were independent predictors of MACE after adjustment for conventional risk factors. Continuation of smoking remained an independent predictor for MACE after additional adjustments for LVEF (hazard ratio 2.154, 95% CI 1.313-3.535, P=.002) or reperfusion treatment (hazard ratio 2.327, 95% CI 1.423-3.804, P=.001). Harrell c statistic showed that the model with persistent smoking had the best discriminatory power compared with models with LVEF or reperfusion treatment. CONCLUSIONS: In the era of statins and reperfusion treatment, continuation of smoking is the strongest independent long-term predictor for recurrent MACE in young survivors of premature AMI. PMID- 25728726 TI - Prognostic significance of serum creatinine and its change patterns in patients with acute coronary syndromes. AB - BACKGROUND: In acute coronary syndromes (ACS), serum creatinine (sCr) levels have short- and long-term prognostic value. However, it is possible that repeated evaluations of sCr during hospitalization, rather than measuring sCr value at admission only, might improve risk assessment. We investigated the relationship between sCr baseline value, its changes, and in-hospital mortality in patients hospitalized with ACS. METHODS: In 2,756 ACS patients, sCr was measured at hospital admission and then daily, until discharge from coronary care unit. Patients were grouped according to the maximum sCr change observed: <0.3 mg/dL change from baseline (stable renal function [SRF] group), >=0.3 mg/dL decrease (improved renal function [IRF] group), and >=0.3 mg/dL increase (worsening renal function [WRF] group). RESULTS: Of the 2,756 patients, 2,163 (78%) had SRF, 292 (11%) had IRF, and 301 (11%) had WRF. In-hospital mortality in the 3 groups was 0.5%, 2%, and 14% (P < .001), respectively. Peak sCr value was a more powerful predictor of mortality (area under the curve 0.86, 95% CI 0.81-0.92) than the initial sCr value (area under the curve 0.69, 95% CI 0.63-0.77; P < .001). When sCr and its change patterns during coronary care unit stay were evaluated together, improved mortality risk stratification was found. CONCLUSIONS: In ACS patients, daily sCr value and its change pattern are stronger predictors of in hospital mortality than the initial sCr value only; thus, their combined evaluation provides a more accurate and dynamic stratification of patients' risk. Finally, the intermediate mortality risk of IRF patients possibly reflects acute kidney injury started before hospitalization. PMID- 25728727 TI - Association of ideal cardiovascular health and calcified atherosclerotic plaque in the coronary arteries: the National Heart, Lung, and Blood Institute Family Heart Study. AB - BACKGROUND: The American Heart Association (AHA) established recommendations based on 7 ideal health behaviors and factors with the goal of improving cardiovascular health (CVH) and reducing both morbidity and mortality from cardiovascular disease by 20% by 2020. Few studies have investigated their association with subclinical coronary heart disease. We sought to examine whether the 7 AHA CVH metrics were associated with calcified atherosclerotic plaque in the coronary arteries. METHODS: In a cross-sectional design, we studied 1,731 predominantly white men and women from the National Heart, Lung, and Blood Institute Family Heart Study without prevalent coronary heart disease. Diet was assessed by a semiquantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC using an Agatston score of 100+ and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. RESULTS: Mean age was 56.8 years, and 41% were male. The median number of ideal CVH metrics was 3, and no participant met all 7. There was a strong inverse relationship between number of ideal CVH metrics and prevalent CAC. Odds ratios (95% CI) for CAC of 100+ were 1.0 (reference), 0.37 (0.29-0.45), 0.35 (0.26-0.44), and 0.27 (0.20-0.36) among subjects with 0 to 1, 2, 3, and 4+ ideal CVH metrics, respectively (P = .0001), adjusting for sex, age, field center, alcohol, income, education, and energy consumption. CONCLUSIONS: These data demonstrate a strong and graded inverse relationship between AHA ideal CVH metrics and prevalent CAC in adult men and women. PMID- 25728728 TI - Availability and utilization of cardiovascular fixed-dose combination drugs in the United States. AB - BACKGROUND: Solid clinical evidence supports the effectiveness and safety of multiple drugs in treating diabetes, dyslipidemia, and hypertension, and numerous fixed-dose combination products (FDCs) containing such drugs have been developed for patients with more severe forms of these diseases. We sought to evaluate the extent to which utilization of treatment combinations for these conditions corresponded to the availability of FDCs. METHODS: Using claims data from a large national commercial insurer, we identified 2 cohorts of patients: those who filled multiple single-agent drugs to treat diabetes, dyslipidemia, and hypertension in 2012, and those who used FDCs containing these products during the same period. We determined the fill rate of single-agent pairs and FDCs, availability of FDCs for the most frequently filled single-agent and drug class pairs, and the number of conditions treated by frequently filled single-agent pairs and FDCs. RESULTS: During our study period, 848,082 patients filled prescriptions for 3,248 unique single-agent pairs (mean 4.7 per patient, standard deviation [SD] 5.0); and 568,923 patients received prescriptions for 43 unique FDCs (mean 1.1 per patient, SD 0.3). Three (15%) of the 20 most frequently filled single-agent pairs were available as FDCs, whereas 9 (45%) of the 20 most frequently filled drug class pairs were available as FDCs. Nearly all of the frequently filled FDCs had lower fill rates than the most frequently filled single-agent pairs. CONCLUSIONS: Utilization of drug combinations to treat cardiovascular conditions does not correspond well with availability of FDCs containing these agents. A concerted set of strategies should be implemented to streamline the development of useful combination products, including expedited approval pathways and increased investment in formulation studies. PMID- 25728730 TI - Female sex is associated with a lower risk of stroke in patients with heart failure. AB - BACKGROUND: Stroke in patients with heart failure is associated with poor outcomes. Risk stratification schemes may improve clinical decision making in this patient population. This study investigated whether female sex is a risk factor for stroke in patients with heart failure in sinus rhythm. METHODS: This is a population-based cohort study of patients diagnosed with heart failure during 2000 to 2012, identified by record linkage between nationwide Danish registries. Our primary outcome was stroke, and secondary outcome was thromboembolic event. We used relative risks (RRs) after 1 and 5 years to compare males with females within each of the following age groups: 50 to 59 years, 60 to 69 years, 70 to 79 years, 80 to 89 years, and 90+ years. Analyses took into account the competing risks of death. RESULTS: During the study period, 84,142 patients were diagnosed with heart failure, of which 39,946 (47.5%) were females. At 5-year follow-up, female sex was associated with a lower risk of stroke compared with males (adjusted overall hazard ratio 0.91, 95% CI 0.85-0.96). The observed lower risks of stroke in females were not present in the older age groups, where the competing risk of death was substantial among males in particular. When considering a more broadly defined thromboembolic end point, a decreased risk among females persisted across nearly all age groups after 5-year follow-up (adjusted overall hazard ratio 0.93, 95% CI 0.91-0.96). CONCLUSIONS: We found an association between female sex and decreased stroke risk in patients with heart failure, which persisted after adjustment for concomitant cardiovascular risk factors. The association was attenuated with increasing age, possibly because of competing risks of death. PMID- 25728729 TI - Implications of the new American College of Cardiology/American Heart Association cholesterol guidelines for primary atherosclerotic cardiovascular disease event prevention in a multi ethnic cohort: Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: The impact of replacing the National Cholesterol Education Program (NCEP)/Adult Treatment Program (ATP) III cholesterol guidelines with the new 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for primary prevention of cardiovascular disease is unclear. METHODS: We used risk factor and 10-year clinical event rate data from MESA, combined with estimates of efficacy of moderate and high-intensity statin therapy from meta analyses of statin primary prevention trials to estimate (a) the change in number of subjects eligible for drug therapy and (2) the anticipated reduction in atherosclerotic cardiovascular disease (ASCVD) events and increment in type 2 diabetes mellitus (T2DM) associated with the change in cholesterol guidelines. RESULTS: Of the 6,814 MESA participants, 5,437 were not on statins at baseline and had complete data for analysis (mean age 61.4+/-10.3). Using the NCEP/ATP III guidelines, 1,334 (24.5%) would have been eligible for statin therapy compared with 3,015 (55.5%) under the new ACC/AHA guidelines. Among the subset of newly eligible, 127/1,742 (7.3%) had an ASCVD event during 10years of follow-up. Assuming 10years of moderate-intensity statin therapy, the estimated absolute reduction in ASCVD events for the newly eligible group was 2.06% (number needed to treat [NNT] 48.6) and the estimated absolute increase in T2DM was 0.90% (number needed to harm [NNH] 110.7). Assuming 10years of high-intensity statin therapy, the corresponding estimates for reductions in ASCVD and increases in T2DM were as follows: ASCVD 2.70% (NNT 37.5) and T2DM 2.60% (NNH 38.6). The estimated effects of moderate-intensity statins on 10-year risk for ASCVD and T2DM in participants eligible for statins under the NCEP/ATP III were as follows: 3.20% (NNT 31.5) and 1.06% (NNH 94.2), respectively. CONCLUSION: Substituting the NCEP/ATP III cholesterol guidelines with the 2013 ACC/AHA cholesterol guidelines in MESA more than doubled the number of participants eligible for statin therapy. If the new ACC/AHA cholesterol guidelines are adopted and extend the primary prevention population eligible for treatment, the risk-benefit profile is much better for moderate-intensity than high-intensity statin treatment. PMID- 25728731 TI - Galectin-3 and mineralocorticoid receptor antagonist use in patients with chronic heart failure due to left ventricular systolic dysfunction. AB - BACKGROUND: Galectin-3 is a prognostic heart failure biomarker associated with aldosterone-induced myocardial fibrosis; mineralocorticoid receptor antagonists (MRAs) may reduce such fibrosis. We sought to examine outcomes of patients with heart failure with reduced ejection fraction (HFrEF) as a function of galectin-3 and MRA therapy. METHODS: A total of 151 patients with chronic HFrEF were categorized by baseline galectin-3 and subsequent MRA therapy trends with regard to cardiovascular (CV) events, left ventricular remodeling, safety, and quality of life, over a mean of 10 months. RESULTS: Although galectin-3 >20 ng/mL was associated with doubling in adjusted risk for CV events, regardless of MRA treatment, there was no difference in CV event rates with regard to MRA use patterns, independent of galectin-3 concentrations. Specifically, in patients with elevated galectin-3 treated with intensified MRA therapy, a significant difference was not detected in CV event rates (P = .79) or the cumulative number of such events (P = .76). Adjusted analysis revealed no difference in time to first CV event if MRA was added/intensified in those with elevated galectin-3 (hazard ratio 0.99, 95% CI 0.97-1.02, P = .74); similarly, cumulative MRA dose was not a specific predictor of benefit. In those with elevated galectin-3, MRA therapy did not affect left ventricular remodeling indices or quality of life at follow-up; these patients had the highest rates of treatment-related adverse events with intensified MRA use. Regardless of MRA use, elevated galectin-3 was associated with more significant renal dysfunction. CONCLUSIONS: Among patients with chronic HFrEF and elevated galectin-3 concentrations, we found no specific benefit from addition or intensification of MRA therapy. PMID- 25728732 TI - Mild renal dysfunction and long-term adverse outcomes in women with chest pain: results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE). AB - BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and adverse cardiovascular outcomes, but mechanisms are unclear. We hypothesized that mild CKD independently predicts adverse outcomes in women with symptoms and signs of ischemia. METHODS: We categorized 876 women from the Women's Ischemia Syndrome Evaluation cohort according to estimated glomerular filtration rate (eGFR) (eGFR >=90 mL/min per 1.73 m(2) [normal], 60-89 mL/min per 1.73 m(2) [mild CKD], <=59 mL/min per 1.73 m(2) [severe CKD]). Time to death from all-cause and cardiovascular causes and major adverse outcomes were assessed by multivariate regression adjusted for baseline covariates. RESULTS: Obstructive coronary artery disease (CAD) was present only in few patients (39%). Even after adjusting for CAD severity, renal function remained a strong independent predictor of all-cause and cardiac mortality (P < .001). Every 10-unit decrease in eGFR was associated with a 14% increased risk of all-cause mortality (adjusted hazard ratio [AHR] 1.14 [1.08-1.20], P < .0001), 16% increased risk of cardiovascular mortality (AHR 1.16 [1.09-1.23], P < .0001), and 9% increased risk of adverse cardiovascular events (AHR 1.09 [1.03-1.15], P = .002). CONCLUSIONS: Even mild CKD is a strong independent predictor of all-cause and cardiac mortality in women with symptoms/signs of ischemia, regardless of underlying obstructive CAD severity, underscoring the need to better understand the interactions between ischemic heart disease and CKD. PMID- 25728733 TI - Effects of acute kidney injury and chronic kidney disease on long-term mortality after coronary artery bypass grafting. AB - BACKGROUND: Both acute kidney injury (AKI) and chronic kidney disease (CKD) are important issues in patients undergoing coronary artery bypass grafting (CABG), particularly with regard to mortality. However, their synergistic or discrete effects on long-term mortality remain unresolved. METHODS: A total of 1,899 patients undergoing CABG were retrospectively analyzed. The adjusted hazard ratios for all-cause mortality were calculated after stratifying the timeframes. To evaluate the synergistic effects between AKI and CKD, the relative excess risk due to interaction was applied. RESULTS: The presence of AKI, CKD, or both increased the hazard ratios for mortality, compared with the absence of both: AKI alone, 1.84 (1.464-2.319); CKD alone, 2.46 (1.735-3.478); and AKI and CKD together, 3.21 (2.301-4.488). However, the relationships with mortality were different between AKI and CKD, according to the timeframes: AKI primarily affected early mortality, particularly within 3 years, whereas CKD had a relatively constant effect on both the early and late periods. When the parameters from the relative excess risk due to interaction were obtained, there was a synergistic additive effect on early mortality between AKI and CKD. CONCLUSIONS: The relationships with mortality after CABG were different between AKI and CKD. However, their effects were not exclusive but synergistic. PMID- 25728734 TI - Cardiovascular deaths in children: general overview from the National Center for the Review and Prevention of Child Deaths. AB - BACKGROUND: Cardiovascular conditions rank sixth in causes of death in 1- to 19 year-olds. Our study is the first analysis of the cardiovascular death data set from the National Center for the Review and Prevention of Child Deaths, which provides the only systematic collection of cardiovascular deaths in children. METHODS: We developed an analytical data set from the National Center for the Review and Prevention of Child Deaths database for cardiovascular deaths in children 0 to 21 years old, reviewing 1,098 cases from 2005 to 2009 in 16 states who agreed to participate. RESULTS: Cardiovascular cases were aged 4.8 +/- 6.6 years; 55.3%, <=1 year; 24.6%, >=10 years; male, 58%; white, 70.5%; black, 22.3%; Hispanic, 19.5%. Prior conditions were present in 48.5%: congenital heart disease, 23%; cardiomyopathies, 4.6%; arrhythmia, 1.7%; and congestive heart failure, 1.6%. Deaths occurred most frequently in urban settings, 49.2%; and in the hospital, 40.4%; home, 26.1%; or at school/work/sports, 4.8%. Emergency medical services were not evenly distributed with differences by age, race, ethnicity, and area. Autopsies (40.4%) occurred more often in those >10 years old (odds ratio [OR] 2.9), blacks (OR 1.6), or in those who died at school/work/sports (OR 3.9). The most common cardiovascular causes of death included congenital heart disease, 40.8%; arrhythmias, 27.1%; cardiomyopathy, 11.8%; myocarditis, 4.6%; congestive heart failure, 3.6%; and coronary artery anomalies, 2.2%. CONCLUSIONS: Our study identified differences in causes and frequencies of cardiovascular deaths by age, race, and ethnicity. Prevention of death may be impacted by knowledge of prior conditions, emergency plans, automated external defibrillator programs, bystander cardiopulmonary resuscitation education, and by a registry for all cardiovascular deaths in children. PMID- 25728735 TI - Incidence of strict versus nonstrict left bundle branch block after transcatheter aortic valve replacement. AB - BACKGROUND: Up to one-third of patients diagnosed with left bundle branch block (LBBB) by conventional electrocardiographic (ECG) criteria are misdiagnosed. Strict LBBB shows decreased left ventricular pumping efficiency compared with nonstrict LBBB. However, no previous study has evaluated the frequency of strict LBBB after transcatheter aortic valve replacement (TAVR). The aim of this study was to determine the incidence of developing strict versus nonstrict LBBB after TAVR and test the hypothesis that preprocedure QRS duration does not predict strict LBBB but predicts development of nonstrict LBBB. METHODS: All patients receiving TAVR between 4/2011 and 2/2013 (n = 71) with no preexisting bundle branch block or permanent pacemaker were included. Twelve-lead ECGs were acquired preprocedure and both 1-day and 1-month postprocedure. All ECGs were classified as strict LBBB, nonstrict LBBB, or no LBBB. RESULTS: Sixty-eight patients had ECGs eligible for final analysis. On postprocedure day 1, 25 (37%) of 68 patients developed strict LBBB, and 2 patients (3%) developed nonstrict LBBB. At 1-month follow-up, the 2 patients diagnosed with nonstrict LBBB had resolved to normal, and 5 (20%) of 25 patients with strict LBBB had resolved to normal. Preprocedure QRS duration did not predict strict LBBB (P = .51). Because of the low incidence of nonstrict LBBB, QRS duration as a predictor of nonstrict LBBB could not be tested. CONCLUSIONS: Almost all patients who developed evidence of LBBB after TAVR met the new strict criteria, indicating probable procedural injury to the left bundle branch. Preprocedural QRS duration did not predict the development of strict LBBB. PMID- 25728736 TI - Letter to the editor regarding the article "cardioprotective role of ischemic postconditioning in acute myocardial infarction: a systematic review and meta analysis". PMID- 25728737 TI - Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy? AB - AIM: Gastrointestinal (GI) symptoms during and after cancer therapy can significantly affect quality of life and interfere with treatment. This study assessed whether bile acid malabsorption (BAM) or bile acid diarrhoea (BAD) are important causes of diarrhoea associated with cancer treatment. METHOD: A retrospective analysis was carried out of consecutive patients assessed for BAM using ((75) Se) Selenium homocholic acid taurocholate (SeHCAT) scanning, after reporting any episodes of loose stool, attending a gastroenterology clinic in a cancer centre. RESULTS: Between 2009 and 2013, 506 consecutive patients (54.5% male; age range: 20-91 years), were scanned. BAM/BAD was diagnosed in 215 (42.5%). It was mild in 25.6%, moderate in 29.3% and severe in 45.1%. Pelvic chemoradiation had induced BAM in > 50% of patients. BAM was also frequent after treatment for conditions not previously associated with BAM, such as anal and colorectal cancer, and was present in > 75% of patients referred after pancreatic surgery. It was also unexpectedly frequent in patients who were treated for malignancy outside the GI tract, such as breast cancer and haematological malignancy. CONCLUSION: BAM/BAD are very common and under-appreciated causes of GI symptoms after cancer treatment. Health professionals should have a low threshold in suspecting this condition, as diagnosis and treatment can significantly improve quality of life. PMID- 25728738 TI - The Raised Potential for Vector-Borne Diseases in European Travelers Following the EU's Biocide Directive on DEET Dosing. PMID- 25728739 TI - Gradual tapering of desmopressin leads to better outcome in nocturnal enuresis. AB - BACKGROUND: Although desmopressin therapy is effective in treating polyuric monosymptomatic nocturnal enuresis (MNE), the relatively high rates of recurrence are problematic. To date, the treatment protocol on the discontinuation of oral desmopressin melt (ODM) tablet, MinirinMelt, has not been established. We tested two protocols of tapering ODM when the patients achieved full response on ODM, and compared the treatment outcomes. METHODS: One hundred and fifty-seven polyuric MNE children were newly treated with ODM at the authors' outpatient clinics (Juntendo Nerima Hospital and Musashi-Murayama Hospital). When the patients did not respond to the 8 week ODM therapy, we added another options such as alarm, anti-cholinergics, and imipramine (92 patients; 58.6%). Sixty-five patients (41.4%) achieved full response on ODM alone, and 49 of them accepted gradual tapering of ODM: group B (n = 25), 240 MUg ODM per day -> 120 MUg ODM per day -> 120 MUg ODM per alternate day -> cessation; and group C (n = 24), 240 MUg ODM per day -> 120 MUg ODM per day -> 60 MUg ODM per day -> 60 MUg ODM per alternate day -> cessation. RESULTS: Fourteen patients in group B (56%) and four in group C (17%) had relapses of enuresis after the discontinuation of ODM (P = 0.026). CONCLUSIONS: Gradual tapering of ODM therapy in MNE patients leads to better outcome. PMID- 25728740 TI - Caudate lobe of the liver as the only content of the umbilical cord hernia. PMID- 25728741 TI - [Usefulness of octreotride in preventing non-variceal gastroinetestinal bleeding in liver cirrhosis: A report of two cases]. PMID- 25728742 TI - Photothermally induced local dissociation of collagens for harvesting of cell sheets. AB - The local heating of poly(3,4-ethylenedioxythiophene) (PEDOT) by a photothermal effect directed by near-infrared (NIR) light induces unfolding of absorbed collagen triple helices, yielding soluble collagen single-helical structures. This dissociation of collagens allowed the harvesting of a living idiomorphic cell sheet, achieved upon irradiation with NIR light (lambda=808 nm). The PEDOT layer was patterned and cells were successfully cultured on the patterned substrate. Cell sheets of various shapes mirroring the PEDOT pattern could be detached after a few minutes of irradiation with NIR light. The PEDOT patterns guided not only the entire shape of the cell sheets but also the spreading direction of the cells in the sheets. This photothermally induced dissociation of collagen provided a fast non-invasive harvesting method and tailor-made cell sheet patterns. PMID- 25728743 TI - Quality of life can be improved by surgical management of giant hepatic haemangioma with enucleation as the preferred option. AB - OBJECTIVES: Surgical resection represents the main curative treatment for giant hepatic haemangioma (GHH). The aim of this study was to compare the respective outcomes of hepatic enucleation (HE) and hepatic resection (HR) for GHH. METHODS: Giant hepatic haemangioma was defined as haemangioma of 5-15 cm in size. A prospectively maintained database consisting of a series of consecutive patients who underwent HE or HR of GHH from January 2004 to December 2013 was analysed. RESULTS: Hepatic enucleation was performed in 386 (52.9%) patients and HR in 344 (47.1%) of a final cohort of 730 patients. The median size of GHH was similar in the HR and HE groups (9.8 and 10.6 cm, respectively; P = 0.752). The HE group had a shorter median operative time (150 min versus 240 min; P = 0.034), shorter median hospital stay (5.7 days versus 8.6 days; P < 0.001), lower median blood loss (400 ml versus 860 ml; P < 0.001), and fewer complications (17.6% versus 28.2%; P < 0.001) than the HR group. Quality of life scores in both the HR and HE groups significantly improved compared with preoperative levels and were similar to those found in healthy Chinese individuals following surgery, confirming the efficacy of both treatments. CONCLUSIONS: Hepatic enucleation was associated with favourable operative outcomes compared with HR and is a safe and effective alternative to partial hepatectomy for GHH. PMID- 25728744 TI - Endovascular therapy for critical limb ischemia. AB - Critical limb ischemia (CLI) represents an advanced disease state of peripheral arterial disease. It manifests as lower extremity ischemic rest pain or ischemic skin lesions leading to ulceration or gangrene. Patients with CLI often have multiple medical comorbidities and a 1-year mortality rate of 25% and a 1-year amputation rate of 25%. Historically, bypass surgery with autogenous veins for flow restoration has been the first-line therapy for CLI. However, advances in endovascular techniques and device technology have changed the treatment paradigm. Catheter-based technologies are rapidly evolving at a rate that is outpacing large-scale studies evaluating relevant clinical outcomes. Patients with CLI require a multidisciplinary management approach centered on aggressive medical therapies, wound care and prompt revascularization, with an emphasis on limb salvage. This review summarizes the contemporary endovascular therapies including balloon angioplasty, atherectomy and bare-metal stenting. In addition, we review emerging technologies, such as drug-eluting stents, drug-coated balloons and chronic total occlusion recanalization devices. PMID- 25728745 TI - Erosive pustular dermatosis of the scalp arising concomitantly with elevation of serum matrix metalloproteinase-3 in a patient with rheumatoid arthritis. PMID- 25728746 TI - Prevalence of malaria and HIV coinfection and influence of HIV infection on malaria disease severity in population residing in malaria endemic area along the Thai-Myanmar border. AB - The objective of the study is to investigate the prevalence of malaria and HIV coinfection and assess the effect of HIV coinfection on malaria disease severity in malaria patients from the endemic area of Thailand along the Thai-Myanmar border. Blood samples were collected from a total of 867 patients with malaria (all species and severity) who attended Mae Tao clinic for migrant workers, Tak Province during 2005-2007 (439 samples), 2008-2010 (273 samples), and 2011-2013 (155 samples). The average prevalence rate of malaria and HIV coinfected cases in this malaria endemic area of the country during the three periods was 1.85%. HIV coinfection was observed only in samples with mono-infection of Plasmodium falciparum or Plasmodium vivax, with similar proportions (0.81 vs. 1.04%). Patients' admission parasite density, an indicator of disease severity, was significantly higher in cases with HIV coinfection observed during 2008-2010. Anemia was found at a significantly higher frequency in patients coinfected with malaria and HIV observed during 2005-2007 compared with those infected with malaria alone. No association was observed between malaria and HIV coinfection and gender, and infected malaria species during the three observation periods. Patients with malaria and HIV coinfection had a significantly lower hemoglobin level than those with malaria infection alone. In conclusion, the prevalence of malaria and HIV coinfection in population of the malaria endemic area along the Thai-Myanmar border is low. HIV coinfection tended to increase parasite density, an indicator of malaria disease severity. PMID- 25728747 TI - A 5-Year Prospective Study on Cone-Anchored Implants in the Edentulous Maxilla. AB - PURPOSE: To investigate dentist- as well as patient-centered outcomes of the implant-supported cone-anchored removable prosthesis in the edentulous maxilla over 5 years. MATERIALS AND METHODS: Ten patients, edentulous in the maxilla, received six Ti implants after which they were delayed loaded through a cone anchored removable prosthesis. Clinical parameters such as plaque and bleeding indices, PTV, implant success, marginal bone loss, device and prosthesis complications, and patient satisfaction (visual analogue scale) were collected at follow-up visits scheduled 1, 3, 6, 12, 24, 36, and 60 months postprosthesis delivery. RESULTS: After at least 5 years of follow-up (mean: 63.7 months), 53/59 implants were rated successful, while two of 59 failed and one implant was kept sleeping. Mean marginal bone loss from prosthesis delivery until 1, 3, and 5 years, respectively, was; 0.15 (SD: 0.87), 0.36 (SD: 1.07), and 0.60 mm (SD: 1.12). The mean Periotest(r) values at baseline and 5 years did not differ significantly. After 1 year, a significant improvement in patient satisfaction was recorded compared with the old denture, and this remained stable over the 5 year period. CONCLUSIONS: Cone-anchored removable dental prostheses retained by secondary splinted implants offer a safe alternative for patients with an edentulous maxilla in need of more comfort. Dentist- as well as patient-centered outcomes compete with reports using other prosthetic anchoring devices. Larger replica studies are encouraged to further validate this concept. PMID- 25728748 TI - Characterization of LGR5 stem cells in colorectal adenomas and carcinomas. AB - LGR5 is known to be a stem cell marker in the murine small intestine and colon, however the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have been limited by the lack of specific antibodies. Here we used in situ hybridization to specifically examine LGR5 mRNA expression in a panel of human adenoma and carcinoma samples (n = 66). We found that a small number of cells express LGR5 at the base of normal colonic crypts. We then showed that conventional adenomas widely express high levels of LGR5, and there is no evidence of stereotypic cellular hierarchy. In contrast, serrated lesions display basal localization of LGR5, and the cellular hierarchy resembles that of a normal crypt. Moreover, ectopic crypts found in traditional serrated adenomas show basal LGR5 mRNA, indicating that they replicate the stem cell organization of normal crypts with the development of a cellular hierarchy. These data imply differences in the stem cell dynamics between the serrated and conventional pathways of colorectal carcinogenesis. Furthermore we noted high LGR5 expression in invading cells, with later development of a stem cell niche in adenocarcinomas of all stages. PMID- 25728749 TI - Evaluation of a high efficiency cabin air (HECA) filtration system for reducing particulate pollutants inside school buses. AB - An increasing number of studies have reported deleterious health effects of vehicle-emitted particulate matter (PM), including PM2.5 (aerodynamic diameter<=2.5 MUm), black carbon (BC), and ultrafine particles (UFPs, diameter<=100 nm). When commuting inside school buses, children are exposed to high level of these pollutants due to emissions from both school bus itself and other on-road vehicles. This study developed an on-board high efficiency cabin air (HECA) filtration system for reducing children's exposure inside school buses. Six school buses were driven on two typical routes to evaluate to what extent the system reduces particulate pollutant levels inside the buses. The testing routes included freeways and major arterial roadways in Los Angeles, CA. UFP number concentrations and size distributions as well as BC and PM2.5 concentrations were monitored concurrently inside and outside of each bus. With the HECA filtration system on, in-cabin UFP and BC levels were reduced by 88+/-6% and 84+/-5% on averages across all driving conditions, respectively. The system was less effective for PM2.5 (55+/-22%) but successfully kept its levels below 12 MUg/m3 inside all the buses. For all three types of particulate pollutants, in cabin reductions were higher on freeways than on arterial roadways. PMID- 25728750 TI - HDAC4 regulates muscle fiber type-specific gene expression programs. AB - Fiber type-specific programs controlled by the transcription factor MEF2 dictate muscle functionality. Here, we show that HDAC4, a potent MEF2 inhibitor, is predominantly localized to the nuclei in fast/glycolytic fibers in contrast to the sarcoplasm in slow/oxidative fibers. The cytoplasmic localization is associated with HDAC4 hyper-phosphorylation in slow/oxidative-fibers. Genetic reprogramming of fast/glycolytic fibers to oxidative fibers by active CaMKII or calcineurin leads to increased HDAC4 phosphorylation, HDAC4 nuclear export, and an increase in markers associated with oxidative fibers. Indeed, HDAC4 represses the MEF2-dependent, PGC-1alpha-mediated oxidative metabolic gene program. Thus differential phosphorylation and localization of HDAC4 contributes to establishing fiber type-specific transcriptional programs. PMID- 25728751 TI - Retinoid X receptor alpha overexpression alleviates mitochondrial dysfunction induced insulin resistance through transcriptional regulation of insulin receptor substrate 1. AB - Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor alpha (RXRalpha) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether RXRalpha activation or overexpression can restore IRS1 expression. Both IRS1 and RXRalpha protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of RXRalpha agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. RXRalpha overexpression also increased IRS1 transcription and mitochondrial function. Because RXRalpha overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRalpha directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that RXRalpha bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor delta (PPARdelta). These results suggest that RXRalpha overexpression or activation alleviates insulin resistance by increasing IRS1 expression. PMID- 25728752 TI - Cell Proliferation and Motility Are Inhibited by G1 Phase Arrest in 15-kDa Selenoprotein-Deficient Chang Liver Cells. AB - The 15-kDa selenoprotein (Sep15) is a selenoprotein residing in the lumen of the endoplasmic reticulum (ER) and implicated in quality control of protein folding. Herein, we established an inducible RNAi cell line that targets Sep15 mRNA in Chang liver cells. RNAi-induced Sep15 deficiency led to inhibition of cell proliferation, whereas cell growth was resumed after removal of the knockdown inducer. Sep15-deficient cells were arrested at the G1 phase by upregulating p21 and p27, and these cells were also characterized by ER stress. In addition, Sep15 deficiency led to the relocation of focal adhesions to the periphery of the cell basement and to the decrease of the migratory and invasive ability. All these changes were reversible depending on Sep15 status. Rescuing the knockdown state by expressing a silent mutant Sep15 mRNA that is resistant to siRNA also reversed the phenotypic changes. Our results suggest that SEP15 plays important roles in the regulation of the G1 phase during the cell cycle as well as in cell motility in Chang liver cells, and that this selenoprotein offers a novel functional link between the cell cycle and cell motility. PMID- 25728753 TI - Overexpression of Long Non-Coding RNA HOTAIR Promotes Tumor Growth and Metastasis in Human Osteosarcoma. AB - Human osteosarcoma usually presented a high tendency to metastatic spread and caused poor outcomes, however, the underlying mechanism was still largely unknown. In the present study, using a series of in vitro experiments and an animal model, we investigated the roles of HOX antisense intergenic RNA (HOTAIR) during the proliferation and invasion of osteosarcoma. According with our results, HOTAIR was commonly overexpressed in osteosarcoma, which significantly correlated with advanced tumor stage, highly histological grade and poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of HOTAIR could notably suppress cellular proliferation, inhibit invasion and decrease the secretion of MMP2 and MMP9 in osteosarcoma. Collectively, our results suggested that HOTAIR might be a potent therapeutic target for osteosarcoma. PMID- 25728754 TI - Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results from a multicenter study. AB - BACKGROUND: Periprocedural anticoagulation management with uninterrupted warfarin and a "therapeutic" international normalized ratio is the best approach for reducing both thromboembolic and bleeding complications in the setting of catheter ablation for atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the safety and feasibility of uninterrupted apixaban in this setting. METHODS: This was a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation at 4 institutions in United States and Europe with uninterrupted apixaban. These patients were compared with an equal number of patients, matched for age, gender, and type of AF, undergoing AF ablation on uninterrupted warfarin. The apixaban group was comprised of consecutive patients who had taken their last dose of apixaban the morning of the procedure. A subset of 29 patients in the apixaban group underwent diffusion magnetic resonance imaging (dMRI) to detect silent cerebral ischemia. RESULTS: A total of 400 patients (200 patients in each group) were included in the study. The average age was 65.9 +/- 9.9 years, 286 (71.5%) were male, and 334 (83.5%) had nonparoxysmal AF. There were no statistical differences with regard to major complications (1% vs 0.5%, P = 1), minor complications (3.5% vs 2.5%, P = .56), or total bleeding complications (4.5% vs 3%, P = .43) between the apixaban and warfarin groups. There were no symptomatic thromboembolic complications. All dMRIs were negative for "new" silent cerebral ischemia in the apixaban group. CONCLUSION: Uninterrupted apixaban administration in patients undergoing AF ablation seems to be feasible and effective in preventing clinical and silent thromboembolic events without increasing the risk of major bleeding. PMID- 25728755 TI - Clinical and electrocardiographic characteristics of idiopathic ventricular arrhythmias with right bundle branch block and superior axis: Comparison of apical crux area and posterior septal left ventricle. AB - BACKGROUND: Right bundle branch block (RBBB) with superior axis electrocardiographic (ECG) morphology is common in patients with idiopathic ventricular arrhythmia (VA) originating from the left posterior fascicle (LPF), from the left ventricular (LV) posterior papillary muscles (PPM), and rarely from the cardiac apical crux. OBJECTIVE: The purpose of this study was to describe the ECG and clinical characteristics of idiopathic VA presenting with RBBB and superior axis. METHODS: We studied 40 patients who underwent successful catheter ablation of idiopathic VAs originating from the LPF (n = 18), LV PPM (n = 15), and apical crux (n = 7). We investigated clinical and ECG characteristics, including maximum deflection index and QRS morphology in leads aVR and V6. RESULTS: Syncope was more frequently seen in apical crux VA compared with other VAs (57% vs 6%, P < .001). Patients with apical crux VA more frequently had an maximum deflection index >=0.55 compared with LPF VA and PPM VA (P = .02). A monophasic R wave in aVR and QS or r/S ratio <0.15 in V6 (P < .001) could distinguish apical crux VA from other VAs with high accuracy. All patients with VA underwent attempted ablation in the endocardium (success rate: LPF 89%, PPM 80%, crux 14%). Only 1 of 7 patients with apical crux VA had acute success with ablation in the middle cardiac vein. In 2 of apical crux patients, epicardial ablation using subxiphoid approach was performed successfully. CONCLUSION: We could distinguish LPF VA, PPM VA, and apical crux VA using a combination of clinical and ECG characteristics. These findings might be useful for counseling patients and planning an ablation strategy. PMID- 25728756 TI - Miniaturized Reveal LINQ insertable cardiac monitoring system: First-in-human experience. AB - BACKGROUND: The Reveal LINQ is a miniaturized insertable cardiac monitor (ICM) with wireless telemetry for remote monitoring of patients with suspected arrhythmias. OBJECTIVE: The primary objective of this study was to evaluate the functionality of the Reveal LINQ system by measuring R-wave sensing and data transmission. METHODS: The Reveal LINQ Usability Study was a nonrandomized, prospective, multicenter trial. The study enrolled 30 patients with any indication for an ICM. Data were collected at baseline, implantation, and 1-month follow-up visits and through daily wireless transmissions. RESULTS: Thirty patients were enrolled and had a Reveal LINQ device implanted. The mean age was 55 +/- 15 years. All patients had successful implantation of the ICM in one of the recommended locations. Ease of implantation procedure was rated as easy or very easy for 90% of implantations. R-wave amplitudes were 0.584 +/- 0.325 mV at implantation and 0.596 +/- 0.336 mV at 1 month (P = .8). Automatic transmissions were successful 79.5% (69.5%-86.9%) of the time. Transmission failures that caused a delay in data transfer occurred because of incomplete data reception or patients being out of range in 45% and 42% of instances, respectively. For all patients, transmission failures were followed by successful automated or manual transmission of information on a subsequent day. The devices stored 217 arrhythmic episodes during 30 days of follow-up, identified as atrial fibrillation (n = 111), asystole (n = 95), bradycardia (n = 4), fast ventricular tachycardia (n = 1), and ventricular tachycardia ( n = 6). No serious procedure- or system-related adverse events occurred during the 1-month follow-up period. CONCLUSION: The miniaturized Reveal LINQ ICM supports arrhythmia detection and monitoring, achieving adequate sensing performance without safety issues. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01965899. PMID- 25728757 TI - Role of the polymer matrix on the photoluminescence of embedded CdSe quantum dots. AB - The photoluminescence (PL) of CdSe quantum dots (QDs) that form stable nanocomposites with polymer liquid crystals (LCs) as smectic C hydrogen-bonded homopolymers from a family of poly[4-(n-acryloyloxyalkyloxy)benzoic acids] is reported. The matrix that results from the combination of these units with methoxyphenyl benzoate and cholesterol-containing units has a cholesteric structure. The exciton PL band of QDs in the smectic matrix is redshifted with respect to QDs in solution, whereas a blueshift is observed with the cholesteric matrix. The PL lifetimes and quantum yield in cholesteric nanocomposites are higher than those in smectic ones. This is interpreted in terms of a higher order of the smectic matrix in comparison to the cholesteric one. CdSe QDs in the ordered smectic matrix demonstrate a splitting of the exciton PL band and an enhancement of the photoinduced differential transmission. These results reveal the effects of the structure of polymer LC matrices on the optical properties of embedded QDs, which offer new possibilities for photonic applications of QD-LC polymer nanocomposites. PMID- 25728758 TI - Detection of influenza A and B with the Alere TM i Influenza A & B: a novel isothermal nucleic acid amplification assay. AB - BACKGROUND: Rapid influenza diagnostic tests (RIDTs) have an important role in clinical decision-making; however, the performances of currently available assays vary widely. OBJECTIVES: We evaluated the performance of the Alere(TM) i Influenza A&B (Alere(TM) iNAT), a rapid isothermal nucleic acid amplification assay that has recently received FDA clearance, for the detection of influenza A and B viruses during the Australian influenza season of 2013. Results were compared to two other RIDTs tested in parallel; Quidel Sofia((r)) Influenza A+B fluorescent immunoassay (FIA) and Alere(TM) BinaxNOW((r)) Influenza A & B immunochromatographic (ICT) assay. METHODS: A total of 202 paired nasopharyngeal swabs collected from patients >= 16 years old with an influenza-like illness (ILI) were eluted in 2 ml of universal transport medium (UTM) that was used to perform all three RIDTs in parallel. Reverse-transcription polymerase chain reaction (RT-PCR) was used as the reference standard. RESULTS: Compared to RT PCR, Alere(TM) iNAT detected 77.8% influenza A positive samples versus 71.4% and 44.4% for the Quidel Sofia((r)) Influenza A+B FIA and BinaxNOW((r)) Influenza A & B ICT assay, respectively. For influenza B, Alere(TM) iNAT detected 75% of those positive by RT-PCR, versus 33.3% and 25.0% for Sofia((r)) and BinaxNOW((r)), respectively. The specificity of Alere(TM) iNAT was 100% for influenza A and 99% for influenza B. CONCLUSIONS: Alere(TM) i Influenza A&B is a promising new rapid influenza diagnostic assay with potential point-of-care applications. PMID- 25728759 TI - Screening method for stimulants in urine by UHPLC-MS/MS: identification of isomeric compounds. AB - A fast screening method for the detection of more than 60 stimulants in urine was developed. The method consisted of a dilution of the urine (1:5 v/v) and analysis by ultra high performance liquid chromatography coupled to tandem mass spectrometry, using a C18 column (1.7 um particle size), a mobile phase containing deionized water and acetonitrile with formic acid, and gradient elution. The chromatographic run time was 5 min. The detection was performed in positive mode electrospray ionization, monitoring one or two specific ion transitions for each analyte. Appropriate repeatability was obtained, with relative standard deviation (RSD) values below 25% for most of the analytes. Regarding intermediate precision, estimated during routine work, higher RSDs were obtained, probably due to between-day differences in the status of the mass spectrometer and in the chromatographic system. Matrix effect ranged from 60 to 255% with RSD lower than 35% for the majority of compounds. Despite the matrix effect observed, the signal/noise ratio of the analytes spiked at 50 ng/mL was greater than three in all tested samples, allowing a correct detection of all substances at the minimum required performance levels required by the World Anti Doping Agency and demonstrating the suitability of the method. The method was tested in administration study samples and satisfactorily in operation for more than one year with routine doping samples. The presence of isomeric stimulants with closely similar chromatographic and/or mass spectrometric properties did not allow the unequivocal identification of these compounds after the first analysis. Different possibilities for separation and identification of isomeric compounds are presented. PMID- 25728760 TI - Development of a fraction collection approach in capillary electrophoresis SELEX for aptamer selection. AB - Aptamers have attracted much attention due to their ability to bind to target molecules with high affinity and specificity. The development of an approach capable of efficiently generating aptamers through systematic evolution of ligands by exponential enrichment (SELEX) is particularly challenging. Herein, a fraction collection approach in capillary electrophoresis SELEX (FCE-SELEX) for the partition of a bound DNA-target complex is developed. By integrating fraction collection with a facile oil seal method for avoiding contamination while amplifying the bound DNA-target complex, in a single round of selection, a streptavidin-binding aptamer (SBA) has been generated. The affinity of aptamer SBA-36 for streptavidin (SA) is determined as 30.8 nM by surface plasmon resonance (SPR). Selectivity and biotin competition experiments demonstrate that the SBA-36 aptamer selected by FCE-SELEX is as efficient as those from other methods. Based on the ability of fraction collection in partition and collection of the aptamer-target complex from the original DNA library, FCE-SELEX can be a universal tool for the development of aptamers. PMID- 25728761 TI - Availability and price of malaria rapid diagnostic tests in the public and private health sectors in 2011: results from 10 nationally representative cross sectional retail surveys. AB - OBJECTIVES: To describe the state of the public and private malaria diagnostics market shortly after WHO updated its guidelines for testing all suspected malaria cases prior to treatment. METHODS: Ten nationally representative cross-sectional cluster surveys were conducted in 2011 among public and private health facilities, community health workers and retail outlets (pharmacies and drug shops) in nine countries (Tanzania mainland and Zanzibar surveyed separately). Eligible outlets had antimalarials in stock on the day of interview or had stocked antimalarials in the past 3 months. RESULTS: Three thousand four hundred and thirty-nine rapid diagnostic test (RDT) products from 39 manufacturers were audited among 12,197 outlets interviewed. Availability was typically highest in public health facilities, although availability in these facilities varied greatly across countries, from 15% in Nigeria to >90% in Madagascar and Cambodia. Private for-profit sector availability was 46% in Cambodia, 20% in Zambia, but low in other countries. Median retail prices for RDTs in the private for-profit sector ranged from $0.00 in Madagascar to $3.13 in Zambia. The reported number of RDTs used in the 7 days before the survey in public health facilities ranged from 3 (Benin) to 50 (Zambia). CONCLUSIONS: Eighteen months after WHO updated its case management guidelines, RDT availability remained poor in the private sector in sub-Saharan Africa. Given the ongoing importance of the private sector as a source of fever treatment, the goal of universal diagnosis will not be achievable under current circumstances. These results constitute national baselines against which progress in scaling-up diagnostic tests can be assessed. PMID- 25728762 TI - Why increased nuchal translucency is associated with congenital heart disease: a systematic review on genetic mechanisms. AB - This overview provides insight into the underlying genetic mechanism of the high incidence of cardiac defects in fetuses with increased nuchal translucency (NT). Nuchal edema, the morphological equivalent of increased NT, is likely to result from abnormal lymphatic development and is strongly related to cardiac defects. The underlying genetic pathways are, however, unknown. This study aims to present a systematic overview of genes involved in both cardiac and lymphatic development in mouse embryos. A search of PubMed and the Mammalian Phenotype Browser was performed. Fifteen candidate genes involved in both cardiac and lymphatic development were identified: Adrenomedullin; Chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII); Cyp51; Ephrin-B2; Forkhead box protein C2 (Foxc2); Nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1); Neurofibromatosis type 1 (Nf1); Phosphoinositide 3-kinase encoding isoform p110alpha (Pik3ca); Podoplanin; Prospero-related homeobox 1 (Prox1); T-box 1 (Tbx1); Tyrosine kinase with immunoglobulin-like and endothelial growth factor like domains 1 (Tie1); vascular endothelial growth factor (Vegf)-A; Vegf receptor 3 (Vegfr-3); and Vascular endothelial zinc finger 1 (Vezf1). Mutations in all but one gene (Pik3ca) resulted in both a cardiac defect and nuchal edema. Candidate genes - mainly encoding for endothelium - are involved in both cardiac and lymphatic development. Alterations in candidate genes are associated with the strong relation between increased NT and cardiac defects. PMID- 25728763 TI - Quantitative assessment of diffusional kurtosis anisotropy. AB - Diffusional kurtosis imaging (DKI) measures the diffusion and kurtosis tensors to quantify restricted, non-Gaussian diffusion that occurs in biological tissue. By estimating the kurtosis tensor, DKI accounts for higher order diffusion dynamics, when compared with diffusion tensor imaging (DTI), and consequently can describe more complex diffusion profiles. Here, we compare several measures of diffusional anisotropy which incorporate information from the kurtosis tensor, including kurtosis fractional anisotropy (KFA) and generalized fractional anisotropy (GFA), with the diffusion tensor-derived fractional anisotropy (FA). KFA and GFA demonstrate a net enhancement relative to FA when multiple white matter fiber bundle orientations are present in both simulated and human data. In addition, KFA shows net enhancement in deep brain structures, such as the thalamus and the lenticular nucleus, where FA indicates low anisotropy. Thus, KFA and GFA provide additional information relative to FA with regard to diffusional anisotropy, and may be particularly advantageous for the assessment of diffusion in complex tissue environments. PMID- 25728764 TI - Raman microscopy for cellular investigations--From single cell imaging to drug carrier uptake visualization. AB - Progress in advanced therapeutic concepts requires the development of appropriate carrier systems for intracellular drug delivery. Consequently, analysis of interaction between carriers, drugs and cells as well as their uptake and intracellular fate is a current focus of research interest. In this context, Raman spectroscopy recently became an emerging analytical technique, due to its non-destructive, chemically selective and label-free working principle. In this review, we briefly present the state-of-the-art technologies for cell visualization and drug internalization. Against this background, Raman microscopy is introduced as a versatile analytical technique. An overview of various Raman spectroscopy investigations in this field is given including interactions of cells with drug molecules, carrier systems and other nanomaterials. Further, Raman instrumentations and sample preparation methods are discussed. Finally, as the analytical limit is not reached yet, a future perspective for Raman microscopy in pharmaceutical and biomedical research on the single cell level is given. PMID- 25728765 TI - Parent-infant art psychotherapy: a creative dyadic approach to early intervention. AB - Art psychotherapy involves the use of the image-making process within a therapeutic relationship to help clients explore and communicate feelings and experiences. This article explores whether art psychotherapy groups can be an effective intervention for parent-infant dyads who may be involved with social work and health teams due to concerns about their relationship, possibly due to postnatal depression or attachment difficulties. We describe a model of parent infant art psychotherapy groups and examine some of the key themes in this intervention alongside vignettes of case work and quantitative and qualitative evidence from the evaluations of two such groups. We believe that the Create Together group demonstrates how knowledge from research into infant mental health and attachments, together with an understanding of the creative process, can be applied in practice to offer a successful early intervention. PMID- 25728766 TI - Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. AB - LKB1 is activated by forming a heterotrimeric complex with STRAD and MO25. Recent studies suggest that LKB1 has pro-oncogenic functions, besides acting as a tumor suppressor. How the LKB1 activity is maintained and how LKB1 regulates cancer development are largely unclear. Here we show that K63-linked LKB1 polyubiquitination by Skp2-SCF ubiquitin ligase is critical for LKB1 activation by maintaining LKB1-STRAD-MO25 complex integrity. We further demonstrate that oncogenic Ras acts upstream of Skp2 to promote LKB1 polyubiquitination by activating Skp2-SCF ubiquitin ligase. Moreover, Skp2-mediated LKB1 polyubiquitination is required for energy-stress-induced cell survival. We also detected overexpression of Skp2 and LKB1 in late-stage hepatocellular carcinoma (HCC), and their overexpression predicts poor survival outcomes. Finally, we show that Skp2-mediated LKB1 polyubiquitination is important for HCC tumor growth in vivo. Our study provides new insights into the upstream regulation of LKB1 activation and suggests a potential target, the Ras/Skp2/LKB1 axis, for cancer therapy. PMID- 25728767 TI - Structure of a biologically active estrogen receptor-coactivator complex on DNA. AB - Estrogen receptor (ER/ESR1) is a transcription factor critical for development, reproduction, metabolism, and cancer. ER function hinges on its ability to recruit primary and secondary coactivators, yet structural information on the full-length receptor-coactivator complex to complement preexisting and sometimes controversial biochemical information is lacking. Here, we use cryoelectron microscopy (cryo-EM) to determine the quaternary structure of an active complex of DNA-bound ERalpha, steroid receptor coactivator 3 (SRC-3/NCOA3), and a secondary coactivator (p300/EP300). Our structural model suggests the following assembly mechanism for the complex: each of the two ligand-bound ERalpha monomers independently recruits one SRC-3 protein via the transactivation domain of ERalpha; the two SRC-3s in turn bind to different regions of one p300 protein through multiple contacts. We also present structural evidence for the location of activation function 1 (AF-1) in a full-length nuclear receptor, which supports a role for AF-1 in SRC-3 recruitment. PMID- 25728768 TI - Proteasomal control of cytokinin synthesis protects Mycobacterium tuberculosis against nitric oxide. AB - One of several roles of the Mycobacterium tuberculosis proteasome is to defend against host-produced nitric oxide (NO), a free radical that can damage numerous biological macromolecules. Mutations that inactivate proteasomal degradation in Mycobacterium tuberculosis result in bacteria that are hypersensitive to NO and attenuated for growth in vivo, but it was not known why. To elucidate the link between proteasome function, NO resistance, and pathogenesis, we screened for suppressors of NO hypersensitivity in a mycobacterial proteasome ATPase mutant and identified mutations in Rv1205. We determined that Rv1205 encodes a pupylated proteasome substrate. Rv1205 is a homolog of the plant enzyme LONELY GUY, which catalyzes the production of hormones called cytokinins. Remarkably, we report that an obligate human pathogen secretes several cytokinins. Finally, we determined that the Rv1205-dependent accumulation of cytokinin breakdown products is likely responsible for the sensitization of Mycobacterium tuberculosis proteasome-associated mutants to NO. PMID- 25728769 TI - Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation. AB - Eosinophils are white blood cells that function in innate immunity and participate in the pathogenesis of various inflammatory and neoplastic disorders. Their secretory granules contain four cytotoxic proteins, including the eosinophil major basic protein (MBP-1). How MBP-1 toxicity is controlled within the eosinophil itself and activated upon extracellular release is unknown. Here we show how intragranular MBP-1 nanocrystals restrain toxicity, enabling its safe storage, and characterize them with an X-ray-free electron laser. Following eosinophil activation, MBP-1 toxicity is triggered by granule acidification, followed by extracellular aggregation, which mediates the damage to pathogens and host cells. Larger non-toxic amyloid plaques are also present in tissues of eosinophilic patients in a feedback mechanism that likely limits tissue damage under pathological conditions of MBP-1 oversecretion. Our results suggest that MBP-1 aggregation is important for innate immunity and immunopathology mediated by eosinophils and clarify how its polymorphic self-association pathways regulate toxicity intra- and extracellularly. PMID- 25728770 TI - Bursty gene expression in the intact mammalian liver. AB - Bursts of nascent mRNA have been shown to lead to substantial cell-cell variation in unicellular organisms, facilitating diverse responses to environmental challenges. It is unknown whether similar bursts and gene-expression noise occur in mammalian tissues. To address this, we combine single molecule transcript counting with dual-color labeling and quantification of nascent mRNA to characterize promoter states, transcription rates, and transcript lifetimes in the intact mouse liver. We find that liver gene expression is highly bursty, with promoters stochastically switching between transcriptionally active and inactive states. Promoters of genes with short mRNA lifetimes are active longer, facilitating rapid response while reducing burst-associated noise. Moreover, polyploid hepatocytes exhibit less noise than diploid hepatocytes, suggesting a possible benefit to liver polyploidy. Thus, temporal averaging and liver polyploidy dampen the intrinsic variability associated with transcriptional bursts. Our approach can be used to study transcriptional bursting in diverse mammalian tissues. PMID- 25728771 TI - MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial mesenchymal transition by regulating the co-repressor CtBP. AB - The ERK pathway not only upregulates growth-promoting genes, but also downregulates anti-proliferative and tumor-suppressive genes. In particular, ERK signaling contributes to repression of the E-cadherin gene during epithelial mesenchymal transition (EMT). The CtBP transcriptional co-repressor is also involved in gene silencing of E-cadherin. However, the functional relationship between ERK signaling and CtBP is unknown. Here, we identified an ERK substrate, designated MCRIP1, which bridges ERK signaling and CtBP-mediated gene silencing. CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E cadherin promoter by inducing chromatin modifications. Our findings reveal a molecular mechanism underlying ERK-induced epigenetic gene silencing during EMT and its dysregulation in cancer. PMID- 25728772 TI - Analysis of low-field isotropic vortex glass containing vortex groups in YBa2Cu3O(7-x) thin films visualized by scanning SQUID microscopy. AB - The glass-like vortex distribution in pulsed laser deposited YBa2Cu3O(7-x) thin films is observed by scanning superconducting quantum interference device microscopy and analysed for ordering after cooling in magnetic fields significantly smaller than the Earth's field. Autocorrelation calculations on this distribution show a weak short-range positional order, while Delaunay triangulation shows a near-complete lack of orientational order. The distribution of these vortices is finally characterised as an isotropic vortex glass. Abnormally closely spaced groups of vortices, which are statistically unlikely to occur, are observed above a threshold magnetic field. The origin of these groups is discussed, but will require further investigation. PMID- 25728773 TI - Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. AB - Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms. PMID- 25728774 TI - A somatic MAP3K3 mutation is associated with verrucous venous malformation. AB - Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM_002401.3, c.1323C>G; NP_002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans. PMID- 25728775 TI - De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay. AB - Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129*]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024*]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease. PMID- 25728778 TI - Prenatal cranial ossification of the humpback whale (Megaptera novaeangliae). AB - Being descendants of small terrestrial ungulate mammals, whales underwent enormous transformations during their evolutionary history, that is, extensive changes in anatomy, physiology, and behavior were evolved during secondary adaptations to life in water. However, still only little is known about whale ontogenetic development, which help to identify the timing and sequence of critical evolutionary events, such as modification of the cetacean ear. This is particularly true for baleen whales (Mysticeti), the group including the humpback whale Megaptera novaeangliae. We use high-resolution X-ray computed tomography to reinvestigate humpback whale fetuses from the Kukenthal collection at the Museum fur Naturkunde, Berlin, thus, extending historic descriptions of their skeletogenesis and providing for the first time sequences of cranial ossification for this species. Principally, the ossification sequence of prenatal Megaptera follows a typical mammalian pattern with the anterior dermal bones being the first ossifying elements in the skull, starting with the dentary. In contrast to other mammals, the ectotympanic bone ossifies at an early stage. Alveolar structure can be observed in both the maxillae and dentaries in these early prenatal specimens but evidence for teeth is lacking. Although the possibility of obtaining new embryological material is unlikely due to conservation issues, our study shows that reexamination of existing specimens employing new technologies still holds promise for filling gaps in our knowledge of whale evolution and ontogeny. PMID- 25728777 TI - Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. AB - Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: NM_001099412.1: c.3116_3117 delCT, p.(Ser1039*); c.3830_3831insTT, p.(Arg1278Serfs*17); c.3879 dupA, p.(Glu1294Argfs*19); c.4108G>T p.(Glu1370*) and c.4292 dupT, p.(Leu1431Phefs*8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects. PMID- 25728776 TI - Mutations in the NHEJ component XRCC4 cause primordial dwarfism. AB - Non-homologous end joining (NHEJ) is a key cellular process ensuring genome integrity. Mutations in several components of the NHEJ pathway have been identified, often associated with severe combined immunodeficiency (SCID), consistent with the requirement for NHEJ during V(D)J recombination to ensure diversity of the adaptive immune system. In contrast, we have recently found that biallelic mutations in LIG4 are a common cause of microcephalic primordial dwarfism (MPD), a phenotype characterized by prenatal-onset extreme global growth failure. Here we provide definitive molecular genetic evidence supported by biochemical, cellular, and immunological data for mutations in XRCC4, encoding the obligate binding partner of LIG4, causing MPD. We report the identification of biallelic mutations in XRCC4 in five families. Biochemical and cellular studies demonstrate that these alterations substantially decrease XRCC4 protein levels leading to reduced cellular ligase IV activity. Consequently, NHEJ dependent repair of ionizing-radiation-induced DNA double-strand breaks is compromised in XRCC4 cells. Similarly, immunoglobulin junctional diversification is impaired in cells. However, immunoglobulin levels are normal, and individuals lack overt signs of immunodeficiency. Additionally, in contrast to individuals with LIG4 mutations, pancytopenia leading to bone marrow failure has not been observed. Hence, alterations that alter different NHEJ proteins give rise to a phenotypic spectrum, from SCID to extreme growth failure, with deficiencies in certain key components of this repair pathway predominantly exhibiting growth deficits, reflecting differential developmental requirements for NHEJ proteins to support growth and immune maturation. PMID- 25728779 TI - The role of the miR-31/FIH1 pathway in TGF-beta-induced liver fibrosis. AB - The miRNAs are small, non-coding RNAs that regulate various biological processes, including liver fibrosis. Hepatic stellate cells (HSCs) play a central role in the pathogenesis of liver fibrosis. By microarray profiling and real-time PCR, we noted that miR-31 expression in HSCs from rats, mice and humans was significantly increased during HSC activation in culture. Overall, miR-31 expression levels were unchanged in the whole-liver RNA extracts from fibrotic rat and human samples. Nevertheless, we found that miR-31 was particularly up-regulated in HSCs but not in hepatocytes during fibrogenesis. Thus, we hypothesized that miR-31 may mediate liver fibrosis. In the present study, we found that inhibition of miR-31 expression significantly inhibited HSC activation, whereas its over-expression obviously promoted HSC activation. Moreover, over-expression of miR-31 promoted HSC migration by enhancing matrix metalloproteinase (MMP)-2 expression whereas inhibition of miR-31 has an opposite effect. The biological function of miR-31 during HSC activation might be through targeting FIH1, a suppressor of hypoxia inducible factor (HIF-1), because a knockdown of FIH1 by shRNA could mimic the effects of miR-31. In addition, primary rat HSCs were isolated and treated with different cytokines, such as transforming growth factor beta (TGF-beta), vascular endothelial growth factor and platelet-derived growth factor-BB, to evaluate upstream regulators of miR-31. We found that only TGF-beta, a pivotal regulator in liver fibrosis, remarkably increased miR-31 expression in HSCs. And the effects of TGF-beta on HSCs can be partially counteracted by inhibition of miR 31. In addition, chromatin immunoprecipitation experiments and the luciferase reporter assay demonstrated that Smad3, a major TGF-beta-downstream transcription factor, stimulated the transcription activity of miR-31 by binding directly to miR-31's promoter. In conclusion, the miR-31/FIH1 pathway associates with liver fibrosis, perhaps by participation in the TGF-beta/Smad3 signalling of HSCs. PMID- 25728780 TI - [Off-label use of calcium channel blockers for tocolysis - Methods and organization]. PMID- 25728781 TI - [Maintenance tocolysis with calcium channel blockers]. AB - AIM OF THE STUDY: The objective of initial tocolysis is to prolong pregnancy for 48 hours, in order to allow fetal lung maturation with corticosteroids. Maintenance tocolysis is defined by the prolongation of tocolytic therapy beyond 48 h. Although the 2002 guidelines of the French College did not recommend to prolong tocolysis beyond 48 h, about 60% of obstetricians prescribe maintenance tocolysis. METHOD: Nifedipine is the most frequently used treatment for maintenance tocolysis. Five randomised studies and two metaanalyses have compared maintenance tocolysis with nifedipine, with placebo or no treatment. RESULTS CONCLUSION: Maintenance tocolysis with calcium channel blockers does not reduce the risk of preterm birth and does not improve perinatal outcome. Tocolytic treatment after 48 hours of initial tocolysis has no beneficial effect (level of evidence 1). PMID- 25728782 TI - [Efficiency and tolerance of calcium channel blockers as first-line tocolysis]. AB - Calcium channel blockers are widely used as first-line tocolytic, but prescribed off-label for this indication. The primary objective of this review is to evaluate the efficiency and safety of calcium channel blockers compared to placebo and to all tocolytic agents used. This review concerns the randomized trials, comparative studies and meta-analyzes of randomized trials on the subject. Nifedipine is superior to placebo in reducing the risk of delivery within 48 hours (RR=0.3; 95 % CI [0.21-0.43]), but induces more maternal side effects (RR=3.8; 95 % CI [1.02-16.92]). The effectiveness of nifedipine is greater than that of betamimetics to prolong pregnancy beyond 48 hours (OR=1.52; 95 % CI [1.03-2.24]), and up to 34 weeks (OR=1.87; 95 % CI [1.11-3.15]), with a lower incidence of adverse events requiring discontinuation of treatment in case of use of nifedipine (RR=0.22; 95 % CI [0.10-0.48]), but no significant difference in neonatal mortality. Efficacy of nifedipine is similar to that of oxytocin antagonists to prolong pregnancy beyond 48 hours (RR=0.92; 95 % CI [0.37 2.30]), but causes more mild maternal adverse events (RR=2.61, 95 % CI [1.43 4.74]). Nicardipine is not evaluated as nifedipine as a tocolytic treatment. It appears as effective as salbutamol and appears to have fewer maternal side effects than IV salbutamol. PMID- 25728783 TI - [Calcium channel blockers pharmacology and their use as tocolytics]. AB - Nifedipine and nicardipine are both calcium channel inhibitors, used off-label as tocolytics in preterm labour. Their use is related to their relaxing effects on uterin muscle by L-type voltage dependent calcium channels blockade. This article describes pharmacological effects, pharmacokinetics properties and tolerance of these drugs. It also discusses serious adverse effects, such as pulmonary edema, reported with both nifedipine and nicardipine in preterm labour. PMID- 25728784 TI - [Use of calcium channel blockers (CCB) for tocolysis in France and abroad]. AB - OBJECTIVES: Calcium channel blockers (CCB) are routinely off-label used for tocolysis. The purpose of this study is to establish an inventory of the use of CCB for tocolysis in France and abroad. MATERIALS AND METHODS: Four complementary approaches were performed: (i) a literature review of clinical practice and guidelines of scientific societies; (ii) a national declarative practice survey among French tertiary care centers; (iii) a regional declarative practice survey among all maternities of the Midi-Pyrenees Perinatal Network (MATERMIP); (iv) an evaluation of outpatient tocolysis prescription, analyzing the departmental database EFEMERIS in order to examine drug prescribing during pregnancy. RESULTS: CCB appear to be currently used as first-line, initial tocolysis, in the majority of French maternity hospitals (82.5% of tertiary care centers). Oral Nifedipine is the predominant regimen (86%). CCB utilization rates appear higher than those reported in 2005 in the EVAPRIMA study. Beta-agonists appear rarely prescribed in 1st line (poor maternal tolerance) and even abandoned by many institutions (75% of tertiary care centers). Using a maintenance tocolysis (usually by long-acting CCB) seems to vary depending on the hospitals. It would be prescribed in more than 50% of cases (and probably more in type 1 or 2 hospitals), despite the lack of demonstrated benefit. Furthermore, we can estimate that about 1.5 to 2% of outpatient pregnant women receive a prescription of Nifedipine LP in France. CONCLUSION: CCB (especially Nifedipine) are widely used in the treatment of threatened preterm labor in France, regardless of the type of hospital. The terms of off-label prescribing are not met. PMID- 25728786 TI - Quantifying protein sequences with reference to the genetic code. AB - Although the analysis of protein molecules is extensive, their primary sequences have yet to be quantified like their mass or size. The composition and particular arrangement of amino acids in proteins confers the distinct biochemical functionality, but it remains unclear why only a tiny proportion of possible character combinations are potentially functional. Here, I offer a simple but effective technique, utilizing the assignment of codons in the genetic code, that permits the quantification of polypeptide sequences and establishes statistical parameters through which they can now be numerically compared. Two main tests were conducted, one analyzing the composition and the other the specific order of the amino acids within the primary sequence. The results confirm that natural proteins are significantly different to random heteropolymers of equivalent size, although this is much more marginal in the case of the arrangement than it is for the composition. Moreover, they reveal that there are key patterns that have hitherto not been identified, relevant to the the study of the evolution of proteins, and which raise doubts about the plausibility of some purported cases of the de novo origination of protein-coding genes from intergenic DNA. Despite the fact that the applicability of quantification to the design of novel proteins is probably limited, it nonetheless provides a useful guideline that could complement much more precise methods. PMID- 25728785 TI - Quantitative proteomics analysis of the Arg/N-end rule pathway of targeted degradation in Arabidopsis roots. AB - According to the Arg/N-end rule pathway, proteins with basic N-termini are targeted for degradation by the Arabidopsis thaliana E3 ligase, PROTEOLYSIS6 (PRT6). Proteins can also become PRT6 substrates following post-translational arginylation by arginyltransferases ATE1 and 2. Here, we undertook a quantitative proteomics study of Arg/N-end rule mutants, ate1/2 and prt6, to investigate the impact of this pathway on the root proteome. Tandem mass tag labelling identified a small number of proteins with increased abundance in the mutants, some of which represent downstream targets of transcription factors known to be N-end rule substrates. Isolation of N-terminal peptides using terminal amine isotope labelling of samples (TAILS) combined with triple dimethyl labelling identified 1465 unique N-termini. Stabilising residues were over-represented among the free neo-N-termini, but destabilising residues were not markedly enriched in N-end rule mutants. The majority of free neo-N-termini were revealed following cleavage of organellar targeting signals, thus compartmentation may account in part for the presence of destabilising residues in the wild-type N-terminome. Our data suggest that PRT6 does not have a marked impact on the global proteome of Arabidopsis roots and is likely involved in the controlled degradation of relatively few regulatory proteins. All MS data have been deposited in the ProteomeXchange with identifier PXD001719 (http://proteomecentral.proteomexchange.org/dataset/PXD001719). PMID- 25728787 TI - Fungal disease dynamics in insect societies: optimal killing rates and the ambivalent effect of high social interaction rates. AB - Entomopathogenic fungi are potent biocontrol agents that are widely used against insect pests, many of which are social insects. Nevertheless, theoretical investigations of their particular life history are scarce. We develop a model that takes into account the main distinguishing features between traditionally studied diseases and obligate killing pathogens, like the (biocontrol-relevant) insect-pathogenic fungi Metarhizium and Beauveria. First, obligate killing entomopathogenic fungi produce new infectious particles (conidiospores) only after host death and not yet on the living host. Second, the killing rates of entomopathogenic fungi depend strongly on the initial exposure dosage, thus we explicitly consider the pathogen load of individual hosts. Further, we make the model applicable not only to solitary host species, but also to group living species by incorporating social interactions between hosts, like the collective disease defences of insect societies. Our results identify the optimal killing rate for the pathogen that minimises its invasion threshold. Furthermore, we find that the rate of contact between hosts has an ambivalent effect: dense interaction networks between individuals are considered to facilitate disease outbreaks because of increased pathogen transmission. In social insects, this is compensated by their collective disease defences, i.e., social immunity. For the type of pathogens considered here, we show that even without social immunity, high contact rates between live individuals dilute the pathogen in the host colony and hence can reduce individual pathogen loads below disease-causing levels. PMID- 25728788 TI - Short nucleotide sequences in herpesviral genomes identical to the human DNA. AB - In 2010, we described many similar DNA sequences in human and viral genomes, including herpesviral ones. The data obtained allowed us to suggest that these motifs may provide the antiviral protection by mating with a complementary potential target and destroying it by the catalytic way like small interfering RNA, siRNA. Since we have analyzed these viruses as a group, two major issues seemed to us curious: (1) the number of such motifs in genomes of various herpesvirus types, and (2) distribution of these motifs in an individual viral genome. Here we searched only the herpesviral genomes for short (>20nt) continuous sequences (hits) that are totally identical to the sequences of human DNA. We found that different viral genes and genomes of different herpesviruses contain different amount of such hits. Assuming like in previous paper that the density of these hits in viral genes is associated with the probability to be targets for cellular siRNA, we consider the genomic allocation of this density as a hypothetical targetome map of the human herpesviruses. We combined all nine types of herpesviruses in the three groups according the hit concentration in their genomes and found that the resulting sequence corresponds to the type of cellular pathology caused by a virus. We do not assert now that this trend also relates to other human viruses or other viruses in general. As the GenBank continues to fill, it would be highly advisable to conduct further relevant research. We also suggested that a high hits concentration we found in the gene RL1 (ICP34.5) of the herpes simplex virus type 1 (HSV1) can make this gene a likely target for putative cellular endogenous siRNA. Artificial blockade of the gene RL1 attaches oncolytic properties to HSV1, and we do not exclude the possibility that part of the HSV1 population in humans with blocked RL1 in vivo, may participate in early anti-cancer protection during the reactivation of the virus from the latent state. PMID- 25728789 TI - Towards a complex system understanding of bipolar disorder: A map based model of a complex winnerless competition. AB - Bipolar disorder is characterized by repeated erratic episodes of mania and depression, which can be understood as pathological complex system behavior involving cognitive, affective and psychomotor disturbance. In order to illuminate dynamical aspects of the longitudinal course of the illness, we propose here a novel complex model based on the notion of competition between recurrent maps, which mathematically represent the dynamics of activation in excitatory (Glutamatergic) and inhibitory (GABAergic) pathways. We assume that manic and depressive states can be considered stable sub attractors of a dynamical system through which the mood trajectory moves. The model provides a theoretical framework which can account for a number of complex phenomena of bipolar disorder, including intermittent transition between the two poles of the disorder, rapid and ultra-rapid cycling of episodes and manicogenic effects of antidepressants. PMID- 25728790 TI - Two-part zero-inflated negative binomial regression model for quantitative trait loci mapping with count trait. AB - Poisson regression models provide a standard framework for quantitative trait locus (QTL) mapping of count traits. In practice, however, count traits are often over-dispersed relative to the Poisson distribution. In these situations, the zero-inflated Poisson (ZIP), zero-inflated generalized Poisson (ZIGP) and zero inflated negative binomial (ZINB) regression may be useful for QTL mapping of count traits. Added genetic variables to the negative binomial part equation, may also affect extra zero data. In this study, to overcome these challenges, I apply two-part ZINB model. The EM algorithm with Newton-Raphson method in the M-step uses for estimating parameters. An application of the two-part ZINB model for QTL mapping is considered to detect associations between the formation of gallstone and the genotype of markers. PMID- 25728791 TI - Quantitative proteomics reveals a novel role of karyopherin alpha 2 in cell migration through the regulation of vimentin-pErk protein complex levels in lung cancer. AB - Karyopherin alpha 2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis. Herein, to understand the essential role of KPNA2 protein complexes in cancer progression, we applied stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomic strategy combined with immunoprecipitation (IP) to investigate the differential KPNA2 protein complexes in lung adenocarcinoma cell lines with different invasiveness potentials. We found that 64 KPNA2-interaction proteins displayed a 2-fold difference in abundance between CL1-5 (high invasiveness) and CL1-0 (low invasiveness) cells. Pathway map analysis revealed that the formation of complexes containing KPNA2 and cytoskeleton-remodeling related proteins, including actin, beta tubulin, tubulin heterodimers, vimentin, keratin 8, keratin 18, and plectin, was associated with cancer invasiveness. IP demonstrated that the levels of KPNA2-vimentin-pErk complexes were significantly higher in CL1-5 cells than in CL1-0 cells. The KPNA2-vimentin-pErk complex was also up-regulated in the advanced stage compared with the early-stage lung adenocarcinoma tissues. Importantly, the levels of pErk as well as cell migration ability were significantly reduced in KPNA2-knockdown cells; however, migration was restored by treatment with pErk phosphatase inhibitors. Collectively, our results demonstrate the usefulness of a SILAC-based proteomic strategy for identifying invasiveness-associated KPNA2 protein complexes and provide new insight into the KPNA2-mediated modulation of cell migration. PMID- 25728793 TI - In silico platform for predicting and initiating beta-turns in a protein at desired locations. AB - Numerous studies have been performed for analysis and prediction of beta-turns in a protein. This study focuses on analyzing, predicting, and designing of beta turns to understand the preference of amino acids in beta-turn formation. We analyzed around 20,000 PDB chains to understand the preference of residues or pair of residues at different positions in beta-turns. Based on the results, a propensity-based method has been developed for predicting beta-turns with an accuracy of 82%. We introduced a new approach entitled "Turn level prediction method," which predicts the complete beta-turn rather than focusing on the residues in a beta-turn. Finally, we developed BetaTPred3, a Random forest based method for predicting beta-turns by utilizing various features of four residues present in beta-turns. The BetaTPred3 achieved an accuracy of 79% with 0.51 MCC that is comparable or better than existing methods on BT426 dataset. Additionally, models were developed to predict beta-turn types with better performance than other methods available in the literature. In order to improve the quality of prediction of turns, we developed prediction models on a large and latest dataset of 6376 nonredundant protein chains. Based on this study, a web server has been developed for prediction of beta-turns and their types in proteins. This web server also predicts minimum number of mutations required to initiate or break a beta-turn in a protein at specified location of a protein. PMID- 25728792 TI - Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver. AB - Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60 mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non-compartmental pharmacokinetic parameters were as follows: half-life 7.37 +/- 1.22 hr; volume of distribution 44.62 +/- 11.45 L; area under the curve 14.82 +/- 2.71 hr/(MUg/mL); and clearance 4.15 +/- 0.70 L/hr. Rapid theophylline distribution across the placenta was observed. Maternal non-compartmental pharmacokinetic parameters were as follows: half-life 6.54 +/- 2.44 hr; volume of distribution 32.48 +/- 9.99 L; area under the curve 16.28 +/- 4.53 hr/(MUg/mL); and clearance 3.69 +/- 1.47 L/hr. Foetal and ewe serum concentration-time profiles were fit together into a 3-compartment population pharmacokinetic model, and parameters were as follows: central volume 1.38 +/- 0.11 L; 2nd peripheral compartment volume 3.11 +/- 0.29 L; 3rd peripheral compartment volume 60.14 +/- 6.02 L; elimination clearance 9.89 +/- 0.90 L/hr; distribution clearance between central and 2nd compartment 30.87 +/- 2.31 L/hr; and distribution clearance between 2nd and 3rd compartments 13.89 +/- 1.11 L/hr. Cytochrome P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7 +/- 4.4 versus 42.0 +/- 3.6%-bound). Free concentrations were lower in the foetus than in the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity. PMID- 25728794 TI - Insomnia and incident depression: role of objective sleep duration and natural history. AB - Longitudinal studies that have examined the association of insomnia with incident depression using objective sleep measures are very limited. The aim of this study was to examine the predictive role of the severity of insomnia for incident depression in a general population sample using psychometric and polysomnographic data. From a random, general population sample of 1741 individuals of the Penn State Adult Cohort, 1137 adults without depression were followed up with a structured telephone interview after 7.5 years. All subjects completed a full medical evaluation, 1-night polysomnogram and Multiphasic Minnesota Personality Inventory at baseline. The incidence of depression was 15%. Poor sleep (odds ratio = 1.5, P = 0.001) and insomnia (odds ratio = 1.9, P = 0.031) were significantly associated with incident depression. The odds of incident depression were highest (odds ratio = 2.2, P = 0.019) in insomnia with objective short sleep duration and independent of Multiphasic Minnesota Personality Inventory Ego Strength scores, an index of poor coping resources. The persistence of insomnia and worsening of poor sleep into insomnia significantly increased the odds of incident depression (odds ratios ranged from 1.8 to 6.3), whereas their full remission did not (odds ratio ranged from 1.2 to 1.8). Insomnia with short sleep duration is associated with incident depression independent of poor coping resources, whereas the association of insomnia with normal sleep duration with incident depression was mediated by poor coping resources. Persistence and worsening of poor sleep or insomnia, but not their full remission, are significant predictors of incident depression. These data suggest that there is a significant relationship between the severity of insomnia and incident depression. PMID- 25728795 TI - Environmentally friendly synthesis of p-doped reduced graphene oxide with high dispersion stability by using red table wine. AB - Reduced graphene oxide (rGO) with high dispersion stability and p-type semiconducting property was synthesized by using environmentally friendly mussel inspired chemistry with red table wine. (+)-Catechin and tannic acid, polyphenolic model compounds present in wine, were selected and successfully utilized for the synthesis of soluble polycatechol-functionalized rGO. PMID- 25728797 TI - Stepwise Information-Filtering Tool (SIFT): A method for using risk assessment metadata in a nontraditional way. AB - Tools exist to evaluate large ecotoxicity databases for risk assessment purposes, but these tools are less useful for alternative analytical purposes. In the present study, the authors developed the Stepwise Information-Filtering Tool (SIFT), a strategic method to select relevant, reliable data from a large ecotoxicity database; demonstrated utility in a case study of chronic toxicity data for statistical endpoint comparison purposes; and evaluated SIFT by comparison with 2 existing data evaluation methods. PMID- 25728796 TI - H2O2 release from the very long chain acyl-CoA dehydrogenase. AB - Enhanced mitochondrial generation of oxidants, including hydrogen peroxide (H2O2), is related to a large number of pathological conditions, including diet induced obesity and steatohepatosis. Indeed, we have previously shown that high fat diets increase the generation of H2O2 in liver mitochondria energized by activated fatty acids. Here, we further study fatty-acid induced H2O2 release in liver mitochondria, and determine the characteristics that regulate it. We find that this production of H2O2 is independent of mitochondrial inner membrane integrity and insensitive to purine nucleotides. On the other hand, palmitate induced H2O2 production is strongly enhanced by high fat diets and is pH sensitive, with a peak at a matrix pH of ~8.5. Using recombinantly expressed human very long chain acyl-CoA dehydrogenase, we are able to demonstrate that palmitate-induced H2O2 release may be ascribed to the activity of this enzyme alone, acting as an oxidase. Our results add to a number of findings indicating that sources outside of the electron transport chain can generate significant, physiopathologically relevant, amounts of oxidants in mitochondria. PMID- 25728798 TI - In-patient step count predicts re-hospitalization after cardiac surgery. AB - BACKGROUND: Clinical significance of in-patient step count after cardiac surgery remains unknown. The aim of this study was to determine whether the number of steps walked during the in-patient stay after cardiac surgery predicts the risk of cardiac re-hospitalization in the following year. METHODS: One hundred and thirty-three patients who underwent cardiac surgery were included in this study. The number of steps was assessed using a triaxial accelerometer. One year after surgery, patients completed a postal survey to determine their health condition and occurrence of cardiac re-hospitalization. RESULTS: The mean number of steps walked during the last three in-patient days was 2460 +/- 1549 (mean +/- standard deviation). Of the 133 patients, there were 16 cases (12.0%) of cardiac re hospitalization during the 1-year follow-up period. The average step count before discharge was significantly lower in the 16 patients who were re-hospitalized for cardiac causes (1297 +/- 1232 versus 2620 +/- 1524, p<0.01). The cut-off value that predicted the occurrence of cardiac re-hospitalization on the receiver operating curve was 1308 steps (area under the curve: 0.783, p<0.001, sensitivity: 0.814, specificity: 0.733). Cox proportional hazards analysis revealed that the strongest predictor of cardiac re-hospitalization was a low step count prior to discharge (<=1308 steps, hazard ratio: 7.58; 95% confidence interval: 2.04-28.22). CONCLUSIONS: In-patient step count appears to be a risk factor for cardiac re-hospitalization within the first year following cardiac surgery. Further studies are needed to clarify the clinical significance of step count both preoperatively and following discharge. PMID- 25728799 TI - Distribution and density of contacts from noradrenergic and serotonergic boutons on the dendrites of neck flexor motoneurons in the adult cat. AB - Serotonergic (5-HT) and noradrenergic (NA) input to spinal motoneurons is essential for generating plateau potentials and self-sustained discharges. Extensor motoneurons are densely innervated by 5-HT and NA synapses and have robust plateau potentials and self-sustained discharges. Conversely, plateau potentials and self-sustained discharges are very rare in flexor motoneurons. The most likely reasons for this difference are that flexor motoneurons have few 5-HT and NA synapses and/or they are distributed distant to the channels responsible for plateau potentials and self-sustained discharges. However, the distribution of 5-HT and NA synapses on flexor motoneurons is unknown. Here we describe the distribution and density of 5-HT and NA synapses on motoneurons that innervate the flexor neck muscle, rectus capitis anterior (RCA), in the adult cat. Using a combination of intracellular staining, fluorescent immunohistochemistry, and 3D reconstruction techniques, we found that 5-HT and NA synapses are widely distributed throughout the dendritic trees of RCA motoneurons, albeit with a strong bias to small-diameter dendrites and to medial dendrites in the case of NA contacts. The number of 5-HT and NA contacts per motoneuron ranged, respectively, from 381 to 1,430 and from 642 to 1,382, which is 2.3- and 1.4-fold less than neck extensor motoneurons (Montague et al., J Comp Neurol 2013;521:638-656). These results suggest that 5-HT and NA synapses on flexor motoneurons may provide a powerful means of amplifying synaptic currents without incurring plateau potentials or self-sustained discharges. This feature is well suited to meet the biomechanical demands imposed on flexor muscles during different motor tasks. PMID- 25728801 TI - Traces of forgotten historical events in mountain communities in Central Italy: A genetic insight. AB - OBJECTIVES: Analysis of human genetic variation in mountain communities can shed light on the peopling of mountainous regions, perhaps revealing whether the remote geographic location spared them from outside invasion and preserved their gene pool from admixture. In this study, we created a model to assess genetic traces of historical events by reconstructing the paternal and maternal genetic history of seven small mountain villages in inland valleys of Central Italy. METHODS: The communities were selected for their geographic isolation, attested biodemographic stability, and documented history prior to the Roman conquest. We studied the genetic structure by analyzing two hypervariable segments (HVS-I and HVS-II) of the mtDNA D-loop and several informative single nucleotide polymorphisms (SNPs) of the mtDNA coding region in 346 individuals, in addition to 17 short tandem repeats (STRs) and Y-chromosome SNPs in 237 male individuals. RESULTS: For both uniparental markers, most of the haplogroups originated in Western Europe while some Near Eastern haplogroups were identified at low frequencies. However, there was an evident genetic similarity between the Central Italian samples and Near Eastern populations mainly in the male genetic pool. CONCLUSIONS: The samples highlight an overall European genetic pattern both for mtDNA and Y chromosome. Notwithstanding this scenario, Y chromosome haplogroup Q, a common paternal lineage in Central/Western Asia but almost Europe-wide absent, was found, suggesting that Central Italy could have hosted a settlement from Anatolia that might be supported by cultural, topographic and genetic evidence. PMID- 25728803 TI - Is there a role for intraoperative flow cytometry in brain tumor surgery? PMID- 25728804 TI - Primary care management of vitamin D deficiency and liver disease. AB - PURPOSE: Vitamin D deficiency is one of the most common medical conditions. Up to 96% of patients with liver disease have this deficiency. The purpose of this manuscript is to educate primary care nurse practitioners (NPs) of vitamin D deficiency and its proper management in patients with liver disease. DATA SOURCES: Information was compiled by reviewing the scientific literature on cirrhosis, liver disease, and vitamin D deficiency (CINAHL, MEDLINE, PubMed search engines). CONCLUSIONS: While the usual supplement dose for vitamin D deficiency is 1000 international units (vitamin D3 ) daily, vitamin D2 supplementation at doses of 50,000 international units can be given for correction. Primary care NPs can assist patients with liver disease with optimal nutrition and vitamin supplementation. IMPLICATIONS FOR PRACTICE: Primary care NPs should be aware of vitamin D deficiency in patients with liver disease. Vitamin D supplementation may be required in high doses in those patients with a moderate to severe deficiency. Repeat 25-hydroxyvitamin D levels should be checked after supplementation is completed and yearly thereafter. PMID- 25728802 TI - Modular organization of the white spruce (Picea glauca) transcriptome reveals functional organization and evolutionary signatures. AB - Transcript profiling has shown the molecular bases of several biological processes in plants but few studies have developed an understanding of overall transcriptome variation. We investigated transcriptome structure in white spruce (Picea glauca), aiming to delineate its modular organization and associated functional and evolutionary attributes. Microarray analyses were used to: identify and functionally characterize groups of co-expressed genes; investigate expressional and functional diversity of vascular tissue preferential genes which were conserved among Picea species, and identify expression networks underlying wood formation. We classified 22 857 genes as variable (79%; 22 coexpression groups) or invariant (21%) by profiling across several vegetative tissues. Modular organization and complex transcriptome restructuring among vascular tissue preferential genes was revealed by their assignment to coexpression groups with partially overlapping profiles and partially distinct functions. Integrated analyses of tissue-based and temporally variable profiles identified secondary xylem gene networks, showed their remodelling over a growing season and identified PgNAC-7 (no apical meristerm (NAM), Arabidopsis transcription activation factor (ATAF) and cup-shaped cotyledon (CUC) transcription factor 007 in Picea glauca) as a major hub gene specific to earlywood formation. Reference profiling identified comprehensive, statistically robust coexpressed groups, revealing that modular organization underpins the evolutionary conservation of the transcriptome structure. PMID- 25728805 TI - Matricellular protein SPARC/osteonectin expression is regulated by DNA methylation in its core promoter region. AB - BACKGROUND: SPARC/osteonectin is an evolutionarily conserved matricellular protein that modulates cell-matrix interaction and cell function. In all vertebrates, SPARC is dynamically expressed during embryogenesis. However, the precise function of SPARC and the regulatory elements required for its expression in particular during early embryogenesis are largely unknown. RESULTS: The present study was undertaken to explore the molecular mechanisms that regulate sparc gene expression by in vivo functional characterization of the sparc promoter and identification of possible putative regulatory elements that govern basal promoter activity. We report here transient expression analyses of eGFP expression from transgenic zebrafish containing a Sparc-iTol2-eGFP-BAC and/or 7.25 kb-sparc-Tol2-eGFP constructs. eGFP expression was specifically found in the notochord, otic vesicle, fin fold, intermediate cell mass, and olfactory placode of BAC and Tol2 transposon vectors injected embryos. Deletion analysis revealed that promoter activity resides in the unique 5'-untranslated intronic region. Computer-based analysis revealed a putative CpG island immediately proximal to the translation start site within the intron sequence. Global inhibition of methylation with 5-Aza-2-deoxycytidine promoted sparc expression in association with decreasing CpG methylation. CONCLUSIONS: Taken together, these data identify a contributory role for DNA methylation in regulating sparc expression in zebrafish embryogenesis. PMID- 25728806 TI - Molecularly imprinted polymer nanomaterials and nanocomposites: atom-transfer radical polymerization with acidic monomers. AB - Molecularly imprinted polymers (MIPs) are artificial receptors which can be tailored to bind target molecules specifically. A new method, using photoinitiated atom-transfer radical polymerization (ATRP) for their synthesis as monoliths, thin films and nanoparticles is described. The synthesis takes place at room temperature and is compatible with acidic monomers, two major limitations for the use of ATRP with MIPs. The method has been validated with MIPs specific for the drugs testosterone and S-propranolol. This study considerably widens the range of functional monomers and thus molecular templates which can be used when MIPs are synthesized by ATRP, as well as the range of physical forms of these antibody mimics, in particular films and lithographic patterns, and their post functionalization from living chain-ends. PMID- 25728807 TI - A discordant monozygotic-twin approach to potential risk factors for chronic widespread pain in females. AB - Chronic widespread pain (CWP) is a common disorder affecting up to 15% of the general population. The objective of the present study was to explore the role of previously reported psychosocial and interpersonal risk factors on variation in CWP by investigating CWP discordant monozygotic (MZ) twins. This approach allows separation of cause and effect relationships, albeit imperfectly, as well the control for critical confounding variables such as common environment or genetics. In a total sample of N = 3,266 female twins aged 18-89 years, MZ (113 full pairs) and DZ twins (180 full pairs) discordant for CWP were selected. Items from the London fibromyalgia symptom screening questionnaire were used to discriminate cases from controls. To assess potential risk factors, including body mass index, anxiety sensitivity (AS), emotional intelligence, personality, obsessive-compulsive behavior, and coping, validated questionnaires were used. A set of univariate and multivariate logistic regression analyses were conducted. Of the variables showing significant links with CWP in the univariate individual level analyses, including age, AS, and emotional intelligence, only emotional intelligence turned out to an independent predictor to the pathogenesis of CWP in both the individual level and discordant MZ analyses. These data indicate that in women having identical genetic risk, emotional intelligence seems to play a key role, although of small effect, in the development and/or maintenance of CWP. It further seems that many of the previously reported risk factors for CWP suffer from genetic confounding. PMID- 25728808 TI - Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. AB - BACKGROUND: Faecal microbiota transplantation (FMT) from healthy donors is considered an effective treatment against recurrent Clostridium difficile infection. AIM: To study the effect of FMT via colonoscopy in patients with recurrent C. difficile infection compared to the standard vancomycin regimen. METHODS: In an open-label, randomised clinical trial, we assigned subjects with recurrent C. difficile infection to receive: FMT, short regimen of vancomycin (125 mg four times a day for 3 days), followed by one or more infusions of faeces via colonoscopy; or vancomycin, vancomycin 125 mg four times daily for 10 days, followed by 125-500 mg/day every 2-3 days for at least 3 weeks. The latter treatment did not include performing colonoscopy. The primary end point was the resolution of diarrhoea related to C. difficile infection 10 weeks after the end of treatments. RESULTS: The study was stopped after a 1-year interim analysis. Eighteen of the 20 patients (90%) treated by FMT exhibited resolution of C. difficile-associated diarrhoea. In FMT, five of the seven patients with pseudomembranous colitis reported a resolution of diarrhoea. Resolution of C. difficile infection occurred in 5 of the 19 (26%) patients in vancomycin (P < 0.0001). No significant adverse events were observed in either of the study groups. CONCLUSIONS: Faecal microbiota transplantation using colonoscopy to infuse faeces was significantly more effective than vancomycin regimen for the treatment of recurrent C. difficile infection. The delivery of donor faeces via colonoscopy has the potential to optimise the treatment strategy in patients with pseudomembranous colitis. PMID- 25728809 TI - Morphological changes in amphibian and fish cell lines infected with Andrias davidianus ranavirus. AB - Andrias davidianus ranavirus (ADRV) is an emerging viral pathogen that causes severe disease in Chinese giant salamanders, the largest extant amphibian in the world. A fish cell line, Epithelioma papulosum cyprinid (EPC), and a new amphibian cell line, Chinese giant salamander spleen cell (GSSC), were infected with ADRV and observed by light and electron microscopy. The morphological changes in these two cell lines infected with ADRV were compared. Cytopathic effect (CPE) began with rounding of the cells, progressing to cell detachment in the cell monolayer, followed by cell lysis. Significant CPE was visualized as early as 24 h post infection (hpi) in EPC cells and at 36 hpi in GSSC cells. Microscopical examination showed clear and significant CPE in EPC cells, while less extensive and irregular CPE with some adherent cells remaining was observed in GSSC cells. Following ADRV infection, CPE became more extensive. Transmission electron micrographs showed many virus particles around cytoplasmic vacuoles, formed as crystalline arrays or scattered in the cytoplasm of infected cells. Infected cells showed alteration in nuclear morphology, with condensed and marginalized nuclear chromatin on the inner aspect of the nuclear membrane and formation of a cytoplasmic viromatrix adjacent to the nucleus in both cell lines. Some virus particles were also detected in the nucleus of infected GSSC cells. Both cell lines are able to support replication of ADRV and can therefore be used to investigate amphibian ranaviruses. PMID- 25728810 TI - High-grade astrocytoma (Glioblastoma Multiforme) in an Atlantic spotted dolphin (Stenella frontalis). AB - This report describes the gross, microscopical and immunohistochemical features of a high-grade astrocytoma (glioblastoma multiforme) in an adult male Atlantic spotted dolphin (Stenella frontalis). On necropsy examination, a 5 * 2.5 * 2 cm, poorly demarcated, red, friable and locally expansile mass effaced the thalamus and the left periventricular region and extended to the left lateral ventricle of the brain. Microscopically, the mass consisted of haphazardly arranged bundles and rows of interweaving polygonal to spindle-shaped cells. These often palisaded along serpentine foci of necrosis and were surrounded by prominent vessels. Immunohistochemically, the neoplastic cells expressed glial fibrillary acidic protein, but not vimentin, S100 protein, neuron-specific enolase or neurofilament protein. A diagnosis of high-grade astrocytoma was made and this represents the first description of a glioma in a cetacean species. PMID- 25728811 TI - Angiofibroma in a cockatiel (Nymphicus hollandicus). AB - Human angiofibromas are rare and arise typically in the nasopharynx. In veterinary medicine they have only been described in the dog. Microscopically, angiofibromas consist of irregular groups of blood vessels within a stroma of connective tissue, with oedema and secondary inflammation often present. A cockatiel (Nymphicus hollandicus) was presented with an oral mass that consisted of aggregates of blood vessels surrounded by a connective tissue stroma, with the presence of oedema and secondary inflammation. Tumours of the oral cavity are uncommon in birds and to the authors' knowledge this is the first case of avian angiofibroma. PMID- 25728812 TI - Lack of correlation between mucosal immunoglobulin A-positive plasma cell numbers and TLR5 genotypes in German shepherd dogs with idiopathic chronic enteropathy. AB - It has been suggested previously that a deficiency in mucosal immunoglobulin (Ig) A production could be involved in the pathogenesis of chronic enteropathy in German shepherd dogs (GSDs). Recent research has shown that single nucleotide polymorphisms in the gene encoding Toll-like receptor (TLR)-5 are associated with an increased risk of development of chronic idiopathic enteropathy in this breed. IgA is essential for mucosal immunity and studies in mice have linked the interaction of TLR5 with its ligand flagellin to class switching of B cells into IgA-producing plasma cells. We hypothesized that dogs carrying the risk associated (RA) genotypes for G22A and C100T genes of TLR5 would have a different number of IgA plasma cells in the duodenal and colonic mucosa compared with dogs carrying the risk-protective (RP) genotypes. Thirty-one GSDs were diagnosed with idiopathic chronic enteropathy by clinical exclusion diagnosis and histopathological confirmation. Immunohistochemistry was performed using goat anti-dog IgA primary antibody. Two sections of duodenum, and colon if available, were examined from each animal. Twelve images were captured from each section and IgA-positive cells were counted and expressed per 10,000 MUm(2). TLR5 genotypes for the G22A and C100T genes were determined by polymerase chain reaction on blood samples. Numbers of IgA-positive cells in the duodenum and colon were slightly higher than those published previously for GSDs with or without chronic enteropathy (mean in the crypt area of the duodenum 52.6 +/- 16.2; mean in the tip of the duodenal villus 51.12 +/- 3.83; mean in the base of the duodenal villus 55.02 +/- 3.3; mean in the crypt area of the colon 67.4 +/- 4.3). There was no correlation between numbers of IgA-positive cells in duodenum or colon between dogs carrying the RA versus the RP alleles of TLR genes. Further studies are needed to assess the production of secretory IgA and its relationship to TLR5 genotypes. PMID- 25728813 TI - Pyogranulomatous panniculitis in ferrets (Mustela putorius furo) with intralesional demonstration of Pseudomonas luteola. AB - One ferret (Mustela putorius furo) from Finland and two ferrets from Austria, aged 1-4.5 years and of both genders, were presented with pyogranulomatous subcutaneous inflammation affecting the inguinal, preputial and femoral regions, respectively. Histologically, microorganisms were detected within the lesions. The organisms had a capsule that stained positively by the periodic acid-Schiff reaction. Pseudomonas spp. were cultured from the lesions in two cases. In the third case, electron microscopy revealed a prokaryotic organism surrounded by an electron lucent matrix. 16S rRNA gene sequencing showed highest sequence homology to Pseudomonas luteola in all three cases. In combination with recent reports of pleuropneumonia in ferrets due to P. luteola infection, these cases might indicate a predisposition of ferrets for infection by these bacteria. PMID- 25728814 TI - The CALLISTO Project: A Summary. AB - The European Union (EU) Framework 7-funded project entitled CALLISTO (Companion Animal multisectoriaL interprofessionaL and interdisciplinary Strategic Think tank On zoonoses) ran between 2012 and 2014 and investigated zoonotic infectious diseases transmitted between companion animals and man and food producing animals. There are large numbers of companion animals throughout Europe and these animals, of varied species, play an integral role in human society, providing very real human health and welfare benefits. There is, however, some risk that close human contact with companion animals may lead to the transmission of zoonotic infectious diseases of numerous different types. Companion animals may also be a source of some infections transmitted to farmed livestock. This risk must be communicated to the pet owning public in a balanced fashion by veterinary and human healthcare professionals, the pet industry and governments. The risk may be somewhat ameliorated if the owners of companion animals subscribe to the principles of responsible pet ownership. Nevertheless, there are further policy and research actions that could be implemented by the EU and/or national governments to further reduce the risks associated with the close integration of companion animals into human society. These include the development of systems for identifying and registering the most common companion animal species and establishing surveillance programmes that capture data on zoonoses that occur in these animals. Closer attention should be paid to the health status of animals entering or re-entering the EU from third countries and the welfare surrounding companion animal cross-border movement. Data collection and pathogen assessment in the less studied exotic companion animals being kept is also needed to better understand risks. Disease and disease vector spread within Europe should be monitored and solutions found to limit such spread. The emergence of antimicrobial resistance in companion animals should be monitored. Controls should be placed on the use of human critically important antibiotics in companion animal species, but new approaches to companion animal antimicrobial therapy must be developed in parallel. PMID- 25728815 TI - Multiple intra-abdominal serosal myxosarcomas in two koalas (Phascolarctos cinereus). AB - Two adult koalas (Phascolarctos cinereus) were presented for necropsy examination without any clinical history. A diffuse, severe gelatinous effusion was found in the abdominal cavity, while numerous 1-3 mm diameter, round, well-demarcated, multifocal to coalescing, raised, firm nodules containing a clear gelatinous fluid were scattered on the surface of the parietal peritoneum, diaphragm, liver, gastrointestinal tract and mesentery. Microscopically, the nodular lesions consisted of spindle-shaped to stellate neoplastic cells, with scant eosinophilic cytoplasm and moderate anisocytosis and anisokaryosis. The neoplastic cells were admixed with and surrounded by abundant acellular pale eosinophilic material that was stained by Alcian blue and only weakly by the periodic acid-Schiff reaction. Serosal proliferations are described rarely in koalas and to the authors' knowledge this is the first reported case of serosal myxosarcoma. The significance and pathogenesis of this condition in the koala population is unknown. PMID- 25728816 TI - Parallels between two geographically and ecologically disparate cave invasions by the same species, Asellus aquaticus (Isopoda, Crustacea). AB - Caves are long-known examples of evolutionary replications where similar morphologies (troglomorphies) evolve independently as the result of strong natural selection of the extreme environment. Recently, this paradigm has been challenged based on observations that troglomorphies are inconsistent across taxa and different subterranean habitats. We investigated the degree of replicated phenotypic change in two independent cave invasions by the freshwater isopod Asellus aquaticus; the first in a sulphidic aquifer in Romania, the second in a sinking river in the Dinaric Karst in Slovenia. Both ancestral surface populations still live alongside the subterranean ones. Phylogenetic analyses show independence of the two colonization events, and microsatellite analysis shows no evidence of ongoing genetic exchange between surface and subterranean ecomorphs. The overall morphology has changed dramatically at both sites (50 of 62 morphometric traits). The amount of phenotypic change did not reflect differences in genetic diversity between the two ancestral populations. Multivariate analyses revealed divergent evolution in caves, not parallel or convergent as predicted by the current paradigm. Still, 18 traits changed in a parallel fashion, including eye and pigment loss and antennal elongation. These changes might be a consequence of darkness as the only common ecological feature, because Romanian caves are chemoautotrophic and rich in food, whereas Slovenian caves are not. Overall, these results show that morphologically alike surface populations can diverge after invading different subterranean habitats, and that only about one-third of all changing traits behave as troglomorphies in the traditional sense. PMID- 25728817 TI - Tissue dissolution ability of sodium hypochlorite activated by photon-initiated photoacoustic streaming technique. AB - INTRODUCTION: The aim of this study was to evaluate the effect of the photon initiated photoacoustic streaming (PIPS) technique on the pulp tissue-dissolving capacity of sodium hypochlorite (NaOCl) and compare it with the EndoActivator System (Dentsply Tulsa Dental Specialties, Tulsa, OK) and the Er:YAG laser with an endodontic fiber tip. METHODS: Bovine pulp tissue samples (45 +/- 15 mg) and dentin powder (10 mg) were placed in 1.5-mL Eppendorf tubes with 1 mL 5.25% NaOCl (Wizard; Rehber Kimya, Istanbul, Turkey) or distilled water (control) for 5 minutes with activation by the EndoActivator System, the Er:YAG laser with an endodontic fiber tip, and the PIPS technique. Nonactivated NaOCl served as the positive control. All testing procedures were performed at room temperature. The tissue samples were weighed before and after treatment, and the percentage of weight loss was calculated. The differences were statistically analyzed. RESULTS: The highest rate of tissue dissolution was observed in the NaOCl + Er:YAG group (P < .05). The NaOCl + PIPS group dissolved more bovine pulp tissue than the nonactivated NaOCl group (P < .05). There was no statistically significant difference between the rates of tissue dissolution of the NaOCl + EA and the nonactivated NaOCl groups (P > .05). CONCLUSIONS: NaOCl activation with the Er:YAG laser with an endodontic fiber tip was the most effective in bovine pulp tissue dissolution. The PIPS technique also promoted superior tissue-dissolving effects when compared with no activation. However, the EndoActivator System had no direct effect on tissue dissolution. PMID- 25728818 TI - Management of a massive resorptive lesion with multiple perforations in a molar: case report. AB - Internal resorption is usually asymptomatic. Large resorption defects may result in penetration of the root dentin leading to perforation. In this case report, we describe the diagnosis and nonsurgical repair of a large resorptive lesion with multiple perforations in a mandibular first molar using cone-beam computed tomographic technology. The 3 different root perforations were located in the mesial root and repaired using Biodentine (Septodont, Saint-Maur des Fosses, France). The mesial root weakened from resorption was reinforced by replacing the lost root dentin with calcium silicate-based cement and placement of a glass fiber post. The 18-month follow-up confirmed remineralization of the osseous defect and asymptomatic function of the tooth. A further follow-up at 43 months revealed retention of the tooth and absence of root fracture. Usually, a tooth with multiple perforations and such a severe tooth material loss would have been destined for extraction. However, with contemporary diagnostic techniques such as cone-beam computed tomography and use of advanced biomaterials and root reinforcement methods, such teeth can be salvaged. PMID- 25728819 TI - Bacteriophage therapy for membrane biofouling in membrane bioreactors and antibiotic-resistant bacterial biofilms. AB - To demonstrate elimination of bacterial biofilm on membranes to represent wastewater treatment as well as biofilm formed by antibiotic-resistant bacterial (ARB) to signify medical application, an antibiotic-resistant bacterium and its lytic bacteriophage were isolated from a full-scale wastewater treatment plant. Based on gram staining and complete 16 S rDNA sequencing, the isolated bacterium showed a more than 99% homology with Delftia tsuruhatensis, a gram-negative bacterium belonging to beta-proteobacteria. The Delftia lytic phage's draft genome revealed the phage to be an N4-like phage with 59.7% G + C content. No transfer RNAs were detected for the phage suggesting that the phage is highly adapted to its host Delftia tsuruhatensis ARB-1 with regard to codon usage, and does not require additional tRNAs of its own. The gene annotation of the Delftia lytic phage found three different components of RNA polymerase (RNAP) in the genome, which is a typical characteristic of N4-like phages. The lytic phage specific to D. tsuruhatensis ARB-1 could successfully remove the biofilm formed by it on a glass slide. The water flux through the membrane of a prototype lab scale membrane bioreactor decreased from 47 L/h m(2) to ~15 L/h m(2) over 4 days due to a biofilm formed by D. tsuruhatensis ARB-1. However, the flux increased to 70% of the original after the lytic phage application. Overall, this research demonstrated phage therapy's great potential to solve the problem of membrane biofouling, as well as the problems posed by pathogenic biofilms in external wounds and on medical instruments. PMID- 25728820 TI - Reduction in hospital costs and resource consumption associated with the use of advanced topical hemostats during inpatient procedures. AB - OBJECTIVE: The use of hemostatic agents has increased over time for all surgical procedures. The purpose of this study was to evaluate the newer topical absorbable hemostat products Surgicel * Fibrillar ? and Surgicel SNoW ? (Surgicel advanced products, abbreviated as SAPs) compared to the older product Surgicel Original (SO) with respect to healthcare resource use and costs in procedures where these hemostats are most commonly used. RESEARCH DESIGN AND METHODS: A retrospective analysis of the Premier hospital database was used to identify adults who underwent brain/cerebral (BC), cardiovascular (CV: valve surgery and coronary artery bypass graft) and carotid endarterectomy (CEA) between January 2011-December 2012. Among these patients, those treated with SAPs were compared to those treated with SO. Propensity score matching (PSM) was used to create comparable groups to evaluate differences between SAPs and SO. MAIN OUTCOME MEASURES: The primary end-points for this study were length of stay (LOS), all cause total cost, number of intensive care unit (ICU) days, ICU cost, transfusion costs and units, and SO/SAP product units per discharge. RESULTS: Matched PSM created patient cohorts for SO and SAPs were created for BC (n = 758 for both groups), CV (n = 3388 for both groups), and CEA (n = 2041 for both groups) procedures. Patients that received SAPs had a 14-16% lower mean LOS for each procedure compared to SO, as well as 12-18% lower total mean cost per discharge for each procedure (p < 0.02 for all results). Mean ICU costs for SAPs were also lower, with a reduction of 20% for BC and 19% for CV compared to SO (p < 0.01). However, for CEA, there was no statistically significant difference in ICU costs for SAPs compared to SO. CONCLUSIONS: In a retrospective hospital database analysis, the use of SAPs were associated with lower healthcare resource utilization and costs compared to SO. PMID- 25728821 TI - Frailty models for pneumonia to death with a left-censored covariate. AB - Frailty models are multiplicative hazard models for studying association between survival time and important clinical covariates. When some values of a clinical covariate are unobserved but known to be below a threshold called the limit of detection (LOD), naive approaches ignoring this problem, such as replacing the undetected value by the LOD or half of the LOD, often produce biased parameter estimate with larger mean squared error of the estimate. To address the LOD problem in a frailty model, we propose a flexible smooth nonparametric density estimator along with Simpson's numerical integration technique. This is an extension of an existing method in the likelihood framework for the estimation and inference of the model parameters. The proposed new method shows the estimators are asymptotically unbiased and gives smaller mean squared error of the estimates. Compared with the existing method, the proposed new method does not require distributional assumptions for the underlying covariates. Simulation studies were conducted to evaluate the performance of the new method in realistic scenarios. We illustrate the use of the proposed method with a data set from Genetic and Inflammatory Markers of Sepsis study in which interlekuin-10 was subject to LOD. PMID- 25728822 TI - Counterion effects in protein nanoparticle electrostatic binding: a theoretical study. AB - Effects of counterions on the folding conformation of proteins, bound electrostatically on the surface of charge-ligand functionalized nanoparticles, have been investigated based on the protein folding energy calculation. The folding energy of a protein has been taken as a sum of the short range interaction energies, like, the van der Waals attraction and the hydrogen bond energies, and the long range coulomb interaction energy. On electrostatic binding, counterions associated with surface ligands of nanoparticles diffuse into bound proteins through the medium of dispersion. As a result, bound proteins partially unfold, as observed in circular dichroism experiments, which has been realized using the "charge-dipole" and the "charge-induced dipole" interactions of counterions with polar and non-polar residues, respectively. The effect of counterions solvation in the dispersing medium, e.g., water, which causes water molecules to polarize around the counterions, has also been considered. The folding energy of bound proteins has been seen to decrease proportionally with the increasing number of diffusion of counterions and their polarizability. PMID- 25728823 TI - Prevalence of unrecognized diabetes, prediabetes and metabolic syndrome in patients undergoing elective percutaneous coronary intervention. AB - BACKGROUND: Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention is not well defined. We aimed to analyse the prevalence and characteristics of patients undergoing percutaneous coronary intervention with previously unrecognized prediabetes, diabetes and metabolic syndrome. METHODS: Data were collected from 740 patients undergoing elective percutaneous coronary intervention between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Haemoglobin A1c (A1c >= 6.5% for DM, A1c 5.7-6.4% for prediabetes). A modified definition was used for metabolic syndrome [three or more of the following criteria: body mass index >=30 kg/m2; triglycerides >= 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure >= 130 mmHg and/or diastolic >= 85 mmHg; and A1c >= 5.7% or on therapy]. RESULTS: Mean age was 67 years, median body mass index was 28.2 kg/m(2) and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of percutaneous coronary intervention. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM). CONCLUSION: Among patients undergoing elective percutaneous coronary intervention, a substantial number were identified with a new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors. PMID- 25728825 TI - A study by electrical conductivity measurements of the semiconductive and redox properties of Nb-doped NiO catalysts in correlation with the oxidative dehydrogenation of ethane. AB - Nb-doped nickel oxides with Nb contents in the range from 1 to 20% and, for comparison, pure NiO, were characterized using in situ electrical conductivity measurements in correlation with their catalytic performances for the oxidative dehydrogenation (ODH) of ethane into ethylene. Their electrical conductivity was studied as a function of temperature and oxygen partial pressure and was followed with time during sequential exposures to air, ethane-air mixture (reaction mixture) and pure ethane in conditions similar to those of catalysis. All the oxides were p-type semiconductors under air. Their electrical conductivity in the reaction temperature range decreased in the following order: NiO > Nb(1)NiO > Nb(5)NiO > Nb(10)NiO > Nb(15)NiO > Nb(20)NiO. This correlates well with the catalytic activity expressed as the intrinsic rate of ethane consumption. All the catalysts were partially reduced under the reaction mixture in the reaction temperature range, an inverse correlation between their conductivity in these conditions and the ODH selectivity being observed. The ODH reaction of ethane takes place via a heterogeneous redox mechanism involving the surface lattice O( ) species. PMID- 25728824 TI - Evaluation of topical hesperetin matrix film for back-of-the-eye delivery. AB - PURPOSE: The goal of the present study was to develop a poly (ethylene oxide) N10 (PEO N10) based melt-cast matrix system for efficient and prolonged delivery of hesperetin (HT), a promising bioflavonoid, to the posterior segment of the eye through the topical route. METHODS: HT film was prepared by melt-cast method using PEO N10 and cut into 4mm*2mm segments, each weighing 8mg. This film was evaluated with respect to in vitro release rates and also transmembrane delivery across Spectra/Por(r) membrane (MWCO: 10,000 Daltons) and isolated rabbit corneas. Ocular tissue concentrations were also determined postapplication of the film in ex vivo and in vivo models. RESULTS: HT release from the film was determined to be about 95.3% within 2h. In vitro transcorneal flux was observed to be 0.58+/-0.05MUg/min/cm(2) across the isolated rabbit cornea. High levels of HT were detected in the retina-choroid (RC) and vitreous humor (VH) in the ex vivo model following topical application of the film. Significant levels of HT were observed in both anterior and posterior segment ocular tissues 1h post topical application of the 10 and 20%w/w HT films on the rabbit eye. Moreover, HT was detected in the VH and RC even after 6h following topical application of the film in vivo. CONCLUSION: The results from this study suggest that the melt-cast films can serve as a viable platform for sustained topical delivery of bioflavonoids, and other therapeutic agents, into the back-of-the eye tissues. PMID- 25728826 TI - Strategies for safe living among lung transplant recipients: a single-center survey. AB - BACKGROUND: Lung transplant (LT) recipients are at high risk for infection owing to lifelong immunosuppression and direct communication of the graft with the environment. Guidelines have been established for safe-living strategies after transplantation. We conducted a survey of LT patients to determine compliance with these strategies. METHODS: Adult LT outpatients completed a survey consisting of questions on a 5-point Likert scale with the following categories: hand washing, gardening, respiratory infections, food and water safety, animal contact, travel, and occupation. RESULTS: A total of 194 LT recipients completed the survey (age 54.4 +/- 13.3 years; time post transplant 4.76 +/- 3.5 years). Regular hand washing was practiced usually or always by 87.6%. Of those who worked with soil/gardened, 70/99 (70.7%) never wore a mask and 15.7% never wore gloves. Pet ownership was common (52%), but most patients used specific precautions during handling. Over one-third of patients continued employment after transplant but, of these, 56% had modified their occupation often because of perceived infectious risks. Most patients were fully compliant with influenza vaccination (92.3%). Patients <40 years of age were less likely to wear long sleeved clothing in mosquito season (P = 0.002), more likely to handle pet feces (P = 0.005), and less likely to wear a mask with sick contacts (P = 0.021). CONCLUSIONS: We provide important insight into safe-living practices following lung transplantation and identify specific areas and subgroups of patients that could be targeted for enhanced education, with potential significant clinical benefit. PMID- 25728827 TI - Case series of pseudoexfoliation material on intra-ocular lenses. PMID- 25728828 TI - High-performance and ultra-stable lithium-ion batteries based on MOF-derived ZnO@ZnO quantum dots/C core-shell nanorod arrays on a carbon cloth anode. AB - MOF-derived ZnO@ZnO Quantum Dots/C core-shell nanorod arrays grown on flexible carbon cloth are successfully fabricated as a binder-free anode for Li-ion storage. In combination with the advantages from the ZnO/C core-shell architecture and the 3D nanorod arrays, this material satisfies both efficient ion and fast electron transport, and thus shows superior rate capability and excellent cycling stability. PMID- 25728829 TI - Role of tridimensional endoanal ultrasound (3D-EAUS) in the preoperative assessment of perianal sepsis. AB - PURPOSE: The aim of this study was to evaluate the accuracy of tridimensional endoanal ultrasound (3D-EAUS) in the diagnosis of perianal sepsis comparing the results with the surgical findings, considered as reference standard. METHODS: From January 2009 to January 2013, all the patients referred for the assessment and treatment of perianal sepsis with suspected anorectal origin were enrolled in the study. All patients gave informed written consent. Prior to surgery, all the patients underwent anamnestic evaluation, clinical examination, and unenhanced and H2O2-enhanced 3D-EAUS. Surgery was performed by a colorectal surgeon blinded to the 3D-EAUS results. RESULTS: A total of 212 patients with suspected perianal suppurations were assessed during the study period. In 12 patients, the H2O2 enhanced 3D-EAUS was not performed, and so, they were excluded from the study. Very good agreement between 3D-EAUS and examination under anesthesia (EUA) in the classification of primary fistula tracts (kappa = 0.93) and in the identification of fistula internal opening (kappa = 0.97) was found. There was a good concordance (kappa = 0.71) between 3D-EAUS and surgery in the detection of fistula secondary extensions. The overall sensitivity and specificity of 3D-EAUS in the diagnosis of perianal sepsis were 98.3 and 91.3% respectively. CONCLUSION: 3D-EAUS is a safe and reliable technique in the assessment of perianal sepsis. It may assist the surgeon in delineating the fistula tract anatomy and in determining the origin of sepsis, supporting the preoperative planning of definitive and appropriate surgical therapy. PMID- 25728830 TI - A case of pediatric cecal diverticulitis mimicking acute appendicitis. PMID- 25728831 TI - A Phase II study of a histamine H3 receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy. AB - This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H3 receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population. PMID- 25728832 TI - Endothelial function, folate pharmacogenomics, and neurocognition in psychotic disorders. AB - Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders. PMID- 25728835 TI - Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: potential roles in GABAergic interneuron pathology. AB - Neuropathological changes of the hippocampus have been associated with psychotic disorders such as schizophrenia and bipolar disorder. Recent work has particularly implicated hippocampal GABAergic interneurons in the pathophysiology of these diseases. However, the molecular mechanisms underlying structural and cellular hippocampal pathology remain poorly understood. We used data from comprehensive difference-in-gel electrophoresis (2-D DIGE) investigations of postmortem human hippocampus of people with schizophrenia and bipolar disorder, covering the acidic (isoelectric point (pI) between pH4 and 7) and, separately, the basic (pI between pH6 and 11) sub-proteome, for Ingenuity Pathway Analysis (IPA) of implicated protein networks and pathways. Comparing disease and control cases, we identified 58 unique differentially expressed proteins in schizophrenia, and 70 differentially expressed proteins in bipolar disorder, using mass spectrometry. IPA implicated, most prominently, 14-3-3 and aryl hydrocarbon receptor signaling in schizophrenia, and gluconeogenesis/glycolysis in bipolar disorder. Both disorders were characterized by alterations of proteins involved in the oxidative stress response, mitochondrial function, and protein endocytosis, -trafficking, -degradation, and -ubiquitination. These findings are interpreted with a focus on GABAergic interneuron pathology in the hippocampus. PMID- 25728833 TI - Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis. AB - BACKGROUND: There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. METHODS: The sample consisted of 34 CHR individuals and 33 healthy comparison subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. RESULTS: CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. CONCLUSIONS: Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function. PMID- 25728836 TI - Prediction, context, and competition in visual recognition. AB - Perception is substantially facilitated by top-down influences, typically seen as predictions. Here, we outline that the process is competitive in nature, in that sensory input initially activates multiple possible interpretations, or perceptual hypotheses, of its causes. This raises the question of how the selection of the correct interpretation from among those multiple hypotheses is achieved. We first review previous findings in support of such a competitive nature of perceptual processing, and then propose which neural regions might provide a platform for rising and using expectations to resolve this competition. Specifically, we propose that it is the rapid extraction and top-down dissemination of a global context signal from the frontal cortices, particularly the orbitofrontal cortex, that affords the quick and reliable resolution of the initial competition among likely alternatives toward a singular percept. PMID- 25728834 TI - Memories reactivated under ketamine are subsequently stronger: A potential pre clinical behavioral model of psychosis. AB - BACKGROUND: Sub-anesthetic doses of the NMDA antagonist ketamine have been shown to model the formation and stability of delusion in human subjects. The latter has been predicted to be due to aberrant prediction error resulting in enhanced destabilization of beliefs. To extend the scope of this model, we investigated the effect of administration of low dose systemic ketamine on memory in a rodent model of memory reconsolidation. METHODS: Systemic ketamine was administered either prior to or immediately following auditory fear memory reactivation in rats. Memory strength was assessed by measuring freezing behavior 24h later. Follow up experiments were designed to investigate an effect of pre-reactivation ketamine on short-term memory (STM), closely related memories, and basolateral amygdala (BLA) specific destabilization mechanisms. RESULTS: Rats given pre reactivation, but not post-reactivation, ketamine showed larger freezing responses 24h later compared to vehicle. This enhancement was not observed 3h after the memory reactivation, nor was it seen in a closely related contextual memory. Prior inhibition of a known destabilization mechanism in the BLA blocked the effect of pre-reactivation ketamine. CONCLUSIONS: Pre- but not post reactivation ketamine enhances fear memory. These data together with recent data in human subjects supports a model of delusion fixity that proposes that aberrant prediction errors result in enhanced destabilization and strengthening of delusional belief. PMID- 25728837 TI - KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation. AB - BACKGROUND: Androgen receptor (AR) is a ligand dependent transcription factor that regulates the transcription of target genes. AR activity is closely involved in the maintenance and progression of prostate cancer. After the binding with androgen, AR moves into nucleus and binds to DNA sequence containing androgen response elements (ARE). Flavin-dependent monoamine oxidase KDM1A is necessary for AR driven transcription while the mechanism remains unclear. METHODS: The association between androgen-dependent transcription and oxidation was tested through pharmaceutical inhibitions and siRNA knockdown of DNA oxidation repair components in prostate cancer cells. The recruitment of involved proteins and the histone methylation dynamics on ARE region was explored by chromatin immunoprecipitation (ChIP). RESULTS: Oxidation inhibition reduced AR dependent expression of KLK3, TMPRSS2, hsa-miR-125b2, and hsa-miR-133b. And such reduction could be restored by H2 O2 treatment. KDM1A recruitment and H3K4me2 demethylation on ARE regions, which produce H2 O2 , are associated with AR targets transcription. AR targets transcription and coupled oxidation recruit 8 oxoguanine-DNA glycosylase (OGG1) and the nuclease APEX1 to ARE regions. Such recruitment depends on KDM1A, and is necessary for AR targets transcription. CONCLUSION: Our work underlined the importance of histone demethylation and DNA oxidation/repairing machinery in androgen-dependent transcription. The present finds have implications for research into new druggable targets for prostate cancer relying on the cascade of AR activity regulation. PMID- 25728838 TI - microRNA-21 promotes osteogenic differentiation of mesenchymal stem cells by the PI3K/beta-catenin pathway. AB - Osteogenesis of mesenchymal stem cells (MSCs) is essential for bone repair. Recently, microRNAs have been proven to play an important role in the regulation of MSC differentiation, including osteogenesis. Here, the function of microRNA-21 (miR-21) in the osteogenic differentiation of human umbilical cord mesenchymal stem cells (hUMSCs) was investigated. Briefly, the miR-21 mimics (m-miR-21) and the antisense miR-21 (as-miR-21) were transfected to hUMSCs, and the capacity of miR-21 for the osteogenic differentiation of hUMSCs was evaluated by the expression of osteogenic markers encoding alkaline phosphatase (ALP), runt related gene-2 (RUNX-2) and osteocalcin (OCN), as well as by Alizarin red S staining. The results indicated that the overexpression of miR-21 elevated the expression level of the osteogenesis-related genes of hUMSCs. During this process, the PI3K-AKT signaling pathway activity had an increasing tendency responding to miR-21 up-regulation. This enhancement promoted the phosphorylation of GSK-3beta, leading to the stabilization and high concentration accumulation of beta-catenin in cytoplasm to activate the transcription of RUNX-2, and finally increased the osteogenesis of hUMSCs. This work demonstrated that miR-21 and its target PI3K-AKT-GSK3beta pathway played an important role in the osteogenic differentiation of hUMSCs by stabilizing beta-catenin. PMID- 25728839 TI - Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1. AB - Unidentified bright objects (UBO) and tumors are well-known cerebellar abnormalities in neurofibromatosis type 1 (NF1). Literature reports on malformative cerebellar anomalies in neurofibromatosis type 1 (NF1), however, are scant. We retrospectively studied the clinical and neuroimaging findings of 5 patients with NF1 (4 females, age 6 to 29 years at last follow-up) and cerebellar anomalies. Cerebellar symptoms on neurological examination were mild or even not evident whereas learning disabilities were more or less pronounced in four patients. Two patients had cerebellar hypoplasia (diffusely enlarged cerebellar interfoliar spaces) and three cerebellar dysmorphias involving mainly one cerebellar hemisphere. In NF1, malformative cerebellar anomalies are rare (estimated prevalence of about 1%), but most likely underestimated and easily overlooked, because physicians tend to focus on more prevalent, obvious, and well known findings such as optic pathway gliomas, other tumors, and UBO. This kind of cerebellar anomaly in NF1 has most likely a malformative origin, but the exact pathogenesis is unknown. The individual clinical significance is difficult to determine. We suggest that cerebellar anomalies should be systematically evaluated in neuroimaging studies of NF1 patients. PMID- 25728840 TI - MiR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF. AB - Atherosclerosis progress is regulated by a variety of factors. Here, we show that miR-320a, an intergenic miRNA, is markedly elevated in the peripheral blood of coronary heart disease patients and high-risk patients. Microarray analysis and qRT-PCR assays showed that circulating miRNA-320a was highly expressed in coronary artery disease patients. In vivo study showed that overexpression of miR 320a resulted in significant increase in levels of plasma lipid (total cholesterol, Triglyceride and low-density lipoprotein) and serum inflammatory cytokines (IL-6, MCP-1, sICAM, pSelectin, TNF-alpha and fibrinogen). In ApoE(-/-) mice, miR-320a expression attenuates endothelium cell function and promotes atherogenesis. Bioinformatics analysis identified serum response factor as a potential target for miR-320a, which was validated by luciferase reporter activity assay and western-blot in vitro and in vivo. Moreover, miR-320a expression inhibits human-derived endothelium cell proliferation and induces apoptosis. We also found that SP1 transcriptionally up-regulates hsa-miR-320a expression. Our observations indicate that miR-320a is a key regulator contributing to multiple aspects of atherogenesis. PMID- 25728841 TI - The case for xenotransplantation. AB - The availability of organs and cells from deceased humans for transplantation is not meeting the demand. Xenotransplantation, specifically the transplantation of organs and cells from genetically engineered pigs, could resolve this problem. Diabetic monkeys have remained normoglycemic and insulin-independent after pig islet transplantation for >one yr, and a pig heterotopic (non-life-supporting) heart transplant recently reached the one-yr milestone in a baboon. With these encouraging results, why is it that, with some notable exceptions, research into xenotransplantation has received relatively little support by industry, government funding agencies, and medical charitable foundations? Industry appears reluctant to support research that will take more than two to three yr to come to clinical trial, and the funding agencies appear to have been "distracted" by the current appeal of stem cell technology and regenerative medicine. It has only been the willingness of living donors to provide organs that has significantly increased the number of transplants being performed worldwide. These altruistic donations are not without risk of morbidity and even mortality to the donor. Although with the best of intentions, we are therefore traversing the Hippocratic Oath of doctors to "do no harm." This should be a stimulus to fund exploration of alternative approaches, including xenotransplantation. PMID- 25728842 TI - Illuminating meningococcal diagnosis with LAMP. PMID- 25728843 TI - Diagnostic accuracy of loop-mediated isothermal amplification as a near-patient test for meningococcal disease in children: an observational cohort study. AB - BACKGROUND: Diagnosis of meningococcal disease relies on recognition of clinical signs and symptoms that are notoriously non-specific, variable, and often absent in the early stages of the disease. Loop-mediated isothermal amplification (LAMP) has previously been shown to be fast and effective for the molecular detection of meningococcal DNA in clinical specimens. We aimed to assess the diagnostic accuracy of meningococcal LAMP as a near-patient test in the emergency department. METHODS: For this observational cohort study of diagnostic accuracy, children aged 0-13 years presenting to the emergency department of the Royal Belfast Hospital for Sick Children (Belfast, UK) with suspected meningococcal disease were eligible for inclusion. Patients underwent a standard meningococcal pack of investigations testing for meningococcal disease. Respiratory (nasopharyngeal swab) and blood specimens were collected from patients and tested with near-patient meningococcal LAMP and the results were compared with those obtained by reference laboratory tests (culture and PCR of blood and cerebrospinal fluid). FINDINGS: Between Nov 1, 2009, and Jan 31, 2012, 161 eligible children presenting at the hospital underwent the meningococcal pack of investigations and were tested for meningococcal disease, of whom 148 consented and were enrolled in the study. Combined testing of respiratory and blood specimens with use of LAMP was accurate (sensitivity 89% [95% CI 72-96], specificity 100% [97-100], positive predictive value 100% [85-100]; negative predictive value 98% [93-99]) and diagnostically useful (positive likelihood ratio 213 [95% CI 13-infinity] and negative likelihood ratio 0.11 [0.04-0.32]). The median time required for near-patient testing from sample to result was 1 h 26 min (IQR 1 h 20 min-1 h 32 min). INTERPRETATION: Meningococcal LAMP is straightforward enough for use in any hospital with basic laboratory facilities, and near-patient testing with this method is both feasible and effective. By contrast with existing UK National Institute of Health and Care Excellence guidelines, we showed that molecular testing of non-invasive respiratory specimens from children is diagnostically accurate and clinically useful. FUNDING: Health and Social Care Research and Development, Public Health Agency, Northern Ireland. PMID- 25728844 TI - The NdhV subunit is required to stabilize the chloroplast NADH dehydrogenase-like complex in Arabidopsis. AB - The chloroplast NADH dehydrogenase-like (NDH) complex is involved in cyclic electron transport around photosystem I (PSI) and chlororespiration. Although the NDH complex was discovered more than 20 years ago, its low abundance and fragile nature render it recalcitrant to analysis, and it is thought that some of its subunits remain to be identified. Here, we identified the NDH subunit NdhV that readily disassociates from the NDH complex in the presence of detergent, salt and alkaline solutions. The Arabidopsis ndhv mutant is partially defective in the accumulation of NDH subcomplex A (SubA) and SubE, resulting in impaired NDH activity. NdhV was mainly detected in the wild-type thylakoid membrane, and its accumulation in thylakoids strictly depended on the presence of the NDH complex. Quantitative immunoblot analysis revealed that NdhV and NdhN occur at close to equimolar concentrations. Furthermore, several NDH subunits were co immunopurified with NdhV using a combination of chemical crosslinking and an affinity chromatography assay. These data indicate that NdhV is an intrinsic subunit of NDH. We found that NdhV did not directly affect NDH activity, but that NDH SubA and SubE were more rapidly degraded in ndhv than in the wild type under high-light treatment. We propose that NdhV is an NDH subunit that stabilizes this complex, especially under high-light conditions. PMID- 25728845 TI - Meta-analysis of direct and indirect comparison of ticagrelor and prasugrel effects on platelet reactivity. AB - Studies have linked on-treatment platelet reactivity (PR) to adverse clinical outcomes. Because new P2Y12 inhibitors (prasugrel and ticagrelor) have been predominantly tested against clopidogrel, data on pharmacodynamic comparisons between these 2 drugs are scarce. We compared ticagrelor with prasugrel in a network meta-analysis. PubMed, Cochrane, and EMBASE were searched for studies assessing PR in patients with coronary artery disease treated with ticagrelor or prasugrel. All studies using prasugrel and/or ticagrelor providing platelet function measurement data using VerifyNow P2Y12 reaction units (PRUs), platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein phosphorylation, or maximal platelet aggregation (MPA) by light transmission aggregometry were considered eligible. Mixed treatment comparison models directly compared ticagrelor and prasugrel and indirectly compared them using clopidogrel as a comparator with data presented as mean difference (95% confidence interval). Data were extracted from 29 studies, including 5,395 patients. Compared with clopidogrel 75 mg, both prasugrel 10 mg and ticagrelor 90 mg twice daily were associated with lower PRU (mean difference -117 [-134.1, -100.5] and -159.7 [ 182.6, -136.6], respectively), a lower PRI (-24.2 [-28.2, -20.3] and -33.6 [ 39.9, -27.6], respectively), and lower MPA (-11.8 [-17, -6.3] and -20.7 [-28.5, 12.8], respectively). Similar results were obtained with clopidogrel 150 mg. Ticagrelor 90 mg twice daily was associated with lower PRU (-42.5 [-62.9, 21.9]), lower PRI (-9.3 [-15.6, -3.5]), and lower MPA (-8.9 [-16.4, -1.2]) compared with prasugrel 10 mg. In conclusion, our meta-analysis suggests that ticagrelor achieved significantly lower on-treatment PR compared with prasugrel, with both being superior to clopidogrel standard or high dose. PMID- 25728846 TI - Changes in serum potassium levels during hospitalization in patients with worsening heart failure and reduced ejection fraction (from the EVEREST trial). AB - Both hyperkalemia and hypokalemia may be related to heart failure (HF) therapy and are associated with adverse outcomes. Abnormalities in serum potassium levels in hospitalized patients with HF and reduced ejection fraction (EF) have not been previously investigated. A post hoc analysis was performed in 1,907 hospitalized patients with worsening HF and reduced EF in the placebo arm of the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST) trial. Serum potassium was measured at randomization and at discharge or day 7. The co-primary end points were all-cause mortality (ACM) and cardiovascular mortality or the first HF hospitalization (CVM + HFH). The association between inhospital change in potassium levels and time to outcomes was evaluated using multivariate Cox regression models. Study participants had a mean age of 65.6 +/- 12.0 years and were on optimal guideline-directed medical therapies, including beta blockers (77%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (85%), and aldosterone antagonists (55%). Baseline potassium concentration was 4.3 +/- 0.6 mEq/l, and hyperkalemia or hypokalemia was seen in 6.5% of the participants. On average, serum potassium level increased by 0.21 +/- 0.66 mEq/l, p <0.0001, during hospitalization. Inhospital potassium change was not associated with either the primary or the secondary end point over a median follow-up of 9.9 months. In conclusion, in patients with reduced EF hospitalized for worsening HF, serum potassium abnormalities are common at baseline (within 48 hours of admission) and potassium levels increase during hospitalization, despite aggressive diuretic therapy. However, they are not associated with all-cause or CVM or HFH. Inhospital changes in potassium may limit the implementation of evidence-based therapies such as mineralocorticoid receptor antagonists. PMID- 25728847 TI - Reply: To PMID 22703861. PMID- 25728848 TI - Dynamic exophthalmos and lateral strabismus in a dog caused by masticatory muscle myositis. AB - CASE DESCRIPTION: A 5.5-year-old neutered male mixed-breed dog was presented for evaluation of a 5-month history of deviation of the right globe upon opening the mouth and a 1-month history of conjunctivitis in the same eye. Clinical findings, diagnostic imaging results, treatment and follow-up are described. CLINICAL FINDINGS: When the mouth was opened, the right globe deviated rostrally and laterally. There was no pain or resistance to opening the mouth, or resistance to retropulsion of the globe. No other abnormalities were observed. Computed tomography was performed, revealing a contrast-enhancing region associated with the right masseter muscle impinging into the right orbit; this was more pronounced with the mouth open. Cytology revealed a small number of mildly to moderately atypical mesenchymal cells. Histopathology was consistent with polyphasic myositis, with a predominance of lymphocytes and plasma cells. No infectious agents were identified. Serum antibody titers for Toxoplasma gondii and Neospora caninum were negative. Serum titers for 2 M antibody were positive at 1:500, consistent with a diagnosis of masticatory muscle myositis. TREATMENT AND OUTCOME: Therapy with prednisone was initiated. During a follow-up period of 5 months, there was no recurrence of clinical signs, and the dose of prednisone was reduced by 25%. CLINICAL SIGNIFICANCE: To the authors' knowledge, this is the first reported case of masticatory muscle myositis causing dynamic exophthalmos and strabismus in a dog. PMID- 25728849 TI - The estimation of imported dengue virus from Thailand. AB - BACKGROUND: Dengue fever is one of the important causes of illness among travelers returning from Thailand. The risk of infection depends on the length of stay, activities, and arrival time. Due to globalization, there is a concern that infected travelers may carry dengue virus (DENV) to their country of residence and cause an outbreak. METHODS: To estimate the infective person-days of travelers returning from Thailand, we developed a model with the following parameters: the probability of travelers being infected, number of arrivals, length of stay of travelers, incubation period, and duration of the infective period. The data used in this study were the dengue incidences in Thailand during 2004-2013 and foreign traveler arrivals in 2013. RESULTS: We estimated the highest infective person-days for each country group. The highest value was from June to August during the rainy season in Thailand for all groups. Infective person-days ranged from 87 to 112 per 100,000 travelers each year. CONCLUSION: Our results provided a fundamental step toward estimation of the risk of the secondary transmission of DENV in non-epidemic countries via travelers, which can serve as an early warning of a dengue outbreak. The highest infective person-day is associated with the rainy season in Thailand. The increasing number of overseas travelers may increase the risk of global transmission of the DENV. Better understanding of the virus transmission dynamics will enable further quantitative predictions of epidemic risk. PMID- 25728851 TI - Age-related decrease of adenosine-mediated relaxation in rat detrusor is a result of A2B receptor downregulation. AB - OBJECTIVES: To analyze the effect of adenosine on detrusor smooth muscle contraction and to assess age-related changes of adenosine function. METHODS: Sustained contractions were induced in young (10-30 days) and old (>60 days) rat detrusor muscle strips by application of 30 mmol/L K(+) and adenosine (0.1-400 umol/L), which was either applied before raising the K(+) concentration or added to the precontracted muscle strip. Quantitative polymerase chain reaction analyses were used to study adenosine receptor expression in rat and human detrusor specimens. RESULTS: Pretreatment with adenosine dose-dependently reduced subsequent K(+) -induced contraction in detrusor muscle strips from young rats (half-maximal effect = 40 umol/L). The residual depolarization-induced contraction strength in young tissue was significantly smaller than in tissue from old animals, showing a greater potency of adenosine in young detrusor samples. Likewise, the relaxing effect of adenosine on precontracted detrusor muscle was also significantly more pronounced in young compared with older detrusor. Quantitative polymerase chain reaction showed an age-related downregulation of the adenosine A2B receptor in rat detrusor tissues, which could be confirmed in human detrusor samples. Furthermore, relaxation of both K(+) induced as well as carbachol-induced contraction by the specific A2B receptor agonist BAY 60-6583 was significantly more pronounced in young than in old rats. CONCLUSIONS: Adenosine powerfully counteracts contraction of detrusor smooth muscle, which is lost in the aging bladder. This is paralleled by an age dependent transcriptional downregulation of the low-affinity A2B receptor. Hence, this might be pathophysiologically relevant in conditions of raised adenosine concentrations, such as hyperactive bladder contractility. PMID- 25728850 TI - Pharmacokinetics, dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose. AB - Docetaxel (Taxotere((r))) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m(2) every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m(2) every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to alpha1-acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m(2). The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m(2), compared to the US/European patients treated with 75-100 mg/m(2) dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m(2) is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy. PMID- 25728852 TI - [Measles epidemics and effectiveness of measles vaccinations]. PMID- 25728853 TI - [Population study of seroprevalence of antibodies against hepatitis A virus in the Community of Madrid, 2008-2009]. AB - INTRODUCTION: Seroprevalence surveys enable the level of endemicity of hepatitis A (HAV) to be assessed. The aim of this study was to estimate the seroprevalence (SP) antibody against HAV by age group, and compare it with those obtained in previous surveys. METHODS: Observational cross-sectional study. The target population consists of residents from 2 to 60 years old in the Community of Madrid. Two-stage cluster sampling was performed with stratification of first stage units. After signing the informed consent, a serum sample was extracted from each participant and sociodemographic data were collected by a questionnaire. RESULTS: SP antibodies to hepatitis A is 46.8% (95% CI 44.6 to 49.0). The SP increases with age. It is higher in the population from more endemic countries and people with less education and lower social class. In relation to the previous survey, SP increased in the population under 30 years old, and a decline after that age is observed. If only the autochthonous population and from countries with very low endemicity is observed, the increase is statistically significant in the 2-5 years age group. CONCLUSIONS: Our region has a very low level of endemicity thus, following the recommendations of WHO, vaccination should be targeted at specific risk groups. PMID- 25728854 TI - Enantioselective catalysis of photochemical reactions. AB - The nature of the excited state renders the development of chiral catalysts for enantioselective photochemical reactions a considerable challenge. The absorption of a 400 nm photon corresponds to an energy uptake of approximately 300 kJ mol( 1) . Given the large distance to the ground state, innovative concepts are required to open reaction pathways that selectively lead to a single enantiomer of the desired product. This Review outlines the two major concepts of homogenously catalyzed enantioselective processes. The first part deals with chiral photocatalysts, which intervene in the photochemical key step and induce an asymmetric induction in this step. In the second part, reactions are presented in which the photochemical excitation is mediated by an achiral photocatalyst and the transfer of chirality is ensured by a second chiral catalyst (dual catalysis). PMID- 25728855 TI - Improved peri-operative outcomes with epidural analgesia in patients undergoing a pancreatectomy: a nationwide analysis. AB - BACKGROUND: In spite of limited evidence demonstrating a benefit, epidural analgesia (EA) is often used for patients undergoing a pancreatectomy. In the present study, the impact of epidural analgesia on post-operative outcomes after a pancreatectomy is examined. METHODS: Utilizing the Nationwide Inpatient Sample, the effect of EA on peri-operative outcomes after a pancreatectomy was examined. Multivariable logistic and linear regression with propensity score matching were utilized for risk adjustment. RESULTS: From 2008-2011, 12,440 patients underwent a pancreatectomy. Of these, 1130 (9.1%) patients received epidural analgesia. Using univariate comparison, patients receiving EA had a significantly decreased length of stay (LOS), hospital charges and post-operative inpatient mortality. In multivariate analyses, EA was independently associated with a decreased post operative LOS (adjusted mean difference = -1.19 days, P < 0.001), decreased hospital charges (adjusted mean difference = -$16,814, P = 0.002) and decreased post-operative inpatient mortality [adjusted odds ratio (OR) = 0.42, P < 0.001]. Using 1:1 propensity score matching, patients who received an EA (n = 1070) had significantly decreased post-operative LOS (11.0 versus 12.1 days, P = 0.011), lower hospital charges ($112,086 versus $128,939, P = 0.001) and decreased post operative inpatient mortality (1.5% versus 3.6%, P = 0.002) compared with matched controls without EA (n = 1070). CONCLUSION: Analysis of a large hospital database reveals that EA is associated with improved peri-operative outcomes after a pancreatectomy. Additional studies are required to understand fully if this relationship is causal. PMID- 25728856 TI - Immunology of chronic myeloid leukemia: current concepts and future goals. AB - Although chronic myeloid leukemia is a rare malignancy, it has developed into a model system for the study of a variety of aspects of cancer biology and immunology. The introduction of tyrosine kinase inhibitors has resulted in a significant prolongation of the survival rates of chronic myeloid leukemia patients but has not resulted in a cure. There is a growing conviction that this aim can be achieved through immunotherapy. For this concept to be successful, a considerable increase in the present understanding of chronic myeloid leukemia immunology is required. The authors attempt to review and evaluate the current findings that demonstrate a number of immunological aberrations in patients prior to the start of any therapy and their normalization after achieving remission. They also discuss the recent clinical trials with experimental therapeutic vaccines and then present their own strategy on how to address the problem. PMID- 25728857 TI - Pustular pyoderma gangrenosum: Report of two cases. PMID- 25728858 TI - Body dysmorphic disorder: prevalence and outcomes in an oculofacial plastic surgery practice. AB - PURPOSE: To determine the prevalence, associated factors, and surgical outcomes of patients with body dysmorphic disorder in an oculofacial surgery practice. DESIGN: Retrospective cross-sectional analysis of a consecutive case series. METHODS: Participants consisted of a consecutive series of 728 patients who completed the Dysmorphic Concern Questionnaire in an oculofacial surgery practice at The Cole Eye Institute between November 2013 and June 2014. A questionnaire score >=9 was used as a positive screen for body dysmorphic disorder. Three control patients scoring <=8 in the same month were randomly selected for each positive-screening patient. Main outcome measures included number of reoperations, surgical complications, and follow-up visits; preoperative and postoperative pain scores; and the technician word count. Categorical variables were analyzed with Pearson chi(2) tests or Fisher exact tests, while continuous variables were analyzed with Wilcoxon rank sum tests or t tests. RESULTS: A total of 728 patients completed the questionnaire and 50 (6.9%) scored 9 or more. Using a confidence interval of 95%, patients in the positive questionnaire screen group were younger (P = .004), had more eyelid surgeries (P = .007), experienced higher rates of complications after surgery (P = .002), reported higher postoperative pain scores (P = .034), required more reoperations (P = .050), and had a higher technician word count compared to the control group (P = .003). CONCLUSIONS: The prevalence of body dysmorphic disorder in an oculofacial surgical setting matches reports from other surgical specialties, and is significantly higher than in the general population. Patients screening positively for body dysmorphic disorder tend to have higher postoperative pain scores and more postoperative complications. PMID- 25728859 TI - Efficient referral thresholds in autorefraction-based preschool screening. AB - PURPOSE: To determine economically efficient referral criteria for a preschool vision-screening program using autorefraction. DESIGN: Retrospective economic evaluation of a screening protocol. METHODS: Preschoolers in 2 cities received preschool-based Retinomax screening with a standard referral protocol and as needed comprehensive eye examinations in 2012-2013. Positive predictive values and referral criteria that minimized cost per case detected were derived using data from San Francisco. These modeled referral criteria were then retrospectively tested for cost-effectiveness against other common criteria in Oakland with sensitivity analysis. Cases were defined by American Association for Pediatric Ophthalmology and Strabismus (AAPOS) criteria for amblyopia risk factors. The perspective was a third-party payer. Costs were obtained from a regional insurance provider. RESULTS: In San Francisco, 3974 children were screened, 631 referred, and 412 examined. Forty-eight percent of referrals, 301 children, met more than 1 of the referral criteria. Positive predictive values ranged from 7% for myopia to 56% for astigmatism. In Oakland, 2359 children were screened and 269 were examined. When applying the modeled referral criteria derived from San Francisco to the population of Oakland, the cost per case detected was $258. When compared in Oakland, the original referral criteria and criteria based on Vision in Preschoolers study cost, respectively, $424 and $371 per additional case detected. The modeled referral criteria had a lower cost per case detected across sensitivity analysis. CONCLUSIONS: More stringent referral criteria may reduce the cost per case detected in vision screening and allow more at-risk children to be detected with the same financial resources. PMID- 25728860 TI - En face optical coherence tomography of foveal microstructure in full-thickness macular hole: a model to study perifoveal Muller cells. AB - PURPOSE: To characterize perifoveal intraretinal cavities observed around full thickness macular holes (MH) using en face optical coherence tomography and to establish correlations with histology of human and primate maculae. DESIGN: Retrospective nonconsecutive observational case series. METHODS: Macular en face scans of 8 patients with MH were analyzed to quantify the areas of hyporeflective spaces, and were compared with macular flat mounts and sections from 1 normal human donor eye and 2 normal primate eyes (Macaca fascicularis). Immunohistochemistry was used to study the distribution of glutamine synthetase, expressed by Muller cells, and zonula occludens-1, a tight-junction protein. RESULTS: The mean area of hyporeflective spaces was lower in the inner nuclear layer (INL) than in the complex formed by the outer plexiform (OPL) and the Henle fiber layers (HFL): 5.0 * 10(-3) mm(2) vs 15.9 * 10(-3) mm(2), respectively (P < .0001, Kruskal-Wallis test). In the OPL and HFL, cavities were elongated with a stellate pattern, whereas in the INL they were rounded and formed vertical cylinders. Immunohistochemistry confirmed that Muller cells followed a radial distribution around the fovea in the frontal plane and a "Z-shaped" course in the axial plane, running obliquely in the OPL and HFL and vertically in the inner layers. In addition, zonula occludens-1 co-localized with Muller cells within the complex of OPL and HFL, indicating junctions in between Muller cells and cone axons. CONCLUSION: The dual profile of cavities around MHs correlates with Muller cell morphology and is consistent with the hypothesis of intra- or extracellular fluid accumulation along these cells. PMID- 25728861 TI - Restoration of Oral Function for Adult Edentulous Patients with Ectodermal Dysplasia: A Prospective Preliminary Clinical Study. AB - BACKGROUND: Therapy with zygomatic implants (ZIs) or conventional implants (CIs) has proven to be an effective method to restore oral function for systemically healthy patients. However, it is still a major challenge to fully restore oral function to edentulous adult patients with ectodermal dysplasia (ED). PURPOSE: The aim of this study was to determine an effective treatment protocol for restoring oral function using ZIs and CIs to edentulous adult ED patients. MATERIALS AND METHODS: Ten edentulous adult ED patients were treated in this study. The treatment protocol involved the following: (1) bone augmentation in the region of the anterior teeth; (2) placement of two ZIs and four CIs in the maxilla, and four CIs in the mandible; (3) fabrication of dental prosthesis; and (4) psychological and oral education. Following treatment of these patients, implant success rates, biological complications, patient satisfaction, and psychological changes were recorded. RESULTS: Although there was evidence of bone graft resorption in the maxilla, bone augmentation of the mandible was successful in all patients. Nine CIs in the maxilla failed and were removed. All ZIs were successful, and the CIs success rates were 77.50% in the maxilla and 100% in the mandible, with a mean of 88.75%. The mean peri-implant bone resorption for the CIs ranged from 1.3 +/- 0.4 mm to 1.8 +/- 0.6 mm, and four cases exhibited gingival hyperplasia in the maxilla and mandible. One hundred percent of the patients were satisfied with the restoration of their oral function, and >50% of the patients exhibited enhanced self-confidence and self-esteem. CONCLUSIONS: This study demonstrates that oral function can be restored in edentulous adult ED patients using a comprehensive and systematic treatment protocol involving psychological and oral education, bone augmentation, implant placement, and denture fabrication. Despite these positive outcomes, bone augmentation remains challenging in the anterior region of the maxilla for edentulous adult ED patients. PMID- 25728862 TI - 6-Gingerol reduces Pseudomonas aeruginosa biofilm formation and virulence via quorum sensing inhibition. AB - Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors via quorum sensing (QS). Interfering with normal QS interactions between signal molecules and their cognate receptors is a developing strategy for attenuating its virulence. Here we tested the hypothesis that 6-gingerol, a pungent oil of fresh ginger, reduces biofilm formation and virulence by antagonistically binding to P. aeruginosa QS receptors. In silico studies demonstrated molecular binding occurs between 6-gingerol and the QS receptor LasR through hydrogen bonding and hydrophobic interactions. Experimentally 6-gingerol reduced biofilm formation, several virulence factors (e.g., exoprotease, rhamnolipid, and pyocyanin), and mice mortality. Further transcriptome analyses demonstrated that 6-gingerol successfully repressed QS induced genes, specifically those related to the production of virulence factors. These results strongly support our hypothesis and offer insight into the molecular mechanism that caused QS gene repression. PMID- 25728863 TI - A very rare case of endometriosis presenting with massive hemoperitoneum. AB - Endometriosis is a cause of acute abdomen because of the leakage or rupture of endometriotic cyst and tubo-ovarian abscess. However, massive hemoperitoneum as a cause of acute abdomen with endometriosis is very rare. We herein present a case of a 48-year-old woman who was urgently referred to our clinic with colic, abdominal distension, and hypovolemic shock during menstruation. Ultrasonography revealed massive hemorrhagic ascites. Exploratory laparoscopy was urgently performed to achieve hemostasis. The volume of hemoperitoneum evacuated from the pelvis was 1,890 mL. Although the uterus and bilateral ovaries were normal, fresh bleeding was observed from endometriosis on the left cul-de-sac peritoneum, and hemostasis was successfully performed. The potential occurrence of hemorrhagic shock associated with endometriosis, depending on the implantation site, needs to be recognized. PMID- 25728864 TI - beta-cyclodextrin in personal care formulations: role on the complexation of malodours causing molecules. AB - OBJECTIVE: The aim of this study was to prove the capability of beta-cyclodextrin (beta-CD) to interact with some representative molecules responsible to cause body malodour, such as carboxylic acids, thiols and steroids, present in sweat and body secretions. METHODS: The association constants in guest-CD were determined by (1) H-NMR spectroscopy for thiols and steroids such as 3-mercapto-1 hexanol, androstenone, androstenol and androsterone, and pH-potentiometric titration for acetic acid, l(+) lactic acid, isobutyric acid, isovaleric acid and 3-hydroxy-3-methyl-hexanoic acid. RESULTS: All considered systems are able to interact with relatively weak association constants with beta-cyclodextrin, in a 1 : 1 host-guest ratio. CONCLUSION: From these findings, it is possible to conclude that beta-CD is capable to interact with different components present in the sweat and body secretion, forming inclusion complexes. For this reason, beta CD could be a component of body care formulations, such as deodorants. PMID- 25728865 TI - ICSH recommendations for the standardization of nomenclature and grading of peripheral blood cell morphological features. AB - These guidelines provide information on how to reliably and consistently report abnormal red blood cells, white blood cells and platelets using manual microscopy. Grading of abnormal cells, nomenclature and a brief description of the cells are provided. It is important that all countries in the world use consistent reporting of blood cells. An international group of morphology experts have decided on these guidelines using consensus opinion. For some red blood cell abnormalities, it was decided that parameters produced by the automated haematology analyser might be more accurate and less subjective than grading using microscopy or automated image analysis and laboratories might like to investigate this further. A link is provided to show examples of many of the cells discussed in this guideline. PMID- 25728866 TI - Separation of polar compounds using a flexible metal-organic framework. AB - A flexible metal-organic framework constructed from a flexible linker is shown to possess the capability of separating mixtures of polar compounds (propanol isomers) by exploiting the differences in the saturation capacities of the constituents. Transient breakthrough simulations show that these sorption-based separations are in favor of the component with higher saturation capacity. PMID- 25728868 TI - New data on noninvasive ventilation in stable chronic obstructive pulmonary disease: revolutionary or evolutionary? PMID- 25728867 TI - Effect of context on respiratory rate measurement in identifying non-severe pneumonia in African children. AB - OBJECTIVE: Cough or difficult breathing and an increased respiratory rate for their age are the commonest indications for outpatient antibiotic treatment in African children. We aimed to determine whether respiratory rate was likely to be transiently raised by a number of contextual factors in a busy clinic leading to inaccurate diagnosis. METHODS: Respiratory rates were recorded in children aged 2 59 months presenting with cough or difficulty breathing to one of the two busy outpatient clinics and then repeated at 10-min intervals over 1 h in a quiet setting. RESULTS: One hundred and sixty-seven children were enrolled with a mean age of 7.1 (SD +/- 2.9) months in infants and 27.6 (SD +/- 12.8) months in children aged 12-59 months. The mean respiratory rate declined from 42.3 and 33.6 breaths per minute (bpm) in the clinic to 39.1 and 32.6 bpm after 10 min in a quiet room and to 39.2 and 30.7 bpm (P < 0.001) after 60 min in younger and older children, respectively. This resulted in 11/13 (85%) infants and 2/15 (13%) older children being misclassified with non-severe pneumonia. In a random effects linear regression model, the variability in respiratory rate within children (42%) was almost as much as the variability between children (58%). Changing the respiratory rates cut-offs to higher thresholds resulted in a small reduction in the proportion of non-severe pneumonia mis-classifications in infants. CONCLUSION: Noise and other contextual factors may cause a transient increase in respiratory rate and consequently misclassification of non-severe pneumonia. However, this effect is less pronounced in older children than infants. Respiratory rate is a difficult sign to measure as the variation is large between and within children. More studies of the accuracy and utility of respiratory rate as a proxy for non-severe pneumonia diagnosis in a busy clinic are needed. PMID- 25728869 TI - Comment on "Correlation between the activity of the autonomic nervous system and endothelial function in patients with acute coronary syndrome". PMID- 25728870 TI - Comment on "Correlation between the activity of the autonomic nervous system and endothelial function in patients with acute coronary syndrome". Authors' reply. PMID- 25728871 TI - Success rate during noninvasive ventilation in acute exacerbation of chronic obstructive pulmonary disease: a real-life study? PMID- 25728872 TI - Success rate during noninvasive ventilation in acute exacerbation of chronic obstructive pulmonary disease: a real-life study? Authors' reply. PMID- 25728873 TI - Comment on "Our prescription drugs kill us in large numbers". PMID- 25728874 TI - Comment on "Our prescription drugs kill us in large numbers". Author's reply. PMID- 25728875 TI - Effectiveness of magnetically aligned collagen for neural regeneration in vitro and in vivo. AB - We investigated the effectiveness of using magnetically aligned collagen (after exposure to a maximum 8-T magnetic field) for nerve regeneration in both an in vitro and in vivo model. Neurite outgrowth from embryonic chick dorsal root ganglion (DRG) neurons was significantly greater on magnetically aligned collagen gel than on control gel, and was dependent on magnetic field strength. Silicone tubes (15 mm length) filled with collagen gel formed bridges between severed rat sciatic nerves. We prepared tubes for four groups: collagen gel only (COL), magnetically aligned collagen gel (M-COL), collagen gel mixed with Schwann cells (S-COL), and magnetically aligned collagen gel mixed with Schwann cells (M-S COL). The ratio of infiltrating regenerated nerves was higher in the M-COL group compared to the COL group at 8 weeks post-operation. There were no significant differences between the two groups with and without Schwann cells. Compound action potentials showed higher amplitude and shorter latency in the M-COL than COL group at 12 weeks post-operation. The number and diameter of regenerated axons increased significantly in the M-COL compared with the COL group at 12 weeks post-operation. Here we demonstrated that magnetically orientated collagen promoted nerve regeneration using both an in vitro and in vivo model. PMID- 25728876 TI - [Phase III study of the efficacy and safety of ciclopirox olamine cream in small children with dermatomycosis]. AB - BACKGROUND: There is scarce information on the use of ciclopirox olamine in children. AIMS: The aim of this study was to evaluate the efficacy and safety of ciclopirox olamine cream 1% for the treatment of dermatomycosis in pediatric patients. METHODS: A multicenter, non-randomized, open-label, phase iii study was conducted on patients aged 3 months to 9 years diagnosed with dermatomycosis confirmed by direct microscopy and culture, and treated with ciclopirox olamine cream 1% for 28 days. Clinical and microbiological evaluations were performed before starting the treatment therapy, at 7, 14 and 28 days after starting the treatment, and 28 days after its completion. RESULTS: Twenty-one patients with a median age of 2.7 years (range 3 months-9 years) were included. The most frequent mycosis location was the inguinal region (72%). The most frequently isolated etiological agent was Candida spp. (71%). No adverse events were reported in 62% of the patients. Among the mild and moderate reported adverse events, only one, irritative dermatitis, was considered as possibly related to the treatment. Safety evaluation was excellent in 95% of the patients, and good in 5%. After the first week of treatment, 12 patients out of 13 (92%) showed a clinical improvement, and 5 out of 7 (71%) had both clinical and mycological improvements. At the end of the treatment, clinical cure was observed in 7 out of 9 patients (78%). No relapses occurred. CONCLUSIONS: Ciclopirox olamine cream 1% is a safe and feasible treatment for superficial cutaneous mycotic infections, especially Candida spp. infection, in children aged between 3 months and 10 years. PMID- 25728877 TI - [Toxocara canis eggs as bait for soil fungus in a subtropical city]. AB - BACKGROUND: The use of different isolation techniques allows the recovery of fungi based on their ability to use selective substrates. The sprinkle method is a technique for the recovery of nematophagous fungi in the soil. These fungi are natural predators of nematodes and are widely distributed in nature. AIMS: To detect possible fungi with nematophagous ability in the soil of city parks in Corrientes (Argentina). METHODS: The soil samples were taken from an area of ground between two trees and to no more than 2cm deep. The isolation was performed according to the sprinkle method with Toxocara canis eggs as bait. RESULTS: Eighteen soil samples were collected, and 6 genera and 8 species of fungi were isolated. The sprinkle method, simple and efficient, has the advantage of using a small amount of untreated soil for the isolation of fungi that can grow on the eggs of geohelminths. The genera Bipolaris, Fusarium, Purpureocillium, Curvularia, Phoma and Scytalidium were isolated in this study. CONCLUSIONS: No other studies describing the interaction between the genera Curvularia, Phoma and Scytalidium with nematode eggs have been found in the literature, thus more studies are required to determine what is their real action on these eggs. PMID- 25728878 TI - [Tinea capitis. Dermoscopic findings in 37 patients]. AB - BACKGROUND: Tinea capitis is a common fungal infection in children. Diagnosis is confirmed by mycological study, including direct examination of the samples with potassium hydroxide/chlorazol black and culture. Previous studies have reported the presence of "comma hairs" and "corkscrew hairs", as well as short hairs and black dots. AIMS: To describe the dermoscopic patterns in the trichoscopic examination in patients with tinea capitis. METHODS: A descriptive, observational and cross-sectional study was conducted on 37 patients with tinea capitis, studied during May, 2012, at Dr. Manuel Gea Gonzalez General Hospital in Mexico, and the Instituto Dermatologico y Cirugia de Piel Dr. Huberto Bogaert Diaz, in the Dominican Republic. Clinical, mycological and dermoscopic evaluations were performed. RESULTS: Of the 37 patients included, 28 were of mixed race from Dominican Republic and 9 mixed race cases from Mexico. Seventy six percent were male and 24% female, and 94% were children. The following dermoscopic patterns were confirmed: "comma hairs" (41%), "corkscrew hairs" (22%), short hairs (49%), and black dots (33%). The presence of scales (89%), peripilar casts (46%), alopecia (65%), pustules (8%), and meliceric crusts (16%), were also observed. CONCLUSIONS: Dermoscopy in tinea capitis showed the presence of "comma hairs", and "corkscrew hairs". Scales, peripilar casts and alopecia were also found. It would be desirable to establish this diagnostic tool, particularly when an optical microscope or a mycology reference laboratory are not available. PMID- 25728879 TI - Quantitative sodium MRI of kidney. AB - One of the main tasks of the human kidneys is to maintain the homeostasis of the body's fluid and electrolyte balance by filtration of the plasma and excretion of the end products. Herein, the regulation of extracellular sodium in the kidney is of particular importance. Sodium MRI ((23)Na MRI) allows for the absolute quantification of the tissue sodium concentration (TSC) and thereby provides a direct link between TSC and tissue viability. Renal (23)Na MRI can provide new insights into physiological tissue function and viability thought to differ from the information obtained by standard (1)H MRI. Sodium imaging has the potential to become an independent surrogate biomarker not only for renal imaging, but also for oncology indications. However, this technique is now on the threshold of clinical implementation. Numerous, initial pre-clinical and clinical studies have already outlined the potential of this technique; however, future studies need to be extended to larger patient groups to show the diagnostic outcome. In conclusion, (23)Na MRI is seen as a powerful technique with the option to establish a non-invasive renal biomarker for tissue viability, but is still a long way from real clinical implementation. PMID- 25728880 TI - Psychological distress may affect nutrition indicators in Australian adults. AB - OBJECTIVE: The purpose of this research was to explore which demographic and health status variables moderated the relationship between psychological distress and three nutrition indicators: the consumption of fruits, vegetables and takeaway. METHOD: We analysed data from the 2009 Self-Reported Health Status Survey Report collected in the state of Queensland, Australia. Adults (N = 6881) reported several demographic and health status variables. Moderated logistic regression models were estimated separately for the three nutrition indicators, testing as moderators demographic (age, gender, educational attainment, household income, remoteness, and area-level socioeconomic status) and health status indicators (body mass index, high cholesterol, high blood pressure, and diabetes status). RESULTS: Several significant interactions emerged between psychological distress, demographic (age, area-level socio-economic status, and income level), and health status variables (body mass index, diabetes status) in predicting the nutrition indicators. Relationships between distress and the nutrition indicators were not significantly different by gender, remoteness, educational attainment, high cholesterol status, and high blood pressure status. CONCLUSIONS: The associations between psychological distress and several nutrition indicators differ amongst population subgroups. These findings suggest that in distressed adults, age, area-level socio-economic status, income level, body mass index, and diabetes status may serve as protective or risk factors through increasing or decreasing the likelihood of meeting nutritional guidelines. Public health interventions for improving dietary behaviours and nutrition may be more effective if they take into account the moderators identified in this study rather than using global interventions. PMID- 25728881 TI - Threatened belonging and preference for comfort food among the securely attached. AB - Research has shown that comfort food triggers relationship-related cognitions and can fulfill belongingness needs for those secure in attachment (i.e., for those with positive relationship cognitions) (Troisi & Gabriel, 2011). Building on these ideas, we examined if securely attached individuals prefer comfort food because of its "social utility" (i.e., its capacity to fulfill belongingness needs) in one experiment and one daily diary study using two samples of university students from the United States. Study 1 (n = 77) utilized a belongingness threat essay among half of the participants, and the results showed that securely attached participants preferred the taste of a comfort food (i.e., potato chips) more after the belongingness threat. Study 2 (n = 86) utilized a 14 day daily diary design and found that securely attached individuals consumed more comfort food in response to naturally occurring feelings of isolation. Implications for the social nature of food preferences are discussed. PMID- 25728883 TI - Food reward. What it is and how to measure it. AB - We investigated the contribution of hunger and food liking to food reward, and the relationship between food reward and food intake. We defined liking as the pleasantness of taste of food in the mouth, and food reward as the momentary value of a food to the individual at the time of ingestion. Liking and food reward were measured, respectively, by ratings of the pleasantness of the taste of a mouthful, and ratings of desire to eat a portion, of the food in question. Hunger, which we view as primarily the absence of fullness, was rated without food being present. Study 1 provided evidence that hunger and liking contribute independently to food reward, with little effect of hunger on liking. Food intake reduced liking and reward value more for the eaten food than uneaten foods. The results were ambiguous as to whether this food-specific decline in reward value ('sensory-specific satiety') involved a decrease in 'wanting' in addition to the decrease in liking. Studies 2 and 3 compared desire to eat ratings with work-for food and pay-for-food measures of food reward, and found desire to eat to be equal or superior in respect of effects of hunger and liking, and superior in predicting ad libitum food intake. A further general observation was that in making ratings of food liking participants may confuse the pleasantness of the taste of food with the pleasantness of eating it. The latter, which some call 'palatability,' decreases more with eating because it is significantly affected by hunger/fullness. Together, our results demonstrate the validity of ratings of desire to eat a portion of a tasted food as a measure of food reward and as a predictor of food intake. PMID- 25728882 TI - Confirmatory factor analysis and measurement invariance of the Child Feeding Questionnaire in low-income Hispanic and African-American mothers with preschool age children. AB - Validation work of the Child Feeding Questionnaire (CFQ) in low-income minority samples suggests a need for further conceptual refinement of this instrument. Using confirmatory factor analysis, this study evaluated 5- and 6-factor models on a large sample of African-American and Hispanic mothers with preschool-age children (n = 962). The 5-factor model included: 'perceived responsibility', 'concern about child's weight', 'restriction', 'pressure to eat', and 'monitoring' and the 6-factor model also tested 'food as a reward'. Multi-group analysis assessed measurement invariance by race/ethnicity. In the 5-factor model, two low-loading items from 'restriction' and one low-variance item from 'perceived responsibility' were dropped to achieve fit. Only removal of the low variance item was needed to achieve fit in the 6-factor model. Invariance analyses demonstrated differences in factor loadings. This finding suggests African-American and Hispanic mothers may vary in their interpretation of some CFQ items and use of cognitive interviews could enhance item interpretation. Our results also demonstrated that 'food as a reward' is a plausible construct among a low-income minority sample and adds to the evidence that this factor resonates conceptually with parents of preschoolers; however, further testing is needed to determine the validity of this factor with older age groups. PMID- 25728884 TI - Examining the predictive utility of an extended theory of planned behaviour model in the context of specific individual safe food-handling. AB - BACKGROUND: In order to minimise the occurrence of food-borne illness, it is recommended that individuals perform safe food-handling behaviours, such as cooking food properly, cleaning hands and surfaces before preparing food, keeping food at the correct temperature, and avoiding unsafe foods. Previous research examining the determinants of safe food-handling behaviour has produced mixed results; however, this may be due to the fact that this research examined these behaviours as a totality, rather than considering the determinants of each behaviour separately. As such, the objective for the present study was to examine the predictors of the four aforementioned safe food-handling behaviours by applying an extended theory of planned behaviour to the prediction of each distinct behaviour. METHOD: Participants were 170 students who completed theory of planned behaviour measures, with the addition of moral norm and habit strength at time 1, and behaviour measures one week later. RESULTS: While the influence of injunctive and descriptive norm and perceived behavioural control differed between behaviours, it appeared that moral norm was an important predictor of intention to engage in each of the four behaviours. Similarly, habit strength was an important predictor of each of the behaviours and moderated the relationship between intention and behaviour for the behaviour of avoiding unsafe food. CONCLUSION: The implication of these findings is that examining safe food handling behaviours separately, rather than as a totality, may result in meaningful distinctions between the predictors of these behaviours. PMID- 25728885 TI - Studying the impact of plating on ratings of the food served in a naturalistic dining context. AB - An experiment conducted in a naturalistic dining context is reported, in which the impact of different styles of plating on diners' experience of the food was assessed. A hundred and sixty three diners were separated into two groups during a luncheon event held in a large dining room. Each group of diners was served the same menu, with a variation in the visual presentation of the ingredients on the plate. The results revealed that the diners were willing to pay significantly more for the appetizer (a salad), when arranged in an artistically-inspired manner (M = L5.94 vs. L4.10). The main course was liked more, and considered more artistic, when the various elements were presented in the centre of the plate, rather than placed off to one side. The participants also reported being willing to pay significantly more for the centred than for the offset plating (M = L15.35 vs. L11.65). These results are consistent with the claim that people "eat first with their eyes", and that a diner's experience of the very same ingredients can be significantly enhanced (or diminished) simply by changing the visual layout of the food elements of the dish. Results such as these suggest that theories regarding the perception of food can potentially be confirmed (or disconfirmed) outside of the confines of the laboratory (i.e., in naturalistic dining settings). PMID- 25728886 TI - An explanatory framework of teachers' perceptions of a positive mealtime environment in a preschool setting. AB - Attending a preschool center may help preschoolers with growth and development that encourage a healthy lifestyle, including sound eating behaviors. Providing a positive mealtime environment (PME) may be one of the keys to fostering a child's healthy eating habits in the classroom. However, a specific definition of a PME, the components of a PME, or directions on how to create one have not been established. The purpose of this study, therefore, was to explore Head Start teachers' perceptions related to a PME and create a conceptual framework representing these perceptions. To achieve this purpose, researchers conducted 65 in-depth phone interviews with Head Start teachers around the US. Applying principles of grounded theory, researchers developed a conceptual framework depicting teachers' perceptions of PME, consisting of five key components: (1) the people (i.e., teachers, kitchen staff, parent volunteers, and children), (2) positive emotional tone (e.g., relaxed and happy), (3) rules, expectations, and routines (e.g., family-style mealtime), (4) operations of a PME (i.e., eating, socialization, and learning), and (5) both short- and long-term outcomes of a PME. With this PME framework, researchers may be able to enhance the effectiveness of nutrition interventions related to a PME, focusing on the factors in the conceptual framework as well as barriers associated with achieving these factors. PMID- 25728887 TI - Ecological risk model of childhood obesity in Chinese immigrant children. AB - Chinese Americans are the largest and fastest growing Asian American subgroup, increasing about one-third during the 2000s. Despite the slender Asian stereotype, nearly one-third of 6-to-11 year old Chinese American children were found to be overweight (above the 85th percentile in BMI). Importantly, unique and severe health risks are associated with being overweight/obese in Chinese. Unfortunately, Chinese immigrant children have been neglected in the literature on obesity. This review aimed to identify factors at various levels of the ecological model that may place Chinese immigrant children at risk for being overweight/obese in the U.S. Key contextual factors at the micro-, meso-, exo-, macro- and chronosystem were identified guided by Bronfenbrenner's ecological systems theory. The corresponding mediating and moderating processes among the factors were also reviewed and proposed. By presenting a conceptual framework and relevant research, this review can provide a basic framework for directing future interdisciplinary research in seeking solutions to childhood obesity within this understudied population. PMID- 25728888 TI - Clinical and microbiological effects of probiotic lozenges in the treatment of chronic periodontitis: a 1-year follow-up study. AB - AIM: The objective of this study was to evaluate the effects of lozenges containing L. reuteri as an adjuvant treatment to initial periodontal therapy for chronic periodontitis patients and to detect the level of L. reuteri colonization in the periodontal pockets of treated patients. MATERIAL AND METHODS: A total of 40 patients were selected and randomly divided into two groups. Each patient had at least two teeth with one approximal site each with a probing depth (PD) of 5-7 mm and gingival index (GI) of >=2 in each quadrant. Group I received scaling and root planing (SRP) plus L. reuteri-containing lozenges, and Group II received SRP plus placebo. The plaque index (PI), GI, bleeding on probing (BoP), PD and relative attachment level were measured. Microbiological sampling was performed at baseline and on days 21, 90, 180 and 360 and were analysed by culturing. The Bonferroni-corrected paired sample t-test, Bonferroni-corrected Wilcoxon signed rank test and paired sample t-test were used to evaluate intra-group differences. The Bonferroni-corrected Student's t-test and the Mann-Whitney U-tests were used to evaluate inter-group differences. RESULTS: After treatment, the measured PI, GI, BoP and PD were significantly (p < 0.05) lower in Group I compared with Group II at all time points. Similar observations were made for the total viable cell counts and the proportions of obligate anaerobes with the exception of day 360. In Group I, significantly fewer patients required surgery on >=3 sites. CONCLUSION: L. reuteri-containing lozenges may be a useful adjuvant agent to slow re-colonization and improve clinical outcomes of chronic periodontitis. Further studies are required to clarify the optimal dose of the lozenges. PMID- 25728889 TI - Hospital-centered violence intervention programs: a cost-effectiveness analysis. AB - BACKGROUND: Hospital-centered violence intervention programs (HVIPs) reduce violent injury recidivism. However, dedicated cost analyses of such programs have not yet been published. We hypothesized that the HVIP at our urban trauma center is a cost-effective means for reducing violent injury recidivism. METHODS: We conducted a cost-utility analysis using a state-transition (Markov) decision model, comparing participation in our HVIP with standard risk reduction for patients injured because of firearm violence. Model inputs were derived from our trauma registry and published literature. RESULTS: The 1-year recidivism rate for participants in our HVIP was 2.5%, compared with 4% for those receiving standard risk reduction resources. Total per-person costs of each violence prevention arm were similar: $3,574 for our HVIP and $3,515 for standard referrals. The incremental cost effectiveness ratio for our HVIP was $2,941. CONCLUSION: Our HVIP is a cost-effective means of preventing recurrent episodes of violent injury in patients hurt by firearms. PMID- 25728890 TI - Body mass index in blunt trauma patients with hemorrhagic shock: opposite ends of the body mass index spectrum portend poor outcome. AB - BACKGROUND: There are controversial data on the relationship between trauma and body mass index. We investigated this relationship in traumatic hemorrhagic shock. METHODS: The "Glue Grant" database was analyzed, stratifying patients into underweight, normal weight (NW), overweight, Class I obesity, Class II obesity, and Class III obesity. Predictors of mortality and surgical interventions were statistically determined. RESULTS: One thousand nine hundred seventy-six patients were included with no difference in injury severity between groups. Marshall's score was elevated in overweight (5.3 +/- 2.7, P = .016), Class I obesity (5.8 +/ 2.7, P < .001), Class II obesity (5.9 +/- 2.8, P < .001), and Class III obesity (6.3 +/- 3.0, P < .001) compared with NW (4.8 +/- 2.6). Underweight had higher lactate (4.8 +/- 4.2 vs 3.3 +/- 2.5, P = .04), were 4 times more likely to die (odds ratio 3.87, confidence interval 2.22 to 6.72), and were more likely to undergo a laparotomy (odds ratio 2.06, confidence interval 1.31 to 3.26) than NW. CONCLUSION: Early assessment of body mass index, with active management of complications in each class, may reduce mortality in traumatic hemorrhagic shock. PMID- 25728891 TI - Laparoscopic versus open colorectal surgery for colon cancer: the effect of surgical trauma on the bacterial translocation. A prospective randomized study. AB - BACKGROUND: Several studies suggest that surgical manipulation of the intestine and increased intra-abdominal pressure promotes bacterial translocation (BT). This prospective randomized study has investigated the effect of surgery on BT in patients undergoing elective colectomy for colon cancer by comparing the laparoscopic with the open approach. METHODS: One hundred nineteen consecutive patients underwent colectomy for colon cancer: 59 cases underwent open resection and 60 cases underwent laparoscopic resection. For bacterial identification, tissue samples were taken from the liver, spleen, and mesenteric lymph nodes. RESULTS: The incidence of BT increased in laparoscopic and open group after bowel mobilization (prior to ligation of the vascular pedicle), compared with the before mobilization (P < .05). There was not a statistically significant difference in BT value between the 2 groups. CONCLUSION: BT increase was observed during the open and laparoscopic resection for colon cancer, without significant statistical difference between the 2 groups. PMID- 25728893 TI - Special issue of electrophoresis on fundamentals. PMID- 25728892 TI - Nitrogen fertilizer dose alters fungal communities in sugarcane soil and rhizosphere. AB - Fungi play important roles as decomposers, plant symbionts and pathogens in soils. The structure of fungal communities in the rhizosphere is the result of complex interactions among selection factors that may favour beneficial or detrimental relationships. Using culture-independent fungal community profiling, we have investigated the effects of nitrogen fertilizer dosage on fungal communities in soil and rhizosphere of field-grown sugarcane. The results show that the concentration of nitrogen fertilizer strongly modifies the composition but not the taxon richness of fungal communities in soil and rhizosphere. Increased nitrogen fertilizer dosage has a potential negative impact on carbon cycling in soil and promotes fungal genera with known pathogenic traits, uncovering a negative effect of intensive fertilization. PMID- 25728894 TI - In memoriam of Georges Guiochon (1931-2014). PMID- 25728899 TI - Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance. AB - Pre-clinical studies have identified nitroxyl (HNO), the reduced congener of nitric oxide (NO*), as a potent vasodilator which is resistant to tolerance development. The present study explores the efficacy of HNO in human blood vessels and describes, for the first time, a vasodilator for humans that is not susceptible to tolerance. Human radial arteries and saphenous veins were obtained from patients undergoing coronary artery graft surgery and mounted in organ baths. Repeated vasodilator responses to the HNO donor Angeli's salt (AS) and NO* donor glyceryl trinitrate (GTN) were determined. AS- and GTN-induced concentration-dependent vasorelaxation of both human radial arteries (AS pEC50: 6.5 +/- 0.2; -log M) and saphenous veins (pEC50: 6.7 +/- 0.1) with similar potency. In human radial arteries, GTN-induced relaxation was reduced by the NO* scavenger hydroxocobalamin (HXC; P<0.05) but was unaffected by the HNO scavenger L-cysteine. Alternately, AS was unaffected by HXC but was reduced by L-cysteine (5-fold shift, P<0.05). The sGC (soluble guanylate cyclase) inhibitor ODQ abolished responses to both AS and GTN in arteries and veins (P<0.05). Inhibition of voltage-dependent potassium channels (Kv channels) with 4-AP also significantly reduced responses to AS (pEC50: 5.5) and GTN, suggesting that the relaxation to both redox congeners is cGMP- and Kv channel-dependent. Critically, a concentration-dependent development of tolerance to GTN (1 and 10 MUM; P<0.05), but not to AS, was observed in both saphenous veins and radial arteries. Like GTN, the HNO donor AS causes vasorelaxation of human blood vessels via activation of a cGMP-dependent pathway. Unlike GTN, however, it does not develop tolerance in human blood vessels. PMID- 25728900 TI - A short synthesis of d-[1-(14) C]-serine of high enantiomeric purity. AB - Herein, we report a short, three-step synthesis of d-[1-(14) C]-serine (4) in high enantiomeric purity. Starting from [(14) C]-KCN and 2 (benzyloxy)acetaldehyde, Strecker reaction using (R)-1-phenylethylamine as the chiral auxiliary gave two diastereomeric aminonitriles 1 and 2 in the ratio of 4:3, which were conveniently separated and purified chromatographically. Following hydrolysis and subsequent hydrogenolysis, the purified major diastereomer 1, was smoothly converted to d-[1-(14) C]-serine (4) in an enantiomeric excess of >99%, thus circumventing time intensive chiral HPLC enantiomeric resolution. PMID- 25728901 TI - Disruption of follistatin by RNAi increases apoptosis, arrests S-phase of cell cycle and decreases estradiol production in bovine granulosa cells. AB - Follistatin (FST), a local regulator of gonadal functions is a powerful inhibitor of follicle stimulating hormone (FSH) secretion. In the present study, the expression of FST was partially silenced at both transcriptional and translational levels by RNAi-Ready pSIREN-RetroQ-ZsGreen Vector mediated recombinant pshRNA vectors in bovine granulosa cells (bGCs). The results showed that transfection with FST-1 and FST-2 vectors significantly down-regulated mRNA and protein expressions of follistatin by 51% (P = 0.0093) and 72% (P = 0.0078) respectively. After down-regulation of FST in bGCs, cell cycle was arrested at S phase (9.2 +/- 0.6 vs 12.5 +/- 0.2, P = 0.0055), and apoptosis was significantly (21.3 +/- 2.7 vs 13.9 +/- 2.5, P = 0.0051) increased. These findings were further verified by down-regulation of protein level of B-cell leukemia/lymphoma 2 (Bcl2, P = 0.0423), and up-regulation of caspase-3 (P = 0.0362), p21 (P = 0.0067) and mRNA levels of Bcl2-associated X protein (Bax, P = 0.041). Knockdown of FST in bGCs significantly increased activin A concentration in culture medium, while level of estradiol (E2) was suppressed without affecting progesterone production. In addition, mRNA levels of all activin receptor subtypes [activin receptor types I (ACRI) and II (ACRIIA and ACRIIB)] and inhibin alpha-subunit were augmented (P < 0.05) without altering both inhibin beta-subunits. These findings suggest that follistatin may participate in caspase3-dependent apoptosis through Bcl2/Bax gene family in bovine GCs, whereas, activin and its receptors are associated with its regulation. Activin-induced up-regulation of inhibin-alpha subunit in bGCs seems to be involved in the regulation of steroidogenesis. PMID- 25728902 TI - Molecular modeling and docking study on dopamine D2-like and serotonin 5-HT2A receptors. AB - Psychiatric disorders, such as schizophrenia, bipolar disorder and major depression, are paid more and more attention by human due to their upward tendency in modern society. D2-like and 5-HT2A receptors have been proposed as targets of antipsychotic drugs. Atypical antipsychotic drugs have been deemed to improve the treatment of positive, negative and extrapyramidal symptoms. Unfortunately, no experimental structures for these receptors are available except D3 receptor (D3R). Therefore, it is necessary to construct structures of D2-like and 5-HT2A receptors to investigate the interaction between these receptors and their antagonists. Accordingly, homology models of dopamine D2, D3, D4 and serotonin 5-HT2A receptors have been built on the high-resolution crystal structure of the beta2-adrenergic receptor, and refined by molecular dynamics simulations. The backbone root-mean-square deviation (RMSD) of D3R model relative to crystal structure is 1.3A, which proves the reliability of homology modeling. Docking studies reveal that the binding modes of four homology models and their antagonists are consistent with experimental site-directed mutagenesis data. The calculated pKi values agree well with the experimental pKi ones. Antagonists with linear structures such as butyrophenones and benzisoxazolyl piperidines are easily docked into D2-like and 5-HT2A receptors. Polycyclic aromatic compounds have weaker affinity with four receptors. Homology models of D2-like and 5-HT2A receptors will be helpful for predicting the affinity of novel ligands, and could be used as three-dimensional (3D) templates for antipsychotic virtual screening and further drug discovery. PMID- 25728903 TI - Localization of Banana bunchy top virus and cellular compartments in gut and salivary gland tissues of the aphid vector Pentalonia nigronervosa. AB - Banana bunchy top virus (BBTV) (Nanoviridae: Babuvirus) is transmitted by aphids of the genus Pentalonia in a circulative manner. The cellular mechanisms by which BBTV translocates from the anterior midgut to the salivary gland epithelial tissues are not understood. Here, we used multiple fluorescent markers to study the distribution and the cellular localization of early and late endosomes, macropinosomes, lysosomes, microtubules, actin filaments, and lipid raft subdomains in the gut and principal salivary glands of Pentalonia nigronervosa. We applied colabeling assays, to colocalize BBTV viral particles with these cellular compartments and structures. Our results suggest that multiple potential cellular processes, including clathrin- and caveolae-mediated endocytosis and lipid rafts, may not be involved in BBTV internalization. PMID- 25728904 TI - Erectile dysfunction as a marker for cardiovascular disease diagnosis and intervention: a cost analysis. AB - INTRODUCTION: Erectile dysfunction (ED) is a risk factor for cardiovascular disease (CVD). We examine the costs of screening men with ED for CVD risk factors and the cost savings of treating these at risk men. AIM: This study aims to evaluate the effect of screening men presenting with ED for CVD risk factors and to determine the cost effectiveness of this screening protocol. METHODS: The known incidence and prevalence of ED and CVD, the rate of undiagnosed CVD, and the effects of CVD treatment were used to model the change in prevalence of acute CVD events and ED as a function of the number of men with ED and CVD. The cost savings associated with reduction in acute cardiovascular (CV) events and ED prevalence was estimated over 20 years. MAIN OUTCOME MEASURES: Acute CVD event rate reduction and associated cost savings were modeled over 20 years. RESULTS: The relative risk of ED in men with CVD is 1.47 and the coprevalence of both ED and CVD was estimated at 1,991,520 men. Approximately 44% of men with CVD risk factors are unaware of their risk. If all men presenting with ED were screened for CVD, 5.8 million men with previously unknown CVD risk factors would be identified over 20 years, costing $2.7 billion to screen. Assuming a 20% decrease in CV events as a result of screening and treatment, 1.1 million cardiovascular events would be avoided, saving $21.3 billion over 20 years. Similarly, 1.1 million cases of ED would be treated, saving $9.7 billion. Together, the reduction in acute CVD and ED treatment cost would save $28.5 billion over 20 years. CONCLUSIONS: Screening for CVD in men presenting with ED can be a cost effective intervention for secondary prevention of both CVD and, over the longer term, ED. PMID- 25728905 TI - Label-free proteomics uncovers energy metabolism and focal adhesion regulations responsive for endometrium receptivity. AB - The menstrual cycle of the female uterus leads to periodic changes of the endometrium. These changes are important for developing the endometrial receptivity and for achieving competency of embryo implantation. However, the molecular events underlying the endometrial receptivity process remain poorly understood. Here we applied an LC-MS-based label-free quantitative proteomic approach to compare the endometrial tissues in the midsecretory (receptive) phase with the endometrial tissues in the proliferative phase from age-matched woman (n = 6/group). The proteomes of endometrial tissues were extracted using an SDS based detergent, digested by the filter-aided sample preparation procedures, and subsequently analyzed by nano-LC-MS/MS (Orbitrap XL) with a 4 h gradient. Reliable protein expression profiles were reproducibly obtained from the endometrial tissues in the receptive and proliferative phases. A total of 2138 protein groups were quantified under highly stringent criteria with a false discovery rate of <1% for peptide and protein groups. Among these proteins, 317 proteins had differences in expression that were statistically significant between the receptive and proliferative phases. Direct protein-protein interaction network analyses of these significantly changed proteins showed that the up-regulation of creatine kinase B-type (CKB) in the receptive phase may be related to endometrium receptivity. The interaction network also showed that proteins related to cell-cell adhesion were down-regulated. Moreover, the results from KEGG pathway analyses are consistent with the protein-protein interaction results. The proteins, including alpha-actinin (ACTN), extracellular matrix proteins, integrin alpha-V, and so on, that are involved in the focal adhesion pathway were down-regulated in the receptive phase compared with the proliferative phase, which may facilitate the implantation of the fertilized ovum. Selected proteins were validated by Western blot analysis and indirect immunofluorescence, including the up-regulation of CKB and down-regulation ACTN in the receptive phase. In summary, our proteomic analysis study shows potential for predicting the endometrial remodeling from the proliferative to the receptivity phase in women, and these results also reveal the key biological mechanisms (such as energy metabolism and focal adhesion) underlying human endometrial receptivity. PMID- 25728906 TI - Balloon Dilation of the Ureter: A Contemporary Review of Outcomes and Complications. AB - PURPOSE: During ureteroscopy ureteral balloon dilation may be necessary to allow for passage of endoscopic instruments or access sheaths. We assessed the efficacy and complications associated with ureteral balloon dilation. MATERIALS AND METHODS: We retrospectively reviewed the records at 2 institutions from 2000 to 2012 to identify patients who underwent ureteral balloon dilation during ureteroscopic treatment of upper tract stones. An 18Fr balloon dilator was used in all cases. Patients with documented ureteral stricture, radiation therapy or urothelial cancer were excluded from analysis. Primary outcomes were the stone free rate, operative complications, balloon dilation failure and the postoperative ureteral stricture rate. Complications were divided into intraoperative and postoperative groups according to the Satava and Clavien-Dindo classifications, respectively. RESULTS: A total of 151 patients fulfilled study criteria. Median followup was 12 months. The stone-free rate was 72% and median time to first postoperative imaging was 2.8 months. Balloon dilation failed in only 8 patients (5%). Eight intraoperative ureteral perforations (5%) were identified, which were managed by a ureteral stent in 7 patients and a percutaneous tube in 1. Endoscopic re-treatment was required in 4 patients with Satava 2b postoperative complications. The postoperative complication rate was 8% (11 cases). A single ureteral stricture was attributable to balloon dilation. CONCLUSIONS: In this contemporary review balloon dilation of the ureter before endoscopic treatment of stone disease was associated with a high success rate and few complications. Ureteral balloon dilation may decrease the need for a secondary procedure in patients undergoing ureteroscopy to manage proximal ureteral and intrarenal stones. PMID- 25728907 TI - A broad cocktail of environmental pollutants found in eggs of three seabird species from remote colonies in Norway. AB - Eggs of 3 seabird species, common eider (Somateria mollisima), European shag (Phalacrocorax aristotelis aristotelis), and European herring gull (Larus argentatus), were surveyed for a broad range of legacy and emerging pollutants to assess chemical mixture exposure profiles of seabirds from the Norwegian marine environment. In total, 201 chemical substances were targeted for analysis ranging from metals, organotin compounds, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and associated metabolites, chlorinated paraffins, chlorinated and nonchlorinated organic pesticides, per- and polyfluoroalkyl substances (PFAS), dechlorane plus, octachlorostyrene, brominated flame retardants (BFRs), organophosphorous compounds, brominated and alkyl phenols, cyclic siloxanes, and phthalates. Of the chemicals targeted, 149 substances were found above the detection limits, with metals dominating the contaminant profile and comprising 60% of the total contaminant load. Polychlorinated biphenyls, pesticides, organophosphorous compounds, and PFAS were the dominant contaminant classes of organic pollutants found within the seabird species, with the highest loads occurring in herring gulls, followed by shag, and common eider. New generation pollutants (e.g., PFAS, organophosphorous compounds, and alkylphenols) were detected at similar or higher concentrations than the legacy persistent organic pollutants (POPs). Time trends of reported concentrations of legacy POPs appear to have decreased in recent decades from the Norwegian coastal environment. Concentrations of detected pollutants do not appear to have a negative effect on seabird population development within the sampling area. Additional stress caused by pollutants, however, may affect seabird health more at the individual level. PMID- 25728908 TI - Validity and reliability of the Spanish version of the Personal and Social Performance scale in adolescents with schizophrenia. AB - BACKGROUND: The Personal and Social Performance (PSP) scale is a widely used tool to evaluate adults with schizophrenia; however, more studies are needed regarding its usefulness in the assessment of adolescent patients, since the evaluation of their functioning could require adaptations according to development. OBJECTIVE: To examine construct validity, convergent validity, internal consistency and interrater reliability of the PSP in a sample of Mexican adolescents with schizophrenia. METHODS: A total of 40 patients with a DSM-IV diagnosis of schizophrenia or schizophreniform disorder were evaluated with PSP, CGAS, PANSS and the MATRICS battery. Construct and convergent validity were determined by the correlation between PSP with PANSS factors, MATRICS dimensions and CGAS. In addition, reliability was evaluated with Cronbach's alpha and intraclass correlation coefficients. RESULTS: PSP scores correlated with negative, excitement and cognitive factors of PANSS, CGAS as well as MATRICS domains. The PSP also showed high internal consistency and interrater reliability. CONCLUSIONS: The PSP is a valid and reliable instrument for the assessment of adolescent patients. PMID- 25728909 TI - Deletion of the amyloid precursor-like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus. AB - Amyloid precursor-like protein 1 (APLP1) is a transmembrane synaptic protein belonging to the amyloid precursor protein (APP) gene family. Although the role of this gene family-in particular of APP-has been intensely studied in the context of Alzheimer's disease, the physiological roles of its family members remain poorly understood. In particular, the function of APLP1, which is predominantly expressed in the nervous system, has remained enigmatic. Since APP has been implicated in synaptic plasticity, we wondered whether APLP1 could play a similar role. First, using in situ hybridization and laser microdissection combined with reverse transcription-quantitative polymerase chain reaction (PCR) we observed that Aplp1 mRNA is highly expressed in dentate granule cells. Having this examined, we studied synaptic plasticity at the perforant path-granule cell synapses in the dentate gyrus of APLP1-deficient mice in vivo. Analysis of field excitatory postsynaptic potentials evoked by stimulation of perforant path fibers revealed increased excitatory transmission in APLP1-deficient mice. Moreover, we observed decreased paired-pulse inhibition of population spikes indicating a decrease in network inhibition upon deletion of APLP1. In contrast, short-term presynaptic plasticity (STP) as well as long-term synaptic plasticity (LTP) was unchanged in the absence of APLP1. Based on these results we conclude that APLP1 deficiency on its own does not lead to defects in synaptic plasticity, but affects synaptic transmission and network inhibition in the dentate gyrus. PMID- 25728910 TI - Facile and gram-scale synthesis of metal-free catalysts: toward realistic applications for fuel cells. AB - Although numerous reports on nonprecious metal catalysts for replacing expensive Pt-based catalysts have been published, few of these studies have demonstrated their practical application in fuel cells. In this work, we report graphitic carbon nitride and carbon nanofiber hybrid materials synthesized by a facile and gram-scale method via liquid-based reactions, without the use of toxic materials or a high pressure-high temperature reactor, for use as fuel cell cathodes. The resulting materials exhibited remarkable methanol tolerance, selectivity, and stability even without a metal dopant. Furthermore, these completely metal-free catalysts exhibited outstanding performance as cathode materials in an actual fuel cell device: a membrane electrode assembly with both acidic and alkaline polymer electrolytes. The fabrication method and remarkable performance of the single cell produced in this study represent progressive steps toward the realistic application of metal-free cathode electrocatalysts in fuel cells. PMID- 25728911 TI - Effect of cloth stoma covers on tracheal climate of laryngectomy patients. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of cloth stoma covers (bibs) to compensate for breathing unconditioned air after laryngectomy and loss of heat-moisture-exchange (HME) functions of the upper airways, which, to the best of our knowledge, has never been reported. In addition, we compared the efficacy of inexpensive, simple, locally made, noncommercial fabric bibs with commercial bibs and stick-over-the-stoma HME devices and to determine whether wetting the bib improves the tracheal climate. METHODS: Tracheal temperature and humidity were studied in 25 patients who underwent a laryngectomy with a purpose built sampling device. RESULTS: Noncommercial and commercial bibs effectively heat and humidify inspired air (p < .05). Both bibs compare favorably with commercial HME devices. There is no benefit in using a commercially produced Buchanan Bib over an inexpensive noncommercial bib. Wetting a bib proved to be counterproductive. CONCLUSION: Inexpensive, noncommercial bibs are effective and improve tracheal climate and benefit patients with laryngectomies. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E480-E487, 2016. PMID- 25728912 TI - Molecular cloning of melatonin 2-hydroxylase responsible for 2-hydroxymelatonin production in rice (Oryza sativa). AB - Although melatonin biosynthetic genes from plants have been cloned, the melatonin catabolism mechanisms remain unclear. To clone the genes responsible for melatonin metabolism, we ectopically expressed 35 full-length cDNAs of rice 2 oxoglutarate-dependent dioxygenase (2-ODD) in Escherichia coli and purified the corresponding recombinant proteins. In vitro 2-ODD assays showed four independent 2-ODD proteins that were able to catalyze melatonin into 2-hydroxymelatonin, exhibiting melatonin 2-hydroxylase (M2H). These M2H proteins had peak activities at pH 8.0 and 30 degrees C. The Km ranged from 121 MUm to 371 MUm with the Vmax ranging from 1.7 to 18.5 pkat/mg protein, respectively. The M2H enzyme activities were dependent on cofactors such as alpha-ketoglutarate, ascorbate, and Fe(2+), similar to the 2-ODD enzymes. M2H activity was inhibited by prohexadione-Ca, an inhibitor of 2-ODD, in a dose-dependent manner. M2H activity was high in the roots of rice seedlings, concurrent with high transcription levels of 2-ODD 21, suggesting that 2-ODD 21 was a major gene for M2H activity. Analogous to the high M2H activity in the roots, 2-hydroxymelatonin was found in large quantities in roots treated with melatonin. These results suggest that melatonin was metabolized into 2-hydroxymelatonin by the M2H genes in plants, but the physiological significance of 2-hydroxymelatonin remains to be examined in the future. PMID- 25728913 TI - Participation in and Satisfaction With an Exercise Program for Inpatient Mental Health Consumers. AB - PURPOSE: This study examines attendance at, and satisfaction with, a group exercise program in an inpatient mental health setting. DESIGN AND METHOD: Thirty two inpatients completed discharge surveys to evaluate group activities. Data were analyzed for participation and satisfaction. FINDINGS: More inpatients (n = 16, 50%) rated exercise as "excellent" compared with all other activities. Nonattendance rates were lowest for cognitive behavioral therapy (n = 2, 6.3%), highest for the relaxation group (n = 6, 18.8%), and 12.5% (n = 4) for the group exercise program. PRACTICE IMPLICATIONS: Group exercise programs delivered by highly trained personnel are well attended and achieve high satisfaction ratings by inpatient mental health consumers. PMID- 25728914 TI - Viscoelasticity of hyaluronic acid-gelatin hydrogels for vocal fold tissue engineering. AB - Crosslinked injectable hyaluronic acid (HA)-gelatin (Ge) hydrogels have remarkable viscoelastic and biological properties for vocal fold tissue engineering. Patient-specific tuning of the viscoelastic properties of this injectable biomaterial could improve tissue regeneration. The frequency-dependent viscoelasticity of crosslinked HA-Ge hydrogels was measured as a function of the concentration of HA, Ge, and crosslinker. Synthetic extracellular matrix hydrogels were fabricated using thiol-modified HA and Ge, and crosslinked by poly(ethylene glycol) diacrylate. A recently developed characterization method based on Rayleigh wave propagation was used to quantify the frequency-dependent viscoelastic properties of these hydrogels, including shear storage and loss moduli, over a broad frequency range; that is, from 40 to 4000 Hz. The viscoelastic properties of the hydrogels increased with frequency. The storage and loss moduli values and the rate of increase with frequency varied with the concentrations of the constituents. The range of the viscoelastic properties of the hydrogels was within that of human vocal fold tissue obtained from in vivo and ex vivo measurements. Frequency-dependent parametric relations were obtained using a linear least-squares regression. The results are useful to better fine tune the storage and loss moduli of HA-Ge hydrogels by varying the concentrations of the constituents for use in patient-specific treatments. PMID- 25728915 TI - Vegetation management with fire modifies peatland soil thermal regime. AB - Vegetation removal with fire can alter the thermal regime of the land surface, leading to significant changes in biogeochemistry (e.g. carbon cycling) and soil hydrology. In the UK, large expanses of carbon-rich upland environments are managed to encourage increased abundance of red grouse (Lagopus lagopus scotica) by rotational burning of shrub vegetation. To date, though, there has not been any consideration of whether prescribed vegetation burning on peatlands modifies the thermal regime of the soil mass in the years after fire. In this study thermal regime was monitored across 12 burned peatland soil plots over an 18 month period, with the aim of (i) quantifying thermal dynamics between burned plots of different ages (from <2 to 15 + years post burning), and (ii) developing statistical models to determine the magnitude of thermal change caused by vegetation management. Compared to plots burned 15 + years previously, plots recently burned (<2-4 years) showed higher mean, maximum and range of soil temperatures, and lower minima. Statistical models (generalised least square regression) were developed to predict daily mean and maximum soil temperature in plots burned 15 + years prior to the study. These models were then applied to predict temperatures of plots burned 2, 4 and 7 years previously, with significant deviations from predicted temperatures illustrating the magnitude of burn management effects. Temperatures measured in soil plots burned <2 years previously showed significant statistical disturbances from model predictions, reaching +6.2 degrees C for daily mean temperatures and +19.6 degrees C for daily maxima. Soil temperatures in plots burnt 7 years previously were most similar to plots burned 15 + years ago indicating the potential for soil temperatures to recover as vegetation regrows. Our findings that prescribed peatland vegetation burning alters soil thermal regime should provide an impetus for further research to understand the consequences of thermal regime change for carbon processing and release, and hydrological processes, in these peatlands. PMID- 25728916 TI - Recovery of energy and iron from oily sludge pyrolysis in a fluidized bed reactor. AB - In the steel industry, about 0.86 ton of oily sludge is produced for every 1000 tons of rolling steel. Due to the adverse impact on human health and the environment, oily sludge is designated as a hazardous waste in the Resource Conservation and Recovery Act (RCRT). In this paper, the pyrolysis treatment of oily sludge is studied in a fluidized bed reactor at a temperature range of 400 600 degrees C. During oily sludge pyrolysis, a maximum oil yield of 59.2% and a minimum energy loss of 19.0% are achieved at 500 degrees C. The energy consumption of treating 1 kg oily sludge is only 2.4-2.9 MJ. At the same time, the energy of produced oil, gas and solid residue are 20.8, 6.32, and 0.83 MJ, respectively. In particular, it is found that the solid residue contains more than 42% iron oxide, which can be used as the raw material for iron production. Thus, the simultaneous recovery of energy and iron from oil sludge by pyrolysis is feasible. PMID- 25728917 TI - Grid-wide subdaily hydrologic alteration under massive wind power penetration in Chile. AB - Hydropeaking operations can severely degrade ecosystems. As variable renewable sources (e.g. wind power) are integrated into a power grid, fluctuations in the generation-demand balance are expected to increase. In this context, compensating technologies, notably hydropower reservoir plants, could operate in a stronger peaking scheme. This issue calls for an integrated modeling of the entire power system, including not only hydropower reservoirs, but also all other plants. A novel methodology to study the link between the short-term variability of renewable energies and the subdaily hydrologic alteration, due to hydropower reservoir operations is presented. Grid operations under selected wind power portfolios are simulated using a short-term hydro-thermal coordination tool. The resulting turbined flows by relevant reservoir plants are then compared in terms of the Richard-Baker flashiness index to both the baseline and the natural flow regime. Those are then analyzed in order to: i) detect if there is a significant change in the degree of subdaily hydrologic alteration (SDHA) due to a larger wind penetration, and ii) identify which rivers are most affected. The proposed scheme is applied to Chile's Central Interconnect System (SIC) for scenarios up to 15% of wind energy penetration. Results show a major degree of SDHA under the baseline as compared to the natural regime. As wind power increases, so does the SDHA in two important rivers. This suggests a need for further ecological studies in those rivers, along with an analysis of operational constraints to limit the SDHA. PMID- 25728918 TI - Effects of nitrogen fertilization on soil nutrient concentration and phosphatase activity and forage nutrient uptake from a grazed pasture system. AB - Over a 3-year period, the effect of differing N-application regimes on soil extractable-P concentration, soil phosphatase activity, and forage P uptake in a P-enriched grazed-pasture system was investigated. In the fall of each year, six 0.28-ha plots were overseeded with triticale ( * Triticosecale rimpaui Wittm.) and crimson clover (Trifolium incarnatum) into a tall fescue (Lolium arundinacea)/bermudagrass (Cynodon dactylon) sod and assigned to 1 of 3 N fertilizer treatments (n = 2): 100% of N recommendation in a split application (100N), 50% in a single application (50N), and 0% of N recommendation (0N) for triticale. Cattle commenced grazing the following spring and grazed until May. In the summer, plots were overseeded with cowpea (Vigna unguiculata), fertilized at the same rates by reference to N recommendations for bermudagrass, and grazed by cattle until September. There were no effects of N fertilization on soil phosphatase activity, electrical conductivity, or concentrations of water-soluble P. Concentrations of extractable P decreased in plots receiving 50N, but increasing N fertilization to 100N resulted in no further reduction in extractable P. Forage biomass, foliar P concentrations, and forage P mass were not affected by N fertilization rates at the plant-community level, but responses were observed within individual forage species. Results are interpreted to mean that N fertilization at 50% of the agronomic recommendation for the grass component can increase forage P mass of specific forages and decrease soil extractable P, thus providing opportunity for decreasing P losses from grazed pasture. PMID- 25728919 TI - District nurses' prescribing practice and its link to structural conditions. AB - PURPOSE: To describe district nurses' (DNs') prescribing practice and examine associations between DNs' self-reported prescribing frequency, opinions about prescribing, and structural conditions/empowerment. DATA SOURCES: A cross sectional and correlational design was employed. Data were collected during 2012 using questionnaires and a prescribing register. A random sample of 150 DNs from 32 primary care centers in Sweden was invited. CONCLUSIONS: DNs' ability to prescribe is used to a relatively small extent and access to "opportunities" and "informal power" seems to be the most important structural empowerment conditions for increased prescribing frequency and positive opinions about prescribing. The results support Kanter's theory of structural empowerment. IMPLICATIONS FOR PRACTICE: This article regarding restricted prescribing shows how important structural conditions/empowerment is to DNs' prescribing and employers have to enhance nurses' access to especially the structures "opportunities" and "informal power" to increase nurse prescribing. More targeted support and training are needed in different prescribing areas to make use of DNs' prescription qualification to a greater extent. PMID- 25728920 TI - Expanding the Mutation Spectrum Affecting alphaIIbbeta3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort. AB - We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the alphaIIbbeta3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual alphaIIbbeta3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent alphaIIbbeta3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in alphaIIb and beta3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin. PMID- 25728921 TI - Lewis acid promoted ruthenium(II)-catalyzed etherifications by selective hydrogenation of carboxylic acids/esters. AB - Ethers are of fundamental importance in organic chemistry and they are an integral part of valuable flavors, fragrances, and numerous bioactive compounds. In general, the reduction of esters constitutes the most straightforward preparation of ethers. Unfortunately, this transformation requires large amounts of metal hydrides. Presented herein is a bifunctional catalyst system, consisting of Ru/phosphine complex and aluminum triflate, which allows selective synthesis of ethers by hydrogenation of esters or carboxylic acids. Different lactones were reduced in good yields to the desired products. Even challenging aromatic and aliphatic esters were reduced to the desired products. Notably, the in situ formed catalyst can be reused several times without any significant loss of activity. PMID- 25728922 TI - Ours is a special community. PMID- 25728923 TI - Anomalous origin of the right pulmonary artery from the ascending aorta accompanied by absent pulmonary valve syndrome and right-sided aortic arch: a rare case in adult congenital heart disease. AB - We present a rare congenital heart disease in a 20-year-old man with anomalous origin of the right pulmonary artery from the ascending aorta, accompanied by absent pulmonary valve syndrome, and a right-sided aortic arch suspected initially in transthoracic echocardiography and subsequently confirmed by cardiac catheterisation and computed tomography angiography. PMID- 25728924 TI - Structural basis of latrophilin-FLRT interaction. AB - Latrophilins, receptors for spider venom alpha-latrotoxin, are adhesion type G protein-coupled receptors with emerging functions in synapse development. The N terminal region binds the endogenous cell adhesion molecule FLRT, a major regulator of cortical and synapse development. We present crystallographic data for the mouse Latrophilin3 lectin and olfactomedin-like (Olf) domains, thereby revealing the Olf beta-propeller fold and conserved calcium-binding site. We locate the FLRT-Latrophilin binding surfaces by a combination of sequence conservation analysis, point mutagenesis, and surface plasmon resonance experiments. In stripe assays, we show that wild-type Latrophilin3 and its high affinity interactor FLRT2, but not the binding-impaired mutants we generated, promote HeLa cell adhesion. In contrast, cortical neurons expressing endogenous FLRTs are repelled by wild-type Latrophilin3 and not by the binding-impaired mutant. Taken together, we present molecular level insights into Latrophilin structure, its FLRT-binding mechanism, and a role for Latrophilin and FLRT that goes beyond a simply adhesive interaction. PMID- 25728925 TI - Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases. AB - Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) is a newly identified substrate for protein tyrosine phosphatase N3 (PTPN3), which belongs to the FERM-containing PTP subfamily comprising five members including PTPN3, N4, N13, N14, and N21. We solved the crystal structures of the PTPN3-Eps15 phosphopeptide complex and found that His812 of PTPN3 and Pro850 of Eps15 are responsible for the specific interaction between them. We defined the critical role of the additional residue Tyr676 of PTPN3, which is replaced by Ile939 in PTPN14, in recognition of tyrosine phosphorylated Eps15. The WPD loop necessary for catalysis is present in all members but not PTPN21. We identified that Glu instead of Asp in the WPE loop contributes to the catalytic incapability of PTPN21 due to an extended distance beyond protonation targeting a phosphotyrosine substrate. Together with in vivo validations, our results provide novel insights into the substrate specificity and plasticity of FERM-containing PTPs. PMID- 25728926 TI - Higher-order architecture of rhodopsin in intact photoreceptors and its implication for phototransduction kinetics. AB - The visual pigment rhodopsin belongs to the family of G protein-coupled receptors that can form higher oligomers. It is controversial whether rhodopsin forms oligomers and whether oligomers are functionally relevant. Here, we study rhodopsin organization in cryosections of dark-adapted mouse rod photoreceptors by cryoelectron tomography. We identify four hierarchical levels of organization. Rhodopsin forms dimers; at least ten dimers form a row. Rows form pairs (tracks) that are aligned parallel to the disk incisures. Particle-based simulation shows that the combination of tracks with fast precomplex formation, i.e. rapid association and dissociation between inactive rhodopsin and the G protein transducin, leads to kinetic trapping: rhodopsin first activates transducin from its own track, whereas recruitment of transducin from other tracks proceeds more slowly. The trap mechanism could produce uniform single-photon responses independent of rhodopsin lifetime. In general, tracks might provide a platform that coordinates the spatiotemporal interaction of signaling molecules. PMID- 25728927 TI - Catalytic pocket inaccessibility of activation-induced cytidine deaminase is a safeguard against excessive mutagenic activity. AB - Activation-induced cytidine deaminase (AID) mutates cytidine to uridine at immunoglobulin loci to initiate secondary antibody diversification but also causes genome-wide damage. We previously demonstrated that AID has a relatively low catalytic rate. The structure of AID has not been solved. Thus, to probe the basis for its catalytic lethargy we generated a panel of free or DNA-bound AID models based on eight recently resolved APOBEC structures. Docking revealed that the majority of AID:DNA complexes would be inactive due to substrate binding such that a cytidine is not positioned for deamination. Furthermore, we found that most AID conformations exhibit fully or partially occluded catalytic pockets. We constructed mutant and chimeric AID variants predicted to have altered catalytic pocket accessibility dynamics and observed significant correlation with catalytic rate. Data from modeling simulations and functional tests of AID variants support the notion that catalytic pocket accessibility is an inherent bottleneck for AID activity. PMID- 25728929 TI - Systematic review with meta-analysis: pharmacological interventions for eosinophilic oesophagitis. AB - BACKGROUND: Eosinophilic oesophagitis (EoE) is a growing cause of dysphagia. Current therapies include dietary manipulation, steroids and biological drugs. AIM: To perform a systematic review and summarise the effect of different medical interventions on EoE. METHODS: Two reviewers searched Pubmed and Embase for studies on treatment for EoE. We included randomised controlled trials (RCT) limited to pharmacological interventions. Two reviewers selected studies. Meta analysis was done using random effects model to estimate odds ratio (OR). Heterogeneity was determined by Cochran's Q statistic and I(2) . RESULTS: Seventeen references met our inclusion criteria. Eleven RCTs involving 455 participants were included in the meta-analysis. 325 participants were evaluated for symptomatic improvement and 330 were evaluated for histological remission. Symptomatic improvement with topical steroids (7 studies, 250 participants) compared to the control group (placebo or PPI) was noted (OR: 3.03, 95% confidence interval, CI: 1.57-5.87). Histological remission was also noted in nine studies involving 330 participants (OR: 13.66, 95% CI: 2.65-70.34) comparing topical steroids to a control (placebo or PPI). There was no difference between anti-IL-5 drugs and placebo in terms of symptomatic improvement (OR: 0.69, 95% CI: 0.34-1.42). CONCLUSIONS: Topical steroids induce significant symptomatic and histological remission, and should be considered as a first line treatment. Anti IL-5 therapy has a minor effect on eosinophilic oesophagitis. Future research in eosinophilic oesophagitis should standardise methodology according to published guidelines to improve quality and allow direct comparison between therapies. PMID- 25728930 TI - Children's developing understanding of what and how they learn. AB - What do children know about learning? Children between 4 and 10 years of age were asked what they thought the word learning meant and then engaged in a structured interview about what kinds of things they learned and how they learned those things. Most of the 4- and 5-year-olds' responses to these questions indicated a lack of awareness about the nature of learning or how learning occurs. In contrast, the 8- to 10-year-olds showed a strong understanding of learning as a process and could often generate explicit metacognitive responses indicating that they understood under what circumstances learning would occur. The 6- and 7-year olds were in a transitional stage between these two levels of understanding. We discuss the implications of this development with children's theory-of-mind development more generally. PMID- 25728928 TI - Structure of the ribosomal oxygenase OGFOD1 provides insights into the regio- and stereoselectivity of prolyl hydroxylases. AB - Post-translational ribosomal protein hydroxylation is catalyzed by 2-oxoglutarate (2OG) and ferrous iron dependent oxygenases, and occurs in prokaryotes and eukaryotes. OGFOD1 catalyzes trans-3 prolyl hydroxylation at Pro62 of the small ribosomal subunit protein uS12 (RPS23) and is conserved from yeasts to humans. We describe crystal structures of the human uS12 prolyl 3-hydroxylase (OGFOD1) and its homolog from Saccharomyces cerevisiae (Tpa1p): OGFOD1 in complex with the broad-spectrum 2OG oxygenase inhibitors; N-oxalylglycine (NOG) and pyridine-2,4 dicarboxylate (2,4-PDCA) to 2.1 and 2.6 A resolution, respectively; and Tpa1p in complex with NOG, 2,4-PDCA, and 1-chloro-4-hydroxyisoquinoline-3-carbonylglycine (a more selective prolyl hydroxylase inhibitor) to 2.8, 1.9, and 1.9 A resolution, respectively. Comparison of uS12 hydroxylase structures with those of other prolyl hydroxylases, including the human hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs), reveals differences between the prolyl 3- and prolyl 4-hydroxylase active sites, which can be exploited for developing selective inhibitors of the different subfamilies. PMID- 25728931 TI - On the potential strength and consequences for nonrandom gene flow caused by local adaptation in flowering time. AB - Gene flow is generally considered a random process, that is the loci under consideration have no effect on dispersal success. Edelaar and Bolnick (Trends Ecol Evol, 27, 2012 659) recently argued that nonrandom gene flow could exert a significant evolutionary force. It can, for instance, ameliorate the maladaptive effects of immigration into locally adapted populations. I examined the potential strength for nonrandom gene flow for flowering time genes, a trait frequently found to be locally adapted. The idea is that plants that successfully export pollen into a locally adapted resident population will be a genetically biased subset of their natal population - they will have resident-like flowering times. Reciprocally, recipients will be more migrant-like than the resident population average. I quantified the potential for biased pollen exchange among three populations along a flowering time cline in Brassica rapa from southern California. A two-generation line cross experiment demonstrated genetic variance in flowering time, both within and among populations. Calculations based on the variation in individual flowering schedules showed that resident plants with the most migrant-like flowering times could expect to have up to 10 times more of the their flowers pollinated by immigrant pollen than the least migrant-like. Further, the mean flowering time of the pollen exporters that have access to resident mates differs by up to 4 weeks from the mean in the exporters' natal population. The data from these three populations suggest that the bias in gene flow for flowering time cuts the impact on the resident population by as much as half. This implies that when selection is divergent between populations, migrants with the highest mating success tend to be resident-like in their flowering times, and so, fewer maladaptive alleles will be introduced into the locally adapting gene pool. PMID- 25728932 TI - High throughput screening of particle conditioning operations: I. System design and method development. AB - The biotech industry is under increasing pressure to decrease both time to market and development costs. Simultaneously, regulators are expecting increased process understanding. High throughput process development (HTPD) employs small volumes, parallel processing, and high throughput analytics to reduce development costs and speed the development of novel therapeutics. As such, HTPD is increasingly viewed as integral to improving developmental productivity and deepening process understanding. Particle conditioning steps such as precipitation and flocculation may be used to aid the recovery and purification of biological products. In this first part of two articles, we describe an ultra scale-down system (USD) for high throughput particle conditioning (HTPC) composed of off-the-shelf components. The apparatus is comprised of a temperature-controlled microplate with magnetically driven stirrers and integrated with a Tecan liquid handling robot. With this system, 96 individual reaction conditions can be evaluated in parallel, including downstream centrifugal clarification. A comprehensive suite of high throughput analytics enables measurement of product titer, product quality, impurity clearance, clarification efficiency, and particle characterization. HTPC at the 1 mL scale was evaluated with fermentation broth containing a vaccine polysaccharide. The response profile was compared with the Pilot-scale performance of a non-geometrically similar, 3 L reactor. An engineering characterization of the reactors and scale-up context examines theoretical considerations for comparing this USD system with larger scale stirred reactors. In the second paper, we will explore application of this system to industrially relevant vaccines and test different scale-up heuristics. PMID- 25728933 TI - Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. AB - BACKGROUND: Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures. METHODS: In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (<=1.3 at 0.5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101. FINDINGS: 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non inferiority and superiority of 4F-PCC over plasma (difference 14.3%, 95% CI 2.8 25.8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non inferiority and superiority of 4F-PCC over plasma (difference 45.3%, 95% CI 31.9 56.4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients). INTERPRETATION: 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures. FUNDING: CSL Behring. PMID- 25728934 TI - Correct coagulopathy: quickly and effectively. PMID- 25728935 TI - A thiacalix[4]crown based chemosensor for Zn2+ and H2PO4-: sequential logic operations at the molecular level. AB - A thiacalix[4]crown based di-topic receptor 3 possessing two types of binding sites viz. crown-5 ring and imino moieties has been synthesized which undergoes fluorescence enhancement in the presence of Zn(2+) ions. The selective binding of Zn(2+) to compound 3 does not allow the K(+) ions to bind with the crown-5 ring and thus a negative allosteric behaviour has been observed between Zn(2+)/K(+) ions. In addition, the 3-Zn(2+) complex can be used for the detection of H2PO4(-) ions with a fluorescence "turn-off" response. Furthermore, based on the fluorescence response, a two input and one output sequential logic circuit has been constructed. PMID- 25728936 TI - Impact of squalene-based adjuvanted influenza vaccination on graft outcome in kidney transplant recipients. AB - BACKGROUND: Safety concerns have been raised about the use of adjuvanted vaccines after kidney transplantation. METHODS: We retrospectively analyzed 65 kidney transplant (KT) recipients who received >=1 dose of influenza vaccine (pandemic or seasonal) during the 2009-2010 campaign. Participants were classified into 2 groups: those who received a squalene-based AS03- or MF59-adjuvanted vaccine ("adjuvanted vaccination" [AV] group, n = 37) and those who exclusively received non-adjuvanted vaccines ("non-adjuvanted vaccination" [NAV] group, n = 28). Primary outcomes included occurrence of biopsy-proven acute graft rejection (BPAR) and graft function at months 6 and 12 after vaccination. Patients were followed up until graft loss, death, or October 2010. RESULTS: Four episodes of BPAR occurred during post-vaccination follow-up, with no differences between the AV and NAV groups, in terms of cumulative incidence (5.4% vs. 7.1%, respectively; P = 0.581), incidence rate (0.22 vs. 0.18 episodes per 1000 transplant-days; P = 0.950), or occurrence of severe episodes (T-cell-mediated BPAR of grade >=2a) (2.7% vs. 3.6%; P = 0.680). No between-group differences were seen in graft function after vaccination. CONCLUSION: Adjuvanted influenza vaccination in KT recipients seems to be safe regarding graft outcome. PMID- 25728937 TI - The cold-water climate shield: delineating refugia for preserving salmonid fishes through the 21st century. AB - The distribution and future fate of ectothermic organisms in a warming world will be dictated by thermalscapes across landscapes. That is particularly true for stream fishes and cold-water species like trout, salmon, and char that are already constrained to high elevations and latitudes. The extreme climates in those environments also preclude invasions by most non-native species, so identifying especially cold habitats capable of absorbing future climate change while still supporting native populations would highlight important refugia. By coupling crowd-sourced biological datasets with high-resolution stream temperature scenarios, we delineate network refugia across >250 000 stream km in the Northern Rocky Mountains for two native salmonids-bull trout (BT) and cutthroat trout (CT). Under both moderate and extreme climate change scenarios, refugia with high probabilities of trout population occupancy (>0.9) were predicted to exist (33-68 BT refugia; 917-1425 CT refugia). Most refugia are on public lands (>90%) where few currently have protected status in National Parks or Wilderness Areas (<15%). Forecasts of refuge locations could enable protection of key watersheds and provide a foundation for climate smart planning of conservation networks. Using cold water as a 'climate shield' is generalizable to other species and geographic areas because it has a strong physiological basis, relies on nationally available geospatial data, and mines existing biological datasets. Importantly, the approach creates a framework to integrate data contributed by many individuals and resource agencies, and a process that strengthens the collaborative and social networks needed to preserve many cold water fish populations through the 21st century. PMID- 25728938 TI - Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. AB - The 17beta-estradiol (E2)/estrogen receptor alpha (ERalpha) signaling pathway is one of the most important pathways in hormone-dependent breast cancer. E2 plays pivotal roles in cancer cell growth, survival, and architecture as well as in gene expression regulatory mechanisms. In this study, we established stably transfected MCF-7 cells by knocking down the ERalpha gene (designated as MCF 7/SP10+ cells), using specific shRNA lentiviral particles, and compared them with the control cells (MCF-7/c). Interestingly, ERalpha silencing in MCF-7 cells strongly induced cellular phenotypic changes accompanied by significant changes in gene and protein expression of several markers typical of epithelial to mesenchymal transition (EMT). Notably, these cells exhibited enhanced cell proliferation, migration and invasion. Moreover, ERalpha suppression strongly affected the gene and protein expression of EGFR and HER2 receptor tyrosine kinases, and various extracellular matrix (ECM) effectors, including matrix metalloproteinases and their endogenous inhibitors (MMPs/TIMPs) and components of the plasminogen activation system. The action caused by E2 in MCF-7/c cells in the expression of HER2, MT1-MMP, MMP1, MMP9, uPA, tPA, and PAI-1 was abolished in MCF-7/SP10+ cells lacking ERalpha. These data suggested a regulatory role for the E2/ERalpha pathway in respect to the composition and activity of the extracellular proteolytic molecular network. Notably, loss of ERalpha promoted breast cancer cell migration and invasion by inducing changes in the expression levels of certain matrix macromolecules (especially uPA, tPA, PAI-1) through the EGFR-ERK signaling pathway. In conclusion, loss of ERalpha in breast cancer cells results in a potent EMT characterized by striking changes in the expression profile of specific matrix macromolecules highlighting the potential nodal role of matrix effectors in breast cancer endocrine resistance. PMID- 25728939 TI - Renewable-juglone-based high-performance sodium-ion batteries. AB - A renewable-biomolecule-based electrode is developed through a facile synchronous reduction and self-assembly process, without any binder or additional conductive agent. The hybridized electrodes can be fabricated with arbitrary size and shape and exhibit superior capacity and cycle performance. The renewable-biomaterial based high-performance electrodes will hold a place in future energy-storage devices. PMID- 25728940 TI - Acquired auditory neuropathy spectrum disorder after an attack of chikungunya: case study. AB - Auditory neuropathy spectrum disorder (ANSD) is a retrocochlear disorder in which the cochlear functioning is normal but the transmission in the auditory neural pathway is affected. The present study reports of a 14-year-old teenager with acquired ANSD after an attack of chikungunya. He reported symptoms of difficulty in understanding speech, tinnitus and vertigo when exposed to loud sounds. The audiological characteristics suggested auditory neuropathy spectrum disorder with raising audiogram configuration. The results of tinnitus evaluation showed low pitched tinnitus and it was persistent causing significant handicap to him based on self report tinnitus handicap questionnaire results. The results of depression, anxiety and stress scale also suggested symptoms of mild depression and anxiety. Chikungunya virus is suspected to be neurotropic in nature which can damage auditory nerve cells and may have caused ANSD. The result also shows presence of tullio's phenomenon and absence of cervical vestibular evoked myogenic potentials suggesting damage to the vestibular neuronal system. The possible pathophysiology of chikungunya virus causing ANSD and vestibular symptoms needs to be explored further in future studies. PMID- 25728941 TI - Splicing abnormality of integrin beta4 gene (ITGB4) due to nucleotide substitutions far from splice site underlies pyloric atresia-junctional epidermolysis bullosa syndrome. AB - BACKGROUND: Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is a rare subgroup of epidermolysis bullosa, which is inherited disorder characterized by skin fragile. PA-JEB is caused by mutation of ITGB4 or ITGA6, which encodes integrin beta4 or alpha6, respectively. OBJECTIVE: To clarify the molecular basis of PA-JEB and to expand the mutational database, we carried out the mutational analysis of a 29-year-old Japanese PA-JEB patient. METHODS: Standard methods were used to prepare, PCR-amplify, and sequence DNA or mRNA in peripheral blood or skin samples, respectively. RESULTS: Sequence analysis revealed two novel mutations in ITGB4, c.264+2TtoA and c.1762-25TtoA. The paternal c.264+2TtoA resided within a splice site consensus region and generated two splice variants resulting in a premature termination codon (PTC). The maternal c.1762-25TtoA was a unique mutation because of its location, 25 bp away from the splice site, and resided in branch-point consensus sequence. This c.1762 25TtoA substitution resulted in generation of two abnormal transcripts each with a PTC. Genotype-phenotype correlation in this case was also unique because the proband showed a non-lethal phenotype regardless of both mutations resulted in only abnormal transcripts with a PTC. CONCLUSION: The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB. PMID- 25728942 TI - Do different decision-analytic modeling approaches produce different results? A systematic review of cross-validation studies. AB - When choosing a modeling approach for health economic evaluation, certain criteria are often considered (e.g., population resolution, interactivity, time advancement mechanism, resource constraints). However, whether these criteria and their associated modeling approach impacts results remain poorly understood. A systematic review was conducted to identify cross-validation studies (i.e., modeling a problem using different approaches with the same body of evidence) to offer insight on this topic. With respect to population resolution, reviewed studies suggested that both aggregate- and individual-level models will generate comparable results, although a practical trade-off exists between validity and feasibility. In terms of interactivity, infectious-disease models consistently showed that, depending on the assumptions regarding probability of disease exposure, dynamic and static models may produce dissimilar results with opposing policy recommendations. Empirical evidence on the remaining criteria is limited. Greater discussion will therefore be necessary to promote a deeper understanding of the benefits and limits to each modeling approach. PMID- 25728943 TI - The relations between metabolic variations and genetic evolution of different species. AB - Metabonomics has been applied in many bio-related scientific fields. Nevertheless, some animal research works are shown to fail when they are extended to humans. Therefore, it is essential to figure out suitable animal modeling to mimic human metabolism so that animal findings can serve humans. In this study, two kinds of commonly selected body fluids, serum and urine, from humans and various experimental animals were characterized by integration of nuclear magnetic resonance (NMR) spectroscopy with multivariate statistical analysis to identify the interspecies metabolic differences and similarities at a baseline physiological status. Our results highlight that the dairy cow and pig may be an optimal choice for transportation and biodistribution studies of drugs and that the Kunming (KM) mouse model may be the most effective for excretion studies of drugs, whereas the Sprague-Dawley (SD) rat could be the most suitable candidate for animal modeling under overall considerations. The biochemical pathways analyses further provide an interconnection between genetic evolution and metabolic variations, where species evolution most strongly affects microbial biodiversity and, consequently, has effects on the species-specific biological substances of biosynthesis and corresponding biological activities. Knowledge of the metabolic effects from species difference will enable the construction of better models for disease diagnosis, drug metabolism, and toxicology research. PMID- 25728944 TI - Fluorogenic DNA ligase and base excision repair enzyme assays using substrates labeled with single fluorophores. AB - Continuing our work on fluorogenic substrates labeled with single fluorophores for nucleic acid modifying enzymes, here we describe the development of such substrates for DNA ligases and some base excision repair enzymes. These substrates are hairpin-type synthetic DNA molecules with a single fluorophore located on a base close to the 3' ends, an arrangement that results in strong fluorescence quenching. When such substrates are subjected to an enzymatic reaction, the position of the dyes relative to that end of the molecules is altered, resulting in significant fluorescence intensity changes. The ligase substrates described here were 5' phosphorylated and either blunt-ended or carrying short, self-complementary single-stranded 5' extensions. The ligation reactions resulted in the covalent joining of the ends of the molecules, decreasing the quenching effect of the terminal bases on the dyes. To generate fluorogenic substrates for the base excision repair enzymes formamido-pyrimidine DNA glycosylase (FPG), human 8-oxo-G DNA glycosylase/AP lyase (hOGG1), endonuclease IV (EndoIV), and apurinic/apyrimidinic endonuclease (APE1), we introduced abasic sites or a modified nucleotide, 8-oxo-dG, at such positions that their enzymatic excision would result in the release of a short fluorescent fragment. This was also accompanied by strong fluorescence increases. Overall fluorescence changes ranged from approximately 4-fold (ligase reactions) to more than 20-fold (base excision repair reactions). PMID- 25728945 TI - Over-expression of lipocalin 2 promotes cell migration and invasion through activating ERK signaling to increase SLUG expression in prostate cancer. AB - BACKGROUND: Metastasis is the primary cause of prostate cancer (PCa) lethality and poses a huge clinical obstacle. Lipocalin 2 (LCN2), a member of the lipocalin family, is aberrantly expressed in some human cancers and has been implicated in the progression of some tumors. However, the role of LCN2 in the metastatic capacity of prostate cancer (PCa) is poorly understood. METHODS: LCN2 expression was examined by RT-qPCR and/or immunoblotting in human prostate tissue specimens and prostate cancer cell lines LNCaP, C4-2, 22RV1, PC3, DU-145, and PC3MM2. LCN2 protein level in human serum samples was determined by ELISA. Lentiviruses mediated over-expression of LCN2 and knockdown of LCN2 was conducted to evaluate the role of LCN2 in cell migratory and invasive capacities of prostate cancer cells. Cell migration and invasion was examined by transwell chamber assay. Knockdown of SLUG by lentivirus was performed to investigate its role in LCN2 promoted cell migration and invasion in vitro (22RV1 cell line) and metastasis in vivo (tail vein metastasis assay in nude mice). Role of ERK signaling in LCN2 mediated up-regulation of SLUG was assayed by using ERK inhibitor U0126. RESULTS: We confirmed that LCN2 levels were correlated positively with invasive prostate cancer in human tissue and serum samples, and were also consistently associated with the invasive capacity of prostate cancer cell lines. The over-expression of LCN2 in 22RV1 cells (not highly invasive) promoted the epithelial-mesenchymal transition (EMT), increasing cell motility and invasiveness, while the knockdown of LCN2 in PC3 cells (highly invasive) inhibited EMT, decreasing cell motility and invasiveness. Among the multiple EMT transcription factors, LCN2 specifically induces the expression of SLUG, which was shown here to be required for the LCN2 induced increase in the invasive capacity of prostate cancer cells both in vitro and in vivo. Mechanistically, LCN2 promoted SLUG expression via activating ERK signaling pathway. CONCLUSION: LCN2 plays an important role in promoting cell migration and invasion of prostate cancer by inducing EMT through the ERK/SLUG axis. Therefore, targeted inhibition of LCN2 may represent a therapeutic strategy to prevent the metastasis of prostate cancer. PMID- 25728947 TI - Causal judgements about temporal sequences of events in single individuals. AB - Stimuli were presented in which values of an outcome variable for a single individual were recorded over 24 time periods, and an intervention was introduced at one of the time periods. Participants judged whether and how much the intervention affected the outcome. Judgements were affected by manipulations of the temporal relation between the intervention and a gradual increase in values on the outcome variable, by the size of the increase, by the time taken for the increase to occur, and by variance in the preincrease data. Most results were predicted by a simple model in which the mean outcome value for the preintervention time periods is subtracted from the mean outcome value for the postintervention time periods, though there was also an effect of temporal contiguity that is not predicted by the simple model. This form of information, which is a kind of quasiexperimental design, is more representative of the kind of information generally available for causal judgement than the more commonly investigated binary variables in which the cause is either present or absent, and the outcome either occurs or does not; as such, it is more revealing of how causal judgements are made under the conditions that prevail in the world. PMID- 25728946 TI - Biology and mechano-response of tendon cells: Progress overview and perspectives. AB - In this review, we summarize the group discussions on Cell Biology & Mechanics from the 2014 ORS/ISMMS New Frontiers in Tendon Research Conference. The major discussion topics included: (1) the biology of tendon stem/progenitor cells (TSPCs) and the potential of stem cell-based tendon therapy using TSPCs and other types of stem cells, namely, embryonic and/or induced pluripotent stem cells (iPSCs), (2) the biological concept and potential impact of cellular senescence on tendon aging, tendon injury repair and the development of degenerative disease, and (3) the effects of tendon cells' mechano-response on tendon cell fate and metabolism. For each topic, a brief overview is presented which summarizes the major points discussed by the group participants. The focus of the discussions ranged from current research progress, challenges and opportunities, to future directions on these topics. In the preparation of this manuscript, authors consulted relevant references as a part of their efforts to present an accurate view on the topics discussed. PMID- 25728948 TI - Multiple sclerosis and pregnancy: a single-centre prospective comparative study. AB - INTRODUCTION: Multiple sclerosis (MS) is a autoimmune disorder which preferentially affects young women of childbearing age. During pregnancy, the annualized relapse rate (AAR) is modified, but pregnancy has no harm effect on the long-term course of the disease. We aimed to study the clinical course of our MS patients during pregnancy, and compare their obstetrics outcomes with a control group of non-MS patients. METHODS: A single centre prospective observational study was conducted. We assessed the reproductive history, MS history, pregnancy course and new-born outcome of a cohort of MS patients who had had a pregnancy between january 2007 and july 2012. We compared the global outcomes with a control cohort of 58 age-matched healthy pregnancies. RESULTS: Complete data from 35 consecutive women were analyzed, 40 deliveries. Control groups: 58 patients, 60 deliveries. EDSS at pregnancy 0,7. ARR before pregnancy 0,5. During pregnancy 0,3, after pregnancy 0,4. Twelve patients were on disease modifying drugs (DMD) before pregnancy, 4 prenatal exposure occurs. The comparison between relapse rate and EDSS before, during and after delivery showed no statistically significant difference. In addition, compared to control group, there were also no differences in the obstetric outcomes. In MS cohort, we found a higher incidence of assisted reproductive treatments and lower breastfeeding rate, both statistically significant. CONCLUSIONS: Our series confirms that pregnancy has no negative long term impact on the progression of MS and also suggest that there is no additional morbidity in the pregnancy, comparing to the rest of the population. PMID- 25728949 TI - Caffeine and headache: specific remarks. AB - Caffeine is the most widely used psychostimulant worldwide. Excessive caffeine consumption induces a series of both acute and chronic biological and physiological changes that may give rise to cognitive decline, depression, fatigue, insomnia, cardiovascular changes, and headache. Chronic consumption of caffeine promotes a pro-nociceptive state of cortical hyperexcitability that can intensify a primary headache or trigger a headache due to excessive analgesic use. This review offers an in-depth analysis of the physiological mechanisms of caffeine and its relationship with headache. PMID- 25728950 TI - Behavioural and psychiatric symptoms in cognitive neurology. AB - : Behavioural and psychiatric symptoms (BPS) are frequent in neurological patients, contribute to disability, and decrease quality of life. We recorded BPS prevalence and type, as well as any associations with specific diagnoses, brain regions, and treatments, in consecutive outpatients examined in a cognitive neurology clinic. METHOD: A retrospective analysis of 843 consecutive patients was performed, including a review of BPS, diagnosis, sensory impairment, lesion topography (neuroimaging), and treatment. The total sample was considered, and the cognitive impairment (CI) group (n=607) was compared to the non-CI group. RESULTS: BPS was present in 59.9% of the patients (61.3% in the CI group, 56.4% in the non-CI group). One BPS was present in 31.1%, two in 17.4%, and three or more in 11.4%. BPS, especially depression and anxiety, are more frequent in women than in men. Psychotic and behavioural symptoms predominate in subjects aged 65 and older, and anxiety in those younger than 65. Psychotic symptoms appear more often in patients with sensory impairment. Psychotic and behavioural symptoms are more prevalent in patients with degenerative dementia; depression and anxiety in those who suffer a psychiatric disease or adverse effects of substances; emotional lability in individuals with a metabolic or hormonal disorder; hypochondria in those with a pain syndrome; and irritability in subjects with chronic hypoxia. Behavioural symptoms are more frequent in patients with anomalies in the frontal or right temporal or parietal lobes, and antipsychotics constitute the first line of treatment. Leaving standard treatments aside, associations were observed between dysthymia and opioid analgesics, betahistine and statins, and between psychotic symptoms and levodopa, piracetam, and vasodilators. PMID- 25728951 TI - Marchiafava-Bignami disease triggered by poorly controlled diabetes mellitus. PMID- 25728952 TI - Reliability of the minimum basic dataset for diagnoses of cerebrovascular disease. AB - INTRODUCTION: The minimum basic dataset is the largest available hospital care administrative database that is used in clinical studies and hospital management in association with diagnosis-related groups (DRGs). In 2011, the quality of the national MBDS in hospital discharges was audited, in order to assess its reliability. This paper presents a sub-analysis of the results from that analysis which are referred to cerebrovascular disease (CVD). METHODS: Using all discharge reports from the Spanish MBDS in 2009, a representative sample was obtained by stratified sampling and 11 209 records were evaluated. Outcome indicators were obtained to measure any differences observed between the national MBDS being evaluated and the hospital's original MBDS. Analysis of codes for CVD as a primary diagnosis was performed for ICD-9-CM diagnostic categories 430 through 438. We evaluated error rates in the selection and classification of main diagnoses, as well as in DRG assignment. RESULTS: There were 397 discharges of cases of CVD which included 21 different DRGs. Diagnostic coding showed a concordance rate of 81.87%; the selection error rate was 2.26% and the classification error rate was 15.87%. The error rate in the DRG was 16.12% and associated with the greatest impact on the mortality risk level. CONCLUSIONS: While the errors we observed must be taken into account, data suggest that the quality of the MBDS for CVD is sufficient to ensure delivery of valid information. The hospital discharge registry serves as a valuable tool for use in studies of this disease. PMID- 25728953 TI - Virchow-Robin spaces: A cause of parkinsonism? PMID- 25728954 TI - Atypical presentation of Wernicke syndrome with magnetic resonance imaging showing cerebellar involvement and no changes in typical regions. PMID- 25728955 TI - Is acute otitis media always banal? Clinical cases and review of intracranial complications. PMID- 25728956 TI - Cerebellar toxicity due to cytarabine: A series of 4 cases. PMID- 25728957 TI - Spinal cord ischaemia after endovascular thoracic aneurysm repair. PMID- 25728958 TI - End-of-life management in patients with amyotrophic lateral sclerosis. AB - Most health-care professionals are trained to promote and maintain life and often have difficulty when faced with the often rapid decline and death of people with terminal illnesses such as amyotrophic lateral sclerosis (ALS). By contrast, data suggest that early and open discussion of end-of-life issues with patients and families allows time for reflection and planning, can obviate the introduction of unwanted interventions or procedures, can provide reassurance, and can alleviate fear. Patients' perspectives regarding end-of-life interventions and use of technologies might differ from those of the health professionals involved in their care, and health-care professionals should recognise this and respect the patient's autonomy. Advance care directives can preserve autonomy, but their legal validity and use varies between countries. Clinical management of the end of life should aim to maximise quality of life of both the patient and caregiver and, when possible, incorporate appropriate palliation of distressing physical, psychosocial, and existential distress. Training of health-care professionals should include the development of communication skills that help to sensitively manage the inevitability of death. The emotional burden for health-care professionals caring for people with terminal neurological disease should be recognised, with structures and procedures developed to address compassion, fatigue, and the moral and ethical challenges related to providing end-of-life care. PMID- 25728959 TI - Palliative care in amyotrophic lateral sclerosis. PMID- 25728960 TI - Myogenic responses occur on a beat-to-beat basis in the resting human limb. PMID- 25728961 TI - Myogenic responses occur on a beat-to-beat basis in the resting human limb. PMID- 25728962 TI - [Pneumatocele]. PMID- 25728963 TI - Surgical anatomy of the aortic annulus: landmarks for external annuloplasty in aortic valve repair. AB - BACKGROUND: Although reduction of a dilated aortic annulus is becoming an essential parameter for durable valve repair, anatomical descriptions of the annulus and surgical landmarks of the subvalvular plane for an external aortic annuloplasty remain to be defined. METHODS: Twenty hearts with normal anatomy with tricuspid aortic valves were studied. Annulus diameter, cusp geometric height, and interleaflet triangles heights were measured. The aortic root was dissected externally down to the subvalvular plane as to perform an external aortic annuloplasty or reimplantation procedure proximal anastomosis. Tissue thickness and dissection heights relative to the annulus were measured at each cusp nadir and at the middle of each interleaflet triangle. RESULTS: The mean annulus diameter, cusp geometric height, and interleaflet triangle heights were, respectively, 24.9 +/- 0.2 mm, 19.7 +/- 0.3 mm, and 20.1 +/- 0.5 mm. External dissection of the aortic root reached the subvalvular plane below the nadir of left coronary cusp (-2.7 +/- 0.4 mm), noncoronary (NC) cusp (-3.1 +/- 0.3 mm), and the base of left-NC interleaflet triangle (-2.1 +/- 0.4 mm). External dissection remained above the nadir of the right coronary cusp (+1.4 +/- 0.4 mm), base of left-right interleaflet triangle (+2.4 +/- 0.6 mm), and right-NC interleaflet triangle (+3.4 +/- 0.3 mm). Mean tissue thickness between the inner and external side of the subvalvular plane was 2.5 +/- 0.1 mm. CONCLUSIONS: External dissection of the aortic annulus allows subvalvular placement of an external aortic ring below the left and NC cusps and below or within 3 mm of the right cusp nadir in 80% of cases. An external aortic annuloplasty would induce at least a 5-mm reduction of annulus diameter, corresponding to tissue thickness. Precise anatomical landmarks are important to standardize aortic valve annuloplasty. PMID- 25728964 TI - Right ventricular outflow tract growth in infants with palliated tetralogy of fallot. AB - BACKGROUND: In symptomatic neonates with tetralogy of Fallot with pulmonary stenosis (TOF/PS), limited contemporary data exist regarding the effect of a modified Blalock-Taussig shunt (mBTS) on pulmonary valve (PV) and pulmonary artery (PA) growth and on the incidence of PV preservation at the time of complete repair. METHODS: We retrospectively studied patients who underwent repair of TOF/PS from 2000 to 2012 at our center. In neonates with TOF/PS palliated with an mBTS, we assessed PV annulus, main PA (MPA), and branch PAs (left PA [LPA] and right PA [RPA]) size by echocardiography before mBTS and surgical repair. RESULTS: Of 172 patients with TOF/PS, 40 (23%) were palliated with an mBTS at a median age of 23 days, and 31 met criteria for echocardiographic analysis. Palliated patients had hypoplastic PV, MPA, RPA, and LPA at baseline. All structures had significant absolute growth before surgical repair (p < 0.001). PV and MPA Z scores were unchanged, whereas branch PAs showed significant improvement (RPA, p = 0.03; LPA, p = 0.008). A PV-sparing repair was performed in 116 of 132 primary repairs (88%) and in 10 of 31 palliated patients (32%). At a median follow-up of 4.0 years (range, 0.7 to 12.6 years), no palliated patients required reintervention for right ventricular outflow tract obstruction. CONCLUSIONS: Significant absolute growth of the PV, MPA, RPA, and LPA occurs after an mBTS in neonates with TOF/PS. Branch PA size normalizes before complete repair. In one-third of patients with hypoplastic PVs, absolute growth after an mBTS may have facilitated valve-sparing repair. PMID- 25728965 TI - Differential microscopic finding and glucose transporter 3 expression in terminal chorionic villi among birth weight-discordant twin placentas. AB - OBJECTIVE: To evaluate differences in microscopic findings and glucose transporter 3 (GLUT3) expression in terminal chorionic villi (TV) among birth weight-discordant twin (BWDT) placentas compared with the birth weight-concordant twin (BWCT) placentas. METHODS: We retrospectively studied a cohort of 26 BWDT, 10 BWCT, 10 pre-eclampsia singleton and 10 normal singleton pregnancies. Placentas were scored for the percentage of TV, the percentage of TV with syncytial knots, the presence of capillary branching patterns of TV, the capillary to terminal villous ratios, the membranous expression of GLUT3 and the nuclear expression of HIF-1alpha in trophoblasts and capillary endothelial cells of TV using immunohistochemistry. The clinical characteristics and microscopic findings were analyzed and compared. RESULTS: BWDT placentas exhibited differential percentages of TV, percentages of TV with syncytial knots, capillary to terminal villous ratios, expression of HIF-1alpha in capillary endothelial cells and expression of GLUT3 in trophoblasts and capillary endothelial cells of TV among each twin pair compared with BWCT placentas (P=0.003, P=0.022, P=0.037, P=0.007, P=0.046 and P=0.002, respectively). Pre-eclampsia singleton placentas exhibited higher GLUT3 expression in trophoblasts, higher HIF-1alpha expression in capillary endothelial cells of TV and high capillary to terminal villous ratios compared with normal singleton placentas (P=0.001, P<0.001 and P=0.001, respectively). CONCLUSIONS: We observed a strong relationship between characteristics of adaptive change to hypoxia (GLUT3 expression, TV and syncytial knotting and higher capillary to terminal villous ratios) and BWDT pregnancy but not BWCT pregnancy. PMID- 25728966 TI - A smart DNAzyme-MnO2 nanosystem for efficient gene silencing. AB - DNAzymes hold promise for gene-silencing therapy, but the lack of sufficient cofactors in the cell cytoplasm, poor membrane permeability, and poor biostability have limited the use of DNAzymes in therapeutics. We report a DNAzyme-MnO2 nanosystem for gene-silencing therapy. MnO2 nanosheets adsorb chlorin e6-labelled DNAzymes (Ce6), protect them from enzymatic digestion, and efficiently deliver them into cells. The nanosystem can also inhibit (1)O2 generation by Ce6 in the circulatory system. In the presence of intracellular glutathione (GSH), MnO2 is reduced to Mn(2+) ions, which serve as cofactors of 10 23 DNAzyme for gene silencing. The release of Ce6 generates (1)O2 for more efficient photodynamic therapy. The Mn(2+) ions also enhance magnetic resonance contrast, providing GSH-activated magnetic resonance imaging (MRI) of tumor cells. The integration of fluorescence recovery and MRI activation provides fluorescence/MRI bimodality for monitoring the delivery of DNAzymes. PMID- 25728967 TI - Mesostructured amorphous manganese oxides: facile synthesis and highly durable elimination of low-concentration NO at room temperature in air. AB - At a high space velocity of 120 000 mL g(-1) h(-1) and a relative humidity of 50 90%, 98% removal of 10 ppm NO has been achieved for over 237 h and no sign of deactivation was observed with mesostructured amorphous manganese oxides (AMO), due to the prevention of the catalyst active sites from deactivation. PMID- 25728968 TI - Prostate-specific antigen level, stage or Gleason score: which is best for predicting outcomes after radical prostatectomy, and does it vary by the outcome being measured? Results from Shared Equal Access Regional Cancer Hospital database. AB - OBJECTIVES: To assess the ability of preoperative prostate-specific antigen level, Gleason score and stage to predict prostate cancer outcomes beyond biochemical recurrence, specifically castration-resistant prostate cancer, metastases and prostate cancer-specific mortality in radical prostatectomy patients. METHODS: We carried out a retrospective study of 2735 men in the Shared Equal Access Regional Cancer Hospital database treated by radical prostatectomy from 1988 to 2011 with data available on pathological stage, grade and preoperative prostate-specific antigen. We used Cox hazards analyses to examine the predictive accuracy (c-index) of the preoperative prostate-specific antigen (log-transformed), path Gleason score (<= 7, 3 + 4, 4 + 3 and 8-10) and path stage grouping (pT2 negative margins; pT2 positive margins; pT3a negative margins; pT3a positive margins; pT3b; vs positive nodes) to predict biochemical recurrence, castration-resistant prostate cancer, metastases and prostate cancer specific mortality. RESULTS: Median follow up was 8.7 years, during which, 937 (34%) had biochemical recurrence, 108 (4%) castration-resistant prostate cancer, 127 (5%) metastases and 68 (2%) prostate cancer-specific mortality. For the outcomes of biochemical recurrence, castration-resistant prostate cancer, metastases and prostate cancer-specific mortality, the c-indices were, respectively: prostate-specific antigen 0.65, 0.66, 0.64 and 0.69; Gleason score 0.66, 0.83, 0.76 and 0.85; and pathological stage group 0.69, 0.76, 0.72 and 0.80. CONCLUSIONS: Gleason score can predict with very high accuracy prostate cancer-specific mortality in patients undergoing radical prostatectomy. Thus, Gleason score should be given more weight in nomograms to predict prostate cancer specific mortality. Furthermore, men with a high Gleason score should be given special consideration for adjuvant treatment or referral to clinical trials because of a higher risk of prostate cancer-specific mortality. PMID- 25728969 TI - Updates and current recommendations for the management of patients with non-ST elevation acute coronary syndromes: what it means for clinical practice. AB - The American Heart Association (AHA) and the American College of Cardiology (ACC) have recently updated their joint guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS, including unstable angina [UA] and non-ST-elevation myocardial infarction [NSTEMI]). These guidelines replace the 2007 guidelines and the focused updates from 2011 and 2012 and now combine UA and NSTEMI into a new classification, NSTE-ACS, and updating the terminology around noninvasive management to ischemia-guided strategy. The latest guidelines include updated recommendations for the use of the oral antiplatelet agents (P2Y12 inhibitors) prasugrel and ticagrelor as part of dual-antiplatelet therapy-the cornerstone of treatment for these patients. This report provides a comprehensive overview of the new and modified recommendations for the management of patients with NSTE-ACS and the evidence supporting them. Also, where appropriate, similarities and differences between the current recommendations of the AHA/ACC and those of the European Society of Cardiology (ESC) are highlighted. For example, the AHA/ACC recommends the P2Y12 inhibitor ticagrelor over clopidogrel in all patients with NSTE-ACS and clopidogrel, prasugrel, or ticagrelor for patients in whom percutaneous coronary intervention is planned, whereas the ESC guidelines specifically recommend individual P2Y12 inhibitors for particular patient subgroups. PMID- 25728970 TI - Acute coronary syndromes: applying practice guidelines and defining the unmet need in clinical practice. PMID- 25728971 TI - Updates to the ACCF/AHA and ESC STEMI and NSTEMI guidelines: putting guidelines into clinical practice. PMID- 25728972 TI - Long-term management and unmet needs after an acute coronary syndrome event. PMID- 25728973 TI - Update on the guidelines for the management of ST-elevation myocardial infarction. PMID- 25728975 TI - Epithelioid angiomatous nodule of the nasal cavity: Report of 2 cases. AB - Epithelioid angiomatous nodule (EAN) is a novel clinicopathological entity characterized by a benign proliferation of endothelial cells with prominent epithelioid features. It can arise from any region of the body although it is increasingly being recognized in the head and neck. This paper presents two cases of EAN arising in the nasal cavity where the clinical presentations were recurrent unilateral epistaxis. In both cases, the lesions were excised endoscopically. Histopathologic analysis showed well-circumscribed proliferation of solid sheets of epithelioid endothelial cells and vascular channels in a background of mild chronic inflammatory infiltrate. Cytologic atypia was absent with rare mitotic figures seen. Immunohistochemical studies with CD31 and CD34 were strongly positive, thus confirming a vascular origin. Postoperative recovery was uneventful and no recurrence was seen in the follow-up period. EAN can be differentiated from other lesions demonstrating epithelioid vascular proliferation by means of clinical and histopathological characteristics. The present series seeks to inform that EAN should be regarded as a possible, albeit rare, cause of recurrent unilateral epistaxis. We advocate for endoscopic excision of EAN of the nasal cavity for diagnostic and therapeutic purposes. PMID- 25728974 TI - Is intraoperative ultrasound still useful for the detection of colorectal cancer liver metastases? AB - BACKGROUND: Debate on the optimal mode of preoperative imaging in the management of colorectal liver metastases (CRLM) is ongoing and, despite its longstanding use, the precise role of intraoperative ultrasonography (IOUS) is not well established. This study evaluates the impact of IOUS in the era of high-quality, cross-sectional imaging techniques. METHODS: All patients who underwent liver resection for CRLM in a tertiary care referral centre from January 2006 to December 2013 were included. All patients were submitted to computed tomography (CT) and/or liver magnetic resonance imaging (MRI) before surgery. Intraoperative US was performed mainly to detect previously non-diagnosed tumours that would change the surgical strategy. RESULTS: A total of 225 liver resections were performed. Liver MRI and CT scans were available for 202 patients (89.8%) and 225 patients (100%), respectively. Radiological reports recorded 632 liver tumours in 219 patients (i.e. 2.9 lesions per patient). The median time between preoperative liver MRI and surgical resection was 36 days. Intraoperative inspection, palpation and US found 20 additional lesions in 18 patients (8.0%), in three of whom lesions were diagnosed only on IOUS (1.4%). Overall, only 12 of the 20 lesions were malignant. CONCLUSIONS: Although CT and liver MRI are commonly used, IOUS alone allows the discovery of a few additional lesions that result in a change of surgical strategy in 1.4% of cases. PMID- 25728976 TI - Delayed diagnosis of high drug-resistant microorganisms carriage in repatriated patients: three cases in a French intensive care unit. AB - We report three cases of high drug-resistant microorganisms (HDRMO) carriage by patients repatriated from a foreign country. National recommendations suggest systematic screening and contact isolation pending results of admission screening of all patients recently hospitalized abroad. HDRMO carriage (carbapenem resistant Acinetobacter baumanii and carbapenemase-producing Enterobacteriaceae) was not isolated on admission screening swabs, but later between 3 and 8 days after admission. In absence of cross-transmission, two hypotheses seem possible: a false-negative test on admission, or a late onset favored by antibiotic pressure. Prolonged isolation may be discussed even in case of negative screening on admission from high-risk patients. PMID- 25728977 TI - Relevance of male-to-female sex mismatch in liver transplantation for primary biliary cirrhosis. AB - BACKGROUND: Because male-to-female transplantations are related to exposure to H Y antigen, sex matching may influence the outcomes after liver transplantation for autoimmune diseases. The purpose of this retrospective study was to evaluate the relevance of male-to-female mismatch in liver transplantation for primary biliary cirrhosis (PBC). MATERIAL AND METHODS: This retrospective study was based on the data of 82 female liver transplant recipients with PBC from a single institution. The primary outcome measure was graft survival at 10 years. The negative effects of well-known risk factors for poor outcomes were evaluated separately and compared between the female-to-female and male-to-female transplantations. RESULTS: Graft survival was similar after female-to-female and male-to-female transplantations (74.7% versus 73.1% at 10 years, respectively, p=0.676). Regarding the differential impact of other risk factors, prolonged cold ischemia and increased amount of blood transfusions adversely influenced outcomes after male-to-female transplantation (p=0.039 and p=0.039, respectively) but not after female-to-female transplantation (p=0.843 and p=0.110, respectively). Sex mismatched transplantations were associated with lower 10-year graft survival in subgroups of patients with blood transfusions >4 units (61.4% versus 100.0%, p=0.063) and >8 hours of cold ischemia (54.7% versus 75.8%, p=0.418). CONCLUSIONS: Although male-to-female sex mismatch does not seem to yield a direct negative impact on outcomes following liver transplantation for PBC, it can aggravate the negative effects of prolonged cold ischemia and blood transfusions. PMID- 25728978 TI - Optical nonreciprocity in asymmetric optomechanical couplers. AB - We propose an all-optical integrated nonreciprocal device on the optomechanical platform with a large nonreciprocal bandwidth and low operating power. The device is based on an asymmetric silicon coupler consisting of two branches. One of them is a conventional strip waveguide fixed on the substrate, and the other is a freestanding nanostring suspended above a groove in the substrate. When light is launched into the coupler, the optical gradient force between the freestanding nanostring and the underlying substrate leads to the deflection of the nanostring, and finally results in destruction of the initial phase-matching condition between the two branches. The suspended branch would achieve distinct deflections when light is incident from different ports. The simulation results show a nonreciprocal bandwidth of 13.1 nm with operating power of 390 MUW. With the advantages of simple structure, low power consumption and large operating bandwidth, our work provides a promising solution for on-chip passive nonreciprocal device. PMID- 25728979 TI - Pre-clinical toxicity evaluation of MB-102, a novel fluorescent tracer agent for real-time measurement of glomerular filtration rate. AB - The fluorescent tracer agent 3,6-diamino-2,5-bis{N-[(1R)-1-carboxy-2 hydroxyethyl]carbamoyl}pyrazine, designated MB-102, has been developed with properties and attributes for use as a direct measure of glomerular filtration rate (GFR). In comparison to known standard exogenous GFR agents in animal models, MB-102 has demonstrated an excellent correlation. A battery of toxicity tests has been completed on this new fluorescent tracer agent, including single dose toxicity studies in rats and dogs to determine overall toxicity and toxicokinetics of the compound. Blood compatibility, mutation assay, chromosomal aberration assay, and several other assays were also completed. Toxicity assessments were based on mortality, clinical signs, body weight, food consumption and anatomical pathology. Doses of up to 200-300 times the estimated human dose were administered. No test-article related effects were noted on body weight, food consumption, ophthalmic observations and no abnormal pathology was seen in either macroscopic or microscopic evaluations of any organs or tissues. All animals survived to scheduled sacrifice. Transient discoloration of skin and urine was noted at the higher dose levels in both species as expected from a highly fluorescent compound and was not considered pathological. Thus initial toxicology studies of this new fluorescent tracer agent MB-102 have resulted in negligible demonstrable pathological test article concerns. PMID- 25728980 TI - Quantitative assessment of maternal biomarkers related to one-carbon metabolism and neural tube defects. AB - Periconceptional supplementation with folic acid reduces the occurrence of neural tube defects (NTDs). The association between maternal abnormalities in homocysteine metabolism (e.g., hyperhomocysteinaemia, folate deficiency and low vitamin B12) and the risk of NTDs-affected pregnancies has been widely evaluated in recent years, although the results are conflicting. To investigate this inconsistency, we performed a meta-analysis of 32 studies, involving 1,890 NTD affected mothers and 3,995 control mothers, to develop an understanding of the relationship between maternal biomarkers related to one-carbon metabolism and NTD. A random-effects model was used to calculate the ratio of means (RoM) between the cases and controls, along with the 95% confidence intervals (CIs). A significant increase in homocysteine levels was observed in NTD-affected mothers compared with controls (RoM: 1.16, 95% CI: 1.09-1.23, P = 1.8 * 10(-6)). The pooled analysis also revealed that NTD-affected mothers had significantly lower levels of folate (RoM: 0.93, 95% CI: 0.88-0.97, P = 0.002), vitamin B12 (RoM: 0.91, 95% CI: 0.87-0.95, P = 3.6 * 10(-5)) and red blood cell folate (RoM: 0.92, 95% CI: 0.86-0.98, P = 0.01). Therefore, altered plasma levels of biomarkers related to one-carbon metabolism are associated with NTD-affected pregnancies. PMID- 25728981 TI - Fine needle aspiration of thyroid nodules in the pediatric population: a 12-year cyto-histological correlation experience at North Shore-Long Island Jewish Health System. AB - BACKGROUND: Diagnostic evaluation of thyroid nodules by FNA is used in the clinical management triage based on the knowledge of the rate of malignancy of each diagnostic category. The Bethesda System for Reporting Thyroid Cytopathology was published in 2007 by the National Cancer Institute (NCI). Using this classification, we studied our institution's experience in the pediatric population calculating the rate of malignancy for each diagnostic category, comparing our findings to our general patient population and that of the literature. METHODS: 13,312 thyroid FNAs were performed at our institution between 1998 and 2010. 282 cases were from patients under 19 years of age. We reviewed and reclassified these cases using the new NCI categories, and pursued cytology-surgical follow-up. RESULTS: Of the 282 FNA cases, 20.92% (59) were classified as unsatisfactory (U), 48.22, % (136) benign (B), 2.12% (6) Atypia of undetermined significance (AUS), 14.18% (40) suspicious for follicular neoplasm (FN), 2.12% (6) suspicious for malignancy (SM) and 12.41% (35) positive for malignancy (P). The U-category was further classified into nondiagnostic (ND) 12.41% (35) and cysts (C) 8.51% (24). Seventy-four children had surgical follow up. The rates of histologically confirmed malignancy were 10% in U (1/10), 0% in B (0/17), 50% in AUS (2/4), 39% in FN (7/18), 100% in SM (4/4) and 100% in P (24/24) categories respectively. Among the U category, malignancy rate was 0% for the ND category and 25% for the C category. CONCLUSIONS: To our knowledge, this is the first study to apply the NCI categories to the pediatric population. The rate of malignancy in the U category was only seen in the specimens with cystic component. AUS and FN categories had a higher malignancy rate (50 and 39% respectively) as compared with that of the general population (15 and 30% respectively). Given that the rates of malignancy are higher for cysts and AUS, the literature recommendation to "follow-up and repeat" may not apply to the pediatric population. Surgery may be reasonable in these categories instead. PMID- 25728982 TI - Redox tuning of a direct asymmetric aldol reaction. AB - Presented herein is a redox tuning strategy for asymmetric aminocatalysis with a designed chiral ferrocenophane. Under redox control, the ferrocenophane catalyst efficiently catalyzes the asymmetric aldol reaction at room temperature with excellent yield and good stereoselectivity. Moreover, the redox-active ferrocene moiety also served as phase-tag to facilitate catalyst recovery and reuse. The catalyst can be reused for five cycles without much loss of activity. Ferrocenium of the oxidized ferrocenophane was proposed to serve as Lewis acidic site, thus accounting for the stereo control. PMID- 25728983 TI - Screening of L-histidine-based ligands to modify monolithic supports and selectively purify the supercoiled plasmid DNA isoform. AB - The growing demand of pharmaceutical-grade plasmid DNA (pDNA) suitable for biotherapeutic applications fostered the development of new purification strategies. The surface plasmon resonance technique was employed for a fast binding screening of l-histidine and its derivatives, 1-benzyl-L-histidine and 1 methyl-L-histidine, as potential ligands for the biorecognition of three plasmids with different sizes (6.05, 8.70, and 14 kbp). The binding analysis was performed with different isoforms of each plasmid (supercoiled, open circular, and linear) separately. The results revealed that the overall affinity of plasmids to l histidine and its derivatives was high (KD > 10(-8) M), and the highest affinity was found for human papillomavirus 16 E6/E7 (K(D) = 1.1 * 10(-10) M and KD = 3.34 * 10(-10) M for open circular and linear plasmid isoforms, respectively). L-Histidine and 1-benzyl-L-histidine were immobilized on monolithic matrices. Chromatographic studies of L-histidine and 1-benzyl-L histidine monoliths were also performed with the aforementioned samples. In general, the supercoiled isoform had strong interactions with both supports. The separation of plasmid isoforms was achieved by decreasing the ammonium sulfate concentration in the eluent, in both supports, but a lower salt concentration was required in the 1-benzyl-L-histidine monolith because of stronger interactions promoted with pDNA. The efficiency of plasmid isoforms separation remained unchanged with flow rate variations. The binding capacity for pDNA achieved with the l-histidine monolith was 29-fold higher than that obtained with conventional L-histidine agarose. Overall, the combination of either L-histidine or its derivatives with monolithic supports can be a promising strategy to purify the supercoiled isoform from different plasmids with suitable purity degree for pharmaceutical applications. PMID- 25728984 TI - Late follow-up of the randomized radiation and concomitant high-dose intra arterial or intravenous cisplatin (RADPLAT) trial for advanced head and neck cancer. AB - BACKGROUND: The radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) phase III trial compared intra-arterial (IA) to intravenous (IV) cisplatin-based chemoradiation for head and neck cancer. Long-term efficacy and toxicity are reported after a median follow-up of 7.5 years. METHODS: Patients with inoperable squamous cell carcinoma (SCC) of the oropharynx, oral cavity, or hypopharynx, were randomized between radiotherapy (RT) + IA cisplatin 150 mg/m(2) , followed by systemic rescue or RT + I.V. cisplatin 100 mg/m(2) . RT consisted of 46 Gy to the affected and elective areas, followed by a boost of 24 Gy. RESULTS: Among 237 patients, 57 recurred locally, 35 regionally, and 80 locoregionally. There were 32 second primary tumors, 65 distant metastases, and 154 deaths. Locoregional control and overall survival were not different between the treatment arms. Late dysphagia was worse in the I.V. arm (log-rank p = .014). CONCLUSION: IA cisplatin did not improve tumor control compared to I.V. administered cisplatin, despite the higher dose in IA delivery of the drug. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E488-E493, 2016. PMID- 25728985 TI - Bisphenol A reduces fertilizing ability and motility by compromising mitochondrial function of sperm. AB - Bisphenol A (BPA) acts as an endocrine disruptor, affects animal reproductive success in vivo and affects sperm functions in vitro at environmentally relevant concentrations, leading to reduction in sperm motility and fertilizing ability in fish. The effect of in vitro BPA on avian sperm functions has not been explored. The present study examined the effect of environmentally relevant concentrations of BPA (0 mM, 0.18 mM, 0.37 mM, and 0.74 mM) on sperm functions in chicken in vitro. Sperm were exposed to concentrations of BPA for 30 min and analyzed for motility, fertilizing ability, live sperm percentage, and mitochondrial membrane potential (Deltapsim). Results showed that BPA at a concentration of 0.74 mM significantly decreased motility, fertilizing ability, live sperm count percentage, and sperm Deltapsim. Sperm motility was positively correlated with fertility (r = 0.73, p <= 0.01), live sperm percentage (r = 0.64, p <= 0.01), and high Deltapsim (r = 0.44, p <= 0.01). A dose-dependent and time-dependent effect of BPA was observed on sperm motility at all BPA concentrations. However, sperm's fertilizing ability was unaffected in low BPA concentration (0.18 mM and 0.37 mM). A significantly higher percentage of moribund sperm was observed at 0.37 mM and 0.74 mM BPA compared with at 0.18 mM BPA, in the negative control, and in the vehicle control. The present study confirms that environmentally relevant concentrations of BPA are capable of compromising sperm functions, leading to reduction in fertilizing ability of chicken sperm. PMID- 25728986 TI - Too much of a good thing: sea ice extent may have forced emperor penguins into refugia during the last glacial maximum. AB - The relationship between population structure and demographic history is critical to understanding microevolution and for predicting the resilience of species to environmental change. Using mitochondrial DNA from extant colonies and radiocarbon-dated subfossils, we present the first microevolutionary analysis of emperor penguins (Aptenodytes forsteri) and show their population trends throughout the last glacial maximum (LGM, 19.5-16 kya) and during the subsequent period of warming and sea ice retreat. We found evidence for three mitochondrial clades within emperor penguins, suggesting that they were isolated within three glacial refugia during the LGM. One of these clades has remained largely isolated within the Ross Sea, while the two other clades have intermixed around the coast of Antarctica from Adelie Land to the Weddell Sea. The differentiation of the Ross Sea population has been preserved despite rapid population growth and opportunities for migration. Low effective population sizes during the LGM, followed by a rapid expansion around the beginning of the Holocene, suggest that an optimum set of sea ice conditions exist for emperor penguins, corresponding to available foraging area. PMID- 25728987 TI - PepShell: visualization of conformational proteomics data. AB - Proteins are dynamic molecules; they undergo crucial conformational changes induced by post-translational modifications and by binding of cofactors or other molecules. The characterization of these conformational changes and their relation to protein function is a central goal of structural biology. Unfortunately, most conventional methods to obtain structural information do not provide information on protein dynamics. Therefore, mass spectrometry-based approaches, such as limited proteolysis, hydrogen-deuterium exchange, and stable isotope labeling, are frequently used to characterize protein conformation and dynamics, yet the interpretation of these data can be cumbersome and time consuming. Here, we present PepShell, a tool that allows interactive data analysis of mass spectrometry-based conformational proteomics studies by visualization of the identified peptides both at the sequence and structure levels. Moreover, PepShell allows the comparison of experiments under different conditions, including different proteolysis times or binding of the protein to different substrates or inhibitors. PMID- 25728988 TI - Periodontitis and retinal microcirculation in the Atherosclerosis Risk in Communities study. AB - AIM: The aim of this cross-sectional study is to explore if periodontitis is associated with alterations of the retinal microcirculation, a predictive marker of cardiovascular events. MATERIAL AND METHODS: Of 457 subjects aged 52 years and more from the ARIC cohort were included. Retinal vascular diameters were measured and summarized as central retinal arteriolar/venular equivalents (CRAE/CRVE). Periodontitis was determined by using the CDC/AAP definition. Multivariable linear regression models were used to estimate the relationships between CRAE, CRVE and periodontitis. RESULTS: No association was found between CRAE and periodontal status. However, CRVE and severe periodontitis were positively and significantly associated. Mean CRVE (+/-SD) was 187.0 +/- 17.2 MUm in the health gingivitis group, and, respectively, 188.5 +/- 16.3 MUm (p = 0.39) and 191.6 +/- 16.8 MUm (p = 0.04) in moderate and severe periodontitis groups, after adjustment for a propensity score based on confounders. Results were consistent when analyses were restricted to participants with diabetes mellitus (n = 66), but not diabetes-free subjects. CONCLUSIONS: Severe periodontitis is associated with larger retinal venular diameter in patients with type 2 diabetes. Further studies are needed to explore the impact of diabetes mellitus on the association between periodontitis and retinal microcirculation. PMID- 25728989 TI - Modified amelogenin is a new and versatile nanomaterial for biomedical applications. AB - Amelogenin self-assembly is crucial for tooth biomineralization and crystallite enamel orientation. Amelogenin forms stable nanoparticles under physiological conditions. Here, we tested whether the surface properties and binding characteristics of these particles could be modified to enhance amelogenin function as a biomaterial. We evaluated different amelogenin fusion proteins for their ability to form hybrid nanoparticles. As a proof-of-concept, the integrin binding tripeptide Arg-Gly-Asp (RGD) sequence from fibronectin was integrated into mouse amelogenin (rM179) at three different positions. Dynamic light scattering (DLS) measurements revealed that these amelogenin fusion proteins still form nanospheres. Additional DLS and isothermal titration calorimetry measurements showed that the mixtures of RGD-modified amelogenin and wild-type amelogenin form stable particles. We determined that insertion of the RGD-loop at the amelogenin C-terminus converts the nanoparticle into a cell-binding substrate. Calvarial osteoblasts efficiently attached and spread on modified amelogenin, whereas almost no binding was observed on wild-type amelogenin. These results establish amelogenin as a new versatile biomaterial that can be easily modified to add additional functions. PMID- 25728990 TI - The interplay of effector and regulatory T cells in cancer. AB - Regulatory T (Treg) cells suppress effector T (Teff) cells and prevent immune mediated rejection of cancer. Much less appreciated are mechanisms by which Teff cells antagonize Treg cells. Herein, we consider how complex reciprocal interactions between Teff and Treg cells shape their population dynamics within tumors. Under states of tolerance, including during tumor escape, suppressed Teff cells support Treg cell populations through antigen-dependent provision of interleukin (IL)-2. During immune activation, Teff cells can lose this supportive capacity and directly antagonize Treg cell populations to neutralize their immunosuppressive function. While this latter state is rarely achieved spontaneously within tumors, we propose that therapeutic induction of immune activation has the potential to stably disrupt immunosuppressive population states resulting in durable cancer regression. PMID- 25728992 TI - Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells. AB - Novel models of autochthonous tumorigenesis and adoptive T cell therapy (ATT) are providing new clues regarding the pro-tumorigenic and immunosuppressive effects of myeloid-derived suppressor cells (MDSC), and their interaction with T cells. New findings are shifting the perception of the main level at which MDSC act, from direct cell-to-cell suppression to others, such as limiting T cell infiltration. Adoptively transferred, high-avidity T cells recognizing peptides with high-affinity for MHC-I eliminated large tumors. However, low-avidity T cells or low-affinity peptides resulted in failure to eradicate tumors. Manipulation of intratumoral myeloid cells improved the outcome of otherwise unsuccessful ATT. Therefore, therapeutic intervention directed at the tumor stroma might be required when using suboptimal T cells for ATT. PMID- 25728993 TI - Special issue on non-rodent animal models for immunology research: what can we learn from large animals? PMID- 25728991 TI - Targeting cancer-specific mutations by T cell receptor gene therapy. AB - The ease of sequencing the cancer genome, identifying all somatic mutations and grafting mutation-specific T cell receptor (TCR) genes into T cells for adoptive transfer allow, for the first time, a truly tumor-specific and effective therapy. Mutation-specific TCR gene therapy might achieve optimal efficacy with least possible toxicity. Recent clinical data confirm the long-standing evidence from experimental cancer models that antigens encoded by the tumor-specific somatic mutations are potentially the best targets for adoptive T cell therapy. Open questions are, how many somatic mutations create suitable epitopes, whether only individual-specific or also recurrent somatic mutations qualify as suitable epitopes and how neoantigen-specific TCRs are most efficiently obtained. Tumor heterogeneity needs to be considered; therefore, it will be important to identify immunogenic driver mutations that occurred early, are essential for cancer cell survival and present in all cancer cells. PMID- 25728994 TI - Exploring the electronic structure of an organic semiconductor based on a compactly fused electron donor-acceptor molecule. AB - A Mott-type semiconductor based on a compactly fused and partially oxidized electron donor-acceptor (D-A) molecule was recently prepared and identified to exhibit a large room-temperature conductivity of 2 S cm(-1) . In a marked contrast to the organic conductors characterized by relatively well decoupled and segregated uniform stacks of D and A moieties, the formally half-oxidized tetrathiafulvalene donors of the actual compound are organized in columnar pi stacks only, whereby the coplanar electron-acceptor units, namely benzothiadiazole, are closely annulated along their ridges. Herein, we present a theoretical study that explores the electronic structure of this novel type of organic semiconductor. The highly symmetric-solid state material behaves as a one dimensional electronic system with strong antiferromagnetic interactions (coupling constant>200 cm(-1) ). The unique shape and local dipole of this redox active fused electron D-A molecule lays the basis for further investigations of the collective electronic structure, mainly in the function of different counterions embedded in the crystalline lattice. PMID- 25728995 TI - Maintenance monotherapy with gemcitabine after standard platinum-based chemotherapy in patients with advanced urothelial cancer. AB - OBJECTIVES: To investigate the outcomes of gemcitabine maintenance monotherapy treatment for metastatic urothelial cancer. METHODS: Gemcitabine maintenance monotherapy was used for metastatic urothelial cancer patients after standard platinum-based chemotherapy. A standard dose of 1000 mg/m(2)/month was given. If patients suffered adverse events or a noticeably compromised quality of life, treatment intervals were extended and doses lowered. Patients with metastatic urothelial cancer receiving only best supportive care after standard chemotherapy served as the retrospective control group. RESULTS: A total of 33 patients were included in the study group as well as in the control group. Maintenance therapy was administered a median of nine times (range 2-49 times) with a median dose of 984.2 mg (range 500-1400 mg) per time. An adverse event of the Common Terminology Criteria of Adverse Events grade 3 or greater was observed in 10 (30.3%) patients, while nine patients (27.3%) experienced hematotoxicity. After standard chemotherapy pretreatment, disease-specific survival in the maintenance therapy group was an average of 15.0 months, significantly more favorable (P < 0.001) than that of the control group (4.0 months). On multivariate analysis, efficacy of prior chemotherapy (P = 0.018), visceral metastasis (P = 0.007) and gemcitabine maintenance therapy (P < 0.001) were statistically significant prognostic parameters of disease-specific survival. CONCLUSION: The present study findings suggest that gemcitabine maintenance monotherapy in metastatic urothelial cancer might not only be useful as a palliative treatment, but it could also have a certain level of therapeutic effectiveness. PMID- 25728996 TI - Cadmium inhibits the vitellogenesis of freshwater crab Sinopotamon henanense. AB - Cadmium (Cd) may pose risks to freshwater organisms, including crabs that live at the interface of sediments and water column all year round. One of the major changes that occur during oocyte maturation of crabs is the production of vitellin. In the present study, the authors investigated the effects of Cd on oocyte size, vitellin level, and vitellogenin (Vtg) messenger RNA (mRNA) expression in the ovary of the freshwater crab Sinopotamon henanense. The authors studied the impacts of Cd on carbohydrate as well as on the protein metabolism, metallothionein, glutathione (GSH) synthesis, energy-related parameters, and mRNA expression of genes involved in energy metabolism. After Cd treatment, vitellin concentration, Vtg mRNA expression, and oocyte diameter decreased. Less carbohydrate and enhanced protein catabolism were found in the ovary. Adenosine triphosphate to adenosine diphosphate (ATP:ADP) ratios, reduced nicotinamide adenine dinucleotide (NADH) to oxidized nicotinamide adenine dinucleotide (NAD(+) ) ratios, mitochondrial membrane potential, and energy production-related mRNA expressions increased in the ovary after 10 d Cd treatment and decreased after 20 d. Metallothionein and GSH synthesis were up-regulated after 10 d on Cd exposure. Moreover, Cd caused a time-dependent up-regulation of malondialdehyde. The authors' findings show significant effects of Cd on vitellogenesis, which suggests that Cd slows down vitellogenesis in S. henanense because of excessive energy consumption and an activated defense system. PMID- 25728997 TI - Pemphigus vulgaris of the cervix: diagnostic difficulties associated with the Pap test. AB - Pemphigus vulgaris (PV) is a rare mucocutaneous disease caused by the abnormal production of antibodies against epithelial cell surface glycoproteins, resulting in loss of cell adhesion and intraepithelial blister formation. Cervical involvement in PV has been poorly reported, and there is little information regarding the criteria about consequential cytological changes identified in a Papanicolaou-stained cervicovaginal smear (Pap smear). Here, we report a case of PV manifesting in the cervix as well as the difficulty associated with the cytomorphological identification and interpretation of acantholytic cells. This case involved a 40-year-old patient with no history of Pap test abnormalities and no prior diagnosis of PV. In the cytological assessment, cells were identified both in isolation and in clusters that exhibited round nuclei of increased volume, inconspicuous nucleoli, and perinuclear halos. The patient underwent a cervical biopsy that revealed vesiculobullous lesions and morphological pattern consistent with PV. A skin biopsy confirmed this diagnosis. We concluded that knowledge of PV cytomorphology is important because difficulties associated with the identification and interpretation of acantholytic cells might be responsible for false positive diagnoses of cervical neoplasia. However, a suspected diagnosis of PV is possible if the cytological findings are carefully correlated with the clinical data. PMID- 25728998 TI - A trefoil knotted polymer produced through ring expansion. AB - A synthetic strategy is reported for the production of a trefoil knotted polymer from a copper(I)-templated helical knot precursor through ring expansion. The expected changes in the properties of the knotted polymer compared to a linear analogue, for example, reduced hydrodynamic radius and lower intrinsic viscosity, together with an atomic force microscopy (AFM) image of individual molecular knots, confirmed the formation of the resulting trefoil knotted polymer. The strategies employed here could be utilized to enrich the variety of available polymers with new architectures. PMID- 25729000 TI - Commentary on: Psychotic symptoms in frontotemporal dementia: a diagnostic dilemma? PMID- 25729001 TI - Low-grade inflammation differentiates between symptoms of apathy and depression in community-dwelling older individuals. AB - BACKGROUND: Systemic low-grade inflammation has repeatedly been associated with depression in old age, but the relationship with apathy is less clear. The present study assessed whether C-reactive protein (CRP) is differentially associated with symptoms of apathy and depression. METHODS: A population-based cohort study was carried-out. At baseline and after two and four years of follow up, CRP levels were assessed and symptoms of apathy and depression were measured using the 15-item Geriatric Depression Scale. Logistic regression analysis was used to investigate the cross-sectional and longitudinal associations of CRP with symptoms of apathy and depression. RESULTS: Two thousand forty-seven community dwelling participants (70-78 years) without a history of cardiovascular disease or stroke were studied. A cross-sectional association was found between CRP and apathy symptoms at three time points (odds ratio (OR) per natural log unit increase in CRP: baseline visit = 1.40, 95% CI = 1.12-1.75; two-year follow-up visit = 1.62, 95% CI = 1.17-2.25; four-year follow-up visit = 1.51, 95% CI = 1.03 2.21). This did not change after adjustment for demographics and depressive symptoms, and was slightly attenuated after adjustment for cardiovascular risk factors. No cross-sectional association was found with depressive symptoms. Baseline CRP did not predict incident apathy or depressive symptoms during four years of follow-up. CONCLUSIONS: Increased CRP levels are associated with apathy symptoms but not with depressive symptoms. This suggests a differential effect of inflammation on apathy and depression. In older persons, symptoms of apathy may be a behavioral manifestation of concurrent low-grade inflammation. PMID- 25729002 TI - Association of a nicotinic receptor gene polymorphism with spontaneous eyeblink rates. AB - Spontaneous eyeblink rates greatly vary among individuals from several blinks to a few dozen blinks per minute. Because dopamine agonists immediately increase the blink rate, individual differences in blink rate are used as a behavioral index of central dopamine functioning. However, an association of the blink rate with polymorphisms in dopamine-related genes has yet not been found. In this study, we demonstrated that a genetic variation of the nicotinic acetylcholine receptor CHRNA4 (rs1044396) increased the blink rate while watching a video. A receiver operating characteristic analysis revealed that the blink rate predicts a genetic variation in the nicotinic receptor gene with a significant discrimination level (0.66, p < 0.004). The present study suggests that differences in sensitivity to acetylcholine because of the genetic variation of the nicotinic receptor are associated with individual differences in spontaneous eye blink rate. PMID- 25729003 TI - Sudden unexpected death in epilepsy. PMID- 25729004 TI - o-Carborane-based anthracene: a variety of emission behaviors. AB - An o-carborane-based anthracene was synthesized, and single crystals, with incorporated solvent molecules, were obtained from the CHCl3 , CH2 Cl2 , and C6 H6 solutions. The anthracene ring in the crystal is highly distorted by the formation of a pi-stacked dimer between the anthracene units. The crystals exhibited a variety of emission behaviors such as aggregation-induced emission (AIE), crystallization-induced emission (CIE), aggregation-caused quenching (ACQ), and multichromism. PMID- 25729005 TI - Evaluation of the short term 12 hour toxicity of 3-trifluoromethyl-4-nitrophenol (TFM) to multiple life stages of Venustaconcha ellipsiformis and Epioblasma triquetra and its host fish (Percina caprodes). AB - The present study evaluated the risk of 12-h exposures of the lampricide 3 trifluoromethyl-4-nitrophenol (TFM) to multiple life stages of the federally endangered snuffbox (Epioblasma triquetra) and its primary host fish the common logperch (Percina caprodes) as well as a surrogate to the snuffbox, the ellipse (Venustaconcha ellipsiformis). Life stages examined included free glochidia, 1-wk juveniles, and adults of the ellipse; free glochidia, glochidia on host fish, and 1-wk juveniles of the snuffbox; and adult logperch. Larval sea lampreys were also tested alongside adult ellipse and logperch for direct comparison. Survival exceeded 82% among all life stages in both mussel species at levels up to 1.8 times what would be applied during treatments, suggesting that routine sea lamprey control operations would not adversely affect mussels. However, substantial mortality of adult logperch was observed at TFM concentrations typically applied to streams, and loss of host fish could adversely affect snuffbox reproduction. In addition, TFM had no significant effect on the number of glochidia that metamorphosed on adult logperch. Although the snuffbox is not likely to be acutely affected from sea lamprey control operations, mitigation efforts to minimize impacts to the host fish should be considered. PMID- 25729006 TI - Factors related to long-term post-stroke cognitive impairment in young adult ischemic stroke. AB - BACKGROUND: Post-stroke cognitive impairment is common and a decisive prognostic factor. However, few studies have reported on post-stroke cognition in young adults, especially long-term cognition. This study was designed to investigate the influence of baseline factors, treatments, and functional outcome on the long term cognitive outcome in young adults with ischemic stroke. MATERIAL AND METHODS: Consecutive patients aged 18-45 years between January 1, 2006 and December 31, 2010, with a first-ever ischemic stroke, were recruited for cognitive assessment by telephone from December 10 to December 31, 2013 using modified versions of "Telephone Instrument for Cognitive Status" (TICS-m) scale. The relationship of cognitive impairment with baseline factors, treatments, and functional outcome were evaluated. RESULTS: A total of 350 patients with an average age of 41.0+/-6.8 years (69.7% males and 30.3% females) were reviewed. The average follow-up period was 5.8+/-3.2 years, and cognitive impairment existed in 39.4% of patients at follow-up. Stroke severity on admission, functional outcome (modified Rankin Scale, mRS >2) at discharge, left anterior circulation syndrome, and stroke recurrence were markedly associated with post stroke cognitive impairment (all P<0.01). Post-stroke cognition was also significantly related to mRS at follow-up (r=-0.563, P<0.001). CONCLUSIONS: Post stroke cognition was related to functional outcome: hence, treatment directed toward reducing functional disability might also reduce cognitive impairment. PMID- 25729007 TI - Accidental retrieval of a fully deployed stent: A case report. AB - We describe a case of accidental retrieval of a fully deployed stent in ostial left anterior descending (LAD) artery. This occurred while attempting stent delivery in obtuse marginal (OM) artery due to entrapment of a wire which inadvertently had passed through the struts of ostial LAD stent. The proposed mechanism and recommendations to avoid this rare complication are discussed. PMID- 25729008 TI - Electrolytic macrocyclizations: scalable synthesis of a diazonamide-based drug development candidate. AB - An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic. PMID- 25729009 TI - Why history matters to nursing. AB - This paper proposes that poor knowledge and understanding of the history of nursing particularly in the UK influences the media and public analysis of nursing practice. Comparing reports of current poor practice with a 'golden age' of nursing in the past undermines public confidence in today's nursing and nurse education and has the potential to lead to simplistic and flawed policy decisions in response. The lack of detailed knowledge of past nursing practice, experience and values suggests the need for more historical research in this field. A greater critical understanding of nursing history could strengthen and enrich nursing identity and further develop critical thinking skills in nursing students. PMID- 25729010 TI - Perception of and satisfaction with the clinical learning environment among nursing students. AB - BACKGROUND: Clinical nursing education provides baccalaureate nursing students an opportunity to combine cognitive, psychomotor, and affective skills in the Middle East. OBJECTIVE: The aim of the paper is to assess the satisfaction with and effectiveness of the clinical learning environment among nursing students in Oman. DESIGN: A cross-sectional descriptive design was used. SETTING AND PARTICIPANTS: A convenience sample consisting of 310 undergraduate nursing students was selected in a public school of nursing in Oman. METHODS: Ethical approval was obtained from the Research and Ethics Committee, College of Nursing in 2011. A standardized, structured, validated and reliable Clinical Learning Environment Supervision Teacher Evaluation instrument was used. Informed consent was obtained from all the students. Data was analyzed with ANOVA and structural equation modeling. RESULTS: Satisfaction with the clinical learning environment (CLE) sub-dimensions was highly significant and had a positive relationship with the total clinical learning environment. In the path model 35% of its total variance of satisfaction with CLE is accounted by leadership style, clinical nurse commitment (variance=28%), and patient relationships (R(2)=27%). Higher age, GPA and completion of a number of clinical courses were significant in the satisfaction with the CLE among these students. CONCLUSIONS: Nurse educators can improvise clinical learning placements focusing on leadership style, premises of learning and nursing care, nurse teacher, and supervision while integrating student, teacher and environmental factors. Hence the clinical learning environment is integral to students' learning and valuable in providing educational experiences. RELEVANCE TO PRACTICE: The CLE model provides information to nurse educators regarding best clinical practices for improving the CLE for BSN students. PMID- 25729011 TI - Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. AB - Tendons are fibrous connective tissues that transmit force between muscle and bone. Whereas the molecular and cellular mechanisms of bone and muscle development have been well studied, that of tendon development is poorly understood. Using the Scx-GFP transgenic mice, we isolated GFP(+) cells from the developing mouse limbs at E11.5, E13.5, and E15.5, respectively, and carried out whole transcriptome RNA-seq analysis. Comparing the gene expression profiles of GFP(+) and GFP(-) cells in the E13.5 limb isolated over 1,500 genes that exhibited enrichment of mRNA expression by at least 1.5-fold in the GFP(+) cells. Of these, 778 genes showed expression up-regulated by more than 1.5-fold from E11.5 to E13.5 and 516 genes showed expression up-regulated by more than 1.5-fold from E13.5 to E15.5 in the GFP(+) cell population. Interestingly, over 30 genes encoding transcription factors are among the early-activated genes in the GFP(+) cells. Whole mount and section in situ hybridization analyses showed that many of these transcription factor genes have distinct patterns of expression during limb development and identified Foxf2 expression as a specific marker for differentiated dorsal limb tendon cells. Together, these data provide a valuable resource for further investigation of the molecular mechanisms regulating tendon development. PMID- 25729012 TI - One-stage DIEP flap breast reconstruction: Algorithm for immediate contralateral symmetrization. AB - The aim of this study was to investigate clinical and aesthetic results of simultaneous contralateral balancing procedures in unilateral DIEP flap reconstructions by means of a symmetrization algorithm. Between 2004 and 2013, 335 patients underwent DIEP flap breast reconstruction with 48 patients (mean age 51.8 years, range 32-69 years) undergoing contralateral procedure. Patients were divided in Group-A including 31 cases who underwent one-stage procedure and Group B including 17 cases who underwent staged procedure. A symmetrization algorithm was proposed to plan immediate breast reduction/mastopexy. The groups were homogeneous regarding patient's age, BMI, mastectomy and flap weight (P > 0.05). All flaps survived. No complications were observed to the mastectomy skin flaps and to the reduction mammaplasty/mastopexy procedures in both groups. The mean operation time was 5 h in Group-A while 5 h and 37 min in Group-B (P = 0.0682). Contralateral procedures included 23 breast reductions and 8 mastopexies in Group A, while 10 breast reductions and 7 mastopexies were performed in Group-B. Two and 6 patients required revision of the balancing procedure in Group-A and Group B, respectively. The follow-up time was 47.3 months (range 14-120 months) in Group-A and 91.3 months (range 41-110 months) in Group-B. Volume, upper/lower pole shape, projection, breast mound placement, IMF, symmetry, overall appearance, and general satisfaction sub-items obtained high-score evaluation without significant difference between the two groups (P > 0.05). One-stage DIEP flap reconstruction by means of the symmetrization algorithm resulted in comparable aesthetic outcomes and patient satisfaction to a staged procedure. PMID- 25729013 TI - Lipoproteins and diabetes. PMID- 25729014 TI - European Society of Cardiology launches Council on Hypertension. PMID- 25729015 TI - Does smooth muscle in an intact airway undergo length adaptation during a sustained change in transmural pressure? AB - In isolated airway smooth muscle (ASM) strips, an increase or decrease in ASM length away from its current optimum length causes an immediate reduction in force production followed by a gradual time-dependent recovery in force, a phenomenon termed length adaptation. In situ, length adaptation may be initiated by a change in transmural pressure (Ptm), which is a primary physiological determinant of ASM length. The present study sought to determine the effect of sustained changes in Ptm and therefore, ASM perimeter, on airway function. We measured contractile responses in whole porcine bronchial segments in vitro before and after a sustained inflation from a baseline Ptm of 5 cmH2O to 25 cmH2O, or deflation to -5 cmH2O, for ~50 min in each case. In one group of airways, lumen narrowing and stiffening in response to electrical field stimulation (EFS) were assessed from volume and pressure signals using a servo controlled syringe pump with pressure feedback. In a second group of airways, lumen narrowing and the perimeter of the ASM in situ were determined by anatomical optical coherence tomography. In a third group of airways, active tension was determined under isovolumic conditions. Both inflation and deflation reduced the contractile response to EFS. Sustained Ptm change resulted in a further decrease in contractile response, which returned to baseline levels upon return to the baseline Ptm. These findings reaffirm the importance of Ptm in regulating airway narrowing. However, they do not support a role for ASM length adaptation in situ under physiological levels of ASM lengthening and shortening. PMID- 25729016 TI - Implant dentistry in predoctoral education: where are we? PMID- 25729017 TI - Implementing a prenatal oral health program through interprofessional collaboration. AB - Interprofessional collaboration has become a critical component of accreditation standards in dentistry and medicine. This article reports on implementation in an academic setting of a prenatal oral health program (pOHP) that addresses coordinated care, accreditation standards, and new clinical practice guidelines. The pOHP is an educational intervention for third-year medical students, residents, and faculty members to deliver preventive oral health information and referral to a dental home for pregnant women. At the same time, senior dental students and faculty members are introduced to prenatal oral health principles and delivery of comprehensive oral health care to pregnant women. A systems-based approach was used to guide the pOHP implementation during the 2012-13 academic year. Participants were 96 third-year medical students (50% of the total in an obstetrics and gynecology clerkship) and all 81 fourth-year dental students. During that academic year, 126 dental referrals were made to the School of Dentistry, and 55 women presented for care, resulting in 50% (n=40) of dental students participating in the clinical experience and delivery of simple to complex oral health procedures. The prenatal period is a frequently missed opportunity to address oral health care. The pOHP is an interprofessional collaboration model designed to educate dental and medical providers and provide a system of referral for comprehensive clinical care of pregnant patients, including educating women about their oral health and that of their children. Such programs can help meet interprofessional accreditation standards and encourage implementation of practice guidelines. PMID- 25729018 TI - Measuring team-based interprofessional education outcomes in clinical dentistry: psychometric evaluation of a new scale at an Australian dental school. AB - Previous research on interprofessional education (IPE) assessment has shown the need to evaluate the influence of team-based processes on the quality of clinical education. This study aimed to develop a valid and reliable instrument to evaluate the effectiveness of interprofessional team-based treatment planning (TBTP) on the quality of clinical education at the Griffith University School of Dentistry and Oral Health, Queensland, Australia. A scale was developed and evaluated to measure interprofessional student team processes and their effect on the quality of clinical education for dental, oral health therapy, and dental technology students (known more frequently as intraprofessional education). A face validity analysis by IPE experts confirmed that items on the scale reflected the meaning of relevant concepts. After piloting, 158 students (61% response rate) involved with TBTP participated in a survey. An exploratory factor analysis using the principal component method retained 23 items with a total variance of 64.6%, suggesting high content validity. Three subscales accounted for 45.7%, 11.4%, and 7.5% of the variance. Internal consistency of the scale (alpha=0.943) and subscales 1 (alpha=0.953), 2 (alpha=0.897), and 3 (alpha=0.813) was high. A reliability analysis yielded moderate (rs=0.43) to high correlations (0.81) with the remaining scale items. Confirmatory factor analyses verified convergent validity and confirmed that this structure had a good model fit. This study suggests that the instrument might be useful in evaluating interprofessional or intraprofessional team-based processes and their influence on the quality of clinical education in academic dental institutions. PMID- 25729019 TI - Implementation of new technologies in U.S. dental school curricula. AB - With dentistry rapidly evolving as new technologies are developed, this study aimed to identify the penetration of emerging dental technologies into the curricula of U.S. dental schools and to explore whether certain school characteristics affected adoption of these technologies. A 19-question survey was sent to the academic deans of all 62 U.S. dental schools. In addition to questions about characteristics of the school, the survey asked respondents to indicate where in their curricula the technology was incorporated: preclinical didactic, preclinical laboratory, clinical didactic, and/or clinical patient experience. Of 62 eligible schools, 33 useable responses were received, for a 52% response rate. The results showed that the greatest overall penetration of dental technologies was in preclinical didactic courses and the lowest was in the preclinical laboratory. Specific technologies implemented in the largest percentage of responding schools were digital radiography and rotary endodontics. The technologies with the lowest penetration were CAD/CAM denture fabrication and hard tissue lasers. These results suggest that the incorporation of technology into dental schools is following that of private practice as the most widely adopted technologies were those with the greatest acceptance and use in private practice. Among the respondents, factors such as class size and age of the school had greater impact on incorporation of technology than funding source and geographic location. PMID- 25729020 TI - An overview of U.S. predoctoral dental implant programs and their directors. AB - The aim of this study was to provide an overview of current predoctoral implant programs in the United States, including curricular characteristics and clinical practices regarding implant therapy education and program directors' characteristics. An electronic survey was sent to predoctoral implant program directors of all 64 accredited U.S. dental schools; 52 of the 60 eligible programs responded, for a response rate of 87%. The responding program directors were primarily affiliated with either prosthodontics departments (44%) or restorative dentistry departments (40%). Structurally, 80.8% of the responding schools integrate their implant programs into the third year of the curriculum. Clinical implant therapy exercises reported were simulation exercises without direct patient care (90.4% of responding schools) and direct patient care under supervision (94.2%). The most frequently taught restorative modalities are posterior single-tooth implant crown (96.2%), mandibular implant-retained overdenture (88.5%), and anterior implant-supported single crown (61.5%). A majority (74.5%) of responding programs utilize analog surgical guide planning, while 25.5% reported use of digital guided surgery planning software. All schools in the Northwest and 66.7% in the South Central regions utilize custom abutments as the primary abutment design, while a majority of schools in the North Central (62.5%), Northeast (53.8%), Southwest (66.7%), and Southeast (80%) regions use stock abutments (p=0.02). Regional differences were significant with regard to fixation modality, with all the Northwest programs using screw retention and 90% of Southeast and 87.5% of North Central programs using cement retention (p=0.002). This study demonstrated that while institutions share program director and curricular similarities, clinical practices and modalities vary significantly by region. PMID- 25729021 TI - How do dental students determine patients' caries risk level using the Caries Management By Risk Assessment (CAMBRA) system? AB - Research has demonstrated the validation of specific caries risk assessment (CRA) systems, but little is known about how dental practitioners assign a caries risk level to their patients. The aim of this study was to explore dental students' decision making in caries risk assignment when using the Caries Management By Risk Assessment (CAMBRA) system. Multiple correspondence analysis and chi-squared automated interaction detector analysis were performed on data collected retrospectively for a period of six years (2003-09) at the University of California, San Francisco predoctoral dental clinic. The study population consisted of 12,952 patients from six years of age through adult who received a baseline CRA during the period, were new to CAMBRA, and had not received any prior CAMBRA recommendations. The results showed variation in decision making and risk level assignment, illustrated by the range of percentages for the three scores (low, moderate, and high/extreme caries risk) when CRA was assigned for the first time. For those first-time CRAs, decision making was mainly based on four factors: cavities or caries lesions into dentin on radiograph, restorations during the last three years due to caries, visible heavy plaque, and interproximal lesions into enamel (by radiographs). This study's findings provide important data regarding one group of CAMBRA users and thus contribute to the development of knowledge about the implementation of caries risk assessment in contemporary dental practice. PMID- 25729022 TI - Lessons from a pilot project in cognitive task analysis: the potential role of intermediates in preclinical teaching in dental education. AB - The purpose of this study was to explore the use of cognitive task analysis to inform the teaching of psychomotor skills and cognitive strategies in clinical tasks in dental education. Methods used were observing and videotaping an expert at one dental school thinking aloud while performing a specific preclinical task (in a simulated environment), interviewing the expert to probe deeper into his thinking processes, and applying the same procedures to analyze the performance of three second-year dental students who had recently learned the analyzed task and who represented a spectrum of their cohort's ability to undertake the procedure. The investigators sought to understand how experts (clinical educators) and intermediates (trained students) overlapped and differed at points in the procedure that represented the highest cognitive load, known as "critical incidents." Findings from this study and previous research identified possible limitations of current clinical teaching as a result of expert blind spots. These findings coupled with the growing evidence of the effectiveness of peer teaching suggest the potential role of intermediates in helping novices learn preclinical dentistry tasks. PMID- 25729023 TI - The gross anatomy laboratory: a novel venue for critical thinking and interdisciplinary teaching in dental education. AB - Reports on the status of dental education have concluded that there is a need for various types of curricular reform, making recommendations that include better integration of basic, behavioral, and clinical sciences, increased case-based teaching, emphasis on student-driven learning, and creation of lifelong learners. Dental schools faced with decreasing contact hours, increasing teaching material, and technological advancements have experimented with alternate curricular strategies. At Southern Illinois University School of Dental Medicine, curricular changes have begun with a series of integrated biomedical sciences courses. During the process of planning and implementing the integrated courses, a novel venue-the gross anatomy laboratory-was used to introduce all Year 1 students to critical thinking, self-directed learning, and the scientific method. The venture included student-driven documentation of anatomical variations encountered in the laboratory using robust scientific methods, thorough literature review, and subsequent presentation of findings in peer review settings. Students responded positively, with over 75% agreeing the experience intellectually challenged them. This article describes the process of re-envisioning the gross anatomy laboratory as an effective venue for small group-based, student-driven projects that focus on key pedagogical concepts to encourage the development of lifelong learners. PMID- 25729024 TI - Concentration of undergraduate dental college admissions in areas with high health and human development in India. AB - The aims of this study were to determine if dental colleges are clustered in selective states in India and if population to dental college admissions (seats) is correlated with regional health, economic, and human development in that country. There are 29 states and seven union territories in India, with 301 dental colleges. This study used publicly available data from the Dental Council of India, Comptroller and Auditor General of India, Ministry of Health and Family Welfare, and Institute of Applied Manpower Research of the Government of India. Non-parametric tests were used to test for associations. In academic year 2013 14, a total of 293 approved and recognized colleges were in existence, and a total of 23,780 seats were available in all dental colleges. Close to 54% of all dental colleges and 55% of all dental college seats were clustered in five states. The mean population per dental college seat was 94,324 (median was 46,898, and range was a minimum of 2,432 to a maximum of 780,139). The population to one dental college seat decreased significantly as the health and human development index increased (p<0.05). The results showed that dental colleges are clustered in a few states, leaving multiple states in India with no dental colleges. Dental colleges appear to be located in states with high health, economic, and human development indices, thus doing little to address the imbalance in dentist to population ratios in states that are disadvantaged in terms of health, economics, and human development. PMID- 25729025 TI - Impact of reflective writing assignments on dental students' views of cultural competence and diversity. AB - To respond to widespread disparities in access to oral health care, the Institute of Medicine, the Commission on Dental Accreditation (CODA), and the U.S. surgeon general have stressed that prospective dentists should become culturally competent, socially responsible practitioners. The aim of this study was to examine linguistic differences in dental students' reflective writing assignments before and after interviewing an individual who was culturally different from themselves. The authors analyzed 160 documents from 80 first-year dental students at the University of Florida in 2012. This cohort consisted of 36 male (45%) and 44 female (55%) students; 26 (32%) were from underrepresented minority (URM) groups and 54 (68%) were identified as white non-minority. Text analysis software identified word counts, categories, frequencies, and contexts. Significantly positive differences occurred for interviews between assignments 1 and 2 (p=0.005 to p<0.001) in five areas of cultural diversity. Differences were observed for Factor 1 ("important others' influence") between assignments (p<0.001), assignments by interview categories (p=0.033), and URM/majority participants by assignments by interview category (p=0.018). Factor 4 ("my social world in relation to others") was statistically different between assignments for URM/majority participants (p=0.019). Factor 5 ("wrong because") was statistically different for gender (p=0.041), suggesting that males may have experienced a rebound effect from stereotype suppression. The findings suggest that the use of reflective writing and interviews affected the students' awareness of how important others had influenced their lives and attitudes and facilitated their questioning preconceived assumptions. Reactions to coursework focusing on social and personal domains warrant further investigation. PMID- 25729026 TI - Graduating dental students' views of competency statements: importance, confidence, and time trends from 2008 to 2012. AB - Competency documents are used in dental education as both an educational framework and an accreditation instrument. The aim of this study was to analyze the perceptions of graduating dental students at the University of British Columbia (UBC) regarding the importance of each competency statement, as well as to assess their confidence in their abilities associated with each statement. The instrument was based on the survey developed by Schonwetter et al. at the University of Manitoba using the Association of Canadian Faculties of Dentistry competency document. The current study surveyed UBC graduating students in the years 2008 through 2012. The response rates ranged from 66.7% to 95.9%, averaging 77.5% across all five years. The results showed that, overall, the students rated all the competencies as important, but they rated their confidence lower than the perceived importance. Correlation coefficients averaged a moderate correlation of 0.376 for all competency statements except the five with the greatest discrepancy between perceived importance and confidence. The competencies the students perceived as most important tended to be associated with tasks frequently performed during predoctoral dental education. The instrument used in this study can help other academic dental institutions identify patterns of students' perceived competency importance and confidence to inform allocation of teaching time and resources and adopt new methodologies to address identified areas of need. PMID- 25729027 TI - Curriculum time compared to clinical procedures in amalgam and composite posterior restorations in U.S. dental schools: a preliminary study. AB - Dental clinicians have an expanding range of biomaterial choices for restoring tooth structure. Scientific developments in cariology, advances in dental biomaterials, and patients' esthetic concerns have led to a reduction in amalgam restorations and an increase in composite restorations. The aim of this study was to compare teaching time with students' clinical procedures in amalgam and composite posterior restorations in dental schools across the United States. Academic deans in 60 schools were invited to complete a survey that asked for the amount of instructional time for amalgam and composite posterior restorations and the number of clinical restorations performed by their Classes of 2009, 2010, and 2011. Of these 60, 12 returned surveys with complete data, for a 20% response rate. Responses from these schools showed little change in lecture and preclinical laboratory instruction from 2009 to 2011. There was a slight increase in two-surface restorations for both amalgam and composites; however, the total number of reported composite and amalgam restorations remained the same. Of 204,864 restorations reported, 53% were composite, and 47% were amalgam. There were twice as many multisurface large or complex amalgam restorations as composites. One-surface composite restorations exceeded amalgams. Among the participating schools, there was little to no change between curriculum time and clinical procedures. Findings from this preliminary study reflect a modest increase in two-surface resin-based restorations placed by dental students from 2009 to 2011 and little change in curricular time devoted to teaching amalgam restorations. The total number of posterior composite restorations placed by students in these schools was slightly higher than amalgams. PMID- 25729028 TI - Predicting academic performance of dental students using perception of educational environment. AB - Greater emphasis on student-centered education means that students' perception of their educational environment is important. The ultimate proof of this importance is its effect on academic performance. The aim of this study was to assess the predictability of dental students' grades as indicator of academic performance through their perceptions of the educational environment. The Dundee Ready Educational Environment Measure (DREEM) questionnaire was used to assess dental students' perceptions of their educational environment at the University of Dammam, Saudi Arabia, in academic year 2012-13. Aggregate grades in courses were collected at the end of the semester and related to levels of perception of the five DREEM domains using regression analysis. The response rate was 87.1% among all students in Years 2-6. As the number of students perceiving excellence in learning increased, the number of students with A grades increased. Perception of an environment with problems in the atmosphere and social life increased the number of students with D and F grades. There was no relation between any of the DREEM domains and past academic performance as measured by GPA. This study concludes that these students' academic performance was affected by various aspects of perceiving the educational environment. Improved perception of learning increased the number of high achievers, whereas increased perception of problems in atmosphere and social life increased the number of low achievers and failing students. PMID- 25729029 TI - Second-to-fourth Digit Ratio in Systemic Lupus Erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) occurs predominantly in women, and sex hormones play an important role in SLE. Variation in the second-to-fourth digit ratio (2D4D ratio) is attributed to sex hormone exposure. Therefore, we evaluated the relationship between sex hormones and SLE by measuring 2D4D ratios. METHODS: We measured 2D4D ratios in 100 patients with SLE and 200 normal healthy controls (NHC). RESULTS: Patients with SLE had a lower 2D4D ratio than NHC. CONCLUSION: Our study suggests that patients with SLE have experienced high prenatal testosterone and low prenatal estrogen. To our knowledge, this is the first study evaluating the association between 2D4D ratio and SLE. PMID- 25729030 TI - Joint Aspiration for Acute Hemarthrosis in Children Receiving Factor VIII Prophylaxis for Severe Hemophilia: 11-year Safety Data. AB - OBJECTIVE: The aims of this study were (1) to document the prevalence of acute hemarthrosis in a cohort of 46 boys with severe hemophilia A receiving full primary prophylaxis in Western Australia (WA), and (2) to investigate the safety of the WA protocol over 11 years for management of hemarthrosis. METHODS: Case review. The WA protocol involves a pediatric rheumatologist washing out all acute hemarthrosis of large joints promptly and then instilling intraarticular (IA) corticosteroids. RESULTS: This study showed that joint bleeds occurred in 22 boys of 46 (47.8%). In over 11 years, 84 washouts were performed on 32 joints in 22 boys. No adverse events occurred. Fifteen of 22 boys had normal joints with a Hemophilic Joint Health Score = 0. Fifteen boys who had had all hemarthrosis washed out had clinically normal joints (100%). Seven boys had sustained joint damage prior to full instigation of the protocol, each having had documented hemarthrosis without aspiration. Parents needed to understand that joint bleeds constituted an emergency. CONCLUSION: Of our cohort, 47.8% of patients with severe hemophilia receiving prophylaxis developed joint bleeding. The WA protocol is safe. There is evidence suggesting joint outcomes of hemophilic patients having hemarthrosis despite factor VIII prophylaxis may be much improved if there is access to a center using a procedure similar to the WA protocol. PMID- 25729031 TI - Relationship between blood plasma and synovial fluid metabolite concentrations in patients with osteoarthritis. AB - OBJECTIVE: To investigate the relationship between plasma and synovial fluid (SF) metabolite concentrations in patients with osteoarthritis (OA). METHODS: Blood plasma and SF samples were collected from patients with primary knee OA undergoing total knee arthroplasty. Metabolic profiling was performed by electrospray ionization tandem mass spectrometry using the AbsoluteIDQ kit. The profiling yielded 168 metabolite concentrations. Correlation analysis between SF and plasma metabolite concentrations was done on absolute concentrations as well as metabolite concentration ratios using Spearman's rank correlation (rho) method. RESULTS: A total of 69 patients with knee OA were included, 30 men and 39 women, with an average age of 66 +/- 8 years. For the absolute metabolite concentrations, the average rho was 0.23 +/- 0.13. Only 8 out of 168 metabolite concentrations had a rho >= 0.45, with a p value <= 2.98 * 10(-4), statistically significant after correcting multiple testing with the Bonferroni method. For the metabolite ratios (n = 28,056), the average rho was 0.29 +/- 0.20. There were 4018 metabolite ratios with a rho >= 0.52 and a p value <= 1.78 * 10(-6), significant after correcting multiple testing. Sex-separate analyses found no difference in rho between men and women. Similarly, there was no difference in rho between people younger and older than 65 years. CONCLUSION: Correlation between blood plasma and SF metabolite concentrations are modest. Metabolite ratios, which are considered proxies for enzymatic reaction rates and have higher correlations, should be considered when using blood plasma as a surrogate of SF in OA biomarker identification. PMID- 25729032 TI - Prevalence of psoriatic arthritis in a large cohort of Brazilian patients with psoriasis. AB - OBJECTIVE: To determine the prevalence of psoriatic arthritis (PsA) in a large cohort of Brazilian patients with psoriasis (PsO) being seen at dermatology centers. METHODS: A multicenter study was conducted in 4 university dermatology clinics. In each center, consecutive patients with confirmed diagnoses of PsO were evaluated by a rheumatologist. Individuals were classified as having PsA according to the ClASsification criteria for Psoriatic ARthritis (CASPAR). Laboratory tests and radiographs were performed, as needed, based on the clinical judgment of the rheumatologist. RESULTS: A total of 524 patients with PsO were evaluated. The mean age was 48.5 +/- 14.5 years, 50% were women, and the mean PsO duration was 15.4 +/- 11.7 years. A diagnosis of PsA was documented in 175 patients (33%), of whom 49% were newly identified by the rheumatologist. Most individuals with PsA (72%) had peripheral involvement, 11% had isolated axial involvement, and 17% had both peripheral and axial involvement. Dactylitis occurred in 20% and clinical enthesitis in 30% of the patients. Laboratory and/or radiograph tests were necessary for a definitive diagnosis of PsA in 42 of 175 individuals (24%). CONCLUSION: In our study, one-third of Brazilian patients with PsO, followed in dermatology settings, were diagnosed with PsA by a rheumatologist. Almost half of subjects with PsA had no previous diagnosis. A collaboration between dermatologists and rheumatologists is greatly needed to establish earlier PsA diagnoses and adequate multidisciplinary management. PMID- 25729033 TI - Anti-dsDNA and Antichromatin Antibody Isotypes in Serologically Active Clinically Quiescent Systemic Lupus Erythematosus. AB - OBJECTIVE: Serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE) are clinically quiescent despite serologic activity. Since studies suggest that antichromatin antibodies are more sensitive than anti-dsDNA antibodies in detecting active SLE, and that immunoglobulin (Ig) G, in particular complement-fixing subclasses, may be more pathogenic than IgM, we investigated the levels of anti-dsDNA and antichromatin isotypes in SACQ patients as compared to non-SACQ patients with SLE. METHODS: Levels of IgM, IgA, IgG, and IgG1-4 antichromatin and anti-dsDNA were measured by ELISA. SACQ was defined as >= 2 years with the SLE Disease Activity Index 2000 (SLEDAI-2K) at 2 or 4 from serologic activity, during which patients could be taking antimalarials, but not corticosteroids or immunosuppressives. Unselected non-SACQ patients with SLE were used as comparators. SACQ patient serum samples were further stratified based on subsequent development of flare, defined as clinical SLEDAI-2K >= 1 and/or treatment initiation. Nonparametric statistics were used, and generalized estimating equations were applied to account for multiple samples in the same patient. RESULTS: SACQ patients' complement-fixing antichromatin and anti-dsDNA IgG subclasses were significantly higher than those of non-SACQ patients. When the sample drawn latest in a SACQ period was analyzed, there was no difference between antichromatin or anti-dsDNA isotype or IgG subclass levels between patients who flared and those who remained SACQ, nor were consistent trends seen when samples were examined during SACQ and flare in the same patient. CONCLUSION: The SACQ phenotype does not arise from a lack of pathogenic anti dsDNA and/or antichromatin autoantibodies. Neither increases in antichromatin nor anti-dsDNA isotype or IgG subclass levels were predictive of or coincident with flare in SACQ patients. PMID- 25729034 TI - Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group. AB - OBJECTIVE: Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research. METHODS: The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as >= 75% agreement among the participants. RESULTS: OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as >= 10% relative decline in forced vital capacity (FVC) or >= 5% to < 10% relative decline in FVC and >= 15% relative decline in DLCO. CONCLUSION: There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed. PMID- 25729035 TI - More than Just Minutes of Stiffness in the Morning: Report from the OMERACT Rheumatoid Arthritis Flare Group Stiffness Breakout Sessions. AB - OBJECTIVE: Stiffness was endorsed within the rheumatoid arthritis (RA) flare core domain set at the previous Outcome Measures in Rheumatology meeting (OMERACT 11). Two stiffness breakout groups at the present OMERACT 12 RA flare workshop discussed results of new qualitative studies in RA stiffness. METHODS: Results from 2 independent studies of RA stiffness were presented to breakout group participants, followed by group discussions about stiffness measurement. RESULTS: Both studies identified stiffness as complex, variable with the level of disease activity, and as encompassing concepts of impact, intensity, timing, location, and duration. That stiffness has an effect on multiple dimensions of health was a common finding. Participants agreed that stiffness is an important aspect of RA flare. Whether measuring only morning stiffness duration, the traditional approach in RA, was sufficient in coverage of the concept was unclear. Groups agreed that more research on stiffness measurement is needed considering the importance patients place on the effect of stiffness. CONCLUSION: Results from independent studies highlight stiffness effect as an important feature of RA, in addition to intensity, timing, location, and duration. Additional work is needed to identify optimal ways to assess stiffness in RA and other rheumatologic diseases. PMID- 25729036 TI - Calprotectin as a biomarker for rheumatoid arthritis: a systematic review. AB - OBJECTIVE: Calprotectin (myeloid-related protein 8/14), a heterodimeric complex of calcium-binding proteins, is expressed in granulocytes and monocytes. Calprotectin levels are high in synovial tissue, particularly in activated cells adjacent to the cartilage-pannus junction. This systematic review evaluates the use of calprotectin as an indicator of disease activity, therapeutic response, and prognosis in rheumatoid arthritis (RA). METHODS: Medline, Scopus, and the Cochrane Library (1970-2013) were searched for studies containing original data from patients with RA in whom calprotectin levels were measured in plasma/serum and/or synovial fluid (SF). We included studies examining associations between calprotectin levels and clinical and laboratory assessments, disease progression, and therapeutic response. There were no restrictions for sample size, disease duration, or length of followup. RESULTS: We evaluated 17 studies (1988-2013) with 1065 patients enrolled; 11 were cross-sectional and 8 had longitudinal designs with 2 studies reporting cross-sectional and longitudinal data. Systemic and SF levels of calprotectin were raised in RA. There was a wide range of levels and marked interstudy and intrastudy variability. Calprotectin levels were high in active disease and were particularly high in rheumatoid factor (RF)-positive patients. Levels fell with effective treatment. Longitudinal data showed that calprotectin was a significant and independent predictor of erosive progression and therapeutic responses, particularly in patients who received effective biological treatments. CONCLUSION: SF calprotectin levels are high, suggesting there is substantial local production by inflamed synovium. Blood calprotectin levels, though highly variable, are elevated in active RA and fall with effective therapy. High baseline calprotectin levels predict future erosive damage. PMID- 25729038 TI - Is the double contour sign specific for gout? Or only for crystal arthritis? PMID- 25729037 TI - Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: To assess surface APRIL (a proliferation-inducing ligand; CD256) expression by circulating myeloid cells in rheumatoid arthritis (RA) and to determine its relationship to disease activity. METHODS: Peripheral blood mononuclear cells (PBMC) and plasma were obtained from patients with RA and healthy donors. PBMC were stained for flow cytometry to detect surface APRIL and blood cell markers to identify circulating myeloid cell subsets. Based on CD14 and CD16 phenotypes, monocyte subsets described as classical (CD14+CD16-), intermediate (CD14+CD16+), and nonclassical (CD14loCD16+) were identified. Levels of surface APRIL expression were measured by flow cytometry and median fluorescence intensity was used for comparisons. Levels of soluble APRIL in the plasma were determined by ELISA. Disease activity was measured by the Disease Activity Score in 28 joints. RESULTS: In patients with RA, total myeloid cells showed expression of surface APRIL that correlated with disease activity and with plasma APRIL levels observed in these patients. In healthy donors, classical monocytes were composed of > 80% of circulating monocytes. However, in patients with RA, the intermediate and nonclassical subsets were elevated and made up the majority of circulating monocytes. In contrast to healthy donors, where high levels of surface APRIL were only observed in nonclassical monocytes, patients with RA showed high levels of surface APRIL expression by all circulating monocyte subsets. CONCLUSION: Surface APRIL is elevated in circulating myeloid cells in patients with RA where it is highly correlated with disease activity. Patients with RA also showed skewing of monocytes toward subsets associated with secretion of tumor necrosis factor-alpha and/or interleukin 1beta. PMID- 25729039 TI - Intestinal dysbiosis and potential consequences of microbiome-altering antibiotic use in the pathogenesis of human rheumatic disease. PMID- 25729040 TI - Is there hope for juvenile idiopathic arthritis patient-reported outcomes in support of clinical decisions? PMID- 25729041 TI - Ultrasound measurement of cartilage thickness in childhood arthritis--target the tissue, tailor the technique. PMID- 25729042 TI - Calcinosis and rapidly destructive arthropathy associated with anti-jo1 antibody. PMID- 25729043 TI - An unusual cause of low back pain. PMID- 25729044 TI - Progressive multifocal leukoencephalopathy associated with belimumab in a patient with systemic lupus erythematosus. PMID- 25729045 TI - Interleukin-34: a potential diagnostic and therapeutic target for rheumatoid arthritis. PMID- 25729046 TI - Drs. Moon and Min reply. PMID- 25729047 TI - Autologous hematopoietic stem cell transplant for systemic sclerosis improves anemia from gastric antral vascular ectasia. PMID- 25729048 TI - A case of rheumatoid arthritis associated with SMAD3 gene mutation: a new clinical entity? PMID- 25729049 TI - Pancytopenia in a patient with psoriatic arthritis treated with methotrexate and concomitant lithium. PMID- 25729050 TI - Anticyclic citrullinated peptide antibodies in rheumatoid and nonrheumatoid rheumatic disorders: experience with 1162 patients. PMID- 25729051 TI - Lessons learned from comparative and evolutionary physiology. PMID- 25729052 TI - Physiology and the BRAIN Initiative. PMID- 25729053 TI - Life at the extreme: physiological adaptation. PMID- 25729054 TI - Persistence, entrainment, and function of circadian rhythms in polar vertebrates. AB - Polar organisms must cope with an environment that periodically lacks the strongest time-giver, or zeitgeber, of circadian organization-robust, cyclical oscillations between light and darkness. We review the factors influencing the persistence of circadian rhythms in polar vertebrates when the light-dark cycle is absent, the likely mechanisms of entrainment that allow some polar vertebrates to remain synchronized with geophysical time, and the adaptive function of maintaining circadian rhythms in such environments. PMID- 25729055 TI - The survival mechanisms of thermophiles at high temperatures: an angle of omics. AB - Thermophiles are referred to as microorganisms with optimal growth temperatures of >60 degrees C. Over the past few years, a number of studies have been conducted regarding thermophiles, especially using the omics strategies. This review provides a systematic view of the survival physiology of thermophiles from an "omics" perspective, which suggests that the adaptive ability of thermophiles is based on a cooperative mode with multi-dimensional regulations integrating genomics, transcriptomics, and proteomics. PMID- 25729056 TI - How bar-headed geese fly over the Himalayas. AB - Bar-headed geese cross the Himalayas on one of the most iconic high-altitude migrations in the world. Heart rates and metabolic costs of flight increase with elevation and can be near maximal during steep climbs. Their ability to sustain the high oxygen demands of flight in air that is exceedingly oxygen-thin depends on the unique cardiorespiratory physiology of birds in general along with several evolved specializations across the O2 transport cascade. PMID- 25729057 TI - Hypoxia tolerance, nitric oxide, and nitrite: lessons from extreme animals. AB - Among vertebrates able to tolerate periods of oxygen deprivation, the painted and red-eared slider turtles (Chrysemys picta and Trachemys scripta) and the crucian carp (Carassius carassius) are the most extreme and can survive even months of total lack of oxygen during winter. The key to hypoxia survival resides in concerted physiological responses, including strong metabolic depression, protection against oxidative damage and-in air-breathing animals-redistribution of blood flow. Each of these responses is known to be tightly regulated by nitric oxide (NO) and during hypoxia by its metabolite nitrite. The aim of this review is to highlight recent work illustrating the widespread roles of NO and nitrite in the tolerance to extreme oxygen deprivation, in particular in the red-eared slider turtle and crucian carp, but also in diving marine mammals. The emerging picture underscores the importance of NO and nitrite signaling in the adaptive response to hypoxia in vertebrate animals. PMID- 25729058 TI - Gaseous modulators in the control of the hypothalamic neurohypophyseal system. AB - Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are gaseous molecules produced by the brain. Within the hypothalamus, gaseous molecules have been highlighted as autocrine and paracrine factors regulating endocrine function. Therefore, in the present review, we briefly discuss the main findings linking NO, CO, and H2S to the control of body fluid homeostasis at the hypothalamic level, with particular emphasis on the regulation of neurohypophyseal system output. PMID- 25729059 TI - The cerebral circulation during pregnancy: adapting to preserve normalcy. AB - The adaptation of the brain and cerebral circulation to pregnancy are unique compared with other organs and circulatory systems, ultimately functioning to maintain brain homeostasis. In this review, the effect of pregnancy on critical functions of the cerebral circulation is discussed, including changes occurring at the endothelium and blood-brain barrier, and changes in the structure and function of cerebral arteries and arterioles, hemodynamics, and cerebral blood flow autoregulation. PMID- 25729060 TI - The baroreflex as a long-term controller of arterial pressure. AB - Because of resetting, a role for baroreflexes in long-term control of arterial pressure has been commonly dismissed in the past. However, in recent years, this perspective has changed. Novel approaches for determining chronic neurohormonal and cardiovascular responses to natural variations in baroreceptor activity and to electrical stimulation of the carotid baroreflex indicate incomplete resetting and sustained responses that lead to long-term alterations in sympathetic activity and arterial pressure. PMID- 25729062 TI - Pathophysiology of venous thrombosis. AB - In this chapter, an overview of some of the prominent risk factors that contribute to the pathophysiology of venous thrombosis will be discussed. In 1856, Dr Rudolf Virchow developed the concept outlining the genesis of intravascular thrombosis. Dr Virchow hypothesized that circulatory stasis due to interrupted blood flow, changes in the blood leading to blood coagulation, and irritation or damage to the vascular endothelium would initiate acute venous thrombus generation. Presently, it is known that these above-mentioned risk factors are influenced by increasing age, gender, and obesity. The current chapter will focus on recent preclinical and clinical investigations that will give the reader insight into the prothrombotic mechanisms that lead to acute venous thrombosis. PMID- 25729061 TI - Multiscale models in the biomechanics of plant growth. AB - Plant growth occurs through the coordinated expansion of tightly adherent cells, driven by regulated softening of cell walls. It is an intrinsically multiscale process, with the integrated properties of multiple cell walls shaping the whole tissue. Multiscale models encode physical relationships to bring new understanding to plant physiology and development. PMID- 25729063 TI - Validation of the LET classification. AB - INTRODUCTION: Acute thrombus removal therapies may reduce post-thrombotic syndrome in certain deep venous thrombosis patients. The LET classification is designed to identify patients at high risk for developing post-thrombotic syndrome in the acute phase using thrombus location and extent. This study evaluates the use of the LET classification to predict post-thrombotic syndrome in a cohort of patients after deep venous thrombosis. METHODS: A cohort of 660 deep venous thrombosis patients was invited to participate and fill out a questionnaire with Quality of life questionnaires, basic information, a modified self-assessment version of the Villalta scale for post-thrombotic syndrome and potential confounders. Original data on thrombus extension was available, and the LET classes were determined. Obtained information was analysed using ANOVA and in a multiple logistic regression model to correct for confounders. All different LET classes were compared to post-thrombotic syndrome occurrence, post-thrombotic syndrome prediction and disease specific quality of life scores (VEINES-Sym/Qol). RESULTS: Three hundred and fifteen patients responded, and in 309 a post thrombotic syndrome score was distilled. LET I,II,III (n = 63) had an odds ratio of 3.4(1.2-9.2) for predicting severe post-thrombotic syndrome, and LET II (n = 17) had an odds ratio of 5.1(1.3-20.8) compared to LET class I (n = 97). Both the VEINES-Sym and VEINES-Qol score were significantly lower for LET I,II,III compared to LET I, and LET II compared to LET I. CONCLUSION: The LET classification can be used to classify patients according to acute thrombus location and extent. Extensive and centrally located (LET I,II,III) deep venous thrombosis showed the highest probability in developing severe post-thrombotic syndrome and lower disease specific quality of life. PMID- 25729064 TI - Thrombus age is ideally measured by history or MRV prior to thrombus removal. AB - Many factors are known to be important in order to achieve optimal results after thrombus removal for iliofemoral DVT. Not much is published in the literature about timing the treatment, though many guidelines recommend treatment within 14 days. This time span lies within the phrase of acute DVT according to the definition given in many reporting standards. This article will highlight the value of information acquired from patients directly regarding onset of symptoms versus information acquired from imaging with the purpose of a more precise selection of patients for catheter-directed thrombolysis for iliofemoral DVT. What is the value of clinical information acquired from patients and does the information from imaging have additional value? PMID- 25729065 TI - Hemodynamic significance of collateral blood flow in chronic venous obstruction. AB - INTRODUCTION: Complaints related to the post-thrombotic syndrome do not always correlate well with the extent of post-thrombotic changes on diagnostic imaging. One explanation might be a difference in development of collateral blood flow. The aim of this study is to investigate the hemodynamic effect of collateralisation in deep venous obstruction. METHODOLOGY: Resting intravenous pressure of the common femoral vein was measured bilaterally in the supine position of patients with unilateral iliofemoral post-thrombotic obstruction. In addition, pressure in control limbs was also measured in the common femoral vein after sudden balloon occlusion in the external iliac vein. RESULTS: Fourteen patients (median age 42 years, 12 female) were tested. In eleven limbs post thrombotic disease extended below the femoral confluence. Median common femoral vein pressure was 17.0 mmHg in diseased limbs compared to 12.8 mmHg in controls (p = 0.001) and 23.5 mmHg in controls after sudden balloon occlusion (p = 0.009). Results remained significant after correcting for non-occlusive post-thrombotic disease. CONCLUSION: This study shows that common femoral vein pressure is increased in post-thrombotic iliofemoral deep venous obstruction, though not as much as after sudden balloon occlusion. The latter difference could explain the importance of collateralisation in deep venous obstructive disease and the discrepancy between complaints and anatomical changes; notwithstanding, the presence of collaterals does not eliminate the need for treatment. PMID- 25729066 TI - Conservative versus surgical treatment of venous leg ulcers: 10-year follow up of a randomized, multicenter trial. AB - INTRODUCTION: Leg ulcers have a large socio-economic impact. Treatment modalities are either conservative or surgical. Conservative treatment involves local treatment and compression therapy. Surgical treatment of venous ulcers is based on correcting venous hypertension, by treating incompetent superficial, deep, and perforating veins. A prospective randomized multicenter trial comparing surgical treatment (combined superficial and perforating vein surgery) with ambulatory compression therapy was conducted during 1998 and 2001. This paper presents the results of a 10-year follow-up period of this trial. MATERIALS AND METHODS: All patients enrolled in the original prospective trial were approached and invited for additional examination and duplex ultrasound evaluation. Secondary, disease specific and generic quality-of-life (QoL) was assessed. Current ulcer state and recurrence during the follow-up period was assessed. RESULTS: After a mean of 97 months follow up, 80 (41%) out of 196 legs could be inspected. The incidence of "ulcer-free", the main outcome, was significantly (p = 0.007) higher in the surgical group (58.9%), compared to the conservative group (39.6%). Observed ulcer recurrence was 48.9% for the surgical group and 94.3% for the conservative group. The number of incompetent perforating veins appears to be a significant (p < 0.001) risk factor for not being ulcer-free. Disease specific QoL showed no significant difference between the surgical and conservative groups. CONCLUSIONS: The addition of surgical treatment in patients with venous ulceration leads to a significantly higher chance of being ulcer-free, than just ambulatory compression therapy. This effect persists after 10 years of follow up. The number of incompetent perforating veins has a significant effect on the ulcer-state and recurrence. PMID- 25729067 TI - Arteriovenous fistula geometry in hybrid recanalisation of post-thrombotic venous obstruction. AB - INTRODUCTION: Post-thrombotic obstruction can be adequately treated by percutaneous transluminal angioplasty and stenting. When post-thrombotic trabeculations extend below the femoral confluence, proper inflow can be facilitated by endophlebectomy and creation of an arteriovenous fistula. The aim of this study was to investigate whether it is more favourable to place the arteriovenous fistula at the cranial or caudal end of the endophlebectomy to prevent stenosis or occlusion. METHODOLOGY: We retrospectively analysed the clinical data of all patients who underwent a hybrid procedure in our two centres. Demographics, interventional details and post-operative imaging were collected. RESULTS: Data on 42 limbs with cranially and 23 limbs with caudally placed arteriovenous fistulas were collected. Post-thrombotic disease of the profunda femoral vein alone or in combination with the femoral vein was observed more often in the cranial group. The caudal group more often received a smaller sized and straight polytetrafluoroethylene fistula, while the cranial group comprised a significantly higher amount of stented segments. Logistic regression showed that only reduced femoral inflow (hazard ratio 2.934 (95%CI, 1.148-7.494)) was a significant predictor of stent stenosis and/or occlusion. Logistic regression for risk of occlusion showed a significant influence of stent-related complications (hazard ratio 4.691 (95%CI, 1.205-18.260)) and a tendency towards influence of arteriovenous fistula geometry in favour of the cranially placed fistula. CONCLUSION: Placement of the arteriovenous fistula in the cranial part of the endophlebectomy during hybrid recanalisation may result in a more favourable outcome, yet this tendency was not statistically significant. Moreover, femoral inflow is pivotal in maintaining patency and should thus be adequately assessed pre-operatively. PMID- 25729068 TI - Valve reconstructions. AB - The history of venous valve reconstruction extends back to 1968 when Robert L Kistner performed the first internal valve plasty to treat deep venous axial reflux. Throughout the past 50 years other techniques of reconstructive deep venous surgery (RDVS) were developed, not only to repair but also to replace venous valves. And the fact that several surgeons and centers have undertaken RDVS in the treatment of chronic venous insufficiency (CVI) reporting outcomes, has added knowledge to define more clearly the role of this kind of specialized surgery. Patients who may benefit from RDVS are among those where conventional treatment with compression stockings combined with superficial surgery has failed. Ulcer-healing rates of up to 70% have been reported after RDVS and ulcer free periods of up to 36 months have been generated. But during five-year follow up, freedom from ulceration period and clinical improvement rates were reduced significantly. This raises then the issue and challenge of durability of RDVS since the average age of patients who can benefit from it is about 50 years. PMID- 25729069 TI - Deep venous thrombosis and postthrombotic syndrome: invasive management. AB - Invasive management of postthrombotic syndrome encompasses the two ends of the deep vein thrombosis spectrum, patients with acute iliofemoral deep vein thrombosis and those with chronic postthrombotic iliofemoral venous obstruction. Of all patients with acute deep vein thrombosis, those with involvement of the iliofemoral segments have the most severe chronic postthrombotic morbidity. Catheter-based techniques now permit percutaneous treatment to eliminate thrombus, restore patency, potentially maintain valvular function, and improve quality of life. Randomized trial data support an initial treatment strategy of thrombus removal. Failure to eliminate acute thrombus from the iliofemoral system leads to chronic postthrombotic obstruction of venous outflow. Debilitating chronic postthrombotic symptoms of the long-standing obstruction of venous outflow can be reduced by restoring unobstructed venous drainage from the profunda femoris vein to the vena cava. PMID- 25729070 TI - Diagnostic imaging of pelvic congestive syndrome. AB - Many female patients are affected by chronic pelvic pain and a significant number of referrals to the gynecology department result in a clinical suspicion of pelvic congestion syndrome. Additionally, patients referred to the vascular surgery department for venous disease can also present with complaints of a persistent dull lower abdominal pain in addition to typically distributed leg varicosities (that extend from the leg through the pelvic floor) which should be evaluated for the presence of pelvic congestion syndrome. In this article, we focus on imaging pelvic vein insufficiency and related (extending) varicosities: how should we evaluate the pelvic veins, what are the signs to look for, and what are the currently established criteria for (pre-interventional) imaging. PMID- 25729071 TI - Clinical outcome after treatment of pelvic congestion syndrome: sense and nonsense. AB - Chronic pelvic pain accounts for approximately 10% of outpatient gynecologic visits and among the varied causes, pelvic congestion syndrome is second only to endometriosis in frequency. Manifestations may include pelvic pain, dyspareunia, dysuria, and dysmenorrhea as well as external varices and a number of psychosocial symptoms. Although a variety of treatments have been proposed including pharmacologic ovarian suppression, hysterectomy with or without oophorectomy, and ovarian vein resection-transcatheter embolization is the least invasive and most efficacious management option. Complete or partial symptom improvement has been reported in 68.2-100% of patients and there has been a consistent reduction in visual analog pain scores after treatment. Based upon these results, recommendation of either pharmacotherapy or other surgical procedures is difficult to justify. However, it is also clear that 6-31.8% of patients do not get substantial relief from pelvic venous embolization. Potential explanations for an inadequate response to treatment include patient variability, procedural variability, and inadequate outcome measures. The latter are particularly important and future investigation should focus on the development of disease-specific quality of life measures as well as identifying those aspects of the procedure, such as choice of embolic agents and extent of embolization, associated with the best clinical outcomes. PMID- 25729072 TI - Embolization is essential in the treatment of leg varicosities due to pelvic venous insufficiency. AB - PURPOSE: Pelvic venous insuffiency (PVI) can be responsible for pelvic congestion syndrome (PCS) and also lower limb varicose veins. MATERIAL AND METHODS: Charts of all women who had pelvic venography for PVI from September 2013 to August 2014 were reviewed. The procedure was performed under local anesthesia through left femoral approach. In case of reflux without associated obstructive lesions, embolization with coils and polidocanol foam was performed during the same procedure. RESULTS: 119 women, with median age 39 years were explored (86 with PCS and 102 with lower limb venous disease). Of these, 78 had an isolated reflux and were embolized and 41 had an obstructive disease (29 iliocaval obstructive lesions (ICOL), 4 nutcracker syndrome (NCS), and 8 with an association of both). Median follow-up was 4 months. Of the 12 NCS, 5 had surgical treatment and 7 had stenting of the left iliac vein without embolization. All patients with ICOL without NCS were treated by stenting in 28 and by a Palma procedure in 1 (failure to recanalize). Primary and secondary patency rates were 97% at 12 months. Embolization led to improvement of PCS in 91% (60% without any pain) and of lower limb varicose veins in 51% by itself. If 82% need an additional treatment of lower limb varicose veins, embolization allowed a switch of strategy from surgery to sclerosis. CONCLUSION: PVI can cause lower limb symptoms. In most cases, it is due to reflux and can be treated under local anesthesia by embolization. This technique is safe and efficient. Obstructive lesions must be recognized and treated. PMID- 25729073 TI - Embolization is not essential in the treatment of leg varices due to pelvic venous insufficiency. AB - AIM: To consider if it is essential to perform embolization in the treatment of leg varices due to pelvic venous insufficiency. METHODS: Review of the current literature concerning treatment options of leg varicose veins of pelvic origin. RESULTS: Pelvic venous insufficiency, vulvar and pudendal varicose veins as well as pelvic congestive syndrome are under diagnosed entities. Embolization of ovarian and pelvic veins is well established in patients with pelvic congestive syndrome. In varicose veins of pelvic origin but without pelvic congestive syndrome, comparative studies comparing the outcome of embolization or treatment of varicose veins by sclerotherapy or phlebectomy alone are missing. Foam sclerotherapy or phlebectomy shows good results in patients with varicose veins of pelvic origin. CONCLUSIONS: Embolization is not essential in the treatment of leg varices of pelvic origin without pelvic congestive syndrome. Foam sclerotherapy or phlebectomy shows good results in patients with vulvar or pudendal varicose veins. Randomized comparative studies using embolization of incompetent pelvic veins or sclerotherapy of varicose veins with pelvic origin should be performed. PMID- 25729074 TI - Quality-of-life in interventionally treated patients with post-thrombotic syndrome. AB - INTRODUCTION: New developments in the treatment of complex deep venous disease have become available in the last decade. Besides analysing patencies as a surrogate outcome for these treatments we analysed the Quality-of-Life (QoL) changes for successful and failed deep venous treatments. MATERIALS AND METHODS: Patients with proven venous occlusive disease, referred to our department of Venous Surgery at the Maastricht University Medical Centre, were included. After inclusion patients were treated by percutaneous transluminal angioplasty and stenting and when indicated endophlebectomy with an arteriovenous fistula. QoL was assessed with the disease specific VEINES-QOL/Sym and the generic Short-Form (SF)-36 questionnaires preoperatively at baseline and post-operatively after 3, 12 and 24 months. RESULTS: One hundred fifty-three interventions were analysed, showing a primary, assisted primary and secondary patency of respectively 65%, 78% and 89% at 24 months. The VEINES-QOL and Sym scores improved at 3, 12 and 24 months. The overall improvement at 24 months is 22.7 for QoL and 18.18 for Sym with respective p values of 0.013 and 0.016. The improvement of the VEINES-QOL and Sym scores after a successful (patent) treatment remained highly significant (QoL: p < 0.001, Sym: p = 0.004). Also the generic QoL (Short-Form 36v2) shows significant improvement after 12 months for physical functioning (p = 0.004) and role physical (p = 0.004) scales. CONCLUSIONS: The overall patencies of interventions for deep venous pathology are exceptionally good after two years. Concomitantly the VEINES-Sym and VEINES-QOL scores improve significantly for 3, 12, and 24 months when compared to the baseline (T0) after treatment. Successful interventions showed, as expected, a significant greater QoL improvement between T0 and T3, T12, T24 for both VEINES-QOL and VEINES-Sym scores when compared to the failed interventions. The one-year linear improvement of two SF-36 scales (PF and RP) is also significant. PMID- 25729075 TI - Progression in venous pathology. AB - AIM: To review epidemiologic data on progression of venous pathology in varicose veins and from varicose veins towards chronic venous insufficiency. METHODS: We searched Medline and PubMed for epidemiologic studies concerning progression of venous pathology. RESULTS: The data suggest that reflux progression may develop from segmental to multisegmental superficial reflux. In younger age, reflux in tributaries and non-saphenous veins is more frequent. In older age, more saphenous reflux develops and more proximal sites seem to be affected. A high proportion of uncomplicated varicose vein (C2) develops skin changes and chronic venous insufficiency (C3-C6). Significant risk factors for the progression of varicose vein towards venous leg ulcers are skin changes, corona phlebectatica, higher body mass index and popliteal vein reflux. During a 13.4-year follow-up period, 57.8% (4.3%/year) of all chronic venous disease patients showed progression of the disease. SUMMARY: Studies on the progression of venous pathology show a high progression rate of chronic venous disease. More follow-up studies are still needed to get better information about the risk of varicose vein patients for progression to venous leg ulcers and to answer the question which patients may benefit from early varicose vein interventions. PMID- 25729076 TI - Persistent incompetent truncal veins should not be treated immediately. AB - BACKGROUND: The traditional attitude for the treatment of chronic venous disorder is to systematically treat incompetent truncal veins. We wanted to evaluate the outcomes of not treating all incompetent truncal veins with regard to our experience of focusing the treatment to the varicose tributaries. METHODS: Retrospective study on all procedures of surgical treatment consecutively performed for varicose veins by single phlebectomy with preservation of a refluxing great saphenous vein (GSV), according to the principles of the ambulatory selective varices ablation under local anesthesia (ASVAL) during four years of practice. The clinical and hemodynamic outcomes have been evaluated at eight days, one year, and once a year. RESULTS: We have included 1212 lower limbs (LLs) that underwent consecutive ASVAL procedures in 816 patients (611 women and 205 men) aged between 19 and 93 years (mean age 53.7 years). The CEAP Class C classification was C0-C1 = 0%; C2 = 85.6%; C3 = 5.4%; C4 = 7.8%; C5 = 0.7%; C6 = 0.7%. Symptoms were present in 854 cases (70.5%). A thrombosis of the GSV was diagnosed at eight days postoperative in 13 cases (1.1%). A total of 1010 LLs were followed after the first postoperative year (mean follow-up of 44.5 months). A secondary major procedure was done in 30 cases during the follow-up: a striping of the GSV in nine cases and a redo phlebectomy in 21 cases. The cumulative incidence of a persistent or recurrent GSV reflux, of a varicose recurrence, and of secondary major procedure at five years after life table analysis was 33.8%, 13%, and 4.5%, respectively. A GSV reflux extended above plus below the knee and multiple connections of the varicose tributaries to the GSV at the calf were associated with a varicose recurrence (respectively 66.7% versus 55.3% p < 0.05 and 46.7% versus 12.8% p < 0.05). CONCLUSION: A treatment limited to the varicose tributaries by phlebectomy is safe and efficient at midterm with preservation of the main veins of the superficial venous system. It can be performed in a large group of patients thanks to a proper exclusion of cases with advanced chronic venous disorder. Therefore, the systematic treatment of an incompetent truncal vein is not relevant in the majority of the cases. PMID- 25729077 TI - Debate: should persistent incompetent truncal veins be treated immediately? The case in support of the statement. AB - BACKGROUND: Debate continues as to the best method of treating patients with varicose veins and which will lead to durable clinical outcomes. Many modern techniques of treating varicose veins rely on ablation of the saphenous vein alone or in combination with phlebectomy or sclerotherapy of varices. However, it has been suggested that methods which leave the saphenous trunk untreated may result in similar outcomes. METHODS: A search of medical databases was made for literature which compared the outcomes of saphenous vein stripping, sclerotherapy and modern methods of vein ablation. SYNTHESIS: Surgical methods which have been used range from simple phlebectomy, ligation of the saphenous trunk to stripping of the saphenous vein. Systematic comparison of striping of the saphenous vein in addition to ligation of the sapheno-femoral junction appears to improve the outcome of varicose veins surgery compared to saphenous ligation alone. The 21st century endovenous treatments for varicose veins all rely on ablating the saphenous trunk. Duplex ultrasound studies show some variation in the efficacy of saphenous ablation with these methods. However, a randomised clinical trial shows similar patient reported outcomes with all endovenous techniques and surgical stripping of the saphenous vein. A clinical series shows that after endovenous thermal ablation recurrent varices arise in residual sections of saphenous trunk, accessory veins and residual tributaries. CONCLUSIONS: Studies based on clinical criteria require follow-up of about six years to yield reliable data. Before this time varices may be forming but cannot be detected clinically and over-optimistic results of treatment are reported. Data from surgical and endovenous treatment studies suggest that the more extensive and effective the ablation of saphenous trunks, accessory veins and tributaries, the better the long-term outcome that is achieved. PMID- 25729078 TI - Position of the European college of phlebology. AB - Chronic venous disease is a common condition, bearing significant morbidity to patients. It is predicted that the population suffering from this disease will significantly increase in the coming years, with a growing demand for specialists in the field of phlebology. Training and delivery of services are highly heterogeneous in the European Union. The establishment of the European College of Phlebology marks the opportunity to address these differences from a European perspective, with the aim of providing all patients with standardised, high quality, accessible medical care. In this paper, we review the current status of phlebology from a European and an international perspective, as well as highlighting the current and future roles of the European College of Phlebology. PMID- 25729079 TI - The Shape of Ecosystem Management to Come: Anticipating Risks and Fostering Resilience. AB - Global change is increasingly challenging the sustainable provisioning of ecosystem services to society. Addressing future uncertainty and risk has therefore become a central problem of ecosystem management. With risk management and resilience-based stewardship, two contrasting approaches have been proposed to address this issue. Whereas one is concentrated on anticipating and mitigating risks, the other is focused on fostering the ability to absorb perturbations and maintain desired properties. While they have hitherto been discussed largely separately in the literature, I here propose a unifying framework of anticipating risks and fostering resilience in ecosystem management. Anticipatory action is advocated when the predictability of risk is high and sufficient knowledge to address it is available. Conversely, in situations in which predictability and knowledge are limited, resilience-based measures are paramount. I conclude that, by adopting a purposeful combination of insights from risk and resilience research, we can make ecosystem services provisioning more robust to future uncertainty and change. PMID- 25729080 TI - Beyond the spine: a new clinical research priority. AB - Over the past two decades, clinical research within the chiropractic profession has focused on the spine and spinal conditions, specifically neck and low back pain. However, there is now a small group of chiropractors with clinical research training that are shifting their focus away from traditional research pursuits towards new and innovative areas. Specifically, these researchers are now delving into areas such as brain injury, work disability prevention, undifferentiated chest pain, hip osteoarthritis, and prevention of pain in children and adolescents to name a few. In this paper, we highlight recent research in these new areas and discuss how clinical research efforts in musculoskeletal areas beyond the spine can benefit patient care and the future of the chiropractic profession. PMID- 25729081 TI - Tuberculosis of the neuromusculoskeletal system: a review of two cases presenting as chiropractic patients. AB - Tuberculosis caused by Mycobacterium tuberculosis is a major public heath problem world-wide, particularly in low-income countries. Increased number of immunocompromised patients and immigration from countries where tuberculosis is endemic has resulted in increased number of cases in high-income countries. Tuberculosis can affect any organ system, but is of particular interest to chiropractors when it affects the neuromusculoskeletal system. Patients with tuberculosis of the neuromusculoskeletal system can present with mechanical low back pain or with complex neurologic deficits. The aim of this paper is to highlight the importance of considering a diagnosis of tuberculosis in susceptible populations and the devastating consequences of the disease. The epidemiology, clinical features and management of tuberculosis will also be presented to facilitate early diagnosis, appropriate referral and multidisciplinary care of these patients. PMID- 25729082 TI - Evidence-based prognostication in a case of sciatica. AB - OBJECTIVE: To present an evidence-based case report on the prognosis of a patient with sciatica. CASE: A 43-year-old man presented with right-sided buttock and lower extremity pain and numbness of 10 weeks' duration. Magnetic resonance imaging revealed a lumbosacral disc herniation. Straight leg raise testing provoked the patient's right sciatic pain, and neurologic examination revealed a diminished right Achilles tendon reflex and mild hypoesthesia along the patient's outer right foot. OUTCOME: PubMed was searched and two cohort studies relevant to sciatic prognosis were found. These articles were critically appraised for their validity, importance, and applicability in making a prognostic estimate for this particular patient. Based on the appraised research evidence, and the confidence intervals calculated therein, the overall prognosis for sciatic pain recovery with conservative care was estimated as favourable for this patient, though sensory recovery (even with surgical care) was not. SUMMARY: This case report illustrates how to use research literature in estimating the clinical prognosis for an individual patient, and how this can be useful towards clinical decision making concerning treatment. PMID- 25729083 TI - Chiropractic management of postpartum pubic symphysis diastasis: A case report. AB - This case report describes the chiropractic management of a 30-year-old female patient with severe postpartum pelvic pain secondary to pubic symphysis diastasis. No literature was found on the chiropractic management of postpartum symphysis pubis diastasis. The existing literature concerning chiropractic care for symphysis pubis dysfunction during pregnancy is limited and indicates a potential benefit. Separation of the pubic symphysis may include ligamentous injury to the sacroiliac joints and may lead to chronic pain. Pubic symphysis separation of 17 millimeters was present on digital radiograph. Management consisted of chiropractic adjustments, trigger point release, electrical stimulation, moist heat, sacroiliac belt, and specific stabilizing exercises. The patient's pain improved immediately following treatment on the initial visit. Pain was reduced from 8/10 VAS at the first visit to 2/10 at the fourth visit. She was able to resume normal activities and reached a final pain level of 1/10. The diastasis was reduced by 7 millimeters at 14-weeks post radiograph for a final separation of just under 10 millimeters. Collaboration between obstetricians, midwives and chiropractors may be warranted. PMID- 25729084 TI - Treatment of a patient with posterior cortical atrophy (PCA) with chiropractic manipulation and Dynamic Neuromuscular Stabilization (DNS): A case report. AB - OBJECTIVE: Posterior cortical atrophy (PCA) is a rare progressive neurodegenerative syndrome which unusual symptoms include deficits of balance, bodily orientation, chronic pain syndrome and dysfunctional motor patterns. Current research provides minimal guidance on support, education and recommended evidence-based patient care. This case reports the utilization of chiropractic spinal manipulation, dynamic neuromuscular stabilization (DNS), and other adjunctive procedures along with medical treatment of PCA. CLINICAL FEATURES: A 54-year-old male presented to a chiropractic clinic with non-specific back pain associated with visual disturbances, slight memory loss, and inappropriate cognitive motor control. After physical examination, brain MRI and PET scan, the diagnosis of PCA was recognized. INTERVENTION AND OUTCOME: Chiropractic spinal manipulation and dynamic neuromuscular stabilization were utilized as adjunctive care to conservative pharmacological treatment of PCA. Outcome measurements showed a 60% improvement in the patient's perception of health with restored functional neuromuscular pattern, improvements in locomotion, posture, pain control, mood, tolerance to activities of daily living (ADLs) and overall satisfactory progress in quality of life. Yet, no changes on memory loss progression, visual space orientation, and speech were observed. CONCLUSION: PCA is a progressive and debilitating condition. Because of poor awareness of PCA by physicians, patients usually receive incomplete care. Additional efforts must be centered on the musculoskeletal features of PCA, aiming enhancement in quality of life and functional improvements (FI). Adjunctive rehabilitative treatment is considered essential for individuals with cognitive and motor disturbances, and manual medicine procedures may be consider a viable option. PMID- 25729085 TI - Diagnosis of a 64-year-old patient presenting with suspected lumbar spinal stenosis: an evidence-based case report. AB - OBJECTIVE: To present an evidence-based case report on the diagnosis of a patient with suspected lumbar spinal stenosis (LSS). CASE: A 64-year-old man presented with signs and symptoms suggestive of LSS, but physical examination and diagnostic imaging findings were inconclusive. Other co-morbidities included diabetes, congestive heart failure, and left hip joint osteoarthritis. OUTCOME: PubMed was searched for systematic reviews of diagnostic studies on LSS. Two recent articles were found and appraised with respect to their validity, importance, and applicability in diagnosing the current patient. Copies of his magnetic resonance imaging were also obtained and used in combination with the appraised literature, including diagnostic test specificities and likelihood ratios, to confirm an LSS diagnosis. SUMMARY: This case illustrates how research evidence can be used in clinical practice, particularly in the diagnosis of an individual patient. PMID- 25729087 TI - A variant extensor indicis muscle and the branching pattern of the deep radial nerve could explain hand functionality and clinical symptoms in the living patient. AB - The purpose of this study is to document the topographic anatomy of an extensor indicis (EI) muscle with a double tendon and the associated distribution of the deep branch of the radial nerve (DBRN). Both EI tendons were positioned deep to the tendons of the extensor digitorum as they traversed the dorsal osseofibrous tunnel. They then joined the medial slips of the extensor expansion of the second and third digits. In all other dissected forearms, a tendon of the EI muscle joined the medial slip of the extensor expansion to the index finger. The DBRN provided short branches to the superficial extensor muscles, long branches to the abductor pollicis longus and extensor pollicis brevis muscles, and terminated as the posterior interosseous nerve. Descending deep to the extensor pollicis longus muscle, the posterior interosseous nerve sent branches to the extensor pollicis brevis and EI muscles. Understanding of the topographic anatomy of an EI with a double tendon, and the associated distribution of the DBRN, may contribute to accurate diagnosis and treatment of hand lesions. PMID- 25729086 TI - Is there a role for neck manipulation in elderly falls prevention? - An overview. AB - Many risk factors exist for falls in the elderly. Dizziness is an important risk factor for such falls. Spinal pain has also been identified as a risk factor for these falls. In this overview of the literature, we examine studies, including trials, of neck manipulation for neck pain, unsteadiness and falls risk relevant to the elderly. We also examine two related, but not mutually exclusive, mechanisms through which a putative beneficial effect may be mediated. These are the effects of neck manipulation on neck pain and on non-specific dizziness. We focus on the available evidence primarily in terms of clinical data rather than laboratory-based measures of balance. We conclude that chiropractors may have a role in falls prevention strategies in the subpopulation of the elderly that suffer from mechanical neck pain or dysfunction and non-specific dizziness. However, this role remains to be rigorously studied and properly defined. PMID- 25729088 TI - Ischemic compression and joint mobilisation for the treatment of nonspecific myofascial foot pain: findings from two quasi-experimental before-and-after studies. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of myofascial therapy involving ischemic compression on trigger points in combination with mobilization therapy on patients with chronic nonspecific foot pain. STUDY DESIGN: Two quasi-experimental before-and-after studies involving two different baseline states. METHOD: Foot pain patients at a private clinic were divided into two separate cohorts: A, custom orthotic users; and B, non-users. In Study A, 31 users received 15 experimental treatments consisting of ischemic compressions on trigger points and mobilization of articulations through the foot immediately after study enrollment. In study B, ten non-users were prescribed a soft prefabricated insole and were monitored for five weeks before subsequently receiving 15 experimental treatments after the initial five-week delay. OUTCOME MEASURES: The Foot Function Index (FFI) and patients' perceived improvement score (PIS) on a scale from 0% to 100%. RESULTS: The Study A group (n=31) maintained a significant reduction in the FFI at all three follow-up evaluations. Mean improvement from baseline in FFI was 47%, 49% and 56% at 0, 1 and 6 months, respectively, post-treatment. Mean PIS was 58%, 57%, and 58%, again at 0, 1 and 6 months post-treatment. For the Study B group, mean improvement in FFI was only 19% after the monitoring period, and 64% after the experimental treatment period. Mean PIS was 31% after monitoring, and 78% after experimental treatment. In repeated measures analyses, experimental treatment was associated with a significant main effect in both of these before-and after studies (all P values<0.01). CONCLUSION: Combined treatment involving ischemic compression and joint mobilization for chronic foot pain is associated with significant improvements in functional and self-perceived improvement immediately and at up to six-months post-treatment. Further validation of this treatment approach within a randomized controlled trial is needed. PMID- 25729090 TI - Disaggregation of legacy soil data using area to point kriging for mapping soil organic carbon at the regional scale. AB - Legacy data in the form of soil maps, which often have typical property measurements associated with each polygon, can be an important source of information for digital soil mapping (DSM). Methods of disaggregating such information and using it for quantitative estimation of soil properties by methods such as regression kriging (RK) are needed. Several disaggregation processes have been investigated; preferred methods include those which include consideration of scorpan factors and those which are mass preserving (pycnophylactic) making transitions between different scales of investigation more theoretically sound. Area to point kriging (AtoP kriging) is pycnophylactic and here we investigate its merits for disaggregating legacy data from soil polygon maps. Area to point regression kriging (AtoP RK) which incorporates ancillary data into the disaggre-gation process was also applied. The AtoP kriging and AtoP RK approaches do not involve collection of new soil measurements and are compared with disaggregation by simple rasterization. Of the disaggregation methods investigated, AtoP RK gave the most accurate predictions of soil organic carbon (SOC) concentrations (smaller mean absolute errors (MAEs) of cross-validation) for disaggregation of soil polygon data across the whole of Northern Ireland. Legacy soil polygon data disaggregated by AtoP kriging and simple rasterization were used in a RK framework for estimating soil organic carbon (SOC) concentrations across the whole of Northern Ireland, using soil sample data from the Tellus survey of Northern Ireland and with other covariates (altitude and airborne radiometric potassium). This allowed direct comparison with previous analysis of the Tellus survey data. Incorporating the legacy data, whether from simple rasterization of the polygons or AtoP kriging, substantially reduced the MAEs of RK compared with previous analyses of the Tellus data. However, using legacy data disaggregated by AtoP kriging in RK resulted in a greater reduction in MAEs. A jack-knife procedure was also performed to determine a suitable number of additional soil samples that would need to be collected for RK of SOC for the whole of Northern Ireland depending on the availability of ancillary data. We recommend i) if only legacy soil polygon map data are available, they should be disaggregated using AtoP kriging, ii) if ancillary data are also available legacy data should be disaggregated using AtoP RK and iii) if new soil measurements are available in addition to ancillary and legacy soil map data, the legacy soil map data should be first disaggregated using AtoP kriging and these data used along with ancillary data as the fixed effects for RK of the new soil measurements. PMID- 25729091 TI - Revisit of the Ramp Filter. AB - An important part of the filtered backprojection (FBP) algorithm is the ramp filter. This paper derives the discrete version of the ramp filter in the Fourier domain and studies the windowing effects. When a window function is used to control the noise, the image amplitude will be affected and reduced. A simple remedy is proposed to improve the image accuracy when a window function must be used. PMID- 25729089 TI - Control and utilization of ruthenium and rhodium metal complex excited states for photoactivated cancer therapy. AB - The use of visible light to produce highly selective and potent drugs through photodynamic therapy (PDT) holds much potential in the treatment of cancer. PDT agents can be designed to follow an O2-dependent mechanism by producing highly reactive species such as 1O2 and/or an O2 independent mechanism through processes such as excited state electron transfer, covalent binding to DNA or photoinduced drug delivery. Ru(II)-polypyridyl and Rh2(II,II) complexes represent an important class of compounds that can be tailored to exhibit desired photophysical properties and photochemical reactivity by judicious selection of the ligand set. Complexes with relatively long-lived excited states and planar, intercalating ligands localize on the DNA strand and photocleave DNA through 1O2 production or guanine oxidation by the excited state of the chromophore. Photoinduced ligand substitution occurs through the population of triplet metal centered (3MC) excited states and facilitates covalent binding of the metal complex to DNA in a mode similar to cisplatin. Ligand photodissociation also provides a route to selective drug delivery. The ability to construct metal complexes with desired light absorbing and excited state properties by ligand variation enables the design of PDT agents that can potentially provide combination therapy from a single metal complex. PMID- 25729092 TI - Associations of maternal and adolescent religiosity and spirituality with adolescent alcohol use in Chile: Implications for social work practice among Chilean social workers. AB - To inform social work practice with adolescents who may consume alcohol, we examined if alcohol use among Chilean adolescents varied as a function of their mothers' and their own religiosity and spirituality. Data were from 787 Chilean adolescents and their mothers. Adolescent spirituality was a protective factor against more deleterious alcohol use. Parental monitoring and alcohol using opportunities mediated the associations. The practice of religious behaviors by themselves without meaningful faith were not associated with alcohol use among adolescents. Implications for social work practice are discussed. PMID- 25729093 TI - Nonlocal Effect on Stiffness Measurements of a Collagen Molecule. AB - Accurate modeling of collagen molecules including their stiffness is essential for our understanding of mechanics of collagen fibers and tissues where these fibers play a prominent role. Studies of mechanical properties of collagen molecules employing various experimental methods and molecular dynamics (MD) simulations yield a broad range of values of the modulus of elasticity. The effect of nonlocal elasticity on the molecule stiffness derived from experiments and simulations is assessed in this brief. The estimate of the correction accounting for the nonlocal effect utilizes the exact solution of the nonlocal elasticity theory for one-dimensional elastic bars. It is demonstrated that the effect of nonlocal elasticity on the stiffness of collagen molecules can be neglected. PMID- 25729094 TI - TOXICOLOGY AND TREATMENT: MEDICAL AUTHORITIES AND SNAKE-BITE IN THE MIDDLE AGES. AB - By end of the thirteenth century, surgeons and university-trained physicians in Western Europe had a plethora of authorities from the Greco-Roman and Arabic tradition from which to consult for the treatment of snake-bites. Venomous animals receive the largest share of attention in the literature on biting animals. Nearly all of the sources focus on the idea of the animal biting or puncturing the skin's surface with their mouths and few poisonous animals where the venom is passed on through the skin or hairs are mentioned. Venomous animals frequently appear in discussions on poisons in general, with poisons of animal, mineral or vegetable origin. The bulk of the discourse dealt with venomous snakes and rabid dogs, the latter considered venomous due to its 'poisonous' saliva, and to a lesser extent, scorpions and spiders. In general the bites of non-venomous animals received scant attention. Unlike modern taxonomical categories, medieval categories for animals were usually connected to the movement or the locale of the animal: flying animals, animals in water, land animals (which mainly covered quadrupeds), and crawling animals. It is in the latter category that snakes were located, along with lizards. PMID- 25729095 TI - Our Cosmic Insignificance. AB - The universe that surrounds us is vast, and we are so very small. When we reflect on the vastness of the universe, our humdrum cosmic location, and the inevitable future demise of humanity, our lives can seem utterly insignificant. Many philosophers assume that such worries about our significance reflect a banal metaethical confusion. They dismiss the very idea of cosmic significance. This, I argue, is a mistake. Worries about cosmic insignificance do not express metaethical worries about objectivity or nihilism, and we can make good sense of the idea of cosmic significance and its absence. It is also possible to explain why the vastness of the universe can make us feel insignificant. This impression does turn out to be mistaken, but not for the reasons typically assumed. In fact, we might be of immense cosmic significance-though we cannot, at this point, tell whether this is the case. PMID- 25729096 TI - A message from the editor. PMID- 25729097 TI - Update on the U.S. public health response to the Ebola outbreak. PMID- 25729099 TI - Progress in Women's Health: 1985-2015. PMID- 25729100 TI - Women's health: 30 years of progress in the U.S. Department of Health and Human Services. PMID- 25729101 TI - Health communications and community mobilization during an Ebola response: partnerships with community and faith-based organizations. PMID- 25729102 TI - Patient-physician language concordance and use of preventive care services among limited English proficient Latinos and Asians. AB - OBJECTIVES: Patient-physician language concordance among limited English proficient (LEP) patients is associated with better outcomes for specific clinical conditions. Whether or not language concordance contributes to use of specific preventive care services is unclear. METHODS: We pooled data from the 2007 and 2009 California Health Interview Surveys to examine mammography, colorectal cancer (CRC) screening, and influenza vaccination use among self identified LEP Latino and Asian (i.e., Chinese, Korean, and Vietnamese) immigrants. We defined language concordance by respondents reporting that their physician spoke their non-English language. Analyses were completed in 2013-2014. RESULTS: Language concordance did not appear to facilitate mammography use among Latinas (adjusted odds ratio [AOR] = 1.02, 95% confidence interval [CI] 0.72, 1.45). Among Asian women, we could not definitively exclude a negative association of language concordance with mammography (AOR=0.55, 95% CI 0.27, 1.09). Patient-physician language concordance was associated with lower odds of CRC screening among Asians but not Latinos (Asian AOR=0.50, 95% CI 0.29, 0.86; Latino AOR=0.85, 95% CI 0.56, 1.28). Influenza vaccination did not differ by physician language use among either Latinos or Asians. CONCLUSIONS: Patient physician language concordance was not associated with higher use of mammography, CRC screening, or influenza vaccination. Language concordance was negatively associated with CRC screening among Asians for reasons that require further research. Future research should isolate the impact of language concordance on the use of preventive care services from health system factors. PMID- 25729103 TI - Screening and monitoring in men prescribed testosterone therapy in the U.S., 2001 2010. AB - OBJECTIVES: The Endocrine Society recommends testosterone therapy only in men with low serum testosterone levels, consistent symptoms of hypogonadism, and no signs of prostate cancer. We assessed screening and monitoring patterns in men receiving testosterone therapy in the U.S. METHODS: We conducted a retrospective cohort study of 61,474 men aged >=40 years, and with data available in one of the nation's largest commercial insurance databases, who received at least one prescription for testosterone therapy from 2001 to 2010. RESULTS: In the 12 months before initiating treatment, 73.4% of male testosterone users received a serum testosterone test and 60.7% received a prostate-specific antigen (PSA) test. Among men who were tested, 19.5% did not meet Endocrine Society guidelines for low testosterone. In the 12 months after initiating treatment, 52.4% received a serum testosterone test and 43.3% received a PSA test. Multivariable analyses showed that those seen by either an endocrinologist or urologist were more likely to receive appropriate tests. CONCLUSIONS: A substantial number of men prescribed testosterone therapy did not receive testosterone or PSA testing before or after initiating treatment. In addition, almost one out of five treated men had baseline serum testosterone values above the threshold defined as normal by the Endocrine Society. Men treated by endocrinologists and urologists were more likely to have been treated according to guideline recommendations than men treated by other specialties, including primary care. PMID- 25729104 TI - Adding industry and occupation questions to the behavioral risk factor surveillance system: new opportunities in public health surveillance. AB - OBJECTIVES: Industry and occupation variables are overlooked in many public health surveillance efforts, yet they are useful for describing the burden and distribution of various public health diseases, behaviors, and conditions. This study is the first ever analysis of the Colorado Behavioral Risk Factor Surveillance System (BRFSS) to describe chronic conditions and risk behaviors by occupation. It is intended to provide a new perspective on this existing data source and demonstrate the value of occupation as a core demographic variable for public health research, policy, and practice. METHODS: Two standardized employment questions were included in the 2012 Colorado BRFSS survey and administered to eligible survey respondents who were employed, self-employed, or out of work for less than one year. Occupation data were coded using the National Institute for Occupational Safety and Health (NIOSH) Industry and Occupation Computerized Coding System. We analyzed health behaviors and conditions by major occupation groups. We calculated prevalence estimates and 95% confidence intervals (CIs). RESULTS: The prevalence of chronic conditions, health statuses, and risk behaviors (e.g., smoking and seatbelt use) varied significantly by occupation. For example, compared with all workers (93.6%, 95% CI 92.7, 94.5), significantly fewer workers in farming, forestry, fishing and construction, extraction jobs (87.0%, 95% CI 82.0, 92.0) reported always or nearly always wearing a seatbelt while driving. Additionally, significantly more office and administrative support workers (27.5%, 95% CI 22.5, 32.4) compared with all workers (20.6%, 95% CI 19.3, 22.0) were obese. Further observation and research is needed to understand the effects of occupation on health outcomes and behaviors. CONCLUSION: There are no other Colorado state-level datasets that link health behaviors and chronic conditions with occupation. This study shows that the prevalence of chronic conditions and risk behaviors varies substantially by occupation. Other states conducting the BRFSS may choose to adopt the NIOSH industry and occupation module and add other questions to further investigate health issues by occupation. PMID- 25729105 TI - Addressing immunization registry population inflation in adolescent immunization rates. AB - OBJECTIVE: While U.S. adolescent immunization rates are available annually at national and state levels, finding pockets of need may require county or sub county information. Immunization information systems (IISs) are one tool for assessing local immunization rates. However, the presence of IIS records dating back to early childhood and challenges in capturing mobility out of IIS areas typically leads to denominator inflation. We examined the feasibility of weighting adolescent immunization records by length of time since last report to produce more accurate county adolescent counts and immunization rates. METHODS: We compared weighted and unweighted adolescent denominators from the Oregon ALERT IIS, along with county-level Census Bureau estimates, with school enrollment counts from Oregon's annual review of seventh-grade school immunization compliance for public and private schools. Adolescent immunization rates calculated using weighted data, for the state as a whole, were also checked against comparable National Immunization Survey (NIS) rates. RESULTS: Weighting individual records by the length of time since last activity substantially improved the fit of IIS data to county populations for adolescents. A nonlinear logarithmic (ogive) weight produced the best fit to the school count data of all examined estimates. Overall, the ogive weighted results matched NIS adolescent rates for Oregon. CONCLUSION: The problem of mobility-inflated counts of teenagers can be addressed by weighting individual records based on time since last immunization. Well-populated IISs can rely on their own data to produce adolescent immunization rates and find pockets of need. PMID- 25729107 TI - Law, medicine, and public health preparedness: the case of Ebola. PMID- 25729109 TI - Big data and public health: navigating privacy laws to maximize potential. PMID- 25729111 TI - Student column: Using academic detailing to improve childhood influenza vaccination rates in San Diego. PMID- 25729112 TI - Learning, Misallocation, and Technology Adoption: Evidence from New Malaria Therapy in Tanzania. AB - I study how the misallocation of new technology to individuals who have low ex post returns to its use affects learning and adoption behavior. I focus on antimalarial treatment, which is frequently over-prescribed in many low-income country contexts where diagnostic tests are inaccessible. I show that misdiagnosis reduces average therapeutic effectiveness, because only a fraction of adopters actually have malaria, and slows the rate of social learning due to increased noise. I use data on adoption choices, the timing and duration of fever episodes, and individual blood slide confirmations of malarial status from a pilot study for a new malaria therapy in Tanzania to show that individuals whose reference groups experienced fewer misdiagnoses exhibited stronger learning effects and were more likely to adopt. PMID- 25729113 TI - Restructuring and aging in a capillary suspension. AB - The rheological properties of capillary suspensions, suspensions with small amounts of an added immiscible fluid, are dramatically altered with the addition of the secondary fluid. We investigate a capillary suspension to determine how the network ages and restructures at rest and under applied external shear deformation. The present work uses calcium carbonate suspended in silicone oil (11 % solids) with added water as a model system. Aging of capillary suspensions and their response to applied oscillatory shear is distinctly different from particulate gels dominated by the van der Waals forces. The suspensions dominated by the capillary force are very sensitive to oscillatory flow, with the linear viscoelastic regime ending at a deformation of only 0.1% and demonstrating power law aging behavior. This aging persists for long times at low deformations or for shorter times with a sudden decrease in the strength at higher deformations. This aging behavior suggests that the network is able to rearrange and even rupture. This same sensitivity is not demonstrated in shear flow where very high shear rates are required to rupture the agglomerates returning the apparent viscosity of capillary suspensions to the same viscosity as for the pure vdW suspension. A transitional region is also present at intermediate water contents wherein the material response depends very strongly on the type, strength, and duration of the external forcing. PMID- 25729114 TI - Basic Conditional Reasoning: How Children Mimic Counterfactual Reasoning. AB - Children approach counterfactual questions about stories with a reasoning strategy that falls short of adults' Counterfactual Reasoning (CFR). It was dubbed "Basic Conditional Reasoning" (BCR) in Rafetseder et al. (Child Dev 81(1):376-389, 2010). In this paper we provide a characterisation of the differences between BCR and CFR using a distinction between permanent and nonpermanent features of stories and Lewis/Stalnaker counterfactual logic. The critical difference pertains to how consistency between a story and a conditional antecedent incompatible with a nonpermanent feature of the story is achieved. Basic conditional reasoners simply drop all nonpermanent features of the story. Counterfactual reasoners preserve as much of the story as possible while accommodating the antecedent. PMID- 25729115 TI - The Role of Contact Line (Pinning) Forces on Bubble Blockage in Microchannels. AB - This paper highlights the influence of contact line (pinning) forces on the mobility of dry bubbles in microchannels. Bubbles moving at velocities less than the dewetting velocity of liquid on the surface are essentially dry, meaning that there is no thin liquid film around the bubbles. For these "dry" bubbles, contact line forces and a possible capillary pressure gradient induced by pinning act on the bubbles and resist motion. Without sufficient driving force (e.g., external pressure), a dry bubble is brought to stagnation. For the first time, a bipartite theoretical model that estimates the required pressure difference across the length of stagnant bubbles with concave and convex back interfaces to overcome the contact line forces and stimulate motion is proposed. To validate our theory, the pressure required to move a single dry bubble in square microchannels exhibiting contact angle hysteresis has been measured. The working fluid was deionized water. The experiments have been conducted on coated glass channels with different surface hydrophilicities that resulted in concave and convex back interfaces for the bubbles. The experimental results were in agreement with the model's predictions for square channels. The predictions of the concave and convex back models were within 19% and 27% of the experimental measurements, respectively. PMID- 25729116 TI - "The Whole Family Suffered, so the Whole Family Needs to Recover": Thematic Analysis of Substance-Abusing Mothers' Family Therapy Sessions. AB - Substance abusing mothers and their children are more likely to experience a range of social, behavioral, and psychological difficulties. Despite the significant challenges faced by these families, little is known about their experiences in treatment. The current study analyzed 12 sessions of family therapy using thematic analysis to identify common themes that arose during substance abusing mothers and their children's discussion during family therapy. Mothers' ages ranged from 28 to 35 years and the children's ages ranged from 12 to 14 years. Four therapy sessions from three families were coded for a total of 12 therapy sessions. An ecological framework was used to classify themes, in which themes related to each level of the families' ecological systems were identified. Thematic analysis of the therapy sessions indicated that mothers and their children primarily discussed topics related to their relational and emotional needs. The findings indicated that substance use disordered mothers and their children have unique treatment needs that should be addressed when the mother seeks treatment. More research is needed to further clarify and confirm the observations in this study. In particular, future research should include a larger sample and quantitative methodology. PMID- 25729117 TI - A Simple Method for Estimating Interactions between a Treatment and a Large Number of Covariates. AB - We consider a setting in which we have a treatment and a potentially large number of covariates for a set of observations, and wish to model their relationship with an outcome of interest. We propose a simple method for modeling interactions between the treatment and covariates. The idea is to modify the covariate in a simple way, and then fit a standard model using the modified covariates and no main effects. We show that coupled with an efficiency augmentation procedure, this method produces clinically meaningful estimators in a variety of settings. It can be useful for practicing personalized medicine: determining from a large set of biomarkers the subset of patients that can potentially benefit from a treatment. We apply the method to both simulated datasets and real trial data. The modified covariates idea can be used for other purposes, for example, large scale hypothesis testing for determining which of a set of covariates interact with a treatment variable. PMID- 25729118 TI - Reliability of using a fixed matrix in coregistration of combined PET-MRI in a split magnet design. AB - We consider the effects of using a fixed linear transformation to match positron emission tomography (PET) and magnetic resonance imaging (MRI) data acquired simultaneously using a split-magnet system. Estimates of the frequency offset in MRI scans were used to calculate geometric variability in MRI reconstruction as a consequence of mis-setting this parameter in addition to repeated estimation of the transformation matrix by manual measurements. None of the measured variability approached the resolution of the PET images so we concluded that a fixed matrix can be reliably used in such a system. PMID- 25729119 TI - Associations between Discussions of Racial and Ethnic Differences in Internationally Adoptive Families and Delinquent Behavior among Korean Adopted Adolescents. AB - Internationally adopted adolescents may have more delinquent behavior than non adopted adolescents. One explanation is these adolescents experience discrimination and loss of culture, and adoptive parents are not adequately addressing these experiences. However, studies have not examined the effects of family discussions of racial and ethnic differences within adoptive families on adopted adolescents' delinquent behavior. To test this relationship, this study utilized data from 111 U.S. internationally adoptive families with 185 South Korean adopted adolescents (55% female, M age = 17.75). During an observational assessment, families discussed the importance of their racial and ethnic differences, and adolescents completed a delinquent behavior questionnaire. Analysis of covariance showed differences in adolescent delinquent behavior across three ways adoptive families discussed racial and ethnic differences; adolescents whose families acknowledged differences had the fewest mean delinquent behaviors. There were no significant differences in delinquent behavior between adolescents whose families acknowledged or rejected the importance of racial and ethnic differences. However, adopted adolescents whose families held discrepant views of differences had significantly more problem behavior than adolescents whose families either acknowledged or rejected the importance of racial and ethnic differences. Clinicians, adoption professionals, and other parenting specialists should focus on building cohesive family identities about racial and ethnic differences, as discrepant views of differences are associated with the most adoptee delinquent behavior. PMID- 25729120 TI - Discrimination of acoustic patterns in rats using the water T-maze. AB - The extraction of abstract rules and their generalization to new items has been proposed to be at the heart of higher cognitive functions such as language. Research with animals has shown that various species can extract rather complex patterns from the input, as well as establish abstract same/different relations. However, much of these findings have been observed after extensive training procedures. Here, we tested rats' capacity to discriminate and generalize tone triplets that entailed a repetition from triplets that followed an ordinal, non repeating pattern following a relatively short discrimination training procedure in a water T-maze. Our findings demonstrate that, under this procedure and after only 12 sessions, rats can learn to discriminate both patterns when a reliable difference in pitch variations is present across them (Experiment 1). When differences in pitch are eliminated (Experiment 2), no discrimination between patterns is found. Results suggest a procedure based on a water T-maze might be used to explore discrimination of acoustic patterns in rodents. PMID- 25729121 TI - Farewell to Diversity? New State Zones of Health Care Service in China's Far West. AB - Using James Scott's (2009) theoretical framework of the interaction between the state and peripheral people, we argue that the welfare state should be regarded as a pull-factor in the context of the state's endeavours to project its power to distant peoples in assigned state zones. Our discussion is based on interviews in Xinyuan County in the Western part of the Xinjiang Uyghur Autonomous Region, China. Presenting current policies and alternative policy options discussed at the local level for providing primary health care in rural China, we argue that decisions made in the implementation process did not respond to the special health needs of mobile pastoralists in the high plains, but were part of the central state logic of homogenising settlement efforts and health care. Der theoretische Ansatz von James Scott zu Expansion von staatlicher Ordnung auf periphere Randgebiete wird auf den Aufbau von Wohlfahrts- und Gesundheitspolitik des modernen Staates angewendet und weiterentwickelt. Anhand mehrjahriger Feldstudien zwischen 2005 und 2009 zur Gesundheitsversorgungsstruktur im Kreis Xinyuan der Autonomen Uighurischen Region Xinjiang in der Volksrepublik China werden zuerst die nationalen Restrukturierungsmabetanahmen vorgestellt und Losungen fur eine bessere Versorgung der halbnomadisierenden kasachischen Hirtenfamilien diskutiert. Lokal entwickelte und an die nomadischen Lebensformen angepasste mobile Losungen zur Gesundheitsfursorge konnten nicht implementiert werden. Die Anstrengungen der staatlichen Akteure sind als Versuch zu sehen, bisher marginalisierte Gruppen aus den peripheren Gebirgsregionen und uber die Integration in eine staatliche Gesundheitsversorgung in den Talern anzusiedeln. PMID- 25729122 TI - The place and practices of well-being in local governance. AB - The concept of well-being has become prominent within national policy goals in the UK since the end of the 1990s. However, the concept of well-being remains ill defined, an instability that is increasingly understood as problematic to policy making. We engage with this terminological instability through an exploration of how the concept of well-being is practised discursively in local governance and critically examine the place of the concept in local policy making. In contrast to the current enthusiasm to define and measure well-being, we argue that the conceptual instability has inherent value for local governance. The concept of well-being is practised through a number of potentially conflicting discourses, but it is exactly this conceptual instability that enables a local negotiation and combination of alternative policy frameworks for local place-shaping strategies. As such, well-being not only is an overarching goal of governance but also contributes to the dynamics of the policy process. PMID- 25729123 TI - Causal Analysis After Haavelmo. AB - Haavelmo's seminal 1943 and 1944 papers are the first rigorous treatment of causality. In them, he distinguished the definition of causal parameters from their identification. He showed that causal parameters are defined using hypothetical models that assign variation to some of the inputs determining outcomes while holding all other inputs fixed. He thus formalized and made operational Marshall's (1890)ceteris paribus analysis. We embed Haavelmo's framework into the recursive framework of Directed Acyclic Graphs (DAGs) used in one influential recent approach to causality (Pearl, 2000) and in the related literature on Bayesian nets (Lauritzen, 1996). We compare the simplicity of an analysis of causality based on Haavelmo's methodology with the complex and nonintuitive approach used in the causal literature of DAGs-the "do-calculus" of Pearl (2009). We discuss the severe limitations of DAGs and in particular of the do-calculus of Pearl in securing identification of economic models. We extend our framework to consider models for simultaneous causality, a central contribution of Haavelmo. In general cases, DAGs cannot be used to analyze models for simultaneous causality, but Haavelmo's approach naturally generalizes to cover them. PMID- 25729124 TI - Slope Estimation of Covariates that Influence Renal Outcome following Renal Transplant Adjusting for Informative Right Censoring. AB - A new statistical model is proposed to estimate population and individual slopes that are adjusted for covariates and informative right censoring. Individual slopes are assumed to have a mean that depends on the population slope for the covariates. The number of observations for each individual is modeled as a truncated discrete distribution with mean dependent on the individual subjects' slopes. Our simulation study results indicated that the associated bias and mean squared errors for the proposed model were comparable to those associated with the model that only adjusts for informative right censoring. The proposed model was illustrated using renal transplant dataset to estimate population slopes for covariates that could impact the outcome of renal function following renal transplantation. PMID- 25729125 TI - Self-consistent magnetic properties of magnetite tracers optimized for magnetic particle imaging measured by ac susceptometry, magnetorelaxometry and magnetic particle spectroscopy. AB - Sensitivity and spatial resolution in Magnetic Particle Imaging are affected by magnetic properties of the nanoparticle tracers used during imaging. Here, we have carried out a comprehensive magnetic characterization of single-core iron oxide nanoparticles that were designed for MPI. We used ac susceptometry, fluxgate magnetorelaxometry, and magnetic particle spectroscopy to evaluate the tracer's magnetic core size, hydrodynamic size, and magnetic anisotropy. Our results present a self-consistent set of magnetic and structural parameters for the tracers that is consistent with direct measurements of size using transmission electron microscopy and dynamic light scattering and that can be used to better understand their MPI performance. PMID- 25729126 TI - Individual responsiveness to shock and colony-level aggression in honey bees: evidence for a genetic component. AB - The phenotype of the social group is related to phenotypes of individuals that form that society. We examined how honey bee colony aggressiveness relates to individual response of male drones and foraging workers. Although the natural focus in colony aggression has been on the worker caste, the sterile females engaged in colony maintenance and defense, males carry the same genes. We measured aggressiveness scores of colonies and examined components of individual aggressive behavior in workers and haploid sons of workers from the same colony. We describe for the first time, that males, although they have no stinger, do bend their abdomen (abdominal flexion) in a posture similar to stinging behavior of workers in response to electric shock. Individual worker sting response and movement rates in response to shock were significantly correlated with colony scores. In the case of drones, sons of workers from the same colonies, abdominal flexion significantly correlated but their movement rates did not correlate with colony aggressiveness. Furthermore, the number of workers responding at increasing levels of voltage exhibits a threshold-like response, whereas the drones respond in increasing proportion to shock. We conclude that there are common and caste-specific components to aggressive behavior in honey bees. We discuss implications of these results on social and behavioral regulation and genetics of aggressive response. PMID- 25729127 TI - Grocery Shopping How Individuals and Built Environments Influence Choice of Travel Mode. AB - This research investigated the influences of socioeconomic characteristics of individual travelers and of the environments where the travelers live and shop on choice of travel mode for grocery shopping. The data on travel for grocery shopping came from 2,001 respondents to the 2009 Seattle Obesity Study survey in King County, Washington. Eighty-eight percent of the respondents drove to their grocery stores, whereas 12% used transit or taxis, walked, biked, or carpooled. The addresses of 1,994 homes and 1,901 primary grocery stores used by respondents were geographically coded. The characteristics of built environments in the neighborhoods around homes and grocery stores and the distances between those homes and stores were measured in a geographic information system. Four binary logistic models estimated the impact of individual socioeconomic characteristics, distance, and built environments around homes and grocery stores on the travel mode used for grocery shopping. Fourteen variables were significantly related to mode choice. The strongest predictors of driving to the grocery store were more cars per adult household member, more adults per household, living in a single family house, longer distances between homes and grocery stores (both the stores used and the nearest stores), and more at-ground parking around the grocery store used. Higher street density, more quick-service restaurants around homes, and more nonchain grocery stores near the primary grocery store used were related to not driving. Results suggested that reductions of distances between homes and grocery stores, clustering of grocery stores and other food establishments, and reductions in the amount of the parking around them could lead to less driving for grocery shopping. PMID- 25729128 TI - What is the Role of Housing Policy? Considering Free Choice and Social Science Evidence. PMID- 25729129 TI - Editorial. PMID- 25729130 TI - What is evidence-based behavior analysis? AB - Although applied behavior analysts often say they engage in evidence-based practice, they express differing views on what constitutes "evidence" and "practice." This article describes a practice as a service offered by a provider to help solve a problem presented by a consumer. Solving most problems (e.g., increasing or decreasing a behavior and maintaining this change) requires multiple intervention procedures (i.e., a package). Single-subject studies are invaluable in investigating individual procedures, but researchers still need to integrate the procedures into a package. The package must be standardized enough for independent providers to replicate yet flexible enough to allow individualization; intervention manuals are the primary technology for achieving this balance. To test whether the package is effective in solving consumers' problems, researchers must evaluate outcomes of the package as a whole, usually in group studies such as randomized controlled trials. From this perspective, establishing an evidence-based practice involves more than analyzing the effects of discrete intervention procedures on behavior; it requires synthesizing information so as to offer thorough solutions to problems. Recognizing the need for synthesis offers behavior analysts many promising opportunities to build on their existing research to increase the quality and quantity of evidence-based practices. PMID- 25729132 TI - The history of behavior analysis in manitoba: a sparsely populated canadian province with an international influence on behavior analysis. AB - This article examines the convergence of factors that led to behavior analysis taking root, flourishing, and bearing fruit in a prairie province of Canada. In the latter half of the 1960s, Garry Martin and Joseph Pear began teaching behavior-analytic courses at the University of Manitoba. They and their students then initiated behavioral treatment and research programs at the Manitoba Developmental Center and St.Amant, the two main residential facilities for persons with intellectual disabilities and autism. Since that time, behavior analysis in Manitoba has flourished, and the knowledge and skills gained have been shared with other behavior analysts throughout the world through conferences, articles, and books. Behavior-analytic books by authors who live and work in Manitoba have been translated into eight languages. Moreover, University of Manitoba graduates in behavior analysis have helped to spread knowledge of behavior analysis throughout the world, and a number have achieved highly influential positions and widespread recognition within the discipline. PMID- 25729131 TI - Behavioral activation for depression in older adults: theoretical and practical considerations. AB - Late-life depression (LLD) is a major public health concern that can have devastating effects on older individuals and their families. Behavioral theories predict that decreases in response-contingent positive reinforcement and increases in negatively reinforced avoidance behaviors, often accompanied by aversive life events, result in the selection and maintenance of depression. Based on these theories, behavioral activation treatments for depression are designed to facilitate structured increases in enjoyable activities that increase opportunities for contact with positive reinforcement. We discuss the applicability of behavioral models for LLD, and we briefly review current behavioral activation interventions for LLD with an emphasis on implications for future behavior-analytic research. Behavioral activation has been demonstrated to be effective in reducing depression and increasing healthy behavior in older adults. Potential challenges and considerations for future research are discussed. We suggest that applied behavior analysts and clinical behavior analysts are particularly well suited to improve and expand on the knowledge base and practical application of behavioral activation interventions with this population. PMID- 25729134 TI - Don'T wag the dog: extending the reach of applied behavior analysis. AB - We argue that the field of behavior analysis would be best served if behavior analysts worked to extend the reach of behavioral services into a more diverse range of settings and with more varied populations, with an emphasis on the establishment of new career opportunities for graduating students. This is not a new proposal, but it is a tall order; it is not difficult to see why many would choose a surer route to gainful employment. Currently, the most fruitful career path for behavior analysts in practice is in the area of autism and developmental disabilities. For the continued growth of the field of behavior analysis, however, it is important to foster new career opportunities for those trained as behavior analysts. Toward this end, we identify several fields that seem well suited to behavior analysts and summarize the training requirements and likely professional outcomes for behavior analysts who pursue education and certification in these fields. These fields require relatively little additional formal training in the hopes of minimizing the response effort necessary for individuals who have already completed a rigorous program of graduate study in behavior analysis. PMID- 25729133 TI - A study in the founding of applied behavior analysis through its publications. AB - This article reports a study of the founding of applied behavior analysis through its publications. Our methods included hand searches of sources (e.g., journals, reference lists), search terms (i.e., early, applied, behavioral, research, literature), inclusion criteria (e.g., the field's applied dimension), and (d) challenges to their face and content validity. Our results were 36 articles published between 1959 and 1967 that we organized into 4 groups: 12 in 3 programs of research and 24 others. Our discussion addresses (a) limitations in our method (e.g., the completeness of our search), (b) challenges to the validity of our methods and results (e.g., convergent validity), and (c) priority claims about the field's founding. We conclude that the claims are irresolvable because identification of the founding publications depends significantly on methods and because the field's founding was an evolutionary process. We close with suggestions for future research. PMID- 25729135 TI - Changing course. AB - Although the field of behavior analysis provided the formative experiences and much of the profession training that have fueled a long and satisfying career, I now find that I am turning away from behavior-analytic research and teaching. My reasons for making this change stem from concerns about the costs and potential benefits of basic behavior-analytic research strategies and the isolation of behavior analysis from mainstream science. I offer some suggestions for strengthening the profession. PMID- 25729136 TI - Go forth and be variable. PMID- 25729137 TI - Moving forward without changing course. PMID- 25729138 TI - The Openness is There. PMID- 25729139 TI - Changing Course through Collaboration. PMID- 25729140 TI - Changing course: a reply. PMID- 25729142 TI - A look back at "where have all the behaviorists gone?". PMID- 25729141 TI - Behavioral coaching. AB - The term behavioral coaching has been used inconsistently in and outside the field of behavior analysis. In the sports literature, the term has been used to describe various intervention strategies, and in the organizational behavior management literature it has been used to describe an approach to training management personnel and staff. This inconsistency is problematic in terms of the replication of behavioral coaching across studies and aligning with Baer, Wolf, and Risley's (1968) technological dimension of applied behavior analysis. The current paper will outline and critique the discrepancies in the use of the term and suggest how Martin and Hrycaiko's (1983) characteristics of behavioral coaching in sports may be used to bring us closer to establishing a consistent definition of the term. In addition, we will suggest how these characteristics can also be applicable to the use of the term behavioral coaching in other domains of behavior analysis. PMID- 25729143 TI - Genome-wide association study identifies three novel genetic markers associated with elite endurance performance. AB - To investigate the association between multiple single-nucleotide polymorphisms (SNPs), aerobic performance and elite endurance athlete status in Russians. By using GWAS approach, we examined the association between 1,140,419 SNPs and relative maximal oxygen consumption rate ([Formula: see text]O2max) in 80 international-level Russian endurance athletes (46 males and 34 females). To validate obtained results, we further performed case-control studies by comparing the frequencies of the most significant SNPs (with P < 10(-5)-10(-8)) between 218 endurance athletes and opposite cohorts (192 Russian controls, 1367 European controls, and 230 Russian power athletes). Initially, six 'endurance alleles' were identified showing discrete associations with [Formula: see text]O2max both in males and females. Next, case-control studies resulted in remaining three SNPs (NFIA-AS2 rs1572312, TSHR rs7144481, RBFOX1 rs7191721) associated with endurance athlete status. The C allele of the most significant SNP, rs1572312, was associated with high values of [Formula: see text]O2max (males: P = 0.0051; females: P = 0.0005). Furthermore, the frequency of the rs1572312 C allele was significantly higher in elite endurance athletes (95.5%) in comparison with non elite endurance athletes (89.8%, P = 0.0257), Russian (88.8%, P = 0.007) and European (90.6%, P = 0.0197) controls and power athletes (86.2%, P = 0.0005). The rs1572312 SNP is located on the nuclear factor I A antisense RNA 2 (NFIA-AS2) gene which is supposed to regulate the expression of the NFIA gene (encodes transcription factor involved in activation of erythropoiesis and repression of the granulopoiesis). Our data show that the NFIA-AS2 rs1572312, TSHR rs7144481 and RBFOX1 rs7191721 polymorphisms are associated with aerobic performance and elite endurance athlete status. PMID- 25729144 TI - Comparison of techniques for the measurement of skin temperature during exercise in a hot, humid environment. AB - Exercising or working in a hot, humid environment can results in the onset of heat-related illness when an individual's temperature is not carefully monitored. The purpose of the present study was to compare three techniques (data loggers, thermal imaging, and wired electrodes) for the measurement of peripheral (bicep) and central (abdominal) skin temperature. Young men and women (N = 30) were recruited to complete the present study. The three skin temperature measurements were made at 0 and every 10-min during 40-min (60% VO2max) of cycling in a hot (39+/-2 degrees C), humid (45+/-5% RH) environment. Data was statistically analyzed using the Bland-Altman method and correlation analysis. For abdominal skin temperature, the Bland-Altman limits of agreement indicated that data loggers (1.5) were a better index of wired than was thermal imaging (3.5), For the bicep skin temperature the limits of agreement was similar between data loggers (1.9) and thermal (1.9), suggesting the both were suitable measurements. We also found that when skin temperature exceeded 35 degrees C, we observed progressively better prediction between data loggers, thermal imaging, and wired skin sensors. This report describes the potential for the use of data loggers and thermal imaging to be used as alternative measures of skin temperature in exercising, human subjects. PMID- 25729145 TI - Effects of heat exposure in the absence of hyperthermia on power output during repeated cycling sprints. AB - The aim of this study was to investigate the effects of heat exposure in the absence of hyperthermia on power output during repeated cycling sprints. Seven males performed four 10-s cycling sprints interspersed by 30 s of active recovery on a cycle ergometer in hot-dry and thermoneutral environments. Changes in rectal temperature were similar under the two ambient conditions. The mean 2-s power output over the 1st-4th sprints was significantly lower under the hot-dry condition than under the thermoneutral condition. The amplitude of the electromyogram was lower under the hot-dry condition than under the thermoneutral condition during the early phase (0-3 s) of each cycling sprint. No significant difference was observed for blood lactate concentration between the two ambient conditions. Power output at the onset of a cycling sprint during repeated cycling sprints is decreased due to heat exposure in the absence of hyperthermia. PMID- 25729146 TI - Repeated bouts of eccentrically biased endurance exercise stimulate salivary IgA secretion rate. AB - To determine the salivary secretory immunoglobulin A (sIgA) response to repeated bouts of unaccustomed, downhill running (eccentrically biased) and examine potential protective immunological adaption from a repeated bout effect. Eleven active but untrained males (age: 19.7+/-0.4 years; VO2peak: 47.8+/- 3.6 ml . kg( 1) . min (-1)) performed two 60 min bouts (Run 1 and Run 2) of downhill running ( 13.5% gradient), separated by 14 days, at a speed eliciting 75% of their VO2peak on a level grade. Saliva samples were collected before (baseline), immediately post exercise (IPE), and every hour for 12 h and every 24 h for 6 days after each run. Salivary sIgA concentration was measured and sIgA secretion rate was calculated. Results were analysed using repeated measures ANOVA (12 h period: 2x14; 24 h intervals: 2x7; p <= 0.05) with Tukey post-hoc tests where appropriate. Results are reported as means +/- SE. There was a significant (p < 0.0001) interaction effect for sIgA secretion rate, IPE, with higher values after Run 2, as well as a significant (p < 0.01) time effect with elevated levels IPE and between 24 h and 144 h. There was a run effect (p < 0.0001), with the sIgA secretion rate significantly higher after Run 2. Repeated bouts of unaccustomed, eccentrically biased exercise induced alterations in the salivary sIgA secretion rate. This may serve as a protective mucosal adaptation to exercise-induced tissue damage. PMID- 25729147 TI - High cycling cadence reduces carbohydrate oxidation at given low intensity metabolic rate. AB - Cycling cadence (RPM)-related differences in blood lactate concentration (BLC) increase with increasing exercise intensity, whilst corresponding divergences in oxygen uptake ([Formula: see text]O2) and carbon dioxide production ([Formula: see text]CO2) decrease. Aim of the present study was to test whether a higher RPM reduces the fraction (%) of the [Formula: see text]O2 used for carbohydrate oxidation (relCHO) at a given BLC. Eight males (23.9 +/- 1.6 yrs; 177 +/- 3 cm; 70.3 +/- 3.4 kg) performed incremental load tests at 50 and 100 RPM. BLC, [Formula: see text]O2 and [Formula: see text]CO2 were measured. At respiratory exchange ratios (RER) < 1, relCHO were calculated and the constant determining 50 % relCHO (kCHO) was approximated as a function of the BLC. At submaximal workload [Formula: see text]O2, [Formula: see text]CO2, and relCHO were lower (all p < 0.002; eta(2) > 0.209) at 50 than at 100 RPM. No differences were observed in [Formula: see text]O2peak (3.96 +/- 0.22 vs. 4.00 +/- 0.25 l . min (-1)) and RERpeak (1.18 +/- 0.02 vs. 1.15 +/- 0.02). BLC was lower (p < 0.001; eta(2) = 0.680) at 50 than at 100 RPM irrespective of cycling intensity. At 50 RPM, kCHO (4.2 +/- 1.4 (mmol . l (-1))(3)) was lower (p = 0.043; eta(2) = 0.466) than at 100 RPM (5.9 +/- 1.9 (mmol . l (-1))(3)). This difference in kCHO reflects a reduced CHO oxidation at a given BLC at 100 than at 50 RPM. At a low exercise intensity, a higher cycling cadence can substantially reduce the reliance on CHO at a given metabolic rate and/or BLC. PMID- 25729148 TI - Effect of unilateral and bilateral resistance exercise on maximal voluntary strength, total volume of load lifted, and perceptual and metabolic responses. AB - The present study investigated the effect of unilateral and bilateral resistance exercise (RE) on maximal voluntary strength, total volume of load lifted (TVLL), rating of perceived exertion (RPE) and blood lactate concentration of resistance trained males. Twelve healthy men were assessed for the leg extension one repetition maximum (1RM) strength using bilateral and unilateral contractions. Following this assessment, an RE session (3 sets of repetitions to failure) was conducted with bilateral and unilateral (both limbs) contractions using a load of 50% 1RM. The TVLL was calculated by the product of the number of repetitions and the load lifted per repetition. RPE and blood lactate were measured before, during and after each set. Session RPE was measured 30 minutes after RE sessions. There was a significant difference in the bilateral (120.0+/-11.9) and unilateral (135.0+/-20.2 kg) 1RM strength (p < 0.05). The TVLL was similar between both RE sessions. Although the repetitions decreased with each successive set, the total number of repetitions completed in the bilateral protocol (48) was superior to the unilateral (40) protocol (p < 0.05). In both bouts, RPE increased with each subsequent set whilst blood lactate increased after set 1 and thereafter remained stable (p < 0.05). The RPE and lactate responses were not significantly different between both sessions. In conclusion, a bilateral deficit in leg extension strength was confirmed, but the TVLL was similar between both RE sessions when exercising to voluntary fatigue. This outcome could be attributed to the number of repetitions completed in the unilateral RE bout. The equal TVLL would also explain the similar perceptual and metabolic responses across each RE session. PMID- 25729149 TI - A preliminary investigation into the relationship between functional movement screen scores and athletic physical performance in female team sport athletes. AB - There is little research investigating relationships between the Functional Movement Screen (FMS) and athletic performance in female athletes. This study analyzed the relationships between FMS (deep squat; hurdle step [HS]; in-line lunge [ILL]; shoulder mobility; active straight-leg raise [ASLR]; trunk stability push-up; rotary stability) scores, and performance tests (bilateral and unilateral sit-and-reach [flexibility]; 20-m sprint [linear speed]; 505 with turns from each leg; modified T-test with movement to left and right [change-of direction speed]; bilateral and unilateral vertical and standing broad jumps; lateral jumps [leg power]). Nine healthy female recreational team sport athletes (age = 22.67 +/- 5.12 years; height = 1.66 +/- 0.05 m; body mass = 64.22 +/- 4.44 kilograms) were screened in the FMS and completed the afore-mentioned tests. Percentage between-leg differences in unilateral sit-and-reach, 505 turns and the jumps, and difference between the T-test conditions, were also calculated. Spearman's correlations (p <= 0.05) examined relationships between the FMS and performance tests. Stepwise multiple regressions (p <= 0.05) were conducted for the performance tests to determine FMS predictors. Unilateral sit-and-reach positive correlated with the left-leg ASLR (r = 0.704-0.725). However, higher scoring HS, ILL, and ASLR related to poorer 505 and T-test performance (r = 0.722 0.829). A higher-scored left-leg ASLR related to a poorer unilateral vertical and standing broad jump, which were the only significant relationships for jump performance. Predictive data tended to confirm the correlations. The results suggest limitations in using the FMS to identify movement deficiencies that could negatively impact athletic performance in female team sport athletes. PMID- 25729150 TI - Validity of the MarkWiiR for kinematic analysis during walking and running gaits. AB - The aim of this study was to validate the MarkWiiR (MW) captured by the Nintendo Wii-Remote (100-Hz) to assess active marker displacement by comparison with 2D video analysis. Ten participants were tested on a treadmill at different walking (1<6 km . h(-1)) and running (10<13 km . h(-1)) speeds. During the test, the active marker for MW and a passive marker for video analysis were recorded simultaneously with the two devices. The displacement of the marker on the two axes (x-y) was computed using two different programs, Kinovea 0.8.15 and CoreMeter, for the camera and MW, respectively. Pearson correlation was acceptable (x-axis r>=0.734 and y-axis r>=0.684), and Bland-Altman plots of the walking speeds showed an average error of 0.24+/-0.52% and 1.5+/-0.91% for the x- and y-axis, respectively. The difference of running speeds showed average errors of 0.67+/-0.33% and 1.26+/-0.33% for the x- and y-axes, respectively. These results demonstrate that the two measures are similar from both the x- and the y axis perspective. In conclusion, these findings suggest that the MarkWiiR is a valid and reliable tool to assess the kinematics of an active marker during walking and running gaits. PMID- 25729151 TI - Validity of Cooper's 12-minute run test for estimation of maximum oxygen uptake in male university students. AB - The present study was conducted to validate the applicability of Cooper's 12 minute run test (CRT) for predicting VO2max in male university students of Kolkata, India, to bypass the exhaustive and complicated protocol of direct estimation of VO2max. Eighty-eight sedentary male university students recruited by simple random sampling from the University of Calcutta, Kolkata, were randomly assigned to the study group (N = 58) and the confirmatory group (N = 30). VO2max of each participant was determined by the direct procedure and the indirect CRT method. The mean value of predicted VO2max (PVO2max) (42.8+/-4.0 ml . kg(-1) . min(-1) with a range of 33.7-50.9) showed a significant difference with VO2max (39.8+/-4.0 ml . kg(-1) . min(-1) with a range of 33.5-47.7) in the study group. Limits of agreement between PVO2max and VO2max were large enough (0.10 to 5.94 ml . kg(-1) . min(-1)) with poor confidence intervals indicating inapplicability of the current protocol of CRT in the studied population. The prediction norm [Y = 21.01X - 11.04 (SEE = 0.193 ml . kg(-1) . min(-1))] was computed from the significant correlation (r = 0.93, P < 0.001) between distance covered in CRT and VO2max. Application of this norm in the confirmatory group revealed an insignificant difference between PVO2max and VO2max. The modified equation is recommended for application of CRT as a valid method to evaluate the cardiorespiratory fitness in terms of VO2max in sedentary male Indian youth. PMID- 25729152 TI - The Yo-Yo intermittent recovery test level 1 is reliable in young high-level soccer players. AB - The aim of the study was to investigate test reliability of the Yo-Yo intermittent recovery test level 1 (YYIR1) in 36 high-level youth soccer players, aged between 13 and 18 years. Players were divided into three age groups (U15, U17 and U19) and completed three YYIR1 in three consecutive weeks. Pairwise comparisons were used to investigate test reliability (for distances and heart rate responses) using technical error (TE), coefficient of variation (CV), intra class correlation (ICC) and limits of agreement (LOA) with Bland-Altman plots. The mean YYIR1 distances for the U15, U17 and U19 groups were 2024 +/- 470 m, 2404 +/- 347 m and 2547 +/- 337 m, respectively. The results revealed that the TEs varied between 74 and 172 m, CVs between 3.0 and 7.5%, and ICCs between 0.87 and 0.95 across all age groups for the YYIR1 distance. For heart rate responses, the TEs varied between 1 and 6 bpm, CVs between 0.7 and 4.8%, and ICCs between 0.73 and 0.97. The small ratio LOA revealed that any two YYIR1 performances in one week will not differ by more than 9 to 28% due to measurement error. In summary, the YYIR1 performance and the physiological responses have proven to be highly reliable in a sample of Belgian high-level youth soccer players, aged between 13 and 18 years. The demonstrated high level of intermittent endurance capacity in all age groups may be used for comparison of other prospective young soccer players. PMID- 25729154 TI - Comparison of posture among adolescent male volleyball players and non-athletes. AB - Due to high training loads and frequently repeated unilateral exercises, several types of sports training can have an impact on the process of posture development in young athletes. The objective of the study was to assess and compare the postures of adolescent male volleyball players and their non-training peers. The study group comprised 104 volleyball players while the control group consisted of 114 non-training individuals aged 14-16 years. Body posture was assessed by the Moire method. The volleyball players were significantly taller, and had greater body weight and fat-free mass. The analysis of posture relative to symmetry in the frontal and transverse planes did not show any significant differences between the volleyball players and non-athletes. Postural asymmetries were observed in both the volleyball players and the control participants. Lumbar lordosis was significantly less defined in the volleyball players compared to non training individuals while no difference was observed in thoracic kyphosis. All athletes demonstrated a loss of lumbar lordosis and an increase in thoracic kyphosis. Significant differences in anteroposterior curvature of the spine between the volleyball players and the non-athletes might be associated with both training and body height. Considering the asymmetric spine overloads which frequently occur in sports training, meticulous posture assessment in young athletes seems well justified. PMID- 25729153 TI - Sprint, agility, strength and endurance capacity in wheelchair basketball players. AB - The aims of the present study were, firstly, to determine the reliability and reproducibility of an agility T-test and Yo-Yo 10 m recovery test; and secondly, to analyse the physical characteristics measured by sprint, agility, strength and endurance field tests in wheelchair basketball (WB) players. 16 WB players (33.06 +/- 7.36 years, 71.89 +/- 21.71 kg and sitting body height 86.07 +/- 6.82 cm) belonging to the national WB league participated in this study. Wheelchair sprint (5 and 20 m without ball, and 5 and 20 m with ball) agility (T-test and pick-up test) strength (handgrip and maximal pass) and endurance (Yo-Yo 10 m recovery test) were performed. T-test and Yo-Yo 10 m recovery test showed good reproducibility values (intraclass correlation coefficient, ICC = 0.74-0.94). The WB players' results in 5 and 20 m sprints without a ball were 1.87 +/- 0.21 s and 5.70 +/- 0.43 s and with a ball 2.10 +/- 0.30 s and 6.59 +/- 0.61 s, being better than those reported in the literature. Regarding the pick-up test results (16.05 +/- 0.52 s) and maximal pass (8.39 +/- 1.77 m), players showed worse values than those obtained in elite players. The main contribution of the present study is the characterization of the physical performance profile of WB players using a field test battery. Furthermore, we demonstrated that the agility T-test and the aerobic Yo-Yo 10 m recovery test are reliable; consequently they may be appropriate instruments for measuring physical fitness in WB. PMID- 25729156 TI - The Pacific Tracker (PacTrac): Development of a dietary assessment instrument for the Pacific. AB - The Pacific Tracker (PacTrac) is a new dietary assessment program that can be used to evaluate dietary data for nutrition studies in the Pacific Islands. PacTrac is a modification of the Interactive Healthy Eating Index (IHEI) developed by the US Department of Agriculture's Center for Nutrition Policy and Promotion as an online interactive dietary assessment tool for use by the public. Creation of PacTrac required several modifications to the IHEI, including a function to save data to allow for later access and addition of Pacific Island foods. Sources for Pacific Island foods included the Cancer Research Center of Hawaii (CRCH) Food Composition Table (FCT) and recipes from Guam and the Commonwealth of the Northern Mariana Islands (CNMI). Initially, 344 foods in the CRCH FCT were added to the IHEI. Feedback from pilot sessions indicated it was too large and therefore difficult to navigate. Therefore, we removed the original IHEI database (over 7000 foods) and replaced it with the CRCH FCT (2778 foods) plus 85 recipes from Guam and 40 recipes from CNMI. We are currently using PacTrac to evaluate dietary data in Hawaii, Guam and CNMI. PMID- 25729155 TI - Mediators of the relationship between life events and memory functioning in a community sample of adults. AB - The present study examines the association of frequency and severity of life events with memory functioning in a community sample of adults. We tested the hypothesis that stress-related cognitive interference mediated the effects of recent life events on cognition, in addition to examining the potential roles of fatigue, sleep disturbances, and depression. The sample consisted of 310 adults (age range 19-83) who received a battery of cognitive tests assessing their primary memory, episodic memory, and working memory. Individuals rated how stressful previous life events were when they occurred, as well as how stressful the events were for them currently. Ratings of current, but not past severity were negatively associated with working memory performance. Both stress-related cognitive interference and depressive symptoms independently mediated this association. These findings highlight the importance of intrusive and avoidant thinking as a potential focus of psychosocial treatment for remediating stress related memory dysfunction. PMID- 25729157 TI - A Cognitive Ecological Model of Women's Response to Male Sexual Coercion in Dating. AB - We offer a theoretical model that consolidates background, environmental, and intrapersonal variables related to women's experience of sexual coercion in dating into a coherent ecological framework and present for the first time a cognitive analysis of the processes women use to formulate responses to sexual coercion. An underlying premise for this model is that a woman's coping response to sexual coercion by an acquaintance is mediated through cognitive processing of background and situational influences. Because women encounter this form of sexual coercion in the context of relationships and situations that they presume will follow normative expectations (e.g., about making friends, socializing and dating), it is essential to consider normative processes of learning, cognitive mediation, and coping guiding their efforts to interpret and respond to this form of personal threat. Although acts of coercion unquestionably remain the responsibility of the perpetrator, a more complete understanding of the multilevel factors shaping women's perception of and response to threats can strengthen future inquiry and prevention efforts. PMID- 25729158 TI - Comparison of the isolated contraction ratios of the hip extensors and erector spinae muscles of the lumbar region and thoracic muscles during different back extension exercises. AB - [Purpose] This study compared the isolated contraction ratios of the hip extensors, erector spinae muscles of the lumbar region, and thoracic muscles during different back extension exercises. [Subjects] Twelve males participated in this study. [Methods] The subjects performed various back extension exercises. The activities of the T7 erector spinae muscles, L3 erector spinae muscles, and the gluteus maximus were measured, and the isolation contraction ratios were calculated. [Results] The isolated contraction ratio of the T7 erector spinae muscles significantly increased during exercise 2. The isolated contraction ratio of the gluteus maximus increased by a significant degree during exercise 1 compared with the other exercises. [Conclusion] This study demonstrated that the back extension exercises 1 and 2 can be applied to selectively exercise the hip extensors, thoracic muscles, and muscles of the lumbar region. PMID- 25729159 TI - Clinical availability of the deep tendon reflex test using a novel apparatus in healthy subjects. AB - [Purpose] The aim of this study was to investigate the clinical usefulness of a novel apparatus intended to improve the consistency and reliability of the deep tendon reflex (DTR) test. [Subjects] The participants included 50 healthy adults (25 male and 25 female) between 20 and 31 years of age who showed no knee abnormalities upon physical examination. [Methods] The intraclass correlation coefficient (ICC) was used to verify inter-rater reliability for two parameters examined in the DTR test using a newly designed apparatus. These parameters were the patellar reflex amplitude and first knee extension angle. Pearson's product correlation coefficient was then used to examine the correlation between these two parameters. [Results] The inter-rater reliability analysis showed a high correlation between the examiners for both DTR parameters (ICCs = 0.91-0.96). In addition, a significant positive correlation was observed between the two parameters (r = 0.91). [Conclusion] The results show that it is possible to use the novel apparatus described herein to obtain reliable results in the DTR test. PMID- 25729160 TI - Relationship between the weight-bearing ratio on the affected lower extremity and gait ability using a portable electronic foot sensor shoe (Step Aid((r))) in hemiplegic stroke patients. AB - [Purpose] This study investigated the association between the weight-bearing ratio (WBR) and gait ability of a paretic lower limb while walking using a shoe type load-measuring apparatus. [Subjects] The Subjects comprised 17 stroke patients who were classified into the following two groups: the independent walking group, and the non-independent walking group. [Methods] The 10-m walking time (inside and outside parallel bars) and the Berg Balance Scale (BBS) were measured. The WBR of the paretic lower limb was measured during static standing and while walking inside and outside parallel bars, and the coefficient of variation (CV) was calculated. WBR was evaluated using the Step Aid. [Results] The BBS and WBR were significantly decreased in the non-independent walking group, while the 10-m walking time and the CV were significantly increased in the non-independent walking group. [Conclusion] The CV and WBR of a paretic lower limb while walking appear to be important indices of achievement of independent gait in hemiplegic stroke patients, and they may be used in gait rehabilitation for diseases requiring weight-bearing training to follow the course of training using a shoe-type load-measuring apparatus. PMID- 25729161 TI - Electrically stimulated ventilation feedback improves the ventilation pattern in patients with COPD. AB - [Purpose] We aimed to determine the effects of ventilation feedback using electrical stimulation on ventilation pattern during exercise in patients with chronic obstructive pulmonary disease (COPD), and develop new rehabilitation methods. [Subjects] This randomized double-blind placebo-controlled trial included 24 patients with COPD. [Methods] Phasic electrical stimulation during expiration (PESE) or a placebo was given to all the cases. Minute ventilation (VE), tidal volume (TV), respiratory rate (RR), expiratory time (Te), total respiratory time (Ttot), dead-space gas volume to tidal gas volume (VD/VT), oxygen uptake (VO2), carbon dioxide output (VCO2), Borg scale (Borg), and percutaneous oxygen saturation (SpO2) during rest and exercise were assessed. [Results] The placebo group showed no obvious change in ventilation measurements at rest or during exercise. However, in the PESE group, TV, Te, and Ttot significantly increased, while RR and VD/VT significantly decreased during exercise compared with the baseline measurements. Borg scores, SpO2, VO2, or VCO2 did not differ significantly. [Conclusion] PESE improves the ventilation pattern during rest and exercise. Furthermore, PESE does not increase VO2, which may indicate an increased workload. Biofeedback may contribute to PESE effects. Stimulation applied during expiration may evoke sensations increasing prolonged expiration awareness, facilitating prolongation. PMID- 25729162 TI - Incidence and related clinical factors of falls among older Chinese veterans in military communities: a prospective study. AB - [Purpose] The aim of this study was to determine fall incidence and explore clinical factors of falls among older Chinese veterans in military communities. [Subjects and Methods] We carried out a 12-month prospective study among 13 military communities in Beijing, China. Fall events were obtained by self-report to military community liaisons and monthly telephone interviews by researchers. [Results] Among the final sample of 447 older veterans, 86 fell once, 25 fell twice or more, and 152 falls occurred altogether. The incidence of falls and fallers were 342/1,000 person-years and 249/1,000 person-years. In Cox regression models, independent clinical factors associated with falls were visual acuity (RR=0.47), stroke (RR=2.43), lumbar diseases (RR=1.73), sedatives (RR=1.80), fall history in the past 6 months (RR=2.77), multiple chronic diseases (RR=1.53), multiple medications (RR=1.34), and five-repetition sit-to-stand test score (RR=1.41). Hearing acuity was close to being statistically significant. [Conclusion] The incidences of falls and fallers among older Chinese veterans were lower than those of Hong Kong and western countries. The clinical risk factors of falls were poor senses, stroke, lumbar diseases, taking sedatives, fall history in the past 6 months, having multiple chronic diseases, taking multiple medications, and poor physical function. The preventive strategies targeting the above risk factors are very significant for reducing falls. PMID- 25729163 TI - The effects of action observation gait training on the static balance and walking ability of stroke patients. AB - [Purpose] The purpose of the study was to investigate the effects of action observation training on the static balance and walking ability of patients who had suffered a stroke. [Subjects] Forty patients with hemiplegia resulting from a stroke were divided into an action observation gait training group (AOGT group, n=20) and a general gait training group (GGT group, n=20). [Methods] The AOGT group watched a training video on flatland gait, slope gait, and stair gait. The GGT group watched a video on nature. Both groups watched their respective video for 10 minutes and then had gait training for 20 minutes per day, five times per week, for eight weeks. [Results] The static balance and gait ability of both groups significantly improved. Although there were significant differences between the groups, the AOTG group showed greater improvements in sway speed, limit of stability, and gait ability. [Conclusion] We recommend action observation training over general gait training for patients with hemiplegia. Action observational training had a positive effect on static balance and gait ability in stroke patients' static balance and gait ability. Further research is needed to generalize the results of this study. PMID- 25729164 TI - Effects of hip exercises for chronic low-back pain patients with lumbar instability. AB - [Purpose] The purpose of this study was to compare hip range of motion between a lumbar stability group and a lumbar instability group, and to evaluate the effectiveness of hip exercises for low-back pain patients with lumbar instability. [Subjects] Seventy-eight patients with chronic low-back pain were the subjects. [Methods] The patients were divided into two groups: a lumbar stability group (n=45) and a lumbar instability group (n=33). They were assessed using the Korean version of the Oswestry Disability Index (KODI) to determine the level of disability of the patients with low-back pain. A 100 mm visual analog scale (VAS) was used to assess low-back pain. [Results] The limitation of hip range of motion of the lumbar instability group was significantly greater than that of the lumbar stability group. Comparisons among four groups at three weeks and six weeks after the start of hip exercises revealed that the VAS score of each group had significantly decreased. Comparisons among four groups at three weeks and at six weeks after the start of hip exercises revealed that the KODI score of each group had significantly decreased. [Conclusion] These findings suggest that the performance of hip exercises by chronic low-back pain patients with lumbar instability is more effective than conventional therapy at reducing low-back pain and levels of disability. PMID- 25729165 TI - Comparison of chronic low-back pain patients hip range of motion with lumbar instability. AB - [Purpose] The purpose of this study was to compare differences in hip range of motion between a lumbar stability group and a lumbar instability group of patients with chronic low-back pain. [Subjects] Sixty-nine patients with chronic low-back pain were divided into two groups: a lumbar stability group (n=39) and a lumbar instability group (n=30). [Methods] The patients were assessed using a goniometer to evaluate the hip range of motion at pre-test. Data were analyzed using SPSS 18.0 software for Windows. The experimental data were analyzed using one-way ANOVA, repeated one-way ANOVA, and the t-test, and a significance level of 0.05. [Results] The limitation of hip range of motion of the lumbar instability group was significantly greater than that of the lumbar stability group. [Conclusion] The chronic low-back pain patients showed greater limitation of hip range of motion than healthy persons, and among them, those who had lumbar instability showed greater limitation than those with lumbar stability. PMID- 25729166 TI - Activity of lower limb muscles during treadmill running at different velocities. AB - [Purpose] The present study aimed to determine changes in muscle activity while moving on a treadmill at various speeds. [Subjects] The activities of the left vastus lateralis, vastus medialis, hip adductors, lateral head of gastrocnemius, medial head gastrocnemius, soleus, and tibialis anterior of 10 healthy male university students were analyzed. [Methods] University students walked, jogged, and ran for 10 minutes each in random order, and then myogenic potentials were measured 10 minutes later for 30 seconds. The flexion angle of the lower limb upon initial contact, mid stance, and toe off were measured. [Results] The average walking, jogging, and running speeds were 3.6 +/- 0.4, 6.7 +/- 0.6, and 10.4 +/- 1.3 km/h, respectively. The average electromyographic activities of the vastus medial, tibialis anterior, medial head of gastrocnemius, and lateral head of gastrocnemius significantly differed. All muscles were more active during jogging and running than walking. Only the soleus was more active during running than walking, and the activities of the hip adductors and vastus lateralis did not significantly differ. [Conclusion] Velocity is faster and the angles of the lower limbs and ground reaction force (GRF) are larger during running than walking. The vastus medialis and soleus worked more easily according to the angle of the knee joint, whereas the tibialis anterior worked more easily at faster velocities and the medial and lateral heads of the gastrocnemius worked more easily with an increased GRF. PMID- 25729167 TI - A comparison of at-home walking and 10-meter walking test parameters of individuals with post-stroke hemiparesis. AB - [Purpose] The purpose of this study was to clarify the difference in gait parameters of at-home walking and the 10-meter walking test results of individuals with hemiparesis. [Subjects] A total of 14 hemiparetic stroke recovery patients participated in this study. Inclusion criteria were: living at home, the ability to walk independently, and demonstrated low extremity on recovery stages III-V on the Brunnstrom Approach. The average age of the subjects was 66 years. [Methods] We used video surveillance and the inked footprint technique to record usual walking speed and maximum speed patterns both in subjects' homes and during the 10-meter walking test. From these methods, walking speed, stride length, and step rate were calculated. [Results] While both usual and maximum walking speeds of the 10-meter walking test correlated with stride length and step rate, at-home walking speeds only significantly correlated with stride length. [Conclusion] Walking patterns of the 10-meter walking test are quantifiably distinct from those demonstrated in patients' homes, and this difference is mainly characterized by stride length. In order to enhance in-home walking ability, exercises that improve length of stride rather than step rate should be recommended. PMID- 25729168 TI - Effects of hatha yoga exercises on spine flexibility in women over 50 years old. AB - [Purpose] The aim of this study was to access the flexibility of the spine in women practicing yoga as a part of the "University for Health" project. [Subjects and Methods] The study included 56 women ranging in age between 50-79 and attending 90 minutes hatha yoga sessions once a week. The measurements were performed twice-at the beginning of the project and after its completion, i.e., after 20 weeks of classes. The range of spine mobility in three planes was measured using a Rippstein plurimeter. The range of motion in the sagittal and frontal planes was measured in a standing position with the feet hip-width apart. The torsional range of motion of the subjects was measured with the trunk bent at a right angle and the legs apart. The flexibility ranges of the spine and hamstrings were also measured by the toe-touch test in a standing position. [Results] This study showed that the applied yoga exercises increased spinal mobility and flexibility of the hamstring muscles regardless of age. [Conclusion] Yoga exercises should be recommended to the elderly to make their muscles more flexible and to increase the range of motion in the joints, which is particularly important for improving their life quality. PMID- 25729169 TI - Effects of selective exercise for the deep abdominal muscles and lumbar stabilization exercise on the thickness of the transversus abdominis and postural maintenance. AB - [Purpose] The purpose of this study was to examine the effects of selective exercise for the deep abdominal muscles (SEDA) and lumbar stabilization exercise (LSE) on the thickness of the transversus abdominis and postural maintenance on an unstable base of support. [Subjects and Methods] The subjects of this study were 20 male and 10 female adults in their 20s without lumbar pain. They were equally and randomly assigned to a SEDA group and a LSE group. The thickness of the transversus abdominis was measured using ultrasound imaging during rest and drawing-in. The thickness of the transversus abdominis was measured when subjects raised their right and left legs while lying on a Swiss ball. [Results] Initially, there were no differences between the two groups. After the intervention, significant differences were observed in all parameters. A significant interaction between group and period was not found for any parameters. [Conclusion] In conclusion, both SEDA and LSE thickened the transversus abdominis, which is a deep abdominal muscle, thereby adjusting posture, and stabilizing the trunk. These exercises increased the thickness of the deep abdominal muscles. They are important exercises for improving the stability of athletes or patients who need postural adjustment. PMID- 25729170 TI - Effect of proprioceptive training on foot posture, lower limb alignment, and knee adduction moment in patients with degenerative knee osteoarthritis: a randomized controlled trial. AB - [Purpose] The purpose of this study was to determine the effect of proprioceptive training on foot progression angle, weight-bearing ratio, and knee adduction moment in patients with degenerative osteoarthritis of the knee. [Subjects] The subjects were 37 patients diagnosed with Kellgren-Lawrence grade 2 or 3 degenerative knee osteoarthritis. They were randomly allocated to three groups: a proprioceptive training group (PT group), quadriceps strengthening group (QS group), and control group. [Methods] The study parameters of the three groups were compared before and after a 12-week training period. Therapeutic exercises were performed twice per week for 12 weeks. Outcomes included the foot progression angle, weight-bearing ratio, and knee adduction moment. [Results] First, a significant difference in the foot progression angle was observed among the groups, significantly increasing in the PTG compared with the CG. Second, a significant difference in the weight-bearing ratio was observed among the groups, significantly increasing in the PTG compared with the CG. Third, a significant difference in the first peak knee adduction moment was observed among the groups, significantly decreasing in the PTG compared with the CG. [Conclusion] The results of the present study indicate that proprioceptive training increased the foot progression angle and weight-bearing ratio and decreased the first peak knee adduction moment. Moreover, incorporating proprioceptive training into a physical therapy exercise program could improve functional ability and delay the progression of degenerative osteoarthritis. PMID- 25729171 TI - Comparison of the gluteus medius and rectus femoris muscle activities during natural sit-to-stand and sit-to-stand with hip abduction in young and older adults. AB - [Purpose] The purpose of this study was to compare the relative levels of activation of the gluteus medius (Gmed) and rectus femoris (RF) muscles during natural (N) sit-to-stand (STS) and STS with hip abduction (ABD) in young and elderly females. [Subjects] We recruited 15 healthy young females and 15 healthy elderly females. [Methods] The activities of the dominant lower extremity gluteus medius (Gmed) and rectus femoris (RF) muscles were measured using a wireless electromyography (EMG) system for natural STS and STS with hip abduction. [Result] In the elderly subjects, the Gmed increased significantly and RF decreased significantly when STS was performed with hip ABD compared with when it was performed naturally. The Gmed in the elderly subjects was significantly increased during natural STS compared with in the young subjects. [Conclusion] These results indicate that the Gmed was recruited to compensate for weakened RF muscle function in the elderly adults. PMID- 25729172 TI - The effect of external cues with vibratory stimulation on spatiotemporal gait parameters in chronic stroke patients. AB - [Purpose] The aim of current study was to investigate the effect of external cues using vibratory stimulation on spatiotemporal gait parameters in patients with chronic stroke. [Subjects] Thirty patients, who had suffered a stroke, were selected from general hospitals in Seoul, Republic of Korea. [Methods] Each participant was subjected to six walking trials: three trials with vibratory stimulation of the tibialis anterior muscle and three trials without any stimulation. The spatiotemporal gait parameters were measured with a GAITRite system. [Results] The global gait parameters-velocity and cadence-were significantly more increased, and the temporal parameters-step time, stride time, and double limb support-were significantly more decreased with vibratory stimulation of the tibialis anterior muscle than with no stimulation. While single limb support was increased under vibratory stimulation, the difference was not significant between the two groups. The spatial gait parameter-stride length showed a significant improvement; however, there was no significant enhancement in gait symmetry with regard to step length and step time [Conclusion] These results indicate that the application of external cues using vibratory stimulation during gait may control gait parameters and improve gait performance. Thus, this intervention could be used for gait rehabilitation in chronic stroke patients. PMID- 25729173 TI - Effects of abdominal drawing-in during prone hip extension on the muscle activities of the hamstring, gluteus maximus, and lumbar erector spinae in subjects with lumbar hyperlordosis. AB - [Purpose] The purpose of this study was to compare the effects of an abdominal drawing-in maneuver (ADIM), measured using a pressure bio-feedback unit, on the activities of the hamstring, gluteus maximus, and erector spinae muscles during prone hip extension. [Subjects and Methods] Thirty healthy adult subjects (14 male, 16 female), were recruited. Subjects' lumbar lordosis and pelvic tilt angles were measured, and based on the results, the subjects were divided into two groups: a hyperlordotic lumbar angle (HLLA) group (n=15) and a normal lordotic lumbar angle (NLLA) group (n=15). The muscle activities of the hamstring and gluteus maximus, and of the erector spinae on the right side of the body, were recorded using surface electromyography. [Results] When performing ADIM with prone hip extension, the muscle activity of the gluteus maximus of the HLLA group significantly improved compared with that the NLLA group. [Conclusion] This study demonstrated that ADIM with prone hip extension was more effective at eliciting gluteus maximus activity in the HLLA group than in the NLLA group. Therefore, ADIM with prone hip extension may be useful for increasing the gluteus maximus activity of individuals with lumbar hyperlordosis. PMID- 25729174 TI - Comparison of gait velocity and center of mass during square and semicircular turning gaits between groups of elderly people with differing visual acuity. AB - [Purpose] The purpose of this study was to investigate gait velocity and center of mass (COM) during square and semicircular turning gaits between two groups of elderly people with differing visual acuity. [Subjects] Twenty elderly Korean women who could walk independently and who lived in the community were recruited. [Methods] We measured gait velocity and COM using an accelerometer during two different turning gaits. [Results] The velocity during square and semicircular turning gaits of participants with good binocular visual acuity (GBVA) was significantly higher than that of participants with poor binocular visual acuity (PBVA). The COM during square and semicircular turning gaits of the GBVA group was significantly decreased compared with that of the PBVA group. [Conclusion] These findings suggest that visual acuity affects velocity and COM during square and semicircular turning gaits of elderly people. PMID- 25729175 TI - Psychometric properties of the stroke specific quality of life scale for the assessment of participation in stroke survivors using the rasch model: a preliminary study. AB - [Purpose] The aim of the present study was to analyze the psychometric properties of the Stroke Specific Quality of Life (SS-QOL) scale for the assessment of social participation following a stroke. [Methods] A preliminary analysis was performed of the SS-QOL items that address the participation category. For this, the scoring patterns of the answers of individuals and internal consistence were determined using the Rasch model. Reliability was assessed by intraclass correlation coefficients (ICC). [Results] The reliability coefficients analyzed by the Rasch model were 0.91 for the items and 0.87 for the patients. The separation index was 3.19 for the items and 2.58 for the patients. The findings indicate that the items separated the patients into three levels of participation: low, medium, and high. Among the 26 items addressing participation, three did not fit the model. All items showed adequate reliability (ICC >= 0.60). [Conclusion] The Rasch analysis detected three items with erratic behavior; however, the erratic patterns of these items may be explained by individual peculiarities among the patients. These items should be monitored to determine if the problems found in the present study persist. If so, the items should also be revised or possibly even eliminated. PMID- 25729176 TI - Association of sarcopenia with swallowing problems, related to nutrition and activities of daily living of elderly individuals. AB - [Purpose] The purpose of the current study was to clarify problems associated with swallowing, related to nutrition and activities of daily living (ADL), in elderly individuals with sarcopenia. [Subjects and Methods] Seventy-seven subjects were assigned to a sarcopenia or a non-sarcopenia group according to a definition used by the European Working Group on Sarcopenia in Older People. Analyses were conducted including and excluding subjects with a central nervous system disorders in order to focus on the influence of sarcopenia. The swallowing ability, ADL, and nutrition levels were compared between the 2 groups. [Results] Swallowing function as well as ADL and nutrition levels were significantly lower in the sarcopenia group than in the non-sarcopenia group. [Conclusion] It is important to include dimensions of swallowing, nutrition, and ADL in the assessment and treatment of swallowing problems in elderly individuals with sarcopenia. PMID- 25729177 TI - The effects of extracorporeal shock wave therapy on pain, disability, and depression of chronic low back pain patients. AB - [Purpose] The purpose of this study was to examine the effects of extracorporeal shock wave therapy on pain, disability, and depression of chronic low back pain patients. [Subjects] In this study, 30 chronic low back pain patients were divided into an extracorporeal shock wave therapy group (ESWTG, n=15) and a conservative physical therapy group (CPTG, n=15). [Methods] The ESWTG received extracorporeal shock wave therapy and the CPTG received general conservative physical therapy two times per week for six weeks. Pain was measured using a visual analog scale (VAS), the degree of disability of the patients was assessed using the Oswestry Disability Index (ODI), and their degree of depression was measured using the Beck depression index (BDI). [Results] In intra-group comparisons, ESWTG and CPTG showed significant decreases in VAS, ODI, and BDI scores. Intergroup comparisons revealed that these decreases in VAS, ODI, and BDI scores were significantly larger in ESWTG than in CPTG. [Conclusion] Extracorporeal shock wave therapy is an effective intervention for the treatment of pain, disability, and depression in chronic low back pain patients. PMID- 25729178 TI - Differences in respiratory pressure and pulmonary function among children with spastic diplegic and hemiplegic cerebral palsy in comparison with normal controls. AB - [Purpose] The purpose of this study was to determine differences in respiratory pressure and pulmonary function among children with spastic diplegic and hemiplegic cerebral palsy (CP) in comparison with children with normal development. [Subjects and Methods] Fourteen children with spastic diplegic CP, 11 children with hemiplegic CP, and 14 children with normal development were recruited. Respiratory pressure was measured and the pulmonary function test (PFT) was performed to evaluate the strength of the respiratory muscles and lung volumetric capacity. [Results] Regarding respiratory pressure, children with spastic diplegic and hemiplegic CP showed significantly lower functions in terms of MIP and MEP compared with children with normal development, although no significant differences were found between children with the two types of CP. In the pulmonary function test, children with spastic diplegic CP showed significantly higher pulmonary function than children with normal development in terms of only FVC and FEV1. [Conclusion] Children with CP showed relatively lower function in terms of respiratory pressure and lung capacity, in comparison with children with normal development. Therefore, respiratory function in children with CP should be carefully evaluated and should receive more attention in a rehabilitation setting. PMID- 25729179 TI - Effect of satisfaction in major at university on academic achievement among physical therapy students. AB - [Purpose] The purpose of this study was to investigate satisfaction in major among physical therapy students and to identify the sub-factors of satisfaction in major affecting academic achievement. [Subjects and Methods] We distributed a self-administered questionnaire, comprising items relating to satisfaction in major and academic achievement to 369 physical therapy students located in Seoul, Daejeon, Jinju, Pohang, and Gunsan. [Results] General satisfaction and academic achievement showed the greatest correlation (r = 0.235), followed by course satisfaction (r = 0.123). [Conclusion] Several sub-factors were found to affect academic achievement. The results of this study can be used as the basis for programs that aim at development of satisfaction in major and academic achievement among clinical physical therapists. PMID- 25729180 TI - Effects of visual perceptual intervention on visual-motor integration and activities of daily living performance of children with cerebral palsy. AB - [Purpose] The purpose of this study was to find the effects of a visual perceptual intervention on visual-motor integration and activities of daily living performance of children with cerebral palsy as subjects. [Methods] This study was conducted with 56 children who were diagnosed as having cerebral palsy. The visual perceptual intervention was implemented for 8 weeks, 3 times a week, for 30 minutes per session, for a total of 24 sessions. All children were assessed using the VMI and WeeFIM to evaluate visual motor integration and activities of daily living skills, immediately before and after the 8-week intervention. [Results] The VMI and WeeFIM scores of all of the 56 children with CP who participated in the study improved, and the improvements were statistically significant. [Conclusion] Visual perceptual intervention had a positive influence on the visual-motor integration and activities of daily living performance of children with cerebral palsy. PMID- 25729181 TI - Effect of isotonic and isokinetic exercise on muscle activity and balance of the ankle joint. AB - [Purpose] This study was performed to examine how the balance of lower limbs and the muscle activities of the tibialis anterior (TA), the medial gastrocnemius (GCM), and the peroneus longus (PL) are influenced by isotonic and isokinetic exercise of the ankle joint. [Subjects] The subjects of this study were healthy adults (n=20), and they were divided into two groups (isotonic=10, isokinetic=10). [Methods] Isotonic group performed 3 sets of 10 contractions at 50% of MVIC and Isokinetic group performed 3 sets of 60 degrees /sec. Muscle activity was measured by EMG and balance was measured by one-leg standing test. [Results] For muscle activity, a main effect of group was found in the non dominant TA, and the dominant TA, GCM and PL. For balance, a main effect of time was found in both groups for the sway area measured support was provided by the non-dominant side. [Conclusion] In terms of muscle activity, the two groups showed a significant difference, and the isokinetic group showed higher muscle activities. In terms of balance, there was a significant difference between the pre-test and the post-test. The results of this study may help in the selection of exercises for physical therapy, because they show that muscle activity and balance vary according to the type of exercise. PMID- 25729182 TI - Effect of forced use of the lower extremity on gait performance and mobility of post-acute stroke patients. AB - [Purpose] The purpose of this study was to investigate the effects of a forced use training program on gait, mobility and quality of life of post-acute stroke patients. [Subjects] Twenty-one individuals with unilateral stroke participated in this study. All participants had suffered from first-ever stroke with time since onset of at least 3 months. [Methods] A single-blinded, non-equivalent, pre post controlled design with 1-month follow-up was adopted. Participants received either a forced-use or a conventional physical therapy program for 2 weeks. The main outcomes assessed were preferred and fastest walking velocities, spatial and temporal symmetry indexes of gait, the timed up and go test, the Rivermead Mobility Index, and the Stroke-Specific Quality of Life Scale (Taiwan version). [Results] Forced-use training induced greater improvements in gait and mobility than conventional physical therapy. In addition, compared to pre-training, patients in the conventional physical therapy group walked faster but more asymmetrically after training. However, neither program effectively improved in hospital quality of life. [Conclusion] The forced-use approach can be successfully applied to the lower extremities of stroke patients to improve mobility, walking speeds and symmetry of gait. PMID- 25729183 TI - A study on the relationship between stress and fatigue and the musculoskeletal symptoms experienced by Korean radiation workers. AB - [Purpose] The purpose of this study was to examine the relationship between factors such as stress and fatigue on musculoskeletal symptoms experienced by radiologists who were working in clinics and hospitals. [Subjects and Methods] A survey was conducted for radiologists in clinics, general hospitals, and university hospitals across the nation in a 20-day period from July 10-31, 2011. [Results] According to the comprehensive results of this study, job stress, psychosocial stress, and fatigue felt by radiologists had impacts on musculoskeletal disease in multiple body regions. First, according to the analysis results, job stress was scored at 2.48 on average on a 4-point Likert scale, while psychosocial stress was scored at 2.27 on average on the same scale, which demonstrated that job stress had a slightly higher score than psychosocial stress. Second, job stress, psychosocial stress, and fatigue had impacts on musculoskeletal symptoms experienced by radiologists; the possibility of musculoskeletal symptoms on the neck area increased as the physical environment got worse, interpersonal conflicts got serious, stress from organizational system increased, and psychosocial stress went up. [Conclusion] We expect that the results of this study would be useful as basic data for systematic and efficient management of resources when taking preventative measures against musculoskeletal disease experienced by radiologists in the future. PMID- 25729184 TI - The effects of aquatic exercise on body composition and nonspecific low back pain in elderly males. AB - [Purpose] The purpose of this study was to investigate the effect of aquatic exercises on nonspecific low back pain (LBP) in elderly males. [Subjects and Methods] Thirty-two elderly men aged 65 or older were recruited and randomly allocated to two groups: aquatic training (3 d/wk for 12 wk) or a control group. Body mass index (BMI), percentage of body fat (PBF), waist-hip ratio (WHR), and trunk muscle mass were measured before and after training. [Results] The results suggested that all obesity variables including BMI, WHR, and PBF of the aquatic training group were decreased significantly, while the trunk muscle mass of the aquatic training group was increased significantly. Furthermore, low back pain was decreased in the subjects after the intervention. [Conclusion] The water based program improved LBP and body composition in the elderly men. PMID- 25729186 TI - Hip rotation range of motion in sitting and prone positions in healthy Japanese adults. AB - [Purpose] The aim of this study was to elucidate the difference in hip external and internal rotation ranges of motion (ROM) between the prone and sitting positions. [Subjects] The subjects included 151 students. [Methods] Hip rotational ROM was measured with the subjects in the prone and sitting positions. Two-way repeated measures analysis of variance (ANOVA) was used to analyze ipsilateral hip rotation ROM in the prone and sitting positions in males and females. The total ipsilateral hip rotation ROM was calculated by adding the measured values for external and internal rotations. [Results] Ipsilateral hip rotation ROM revealed significant differences between two positions for both left and right internal and external rotations. Hip rotation ROM was significantly higher in the prone position than in the sitting position. Hip rotation ROM significantly differed between the men and women. Hip external rotation ROM was significantly higher in both positions in men; conversely, hip internal rotation ROM was significantly higher in both positions in women. [Conclusion] Hip rotation ROM significantly differed between the sexes and between the sitting and prone positions. Total ipsilateral hip rotation ROM, total angle of external rotation, and total angle of internal rotation of the left and right hips greatly varied, suggesting that hip joint rotational ROM is widely distributed. PMID- 25729185 TI - Evaluation of knee joint proprioception and balance of young female volleyball players: a pilot study. AB - [Purpose] The main purpose of our study was the evaluation of the effects of long term volleyball practice on knee joint proprioception and balance of young female athletes. [Subjects and Methods] An observational case-control study was performed. The study enrolled 19 female volleyball players in the experimental group and 19 sedentary counterparts as controls. A Biodex balance system and dynamometer were used for the evaluations. The paired t-test was used to determine the significance of differences between the performance of athletes and controls. [Results] The knee proprioception analysis showed a significant difference at 60 degrees joint position in active and passive tests. A similar trend, but without significance, was found for the 20 degrees joint position. In the postural stability tests both groups showed similar results with no significant differences between them. [Conclusion] In conclusion, the results indicate a significant influence on joint proprioception is elicited by long-term exposure to a team sport like volleyball. However, the postural stability indexes showed similar trends in both groups, highlighting the analogous ontogenesis of the subjects investigated and the low influence of volleyball practice on postural stability. PMID- 25729187 TI - Reliability of the modified Thomas test using a lumbo-plevic stabilization. AB - [Purpose] The purpose of this study was to examine the test-retest reliability of the modified Thomas test using lumbo-pelvic stabilization. [Subjects] Thirteen subjects (male=10, female=3) with hip flexor tightness voluntarily participated in the study. [Methods] The participants underwent the modified Thomas test under three conditions: 1) the general modified Thomas test (GM), 2) active lumbo pelvic stabilization (ALS), and 3) passive lumbo-pelvic stabilization (PLS). Intra-class correlation coefficients (ICC) were used to determine the test-retest reliability of the knee joint angle measurement under three conditions. The standard error of measurement (SEM) and minimal detectable difference (95% confidence interval) (MDD(95)) were calculated for each measurement to assess absolute consistency. [Results] The ALS (ICC = 0.99) and PLS (ICC = 0.98) methods for the modified Thomas test were more reliable than GM method (ICC = 0.97). The MDD(95) score for the ALS method, 2.35 degrees, indicated that a real difference existed between two testing sessions compared with the scores for the PLS (3.70 degrees) and GM methods (4.17 degrees) [Conclusion] Lumbo-pelvic stabilization is one of the considerations for precise measurement and may help to minimize measurement error when evaluating hip flexor tightness using the modified Thomas test. PMID- 25729188 TI - The effect of chest expansion resistance exercise in chronic stroke patients: a randomized controlled trial. AB - [Purpose] The aim of this study was to examine the initial effects of chest expansion resistance exercise (CERE) applied to chronic stroke patients on their pulmonary functions, chest expansion, and functional gait ability. [Subjects] Forty chronic stroke patients without any respiration-related rehabilitation program experience (21 men and 19 women; times elapsed since occurrence of stroke: 21.8 +/- 5.3 months) were randomly and equally allocated to a CERE group (experimental group) and a control group. [Methods] An ordinary stroke rehabilitation program was performed on the subjects. While the experimental group received a CERE intervention, the control group performed passive range of motion exercise with automatic instruments. [Results] The CERE group's chest expansion significantly increased after the intervention, whereas the control group did not see any significant difference. As regards VC (vital capacity), FVC (forced vital capacity), and FEV1 (forced expiratory volume in one second), there were no significant changes in either the CERE or control group. In the 10MTWT (10-meter timed walking test), there were no significant changes in either group, but in the 6MWT (6-minute walk test), while there were no significant differences in the control group, the CERE group saw significant changes. [Conclusion] The results of application of CERE to chronic stroke patients demonstrated the importance of respiratory exercise in an approach to stroke rehabilitation treatment intervention and the need to add respiratory exercise to a rehabilitation intervention program. PMID- 25729189 TI - Comparison of foot pressure in stretching exercises according to the type of ankle ramp. AB - [Purpose] This study compared and analyzed use of an existing ankle ramp and a newly developed ankle ramp for stretching exercises. [Subjects] Fourteen subjects were included; they were stroke patients more than 6 months after onset, with no orthopedic or biological problems in the legs, so independent gait was possible. [Methods] The subjects performed stretching exercises for 5 min with an existing ankle ramp and a newly developed ankle ramp; foot pressure was then measured. [Results] The averaged percentage and kilopascal data for weight bearing and foot pressure on the affected side with the newly developed ankle ramp for stretching exercises were significantly higher than those with the existing ankle ramp. [Conclusion] Our results suggest that stretching exercises using the newly developed ankle ramp more effectively increase foot pressure than the existing ankle ramp. PMID- 25729190 TI - The effects of kinesio taping on architecture, strength and pain of muscles in delayed onset muscle soreness of biceps brachii. AB - [Purpose] This study aimed to confirm the effects of kinesio taping (KT) on muscle function and pain due to delayed onset muscle soreness (DOMS) of the biceps brachii. [Subjects and Methods] Thirty-seven subjects with induced DOMS were randomized into either Group I (control, n=19) or Group II (KT, n=18). Outcome measures were recorded before the intervention (application of KT) and at 24, 48, and 72 hours after the intervention. DOMS was induced, and muscle thickness was measured using ultrasonic radiography. Maximal voluntary isometric contraction (%MVIC) was measured via electromyography (EMG). Subjective pain was measured using a visual analogue scale (VAS). [Results] Group I exhibited a positive correlation between muscle thickness and elapsed time from intervention (24, 48, and 72 hours post induction of DOMS); they also showed a significant decrease in MVIC(%). Group II showed significant increases in muscle thickness up to the 48-hour interval post induction of DOMS, along with a significant decrease in MVIC (%). However, in contrast to Group I, Group II did not show a significant difference in muscle thickness or MVIC (%) at the 72-hour interval in comparison with the values prior to DOMS induction. [Conclusion] In adults with DOMS, activation of muscles by applying KT was found to be an effective and faster method of recovering muscle strength than rest alone. PMID- 25729191 TI - Outcomes of asymmetry in infants with congenital muscular torticollis. AB - [Purpose] The purpose of this study was to assess the outcomes of asymmetry in infants with congenital muscular torticollis (CMT). [Subjects] A total of 102 patients with CMT under the age of 6 months were studied. [Methods] Asymmety was evaluated by determining the difference in the thicknesses of the two sternocleidomastoid muscles (DTSM) using ultrasonography, head tilt (HT) based on a physical examination, and the torticollis overall assessment (TOA). Patients received ultrasound and massage therapy for 30 minutes, in conjunction with passive stretching exercises, 3 times a week. [Results] The DTSM, HT, and TOA scores were significantly different after treatment. Pretest DTSM, HT, and TOA scores and pre-posttest change scores for DTSM, HT, and TOA scores were correlated with treatment duration in infants with CMT. [Conclusion] The findings of this study suggest that treatment duration is correlated with asymmetry evaluation parameters (DTSM, HT, and TOA) in infants with CMT. We propose that these results will help in reducing the treatment duration, and also in improving communication between doctors and therapists during the diagnosis and evaluation of torticollis. PMID- 25729192 TI - Ultrasound evaluation of the symmetry of abdominal muscles in mild adolescent idiopathic scoliosis. AB - [Purpose] The objective of the study was to evaluate the symmetry of the thickness of the abdominal muscles at rest and while standing in patients with adolescent idiopathic scoliosis. [Subjects and Methods] An ultrasound assessment was performed of the side-to-side differences of the external oblique (EO), internal oblique (IO), and transversus abdominalis (TrA) muscles in the supine and standing positions in adolescent idiopathic scoliosis (AIS) and control groups. [Results] In the AIS group, 64.3% of the patients had left scoliosis with a mean Cobb angle of 10.7 degrees , and 35.7% of the patients had right scoliosis with a mean Cobb angle of 10 degrees . In the supine position, the thickness asymmetry of the TrA was greater in the AIS compared with the control group by an average of 14% (95% CI 3.9-24.2). [Conclusion] Among the abdominal muscles examined, patients with AIS exhibited more asymmetry only for the TrA. In the standing position, the TrA was as symmetric in the patients as in the control group. Mild scoliosis has no impact on the symmetry of the thickness of the OE and OI in the supine and standing positions. The direction of curvature had no effect on the symmetry of the abdominal muscles studied. PMID- 25729193 TI - Influence of light touch using the fingertips on postural stability of poststroke patients. AB - [Purpose] The purpose of this study was to investigate the influence of fingertip light touch on the postural control in poststroke patients. [Subjects] In the study, the subjects were recruited through a rehabilitation hospital, and 21 patients were screened from among 30 volunteers. [Methods] The subjects participated in an experiment that measured postural sway during the static standing posture without light touch and postural sway during the static standing posture with light touch as follows: visual information not blocked without light touch, visual information blocked without light touch, visual information blocked with light touch using fingertips, and visual information not blocked with light touch using fingertips. The measurements were performed using a force platform. The variables measured by the force platform included sway velocities of the COP in the anterior and posterior directions and, medial and lateral directions and sway velocity moments. [Results] In the results of the study, there were significant differences between the state without light touch and state with light touch in terms of the postural sway velocity and velocity moment under all conditions. The rate of decease of the sway velocity and moment velocity under the eyes closed condition were higher compared with those under the eyes open condition. [Conclusion] Through this study, we confirmed the influence of fingertip light touch on the decrease in postural sway. The results show that active light touch may be supplemental means of improving postural sway in stroke patients. PMID- 25729194 TI - Effect of evidence-based trunk stability exercises on the thickness of the trunk muscles. AB - [Purpose] This study was conducted to investigate the effect of four spine stability exercises on the thickness of the internal and external oblique abdominal muscles, the transverses abdominis, and the multifidus muscles. [Subjects and Methods] Forty healthy adults were enrolled and randomly allocated to four groups. Ten participants performed bridge exercises (BE) while lying on their back; 10 others performed the same exercises with their right legs up (BERL); another 10 performed the same exercises on their side (SBE); and the remaining 10 performed them in a quadruped position with left arm and right leg lifts (QLARL). The participants performed the exercises three times a week for five weeks. The thicknesses of the muscles before and after the interventions were measured using ultrasound. [Results] The results show that the normal bridge exercise significantly thickened the TrA; BERL, the LM; QLARL, the IO; and SBE, the EO and the IO. [Conclusion] All four spine stability exercises were effective. The normal bridge exercise and BERL selectively strengthened the local muscles at the early stage of the treatment. We consider SBE and QLARL should be used in the later stages of treatments because they strengthen both the local and global muscles. PMID- 25729195 TI - Changes of kinematic parameters of lower extremities with gait speed: a 3D motion analysis study. AB - [Purpose] The purpose of this study was to investigate the changes in hip, knee and ankle kinematic variables of the lower extremities at different gait speeds. [Subjects and Methods] Forty healthy subjects who had no previous history of neurological, musculo-skeletal or other medical conditions that could affect gait were recruited. The subjects were asked to walk 10 m down a walkway at three different gait speeds: normal gait speed, and self-selected fast, and slow speeds. The experimental order was randomly chosen across these gaits. The hip, knee and ankle kinematic data were evaluated using a VICON 3D motion analysis system and force plates. [Results] The flexion peak and external rotation peak of the knee joint significantly increased with the increase of gait speed. The plantarflexion peaks of the ankle joint significantly increased with increase of gait speed. However, none of the kinematic data of the hip joint were significantly dependent on increase of gait speed. [Conclusion] The relationship of the knee and ankle joint can be described as coupling motion which is dependent on gait speed. Our present findings suggest that coupling motion of the knee joint and plantarflexion of the ankle joint significantly increase with increase of gait speed. These results will provide important insight into gait mechanisms for the evaluation of pathological populations. PMID- 25729196 TI - Influences of spinal decompression therapy and general traction therapy on the pain, disability, and straight leg raising of patients with intervertebral disc herniation. AB - [Purpose] The purpose of this study was to identify how spinal decompression therapy and general traction therapy influence the pain, disability, and straight leg raise (SLR) ability of patients with intervertebral disc herniation. [Subjects] The subjects were 30 patients with chronic lumbar pain who were divided into a spinal decompression therapy group (SDTG, n=15), and a general traction therapy group (GTTG, n=15). [Methods] The SDTG used a spinal decompression device, and the GTTG used a lumbar traction device. Both groups received conservative physical therapy three times a week for four weeks. A visual analog scale (VAS) was used to measure the degree of pain the patients with chronic lumbar pain. The Oswestry Disability Index (ODI) was used to measure the degree of functional disability. A goniometer was used to measure the patients' SLR ability. [Results] Both SDTG and GTTG showed statistically significant decreases in VAS and ODI scores and a statistically significant increase in SLR angle. A comparison of the two groups found no statistically significant differences. [Conclusion] Spinal decompression therapy and general traction therapy are effective at improving the pain, disability, and SLR of patients with intervertebral disc herniation. Thus, selective treatment may be required. PMID- 25729197 TI - Effects of different frequencies of rhythmic auditory cueing on the stride length, cadence, and gait speed in healthy young females. AB - [Purpose] The aim of this study was to explore the effects of different frequencies of rhythmic auditory cueing (RAC) on stride length, cadence, and gait speed in healthy young females. The findings of this study might be used as clinical guidance of physical therapy for choosing the suitable frequency of RAC. [Subjects] Thirteen healthy young females were recruited in this study. [Methods] Ten meters walking tests were measured in all subjects under 4 conditions with each repeated 3 times and a 3-min seated rest period between repetitions. Subjects first walked as usual and then were asked to listen carefully to the rhythm of a metronome and walk with 3 kinds of RAC (90%, 100%, and 110% of the mean cadence). The three frequencies (90%, 100%, and 110%) of RAC were randomly assigned. Gait speed, stride length, and cadence were calculated, and a statistical analysis was performed using the SPSS (version 17.0) computer package. [Results] The gait speed and cadence of 90% RAC walking showed significant decreases compared with normal walking and 100% and 110% RAC walking. The stride length, cadence, and gait speed of 110% RAC walking showed significant increases compared with normal walking and 90% and 100% RAC walking. [Conclusion] Our results showed that 110% RAC was the best of the 3 cueing frequencies for improvement of stride length, cadence, and gait speed in healthy young females. PMID- 25729198 TI - Effects of pulmonary rehabilitation education for caregivers on pulmonary function and pain in patients with lung cancer following lung resection. AB - [Purpose] The purpose of this study was to evaluate the effects of a pulmonary rehabilitation education program for caregivers on patients who underwent lung resection surgery. [Subjects] Subjects who underwent lung resection by visual assisted thoracotomy (VATs) were selected and divided into a control group of 19 and an experimental group of 22. [Methods] The experimental group received a pulmonary rehabilitation education program for caregivers, while the control group received typical care for 4 weeks. This study assessed the subjects 2 weeks (baseline) and 6 weeks after surgery (4 weeks). The forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) were measured to evaluate pulmonary function. A visual analogue scale (VAS) was utilized to evaluate pain. [Results] Pulmonary function (FVC and FEV1) increased more in the experimental group compared with the control group. Furthermore, VAS scores were lower in the experimental group compared with the control group. [Conclusion] A pulmonary rehabilitation education program for caregivers had a positive effect on pulmonary function in patients with lung cancer after lung resection. PMID- 25729199 TI - The influences of position and forced respiratory maneuvers on spinal stability muscles. AB - [Purpose] The purposes of this study were to investigate the influences of position on %MVIC of spinal stability muscles to establish for the most effective breathing pattern for activation of spinal stability muscles in order to provide an additional treatment method for use in spinal stability exercise programs. [Subjects and Methods] Thirty-three healthy subjects performed quiet breathing and four different forced respiratory maneuvers (FRM); [pursed lip breathing (PLB), diaphragmatic breathing (DB), combination breathing (CB) and respiration muscle endurance training (RMET)] in both standing and sitting positions. %MVIC of them (the multifidus (MF), erector spinae (ES), internal oblique/transversus abdominis (IO/TrA), external oblique (EO), rectus abdominis (RA) measured. [Results] IO/TrA, MF and EO showed greater activation in standing than in sitting, while RA and ES showed greater activation in sitting than in standing. RMET induced significantly greater activation of spinal stability muscles then other breathing patterns. %MVIC changes of muscle activities induced by FRM were independent of position with a few exceptions. [Conclusion] The increased respiratory demands of FRM induced greater activation of spinal stability muscles than QB. RMET was found to be the most effective breathing pattern for increasing the activation of the spinal stability muscles. PMID- 25729200 TI - Joystick-controlled video console game practice for developing power wheelchairs users' indoor driving skills. AB - [Purpose] This study aimed to determine the effectiveness of joystick-controlled video console games in enhancing subjects' ability to control power wheelchairs. [Subjects and Methods] Twenty healthy young adults without prior experience of driving power wheelchairs were recruited. Four commercially available video games were used as training programs to practice joystick control in catching falling objects, crossing a river, tracing the route while floating on a river, and navigating through a garden maze. An indoor power wheelchair driving test, including straight lines, and right and left turns, was completed before and after the video game practice, during which electromyographic signals of the upper limbs were recorded. The paired t-test was used to compare the differences in driving performance and muscle activities before and after the intervention. [Results] Following the video game intervention, participants took significantly less time to complete the course, with less lateral deviation when turning the indoor power wheelchair. However, muscle activation in the upper limbs was not significantly affected. [Conclusion] This study demonstrates the feasibility of using joystick-controlled commercial video games to train individuals in the control of indoor power wheelchairs. PMID- 25729201 TI - Abnormal sitting pressures of hemiplegic cerebral palsy children on a school chair. AB - [Purpose] The purpose of this study was to investigate the differences in symmetry of sitting posture between typical developmental (TD) children and hemi cerebral palsy (CP) children. [Subjects and Methods] A school chair mounted on a force platform was used to assess the quiet-sitting pressure distribution of 10 TD and 10 CP children. [Results] The symmetry index of the TD children was significantly closer to zero than that of the CP children irrespective of the latter group's hemiparetic side. [Conclusions] Sitting posture on school chairs of CP children was more asymmetrical than that of TD children. PMID- 25729202 TI - Effects of performing an abdominal hollowing exercise on trunk muscle activity during curl-up exercise on an unstable surface. AB - [Purpose] The purpose of this study was to investigate the effects of the abdominal hollowing exercise on trunk muscle activity during the curl-up exercise on an unstable surface by measuring electromyography (EMG) activity. [Subjects] Fourteen young healthy adults (nine male, five female) voluntarily participated in this study. [Methods] Each subject was asked to perform a curl-up exercise on two supporting surfaces (stable and unstable surfaces) combined with the abdominal hollowing exercise on an unstable surface. The muscle activities of the rectus abdominis (RA), external oblique (EO), internal oblique (IO), and transverse abdominis (TrA) were measured using surface EMG during performance of the curl-up exercise. [Results] The EMG activity of the RA and EO was significantly higher on an unstable surface than on a stable surface during the curl-up exercise. The EMG activities of the TrA and IO were greater in combination with the abdominal hollowing exercise on an unstable surface than during the curl-up exercise on both a stable and unstable surface. [Conclusion] These findings suggest that the local trunk muscle activity during the curl-up exercise is more strongly affected by combination with the abdominal hollowing exercise than by performance on an unstable supporting surface. PMID- 25729203 TI - Effects of Thai massage on physical fitness in soccer players. AB - [Purpose] The aim of this study was to determine the effects of Thai massage on physical fitness in soccer players. [Subjects and Methods] Thirty-four soccer players were randomly assigned to receive either rest (the control group) or three 30-minute sessions of Thai massage over a period of 10 days. Seven physical fitness tests consisting of sit and reach, hand grip strength, 40 yards technical agility, 50-meter sprint, sit-ups, push-ups, and VO2, max were measured before and after Thai massage or rest. [Results] All the physical fitness tests were significantly improved after a single session of Thai massage, whereas only the sit and reach, and the sit-ups tests were improved in the control group. [Conclusion] Thai massage could provide an improvement in physical performance in soccer players. PMID- 25729204 TI - The effect of active core exercise on fitness and foot pressure in Taekwondo club students. AB - [Purpose] The effects of core training using slings and Togus on the improvement of posture control in Taekwondo club students, that is, balance ability, were investigated. To that end, changes in the Taekwondo players' balance ability resulting from active core training for eight weeks were examined through fitness and foot pressure. [Subjects] The present study was conducted with 13 male Taekwondo players of K University in Deagu, South Korea. Once the experiment process was explained, consent was obtained from those who participated voluntarily. [Methods] Air cushions (Germany), Jumpers (Germany), and Aero-Steps (Germany) were used as lumbar stabilization exercise tools. As a method of training proprioceptive senses by stimulating somatesthesia in standing postures, the subjects performed balance squats, supine pelvic lifts, and push-up plus exercise using slings while standing on an Aero-Step and performed hip extension parallel squats (Wall Gym Ball), and standing press-ups on a Togu using their own weight. The subjects performed four sets of these isometric exercises while maintaining an exercise time per set at 30 seconds in each session and repeated this session three times per week. [Result] Left grip strength significantly increased and number of sit-ups, which indicates muscle endurance, also significantly increased after the eight weeks exercise compared with before the exercise. The values measured during the sit and reach test, which indicate flexibility, also significantly increase after the eight weeks of exercise compared with before the exercise but only in the left foot. [Conclusion] The result of present study suggest that active core exercise using Slings and Togus can be applied as a very effective exercise program for enhancing balance, which is an important physical factor for Taekwondo club students. PMID- 25729205 TI - Effects of brain-computer interface-based functional electrical stimulation on balance and gait function in patients with stroke: preliminary results. AB - [Purpose] The purpose of this study was to determine the effects of brain computer interface (BCI)-based functional electrical stimulation (FES) on balance and gait function in patients with stroke. [Subjects] Subjects were randomly allocated to a BCI-FES group (n=5) and a FES group (n=5). [Methods] The BCI-FES group received ankle dorsiflexion training with FES according to a BCI-based program for 30 minutes per day for 5 days. The FES group received ankle dorsiflexion training with FES for the same duration. [Results] Following the intervention, the BCI-FES group showed significant differences in Timed Up and Go test value, cadence, and step length on the affected side. The FES group showed no significant differences after the intervention. However, there were no significant differences between the 2 groups after the intervention. [Conclusion] The results of this study suggest that BCI-based FES training is a more effective exercise for balance and gait function than FES training alone in patients with stroke. PMID- 25729206 TI - Reliability and validity of the Japanese version of the short questionnaire to assess health-enhancing physical activity (SQUASH) scale in older adults. AB - [Purpose] We tested the reliability and validity of the Japanese version of the Short Questionnaire to Assess Health-enhancing Physical Activity scale in asymptomatic older adults and sought to confirm discriminator validity in women with osteoarthritis. [Subjects] The participants included an asymptomatic comparison group (men and women) and women with knee or hip osteoarthritis. [Methods] The test-retest method was used to assess reliability. The International Physical Activity Questionnaire was chosen to assess criterion related validity. Discriminator validity was assessed by comparing the asymptomatic and osteoarthritis groups. [Results] Mean age for the asymptomatic groups was 63 +/- 6 years for men (n = 23) and 61 +/- 7 years for women (n = 51), and it was 63 +/- 9 years for the osteoarthritis group (n = 32). The total score and scores for all items, except for heavy housework items, were significantly correlated with the retest. Criterion-related validity showed significantly weak to moderate correlations between the respective scale categories. For discriminator validity, the total scores and scores for bicycle commuting, light housework, and three leisure items differed significantly between the asymptomatic and osteoarthritis groups. [Conclusion] The Short Questionnaire to Assess Health-enhancing Physical Activity scale is a reliable and valid measure in asymptomatic older adults, and can discriminate between osteoarthritic and asymptomatic women. PMID- 25729207 TI - The effects of extracorporeal shock wave therapy on stroke patients with plantar fasciitis. AB - [Purpose] The purpose of this research was to analyze the efficacy of extracorporeal shock wave therapy for the treatment of stroke patients with plantar fasciitis. [Subjects and Methods] This study included 10 stroke patients diagnosed with plantar fasciitis who were administered 3 sessions of extracorporeal shock wave therapy per week. After the last session, they performed stretching exercises for their Achilles tendon and plantar fascia for 30 min/day, 5 times a week for 6 months. The following parameters were measured and compared prior to therapy, 6 weeks after therapy, and 6 months after therapy: thickness of the plantar fascia, using an ultrasonic imaging system; degree of spasticity, using a muscle tension measuring instrument; degree of pain, using the visual analogue scale; and gait ability, using the Functional Gait Assessment. [Results] Decreased plantar fascia thickness, spasticity, and pain and increased gait ability were noted after therapy. These changes were significantly greater at 6 months after therapy than at 6 weeks after therapy. [Conclusion] These results indicated that extracorporeal shock wave therapy reduced tension in the plantar fascia, relieving pain and improving gait ability in stroke patients. PMID- 25729208 TI - The effects on dynamic balance of dual-tasking using smartphone functions. AB - [Purpose] This study aimed to compare dynamic balance with respect to completing a single task while not using smartrphone function and completing two task while using different smartphone functions, therby preventing falls or injuries resulting from completion of dual tasks. [Subjects and Methods] The subjects of this study were 36 healthy males and females. The experiment was conducted for five situations: a Star Excursion Balance Test (SEBT) was performed (1) during single-tasking without a smartphone and during dual-tasking with a smartphone, (2) when listening to music using a smartphone, (3) when sending message using a smartphone, (4) when surfing the web using a smartphone, and (5) when playing a game using a smartphone. The condition were the same for all five experimentes. Random selection was done to prevent learing. All experiments were conducted three times, and the averaged values were used for analysis. The SEBT was performed in three directions: anterior, posterolateral, and posterormedial. In consideration the differences in leg length of the subjects, their actual leg length were measured to be used as percentages. Their leg length was measured from the anterior superior iliac spine of the femur to the medial malleolus. [Results] Compared with single task not done using a smartphone, dynamic balance statistically significantly changed for dual tasks done using a smartphone in all three directions. Dynamic balance decreased in all three directions when playing games, sending messages, web surfing, and listening to music. [Conclusion] Completing two tasks using a smartphone reduced cognitive ability, decreasing dynamic balance. Therefore, performing a single task rather than using the diverse functions of a smartphone while walking or working is considered a factor that can prevent falls and injuries. PMID- 25729209 TI - Evaluation of muscle damage using ultrasound imaging. AB - [Purpose] This study aimed to quantitatively analyze characteristics of and changes in internal muscle structure according to the time of delayed onset muscle soreness (DOMS) using ultrasound imaging, thereby presenting clinical evidential data for evaluation of muscle damage. [Subjects] We recruited 38 male subjects. [Methods] Ultrasound images of the medial gastrocnemius muscle prior to induction of DOMS and immediately after, 24 hours after, 48 hours after, and 72 hours after induction of DOMS were obtained, and the thickness and pennation angle of the muscle were measured. [Results] The muscle thickness gradually increased until 48 hours after induction of DOMS and decreased after 72 hours. The pennation angle also gradually increased until 48 hours after induction of DOMS and decreased after 72 hours. [Conclusion] Ultrasound imaging is considered useful for assessment of structural characteristics of muscles when muscle damage like DOMS takes place. PMID- 25729210 TI - Effect of modified hold-relax stretching and static stretching on hamstring muscle flexibility. AB - [Purpose] The aim of present study was to compare the effectiveness of modified hold-relax stretching and static stretching in improving the hamstring muscle flexibility. [Subjects and Methods] Forty-five male subjects with hamstring tightness were included in this study. The subjects were randomly placed into three groups: the modified hold-relax stretching, static stretching and control groups. The modified hold-relax stretching group performed 7 seconds of isometric contraction and then relaxed for 5 seconds, and this was repeated five times daily for five consecutive days. The static stretching group received 10 minutes of static stretching with the help of a pulley and weight system for five consecutive days. The control group received only moist heat for 20 minutes for five consecutive days. A baseline reading of passive knee extension (PKE) was taken prior to the intervention; rest measurements were taken immediate post intervention on day 1, day 3, day 5, and after a 1 week follow-up, i.e., at the 12th day. [Results] On comparing the baseline readings of passive knee extension (PKE), there was no difference noted between the three groups. On comparing the posttest readings on day 5 between the 3 groups, a significant difference was noted. However, post hoc analysis revealed an insignificant difference between the modified hold-relax stretching and static stretching groups. There was a significant difference between the static stretching and control groups and between the modified hold-relax stretching and control groups. [Conclusion] The results of this study indicate that both the modified hold-relax stretching technique and static stretching are equally effective, as there was no significant difference in improving the hamstring muscle flexibility between the two groups. PMID- 25729211 TI - Comparison of supraspinatus cross-sectional areas according to shoulder abduction angles. AB - [Purpose] The purpose of this study was to determine the changes in the supraspinatus cross-sectional areas according to shoulder abduction angles, using ultrasonography. [Subjects and Methods] The subjects consisted of 40 individuals (20 males and 20 females). The cross-sectional areas of the supraspinatus of all subjects were measured with ultrasonography at abduction angle of 0 degrees , 30 degrees , 60 degrees , 90 degrees , and 120 degrees . We set four abduction angle levels (I, II, III, and IV), 0 degrees to 30 degrees , 30 degrees to 60 degrees , 60 degrees to 90 degrees , and 90 degrees to 120 degrees , respectively, when determining the largest change in cross-sectional area. [Results] The results revealed that cross-sectional areas of the supraspinatus increased at all levels, but the abduction angle level with the largest increase in cross-sectional area of the supraspinatus was Level III. [Conclusion] The above results indicate that performing exercises at an abduction angle between 60 degrees and 90 degrees will be the most effective for supraspinatus strengthening in clinical practice. PMID- 25729212 TI - Cognitive rehabilitation for elderly people with early-stage Alzheimer's disease. AB - [Purpose] The purpose of this study was to investigate the effect of cognitive rehabilitation including tasks of cognitive training on performance of everyday activities in elderly people with early-stage Alzheimer's disease. [Subjects and Methods] Forty-three elderly people (15 men, 28 women) with a diagnosis of Alzheimer's disease who had a Mini-Mental State Examination (MMSE) score of 18 or above were randomly assigned to two groups: the cognitive rehabilitation group (experimental) and control group. This study used a randomized controlled trial design. Cognitive rehabilitation is consisted of 8 sessions, each lasting 60 minutes (individual 30 min, group 30 min). The eight weekly individual sessions of cognitive rehabilitation were performed consisting of an individualized intervention focusing on a personally meaningful goal. The eight weekly group sessions involved practicing time-and-place orientation, matching faces and names, and learning memory and sustaining attention. [Results] Significant improvements were observed in rating of occupation performance and satisfaction, Quality of Life in Alzheimer's Disease (QOL-AD), and the orientation subscale of the MMSE in the experimental group, whereas participants in the control group did not show any significant difference in any tests between before and after the intervention. [Conclusion] Cognitive rehabilitation including tasks of cognitive training is an effective intervention for improving performance and satisfaction with respect to activities of daily living and specific cognitive functions. PMID- 25729213 TI - Effects of scapula-upward taping using kinesiology tape in a patient with shoulder pain caused by scapular downward rotation. AB - [Purpose] The aim of this study was to evaluate the effects of scapula-upward taping (SUT) in a patient with shoulder pain caused by scapular downward rotation (SDR). [Subject] A 26-year-old male with SDR experienced severe pain in the left shoulder when he lifted his left upper extremity to hold the handle in a bus and during and after push-up exercise. [Methods] The patient underwent SUT for a period of 1 month, 5 times per week, for an average of 9 h/d. [Results] The patient's radiographs showed that the degree of SDR had decreased; the left shoulder pain also decreased in the resting state and during and after push-up exercise. The manual muscle strength test grades of the upper trapezius, lower trapezius, and serratus anterior had increased. The patient was able to lift the left upper extremity to hold the handle in a bus and perform the push-up exercise without experiencing any pain. [Conclusion] Repeated SUT application may be a beneficial treatment method for alleviating the degree of SDR and shoulder pain in SDR patients. PMID- 25729214 TI - Variations in key artemisinic and other metabolites throughout plant development in Artemisia annua L. for potential therapeutic use. AB - Dried leaves of Artemisia annua show promise as an inexpensive and sustainable antimalarial therapeutic, especially for use in developing countries. Along with the potent terpene, artemisinin, many other small molecules produced by the plant seem to aid in the therapeutic response. However, little is known about the ontogenic and phenological production of artemisinin in the plant, and its plethora of other important secondary metabolites. From a consistently high artemisinin-producing A. annua clone (SAM) we extracted and analyzed by GC/MS 22 different metabolites including terpenes, flavonoids, a coumarin, and two phenolic acids as they varied during leaf development and growth of the plant from the vegetative stage through the reproductive, full flower stage. As leaves developed, the maximum amount of most metabolites was in the shoot apical meristem. Artemisinin, on the other hand, maximized once leaves matured. Leaf and apical tissues (e.g. buds, flowers) varied in their metabolite content with growth stage with maximum artemisinin and other important secondary metabolites determined to be at floral bud emergence. These results indicated that plants at the floral bud stage have the highest level of artemisinin and other therapeutic compounds for the treatment of malaria. PMID- 25729215 TI - Autophagy upregulation and apoptosis downregulation in DAHP and triptolide treated cerebral ischemia. AB - It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4 diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (NOS) inhibiting neuroprotective effect, and triptolide (TP), for its anti-inflammatory property, were selected to administer pre middle cerebral artery occlusion (MCAO). The drugs were administered 12 hours prior to MCAO. Both magnetic resonance imaging (MRI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the drugs reduce the area of infarction. Immunoblotting analysis revealed increases in Beclin-1 and myeloid cell leukelia-1(Mcl-1) in treated rats. This could be a contributing factor to the reduction in autophagy induced damage. Immunochemistry and western blot showed that mTOR expression in treated rats was marginally different 24 h after injury, and this could also be significant in the mechanism. Furthermore, terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) staining proved that the drugs are effective in reducing apoptosis. The upregulation of Beclin-1 and Mcl-1 and downregulation of Bcl-2, caspase-3, and the Bcl-2/Beclin-1 ratio infer that the neuroprotective effect of DAHP and TP act via the mediation of autophagy and apoptosis pathways. PMID- 25729217 TI - Allicin alleviates inflammation of trinitrobenzenesulfonic acid-induced rats and suppresses P38 and JNK pathways in Caco-2 cells. AB - Background. Allicin has anti-inflammatory, antioxidative and proapoptotic properties. Aims. To evaluate the effects and investigate the mechanism of allicin on trinitrobenzenesulfonic acid-induced colitis, specifically with mesalazine or sulfasalazine. Methods. 80 rats were divided equally into 8 groups: control; trinitrobenzenesulfonic acid; allicin prevention; allicin; mesalazine; sulfasalazine; allicin + sulfasalazine, and mesalazine + allicin. Systemic and colonic inflammation parameters were analysed. In addition, protein and culture medium of Caco-2 cells treated with various concentrations of IL-1beta or allicin were collected for investigation of IL-8, NF-kappaB p65 P38, ERK, and JNK. One way ANOVA and Kruskal-Wallis H test were used for parametric and nonparametric tests, respectively. Results. Allicin reduced the body weight loss of trinitrobenzenesulfonic acid-induced rats, histological score, serum TNF-alpha and IL-1beta levels, and colon IL-1beta mRNA level and induced serum IL-4 level, particularly in combination with mesalazine. In addition, 1 ng/mL IL-1beta stimulated the P38, ERK, and JNK pathways, whereas pretreatment with allicin depressed this phenomenon, except for the ERK pathway. Conclusions. The inflammation induced by trinitrobenzenesulfonic acid is mitigated significantly by allicin treatment, particularly combined with mesalazine. Allicin inhibits the P38 and JNK pathways and the expression of NF-kappaB which explained the potential anti-inflammatory mechanisms of allicin. PMID- 25729216 TI - Role of COX-2/mPGES-1/prostaglandin E2 cascade in kidney injury. AB - COX-2/mPGES-1/PGE2 cascade plays critical roles in modulating many physiological and pathological actions in different organs. In the kidney, this cascade is of high importance in regulating fluid metabolism, blood pressure, and renal hemodynamics. Under some disease conditions, this cascade displays various actions in response to the different pathological insults. In the present review, the roles of this cascade in the pathogenesis of kidney injuries including diabetic and nondiabetic kidney diseases and acute kidney injuries were introduced and discussed. The new insights from this review not only increase the understanding of the pathological role of the COX-2/mPGES-1/PGE2 pathway in kidney injuries, but also shed new light on the innovation of the strategies for the treatment of kidney diseases. PMID- 25729219 TI - Clinical evaluation of anodized surface implants submitted to a counter torque of 25 ncm after 60 days of osseointegration: study in humans. AB - INTRODUCTION: Decreasing the time needed for osseointegration has always been a big challenge for modern implantodontics. The main factor which helps to decrease the time needed for osseointegration is the newly developed surfaces being used, as well as their microstructures, in relation to their osseoinductive properties. The aim of this work is to clinically evaluate the osseointegration of the implants when using The anodized surfaces in humans, following a 60 days-period of osseointegration. METHODOLOGY: Forty-Five implants were placed in different kinds of bones, according to the technique recommended by the manufacturer. Those implants were opened after 60 days of osseointegration. The success of evaluation was made through assessing the counter torque resistance of 25 Ncm. The implants which could withstand the applied torque were considered osseointegrated. RESULTS: Of the forty-five implants made in different kinds of bones, only one failed to present osseointegration, resulting in a success rate of 97.7 %. CONCLUSIONS: With this methodology it was possible to conclude that anodized surface implants present primary osseointegration after 60 days of healing, after which they can function normally. PMID- 25729218 TI - Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. AB - Autism is a disorder of neurobiological origin characterized by problems in communication and social skills and repetitive behavior. After more than six decades of research, the etiology of autism remains unknown, and no biomarkers have been proven to be characteristic of autism. A number of studies have shown that the cytokine levels in the blood, brain, and cerebrospinal fluid (CSF) of autistic subjects differ from that of healthy individuals; for example, a series of studies suggests that interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), and interferon-gamma (IFN-gamma) are significantly elevated in different tissues in autistic subjects. However, the expression of some cytokines, such as IL-1, IL-2, transforming growth factor-beta (TGF-beta), and granulocyte macrophage colony-stimulating factor (GM-CSF), is controversial, and different studies have found various results in different tissues. In this review, we focused on several types of proinflammatory and anti-inflammatory cytokines that might affect different cell signal pathways and play a role in the pathophysiological mechanism of autistic spectrum disorders. PMID- 25729220 TI - Effect of age, sex and level of surgical difficulty on inflammatory complications after third molar surgery. AB - BACKGROUND: Patients' factors such as age and sex and surgical variables such as level of difficulty have been linked with surgical outcome in third molar surgery. The aim of this study was to determine the effect of these variables on inflammatory complications in patients undergoing third molar surgery. METHODS: Patients referred to our institution for surgical extraction of their impacted lower third molar between January 2007 and December 2008 were the subjects of the study. Patients' demographics as well as types of impaction, indication and level of difficulty based on Pederson criteria were obtained. Post operative pain, swelling and mouth opening limitation were evaluated at day 1, day 2, day 3, day 5 and 1 week after the surgery and analyzed. A p value of less than 0.05 was considered significant. RESULTS: A total of 150 patients aged 16-38 years (25.9 +/- 4.47) met the inclusion criteria. Male accounted for 66 (44.0 %) while females were 84 (56.0 %), giving male to female ratio of 1:1.3. Age, sex and difficulty index had no effect on pain and trismus throughout the periods of postoperative evaluation (p > 0.05). Postoperative swelling was not affected by gender but patients above 25 years who had high scores of difficulty index had more facial swelling. CONCLUSION: The results of this study shows that age, gender and the level of surgical difficulty have no effect on pain and mouth opening limitation after third molar surgery. PMID- 25729221 TI - Vertically unstable fractured mandibular segment with attached genial tubercles as a parameter for difficulty during intubation for general anaesthesia. AB - PURPOSE: It remains vital for the trauma management team including the anaesthetist and the operating surgeon to assess and evaluate the anticipated difficulty in intubation to secure airway and for administration of anaesthesia. This study assesses the difficulty in intubating patients with vertically unstable mandibular parasymphysis fracture with attached genial tubercles and associated musculature to the fractured segment. METHODS: Randomized sampling was done from the cases with maxillofacial trauma planned for a surgical procedure under general anaesthesia. The inclusion criteria was to prospectively identify ten patients each of unilateral unfavourable mandibular parasymphysis fracture with genial tubercle attached to the displaced segment, with bilateral unfavourable mandibular parasymphysis fracture with genial tubercle attached to the displaced segment and with unilateral favourable mandibular parasymphysis fracture with genial tubercle attached to the un-displaced segment. All the patients were intubated by a single anaesthetist, who documented the difficulty in nasoendotracheal intubation using Intubation Difficulty Scale. RESULTS: Nasoendotracheal intubation was found relatively easy in the study group with unilateral favourable mandibular parasymphysis fracture with genial tubercle attached to the un-displaced segment. Clinical difficulty in intubating the patients was maximum in the study group with bilateral unfavourable mandibular parasymphysis fracture with genial tubercle attached to the displaced segment. CONCLUSION: Displacement of fractured mandible and resultant displacement of the genial musculature should be considered as a vital parameter for assessing difficulty during intubation. PMID- 25729222 TI - Factors Influencing Treatment Plan and Post Operative Compliance in TMJ Ankylosis Patients: A Retrospective Analysis of Long Term Post Surgical Evaluation. AB - BACKGROUND AND OBJECTIVE: Ankylosis of the temporomandibular joint is a clinical entity significant for a maxillofacial surgeon. Since time immemorial humanity is battling with this condition which is not just disfiguring the normal anatomy of the face but severely hampers the function of mastication. In this study we have tried to evaluate and correlate various factors leading to causation of ankylosis of TM Joint along with clinical manifestation and treatment planning as well as outcomes. STUDY DESIGN: This is a retrospective study, records of 60 patients were selected out of which 28 patients reported for recall. Based on a predefined format, patients were evaluated and correlation was looked up on various accounts such as age of occurrence and age of reporting to the surgeon, probable etiology, sex distribution, treatment modality and postoperative outcome. RESULTS: The mean age of onset or occurrence was 4-7 years of age whereas age of reporting to the clinic was 16-17 years. Highest percentage of patients had trauma as an etiology (64 %) and the lowest percentage had congenital deformity (21 %). Three surgical techniques were evaluated and compared for their post surgical mouthopening, gap arthroplasty was done in 61 %, interpositional arthroplasty in 39 % and low ramus osteotomy in 21 %. CONCLUSION: This study was aimed at analyzing the clinical form and function of the post surgical patient reviewing the recent radiographs to analyze the surgical site. The data collected was (1) Age of occurrence and age of reporting with the deformity (2) Etiological history (3) Sex and Side predisposition (4) Procedure used for correction of deformity (5) Recall (follow up) data especially recurrence and physiotherapy. We arrived at a conclusion that mean age of occurrence of deformity was approximately 4.7 years and age at which patient reported to clinic was 16.2 years. The main etiological factor was trauma (51 %) and ear infection (21 %). 57 % patients presented with unilateral deformity, with both the sides equally effected. The effectiveness of gap arthroplasty, interpositional arthroplasty and low ramus osteotomy procedures was evaluated. Gap arthroplasty and interpositional arthroplasty were found to be effective procedures. The importance of post operative physiotherapy was emphasised yet again through this study. PMID- 25729223 TI - Evaluation of neurosensory disturbance following orthognathic surgery: a prospective study. AB - AIM AND OBJECTIVES: The prospective study was to evaluate the incidence, type of neurosensory disturbance (NSD), grade its severity and monitor its recovery occurring in the lower lip and chin due to damage to inferior alveolar nerve following orthognathic surgery involving mandible. MATERIALS AND METHODS: The study included 10 patients who have undergone sagittal split osteotomy, genioplasty, and anterior subapical osteotomy (ASO). All the patients examined preoperatively and post operatively 1 week, 1 and 6 months according to standardized test to clarify the subjective and objective neurosensory status of the injured nerve. Pin prick test, blunt test, two-point discrimator test, brush stoke direction, light touch test, warm and cold test were used bilaterally to lower lip and chin area. RESULTS: Seven patients underwent bilateral sagittal split osteotomy (BSSO) (70 %), one patient had BSSO with genioplasty (10 %), two patients had BSSO with ASO (20 %). During the operation none of the nerves were transectioned, in 60 % of patients nerve was not visible and in 40 % of patients nerve was seen in distal segment. 70 % of patients underwent setback, 30 % of patients underwent advancement. The subjective evaluation of the patients revealed the incidence of 90 % at 1 week, 30 % at 1 month, 20 % at 6 months and 10 % at 1 year post operatively. The altered sensation reported subjectively was hypoesthesia in 50 % of the patients, anaesthesia in 40 % of the patients. There was 100 % recovery in advancement cases and 93.5 % recovery in setback cases. CONCLUSION: There is a high incidence of NSD of the lower lip and chin after BSSO related to advancement, setback, intraoperative nerve encounter and surgical skill. However, recovery of sensation occurs with increasing frequency during the follow-up period. The clinical neurosensory tests are effective guides to study the neurosensory deficit. PMID- 25729224 TI - Study of the pattern of maxillofacial fractures seen at a tertiary care hospital in north India. AB - AIM: The present study was planned to investigate the etiology of maxillofacial injuries and to analyze the pattern of maxillofacial factures as well as the various factors influencing their distribution. STUDY DESIGN: A one year cross sectional study was done and 1,108 patients with maxillofacial fractures were analyzed consecutively from April 2010 to March 2011 who reported to the department of Oral and Maxillofacial Surgery in the Centre for Dental Education & Research and Jai Prakash Narayan Apex Trauma Centre, AIIMS, New Delhi. A performa was designed to collect the data that included age and sex distribution, etiology, influence of alcohol, type of fractures, use of restraints devices, associated injuries and treatment delivered. RESULTS: Out of 1,108 patients, 89.62 % were males with a male:female ratio of 8.63:1. The 21-30 year age group was found to be maximum (39.98 %). Road traffic accidents accounted for 49.01 %, followed by assault (22.38 %) and fall from height (21.66 %). Two wheelers were the most commonly involved vehicle. Out of 437 road traffic accident patients (excluding pedestrian, n = 106), only 52.40 % were found to be using restraints devices at the time of accident. Totally 25.45 % patients were under the influence of alcohol at the time of injury. According to anatomical distribution of fractures, mandibular fractures (33.57 %) were most prevalent, followed by maxilla (31.13 %), nasal (28.33 %) and zygoma (24.36 %). Head injuries (18.32 %) were found to be the most common associated injuries followed by lower limb fractures. CONCLUSION: The motive behind executing this article is to analyze the various trends of facial fractures and all those factors that affect their distribution. A perfect understanding of pattern of maxillofacial fracture will assist the executors of health care in the treatment planning and management of facial injuries. Knowledge gained from the present study would influence in assessing the effectiveness of existing preventive measures and elaboration of future preventive measures and conducting new research. PMID- 25729225 TI - Value of immunohistochemistry in diagnosing a rare case of maxillofacial plasma cell granuloma masquerading as a gingival epulis. AB - BACKGROUND: Plasma cell granuloma is a non-neoplastic lesion rather uncommonly seen in the maxillofacial region. Its etiology, biological behavior, ideal treatment and prognosis are still unclear and rather controversial. STUDY: A detailed histopathological examination and immunohistochemical study of the excised specimen was carried out, both for making a confirmatory diagnosis as well as to determine the etiopathology, biological behavior and prognosis of the lesion. RESULTS: Light microscopy revealed a hyperplastic stratified squamous epithelial lining, overlying a densely fibrocellular granulation tissue containing a rich proliferation of mononuclear inflammatory cells, among which there was a predominance of plasma cells with their typical eccentric, cartwheel shaped, "clock-faced" nuclei. Strong immunohistochemical positivity was observed for CD-138 by numerous cells of the connective tissue of the lesion, thus confirming them to indeed be plasma cells. Further, immunohistochemistry (IH) analysis also demonstrated the expression of both, the lambda and kappa light chain immunoglobulins by the plasma cell population, thus confirming them to be polyclonal and of an inflammatory, non-neoplastic origin. SUMMARY AND CONCLUSION: As a plasma cell granuloma is rarely encountered in the oral and maxillofacial region, its diagnosis could have been very easily missed, had it not been for the detection of the large numbers of plasma cells by light microscopy, which was further confirmed by IH. IH also helped in establishing the likely etiopathology of the lesion and confirmed it to be of a non-neoplastic reactive/inflammatory origin. PMID- 25729226 TI - Evaluation of mandibular wing osteotomy in obstructive sleep apnea cases with retrognathia. AB - OBJECTIVE: The aim of this study is to evaluate the efficacy of wing osteotomy for treating obstructive sleep apnea (OSA). MATERIALS AND METHODS: We performed mandibular wing osteotomy in subjects who had an apnea-hypopnea index (AHI) of more than 15, a previous unresponsive conservative treatment for the OSA, moderate to severe retrognathia and no suggested conventional orthognathic surgery because of dentition or lack of willingness. The subjects were evaluated using the Epworth Sleepiness Scale (ESS), AHI and posterior airway space (PAS) before and 1 year after surgery. RESULTS: We evaluated 10 subjects (4 males, 6 females) who underwent wing mandibular osteotomy. The mean age of the subjects was 37.8 +/- 7.26 years. Analysis of the data demonstrated a significant change in ESS and AHI 1 year after operation. However, PAS was not changed 1 year after surgery. Results did not show any correlation between age, ESS and AHI before and 1 year after surgery. CONCLUSION: Mandibular wing osteotomy is a novel procedure that improves signs of OSA. It may be a surgical option in retrognathic patients with OSA who are not candidates for conventional maxillomandibular advancement. PMID- 25729227 TI - Knowledge, attitude and awareness of speciality of oral and maxillofacial surgery amongst medical consultants of vadodara district in gujarat state. AB - BACKGROUND AND AIM: Aim of this study was to survey the knowledge, attitude and awareness of the subject of oral and maxillofacial surgery speciality amongst the consultants and practitioners of medicine in district of Vadodara. MATERIALS AND METHODS: List of members of various specialities in medical faculty were obtained from Indian Medical Association, Baroda branch and staff members of medical colleges of Vadodara district. A questionnaire survey was made which was distributed and their options were noted. RESULTS: Surgical removal of third molar, oral submucous fibrosis and implants were the problems where oral surgeons were preferred. For maxillofacial trauma plastic surgeons and orthopaedic surgeons were preferred than oral surgeons. For maxillofacial pathology E.N.T surgeons were mostly preferred. There is low awareness regarding oral and maxillofacial surgery amongst the general practitioners and medical consultants in Vadodara district. CONCLUSION: Survey shows that our training needs to be upgraded and revamped so that our trainees (post graduates in oral surgery) and have a greater "hands-on" exposure during their postgraduate training. They will then be able to handle increasingly complex cases in a multispecialty setup when they graduate and earn the mutual respect of the medical and dental fraternity and also the general public. MBBS students during their dental postings should be made aware of the depth and scope of oral surgery branch. PMID- 25729228 TI - Submental flap in intraoral reconstruction after pathologic resections: indications and limitations. AB - INTRODUCTION: Submental flap is used to reconstruct intraoral and facial soft tissue defects. Submental flap is used for intraoral reconstruction in eighteen patients. Complications of this flap that includes local recurrence, remaining metastatic lymph node in the field of neck dissection, wound dehiscence at donor site and probability of transferring metastatic tissue are evaluated. MATERIALS AND METHODS: This flap is used as an alternative to free tissue transfer, and this article presents 18 cases after pathologic lesion resections, such as verrocous carcinoma (2 patients), odontogenic myxoma (1 patient), oral squamous cell carcinoma (SCC) (10 patients), adenoid cystic carcinoma (2 patients), leukoplakia (2 patients) as well as osteosarcoma in one patient. RESULTS: There was no case of local recurrence and remaining metastatic lymph node in the field of neck dissection. A case of metastatic lymph node involvement in posterior triangle of the neck, 2 years after surgery was occurred. One case of metastatic tissue transfer and a case of wound dehiscence in submental region are reported. CONCLUSION: Submental flap is an useful aid for reconstruction of oral cavity mucosal defects. Its use in oral SCC reconstruction should be done in carefully selected cases. PMID- 25729229 TI - KOr.U Face Lift: Personal Technique. AB - AIM: Facial aging is the union of multiple effects such as exposure to the sun, ambiental stress, smog, tobacco. It reflects the dynamic, cumulative effects of time on the skin, soft tissues, and deep structural components of the face showing skin textural changes and loss of facial volume. There are a multitude of techniques currently used to perform face lifts, but the unique objective is to achieve a good and safe result. METHODS: This paper describes a new safe approach to midfacial rejuvenation that combines the elements of superficial musculoaponeurotic system (SMAS) plication, about four vectors, with a blepharoplasty to achieve long-lasting improvement of the aging midface and a more natural effect. Plication of the SMAS over the suture, provides three vectors of elevation beneath the skin in midface rhytidectomy linked to the Lore's fascia and the third vector of elevation of platysma behind the ear. RESULTS: This new technique, called KOr.U technique, was used in 31 patients between October 2010 and October 2012, producing effective long-lasting results, returning a volume of midface with no injury. DISCUSSION: This simplified approach is safe and can be easily performed under local anesthesia as an isolated midface procedure, avoiding the facial nerve. PMID- 25729230 TI - Clinical evaluation of use of platelet rich plasma in bone healing. AB - BACKGROUND: Tooth extraction is performed for a wide variety of reasons as we know. Several techniques aiming at enhancing the regeneration process in the extraction socket have been adopted such as filling the socket with autogenous bone grafts or bone substitutes. We know platelets play a central role in hemostasis and healing processes but relative contradictory effect of platelet in bone regenerating capacity have been published in different in vitro and in vivo studies. METHOD: To explore this we used platelet-rich plasma (PRP) (autogenous) alone in empty extraction socket of bilateral impacted mandibular third molars. For that we selected five patients having bilateral impacted teeth. Out of two sockets one was used as intervention by filling with PRP and the other was allowed to heal without PRP. All patients were followed for clinical and radiological evaluation by using digital OPG view after 1 week, 1, 2 and 4 months period. RESULT AND CONCLUSION: PRP enhanced the osteogenic response in initial bone healing at 1 month duration but there was no added benefit in late bone healing at 4 months period compared in both intervention and control groups. However PRP significantly improved the soft tissue healing in PRP treated sites compared to control group. PMID- 25729231 TI - Pentoxifylline in patients with oral submucous fibrosis-a randomized clinical trial. AB - BACKGROUND AND AIM: As far as research regarding any disease is concerned, each and every aspect poses a challenge. One such entity that poses a challenge in our arena is oral submucous fibrosis (OSF) as no effective treatment is available for this progressively disabling condition with high malignant potential. Hence the present study was undertaken with the aim to determine the use of pentoxifylline (PTX) on the clinical and histopathologic course of OSF. METHOD: Thirty clinically confirmed OSF patients were categorized randomly into group I and group II. In group I, drug PTX was administered as an adjunct along with other conventional therapies. Group II patients were advised conventional therapies only. Pre- and post-treatment biopsies were obtained for the following parameters:Micro-vascular density (MVD),Area percentage of blood vessels,Severity of fibrosis, andInflammatory components. RESULTS: On comparing MVD in groups I and II there was no significant difference in pre- and post-treatment.On comparing the average area percentage occupied by blood vessels, significant difference was seen in pre- and post-treatment biopsies in group I.On assessment of mouth opening and tongue protrusion, there was no significant improvement in either of the groups individually or in comparison. But when burning sensation of mucosa was assessed, pre- and post-treatment, both groups showed quite significant improvement individually. CONCLUSION: Use of pentoxifylline seemed to be questionable, and taking into consideration the long administration time, its use is not recommended for the treatment of OSF patients. PMID- 25729232 TI - A study of promethazine hydrochloride and pentazocine intramuscular sedation along with 2 % lidocaine hydrochloride and adrenaline and comparison to placebo along with 2 % lidocaine hydrochloride and adrenaline for surgical extraction of mandibular third molar. AB - BACKGROUND AND OBJECTIVES: The main objective is to study and compare the sedative and analgesic effects of intramuscular injection fortwin-phenergan along with local anesthetic and normal saline placebo along with local anesthetics in mandibular third molar surgery. We also assessed and compared the postoperative experience of the patient in relation to the pain intensity, time to first analgesic taken and total number of analgesics consumed over a period of 48 h in the two groups. MATERIALS AND METHODS: Patients who came to the Department of Oral and Maxillofacial Surgery, The Regional Dental College; with complaints regarding mandibular third molar were chosen for the treatment. Patients were evaluated using Corah Dental Anxiety Scale (CDAS) and those patients having a score of CDAS 13 and above were selected. Sixty patients were selected out of which 30 patients formed group 1 and another 30 patients group 2. The patients were randomly divided with flip method into group 1 (study group) and or group 2 (controlled group). RESULTS: Our study results showed that the operating conditions for both the groups at the end of surgery were similar without significant difference. Most of the surgical procedures were graded as excellent and good in both the groups except that difficulty was encountered in two patients from group 1 and one from group 2. CONCLUSION: It could be concluded that particular drugs do not have much influence on the surgical procedure in our study, but it was found that patients from group 1 were more cooperative as compared to group 2 when difficulty was encountered during the surgical procedure. PMID- 25729233 TI - The effect of alloplastic bone graft and absorbable gelatin sponge in prevention of periodontal defects on the distal aspect of mandibular second molars, after surgical removal of impacted mandibular third molar: a comparative prospective study. AB - AIM: Recent studies claim that haemostatic agents can be used as bone graft substitutes. The aim of this study was to compare the efficacy of alloplastic bone graft with absorbable gelatin sponge in prevention of periodontal defects distal to mandibular second molar after the surgical removal of impacted mandibular third molars. MATERIALS AND METHODS: A prospective, randomized, single blind split-mouth study was designed. The study consisted of 25 patients requiring surgical removal of bilateral impacted mandibular 3rd molars. The surgical sites were randomly divided into 2 groups: group I: G-graft (hydroxyapatite + collagen, study group) and group II: Abgel (absorbable gelatin sponge, control group). Patients were recalled on lst and 7th postoperative days and 3rd and 6th postoperative months. Probing depth, alveolar bone levels and soft tissue wound healing were evaluated. Paired t test was used to compare pre and post-operative alveolar bone levels and probing depth (PD). Wilcoxon signed ranks test was used to compare the wound healing. RESULTS: The soft tissue wound healing, PD and the distance between the cemento-enamel junction on the distal aspect of mandibular second molar (point A) and the alveolar crest on the distal aspect of the same tooth (point B) were significantly higher in group I as compared to group II. CONCLUSION: This study reveals an increase in the alveolar bone level, improvement of PD and better wound healing in group I. Group II subjects required longer healing time than the normal. The authors disagree the claim that the haemostatic agents can be used as bone graft substitutes. However, long-term, multicenter, randomized controlled clinical trials are required. PMID- 25729234 TI - Eosinophilic granuloma of mandibular condyle: resection and complete regeneration. AB - Eosinophilic granuloma is a rare disease of abnormal proliferation of Langerhan cells affecting the jaws of young individuals. We report a case of complete regeneration of condyle in a 13 year old boy with eosinophilic granuloma condyle, who had undergone condylectomy. PMID- 25729235 TI - Orthopaedic protraction of the maxilla with miniplates: treatment of midface deficiency. AB - Class III malocclusion is a consequence of maxillary deficiency and/or mandibular prognathism, resulting in an anterior crossbite and a concave profile. Early class III malocclusion treatment with reverse pull headgear generally results in maxillary skeletal protraction but is frequently also accompanied by unfavourable dentoalveolar effects. Titanium miniplates used as temporary anchorage device might permit equivalent favourable skeletal changes without unwanted dentoalveolar effects. We report two cases having class III malocclusion with maxillary deficiency treated by using titanium miniplates. Cephalometric tracings were done pre and post treatment to determine the anatomic changes during the course of treatment. PMID- 25729236 TI - Posterior auricular approach for decompression and drainage of superficial temporal space infections of odontogenic origin. AB - Involvement of superficial temporal space secondary to odontogenic infections of the maxillary and mandibular teeth is not uncommon. Usually, infections of the temporal space are drained via temporal approach. Authors propose a new approach for decompression and drainage of superficial temporal space which offers an advantage of dependent drainage and hidden scar. PMID- 25729237 TI - Closure of oroantral fistula using titanium plate with transalveolar wiring. AB - BACKGROUND: Alloplastic materials such as tantalum, gold plates and foils, hydroxyapatite blocks have been used for closure of oroantral fistula (OAF). However, these materials are not widely accepted in routine surgical closure of OAF due to cost, difficult handling, increased rate of infection, and exfoliation. PURPOSE: To overcome the above drawbacks this study aimed to use titanium plates (0.3 mm) with transalveolar wiring fixation for closure of OAF. PATIENTS AND METHODS: Ten patients with OAFs who consented to undergo this trial were selected and treated under an outpatient basis in the Oral Surgery Department, Faculty of Dentistry, Mansoura University, Egypt. RESULTS: All OAFs were successfully treated with no eventful complications. CONCLUSION: This study concludes that titanium plates with transalveolar wiring fixation is an excellent technique for closure of OAF. The high success rate with this technique warrants its use for closure of OAF. PMID- 25729238 TI - Use of mono cortical screws as an aid to zygomatic complex fracture reduction. AB - INTRODUCTION: Zygomatic complex fractures by virtue of its anatomic area poses a great challenge in reduction of the fracture. Uses of various methods have been mentioned in English literature. METHOD: A new technique describing the use of reduction screw with a self-holding screwdriver in reduction of the zygomatic complex fracture. CONCLUSION: We found the method to be simple and effective and recommend its application in daily practice. PMID- 25729240 TI - Post-traumatic stress disorder is an important issue for Korea in 2015. PMID- 25729239 TI - On the evolution of development. AB - Perhaps development is more than just morphogenesis. We now recognize that the conceptus expresses epigenetic marks that heritably affect it phenotypically, indicating that the offspring are to some degree genetically autonomous, and that ontogeny and phylogeny may coordinately determine the fate of such marks. This scenario mechanistically links ecology, ontogeny and phylogeny together as an integrated mechanism for evolution for the first time. As a functional example, the Parathyroid Hormone-related Protein (PTHrP) signaling duplicated during the Phanerozoic water-land transition. The PTHrP signaling pathway was critical for the evolution of the skeleton, skin barrier, and lung function, based on experimental evidence, inferring that physiologic stress can profoundly affect adaptation through internal selection, giving seminal insights to how and why vertebrates were able to evolve from water to land. By viewing evolution from its inception in unicellular organisms, driven by competition between pro- and eukaryotes, the emergence of complex biologic traits from the unicellular cell membrane offers a novel way of thinking about the process of evolution from its beginnings, rather than from its consequences as is traditionally done. And by focusing on the epistatic balancing mechanisms for calcium and lipid homeostasis, the evolution of unicellular organisms, driven by competition between pro- and eukaryotes, gave rise to the emergence of complex biologic traits derived from the unicellular plasma lemma, offering a unique way of thinking about the process of evolution. By exploiting the cellular-molecular mechanisms of lung evolution as ontogeny and phylogeny, the sequence of events for the evolution of the skin, kidney and skeleton become more transparent. This novel approach to the evolution question offers equally novel insights to the primacy of the unicellular state, hologenomics and even a priori bioethical decisions. PMID- 25729241 TI - Interactive effect of smoking and NQO1 haplotypes on lung cancer risk. AB - The role of genetic polymorphisms of NAD(P)H: quinone oxidoreductase 1 (NQO1), which is known to be related to carcinogen metabolism and oxidative status, was evaluated for lung cancer development. The genotypes of two NQO1 polymorphisms, namely, IVS1-27C>G and Ex6+40C>T, were determined in 616 lung cancer cases and 616 lung cancer-free controls and haplotypes composed of the two polymorphisms were estimated. In the evaluation of the effect of the NQO1 genotypes or diplotypes, we did not find any significant association with lung cancer risk after adjusting for body mass index and smoking status. However, when we evaluated the effect of the NQO1 diplotypes for lung cancer risk in combination with smoking, smokers without the C-T/C-T diplotype showed a significantly increased risk of lung cancer compared with nonsmokers without the C-T/C-T diplotype (adjusted OR, 2.2; 95% CI, 1.67-3.02), and smokers with the C-T/C-T diplotype showed the highest OR of lung cancer (adjusted OR, 2.7; 95% CI, 1.78 4.21). Moreover, a trend test showed an additive interaction between smoking and the NQO1 C-T/C-T diplotype (P trend < 0.01). The additive effect of smoking and the NQO1 C-T/C-T diplotype was more apparent in squamous cell carcinoma, although this effect was statistically significant in all lung cancer cell types (all cell types, P trend < 0.05). This result suggests that haplotypes of the NQO1 gene play an important role in the development of lung cancer by interaction with smoking. PMID- 25729242 TI - Detection of Encephalitozoon spp. from human diarrheal stool and farm soil samples in Korea. AB - Microsporidia are eukaryotic organisms that cause zoonosis and are major opportunistic pathogens in HIV-positive patients. However, there is increasing evidence that these organisms can also cause gastrointestinal and ocular infections in immunocompetent individuals. In Korea, there have been no reports on human infections with microsporidia to date. In the present study, we used real-time PCR and nucleotide sequencing to detect Encephalitozoon intestinalis infection in seven of 139 human diarrheal stool specimens (5%) and Encephalitozoon hellem in three of 34 farm soil samples (8.8%). Genotype analysis of the E. hellem isolates based on the internal transcribed spacer 1 and polar tube protein genes showed that all isolates were genotype 1B. To our knowledge, this is the first report on human E. intestinalis infection in Korea and the first report revealing farm soil samples as a source of E. hellem infection. Because microsporidia are an important public health issue, further large-scale epidemiological studies are warranted. PMID- 25729243 TI - Eupatilin ameliorates collagen induced arthritis. AB - Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of eupatilin in a murine arthritis model and human rheumatoid synoviocytes. DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-alpha and then treated with eupatilin, and the levels of IL-6 and IL-1beta mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-alpha treatment of synoviocytes increased the expression of IL-6 and IL-1beta mRNAs, which was inhibited by eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner. These findings, showing that eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that eupatilin and DA-9601 is a candidate anti-inflammatory agent. PMID- 25729244 TI - Seasonality of gout in Korea: a multicenter study. AB - The object of this study was to evaluate the seasonality of gout in Korea. We retrospectively examined data from 330 patients seen at nine rheumatology clinics, treated with urate lowering therapy (ULT) more than one year after stopping prophylactic medication. Demographic data, clinical and laboratory features, and seasonality of gout onset and flares were collected. Season was classified in three-month intervals. The mean age was 52.2 yr and mean disease duration was 26.8 months. The male to female count was 318:12. The onset of acute gouty attacks was obtained in 256 patients. Gout developed most commonly in summer season (36.7%) (P<0.001) and in June (15.6%, P=0.002). During ULT, there were 147 (male 97.3%) gout flares. Although there was no statistically significant difference, gout flares were more common in summer (30.6%). Aggravating factors were identified in 57 flares: alcohol (72.0%) was most common. In the patients who attained target serum uric acid (<6 mg/dL) at the end of prophylaxis, gout flares were high in fall (35.8%) and September (17.0%). In Korea, the summer is most common season of gout onset and there is a tendency for gout flares to increase during ULT in summer/fall season. PMID- 25729245 TI - The potential utility of iodinated contrast media (ICM) skin testing in patients with ICM hypersensitivity. AB - Both immediate and delayed hypersensitivity reactions to iodinated contrast media (ICM) are relatively common. However, there are few data to determine the clinical utility of immunologic evaluation of ICM. To evaluate the utility of ICM skin testing in patients with ICM hypersensitivity, 23 patients (17 immediate and 6 delayed reactions) were enrolled from 3 university hospitals in Korea. With 6 commonly used ICM including iopromide, iohexol, ioversol, iomeprol, iopamidol and iodixanol, skin prick (SPT), intradermal (IDT) and patch tests were performed. Of 10 patients with anaphylaxis, 3 (30.0%) and 6 (60.0%) were positive respectively on SPTs and IDTs with the culprit ICM. Three of 6 patients with urticaria showed positive IDTs. In total, 11 (64.7%) had positive on either SPT or IDT. Three of 6 patients with delayed rashes had positive response to patch test and/or delayed IDT. Among 5 patients (3 anaphylaxis, 1 urticaria and 1 delayed rash) taken subsequent radiological examinations, 3 patients administered safe alternatives according to the results of skin testing had no adverse reaction. However, anaphylaxis developed in the other 2 patients administered the culprit ICM again. With 64.7% (11/17) and 50% (3/6) of the sensitivities of corresponding allergic skin tests with culprit ICM for immediate and delayed hypersensitivity reactions, the present study suggests that skin tests is useful for the diagnosis of ICM hypersensitivity and for selecting safe ICM and preventing a recurrence of anaphylaxis caused by the same ICM. PMID- 25729246 TI - Is intravesical Bacillus Calmette-Guerin therapy superior to chemotherapy for intermediate-risk non-muscle-invasive bladder cancer? An ongoing debate. AB - The objective of this study was to evaluate the risk of recurrence in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) after intravesical instillation with chemotherapeutic agents or Bacillus Calmette Guerin (BCG) therapy. A cohort of 746 patients with intermediate-risk NMIBC comprised the study group. The primary outcome was time to first recurrence. The recurrence rates of the transurethral resection (TUR) alone, chemotherapy, and BCG groups were determined using Kaplan-Meier analysis. Risk factors for recurrence were identified using Cox regression analysis. In total, 507 patients (68.1%), 78 patients (10.5%), and 160 (21.4%) underwent TUR, TUR+BCG, or TUR+chemotherapy, respectively. After a median follow-up period of 51.7 months (interquartile range=33.1-77.8 months), 286 patients (38.5%) developed tumor recurrence. The 5-yr recurrence rates for the TUR, chemotherapy, and BCG groups were 53.6%+/-2.7%, 30.8%+/-5.7%, and 33.6%+/-4.7%, respectively (P<0.001). Chemotherapy and BCG treatment were found to be predictors of reduced recurrence. Cox-regression analysis showed that TUR+BCG did not differ from TUR+chemotherapy in terms of recurrence risk. Adjuvant intravesical instillation is an effective prophylactic that prevents tumor recurrence in intermediate-risk NMIBC patients following TUR. In addition, both chemotherapeutic agents and BCG demonstrate comparable efficacies for preventing recurrence. PMID- 25729247 TI - Postoperative carcinoembryonic antigen as a complementary tumor marker of carbohydrate antigen 19-9 in pancreatic ductal adenocarcinoma. AB - The role of carcinoembryonic antigen (CEA) in pancreatic cancer remains poorly understood. Therefore, this study aimed to determine whether CEA is complementary to carbohydrate antigen 19-9 (CA19-9) in prognosis prediction after pancreatic cancer curative resection. We retrospectively reviewed records of 144 stage II curatively resected pancreatic cancer patients with preoperative and postoperative CEA and CA19-9 levels. Patients with normal preoperative CA19-9 were excluded. R0 resection margin, adjuvant treatment, and absence of angiolymphatic invasion were associated with better overall survival. There was no significant difference in median survival according to preoperative CEA levels. However, patients with normal postoperative CA19-9 (59.8 vs.16.2 months, P < 0.001) and CEA (29.4 vs. 9.3 months, P = 0.001) levels had longer overall survival than those with elevated levels. Among 76 patients with high postoperative CA19-9 levels, a better prognosis was observed in those with normal postoperative CEA levels than in those with elevated levels (19.1 vs. 9.3 months, P = 0.004). Postoperative CEA and CA19-9 levels are valuable prognostic markers in resected pancreatic cancer. Normal postoperative CEA levels indicate longer survival, even in patients with elevated postoperative CA19-9. PMID- 25729248 TI - Relationship between sarcopenic obesity and cardiovascular disease risk as estimated by the Framingham risk score. AB - This study was conducted to assess the association between sarcopenic obesity and cardiovascular disease (CVD) risk in Korean adults (n=3,320; >=40 yr) who participated in the 5th Korean National Health and Nutrition Examination Survey in 2010. The appendicular skeletal muscle mass divided by body weight was calculated for each participant; participants with values <1 standard deviation below the mean reference value (i.e., aged 20-39 yr) were considered sarcopenic. Subjects were further classified into 4 groups according to their obesity (i.e., body mass index >=25 kg/m(2)) and sarcopenic status. Individuals' 10-yr CVD risk was determined using the Framingham risk model. The sarcopenic obese group had more participants (43.8% men, 14.6% women) with a high risk of CVD (>=20%). The sarcopenic obese group was associated with an increased 10-yr CVD risk than the non-sarcopenic, non-obese group (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.53-4.06, P<0.001 in men; OR, 1.87; 95% CI, 1.02-3.41, P=0.041 in women). Sarcopenic non-obese and non-sarcopenic obese subjects were not associated with an increased 10-yr CVD risk. Sarcopenic obesity, but not non-sarcopenic obesity, was closely associated with an increased CVD risk in Korean adults. PMID- 25729249 TI - Environmental heavy metal exposure and chronic kidney disease in the general population. AB - Lead (Pb), mercury (Hg), and cadmium (Cd) are common heavy metal toxins and cause toxicological renal effects at high levels, but the relevance of low-level environmental exposures in the general population is controversial. A total of 1,797 adults who participated in the KNHANES (a cross-sectional nationally representative survey in Korea) were examined, and 128 of them (7.1%) had chronic kidney disease (CKD). Our study assessed the association between Pb, Hg, Cd exposure, and CKD. Blood Pb and Cd levels were correlated with CKD in univariate logistic regression model. However, these environmental heavy metals were not associated with CKD after adjustment for age, sex, BMI, smoking, hyperlipidemia, hypertension, diabetes, and these metals in multivariate logistic regression models. We stratified the analysis according to hypertension or diabetes. In the adults with hypertension or diabetes, CKD had a significant association with elevated blood Cd after adjustment, but no association was present with blood Pb and Hg. The corresponding odds ratio [OR] of Cd for CKD were 1.52 (95% confidence interval [CI], 1.05-2.19, P=0.026) in adults with hypertension and 1.92 (95% CI, 1.14-3.25, P=0.014) in adults with diabetes. Environmental low level of Pb, Hg, Cd exposure in the general population was not associated with CKD. However, Cd exposure was associated with CKD, especially in adults with hypertension or diabetes. This finding suggests that environmental low Cd exposure may be a contributor to the risk of CKD in adults with hypertension or diabetes. PMID- 25729250 TI - Percutaneous papillary large balloon dilation during percutaneous cholangioscopic lithotripsy for the treatment of large bile-duct stones: a feasibility study. AB - When access to a major duodenal papilla or endoscopic retrograde cholangiopancreatography has failed, percutaneous transhepatic cholangioscopic lithotripsy (PTCS-L) may be useful for removing common bile duct (CBD) stones. However, the feasibility and usefulness of percutaneous transhepatic papillary large-balloon dilation (PPLBD) during PTCS-L for the removal of large CBD stones has not been established. We aimed to determine the safety and efficacy of PPLBD for the treatment of large CBD stones. Eleven patients with large CBD stones in whom the access to the major papilla or bile duct had failed were enrolled prospectively. Papillary dilation was performed using a large (12-20 mm) dilation balloon catheter via the percutaneous transhepatic route. Post-procedure adverse events and efficacy of the stone retrieval were measured. The initial success rate of PPLBD was 100%. No patient required a basket to remove a stone after PPLBD. Electrohydraulic lithotripsy was required in 2 (18.2%) patients. The median time to complete stone removal after PPLBD was 17.8 min and no adverse events occurred after PPLBD. Asymptomatic hyperamylasemia was not encountered in any patients. This study indicates that PPLBD is safe and effective for removal of large CBD stones. PMID- 25729251 TI - Early sodium and fluid intake and severe intraventricular hemorrhage in extremely low birth weight infants. AB - Hypernatremic dehydration is an important cause of intracranial hemorrhage. A possible association of intraventricular hemorrhage (IVH) with hypernatremia and/or high sodium intake has been suggested in preterm infants. To investigate the associations of early fluid and sodium intake or serum sodium concentrations with severe intraventricular hemorrhage (IVH) in extremely low birth weight (ELBW) infants, we reviewed the medical records of 169 inborn ELBW infants. Daily fluid and sodium intake, urine output, weight loss and serum sodium concentration during the first 4 days of life were obtained. Patients were divided into the severe IVH (grade 3/4) and the control (no or grade 1/2 IVH) group. The maximum serum sodium concentration and the incidence of hypernatremia did not differ between the two groups. Related to the fluid balance and sodium intake, the risk for severe IVH was strongly associated with total fluid and sodium intake during the initial four days of life. With respect to the fluids other than transfusion, severe IVH can be discriminated only by sodium intake but not by fluid intake. Large randomized controlled trials are required to clarify the causal relationship between the early sodium intake and severe IVH in ELBW infants. PMID- 25729252 TI - Efficacy of random-start controlled ovarian stimulation in cancer patients. AB - This study aimed to evaluate the efficacy of random-start controlled ovarian stimulation (COS) in cancer patients for emergency fertility preservation. In this retrospective comparative study, 22 patients diagnosed with cancer and 44 infertile women undergoing conventional in vitro fertilization (IVF) were included. In cancer patients, ovarian stimulation was started on the day of referral, irrespective of their menstrual cycle date. The control group was selected by age matching among women undergoing conventional IVF. COS outcomes were compared between groups. The number of total and mature oocytes retrieved and the oocyte maturity rate were higher in the random-start group than in the conventional-start group. However, duration of ovarian stimulation was longer in the random-start group (11.4 vs. 10.3 days, P = 0.004). The addition of letrozole to lower the estradiol level during COS did not adversely affect total oocytes retrieved. However, oocyte maturity rate was lower in cycles with letrozole than in cycles without letrozole (71.6% vs. 58.2%, P = 0.019). Our study confirms the feasibility and effectiveness of random-start COS in cancer patients. PMID- 25729253 TI - Correlation between the serum luteinizing hormone to folliclestimulating hormone ratio and the anti-Mullerian hormone levels in normo-ovulatory women. AB - Serum anti-Mullerian hormone (AMH) levels are regarded as an age-specific marker for predicting the ovarian reserve in women of reproductive age. Some studies have shown that the luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio can be used as a predictor of ovarian reserve. The purpose of this study was to assess the variation of LH/FSH ratio with aging and to evaluate the correlation between serum LH/FSH ratio and AMH levels as a predictor of the ovarian reserve in normo-ovulatory women. We retrospectively analyzed the day 3 serum hormone levels in 1,251 patients (age range: 20-50 yr) between January 2010 and January 2011. We divided the patients into 6 groups according to their age. Relation between serum AMH level and LH/FSH ratio was analyzed statistically. The serum AMH level was inversely correlated with age (r = -0.400, P < 0.001). A significant negative correlation was found between serum LH/FSH ratio and age (r = -0.213, P < 0.001). There was a significant partial correlation between serum LH/FSH ratio and AMH level when adjusted by age (r = 0.348, P < 0.001). The LH/FSH ratio could be considered as a useful marker for the ovarian reserve and could be applied to the clinical evaluation with AMH. PMID- 25729254 TI - Urethroplasty using autologous urethral tissue-embedded acellular porcine bladder submucosa matrix grafts for the management of long-segment urethral stricture in a rabbit model. AB - We conducted this study to evaluate the combined effect of acellular bladder submucosa matrix (BSM) and autologous urethral tissue for the treatment of long segment urethral stricture in a rabbit model. To prepare the BSM, porcine bladder submucosa was processed, decellularized, configured into a sheet-like shape, and sterilized. Twenty rabbits were randomized to normal control, urethral stricture, urethroplasty using BSM only or BSM/autologous urethral tissue (n=5 per group). Retrograde urethrography was performed at 4, 8, and 12 weeks postoperatively, and the grafted specimens were harvested at week 12 to evaluate urethral reconstruction through histopathologic and immunohistochemical analysis. The mean urethral width of the control, stricture, BSM, and BSM/autologous urethral tissue groups at week 12 was 10.3+/-0.80, 3.8+/-1.35, 8.8+/-0.84, and 9.1+/-1.14 mm, respectively. The histopathologic study revealed that the BSM/autologous urethral tissue graft had a normal area of urethral lumen, compact muscular layers, complete epithelialization, and progressive infiltration by vessels in the regenerated urethra. In contrast, the BSM grafts revealed keratinized epithelium, abundant collagenized fibrous connective tissue, and were devoid of bundles of circular smooth muscle. Nontransected ventral onlay-augmented urethroplasty using an acellular BSM scaffold combined with an autologous urethral tissue graft represents a feasible procedure for urethral reconstruction. PMID- 25729255 TI - P70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression in orthotopic mouse non-muscle invasive bladder tumor model. AB - We investigated how the dual inhibition of the molecular mechanism of the mammalian target of the rapamycin (mTOR) downstreams, P70S6 kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E), can lead to a suppression of the proliferation and progression of urothelial carcinoma (UC) in an orthotopic mouse non-muscle invasive bladder tumor (NMIBT) model. A KU-7-luc cell intravesically instilled orthotopic mouse NMIBC model was monitored using bioluminescence imaging (BLI) in vivo by interfering with different molecular components using rapamycin and siRNA technology. We then analyzed the effects on molecular activation status, cell growth, proliferation, and progression. A high concentration of rapamycin (10 uM) blocked both P70S6K and elF4E phosphorylation and inhibited cell proliferation in the KU-7-luc cells. It also reduced cell viability and proliferation more than the transfection of siRNA against p70S6K or elF4E. The groups with dual p70S6K and elF4E siRNA, and rapamycin reduced tumor volume and lamina propria invasion more than the groups with p70S6K or elF4E siRNA instillation, although all groups reduced photon density compared to the control. These findings suggest that both the mTOR pathway downstream of eIF4E and p70S6K can be successfully inhibited by high dose rapamycin only, and p70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression. PMID- 25729256 TI - Comparison of pathological and biochemical outcomes after radical prostatectomy in Korean patients with serum PSA ranges. AB - The aim of this study was to assess surgical outcome at radical prostatectomy (RP) in Korean men with a serum prostate-specific antigen (PSA) level of 2.5 to 3.0 ng/mL and compared with those of patients who had a PSA level of 3.0-4.0 and 4.0-10.0 ng/mL. We retrospectively compared clinico-pathological characteristics and biochemical recurrence (BCR) risk in patients with PSA level of 2.5-3.0 (group 1, n = 92, 5.7%), 3.0-4.0 (group 2, n = 283, 17.5%), or 4.0-10.0 ng/mL (group 3, n = 1,242, 76.8%) who underwent RP between 1995 and 2013. The pathologic characteristics including Gleason score, pathologic stage, and percentage of significant cancer in group 1 were similar to those in group 2 and group 3. Furthermore, pathological upgrading and upstaging were found in 23 (30.7%) and 10 (14.7%) in group 1, 84 (33.9%) and 19 (8.8%) in group 2, and 321 (32.8%) and 113 (12.8%) in group 3, respectively, with no significant differences among the three groups (all P > 0.05). In multivariate analysis, PSA grouping was not an independent predictor of BCR. Within the population with PSA lower than 10 ng/mL, substratification of PSA is not a significant predictor for upgrading, upstaging, or adverse prognosis. PMID- 25729257 TI - Language-specific dysgraphia in Korean patients with right brain stroke: influence of unilateral spatial neglect. AB - The purpose of the present study was to investigate the relationship between Korean language-specific dysgraphia and unilateral spatial neglect in 31 right brain stroke patients. All patients were tested for writing errors in spontaneous writing, dictation, and copying tests. The dysgraphia was classified into visuospatial omission, visuospatial destruction, syllabic tilting, stroke omission, stroke addition, and stroke tilting. Twenty-three (77.4%) of the 31 patients made dysgraphia and 18 (58.1%) demonstrated unilateral spatial neglect. The visuospatial omission was the most common dysgraphia followed by stroke addition and omission errors. The highest number of errors was made in the copying and the least was in the spontaneous writing test. Patients with unilateral spatial neglect made a significantly higher number of dysgraphia in the copying test than those without. We identified specific dysgraphia features such as a right side space omission and a vertical stroke addition in Korean right brain stroke patients. In conclusion, unilateral spatial neglect influences copy writing system of Korean language in patients with right brain stroke. PMID- 25729258 TI - Optical coherence tomography for the diagnosis and evaluation of human otitis media. AB - We report the application of optical coherence tomography (OCT) to the diagnosis and evaluation of otitis media (OM). Whereas conventional diagnostic modalities for OM, including standard and pneumatic otoscopy, are limited to visualizing the surface of the tympanic membrane (TM), OCT effectively reveals the depth-resolved microstructure below the TM with very high spatial resolution, with the potential advantage of its use for diagnosing different types of OM. We examined the use of 840-nm spectral domain-OCT (SD-OCT) clinically, using normal ears and ears with the adhesive and effusion types of OM. Specific features were identified in two dimensional OCT images of abnormal TMs, compared to images of healthy TMs. Analysis of the A-scan (axial depth scan) identified unique patterns of constituents within the effusions. The OCT images could not only be used to construct a database for the diagnosis and classification of OM but OCT might also represent an upgrade over current otoscopy techniques. PMID- 25729259 TI - Effective transport for trauma patients under current circumstances in Korea: a single institution analysis of treatment outcomes for trauma patients transported via the domestic 119 service. AB - In Korea, which still lacks a well-established trauma care system, the inability to transport patients to adequate treatment sites in a timely manner is a cause of low trauma patient survival. As such, this study was conducted to serve as a basis for the establishment of a future trauma transport system. We performed a comparative analysis of the transport time, and treatment outcomes between trauma victims transported by ground ambulance (GAMB) and those transported via the helicopter emergency medical service (HEMS) through the National Emergency Management Agency's 119 reporting system, which is similar to the 911 system of the United States, from March 2011 to May 2014. The HEMS-transported patients received treatment instructions, by remote communication, from our trauma specialists from the time of accident reporting; in certain instances, members of the trauma medical staff provided treatment at the scene. A total of 1,626 patients were included in the study; the GAMB and HEMS groups had 1,547 and 79 patients, respectively. The median transport time was different between 2 groups (HEMS, 60 min vs. GAMB, 47 min, P<0.001) but for all patients was 49 min (less than the golden hour). Outcomes were significantly better in the HEMS compared to the GAMB, using the trauma and injury severity score (survival rate, 94.9% vs. 90.5%; Z score, 2.83 vs. -1.96; W score, 6.7 vs. -0.8). A unified 119 service transport system, which includes helicopter transport, and the adoption of a trauma care system that allows active initial involvement of trauma medical personnel, could improve the treatment outcome of trauma patients. PMID- 25729260 TI - The first reported case of West Nile encephalitis in Korea. AB - West Nile encephalitis was first identified in 1937, but until now, it was never diagnosed in Korea. A 58-yr-old Korean man was admitted with headache and cognitive dysfunction. The patient had been on a business trip in Guinea. Cerebrospinal fluid (CSF) showed pleocytosis. The patient complained of both leg weakness,and arachnoiditis and myelitis were observed on lumbar magnetic resonance imaging (MRI). A specific neutralizing antibody for West Nile virus was positive in serum. After a treatment with interferon-alpha 3mu, follow up CSF findings recovered completely after 3 months later. The first case of West Nile encephalitis in Korea was imported from Guinea, and was cured successfully. PMID- 25729261 TI - Diffuse unilateral subacute neuroretinitis in a healthy Korean male: the first case report in Korea. AB - A 52-yr-old male was referred for progressive visual loss in the left eye. The decimal best-corrected visual acuity (BCVA) was 0.01. Fundus examination revealed diffuse retinal pigment epithelial degeneration, focal yellow-white, infiltrative subretinal lesion with fuzzy border and a live nematode within the retina. Diffuse unilateral subacute neuroretinitis (DUSN) was diagnosed and the direct laser photocoagulation was performed to destroy the live nematode. During eight months after treatment, BCVA gradually improved to 0.2 along with the gradual restoration of outer retinal layers on SD-OCT. We report on the first case of DUSN in Korea. DUSN should be included in the differential diagnosis of unexplained unilateral visual loss in otherwise healthy subjects. PMID- 25729262 TI - Data Interpretation in the Digital Age. AB - The consultation of internet databases and the related use of computer software to retrieve, visualise and model data have become key components of many areas of scientific research. This paper focuses on the relation of these developments to understanding the biology of organisms, and examines the conditions under which the evidential value of data posted online is assessed and interpreted by the researchers who access them, in ways that underpin and guide the use of those data to foster discovery. I consider the types of knowledge required to interpret data as evidence for claims about organisms, and in particular the relevance of knowledge acquired through physical interaction with actual organisms to assessing the evidential value of data found online. I conclude that familiarity with research in vivo is crucial to assessing the quality and significance of data visualised in silico; and that studying how biological data are disseminated, visualised, assessed and interpreted in the digital age provides a strong rationale for viewing scientific understanding as a social and distributed, rather than individual and localised, achievement. PMID- 25729263 TI - Continuous Maximal Flows and Wulff Shapes: Application to MRFs. AB - Convex and continuous energy formulations for low level vision problems enable efficient search procedures for the corresponding globally optimal solutions. In this work we extend the well-established continuous, isotropic capacity-based maximal flow framework to the anisotropic setting. By using powerful results from convex analysis, a very simple and efficient minimization procedure is derived. Further, we show that many important properties carry over to the new anisotropic framework, e.g. globally optimal binary results can be achieved simply by thresholding the continuous solution. In addition, we unify the anisotropic continuous maximal flow approach with a recently proposed convex and continuous formulation for Markov random fields, thereby allowing more general smoothness priors to be incorporated. Dense stereo results are included to illustrate the capabilities of the proposed approach. PMID- 25729265 TI - Considerations for Introducing SBIRT into a Jail Setting. PMID- 25729266 TI - How Many proteins are Missed in Quantitative proteomics Based on Ms/Ms sequencing Methods? AB - Current bottom-up quantitative proteomics methods based on MS/MS sequencing of peptides are shown to be strongly dependent on sample preparation. Using cytosolic proteins from MCF-7 breast cancer cells, it is shown that protein pre fractionation based on pI and MW is more effective than pre-fractionation using only MW in increasing the number of observed proteins (947 vs. 704 proteins) and the number of spectral counts per protein. Combination of MS data from the different pre-fractionation methods results in further improvements (1238 proteins). We discuss that at present the main limitation on quantitation by MS/MS sequencing is not MS sensitivity and protein abundance, but rather extensive peptide overlap and limited MS/MS sequencing throughput, and that this favors internally calibrated methods such as SILAC, ICAT or ITRAQ over spectral counting methods in attempts to drastically improve proteome coverage of biological samples. PMID- 25729264 TI - C596G mutation in FBN1 causes Marfan syndrome with exotropia in a Chinese family. AB - PURPOSE: To screen mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). METHODS: Patients and unaffected family members were given ophthalmic, cardiovascular, and physical examinations with a 5-year follow-up. Genomic DNA was extracted from the leukocytes of venous blood from all patients and their relatives. The entire coding region of the FBN1gene was screened with an ABI 9700 GeneAmp PCR System. The mutation identified was screened in 100 healthy and ethnically unrelated Chinese individuals. RESULTS: Mutation screening in FBN1 identified a T>G transition at position c.1786 in exon 14, leading to substitution of cysteine for glycine at codon 596 (C596G) in this four-generation Chinese family. The C596G mutation was associated with the disease phenotypes in all six patients but not found in 14 unaffected family members or the 100 ethnically unrelated and healthy controls. CONCLUSIONS: A C596G mutation in FBN1 was identified in a Chinese family with MFS. Our results expand the spectrum of FBN1 mutations and contribute to the understanding of the role of FBN1 in the pathogenesis of Marfan syndrome. PMID- 25729267 TI - On the impact of covariate measurement error on spatial regression modelling. AB - Spatial regression models have grown in popularity in response to rapid advances in GIS (Geographic Information Systems) technology that allows epidemiologists to incorporate geographically indexed data into their studies. However, it turns out that there are some subtle pitfalls in the use of these models. We show that presence of covariate measurement error can lead to significant sensitivity of parameter estimation to the choice of spatial correlation structure. We quantify the effect of measurement error on parameter estimates, and then suggest two different ways to produce consistent estimates. We evaluate the methods through a simulation study. These methods are then applied to data on Ischemic Heart Disease (IHD). PMID- 25729268 TI - Dynamic Frequency of Blood CD4+CD25+ Regulatory T Cells in Rats with Collagen induced Arthritis. AB - CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) have been shown to play a regulatory or suppressive role in the immune response and are possibly relevant to the pathogenesis of autoimmune diseases. In the present study, we attempted to investigate the frequency of CD4+CD25+ Tregs in peripheral blood (PB) of collagen induced arthritis (CIA) rats during the development of arthritis, to determine whether their frequency is involved in the immunoregulation of this disease. The results showed that normal rats had similar frequencies of CD4+CD25+ Tregs in PB during the experiment time, expressed as a percentage of CD4+CD25+Foxp3+ T cells among the CD4+ T lymphocyte population. In contrast, the frequency of CD4+CD25+Foxp3+ T cells in CIA rats was found to change during the development of arthritis. In CIA rats, there is a significant negative correlation between the frequency of CD4+CD25+Foxp3+ T cells and paw swelling (r=-0.786, p< 0.01). The relationship between the frequency of CD4+CD25+Foxp3+ T and immune activation was not found in normal rats. During the time course, the frequency of CD4+CD25+Foxp3+ T was lower in CIA rats than in normal ones. The data suggest that the frequency of PB CD4+CD25+ Tregs may be a promising marker for arthritis activity. PMID- 25729269 TI - Predominant D1 Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration. AB - The aim of this study was to investigate the involvement of dopaminergic receptors (DR) in behavioral sensitization, as measured by locomotor activity, and the over-expression of cocaine- and amphetamine-regulated transcript (CART) peptides after repeated administration of cocaine in mice. Repeated administrations of cocaine induced behavioral sensitization and CART over expression in mice. The levels of striatal CART mRNA were significantly increased on the 3(rd) day. CART peptides were over-expressed on the 5(th) day in the striata of behaviorally sensitized mice. A higher proportion of CART(+) cells in the cocaine-treated mice were present in the nucleus accumbens (NAc) shell than in the dorsolateral (DL) part of caudate putamen (CP). The concomitant administration of both D1R and D2R antagonists, SCH 23390 (D1R selective) and raclopride (D2R selective), blocked cocaine induced-behavioral sensitization, CART over-expression, and cyclic adenosine 5'-monophosphate (cAMP)/protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signal pathways. SCH 23390 more predominantly inhibited the locomotor activity, CART over expression, pCREB and PKA activity than raclopride. Cocaine induced-behavioral sensitization was also attenuated in the both D1R and D2R knockout (KO) mice, respectively. CART over-expression and activated cAMP/PKA/pCREB signal pathways were inhibited in the D1R-KO mice, but not in the D2R-KO mice. It is suggested that behavioral sensitization, CART over-expression and activated cAMP/PKA/pCREB signal pathways induced by repeated administration of cocaine could be more predominantly mediated by D1R. PMID- 25729270 TI - Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model. AB - The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra abdominal infected human. 12 male rats with intra-abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, Cmax was 11.151 ug/mL at 5 min after the intravenous injection and t1/2 was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents. PMID- 25729271 TI - NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3. AB - NgR1, a Nogo receptor, is involved in inhibition of neurite outgrowth and axonal regeneration and regulation of synaptic plasticity. P19 embryonal carcinoma cells were induced to differentiate into neuron-like cells using all trans-retinoic acid and the presence and/or function of cellular molecules, such as NgR1, NMDA receptors and STAT3, were examined. Neuronally differentiated P19 cells expressed the mRNA and protein of NgR1, which could stimulate the phosphorylation of STAT3 when activated by Nogo-P4 peptide, an active segment of Nogo-66. During the whole period of differentiation, mRNAs of all of the NMDA receptor subtypes tested (NR1, NR2A-2D) were consistently expressed, which meant that neuronally differentiated P19 cells maintained some characteristics of neurons, especially central nervous system neurons. Our results suggests that neuronally differentiated P19 cells expressing NgR1 may be an efficient and convenient in vitro model for studying the molecular mechanism of cellular events that involve NgR1 and its binding partners, and for screening compounds that activate or inhibit NgR1. PMID- 25729272 TI - Long Term Effect of High Glucose and Phosphate Levels on the OPG/RANK/RANKL/TRAIL System in the Progression of Vascular Calcification in rat Aortic Smooth Muscle Cells. AB - Osteoprotegerin (OPG), receptor activator of NF-kappaB ligand (RANKL)/receptor activator of NF-kappaB (RANK) axis, and TNF-related apoptosis-inducing ligand (TRAIL) participate in vascular calcification process including atherosclerosis, but their contributions under high glucose (HG) and phosphate (HP) condition for a long-term period (more than 2 weeks) have not been fully determined. In this study, we evaluated the effects of HG and HP levels over 2 or 4 weeks on the progression of vascular calcification in rat vascular smooth muscle cells (VSMCs). Calcium deposition in VSMCs was increased in medium containing HG (30 mmol/L D-glucose) with beta-glycerophosphate (beta-GP, 12 mmol/L) after 2 weeks and increased further after 4 weeks. OPG mRNA and protein expressions were unchanged in HG group with or without beta-GP after 2 weeks. However, after 4 weeks, OPG mRNA and protein expressions were significantly lower in HG group with beta-GP. No significant expression changes were observed in RANKL, RANK, or TRAIL during the experiment. After 4 weeks of treatment in HG group containing beta-GP and rhBMP-7, an inhibitor of vascular calcification, OPG expressions were maintained. Furthermore, mRNA expression of alkaline phosphatase (ALP), a marker of vascular mineralization, was lower in the presence of rhBMP-7. These results suggest that low OPG levels after long term HG and phosphate stimulation might reduce the binding of OPG to RANKL and TRAIL, and these changes could increase osteo-inductive VSMC differentiation, especially vascular mineralization reflected by increased ALP activity during vascular calcification. PMID- 25729273 TI - Effects on g2/m phase cell cycle distribution and aneuploidy formation of exposure to a 60 Hz electromagnetic field in combination with ionizing radiation or hydrogen peroxide in l132 nontumorigenic human lung epithelial cells. AB - The aim of the present study was to assess whether exposure to the combination of an extremely low frequency magnetic field (ELF-MF; 60 Hz, 1 mT or 2 mT) with a stress factor, such as ionizing radiation (IR) or H2O2, results in genomic instability in non-tumorigenic human lung epithelial L132 cells. To this end, the percentages of G2/M-arrested cells and aneuploid cells were examined. Exposure to 0.5 Gy IR or 0.05 mM H2O2 for 9 h resulted in the highest levels of aneuploidy; however, no cells were observed in the subG1 phase, which indicated the absence of apoptotic cell death. Exposure to an ELF-MF alone (1 mT or 2 mT) did not affect the percentages of G2/M-arrested cells, aneuploid cells, or the populations of cells in the subG1 phase. Moreover, when cells were exposed to a 1 mT or 2 mT ELF-MF in combination with IR (0.5 Gy) or H2O2 (0.05 mM), the ELF-MF did not further increase the percentages of G2/M-arrested cells or aneuploid cells. These results suggest that ELF-MFs alone do not induce either G2/M arrest or aneuploidy, even when administered in combination with different stressors. PMID- 25729274 TI - Effect of the Combination of CI-988 and Morphine on Neuropathic Pain after Spinal Cord Injury in Rats. AB - Cholecystokinin is known to be involved in the modulation of nociception and to reduce the efficacy of morphine analgesia. This study investigated the effects of intrathecal administration of morphine and the cholecystokinin type B antagonist CI-988 on below-level neuropathic pain after spinal cord injury in rats. We also examined the interaction of morphine and CI-988 in the antinociceptive effect. Both morphine and CI-988 given individually increased the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner. The combination of ineffective doses of intrathecally administered CI-988 and morphine produced significant analgesic effects and the combination of effective doses resulted in analgesic effects that were greater than the sum of the individual effects of each drug. Thus, morphine showed a synergistic interaction with CI-988 for analgesia of central neuropathic pain. PMID- 25729275 TI - Association of Angiotensin Converting Enzyme I/D and alpha-actinin-3 R577X Genotypes with Growth Factors and Physical Fitness in Korean Children. AB - This study analyzed the differences in aerobic and anaerobic exercise ability and growth-related indicators, depending on the polymorphism of the ACE and the ACTN3 genes, to understand the genetic influence of exercise ability in the growth process of children. The subjects of the study consisted of elementary school students (n=856, age 10.32+/-0.07 yr). The anthropometric parameters, physical fitness and growth factors were compared among groups of the ACE I/D or the ACTN3 R577X polymorphisms. There were no significant differences between the anthropometric parameters, physical fitness and growth factors for the ACE gene ID or the ACTN3 gene R577X polymorphism. However, the DD type of ACE gene was highest in the side step test (p<0.05), and the DD type was significantly higher than the II+ID type (p<0.05) in the early bone age. The combined group of the ACE gene II+ID and the ACTN3 gene XX type significantly showed lower early bone age (p< 0.05). This study did not find any individual or compounding effects of the polymorphism in the ACE I/D or the ACTN3 R577X polymorphisms on the anthropometric parameters, physical fitness and growth factors of Korean children. However, the exercise experience and the DD type of the ACE gene may affect the early maturity of the bones. PMID- 25729276 TI - Differential Gene Expression in GPR40-Overexpressing Pancreatic beta-cells Treated with Linoleic Acid. AB - "G protein-coupled receptor 40" (GPR40), a receptor for long-chain fatty acids, mediates the stimulation of glucose-induced insulin secretion. We examined the profiles of differential gene expression in GPR40-activated cells treated with linoleic acid, and finally predicted the integral pathways of the cellular mechanism of GPR40-mediated insulinotropic effects. After constructing a GPR40 overexpressing stable cell line (RIN-40) from the rat pancreatic beta-cell line RIN-5f, we determined the gene expression profiles of RIN-5f and RIN-40. In total, 1004 genes, the expression of which was altered at least twofold, were selected in RIN-5f versus RIN-40. Moreover, the differential genetic profiles were investigated in RIN-40 cells treated with 30 uM linoleic acid, which resulted in selection of 93 genes in RIN-40 versus RIN-40 treated with linoleic acid. Based on the Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG, http://www.genome.jp/kegg/), sets of genes induced differentially by treatment with linoleic acid in RIN-40 cells were found to be related to mitogen-activated protein (MAP) kinase- and neuroactive ligand-receptor interaction pathways. A gene ontology (GO) study revealed that more than 30% of the genes were associated with signal transduction and cell proliferation. Thus, this study elucidated a gene expression pattern relevant to the signal pathways that are regulated by GPR40 activation during the acute period. Together, these findings increase our mechanistic understanding of endogenous molecules associated with GPR40 function, and provide information useful for identification of a target for the management of type 2 diabetes mellitus. PMID- 25729277 TI - The Effect of Polyphenols Isolated from Cynanchi wilfordii Radix with Anti inflammatory, Antioxidant, and Anti-bacterial Activity. AB - Recently, Cynanchi wilfordii Radix has gained wide use in Asian countries as a functional food effective for relieving fatigue, osteoporosis, and constipation, particularly in menopausal disorders. However, its anti-inflammatory and anti microbial activities have not been explored in detail to date. The anti inflammatory, antioxidant, and anti-bacterial properties of the Cynanchi wilfordii Radix extracts obtained with water, methanol, ethanol, and acetone were compared. All 4 polyphenol-containing extracts exhibited anti-inflammatory and antioxidant effects. The ethanol extract was found to elicit the most potent reduction of nitric oxide (NO), prostaglandin E2 (PGE2), and cytokine (IL-1beta, IL-6, IL-10, and TNF-alpha) levels, as well as inhibit the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a concentration-dependent manner. The evaluation of antioxidant activity also revealed the ethanol extract to have the highest free radical scavenging activity, measured as 85.3+/-0.4%, which is equivalent to 99.9% of the activity of alpha -tocopherol. In the assessment of anti-bacterial activity, only ethanol extract was found to inhibit the growth of the Bacillus species Bacillus cereus and Bacillus anthracis. These results show that polyphenols of Cynanchi wilfordii Radix have anti-inflammatory, antioxidant, and anti-bacterial properties that can be exploited and further improved for use as a supplementary functional food, in cosmetics, and for pharmaceutical purposes. PMID- 25729278 TI - Analysis of the Baroreceptor and Vestibular Receptor Inputs in the Rostral Ventrolateral Medulla following Hypotension in Conscious Rats. AB - Input signals originating from baroreceptors and vestibular receptors are integrated in the rostral ventrolateral medulla (RVLM) to maintain blood pressure during postural movement. The contribution of baroreceptors and vestibular receptors in the maintenance of blood pressure following hypotension were quantitatively analyzed by measuring phosphorylated extracellular regulated protein kinase (pERK) expression and glutamate release in the RVLM. The expression of pERK and glutamate release in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) following hypotension induced by a sodium nitroprusside (SNP) infusion. The expression of pERK was significantly increased in the RVLM in the control group following SNP infusion, and expression peaked 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than seen in the control group. The SAD group showed a relatively higher reduction in pERK expression when compared with the BL group. The level of glutamate release was significantly increased in the RVLM in control, BL, SAD groups following SNP infusion, and this peaked 10 min after SNP infusion. The SAD group showed a relatively higher reduction in glutamate release when compared with the BL group. These results suggest that the baroreceptors are more powerful in pERK expression and glutamate release in the RVLM following hypotension than the vestibular receptors, but the vestibular receptors still have an important role in the RVLM. PMID- 25729279 TI - Effect of Stimulus Waveform of Biphasic Current Pulse on Retinal Ganglion Cell Responses in Retinal Degeneration (rd1) mice. AB - A retinal prosthesis is being developed for the restoration of vision in patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Determining optimal electrical stimulation parameters for the prosthesis is one of the most important elements for the development of a viable retinal prosthesis. Here, we investigated the effects of different charge-balanced biphasic pulses with regard to their effectiveness in evoking retinal ganglion cell (RGC) responses. Retinal degeneration (rd1) mice were used (n=17). From the ex-vivo retinal preparation, retinal patches were placed ganglion cell layer down onto an 8*8 multielectrode array (MEA) and RGC responses were recorded while applying electrical stimuli. For asymmetric pulses, 1st phase of the pulse is the same with symmetric pulse but the amplitude of 2nd phase of the pulse is less than 10 uA and charge balanced condition is satisfied by lengthening the duration of the pulse. For intensities (or duration) modulation, duration (or amplitude) of the pulse was fixed to 500 us (30 uA), changing the intensities (or duration) from 2 to 60 uA (60 to 1000 us). RGCs were classified as response-positive when PSTH showed multiple (3~4) peaks within 400 ms post stimulus and the number of spikes was at least 30% more than that for the immediate pre-stimulus 400 ms period. RGC responses were well modulated both with anodic and cathodic phase-1st biphasic pulses. Cathodic phase-1st pulses produced significantly better modulation of RGC activity than anodic phase-1st pulses regardless of symmetry of the pulse. PMID- 25729280 TI - Low Non-NMDA Receptor Current Density as Possible Protection Mechanism from Neurotoxicity of Circulating Glutamate on Subfornical Organ Neurons in Rats. AB - The subfornical organ (SFO) is one of circumventricular organs characterized by the lack of a normal blood brain barrier. The SFO neurons are exposed to circulating glutamate (60~100 uM), which may cause excitotoxicity in the central nervous system. However, it remains unclear how SFO neurons are protected from excitotoxicity caused by circulating glutamate. In this study, we compared the glutamate-induced whole cell currents in SFO neurons to those in hippocampal CA1 neurons using the patch clamp technique in brain slice. Glutamate (100 uM) induced an inward current in both SFO and hippocampal CA1 neurons. The density of glutamate-induced current in SFO neurons was significantly smaller than that in hippocampal CA1 neurons (0.55 vs. 2.07 pA/pF, p<0.05). To further identify the subtype of the glutamate receptors involved, the whole cell currents induced by selective agonists were then compared. The current densities induced by AMPA (0.45 pA/pF) and kainate (0.83 pA/pF), non-NMDA glutamate receptor agonists in SFO neurons were also smaller than those in hippocampal CA1 neurons (2.44 pA/pF for AMPA, p<0.05; 2.34 pA/pF for kainate, p< 0.05). However, the current density by NMDA in SFO neurons was not significantly different from that of hippocampal CA1 neurons (1.58 vs. 1.47 pA/pF, p>0.05). These results demonstrate that glutamate-mediated action through non-NMDA glutamate receptors in SFO neurons is smaller than that of hippocampal CA1 neurons, suggesting a possible protection mechanism from excitotoxicity by circulating glutamate in SFO neurons. PMID- 25729281 TI - Foeniculum vulgare Mill. Protects against Lipopolysaccharide-induced Acute Lung Injury in Mice through ERK-dependent NF-kappaB Activation. AB - Foeniculum vulgare Mill. (fennel) is used to flavor food, in cosmetics, as an antioxidant, and to treat microbial, diabetic and common inflammation. No study to date, however, has assessed the anti-inflammatory effects of fennel in experimental models of inflammation. The aims of this study were to investigate the anti-inflammatory effects of fennel in model of lipopolysaccharide (LPS) induced acute lung injury. Mice were randomly assigned to seven groups (n=7~10). In five groups, the mice were intraperitoneally injected with 1% Tween 80-saline (vehicle), fennel (125, 250, 500ul/kg), or dexamethasone (1 mg/kg), followed 1 h later by intratracheal instillation of LPS (1.5 mg/kg). In two groups, the mice were intraperitoneally injected with vehicle or fennel (250ul/kg), followed 1 h later by intratracheal instillation of sterile saline. Mice were sacrificed 4 h later, and bronchoalveolar lavage fluid (BALF) and lung tissues were obtained. Fennel significantly and dose-dependently reduced LDH activity and immune cell numbers in LPS treated mice. In addition fennel effectively suppressed the LPS induced increases in the production of the inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, with 500ul/kg fennel showing maximal reduction. Fennel also significantly and dose-dependently reduced the activity of the proinflammatory mediator matrix metalloproteinase 9 and the immune modulator nitric oxide (NO). Assessments of the involvement of the MAPK signaling pathway showed that fennel significantly decreased the LPS-induced phosphorylation of ERK. Fennel effectively blocked the inflammatory processes induced by LPS, by regulating pro-inflammatory cytokine production, transcription factors, and NO. PMID- 25729282 TI - A Commentary on Real-Time Biofeedback to Augment Neuromuscular Training for ACL Injury Prevention in Adolescent Athletes. AB - Anterior cruciate ligament injury and the associated long-term sequelae, such as immediate reductions in physical inactivity, increased adiposity and increased risk of osteoarthritis throughout adulthood, are a major health concern for adolescent athletes. Current interventions for injury prevention may have limited effectiveness, are susceptible to issues of compliance and have not achieved the widespread acceptance necessary to promote full adoption. Neuromuscular training (NMT) is a well-established training intervention introduced to affect change in modifiable biomechanical risk factors to reduce the risk of injury in these athletes. Despite moderate success, neuromuscular training is still limited by its reliance on subjective feedback and after the fact (i.e., offline) objective feedback techniques. The purpose of this commentary is to discuss technological tools that could be used to enhance and objectify targeted biofeedback interventions to complement NMT. Electromyography, force plates, motion sensors, and camera-based motion capture systems are innovative tools that may have realistic feasibility for integration as biofeedback into NMT programs to improve training outcomes. Improved functional deficit identification and corrective analysis may further improve and optimize athletic performance, and decrease the risk of sports-related injury during sport performance. Key pointsSpecific, targeted interventions that isolate injury risk factors and can help correct modifiable neuromuscular deficits are essential.Current training interventions for anterior cruciate ligament (ACL) injury prevention have only demonstrated limited effectiveness and have not achieved the widespread acceptance necessary to promote full adoption to reduce ACL injury rates.The paper provides an overview of innovative strategies and technological tools that could be used to enhance and objectify targeted biofeedback interventions to complement neuromuscular training (NMT) including electromyography, force plates, motion sensors, and camera-based motion capture systems.These strategies utilize biomechanical, physiological, or neuromotor variables for training, automate the quantitative measurement of those variables through a variety of technological modalities, and then feed those measured variables via software to provide information in simplified form for online, visual biofeedback displays. PMID- 25729283 TI - Seasonal strength performance and its relationship with training load on elite runners. AB - The aim of this study was to analyze the time-course of force production of elite middle and long-distance runners throughout an entire season and at the end of the off-season, as well as its relationships with training load and hormonal responses. Training load was recorded daily throughout an entire season by measuring and evaluating the session distance (km), training zone and session-RPE in a group of 15 elite middle and long-distance runners (12 men, 3 women; age = 26.3 +/- 5.1yrs, BMI = 19.7 +/- 1.1). Also, basal salivary-free cortisol levels were measured weekly, and 50-metre sprints, mean propulsive velocity (MPV), mean propulsive power (MPP), repetition maximum (RM) and peak rate of force development (RFD) of half-squats were measured 4 times during the season, and once more after the off-season break. There were no significant variations in force production during the season or after the off-season break, except for the RFD (-30.2%, p = 0.005) values, which changed significantly from the beginning to the end of the season. Significant correlations were found between session-RPE and MPV (r = -0.650, p = 0.004), MPP (r = -0.602, p = 0.009), RM (r = -0.650, p = 0.004), and the 50-metre sprint (r = 0.560, p = 0.015). Meanwhile, salivary-free cortisol correlated significantly with the 50-metre sprint (r = 0.737, p < 0.001) and the RM ( r = -0.514, p = 0.025). Finally, the training zone correlated with the 50-metre sprint (r = -0.463, p = 0.041). Session-RPE, training zone and salivary-free cortisol levels are related to force production in elite middle and long-distance runners. Monitoring these variables could be a useful tool in controlling the training programs of elite athletes. Key pointsSession-RPE, training zone and salivary free cortisol levels correlate significantly with strength-related variables in middle and long-distance elite runners.A month of active rest during the off-season break is enough to prevent decreases in force production of such athletes.Monitoring training loads through session-RPE is a suitable and simple method for controlling the training process in elite middle and long-distance runners. PMID- 25729284 TI - The relative age effect and the influence on performance in youth alpine ski racing. AB - The relative age effect (RAE), which refers to an over representation of athletes born early in a selection year, recently was proven to be present in alpine skiing. However, it was not made apparent whether the RAE exists as early as at the youngest level of youth ski racing at national level, nor whether the relative age influences racing performance. As a consequence, the purpose of the present study was twofold: first, to examine the extent of the RAE and second, to assess the influence the relative age has on the overall performance at the youngest levels of youth ski racing. The study included the investigation of 1,438 participants of the Austrian Kids Cup and 1,004 participants of the Teenager Cup at the provincial level, as well as 250 finalists of the Kids Cup and 150 finalists of the Teenager Cup at the national level. Chi2-tests revealed a highly significant RAE already at the youngest level of youth ski racing (Kids Cup) at both the provincial and national levels. There are not again favorably selected the relatively older athletes from the first into the second level of youth ski racing (Teenager Cup). Among the athletes of the Kids Cup, the relative age quarter distribution differed highly significantly from the distribution of the total sample with an over representation of relatively older athletes by comparison taking the top three positions. The data revealed that relative age had a highly significant influence on performance. This study demonstrated that the RAE poses a problem as early as the youngest level of youth ski racing, thereby indicating that many young talented kids are discriminated against, diminishing any chance they might have of becoming elite athletes despite their talents and efforts. The RAE influences not only the participation rate in alpine skiing, but also the performances. As a result, changes in the talent development system are imperative. Key pointsThe relative age influences not only the participation in youth ski racing, but also the performance.The relative age effect is present in all age categories in alpine skiing at national, as well as international level; this indicates that there is a severe loss of talents.From an ethical point of view, the entire talent identification and development process in alpine ski racing is discriminatory against young talented kids; consequently, this process should be reevaluated and changed to reduce the impact of RAE on young alpine ski racers in the future.The system for the competition category classification based on a rotating cut-off-date appears to be an interesting proposal for the reduction of the relative age effect in alpine skiing as well. PMID- 25729285 TI - Pre-Practice Hydration Status and the Effects of Hydration Regimen on Collegiate Division III Male Athletes. AB - Pre-practice euhydration is key in the prevention of heat related injuries. The pre-practice hydration status of male National Collegiate Athletic Association (NCAA)-Division III athletes and the effects of a direct hydration regimen have yet to be investigated therefore; the aim of the study was 1) to analyze the pre practice hydration status of current NCAA-DIII male athletes and 2) assess the impact of a directed intervention on pre-practice hydration status. The study was divided into baseline, pre and post intervention phases. For baseline, hydration status through urine specific gravity (USG) and anthropometric indices were measured prior to morning practice. Following baseline, pre-intervention commenced and participants were assigned to either control (CON) or experimental (EXP) groups. The CON and EXP group participants were instructed to maintain normal hydration and diet schedules and record fluid intake for seven days leading to post-intervention. The EXP group participants were asked to consume an additional 23.9 fl oz (~ 750 ml) per day for one week (7 days) leading to post intervention. After 7 days the same measures were taken. At baseline, the majority of the participants were hypohydrated. Following the intervention, the EXP group participants consumed significantly more fluids than the participants in the CON group (3277.91 +/- 1360. 23 ml vs 1931.54 +/- 881.81 ml; p < 0.05). A two-way repeated measure ANOVA revealed a non-significant time or treatment effect for USG or body mass but did demonstrate a significant USG interaction. In addition, an independent t-test examining absolute changes in USG demonstrated a significant difference between groups in which the EXP group improved hydration status and the CON group did not (-0.02 +/- 0.006 vs 0.001 +/- 0.005 ml; p < 0.05). In addition, there was no significant (p >0.05) difference in the regression slopes or intercepts between the CON and EXP groups when expressed as daily fluid intake per kg body (ml.kg(-1)) and change in USG from pre intervention to post-intervention. Most of the participants were hypohydrated at baseline/pre-intervention and the direct hydration intervention improved post intervention hydration status but only to a small extent. Key pointsThe majority of NCAA-DIII male athletes whom we assessed prior to practice through the use of USG appeared to be hypohydrated.The hydration intervention of adding 24.9 fl oz (~750ml) per day to an athlete's daily fluid intake led to a significant increase in fluid consumption but resulted in only small improvements in USG.The only small improvement in hydration status following the intervention may be a result of an intervention volume that is too small or an under-reporting of fluid consumption. PMID- 25729286 TI - How to regulate the acute physiological response to "aerobic" high-intensity interval exercise. AB - The acute physiological processes during "aerobic" high-intensity interval exercise (HIIE) and their regulation are inadequately studied. The main goal of this study was to investigate the acute metabolic and cardiorespiratory response to long and short HIIE compared to continuous exercise (CE) as well as its regulation and predictability. Six healthy well-trained sport students (5 males, 1 female; age: 25.7 +/- 3.1 years; height: 1.80 +/- 0.04 m; weight: 76.7 +/- 6.4 kg; VO2max: 4.33 +/- 0.7 l.min(-1)) performed a maximal incremental exercise test (IET) and subsequently three different exercise sessions matched for mean load (Pmean) and exercise duration (28 min): 1) long HIIE with submaximal peak workloads (Ppeak = power output at 95 % of maximum heart rate), peak workload durations (tpeak) of 4 min, and recovery durations (trec) of 3 min, 2) short HIIE with Ppeak according to the maximum power output (Pmax) from IET, tpeak of 20 s, and individually calculated trec (26.7 +/- 13.4 s), and 3) CE with a target workload (Ptarget) equating to Pmean of HIIE. In short HIIE, mean lactate (Lamean) (5.22 +/- 1.41 mmol.l(-1)), peak La (7.14 +/- 2.48 mmol.l(-1)), and peak heart rate (HRpeak) (181.00 +/- 6.66 b.min(-1)) were significantly lower compared to long HIIE (Lamean: 9.83 +/- 2.78 mmol.l(-1); Lapeak: 12.37 +/- 4.17 mmol.l( 1), HRpeak: 187.67 +/- 5.72 b.min(-1)). No significant differences in any parameters were found between short HIIE and CE despite considerably higher peak workloads in short HIIE. The acute metabolic and peak cardiorespiratory demand during "aerobic" short HIIE was significantly lower compared to long HIIE and regulable via Pmean. Consequently, short HIIE allows a consciously aimed triggering of specific and desired or required acute physiological responses. Key pointsHigh-intensity interval exercise (HIIE) with short peak workload durations (tpeak) induce a lower acute metabolic and peak cardiorespiratory response compared to intervals with long tpeak despite higher peak workload intensities (Ppeak) and identical mean load (Pmean).Short HIIE response is the same as in continuous exercise (CE) matched for Pmean.It is possible to regulate and predict the acute physiological response by means of Pmean for short HIIE but not for long HIIE.The use of fixed percentages of maximal heart rate (HRmax) for exercise intensity prescription yields heterogeneous exercise stimuli across subjects. Therefore, objective individual markers such as the first and the second lactate turn point are recommend prescribing exercise intensity not only for continuous but also for intermittent exercise. PMID- 25729287 TI - Stress fracture of the ulna in an elite ice dancer. AB - Stress fracture of the ulna is a rare overuse injury often arising from repetitive excessive forearm rotation. Here we report the first case of ulnar stress fracture in a female ice dancer. Diagnosis was made by history and physical examination, with the aid of imaging studies (plain x-ray, computed tomography, and magnetic resonance imaging), and biomechanical analysis of forearm pronation and supination. Following identification and modification of the causal technical element, the ice dancer was able to continue training and competing without cessation of activity. Treatment was with a 30-day course of capacitively coupled bone stimulation to promote fracture healing, confirmed on radiography and magnetic resonance imaging. Such injuries to ice dancers may be prevented at the planning stage of technical elements in the dance program if coaches place more attention on the potentially deleterious effects of difficult positions the lifted dancer must sustain to reward points on the technical elements score. Key pointsThe technical elements in ice dancing can overload joints and bones due to the positions held by the skaters.To project a competition program as much as possible safe regarding overuse injury prevention an accurate knowledge of physiological parameters of the ice dancer and of ISU rules is necessary. PMID- 25729288 TI - Self-Paced and Temporally Constrained Throwing Performance by Team-Handball Experts and Novices without Foreknowledge of Target Position. AB - The fixed duration of a team-handball game and its continuously changing situations incorporate an inherent temporal pressure. Also, the target's position is not foreknown but online determined by the player's interceptive processing of visual information. These ecological limitations do not favour throwing performance, particularly in novice players, and are not reflected in previous experimental settings of self-paced throws with foreknowledge of target position. The study investigated the self-paced and temporally constrained throwing performance without foreknowledge of target position, in team-handball experts and novices in three shot types (Standing Shot, 3Step Shot, Jump Shot). The target position was randomly illuminated on a tabloid surface before (self-paced condition) and after (temporally constrained condition) shot initiation. Response time, throwing velocity and throwing accuracy were measured. A mixed 2 (experience) X 2 (temporal constraint condition) ANOVA was applied. The novices performed with significantly lower throwing velocity and worse throwing accuracy in all shot types (p = 0.000) and, longer response time only in the 3Step Shot (p = 0.013). The temporal constraint (significantly shorter response times in all shot types at p = 0.000) had a shot specific effect with lower throwing velocity only in the 3Step Shot (p = 0.001) and an unexpected greater throwing accuracy only in the Standing Shot (p = 0.002). The significant interaction between experience and temporal constraint condition in throwing accuracy (p = 0.003) revealed a significant temporal constraint effect in the novices (p = 0.002) but not in the experts (p = 0.798). The main findings of the study are the shot specificity of the temporal constraint effect, as well as that, depending on the shot, the novices' throwing accuracy may benefit rather than worsen under temporal pressure. Key pointsThe temporal constraint induced a shot specific significant difference in throwing velocity in both the experts and the novices.The temporal constraint induced a shot specific significant difference in throwing accuracy only in the novices.Depending on the shot demands, the throwing accuracy of the novices may benefit under temporally constrained situations. PMID- 25729289 TI - Prior Knowledge of Trial Number Influences the Incidence of Plateau at VO2max. AB - The purpose of this study was to assess the VO2max plateau response at VO2max during a series of pre-determined trials. METHODS: Ten male well-trained athletes (age, 23.0 +/- 3.2; height, 183.3 +/- 5.5 cm; mass 77.5 +/- 11.1 Kg; VO2max 66.5 +/- 5.0 ml(.)kg(-1,)min(-1)), but who were VO2max testing naive and with prior knowledge of trial number completed four incremental tests to volitional exhaustion, separated by ~72-h for the determination of VO2max and gas exchange threshold. Throughout all trials VO2max was recorded on a breath-by-breath basis using a pre-calibrated metabolic cart, using a plateau criterion of Delta VO2 <=1.5 ml(.)kg(-1.)min(-1) over the final 2 consecutive 30 s sampling periods. A significant difference was observed between trial-1 and trial-4 for plateau incidence (p = 0.0285) rising from 20% in trial-1 to a 70% response rate in trial 4. Furthermore a significant difference was observed for VO2dif (difference between criterion value and Delta VO2) in trial-1, 1.02 +/- 1.69 ml(.)kg(-1.)min( 1) (p = 0.038), with non-significant differences observed for all other trials, despite a non-significant difference for VO2max across all trials (p > 0.05). Finally, a significant difference was observed for effort perception (RPE) at volitional exhaustion between trial-1 (17.7 +/- 1.3) and trial-4 (19.0 +/- 1.4) (p = 0.0052). These data indicate that prior-knowledge of trial number can influence the manifestation of the VO2 plateau in a group of well-trained male athletes, thereby suggesting that a form of effort control is established in order to preserve the finite anaerobic capacity. Key pointsIn well-trained athletes the incidence of plateau at VO2max increases in conjunction with an increase in trial number and the associated sensations of pain and fatigue.By informing the participant of the number of trials to be completed a closed-loop condition is developed whereby effort in all trials is compared to a perceptually developed template.Closed-loop condition leads to a sparing of the finite anaerobic capacity during incremental tests when the number of trials to be completed is known. PMID- 25729290 TI - sEMG during Whole-Body Vibration Contains Motion Artifacts and Reflex Activity. AB - The purpose of this study was to determine whether the excessive spikes observed in the surface electromyography (sEMG) spectrum recorded during whole-body vibration (WBV) exercises contain motion artifacts and/or reflex activity. The occurrence of motion artifacts was tested by electrical recordings of the patella. The involvement of reflex activity was investigated by analyzing the magnitude of the isolated spikes during changes in voluntary background muscle activity. Eighteen physically active volunteers performed static squats while the sEMG was measured of five lower limb muscles during vertical WBV using no load and an additional load of 33 kg. In order to record motion artifacts during WBV, a pair of electrodes was positioned on the patella with several layers of tape between skin and electrodes. Spectral analysis of the patella signal revealed recordings of motion artifacts as high peaks at the vibration frequency (fundamental) and marginal peaks at the multiple harmonics were observed. For the sEMG recordings, the root mean square of the spikes increased with increasing additional loads (p < 0.05), and was significantly correlated to the sEMG signal without the spikes of the respective muscle (r range: 0.54 - 0.92, p < 0.05). This finding indicates that reflex activity might be contained in the isolated spikes, as identical behavior has been found for stretch reflex responses evoked during direct vibration. In conclusion, the spikes visible in the sEMG spectrum during WBV exercises contain motion artifacts and possibly reflex activity. Key pointsThe spikes observed in the sEMG spectrum during WBV exercises contain motion artifacts and possibly reflex activityThe motion artifacts are more pronounced in the first spike than the following spikes in the sEMG spectrumReflex activity during WBV exercises is enhanced with an additional load of approximately 50% of the body mass. PMID- 25729291 TI - A self-paced intermittent protocol on a non-motorised treadmill: a reliable alternative to assessing team-sport running performance. AB - This study assessed the reliability of a 'self-paced' 30-min, team-sport running protocol on a Woodway Curve 3.0 non-motorised treadmill (NMT). Ten male team sport athletes (20.3 +/- 1.2 y, 74.4 +/- 9.7 kg, VO2peak 57.1 +/- 4.5 ml.kg( 1).min(-1)) attended five sessions (VO2peak testing + familiarisation; four reliability trials). The 30-min protocol consisted of three identical 10-min activity blocks, with visual and audible commands directing locomotor activity; however, actual speeds were self-selected by participants. Reliability of variables was estimated using typical error +/- 90% confidence limits expressed as a percentage [coefficient of variation (CV)] and intraclass correlation coefficient. The smallest worthwhile change (SWC) was calculated as 0.2 * between participant standard deviation. Peak/mean speed and distance variables assessed across the 30-min protocol exhibited a CV < 5%, and < 6% for each 10-min activity block. All power variables exhibited a CV < 7.5%, except walking (CV 8.3-10.1%). The most reliable variables were maximum and mean sprint speed (CV < 2%). All variables produced a CV% greater than the SWC. A self-paced, team-sport running protocol performed on a NMT produces reliable speed/distance and power data. Importantly, a single familiarisation session allowed for adequate test-retest reliability. The self-paced design provides an ecologically-valid alternative to externally-paced team-sport running simulations. Key pointsSelf-paced team-sport running protocols on a curved NMT that closely match the locomotor demands of competition deliver reliable test-retest measures of speed, distance and power.Such protocols may be sensitive to changes in running profile following an intervention that may not be detectable during externally-paced protocols.One familiarisation session is adequate to ensure test-retest reliability. PMID- 25729292 TI - Path Linearity of Elite Swimmers in a 400 m Front Crawl Competition. AB - In the frontal crawl, the propulsive action of the limbs causes lateral fluctuations from the straight path, which can be theoretically seen as the best time saving path of the race. The purpose of the present work was to analyze the head trajectory of 10 elite athletes, during a competition of 400 m front crawl, in order to give information regarding the path linearity of elite swimmers. The kinematic analysis of the head trajectories was performed by means of stereo photogrammetry. Results showed that the forward speed and lateral fluctuations speed are linearly related. Multiple regression analysis of discrete Fourier transformation allowed to distinguish 3 spectral windows identifying 3 specific features: strokes (0.7-5 Hz), breathings (0.4-0.7 Hz), and voluntary adjustments (0-0.4 Hz), which contributed to the energy wasting for 55%, 10%, and 35%, respectively. Both elite swimmers race speed and speed wastage increase while progressing from the 1(st) to the 8(th) length during a 400 m front crawl official competition. The main sources of the lateral fluctuations that lead to the increasing speed wastage could be significantly attributed to strokes and voluntary adjustments, while breathings contribution did not reach statistical significance. In conclusion, both strokes and voluntary adjustments are the main energy consuming events that affect path linearity. Key pointsThe lateral fluctuations (LF) represent indexes of elite performance swimmers during 400 m competitions.The voluntary adjustments needed to go back to the ideal trajectory are more energy consuming than the movements of the swimmer for maintaining the path linearity.The diverge from the ideal swimming trajectory during a high level competition explain about 14.7% of the variations of the average forward velocity during the race. PMID- 25729293 TI - Compression garments and exercise: no influence of pressure applied. AB - Compression garments on the lower limbs are increasingly popular among athletes who wish to improve performance, reduce exercise-induced discomfort, and reduce the risk of injury. However, the beneficial effects of compression garments have not been clearly established. We performed a review of the literature for prospective, randomized, controlled studies, using quantified lower limb compression in order to (1) describe the beneficial effects that have been identified with compression garments, and in which conditions; and (2) investigate whether there is a relation between the pressure applied and the reported effects. The pressure delivered were measured either in laboratory conditions on garments identical to those used in the studies, or derived from publication data. Twenty three original articles were selected for inclusion in this review. The effects of wearing compression garments during exercise are controversial, as most studies failed to demonstrate a beneficial effect on immediate or performance recovery, or on delayed onset of muscle soreness. There was a trend towards a beneficial effect of compression garments worn during recovery, with performance recovery found to be improved in the five studies in which this was investigated, and delayed-onset muscle soreness was reportedly reduced in three of these five studies. There is no apparent relation between the effects of compression garments worn during or after exercise and the pressures applied, since beneficial effects were obtained with both low and high pressures. Wearing compression garments during recovery from exercise seems to be beneficial for performance recovery and delayed-onset muscle soreness, but the factors explaining this efficacy remain to be elucidated. Key pointsWe observed no relationship between the effects of compression and the pressures applied.The pressure applied at the level of the lower limb by compression garments destined for use by athletes varies widely between products.There are conflict results regarding the effects of wearing compression garments during exercise.There is a trend towards a beneficial effect of compression garments worn during recovery. PMID- 25729294 TI - Physiological responses of water-polo players under different tactical strategie. AB - The aim of this study was to investigate the effect of defense tactical strategy on physiological responses characterizing playing intensity in water-polo game. In the first part of the study, fourteen players were assigned to defending (n = 7) and offending (n = 7) groups and participated in nine 4-min plays applying three different defending systems: press, static-zone and zone-press, in front of the defense court of one goalpost. In the second part, 18 players participated in nine different real full court water-polo games consisting of 3X15min of live time playing periods. Both in defense court plays and real games, the three defense systems were played in a counterbalanced order and heart rate (HR) was continuously recorded. Additionally, in defense court plays, blood lactate concentration (La) was measured at the end of each 4-min period. Mean HR within defense court plays was higher in press (153 +/- 10 beats(.)min(-1)) than in static-zone (140 +/- 11 beats(.)min(-1)) and zone-press (143 +/- 16 beats(.)min( 1), p < 0.01). Furthermore, shorter amount of playing time was spent with HR <=85% of HR peak in press (46.3 +/- 22.8%) than in static-zone (81.8 +/- 20.5%) and zone-press (75.7 +/- 32.0%, p < 0.01). Likewise, mean La was higher in press (6.5+/-2.9 mmol(.)l(-1)) than in static-zone (4.7 +/- 2.5 mmol(.)l(-1)) and zone press (4.6 +/- 1.8 mmol(.)l(-1), p < 0.01). In real games, however, mean HR was similar between tactical strategies (p > 0.05). Defenders and offenders showed similar HR and La responses across the tactical modes. In conclusion, defense tactical strategies affect physiological responses within a part of the game but do not affect the overall playing intensity of a real water-polo game. Tactical strategies similarly affect offenders and defenders. Key pointsWithin defence court plays, exercise intensity in press is higher than zone-press and static zone tactical systems.In real game the physiological response is similar between defense systems.Tactical strategies similarly affect offenders and defenders. PMID- 25729295 TI - Acute pro- and anti-inflammatory responses to resistance exercise in patients with coronary artery disease: a pilot study. AB - Little is known about the inflammatory effects of resistance exercise in healthy and even less in diseased individuals such as cardiac patients. The purpose of this study was to examine the acute pro- and anti-inflammatory responses during resistance exercise (RE) in patients with coronary artery disease. Eight low risk patients completed two acute RE protocols at low (50% of 1 RM; 2x18 rps) and moderate intensity (75% of 1 RM; 3x8 rps) in random order. Both protocols included six exercises and had the same total load volume. Blood samples were obtained before, immediately after and 60 minutes after each protocol for the determination of lactate, TNFalpha, INF-gamma, IL-6, IL-10, TGF-beta1, and hsCRP concentrations. IL-6 and IL-10 levels increased (p < 0.05) immediately after both RE protocols with no differences between protocols. INF-gamma was significantly lower (p < 0.05) 60 min after the low intensity protocol, whereas TGF-beta1 increased (p < 0.05) immediately after the low intensity protocol. There were no differences in TNF-& and hs-CRP after both RE protocols or between protocols. The above data indicate that acute resistance exercise performed at low to moderate intensity in low risk, trained CAD patients is safe and does not exacerbate the inflammation associated with their disease. Key pointsAcute resistance exercise is safe without exacerbating inflammation in patients with CAD.Both exercise intensities (50 and 75% of 1 RM) elicit desirable pro-and anti-inflammatory responses.With both exercise intensities (50 and 75% of 1 RM) acceptable clinical hemodynamic alterations were observed. PMID- 25729296 TI - Relative Match Intensities at High Altitude in Highly-Trained Young Soccer Players (ISA3600). AB - To compare relative match intensities of sea-level versus high-altitude native soccer players during a 2-week camp at 3600 m, data from 7 sea-level (Australian U17 National team, AUS) and 6 high-altitude (a Bolivian U18 team, BOL) native soccer players were analysed. Two matches were played at sea-level and three at 3600 m on Days 1, 6 and 13. The Yo-Yo Intermittent recovery test (vYo-YoIR1) was performed at sea-level, and on Days 3 and 10. Match activity profiles were measured via 10-Hz GPS. Distance covered >14.4 km.h(-1) (D>14.4 km.h(-1)) and >80% of vYo-YoIR1 (D>80%vYo-YoIR1) were examined. Upon arrival at altitude, there was a greater decrement in vYo-YoIR1 (Cohen's d +1.0, 90%CL +/- 0.8) and D>14.4 km.h(-1) (+0.5 +/- 0.8) in AUS. D>14.4 km.h(-1) was similarly reduced relative to vYo-YoIR1 in both groups, so that D>80%vYo-YoIR1 remained similarly unchanged ( 0.1 +/- 0.8). Throughout the altitude sojourn, vYo-YoIR1 and D>14.4 km.h(-1) increased in parallel in AUS, so that D>80%vYo-YoIR1 remained stable in AUS (+6.0%/match, 90%CL +/- 6.7); conversely D>80%vYo-YoIR1 decreased largely in BOL (-12.2%/match +/- 6.2). In sea-level natives competing at high-altitude, changes in match running performance likely follow those in high-intensity running performance. Bolivian data confirm that increases in 'fitness' do not necessarily translate into greater match running performance, but rather in reduced relative exercise intensity. Key pointsWhen playing at high-altitude, players may alter their activities during matches in relation to their transient maximal physical capacities, possibly to maintain a 'tolerable' relative exercise intensity.While there is no doubt that running performance per se in not the main determinant of match outcomes (Carling, 2013), fitness levels influence relative match intensity (Buchheit et al., 2012, Mendez-Villanueva et al., 2013), which in-turn may impact on decision making and skill performance (Rampinini et al., 2008).In the context of high-altitude competitions, it is therefore recommended to arrive early enough (i.e., ~2 weeks) to allow (at least partial) acclimatisation, and in turn, allow sea-level native players to regulate their running activities in relation to both actual game demands and relative match intensity. PMID- 25729297 TI - Physical Activity is Related to Fatty Liver Marker in Obese Youth, Independently of Central Obesity or Cardiorespiratory Fitness. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent complications associated with excess adiposity and has been identified as the leading cause of liver disease in pediatric populations worldwide. Because cardiorespiratory fitness (CRF) is related to physical activity (PA) levels, and increased PA plays a protective role against NAFLD risk factors, the aim of this study was to analyze the association between PA and a fatty liver marker (alanine aminotransferase - ALT) in obese children and adolescents, independently of central adiposity or CRF. 131 obese children (83 girls, 7-15 year-olds) involved in a PA promotion program comprised the sample. Measurements included anthropometric and body composition evaluations (DEXA), biological measurements (venipuncture), CRF (progressive treadmill test), PA (accelerometry), and maturational stage (Tanner criteria). The associations between ALT with PA intensities, central obesity, and CRF were calculated by three different models of linear regression, adjusted for potential confounders. Level of significance was set at 95%. RESULTS: ALT was negatively associated with MVPA (beta = -0.305), and CRF (beta = -0.426), and positively associated with central obesity (beta=.468). After adjustment for central obesity the negative and statistically significant association between ALT with MVPA (beta = -0.364) and CRF (beta = 0.550) still persists while a positive and significantly correlation was shown between ALT and SB (beta = 0.382). Additional adjustment for CRF (Model 3) showed significant associations for all the PA intensities analyzed including light activity. PA at different intensities is associated to a fatty liver marker in obese children and adolescents, independently of central adiposity or CRF. Key pointsIn a previous study our group observed that there might be a potential protective effect of cardiorespiratory fitness (CRF) against abnormal ALT values;Considering that CRF is related to physical activity (PA), and increased PA plays a protective role against fatty liver, we hypothesized that it might be an association between PA and fatty liver in obese youth, independently of central adiposity or CRF;No other study has investigated these associations in obese youth;Our findings stresses the fact that moderate-to-vigorous and light physical activities, as well as lower sedentary behavior, is associated with lower fatty liver marker, independent of the effect of potential mediators, such as central obesity or CRF. PMID- 25729298 TI - Shaping physiological indices, swimming technique, and their influence on 200m breaststroke race in young swimmers. AB - The aim of this study was to investigate somatic properties and physiological capacity, and analyze kinematic parameters in the 200 m breaststroke swimming race. Twenty-seven male swimmers participated in the study. They were 15.7+/-1.98 years old. Their average height was 1.80 +/- 0.02 m and lean body mass (LBM) was 62.45 +/- 8.29 kg. Physiological exercise capacity was measured in two separate 90 sec. all-out tests, one for the arms and second for legs. During the tests total work of arm cranking (TWAR) and cycling (TWLG) as well as peak of VO2 for arm (VO2peakAR) and leg (VO2peakLG) were measured. The underwater swimmers body movements were recorded during the all-out swimming 200m breaststroke speed test using an underwater camera installed on a portable trolley. The swimming kinematic parameters and propulsive or non-propulsive movement phases of the arms and legs as well as average speed (V200), surface speed (V200surface) and swimming speed in turn zones (V200turns) were extracted. V200surface was significantly related to the percentage of leg propulsion and was shown to have large effect on VO2peakLG in the Cohen analysis. V200turns depended significantly on the indicators of physiological performance and body structure: TWAR, VO2peak LG and LBM, LBM, which in turn strongly determined the measured results of TWAR, TWLG, VO2peakAR and VO2peakLG. The V200turns and V200surface were strongly associated with V200, 0.92, p < 0.001 and 0.91, p < 0.001 respectively. In each lap of the 200m swimming there was an increased percentage of propulsion of limb movement observed simultaneously with a reduction in the gliding phase in the breaststroke cycles. Key pointsThis study investigated the influence of the selected indicators of somatic properties and physiological capacity as well kinematic and coordination parameters on breaststroke swimming.In this observations the body's functional capacity have an important impact on achieving good breaststroke swimming results, the V200 was moderately associated on VO2peakLG, moreover, separate V200turns depended with VO2peakLG and on LBM and TWAR.The speed of surface breaststroke swimming - V200surface similarly as V200turns had a very strong influence on the end result of V200 , 0.91, p<0.001 and 0.92, p<0.001 respectively.The ability to swim fast on the surface (V200surface) was positively and significantly associated with the percentage time of propulsion generation -LP in the breaststroke cycle. PMID- 25729299 TI - A comparative study of students' track and field technical performance in sport education and in a direct instruction approach. AB - This study examined students' technical performances improvements in three track and field events (hurdles, shot put, and long jump) following either a Sport Education season or a Direct Instruction unit. An experienced Physical Education teacher taught two classes totalling 47 sixth-grade students (25 boys and 22 girls, aged between 10 and 13 years old) in 20, 45-minute lessons over 10 weeks. The students' technical performances were analysed and evaluated through systematic observation of videos. The Wilcoxon signed-rank test was used to compare scores at three time points (pre-test, post-test and retention), and the Mann-Whitney U test was used to examine the differences within each instructional model at each assessment moment, as well as by gender and skill level. The impact of each instructional model in student learning was markedly distinct. While in Sport Education students of both genders and skill levels improved significantly in all events, in Direct Instruction, evidence of significant improvements was limited to boys and students of higher skill level. Key pointsThe impact of each teaching approach in student learning was distinct. While in Sport Education the technical performance improvements spread throughout students of both genders and skill levels, in Direct Instruction significant improvements were exclusive to boys and students of higher skill level.The extended analysis in the current study, taking into account student gender and skill level, permitted a more comprehensive measure of the learning impact of the two approaches. More sophisticated analyses of the tasks and instructional strategies of each approach are encouraged. PMID- 25729300 TI - Reliability and validity assessment of a linear position transducer. AB - The objectives of the study were to determine the validity and reliability of peak velocity (PV), average velocity (AV), peak power (PP) and average power (AP) measurements were made using a linear position transducer. Validity was assessed by comparing measurements simultaneously obtained using the Tendo Weightlifting Analyzer Systemi and T-Force Dynamic Measurement Systemr (Ergotech, Murcia, Spain) during two resistance exercises, bench press (BP) and full back squat (BS), performed by 71 trained male subjects. For the reliability study, a further 32 men completed both lifts using the Tendo Weightlifting Analyzer Systemz in two identical testing sessions one week apart (session 1 vs. session 2). Intraclass correlation coefficients (ICCs) indicating the validity of the Tendo Weightlifting Analyzer Systemi were high, with values ranging from 0.853 to 0.989. Systematic biases and random errors were low to moderate for almost all variables, being higher in the case of PP (bias +/-157.56 W; error +/-131.84 W). Proportional biases were identified for almost all variables. Test-retest reliability was strong with ICCs ranging from 0.922 to 0.988. Reliability results also showed minimal systematic biases and random errors, which were only significant for PP (bias -19.19 W; error +/-67.57 W). Only PV recorded in the BS showed no significant proportional bias. The Tendo Weightlifting Analyzer Systemi emerged as a reliable system for measuring movement velocity and estimating power in resistance exercises. The low biases and random errors observed here (mainly AV, AP) make this device a useful tool for monitoring resistance training. Key pointsThis study determined the validity and reliability of peak velocity, average velocity, peak power and average power measurements made using a linear position transducerThe Tendo Weight-lifting Analyzer Systemi emerged as a reliable system for measuring movement velocity and power. PMID- 25729301 TI - Monitoring athletes through self-report: factors influencing implementation. AB - Monitoring athletic preparation facilitates the evaluation and adjustment of practices to optimize performance outcomes. Self-report measures such as questionnaires and diaries are suggested to be a simple and cost-effective approach to monitoring an athlete's response to training, however their efficacy is dependent on how they are implemented and used. This study sought to identify the perceived factors influencing the implementation of athlete self-report measures (ASRM) in elite sport settings. Semi-structured interviews were conducted with athletes, coaches and sports science and medicine staff at a national sporting institute (n = 30). Interviewees represented 20 different sports programs and had varying experience with ASRM. Purported factors influencing the implementation of ASRM related to the measure itself (e.g., accessibility, timing of completion), and the social environment (e.g., buy-in, reinforcement). Social environmental factors included individual, inter-personal and organizational levels which is consistent with a social ecological framework. An adaptation of this framework was combined with the factors associated with the measure to illustrate the inter-relations and influence upon compliance, data accuracy and athletic outcomes. To improve implementation of ASRM and ultimately athletic outcomes, a multi-factorial and multi-level approach is needed. Key pointsEffective implementation of a self-report measure for monitoring athletes requires a multi-factorial and multi-level approach which addresses the particular measure used and the surrounding social environment.A well-designed self-report measure should obtain quality data with minimal burden on athletes and staff.A supportive social environment involves buy-in and coordination of all parties, at both an individual and organization level. PMID- 25729302 TI - The development and validation of a golf swing and putt skill assessment for children. AB - The aim was to describe development of a process-oriented instrument designed to assess the golf swing and putt stroke, and to assess the instrument's discriminative validity in terms of age and reliability (intra-rater and re test). A Delphi consultation (with golf industry professionals and researchers in movement skill assessment) was used to develop an assessment for each skill based on existing skill assessment protocols. Each skill had six components to be marked as present/absent. Individual scores were based on the number of performance components successfully demonstrated over two trials for each skill (potential score range 0 to 24). Children (n = 43) aged 6-10 years (M = 7.8 years, SD = 1.3) were assessed in both skills live in the field by one rater at Time 1(T1). A subset of children (n = 28) had consent for assessments to be videoed. Six weeks later 19 children were reassessed, five days apart (T2, T3). An ANOVA assessed discriminative validity i.e. whether skill competence at T1 differed by age (6 years, 7/8 years and 9/10 years). Intraclass correlations (ICC) assessed intra-rater reliability between the live and video assessment at T1 and test-retest reliability (between T2 and T3). Paired t-tests assessed any systematic differences between live and video assessments (T1) and between T2 and T3. Older children were more skilled (F (2, 40) = 11.18, p < 0.001). The live assessment reflected the video assessment (ICC = 0.79, 95% CI 0.59, 0.90) and scores did not differ between live and video assessments. Test retest reliability was acceptable (ICC = 0.60, 95% CI 0.23, 0.82), although the mean score was slightly higher at retest. This instrument could be used reliably by golf coaches and physical education teachers as part of systematic early player assessment and feedback. Key pointsGolf is becoming an increasingly popular sport among young children, however there is no standard protocol available to assess and identify skill deficits, mastery level, and talent identification in beginner young golf players.Process rather than product oriented outcomes better identify areas of skill deficit in young children.The proposed swing and putt instrument can reliably identify skill deficits in children of elementary school age who are new to golf and can be used by a range of stakeholders including golf coaches, generalist sport coaches and physical education teachers. PMID- 25729303 TI - Acute effects of whole-body vibration on trunk and neck muscle activity in consideration of different vibration loads. AB - The intention of this study was to systematically analyze the impact of biomechanical parameters in terms of different peak-to-peak displacements and knee angles on trunk and neck muscle activity during whole-body vibration (WBV). 28 healthy men and women (age 23 +/- 3 years) performed four static squat positions (2 peak-to-peak displacements x 2 knee angles) on a side alternating vibration platform with and without vibration stimulus. Surface electromyography (EMG) was used to record the neuromuscular activity of the erector spinae muscle, the rectus abdominis muscle, and of the splenius muscle. EMG levels normalized to maximal voluntary contractions ranged between 3.2 - 27.2 % MVC during WBV. The increase in muscle activity caused by WBV was significant, particularly for the back muscles, which was up to 19.0 % MVC. The impact of the factor 'condition' (F values ranged from 13.4 to 132.0, p <= 0.001) and of the factor 'peak-to-peak displacement' (F-values ranged from 6.4 to 69.0 and p-values from < 0.001 to 0.01) were statistically significant for each muscle tested. However, the factor 'knee angle' only affected the back muscles (F-value 10.3 and 7.3, p <= 0.01). The results of this study should give more information for developing effective and safe training protocols for WBV treatment of the upper body. Key pointsThe maximum levels of muscle activity were significantly reached at high amplitudes at a vibration frequency of 30 Hz.WBV leads to a higher muscle activation of the lower back muscles than of the abdominal muscles.Both knee angles of 30 degrees and 45 degrees have similar effects on the vibration load and represent safe positions to prevent any actual harm.Certain combinations of the biomechanical variables have similar effects on the level of muscle activity. PMID- 25729304 TI - A multilevel latent growth modelling of the longitudinal changes in motivation regulations in physical education. AB - The purpose of this study was to examine individual- and classroom-level differences in the longitudinal change in motivational regulations during physical education students' transition from elementary (Grade 6) across middle school (Grades 7 to 9). A sample of 757 Finnish adolescents (M = 12.71, SD = 0.23) participated in this study. Participants of the study responded to questionnaires collected six times. A multilevel latent growth modelling approach was used to analyze the data. Results showed that motivational regulations in physical education developed at different rates during middle school. More specifically, students': (a) identified regulation increased across Grades 6 to 9; (b) amotivation increased during middle school transition from Grade 6 to 7; and (c) introjected regulation declined from Grade 8 to 9. Other motivational regulations remained stable across time. The changes in amotivation and introjected regulation were largely due to individual factors, whereas the changes in identified regulation were due to environmental factors. Key pointsStudents' identified regulation increased across Grades 6 to 9.Students' amotivation increased across middle school transition from Grade 6 to 7.Students' introjected regulation declined from Grade 8 to 9.Other motivational regulations remained stable across time. PMID- 25729305 TI - Effects of oral sodium supplementation on indices of thermoregulation in trained, endurance athletes. AB - Guidelines recommend the consumption of sodium during exercise to replace losses in sweat; however, the effects of sodium on thermoregulation are less clear. To determine the effects of high-dose sodium supplementation on indices of thermoregulation and related outcomes, 11 endurance athletes participated in a double-blind, randomized-sequence, crossover study in which they underwent 2-hrs of endurance exercise at 60% heart rate reserve with 1800 mg of sodium supplementation (SS) during one trial and placebo (PL) during the other trial. A progressive intensity time-to-exhaustion test was performed after the 2-hr steady state exercise as an assessment of exercise performance. Sweat rate was calculated from changes in body weight, accounting for fluid intake and urinary losses. Ratings of perceived exertion (RPE) and heat stress were assessed using verbal numeric scales. Cardiovascular drift was determined from the rise in HR during the 2-hr steady state exercise test. Skin temperature was measured with an infrared thermometer. Dehydration occurred in both SS and PL trials, as evidenced by substantial weight loss (2.03 +/- 0.43% and 2.27 +/- 0.70%, respectively; p = 0.261 between trials). Sweat rate was 1015.53 +/- 239.10 ml.hr(-1) during the SS trial and 1053.60+/-278.24 ml/hr during the PL trial, with no difference between trials (p = 0.459). Heat stress ratings indicated moderate heat stress ("warm/hot" ratings) but were not different between trials (p = 0.825). Time to exhaustion during the SS trial was 6.88 +/- 3.88 minutes and during the PL trial averaged 6.96 +/- 3.61 minutes, but did not differ between trials (p = 0.919). Cardiovascular drift, skin temperature, and RPE did not differ between trials (all p > 0.05). High-dose sodium supplementation does not appear to impact thermoregulation, cardiovascular drift, or physical performance in trained, endurance athletes. However, in light of the possibility that high sodium intakes might have other adverse effects, such as hypertension, it is our recommendation that athletes interpret professional recommendations for sodium needs during exercise with caution. Key pointsBased on current professional recommendations to replace sodium losses in sweat during exercise, some endurance athletes consume salt or other electrolyte supplements containing sodium during training and competition, however the effects of sodium on thermoregulation are less clear.High-dose sodium supplementation does not appear to impact thermoregulation, cardiovascular drift, or physical performance in trained, endurance athletes.The possibility remains that high sodium intakes might have other adverse effects. It is our recommendation that athletes interpret professional recommendations for sodium needs during exercise with caution. PMID- 25729307 TI - Critical velocity and anaerobic paddling capacity determined by different mathematical models and number of predictive trials in canoe slalom. AB - The purpose of this study was to analyze if different combinations of trials as well as mathematical models can modify the aerobic and anaerobic estimates from critical velocity protocol applied in canoe slalom. Fourteen male elite slalom kayakers from Brazilian canoe slalom team (K1) were evaluated. Athletes were submitted to four predictive trials of 150, 300, 450 and 600 meters in a lake and the time to complete each trial was recorded. Critical velocity (CV-aerobic parameter) and anaerobic paddling capacity (APC-anaerobic parameter) were obtained by three mathematical models (Linear1=distance-time; Linear 2=velocity 1/time and Non-Linear = time-velocity). Linear 1 was chosen for comparison of predictive trials combinations. Standard combination (SC) was considered as the four trials (150, 300, 450 and 600 m). High fits of regression were obtained from all mathematical models (range - R2 = 0.96-1.00). Repeated measures ANOVA pointed out differences of all mathematical models for CV (p = 0.006) and APC (p = 0.016) as well as R2 (p = 0.033). Estimates obtained from the first (1) and the fourth (4) predictive trials (150 m = lowest; and 600 m = highest, respectively) were similar and highly correlated (r=0.98 for CV and r = 0.96 for APC) with the SC. In summary, methodological aspects must be considered in critical velocity application in canoe slalom, since different combinations of trials as well as mathematical models resulted in different aerobic and anaerobic estimates. Key pointsGreat attention must be given for methodological concerns regarding critical velocity protocol applied on canoe slalom, since different estimates were obtained depending on the mathematical model and the predictive trials used.Linear 1 showed the best fits of regression. Furthermore, to the best of our knowledge and considering practical applications, this model is the easiest one to calculate the estimates from critical velocity protocol. Considering this, the abyss between science and practice may be decreased. Coaches of canoe slalom may simply apply critical velocity protocol and calculate by themselves the aerobic and anaerobic estimates.Still considering practical application, the results of this study showed the possibility of calculating the critical velocity estimates by using just two trials. These results are extremely relevant regarding saving time and easy applicability of this protocol for canoe slalom. PMID- 25729306 TI - Protocol design for large-scale cross-sectional studies of sexual abuse and associated factors in individual sports: feasibility study in Swedish athletics. AB - To ensure health and well-being for their athletes, sports organizations must offer preventive measures against sexual abuse. The aim of this study was to design and evaluate feasibility of a research protocol for cross-sectional epidemiological studies of sexual abuse in athletics. Examination of the requirements on the study of sexual abuse in athletics was followed by iterated drafting of protocol specifications and formative evaluations. The feasibility of the resulting protocol was evaluated in a national-level study among elite athletics athletes (n = 507) in Sweden. The definition of sexual abuse, the ethical soundness of the protocol, reference populations and study of co morbidity, and the means for athlete-level data collection were identified as particularly complex issues in the requirements analyses. The web-based survey defined by the protocol facilitates anonymous athlete self-reporting of data on exposure to sexual abuse. 198 athletes (39%) fully completed the feasibility survey. 89% (n = 177) reported that they agreed with that the questions in the survey were important, and 95% (n = 189) reported that they answered truthfully to all questions. Similarly, 91% (n = 180) reported that they did not agree with that the questions were unpleasant for them. However, 16% (n = 32) reported that they did not find the survey to be of personal value, and 12% (n = 23) reported that the survey had caused them to think about issues that they did not want to think about. Responding that participation was not personally gratifying was associated with training more hours (p = 0.01). There is a scarcity of research on the prevention of sexual abuse in individual sports. The present protocol should be regarded as a means to overcome this shortcoming in athletics. When implementing the protocol, it is necessary to encourage athlete compliance and to adapt the web-based survey to the particular infrastructural conditions in the sports setting at hand. Key pointsA research protocol for cross-sectional epidemiological studies of sexual abuse in athletics was designed and its feasibility evaluated.The definition of sexual abuse, ethical soundness of the protocol, reference populations and study of co-morbidity, and means for athlete level data collection were in requirements analyses identified as particularly complex design issues.The feasibility evaluation showed a high non-participation rate (61%), but also that the large majority of participants found the study important and that questions were answered truthfully.Responding that partaking in the study was not personally gratifying was associated with training more hours.When implementing cross-sectional epidemiological studies of sexual abuse in athletics, it is necessary to promote and facilitate athlete participation. PMID- 25729308 TI - Performance factors related to the different tennis backhand groundstrokes: a review. AB - The backhand is one of the two basic groundstrokes in tennis and can be played both with one or two hands, with topspin or backspin. Despite its variety of derivatives, the scientific literature describing the backhand groundstroke production has not been reviewed as extensively as with the serve and the forehand. The purpose of this article is to review the research describing the mechanics of one and two-handed backhands, with a critical focus on its application to clinicians and coaches. One hundred and thirty four articles satisfied a key word search (tennis, backhand) in relevant databases and manual search, with only 61 of those articles considered directly relevant to our review. The consensus of this research supports major differences between both the one- and two-handed strokes, chiefly about their respective contributions of trunk rotation and the role of the non-dominant upper extremity. Two-handed backhand strokes rely more on trunk rotation for the generation of racquet velocity, while the one-handed backhands utilize segmental rotations of the upper limb to develop comparable racquet speeds. There remains considerable scope for future research to examine expertise, age and/or gender-related kinematic differences to strengthen the practitioner's understanding of the key mechanical considerations that may shape the development of proficient backhand strokes. Key pointsOne-and two-handed backhands require different motor coordinationTwo-handed backhand strokes rely more on trunk rotation for racquet velocity generation, whereas one-handed backhand strokes rely more on segmental rotations of the upper limbPlayers using a two-handed backhand should learn early a slice one-handed backhand because of the different co-ordination pattern involvedEquipment scaling is a great tool for coaches to learn early proper one-handed backhand strokesFuture research related to the interaction between backhand technique, gender and skill level is needed. PMID- 25729309 TI - Reliability and accuracy of six hand-held blood lactate analysers. AB - The reliability and accuracy of five portable blood lactate (BLa) analysers (Lactate Pro, Lactate Pro2, Lactate Scout+, XpressTM, and Edge) and one handheld point-of-care analyser (i-STAT) were compared to a criterion (Radiometer ABL90). Two devices of each brand of analyser were assessed using 22 x 6 mL blood samples taken from five subjects at rest and during exercise who generated lactate ranging ~1-23 mM. Each sample was measured simultaneously ~6 times on each device. Reliability was assessed as the within-sample standard deviation (wsSD) of the six replicates; accuracy as the bias compared with the ABL90; and overall error (the root mean squared error (?MSE)) was calculated as the square root of (wsSD(2) and bias(2)). The ?MSE indicated that both the Edge and Xpress had low total error (~0-2 mM) for lactate concentrations <15 mM, whereas the Edge and Lactate Pro2 were the better of the portable analysers for concentrations >15 mM. In all cases, bias (negative) was the major contribution to the ?MSE. In conclusion, in a clinical setting where BLa is generally <15 mM the Edge and Xpress devices are relevant, but for athlete testing where peak BLa is important for training prescription the Edge and Lactate Pro2 are preferred. Key pointsThe reliability of five common portable blood lactate analysers were generally <0.5 mM for concentrations in the range of ~1.0-10 mM.For all five portable analysers, the analytical error within a brand was much smaller than the biological variation in blood lactate (BLa).Compared with a criterion blood lactate analyser, there was a tendency for all portable analysers to under-read (i.e. a negative bias), which was particularly evident at the highest concentrations (BLa ~15-23 mM).The practical application of these negative biases would overestimate the ability of the athlete and prescribe a training intensity that would be too high. PMID- 25729310 TI - Reliability of the elliptical zone method of estimating body segment parameters of swimmers. AB - Due to the difficulty of measuring forces and torques acting on a swimmer during mid-pool swimming, an inverse dynamics approach is required. Personalised body segment parameter (BSP) data enabling calculation of net forces and torques can be obtained using the elliptical zone method. The purpose of this study was to establish the reliability of estimating BSP data of swimmers by the elliptical zone method with segment outlines being traced manually on a personal computer screen. Five assessors digitised the segment landmarks and traced the body segments from front and side view digital photographs of 11 single arm amputee swimmers. Each swimmer was assessed five times by each of the five assessors. The order was fully randomised. Within assessor variability was less than 5% for the segment centre of mass position of all segments, for segment length except the neck (5.2%), and for segment mass except neck (11.9%), hands (Left: 8.1%; Right: 5.8%) and feet (Left: 7.3%; Right: 7.3%). Analysis of mean variability within and between assessors indicated that between assessor variability was generally as large or larger than within assessor variability. Consequently it is recommended that when seeking personalised BSP data to maximise the accuracy of derived kinetics and sensitivity for longitudinal and bilateral within-subject comparisons the individual should be assessed by the same assessor with mean values obtained from five repeat digitisations. This study established that using the elliptical zone method using E-Zone software is a reliable and convenient way of obtaining personalised BSP data for use in analysis of swimming. Key pointsA unique (not been attempted previously) study of reliability of calculating personalised Body Segment Parameter (BSP) data using the elliptical zone methodEstablishes benchmark data regarding the reliability of BSP data for comparison with emerging technologies for obtaining personalised BSP data non invasively.Provides a description and guidelines for good practice for maximising the accuracy of derived kinematics and kinetics in swimming.The method of body modelling described can also be applied to studies in other sports and in assessing change in health status related to body shape characteristics for sport and non-sport populations. PMID- 25729311 TI - Effect of Acute Alterations in Foot Strike Patterns during Running on Sagittal Plane Lower Limb Kinematics and Kinetics. AB - The purpose of this study was to determine the effect of foot strike patterns and converted foot strike patterns on lower limb kinematics and kinetics at the hip, knee, and ankle during a shod condition. Subjects were videotaped with a high speed camera while running a 5km at self-selected pace on a treadmill to determine natural foot strike pattern on day one. Preferred forefoot group (PFFG, n = 10) and preferred rear foot group (PRFG, n = 11) subjects were identified through slow motion video playback (n = 21, age = 22.8+/-2.2 years, mass = 73.1+/ 14.5 kg, height 1.75 +/- 0.10 m). On day two, subjects performed five overground run trials in both their natural and unnatural strike patterns while motion and force data were collected. Data were collected over two days so that foot strike videos could be analyzed for group placement purposes. Several 2 (Foot Strike Pattern -forefoot strike [FFS], rearfoot strike [RFS]) x 2 (Group - PFFG, PRFG) mixed model ANOVAs (p < 0.05) were run on speed, active peak vertical ground reaction force (VGRF), peak early stance and mid stance sagittal ankle moments, sagittal plane hip and knee moments, ankle dorsiflexion ROM, and sagittal plane hip and knee ROM. There were no significant interactions or between group differences for any of the measured variables. Within subject effects demonstrated that the RFS condition had significantly lower (VGRF) (RFS = 2.58 +/ .21 BW, FFS = 2.71 +/- 0.23 BW), dorsiflexion moment (RFS = -2.6 1+/- 0.61 Nm.kg(-1), FFS = -3.09 +/- 0.32 Nm.kg(-1)), and dorsiflexion range of motion (RFS = 17.63 +/- 3.76 degrees , FFS = 22.10 +/- 5.08 degrees ). There was also a significantly higher peak plantarflexion moment (RFS = 0.23 +/- 0.11 Nm.kg(-1), FFS = 0.01 +/- 0.01 Nm.kg(-1)), peak knee moment (RFS = 2.61 +/- 0.54 Nm.kg(-1), FFS = 2.39 +/- 0.61 Nm.kg(-1)), knee ROM (RFS = 31.72 +/- 2.79 degrees , FFS = 29.58 +/- 2.97 degrees ), and hip ROM (RFS = 42.72 +/- 4.03 degrees , FFS = 41.38 +/- 3.32 degrees ) as compared with the FFS condition. This research suggests that acute changes in foot strike patterns during shod running can create alterations in certain lower limb kinematic and kinetic measures that are not dependent on the preferred foot strike pattern of the individual. This research also challenges the contention that the impact transient spike in the vertical ground reaction force curve is only present during a rear foot strike type of running gait. Key pointsFootstrike pattern changes should be individually considered and implemented based on individual histories/abilitiesForefoot strike patterns increase external dorsiflexion momentsRearfoot strike patterns increase external knee flexion momentsRecreational shod runners are able to mimic habitual mechanics of different foot strike patterns. PMID- 25729312 TI - Repeated-sprint cycling does not induce respiratory muscle fatigue in active adults: measurements from the powerbreathe(r) inspiratory muscle trainer. AB - This study examined respiratory muscle strength using the POWERbreathe(r) inspiratory muscle trainer (i.e., 'S-Index') before and after repeated-sprint cycling for comparison with maximal inspiratory pressure (MIP) values obtained during a Mueller maneuver. The S-Index was measured during six trials across two sessions using the POWERbreathe(r) and MIP was measured during three trials in a single session using a custom-made manometer in seven recreationally active adults. Global respiratory muscle strength was measured using both devices before and after the performance of sixteen, 6-s sprints on a cycle ergometer. Intraclass correlation coefficients for the POWERbreathe(r) S-index indicated excellent (p < 0.05) trial-to-trial (r = 0.87) and day-to-day (r = 0.90) reliability yet there was no significant correlation (r = -0.35, p = 0.43) between the S-Index measured using the POWERbreathe(r) and MIP measured during a Mueller maneuver. Repeated-sprint cycling had no effect on respiratory muscle strength as measured by the POWERbreathe(r) (p > 0.99) and during the Mueller maneuver (p > 0.99). The POWERbreathe(r) S-Index is a moderately reliable, but not equivalent, measure of MIP determined during a Mueller maneuver. Furthermore, repeated-sprint cycling does not induce globalized respiratory muscle fatigue in recreationally-active adults. Key pointsThe S-Index as measured by the POWERbreathe(r) is a reliable measure of respiratory muscle strengthThe S-Index does not accurately reflect maximal inspiratory pressure obtained from a Mueller maneuverRepeated-sprint cycling does not induce respiratory muscle fatigue as measured by the POWERbreathe(r) and the Manometer. PMID- 25729313 TI - Treatment-seeking Paths in the Management of Severe Malaria in Children under 15 Years of Age Treated in Reference Hospitals of Kinshasa, Democratic Republic of Congo. AB - BACKGROUND: In the Democratic Republic of Congo (DRC), few studies have focused on treatment-seeking paths selected by caretakers for the management of severe childhood malaria in an urban environment. The present study aims at describing the treatment-seeking paths according to the characteristics of households, as well as the subsequent impact on pre-hospitalisation delay and malarial fatality and on the main syndromes associated with severe childhood malaria. METHODS: This descriptive study included data collected at nine hospitals in Kinshasa between January and November 2011. A total of 1,350 children, under 15 years of age and hospitalised for severe malaria, were included in the study. RESULTS: Regarding the management of malaria, 31.5% of households went directly to the health centre or hospital while 68.5% opted for self-medication, church and/or traditional healing therapy. The most frequent first-line option was self-medication, adopted by more than 61.5% of households. Nevertheless, rational self-medication using antimalarial drugs recommended by the WHO (artemisinin-based combinations) was reported for only 5.5% of children. Only 12.5% of households combined 2 or 3 traditional options. The following criteria influenced the choice of a modern vs. traditional path: household socioeconomic level, residential environment, maternal education level and religious beliefs. When caretakers opted for traditional healing therapy, the pre-hospitalisation delay was longer and the occurrence of respiratory distress, severe anaemia and mortality was higher. CONCLUSION: The implementation of a malaria action plan in the Democratic Republic of Congo should take into account the diversity and pluralistic character of treatment-seeking behaviours in order to promote the most appropriate options (hospital and rational self-medication) and to avoid detrimental outcomes. PMID- 25729314 TI - Forgetting induced by recognition of visual images. AB - Retrieval-induced forgetting is a phenomenon in which groups of stimuli are initially learned, but then a subset of those stimuli are subsequently remembered via retrieval practice, causing the forgetting of the other initially learned items. This phenomenon has almost exclusively been studied using linguistic stimuli. The goal of the present study was to determine whether our memory for simultaneously learned visual stimuli was subject to a similar type of memory impairment. Participants were shown real-world objects, then they practiced recognizing a subset of these remembered objects, and finally their memory was tested for all learned objects. We found that practicing recognition of a subset of items resulted in forgetting of other objects in the group. However, impaired recognition did not spread to new objects belonging to the same category. Our findings have important implications for how our memories operate in real-world tasks, where remembering one object or aspect of a visual scene can cause us to forget other information encoded at the same time. PMID- 25729315 TI - Intergenerational pathways leading to foster care placement of foster care alumni's children. AB - This study examined a path model that postulated intergenerational relationships between biological parent psychosocial functioning and foster care alumni mental health, economic status, and social support; and from these to the likelihood of children of foster care alumni being placed in foster care. The sample included 742 adults who spent time in foster care as children with a private foster care agency and who reported having at least one biological child. A full pathway was found between poorer father's functioning to greater alumni depression, which was in turn associated with negative social support, and then a greater likelihood of child out of home placement. Other parent to alumni paths were that poorer father functioning was associated with alumni anxiety and PTSD, and poorer mother's mental health was associated with PTSD; however, anxiety and PTSD were not implicated as precursors of foster care placement of the child. Findings support the need for increased practice and policy support to address the mental health needs of parents of children in or at risk of foster care, as well as the children themselves, as family history may have a lasting influence on quality of life, even when children are raised apart from biological parents. PMID- 25729316 TI - Capillary suspensions: Particle networks formed through the capillary force. AB - The addition of small amounts of a secondary fluid to a suspension can, through the attractive capillary force, lead to particle bridging and network formation. The capillary bridging phenomenon can be used to stabilize particle suspensions and precisely tune their rheological properties. This effect can even occur when the secondary fluid wets the particles less well than the bulk fluid. These materials, so-called capillary suspensions, have been the subject of recent research studying the mechanism for network formation, the properties of these suspensions, and how the material properties can be modified. Recent work in colloidal clusters is summarized and the relationship to capillary suspensions is discussed. Capillary suspensions can also be used as a pathway for new material design and some of these applications are highlighted. Results obtained to date are summarized and central questions that remain to be answered are proposed in this review. PMID- 25729317 TI - Memoir and the Diagnosis of Schizophrenia: Reflections on The Center Cannot Hold, Me, Myself, and Them, and the 'Crumbling Twin Pillars' of Kraepelinian Psychiatry. AB - In 1896 Emil Kraepelin revolutionised the classification of psychosis by identifying what he argued were two natural disease entities: manic-depressive psychosis (bipolar disorder) and dementia praecox (schizophrenia). Kraepelin's twin pillars have governed psychiatric thinking, practice and research for over a century. However, a growing number of researchers, clinicians, and mental health service users argue contest the claim that there are fundamental differences between schizophrenia and bipolar disorder, and call for a symptom-led approach which prioritises subjective experience over diagnostic category. How can the published first-person accounts of experts by experience contribute to this debate? This short paper looks at the representation of psychiatric diagnosis in two much-lauded autobiographies: Kurt Snyder's Me, Myself, and Them: A Firsthand Account of One Young Person's Experience with Schizophrenia (2007) and Elyn Saks' The Center Cannot Hold: My Journey Through Madness (2007). As well as providing a prognosis and a plan for treatment, the psychiatric diagnosis of schizophrenia, for both these writers, gives shape and meaning to the illness experience and ultimately becomes the pivot or platform from which identity and memoir unfold. Saks and Snyder do not claim to speak for all people who receive a diagnosis of schizophrenia and it would be a mistake to read their texts in this way even if they did. But if the debate about the future of psychiatric nosology is going to respect subjective experience, the insights they and others offer in to the multiple meanings and effects of psychiatric diagnosis more than compel our attention. PMID- 25729318 TI - A comparison of multiple indicator kriging and area-to-point Poisson kriging for mapping patterns of herbivore species abundance in Kruger National Park, South Africa. AB - Kruger National Park (KNP), South Africa, provides protected habitats for the unique animals of the African savannah. For the past 40 years, annual aerial surveys of herbivores have been conducted to aid management decisions based on (1) the spatial distribution of species throughout the park and (2) total species populations in a year. The surveys are extremely time consuming and costly. For many years, the whole park was surveyed, but in 1998 a transect survey approach was adopted. This is cheaper and less time consuming but leaves gaps in the data spatially. Also the distance method currently employed by the park only gives estimates of total species populations but not their spatial distribution. We compare the ability of multiple indicator kriging and area-to-point Poisson kriging to accurately map species distribution in the park. A leave-one-out cross validation approach indicates that multiple indicator kriging makes poor estimates of the number of animals, particularly the few large counts, as the indicator variograms for such high thresholds are pure nugget. Poisson kriging was applied to the prediction of two types of abundance data: spatial density and proportion of a given species. Both Poisson approaches had standardized mean absolute errors (St. MAEs) of animal counts at least an order of magnitude lower than multiple indicator kriging. The spatial density, Poisson approach (1), gave the lowest St. MAEs for the most abundant species and the proportion, Poisson approach (2), did for the least abundant species. Incorporating environmental data into Poisson approach (2) further reduced St. MAEs. PMID- 25729319 TI - Uniqueness and Overlap: Characteristics and Longitudinal Correlates of Native Chinese Children's Writing in English as a Foreign Language. AB - Longitudinal predictors of writing composition in Chinese and English written by the same 153 Hong Kong nine-year-old children were tested, and their production errors within the English essays across ten categories, focusing on punctuation, spelling, and grammar, were compared to errors made by ninety American nine-year olds writing on the same topic. The correlation between quality of the compositions in Chinese and English was .53. In stepwise regression analyses examining early predictors at ages between five and nine years, tasks of speed or fluency were consistently uniquely associated with Chinese writing composition; measures of English vocabulary knowledge, word reading, or both were consistently uniquely associated with English writing quality. Compared to the American children, Chinese children's writing reflected significantly higher proportions of errors in all grammatical categories but did not differ in punctuation or spelling. Findings underscore both similarities and differences in writing at different levels across languages. PMID- 25729320 TI - Aqueous Two-Phase Systems formed by Biocompatible and Biodegradable Polysaccharides and Acetonitrile. AB - In this work, it is shown that novel aqueous two-phase systems can be formed by the combination of acetonitrile and polysaccharides, namely dextran. Several ternary phase diagrams were determined at 25 degrees C for the systems composed of water + acetonitrile + dextran. The effect of the dextran molecular weight (6,000, 40,000 and 100,000 g.mol-1) was ascertained toward their ability to undergo liquid-liquid demixing. An increase in the dextran molecular weight favors the phase separation. Furthermore, the effect of temperature (25, 35 and 45 degrees C) was evaluated for the system constituted by the dextran of higher molecular weight. Lower temperatures are favorable for phase separation since lower amounts of dextran and acetonitrile are required for the creation of aqueous two-phase systems. In general, acetonitrile is enriched in the top phase while dextran is majorly concentrated in the bottom phase. The applicability of this new type of two-phase systems as liquid-liquid extraction approaches was also evaluated by the study of the partition behavior of a well-known antioxidant - vanillin - and used here as a model biomolecule. The optimized conditions led to an extraction efficiency of vanillin of 95% at the acetonitrile-rich phase. PMID- 25729321 TI - Post-Narrative - An Appeal. AB - As the narrative turn enters its fourth decade, the task of identifying the limits of narrative and of exploring alternative approaches to interpreting the self and social world is growing in urgency. This article calls for scholars in the medical humanities to undertake this project through critically (re)engaging the work of Galen Strawson, Paul Atkinson and Crispin Sartwell. PMID- 25729322 TI - Dispensing with marriage: Marital and partnership trends in rural KwaZulu-Natal, South Africa 2000-2006. AB - This paper describes marriage and partnership patterns and trends in rural KwaZulu-Natal, South Africa from 2000-2006. The study is based on longitudinal, population-based data collected by the Africa Centre demographic surveillance system. We consider whether the high rates of non-marriage among Africans in South Africa reported in the 1980s were reversed following the political transformation underway by the 1990s. Our findings show that marriage has continued to decline with a small increase in cohabitation among unmarried couples, particularly in more urbanised areas. Comparing surveillance and census data, we highlight problems with the use of the 'living together' marital status category in a highly mobile population. PMID- 25729323 TI - Exploring agent-level calculations of risk and returns in relation to observed land-use changes in the US Great Plains, 1870-1940. AB - Land-use change in the U.S. Great Plains since agricultural settlement in the second half of the nineteenth century has been well documented. While aggregate historical trends are easily tracked, the decision-making of individual farmers is difficult to reconstruct. We use an agent-based model to tell the history of the settlement of the West by simulating farm-level agricultural decision making based on historical data about prices, yields, farming costs, and environmental conditions. The empirical setting for the model is the period between 1875 and 1940 in two townships in Kansas, one in the shortgrass region and the other in the mixed grass region. Annual historical data on yields and prices determine profitability of various land uses and thereby inform decision-making, in conjunction with the farmer's previous experience and randomly assigned levels of risk aversion. Results illustrating the level of agreement between model output and unique and detailed household-level records of historical land use and farm size suggest that economic behavior and natural endowments account for land change processes to some degree, but are incomplete. Discrepancies are examined to identify missing processes through model experiments, in which we adjust input and output prices, crop yields, agent memory, and risk aversion. These analyses demonstrate how agent-based modeling can be a useful laboratory for thinking about social and economic behavior in the past. PMID- 25729324 TI - Perception of hypertension management by patients and doctors in Asia: potential to improve blood pressure control. AB - BACKGROUND: Hypertension is one of the world's most common health conditions and is a leading risk factor for mortality. Although blood pressure can be modified, there is a large proportion of patients whose blood pressure remains uncontrolled. The aim of this study, termed Edvantage 360 degrees , was to gain a deeper understanding of hypertension management in Asia from the perspective of patients and doctors, and to propose strategies to improve blood pressure control. METHODS: Conducted in Hong Kong, Indonesia, Malaysia, the Philippines, South Korea, Taiwan, and Thailand, Edvantage 360 degrees was a mixed-methods observational study that used both qualitative and quantitative elements: qualitative interviews and focus groups with patients (N = 110), quantitative interviews with patients (N = 709), and qualitative interviews with doctors (N = 85). RESULTS: This study found that, although there is good understanding of the causes and consequences of hypertension among Asian patients, there is a lack of urgency to control blood pressure. Doctors and patients have different expectations of each other and a divergent view on what constitutes successful hypertension management. We also identified a fundamental gap between the beliefs of doctors and patients as to who should be most responsible for the patients' hypertension management. In addition, because patients find it difficult to comply with lifestyle modifications (often because of a decreased understanding of the changes required), adherence to medication regimens may be less of a limiting factor than doctors believe. CONCLUSIONS: Doctors may provide better care by aligning with their patients on a common understanding of successful hypertension management. Doctors may also find it helpful to provide a more personalized explanation of any needed lifestyle modifications. The willingness of the doctor to adjust their patient interaction style to form a 'doctor-patient team' is important. In addition, we recommend that doctors should not attribute ineffectiveness of the treatment plan to patient non-adherence to medications, but rather adjust the medication regimen as needed. PMID- 25729325 TI - Good's buffers as a basis for developing self-buffering and biocompatible ionic liquids for biological research. AB - This work reports a promising approach to the development of novel self-buffering and biocompatible ionic liquids for biological research in which the anions are derived from biological buffers (Good's buffers, GB). Five Good's buffers (Tricine, TES, CHES, HEPES, and MES) were neutralized with four suitable hydroxide bases (1-ethyl-3-methylimidazolium, tetramethylammonium, tetraethylammonium, and tetrabutylammonium) producing 20 Good's buffer ionic liquids (GB-ILs). The presence of the buffering action of the synthesized GB-ILs was ascertained by measuring their pH-profiles in water. Moreover, a series of mixed GB-ILs with wide buffering ranges were formulated as universal buffers. The impact of GB-ILs on bovine serum albumin (BSA), here used as a model protein, is discussed and compared with more conventional ILs using spectroscopic techniques, such as infrared and dynamic light scattering. They appear to display, in general, a greater stabilizing effect on the protein secondary structure than conventional ILs. A molecular docking study was also carried out to investigate on the binding sites of GB-IL ions to BSA. We further used the QSAR-human serum albumin binding model, log K(HSA), to calculate the binding affinity of some conventional ILs/GB-ILs to HSA. The toxicity of the GB and GB-ILs was additionally evaluated revealing that they are non-toxic against Vitro fischeri. Finally, the GB-ILs were also shown to be able to form aqueous biphasic systems when combined with aqueous solutions of inorganic or organic salts, and we tested their extraction capability for BSA. These systems were able to extract BSA with an outstanding extraction efficiency of 100% in a single step for the GB-IL-rich phase, and, as a result, the use of GB-IL-based ABS for the separation and extraction of other added-value biomolecules is highly encouraging and worthy of further investigation. PMID- 25729326 TI - Stable and destabilised states of subjective well-being: dance and movement as catalysts of transition. AB - The pursuit of subjective well-being has become an important object of policy and personal action, which within geography has been engaged largely by those with an interest in health. But to date, geography has given little attention to the ways in which subjective well-being changes and in particular, the ways in which it may be understood as both stable and amenable to change. Similarly, the field of arts and health asserts the value of participation in the creative arts for enhancing subjective well-being, but has also hardly addressed how this may come about. The paper explores stability and change in well-being through a case study of a dance and movement intervention in an English primary school. We draw on Deleuze and Guattari's notions of assemblages and of striated and smooth space to explore how participation in the arts may enable escape from habituated practices. This exploration expands the scope of geographies of health towards capturing the moments and processes through which transitions in subjective well being may occur. The study indicates the need for greater attention to gentler and gendered forms of transition. PMID- 25729327 TI - Suberoyl bis-hydroxamic acid enhances cytotoxicity induced by proteasome inhibitors in breast cancer cells. AB - BACKGROUND: Suberoyl bis-hydroxamic acid (SBHA) is a histone deacetylase (HDAC) inhibitor and exerts anti-growth effects in several malignancies including breast cancer. Proteasome inhibitors such as Bortezomib and MG-132 constitute novel anticancer agents. In this study, we investigated the synergistic antitumour activity of SBHA in combination with proteasome inhibitors. METHODS: MCF-7 and MDA-MB-231 breast cancer cells were treated with SBHA, Bortezomib, and MG-132 alone or in combination for 72 h. Cell proliferation, colony formation, apoptosis and gene expression changes were examined. RESULTS: SBHA, Bortezomib, and MG-132 alone significantly inhibited the proliferation and colony formation and induced apoptosis in MCF-7 and MDA-MB-231 cells. Combined treatment showed a good synergistic antitumour effect against breast cancer cells. The p53 protein level was significantly elevated by combined treatment with SBHA and proteasome inhibitors. Moreover, combined treatment increased the expression of Bax, Bcl-xS, and Bak and decreased the expression of Bcl-2. Combination of SBHA with proteasome inhibitors causes synergistic anticancer effects on breast cancer cells. The potential molecular mechanism may involve induction of p53 and modulation of the Bcl-2 family proteins. CONCLUSION: These findings warrant further investigation of the therapeutic benefits of combination of SBHA with proteasome inhibitors in breast cancer. PMID- 25729328 TI - EGF +61A/G polymorphism contributes to increased gastric cancer risk: evidence from a meta-analysis. AB - BACKGROUND: Epidermal growth factor (EGF) plays a pivotal role in cell proliferation, differentiation, and tumorigenesis of epithelial tissues. Variation of the EGF +61A/G (rs4444903) can lead to an alteration in EGF production and/or activity, which may result in individual susceptibility to gastric cancer. Studies investigating the association between EGF +61A/G polymorphism and gastric cancer risk produced inconsistent results. The aim of this study was to quantitatively summarize the evidence for such an association. METHODS: Eligible studies on the association between EGF +61A/G polymorphism and gastric cancer risk were identified by search of electronic databases including PubMed, EMBASE, Cochrane Library, and Chinese Biomedical Literature database (CBM). Data were extracted by two independent authors and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS: Finally, six case-control studies with 1547 gastric cancer cases and 2762 controls were eventually identified. Overall, significant increased gastric cancer risk was found when all studies were pooled in the meta-analysis (GG vs. AA: OR = 1.438, 95% CI 1.021-2.025, P = 0.038; GG + AG vs. AA: OR = 1.256, 95% CI 1.025-1.539, P = 0.028; GG vs. AG + AA: OR = 1.265, 95% CI 1.002-1.596, P = 0.048). In subgroup analysis by ethnicity, source of control, study quality, and HWE in controls, significant increased gastric cancer risk was observed in Asians, population-based studies, high quality studies, and studies consistent with HWE. In subgroup analysis according to tumor location, and histological type, significant association was observed in all subgroups. CONCLUSIONS: This meta-analysis suggested that the EGF +61A/G polymorphism contributes to increased gastric cancer risk, especially in Asian populations. Further well-designed studies based on large sample size in diverse populations are needed to confirm this association. PMID- 25729329 TI - Adenovirus-mediated co-expression of the TRAIL and HN genes inhibits growth and induces apoptosis in Marek's disease tumor cell line MSB-1. AB - BACKGROUND: The objective of this study was to determine the in vitro tumor inhibitory effect of a recombinant adenovirus expressing a fusion protein of tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) and hemagglutinin-neuraminidase (HN) genes on the MSB-1 Marek's disease tumor cell line. METHODS: TRAIL and HN genes were amplified from lymphocytes in the peripheral blood of chickens and the LaSota strain of Newcastle disease virus (NDV), respectively, using RT-PCR. The two genes were connected with a 2A connecting peptide by site-directed mutagenesis and gene splicing by overlap extension (SOE). The target gene TRAIL-2A-HN was cloned into the shuttle vector pShuttle-CMV. Homologous recombination was carried out with the vector pAdeasy-1 in the bacterium BJ5183 to construct the recombinant adenovirus plasmid pAd-TRAIL 2A-HN. After linearization, the plasmid was transfected into AD293 cells and packaged. Real-time quantitative PCR (RT-PCR) and fluorescence microscopy confirmed the introduction of the recombinant adenovirus into AD293 cells. The TCID50 method (50% tissue culture infectious dose) was employed to determine viral titers for the exprimental and control viruses, which met criteria for use. The Marek's disease tumor cell line MSB-1 was transfected with the constructed recombinant adenovirus. The infectivity of the recombinant adenovirus and the expression levels of exogenous genes were detected with RT-PCR and western blotting. The effects of the recombinant adenovirus on the growth of MSB-1 cells and cellular apoptosis were determined using flow cytometry. RESULTS: The recombinant adenovirus infected the cultured cells in vitro, and replicated and expressed exogenous genes in the cells. The recombinant adenovirus Ad-TRAIL-2A-HN inhibited the growth of MSB-1 cells and induced apoptosis by expressing exogenous genes. The rate of induced MSB-1 cell apoptosis reached 11.61%, which indicated that TRAIL and HN produced synergistic tumor-inhibiting effects. CONCLUSION: The constructed TRAIL-2A-HN fusion gene combined the apoptosis-inducing function of TRAIL and the adsorptive capacity of HN from NDV for tumor cells, and the capacity of the recombinant adenovirus expressing this fusion gene to induce tumor cell apoptosis was reported. These results provide a basis for future in vivo tumor suppression studies using recombinant adenoviruses. PMID- 25729330 TI - Differential effects of HIF-alpha isoforms on apoptosis in renal carcinoma cell lines. AB - BACKGROUND: Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose individuals to clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product forms an ubiquitin E3 ligase complex, with regulation of hypoxia-inducible factor alpha (HIF-alpha) as its best known function. Lack of VHL expression has been shown previously to sensitize renal cells to apoptosis caused by certain cellular stresses. In this report, the role of HIF-alpha in apoptosis was investigated using two parent VHL-null renal carcinoma cell lines. METHODS: 786-O and RCC10 renal carcinoma cell lines with manipulated levels of VHL, HIF-1alpha, or HIF-2alpha were subjected to cellular stresses and analyzed by western blotting for the abundance of apoptotic markers. RESULTS: Cell lines expressing mutant VHL proteins that were unable to regulate HIF-alpha had increased levels of apoptosis when irradiated with ultraviolet (UV) light. The influences of the two major isoforms of HIF-alpha, HIF-1alpha and HIF 2alpha, on apoptosis, were compared by creating cell lines in which levels of each isoform were modulated via short hairpin RNA interference. In UV-irradiated cells, HIF-2alpha expression was determined to promote apoptosis, whereas HIF 1alpha was anti-apoptotic. In cells deprived of either glucose or serum, HIF 1alpha expression was generally anti-apoptotic, while HIF-2alpha expression was observed to either promote apoptosis or have less of an influence on apoptosis, depending on the cell line used. CONCLUSIONS: HIF-1alpha and HIF-2alpha exerted distinct effects in each of the conditions tested, with expression of HIF-1alpha largely blocking apoptosis and HIF-2alpha generally promoting apoptosis. These results reinforce that HIF-1alpha and HIF-2alpha have distinct biological roles and that their relative expression levels may influence some therapeutic interventions that are dependent on apoptosis. PMID- 25729331 TI - Anti-inflammatory effects of an injectable copolymer of fatty acids (Ara 3000 beta(r)) in joint diseases. AB - BACKGROUND: In inflammatory joint disease, such as osteoarthritis or arthritis, there is an increased level of pro-inflammatory cytokines, such as interleukin 1beta. These cytokines stimulate the expression and release of matrix metalloproteases (MMP), leading to the degradation of cartilage extracellular matrix and subsequently mobility difficulty and suffering for patients. The aim of this study was to examine the therapeutic potential of a fatty acid copolymer in in vitro and in vivo models of cartilage inflammation. METHODS: Inflammation was mimicked in vitro by treatment of human articular chondrocytes with interleukin-1beta. Effects of a co-treatment with a copolymer of fatty acids (Ara 3000 beta(r)) were determined by evaluating MMP production by RT-PCR and ELISA, NO release by Griess assay, and PGE2 expression by ELISA. In addition, in vivo analysis (evolution of weight and edema) were also performed after injection of Freund adjuvant in rats treated or not with the copolymer of fatty acids. RESULTS: The copolymer of fatty acids clearly reduces inflammation in joint. In vitro, it impairs IL1 stimulated-MMP production and release, as well as the release of NO and PGE2 and the activation of NFkappaB. Furthermore, in vivo experiments using adjuvant induced-arthritis corroborates the anti-inflammatory effects of the copolymer of fatty acids, with a reduction of edemas, erythemas and ankylosis in arthritic rats. CONCLUSIONS: The results support the hypothesis that a copolymer of fatty acids, such as Ara 3000 beta(r), is a powerful anti inflammatory compounds, suggesting that it has a potential for preventing cartilage degradation associated with chronic inflammatory joint disease. PMID- 25729332 TI - Family structure and multiple domains of child well-being in the United States: a cross-sectional study. AB - BACKGROUND: We examine the association between family structure and children's health care utilization, barriers to health care access, health, and schooling and cognitive outcomes and assess whether socioeconomic status (SES) accounts for those family structure differences. We advance prior research by focusing on understudied but increasingly common family structures including single father families and five different family structures that include grandparents. METHODS: Our data on United States children aged birth through 17 (unweighted N = 198,864) come from the 1997-2013 waves of the National Health Interview Survey, a nationally representative, publicly available, household-based sample. We examine 17 outcomes across nine family structures, including married couple, cohabiting couple, single mother, and single father families, with and without grandparents, and skipped-generation families that include children and grandparents but not parents. The SES measures include family income, home ownership, and parents' or grandparents' (depending on who is in the household) employment and education. RESULTS: Compared to children living with married couples, children in single mother, extended single mother, and cohabiting couple families average poorer outcomes, but children in single father families sometimes average better health outcomes. The presence of grandparents in single parent, cohabiting, or married couple families does not buffer children from adverse outcomes. SES only partially explains family structure disparities in children's well-being. CONCLUSIONS: All non-married couple family structures are associated with some adverse outcomes among children, but the degree of disadvantage varies across family structures. Efforts to understand and improve child well-being might be most effective if they recognize the increasing diversity in children's living arrangements. PMID- 25729333 TI - Health Reform in Ceara: the process of decentralisation in the 1990s. AB - The objective of this article is to offer an overview of the health reform in Ceara focusing on the decentralisation process in the 1990s. The driving factor behind the Brazilian health reform movement was the necessity to reorganise the national health system and overcome inequalities. For the reformists, decentralisation, and together with it the idea of popular participation, is seen as essential to guarantee the fulfilment of the people's needs and to incorporate their voice in the decision-making processes of the health system. In the state of Ceara, after the 1986 elections, health reform movement members took control over the management of the state Health Secretariat. This is the main cause of the acceleration of the decentralisation process with the transference of responsibility over the management of health care delivery to municipalities. PMID- 25729334 TI - Update on Pharmacotherapy for Prevention and Treatment of Post-operative Delirium: A Systematic Evidence Review. AB - Delirium is highly prevalent among elderly post-operative patients with no pharmacological intervention approved by the Food and Drug Administration for prevention or treatment. We conducted a systematic evidence review to critically appraise literature related to the pharmacotherapy of post-operative delirium. Ten studies fulfilled our inclusion criteria with two interventions for delirium treatment and eight interventions for delirium prevention in post-operative patients. The quality of evidence of delirium treatment studies was poor, whereas the quality of evidence in delirium prevention studies ranges from moderate to high. Delirium treatment studies find similar delirium duration and length-of stay outcomes between haloperidol and either morphine or ondansetron. Risperidone was found to reduce the conversion of sub-syndromal delirium to delirium in one study compared to placebo. Haloperidol, olanzapine, and ketamine were each found to reduce delirium incidence, whereas rivastigmine had no impact on delirium incidence or duration. Lighter anesthesia as monitored by bi-spectral index led to a decreased delirium incidence. Considering results from studies conducted prior to the dates of this review, the current evidence suggests that certain pharmacologic classes and lighter sedation using BIS monitoring may prevent post operative delirium, although a conclusive recommendation for clinical practice must await further research. PMID- 25729335 TI - Different mixing techniques in experimental mesocosms-does mixing affect plankton biomass and community composition? AB - Over the past four decades, mesocosm studies have been successfully used for a wide range of applications and have provided a lot of information on trophic interactions and biogeochemical cycling of aquatic ecosystem. However, the setup of such mesocosms (e.g., dimensions and duration of experiments) needs to be adapted to the relevant biological processes being investigated. Mixing of the water column is an important factor to be considered in mesocosm experiments because enclosing water in an artificial chamber always alters the mixing regime. Various approaches have been applied to generate mixing in experimental ecosystems, including pure mechanical mixing (e.g., using a disc), airlifts, bubbling with compressed air, and pumping. In this study, we tested different mixing techniques for outdoor mesocosms and their impact on plankton biomass and community composition. We compared mesocosms mixed with a disc, an airlift system, and bubbling, and used a nonactively mixed mesocosm as a control. We investigated phytoplankton, ciliate, and zooplankton communities during a 19-d mesocosm experiment. Based on our results, we concluded that mechanical mixing with a disc was the most effective technique due to the undertow produced by lowering and lifting the disc. While no mixing technique affected seston biomass, zooplankton biomass was highest in the treatments mixed with the disc. The airlift treatments had the lowest relative share of small flagellates. However, no further differences in phytoplankton community composition occurred and no differences in zooplankton community composition existed between all actively mixed treatments. PMID- 25729336 TI - Do Stereotypic Images in Video Games Affect Attitudes and Behavior? Adolescents' Perspectives. AB - This study examined adolescents' attitudes about video games along with their self-reported play frequency. Ninth and eleventh grade students (N = 361), approximately evenly divided by grade and gender, were surveyed about whether video games have stereotypic images, involve harmful consequences or affect one's attitudes, whether game playing should be regulated by parents or the government, and whether game playing is a personal choice. Adolescents who played video games frequently showed decreased concern about the effects that games with negatively stereotyped images may have on the players' attitudes compared to adolescents who played games infrequently or not at all. With age, adolescents were more likely to view images as negative, but were also less likely to recognize stereotypic images of females as harmful and more likely to judge video-game playing as a personal choice. The paper discusses other findings in relation to research on adolescents' social cognitive judgments. PMID- 25729338 TI - Classification of 3D Multicellular Organization in Phase Microscopy for High Throughput Screening of Therapeutic Targets. AB - The current trend in high throughput screening is the utilization of more complex model systems that mimic both structural and functional properties of cellular processes in vivo. In this context, 3D cell culture models have emerged as effective systems to study tumor initiation and cancer behavior, where colony organization represents distinct phenotypic signatures that enable differentiation of cancer cells in culture using phase imaging and in the absence of clinical markers. If the colony organization can be classified into different phenotypes, it will enable rapid drug screening using phase microscopy. In this paper, we propose a novel method based on locality-constrained dictionary learning for the discrimination of aberrant colony organization in phase images, which encodes original SIFT (Scale-Invariant Feature Transform) features into high dimensional sparse codes with locality-preserving landmark points on the nonlinear manifold, and summarizes the sparse features at various locations and scales through spatial pyramid matching for robust representation. Experimental results demonstrate the significant improvement of performance, compared to the state-of-art in the field. PMID- 25729337 TI - Intersection of Stress, Social Disadvantage, and Life Course Processes: Reframing Trauma and Mental Health. AB - This paper describes the intersection of converging lines of research on the social structural, psychosocial, and physiological factors involved in the production of stress and implications for the field of mental health. Of particular interest are the stress sensitization consequences stemming from exposure to adversity over the life course. Contemporary stress sensitization theory provides important clinical utility in articulating mechanisms through which these multiple levels exert influence on mental health. Stress sensitization models (a) extend understanding of neurobiological and functional contexts within which extreme stressors operate and (b) make clear how these can influence psychologically traumatic outcomes. The value of interventions that are sensitive to current contexts as well as life course profiles of cumulative stress are illustrated through recent treatment innovations. PMID- 25729339 TI - An Engineered Community Approach for Industrial Cultivation of Microalgae. AB - Although no species lives in isolation in nature, efforts to grow organisms for use in biotechnology have generally focused on a single-species approach, particularly where a product is required at high purity. In such scenarios, preventing the establishment of contaminants requires considerable effort that is economically justified. However, for some applications in biotechnology where the focus is on lower-margin biofuel production, axenic culture is not necessary, provided yields of the desired strain are unaffected by contaminants. In this article, we review what is known about interspecific interactions of natural algal communities, the dynamics of which are likely to parallel contamination in industrial systems. Furthermore, we discuss the opportunities to improve both yields and the stability of cultures by growing algae in multi-species consortia. PMID- 25729340 TI - Implementation of Parent Child Interaction Therapy Within Foster Care: An Attempt to Translate an Evidence-Based Program Within a Local Child Welfare Agency. AB - This paper describes an innovative adaptation of an evidence-based intervention - Parent Child Interaction Therapy or PCIT - to foster parent training services. The authors faced multiple problems that commonly plague translational child welfare research as they developed, implemented and tested their model. The paper discusses how the authors addressed these problems when: 1) specifying the child welfare context in which the intervention model was implemented and tested, choosing an intervention model that responded to child welfare service needs, and tailoring the model for a child welfare context; 2) securing external funding and initiating sustainability plans for model uptake; and 3) forging a university community partnership to overcome logistical and ethical obstacles. Concluding with a summary of promising preliminary study results, a description of future plans to replicate and spread the model, and a distillation of project lessons, the paper suggests that child welfare translational research with PCIT is very promising. PMID- 25729342 TI - Methyl bromide fumigation and delayed mortality: safe trade of live pests? AB - Live organisms intercepted from treated commodities during phytosanitary inspections usually arouse suspicions of treatment failure, sub-standard treatment application, or post-treatment infestation. The additional possibility that some treatments could kill slowly, meaning commodities might be inspected before pests have succumbed, is seldom considered for treatments other than irradiation. We used a novel biochemical viability assay to measure delays between methyl bromide fumigation and mortality of dipteran eggs, and evaluated the correspondence between egg viability and egg morphological features. Our experimental conditions simulated shipping of rock melons from Australia to New Zealand by sea and air. No eggs survived fumigation, but they took 3-20 days to die, whereas phytosanitary inspections of rock melons occur within 2-7 days. Delays were not influenced by methyl bromide concentration, but were significantly lengthened by cooler storage temperatures. Methyl bromide's preservative effects delayed degradation of egg morphology, so the biochemical assay detected mortality long before morphological signs of egg death appeared. The results show that commodities subjected to effective methyl bromide treatments are at risk of being inspected before all pests have either died, or started to exhibit morphological signs of death. This could cause commodities to be unnecessarily rejected by quarantine authorities. Better methods than inspection for live pests are needed to assist authorities to gain assurance that treated commodities have been effectively disinfested. These could be developed by exploiting biochemical responses of pests and commodities to treatments. PMID- 25729341 TI - The bidirectional relationship between exercise and sleep: Implications for exercise adherence and sleep improvement. AB - Exercise has long been associated with better sleep, and evidence is accumulating on the efficacy of exercise as a nonpharmacologic treatment option for disturbed sleep. Recent research, however, has noted that poor sleep may contribute to low physical activity levels, emphasizing a robust bidirectional relationship between exercise and sleep. This article will briefly review the evidence supporting the use of exercise as a nonpharmacologic treatment for sleep disturbance, outline future research that is needed to establish the viability of exercise as a behavioral sleep treatment, describe recent research that has emphasized the potential influence of poor sleep on daytime activity levels, and discuss whether improving sleep may facilitate adoption and/or better adherence to a physically active lifestyle. With poor sleep and physical inactivity each recognized as key public health priorities, additional research into the bidirectional relationship between exercise and sleep has significant implications for facilitating greater exercise adherence and improving sleep in society. PMID- 25729343 TI - Mild and General Access to Diverse 1H-Benzotriazoles via Diboron-Mediated N-OH Deoxygenation and Palladium-Catalyzed C-C and C-N Bond Formation. AB - Benzotriazoles are a highly important class of compounds with broad-ranging applications in such diverse areas as medicinal chemistry, as auxiliaries in organic synthesis, in metallurgical applications, in aircraft deicing and brake fluids, and as antifog agents in photography. Although there are numerous approaches to N-substituted benzotriazoles, the essentially one general method to N-unsubstituted benzotriazoles is via diazotization of o-phenylenediamines, which can be limited by the availability of suitable precursors. Other methods to N unsubstitued benzotriazoles are quite specialized. Although reduction of 1 hydroxy-1H-benzotriazoles is known the reactions are not particularly convenient or broadly applicable. This presents a limitation for easy access to and availability of diverse benzotriazoles. Herein, we demonstrate a new, broadly applicable method to diverse 1H-benzotriazoles via a mild diboron-reagent mediated deoxygenation of 1-hydroxy-1H-benzotriazoles. We have also evaluated sequential deoxygenation and Pd-mediated C-C and C-N bond formation as a one-pot process for further diversification of the benzotriazole moiety. However, results indicated that purification of the deoxygenation product prior to the Pd-mediated reaction is critical to the success of such reactions. The overall chemistry allows for facile access to a variety of new benzotriazoles. Along with the several examples presented, a discussion of the advantages of the approaches is described, as also a possible mechanism for the deoxygenation process. PMID- 25729344 TI - Theranostic USPIO-Loaded Microbubbles for Mediating and Monitoring Blood-Brain Barrier Permeation. AB - Efficient and safe drug delivery across the blood-brain barrier (BBB) remains to be one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, we show that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles within their shell, can be used to mediate and monitor BBB permeation. Upon exposure to transcranial ultrasound pulses, USPIO-MB are destroyed, resulting in acoustic forces inducing vessel permeability. At the same time, USPIO are released from the MB shell, they extravasate across the permeabilized BBB and they accumulate in extravascular brain tissue, thereby providing non-invasive R2*-based magnetic resonance imaging information on the extent of BBB opening. Quantitative changes in R2* relaxometry were in good agreement with 2D and 3D microscopy results on the extravascular deposition of the macromolecular model drug FITC-dextran into the brain. Such theranostic materials and methods are considered to be useful for mediating and monitoring drug delivery across the BBB, and for enabling safe and efficient treatment of CNS disorders. PMID- 25729345 TI - The inner CSF-brain barrier: developmentally controlled access to the brain via intercellular junctions. AB - In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially consisting of neuroepithelial cells and later radial glial cells, is characterized by "strap" junctions, which limit the exchange of different sized molecules between cerebrospinal fluid and the brain parenchyma. Here we provide a systematic study of permeability properties of this inner cerebrospinal fluid-brain barrier during mouse development from embryonic day, E17 until adult. Results show that at fetal stages exchange across this barrier is restricted to the smallest molecules (286Da) and the diffusional restraint is progressively removed as the brain develops. By postnatal day P20, molecules the size of plasma proteins (70 kDa) diffuse freely. Transcriptomic analysis of junctional proteins present in the cerebrospinal fluid-brain interface showed expression of adherens junctional proteins, actins, cadherins and catenins changing in a development manner consistent with the observed changes in the permeability studies. Gap junction proteins were only identified in the adult as was claudin-11. Immunohistochemistry was used to localize at the cellular level some of the adherens junctional proteins of genes identified from transcriptomic analysis. N cadherin, beta - and alpha-catenin immunoreactivity was detected outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11 was only immunopositive in the adult, consistent with results obtained from transcriptomic analysis. These results provide information about physiological, molecular and morphological-related permeability changes occurring at the inner cerebrospinal fluid-brain barrier during brain development. PMID- 25729346 TI - Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning. AB - Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function. PMID- 25729347 TI - Reinforcement learning for adaptive threshold control of restorative brain computer interfaces: a Bayesian simulation. AB - Restorative brain-computer interfaces (BCI) are increasingly used to provide feedback of neuronal states in a bid to normalize pathological brain activity and achieve behavioral gains. However, patients and healthy subjects alike often show a large variability, or even inability, of brain self-regulation for BCI control, known as BCI illiteracy. Although current co-adaptive algorithms are powerful for assistive BCIs, their inherent class switching clashes with the operant conditioning goal of restorative BCIs. Moreover, due to the treatment rationale, the classifier of restorative BCIs usually has a constrained feature space, thus limiting the possibility of classifier adaptation. In this context, we applied a Bayesian model of neurofeedback and reinforcement learning for different threshold selection strategies to study the impact of threshold adaptation of a linear classifier on optimizing restorative BCIs. For each feedback iteration, we first determined the thresholds that result in minimal action entropy and maximal instructional efficiency. We then used the resulting vector for the simulation of continuous threshold adaptation. We could thus show that threshold adaptation can improve reinforcement learning, particularly in cases of BCI illiteracy. Finally, on the basis of information-theory, we provided an explanation for the achieved benefits of adaptive threshold setting. PMID- 25729348 TI - Hypothalamic miRNAs: emerging roles in energy balance control. AB - The hypothalamus is a crucial central nervous system area controlling appetite, body weight and metabolism. It consists in multiple neuronal types that sense, integrate and generate appropriate responses to hormonal and nutritional signals partly by fine-tuning the expression of specific batteries of genes. However, the mechanisms regulating these neuronal gene programmes in physiology and pathophysiology are not completely understood. MicroRNAs (miRNAs) are key regulators of gene expression that recently emerged as pivotal modulators of systemic metabolism. In this article we will review current evidence indicating that miRNAs in hypothalamic neurons are also implicated in appetite and whole body energy balance control. PMID- 25729349 TI - Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine. AB - The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8 s; ~50 MUM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 MUM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells. PMID- 25729351 TI - Cilia in the choroid plexus: their roles in hydrocephalus and beyond. AB - Cilia are whip-like projections that are widely conserved in eukaryotes and function as a motile propeller and/or sensory platform to detect various extracellular stimuli. In vertebrates, cilia are ubiquitously found in most cells, showing structural and functional diversities depending on the cell type. In this review, we focus on the structure and function of cilia in choroid plexus epithelial cells (CPECs). CPECs form one or two dozen non-motile 9+0 cilia, which display transient acquisition of motility during development. Genetic malfunction of cilia can lead to failure of multiple organs including the brain. Especially, several groups have demonstrated that the defects in CPEC cilia cause the communicating form of hydrocephalus. In order to elucidate the molecular mechanisms underlying the hydrocephalus, we have previously demonstrated that the cilia possess an NPFF receptor for autocrine signaling to regulate transepithelial fluid transport. In this perspective, we also discuss the potential involvement of cilia in the other aspects of choroid plexus functions, such as the regulation of brain development and neuroinflammation. PMID- 25729350 TI - Morphological and functional aspects of progenitors perturbed in cortical malformations. AB - In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area. PMID- 25729352 TI - Fragile X mental retardation protein: from autism to neurodegenerative disease. PMID- 25729354 TI - Cell-attached single-channel recordings in intact prefrontal cortex pyramidal neurons reveal compartmentalized D1/D5 receptor modulation of the persistent sodium current. AB - The persistent Na(+) current (I(Nap)) is believed to be an important target of dopamine modulation in prefrontal cortex (PFC) neurons. While past studies have tested the effects of dopamine on I(Nap), the results have been contradictory largely because of difficulties in measuring I(Nap) using somatic whole-cell recordings. To circumvent these confounds we used the cell-attached patch-clamp technique to record single Na(+) channels from the soma, proximal dendrite (PD) or proximal axon (PA) of intact prefrontal layer V pyramidal neurons. Under baseline conditions, numerous well resolved Na(+) channel openings were recorded that exhibited an extrapolated reversal potential of 73 mV, a slope conductance of 14-19 pS and were blocked by tetrodotoxin (TTX). While similar in most respects, the propensity to exhibit prolonged bursts lasting >40 ms was many fold greater in the axon than the soma or dendrite. Bath application of the D1/D5 receptor agonist SKF81297 shifted the ensemble current activation curve leftward and increased the number of late events recorded from the PD but not the soma or PA. However, the greatest effect was on prolonged bursting where the D1/D5 receptor agonist increased their occurrence 3 fold in the PD and nearly 7 fold in the soma, but not at all in the PA. As a result, D1/D5 receptor activation equalized the probability of prolonged burst occurrence across the proximal axosomatodendritic region. Therefore, D1/D5 receptor modulation appears to be targeted mainly to Na(+) channels in the PD/soma and not the PA. By circumventing the pitfalls of previous attempts to study the D1/D5 receptor modulation of I(Nap), we demonstrate conclusively that D1/D5 receptor activation can increase the I(Nap) generated proximally, however questions still remain as to how D1/D5 receptor modulates Na(+) currents in the more distal initial segment where most of the I Nap is normally generated. PMID- 25729353 TI - Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex. AB - Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic. PMID- 25729355 TI - Coexpression analysis of nine neuropeptides in the neurosecretory preoptic area of larval zebrafish. AB - The paraventricular nucleus (PVN) of the hypothalamus in mammals coordinates neuroendocrine, autonomic and behavioral responses pivotal for homeostasis and the stress response. A large amount of studies in rodents has documented that the PVN contains diverse neuronal cell types which can be identified by the expression of distinct secretory neuropeptides. Interestingly, PVN cell types often coexpress multiple neuropeptides whose relative coexpression levels are subject to environment-induced plasticity. Due to their small size and transparency, zebrafish larvae offer the possibility to comprehensively study the development and plasticity of the PVN in large groups of intact animals, yet important anatomical information about the larval zebrafish PVN-homologous region has been missing. Therefore we recently defined the location and borders of the larval neurosecretory preoptic area (NPO) as the PVN-homologous region in larval zebrafish based on transcription factor expression and cell type clustering. To identify distinct cell types present in the larval NPO, we also generated a comprehensive 3D map of 9 zebrafish homologs of typical neuropeptides found in the mammalian PVN (arginine vasopressin (AVP), corticotropin-releasing hormone (CRH), proenkephalin a (penka)/b (penkb), neurotensin (NTS), oxytocin (OXT), vasoactive intestinal peptide (VIP), cholecystokinin (CCK), and somatostatin (SST)). Here we extend this chemoarchitectural map to include the degrees of coexpression of two neuropeptides in the same cell by performing systematic pairwise comparisons. Our results allowed the subclassification of NPO cell types, and differences in variability of coexpression profiles suggest potential targets of biochemical plasticity. Thus, this work provides an important basis for the analysis of the development, function, and plasticity of the primary neuroendocrine brain region in larval zebrafish. PMID- 25729356 TI - Developing highER-throughput zebrafish screens for in-vivo CNS drug discovery. AB - The high prevalence of brain disorders and the lack of their efficient treatments necessitate improved in-vivo pre-clinical models and tests. The zebrafish (Danio rerio), a vertebrate species with high genetic and physiological homology to humans, is an excellent organism for innovative central nervous system (CNS) drug discovery and small molecule screening. Here, we outline new strategies for developing higher-throughput zebrafish screens to test neuroactive drugs and predict their pharmacological mechanisms. With the growing application of automated 3D phenotyping, machine learning algorithms, movement pattern- and behavior recognition, and multi-animal video-tracking, zebrafish screens are expected to markedly improve CNS drug discovery. PMID- 25729357 TI - The effects of intergroup competition on prosocial behaviors in young children: a comparison of 2.5-3.5 year-olds with 5.5-6.5 year-olds. AB - Group-based competition is considered to be a ubiquitous social context in human society. However, little is known about its potential effects on children's prosocial behaviors. To this end, we designed an experiment in which two age groups (2.5-3.5 years of age and 5.5-6.5 years of age) engaged in an intergroup competition task where they did a so-called "game" where each child transferred table tennis balls with a spoon from one container to the other. The non intergroup competition condition was identical to the intergroup competition condition with one exception-no intergroup competition manipulation was involved. Then, they were required to perform two economic games used to measure their prosocial behaviors. We found that under the non-intergroup competition condition, as children aged, their behaviors tended to be more fairness-oriented (such as an increase in egalitarian behaviors). However, under the intergroup competition condition, children at 2.5-3.5 years of age tended to behave prosocially towards their ingroup members compared with those who are at 5.5-6.5 years of age. The behavioral pattern under the intergroup competition condition reflects strengthening prosocial tendencies driven by the intergroup competition in younger children and simultaneously weakening intergroup competition-driven prosocial tendencies possibly due to the development of fairness-oriented behaviors in older children. Taken together, these results point to the importance of considering the effects of competitive contexts on children's social behaviors and may have important implications for further research on the role of competitive contexts in the development of human prosocial behaviors. PMID- 25729358 TI - The neural basis of deception in strategic interactions. AB - Communication based on informational asymmetries abounds in politics, business, and almost any other form of social interaction. Informational asymmetries may create incentives for the better-informed party to exploit her advantage by misrepresenting information. Using a game-theoretic setting, we investigate the neural basis of deception in human interaction. Unlike in most previous fMRI research on deception, the participants decide themselves whether to lie or not. We find activation within the right temporo-parietal junction (rTPJ), the dorsal anterior cingulate cortex (ACC), the (pre)cuneus (CUN), and the anterior frontal gyrus (aFG) when contrasting lying with truth telling. Notably, our design also allows for an investigation of the neural foundations of sophisticated deception through telling the truth-when the sender does not expect the receiver to believe her (true) message. Sophisticated deception triggers activation within the same network as plain lies, i.e., we find activity within the rTPJ, the CUN, and aFG. We take this result to show that brain activation can reveal the sender's veridical intention to deceive others, irrespective of whether in fact the sender utters the factual truth or not. PMID- 25729359 TI - Consciousness, not only intentionality, yields self-harming behavior. PMID- 25729360 TI - On the danger of detecting network states in white noise. PMID- 25729361 TI - Probabilistic inference in discrete spaces can be implemented into networks of LIF neurons. AB - The means by which cortical neural networks are able to efficiently solve inference problems remains an open question in computational neuroscience. Recently, abstract models of Bayesian computation in neural circuits have been proposed, but they lack a mechanistic interpretation at the single-cell level. In this article, we describe a complete theoretical framework for building networks of leaky integrate-and-fire neurons that can sample from arbitrary probability distributions over binary random variables. We test our framework for a model inference task based on a psychophysical phenomenon (the Knill-Kersten optical illusion) and further assess its performance when applied to randomly generated distributions. As the local computations performed by the network strongly depend on the interaction between neurons, we compare several types of couplings mediated by either single synapses or interneuron chains. Due to its robustness to substrate imperfections such as parameter noise and background noise correlations, our model is particularly interesting for implementation on novel, neuro-inspired computing architectures, which can thereby serve as a fast, low power substrate for solving real-world inference problems. PMID- 25729362 TI - Axon-somatic back-propagation in detailed models of spinal alpha motoneurons. AB - Antidromic action potentials following distal stimulation of motor axons occasionally fail to invade the soma of alpha motoneurons in spinal cord, due to their passing through regions of high non-uniformity. Morphologically detailed conductance-based models of cat spinal alpha motoneurons have been developed, with the aim to reproduce and clarify some aspects of the electrophysiological behavior of the antidromic axon-somatic spike propagation. Fourteen 3D morphologically detailed somata and dendrites of cat spinal alpha motoneurons have been imported from an open-access web-based database of neuronal morphologies, NeuroMorpho.org, and instantiated in neurocomputational models. An axon hillock, an axonal initial segment and a myelinated axon are added to each model. By sweeping the diameter of the axonal initial segment (AIS) and the axon hillock, as well as the maximal conductances of sodium channels at the AIS and at the soma, the developed models are able to show the relationships between different geometric and electrophysiological configurations and the voltage attenuation of the antidromically traveling wave. In particular, a greater than usually admitted sodium conductance at AIS is necessary and sufficient to overcome the dramatic voltage attenuation occurring during antidromic spike propagation both at the myelinated axon-AIS and at the AIS-soma transitions. PMID- 25729363 TI - Insights into muscle degeneration from heritable inclusion body myopathies. AB - Muscle mass and function are gradually lost in age-related, degenerative neuromuscular disorders, which also reflect the clinical hallmarks of sarcopenia. The consensus definition of sarcopenia includes a condition of age-related loss of muscle mass, quality, and strength. The most common acquired muscle disease affecting adults aged over 50 years is sporadic inclusion body myositis (sIBM). Besides inflammatory effects and immune-mediated muscle injury, degenerative myofiber changes are characteristic features of the disease. Although the earliest triggering events in sIBM remain elusive, a plethora of downstream mechanisms are implicated in the pathophysiology of muscle wasting. Although it remains controversial whether hereditary forms of inclusion body myopathy (IBM) may be considered as degenerative sIBM disease models, partial pathophysiological aspects can mimic the much more frequent sporadic condition, in particular the occurrence of inclusion bodies in skeletal muscle. Various clinical aspects in genetically determined skeletal muscle disorders reflect age-related alterations observed in sarcopenia. Several intriguing clues from monogenic defects in heritable IBMs contributing to the molecular basis of muscle loss will be discussed with special emphasis on inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and GNE myopathy. Finally, also the recently identified dominant multisystem proteinopathy will be considered, which may rarely present as IBM. PMID- 25729365 TI - An attempt to improve Ferreira-Junior model concerning the anti-inflammatory action of whole-body cryotherapy after exercise induced muscular damage (EIMD). PMID- 25729364 TI - Advantages and applications of CAR-expressing natural killer cells. AB - In contrast to donor T cells, natural killer (NK) cells are known to mediate anti cancer effects without the risk of inducing graft-versus-host disease (GvHD). In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR) expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/on target toxicity by CAR engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy. PMID- 25729367 TI - The emerging role of microRNAs in Alzheimer's disease. AB - MicroRNAs (miRNAs) are small non-coding RNA which have been shown to regulate gene expression. The alteration ofmiRNAs expression has been associated with several pathological processes, including neurodegeneration. In the search for easily accessible and non-invasive biomarkers for Alzheimer's disease (AD) diagnosis and prognosis, circulating miRNAs are among the most promising candidates. Some of them have been consistently identified as AD-specific miRNAs and their targets also seem implicated in pathophysiological processes underlying AD. Here, we review the emerging role for miRNA in AD, giving an overview on general miRNAs biology, their implications in AD pathophysiology and their potential role as future biomarkers. PMID- 25729366 TI - Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction. AB - Heart rhythm is initialized and controlled by the Sinoatrial Node (SAN), the primary pacemaker of the heart. The SAN is a heterogeneous multi-compartment structure characterized by clusters of specialized cardiomyocytes enmeshed within strands of connective tissue or fibrosis. Intranodal fibrosis is emerging as an important modulator of structural and functional integrity of the SAN pacemaker complex. In adult human hearts, fatty tissue and fibrosis insulate the SAN from the hyperpolarizing effect of the surrounding atria while electrical communication between the SAN and right atrium is restricted to discrete SAN conduction pathways. The amount of fibrosis within the SAN is inversely correlated with heart rate, while age and heart size are positively correlated with fibrosis. Pathological upregulation of fibrosis within the SAN may lead to tachycardia-bradycardia arrhythmias and cardiac arrest, possibly due to SAN reentry and exit block, and is associated with atrial fibrillation, ventricular arrhythmias, heart failure and myocardial infarction. In this review, we will discuss current literature on the role of fibrosis in normal SAN structure and function, as well as the causes and consequences of SAN fibrosis upregulation in disease conditions. PMID- 25729368 TI - Corrigendum: Expression analysis of candidate genes regulating successional tooth formation in the human embryo. AB - [This corrects the article on p. 445 in vol. 5, PMID: 25484868.]. PMID- 25729369 TI - An imagery-based road map to tackle maladaptive motivation in clinical disorders. PMID- 25729370 TI - Taxing Working Memory during Retrieval of Emotional Memories Does Not Reduce Memory Accessibility When Cued with Reminders. AB - Earlier studies have shown that when individuals recall an emotional memory while simultaneously doing a demanding dual-task [e.g., playing Tetris, mental arithmetic, making eye movements (EM)], this reduces self-reported vividness and emotionality of the memory. These effects have been found up to 1 week later, but have largely been confined to self-report ratings. This study examined whether this dual-tasking intervention reduces memory performance (i.e., accessibility of emotional memories). Undergraduates (N = 60) studied word-image pairs and rated the retrieved image on vividness and emotionality when cued with the word. Then they viewed the cues and recalled the images with or without making EM. Finally, they re-rated the images on vividness and emotionality. Additionally, fragments from images from all conditions were presented and participants identified which fragment was paired earlier with which cue. Findings showed no effect of the dual task manipulation on self-reported ratings and latency responses. Several possible explanations for the lack of effects are discussed, but the cued recall procedure in our experiment seems to explain the absence of effects best. The study demonstrates boundaries to the effects of the "dual-tasking" procedure. PMID- 25729371 TI - A comparison of actigraphy and sleep diaries for infants' sleep behavior. AB - Detecting the effectiveness of behavioral interventions to reduce infant night waking requires valid sleep measures. Although viewed as an objective measure, actigraphy has overestimated night-waking. Sleep diaries are criticized for only documenting night-waking with infant crying. To support potential outcome measure validity, we examined differences between sleep diaries and actigraphy in detecting night-waking and sleep duration. We recruited 5.5 to 8-month-old infants for a behavioral sleep intervention trial conducted from 2009 to 2011. Intervention (sleep education and support) and control groups (safety education and support) collected infant diary and actigraphy data for 5 days. We compared night-time sleep actigraphy with diary data at baseline (194 cases), and 6 weeks (166 cases) and 24 weeks post-education (118 cases). We hypothesized numbers of wakes and wakes of >=20 min would be higher and longest sleep time and total sleep time shorter by actigraphy compared with diaries. Using paired t-tests, there were significantly more actigraphy night wakes than diary wakes at baseline (t = 29.14, df = 193, p < 0.001), 6 weeks (t = 23.99, df = 165, p < 0.001), and 24 weeks (t = 22.01, df = 117, p < 0.001); and significantly more night wakes of >=20 min by actigraphy than diary at baseline (t = 5.03, df = 183, p < 0.001), and 24 weeks (t = 2.19, df = 107, p < 0.05), but not 6 weeks (t = 1.37, df = 156, n.s.). Longest sleep duration was significantly higher by diary than actigraphy at baseline (t = 14.71, df = 186, p < 0.001), 6 weeks (t = 7.94, df = 158, p < 0.001), and 24 weeks (t = 17.18, df = 114, p < 0.001). Night sleep duration was significantly higher by diary than actigraphy at baseline (t = 9.46, df = 185, p < 0.001), 6 weeks (t = 13.34, df = 158, p < 0.001), and 24 weeks (t = 13.48, df = 114, p < 0.001). Discrepancies in actigraphy and diary data may indicate accurate actigraphy recording of movement but not sleep given active infant sleep and self soothing. PMID- 25729372 TI - Mindfulness meditation modulates reward prediction errors in a passive conditioning task. AB - Reinforcement learning models have demonstrated that phasic activity of dopamine neurons during reward expectation encodes information about the predictability of reward and cues that predict reward. Self-control strategies such as those practiced in mindfulness-based approaches is claimed to reduce negative and positive reactions to stimuli suggesting the hypothesis that such training may influence basic reward processing. Using a passive conditioning task and fMRI in a group of experienced mindfulness meditators and age-matched controls, we tested the hypothesis that mindfulness meditation influence reward and reward prediction error (PE) signals. We found diminished positive and negative PE-related blood oxygen level-dependent (BOLD) responses in the putamen in meditators compared with controls. In the meditator group this decrease in striatal BOLD responses to reward PE was paralleled by increased activity in posterior insula, a primary interoceptive region. Critically, responses in the putamen during early trials of the conditioning procedure (run 1) were elevated in both meditators and controls. Overall, these results provide evidence that experienced mindfulness meditators are able to attenuate reward prediction signals to valenced stimuli, which may be related to interoceptive processes encoded in the posterior insula. PMID- 25729373 TI - The effect of somatosensory input on motor imagery depends upon motor imagery capability. AB - We investigated that the relationship between motor imagery ability and the effect of tactile input associated with holding a tennis racket on motor imagery of the forehand and backhand swings. The effect was assessed by the time utilized for motor imagery (mental chronometry). Seventeen tennis players imagined forehand and backhand swings with a forehand grip, a backhand grip or while holding nothing. In all cases, imaging the swings took longer than the time taken for a real swing. For imagery of the backhand swing, holding a racket with a backhand grip decreased the imaging time (p < 0.05) as compared to the trials with a forehand grip or while holding nothing. On the other hand, holding the racket with a backhand grip tended to increase the time required for forehand swing imagery. These results suggest that a congruent grip improves, and an incongruent grip deteriorates, motor imagery of the backhand swing. For players who took a longer time in the condition where they held nothing (i.e., poor imaging ability), the effect of a congruent backhand grip was greater (r = 0.67, p < 0.01). However, a congruent forehand grip did not improve motor imagery of the forehand swing. Since 15 of the participants in the present study favored the forehand swing compared to the backhand swing, the participants would have been more familiar with the forehand swing. Thus it would have been easy to vividly imagine the (familiar) forehand swing even when they were not holding a racket. We speculate that tactile input associated with holding a tool improves a vividness of motor imagery of a less familiar movement, especially for those who have poor imaging ability. In the future, it will be important to clarify whether the effect of tactile input associated with holding a tool is dependent upon movement familiarity/performance level. PMID- 25729375 TI - Educational neuroscience, constructivism, and the mediation of learning and creativity in the 21st century. PMID- 25729376 TI - Do iPads promote symbolic understanding and word learning in children with autism? AB - The use of the Apple iPad has skyrocketed in educational settings, along with largely unsubstantiated claims of its efficacy for learning and communication in children with autism spectrum disorder (ASD). Here, we examine whether children with ASD are better able to learn new word-referent relations using an iPad or a traditional picture book. We also examine the hypothesis that presenting multiple, differently colored, exemplars of a target referent will promote adaptive label generalization compared to the use of a single exemplar. Sixteen minimally verbal children with ASD were taught a new word in four within-subjects conditions, which varied by media (iPad vs. book) and content (single vs. multiple exemplar presentation). Children were then tested on the ability to symbolically relate the word to a 3-D referent (real-life depicted object) and generalize it to a differently colored category member (another similarly shaped object). The extent of symbolic understanding did not differ between the two media, and levels of generalization did not differ across conditions. However, presentation of multiple exemplars increased the rate that children with ASD extended labels from pictures to depicted objects. Our findings are discussed in terms of the importance of content to picture-based learning and the potential benefits and challenges of using the Apple iPad as an educational resource for children with ASD. PMID- 25729374 TI - The neural mediators of kindness-based meditation: a theoretical model. AB - Although kindness-based contemplative practices are increasingly employed by clinicians and cognitive researchers to enhance prosocial emotions, social cognitive skills, and well-being, and as a tool to understand the basic workings of the social mind, we lack a coherent theoretical model with which to test the mechanisms by which kindness-based meditation may alter the brain and body. Here, we link contemplative accounts of compassion and loving-kindness practices with research from social cognitive neuroscience and social psychology to generate predictions about how diverse practices may alter brain structure and function and related aspects of social cognition. Contingent on the nuances of the practice, kindness-based meditation may enhance the neural systems related to faster and more basic perceptual or motor simulation processes, simulation of another's affective body state, slower and higher-level perspective-taking, modulatory processes such as emotion regulation and self/other discrimination, and combinations thereof. This theoretical model will be discussed alongside best practices for testing such a model and potential implications and applications of future work. PMID- 25729378 TI - Fatigue in multiple sclerosis: a look at the role of poor sleep. AB - Fatigue is a frequent and debilitating symptom of multiple sclerosis (MS) with rates ranging anywhere from 53 to 90%. Despite its high prevalence and grave impact on overall functioning and quality of life, the accurate definition, quantification, and etiology of fatigue have plagued the MS literature and clinical care for decades. With regard to its etiology, MS-related fatigue has been construed as being either primary or secondary. Primary fatigue is purported to be related to centrally mediated processes of the disease whereas secondary fatigue is thought to be a result of the host of factors that may accompany MS (e.g., depression, sleep disturbance). The present paper focuses on secondary fatigue and the role of sleep disturbance, in particular. Despite the intuitive assumption that sleep problems could contribute to fatigue, sleep problems in MS have gone fairly unrecognized until recently. The present paper provides a brief review of the literature pertaining to the prevalence and nature of sleep problems in MS as well as their association with fatigue. A replication of this author's and others work is presented further demonstrating that sleep disturbance is a significant contributor to fatigue in MS when taking into account disease variables, depression, and sleep disturbance. PMID- 25729379 TI - A sufficient role of MHC class I molecules on hepatocytes in anti-plasmodial activity of CD8 (+) T cells in vivo. AB - Although CD8(+) T cells are shown to mediate the protective immunity against the liver stages of malaria parasites in mice, whether the direct presentation of malaria antigen by major histocompatibility complex (MHC) class I molecules expressed on the liver of infected host is required for anti-plasmodial activity of CD8(+) T cells is still unknown. Presently, there is only one CD8(+) epitope, SYVPSAEQI, derived from the circumsporozoite protein of Plasmodium yoelii (PyCS), that mediates anti-malarial protection and is presented in the context of a K(d) molecule. Therefore, to investigate the mode of anti-plasmodial activity of CD8+ T cells, we have previously generated C57BL/6 transgenic (Tg) mice, in which a K(d) molecule is expressed only on hepatocyte (Alb-K(d)) or dendritic cell (DC; CD11c-K(d)), by using albumin promoter or CD11c promoter, respectively. We have also generated MHC-I-K(d) Tg mice, which express the K(d) molecule under the MHC class I (MHC-I) promoter, as a positive control. From splenocytes collected from CD11c-K(d) Tg mice immunized with a synthetic peptide, SYVPSAEQI, which corresponds to the CD8(+) T-cell epitope of PyCS, emulsified in incomplete Freund's adjuvant , a PyCS-specific CD8(+) T-cell line was generated. This PyCS specific CD8(+)T-cell line was then adoptively transferred into a cohort of either MHC-K(d) Tg or Alb-K(d) Tg mice listed above, as well as wild-type C57BL/6 mice. Then both transferred and non-transferred mice were challenged with live malaria parasites. We found that the adoptive transfer of a PyCS-specific CD8(+) T-cell line resulted in a significant inhibition of the parasite burden in the liver of Alb-K(d) Tg, as well as MHC-I-K(d) Tg mice, but not of C57BL/6 mice. These results indicate that the K(d) molecule expressed by hepatocytes is sufficient in mediating the anti-plasmodial activity of PyCS-specific CD8(+) T cells in vivo. PMID- 25729377 TI - Effects of blast overpressure on neurons and glial cells in rat organotypic hippocampal slice cultures. AB - Due to recent involvement in military conflicts, and an increase in the use of explosives, there has been an escalation in the incidence of blast-induced traumatic brain injury (bTBI) among US military personnel. Having a better understanding of the cellular and molecular cascade of events in bTBI is prerequisite for the development of an effective therapy that currently is unavailable. The present study utilized organotypic hippocampal slice cultures (OHCs) exposed to blast overpressures of 150 kPa (low) and 280 kPa (high) as an in vitro bTBI model. Using this model, we further characterized the cellular effects of the blast injury. Blast-evoked cell death was visualized by a propidium iodide (PI) uptake assay as early as 2 h post-injury. Quantification of PI staining in the cornu Ammonis 1 and 3 (CA1 and CA3) and the dentate gyrus regions of the hippocampus at 2, 24, 48, and 72 h following blast exposure revealed significant time dependent effects. OHCs exposed to 150 kPa demonstrated a slow increase in cell death plateauing between 24 and 48 h, while OHCs from the high-blast group exhibited a rapid increase in cell death already at 2 h, peaking at ~24 h post-injury. Measurements of lactate dehydrogenase release into the culture medium also revealed a significant increase in cell lysis in both low- and high-blast groups compared to sham controls. OHCs were fixed at 72 h post injury and immunostained for markers against neurons, astrocytes, and microglia. Labeling OHCs with PI, neuronal, and glial markers revealed that the blast-evoked extensive neuronal death and to a lesser extent loss of glial cells. Furthermore, our data demonstrated activation of astrocytes and microglial cells in low- and high-blasted OHCs, which reached a statistically significant difference in the high-blast group. These data confirmed that our in vitro bTBI model is a useful tool for studying cellular and molecular changes after blast exposure. PMID- 25729380 TI - Specific in vitro interferon-gamma and IL-2 production as biomarkers during treatment of chronic Q fever. AB - BACKGROUND: Antibiotic treatment of chronic Q fever is cumbersome and of long duration. To monitor treatment, there is a need for alternative biomarkers. Coxiella burnetii-specific interferon (IFN)-gamma and interleukin (IL)-2 production reflect the type of effector and memory T-cell response. In chronic Q fever, C. burnetii-specific IFN-gamma production is higher and IL-2 production is lower than in individuals with past Q fever. Here we explore whether C. burnetii specific IFN-gamma and IL-2 production correlate to treatment response. METHODS: We studied the longitudinal C. burnetii-specific IFN-gamma/IL-2 ratio in fifteen proven chronic Q fever patients. All patients were followed for at least 18 months during antibiotic treatment. Treatment was considered successful when clinical recovery was observed, a positive PCR for C. burnetii DNA in blood became persistently negative, anti-phase I IgG showed a fourfold decrease or more, and imaging techniques showed disappearance of infectious foci. RESULTS: Overall, the IFN-gamma/IL-2 ratio declined when patients experienced a successful treatment outcome. When treatment failed, IFN-gamma/IL-2 ratios did not significantly decrease. The median (+/-IQR) slope of the longitudinal IFN gamma/IL-2 ratio with successful treatment was -2.10 (-7.02 to -0.06), and -0.15 (-1.13 to 0.25) with unsuccessful treatment (P = 0.19). Q fever endocarditis patients had higher IFN-gamma/IL-2 ratios than patients with endovascular infections. CONCLUSION: We propose that the IFN-gamma/IL-2 ratio can be used as an additional biomarker for monitoring chronic Q fever treatment, with declining ratios being indicative of successful treatment. PMID- 25729381 TI - TyrR, the regulator of aromatic amino acid metabolism, is required for mice infection of Yersinia pestis. AB - Yersinia pestis, the causative agent of plague, poses a serious health threat to rodents and human beings. TyrR is a transcriptional regulator (TyrR) that controls the metabolism of aromatic amino acids in Escherichia coli. In this paper, TyrR played an important role in Y. pestis virulence. Inactivation of tyrR did not seem to affect the in vitro growth of this organism, but resulted in at least 10,000-fold attenuation compared with the wild-type (WT) strain upon subcutaneous infection to mice. In addition, loads of tyrR mutant within mice livers and spleens significantly decreased compared with the WT strain. Transcriptome analysis revealed that TyrR, directly or indirectly, regulated 29 genes encoded on Y. pestis chromosome or plasmids under in vitro growth condition. Similar to the regulatory function of this protein in E. coli, five aromatic-pathway genes (aroF-tyrA, aroP, aroL, and tyrP) were significantly reduced upon deletion of the tyrR gene. Two genes (glnL and glnG) that encode sensory histidine kinase and regulator in a two-component regulatory system involved in nitrogen assimilation were downregulated in the tyrR mutant. Several genes encoding type III secretion proteins were transcribed by 2.0-4.2-fold in a tyrR mutant relative to the WT strain. Interestingly, the acid-stressed genes, hdeB and hdeD, were downregulated, and such downregulation partly accounted for the decrease in tolerance of the tyrR mutant under acidic conditions. In conclusion, regulation of TyrR in Y. pestis is similar to, but distinct from, that in E. coli. TyrR is a metabolic virulence determinant in Y. pestis that is important for extracellular survival and/or proliferation. PMID- 25729382 TI - ATP-Induced IL-1beta Specific Secretion: True Under Stringent Conditions. AB - Interleukin-1beta is a potent proinflammatory cytokine, of which processing and secretion are tightly regulated. After exposure to various stimuli, mononuclear phagocytes synthesize the inactive precursor (pro-IL-1beta), which is then cleaved intracellularly by caspase-1 and secreted. A widely used method for in vitro secretion of IL-1beta employs LPS-primed human peripheral blood monocytes. Subsequently, adenosine triphosphate (ATP) is added to the cells in order to trigger the P2X7 receptor resulting in processing and secretion of mature IL 1beta. However, it is often reported that secretion is due to cytotoxic effects of ATP with P2X7 receptor-activation-related cell death. We have challenged this concept and demonstrate IL-1beta specific secretion, since there is no increase in cell death and IL-1alpha and IL-18 are not released in the same cultures. More importantly we show that these conclusions can only be drawn under stringent experimental conditions. PMID- 25729384 TI - The Coevolution of IDO1 and AhR in the Emergence of Regulatory T-Cells in Mammals. PMID- 25729383 TI - Antimicrobial peptides and complement in neonatal hypoxia-ischemia induced brain damage. AB - Hypoxic-ischemic encephalopathy (HIE) is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1-5/1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy, and cognitive disabilities. Even though the brain is considered as an immune-privileged site, it has innate and adaptive immune response and can produce complement (C) components and antimicrobial peptides (AMPs). Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain. Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS), including neonatal hypoxia-ischemia (HI), resident microglia, and astroglia are the main cells providing immune defense to the brain in a stimulus-dependent manner. They can express and secrete pro inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express beta defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI injury and the effect of that balance on the subsequent brain damage. PMID- 25729386 TI - Ethylene is all around. PMID- 25729385 TI - Biosynthesis and possible functions of inositol pyrophosphates in plants. AB - Inositol phosphates (InsPs) are intricately tied to lipid signaling, as at least one portion of the inositol phosphate signaling pool is derived from hydrolysis of the lipid precursor, phosphatidyl inositol (4,5) bisphosphate. The focus of this review is on the inositol pyrophosphates, which are a novel group of InsP signaling molecules containing diphosphate or triphosphate chains (i.e., PPx) attached to the inositol ring. These PPx-InsPs are emerging as critical players in the integration of cellular metabolism and stress signaling in non-plant eukaryotes. Most eukaryotes synthesize the precursor molecule, myo-inositol (1,2,3,4,5,6)-hexakisphosphate (InsP6), which can serve as a signaling molecule or as storage compound of inositol, phosphorus, and minerals (referred to as phytic acid). Even though plants produce huge amounts of precursor InsP6 in seeds, almost no attention has been paid to whether PPx-InsPs exist in plants, and if so, what roles these molecules play. Recent work has delineated that Arabidopsis has two genes capable of PP-InsP5 synthesis, and PPx-InsPs have been detected across the plant kingdom. This review will detail the known roles of PPx InsPs in yeast and animal systems, and provide a description of recent data on the synthesis and accumulation of these novel molecules in plants, and potential roles in signaling. PMID- 25729387 TI - Toxicogenomics profiling of bone marrow from rats treated with topotecan in combination with oxaliplatin: a mechanistic strategy to inform combination toxicity. AB - Combinations of anticancer agents may have synergistic anti-tumor effects, but enhanced hematological toxicity often limit their clinical use. We examined whether "microarray profiles" could be used to compare early molecular responses following a single dose of agents administered individually with that of the agents administered in a combination. We compared the mRNA responses within bone marrow of Sprague-Dawley rats after a single 30 min treatment with topotecan at 4.7 mg/kg or oxaliplatin at 15 mg/kg alone to that of sequentially administered combination therapy or vehicle control for 1, 6, and 24 h. We also examined the histopathology of the bone marrow following all treatments. Drug-related histopathological lesions were limited to bone marrow hypocellularity for animals dosed with either agent alone or in combination. Lesions had an earlier onset and higher incidence for animals given topotecan alone or in combination with oxaliplatin. Severity increased from mild to moderate when topotecan was administered prior to oxaliplatin compared with administering oxaliplatin first. Notably, six patterns of co-expressed genes were detected at the 1 h time point that indicate regulatory expression of genes that are dependent on the order of the administration. These results suggest alterations in histone biology, chromatin remodeling, DNA repair, bone regeneration, and respiratory and oxidative phosphorylation are among the prominent pathways modulated in bone marrow from animals treated with an oxaliplatin/topotecan combination. These data also demonstrate the potential for early mRNA patterns derived from target organs of toxicity to inform toxicological risk and molecular mechanisms for agents given in combination. PMID- 25729388 TI - Recent advances in understanding the genetic resources of sheep breeds locally adapted to the UK uplands: opportunities they offer for sustainable productivity. AB - Locally adapted breeds of livestock are of considerable interest since they represent potential reservoirs of adaptive fitness traits that may contribute to the future of sustainable productivity in a changing climate. Recent research, involving three hill sheep breeds geographically concentrated in the northern uplands of the UK has revealed the extent of their genetic diversity from one another and from other breeds. Results from the use of SNPs, microsatellites, and retrovirus insertions are reviewed in the context of related studies on sheep breeds world-wide to highlight opportunities offered by the genetic resources of locally adapted hill breeds. One opportunity concerns reduced susceptibility to Maedi Visna, a lentivirus with massive impacts on sheep health and productivity globally. In contrast to many mainstream breeds used in farming, each of the hill breeds analyzed are likely to be far less susceptible to the disease threat. A different opportunity, relating specifically to the Herdwick breed, is the extent to which the genome of the breed has retained primitive features, no longer present in other mainland breeds of sheep in the UK and offering a new route for discovering unique genetic traits of use to agriculture. PMID- 25729389 TI - Helicases and human diseases. PMID- 25729390 TI - Synthetic biodegradable functional polymers for tissue engineering: a brief review. AB - Scaffolds play a crucial role in tissue engineering. Biodegradable polymers with great processing flexibility are the predominant scaffolding materials. Synthetic biodegradable polymers with well-defined structure and without immunological concerns associated with naturally derived polymers are widely used in tissue engineering. The synthetic biodegradable polymers that are widely used in tissue engineering, including polyesters, polyanhydrides, polyphosphazenes, polyurethane, and poly (glycerol sebacate) are summarized in this article. New developments in conducting polymers, photoresponsive polymers, amino-acid-based polymers, enzymatically degradable polymers, and peptide-activated polymers are also discussed. In addition to chemical functionalization, the scaffold designs that mimic the nano and micro features of the extracellular matrix (ECM) are presented as well, and composite and nanocomposite scaffolds are also reviewed. PMID- 25729392 TI - Long-term effects of gonadotropin-releasing hormone analogs in girls with central precocious puberty. AB - Gonadotropin-releasing hormone analogs (GnRHa) are widely used to treat central precocious puberty (CPP). The efficacy and safety of GnRHa treatment are known, but concerns regarding long-term complications are increasing. Follow-up observation results after GnRHa treatment cessation in female CPP patients up to adulthood showed that treatment (especially <6 years) was beneficial for final adult height relative to that of pretreated or untreated patients. Puberty was recovered within 1 year after GnRHa treatment discontinuation, and there were no abnormalities in reproductive function. CPP patients had a relatively high body mass index (BMI) at the time of CPP diagnosis, but BMI standard deviation score maintenance during GnRHa treatment seemed to prevent the aggravation of obesity in many cases. Bone mineral density decreases during GnRHa treatment but recovers to normal afterwards, and peak bone mass formation through bone mineral accretion during puberty is not affected. Recent studies reported a high prevalence of polycystic ovarian syndrome in CPP patients after GnRHa treatment, but it remains unclear whether the cause is the reproductive mechanism of CPP or GnRHa treatment itself. Studies of the psychosocial effects on CPP patients after GnRHa treatment are very limited. Some studies have reported decreases in psychosocial problems after GnRHa treatment. Overall, GnRHa seems effective and safe for CPP patients, based on long-term follow-up studies. There have been only a few long-term studies on GnRHa treatment in CPP patients in Korea; therefore, additional long term follow-up investigations are needed to establish the efficacy and safety of GnRHa in the Korean population. PMID- 25729393 TI - Recent update of autism spectrum disorders. AB - In patients with a language developmental delay, it is necessary to make a differential diagnosis for autism spectrum disorders (ASDs), specific language impairment, and mental retardation. It is important that pediatricians recognize the signs and symptoms of ASDs, as many patients with language developmental delays are ultimately diagnosed with ASDs. Pediatricians play an important role in the early recognition of ASDs, because they are usually the first point of contact for children with ASDs. A revision of the diagnostic criteria of ASDs was proposed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) that was released in May 2013. The autism spectrum describes a range of conditions classified as neurodevelopmental disorders in the fifth edition of the DSM. The new diagnostic criteria encompasses previous elements from the diagnosis of autistic disorder, Asperger disorder, childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified. An additional change to the DSM includes synthesizing the section on social and communication deficits into one domain. In ASD patients, the appropriate behavioral therapies and rehabilitation treatments significantly affect the prognosis. Therefore, this makes early diagnosis and treatment very important. In conclusion, pediatricians need to be able to recognize the signs and symptoms of ASDs and be attentive to them in order to make an early diagnosis and provide treatment. PMID- 25729394 TI - The usefulness of soluble transferrin receptor in the diagnosis and treatment of iron deficiency anemia in children. AB - PURPOSE: Soluble transferrin receptor (sTfR) is a truncated extracellular form of the membrane transferrin receptor produced by proteolysis. Concentrations of serum sTfR are related to iron status and erythropoiesis in the body. We investigated whether serum sTfR levels can aid in diagnosis and treatment of iron deficiency anemia (IDA) in children. METHODS: Ninety-eight patients with IDA were enrolled and were classified according to age at diagnosis. Group 1 comprised 78 children, aged 6-59 months, and group 2 comprised 20 adolescents, aged 12-16 years. RESULTS: In group 1, patients' serum sTfR levels correlated negatively with mean corpuscular volume; hemoglobin (Hb), ferritin, and serum iron levels; and transferrin saturation and positively with total iron binding capacity (TIBC) and red cell distribution width. In group 2, patients' serum sTfR levels did not correlate with ferritin levels and TIBC, but had a significant relationship with other iron indices. Hb and serum sTfR levels had a significant inverse relationship in both groups; however, in group 1, there was no correlation between Hb and serum ferritin levels. In 30 patients of group 1, serum sTfR levels were significantly decreased with an increase in Hb levels after iron supplementation for 1 month. CONCLUSION: Serum sTfR levels significantly correlated with other diagnostic iron parameters of IDA and inversely correlated with an increase in Hb levels following iron supplementation. Therefore, serum sTfR levels can be a useful marker for the diagnosis and treatment of IDA in children. PMID- 25729395 TI - Molecular typing of uropathogenic Escherichia coli isolated from Korean children with urinary tract infection. AB - PURPOSE: We investigated the molecular types of uropathogenic Escherichia coli (UPEC) by using conventional phylogrouping, multilocus sequence typing (MLST), and fimH genotyping. METHODS: Samples of patients younger than 18 years of age were collected from the Chung-Ang University Hospital over 2 years. Conventional phylogenetic grouping for UPEC strains was performed by polymerase chain reaction (PCR). Bacterial strain sequence types (STs) were classified on the basis of the results of partial sequencing of seven housekeeping genes. In addition, we analyzed nucleotide variations in a 424-base pair fragment of fimH, a major virulence factor in UPEC. RESULTS: Sixty-four UPEC isolates were analyzed in this study. Phylogenetic grouping revealed that group B2 was the most common type (n=54, 84%). We identified 16 distinctive STs using MLST. The most common STs were ST95 (35.9%), ST73 (15.6%), ST131 (12.5%), ST69 (7.8%), and ST14 (6.3%). Fourteen fimH allele types were identified, of which 11 had been previously reported, and the remaining three were identified in this study. f1 (n=28, 45.2%) was found to be the most common allele type, followed by f6 and f9 (n=7, 11.3% each). Comparative analysis of the results from the three different molecular typing techniques revealed that both MLST and fimH typing generated more discriminatory UPEC types than did PCR-based phylogrouping. CONCLUSION: We characterized UPEC molecular types isolated from Korean children by MLST and fimH genotyping. fimH genotyping might serve as a useful molecular test for large epidemiologic studies of UPEC isolates. PMID- 25729396 TI - Diencephalic syndrome: a frequently neglected cause of failure to thrive in infants. AB - PURPOSE: Diencephalic syndrome is an uncommon cause of failure to thrive in early childhood that is associated with central nervous system neoplasms in the hypothalamic-optic chiasmatic region. It is characterized by complex signs and symptoms related to hypothalamic dysfunction; such nonspecific clinical features may delay diagnosis of the brain tumor. In this study, we analyzed a series of cases in order to define characteristic features of diencephalic syndrome. METHODS: We performed a retrospective study of 8 patients with diencephalic syndrome (age, 5-38 months). All cases had presented to Seoul National University Children's Hospital between 1995 and 2013, with the chief complaint of poor weight gain. RESULTS: Diencephalic syndrome with central nervous system (CNS) neoplasm was identified in 8 patients. The mean age at which symptoms were noted was 18+/-10.5 months, and diagnosis after symptom onset was made at the mean age of 11+/-9.7 months. The mean z score was -3.15+/-1.14 for weight, -0.12+/-1.05 for height, 1.01+/-1.58 for head circumference, and -1.76+/-1.97 for weight-for height. Clinical features included failure to thrive (n=8), hydrocephalus (n=5), recurrent vomiting (n=5), strabismus (n=2), developmental delay (n=2), hyperactivity (n=1), nystagmus (n=1), and diarrhea (n=1). On follow-up evaluation, 3 patients showed improvement and remained in stable remission, 2 patients were still receiving chemotherapy, and 3 patients were discharged for palliative care. CONCLUSION: Diencephalic syndrome is a rare cause of failure to thrive, and diagnosis is frequently delayed. Thus, it is important to consider the possibility of a CNS neoplasm as a cause of failure to thrive and to ensure early diagnosis. PMID- 25729397 TI - Neonatal invasive Streptococcus gallolyticus subsp. pasteurianus infection with delayed central nervous system complications. AB - Group D streptococci are known to cause newborn septicemia and meningitis, but the Streptococcus bovis group strains rarely cause serious neonatal infections in Korea. Central nervous system (CNS) complications of neonatal S. bovis group infection have rarely been reported. In adults, S. bovis group strains cause bacteremia and endocarditis, and are associated with gastrointestinal malignancy. However, only a few studies have reported meningitis and septicemia in infants. Here, we describe a case of bacteremia and meningitis due to Streptococcus gallolyticus subsp. pasteurianus with a delayed CNS complication in an infant. A 28-day-old male infant was admitted to the hospital with a 1-day history of fever. Cultures of blood, cerebrospinal fluid, and urine showed the presence of S. bovis group strain-S. gallolyticus subsp. pasteurianus. He was discharged after 21 days of intravenous ampicillin and cefotaxime administration. Two weeks later, he was readmitted with a fever and short episodes of tonic-clonic movements. Brain magnetic resonance imaging showed marked bilateral frontal subdural effusion. He was discharged after 31 days of antibiotic therapy, and no neurological sequelae were observed at the 9-month follow-up. In conclusion, we present a rare case of neonatal S. gallolyticus subsp. pasteurianus infection causing urinary tract infection, septicemia, meningitis, and delayed CNS complications. This case emphasizes the need for physicians to be aware of S. bovis infection in infants. PMID- 25729398 TI - A rare type of single coronary artery with right coronary artery originating from the left circumflex artery in a child. AB - The presence of a single coronary artery is a rare congenital anomaly; such patients often present with severe myocardial ischemia. We experienced the case of a 13-year-old girl with the right coronary artery originating from the left circumflex artery. She visited our Emergency Department owing to severe chest pain; her cardiac enzyme levels were elevated, but her initial electrocardiogram (ECG) was normal. Echocardiography showed normal anatomy and normal regional wall motion. When she presented with recurrent chest pain on admission, the ECG showed significant ST-segment elevation in the left precordial leads and inferior leads with ST-segment depression in aVR lead, suggesting myocardial ischemia, and her cardiac enzyme levels were also elevated. We performed coronary angiography that showed a single right coronary artery originating from the left circumflex artery without stenosis. We confirmed the presence of a single coronary artery using coronary computed tomography. In addition, the treadmill test that was performed showed normal results. She was discharged from the hospital without any medications but with a recommendation of a regular follow-up. PMID- 25729399 TI - The immunosenescence-related gene Zizimin2 is associated with early bone marrow B cell development and marginal zone B cell formation. AB - We originally cloned and identified murine Zizimin2 (Ziz2, Dock11) as a guanine nucleotide exchange factor (GEF) for Cdc42 and demonstrated that it activated the formation of filopodia. Since its expression pattern is restricted in immune tissues and Rho GTPases such as Cdc42 function in B cell development and immune responses, we expected Ziz2 to also be associated with B cell development and immune responses. However, the function of Ziz2 has not yet been fully examined in vivo. We also recently discovered that Ziz2 expression levels in immune tissues were reduced with aging in the mouse, suggesting that its expression is also associated with the mechanisms of immuno-senescence. To gain insights into the mechanisms underlying immuno-senescence, we generated Ziz2 knock out (KO) mice and examined the functions of Ziz2 in B cell development and immune responses. We also obtained Zizimin3 (Ziz3; Dock10) KO mice and examined the functions of Ziz3. The results revealed that Ziz2 KO mice had a higher percentage of early bone marrow B cells (Fraction A), but a reduced fraction of marginal zone (MZ) B cells. In addition, an examination of B cell-specific Ziz2 KO mice revealed that Ziz2 was intrinsically required for MZ B cell development, but not for mature follicular B cells. However, immune responses against NP-CGG (T cell dependent), TNP-LPS (T cell-independent, TI, type I), and TNP-Ficoll (TI, type II) were not altered in KO mice. We finally demonstrated that CD1d-positive MZ B cell region outside CD169-positive marginal metallophilic macrophages (MMM) was narrowed in Ziz2 KO mice. Furthermore, MMM morphology appeared to be altered in Ziz2 KO mice. In conclusion, we herein showed that Ziz2 was associated with early bone marrow B cell development, MZ B cell formation, MZ B number/localization around MZ, and MMM morphology which may explain in part the mechanism underlying immuno-senescence. PMID- 25729400 TI - Fractional excitations in the square lattice quantum antiferromagnet. AB - Quantum magnets have occupied the fertile ground between many-body theory and low temperature experiments on real materials since the early days of quantum mechanics. However, our understanding of even deceptively simple systems of interacting spins-1/2 is far from complete. The quantum square-lattice Heisenberg antiferromagnet (QSLHAF), for example, exhibits a striking anomaly of hitherto unknown origin in its magnetic excitation spectrum. This quantum effect manifests itself for excitations propagating with the specific wave vector (pi, 0). We use polarized neutron spectroscopy to fully characterize the magnetic fluctuations in the metal-organic compound CFTD, a known realization of the QSLHAF model. Our experiments reveal an isotropic excitation continuum at the anomaly, which we analyse theoretically using Gutzwiller-projected trial wavefunctions. The excitation continuum is accounted for by the existence of spatially-extended pairs of fractional S=1/2 quasiparticles, 2D analogues of 1D spinons. Away from the anomalous wave vector, these fractional excitations are bound and form conventional magnons. Our results establish the existence of fractional quasiparticles in the high-energy spectrum of a quasi-two-dimensional antiferromagnet, even in the absence of frustration. PMID- 25729401 TI - Strong magneto-chiral dichroism in a paramagnetic molecular helix observed by hard X-ray. AB - Magneto-chiral dichroism (MchiD) is a non-reciprocal, i. e. directional, effect observed in magnetised chiral systems featuring an unbalanced absorption of unpolarised light depending on the direction of the magnetisation. Despite the fundamental interest in a phenomenon breaking both parity and time reversal symmetries, MchiD is one of the least investigated aspects of light-matter interaction because of the weakness of the effect in most reported experiments. Here we have exploited the element selectivity of hard X-ray radiation to investigate the magneto-chiral properties of enentiopure crsytals of two isostructural molecular helicoidal chains comprising Cobalt(II) and Manganese (II) ions, respectively. A strong magneto-chiral dichroism, with Kuhn asymmetry of the order of a few percent, has been observed in the Cobalt chain system, while it is practically absent for the Manganese derivative. The spectral features of the XMchiD signal differ significantly from the natural and magnetic dichroic contributions and have been here rationalized using the simple multipolar expansion of matter-radiation interaction. PMID- 25729402 TI - A Study into the Evolutionary Divergence of the Core Promoter Elements of PRPF31 and TFPT. AB - Mutations in PRPF31 have been implicated in retinitis pigmentosa, a blinding disease caused by degeneration of rod photoreceptors. The disease mechanism in the majority of cases is haploinsufficiency. Crucially, attempts at generation of animal models of disease have proved unsuccessful, yielding animals with a visual phenotype that does not mirror human disease. This suggests that, in these animals, the transcriptional regulation of PRPF31 is different to humans and compared to other species. Study of the evolution of the PRPF31 core promoter has important implications for our understanding of human disease, as disease phenotype is modified by differentially expressed alleles in the population. PRPF31 lies in a head-to-head arrangement with TFPT, a gene involved in cellular apoptosis. The two genes were shown to share common regulatory elements in the human genome. In this study, the core promoters of PRPF31 and TFPT were characterised by dual-luciferase reporter assay using genomic DNA from the green monkey, domestic dog and house mouse. It was found that the core promoters were conserved between human and monkey. In dog, the TFPT core promoter was conserved, but different PRPF31 gene architecture meant the gene was controlled by a long range promoter lying some 2000bp from the transcription start site. There was very low level of conservation (<20%) of the PRPF31 5' region between mouse and human. It was shown that mouse populations did not show variable Prpf31 expression levels, revealing a potential explanation for the lack of phenotype observed in the Prpf31 knock-out mouse model. PMID- 25729404 TI - Simulation of charge transport in pixelated CdTe. AB - The Voxel Imaging PET (VIP) Pathfinder project intends to show the advantages of using pixelated semiconductor technology for nuclear medicine applications to achieve an improved image reconstruction without efficiency loss. It proposes designs for Positron Emission Tomography (PET), Positron Emission Mammography (PEM) and Compton gamma camera detectors with a large number of signal channels (of the order of 106). The design is based on the use of a pixelated CdTe Schottky detector to have optimal energy and spatial resolution. An individual read-out channel is dedicated for each detector voxel of size 1 * 1 * 2 mm3 using an application-specific integrated circuit (ASIC) which the VIP project has designed, developed and is currently evaluating experimentally. The behaviour of the signal charge carriers in CdTe should be well understood because it has an impact on the performance of the readout channels. For this purpose the Finite Element Method (FEM) Multiphysics COMSOL software package has been used to simulate the behaviour of signal charge carriers in CdTe and extract values for the expected charge sharing depending on the impact point and bias voltage. The results on charge sharing obtained with COMSOL are combined with GAMOS, a Geant based particle tracking Monte Carlo software package, to get a full evaluation of the amount of charge sharing in pixelated CdTe for different gamma impact points. PMID- 25729403 TI - Differential distribution of HP1 proteins after trichostatin a treatment influences chromosomal stability in HCT116 and WI-38 cells. AB - BACKGROUND: Heterochromatin protein 1 (HP1) is important in the establishment, propagation, and maintenance of constitutive heterochromatin, especially at the pericentromeric region. HP1 might participate in recruiting and directing Mis12 to the centromere during interphase, and HP1 disruption or abrogation might lead to the loss of Mis12 incorporation into the kinetochore. Therefore, the centromere structure and kinetochore relaxation that are promoted in the absence of Mis12 could further induce chromosome instability (CIN) by reducing the capacity of the kinetochore to anchor microtubules. The aim of this study was to determine whether alterations in the localization of HP1 proteins induced by trichostatin A (TSA) modify Mis12 and Centromere Protein A (CENP-A) recruitment to the centromere and whether changes in the expression of HP1 proteins and H3K9 methylation at centromeric chromatin increase CIN in HCT116 and WI-38 cells. METHODS: HCT116 and WI-38 cells were cultured and treated with TSA to evaluate CIN after 24 and 48 h of exposure. Immunofluorescence, Western blot, ChIP, and RT PCR assays were performed in both cell lines to evaluate the localization and abundance of HP1alpha/beta, Mis12, and CENP-A and to evaluate chromatin modifications during interphase and mitosis, as well as after 24 and 48 h of TSA treatment. RESULTS: Our results show that the TSA-induced reduction in heterochromatic histone marks on centromeric chromatin reduced HP1 at the centromere in the non-tumoral WI-38 cells and that this reduction was associated with cell cycle arrest and CIN. However, in HCT116 cells, HP1 proteins, together with MIS12 and CENP-A, relocated to centromeric chromatin in response to TSA treatment, even after H3K9me3 depletion in the centromeric nucleosomes. The enrichment of HP1 and the loss of H3K9me3 were associated with an increase in CIN, suggesting a response mechanism at centromeric and pericentromeric chromatin that augments the presence of HP1 proteins in those regions, possibly ensuring chromosome segregation despite serious CIN. Our results provide new insight into the epigenetic landscape of centromeric chromatin and the role of HP1 proteins in CIN. PMID- 25729405 TI - Measurement of mobility and lifetime of electrons and holes in a Schottky CdTe diode. AB - We report on the measurement of drift properties of electrons and holes in a CdTe diode grown by the travelling heating method (THM). Mobility and lifetime of both charge carriers has been measured independently at room temperature and fixed bias voltage using charge integration readout electronics. Both electrode sides of the detector have been exposed to a 241Am source in order to obtain events with full contributions of either electrons or holes. The drift time has been measured to obtain the mobility for each charge carrier. The Hecht equation has been employed to evaluate the lifetime. The measured values for MUtaue/h (mobility-lifetime product) are in agreement with earlier published data. PMID- 25729406 TI - SEAS (Scientific Exercises Approach to Scoliosis): a modern and effective evidence based approach to physiotherapic specific scoliosis exercises. AB - BACKGROUND: SEAS is the acronym for "Scientific Exercise Approach to Scoliosis", a name related to the continuous changes of the approach based on results published in the literature. REHABILITATION PROGRAM: SEAS is an individualized exercise program adapted to all situations of conservative treatment of scoliosis: stand-alone in low-medium degree curves during growth to reduce the risk of bracing; complimentary to bracing in medium-high degree curves during growth, with the aim to increase correction, prepare weaning, and avoid/reduce side-effects; for adults either progressing or fused, to help stabilising the curve and reduce disability. SEAS is based on a specific active self-correction technique performed without external aid, and incorporated in functional exercises. Evaluation tests guide the choice of the exercises most appropriate to the individual patient. Improvement of the stability of the spine in active self correction is the primary objective of SEAS. SEAS exercises train neuromotor function so to stimulate by reflex a self-corrected posture during the activities of daily life. SEAS can be performed as an outpatient (two/three times a week 45 for minutes) or as a home program to be performed 20 minutes daily. In the last case, expert physiotherapy sessions of 1.5 hours every three months are proposed. RESULTS: Different papers, including a randomized controlled trial (2014), published over the past several years, documented the efficacy of the SEAS approach applied in the various phases of scoliosis treatment in reducing Cobb angle progression and the need to wear a brace. CONCLUSIONS: SEAS is an approach to scoliosis exercise treatment with a strong modern neurophysiological basis, to reduce requirements for patients and possibly the costs for families linked to the frequency and intensity of treatment and evaluations. Therefore, SEAS allows treating a large number of patients coming from far away. Even if SEAS appears simple by requiring less physiotherapist supervision and by using fewer home exercises prescribed at a lower dose than some of the other scoliosis-specific exercise approaches, real expertise in scoliosis, exercises, and patient and family management is required. The program has no copyrights, and teachers are being trained all over the world. PMID- 25729408 TI - Delayed Optochiasmal Arachnoiditis following Intervention for a Subarachnoid Haemorrhage. AB - Visual morbidity following a subarachnoid haemorrhage is common among survivors and it is usually the result of vascular ischaemia at the time of the initial insult. In this report, we present an unusual case of delayed, progressive visual loss following intervention for a ruptured anterior communicating artery aneurysm. We discuss the possible etiological factors and highlight potential diagnostic pitfalls. PMID- 25729407 TI - Does bracing affect bone health in women with adolescent idiopathic scoliosis? AB - PURPOSE: Adolescent idiopathic scoliosis (AIS) is often associated with low bone mineral content and density (BMC, BMD). Bracing, used to manage spine curvature, may interfere with the growth-related BMC accrual, resulting in reduced bone strength into adulthood. The purpose of this study was to assess the effects of brace treatment on BMC in adult women, diagnosed with AIS and braced in early adolescence. METHODS: Participants included women with AIS who: (i) underwent brace treatment (AIS-B, n = 15, 25.6 +/- 5.8 yrs), (ii) underwent no treatment (AIS, n = 15, 24.0 +/- 4.0 yrs), and (iii) a healthy comparison group (CON, n = 19, 23.5 +/- 3.8 yrs). BMC and body composition were assessed using dual-energy X ray absorptiometry. Differences between groups were examined using a oneway ANOVA or ANCOVA, as appropriate. RESULTS: AIS-B underwent brace treatment 27.9 +/- 21.6 months, for 18.0 +/- 5.4 h/d. Femoral neck BMC was lower (p = 0.06) in AIS-B (4.54 +/- 0.10 g) compared with AIS (4.89 +/- 0.61 g) and CON (5.07 +/- 0.58 g). Controlling for lean body mass, calcium and vitamin D daily intake, and strenuous physical activity, femoral neck BMC was statistically different (p = 0.02) between groups. A similar pattern was observed at other lower extremity sites (p < 0.05), but not in the spine or upper extremities. BMC and BMD did not correlate with duration of brace treatment, duration of daily brace wear, or overall physical activity. CONCLUSION: Young women with AIS, especially those who were treated with a brace, have significantly lower BMC in their lower limbs compared to women without AIS. However, the lack of a relationship between brace treatment duration during adolescence and BMC during young adulthood, suggests that the brace treatment is not the likely mechanism of the low BMC. PMID- 25729409 TI - Inequalities, the arts and public health: Towards an international conversation. AB - This paper considers how participatory arts informed by thinking in public health can play a significant part internationally in addressing inequalities in health. It looks beyond national overviews of arts and health to consider what would make for meaningful international practice, citing recent initiatives of national networks in English-speaking countries and examples of influential developments in South America and the European Union. In the context of public health thinking on inequalities and social justice, the paper posits what would make for good practice and appropriate research that impacts on policy. As the arts and health movement gathers momentum, the paper urges the arts to describe their potency in the policy-making arena in the most compelling ways to articulate their social, economic and cultural values. In the process, it identifies the reflexive consideration of participatory practice - involving people routinely marginalised from decision-making processes - as a possible avenue into this work. PMID- 25729410 TI - Beyond the borders: The use of art participation for the promotion of health and well-being in Britain and Denmark. AB - BACKGROUND: This article compares British and Danish promotion of well-being through participation in art activity to empower the individual. It examines the influence of national, social and political contexts on art and health community projects by comparing practice and project outcomes. METHOD: Based on two case studies, the article draws on specific evidence in Britain and Denmark. The approach taken is one of the psychosocial inquiries allowing reflection on practice including participants' testimonies. RESULTS: The two cases showed comparable problems with restricted resources, funding and organisational limitations to service delivery. The British case study shows a bottom-up approach in contrast to the Danish case study where the approach is top-down. Although the benefits from participation in art activities in the two countries were influenced by a complex set of different interacting factors, outcomes were typically similarly positive: finding identity, feeling a sense of well-being and increased self-confidence. CONCLUSION: In terms of practice, policy and research and in the recognition of value of art participation, the comparison demonstrates how different stories, contexts and institutions engage in different ways to facilitate and enable service users as well as generating different challenges; recognising the benefits of developing best practice guidelines in art practice in health settings. PMID- 25729411 TI - Evidence of a transnational arts and health practice methodology? A contextual framing for comparative community-based participatory arts practice in the UK and Mexico. AB - BACKGROUND: This paper draws on new research exploring community-based, participatory arts practice in Northern England and Mexico City to discuss contextual influences on artists' practice, and whether a common practice model can be identified. The international comparison is used to interrogate whether such a practice model is transnational, displaying shared characteristics that transcend contextual differences. METHODS: The study used multi-site ethnography to investigate the participatory practice of more than 40 artists. Participant observation and extended individual and group dialogues provided data on practice in a diverse range of art forms and settings, analysed using open coding and grounded theory principles. RESULTS: Findings locate differences in practitioners' motivations, and perceptions of the work's function; however, key similarities emerge across both sites, in practitioners' workshop methodologies and crucially in their creative strategies for catalysing change. A model is presented distilling the key elements of a common practice methodology, found across the study and across art forms. CONCLUSIONS: The discussion notes where divergences echo nationalities of contributors, drawing inferences about the level of influence of national context in this work, and concludes with the implications of these findings for potential international collaboration, to face challenges within the community arts and health sector globally. PMID- 25729412 TI - Visible Voices: Expressive arts with isolated seniors using trained volunteers. AB - This practice-based paper describes an innovative program from Ontario, Canada that explored the potential for volunteer-facilitated expressive arts to contribute to the well-being of socially isolated rural seniors. Inspired by Arts on Prescription initiatives in the UK and coordinated by a Registered Expressive Arts Consultant/Educator, the program involved eight older volunteers and eight older participants engaged in a 10-week series of one-on-one intermodal art making activities in the participants' homes and institutional settings in 2009 2010. An evaluation of the program design and implementation is presented and the challenges and opportunities of expressive arts with isolated seniors using trained volunteers are discussed. PMID- 25729413 TI - Deep listening: towards an imaginative reframing of health and well-being practices in international development. AB - This paper challenges the "intervention-as-solution" approach to health and well being as commonly practised in the international development sector, and draws on the disciplinary intersections between Community Music Therapy and ethnomusicology in seeking a more negotiated and situationally apposite framework for health engagement. Drawing inspiration from music-based health applications in conflict or post-conflict environments in particular, and focusing on case studies from Lebanon and South Sudan respectively, the paper argues for a re imagined international development health and well-being framework based on the concept of deep listening. Defined by composer Pauline Oliveros as listening which "digs below the surface of what is heard ... unlocking layer after layer of imagination, meaning, and memory down to the cellular level of human experience" (Oliveros, 2005), the paper explores the methodological applications of such a dialogic, discursive approach with reference to a range of related listening stances - cultural, social and therapeutic. In so doing, it explores opportunities for multi-levelled and culturally inclusive health and well-being practices relevant to different localities in the world and aimed at the re integration of self, place and community. PMID- 25729414 TI - Phase I trials of antitumour agents: fundamental concepts. AB - Phase I trials are an important step in the development of new drugs. Because of the advancing knowledge of cancer's molecular biology, these trials offer an important platform for the development of new agents and also for patient treatment. Therefore, comprehension of their peculiar terminology and methodology are increasingly important. Our objectives were to review the fundamental concepts of phase I designs and to critically contextualise this type of study as a therapeutic option for patients with refractory cancer. PMID- 25729415 TI - How do medical journalists treat cancer-related issues? AB - Cancer patients can obtain information about their illness through a variety of media sources. Therefore, it is important to know how medical journalists treat cancer-related issues; to that end, we sent self-administered questionnaires to 364 journalists in 82 organisations who had reported on medical issues for the Japanese media, asking for their reasons for reporting on cancer-related issues and the difficulties they had faced. The most common reason for reporting on health-related issues was their personal interest in a particular issue (n = 36). They mainly covered conventional therapies (n = 33), healthcare policy (n = 30), new therapies (n = 25), and diagnosis (n = 25). All of the journalists that were surveyed experienced some difficulties in reporting health issues. Significant concerns included the quality of information (n = 36), social impact (n = 35), lack of technical knowledge (n = 35), and difficulty in understanding technical terms (n = 35). Journalists commonly used personal networks, including physicians, as information sources (n = 42), as well as social media (e.g., e mail, Twitter and Facebook) (n = 32). Topic selection was biased, with 35 of 48 journalists having never reported on topics concerning hospices. Physicians were the most trusted source of information about cancer, and journalists attached high importance to interviewing them. As medical knowledge is advancing rapidly, journalists may have increasing difficulty covering cancer-related issues. PMID- 25729417 TI - Ovarian stimulation in patients with breast cancer. AB - Breast cancer is the most prevalent malignancy among women under 50. Improvements in diagnosis and treatment have yielded an important decrease in mortality in the last 20 years. In many cases, chemotherapy and radiotherapy develop side effects on the reproductive function. Therefore, before the anti-cancer treatment impairs fertility, clinicians should offer some techniques for fertility preservation for women planning motherhood in the future. In order to obtain more available oocytes for IVF, the ovary must be stimulated. New protocols which prevent exposure to increased estrogen during gonadotropin stimulation, measurements to avoid the delay in starting anti-cancer treatment or the outcome of ovarian stimulation have been addressed in this review. There is no evidence of association between ovarian stimulation and breast cancer. It seems that there are more relevant other confluent factors than ovarian stimulation. Factors that can modify the risk of breast cancer include: parity, age at full-term birth, age of menarche, and family history. There is an association between breast cancer and exogenous estrogen. Therefore, specific protocols to stimulate patients with breast cancer include anti-estrogen agents such as letrozole. By using letrozole plus recombinant follicular stimulating hormone, patients develop a multifollicular growth with only a mild increase in estradiol serum levels. Controlled ovarian stimulation (COS) takes around 10 days, and we discuss new strategies to start COS as soon as possible. Protocols starting during the luteal phase or after inducing the menses currently prevent a delay in starting ovarian stimulation. Patients with breast cancer have a poorer response to COS compared with patients without cancer who are stimulated with conventional protocols of gonadotropins. Although many centres offer fertility preservation and many patients undergo ovarian stimulation, there are not enough studies to evaluate the recurrence, breast cancer-free interval or mortality rates in these women. PMID- 25729418 TI - Hysteroscopic surgery for conservative management in endometrial cancer: a review of the literature. AB - Endometrial cancer is the most common gynaecologic malignancy, usually diagnosed in postmenopausal women. However, an incidence rate of 2-14% of cases consisting of women under the age of 45 years old has been reported. Multiple reports have described the conservative treatment of this tumour in selected patients with the objective of preserving fertility. In this article, we review the literature to evaluate the results of conservative treatment of endometrial cancer with hysteroscopic resection. PMID- 25729416 TI - Fertility preservation and breast cancer: a review. AB - Breast cancer is the most common malignancy in women, and its incidence increases with age, with the majority of patients diagnosed after menopause. However, in 15 25% of cases, patients are premenopausal at the time of diagnosis, and about 7% of them are below the age of 40. Therefore, a considerable amount of young women are diagnosed with breast cancer during their reproductive life. Within this group, most cancer cases require cytotoxic chemotherapy and/or hormone therapy, which are responsible for a decrease in the patients' reproductive function, along with their age. The efficacy of such treatments, among other factors, has led to a high five-year-survival rate, which results in an increasing number of young women who survive breast cancer before having fulfilled their reproductive wishes, especially considering the current trend to delay pregnancy until the late 30s or early 40s in developed countries. The combination of these factors justifies the importance of fertility preservation and reproductive counselling at the time of breast cancer diagnosis in young women. A wide range of fertility preservation techniques has been developed, such as ovarian suppression, oocyte and embryo cryopreservation, immature oocyte retrieval and in vitro maturation, and ovarian tissue cryopreservation. Early counselling and referral of these patients to fertility specialists are fundamental factors in order to maximise their chances of pregnancy. This review aims to update the knowledge about the influence of breast cancer in fertility, the influence of pregnancy and fertility preservation techniques in breast cancer patients and assessment of ovarian reserve for a better treatment choice. A special section dedicated to BRCA mutation carriers has been included because of their specific features. A comprehensive literature search has been conducted, including publications from the last five years. PMID- 25729419 TI - The role of trachelectomy in cervical cancer. AB - Cervical cancer is one of the most common cancers in women worldwide. Because it often affects women of childbearing age (19-45 years), fertility-sparing surgery is an important issue. The article reviews current viable fertility-sparing options with a special focus on trachelectomy, including vaginal radical trachelectomy, abdominal radical trachelectomy and simple trachelectomy. Neoadjuvant chemotherapy is also discussed. Finally, the decision to proceed with fertility-sparing treatment should be a patient-driven process. PMID- 25729421 TI - Report from the 37th san antonio breast cancer symposium, 9-13th december 2014, Texas, USA. AB - The 37th San Antonio Breast Cancer Symposium (SABCS) was held at the Henry B. Gonzalez Conference Centre in San Antonio, Texas, USA between the 9 and 13th of December 2014. It brought together an interaction between basic scientists and clinicians involved in the management of breast cancer. The symposium included six general sessions, poster discussion, and poster sessions. The most important highlights in the fields of advancing endocrine therapy; hormone receptor positive advanced breast cancer and hormonal resistant therapy; targeted therapies; genetics and genomics; supportive (adjunct) care; chemotherapy treatments; breast screening and risk stratification; male breast cancer and future potential directions were included here. PMID- 25729422 TI - Report on the 2014 UKONS Annual Conference Belfast, 14-15 November 2014: focus on living with and beyond cancer, patient information and support, and innovations in treatment and care. AB - The UK Oncology Nursing Society's (UKONS) annual conference focused on three major themes. These were 'Living With and Beyond Cancer', 'Patient Information and Support', and 'Innovations in Treatment and Care'. It featured a wide range of presentations, industry satellites, exhibitions, poster discussions. and workshops. Presenters ranged from those eminent in their particular field to those gracing the speaker's podium for the first time. The rich variety of presentations covered policy, cancer trends, clinical developments, care initiatives, personal development, and advances in practice. There was a strong emphasis on skills, knowledge, values, and attitudes, with the most junior and novice nurses mixing with experienced and highly esteemed practitioners. PMID- 25729420 TI - Fertility sparing treatment in borderline ovarian tumours. AB - Borderline ovarian tumours are low malignant potential tumours. They represent 10 15% of all epithelial ovarian malignancies. Patients with this type of tumour are younger at the time of diagnosis than patients with invasive ovarian cancer. Most of them are diagnosed in the early stages and have an excellent prognosis. It has been quite clearly established that the majority of borderline ovarian tumours should be managed with surgery alone. Because a high proportion of women with this malignancy are young and the prognosis is excellent, the preservation of fertility is an important issue in the management of these tumours. In this systemic review of the literature, we have evaluated in-depth oncological safety and reproductive outcomes in women with borderline ovarian tumours treated with fertility-sparing surgery, reviewing the indications, benefits, and disadvantages of each type of conservative surgery, as well as new alternative options to surgery to preserve fertility. PMID- 25729423 TI - The epidemiology of cancer in Angola-results from the cancer registry of the national oncology centre of Luanda, Angola. AB - Knowledge of the epidemiological profile of cancer is a key step in planning national cancer policy. The main objective of this study was to characterize the epidemiological profile of cancer in Angola based on cases of cancer registered at the National Oncology Centre (NOC) of Luanda, the only Angolan hospital to specialize in cancer treatment and diagnosis. The study consisted of a cross sectional historical review of cases treated at the NOC between 2007 and 2011. The following variables were analysed: tumour location, diagnostic basis, and source of referral, as well as patient age, sex, place of residence, and the stage of the disease. The NOC registered a total of 4,791 patients throughout the study period, at an annual average of 958 cases. The most commonly diagnosed cancers were breast (20.5%), cervical (16.5%), and head and neck cancer (10.6%), followed by lymphoma (7.2%), Kaposi sarcoma (6.1%), and prostate cancer (4%). A total of 76% of patients were under 60 years old, and 10% were less than 15 years old. Of the total number of patients with cancer treated at the NOC, 77.3% lived in the Luanda province. Staging data were only available for patients with breast or cervical cancer, and an analysis of this variable showed that most of these individuals were in advanced stages of the disease. In the absence of a population-based cancer registry, this study constitutes a reasonable assessment of the epidemiological profile of cancer in Angola. PMID- 25729424 TI - Report from the second MIB (Melanoma Independent Board) Conference, 27-28 October 2014. AB - The second Melanoma Independent Board (MIB) meeting was held in Rome, Italy from 27-28 October 2014. The themes of this meeting were once again innovation and sustainability and it brought together health providers, researchers, government representatives, journalists, patients, and pharmaceutical representatives. PMID- 25729425 TI - Meeting report from the second EurocanPlatform summer school on translational cancer research, Portugal, 20-24 October 2014. AB - The second EurocanPlatform summer school was held in Algarve, Portugal and attracted scientists, clinicians and pathologists with a common interest in cancer research to discuss the latest developments and challenges in the field. The meeting focused on translational cancer research and also included lectures, workshops and discussions, which covered all aspects of the translational research continuum, from early detection through treatment to survivorship. The rate of new cancer cases and cancer mortality increases every year. Although the last decade witnessed enormous progress in understanding cancer biology and the development of new therapies, the efficacy of these therapies is challenged by cancer resistance. It clearly suggests that new druggable targets are required and their translation from laboratory to bedside must be faster and more efficient to improve survival rates and standards of care. PMID- 25729427 TI - Report on the 56th ASH Annual Meeting, San Francisco, 4-9 December 2014. AB - The 56th annual ASH (American Society of Haematology) meeting was held in San Francisco (CA). More than 3,000 abstracts were selected for presentation due to the huge amount of information from basic science to clinical experience. The future direction in haematoncology is targeted therapies for most diseases; for instance, anti-PD-1 and CAR-T cells in lymphoproliferative disorders and novel immunomodulatory agents active in the contest of bone marrow milieu in multiple myeloma. On the other hand, in aggressive haematological diseases (AML, ALL), clinical studies demonstrated the feasibility of a more intensive chemotherapy approach in older patients. PMID- 25729428 TI - Greater patient access to immuno-oncology therapies-what can policymakers do? PMID- 25729426 TI - Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent. AB - Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients. PMID- 25729429 TI - Trichoderma reesei meiosis generates segmentally aneuploid progeny with higher xylanase-producing capability. AB - BACKGROUND: Hypocrea jecorina is the sexual form of the industrial workhorse fungus Trichoderma reesei that secretes cellulases and hemicellulases to degrade lignocellulosic biomass into simple sugars, such as glucose and xylose. H. jecorina CBS999.97 is the only T. reesei wild isolate strain that is sexually competent in laboratory conditions. It undergoes a heterothallic reproductive cycle and generates CBS999.97(1-1) and CBS999.97(1-2) haploids with MAT1-1 and MAT1-2 mating-type loci, respectively. T. reesei QM6a and its derivatives (RUT C30 and QM9414) all have a MAT1-2 mating type locus, but they are female sterile. Sexual crossing of CBS999.97(1-1) with either CBS999.97(1-2) or QM6a produces fruiting bodies containing asci with 16 linearly arranged ascospores (the sexual spores specific to ascomycetes). This sexual crossing approach has created new opportunities for these biotechnologically important fungi. RESULTS: Through genetic and genomic analyses, we show that the 16 ascospores are generated via meiosis followed by two rounds of postmeiotic mitosis. We also found that the haploid genomes of CBS999.97(1-2) and QM6a are similar to that of the ancestral T. reesei strain, whereas the CBS999.97(1-1) haploid genome contains a reciprocal arrangement between two scaffolds of the CBS999.97(1-2) genome. Due to sequence heterozygosity, most 16-spore asci (>90%) contain four or eight inviable ascospores and an equal number of segmentally aneuploid (SAN) ascospores. The viable SAN progeny produced higher levels of xylanases and white conidia due to segmental duplication and deletion, respectively. Moreover, they readily lost the duplicated segment approximately two weeks after germination. With better lignocellulosic biomass degradation capability, these SAN progeny gain adaptive advantages to the natural environment, especially in the early phase of colonization. CONCLUSIONS: Our results have not only further elucidated T. reesei evolution and sexual development, but also provided new perspectives for improving T. reesei industrial strains. PMID- 25729430 TI - Cancer based pharmacogenomics network supported with scientific evidences: from the view of drug repurposing. AB - BACKGROUND: Pharmacogenomics (PGx) as an emerging field, is poised to change the way we practice medicine and deliver health care by customizing drug therapies on the basis of each patient's genetic makeup. A large volume of PGx data including information among drugs, genes, and single nucleotide polymorphisms (SNPs) has been accumulated. Normalized and integrated PGx information could facilitate revelation of hidden relationships among drug treatments, genomic variations, and phenotype traits to better support drug discovery and next generation of treatment. METHODS: In this study, we generated a normalized and scientific evidence supported cancer based PGx network (CPN) by integrating cancer related PGx information from multiple well-known PGx resources including the Pharmacogenomics Knowledge Base (PharmGKB), the FDA PGx Biomarkers in Drug Labeling, and the Catalog of Published Genome-Wide Association Studies (GWAS). We successfully demonstrated the capability of the CPN for drug repurposing by conducting two case studies. CONCLUSIONS: The CPN established in this study offers comprehensive cancer based PGx information to support cancer orientated research, especially for drug repurposing. PMID- 25729431 TI - Triple modality testing by endoscopic retrograde cholangiopancreatography for the diagnosis of cholangiocarcinoma. AB - OBJECTIVES: Brush cytology has a low sensitivity for the diagnosis of cholangiocarcinoma. This study aimed to compare the standard approach (brush cytology) with a triple modality approach utilizing brush cytology, forceps biopsy and fluorescence in situ hybridization in terms of sensitivity and specificity for the diagnosis of cholangiocarcinoma. METHODS: In a retrospective study at a single academic center, 50 patients underwent triple modality testing. Additionally, 61 patients underwent brush cytology alone. Intervention was endoscopic retrograde cholangiopancreatography with brush cytology, fluorescence in situ hybridization, and forceps biopsy. The main outcome measures included sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: Overall, 50 patients underwent triple tissue sampling, and 61 patients underwent brush cytology alone. Twenty-two patients were eventually diagnosed with cholangiocarcinoma. Brush cytology had a sensitivity of 42%, specificity of 100%, positive predictive value of 100% and negative predictive value of 88%. Triple tissue sampling had an overall sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 87%. Within the triple test group, brush cytology had a sensitivity of 27%, forceps biopsy had a sensitivity of 50%, and fluorescence in situ hybridization analysis had a sensitivity of 59%. CONCLUSIONS: A triple modality approach results in a marked increase in sensitivity for the diagnosis of cholangiocarcinoma compared with single modality testing such as brush cytology and should be considered in the evaluation of indeterminate or suspicious biliary strictures. PMID- 25729432 TI - Current, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases. AB - Biological agents for inflammatory bowel diseases (IBD) targeting tumor necrosis factor (TNF) have changed the way to treat IBD refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission. A better understanding of the components of the pathological processes that are a hallmark of IBD has led to the development of a new family of biological agents in Crohn's disease and ulcerative colitis. Biosimilars, which are copy versions of currently licensed biological agents, will be soon available. The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions, while a new anti-TNF agent, namely golimumab, has been recently approved for refractory ulcerative colitis. Beyond TNF blockers, anti-adhesion molecules appear to be a potent drug class for IBD. Vedolizumab was recently approved for both Crohn's disease and ulcerative colitis. Numerous other compounds are in the pipeline. Ustekinumab looks very promising for Crohn's disease. Smad7 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials. Herein, we review the efficacy and safety of new and emerging biological agents that are currently investigated in IBD clinical trials. PMID- 25729433 TI - Treatment and management of ascites and hepatorenal syndrome: an update. AB - Ascites and renal dysfunction are frequent complications experienced by patients with cirrhosis of the liver. Ascites is the pathologic accumulation of fluid in the peritoneal cavity, and is one of the cardinal signs of portal hypertension. The diagnostic evaluation of ascites involves assessment of its granulocyte count and protein concentration to exclude complications such as infection or malignoma and to allow risk stratification for the development of spontaneous peritonitis. Although sodium restriction and diuretics remain the cornerstone of the management of ascites, many patients require additional therapy when they become refractory to this treatment. In this situation, the treatment of choice is repeated large-volume paracentesis. Alteration in splanchnic hemodynamics is one of the most important changes underlying the development of ascites. Further splanchnic dilation leads to changes in systemic hemodynamics, activating vasopressor agents and leading to decreased renal perfusion. Small alterations in renal function influence the prognosis, which depends on the cause of renal failure. Prerenal failure is evident in about 70% of patients, whereas in about 30% of patients the cause is hepatorenal syndrome (HRS), which is associated with a worse prognosis. Therefore, effective therapy is of great clinical importance. Recent data indicate that use of the new definition of acute kidney injury facilitates the identification and treatment of patients with renal insufficiency more rapidly than use of the current criteria for HRS. In this review article, we evaluate approaches to the management of patients with ascites and HRS. PMID- 25729434 TI - Hypersensitivity reaction to omeprazole in a patient treated for Helicobacter pylori. PMID- 25729436 TI - An evaluation of seasonal variations in footwear worn by adults with inflammatory arthritis: a cross-sectional observational study using a web-based survey. AB - BACKGROUND: Foot problems are common in adults with inflammatory arthritis and therapeutic footwear can be effective in managing arthritic foot problems. Accessing appropriate footwear has been identified as a major barrier, resulting in poor adherence to treatment plans involving footwear. Indeed, previous New Zealand based studies found that many people with rheumatoid arthritis and gout wore inappropriate footwear. However, these studies were conducted in a single teaching hospital during the New Zealand summer therefore the findings may not be representative of footwear styles worn elsewhere in New Zealand, or reflect the potential influence of seasonal climate changes. The aim of the study was to evaluate seasonal variations in footwear habits of people with inflammatory arthritic conditions in New Zealand. METHODS: A cross-sectional study design using a web-based survey. The survey questions were designed to elicit demographic and clinical information, features of importance when choosing footwear and seasonal footwear habits, including questions related to the provision of therapeutic footwear/orthoses and footwear experiences. RESULTS: One hundred and ninety-seven participants responded who were predominantly women of European descent, aged between 46-65 years old, from the North Island of New Zealand. The majority of participants identified with having either rheumatoid arthritis (35%) and/or osteoarthritis (57%) and 68% reported established disease (>5 years duration). 18% of participants had been issued with therapeutic footwear. Walking and athletic shoes were the most frequently reported footwear type worn regardless of the time of year. In the summer, 42% reported wearing sandals most often. Comfort, fit and support were reported most frequently as the footwear features of greatest importance. Many participants reported difficulties with footwear (63%), getting hot feet in the summer (63%) and the need for a sandal which could accommodate a supportive insole (73%). CONCLUSIONS: Athletic and walking shoes were the most popular style of footwear reported regardless of seasonal variation. During the summer season people with inflammatory arthritis may wear sandals more frequently in order to accommodate disease-related foot deformity. Healthcare professionals and researchers should consider seasonal variation when recommending appropriate footwear, or conducting footwear studies in people with inflammatory arthritis, to reduce non-adherence to prescribed footwear. PMID- 25729435 TI - Ploidy-Seq: inferring mutational chronology by sequencing polyploid tumor subpopulations. AB - Human cancers are frequently polyploid, containing multiple aneuploid subpopulations that differ in total DNA content. In this study we exploit this property to reconstruct evolutionary histories, by assuming that mutational complexity increases with time. We developed an experimental method called Ploidy Seq that uses flow-sorting to isolate and enrich subpopulations with different ploidy prior to next-generation genome sequencing. We applied Ploidy-Seq to a patient with a triple-negative (ER-/PR-/HER2-) ductal carcinoma and performed whole-genome sequencing to trace the evolution of point mutations, indels, copy number aberrations, and structural variants in three clonal subpopulations during tumor growth. Our data show that few mutations (8% to 22%) were shared between all three subpopulations, and that the most aggressive clones comprised a minority of the tumor mass. We expect that Ploidy-Seq will have broad applications for delineating clonal diversity and investigating genome evolution in many human cancers. PMID- 25729437 TI - Intra-observer reliability for measuring first and second toe and metatarsal protrusion distance using palpation-based tests: a test-retest study. AB - BACKGROUND: Measurement of first and second metatarsal and toe protrusion is frequently used to explain foot problems using x-rays, osteological measurements or palpation-based tests. Length differences could be related to the appearance of problems in the foot. A test-retest design was conducted in order to establish the intra-rater reliability of three palpation-based tests. METHODS: 202 feet of physical therapy students and teachers of the CEU San Pablo University of Madrid, 39 men and 62 women, were measured using three different tests. Data were analysed using SPSS version 15.0. Mean, SD and 95% CI were calculated for each variable. A normal distribution of quantitative data was assessed using the Kolmogorov-Smirnov test. The test-retest intra-rater reliability was assessed using an Intraclass Correlation Coefficient (ICC). The Standard Error Mean (SEM) and the Minimal Detectable Change (MDC) were also obtained. RESULTS: All the ICC values showed a high degree of reliability (Test 1 = 0.97, Test 2 = 0.86 and Test 3 = 0.88) as did the SEM (Test 1 = 0.07, Test 2 = 0.10 and Test 3 = 0.11) and the MDC (Test 1 = 0.21, Test 2 = 0.30 and Test 3 = 0.31). CONCLUSIONS: Reliability of measuring first and second metatarsal and toe protrusion using the three palpation-based tests showed a high degree of reliability. PMID- 25729438 TI - Cocktails of probiotics pre-adapted to multiple stress factors are more robust under simulated gastrointestinal conditions than their parental counterparts and exhibit enhanced antagonistic capabilities against Escherichia coli and Staphylococcus aureus. AB - BACKGROUND: The success of the probiotics in delivery of health benefits depends on their ability to withstand the technological and gastrointestinal conditions; hence development of robust cultures is critical to the probiotic industry. Combinations of probiotic cultures have proven to be more effective than the use of single cultures for treatment and prevention of heterogeneous diseases. We investigated the effect of pre- adaptation of probiotics to multiple stresses on their stability under simulated gastrointestinal conditions and the effect of their singular as well as their synergistic antagonistic effect against selected enteric pathogens. METHODS: Probiotic cultures were inoculated into MRS broth adjusted to pH 2 and incubated for 2 h at 37 degrees C. Survivors of pH 2 were subcultured into 2% bile acid for 1 h at 37 degrees C. Cells that showed growth after exposure to 2% bile acid for 1 h were finally inoculated in fresh MRS broth and incubated at 55 degrees C for 2 h. The cells surviving were then used as stress adapted cultures. The adapted cultures were exposed to simulated gastrointestinal conditions and their non- adapted counterparts were used to compare the effects of stress adaptation. The combination cultures were tested for their antipathogenic effects on Escherichia coli and Staphylococcus aureus. RESULTS: Acid and bile tolerances of most of the stress-adapted cells were higher than of the non-adapted cells. Viable counts of all the stress-adapted lactobacilli and Bifidobacterium longum LMG 13197 were higher after sequential exposure to simulated gastric and intestinal fluids. However, for B. longum Bb46 and B. bifidum LMG 13197, viability of non-adapted cells was higher than for adapted cells after exposure to these fluids. A cocktail containing L. plantarum + B. longum Bb46 + B. longum LMG 13197 best inhibited S. aureus while E. coli was best inhibited by a combination containing L. acidophilus La14 150B + B. longum Bb46 + B. bifidum LMG 11041. A cocktail containing the six non- adapted cultures was the least effective in inhibiting the pathogens. CONCLUSION: Multi-stress pre adaptation enhances viability of probiotics under simulated gastrointestinal conditions; and formulations containing a mixture of multi stress-adapted cells exhibits enhanced synergistic effects against foodborne pathogens. PMID- 25729439 TI - Parity and diabetes risk among hispanic women from Colombia: cross-sectional evidence. AB - OBJECTIVE: The association between parity and type 2 diabetes has been studied in developed countries and in Singapore and Chinese women but not in Hispanics. Herein we evaluated the association between parity (number of live births) with diabetes in a group of Hispanic postmenopausal women from Colombia. RESEARCH DESIGN AND METHODS: Herein we evaluated the association between parity and diabetes in a population of 1,795 women from Colombia. Women were divided in birth categories (0 [referent], 1 or 2, 3-5, 6 or > births). Medical history of diabetes and anthropometric characteristics were recorded. Logistic regressions were performed in order to find the association between parity and diabetes in bivariable and multivariable models after controlling for age, body mass index (BMI), waist hip ratio (WHR) and diabetes family history, among other variables. RESULTS: In our study, there was an association between parity and diabetes after adjusting for age, BMI and diabetes family history in the multiparous women groups when compared to the women with no births (Referent group) [1-2 births vs. referent OR 5.2 (95 CI 1.2-22.9), 3-5 births vs. referent OR 5.5 (1.3-23.0) and >=6 births vs. referent OR 7.5 (1.8-31.8), respectively]. The association was maintained in two of the groups in the multivariable analysis [OR 5.0 (1.1-22.9) and 5.3 (1.2-23.5)], for 1 or 2 births and 6 or > births versus 0 births, respectively. Positive diabetes family history and WHR were also associated with an increased risk of diabetes [OR 4.6 (3.0-7.0) and 4.1 (2.0-8.1), respectively]. CONCLUSIONS: In postmenopausal Hispanic women, multiparity, as well as a positive family history of diabetes and a high waist-hip ratio were associated with higher diabetes risk. PMID- 25729440 TI - A large ozone-circulation feedback and its implications for global warming assessments. AB - State-of-the-art climate models now include more climate processes which are simulated at higher spatial resolution than ever1. Nevertheless, some processes, such as atmospheric chemical feedbacks, are still computationally expensive and are often ignored in climate simulations1,2. Here we present evidence that how stratospheric ozone is represented in climate models can have a first order impact on estimates of effective climate sensitivity. Using a comprehensive atmosphere-ocean chemistry-climate model, we find an increase in global mean surface warming of around 1 degrees C (~20%) after 75 years when ozone is prescribed at pre-industrial levels compared with when it is allowed to evolve self-consistently in response to an abrupt 4*CO2 forcing. The difference is primarily attributed to changes in longwave radiative feedbacks associated with circulation-driven decreases in tropical lower stratospheric ozone and related stratospheric water vapour and cirrus cloud changes. This has important implications for global model intercomparison studies1,2 in which participating models often use simplified treatments of atmospheric composition changes that are neither consistent with the specified greenhouse gas forcing scenario nor with the associated atmospheric circulation feedbacks3-5. PMID- 25729441 TI - mHealth is an Innovative Approach to Address Health Literacy and Improve Patient Physician Communication - An HIV Testing Exemplar. AB - Low health literacy is a barrier for many patients in the U.S. Patients with low health literacy have poor communication with their physicians, and thus face worse health outcomes. Several government agencies have highlighted strategies for improving and overcoming low health literacy. Mobile phone technology could be leveraged to implement these strategies to improve communication between patients and their physicians. Text messaging, in particular, is a simple and interactive platform that may be ideal for patients with low health literacy. We provide an exemplar for improving patient-physician communication and increasing HIV testing through a text message intervention. PMID- 25729442 TI - Burnei's technique of femoral neck variation and valgisation by using the intramedullary rod in Osteogenesis imperfecta. AB - BACKGROUND: Varus or valgus deviations of the femoral neck in osteogenesis imperfecta have been an ignored chapter because the classic correction procedures were applied in medical practice with unsatisfying results. Until the use of telescopic rods, coronal deviations remained unsolved and the distal configuration of the proximal femoral extremity remained uncorrected or partially corrected, which required an extensive use of the wheel chair or bed immobilization of the patient. The concomitant correction of the complex deformities, coxa vara/valga and femoral integrated configuration, have been a progress which allowed the patients to walk with or without support. PURPOSE: The purpose of this study is to present the Burnei's technique, a therapeutic alternative in deformity corrections of the varus or valgus hip in children with osteogenesis imperfecta. STUDY DESIGN: The paper is about a retrospective study done in a single center, which analyses Burnei technique and other procedures described in literature. PATIENT SAMPLE: The content of the article is based on a 12 years experience on a batch of 51 patients with osteogenesis imperfecta from which 10 patients (13 hips) presented frontal plane deviations of the femoral neck. OUTCOME MEASURES: All the patients with osteogenesis imperfecta who presented coxa vara or valga were submitted to investigations with the purpose of measuring blood loss, the possibility of extending the surgical intervention to the leg, the association of severe deformities of the proximal extremity of the femur and the necessity of postoperative intensive care. Burnei's technique: The operation was first performed in 2002. A subtrochanteric osteotomy was made in an oblique cut, from the internal side to the external side and from proximal to distal for coxa vara, or by using a cuneiform resection associated with muscular disinsertions. Only telescopic rods were used for osteosynthesis. DISCUSSIONS: There are a few articles in literature, which approach corrections of vara or valgus deviations in osteogenesis imperfecta. Some of them are the techniques described by Finidori, Wagner and Fassier. CONCLUSIONS: Burnei's technique is simple; it corrects the varus and valgus deviations concomitantly with Sofield Millar. Even though only a telescopic rod is used, no stress fractures were seen postoperatively, deviation recurrence or assembly loss. PMID- 25729443 TI - Electrocutions--treatment strategy (case presentation). AB - Electrical injuries are a form of trauma with extreme gravity and a unique pathophysiology: they affect the entire organism. A wide range of voltages may cause electrical accidents. Complications should be anticipated and prevented in order to minimize the complication risk and assure a vital, functional and esthetic prognosis as good as possible. The article presents a case treated in our clinic together with the unique particular clinical situation and algorithm that led to a favorable result. PMID- 25729444 TI - Errata. PMID- 25729445 TI - Western-Chinese Academic Collaboration in the Social Sciences. PMID- 25729446 TI - "Embedded Research" in Collaborative Fieldwork. AB - In the era of the "scientific development concept" of the Hu/Wen leadership, agents of knowledge transfer that eventually translates into policy comprise not only think tanks for policy formulation in central-state institutions but also researchers in universities supporting policy implementation at local levels. Well-established patterns of local scientific advisory frame collaborative fieldwork in Sino-Western scientific projects on local governance. However, there is a gap between our active integration into these patterns during fieldwork and our ability to clarify them as resources, reconstruct the selection of research topics and contextualize the research results within our academic discourses. Analysing site-finding, data collection, aggregation and dissemination of a research project with Chinese public health researchers on rural health service reform in Xinjiang between 2005 and 2010, I argue that fieldwork and the role performed as a scientific advisor for the political principal is the localized and daily interface where politics crosses into science. PMID- 25729447 TI - DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia. AB - BACKGROUND: We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL. RESULTS: We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5. CONCLUSIONS: Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients. PMID- 25729448 TI - Bridging the gap between research and practice: an assessment of external validity of community-based physical activity programs in Bogota, Colombia, and Recife, Brazil. AB - For more than a decade, physical activity classes have been offered in public places at no cost to the participants in some Latin American cities, however, internal and external validity evidence of these programs is limited. The goals of this study were to assess, report, and compare the external validity of the Recreovia program (RCP) in Colombia, and the Academia da Cidade program (ACP) in Brazil. Interviews to assess external validity of the RCP and ACP were conducted in 2012. The interview guide was developed based on the RE-AIM framework. Seventeen key informants were selected to participate in the study. Interviews were recorded and transcribed verbatim. Transcripts were analyzed using a constant comparative qualitative method and experts validated common themes. RCP and ACP key informants reported that both programs reach underserved population. There is no information available about effectiveness. Both programs take place in public spaces (e.g., parks and plazas), which are selected for adoption mainly based on community demand. RCP and ACP offer free physical activity classes with educational and cultural components, have a strong organizational structure for implementation, and differ on schedule and content of classes. Funding sources were reported to play an important role on long-term maintenance. Facilitators and barriers were identified. Programs are similar in the reach and adoption elements; the main differences were found on implementation and maintenance, whereas information on effectiveness was not found. Reporting external validity of these programs is useful to bridge the gap between research and practice. PMID- 25729449 TI - Scientific collaboration and team science: a social network analysis of the centers for population health and health disparities. AB - The past decade has seen dramatic shifts in the way that scientific research is conducted as networks, consortia, and large research centers are funded as transdisciplinary, team-based enterprises to tackle complex scientific questions. Key investigators (N = 167) involved in ten health disparities research centers completed a baseline social network and collaboration readiness survey. Collaborative ties existed primarily between investigators from the same center, with just 7 % of ties occurring across different centers. Grants and work groups were the most common types of ties between investigators, with shared presentations the most common tie across different centers. Transdisciplinary research orientation was associated with network position and reciprocity. Center directors/leaders were significantly more likely to form ties with investigators in other roles, such as statisticians and trainees. Understanding research collaboration networks can help to more effectively design and manage future team based research, as well as pinpoint potential issues and continuous evaluation of existing efforts. PMID- 25729450 TI - Systematic review of health branding: growth of a promising practice. AB - Brands are marketing tools that create mental representations in the minds of consumers about products, services, and organizations. Brands create schema that help consumers decide whether to initiate or continue use of a product or service. Health branding determines behavioral choice by building consumer relationships and identification with health behaviors and their benefits. Health branding can be measured by the associations individuals form with health behaviors. In 2008, Evans and colleagues systematically reviewed the literature on health brands, reported on branded health messages and campaigns worldwide, and examined specific branding strategies in multiple subject areas. This paper extends that review. We replicated the comprehensive online literature search strategy from 2008. We screened a total of 311 articles and included 130 for full text review. This included both articles from the 2008 review and new articles. After excluding those new articles that did not meet full-text inclusion criteria, we reviewed 69 in total. Of these, 32 were new articles since the 2008 review. Branded health campaigns cover most major domains of public health and appear worldwide. Since 2008, we observed improvement in evaluation, application of theory, and description of campaign strategies in published work. We recommend enhanced education of public health practitioners and researchers on the use and evaluation of branding. PMID- 25729451 TI - Virtual small groups for weight management: an innovative delivery mechanism for evidence-based lifestyle interventions among obese men. AB - While group interventions for weight management have been shown to be efficacious, adherence is often low, especially among men. This pilot study seeks to test whether group interventions using web-based group video conferencing (VC) technology is effective for weight loss. We adapted a 12-week curriculum based on the Diabetes Prevention Program, and delivered this intervention to a small group of men (BMI >=30 kg/m(2)), using web-based group VC. Participants were randomized to intervention (n = 32) or delayed-intervention control group (n = 32). The intervention group lost 3.5 % (95 % CI 2.1 %, 4.9 %) of their initial body weight. Difference in mean weight loss was 3.2 kg (p = 0.0002) and mean BMI decrease was 1.0 kg/m(2) (p = 0.0010) between the two groups. Virtual small groups may be an effective means of allowing face-to-face group interaction, while overcoming some barriers to access. PMID- 25729452 TI - Using online crowdsourcing to understand young adult attitudes toward expert authored messages aimed at reducing hazardous alcohol consumption and to collect peer-authored messages. AB - Text message delivered prevention interventions have the potential to improve health behaviors on a large scale, including reducing hazardous alcohol consumption in young adults. Online crowdsourcing can be used to efficiently develop relevant messages, but remains largely understudied. This study aims to use online crowdsourcing to evaluate young adult attitudes toward expert-authored messages and to collect peer-authored messages. We designed an online survey with four drinking scenarios and a demographic questionnaire. We made it available to people who reported age 18-25 years, residence in the US, and any lifetime alcohol consumption via the Amazon Mechanical Turk crowdsourcing platform. Participants rated 71 sample text messages on instrumental (helpful) and affective (interesting) attitude scales and generated their own messages. All messages were coded as informational, motivational, or strategy facilitating. We examined differences in attitudes by message type and by drinking status and sex. We surveyed 272 participants in 48 h, and 222 were included in analysis for a total participant payment cost of $178. Sample mean age was 23 years old, with 50 % being female, 65 % being of white race, and 78 % scored as hazardous drinkers. Informational messages were rated the most helpful, whereas motivational messages were rated the most interesting. Hazardous drinkers rated informational messages less helpful than non-hazardous drinkers. Men reported messages less helpful and interesting than women for most categories. Young adults authored 161 messages, with the highest proportion being motivational. Young adults had variable instrumental and affective attitudes toward expert-authored messages. They generated a substantial number of peer-authored messages that could enhance relevance of future alcohol prevention interventions. PMID- 25729453 TI - It takes a (virtual) village: crowdsourcing measurement consensus to advance survivorship care planning. AB - We report results from the use of an innovative tool (the Grid-Enabled Measures (GEM) database) to drive consensus on the use of measures evaluating the efficacy and implementation of survivorship care plans. The goal of this initiative was to increase the use of publicly available shared measures to enable comparability across studies. Between February and August 2012, research and practice communities populated the GEM platform with constructs and measures relevant to survivorship care planning, rated the measures, and provided qualitative feedback on the quality of the measures. Fifty-one constructs and 124 measures were entered into the GEM-Care Planning workspace by participants. The greatest number of measures appeared in the domains of Health and Psychosocial Outcomes, Health Behaviors, and Coordination of Care/Transitional Care. Using technology-mediated social participation, GEM presents a novel approach to how we measure and improve the quality of survivorship care. PMID- 25729454 TI - Reasons for non-response to a direct-mailed FIT kit program: lessons learned from a pragmatic colorectal-cancer screening study in a federally sponsored health center. AB - Colorectal cancer screening rates are below optimal. As part of a pilot clinic based pragmatic study aiming to raise rates of colorectal-cancer screening, we explored patients' reasons for not responding to a direct-mailed screening invitation. We conducted telephone interviews with patients who were mailed a fecal immunochemical test (FIT) but who did not return it to the lab. Interviews were audio-recorded, transcribed, and coded for thematic analysis. We met our goal of 20 interviews (10 in English and 10 Spanish; 75 % female). Reasons for not completing tests were fear of results or cost of follow-up colonoscopy (n = 9); not having received the test in the mail (n = 7); concerns about mailing fecal matter or that test results could be mixed up (n = 6); and being busy or forgetful (n = 4). Efforts to improve uptake of colorectal cancer screening in a direct-mailed program ought to address concerns identified in our study. PMID- 25729455 TI - Clinicians' panel management self-efficacy to support their patients' smoking cessation and hypertension control needs. AB - Panel management, a set of tools and processes for proactively caring for patient populations, has potential to reduce morbidity and improve outcomes between office visits. We examined primary care staff's self-efficacy in implementing panel management, its correlates, and an intervention's impact on this self efficacy. Primary care teams at two Veterans Health Administration (VA) hospitals were assigned to control or intervention conditions. Staff were surveyed at baseline and post-intervention, with a random subset interviewed post intervention. Panel management self-efficacy was higher among staff participating in the panel management intervention. Self-efficacy was significantly correlated with sufficient training, aspects of team member interaction, and frequency of panel management use. Panel management self-efficacy was modest among primary care staff at two VA hospitals. Team level interventions may improve primary care staff's confidence in practicing panel management, with this greater confidence related to greater team involvement with, and use of panel management. PMID- 25729456 TI - "Go Girls!": psychological and behavioral outcomes associated with a group-based healthy lifestyle program for adolescent girls. AB - The objective of this study was to assess changes in adolescent girls' health enhancing cognitions and behaviors targeted by the Go Girls! group-based mentorship lifestyle program. Three hundred and ten adolescent girls (nested within 40 Go Girls! groups) completed questionnaires that assessed cognitions (attitudes, self-regulatory efficacy, and intentions) and behaviors (physical activity and dietary) at four time points (two pre-program, one at the end of the program, and one at 7-week follow-up). Hierarchical linear modeling was used to examine changes in the outcome variables among Go Girls! participants (M age = 11.68 years, SD = 0.80). No significant changes occurred in the outcome variables during the baseline comparison period (Time 1-2). When compared to the average of the baseline assessments, 7 weeks after completing the program, girls reported significant improvements in physical activity (M Baseline PAtotal = 3.82, SD = 3.49; M T4 PAtotal = 4.38, SD = 3.75) and healthy eating (M Baseline = 10.71, SD = 1.13; M T4 = 11.35, SD = 1.05) behavior and related cognitions (d values >=0.65). Findings provide preliminary support for programs that foster belongingness and target health behaviors through mentorship models. PMID- 25729457 TI - Physician use of persuasion and colorectal cancer screening. AB - The impact of patient-physician communication on subsequent patient behavior has rarely been evaluated in the context of colorectal cancer (CRC) screening discussions. We describe physicians' use of persuasive techniques when recommending CRC screening and evaluate its association with patients' subsequent adherence to screening. Audio recordings of N = 414 periodic health examinations were joined with screening use data from electronic medical records and pre-/post visit patient surveys. The association between persuasion and screening was assessed using generalized estimating equations. According to observer ratings, primary care physicians frequently use persuasive techniques (63 %) when recommending CRC screening, most commonly argument or refutation. However, physician persuasion was not associated with subsequent screening adherence. Physician use of persuasion may be a common vehicle for information provision during CRC screening discussions; however, our results do not support the sole reliance on persuasive techniques if the goal is to improve adherence to recommended screening. PMID- 25729458 TI - The StrongWomen-Healthy Hearts program in Pennsylvania: RE-AIM analysis. AB - Dissemination of evidence-based programs is needed to reduce CVD risk among midlife and older women. The aim of this study is to examine the public health impact of StrongWomen-Healthy Hearts in Pennsylvania using the RE-AIM framework. Reach, adoption, implementation, and maintenance were assessed using qualitative and quantitative measures; effectiveness was assessed using a pretest-posttest within-participants design. Reach into the target population was 5 in 100,000. Compared to the target population, a greater percentage of participants were white, married, middle-class, and had a graduate degree. Effectiveness was demonstrated (weight loss -2.0 kg, p < 0.001). Adoption among trained leaders was high (83.3 %), as was fidelity in implementation (average score 9.3 of 10). No leaders maintained the program. To increase impact of the StrongWomen-Healthy Hearts Program, it will be important to lower the costs and modify the recruitment and training strategies to better reach low-income and minority women. Such strategies may also improve program maintenance. PMID- 25729459 TI - Dissemination of an evidence-based treatment for cancer patients: training is the necessary first step. AB - Evidence-based psychological treatments (EBTs) for cancer patients have not been disseminated in part due to lack of available training. The biobehavioral intervention (BBI) is an EBT designed to alleviate cancer stress and enhance coping. The current study evaluates a training program and uses the Theory of Planned Behavior (TpB) to analyze factors related to intentions to implement BBI. Mental health providers (n = 62) attended a training for BBI. Attendees' supervisors (n = 40) were later surveyed. Repeated measure ANOVAs assessed change over time in knowledge gains, attitudes towards EBTs/BBI, and self-efficacy. Linear multiple regression analyses assessed relationships between these factors and implementation intentions. BBI knowledge and attitude scores increased from pre- to post-training (ps < 0.01). Significant predictors in the final model were BBI-specific attitudes and self-efficacy (ps < 0.05). The BBI training program was an effective dissemination vehicle. Intervention-specific attitudes and self efficacy were key factors in predicting providers' implementation intentions. PMID- 25729460 TI - A brief primary care intervention to reduce fear of movement in chronic low back pain patients. AB - Fear avoidance model of chronic pain-based interventions are effective, but have not been successfully implemented into primary care. It was hypothesized that speed walking times and key measures of the fear avoidance model would improve following the brief intervention delivered in primary care. A brief primary care based intervention (PCB) that included a single educational session, speed walking (an in vivo desensitization exposure task), and visual performance feedback was designed to reduce fear avoidance beliefs and improve function in 4 patients with chronic low back pain. A multiple baseline across subjects with a changing criterion design indicated that speed walking times improved from baseline only after the PCB intervention was delivered. Six fear avoidance model outcome measures improved from baseline to end of study and five of six outcome measures improved from end of study to follow-up. This study provides evidence for the efficacy of a brief PCB fear avoidance intervention that was successfully implemented into a busy clinic for the treatment of chronic pain. PMID- 25729461 TI - Society of Behavioral Medicine position statement: early care and education (ECE) policies can impact obesity prevention among preschool-aged children. AB - The Society of Behavioral Medicine (SBM) urges policymakers to help prevent childhood obesity by improving state regulations for early care and education (ECE) settings related to child nutrition, physical activity, and screen time. More than three quarters of preschool-aged children in the USA attend ECE settings, and many spend up to 40 h per week under ECE care. ECE settings provide meals and snacks, as well as opportunities for increasing daily physical activity and reducing sedentary screen time. However, many states' current policies do not adequately address these important elements of obesity prevention. A growing number of cities and states, child health organizations, medical and early childhood associations, and academic researchers are beginning to identify specific elements of policy and regulations that could transform ECE settings into environments that contribute to obesity prevention. Let's Move! Child Care recommends a set of straightforward regulations addressing nutrition, physical activity, and screen time in ECE settings. These emerging models provide local and state leaders with concrete steps to implement obesity prevention initiatives. We provide a set of recommendations based upon these models that will help state and local policymakers to improve current policies in ECE settings. PMID- 25729462 TI - A patient-centered approach to the development and pilot of a warfarin pharmacogenomics patient education tool for health professionals. AB - OBJECTIVE: To describe an exploratory project to develop and pilot a novel patient educational tool that explains the concept of pharmacogenomics and its impact on warfarin dosing that can be utilized by health professionals providing patient counseling. METHODS: A pharmacogenomics educational tool prototype was developed by an interdisciplinary team. During the pilot of the tool, focus group methodology was used to elicit input from patients based upon their perspectives and experiences with warfarin. Focus group sessions were audio-recorded and transcribed, and the data was analyzed through consensus coding in NVivo. RESULTS: The focus group participants were generally unfamiliar with the concept of pharmacogenomics but were receptive to the information. They thought the patient education tool was informative and would provide the most benefit to patients newly initiated on warfarin therapy. CONCLUSIONS: Preliminary results from this exploratory project suggest that implementation and further feasibility testing of this pharmacogenomics patient education tool should be performed in a population of newly initiated patients taking warfarin. PMID- 25729463 TI - Frontiers in Non-invasive Cardiac Mapping: Rotors in Atrial Fibrillation-Body Surface Frequency-Phase Mapping. AB - Experimental and clinical data demonstrate that atrial fibrillation (AF) maintenance in animals and groups of patients depends on localized reentrant sources localized primarily to the pulmonary veins (PVs) and the left atrium(LA) posterior wall in paroxysmal AF but elsewhere, including the right atrium (RA), in persistent AF. Moreover, AF can be eliminated by directly ablating AF-driving sources or "rotors," that exhibit high-frequency, periodic activity. The RADAR-AF randomized trial demonstrated that an ablation procedure based on a more target specific strategy aimed at eliminating high frequency sites responsible for AF maintenance is as efficacious as and safer than empirically isolating all the PVs. In contrast to the standard ECG, global atrial noninvasive frequency analysis allows non-invasive identification of high-frequency sources before the arrival at the electrophysiology laboratory for ablation. Body surface potential map (BSPM) replicates the endocardial distribution of DFs with localization of the highest DF (HDF) and can identify small areas containing the high-frequency sources. Overall, BSPM had a sensitivity of 75% and specificity of 100% for capturing intracardiac EGMs as having LARA DF gradient. However, raw BSPM data analysis of AF patterns of activity showed incomplete and instable reentrant patterns of activation. Thus, we developed an analysis approach whereby a narrow band-pass filtering allowed selecting the electrical activity projected on the torso at the HDF, which stabilized the projection of rotors that potentially drive AF on the surface. Consequently, driving reentrant patterns ("rotors") with spatiotemporal stability during >70% of the AF time could be observed noninvasibly after HDF-filtering. Moreover, computer simulations found that the combination of BSPM phase mapping with DF analysis enabled the discrimination of true rotational patterns even during the most complex AF. Altogether, these studies show that the combination of DF analysis with phase maps of HDF-filtered surface ECG recordings allows noninvasive localization of atrial reentries during AF and further a physiologically-based rationale for personalized diagnosis and treatment of patients with AF. PMID- 25729464 TI - MODELING TIME DISPERSION DUE TO OPTICAL PATH LENGTH DIFFERENCES IN SCINTILLATION DETECTORS. AB - We characterize the nature of the time dispersion in scintillation detectors caused by path length differences of the scintillation photons as they travel from their generation point to the photodetector. Using Monte Carlo simulation, we find that the initial portion of the distribution (which is the only portion that affects the timing resolution) can usually be modeled by an exponential decay. The peak amplitude and decay time depend both on the geometry of the crystal, the position within the crystal that the scintillation light originates from, and the surface finish. In a rectangular parallelpiped LSO crystal with 3 mm * 3 mm cross section and polished surfaces, the decay time ranges from 10 ps (for interactions 1 mm from the photodetector) up to 80 ps (for interactions 50 mm from the photodetector). Over that same range of distances, the peak amplitude ranges from 100% (defined as the peak amplitude for interactions 1 mm from the photodetector) down to 4% for interactions 50 mm from the photodetector. Higher values for the decay time are obtained for rough surfaces, but the exact value depends on the simulation details. Estimates for the decay time and peak amplitude can be made for different cross section sizes via simple scaling arguments. PMID- 25729465 TI - Combining Ground-Truthing and Technology to Improve Accuracy in Establishing Children's Food Purchasing Behaviors. AB - Developing nutrition-focused environmental interventions for youth requires accurate assessment of where they purchase food. We have developed an innovative, technology-based method to improve the accuracy of food source recall among children using a tablet PC and ground-truthing methodologies. As part of the B'more Healthy Communties for Kids study, we mapped and digitally photographed every food source within a half-mile radius of 14 Baltimore City recreation centers. This food source database was then used with children from the surrounding neighborhoods to search for and identify the food sources they frequent. This novel integration of traditional data collection and technology enables researchers to gather highly accurate information on food source usage among children in Baltimore City. Funding is provided by the NICHD U-54 Grant #1U54HD070725-02. PMID- 25729466 TI - Identification as Gifted and Implicit Beliefs About Intelligence: An Examination of Potential Moderators. AB - The current study investigated whether the developmental timing of a student's identification as gifted (i.e., when a student is first identified) was associated with later implicit beliefs about intelligence, and whether this relation is moderated by academic ability. A sample of 1,743 high-ability college students reported on whether and when they had been identified as gifted, academic ability (SAT scores), and implicit beliefs of intelligence. Timing of identification was unrelated to implicit beliefs; academic ability was the only significant predictor. Higher ability students who had been previously identified as gifted at any point in time reported implicit beliefs more toward entity beliefs than relatively lower ability students who had also been identified; however, this effect was quite small. Implicit beliefs did not vary by ability level for nonidentified students. These findings suggest that identification as gifted at any age modestly (but not necessarily meaningfully) relates to implicit beliefs for high-ability students. PMID- 25729467 TI - A Passive Parallel Master-Slave Mechanism for Magnetic Resonance Imaging-Guided Interventions. AB - A passive, parallel master-slave mechanism is presented for magnetic resonance imaging (MRI)-guided interventions in the pelvis. The mechanism allows a physician to stand outside the MRI scanner while manipulating a needle inside the bore and, unlike a powered robot, does not place actuators in proximity to the patient. The manipulator combines two parallel mechanisms based on the Delta robot architecture. The mechanism also includes a two-axis gimbal to allow for tool angulation, giving a total of five degrees of freedom so that the physician can insert and steer a needle using continuous natural arm and wrist movements, unlike simple needle guides. The need for access between the patient's legs and within the MRI scanner leads to an unusual asymmetric design in which the sliding prismatic joints form the vertices of an isosceles triangle. Kinematic analysis shows that the dexterity index of this design is improved over the desired workspace, as compared to an equilateral design. The analysis is extended to estimate the effect of friction and model the input:output force transmission. Prototypes, with final dimensions selected for transperineal prostate interventions, showed force transmission behavior as predicted by simulation, and easily withstood maximum forces required for tool insertion. PMID- 25729468 TI - Neural Activity Reveals Preferences Without Choices. AB - We investigate the feasibility of inferring the choices people would make (if given the opportunity) based on their neural responses to the pertinent prospects when they are not engaged in actual decision making. The ability to make such inferences is of potential value when choice data are unavailable, or limited in ways that render standard methods of estimating choice mappings problematic. We formulate prediction models relating choices to "non-choice" neural responses and use them to predict out-of-sample choices for new items and for new groups of individuals. The predictions are sufficiently accurate to establish the feasibility of our approach. PMID- 25729469 TI - Portal hypertensive enteropathy. AB - Portal hypertensive enteropathy (PHE) is a condition that describes the pathologic changes and mucosal abnormalities observed in the small intestine of patients with portal hypertension. This entity is being increasingly recognized and better understood over the past decade due to increased accessibility of the small intestine made possible by the introduction of video capsule endoscopy and deep enteroscopy. Though challenged by its diverse endoscopic appearance, multiple scoring systems have been proposed to classify the endoscopic presentation and grade its severity. Endoscopic findings can be broadly categorized into vascular and non-vascular lesions with many subtypes of both categories. Clinical manifestations of PHE can range from asymptomatic incidental findings to fatal gastrointestinal hemorrhage. Classic endoscopic findings in the setting of portal hypertension may lead to a prompt diagnosis. Occasionally histopathology and cross sectional imaging like computed tomography or magnetic resonance imaging may be helpful in establishing a diagnosis. Management of overt bleeding requires multidisciplinary approach involving hepatologists, endoscopists, surgeons, and interventional radiologists. Adequate resuscitation, reduction of portal pressure, and endoscopic therapeutic intervention remain the main principles of the initial treatment. This article reviews the existing evidence on PHE with emphasis on its classification, diagnosis, clinical manifestations, endoscopic appearance, pathological findings, and clinical management. A new schematic management of ectopic variceal bleed is also proposed. PMID- 25729470 TI - Current biomarkers for hepatocellular carcinoma: Surveillance, diagnosis and prediction of prognosis. AB - Biomarkers for surveillance, diagnosis and prediction of prognosis in patients with hepatocellular carcinoma (HCC) are currently not ready for introduction into clinical practice because of limited sensitivity and specificity. Especially for the early detection of small HCC novel biomarkers are needed to improve the current effectiveness of screening performed by ultrasound. The use of high throughput technologies in hepatocellular research allows to identify molecules involved in the complex pathways in hepatocarcinogenesis. Several invasive and non-invasive biomarkers have been identified already and have been evaluated in different clinical settings. Gene signatures with prognostic potential have been identified by gene expression profiling from tumor tissue. However, a single "all in-one" biomarker that fits all-surveillance, diagnosis, prediction of prognosis has not been found so far. The future of biomarkers most probably lies in a combination of non-invasive biomarkers, imaging and clinical parameters in a surveillance setting. Molecular profiling of tumorous and non-tumorous liver tissue may allow a prediction of prognosis for the individual patient and hopefully clear the way for individual treatment approaches. This article gives an overview on current developments in biomarker research in HCC with a focus on currently available and novel biomarkers, in particular on microRNA. PMID- 25729471 TI - Gene therapeutic approaches to inhibit hepatitis B virus replication. AB - Acute and chronic hepatitis B virus (HBV) infections remain to present a major global health problem. The infection can be associated with acute symptomatic or asymptomatic hepatitis which can cause chronic inflammation of the liver and over years this can lead to cirrhosis and the development of hepatocellular carcinomas. Currently available therapeutics for chronically infected individuals aim at reducing viral replication and to slow down or stop the progression of the disease. Therefore, novel treatment options are needed to efficiently combat and eradicate this disease. Here we provide a state of the art overview of gene therapeutic approaches to inhibit HBV replication. We discuss non-viral and viral approaches which were explored to deliver therapeutic nucleic acids aiming at reducing HBV replication. Types of delivered therapeutic nucleic acids which were studied since many years include antisense oligodeoxynucleotides and antisense RNA, ribozymes and DNAzymes, RNA interference, and external guide sequences. More recently designer nucleases gained increased attention and were exploited to destroy the HBV genome. In addition we mention other strategies to reduce HBV replication based on delivery of DNA encoding dominant negative mutants and DNA vaccination. In combination with available cell culture and animal models for HBV infection, in vitro and in vivo studies can be performed to test efficacy of gene therapeutic approaches. Recent progress but also challenges will be specified and future perspectives will be discussed. This is an exciting time to explore such approaches because recent successes of gene therapeutic strategies in the clinic to treat genetic diseases raise hope to find alternative treatment options for patients chronically infected with HBV. PMID- 25729472 TI - Targeting the tumor stroma in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. In ninety percent of the cases it develops as a result of chronic liver damage and it is thus a typical inflammation-related cancer characterized by the close relation between the tumor microenvironment and tumor cells. The stromal environment consists out of several cell types, including hepatic stellate cells, macrophages and endothelial cells. They are not just active bystanders in the pathogenesis of HCC, but play an important and active role in tumor initiation, progression and metastasis. Furthermore, the tumor itself influences these cells to create a background that is beneficial for sustaining tumor growth. One of the key players is the hepatic stellate cell, which is activated during liver damage and differentiates towards a myofibroblast-like cell. Activated stellate cells are responsible for the deposition of extracellular matrix, increase the production of angiogenic factors and stimulate the recruitment of macrophages. The increase of angiogenic factors (which are secreted by macrophages, tumor cells and activated stellate cells) will induce the formation of new blood vessels, thereby supplying the tumor with more oxygen and nutrients, thus supporting tumor growth and offering a passageway in the circulatory system. In addition, the secretion of chemokines by the tumor cells leads to the recruitment of tumor associated macrophages. These tumor associated macrophages are key actors of cancer-related inflammation, being the main type of inflammatory cells infiltrating the tumor environment and exerting a tumor promoting effect by secreting growth factors, stimulating angiogenesis and influencing the activation of stellate cells. This complex interplay between the several cell types involved in liver cancer emphasizes the need for targeting the tumor stroma in HCC patients. PMID- 25729474 TI - Antiviral treatment for chronic hepatitis B in renal transplant patients. AB - Chronic hepatitis B infection is frequent in renal transplant patients. It negatively impacts long term outcomes reducing graft and patient survival. Current guidelines clearly define who needs treatment, when to start, what is the first line therapy, how to monitor treatment response, when to stop, and how patients must be controlled for its safety. There is some data showing a favorable safety and efficacy profile of nucleos(t)ide analogue (NUC) treatment in the renal transplant setting. Entecavir, a drug without major signs of nephrotoxicity, appears to be the first option for NUC naive patients and tenofovir remains the preferred choice for patients with previous resistance to lamivudine or any other NUC. Renal transplant recipients under antiHBV therapy should be monitored for its efficacy against HBV but also for its safety with a close renal monitoring. Studies including a large number of patients with long term treatment and follow up are still needed to better demonstrate the safety and efficacy of newer NUCs in this population. PMID- 25729473 TI - Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. AB - Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID- 25729475 TI - Recent advances in dietary supplementation, in treating non-alcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is currently known as the most common liver problem, characterized by excessive lipid accumulation in hepatocytes, which may progress to other liver diseases such as nonalcoholic steatohepatitis, hepatic tissue fibrosis, liver cirrhosis, and failure or hepatocellular carcinoma. Since NAFLD is positively associated with the development of obesity, insulin resistance, and ultimately type 2 diabetes mellitus, it is often regarded as the hepatic manifestation of the metabolic syndrome. No pharmacologic treatment has yet been proven for this disease. For most patients with presumed or confirmed NAFLD, the only proven strategy is to offer lifestyle advice that can lead to sustained weight loss. Since insulin resistance, oxidative stress, inflammation, and necro-apoptosis are involved in NAFLD pathogenesis, it seems that every potential therapeutic agent should target one or some of these pathologic events. There are many well known anti-oxidants, anti-inflammatory, and insulin sensitizer dietary supplements which have shown beneficial effects on NAFLD improvement in animal and human studies. The purpose of this review is to explore the existing evidences on dietary supplements considered to have hepatoprotective properties, and to present some proposed mechanisms by which they may protect against NAFLD. PMID- 25729477 TI - Micro RNAs in the development of non-alcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known about the underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs (miRNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target mRNAs. Several miRNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of miRNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including miRNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of miRNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of miRNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression. PMID- 25729476 TI - Management of patients with hepatitis C infection and renal disease. AB - Hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD) is associated with more rapid liver disease progression and reduced renal graft and patients' survival following kidney transplantation. Evaluations and management of HCV in patients with renal disease are challenging. The pharmacokinetics of interferons (IFN), ribavirin (RBV) and some direct acting antiviral (DAA), such as sofosbuvir, are altered in patients with ESRD. With dose adjustment and careful monitoring, treatment of HCV in patients with ESRD can be associated with sustained virological response (SVR) rates nearly comparable to that of patients with normal renal function. DAA-based regimens, especially the IFN-free and RBV-free regimens, are theoretically preferred for patients with ESRD and KT in order to increase SVR rates and to reduce treatment side effects. However, based on the data for pharmacokinetics, dosing safety and efficacy of DAA for patients with severe renal impairment are lacking. This review will be focused on the evaluations, available pharmacologic data, and management of HCV in patients with severe renal impairment, patients who underwent KT, and those who suffered from HCV-related renal disease, according to the available treatment options, including DAA. PMID- 25729479 TI - Surgical management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumour-related and hepatic function-related considerations. As such, HCC is currently managed largely through non-surgical means as the criteria, in relation to the above considerations, for surgical management is still largely restrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes (5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation. PMID- 25729478 TI - Image-guided therapies in the treatment of hepatocellular carcinoma: A multidisciplinary perspective. AB - A multidisciplinary approach to the treatment of patients with unresectable hepatocellular carcinoma (HCC) has led to improvements in screening, detection, and treatments. Interventional techniques include thermal ablation, transarterial chemoembolization, and radioembolization whilst stereotactic body radiation therapy also uses imaging to target the radiation. Both survival rates and cure rates have improved markedly since the introduction of these techniques. This review article describes the image guided techniques used for the treatment of HCC. PMID- 25729480 TI - Occult hepatitis B virus co-infection in human immunodeficiency virus-positive patients: A review of prevalence, diagnosis and clinical significance. AB - The prevalence of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) co-infection is high as they share similar mechanisms of transmission. The development and widespread use of highly sensitive tests for HBV diagnosis has demonstrated that a significant proportion of apparently healthy individuals with evidence of exposure to HBV continue to carry fully functional HBV DNA in their hepatocytes, a situation that predisposes them to the development of progressive liver disease and hepatocellular carcinoma. The presence of co-infections frequently influences the natural evolution of each of the participating infections present by either facilitating their virulence or competing for resources. Furthermore, the drugs used to treat these infections may also contribute to changes in the natural course of these infections, making the analysis of the impact of co-infection more difficult. The majority of studies has examined the impact of HIV on overt chronic hepatitis B, finding that co infection carries an increased risk of progressive liver disease and the development of hepatocellular carcinoma. Although the effect of HIV on the natural history of occult hepatitis B infection (OBI) has not been fully assessed, all available data suggest a persisting risk of repeated flares of hepatitis and progressive liver disease. We describe studies regarding the diagnosis, prevalence and clinical significance of OBI in HIV-positive patients in this short review. Discrepancies in worldwide prevalence show the urgent need for the standardization of diagnostic criteria, as established by the Taormina statements. Ideally, standardized protocols for testing should be employed to enable the comparison of data from different groups. Additional studies are needed to define the differences in risk for OBI without HIV and in HIV-HBV co infected patients with or without overt disease. PMID- 25729481 TI - Role of surgical resection for hepatocellular carcinoma based on Japanese clinical guidelines for hepatocellular carcinoma. AB - In the Algorithm for Diagnosis and Treatment in the Japanese Evidence-Based Clinical Practice Guidelines for Hepatocellular Carcinoma, the treatment strategy is determined by three major factors: liver function and the number and size of tumors. The algorithm is quite simple, consisting of fewer components than the Barcelona-Clinic Liver Cancer staging system. In this article, we describe the roles of the treatment algorithm in hepatectomy and perioperative management of hepatocellular carcinoma. PMID- 25729482 TI - Immune response to hepatitis B vaccine among patients on hemodialysis. AB - Infection with hepatitis B virus (HBV) poses a major health threat worldwide, where the magnitude and overburden of chronic carrier state approaches 150 million chronic carriers. The prevalence of HBV is greater among dialyzed patients compared to the general population owing to their increased vulnerability to blood and its products, along with hazards posed by contaminated hemodialysis tools and devices. An electronic systematic search of the published literature was carried and data on the immunological riposte to hepatitis B vaccination among hemodialysis patients was extracted from relevant studies. End stage renal disease patients on hemodialysis have a lower or an absolutely negative riposte to HBV vaccine. Several means have been tried to improve this response with some success, nevertheless none have been universally adopted. Genetic investigations are foreseen to make a break through concerning HBV vaccination. PMID- 25729483 TI - Post-transplantation hepatocellular carcinoma recurrence: Patterns and relation between vascularity and differentiation degree. AB - AIM: To evaluate the relationship between hepatocellular carcinoma (HCC) vascularity and grade; to describe patterns and vascular/histopathological variations of post-transplantation recurrence. METHODS: This retrospective study included 165 patients (143 men, 22 women; median age 56.8 years, range 28-70.4 years) transplanted for HCC who had a follow-up period longer than 2 mo. Pre transplantation dynamic computed tomography or magnetic resonance examinations were retrospectively reviewed, classifying HCC imaging enhancement pattern into hypervascular and hypovascular based on presence of wash-in during arterial phase. All pathologic reports of the explanted livers were reviewed, collecting data about HCC differentiation degree. The association between imaging vascular pattern and pathological grade was estimated using the Fisher exact test. All follow-up clinical and imaging data were reviewed for evidence of recurrence. Recurrence rate was calculated and imaging features of recurrent tumor were collected, classifying early and late recurrences based on timing (< or >= 2 years after transplantation) and intrahepatic, extrahepatic and both intrahepatic and extrahepatic recurrences based on location. All intrahepatic recurrences were classified as hypervascular or hypovascular and the differentiation degree was collected where available. The presence of variations in imaging enhancement pattern and pathological grade between the primary tumor and the intrahepatic recurrence was evaluated and the association between imaging and histopatholgical variations was estimated by using the chi(2) test. RESULTS: Of the 163 patients with imaging evidence of viable tumor, 156 (95.7%) had hypervascular and 7 (4.3%) hypovascular HCC. Among the 125 patients with evidence of viable tumor in the explanted liver, 19 (15.2%) had grade 1, 56 (44.8%) grade 2, 40 (32%) grade 3 and 4 (3.2%) grade 4 HCC, while the differentiation degree was not assessable for 6 patients (4.8%). A significant association was found between imaging vascularity and pathological grade (P = 0.035). Post-transplantation recurrence rate was 14.55% (24/165). All recurrences occurred in patients who had a hypervascular primary tumor. Three patients (12.5%) experienced late recurrence; the location of the first recurrence was extrahepatic in 14 patients (58.3%), intrahepatic in 7 patients (29.2%) and both intrahepatic and extrahepatic in 3 patients (12.5%). Two patients had a variation in imaging characteristics between the primary HCC (hypervascular) and the intrahepatic recurrent HCC (hypovascular), while 1 patient had a variation of histopathological characteristics (from moderate to poor differentiation), however no association was found between imaging and histopathological variations. CONCLUSION: A correlation was found between HCC grade and vascularity; some degree of variability may exist between the primary and the recurrence imaging/histopathological characteristics, apparently not correlated. PMID- 25729484 TI - Lesser celandine (pilewort) induced acute toxic liver injury: The first case report worldwide. AB - Lesser celandine, also known as Ranunculus ficaria, is a herbaceous perennial plant that commonly utilizes piles and is taken either internally or used externally. The causality assessment of several reports provided evidence for the existence of Greater Celandine hepatotoxicity. However, there hasn't been any case report published thus far, about lesser celandine induced liver injury. Here, we present a case of 36-year-old woman admitted to the hospital with acute hepatitis and jaundice on her sclera with no history of drug abuse or alcohol consumption. However, the patient had a recent history of lesser celandine extract consumption for hemorrhoids, for about 10 d, prior to the admission. Viral hepatitis, autoimmune hepatitis, and drug induced toxic hepatitis were ruled out by further imaging studies and laboratory analysis. Using the Council for International Organizations of Medical Sciences scale, the type of liver injury was assumed as hepatocellular and was scored as 7 which shows probable causality. Immediate discontinuation of lesser celandine extract resulted in rapid decrease of the elevated enzymes. Herbs have been reported to cause liver injury and therefore should be suspected in the case of acute hepatitis with an unknown etiology. This case is important to be the first to explain hepatotoxicity caused by lesser celandine. Physicians should consider lesser celandine as a causative agent for hepatotoxicity. PMID- 25729486 TI - Evaluation of changes of intracranial blood flow after carotid artery stenting using digital subtraction angiography flow assessment. AB - AIM: To evaluate the changes of intracranial blood flow after carotid artery stenting (CAS), using the flow assessment application "Flow-Insight", which was developed in our department. METHODS: Twenty patients treated by CAS participated in this study. We analyzed the change in concentration of the contrast media at the anterior-posterior and profile view image with the flow assessment application "Flow-Insight". And we compared the results with N-isopropyl-p-[123I] iodoamphetamine-single-photon emission computed tomography (IMP SPECT) performed before and after the treatment. RESULTS: From this study, 200% of the parameter "blood flow" change in the post/pre-treatment is suggested as the critical line of the hyperperfusion syndrome arise. Although the observed blood flow increase in the digital subtraction angiography system did not strongly correlate with the rate of increase of SPECT, the "Flow-Insight" reflected the rate of change of the vessels well. However, for patients with reduced reserve blood flow before CAS, a highly elevated site was in agreement with the site analysis results. CONCLUSION: We concluded that the cerebral angiography flow assessment application was able to more finely reveal hyperperfusion regions in the brain after CAS compared to SPECT. PMID- 25729485 TI - Imaging and interventions in hilar cholangiocarcinoma: A review. AB - Hilar cholangiocarcinoma is a common malignant tumor of the biliary tree. It has poor prognosis with very low 5-year survival rates. Various imaging modalities are available for detection and staging of the hilar cholangiocarcinoma. Although ultrasonography is the initial investigation of choice, imaging with contrast enhanced computed tomography scan or magnetic resonance imaging is needed prior to management. Surgery is curative wherever possible. Radiological interventions play a role in operable patients in the form of biliary drainage and/or portal vein embolization. In inoperable cases, palliative interventions include biliary drainage, biliary stenting and intra-biliary palliative treatment techniques. Complete knowledge of application of various imaging modalities available and about the possible radiological interventions is important for a radiologist to play a critical role in appropriate management of such patients.We review the various imaging techniques and appearances of hilar cholangiocarcinoma and the possible radiological interventions. PMID- 25729487 TI - Transcranial Doppler screening in sickle cell disease: The implications of using peak systolic criteria. AB - AIM: To compare time average maximum mean velocity (TAMV) and peak systolic velocity (PSV) criteria of Trans Cranial Doppler (TCD) in their ability to predict abnormalities on magnetic resonance imaging (MRI)/magnetic resonance angiogram (MRA) in patients with sickle cell disease. METHODS: A retrospective evaluation was performed of the outcomes in all patients with a Transcranial Doppler examination at our institution since the implementation of the hospital picture archiving and communication system (PACS) system in January 2003 through December 2012. All ultrasound imaging exams were performed by the same technologist with a 3 MHz transducer. Inclusion criteria was based upon the Transcranial Doppler procedure code in our PACS which had an indication of sickle cell disease in the history. The patient's age and gender along with the vessel with the highest time averaged mean velocity as well as the highest peak systolic velocity was recorded for analysis. A subset of the study cohort also had subsequent MR imaging and Angiograms performed within 6 mo of the TCD examination. MRI results were categorized as having a disease related abnormality (vessel narrowing, collateral formation/moya-moya, or abnormal fluid attenuation inversion recovery signal in parenchyma indicative of prior stroke) or normal. The MRI results formed the comparison standards for TCD exams in evaluating intracranial injury. Sensitivity and specificity for the two TCD criteria (TAMV and PSV) were calculated to determine which could be a better predictor for intracranial vasculopathy /clinically occult strokes. RESULTS: The study cohort for our institution was 110 patients with a total of 291 TCD examinations. These patients had a mean age of 7.6 years with a range from 2-18 years of age. Sixty two of the 110 patients (56%) had two or more TCD exams. Thirty-seven patients (34%) had at least one MRI following a TCD examination. Of the 291 TCD examinations, 46 (16%) were conditional or abnormal by TAMV criteria. One hundred and sixteen (40%) were conditional or abnormal by PSV criteria. All studies that were abnormal by TAMV were also abnormal by PSV criteria. Seventy of the 116 (60%) studies which were conditional or abnormal by peak systolic criteria would not have been identified by time averaged mean maximum velocity criteria. The most frequent location of highest velocity measurement was noted to be in the middle cerebral artery regardless of whether it was measured by PSV or TAMV. From the 37 patients having one or more MRIs, 43 MRI exams were performed within 6 mo of a TCD examination. Twenty two (51%) MRIs had a disease related abnormality reported. When evaluating conditional or abnormal exams by PSV criteria against follow-up MRI/MRA, the sensitivity was 73% [16/(16 + 6)] and specificity was 81% [17/(4 + 17)]. When evaluating conditional or abnormal exams by TAMV criteria by follow-up MRI/MRA as the gold standard, the sensitivity was 41% [9/(9 + 13)] and the specificity was 100% [21/(21 + 0)]. In using conditional or abnormal criteria from PSV and TAMV to predict abnormalities on follow-up MRI/MR Angiogram, PSV was more sensitive (73% vs 41%) while TAMV was more specific (100% vs 81%). CONCLUSION: Based on the data obtained at our institution and using the assumption that the best screening test is the one with the highest sensitivity, the peak systolic velocity could be the measurement of choice for TCD screening. PMID- 25729488 TI - Do all antioxidant supplements have the same potential effect on preventing myringosclerosis? AB - OBJECTIVES: Myringosclerosis is an irreversible pathological healing mechanism of the tympanic membrane which can result in the formation of sclerotic plaques. Antioxidant treatment is a recognised prevention therapy and coenzyme Q10 (CoQ10), lycopene, and grape seed extract (GSE), were used in this manner. METHODS: Forty-four Wistar rats were used in this experiment, and, following myringotomies, the animals were randomly divided into four groups. CoQ10, lycopene or GSE was administered orally to the respective groups, starting from the day of surgery. Otomicroscopy examination was performed on the 14th day. All tympanic membrane lesions were evaluated and compared otomicroscopically and histopathologically. RESULTS: The otomicroscopy and histopathological findings, compared against a control (saline) group, showed the CoQ10, lycopene, and GSE groups had statistically significant differences of degree of sclerosis (P<0.001). CONCLUSION: CoQ10, lycopene, and GSE were compared against a saline group and their antioxidative and anti-inflammatory effects were similar. The formation of myringosclerotic plagues after experimental myringotomy in rats significantly decreased and diminished after systemic administration of the three different antioxidant supplements. PMID- 25729489 TI - Single-center 10-year experience in treating patients with vascular tinnitus: diagnostic approaches and treatment outcomes. AB - OBJECTIVES: Vascular tinnitus is the most common form of pulsatile tinnitus, particularly when the tinnitus corresponds with the pulse of patients. In this study, we reviewed the 10-year clinical data on vascular tinnitus of our tinnitus clinic to investigate the frequency of the underlying etiologies, to introduce a diagnostic protocol, and to evaluate the treatment outcomes. METHODS: We retrospectively collected the data of 57 patients who were diagnosed as vascular tinnitus between April 2001 and December 2011. Careful history taking, otoscopy, thorough physical examinations, audiometry, laboratory tests, as well as radiologic examinations were performed according to our diagnostic protocol to find the origin of pulsatile tinnitus. Treatment options were individualized based on the specific etiology, and the outcomes were assessed using patient's subjective reports at the follow-up interviews. RESULTS: High jugular bulb was the most common cause (47.4%) of vascular tinnitus, and venous hum was the next (17.5%). Dural arteriovenous fistula, intracranial aneurysm, atherosclerotic carotid artery disease, and hypertension were less common causes. Vascular tinnitus was alleviated in most patients after the appropriate treatment: surgical intervention, tinnitus retraining therapy, reassurance, and medications. CONCLUSION: Vascular tinnitus can be successfully diagnosed by the regular use of the suggested protocol. Many patients with vascular tinnitus have treatable underlying etiologies. Treatment of those etiologies or at least counseling about the tinnitus itself can benefit the patients with troublesome vascular tinnitus. PMID- 25729490 TI - Donor-site morbidity following minimally invasive costal cartilage harvest technique. AB - OBJECTIVES: Autologous costal cartilage is a promising alternative for mastoid obliteration. However, donor-site morbidities of the chest wall limit the use of this graft. To address this issue, we have developed a minimally-invasive technique of harvesting costal cartilage and report donor site morbidity associated with the procedure. METHODS: Donor site morbidities were evaluated for 151 patients who underwent costal cartilage harvest, canal wall down mastoidectomy, and mastoid obliteration. Pain and cosmetic concern were evaluated via visual analogue scale (VAS). Scars were evaluated via the modified Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS). Postoperative complications were assessed during the follow-up period. RESULTS: The mean duration of noticeable pain was 5.3 days post operation. The mean VAS score for pain was 3.0 of 10 on the first day after the operation and gradually declined. At the 6 months post operation, the mean VAS cosmetic score at the costal cartilage harvest site was 0.6 of 10. The mean VSS score was 9.5 out of 10 total, and the mean POSAS score was 23.27 out of 110 total. CONCLUSION: The minimally-invasive chopped costal cartilage harvest technique resulted in acceptable pain, cosmetic concern, and postoperative complications for most patients. There were no major postoperative complications. Costal cartilage is an acceptable donor for mastoid obliteration in canal wall down mastoidectomy, especially in the context of the extremely low donor site morbidity of the minimally-invasive technique presented in the study. PMID- 25729491 TI - Critical evaluation of round window membrane sealing in the treatment of idiopathic sudden unilateral hearing loss. AB - OBJECTIVES: Rupture of the round window membrane with consecutive development of a perilymphatic fistula (PLF) is still a matter of controversial debate in the pathogenesis of idiopathic sudden sensorineural hearing loss (SSHL). Until now no consensus exists about whether these patients benefit from performing an exploratory tympanotomy with sealing of the round window. The aim of the present study was to analyze critically the effectiveness of sealing the round window membrane in patients with SSHL. METHODS: The clinical data of 51 patients with SSHL and a mean hearing decline of at least 60 dB over 5 frequencies who were treated with tympanotomy and sealing of the round window membrane were retrospectively analyzed. The results have been compared to the current state of the literature. RESULTS: Intraoperatively a round window membrane rupture or fluid leak was observed in none of the patients. After performing tympanotomy the mean improvement of hearing level was 32.7 dB. Twenty of 51 examined patients (39.2%) showed a mean improvement of the hearing level of more than 30 dB and a complete remission could be detected in 12 patients (23.5%). Reviewing the literature revealed no standard guidelines for definition or treatment of SSHL as well as for evaluation of hearing loss and its recovery. CONCLUSION: The results of the present study and the literature should be discussed critically. It is unclear whether tympanotomy and sealing of the round window membrane may be a meaningful treatment for SSHL. Therefore this procedure should be discussed as a therapeutic option only in selected patients with sudden deafness or profound hearing loss in which PLF is strongly suspicious or conservative treatment failed. PMID- 25729492 TI - Vowel perception in listeners with normal hearing and in listeners with hearing loss: a preliminary study. AB - OBJECTIVES: To determine the influence of hearing loss on perception of vowel slices. METHODS: Fourteen listeners aged 20-27 participated; ten (6 males) had hearing within normal limits and four (3 males) had moderate-severe sensorineural hearing loss (SNHL). Stimuli were six naturally-produced words consisting of the vowels /i a u ae E v/ in a /b V b/ context. Each word was presented as a whole and in eight slices: the initial transition, one half and one fourth of initial transition, full central vowel, one-half central vowel, ending transition, one half and one fourth of ending transition. Each of the 54 stimuli was presented 10 times at 70 dB SPL (sound press level); listeners were asked to identify the word. Stimuli were shaped using signal processing software for the listeners with SNHL to mimic gain provided by an appropriately-fitting hearing aid. RESULTS: Listeners with SNHL had a steeper rate of decreasing vowel identification with decreasing slice duration as compared to listeners with normal hearing, and the listeners with SNHL showed different patterns of vowel identification across vowels when compared to listeners with normal hearing. CONCLUSION: Abnormal temporal integration is likely affecting vowel identification for listeners with SNHL, which in turn affects vowel internal representation at different levels of the auditory system. PMID- 25729493 TI - Extended draf IIb procedures in the treatment of frontal sinus pathology. AB - OBJECTIVES: Draf IIb approach provides wide, unilateral access to the frontal sinus. This approach can be extended without destruction of the contralateral frontal sinus drainage pathway, performed during Draf III (modified Lothrop) procedure. There is limited data in the literature regarding the use of modified Draf IIb procedures. METHODS: Patients treated with extended Draf IIb procedures in a single center were retrospectively assessed. RESULTS: Ten patients were identified, including 2 cases of osteoma, 1 inverted papilloma, 1 carcinoma, 5 mucoceles, and 1 chronic rhinosinusitis patient. Six patients had undergone prior surgery, including external procedures in 3 cases. Modifications of Draf IIb were classified as the following: removal of the anterosuperior nasal septum adjacent to the nasal beak, removal of the intersinus septum, and a combination of the above-mentioned methods (upper nasal septum and intersinus septum removal). There were 3 patients operated on with type 1 modification, one patient with type 2 modification, and 6 patients with type 3 modification. There were no perioperative complications. CONCLUSION: In selected cases, extended Draf IIb procedures are safe and effective in the treatment of frontal sinus disease. PMID- 25729494 TI - Categorization and clinicopathological features of chronic rhinosinusitis with eosinophilic mucin in a korean population. AB - OBJECTIVES: Chronic rhinosinusitis (CRS) with eosinophilic mucin is relatively rare in Korea. We categorized CRS patients with characteristic eosinophilic mucin into several groups and compared the groups based on their clinicopathological features. METHODS: In total, 52 CRS patients with eosinophilic mucin were enrolled. Based on the presence or absence of an allergy (A) to a fungus or fungal element (F) in the mucin, the patients were divided into four groups: allergic fungal rhinosinusitis (AFRS, A+F+), AFRS-like sinusitis (A+F-), eosinophilic fungal rhinosinusitis (EFRS, A-F+), and eosinophilic mucin rhinosinusitis (EMRS, A-F-). Clinical and immunological variables were compared between the groups. RESULTS: There were 13 patients in the AFRS group, 13 in the EFRS group, and 26 in the EMRS group. No patient was assigned to the AFRS-like sinusitis group. The AFRS group showed a significantly higher association with allergic rhinitis than did the EFRS and EMRS groups. The mean total serum IgE level in the AFRS patients was significantly higher than in the EFRS and EMRS patients. While 7.7% of the patients with AFRS and EFRS were asthmatic, 65.4% of the patients with EMRS had bronchial asthma. In the AFRS and EFRS groups, 31% had bilateral disease, in contrast to 100% of EMRS patients with bilateral disease. The prevalence of high attenuation areas by computed tomography was significantly higher in the AFRS group than in the EMRS group, and the mean Hounsfield unit values of the areas of high attenuation in the AFRS patients were significantly greater than those in the EMRS patients. CONCLUSION: AFRS is believed to be an allergic response to colonizing fungi in atopic individuals. In EFRS, local allergies to fungi may play a role in the pathogenesis of the disease. EMRS is thought to be unconnected with fungal allergies. PMID- 25729495 TI - Risk factors of emergence agitation in adults undergoing general anesthesia for nasal surgery. AB - OBJECTIVES: To identify the incidence and the risk factors of emergence agitation in adults undergoing general anesthesia for nasal surgery. METHODS: We retrospectively examined 792 patients aged >=18 years who underwent general anesthesia for elective nasal surgery between July 2012 and August 2013. Patients in the postanesthesia care unit with a Richmond Agitation Sedation Scale>=+1 at any time were considered to have emergence agitation. RESULTS: The overall incidence of emergence agitation is 22.2%. From multivariate regression analysis, the following six variables were found to be significantly associated with emergence agitation (P<0.05): younger age, recent smoking, sevoflurane anesthesia, postoperative pain on the numerical rating scale (NRS)>=5, presence of a tracheal tube, and presence of a urinary catheter. Presence of a tracheal tube was the greatest risk factor, increasing the risk of developing emergence agitation by approximately fivefold (odds ratio, 5.448; 95% confidence interval, 2.973 to 9.982). Younger age was also a strong risk factor (odds ratio, 0.975 for each 1-year increase; 95% confidence interval, 0.964 to 0.987). Current smoking, sevoflurane anesthesia, postoperative pain of NRS>=5, and the presence of a urinary catheter nearly doubled the risk of emergence agitation. CONCLUSION: Emergence agitation following general anesthesia is a common complication in adult nasal surgery patients. To reduce the occurrence and consequences of agitation episodes, elimination of the associated risk factors is necessary, especially in at-risk patients. PMID- 25729496 TI - Reconstruction of the orbit with a temporalis muscle flap after orbital exenteration. AB - OBJECTIVES: This study presents the role of the temporalis muscle flap in primary reconstruction after orbital exenteration. METHODS: A retrospective nonrandomized study of orbital exenterations performed between 1990 and 2010 for malignant tumors of the skin, paranasal sinus, and nasal cavity is presented. RESULTS: The study included 13 patients (nine men, four women; age range, 30-82 years) with paranasal sinus, nasal cavity, or skin carcinomas. Primary reconstruction of the cavity was performed in all patients after orbital exenteration. No visible defects in the muscle flap donor site were present. Local recurrences were readily followed up with nasal endoscopy, whereas radiology helped to diagnose intracranial involvement in three patients. Two patients died of systemic metastases and five died for other reasons. CONCLUSION: The temporalis muscle flap is readily used to close the defect after orbital exenteration, and does not prevent the detection of recurrence. PMID- 25729497 TI - Characteristics of Expression of Matrix Metalloproteinases (MMP-2 and MMP-9) in Glottic Squamous Cell Carcinoma and Benign Vocal Fold Lesions. AB - OBJECTIVES: The aim of this study was to investigate expression profile of matrix metalloproteinases (MMP-2 and MMP-9) in glottic squamous cell carcinoma (SCC) and benign vocal fold lesions (BVFLs) and to correlate it with clinical and pathological features. METHODS: The immunohistochemical expression of MMP-2 and MMP-9 was investigated in specimens taken from 217 patients group, including vocal fold polyps (n=39), recurrent respiratory papillomatosis (n=30), laryngeal keratosis (n=36), glottic SCC (n=112), and the normal tissue of vocal fold (n=12, control group). The expression of MMP-2 and MMP-9, both in epithelium and stroma cells, was graded on a semiquantitative scale, ranging from 0 (no expression) to 18 points (high expression). RESULTS: Expressions of both, MMP-2 and MMP-9 were significantly higher in the glottic SCC group comparing with BVFL group. Significant higher expression of parenchymal MMP-2 (P<0.001) and stromal MMP-9 (P=0.01) was revealed in the group of moderate/poorly differentiated glottic SCC comparing with well differentiated glottic SCC group. Expression of stroma MMP-2 was found to be correlated with nodal metastasis (P=0.030). Expressions of both, MMP-2 and MMP-9 were not correlated with clinical stage, tumor T value, smoking, alcohol use, age in the glottic SSC patients group. The MMP-2 stroma value of 11.2 points was determined as the optimum point (limiting value) for separating BVFL and glottic SCC patient groups. CONCLUSION: Our results suggest that expressions of both MMP-2 and MMP-9 are up-regulated already in the development of BVFL, the next determinant step is concerned with occurrence of malignization. Limiting value of stroma MMP-2 demonstrates prognostic importance of MMP-2 in glottic SCC carcinogenesis. PMID- 25729498 TI - Benzydamine oral spray inhibiting parasympathetic function of tracheal smooth muscle. AB - OBJECTIVES: Benzydamine is a nonsteroidal anti-inflammatory agents agent with anti-inflammatory and local anesthesia properties that is available in the entire world as an oral spray for oral mucositis patients who are suffering from radiation effects. The effect of benzydamine on oral mucositis in vivo is well known; however, the effect of the drug on tracheal smooth muscle has rarely been explored. During administration of the benzydamine for oral symptoms, it might affect the trachea via oral intake or inhalation. METHODS: We examined the effectiveness of benzydamine on isolated rat tracheal smooth muscle. The following assessments of benzydamine were performed: effect on tracheal smooth muscle resting tension; effect on contraction caused by 10(-6)M methacholine as a parasympathetic mimetic; and effect of the drug on electrically induced tracheal smooth muscle contractions. RESULTS: Addition of methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of benzydamine at doses of 10(-5)M or above elicited a significant relaxation response to 10(-6)M methacholine-induced contraction. Benzydamine could inhibit electrical field stimulation-induced spike contraction. It alone had a minimal effect on the basal tension of trachea as the concentration increased. CONCLUSION: This study indicated that high concentrations of benzydamine might actually inhibit parasympathetic function of the trachea. Benzydamine might reduce asthma attacks in oral mucositis patients because it could inhibit parasympathetic function and reduce methacholine-induced contraction of tracheal smooth muscle. PMID- 25729499 TI - Evaluation of an active humidification system for inspired gas. AB - OBJECTIVES: The effectiveness of the active humidification systems (AHS) in patients already weaned from mechanical ventilation and with an artificial airway has not been very well described. The objective of this study was to evaluate the performance of an AHS in chronically tracheostomized and spontaneously breathing patients. METHODS: Measurements were quantified at three levels of temperature (T degrees ) of the AHS: level I, low; level II, middle; and level III, high and at different flow levels (20 to 60 L/minute). Statistical analysis of repeated measurements was performed using analysis of variance and significance was set at a P<0.05. RESULTS: While the lowest temperature setting (level I) did not condition gas to the minimum recommended values for any of the flows that were used, the medium temperature setting (level II) only conditioned gas with flows of 20 and 30 L/minute. Finally, at the highest temperature setting (level III), every flow reached the minimum absolute humidity (AH) recommended of 30 mg/L. CONCLUSION: According to our results, to obtain appropiate relative humidity, AH and T degrees of gas one should have a device that maintains water T degrees at least at 53C for flows between 20 and 30 L/m, or at T degrees of 61C at any flow rate. PMID- 25729500 TI - Does Postthyroidectomy Syndrome Really Exist Following Thyroidectomy? Prospective Comparative Analysis of Open vs. Endoscopic Thyroidectomy. AB - OBJECTIVES: This study prospectively evaluated postthyroidectomy syndrome (PTS) through objective and subjective voice changes following thyroidectomy of open vs. endoscopic thyroidectomy. METHODS: A prospective clinical trial (SCHBC IRB 09 26) was performed from Jan 2008 to Aug 2010 to compare the open thyroidectomy (OPEN group) and endoscopic thyroidectomy (ENDO group). Of the 110 patients, 75 completed the evaluation before and 1 and 6 months after surgery. Subjective parameters included perceptual analysis (GRBAS [grade, roughness, breathiness, asthenia, and strain] scale), stroboscopic or flexible fiberscopic analysis, voice handicap index, and 5-point visual analog scales for vocal fatigue, singing difficulty, difficulty with high-pitch phonation, and neck discomfort. Objective parameters included acoustic, aerodynamic analysis and the electroglottograph. RESULTS: For the ENDO group (n=36), the operation time was longer than in the OPEN group (n=39; P<0.01). For the OPEN group, two objective and five subjective parameters were worse 1 month postoperatively; of these, two subjective parameters persisted for 6 months (P<0.05). For the ENDO group, three objective and six subjective parameters were worse 1 month postoperatively, and three of the subjective parameters persisted 6 months postoperatively (P<0.05). CONCLUSION: PTS really exists following simple thyroidectomy and are very common for both OPEN and ENDO groups. Most of the parameters improved gradually over time, but some subjective changes persisted 6 months postoperatively. PMID- 25729501 TI - Bringing retracted papers into focus. PMID- 25729502 TI - In reply: bringing retracted papers into focus. PMID- 25729503 TI - The view from here. PMID- 25729504 TI - From the Eyes of the Front Line: BCBAs Evaluate BAP. AB - Master's-level Board Certified Behavior Analysts((r)) were emailed an anonymous webbased survey regarding the journal Behavior Analysis in Practice (BAP). Following a 96-hour response window, 284 completed surveys were obtained. Data revealed that many participants regard the journal as beneficial to their profession, yet considered it too expensive and in need of a sharper focus on practitioner issues. Most supported BAP's emphasis on empirical research, and many recommended additional content areas such as clinical case formulations, objective product information, and a layout that blends the features of an empirical journal and a popular magazine. In summary, this survey indicates that, as a practitioner-oriented journal, BAP has the potential to occupy a valuable niche for master's-level behavior analysts and that journal leaders might enhance its value by modifying its marketing, content, and structure. PMID- 25729505 TI - An Assessment-based Solution to a Human-Service Employee Performance Problem: An Initial Evaluation of the Performance Diagnostic Checklist - Human Services. AB - The PDC-HS implicated a lack of proper training on participant duties and a lack of performance feedback as contributors to the performance problems. As a result, an intervention targeting training on participant duties and performance feedback was implemented across eight treatment rooms; the intervention increased performance in all rooms. This preliminary validation study suggests the PDC-HS may prove useful in solving performance problems in human-service settings. PMID- 25729506 TI - Behavioral economics: a tutorial for behavior analysts in practice. AB - In recent years, behavioral economics has gained much attention in psychology and public policy. Despite increased interest and continued basic experimental studies, the application of behavioral economics to therapeutic settings remains relatively sparse. Using examples from both basic and applied studies, we provide an overview of the principles comprising behavioral economic perspectives and discuss implications for behavior analysts in practice. A call for further translational research is provided. PMID- 25729507 TI - Teaching receptive language skills: recommendations for instructors. AB - Receptive language refers to responding appropriately to another person's spoken language. Most curricula dedicate a proportion of early intervention to developing receptive language skills. The specific terms used to refer to the receptive language programs and the recommendations for teaching such skills vary considerably across the early intervention curricula. The present paper will provide a conceptual analysis of the desired controlling variables for different receptive language programs, teaching recommendations, a brief review of the literature to substantiate the teaching recommendations, and a discussion of the potential negative effects of deviating from the recommendations. PMID- 25729508 TI - Stepping stones learning center. AB - Stepping Stones Learning Center, located in West Irondequoit, NY, has sustained high-quality, specialized applied behavior analytic programs since 1996 within an agency that has a broad mission of serving children with and without special needs. The agency's success reflects long-standing commitment from its leaders, frequent expert consultation, substantial experience and knowledge within the agency, and well-established relationships with community partners. PMID- 25729509 TI - Don'T stop believing: journeys school. AB - This report showcases an alternative school for children with emotional and behavioral disorders that is engaging in the practice of behavior analysis. The core principles of behavioral science at work include contingency management, goal setting, teaching self-control, mindfulness, and acceptance and commitment therapy. Student outcomes appear extremely promising. PMID- 25729510 TI - HomeLink Support Technologies at Community Living Opportunities. AB - What if your existing home could be made smarter and detect when you need support? What if there was a new way to deliver care to you right when you needed and only for as long as necessary? These questions, and others like them, have guided Community Living Opportunities, Inc. (CLO) in the innovation of service delivery methods. In concert with HomeLink Support Technologies, CLO has pioneered technology that revolutionizes the manner with which services are delivered to adults with disabilities. PMID- 25729511 TI - SkillsTM. AB - The SKILLS curriculum is a web-based curriculum of (4k) targets for designing and managing applied behavior analysis-based treatment programs for children with autism and related disorders. PMID- 25729512 TI - Achilles tendinosis: treatment options. AB - Athletes usually complain of an ongoing or chronic pain over the Achilles tendon, but recently even non-athletes are experiencing the same kind of pain which affects their daily activities. Achilles tendinosis refers to a degenerative process of the tendon without histologic or clinical signs of intratendinous inflammation. Treatment is based on whether to stimulate or prevent neovascularization. Thus, until now, there is no consensus as to the best treatment for this condition. This paper aims to review the common ways of treating this condition from the conservative to the surgical options. PMID- 25729513 TI - External fixation using femoral less invasive stabilization system plate in tibial proximal metaphyseal fracture. AB - BACKGROUND: The locking plates are often used for internal fixation of closed tibial fractures. The use of a locking plate as an external fixator is still controversial, particularly for closed fractures. The purpose of this study is to evaluate the results of external fixation using the femoral less invasive stabilization system (LISS) plate in proximal metaphyseal fractures of the tibia. METHODS: We prospectively evaluated 35 patients (26 males and 9 females) with a mean age of 42 years (range, 21 to 62 years) who presented with fresh tibial proximal metaphyseal fractures. According to the AO Foundation and Orthopaedic Trauma Association (AO/OTA) classification, the fractures were identified as type 41-A2 in 18 cases and type 41-A3 in 17 cases, including 25 closed fractures and 10 open fractures. The femoral LISS plate was used to fix these fractures, which was placed on the anteromedial aspect of the tibia as an external fixator. The mean follow-up period was 18 months (range, 13 to 22 months). RESULTS: All fractures healed in a mean time of 14 weeks (range, 10 to 20 weeks). There was no case of nonunion, deep infection, and loosening of screws and plates. One month after the appearance of cortical bridging on biplanar radiographs, the locking plate was removed within 3 minutes in the clinic without any difficulty. According to the Hospital for Special Surgery (HSS) knee scoring system and American Orthopaedic Foot & Ankle Society (AOFAS) ankle scoring system, the mean HSS score was 91 (range, 85 to 100) and 98 (range, 93 to 100), and the mean AOFAS score was 94 (range, 90 to 100) and 98 (range, 95 to 100) at 4 weeks postoperatively and final follow-up, respectively. CONCLUSIONS: For proximal metaphyseal fracture of the tibia, external fixation using the femoral LISS plate is a safe and reliable technique with minimal complications and excellent outcomes. Its advantages include ease of performing the surgery, use of a less invasive technique, and convenience of plate removal after fracture healing. PMID- 25729514 TI - Paratrooper's ankle fracture: posterior malleolar fracture. AB - BACKGROUND: We assessed the frequency and types of ankle fractures that frequently occur during parachute landings of special operation unit personnel and analyzed the causes. METHODS: Fifty-six members of the special force brigade of the military who had sustained ankle fractures during parachute landings between January 2005 and April 2010 were retrospectively analyzed. The injury sites and fracture sites were identified and the fracture types were categorized by the Lauge-Hansen and Weber classifications. Follow-up surveys were performed with respect to the American Orthopedic Foot and Ankle Society ankle-hindfoot score, patient satisfaction, and return to preinjury activity. RESULTS: The patients were all males with a mean age of 23.6 years. There were 28 right and 28 left ankle fractures. Twenty-two patients had simple fractures and 34 patients had comminuted fractures. The average number of injury and fractures sites per person was 2.07 (116 injuries including a syndesmosis injury and a deltoid injury) and 1.75 (98 fracture sites), respectively. Twenty-three cases (41.07%) were accompanied by posterior malleolar fractures. Fifty-five patients underwent surgery; of these, 30 had plate internal fixations. Weber type A, B, and C fractures were found in 4, 38, and 14 cases, respectively. Based on the Lauge Hansen classification, supination-external rotation injuries were found in 20 cases, supination-adduction injuries in 22 cases, pronation-external rotation injuries in 11 cases, tibiofibular fractures in 2 cases, and simple medial malleolar fractures in 2 cases. The mean follow-up period was 23.8 months, and the average follow-up American Orthopedic Foot and Ankle Society ankle-hindfoot score was 85.42. Forty-five patients (80.36%) reported excellent or good satisfaction with the outcome. CONCLUSIONS: Posterior malleolar fractures occurred in 41.07% of ankle fractures sustained in parachute landings. Because most of the ankle fractures in parachute injuries were compound fractures, most cases had to undergo surgical repairs. PMID- 25729515 TI - The Targon FN system for the management of intracapsular neck of femur fractures: minimum 2-year experience and outcome in an independent hospital. AB - BACKGROUND: The Targon FN implant was developed in 2007 to treat intracapsular neck of femur fractures. Early results from the design centre have shown good results in terms of fracture complications. We wished to see if these results can be reproduced in an independent institution. METHODS: The records of consecutive patients, treated with this implant between 2008 and 2011 at Queen Elizabeth Hospital, were identified and collected for this study. Operations were performed by all grades of surgeons under supervision as appropriate. These patients went on to have both clinical and radiological assessment for fracture healing and function. RESULTS: Fifty-one patients were identified with 43 patients available for final follow-up. The average age was 66 years with a minimum follow-up of 24 months. A non-union rate of 0% in the undisplaced fracture group and 1 in 12 (8%) in the displaced fracture group was observed. An avascular necrosis rate of 6% and 8% was observed for undisplaced and displaced fracture types, respectively. No significant change in premorbid to postoperative ambulation was observed and there was no wound complication. CONCLUSIONS: Our study shows similar results with those of the design centre and which are superior to those currently found in the literature for the more traditional fixation methods. It also shows that the promising results with this new implant as seen from the design institutions can be reproduced by all cadres of surgeons in non-specialist practice. PMID- 25729516 TI - Modified Stoppa approach for surgical treatment of acetabular fracture. AB - BACKGROUND: We analyzed the extent of the comminution in the acetabular weight bearing area, the clinical and radiographic results, and the complications after a minimum 2-year follow-up of the modified Stoppa approach for the treatment of acetabular fractures, and we attempted to evaluate the efficacy of the operative technique. METHODS: All of the 22 patients, who needed the anterior approach for the treatment of acetabular fractures at our hospital from November 2007 to November 2010, were subjected to surgery via the modified Stoppa approach. Fracture pattern, operative time, blood loss during the operation, quality of reduction, number of bony fragments in the acetabular weight-bearing area, and postoperative complications were assessed by retrospectively analyzing the medical records and the radiographic examinations. The results after the operation were analyzed based on the criteria of Matta. RESULTS: The clinical results were excellent in 3 cases, good in 13 cases, and poor in 4 cases, while the radiographic results were excellent in 5 cases, good in 13 cases, and poor in 2 cases. Although the quality of reduction and the clinical results according to the extent of comminution were statistically significant (p = 0.03 and p = 0.04, respectively), the radiographic results were not statistically significant (p = 0.74). CONCLUSIONS: It can be concluded that the modified Stoppa approach could be used as an alternative to the classic ilioinguinal approach. In addition, comminution of the acetabular fracture was an important factor causing non anatomic reduction and finally unsatisfactory clinical results. PMID- 25729517 TI - Contemporary ceramic total hip arthroplasty in patients with cerebral palsy: does it work? AB - BACKGROUND: Adult patients with cerebral palsy (CP), who have advanced degenerative arthritis of the hip, have been treated with resection arthroplasty and arthrodesis. Although total hip arthroplasty (THA) has also been used as one of the alternative options, there are few studies on contemporary bearings used in THA. Therefore, we evaluated the results of the contemporary ceramic-on ceramic THA in adult patients with CP. METHODS: From January 2005 to December 2007, five adult CP patients (5 hips) underwent THA using contemporary ceramic-on ceramic bearings. All patients were able to stand or ambulate with intermittent use of assistive devices at home. We retrospectively reviewed the series to determine the results of THA in terms of pain relief, improved function, and durability of prosthesis. RESULTS: There were 3 men and 2 women with a mean age of 35.9 years. All patients had pain relief without decline in mobility postoperatively. One hip was dislocated, which was treated successfully with closed reduction and an abduction brace for 2 months. There was no ceramic fracture, loosening, or osteolysis during the mean follow-up of 6.8 years (range, 5.8 to 8.3 years). CONCLUSIONS: Cementless THA using contemporary ceramic-on ceramic bearings is a useful option for the treatment of advanced degenerative arthritis of the hip in ambulatory adults with CP. PMID- 25729518 TI - The result of revision total hip arthroplasty in patients with metallosis following a catastrophic failure of a polyethylene liner. AB - BACKGROUND: Wear cannot be completely prevented after total hip arthroplasty. If severe polyethylene (PE) liner wear develops, the so-called catastrophic failure occurs and metallosis develops. We postulated that longevity of the new implant may be affected after revision surgery for metallosis following a catastrophic failure of a PE liner due to the substantial amount of PE wear particles and infiltration of the metal particles in this catastrophic condition. METHODS: Twenty-three hips of 23 patients were identified because they showed metallosis during revision total hip arthroplasties performed in Seoul National University Hospital between January 1996 and August 2004. They were followed for at least 6.5 years after the index revision total hip arthroplasty. The clinical and radiological results of revision total hip arthroplasties in these patients were evaluated. RESULTS: The median Harris hip score increased from 60 points before revision total hip arthroplasties to 90 points at the final follow-up. Osteolysis was detected at an average of 9.3 years after revision total hip arthroplasties in 13 hips and acetabular cup loosening at average 9.8 years after revision total hip arthroplasties in 9 hips. With radiographic evidence of osteolysis and loosening as the end points, the 15-year survival rates were 28.2% and 56.0%, respectively. CONCLUSIONS: The survival rate of revision total hip arthroplasty in patients with metallosis following a catastrophic failure of a PE liner was low. PMID- 25729519 TI - Advantage of minimal anterior knee pain and long-term survivorship of cemented single radius posterior-stabilized total knee arthroplasty without patella resurfacing. AB - BACKGROUND: The single radius total knee prosthesis was introduced with the advantage of reduced patellar symptoms; however, there is no long-term follow-up study of the same. The purpose of this study was to determine the survival rate of single radius posterior-stabilized total knee arthroplasty and patellofemoral complication rates in a consecutive series. METHODS: Seventy-one patients (103 knees) who underwent arthroplasty without patellar resurfacing using a single radius posterior-stabilized total knee prosthesis were followed up for a minimum 10 years. Clinical evaluation using Knee Society knee and function scores and radiologic evaluation were performed at regular intervals. Anterior knee pain as well as patellofemoral complications were evaluated with a simple questionnaire. The Kaplan-Meier product-limit method was used to estimate survival. RESULTS: Seventeen patients (23 knees) were excluded due to death (12 knees) or lost to follow-up (11 knees). Of the 80 knees enrolled, all femoral components and 78 tibial components were well fixed without loosening at final follow-up. Two revisions were performed because of tibial component loosening and periprosthetic joint infection. One patient with tibial component loosening refused to have revision surgery. No obvious tibial insert polyethylene wear was observed. The survivorships at 132 months were 96.7% using revision or pending revision as end points. Anterior knee pain was present in 6 patients (6 knees, 7.5%) at the latest follow-up. No patellofemoral complication requiring revision was encountered. CONCLUSIONS: The single radius posterior-stabilized total knee prosthesis demonstrated an excellent minimum 10-year survivorship. The low rates of implant loosening and 7.5% of anterior knee pain as a patellofemoral complication are comparable with those reported for other modern total knee prosthesis. PMID- 25729520 TI - Total knee replacement arthroplasty with Buechel and Pappas knee: minimum 2-year follow-up. AB - BACKGROUND: Clinical and radiologic evaluation and analyses of the surgeries using Buechel and Pappas (B-P) knee implants. METHODS: The study was conducted on 60 patients who underwent 94 total knee replacement arthroplasty with B-P knee implants from May 2009 to December 2010. The results were compared to the results of 41 patients who underwent 60 knee joint surgeries using NexGen-LPS implants from January 2008 to August 2009. RESULTS: The American Knee Society score of the B-P knee group increased from an average of 66.9 (clinical score) and 65.5 (functional score) to 93.4 and 90.3, respectively; while those for the NexGen-LPS group increased from an average of 68.8 (clinical score) and 62.4 (functional score) to 86.3 and 76, respectively. The average ranges of motion of the B-P knee group and the NexGen-LPS group were 119.1 degrees and 114.8 degrees , respectively, before surgery and improved to 121.0 degrees and 123.0 degrees at final follow-up after the surgery. The visual analogue scale scores for the B-P knee group and the NexGen-LPS group improved from 4.7 and 4.6 to 1.4 and 1.8, respectively. The flexion contracture also improved from 5.1 degrees and 6.3 degrees to 0.64 degrees and 1.72 degrees . The tibio-femoral angle for the B-P knee group and the NexGen-LPS group also improved greatly after the surgery, from varus 0.34 degrees and 0.73 degrees each to valgus 6.7 degrees and 6.9 degrees , respectively. CONCLUSIONS: The evaluation of more than 2 years of total knee replacement arthroplasty using B-P knee implants showed good results. B-P knee implants showed a relatively higher degree of satisfaction in clinical knee score and less intraoperative bone mass removal than NexGen-LPS implants. PMID- 25729521 TI - The parameters affecting the success of irrigation and debridement with component retention in the treatment of acutely infected total knee arthroplasty. AB - BACKGROUND: The aims of our study were to evaluate the success rate of irrigation and debridement with component retention (IDCR) for acutely infected total knee arthroplasty (TKA) (< 4 weeks of symptom duration) and to analyze the factors affecting prognosis of IDCR. METHODS: We retrospectively reviewed 28 knees treated by IDCR for acutely infected TKA from 2003 to 2012. We evaluated the success rate of IDCR. All variables were compared between the success and failure groups. Multivariable logistic regression analysis was also used to examine the relative contribution of these parameters to the success of IDCR. RESULTS: Seventeen knees (60.7%) were successfully treated. Between the success and failure groups, there were significant differences in the time from primary TKA to IDCR (p = 0.021), the preoperative erythrocyte sedimentation rate (ESR; p = 0.021), microorganism (p = 0.006), and polyethylene liner exchange (p = 0.017). Multivariable logistic regression analysis of parameters affecting the success of IDCR demonstrated that preoperative ESR (odds ratio [OR], 1.02; p = 0.041), microorganism (OR, 12.4; p = 0.006), and polyethylene liner exchange (OR, 0.07; p = 0.021) were significant parameters. CONCLUSIONS: The results show that 60.7% of the cases were successfully treated by IDCR for acutely infected TKA. The preoperative ESR, microorganism, and polyethylene liner exchange were factors that affected the success of IDCR in acutely infected TKA. PMID- 25729522 TI - The importance of proximal fusion level selection for outcomes of multi-level lumbar posterolateral fusion. AB - BACKGROUND: There are few studies about risk factors for poor outcomes from multi level lumbar posterolateral fusion limited to three or four level lumbar posterolateral fusions. The purpose of this study was to analyze the outcomes of multi-level lumbar posterolateral fusion and to search for possible risk factors for poor surgical outcomes. METHODS: We retrospectively analyzed 37 consecutive patients who underwent multi-level lumbar or lumbosacral posterolateral fusion with posterior instrumentation. The outcomes were deemed either 'good' or 'bad' based on clinical and radiological results. Many demographic and radiological factors were analyzed to examine potential risk factors for poor outcomes. Student t-test, Fisher exact test, and the chi-square test were used based on the nature of the variables. Multiple logistic regression analysis was used to exclude confounding factors. RESULTS: Twenty cases showed a good outcome (group A, 54.1%) and 17 cases showed a bad outcome (group B, 45.9%). The overall fusion rate was 70.3%. The revision procedures (group A: 1/20, 5.0%; group B: 4/17, 23.5%), proximal fusion to L2 (group A: 5/20, 25.0%; group B: 10/17, 58.8%), and severity of stenosis (group A: 12/19, 63.3%; group B: 3/11, 27.3%) were adopted as possible related factors to the outcome in univariate analysis. Multiple logistic regression analysis revealed that only the proximal fusion level (superior instrumented vertebra, SIV) was a significant risk factor. The cases in which SIV was L2 showed inferior outcomes than those in which SIV was L3. The odds ratio was 6.562 (95% confidence interval, 1.259 to 34.203). CONCLUSIONS: The overall outcome of multi-level lumbar or lumbosacral posterolateral fusion was not as high as we had hoped it would be. Whether the SIV was L2 or L3 was the only significant risk factor identified for poor outcomes in multi-level lumbar or lumbosacral posterolateral fusion in the current study. Thus, the authors recommend that proximal fusion levels be carefully determined when multi-level lumbar fusions are considered. PMID- 25729523 TI - Radiologic and clinical outcomes of surgery in high grade spondylolisthesis treated with temporary distraction rod. AB - BACKGROUND: Surgical techniques used in the treatment of patients with high grade lumbar spondylolisthesis (> 50% slippage) are usually associated with a great deal of controversies. We aim to evaluate the surgical outcomes of high grade spondylolisthesis treated with an intraoperative temporary distraction rod. METHODS: We retrospectively studied 21 patients (14 females and 7 males), aged 50.4 +/- 9.2 years, who had high grade lumbar spondylolisthesis that was treated with intraoperative temporary distraction rods, neural decompression, pedicular screw fixation, and posterolateral fusion involving one more intact upper vertebra. The mean follow-up period was 39.2 months. Radiologic and clinical outcomes were measured by slip angle, slip percentage, correction rate, Oswestry Disability Index (ODI), visual analogue scale (VAS), patient's satisfaction rate in the pre- and postoperative period. Data were analyzed by SPSS ver. 11.5. RESULTS: Analysis of the preoperative visits and final follow-up visits indicated that surgery could improve ODI, lumbar VAS, and leg VAS from 60.5% to 8.2%, from 6.7 to 2.2, and from 6.9 to 1.3, respectively. Slip angle and slip percentage were also changed from -8 degrees to -15 degrees and from 59.2% to 21.4%, respectively. Mean correction rate at the final follow-up visit was 64.1%. Loss of correction was insignificant and a neurologic complication occurred in one patient due to misplacement of one screw. Excellent and good levels of satisfaction were observed in 90.5% of the patients. CONCLUSIONS: In the surgical treatment of refractory high grade spondylolisthesis, the use of a temporary distraction rod to reduce the slipped vertebra in combination with neural decompression, posterolateral fusion, and longer instrumentation is associated with satisfactory clinical and radiologic outcomes. PMID- 25729524 TI - Perioperative surgical complications and learning curve associated with minimally invasive transforaminal lumbar interbody fusion: a single-institute experience. AB - BACKGROUND: As surgical complications tend to occur more frequently in the beginning stages of a surgeon's career, knowledge of perioperative complications is important to perform a safe procedure, especially if the surgeon is a novice. We sought to identify and describe perioperative complications and their management in connection with minimally invasive transforaminal lumbar interbody fusion (TLIF). METHODS: We performed a retrospective chart review of our first 124 patients who underwent minimally invasive TLIF. The primary outcome measure was adverse events during the perioperative period, including neurovascular injury, implant-related complications, and wound infection. Pseudarthroses and adjacent segment pathologies were not included in this review. Adverse events that were not specifically related to spinal surgery and did not affect recovery were also excluded. RESULTS: Perioperative complications occurred in 9% of patients (11/124); including three cases of temporary postoperative neuralgia, two deep wound infections, two pedicle screw misplacements, two cage migrations, one dural tear, and one grafted bone extrusion. No neurologic deficits were reported. Eight complications occurred in the first one-third of the series and only 3 complications occurred in the last two-thirds of the series. Additional surgeries were performed in 6% of patients (7/124); including four reoperations (two for cage migrations, one for a misplaced screw, and one for an extruded graft bone fragment) and three hardware removals (one for a misplaced screw and two for infected cages). CONCLUSIONS: We found perioperative complications occurred more often in the early period of a surgeon's experience with minimally invasive TLIF. Implant-related complications were common and successfully managed by additional surgeries in this series. We suggest greater caution should be exercised to avoid the potential complications, especially when surgeon is a novice to this procedure. PMID- 25729525 TI - Comparison of results between hook plate fixation and ligament reconstruction for acute unstable acromioclavicular joint dislocation. AB - BACKGROUND: In the present study, we aimed to compare clinical and radiographic outcomes between hook plate fixation and coracoclavicular (CC) ligament reconstruction for the treatment of acute unstable acromioclavicular (AC) joint dislocation. METHODS: Forty-two patients who underwent surgery for an unstable acute dislocation of the AC joint were included. We divided them into two groups according to the treatment modality: internal fixation with a hook plate (group I, 24 cases) or CC ligament reconstruction (group II, 18 cases). We evaluated the clinical outcomes using a visual analog scale (VAS) for pain and Constant-Murley score, and assessed the radiographic outcomes based on the reduction and loss of CC distance on preoperative, postoperative, and final follow-up plain radiographs. RESULTS: The mean VAS scores at the final follow-up were 1.6 +/- 1.5 and 1.3 +/- 1.3 in groups I and II, respectively, which were not significantly different. The mean Constant-Murley scores were 90.2 +/- 9.9 and 89.2 +/- 3.5 in groups I and II, respectively, which were also not significantly different. The AC joints were well reduced in both groups, whereas CC distance improved from a mean of 215.7% +/- 50.9% preoperatively to 106.1% +/- 10.2% at the final follow up in group I, and from 239.9% +/- 59.2% preoperatively to 133.6% +/- 36.7% at the final follow-up in group II. The improvement in group I was significantly superior to that in group II (p < 0.001). Furthermore, subluxation was not observed in any case in group I, but was noted in six cases (33%) in group II. Erosions of the acromion undersurface were observed in 9 cases in group I. CONCLUSIONS: In cases of acute unstable AC joint dislocation, hook plate fixation and CC ligament reconstruction yield comparable satisfactory clinical outcomes. However, radiographic outcomes based on the maintenance of reduction indicate that hook plate fixation is a better treatment option. PMID- 25729526 TI - Ligament preserving technique for a locked metacarpophalangeal joint of the index finger. AB - BACKGROUND: Locking of metacarpophalangeal joint (MPJ) of the index finger occurs when volar radial osteophytes of the metacarpal head catch the accessory collateral ligament. We devised a ligament-preserving approach to quickly restore the MPJ motion while protecting the radial collateral ligament. METHODS: We retrospectively reviewed the results of nine patients treated for a locked MPJ of the index finger. In three patients, closed reduction was successful. In six cases, volar radial osteophytes were excised from the metacarpal head using a ligament-preserving technique through a longitudinal incision on the radial side. We analyzed osteophyte shape and height as demonstrated by X-ray and computed tomography (CT). Function was evaluated by examining the range of motion, recurrence, Disabilities of the Arm, Shoulder and Hand (DASH) score, and MPJ stability based on the key pinch strength. One male and eight female patients were followed for an average of 33 months (range, 12 to 65 months); the average age of patients was 41 years (range, 34 to 47 years). The average duration of locking of the MPJ was 23 days (range, 1 to 53 days). RESULTS: The sharp type of osteophytes was identified in six patients and the blunt type of osteophytes was indentified in three patients. The average height of radial osteophytes on the index finger metacarpal was 4.6 +/- 0.4 mm in the axial CT image. At the final follow-up, the average extension limitation decreased from 26 degrees (range, 10 degrees to 45 degrees ) to 0 degrees , and further flexion increased from 83 degrees (range, 80 degrees to 90 degrees ) to 86 degrees . There was no recurrent locking after surgery. The DASH score improved from 24.3 to 7.2. Key pinch strength improved from 67.3% to 90.4%. CONCLUSIONS: We obtained satisfactory outcomes in irreducible locking of the MPJ of the index finger by excising volar radial osteophytes of the metacarpal head using a ligament preserving approach. PMID- 25729527 TI - Prognostic factors of septic arthritis of hip in infants and neonates: minimum 5 year follow-up. AB - BACKGROUND: The authors conducted the present study to identify clinical and radiological prognostic factors in infants and neonates with septic arthritis of the hip. METHODS: The authors retrospectively reviewed the records of 31 patients with septic arthritis of the hip. All of the patients were younger than 18 months old. Follow-up periods ranged from 5 to 17 years. The following potential variables for predicting the prognosis were included in the assessment: gender, age, underlying diseases, duration of symptoms, changes of hip joint in X-ray, concomitant osteomyelitis, elevation of erythrocyte sedimentation rate and C reactive protein, sepsis, pus drainage, synovial fluid culture, and infecting organisms. Clinical and radiological prognoses were analyzed at the final follow up. RESULTS: Univariate analysis demonstrated that radiological prognoses were poorer in patients who had underlying diseases, a longer duration of symptoms, and pus drainage. However, on multivariate analysis, only the variable-duration of symptoms-was found to be statistically related with a poor radiological prognosis. CONCLUSIONS: Although poor prognosis for patients with several underlying diseases and radiological changes has already been established, a favorable outcome might be expected with prompt surgical drainage and appropriate antibiotics. PMID- 25729528 TI - Comorbidity is independently associated with poor outcome in extremity soft tissue sarcoma. AB - BACKGROUND: Comorbidity has not been examined as an independent prognostic factor in soft tissue sarcoma (STS). We examined the prognostic impact of comorbidity on oncologic outcome in STS with an adjustment for possible confounding factors. METHODS: A retrospective review was performed on 349 patients who had undergone surgery for high-grade localized STS of extremity at our institute. Conditions known to alter the risk of mortality, as defined in the Charlson comorbidity index, were classified as comorbidities and 43 patients (12%) had at least one comorbidity at the time of surgery. The association of comorbidity and oncologic outcomes of local recurrence-free survival (LRFS) and disease-specific survival (DSS) were tested with adjustment for confounding factors. RESULTS: Comorbidity was associated with old age, high tumor grade, and large tumor size. The presence of comorbidity was independently associated with poor LRFS and DSS, even after adjusting for confounding factors including age and treatment variables. CONCLUSIONS: Our data suggest that the presence of comorbidity is an independent prognostic factor for extremity STS. PMID- 25729529 TI - Acromioclavicular septic arthritis and sternoclavicular septic arthritis with contiguous pyomyositis. AB - Acromioclavicular (AC) and sternoclavicular (SC) septic arthritis with contiguous pyomyositis are rare, especially in immunocompetent individuals. We report a case of septic AC joint with pyomyositis of the deltoid and supraspinatus muscles and a separate case with septic SC joint with pyomysitis of the sternocleidomastoid muscle. Both patients had similar presentations of infections with Staphylococcus aureus and were successfully treated with surgical incision and drainage followed by prolonged antibiotic therapy. PMID- 25729530 TI - Lessons learnt from an atypical mycobacterium infection post-anterior cruciate ligament reconstruction. AB - Infections following anterior cruciate ligament reconstruction are rare, with no previous reports citing Mycobacterium abscessus as the culprit pathogen. A 22 year-old man presented twice over three years with a painful discharging sinus over his right tibia tunnel site necessitating repeated arthroscopy and washout, months of antibiotic therapy, and ultimately culminating in the removal of the implants. In both instances, M. abscessus was present in the wound cultures, along with a coinfection of Staphyloccocus aureus during the second presentation. Though rare, M. abscessus is an important pathogen to consider in postoperative wounds presenting with chronic discharging sinuses, even in healthy non immunocompromised patients. This case illustrates how the organism can cause an indolent infection, and how the removal of implants can be necessary to prevent the persistence of infection. Coinfection with a second organism is not uncommon and necessitates a timely change in treatment regime as well. PMID- 25729531 TI - Anterior knee pain in patients with cerebral palsy. PMID- 25729532 TI - Some risk factors associated with Acid-alcohol-fast bacilli in patients with suspected pulmonary tuberculosis in jos, central Nigeria. AB - BACKGROUND: Mycobacterium tuberculosis remains a very serious public health problem due to its high tendency of person to person transmission, morbidity, and mortality. This study aimed at determining some risk factors associated with the prevalence of acid-alcohol-fast-bacilli (AAFB) within the study area. MATERIALS AND METHODS: Sputum samples were collected from three hundred and three (303) patients with suspected cases of pulmonary tuberculosis in Jos. The samples were examined using Ziehl Neelson method. Structured questionnaires were administered to obtain some demographic data from patients that consented. Results were tested statistically for significance at p < 0.05 using Chi-square test. RESULTS: Out of the samples examined, 29 (9.60%), were positive for AAFB. The study showed that the prevalence of smear-positive increased with increase in number of persons sharing the same room. Statistically the study reveals that some risk factors such as alcoholism, cigarette smoking and number of persons staying in a household had a significant effects on the prevalence (p < 0.05),while HIV status had no significant effect on the prevalence (p > 0.05). CONCLUSION: There was high prevalence of AAFB in the study area especially among people living in poor/congested housing facilities and people with HIV/AIDS. This calls for more collaborative efforts and political will by government and non-governmental agencies in order to eradicate the infection rate within the area, and the country at large. PMID- 25729533 TI - Prevalence Pattern and Determinants of Disclosure of HIV Status in an Anti Retroviral Therapy Clinic in the Niger Delta Region of Nigeria. AB - BACKGROUND: In order to advance the extent of self-disclosure of HIV sero-status in Nigeria, we evaluated the prevalence, pattern and determinants of disclosure of HIV status amongst adult patients in a hospital in the Niger Delta. MATERIALS AND METHODS: In a three month cross sectional study undertaken in March 2012, the demographic and clinical data as well as HIV sero-status disclosure frequency and pattern were obtained using a pre-tested questionnaire from consenting HIV infected adults attending the Anti-Retroviral Therapy Clinic in the Niger Delta. Independent determinants of HIV disclosure to current sexual partner were determined using an unconditional logistic model. P<0.05 was considered statistically significant. RESULTS: A total of 260 patients were studied out of which 184(71%) were females. Disclosure to current sexual partner was found to be 62.0% and students had the least disclosure rate. Majority of study participants preferred to disclose to family members (57%) than past sexual partner (2.5%) or friend (4.9%). Although HIV disclosure was significantly associated with male sex, living with sexual partner, partner being HIV positive; the only independent determinants of HIV disclosure were partner being on ART (OR-12.7, 95% CI 1.2 132.7) and being currently married (OR-8.8, 95% CI 2.1-36.8). CONCLUSION: The results of our study suggest low rate of HIV status disclosure among HIV infected patients in the Niger Delta. We found that receiving ART and being currently married promoted disclosure. There is need for clinicians and policy makers to foster disclosure of HIV sero-status in Nigeria especially among HIV infected students and unmarried sexual partners. PMID- 25729534 TI - Investigation of an outbreak of acute respiratory disease in cote d'ivoire in april 2007. AB - BACKGROUND: This study aim was to investigate an outbreak of human cases of unexplained influenza-like illness and fatal acute respiratory infection (ARI), with simultaneous poultry illness and high mortality raising concerns of possible influenza A (H5N1), virus in Cote d'Ivoire in February and March 2007. MATERIALS AND METHODS: To investigate the outbreak, we conducted active surveillance in the community and reviewed health registries. Persons meeting the case definition were asked to provide nasopharyngeal specimens. On the basis of clinical and epidemiological information, specimens were tested using conventional RT-PCR for the M gene of the influenza viruses and hemagglutinin H5 of avian influenza A (H5N1), virus; negative samples were tested for other respiratory viruses. Specimens from healthy animals were also collected. RESULTS: Between October 2006, and February 2007, 104 suspected cases of Acute Respiratory Disease that included; 31 deaths recorded. We collected and tested 73 nasopharyngeal specimens; of which, 2, were positive for human Coronavirus OC43 and 1 for influenza C virus. No pathogens were identified in animal specimens. CONCLUSIONS: The investigation quickly ruled out influenza A (H5N1), virus as the cause and found laboratory-confirmed cases of influenza C virus and human Coronavirus OC 43 for the first time in both Cote d'Ivoire and in a Sub-Saharan African country. However we were not able to show that these viruses caused the outbreak. Monitoring of influenza viruses must be a priority but other respiratory viruses and non-viral causes may be of interest too. PMID- 25729535 TI - Evaluation of IgG Antibodies Against Respiratory Syncytial Virus (RSV), and Associated Risk Factors for Severe Respiratory Tract Infections in Pre-School Children in North-Central, Nigeria. AB - BACKGROUND: Childhood mortality and morbidity due to RSV is increasing. Our current study was aimed at determining the sero-prevalence rate of RSV IgG antibodies and investigates certain known risk factors for RSV disease severity in infants and pre-school children presenting with various forms of respiratory tract infections in Ilorin, Nigeria. MATERIALS AND METHODS: About 280, children and 30, aged matched controls were enrolled into the study at the specialist hospital Ilorin. Blood testing for anti RSV IgG was done using a commercial ELISA kit by IVD Research Inc(r) Carlsbad. California U.S.A. Information regarding Nutritional status, socio-economic status and other demographic variables were collected. RESULTS: A prevalence rate of 85.7% was recorded among tested children and 23.3%, in controls, across age groups and gender. A statistically significant difference in age groups were recorded among patients with LRTI, (p <0.05), age <1 41%, age 1 <5, 27.6%. This was also the case for children with SRTI (Pneumonia and Bronchiolitis), with age < 1yr, 9%, and 1 <5yr, 19.8%. Analysed risk factors for disease severity showed thatnutritional status of children were statistically significant for disease severity, p-value, 0.039 (Chi square test). CONCLUSIONS: We report a high level of exposure to RSV in infancy and early childhood among children from a representative population in a major central Nigerian City, further studies into neutralising antibody levels and subtype distribution of RSV are advocated. PMID- 25729536 TI - Prevalence of hepatitis C virus antibody among undergraduates in ogbomoso, southwestern Nigeria. AB - BACKGROUND: This study was conducted to determine the prevalence of hepatitis C virus antibody (anti-HCV), among a healthy university undergraduate population in south-western Nigeria. MATERIALS AND METHODS: Relevant medical information of students who underwent the post-admission screening exercise for the year 2012, at the Ladoke Akintola University of Technology (LAUTECH), Health Center, Ogbomoso were extracted from the laboratory log book. All tests were done using rapid anti-HCV test kit by Health - Chem diagnostics, USA. A total of 1,572 students were included in the study. The mean age was 19.61 (+/- 2.75) years while the age range was 15-50 years. A total of 821 (52.20%), of the subjects were males while 751 (47.80%) were females. More than ninety nine percent (99.90%) of the subjects were aged 15-30 years, whereas those aged >=31 years were comparatively few (0.60%). RESULTS: Of the 1572 students, 6 tested positive, giving an overall prevalence of 0.40%. Three (0.37%) of the 821 male subjects tested positive while 3(0.40%) also of the 751 female subjects tested positive. Age-group 21-30 years had the highest prevalence of anti -HCV (0.50%), followed by age-groups <= 20 years with 0.30% prevalence. None of the subjects in age groups 31-40 and >= 41 years tested positive. CONCLUSION: These observed differences were not statistically significant. The prevalence of Hepatitis C Virus is low among the young healthy undergraduate population in the south - western region of Nigeria. PMID- 25729537 TI - Molecular detection of measles virus from children during a sporadic outbreak in two semi-urban areas in Nigeria. AB - BACKGROUND: According to the World Health Organization (WHO), African region accounts for 36% of deaths caused by measles worldwide. Nigeria has, over the years, recorded the highest average annual measles incidence per 100,000 populations in Africa. Measles epidemics have consistently been reported in northern Nigeria, but not in the South; reports of reduced protective haemagglutination inhibition antibody titers among children in Ibadan, southern Nigeria was made. Investigation of the viral agent responsible for the disease outbreak among children presenting with rash in two semi urban areas in southern Nigeria was carried out to confirm the etiology of the disease. METHODOLOGY: Twenty six throat swabs (TS), and nineteen urine samples were collected from twenty six children residing in Onireke and Sabo areas of Ibadan following the report of an outbreak of rashes among children. Active case finding with the support of community leaders was used to locate the affected children. Multiplex reverse transcriptase polymerase chain reaction (MRT-PCR), was used to identify the agent. RESULTS: 21 of the 26 children screened tested positive for measles virus, but none was positive for Rubella virus. There was significant association between measles infection, and households with higher number of persons. CONCLUSION: Mass measles vaccination that targets overcrowded, rural and inaccessible areas is needed to increase herd immunity. Public health enlightenment on the benefits of vaccination is encouraged. PMID- 25729538 TI - Prevalence and determinants of occupational exposures to blood and body fluids among health workers in two tertiary hospitals in Nigeria. AB - BACKGROUND: Healthcare associated infections among health workers commonly follow occupational exposures to pathogens infecting blood or body fluids of patients. We evaluated the prevalence and determinants of occupational exposures to blood/body fluids among health workers in two tertiary hospitals in Nigeria. METHODS: In a cross section study undertaken in two tertiary hospitals in North central and South-south Nigeria in 2011, a structured self-administered questionnaire was used to obtain demographic data and occupational exposures to blood/body fluids in the previous year from doctors, nurses and laboratory scientists. Independent predictors of occupational exposures were determined in an unconditional logistic regression model. RESULTS: Out of 290 health workers studied, 75.8%, 44.7%, 32.9%, 33.9% and 84.4% had skin contact with patient's blood, needle stick injuries, cut by sharps, blood/body fluid splashes to mucous membranes and one or more type of exposures respectively. Ninety one percent, 86%, 71.1%, 87.6%, 81.3%, and 84.4% of house officers, resident doctors, consultant doctors, staff nurses, principal/chief nursing officers and laboratory scientists, respectively had one or more type of exposures in the previous year (P>0.05). Professional group was found to be the only independent predictor of cut by sharps. House officers and nurses had higher and more frequent occupational exposures than other professional groups. CONCLUSION: Our results suggest high rates of occupational exposures to blood/body fluid among health workers in Nigeria, especially among newly qualified medical doctors and nurses. Health facilities in Nigeria ought to strengthen infection prevention and control practices while targeting high risk health workers such as house officers and nurses. PMID- 25729539 TI - The relationship between the serum levels of ferritin and the radiological brain injury indices in patients with spontaneous intracerebral hemorrhage. AB - OBJECTIVES: Preclinical studies show that iron plays a key role in mediating neuronal injury. This study was performed in order to identify the relationship between the serum level of ferritin and severity of the brain injury which occur after an Intracerebral hemorrhage (ICH). MATERIALS AND METHODS: This was a cross sectional descriptive - analytic study, which was conducted on those patients who had suffered from an ICH and had attended Poursina Hospital. The Serum levels of ferritin were measured at admittance. A Cranial CT scan was performed at admission and also 72 hr afterward. Hematoma and edema surrounding the hematoma volumes were also measured at entrance and 72 hr afterward. Data analysis was carried out by a descriptive - analytic statistics approach and calculated later on by the Spss-20 software. RESULTS: In this investigation, 63 patients were studied, from which 34 (54%) were male and 29 (46%) female. The average age of the patients was 69.7+/- 11.9 (Min 43 and Max 94 years old). A significant relationship was observed between the level of ferritin and the edema volume surrounding the hematoma at first and next 72 hr after the patients were admitted. CONCLUSION: These results delineated the effective role of iron on the edema volume elevation. More studies are essentially urged to ascertain the clinical evaluation of the curing effect of iron chelators in those patients who suffer from ICH. PMID- 25729540 TI - An Iranian familial amyotrophic lateral sclerosis pedigree with p.Val48Phe causing mutation in SOD1: a genetic and clinical report. AB - OBJECTIVES: Amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disorder, is the most common motor neuron disease in European populations. Approximately 10% of ALS cases are familial (FALS) and the other patients are considered as sporadic ALS (SALS). Among many ALS causing genes that have been identified, mutations in SOD1 and C9orf72 are the most common genetic causes of the disease. In Iranian patients, it has been shown that SOD1, as compared to C9orf72, plays a much more prominent role. To date, more than 170 mutations have been reported in SOD1. Genotype/phenotype correlation with respect to either different causative genes or different mutations of a specific gene has not been well established. MATERIALS AND METHODS: Five exons of SOD1 and flanking intronic sequences of an Iranian FALS proband were screened for mutations by direct sequencing. Also, the clinical features of the proband were described. RESULTS: Heterozygous p.Val48Phe causing mutation was identified in SOD1. Age at onset was 29 years and site of the first presentation was the lower extremity in the proband. CONCLUSION: The p.Val48Phe causing mutation appears to cause early onset of ALS. PMID- 25729541 TI - Chinese green tea consumption reduces oxidative stress, inflammation and tissues damage in smoke exposed rats. AB - OBJECTIVES: One cause of cigarette smoking is oxidative stress that may alter the cellular antioxidant defense system, induce apoptosis in lung tissue, inflammation and damage in liver, lung, and kidney. It has been shown that Chinese green tea (CGT) (Lung Chen Tea) has higher antioxidant property than black tea. In this paper, we will explore the preventive effect of CGT on cigarette smoke-induced oxidative damage, apoptosis and tissues inflammation in albino rat model. MATERIALS AND METHODS: Albino rats were randomly divided into four groups, i.e. sham air (SA), cigarette smoke (CS), CGT 2% plus SA or plus CS. The exposure to smoking was carried out as a single daily dose (1 cigarette/rat) for a period of 90 days using an electronically controlled smoking machine. Sham control albino rats were exposed to air instead of cigarette smoke. Tissues were collected 24 hr after last CS exposure for histology and all enzyme assays. Apoptosis was evidenced by the fragmentation of DNA using TUNEL assay. RESULTS: Long-term administration of cigarette smoke altered the cellular antioxidant defense system, induced apoptosis in lung tissue, inflammation and damage in liver, lung, and kidney. All these pathophysiological and biochemical events were significantly improved when the cigarette smoke-exposed albino rats were given CGT infusion as a drink instead of water. CONCLUSION: Exposure of albino rat model to cigarette smoke caused oxidative stress, altered the cellular antioxidant defense system, induced apoptosis in lung tissue, inflammation and tissues damage, which could be prevented by supplementation of CGT. PMID- 25729542 TI - Oxytocin alleviates cisplatin-induced renal damage in rats. AB - OBJECTIVES: The purpose of the present study was to investigate the protective effect of oxytocin on cisplatin (CP)-induced renal damage in rats. MATERIALS AND METHODS: Fourteen adult Sprague Dawley rats, weighing 200 to 210, were administered by cisplatin (CP, 2 mg/kg/day) twice a week for five weeks. Then, they were randomly divided into two groups and treated with either saline (1 ml/kg/day) or OT (200 ug/kg/day) for five weeks. Seven rats served as control group. At the end of the treatment period, animals were sacrificed and their kidneys were assessed histologically. In addition, C-reactive protein (CRP), TGF beta and Akt expression were evaluated immunohistochemically. RESULTS: Both tubules and glomeruli were found to be severely damaged with marked medullary tubulo-interstitial inflammation due to chronic cisplatin exposure, particularly in the salinetreated group (Group 1) compared to control group. Oxytocin treatment spared renal-tissue significantly by suppressing CRP and TGF-beta , and enhancing Akt expression. CONCLUSION: CONCLUSION: We conclude that renal damage due to cisplatin toxicity was prevented to a great extent by the anti inflammatory effect of oxytocin. PMID- 25729543 TI - Gabapentin enhances anti-nociceptive effects of morphine on heat, cold, and mechanical hyperalgesia in a rat model of neuropathic pain. AB - OBJECTIVES: Neuropathic pain is caused by lesions or diseases affecting the somatosensory system and often responds poorly to typical medications. In this study, we evaluated anti-nociceptive effects of morphine, gabapentin and their combination on heat hyperalgesia, cold and mechanical allodynia in chronic constriction injury (CCI) model of neuropathic pain in rats. MATERIALS AND METHODS: Morphine (2, 4 and 8 mg/kg) and gabapentin (5, 10 and 20 mg/kg) were administered either alone or in combination (morphine 2 mg/kg and gabapentin 5 mg/kg). RESULTS: Our results showed that morphine and gabapentin alone produce anti-nociceptive effects at higher doses (morphine 4 and 8 mg/kg and gabapentin 10 and 20 mg/kg) whereas their combination resulted in better analgesia at lower doses as compared to other treatment groups (morphine 2 mg/kg or gabapentin 5 mg/kg). CONCLUSION: These findings suggest that gabapentin potentiates the analgesic effects of morphine in the chronic constriction injury (CCI) model of neuropathic pain and combination of these drugs may be considered as a beneficial treatment for neuropathic pain. PMID- 25729544 TI - Enhancement of transdermal delivery of ibuprofen using microemulsion vehicle. AB - OBJECTIVES: The objective of this study was to find a stable microemulsion vehicle for transdermal delivery of ibuprofen to improve the skin permeability. MATERIALS AND METHODS: Microemulsion was prepared using different sorts of oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were used to evaluate the microemulsion domain. The effects of oleic acid and surfactant mixture on skin permeation of ibuprofen were evaluated with excised skins. RESULTS: The optimum formulation F3 consisting of 6% oleic acid, 30% Cremophor RH40/Transcutol P (2:1, w/w) and 59% water phase, showed a high permeation rate of 42.98 ug/cm(2)/hr. The mean droplet size of microemulsion was about 43 nm and no skin irritation signs were observed on the skin of rabbits. CONCLUSION: These results indicated that this novel microemulsion is a useful formulation for the transdermal delivery of ibuprofen. PMID- 25729545 TI - Expression profile of ZFX isoform3/variant 5 in gastric cancer tissues and its association with tumor size. AB - OBJECTIVES: Previous studies demonstrate that changes in pre-mRNA splicing play a significant role in human disease development. Furthermore, many cancer associated genes are regulated by alternative splicing. There are mounting evidences that splice variants which express predominantly in tumors, have clear diagnostic value and may provide potential drug targets. Located on the X chromosome, ZFX gene functions as a transcription regulator for self-renewal of stem cells. This gene has 5 splice variants that encode 3 isoforms. In the present study, we evaluated the clinicopathological relevance of the expression of ZFX isoform 3/variant 5 gene in gastric carcinoma. MATERIALS AND METHODS: A total of 60 tumoral and non-tumoral gastric specimens were evaluated for ZFX isoform 3/variant 5 gene expression using quantitative real-time PCR. RESULTS: Our results showed that the expression of ZFX isoform 3/variant 5 transcript was heterogeneous in gastric specimens. We further showed that there was a positive correlation between the variant expression and tumor size, but not with other clinicopathological features of gastric tumors. CONCLUSION: This report shows that the expression of ZFX isoform 3/variant 5 transcript was heterogeneous in gastric specimens. Furthermore, there was no significant association between ZFX isoform 3/variant 5 expression and most of clinicopathological features of gastric tumors except for a positive correlation with tumor size. The elucidation of the precise molecular mechanisms governed by the ZFX isoforms/variants needs further investigation. PMID- 25729546 TI - Engraftment of plasma membrane vesicles into liposomes: A new method for designing of liposome-based vaccines. AB - OBJECTIVES: One of the major challenges in the field of vaccine design is choosing immunogenic antigens which can induce a proper immune response against complex targets like malignant cells or recondite diseases caused by protozoan parasites such as leishmaniasis. The aim of this study was to find a way to construct artificial liposome-based cells containing fragments of target's cell membrane. This structure not only mimics the real biological properties of proteins in the cell membrane of target cells, but also may induce the required immune responses, which culminate in eradication of target cells. MATERIALS AND METHODS: Five different techniques have been investigated to engraft the plasma membrane's vesicles (PMVs) derived from a characterized Leishmania parasite into liposomes. The most efficient method was tested again on the PMVs derived from well-known breast cancer cell line SK-BR-3. The percentage of engraftment was determined by two-color flowcytometry after staining the engrafted dioctadecyl 3,3,3'3'-tetramethylindocarbocyanine DiI-labeled liposomes with FITC-labeled PMVs. RESULTS: Among the investigated techniques, freeze-drying method with 91+/ 2% and 90+/-3% of engraftment for Leishmania and SK-BR-3 derived PMVs, respectively, showed superiority over the other methods. In addition, after 9 weeks storage in refrigerator, freeze-dried fused particles kept their original size (660+/-350 nm) and fusion efficiency (94+/-3%). CONCLUSION: Among five different engraftment techniques, freeze-drying is preferred over the other methods due to its simplicity, more fusion efficiency and stability of produced particles during storage. PMID- 25729547 TI - Changing pattern of epithelial cell abnormalities using revised Bethesda system. AB - OBJECTIVES: In developing countries and worldwide cervical cancer is an important cause of female mortality. Reports describing the frequency and pattern of abnormal Pap smears in Saudi Arabia, using the revised Bethesda system (RBS) are very few. The current study was conducted to explore the changing pattern of epithelial cell abnormalities (ECA) detected in Pap smears (PS) in females of the Western region of Saudi Arabia at King Abdulaziz University Hospital, Jeddah using the RBS. MATERIALS AND METHODS: A retrospective study was designed to review all the PSs from the archives of Cytopathology Department at King Abdulaziz University Hospital, starting from January 2000 to October 2012 using RBS. Cytological aspects of PSs were reviewed with age distribution. RESULTS: Of the 15805 PS, 84 (0.53%) unsatisfactory smears were excluded. There were 2295 cases (14.52%) with ECA. In the abnormal squamous cell category the distribution of lesions was as follows: Atypical squamous cells of indeterminate significance (ASC-US) were 7.1%; atypical squamous cells, cannot exclude high squamous intraepithelial lesion (ASC-H) were 1.08%; low grade squamous intraepithelial lesion (LSIL) including human papillomavirus was 2.2%, high grade squamous intraepithelial lesion (HSIL) was 0.8% and high grade squamous intraepithelial lesion with suspicious invasion was 0.06% smears. The mean age (MA) incidence was 39,43,45,46 and 45 years respectively. CONCLUSION: The percentage of abnormal PS is increasing (14.52%) over the last decade. This increase is evident by different studies conducted across Saudi Arabia. Under present circumstances the need for mass screening. PMID- 25729548 TI - Vitamin D3 influence the Th1/Th2 ratio in C57BL/6 induced model of experimental autoimmune encephalomyelitis. AB - OBJECTIVES: Multiple Sclerosis (MS) is known as a progressive inflammatory CNS disease. Cytokines belong to Th1 or Th2 family and inflammatory cells, play significant role in pathophysiology of MS. Thus, any treatment supposed to influence the relation between Th1 to Th2 cytokines expression. Although vitamin D has been prescribed as a therapeutic supplement of MS for a long time, it is not clear how much it may affect the Th1/Th2 ratio. To answer this question the present research was designed. MATERIALS AND METHODS: Thirty C57BL/6 adult female mice were used. The animals were randomly divided into trial and control groups. Experimental Autoimmune Encephalomyelitis (EAE) modeling for MS and clinical scoring as cited by others was used. Based on scoring and step of the disease vitamin D3 prescription (5 mg/kg) started and continued for three weeks. RESULTS: By using ELISA and RT-PCR the brain level of TNF-alpha, IL-10, IL-4 and IL-12 determined. Significant decrease of clinical symptoms in trial group which received vitamin D was seen comparing to control animals (P<0.05). The level of TNF-alpha but not IL-10 significantly decreased following vitamin D3 administration. By comparing the level of Th1 and Th2 Interleukins and counting the ratio of them we found that in treated animals the ratio was significantly less than non-treated (P=0.01). CONCLUSION: According to the results, vitamin D3 may be able to suppress the inflammatory ways that lead to progression of MS. Whether this ability is clinically valuable in human subjects is not clear and needs more clinical research. PMID- 25729549 TI - Analgesic effect of Persian Gulf Conus textile venom. AB - OBJECTIVES: Cone snails are estimated to consist of up to 700 species. The venom of these snails has yielded a rich source of novel peptides. This study was aimed to study the analgesic effect of Persian Gulf Conus textile and its comparison with morphine in mouse model. MATERIALS AND METHODS: Samples were collected in Larak Island. The venom ducts were Isolated and kept on ice then homogenized. The mixture centrifuged at 10000 * g for 20 min. Supernatant was considered as extracted venom. The protein profile of venom determined using 15% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Venom was administered intraperitoneally (IP) to evaluate the LD50 in Swiss albino mice. Different concentrations of Conus textile venom were injected intrathecally to mice to evaluate their analgesic effect in comparison to morphine. Injection was carried out between the L5 and L6 vertebrae. Differences between groups in the first and second phase were tested with Two-Way analysis of variance (ANOVA). RESULTS: SDS PAGE indicated 12 bands ranged between 6 and 180 KDa. Finally, ten ng of Conus crude venom showed the best analgesic activity in formalin test. No death observed up to 100 mg/kg. Analgesic activity of crude venom was more significant (P<0.05) in acute pain than inflammatory pain. The analgesic effect of 10 ng Conus venom was the same as morphine for reduction of inflammatory pain (P=0.27). CONCLUSION: The venom of Persian Gulf Conus textile contains an analgesic component for reliving of acute pain which can lead to find an analgesic drug. PMID- 25729550 TI - Association between HLA-DQB1 alleles and HAM/TSP patients in Khorasan Province. AB - OBJECTIVES: HTLVI-1 is the first human retrovirus with limited endemic regions in the world. The epidemiological studies have shown that the genetic background and immune response to the virus have a significant role in HTLV-I-associated diseases. Among the genes are involved in HTLV-I infection, the role of human leukocytes antigen (HLA) have been studied in different population. In the present study we examined the association between HLA-DQB1 alleles and HTLV-I infection in HAM/TSP patients, HTLV-I carriers and healthy controls in north east of Iran, Mashhad. MATERIALS AND METHODS: The blood samples of 16 patients with HAM/TSP, 20 HTLV-1 carriers, and 30 healthy individuals were taken and DNA was extracted by salting out method. HLA-DQB1 typing was performed using PCR-SSP method and the frequency of HLA-DQB1 alleles were compared by Fischer Exact Test. RESULTS: There was a significant difference between HAM/TSP patients and healthy controls in the frequency of HLA-DQB1*07 (P=0.004, RR=7). Furthermore, we found that possession of HLA- DQB1*02 or HLA-DQB1*05 increased the risk of disease 1.5 times. CONCLUSION: The data presented here suggest that both HLA-DQB1*07 and HLA DQB1*06 are associated with disease development. PMID- 25729551 TI - Effect of renal ischemia-reperfusion on lung injury and inflammatory responses in male rat. AB - OBJECTIVES: Acute kidney injury (AKI), a syndrome characterized by decreased glomerular filtration, occurs in every 1 of 5 hospitalized patients. Renal ischemia-reperfusion, one of the main causes of AKI, is of particular importance in the setting of kidney transplantation. MATERIALS AND METHODS: Sixty male rats were divided into four groups including control, nephrectomy, sham surgery and renal ischemia-reperfusion (IRI) group. The rats were anesthetized with intraperitonealketamin and xylazin. For making IRI group, right nephrectomywas performed, and after a week, the left kidney pedicle was occluded for 45 min for making ischemia that followed by 24 hr reperfusion. At the end of reperfusion phase, the lung tissues were isolated to be used in immunohistochemical and histological assays. Immunohistochemical assay was used to evaluate Bcl-2 and TNF alpha, and hematoxylin-eosin staining assay was used to histopathology. RESULTS: lung tissues injury after renal ischemia-reperfusion was revealed by immunohistochemistry analysis to increase TNF-alpha level and decrease Bcl-2 (an anti-apoptotic protein) level. Lung injury and necrosis was discovered by hematoxylin-eosin staining to be more evident in IRI group than sham and control groups. CONCLUSION: The results demonstrated that increase in TNF-alpha and decrease in Bcl-2 levels in lungs induces the pulmonary inflammatory damage in renal IRI model. PMID- 25729552 TI - Antidiabetic and hypolipidemic effects of Dorema aucheri hydroalcoholic leave extract in streptozotocin-nicotinamide induced type 2 diabetes in male rats. AB - OBJECTIVES: The present study investigated the antidiabetic and hypolipidemic properties of Dorema aucheri leave hydroalcoholic extract in nicotinamide streptozotocin induced type 2 diabetic rats. MATERIALS AND METHODS: nicotinamide/streptozotocin-induced diabetic rats were supplemented orally with three different doses of D. aucheri (100, 200 and 400 mg/kg BW) or glibenclamide (0.25 mg/kg) for 4 weeks. Ultimately, blood of animals has taken and glucose, insulin, lipid profiles, SGPT, alkaline phosphatase, SGOT, leptin levels were assayed. RESULTS: D. aucheri has highly significant blood glucose lowering effect. Administration of the extract to diabetic rats resulted in a remarkable change in serum lipid profiles, insulin and leptin levels relative to diabetic group. Also the extract reversed back the serum levels of SGPT, alkaline phosphatase and SGOT to near normal in treated diabetic rats. CONCLUSION: D. aucheri could be useful in treatment of diabetes. Moderate dose of D. aucheri (200 mg/kg) was more effective than the others. PMID- 25729553 TI - Effects of Lactobacillus plantarum A7 with probiotic potential on colon cancer and normal cells proliferation in comparison with a commercial strain. AB - OBJECTIVES: Several beneficial effects have been attributed to the probiotic lactic acid bacteria. It was determined that lactobacilli can exert antiproliferative effects on the various cancer cell lines including colon cancer. Effects of lactic acid bacteria on colon cancer may vary from strain to strain and there is a need to find the new probiotic strains with tumor suppressing properties through in vitro studies. MATERIALS AND METHODS: Anti proliferative activities of heat-killed cells and cell-free supernatants of a native strain of Lactobacillus plantarum A7 and a commercial strain of lactobacillus rhamnosus GG were assessed on human colon cancer cell lines (Caco-2 and HT-29) and normal cells (L-929), using MTT assay. Cells were seeded at 2*10(4) cells/mlin 96 well plates and incubated for 24 hr. Then heat-killed cells (OD620: 0.025, 0.0.05, 0.1) and cell-free supernatants of bacteria were added at concentration of 2.5, 5 and 10 mg/ml. After 48 hr incubation MTT (5 mg/ml) was added and the absorbance was measured at 540 nm using ELISA plate reader. RESULTS: Results showed that heat-killed cells and cell-free supernatants of both probiotic strains reduced the growth rate of cancer and normal cells. These results suggested that anti-proliferative effect may not be an exclusive characteris ticwhich is dedicated to officially approved probiotics. CONCLUSION: L. plantarum A7 could be considered as colon cancer biological product, most likely due to its advantages in significant organic acid production. PMID- 25729554 TI - Structure activity relationship study of Mezzettiasides natural products and their four new disaccharide analogues for anticancer/antibacterial activity. AB - Ten members of the mezzettiaside family of natural products were synthesized and evaluated for anticancer and antibacterial activity. Complete anticancer (H460) and antibacterial (B. subtilis) activities for the ten natural products and four new analogues were found. Comparison to the cleistrioside and cleistetroside classes of natural products were made. PMID- 25729555 TI - Lubiprostone in constipation: clinical evidence and place in therapy. AB - Constipation is one of the most common function bowel disorders encountered by primary care providers and gastroenterologists. Disorders of chronic constipation, including irritable bowel syndrome with constipation, chronic idiopathic constipation, and opioid-induced chronic constipation, are associated with significant medical costs and a negative impact on quality of life. Although there is evidence supporting the effectiveness of some over-the-counter laxatives in chronic constipation, currently there is no evidence supporting lifestyle modification, dietary change or over-the-counter laxatives as effective long-term therapy for patients with chronic constipation. Lubiprostone is a prostaglandin derived bicyclic fatty acid available to use for long-term treatment of constipation. Lubiprostone works by increasing intraluminal chloride ion secretion, which results in a passive influx of water and sodium, leading to increased intestinal peristalsis and colonic laxation with decreased intestinal stool transit time. Randomized, double-blind, placebo-controlled trials of lubiprostone in patients with chronic constipation, irritable bowel syndrome and opioid-induced constipation have shown it to be effective and free of serious adverse effects. The most common side effects associated with lubiprostone are mild to moderate nausea and diarrhea. Currently lubiprostone is approved for treatment of chronic constipation and opioid-induced constipation for men and women at 24 ug twice daily and for treatment of irritable bowel syndrome with constipation in women at 8 ug twice daily. Additional research continues to shed light on the molecular mechanisms of lubiprostone and further work may expand its clinical applications. PMID- 25729556 TI - Lifestyle measures in the management of gastro-oesophageal reflux disease: clinical and pathophysiological considerations. AB - Several lifestyle and dietary factors are commonly cited as risk factors for gastro-oesophageal reflux disease (GORD) and modification of these factors has been advocated as first-line measures for the management of GORD. We performed a systematic review of the literature from 2005 to the present relating to the effect of these factors and their modification on GORD symptoms, physiological parameters of reflux as well as endoscopic appearances. Conflicting results existed for the association between smoking, alcohol and various dietary factors in the development of GORD. These equivocal findings are partly due to methodology problems. There is recent good evidence that weight reduction and smoking cessation are beneficial in reducing GORD symptoms. Clinical and physiological studies also suggest that some physical measures as well as modification of meal size and timing can also be beneficial. However, there is limited evidence for the role of avoiding alcohol and certain dietary ingredients including carbonated drinks, caffeine, fat, spicy foods, chocolate and mint. PMID- 25729558 TI - Assessment of Routine Immunization Coverage in Nyala Locality, Reasons behind Incomplete Immunization in South Darfur State, Sudan. AB - Little is known about the coverage of routine immunization service in South Darfur state, Sudan. Therefore, this study was conducted to determine the vaccination rate and barriers for vaccination. A cross-sectional community-based study was undertaken in Nyala locality, south Darfur, Sudan, including urban, rural and Internal Displaced Peoples (IDPs) population in proportional representation. Survey data were collected by a questionnaire which was applied face to face to parents of 213 children 12-23 months. The collected data was then analyzed with SPSS software package. Results showed that vaccination coverage as revealed by showed vaccination card alone was 63.4% while it was increased to 82.2% when both history and cards were used. Some (5.6%) of children were completely non-vaccinated. The factors contributing to the low vaccination coverage were found to be knowledge problems of mothers (51%), access problems (15%) and attitude problems (34%). Children whose mother attended antenatal care and those from urban areas were more likely to complete their immunization schedule. In conclusion, the vaccination coverage in the studied area was low compared to the national coverage. Efforts to increase vaccination converge and completion of the scheduled plan should focus on addressing concerns of caregivers particularly side effects and strengthening the Expanded Programmer on Immunization services in rural areas. PMID- 25729557 TI - Management of arthropathy in inflammatory bowel diseases. AB - The most common extra-intestinal manifestation in patients with inflammatory bowel disease (IBD) is articular involvement, with a prevalence ranging between 17% and 39%. It is frequently characterized by an involvement of the axial joints but may also be associated with peripheral arthritis. The target of therapy in the management of arthritis associated with IBD is to reduce the inflammation and prevent any disability and/or deformity. This requires active cooperation between gastroenterologist and rheumatologist. The treatment of axial involvement has focused on the combination of exercise with nonsteroidal anti-inflammatory drugs. Immunomodulators have been efficacious in patients with peripheral arthritis and other extra-intestinal manifestations, but they are not effective for the treatment of axial symptoms of spondylitis. Tumor necrosis factor (TNF) alpha inhibitors have been proven to be highly effective in the treatment of IBD patients which are steroid-dependent or refractory to conventional therapy and in patients with associated articular manifestations. The treatment of peripheral involvement and/or enthesitis and/or dactylitis is based on local steroid injections, while sulfasalazine and/or low doses of systemic steroids may be useful in case of inadequate response to intra-articular steroids. Sulfasalazine induces only a little improvement in peripheral arthritis. Immunomodulators such as methotrexate, azathioprine, cyclosporine and leflunomide show their efficacy in some patients with peripheral arthritis and other extra-intestinal components. TNF-alpha inhibitors should be considered the first-line therapeutic approach when moderate-to-severe luminal Crohn's disease or ulcerative colitis is associated with polyarthritis. The aim of this review is to provide a fair summary of current treatment options for the arthritis associated with IBD. PMID- 25729559 TI - De novo asymmetric synthesis of the mezzettiaside family of natural products via the iterative use of a dual B-/Pd-catalyzed glycosylation. AB - The first synthesis of any and all members of the mezzettiaside family of natural products has been achieved. The reported synthesis features the iterative use of the Taylor catalyst in a dual nucleophilic boron/electrophilic palladium catalyzed regioselective glycosylation. In addition, the de novo approach utilizes atomless protecting groups and the minimal use of protecting groups (2 chloroacetates for the synthesis of 10 natural products). These divergent syntheses occurred in a range of 13 to 22 longest linear steps and required only 41 total steps to prepare the entire family of mezzettiasides. PMID- 25729560 TI - Mechanistic analysis of an asymmetric palladium-catalyzed conjugate addition of arylboronic acids to beta-substituted cyclic enones. AB - An asymmetric palladium-catalyzed conjugate addition reaction of arylboronic acids to enone substrates was investigated mechanistically. Desorption electrospray ionization coupled to mass spectrometry was used to identify intermediates of the catalytic cycle and delineate differences in substrate reactivity. Our findings provide evidence for the catalytic cycle proceeding through formation of an arylpalladium(II) cation, subsequent formation of an arylpalladium-enone complex, and, ultimately, formation of the new C-C bond. Reaction monitoring in both positive and negative ion modes revealed that 4 iodophenylboronic acid formed a relatively stable trimeric species under the reaction conditions. PMID- 25729561 TI - Data fraud in clinical trials. AB - Highly publicized cases of fabrication or falsification of data in clinical trials have occurred in recent years and it is likely that there are additional undetected or unreported cases. We review the available evidence on the incidence of data fraud in clinical trials, describe several prominent cases, present information on motivation and contributing factors and discuss cost-effective ways of early detection of data fraud as part of routine central statistical monitoring of data quality. Adoption of these clinical trial monitoring procedures can identify potential data fraud not detected by conventional on-site monitoring and can improve overall data quality. PMID- 25729562 TI - Examination of the genetic basis for sexual dimorphism in the Aedes aegypti (dengue vector mosquito) pupal brain. AB - BACKGROUND: Most animal species exhibit sexually dimorphic behaviors, many of which are linked to reproduction. A number of these behaviors, including blood feeding in female mosquitoes, contribute to the global spread of vector-borne illnesses. However, knowledge concerning the genetic basis of sexually dimorphic traits is limited in any organism, including mosquitoes, especially with respect to differences in the developing nervous system. METHODS: Custom microarrays were used to examine global differences in female vs. male gene expression in the developing pupal head of the dengue vector mosquito, Aedes aegypti. The spatial expression patterns of a subset of differentially expressed transcripts were examined in the developing female vs. male pupal brain through in situ hybridization experiments. Small interfering RNA (siRNA)-mediated knockdown studies were used to assess the putative role of Doublesex, a terminal component of the sex determination pathway, in the regulation of sex-specific gene expression observed in the developing pupal brain. RESULTS: Transcripts (2,527), many of which were linked to proteolysis, the proteasome, metabolism, catabolic, and biosynthetic processes, ion transport, cell growth, and proliferation, were found to be differentially expressed in A. aegypti female vs. male pupal heads. Analysis of the spatial expression patterns for a subset of dimorphically expressed genes in the pupal brain validated the data set and also facilitated the identification of brain regions with dimorphic gene expression. In many cases, dimorphic gene expression localized to the optic lobe. Sex-specific differences in gene expression were also detected in the antennal lobe and mushroom body. siRNA-mediated gene targeting experiments demonstrated that Doublesex, a transcription factor with consensus binding sites located adjacent to many dimorphically expressed transcripts that function in neural development, is required for regulation of sex-specific gene expression in the developing A. aegypti brain. CONCLUSIONS: These studies revealed sex-specific gene expression profiles in the developing A. aegypti pupal head and identified Doublesex as a key regulator of sexually dimorphic gene expression during mosquito neural development. PMID- 25729563 TI - Extracellular vesicles in urine of women with but not without kidney stones manifest patterns similar to men: a case control study. AB - BACKGROUND: The lifetime incidence of kidney stones is about two times greater in men compared to women. Extracellular vesicles (EVs) shed from activated cells are present in the urine and may reflect or even mediate renal physiology and/or pathology. This study was designed to standardize methodology to characterize urinary EVs by digital flow cytometry and to identify possible sex differences in EVs in persons with and without their first symptomatic kidney stones. METHODS: Twenty-four-hour urine collections were obtained from persons presenting with their first kidney stone episode (n = 50 women, 60 men; age 19-76 years) and sex- and age-matched controls from the general population (n = 24 women, 36 men). RESULTS: Standardization: Size of EV was variable within all groups. EV positivity was verified with two fluorophores for surface phosphatidylserine and/or using two different protein markers specific for renal-specific cells. The number of phosphatidylserine- and exosome marker-positive EVs did not correlate with urine osmolality and were similar in fresh vs. frozen and between two sequential urine collections from the same individual. Sex differences: Urine from women controls contained greater (P < 0.05) numbers of EVs positive for phosphatidylserine, exosomes, inflammatory factors and adhesion molecules, and cell-specific markers from different segments of the nephron, renal pelvis, and bladder compared to control men. In contrast, urine from women with kidney stones contained significantly (P < 0.05) lower numbers of EVs derived from podocytes, parietal cells, proximal convoluted tubule, thin and thick loop of Henle, distal tubule, collecting duct, renal pelvis, and bladder compared to control women and contained similar quantities of these types of EVs in men with and without kidney stones. There were also no sex differences in EVs positive for cell adhesion (E cadherin and inter-cellular adhesion molecule-1 [ICAM-1]) molecules. CONCLUSIONS: Unlike women who do not have kidney stones, EVs in urine from women with nephrolithiasis are similar to men with and without kidney stones. Thus, EVs may mediate or reflect aspects of kidney stone pathogenesis and perhaps provide clues regarding sex differences in kidney stone incidence rates. PMID- 25729565 TI - High performance team-based care for persons with chronic conditions. AB - Care for patients with complex chronic conditions such as diabetes requires a coordinated and collaborative team working in partnership with the patient. Israel has taken important steps forward with the development of structured diabetes follow-up by Clalit Health Services, including several measures of diabetes care in the National Program for Quality Indicators in Community Healthcare, and efforts to develop health information exchange and measures of continuity between hospital and community-based care. Achieving even better results will require purposeful development of health care teams to meet the needs of patients with single and multiple chronic conditions, including robust interprofessional education programs for the next generation of health professionals, and developing partnerships between the teams and the patients. PMID- 25729564 TI - Increased microenvironment stiffness in damaged myofibers promotes myogenic progenitor cell proliferation. AB - BACKGROUND: The stiffness of the myogenic stem cell microenvironment markedly influences the ability to regenerate tissue. We studied the effect of damaged myofibers on myogenic progenitor cell (MPC) proliferation and determined whether the structural integrity of the microenvironment contributes to phenotypic changes. METHODS: Individual myofibers were isolated and cultured for 6 days. During this period, the cytoskeleton of myofibers and transcription factors regulating MPC differentiation were characterized by immunostaining. Atomic Force Microscopy (AFM) was performed to measure stiffness of cultured myofibers. Healthy and damaged myofibers, and their associated MPCs, were studied in skeletal muscle from dystrophic and tenotomy mouse models. MPCs were cultured on stiffness-tunable substrates, and their phenotypes were assessed by immunostaining of myogenic transcription factors. RESULTS: We showed that individual myofibers tend to shrink or collapse when cultured ex vivo starting from day 1 and that this is associated with a marked increase in the number of proliferative MPCs (Pax7(+)MyoD(+)). The myofibers collapsed due to a loss of viability as shown by Evans blue dye uptake and the disorganization of their cytoskeletons. Interestingly, collapsed myofibers in mdx skeletal muscles were similar to damaged myofibers in that they lose their viability, have a disorganized cytoskeleton (actin and alpha-actinin), and display local MPC (MyoD(+)) proliferation at their periphery. In a tenotomy model that causes loss of muscle tension, the cytoskeletal disorganization of myofibers also correlated with the activation/proliferation of MPCs. A deeper analysis of collapsed myofibers revealed that they produce trophic factors that influence MPC proliferation. In addition, collapsed myofibers expressed several genes related to the basal lamina. Immunostaining revealed the presence of fibronectin in the basal lamina and the cytoplasm of damaged myofibers. Lastly, using atomic force microscopy (AFM), we showed that collapsed myofibers exhibit greater stiffness than intact myofibers. Growing MPCs on a 2-kPa polyacrylamide-based substrate, exempt of additional microenvironmental cues, recapitulated proliferation and reduced spontaneous differentiation compared to growth on a 0.5-kPa substrate. CONCLUSIONS: Our results support the notion that collapsed or damaged myofibers increase the structural stiffness of the satellite cell microenvironment, which in addition to other cues such as trophic factors and changes in extracellular matrix composition, promotes the proliferation and maintenance of MPCs, required for myofiber repair. PMID- 25729566 TI - The location of the inferior angle of the scapula in relation to the spine in the upright position: a systematic review of the literature and meta-analysis. AB - Practitioners in several of the health care professions use anatomical landmarks to identify spinal levels, both in order to enhance diagnostic accuracy and to specifically target the site of intervention. Authoritative sources usually state the upright inferior scapular angle (IAS) aligns with the spinous process (SP) of T7, but some specify the T7-8 interspace or the T8 SP. The primary goals of this study were to systematically review the relevant literature; and conduct a meta analysis of the pooled data from retrieved studies to increase their statistical power. Electronic searching retrieved primary studies relating the IAS to a spinal level, as determined by an imaging reference standard, using combinations of these search terms: scapula, location, landmark, spinous process, thoracic vertebrae, vertebral level, palpation, and spine. Only primary studies were included; review articles and reliability studies related to scapular position but lacking spinal correlations were excluded. Eight-hundred and eighty (880) articles of interest were identified, 43 abstracts were read, 22 full text articles were inspected, and 5 survived the final cut. Each article (with one exception) was rated for quality using the QUADAS instrument. Pooling data from 5 studies resulted in normal distribution in which the upright IAS on average aligns closely with the T8 SP, range T4-T11. Since on average the IAS most closely identifies the T8 SP in the upright position, it is very likely that health professionals, both manual therapists and others, who have been diagnosing and treating patients based on the IAS = T7 SP rule (the conventional wisdom), have not been as segmentally accurate as they may have supposed. They either addressed non-intended levels, or made numeration errors in their charting. There is evidence that using the IAS is less preferred than using the vertebra prominens, and may be less preferred than using the iliac crest for identifying spinal levels Manual therapists, acupuncturists, anesthesiologists, nurses, and surgeons should reconsider their procedures for identifying spinal sites in light of this modified information. Inaccurate landmark benchmark rules will add to patient variation and examiner errors in producing spine care targeting errors, and confound research on the importance of specificity in treating spinal levels. PMID- 25717362 TI - Deletion of ENTPD3 does not impair nucleotide hydrolysis in primary somatosensory neurons or spinal cord. AB - Ectonucleotidases are membrane-bound or secreted proteins that hydrolyze extracellular nucleotides. Recently, we identified three ectonucleotidases that hydrolyze extracellular adenosine 5'-monophosphate (AMP) to adenosine in primary somatosensory neurons. Currently, it is unclear which ectonucleotidases hydrolyze ATP and ADP in these neurons. Ectonucleoside triphosphate diphosphohydrolases (ENTPDs) comprise a class of enzymes that dephosphorylate extracellular ATP and ADP. Here, we found that ENTPD3 (also known as NTPDase3 or CD39L3) was located in nociceptive and non-nociceptive neurons of the dorsal root ganglion (DRG), in the dorsal horn of the spinal cord, and in free nerve endings in the skin. To determine if ENTPD3 contributes directly to ATP and ADP hydrolysis in these tissues, we generated and characterized an Entpd3 knockout mouse. This mouse lacks ENTPD3 protein in all tissues examined, including the DRG, spinal cord, skin, and bladder. However, DRG and spinal cord tissues from Entpd3 (-/-) mice showed no reduction in histochemical staining when ATP, ADP, AMP, or UTP were used as substrates. Additionally, using fast-scan cyclic voltammetry (FSCV), adenosine production was not impaired in the dorsal spinal cord of Entpd3 (-/-) mice when the substrate ADP was applied. Further, Entpd3 ( /-) mice did not differ in nociceptive behaviors when compared to wild-type mice, although Entpd3 (-/-) mice showed a modest reduction in beta-alanine-mediated itch. Taken together, our data indicate that deletion of Entpd3 does not impair ATP or ADP hydrolysis in primary somatosensory neurons or in dorsal spinal cord. Moreover, our data suggest there could be multiple ectonucleotidases that act redundantly to hydrolyze nucleotides in these regions of the nervous system. PMID- 25717367 TI - Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions. AB - Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such 'hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the 'largest Ebola epidemic, affecting multiple countries in West Africa' ( http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html). PMID- 25717366 TI - Breaking a Guinness World Record on Hand Sanitizing Relay, initiating a call for vital research in overcoming campaign fatigue for hand hygiene. AB - Hand hygiene has been shown to be effective in significantly reducing hospital acquired infections for many years. However it is difficult to maintain and enhance compliance with hand hygiene guidelines. In Hong Kong, we previously reported a strategy to counter campaign fatigue from 50%-55% in 2009-11 to 83% in 2012. Here we report a creative activity that we used to sustain and enhance hand hygiene compliance. In May 2014 we broke the first Guinness World Record for a Hand Sanitizing Relay. A total of 277 participants performed hand hygiene before two official and approved witnesses. Following this team-directed strategy, an increase in hand hygiene compliance was identified in June 2014 in two clinical areas with previously poor compliance. The longer term impact of this strategy remains to be determined. More broadly, further research is urgently needed on meeting the challenge of campaign fatigue, and maintaining and enhancing compliance with hand hygiene guidelines. PMID- 25717367 TI - Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions. AB - Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such 'hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the 'largest Ebola epidemic, affecting multiple countries in West Africa' ( http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html). PMID- 25729571 TI - Viewpoint: a response to "Screening and isolation to control methicillin resistant Staphylococcus aureus: sense, nonsense, and evidence". AB - Surveillance and isolation for the prevention of methicillin-resistant Staphylococcus aureus (MRSA) has become a controversial topic, one that causes heated debate and appears to be surrounded by both politics and industrial conflicts-of-interest. There have been calls from numerous authors for a movement away from rigid mandates and toward an evidence-based medicine approach. However, much of the evidence can be viewed with an entirely different interpretation. Two major studies with negative findings have had an adverse impact on recommendations regarding active detection and isolation (ADI) for MRSA. However the negative findings in these studies can be explained by shortcomings in study implementation rather than the ineffectiveness of ADI. The use of daily chlorhexidine bathing has also been proposed as an alternative to ADI in ICU settings. There are shortcomings regarding the evidence in the literature concerning the effectiveness of daily chlorhexidine bathing. One of the major concerns with universal daily chlorhexidine bathing is the development of bacterial resistance. The use of surveillance and isolation to address epidemics and common dangerous pathogens should solely depend upon surveillance and isolation's ability to prevent further spread to and infection of other patients through indirect contact. At present, there is a preponderance of evidence in the literature to support continuing use of surveillance and isolation to prevent the spread of MRSA. PMID- 25729572 TI - Teacher Burnout: A Comparison of Two Cultures Using Confirmatory Factor and Item Response Models. AB - The present study addresses teacher burnout and in particular cultural differences and similarities in burnout. We used the Maslach Burnout Inventory Education Survey (MBI-ES) as the starting point for developing a latent model of burnout in two cultures; Jamaica W.I. teachers (N= 150) and New York City teachers (N= 150). We confirm a latent 3 factor structure, using a subset of the items from the MBI-ES that adequately fit both samples. We tested different degrees of measurement invariance (model fit statistics, scale reliabilities, residual variances, item thresholds, and total variance) to describe and compare cultural differences. Results indicate some differences between the samples at the structure and item levels. We found that factor variances were slightly higher in the New York City teacher sample. Emotional Exhaustion (EE) was a more informative construct for differentiating among teachers at moderate levels of burnout, as opposed to extreme high or low levels of burnout, in both cultures. In contrast, Depersonalization in the Workplace (DW) was more informative at the more extreme levels of burnout among both teacher samples. By studying the influence of culture on the experience of burnout we can further our understanding of burnout and potentially discover factors that might prevent burnout among primary and secondary school teachers. PMID- 25729573 TI - Recommendations for the early diagnosis of COPD: the AIMAR view. PMID- 25729575 TI - A (1;19) translocation involving TCF3-PBX1 fusion within the context of a hyperdiploid karyotype in adult B-ALL: a case report and review of the literature. AB - BACKGROUND: The t(1;19)(q23;p13), which can result in the TCF3-PBX1 chimeric gene, is one of the most frequent translocations in B-acute lymphoblastic leukemia (B-ALL) and is observed in both adult and pediatric populations at an overall frequency of 6%. It can occur in a balanced or unbalanced form and as a sole abnormality is associated with an intermediate prognosis. Additionally, this translocation is observed in the context of hyperdiploid B-ALL, in which case it is associated with a poor prognosis. However, due to different translocation partner genes at chromosomes 1 and 19, distinct subtypes of hyperdiploid B-ALL with t(1;19)/der(19)t(1;19) are recognized based on the presence or absence of the TCF3-PBX1 fusion gene, but the cytogenetic and etiologic differences between the two remain understudied. FINDINGS: We report a case of an adult with a history of relapsed precursor B-ALL whose conventional cytogenetics showed an abnormal female karyotype with both hyperdiploidy and a t(1;19)(q23;p13). Fluorescence in situ hybridization (FISH) on previously G-banded metaphases using the LSI TCF3/PBX1 Dual Color, Dual Fusion Translocation Probe confirmed the presence of the TCF3-PBX1 gene fusion. CONCLUSIONS: This particular pattern with a TCF3-PBX1 fusion within the context of a hyperdiploid karyotype is seen in B ALL and is usually associated with a poor outcome. This case is one of only a few cases with both hyperdiploidy and a confirmed TCF3-PBX1 fusion, demonstrating the importance of using FISH for proper molecular classification of these cases in order to distinguish them from those with hyperdiploidy but no TCF3-PBX1 fusion gene. Such molecular studies may provide insight into the precise differences between TCF3-PBX1 positive and negative hyperdiploid B-ALL bearing the t(1;19)(q23;p13). PMID- 25729574 TI - Biomarkers of a five-domain translational substrate for schizophrenia and schizoaffective psychosis. AB - BACKGROUND: The Mental Health Biomarker Project (2010-2014) selected commercial biochemistry markers related to monoamine synthesis and metabolism and measures of visual and auditory processing performance. Within a case-control discovery design with exclusion criteria designed to produce a highly characterised sample, results from 67 independently DSM IV-R-diagnosed cases of schizophrenia and schizoaffective disorder were compared with those from 67 control participants selected from a local hospital, clinic and community catchment area. Participants underwent protocol-based diagnostic-checking, functional-rating, biological sample-collection for thirty candidate markers and sensory-processing assessment. RESULTS: Fifteen biomarkers were identified on ROC analysis. Using these biomarkers, odds ratios, adjusted for a case-control design, indicated that schizophrenia and schizoaffective disorder were highly associated with dichotic listening disorder, delayed visual processing, low visual span, delayed auditory speed of processing, low reverse digit span as a measure of auditory working memory and elevated levels of catecholamines. Other nutritional and biochemical biomarkers were identified as elevated hydroxyl pyrroline-2-one as a marker of oxidative stress, vitamin D, B6 and folate deficits with elevation of serum B12 and free serum copper to zinc ratio. When individual biomarkers were ranked by odds ratio and correlated with clinical severity, five functional domains of visual processing, auditory processing, oxidative stress, catecholamines and nutritional-biochemical variables were formed. When the strengths of their inter domain relationships were predicted by Lowess (non-parametric) regression, predominant bidirectional relationships were found between visual processing and catecholamine domains. At a cellular level, the nutritional-biochemical domain exerted a pervasive influence on the auditory domain as well as on all other domains. CONCLUSIONS: The findings of this biomarker research point towards a much-required advance in Psychiatry: quantification of some theoretically understandable, translationally-informative, treatment-relevant underpinnings of serious mental illness. This evidence reveals schizophrenia and schizoaffective disorder in a somewhat different manner, as a conglomerate of several disorders many of which are not currently being assessed-for or treated in clinical settings. Currently available remediation techniques for these underlying conditions have potential to reduce treatment-resistance, relapse-prevention, cost burden and social stigma in these conditions. If replicated and validated in prospective trials, such findings will improve progress-monitoring and treatment response for schizophrenia and schizoaffective disorder. PMID- 25729577 TI - Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism. AB - Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae which kill drug-sensitive and multidrug-resistant breast cancer cells in culture. Currently, the mechanisms of jadomycin cytotoxicity are poorly understood; however, reactive oxygen species (ROS)-induced DNA cleavage is suggested based on bacterial plasmid DNA cleavage studies. The objective of this study was to determine if and how ROS contribute to jadomycin cytotoxicity in drug-sensitive MCF7 (MCF7-CON) and taxol-resistant MCF7 (MCF7-TXL) breast cancer cells. As determined using an intracellular, fluorescent, ROS-detecting probe, jadomycins B, S, SPhG, and F dose dependently increased intracellular ROS activity 2.5- to 5.9-fold. Cotreatment with the antioxidant N-acetyl cysteine lowered ROS concentrations to below baseline levels and decreased the corresponding cytotoxic potency of the four jadomycins 1.9- to 3.3-fold, confirming a ROS-mediated mechanism. Addition of CuSO4 enhanced, whereas addition of the Cu(II)-chelator d-penicillamine reduced, the ROS generation and cytotoxicity of each jadomycin. Specific inhibitors of the antioxidant enzymes, superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase, but not catalase, enhanced jadomycin-mediated ROS generation and anticancer activity. In conclusion, the results indicate that jadomycin cytotoxicity involves the generation of cytosolic superoxide via a Cu(II)-jadomycin reaction, a mechanism common to all jadomycins tested and observed in MCF7-CON and drug-resistant MCF7 TXL cells. The superoxide dismutase 1, glutathione, and peroxiredoxin/thioredoxin cellular antioxidant enzyme pathways scavenged intracellular ROS generated by jadomycin treatment. Blocking these antioxidant pathways could serve as a strategy to enhance jadomycin cytotoxic potency in drug-sensitive and multidrug resistant breast cancers. PMID- 25729578 TI - Density of alpha4beta2* nAChR on the surface of neurons is modulated by chronic antagonist exposure. AB - The expression of high-affinity alpha4beta2* nicotinic acetylcholine receptors (nAChR) increases following chronic exposure to nicotinic agonists. While, nAChR antagonists can also produce upregulation, these changes are often less pronounced than achieved with agonists. It is unknown if nAChR agonists and antagonists induce receptor upregulation by the same mechanisms. In this study, primary neuronal cultures prepared from cerebral cortex, hippocampus, diencephalon, and midbrain/hindbrain of C57BL/6J mouse embryos were treated chronically with nicotine (agonist), mecamylamine (noncompetitive antagonist) or dihydro-beta-erythroidine (competitive antagonist) or the combination of nicotine with each antagonist. The distribution of intracellular and surface [(125)I]epibatidine-binding sites were subsequently measured. Treatment with 1 MUmol/L nicotine upregulated intracellular and cell surface [(125)I]epibatidine binding after 96 h. Chronic dihydro-beta-erythroidine (10 MUmol/L) treatment also increased [(125)I]epibatidine binding on the cell surface; however, mecamylamine was ineffective in upregulating receptors by itself. The combination of 1 MUmol/L nicotine plus 10 MUmol/L mecamylamine elicited a significantly higher upregulation than that achieved by treatment with nicotine alone due to an increase of [(125)I]epibatidine binding on the cell surface. This synergistic effect of mecamylamine and nicotine was found in neuronal cultures from all four brain regions. Chronic treatment with nicotine concentrations as low as 10 nmol/L produced upregulation of [(125)I]epibatidine binding. However, the effect of mecamylamine was observed only after coincubation with nicotine concentrations equal to or greater than 100 nmol/L. Vesicular trafficking was required for both nicotine and nicotine plus mecamylamine-induced upregulation. Results presented here support the idea of multiple mechanisms for nAChR upregulation. PMID- 25729579 TI - Small caliber arterial endothelial cells calcium signals elicited by PAR2 are preserved from endothelial dysfunction. AB - Endothelial cell (EC)-dependent vasodilation by proteinase-activated receptor 2 (PAR2) is preserved in small caliber arteries in disease states where vasodilation by muscarinic receptors is decreased. In this study, we identified and characterized the PAR2-mediated intracellular calcium (Ca(2+))-release mechanisms in EC from small caliber arteries in healthy and diseased states. Mesenteric arterial EC were isolated from PAR2 wild-type (WT) and null mice, after saline (controls) or angiotensin II (AngII) infusion, for imaging intracellular calcium and characterizing the calcium-release system by immunofluorescence. EC Ca(2+) signals comprised two forms of Ca(2+)-release events that had distinct spatial-temporal properties and occurred near either the plasmalemma (peripheral) or center of EC. In healthy EC, PAR2-dependent increases in the densities and firing rates of both forms of Ca(2+)-release were abolished by inositol 1,4,5- trisphosphate receptor (IP3R) inhibitor, but partially reduced by transient potential vanilloid channels inhibitor ruthenium red (RR). Acetylcholine (ACh)-induced less overall Ca(2+)-release than PAR2 activation, but enhanced selectively the incidence of central events. PAR2-dependent Ca(2+) activity, inhibitors sensitivities, IP3R, small- and intermediate-conductance Ca(2+)-activated potassium channels expressions were unchanged in EC from AngII WT. However, the same cells exhibited decreases in ACh-induced Ca(2+)-release, RR sensitivity, and endothelial nitric oxide synthase expression, indicating AngII induced dysfunction was differentiated by receptor, Ca(2+)-release, and downstream targets of EC activation. We conclude that PAR2 and muscarinic receptors selectively elicit two elementary Ca(2+) signals in single EC. PAR2 selective IP3R-dependent peripheral Ca(2+)-release mechanisms are identical between healthy and diseased states. Further study of PAR2-selective Ca(2+) release for eliciting pathological and/or normal EC functions is warranted. PMID- 25729580 TI - A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma. AB - Vemurafenib, a selective inhibitor of oncogenic BRAF kinase carrying the V600 mutation, is approved for treatment of advanced BRAF mutation-positive melanoma. This study characterized mass balance, metabolism, rates/routes of elimination, and disposition of (14)C-labeled vemurafenib in patients with metastatic melanoma. Seven patients with metastatic BRAF-mutated melanoma received unlabeled vemurafenib 960 mg twice daily for 14 days. On the morning of day 15, patients received (14)C-labeled vemurafenib 960 mg (maximum 2.56 MBq [69.2 MUCi]). Thereafter, patients resumed unlabeled vemurafenib (960 mg twice daily). Blood, urine, and feces were collected for metabolism, pharmacokinetic, and dose recovery analysis. Within 18 days after dose, ?95% of (14)C-vemurafenib-related material was recovered from feces (94.1%) and urine (<1%). The parent compound was the predominant component (95%) in plasma. The mean plasma elimination half life of (14)C-vemurafenib-related material was 71.1 h. Each metabolite accounted for <0.5% and <=6% of the total administered dose in urine and feces, respectively (0-96 h postdose). No new metabolites were detected. Vemurafenib was well-tolerated. Excretion of vemurafenib via bile into feces is considered the predominant elimination route from plasma with minor renal elimination (<1%). e00113. PMID- 25729581 TI - Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates. AB - The multidrug efflux pump P-glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug-protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a "cage" of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp. PMID- 25729582 TI - Target validation and structure-activity analysis of a series of novel PCNA inhibitors. AB - Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 was most potent. The purpose of this study is to further establish targeting of PCNA by PCNA-I1 and to identify PCNA-I1 analogs with superior potencies. We found that PCNA-I1 does not affect the level of chromatin-associated PCNA harboring point mutations at the predicted binding site of PCNA-I1. Forty-six PCNA-I1 analogs with structures of 1 hydrazonomethyl-2-hydroxy (scaffold A), 2-hydrazonomethyl-1-hydroxy (scaffold B), 2-hydrazonomethyl-3-hydroxy (scaffold C), and 4-pyridyl hydrazine (scaffold D) were analyzed for their effects on cell growth in four tumor cell lines and PCNA trimer stabilization. Compounds in scaffold group A and group B showed the highest trimer stabilization and the most potent cell growth inhibitory activities with a significant potency advantage observed in the Z isomers of scaffold A. The absence of trimer stabilization and growth inhibitory effects in compounds of scaffold group D confirms the essentiality of the hydroxynaphthyl substructure. Compounds structure-activity relationship (SAR)-6 and SAR-24 were analyzed for their effects on and found to reduce chromatin-associated PCNA in tumor cells. This study led to the identification of SAR-24, a compound with superior potencies and potentially improved solubility, which will be used for future development of PCNA-targeting cancer therapies. PMID- 25729583 TI - Bacteriological quality of effluent submitted consecutively to a macrofiltration and ultraviolet light systems in the Tunisian conditions. AB - This paper deals with the study of bacteriological quality of effluents that have undergone consecutively different macrofiltration system (pressure sand filter or disc filter used as a secondary treatment) and UV254 irradiation process (used as a tertiary treatment). These two successive systems of treatment were evaluated to determine their possible application as commonly alternatives to the conventional system of wastewater treatment and disinfection before wastewater reuse. They both combined systems of wastewater treatment released effluent of excellent bacteriological quality, with almost total absence of feacal coliforms, of E. coli and of P. aeruginosa). However, if the bacteriological quality of the effluent remained constant in the case of macrofiltration system (disc filter or pressure sand filter); the UV disinfection process showed to deeply depend on the quality of effluent, particularly with regard to UV transmittance. The daily bacteriological monitoring of the secondary effluent at the exit of the pressure sand filter by UV reactor and by using a dose of 96 mJ/cm(2), corresponding to an exposure of 16 min, showed an average rate of inactivation of around 3 U-Log, for feacal coliforms, E. coli and P. aeruginosa, respectively. Therefore, the average bacterial concentration remaining in the water at the exit of the UV reactor is less than 1000 cfu/100 ml for feacal coliform and E. coli. For P. aeruginosa, the remaining number is less than 100 bacteria/100 ml. These two last values coincide substantially with the range recommended by several standardized international guidelines. Therefore, numerous authors reported that P. aeruginosa is very resistant to UV irradiation compared to the other bacterial indicators. In contrast, our study revealed that feacal coliforms and E. coli were more UV light resistant than P. aeruginosa. This finding could be explained by the fact that E. coli and feacal coliform forms aggregates in the treated effluent, while P. aeruginosa exists either as discrete cells or as cell pairs. PMID- 25729584 TI - The effect of organisational system on self-rated depression in a panel of male municipal firefighters. AB - OBJECTIVES: The present study evaluated the effects of job stress, including organisational system to self-rated depression through a panel study of male municipal firefighters in the Republic of Korea. METHODS: A panel of 186 municipal firefighters reported self-rated depressive symptoms according to the Beck Depression Inventory (BDI). The effects of job stress were evaluated using the Korea Occupational Stress Scale, taken one year earlier and classified by the median value. Panel members were classified into Depression or Control groups according to BDI scores, with a cut-off level of 'over mild depression' in a follow-up survey. RESULTS: The Depression group included 17 (9.1%) workers. Firefighters who scored high on occupational system had an 8.3 times greater risk of being assigned to the Depression group than those who had not (adjusted odds ratio [OR] = 8.03, 95% confidence interval (CI) = [1.73-37.22]). In contrast, job stress from a 'difficult physical environment' revealed negative risks related to being classified in the Depression group (AOR = 0.20, 95% CI = [0.04-0.92]). CONCLUSIONS: Although the healthy worker effect may be involved, job stress based on perceptions of organisational system was a strong risk factor for depression. A comprehensive approach should be considered that encompasses social issues when assessing or mental health in high-risk groups, as well as the practical issue of physiochemical hazards. PMID- 25729586 TI - What Difference Does Quantity Make? On the Epistemology of Big Data in Biology. AB - Is big data science a whole new way of doing research? And what difference does data quantity make to knowledge production strategies and their outputs? I argue that the novelty of big data science does not lie in the sheer quantity of data involved, but rather in (1) the prominence and status acquired by data as commodity and recognised output, both within and outside of the scientific community; and (2) the methods, infrastructures, technologies, skills and knowledge developed to handle data. These developments generate the impression that data-intensive research is a new mode of doing science, with its own epistemology and norms. To assess this claim, one needs to consider the ways in which data are actually disseminated and used to generate knowledge. Accordingly, this paper reviews the development of sophisticated ways to disseminate, integrate and re-use data acquired on model organisms over the last three decades of work in experimental biology. I focus on online databases as prominent infrastructures set up to organise and interpret such data; and examine the wealth and diversity of expertise, resources and conceptual scaffolding that such databases draw upon. This illuminates some of the conditions under which big data need to be curated to support processes of discovery across biological subfields, which in turn highlights the difficulties caused by the lack of adequate curation for the vast majority of data in the life sciences. In closing, I reflect on the difference that data quantity is making to contemporary biology, the methodological and epistemic challenges of identifying and analyzing data given these developments, and the opportunities and worries associated to big data discourse and methods. PMID- 25729585 TI - A bioinformatics expert system linking functional data to anatomical outcomes in limb regeneration. AB - Amphibians and molting arthropods have the remarkable capacity to regenerate amputated limbs, as described by an extensive literature of experimental cuts, amputations, grafts, and molecular techniques. Despite a rich history of experimental efforts, no comprehensive mechanistic model exists that can account for the pattern regulation observed in these experiments. While bioinformatics algorithms have revolutionized the study of signaling pathways, no such tools have heretofore been available to assist scientists in formulating testable models of large-scale morphogenesis that match published data in the limb regeneration field. Major barriers preventing an algorithmic approach are the lack of formal descriptions for experimental regenerative information and a repository to centralize storage and mining of functional data on limb regeneration. Establishing a new bioinformatics of shape would significantly accelerate the discovery of key insights into the mechanisms that implement complex regeneration. Here, we describe a novel mathematical ontology for limb regeneration to unambiguously encode phenotype, manipulation, and experiment data. Based on this formalism, we present the first centralized formal database of published limb regeneration experiments together with a user-friendly expert system tool to facilitate its access and mining. These resources are freely available for the community and will assist both human biologists and artificial intelligence systems to discover testable, mechanistic models of limb regeneration. PMID- 25729587 TI - Pseudomonas aeruginosa resistance phenotypes and phenotypic highlighting methods. AB - Pseudomonas aeruginosa genus bacteria are well known for their increased drug resistance (phenotypic ang genotypic resistance). The most important resistance mechanisms are: enzyme production, reduction of pore expression, reduction of the external membrane proteins expression, efflux systems, topoisomerase mutations. These mechanisms often accumulate and lead to multidrug ressitance strains emergence. The most frequent acquired resistance mechanisms are betalactamase type enzyme production (ESBLs, AmpC, carbapenemases), which determine variable phenotypes of betalactamines resistance, phenotypes which are associated with aminoglycosides and quinolones resistance. The nonenzymatic drug resistance mechanisms are caused by efflux systems, pore reduction and penicillin-binding proteins (PBP) modification, which are often associated to other resistance mechanisms. Phenotypic methods used for testing these mechanisms are based on highlighting these phenotypes using Kirby Bauer antibiogram, clinical breakpoints, and "cut off" values recommended by EUCAST 2013 standard, version 3.1. PMID- 25729588 TI - Psychosocial issues in patients with chronic hepatitis B and C. AB - Psychosocial issues and the quality of life are important components at the patients diagnosed with chronic hepatitis B and C. In function of the severity of the infection with virus B or the patients who already have cirrhosis, the treatment and psychosocial education should be improved because they have bigger problems. The frequency of psychosocial disorders seems to be raised at the patients diagnosed with chronic hepatitis B. Factors as alcohol abuse and a low social support have a negatively impact above mental health of these patients. The prevalence rate of chronic hepatitis C infection at patients with severe mental illness can be nine times higher than in healthy population. Usually patients with chronic hepatitis B have a quality of life and a mental health better than patients with chronic hepatitis C. Patients with psychiatric affections (especially institutionalized people) have generally a higher risk of being infected with virus B in comparison with general population. Patients with chronic hepatitis B and C suggest a higher grade of stigmatization from society. Despite clinical challenges which treatment with interferon at patients with chronic hepatitis and comorbidities represents, recent studies indicate the fact that treatment can be administrated in safe conditions at patients with viral chronic hepatitis and psychiatric disorders. PMID- 25729589 TI - The association of sleep deprivation on the occurrence of errors by nurses who work the night shift. AB - PURPOSE: To determine the influence of sleep deprivation on the occurrence of errors by registered nurses working in night shift in intensive care departments. METHODS: The study utilized a multi-part questionnaire which included items about demographic characteristics, reported medical errors, and Pittsburgh Sleep Quality Index (PSQI) 300 questionnaires were distributed to registered nurses working in intensive care departments. 138 of the 153 (51% response rate) collected questionnaires were analyzed using correlation and stepwise logistic multiple regression. RESULTS: Registered nurses who were sleep deprived had worse sleep quality in terms of high PSQI than those who were not. None of the demographic variables was statistically significant, not providing evidence that these variables may explain odds for being sleep deprived in the population. CONCLUSIONS: Work schedule changes, offering shorter periods of time on night shift and less working hours in the week may lead to better sleep quality and less sleep deprivation. PMID- 25729590 TI - Learning styles of medical students - implications in education. AB - BACKGROUND: The term "learning style" refers to the fact that each person has a different way of accumulating knowledge. While some prefer listening to learn better, others need to write or they only need to read the text or see a picture to later remember. According to Fleming and Mills the learning styles can be classified in Visual, Auditory and Kinesthetic. There is no evidence that teaching according to the learning style can help a person, yet this cannot be ignored. SUBJECTS AND METHODS: In this study, a number of 230 medical students were questioned in order to determine their learning style. RESULTS: We determined that 73% of the students prefer one learning style, 22% prefer to learn using equally two learning style, while the rest prefer three learning styles. According to this study the distribution of the learning styles is as following: 33% visual, 26% auditory, 14% kinesthetic, 12% visual and auditory styles equally, 6% visual and kinesthetic, 4% auditory and kinesthetic and 5% all three styles. 32 % of the students that participated at this study are from UMF Craiova, 32% from UMF Carol Davila, 11% University of Medicine T Popa, Iasi, 9% UMF Cluj Iulius Hatieganu. DISCUSSIONS: The way medical students learn is different from the general population. This is why it is important when teaching to considerate how the students learn in order to facilitate the learning. PMID- 25729591 TI - Magnetic resonance imaging criteria for thrombolysis in hyperacute cerebral infarction. AB - PURPOSE: Selection of patients with cerebral infarction for MRI that is suitable for thrombolytic therapy as an emerging application. Although the efficiency of the therapy with i.v. tissue plasminogen activator (tPA) within 3 hours after onset of symptoms has been proven in selected patients with CT, now these criteria are determined by MRI, as the data we gather are fast and accurate in the first hours. MATERIAL AND METHODS: MRI screening in patients with acute cerebral infarction before application of thrombolytic therapy was done in a UCC Mannheim in Germany. Unlike trials with CT, MRI studies demonstrated the benefits of therapy up to 6 hours after the onset of symptoms. We studied 21 patients hospitalized in Clinic of Neuroradiology at University Clinical Centre in Mannheim-Germany. They all undergo brain MRI evaluation for stroke. This article reviews literature that has followed application of thrombolysis in patients with cerebral infarction based on MRI. RESULTS: We have analyzed the MRI criteria for i.v. application of tPA at this University Centre. Alongside the personal viewpoints of clinicians, survey reveals a variety of clinical aspects and MRI features that are opened for further more exploration: therapeutic effects, the use of the MRI angiography, dynamics, and other. CONCLUSIONS: MRI is a tested imaging method for rapid evaluation of patients with hyperacute cerebral infarction, replacing the use of CT imaging and clinical features. MRI criteria for thrombolytic therapy are being applied in some cerebral vascular centres. In Kosovo, the application of thrombolytic therapy has not started yet. PMID- 25729592 TI - Correlations between Areas, Volumes or Body Fat and Anthropometric Variables. AB - Body fat is an important determinant of nutritional status and health. This paper aims to demonstrate the existence of significant correlations between areas, or volumes of fat and anthropometric variables. PMID- 25729593 TI - Theoretical study on the mechanics of the conjunct gnatoprothetic devices in the context of occlusive function rehabilitation. AB - The partially intercalated edentation offers the practitioner the possibility of the functional rehabilitation of the dental arcades through conjunct gnato prosthetic devices. The functions of the dento-maxilar device, disturbed by the presence of edentation, require a treatment approach so that, without pre planning or estimating, the result can lead most of the times to failure in terms of functionality. Clinical evaluation associated with pre- and proprosthetic treatment can also impose, in some situations the evaluation of the dental units involved in prosthetic rehabilitation. The association and implementation of the prosthetic construction in the occlusive-articular ensemble, as well as the counterbalancing of the mastication forces per dental unit and whole interarch system, linked to the distribution of the forces at the level of the pillar teeth and prosthetic construction, represent the goal of this theoretical study. PMID- 25729594 TI - Acetylsalicylic Acid in migraine with aura prevention - a retrospective study. AB - In a retrospective study we evaluated the efficacy and tolerability of Acetylsalicylic Acid (ASA), an antiplatelet drug, in the prophylactic treatment of migraine with aura (MA). We reviewed the charts of 203 patients suffering from MA according to the ICHD II criteria, attending to Turin University Headache Centre. 95 subjects (46.8%) were treated with ASA at low dose, 108 (53.2%) with other prophylactic therapies normally used for migraine for a period that ranged from at least 4 months to 194 months. Eighty-four patients (88.4%) treated with ASA referred positive results, while only 64 patients (59.3%) who underwent other prophylactic treatments did (p < 0.001). The attacks' frequency of patients treated with ASA decreased significantly from 3.83+/-1.57 pre-treatment to 1.38+/ 0.87 after treatment (p<0.001). Aura duration was markedly reduced from 36.21+/ 19.80 pre-treatment to 22.0+/-15.5 after treatment (p<0.001). ASA was well tolerated. ASA is a safe drug with minor possible side effects that can be routinely used when prophylactic treatment of MA is required. PMID- 25729595 TI - The Physician's Attitude towards the End of the Existence. AB - The physician's attitude towards death, a phenomenon which he frequently encounters in his work practice, is most of the times ambiguous, uncertain, lacking a philosophical significance coherent enough. During the period corresponding to the transition from life to death, when the human being who is about to relinquish life for good lives, suffers, understands and needs assistance, most of the physicians adopt a particular detachment conduct. The physician's participation in assisting the patient, constant until then, natural, sharply decreases the moment the diagnosis has become, "there is nothing else to be done". This phrase "there is nothing else to be done" should be only the conclusion of one phase of the assistance given by a physician, the curative, healing assistance and the beginning of another one, the phase of "assisting the dying person", a phase that has to be an integral part of the physician's mission which represents a more difficult medicine, much more demanding for the physician. At this point, assistance, treatments depend on the ability of the person providing assistance to endure the fear of death in which he is included himself. The necessity of meeting the needs of the dying people has led to the drafting of "a charter of the rights of the dying". Such charter was drafted during the symposium, "Terminally ill patient and helping person" organized by Wayne State University, Detroit, USA. Taking into account the idea that the dying person "has the right to live until the end" within the best possible conditions the palliative care have been developed. According to the French Society of Palliative Care, 1996, the palliative care aim is to ensuring the patient's quality of life (and not extending it by any means) and that of his family. In these conditions the pain control, the psychological, social and spiritual development are essential. PMID- 25729596 TI - An Extremely Rare Situation - Subcutaneously Filariasis Presented at ED Craiova. AB - A 32 year old male patient presented to the ED Craiova with migratory, burning pain, to the right cervical and left upper eyelid. Sudden, transient, bilateral knee swelling six months ago. An inflammatory trace and a renitent cord can feel at this level, with spontaneous mobility. A microfilaraemic parasite was surgically extracted from upper eyelid. Mobility of the parasite was the key element of an extremely quick and easy diagnosis for a very rare disease but the specific circumstances of the contamination remains unclear. Even uncommon, multiple determinations are possible requiring systematic and long term investigation and medical surveillance. PMID- 25729597 TI - Deficiency Of Antithrombin III (AT III) - Case Report and Review of the Literature. AB - Antithrombin III (AT III) is a plasmatic alpha-glicoprotein formed by a single peptidic chain. AT III inhibits thrombin (first target) and free Xa, IXa ,VIIa plasmatic factors. In plasma AT III is found under two forms: alpha-antithrombin and beta-antithrombin. Deficiency of AT III represents a risk factor for thromboembolic disease. There are known both quantitative and qualitative AT III deficiencies. Incidence of AT III inherited deficiency is relative rare (1:10.000). Acquired deficiency of AT III is more frequent. The transmission of AT III deficiency is autosomal dominant with variable shield factor. Homozygous is incompatible with life (death immediately after birth). Thrombosis appears around the age of twenty years, and in 4-5 decades of life 2/3 of patients are symptomatics. Traumatisms, surgical interventions, estrogenic treatment, precipitated thrombotic complications. Obesity and dyslipidemic syndrome are risk factors. Thrombosis affects the venous system at these patients. Arterial thrombosis are less reported. The most frequent localisations are: the veins of the legs, mesenteric veins, cave veins, superficial periombilical veins. Treatment of AT III deficiency is: administration of AT III concentrates (with a plasmatic level by 80% from normal value) and heparinotherapy. The treatment with AT III concentrates is for patients which faced major surgical interventions, pregnant women with AT III deficiency. The women with AT III deficiency should avoid the utilisation of oral contraceptives. PMID- 25729598 TI - Importance of Laparoscopic Assessment of the Uterine Adnexa in a Mayer-Rokitansky Kuster-Hauser Syndrome Type II Case. AB - In the case reported, diagnosed with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, the presence of normal ovaries proved to be challenging to confirm due to unusual high positioned (ectopic) ovaries. MRKH syndrome is a rare pathological condition characterized by a spectrum of the Mullerian duct abnormalities resulting in congenital aplasia of the uterus and of the upper part (2/3) of the vagina, developed during embryogenesis. At the same time, the mullerian development is interdependent with the Wolffian (mesonephric) duct and this explains the associated renal abnormalities (MRKH type II). Laparoscopic assessment was of great importance in defining the exact anatomic characteristics of MRKH syndrome. PMID- 25729599 TI - Stem cells, colorectal cancer and cancer stem cell markers correlations. AB - : The idea of stem cells as being progenitors of cancer was initially controversial, but later supported by research in the field of leukemia and solid tumors. Afterwards, it was established that genetic abnormalities can affect the stem and progenitor cells, leading to uncontrolled replication and deregulated differentiation. These alterations will cause the changeover to cancerous stem cells (CSC) having two main characteristics: tumor initiation and maintenance. This review will focus on the colorectal cancer stem cell (CR-CSCs) theory which provides a better understanding of different tumor processes: initiation, aggressive growth, recurrence, treatment resistance and metastasis. A search in PubMed/Medline was performed using the following keywords: colorectal cancer stem cells (CR-CSCs), colorectal neoplasms stem cells, colorectal cancer stem cell (CR CSCs) markers, etc. Electronic searches were supplemented by hand searching reference lists, abstracts and proceedings from meetings. Isolation of CR-CSCs can be achieved by targeting and selecting subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer self renewal, markers as: CD133, CD166, CD44, CD24, beta1 integrin-CD29, Lgr5, EpCAM (ESA), ALDH-1, Msi-1, DCAMLK1 or EphB receptors. The identification and localization of CR-CSCs through different markers will hopefully lead to a better stratification of prognosis and treatment response, as well as the development of new effective strategies for cancer management. PMID- 25729600 TI - Current principles and practice of ethics and law in perinatal medicine. AB - One of the most controversial discussion topics in modern bioethics, science or philosophy is represented by the beginning of the individual human life. It is ethically, medically and scientifically correct that the human conception product to be born, so to gain personality and individuality, to be treated as a patient since the intrauterine life. Intrauterine foetal interventions, performed in various therapeutic purposes are still in the experimental stage even in centres with rich experience in perinatal medicine. Progresses truly outstanding are present especially in the prenatal diagnostic methods. Non invasive prenatal testing represents without a doubt a great progress in prenatal diagnosis, but from this point of view, the role of practitioners in the field of perinatal medicine, on counselling and addressing the indication of this test becomes essential. Beyond cultural, national, social or related differences, in perinatal medicine practice is particularly important to respect and permanently reassess the ethical codes. Our paper is targeting to spotlight the essential principles and practice of ethics and law in perinatal medicine nowadays on one hand, and to bring an update review on a controversial topic on the other hand. PMID- 25729601 TI - Non-alcoholic Fatty liver disease in children. AB - In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children. PMID- 25729602 TI - Evaluation of the psychoneurotic tendencies risk using the woodworth mathews personality inventory in non-institutionalized persons. AB - INTRODUCTION: Multiple factors of vulnerability may lead to development of abnormal social behaviour and to important psychiatric diseases. The psychopathological characteristics present at individual level can lead to a pattern of population groups that are subject to developing mental illness risks. MATERIAL AND METHODS: Multidisciplinary study (2009-2011) to assessing the current situation of mental health and identifying population risk groups for developing psychiatric disorders in a non-institutionalised population. We used the Woodworth Mathews Inventory (76 items) to a randomly selected sample of 1,200 men and women, residents in urban and rural areas. RESULTS: The extreme scores for emotiveness had a frequency more than triple for women, and we found a similar situation for obsessive-neurasthenic and depressive tendencies. People aging over 35 years had a double score (limit and poignancy) for depression than younger people, meanwhile correlation between age under 35 years and instability and antisocial tendencies is highly statistically significant (p<0.001), the frequency of extreme scores being almost double than in the older people. CONCLUSIONS: Female gender has a vulnerability for develop depressive and emotional disorders and age over 35 is also significant correlated with depressive tendencies. Younger people (under 35 years) are predisposed for pathological antisocial behaviour, fact revealed by the high scores for instability and antisocial tendencies. It is necessary to develop a program focused on the two risk categories to prevent the possible occurrence of psychiatric disorders. PMID- 25729603 TI - The expression of twist in differentiated thyroid carcinomas. AB - Differentiated thyroid carcinoma are lesions with a generally favorable prognosis, although there are patients with risk of recurrence and metastasis. In this study we analyzed 43 thyroid carcinomas referring to Twist expression in relation to clinicopathological parameters. The immunoreaction was identified in 79% of cases, the expression of twist being low or high, with no differences in relation to the tumors type or subtype. Twist immunoexpression differ depending on tumor stage and presence of metastases, the immunostain being significantly higher in invasive tumors to adjacent structures and in cases of tumors with metastasized. In differentiated thyroid carcinomas overexpression of Twist is associated with an invasive and metastatic immunophenotype. PMID- 25729604 TI - Graves' disease in Albanian children. AB - BACKGROUND: Graves' disease (GD) accounts for 10-15% of thyroid disorders in patients less than 18 years of age. It is the most common cause of thyrotoxicosis in children and accounts for at least 95% of cases in children. Pediatric Treatment of Graves' disease consists of anti-thyroid drugs, radioactive iodide and thyroidectomy but the optimal treatment of GD in children is still controversial. OBJECTIVE: To review treatment outcome of pediatric Graves' disease in Albania. MATERIAL AND METHOD: Descriptive review of 15 children with Graves' disease, diagnosed from Jan.2007 to Dec. 2013, at the Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital Centre "Mother Teresa", Albania was performed. RESULTS: All patients, mean age 10.56 +/- 3.37 years, (range 2.02-16.09 years) were presented with goiter and increased serum FT4, mean 39.80 +/- 16.02 ng/mL, (range 21.0-74.70 ng/mL), serum FT3, mean 12.98 +/- 3.45 pg/mL, (range 6.90 -17.90 pg/mL) and suppressed TSH levels, mean 0.02 +/- 0.01 mUI/L, (range 0.01-0.05 mUI/L). Anti TSH Receptor were positive in 100% of patients mean value 6.51 +/- 3.61 UI/mL (range 1.63 - 14.10 UI/mL). Anti thyroglobulin and Anti-TPO antibodies were positive in 60% and 46.6% respectively. Clinical course of 15 patients after treatment with anti-thyroid drugs mainly MMI for 3.19 +/- 1.48 (range 0.60 - 6.20) years is as follows: seven (46.66%) underwent remission, five out of seven (71.41%) who underwent remission, relapsed. Three of them (20%) were treated with I(131), and two (13.3%) underwent to total thyroidectomy. CONCLUSION: MMI was the most common first line therapy in the presented patients with Graves' disease. Remission rate was 46.66% after an average 1.48 +/- 0.71 years (range 0.60 - 2.70 years) of treatment with anti thyroid drugs. Remission period was 2.70 +/- 0.36 years (2.1 - 3.1 years) Relapse occurred in 71.41% of patient. I(131) and thyroidectomy were used as second line therapy in the present study. PMID- 25729605 TI - Study of school fatigue on a group of teenagers studying at "dimitrie cantemir" highschool, iasi. AB - Purpose. Fatigue is a physiological phenomenon which is permanently present at students because of the scholar demands. Excessive demands can cause pathological fatigue phenomenon, which should be avoided. Subjects and method. The study included a group of 203 students from Dimitrie Cantemir Highschool in Iasi. The teenagers were questioned about the presence of the fatigue phenomenon. Results. Fatigue is rarely present at 62.6% of the questioned students. During the week, this phenomenon appears especially at the beginning (22.2%) or in the middle of the week (34.5%). In a few cases it appears at the end of the week, as it should. Night sleep is only of 6-7 hours (37.4%) or 7-8 hours (36.9%), which is not enough.The insufficient number of sleeping hours can be paid by day sleep, but most of the responses are "rarely" (50.7%). Active rest is represented by sport or other activities of choice. Sport is the only less attractive option - in most cases children allocate only 15-30 minutes a day for it (33.5%). They stay in front of the TV between 0.5 and 1 hour (42.9%) and of the computer between 2-3 hours (44.3%) daily. Conclusions. Children's daily schedule isn't balanced, so the risk of excessive fatigue really exists. PMID- 25729606 TI - Correlations between craniofacial morphology and dento-maxillary anomalies in a population of children in the South west region of romania. AB - Purpose. Craniofacial morphology is usualy described by the head (cephalic index) and face form (prosopic index). The aim of this study was to establish the existence of correlations between the cranial and facial types and the dento maxillary anomalies. Material and Methods. Data were collected from two groups of patients (a control group of 42 patients without dental anomalies and a test group of 76 patients with dento-maxillary anomalies) of both sexes and age range 11-16 years. Results. Both in the control and test groups, 50% of patients were classified in mesocephalic type and mesoprosopic type. Conclusions. Groups studied by us showed correlations between anomalies in the transverse plane and dolichocephalic type and correlations between anomalies in the sagittal plane and leptoprosopic type. PMID- 25729607 TI - Considerations on implications of risk behavior in mental condition at students. AB - Social and family factors significantly influence somatic and psychical development of children and young people, differentiated by social gradient. Their behavior externalizes their capacities to adapt to family and social environment. It is the result of positive or negative influences of actions of factors in these environments. In adolescence, the social motivation of these behaviors is determined by their social relations (family, school, friends, entourage). By our conducted study we aimed to identify such behaviors, which, under various influences may gain risk or impact on health condition. 160 students, by random sex and aged between 11 and 18, were investigated anthropometric and physiometric were asked to respond to a complex set of questionnaires. The research has shown that subjects with reduced anthropometric and physiometric parameters (of the head) have serious school concerns, they are frequently extracurricular pursuits with a good academic situation, they meet the program of rest, have a peaceful sleep, have a balanced diet, no violent events, do not smoke or consume alcohol. PMID- 25729608 TI - Stress in romanian first year nursing students. AB - OBJECTIVE: This study aims to analyze the stress of the students from the nursing department within the Medical Midwife and Nurse School from our University. SUBJECTS AND METHODS: For this purpose a questionnaire, comprising the factors the students consider important for their academic preparation during the first year, was elaborated and applied to 100 students. RESULTS: The result analysis revealed no significant differences as far as the genders of the subjects were concerned. In the same way, the prior academic background or the student experience did not influence the level of stress. The social and economic factors seem to be involved in choosing a career and thus influence the academic stress. For this purpose, a questionnaire comprising the factors the students consider important for their academic preparation during the first year, was elaborated and applied to 100 students. We used the Students t-test to determine differences between groups and considered p<0.05 as significant. CONCLUSIONS: The stress equally affects the nursing department students, regardless of their gender or prior studies. Social and economic factors play a role in adapting to a new academic environment, having higher expectations and requirements. PMID- 25729609 TI - Uterine artery emerging variants - angiographic aspects. AB - Uterine artery embolization as a therapeutic method in fibromyoma requires a good knowledge of the origin of the uterine artery to the success of this procedure involving selective catheterization. This study presents a classification of anatomical variants of uterine artery as a retrospective review of consecutive arteriogram, complete with various aspects of the origin of the uterine artery in cadaver dissection, in the Department of Anatomy. PMID- 25729610 TI - Systemic atheromatosis influence on retinal vascular disease. AB - Clinical study on a group of 48 patients over 3 months: 27 patients were recruited from ophtalmology and 21 recruited from cardiology, 25 % of these patients coming for routine check. Patients were investigated by ophthalmic, cardiologic examination, imaging and laboratory tests. The study demonstrated the need for interdisciplinary consultation for patients with vascular complaints in carotid territory and a close correlation between the vascular pathology and ophthalmology at this level. PMID- 25729611 TI - Paradoxical Growth of Optochiasmatic Tuberculoma during the Treatment of Tuberculous Meningitis. AB - Intracranial brain parenchymal tuberculomas may form paradoxically, days to months after starting antituberculous drug therapy. They may develop in and around optic chiasm and optic nerves after antituberculous treatment as a quite rare occurrence in tuberculous meningitis (TBM) this may lead to severe visual loss if not treated properly. We describe a 5 year-old child with documented TBM being treated with first line antituberculous drugs which developed visual impairment 3 months after starting the treatment. MRI after gadolinium administration revealed multiple perichiasmatic ring enhancing lesions due to tuberculomas. Visual impairment developing in a patient on treatment with antituberculous drugs should give rise to a suspicion of rare optochiasmatic tuberculomas; this necessitates urgent contrast-enhanced MRI of the brain and prompt treatment with steroids. PMID- 25729612 TI - Habitat requirements of the pulmonate land snails Trochulus oreinos oreinos and Cylindrus obtusus endemic to the Northern Calcareous Alps, Austria. AB - The habitat needs and potential threats to Trochulus oreinos oreinos (Wagner 1915) and Cylindrus obtusus (Draparnaud 1805) were assessed by comparing vegetation maps and our own records. We selected four sites from which we had adequate samples and for which exact vegetation maps were available: the mountains Hoch-schwab, Schneealpe, Rax and Schneeberg. Both taxa prefer open dry alpine grassland with diggable soil and/or stones. T. oreinos oreinos is restricted to subalpine and alpine boulder societies and Caricetum firmae. While C. obtusus dwells on several communities of plants, it seems to be bound to unconsolidated stony ground. As both taxa prefer naturally forest-free areas, they are not affected by structural changes of the habitat, such as reforestation caused by the abandonment of grazing and the shift of vegetation zones. But it has to be considered that T. oreinos oreinos and C. obtusus are limited by microclimatic factors, as they prefer cooler habitats. The mountains Schneealpe, Rax and Schneeberg, reaching barely 2000 m in height, are on the climatic limit of the species distribution. Therefore, the investigated taxa are vulnerable to the upward shift of climate zones. T. oreinos oreinos shows striking similarities in its habitat preference to the Swiss endemic T. biconicus, as both taxa prefer the same dry alpine habitats which are quite different to those of other representatives of the genus, which prefer damp habitats. PMID- 25729613 TI - Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration. AB - The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains genes encoding complement factor H (FH) and the factor H related proteins (FHR proteins). In macular tissue, especially Bruch's membrane, relatively high levels of a truncated splice variant of FH called factor H-like protein 1 (FHL-1) are present. Here we discuss how genetic variations may alter the amounts, or by altering their protein sequences, the functions of these proteins. In particular, the common Y402H polymorphism affects the ability of FHL-1 and FH to localize to Bruch's membrane and the inner choroid because it alters the ability of these complement regulators to bind heparan sulphate (HS) in these structures. In addition, there is an age-related loss of HS from Bruch's membrane. We hypothesize that a combination of poor binding of the 402H variants of FHL-1 and FH to Bruch's membrane, combined with a decrease in binding due to age-related HS loss, eventually results in insufficient FHL-1 and FH binding to Bruch's membrane. This could result in complement activation, inflammation and thereby predispose to AMD. PMID- 25729614 TI - Race, Socioeconomic Status, and Age: Exploring Intersections in Preterm Birth Disparities among Teen Mothers. AB - Few studies have examined disparities in adverse birth outcomes and compared contributing socioeconomic factors specifically between African-American and White teen mothers. This study examined intersections between neighborhood socioeconomic status (as defined by census-tract median household income), maternal age, and racial disparities in preterm birth (PTB) outcomes between African-American and White teen mothers in North Carolina. Using a linked dataset with state birth record data and socioeconomic information from the 2010 US Census, disparities in preterm birth outcomes for 16,472 teen mothers were examined through bivariate and multilevel analyses. African-American teens had significantly greater odds of PTB outcomes than White teens (OR = 1.38, 95% CI 1.21, 1.56). Racial disparities in PTB rates significantly varied by neighborhood income; PTB rates were 2.1 times higher for African-American teens in higher income neighborhoods compared to White teens in similar neighborhoods. Disparities in PTB did not vary significantly between teens younger than age 17 and teens ages 17-19, although the magnitude of racial disparities was larger between younger African-American and White teens. These results justify further investigations using intersectional frameworks to test the effects of racial status, neighborhood socioeconomic factors, and maternal age on birth outcome disparities among infants born to teen mothers. PMID- 25729615 TI - Outcome of sublingual immunotherapy in patients with allergic rhinitis sensitive to house dust mites. PMID- 25729616 TI - Natural history and risk factors of atopic dermatitis in children. AB - Atopic dermatitis (AD) is one of the most common inflammatory allergic diseases with pruritic skin lesions particularly in infancy. It is considered to be the first step of atopic march and has variable disease courses. Many children with AD may resolve their AD symptoms with increasing age and may develop respiratory allergies such as asthma and rhinoconjunctivitis at certain ages. Natural course of AD has been supported by many cross-sectional and longitudinal studies in many countries. In general, atopic dermatitis tends to be more severe and persistent in young children, particularly if they have some risk factors including genetic factors. It appears that approximately 40%-70% of childhood AD will get resolved when they reach the age of 6-7 years. However, it is also observed that over half of the children with AD developed respiratory allergy during late childhood. PMID- 25729617 TI - Endoplasmic reticulum stress and the related signaling networks in severe asthma. AB - The endoplasmic reticulum (ER) is a specialized organelle that plays a central role in biosynthesis, correct protein folding, and posttranslational modifications of secretory and membrane proteins. Loss of homeostasis in ER functions triggers the ER stress response, resulting in activation of unfolded protein response (UPR), a hallmark of many inflammatory diseases. These pathways have been reported as critical players in the pathogenesis of various pulmonary disorders, including pulmonary fibrosis, lung injury, and chronic airway disorders. More interestingly, ER stress and the related signaling networks are emerging as important modulators of inflammatory and immune responses in the development of allergen-induced bronchial asthma, especially severe asthma. PMID- 25729618 TI - Three-Year Follow-up Results of Sublingual Immunotherapy in Patients With Allergic Rhinitis Sensitized to House Dust Mites. AB - PURPOSE: This study investigated the long-term efficacy, safety, and compliance associated with sublingual immunotherapy (SLIT) in Korean patients with allergic rhinitis sensitized to house dust mites. METHODS: This is a retrospective cohort study. A total of 164 patients who were sensitized to Dermatophagoides pteronyssinus and Dermatophagoides farinae and who received SLIT were enrolled between November 2007 and January 2010. Each patient was followed up using a diary card, on which a symptom score, rescue medication score, and adverse events (AEs) were recorded. RESULTS: All allergic rhinitis symptoms improved after 3 years of SLIT (P<0.05), and the rescue medication score decreased with time (P<0.05). The incidence of AEs associated with SLIT was 31% (51 of 164 patients) during the first month of therapy, and there were no severe AEs. The dropout rate was 19.5% (32 of 164 patients) during the first month, 34% (56 of 164 patients) after 6 months, and 41% (68 of 164 patients) after 1 year of SLIT. The 3-year compliance rate was approximately 40% (65 of 164 patients). The most common causes of dropout during the first month of SLIT were high cost and inconvenience. The improvement in allergic symptoms was the most common cause of dropout after 6 months. CONCLUSIONS: Allergic symptoms significantly decreased after 1 year of SLIT treatment, and this effect was sustained after 2 or 3 years of treatment. By increasing compliance through patient education, the 3-year use of SLIT for house dust mite allergies may be effective in the management of allergic rhinitis. PMID- 25729619 TI - In vitro evaluation of allergen potencies of commercial house dust mite sublingual immunotherapy reagents. AB - PURPOSE: The clinical efficacy of allergen-immunotherapy is known to be dose dependent. However, optimal maintenance dosage has not yet been determined for sublingual immunotherapy (SLIT). Furthermore, since companies adopt their own units for expression of allergenicity, the allergen concentrations of individual reagents cannot be compared easily. We sought to measure and compare the allergenicities of 3 commercially available house dust mite (HDM) SLIT regents and a subcutaneous immunotherapy reagent. METHODS: We measured the HDM allergenic potency of the maintenance dosages of three SLIT reagents: Staloral(r) (300 index of reactivity [IR] /mL, recommended maintenance dosage [MD]: 120 IR), SLITone(r) (1,000 standard therapeutic unit [STU]/mL, recommended MD: 200 STU), Wolwopharma(r) (100 ug/mL, recommended MD: 20 ug), and subcutaneous immunotherapy regents of Hollister-Stier (10,000 allergy unit [AU] /mL). The allergenic potency was assessed by measuring the total protein concentrations, mite group 1 and 2 allergens using 2-site ELISA, and an inhibition test against IgE specific to Dermatophagoides farinae and Dermatophagoides pteronyssinus. RESULTS: The protein content of the Wolwopharma(r) reagent was 1.5-261.4 times higher than that of the other 2 SLIT reagents. The concentration of group 1 major allergens in Staloral(r) (132.03 ug/mL) was 33- to 44.5-fold higher than in SLITone(r) (4.00 ug/mL) and Wolwopharma(r) (2.97 ug/mL). The concentration of group 2 major allergen was also 8.9- to 10.5-fold higher in Staloral(r) (15.7 ug/mL) than in SLITone(r) (1.8 ug/mL) or Wolwopharma(r) (1.5 ug/mL). An ELISA inhibition study against HDM-specific IgE showed that the allergen potency of Staloral(r) reagent is 8.5-fold and 21-fold higher than that of SLITone(r) or Wolwopharma(r), respectively. The differences between the maintenance dosages are further exaggerated by the differences in the recommended volumes of SLIT reagents. CONCLUSIONS: The allergen potencies of commercially available HDM SLIT reagents are markedly different. Consensus regarding the optimal allergen concentration for SLIT reagents used to treat HDM respiratory allergies is needed. PMID- 25729621 TI - The quality of health information on allergic rhinitis, rhinitis, and sinusitis available on the internet. AB - PURPOSE: The internet has become one of the most important media outlets used to obtain health information. Therefore, the quality of health information available on the internet is very important. We evaluated the quality of internet-derived health information on allergic rhinitis, rhinitis and sinusitis and compared these results to those of previous studies performed five years ago. METHODS: The terms "allergic rhinitis (AR)", "rhinitis" and "sinusitis" were searched among the four most commonly used search engines in South Korea. These websites were evaluated according to the author, the Journal of the American Medical Association (JAMA) benchmarks, the DISCERN questionnaire and the Allergic rhinitis and its Impact on Asthma (ARIA) 2008 Update. RESULTS: A total of 120 websites were obtained and analyzed. For all diseases, "Oriental physician" had the largest portion (almost half of all websites), followed by "Western physician". Based on analyses using the JAMA benchmark, "Attribution" and "Disclosure" were ignored in almost all surveyed websites. According to the scores of the DISCERN question, the majority of websites did not supply appropriate references for their health information, and information on the negative aspects of treatment such as risks and uncertainty was not provided in several websites. In an analysis based on the ARIA 2008 Update concepts, 65% of websites pertaining to health information on AR contained unreliable information. CONCLUSIONS: The quality of health information on the internet was not acceptable. Thus, governmental regulation or control to improve the quality of health information is required. PMID- 25729620 TI - Association of Single Nucleotide Polymorphisms in Toll-like Receptor Genes With Asthma Risk: A Systematic Review and Meta-analysis. AB - PURPOSE: Asthma is a complex disease, with contributions from multiple genes, various genetic backgrounds, and environmental factors. Many human epidemiological studies have demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are inconsistently associated with asthma risk. Some have demonstrated differences concerning the study design and effect size, and conflicting results have been reported. A meta-analysis is necessary to determine the magnitude of this association. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association of SNPs in TLR genes with asthma risk. We screened the medical literature based on the following keyword searches in MEDLINE and EMBASE databases: 'TLR', 'polymorphism', 'asthma', and their combinations. RESULTS: Meta analysis of eight studies on TLR4 Asp299Gly showed a marginal association of TLR4 with asthma risk (odds ratio [OR]=0.814 [95% confidence interval [CI], 0.652 1.016; P=0.069]) in the recessive model. TLR4 Thr399Ile was not associated with asthma risk under any genetic model. Meta-analysis of four studies on TLR2 Arg753Gln indicated that TLR2 might be significantly associated with asthma in the dominant and codominant models (P=0.029, P=0.030, and P=0.009, respectively). TLR9 -1237 was marginally associated with asthma risk (OR=0.408 [95% CI, 0.163 1.021; P=0.065]) in the codominant model. Analysis using the allele contrast model showed that the major TLR9 -1237 T allele tended to be a significant protective factor with OR=0.689 (95% CI, 0.471-1.007; P=0.055). CONCLUSIONS: The results showed that TLR4 Asp299Gly, TLR2 Arg753Gln, and TLR9-1237 might contribute significantly to asthma susceptibility. Future genetic association studies would consolidate these findings. PMID- 25729622 TI - Prevalence of allergic rhinitis among adults in urban and rural areas of china: a population-based cross-sectional survey. AB - PURPOSE: The aim of the present study was to compare the prevalence of self reported and confirmable allergic rhinitis (AR) with positive skin prick test (SPT) results among adults living in urban and rural areas of China. METHODS: Adults from a community in Beijing and a village in Baoding were selected as representative urban and rural dwellers, respectively. All eligible residents were enrolled from the population register and received a face-to-face interview using modified validated questionnaires. Equal sets of randomly selected self reporting AR-positive and AR-negative participants who responded to the questionnaires were also investigated using skin prick tests. RESULTS: A total of 803 participants in the rural area and a total of 1,499 participants in the urban area completed the questionnaires, with response rates being 75.9% and 81.5% respectively. The prevalence of self-reported AR of the rural area (19.1%) was significantly higher than that of the urban area (13.5%). The elementary school of educational level increased the risk of having AR (adjusted OR=2.198, 95% CI=1.072-2.236) .The positive SPT rates among subjects with self-reported AR in the rural and urban areas were 32.5% and 53.3%, respectively; the confirmable AR prevalence of 6.2% and 7.2% among the rural and urban adults, respectively. CONCLUSIONS: The prevalence of confirmable AR is similar between rural and urban areas in China, although there is a higher prevalence of self-reported AR in the former. PMID- 25729623 TI - Comparison of intranasal ciclesonide, oral levocetirizine, and combination treatment for allergic rhinitis. AB - PURPOSE: To evaluate the efficacy and safety of once-daily ciclesonide in comparison to both levocetirizine alone, and a ciclesonide/levocetirizine combination in patients with seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). METHODS: Subjects exhibiting moderate to severe allergic rhinitis for longer than 1 year were randomized in an open-label, 3-arm, parallel group, multicenter study. Subjects received 200 ug ciclesonide, 5 mg levocetirizine, or a combination of both. Changes from baseline until the end-of study visit (2 weeks following) were evaluated by reflective total nasal symptom scores (rTNSSs), reflective total ocular symptom scores (rTOSSs), physician assessed overall nasal signs and symptoms severity (PANS), and rhinoconjunctivitis quality-of-life questionnaires (RQLQ). RESULTS: Significant improvements in rTNSS, PANS, and RQLQ in the ciclesonide monotherapy group were observed in comparison to the levocetirizine alone group. Three individual symptoms of rTNSS, including runny nose, nasal itching, and congestion, were improved in the ciclesonide-treated group. rTOSS scores for ciclesonide monotherapy improved from baseline, but no superiority over levocetirizine was shown. The absolute score and changes in rTNSS and PANS were positively correlated. Ciclesonide spray was more effective than levocetirizine in reducing nasal symptoms in both SAR and PAR patients. Ciclesonide and levocetrizine were well tolerated alone and in combination. CONCLUSIONS: Our results provide support for an AR and its Impact on Asthma (ARIA) recommendation stipulating that ciclesonide is superior to levocetirizine for the treatment of AR, with tolerable safety. Addition of levocetirizine to ciclesonide did not give further clinical benefit over monotherapy. PMID- 25729624 TI - Association Between Antibiotic Exposure, Bronchiolitis, and TLR4 (rs1927911) Polymorphisms in Childhood Asthma. AB - PURPOSE: The complex interplay between environmental and genetic factors plays an important role in the development of asthma. Several studies have yielded conflicting results regarding the 2 asthma-related risk factors: antibiotic usage during infancy and/or a history of bronchiolitis during early life and the development of asthma. In addition to these risk factors, we also explored the effects of Toll-like receptor 4 (TLR4) polymorphism on the development of childhood asthma. METHODS: This cross-sectional study involved 7,389 middle school students who were from 8 areas of Seoul, Korea, and completed the International Study of Asthma and Allergies in Childhood questionnaire. The TLR4 polymorphism rs1927911 was genotyped in 1,395 middle school students from two areas using the TaqMan assay. RESULTS: Bronchiolitis in the first 2 years of life, antibiotic exposure during the first year of life, and parental history of asthma were independent risk factors for the development of asthma. When combined, antibiotic use and a history of bronchiolitis increased the risk of asthma (adjusted odds ratio [aOR]: 4.64, 95% confidence interval [CI]: 3.09-6.97, P value for interaction=0.02). In subjects with CC genotype of TLR4, antibiotic exposure and a history of bronchiolitis during infancy, the risk of asthma was increased, compared to subjects without these risk factors (aOR: 5.72, 95% CI: 1.74-18.87). CONCLUSIONS: Early-life antibiotic exposures and a history of bronchiolitis are risk factors for asthma in young adolescents. Polymorphisms of TLR4 modified the influence of these environmental factors. Reducing antibiotic exposure and preventing bronchiolitis during infancy may prevent the development of asthma, especially in genetically susceptible subjects. PMID- 25729625 TI - The Association of GSDMB and ORMDL3 Gene Polymorphisms With Asthma: A Meta Analysis. AB - PURPOSE: ORM1-like 3 (ORMDL3) belongs to a highly conserved protein family which is anchored as transmembrane protein in the endoplasmic reticulum. Gasdermin B (GSDMB) is adjacent to ORMDL3 on chromosome 17q21.2 and belongs to the gasdermin domain containing the protein family (GSDM family). Recent reports suggest that GSDMB and ORMDL3 are associated with asthma in several populations. However, genetic association studies that examined the association of GSDMB and ORMDL3 gene variants with asthma showed conflicting results. To assess whether combined evidence shows the association between GSDMB/ORMDL3 polymorphism and asthma. METHODS: A bibliographic search from MEDLINE identified 13 original articles using the search keywords 'GSDMB', 'ORMDL3', and 'asthma'. An updated literature based meta-analysis involving 6,691 subjects with asthma, 9,281 control individuals, and 1,360 families were conducted. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on the fixed effects model or the random effects model depended on Cochran's Q-statistic and I(2) values. Data from case-control and TDT studies were analyzed in an allelic model using the Catmap software. RESULTS: We selected and identified 3 SNPs of ORMDL3 associated with asthma (rs8076131: OR=1.10; 95% CI, 1.02-1.20; P=0.012. rs12603332: OR=1.15; 95% CI, 1.05-1.25; P=0.002. rs3744246: OR=1.10; 95% CI, 1.02-1.17; P=0.008) and 1 SNP of GSDMB associated with asthma (rs7216389: OR=1.37; 95% CI, 1.27-1.47; P<0.01). Publication bias was estimated using modified Egger's linear regression test proposed by Harbordetal and revealed no evidence of biases. Furthermore, cumulative meta-analysis in chronological order showed the inclination toward significant association for rs7216389 and rs12603332 with continually adding studies, and the inclination toward null-significant association for rs3744246 and rs8076131. CONCLUSIONS: Moderate evidence exists for associations of the ORMDL3 rs8076131, rs12603332, and rs3744246 and GSDMB rs7216389 variants with asthma. Large sample size and representative population-based studies and TDT studies with homogeneous asthmatic patients and well-matched controls are warranted to confirm this finding. PMID- 25729626 TI - Butter Tolerance in Children Allergic to Cow's Milk. AB - We performed an oral food challenge (OFC) with 10 g of butter (equivalent of 2.9 mL cow's milk) and 25-mL heated cow's milk for 68 children with cow's milk allergy. Thirty-eight children reacted only to heated cow's milk. Twenty-four children reacted to neither heated milk nor butter. Thirty-eight (86.4%) of 44 patients with positive results to the OFC for heated milk could safely tolerate butter. It is highly likely that even children with cow's milk-allergy who show positive results to an OFC for heated milk can consume butter. The milk-specific IgE value indicative of a negative predictive value of over 95% was 17.8 kUA/L, and patients with low milk-specific IgE values may be able to safely consume butter. Including butter in the diets of patients with milk-allergy after a butter challenge may improve quality of life. PMID- 25729627 TI - Eosinophils Modulate CD4(+) T Cell Responses via High Mobility Group Box-1 in the Pathogenesis of Asthma. AB - Eosinophils have been reported to modulate T cell responses. Previously, we reported that high-mobility group box 1 protein (HMGB1) played a key role in the pathogenesis of asthma. This study was conducted to test our hypothesis that eosinophils could modulate T cell responses via HMGB1 in the pathogenesis of asthma characterized by eosinophilic airway inflammation. We performed in vitro experiments using eosinophils, dendritic cells (DCs), and CD4(+) T cells obtained from a murine model of asthma. The supernatant of the eosinophil culture was found to significantly increase the levels of interleukin (IL)-4 and IL-5 in the supernatant of CD4(+) T cells co-cultured with DCs. HMGB1 levels increased in the supernatant of the eosinophil culture stimulated with IL-5. Anti-HMGB1 antibodies significantly attenuated increases of IL-4 and IL-5 levels in the supernatant of CD4(+) T cells co-cultured with DCs that were induced by the supernatant of the eosinophil culture. In addition, anti-HMGB1 antibodies significantly attenuated the expressions of activation markers (CD44 and CD69) on CD4(+) T cells. Our data suggest that eosinophils modulate CD4(+) T cell responses via HMGB1 in the pathogenesis of asthma. PMID- 25729628 TI - An IgE-Mediated Allergic Reaction Caused by Mulberry Fruit. AB - Mulberry (Morus spp.) is a widespread deciduous tree and its fruit is commonly eaten in Korea and eastern Asia. Some reports demonstrate that mulberry fruit is a food allergen in the Mediterranean area. However, there has been no report of systemic allergic reactions after ingesting mulberry fruit in Korea. An 18-year old boy with a mulberry fruit allergy visited our allergy clinic. He had experienced generalized urticaria, chest tightness, breathing difficulty, and abdominal cramping after ingesting mulberry fruit. The patient had a positive skin reaction to mulberry fruit extract (mean wheal size, 5 mm). We performed an ELISA to detect specific IgE antibody (Ab) to mulberry fruit extract in the patient's serum compared to those of non-atopic healthy controls and birch sensitized individuals. Specific IgE Ab to mulberry fruit extract was detected in the patient's serum, as compared to non-atopic healthy controls. Another subject, who was strongly sensitized to birch pollen, also had a positive serum-specific IgE Ab to mulberry fruit. We performed IgE immunoblot analysis using the patient's and the other subject's sera, who had serum-specific IgE to mulberry fruit, to identify the IgE-binding component. An identical IgE-binding component to mulberry extract was detected in the two subjects at around 17 kDa, and which might be PR 10 of Bet v 1. In conclusion, mulberry fruit could induce a systemic allergic reaction through an IgE-mediated mechanism, and cross-reactivity might occur between mulberry fruit and birch pollen. PMID- 25729629 TI - Toxic epidermal necrolysis in polymedicated patient treated with radiotherapy. AB - Temozolomide is an oral alkylating agent indicated for the treatment of patients with glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment. We report the case of a patient who developed toxic epidermal necrolysis (TEN) while she was being treated with chemoradiotherapy and several drugs. Cutaneous tests were performed with the drugs involved with negative result. Although the occurrence of TEN contraindicates suspected drug readministration, we based the decision to perform the controlled administration of temozolomide on the following reasons: (1) the poor prognosis of the underlying disease, (2) the lack of therapeutic alternatives, (3) the suspicion that other drugs taken by the patient simultaneously may be responsible (as anticonvulsants and trimethoprim sulfamethoxazole [TMP-SMX]), and (4) temozolomide was the first choice for treating the patient's disease. The administration of a cumulative dose of 60 mg of temozolomide caused a slight skin reaction. Given this result, we conducted controlled administration of other drugs involved. Dexamethasone, codeine, omeprazole and levetiracetam were well tolerated. However, TMP-SMX produced a similar reaction to that caused by temozolomide. In conclusion, we present the first case of TEN induced by temozolomide and TMP-SMX associated with cranial radiotherapy confirmed by controlled administration. Radiotherapy in combination with these drugs could have favored TEN, as some authors have postulated, but we cannot prove this. PMID- 25729630 TI - Unraveling the genetics of Joubert and Meckel-Gruber syndromes. AB - Joubert (JBTS) and Meckel-Gruber (MKS) syndromes are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone (TZ), and act as structural components of the so-called "ciliary gate" to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of TZ function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cAMP. However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies. PMID- 25729631 TI - "I suffer in an unknown manner that is hieroglyphical": Jung and Babette en route to Freud and Schreber. PMID- 25729632 TI - Validity of the Expressed Emotion Adjective Checklist (EEAC) in Caregivers of Children with Mood Disorders. AB - Expressed Emotion (EE; criticism/hostility and emotional overinvolvement) displayed in family interactions has been associated with the presence and poorer course of multiple disorders in adults and children. As such, validating appropriate tools for measuring EE could have important implications for research and clinical practice. Child EE measures are limited though there are some established methods of assessing EE in adults. The Expressed Emotion Adjective Checklist (EEAC), a self-report measure of EE, has demonstrated validity with adults but has not been evaluated in child samples. The present study examined reliability, stability, and validity of the EEAC in measuring EE in caregivers of children with mood disorders. EEAC scores were associated with the criticism component of the Five Minute Speech Sample (FMSS), a commonly used EE measure in children. EEAC scores were also stable and predicted manic symptom severity and global impairment one year later. These data suggest the EEAC may be a useful self-report measure of EE in children. PMID- 25729633 TI - The Look AHEAD Trial: A Review and Discussion Of Its Outcomes. AB - The LookAhead trial was a randomized controlled trial comparing an Intensive Lifestyle Intervention (ILI) to a Diabetes Support and Education (DSE) in overweight and obese type 2 diabetes patients to track the development of cardiovascular disease over time. The triaI intervention was stopped for futility after a median follow-up of 9.6 years. While there was a differential effect on weight loss and fitness between the two groups, there was no effect on cardiovascular outcomes. Cardiovascular events were less than half the projected rate per year in the DSE group: thus there was a very low over-all rate of events in both groups. There were many other health benefits of ILI, including improved biomarkers of glucose and lipid control, less sleep apnea, lower liver fat, less depression, improved insulin sensitivity, less urinary incontinence, less kidney disease, reduced need of diabetes medications, maintenance of physical mobility, improved quality of life and lower costs. PMID- 25729634 TI - Caffeine in surface and wastewaters in Barbados, West Indies. AB - Caffeine, a purine alkaloid drug, has been recognized as a contaminant of water bodies in various climatic regions, however, these environmental caffeine concentrations are the first to be reported in the tropical Caribbean. The major objective of this study was to develop an improved method to extract caffeine from surface and wastewaters in the warm Caribbean environment and measure caffeine concentrations in highly populated areas in Barbados. Caffeine was extracted from water via solid phase extraction (SPE); the acidified water samples were loaded onto C-18 cartridges and eluted with pure chloroform. The extracted caffeine was quantified using gas chromatography - mass spectroscopy - multiple reaction monitoring (GC-MS/MS-MRM). Method detection limits of 0.2 ng L( 1) from 1 L water samples were achieved. Caffeine was detected in all environmental water samples investigated. The concentrations of caffeine in surface waters were detected in the range 0.1 - 6.9 MUg L(-1). The two wastewater treatment plants, primary and secondary treatment systems, significantly differed in their ability to eliminate caffeine in the raw sewage (38% and 99% caffeine removal efficiencies respectively). Thus, it may be essential to employ secondary treatment to effectively remove caffeine from wastewater systems in Barbados. Caffeine in water bodies are principally attributed to anthropogenic sources as caffeine-producing plants are not commonly grown on the island of Barbados. The study also shows the recalcitrance of caffeine to hydrolytic degradation. PMID- 25729635 TI - Warming and neighbor removal affect white spruce seedling growth differently above and below treeline. AB - Climate change is expected to be pronounced towards higher latitudes and altitudes. Warming triggers treeline and vegetation shifts, which may aggravate interspecific competition and affect biodiversity. This research tested the effects of a warming climate, habitat type, and neighboring plant competition on the establishment and growth of white spruce (Picea glauca (Moench) Voss) seedlings in a subarctic mountain region. P. glauca seedlings were planted in June 2010 under 4 different treatments (high/control temperatures, with/without competition) in 3 habitats (alpine ridge above treeline/tundra near treeline /forest below treeline habitats). After two growing seasons in 2011, growth, photosynthesis and foliar C and N data were obtained from a total of 156, one-and a-half year old seedlings that had survived. Elevated temperatures increased growth and photosynthetic rates above and near treeline, but decreased them below treeline. Competition was increased by elevated temperatures in all habitat types. Our results suggest that increasing temperatures will have positive effects on the growth of P. glauca seedlings at the locations where P. glauca is expected to expand its habitat, but increasing temperatures may have negative effects on seedlings growing in mature forests. Due to interspecific competition, possibly belowground competition, the upslope expansion of treelines may not be as fast in the future as it was the last fifty years. PMID- 25729636 TI - Underpricing, underperformance and overreaction in initial public offerings: Evidence from investor attention using online searches. AB - Online activity of Internet users has proven very useful in modeling various phenomena across a wide range of scientific disciplines. In our study, we focus on two stylized facts or puzzles surrounding the initial public offerings (IPOs) the underpricing and the long-term underperformance. Using the Internet searches on Google, we proxy the investor attention before and during the day of the offering to show that the high attention IPOs have different characteristics than the low attention ones. After controlling for various effects, we show that investor attention still remains a strong component of the high initial returns (the underpricing), primarily for the high sentiment periods. Moreover, we demonstrate that the investor attention partially explains the overoptimistic market reaction and thus also a part of the long-term underperformance. PMID- 25729637 TI - Genome-Wide Analyses of Working-Memory Ability: A Review. AB - Working memory, a theoretical construct from the field of cognitive psychology, is crucial to everyday life. It refers to the ability to temporarily store and manipulate task-relevant information. The identification of genes for working memory might shed light on the molecular mechanisms of this important cognitive ability and-given the genetic overlap between, for example, schizophrenia risk and working-memory ability-might also reveal important candidate genes for psychiatric illness. A number of genome-wide searches for genes that influence working memory have been conducted in recent years. Interestingly, the results of those searches converge on the mediating role of neuronal excitability in working memory performance, such that the role of each gene highlighted by genome-wide methods plays a part in ion channel formation and/or dopaminergic signaling in the brain, with either direct or indirect influence on dopamine levels in the prefrontal cortex. This result dovetails with animal models of working memory that highlight the role of dynamic network connectivity, as mediated by dopaminergic signaling, in the dorsolateral prefrontal cortex. Future work, which aims to characterize functional variants influencing working-memory ability, might choose to focus on those genes highlighted in the present review and also those networks in which the genes fall. Confirming gene associations and highlighting functional characterization of those associations might have implications for the understanding of normal variation in working-memory ability and also for the development of drugs for mental illness. PMID- 25729638 TI - Bioreactor Development for Lung Tissue Engineering. AB - RATIONALE: Much recent interest in lung bioengineering by pulmonary investigators, industry and the organ transplant field has seen a rapid growth of bioreactor development ranging from the microfluidic scale to the human-sized whole lung systems. A comprehension of the findings from these models is needed to provide the basis for further bioreactor development. OBJECTIVE: The goal was to comprehensively review the current state of bioreactor development for the lung. METHODS: A search using PubMed was done for published, peer-reviewed papers using the keywords "lung" AND "bioreactor" or "bioengineering" or "tissue engineering" or "ex vivo perfusion". MAIN RESULTS: Many new bioreactors ranging from the microfluidic scale to the human-sized whole lung systems have been developed by both academic and commercial entities. Microfluidic, lung-mimic and lung slice cultures have the advantages of cost-efficiency and high throughput analyses ideal for pharmaceutical and toxicity studies. Perfused/ventilated rodent whole lung systems can be adapted for mid-throughput studies of lung stem/progenitor cell development, cell behavior, understanding and treating lung injury and for preliminary work that can be translated to human lung bioengineering. Human-sized ex vivo whole lung bioreactors incorporating perfusion and ventilation are amenable to automation and have been used for whole lung decellularization and recellularization. Clinical scale ex vivo lung perfusion systems have been developed for lung preservation and reconditioning and are currently being evaluated in clinical trials. CONCLUSIONS: Significant advances in bioreactors for lung engineering have been made at both the microfluidic and the macro scale. The most advanced are closed systems that incorporate pressure-controlled perfusion and ventilation and are amenable to automation. Ex vivo lung perfusion systems have advanced to clinical trials for lung preservation and reconditioning. The biggest challenges that lie ahead for lung bioengineering can only be overcome by future advances in technology that solve the problems of cell production and tissue incorporation. PMID- 25729640 TI - DNA nanostructures: a shift from assembly to applications. AB - The specificity of DNA hybridization allows for the modular design of 2D and 3D shapes with wide-ranging applications including sensors, actuators, and even logic devices. The inherent biocompatibility of DNA and the ability to produce monodisperse structures of controlled shape and size make DNA nanostructures of interest as potential drug and gene delivery vehicles. In this review, we discuss several new approaches for the assembly of DNA nanostructures, advances in the modeling of these structures, and we highlight recent studies on the use of DNA nanotechnology for therapeutic applications such as drug delivery in tumor models. PMID- 25729639 TI - Place of birth,age of immigration,and disability in Hispanics with multiple sclerosis. AB - BACKGROUND: Hispanics in the US are a diverse community where their knowledge and risk for developing disability in multiple sclerosis (MS) may relate to their level of acculturation. OBJECTIVE: To compare the risk of disability in Hispanics with MS in the US by place of birth and age of immigration. METHODS: We conducted a cross-sectional study of 304 Hispanics with MS residing in Southern California. Place of birth and age of immigration were used as proxies to acculturation. Individuals were classified as US-born, early and late-immigrant (<15 and >=15 years at immigration to the US, respectively). Risk of disability (expanded disability status scale >=6) was adjusted for age at symptom onset, sex, socioeconomic status, and disease duration, using logistic regression. RESULTS: Late-immigrants were older at symptom onset (34.2+/-11.9 vs. 31.9+/-12.9 vs. 28.5+/-9.7 years, p<0.001) and had more disability (28% vs. 9% vs. 18%, p=0.04) compared to early-immigrant and US-born respectively. There was no difference between groups by female sex, type of MS, ethnicity, chronic medical conditions, and disease duration while differences were noted by socioeconomic status. Being late-immigrant was independently associated with increased disability (adjusted OR 2.3 95% CIs 1.07-4.82; p=0.03) compared to US-born. CONCLUSION: Later immigration to the US in Hispanics with MS is associated with greater disability. These findings may reflect differences in social, environmental and cultural factors that may act as barriers for accessibility and utilization of health services. An in-depth assessment of the perceptions and attitudes about MS are warranted in this population. PMID- 25729641 TI - Motives for Acquiring and Saving in Hoarding Disorder, OCD, and Community Controls. AB - Hoarding Disorder (HD) was classified as a separate disorder in DSM-5 (APA, 2013). However, only recently has research on hoarding begun in earnest, and as of yet, very little research exists on the motivation to acquire and save the excessive volume of possessions seen in patients with this disorder. This investigation examined the frequency of four motives for acquiring and saving possessions that are often reported anecdotally by people with HD (information, emotional reasons, avoid waste, and aesthetic reasons). Comparisons in a sample of 443 participants indicated that those with HD reported higher frequencies of each of these four motives for acquiring and saving compared to OCD participants and community controls. The intention to avoid waste emerged as the most prominent motive in people with HD. Understanding waste avoidance may be key to better understanding and treating HD. PMID- 25729642 TI - Leber Hereditary Optic Neuropathy - Therapeutic Challenges and Early Promise. AB - Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the general population. It is an important cause of severe, usually irreversible, visual loss among young adults with a peak age of onset in the second and third decades of life. Management is currently mostly supportive but recent developments in LHON research are pointing the way towards more effective treatments for this blinding mitochondrial disorder. PMID- 25729643 TI - Genomic analysis to define molecular basis of aggressiveness in a mouse model of oral cancer. AB - To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC), our laboratory developed a carcinogen-induced mouse oral cancer (MOC) cell line model that encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS) and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of the model. Here we describe the comparative analysis of NGS (www.ncbi.nlm.nih.gov/biosample?LinkName=bioproject_biosample_all&from_uid=247825 and expression microarray (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50041) data from the MOC lines and corresponding human data, as described in our recent publication [1]. PMID- 25729644 TI - Dynamics of GATA1 binding and expression response in a GATA1-induced erythroid differentiation system. AB - During the maturation phase of mammalian erythroid differentiation, highly proliferative cells committed to the erythroid lineage undergo dramatic changes in morphology and function to produce circulating, enucleated erythrocytes. These changes are caused by equally dramatic alterations in gene expression, which in turn are driven by changes in the abundance and binding patterns of transcription factors such as GATA1. We have studied the dynamics of GATA1 binding by ChIP-seq and the global expression responses by RNA-seq in a GATA1-dependent mouse cell line model for erythroid maturation, in both cases examining seven progressive stages during differentiation. Analyses of these data should provide insights both into mechanisms of regulation (early versus late targets) and the consequences in cell physiology (e.g. distinctive categories of genes regulated at progressive stages of differentiation). The data are deposited in the Gene Expression Omnibus, series GSE36029, GSE40522, GSE49847, and GSE51338. PMID- 25729646 TI - A method for conducting suppression assays using small numbers of tissue-isolated regulatory T cells. AB - The suppression assay is a commonly performed assay, measuring the ability of regulatory T cells (Treg) to suppress T cell proliferation. Most frequently, Treg are obtained from the peripheral blood or spleen. Lower yields are obtained by isolation from other tissues, rendering downstream suppression assays challenging to perform. Furthermore, the importance of suppressive subpopulations of Treg favours their isolation by fluorescent-activated cell sorting. Here we describe a method to isolate Treg from human tissues, using colorectal cancer tissue as an example. Treg suppressive capacity was further examined by expression of CCR5 to demonstrate the ability of our method to assess the suppressive capacity of regulatory T cell subsets. To optimise the standard suppression assay to achieve our research aims, the following modifications were made: Treg, isolated from tissues, were sorted directly into a well-plate.Responder T cells, which had been fluorescently-labelled prior to sorting, were added directly into the well plate.Human Treg Suppression Inspector beads (Miltenyi Biotec Ltd, UK) provided a polyclonal stimulus for proliferation and were added to each well at a bead:lymphocyte ratio of 1:2. This method quantified the suppression of responder T cell proliferation by small numbers of strictly-defined Treg populations isolated from tissues. PMID- 25729647 TI - Postoperative pain management. PMID- 25729645 TI - Genetic Modifiers for Neuromuscular Diseases. AB - Neuromuscular diseases, which encompass disorders that affect muscle and its innervation, are highly heritable. Genetic diagnosis now frequently pinpoints the primary mutation responsible for a given neuromuscular disease. However, the results from genetic testing indicate that neuromuscular disease phenotypes may vary widely, even in individuals with the same primary disease-causing mutation. Clinical variability arises from both genetic and environmental factors. Genetic modifiers can now be identified using candidate gene as well as genomic approaches. The presence of genetic modifiers for neuromuscular disease helps define the clinical outcome and also highlights pathways of potential therapeutic utility. Herein, we will focus on single gene neuromuscular disorders, including muscular dystrophy, spinal muscular atrophy, and amyotrophic lateral sclerosis, and the methods that have been used to identify modifier genes. Animal models have been an invaluable resource for modifier gene discovery and subsequent mechanistic studies. Some modifiers, identified using animal models, have successfully translated to the human counterpart. Furthermore, in a few instances, modifier gene discovery has repetitively uncovered the same pathway, such as TGFbeta signaling in muscular dystrophy, further emphasizing the relevance of that pathway. Knowledge of genetic factors that influence disease can have direct clinical applications for prognosis and predicted outcome. PMID- 25729648 TI - Clonidine: an old friend newly rediscovered. PMID- 25729649 TI - Comparison of the efficacy of adding clonidine, chlorpromazine, promethazine, and midazolam to morphine pumps in postoperative pain control of addicted patients. AB - BACKGROUND: Addicted patients present difficulties for pain management because they have another problem besides their pain. Adding adjuvants to opioid pumps to intensify quality, control other problems, lengthen analgesia, and reduce side effects has been considered in the field. OBJECTIVES: The objective of this study was to evaluate the analgesic effects of adding clonidine, promethazine, chlorpromazine, and midazolam to morphine in patient-controlled intravenous analgesia (PCIA) in orthopedic patients with addiction problems. PATIENTS AND METHODS: 90 patients with histories of substance abuse were enrolled in this randomized controlled trial. Patients were randomly divided into three groups. The first group received 20 mg of morphine sulfate +50 mg of chlorpromazine + 50 mg of promethazine +10 mg of midazolam (M20P). The second group received the first group's regimen plus 150 micrograms of clonidine (M20PC). The third group received 40 mg of morphine sulfate (M40). A pump with a flow rate of 5 mL/h was chosen. Patients were evaluated every 12 hours, and VAS, VRS, extra opioid usage, nausea and vomiting, and sedation scores were recorded. RESULTS: Patients' nausea and vomiting and sedation scores were not statistically different between the three groups. Mean VAS and VRS scores were found to be statistically lower in the M20PC group than in the other groups. Extra opioid usage between the three groups was statistically lower in the M20PC group than in the other groups. The percentage of patients satisfaction was significantly higher in the M20PC group than in the other two groups. CONCLUSIONS: This study showed that, compared to simply increasing the dose of morphine, adding chloropromazine, promethazine, midazolam, and clinidine to morphine significantly controlled pain scores and increased treatment satisfaction in addicted patients without notable side effects. PMID- 25729651 TI - Effects of lumbar discectomy on disability and depression in patients with chronic low back pain. AB - BACKGROUND: Back pain is one of the most prevalent health problems for which physicians are consulted. Back pain has many economic impacts, such as sickness absences and long-term disability. The prevalence of major depression in patients with chronic low back pain is approximately 3 to 4 times greater than the prevalence rate reported in the general population. OBJECTIVES: This study was designed to evaluate the depression and disability improvement after lumbar discectomy compared with presurgery levels in patients with chronic low back pain and radicular leg pain. PATIENTS AND METHODS: One hundred forty-eight patients with chronic low back pain and radicular leg pain were included in this analytic observational study. The study evaluated several main variables, including age; sex; educational level; job; height; weight; and patient history of abortion, leg pain, back pain, smoking, trauma, number of previous pregnancies, driving, long term sitting, lifting heavy bodies, and disability and depression before and 6 and 12 months after laminectomy. RESULTS: The depression and disability scores of patients before lumbar discectomy significantly decreased after surgery. CONCLUSIONS: Our results indicate that lumbar discectomy surgery significantly improved depression and disability in patients with chronic herniated discs. PMID- 25729650 TI - Evaluation of the efficacy of intrathecal injection of amitriptyline and doxepin in spinal anesthesia in comparison with bupivacaine in rats. AB - BACKGROUND: Tricyclic antidepressants (TCAs) are commonly used orally for treating chronic pain states, such as neuropathic pain. TCAs produce analgesia by various mechanisms, including sodium channels, N-methyl-d-aspartate receptors, biogenic amines, opioids, inflammatory mediators, and substance P. Studies have shown that intrathecal tricyclic administration effectively attenuates pain and thermal hyperalgesia in inflammatory and neuropathic pain in rats. OBJECTIVES: The aim of this study was to evaluate the effect of two tertiary TCAs in sensory and motor block. We also used bupivacaine as a strong local anesthetic for the control group. MATERIALS AND METHODS: In a double-blind randomized controlled trial in an animal lab, intrathecal injection of drugs was performed in 30 Wistar male rats. We divided the subjects into 3 groups: group 1: 90 uL Doxepine (50 mM), group 2: 90 ul amitriptyline (60 mM). and group 3: 90 uL bupivacaine (23 mM). Then sensory, motor, and proprioceptive changes were measured at 1, 2, 3, 4, 6, and 12 hours by one examiner. RESULTS: In Groups 1 and 2, a total of 3 rats died. After adjusting the concentrations, amitriptyline had a similar potency but a longer duration of spinal blockade of motor, proprioception, and nociception than did bupivacaine (p < 0.05), whereas doxepin had a reasonable but lower efficacy and shorter duration of spinal blockade than did bupivacaine (p < 0.05). The full recovery time for Group 2 was significantly longer. CONCLUSIONS: It seems that tertiary amine drugs such as amitriptyline and doxepin had reasonable potencies of spinal blockade when compared to bupivacaine. However, amitriptyline had a more potent and long-acting spinal anesthetic effect. Amitriptyline may turn out to be a clinically valuable local anesthetic. PMID- 25729652 TI - The maternal and neonatal effects of adding tramadol to 2% lidocaine in epidural anesthesia for cesarean section. AB - BACKGROUND: Opioid analgesics are commonly added to epidural local anesthetics to improve analgesia during surgery. OBJECTIVES: The goal of this study was to evaluate the maternal and neonatal effects of adding different doses of tramadol to 2% lidocaine in the epidural anesthesia for cesarean section. PATIENTS AND METHODS: Ninety pregnant patients who were candidates for cesarean section under epidural anesthesia were randomly categorized into three groups. Group L received 2% lidocaine. In the LT50 and LT100 groups, 50 and 100 mg of tramadol were added to epidural 2% lidocaine. For additional analgesia during surgery, 2% lidocaine through epidural catheter or IV sufentanil were administered. Analgesia after surgery was provided by IV injection of meperidine. Onset and duration of sensory and motor blockades, total drug consumption, neonatal Apgar score, and complications were recorded. RESULTS: In the LT100 group, onset of complete sensory and motor blockade at T6 was less than in the two other groups, but the highest level of sensory blockade and two segment regression and duration of motor blockades between the LT50 and LT100 groups were not significantly different, although they were higher and more prolonged than in the L group. Average lidocaine and sufentanil consumption during surgery between the LT50 and LT100 groups were not significantly different but were lower than in the L group. The incidence of maternal complications and neonatal Apgar scores were not significantly different between the three groups. In the LT50 and LT100 groups, the time until the first request for analgesics after surgery was prolonged, and average meperidine consumption was less than in the L group. CONCLUSIONS: The addition of tramadol to epidural 2% lidocaine offers advantages in cesarean section. PMID- 25729653 TI - Premedication with oral clonidine decreases intraoperative bleeding and provides hemodynamic stability in cesarean section. AB - BACKGROUND: Intentional lowering of blood pressure helps to produce a desirably clean surgical field. Many drugs can be used to induce a hypotensive state, but due to their high potency and rapid effect, drugs that more easily and safely control the induction of hypotension are desirable. OBJECTIVES: To investigate the effects of premedication with oral clonidine on intraoperative bleeding and hemodynamic variables in patients undergoing cesarean sections. PATIENTS AND METHODS: A total of 110 patients classified as American Society of Anesthesiologists (ASA) physical status I and II and who were scheduled for elective cesarean section under general anesthesia were enrolled. The patients were randomized to receive either oral clonidine (0.2 mg) or identical-looking placebo tablets 90 minutes before arriving at the operating room. Induction of anesthesia was performed by the same standard protocol in all patients. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were recorded before and after induction; immediately after intubation; 5, 10, and 15 minutes thereafter; at the time of extubation; and one hour after the operation. The surgeons were asked to rate the quality of the operative field on a four point scale that ranged from mild (1) to abundant bleeding (2). RESULTS: Intraoperative SBP was lower in the clonidine group. After both intubation and extubation, the increases in SBP, DBP, and HR in clonidine-treated subjects were significantly less than the changes in the control patients. The amount of fentanyl given to control blood pressure and HR was significantly less in the clonidine group (18 +/- 38 vs. 39 +/- 53 MUg, P = 0.02). The responses to the four-point scale indicated that intraoperative bleeding in the clonidine group was less than in the placebo group (1.2 +/- 0.4 vs. 1.7 +/- 0.6, P < 0.05). CONCLUSIONS: Premedication with oral clonidine can improve the hemodynamic management of cesarean cases. PMID- 25729654 TI - Post-operative headache and psychomotor agitation in the recovery room caused by subarachnoid hemorrhage after orbital decompression surgery. AB - There are several etiologies for agitation and headache in the recovery room, including preoperative or intraoperative drug administrations, physical disorders such as painful surgical procedures, and finally, unusual consequences of some operations such as subarachnoid hemorrhage after orbital decompression, a disastrous complication that should be particularly considered whenever facing any sort of headache or unattainable full recovery. In this study a rare case of subarachnoid hemorrhage is presented. PMID- 25729655 TI - "Pain Relief is an Essential Human Right", We Should be Concerned about It. PMID- 25729656 TI - Probiotics in critically ill patients. PMID- 25729657 TI - Use of remifentanil and alfentanil in endotracheal intubation: a comparative study. AB - BACKGROUND: Opioids, such as alfentanil, are used to facilitate endotracheal intubation without the use of neuromuscular blocking agents in patients undergoing elective surgery. OBJECTIVES: The goal of this study was to evaluate the endotracheal intubation conditions when remifentanil or alfentanil was used with propofol without the application of neuromuscular blocking agents. PATIENTS AND METHODS: One hundred American Society of Anesthesiologists (ASA) grade I patients scheduled for elective surgery were enrolled in this prospective, randomized, triple-blinded study. The patients were randomized to group A (alfentanil) or R (remifentanil). In group A, alfentanil (50 mcg/kg) was intravenously injected over 10 seconds, and after 45 seconds or at the occurrence of apnea, propofol (2 mg/kg) was intravenously injected over 5 seconds. Thirty seconds after the administration of propofol, laryngoscopy and endotracheal intubation were attempted. In group R, remifentanil (5 mcg/kg) was administered instead of alfentanil. Intubation conditions, including ease of laryngoscopy, patency of the vocal cords, jaw relaxation, limb movement (1-4 score), and also, demographic data were evaluated. RESULTS: There were no demographic data differences between groups (age, weight, and sex). Further, laryngoscopy, jaw relaxation, and limb movement scores were similar in the R and A groups and there were no significant differences, but vocal cords were significantly more patent in group R than those in group A (P = 0. 028). CONCLUSIONS: The results of this study showed that remifentanil, similar to alfentanil, provided excellent conditions for endotracheal intubation when used with propofol for the induction of anesthesia; however, remifentanil improved the patency of the vocal cords to a greater extent than alfentanil. PMID- 25729658 TI - Post-dural Puncture Headache: A Comparison Between Median and Paramedian Approaches in Orthopedic Patients. AB - BACKGROUND: Post-dural puncture headache (PDPH) is an iatrogenic complication of spinal anesthesia. Reported risk factors for PDPH include sex, age, pregnancy, needle tip shape and size, bevel orientation, approach and others. Little is known regarding the effect of different approaches on the incidence of PDPH. OBJECTIVES: In this study we aimed to compare the incidence of PDPH in the case of median and paramedian approaches in patients undergoing spinal anesthesia for orthopedic operations. PATIENTS AND METHODS: Patients scheduled for orthopedic surgery under spinal anesthesia between 2007 and 2008 were studied in a double blinded randomized controlled trial. The patients were randomized to receive spinal anesthesia by either a median (n = 75) or paramedian (n = 75) approach through a 25-gauge Crawford needle. No premedication was given, and all patients received 500 mL of normal saline intravenously and 4 mL of 0.5% isobaric Marcaine 30 minutes prior to surgery in both approaches. RESULTS: Fifteen patients (10%) developed PDPH. There was no significant difference in the incidence of PDPH in both groups, with 7 (9.3%) patients in the median approach group versus 8 (10.7%) in the paramedian approach group developing typical PDPH (P = 0.875). However, a significant difference in PDPH incidence (P = 0.041) was observed between females (9; 16.7%) and males (6; 6.3%). CONCLUSIONS: There is no difference between median and paramedian approaches with respect to PDPH incidence; the paramedian approach is therefore recommended, especially for older patients with degenerative changes in the spine and intervertebral spaces and those who cannot take the proper position. Moreover, the rate of PDPH was found to be significantly higher in females than in males. PMID- 25729659 TI - Trigeminal neuralgia: frequency of occurrence in different nerve branches. AB - BACKGROUND: Trigeminal neuralgia (TN) is neuropathic pain which can involve any part or side of the face. OBJECTIVES: The objectives of this study were to find the most common branch of trigeminal nerve affected and the most common side involved. PATIENTS AND METHODS: This Cross sectional study was carried out on 100 patients of trigeminal neuralgia in one year time. The diagnosis was based on a detailed history, clinical examination and control of pain by carbamazepine being taken supplemented by radiographic investigations. The collected data was analysed by SPSS 16. RESULTS: The age of the patients varied from 40 to 80 years with a mean age 54 years at the time of presentation. The males to females ratio was 1:2. The right side of the face was found to be involved in seventy patients (64 %) and left side in (36 %). No case presented with bilateral involvement. The Mandibular division was most commonly involved in this study (n = 55; 55%) and least was ophthalmic divisions (n = 6; 6%). CONCLUSIONS: This study demonstrated numerous clinical similarities of trigeminal neuralgia afflicting different populations. Right side was more involved along with mandibular division the most commonly affected. However studies needs to be done to know the exact reasons of involvement of the affected side and branches. PMID- 25729660 TI - Quality-of-Life Evaluation of Patients Undergoing Lumbar Discectomy Using Short Form 36. AB - BACKGROUND: Back pain is one of the most common health problems for which physicians are consulted, and it can considerably decrease the quality of life of patients during a great part of their lives. OBJECTIVES: Our study was designed for assessing the improvement in the quality of life of patients undergoing lumbar discectomy for chronic low back pain. PATIENTS AND METHODS: We included 148 patients with chronic low back pain in the analytic observational study. Using the 36-Item Short-Form Health Survey (SF-36), we evaluated the quality of life before and 6 and 12 months after lumbar discectomy. RESULTS: Physical and mental health scores of patients significantly improved after 6 and 12 months of lumbar discectomy. The mean improvement in physical health scores was significantly higher in female patients than in male patients. However, the improvement in mental health scores was not significantly difference between the 2 sexes and the educational and body mass index (BMI) groups. CONCLUSIONS: Lumbar discectomy improves both the physical and mental health subscale of the quality of life in patients with chronic disc herniation. PMID- 25729661 TI - Efficacy of botulinum toxin type a for treating chronic low back pain. AB - BACKGROUND: Low back pain is a major cause of disability and can result in substantial morbidity and high healthcare costs. Botulinum toxin has been used successfully to alleviate pain for a number of conditions caused by muscle contractions or spasms. OBJECTIVES: The aim of this study was to investigate the efficacy of botulinum toxin type A (BoNT-A; Dysport(r), Ipsen, UK) for treating chronic low back pain (CLBP). PATIENTS AND METHODS: This was a single-blind, randomized clinical trial study. Fifty patients with CLBP received either BoNT-A (40 Ipsen units per injection) or saline in 5 sites in the paraspinal muscles (n = 25 per group). A visual analogue system (VAS) was used to measure pain levels at baseline and at 4 and 8 weeks post-injection. Disability was assessed using the Oswestry low back pain disability questionnaire at baseline and at 8 weeks post-injection. RESULTS: After 4 weeks, 76% of patients in the BoNT-A group reported pain relief compared to 20% in the saline group (P < 0. 005). Additionally, greater pain relief was experienced by patients in the BoNT-A group at 8 weeks (64% vs. 12%; P < 0. 001). By week 8, significant functional improvement (a minimum two-grade improvement between baseline and post-treatment assessments) was demonstrated in a higher number of patients receiving BoNT-A than in the saline group (68% vs. 12% , respectively; P < 0. 005). Patients experienced only minor side effects. CONCLUSIONS: BoNT-A improves CLBP with a low incidence of side effects and can be used as a therapeutic tool in the management of these patients. PMID- 25729662 TI - Attenuation of the pressor response to tracheal intubation in severe preeclampsia: relative efficacies of nitroglycerine infusion, sublingual nifedipine, and intravenous hydralazine. AB - BACKGROUND: The pressor response to laryngoscopy is known to be exaggerated in patients with severe preeclampsia. OBJECTIVES: The aim of the present study was to compare the efficacies of continuous intravenous (IV) infusion of nitroglycerine, IV hydralazine, or sublingual nifedipine in modifying cardiovascular responses to endotracheal intubation, in women with severe preeclampsia undergoing cesarean delivery under general anesthesia. PATIENTS AND METHODS: A total of 120 patients undergoing cesarean delivery were randomly divided into 3 groups, each receiving one of the following drugs before intubation: 5 ug/min nitroglycerine administered by continuous IV infusion (Group NTG, n = 40); a 10-mg capsule of nifedipine deposited sublingually (Group NIF, n = 40); or 5-10 mg hydralazine intravenously (Group H, n = 40). Heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) were simultaneously recorded in the mother at pre induction, pre-intubation, and at 1, 3, 5, and 10 min after intubation. RESULTS: In contrast to those in group NIF and group H, the patients in group NTG showed no significant increases in HR, SAP, DAP, or MAP after intubation, compared to baseline. The incidence of hypotension was significantly greater in group NIF than in group H or group NTG [15 (37. 5%) vs. 8 (20%) vs. 5 (12. 5%) respectively, P = 0. 025]. CONCLUSIONS: In patients with severe preeclampsia undergoing cesarean delivery, a continuous IV infusion of nitroglycerine was able to attenuate the cardiovascular response to intubation to a greater extent than the use of sublingual nifedipine or IV hydralazine, without significant adverse effects on the newborn. PMID- 25729663 TI - Measurement of mental workload in clinical medicine: a review study. AB - BACKGROUND: Measures of mental workload are now commonly used in industries to identify sources of error and to improve performance. OBJECTIVES: This study aimed to review the evidence for the use of this technique within medicine. PATIENTS AND METHODS: We used search engines and the internet to identify experimental studies that included a measure of mental workload in medical practitioners or trainees/students. Studies that aimed to measure mental "stress" as a disorder, or "productivity" were excluded. Each abstract and then the full paper were appraised prior to inclusion. RESULTS: Thirty-three studies were identified that matched the inclusion criteria. Although these covered a variety of settings, common methods were identifiable. The results support the concept of mental workload measurement as an important factor in medical performance. CONCLUSIONS: The limited number of studies and the variety of definitions and measurement techniques used in these studies, make direct comparisons difficult. However, the utility of this methodology in medical education appears to have been established, and guidelines for further research methods are proposed. PMID- 25729664 TI - Cocaine: What is the Crack? A Brief History of the Use of Cocaine as an Anesthetic. PMID- 25729665 TI - Effect of surgical outcome on the psychologic aspect of pain. PMID- 25729666 TI - Disability and depression improve after lumbar discectomy, but may not change for other causes of back pain. PMID- 25729667 TI - Role of depression after lumbar disc surgery. PMID- 25729668 TI - Efficacy of additives to morphine pumps in post-operative pain control of addicted patients. PMID- 25729669 TI - Disability, Depression and Disc Surgery: Lets be Careful with the Evidence. PMID- 25729670 TI - Tricyclic antidepressants: old drugs-new applications. PMID- 25729671 TI - Minimally invasive percutaneous techniques for the relief of pain in lumbar disc disease. PMID- 25729672 TI - Epidural Tramadol, is it a Good Option for Cesarean Section? PMID- 25729673 TI - Commentary on: Effects of Lumbar Discectomy on Disability and Depression in Patients with Chronic Low Back Pain. PMID- 25729674 TI - Intrathecal injection of amitriptyline and doxepin for spinal anesthesia in animal studies. PMID- 25729675 TI - Intravenous patient-controlled remifentanil versus paracetamol in post-operative pain management in patients undergoing coronary artery bypass graft surgery. AB - BACKGROUND: Pain management after cardiac surgery has been based on parenteral long-acting opioids such as morphine. The other alternatives are paracetamol and remifentanil. OBJECTIVES: In this prospective, double-blind, randomized study, we compared the efficacy of intravenous patient-controlled analgesia (IV-PCA) paracetamol and remifentanil for post cardiac surgery pain relief. MATERIALS AND METHODS: One-hundred patients scheduled for elective coronary artery bypass grafting from May to October 2011, were randomized into two groups after the surgery. For the first group (group R, n = 50, with mean age of 58.16 +/- 11.80), the IV-PCA protocol was remifentanil infusion 100 MUg/h; bolus of 25 MUg and lockout time of 15 minutes. In the second group (group P, n = 50, with mean age of 53.8 +/- 15.08), patients received paracetamol 15 mg/kg as a bolus at the end of surgery and then IV-PCA protocol was 100 MUg/h, bolus of 25 MUg; and lockout time of 15 minutes. Pain was assessed with visual analog scale score (VAS) in the first 24 hours after surgery for seven times. RESULTS: The trend of pain scores did not have any significantly difference between group R and group P except for hour 8 and hour 18 after surgery that VAS was significantly lower in group P than group R (P = 0.031, P = 0.023, respectively). Respiratory rate (RR) was also statistically lower in group R comparing to group P in all seven evaluating times. The groups were similar in terms of hemodynamic, ABG results (except for PaO2, which was significantly lower in group R than group P at 6 evaluating times), intubation time, renal function tests, and incidences of atelectasis, myocardial infarction or adverse effects. CONCLUSIONS: Both PCA techniques provided effective pain scores (< 3) after cardiac surgery; but generally, PCA paracetamol infusion has a better analgesic effect. PMID- 25729676 TI - Hemodynamic parameters of low-flow isoflurane and low-flow sevoflurane anesthesia during controlled ventilation with laryngeal mask airway. AB - BACKGROUND: Nowadays laryngeal mask airway (LMA) is popular as one of the best choices for airway management. Low-flow anesthesia has some advantages like lower pollution, hemodynamic stability and cost effectiveness. Volatile anesthetics are widely used for anesthesia maintenance during operations. Sevoflurane has more hemodynamic stability compared to isoflurane, but there are few studies comparing the hemodynamic stabilities of these two anesthetics during controlled low flow anesthesia with LMA. OBJECTIVES: The aim of this study was to compare the effects of low-flow sevoflurane and low-flow isoflurane on hemodynamic parameters of patients through LMA. PATIENTS AND METHODS: Eighty patients, scheduled for elective ophthalmic surgery, were randomly divided into two groups. After induction, an LMA with an appropriate size was inserted in all the patients and they were randomly allocated to two groups of low-flow sevoflurane (n = 40) and low-flow isoflurane (n = 40). Hemodynamic parameters (heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and Mean Arterial Pressure (MAP) were recorded at 5, 10, 15, 20, 25 and 30 minutes after the anesthesia induction. RESULTS: The mean heart rate values were significantly less in the sevoflurane group (P value < 0.05) at 25 minutes after the surgery. The mean Blood Pressure in the isoflurane group was significantly higher compared with the sevoflurane group in 10, 20 and 30 minutes after the surgery (P values = 0.0131, 0.0373 and 0.0028, respectively). These differences were clinically unimportant because heart rate and mean blood pressure were on normal ranges. CONCLUSIONS: Seemingly, low-flow sevoflurane with LMA did not have any significant hemodynamic effect on clinical practice. Therefore, low-flow sevoflurane anesthesia with LMA might be considered in patients with short operations who need rapid recovery from anesthesia. PMID- 25729677 TI - Ventilator-associated pneumonia in patients admitted to intensive care units, using open or closed endotracheal suctioning. AB - BACKGROUND: Critically ill patients under mechanical ventilation require frequent suctioning of airway secretion. Closed suction permits suctioning without disconnection from ventilator; so it might decrease hypoxemia and infection rate. OBJECTIVES: This study aimed to evaluate the effect of closed tracheal suction system (CTSS) versus open tracheal suction system (OTSS). PATIENTS AND METHODS: This is a prospective randomized study, which was carried on 100 patients in surgical Intensive Care Unit requiring mechanical ventilation for more than 48 hours from June 2012 to November 2013. In two groups, suction was performed based on the patients' need as well as physician's or nurses' decision on tracheal secretions. Patients randomly allocated into two groups (50 patients each): CTSS group and OTSS group. Patients were monitored for developing ventilator associated pneumonia (VAP) during the study. Throat samples were taken on admission and two times per week from each patient. Tracheal samples were performed during endotracheal intubation, two times per week during mechanical ventilation and during extubation. RESULTS: Drainage of subglottic secretions decreased the incidence of VAP (P < 0.05). Also type of the pharmacologic medicine for stress ulcer prophylaxis has significant effect on VAP incidence. Among the patients in OTSS and CTSS groups, 20% and 12% developed VAP, respectively. Use of CTSS compared with OTSS did not show statistically significant effect on VAP incidence in multivariate analysis; however, OR (odds ratio) tended to identify OTSS as an exposure factor for the development of VAP (OR = 1.92; CI = 0.45-8.30; = 0.38) compared with the CTSS. Higher levels of APACHE II score, sinusitis and tracheostomy put the patients at the risk of VAP. However, using heat and moisture exchanger (HME) instead of humidifier decreased this risk. CONCLUSIONS: Based on the results obtained from our study, impact of suctioning is similar between CTSS and OTSS regarding the occurrence of VAP. It seems that physicians must consider many factors such as duration of mechanical ventilation, comorbidities, oxygenation parameters, number of required suctioning, and the cost prior to using each type of tracheal suction system. PMID- 25729678 TI - The effect of reciting the word "allah" on pain severity after coronary artery bypass graft surgery: a randomized clinical trial study in iran. AB - BACKGROUND: One of the most expressed complains following coronary artery bypass graft (CABG) surgery is chest wall pain. Due to side effects of opioids used commonly for pain relief after heart surgeries, it is important to use low-cost and non-pharmacological methods independently or combined with palliatives to alleviate pain and consequently prevent undesirable drug adverse effects. OBJECTIVES: This study aimed to investigate the effect of Hazrate Zahra's praises, which is one of the most known praises among Muslims in which the word "Allah" is repeated 100 times, on pain severity after CABG surgery. PATIENTS AND METHODS: This randomized clinical trial study was performed on 80 patients in Busheher Bentolhoda Hospital, Iran, in 2013. Data was collected by a researcher made questionnaire and Visual Analogue Scale (VAS). Patients were randomly assigned into intervention (n = 40) and control (n = 40) groups. In intervention group, we asked patients to recite Hazrate Zahra's praises (AS) as one of the most known praises among Muslims in which the word "Allah" is repeated 100 times. In the control group, patients received routine procedures of hospital. Pain was assessed before and immediately after the intervention in three days after the operation in the both groups. Data was analyzed by SPSS 19 software using descriptive and analytic (Chi-square and independent and paired sample t test) statistical methods. RESULTS: There was a significant difference regarding pain severity after the intervention between the two groups during three days after the operation (respectively P <= 0.001, P <= 0.001 and P <= 0.003), but no significant difference was found between the two studied groups before the intervention. Moreover, a significant difference was seen before and after recitation in the intervention group during three days after the operation (for three days P <= 0.001), while in control group no significant difference was revealed before and after the intervention (respectively P = 0.493, P = 0.541 and P = 0.119). CONCLUSIONS: Reciting the word "Allah" as a non-pharmacological, low cost and non-invasive method with no side effects can be effective on pain relief after CABG surgery. PMID- 25729679 TI - Glycemic monitoring with once-weekly Glucagon-like peptide 1 receptor agonist (GLP1RA) use. PMID- 25729680 TI - Can cardiac autonomic neuropathy be a predictor of cardiovascular outcomes in diabetes? PMID- 25729681 TI - Fasts, feasts and festivals in diabetes-1: Glycemic management during Hindu fasts. AB - This communication is the first of a series on South Asian fasts, festivals, and diabetes, designed to spread awareness and stimulate research on this aspect of diabetes and metabolic care. It describes the various fasts observed as part of Hindu religion and offers a classification scheme for them, labeling them as infrequent and frequent. The infrequent fasts are further sub-classified as brief and prolonged, to facilitate a scientific approach to glycemic management during these fasts. Pre-fast counseling, non-pharmacological therapy, pharmacological modification, and post-fast debriefing are discussed in detail. All available drug classes and molecules are covered in this article, which provides guidance about necessary changes in dosage and timing of administration. While in no way exhaustive, the brief review offers a basic framework which diabetes care professionals can use to counsel and manage persons in their care who wish to observe various Hindu fasts. PMID- 25729682 TI - Need for neonatal screening program in India: A national priority. AB - In India, out of 342 districts surveyed, 286 have been identified as endemic to iodine deficiency (ID). Research studies conducted in school age children (SAC), Adolescent girls, Pregnant Mothers (PMs) and Neonates have documented poor iodine nutritional status. As observed by total goiter rate of more than 5% and median urinary iodine concentration level of <100 MUg/l in SAC and <150 MUg/l in PMs as prescribed cutoff of World Health Organization. And higher thyroid stimulating hormone levels among neonates. ID leads to compromised mental development and hence which remain hidden and not visible to family, program managers and administrator. The present review describes the current status of ID in different parts of the country. With a view to strongly recommend the implementation of Neonatal screening program for ID so that the optimal mental development of children can be achieved. PMID- 25729683 TI - Congenital hypothyroidism. AB - Congenital hypothyroidism (CH) is the one of the most common preventable cause of mental retardation. In the majority of patients, CH is caused by an abnormal development of the thyroid gland (thyroid dysgenesis) that is a sporadic disorder and accounts for 85% of cases and the remaining 15% of cases are caused by dyshormonogenesis. The clinical features of congenital hypothyroidism are so subtle that many newborn infants remain undiagnosed at birth and delayed diagnosis leads to the most severe outcome of CH, mental retardation, emphasizing the importance of neonatal screening. Dried capillary blood is used for screening and it is taken from heel prick optimally between 2 and 5 days of age. Blood spot TSH or thyroxine (T4) or both are being used for CH screening in different programs around the world. Neonates with abnormal thyroid screening tests should be recalled immediately for examination and a venipuncture blood sample should be drawn for confirmatory serum testing. Confirmatory serum should be tested for TSH and free T4, or total T4. Serum TSH and T4 undergo dynamic changes in the first weeks of life; it is important to compare serum results with age-normal reference ranges. Treatment should be started promptly and infant should be rendered euthyroid as early as possible, as there is an inverse relationship between intelligence quotient (IQ) and the age at diagnosis. Levothyroxine (l-thyroxine) is the treatment of choice and American academy of pediatrics and European society of pediatric endocrinology recommend 10-15MUgm/kg/day as initial dose. The immediate goal of therapy is to normalize T4 within 2 weeks and TSH within one month. The overall goal of treatment is to ensure growth and neurodevelopmental outcomes as close as possible to their genetic potential. PMID- 25729684 TI - Challenges and controversies in diagnosis and management of gonadotropin dependent precocious puberty: An Indian perspective. AB - Managing precocious puberty (PP) has been a challenge due to lack of standardized definition, gonadotrophins assay, gonadotrophin stimulation, timings for blood sampling, and parameters for assessing outcomes. This review evaluated available literature to simplify the algorithm for managing gonadotrophin dependent/central PP (CPP), with an Indian perspective. CPP is one of the commonest forms of PP and mimics the normal course of puberty, at an age <8 and 9 years for girls and boys respectively. Basal and post gonadotrophin hormone releasing hormone analog (GnRHa) luteinizing hormone (LH) >=0.3-0.6 IU/L and >=4-5 IU/L (30-60 min after GnRH/GnRHa administration) respectively, using modern ultrasensitive automated chemiluminescence assays, can be considered positive for central puberty initiation. Uterine length of >3.5 cm and uterine volume of >1.8 ml are two most specific indicators for true CPP. Therapy is indicated in children with CPP with accelerated bone age, height advancement, or psychosocial stress. Treatment goal is to halt puberty progression to a socially acceptable age, allowing the child to attain optimal height potential. GnRHa is the treatment of choice, with best height outcomes when initiated <6 years age. Treatment is recommended till 11 years age. LH suppression to <3 U/L may be a reasonable target in patients on GnRHa therapy. Medroxyprogesterone acetate holds an important place in managing PP in India, cause of high costs associated with GnRHa therapy. There is an urgent need for clinical trials from India, for establishing Indian cut-off for diagnosis, treatment and follow-up of children with PP. PMID- 25729685 TI - Metformin in gestational diabetes: An emerging contender. AB - Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance occurring first time during pregnancy. Its prevalence is simultaneously increasing with the global rise of diabesity. GDM commonly develops, when maternal glucose metabolism is unable to compensate for the progressive development of insulin resistance, arising primarily from the consistently rising diabetogenic placental hormones. It classically develops during the second or third trimester. Theoretically, insulin sensitizers should have been the ideal agent in its treatment, given the insulin resistance, the major culprit in its pathogenesis. Fortunately, majority of women can be treated satisfactorily with lifestyle modification, and approximately 20% requires more intensive treatment. For several decades, insulin has been the most reliable treatment strategy and the gold standard in GDM. Metformin is effective insulin sensitizing agent and an established first line drug in type 2 diabetes currently. As it crosses the placenta, a safety issue remains an obstacle and, therefore, metformin is currently not recommended in the treatment of GDM. Nevertheless, given the emerging clinically equivalent safety and efficacy data of metformin compared to insulin, it appears that it may perhaps open a rather new door in managing GDM. The aim of this review is to critically analyze, the safety and efficacy data of metformin regarding its use in GDM and pregnant mothers with polycystic ovarian disease, which has emerged in past decades. PMID- 25729687 TI - Depression among patients with diabetes mellitus in North India evaluated using patient health questionnaire-9. AB - BACKGROUND: Depression is common among diabetes, and is associated with poor outcomes. However, the data on this important relationship are limited from India. OBJECTIVE: The aim was to estimate the prevalence of depression in patients with diabetes and to determine the association of depression with age, sex, and other related parameters. MATERIALS AND METHODS: The study was cross sectional carried out in endocrinology clinic of tertiary care hospital in North India. Cases were patients with type 2 diabetes mellitus (T2DM) above 30 years of age. Depression was assessed using the patient health questionairre-9 (PHQ-9). The relationship with sociodemographic profile, duration of diabetes, hypertension and microvascular complications was also analyzed. RESULTS: Seventy three subjects (57.5% females) with mean age 50.8 +/- 9.2 years were evaluated. The prevalence of depression was 41%. Severe depression (PHQ score >=15) was present in 3 (4%) subjects, moderate depression (PHQ score >=10) in 7 (10%) subjects, and mild depression was present in 20 (27%) of subjects. Depression was significantly more prevalent in rural subjects (57%) when compared to urban ones (31%, P = 0.049). Depression increased with presence of microvascular complications, fasting plasma glucose, hypertension, but the differences were not statistically significant. CONCLUSIONS: Our study demonstrates higher prevalence of depression in patients with type 2 diabetes. Apart from being belonging to the rural area, no other factor was significantly associated with depression. Therefore, depression should be assessed in each and every patient, irrespective of other factors. PMID- 25729686 TI - Insulin-like growth factor- I and factors affecting it in thalassemia major. AB - Despite improvement of blood transfusion regimens and iron chelation therapy growth and maturational delay, cardiomyopathy, endocrinopathies and osteoporosis still occur in good number of thalassemic patients. Decreased IGF-1 secretion occurs in the majority of the thalassemic patients particularly those with growth and pubertal delay. Many factors contribute to this decreased synthesis of IGF-I including disturbed growth hormone (GH) - insulin-like growth factor - I (IGF-I) axis. The possible factors contributing to low IGF-I synthesis in thalassemia and the possible interaction between low IGF-I secretion and the occurrence of these complications is discussed in this mini-review. Improvement of IGF-I secretion in thalassemic patients should be intended to improve linear growth and bone mineral accretion in thalassemic patients. This can be attained through adequate correction of anemia and proper chelation, nutritional supplementation (increasing caloric intake), correction of vitamin D and zinc deficiencies, induction of puberty and correction of hypogonadism at the proper time and treating GH deficiency. This review paper provides a summary of the current state of knowledge regarding IGF-I and factors affecting it in patients with thalassaemia major (TM). Search on PubMed and reference lists of articles with the term 'IGF-I, GH, growth, thalassemia, thyroxine, anemia, vitamin D, and zinc' was carried out. A hundred and forty-eight articles were found and used in the write up and the data analyzed was included in this report. PMID- 25729688 TI - Safety and efficacy of initial combination of linagliptin and metformin in patients with type 2 diabetes: A subgroup analysis of Indian patients from a randomized, double-blind, placebo-controlled study. AB - CONTEXT AND OBJECTIVES: The number of people with diabetes is increasing exponentially in India. Owing to a unique "Asian Indian Phenotype," Indians develop diabetes a decade earlier and have an earlier onset of complications than Western populations. Therefore, it is essential to evaluate more effective treatment strategies at an earlier stage of disease progression, such as initial combination therapy, in Indian patients. In this study, we evaluated the efficacy and safety of initial combination therapy with linagliptin plus metformin in comparison to linagliptin or metformin monotherapy in Indian patients with type 2 diabetes mellitus. METHODS: This is a subgroup analysis of Indian patients who participated in a Phase III, 24-week, double-blind, placebo-controlled, trial. Overall, 249 Indian patients were randomized to one of six treatment arms (Two free combination therapy arms: Linagliptin 2.5 mg twice daily [bid] + either low [500 mg, n = 36] or high [1000 mg, n = 44] dose metformin bid and four monotherapy arms: Linagliptin 5 mg once daily [qd, n = 40], metformin 500 mg [n = 49] or 1000 mg bid [n = 45], or placebo [n = 23]). RESULTS: The placebo-corrected mean change in glycated hemoglobin from baseline (8.9%) to week 24 was -1.83% for linagliptin + metformin 1000 mg bid; -1.46% for linagliptin + metformin 500 mg bid; -1.30% for metformin 1000 mg bid; -1.00% for metformin 500 mg bid; and 0.77% for linagliptin 5 mg qd. None of the patients in the combination therapy arms had hypoglycemia, whereas there was one event in the metformin 1000 mg bid arm. Rates of adverse event were similar across various treatments. CONCLUSIONS: In this subgroup analysis of Indian patients, initial combination therapy with linagliptin + metformin was more efficacious in improving glycemic control than the monotherapy arms, with a comparable tolerability profile. The results were comparable to the overall population. PMID- 25729689 TI - Carotid, aorta and renal arteries intima-media thickness in patients with sporadic idiopathic hypoparathyroidism. AB - BACKGROUND: Alteration in homeostasis of calcium, phosphate and parathyroid hormone (PTH) predispose to vascular calcification that increases the risk of cardiovascular morbidity and mortality. The data on this aspect are scarce in patients with sporadic idiopathic hypoparathyroidism (SIH). OBJECTIVE: The aim was to assess the effect of altered calcium, phosphate and PTH homeostasis in patients with SIH on intima media thickness (IMT), a surrogate marker of increased vascular risk. METHODS: In this case-control study, we measured carotid IMT (CIMT), aortic IMT (AIMT) and renal arteries IMT (RIMT) in 30 consecutive patients with SIH, and compared with healthy subjects. IMT was measured by ultrasound by a single operator blinded to subject's details. RESULTS: CIMT, AIMT, RIMT values in patients with SIH were significantly more than healthy subjects (0.60 +/- 0.08 mm vs. 0.52 +/- 0.09 mm, P = 0.001; 0.73 +/- 0.09 mm vs. 0.65 +/- 0.10, P = 0.004; and 0.34 +/- 0.04 mm vs. 0.30 +/- 0.05, P = 0.003, respectively). Clinical or biochemical parameters did not correlate with CIMT, AIMT and RIMT in patients with SIH. CONCLUSION: The vascular risk is increased in patients with SIH as assessed by CIMT, AIMT, and RIMT. PMID- 25729690 TI - Effect of gonadotropin-releasing hormone agonist therapy on body mass index and growth in girls with idiopathic central precocious puberty. AB - OBJECTIVE: The study aimed to assess the effect of gonadotropin-releasing hormone (GnRH) agonist therapy on body mass index (BMI) and growth in girls diagnosed with idiopathic central precocious puberty (CPP). MATERIALS AND METHODS: Hospital records of 32 girls with idiopathic CPP who have been receiving GnRH agonist therapy for at least 12 months were retrospectively reviewed and auxological, clinical and laboratory parameters of the patients were recorded. BMI, body mass index standard deviation score (BMI SDS) for chronological age body mass index standard deviation score (CA-BMI SDS), BMI SDS for bone age body mass index standard deviation score (BA-BMI SDS), ratios of obesity and overweight were assessed before treatment and on the 12(th) month of therapy in patients diagnosed with idiopathic CPP. RESULTS: The study comprised of 32 girls diagnosed with idiopathic CPP. BMI values showed statistically significant increase in the 1(st) year of treatment (19.16 +/- 2.8 vs. 20.7 +/- 3.4, P = 0.001). Despite a mild increase in CA-BMI SDS in the 1(st) year of treatment versus before treatment, it was no statistically significant (1.0 +/- 0.8 vs. 1.1 +/- 0.9, P = 0.061). However, significant increase was observed in BA-BMI SDS in the 1(st) year of treatment versus before treatment (0.8 +/- 0.7 vs. 0.4 +/- 0.8, P < 0.001). Before treatment, 37.5% (12/32) of the patients were overweight and 21.9% (5/32) were obese, whereas in the 1(st) year, 34.4% (11/32) of the patients were overweight and 31.3% were obese (P = 0.001). CONCLUSION: Whilst 1/3 of the cases diagnosed with idiopathic CPP were overweight and obese at the time of diagnosis, GnRH agonist therapy caused statistically significant weight gain in patients diagnosed with CPP. Therefore, these patients should be closely monitored and weight control should be provided by diet and exercise programs in the course of treatment. PMID- 25729691 TI - Thyroid dysfunction in human immunodeficiency virus-infected children and its correlation with CD4(+) T lymphocyte count. AB - CONTEXT: Thyroid dysfunction has been reported in human immunodeficiency virus (HIV)-infected individuals including children. Some studies have reported that thyroid dysfunction may be a marker of severity or progression of HIV. AIMS: The aim was to study thyroid function in HIV-infected children with and without highly active anti-retroviral therapy (HAART). SETTINGS AND DESIGN: Cross sectional study carried out at a teaching hospital with Anti-Retroviral Therapy Centre (Centre of Excellence) of National AIDS Control Organization. SUBJECTS AND METHODS: Thyroid stimulating hormone (TSH), total thyroxine (T4), and total tri iodothyronine (T3) were analyzed in 60 pediatric HIV cases: 30 on HAART and 30 HAART naive. Correlation of T3, T4, and TSH with CD4 count was assessed. STATISTICAL ANALYSIS USED: Data reported as mean +/- standard deviation and as the number of cases and percentages. Comparison between groups was done by independent sample t-test and chi(2)-test. Spearman's correlation coefficient is used to assess the association between thyroid dysfunction and CD4 count. RESULTS: Thyroid function abnormality was seen in five out of 30 patients in both patients on HAART or without HAART therapy. Among patients on HAART, three had hypothyroidism, and two had biochemical feature of sick euthyroid syndrome. Among the HAART naive group, sub-clinical hypothyroisim was seen in four, and one had biochemical feature of sick euthyroid syndrome. None of the patients had clinical features of thyroid dysfunction. There is a highly significant correlation (P = 0.01) between TSH and CD4 count. CONCLUSIONS: Thyroid dysfunction is quite common among pediatric HIV cases. An inverse correlation is seen between TSH and CD4 count indicating trend for hypothyroidism as HIV disease progress. PMID- 25729692 TI - Metabolic syndrome: An independent risk factor for erectile dysfunction. AB - OBJECTIVE: The objective was to determine the role of various components of metabolic syndrome (MetS) as independent risk factor for erectile dysfunction (ED). MATERIALS AND METHODS: A total of 113 subjects of MetS, as recommended by recent IDF and AHA/NHLBI joint interim statement were selected for study who presented for ED. After doing Anthropometric examination, fasting laboratory assay for fasting plasma glucose (FPG), fasting insulin, hemoglobin A1c, triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and 2 h oral glucose tolerance test (OGTT) was done. Erectile function was assessed by completing questions one through five of the International Index of Erectile Function (IIEF-5). A multiple linear regression analysis was carried out on 66 subjects with IIEF-5 score as dependent variable and components of MetS FPG, 2 h OGTT, TG, HDL, and waist circumference as independent variables. RESULTS: Using a multiple linear regression analysis, we observed that presence of the various components of MetS was associated with ED and a decrease IIEF-5 score and this effect was greater than the effect associated with any of the individual components. Of the individual components of the MetS, HDL (B = 0.136; P = 0.004) and FPG (B = -0.069; P = 0.007) conferred the strongest effect on IIEF 5 score. However, overall age had most significant effect on IIEF-5 score. CONCLUSION: It is crucial to formulate strategies and implement them to prevent or control the epidemic of the MetS and its consequences. The early identification and treatment of risk factors might be helpful to prevent ED and secondary cardiovascular disease, including diet and lifestyle interventions. PMID- 25729693 TI - Effect of social and environmental determinants on overweight and obesity prevalence among adolescent school children. AB - BACKGROUND: Overweight and obesity among children and adolescents is a public health concern. OBJECTIVE: To assess the prevalence of overweight and obesity and its association with social and environmental determinants among the adolescent school children of Tirupati town of Andhra Pradesh, India. MATERIALS AND METHODS: Data was collected by interviewer-administered method from school children aged between 12 to 16 years. The sample consisted of 2258 subjects (1097 boys and 1161 girls). Overweight and obesity were defined by body mass index (BMI) based on the current method recommended by the Centre for Disease Control and Prevention 2000. Data on social and environmental determinants were collected by using a pre tested and validated questionnaire. RESULTS: In the present sample, 11.2 percent and 4.8 percent of boys and 10.3 percent and 4.8 percent of girls were overweight and obese. The literacy level of parents, family income and child sleep duration significantly associated with overweight. Parental level of education was a risk factor for overweight (Mother: 1.570; 95% CI: 1.048-2.354). Similarly increase in family income (OR = 1.529; 95% CI: 1.089-2.148) and child sleep duration <7 hrs per day (OR = 2.006; 95% CI: 1.194-3.371) raised children's association in gaining weight. CONCLUSION: Our study reinforces the burgeoning prevalence of overweight and obesity among the adolescents. Interventional measures taken should consider family, school and physical environment to check the problem of overweight/obesity. PMID- 25729694 TI - Comparison of body composition between professional sportswomen and apparently healthy age- and sex-matched controls. AB - INTRODUCTION: In view of the relationship between physical activity and nutrition on body composition, we assessed lean and fat mass and BMC (total and regional) in professional Indian sportswomen and compared it with apparently healthy age- and sex-matched females. MATERIALS AND METHODS: This cross-sectional study included 104 sportswomen and an equal number of age-matched normal healthy females (controls). They were evaluated for anthropometry and body composition (fat, lean mass, and bone mineral content (BMC) by DXA. RESULTS: Mean age (19.1 +/- 1.3 vs. 19.4 +/- 1.5 years) and body mass index (21.34 +/- 3.02 vs. 21.26 +/- 4.05 kg/m(2)) were comparable in both groups. Sportswomen had higher intake of energy, macronutrients, calcium, phosphorus and magnesium. Total lean mass (33.67 +/- 3.49 vs. 31.14 +/- 3.52 kg, P < 0.0001), appendicular skeletal muscle index (5.84 +/- 0.57 vs. 5.46 +/- 0.63 kg/m(2); P < 0.0001) and BMC (2.27 +/- 0.32 vs. 2.13 +/- 0.34 kg, P < 0.002) was significantly higher and percentage fat mass was significantly lower (33.1 +/- 7.5 vs. 37.0 +/- 8.3; P < 0.0001) among sportswomen when compared to controls. CONCLUSIONS: Indian sportswomen have a higher total and regional lean mass, BMC, and lower percentage fat mass when compared with healthy females. Physical activity, energy, protein and calcium intake were positively associated with lean mass and BMC. PMID- 25729695 TI - Addressing challenges and needs in patient education targeting hardly reached patients with chronic diseases. AB - Some patients do not benefit from participation in patient education due to reasons related to disease burden, literacy, and socioeconomic challenges. In this communication, we address more specifically both the challenges that these hardly reached patients face in relation to patient education programs and the challenges educators face when conducting patient education with hardly reached patients. We define principles for the format and content of dialogue tools to better support this patient group within the population of individuals with diabetes. PMID- 25729696 TI - Seroprevalence of hepatitis C infection in type 2 diabetes mellitus. AB - INTRODUCTION: Hepatitis C is an emerging disease with different studies showing varying prevalence rates across India. In several studies, prevalence of hepatitis C infection was found to be higher in diabetics than nondiabetics. However, none has been reported from India. OBJECTIVES: The aim was to determine the sero-prevalence of hepatitis C infection in type 2 diabetes mellitus (T2DM). SETTINGS AND DESIGN: Cross-sectional study of all T2DM patients attending endocrine clinic in Regional Institute of Medical Sciences, Imphal from October 2011 to September 2013. SUBJECTS AND METHODS: All T2DM patients included and exclusion criteria are patients with other forms of diabetes, liver failure, renal failure, malignancy or other chronic illness. Patient's age, sex, height, weight, body mass index, history of risk factors, etc., collected and investigated for blood glucose fasting and prandial levels, transaminases levels, hepatitis C virus (HCV) screening, etc.. STATISTICAL ANALYSIS: Statistical analysis was performed using Statistical Package for the Social Sciences version 20; appropriate test used where applicable. RESULTS: Out of the 192 T2DM patients screened, prevalence rate of HCV sero-positivity is found to be 5.7% (11/192), higher in males. History of jaundice in the past was the only significant history among sero-positive patients. Transaminases levels are significantly higher in sero-postive cases. They had higher fasting and postprandial blood glucose, fasting glucose levels being significantly higher. CONCLUSION: Our study shows a slightly higher prevalence of hepatitis C infection in type 2 diabetics. PMID- 25729697 TI - Demographic data of thyroiditis from a south Indian city. AB - BACKGROUND: Thyroiditis involves thyroid gland inflammation due to a wide variety of causes. The common varieties are subacute, silent and postpartum thyroiditis. AIMS AND OBJECTIVES: To retrospectively collect demographic data of thyroiditis from Bangalore over the past 5 years. MATERIALS AND METHODS: Data were collected from three major nuclear medicine centers in Bangalore of the patients who came for technetium (Tc) 99m pertechnetate scan of the thyroid. The diagnosis was based on the Tc 99 scan evidence of thyroiditis in these patients and biochemical evidence of thyrotoxicosis. RESULTS: The total number of cases recorded were 2513. The females were more commonly affected compared with males with sex distribution of 1698 females and 815 females (2:1). The mean age of females was 32.5 +/- 11.3 years whereas the mean age of males was 37.2 +/- 12.4 years. The highest numbers of cases were recorded in the months of June and August. CONCLUSIONS: The females developed thyroiditis frequently and at an earlier age when compared with males. This data could give us an insight into the demographic pattern of thyroiditis in our country and may help in planning future preventive strategies. PMID- 25729698 TI - Hepatitis C virus infection in thalassemic patients with and without insulin dependent diabetes. PMID- 25729699 TI - Women's health at the first South Asian Federation of Endocrine Society conference. PMID- 25729700 TI - Gall bladder agenesis in Prader Willi syndrome. PMID- 25729701 TI - Type 2 diabetes and Helicobacter pylori infection: Starting point for the reality? PMID- 25729702 TI - The recommendation of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine for the assessment of growth hormone secretion in thalassemia. PMID- 25729703 TI - Vitamin D levels in newly detected Type 2 diabetes. PMID- 25729704 TI - Starting with low dose sulfonylurea and metformin in early stage type 2 diabetes mellitus. PMID- 25729705 TI - Vitamin A supplementation among children in India: Does their socioeconomic status and the economic and social development status of their State of residence make a difference? AB - BACKGROUND: India has the largest percentage/number of vitamin A deficient children in the world. However, the effectiveness of a program of vitamin A supplementation at the population level has been rarely examined. We aim to examine the status of vitamin A supplementation among preschool children in India and its association with their socioeconomic and demographic characteristics and the social and economic development level of the State in which they reside. MATERIALS AND METHODS: Data are from a cross-sectional study of 20,802 children aged 12-35 months whose mothers participated in the National Family Health Survey 3 (NFHS-3) conducted during 2005-2006. The association between the socioeconomic and demographic characteristics of the children, the social and economic development status of the State in which they reside and vitamin A supplementation status was examined by means of unadjusted and adjusted logistic regression models. RESULTS: Only 25% of the children in India received vitamin A supplementation, indicating a poor coverage, and the differences between the States were wide (<10% to >45%). Rural children (OR: 1.20; 95% CI: 1.10-1.30; P < 0.0001) and children of educated mothers (OR: 2.40; 95% CI: 2.04-2.83; P < 0.0001) were more likely to receive vitamin A supplementation than others. Children born in a higher birth order (6+) (OR: 0.54; 95% CI: 0.46-0.63; P < 0.0001) and those residing in states with low levels of social and economic development (OR: 0.51; 95% CI: 0.46-0.57; P < 0.0001) were only about half as likely to receive vitamin A supplementation as their counterparts. CONCLUSION: The national vitamin A supplementation program in India did not reach a majority of preschool children in 2005. Greater maternal formal education, higher household wealth status and high social development status of their State of residence appears to be an important determinant for receipt of a vitamin A supplementation by preschool children in India. PMID- 25729706 TI - Pancreatic alpha-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block. AB - Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from alpha-cell has languished whereas beta-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant alpha-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted alpha-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of alpha-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from alpha cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on alpha-cell dysfunction and therapeutic potentials of targeting alpha cell in T2D. PMID- 25729707 TI - Hepatokines as a Link between Obesity and Cardiovascular Diseases. AB - Non-alcoholic fatty liver disease, which is considered a hepatic manifestation of metabolic syndrome, independently increases the risks of developing cardiovascular disease (CVD) and type 2 diabetes mellitus. Recent emerging evidence suggests that a group of predominantly liver-derived proteins called hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls. Here, we summarize the role of the representative hepatokines fibroblast growth factor 21, fetuin-A, and selenoprotein P in the progression of CVD. PMID- 25729708 TI - The optimal cutoff value of glycated hemoglobin for detection of diabetic retinopathy. AB - With standardization of measurement of glycated hemoglobin (A1C), the International Expert Committee Report in 2009 and the American Diabetes Association in 2010 recommended incorporating A1C >=6.5% into the previous diagnostic criteria using fasting plasma glucose and/or 2-hour plasma glucose. Whereas the association of A1C with cardiovascular diseases and other diabetic microvascular complications was linear without evidence of a distinct threshold, several studies suggested a threshold value for A1C in diabetic retinopathy (DR). In studies about the optimal cutoff value for A1C in DR, the A1C values range from 5.2% to 7.8%. There are several possible reasons why these values for DR differ so widely (differences in the definition and/or methods for DR, variation in statistical methods, differences in study population, differences in exclusion criteria, and difference in methods for measuring A1C). With these wide variations in the study method, drawing a conclusive cutoff value for A1C in DR is impossible. In published studies, the cutoff values for moderate or severe DR were higher than those for any or mild DR (6.4% to 7.0% vs. 5.5% to 6.5%). PMID- 25729709 TI - Can Tea Extracts Exert a Protective Effect Against Diabetes by Reducing Oxidative Stress and Decreasing Glucotoxicity in Pancreatic beta-Cells? PMID- 25729710 TI - Subjective Assessment of Diabetes Self-Care Correlates with Perceived Glycemic Control but not with Actual Glycemic Control. AB - BACKGROUND: We investigated whether patients' perceived glycemic control and self reported diabetes self-care correlated with their actual glycemic control. METHODS: A survey was administered among patients with diabetes mellitus at an outpatient clinic with structured self-report questionnaires regarding perceived glycemic control and diabetes self-management. Actual glycemic control was defined as a change in glycated hemoglobin (A1C) or fasting plasma glucose (FPG) since the last clinic visit. RESULTS: Patients who perceived their glycemic control as "improved" actually showed a mild but significant decrease in the mean A1C (-0.1%, P=0.02), and those who perceived glycemic control as "aggravated" had a significant increase in the mean FPG (10.5 mg/dL or 0.59 mmol/L, P=0.04) compared to the "stationary" group. However, one-half of patients falsely predicted their actual glycemic control status. Subjective assessment of diabetes self-care efforts, such as adherence to a diet regimen or physical activity, correlated positively with perceived glycemic control but showed no association with actual glycemic control. CONCLUSION: Patients should be encouraged to assess and monitor diabetes self-care more objectively to motivate behavioral modifications and improve their actual glycemic control. PMID- 25729711 TI - Appendicular skeletal muscle mass and insulin resistance in an elderly korean population: the korean social life, health and aging project-health examination cohort. AB - BACKGROUND: Increasing evidence supports an association between age-related loss of muscle mass and insulin resistance. However, the association has not been fully investigated in the general population. Thus, we investigated the association between appendicular skeletal muscle mass (ASM) and insulin resistance in an elderly Korean population. METHODS: This cross-sectional study included 158 men (mean age, 71.8) and 241 women (mean age, 70.6) from the Korean Social Life, Health and Aging Project, which started in 2011. In this study, ASM was measured by bioelectrical impedance analysis and was analyzed in three forms: ASM (kg), ASM/height(2) (kg/m(2)), and ASM/weight (%). The homeostasis model assessment of insulin resistance (HOMA-IR) was used as a measure of insulin resistance. The relationships between the ASM values and the HOMA-IR were investigated by multiple linear regression models. RESULTS: The HOMA-IR was positively associated with ASM (beta=0.43, P<0.0001) and ASM/height(2) (beta=0.36, P<0.0001) when adjusted for sex and age. However, after additional adjustment for body weight, HOMA-IR was inversely associated with ASM (beta= 0.43, P<0.001) and ASM/height(2) (beta=-0.30, P=0.001). Adjustment for other potential confounders did not change these associations. Conversely, HOMA-IR was consistently and inversely associated with ASM/weight before and after adjustment for other potential confounders. CONCLUSION: Our results support the idea that lower skeletal muscle mass is independently associated with insulin resistance in older adults. When evaluating sarcopenia or muscle-related conditions in older adults, their whole body sizes also need to be considered. PMID- 25729712 TI - Intravitreal ranibizumab for subfoveal choroidal neovascularization from age related macular degeneration with combined severe diabetic retinopathy. AB - BACKGROUND: To evaluate the efficacy of intravitreal ranibizumab for subfoveal choroidal neovascularization (CNV) from age-related macular degeneration (AMD) with combined severe diabetic retinopathy (DR). METHODS: This retrospective, interventional case series included eleven patients (mean age, 70.09 years; range, 54 to 83 years) with at least severe non-proliferative DR and subfoveal CNV secondary to AMD. Each subject was treated with intravitreal injections of 0.5 mg ranibizumab. The primary outcomes included change in best-corrected visual acuity and central subfield thickness (CST) on optical coherence tomography (OCT). RESULTS: The mean follow-up time was 16.7+/-14 months (range, 6 to 31 months). Mean visual acuity improved from 1.21+/-0.80 logarithm of the minimum angle of resolution (logMAR) to 1.0+/-0.6 logMAR (P=0.107), 0.95+/-0.62 logMAR (P=0.044), 1.10+/-0.68 logMAR (P=0.296), and 1.13+/-0.66 logMAR (P=0.838) at 1, 3, 6, and 12 months after injection, respectively. Eight patients (72.7%) gained or maintained vision (mean 0.32 logMAR), whereas three patients (27.3%) lost more than one line of vision (mean 0.51 logMAR). The mean OCT CST was 343.9+/-134.6 um at baseline, and the mean CST at 1, 3, 6, 12 months after the injection was 367.8+/-172.1 (P=0.864), 346.2+/-246.2 (P=0.857), 342+/-194.1 (P=0.551), and 294.2+/-108.3 um (P=0.621), respectively. CONCLUSION: Intravitreal ranibizumab injection can be considered to be a therapy for the stabilization of subfoveal CNV secondary to AMD with combined severe DR. However, these patients might exhibit limited visual improvement after treatment. PMID- 25729713 TI - Hexane Extract of Orthosiphon stamineus Induces Insulin Expression and Prevents Glucotoxicity in INS-1 Cells. AB - BACKGROUND: Hyperglycemia, a characteristic feature of diabetes, induces glucotoxicity in pancreatic beta-cells, resulting in further impairment of insulin secretion and worsening glycemic control. Thus, preservation of insulin secretory capacity is essential for the management of type 2 diabetes. In this study, we evaluated the ability of an Orthosiphon stamineus (OS) extract to prevent glucotoxicity in insulin-producing cells. METHODS: We measured insulin mRNA expression and glucose-stimulated insulin secretion (GSIS) in OS-treated INS 1 cells after exposure to a high glucose (HG; 30 mM) concentration. RESULTS: The hexane extract of OS elevated mRNA expression of insulin as well as pancreatic and duodenal homeobox-1 of INS-1 cells in a dose-dependent manner. The hexane OS extract also increased the levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) in a concentration-dependent manner. Additionally, Akt phosphorylation was elevated by treatment with 100 and 200 umol of the hexane OS extract. Three days of HG exposure suppressed insulin mRNA expression and GSIS; these expressions were restored by treatment with the hexane OS extract. HG elevated peroxide levels in the INS-1 cells. These levels were unaffected by OS treatment under both normal and hyperglycemic conditions. CONCLUSION: Our results suggested that the hexane extract of OS elevates insulin mRNA expression and prevents glucotoxicity induced by a 3-day treatment with HG. This was associated with the activation of PI-3K and Akt. PMID- 25729714 TI - Myeloperoxidase is associated with insulin resistance and inflammation in overweight subjects with first-degree relatives with type 2 diabetes mellitus. AB - BACKGROUND: Family history of type 2 diabetes mellitus (T2DM) is one of risk factors for that in future a subject can develop diabetes. Insulin resistance (IR) is important in the pathogenesis of T2DM. There is evidence that oxidative stress plays an important role in the etiology and/or progression of diabetes. Myeloperoxidase (MPO) participates in developing of inflammation. The objective was to investigate if MPO is associated with IR and inflammation in individuals with first-degree relatives of T2DM. METHODS: Cross-sectional study in 84 overweight individuals with family history of T2DM divided in two groups according to IR, group with IR (homeostasis model assessment [HOMA] >=2.5; n=43) and control group (CG; HOMA <2.5; n=41). Complete clinical history and a venous blood sample were collected for measuring glucose and lipids profile, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), MPO, glutathione reductase (GRd), glutathione peroxidase, and superoxide dismutase. RESULTS: MPO, TNF-alpha, and IL-6 were higher in patients with IR than in CG (MPO: 308.35 [190.85 to 445.42] vs. 177.35 [104.50 to 279.85], P=0.0001; TNF-alpha: 13.46 [10.58 to 18.88] vs. 9.39 [7.53 to 11.25], P=0.0001; IL-6: 32.93 [24.93 to 38.27] vs. 15.60 [12.93 to 26.27]; P=0.0001, respectively). MPO was associated with IR (rho de Spearman=0.362, P=0.001). In the analysis of lineal regression, MPO predicts IR (beta, 0.263; t, 2.520; P=0.014). In the univariate analysis, MPO had an odds ratio of 9.880 for risk of IR (95% confidence interval, 2.647 to 36.879). CONCLUSION: MPO had relation with IR and inflammation parameters in overweight subjects with first-degree relatives of T2DM. We need studies on a casual relationship and molecular mechanisms among the increased serum MPO levels, inflammation markers, and IR. PMID- 25729715 TI - Pattern of thyroid dysfunction in patients with metabolic syndrome and its relationship with components of metabolic syndrome. AB - BACKGROUND: Thyroid dysfunction (TD) and metabolic syndrome (MetS) are known risk factors for atherosclerotic cardiovascular disease (ASCVD). TD is risk factor for ASCVD mediated by the effects of thyroid hormones on lipid metabolism and blood pressure hence the components of MetS. It is possible that coexistence of these two disease entities and unrecognized TD in patients with MetS might substantially increase ASCVD risk. Moreover, little is known about the relationship between TD and the components of MetS. Thus, the purpose of this study was to evaluate the pattern of TD in patients with MetS and its relationship with components of the MetS. METHODS: A total of 358 previously diagnosed patients with MetS were recruited in the study. The thyroid function test parameters were measured to classify TD at Dhulikhel Hospital-Kathmandu University Hospital, Dhulikhel, Nepal. Statistical analyses were performed using SPSS version 16.0 to evaluate pattern and relationship. RESULTS: The overall prevalence of TD in patients with MetS was 31.84% with high prevalence of subclinical hypothyroidism (29.32%). We found no evidence of a relationship between TD and components of MetS, although there was significant difference in waist circumference between four groups of TD. CONCLUSION: Patients with MetS had subclinical hypothyroidism greatly. Although there was no evidence of any relationship between thyroid status and all components of MetS, TD should be taken into account when evaluating and treating patients with MetS to reduce the impending risk. PMID- 25729716 TI - Economic impact of combining metformin with dipeptidyl peptidase-4 inhibitors in diabetic patients with renal impairment in spanish patients. AB - BACKGROUND: To evaluate resource use and health costs due to the combination of metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetes and renal impairment in routine clinical practice. METHODS: An observational, retrospective study was performed. Patients aged >=30 years treated with metformin who initiated a second oral antidiabetic treatment in 2009 to 2010 were included. Two groups of patients were analysed: metformin+DPP-4 inhibitors and other oral antidiabetics. The main measures were: compliance, persistence, metabolic control (glycosylated hemoglobin< 7%) and complications (hypoglycemia, cardiovascular events) and total costs. Patients were followed up for 2 years. RESULTS: We included 395 patients, mean age 70.2 years, 56.5% male: 135 patients received metformin+DPP-4 inhibitors and 260 patients received metformin+other oral antidiabetics. Patients receiving DPP-4 inhibitors showed better compliance (66.0% vs. 60.1%), persistence (57.6% vs. 50.0%), and metabolic control (63.9% vs. 57.3%), respectively, compared with those receiving other oral antidiabetics (P<0.05), and also had a lower rate of hypoglycemia (20.0% vs. 47.7%) and lower total costs (? 2,486 vs. ? 3,002), P=0.001. CONCLUSION: Despite the limitations of the study, patients with renal impairment treated with DPP-4 inhibitors had better metabolic control, lower rates (association) of hypoglycaemia, and lower health costs for the Spanish national health system. PMID- 25729717 TI - Letter: GDF15 Is a Novel Biomarker for Impaired Fasting Glucose (Diabetes Metab J 2014;38:472-9). PMID- 25729718 TI - Response: GDF15 Is a Novel Biomarker for Impaired Fasting Glucose (Diabetes Metab J 2014;38:472-9). PMID- 25729719 TI - Bone marrow flow cytometry in staging of patients with B-cell non-Hodgkin lymphoma. AB - BACKGROUND: Bone marrow biopsies are routinely performed for staging patients with B-cell non-Hodgkin lymphoma (NHL). In addition to histomorphological studies, ancillary tools may be needed for accurate diagnosis. We investigated the clinical utility of multiparameter flow cytometric examination of bone marrow aspirates. METHODS: A total of 248 bone marrow specimens from 232 patients diagnosed with B-cell NHL were examined. Monoclonal antibodies directed against CD19, CD20, CD10 (or CD5), and kappa and lambda immunoglobulins were used. Multi stage sequential gating was performed to select specific cells of interest, and the results were compared with bone marrow histology. RESULTS: The concordance rate between histomorphology and flow cytometry was 91.5% (n=227). Eight cases (3.2%) were detected by flow cytometry alone and were missed by histomorphology analysis, and 6 of these 8 cases showed minimal bone marrow involvement (0.09 2.2%). The diagnosis in these cases included large cell lymphoma (n=3), mantle cell lymphoma (n=3), and mucosa-associated lymphoid tissue (MALT) lymphoma (n=2). Thirteen cases were histopathologically positive and immunophenotypically negative, and the diagnoses in these cases included diffuse large cell lymphoma (n=7), T-cell/histiocyte-rich large B-cell lymphoma (n=2), anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (n=1), follicular lymphoma (n=1), MALT lymphoma (n=1), and unclassifiable lymphoma (n=1). CONCLUSIONS: Multi-color flow cytometry can be a useful method for assessing bone marrow in staging NHL and also plays a complementary role, especially in detecting small numbers of lymphoma cells. PMID- 25729720 TI - Comparison of red blood cell hemolysis using plasma and serum separation tubes for outpatient specimens. AB - BACKGROUND: To rapidly obtain outpatient results, we use plasma separation tubes (PST) for chemistry analysis. If lactate dehydrogenase measurement is required, serum separation tubes (SST) are used. There has been no evaluation of hemolysis with these tubes. We compared the hemolytic index (HI) obtained by using PST and SST and applied this for choosing appropriate tubes for clinical laboratories. METHODS: The HI of specimens obtained from outpatients visiting Asan Medical Center between July and December 2012 was analyzed. The HI was scored from 0 to 10 by using the Toshiba 200FR (Toshiba Medical Systems Co., Japan). HI was classified by sample tube type, and significant hemolysis was defined as a HI of 2 or more. For significant hemolysis cases, medical records were reviewed to identify the causes. RESULTS: Among 171,519 specimens, significant hemolysis was observed in 0.66% of specimens (0.68% of PST specimens, 0.46% of SST specimens). The mean HI in PST was 0.18 (SD: 0.43) and that in SST was 0.14 (SD: 0.37). The proportion of significant hemolysis was significantly higher in PST than in SST (P=0.001). The cause of significant hemolysis was identified as chemotherapy and prosthetic valve in 48.1% of specimens. Complex sampling errors may have caused significant hemolysis in the remaining 51.9% of specimens. CONCLUSIONS: The incidence of hemolysis was slightly higher for PST than SST, although both were <1%. PST are thought to be more useful than SST in outpatient testing because of rapid turnaround time, greater sample volume, and less risk of random errors due to fibrin strands. PMID- 25729721 TI - Establishment of trimester-specific reference intervals for thyroid hormones in Korean pregnant women. AB - BACKGROUND: Establishment of trimester- and assay-specific reference intervals for every population is recommended. The aim of this study was to establish a trimester- and assay-specific reference interval for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in Korean pregnant women. METHODS: From April 2012 to December 2012, 531 pregnant women receiving prenatal care and 238 age-matched, non-pregnant women were enrolled in this study. After excluding patients with pregnancy-associated complications or thyroid-specific autoantibody, 465 pregnant and 206 non-pregnant women were included. Non-parametric analysis (2.5-97.5th percentile) was performed to determine the reference interval. Levels of TSH and FT4 were determined by electrochemiluminescence immunoassay (Elecsys thyroid tests, Roche Diagnostics, Germany). RESULTS: The TSH reference intervals were 0.01-4.10, 0.01-4.26, and 0.15-4.57 mIU/L for the first, second, and third trimester, respectively. From the first trimester to the third trimester, the median TSH levels showed a significantly increasing trend (P<0.0001). The FT4 reference intervals were 0.83-1.65, 0.71-1.22, and 0.65-1.13 ng/dL for the first, second, and third trimester, respectively, showing a significantly decreasing trend (P<0.0001). CONCLUSIONS: Establishing trimester-specific reference intervals in pregnant women is essential for accurate assessment of thyroid function. Our population-specific and method-specific reference intervals will be useful for screening Korean pregnant women for thyroid disease. PMID- 25729722 TI - Species-specific difference in antimicrobial susceptibility among viridans group streptococci. AB - BACKGROUND: Viridans group streptococci (VGS) are both commensal microbes and potential pathogens. Increasing resistance to penicillin in VGS is an ongoing issue in the clinical environment. We investigated the difference in susceptibility and resistance to penicillin among various VGS species. METHODS: In total 1,448 VGS isolated from various clinical specimens were analyzed over a two-yr period. Identification and antimicrobial susceptibility test was performed by the automated VITEK 2 system (bioMerieux, France) or the MicroScan MICroSTREP system (Siemens, Germany). RESULTS: Among the 1,448 isolates, 412 were isolated from blood (28.4%). Streptococcus mitis group was the most frequently isolated (589 isolates, 40.7%), followed by the S. anginosus group (290 isolates, 20.0%), S. sanguinis group (179 isolates, 12.4%) and S. salivarius group (57 isolates, 3.9%). In total, 314 isolates could not be identified up to the species level. The overall non-susceptibility to penicillin was observed to be 40.0% (resistant, 11.2% and intermediately resistant, 28.8%) with uneven distribution among groups; 40.2% in S. sanguinis group (resistant, 5.0% and intermediately resistant, 35.2%), 60.3% in S. mitis group (resistant, 20.9% and intermediately resistant, 39.4%), 78.9% in S. salivarius group (resistant, 8.8% and intermediately resistant, 70.1%), and 6.2% in S. anginosus group (resistant, 1.7% and intermediately resistant, 4.5%). CONCLUSIONS: Antimicrobial resistance patterns towards penicillin show differences among various VGS; this should be considered while devising an effective antimicrobial treatment against VGS. PMID- 25729723 TI - Combined use of the modified Hodge test and carbapenemase inhibition test for detection of carbapenemase-producing Enterobacteriaceae and metallo-beta lactamase-producing Pseudomonas spp. AB - BACKGROUND: We evaluated the combined use of the modified Hodge test (MHT) and carbapenemase inhibition test (CIT) using phenylboronic acid (PBA) and EDTA to detect carbapenemase-producing Enterobacteriaceae (CPE) and metallo-beta lactamase (MBL)-producing Pseudomonas spp. METHODS: A total of 49 isolates of CPE (15 Klebsiella pneumoniae carbapenemase [KPC], 5 Guiana extended-spectrum beta lactamase [GES]-5, 9 New Delhi metallo-beta-lactamase [NDM]-1, 5 Verona integron encoded metallo-beta-lactamase [VIM]-2, 3 imipenem-hydrolyzing beta-lactamase [IMP], and 12 oxacillinase [OXA]-48-like), 25 isolates of MBL-producing Pseudomonas spp. (14 VIM-2 and 11 IMP), and 35 carbapenemase-negative controls were included. The MHT was performed for all isolates as recommended by the Clinical and Laboratory Standards Institute. Enhanced growth of the indicator strain was measured in mm with a ruler. The CIT was performed by directly dripping PBA and EDTA solutions onto carbapenem disks that were placed on Mueller Hinton agar plates seeded with the test strain. RESULTS: Considering the results of the MHT with the ertapenem disk in Enterobacteriaceae and Pseudomonas spp., the CIT with the meropenem disk in Enterobacteriaceae, and the imipenem disk in Pseudomonas spp., three combined disk tests, namely MHT-positive plus PBA positive, EDTA-positive, and MHT-positive plus PBA-negative plus EDTA-negative, had excellent sensitivity and specificity for the detection of KPC- (100% sensitivity and 100% specificity), MBL- (94% sensitivity and 100% specificity), and OXA-48-like-producing isolates (100% sensitivity and 100% specificity), respectively. CONCLUSIONS: Combined use of the MHT and CIT with PBA and EDTA, for the detection of CPE and MBL-producing Pseudomonas spp., is effective in detecting and characterizing carbapenemases in routine laboratories. PMID- 25729724 TI - Clinical usefulness of bronchoalveolar lavage cellular analysis and lymphocyte subsets in diffuse interstitial lung diseases. AB - BACKGROUND: Diffuse interstitial lung diseases (DILDs) form a part of a heterogeneous group of respiratory diseases. Bronchoalveolar lavage (BAL) analysis has been used for differential diagnosis of DILDs, but their clinical usefulness is controversial. The aim of this study was to investigate the clinical usefulness of BAL cellular analysis with lymphocyte subsets for the differential diagnosis of DILDs. METHODS: A total of 69 patients diagnosed with DILDs were enrolled. Basic demographic data, BAL cellular analysis with lymphocyte subsets, histology, and high resolution computed tomogram (HRCT) findings were analyzed and compared as per disease subgroup. RESULTS: Significant differences were found between groups in the proportion of neutrophils (P=0.0178), eosinophils (P=0.0003), T cells (P=0.0305), CD4 cells (P=0.0002), CD8 cells (P<0.0001), and CD4/CD8 ratio (P<0.0001). These findings were characteristic features of eosinophilic pneumonia and sarcoidosis. Other parameters were not significantly different between groups. At the cut-off value of 2.16 for sarcoidosis, CD4/CD8 ratio showed sensitivity of 91.7% (95% CI, 61.5 98.6%) and specificity of 84.2% (95% CI, 72.1-92.5%). CONCLUSIONS: Routine analysis of BAL lymphocyte subset may not provide any additional benefit for differential diagnosis of DILDs, except for conditions where BAL is specifically indicated, such as eosinophilic pneumonia or sarcoidosis. PMID- 25729725 TI - Quantitative measurement of serum microRNA-21 expression in relation to breast cancer metastasis in Chinese females. AB - BACKGROUND: Breast cancer is the most common type of cancer in females. Aberrant expression of microRNA-21 (miR-21) has previously been reported in breast cancer tissue. The aim of this study was to investigate expression levels of serum miR 21 in breast cancer patients and evaluate its prognostic value in Chinese females. METHODS: Real-time quantitative (RQ)-PCR was used to analyze miR-21 expression in archived serum, tumor tissue, and adjacent normal tissue from 549 participants (326 with breast cancer, 223 without breast cancer). We also analyzed associations between serum miR-21 expression and breast cancer subtypes and patient prognosis. Recurrence and survival were analyzed by using the multivariate Cox proportional hazards model. RESULTS: Expression of miR-21 was significantly higher in breast cancer tissues compared with normal adjacent breast tissues (P<0.001). The 2(-DeltaDeltaCt) values for serum miR-21 in breast cancer patients versus healthy controls were 9.12+/-3.43 and 2.96+/-0.73, respectively. Multivariate Cox proportional hazards model suggested that serum miR-21 expression was an independent poor prognostic factor for both recurrence (hazard ratio [HR]= 2.942; 95% confidence interval [CI]=1.420-8.325; P=0.008) and disease-free survival (HR=2.732; 95% CI=1.038-7.273, P=0.003) in breast cancer. CONCLUSIONS: Increased serum miR-21 expression level was correlated with poor prognosis of breast cancer patients, indicating that serum miR-21 may be a novel prognostic marker for recurrence and survival of breast cancer patients before resection. PMID- 25729726 TI - Incidence, clinical features, and prognostic impact of CALR exon 9 mutations in essential thrombocythemia and primary myelofibrosis: an experience of a single tertiary hospital in Korea. AB - We evaluated the incidence, clinical characteristics, and prognostic impact of calreticulin (CALR) mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. In all, 48 ET and 14 PMF patients were enrolled, and the presence of CALR mutations was analyzed by direct sequencing. Patients were classified into three subgroups according to Janus kinase 2 (JAK2) V617F and CALR mutation status, and their clinical features and prognosis were compared. CALR mutations were detected in 15 (24.2%) patients, and the incidence increased to 50.0% in 30 JAK2 V617F mutation-negative cases. These included 11 patients with three known mutations (c.1092_1143del [seven cases], c.1154_1155insTTGTC [three cases], and c.1102_1135del [one case]) and 4 patients with novel mutations. ET patients carrying CALR mutation were younger, had lower white blood cell counts, and experienced less thrombosis during follow-up than those carrying JAK2 V617F mutation, while both patient groups showed similar clinical features and prognosis. In ET patients without JAK2 V617F mutation, CALR mutation did not significantly affect clinical manifestation and prognosis. In conclusion, CALR mutation analysis could be a useful diagnostic tool for ET and PMF in 50% of the cases without JAK2 V617F mutations. The prognostic impact of CALR mutations needs further investigation. PMID- 25729728 TI - Molecular characteristics of noroviruses genogroup I and genogroup II detected in patients with acute gastroenteritis. AB - Noroviruses are the leading cause of epidemic gastroenteritis, including foodborne outbreak, in Korea. The prevalence of human noroviruses was studied in diarrheal stool samples of patients with acute gastroenteritis by conventional duplex reverse transcription (RT)-PCR. Diarrheal stool samples were collected from 1,685 patients from the local hospitals in Seoul. The prevalence of the noroviruses was 22.8% (222/972 patients) in 2012 and 11.2% (80/713 patients) in 2013, with a total of 17.9% (302/1,685 patients). Genotyping was performed on 302 norovirus-positive stool samples to reveal 5.6% prevalence of genogroup I (GI) (17/302) and 94.4% prevalence of genogroup II (GII) (285/302). The patients with norovirus-associated acute gastroenteritis mostly showed prevalence of GII norovirus, especially GII.4 (64.6%; 195/302). PMID- 25729727 TI - Evaluation of random urine sodium and potassium compensated by creatinine as possible alternative markers for 24 hours urinary sodium and potassium excretion. AB - Sodium and potassium intake was assessed on the basis of its respective excretion levels in 24 hr urine samples. However, owing to the inconvenience of collection, we evaluated random spot urine for alternative sodium and potassium excretion markers. We included 250 patients who submitted 24 hr- and spot urine for clinical tests. However, 22 patients who showed 24 hr urine creatinine excretion levels <500 mg/day were excluded, because these samples possibly resulted from incomplete urine collection. Moreover, 24 patients were excluded because of their use of diuretics during the urine collection period. We observed significant correlations between 24 hr urine sodium excretion and both the sodium/creatinine (r=0.34, P<0.0001) and the sodium/specific gravity unit (SGU) ratios (r=0.19, P=0.007) in random urine samples. Similarly, 24 hr urine potassium excretion and both the spot urine potassium/creatinine (r=0.47, P<0.0001) and potassium/SGU ratios (r=0.28, P<0.0001) were significantly correlated. Although the estimated sodium/creatinine and potassium/creatinine ratios showed a significant correlation with 24 hr urine sodium and potassium excretion, respectively, further studies are required to develop a spot urine test for individualized monitoring of sodium and potassium excretion. PMID- 25729729 TI - The sul1 gene in Stenotrophomonas maltophilia with high-level resistance to trimethoprim/sulfamethoxazole. AB - Emerging resistance to trimethoprim/sulfamethoxazole (SXT) poses a serious threat to the treatment of Stenotrophomonas maltophilia infections. We determined the prevalence and molecular characteristics of acquired SXT resistance in recent clinical S. maltophilia isolates obtained from Korea. A total of 252 clinical isolates of S. maltophilia were collected from 10 university hospitals in Korea between 2009 and 2010. Antimicrobial susceptibility was determined by using the CLSI agar dilution method. The sul1, sul2, and sul3 genes, integrons, insertion sequence common region (ISCR) elements, and dfrA genes were detected using PCR. The presence of the sul1 gene and integrons was confirmed through sequence analysis. Among the 32 SXT-resistant isolates, sul1 was detected in 23 isolates (72%), all of which demonstrated high-level resistance (>=64 mg/L) to SXT. The sul1 gene (varying in size and structure) was linked to class 1 integrons in 15 of the 23 isolates (65%) harboring this gene. None of the SXT-susceptible isolates or the SXT-resistant isolates with a minimum inhibitory concentration of 4 and 8 mg/L were positive for sul1. Moreover, the sul2, sul3, and dfrA genes or the ISCR elements were not detected. The sul1 gene may play an important role in the high-level SXT resistance observed in S. maltophilia. PMID- 25729730 TI - Clinical and microbiological characteristics of six Staphylococcus pettenkoferi isolates from blood samples. AB - Coagulase-negative staphylococci (CoNS) are reported to be the leading cause of nosocomial bloodstream infections. Staphylococcus pettenkoferi is a novel member of CoNS that was first isolated from the human blood and bursitis wound in 2002. We have reported cases of 6 S. pettenkoferi strains isolated from blood specimens, including one pathogen and 5 contaminants and catheter colonizers. Brucker Biotyper (Brucker Daltonics, Bremen, Germany) and molecular typing with 16S rRNA gene sequencing confirmed the 6 isolates as S. pettenkoferi. The conventional phenotypic identification of these isolates is not reliable owing to their inconsistent biochemical characteristics. Five of the 6 isolates were found to be resistant to oxacillin, and all isolates showed susceptibility to vancomycin and linezolid. For accurate identification of this novel species, advanced methods by using Brucker Biotyper or molecular methods such as 16S rRNA gene sequencing are required. PMID- 25729731 TI - Pediatric B-cell lymphoma, unclassifiable, with intermediate features between those of diffuse large B-cell lymphoma and Burkitt lymphoma: a report of two cases. PMID- 25729732 TI - BRAF V600E and MAP2K1 mutations in hairy cell leukemia and splenic marginal zone lymphoma cases. PMID- 25729733 TI - De novo leukemic variant of mast cell leukemia with KIT D816V. PMID- 25729734 TI - Efficacy of the measurement of 25-hydroxyvitamin D2 and D3 levels by using PerkinElmer liquid chromatography-tandem mass spectrometry vitamin D kit compared with DiaSorin radioimmunoassay kit and Elecsys vitamin D total assay. PMID- 25729735 TI - First Korean case of Cedecea lapagei pneumonia in a patient with chronic obstructive pulmonary disease. PMID- 25729736 TI - Two cases of Shwachman-Diamond syndrome in adolescents confirmed by genetic analysis. PMID- 25729737 TI - A Korean case of de novo 18q deletion syndrome with a large atrial septal defect and cyanosis. PMID- 25729738 TI - First Korean case of SATB2-associated 2q32-q33 microdeletion syndrome. PMID- 25729739 TI - The cis-AB01 allele originated from the A105 allele, and not from the A102 allele. PMID- 25729740 TI - Support after brain tumor means different things: family caregivers' experiences of support and relationship changes. AB - Shorter hospital stays and greater emphasis on outpatient care means that family members have the primary responsibility for supporting a person with brain tumor to manage the physical, cognitive, behavioral, and emotional effects of the illness and its treatment. Given the integral role of family caregivers, it is essential to understand their experience of the impact of brain tumor and their own support needs. Accordingly, this qualitative study aimed to investigate family caregivers' experiences of support and relationship changes in the context of brain tumor. In-depth interviews were conducted with 11 family caregivers (8 spouse/partner, 3 parents) of people with malignant or benign tumor. A thematic analysis of interview transcripts identified two major themes, namely, "Meanings of Support" and "Relationship Impacts." The Meanings of Support theme was characterized by intertwined and distinct support needs, varied expectations of support and factors influencing support expectations. The Relationship Impacts theme depicted mixed experiences of strengthened, maintained, and strained relations with the person with brain tumor. Overall, the findings highlight that there is considerable variability in caregivers' experiences and expectations of support and the impact of brain tumor on relationships. The implications of these findings for the provision of caregiver support are discussed. PMID- 25729742 TI - Editorial: HEAD AND NECK MALGNANCIES. PMID- 25729741 TI - Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis. AB - INTRODUCTION: Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO)-associated bacteremia. MATERIALS AND METHODS: This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012. It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR) and MDRO associated bacteremia. RESULTS: Out of 75 bacteremias, 42.7% were gram-positive (GP), and 57.3% were gram-negative (GN). GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias). Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms) and Klebsiella pneumoniae(13.3% of total, 23.3% of GN organisms) were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS) bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p < 0.05). CONCLUSION: Our findings have major implications for the management of febrile neutropenia, especially in breakthrough bacteremia and fever when patients are already on broadspectrum antibiotics. Emergence of resistance to 3GCs and, to a lesser extent, to carbapenems in GN isolates has to be considered seriously in our local guidelines for empiric treatment of febrile neutropenia, especially given that their occurrence was proven to be associated with poorer outcomes. PMID- 25729744 TI - Clinical changes of TMD and condyle stability after two jaw surgery with and without preceding TMD treatments in class III patients. AB - BACKGROUND: This study are to identify the symptomatic changes and condylar stability after 2 jaw surgery without preceding treatments for Temporomandibular joints(TMJ) in class III patients with the TMJ symptoms; and to assess therapeutic effect of 2 jaw surgery and the necessity of preceding treatment for alleviation of TMJ symptoms. METHODS: 30 prognathic patients with preexisting TMJ symptoms were divided into 2 groups according to presence or absence of preceding treatments before the surgery. We evaluated symptomatic changes on both TMJ by questionnaires and clinical examinations. And we reconstructed 3D cone beam computed tomography images before 2 jaw surgery, immediately after the surgery, and 6 months or more after the surgery with SimPlant software, and analyzed the stability of condylar position on 3D reconstruction model. Significances were assessed by the Wilcoxon signed rank test on SPSS ver. 20.0. RESULTS: Both groups had favorable changes of TMJ symptoms after orthognathic surgery. And postoperative position of condyle had good stability during follow-up period. CONCLUSION: 2 jaw surgery without preceding treatments for TMD can have therapeutic effect for TMD patients with class III malocclusion. PMID- 25729745 TI - Robotic Surgery may Not "Make the Cut" in Pediatrics. AB - Since the introduction of robotic surgery in children in 2001, it has been employed by select pediatric laparoscopic surgeons, but not to the degree of adult surgical specialists. It has been suggested that the technical capabilities of the robot may be ideal for complex pediatric surgical cases that require intricate dissection. However, due to the size constraints of the robot for small pediatric patients, the tight financial margins that pediatric hospitals face, and the lack of high level data displaying patient benefit when compared to conventional laparoscopic surgery, it may be some time before the robotic surgical platform is widely embraced in pediatric surgical practice. PMID- 25729746 TI - Diagnostic approach for monitoring hydroclimatic conditions related to emergence of west nile virus in west virginia. AB - West Nile virus (WNV), mosquito-borne and water-based disease, is increasingly a global threat to public health. Since its appearance in the northeastern United States in 1999, WNV has since been reported in several states in the continental United States. The objective of this study is to highlight role of hydroclimatic processes estimated through satellite sensors in capturing conditions for emergence of the vectors in historically disease free regions. We tested the hypothesis that an increase in surface temperature, in combination with intensification of vegetation, and enhanced precipitation, lead to conditions favorable for vector (mosquito) growth. Analysis of land surface temperature (LST) pattern shows that temperature values >16 degrees C, with heavy precipitation, may lead to abundance of the mosquito population. This hypothesis was tested in West Virginia where a sudden epidemic of WNV infection was reported in 2012. Our results emphasize the value of hydroclimatic processes estimated by satellite remote sensing, as well as continued environmental surveillance of mosquitoes, because when a vector-borne infection like WNV is discovered in contiguous regions, the risk of spread of WNV mosquitoes increase at points where appropriate hydroclimatic processes intersect with the vector niche. PMID- 25729743 TI - Therapeutic application of neural stem cells and adult neurogenesis for neurodegenerative disorders: regeneration and beyond. AB - With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease. PMID- 25729747 TI - Commentary on "Questioning the HIV-AIDS Hypothesis: 30 Years of Dissent". PMID- 25729748 TI - Publisher Statement on "Questioning the HIV-AIDS Hypothesis: 30 Years of Dissent". PMID- 25729751 TI - Current status of blood transfusion and antifibrinolytic therapy in orthopedic surgeries. PMID- 25729749 TI - Primary endosymbiosis and the evolution of light and oxygen sensing in photosynthetic eukaryotes. AB - The origin of the photosynthetic organelle in eukaryotes, the plastid, changed forever the evolutionary trajectory of life on our planet. Plastids are highly specialized compartments derived from a putative single cyanobacterial primary endosymbiosis that occurred in the common ancestor of the supergroup Archaeplastida that comprises the Viridiplantae (green algae and plants), red algae, and glaucophyte algae. These lineages include critical primary producers of freshwater and terrestrial ecosystems, progenitors of which provided plastids through secondary endosymbiosis to other algae such as diatoms and dinoflagellates that are critical to marine ecosystems. Despite its broad importance and the success of algal and plant lineages, the phagotrophic origin of the plastid imposed an interesting challenge on the predatory eukaryotic ancestor of the Archaeplastida. By engulfing an oxygenic photosynthetic cell, the host lineage imposed an oxidative stress upon itself in the presence of light. Adaptations to meet this challenge were thus likely to have occurred early on during the transition from a predatory phagotroph to an obligate phototroph (or mixotroph). Modern algae have recently been shown to employ linear tetrapyrroles (bilins) to respond to oxidative stress under high light. Here we explore the early events in plastid evolution and the possible ancient roles of bilins in responding to light and oxygen. PMID- 25729752 TI - Perceived Characteristics of E-cigarettes as an Innovation by Young Adults. AB - OBJECTIVES: We examined channels through which information about e-cigarettes has flowed, public perception of e-cigarettes as an innovation, and how these may influence use. METHODS: An online survey of US adults aged 18-24 years (N = 874) was used. Measures included information channels, perception of e-cigarettes as an innovation, and intention to use. RESULTS: Television ranked first for exposure to e-cigarette information. The most positive innovation attributes were observability and relative advantage. A structural model showed that information exposure and favorable perception as an innovation predicted use. CONCLUSIONS: The high degree of e-cigarette awareness combined with depiction of the devices as a favorable innovation may contribute to their wider adoption and may argue for regulation of e-cigarette advertising. PMID- 25729750 TI - Bronchopulmonary dysplasia early changes leading to long-term consequences. AB - Neonatal chronic lung disease, i.e., bronchopulmonary dysplasia, is characterized by impaired pulmonary development resulting from the impact of different risk factors including infections, hyperoxia, and mechanical ventilation on the immature lung. Remodeling of the extracellular matrix, apoptosis as well as altered growth factor signaling characterize the disease. The immediate consequences of these early insults have been studied in different animal models supported by results from in vitro approaches leading to the successful application of some findings to the clinical setting in the past. Nonetheless, existing information about long-term consequences of the identified early and most likely sustained changes to the developing lung is limited. Interesting results point towards a tremendous impact of these early injuries on the pulmonary repair capacity as well as aging related processes in the adult lung. PMID- 25729753 TI - Orientation of US Young Adults toward E-cigarettes and their Use in Public. AB - OBJECTIVES: We examined use of e-cigarettes and views toward their use in public. METHODS: An online survey of US adults aged 18-24 (N = 874) was used. Measures included tobacco/e-cigarette use, acceptability of public cigarette/e-cigarette use, intention to use e-cigarettes, attitudes and norms. RESULTS: There was greater acceptance of public e-cigarette use than cigarettes. A path model revealed that attitudes and norms concerning e-cigarettes predicted the use of e cigarettes beyond the effect of smoking. Attitudes also were shown to predict intention for future e-cigarette use above the effect of current and past smoking, and to predict acceptability of public use of e-cigarettes. CONCLUSIONS: Normative acceptance of e-smoking in public may contribute to the wider adoption of e-cigarettes. PMID- 25729754 TI - Technology and Health Care: Efficiency, Frustration, and Disconnect in the Transition to Electronic Medical Records. AB - This study investigates one medical facility's transition to electronic medical records (becoming "paperless"). We utilized face-to-face interviews to investigate the transition process with one implementer (the vice president of the medical facility) and three stakeholders from one of the four offices (an assistant office manager, a nurse, and a medical technician). We discuss the dominant themes of efficiency, frustration, and disconnect as well as conclusions and implications. PMID- 25729755 TI - Attachment and Health-Related Physiological Stress Processes. AB - People who are more securely attached to close partners show health benefits, but the mechanisms underlying this link are not well specified. We focus on physiological pathways that are potential mediators of the connection between attachment in childhood and adulthood and health and disease outcomes. Growing evidence indicates that attachment insecurity (vs. security) is associated with distinctive physiological responses to stress, including responses involving the HPA, SAM and immune systems, but these responses vary with type of stressor (e.g., social/nonsocial) and contextual factors (e.g., partner's attachment style). Taking this more nuanced perspective will be important for understanding the conditions under which attachment shapes health-related physiological processes as well as downstream health and disease consequences. PMID- 25729756 TI - Attachment and Dyadic Regulation Processes. AB - Insecurely attached people have relatively unhappy and unstable romantic relationships, but the quality of their relationships depends on how their partners regulate them. Some partners find ways to regulate the emotional and behavioral reactions of insecurely attached individuals, which promotes greater relationship satisfaction and security. We discuss attachment theory and interdependence dilemmas, and then explain how and why certain responses by partners assuage the cardinal concerns of insecure individuals in key interdependent situations. We then review recent studies illustrating how partners can successfully regulate the reactions of anxiously and avoidantly attached individuals, yielding more constructive interactions. We finish by considering how these regulation processes can create a more secure dyadic environment, which helps to improve relationships and attachment security across time. PMID- 25729757 TI - Culture and emotion regulation. AB - While anthropological research has long emphasized cultural differences in whether emotions are viewed as beneficial versus harmful, psychological science has only recently begun to systematically examine those differences and their implications for emotion regulation and well-being. Underscoring the pervasive role of culture in people's emotions, we summarize research that has examined links between culture, emotion regulation, and well-being. Specifically, we focus on two questions. First, how does culture lead individuals to regulate their emotions? And second, how does culture modulate the link between emotion regulation and well-being? We finish by suggesting directions for future research to advance the study of culture and emotion regulation. PMID- 25729758 TI - Cognitive Therapy to Prevent Depressive Relapse in Adults. AB - The high prevalence, frequent relapse, and recurrence of major depressive disorder (MDD) increase its personal and societal costs. Cognitive therapy (CT) aims to decrease depressive symptoms and prevent relapse/recurrence. We review prevention evidence for acute, continuation, and maintenance CTs for patients whose depression is active, remitted, and recovered, respectively. Evidence suggests that patients relapse less often after discontinuing acute phase CT versus discontinuing pharmacotherapy. Continuation CT further decreases relapse relative to inactive controls and similarly to active pharmacotherapy. Maintenance CT may decrease recurrence but needs rigorous evaluation. Post-acute CT's preventive effects appear greater for higher-risk patients (e.g., with residual depressive symptoms, unstable acute-phase treatment response, childhood trauma, more prior depressive episodes), although risks may vary by specific CTs. PMID- 25729759 TI - Sex differences in PTSD resilience and susceptibility: Challenges for animal models of fear learning. AB - PTSD occurs in only a small fraction of trauma-exposed individuals, but risk is twice as high in women as in men. The neurobiological basis for this discrepancy is not known, but the identification of biological determinants of resilience and susceptibility in each sex could lead to more targeted preventions and treatments. Animal models are a useful tool for dissecting the circuits and mechanisms that underlie the brain's response to stress, but the vast majority of this work has been developed and conducted in males. The limited work that does incorporate female animals is often inconsistent across labs and does not broadly reflect human populations in terms of female susceptibility to PTSD-like behaviors. In this review, we suggest that interpreting male vs. female comparisons in these models be approached carefully, since common behavioral outcome measures may in fact reflect distinct neural processes. Moreover, since the factors that determine resilience and susceptibility are likely at least in part distinct in men and women, models that take a within-sex approach to response variability may be more useful in identifying critical mechanisms for manipulation. PMID- 25729760 TI - Glucocorticoid Mechanisms of Functional Connectivity Changes in Stress-Related Neuropsychiatric Disorders. AB - Stress-especially chronic, uncontrollable stress-is an important risk factor for many neuropsychiatric disorders. The underlying mechanisms are complex and multifactorial, but they involve correlated changes in structural and functional measures of neuronal connectivity within cortical microcircuits and across neuroanatomically distributed brain networks. Here, we review evidence from animal models and human neuroimaging studies implicating stress-associated changes in functional connectivity in the pathogenesis of PTSD, depression, and other neuropsychiatric conditions. Changes in fMRI measures of corticocortical connectivity across distributed networks may be caused by specific structural alterations that have been observed in the prefrontal cortex, hippocampus, and other vulnerable brain regions. These effects are mediated in part by glucocorticoids, which are released from the adrenal gland in response to a stressor and also oscillate in synchrony with diurnal rhythms. Recent work indicates that circadian glucocorticoid oscillations act to balance synapse formation and pruning after learning and during development, and chronic stress disrupts this balance. We conclude by considering how disrupted glucocorticoid oscillations may contribute to the pathophysiology of depression and PTSD in vulnerable individuals, and how circadian rhythm disturbances may affect non psychiatric populations, including frequent travelers, shift workers, and patients undergoing treatment for autoimmune disorders. PMID- 25729762 TI - Death Receptor-Mediated Cell Death and Proinflammatory Signaling in Nonalcoholic Steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is becoming public health problem worldwide. A subset of patients develop an inflammatory disease, nonalcoholic steatohepatitis (NASH), characterized by steatosis, hepatocellular death, macrophage and neutrophil accumulation and varying stages of fibrosis. Hepatocyte cell death triggers the cellular inflammatory response and, therefore, reducing cell death may be salutary in the steatohepatitis disease process. Recently, a better understanding of hepatocyte apoptosis in NASH has been obtained and new information regarding other cell death modes, such as necroptosis and pyroptosis, has been reported. Hepatocyte lipotoxicity is often triggered by death receptors. In addition to causing apoptosis, death receptors have been shown to mediate proinflammatory signaling, suggesting that apoptosis in this context is not an immunologically silent process. Here we review recent developments in our understanding of hepatocyte cell death by death receptors and its mechanistic link to inflammation in NASH. We emphasize how proapoptotic signaling by death receptors may induce the release of proinflammatory extracellular vesicles, thereby recruiting and activating macrophages and promoting the steatohepatitis process. Potential therapeutic strategies are discussed based on this evolving information. PMID- 25729764 TI - Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis. AB - BACKGROUND AND AIMS: Cathelicidin (LL-37 in human and mCRAMP in mice) represents a family of endogenous antimicrobial peptides with anti-inflammatory effects. LL 37 also suppresses collagen synthesis, an important fibrotic response, in dermal fibroblasts. Here we determined whether exogenous cathelicidin administration modulates intestinal fibrosis in two animal models of intestinal inflammation and in human colonic fibroblasts. METHODS: C57BL/6J mice (n=6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6-7 weeks) colitis with fibrosis. mCRAMP peptide (5 mg/kg every 3 day, week 5-7) or cathelicidin gene (Camp)-expressing lentivirus (107 infectious units week 4) were administered intracolonically or intravenously, respectively. 129Sv/J mice were infected with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp expressing lentivirus (107 infectious units day 11) was administered intravenously. RESULTS: TNBS-induced chronic colitis was associated with increased colonic collagen (col1a2) mRNA expression. Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice, compared to vehicle administration. Salmonella infection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery of Camp-expressing lentivirus. Exposure of human primary intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor-beta1 (TGF-beta1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, that was reduced by LL-37 (3-5 uM) through a MAP kinase-dependent mechanism. CONCLUSION: Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts. PMID- 25729763 TI - Microbial activities and intestinal homeostasis: A delicate balance between health and disease. AB - The concept that the intestinal microbiota modulates numerous physiological processes including immune development and function, nutrition and metabolism as well as pathogen exclusion is relatively well established in the scientific community. The molecular mechanisms driving these various effects and the events leading to the establishment of a "healthy" microbiome are slowly emerging. The objective of this review is to bring into focus important aspects of microbial/host interactions in the intestine and to discuss key molecular mechanisms controlling health and disease states. We will discuss recent evidence on how microbes interact with the host and one another and their impact on intestinal homeostasis. PMID- 25729765 TI - Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice. AB - BACKGROUND & AIMS: In the pancreas, activation of primary sensory nerves through the transient receptor potential ion channel TRPV1 contributes to the early stages of development of pancreatitis. Little is known about the mechanism by which this occurs. We investigated whether leukotriene B4 (LTB4) is an endogenous agonist of TRPV1 and mediates pancreatitis. METHODS: Acute inflammation was induced in the pancreata of Trpv1-/- mice and their wild-type littermates by retrograde infusion of the main pancreatic duct with 2% sodium taurocholate (NaT) or intraperitoneal injections of caerulein. Mice were also given injections of resiniferatoxin (an excitotoxin that desensitizes TRPV1) or MK886 (a drug that inhibits LTB4 biosynthesis). Pancreatic tissues and plasma were collected and analyzed. RESULTS: Retrograde perfusion of the main pancreatic ducts of wild-type mice with NaT caused severe acute pancreatitis; severity was reduced by co administration of resiniferatoxin. Trpv1-/- mice developed a less severe pancreatitis following NaT administration than controls. Administration of MK886 before perfusion with NaT also significantly reduced the severity of pancreatitis in wild-type mice. Pancreatic tissues from mice given NaT had a marked increase in the level of 5-lipoxygenase immunoreactivity specifically in acinar cells. Bile acid and caerulein induced secretion of LTB4 by cultured pancreatic acinar cells; MK886 inhibited this process. CONCLUSIONS: Administration of caerulein or intraductal bile acids in mice causes production of LTB4 by pancreatic acinar cells. This activates TRPV1 on primary sensory nerves to induce acute pancreatitis. PMID- 25729767 TI - Representations for the generalized Drazin inverse of the sum in a Banach algebra and its application for some operator matrices. AB - We investigate additive properties of the generalized Drazin inverse in a Banach algebra A. We find explicit expressions for the generalized Drazin inverse of the sum a + b, under new conditions on a, b ? A. As an application we give some new representations for the generalized Drazin inverse of an operator matrix. PMID- 25729766 TI - Compensatory Enlargement of Ossabaw Miniature Swine Coronary Arteries in Diffuse Atherosclerosis. AB - Studies in human and non-human primates have confirmed the compensatory enlargement or positive remodeling (Glagov phenomenon) of coronary vessels in the presence of focal stenosis. To our knowledge, this is the first study to document arterial enlargement in a metabolic syndrome animal model with diffuse coronary artery disease (DCAD) in the absence of severe focal stenosis. Two different groups of Ossabaw miniature pigs were fed a high fat atherogenic diet for 4 months (Group I) and 12 months (Group II), respectively. Group I (6 pigs) underwent contrast enhanced computed tomographic angiography (CCTA) and intravascular ultrasound (IVUS) at baseline and after 4 months of high fat diet, whereas Group II (7 pigs) underwent only IVUS at 12 months of high fat diet. IVUS measurements of the left anterior descending (LAD), left circumflex (LCX) and right coronary (RCA) arteries in Group I showed an average increase in their lumen cross-sectional areas (CSA) of 25.8%, 11.4%, and 43.4%, respectively, as compared to baseline. The lumen CSA values of LAD in Group II were found to be between the baseline and 4 months values in Group I. IVUS and CCTA measurements showed a similar trend and positive correlation. Fractional flow reserve (FFR) was 0.91+/-0.07 at baseline and 0.93+/-0.05 at 4 months with only 2.2%, 1.6% and 1% stenosis in the LAD, LCX and RCA, respectively. The relation between percent stenosis and lumen CSA shows a classical Glagov phenomenon in this animal model of DCAD. PMID- 25729768 TI - Sublethal heavy metal stress stimulates innate immunity in tomato. AB - Effect of sublethal heavy metal stress as plant biotic elicitor for triggering innate immunity in tomato plant was investigated. Copper in in vivo condition induced accumulation of defense enzymes like peroxidase (PO), polyphenol oxidase (PPO), phenylalanine ammonia-lyase (PAL), and beta-1,3 glucanase along with higher accumulation of total phenol, antioxidative enzymes (catalase and ascorbate peroxidase), and total chlorophyll content. Furthermore, the treatment also induced nitric oxide (NO) production which was confirmed by realtime visualization of NO burst using a fluorescent probe 4,5-diaminofluorescein diacetate (DAF-2DA) and spectrophotometric analysis. The result suggested that the sublethal dose of heavy metal can induce an array of plant defense responses that lead to the improvement of innate immunity in plants. PMID- 25729770 TI - Do United States' teachers know and adhere to the national guidelines on asthma management in the classroom? A systematic review. AB - Proper asthma management in schools is important in achieving optimum asthma control in children with asthma. The National Heart, Lung, and Blood Institute (NHLBI) has developed guidelines on classroom asthma management. We conducted a systematic review to examine teacher knowledge of the NHLBI guidelines on asthma management in the classroom. We searched PubMed and EMBASE using search terms "asthma management," "teacher(s)," "school teacher," and "public school." The inclusion criteria were articles published in English from 1994 to May 2014 that focus on schools in the United States (US). From 535 titles and abstracts, 9 studies met inclusion criteria. All studies reported that school teachers did not know the policies and procedures of asthma management. Teachers relied on school nurses to handle medical emergencies. Some studies identified that lack of full time school nurses was a barrier to asthma management. Only one study showed directly that classroom teachers were not following the NHLBI guidelines on asthma management. Our literature review revealed that US teachers do not know the NHLBI guidelines on asthma management in the classroom. Future research should focus on interventions targeted toward training classroom teachers on asthma management as per NHLBI guidelines to ultimately improve asthma management in schools. PMID- 25729771 TI - Evaluation of single-bundle versus double-bundle PCL reconstructions with more than 10-year follow-up. AB - BACKGROUND: Posterior cruciate ligament (PCL) injuries are not rare in acute knee injuries, and several recent anatomical studies of the PCL and reconstructive surgical techniques have generated improved patient results. Now, we have evaluated PCL reconstructions performed by either the single-bundle or double bundle technique in a patient group followed up retrospectively for more than 10 years. METHODS: PCL reconstructions were conducted using the single-bundle (27 cases) or double-bundle (13 cases) method from 1999 to 2002. The mean age at surgery was 34 years in the single-bundle group and 32 years in the double-bundle group. The mean follow-up period was 12.5 years. Patients were evaluated by Lysholm scoring, the gravity sag view, and knee arthrometry. RESULTS: The Lysholm score after surgery was 89.1 +/- 5.6 points for the single-bundle group and 91.9 +/- 4.5 points for the double-bundle group. There was no significant difference between the methods in the side-to-side differences by gravity sag view or knee arthrometer evaluation, although several cases in both groups showed a side-to side difference exceeding 5 mm by the latter evaluation method. CONCLUSIONS: We found no significant difference between single- and double-bundle PCL reconstructions during more than 10 years of follow-up. PMID- 25729769 TI - DNA damage and repair in plants under ultraviolet and ionizing radiations. AB - Being sessile, plants are continuously exposed to DNA-damaging agents present in the environment such as ultraviolet (UV) and ionizing radiations (IR). Sunlight acts as an energy source for photosynthetic plants; hence, avoidance of UV radiations (namely, UV-A, 315-400 nm; UV-B, 280-315 nm; and UV-C, <280 nm) is unpreventable. DNA in particular strongly absorbs UV-B; therefore, it is the most important target for UV-B induced damage. On the other hand, IR causes water radiolysis, which generates highly reactive hydroxyl radicals (OH(*)) and causes radiogenic damage to important cellular components. However, to maintain genomic integrity under UV/IR exposure, plants make use of several DNA repair mechanisms. In the light of recent breakthrough, the current minireview (a) introduces UV/IR and overviews UV/IR-mediated DNA damage products and (b) critically discusses the biochemistry and genetics of major pathways responsible for the repair of UV/IR accrued DNA damage. The outcome of the discussion may be helpful in devising future research in the current context. PMID- 25729772 TI - CaLRS: a critical-aware shared LLC request scheduling algorithm on GPGPU. AB - Ultra high thread-level parallelism in modern GPUs usually introduces numerous memory requests simultaneously. So there are always plenty of memory requests waiting at each bank of the shared LLC (L2 in this paper) and global memory. For global memory, various schedulers have already been developed to adjust the request sequence. But we find few work has ever focused on the service sequence on the shared LLC. We measured that a big number of GPU applications always queue at LLC bank for services, which provide opportunity to optimize the service order on LLC. Through adjusting the GPU memory request service order, we can improve the schedulability of SM. So we proposed a critical-aware shared LLC request scheduling algorithm (CaLRS) in this paper. The priority representative of memory request is critical for CaLRS. We use the number of memory requests that originate from the same warp but have not been serviced when they arrive at the shared LLC bank to represent the criticality of each warp. Experiments show that the proposed scheme can boost the SM schedulability effectively by promoting the scheduling priority of the memory requests with high criticality and improves the performance of GPU indirectly. PMID- 25729773 TI - Genetic divergence in northern Benin sorghum (Sorghum bicolor L. Moench) landraces as revealed by agromorphological traits and selection of candidate genotypes. AB - Sorghum [Sorghum bicolor (L.) Moench] is an important staple food crop in northern Benin. In order to assess its diversity in Benin, 142 accessions of landraces collected from Northern Benin were grown in Central Benin and characterised using 10 qualitative and 14 quantitative agromorphological traits. High variability among both qualitative and quantitative traits was observed. Grain yield (0.72-10.57 tons/ha), panicle weight (15-215.95 g), days to 50% flowering (57-200 days), and plant height (153.27-636.5 cm) were among traits that exhibited broader variability. Correlations between quantitative traits were determined. Grain yield for instance exhibited highly positive association with panicle weight (r = 0.901, P = 0.000) and 100 seed weight (r = 0.247, P = 0.000). UPGMA cluster analysis classified the 142 accessions into 89 morphotypes. Based on multivariate analysis, twenty promising sorghum genotypes were selected. Among them, AT41, AT14, and AT29 showed early maturity (57 to 66 days to 50% flowering), high grain yields (4.85 to 7.85 tons/ha), and shorter plant height (153.27 to 180.37 cm). The results obtained will help enhancing sorghum production and diversity and developing new varieties that will be better adapted to the current soil and climate conditions in Benin. PMID- 25729774 TI - Community-Based Supports and Services for Older Adults: A Primer for Clinicians. AB - Although 20% of adults 60 years and older receive community-based supports and services (CBSS), clinicians may have little more than a vague awareness of what is available and which services may benefit their patients. As health care shifts toward more creative and holistic models of care, there are opportunities for CBSS staff and primary care clinicians to collaborate toward the goal of maintaining patients' health and enabling them to remain safely in the community. This primer reviews the half-century history of these organizations in the United States, describes the most commonly used services, and explains how to access them. PMID- 25729775 TI - Evaluation of Early versus Delayed Laparoscopic Cholecystectomy in Acute Cholecystitis. AB - Background. The role of early laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis is not yet established. The aim of our prospective randomized study was to evaluate the safety and feasibility of early LC for acute cholecystitis and to compare the results with delayed LC. Methods. Between March 2007 to December 2008, 50 patients with diagnosis of acute cholecystitis were assigned randomly to early group, n = 25 (LC within 24 hrs of admission), and delayed group, n = 25 (initial conservative treatment followed by delayed LC, 6-8 weeks later). Results. We found in our study that the conversion rate in early LC and delayed LC was 16% and 8%, respectively, Operation time for early LC was 69.4 min versus 66.4 min for delayed LC, postoperative complications for early LC were 24% versus 8% for delayed LC, and blood loss was 159.6 mL early group versus 146.8 mL for delayed group. However early LC had significantly shorter hospital stay (4.1 days versus 8.6 days). Conclusions. Early LC for acute cholecystitis with cholelithiasis is safe and feasible, offering the additional benefit of shorter hospital stay. It should be offered to the patients with acute cholecystitis, provided that the surgery is performed within 96 hrs of acute symptoms by an experienced surgeon. PMID- 25729776 TI - Maternal Fetal Attachment, Locus of Control and Adherence to STI/HIV Prevention and Prenatal Care Promotion Behaviors in Urban Women. AB - Young women of childbearing age are disproportionately affected by sexually transmitted infections (STIs) including HIV. In particular, young women have more frequent and more serious health problems from STI or HIV infection than men, and among women, African American women have especially high rates of infection. Pregnancy is an important time for beginning or continued STI and HIV prevention behaviors as discontinuing condom use when the contraceptive motivation is gone puts women and their fetuses at risk for contraction of STIs and HIV if they remain sexually active. There are many personal attributes that predict adherence to STI risk reduction behaviors including health related locus of control. The current study surveyed a group of 100 low-income, urban dwelling minority women during their pregnancies to determine whether maternal-fetal attachment, a characteristic specific to pregnancy, favorably influences pregnant women's health related locus of control such that women might be more inclined to engage in preventative STI/HIV risk reduction behaviors. Our findings revealed that while our sample has very high levels of MFA despite the high rate of unplanned pregnancy, condom use is not the method used to reduce the risk of contracting STIs/HIV. Rather, women are more likely to limit their number of sexual partners during pregnancy. While this is beneficial, pregnant women in non-monogamous relationships may discount the importance of condom use during pregnancy. Prenatal care providers can provide education about condom use as a beneficial prenatal care behavior similar to taking prenatal vitamins. PMID- 25729777 TI - Identification of signaling pathways related to drug efficacy in hepatocellular carcinoma via integration of phosphoproteomic, genomic and clinical data. AB - Hepatocellular Carcinoma (HCC) is one of the leading causes of death worldwide, with only a handful of treatments effective in unresectable HCC. Most of the clinical trials for HCC using new generation interventions (drug-targeted therapies) have poor efficacy whereas just a few of them show some promising clinical outcomes [1]. This is amongst the first studies where the mode of action of some of the compounds extensively used in clinical trials is interrogated on the phosphoproteomic level, in an attempt to build predictive models for clinical efficacy. Signaling data are combined with previously published gene expression and clinical data within a consistent framework that identifies drug effects on the phosphoproteomic level and translates them to the gene expression level. The interrogated drugs are then correlated with genes differentially expressed in normal versus tumor tissue, and genes predictive of patient survival. Although the number of clinical trial results considered is small, our approach shows potential for discerning signaling activities that may help predict drug efficacy for HCC. PMID- 25729778 TI - Left Ventricular Diastolic and Systolic Material Property Estimation from Image Data: LV Mechanics Challenge. AB - Cardiovascular simulations using patient-specific geometries can help researchers understand the mechanical behavior of the heart under different loading or disease conditions. However, to replicate the regional mechanics of the heart accurately, both the nonlinear passive and active material properties must be estimated reliably. In this paper, automated methods were used to determine passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Two different approaches were used to model systole. In the first, a physiologically-based active contraction model [1] coupled to a hemodynamic three-element Windkessel model of the circulation was used to simulate ventricular ejection. In the second, developed active tension was directly adjusted to match ventricular volumes at end-systole while prescribing the known end-systolic pressure. These methods were tested in four normal dogs using the data provided for the LV mechanics challenge [2]. The resulting end-diastolic and end-systolic geometry from the simulation were compared with measured image data. PMID- 25729779 TI - Desalting large protein complexes during native electrospray mass spectrometry by addition of amino acids to the working solution. AB - Native mass spectrometry is a rapidly emerging field for characterising the structure of proteins and protein assemblies. The technique relies on electrospray ionisation (ESI) to efficiently ionise the protein analyte and transmit it into the gas phase with retention of protein structure, non-covalent protein-ligand and protein-protein interactions. In native ESI, both the ionisation efficiency and the resulting mass spectral signal is adversely effected by the presence of non-volatile inorganic salts, such as sodium chloride, which form extensive adducts with the protein ions. Consequently, there is great interest in finding experimental strategies that mitigate these phenomena. Here we report our findings that the addition of 10 mM l-serine to the ESI spray solution reduces the adverse effects of sodium adduction to proteins. In the analysis of bovine serum albumin (BSA; 66 kDa), 10 mM serine increased signal to noise ratio (S/N) ~4 fold. This increase in sensitivity was accompanied by peak narrowing (~10 fold), which allowed more precise assignment of molecular mass. Similar effects were observed when analysing protein complexes - serine palmitoyl transferase (SPT, a 92 kDa homodimer), enolase (a 93 kDa homodimer); and alcohol dehydrogenase (ADH, a 148 kDa tetramer). Reduction in sodium ion adduction occurs with no loss of the non-covalent protein-protein interactions, and with little effect on the overall observed charge state-distribution. As a consequence of increasing signal intensity, the addition of serine to the ESI spray solution greatly improved the quality of the data obtained from native top down electron-capture dissociation (ECD) experiments. In ECD analysis of native BSA, we observed an increasing in the S/N of all ECD fragments upon addition of 10 mM l-serine. The number of ECD fragments we observed with S/N > 1.5 increased from 15 to 44 and the number of assigned c and z ions increased from 5 to 16. Finally we show that this phenomenon is not specific to l-serine, and occurs with several amino acids such as l-alanine. Our findings suggest that desalting may occur via binding of sodium ion to the amino acid in solution. This simple and inexpensive strategy has broad utility for improving the mass spectra obtained in a range of MS-based structural proteomic studies. PMID- 25729780 TI - Supramolecular electron transfer-based switching involving pyrrolic macrocycles. A new approach to sensor development? AB - This Feature focuses on pyrrolic macrocycles that can serve as switches via energy- or electron transfer (ET) mechanisms. Macrocycles operating by both ground state (thermodynamic) and photoinduced ET pathways are reviewed and their ability to serve as the readout motif for molecular sensors is discussed. The aim of this article is to highlight the potential utility of ET in the design of systems that perform molecular switching or logic functions and their applicability in chemical sensor development. The conceptual benefits of this paradigm are illustrated with examples drawn mostly from the authors' laboratories. PMID- 25729781 TI - Highly durable carbon-supported Pt catalysts prepared by hydrosilane-assisted nanoparticle deposition and surface functionalization. AB - Hydrosilane enabled the formation of Pt nanoparticles and the silane functionalization of a carbon support material in one pot. The metal/Si-modified carbon composites are highly durable during catalytic methane oxidation. PMID- 25729782 TI - Synthesis of 3-bromosubstituted pyrroles via palladium-catalyzed intermolecular oxidative cyclization of bromoalkynes with N-allylamines. AB - This paper describes a novel palladium-catalyzed oxidative cyclization of bromoalkynes with N-allylamines via cascade formation of C-N and C-C bonds. During this process, the bromine atom was retained to form 3-bromo-pyrroles, which can undergo the subsequent structural modifications. PMID- 25729783 TI - High activity and stability in the cross-coupling of aryl halides with disulfides over Cu-doped hierarchically porous zeolite ZSM-5. AB - A Cu-doped zeolite ZSM-5 (Cu-ZSM-5-M) with a micro-meso-macroporous structure was directly synthesized, and it exhibits excellent catalytic activity and good recyclability in the cross-coupling of aryl halides with diphenyl disulfides. This feature should be attributed to the structural characteristics of meso macropores and homogeneous dispersion of active Cu(delta+) (delta < 2) species in Cu-ZSM-5-M. PMID- 25729784 TI - Molecular structure and thermal stability of the oxide-supported phosphotungstic Wells-Dawson heteropolyacid. AB - We present, for the first time in the literature, a systematic study of the molecular structure of the Wells-Dawson heteropolyacid H6P2W18O62.24H2O (HPA) dispersed on TiO2, SiO2, ZrO2 and Al2O3. The heteropolyacid-based materials were synthesized through a conventional impregnation method (in aqueous and ethanol media) at a loading that corresponds to the theoretical "monolayer" coverage (dispersion limit loading). The combination of Raman and infrared studies demonstrates the presence of crystals of HPA (regardless of the nature of the medium used during the synthesis) suggesting that the dispersion limit loading was greatly exceeded. In situ temperature programmed spectroscopy analyses demonstrated that the Raman shift of the distinctive W[double bond, length as m dash]O Raman mode of the phosphotungstic Wells-Dawson heteropolyacid is sensitive to the local environment, that is, the amount of water molecules associated with the structure. Moreover, the aqueous based species associated with such structures are recognizable through infrared spectroscopy. PMID- 25729785 TI - Quantifying non-Markovianity for a chromophore-qubit pair in a super-Ohmic bath. AB - An approach based on a non-Markovian time-convolutionless polaron master equation is used to probe the quantum dynamics of a chromophore-qubit in a super-Ohmic bath. Utilizing a measure of non-Markovianity based on dynamical fixed points, we study the effects of the environmental temperature and the coupling strength on the non-Markovian behavior of the chromophore in a super-Ohmic bath. It is found that an increase in the temperature results in a reduction in the backflow information from the environment to the chromophore, and therefore, a suppression of non-Markovianity. In the weak coupling regime, increasing the coupling strength will enhance the non-Markovianity, while the effect is reversed in the strong coupling regime. PMID- 25729786 TI - Unraveling the mechanism of 720 nm sub-band-gap optical absorption of a Ta3N5 semiconductor photocatalyst: a hybrid-DFT calculation. AB - The Ta3N5 semiconductor photocatalyst possesses a 720 nm (about 1.72 eV) sub-band gap optical absorption but the mechanism of this optical absorption is still controversial. In this study, the hybrid density functional theory calculations are performed to unravel the mechanism of 720 nm sub-band-gap optical absorption of Ta3N5. By studying the possible optical absorption initiated by the ON impurity and the VN defect, we find that the 720 nm sub-band-gap optical absorption of Ta3N5 may be ascribed to the electron transition from V(.)(N) to V(...)(N). In addition, we propose that the 720 nm sub-band-gap optical absorption can be used to qualitatively evaluate the photocatalytic water splitting ability of Ta3N5. PMID- 25729787 TI - Structure and dynamics of the fibronectin-III domains of Aplysia californica cell adhesion molecules. AB - Due to their homophilic and heterophilic binding properties, cell adhesion molecules (CAMs) such as integrin, cadherin and the immunoglobulin superfamily CAMs are of primary importance in cell-cell and cell-substrate interactions, signalling pathways and other crucial biological processes. We study the molecular structures and conformational dynamics of the two fibronectin type III (Fn-III) extracellular domains of the Aplysia californica CAM (apCAM) protein, by constructing and probing an atomically-detailed structural model based on apCAM's homology with other CAMs. The stability and dynamic properties of the Fn-III domains, individually and in tandem, are probed and analysed using all-atom explicit-solvent molecular dynamics (MD) simulations and normal mode analysis of their corresponding elastic network models. The refined structural model of the Fn-III tandem of apCAM reveals a specific pattern of amino acid interactions that controls the stability of the beta-sheet rich structure and could affect apCAM's response to physical or chemical changes of its environment. It also exposes the important role of several specific charged residues in modulating the structural properties of the linker segment connecting the two Fn-III domains, as well as of the inter-domain interface. PMID- 25729788 TI - Carbon nanotubes enhanced Seebeck coefficient and power factor of rutile TiO2. AB - The Seebeck coefficient, according to Ioffe's approximation, is inversely proportional to carrier density and decreases with doping. Herein, we find that the incorporation of multi-walled carbon nanotubes into rutile TiO2 improves the electrical conductivity and Seebeck coefficient at a low filling fraction of tubes; moreover, the former was due to the lengthening of the mean free path and doping modified carrier mobility for the latter. Tube-oxide mixing also causes significant phonon drag at the interfaces and the reduced thermal conductivity was verified by the promoted figure of merit. PMID- 25729789 TI - A facile in situ approach to fabricate N,S-TiO2/g-C3N4 nanocomposite with excellent activity for visible light induced water splitting for hydrogen evolution. AB - A series of novel N,S-TiO2/g-C3N4 nanocomposite (abbreviated as TuT) photocatalysts has been synthesized via a facile, cost effective, in situ thermal induced polymerization method. The as-synthesized nanocomposites were thoroughly characterized through X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), UV-vis diffuse reflectance spectroscopy (UV-Vis DRS), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and photo luminescence spectroscopy (PL). Using UV-Vis DRS, a gradual enhancement in visible light absorption towards the red end was observed for the xTuT photocatalyst in comparison to bare g-C3N4 (Tu). The result demonstrates that thermal reaction of a higher wt% of thiourea with respect to Ti precursor causes coupling of the N,S-TiO2 and g-C3N4 nanocomposite, however at a lower wt% only N,S-TiO2 forms. The photocatalytic activity has been evaluated through H2 evolution. The synergistic combination of small crystallite size, the crystalline anatase phase, enhanced visible light absorption ability, enhanced specific surface area and the effective charge separation properties of the 10TuT photocatalyst makes the system pivotal for photocatalytic H2 evolution under visible light irradiation. PMID- 25729790 TI - Enhanced performance and morphological evolution of PTB7:PC71BM polymer solar cells by using solvent mixtures with different additives. AB - Organic photovoltaics (OPVs) were fabricated with blended active layers of poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro 2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]]:[6,6]-phenylC71-butyric acid methyl ester (PTB7:PC71BM). The active layers were prepared in chlorobenzene (CB) with different additives of 1,8-diiodooctane (DIO) and 1,8-dibromooctane and different concentrations using a wet process with spin coating. The effects of different solvent additives were studied with respect to photovoltaic parameters such as fill factor, short circuit current density, and power conversion efficiency. The absorption and surface morphology of the active layers were investigated by UV-visible spectroscopy, atomic force microscopy (AFM) and time of-flight secondary ion mass spectrometry (TOF-SIMS), respectively. The results indicated that structural and morphological changes were induced by the solvent additives. The polymer solar cells (PSCs) of PTB7/PC71BM prepared by a spin coating method using DIO and 1,8-dibromooctane showed more improved PCE of 6.76%. The enhancement of performance of PSCs could be mainly attributed to the absorption enhancement and the improved charge carrier transportation. PMID- 25729791 TI - Tunable thermal conductivity of thin films of polycrystalline AlN by structural inhomogeneity and interfacial oxidation. AB - The effect of the structural inhomogeneity and oxygen defects on the thermal conductivity of polycrystalline aluminum nitride (AlN) thin films deposited on single-crystal silicon substrates is experimentally and theoretically investigated. The influence of the evolution of crystal structure, grain size, and out-of plane disorientation along the cross plane of the films on their thermal conductivity is analyzed. The impact of oxygen-related defects on thermal conduction is studied in AlN/AlN multilayered samples. Microstructure, texture, and grain size of the films were characterized by X-ray diffraction and scanning and transmission electron microscopy. The measured thermal conductivity obtained with the 3-omega technique for a single and multiple layers of AlN is in fairly good agreement with the theoretical predictions of our model, which is developed by considering a serial assembly of grain distributions. An effective thermal conductivity of 5.92 W m(-1) K(-1) is measured for a 1107.5 nm-thick multilayer structure, which represents a reduction of 20% of the thermal conductivity of an AlN monolayer with approximately the same thickness, due to oxygen impurities at the interface of AlN layers. Our results show that the reduction of the thermal conductivity as the film thickness is scaled down, is strongly determined by the structural inhomogeneities inside the sputtered films. The origin of this non homogeneity and the effect on phonon scattering are also discussed. PMID- 25729793 TI - [Some long-term results of laparoscopic resection after neoadjuvant chemotherapy in locally advanced rectal cancer as compared to conventional open surgery]. PMID- 25729792 TI - Inside-outside self-assembly of light-activated fast-release liposomes. AB - Building additional functionality into both the membrane and the internal compartments of biocompatible liposomes by self-assembly can provide ways of enhancing colloidal stability and spatial and temporal control of contents release. An interdigitation-fusion process is used to encapsulate near infrared light absorbing copper sulfide nanoparticles in the interior compartments of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol liposomes. Once formed, the liposome membrane is modified to include lysolipids and polyethylene glycol lipids by partitioning from lysolipid and PEG-lipid micelles in solution. This results in sterically stable, thermosensitive liposomes with a permeability transition near physiological temperature that can be triggered by NIR light irradiation. Rapid changes in local concentration can be induced with spatial and temporal control using NIR laser light. PMID- 25729794 TI - [Is the waiver of chemotherapy for small, node-negative breast cancer justified? ]. PMID- 25729795 TI - [Patients with "extensive disease" form of small cell bronchial carcinoma also benefit from consolidating mediastinal irradiation similarly to the procedure used in "limited disease"]. PMID- 25729796 TI - Reduction of sodium intake is a prerequisite for preventing and curing high blood pressure in hypertensive patients - first part: therapy. AB - The studies on the relation between Na intake and blood pressure were started at the Brookhaven National Laboratories in Upton (New York) by Lewis K Dahl in 1961, however the story goes back to our hunter-gatherer predecessors who, between 750,000 and 10,000 years ago, ate diets proving a Na intake of 690 mg/day. The relevance of this finding became evident when the data of the studies on Yanomamo Indians of Brazil and Venezuela (living in the tropical forest) became available. They showed that in these populations sodium intake averages 1.34+/-2.01 mEq/24 hours,and that their blood pressure increases from the first to the second decade of life and then tapers down. Studies inc himpanzees, a species genetically similar to humans, the DASH Trial, the Intersalt Study, various meta-analyses, the data in persons with stroke, the blood pressure profile of newborns on low Na intake, and various studies in hypertensives with and without Chronic Kidney Disease, have demonstrated the beneficial effects of a restricted low salt intake alone or as an adjunct to drug therapy on blood pressure profiles. PMID- 25729797 TI - Spatial and temporal variation in plant hydraulic traits and their relevance for climate change impacts on vegetation. AB - Plant hydraulics mediate terrestrial woody plant productivity, influencing global water, carbon, and biogeochemical cycles, as well as ecosystem vulnerability to drought and climate change. While inter-specific differences in hydraulic traits are widely documented, intra-specific hydraulic variability is less well known and is important for predicting climate change impacts. Here, I present a conceptual framework for this intra-specific hydraulic trait variability, reviewing the mechanisms that drive variability and the consequences for vegetation response to climate change. I performed a meta-analysis on published studies (n = 33) of intra-specific variation in a prominent hydraulic trait - water potential at which 50% stem conductivity is lost (P50) - and compared this variation to inter-specific variability within genera and plant functional types used by a dynamic global vegetation model. I found that intra-specific variability is of ecologically relevant magnitudes, equivalent to c. 33% of the inter-specific variability within a genus, and is larger in angiosperms than gymnosperms, although the limited number of studies highlights that more research is greatly needed. Furthermore, plant functional types were poorly situated to capture key differences in hydraulic traits across species, indicating a need to approach prediction of drought impacts from a trait-based, rather than functional type-based perspective. PMID- 25729798 TI - Innovative empirical approaches for inferring climate-warming impacts on plants in remote areas. AB - The prediction of the effects of climate warming on plant communities across the globe has become a major focus of ecology, evolution and biodiversity conservation. However, many of the frequently used empirical approaches for inferring how warming affects vegetation have been criticized for decades. In addition, methods that require no electricity may be preferred because of constraints of active warming, e.g. in remote areas. Efforts to overcome the limitations of earlier methods are currently under development, but these approaches have yet to be systematically evaluated side by side. Here, an overview of the benefits and limitations of a selection of innovative empirical techniques to study temperature effects on plants is presented, with a focus on practicality in relatively remote areas without an electric power supply. I focus on methods for: ecosystem aboveground and belowground warming; a fuller exploitation of spatial temperature variation; and long-term monitoring of plant ecological and microevolutionary changes in response to warming. An evaluation of the described methodological set-ups in a synthetic framework along six axes (associated with the consistency of temperature differences, disturbance, costs, confounding factors, spatial scale and versatility) highlights their potential usefulness and power. Hence, further developments of new approaches to empirically assess warming effects on plants can critically stimulate progress in climate-change biology. PMID- 25729799 TI - Microtubule nucleating and severing enzymes for modifying microtubule array organization and cell morphogenesis in response to environmental cues. AB - In higher plants, reorientation of cortical microtubule arrays has been postulated to be of importance for modifying cell growth to adapt to environmental conditions. However, the process of microtubule reorientation is largely unknown. Recent genetic and live cell imaging studies of microtubule dynamics shed light on the regulatory mechanisms of microtubule molecular nucleation and severing apparatuses, which are required for array reorientation in response to blue light signaling. Branching nucleation from gamma-tubulin complexes creates a small population of discordant microtubules that are acted on by KATANIN-mediated severing in two ways. KATANIN releases microtubules from nucleation sites and rapidly amplifies discordant microtubules by severing at microtubule crossovers. In this review, I focus on the molecular details of these two enzymes, which enable microtubule array transition. PMID- 25729800 TI - Hitchhiker's guide to multi-dimensional plant pathology. AB - Filamentous pathogens pose a substantial threat to global food security. One central question in plant pathology is how pathogens cause infection and manage to evade or suppress plant immunity to promote disease. With many technological advances over the past decade, including DNA sequencing technology, an array of new tools has become embedded within the toolbox of next-generation plant pathologists. By employing a multidisciplinary approach plant pathologists can fully leverage these technical advances to answer key questions in plant pathology, aimed at achieving global food security. This review discusses the impact of: cell biology and genetics on progressing our understanding of infection structure formation on the leaf surface; biochemical and molecular analysis to study how pathogens subdue plant immunity and manipulate plant processes through effectors; genomics and DNA sequencing technologies on all areas of plant pathology; and new forms of collaboration on accelerating exploitation of big data. As we embark on the next phase in plant pathology, the integration of systems biology promises to provide a holistic perspective of plant-pathogen interactions from big data and only once we fully appreciate these complexities can we design truly sustainable solutions to preserve our resources. PMID- 25729801 TI - Polyploidy: adaptation to the genomic environment. AB - Genomic evidence of ancestral whole genome duplication (WGD) and polyploidy is widespread among eukaryotic species, and especially among plants. WGD is thought to provide the raw material for adaptation in the form of duplicated genes, and polyploids are thought to benefit from both physiological and genetic buffering. Comparatively little attention has focused on the genomic challenge of polyploidy, however, although much evidence exists that polyploidy severely perturbs important cellular functions. Here, I review recent progress in the study of the re-establishment of stable meiosis in recently evolved polyploids, focusing on four plant species. This work has yielded an insight into the mechanisms underlying stabilization of genome transmission in polyploids, and is revealing remarkable parallels among diverse taxa. Importantly, these studies also provide a road map for investigating how polyploids respond to the challenge of WGD. PMID- 25729802 TI - Using plants to elucidate the mechanisms of cytonuclear co-evolution. AB - The presence of both cytoplasmic and nuclear genomes within eukaryotic cells raises fascinating questions about co-evolution between genomic compartments that experience fundamentally different mutation rates and modes of inheritance. The highly mutagenic environments found in the mitochondria of some eukaryotes have generated interest in the role that mitochondrial mutation accumulation plays in phenomena such as intracellular gene transfer, compensatory evolution in the nucleus and the evolution of reproductive isolation. Although plant systems have played an important historical role in the study of cytonuclear co-evolution, they remain underutilized in many respects. In particular, the enormous natural variation in DNA substitution rates, gene content and genome architecture in plant mitochondria - much of which has even been found within a single genus - provides opportunities to resolve longstanding evolutionary questions about the consequences of mitochondrial mutation accumulation. This review summarizes some of the classic questions about cytonuclear co-evolution that could be addressed by taking advantage of the variation in plants and highlights a recent analysis of the effect of mitochondrial mutation accumulation on rates of molecular evolution in the nucleus. PMID- 25729803 TI - Ecological mechanisms for the coevolution of mating systems and defence. AB - The diversity of flowering plants is evident in two seemingly unrelated aspects of life history: sexual reproduction, exemplified by the stunning variation in flower form and function, and defence, often in the form of an impressive arsenal of secondary chemistry. Researchers are beginning to appreciate that plant defence and reproduction do not evolve independently, but, instead, may have reciprocal and interactive (coevolutionary) effects on each other. Understanding the mechanisms for mating-defence interactions promises to broaden our understanding of how ecological processes can generate these two rich sources of angiosperm diversity. Here, I review current research on the role of herbivory as a driver of mating system evolution, and the role of mating systems in the evolution of defence strategies. I outline different ecological mechanisms and processes that could generate these coevolutionary patterns, and summarize theoretical and empirical support for each. I provide a conceptual framework for linking plant defence with mating system theory to better integrate these two research fields. PMID- 25729804 TI - PRO view: treat to prevent recurrence of HCV. PMID- 25729805 TI - Are above- and below-ground phenology in sync? AB - Globally, root production accounts for 33-67% of terrestrial net primary productivity and influences decomposition via root production and turnover, carbon (C) allocation to mycorrhizal fungi and root exudation. As recognized above ground, the timing of phenological events affects terrestrial C balance, yet there is no parallel understanding for below-ground phenology. In this paper we examine the phenology of root production and its relationship to temperature, soil moisture, and above-ground phenology. Synthesizing 87 observations of whole plant phenology from 40 studies, we found that, on average, root growth occurs 25 +/- 8 d after shoot growth but that the offset between the peak in root and shoot growth varies > 200 d across biomes (boreal, temperate, Mediterranean, and subtropical). Root and shoot growth are positively correlated with median monthly temperature and mean monthly precipitation in boreal, temperate, and subtropical biomes. However, a temperature hysteresis in these biomes leads to the hypothesis that internal controls over C allocation to roots are an equally, if not more, important driver of phenology. The specific mechanisms are as yet unclear but they are likely mediated by some combination of photoassimilate supply, hormonal signaling, and growth form. PMID- 25729806 TI - Woody plant encroachment of grasslands: a comparison of terrestrial and wetland settings. AB - A global trend of woody plant encroachment of terrestrial grasslands is co incident with woody plant encroachment of wetland in freshwater and saline intertidal settings. There are several arguments for considering tree encroachment of wetlands in the context of woody shrub encroachment of grassland biomes. In both cases, delimitation of woody shrubs at regional scales is set by temperature thresholds for poleward extent, and by aridity within temperature limits. Latitudinal expansion has been observed for terrestrial woody shrubs and mangroves, following recent warming, but most expansion and thickening has been due to the occupation of previously water-limited grassland/saltmarsh environments. Increases in atmospheric CO2, may facilitate the recruitment of trees in terrestrial and wetland settings. Improved water relations, a mechanism that would predict higher soil moisture in grasslands and saltmarshes, and also an enhanced capacity to survive arid conditions, reinforces local mechanisms of change. The expansion of woody shrubs and mangroves provides a negative feedback on elevated atmospheric CO2 by increasing carbon sequestration in grassland and saltmarsh, and is a significant carbon sink globally. These broad-scale vegetation shifts may represent a new stable state, reinforced by positive feedbacks between global change drivers and endogenic mechanisms of persistence in the landscape. PMID- 25729807 TI - Environmental technology: Green light. PMID- 25729808 TI - Erratum to "Assessment of serum leptin and resistin levels in association with the metabolic risk factors of pre- and postmenopausal rural women in South India" [Diabetes Metab. Syndr.: Clin. Res. Rev. 7 (2013) 233-237]. PMID- 25729809 TI - What is the value of a neurologist? PMID- 25729810 TI - Author response. PMID- 25729811 TI - Author response. PMID- 25729813 TI - [Editorial]. PMID- 25729812 TI - Retraction: A mechanochemical approach to deracemization. PMID- 25729814 TI - Stenting and angioplasty for idiopathic intracranial hypertension: a case series with clinical, angiographic, ophthalmological, complication, and pressure reporting. AB - BACKGROUND: Previous studies have demonstrated that cerebral dural sinus stenosis (DSS) may be a potential patho-physiological cause of idiopathic intracranial hypertension (IIH). Endovascular therapy for DSS is emerging as a potential alternative to treat IIH. Here, we present the results of our case series. METHOD: We prospectively collected angiographic and manometric data on patients that underwent angioplasty/stenting for IIH. All patients had failed maximal medical therapy (MMT) and had confirmed sinus stenosis. Demographic, clinical and radiological presentation, and outcomes were collected retrospectively. RESULTS: A total of 18 patients underwent 25 procedures. Demographics revealed a mean age of 30 (range 15-59), 83% (15/18) were female, 72% (13/18) were white, and mean body mass index of 36 (range 23-59.2). All patients presented with classic IIH. Symptom improvement or resolution was reported in 94% (17/18) of patients. All patients had resolution and/or stabilization/improvement of their papilledema. Headaches related to increased pressure improved in 56% (10/18). Re-stenosis and retreatment occurred in 33% (6/18). No procedural related complications were reported. CONCLUSION: Dural sinus angioplasty and stenting is relatively safe, feasible, and clinically efficacious for patients with symptomatic sinus stenosis who have failed standard therapy. The long-term durability of patency and clinical improvement remains unknown. PMID- 25729815 TI - [Not Available]. PMID- 25729816 TI - Internal carotid artery floating thrombus in relapsing polychondritis. AB - Relapsing polychondritis is a rare autoimmune disease characterized by inflammation of cartilaginous tissues. It may be associated with systemic and cerebral vasculitis and exceptionally with ischemic stroke. Brain infarction associated with internal carotid artery thrombus, in a setting of relapsing polychondritis, has never been reported. We present a 52-year-old man without any known risk factors for stroke, treated with prednisone and azathioprine for relapsing polychondritis, who presented a minor left hemisphere stroke. Ultrasound of the neck vessels revealed an isoechogenic thrombus in the left internal carotid artery superimposed on a smooth moderately stenosing isoechogenic atheroma of the carotid bulb. The patient was treated with high-dose tinzaparin and was followed with serial ultrasound. After 16 days, the thrombus demonstrated a hypoechogenic core surrounded by a hyperechogenic rim and the following day it resolved completely. Thrombus formation on a small unruptured plaque may reflect involvement by relapsing polychondritis of the intimal proteoglycans that hold a role in the development of atheromatosis. PMID- 25729818 TI - Absence of left pulmonary artery in tetralogy of Fallot with absent pulmonary valve syndrome. AB - The rare combination of tetralogy of Fallot (TOF), absent pulmonary valve syndrome (APVS), and absent left pulmonary artery (ALPA) is reviewed herein. Children with TOF with APVS and ALPA should be closely monitored, even if they are asymptomatic or mildly symptomatic, and should undergo elective surgery at the end of infancy. PMID- 25729817 TI - Mild encephalitis/encephalopathy with reversible splenial and cerebellar lesions (MERS type II) in a patient with hemolytic uremic syndrome (HUS). AB - The typical form of mild encephalitis/encephalopathy with a reversible splenial lesion- called MERS type I-is characterized by a singular, reversible lesion in the midline of the splenium. Very rarely, additional lesions with similar signal characteristics can occur in other brain areas, which is then referred to as MERS type II. We present the case of a patient with a reversible splenial lesion and concomitant reversible cerebellar lesions within the scope of an atypical hemolytic uremic syndrome (HUS). PMID- 25729819 TI - [Dra. Teresa Cerda Mota]. PMID- 25729820 TI - DSM-5: riddled with conflicts of interest. PMID- 25729821 TI - No compelling reason to adopt new antivirals whenever it is reasonable to wait. PMID- 25729822 TI - Vismodegib (ERIVEDGE degrees ) In basal cell carcinoma: too many unknowns. AB - Basal cell carcinomas are the most common skin cancers. They are usually localised and carry a good prognosis. There is no standard treatment for the rare patients with metastatic basal cell carcinoma or very extensive basal cell carcinoma for whom surgery or radiotherapy is inappropriate. Vismodegib, a cytotoxic drug, is claimed to prevent tumour growth by inhibiting a pathway involved in tissue repair and embryogenesis. It has been authorised in the European Union for patients with metastatic or locally advanced and extensive basal cell carcinoma. Clinical evaluation of vismodegib is based on a non comparative clinical trial involving 104 patients, providing only weak evidence. Twenty-one months after the start of the trial, 7 patients with metastases (21%) and 6 patients with advanced basal cell carcinoma (10%) had died. Given the lack of a placebo group, there is no way of knowing whether vismodegib had any effect, positive or negative, on survival. There were no complete responses among patients with metastases, but about one-third of them had partial responses. Among the 63 patients with locally advanced basal cell carcinoma, there were 14 complete responses and 16 partial responses. The recurrence rate in patients with complete responses was not reported. Similar results were reported in two other uncontrolled trials available in mid-2014. Vismodegib has frequent and sometimes serious adverse effects, including muscle spasms, fatigue and severe hyponatraemia. Cases of severe weight loss, alopecia, ocular disorders, other cancers (including squamous cell carcinoma) and anaemia have also been reported. More data are needed on possible hepatic and cardiovascular adverse effects. A potent teratogenic effect was seen in experimental animals. As vismodegib enters semen, contraception is mandatory for both men (condoms) and women. In practice, vismodegib has frequent and varied adverse effects, some of which are serious, while its benefits are poorly documented. Vismodegib should only be proposed to patients in whom basal cell cancer markedly undermines quality of life, and only in the context of clinical research. PMID- 25729823 TI - Strontium still authorised despite an unfavourable opinion of the European Pharmacovigilance committee. AB - In 2014 the indications of strontium ranelate were further restricted in the European Union, and the French pharmacoeconomic committee has finally judged strontium ranelate to have "insufficient medical benefit". PMID- 25729824 TI - Semen abnormalities with SSRI antidepressants. AB - Despite decades of widespread use, the adverse effect profile of "selective" serotonin reuptake inhibitor (SSRI) antidepressants has still not been fully elucidated. Studies in male animals have shown delayed sexual development and reduced fertility. Three prospective cohort studies conducted in over one hundred patients exposed to an SSRI for periods ranging from 5 weeks to 24 months found altered semen param-eters after as little as 3 months of exposure: reduced sperm concentration, reduced sperm motility, a higher percentage of abnormal spermatozoa, and increased levels of sperm DNA fragmentation. One clinical trial showed growth retardation in children considered depressed who were exposed to SSRls. SSRls may have endocrine disrupting properties. Dapoxetine is a short acting serotonin reuptake inhibitor that is chemically related to fluoxetine and marketed in the European Union for men complaining of premature ejaculation. But the corresponding European summary of product characteristics does not mention any effects on fertility. In practice, based on the data available as of mid 2014, the effects of SSRI exposure on male fertility are unclear. However, it is a risk that should be taken into account and pointed out to male patients who would like to father a child or who are experiencing fertility problems. PMID- 25729825 TI - Ustekinumab: cutaneous disorders, malignancies, infections. PMID- 25729826 TI - Drug-induced true vertigo and balance disorders. PMID- 25729827 TI - Miconazole and oral anticoagulants: bleeding. AB - Increases in the INR and cases of bleeding have been reported during concomitant use of miconazole oral gel or mucoadhesive buccal tablets and a vitamin K antagonist (fluindione or warfarin). PMID- 25729828 TI - NSAIDs and atrial fibrillation? PMID- 25729829 TI - Cefepime: serious neurological adverse effects. PMID- 25729830 TI - Pazopanib: retinal detachment. PMID- 25729831 TI - Lamotrigine: nightmares. PMID- 25729832 TI - Regorafenib: Dress. PMID- 25729833 TI - Electronic cigarettes: poisoning in children. PMID- 25729834 TI - Voriconazole: alopecia and nail changes. PMID- 25729835 TI - Ginkgo biloba: reduced efficacy of efavirenz. PMID- 25729836 TI - Acute uncomplicated cystitis in women. The essentials of first-line management. AB - In the absence of fever and low back pain, there is a high probability that a female patient has acute uncomplicated cystitis if she reports dysuria' and urinary frequency but no vaginal discharge or pruritus. The antibiotic therapy of choice for an episode of acute uncomplicated cystitis is a single oral dose of fosfomycin trometamol. In patients with recurrent infections, the strategy that results in the lowest antibiotic exposure without impairing efficacy is to treat each episode as soon as the first clinical symptoms appear. PMID- 25729837 TI - Carpal tunnel syndrome and corticosteroid injections. AB - In a randomised trial in 111 patients, one injection of methylprednisolone reduced the symptoms of carpal tunnel syndrome and the need for surgery during the subsequent year. PMID- 25729838 TI - Heart failure in sinus rhythm: no routine antithrombotic therapy. AB - Several trials have compared aspirin or warfarin with either placebo or no antithrombotic drug therapy in a total of a few hundred patients with heart failure in sinus rhythm and no particular thrombotic risk.There is no evidence that antiplatelet or anticoagulant therapy reduces mortality or cardiovascular events, but antithrombotic drugs can provoke severe bleeding. PMID- 25729839 TI - Ensuring the quality of articles published in Prescrire: the important role of reviewers. AB - All draft articles intended for publication in Prescrire are first reviewed by a diverse panel of professionals. Their comments and suggestions, and the additional references they sometimes provide, help to guarantee the quality of the published articles. PMID- 25729840 TI - The high price of cancer drugs: enough is enough. AB - In 2013, a group of about a hundred oncologists from around the world spoke out against the soaring prices of tyrosine kinase inhibitors, pointing out that unaffordable drug prices prevent many patients from accessing treatment. A study conducted in 2009 showed that France's expenditure on certain cancer drugs was the highest in Europe. PMID- 25729841 TI - [Functions of microglia in the healthy brain: focus on neuroplasticity]. AB - Microglia is in the center of modern research because it is involved in neuroinflammation processes, which is considered as an important part of pathogenesis of many brain pathologies. On the contrary, normal physiological functions of microglia are less studied. Here we review modern data on functioning of microglia in the healthy brain. We consider involvement of microglia in angiogenesis, neurogenesis, synaptogenesis, long-term potentiation, and the mechanisms of microglia-neuron interaction. We further consider modern concept on active interaction of microglia with neurons in developing and healthy mature brain and the essential role of microglia in neuroplasticity mechanisms at various levels. PMID- 25729842 TI - [Dual effects of glucocorticoids on the gastric mucosa]. AB - In this review we systematise and analyze data of literature about the effect of glucocorticoids on the gastric mucosa. There are convincing results that show the adaptive gastoprotective nature of endogenous glucocorticoids, which are produced during acute stress-induced activation of the HPA axis. The role glucocorticoid hormones play in the effect of chronic stress remains little-studied. We have seen that after single administration of glucocorticoids, there can arise gastroprotective and ulcerogenic effects. Although. the question about the effect of therapy using glucocorticoid hormones on gastric ulceration is being debated, the data confirm the ulcerogenic influence that large doses of these hormones have on experimental animals. The initial gastroprotective effect that glucocorticoid hormones have, even after their single administration can be transformed into an ulcerogenic effect with a prolongation of the hormonal action, but not of the hormone dose. We are discussing the possible mechanism behind the transformation. PMID- 25729843 TI - [Endothelial cell adhesion molecules]. AB - The review presents current data concerning the functional role of endothelial cell adhesion molecules belonging to different structural families: integrins, selectins, cadherins, and the immunoglobulin super-family. In this manuscript the regulatory mechanisms and factors of adhesion molecules expression and distribution on the surface of endothelial cells are discussed. The data presented reveal the importance of adhesion molecules in the regulation of structural and functional state of endothelial cells in normal conditions and in pathology. Particular attention is paid to the importance of these molecules in the processes of physiological and pathological angiogenesis, regulation of permeability of the endothelial barrier and cell transmigration. PMID- 25729844 TI - [Functional magnetic resonance imaging and dynamic neuroanatomy of addictive disorders]. AB - Research into the cerebral patterns that govern the formation and development of addictive behavior is one of the most interesting goals of neurophysiology. Authors of contemporary papers on the matter define a number of symptoms that are all part of substance or non-substance dependence, each one of them leading to abnormalities in the corresponding system of the brain. During the last twenty years the functional magnetic resonance imaging (fMR1) technology has been instrumental in locating such abnormalities, identifying specific parts of the brain that, when dysfunctional, may enhance addiction and cause its positive or negative symptoms. This article reviews fMRI studies aimed toward locating areas in the brain that are responsible for cognitive, emotional, and motivational dysfunction. Cerebral correlatives of impulsiveness, behavior control, and drug cravings are reviewed separately. The article also contains an overview of possibilities to further investigate the Selves of those dependent on substances, identify previously unknown diagnostic markers of substance dependence, and evaluate the effectiveness of therapy. The research under review in this article provides data that points to a special role of the nucleus caudatus as well as the nucleus accumbens, the thalamus, the insular cortex (IC), the anterior cingulate, prefrontal and orbitofrontal areas in psychological disorders that are part of substance dependence. General findings of the article are in accordance with contemporary models of addictive pattern. PMID- 25729846 TI - [P-glycoprotein: structure, physiological role and molecular mechanisms of modulation functional activity]. AB - In the review of literature the structure, localization and a physiological role of efflux biobiotics and xenobiotics transporter - P-glycoprotein - is characterized, molecular mechanisms of induction and inhibition of its functional activity are systematized. PMID- 25729845 TI - [Serotonergic regulation of the immune system]. AB - The paper presents evidence on the important contribution of the peripheral serotonin system in the process of immunomodulation. The main components of the system - serotonin, receptors and serotonin transporter - are described. Possible mechanisms of serotonin regulation of activity of immune cells - lymphocytes, macrophages and dendritic cells - are reviewed. PMID- 25729847 TI - [The ethical aspects of physiological experiment]. AB - A modern classification of invasive procedures developed according to International Bioethical Principles has been presented. The experimental data convincingly demonstrate that using of noninvasive approaches and techniques give a good opportunity to reduce a number of animals recruited in experiment as well as to keep the normal (not distressful) physiological functions of animals. The data presented stress that development of noninvasive techniques is closely related both to scientific and social aspects of our life, allowing the scientists to provide high validity of experimental data obtained as well as to keep themselves as a human beings. PMID- 25729848 TI - Snooker structure-based pharmacophore model explains differences in agonist and blocker binding to bitter receptor hTAS2R39. AB - The human bitter taste receptor hTAS2R39 can be activated by many dietary (iso)flavonoids. Furthermore, hTAS2R39 activity can be blocked by 6 methoxyflavanones, 4'-fluoro-6-methoxyflavanone in particular. A structure-based pharmacophore model of the hTAS2R39 binding pocket was built using Snooker software, which has been used successfully before for drug design of GPCRs of the rhodopsin subfamily. For the validation of the model, two sets of compounds, both of which contained actives and inactives, were used: (i) an (iso)flavonoid dedicated set, and (ii) a more generic, structurally diverse set. Agonists were characterized by their linear binding geometry and the fact that they bound deeply in the hTAS2R39 pocket, mapping the hydrogen donor feature based on T5.45 and N3.36, analogues of which have been proposed to play a key role in activation of GPCRs. Blockers lack hydrogen-bond donors enabling contact to the receptor. Furthermore, they had a crooked geometry, which could sterically hinder movement of the TM domains upon receptor activation. Our results reveal characteristics of hTAS2R39 agonist and bitter blocker binding, which might facilitate the development of blockers suitable to counter the bitterness of dietary hTAS2R39 agonists in food applications. PMID- 25729849 TI - The gut connectome: making sense of what you eat. AB - The enteric nervous system has been studied thus far as an isolated unit. As researchers probe deeper into the function of this system, it is evident that the neural network stretches beyond enteric neurons. It is formed by both intrinsic and extrinsic neurons innervating the gut, enteric glia, and innervated sensory epithelial cells, such as enteroendocrine cells. This Review series summarizes recent knowledge on function and disease of nerves, glia, and sensory epithelial cells of the gut in eight distinctive articles. The timing and growing knowledge for each individual field calls for an appropriate term encompassing the entire system. We call this neuronal ensemble the "gut connectome" and summarize the work from a food sensory perspective. PMID- 25729850 TI - Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms. AB - Bariatric surgery is the most effective treatment for severe obesity, producing marked sustained weight loss with associated reduced morbidity and mortality. Roux-en-Y gastric bypass surgery (RYGBP), the most commonly performed procedure, was initially viewed as a hybrid restrictive-malabsorptive procedure. However, over the last decade, it has become apparent that alternative physiologic mechanisms underlie its beneficial effects. RYGBP-induced altered feeding behavior, including reduced appetite and changes in taste/food preferences, is now recognized as a key driver of the sustained postoperative weight loss. The brain ultimately determines feeding behavior, and here we review the mechanisms by which RYGBP may affect central appetite-regulating pathways. PMID- 25729851 TI - Colitis-induced neuroplasticity disrupts motility in the inflamed and post inflamed colon. AB - Effective colonic motility involves an intricate pattern of excitatory and inhibitory neuromuscular signals that arise from the enteric neural circuitry of the colon. Recent investigations have demonstrated that inflammation leads to a variety of changes in the physiological properties of the neurons in this circuitry, including hyperexcitability of neurons at the afferent end of the peristaltic reflex, synaptic facilitation, and attenuated inhibitory neuromuscular transmission. Furthermore, links have been established between these changes and disrupted motor activity in the colon, and we now know that some of these changes persist long after recovery from inflammation. It is highly likely that inflammation-induced neuroplasticity, which is not detectable by clinical diagnostics, contributes to disrupted motility in active and quiescent inflammatory bowel disease and in functional gastrointestinal disorders. PMID- 25729853 TI - Corrigendum. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. PMID- 25729852 TI - Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system. AB - The enteric nervous system (ENS) consists of neurons and glial cells that differentiate from neural crest progenitors. During embryogenesis, development of the ENS is controlled by the interplay of neural crest cell-intrinsic factors and instructive cues from the surrounding gut mesenchyme. However, postnatal ENS development occurs in a different context, which is characterized by the presence of microbiota and an extensive immune system, suggesting an important role of these factors on enteric neural circuit formation and function. Initial reports confirm this idea while further studies in this area promise new insights into ENS physiology and pathophysiology. PMID- 25729854 TI - Corrigendum. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. PMID- 25729855 TI - Corrigendum. HIF2alpha signaling inhibits adherens junctional disruption in acute lung injury. PMID- 25729856 TI - Corrigendum. CD4+ T cell-independent DNA vaccination against opportunistic infections. PMID- 25729857 TI - Corrigendum. Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis. PMID- 25729858 TI - Corrigendum. Complement as a multifaceted modulator of kidney transplant injury. PMID- 25729861 TI - Correction: the dynamics of democracy, development and cultural values. PMID- 25729859 TI - Molecular dynamics simulations of the bacterial UraA H+-uracil symporter in lipid bilayers reveal a closed state and a selective interaction with cardiolipin. AB - The Escherichia coli UraA H+-uracil symporter is a member of the nucleobase/ascorbate transporter (NAT) family of proteins, and is responsible for the proton-driven uptake of uracil. Multiscale molecular dynamics simulations of the UraA symporter in phospholipid bilayers consisting of: 1) 1-palmitoyl 2 oleoyl-phosphatidylcholine (POPC); 2) 1-palmitoyl 2-oleoyl phosphatidylethanolamine (POPE); and 3) a mixture of 75% POPE, 20% 1-palmitoyl 2 oleoyl-phosphatidylglycerol (POPG); and 5% 1-palmitoyl 2-oleoyl diphosphatidylglycerol/cardiolipin (CL) to mimic the lipid composition of the bacterial inner membrane, were performed using the MARTINI coarse-grained force field to self-assemble lipids around the crystal structure of this membrane transport protein, followed by atomistic simulations. The overall fold of the protein in lipid bilayers remained similar to the crystal structure in detergent on the timescale of our simulations. Simulations were performed in the absence of uracil, and resulted in a closed state of the transporter, due to relative movement of the gate and core domains. Anionic lipids, including POPG and especially CL, were found to associate with UraA, involving interactions between specific basic residues in loop regions and phosphate oxygens of the CL head group. In particular, three CL binding sites were identified on UraA: two in the inner leaflet and a single site in the outer leaflet. Mutation of basic residues in the binding sites resulted in the loss of CL binding in the simulations. CL may play a role as a "proton trap" that channels protons to and from this transporter within CL-enriched areas of the inner bacterial membrane. PMID- 25729860 TI - Effect of donor age on the proportion of mesenchymal stem cells derived from anterior cruciate ligaments. AB - The characteristics of anterior cruciate ligament (ACL)-derived mesenchymal stem cells (MSCs), such as proportion and multilineage potential, can be affected by donor age. However, the qualitative and quantitative features of ACL MSCs isolated from younger and older individuals have not yet been compared directly. This study assessed the phenotypic and functional differences in ACL-MSCs isolated from younger and older donors and evaluated the correlation between ACL MSC proportion and donor age. Torn ACL remnants were harvested from 36 patients undergoing ACL reconstruction (young: 29.67 +/- 10.92 years) and 33 undergoing TKA (old: 67.96 +/- 5.22 years) and the proportion of their MSCs were measured. The mean proportion of MSCs was slightly higher in older ACL samples of the TKA group than of the younger ACL reconstruction group (19.69 +/- 8.57% vs. 15.33 +/- 7.49%, p = 0.024), but the proportions of MSCs at passages 1 and 2 were similar. MSCs from both groups possessed comparable multilineage potentiality, as they could be differentiated into adipocytes, osteocytes, and chondrocytes at similar level. No significant correlations were observed between patient age and MSC proportions at passages 0-2 or between age and MSC proportion in both the ACL reconstruction and TKA groups. Multiple linear regression analysis found no significant predictor of MSC proportion including donor age for each passage. Microarray analysis identified several genes that were differentially regulated in ACL-MSCs from old TKA patients compared to young ACL reconstruction patients. Genes of interest encode components of the extracellular matrix (ECM) and may thus play a crucial role in modulating tissue homeostasis, remodeling, and repair in response to damage or disease. In conclusion, the proportion of freshly isolated ACL-MSC was higher in elderly TKA patients than in younger patients with ACL tears, but their phenotypic and multilineage potential were comparable. PMID- 25729862 TI - Beyond chance? The persistence of performance in online poker. AB - A major issue in the widespread controversy about the legality of poker and the appropriate taxation of winnings is whether poker should be considered a game of skill or a game of chance. To inform this debate we present an analysis into the role of skill in the performance of online poker players, using a large database with hundreds of millions of player-hand observations from real money ring games at three different stakes levels. We find that players whose earlier profitability was in the top (bottom) deciles perform better (worse) and are substantially more likely to end up in the top (bottom) performance deciles of the following time period. Regression analyses of performance on historical performance and other skill-related proxies provide further evidence for persistence and predictability. Simulations point out that skill dominates chance when performance is measured over 1,500 or more hands of play. PMID- 25729863 TI - [The end of the third lap]. PMID- 25729864 TI - Compliance with antibiotic prophylaxis in spinal fusion surgery and surgical wound infection. AB - BACKGROUND: Surgical wound infection is an important complication of spinal surgery. Antibiotic prophylaxis has served to decrease its rates significantly, with the ensuing reduction in hospital stay, costs, and morbidity and mortality. To date, a large assessment of the degree of compliance with antibiotic prophylaxis in spinal fusion surgery has not been undertaken in Spain with large prospective studies. We sought to assess the degree of compliance with our antibiotic prophylaxis protocol among patients who underwent spinal fusion surgery and its effect on surgical wound infection. MATERIAL AND METHODS: A prospective cohort study was carried out. Six hundred and forty patients with at least 1-year clinical followup who underwent spinal fusion surgery were included. Percentage of administration and degree of compliance with protocol was studied. Both overall and the different aspects of prophylaxis received by patients to those stipulated in the protocol in force at our hospital were compared. Percentages of compliance were assessed and the effect of prophylaxis compliance on the incidence of infection was estimated using the Relative Risk. RESULTS: The study covered 640 patients. Overall compliance with the protocol was 71.5% (95% CI = 67.9- 75.1). The most frequent cause of non-compliance with the protocol was the duration of recommended antibiotic prophylaxis (77.8%). Incidence of surgical wound infection was 4.1% (95% CI: 2.5-5.5). No relationship was found between surgical wound infection and antibiotic prophylaxis non-compliance (RR 0.92, 95% CI = 0.38-2.22). CONCLUSIONS: Compliance and administration of antibiotic prophylaxis were high. Surgical wound infection rate was similar to those found in the literature although there is always room for improvement. PMID- 25729865 TI - [Is effective a shortened surveillance system of bloodstream infection?]. AB - INTRODUCTION: Surveillance is necessary for bloodstream infection control. Daily monitoring of the central venous catheter (CVC) use, a time-demanding process, is the standard denominator to calculate the infection rate; surveillance of only one day per week has been proposed as alternative. OBJECTIVE: To determine whether surveillance of one day per week is similar to daily monitoring in a second-level hospital. MATERIAL AND METHODS: Daily monitoring of CVC utilization ratio was done during nine weeks in four locations of a second-level hospital. For each day, proportional differences respect to the global CVC utilization ratio was estimated. An ANOVA test was done to find differences between each weekday. RESULTS: CVC usage surveillance was performed for 9 weeks, so nine determinations were obtained for each weekday. No significant differences were found between each day (F = 2.20, p = 0.056). The lowest sampling discrepancy was found on Wednesdays. CONCLUSIONS: According to previous studies, and our own data, monitoring the CVC use one day per week is a reasonable alternative to the daily surveillance. PMID- 25729866 TI - Coping and emotional discomfort in primary caregivers of cancer patients. AB - OBJECTIVES: To assess the psychometric properties of the Carer's Assessment of Managing Index. To compare coping styles in caregivers of patients with terminal cancer (CPTC) and caregivers of patients on oncologic treatment (CPOT). To revise the association between coping styles, socio-demographic variables, and emotional discomfort in caregivers. MATERIAL AND METHODS: A cross-sectional and correlational study was conducted, in which 133 caregivers, 59 CPOT and 74 CPTC, were interviewed. Emotional discomfort (depression, anxiety, caregiver's burden) and coping styles were measured. RESULTS: The instrument was defined by three factors (alternate perception of events, active coping, and emotional regulation), with an internal consistency of alpha = 0.78. The alternate perception of events was the only coping style with statistically significant difference between CPOT and CPTC, and CPOT score higher in this regard. Different coping styles allow for more accurate prediction of emotional discomfort in CPTC, which showed more symptoms of anxiety, depression, caregiver's burden and physical illness. The study found a high occurrence of behaviors such as crying, screaming, smoking, anxiety eating and alcohol consumption in both CPOT and CPTC, all of which related to intense emotional discomfort. Active coping scores were higher when the caregivers had social support and a higher level of education (bachelor's degree or postgraduate studies). Active coping scores went down when different aspects of the caregiver's life were affected, when physical or psychological symptoms were present, and when the caregivers had more time in their role. PMID- 25729867 TI - [Experience, prevalence, severity, treatment needs for dental caries and care index in Mexican adolescents and young adults]. AB - OBJECTIVE: To determine the experience, prevalence and severity of dental caries as well as to establish the treatment needs and restorative care in adolescents and young adults. MATERIAL AND METHODS: This cross-sectional study included 638 subjects 16-25 years old candidates to enter to state public university of San Luis Potosi, Mexico. For caries detection was used the DMFT index (sum of decayed teeth + missing teeth + filled teeth in the permanent dentition). With DMFT index data were calculated the experience, the prevalence and the severity of caries. Also are reported the significant caries index (SiC), the treatment needs index (TNI) and the care index (CI). Statistical analysis was performed using nonparametric tests. RESULTS: The mean DMFT index was 4.24 +/- 3.85, prevalence 76.5% and severity of 52.3% for DMFT > 3 and 26.2% for DMFT > 6. The SiC index was 8.7. The TNI was 43.0% and 52.8% CI. No variation was observed (p > 0.05) on the experience, prevalence and severity of caries by age. The component "filled teeth" showed differences by age (p < 0.05). Women had higher caries experience and severity than men (p < 0.05), equally "decay teeth" and "filled teeth" (p < 0.05). CONCLUSIONS: We observed high levels of experience, prevalence and severity of dental caries in this sample of adolescents and young adults. We found almost 40% of untreated caries lesions. We found some differences by sex. PMID- 25729868 TI - [Association between dental caries and the body mass index in a school population in Iztapalapa, Mexico City]. AB - OBJECTIVE: To identify the association between dental caries and body mass index in school children from six to twelve years of 20 elementary schools located in the four educational regions of Iztapalapa, in Mexico City. MATERIAL AND METHODS: The study was cross-comparative-descriptive, observational, with a nonrandom convenience sample of 6,230 schoolchildren, composed of the school who gave their prior informed permission signed by parents or guardians to participate in this study consent rate. The results were captured in the computer program SPSS version 15.0. RESULTS: Of all schools, 10.5% were underweight, with an average of 2.3 dental caries. 49.6% reported normal weight, with 2.8 decayed teeth. 21.1% overweight, and 3.1. The 9.5% obese and 3.1, 9.3% with endogenous obesity and 3.2 decayed teeth respectively. CONCLUSIONS: In this study exist an association between dental caries and obesity, which makes him a multidimensional problem, where economic, cultural, political and social processes interact there. PMID- 25729869 TI - [Aortic valve calcification evaluated by echocardiography associated with baseline conduction abnormalities as a predictor for pacemaker placement after aortic valve replacement]. AB - INTRODUCTION: Aortic valve replacement in patients with severe aortic stenosis may be complicated by complete atrioventricular block (CAVB), requiring a permanent pacemaker (PPM) implantation. Predicting this complication could help to plan the surgical. OBJECTIVE: Determine whether electrocardiography and echocardiography are useful methods for predicting the need for PPM. MATERIAL AND METHODS: A retrospective, observational and transversal study was performed. An echocardiography based semi-quantitative classification was implemented to graduate the extent of calcification of the aortic valve. RESULTS: We included 95 patients; 10 of them required PPM implantation (10.52%). In the pre-surgical basal electrocardiogram we observed that 90% of patients that required PPM had conduction abnormalities as opposed to only 24.7% in the other group, p = 0.001. A 1st and 2nd degree AV block (AVB 1 and 2) was identified in 8 patients that subsequently needed PPM (80%) vs. 5 patients (5.9%), in the group that did not required it, p = 0.001.OR 41.7, IC 95% 6.5-68. We found a grade 3 calcification extent in 80% of patients who required PPM implant compared with only 17.6% of patients in the other group, p = 0.04, OR 4.8, IC 95% 0.76-29. The AVB 1 and 2 were the single predictor in multivariate analysis but the calcification 3 + AVB 1 and 2, increased sensibility. CONCLUISON: In patients with aortic stenosis in whom aortic valve replacement was performed, identifying AVB 1 and 2 on the basal electrocardiogram is a useful tool in order to identify requirement of PPM. The grade 3 of calcification extent increased the sensibility of this prediction. PMID- 25729870 TI - In vitro determination of the short-chain synthetic peptide RP13 antimicrobial activity. AB - BACKGROUND: The proliferation of antibiotic-resistant microorganisms, along with the lack of new drugs against them, has elicited the interest of the scientific community on the study and development of endogenous synthetic compounds with bacteriostatic or bactericidal activity. In recent years, several short-chain, low molecular weight peptides isolated from natural sources such as plants and animals have demonstrated an array of antimicrobial activities. Despite having structural characteristics similar to microbicidal peptides isolated from human platelets, peptide RP11 does not exhibit antimicrobial activity. OBJECTIVE: In vitro determination of the antimicrobial activity of the synthetic peptide RP13. MATERIAL AND METHODS: Peptide RP13 was prepared modifying the original amino acids sequence of peptide RP11, reversing the position of the amino acids lysine and tyrosine in order to modify the conformation of the original peptide. These amino acids are localized close to the N-terminus of the peptidic chain. Peptide RP13 was prepared in solution using conventional methods for peptide synthesis. The antimicrobial activity of RP13 was assessed against the microorganisms S. aureus, E. faecalis and E. coli in a test solution and later evaluated by cultivation of plates during the first 2 h after inoculation of bacteria. RP13 activity antimicrobial was compared against tetracycline, a broad-spectrum antibiotic. RESULTS: The new peptide RP13, resulting form the structural modification of the amino acid sequence of peptide RP11, displayed antimicrobial activity. RP13 demonstrated to be more efficient inhibiting the growth of gram positive than gramnegative bacteria. CONCLUSIONS: The structural modification of peptide RP11, obtained from human platelets, resulted in a new peptide with improved antimicrobial activity. These results clearly demonstrate that peptides of natural origin, as well as their synthetic analogs, represent an attractive alternative against pathogenic agents. PMID- 25729871 TI - [Indications for liver transplant]. AB - Liver transplantation (LT) is the treatment of choice in selected patients with end-stage liver disease and in some with acute liver failure, hepatocellular carcinoma (HCC) and other diseases with no synthetic liver failure. Currently, LT has an overall survival > 90 % at 1 year. Proper selection of LT candidates is important given the shortage in organ donation. The allocation and priorization of organs to patients with chronic liver failure (CLF) in waiting lists, is determined by the MELD priority score (Model of End Stage Liver Disease). Indications for LT in patients with CLF are the same regardless of the etiology (any type of hepatic decompensation or development of HCC). Priority MELD is a variant to this classification used only in special cases such as in those with stable hepatopathy but severe extra-hepatic features (e.g., HCC or hepato pulmonary syndrome). The indication for LT in patients with acute liver failure (ALF) and acute failure associated to chronic liver failure (ACLF) are not fully established; there are prognostic factors that may guide the decision for urgent LT and some centers, like the King's College Hospital criteria in the UK. Currently, LT is a therapeutic modality in some primary liver tumors (HCC, cholangiocarcinoma) and neuroendocrine liver metastatic tumors. These protocols have provided significant opportunities for long-term survival (> 70% at 5 years). The high demand and shortage of organs have fostered the development of new strategies to benefit more patients, such as the use of extended criteria donors, or "domino" transplants. This review focuses on the most relevant data on the different indications of LT. PMID- 25729872 TI - [Clinical Forum: Breast cancer in young women in Mexico: unmet needs and clinical challenges]. PMID- 25729873 TI - [Structural functional and pathological aspects of the NaCl contransporter thiazide sensitive]. AB - NCC cotransporter is the mayor pathway for sodium chloride reabsorption in the distal nephron and the target of thiazide diuretics which, given their clinical utility in the management of arterial hypertension, are amongst the top sold drugs in the world. NCC protein is of great physiological importance given its role in the maintenance of water and salt homeostasis on the organism. Inactivating mutations in the gene that codes for NCC cause Gitelman's syndrome: an autosomal recessive disease associated with arterial hypotension, metabolic alkalosis, hipokalemia and hypocalciuria. This syndrome represents strong evidence of the relevance of the role of NCC in blood pressure regulation, electrolyte and acid base balance. In this work we review the up to date knowledge regarding this cotransporter with special attention to the molecular aspects of the protein that determine is physiological function and pathological roles. PMID- 25729876 TI - Two types of nitrito support for MU4-oxido-bridged [Cu4] complexes: synthesis, crystal structures, magnetic properties and DFT analysis. AB - Novel nitrito supported and MU4-oxido bridged Cu(II) aggregates have been found in two tetranuclear complexes, [Cu4(MU4-O)L2(MU(1,3)-ONO)4] (1) and [Cu4(MU4 O)L2(MU(1,3)-OAc)2(MU1,2-NO2)2] (2), of the chiral Schiff base HL (HL = 4-methyl 2,6-bis-(1-phenyl-ethylimino)-methylphenol). The structures contain either in situ generated or externally added peripheral MU-nitrito groups, in kappa(2)O/O and kappa(2)N/O bridging modes. Four NO2(-) bridges in 1 and two AcO(-) co ligands along with two NO2(-) bridges in 2 are essential for the stabilization of these tetranuclear aggregates. The complexes have been characterized by X-ray crystal structure determination, spectroscopic and magnetic measurements, and density functional theory (DFT) analysis. They are formed from the assembly of two [Cu2L](3+) fragments around a water-derived oxido ligand under the control of nitrite or mixed nitrite/acetate bridges. Variable temperature magnetic susceptibility measurements reveal strong intramolecular antiferromagnetic exchange interactions within the tetranuclear clusters to yield S(T) = 0 ground state. The capacity of the two different nitrite bridging modes to mediate magnetic coupling has been examined through measurements and numerical fitting procedures, and rationalized by means of DFT calculations. PMID- 25729877 TI - The effect of steric changes on the isoselectivity of dinuclear indium catalysts for lactide polymerization. AB - A series of (+/-)- and (R,R)-tridentate diamino, ortho/para disubstituted phenolate proligands H(NNO(R)) with various phenolate substituents was synthesized and used to prepare indium dichloride complexes (NNO(R))InCl2via salt metathesis of the deprotonated ligands with indium trichloride. These complexes are dinuclear in the solid state, in contrast to previously reported complexes with t-butyl or methyl phenolate substituents. Solution state (1)H and PGSE NMR spectroscopy suggests that a fast exchange between the monomeric and dimeric forms of these complexes may exist in solution and is likely influenced by the chirality of the complexes undergoing aggregation. The indium dichloride complexes were utilized to synthesize dinuclear indium ethoxide complexes via salt metathesis with sodium ethoxide. These complexes were active for the polymerization of lactide. In situ and bulk polymerization data confirmed differences in the activity and selectivity of these systems based on the phenolate substituents as well as the ligand chirality. PMID- 25729878 TI - N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study. AB - INTRODUCTION: N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD. METHODS: A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (CO(EXH)) (secondary outcome), and quit rates as defined by CO(EXH) < 6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses. RESULTS: NAC treatment significantly reduced the daily number of cigarettes used (Delta mean +/- SD = 10.9 +/- 7.9 in the NAC-treated versus -3.2 +/- 6.1 in the placebo group) and CO(EXH) (Delta mean +/- SD = -10.4 +/- 8.6 ppm in the NAC-treated versus -1.5 +/- 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by CO(EXH) < 6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder. CONCLUSIONS: These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD. PMID- 25729879 TI - Evaluating Neurocognitive Deficits in Patients With Multiple Sclerosis Via a Brief Neuropsychological Approach. AB - Recent research demonstrates neurocognitive deficits are present early in the sequelae of multiple sclerosis (MS). This is an important consideration given the functional activities of daily living, such as employment, that can be impacted by neurocognitive dysfunction. This study investigated the utility of a brief neuropsychological battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), to evaluate neurocognitive deficits in patients with MS and to examine the relationship between a measure of functional disability (Expanded Disability Status Scale [EDSS]) and the RBANS. Participants were 49 patients with MS (Mage = 45.39 years) who completed the RBANS as part of a neuropsychological assessment and 49 demographically matched healthy controls (Mage = 45.39 years). Multivariate analysis of variance revealed that the two groups differed on the RBANS. Descriptive discriminant analysis indicated the groups differed on domains of attention, language, immediate memory, and delayed memory. EDSS scores were a good predictor of neurocognitive dysfunction in patients with advanced disability but not for patients with mild disability. The RBANS seems to be effective in identifying cognitive dysfunction in patients with MS, and caution should be used in extrapolating cognitive deficits for patients with low EDSS scores. PMID- 25729880 TI - Effect of polar and movable (OH or NH2 groups) on the photocatalytic H2 production of alkyl-alkanolamine: a comparative study. AB - The photocatalytic production of molecular hydrogen (H2) from aqueous solutions of alkyl-alkanolamines (triethanolamine (tri-EOA), diethanolamine (di-EOA), ethanolamine (EOA), ethylamine (EA) and ethanol over Pt-loaded commercial (Sachtleben Hombikat UV100) nanoparticle titanium dioxide photocatalysts was studied. These photocatalysts were characterized using X-ray diffraction, Brunauer-Emmett-Teller, field-emission scanning electron microscopy, atomic force microscopy and UV-vis diffuse reflectance spectroscopy techniques. Effect of pH and temperature on photocatalytic hydrogen production of alkyl-alkanolamines was investigated. It was found for all molecules under study that the amount of hydrogen produced at a constant illumination time is a function of pH and temperature. At all temperatures investigated the rate of hydrogen production at pH 9 followed the order tri-EOAethanolamine >> di-EOA ~ EOA > ethanol > EA. From the values of the photocatalytic rate constants at various temperatures, the apparent activation energies were determined for the hydrogen production. The observed dependence of the reaction rate on solution temperature cannot be related to light-driven reaction steps, because the band-gap energy of the semiconductor is too high for thermal excitation to become significant in the temperature range investigated. PMID- 25729881 TI - Enhanced in vitro and in vivo cellular imaging with green tea coated water soluble iron oxide nanocrystals. AB - Fully green and facile redox chemistry involving reduction of colloidal iron hydroxide (Fe(OH)3) through green tea (GT) polyphenols produced water-soluble Fe3O4 nanocrystals coated with GT extracts namely epigallocatechin gallate (EGCG) and epicatechin (EC). Electron donating polyphenols stoichiometrically reduced Fe(3+) ions into Fe(2+) ions resulting in the formation of magnetite (Fe3O4) nanoparticles and corresponding oxidized products (semiquinones and quinones) that simultaneously served as efficient surface chelators for the Fe3O4 nanoparticles making them dispersible and stable in water, PBS, and cell culture medium for extended time periods. As-formed iron oxide nanoparticles (2.5-6 nm) displayed high crystallinity and saturation magnetization as well as high relaxivity ratios manifested in strong contrast enhancement observed in T2 weighted images. Potential of green tea-coated superparamagnetic iron oxide nanocrystals (SPIONs) as superior negative contrast agents was confirmed by in vitro and in vivo experiments. Primary human macrophages (J774A.1) and colon cancer cells (CT26) were chosen to assess cytotoxicity and cellular uptake of GT , EGCGq-, and ECq-coated Fe3O4 nanoparticles, which showed high uptake efficiencies by J774A.1 and CT26 cells without any additional transfection agent. Furthermore, the in vivo accumulation characteristics of GT-coated Fe3O4 nanoparticles were similar to those observed in clinical studies of SPIONs with comparable accumulation in epidermoid cancer-xenograft bearing mice. Given their promising transport and uptake characteristics and new surface chemistry, GT SPIONs conjugates can be applied for multimodal imaging and therapeutic applications by anchoring further functionalities. PMID- 25729883 TI - Effect of dependent coverage expansion of the Affordable Care Act on health and access to care for young adults. PMID- 25729882 TI - Effects of epidermal growth factor-loaded mucoadhesive films on wounded oral tissue rafts. AB - Current treatments for traumatic oral mucosal wounds include the gold standard of autologous tissue and alternative tissue-engineered grafts. While use of autografts has disadvantages of minimal availability of oral keratinized tissue, second surgery, and donor site discomfort, tissue-engineered grafts are limited by their unavailability as off-the-shelf products owing to their fabrication time of 4-8 weeks. Hence, the current work aimed to develop a potentially cost effective, readily available device capable of enhancing native mucosal regeneration. Considering the key role of epidermal growth factor (EGF) in promoting mucosal wound regeneration and the advantages of mucoadhesive delivery systems, mucoadhesive films composed of polyvinylpyrrolidone and carboxymethylcellulose were developed to provide sustained release of EGF for a minimum of 6 h. Bioactivity of released EGF supernatants was then confirmed by its ability to promote proliferation of BALB/3T3 fibroblasts. Efficacy of the developed system was then investigated in vitro using buccal tissues (ORL 300-FT) as a potential replacement for small animal studies. Although the mucoadhesive films achieved their desired role of delivering bioactive EGF in a sustained manner, treatment with EGF, irrespective of its release from the films or solubilized in medium, caused a hyperparakeratotic response from in vitro tissues with distinguishable histological features including thickening of the spinous layer, intra- and intercellular edema, and pyknotic nuclei. These significant morphological changes were associated with no improvements in wound closure. These observations raise questions about the potential of using in vitro tissues as a wound healing model and substitute for small animal studies. The mucoadhesive delivery system developed, however, with its potential for sustained release of bioactive growth factors and small molecules, may be loaded with other desired compounds, with or without EGF, to accelerate the process of wound healing. PMID- 25729886 TI - Gastric Emptying and Curding of Pasteurized Donor Human Milk and Mother's Own Milk in Preterm Infants. AB - We evaluated the effects of fortification and composition on gastric emptying and curding in un/fortified pairs of mother's own milk (MOM, n = 17) and pasteurized donor human milk (PDHM, n = 15) in preterm infants. Retained meal proportions (%) and curding were determined from sonography. Immediate and subsequent postprandial % were higher for PDHM (23%, P = 0.026; 15%, P = 0.006) and fortified meals (31.5%; 8.8%, both P < 0.001), whereas higher casein, whey, and lactose concentrations were associated with lower immediate postprandial % (all P < 0.006). Curding did not affect emptying. Influences of fortification, pasteurization, and differing breast milk compositions are small and unlikely implicated in preterm feeding intolerance. PMID- 25729885 TI - Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking. AB - Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment. PMID- 25729887 TI - Chemical clearance in infants and children with Acid reflux in the physiologic range. AB - BACKGROUND AND AIM: We reported that chemical clearance (CC) of acid gastroesophageal reflux (AGER) is relatively prolonged in children with cystic fibrosis (CF). Disparity in CC values within our CF cohort sparked curiosity as to what CC looks like in infants and children with AGER in the physiologic range. The aim of the study was to assess CC in infants and children with normal AGER. METHODS: Impedance-pH tracings from our database for infants (<= 12 months) and children (>12 months-18 years) were manually scanned for 2-phase AGER episodes. Tracings were excluded for patients who had AGER Indices >3% (children) or >6% (infants), had positive GER-symptom associations, were on antireflux medications, had a fundoplication, or had impedance studies shorter than 18 hour. In addition to medians (25%-75% interquartile range), we calculated the 95th percentile for the CC duration and the fifth percentile for the CC rate. RESULTS: Two-phase AGER episodes were detected in 44 infants and 60 children. The median CC duration was 64.3 seconds (51.0-91.6 seconds) for infants and 37.5 seconds (27.7-52.4 seconds) for children. The median CC rate was 0.0622 pH units/second (PU/second) (0.0354 0.0946 PU/second) for infants and 0.0928 PU/second (0.0631-0.2057 PU/second) for children. The CC duration at the 95th percentile was 148.5 seconds for infants and 114.4 seconds for children. The CC rate at the fifth percentile was 0.0088 PU/second for infants and 0.0465 PU/second for children. CONCLUSIONS: We report reference values for CC in infants and children who have normal acid reflux. These values should not be used as "cutoff values" because they were derived from infant and children cohorts that did not include individuals with intermediate AGER. PMID- 25729888 TI - Serum Bile Acid Levels in Children With Nonalcoholic Fatty Liver Disease. AB - OBJECTIVE: Because the prevalence of obesity in children is increasing, the frequency of pediatric nonalcoholic fatty liver disease (NAFLD) is growing. A reliable noninvasive biomarker for monitoring progression of liver fibrosis would be useful. In cirrhotic persons serum bile acid (BA) levels are significantly elevated. We hypothesized that BA levels and composition in pediatric NAFLD vary depending on the stage of fibrosis. METHODS: Children with NAFLD were compared with controls and classified by stages of fibrosis (NAFLD-F0, n = 27; NAFLD-F>=1, n = 65) based on liver-biopsy findings. Fasted metabolic and cholestasis status was assessed by several blood tests. BA profiles were measured by tandem mass spectrometry and compared with healthy controls (n = 105). RESULTS: Compared with controls, all of the NAFLD patients were overweight and showed significantly elevated glucose, insulin, aspartate transaminase, and alanine transaminase levels. Total serum BAs were lower in nonfibrotic NAFLD children than in a control cohort (1.73 vs 3.6 MUmol/L) because low glycine-conjugated BA levels were incompletely compensated by increases in taurine-conjugated or unconjugated BA. In patients with fibrotic NAFLD, BA levels were lower than in controls (2.45 vs 3.6 MUmol/L) but higher than in nonfibrotic patients (2.45 vs 1.73 MUmol/L), and the BA pattern resembled that of healthy controls. Fibroblast growth factor 19 levels were significantly lower in both NAFLD groups than in controls (P <= 0.001) and were positively correlated with ursodeoxycholic acid levels. CONCLUSIONS: Our data indicate that serum BA levels decrease in early NAFLD and increase during progression to fibrosis. Given that BA levels are increased in cirrhotic adults, we postulate a continuous rise as NAFLD advances. BA may have a value as a noninvasive biomarker in pediatric NAFLD progression. PMID- 25729889 TI - Refined Multidisciplinary Protocol-Based Approach to Short Bowel Syndrome Improves Outcomes. AB - OBJECTIVE: Management of short bowel syndrome (SBS) has significantly evolved recently. We present our single-center, 25-year experience focusing on the implementation of a refined multidisciplinary SBS care protocol. METHODS: This is a retrospective review of the patients with SBS treated at our tertiary center from 1988 to 2014, with either <25% short bowel remaining or duration of parenteral nutrition (PN) >3 months. Patients with primary intestinal motility disorders were excluded. Clinical characteristics, including intestinal anatomy, markers of cholestasis, and catheter-related infections (CRIs), were analyzed. The implementation of a refined modern uniform management protocol in 2009 divided the cohort into 2 subgroups, whose outcomes are compared. RESULTS: Forty eight patients with SBS were identified (median gestational age 33 weeks). Of them, 22 were born between 2009 and 2014. The main causes of SBS were necrotizing enterocolitis (46%) and midgut volvulus (23%). Median remaining small bowel length was 36 cm. The overall survival was 23 of 26 (88%) before 2009 and 21 of 22 (95%) thereafter, whereas none were transplanted. Duration of PN shortened from a median of 15 to 6 months (P = 0.0015) in the latter cohort, whereas frequency of autologous intestinal reconstruction surgery (31%) remained unchanged. Frequency of neonatal cholestasis was similar in both groups (75%), but cleared in all after 2009. Before 2009, 2 patients died of progressive cholestatic liver failure. The CRI rates decreased from 1.7 to 0.7 per 1000 catheter-days between 2000-2008 and 2009-2014, respectively (P = 0.0178). CONCLUSIONS: Uniform refined multidisciplinary approach decreased the duration of PN and CRI rates with high transplant-free survival and avoidance of liver failure, although the frequency of transient neonatal cholestasis remained unchanged. PMID- 25729890 TI - Celiac disease diagnosis without endoscopy: is it really effective among screened patients? PMID- 25729891 TI - Author's Response. PMID- 25729892 TI - Women's veteran identity and utilization of VA health services. AB - Women have participated in the United States military since its founding. However, until the mid-20th century, there had been limited recognition of women as official members of the military, and women remain a statistical minority within military and veteran populations. It is therefore important to better understand women's veteran identity (which we define here as one's self-concept as derived from their veteran status) and associated implications for service use and experiences in the Department of Veterans Affairs (VA) health care setting. The present research examined the centrality of, and positive regard for, women's veteran identity among 407 female veterans deployed in support of the recent wars in Iraq and Afghanistan. Data were collected via a mailed national survey. Positive regard for veteran identity, but not veteran identity centrality,was positively associated with participants' age and length of time spent in the military. Results also showed that the centrality of women's veteran identity was positively related to their choice to use VA for health care and their feelings of belonging within VA, and that veteran identity centrality and positive regard for veteran identity are differentially associated with participants' military experiences (e.g., combat exposure, deployment sexual harassment) and mental health symptomatology (e.g., depression). PMID- 25729893 TI - How to Appropriately Calculate Effective Dose for CT Using Either Size-Specific Dose Estimates or Dose-Length Product. AB - OBJECTIVE: The purpose of this study is to show how to calculate effective dose in CT using size-specific dose estimates and to correct the current method using dose-length product (DLP). MATERIALS AND METHODS: Data were analyzed from 352 chest and 241 abdominopelvic CT images. Size-specific dose estimate was used as a surrogate for organ dose in the chest and abdominopelvic regions. Organ doses were averaged by patient weight-based populations and were used to calculate effective dose by the International Commission on Radiological Protection (ICRP) report 103 method using tissue-weighting factors (EICRP). In addition, effective dose was calculated using population-averaged CT examination DLP for the chest and abdominopelvic region using published k-coefficients (EDLP = k * DLP). RESULTS: EDLP differed from EICRP by an average of 21% (1.4 vs 1.1) in the chest and 42% (2.4 vs 3.4) in the abdominopelvic region. The differences occurred because the published kcoefficients did not account for pitch factor other than unity, were derived using a 32-cm diameter CT dose index (CTDI) phantom for CT examinations of the pediatric body, and used ICRP 60 tissue-weighting factors. Once it was corrected for pitch factor, the appropriate size of CTDI phantom, and ICRP 103 tissue-weighting factors, EDLP improved in agreement with EICRP to better than 7% (1.4 vs 1.3) and 4% (2.4 vs 2.5) for chest and abdominopelvic regions, respectively. CONCLUSION: Current use of DLP to calculate effective dose was shown to be deficient because of the outdated means by which the k coefficients were derived. This study shows a means to calculate EICRP using patient size-specific dose estimate and how to appropriately correct EDLP. PMID- 25729894 TI - Addressing Ebola and other outbreaks: a communication checklist for global health leaders, policymakers, and practitioners. PMID- 25729895 TI - Enhanced light emission from large-area monolayer MoS2 using plasmonic nanodisc arrays. AB - Single-layer direct band gap semiconductors such as transition metal dichalcogenides are quite attractive for a wide range of electronics, photonics, and optoelectronics applications. Their monolayer thickness provides significant advantages in many applications such as field-effect transistors for high performance electronics, sensor/detector applications, and flexible electronics. However, for optoelectronics and photonics applications, inherent monolayer thickness poses a significant challenge for the interaction of light with the material, which therefore results in poor light emission and absorption behavior. Here, we demonstrate enhanced light emission from large-area monolayer MoS2 using plasmonic silver nanodisc arrays, where enhanced photoluminescence up to 12-times has been measured. Observed phenomena stem from the fact that plasmonic resonance couples to both excitation and emission fields and thus boosts the light-matter interaction at the nanoscale. Reported results allow us to engineer light-matter interactions in two-dimensional materials and could enable highly efficient photodetectors, sensors, and photovoltaic devices, where photon absorption and emission efficiency highly dictate the device performance. PMID- 25729896 TI - Correction: poloxomer 188 has a deleterious effect on dystrophic skeletal muscle function. PMID- 25729897 TI - Time series analyses of hand, foot and mouth disease integrating weather variables. AB - BACKGROUND: The past decade witnessed an increment in the incidence of hand foot mouth disease (HFMD) in the Pacific Asian region; specifically, in Guangzhou China. This emphasized the requirement of an early warning system designed to allow the medical community to better prepare for outbreaks and thus minimize the number of fatalities. METHODS: Samples from 1,556 inpatients (hospitalized) and 11,004 outpatients (non-admitted) diagnosed with HFMD were collected in this study from January 2009 to October 2013. Seasonal Autoregressive Integrated Moving Average (SARIMA) model was applied to establish high predictive model for inpatients and outpatient as well as three viral serotypes (EV71, Pan-EV and CA16). To integrate climate variables in the data analyses, data from eight climate variables were simultaneously obtained during this period. Significant climate variable identified by correlation analyses was executed to improve time series modeling as external repressors. RESULTS: Among inpatients with HFMD, 248 (15.9%) were affected by EV71, 137 (8.8%) were affected by Pan-EV+, and 436 (28.0%) were affected by CA16. Optimal Univariate SARIMA model was identified: (2,0,3)(1,0,0)52 for inpatients, (0,1,0)(0,0,2)52 for outpatients as well as three serotypes (EV71, (1,0,1)(0,0,1)52; CA16, (1,0,1)(0,0,0)52; Pan-EV, (1,0,1)(0,0,0)52). Using climate as our independent variable, precipitation (PP) was first identified to be associated with inpatients (r = 0.211, P = 0.001), CA16-serotype (r = 0.171, P = 0.007) and outpatients (r = 0.214, P = 0.01) in partial correlation analyses, and was then shown a significant lag in cross autocorrelation analyses. However, inclusion of PP [lag -3 week] as external repressor showed a moderate impact on the predictive performance of the SARIMA model described here-in. CONCLUSION: Climate patterns and HFMD incidences have been shown to be strongly correlated. The SARIMA model developed here can be a helpful tool in developing an early warning system for HFMD. PMID- 25729898 TI - Spatial and temporal variations in indoor environmental conditions, human occupancy, and operational characteristics in a new hospital building. AB - The dynamics of indoor environmental conditions, human occupancy, and operational characteristics of buildings influence human comfort and indoor environmental quality, including the survival and progression of microbial communities. A suite of continuous, long-term environmental and operational parameters were measured in ten patient rooms and two nurse stations in a new hospital building in Chicago, IL to characterize the indoor environment in which microbial samples were taken for the Hospital Microbiome Project. Measurements included environmental conditions (indoor dry-bulb temperature, relative humidity, humidity ratio, and illuminance) in the patient rooms and nurse stations; differential pressure between the patient rooms and hallways; surrogate measures for human occupancy and activity in the patient rooms using both indoor air CO2 concentrations and infrared doorway beam-break counters; and outdoor air fractions in the heating, ventilating, and air-conditioning systems serving the sampled spaces. Measurements were made at 5-minute intervals over consecutive days for nearly one year, providing a total of ~8*106 data points. Indoor temperature, illuminance, and human occupancy/activity were all weakly correlated between rooms, while relative humidity, humidity ratio, and outdoor air fractions showed strong temporal (seasonal) patterns and strong spatial correlations between rooms. Differential pressure measurements confirmed that all patient rooms were operated at neutral pressure. The patient rooms averaged about 100 combined entrances and exits per day, which suggests they were relatively lightly occupied compared to higher traffic environments (e.g., retail buildings) and more similar to lower traffic office environments. There were also clear differences in several environmental parameters before and after the hospital was occupied with patients and staff. Characterizing and understanding factors that influence these building dynamics is vital for hospital environments, where they can impact patient health and the survival and spread of healthcare associated infections. PMID- 25729899 TI - Template for Reporting Results of Biomarker Testing of Specimens From Patients With Gastrointestinal Stromal Tumors. PMID- 25729900 TI - Who tweets? Deriving the demographic characteristics of age, occupation and social class from twitter user meta-data. AB - This paper specifies, designs and critically evaluates two tools for the automated identification of demographic data (age, occupation and social class) from the profile descriptions of Twitter users in the United Kingdom (UK). Meta data data routinely collected through the Collaborative Social Media Observatory (COSMOS: http://www.cosmosproject.net/) relating to UK Twitter users is matched with the occupational lookup tables between job and social class provided by the Office for National Statistics (ONS) using SOC2010. Using expert human validation, the validity and reliability of the automated matching process is critically assessed and a prospective class distribution of UK Twitter users is offered with 2011 Census baseline comparisons. The pattern matching rules for identifying age are explained and enacted following a discussion on how to minimise false positives. The age distribution of Twitter users, as identified using the tool, is presented alongside the age distribution of the UK population from the 2011 Census. The automated occupation detection tool reliably identifies certain occupational groups, such as professionals, for which job titles cannot be confused with hobbies or are used in common parlance within alternative contexts. An alternative explanation on the prevalence of hobbies is that the creative sector is overrepresented on Twitter compared to 2011 Census data. The age detection tool illustrates the youthfulness of Twitter users compared to the general UK population as of the 2011 Census according to proportions, but projections demonstrate that there is still potentially a large number of older platform users. It is possible to detect "signatures" of both occupation and age from Twitter meta-data with varying degrees of accuracy (particularly dependent on occupational groups) but further confirmatory work is needed. PMID- 25729901 TI - Interpreting physical and behavioral health scores from new work disability instruments. AB - OBJECTIVE: To develop a system to guide interpretation of scores generated from 2 new instruments measuring work-related physical and behavioral health functioning (Work Disability - Physical Function (WD-PF) and WD - Behavioral Function (WD BH)). DESIGN: Cross-sectional, secondary data from 3 independent samples to develop and validate the functional levels for physical and behavioral health functioning. SUBJECTS: Physical group: 999 general adult subjects, 1,017 disability applicants and 497 work-disabled subjects. Behavioral health group: 1,000 general adult subjects, 1,015 disability applicants and 476 work-disabled subjects. METHODS: Three-phase analytic approach including item mapping, a modified-Delphi technique, and known-groups validation analysis were used to develop and validate cut-points for functional levels within each of the WD-PF and WD-BH instrument's scales. RESULTS: Four and 5 functional levels were developed for each of the scales in the WD-PF and WD-BH instruments. Distribution of the comparative samples was in the expected direction: the general adult samples consistently demonstrated scores at higher functional levels compared with the claimant and work-disabled samples. CONCLUSION: Using an item-response theory-based methodology paired with a qualitative process appears to be a feasible and valid approach for translating the WD-BH and WD-PF scores into meaningful levels useful for interpreting a person's work-related physical and behavioral health functioning. PMID- 25729913 TI - Validation of the cross-linguistic naming test: a naming test for different cultures? A preliminary study in the Spanish population. AB - BACKGROUND: Despite the consensus pointing out the importance of cultural variables in neuropsychological assessments, empirical studies within cross cultural neuropsychology continue to be limited. The Cross-Linguistic Naming Test (CLNT) is a naming test that is supposed to have no influence from cultural variables. The aim of this paper is to determine the psychometric properties of the CLNT and its discriminatory validity (Experiment 1) and to determine the performance of the CLNT in different cultures (Experiment 2). METHOD: Three groups followed the CLNT in Experiment 1: dementia patients, individuals with subjective memory complaints, and neurologically healthy volunteers. Three groups followed the CLNT in Experiment 2: Colombians, Moroccans, and Spaniards. RESULTS: The results showed that the psychometric properties of the CLNT are appropriate and that this test obtains a high specificity but a low sensitivity. Furthermore, no differences were found in the CLNT among the three cultural groups. DISCUSSION: The CLNT may be appropriate for the screening of naming impairment in Colombian, Moroccan, and Spanish cultures. PMID- 25729915 TI - Deficiencies with current aortic endografts. AB - Endovascular aortic aneurysm repair (EVAR) has currently replaced open surgical repair as the primary method for treating aneurysm disease of the abdominal aorta and common iliac artery. Current EVAR devices, despite undergoing multiple improvement iterations, continue to have relatively high secondary intervention rates. Device migration, endoleak and limb occlusion continue to be challenges not completely met by any of the current devices. Investigational devices presently in clinical trials may provide significant resolution for many of the identified endograft deficiencies. PMID- 25729914 TI - The dynamics of growth cone morphology. AB - BACKGROUND: Normal brain function depends on the development of appropriate patterns of neural connections. A critical role in guiding axons to their targets during neural development is played by neuronal growth cones. These have a complex and rapidly changing morphology; however, a quantitative understanding of this morphology, its dynamics and how these are related to growth cone movement, is lacking. RESULTS: Here we use eigenshape analysis (principal components analysis in shape space) to uncover the set of five to six basic shape modes that capture the most variance in growth cone form. By analysing how the projections of growth cones onto these principal modes evolve in time, we found that growth cone shape oscillates with a mean period of 30 min. The variability of oscillation periods and strengths between different growth cones was correlated with their forward movement, such that growth cones with strong, fast shape oscillations tended to extend faster. A simple computational model of growth cone shape dynamics based on dynamic microtubule instability was able to reproduce quantitatively both the mean and variance of oscillation periods seen experimentally, suggesting that the principal driver of growth cone shape oscillations may be intrinsic periodicity in cytoskeletal rearrangements. CONCLUSIONS: Intrinsically driven shape oscillations are an important component of growth cone shape dynamics. More generally, eigenshape analysis has the potential to provide new quantitative information about differences in growth cone behaviour in different conditions. PMID- 25729916 TI - Proangiogenic potency of MUC18 in arteriosclerotic disease. AB - AIM: Stenotic peripheral and dilatative arteriosclerotic diseases have different pathomechanism although associations between both diseases are well known. The adhesion molecule MUC18 is a cell membrane glycoprotein also known as the melanoma cell adhesion molecule. As MUC18 has proangiogenic potency in melanoma and prostate cancer this study investigated the role of MUC18 in patients with stenotic or dilatative arteriosclerotic disease as a putative biochemical marker. METHODS: Using qRT-PCR, Western Blot and immunohistochemistry techniques, the expression of MUC18 in arteriosclerotic arteries from major lower limb amputates (AP, N.=15) as well as specimen from femoral endarterectomies (TEA, N.=20) and in dilatative aortic diseases using abdominal aortic aneurysms (AAA, N.=13) was evaluated. Human visceral arteries without macroscopic arteriosclerosis from liver transplants served as controls (AN, N.=19). RESULTS: MUC18 mRNA and protein expression could be found in AN, AP, TEA and AAA tissues. Immunohistochemical analysis showed that a complete and intact intima was the predominant location of MUC18 expression. Although in stenotic arteriosclerotic disease (AP and TEA) the intima was widely calcified, qRT-PCR analysis showed overexpression compared to normal tissue. Interestingly, MUC18 expression was significantly down-regulated in dilatative compared to stenotic arteriosclerotic disease and normal arteries. CONCLUSION: In peripheral stenotic arteriosclerotic disease the proangiogenic potency of MUC18 may play a role in angiogenesis of collaterals, whereas in dilatative aortic diseases the induction of collaterals is typically not evident. The results support the hypothesis of a role in angiogenesis of MUC18 in stenotic arteriosclerotic disease. PMID- 25729917 TI - Catheter-directed thrombolysis for acute upper extremity ischemia. AB - AIM: Acute nontraumatic upper extremity ischemia has significant chronic disability when not treated adequately and timely. As surgical treatment can be challenging, this study evaluates catheter-directed thrombolysis as first-line treatment for acute upper extremity ischemia. METHODS: Between January 2006 and December 2010, 28 patients (22 women; mean age, 63+/-16 years) underwent catheter directed thrombolysis for acute upper extremity ischemia, Rutherford class I or IIa. Proximal extent of the occlusion was in the subclavian (32%), axillary (7%), brachial (25%) and forearm arteries (36%). Median occlusion length was 18 cm (range, 12-43). Causes were embolus (14%), thrombus (39%), thoracic outlet syndrome (14%), paraneoplastic (4%), or unknown (29%). RESULTS: Technical success was 96%, radiologic success (>95% clot lysis) 61%, and clinical success 68%. Median duration of thrombolysis was 24 hours (range, 18-96). Of the 11 radiologically unsuccessful patients (39%), five were treated conservatively and six underwent surgical intervention. In-hospital amputation-rate was 7%. Four complications occurred: embolization to the lower extremity, a transient ischemic attack, a subcapsular splenic hematoma and a pseudoaneurysm. Cumulative amputation-free survival at six months was 93%, standard error (SE) 4.87 and at one year 88%, SE 6.50. CONCLUSION: These results show that catheter-directed thrombolysis is effective in over 60% of patients as first-line treatment of extensive acute upper extremity ischemia and can prevent surgical intervention in these patients. PMID- 25729918 TI - Performance of the EuroSCORE II and the Society of Thoracic Surgeons Score in patients undergoing aortic valve replacement for aortic stenosis. AB - Aim. The aim of this study was to evaluate the performance of the new European System for Cardiac Operative Risk Evaluation (EuroSCORE) II and the Society of Thoracic Surgeons (STS) score in patients undergoing aortic valve replacement (AVR) for aortic stenosis (AS). This study also evaluated the performance of the EuroSCORE II in high-risk patients. Methods. Three hundred and six consecutive adult patients underwent AVR with or without coronary artery bypass grafting at our institution from August 2002 to June 2012. The cut-off value of 6% for the EuroSCORE II and 10% for the STS score was used to identify high-risk in this study. Results. Operative mortality was 3.5% (N.=11). The mean expected mortality for all patients was 3.1% (O/E ratio=1.12) for the EuroSCORE II and 5.1% (O/E ratio=0.68) for the STS score. Observed versus expected mortality for the high risk patients was 17.2% versus 11.9% (O/E ratio=1.44) for the EuroSCORE II (N.=29) and 19.3% versus 18.5% (O/E ratio=1.04) for the STS score (N.=31), and that for the low-risk was 2.1% versus 2.2% (O/E ratio=0.95) for the EuroSCORE II and 1.8% versus 3.5% (O/E ratio=0.51) for the STS score. Discrimination power of the STS score was good (area under the receiver operating characteristics curve [AUC] 0.74), but that of the EuroSCORE II was suboptimal (AUC 0.66). Conclusion. Good calibration ability of the EuroSCORE II for low-risk patients and that of the STS score for high-risk are observed. However, the EuroSCORE II underestimates the operative mortality in high-risk patients and the STS score overestimates the risk in low-risk patients. PMID- 25729919 TI - Big five personality and residential mobility: a state-level analysis of the USA. AB - Relations of the state-aggregated Big Five personality scores of 619,397 residents to four 2005 state-level residential mobility criteria were examined with the 50 states as cases. Multiple regression controlling for five state demographic variables showed (a) higher state neuroticism was strongly associated with lower mobility, lower same-county mobility, and lower between-county mobility; (b) higher state extraversion was associated with lower mobility and lower same-county mobility, but only with neuroticism and/or conscientiousness controlled; and (c) conscientiousness was related to same-residence, same-county, and different-county mobility, but only without demographic variables controlled. Discussion is grounded in the dangers of cross-level speculation and the potential of a basic assumption of geographical psychology that an area's aggregate position on a dispositional variable is associated there with behavioral and psychological tendencies related to that variable. PMID- 25729920 TI - Differences between magnitudes and health impacts of BC emissions across the United States using 12 km scale seasonal source apportionment. AB - Recent assessments have analyzed the health impacts of PM2.5 from emissions from different locations and sectors using simplified or reduced-form air quality models. Here we present an alternative approach using the adjoint of the Community Multiscale Air Quality (CMAQ) model, which provides source-receptor relationships at highly resolved sectoral, spatial, and temporal scales. While damage resulting from anthropogenic emissions of BC is strongly correlated with population and premature death, we found little correlation between damage and emission magnitude, suggesting that controls on the largest emissions may not be the most efficient means of reducing damage resulting from anthropogenic BC emissions. Rather, the best proxy for locations with damaging BC emissions is locations where premature deaths occur. Onroad diesel and nonroad vehicle emissions are the largest contributors to premature deaths attributed to exposure to BC, while onroad gasoline emissions cause the highest deaths per amount emitted. Emissions in fall and winter contribute to more premature deaths (and more per amount emitted) than emissions in spring and summer. Overall, these results show the value of the high-resolution source attribution for determining the locations, seasons, and sectors for which BC emission controls have the most effective health benefits. PMID- 25729921 TI - NK cells link obesity-induced adipose stress to inflammation and insulin resistance. AB - An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-gamma (IFN-gamma) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-gamma prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress. PMID- 25729922 TI - A lectin S-domain receptor kinase mediates lipopolysaccharide sensing in Arabidopsis thaliana. AB - The sensing of microbe-associated molecular patterns (MAMPs) triggers innate immunity in animals and plants. Lipopolysaccharide (LPS) from Gram-negative bacteria is a potent MAMP for mammals, with the lipid A moiety activating proinflammatory responses via Toll-like receptor 4 (TLR4). Here we found that the plant Arabidopsis thaliana specifically sensed LPS of Pseudomonas and Xanthomonas. We isolated LPS-insensitive mutants defective in the bulb-type lectin S-domain-1 receptor-like kinase LORE (SD1-29), which were hypersusceptible to infection with Pseudomonas syringae. Targeted chemical degradation of LPS from Pseudomonas species suggested that LORE detected mainly the lipid A moiety of LPS. LORE conferred sensitivity to LPS onto tobacco after transient expression, which demonstrated a key function in LPS sensing and indicated the possibility of engineering resistance to bacteria in crop species. PMID- 25729923 TI - IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. AB - Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL 37-IL-1R8-IL-18Ralpha. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Ralpha impaired the anti-inflammatory activity of IL 37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-kappaB, as well as mitogen-activated protein kinases. Furthermore, IL 37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Ralpha and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program. PMID- 25729926 TI - Brown capuchin monkeys (Sapajus apella) plan their movements on a grasping task. AB - Motor planning is a relatively complex cognitive skill in which an actor modifies a behavior to anticipate the future consequences of the action. Studying motor planning in nonhuman primates may provide a better understanding of the roots of human planning abilities. In this study we presented capuchin monkeys (Sapajus apella) with a horizontal dowel baited on either the left or right end. A radial grasp on the dowel with the thumb facing toward the baited end would be the most efficient grip selection when bringing the dowel to one's mouth and indicate motor planning. Ten of the 12 monkeys tested spontaneously used a radial grasp significantly more often than expected by chance. Results demonstrate a more ubiquitous expression of motor planning abilities than previously seen in capuchin monkeys. Adaptation of this method of testing may be useful in evaluating motor planning capacity in other primates. PMID- 25729924 TI - Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection. AB - Neutrophils express Toll-like receptors (TLRs) for the recognition of conserved bacterial elements to initiate antimicrobial responses. However, whether other cytosolic DNA sensors are expressed by neutrophils remains elusive. Here we found constitutive expression of the transcription factor Sox2 in the cytoplasm of mouse and human neutrophils. Neutrophil-specific Sox2 deficiency exacerbated bacterial infection. Sox2 directly recognized microbial DNA through its high mobility-group (HMG) domain. Upon challenge with bacterial DNA, Sox2 dimerization was needed to activate a complex of the kinase TAK1 and its binding partner TAB2, which led to activation of the transcription factors NF-kappaB and AP-1 in neutrophils. Deficiency in TAK1 or TAB2 impaired Sox2-mediated antibacterial immunity. Overall, we reveal a previously unrecognized role for Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils, which might provide potential therapeutic strategies for the treatment of infectious diseases. PMID- 25729927 TI - How conflicted authors undermine the World Health Organization (WHO) campaign to stop all use of asbestos: spotlight on studies showing that chrysotile is carcinogenic and facilitates other non-cancer asbestos-related diseases. AB - The silicate mineral asbestos is categorized into two main groups based on fiber structure: serpentine asbestos (chrysotile) and amphibole asbestos (crocidolite, amosite, anthophyllite, tremolite, and actinolite). Chrysotile is used in more than 2 000 applications and is especially prevalent in the construction industry. Although its use is banned or restricted in more than 52 countries, an estimated 107 000 workers die from asbestos exposure each year, and approximately 125 million workers continue to be exposed. Furthermore, ambient exposures persist to which the public is exposed, globally. Today, the primary controversies regarding the use of asbestos are the potencies of different types of asbestos, as opposed whether or not asbestos causes morbidity and mortality. The asbestos industry has promoted and funded research based on selected literature, ignoring both clinical and scientific knowledge. In this piece, we highlight a prominent example of a conflicted publication that sought to undermine the World Health Organization (WHO) campaign to stop the use of all forms of asbestos, including chrysotile asbestos. Independent and rigorous scientific data provide sufficient evidence that chrysotile asbestos, like other forms of asbestos, is a cause of asbestos related morbidity and premature mortality. PMID- 25729925 TI - IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte beta-selection. AB - Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (beta-selection) of TCRbeta(+) CD4(-)CD8(-) double negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4(+)CD8(+) double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR alpha-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRbeta(-) DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during beta-selection have remained unclear. Here we found that IL-7 signaled TCRbeta(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notch1 to coordinate proliferation, differentiation and Tcra recombination during beta selection. PMID- 25729928 TI - Carbohydrate microarray for the detection of glycan-protein interactions using metal-enhanced fluorescence. AB - Carbohydrate arrays are potentially one of the most attractive tools to study carbohydrate-based interactions. This paper describes a new analytical platform that exploits metal-enhanced fluorescence for the sensitive and selective screening of carbohydrate-lectin interactions. The chip consists of a glass slide covered with gold nanostructures, postcoated with a thin layer of amorphous silicon-carbon alloy (a-Si0.8C0.2:H). An immobilization strategy based on the formation of a covalent bond between propargyl-terminated glycans and surface linked azide groups was used to attach various glycans at varying surface densities onto the interface and to fabricate a carbohydrate array via efficient local "click" chemistry strategy. The specific association of the new interface with fluorescently labeled lectins was assessed by fluorescence imaging and an excellent selectivity to specific proteins was achieved. Optimization of the surface architecture and the plasmonic transducer resulted in an enhancement of the fluorescence intensity by 1 order of magnitude, when compared to the corresponding substrate devoid of gold nanostructures. The limit of detection (LOD) of such microarrays is in the picomolar range, making it a promising system for development in pharmaceutical or biomedical applications. PMID- 25729929 TI - Genetic polymorphisms of the BMAP-28 and MASP-2 genes and their correlation with the somatic cell score in Chinese Holstein cattle. AB - DNA sequencing, nested polymerase chain reaction (PCR), and PCR-restriction fragment length polymorphism were used to investigate mutations in the coding regions of the bovine myeloid antimicrobial peptide-28 (BMAP-28) and mannan binding lectin-associated serine protease-2 (MASP-2) genes in 249 Chinese Holstein dairy cows. The associations between the polymorphisms and somatic cell score (SCS) were analyzed to determine the potential of these genes as genetic markers for breeding mastitis-resistant dairy cattle. The results revealed a C 86G synonymous mutation in the BMAP-28 gene that caused no alteration in the amino acid sequence. G553A mutation was found in the MASP-2 gene that led to the substitution of glycine with serine. The chi-square test showed that the G553A mutation was in Hardy-Weinberg equilibrium in the Chinese Holstein dairy cows, whereas the C-86G mutation was not. The variance analysis of the influence of group loci and different genotypes on the SCS showed that the SCS of genotype CC was significantly lower than those of genotypes CG and GG (P < 0.05) of the C-86G mutation, and that the SCS of genotype GG was significantly lower than those of genotypes GA and AA (P < 0.05) of the G553A mutation. Genotype combination analysis showed that the combination of the BMAP-28 genotype CC and the MASP-2 genotype GG was the best one, in which the SCS was significantly lower than those in the other combinations. Thus, this combination might be useful as a molecular and genetic marker of mastitis in Chinese Holstein dairy cows. PMID- 25729930 TI - Correlation analysis of ultrasonic characteristics, pathological type, and molecular markers of thyroid nodules. AB - The present study was conducted to analyze the correlation between ultrasonic characteristics, pathological type, and molecular markers of thyroid-tumor related genes as well as to evaluate the diagnosis and prognosis of thyroid nodules. The acoustic characteristics of 130 thyroid specimens were detected. Pathological sectioning and immunohistochemical detection were performed to determine the correlation between tumor gene expression and ultrasonic characteristics. Ultrasonic testing revealed that malignant nodules were normally accompanied by lymph nodes. Expression of the human telomerase reverse transcriptase, Ki67, vascular endothelial growth factor, Ret, and P53 genes exhibited statistically significant differences in malignant, benign, and normal tissues. The performance of thyroid malignant nodules showed different degrees of correlation with the expression of the human telomerase reverse transcriptase, Ki67, VEGF, Ret, and P53 genes. Color Doppler ultrasound is highly sensitive for thyroid nodules and is therefore effective for identifying thyroid nodules and early diagnosis of thyroid cancer. Color Doppler ultrasound can identify benign or malignant thyroid nodules based on 5 characteristic indicators. Tumor pathology and gene expression are associated with the sonographic features of thyroid cancer. Therefore, determining the pathological basis of ultrasonography would facilitate prognostic assessments of thyroid cancer. PMID- 25729931 TI - Roles of peripheral B1 cells in the individualized treatment of adult idiopathic thrombocytopenic purpura. AB - We aimed to explore the changes of peripheral B1 cells before and after treatment of adult idiopathic thrombocytopenic purpura (ITP) and to investigate the association of these changes with the disease condition and prognosis. Ninety seven ITP patients were divided into the effective or ineffective groups, based on their response to hormone therapy. Forty healthy volunteers were enrolled into the control group (HC). The percentages of CD19+ cells, B1 cells, and platelet associated immunoglobulin (PAIg) in peripheral blood from healthy volunteers and ITP patients before and after treatment were evaluated, and blood platelet (PLT) counts were determined. The percentages of CD19+ cells [(21 +/- 10.0) vs (11.2 +/ 7.1)%], B1 cells [(8.85 +/- 5.23) vs (2.2 +/- 1.3)%], and PAIg [(28 +/- 19) vs (11.7 +/- 8)%] in whole blood from ITP patients before treatment were significantly higher than those in whole blood from healthy controls (P < 0.05). Before treatment, the percentage of B1 cells and PAIg in ITP patients was negatively correlated with the PLT level (r = -0.89, P < 0.05 and r = -0.814, P < 0.05, respectively). Further, the B1 cell percentage was positively associated with the PAIg percentage in ITP patients before treatment. In the effective group, the B1 cell percentage was reduced sharply at 1 month after treatment [(2.45 +/- 1.75) vs (8.74 +/- 5.04)%, P < 0.05)], so as at 3 and 6 months. However, in the ineffective group, there was no difference in the B1 cell percentage before and after treatment [(7.9 +/- 5.6) vs (8.76 +/- 5.26)%]. This obvious association of changes in peripheral B1 cells with disease condition and prognosis in ITP patients may be of certain clinical significance for guiding the individualized treatment of ITP. PMID- 25729932 TI - Short Communication FYB polymorphisms in Brazilian patients with type I diabetes mellitus and autoimmune polyglandular syndrome type III. AB - The aim of this study was to perform an association study between seven Fyn binding protein gene (FYB)-tag single nucleotide polymorphisms (SNPs) and type I diabetes mellitus (T1DM), as well as with disease age of onset. We also assessed the role of FYB SNPs in the insurgence of autoimmune polyglandular syndrome type III (APSIII), characterized by the simultaneous presence of autoimmune thyroid disease and celiac disease, in patients with T1DM from a Northeastern Brazilian population. One hundred and seventy-seven patients with T1DM and 190 healthy individuals were genotyped for seven tag SNPs, covering most of the FYB locus, using real-time polymerase chain reaction amplification. There was no significant difference in the distribution of allele and genotype frequencies among patients and healthy individuals. Moreover, none of the tag SNPs were associated either to T1DM age of onset or to the insurgence of APSIII. However, since the FYB protein is a key component in T cell response, its gene variants might play a role in protein function, which might be testable in a population with different genetic backgrounds or by using functional assays. PMID- 25729933 TI - Electroacupuncture decreases the urinary bladder pressure in patients with acute gastrointestinal injury. AB - The present study investigates the effects of electroacupuncture (EA) on urinary bladder pressure (UBP) in patients with acute gastrointestinal injury (AGI). Twenty patients with AGI admitted to the First Hospital of Jiaxing intensive care unit from December 2011 to June 2013 were evaluated. Conventional group patients (n = 10) were administered moderate enteral nutritional support, and electroacupuncture group patients (n = 10) were administered enteral nutritional support followed by EA at bilateral Zusanli (ST-36), Shangjuxu (ST-37), Hegu (LI 4), and QuChi (LI-11) acupoints. UBP was then measured every 6 h and the serum creatinine once daily for 7 days. There were no statistically significant patient demographic differences in the study groups (P > 0.05). The initial UBP of both patient groups was >=12 mmHg. On days 6 and 7, the UBP significantly decreased in the EA group compared to the conventional group (P < 0.05). The serum creatinine concentration on day 7 was significantly lower in the EA group than in the conventional group (P < 0.05). Based on these results, electroacupuncture contributed to gastrointestinal motility recovery in patients with AGI. This procedure may reduce UBP and provide organ-protective effects in AGI patients. PMID- 25729934 TI - Protective effect of p38 MAPK inhibitor on wear debris-induced inflammatory osteolysis through downregulating RANK/RANKL in a mouse model. AB - Aseptic loosening associated with wear particle-induced inflammation is a major cause of joint implant failure. Recent studies have demonstrated the therapeutic effects of p38 mitogen-activated protein kinase (MAPK)-based therapies on chronic inflammatory diseases. The purpose of this study was to investigate whether SB203580, a p38 MAPK inhibitor, inhibits wear debris-induced inflammatory osteolysis in mice through downregulation of receptor activator of nuclear factor kbeta (RANK)/RANK ligand (RANKL). We used a murine osteolysis model to study the effect of SB203580 on RANKL/RANK signaling and titanium particle-induced osteolysis in vivo. Pouch membranes with intact bone implants were analyzed using histological analysis and transmission electron microscopy, and the levels of RANK and RANKL protein and mRNA were evaluated by immunohistological staining and real-time reverse transcriptase-polymerase chain reaction. SB203580 had less of an effect on RANK and RANKL expression under wear debris-induced conditions. The number of TRAP-positive cells was remarkably reduced in Ti-particle-induced pouch tissues. These effects were confirmed through the transmission electron microscopy results. These results suggest that p38 MAPK-based therapies are beneficial in preventing aseptic loosening associated with total joint replacement by modulating RANK-RANKL signaling. PMID- 25729935 TI - Generation of bovine (Bos indicus) and buffalo (Bubalus bubalis) adipose tissue derived stem cells: isolation, characterization, and multipotentiality. AB - Adult stem cells are known for their plasticity and their potential to differentiate into several different cell types; these characteristics have implications for cell therapy and reproductive biotechnologies. In this study, we report on the isolation and characterization of mesenchymal stem cells (MSC) derived from bovine and buffalo adipose tissue. Cells isolated using enzymatic digestion of bovine and buffalo adipose-tissue biopsy samples were grown in vitro for at least 15 passages, verifying their capacity to proliferate. These cells were also subjected to immunophenotypic characterization for the presence of CD90, CD105, and CD79, and the absence of CD45, CD34, and CD73, which are positive and negative markers of MSC, respectively. To prove their multipotency, the cells were induced to differentiate into three different cell types, chondrocytes, osteoblasts, and adipocytes, which were stained with tissue specific dyes (Chondrogenic-Alcian Blue, Osteogenic-Alizarin Red, and Adipogenic Oil-Red O, respectively) to confirm differentiation. Gene expression analysis of pluripotency-related genes was also conducted. Our results suggest that adipose tissue from bovines and buffalos can be used as a source of MSC, making adipose tissue-derived cells an interesting option for cell therapy and regenerative medicine. Additionally, these findings have implications for reproductive biotechnology because the use of MSC as nuclear donors has been linked to an increase in the efficiency of nuclear transfer. PMID- 25729936 TI - Association of PTPN22 gene polymorphism with type 1 diabetes mellitus in Chinese children and adolescents. AB - Previous studies have indicated that the protein tyrosine phosphatase nonreceptor type 22 gene (PTPN22) is associated with type 1 diabetes (T1DM) in the Caucasian population. In the present study, we investigated the relationship between PTPN22 genetic polymorphisms and T1DM in Chinese children. A total of 202 children and adolescents with T1DM and 240 healthy control subjects of Chinese Han origin were included in our analysis. Polymerase chain reaction-restriction fragment length polymorphism was used to determine the presence of the C1858T polymorphism in the PTPN22 gene. We found that the TT +TC genotype and the T allele of C1858T were more frequent in T1DM patients (19.40 and 10.0%, respectively) than in healthy subjects (7.51 and 4.0%, respectively), and the difference was significant (both P < 0.001). After adjusting for confounding variables such as gender, age, and family history of T1DM, the difference remained significant (P = 0.007, odds ratio = 2.88, 95% confidence interval 1.76-4.32). Our results indicate that genetic polymorphisms in the PTPN22 gene may increase the risk of T1DM in Chinese children and adolescents. PMID- 25729937 TI - A discriminative method for protein remote homology detection based on N-Gram. AB - Protein remote homology detection refers to detecting structural homology in proteins with an extremely low rate of sequence similarity. Such detection is primarily conducted using 3 methods: pairwise sequence comparisons, generative models for protein families, and discriminative classifiers. In this study, a discriminative classification method involving N-Grams was adopted to extract features using a random forest algorithm to classify data sets. Experiments in the SCOP 1.53 data set showed that our approach improved the receiver operating characteristic by 6% compared with well-known methods. To determine a score threshold that could be used to divide the data set, we also used a heuristic method through which the precision of positive examples and recall rate reached 0.5647 and 0.8647, respectively. Few other studies have investigated the recall and precision of such examples. PMID- 25729938 TI - Anticancer activity of Bombyx batryticatus ethanol extract against the human tumor cell line HeLa. AB - Anticancer activity of Bombyx batryticatus ethanol extract (BBE) against HeLa cells was studied using cell viability, DNA fragmentation, real-time polymerase chain reaction, and Western blot analyses. The BBE inhibited the growth and induced apoptosis of HeLa cells. The MTT assay indicated that the BBE induced cytotoxicity in HeLa cells in a time- and concentration-dependent manner. When HeLa cells were treated for 48 h, the 50% inhibitory concentration (IC50) value for the BBE was 1.564 mg/mL. The microscopy results showed that HeLa cells were severely distorted and showed slow growth; some cells became round in shape when treated with 5 mg/mL BBE for 24 h. The DNA ladder results revealed excessive DNA fragmentation in HeLa cells treated with 7 mg/mL BBE for 36 h. The proapoptotic activity of the BBE was attributed to its ability to modulate the expression of Bcl-2 and Bax genes. The mRNA and protein expression levels of Bax were remarkably higher whereas those of Bcl-2 were lower than those in the control cells; this led to an increased Bax/Bcl-2 ratio in cells treated with the BBE for 36 h. The results suggest that the BBE might play an important role in tumor growth suppression by inducing apoptosis in human cervical cancer cells via the regulation of the Bcl-2- and Bax-mediated apoptotic pathways. PMID- 25729939 TI - Isolation and characterization of novel microsatellite markers for molecular genetic diversity in Siganus fuscescens. AB - The rabbitfish Siganus fuscescens is an economically valuable species that is widely distributed throughout the estuaries, intertidal, and offshore coasts of the Indo-Pacific and eastern Mediterranean. Ten novel microsatellite loci from the genome of S. fuscescens were developed using the fast isolation protocol with amplified fragment length polymorphism of sequences containing repeats. Polymorphisms in these 10 microsatellite markers were determined from 32 wild individuals. The number of alleles per locus and the polymorphism information content ranged from 2 to 5 and from 0.059 to 0.668, respectively. The observed and expected heterozygosities varied from 0.063 to 0.781 and from 0.062 to 0.731, respectively. Although 1 locus (LZY-X7, P < 0.005) showed significant deviation from the Hardy-Weinberg equilibrium, no deviations were detected in the other 9 loci. These microsatellite loci may be useful for further population genetic studies, conservation studies, population structure assessment, and linkage map construction of S. fuscescens. PMID- 25729940 TI - Identification of molecular markers in patients with hypertensive heart disease accompanied with coronary artery disease. AB - We investigated the plasma hypersensitive C-reactive protein (hs-CRP), oxidized low-density lipoprotein (ox-LDL), and apelin levels in patients with hypertensive heart disease (HHD) plus coronary artery disease (CAD). Patients with hypertension hospitalized in Xuzhou Central Hospital were categorized into the HHD group and the HHD plus CAD group; 40 healthy subjects served as the control group. hs-CRP expression was determined with chemiluminescence. The expression of ox-LDL and apelin was analyzed with enzyme-linked immunosorbent assay. HHD was chiefly responsible for left atrial enlargement (P < 0.05) and left ventricle diastolic function insufficiency (P < 0.05). hs-CRP and ox-LDL were significantly higher in the HHD group than in the control group (P < 0.05). Compared with the control and HHD groups, significant increases in hs-CRP and ox-LDL levels were observed in the HHD plus CAD group. Apelin expression significantly decreased in the HHD group compared with that in controls (P < 0.05). Meanwhile, apelin expression significantly decreased in the HHD plus CAD group compared with that in the HHD (P < 0.05) and control (P < 0.05) groups. Logistic regression analysis for the binomial response variable indicated that high systolic pressure/diastolic pressure, increase in hs-CRP level, and decrease in apelin concentration were the risk factors for hypertension and cardiac impairments. HHD plus CAD has a greater influence on cardiac function than HHD alone. Increased inflammation and oxidative stress, as well as decreased secretion of cardiac protective factors, may be associated with the simultaneous onset of HHD and CAD. PMID- 25729941 TI - Diversity, population structure, and evolution of local peach cultivars in China identified by simple sequence repeats. AB - The fruit peach originated in China and has a history of domestication of more than 4000 years. Numerous local cultivars were selected during the long course of cultivation, and a great morphological diversity exists. To study the diversity and genetic background of local peach cultivars in China, a set of 158 accessions from different ecological regions, together with 27 modern varieties and 10 wild accessions, were evaluated using 49 simple sequence repeats (SSRs) covering the peach genome. Broad diversity was also observed in local cultivars at the SSR level. A total of 648 alleles were amplified with an average of 13.22 observed alleles per locus. The number of genotypes detected ranged from 9 (UDP96015) to 58 (BPPCT008) with an average of 27.00 genotypes per marker. Eight subpopulations divided by STRUCTURE basically coincided with the dendrogram of genetic relationships and could be explained by the traditional groups. The 8 subpopulations were juicy honey peach, southwestern peach I, wild peach, Buddha peach + southwestern peach II, northern peach, southern crisp peach, ornamental peach, and Prunus davidiana + P. kansuensis. Most modern varieties carried the genetic backgrounds of juicy honey peach and southwestern peach I, while others carried diverse genetic backgrounds, indicating that local cultivars were partly used in modern breeding programs. Based on the traditional evolution pathway, a modified pathway for the development of local peach cultivars in China was proposed using the genetic background of subpopulations that were identified by SSRs. Current status and prospects of utilization of Chinese local peach cultivars were also discussed according to the SSR information. PMID- 25729942 TI - Association of liver X receptor alpha (LXRalpha) gene polymorphism and ischemic stroke. AB - We examined the relationship between the liver X receptor a gene (LXRalpha) rsl2221497 polymorphism and the susceptibility to ischemic stroke in a Chinese population. The polymerase chain reaction-restriction fragment length polymorphism technique was used to detect the genotype of rsl2221497 in the LXRalphagene of 300 stroke patients and 300 healthy control subjects. The chi square test was used to analyze the genotype distribution between the 2 groups. We found that the risk of stroke in carriers with the AA + GA genotype was 2.12 fold higher than that in GG genotype carriers (odds ratio = 2.12, 95% confidence interval: 1.58-2.99, P < 0.05). The risk of stroke in carriers of the A allele increased by 1.03-fold compared to that in G allele carriers (odds ratio = 2.03, 95% confidence interval: 1.44-3.01, P < 0.01). After adjusting for other confounding factors such smoking, hypertension, and diabetes, the A allele was found to be an independent risk factor for stroke. Therefore, the rsl2221497 polymorphism in the LXRalphagene was associated with the susceptibility to stroke in a Chinese population. PMID- 25729943 TI - imDC: an ensemble learning method for imbalanced classification with miRNA data. AB - Imbalances typically exist in bioinformatics and are also common in other areas. A drawback of traditional machine learning methods is the relatively little attention given to small sample classification. Thus, we developed imDC, which uses an ensemble learning concept in combination with weights and sample misclassification information to effectively classify imbalanced data. Our method showed better results when compared to other algorithms with UCI machine learning datasets and microRNA data. PMID- 25729944 TI - Selection of maize hybrids for tolerance to aluminum in minimal solution. AB - The aim of this study was to determine the Al concentration and the period of exposure of the roots of maize hybrids in minimal solution for efficient selection of genotypes that are Al-tolerant. Two experiments were performed (48 and 96 h of exposure) with increasing doses of Al in minimal solution; the block design was completely randomized in a split-plot design with 3 replications. By assessing differences in root growth (cm) and the percentage of inhibition of the growth of the main root (%), a marked decrease was observed in maize root growth with increasing Al concentration in the solution. Exposure of the roots to 2 mg/L Al for 48 h in minimal solution was the most efficient for selecting sources of tolerance, particularly for the hybrids H 44 and H 38. PMID- 25729945 TI - Polymorphic microsatellite loci for the razor clam, Sinonovacula constricta. AB - The razor clam, Sinonovacula constricta, is an important commercial bivalve and a popular mollusca food in China. Twelve polymorphic microsatellite markers were isolated from the razor clam using a partial genomic library enriched for tandem repeat sequences of (CA)16, (GA)16. Polymorphisms of these loci were evaluated in a wild population of 30 individuals. The allele number of these polymorphic markers ranged from 5-15 per locus with an average of 9.333. Observed and expected heterozygosity values ranged from 0.192-1.000 and 0.219-0.906. Polymorphism information content ranged from 0.209-0.892 with an average of 0.704. Three loci significantly deviated from Hardy-Weinberg equilibrium after Bonferroni correction. No significant linkage disequilibrium was detected between these loci. This set of microsatellite loci are useful for genetic studies in S. constricta. PMID- 25729946 TI - Mitochondria-dependent apoptogenic activity of the aqueous root extract of Croton membranaceus against human BPH-1 cells. AB - Croton membranaceus aqueous root extract (CMARE) is among the widely used phytotherapeutics in Ghana for the management of benign prostatic hyperplasia (BPH) and prostate cancer. However, the mechanism of action of CMARE remains to be elucidated. This study aimed to establish whether apoptosis is involved in the antiproliferative effect of CMARE on human BPH-1 cells. We determined the effect of treatment with 0, 1, 3, and 5 mg/mL CMARE for 24, 48, and 72 h on the viability and morphology of BPH-1 cells using the MMT assay and phase-contrast microscopy, respectively. We examined the apoptosis-inducing effects of CMARE after 48 h at the cellular level using Hoescht 33258 and JC-1 dye staining and flow cytometry analysis. We performed reverse transcription polymerase chain reaction and Western blotting to confirm the apoptotic effects of CMARE at the molecular level. CMARE induced a significant dose-dependent inhibition in the proliferation of BPH-1 cells (P < 0.05) and an alteration in their morphology and a reduction their density. Furthermore, CMARE induced dose-dependent staining of the nuclear chromatin, significant DNA fragmentation with G0/G1 sub-diploid cells (P < 0.01), and loss of the mitochondrial membrane potential in the treated cells compared to the controls after 48 h (P < 0.01). Additionally, while CMARE induced a significant upregulation of the mRNA and protein levels of Bax, those of Bcl2 did not change significantly. Therefore, induction of mitochondria-dependent apoptosis of BPH-1 cells may be a possible mechanism of action of CMARE. PMID- 25729947 TI - Lack of association between IL-6 -174G>C polymorphism and lung cancer: a meta analysis. AB - The results of previous case-control studies examining the relationship between the interleukin (IL)-6 gene -174G>C polymorphism and lung cancer are controversial. In this study, we evaluated the relationship between the IL-6 gene -174G>C polymorphism and lung cancer. We selected 5 case-control studies related to the IL-6 gene -174G>C polymorphism and lung cancer by searching the PubMed, EMBase, Chinese Biomedical Literature Database, and Wanfang database. We utilized the Q-test and I2 test to determine heterogeneity between each study. To merge the odds ratios (OR) and 95% confidence intervals (CI), we utilized the fixed effects model and random effect model for analyses. The present study included 2801 patients with lung cancer and 3234 cancer-free control subjects. The meta analysis revealed no association between the IL-6 gene -174G>C polymorphism and lung cancer in either genotype or allele distribution [CC+GC vs GG: OR = 1.04, 95%CI (0.86-1.26), P = 0.70; GG+GC vs CC: OR = 0.93, 95%CI (0.82-1.05), P = 0. 23; CC vs GG: OR = 1.08, 95%CI (0.95-1.23), P = 0.23; C allele vs D allele: OR = 1.03, 95%CI (0.96-1.11), P = 0.44]. We concluded that the IL-6 gene -174G>C polymorphism was not associated with lung cancer. PMID- 25729948 TI - Application of 64-slice spiral computed tomography angiography in extremity vascular injuries. AB - The objective of the current study was to assess the utility of 64-row helical computed tomography angiography (CTA) in the evaluation of extremity vascular traumas. The extremities from 17 clinical cases of suspected traumatic vascular damage were evaluated using 64-row helical CTA. To evaluate extremity vascular traumas using CTA, volume rendering, multiple planar reconstruction, and curved planar reconstruction technology were applied to accurately and rapidly indicate the type and extent of blood vessel damage, as well as any relationship with injuries to adjacent bones, joints, soft tissue swelling, or hematomas. The types of extremity vascular traumas evaluated included damaged arteries, artery spasms or block, blood vessels shifted because of pressure, pseudo aneurysms, arteriovenous fistula, and vein occlusion. The results of the study indicated that 64-row helical CTA could be highly efficient and accurate in the evaluation of extremity vascular traumas, and could aid in making clinical assessments. PMID- 25729949 TI - Dopamine receptor D1 but not D3 essential for morphine-induced conditioned responses. AB - Recent studies indicate the involvement of dopamine receptors D1 and D3 in the regulation of locomotor stimulant and conditioned responses to morphine in mice. Moreover, expression of brain-derived neurotrophic factor (BDNF) may be modulated by D1 and D3 receptor activities in the nucleus accumbens (NAc) and prefrontal cortex (PFC). However, the underlying interactions between D1 and D3 receptors and BDNF in the expression of behavioral responses controlled by drug-associated cues have not yet been fully elucidated. In this study, we used dopamine receptor mutant mice to explore the roles of the D1 and D3 receptors in locomotion and morphine-induced place preference; furthermore, we investigated the effects of morphine on BDNF expression in the NAc and PFC of the mouse brain. Our results show that D1 receptor but not D3 receptor mutant mice had decreased sensitivity to acute morphine-induced (10 mg/kg) locomotion (D1: 3814.82 +/- 319.9 cm vs D3: 8089.64 +/- 967.4 cm). Furthermore, D1 receptor mutant mice did not acquire morphine-conditioned place preference (D1: -18.3 +/- 59.9, D3: 217.7 +/- 64.1) and showed decreased BDNF expression in the NAc (D1: 0.33 +/- 0.07 fold, D3: 2.21 +/- 0.18 fold) and PFC (D1: 0.74 +/- 0.15 fold, D3: 1.68 +/- 0.22 fold) compared with wild-type and D3 receptor mutant mice. These findings suggest that the D1 receptor is necessary for the induction of cue-associated morphine seeking and modulates locomotor habituation processes in response to acute morphine. The dopamine receptor D1 but not the D3 is also critical for morphine-induced BDNF expression in the NAc and PFC. PMID- 25729950 TI - Bioinformatic analysis of phage AB3, a phiKMV-like virus infecting Acinetobacter baumannii. AB - The phages of Acinetobacter baumannii has drawn increasing attention because of the multi-drug resistance of A. baumanni. The aim of this study was to sequence Acinetobacter baumannii phage AB3 and conduct bioinformatic analysis to lay a foundation for genome remodeling and phage therapy. We isolated and sequenced A. baumannii phage AB3 and attempted to annotate and analyze its genome. The results showed that the genome is a double-stranded DNA with a total length of 31,185 base pairs (bp) and 97 open reading frames greater than 100 bp. The genome includes 28 predicted genes, of which 24 are homologous to phage AB1. The entire coding sequence is located on the negative strand, representing 90.8% of the total length. The G+C mol% was 39.18%, without areas of high G+C content over 200 bp in length. No GC island, tRNA gene, or repeated sequence was identified. Gene lengths were 120-3099 bp, with an average of 1011 bp. Six genes were found to be greater than 2000 bp in length. Genomic alignment and phylogenetic analysis of the RNA polymerase gene showed that similar to phage AB1, phage AB3 is a phiKMV like virus in the T7 phage family. PMID- 25729951 TI - Construction and identification of recombinant adenovirus carrying human TIMP 1shRNA gene. AB - The aim of this study was to construct the recombinant adenovirus carrying human TIMP-1shRNA gene expression system for preliminary identification to lay the foundation for the further study of gene therapy. Using the Adeno-X system, the recombinant adenovirus plasmid pAdeno-X green fluorescent protein (GFP)-tissue inhibitor of metalloprotease (TIMP)-1 small hairpin (1shRNA) was constructed by including the target gene fragment of the TIMP-1shRNA shuttle plasmid pShuttle2 GFP-TIMP-1shRNA and the backbone plasmid pAdeno-X by homologous recombination in Escherichia coli. Recombinant plasmids were transfected into HEK293A cells to package the recombinant adenovirus rvAdeno-XGFP-TIMP-1shRNA. The recombinant adenovirus was identified by polymerase chain reaction, and the viral titer and infection efficiency were detected using GFP. Polymerase chain reaction and restriction endonuclease digestion demonstrated that rvAdeno-XGFP-TIMP-1shRNA had been successfully constructed, which has a strong ability to infect the kidney. The TIMP-1shRNA adenovirus expression vector was successfully constructed using homologous recombination methods. PMID- 25729952 TI - Relationship between liver and low rumen pH in goat. AB - The aim of this study was to analyze the response of dry goat liver to sub-acute ruminal acidosis induced by a highly concentrated diet. Non-pregnant, non lactating female Poll-goats (N = 12) were randomly assigned to either a high concentrate (HG) or a low-concentrate (LG) diet. Low rumen pH was successfully induced with HG (more than 3 h with rumen pH < 5.8). The plasma lipopolysaccharide concentration was significantly decreased in the HG compared with LG group (P < 0.05). Proteomic analysis showed that aldehyde dehydrogenases and microsomal glutathione S-transferase was downregulated in the HG group, whereas aldo-keto reductase was upregulated compared in the LG group. The abundance of mRNA for these proteins were also correspondingly increased (aldehyde dehydrogenases and microsomal glutathione-S-transferase) or decreased (aldo-keto reductase) in the HG group. Malondialdehyde content in the liver was decreased in the HG group compared to the LG group. These data indicate that the expression of hepatic proteins alters the regulation of endogenous lipopolysaccharide during low rumen pH in dry dairy goats. In particular, the protective effect of the liver may occur through inhibition of aldehyde and/or peroxide formation. PMID- 25729953 TI - Karyotype of Rhodnius montenegrensis (Hemiptera, Triatominae). AB - The Triatominae subfamily comprises 6 tribes. The tribe Rhodniini comprises 2 genera and 22 nominal species. Rhodnius montenegrensis (Hemiptera, Triatominae) was recently described as evolutionarily related to R. robustus. Therefore, in order to contribute to karyosystematic study of the tribe Rhodniini, this report describes the number of chromosomes and compares the karyotype of R. montenegrensis to that of all other species in the tribe, in order to determine the karyotypic evolution of the tribe Rhodniini. The seminiferous tubules of adult males, after being removed and fixated on a cover slip, were processed with lacto-aceto-orcein for cytogenetic analysis. R. montenegrensis, as well as all other species of the tribe Rhodniini showed 22 chromosomes (20 autosomes + XY). Thus, we hereby describe the karyotype of the species R. montenegrensis and mainly highlight that the tribe Rhodniini displays karyotypic homogeneity, demonstrating itself as a derived group to a lesser extent when compared to the number of chromosomes of the common ancestors of the subfamily Triatominae. PMID- 25729954 TI - Evaluation of methods of DNA extraction from Staphylococcus aureus in milk for use in real-time PCR. AB - The aim of this study was to evaluate the repeatability and performance of 4 methods of extracting DNA from Staphylococcus aureus (SAU) and the gene encoding bovine mitochondrial cytochrome B (BMCB) in milk samples from cows with subclinical mastitis for use in amplification by real-time polymerase chain reaction. Two milk samples were obtained from cows naturally infected with S. aureus and subjected to the following extraction methods: Qiagen DNA extraction kit; Axyprep DNA extraction kit; in silica column boil and in silica column method. After extraction in duplicate, eluates were subjected to purification and precipitation to determine purity (A260/A280 ratio) and concentration (MUg/MUL) by spectrophotometry and amplification by real-time polymerase chain reaction of target genes (SAU and BMCB). There was no effect of the DNA extraction method on DNA concentration and threshold cycle for BMCB and SAU. The purity ratio (A260/A280 ) was higher when using Qiagen DNA extraction (1.76 +/- 0.136) compared to the other methods tested. Our results indicate that the DNA extraction kit from Qiagen produces samples of the highest purity ratio compared to other methods. PMID- 25729955 TI - Study of lipid metabolism-related genes as candidate genes of sexual precocity in Nellore cattle. AB - The objective of this study was to identify associations between known polymorphisms in genes related to adipose tissue and sexual precocity in Nellore cattle. A total of 1689 precocious and non-precocious heifers belonging to farms participating in Conexao Delta G breeding program were studied. SNPs from the Illumina High-Density Bovine SNP BeadChip were used. This chip contains 777,000 SNPs located within the region of the candidate genes at a distance of up to 5 kb, considering that linkage disequilibrium (LD) exists at this distance. Linear models were used for statistical analysis. The fastPHASE and GenomeStudio programs were used for haplotype reconstruction and LD analysis based on r2 statistics. Fifty-seven candidate genes and 443 SNPs were analyzed: among the latter, 370 SNPs formed 83 haplotypes, while the remaining SNPs were studied separately. Statistical analysis showed that only three haplotypes, one haplotype consisting of two SNPs located in the FABP4 gene and two haplotypes consisting of four and two SNPs located in the PPP3CA gene, had a significant effect on sexual precocity at P < 0.05. It can be concluded that the FABP4 and PPP3CA genes influence sexual precocity and may therefore be used in selection programs designed to improve sexual precocity in Nellore cattle. PMID- 25729956 TI - Indirect selection of industrial tomato genotypes that are resistant to spider mites (Tetranychus urticae). AB - Acyl sugars present in the tomato Solanum lycopersicum 'LA-716' accession confer good levels of resistance to arthropod pests. The objective of the present study was to select F2 plants from the interspecific cross Solanum pennellii 'LA-716' x Solanum lycopersicum 'Redencao' to assess resistance to spider mites (Tetranychus urticae) based on the leaf acyl sugar content and repellence tests. Four genotypes were selected with high leaflet acyl sugar content (RVTA-2010 pl#31, RVTA-2010 pl#75, RVTA-2010 pl#83, and RVTA-2010 pl#94), and an additional three genotypes with low acyl sugar content were also selected (RVTA-2010 pl#33, RVTA 2010 pl#39, and RVTA-2010 pl#73). The results from the in vivo tests used to confirm the selection of plants resistant to mites indicated that the genotypes with high acyl sugars content did not differ from the resistant parent LA-716. The negative correlation between acyl sugar content and the distance run by the mite along the leaflet surface confirmed the association between high and low allelochemical content and resistance. The medium degree of dominance (MDD) was estimated (MDD = -0.83), indicating that the high acyl sugar content was due to incomplete dominance of a recessive allele. A value of 81.85% was found for the broad sense heritability estimate, which suggests that most among-plant variation in the F2 generation is genetically based. Furthermore, 0.69 genes were estimated, which presumably confirms monogenic inheritance. Thus, indirect selection was an efficient method used to obtain industrial tomato plants that are resistant to spider mites. PMID- 25729957 TI - Short Communication Molecular conservation of the mammalian leptin protein. AB - In this study, we comparatively assessed multiple sequences of the leptin protein from different animal species to establish new insights into conservation degree of biological sequences and evolutionary biology among mammals using computational biology tools. First, amino acid sequences of the leptin protein from Homo sapiens (human, P41159), Sus scrofa (wild pig, Q29406), Felis catus (domestic cat, Q29406), Rattus norvegicus (rat, P50596), and Mus musculus (mouse, P41160) were randomly searched in the high-quality annotated and non-redundant protein sequence database UniProtKB/Swiss-Prot. A dendogram showing the evolutionary relationships among specimens was constructed from the sequences of interest using the Mega 6.0 software with the neighbor-joining method. The resulting tree presenting the evolutionary relationships among specimens inferred from amino acid sequences of the leptin protein in mammals demonstrated 2 main branches: 1 cluster including the rat and mouse species (0.02) and a second cluster containing both wild pig and domestic cat species grouped in a sub-branch (0.04 and 0.06, respectively), linking them to the human sequence (0.08). These findings were reinforced by comparing estimates of evolutionary divergence among leptin sequences analyzed. Based on comparative analyses of multiple sequence alignments in the present study, there was a stronger conservation degree of the leptin protein in evolutionarily close species and several conservative changes along the sequences of interest, revealing information regarding the evolutionary biology among mammals. PMID- 25729958 TI - Genetic control and transgressive segregation of zinc, iron, potassium, phosphorus, calcium, and sodium accumulation in cowpea (Vigna unguiculata) seeds. AB - Cowpea crop, through combining a range of essential minerals with high quality proteins, plays an important role in providing nutritional security to human population living in semi-arid regions. Studies on genetics of biofortification with essential minerals are still quite scarce, and the major objective of the present study was to provide genetic information on development of cowpea cultivars with high seed mineral contents. Genetic parameters heritability and minimum number of genes were estimated for seed accumulation of zinc (Zn), iron (Fe), calcium (Ca), phosphorus (P), potassium (K), and sodium (Na). Generation mean and variance analyses were conducted using contrasting parental lines, F1, F2, and backcross populations derived from IT97K-1042-3 x BRS Tapaihum and IT97K 1042-3 x Canapu crosses. High narrow-sense heritability (h2) values were found for accumulation of Fe (65-86%), P (74-77%), and K (77-88%), whereas moderate h(2) values were observed for accumulation of Ca (41-56%), Zn (51-83%), and Na (50-55%) in seeds. Significant additive genetic effects as well as parental mean effects were detected in both crosses for all minerals, whereas epistasis was important genetic component in Zn content. The minimum number of genes controlling the accumulation of minerals ranged from two (K) to 11 (P). Transgressive segregation was observed in F2 populations of both crosses for all minerals analyzed. The results suggest that, although under either oligogenic or polygenic control, the seed content of these six minerals in cowpea can be improved via standard breeding methods largely used for self-pollinated crops. PMID- 25729959 TI - Microsatellite markers linked to the locus of the watermelon fruit stripe pattern. AB - Agronomic performance and external and internal appearance of watermelon (Citrullus lanatus) fruit are important traits that should be taken into consideration during the development of a new cultivar, as well as being the principal identification elements used by the consumer, which are based on the external appearance and quality of the fruit. Externally, the fruit can be characterized in terms of the shape, the color of the lower rind, and the presence of grooves and stripes, the stripes can be classified as clearly defined or diffuse. The objective of this study was to identify microsatellite markers linked to the stripe pattern of watermelon fruit to support watermelon improvement programs, with the selection of this characteristic in the plantlet stage. F1 and F2 populations, result of a cross between the cultivars BRS Opara (clearly defined stripes) and Perola (diffuse stripes), were phenotyped for their fruit stripe pattern. The CTAB 2X protocol was used for DNA extraction and 116 microsatellite markers were examined in a group of F2 plants that had fruit with well-defined stripes and fruit with diffuse stripes. The microsatellite loci MCPI_05 and MCPI_16 exhibited a linkage to the stripe pattern at a distance of 1.5 and 1.8 cM, respectively, with LOD scores of 39.28 and 38.11, respectively, which were located on chromosome six of the watermelon genome. These markers can be used in marker-assisted selection in watermelon improvement programs, by various research institutions. PMID- 25729960 TI - Changes of peripheral-type benzodiazepine receptors in the penumbra area after cerebral ischemia-reperfusion injury and effects of astragaloside IV on rats. AB - This study investigated the changes in peripheral benzodiazepine receptors (PBRs) in the penumbra after cerebral ischemia-reperfusion injury, and examined the effects of astragaloside IV (AST) on PBRs in rats. Sixty Sprague-Dawley rats were divided into a sham operation group, a model group, and three AST treatment groups. Cerebral ischemic models were induced by the clue-blocked method. Neurological deficits were examined. The animals were sacrificed after 2 h of ischemia and 24 h of reperfusion, and mitochondria from the penumbra were purified. PBR density (Bmax) and affinity were measured by radioligand assays. Mitochondrial [(3)H]PK11195 binding was correlated with neurological deficits in rats. Compared to the model group, the 10 mg/kg AST group, 40 mg/kg AST group, and 100 mg/kg AST group had fewer neurological deficits. The effects in the 40 mg/ kg group did not significantly differ from the effects in the 100 mg/ kg group. Compared to the model group, the 10 mg/kg AST group, 40 mg/kg group, and 100 mg/kg group had a decreased Bmax in the penumbra. The Bmax decreased in the 40 mg/kg AST group and in the 100 mg/kg AST group compared with the 10 mg/kg group. The Bmax and neurological deficits in the 40 mg/kg did not significantly differ from those in the 100 mg/kg group. By contrast, the AST-treated rats showed no significant changes in the binding parameter equilibrium dissociation constant compared with those in the sham operation group and the model group. AST protects ischemic brain tissue by inhibiting PBR expression after cerebral ischemia. PMID- 25729961 TI - Genetic association between the HLA-G 14-bp insertion/deletion polymorphism and the recurrent spontaneous abortions in Saudi Arabian women. AB - The non-classical class I human leukocyte antigen (HLA)-G molecule was found to be predominately expressed in the extravillous cytotrophoblasts at the fetal maternal interface during pregnancy. This molecule is critically important for successful implantation during human pregnancy. The polymorphic insertion deletion (indel) 14-base pair (bp) site localized at the 3' untranslated region was associated with HLA-G mRNA stability and isoform alternative splicing patterns, and thus may influence HLA-G function during pregnancy. We studied the association between the 14-bp indel polymorphism (rs16375) at the 3' untranslated region with recurrent spontaneous abortions in a Saudi population living in Riyadh. A group of 64 women with 2-11 successive abortions were included in this study. The control group included 62 women without reported abortions and at least 2 pregnancies, all visiting the King Khaled Hospital in Riyadh. The 14-bp indel was genotyped in the case and control groups. The frequency of the genotype +14/+14 was slightly higher in women with recurrent spontaneous abortions, but no significant differences were observed in the distribution of alleles and genotypes. PMID- 25729962 TI - Identification and association of single-nucleotide polymorphisms in gonadotropin inhibitory hormone (GnIH) gene with egg production traits in Erlang mountainous chickens. AB - Gonadotropin-inhibitory hormone (GnIH) gene is an important gene in reproduction. In this study, we screened single-nucleotide polymorphisms (SNPs) in the chicken GnIH gene among 204 individuals in Erlang mountainous chickens. We then analyzed the associations between polymorphisms of the GnIH gene and 5 egg production traits in chickens. Five SNPs (T3305C, T3310C, G3403C, G3411A, and T3591C) were detected. Associations between polymorphic loci and age at first egg, body weight at first egg, weight at first egg, egg weight in 300 days, and egg production in 300 days were analyzed using analysis of covariance. The results showed that SNP1, SNP3, and SNP4 had large effects on age at first egg, while SNP5 had a large effect on body weight at first egg; of the effect of the TT genotype was significantly higher than that of CT (P < 0.01). Further analysis show that the highest frequency (0.2353) haplotype H1H1 was associated with the latest age at first egg. The H4H5 haplotype had a positive effect on egg production in 300 days and a negative effect on weight at first egg. We observed no association between the H3H3 haplotype and body weight at first egg. PMID- 25729963 TI - Phylogeny of Marmosops and the occurrence of Marmosops pinheiroi (Pine, 1981) (Didelphimorphia, Didelphidae) in the Cerrado savanna of Maranhao, Brazil. AB - The present study reviews the phylogeny of the genus Marmosops and expands the geographic range of Marmosops pinheiroi to the Brazilian State of Maranhao. Five specimens of M. pinheiroi were collected from the Inhamum Municipal Environmental Protection Area in Caxias, Maranhao. Total DNA was extracted and the mitochondrial cytochrome b gene was sequenced in an ABI PRISM 3500. Additional sequences of Marmosops were obtained from GenBank for specimens from southeastern and northeast Brazil and the northern Amazon Forest. The results of the analysis indicated that M. incanus and M. paulensis form a well-supported clade, and that M. pinheiroi, M. pakaraimae, and M. parvidens are sister groups, with 71% support. The M. pinheiroi specimens from different regions grouped with high bootstrap values (99 and 100%). Interspecific genetic divergence varied from 8.3 to 21.5%, while intraspecific divergence ranged from 0.2 to 6.3% in M. pinheiroi, 0.3 to 2.9% in M. parvidens, and 0.4 to 6.9% in M. incanus. Given the taxonomic complexity of the genus, the results of the present study offer important insights into the taxonomic status of M. pinheiroi, as well as extend its known distribution 670 km south and east to the Brazilian State of Maranhao. PMID- 25729964 TI - Application value of multislice spiral computed tomography angiography in the evaluation of renal artery variation in living donor kidney transplantation. AB - This study aims to investigate the accuracy and value of multislice spiral computed tomography (MSCT) angiography in the evaluation of renal artery variation in living donor kidney transplantation. Two hundred seventy-three kidney transplantation donors underwent preoperative MSCT scanning. Two doctors determined the running direction and variation of the renal artery through joint analysis of the preoperative original MSCT image and the recombination image using the blind reading method, compared the imaging results with the intraoperative results, and evaluated the accuracy and application value of MSCT angiography in the evaluation of renal artery variation in living donor kidney transplantation. CT angiography (CTA) can better show the renal artery and its variation. A total of 52 accessory renal arteries were found in the 273 kidney transplant operations, whereas 55 accessory renal arteries were found in preoperative MSCT. Four accessory renal arteries indicated in the MSCT were not found during the operation, and one accessory renal artery found during the operation was not indicated in the preoperative MSCT. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MSCT in the diagnosis of accessory renal arteries were 98.1, 98.2, 92.7, 99.5, and 98.2%, respectively. MSCT angiography can sensitively and accurately show the renal artery and its variation in living donor kidney transplantation, and has important clinical value for the formulation of the operative scheme before the transplantation. PMID- 25729965 TI - Proteomic analysis identifies differentially expressed proteins participating in forming Type III brush hair in Yangtze River Delta white goat. AB - The Yangtze River Delta white goat is a goat breed that can produce high quality brush hair (Type III hair) around the world. This study aimed to compare Type III hair and non-Type III hair goat skin tissues using differentially expressed proteins based on 2-dimensional gel electrophoresis technology. The differentially expressed protein spots were analyzed using the PDquest 8.0 software. Ten protein spots were detected as positive for mass spectrometric analysis based on a threshold of 2-fold change. Through matching based on Ultraflex III TOF/TOF and MASCOT database, four differentially expressed proteins were identified. Fibrinogen beta chain isoform 1 and ATP synthase beta subunit were upregulated in Type III hair, while succinyl-CoA:3-ketoacid-coenzyme A transferase 1-mitochondrial-like and actin-cytoplasmic 1 were upregulated in non Type III hair. The 4 proteins play important roles in different aspects of hair follicle development. These findings could pave a good foundation for explaining the mechanism of forming Type III hair. PMID- 25729966 TI - Evaluation of pH effects on genomic integrity in adipose-derived mesenchymal stem cells using the comet assay. AB - The use of mesenchymal stem cells (MSCs) in experimental, clinical, and therapeutic trials has grown in recent years. However, the issue remains of whether these procedures are completely safe for transplant patients. Therefore, this study was designed and carried out with the aim of evaluating two different comet assay protocols for genomic damage pattern analysis in MSCs derived from adipose tissue. The analyzed and interpreted results suggest that genetic testing is needed to support clonal expansion safety in cell therapy procedures with MSCs. Furthermore, they also suggest that if the comet assay technique would be used as a genomic integrity screening assay, the protocol performed at pH = 12 (that yielded a frequency of damaged cells: tail intensity = 9.50 +/- 0.60, tail moment = 0.0122 +/- 0.0007; results are reported as means +/- standard deviation) would be indicated as genomic damage, and that subsequent single-strand breaks occur at pH > 13 (frequency of damaged cells: tail intensity = 30.71 +/- 4.23, tail moment = 0.0447 +/- 0.0073). Our study demonstrates that, in the era of regenerative medicine, it is necessary to standardize and establish a battery of tests in order to identify genomic damage prior to MSC transplantation. PMID- 25729967 TI - Cloning and characterization of a farnesyl pyrophosphate synthase from Matricaria recutita L. and its upregulation by methyl jasmonate. AB - Matricaria recutita (L.), commonly known as chamomile, is one of the most valuable medicinal plants because it synthesizes a large number of pharmacologically active secondary metabolites known as alpha-bisabolol and chamazulene. Although the plant has been well characterized in terms of chemical constituents of essential oil as well as pharmacological properties, little is known about the genes responsible for biosynthesis of these compounds. In this study, we report a new full-length cDNA encoding farnesyl diphosphate synthase (FPS), a key enzyme in the pathway of biosynthesis of isoprenoids, from M. recutita. The cDNA of MrFPS comprises 1032 bp and encodes 343 amino acid residues with a calculated molecular mass of 39.4 kDa. The amino acid sequence homology and phylogenetic analysis indicated that MrFPS belongs to the plant FPS super family and is closely related to FPS from the Asteraceae family. Expression of the MrFPS gene in Escherichia coli yielded FPS activity. Using real-time quantitative PCR, the expression pattern of the MrFPS gene was analyzed in different tissues of M. recutita as well as in response to methyl jasmonate. The expression analysis demonstrated that MrFPS expression varies in different tissues (with maximal expression in flowers and stems) and was significantly elevated in response to methyl jasmonate. This study will certainly enhance our understanding of the role of MrFPS in the biosynthesis and regulation of valuable secondary metabolites in M. recutita at a molecular level. PMID- 25729968 TI - Effect of ZNF217 gene polymorphisms on colorectal cancer development in a Mexican population. AB - The ZNF217 gene, a potential oncogene amplified and overexpressed in several cancers including colorectal cancer (CRC), acts as a transcription factor that activates or represses target genes. The polymorphisms rs16998248 (T>A) and rs35720349 (C>T) in coronary artery disease have been associated with reduced expression of ZNF217. In this study, we analyzed the 2 polymorphisms in Mexican patients with CRC. Genotyping of rs16998248 and rs35720349 sites was performed by polymerase chain reaction-restriction fragment length polymorphism in 203 Mexican Mestizos, 101 CRC patients, and 102 healthy blood donors. Although no statistical differences regarding genotype and allele frequencies of ZNF217 polymorphisms were observed (P > 0.05), linkage disequilibrium was significant in CRC patients (r(2) = 0.39, P < 0.0001), as a result of reduced AC haplotype frequency. Thus, the AC haplotype may protect against CRC. PMID- 25729969 TI - Cloning and expression analysis of pepper chlorophyll catabolite reductase gene CaRCCR. AB - Opening the porphyrin macrocycle of pheophorbide a and forming the primary fluorescent chlorophyll catabolites are key steps in the chlorophyll catabolism pathway. These steps are catalyzed by pheophorbide a oxygenase and red chlorophyll catabolite reductase (RCCR). In this study, a novel RCCR gene, CaRCCR, was isolated from the pepper (Capsicum annuum L.). The full-length CaRCCR complementary DNA is comprised of 1173 bp, contains an open reading frame of 945 bp, and encodes a 314-amino acid protein. This deduced protein belongs to the ferredoxin-dependent bilin reductase family. Amino acid sequence alignment showed that CaRCCR shared a high homology to other higher plant RCCR proteins. CaRCCR expression, as determined by quantitative real-time polymerase chain reaction, was higher in the leaves than the roots, stems, flowers, and immature fruits. CaRCCR expression was almost constant during all phases of leaf development. It was upregulated by abscisic acid, methyl jasmonate, and salicylic acid. Moreover, CaRCCR was induced by high salinity and drought stress treatments; it was also slightly regulated by Phytophthora capsici. Taken together, these results suggest that CaRCCR is involved in defense responses to various stresses. PMID- 25729970 TI - Expression of the RORalpha gene in Inner Mongolian cashmere goat hair follicles. AB - The expression of retinoid-acid-related orphan receptor alpha (RORalpha) was evaluated at the mRNA level using real-time polymerase chain reaction (qRT-PCR), and its expression localization was determined by in situ hybridization of adult Inner Mongolian cashmere goats at different times of the year. In situ hybridization demonstrated that RORalphawas expressed in secondary hair follicles of the hair shaft, inner root sheath, outer root sheath, medulla, and other parts that are target organs of the RORalphareceptor gene. qRT-PCR results showed that there was no significant difference in the RORa mRNA abundance in February, April, August, and October (P > 0.05), and the only difference occurred in December relative to February, August, and October (P < 0.05). This difference revealed that melatonin possibly promotes cashmere growth through the nuclear receptor RORalpha. This study provides a good foundation for future studies on the relationship between the melatonin receptor and cashmere growth; in addition, it provides new insights for increased cashmere production and quality. PMID- 25729971 TI - Molecular characterization, tissue expression, and polymorphism analysis of liver type fatty acid binding protein in Landes geese. AB - Liver weight is an important economic trait in the fatty goose liver industry. Liver-type fatty acid binding protein (L-FABP) is involved in the formation and metabolism of fatty acids. Thus, we hypothesized that sequence polymorphisms in L FABP were associated with fatty liver weight in goose. We first isolated, sequenced, and characterized the goose L-FABP gene, which had not been previously reported. The goose L-FABP gene was 2490 bp and included 4 exons coding for a 126 amino acid protein. Analysis of expression levels of the goose L-FABP gene in different tissues showed that the expression level in the liver tissue was higher than in other tissues, and was significantly higher in the liver tissue of overfed geese than in control geese. Moreover, a single nucleotide polymorphism located at 774 bp in the gene was identified in a Landes goose population. To test whether this single nucleotide polymorphism was associated with fatty liver production, liver weight and the ratio of liver to carcass weights were determined for the 3 genotypes with this single nucleotide polymorphism (TT, TG, GG) in overfed Landes geese. Our data indicate that individuals with the GG genotype had higher values for the variables measured than those with the other 2 genotypes, suggesting that L-FABP can be a selection marker for the trait of fatty liver production in goose. PMID- 25729972 TI - Comparison of DNA extraction methods for polymerase chain reaction amplification of guanaco (Lama guanicoe) fecal DNA samples. AB - Feces-based population genetic studies have become increasingly popular. However, polymerase chain reaction (PCR) amplification rates from fecal material vary depending on the species, populations, loci, and extraction protocols. Here, we assessed the PCR amplification success of three microsatellite markers and a segment of the mitochondrial control region of DNA extracted from field-collected feces of guanaco (Lama guanicoe) using two protocols - Qiagen DNA Stool Kit and 2 cetyltrimethylammonium bromide/phenol:chloroform:isoamyl alcohol (2CTAB/PCI) method. Chelex resin treatment to remove inhibitors was also tested. Our results show that the mitochondrial locus was the most difficult to amplify. PCR success rates improved for all markers after Chelex treatment of extracted DNA, and 2CTAB/PCI method (95.83%) appeared to perform slightly better than stool kit (91.67%) for the nuclear markers. Amplification success was significantly influenced by the extraction method, Chelex treatment, and locus (P < 0.001) but not by the freshness of the feces (fresh vs old, P = 0.17). The repeatability levels were high without Chelex treatment (> 0.89), but they decreased slightly after treatment for amplification of nuclear markers and markedly after treatment for amplification of the mitochondrial control region. Thus, we showed that Chelex treatment gives high PCR success, especially for nuclear markers, and adequate DNA extraction rates can be achieved from L. guanicoe feces even from non-fresh fecal material. Although not significant, 2CTAB/PCI method tended to provide higher successful amplification rates on a whole set of samples, suggesting that the method could be particularly useful when using small sample sizes. PMID- 25729973 TI - Polymorphism analysis of the intron one of insulin-like growth factor 2 receptor gene (IGF2R) in FFRC strain common carp (Cyprinus carpio L.) and its relationship with growth performance. AB - The insulin-like growth factor 2 receptor gene (IGF2R) encodes a transmembrane protein receptor and acts to sequester and degrade excess circulating insulin like growth factor 2, which is critical for normal mammalian growth and development. Thus, IGF2R may serve as a candidate gene underlying growth trait in the common carp. In this study, we isolated the intron one of common carp IGF2R and detected the diversity in 3 continuous generations of FFRC strain common carp. A total of 8 loci were detected within this region, which were named in accordance with their location (i.e., Loc84, Loc106, Loc119, Loc130, Loc145, Loc163, Loc167, and Loc265). Loc106, Loc119, and Loc145 were moderately polymorphic; while Loc84, Loc130, Loc163, Loc167, and Loc265 exhibited slight level of polymorphism. However, significant differences between polymorphism information content values were not observed among the different generations. For Loc145, all generations deviated from Hardy-Weinberg equilibrium. The total number of significant linkage disequilibria for all generations equaled 40. Among them, 4 pairs were detected in each population, while 8 pairs were found in the 2nd and 3rd generations. For Loc130, the G/T genotype exhibited higher body weight when compared to that of the G/G genotype. The frequency of the homozygous G/G genotype reached 87.96%; thus, we can improve FFRC strain common carp growth performance by increasing the percentage of the G/T genotype within a breeding population. Therefore, the G/T genotype could be used as a molecular marker for superior growth traits. PMID- 25729974 TI - A novel stop codon mutation in exon 1 (558C>A) of the UGT1A1 gene in a Thai neonate with Crigler-Najjar syndrome type I. AB - Human uridine 5'-diphosphate-glucuronosyltransferases play a critical role in detoxification by conjugating bilirubin with glucoronic acid. Impaired or reduced enzymatic activity causes a spectrum of clinical disorders such as Crigler-Najjar syndrome type I (CN1), Crigler-Najjar syndrome type II, and Gilbert's syndrome. CN1 is a severe form of unconjugated hyperbilirubinemia caused by homozygous or compound heterozygous mutations in the gene for uridine 5'-diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), resulting in complete loss of enzyme function. Here, we report a novel homozygous mutation of UGT1A1 in a female Thai infant who was diagnosed with CN1, and her parents were found to be heterozygous carriers. The patient was homozygous for the c.558C>A mutation, which resulted in a premature stop codon in exon 1. Her asymptomatic parents were carriers of the nonsense c.558C>A mutation. Our result suggests an important role for homozygous c.558C>A mutations in the UGT1A1 gene in the development of severe unconjugated hyperbilirubinemia. PMID- 25729975 TI - A novel 3-base pair deletion of the CRYAA gene identified in a large Chinese pedigree featuring autosomal dominant congenital perinuclear cataract. AB - Congenital cataract is caused by reduced transparency of the lens resulting from metabolic disorders during the fetal period. The disease shows great heterogeneity both clinically and genetically. We identified a 4-generation ethnic Han Chinese family affected by autosomal dominant congenital perinuclear cataract. The patients underwent full clinical and ophthalmologic examinations to rule out any concomitant disorders. Blood samples were collected and genomic DNA was extracted. Potential mutations in the candidate gene alpha A crystallin (CRYAA) were screened. Prenatal diagnosis was then provided for a fetus of the affected proband by chorionic villus sampling. In all patients, DNA sequencing of the CRYAA gene revealed a novel 3-bp deletion mutation in exon 3 (c.246_248delCGC), which led to deletion of codon 117 encoding arginine (p.117delR) in the peptide chain. The same mutation was not found among unaffected and healthy individuals. Bioinformatic analysis revealed that although the c.246_248delCGC is an 'in-frame' mutation, removal of arginine resulted in a significant change in the protein structure. The fetus did not possess this mutation and was confirmed to be healthy at 1-year follow-up. A novel disease causing mutation, c.246_248delCGC (p.117delR), of the CRYAA gene has been identified in a Chinese family with autosomal-type perinuclear congenital cataracts. This is also the first report of prenatal diagnosis of this type of congenital cataract. PMID- 25729976 TI - Novel NPHS1 splice site mutations in a Chinese child with congenital nephrotic syndrome. AB - Congenital nephrotic syndrome (CNS) is defined as heavy proteinuria or nephrotic syndrome occurring before 3 months of age. It is characterized by early onset and progresses to end-stage renal disease. Recently, several genes associated with CNS have been identified, including NPHS1 and NPHS2. Mutations in the NPHS1 gene have been identified in patients with CNS in Finland with relatively high frequency. Thus far, only a few case reports about CNS have described an NPHS1 mutation in China. In this study, mutational analyses of NPHS1 and NPHS2 were performed in a Chinese child with CNS. Mutations were analyzed in all exons and exon/intron boundaries of NPHS1 and NPHS2 in the patient and his parents as well as in 50 unrelated controls using polymerase chain reaction and direct sequencing techniques. No mutations were detected in NPHS2. A novel splice site mutation (IVS11+1G>A) within intron 11 and a missense mutation within exon 8 (c.928G>A) in the NPHS1 gene were detected in the child. The child's mother had normal urinalysis and a c.928G>A (D310N) heterozygous mutation, and his father had normal urinalysis and IVS11+1G>A. These were not identified in the 50 unrelated controls. The novel splice site mutation of IVS11+1G>A and a missense mutation at c.928G>A in NPHS1 were found to cause CNS in this Chinese child. PMID- 25729977 TI - Activin A is associated with asthma in underweight and overweight patients. AB - There are limited data regarding the effects of activin A on underweight, normal weight, and overweight patients with asthma. We determined serum levels of activin A in asthmatic patients in relation to body mass index. The study protocol included questionnaires, measurement of exhaled nitric oxide, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening. Serum and sputum activin A levels were measured using an enzyme-linked immunosorbent assay in 94 asthmatic patients. Mean serum levels of activin A were significantly (P = 0.001) higher in underweight (1781 +/- 327.3 pg/mL) than in normal weight and overweight asthmatic patients, regardless of gender. After stratification by gender, significantly higher mean values of activin A were observed in females compared to males in the normal and underweight groups (P = 0.003 and P = 0.0002, respectively). Significant differences between groups were found in airway wall area (%) (P < 0.0001). We also observed a much higher percentage of sputum lymphocytes in the underweight group compared to the other groups (P < 0.0001). Correlations between bronchial wall thickness and activin A were found in the underweight (r = 0.67, P = 0.48) and normal weight groups (r = 0.51, P = 0.042). Correlations between fractional of exhaled nitric oxide, forced expiratory volume in 1 s, delayed treatment years, and activin A in different groups were also observed. Increased serum level of activin A indicates its role in the pathogenesis of asthma, particularly in underweight and overweight patients. PMID- 25729978 TI - Isolation and characterization of microsatellite loci for Cunninghamia lanceolata (Lamb.) Hook. AB - As a result of human activities, wild populations of Cunninghamia lanceolata (Cupressaceae) have sharply declined in recent years. The development and implementation of a valid conservation strategy require a clear understanding of the genetic makeup of this species. Eleven polymorphic microsatellite loci were isolated and characterized from samples of 52 individuals from the Provenance Test Plantation in Fenyi, Jiangxi Province, China. Among the loci, 10 were polymorphic and 1-34 (average 18.182) alleles per locus were identified. Observed and expected heterozygosities ranged from 0 to 0.750 (mean 0.456) and 0 to 0.968 (mean 0.749), respectively. These microsatellite loci may facilitate further research on the molecular breeding and population genetics of C. lanceolata and its relatives. PMID- 25729979 TI - Characterization of a novel CAPN3 transcript generated by alternative splicing in cattle. AB - Calpain-3 (CAPN3) is a member of the calpain family of Ca(2+)-regulated cysteine proteases, which play an important role in sarcomere remodeling and mitochondrial protein turnover, and thus, regulating beef tenderness in cattle. Currently, multiple CAPN3 transcripts have been detected in human, monkey, rat, and rabbit. However, whether this transcript is present in cattle remains unknown. In this study, we identified 2 CAPN3 transcripts in the skeletal muscle individuals of local black cattle from Jilin, China. One transcript corresponded to the known full-length protein and was referred to as CAPN3a, while the second transcript did not contain exons 2-19 and contained a single-nucleotide insert in the penultimate base of exon 1 compared to CAPN3a; this protein was referred to as CAPN3b. The expression level of CAPN3b was approximately 50-fold lower than that of CAPN3a. Moreover, CAPN3b mRNA was not translated into a functional protein because it had lost essential domains according to bioinformatic analysis. Our results not provide a foundation for understanding the function of CAPN3, but also are useful for further elucidating the effect of CAPN3 on meat quality in cattle. PMID- 25729980 TI - First transcriptional survey of the Malpighian tubules of giant mealworm, Zophobas morio (Coleoptera: Tenebrionidae). AB - The Malpighian tubules play a key role in insect osmoregulation. Although a transcriptional analysis has been done for the Malpighian tubules in Drosophila melanogaster (Diptera), no functional genomics analysis has yet been carried out for any Coleoptera species. Recently, we constructed a cDNA library from Malpighian tubules of larval Zophobas morio, a close relative of Tribolium castaneum, and cloned the cDNA for an AMP/CoA-ligase with luciferase-like enzyme properties. Using this cDNA library, we randomly isolated, partially sequenced and analyzed ca. 540 clones, obtaining the first transcriptional profile of the most representative expressed genes, and associated them with their possible biological functions. A high percentage of mitochondrial genes was found, which is consistent with the high metabolic activity required by this organ during the formation of primary urine. Common transcripts included those for enzymes involved in osmoregulation, such as solute transporters and ATPases, and in detoxification and excretion, such as cytochrome P450, glutathione S-transferase, alcohol dehydrogenase. The presence of AMP/CoA-ligases, which activate exogenous carboxylic acids such as firefly D-luciferin suggests their participation in important new xenobiotic excretion/detoxification roles in Malpighian tubule physiology. PMID- 25729981 TI - Impact of BMMSCs from different sources on proliferation of CD34+ cells. AB - There are significant differences on the biological characteristics of bone marrow mesenchymal stem cells (BMMSCs), immunological response, and antigen presenting functions between patients with psoriasis and normal subjects, but there are no significant differences in aborted fetuses. We examined the differences in BMMSCs between aborted fetuses and patients with psoriasis in this study. Bone marrow from normal subjects, aborted fetuses, and patients with psoriasis were obtained using a MidiMACS machine. Density gradient centrifugation method was used to isolate the bone marrow mononuclear cells of patients with psoriasis and aborted fetus and the cells were cultivated. Bone marrow CD34(+) cells from normal subjects were isolated. MTT colorimetric detection was used to test the proliferation activity of bone marrow CD34(+) cells. The purity of bone marrow CD34(+) cells and BMMSCs was determined by flow cytometry. The BMMSC culture supernatant fluid of patients with psoriasis and aborted fetuses showed no statistically significant difference with bone marrow CD34(+) cell proliferation in normal subjects (P > 0.05). PMID- 25729982 TI - Characterization of a protein-protein interaction network of the CBL-interacting protein kinase 8 from sugarcane. AB - Plants are sessile organisms and have evolved to tolerate a constantly changing environment. After the onset of different stress conditions, calcineurin B-like (CBL) proteins can sense calcium signals and activate CBL-interacting protein kinase (CIPK) proteins, which can phosphorylate downstream proteins to reestablish plant homeostasis. Previous studies in the bioenergy crop sugarcane showed that the ScCIPK8 gene is induced by drought stress and is also related to sucrose content. Here, we have characterized the protein-protein interactions of ScCIPK8 with six CBL proteins (ScCBL1, ScCBL2, ScCBL3, ScCBL6, ScCBL9, and ScCBL10). Yeast two-hybrid assays showed that ScCIPK8 interacts with ScCBL1, ScCBL3, and ScCBL6. Bimolecular fluorescence complementation assays confirmed in planta the interactions that were observed in yeast cells. These findings give insights on the regulatory networks related to sugar accumulation and drought stress responses in sugarcane. PMID- 25729983 TI - Role of Nrf2 signal pathway in rats with deep hypothermia ischemia/reperfusion injury undergoing remote postconditioning. AB - We investigated the protective effects of remote postconditioning (RPC) in the lungs of rats with deep hypothermia ischemia/reperfusion (I/R) injury and the role of nuclear factor E2-related factor 2 (Nrf2) signaling in this process. Forty-nine rats were randomly divided into a sham control group, deep hypothermia I/R group, RPC group, I/R+all-trans retinoic acid (ATRA) group, I/R+RPC+ATRA group, I/R+tert-butylhydroquinone (tBHQ) group, and I/R+RPC+tBHQ group. Real-time polymerase chain reaction and Western blot analysis were used to examine Nrf2 mRNA and protein expression, respectively. Compared with the sham control group, Nrf2 expression, malondialdehyde (MDA) content, and the wet/dry weight (W/D) ratio were significantly increased in the I/R group, while superoxide dismutase (SOD) activity was significantly decreased. Pulmonary Nrf2 expression and SOD activity was significantly increased, and MDA content and the W/D ratio were significantly decreased in the RPC group compared with the I/R group. Compared with the I/R group, MDA and W/D ratio significantly decreased and SOD activity remarkably increased in I/R+tBHQ group. After ATRA intervention in the I/R+ATRA group, MDA content and W/D ratio increased and SOD activity decreased compared to the I/R group. MDA content and W/D ratio in the RPC+tBHQ group significantly decreased and SOD activity increased compared with in the RPC group (P < 0.01). In the RPC+ATRA group, MDA content and W/D ratio decreased while SOD activity increased compared with the RPC group (P < 0.01). RPC alleviated deep hypothermia I/R injury; the Nrf2 signaling pathway may be involved in the protective effects induced by RPC. PMID- 25729984 TI - XPG polymorphisms are associated with prognosis of advanced non-small cell lung cancer treated with platinum-based doublet chemotherapy. AB - We conducted a cohort study to investigate whether 3 potential single nucleotide polymorphisms (SNPs) in the xeroderma pigmentosum complementation group G (XPG) gene could predict the survival of advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based doublet chemotherapy. We enrolled 262 patients with histologically confirmed NSCLC between November 2007 and December 2008 in this study. The 3 SNPs (rs2296147T>C, rs2094258C>T, and rs873601G>A) were genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis. Older age, Eastern Cooperative Oncology Group performance score >=2 and higher disease stage were associated with shorter survival. In the Cox proportional hazard model, patients carrying the rs2296147 TT genotype and the T allele had a significantly reduced risk of developing progressive disease or dying from NSCLC. The HRs (95%CI) were 0.31 (0.13-0.73) and 0.44 (0.24-0.83) for progression-free survival and 0.32 (0.14-0.71) and 0.54 (0.32-0.98) for overall survival, respectively. Moreover, advanced NSCLC patients carrying the rs2094258 GG and the G allele had a significantly decreased risk of developing progressive disease. The HRs (95%CI) for the rs2094258 GG genotype and the G allele were 0.35 (0.16-0.80) and 0.45 (0.23-0.86) for overall survival, respectively. We suggest that the rs2296147 and rs2094258 polymorphisms could be used as surrogate markers, leading to individualization of NSCLC treatment strategies. PMID- 25729985 TI - A possible way that phiC31 integrase regulates the recombination direction. AB - phiC31 integrase encoded by Streptomyces phage can mediate site-specific recombination between phage and host genomes. The recombination direction is generally considered to be accurately regulated, but the regulatory mechanisms involved are still unclear. Recently, some hyperactive mutants of phiC31 integrase that can bypass the regulatory steps have been isolated and extensively studied. A putative coiled-coil region is found to play a critical role in controlling recombination direction. Further analysis led us to the speculation that at least two regions in the N-terminal domain of phiC31 integrase are involved in the tetrameric interfaces and that the putative coiled coil interacts with one of the regions to regulate the recombination direction. PMID- 25729986 TI - Expression profiles of DNA repair-related genes in rat target organs under subchronic cadmium exposure. AB - We aimed to evaluate the toxicity of long-term exposure to different cadmium (Cd) doses in rats and expression profiles of DNA repair-related genes. The model rats were exposed to different concentrations of CdCl2 for 3 months, and 5 DNA repair related genes - hMSH2, MLH1, XRCC1, hOGG1, ERCC1 - were cloned in different tissues, including the liver, kidney, heart, and lung. Accumulated amounts of Cd were detected in the tissues. Gene and protein detections were conducted via fluorescence quantitative real-time polymerase chain reaction and Western blotting, respectively. Methylated sequences of the 5 DNA repair-related gene promoters were used to investigate whether the low expression levels of the genes were related to methylation of the promoter. In the Cd-exposed group, 3 DNA repair genes (i.e., XRCC1, hOGG1, and ERCC1) significantly decreased in the rat liver, kidney, heart, and lung according to the beta-actin internal standard (P < 0.01). Western blotting indicated the same trend for the different tissues. Each of the DNA repair genes had special characteristics; for example, hOGG1 gene expression decreased by 75% in the kidney, and XRCC1 gene expression decreased by 5% in the liver and heart when compared to the control group (P < 0.01). A negative correlation between the DNA repair gene expression levels and the cumulative levels of Cd was also suggested by malignancy pathology. The expression levels of 3 DNA repair genes (i.e., ERCC1, XRCC1, and hOGG1) played an important role in the rat response to Cd exposure but not DNA methylated protection. PMID- 25729987 TI - Development of novel and polymorphic microsatellite DNA loci from Haliotis ovina. AB - Twelve microsatellite loci were developed from Haliotis ovina by the magnetic bead hybridization method. Genetic variability was assessed using 30 individuals from 3 wild populations. The number of alleles per locus ranged from 2 to 5, and the polymorphism information content ranged from 0.1228 to 0.6542. Observed and expected heterozygosities ranged from 0.0000 to 0.7778 and 0.1288 to 0.6310, respectively. These loci should provide useful information for genetic studies such as genetic diversity, pedigree analysis, construction of genetic linkage maps, and marker-assisted selection breeding in H. ovina. PMID- 25729988 TI - Assessment of the genetic diversity of tomato yellow leaf curl virus. AB - The objective of the present study was to analyze the genetic diversity of tomato yellow leaf curl virus (TYLCV). Representative TYLCV sequences were searched in the National Center for Biotechnology Information database. Comprehensive analysis of TYLCV was performed using bioinformatics by examining gene structure, sequence alignments, phylogeny, GC content, and homology. Forty-eight representative TYLCV sequences were selected from 48 regions in 29 countries. The results showed that all TYLCV sequences were 2752-2794 nucleotides in length, which encoded 6 open reading frames (AV1, AV2, AC1, AC2, AC3, and AC4). GC content ranged from 0.41-0.42. Sequence alignment showed a number of insertions and deletions within these TYLCV sequences. Phylogenetic tree results revealed that the sequences were divided into 10 classes; homology of the sequences ranged from 72.8 to 98.6%. All 48 sequences contained the typical structure of TYLCV, including open reading frames and intergenic regions. These results provide a theoretical basis for the identification and evolution of the virus in the future. PMID- 25729989 TI - Development and characterization of polymorphic microsatellite loci in the sea cucumber Holothuria leucospilota. AB - Holothuria leucospilota is a tropical holothurian species that is widely distributed in the tropical and sub-tropical India-Western Pacific Region. Eight polymorphic microsatellite loci were developed from H. leucospilota by using the protocol fast isolation by amplified fragment length polymorphism of sequences containing repeats and tested in 30 individuals from Hainan Island in China. The number of alleles was 2-6 and polymorphism information content ranged from 0.371 0.694. The levels of expected and observed heterozygosities varied from 0.3913 0.6701 and from 0.1154-0.7000, respectively. No significant linkage disequilibrium was detected for any pairwise combination of loci. Only loci YZHS1 42 deviated from Hardy-Weinberg equilibrium. These polymorphic microsatellite loci may be useful for germplasm conservation of H. leucospilota. PMID- 25729990 TI - Molecular characterization and tissue expression profile analysis of the porcine JAZF1 gene. AB - A recent study indicated that the JAZF1 gene was related to lipid metabolism by regulating the level of gene expression in humans and mice. In order to investigate whether JAZF1 gene expression was associated with fat deposition in pig, we cloned the full-coding region of the JAZF1 gene (GenBank accession No. KF307636) from porcine longissimus dorsi. Results showed that the open reading frame of JAZF1 covered 732 bp and encoded 243 amino acids. Multiple alignment of isoform sequences revealed that the deduced amino acid sequence of JAZF1 had a high degree of sequence similarity to other vertebrates, indicating that it was highly conserved during evolution. Bioinformatic analysis indicated that pig JAZF1 contained 23 phosphorylation sites and 19 glycosyl sites. JAZF1 was predicted to have 3 ZnF-C2H2 and 2 low-complexity domains. The JAZF1 mRNA expression pattern indicated that JAZF1 mRNA expression level in the liver was significantly different in 2 divergent breeds (P < 0.05). This article perhaps provided an important experimental basis for further research on the mechanisms of lipid metabolism and fat deposition in pigs. PMID- 25729991 TI - Molecular characterization and expression analysis of purple acid phosphatase gene from pearl oyster Pinctada martensii. AB - Purple acid phosphatases (PAPs), also known as type 5 acid phosphatases, are widely present in animals, plants, and fungi. In mammal, PAP was reported to participate in immune defense and bone resorption. In this study, the characteristics and potential functions of a PAP gene from pearl oyster Pinctada martensii (pm-PAP) were examined. The Pm-PAP cDNA was found to be 2777 base pairs, containing a 1581-base pair open reading fragment encoding for 526 amino acids with an estimated molecular mass of 60.1 kDa and theoretical isoelectric point of 5.82. One signal peptide and five conserved motifs [GDXX/GDXXY/GNH(D/E)/XXXH/(A/G)HXH] were present in the entire sequence. Tissue expression profile analysis showed that pm-PAP mRNA was constitutively expressed in all tissues studied with abundant mRNA found in mollusk defense system, including hepatopancreas, gill, and hemocytes. After lipopolysaccharide stimulation, the expression of pm-PAP mRNA in hemocytes was dramatically upregulated at 2 h and achieved the highest level at 36 h. Additionally, pm-PAP mRNA expression was significantly increased and achieved the highest level at 2 days after the surgical implantation during pearl production. These results suggest that pm-PAP is a constitutive and inducible protein that may be involved in the immune defense of pearl oyster. PMID- 25729992 TI - TNF-alphaG-308A polymorphism is associated with insulin resistance: a meta analysis. AB - Tumor necrosis factor-alpha (TNF-alpha) promoter polymorphisms has been reported to be associated with obesity and insulin resistance and gained widespread attention. However, results obtained so far are quite conf??licting. We therefore performed a meta-analysis to address this issue, basing on 17 studies from electronic databases (MEDLINE and EMBASE). No evidence of significant effect of TNF-alphaG-308A polymorphism on body mass index (BMI) or obesity risk was detected (BMI: WMDRE = 0.05, 95%CI: -0.62 to 0.73; risk of obesity: ORFE = 1.09, 95%CI: 0.87 to 1.35). G-308A variant was significantly associated with increased insulin levels in the overall (SMDFE = 0.12, 95%CI: 0.03 to 0.20) and obese subgroup analysis (SMDFE = 0.16, 95%CI: 0.03 to 0.29). In total, no significant result was observed for the association between TNF-alpha G-308A variant and HOMA IR index. Nevertheless, subgroup analysis showed G-308A polymorphism was significantly associated with increased HOMA-IR in Caucasians (WMDFE = 0.49, 95%CI: 0.03 to 0.94). Our results indicate that TNF-alphaG-308A polymorphism has a significant effect on insulin resistance. However, it is unlikely that G-308A variant contributes to obesity. PMID- 25729993 TI - Relationship between male sterility and beta-1,3-glucanase activity and callose deposition-related gene expression in wheat (Triticum aestivum L.). AB - In previous studies, we first isolated one different protein beta-1,3-glucanase using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry from normal wheat (Triticum aestivum L.) and chemical hybridization agent-induced male sterility (CIMS) wheat. In this experiment, beta-1,3-glucanase activity and the expression of a callose deposition-related gene, UDP-glucose phosphorylase (UGPase), were determinate in normal, CIMS, and genetic male sterility (GS) wheat. beta-1,3 glucanase activity was significantly different between the fertile and sterile lines during callose synthesis and degradation, but there was no difference between CIMS and GS wheat. The UGPase gene of callose deposition was highly expressed in the meiophase and sharply decreased in the tetrad stage. However, the expression of the UGPase gene was significantly different between the fertile and sterile lines. These data indicated that beta-1,3-glucanase activity and the expression of the UGPase gene play important roles in the male sterility of wheat. Consequently, pollen mother cells (PMCs) might degenerate at the early meiosis stage, and differences in UGPase gene expression and beta-1,3-glucanase activity might eventually result in complete pollen collapse. In addition, the critical period of anther abortion might be the meiosis stage to the tetrad stage rather than what we previously thought, the mononuclear period. PMID- 25729994 TI - Assessment of the cytotoxic, genotoxic, and mutagenic potential of Acrocomia aculeata in rats. AB - Acrocomia aculeata (Jacq.) Lodd. ex Mart. is a plant species commonly used as a foodstuff and also for treating diseases, since it contains high concentrations of antioxidant compounds and monounsaturated fatty acids. Considering its ethnopharmacological relevance, the aim of the present study was to assess the cytotoxic, genotoxic, and mutagenic effects of an oil extracted from the pulp of A. aculeata (OPAC) in rats. In addition, a chromatographic characterization of the fatty acids present in OPAC was performed. Male and female Wistar rats were treated orally with 125, 250, 500, 1000, or 2000 mg/kg/body weight OPAC. The effects of OPAC ingestion were determined by performing the comet assay and micronucleus test. The comet assay data demonstrated that OPAC did not increase the frequency or rate of DNA damage in groups treated with any of the concentrations assessed compared to that in the negative control group. In the micronucleus test, the animals treated did not exhibit any cytotoxic or mutagenic changes in peripheral blood erythrocytes. The results demonstrated that OPAC did not exhibit cytotoxic, genotoxic, or mutagenic effects in Wistar rats, thereby increasing the evidence for the safety of oil extracted from this plant. PMID- 25729995 TI - Agrobacterium-mediated transformation of tomato with the ICE1 transcription factor gene. AB - ICE1 genes play a very important role in plants in cold conditions. To improve the cold resistance of tomato, the ICE1 gene of Arabidopsis thaliana was used to construct the plant expression vector p3301-ICE1, and was overexpressed in tomato through Agrobacterium-mediated transformation. Five strains of resistant plants were obtained. PCR and half-quantitative results showed that the ICE1 gene was transferred to tomato; three strains tested positive. After low-temperature stress treatment, praline content and peroxide and catalase activities in the transgenic tomato plants were higher compared with non-transgenic controls, while malondialdehyde content was clearly lower. PMID- 25729996 TI - Development of simple sequence repeat markers in persimmon (Diospyros L.) and their potential use in related species. AB - Persimmon (Diospyros L.) is an economically important fruit in the world, and it has been recognized as a healthy nutrient supply for human consumption. In this study, 14 microsatellite markers were developed from an AG/TC and AC/TG-enriched genomic library of Chinese persimmon Mopanshi. Twelve polymorphic markers were selected in 4 related species; these markers showed transferability to the 4 related persimmon species. In addition, 10 simple sequence repeat (SSR) markers were used to detect the genetic diversity among 51 persimmon accessions from China, Japan, and Korea. A total of 57 polymorphic bands with an average of 5.7 bands per primer pair were observed. According to cluster analysis and principal coordinate analysis, all persimmon accessions could be divided into 4 groups. A close relationship existed between D. kaki and D. oleifera, and D. glaucifolia and D. lotus. Jinzaoshi could be considered a separate species of persimmon. These new SSR markers provide tools for evaluating genetic relatedness among different persimmon species. PMID- 25729997 TI - Genetic variation of Sargassum horneri populations detected by inter-simple sequence repeats. AB - The seaweed Sargassum horneri is an important brown alga in the marine environment, and it is an important raw material in the alginate industry. Unfortunately, the fixed resource that was originally reported is now reduced or disappeared, and increased floating populations have been reported in recent years. We sampled a floating population and 4 fixed cultivated populations of S. horneri along the coast of Zhejiang, China. Inter-simple sequence repeat (ISSR) markers were applied in this research to analyze the genetic variation between floating populations and fixed cultivated populations of S. horneri. In total, 220 loci were amplified with 23 ISSR primers. The percentage of polymorphic loci within each population ranged from 53.64 to 95.45%. The highest diversity was observed in population 3, which was the local species that was suspension cultured in the lab and then fixed cultivated in the Nanji Islands before sampling. The lowest diversity was obtained in the floating population 4. The genetic distances among the 5 S. horneri populations ranged from 0.0819 to 0.2889, and the distance tendency confirmed the genetic diversity. The results suggest that the floating population had the lowest genetic diversity and could not be joined into the cluster branch of the fixed cultivated populations. PMID- 25729998 TI - Hemodynamic changes of unexplained syncope patients in head-up tilt test. AB - The purpose of this study was to observe the hemodynamic changes of unexplained syncope patients in the head-up tilt test and their correlations with age and gender. Eighty-six patients with unexplained syncope were administered the basic head-up test and nitroglycerin provocation test with continuous monitoring and recording of electrocardiogram and blood pressure changes. Basic characteristics of the patients and their hemodynamic responses throughout the tests were analyzed. All 86 patients tolerated and completed the head-up test. Forty-nine (56.98%) of the patients displayed a positive reaction, 37 (43.02%) patients displayed a negative reaction. Patients were divided into groups as follows: Group A, age <= 35 years; Group B, age 36-45 years; and Group C, age >= 46 years. Older patients were more prone to chronotropic incompetence, and younger patients were more prone to an excessive increase in heart rate. Older age correlated with the occurrence of autonomic nerve reaction disorder and mixed vasovagal syncope, whereas younger age was related to the occurrence of vasodepressor type vasovagal syncope (P < 0.01). Gender did not significantly correlate with negative or positive head-up test results (P = 0.184). During the head-up test, younger patients mainly manifested an excessive heart rate increase, whereas older patients did not have significant heart rate changes. Analyzing the hemodynamic changes in the head-up test and studying the relationships between age, gender, and hemodynamic responses are crucial to determine etiologies of syncope and select appropriate treatment. PMID- 25729999 TI - LAMP-PCR detection of ochratoxigenic Aspergillus species collected from peanut kernel. AB - Over the last decade, ochratoxin A (OTA) has been widely described and is ubiquitous in several agricultural products. Ochratoxins represent the second most important mycotoxin group after aflatoxins. A total of 34 samples were surveyed from 3 locations, including Mecca, Madina, and Riyadh, Saudi Arabia, during 2012. Fungal contamination frequency was determined for surface-sterilized peanut seeds, which were seeded onto malt extract agar media. Aspergillus niger (35%), Aspergillus ochraceus (30%), and Aspergillus carbonarius (25%) were the most frequently observed Aspergillius species, while Aspergillus flavus and Aspergillus phoenicis isolates were only infrequently recovered and in small numbers (10%). OTA production was evaluated on yeast extract sucrose medium, which revealed that 57% of the isolates were A. niger and 60% of A. carbonarius isolates were OTA producers; 100% belonged to A. ochraceus. Only one isolate, morphologically identified as A. carbonarius, and 3 A. niger isolates unstably produced OTA. A polymerase chain reaction (PCR)-based identification and detection assay was used to identify A. ochraceus isolates. Using the primer sets OCRA1/OCRA2, 400-base pair PCR fragments were produced only when genomic DNA from A. ochraceus isolates was used. Recently, the loop-mediated isothermal amplification assay using recombinase polymerase amplification chemistry was used for A. carbonarius and A. niger DNA identification. As a non-gel-based technique, the amplification product was directly visualized in the reaction tube after adding calcein for naked-eye examination. PMID- 25730000 TI - Effects of conservative laparoscopic endometrial cystectomy and use of kidney reinforcing and blood activating traditional Chinese medicine on ovarian functions. AB - This study investigated functional changes in the ovaries of women who have had conservative laparoscopic endometrial cystectomy and the effects of traditional kidney-reinforcing and blood-activating Traditional Chinese Medicine (TCM) on ovarian function. Seventy female patients who underwent laparoscopic endometrial cystectomy were randomized into two groups: TCM group receiving kidney reinforcing and blood-activating Chinese medicine (N = 35) and control group receiving only routine follow-up (N = 35). The serum levels of all study participants were measured for follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and inhibin B (INHB) prior to and after endometrial surgery. Postoperative menstruation conditions were also assessed. Compared to preoperative conditions, both LH and FSH levels during the postoperative 1st month increased in both groups, while E2 and INHB levels decreased (P < 0.05). In the TCM group, in contrast to the control group and the postoperative 1st month, we observed a decrease in LH and FSH levels during the postoperative 4th month, while E2 and INHB levels increased (P < 0.05). In this study, we found that certain TCM prescriptions lowered postoperative serum FSH and LH levels and increased the serum INHB and basal E2 levels, thereby improving the ovarian reserve. PMID- 25730001 TI - Changes in hippocampal ultrastructure and vimentin expression in rhesus monkeys following selective deep hypothermia and blood occlusion. AB - Previous studies have shown that selective cerebral profound hypothermia combined with antegrade cerebral perfusion can improve resistance to cerebral hypoxia ischemia in monkeys. The aim of this study was to observe the effect of selective cerebral profound hypothermia on the ultrastructure and vimentin expression in monkey hippocampi after severe cerebral ischemia. Eight healthy adult rhesus monkeys were randomly divided into two groups: profound hypothermia (N = 5) and normothermia (N = 3). Monkeys in the profound hypothermia group underwent bilateral carotid artery and jugular vein occlusion for 10 minutes at room temperature. Ringer's solution at 4 degrees C was then perfused through the right internal carotid artery and out of the right jugular vein, maintaining the brain temperature below 18 degrees C. Sixty minutes later, cerebral blood flow was restored. The normothermia group underwent all procedures with the exception that the Ringer's solution was 37 degrees C during perfusion. All animals in the profound hypothermia group were successfully resuscitated. No significant abnormalities of hippocampal morphology or ultrastructure were observed. In contrast, no monkeys were alive after perfusion in the normothermia group and they had abnormal hippocampal morphology and ultrastructure to different extents. Vimentin expression in the hippocampus was significantly lower in the profound hypothermia group (47.88% +/- 1.66) than the normothermia group (79.51% +/- 1.00; P < 0.01). We conclude that selective cerebral profound hypothermia following 10 min occlusion of the bilateral common carotid arteries was able to downregulate vimentin expression in the hippocampus and protect it from severe cerebral ischemia. PMID- 25730002 TI - CYP4F2 gene single nucleotide polymorphism is associated with ischemic stroke. AB - The objective of this study was to explore the relationship between CYP4F2 gene polymorphism and ischemic stroke (IS) in the Han Chinese population. We performed a case-control study to genotype four single nucleotide polymorphisms (SNPs) (rs2108622, rs3093100, rs3093105, rs3093135) in the CYF4F2 gene. The genotype and haplotype distributions were compared between the case and control groups. We found that the GG genotype of rs2108622 in the CYP4F2 gene was associated with risk of IS (P = 0.023). Haplotype analysis indicated that the GGGT haplotype comprising rs2108622-rs3093100-rs3093105-rs3093135 was associated with IS, which suggests that the GGGT haplotype may be a risk factor for IS (P = 0.012). CYP4F2 gene polymorphism might increase the risk of IS in the Chinese population. PMID- 25730003 TI - Association of the ApoE gene polymorphism and dietary factors with cerebral infarction and circulating lipid concentrations. AB - The aim of this study was to explore the relationship between the ApoE gene polymorphism and dietary factors with stroke and circulating lipid levels in the Chinese population. We selected 580 patients with stroke and 580 age- and gender matched healthy controls, and examined their ApoE polymorphism genotype using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. We also analyzed the relationship between the ApoE gene polymorphism and dietary factors as well as plasma lipid concentrations in this cohort. We detected six ApoE genotypes in the study populations, and determined that the E4 allele was positively associated with cerebral infarction (CI), whereas allele E2 was negatively associated with total cholesterol (TC) and low-density lipoprotein cholesterol levels. The dietary habits of the subjects with descending order of average total TC and triglyceride levels were: subjects addicted to oily food > subjects addicted to sweets > subjects addicted to smoking > subjects addicted to alcohol > subjects following a vegetarian diet (P < 0.05). Our results demonstrated that the ApoE gene polymorphism was associated with a risk for CI in a Chinese population. PMID- 25730004 TI - Effects of VEGF/VEGFR/K-ras signaling pathways on miRNA21 levels in hepatocellular carcinoma tissues in rats. AB - The aim of this study was to investigate the effects of the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)/K-ras signaling pathways on miRNA21 levels in hepatocellular carcinoma tissues in rats. Eighteen male Sprague-Dawley rats were randomly divided into normal control, model, and VEGF blocking agent groups (N = 6/group). The expression of VEGF mRNA, K-ras protein, and miRNA21 increased significantly (P < 0.05) in the model group compared with the normal control group, and decreased dramatically in the VEGF blocking agent group compared to the model group. The expression of VEGFR mRNA in the model group was higher than that of the control group, and the expression of VEGFR mRNA in the VEGF blocking agent group was significantly higher than that of the control group (P < 0.05). Statistically, there was no difference between the expression of VEGFR mRNA for the VEGF blocking agent group and the model group (P > 0.05). Finally, the expression of the miRNA21 gene in the VEGF blocking agent group was higher than in the control group, and there was a significant statistical difference noted; Pearson's correlation analysis demonstrated that the expression of K-ras protein was positively correlated with miRNA21 in the experimental groups (P = 0.001). The above results showed that the VEGF/VEGFR/K-ras signaling pathway might promote the occurrence and development of hepatocellular carcinoma cells through regulating expression of miRNA21, which has potential clinical value for the development of therapies against biological targets and determining prognosis for patients with hepatocellular carcinoma. PMID- 25730006 TI - Allele frequencies of microsatellite loci for genetic characterization of a Sicilian bovine population. AB - Short tandem repeats are used as an effective method to trace DNA markers in genotyping. Using a standardized kit, we tested 11 microsatellite markers recommended by the International Society for Animal Genetics (ISAG) in a sample of 495 Sicilian cattle. The aim of this study was to investigate the allele frequencies in the Sicilian cattle population to provide a reference database and at the same time to assess the use of the ISAG microsatellite panel for pedigree analysis. DNA samples were collected from blood and amplified in an 11-plex polymerase chain reaction (PCR); PCR products were injected in a 3130 Genetic Analyzer. All loci showed high mean polymorphism information content (0.768), and the observed mean heterozygosity was less than the expected value (0.732 vs 0.794, respectively). The exact test for Hardy-Weinberg proportions, allele number, and inbreeding coefficient were calculated. Our results indicated that equilibrium was not always maintained. The observed mean homozygote value exceeded the expected value (132.81 vs 102.14), but no evidence for allele dropout was found. These results could be explained by a non-random mating; further studies using a larger number of animals could confirm or invalidate this hypothesis. The probability of identity and exclusion of a locus were also estimated and proved to be useful in paternity testing. The ISAG microsatellite panel is useful to screen the Sicilian bovine kinship. Currently, an allele frequency database is being constructed. PMID- 25730005 TI - Uneven evolutionary rate of the melatonin-related receptor gene (GPR50) in primates. AB - The melatonin-related receptor GPR50 plays an important role in mammalian adaptive thermogenesis in response to calorie intake. The evolutionary history of the GPR50 gene is poorly understood in primates; however, it has been reported that GPR50 is the mammalian ortholog of Mel1c, which has been well characterized. In this study, the complete coding sequences of the GPR50 gene in the Sichuan snub-nosed monkeys (Rhinopithecus roxellana) and Tibetan macaques (Macaca thibetana) were sequenced, and the orthologous nucleotide acid sequences of the GPR50 gene in 11 other primate species were downloaded from GenBank. Thirteen species representing 6 major primate lineages (human, great ape, lesser ape, Old World monkey, New World monkey, and prosimian monkey) were subjected to statistical analyses. A selective test showed that the entire GPR50 gene sequence is under strong purifying selection in these primates but has a significantly different evolutionary rate among the 6 major primate lineages. Notably, both the Homo and Pan branches exhibited an omega ratio >1, indicating accelerated evolution of the two lineages. Further analysis of different domains revealed that the acceleration trend was more significant in the C-terminal domain (CTD). Interestingly, in the alignment of 13 primate GPR50 nucleotide acid sequences, numerous insertions or deletions were only found in the CTD region, implying that this region may play a key role in the process of primate GPR50 evolution. The results provide deeper insight into the functional evolution of GPR50 in mammals at the molecular level. PMID- 25730007 TI - Association between ERCC1 and XPF polymorphisms and risk of colorectal cancer. AB - We conducted a hospital-based case-control study to evaluate the association between polymorphisms in excision repair cross-complementing group 1-xeroderma pigmentosum group F (ERCC1-XPF) variants and the risk of colorectal cancer in a Chinese population. Genotyping of the ERCC1 rs2298881 and rs11615 and XPF rs2276466 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Colorectal cancer cases were more likely to be smokers, consume alcohol, have higher energy intake, and have a family history of cancer. Using conditional regression analysis, subjects carrying the ERCC1 rs2298881CC genotype and C allele showed a significantly increased risk of colorectal cancer compared with those carrying the AA genotype. However, we found no association between the rs11615 and rs2276466 polymorphisms and the risk of colorectal cancer. In conclusion, the ERCC1 rs2298881 polymorphism may be used as a predictive factor for determining the risk of colorectal cancer in a Chinese population. This finding may be useful for identifying the genetic characteristics of colorectal cancer and developing more efficient strategies for prevention and treatment. PMID- 25730008 TI - Intracellular survival of virulence and low-virulence strains of Vibrio parahaemolyticus in Epinephelus awoara macrophages and peripheral leukocytes. AB - In this study, we examined the virulence factors and pathogenesis of Vibrio parahaemolyticus in Epinephelus awoara. The chemotactic motility of V. parahaemolyticus for phagocytosis and intracellular survival in fish macrophages was determined using virulence strains and low-virulence strains of V. parahaemolyticus. We found that the intracellular mean number of virulence strains of V. parahaemolyticus ranged from 0-180 min after co-incubation with macrophages and peripheral leukocytes, was relatively low, and decreased steadily over the observation period. Low-virulence strains of V. parahaemolyticus were unable to survive in peripheral leukocytes and macrophages. Cell viability in response to V. parahaemolyticus was assessed using the MTT assay. Low-virulence V. parahaemolyticus strains exhibited lower cytotoxicity compared to virulent strains. The average percent of live macrophages and peripheral leukocytes infected by V. parahaemolyticus ranged from 13.50-79.20%. These results indicate that V. parahaemolyticus in E. awoara is a facultative intracellular bacterium that may be involved in virulence. PMID- 25730009 TI - Role of fibroblast growth factor-23 in the pathogenesis of atherosclerosis in peritoneal dialysis patients. AB - Several previous studies have demonstrated that elevated levels of fibroblast growth factor-23 (FGF-23) may be involved in atherosclerosis and contribute to the high mortality rate of peritoneal dialysis (PD) patients. The aim of this study was to determine the precise role of FGF-23 in the pathogenesis of atherosclerosis in PD patients. Between April 2009 and January 2012, 62 PD patients and 25 control subjects were included in the study. An enzyme-linked immunosorbent assay was conducted to test for plasma FGF-23 levels. Carotid artery intima-media thickness (CIMT), left ventricular mass index (LVMI), and myocardial performance index (MPI) were determined by ultrasonography. Plasma Ca(2+), P(3+), calcium-phosphorus product, parathyroid hormone, N-terminal pro brain natriuretic peptide, and cardiac troponin I were also detected. Plasma FGF 23 levels in PD patients were significantly higher than those in control subjects. PD patients with CIMT > 1.0 mm showed the highest levels of FGF-23. Plasma P(3+), calcium-phosphorous product, plasma parathyroid hormone, CIMT, LVMI, and MPI levels were positively associated with plasma FGF-23 levels. Multiple-stepwise regression analyses revealed that plasma P(3+), plasma parathyroid hormone, CIMT, LVMI, and MPI levels were strongly associated with plasma FGF-23 levels. However, no correlations were observed in plasma N-terminal pro-brain natriuretic hormone and cardiac troponin I levels. Plasma FGF- 23 levels may play an important role in the initiation and progression of atherosclerosis. Thus, detecting and defining plasma FGF-23 levels may be a promising biomarker for the early detection of atherosclerosis in PD patients. PMID- 25730010 TI - Comparison of extraction methods of total microbial DNA from freshwater. AB - The demand for molecular analysis of aquatic microbial communities in freshwater has highlighted the need for efficient methods of DNA extraction. The centrifugation method and filtration-membrane method are 2 widely used methods for extracting DNA. The objective of this study was to compare the extraction efficiency of 3 methods, including the centrifugation method, filtration-membrane method, and modified filtration-membrane method, by evaluating the quantity and purity of DNA extracts obtained from water. DNA extraction was analyzed by agarose gel electrophoresis, ultraviolet-spectroscopy, restriction enzyme digestion, and polymerase chain reaction. The results showed that the modified filtration-membrane method was the most efficient for extracting microbial DNA from freshwater with high integrity and purity and is suitable for molecular applications. PMID- 25730011 TI - Differential microRNA expression in signet-ring cell carcinoma compared with tubular adenocarcinoma of human gastric cancer. AB - Gastric cancer is a disease with a heterogeneous pathology; its pathological mechanisms remain unclear because there is a poor understanding of its etiology. In this study, we identified differentially expressed microRNAs (miRNAs) among various gastric cancer subtypes. miRNA microarray analysis and bioinformatic analysis were used to compare miRNA expression between the signet-ring cell carcinoma and tubular adenocarcinoma subtypes of gastric cancer. Thirteen dysregulated miRNAs were identified in signet-ring cell carcinoma compared with tubular adenocarcinoma: miR-30a, miR-26b, miR-381, let-7i, miR-29c, miR-543, miR 499-3p, miR-628-3p, miR-524-5p, miR-181b, miR-1914, miR-663b, and miR-676. This is the first time that miR-499-3p, miR-628-3p, miR-524-5p, and miR-1914 have been identified in gastric cancer tissues. Bioinformatic analysis using target prediction algorithms indicated that these miRNAs are directly involved in gastric cancer pathogenesis and have different pathological mechanisms in various subtypes of signet-ring cell carcinoma and tubular adenocarcinoma. The miRNA expression patterns in different gastric adenocarcinoma subtypes may help discriminate between signet-ring cell and tubular gland cancer or other gastric cancer subtypes that would otherwise be difficult to identify using routine histological and immunohistochemical analyses. These preliminary data should be verified in further prospective studies. PMID- 25730012 TI - Distribution of Candida albicans in the oral cavity of children aged 3-5 years of Uygur and Han nationality and their genotype in caries-active groups. AB - We analyzed the distribution of Candida albicans in the oral cavity of 3-5-year old children of Uygur and Han nationalities as well as their genotypes in caries active groups in the Urumqi municipality. CHROMagar Candida was separately cultivated, and we identified 359 Uygur and Han children aged 3-5 years. We randomly selected 20 Han children and 20 Uygur children for this study. We chose a bacterial strain for polymerase chain reaction (PCR) 25S rDNA genotyping and random amplified polymorphic DNA (RAPD) genotyping. The rate of caries-active in Han children was higher than that in Uygur children, with values of 39.6 and 24.3%, respectively. The detection rate of C. albicans was closely correlated to the caries filling index classification (X(2) = 31.037, P = 0.000, r = 0.421; X(2) = 80.454, P = 0.000, r = 0.497). PCR of 25S rDNA from 40 strains of Han and Uygur children revealed 3 genotypes, while RAPD analysis revealed 5 genotypes. The distribution of 25S rDNA genotyping of Han children from PCR differed from that of Uygur children (X(2) = 7.697, P = 0.021), both of which were mainly the A type. RAPD genotyping of both Han and Uygur children showed similar results (X(2) = 1.573, P = 0.814). There were differences in the distributions of C. albicans in children of different nationalities. C. albicans is a key factor causing caries. The PCR 25S rDNA genotyping method is simple and sensitive, while the RAPD genotyping method is reliable and comprehensive. PMID- 25730013 TI - Isolation of new polymorphic microsatellite markers from the marbled rockfish Sebastiscus marmoratus. AB - The marbled rockfish, Sebastiscus marmoratus, is an important commercially near shore fish that inhabits the beach rocky bottom from Japan to the South China Sea. Eleven polymorphic microsatellite loci were developed from S. marmoratus and were used to identify polymorphisms in 30 samples from a wild population. The allele locus number ranged from 2 to 7. Polymorphism data content ranged from 0.032 to 0.751. The observed and expected heterozygosity levels were 0.0333 0.9667 and 0.0328-0.7675, respectively. Two loci, Smd1-112 and Smd2-80, deviated from Hardy-Weinberg equilibrium. These polymorphic microsatellite markers will facilitate further studies of genetic diversity and genetic differentiation of S. marmoratus. PMID- 25730014 TI - Construction and analysis of a suppression subtractive hybridization library of regeneration-related genes in soybean. AB - The development of a genetic transformation system is needed to address the problem of the low efficiency associated with soybean regeneration. To contribute to the enhancement of the soybean regenerative capacity, we explored the developmental mechanisms of soybean regeneration at the molecular level using a suppression subtractive hybridization cDNA library constructed from cotyledonary nodes of soybean cultivar DN50. A total of 918 positive clones were identified and screened, with most inserted fragments ranging from 100 to 750 bp. Of these, 411 differentially expressed functional expressed sequence tags were identified and annotated based on their similarity to orthologs and paralogs detected in GenBank using the nucleotide and translated nucleotide Basic Local Alignment Search Tools. Functional analysis revealed that the associated genes were involved in signal transduction, synthesis, and metabolism of macromolecules, glucose and protein synthesis and metabolism, light and leaf morphogenesis, regulation of apoptosis, cell defense, cell wall differentiation, and a variety of hormone and cytokinin-mediated signaling pathways. The information uncovered in our study should serve as a foundation for the establishment of an efficient and stable genetic transformation system for soybean regeneration. PMID- 25730015 TI - Genome-wide analysis and identification of KT/HAK/KUP potassium transporter gene family in peach (Prunus persica). AB - The KT/HAK/KUP family members encoding high-affinity potassium (K(+)) transporters mediate K(+) transport across the plasma membranes of plant cells to maintain plant normal growth and metabolic activities. In this paper, we identified 16 potassium transporter genes in the peach (Prunus persica) using the Hidden Markov model scanning strategy and searching the peach genome database. Utilizing the Arabidopsis KT/HAK/KUP family as a reference, phylogenetic analysis indicates that the KT/HAK/KUP family in the peach can be classified into 3 groups. Genomic localization indicated that 16 KT/HAK/KUP family genes were well distributed on 7 scaffolds. Gene structure analysis showed that the KT/HAK/KUP family genes have 6-9 introns. In addition, all of the KT/HAK/KUP family members were hydrophobic proteins; they exhibited similar secondary structure patterns and homologous tertiary structures. Putative cis-elements involved in abiotic stress adaption, Ca(2+) response, light and circadian rhythm regulation, and seed development were observed in the promoters of the KT/HAK/KUP family genes. Subcellular localization prediction indicated that the KT/HAK/KUP members were mainly located in the plasma membrane. Expression levels of the KT/HAK/ KUP family genes were much higher in the fruit and flower than those in the other 7 tissues examined, indicating that the KT/HAK/KUP family genes may have important roles in K(+) uptake and transport, which mainly contribute to flower formation and fruit development in the peach. PMID- 25730016 TI - Retraction. RETRACTION of "ZNF797 plays an oncogenic role in gastric cancer" by D. Momenzadeh, S. Rahman Zadeh, M. Rezaei-Tavirani, A. Baradaran-Rafii, F. Ghasemvand and S. Heidari-Keshel. Genet. Mol. Res. 13 (4): 8421-8427 (2014). AB - The article "ZNF797 plays an oncogenic role in gastric cancer" by D. Momenzadeh, S. Rahman Zadeh, M. Rezaei-Tavirani, A. Baradaran-Rafii, F. Ghasemvand and S. Heidari-Keshel published in Genetics and Molecular Research vol. 13 (4), pp. 8421 8427 in 2014, DOI: http://dx.doi.org/10.4238/2014.October.20.18, has been found to be substantially equal to the article "Role of SALL4 in the progression and metastasis of colorectal cancer" published in the Journal of Biomedical Science, vol. 20, p. 6 in 2013, DOI: 10.1186/1423-0127-20-6, by other authors. The corresponding author of the article published in Genetics and Molecular Research, Saeed Heidari-keshel, alerted our editorial staff about this situation and requested that the article should be retracted. After review and after contacting the authors, the editors of Genetics and Molecular Research have decided to retract the article. The authors and their institutions have been advised of this serious breach of ethics. PMID- 25730017 TI - RETRACTION of "Absolute quantification of free tumor cells in the peripheral blood of gastric cancer patients" by N. Bayat, M.M. Mokhtari, M. Rezaei-Tavirani, A. Baradaran-Rafii, S. Rahman Zadeh, S. Heidari-Keshel and F. Ghasemvand. Genet. Mol. Res. 13 (2): 4425-4432 (2014). AB - The article "Absolute quantification of free tumor cells in the peripheral blood of gastric cancer patients" by N. Bayat, M.M. Mokhtari, M. Rezaei-Tavirani, A. Baradaran-Rafii, S. Rahman Zadeh, S. Heidari-Keshel and F. Ghasemvand published in Genetics and Molecular Research vol. 13 (2), pp. 4425-4432 in 2014, DOI: http://dx.doi.org/10.4238/2014.June.16.1, has been found to be substantially equal to the article "Quantitative analysis of TEM-8 and CEA tumor markers indicating free tumor cells in the peripheral blood of colorectal cancer patients". published in International Journal of Colorectal Disease vol. 26 (10), pp. 1265-1270 in 2011, DOI: 10.1007/s00384-011-1230-8, by other authors. The corresponding author of the article published in Genetics and Molecular Research, Saeed Heidari-keshel, alerted our editorial staff about this situation and requested that the article should be retracted. The results are surprisingly similar, with the number of positive patients being almost the same, for example. After review and after contacting the authors, the editors of Genetics and Molecular Research have decided to retract the article. The authors and their institutions have been advised of this serious breach of ethics. PMID- 25730018 TI - Analysis of prognostic factors for infantile rotavirus infection. AB - In this study, we investigated the prognostic factors of infantile rotavirus (RV) infection. A total of 102 infants with RV enteritis were divided into 2 groups according to the standards of improvement and cure at the time of discharge from the hospital: improvement group (N = 58; 47 males and 11 females with an average age of 15.19 +/- 5.03 months) and the cure group (N = 44; 34 males and 10 females with an average age of 10.02 +/- 4.92 months). Both groups were phlebotomized for the detection of serum glutamic oxaloacetic aminotransferase, creatine kinase-MB, and lactate dehydrogenase. Prognostic factors and clinical data were analyzed by univariate and multivariate logistic analysis. Among the 102 cases of RV infection, 58 were cured and 44 were improved. Univariate analysis showed that the 2 groups were significantly different in age, feeding pattern, concentrations of serum glutamic oxaloacetic aminotransferase, creatine kinase-MB, and lactate dehydrogenase, and central nervous system damage. Logistic regression analysis showed that age, feeding, and central nervous system damage were significant independent prognostic factors for RV enteritis (P < 0.05). There were no statistical differences in gender, course of disease, and respiratory infection (P < 0.05). Both myocardial and hepatic damages presented a temporary feature in the infants and had no significant influence on prognosis. Age, feeding pattern, and central nervous system damage are significant independent prognostic factors for RV infection. These factors should be carefully considered in clinical practice. PMID- 25730019 TI - Association between macrophage migration inhibitory factor rs1007888 and GDM. AB - We investigated the association between macrophage migration inhibitory factor (MIF) rs1007888 single-nucleotide polymorphisms and the genetic susceptibility to gestational diabetes mellitus (GDM). A total of 240 GDM pregnant women (GDM group) and 330 healthy pregnant women (control group) were included in the study. Differences in the MIF rs1007888 genotype and allele frequencies and differences between fasting blood glucose, fasting insulin, homeostatic model assessment (HOMA)-insulin resistance, and HOMA-b levels of pregnant women with different genotypes were compared. MIF genotype distributions were significantly different in the GDM group compared to the control group (P < 0.05). No significant difference was observed in the allele distributions of MIF rs1007888 between the GDM group and control group (P > 0.05). GDM patients had higher fasting blood glucose, fasting insulin, and HOMA-insulin resistance levels, but lower HOMA-b levels than normal gestational women (P < 0.05). Fasting blood glucose, fasting insulin, and HOMA-insulin resistance in pregnant women with the GG genotype were significantly higher than those with GA and AA genotypes, while HOMA-b in pregnant women with the GG genotype was lower (all P < 0.05). Our findings demonstrated the associations among MIF polymorphism rs1007888, insulin resistance, and pancreatic beta cell functions in GDM patients. The GG genotype of MIF rs1007888 may be a genetic susceptibility factor in the pathogenesis of GDM. PMID- 25730020 TI - Genetic variability analysis of Zymomonas mobilis strains from the UFPEDA microorganisms collection. AB - Zymomonas mobilis is a Gram-negative bacterium that has drawn attention in the bioethanol industry. Besides bioethanol, this bacterium also produces other biotechnological products such as levans, which show antitumor activity. Molecular studies involving Z. mobilis have advanced to the point that allows us to characterize interspecies genetic diversity and understand their metabolism, and these data are essential for better utilization of this species. In this study, the genetic diversity of 24 strains from the Microorganisms Collection of Departamento de Antibioticos (UFPEDA) from Universidade Federal de Pernambuco were characterized. The methods used were amplified ribosomal DNA restriction analysis and diversity analysis of the internally transcribed 16S-23S rDNA spacer region (ISR). These analyses revealed low genetic variability of the 16S rDNA gene. These data confirm that these isolates are, or are closely related to, Z. mobilis. Moreover, the analysis of the ISR confirmed the genetic variability of strains deposited in the UFPEDA collection of microorganisms and grouped these strains into ten ribotypes, which can be used in the future for breeding programs and for the preservation of biodiversity. Furthermore, this study characterized the genetic variability between the UFPEDA 205/ ZAP, UFPEDA 98/AG11, and ZAG strains, which were obtained by spheroplast fusion among them. The data also indicate that there is genetic variability among the UFPEDA 202/CP4 and UFPEDA 633/ ZM4 strains, demonstrating that these important Z. mobilis strains are distinct, as suggested in previous studies. PMID- 25730021 TI - Identification of EeSt-genome species in Pseudoroegneria and Elytrigia (Poaceae: Triticeae) by using SCAR markers from ITS sequences. AB - To detect E(e)St-genome species in Pseudoroegneria and Elytrigia, the primers ES45 (5'-GTAGGCGACGGTTTTCA-3') and ES261 (5'-TCGCTACGTTCTTCATC-3') were designed as sequence characterized amplified region markers based on the 6-base pair indel in internal transcribed spacer 1 (ITS1) regions and conserved sites in the 5.8S regions, respectively. Polymerase chain reaction of ITS fragments in 27 Triticeae accessions was used for amplification with a touchdown thermocycling profile. Two amplicons were purified, sequenced, and aligned. The results indicated that: 1) primers ES45 and ES261 generated the expected products, 2) ITS sequences of E(e)St-genome species are characterized by a 6-base pair indel, and 3) 13 taxa in Pseudoroegneria and Elytrigia should be included in Trichopyrum. The primers ES45 and ES261 were useful for detecting ITS fragments with 6-bp indel and are helpful for clarifying taxonomic classifications of EeSt-genome species in Triticeae. PMID- 25730022 TI - Diversity and genetic structure of mangaba remnants in states of northeastern Brazil. AB - In this study, we analyzed the genetic diversity and structure of remnants of mangaba populations in states of northeastern Brazil by applying 9 microsatellite markers previously developed to establish conservation strategies for germplasm and species preservation. Six to 20 individuals per population were analyzed, with a total of 94 individuals and 6 populations from the states of Ceara, Pernambuco, and Sergipe, Brazil. The intra-population positive fixation index (f) in all populations indicated inbreeding resulting from the lack of random mating. The mean genetic diversity index values GST, FST, and RST estimated for divergence among the 6 populations were 0.14 (P < 0.05), revealing moderate genetic differentiation. The smallest FST value (P >= 0.05) was observed between the Jacarecoara and Tapera populations (0.005) and the highest between the Barra dos Coqueiros and Jacarecoara populations (0.287). The Jacarecoara population was the most divergent among the populations analyzed. According to analysis of molecular variance results, the largest variation percentage resulted from variability within populations (83.18%). Bayesian clustering analysis showed the formation of 2 sets (K = 2). Our results are important for developing strategies for in situ conservation of the species, seed collection, and ex situ conservation. For both methods, conservation of the greatest possible genetic variability of the species is essential. PMID- 25730023 TI - 6-Dimethylaminopurine and cyclohexamide are mutagenic and alter reproductive performance and intrauterine development in vivo. AB - The compounds 6-dimethylaminopurine (6-DMAP) and cyclohexamide (CHX) are currently used to stimulate the development of embryos produced by nuclear transfer in the production of cloned mammals with a great deal success. This study investigated the effects of 6-DMAP and CHX in vivo using biological assays to evaluate reproductive performance in females, teratogenesis, and mutagenesis. The results of this study demonstrated that the activating agents of oocyte cytoplasm, 6-DMAP and CHX, altered the reproductive performance of the experimental animals, as well as increased the rate malformations. In addition to these adverse effects, the administration of these compounds in pregnant females resulted in genotoxic and mutagenic toxicity, as determined by comet and micronucleus assays carried out in peripheral blood samples, respectively. Based on these findings and that alterations in DNA are important, morpho-functional teratogenesis and diminished embryonic viability, suggesting that 6-DMAP and CHX, which are utilized during the cloning of mammals, are responsible for the fact that embryos produced by nuclear transfer show low viability after implantation in utero or after birth because of congenital malformations and/or alterations in their DNA. PMID- 25730024 TI - Association between SNPs in genes involved in folate metabolism and preterm birth risk. AB - We investigated the association between 12 single nucleotide polymorphisms (SNPs) in 11 genes involved in folate metabolic and preterm birth. A subset of SNPs selected from 11 genes/loci involved in the folic acid metabolism pathway were subjected to SNaPshot analysis in a case-control study. Twelve SNPs (CBS-C699T, DHFR-c594+59del19, GST01-C428T, MTHFD-G1958A, MTHFR-C677T, MTHFR-A1298C, MTR A2756G, MTRR-A66G, NFE2L2-ins1+C11108T, RFC1-G80A, TCN2-C776G, and TYMS-1494del6) in 503 DNA samples were simultaneously tested, and included 315 preterm births and 188 controls. None of the 12 SNP genotype distributions related to the folic acid metabolism pathway showed a significant difference between preterm and term babies. The frequency of the compound mutation genotype of MTHFD-G1958A, MTR A2756G and RFC1-G80A in preterm babies was 7.3%, which was significantly higher than the 2.7% in term babies. Seven babies carried the compound mutation genotype of MTHFD-G1958A, MTR-A2756G, and CBS-C699T, but this was not observed in term babies. The frequency of the combined wild-type genotype of MTHFD-G1958A, MTR A2756G, MTRR-A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1- G80A in preterm babies was 3.17%, which was significantly lower than the 7.4% in term babies. The 12 SNPs screened in this study were not independent risk factors of preterm birth. Compound mutation genotypes, including MTHFD-G1958A, MTR-A2756G, and RFC1- G80A and MTHFD-G1958A, MTR-A2756G, and CBS-C699T, may increase the risk of preterm birth. The combined wild-type genotype MTHFD-G1958A, MTR-A2756G, MTRR A66G, MTHFR-A1298C, NFE2L2-ins1+C11108T, and RFC1-G80A may decrease the risk of preterm birth. PMID- 25730025 TI - Cohn process influences the functional anticoagulant activity of human protein C. AB - Cohn fraction IV (CFIV) is a byproduct of a plasma fractionation process known as the Cohn process. It is an inexpensive source of protein C, retaining about 90% of protein C (PC) in human plasma. We investigated whether PC is affected during the Cohn process and evaluated correlations among coagulant activity, amidolytic activity and PC antigen during the Cohn process. CFIV was redissolved with citrate-buffered saline for 5 h at 4 degrees C, and then centrifuged at 3500 g for 40 min at 4 degrees C. Functional anticoagulant activity was measured with a one-stage coagulation method based on activated partial thromboplastin time. The functional amidolytic activity of PC was determined using chromogenic substrate assay, and measurement of PC antigen was performed by ELISA. In CFIV, anticoagulant activity declined significantly, with a loss of >80%, while amidolytic activity was not significantly altered, compared to PC antigen. Prior to the Cohn process, high-rank correlations were observed in cryosupernatant, with rs = 0.921 for anticoagulant and amidolytic activities (P = 0.009), 0.896 for anticoagulant activity and antigen (P = 0.014) and 0.832 for amidolytic activity and antigen (P = 0.031). After the Cohn process in CFIV, there was also a high correlation between amidolytic activity and antigen (rs = 0.782, P = 0.038). There were no significant correlations between anticoagulant activity and antigen (rs = 0.223, P = 0.653), or anticoagulant and amidolytic activity (rs = 0.236, P = 0.675). We conclude that the Cohn process significantly influences the anticoagulant activity of PC. Compared to the antigen, PC lost greater than 80% of its anticoagulant activity, but retained its amidolytic activity, during the Cohn process. PMID- 25730026 TI - Expression divergence of FRUITFULL homeologs enhanced pod shatter resistance in Brassica napus. AB - To improve pod shatter resistance in the important oilseed crop Brassica napus, the phenotypic diversity of B. napus was tested using 80 B. napus varieties for pod shatter resistance by a random impact test. Among these varieties, R1-1 was identified as resistant, while R2, 8908B was susceptible to shatter. To understand the molecular basis for this phenotypic difference based on the candidate gene approach, B. napus FRUITFULL (FUL) homologs were identified and characterized. Two FUL loci in the A and C genomes of B. napus were identified. In the susceptible variety, both BnaA.FUL and BnaC.FUL were expressed in the same tissues. However, the expression level of BnaC.FUL differed in varieties with different pod shatter resistance. In the most resistant variety, R1-1, only BnaA.FUL was expressed, while BnaC.FUL was silenced. Therefore, the functional divergence and differing expression of BnaX.FUL homeologs may significantly affect phenotypic variation, which is an important consequence of allopolyploid evolution. This expression level divergence may be useful for selecting pod shatter resistant lines through marker-assisted selection in B. napus-breeding programs. PMID- 25730027 TI - Phylogenetic analysis of widely cultivated Ganoderma in China based on the mitochondrial V4-V6 region of SSU rDNA. AB - Ganoderma mushroom is one of the most prescribed traditional medicines and has been used for centuries, particularly in China, Japan, Korea, and other Asian countries. In this study, different strains of Ganoderma spp and the genetic relationships of the closely related strains were identified and investigated based on the V4-V6 region of mitochondrial small subunit ribosomal DNA of the Ganoderma species. The sizes of the mitochondrial ribosomal DNA regions from different Ganoderma species showed 2 types of sequences, 2.0 or 0.5 kb. A phylogenetic tree was constructed, which revealed a high level of genetic diversity in Ganoderma species. Ganoderma lucidum G05 and G. eupense G09 strains were clustered into a G. resinaceum group. Ganoderma spp G29 and G22 strains were clustered into a G. lucidum group. However, Ganoderma spp G19, G20, and G21 strains were clustered into a single group, the G. lucidum AF214475, G. sinense, G. strum G17, G. strum G36, and G. sinense G10 strains contained an intron and were clustered into other groups. PMID- 25730028 TI - Efficacy of dendritic cell-cytokine-induced killer immunotherapy plus intensity modulated radiation therapy in treating elderly patients with esophageal carcinoma. AB - We investigated the clinical efficacy of adoptive cytokine-induced killer (CIK) cell and dendritic cell (DC) therapy plus intensity-modulated radiation therapy (IMRT) for treating elderly patients with esophageal carcinoma (EC). In total, 68 elderly patients with EC were randomized to receive IMRT plus DC-CIK immunotherapy (study group, N = 34) or IMRT only (control group, N = 34). Clinical efficacy, immune function, toxicity and side effects, and life quality were evaluated after treatment. The efficacy rate was significantly higher in the study group than in the control group. Remarkable increases were noted for quality of life and immune function in the study group relative to the control group. Regarding toxicity and side effects, compared with the control group, the study group displayed a higher fever rate, a lower incidence rate of bone marrow suppression, and a similar rate of digestive tract reactions. DC-CIK immunotherapy plus IMRT exhibited better short-term efficacy than IMRT alone in elderly patients with EC. The therapy could improve patients'quality of life and immune function, decrease bone marrow suppression, and lengthen survival time. PMID- 25730029 TI - Classification of cassava genotypes based on qualitative and quantitative data. AB - We evaluated the genetic variation of cassava accessions based on qualitative (binomial and multicategorical) and quantitative traits (continuous). We characterized 95 accessions obtained from the Cassava Germplasm Bank of Embrapa Mandioca e Fruticultura; we evaluated these accessions for 13 continuous, 10 binary, and 25 multicategorical traits. First, we analyzed the accessions based only on quantitative traits; next, we conducted joint analysis (qualitative and quantitative traits) based on the Ward-MLM method, which performs clustering in two stages. According to the pseudo-F, pseudo-t2, and maximum likelihood criteria, we identified five and four groups based on quantitative trait and joint analysis, respectively. The smaller number of groups identified based on joint analysis may be related to the nature of the data. On the other hand, quantitative data are more subject to environmental effects in the phenotype expression; this results in the absence of genetic differences, thereby contributing to greater differentiation among accessions. For most of the accessions, the maximum probability of classification was >0.90, independent of the trait analyzed, indicating a good fit of the clustering method. Differences in clustering according to the type of data implied that analysis of quantitative and qualitative traits in cassava germplasm might explore different genomic regions. On the other hand, when joint analysis was used, the means and ranges of genetic distances were high, indicating that the Ward-MLM method is very useful for clustering genotypes when there are several phenotypic traits, such as in the case of genetic resources and breeding programs. PMID- 25730030 TI - Interleukin-10 polymorphisms associated with susceptibility to acute myeloid leukemia. AB - We investigated the association between polymorphisms in interleukin-10 (IL-10) 1082G/A (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872) and the risk of acute myeloid leukemia (AML) in a Chinese population. A total of 167 primary AML cases and 328 healthy control subjects were recruited at the First People's Hospital of Yunnan Province between March 2009 and January 2012. The polymorphisms rs1800896, rs1800871, and rs1800872 were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Multivariate regression analyses showed that subjects carrying the rs1800871 CC genotype and C allele had a significantly increased risk of AML, with adjusted odds ratios (95% confidence intervals) of 1.72 (1.01-2.97) and 1.38 (1.04-1.81), respectively. Those carrying the rs1800872 G allele had a slightly increased risk of AML, with an adjusted odds ratio (95% confidence interval) of 1.30 (1.01-1.72). Moreover, genotyping results demonstrated that subjects carrying both the rs1800871 C allele and rs1800872 G allele had a moderately increased risk of AML, indicating that the 2 genotypes had a synergistic effect on AML risk (odds ratio = 2.03, 95% confidence interval = 1.24- 3.15). Our results demonstrated that polymorphisms in rs1800871 and rs1800872 enhance the risk of AML, and these 2 single nucleotide polymorphisms have a synergistic effect on AML risk. PMID- 25730031 TI - Construction of the mammalian expressing vector pEGFP-N1-P53 and its expression successful in chicken fibroblast cells and blastoderm. AB - The enhanced green fluorescent protein (EGFP) pEGFP-N1-P53 eukaryotic expression vector, which contains the human tumor suppressor p53, was constructed and transfected into chicken fibroblast cells and stage-X blastoderm to analyze the transfection efficiency. The complementary DNA of the human p53 gene was cloned by reverse transcription-polymerase chain reaction from human peripheral blood and inserted into the pEGFP-N1 vector by HindIII and BamHI double digestion. The pEGFP-N1-P53 vector was transfected into chicken embryo fibroblasts by Lipofectamine 2000 liposomes, and the transfection efficiency was analyzed by fluorescence microscope after 36 h of transfection. The stage-X blastoderm was also transfected by blastoderm injection using Lipofectamine 2000 liposomes at room temperature after 12-24 h; then hatching occurred until seventh day, and the transfection efficiency was analyzed by fluorescence microscope in the dead embryo. A total of 90 hatching eggs were transfected by the pEGFP-N1-P53 vector, and 20 chicken embryos expressed the reporter gene, which indicated that recombinant pEGFP-N1-P53 could be transfected and expressed in stage-X blastoderm by liposomes. Chicken embryo fibroblasts were transfected and expressed the reporter gene. The pEGFP-N1-P53 vector was constructed successfully and could be transfected and expressed in chicken embryo fibroblasts and stage-X blastoderms efficiently. PMID- 25730032 TI - Cross-reactivity of anti-human cytokine monoclonal antibodies used as a tool to identify novel immunological biomarkers in domestic ruminants. AB - Eleven commercially available PE-labeled anti-human (IL-1-alpha, IL-6, IL-8, TNF alpha, IL-17A, IL-5, IL-10, IL-12 and IL-13) and anti-mouse (IL-10, TNF-alpha) cytokine monoclonal antibodies (mAbs) were tested for cross-reactivity with cattle, goat, and sheep cytokines. Cross-reactivity was assessed by comparative analysis with the standard reactivity of the target species. Our data demonstrated that anti-human IL-1-alpha, IL-6, IL-8, IL-17A and IL-10 mAbs cross react with all ruminant species tested. Anti-human IL-5 mAb showed a strong cross reactivity with cattle and goat IL-5, while anti-human TNF-alpha mAb showed a selective cross-reactivity with goat TNF-alpha. No cross-reactivity with the ruminant cytokines was observed for anti-human IL-12 and IL-13 mAbs or for the two anti-mouse cytokine mAbs tested. The present study demonstrated the cross reactivity of various anti-human cytokine mAbs with cattle, sheep, and goat cytokines, increasing the range of immunological biomarkers for studies in veterinary medicine. PMID- 25730033 TI - Craniocervical decompression with duraplasty and cerebellar tonsillectomy as treatment for Chiari malformation-I complicated with syringomyelia. AB - This study aimed to investigate the therapeutic effects of craniocervical decompression with duraplasty and cerebellar tonsillectomy for the treatment of Chiari malformation-I with syringomyelia (CM I-SM). From January 2005 to December 2011, 127 patients with CM I-SM underwent craniocervical decompression with duraplasty and cerebellar tonsillectomy and the therapeutic effects of these surgeries were evaluated using Tator scores. No patient in this study died or showed disease deterioration after the surgery. Re-examination by magnetic resonance imaging (MRI) showed that the cisterna magna was obviously larger after the operation in all but one patient. Moreover, syringomyelia (SM) was reduced in 76 patients. CM I-SM symptoms disappeared or decreased in 112 patients after following discharge. Follow-up was conducted in 84 of the patients and 79 of these patients exhibited improved symptoms. A second MRI re-examination showed that the cisterna magna was successfully constructed in 44 patients; 42 of these patients showed further eliminated or obviously reduced SM. Craniocervical decompression with duraplasty and cerebellar tonsillectomy achieved favorable therapeutic effects. Thus, craniocervical decompression with duraplasty and cerebellar tonsillectomy is a rational surgical approach with beneficial clinical effects. The proposed approach may have useful applications in the treatment of CM I-SM. PMID- 25730034 TI - Meta-analysis of constitutive QTLs for disease resistance in maize and its synteny conservation in the rice genome. AB - We collected data regarding 340 disease resistance quantitative trait loci (QTLs) from the maize genomic database (MaizeGDB). We constructed an integrated linkage map and analyzed this map by using the BioMercator 2.1 software with IBM2 2008 Neighbors genetic linkage map as a reference. We used a meta-analysis method to identify five "consensus" synthetic resistance QTLs located on maize chromosomes 1, 3, 6, and 10, with map intervals of 5.14, 9.00, 28.50, 1.73, and 33.34 cM, respectively. The gene and marker sequences within the five "consensus" QTLs were downloaded from the MaizeGDB website. We identified eight resistance gene analogs (RGAs), through comparison of these sequences with the resistance genes of other members of Poaceae by using the online BLASTx software. On the basis of comparative mapping between the maize genetic map and the rice physical map, 54 rice and 44 maize resistance genes were projected onto the maize IBM2 2008 Neighbors genetic linkage map by using a synteny conservation approach. Additionally, 15 resistance genes in the "consensus" QTL regions were found in two "consensus" QTLs on chromosomes 3 and 6; these resistance genes included rp3, scmv2, wsm2, RG3, RG16, RG36, RG51, RG53, scmv1, mdm1, RG5, RG8, RG10, RG14, and RG29. Our results provide valuable information for fine-mapping QTL, gene cloning, and molecular breeding for resistance in maize. PMID- 25730035 TI - Development of a novel set of microsatellite markers for Lippia alba (Verbenaceae). AB - Microsatellite primers were developed and optimized for Lippia alba to characterize the L. alba germplasm bank of Universidade de Sao Paulo. A genomic library enabled the design of 9 microsatellite primers. Six of the 9 primers yielded polymorphic products, which defined 2 groups in the bank. The data provide support to characterize germplasm banks, genetic breeding programs for L. alba, and other genetic diversity studies and classifications of species in the genus Lippia. PMID- 25730036 TI - Influence of interleukin-1beta and interleukin-6 gene polymorphisms on the development of acute pancreatitis. AB - We investigated the association between 3 main proinflammatory cytokines [interleukin (IL)-1beta and IL-6] and the risk of acute pancreatitis. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype IL 1beta+3954 C/T (rs1143634) and IL-1beta-511 C/T (rs16944) and IL-6 -174 G/C (rs1800795) and IL-6 -634 C/G (rs1800796). The genotype distributions of IL 1beta+3954 C/T (rs1143634) and IL-1beta-511 C/T (rs16944) and IL-6 -174 G/C (rs1800795) and IL-6 -634 C/G (rs1800796) were in Hardy-Weinberg equilibrium for the control group. Multivariate regression analyses showed that subjects carrying the rs1143634 TT genotype had a significantly increased risk of acute pancreatitis, with an adjusted odds ratio (95% confidence interval) of 2.11 (1.03 4.51). Subjects carrying the IL-1beta rs1143634 TT genotype had a significantly increased risk of acute pancreatitis in our Chinese population. PMID- 25730037 TI - Relationship between vitamin D (1,25-dihydroxyvitamin D3) receptor gene polymorphisms and primary biliary cirrhosis risk: a meta-analysis. AB - The vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene encodes a protein that functions in the transcriptional regulation of vitamin D-responsive genes and plays a role in innate immunity and adaptive immune responses. In this study, we investigated the relationship between VDR polymorphisms (BsmI, ApaI, and TaqI) and primary biliary cirrhosis (PBC) risk. We conducted an overall meta-analysis and subgroup meta-analysis based on ethnicity that included a total of 6 eligible studies (672 cases and 1148 controls). We detected no significant PBC risk variation for all genetic models in the overall analysis and in the subgroup analysis based on ethnicity for the BsmI polymorphism. For the ApaI polymorphism, significant associations were observed in the overall analysis as well as in the Asian subgroup. Furthermore, in the subgroup analysis based on ethnicity, a significant association was observed in the Caucasian subgroup but not in the Asian subgroup for the TaqI polymorphism. Based on the results of our meta analysis, the VDR BsmI polymorphism may not be associated with PBC risk, while the VDR ApaI polymorphism is likely associated with PBC risk, particularly in Asians. The VDR TaqI polymorphism may be associated with PBC risk in Caucasians. PMID- 25730038 TI - Association between V4 polymorphism in the ADAM33 gene and asthma risk: a meta analysis. AB - In this study, we evaluated the associations between the V4 (rs2787094 G>C) polymorphism in a disintegrin and metalloproteinase domain 33 (ADAM33) gene and asthma risk. We searched Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 2013, without language restrictions. Meta-analysis was performed using the STATA 12.0 software. Crude odds ratios and 95% confidence intervals were calculated. Eight case-control studies were included, with a total of 2128 asthma patients and 3134 healthy controls. Our results suggest that the ADAM33 V4 polymorphism increases the risk of asthma. Subgroup analysis according to the source of controls revealed significant associations between the ADAM33 V4 polymorphism and risk of asthma in population- and hospital-based subgroups under allele and dominant models (all P < 0.05). Further subgroup analysis using the genotyping method suggested that the ADAM33 V4 polymorphism is correlated with asthma risk in the polymerase chain reaction-restriction fragment length polymorphism subgroup. However, no association was found in the non-polymerase chain reaction-restriction fragment length polymorphism subgroup. Meta-regression analyses showed that the genotyping method may be a main source of heterogeneity (P = 0.003). Our meta-analysis suggests that the ADAM33 V4 polymorphism contributes to the risk of asthma and may be utilized as a biomarker for the early diagnosis of asthma. PMID- 25730039 TI - Decreased MEFV gene expression in rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and an autoimmune disease of unknown etiology in which the inflammatory pathology involves T cell activation. Genetic mutations in the Mediterranean fever (MEFV) gene, encoding pyrin, influence the severity of RA, but the underlying mechanisms are not completely understood. In this study, we investigated whether the full-length MEFV gene (MEFV-fl) and the exon 2-deleted splice isoform (MEFV-d2) expression are associated with or responsible for the clinical conditions of RA. This study include 47 patients with RA and 47 age- and gender-matched healthy controls. Quantitative real-time polymerase chain reaction analysis was performed to examine transcriptional changes in MEFV gene expression from peripheral blood samples. Reverse transcription-polymerase chain reaction of peripheral blood cells revealed the downregulation of MEFV-fl mRNA in non-treated patients compared with healthy controls and treated patients. MEFV-d2 expression was not different between groups. This is the first study to investigate the expression of MEFV transcript in RA. Deregulation of the MEFV gene is likely to result in uncontrolled inflammation as observed in RA. Therefore, downregulation of MEFV-fl may be involved in the pathogenesis of early-stage RA and treatment and may ameliorate MEFV-fl expression. PMID- 25730040 TI - MYH9 gene polymorphisms may be associated with cerebrovascular blood flow in patients with type 2 diabetes. AB - Genetic factors play an important role in type 2 diabetes (T2D) complications. Alteration of cerebrovascular blood flow (CBF) is a direct result of cerebrovascular diseases. However, few studies have reported the role of genetics on CBF in patients with T2D. We investigated whether single-nucleotide polymorphisms (SNPs) in metabolic disease genes are associated with CBF in patients with T2D. CBF velocities of CBF were measured in 337 Han Chinese patients with T2D using transcranial Doppler sonography, with 54 cerebrovascular blood flow parameters documented. Fifty-two SNPs from 31 metabolic disease candidate genes were genotyped in patients. Quantitative allelic association and haplotype analyses were performed for candidate gene SNPs and CBF phenotypes. Spearman correlation was used to determine the relationship between CBF parameters and basic clinical characteristics, particularly, body mass index, lipids, fibrinogen, and GHbA1c. MYH9 gene SNPs (rs875726 and rs735853) may be associated with the peak velocity of the right-middle cerebral artery. SNPs rs875726, rs2009930, and rs375246 of the MYH9 gene may be associated with the mean velocity of the right-anterior and posterior cerebral artery. The haplotype G-C-A (rs2239782-rs3752462- rs2269532) of MYH9 may be associated with CBF. MYH9 gene polymorphisms may be associated with multiple CBF phenotypes in Chinese patients with T2D. However, whether MYH9 is a candidate gene for cerebrovascular diseases in Chinese patients with T2D remains unknown. PMID- 25730041 TI - Association of PS1 1/2, ACE I/D, and LRP C/T polymorphisms with Alzheimer's disease in the Chinese population: a meta-analysis of case-control studies. AB - The objective of this study was to assess the associations of presenilin 1 (PS1) 1/2, angiotensin I-converting enzyme (ACE) insertion/deletion (I/D), and low density lipoprotein receptor-related protein (LRP) C/T polymorphisms with the risk of Alzheimer's disease (AD) in the Chinese population. PS1 1/2, ACE I/D, and LRP C/T, which are commonly investigated polymorphisms, were evaluated to obtain summary estimates regarding their associations with AD. In total, the data from 24 studies (2611 patients with AD and 2822 control subjects from 23 provinces and special districts in China) that were obtained from the Chinese Biomedicine Database, China National Knowledge Infrastructure, PubMed, and Medline were included. Different models (i.e., dominant, recessive, etc.) of these polymorphisms were analyzed using the Cochrane Review Manager. Statistically significant associations among patients with AD for the 1/1 genotype of the PS1 1/2 polymorphism [odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.03 3.04; P = 0.04] and the I/I genotype of the ACE I/D polymorphism (OR = 2.44, 95%CI = 1.78-3.35; P < 0.01) were identified. Statistically significant associations were also found for the PS1 1/2 polymorphism in both the dominant and recessive genetic models, whereas no association was found for the LRP C/T polymorphism. All studies exhibited heterogeneity (P < 0.05). This meta-analysis suggests that the 1/1 genotype of the PS1 1/2 polymorphism and the I/I genotype of the ACE I/D polymorphism are significantly associated with an increased risk of AD in the Chinese population. PMID- 25730042 TI - DNA sequence polymorphism within the bovine adenosine monophosphate deaminase 1 (AMPD1) is associated with production traits in Chinese cattle. AB - The objectives of the present study were to detect an 18-bp deletion mutation in the bovine adenosine monophosphate deaminase 1 (AMPD1) gene and analyze its effect on growth traits in 2 Chinese cattle breeds using DNA sequencing and agarose electrophoresis. The five 19-bp polymerase chain reaction products of the AMPD1 gene exhibited 3 genotypes and 2 alleles: WW: homozygote genotype (wild type); DD: homozygote genotype (mutant-type); WD: heterozygote genotype. Frequencies of the W allele varied from 66.15-70.35%. The associations between the 18-bp deletion mutation in the AMPD1 gene with production traits in 226 Jia Xian red cattle was analyzed. The animals with genotype WW showed significantly higher heart girth and body weight than those with genotypes WD and DD at 24 months (P < 0.01). Our results indicate that the deletion mutation in the AMPD1 gene is associated with production traits, and may be used for marker-assisted selection in beef cattle breeding programs. PMID- 25730043 TI - Genetic diversity and taxonomic status of Pinus tabulaeformis f. shekanensis revealed by ISSR markers. AB - Pinus tabulaeformis f. shekanensis is a rare taxon endemic in the Ziwuling Loess Plateau, of which only one population is known. Inter-simple sequence repeat molecular markers were employed to compare the taxon's genetic diversity with its 4 nearest wild relatives (P. tabulaeformis, P. tabulaeformis var. mukdensis, P. massoniana, and P. henryi) to assess the taxonomic status of P. tabulaeformis f. shekanensis. Inter-simple sequence repeat marker data revealed higher genetic diversity in the P. tabulaeformis f. shekanensis population than in the other populations. Population genetic analysis (neighbor-joining cluster analysis, principal coordinate analysis, and structure clustering) revealed that P. tabulaeformis f. shekanensis and P. tabulaeformis are likely conspecific (the former may be a variety of the latter). Strategies are also proposed for the conservation of P. tabulaeformis f. shekanensis. PMID- 25730044 TI - Quantitative real-time polymerase chain reaction as an efficient molecular tool for detecting minimal residual disease in Moroccan chronic myeloid leukemia patients. AB - Chronic myeloid leukemia (CML) is characterized by BCR-ABL translocation and an increased number and migration of immature myeloid cells into the peripheral blood. The detection limit of the BCR-ABL transcript, particularly after treatment, is controversial. In the present study, we used quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) to monitor BCR-ABL expression in Moroccan CML patients undergoing imatinib treatment, and compared the results with those of conventional PCR and fluorescence in situ hybridization (FISH). The aim of this study was to establish a new molecular tool for in vitro diagnosis of CML. In a retrospective comparative analysis, 20 CML Moroccan patients who had received imatinib treatment (N = 20) were analyzed by real-time PCR, conventional RT-PCR, and FISH. Half of the samples analyzed (N = 10) were positive for BCR-ABL gene expression, while the other half (N = 10) were negative according to conventional PCR. Interestingly, 5 of the 10 samples shown to be negative by conventional PCR showed positive expression of the BCR-ABL gene according to RT-qPCR. The RT-qPCR results were confirmed by FISH, which revealed a high concordance (100%) rate. We found that real-time RT-qPCR is more reliable and should be used in Moroccan biomedical analysis laboratories to monitor CML progression, particularly for minimal residual disease, following imatinib treatment. PMID- 25730045 TI - Effect of curcumin on the proliferation, apoptosis, migration, and invasion of human melanoma A375 cells. AB - Malignant melanoma is a melanocytic tumor with a high potential of invasion and metastasis. Curcumin is extracted from Curcuma longa L.; curcumin has anti-tumor efficacy in multiple systemic malignancies. Here, we investigated the effect of curcumin on A375 human melanoma cells. A375 cells were cultivated, passaged, and treated with different concentrations of curcumin. We observed the cellular morphology and determined the migration, invasion, proliferation, and apoptosis of A375 cells in vitro. Our results showed that curcumin induced a significant change in the morphology of A375 cells. Compared to the control group, the groups treated with curcumin showed significantly wider scratches, and the number of A375 cells significantly decreased in the 12.5, 25, and 50 mM curcumin groups (P < 0.05 or < 0.01). The rates of proliferation inhibition in the 5 curcumin groups were 19.38 +/- 3.57%, 35.56 +/- 4.37%, 63.98 +/- 5.95%, 86.38 +/- 3.91%, and 95.56 +/- 3.15%. The half-maximal inhibitory concentration of curcumin at 48 h was 10.05 mM. The rates of apoptosis in 6.25 and 12.5 mM curcumin groups were significantly higher (P < 0.05), phosphorylation levels of JAK-2 and STAT-3 in 10 and 20 mM curcumin groups were significantly lower (P < 0.05), and Bcl-2 protein expression in 1, 2.5, 5, 10, and 20 curcumin groups was significantly lower (P < 0.05) than that in the control group. In conclusion, curcumin has antiproliferative and proapoptotic activities on A375 cells, the mechanism of which may be related to the inhibition of JAK-2/STAT-3 signaling pathway. PMID- 25730046 TI - Chest wall recurrence location and the lower-bound target of preventive radiotherapy after transverse incision in modified radical mastectomy. AB - We investigated the relationship between the lower-bound target of preventive radiation to the chest wall after modified radical mastectomy with a transverse incision and preoperative breast carcinoma characteristics to provide a basis for reducing radiation injury to neighboring tissues and individualizing preventive chest wall radiation targets. We analyzed the relationship between clinical stage, pathology, diseased region, condition of vessel tumor embolus, sex hormone levels, HER-2 expression levels, receipt of chemotherapy, and the distance of local chest wall recurrence under the edge of the transverse incision in 112 patients with local chest wall recurrence after radical mastectomy. There were 64 cases (57.1%) with local chest wall recurrence within 3 cm below the transverse incision fringe, 31 cases (27.7%) within 3-5 cm, 14 cases (12.5%) within 5-7 cm, and 3 cases (2.7%) exceeded 7 cm. There were statistically significant correlations between the distance from the focus of the chest wall recurrence to the inferior margin of the transverse incision and the T stage, HER-2 expression levels, and receipt of chemotherapy. For more than 97% of patients undergoing radical mastectomy with a transverse incision, the distance of local chest wall recurrence under the edge of the transverse incision was less than 7 cm. To accomplish individualized treatment in defining radiotherapy targets, we should pay attention to T stage, HER- 2 expression levels, and the receipt of chemotherapy when determining the lower-bound location of the target for preventive chest wall radiation after modified radical mastectomy with a transverse incision. PMID- 25730047 TI - Association between the CYP1A1 polymorphisms and hepatocellular carcinoma: a meta analysis. AB - Numerous studies have evaluated the association between CYP1A1 gene polymorphisms and hepatocellular carcinoma (HCC) risk. However, the specific association is still controversial. The aim of our study was to clarify the effects of CYP1A1 gene polymorphisms (3801 T>C and A2455G) on HCC risk by conducting a meta analysis. We conducted searches of the literature published in PubMed and EMBASE databases up to April 2014. We estimated the pooled odds ratio with its 95% confidence interval to assess the association using a fixed or random-effects model. Publication bias was investigated by the Begg funnel plot. Meta-analysis was performed using the STATA package version 12.0. Meta-analysis results showed no significant association between the CYP1A1 3801 T>C polymorphism and HCC risk. In a subgroup analysis by nationality, we found a significant association between 3801 T>C polymorphism and HCC risk in Asians (TT vs TC: OR = 0.77, 95%CI = 0.60 0.99). As for A2455G, the meta-analysis indicated no significant association between the CYP1A1 A2455G polymorphism and HCC risk. In conclusion, the 3801 T>C polymorphism in the CYP1A1 gene may be related to increased risk of HCC in Asians. Conclusive evidence on the effects of the variants in HCC should be addressed in further studies. PMID- 25730048 TI - Transcriptome analysis of skeletal muscle at prenatal stages in Polled Dorset versus Small-tailed Han sheep. AB - The objectives of the present study were to identify additional genes that may play important roles in the regulation of skeletal muscle growth and development, and to provide fundamental information for understanding the underlying molecular mechanisms. Eighteen cDNA libraries were constructed from the longissimus muscle of Polled Dorset (PD) and Small-tailed Han (SH) fetuses. To reveal the differences between the two species, we analyzed the differences in gene expression in 60-, 90- and 120-day fetal skeletal muscle by applying Agilent ovine genome-wide microarray. In this study, we obtained 17,704 genes using a chip containing 39,242 probes. There were 88 differentially expressed genes in the 60-day group (P < 0.05), 128 genes in the 90-day group (P < 0.05), and 340 genes in the 120-day group (P < 0.05) between the two breeds. The differentially expressed genes were grouped in different GO categories and signaling pathways. These results suggested that there are many genetic differences in the muscle growth and development transcriptomes between these two breeds. This study laid the foundation for future genomic research in sheep. PMID- 25730049 TI - Expression and genomic integration of transgenes after Agrobacterium-mediated transformation of mature barley embryos. AB - Mature embryos in tissue cultures are advantageous because of their abundance and rapid germination, which reduces genomic instability problems. In this study, 2 day-old isolated mature barley embryos were infected with 2 Agrobacterium hypervirulent strains (AGL1 and EHA105), followed by a 3-day period of co cultivation in the presence of L-cystein amino acid. Chimeric expression of the b glucuronidase gene (gusA) directed by a viral promoter of strawberry vein banding virus was observed in coleoptile epidermal cells and seminal roots in 5-day-old germinated seedlings. In addition to varying infectivity patterns in different strains, there was a higher ratio of transient b-glucuronidase expression in developing coleoptiles than in embryonic roots, indicating the high competency of shoot apical meristem cells in the mature embryo. A total of 548 explants were transformed and 156 plants developed to maturity on G418 media after 18-25 days. We detected transgenes in 74% of the screened plant leaves by polymerase chain reaction, and 49% of these expressed neomycin phosphotransferase II gene following AGL1 transformation. Ten randomly selected T0 transformants were analyzed using thermal asymmetric interlaced polymerase chain reaction and 24 fragments ranged between 200-600 base pairs were sequenced. Three of the sequences flanked with transferred-DNA showed high similarity to coding regions of the barley genome, including alpha tubulin5, homeobox 1, and mitochondrial 16S genes. We observed 70-200-base pair filler sequences only in the coding regions of barley in this study. PMID- 25730050 TI - Diploid chromosome set of kissing bug Triatoma baratai (Hemiptera, Triatominae). AB - Triatomines are insects that are taxonomically included in the Hemiptera order and Triatominae subfamily. Based on phenotypic similarity, capacity hybridization, and genetic and ecological aspects, the triatomine species can be grouped into specific complexes and subcomplexes. However, these groupings have not been confirmed. Cytogenetic analyses are important cytotaxonomic tools for improving the taxonomic knowledge of triatomines. Thus, we examined the karyotype of Triatoma baratai and compared the results with those of other species in the Matogrossensis subcomplex in order increase the understanding of vector potential. We also examined the cytotaxonomic classification of this insect. Triatoma baratai, similarly to other species that currently compose the Matogrossensis subcomplex, contains 22 chromosomes (20A + XY). Here, we describe the diploid chromosome set of T. baratai. We confirmed their current classification in the Matogrossensis subcomplex and demonstrated that the species in this subcomplex present karyotype homogeneity. PMID- 25730051 TI - Identification of BPI protein produced in different expression system and its association with Escherichia coli F18 susceptibility. AB - The super antibiotic bactericidal/permeability-increasing (BPI) protein is a member of a new generation of proteins that have been implicated as endotoxin neutralizing agents. In this study, recombinant porcine BPI protein was obtained by generating porcine BPI encoding prokaryotic, eukaryotic, and yeast expression vectors. Recombinant protein expression was detected in yeast GS115, Escherichia coli, and 293-6E cells by gel electrophoresis and Western blotting. Escherichia coli F18 is the primary Gram-negative bacteria in the gut and the main pathogen leading to diarrhea and edema dis-ease in weaning piglets. Therefore, E. coli F18 resistant and -sensitive Sutai piglets were used to test differential expression of BPI protein by Western blotting and to investigate the potential correlation between BPI protein expression and E. coli F18-susceptibility. Recombinant porcine BPI protein expression was not detected in the prokaryotic and yeast expression systems; however, soluble protein was detected in the eukaryotic expression system. These data indicate the strong bacterio-static action of the BPI protein and confirm the feasibility of obtaining large amounts of recombinant porcine BPI recombinant protein using this eukaryotic expression system. In addition, the BPI protein expres-sion levels in the E. coli F18-resistant group were significantly higher than those in the sensitive group, indicating that high BPI protein ex-pression is associated with resistance to E. coli F18. Our findings pro-vide a basis for further investigations into the development of a drug designed to confer resistance to E. coli F18 in weaning piglets. PMID- 25730052 TI - Identification of QTLs of resistance to white mold in common bean from multiple markers by using Bayesian analysis. AB - In this study, we identified simple sequence repeat, ampli-fied fragment length polymorphism, and sequence-related amplified poly-morphism markers linked to quantitative trait loci (QTLs) for resistance to white mold disease in common bean progenies derived from a cross between lines CNFC 9506 and RP-2, evaluated using the oxalic acid test and using Bayesian analysis. DNA was extracted from 186 F2 plants and their parental lines for molecular analysis. Fifteen experiments were car-ried out for phenotypic analysis, which included 186 F2:4 progenies, the F1 generation, the F2 generation, and the lines CNFC 9506, RP-2, and G122 as common treatments. A completely randomized experimental design with 3 replications was used in controlled environments. The adjusted means for the F2:4 generation were to identify QTLs by Bayesian shrink-age analysis. Significant differences were observed among the progenies for the reaction to white mold. The moving away method under the Bayes-ian approach was effective for identifying QTLs when it was not possible to obtain a genetic map because of low marker density. Using the Wald test, 25 markers identified QTLs for resistance to white mold, as well as 16 simple sequence repeats, 7 amplified fragment length polymorphisms, and 2 sequence-related amplified polymorphisms. The markers BM184, BM211, and PV-gaat001 showed low distances from QTLs related white mold resistance. In addition, these markers showed, signal effects with increasing resistance to white mold and high heritability in the analysis with oxalic acid, and thus, are promising for marker-assisted selection. PMID- 25730053 TI - Evaluation of concentrations of botulinum toxin A for the treatment of hemifacial spasm: a randomized double-blind crossover trial. AB - The aim of our study was to evaluate the efficacy and safety of two concentrations of botulinum toxin A (BTX-A) for the treatment of hemifacial spasm. We randomly divided 20 patients with hemifacial spasm into high- and low concentration groups; they were administered 50 and 25 U/mL BTX-A injection, respectively. Further, we compared the curative effects and the occurrence of adverse reactions in the two groups. Our results showed that both the concentrations of BTX-A were effective and no significant difference was observed in the onset time and therapeutic efficacy between the two groups; however, the duration of efficacy was longer in the high-concentration group than in the low concentration group. Patients in both groups had no allergic reactions and systemic toxic reactions, but those in the high-concentration group had more serious adverse reactions and they lasted for longer durations. The adverse reactions in the two groups were not specifically treated, and they resolved in a relatively short time. In conclusion, local injection of BTX-A was effective in treating hemifacial spasm and each concentration of BTX-A had advantages and disadvantages, which indicated that the concentration of BTX-A can be selected according to the clinical characteristics and willingness of the patients. PMID- 25730054 TI - Early diagnosis of a Mexican variant of Papaya meleira virus (PMeV-Mx) by RT-PCR. AB - Papaya meleira disease was identified in Brazil in the 1980s. The disease is caused by a double-stranded RNA virus known as Papaya meleira virus (PMeV), which has also been recently reported in Mexico. However, previously reported PMeV primers failed to diagnose the Mexican form of the disease. A genomic approach was used to identify sequences of the Mexican virus isolate, referred here to as PMeV-Mx, to develop a diagnostic method. A mini cDNA library was generated using total RNA from the latex of fruits; this RNA was also sequenced using the Illumina platform. Sequences corresponding to the previously reported 669-base pair sequence for PMeV from Brazil (PMeV-Br) were identified within the PMeV-Mx genome, exhibiting 79-92% identity with PMeV-Br. In addition, a new sequence of 1154-base pairs encoding a putative RNA-dependent RNA polymerase was identified in PMeV-Mx. Primers designed against this sequence detected both virus isolates, 2 amplicons of 173 and 491 base pairs from PMeV-Br and PMeV-Mx, and shared 100 and 98% identity, respectively. PMeV-Mx was found in the latex of fruits, in seedlings, and in the leaves, flowers, petioles, and seeds of mature plants. PMeV Mx was more abundant in the latex of fruits than in the leaves. The limit of detection of the CB38/CB39 primer pair was 1 fg and 1 pg using total RNA extracted from the latex of fruits and from seedlings, respectively. A sensitive and early diagnosis protocol was developed; this method will enable the certification of seeds and seedlings prior to transplantation to the field. PMID- 25730055 TI - Association of the FABP2 Ala54Thr polymorphism with type 2 diabetes, obesity, and metabolic syndrome: a population-based case-control study and a systematic meta analysis. AB - Previous studies have reported associations between the functional FABP2 Ala54Thr (rs1799883) polymorphism and type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome in different populations with conflicting results. We investigated the association between the FABP2 Ala54Thr polymorphism and T2DM (235 cases, 431 controls), obesity (377 cases, 431 controls), and metabolic syndrome (315 cases, 323 controls) by logistic regression analysis in a Chinese study cohort recruited from Yichang, Hubei Province. We then comprehensively reviewed the association of the FABP2 Ala54Thr polymorphism with T2DM, obesity, and metabolic syndrome via meta-analysis. The strength of association was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). The FABP2 Ala54Thr polymorphism was significantly associated with obesity (AT vs AA: OR = 2.633, 95%CI = 1.065-6.663, P = 0.036; TT vs AA: OR = 4.160, 95%CI = 1.609 10.757, P = 0.003) and metabolic syndrome (TT vs AA: OR = 2.273, 95%CI = 1.242 4.156, P = 0.008) by logistic regression with adjustment for covariates. However, no significant association was found between T2DM and the FABP2 Ala54Thr polymorphism. We identified 24 studies on T2DM (4517 cases, 5224 controls), 9 studies on obesity (949 cases, 2002 controls), and 6 studies on metabolic syndrome (2194 cases, 3282 controls) by literature search. The meta-analyses revealed significant associations for metabolic syndrome (T allele: OR = 1.179, 95%CI = 1.015-1.362, P = 0.031) and T2DM (T allele: OR = 1.160, 95%CI = 1.08 1.24, P < 0.001), but no association for obesity (T allele: OR = 1.069, 95%CI = 0.925-1.235, P = 0.367). PMID- 25730056 TI - Differential expression of interleukin-12 p35 and p40 subunits in response to Aeromonas hydrophila and Aquareovirus infection in grass carp, Ctenopharyngodon idella. AB - The grass carp (Ctenopharyngodon idella) aquaculture industry in Asia is prone to bacterial and viral hemorrhagic diseases. Effective adjuvants for vaccine formulation are the need of the hour for control of these diseases and long-term sustainability of grass carp farming. In this study, the involvement of interleukin-12 (IL-12) from grass carp (gcIL-12) in anti-bacterial and anti-viral immune responses was demonstrated via expression profiles of gcIL-12 subunits in immune tissues of the fish, following infection by Aeromonas hydrophila and Aquareovirus. Additionally, cDNA of the gcIL-12 subunits, p35 and p40 was cloned and characterized. We found that most of the structurally and functionally important features of vertebrate orthologues were conserved in gcIL-12 subunits, p35 and p40, with some features specific to grass carp. High levels of gcIL-12 p35 expression in the brain and gills suggest that IL-12 plays an important role in neural and immune systems. High expression levels in the heart, blood, and immune-related tissues suggest an important role in circulation and the immune system as well. Infections by both, A. hydrophila and Aquareovirus stimulated the mRNA expression of gcIL-12 subunits, p35 and p40 in most immune tissues. Significant upregulation or downregulation of gcIL-12 subunits, p35 and p40 by bacterial and viral infection confirms their potential role in anti-bacterial and anti-viral immune responses in fish. PMID- 25730057 TI - Variability and inbreeding in semiexotic maize populations. AB - Three semiexotic populations (CRE-01, CRE-02, CRE-03) obtained by incorporation of exotic germplasm (lines from CIMMYT, Colombia; selected for resistance to corn stunt complex) were evaluated in two cycles of recurrent selection with half-sib families. In cycle-I, samples comprising 50, 70, and 50 half-sib families were evaluated at Jatai (GO) and traits analyzed were ear yield, plant height, and ear height. For yield (t/ha), populations means were 5.86, 6.19, and 5.31, representing approximately 73% of hybrid check. Sets of parameters estimates representing the three populations were: [237, 485, and 608] for the additive genetic variance (sigma(2)A: g/plant); [0.393, 0.584, 0.658] for the coefficient of heritability (h(2)m: progeny mean basis), and [0.464, 0.684, and 0.801] for the index of variation (theta). In cycle-II, materials analyzed included 60 non inbred (half-sib) and 60 inbred (S1) families from each population, evaluated at Anhembi (SP) with two replications; traits analyzed included ear yield plus ear weight and grains weight of four ears, two plant traits (plant height and ear height), two ear traits (length and diameter), two tassel traits (branch number and length), and resistance to corn stunt complex. Means of half-sib families for ear yield (t/ha) were [10.614, 10.419, 10.842], representing 83 to 86% of the hybrid check. The same pattern of variation was observed for ear weight and grain weight of four ears. Means of S1 families were [6.465, 5.527, 5.925] and the inbreeding depression in percent of the non-inbred families were [39.1, 46.9, 45.3]. Estimates for other traits are also shown. PMID- 25730058 TI - Analysis of agouti signaling protein (ASIP) gene polymorphisms and association with coat color in Tibetan sheep (Ovis aries). AB - Tibetan sheep, an indigenous breed, have a wide variety of phenotypes and a colorful coat, which make this breed an interesting model for evaluating the effects of coat-color gene mutations on this phenotypic trait. The agouti signaling protein (ASIP) gene is a positional candidate gene, as was inferred based on previous study. In our research, ASIP gene copy numbers in genomic DNA were detected using a novel approach, and the exon 2 g.100-104 mutation and copy number variation (CNV) of ASIP were associated with coat color in 256 sheep collected from eight populations with different coat colors by high-resolution melting curve assay. We found that the relative copy numbers of ASIP ranged from one to eight in Tibetan sheep. All of the g.100-104 genotypes in the populations were in Hardy-Weinberg equilibrium, and there was no relationship between the g.100-104 genotype and coat color (P > 0.05). The single ASIP CNV allele was found to be almost entirely associated with solid-black coat color; however, not all solid-black sheep displayed the putative single ASIP CNV genotype. From our study, we speculate that the ASIP CNV is under great selective pressure and the single ASIP CNV allows selection for black coat color in Tibetan sheep, but this does not explain all black phenotypes in Tibetan sheep. PMID- 25730059 TI - Microsatellite marker analysis reveals the distinction between the north and south groups of hard clam (Meretrix meretrix) in China. AB - Meretrix meretrix is one of the important commercial bivalves in China. A total of 198 individual clams were collected from 5 locations characteristic of the clam's 5 main natural habitats in China, that is, Shandong, Jiangsu, Fujian, Guangdong, and Guangxi. Ten polymorphic microsatellite markers were selected to examine the genetic diversity and identify genetic differences between the 5 populations. A total of 183 alleles across 10 loci were detected in the individual clams. The observed heterozygosity and expected heterozygosity ranged from 0.197 to 0.7026 and from 0.6264 to 0.9408, respectively. The genetic diversity within samples was high (8.6-11.2 alleles per locus, observed heterozygosity = 0.25-0.875 and expected heterozygosity = 0.6848-0.9259). Most of the genotype distributions significantly deviated from Hardy-Weinberg equilibrium. Genetic structure analysis showed that the 5 populations could be divided into 2 groups, the north and south groups. Neighbor-joining analysis revealed a clear distinction between the north group (Shandong and Jiangsu) and the south group (Fujian, Guangdong, and Guangxi). Locus MM1031 was used to distinguish between groups. Our results can be used for population identification and crossbreeding of M. meretrix. PMID- 25730060 TI - Confined housing system increased abdominal and subcutaneous fat deposition and gene expressions of carbohydrate response element-binding protein and sterol regulatory element-binding protein 1 in chicken. AB - Free-range production system is increasingly being used in poultry breeding and feed production in many countries. The objective of the current experiment was to evaluate the effects of different raising systems on fat-related traits and mRNA levels of liver lipogenesis genes in Erlang Mountainous chicken. Each of 10 birds (91 day old) from caged, indoor-floor housed, and free-range housing systems was slaughtered, and fat-related traits, live body weight (BW), subcutaneous fat thickness (SFT), abdominal fat weight (AFW), abdominal fat percentage (AFP), and intramuscular fat content were determined. The mRNA levels of liver X receptor alpha, carbohydrate response element-binding protein (ChREBP), sterol regulatory element-binding protein-1 (SREBP1), and fatty acid synthase were detected. The caged chicken exhibited significantly higher BW, SFT, and AFW than those of free ranged chicken (P < 0.05). All the 4 genes had a similar expression pattern, and they showed the highest level in caged chicken, while the lowest level was found in free-ranged chicken. Association analysis indicated that there were significant (P < 0.05) or highly significant (P < 0.01) positive correlations between the mRNA levels of ChREBP, SREBP1, and fat traits of SFT, AFW, and AFP. Thus, we deduced that increased fat deposition in caged chicken was probably induced by increased gene expression of ChREBP and SREBP1 in the liver. PMID- 25730061 TI - Interleukin-10 gene promoter polymorphism and risk of liver cirrhosis. AB - We conducted a hospital-based case-control study to assess the association between IL-10-592 A/C, IL-10-819 C/T, and IL-10-1082 A/G polymorphisms and the risk of liver cirrhosis in a Chinese population. This 1:1-matched case-control study included 192 patients from the Chinese PLA General Hospital. Genotypes of IL-10-592 A/C, IL-10-819 C/T, and IL-10-1082 A/G were detected by polymerase chain reaction amplification-restriction fragment length polymorphism analysis. Conditional regression analysis showed that individuals carrying the IL-10-1082 G allele had an only slightly increased risk of liver cirrhosis, with an adjusted odds ratio (95% confidence interval) of 2.14 (0.97-1.68). However, we did not identify a significant association between polymorphisms in IL-10-592 A/C and IL 10-819 C/T and the risk of liver cirrhosis. These findings may provide important clues for future studies of early detection screening of liver cirrhosis. PMID- 25730062 TI - Natural variation of rice blast resistance gene Pi-d2. AB - Studying natural variation in rice resistance genes of cultivated and wild rice relatives can predict resistance stability to rice blast fungus. In the present study, the protein coding regions of the rice R gene Pi-d2 in 35 rice accessions, including Oryza sativa L. subsp. indica Kato (Aus), indica (IND), temperate japonica (TEJ), tropical japonica (TRJ), aromatic (ARO); subgroups of Oryza sativa; 6 accessions of wild rice varieties; O. nivara; and O. rufipogon were analyzed. A total of 13 nucleotide differences were found in the open reading frames (ORFs) of Pi-d2. Translation of these ORFs revealed 9 variants; 3 were novel Pi-d2 variants. Variants H2 and H5 were identified in accessions of cultivated rice and O. nivara, H1, H3, H4, H6, and H8 were only identified in cultivated rice. H2 and H5 were the common types of IND and O. nivara, H8 was the common type of TRJ and AUS, H6 was the specific type of AUS, and H3 was the specific type of ARO. H7 and H9 were specific haplotypes of O. nivara and O. rufipogon, respectively. These findings demonstrate that Pi-d2 variants are useful indicators for each subgroup, and Pi-d2 is an ancient gene that predates speciation of rice subgroups. PMID- 25730063 TI - 1236 C/T and 3435 C/T polymorphisms of the ABCB1 gene in Mexican breast cancer patients. AB - MDR1, which is encoded by the ABCB1 gene, is involved in multidrug resistance (hydrophobic), as well as the elimination of xenotoxic agents. The association between ABCB1 gene polymorphisms and breast cancer risk in different populations has been described previously; however, the results have been inconclusive. In this study, we examined the association between polymorphisms 3435 C/T and 1236 C/T in the ABCB1 gene and breast cancer development in Mexican women according to their menopausal status and molecular classification. Molecular subtypes as well as allele and genotype frequencies were analyzed. A total of 248 women with initial breast cancer diagnosis and 180 ethnically matched, healthy, unrelated individuals were enrolled. Polymerase chain reaction-restriction fragment length polymorphism was performed to detect polymorphisms 3435 C/T and 1236 C/T in the ABCB1 gene. Premenopausal T allele carriers of the 3435 C/T polymorphism showed a 2-fold increased risk of breast cancer with respect to the reference and postmenopausal groups, as well as triple-negative expression regarding the luminal A/B molecular subrogated subtypes. In contrast, the CT genotype of the 1236 polymorphism was a protective factor against breast cancer. We conclude that the T allele carrier of the 3435 C/T polymorphism in the ABCB1 gene in combination with an estrogen receptor-negative status may be an important risk factor for breast cancer development in premenopausal women. PMID- 25730064 TI - Genome-wide identification and expression analysis of the CPP-like gene family in soybean. AB - Cysteine-rich polycomb-like protein (CPP-like) genes are a group of transcription factors with highly conserved cysteine-rich domains and are widely distributed in animals and plants, but do not present in yeast. Previous studies have shown that members of this family play important roles in the development of reproductive tissue and in the control of cell division in plants. In this study, whole genome identification of soybean CPP transcription factors was performed using bioinformatic methods. The results showed that there were 20 CPP transcription factors in the soybean genome, which encoded for 28 distinct CPP proteins. These transcription factors were distributed on 16 of 20 chromosomes. Phylogenetic relationship analysis showed that expression of CPP gene family members occurred before the differentiation of monocotyledons and dicotyledons. RNA-Seq analysis showed that 5 genes were highly expressed in all tissues, including Glyma10g39080, Glyma01g44670, Glyma101g66920, Glyma02g01540, and Glyma20g28740. One gene (Glyma14g14750) was specifically expressed in young leaves, while 2 genes (Glyma02g01540 and Glyma10g01580) were highly expressed in root nodules. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed that the expression levels of most genes increased in the roots under high temperature stress. Our findings indicate that these genes are not only involved in growth and development, but also in the responses to high temperature stress in soybean roots. PMID- 25730065 TI - Effect of nimodipine on rat spinal cord injury. AB - We evaluated the potentially protective effect of nimodipine on rat spinal cord injury. Sprague-Dawley rats received spinal cord injury, and were separated into nimodipine (N = 12) and saline groups (N = 12). Within 1 h of the injury, rats were treated intraperitoneally with nimodipine (1.0 mg/kg) or an equal amount of saline. Treatment was performed 3 times a day for 1 week. Operation BBB score and track experiment were used to measure the physical function of the hind legs 1 and 2 weeks after injury. Two weeks after the injury, malondialdehyde (MDA) content and spinal cord myeloperoxidase (MPO) activity of the injured part were determined, and the glial scar and dead room were studied using the immune tissue chemical test. ED1 was used to observe active gitter cell and macrophages. The physical function of the nimodipine group improved significantly (P < 0.01). Two weeks after injury, spinal cord MDA content in the spinal cord in the nimodipine group (nmol/g, 25.6 +/- 9.7 vs 68.5 +/- 16.7) and MPO activity (U/g, 252.2 +/- 63.9 vs 382.8 +/- 108.2) decreased significantly (P < 0.01); nimodipine whole dead space (mm2, 4.45 +/- 1.28 vs 6.16 +/- 2.65) and ED1 antibody immunity colored positive room (mm2, 1.87 +/- 0.42 vs 2.86 +/- 1.01) reduced significantly (P < 0.01). Nimodipine treatment could reduce oxidative injury after spinal cord injury, reduce the whole dead space and inflammation, and repair spinal cord injury. PMID- 25730066 TI - Association between B7-H1 expression and bladder cancer: a meta-analysis. AB - B7 homolog 1 (B7-H1), which is also known as programmed death-L1, is an important member of the B7/CD28 costimulatory factor superfamily, which are emerging as important mediators of various host immune responses. B7-H1 is differentially expressed in various cell subsets and to different extents in human and murine cells. Human B7-H1 is constitutively expressed at low levels in dendritic cells and activated T cells (compared with high expression in activated murine T cells) and is highly expressed in monocytes and tumor cells. We conducted a meta analysis to explore the association between B7-H1 expression and bladder cancer risk. Two groups were examined, including 352 bladder cancer cases and 60 healthy controls. Meta-analysis results revealed that B7-H1 expression is positively associated with bladder cancer and is strongly associated with the clinical stage of bladder cancer. However, no significant difference was found with respect to gender and the pathological grade of bladder cancer. PMID- 25730067 TI - Developmental changes in the expression of the GLUT2 and GLUT4 genes in the longissimus dorsi muscle of Yorkshire and Tibetan pigs. AB - Glucose transporter proteins 2 and 4 (GLUT2 and GLUT4) play important roles in glucose transport and energy metabolism. Changes in the levels of GLUT2 and GLUT4 mRNA were measured in longissimus dorsi muscle from the lean Yorkshire and fat Tibetan pig breeds at six different time points (1, 2, 3, 4, 5, and 6 months) with quantitative real-time polymerase chain reactions. The results showed that GLUT2 and GLUT4 mRNA were abundantly expressed in the longissimus dorsi muscle and that the developmental expression patterns were similar in both breeds. Tibetan pigs exhibited higher intramuscular fat and GLUT2 mRNA levels, while Yorkshire pigs exhibited a higher myofiber cross-sectional area (CSA) and GLUT4 mRNA levels. Furthermore, the changes in the GLUT4 mRNA levels were strongly and positively correlated with the CSA over a period of six months. These results exhibit time- and breed-specific expression patterns of GLUT2 and GLUT4, which highlight their potential as candidate genes for assessing adipose deposition and muscle development in pigs. These differences in the expression of GLUT family genes may also have indications for meat quality. PMID- 25730068 TI - Estrogen receptor alpha gene PvuII polymorphism and risk of fracture in postmenopausal women: a meta-analysis. AB - Numerous studies have evaluated the association between estrogen receptor alpha (ESR1) gene PvuII polymorphism and fracture risk in postmenopausal women. However, the results have been inconsistent. We performed a meta-analysis to examine the association between the ESR1 gene PvuII polymorphism and fracture risk in postmenopausal women. Studies published from PubMed, Google Scholar, and China National Knowledge Infrastructure data were retrieved. Pooled odds ratios with 95% confidence intervals were calculated using fixed- or random-effects models. A total of 6 case-control studies containing 592 patients and 705 controls were included in this meta-analysis. We found no association between the PvuII polymorphism in the ESR1 gene and fracture in postmenopausal women. Taking into account the effect of ethnicity, further stratified analyses were performed. In the subgroup analysis, no significant association was found in Caucasians and in Asians. No publication bias was found in the present study (all P > 0.05). In conclusion, the ESR1 gene PvuII polymorphism may not be associated with fracture risk in postmenopausal women. Additional larger studies are needed to confirm this conclusion. PMID- 25730069 TI - Clinical application of three-dimensional reconstruction and rapid prototyping technology of multislice spiral computed tomography angiography for the repair of ventricular septal defect of tetralogy of Fallot. AB - Three-dimensional (3D) reconstruction and rapid prototyping technology (RPT) of multislice spiral computed tomography angiography (CTA) was applied to prepare physical models of the heart and ventricular septal defects of tetralogy of Fallot (ToF) patients in order to explore their applications in the diagnosis and treatment of this complex heart disease. CTA data of 35 ToF patients were collected to prepare l:l 3D solid models using digital 3D reconstruction and RPT, and the resultant models were used intraoperatively as reference. The operations of all 35 patients were completed under the guidance of the 3D solid model, without difficulty. Intraoperative findings of the patients were consistent with the morphological and size changes of the 3D solid model, and no significant differences were found between the patches obtained from the 3D solid model and the actual intraoperative measurements (t = 0.83, P = 0.412). 3D reconstruction and RPT of multislice spiral CTA can accurately and intuitively reflect the anatomy of ventricular septal defects in ToF patients, providing the foundation for a solid model of the complex congenital heart. PMID- 25730070 TI - Research note. Clinical reports and analysis of patients with clinical manifestations of migraine-like headache and unruptured aneurysm. AB - A retrospective analysis of three cases of clinical manifestations of migraine like headache, including clinical features, imaging findings, and follow-up results was done to explore the potential correlation between migraine and unruptured aneurysm. Clinical data and digital subtraction angiography (DSA) results were retrospectively analyzed. All three patients met the diagnostic criteria for migraine without aura stated in the second edition of the International Classification of Headache Disorders, established by the International Headache Society in 2004. The DSA results suggested that the aneurysms occurred in the anterior communicating artery (two cases) and in the internal carotid artery (one case); the migraine attacks disappeared after aneurysm embolization, with a follow-up time of 6, 10, and 16 months in the three cases, respectively. The pathogenesis of migraine is not fully understood; however, the potential correlation between migraine attack and unruptured saccular aneurysm needs attention, and the specific pathogenesis should be further investigated. PMID- 25730071 TI - Genetic control of the number of leaves above the ear in maize. AB - In this study, we examined the genetic control of the number of leaves above the first ear in maize. The F2 generations and the backcrosses were obtained from 2 contrasting lines for this trait. All generations were assessed in a completely randomized block design with 2 replications. The number of leaves above the ear was counted when the plants were in the tasseling stage at the level of plants per plot. Mean and variance components were estimated using the weighted least square method. We observed a predominance of non-additive effects in the genetic control of number of leaves above the ear. These results indicate that this trait shows high heritability. PMID- 25730072 TI - Random amplified polymorphic DNA analysis of salt-tolerant tobacco mutants generated by gamma radiation. AB - Salinity is one of the major problems limiting the yield of agricultural products. Radiation mutagenesis is used to improve salt-tolerant mutant plants. In this study, we aimed to improve salt-tolerant mutants of two oriental tobacco varieties. One thousand seeds of each variety (M0) were irradiated with 100, 200, 300, and 400 Gy gamma rays by Cs-137 gamma. In the M1 generation, 2999 single plants were harvested. The next season, these seeds were bulked and planted to obtain M2 progeny. The seeds of 1900 M2 plants were picked separately. Salinity tolerance was tested in the M3 generation. Among M3 plantlets, 10 salt-tolerant tobacco mutants were selected. According to the results of the selection studies, 100- and 200-Gy gamma radiation doses were the effective doses to obtain the desired mutants. Glutathione reductase enzyme activities of salt-tolerant tobacco mutants were determined biochemically as a stress-tolerance marker. The differences between control and salt-tolerant mutants belonging to the Akhisar 97 and Izmir Ozbas tobacco varieties were evaluated by random amplified polymorphic DNA analysis. The total polymorphism rate was 73.91%. PMID- 25730073 TI - Relationship between polymorphism of SOCS-3 and dyslipidemia in China Xinjiang Uygur. AB - We investigated the relationship between the polymorphism of SOCS-3 and dyslipidemia of people from Uygur in Xinjiang, China. This cross-sectional study included 1379 participants in a Hetian Xinjiang Uygur population who were 30-70 years of age and were not from interracial marriages of 3 generations; all subjects were genotyped (909 dyslipidemia subjects, 470 healthy subjects). Allele (P = 0.002) and genotype (P = 0.003) frequencies of the distribution of rs12953258 was significantly different between dyslipidemia and control groups. Between the total cholesterol abnormal and control groups, high-density lipoprotein cholesterol abnormal and control groups, triglycerides abnormal and control groups, the frequencies of genotype in rs12953258 were significantly different (P = 0.007, 0.012, 0.0004, respectively). Based on the logistic regression analysis, genotype CA and AA of rs12953258 were independent and risk factors for dyslipidemia in Uygur (CC vs CA; odds ratio = 1.48, 95% confidence interval = 1.11-1.98, P = 0.008), (CC vs AA; odds ratio = 2.48, 95% confidence interval1.07-5.79, P = 0.035). Genotype AA of rs12953258 merged with subjects whose waist-to-hip ratio was abnormal, indicating the presence of dyslipidemia. The frequency of haplotype 4(H4) A-G-C in the dyslipidemia group was higher than in the control group (8.44 vs 5.37%, P = 0.003). rs12953258 site of the SOCS-3 gene showed a close relationship with dyslipidemia in Uygur. Combining genotype AA with subjects whose waist-to-hip ratios were abnormal will increase prevalence of dyslipidemia obviously. PMID- 25730074 TI - Genetic analysis of seed-shattering genes in rice using an F3:4 population derived from an Oryza sativa x Oryza rufipogon cross. AB - Seed shattering of wild plant species is thought to be an adaptive trait to facilitate seed dispersal. For rice breeding, seed shatter-ing is an important trait for improving breeding strategies, particularly when developing lines use interspecific hybrids and introgression of genes from wild species. We developed F3:4 recombinant inbred lines from an interspecific cross between Oryza sativa cv. Ilpoombyeo and Oryza rufipogon. In this study, we genetically analyzed known shat-tering-related loci using the F3:4 population of O. sativa/O. rufipogon. CACTA-AG190 was significantly associated with the shattering trait CACTA-TD according to bulked segregant analysis results, and was found in the qSH-1 region of chromosome 1. Fine genetic mapping of the flanking regions around qSH-1 based on CACTA-AG190 revealed multiple-sequence variations. The highest limit of detection based on quantitative trait locus analysis was observed between shaap 7715 and a 518-bp insertion site. Two other quantitative trait locus analyses of seed-shattering-related loci, qSH-4 and sh-h, were performed using simple sequence repeat and allele-pecific single nucleotide polymor-phism markers. Our results can be applied for rice-breeding research, such as marker-assisted selection between cultivated and wild rice. PMID- 25730075 TI - Effectiveness of microsatellite and single nucleotide polymorphism markers for parentage analysis in European domestic pigs. AB - Parentage analysis and individual identification are recent, promising methods that have been applied to evolutionary and ecological studies, as well as conservation management. Parental exclusion relying on polymorphic microsatellites has been used worldwide in parentage determination, while the low mutation rate and genotyping error rate of single nucleotide polymorphisms (SNPs) make them another important marker for pedigree tracing. Here, we compared the effectiveness of microsatellites and SNP markers in European pigs. We also measured and presented the minimum and optimal criteria for SNP markers to be used in paternity and identity analysis. Our findings may contribute to the development of techniques for future molecular evolution and conservation studies, as well as breeding programs. PMID- 25730076 TI - De novo assembly and characterization of skin transcriptome using RNAseq in sheep (Ovis aries). AB - Wool is produced via synthetic processes of wool follicles, which are embedded in the skin of sheep. The development of new-generation sequencing and RNA sequencing provides new approaches that may elucidate the molecular regulation mechanism of wool follicle development and facilitate enhanced selection for wool traits through gene-assisted selection or targeted gene manipulation. We performed de novo transcriptome sequencing of skin using the Illumina Hiseq 2000 sequencing system in sheep (Ovis aries). Transcriptome de novo assembly was carried out via short-read assembly programs, including SOAPdenovo and ESTScan. The protein function, clusters of orthologous group function, gene ontology function, metabolic pathway analysis, and protein coding region prediction of unigenes were annotated by BLASTx, BLAST2GO, and ESTScan. More than 26,266,670 clean reads were collected and assembled into 79,741 unigene sequences, with a final assembly length of 35,447,962 nucleotides. A total of 22,164 unigenes were annotated, accounting for 36.27% of the total number of unigenes, which were divided into 25 classes belonging to 218 signaling pathways. Among them, there were 17 signal paths related to hair follicle development. Based on mass sequencing data of sheepskin obtained by RNA-Seq, many unigenes were identified and annotated, which provides an excellent platform for future sheep genetic and functional genomic research. The data could be used for improving wool quality and as a model for human hair follicle development or disease prevention. PMID- 25730077 TI - Association between GSTM1 polymorphisms and lung cancer: an updated meta analysis. AB - The relationship between glutathione S-transferase M1 (GSTM1) genetic polymorphisms and lung cancer has been reported previously. However, the results are not consistent. Therefore, to clarify the association between GSTM1 polymorphisms and lung cancer, we performed a meta-analysis based on published studies. We used the Revman 5.0 software to perform literature retrieval, article selection, data collection, and statistical analysis. We utilized a random-effect model to pool the odds ratios (ORs) and 95% confidence intervals (CIs). A total of 38 eligible studies including 5737 lung cancer patients and 6843 cancer-free control subjects were analyzed. We found no association between GSTM1 genetic polymorphisms and lung cancer risk (OR = 1.15, 95%CI = 0.98-1.36, P = 0.08). Including only Chinese individuals, we found no association between GSTM1 genetic polymorphisms and lung cancer risk (OR = 1.13, 95%CI = 0.97-1.32, P = 0.13). In conclusion, we found that GSTM1 polymorphisms are not associated with lung cancer risk. PMID- 25730078 TI - Analysis of the genetic effects of CAPN1 gene polymorphisms on chicken meat tenderness. AB - The micromolar calcium-activated neutral protease gene (CAPN1) is a physiological candidate gene for meat tenderness. Four previously identified single nucleotide polymorphism (SNP) markers located within the CAPN1 gene were evaluated for their associations with variation in the meat tenderness of a Chinese indigenous chicken breed, a higher meat quality breed (i.e., Qingyuan partridge chicken), and the commercial Recessive White chicken breed. Warner-Bratzler shear force measurements were used to determine tenderness phenotypes for all animals; intramuscular fat (IMF) content and rate of water loss in the breast muscles were also measured. Genotyping was performed by the polymerase chain reaction-ligase detection reaction method. Polymorphisms were identified for all markers, except CAPN1 2546. The frequency of allele T was zero, and allele C was fixed for CAPN1 2546 in the studied populations. The SNP CAPN1 3535 in the CAPN1 gene was significantly associated with tenderness and other meat quality traits, where animals inheriting the AA genotype had smaller shear force values, lower water loss rates, and higher IMF contents. Moreover, H1 (AAA) was the most advantageous haplotype for meat tenderness. The results of this study confirm some previously documented associations. Furthermore, novel associations have been identified that, following validation in other populations, could be incorporated into breeding programs to improve meat quality. PMID- 25730079 TI - Relationship between clinicopathological features and HIF-2alpha in gastric adenocarcinoma. AB - Hypoxia influences tumor growth by inducing angiogenesis and genetic alterations. Hypoxia-inducible factor-2alpha (HIF-2alpha) plays an essential role in oxygen homeostasis. Expression of HIF-2alpha-inducible genes is associated with tumor progression. In this study, we investigated this correlation immunohistochemically and using quantitative reverse transcription-polymerase chain reaction to examine various clinical and pathological features in 55 specimens of gastric cancer and 40 specimens of normal gastric tissue. The HIF 2alpha mRNA expression level and protein expression were significantly higher in gastric cancer tissue samples than in adjacent tissue samples. The positive rates of HIF-2alpha, matrix metalloprotease-9 (MMP-9), and vascular endothelial growth factor (VEGF) protein were 63.6% (35/55), 80.0% (44/55), and 65.5% (36/55) in gastric cancer tissue specimens, respectively. These values were significantly higher than those in normal gastric tissue samples (P = 0.001, P = 0.000, and P = 0.007, respectively). HIF-2alpha and MMP-9 were significantly correlated with primary tumor size (P = 0.0065 and P = 0.036, respectively) and invasion depth (P = 0.012 and P = 0.008, respectively). HIF-2alpha and VEGF were significantly correlated with lymph node involvement (P = 0.030 and P = 0.016, respectively). Expression of HIF-2alpha was positively correlated with the expression of VEGF and MMP-9 (P = 0.036 and P = 0.000, respectively). These results suggest that HIF 2alpha is involved in gastric carcinogenesis and disease progression and is a potential therapeutic target for gastric carcinoma. PMID- 25730080 TI - Analysis of synonymous codon usage in FAD7 genes from different plant species. AB - In this study, the codon bias of the FAD7 genes among 10 different plant species was analyzed to identify general patterns of codon usage in the FAD7 genes. Our results showed that U-ended or A-ended codons were preferentially used in FAD7 for dicots, whereas G-ended or C-ended codons were preferentially used in FAD7 for monocots. An ENC-plot showed that some other factors may influence the codon usage of FAD7, except mutation bias in plant species. A correlation analysis between the codon adaptation index and GC or GC3s contents demonstrated that the codon usage bias of the FAD7 gene in plant species could be influenced by the gene expression level. The cluster analysis of relative synonymous codon usage values and phylogenetic trees of protein sequences for FAD7 genes confirm that the codon preference of FAD7 is influenced by genetic relationships. Moreover, Arabidopsis thaliana and Nicotiana tabacum were predicted to be the most appropriate expression hosts for the FAD7 genes from dicots, and Zea mays may be suitable for the expression of the FAD7 genes from monocots. Our results provide useful insights into the evolutionary relationships of plant species. PMID- 25730081 TI - Genetic diversity and phylogenetic relationship among Tunisian cactus species (Opuntia) as revealed by random amplified microsatellite polymorphism markers. AB - Opuntia ficus indica is one of the most economically important species in the Cactaceae family. Increased interest in this crop stems from its potential contribution to agricultural diversification, application in the exploitation of marginal lands, and utility as additional income sources for farmers. In Tunisia, O. ficus indica has been affected by drastic genetic erosion resulting from biotic and abiotic stresses. Thus, it is imperative to identify and preserve this germplasm. In this study, we focused on the use of random amplified microsatellite polymorphisms to assess genetic diversity among 25 representatives of Tunisian Opuntia species maintained in the collection of the National Institute of Agronomic Research of Tunisia. Seventy-two DNA markers were screened to discriminate accessions using 16 successful primer combinations. The high percentage of polymorphic band (100%), the resolving power value (5.68), the polymorphic information content (0.94), and the marker index (7.2) demonstrated the efficiency of the primers tested. Therefore, appropriate cluster analysis used in this study illustrated a divergence among the cultivars studied and exhibited continuous variation that occurred independently of geographic origin. O. ficus indica accessions did not cluster separately from the other cactus pear species, indicating that their current taxonomical classifications are not well aligned with their genetic variability or locality of origin. PMID- 25730082 TI - Diversity of platelet function and genetic polymorphism in clopidogrel-treated Chinese patients. AB - We investigated the correlation between genetic polymorphisms of cytochrome P450 enzyme genes and the outcome of clopidogrel treatment in 118 coronary disease patients after percutaneous coronary intervention at the Chinese PLA General Hospital. Patients were divided into an ischemia event relapse group (IERG) and a non-IERG group (NIERG) based on relapse of ischemia events within 6 months after percutaneous coronary intervention. Ischemia occurred in 26.27% of patients. Thromboelastogram platelet mapping results showed that compared with the NIERG, the ADP-induced platelet inhibition ratio in the IERG was significantly lower (31.33 +/- 24.91% vs 54.68 +/- 26.63%, P < 0.05). The platelet inhibition ratio of patients carrying mutant alleles CYP3A5*3 (41.98 +/- 29.33% vs 52.89 +/- 26.49%), CYP2C19*2 (43.15 +/- 27.97% vs 55.89 +/- 26.71%), and P2Y12*1 (38.74 +/- 24.36% vs 52.19 +/- 28.58%) was lower than patients with the wild-type alleles. The frequency of ischemia event relapse in patients with the mutant alleles CYP3A5*3 and CYP2C19*2 was significantly higher than patients carrying the G/G genotype; however, there was no significant difference between patients carrying the T/T genotype and C allele of P2Y12*1. Thus, coexisting polymorphisms of CYP3A5*3 and 2C19*2, but not P2Y12*1, play an important role in the variability of clopidogrel's curative effect. PMID- 25730083 TI - Retrospective analysis of pathologic nipple discharge. AB - The cause of pathologic nipple discharge is mainly benign lesions, but there is still a possibility of malignancy. Pathologic nipple discharge may be the only or the first symptom of breast cancer. This study aimed to investigate the clinical factors associated with lesions in patients with pathologic nipple discharge using a retrospective analysis of clinical data in 207 cases. The univariate analysis showed that age >50 years, breast lumps, or breast calcifications were risk factors associated with breast cancer in nipple discharge patients (P < 0.05). Discharge characteristics, duration of disease, and identification of lesions had no clear clinical significance (P > 0.05). The multivariate analysis also showed that age >50 years, breast lumps, and breast calcifications were risk factors associated with breast cancer in nipple discharge patients (P < 0.05). Age, breast lumps, and breast calcifications had important clinical significance in identification of benign and malignant nipple discharge. PMID- 25730084 TI - Clinical applications of internal heat source analysis for breast cancer identification. AB - Nondestructive preoperative breast imaging techniques are widely used for breast cancer testing and diagnosis. This study aimed to evaluate the feasibility and efficacy of quantitative diagnosis via the thermal analysis of abnormal metabolism. Nine hundred forty-eight women who underwent breast biopsy from 2009 to 2013 were investigated. Thermal analysis was used to calculate the internal heat source (i.e., tumor) thermal power for each participant. The applicability and effectiveness of our approach were estimated using the chi-square test, kappa statistics (k), and odds ratios (OR). Breast density and tumor size were considered during this estimation. A thermal power q = 0.2 w was determined as the optimal separation threshold between breast cancer and benign disease. Moreover, good agreement (k = 0.837) with the gold-standard assessment (breast biopsy) was confirmed in 93.2% of the patients (N = 884/948), and the sensitivity and specificity were 94.2 and 92.9%, respectively. The results also found no significant differences in methodological accuracy between the fatty and dense breasts (OR = 1.194, P = 0.524). Furthermore, after dividing the cohort into three groups according to tumor size (T1: <2 cm; T2: 2 to 5 cm; T3: >5 cm), the tumor size had no effect on the proposed method (ORs = 1, P = 0.724). Internal heat source analysis can feasibly and efficiently distinguish between breast cancer and benign disease. PMID- 25730085 TI - Biosom: gene synonym analysis by self-organizing map. AB - There are several guidelines for gene nomenclature, but they are not always applied to the names of newly identified genes. The lack of standardization in naming genes generates inconsistent databases with errors such as genes with the same function and different names, genes with different functions and the same name, and use of an abbreviated name. This paper presents a methodology for predicting synonyms in a given gene nomenclature, thereby detecting and minimizing naming redundancy and inconsistency and facilitating the annotation of new genes and data mining in public databases. To identify gene synonyms, i.e., gene ambiguity, the methodology proposed begins by grouping genes according to their names using a Kohonen self-organizing map artificial neural network. Afterwards, it identifies the groups generated employing the Matrix-U technique. The employment of such techniques allows one to infer the synonyms of genes, to predict probable hypothetical gene names and to point out possible errors in a database record. Many mistakes related to gene nomenclature were detected in this research, demonstrating the importance of predicting synonyms. The methodology developed is applicable for describing hypothetical, putative and other types of genes without a known function. Moreover, it can also indicate a possible function for genes after grouping them. PMID- 25730086 TI - Short communication. Characterization of chloroplast region rrn16-rrn23S from the tropical timber tree Cedrela odorata L. and de novo construction of a transplastomic expression vector suitable for Meliaceae trees and other economically important crops. AB - The forest tree Spanish cedar (Cedrela odorata L.) is well-known for its high value timber; however, this species is attacked by the shoot borer (Hypsipyla grandella) during its early years of development, resulting in branched stems and making the plants useless for high-quality wood production. The generation of resistant varieties expressing entomotoxic proteins may be an alternative to pesticide treatments. The use of plastid transformation rather than nuclear transformation should be used because it reduces the risk of transgene dissemination by pollen. Chloroplast transformation vectors require an expression cassette flanked by homologous plastid sequences to drive plastome recombination. Thus, C. odorata plastome sequences are a prerequisite. The rrn16-rrn23 plastome region was selected, cloned, and characterized. When the sequence identity among the rrn16-rrn23 regions from C. odorata and Nicotiana tabacum was compared, 3 inDels of 240, 104, and 39 bp were found that might severely affect transformation efficiency. Using this region, a new transformation vector was developed using pUC19 as a backbone by inserting the rrn16-trnI and trnA-rrn23 sequences from C. odorata and adding 2 independent expression cassettes into the trnI-trnA intergenic region, conferring spectinomycin resistance, the ability to express the gfp reporter gene, and a site that can be used to express any other gene of interest. PMID- 25730087 TI - Establishment of a rabbit model of coronary artery bypass graft and endothelial nitric oxide synthase gene transfection. AB - This study established an animal model of coronary artery bypass graft (CABG) surgery. The human endothelial nitric oxide synthase (eNOS) gene was transfected into grafted arterial walls to verify transfection efficiency. Forty rabbits were randomized into the following 4 equal groups: 1) eNOS gene transfection group (eNOS group); 2) empty eNOS gene transfection group (empty gene group); 3) control group; 4) normal femoral artery group. Grafted arteries, and normal carotid and femoral artery specimens were obtained 3 weeks later. Immunohistochemistry and analyses of tissue nitric oxide (NO) levels, eNOS activity, and eNOS protein western blotting were performed. The effectiveness and efficiency of transfection were observed and confirmed. All rabbits survived. The grafted arteries retained patency. Varying degrees of adaptability changes were observed in grafted arteries in each group. The eNOS group exhibited vascular wall thickening and significantly increased eNOS protein expression. The control and empty gene groups exhibited vessel wall degeneration, and eNOS protein was weakly or not expressed (P < 0.05). The arterial wall NO concentration and total eNOS activity in the eNOS group were significantly higher than those in the other groups (P < 0.05). Western blotting demonstrated that the vascular wall eNOS protein concentration was significantly greater than that in the other groups (P < 0.05). Furthermore, the eNOS gene transfection can increase eNOS expression and activity in vessel walls, increasing local NO concentration and expression. PMID- 25730088 TI - Molecular and morphological characterization of local apple cultivars in Southern Spain. AB - The number of local and traditional fruit cultivars in Andalusia (Southern Spain) has decreased dramatically since the 1970s when new commercial cultivars from breeding programs were introduced, replacing old varieties, and thus decreasing genetic diversity. The present study was included in a genetic resources project with the objective of identifying and preserving traditional fruit tree cultivars in Southern Spain. The goal of this study was to begin the characterization of 29 apple accessions (Malus x domestica Borkh) belonging to 13 traditional cultivar denominations. For molecular characterization studies, 12 simple sequence repeat markers previously developed for apple species were used. Morphological characterization was performed using 33 fruit traits. A total of 115 alleles were amplified for the 12 loci, ranging from 7 (CH01h01, CH01h10, and GD 12) to 13 alleles per locus (CH02c11). Forty-one alleles were unique to specific genotypes. The locus with the highest number of detected unique alleles was CH01f03b with 6 alleles. Expected heterozygosity ranged from 0.74 for CH01h10 to 0.88 for CH02c11, with an average of 0.82. Observed heterozygosity varied from 0.45 for CH01h01 to 1.0 for CH02d08, with an average of 0.86. Three homonyms were found for accessions belonging to varieties 'Maguillo', 'Pero Minguela', and 'Castellana'. The most discriminant morphological characters studied revealed no homonyms or synonyms among cultivar denominations, although they are useful for describing varietal characteristics that have not been previously defined. PMID- 25730089 TI - Multivariate analysis of molecular markers in peripheral blood associated with recurrence and metastasis of hepatocellular carcinoma. AB - Invasion, metastasis, and recurrence are the most common causes of death in patients with hepatocellular carcinoma (HCC) and are therefore critical factors for both therapy and prognosis. Current methods for diagnosis of HCC rely mainly on serological markers such as alpha-fetoprotein and liver enzymes, together with physical assessment and imaging techniques. The availability of more accurate serum markers may facilitate screening and early diagnosis, which will improve prognosis. This retrospective cohort analysis included 50 consecutive patients with cirrhosis and single or multifocal HCC and 40 control subjects with no liver disease or risk factors for viral hepatitis. Expression of epidermal growth factor-like domain 7 (EGFL7), osteopontin (OPN), and prostaglandin E2 (PGE2) were detected using an enzyme-linked immunosorbent assay. The mean serum levels of EGFL7, OPN, and PGE2 in the HCC group were 132.11 pg/mL, 11.77 ng/mL, and 179.37 pg/mL, respectively, which were all significantly higher than the levels in the control group (23.03 pg/mL, 2.31 ng/mL, and 47.36 pg/mL, respectively; P < 0.001). Serum levels of EGFL7, OPN, and PGE2 levels may thus be useful for screening and surveillance of HCC among high-risk populations, and have the potential to improve prognosis of these patients. PMID- 25730090 TI - IL-8 -251T/A polymorphism is associated with susceptibility to acute pancreatitis. AB - We conducted a case-control study to clarify the asso-ciations between inflammatory cytokine, including interleukin (IL)-1b, IL-6, IL-8, and IL-10, polymorphisms and risk of acute pancreatitis. Genotyping analyses of IL 1beta+3954 C/T (rs1143634), IL-1beta-511 C/T (rs16944), IL-6 -174 G/C (rs1800795), IL-6 -634 C/G (rs1800796), IL-8 -251T/A (rs4073), IL-10 -1082A/G (rs1800896), and IL-10 -819C/T (rs1800871) were conducted using polymerase chain reaction-restriction fragment length of polymorphism. Unconditional logistic regression analysis was utilized to assess the potential association be-tween genotype frequencies and risk of acute pancreatitis. Multivari-ate regression analyses showed that subjects carrying the IL-8 -251 AA genotype had a significantly increased risk of acute pancreatitis, with an adjusted odds ratio (95% confidence interval) of 1.55 (1.02-2.36). However, we found no significant association between IL-1beta +3954 C/T, IL-1beta -511 C/T, IL-6 -174 G/C, IL-6 174 G/C, IL-6 -634 C/G, IL-10 -1082A/G, or IL-10 -819C/T polymorphisms and risk of acute pancreatitis. We found that the IL-8 -251T/A polymorphism was associated with a higher susceptibility to acute pancreatitis in a Chinese population. PMID- 25730091 TI - Phylogenetic analysis of endophytic bacterial isolates from leaves of the medicinal plant Trichilia elegans A. Juss. (Meliaceae). AB - Various organisms such as fungi and bacteria can live inside plants, inhabiting the aerial parts (primarily the leaves) without causing damage. These microorganisms, called endophytes, produce an extensive variety of compounds that can be useful for medical and agronomic purposes. Trichilia elegans A. Juss., belonging to the Meliaceae family, shows wide dispersion in South America, and phytochemical analyses from these plants and endophyte isolates have shown biological activity. Accordingly, the aim of this study was to verify the diversity of bacterial endophytes from T. elegans using partial sequencing of 16S rRNA, followed by phylogenetic analysis. Isolation was performed by cutting the leaves, after disinfection with 5% sodium hypochlorite (NaOCl), in 1-2-mm2 fragments, which were equally placed on dishes containing TSA and fungicide BENLATE at 75 MUg/mL. All dishes were incubated at 28 degrees C in the biochemical oxygen demand system for 5 days and periodically checked. Afterwards, the colonization frequency (%) was determined: (number of fragments colonized by bacteria/total number of fragments) x 100. Three isolations between September 2011 and March 2012 were performed; the growth frequency ranged between 1.6 and 13.6%. Following sequencing of 16S rRNA and phylogenetic analysis, the genera identified were: Staphylococcus, Bacillus, Microbacterium, Pseudomonas, and Pantoea. These results will provide important knowledge on the diversity of endophytic bacteria inhabiting medicinal plants, and a better understanding of the microbiome of T. elegans would reinforce the necessity of endophyte studies with a focus on their future applications in biotechnological areas of agriculture, medicine, and the environment. PMID- 25730092 TI - Determining the role of a probiotic in the restoration of intestinal microbial balance by molecular and cultural techniques. AB - The human intestine has a vast variety of microorganisms, and their balance is dependent on several factors. Antibiotics affect microfloral balance and allow naturally opportunistic organisms to multiply. Azithromycin is the most widely used macrolide antibiotic, active against a wide number of pathogens including Pseudomonas aeruginosa and Staphylococcus aureus. It is currently used in the treatment of cystic fibrosis patients. The use of probiotics has advantages in gastrointestinal conditions, including infectious diarrhea and imbalance due to antibiotic use. In this research, the effect of azithromycin on the intestinal microbiota of Sprague Dawley rats and the role of Lactobacillus acidophilus in the restoration of the balance by employing molecular and cultural techniques was investigated. PCR with universal primers targeting the V3 region of the 16S rRNA gene followed by DGGE was used to characterize the overall intestinal microbiota composition. Cultivable fecal bacteria count using microbiological media and semi quantitative PCR with group-specific primers were also utilized to analyze the effects of antibiotic and probiotic on microflora. We found that the total amount of 16S rRNA gene and fecal aerobic bacterial count was reduced following azithromycin administration along with elimination of non-pathogenic Escherichia coli, but it was restored by the use of the probiotic. The results from PCR with group-specific primers showed that Bacteroides sp was present in the control and probiotic groups, but it was nearly eliminated in the antibiotic group. Moreover, semi-quantitative PCR revealed that the numbers of Enterobacteriaceae were nearly the same in the probiotic group and decreased in the antibiotic group, while Bifidobacterium was significantly increased in the probiotic group and decreased in the antibiotic group (P < 0.05) as compared with that in the control group. Azithromycin-induced dysbiosis can result in prolonged deleterious effects on the host. The present study revealed that the use of lactic acid bacteria particularly L. acidophilus helped to restore intestinal microfloral balance. PMID- 25730093 TI - Quantitative characterization of the colloidal stability of metallic nanoparticles using UV-vis absorbance spectroscopy. AB - Plasmonic nanoparticles are used in a wide variety of applications over a broad array of fields including medicine, energy, and environmental chemistry. The continued successful development of this material class requires the accurate characterization of nanoparticle stability for a variety of solution-based conditions. Although many characterization methods exists, there is an absence of a unified, quantitative means for assessing the colloidal stability of plasmonic nanoparticles. We present the particle instability parameter (PIP) as a robust, quantitative, and generalizable characterization technique based on UV-vis absorbance spectroscopy to characterize colloidal instability. We validate PIP performance with both traditional and alternative characterization methods by measuring gold nanorod instability in response to different salt (NaCl) concentrations. We further measure gold nanorod stability as a function of solution pH, salt, and buffer (type and concentration), nanoparticle concentration, and concentration of free surfactant. Finally, these results are contextualized within the literature on gold nanorod stability to establish a standardized methodology for colloidal instability assessment. PMID- 25730094 TI - The future of comparative effectiveness and relative efficacy of drugs: an international perspective. AB - Drug development takes place in a global marketplace, albeit with the USA and EU markets currently dominating. In the USA, demands for comparative effectiveness research have gained traction against a backdrop of health delivery reform, while European stakeholders deliberate the role of relative effectiveness in health technology assessment, trying to reduce the duplication of effort by regulators and health technology assessment bodies. In both arenas, drug-makers are faced with mounting drug development costs, and uncertainty over the types of evidence acceptable for a growing list of stakeholders. This article reports and compares future scenarios for evidence expectations for drugs for the USA and EU in 2020. The similarities, differences, and joint implications of the scenarios are considered to create an view of future evidence generation for drugs developed for these markets. PMID- 25730095 TI - Religiosity and Spirituality During Cardiac Rehabilitation: A LONGITUDINAL EVALUATION OF PATIENT-REPORTED OUTCOMES AND EXERCISE CAPACITY. AB - PURPOSE: This study is a longitudinal evaluation of religiosity/spirituality (R/S) and religious coping in post-myocardial infarction and post-coronary artery bypass surgery patients during a 12-week cardiac rehabilitation program. This study examines change in R/S and the relationship between R/S and psychosocial outcomes and exercise capacity over time. METHODS: Cardiac rehabilitation patients (N = 105) completed measures of R/S, religious coping, quality of life (QOL), self-efficacy (SE), and energy expenditure (EE) at the beginning (baseline) and end of a 12-week program. Relationships between R/S and religious coping and QOL, SE, and EE were evaluated. RESULTS: A negative relationship emerged between baseline measures of R/S and religious coping and QOL, SE, and EE. There were significant increases in Good Deeds Coping, QOL, SE, and EE from baseline to end of program (Ps < .05). Baseline measures of Interpersonal Religious Support Coping were positively correlated with the change in EE from baseline to end (r = 0.21; P = .059), and there were positive correlations between the change in Experiential Religiosity (r = 0.32; P = .004) and Overall Religiosity (r = 0.25; P = .024) with the change in EE. DISCUSSION: The demonstrated relationships between R/S and Religious Coping and outcomes in cardiac patients provide compelling support for the development of spiritual care interventions for cardiac patients and evaluation of the impact of these interventions on physiological, medical, and psychological outcomes in these patients. PMID- 25730096 TI - Cardiac rehabilitation after spontaneous coronary artery dissection. AB - PURPOSE: Although cardiac rehabilitation (CR) improves outcomes in patients after atherosclerotic myocardial infarctions, little is known of the CR benefit among patients with spontaneous coronary artery dissection (SCAD), who are primarily young, otherwise healthy women. The purpose of this study was to describe SCAD patient outcomes in phase 2 outpatient CR. METHODS: Patients with SCAD who enrolled in CR were retrospectively identified. Patients participated in standard CR, which included supervised and independent flexibility, stretching, aerobic, and strength training exercises. Patients received counseling regarding nutrition, weight and stress management. Assessments at baseline and program completion included cardiopulmonary exercise testing or 6-Minute Walk Test, body composition using plethysmography, depression (Patient Health Questionnaire-9), and stress (a scale of 1-10) scores. RESULTS: Nine patients, all women, enrolled in CR an average of 12.3 days (range, 7-21 days) after their SCAD event, with one enrolling again after a recurrence. Cardiac rehabilitation was well received, with participants completing an average of 28 CR sessions (range, 5-39 sessions). Patients did not report cardiac symptoms and there were no adverse events during exercise testing or training. Peak oxygen uptake increased by an average of 18% (n = 4) and 6-minute walk distance increased 22% (n = 4). Average body mass decreased 1.1 kg, fat mass decreased 1.6 kg, and lean mass increased 0.4 kg. Depression and stress scores improved by an average of 2.3 and 1.3 points, respectively. CONCLUSIONS: Standard CR beginning 1 to 2 weeks after SCAD seems to be feasible and safe and results in improved aerobic capacity, body composition, and measures of depression and stress. Because of these benefits, we recommend that patients with SCAD participate in CR. PMID- 25730097 TI - ZnI2-Catalyzed Diastereoselective [4 + 2] Cycloadditions of beta,gamma Unsaturated alpha-Ketothioesters with Olefins. AB - The potential of beta,gamma-unsaturated alpha-ketothioesters participating in hetero-Diels-Alder reaction has remained unexplored. We report herein the first study of a ZnI2-catalyzed highly diastereoselective inverse electron demand hetero-Diels-Alder reaction of beta,gamma-unsaturated alpha-ketothioesters with olefins to access highly substituted 3,4-dihydro-2H-pyrans. All the reactions proceed with cis-selectivity in moderate to excellent yields. Under similar reaction conditions, terminal alkynes undergo direct conjugate 1,4-addition to yield delta,epsilon-acetylenic alpha-ketothioesters. Furthermore, the utility of these cycloadducts has been demonstrated by an NBS-MeOH mediated stereospecific efficient access to fully substituted pyran rings. The product bromoethers undergo E2 elimination with DBU, resulting in substituted 3,6-dihydro-2H-pyrans. In addition, the thioester moiety of the products has been used for further transformations, such as amidations and Fukuyama coupling reactions. PMID- 25730099 TI - Symmetry protected topological superfluid (3)He-B. AB - Owing to the richness of symmetry and well-established knowledge of bulk superfluidity, the superfluid (3)He has offered a prototypical system to study intertwining of topology and symmetry. This article reviews recent progress in understanding the topological superfluidity of (3)He in a multifaceted manner, including symmetry considerations, the Jackiw-Rebbi's index theorem, and the quasiclassical theory. Special focus is placed on the symmetry protected topological superfuidity of the (3)He-B confined in a slab geometry. The (3)He-B under a magnetic field is separated to two different sub-phases: the symmetry protected topological phase and non-topological phase. The former phase is characterized by the existence of symmetry protected Majorana fermions. The topological phase transition between them is triggered by the spontaneous breaking of a hidden discrete symmetry. The critical field is quantitatively determined from the microscopic calculation that takes account of magnetic dipole interaction of the (3)He nucleus. It is also demonstrated that odd-frequency even parity Cooper pair amplitudes are emergent in low-lying quasiparticles. The key ingredients, symmetry protected Majorana fermions and odd-frequency pairing, bring an important consequence that the coupling of the surface states to an applied field is prohibited by the hidden discrete symmetry, while the topological phase transition with the spontaneous symmetry breaking is accompanied by anomalous enhancement and anisotropic quantum criticality of surface spin susceptibility. We also illustrate common topological features between topological crystalline superconductors and symmetry protected topological superfluids, taking UPt3 and Rashba superconductors as examples. PMID- 25730100 TI - Synthesis and tunability of highly electron-accepting, N-benzylated "phosphaviologens". AB - We report a structure-property study on phosphoryl-bridged viologen analogues with a remarkably low reduction threshold. Utilizing different benzyl groups for N-quaternization, we were able to confirm the p-benzyl substituent effect on the electronic tunability of the system while maintaining the characteristic chromic response of viologens with two fully reversible one-electron reductions. Due to the considerably increased electron-acceptor properties of the phosphoryl-bridged bipyridine precursor, N-benzylation was found to be very challenging and required the development of new synthetic strategies toward the target viologen species. This study also introduces a new and convenient way for the anion exchange of viologen systems by utilizing methyl triflate. Finally, the practical utility of the new species was verified in simplified proof-of-concept electrochromic devices. PMID- 25730098 TI - PHABULOSA controls the quiescent center-independent root meristem activities in Arabidopsis thaliana. AB - Plant growth depends on stem cell niches in meristems. In the root apical meristem, the quiescent center (QC) cells form a niche together with the surrounding stem cells. Stem cells produce daughter cells that are displaced into a transit-amplifying (TA) domain of the root meristem. TA cells divide several times to provide cells for growth. SHORTROOT (SHR) and SCARECROW (SCR) are key regulators of the stem cell niche. Cytokinin controls TA cell activities in a dose-dependent manner. Although the regulatory programs in each compartment of the root meristem have been identified, it is still unclear how they coordinate one another. Here, we investigate how PHABULOSA (PHB), under the posttranscriptional control of SHR and SCR, regulates TA cell activities. The root meristem and growth defects in shr or scr mutants were significantly recovered in the shr phb or scr phb double mutant, respectively. This rescue in root growth occurs in the absence of a QC. Conversely, when the modified PHB, which is highly resistant to microRNA, was expressed throughout the stele of the wild-type root meristem, root growth became very similar to that observed in the shr; however, the identity of the QC was unaffected. Interestingly, a moderate increase in PHB resulted in a root meristem phenotype similar to that observed following the application of high levels of cytokinin. Our protoplast assay and transgenic approach using ARR10 suggest that the depletion of TA cells by high PHB in the stele occurs via the repression of B-ARR activities. This regulatory mechanism seems to help to maintain the cytokinin homeostasis in the meristem. Taken together, our study suggests that PHB can dynamically regulate TA cell activities in a QC-independent manner, and that the SHR-PHB pathway enables a robust root growth system by coordinating the stem cell niche and TA domain. PMID- 25730102 TI - When remembering the past suppresses memory for future actions. AB - Remembering planned actions at the correct time in the future is an integral component of prospective cognition. Recent studies on future remembering have led to suggestions that prospective cognition might be based on past experience. To test this hypothesis, we focused on retrieval-induced forgetting (RIF), which usually indicates that remembering past events suppresses memory for related but different past events. The current study assessed RIF in two kinds of event-based prospective memory (PM) tasks using either focal or non-focal cues for ongoing tasks. Participants studied six members from each of eight taxonomic categories and then practiced recalling three of the six members from four of the eight categories using category-stem cues. This retrieval practice suppressed the detection of non-practiced members of the practiced categories during the PM task with non-focal cues (Experiment 1) but not with focal cues (Experiment 2). The results suggest that recall of certain items inhibits the function of the others as PM cues, but only if the PM task does not largely share its processing with the ongoing task. PMID- 25730101 TI - Prospective evaluation of the association of nut/peanut consumption with total and cause-specific mortality. AB - IMPORTANCE: High intake of nuts has been linked to a reduced risk of mortality. Previous studies, however, were primarily conducted among people of European descent, particularly those of high socioeconomic status. OBJECTIVE: To examine the association of nut consumption with total and cause-specific mortality in Americans of African and European descent who were predominantly of low socioeconomic status (SES) and in Chinese individuals in Shanghai, China. DESIGN, SETTING, AND PARTICIPANTS: Three large cohorts were evaluated in the study. One included 71 764 US residents of African and European descent, primarily of low SES, who were participants in the Southern Community Cohort Study (SCCS) in the southeastern United States (March 2002 to September 2009), and the other 2 cohorts included 134 265 participants in the Shanghai Women's Health Study (SWHS) (December 1996 to May 2000) and the Shanghai Men's Health Study (SMHS) (January 2002 to September 2006) in Shanghai, China. Self-reported nut consumption in the SCCS (approximately 50% were peanuts) and peanut-only consumption in the SMHS/SWHS were assessed using validated food frequency questionnaires. MAIN OUTCOMES AND MEASURES: Deaths were ascertained through linkage with the National Death Index and Social Security Administration mortality files in the SCCS and annual linkage with the Shanghai Vital Statistics Registry and by biennial home visits in the SWHS/SMHS. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs. RESULTS: With a median follow-up of 5.4 years in the SCCS, 6.5 years in the SMHS, and 12.2 years in the SWHS, 14,440 deaths were identified. More than half of the women in the SCCS were ever smokers compared with only 2.8% in the SWHS. The ever-smoking rate for men was 77.1% in the SCCS and 69.6% in the SMHS. Nut intake was inversely associated with risk of total mortality in all 3 cohorts (all P<.001 for trend), with adjusted HRs associated with the highest vs lowest quintiles of intake being 0.79 (95% CI, 0.73-0.86) and 0.83 (95% CI, 0.77-0.88), respectively, for the US and Shanghai cohorts. This inverse association was predominantly driven by cardiovascular disease mortality (P<.05 for trend in the US cohort; P<.001 for trend in the Shanghai cohorts). When specific types of cardiovascular disease were examined, a significant inverse association was consistently seen for ischemic heart disease in all ethnic groups (HR, 0.62; 95% CI, 0.45-0.85 in blacks; HR, 0.60; 95% CI, 0.39-0.92 in whites; and HR, 0.70; 95% CI, 0.54-0.89 in Asians for the highest vs lowest quintile of nut intake). The associations for ischemic stroke (HR, 0.77; 95% CI, 0.60-1.00 for the highest vs lowest quintile of nut intake) and hemorrhagic stroke (HR, 0.77; 95% CI, 0.60-0.99 for the highest vs lowest quintile of nut intake) were significant only in Asians. The nut-mortality association was similar for men and women and for blacks, whites, and Asians and was not modified by the presence of metabolic conditions at study enrollment. CONCLUSIONS AND RELEVANCE: Nut consumption was associated with decreased overall and cardiovascular disease mortality across different ethnic groups and among individuals from low SES groups. Consumption of nuts, particularly peanuts given their general affordability, may be considered a cost-effective measure to improve cardiovascular health. PMID- 25730103 TI - N-linked glycan profiling in neuroblastoma cell lines. AB - Although MYCN amplification has been associated with aggressive neuroblastoma, the molecular mechanisms that differentiate low-risk, MYCN-nonamplified neuroblastoma from high-risk, MYCN-amplified disease are largely unknown. Genomic and proteomic studies have been limited in discerning differences in signaling pathways that account for this heterogeneity. N-Linked glycosylation is a common protein modification resulting from the attachment of sugars to protein residues and is important in cell signaling and immune response. Aberrant N-linked glycosylation has been routinely linked to various cancers. In particular, glycomic markers have often proven to be useful in distinguishing cancers from precancerous conditions. Here, we perform a systematic comparison of N-linked glycomic variation between MYCN-nonamplified SY5Y and MYCN-amplified NLF cell lines with the aim of identifying changes in sugar abundance linked to high-risk neuroblastoma. Through a combination of liquid chromatography-mass spectrometry and bioinformatics analysis, we identified 16 glycans that show a statistically significant change in abundance between NLF and SY5Y samples. Closer examination revealed the preference for larger (in terms of total monosaccharide count) and more sialylated glycan structures in the MYCN-amplified samples in comparison to smaller, nonsialylated glycans that are more dominant in the MYCN-nonamplified samples. These results offer clues for deriving marker candidates for accurate neuroblastoma risk diagnosis. PMID- 25730104 TI - Continental reference point: harmonized human biomonitoring across Europe. PMID- 25730105 TI - Vitamin D limits chemokine expression in adipocytes and macrophage migration in vitro and in male mice. AB - Vitamin D (VD) displays immunoregulatory effects and reduces adipocyte inflammation, which may participate to a reduction of adipose tissue macrophage infiltration in the context of obesity-associated low-grade inflammation. These observations have been described mainly in vitro, through the evaluation of a limited number of inflammatory markers. Here, we studied the effects of 1,25 dihydroxy-VD on chemokine network expression in adipocytes (by transcriptomic approach), and we confirm the physiological relevance of these data in vivo, by demonstrating the effect of VD on cytokine and chemokine gene expression as well as on macrophage infiltration in adipose tissue. 1,25 dihydroxy-VD down-regulated (-1.3- to -10.8-fold) the mRNA expression of 29 chemokines and limited macrophage migration in TNFalpha-conditioned adipocyte medium (1.5-fold; P < .05). This effect was associated with a reduction in p65 and IkappaB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation (2-fold compared with TNFalpha; P < .05). The effects of VD were confirmed in mice injected ip with lipopolysaccharide (acute inflammation) and diet-induced obese mice (metabolic inflammation), where the levels of mRNA encoding proinflammatory cytokines and chemokines (~2-fold) were reduced in adipocytes (acute and metabolic inflammation) and adipose tissue and that macrophage infiltration was also inhibited in the adipose tissue of obese mice (metabolic inflammation). Altogether, these results showed that VD displayed a global immunoregulatory impact on adipocytes, notably via the inhibition of chemokine expression and macrophage infiltration in inflamed adipose tissue. PMID- 25730106 TI - Aldose reductases influence prostaglandin F2alpha levels and adipocyte differentiation in male mouse and human species. AB - Aldose reductases (AKR1B) are widely expressed oxidoreductases whose physiological function remains elusive. Some isoforms are genuine prostaglandin F2alpha (PGF2alpha) synthases, suggesting they might influence adipose homeostasis because PGF2alpha inhibits adipogenesis. This was shown by Akr1b7 gene ablation in the mouse, which resulted in increased adiposity related to a lower PGF2alpha content in fat. Yet humans have no ortholog gene for Akr1b7, so the role of aldose reductases in human adipose homeostasis remains to be explored. We analyzed expression of genes encoding human and mouse aldose reductase isoforms in adipose tissues and differentiating adipocytes to assess conserved mechanisms regulating PGF2alpha synthesis and adipogenesis. The Akr1b3 gene encoded the most abundant isoform in mouse adipose tissue, whereas Akr1b7 encoded the only isoform enriched in the stromal vascular fraction. Most mouse aldose reductase gene expression peaked in early adipogenesis of 3T3-L1 cells and diminished with differentiation. In contrast with its mouse ortholog Akr1b3, AKR1B1 expression increased throughout differentiation of human multipotent adipose-derived stem cells, paralleling PGF2alpha release, whereas PGF2alpha receptor (FP) levels collapsed in early differentiation. Pharmacological inhibition of aldose reductase using Statil altered PGF2alpha production and enhanced human multipotent adipose-derived stem adipocyte differentiation. As expected, the adipogenic effects of Statil were counteracted by an FP agonist (cloprostenol). Thus, in both species aldose reductase-dependent PGF2alpha production could be important in early differentiation to restrict adipogenesis. PGF2alpha antiadipogenic signaling could then be toned down through the FP receptor or aldose reductases down-regulation in human and mouse cells, respectively. Our data suggest that aldose reductase inhibitors could have obesogenic potential. PMID- 25730107 TI - Classical and membrane-initiated estrogen signaling in an in vitro model of anterior hypothalamic kisspeptin neurons. AB - The neuropeptide kisspeptin is essential for sexual maturation and reproductive function. In particular, kisspeptin-expressing neurons in the anterior rostral periventricular area of the third ventricle are generally recognized as mediators of estrogen positive feedback for the surge release of LH, which stimulates ovulation. Estradiol induces kisspeptin expression in the neurons of the rostral periventricular area of the third ventricle but suppresses kisspeptin expression in neurons of the arcuate nucleus that regulate estrogen-negative feedback. To focus on the intracellular signaling and response to estradiol underlying positive feedback, we used mHypoA51 cells, an immortalized line of kisspeptin neurons derived from adult female mouse hypothalamus. mHypoA51 neurons express estrogen receptor (ER)-alpha, classical progesterone receptor (PR), and kisspeptin, all key elements of estrogen-positive feedback. As with kisspeptin neurons in vivo, 17beta-estradiol (E2) induced kisspeptin and PR in mHypoA51s. The ERalpha agonist, 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, produced similar increases in expression, indicating that these events were mediated by ERalpha. However, E2-induced PR up-regulation required an intracellular ER, whereas kisspeptin expression was stimulated through a membrane ER activated by E2 coupled to BSA. These data suggest that anterior hypothalamic kisspeptin neurons integrate both membrane-initiated and classical nuclear estrogen signaling to up-regulate kisspeptin and PR, which are essential for the LH surge. PMID- 25730108 TI - The melanocortin-4 receptor integrates circadian light cues and metabolism. AB - The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system. PMID- 25730109 TI - The forgotten lactogenic activity of growth hormone: important implications for rodent studies. AB - Studies of the effects of GH and the mechanisms of its actions frequently use rats or mice and various recombinant human GH preparations. Authors of many of these studies appear unaware of the fact that, in rodents, human GH signals through both GH and prolactin (PRL) receptors; thus, treatment with human GH is equivalent to a combined treatment with GH and PRL. GH receptors and PRL receptors are present in multiple cell types. Importantly, PRL exerts major effects on brain neuroendocrine action, female and male reproduction, metabolism, body composition, immune responses, and a host of other functions; thus, treatment of rodents with recombinant human GH could affect these important physiological parameters. PMID- 25730110 TI - Successively recycle waste as catalyst: a one-pot Wittig/1,4-reduction/Paal-Knorr sequence for modular synthesis of substituted furans. AB - A one-pot tandem Wittig/conjugate reduction/Paal-Knorr reaction is reported for the synthesis of di- or trisubstituted furans. This novel sequence first demonstrates the possibility of successively recycling waste from upstream steps to catalyze downstream reactions. PMID- 25730112 TI - Attentional switches and dual-task interference. AB - In four experiments, we studied the time course of interference between detection of an oddball orientation target (OT) in an 8-item circular search display, and identification of a letter target (LT) in a central stream of distractor letters. Dual-task performance for different temporal lags between targets was compared to single-task performance. When the LT preceded the OT, dual-task performance levels were reduced at short inter-target intervals of 0 and 166 ms; when the OT preceded the LT, the dual-task interference was unexpectedly stronger and lasted for up to 500 ms. Resource competition due to temporally overlapping target processing cannot account for this result, because the feature search task is easier than the letter identification task, and therefore would have generated less interference when presented first. Two alternative explanations were explored. First, by manipulating the spatial inter-target distance, we investigated to what degree there is a penalty associated with directing the attentional window from a large object (the search display) to a smaller object (the central letter stream). Second, by varying the duration of the OT and subsequent mask, we studied whether the interference was caused by the difficulty of disengaging attention from the search display. Results support this second explanation and thus indicate that switching attention to the letter stream is hampered by the continuing presence of (masked) search display items. This result shows that attentional effects may play a major role in dual-task execution and can easily obscure interference due to other factors such as resource competition. PMID- 25730111 TI - The diaphanous gene of Drosophila interacts antagonistically with multiple wing hairs and plays a key role in wing hair morphogenesis. AB - The Drosophila wing is covered by an array of distally pointing hairs that has served as a key model system for studying planar cell polarity (PCP). The adult cuticular hairs are formed in the pupae from cell extensions that contain extensive actin filaments and microtubules. The importance of the actin cytoskeleton for hair growth and morphogenesis is clear from the wide range of phenotypes seen in mutations in well-known actin regulators. Formin proteins promote the formation of long actin filaments of the sort thought to be important for hair growth. We report here that the formin encoding diaphanous (dia) gene plays a key role in hair morphogenesis. Both loss of function mutations and the expression of a constitutively active Dia led to cells forming both morphologically abnormal hairs and multiple hairs. The conserved frizzled (fz)/starry night (stan) PCP pathway functions to restrict hair initiation and activation of the cytoskeleton to the distal most part of wing cells. It also ensures the formation of a single hair per cell. Our data suggest that the localized inhibition of Dia activity may be part of this mechanism. We found the expression of constitutively active Dia greatly expands the region for activation of the cytoskeleton and that dia functions antagonistically with multiple wing hairs (mwh), the most downstream member of the fz/stan pathway. Further we established that purified fragments of Dia and Mwh could be co-immunoprecipitated suggesting the genetic interaction could reflect a direct physical interaction. PMID- 25730113 TI - Live Longer...for Peanuts. PMID- 25730118 TI - Microsurgical clipping of a superior hypophyseal artery aneurysm: part 1: intradural anterior clinoidectomy: 3-dimensional operative video. PMID- 25730114 TI - Small GTPase Rab21 mediates fibronectin induced actin reorganization in Entamoeba histolytica: implications in pathogen invasion. AB - The protozoan parasite Entamoeba histolytica causes a wide spectrum of intestinal infections. In severe cases, the trophozoites can breach the mucosal barrier, invade the intestinal epithelium and travel via the portal circulation to the liver, where they cause hepatic abscesses, which can prove fatal if left untreated. The host Extra Cellular Matrix (ECM) plays a crucial role in amoebic invasion by triggering an array of cellular responses in the parasite, including induction of actin rich adhesion structures. Similar actin rich protrusive structures, known as 'invadosomes', promote chemotactic migration of the metastatic cancer cells and non-transformed cells by remodeling the ECM. Recent studies showed a central role for Rab GTPases, the master regulators of vesicular trafficking, in biogenesis of invadosomes. Here, we showed that fibronectin, a major host ECM component induced actin remodeling in the parasite in a Rab21 dependent manner. The focalized actin structures formed were reminiscent of the mammalian invadosomes. By using various approaches, such as immunofluorescence confocal microscopy and scanning electron microscopy, along with in vitro invasion assay and matrix degradation assay, we show that the fibronectin induced formation of amoebic actin dots depend on the nucleotide status of the GTPase. The ECM components, fibronectin and collagen type I, displayed differential control over the formation of actin dots, with fibronectin positively and collagen type I negatively modulating it. The cell surface adhesion molecule Gal/GalNAc complex was also found to impose additional regulation on this process, which might have implication in collagen type I mediated suppression of actin dots. PMID- 25730119 TI - Ceramic membrane fouling during ultrafiltration of oil/water emulsions: roles played by stabilization surfactants of oil droplets. AB - Oil/water (O/W) emulsion stabilized by surfactants is the part of oily wastewater that is most difficult to handle. Ceramic membrane ultrafiltration presently is an ideal process to treat O/W emulsions. However, little is known about the fouling mechanism of the ceramic membrane during O/W emulsion treatment. This paper investigated how stabilization surfactants of O/W emulsions influence the irreversible fouling of ceramic membranes during ultrafiltration. An unexpected phenomenon observed was that irreversible fouling was much less when the charge of the stabilization surfactant of O/W emulsions is opposite to the membrane. The less ceramic membrane fouling in this case was proposed to be due to a synergetic steric effect and demulsification effect which prevented the penetration of oil droplets into membrane pores and led to less pore blockage. This proposed mechanism was supported by cross section images of fouled and virgin ceramic membranes taken with scanning electron microscopy, regression results of classical fouling models, and analysis of organic components rejected by the membrane. Furthermore, this mechanism was also verified by the existence of a steric effect and demulsification effect. Our finding suggests that ceramic membrane oppositely charged to the stabilization surfactant should be applied in ultrafiltration of O/W emulsions to alleviate irreversible membrane fouling. It could be a useful rule for ceramic membrane ultrafiltration of oily wastewater. PMID- 25730121 TI - Side of basal ganglia degeneration influences freezing of gait in Parkinson's disease. AB - Although the role of hemispheric laterality in freezing of gait (FOG) remains a topic of debate, important new evidence has suggested that individuals with Parkinson's disease (PD) who experience freezing of gait (PD-FOG) may have decreased activity in the circuitry of the right fronto-parietal cortices, irrespective of the side of basal ganglia (BG) degeneration. Because the right hemisphere plays an important role in monitoring sensorimotor information during movements, and cortical regions interact with BG loops, one could expect that right cortical dysfunction in PD-FOG might be exacerbated by right sided BG damage (compared to left). The current study aimed to evaluate the influence of asymmetrical BG degeneration on self-paced gait in PD-FOG and PD-nonFOG. This study compared gait performance in predominantly left- or right-side affected PD patients with or without freezing of gait (LFOG = 11, RFOG = 10, LPD = 15, RPD = 11). Participants were instructed to walk 10m on a GaitRite(r) carpet. As expected, gait parameters in PD-FOG were worse compared to PD-nonFOG. The spatiotemporal aspects of gait did not differ between LPD and RPD (nonFOG patients). Contrary to our hypothesis, RFOG (predominantly right side symptoms) had a shorter step length, increased step time variability and tended to walk slower compared with LFOG. Thus, rather than severely impaired right hemisphere circuitries exacerbating gait impairments, worse gait may be a consequence of both hemispheres being affected in PD-FOG. PMID- 25730120 TI - Amygdalo-striatal interaction in the enhancement of stimulus salience in associative learning. AB - Function of the central nucleus of the amygdala (CeA) is critical to 2 aspects of attention in associative learning: the conditioning of orienting responses (ORs) to cues paired with food, and the enhancement of cue salience by the surprising omission of expected events. Such salience enhancements have been found to depend on interactions within a circuit that includes CeA, the substantia nigra pars compacta (SNc), the substantia innominata (SI), and the posterior parietal cortex (PPC). The acquisition and expression of conditioned ORs requires interactions among CeA, SNc, and the dorsal lateral striatum (DLS), but not SI or PPC. Here, we considered whether CeA-DLS interactions are also important in surprise-induced salience enhancements in a serial prediction task. Rats received unilateral lesions of CeA and DLS, either contralaterally, which disrupted interactions between those structures, or ipsilaterally, which produced comparable damage to each structure but permitted interactions between them in 1 hemisphere. Rats with ipsilateral lesions of CeA and DLS showed the salience enhancements normally observed in this task, but rats with contralateral lesions of those structures did not. Thus, convergence of information processing by CeA and DLS is essential for surprise-induced salience enhancements, as well as for conditioned ORs. PMID- 25730122 TI - Persistent hyperactivity and distinctive strategy features in the Morris water maze in 3xTg-AD mice at advanced stages of disease. AB - Search strategies in the Morris water maze provide useful insights on cognitive function that may reveal genotype differences not reflected by escape latency or distance. Its analysis is pointed out as a complementary tool to better define the phenotype and the effect of treatments in animal models in which both cognitive impairment and behavioral symptoms reproduce the clinical complexity of the Alzheimer's disease patient. Here, we studied the performance of 13-month-old male 3xTg-AD mice in 3 different paradigms (cue learning, place task, and probe trial) and as compared with age-matched nontransgenic mice. The quantitative analysis (escape latency, distance, and speed) showed that in all tasks, the cognitive performance of 3xTg-AD mice was interfered with by a persistent hyperactive pattern. Their worse cognitive function was revealed by the qualitative features of nonsearch behaviors (floating and circling) and search strategies (single and /mixed, goal directed and nongoal directed). The search pattern was based on mixed and nongoal-directed strategies, in contrast to the single and goal-directed strategies used by controls. In the place task, poor cognitive flexibility of 3xTg-AD mice was also shown in persistence of search in the cue-trained position and the need to correct the strategy to find the new location. Trials involving a naive situation (first trial of the cue task) or the difficulty of a new task (first trial of the place task and the probe trial) were the most suitable to show the deficits. This qualitative analysis may also be useful in the assessment of preventive or therapeutical treatments. PMID- 25730123 TI - Traumatic brain injury in late adolescent rats: effects on adulthood memory and anxiety. AB - The consequences of traumatic brain injury (TBI) sustained during late adolescence (7 weeks old) on spontaneous object recognition memory and on anxiety like behaviors in the elevated plus maze were tested in rats during adulthood. Testing took place at 2 different postinjury times, in separate groups: 3 and 6 weeks, when animals were 10 and 13 weeks old, respectively. The rats were either submitted to controlled cortical impact injury, an experimental model of focal TBI with contusion, or were sham-operated. TBI animals failed to remember the familiar object and had a significantly lower performance than sham-operated animals, indicating memory disruption, when the retention delay was 24 hr, but not when it was 3 hr. TBI did not have any significant effect on the main anxiety related behaviors, but it reduced time in the central platform of the elevated plus maze. The effects of TBI on memory and on anxiety-like behaviors were similar at the 2 postinjury times. In both TBI and sham-operated groups, animals tested 6 weeks after surgery had lower anxiety-related indices than those tested at 3 weeks, an effect that might be indicative of reduced anxiety levels with increasing age. In summary, focal TBI with contusion sustained during late adolescence led to object recognition memory deficits in a 24-hr test during adulthood but did not have a major impact on anxiety-like behaviors. Memory deficits persisted for at least 6 weeks after injury, indicating that spontaneous modifications of these functional disturbances did not take place along this time span. PMID- 25730125 TI - Inhibition of motor-related activation during a simple reaction time task requiring visuomotor mental rotation. AB - The present study investigated whether differences in reaction time (RT) between movements initiated to a visual cue (directly cued) versus movements initiated to a location other than the visual cue (indirectly cued) arise because of varying levels of inhibition within the motor system during response preparation. Unlike typical visuomotor mental rotation (VMR) experiments, this study employed a simple RT paradigm to allow response preparation to occur in advance of the imperative stimulus (IS). Participants responded to the IS by either moving directly to the location of a visual cue or to a location that required a mental transformation between the visual cue and the intended movement goal (i.e., a location 60, 90, or 120 degrees rotated with respect to the visual cue). To probe motor-related activation during response preparation, a startling acoustic stimulus (SAS, 124 dB) was randomly presented 500 ms, 1,000 ms, or 1,500 ms after visual cue onset, but before the IS. Results showed similar RTs during nonstartle control trials regardless of rotation angle and whether trials were completed in a random or blocked design. Additionally, SAS trials showed a low incidence of early response triggering across all time points regardless of whether the movement was directly or indirectly cued. In contrast, directly cued movements performed outside of the VMR context showed a high incidence of SAS response triggering. These results suggest that when a stimulus to target-goal transformation might be required, inhibitory suppression of motor-related activation arises regardless of whether the final movement is directly or indirectly cued. PMID- 25730124 TI - Anxiety is correlated with running in adolescent female mice undergoing activity based anorexia. AB - Activity-based anorexia (ABA) is a widely used animal model for identifying the biological basis of excessive exercise and starvation, 2 hallmarks of anorexia nervosa (AN). Anxiety is correlated with exercise in AN. Yet the anxiety level of animals in ABA has not been reported. We asked: Does food restriction as part of ABA induction change the anxiety level of animals? If so, is the degree of anxiety correlated with degree of hyperactivity? We used the open field test before food restriction and the elevated plus maze test (EPM) during food restriction to quantify anxiety among singly housed adolescent female mice and determined whether food restriction alone or combined with exercise (i.e., ABA induction) abates or increases anxiety. We show that food restriction, with or without exercise, reduced anxiety significantly, as measured by the proportion of entries into the open arms of EPM (35.73%, p = .04). Moreover, ABA-induced individuals varied in their open arm time measure of anxiety and this value was highly and negatively correlated to the individual's food restriction-evoked wheel activity during the 24 hr following the anxiety test (R = -.75, p = .004, N = 12). This correlation was absent among the exercise-only controls. In addition, mice with higher increase in anxiety ran more following food restriction. Our data suggest that food restriction-evoked wheel running hyperactivity can be used as a reliable and continuous measure of anxiety in ABA. The parallel relationship between anxiety level and activity in AN and ABA-induced female mice strengthens the animal model. PMID- 25730126 TI - Electron transfer, decoherence, and protein dynamics: insights from atomistic simulations. AB - Electron transfer in biological systems drives the processes of life. From cellular respiration to photosynthesis and enzymatic catalysis, electron transfers (ET) are chemical processes on which essential biological functions rely. Over the last 40 years, scientists have sought understanding of how these essential processes function in biology. One important breakthrough was the discovery that Marcus theory (MT) of electron transfer is applicable to biological systems. Chemists have experimentally collected both the reorganization energies (lambda) and the driving forces (DeltaG degrees ), two parameters of Marcus theory, for a large variety of ET processes in proteins. At the same time, theoretical chemists have developed computational approaches that rely on molecular dynamics and quantum chemistry calculations to access numerical estimates of lambda and DeltaG degrees . Yet another crucial piece in determining the rate of an electron transfer is the electronic coupling between the initial and final electronic wave functions. This is an important prefactor in the nonadiabatic rate expression, since it reflects the probability that an electron tunnels from the electron donor to the acceptor through the intervening medium. The fact that a protein matrix supports electron tunneling much more efficiently than vacuum is now well documented, both experimentally and theoretically. Meanwhile, many chemists have provided examples of the rich physical chemistry that can be induced by protein dynamics. This Account describes our studies of the dynamical effects on electron tunneling. We present our analysis of two examples of natural biological systems through MD simulations and tunneling pathway analyses. Through these examples, we show that protein dynamics sustain efficient tunneling. Second, we introduce two time scales: taucoh and tauFC. The former characterizes how fast the electronic coupling varies with nuclear vibrations (which cause dephasing). The latter reflects the time taken by the system to leave the crossing region. In the framework of open quantum systems, tauFC is a short time approximation of the characteristic decoherence time of the electronic subsystem in interaction with its nuclear environment. The comparison of the respective values of taucoh and tauFC allows us to probe the occurrence of non-Condon effects. We use ab initio MD simulations to analyze how decoherence appears in several biological cofactors. We conclude that we cannot account for its order of magnitude by considering only the atoms or bonds directly concerned with the transfer. Decoherence results from contributions from all atoms of the system appearing with a time delay that increases with the distance from the primarily concerned atoms or bonds. The delay and magnitude of the contributions depend on the chemical nature of the system. Finally, we present recent developments based on constrained DFT for efficient and accurate evaluations of the electronic coupling in ab initio MD simulations. These are promising methods to study the subtle fluctuations of the electronic coupling and the mechanisms of electronic decoherence in biological systems. PMID- 25730128 TI - The relevance of the public-private partnership paradigm to the prevention of diet-associated non-communicable diseases in wealthy countries. AB - The public-private partnership (PPP) paradigm emerged as a form of global health governance in the mid-1990s to overcome state and market failures constraining access to essential medicines among populations with limited purchasing power in low- and middle-income countries. PPPs are now ubiquitous across the development spectrum. Yet while the narrative that the private sector must be engaged if complex health challenges are to be overcome is now dominant in development discourse, it does not yet appear to be shaping government approaches to addressing health inequalities within high-income welfare states such as Canada. This is significant as both the actions and inactions of firms factor heavily into why low-income Canadians face a disproportionate risk of developing diet associated chronic diseases, such as type II diabetes. In the same ways PPPs have been an effective policy tool for strengthening public health in poor countries, this paper illuminates how the PPP model may have utility for mitigating poverty associated food insecurity giving rise to diet-associated non-communicable diseases within the context of wealthy states. PMID- 25730131 TI - Relapse prevention for chemically addicted adolescents in recovery: so which model works? AB - In line with international trends, adolescent chemical addiction remains a significant challenge in South African communities, specifically in the Western Cape. Much emphasis is placed on prevention and treatment, while aftercare as part of treatment receives limited attention. Research does highlight specific aftercare needs of addicted adolescents, while literature provides different models of relapse prevention as part of aftercare, aimed at adults. However, the needs of addicted adolescents in recovery and the different models need to be linked. In this article the author first lists specific needs of chemically addicted adolescents, and secondly explores different models of care. Thirdly, functional elements related to the identified needs are identified. Recommendations for a comprehensive aftercare program are made based on the identified functional elements. PMID- 25730130 TI - A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach. AB - Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular pruning approach to the hardly optimizable and not very cell-permeable garcinol core structure, we prepared many analogues that were screened for their inhibitory effects using biochemical and biophysical (SPR) assays. Further optimization led to the discovery of the benzylidenebarbituric acid derivative 7h (EML425) as a potent and selective reversible inhibitor of CBP/p300, noncompetitive versus both acetyl-CoA and a histone H3 peptide, and endowed with good cell permeability. Furthermore, in human leukemia U937 cells, it induced a marked and time-dependent reduction in the acetylation of lysine H4K5 and H3K9, a marked arrest in the G0/G1 phase and a significant increase in the hypodiploid nuclei percentage. PMID- 25730129 TI - The impact of health behaviours on incident cardiovascular disease in Europeans and South Asians--a prospective analysis in the UK SABRE study. AB - BACKGROUND: There is consistent evidence on the impact of health behaviours on risk of cardiovascular disease (CVD) in European populations. As South Asians in the UK have an excess risk of CVD and coronary heart disease (CHD) compared to Europeans, we investigated whether a similar association between combined health behaviours and risk of CVD and CHD among this high-risk group exists, and estimated the population impact. METHODS AND FINDINGS: In a prospective cohort of 1090 Europeans and 1006 South Asians (40-69 y) without prevalent CVD at baseline (1988-1990), followed up for 21 years to 2011, there were 601 incident CVD events [Europeans n = 255; South Asians n = 346] of which 520 were CHD events [n = 207 and 313 respectively]. Participants scored between 0 to 4 points for a composite score including four baseline healthy behaviours (non-smoker, moderate alcohol intake, physically active, frequent fruit/vegetable intake). Adjusted hazard ratios (95% confidence intervals) for incident CHD in Europeans who had three, two, one, and zero compared to four health behaviours were 1.33 (0.78-2.29), 1.96 (1.15-3.33), 1.36 (0.74-2.48) and 2.45 (1.18-5.10), respectively, p-trend = 0.025. In South Asians, corresponding HRs were 2.88 (1.33-6.24), 2.28 (1.06 4.91), 3.36 (1.53-7.39) and 3.48 (1.38-8.81), p-trend = 0.022. The results were similar for incident CVD; Europeans HR 2.12 (1.14-3.94), p-trend = 0.014; South Asians HR 2.73 (1.20-6.21), p-trend = 0.018. The population attributable fraction in Europeans was 43% for CHD and 28% for CVD. In South Asians it was 63% and 51% respectively. CONCLUSIONS: Lack of adherence to four combined health behaviours was associated with 2 to 3-fold increased risk of incident CVD in Europeans and South Asians. A substantial population impact in the South Asian group indicates important potential for disease prevention in this high-risk group by adherence to healthy behaviours. PMID- 25730132 TI - Obstetric ultrasound quality improvement initiative-utilization of a quality assurance process and standardized checklists. AB - OBJECTIVE: Our aim was to assess whether mandated completion of an electronic checklist and a quality assurance (QA) process improved obstetric (OB) ultrasound image documentation. STUDY DESIGN: A checklist of mandated images based on the American Institute of Ultrasound in Medicine guidelines was created. A baseline QA assessment was performed with a lead senior sonographer reviewing eight random OB examinations for each sonographer. An electronic checklist was then instituted for all OB examinations on each ultrasound machine. It was mandated that each anatomical structure be checked off during real-time image acquisition. A repeat QA assessment of each sonographer was then performed quarterly. RESULTS: Baseline assessments were performed between September 2011 and November 2011. Out of the 110 examinations analyzed, only 49% were deemed "complete" with none of the sonographers having a 100% complete examination rate. Following institution of the mandated electronic checklist, a repeat assessment revealed an 81% complete examination rate for the next quarter, and 90% were complete at the end of a year. All sonographers improved their image acquisition regardless of baseline skill level at the initial QA. CONCLUSION: A QA process and a mandated standardized electronic checklist improved the image documentation. PMID- 25730134 TI - Ultrasonographic Fetal Weight Estimation: Should Macrosomia-Specific Formulas Be Utilized? AB - OBJECTIVE: This study aims to derive an estimated fetal weight (EFW) formula in macrosomic fetuses, compare its accuracy to the 1986 Hadlock IV formula, and assess whether including maternal diabetes (MDM) improves estimation. STUDY DESIGN: Retrospective review of nonanomalous live-born singletons with birth weight (BWT) >= 4 kg and biometry within 14 days of birth. Formula accuracy included: (1) mean error (ME = EFW - BWT), (2) absolute mean error (AME = absolute value of [1]), and (3) mean percent error (MPE, [1]/BWT * 100%). Using loge BWT as the dependent variable, multivariable linear regression produced a macrosomic-specific formula in a "training" dataset which was verified by "validation" data. Formulas specific for MDM were also developed. RESULTS: Out of the 403 pregnancies, birth gestational age was 39.5 +/- 1.4 weeks, and median BWT was 4,240 g. The macrosomic formula from the training data (n = 201) had associated ME = 54 +/- 284 g, AME = 234 +/- 167 g, and MPE = 1.6 +/- 6.2%; evaluation in the validation dataset (n = 202) showed similar errors. The Hadlock formula had associated ME = -369 +/- 422 g, AME = 451 +/- 332 g, MPE = -8.3 +/- 9.3% (all p < 0.0001). Diabetes-specific formula errors were similar to the macrosomic formula errors (all p = NS). CONCLUSIONS: With BWT >= 4 kg, the macrosomic formula was significantly more accurate than Hadlock IV, which systematically underestimates fetal/BWT. Diabetes-specific formulas did not improve accuracy. A specific formula should be considered when macrosomia is suspected. PMID- 25730137 TI - A retrospective study of peanut and tree nut allergy: Sensitization and correlations with clinical manifestations. AB - Peanut (PN) and tree nut (TN) allergies are among the leading causes of fatal food-induced anaphylaxis and are increasing in prevalence, especially in children. Their cosensitization and concurrent clinical allergy have been understudied. This retrospective study investigated the correlation between PN and TN allergy, both in terms of in vitro sensitization (IVS) and clinical allergic manifestations. We conducted a retrospective medical record review at the Allergy Clinic at University Hospital of Brooklyn. Fourteen hundred six charts were reviewed, of which 76 (5.4%) had documented relevant clinical allergy: PN allergy but not TN allergy (n = 29) or TN allergy but not PN allergy (n = 11) or both (n = 30). Six patients with PN allergy but no TN exposure history were not included in the analysis. The majority of patients (67/76, 88.1%) had a concurrent history of asthma, rhinoconjunctivitis, or AD. Sensitivity of TN IVS predicting PN IVS was 38/39 (97%). Similarly, sensitivity of PN IVS predicting TN IVS was 38/42 (91%). Sensitivity of TN clinical allergy predicting PN allergy was 30/59 (51%). Sensitivity of PN clinical allergy predicting TN allergy was 30/41 (73%). The total number of organ systems involved in reported clinical reactions correlated with IVS to TN (p = 0.004) but not IVS to PN (p = 0.983). In summary, we found PN sensitization predicts TN sensitization in vitro, with lower predictability for clinical reactions. PMID- 25730135 TI - Screening Cranial Imaging at Multiple Time Points Improves Cystic Periventricular Leukomalacia Detection. AB - OBJECTIVE: The aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points. DESIGN: We retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants < 1,000 g birth weight or < 29 weeks' gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS] < 28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria. RESULTS: About 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants < 26 weeks' gestation versus infants of 26 to 28 weeks' gestation (18.5 vs. 11.5%; p = 0.013). CONCLUSIONS: Cranial imaging at both < 28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants. PMID- 25730138 TI - Novel supercritical carbon dioxide impregnation technique for the production of amorphous solid drug dispersions: a comparison to hot melt extrusion. AB - The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the gamma-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations. PMID- 25730139 TI - Fabrication of ultrathin CoMoO4 nanosheets modified with chitosan and their improved performance in energy storage device. AB - Ultrathin nanosheet-assembled cobalt molybdate (CoMoO4) with a mesoporous morphology was synthesized by a urea-assisted solution combustion route at a temperature of 400 degrees C. The as-prepared CoMoO4 was modified using chitosan cross-linked with glutaraldehyde (glu) and employed as a cathode material in an aqueous hybrid capacitor. The physical and electrochemical behaviour of CoMoO4 modified with chitosan and the as-prepared (chitosan free) CoMoO4 has been compared and discussed. The modified CoMoO4 exhibited excellent electrochemical performance with a specific capacitance of 135 F g(-1) at 0.6 A g(-1) and an energy density of 31 W h kg(-1). It also exhibited good cycling stability with high coulombic efficiency over 2000 cycles retaining a specific capacitance of 81 F g(-1) at 3 A g(-1), comparatively much better than that of nanostructured chitosan free CoMoO4 which yielded 17 F g(-1). The results indicated that chitosan gel strongly adheres to the molybdate moiety of CoMoO4 and increases the capacitance four-fold compared to a chitosan free material. The modified CoMoO4 electrode shows potential for high performance, and is an environmentally friendly and low-cost energy storage device. PMID- 25730133 TI - Relation between birth weight and weight and height at the age of 2 in children born preterm. AB - OBJECTIVE: The aim of the study was to evaluate associations between fetal growth and weight at 2 years in infants born preterm using a customized approach for birth weight. STUDY DESIGN: This is a secondary analysis of a multicenter trial that included a 2-year follow-up of children born prematurely. Customized birth weight percentiles were calculated using the Gardosi model for a U.S. population, and the relation between customized percentile and weight and height at 2 years (adjusted for gender using z-score) was determined using regression analysis and by comparing z-scores for children with birth weight <10th versus >=10th percentile. RESULTS: Weight z-score at 2 years was significantly lower in the <10th than in the >=10th percentile group (median [interquartile range, IQR]: 0.66 [-1.58, -0.01] vs. -0.23 [-1.05, 0.55]; p < 0.001), and remained after adjusting for maternal education (p < 0.001). A similar relationship was noted for height z-score between groups (median [IQR]: -0.56 [-1.29, 0.19] vs. -0.24 [ 0.99, 0.37]; p < 0.001). Positive relationships between customized birth weight percentile and weight and height at 2 years were noted (p < 0.001 for both), but were not strong (R (2) = 0.04 and 0.02, respectively). CONCLUSION: Customized birth weight percentile is a minor determinant of weight at 2 years among children born preterm. PMID- 25730140 TI - Action-at-a-distance mutagenesis induced by oxidized guanine in Werner syndrome protein-reduced human cells. AB - 8-Oxo-7,8-dihydroguanine (G(O), 8-hydroxyguanine) in DNA is one of the most important oxidatively damaged bases and causes G:C -> T:A substitution mutations. The Werner syndrome protein (WRN) is a cancer-related RecQ DNA helicase and plays many roles in DNA replication and repair. To examine the relationships between G(O)-induced mutations and WRN, shuttle plasmid DNA containing a G(O):C pair in the supF gene was transfected into human U2OS cells, in which WRN was knocked down. The plasmid DNA replicated in the knockdown cells was introduced into an Escherichia coli indicator strain. The knockdown of WRN increased the mutant frequency of the G(O)-plasmid DNA. Unexpectedly, however, the WRN knockdown only slightly enhanced the targeted G:C -> T:A mutation. Instead, base-substitution mutations at various positions were more frequently detected, with statistical significance. The results obtained in this study suggested that the reduction of the cancer-related WRN induced action-at-a-distance mutagenesis by the G(O):C pair in human cells. In addition, the WRN knockdown decreased the G(O):A-induced A:T -> C:G mutations, suggesting that WRN may enhance the mutations caused by G(O) in the nucleotide pool. PMID- 25730142 TI - Necrotizing enterocolitis as an adverse effect of recombinant interleukin-2 and Ch14.18 in maintenance therapy for high-risk neuroblastoma. AB - Recombinant interleukin-2 is used with ch14.18/CHO to improve the cytotoxic activity of NK lymphocytes against neoplastic cells. The efficacy of this treatment is limited by its potential side effects. We report an unusual case of necrotizing enterocolitis associated with the administration of interleukin-2 and ch14.18/CHO in maintenance therapy for localized NMyc amplified neuroblastoma (NBL). This case highlights the potentially significant toxicity of this immunotherapy that is currently being tested in the high-risk NBL-1.5 protocol. Further, short-term, medium-term, and long-term follow-up in this patient population will be warranted to judge the potential benefit of this treatment versus the short-term, medium-term, and long-term side effects in a patient population with an outcome that is better than that of stage 4 NBL patients. PMID- 25730141 TI - Visualizing the interior architecture of focal adhesions with high-resolution traction maps. AB - Focal adhesions (FAs) are micron-sized protein assemblies that coordinate cell adhesion, migration, and mechanotransduction. How the many proteins within FAs are organized into force sensing and transmitting structures is poorly understood. We combined fluorescent molecular tension sensors with super resolution light microscopy to visualize traction forces within FAs with <100 nm spatial resolution. We find that alphavbeta3 integrin selectively localizes to high force regions. Paxillin, which is not generally considered to play a direct role in force transmission, shows a higher degree of spatial correlation with force than vinculin, talin, or alpha-actinin, proteins with hypothesized roles as force transducers. These observations suggest that alphavbeta3 integrin and paxillin may play important roles in mechanotransduction. PMID- 25730143 TI - Teen Dating Violence (Physical and Sexual) Among US High School Students: Findings From the 2013 National Youth Risk Behavior Survey. AB - IMPORTANCE: National estimates of teen dating violence (TDV) reveal high rates of victimization among high school populations. The Centers for Disease Control and Prevention's national Youth Risk Behavior Survey has provided often-cited estimates of physical TDV since 1999. In 2013, revisions were made to the physical TDV question to capture more serious forms of physical TDV and to screen out students who did not date. An additional question was added to assess sexual TDV. OBJECTIVES: To describe the content of new physical and sexual TDV victimization questions first administered in the 2013 national Youth Risk Behavior Survey, to share data on the prevalence and frequency of TDV (including the first-ever published overall "both physical and sexual TDV" and "any TDV" national estimates using these new questions), and to assess associations of TDV experience with health-risk behaviors. DESIGN, SETTING, AND PARTICIPANTS: Secondary data analysis of a cross-sectional survey of 9900 students who dated, from a nationally representative sample of US high school students, using the 2013 national Youth Risk Behavior Survey. MAIN OUTCOMES AND MEASURES: Two survey questions separately assessed physical and sexual TDV; this analysis combined them to create a 4-level TDV measure and a 2-level TDV measure. The 4-level TDV measure includes "physical TDV only," "sexual TDV only," "both physical and sexual TDV," and "none." The 2-level TDV measure includes "any TDV" (either or both physical and sexual TDV) and "none." Sex-stratified bivariate and multivariable analyses assessed associations between TDV and health-risk behaviors. RESULTS: In 2013, among students who dated, 20.9% of female students (95% CI, 19.0%-23.0%) and 10.4% of male students (95% CI, 9.0%-11.7%) experienced some form of TDV during the 12 months before the survey. Female students had a higher prevalence than male students of physical TDV only, sexual TDV only, both physical and sexual TDV, and any TDV. All health-risk behaviors were most prevalent among students who experienced both forms of TDV and were least prevalent among students who experienced none (all P < .001). CONCLUSIONS AND RELEVANCE: The 2013 TDV questions allowed for new prevalence estimates of TDV to be established that represent a more complete measure of TDV and are useful in determining associations with health-risk behaviors among youth exposed to these different forms of TDV. PMID- 25730144 TI - Insights into the molecular basis of a bispecific antibody's target selectivity. AB - Bispecific antibodies constitute a valuable class of therapeutics owing to their ability to bind 2 distinct targets. Dual targeting is thought to enhance biological efficacy, limit escape mechanisms, and increase target selectivity via a strong avidity effect mediated by concurrent binding to both antigens on the surface of the same cell. However, factors that regulate the extent of target selectivity are not well understood. We show that dual targeting alone is not sufficient to promote efficient target selectivity, and report the substantial roles played by the affinity of the individual arms, overall avidity and valence. More particularly, various monovalent bispecific IgGs composed of an anti-CD70 moiety paired with variants of the anti-CD4 mAb ibalizumab were tested for preferential binding and selective depletion of CD4(+)/CD70(+) T cells over cells expressing only one of the target antigens that resulted from antibody dependent cell-mediated cytotoxicity. Variants exhibiting reduced CD4 affinity showed a greater degree of target selectivity, while the overall efficacy of the bispecific molecule was not affected. PMID- 25730145 TI - Comparison of the QMS Analyzer With HPLC-UV for the Quantification of Lamotrigine Concentrations in Human Plasma Samples. AB - BACKGROUND: Recently, a turbidimetric immunoassay method has been developed for use in the form of a QMS lamotrigine (LTG) commercial immunoassay. This study was designed to evaluate the performance of this immunoassay using a validated high performance liquid chromatography-ultraviolet (HPLC-UV) method as the reference. METHODS: The performance of QMS was initially tested using drug-free plasma spiked with different amounts of LTG and, subsequently, by analyzing 61 trough plasma samples from epileptic patients given the drug as part of their maintenance antiepileptic therapies. RESULTS: The correlation between LTG concentrations measured by QMS and HPLC was good, with a Pearson coefficient of 0.968 (P < 0.0001). The Bland-Altman approach showed that LTG concentrations measured with QMS exceeded HPLC on an average by 15.6% (limits of agreement, -18% to +63%), with a concentration-dependent performance (mean percent bias, 49.5 +/- 8.2% and 0.6 +/- 12.7% for concentrations less than 2 mg/L and greater than 14.9 mg/L, respectively). CONCLUSIONS: The QMS provided acceptable analytical performance across a wide concentration range for routine LTG measurements, being at least comparable with the other commercial immunoassays. It could be, therefore, considered as a viable alternative to HPLC methods for routine LTG monitoring in the clinical practice, although its suitability for accurate analysis of samples with low concentration is limited. PMID- 25730146 TI - Temperature dependent phonon shifts in few-layer black phosphorus. AB - Atomically thin two-dimensional (2D) sheets of black phosphorus have attracted much attention due to their potential for future nanoelectronic and photonics device applications. Present investigations deal with the temperature dependent phonon shifts in a few-layer black phosphorus nanosheet sample prepared using micromechanical exfoliation on a 300 nm SiO2/Si substrate. The temperature dependent Raman spectroscopy experiments were carried out on a few-layer black phosphorus sample, which depicts softening of Ag(1), B2g, and Ag(2) modes as temperature increases from 77 to 673 K. The calculated temperature coefficients for Ag(1), B2g, and Ag(2) modes of the few-layer black phosphorus nanosheet sample were observed to be -0.01, -0.013, and -0.014 cm(-1) K(-1), respectively. The temperature dependent softening modes of black phosphorus results were explained on the basis of a double resonance process which is more active in an atomically thin sample. This process can also be fundamentally pertinent in other promising and emerging 2D ultrathin layer and heterostructured materials. PMID- 25730154 TI - Replacement of Retained Deciduous Tooth by Immediate Implant Placement. PMID- 25730155 TI - An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease. AB - We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12 lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing. PMID- 25730156 TI - Tacrolimus Toxicity With Minimal Clinical Manifestations: A Case Report and Literature Review. AB - Tacrolimus (FK 506 or Fujimycin) is an effective anti-T-cell agent derived from the fungus Streptomyces tsukubaensis. Some in vitro studies have demonstrated that the potency of tacrolimus can be up to 100 times to that of cyclosporine. Despite being a very potent immunosuppressant, its use is complicated by narrow therapeutic range, individual variation in pharmacokinetics, and a broad spectrum of drug interactions. We report a case of very high tacrolimus level (>120 ng/mL) in a patient who was on antiretroviral medication and tacrolimus. Despite having such high drug levels, patient's clinical presentation and course was benign. He was managed conservatively and this ordeal resulting in no long-term sequela. PMID- 25730157 TI - Toward Large-Scale Process Control to Enable Consistent CT Radiation Dose Optimization. AB - OBJECTIVE: This article reviews the concepts of CT radiation dose optimization and process control, discusses how to achieve optimization and how to verify that it is consistently accomplished, and proposes strategies to move toward large scale application. CONCLUSION: CT dose optimization is achieved when the least amount of radiation necessary is used to achieve adequate image quality. The key to consistent optimization is minimization of unnecessary variation. This minimization is accomplished through local process control mechanisms. PMID- 25730158 TI - Layer-by-layer assembly of aquaporin Z-incorporated biomimetic membranes for water purification. AB - We fabricated a biomimetic nanofiltration (NF) membrane by immobilizing an Aquaporin Z (AqpZ)-incorporated supported lipid bilayer (SLB) on a layer-by-layer (LbL) complex polyelectrolyte membrane to achieve excellent permeability and salt rejection with a high stability. The polyelectrolyte membranes were prepared by LbL assembly of poly(ethylenimine) (PEI) with positive charges and poly(sodium 4 styrenesulfonate) (PSS) with negative charges alternately on a porous hydrolyzed polyacrylonitrile (H-PAN) substrate. AqpZ-incorporated 1,2-dioleloyl-sn-glycero-3 phosphocholine (DOPC)/1,2-dioleoyl-3-trimethylammo-nium-propane (chloride salt) (DOTAP) vesicles with positive charges were deposited on the H-PAN/PEI/PSS polyelectrolytes membrane surface. The resulting biomimetic membrane exhibited a high flux of 22 L.m(-2).h(-1) (LMH), excellent MgCl2 rejection of ~97% and NaCl rejection of ~75% under an operation pressure of 0.4 MPa. Due to the attractive electrostatic interaction between SLB and the polyelectrolyte membrane, the biomimetic membrane showed satisfactory stability and durability as well as stable NF flux and rejection for at least 36 h. In addition, the AqpZ-containing biomimetic membrane was immersed in a 0.24 mM (critical micellar concentration, CMC) Triton X-100 solution for 5 min. The flux and rejection were slightly influenced by the Triton X-100 treatment. The current investigation demonstrated that the AqpZ-incorporated biomimetic membranes fabricated by the LbL method led to excellent separation performances and robust structures that withstand a high operation pressure for a relatively long time. PMID- 25730159 TI - Microfluidic fabrication and micromechanics of permeable and impermeable elastomeric microbubbles. AB - We use droplet microfluidics to produce monodisperse elastomeric microbubbles consisting of gas encapsulated in a polydimethylsiloxane shell. These microbubbles withstand large, repeated deformations without rupture. We perform MUN-scale compression tests on individual microbubbles and find their response to be highly dependent on the shell permeability; during deformation, the pressure inside impermeable microbubbles increases, resulting in an exponential increase in the applied force. Finite element models are used to interpret and extend these experimental results enabling the design and development of deformable microbubbles with a predictable mechanical response. Such microbubbles can be designed to repeatedly transit through the narrow constrictions found in a porous medium functioning as probes of the local pressure. PMID- 25730160 TI - Multi-item direct behavior ratings: Dependability of two levels of assessment specificity. AB - Direct Behavior Rating-Multi-Item Scales (DBR-MIS) have been developed as formative measures of behavioral assessment for use in school-based problem solving models. Initial research has examined the dependability of composite scores generated by summing all items comprising the scales. However, it has been argued that DBR-MIS may offer assessment of 2 levels of behavioral specificity (i.e., item-level, global composite-level). Further, it has been argued that scales can be individualized for each student to improve efficiency without sacrificing technical characteristics. The current study examines the dependability of 5 items comprising a DBR-MIS designed to measure classroom disruptive behavior. A series of generalizability theory and decision studies were conducted to examine the dependability of each item (calls out, noisy, clowns around, talks to classmates and out of seat), as well as a 3-item composite that was individualized for each student. Seven graduate students rated the behavior of 9 middle-school students on each item over 3 occasions. Ratings were based on 10-min video clips of students during mathematics instruction. Separate generalizability and decision studies were conducted for each item and for a 3-item composite that was individualized for each student based on the highest rated items on the first rating occasion. Findings indicate favorable dependability estimates for 3 of the 5 items and exceptional dependability estimates for the individualized composite. PMID- 25730161 TI - Initial and noninitial name-letter preferences as obtained through repeated letter rating tasks continue to reflect (different aspects of) self-esteem. AB - We tested the usefulness of name-letter preference scores as indirect indicators of self-esteem by exploring whether multiple unsupervised self-administrations of letter rating tasks within a short period of time yield useful data. We also examined whether preferences for initials and noninitial name-letters tap different aspects of self-esteem. Participants from a community sample (N = 164; 58 men and 106 women, 17-67 years, Mage = 34.57, SD = 13.28) completed daily letter rating tasks and state self-esteem questionnaires for 7 consecutive days. They also completed a trait self-esteem questionnaire on the first measurement day as well as 6 months later. Preference scores for first-name initials were stronger but more unstable than preference scores for other name-letters. Preferences for first-name initials were primarily associated with directly measured state self-esteem whereas preferences for noninitials were primarily associated with directly measured trait self-esteem even if the latter was measured 6 months later. Thus, we showed that preferences for initials and noninitials are not simply interchangeable. Previous letter rating studies, which almost exclusively used initial preferences, should be interpreted in terms of state rather than trait self-esteem. In future studies, researchers should focus on the name-letter preference that reflects the aspect of self-esteem they wish to address. PMID- 25730164 TI - Analysis of Minnesota Multiphasic Personality Inventory-2-Restructured Form response bias indicators as suppressors or moderators in a medical setting. AB - The use of response bias indicators in psychological measurement has been contentious, with debate as to whether they actually suppress or moderate the ability of substantive psychological indicators to identify the construct of interest. Suppression would indicate that predictor variables contain invalid variance that the bias indicators can suppress, while moderation would indicate differential levels of predictive validity at different levels of bias. Response bias indicators on the Minnesota Multiphasic Personality Inventory (MMPI)-2 Restructured Form (MMPI-2-RF) [infrequent responses (F-r), infrequent somatic responses (Fs), infrequent psychopathology responses (Fp-r), adjustment validity (K-r), uncommon virtues (L-r), symptom validity (FBS-r), and Response Bias Scale (RBS)] were tested to determine whether they suppressed or moderated the ability of the Restructured Clinical Scale 1 (RC1) and Neurologic Complaints (NUC) scale to discriminate between epileptic seizures (ES) and nonepileptic seizures (NES, a conversion disorder that is often misdiagnosed as ES). The MMPI-2-RF was completed by 399 patients with a confirmed diagnosis of ES or NES via Epilepsy Monitoring Unit evaluation. Moderated logistic regression was used to test for moderation, and logistic regression was used to test for suppression. Most of the response bias variables showed a suppressor effect, but moderator effects were not found. These findings extend the use of bias indicators to a psychomedical context. PMID- 25730162 TI - Integration of symptom ratings from multiple informants in ADHD diagnosis: a psychometric model with clinical utility. AB - The Diagnostic and Statistical Manual of Mental Disorder-Fifth Edition explicitly requires that attention-deficit/hyperactivity disorder (ADHD) symptoms should be apparent across settings, taking into account reports from multiple informants. Yet, it provides no guidelines how information from different raters should be combined in ADHD diagnosis. We examined the validity of different approaches using structural equation modeling (SEM) for multiple-informant data. Participants were 725 children, 6 to 17 years old, and their primary caregivers and teachers, recruited from the community and completing a thorough research based diagnostic assessment, including a clinician-administered diagnostic interview, parent and teacher standardized rating scales, and cognitive testing. A best-estimate ADHD diagnosis was generated by a diagnostic team. An SEM model demonstrated convergent validity among raters. We found relatively weak symptom specific agreement among raters, suggesting that a general average scoring algorithm is preferable to symptom-specific scoring algorithms such as the "or" and "and" algorithms. Finally, to illustrate the validity of this approach, we show that averaging makes it possible to reduce the number of items from 18 items to 8 items without a significant decrease in validity. In conclusion, information from multiple raters increases the validity of ADHD diagnosis, and averaging appears to be the optimal way to integrate information from multiple raters. PMID- 25730163 TI - Factor structure and factorial invariance of the Multidimensional Acculturative Stress Inventory. AB - Using a national data set, this study examined the factor structure and factorial invariance of the Multidimensional Acculturative Stress Inventory (MASI) across Latino and Asian Americans, gender, and nativity (U.S.- vs. foreign-born). Results showed that a 4-factor model of acculturative stress provided good fit to the data. Tests of factorial invariance provided evidence of measurement equivalence across all of the groupings tested. These findings suggest that the MASI operationalizes acculturative stress in an equivalent manner across Latino and Asian American students, gender, and nativity. PMID- 25730165 TI - The Oxford Cognitive Screen (OCS): validation of a stroke-specific short cognitive screening tool. AB - There is currently no existing freely available short screen for cognitive problems that targets stroke survivors specifically. We have developed a short cognitive screen, the Oxford Cognitive Screen (OCS), to be completed in 15-20 min, designed for use with stroke patients. To maximize inclusion, the test is aphasia- and neglect friendly and covers domains of cognition where deficits frequently occur after stroke, including apraxia and unilateral neglect as well as memory, language, executive function, and number abilities. Domain-specific scores are returned to help direct rehabilitation. This article presents the normative data in a large sample of 140 neurologically healthy participants, a report on incidences of impairments in a sample of 208 acute stroke patients (within 3 weeks of stroke onset), measures of test-retest reliability on an alternate form and convergent and divergent validity. In addition, the full test materials are made freely available for clinical use. PMID- 25730166 TI - Correction to Price et al. (2014). PMID- 25730167 TI - The utility of set-loss error scores in the general population. AB - Although the measurement of cognitive performance usually relies on achievement sum scores, a growing body of research suggests that the analysis of errors made may have a predictive validity beyond that provided by the number of items correct. This study examined the validity related to one such kind of error scores--the set-loss errors--in the general population of 8- to 11-year-old children. Set-loss errors (also called rule violations) can be conceptualized as a breakdown in the adherence to task-specific rules, and in clinical populations, the propensity to make these errors has shown some specificity for identifying disorders connected with frontal lobes dysfunction. The results, however, indicate that set-loss errors derived from distinct tests could not be effectively explained by a single latent dimension; hence, they do not tap a single construct that could be called set loss or the ability to maintain set. At the same time, there were only few weak associations between various kinds of error scores as well as between the set-loss error scores and relevant constructs such as the ability to learn, attentional control, working memory, fluid and crystallized intelligence, and executive functions-related real-world behaviors, indicating an overrepresentation of construct-irrelevant variance in these kinds of scores. These indications were further accentuated by the analysis of sensitivity and specificity where any elevated number of set-loss error scores was unable to classify individuals on theoretically relevant constructs beyond chance levels. The evidence thus speaks against the use of set-loss error scores in the general population of 8- to 11-year-old children. PMID- 25730168 TI - Luminescence blinking of a reacting quantum dot. AB - Luminescence blinking is an inherent feature of optical emission from individual fluorescent molecules and quantum dots. There have been intense efforts, although not with complete resolution, toward the understanding of the mechanistic origin of blinking and also its mitigation in quantum dots. As an advance in our microscopic view of blinking, we show that the luminescence blinking of a quantum dot becomes unusually heavy in the temporal vicinity of a reactive transformation. This stage of heavy blinking is a result of defects/dopants formed within the quantum dot on its path to conversion. The evolution of blinking behavior along the reaction path allows us to measure the lifetime of the critical dopant-related intermediate in the reaction. This work establishes luminescence blinking as a single-nanocrystal level probe of catalytic, photocatalytic, and electrochemical events occurring in the solid-state or on semiconductor surfaces. PMID- 25730169 TI - Errors of commission and omission in novice group counseling trainees' knowledge structures of group counseling situations. AB - This study investigated how novice group counseling trainees' knowledge structures about group situations differed from experts.' Eight highly experienced group therapists and 54 novice trainees indicated which of the 19 leader interventions they would consider using to respond to the 21 group situations described in the Group Therapy Questionnaire (GTQ, Wile, Bron, & Pollack, 1970). Pathfinder Network Analysis (Schvaneveldt, 1990) was used to generate knowledge structures (cognitive maps) about group situations based on the aggregated response of experts and each trainee's response to GTQ. Comparing trainees' maps with the referent expert map, we found no common errors of commission, that is, relationship between situations in trainees' knowledge maps but not in experts' knowledge maps, but 10 common errors of omission, that is, relationships among group situations in experts' knowledge maps but not in trainees' knowledge maps. Cluster analysis identified 2 subgroups of trainees. Neither of these trainee subgroups incorporated the group's developmental stage into their map of group situations as experts did: experts saw the situations during the beginning and ending phases of the group as similar but different from situations in the middle phase of the group. The first group of trainees had a holistic approach to group situations but tended to make errors in dealing with group situations involving a problematic member. The second group had an atomistic approach to group situations but lacked a clearly differentiated and structured general organization for the situations. They tended to make errors in dealing with challenging situations where the group is avoidant and lacks engagement. PMID- 25730170 TI - Social cognitive predictors of first- and non-first-generation college students' academic and life satisfaction. AB - The present study tested Lent's (2004) social-cognitive model of normative well being in a sample (N = 414) of first- and non-first-generation college students. A model depicting relationships between: positive affect, environmental supports, college self-efficacy, college outcome expectations, academic progress, academic satisfaction, and life satisfaction was examined using structural equation modeling. The moderating roles of perceived importance of attending college and intrinsic goal motivation were also explored. Results suggested the hypothesized model provided an adequate fit to the data while hypothesized relationships in the model were partially supported. Environmental supports predicted college self efficacy, college outcome expectations, and academic satisfaction. Furthermore, college self-efficacy predicted academic progress while college outcome expectations predicted academic satisfaction. Academic satisfaction, but not academic progress predicted life satisfaction. The structural model explained 44% of the variance in academic progress, 56% of the variance in academic satisfaction, and 28% of the variance in life satisfaction. Mediation analyses indicated several significant indirect effects between variables in the model while moderation analyses revealed a 3-way interaction between academic satisfaction, intrinsic motivation for attending college, and first-generation college student status on life satisfaction. Results are discussed in terms of applying the normative model of well-being to promote first- and non-first generation college students' academic and life satisfaction. PMID- 25730171 TI - Comparing two books and establishing probably efficacious treatment for low sexual desire. AB - Using a sample of 45 women, this study compared the effectiveness of a previously studied (Mintz, Balzer, Zhao, & Bush, 2012) bibliotherapy intervention (Mintz, 2009), a similar self-help book (Hall, 2004), and a wait-list control (WLC) group. To examine intervention effectiveness, between and within group standardized effect sizes (interpreted with Cohen's, 1988 benchmarks .20 = small, .50 = medium, .80+ = large) and their confidence limits are used. In comparison to the WLC group, both interventions yielded large between-group posttest effect sizes on a measure of sexual desire. Additionally, large between-group posttest effect sizes were found for sexual satisfaction and lubrication among those reading the Mintz book. When examining within-group pretest to posttest effect sizes, medium to large effects were found for desire, lubrication, and orgasm for both books and for satisfaction and arousal for those reading the Mintz book. When directly comparing the books, all between-group posttest effect sizes were likely obtained by chance. It is concluded that both books are equally effective in terms of the outcome of desire, but whether or not there is differential efficacy in terms of other domains of sexual functioning is equivocal. Tentative evidence is provided for the longer term effectiveness of both books in enhancing desire. Arguing for applying criteria for empirically supported treatments to self-help, results are purported to establish the Mintz book as probably efficacious and to comprise a first step in this designation for the Hall book. PMID- 25730172 TI - Set-up of a multivariate approach based on serum biomarkers as an alternative strategy for the screening evaluation of the potential abuse of growth promoters in veal calves. AB - A chemometric class modelling strategy (unequal dispersed classes - UNEQ) was applied for the first time as a possible screening method to monitor the abuse of growth promoters in veal calves. Five serum biomarkers, known to reflect the exposure to classes of compounds illegally used as growth promoters, were determined from 50 untreated animals in order to design a model of controls, representing veal calves reared under good, safe and highly standardised breeding conditions. The class modelling was applied to 421 commercially bred veal calves to separate them into 'compliant' and 'non-compliant' with respect to the modelled controls. Part of the non-compliant animals underwent further histological and chemical examinations to confirm the presence of either alterations in target tissues or traces of illegal substances commonly administered for growth-promoting purposes. Overall, the congruence between the histological or chemical methods and the UNEQ non-compliant outcomes was approximately 58%, likely underestimated due to the blindness nature of this examination. Further research is needed to confirm the validity of the UNEQ model in terms of sensitivity in recognising untreated animals as compliant to the controls, and specificity in revealing deviations from ideal breeding conditions, for example due to the abuse of growth promoters. PMID- 25730173 TI - Effects of chronic malnourishment and aging on the ultrastructure of pyramidal cells of the dorsal hippocampus. AB - OBJECTIVES: Malnourishment (M) produces permanent alterations during the development of the CNS and might modify the aging process. In pyramidal neurons (PN) of the hippocampus, which are associated with learning and memory performance, few studies have focused on changes at the subcellular level under chronic malnutrition (ChM) in young (Y, 2 months old) and aged (A, 22 months old) rats. The present work evaluated the extent to which ChM disrupts organelles in PN of the dorsal hippocampus CA1 as compared to controls (C). METHODS: Ultrastructural analysis was performed at 8000* and 20 000* magnification: Nucleus eccentricity and somatic, cytoplasmic, and nuclear areas were measured; and in the PN perikaryon, density indices (number of organelles/cytoplasmic area) of Golgi membrane systems (GMS, normal, and swollen), mitochondria (normal and abnormal), and vacuolated organelles (lysosomes, lipofuscin granules, and multivesicular bodies (MVB)) were determined. RESULTS: The density of abnormal mitochondria, swollen GMS, and MVB increased significantly in the AChM group compared to the other groups. The amount of lipofuscin was significantly greater in the AChM than in the YChM groups - a sign of oxidative stress due to malnutrition and aging; however, in Y animals, ChM showed no effect on organelle density or the cytoplasmic area. An increased density of lysosomes as well as nucleus eccentricity was observed in the AC group, which also showed an increase in the cytoplasmic area. DISCUSSION: Malnutrition produces subcellular alterations in vulnerable hippocampal pyramidal cells, and these alterations may provide an explanation for the previously reported deficient performance of malnourished animals in a spatial memory task in which aging and malnutrition were shown to impede the maintenance of long-term memory. PMID- 25730174 TI - The effect of plastic rearrangements on the flow of two-dimensional wet foam. AB - The effect of the elementary plastic events on the flow behavior of the two dimensional wet foam is investigated by quasistatic simulation on the bubble scale. The position where the plastic event occurs is traced by recording the coordinate at which two bubbles separate in the simulation. A localized shear band is found, and the width of this band increases with the increase of foam quality. From the displacement fields of these bubbles, it shows that the T1 plastic events can give rise to an increase in local bubble displacements due to the separation between these bubbles. The average relative pressure as well as normal stress difference of bubbles increases with the flow of foam in the initial elastic domain and then decreases as the elastic domain turns into the plastic domain. In the plastic domain, the plastic events rearrange the local structure of foam, which leads to decreasing both the average pressure and the normal stress difference. Additionally, the wall slip of foam is discussed in the simulation as well. The width of the localized shear band is narrower under the slip boundary condition. Meanwhile, the plastic events occurring between the first and second layers of bubbles change the pulling force of the films near the wall and cause an instantaneous increase in the slip velocity. PMID- 25730175 TI - Interassociation recommendations for developing a plan to recognize and refer student-athletes with psychological concerns at the secondary school level: a consensus statement. PMID- 25730176 TI - Immunoglobulin G4-related cholangiopathy: clinical and experimental insights. AB - PURPOSE OF REVIEW: The clinical spectrum of immunoglobulin G4-related disease (IgG4-RD) is diverse and the disease may affect multiple organ systems. The pancreatobiliary tract probably is the clinically most important localization of the disease but diagnosing IgG4-related cholangiopathy (synonym: IgG4-associated cholangitis) or autoimmune pancreatitis is often challenging. This review summarizes the current best practice in diagnosing and treating IgG4-related cholangiopathy and recent advances in our understanding of its cause. RECENT FINDINGS: The identification of IgG4-switched B-cell and plasma cell populations in patients with IgG4-related cholangiopathy and IgG4-RD and their disappearance upon successful treatment have established the role of these cells in the disorder. Ultimately, these findings may lead to the development of more sensitive diagnostic tests. The observation that many of the predominantly 50-70 years old male patients have been exposed lengthily to occupational hazardous compounds further supports the idea that chronic antigenic stimulation may be a pivotal etiological aspect of the disease. Immunosuppressive treatment remains the therapeutic cornerstone in IgG4-RD. SUMMARY: Currently available experimental evidence classifies IgG4-RD as an immune-mediated disorder, providing support to the use of immunosuppressants and possibly even more specific therapies targeting the B-cell and plasma cell lineages. PMID- 25730177 TI - Vibration-controlled transient elastography: a practical approach to the noninvasive assessment of liver fibrosis. AB - PURPOSE OF REVIEW: Therapeutic advances for hepatitis C and the increasing prevalence on nonalcoholic fatty liver disease are reshaping the diagnostic approach to disease staging in clinical hepatology. Well tolerated, inexpensive and reliable alternatives to liver biopsy are a critical need for clinicians and patients alike. RECENT FINDINGS: Vibration-controlled transient elastography (VCTE, also known as 'transient elastography') is a robust, point-of-care tool for the noninvasive assessment of liver fibrosis. This tool efficiently prioritizes the treatment for patients with viral hepatitis at risk for advanced liver disease and identifies the subgroups with metabolic or cholestatic liver disease who are at the highest risk. Rather than staging fibrosis, VCTE provides an accurate risk estimate of advanced fibrosis. In addition, it is increasingly recognized that elastography can predict outcomes including hepatic decompensation and mortality. The ideal use of this tool is to perform it in conjunction with a serologic marker of fibrosis to confirm its findings. SUMMARY: When combined with serologic markers of fibrosis, VCTE allows the vast majority of patients to avoid a liver biopsy. PMID- 25730178 TI - Active versus expectant management for women in the third stage of labour. AB - BACKGROUND: Active management of the third stage of labour involves giving a prophylactic uterotonic, early cord clamping and controlled cord traction to deliver the placenta. With expectant management, signs of placental separation are awaited and the placenta is delivered spontaneously. Active management was introduced to try to reduce haemorrhage, a major contributor to maternal mortality in low-income countries. OBJECTIVES: To compare the effectiveness of active versus expectant management of the third stage of labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 September 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing active versus expectant management of the third stage of labour. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. MAIN RESULTS: We included seven studies (involving 8247 women), all undertaken in hospitals, six in high-income countries and one in a low-income country. Four studies compared active versus expectant management, and three compared active versus a mixture of managements. We used random-effects in the analyses because of clinical heterogeneity. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes. The evidence suggested that for women at mixed levels of risk of bleeding, active management showed a reduction in the average risk of maternal primary haemorrhage at time of birth (more than 1000 mL) (average risk ratio (RR) 0.34, 95% confidence interval (CI) 0.14 to 0.87, three studies, 4636 women, GRADE:very low quality) and of maternal haemoglobin (Hb) less than 9 g/dL following birth (average RR 0.50, 95% CI 0.30 to 0.83, two studies, 1572 women, GRADE:low quality). We also found no difference in the incidence in admission of infants to neonatal units (average RR 0.81, 95% CI 0.60 to 1.11, two studies, 3207 infants, GRADE:low quality) nor in the incidence of infant jaundice requiring treatment (0.96, 95% CI 0.55 to 1.68, two studies, 3142 infants, GRADE:very low quality). There were no data on our other primary outcomes of very severe postpartum haemorrhage (PPH) at the time of birth (more than 2500 mL), maternal mortality, or neonatal polycythaemia needing treatment.Active management also showed a significant decrease in primary blood loss greater than 500 mL, and mean maternal blood loss at birth, maternal blood transfusion and therapeutic uterotonics during the third stage or within the first 24 hours, or both, and significant increases in maternal diastolic blood pressure, vomiting after birth, after-pains, use of analgesia from birth up to discharge from the labour ward and more women returning to hospital with bleeding (outcome not pre-specified). There was also a decrease in the baby's birthweight with active management, reflecting the lower blood volume from interference with placental transfusion.In the subgroup of women at low risk of excessive bleeding, there were similar findings, except there was no significant difference identified between groups for severe haemorrhage or maternal Hb less than 9 g/dL (at 24 to 72 hours).Hypertension and interference with placental transfusion might be avoided by using modifications to the active management package, e.g. omitting ergot and deferring cord clamping, but we have no direct evidence of this here. AUTHORS' CONCLUSIONS: Although there is a lack of high-quality evidence, active management of the third stage reduced the risk of haemorrhage greater than 1000 mL at the time of birth in a population of women at mixed risk of excessive bleeding, but adverse effects were identified. Women should be given information on the benefits and harms of both methods to support informed choice. Given the concerns about early cord clamping and the potential adverse effects of some uterotonics, it is critical now to look at the individual components of third-stage management. Data are also required from low-income countries. PMID- 25730179 TI - Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats. AB - BACKGROUND: Gentamicin-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI). The phenotypic alterations that contribute to acute kidney injury include inflammatory response and oxidative stress. Curcumin has a wide range biological functions, especially as an antioxidant. This study was designed to evaluate the renoprotective effects of curcumin treatment in gentamicin-induced AKI. METHODS: Gentamicin-induced AKI was established in female Sprague-Dawley rats. Rats were treated with curcumin (100 mg/kg body mass) by intragastric administration, once daily, followed with an intraperitoneal injection of gentamicin sulfate solution at a dose of 80 mg/kg body mass for 8 consecutive days. At days 3 and 8, the rats were sacrificed, and the kidneys and blood samples were collected for further analysis. RESULTS: The animals treated with gentamicin showed marked deterioration of renal function, together with higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the plasma as compared with the controls. Animals that underwent intermittent treatment with curcumin exhibited significant improvements in renal functional parameters. We also observed that treatment with curcumin significantly attenuated renal tubular damage, apoptosis, and oxidative stress. Curcumin treatment exerted anti-apoptosis and anti-oxidative effects by up-regulating Nrf2/HO-1 and Sirt1 expression. CONCLUSIONS: Our data clearly demonstrate that curcumin protects kidney from gentamicin-induced AKI via the amelioration of oxidative stress and apoptosis of renal tubular cells, thus providing hope for the amelioration of gentamicin-induced nephrotoxicity. PMID- 25730180 TI - Emerging targets and therapeutic approaches for the treatment of osteoarthritis pain. AB - PURPOSE OF REVIEW: Osteoarthritis is a complex and often painful disease that is inadequately controlled with current analgesics. This review discusses emerging targets and therapeutic approaches that may lead to the development of better analgesics. RECENT FINDINGS: Aberrant excitability in peripheral and central pain pathways drives osteoarthritis pain, reversing this via modulation of nerve growth factor, voltage-gated sodium channel, voltage-gated calcium channel and transient receptor potential vanilloid one activity, and increasing inhibitory mechanisms through modulation of cannabinoid and descending modulatory systems hold promise for osteoarthritis pain therapy. Somatosensory phenotyping of chronic pain patients, as a surrogate of putative pain generating mechanisms, may predict patient response to treatment. SUMMARY: Identification of new targets will inform and guide future research, aiding the development of more effective analgesics. Future clinical trial designs should implement sensory phenotyping of patients, as an inclusion or stratification criterion, in order to establish an individualized, mechanism-based treatment of osteoarthritis pain. PMID- 25730181 TI - Critical evaluation of the colossal Seebeck coefficient of nanostructured rutile MnO2. AB - We have explored the correlation between the Seebeck coefficient and the electronic structure of nanostructured rutile MnO2 using density functional theory to critically appraise the three orders of magnitude scatter in literature data. Our hypothesis is that the microstructure and morphology on the nanoscale is causing this behaviour, which we have tested by comparing the Seebeck coefficient of bulk MnO2 with two low-energy surfaces: MnO2(1 1 0) and MnO2(0 0 1). From these data, it is evident that variations over two orders of magnitude in the Seebeck coefficient can be attained by affecting domain size and texture on the nanoscale. This may be understood by analysing the electronic structure. Surface hybridized Mn d-O p states fill the band gap of MnO2 and thus substantially alter the transport properties. PMID- 25730182 TI - Related hematopoietic cell donor care: is there a role for unrelated donor registries? AB - In almost half of allogeneic hematopoietic progenitor cell (HPC) transplants, a related donor (RD) is used, yet a lack of standardized guidelines means that their care is heterogeneous. Changes to regulatory standards aim to improve uniformity, but adherence to these regulations can prove logistically difficult for the transplant centers (TCs) managing RDs. Discussion has ensued around possible alternative models of related donor care and a session at the European Society for Blood and Marrow Transplantation (EBMT) annual meeting in 2013 debated the question of whether a role exists for unrelated donor registries in the management of 'related' donors. In this overview, we discuss the issues raised at this debate and the pros and cons of donor registry involvement in various aspects of RD management. By examining existing models of related donor care that have been adopted by members of the World Marrow Donor Association (WMDA), we look for ways to enhance and homogenize RD care, while also enabling transplant centers to meet standards required for mandatory accreditation. PMID- 25730183 TI - Once-daily i.v. BU-based conditioning regimen before allogeneic hematopoietic SCT: a study of influence of GST gene polymorphisms on BU pharmacokinetics and clinical outcomes in Chinese patients. AB - I.v. BU has been proven to have better bioavailability, reliable systemic drug exposure with more predictable blood levels and lower toxicity than oral BU when used as part of conditioning regimens before hematopoietic SCT (HSCT). Some studies have shown that once-daily i.v. BU had the same clinical efficacy as i.v. BU administered four times daily. To observe the clinical efficacy and pharmacokinetics (PK) of once-daily i.v. BU and to evaluate the influence of glutathione S-transferase (GST) gene polymorphisms on once-daily i.v. BU PK in adult Chinese patients with allogeneic HSCT, we analyzed 25 patients receiving related or unrelated donor transplant conditioned with i.v. BU-based regimens. With a median follow-up of 32.7 months, the 2-year OS and EFS were 64 and 63.8% for all the patients, respectively, and the 2-year cumulative incidence of relapse for all patients was 18.3%. On the basis of HPLC analysis, the mean clearance and mean daily area under the curve (AUC) of i.v. BU were calculated as 4.02 mL/min per kg and 3380.77 MUM/min, respectively. The estimated Cmax was 1.031+/-0.0325 MUg/mL. The estimated t1/2 and Vd values were 3.618+/-0.1932 h and 1.212+/-0.0352 L/kg. The once-daily i.v. BU-based conditioning regimen was very well tolerated with minor toxicity in patients, most likely because of dose assurance with predictable PK. There was no GSTA1 *B/*B homozygous patient in our Chinese patients. A significant association between BU metabolism and GSTA1 polymorphism was observed. The GSTA1 *A/*B genotype group showed a significantly higher AUC (P<0.0001), higher Cmax (P=0.0003) and lower clearance (P=0.0007) than the GSTA1 *A/*A genotype group. AUC was lower in GSTP1 *A/*A genotypes compared with*A/*G (P=0.0283) and *G/*G genotypes (P=0.0111). The BU clearance in GSTP1 *A/*A genotype was shown to be higher than *A/*G (P=0.0255) and *G/*G genotypes (P=0.0111). In addition, the differences of PK in BU among different ethnic groups existed because of the different distribution frequencies of GST gene polymorphism in Chinese patients and Caucasian patients. PMID- 25730184 TI - Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study. AB - Patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor need new therapeutic approaches. Hematopoietic SCT (HSCT) using mismatched or haploidentical related donors has been used in the past, but was associated with a significant risk of GVHD and mortality. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but the majority of reports have focused on patients with hematology malignancies. We describe the outcome of 16 patients who underwent haploidentical transplantation using a reduced-intensity conditioning regimen with post-transplant Cy. Stem cell sources were BM (N=13) or PBSCs (N=3). The rate of neutrophil engraftment was 94% and of platelet engraftment was 75%. Two patients had secondary graft failure and were successfully salvaged with another transplant. Three patients developed acute GVHD being grades 2-4 in two. Five patients have died and the 1-year OS was 67.1% (95% confidence interval: 36.5-86.4%). In our small series, the use of a reduced intensity conditioning with post-transplant Cy in haploidentical BMT was associated with high rates of engraftment and low risk of GVHD in patients with relapsed/refractory SAA. PMID- 25730185 TI - G-CSF-primed BM for allogeneic SCT: revisited. AB - G-SCF-mobilized PBSC (GPB) grafts have a higher cell dose and somewhat more committed progenitor cells than steady-state BM (SBM), resulting in faster engraftment and faster immunological reconstitution. On the other hand, transplant related mortality (TRM), disease-free survival (DFS) and overall survival (OS) are similar both for PB and for BM. In contrast to SBM, G-CSF primed BM (GBM) grafts stimulate HSC proliferation, increasing cell dose and thus resulting in faster engraftment because of higher cell dose infused, or because of treatment with G-CSF. Furthermore, GBM may induce tolerance and functional modulations in donor hematopoiesis and immunity, further reducing GVHD incidence, which is already lower with SBM compared with GPB grafts. Overall, a growing body of clinical evidence suggests that GBM transplants may share the advantages of GPB transplantations, without the associated increased risk of GVHD, and might be an attractive graft source for allogeneic SCTs. PMID- 25730187 TI - Familial haploidentical challenging unrelated donor Allo-SCT in advanced non Hodgkin lymphomas when matched related donor is not available. PMID- 25730186 TI - Reduced-intensity conditioned allogeneic SCT in adults with AML. AB - AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. PMID- 25730188 TI - Therapy-related ALL: cytogenetic features and hematopoietic cell transplantation outcome. PMID- 25730189 TI - A time to stop, a time to start: high-dose chemotherapy in overweight and obese patients. PMID- 25730190 TI - Utilization of stored autologous PBSCs to support second autologous transplantation in multiple myeloma patients in the era of novel agent therapy. AB - Outcomes in multiple myeloma (MM) have improved significantly with novel agent therapy and autologous stem cell transplantation (ASCT). ASCTs are typically planned as either tandem or a single transplant with additional stored PBSCs available for a second salvage transplant. To accommodate these strategies, many centers routinely collect and store adequate PBSCs for two ASCTs. We analyzed the cost associated with this practice by determining the expenses of PBSC collection, cryopreservation and storage, and the ultimate use of additional cryopreserved PBSCs in patients who had undergone at least one ASCT. There were 889 MM patients transplanted between 1993 and 2011 at our center. Most (N=726) had residual PBSCs in storage after their first ASCT (ASCT1). Only 135 patients underwent a second ASCT within a median of 14 months after ASCT1. The percentage of patients receiving a second ASCT declined over time. The resources required to collect and store unused PBSCs added up to 336 extra patient days of apheresis and 41 587 extra patient months of cryopreservation, translating into an average extra cost per patient of US$4981.12. A reconsideration of conventional PBSC collection and storage practices would save significant cost for the majority of MM patients who never undergo a second ASCT. PMID- 25730191 TI - Clinical significance of pretransplant serum ferritin on the outcome of allogeneic hematopoietic SCT: a prospective cohort study by the Kanto Study Group for Cell Therapy. AB - This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (?1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ?1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes. PMID- 25730192 TI - High-dose therapy with auto-SCT is feasible in high-risk cardiac amyloidosis. AB - Cardiac involvement in light-chain amyloidosis (AL) predicts poor prognosis and is associated with higher TRM and morbidity during high-dose therapy and auto-SCT (HDT-ASCT). We studied the outcomes of 30 patients with cardiac amyloidosis undergoing HDT-ASCT at our center between January 1998 and March 2012. The median age of the patients was 53 years (range, 36-74) with a median follow-up of 35 months (range, 0.4-97 months). Twenty-seven patients (90%) had more than one organ involved besides the heart with 37% with cardiac stage ?3. Melphalan-based conditioning regimen (140-200 mg/m(2)) was used for HDT-ASCT. One-year TRM is 10%. Three-year OS and EFS from HDT-ASCT was 83% and 56.8%, respectively. Cumulative incidence of relapse at 3 years was 38.5%. Negative factors affecting survival included age >60 years, lack of novel induction therapy and BM plasmacytosis >10%. We conclude that HDT-ASCT is well tolerated in patients with high-risk cardiac amyloidosis and can lead to improved overall outcomes. PMID- 25730193 TI - Kinetics of peripheral blood chimerism for surveillance of patients with leukemia and chronic myeloid malignancies after reduced-intensity conditioning allogeneic hematopoietic SCT. PMID- 25730194 TI - Association between educational status and dual-task performance in young adults. AB - The influence of educational status on perceptual-motor performance has not been investigated. The single- and dual-task performances of 15 Low educated adults (9 men, 6 women; M age=24.1 yr.; 6-9 yr. of education) and 15 Higher educated adults (8 men, 7 women; M age=24.7 yr.; 10-13 yr. of education) were compared. The perceptual task consisted of verbally classifying two figures (equal or different). The motor task consisted of alternating steps from the floor to a stool. Tasks were assessed individually and simultaneously. Two analyses of variance (2 groups*4 blocks) compared the errors and steps. The Low education group committed more errors and had less improvement on the perceptual task than the High education group. During and after the perceptual-motor task performance, errors increased only in the Low education group. Education correlated to perceptual and motor performance. The Low education group showed more errors and less step alternations on the perceptual-motor task compared to the High education group. This difference on the number of errors was also observed after the dual-task, when the perceptual task was performed alone. PMID- 25730195 TI - Empirical links between instruction with teaching tools and the hierarchical model of intrinsic and extrinsic motivation in a Korean college tennis class. AB - The objective of this study was to demonstrate the sequential process (i.e., social factors->mediators->motivation->consequences) underlying the Hierarchical Model of Intrinsic and Extrinsic Motivation at the contextual level in instruction using three teaching tools, modified balls, a high net, and colored balls and cones in a college-level tennis class in South Korea. 126 students enrolled in a 15-week tennis class participated in the study. The results indicate that the three teaching tools positively affected students' perceived competence, with perceived competence's beta on intrinsic motivation equal to 0.45. Intrinsic motivation was found to reduce negative affect further by -0.33, thereby demonstrating the sequential process of the Hierarchical Model of Intrinsic and Extrinsic Motivation. PMID- 25730196 TI - Method of induction could affect emotional outcomes: comment on markey, chin, vanepps, and loewenstein (2014 ). AB - Markey, Chin, Vanepps, and Loewenstein (2014) demonstrated six methods for the induction of boredom. However, a clear and testable definition of boredom should be established prior to experimental manipulation of the construct. Defining boredom from a functional emotion perspective is one approach that affords a definition separable from the outcomes associated with boredom and insight into which manipulations may effectively target the construct. PMID- 25730197 TI - Effects of cognitive stimulation with a self-modeling video on time to exhaustion while running at maximal aerobic velocity: a pilot study. AB - This study assessed whether video self-modeling improves running performance and influences the rate of perceived exertion and heart rate response. Twelve men (M age=26.8 yr., SD=6; M body mass index=22.1 kg.m(-2), SD=1) performed a time to exhaustion running test at 100 percent maximal aerobic velocity while focusing on a video self-modeling loop to synchronize their stride. Compared to the control condition, there was a significant increase of time to exhaustion. Perceived exertion was lower also, but there was no significant change in mean heart rate. In conclusion, the video self-modeling used as a pacer apparently increased endurance by decreasing perceived exertion without affecting the heart rate. PMID- 25730198 TI - Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. AB - IMPORTANCE: Clostridium difficile infection (CDI) is associated with significant morbidity, mortality, and a high risk of recurrence. Proton pump inhibitor (PPI) use is associated with an initial episode of CDI, and PPIs are frequently overprescribed. For many, the use of PPIs could likely be discontinued before CDI recurrence. OBJECTIVES: To determine whether PPI use was associated with a risk of initial CDI recurrence, to assess what proportion of patients who developed CDI were taking a PPI for a non-evidence-based indication, and to evaluate whether physicians discontinued unnecessary PPIs in the context of CDI. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort study of incident health care-associated CDI cases to determine the association between continuous PPI use and CDI recurrence within 90 days. The setting was 2 university affiliated hospitals, the 417-bed Montreal General Hospital (Montreal, Quebec, Canada) and the 517-bed Royal Victoria Hospital (Montreal, Quebec, Canada). The cohort consisted of 754 patients who developed health care-associated CDI between January 1, 2010, and January 30, 2013, and who survived for a minimum of 15 days after their initial episode of nosocomial CDI. EXPOSURE: Continuous PPI use. MAIN OUTCOMES AND MEASURES: Recurrence of CDI within 15 to 90 days of the initial episode. RESULTS: Using a multivariable Cox proportional hazards model, the cause specific hazard ratios for recurrence were 1.5 (95% CI, 1.1-2.0) for age older than 75 years, 1.5 (95% CI, 1.1-2.0) for continuous PPI use, 1.003 (95% CI, 1.002 1.004) per day for length of stay, and 1.3 (95% CI, 0.9-1.7) for antibiotic reexposure. The use of PPIs was common (60.7%), with only 47.1% of patients having an evidence-based indication. Proton pump inhibitors were discontinued in only 3 patients with CDI. CONCLUSIONS AND RELEVANCE: After adjustment for other independent predictors of recurrence, patients with continuous PPI use remained at elevated risk of CDI recurrence. We suggest that the cessation of unnecessary PPI use should be considered at the time of CDI diagnosis. PMID- 25730199 TI - Military medical ethics: a call to regulatory and educational arms. PMID- 25730200 TI - Chiral phosphoric acid catalyzed enantioselective decarboxylative alkylation of beta-keto acids with 3-hydroxy-3-indolyloxindoles. AB - A chiral phosphoric acid catalyzed enantioselective decarboxylative alkylation of beta-keto acids with 3-hydroxy-3-indolyloxindoles is described in this context. This method tolerates a series of aromatic and aliphatic beta-keto acids as well as substituted 3-hydroxy-3-indolyloxindoles, affording the corresponding chiral 3 functionalized 3-indolyloxindoles in high yields (up to 98%) and enantioselectivities (up to 99% ee). PMID- 25730201 TI - Improving quality of care for serious illness: findings and recommendations of the Institute of Medicine report on dying in America. PMID- 25730202 TI - Fast forward genetics to identify mutations causing a high light tolerant phenotype in Chlamydomonas reinhardtii by whole-genome-sequencing. AB - BACKGROUND: High light tolerance of microalgae is a desired phenotype for efficient cultivation in large scale production systems under fluctuating outdoor conditions. Outdoor cultivation requires the use of either wild-type or non-GMO derived mutant strains due to safety concerns. The identification and molecular characterization of such mutants derived from untagged forward genetics approaches was limited previously by the tedious and time-consuming methods involving techniques such as classical meiotic mapping. The combination of mapping with next generation sequencing technologies offers alternative strategies to identify genes involved in high light adaptation in untagged mutants. RESULTS: We used the model alga Chlamydomonas reinhardtii in a non-GMO mutation strategy without any preceding crossing step or pooled progeny to identify genes involved in the regulatory processes of high light adaptation. To generate high light tolerant mutants, wildtype cells were mutagenized only to a low extent, followed by a stringent selection. We performed whole-genome sequencing of two independent mutants hit1 and hit2 and the parental wildtype. The availability of a reference genome sequence and the removal of shared bakground variants between the wildtype strain and each mutant, enabled us to identify two single nucleotide polymorphisms within the same gene Cre02.g085050, hereafter called LRS1 (putative Light Response Signaling protein 1). These two independent single amino acid exchanges are both located in the putative WD40 propeller domain of the corresponding protein LRS1. Both mutants exhibited an increased rate of non-photochemical-quenching (NPQ) and an improved resistance against chemically induced reactive oxygen species. In silico analyses revealed homology of LRS1 to the photoregulatory protein COP1 in plants. CONCLUSIONS: In this work we identified the nuclear encoded gene LRS1 as an essential factor for high light adaptation in C. reinhardtii. The causative random mutation within this gene was identified by a rapid and efficient method, avoiding any preceding crossing step, meiotic mapping, or pooled progeny. Our results open up new insights into mechanisms of high light adaptation in microalgae and at the same time provide a simplified strategy for non-GMO forward genetics, a crucial precondition that could result in the identification of key factors for economically relevant biological processes within algae. PMID- 25730208 TI - Newly identified transcripts of UL4 and UL5 genes of human cytomegalovirus. AB - Human cytomegalovirus (HCMV) UL4 and UL5 genes are two members of the RL11 gene family. In an earlier study, three UL4 transcripts of about 1.7, 1.5 and 1.4 kb were found in early and late classes after infection by the Towne strain by nuclease protection and primer extension analyses. In the present study, two UL4 transcripts (1.5 and 1.7 kb) were found by cDNA library screening, Northern blot, 3' and 5' RACE analyses to appear initially in the immediate early phase and one UL4 transcript (1.4 kb) in the late phase in a low-passage clinical isolate. Furthermore, two novel low-abundance UL5 transcripts with the same 3' terminus as the identified UL4 transcripts in the UL4-UL5 gene region were found in late class RNAs. PMID- 25730203 TI - Prospective study in a porcine model of sarcoptes scabiei indicates the association of Th2 and Th17 pathways with the clinical severity of scabies. AB - BACKGROUND: Understanding of scabies immunopathology has been hampered by the inability to undertake longitudinal studies in humans. Pigs are a useful animal model for scabies, and show clinical and immunologic changes similar to those in humans. Crusted scabies can be readily established in pigs by treatment with the glucocorticoid dexamethasone (Dex). METHODOLOGY/ PRINCIPAL FINDINGS: Prospective study of 24 pigs in four groups: a) Scabies+/Dex+, b) Scabies+/Dex-, c) Scabies /Dex+ and d) Scabies-/Dex-. Clinical symptoms were monitored. Histological profiling and transcriptional analysis of skin biopsies was undertaken to compare changes in cell infiltrates and representative cytokines. A range of clinical responses to Sarcoptes scabiei were observed in Dex treated and non immunosuppressed pigs. An association was confirmed between disease severity and transcription of the Th2 cytokines IL-4 and IL-13, and up-regulation of the Th17 cytokines IL-17 and IL-23 in pigs with crusted scabies. Immunohistochemistry revealed marked infiltration of lymphocytes and mast cells, and strong staining for IL-17. CONCLUSIONS/ SIGNIFICANCE: While an allergic Th2 type response to scabies has been previously described, these results suggest that IL-17 related pathways may also contribute to immunopathology of crusted scabies. This may lead to new strategies to protect vulnerable subjects from contracting recurrent crusted scabies. PMID- 25730209 TI - Preliminary result of a genetic polymorphism of beta-lactoglobulin gene and the phylogenetic study of ten balkan and central european indigenous sheep breeds. AB - Genetic polymorphism at the beta-lactoglobulin (beta-LG) loci in indigenous sheep breeds (Tsigai, Racka, Pramenka) was determined. Altogether 904 sheep were genotyped for the presence of the A, B and C alleles of beta-lactoglobulin by PCR RFLP. The AB genotype was the most common and the beta-lactoglobulin A was the most frequent in the Cokanski Tsigai (54%), while the B allele was the most common in the Rusty and the Zomborski Tsigai (59%, 60%). The C allele was found only in one individual from Serbian Cokanski flock. These results differ from those that refer to other native sheep breeds. In the Cokanski Tsigai, deviation from the Hardy-Weinberg equilibrium was detected. Genetic relationship based on beta-lactoglobulin polymorphism was the closest between the Rusty and the Cokanski Tsigai among the studied populations and between sheep and goat among the other ruminants. Part of the promoter region (254 bp) of beta-LG in studied sheep breeds were sequenced in order to identify polymorphisms, analyze haplotypes, and phylogenetic relationship among them. Sequencing analysis and alignment of the obtained sequences showed one haplotype. Analysis of more samples and longer parts of the promoter region of beta-LG are needed to reconstruct a phylogenetic tree. PMID- 25730210 TI - The nomenclature of 1-aminoalkylphosphonic acids and derivatives: evolution of the code system. AB - The approach for the unification of published proposals for the nomenclature and abbreviations of aminoalkylphosphonic acids and their derivatives is presented. Their modification was made on the basis of the IUPAC-IUB rules concerning the nomenclature and code system of proteinogenic amino acids. Our present proposal formulates the supplementary code and nomenclature system allowing unambiguous description of phosphonic analogs of proteinogenic amino acids, their analogs, homologs, metabolites, and derivatives including phosphonopeptides. PMID- 25730211 TI - Pelvic floor recovery after childbirth. PMID- 25730212 TI - Postpartum recovery of levator hiatus and bladder neck mobility in relation to pregnancy. AB - OBJECTIVE: To study postpartum changes in pelvic floor morphology in a cohort of primiparous women. METHODS: Transperineal ultrasound measurements taken at five examination points, both prepartum and postpartum, provided data for comparison. Three hundred nulliparous pregnant women were examined at 21 weeks of gestation and 274 (91%) at 37 weeks of gestation. At 6 weeks postpartum, 285 (95%) women were examined, 198 (66%) at 6 months, and 178 (59%) at 12 months using transperineal ultrasonography at rest, during contraction, and during Valsalva maneuver. The levator hiatus area, bladder neck mobility, and rest-to-Valsalva hiatal area difference were assessed. RESULTS: Approximately 85% had vaginal and 15% had cesarean deliveries. Demographic characteristics of the patients lost to follow-up were similar to the patients not lost to follow-up. In the vaginal group, a significant decrease in all measurements was seen during the first 6 months postpartum, being most pronounced for the levator hiatus area during Valsalva maneuver (-3.5 cm; P<.001). In the cesarean delivery group, no significant changes between examination points were found postpartum. Only the vaginal delivery group showed significant increases in all measurements when comparing the status at 12 months postpartum with 21 weeks of gestation, most pronounced for levator hiatus area during Valsalva maneuver (3 cm; P<.001). However, comparing the two delivery groups at 12 months postpartum, the only significant difference found was levator hiatus area during contraction. CONCLUSION: The levator ani muscle has the ability to recover after pregnancy and delivery, although not all women recover to pregnancy level. Most of the recovery occurs during the first 6 months postpartum. Significant pregnancy-induced changes are not shown to persist 1 year postpartum. LEVEL OF EVIDENCE: : II. PMID- 25730213 TI - A vaginal bowel-control system for the treatment of fecal incontinence. AB - OBJECTIVE: To evaluate the effectiveness and safety of a vaginal bowel-control device and pump system for fecal incontinence treatment. METHODS: Women with a minimum of four fecal incontinence episodes over 2 weeks were fit with the intravaginal device. Treatment success, defined as a 50% or greater reduction of incontinent episodes, was assessed at 1 month. Participants were invited into an optional extended-wear period of another 2 months. Secondary outcomes included symptom improvement measured by the Fecal Incontinence Quality of Life, Modified Manchester Health Questionnaire, and Patient Global Impression of Improvement. Adverse events were collected. Intention-to-treat analysis included participants who were successfully fit entering treatment. Per protocol, analysis included participants with a valid 1-month treatment diary. RESULTS: Sixty-one of 110 (55.5%) participants from six clinical sites were successfully fit and entered treatment. At 1 month, intention-to-treat success was 78.7% (48/61, P<.001); per protocol success, 85.7% (48/56, P<.001) and 85.7% (48/56) considered bowel symptoms "very much better" or "much better." There was significant improvement in all Fecal Incontinence Quality of Life (P<.001) and Modified Manchester (P<=.007) subscales. Success rate at 3 months was 86.4% (38/44; 95% confidence interval 73-95%). There were no serious adverse events; the most common study wide device-related adverse event was pelvic cramping or discomfort (25/110 participants [22.7%]), the majority of events (16/25 [64%]) occurring during the fitting period. CONCLUSION: In women successfully fit with a vaginal bowel control device for nonsurgical treatment for fecal incontinence, there was significant improvement in fecal incontinence by objective and subjective measures. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01655498. LEVEL OF EVIDENCE: : II. PMID- 25730214 TI - Sodium fluorescein use during intraoperative cystoscopy. AB - BACKGROUND: Indigotindisulfonate sodium has been used during cystoscopy to identify the ureteral meatuses and to verify ureteral efflux during pelvic surgery. The U.S. Food and Drug Administration announced the shortage of indigotindisulfonate sodium in June 2014. Surgeons have since been searching for safe alternatives with comparable visualization and an economically favorable profile. METHOD: The recent shortage of indigotindisulfonate sodium prompted our search for alternative options for visualizing ureteral patency during intraoperative cystoscopy. Multiple methods were considered, including instilling the bladder with D50 water, sterile water, or methylene blue-tinged saline and visualizing the contrast in either viscosity or color of the urine against the instilled medium, preoperative oral phenazopyridine, and intravenous methylene blue. Collectively, these methods proved suboptimal. As an alternative, we injected the 10% preparation of sodium fluorescein at 0.25-1 mL intravenously and observed a brilliant yellow ureteral jet minutes after injection (see Video 1). EXPERIENCE: Ten percent sodium fluorescein given intravenously in doses ranging from 0.25 to 1.0 cc results in good visualization of ureteral jets. One patient experienced transient yellowing of the sclera and palms. CONCLUSION: Sodium fluorescein is an effective alternative to indigotindisulfonate sodium for visualization of ureteral jets during intraoperative cystoscopy. PMID- 25730215 TI - Short-term postoperative functional outcomes in older women undergoing prolapse surgery. AB - OBJECTIVE: To evaluate whether preoperative markers of functional status predict postoperative functional outcomes in older women undergoing surgery for pelvic organ prolapse (POP). METHODS: Prospective cohort study of women aged 60 years or older who underwent surgery for prolapse. Preoperative functional status was measured using number of functional limitations (such as difficulty walking or climbing), American Society of Anesthesiologists class, anemia, and history of recent weight loss. Our primary outcome was the number of postoperative functional limitations and secondary outcomes were failure to return to baseline functional status and length of stay after surgery. We determined the association of preoperative functional status markers with postoperative outcomes using univariable and multivariable regression. RESULTS: In 127 women, presence of a preoperative functional limitation was a significant predictor of a 0.55 (95% confidence interval [CI] 0.36-0.74) increase in the number of postoperative functional limitations after controlling for age, number of preoperative functional limitations, comorbidities, depression, surgeon, type of procedure, and complications (P<.001). History of recent weight loss and anemia increased risk for failure to return to baseline functional status after controlling for surgeon, type of surgery, and complications (relative risk 2.44, 95% CI 1.26-4.71 and relative risk 2.72, 95% CI 1.29-5.75), respectively). Preoperative markers associated with longer length of stay after surgery were American Society of Anesthesiologists class III (0.83 days, 95% CI 0.20-1.46) and history of weight loss (0.84 days, 95% CI 0.13-1.54). CONCLUSION: Preoperative markers of functional status are useful in predicting short-term postoperative functional outcomes in older women undergoing surgery for POP. LEVEL OF EVIDENCE: : II. PMID- 25730216 TI - Trends and patterns of urodynamic studies in U.S. women, 2000-2012. AB - OBJECTIVE: To estimate utilization rates for cystometrograms and describe trends in urodynamic procedures among U.S. women from 2000 to 2012. METHODS: We analyzed outpatient administrative health care claims for women aged 18 years or older from 2000 to 2012. The database contains deidentified and adjudicated claims from approximately 150 U.S. payers for employees, spouses, and retirees. We identified cystometrograms, which occur during bladder filling and represent a major component of complex urodynamics, and concurrent procedures; we also assessed age, year, region, health care provider specialty, and associated diagnosis codes. We estimated standardized cystometrogram utilization rates per 10,000 person-years and 95% confidence intervals (CIs) and used stratified Poisson models to estimate the independent (adjusted) effects of year and region. RESULTS: During 142,928,847 person-years of observation among 57,629,961 eligible women, we identified 561,823 cystometrograms for an overall utilization rate of 39.3 per 10,000 person-years (95% CI 39.2-39.4). Cystometrogram utilization increased with age with a peak at age 76 years (86.6/10,000 person-years, 95% CI 84.5-88.7). Standardized rates were relatively constant from 2000 to 2004 and then increased and peaked in 2009 (43.3/10,000 person-years, 95% CI 43.0-43.7). In 2012, they were substantially lower (27.6/10,000 person-years, 95% CI 27.4 27.9). CONCLUSION: Urodynamic procedures were more commonly performed in women aged 65 years or older. Utilization peaked in 2009 and declined sharply in 2012. Clinically, we need to assess the underlying reasons for these trends (ie, whether they reflect a decrease in urodynamics before stress urinary incontinence surgery) and whether these trends reflect appropriate use of this diagnostic study. LEVEL OF EVIDENCE: : II. PMID- 25730217 TI - Weight loss in obese pregnant women and risk for adverse perinatal outcomes. AB - OBJECTIVE: To examine the association between weight loss in obese pregnant women and relevant maternal and neonatal outcomes. METHODS: All liveborn singleton term (37 weeks of gestation or greater) births in obese women between 2009 and 2011 in Flanders (the northern part of Belgium) were included (N=18,053). Outcomes assessed included gestational hypertension, low (2,500 g or less) birth weight, small-for-gestational-age (less than the 10th percentile) neonates, macrosomia (birth weight 4,000 g or greater), large-for-gestational-age (greater than 90th percentile) neonates, emergency caesarean delivery, and admission to a neonatal intensive care unit. Risk for adverse outcomes was calculated by multiple logistic regression analysis for weight change categories (greater weight loss [5 kg or greater], lesser weight loss [between 0 and 5 kg], low gestational weight gain [0 or greater and less than 5 kg], adequate gestational weight gain [5 or greater to 9 kg or less, reference], and excessive gestational weight gain [greater than 9 kg]) in each obesity class (I 30-34.9, II 35-39.9, III 40 or greater) adjusted for parity and maternal and gestational age. RESULTS: In the total population, 854 (4.7%) obese pregnant women reported weight loss. Weight loss and low weight gain were associated with a decreased incidence of gestational hypertension for women with class I obesity (greater weight loss adjusted odds ratio [OR] 0.31, 95% confidence interval [CI] 0.11-0.84; lesser weight loss adjusted OR 0.46 95% CI 0.21-0.99; low gain adjusted OR 0.71 95% CI 0.54-0.93), a reduction in the rate of emergency cesarean delivery, but only in those with class II obesity (greater weight loss adjusted OR 0.24, 95% CI 0.07 0.78; lesser weight loss adjusted OR 0.50, 95% CI 0.26-0.97; low gain adjusted OR 0.55, 95% CI 0.38-0.79), and decreased macrosomia and large-for-gestational-age neonates in women in all classes of obesity, with the highest decrease for women with class III obesity (greater weight loss adjusted OR 0.15, 95% CI 0.05-0.49; lesser weight loss adjusted OR 0.37, 95% CI 0.15-0.90 for macrosomia). No association between weight loss and low birth weight, small-for-gestational-age neonates, or admission to the neonatal intensive care unit was shown in the different obesity classes. CONCLUSION: Weight loss in obese pregnant women was associated with reduced perinatal risks but not with the rate of low birth weight or small-for-gestational-age neonates in obese women from class III in this affluent region. Stratification of recommended gestational weight gain ranges in obese women should be considered. LEVEL OF EVIDENCE: II. PMID- 25730218 TI - Physical activity interventions in pregnancy and risk of gestational diabetes mellitus: a systematic review and meta-analysis. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is a common complication of pregnancy associated with an increased incidence of pregnancy complications, adverse pregnancy outcomes, and maternal and fetal risks of chronic health conditions later in life. Physical activity has been proposed to reduce the risk of GDM and is supported by observational studies, but experimental research assessing its effectiveness is limited and conflicting. We aimed to use meta analysis to synthesize existing randomized controlled studies of physical activity and GDM. DATA SOURCES: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for eligible studies. METHODS OF STUDY SELECTION: The following combination of keywords was used: (pregnant or pregnancy or gestation or gestate or gestational or maternity or maternal or prenatal) AND (exercise or locomotion or activity or training or sports) AND (diabetes or insulin sensitivity or glucose tolerance) AND (random* or trial). Eligibility was restricted to studies that randomized participants to an exercise-only-based intervention (ie, separate from dietary interventions) and presented data regarding GDM risk. Two authors performed the database search, assessment of eligibility, and abstraction of data from included studies, and a third resolved any discrepancies. A total of 469 studies was retrieved, of which 10 met inclusion criteria and could be used for analysis (3,401 participants). TABULATION, INTEGRATION, AND RESULTS: Fixed-effects models were used to estimate summary relative risk (RR) and 95% confidence interval (CI) and I to assess heterogeneity. There was a 28% reduced risk (95% CI 9-42%) in the intervention group compared with the control group (RR 0.72, P=.005). Heterogeneity was low (I=12%) and nonsignificant (P=.33). CONCLUSION: The results from this meta analysis suggest that physical activity in pregnancy provides a slight protective effect against the development of GDM. Studies evaluating type, timing, duration, and compliance of physical activity regimens are warranted to best inform obstetric guidelines. PMID- 25730219 TI - Glyburide transport across the human placenta. AB - OBJECTIVE: To estimate the magnitude of transplacental transfer of glyburide in women with gestational diabetes mellitus (GDM). METHODS: A prospective, observational study was conducted on women with GDM on glyburide therapy. On delivery admission, the glyburide dose and time of last dose were recorded. Immediately postdelivery, maternal and umbilical venous blood samples were obtained and the concentrations of glyburide were determined by high-performance liquid chromatography-mass spectrometry with a limit of detection of 0.25 ng/mL. RESULTS: Nineteen patient dyads were analyzed. The mean total daily maternal glyburide dose was 6.6+/-6.3 mg per day and the mean time between last dose and sampling was 13.3+/-6.5 hours. The mean maternal serum glyburide level at birth was 15.4+/-20.8 ng/mL, whereas the mean umbilical glyburide level was 7.5+/-8.2 ng/mL, which showed a statistical correlation (r=0.72, P<.01). There were statistically significant relationships between total maternal glyburide dose (1.25-20 mg per day) and maternal glyburide levels (0.93-70.71 ng/mL; r=0.46, P<=.01) and between total maternal glyburide dose and umbilical glyburide levels (0.95-32.41 ng/mL; r=0.43, P<=.01) However, we observed wide variability in maternal and umbilical glyburide levels at both extremes of the total glyburide dose. Seventy-nine percent of cord samples (15/19) had glyburide levels less than 10 ng/mL (the limit of detection reported in earlier studies) and 37% (7/19) were higher than the corresponding maternal samples. CONCLUSION: Transplacental transfer of glyburide is highly variable among patients, corroborating ex vivo placental perfusion studies showing a transport-mediated glyburide efflux from the fetal to the maternal circulation. In most neonates (79%), glyburide levels were below 10 ng/mL. LEVEL OF EVIDENCE: III. PMID- 25730220 TI - Association of body mass index and morbidity after abdominal, vaginal, and laparoscopic hysterectomy. AB - OBJECTIVE: To examine the association of body mass index (BMI) and operative time and perioperative morbidity after hysterectomy and determine whether the association varies among abdominal, laparoscopic, and vaginal approaches. METHODS: Data abstracted from the American College of Surgeons National Safety and Quality Improvement Project registry included 55,409 women who underwent hysterectomy for benign conditions between January 2005 and December 2012. The relationships among BMI, operative time, and morbidity were examined, adjusting for age, race, ethnicity, year of surgery, smoking, diabetes, and American Society for Anesthesiologists physical classification. Adjusted means, incidence rate ratios, or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using linear, Poisson, or logistic regression, respectively. RESULTS: Body mass index was positively correlated with risk of wound complications and infection in women undergoing abdominal hysterectomy. Compared with those of normal BMI, women with BMIs 40 or higher had five times the odds of wound dehiscence (2.1% compared with 0.3%, crude OR 7.35, CI 3.78-14.30; adjusted OR 5.33, CI 2.63-10.8), five times the odds of wound infection (8.9% compared with 1.4%, crude OR 6.81, CI 5.00-9.27; adjusted OR 5.34, CI 3.85-7.41), and 89% higher odds of sepsis (1.3% compared with 0.6%, crude OR 2.39, CI 1.35-4.24; adjusted OR 1.89, CI 1.01-3.52). The magnitude of the association between wound infection and BMI was smaller after vaginal hysterectomy, and no increased odds of wound complications or sepsis were noted with a laparoscopic approach despite longer operative times. Operative time increased with BMI regardless of surgical approach. No associations were noted between BMI and hospital stay or thromboembolism. CONCLUSION: Obesity is associated with increased wound complications and infection in women undergoing abdominal hysterectomy and with longer operative times regardless of surgical approach. Vaginal or laparoscopic hysterectomy should be performed whenever feasible. LEVEL OF EVIDENCE: II. PMID- 25730221 TI - Use of the etonogestrel implant and levonorgestrel intrauterine device beyond the U.S. Food and Drug Administration-approved duration. AB - OBJECTIVE: To evaluate the effectiveness of the contraceptive implant and the 52 mg hormonal intrauterine device (IUD) in women using the method beyond the current U.S. Food and Drug Administration (FDA)-approved duration of 3 and 5 years, respectively. METHODS: Women willing to continue using their implant or 52 mg levonorgestrel IUD beyond the FDA-approved duration were followed prospectively for contraceptive effectiveness. Unintended pregnancy rate per 100 women-years was calculated. Implant users are offered periodic venipuncture for analysis of serum etonogestrel levels. The Kruskal-Wallis test was used to compare the etonogestrel levels across body mass index (BMI) groups. RESULTS: Implant users (n=237) have contributed 229.4 women-years of follow-up, with 123 using the etonogestrel implant for 4 years and 34 using it for 5 years. Zero pregnancies have been documented, for a failure rate of 0 (one-sided 97.5% confidence interval [CI] 0-1.61) per 100 women-years. Among 263 levonorgestrel IUD users, 197.7 women-years of follow-up have been completed. One pregnancy was confirmed, for a failure rate of 0.51 (95% CI 0.01-2.82) per 100 women-years. Among implant users with serum etonogestrel results, the median and range of etonogestrel level at 3 years of use was 188.8 pg/mL (range 63.8-802.6 pg/mL) and 177.0 pg/mL (67.9-470.5 pg/mL) at 4 years of use. Etonogestrel levels did not differ by BMI at either time point (3 years: P=.79; 4 years: P=.47). CONCLUSION: Preliminary findings indicate the contraceptive implant and 52-mg hormonal IUD continue to be highly effective for an additional year beyond the FDA-approved 3 and 5 years. Serum etonogestrel levels indicate the implant contains adequate hormone for ovulation suppression at the end of both 3 and 4 years of use. LEVEL OF EVIDENCE: II. PMID- 25730222 TI - Effects of cross-sex hormone treatment on transgender women and men. AB - OBJECTIVE: To describe weight, body mass index (BMI), blood pressure (BP), lipids, and hormone levels in transgender women and men presenting for initiation of cross-sex hormone therapy at a community clinic in the United States. METHODS: Twenty-three transgender women (persons assigned male at birth who identify as female and want to use estrogen to develop female secondary sex characteristics) and 34 transgender men (persons assigned female at birth who identify as male and want to use testosterone to develop male secondary sex characteristics) presenting for initiation of hormone therapy at a community health center were enrolled. Body mass index, BP, lipids, and sex hormone levels were measured at baseline and 6 months. Persistence of menses at 6 months in transgender men was recorded. RESULTS: Sixteen transgender women and 31 transgender men completed the study. Baseline and 6-month median BPs and lipid values were within a normal clinical range. Median systolic BP in transgender women dropped from baseline 130.5 mmHg (interquartile range 11.5) to 120.5 mmHg (interquartile range 15.5) at 6 months (P=.006). Testosterone levels remained elevated in 33% and estradiol (E2) levels were supratherapeutic in 19% of transgender women at 6 months. Median BMI for transgender men was 29.1 kg/m (interquartile range 11.2) at baseline and 30.0 kg/m (interquartile range 11.4) at 6 months (P=.024). Six-month total testosterone levels were subtherapeutic in 32% and E2 levels remained elevated in 71% of transgender men. CONCLUSION: In transgender women, estrogen therapy, with or without antiandrogen therapy, was associated with lower BP. In transgender men, testosterone therapy was associated with increased BMI. The study had insufficient power to detect other associations. Monitoring of hormone levels to guide therapy appears to be useful. LEVEL OF EVIDENCE: III. PMID- 25730223 TI - Diagnosis and treatment of adnexal masses in children and adolescents. AB - OBJECTIVE: To evaluate the diagnosis and treatment decisions made in children and adolescents with an adnexal mass. METHODS: This was a retrospective cohort study among patients younger than age 18 years who were diagnosed with or treated for an adnexal mass at the Radboud University Medical Center, Nijmegen, the Netherlands, between January 1999 and October 2013. Age, signs and symptoms, laboratory results, imaging data, type of surgery including surgeon specialty, and histologic diagnosis were analyzed. Published criteria for characterizing a mass as benign (Papic et al) were applied to the present data set. RESULTS: One hundred eleven patients were included. The mean age of the patients was 10.2+/ 5.6 years, ranging between 0 and 17 years. Ovarian masses were malignant in 28 patients (25.2%). Surgical therapy was applied in 83.1% of the benign masses and in 100% of the malignant masses. Oophorectomy was performed in 46.4% of the benign masses. The presence of a gynecologist was the only factor that significantly lowered the chance of oophorectomy in benign masses (odds ratio 0.14, 95% confidence interval 0.04-0.47). Papic et al's model had a sensitivity of 40.91% and a specificity of 100%. CONCLUSION: The malignancy rate among patients with adnexal masses in our cohort was one in four patients. Most patients with an adnexal mass were treated surgically, and oophorectomy was performed in almost half of the benign masses. The presence of a gynecologic surgeon protected against oophorectomy in benign cases. LEVEL OF EVIDENCE: II. PMID- 25730224 TI - Underrepresentation of women in clinical trials: why gynecologic oncologists are worried. AB - In gynecologic oncology, significant advances with improved patient outcomes have clearly and thankfully resulted from randomized clinical trials. The recent restructuring of cooperative groups and decreased funding for phase III clinical trials have unintentionally resulted in a 90% reduction of available trials and accrual in gynecologic oncology. This Commentary reviews the history of the underrepresentation of women in clinical trials, highlighting the challenges that threaten the viability of gynecologic oncology clinical research, resulting in a decreased likelihood of improving the survival of women with gynecologic cancer. We suggest an opportunity for partnering with the U.S. government and the private sector to enhance research funding opportunities while increasing advocacy efforts to reinvigorate our clinical trials platform. PMID- 25730225 TI - Factors associated with second-trimester pregnancy loss in women with normal uterine anatomy undergoing in vitro fertilization. AB - OBJECTIVE: To evaluate factors associated with second-trimester pregnancy loss in patients with normal uterine anatomy who conceived through in vitro fertilization. METHODS: Women aged 21-44 years with ongoing in vitro fertilization pregnancy (at least one fetus with fetal heart tones at 12 weeks of gestation) at an academic hospital from 2001 to 2012 were eligible for inclusion in this retrospective cohort. Comprehensive uterine evaluation permitted inclusion of only women with anatomically normal uterine cavities. Maternal and clinical characteristics associated with spontaneous second-trimester pregnancy loss (between 12 1/7 and 23 6/7 weeks of gestation) were assessed. Multivariable logistic regression generated adjusted odds ratios (ORs), 95% confidence intervals (CIs), and Wald two-sided P values. RESULTS: Among ongoing second trimester pregnancies, 60 (2.1%) ended in spontaneous pregnancy loss and 2,841 (97.9%) ended in live birth. Multiple gestations (twins or more) conferred greater odds of pregnancy loss (adjusted OR 1.93, CI 1.15-3.24, P=.01) and were more prevalent among losses (48.3%) than live births (34.1%). Uterine leiomyomas were present in 16.7% of losses and 4.7% of live births and were associated with a nearly fourfold increased odds of second-trimester pregnancy loss (adjusted OR 3.82, CI 1.85-7.89, P<.001). Women with obese body mass index ([BMI] 30 or higher) at cycle start experienced twofold greater odds of pregnancy loss compared with normal-weight women (adjusted OR 2.38, CI 1.05-5.65, P=.04). There were eight obese women (32%) among losses and 209 obese women (16.5%) among live births. In vitro fertilization treatment parameters were not associated with odds of second-trimester loss nor were maternal age, ethnicity, or history of recurrent pregnancy loss. CONCLUSION: Odds of second-trimester spontaneous pregnancy loss among in vitro fertilization conceived pregnancies were greater with multiple gestations, leiomyomas, and obese maternal BMI. LEVEL OF EVIDENCE: II. PMID- 25730226 TI - Risk of fetal death with preeclampsia. AB - OBJECTIVE: To estimate gestational age-specific risks of fetal death in pregnancies complicated by preeclampsia. METHODS: Population-based cohort study comprising all singleton births (N=554,333) without preexisting chronic hypertension recorded in the Norwegian Medical Birth Registry from 1999 to 2008. Additional data come from a subset of preeclamptic pregnancies enrolled in the Norwegian Mother and Child Cohort Study with available medical records (n=3,037). The risk of fetal death, expressed per 1,000 fetuses exposed to preeclampsia, was calculated using a life table approach. RESULTS: Preeclampsia was recorded in 3.8% (n=21,020) of all pregnancies. Risk of stillbirth was 3.6 per 1,000 overall and 5.2 per 1,000 among pregnancies with preeclampsia (relative risk 1.45, 95% confidence interval [CI] 1.20-1.76). However, relative risk of stillbirth was markedly elevated with preeclampsia in early pregnancy. At 26 weeks of gestation, there were 11.6 stillbirths per 1,000 pregnancies with preeclampsia compared with 0.1 stillbirths per 1,000 pregnancies without (relative risk 86, 95% CI 46-142). Fetal risk with preeclampsia declined as pregnancy advanced, but at 34 weeks of gestation remained more than sevenfold higher than pregnancies without preeclampsia. CONCLUSION: For clinical purposes, the fetal risk of death associated with preeclampsia begins when preeclampsia becomes clinically apparent. Using a method that takes into account the clinical diagnosis of preeclampsia and the population of fetuses at risk, we find a remarkably high relative risk of fetal death among pregnancies diagnosed with preeclampsia in the preterm period. LEVEL OF EVIDENCE: II. PMID- 25730227 TI - Preterm cesarean delivery for nonreassuring fetal heart rate: neonatal and neurologic morbidity. AB - OBJECTIVE: To compare the rates of neonatal morbidity and cerebral palsy among preterm neonates (less than 37 weeks of gestation) delivered by cesarean for a nonreassuring fetal heart rate (FHR) tracing compared with those who did not. METHODS: This was a secondary analysis of a multicenter randomized trial of MgSO4 for the prevention of cerebral palsy. Newborns of women delivered by cesarean delivery for nonreassuring FHR were compared with a control group composed of the offspring of women who labored for 2 hours or longer but did not undergo cesarean delivery for nonreassuring FHR regardless of the mode of delivery. Using multivariable analysis to adjust for potential confounders, our objective was to compare two outcomes: 1) composite neonatal morbidity (Apgar score 3 or less at 5 minutes, seizure, sepsis, necrotizing enterocolitis grade II or III, intraventricular hemorrhage grade III or IV, or death before discharge) and 2) neurologic injury (cerebral palsy) at 2 years or more of corrected age between the groups. RESULTS: Of the 1,291 preterm neonates who met the inclusion criteria, 177 (14%) were delivered by cesarean for nonreassuring FHR compared with 1,114 (86%) in the control group. Composite neonatal morbidity was similar between the groups (30.5 compared with 22.2%, adjusted odds ratio [OR] 1.4, 95% confidence interval [CI] 0.9-2.1). The rate of cerebral palsy of any severity (8.3 compared with 4.0%, adjusted OR 2.3, 95% CI 1.2-4.5) and moderate-to-severe cerebral palsy at 2 years of corrected age (6.0 compared with 2.2%, adjusted OR 3.2, 95% CI 1.4-7.1) was significantly higher in children born through cesarean delivery for nonreassuring FHR. CONCLUSION: Nonreassuring fetal tracing deemed so serious as to require cesarean delivery is associated with an increased risk of cerebral palsy in preterm neonates. LEVEL OF EVIDENCE: II. PMID- 25730229 TI - Innovation in maternal-fetal therapy: a position statement from the North American Fetal Therapy Network. AB - For conscientious practitioners, innovative medical therapy often occupies an uncomfortable space between formal research and established clinical practice. Newer and more rapid methods of information dissemination increase the risk of advertising unproven therapies. These and other concerns should not stifle medical progress and innovation but require guidelines and boundaries. The problem is not unique to fetal therapy, but rarely do other fields consider the well-being of two individuals at the same time. Herein, the North American Fetal Therapy Network offers expanded guidelines and suggestions regarding medical innovation that are particular to maternal-fetal therapy. PMID- 25730228 TI - Risk factors for classical hysterotomy in twin pregnancies. AB - OBJECTIVE: To describe the rate of classical hysterotomy in twin pregnancies across gestational age and examine risk factors that increase its occurrence. METHODS: This is a secondary analysis of the Cesarean Registry, a cohort study of women who underwent a cesarean delivery or a trial of labor after cesarean delivery at 19 academic centers between 1999 and 2002. Our study included all women with twin pregnancies and a recorded hysterotomy type who underwent cesarean delivery between 23 0/7 and 41 6/7 weeks of gestation. Primary exposures were gestational age at delivery and combined birth weight of twin A and twin B. Multivariate logistic regression was used to study factors thought to influence hysterotomy type including maternal age, body mass index (BMI) at delivery, obesity (BMI 30 or higher), nulliparity, labor, prior cesarean delivery, emergent delivery, and fetal presentation at delivery. RESULTS: Of 1,820 women meeting inclusion criteria, 125 (7%) underwent a classical hysterotomy. The risk of classical hysterotomy was greatest at 25 weeks of gestation (41%) and declined thereafter. The adjusted odds ratio (OR) for cesarean delivery declined as gestation age advanced (OR 0.87, 95% confidence interval 0.78-0.98). African American race and emergent delivery were associated risk factors for classical hysterotomy at 32 weeks of gestation or greater. CONCLUSION: Among women with twin pregnancies who deliver by cesarean, the incidence of classical hysterotomy is inversely related to gestational age but does not exceed 50% at any week; African American race and emergent delivery are associated risk factors at 32 weeks of gestation or greater. LEVEL OF EVIDENCE: II. PMID- 25730230 TI - Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. AB - The Perinatal Quality Foundation and the American College of Medical Genetics and Genomics, in association with the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the National Society of Genetic Counselors, have collaborated to provide education for clinicians and laboratories regarding the use of expanded genetic carrier screening in reproductive medicine. This statement does not replace current screening guidelines, which are published by individual organizations to direct the practice of their constituents. As organizations develop practice guidelines for expanded carrier screening, further direction is likely. The current statement demonstrates an approach for health care providers and laboratories who wish to or who are currently offering expanded carrier screening to their patients. PMID- 25730231 TI - Omega-3 long chain polyunsaturated fatty acids to prevent preterm birth: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of omega-3 in reducing the incidence of preterm birth. DATA SOURCES: Searches were performed in MEDLINE, OVID, Scopus, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, and the Cochrane Central Register of Controlled Trials with the use of a combination of keywords related to "fish oil," "pregnancy," and "omega 3." METHODS OF STUDY SELECTION: We included all randomized controlled trials of asymptomatic women with singleton gestations who were randomized to prophylactic treatment with either omega-3 supplementation or control (either placebo or no treatment). Exclusion criteria included trials in women with multiple gestations, intrauterine growth restriction, gestational hypertension or preeclampsia at randomization, prior preterm birth, and trials with polyunsaturated fatty acids as control. TABULATION, INTEGRATION, AND RESULTS: Nine randomized trials including 3,854 eligible women were identified. Women who received omega-3 had a similar rate of preterm birth before 37 weeks of gestation compared with women in the control group (7.7% compared with 9.1%, respectively; relative risk 0.90, 95% confidence interval [CI] 0.72-1.11). There were no significant differences in birth weight, neonatal intensive care unit admission, necrotizing enterocolitis, sepsis, or perinatal death in the omega-3 compared with control groups, respectively. There were no significant differences in the subgroup analyses, except for the rate of perinatal death, which was lower (0.3% compared with 1.2%; relative risk 0.27, 95% CI 0.09-0.80) in the women who received omega-3 before 21 weeks of gestation and in trials with low risk of bias (0.3% compared with 1.0%; relative risk 0.28, 95% CI 0.09-0.89) compared with women in the control group. However, in no randomized controlled trial was perinatal death the primary outcome. CONCLUSION: Omega-3 supplementation during pregnancy does not reduce the incidence of preterm birth or improve neonatal outcome. PMID- 25730232 TI - Fetal growth, cognitive function, and brain volumes in childhood and adolescence. AB - OBJECTIVE: To evaluate the association between fetal growth pattern and cognitive function at 5 and 9 years and regional brain volumes at 15 years. METHODS: Eighty three term-born small-for-gestational-age (SGA) neonates and 105 non-SGA neonates in a control group were available for follow-up. Based on serial fetal ultrasound measurements from gestational weeks 25-37, SGA neonates were classified with fetal growth restriction (n=13) or non-fetal growth restriction (n=36). Cognitive function was assessed at 5 and 9 years, and brain volumes were estimated with cerebral magnetic resonance imaging at 15 years. RESULTS: Small-for-gestational age children had lower performance intelligence quotient at 5 years compared with those in a control group (107.3 compared with 112.5, P<.05). Although there were no differences between the SGA non-fetal growth restriction and control groups, the SGA fetal growth restriction group had significantly lower performance intelligence quotient at 5 years (103.5 compared with 112.5, P<.05) and 9 years (96.2 compared with 107.5, P<.05) compared with those in the control group. There were some brain volume differences at 15 years between SGA children and those in the control group, but after adjustment for total intracranial volume, age at examination, and sex, there were only significant differences between the SGA fetal growth restriction and control groups for thalamic (17.4 compared with 18.6 cm, P<.01) and cerebellar white matter volumes (21.5 compared with 24.3 cm, P<.01). CONCLUSION: Small-for-gestational-age children had lower intelligence quotient scores at 5 and 9 years and smaller brain volumes at 15 years compared with those in the control group, but these findings were only found in those with fetal growth restriction, indicating a possible relationship to decelerated fetal growth. LEVEL OF EVIDENCE: II. PMID- 25730234 TI - Racial and ethnic disparities in maternal morbidity and mortality. PMID- 25730235 TI - Persistent occiput posterior. AB - Persistent occiput posterior (OP) is associated with increased rates of maternal and newborn morbidity. Its diagnosis by physical examination is challenging but is improved with bedside ultrasonography. Occiput posterior discovered in the active phase or early second stage of labor usually resolves spontaneously. When it does not, prophylactic manual rotation may decrease persistent OP and its associated complications. When delivery is indicated for arrest of descent in the setting of persistent OP, a pragmatic approach is suggested. Suspected fetal macrosomia, a biparietal diameter above the pelvic inlet or a maternal pelvis with android features should prompt cesarean delivery. Nonrotational operative vaginal delivery is appropriate when the maternal pelvis has a narrow anterior segment but ample room posteriorly, like with anthropoid features. When all other conditions are met and the fetal head arrests in an OP position in a patient with gynecoid pelvic features and ample room anteriorly, options include cesarean delivery, nonrotational operative vaginal delivery, and rotational procedures, either manual or with the use of rotational forceps. Recent literature suggests that maternal and fetal outcomes with rotational forceps are better than those reported in older series. Although not without significant challenges, a role remains for teaching and practicing selected rotational forceps operations in contemporary obstetrics. PMID- 25730236 TI - Pharmacologic intervention for retained placenta: a systematic review and meta analysis. AB - OBJECTIVE: To assess the effectiveness and safety of pharmacologic interventions for the treatment of retained placenta (when the placenta remains undelivered after 30 minutes of active management of the third stage of labor). DATA SOURCES: We searched: 1) Cochrane Central Register of Controlled Trials (CENTRAL), 2) Cochrane Pregnancy and Childbirth Group's Trials Register, 3) EMBASE, and 4) MEDLINE from inception to June 2014. METHODS OF STUDY SELECTION: Randomized controlled trials comparing a pharmacologic intervention(s) with a placebo for the treatment of retained placenta were included. TABULATION, INTEGRATION, AND RESULTS: Sixteen randomized controlled trials, including 1,683 participants, were included. Study characteristics and quality were recorded. The meta-analysis was based on random-effects methods for pooled data. There were no statistically significant differences in the requirement to perform manual removal of a placenta in patients treated with oxytocin (55% compared with 60%; relative risk [RR] 0.86, 95% confidence interval [CI] 0.73-1.02; 10 randomized controlled trials [RCTs]), prostaglandins (44% compared with 55%; RR 0.82, 95% CI 0.58-1.15; four RCTs), nitroglycerin (85% compared with 80%; RR 1.06, 95% CI 0.80-1.41; one RCT), or oxytocin and nitroglycerin (52% compared with 79%; RR 0.23, 95% CI 0.01 8.48; two RCTs) compared with placebo. There was limited reporting of secondary outcomes. CONCLUSION: As opposed to the use of oxytocin as part of the active management of the third stage of labor that has been shown to diminish bleeding in the third stage, once the diagnosis of retained placenta has been made, no pharmacologic treatment has been shown to be effective. When retained placenta is diagnosed, immediate manual removal of the placenta should be considered. SYSTEMATIC REVIEW REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews, http://www.crd.york.ac.uk/PROSPERO/, CRD42014010641. PMID- 25730233 TI - Morbidly adherent placenta treatments and outcomes. AB - OBJECTIVE: To describe recent maternal and neonatal delivery outcomes among women with a morbidly adherent placenta in major centers across the United States. METHODS: This study reviewed a cohort of 115,502 women and their neonates born in 25 hospitals in the United States between March 2008 and February 2011 from the Assessment of Perinatal EXcellence data set. All cases of morbidly adherent placenta were identified. Maternal demographics, procedures undertaken, and maternal and neonatal outcomes were analyzed. RESULTS: There were 158 women with a morbidly adherent placenta (1/731 births, 95% confidence interval 1/632-866). Eighteen percent of women with a morbidly adherent placenta were nulliparous and 37% had no prior cesarean delivery. Only 53% (84/158) were suspected to have a morbidly adherent placenta before delivery. Women with a prenatally suspected morbidly adherent placenta experienced large blood loss (33%), hysterectomy (92%), and intensive care unit admission (39%) compared with 19%, 45%, and 22%, respectively, in those not suspected prenatally to have a morbidly adherent placenta (P<.05 for all). CONCLUSION: Eighteen percent of women with a morbidly adherent placenta were nulliparous. Half of the morbidly adherent placenta cases were suspected before delivery and outcomes were poorer in this group, probably because the more clinically significant morbidly adherent placentas are more likely to be suspected before delivery. LEVEL OF EVIDENCE: : II. PMID- 25730239 TI - Factitious disorder-by-proxy simulating fetal growth restriction. AB - BACKGROUND: Although a variety of presentations have been described in the literature, the true prevalence of factitious disorder, also commonly known as Munchausen syndrome, and factitious disorder-by-proxy in pregnancy is unknown. The authors present a unique case in which intrauterine fetal growth restriction was simulated through fabrication of prenatal records. CASE: A 30-year-old woman, gravida 6 para 3113, was transferred at 38 4/7 weeks of gestation for severe fetal growth restriction. The clinic listed in the patient-provided prenatal record was contacted to obtain original ultrasonographic reports for verification of gestational age; however, further investigation revealed the patient had never attended this clinic nor was the ostensible treating physician ever employed there. The initial prenatal record subsequently was determined to be entirely fabricated. CONCLUSION: In this era of extensive technologic resources, health care providers should consider the possibility of factitious disorder when patient-provided medical record-derived information is inconsistent with the clinical presentation. PMID- 25730237 TI - Association of chronic pelvic pain and endometriosis with signs of sensitization and myofascial pain. AB - OBJECTIVE: To evaluate sensitization, myofascial trigger points, and quality of life in women with chronic pelvic pain with and without endometriosis. METHODS: A cross-sectional prospective study of women aged 18-50 years with pain suggestive of endometriosis and healthy, pain-free volunteers without a history of endometriosis. Patients underwent a physiatric neuromusculoskeletal assessment of clinical signs of sensitization and myofascial trigger points in the abdominopelvic region. Pain symptoms, psychosocial, and quality-of-life measures were also assessed. All participants with pain underwent laparoscopic excision of suspicious lesions to confirm endometriosis diagnosis by histologic evaluation. RESULTS: Patients included 18 with current, biopsy-proven endometriosis, 11 with pain only, and 20 healthy volunteers. The prevalence of sensitization as measured by regional allodynia and hyperalgesia was similar in both pain groups (83 and 82%) but much lower among healthy volunteers (15%, P<.001). Nearly all women with pain had myofascial trigger points (94 and 91%). Adjusting for study group, those with high anxiety (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.004 1.099, P=.031) and depression (OR 1.06, 95% CI 1.005-1.113, P=.032) scores were more likely to have sensitization. Pain patients with any history of endometriosis had the highest proportion of sensitization compared with the others (87% compared with 67% compared with 15%; P<.001). Adjusting for any history of endometriosis, those with myofascial trigger points were most likely sensitized (OR 9.41, 95% CI 1.77-50.08, P=.009). CONCLUSION: Sensitization and myofascial trigger points were common in women with pain regardless of whether they had endometriosis at surgery. Those with any history of endometriosis were most likely to have sensitization. Traditional methods of classifying endometriosis-associated pain based on disease, duration, and anatomy are inadequate and should be replaced by a mechanism-based evaluation, as our study illustrates. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00073801. LEVEL OF EVIDENCE: II. PMID- 25730240 TI - Conservative management of maternal cervical vertebral hemangioma complicating pregnancy. AB - BACKGROUND: Although vertebral hemangiomas are found in 10% of the population, they rarely become symptomatic. We describe management of an enlarging cervical vertebral hemangioma during pregnancy. CASE: A primiparous woman at 33 weeks of gestation presented with neck pain and paresthesias. She had a known cervical hemangioma. Imaging revealed a C6-C7 hemangioma with extradural extension. Her symptoms fluctuated, and she was delivered by cesarean at 36 weeks of gestation. Improvement occurred after delivery, and radiographic regression of the hemangioma was demonstrated. CONCLUSION: Hormonal and vascular changes of pregnancy may exacerbate spinal hemangiomas. Depending on the location, these may lead to profound neurologic disability and management depends on the degree of myelopathy. Surgical intervention may be necessary to avoid neurologic injury, but amelioration after delivery is possible. PMID- 25730241 TI - Intracorporeal electromechanical tissue morcellation: a critical review and recommendations for clinical practice. PMID- 25730242 TI - In reply. PMID- 25730243 TI - Body mass index and operative times at cesarean delivery. PMID- 25730244 TI - In reply. PMID- 25730245 TI - Predicting fetal acidemia using umbilical venous cord gas parameters. PMID- 25730246 TI - Outpatient cervical ripening by nitric oxide donors for prolonged pregnancy: a randomized controlled trial. PMID- 25730247 TI - No room at the inn: where are pregnant patients to go? PMID- 25730248 TI - In reply. PMID- 25730253 TI - Committee opinion no. 625: management of women with dense breasts diagnosed by mammography. AB - Women with dense breasts have a modestly increased risk of breast cancer and experience reduced sensitivity of mammography to detect breast cancer. However, evidence is lacking to advocate for additional testing until there are clinically validated data that indicate improved screening outcomes. Currently, screening mammography remains the most useful tool for breast cancer detection and consistently has demonstrated a reduction in breast cancer mortality. The American College of Obstetricians and Gynecologists does not recommend routine use of alternative or adjunctive tests to screening mammography in women with dense breasts who are asymptomatic and have no additional risk factors. The American College of Obstetricians and Gynecologists recommends that health care providers comply with state laws that may require disclosure to women of their breast density as recorded in a mammogram report. PMID- 25730254 TI - Committee opinion no. 626: the transition from pediatric to adult health care: preventive care for young women aged 18-26 years. AB - Young women (aged 18-26 years) are a heterogeneous population transitioning from adolescence into adulthood who may present with unique issues and challenges, including a potential gap in health care after pediatric health care. Obstetrician-gynecologists should note that these patients may need assistance in transitioning from a pediatrician to a provider of adult health care (an internist, family practitioner, or obstetrician-gynecologist), especially in the absence of a parent. Preventive counseling is crucial for helping young women anticipate changes and stressors and for easing their life transitions. A preventive health care visit offers the obstetrician-gynecologist an opportunity to screen for health issues and counsel the patient about a variety of health topics, some of which are particularly relevant to young women. PMID- 25730255 TI - Committee opinion no. 627: health care for unauthorized immigrants. AB - Unauthorized (undocumented) immigrants are less likely than other residents of the United States to have health insurance. The American College of Obstetricians and Gynecologists has long supported a basic health care package for all women living within the United States without regard to their country of origin or documentation. Providing access to quality health care for unauthorized immigrants and their children, who often were born in the United States and have U.S. citizenship, is essential to improving the nation's public health. PMID- 25730256 TI - Committee opinion no. 628: robotic surgery in gynecology. AB - The field of robotic surgery has developed rapidly, and its use for gynecologic conditions has grown exponentially. Surgeons should be skilled at abdominal and laparoscopic approaches for a specific procedure before undertaking robotic approaches. Surgeon training, competency guidelines, and quality metrics should be developed at the institutional level. Robot-assisted cases should be appropriately selected based on the available data and expert opinion. As with any surgical procedure, repetition drives competency. Ongoing quality assurance is essential to ensure appropriate use of the technology and, most importantly, patient safety. Adoption of new surgical techniques should be driven by what is best for the patient, as determined by evidence-based medicine rather than external pressures. Well-designed randomized controlled trials or comparably rigorous nonrandomized prospective trials are needed to determine which patients are likely to benefit from robot-assisted surgery and to establish the potential risks. PMID- 25730257 TI - Correction to storm, Tressoldi, and di Risio (2010). AB - Reports an error in "Meta-analysis of free-response studies, 1992-2008: Assessing the noise reduction model in parapsychology" by Lance Storm, Patrizio E. Tressoldi and Lorenzo Di Risio (Psychological Bulletin, 2010[Jul], Vol 136[4], 471-485). In the article, the sentence giving the formula in the second paragraph on p. 479 was stated incorrectly. The corrected sentence is included. (The following abstract of the original article appeared in record 2010-12718-001.) [Correction Notice: An erratum for this article was reported in Vol 136(5) of Psychological Bulletin (see record 2010-17510-009). In the article, the second to last sentence of the abstract (p. 471) was stated incorrectly. The sentence should read as follows: "The mean effect size value of the ganzfeld database was significantly higher than the mean effect size of the standard free-response database but was not higher than the effect size of the nonganzfeld noise reduction database."] We report the results of meta-analyses on 3 types of free response study: (a) ganzfeld (a technique that enhances a communication anomaly referred to as "psi"); (b) nonganzfeld noise reduction using alleged psi enhancing techniques such as dream psi, meditation, relaxation, or hypnosis; and (c) standard free response (nonganzfeld, no noise reduction). For the period 1997 2008, a homogeneous data set of 29 ganzfeld studies yielded a mean effect size of 0.142 (Stouffer Z = 5.48, p = 2.13 * 10-8). A homogeneous nonganzfeld noise reduction data set of 16 studies yielded a mean effect size of 0.110 (Stouffer Z = 3.35, p = 2.08 * 10-4), and a homogeneous data set of 14 standard free-response studies produced a weak negative mean effect size of -0.029 (Stouffer Z = -2.29, p = .989). The mean effect size value of the ganzfeld database were significantly higher than the mean effect size of the nonganzfeld noise reduction and the standard free-response databases. We also found that selected participants (believers in the paranormal, meditators, etc.) had a performance advantage over unselected participants, but only if they were in the ganzfeld condition. PMID- 25730258 TI - Photosynthetic water oxidation: insights from manganese model chemistry. AB - Catalysts for light-driven water oxidation are a critical component for development of solar fuels technology. The multielectron redox chemistry required for this process has been successfully deployed on a global scale in natural photosynthesis by green plants and cyanobacteria using photosystem II (PSII). PSII employs a conserved, cuboidal Mn4CaOX cluster called the O2-evolving complex (OEC) that offers inspiration for artificial O2-evolution catalysts. In this Account, we describe our work on manganese model chemistry relevant to PSII, particularly the functional model [Mn(III/IV)2(terpy)2(MU-O)2(OH2)2](NO3)3 complex (terpy = 2,2';6',2"-terpyridine), a mixed-valent di-MU-oxo Mn dimer with two terminal aqua ligands. In the presence of oxo-donor oxidants such as HSO5(-), this complex evolves O2 by two pathways, one of which incorporates solvent water in an O-O bond-forming reaction. Deactivation pathways of this catalyst include comproportionation to form an inactive Mn(IV)Mn(IV) dimer and also degradation to MnO2, a consequence of ligand loss when the oxidation state of the complex is reduced to labile Mn(II) upon release of O2. The catalyst's versatility has been shown by its continued catalytic activity after direct binding to the semiconductor titanium dioxide. In addition, after binding to the surface of TiO2 via a chromophoric linker, the catalyst can be oxidized by a photoinduced electron-transfer mechanism, mimicking the natural PSII process. Model oxomanganese complexes have also aided in interpreting biophysical and computational studies on PSII. In particular, the MU-oxo exchange rates of the Mn terpy dimer have been instrumental in establishing that the time scale for MU-oxo exchange of high-valent oxomanganese complexes with terminal water ligands is slower than O2 evolution in the natural photosynthetic system. Furthermore, computational studies on the Mn-terpy dimer and the OEC point to similar Mn(IV) oxyl intermediates in the O-O bond-forming mechanism. Comparison between the OEC and the Mn-terpy dimer indicates that challenges remain in the development of synthetic Mn water-oxidation catalysts. These include redox leveling to couple multielectron reactions with one-electron steps, avoiding labile Mn(II) species during the catalytic cycle, and protecting the catalyst active site from undesired side reactions. As the first example of a functional manganese O2 evolution catalyst, the Mn-terpy dimer exemplifies the interrelatedness of biomimetic chemistry with biophysical studies. The design of functional model complexes enriches the study of the natural photosynthetic system, while biology continues to provide inspiration for artificial photosynthetic technologies to meet global energy demand. PMID- 25730259 TI - Over-expression of telomere binding factors (TRF1 & TRF2) in renal cell carcinoma and their inhibition by using SiRNA induce apoptosis, reduce cell proliferation and migration invitro. AB - Telomere binding factors viz. TRF1 and TRF2 are a part of sheltrin complex that are present exclusively at the ends of chromosomes. These factors play an important role in maintaining chromosomal integrity at the ends. However, their status and role are not clear in renal cell carcinoma (RCC). Therefore, the present study was conducted to evaluate TRF1 and TRF2 expressions in RCC tissues. Further, the role of these factors involved in tumorigenesis was elucidated by gene silencing using siRNA in RCC cell line (A498). The present study documented a significant over-expression of TRF1 (P = 0.005) and TRF2 (P = 0.0048) mRNAs by real time PCR in RCC tissues as compared with adjacent normal kidney tissues. Immunohistochemistry studies also revealed higher expression of TRF1 and TRF2 proteins in RCC. Moreover, TRF1 or TRF2 gene silencing using siRNA showed marked reduction in proliferation of RCC cells (P = 0.000). Further, significantly induced cell cycle arrest (P = 0.000) and apoptosis of RCC cells (P = 0.000) was documented upon TRF1 or TRF2 gene silencing. Henceforth, the results deduce that TRF1 or TRF2 inhibitions play an important role in the induction of apoptosis in A498 cells, which may serve as a potential therapeutic target in RCC. PMID- 25730261 TI - Testing Cognitive and Emotion-Focused Models of Worry in Black and White Samples. AB - Several models have been proposed to conceptualize worry. Broadly, the models can be classified as cognitive (including the Avoidance Model, the Intolerance of Uncertainty Model, and the Metacognitive Model) and emotion-focused (including Emotion Dysregulation and Acceptance-Based models). Although these models have received strong empirical investigation in primarily non-Hispanic White samples, no known study has examined the applicability to racial and ethnic minority groups. The current study compared the proportion of variance explained by cognitive and emotion-focused models of worry in White and Black samples. Results indicated that cognitive and emotion-focused models significantly predicted worry in both Black and White samples. However, the overall amount of variance in worry explained by the models was less for Black samples. Specifically, controlling for gender, the cognitive models explained 53% of the variance in worry in the White sample compared with 19% in the Black sample. Similarly, the emotion-focused models explained 34% of the variance in worry in the White sample but only 13% in the Black sample. These findings suggest that well-established conceptual frameworks for worry failed to explain the bulk of the variance in worry in Black samples, leaving much unknown. Additional research is needed to identify key variables that may further explain worry in ethnic minority samples. PMID- 25730260 TI - The association between three cyclooxygenase-2 polymorphisms and hepatocellular carcinoma risk: a meta-analysis. AB - BACKGROUND: A quantity of case-control studies have been performed to address the association between three cyclooxygenase-2(COX-2) polymorphisms (-1195G/A, 765G/C and +8473T/C) and the risk of hepatocellular carcinoma (HCC). However, previous research results are inconsistent. We conducted this meta-analysis to clarify the correlation between these COX-2 polymorphisms and HCC risk. METHODS: The authors searched in PubMed, EMBASE, Google Scholar, CNKI and WanFang database for relevant articles up to April 28, 2014. The data were extracted by two independent reviewers. Odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: A total of 8 studies consisting of 2182 cases and 3324 controls were included in this meta-analysis. For COX-2 polymorphism -1195G/A, an association with increased risk was observed under the heterogeneous, homozygous, dominant model. However, COX-2 polymorphisms (-765G/C and +8473T/C) were not related to HCC risk in this study. We also found a similar result in the subgroup analysis of Chinese population that -1195G/A polymorphism, instead of -765G/C or +8473T/C polymorphism, was correlated with the risk of HCC. CONCLUSIONS: Polymorphism -1195G/A of COX-2 might be associated with susceptibility to HCC, but no similar correlations were observed between polymorphisms (-765G/C and +8473T/C) and HCC risk. Further large and well-designed studies are required to validate this association. PMID- 25730262 TI - 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of DYRK1A. AB - The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6 carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID- 25730263 TI - Rapid mass spectrometric conversion of tissue biopsy samples into permanent quantitative digital proteome maps. AB - Clinical specimens are each inherently unique, limited and nonrenewable. Small samples such as tissue biopsies are often completely consumed after a limited number of analyses. Here we present a method that enables fast and reproducible conversion of a small amount of tissue (approximating the quantity obtained by a biopsy) into a single, permanent digital file representing the mass spectrometry (MS)-measurable proteome of the sample. The method combines pressure cycling technology (PCT) and sequential window acquisition of all theoretical fragment ion spectra (SWATH)-MS. The resulting proteome maps can be analyzed, re-analyzed, compared and mined in silico to detect and quantify specific proteins across multiple samples. We used this method to process and convert 18 biopsy samples from nine patients with renal cell carcinoma into SWATH-MS fragment ion maps. From these proteome maps we detected and quantified more than 2,000 proteins with a high degree of reproducibility across all samples. The measured proteins clearly distinguished tumorous kidney tissues from healthy tissues and differentiated distinct histomorphological kidney cancer subtypes. PMID- 25730265 TI - Developmental critical windows and sensitive periods as three-dimensional constructs in time and space. AB - A critical window (sensitive period) represents a period during development when an organism's phenotype is responsive to intrinsic or extrinsic (environmental) factors. Such windows represent a form of developmental phenotypic plasticity and result from the interaction between genotype and environment. Critical windows have typically been defined as comprising discrete periods in development with a distinct starting time and end time, as identified by experiments following an on and an off protocol. Yet in reality, periods of responsiveness during development are likely more ambiguous that depicted. Our goal is to extend the concept of the developmental critical window by introducing a three-dimensional construct in which time during development, dose of the stressor applied, and the resultant phenotypic modification can be utilized to more realistically define a critical window. Using the example of survival of the brine shrimp (Artemia franciscana) during exposure to different salinity levels during development, we illustrate that it is not just stressor dose or exposure time but the interaction of these two factors that results in the measured phenotypic change, which itself may vary within a critical window. We additionally discuss a systems approach to critical windows, in which the components of a developing system--whether they be molecular, physiological, or morphological--may show differing responses with respect to time and dose. Thus, the plasticity of each component may contribute to a broader overall system response. PMID- 25730264 TI - A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. AB - Detection of cyclic-di-adenosine monophosphate (c-di-AMP), a bacterial second messenger, by the host cytoplasmic surveillance pathway (CSP) is known to elicit type I interferon (IFN) responses, which are crucial to antimicrobial defense. However, the mechanisms and role of c-di-AMP signaling in Mycobacterium tuberculosis virulence remain unclear. Here we show that resistance to tuberculosis requires CSP-mediated detection of c-di-AMP produced by M. tuberculosis and that levels of c-di-AMP modulate the fate of infection. We found that a di-adenylate cyclase (disA or dacA)-overexpressing M. tuberculosis strain that secretes excess c-di-AMP activates the interferon regulatory factor (IRF) pathway with enhanced levels of IFN-beta, elicits increased macrophage autophagy, and exhibits substantial virulence attenuation in mice. We show that c-di-AMP mediated IFN-beta induction during M. tuberculosis infection requires stimulator of interferon genes (STING)-signaling. We observed that c-di-AMP induction of IFN beta is independent of the cytosolic nucleic acid receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), but cGAS nevertheless contributes substantially to the overall IFN-beta response to M. tuberculosis infection. In sum, our results reveal c-di AMP to be a key mycobacterial pathogen-associated molecular pattern (PAMP) driving host type I IFN responses and autophagy. These findings suggest that modulating the levels of this small molecule may lead to novel immunotherapeutic strategies against tuberculosis. PMID- 25730266 TI - Critical Windows of Cardiovascular Susceptibility to Developmental Hypoxia in Common Snapping Turtle (Chelydra serpentina) Embryos. AB - Environmental conditions fluctuate dramatically in some reptilian nests. However, critical windows of environmental sensitivity for cardiovascular development have not been identified. Continuous developmental hypoxia has been shown to alter cardiovascular form and function in embryonic snapping turtles (Chelydra serpentina), and we used this species to identify critical periods during which hypoxia modifies the cardiovascular phenotype. We hypothesized that incubation in 10% O2 during specific developmental periods would have differential effects on the cardiovascular system versus overall somatic growth. Two critical windows were identified with 10% O2 from 50% to 70% of incubation, resulting in relative heart enlargement, either via preservation of or preferential growth of this tissue, while exposure to 10% O2 from 20% to 70% of incubation resulted in a reduction in arterial pressure. The deleterious or advantageous aspects of these embryonic phenotypes in posthatching snapping turtles have yet to be explored. However, identification of these critical windows has provided insight into how the developmental environment alters the phenotype of reptiles and will also be pivotal in understanding its impact on the fitness of egg-laying reptiles. PMID- 25730267 TI - The impact of extended preovipositional arrest on embryonic development and hatchling fitness in the flatback sea turtle. AB - Turtle embryos pause development before oviposition in a process known as preovipositional arrest. Embryonic development arrests due to hypoxia (low oxygen) in the maternal oviducts and resumes only after exposure to normoxia when eggs are laid. Recently, several studies have hypothesized that the prolonged periods of preovipositional arrest may have a detrimental effect on embryo survival and development after eggs are laid. We tested this hypothesis by comparing embryo survival (determined by white spot formation and hatching success) and hatchling fitness (measured by self-righting, crawling, and swimming ability) of flatback sea turtle (Natator depressus) eggs following incubation in hypoxic (~ 1%) and normoxic (~ 21%) treatments for 5 d immediately following oviposition. We also measured embryo survival and hatchling fitness when eggs were incubated in hyperoxic conditions (42% oxygen), to determine whether hyperoxia could improve developmental outcome or whether some consequence of oxidative stress might manifest. Eggs incubated in hypoxia remained arrested during the 5-d treatment, and 97.5% of the eggs successfully recommenced development after exposure to normoxia when the treatment finished. At treatment commencement, 100% and 97.5% of eggs in the hyperoxic and normoxic treatments, respectively, began developing. Although hatching success was significantly lower following hypoxia (15%) compared to normoxia (80%) and hyperoxia (85%), hatchings from the hypoxic treatment were larger (carapace length and width and plastron length) than normoxic hatchlings. Similarly, hypoxic hatchings also swam significantly faster than hyperoxic hatchlings. Considering larger hatchlings may have a greater chance of survival, the production of larger hatchings may offset the high cost (lower hatching success) when preovipositional arrest is prolonged. Hyperoxia does not appear to have deleterious consequences for development. PMID- 25730268 TI - Genetically Determined Variation in Developmental Physiology of Bivalve Larvae (Crassostrea gigas). AB - Understanding the complex interactions that regulate growth and form is a central question in developmental physiology. We used experimental crosses of pedigreed lines of the Pacific oyster, Crassostrea gigas, to investigate genetically determined variations in larval growth and nutrient transport. We show that (i) transport rates at 10 and 100 MUM glycine scale differentially with size; (ii) size-specific maximum transport capacity (Jmax) is genetically determined; and (iii) Jmax serves as an early predictive index of subsequent growth rate. This relationship between genetically determined Jmax and growth suggests the potential use of transporter genes as biomarkers of growth potential. Analysis of the genome of C. gigas revealed 23 putative amino acid transporter genes. The complexity of gene families that underpin physiological traits has additional precedents in this species and others and warrants caution in the use of gene expression as a biomarker for physiological state. Direct in vivo measurements of physiological processes using species with defined genotypes are required to understand genetically determined variance of nutrient flux and other processes that regulate development and growth. PMID- 25730269 TI - Nitrogenous Waste Handling by Larval Zebrafish Danio rerio in Alkaline Water. AB - Although adult fish excrete their nitrogenous waste primarily as ammonia, larval fish may excrete a higher proportion as urea, an evolutionary strategy that lessens nitrogenous waste toxicity during early development. Previous studies firmly established that ammonia excretion is inhibited in adult fish acutely exposed to alkaline water. This study was designed to test the hypothesis that total nitrogen excretion is maintained in larval zebrafish raised in alkaline water (pH ~ 10.0) as a result of compensatory adjustments to urea and/or ammonia transport pathways. Raising zebrafish in alkaline water from 0 to 4 d postfertilization (dpf) reduced ammonia excretion at 4 dpf, whereas urea excretion was elevated by 141%. The increase in urea excretion at 4 dpf served to maintain total nitrogen excretion constant, despite the persistent inhibition of ammonia excretion. Whole body ammonia and urea contents were not significantly altered by exposure to alkaline water. Protein and mRNA expression of Rhcg1, an apically expressed ammonia-conducting channel, were significantly elevated after 4-d exposure to alkaline water, whereas the mRNA expression of Rhag, Rhbg, and urea transporter were unaffected. The acute exposure to alkaline water of 4-dpf larvae reared in control water caused a rapid inhibition of ammonia excretion that had partially recovered within 6 h of continued exposure. The partial recovery of ammonia excretion despite continued exposure to alkaline water suggested an increased ammonia excretion capacity. In agreement with an increased capacity to excrete ammonia, the transfer of larvae back to the control (normal pH) water was accompanied by increased rates of ammonia excretion. Urea excretion was not stimulated during 6-h exposure to alkaline water. Following both chronic and acute exposure to alkaline water, the rate of uptake of methylamine (an ammonia analog) was significantly elevated, consistent with increased protein expression of the apical ammonia channel, Rhcg1. Taken together, this study demonstrates a complex interplay between ammonia and urea excretion in larval zebrafish exposed to alkaline water. PMID- 25730270 TI - Multiplicity of hypoxia-inducible transcription factors and their connection to the circadian clock in the zebrafish. AB - In zebrafish, as in most vertebrates, three different isoforms of the hypoxia inducible transcription factor, Hif-1alpha, Hif-2alpha, and Hif-3alpha, have been identified. The expression data of genes encoding these three proteins, as analyzed so far, show distinct expression patterns for all three isoforms during early development, under hypoxic conditions, and during exercise, suggesting differential roles for all three proteins under these different conditions. While isoform-specific functions for Hif-1alpha and Hif-2alpha have been identified in recent years, the role of Hif-3alpha remains somewhat elusive. Several studies mostly using mammalian cells or tissues discussed Hif-3alpha as a competitive inhibitor of Hif-1alpha and Hif-2alpha. In zebrafish, the expression changes for Hif-1alpha and Hif-3alpha observed during development and under environmental stress conditions do not support this hypothesis, and recent studies indicate that Hif-3alpha is also able to directly control transcriptional activity of certain genes. The Hif signaling pathway is tightly connected to cell circuitries such as glucose and lipid metabolism, and only very recently a further linkage to the circadian clock has been described. In this context a detailed analysis of the mRNA concentrations of hif-1alpha, hif-2alpha, and hif-3alpha also revealed a circadian expression pattern for hif-3alpha mRNA under normoxic conditions in zebrafish larvae. In addition, accumulation of Hif-1alpha protein during short term hypoxia was found to depend on the time within the daily light and dark cycle at which hypoxia was encountered, suggesting that the hypoxia signaling pathway may be regulated by the circadian clock. This is supported by the fact that some of the downstream genes of the Hif signaling pathway, namely, erythropoietin and vascular endothelial growth factor, are known to be clock controlled as well. Furthermore, in developing zebrafish, the disruption of the circadian rhythm was shown to result in a diminished hypoxic response with a modified life cycle of erythrocytes and an altered patterning of the vascular bed, leading to even higher mortality rates of chronodisrupted animals. Hif protein, in turn, is known to affect the circadian clock pathway in zebrafish. Previously, we demonstrated that Hif-1alpha directly binds to defined E-boxes of the period 1 gene, leading to a sustained dampening of its oscillation amplitude. Here we show that Hif-1alpha also binds to the promoter of the period 2 gene, indicating that multiple connections between the Hif signaling pathway and the circadian clock exist. The redundancy of the coupling between both pathways might be evidence for the coevolution of both circuits after the great oxygenation event about 2.5 billion years ago. Coupling the circadian clock and the hypoxic signaling pathway may have conferred selective advantages by facilitating a coordinated response of cells and organisms to alternating day-night cycles and concomitant variable food availabilities in the face of varying oxygen supply. PMID- 25730271 TI - The fat and the furriest: morphological changes in harp seal fur with ontogeny. AB - Ontogenetic changes in physiological performance often exemplify the development of adaptations to environmental challenges. For mammals in polar regions, the extreme cold of the environment presents a constant challenge to thermal homeostasis. The harp seal (Pagophilus groenlandicus) is an Arctic species that shifts its thermoregulatory strategy with ontogeny. Adult harp seals primarily use blubber for insulation, but newborn harp seals instead rely on their fur coat while their blubber layer develops. Harp seal pups are weaned abruptly, less than 2 wk after birth, and must subsequently learn to swim and dive in frigid waters on their own. This study examined how the morphological characteristics of harp seal fur change with ontogeny. We compared hair length, hair circularity, and hair density for neonates (1 d old; n = 7), early-nursing pups (4 d old; n = 3), late-nursing pups (9 d old; n = 4), newly weaned (molting) pups (2 wk old; n = 5), late-weaned (molted) pups (3 wk old; n = 4), and adult harp seals (n = 4). Hairs were shorter (P < 0.001) and flatter (P < 0.001) in older animals. Additionally, hair density decreased with age (P < 0.001), in terms of both the average number of hair bundles per unit area and the average number of underhairs present in any given bundle. These morphological changes were associated with a reduced thermal resistance of the pelt in late-weaned (molted) pups and adults (P < 0.001). Results are consistent with known evolutionary patterns of fur morphology associated with the transition from fur to blubber in aquatic species, yet this is the first time such morphological differences have been demonstrated across age classes within a single species. Thus, the ontogenetic patterns described here for harp seals recapitulate the convergent phylogenetic patterns observed across secondarily aquatic species. Overall, the timing of these ontogenetic changes may limit the ability of harp seals to adapt to the deterioration of sea ice in the Arctic, as predicted with continued climate change. PMID- 25730272 TI - Preparing Muscles for Diving: Age-Related Changes in Muscle Metabolic Profiles in Harp (Pagophilus groenlandicus) and Hooded (Cystophora cristata) Seals. AB - In adult marine mammals, muscles can sustain aerobic metabolism during dives in part because they contain large oxygen (O2) stores and metabolic rates are low. However, young pups have significantly lower tissue O2 stores and much higher mass-specific metabolic rates. To investigate how these differences may influence muscle function during dives, we measured the activities of enzymes involved in aerobic and anaerobic metabolic pathways (citrate synthase [CS], beta-hydroxyacyl coenzyme A dehydrogenase [HOAD], lactate dehydrogenase [LDH]) and the LDH isoform profile in six muscles from 41 harp (Pagophilus groenlandicus) and 30 hooded (Cystophora cristata) seals ranging in age from fetal to adult. All neonatal muscles had significantly higher absolute but lower metabolically scaled CS and HOAD activities than adults (~ 70% and ~ 85% lower, respectively). Developmental increases in LDH activity lagged that of aerobic enzymes and were not accompanied by changes in isozyme profile, suggesting that changes in enzyme concentration rather than structure determine activity levels. Biochemical maturation proceeded faster in the major locomotory muscles. In combination, findings suggest that pup muscles are unable to support strenuous aerobic exercise or rely heavily on anaerobic metabolism during early diving activities and that pups' high mass specific metabolic rates may play a key role in limiting the ability of their muscles to support underwater foraging. PMID- 25730273 TI - Early-life stress has sex-specific effects on immune function in adult song sparrows. AB - Multiple components of the immune system are modulated by environmental factors, including exposure to stressors. In particular, chronic stressors can impair development of the immune system, leading to alterations in immune function in adulthood. While these effects have been well established in mammals, less is known about how developmental stress modulates immunity in nonmammalian species. We determined the long-term effects of exposure to early-life stressors on immunity in song sparrows including the swelling response to phytohemagglutinin (PHA) and several measures of constitutive innate immunity. Song sparrows were reared in captivity from 3 d of age and exposed to control conditions, food restriction, or corticosterone (CORT) treatment. Males exposed to food restriction or CORT treatment had less swelling of the wing web in response to PHA than control males; however, neither treatment affected the swelling response to PHA in females. The treatments also had sex-specific effects on constitutive innate immune function. Specifically, CORT-treated males had lower antimicrobial capacity toward a strain of the bacterium E. coli but higher antimicrobial activity toward a strain of the fungus Candida albicans compared to food restricted or control males. In contrast, neither treatment affected constitutive innate immunity in females. These results suggest that male and female song sparrows may differ in how they allocate resources to development of the immune system when reared in stressful or food-limited conditions. PMID- 25730274 TI - Impacts of short-term food restriction on immune development in altricial house sparrow nestlings. AB - Food limitation is a common ecological scenario for nestling altricial birds, and reductions in growth and maintenance have been observed in resource-limited nestlings. Substantial development of the immune system occurs during the nestling period, yet the resource dependence of this immune development is understudied. We examined constitutive immune system development as well as acute phase responses to lipopolysaccharide (LPS) injection after 48 h of food restriction in house sparrows at 7 and 13 d posthatch. We also examined nestlings that were restricted early (5-7 d) but refed and tested at 13 d posthatch to determine whether altered immune function and growth early in the nestling period were recovered upon return to adequate resource supply. Induced acute-phase protein response was reduced in food-restricted birds, yet no lasting reductions in acute-phase protein levels were observed in previously restricted nestlings that were challenged with LPS after refeeding. Food restriction did not significantly impact constitutive levels of complement-mediated lysis or circulating IgY antibodies. As a comparator to immune measures, we found that organ and tarsus size, as well as muscle size and citrate synthase enzyme activity (an index of muscle cellular aerobic capacity), were significantly reduced in food-restricted nestlings. Reductions in flight muscle mass and function persisted in birds refed after early food restriction, which may have contributed to persistent body temperature reductions observed in refed birds. PMID- 25730275 TI - No Trade-Offs between Lipid Stores and Structural Growth in Juvenile Zebra Finches Undergoing Nutritional Stress during Development. AB - Nutritional conditions during development can affect both structural growth and body fat deposition. Body size and body fat each have significant consequences for fitness, yet few studies have investigated how young birds balance resource allocation between structural growth and fat reserves. We raised zebra finches (Taeniopygia guttata) in consistently high- or low-food conditions until posthatch day 35 (PHD 35). From this age until PHD 62, half of the birds in each condition were switched to the other treatment, while the rest were maintained on the same conditions. Body mass, lean mass, body fat, and tarsus length were measured before (PHD 25) and after (PHD 55) nutritional independence. Precise measures of body composition were obtained noninvasively at both ages using quantitative magnetic resonance analysis. At PHD 25, birds in the high treatment had more body mass and lean mass than birds in the low treatment, but nutritional treatments did not affect body fat at this age. Unexpectedly, the strategic response of birds that experienced deteriorating food availability was to maintain body mass by increasing body fat and decreasing lean mass. Birds that experienced an improvement in food availability significantly increased body mass by increasing lean mass and not body fat. Birds maintained on a low diet throughout did not significantly increase body mass, lean mass, or body fat. Tarsus length was not affected by nutritional manipulations. These findings indicate that nutritional stress did not affect the relationship between skeletal growth and body fat deposition because lean mass, body fat, and tarsus length can be independently regulated at different developmental periods depending on nutritional conditions. PMID- 25730276 TI - Biphasic Allometry of Cardiac Growth in the Developing Kangaroo Macropus fuliginosus. AB - Interspecific studies of adult mammals show that heart mass (M(h), g) increases in direct proportion to body mass (M(b), kg), such that M(h) ? M(b)(1.00). However, intraspecific studies on heart mass in mammals at different stages of development reveal considerable variation between species, M(h) ? M(b)(0.70 1.00). Part of this variation may arise as a result of the narrow body size range of growing placental mammals, from birth to adulthood. Marsupial mammals are born relatively small and offer an opportunity to examine the ontogeny of heart mass over a much broader body size range. Data from 29 western grey kangaroos Macropus fuliginosus spanning 800-fold in body mass (0.084-67.5 kg) reveal the exponent for heart mass decreases significantly when the joey leaves the pouch (ca. 5-6 kg body mass). In the pouch, the heart mass of joeys scales with hyperallometry, M(h(in-pouch)) = 6.39 M(b)(1.10 +/- 0.05), whereas in free-roaming juveniles and adults, heart mass scales with hypoallometry, M(h(postpouch)) = 14.2 Mb(0.77 +/- 0.08). Measurements of heart height, width, and depth support this finding. The relatively steep heart growth allometry during in-pouch development is consistent with the increase in relative cardiac demands as joeys develop endothermy and the capacity for hopping locomotion. Once out of the pouch, the exponent decreases sharply, possibly because the energy required for hopping is independent of speed, and the efficiency of energy storage during hopping increases as the kangaroo grows. The right:left ventricular mass ratios (0.30-0.35) do not change over the body mass range and are similar to those of other mammals, reflecting the principle of Laplace for the heart. PMID- 25730277 TI - Immune Defense Varies within an Instar in the Tobacco Hornworm, Manduca sexta. AB - Research on how insect immunity changes with age as insects develop within an instar, or larval developmental stage, is limited and contradictory. Insects within an instar are preparing for the next developmental stage, which may involve changes in morphology or habitat. Immunity may also vary accordingly. To determine how immunity varies in the fifth instar, we tested humoral immune responses, antimicrobial peptide activity, and phenoloxidase activity using the tobacco hornworm, Manduca sexta. We determined that while M. sexta have more robust antimicrobial peptide and phenoloxidase responses at the beginning of their fifth instar, this did not translate into better survival of bacterial infection or lower bacterial load in the hemolymph. We also determined that M. sexta injected with bacteria early in the fifth instar experience lower growth rates and longer development times than caterpillars of the same age injected with sham. This could indicate a shift in energy allocation from growth and development to metabolically costly immune responses. Because of the importance of insects as pests and pollinators, understanding how immunity varies throughout development is critical. PMID- 25730278 TI - Conversion of non-adipogenic fibroblasts into adipocytes by a defined hormone mixture. AB - Obesity is accompanied by an increase in the size and the number of adipocytes. As adipocytes are thought to differentiate from pre-adipocytes, we postulate that non-adipogenic fibroblasts contribute to adipocyte formation under certain conditions such as obesity. We report for the first time that NIH-3T3 fibroblasts, which are generally considered to be non-adipogenic, can be converted into mature adipocytes by treatment with a defined hormone mixture comprising EGF (epidermal growth factor), HGF (hepatocyte growth factor), Dex (dexamethasone) and insulin. Furthermore, NIH-3T3 cells transplanted into obese immunodeficient NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice formed adipocytes in vivo. Interestingly, the mixture elicited conversion of NIH-3T3 cells directly into adipocytes without a preceding pre-adipocyte stage. Functional analysis revealed that each component of the mixture was necessary for the induction of adipogenesis, including Dex which inhibited the cell proliferation stimulated by EGF. Upon profiling the signalling pathways employed by EGF and HGF, we found STAT5 (signal transducer and activator of transcription 5) signalling to be activated, predominantly at the levels of both transcription and post-translational modification. Inhibition of the STAT5 pathway, either by genetic knockdown or a specific pharmacological agent, blocked adipogenesis in NIH-3T3 cells. Taken together, these data not only establish a newly recognized grouping of factors that can induce trans-differentiation of non-adipogenic fibroblasts into adipocytes, but also give us a greater understanding of obesity. PMID- 25730279 TI - Fusion of MODIS and landsat-8 surface temperature images: a new approach. AB - Here, our objective was to develop a spatio-temporal image fusion model (STI-FM) for enhancing temporal resolution of Landsat-8 land surface temperature (LST) images by fusing LST images acquired by the Moderate Resolution Imaging Spectroradiometer (MODIS); and implement the developed algorithm over a heterogeneous semi-arid study area in Jordan, Middle East. The STI-FM technique consisted of two major components: (i) establishing a linear relationship between two consecutive MODIS 8-day composite LST images acquired at time 1 and time 2; and (ii) utilizing the above mentioned relationship as a function of a Landsat-8 LST image acquired at time 1 in order to predict a synthetic Landsat-8 LST image at time 2. It revealed that strong linear relationships (i.e., r2, slopes, and intercepts were in the range 0.93-0.94, 0.94-0.99; and 2.97-20.07) existed between the two consecutive MODIS LST images. We evaluated the synthetic LST images qualitatively and found high visual agreements with the actual Landsat-8 LST images. In addition, we conducted quantitative evaluations of these synthetic images; and found strong agreements with the actual Landsat-8 LST images. For example, r2, root mean square error (RMSE), and absolute average difference (AAD) values were in the ranges 084-0.90, 0.061-0.080, and 0.003-0.004, respectively. PMID- 25730280 TI - Alexa fluor-labeled fluorescent cellulose nanocrystals for bioimaging solid cellulose in spatially structured microenvironments. AB - Methods to covalently conjugate Alexa Fluor dyes to cellulose nanocrystals, at limiting amounts that retain the overall structure of the nanocrystals as model cellulose materials, were developed using two approaches. In the first, aldehyde groups are created on the cellulose surfaces by reaction with limiting amounts of sodium periodate, a reaction well-known for oxidizing vicinal diols to create dialdehyde structures. Reductive amination reactions were then applied to bind Alexa Fluor dyes with terminal amino-groups on the linker section. In the absence of the reductive step, dye washes out of the nanocrystal suspension, whereas with the reductive step, a colored product is obtained with the characteristic spectral bands of the conjugated dye. In the second approach, Alexa Fluor dyes were modified to contain chloro-substituted triazine ring at the end of the linker section. These modified dyes then were reacted with cellulose nanocrystals in acetonitrile at elevated temperature, again isolating material with the characteristic spectral bands of the Alexa Fluor dye. Reactions with Alexa Fluor 546 are given as detailed examples, labeling on the order of 1% of the total glucopyranose rings of the cellulose nanocrystals at dye loadings of ca. 5 MUg/mg cellulose. Fluorescent cellulose nanocrystals were deposited in pore network microfluidic structures (PDMS) and proof-of-principle bioimaging experiments showed that the spatial localization of the solid cellulose deposits could be determined, and their disappearance under the action of Celluclast enzymes or microbes could be observed over time. In addition, single molecule fluorescence microscopy was demonstrated as a method to follow the disappearance of solid cellulose deposits over time, following the decrease in the number of single blinking dye molecules with time instead of fluorescent intensity. PMID- 25730281 TI - The string sign for diagnosis of mucinous pancreatic cysts. AB - BACKGROUND AND STUDY AIMS: Pancreas cyst fluid analysis does not provide optimal discrimination between mucinous and nonmucinous cysts. The aim of this study was to assess the performance characteristics of the "string sign" - a test performed at the time of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), for the diagnosis of mucinous pancreatic cysts (branch duct intraductal papillary mucinous neoplasms [bIPMN] and mucinous cystic neoplasms). PATIENTS AND METHODS: Patients undergoing EUS-FNA of pancreatic cystic lesions at one referral center between 2003 and 2012 were included. The string sign was performed prospectively, and was considered positive if >= 1 cm string formed in cyst fluid and lasted for >= 1 second. Performance characteristics of the string sign and a sequential cyst fluid test interpretation model were assessed. RESULTS: For 98 histologically proven cases, the sensitivity, specificity, positive predictive value, and negative predictive value of the string sign for diagnosis of mucinous cysts were 58 % (95 % confidence interval [CI] 44 % - 70 %), 95 % (83 % - 99 %), 94 % (81 % 99 %), and 60 % (46 % - 72 %), respectively. When string sign results and carcinoembryonic antigen (CEA) concentration (>= 200 ng/mL) were combined, diagnostic accuracy improved from 74 % and 83 %, respectively, to 89 % (P <= 0.03). Among bIPMN, a positive string sign was associated with gastric and intestinal epithelial subtypes. The sequential cyst fluid test interpretation model (including cytology, mucin stain, CEA, and string sign) yielded an overall sensitivity for mucinous lesions of 96 %, with a specificity of 90 %. CONCLUSIONS: The string sign is highly specific for diagnosis of mucinous pancreatic cysts, and improves overall diagnostic accuracy of pancreatic cyst fluid analysis. Sequential cyst fluid test interpretation yields high diagnostic sensitivity and specificity for mucinous cysts. PMID- 25730282 TI - ERCP in patients with prior Billroth II gastrectomy: report of 30 years' experience. AB - BACKGROUND AND STUDY AIM: Endoscopic retrograde cholangiopancreatography (ERCP) is difficult in patients with altered anatomy following Billroth II gastrectomy. Afferent loop intubation, selective cannulation, and sphincterotomy are the main issues. Experience from a tertiary referral endoscopy center is reported. PATIENTS AND METHODS: A total of 713 patients with Billroth II reconstruction who underwent ERCP between October 1982 and October 2012 were retrospectively identified from a prospectively collected database (mean age 69 +/- 27 years; 567 males). The main indications for ERCP were common bile duct stones (51.2 %) and obstructive jaundice (24.8 %). Procedures were always started with a duodenoscope; in cases of failure to reach the papilla the duodenoscope was changed to a gastroscope. Endoscopic sphincterotomy was performed using a long nose sigmoid inverted sphincterotome. RESULTS: The successful duodenal intubation rate was 86.7 % (618/713 patients). The main reason for intubation failure was a long and angulated afferent loop. Successful cannulation/opacification of the desired biliopancreatic duct was 93.8 % (580/618). Biliary and/or pancreatic sphincterotomy were performed in 490 (84.5 %) and 23 (4.0 %) patients, respectively. The adverse event rate was 4.3 % (45/1050 procedures). Peritoneal perforation occurred in 1.8 % of the cases (19/1050 procedures) and always required immediate surgery. Two patients died after surgery (overall mortality 0.3 %). The other adverse events resolved following conservative management or endoscopic reintervention. CONCLUSIONS: In experienced centers, ERCP in Billroth II patients had morbidity and mortality rates that were comparable to patients with normal anatomy. The main reasons for failure were related to the inability to reach the papilla. Peritoneal perforation was the most common adverse event, and required a prompt surgical approach. PMID- 25730283 TI - Comparison of hemostatic forceps with soft coagulation versus argon plasma coagulation for bleeding peptic ulcer--a randomized trial. AB - BACKGROUND AND STUDY AIMS: Endoscopic high-frequency soft coagulation is used to manage visible bleeding or nonbleeding vessels during endoscopic submucosal dissection. The aim of the present study was to compare the efficacy of hemostasis by soft coagulation (using hemostatic forceps) with argon plasma coagulation (APC), in a prospective randomized trial. PATIENTS AND METHODS: From January 2013 to June 2014, 276 patients were randomly assigned into two groups: epinephrine injection plus APC (the APC group); or epinephrine injection plus soft coagulation using hemostatic forceps (the HFSC group). As the primary outcome we compared recurrent bleeding rates within 30 days after initial hemostasis in a noninferiority design. RESULTS: After exclusion, 75 patients in the APC group and 76 in the HFSC group were finally evaluated. In the APC group 72 patients (96 %) were successfully treated with the assigned treatment alone vs. 73 (96 %) in the HFSC group. Initial endoscopic hemostasis using a single or combined modality was achieved in all patients. Recurrent bleeding within 30 days was experienced by five patients (6.7 %) and seven patients (9.2 %) in the AFC and HFSC groups, respectively (P = 0.563), and within 7 days by three patients (4.0 %) and five patients (6.6 %), respectively (P = 0.719). We found no significant difference in the rates of adverse events (1.3 % vs. 2.6 %) or mortality (2.7 % vs. 2.6 %) between the groups. CONCLUSIONS: The efficacy and safety of soft coagulation using endoscopic hemostatic forceps is not inferior to APC when used to treat patients with bleeding peptic ulcers. Clinicaltrials.gov NCT02020603. PMID- 25730284 TI - Screening of esophageal varices by esophageal capsule endoscopy: results of a French multicenter prospective study. AB - BACKGROUND AND STUDY AIM: Esophageal video capsule endoscopy (ECE) is a new technique that allows examination of the esophagus using a noninvasive approach. The aim of this study was to compare ECE with esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal varices in patients with cirrhosis. PATIENTS AND METHODS: A total of 330 patients with cirrhosis and with no known esophageal varices were prospectively enrolled. Patients underwent ECE first, followed by EGD (gold standard). The endoscopists who performed EGD were blind to the ECE result. Patient satisfaction was assessed using a visual analog scale (maximum score 100). RESULTS: A total of 30 patients were excluded from the analysis because they did not undergo any endoscopic examinations. Patients (mean age 56 years; 216 male) had mainly alcoholic (45 %) or viral (27 %) cirrhosis. The diagnostic indices of ECE to diagnose and correctly stage esophageal varices were: sensitivity 76 % and 64 %, specificity 91 % and 93 %, positive predictive value 88 % and 88 %, and negative predictive value 81 % and 78 %, respectively. ECE patient satisfaction scored significantly higher than EGD (87 +/- 22 vs. 58 +/- 35; P < 0.0001). CONCLUSIONS: ECE was well tolerated and safe in patients with liver cirrhosis and suspicion of portal hypertension. The sensitivity of ECE is not currently sufficient to replace EGD as a first exploration in these patients. However, due to its excellent specificity and positive predictive value, ECE may have a role in cases of refusal or contraindication to EGD. ECE might also improve compliance to endoscopic follow-up and aid important therapeutic decision making in the prophylaxis of bleeding. TRIAL REGISTRATION: EudraCT (ID RCB 2009-A00532-55) and ClinicalTrials.gov (NCT00941421). PMID- 25730285 TI - Hydroxyl radical formation during ozonation of multiwalled carbon nanotubes: performance optimization and demonstration of a reactive CNT filter. AB - We explored factors influencing hydroxyl radical (*OH) formation during ozonation of multiwalled carbon nanotubes (MWCNTs) and assessed this system's viability as a next-generation advanced oxidation process (AOP). Using standard reactivity metrics for ozone-based AOPs (RCT values), MWCNTs promoted *OH formation during ozonation to levels exceeding ozone (both alone and with activated carbon) and equivalent to ozone with hydrogen peroxide. MWCNTs oxidized with nitric acid exhibited vastly greater rates of ozone consumption and *OH formation relative to as-received MWCNTs. While some of this enhancement reflects their greater suspension stability, a strong correlation between RCT values and surface oxygen concentrations from X-ray photoelectron spectroscopy suggests that surface sites generated during MWCNT oxidation promote *OH exposure. Removal of several ozone recalcitrant species [para-chlorobenzoic acid (p-CBA), atrazine, DEET, and ibuprofen] was not significantly inhibited in the presence of radical scavengers (humic acid, carbonate), in complex aquatic matrices (Iowa River water) and after 12 h of continuous exposure of MWCNTs to concentrated ozone solutions. As a proof of-concept, oxidized MWCNTs deposited on a ceramic membrane chemically oxidized p CBA in a flow through system, with removal increasing with influent ozone concentration and mass of deposited MWCNTs (in mg/cm2). This hybrid membrane platform, which integrates adsorption, oxidation, and filtration via an immobilized MWCNT layer, may serve as the basis for future novel nanomaterial enabled technologies, although long-term performance trials under representative treatment scenarios remain necessary. PMID- 25730286 TI - High-pressure synthesis, crystal structure and magnetic properties of TlCrO3 perovskite. AB - TlMO(3) perovskites (M(3+) = transition metals) are exceptional members of trivalent perovskite families because of the strong covalency of Tl(3+)-O bonds. Here we report on the synthesis, crystal structure and properties of TlCrO(3) investigated by Mossbauer spectroscopy, specific heat, dc/ac magnetization and dielectric measurements. TlCrO(3) perovskite is prepared under high pressure (6 GPa) and high temperature (1500 K) conditions. The crystal structure of TlCrO(3) is refined using synchrotron X-ray powder diffraction data: space group Pnma (no. 62), Z = 4 and lattice parameters a = 5.40318(1) A, b = 7.64699(1) A and c = 5.30196(1) A at 293 K. No structural phase transitions are found between 5 and 300 K. TlCrO(3) crystallizes in the GdFeO(3)-type structure similar to other members of the perovskite chromite family, ACrO(3) (A(3+) = Sc, In, Y and La-Lu). The unit cell volume and Cr-O-Cr bond angles of TlCrO(3) are close to those of DyCrO(3); however, the Neel temperature of TlCrO(3) (TN~ 89 K) is much smaller than that of DyCrO(3) and close to that of InCrO(3). Isothermal magnetization studies show that TlCrO(3) is a fully compensated antiferromagnet similar to ScCrO(3) and InCrO(3), but different from RCrO(3) (R(3+) = Y and La-Lu). Ac and dc magnetization measurements with a fine step of 0.2 K reveal the existence of two Neel temperatures with very close values at T(N2) = 87.0 K and T(N1) = 89.3 K. Magnetic anomalies near T(N2 )are suppressed by static magnetic fields and by 5% iron doping. PMID- 25730287 TI - Successful desensitization of a patient with aplastic anemia to antithymocyte globulin. AB - Antithymocyte globulin (ATG) is a polyclonal gamma immunoglobulin derived from either rabbit or equine serum that serves as therapy for aplastic anemia; however, ATG causes serum sickness in up to 70% and anaphylaxis in up to 5% of recipients. Intradermal (ID) skin testing has been the primary technique used to evaluate for a preexisting Gell and Coombs type I hypersensitivity reaction to ATG. There are no data reporting the predictive value of delayed reactions to ID testing on the risk of serum sickness. This study was designed to establish the importance of epicutaneous and ID skin testing before the administration of ATG through a case report and literature discussion. We report a patient with severe aplastic anemia that was successfully desensitized to ATG after a negative epicutaneous skin test and positive ID skin test. The patient had neither systemic nor localized reactions during the desensitization. Desensitization to ATG in patients with positive epicutaneous skin testing has been shown to be associated with serious and potentially life-threatening complications and should only be considered when the benefits outweigh the risks. Epicutaneous skin testing should be considered in conjunction with ID skin testing when screening for potential sensitivity to ATG. Because of the serious risk of anaphylaxis, desensitization should be performed in an intensive care unit setting in conjunction with a physician familiar with drug desensitization and the management of anaphylaxis. PMID- 25730289 TI - Reconstruction of genome-scale human metabolic models using omics data. AB - The impact of genome-scale human metabolic models on human systems biology and medical sciences is becoming greater, thanks to increasing volumes of model building platforms and publicly available omics data. The genome-scale human metabolic models started with Recon 1 in 2007, and have since been used to describe metabolic phenotypes of healthy and diseased human tissues and cells, and to predict therapeutic targets. Here we review recent trends in genome-scale human metabolic modeling, including various generic and tissue/cell type-specific human metabolic models developed to date, and methods, databases and platforms used to construct them. For generic human metabolic models, we pay attention to Recon 2 and HMR 2.0 with emphasis on data sources used to construct them. Draft and high-quality tissue/cell type-specific human metabolic models have been generated using these generic human metabolic models. Integration of tissue/cell type-specific omics data with the generic human metabolic models is the key step, and we discuss omics data and their integration methods to achieve this task. The initial version of the tissue/cell type-specific human metabolic models can further be computationally refined through gap filling, reaction directionality assignment and the subcellular localization of metabolic reactions. We review relevant tools for this model refinement procedure as well. Finally, we suggest the direction of further studies on reconstructing an improved human metabolic model. PMID- 25730288 TI - Synthesis of functionalized gamma-lactone via Sakurai exo cyclization/rearrangement of 3,3-bis(silyl) enol ester with a tethered acetal. AB - An efficient synthesis of functionalized gamma-lactones has been developed involving Sakurai exo-cyclization/rearrangement of 3,3-bis(silyl) enol esters with a tethered acetal. While the steric and electronic effects of geminal bis(silane) favor the desired Sakurai pathway, the methoxy species formed in the deprotection step also facilitates both cyclization and rearrangement. The synthetic value of this approach has been demonstrated by efficiently transforming the E-vinylsilane into enyne and the gamma-lactone moiety into multisubstituted THF. PMID- 25730290 TI - Safety and Efficacy of Botulinum Toxin A in Children Undergoing Lower Limb Lengthening and Deformity Correction: Results of a Double-blind, Multicenter, Randomized Controlled Trial. AB - BACKGROUND: Lengthening of the lower limb is a complex procedure in which pain management and complications such as pin-site infections and muscle contractures impact the family and affect the child's quality of life. As a result, the paralytic and antinociceptive actions of neurotoxins may be indicated in managing these complications; however, few studies have explored ways to improve outcomes after lengthenings. The objective of this study was to evaluate the safety and efficacy of botulinum toxin A (BTX-A) in children undergoing lower limb lengthenings and deformity correction. METHODS: Participants with a congenital or acquired deformity of the lower extremity requiring surgery to one limb were randomized to receiving either BTX-A as a single dose of 10 units per kilogram body weight, or an equivalent volume of saline solution. Pain, medication, quality of life, and physical function were assessed at different time-points. Adverse events were recorded in all participants. T test and chi tests were used to compare potential differences across both groups. RESULTS: Mean age of the 125 participants was 12.5 years (range, 5 to 21 y), and lengthenings averaged 4.2 cm. Maximum pain scores on day 1 postoperatively were lower in the BTX-A group (P=0.03) than in the placebo group, and remained significant favoring botox when stratifying by location of lengthening (femur vs. tibia). Clinical benefits for BTX-A were found for 3 quality of life domains at mid-distraction and end distraction. When stratifying according to location of lengthening, there were significantly fewer pin-site infections in the tibia favoring botox (P=0.03). The amount of adverse events and bone healing indices were no different in both groups. CONCLUSIONS: The clinical differences in quality of life, the lower pain on the first postoperative day, and the lower number of pin-site infections in the tibia favoring BTX-A support its use as an adjunctive treatment to the lengthening process. The detailed analyses of pain patterns help inform families on the pain expectations during lower limb lengthenings. The amount of adverse events were no different in both groups, and bone healing rates were similar, indicating that the use of BTX-A in children undergoing limb lengthening and deformity correction is safe. LEVEL OF EVIDENCE: Level I. PMID- 25730291 TI - Initial Correction Predicts the Need for Secondary Achilles Tendon Procedures in Patients With Idiopathic Clubfoot Treated With Ponseti Casting. AB - BACKGROUND: The Ponseti method is the most common method to treat idiopathic clubfoot in North America. Despite initial correction, recurrence is common with this method. The factors predictive of recurrence are not well defined in the literature. METHODS: A retrospective chart review was done of procedures performed at our institution from 2005 to 2010 in children undergoing general anesthesia for primary percutaneous Achilles tenotomy for the treatment of idiopathic clubfoot using the Ponseti casting method (101 patients, 148 feet). All patients were followed up for at least 2 years postoperatively (2 to 7.5 y, average 3.5 y). The patients were divided into 2 groups: group N with no repeat procedures on Achilles tendon and group R with a secondary procedure to address the residual equinus deformity. We looked at postoperative equinus correction through the use of postoperative measurements on digital images using a goniometer. The amount of postoperative dorsiflexion at the initial procedure was compared between the 2 groups using the paired t test. The feet were then divided into 3 groups on the basis of the amount of initial correction, and the rates of future surgical procedures were compared among these groups. RESULTS: A total of 101 patients (148 feet) were evaluated. Seventy-two patients (106 feet) did not have any future procedures to address equinus deformity (group N). Twenty-nine patients (42 feet) underwent future procedure (group R) to correct the residual equinus. The N and R groups differed in amount of postoperative dorsiflexion (14.0 vs. 5.1; P<0.01). Patients in whom at least 10 degrees of dorsiflexion was achieved after the initial tenotomy had only a 12% rate of future procedures. Patients with neutral or less than neutral dorsiflexion had 64% chance of future procedures to address the residual equinus. CONCLUSIONS: Residual equinus deformity after Achilles tenotomy in clubfeet treated by the Ponseti method is associated with a high rate of future surgical procedures. Correction of this deformity before bracing could potentially decrease the rate of future surgery. LEVEL OF EVIDENCE: Level III-Retrospective. PMID- 25730292 TI - Does Topical Anesthetic Reduce Pain During Intraosseous Pin Removal in Children? A Randomized Controlled Trial. AB - BACKGROUND: The purpose of this study was to determine the effectiveness of topical liposomal lidocaine in reducing the pain perceived by children undergoing percutaneous intraosseous pin (PP) removal in the outpatient orthopaedic clinic. METHODS: A triple-blinded, randomized, placebo-controlled clinical trial comparing topical liposomal lidocaine to a placebo was conducted at the Stollery Children's Hospital between September 2008 and February 2011. Subjects undergoing the removal of PP in the orthopaedic outpatient clinic between ages 3 and 16 years were recruited. A computer-generated variable-block randomization scheme was used to determine each subject's group assignment. Pain was recorded just before randomization and immediately after the procedure using the Oucher Scale (for subjects) and a 10-cm Visual Analog Scale (for parents and an observing orthopaedic technician). In a subset of individuals, follow-up telephone calls were made 24 hours postprocedure to inquire about any adverse event from the use of the topical liposomal lidocaine. Data were analyzed using the Student t test. RESULTS: Of a total of 296 recruited subjects, complete data were available on 281 subjects (140 intervention and 141 control). There were no significant differences between the 2 groups with regards to baseline characteristics, including preprocedure pain scores. Although postprocedure pain scores demonstrated an increase in pain in both groups (2.3 points in the treatment group and 2.0 points in the placebo group), no statistically significant difference was seen in postprocedure pain scores between groups (P=0.81). No adverse events were observed or reported. CONCLUSIONS: Topically applied liposomal lidocaine was not effective in reducing pain during this procedure, compared with a placebo. However, this study demonstrates that PP removal is a painful procedure in children. Given the large volume of patients who undergo this procedure and the long-term consequences of experiencing painful procedures in childhood, it is important to find safe and fast-acting methods to decrease procedural pain associated with PP removal. PMID- 25730294 TI - Freezing/Thawing without Cryoprotectant Damages Native but not Decellularized Porcine Renal Tissue. AB - Whole organ decellularization of porcine renal tissue and recellularization with a patient's own cells would potentially overcome immunorejection, which is one of the most significant problems with allogeneic kidney transplantation. However, there are obstacles to achieving this goal, including preservation of the decellularized extracellular matrix (ECM), identifying the proper cell types, and repopulating the ECM before transplantation. Freezing biological tissue is the best option to avoid spoilage; however, it may damage the structure of the tissue or disrupt cellular membranes through ice crystal formation. Cryoprotectants have been used to repress ice formation during freezing, although cell toxicity can still occur. The effect of freezing/thawing on native (n = 10) and decellularized (n = 10) whole porcine kidneys was studied without using cryoprotectants. Results showed that the elastic modulus of native kidneys was reduced by a factor of 22 (P < 0.0001) by freezing/thawing or decellularization, while the elastic modulus for decellularized ECM was essentially unchanged by the freezing/thawing process (p = 0.0636). Arterial pressure, representative of structural integrity, was also reduced by a factor of 52 (P < 0.0001) after freezing/thawing for native kidneys, compared to a factor of 43 (P < 0.0001) for decellularization and a factor of 4 (P < 0.0001) for freezing/thawing decellularized structures. Both freezing/thawing and decellularization reduced stiffness, but the reductions were not additive. Investigation of the microstructure of frozen/thawed native and decellularized renal tissues showed increased porosity due to cell removal and ice crystal formation. Orcein and Sirius staining showed partial damage to elastic and collagen fibers after freezing/thawing. It was concluded that cellular damage and removal was more responsible for reducing stiffness than fibril destruction. Cell viability and growth were demonstrated on decellularized frozen/thawed and non-frozen samples using human renal cortical tubular epithelial (RCTE) cells over 12 d. No adverse effect on the ability to recellularize after freezing/thawing was observed. It is recommended that porcine kidneys be frozen prior to decellularization to prevent contamination, and after decellularization to prevent protein denaturation. Cryoprotectants may still be necessary, however, during storage and transportation after recellularization. PMID- 25730293 TI - Cardiovascular Risk Factors in Severely Obese Adolescents: The Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study. AB - IMPORTANCE: Severe obesity is increasingly common in the adolescent population but, as of yet, very little information exists regarding cardiovascular disease (CVD) risks in this group. OBJECTIVE: To assess the baseline prevalence and predictors of CVD risks among severely obese adolescents undergoing weight-loss surgery. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted from February 28, 2007, to December 30, 2011, at the following 5 adolescent weight-loss surgery centers in the United States: Nationwide Children's Hospital in Columbus, Ohio; Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio; Texas Children's Hospital in Houston; University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania; and Children's Hospital of Alabama in Birmingham. Consecutive patients aged 19 years or younger were offered enrollment in a long-term outcome study; the final analysis cohort consisted of 242 participants. MAIN OUTCOMES AND MEASURES: This report examined the preoperative prevalence of CVD risk factors (ie, fasting hyperinsulinemia, elevated high-sensitivity C-reactive protein levels, impaired fasting glucose levels, dyslipidemia, elevated blood pressure, and diabetes mellitus) and associations between risk factors and body mass index (calculated as weight in kilograms divided by height in meters squared), age, sex, and race/ethnicity. Preoperative data were collected within 30 days preceding bariatric surgery. RESULTS: The mean (SD) age was 17 (1.6) years and median body mass index was 50.5. Cardiovascular disease risk factor prevalence was fasting hyperinsulinemia (74%), elevated high-sensitivity C-reactive protein levels (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%). The risk of impaired fasting glucose levels, elevated blood pressure, and elevated high-sensitivity C-reactive protein levels increased by 15%, 10%, and 6%, respectively, per 5-unit increase in body mass index (P < .01). Dyslipidemia (adjusted relative risk = 1.60 [95% CI, 1.26-2.03]; P < .01) and elevated blood pressure (adjusted relative risk = 1.48 [95% CI, 1.16-1.89]; P < .01) were more likely in adolescent boys compared with adolescent girls. White individuals were at greater risk of having elevated triglyceride levels (adjusted relative risk = 1.76 [95% CI, 1.14-2.72]; P = .01) but were less likely to have impaired fasting glucose levels (adjusted relative risk = 0.58 [95% CI, 0.38 0.89]; P = .01). CONCLUSIONS AND RELEVANCE: Numerous CVD risk factors are apparent in adolescents undergoing weight-loss surgery. Increasing body mass index and male sex increase the relative risk of specific CVD risk factors. These data suggest that even among severely obese adolescents, recognition and treatment of CVD risk factors is important to help limit further progression of disease. PMID- 25730295 TI - Salmonella and eggs: from production to plate. AB - Salmonella contamination of eggs and egg shells has been identified as a public health concern worldwide. A recent shift in consumer preferences has impacted on the egg industry, with a push for cage-free egg production methods. There has also been an increased desire from consumers for raw and unprocessed foods, potentially increasing the risk of salmonellosis. In response to these changes, this review explores the current literature regarding Salmonella contamination of eggs during the production processing through to food handling protocols. The contamination of eggs with Salmonella during the production process is a complex issue, influenced by many variables including flock size, flock age, stress, feed, vaccination, and cleaning routines. Currently there is no consensus regarding the impact of caged, barn and free range egg production has on Salmonella contamination of eggs. The literature regarding the management and control strategies post-collection, during storage, transport and food handling is also reviewed. Pasteurisation and irradiation were identified as the only certain methods for controlling Salmonella and are essential for the protection of high risk groups, whereas control of temperature and pH were identified as potential control methods to minimise the risk for foods containing raw eggs; however, further research is required to provide more detailed control protocols and education programs to reduce the risk of salmonellosis from egg consumption. PMID- 25730297 TI - Layer-by-layer evolution of structure, strain, and activity for the oxygen evolution reaction in graphene-templated Pt monolayers. AB - In this study, we explore the dimensional aspect of structure-driven surface properties of metal monolayers grown on a graphene/Au template. Here, surface limited redox replacement (SLRR) is used to provide precise layer-by-layer growth of Pt monolayers on graphene. We find that after a few iterations of SLRR, fully wetted 4-5 monolayer Pt films can be grown on graphene. Incorporating graphene at the Pt-Au interface modifies the growth mechanism, charge transfers, equilibrium interatomic distances, and associated strain of the synthesized Pt monolayers. We find that a single layer of sandwiched graphene is able to induce a 3.5% compressive strain on the Pt adlayer grown on it, and as a result, catalytic activity is increased due to a greater areal density of the Pt layers beyond face centered-cubic close packing. At the same time, the sandwiched graphene does not obstruct vicinity effects of near-surface electron exchange between the substrate Au and adlayers Pt. X-ray photoelectron spectroscopy (XPS) and extended X-ray absorption fine structure (EXAFS) techniques are used to examine charge mediation across the Pt-graphene-Au junction and the local atomic arrangement as a function of the Pt adlayer dimension. Cyclic voltammetry (CV) and the oxygen reduction reaction (ORR) are used as probes to examine the electrochemically active area of Pt monolayers and catalyst activity, respectively. Results show that the inserted graphene monolayer results in increased activity for the Pt due to a graphene induced compressive strain, as well as a higher resistance against loss of the catalytically active Pt surface. PMID- 25730296 TI - A count model to study the correlates of 60 min of daily physical activity in Portuguese children. AB - This study aimed to present data on Portuguese children (aged 9-11 years) complying with moderate-to-vigorous physical activity (MVPA) guidelines, and to identify the importance of correlates from multiple domains associated with meeting the guidelines. Physical activity (PA) was objectively assessed by accelerometry throughout seven days on 777 children. A count model using Poisson regression was used to identify the best set of correlates that predicts the variability in meeting the guidelines. Only 3.1% of children met the recommended daily 60 min of MVPA for all seven days of the week. Further, the Cochrane Armitage chi-square test indicated a linear and negative trend (p<0.001) from none to all seven days of children complying with the guidelines. The count model explained 22% of the variance in meeting MVPA guidelines daily. Being a girl, having a higher BMI, belonging to families with higher income, sleeping more and taking greater time walking from home to a sporting venue significantly reduced the probability of meeting daily recommended MVPA across the seven days. Furthermore, compared to girls, increasing sleep time in boys increased their chances of compliance with the MVPA recommendations. These results reinforce the relevance of considering different covariates' roles on PA compliance when designing efficient intervention strategies to promote healthy and active lifestyles in children. PMID- 25730298 TI - The Effect of beta2-Adrenoceptor Genotype on Phenylephrine Dose Administered During Spinal Anesthesia for Cesarean Delivery. AB - BACKGROUND: The beta2-adrenoceptor (ADRB2 gene) possesses several polymorphic sites that have physiologic and/or pharmacologic significance. Previous work has demonstrated that the ADRB2 genotype affects the amount of ephedrine administered to maintain blood pressure during cesarean delivery with spinal anesthesia. This study investigated whether the ADRB2 genotype affected phenylephrine dose requirements during cesarean delivery. Our hypothesis was that the ADRB2 genotype altered the ephedrine dose-response and that we would not see this effect if phenylephrine was the vasopressor used to maintain blood pressure because phenylephrine does not act via the beta2-adrenoceptor. METHODS: Women undergoing elective cesarean delivery were studied. Baseline systolic blood pressure (SBP) was determined, and spinal anesthesia was initiated with hyperbaric bupivacaine 12 mg, fentanyl 20 MUg, and morphine 200 MUg. Hypotension was treated with a phenylephrine infusion using a standardized algorithm (50 MUg/min if SBP was 90% 99% of baseline, 100 MUg/min for SBP 80%-89% baseline, and 200 MUg/min plus boluses for SBP <80% baseline) for 15 minutes after the administration of spinal anesthesia. ADRB2 genotype at codons 16 and 27 was determined. The effect of genotype on administered phenylephrine was compared by analysis of variance and linear regression. RESULTS: Ninety-six women completed the protocol with full data available for analysis. In the unadjusted analysis, there were no significant differences in phenylephrine dose administered among different genotypes at codons 16 and 27. When adjusted for covariates (maternal body mass index, baseline systolic and diastolic blood pressure, neonatal weight, and ethnicity), there was an increase of 200 MUg (95% confidence interval, 4-396; P = 0.04) in phenylephrine administered to Arg16 homozygous genotype subjects compared with Gly16 homozygous genotype subjects. CONCLUSIONS: Phenylephrine dose requirements to maintain SBP after spinal anesthesia are affected by ADRB2 genotype but to a lesser extent than ephedrine. This suggests that previous work demonstrating a large effect of ADRB2 genotype on ephedrine dose requirements may be explained, at least in part, by a differential response to ephedrine based on ADRB2 genotype. It also suggests that there may be ADRB2-mediated differences in the physiologic response to spinal anesthesia. PMID- 25730299 TI - Elucidating the Life History and Ecological Aspects of Allodero hylae (Annelida: Clitellata: Naididae), A Parasitic Oligochaete of Invasive Cuban Tree Frogs in Florida. AB - Given their ubiquitous nature, it is surprising that more oligochaete annelid worms (Annelida: Clitellata) have not adopted an endoparasitic lifestyle. Exceptions, however, are the understudied members of the genus Dero (Allodero) that parasitize the ureters of tree frogs and toads. This study experimentally explores the life cycle and host specificity of Allodero hylae, the worm's use of chemical cues in host searching, and its seasonal prevalence and abundance over a year-long collection period on the Florida Southern College campus. A total of 2,005 A. hylae was collected from the ureter, urinary bladder, or expressed urine of wild Osteopilus septentrionalis ; a significant positive correlation was found between host snout-vent length and parasite intensity for female but not male hosts. Monthly prevalence of A. hylae reached a peak of 58% in April, but never dropped below 20% in any month; mean abundance peaked March-May, whereas few worms were recovered in December and January. Confirming a parasitic lifestyle, wild-collected hosts with intense infections, typically >40 worms, showed obvious dilatation of the ureter wall, and some young-of-the-year O. septentrionalis exposed to A. hylae in the laboratory were killed by the apparent rupture of the host's ureter. The worm has a direct life cycle: worms expelled in the host's urine are capable of locating and re-infecting other hosts within aquatic microhabitats such as bromeliad tanks, and worms can survive for weeks in a free living environment, even undergoing a morphological change. Further, chemotaxis assays found a positive response to a tree frog attractant for worms recently removed from hosts. Overall, this study provides the first multifaceted investigation on the life history and ecology of any Allodero spp., which offers new insights into an understudied endoparasitic oligochaete. PMID- 25730301 TI - Contrast media controversies in 2015: imaging patients with renal impairment or risk of contrast reaction. AB - OBJECTIVE: The incidence and significance of complications related to intravascular contrast material administration have become increasingly controversial. This review will highlight current thinking regarding the imaging of patients with renal impairment and those at risk for an allergiclike contrast reaction. CONCLUSION: The risk of contrast-induced acute kidney injury remains uncertain for patients with an estimated glomerular filtration rate (GFR) less than 45 mL/min/1.73 m(2), but if there is a risk, it is greatest in those with estimated GFR less than 30 mL/min/1.73 m(2). In this population, low-risk gadolinium-based contrast agents appear to have a large safety margin. Corticosteroid prophylaxis remains the standard of care in the United States for patients identified to be at high risk of a contrast reaction, but it has an incomplete mitigating effect on contrast reaction rates and the number needed to treat is large. PMID- 25730300 TI - Episodic Memory in Alzheimer Disease, Frontotemporal Dementia, and Dementia With Lewy Bodies/Parkinson Disease Dementia: Disentangling Retrieval From Consolidation. AB - INTRODUCTION: Differences in episodic memory performance in patients with Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB)/Parkinson disease with dementia (PDD) are inconsistent and task dependent. The inconsistencies may be attributed to the different tasks drawing on different memory processes. Few studies have examined episodic memory impairment in the above groups using memory tests that facilitate encoding, to distinguish memory deficits due to impairment of specific processes. METHODS: We examined the memory performance of 106 AD patients, 51 FTD patients, 26 DLB/PDD patients, and 37 controls using the Five-Words Test, a 5-item memory test that facilitates encoding. RESULTS: The patient groups did not differ in modified Mini Mental State Examination scores. AD patients scored lowest on the Five-Words Test overall, and showed the greatest reduction from immediate total recall to delayed free recall relative to the other 2 groups, consistent with a predominantly consolidation deficit. DLB/PDD patients showed the largest improvement from delayed free to delayed total recall relative to the other 2 groups, consistent with a predominantly retrieval deficit. DISCUSSION: Deficits in both consolidation and retrieval underlie the memory impairment of the patients, to different extents, and contribute to the theoretical understanding of the nature of the memory impairment of the patient groups. PMID- 25730302 TI - Ion-transfer voltammetric determination of folic acid at meso-liquid-liquid interface arrays. AB - Voltammetric studies on the simple ion transfer (IT) behaviors of an important water-soluble B-vitamin, folic acid (FA), at the liquid-liquid (L-L) interface were firstly performed and then applied as a novel detection method for FA under physiological conditions. Meso-water-1,6-dichlorohexane (W-DCH) and meso-water organogel interface arrays were built by using a hybrid mesoporous silica membrane (HMSM) with a unique structure of pores-in-pores and employed as the new platforms for the IT voltammetric study. In view of the unique structure of the HMSM, the impact of the ionic surfactant cetyltrimethylammonium bromide (CTAB), self-assembled within the silica nanochannels of the HMSM, was investigated. In particular, its effect on the IT voltammetric behavior and detection of FA at meso-L-L interface arrays was systematically examined by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and differential pulse stripping voltammetry (DPSV). It was found that all the voltammetric responses of CV, DPV, and DPSV and the corresponding detection limit of FA at such meso-L-L interface arrays are closely related to the CTAB in the HMSM. Significantly, the calculated detection limit of FA could be improved to 80 nM after the combination of the DPSV technique with the additional preconcentration of FA in the silica-CTAB nanochannels, achieved through an anion-exchange process between FA(-) and the bromide of CTAB in HMSM. This provides a new and attractive strategy for the detection of those biological anions. PMID- 25730303 TI - Response of global particulate-matter-related mortality to changes in local precursor emissions. AB - Recent Global Burden of Disease (GBD) assessments estimated that outdoor fine particulate matter (PM2.5) is a causal factor in over 5% of global premature deaths. PM2.5 is produced by a variety of direct and indirect, natural and anthropogenic processes that complicate PM2.5 management. This study develops a proof-of-concept method to quantify the effects on global premature mortality of changes to PM2.5 precursor emissions. Using the adjoint of the GEOS-Chem chemical transport model, we calculated sensitivities of global PM2.5-related premature mortality to emissions of precursor gases (SO2, NOx, NH3) and carbonaceous aerosols. We used a satellite-derived ground-level PM2.5 data set at approximately 10 * 10 km(2) resolution to better align the exposure with population density. We used exposure-response functions from the GBD project to relate mortality to exposure in the adjoint calculation. The response of global mortality to changes in local anthropogenic emissions varied spatially by several orders of magnitude. The largest reductions in mortality for a 1 kg km(-2) yr(-1) decrease in emissions were for ammonia and carbonaceous aerosols in Eastern Europe. The greatest reductions in mortality for a 10% decrease in emissions were found for secondary inorganic sources in East Asia. In general, a 10% decrease in SO2 emissions was the most effective source to control, but regional exceptions were found. PMID- 25730304 TI - Long-term phonological knowledge supports serial ordering in working memory. AB - Serial ordering mechanisms have been investigated extensively in psychology and psycholinguistics. It has also been demonstrated repeatedly that long-term phonological knowledge contributes to serial ordering. However, the mechanisms that contribute to serial ordering have yet to be fully understood. To understand these mechanisms, we demonstrate 2 effects using triples of Japanese nonwords in immediate serial recall. One, a type of bielement frequency effect, is a retrograde compatibility effect. Bielement frequency effects are well-established phenomena whereby a 2-element sequence (e.g., "ka-re") that frequently appears in a language instantiates better recall of any sequence that includes this element (e.g., "ka-re-su-mo"). We demonstrate that bielement frequency affected both the first (e.g., "ka" for "ka-re"; retrograde compatibility effect) and second part of a sequence, indicating the existence of minicontext representations of 2 element sequences. The other effects are the position-element(s) frequency effects, whereby an element (e.g., the mora "ka") that more frequently appears in 1 position of a sequence (e.g., in the first mora of a word) than in other positions facilitates better recall of that element (i.e., the first mora). The effects demonstrated in this article indicate the long-term associations of position representations and elements. These effects are discussed in terms of the extensive learning hypothesis, which assumes that phonological structures are learned gradually. Implications for computational models are also discussed. PMID- 25730305 TI - Why segmentation matters: Experience-driven segmentation errors impair "morpheme" learning. AB - We ask whether an adult learner's knowledge of their native language impedes statistical learning in a new language beyond just word segmentation (as previously shown). In particular, we examine the impact of native-language word form phonotactics on learners' ability to segment words into their component morphemes and learn phonologically triggered variation of morphemes. We find that learning is impaired when words and component morphemes are structured to conflict with a learner's native-language phonotactic system, but not when native language phonotactics do not conflict with morpheme boundaries in the artificial language. A learner's native-language knowledge can therefore have a cascading impact affecting word segmentation and the morphological variation that relies upon proper segmentation. These results show that getting word segmentation right early in learning is deeply important for learning other aspects of language, even those (morphology) that are known to pose a great difficulty for adult language learners. PMID- 25730306 TI - Motivation, intentionality, and mind wandering: Implications for assessments of task-unrelated thought. AB - Researchers of mind wandering frequently assume that (a) participants are motivated to do well on the tasks they are given, and (b) task-unrelated thoughts (TUTs) that occur during task performance reflect unintentional, unwanted thoughts that occur despite participants' best intentions to maintain task-focus. Given the relatively boring and tedious nature of most mind-wandering tasks, however, there is the possibility that some participants have little motivation to do well on such tasks, and that this lack of motivation might in turn result in increases specifically in intentional TUTs. In the present study, we explored these possibilities, finding that individuals reporting lower motivation to perform well on a sustained-attention task reported more intentional relative to unintentional TUTs compared with individuals reporting higher motivation. Interestingly, our results indicate that the extent to which participants engage in intentional versus unintentional TUTs does not differentially relate to performance: both types of off-task thought were found to be equally associated with performance decrements. Participants with low levels of task-motivation also engaged in more overall TUTs, however, and this increase in TUTs was associated with greater performance decrements. We discuss these findings in the context of the literature on mind wandering, highlighting the importance of assessing the intentionality of TUTs and motivation to perform well on tasks assessing mind wandering. PMID- 25730307 TI - Representation of item position in immediate serial recall: Evidence from intrusion errors. AB - In immediate serial recall, participants are asked to recall novel sequences of items in the correct order. Theories of the representations and processes required for this task differ in how order information is maintained; some have argued that order is represented through item-to-item associations, while others have argued that each item is coded for its position in a sequence, with position being defined either by distance from the start of the sequence, or by distance from both the start and the end of the sequence. Previous researchers have used error analyses to adjudicate between these different proposals. However, these previous attempts have not allowed researchers to examine the full set of alternative proposals. In the current study, we analyzed errors produced in 2 immediate serial recall experiments that differ in the modality of input (visual vs. aural presentation of words) and the modality of output (typed vs. spoken responses), using new analysis methods that allow for a greater number of alternative hypotheses to be considered. We find evidence that sequence positions are represented relative to both the start and the end of the sequence, and show a contribution of the end-based representation beyond the final item in the sequence. We also find limited evidence for item-to-item associations, suggesting that both a start-end positional scheme and item-to-item associations play a role in representing item order in immediate serial recall. PMID- 25730308 TI - Ultralow voltage irreversible electrowetting dynamics of an aqueous drop on a stainless steel surface. AB - The electrowetting dynamics of a water drop on a stainless steel surface in air is investigated under ultralow voltages. The spreading behavior can be classified into three regimes. The drop expands slowly in regime I, but the spreading accelerates quite rapidly in regime II. The spreading becomes insignificant in regime III. The experimental results are compared to the equilibrium shapes acquired by Surface Evolver simulations. The good agreement between them indicates that the slow electrowetting dynamics can be considered to be a quasi equilibrium process. The influences of the electric field and drop size on the spreading dynamics are examined. The variation of both the contact angle and base diameter with time in regimes II and III can be well described by the exponential change with a characteristic time, which grows with the drop volume but is inversely proportional to the electric field. A simple model based on the electromechnical mechanism is proposed to explain the spreading dynamics. The exponential change is attributed to ion migration from the bulk of the drop to the contact line. The experimental results agree well with the prediction of our simple theory. PMID- 25730309 TI - Space-charge limited transport in large-area monolayer hexagonal boron nitride. AB - Hexagonal boron nitride (hBN) is a wide-gap material that has attracted significant attention as an ideal dielectric substrate for 2D crystal heterostructures. We report here the first observation of in-plane charge transport in large-area monolayer hBN, grown by chemical vapor deposition. The quadratic scaling of current with voltage at high bias corresponds to a space charge limited conduction mechanism, with a room-temperature mobility reaching up to 0.01 cm(2)/(V s) at electric fields up to 100 kV/cm in the absence of dielectric breakdown. The observation of in-plane charge transport highlights the semiconducting nature of monolayer hBN, and identifies hBN as a wide-gap 2D crystal capable of supporting charge transport at high field. Future exploration of charge transport in hBN is motivated by the fundamental study of UV optoelectronics and the massive Dirac fermion spectrum of hBN. PMID- 25730311 TI - A longitudinal study of midage women with indicators of disordered eating. AB - This longitudinal study of midage women has two main aims: to examine the effect of disordered eating (DE) on quality of life (QoL) among women, including a comparison with a younger cohort and to investigate the mediating roles of both depressive symptoms and social support on the longitudinal relationship between DE and QoL as potential mechanisms of action. We used self-report data from six waves of the Australian Longitudinal Study on Women's Health over 14 years. A total of 12,338 women participating in the midage cohort (aging from 45-50 to 59 64) provided self-report indications of DE at Surveys 1 and 2, and QoL (SF-36 component scales-mental [MCS] and physical [PCS]) at Surveys 2-6. DE was reported by 10.98% of the women; this group also reported significantly poorer mental and physical QoL than those without DE, and this effect was sustained over time. Comparison with a parallel analysis of a younger cohort of women showed that the effect on midage women's physical QoL is greater than that of the younger women. The relationships between baseline DE and changes in QoL (both physical and mental) over time were mediated by levels of depressive symptoms and of social support over time. This study underscores the significant effect of DE on QoL in midage, an effect which is partially or fully mediated by depressive symptoms or social support. Well-being of midage women with indicators of DE needs to be supported by tailoring prevention and interventions activities specifically for this group. PMID- 25730310 TI - Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in Bihar, India: a retrospective cohort study. AB - BACKGROUND: In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites. METHODS: A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic. RESULTS: One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 MUg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels >= 10 MUg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected. DISCUSSION/CONCLUSION: This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation. PMID- 25730312 TI - The negative effects of prejudice on interpersonal relationships within adolescent peer groups. AB - Social development theories highlight the centrality of peer groups during adolescence and their role in socializing attitudes and behaviors. In this longitudinal study, we tested the effects of group-level prejudice on ensuing positive and negative interpersonal interactions among peers over a 7-month period. We used social network analysis to identify peer groups based on sociometric nominations, followed by multilevel modeling of the effects of sexual prejudice at the group level on interpersonal interactions among individuals in these groups. As hypothesized, the interpersonal interactions in peer groups with stronger group-level sexual prejudice were distinct from and poorer than those in groups with weaker group-level sexual prejudice. Moreover, longitudinal models indicated that adolescents in groups with stronger initial sexual prejudice reported worse interpersonal interactions with their peers seven months later. These findings provide a contextual understanding of prejudice and its negative effects on how adolescents come to relate with one another over time. PMID- 25730313 TI - The role of goal structures and peer climate in trajectories of social achievement goals during high school. AB - Students' social goals--reasons for engaging in interpersonal relationships with peers--are consequential for students' interactions with their peers at school and for their well-being. Despite the salience of peer relationships during adolescence, research on social goals is generally lacking compared with academic goals, and it is unknown how these social goals develop over time, especially among high school students. The aim of the study was to assess trajectories of students' social goals and to determine how relevant individual and contextual variables predicted initial levels and trajectories of students' social goals. Participants were 9th through 12th grade students (N = 526) attending a U.S. high school. Students filled out surveys of their social goals (social development, social demonstration-approach, and social demonstration-avoidance) 6 times across 2 school years. Nonlinear growth curve analyses and piecewise growth curve analyses were used to assess trajectories of social goals across time. Students' initial levels of social goals differed based on their gender, grade level, prior achievement, and perceptions of classroom goals structures and peer climate. Furthermore, despite substantial stability over time, the shapes of these goal trajectories were predicted by students' gender, grade level, and perceptions of classroom goal structures and peer climate. In particular, students who perceived an increase in performance-avoidance classroom goals maintained higher demonstration social goals and decreased in developmental social goals over time, and students who perceived an increase in positive peer climate decreased in demonstration-avoidance social goals. Implications and directions for future research on social goals are discussed. PMID- 25730314 TI - A probabilistic model for hydrokinetic turbine collision risks: exploring impacts on fish. AB - A variety of hydrokinetic turbines are currently under development for power generation in rivers, tidal straits and ocean currents. Because some of these turbines are large, with rapidly moving rotor blades, the risk of collision with aquatic animals has been brought to attention. The behavior and fate of animals that approach such large hydrokinetic turbines have not yet been monitored at any detail. In this paper, we conduct a synthesis of the current knowledge and understanding of hydrokinetic turbine collision risks. The outcome is a generic fault tree based probabilistic model suitable for estimating population-level ecological risks. New video-based data on fish behavior in strong currents are provided and models describing fish avoidance behaviors are presented. The findings indicate low risk for small-sized fish. However, at large turbines (>=5 m), bigger fish seem to have high probability of collision, mostly because rotor detection and avoidance is difficult in low visibility. Risks can therefore be substantial for vulnerable populations of large-sized fish, which thrive in strong currents. The suggested collision risk model can be applied to different turbine designs and at a variety of locations as basis for case-specific risk assessments. The structure of the model facilitates successive model validation, refinement and application to other organism groups such as marine mammals. PMID- 25730315 TI - alpha-Thalassemia associated with hb instability: a tale of two features. the case of Hb Rogliano or alpha1 Cod 108(G15)Thr->Asn and Hb Policoro or alpha2 Cod 124(H7)Ser->Pro. AB - We identified two new variants in the third exon of the alpha-globin gene in families from southern Italy: the Hb Rogliano, alpha1 cod108 ACC>AAC or alpha1[alpha108(G15)Thr->Asn] and the Hb Policoro, alpha2 cod124 TCC>CCC or alpha2[alpha124(H7)Ser->Pro]. The carriers showed mild alpha-thalassemia phenotype and abnormal hemoglobin stability features. These mutations occurred in the G and H helices of the alpha-globin both involved in the specific recognition of AHSP and beta1 chain. Molecular characterization of mRNA, globin chain analyses and molecular modelling studies were carried out to highlight the mechanisms causing the alpha-thalassemia phenotype. The results demonstrated that the alpha-thalassemia defect associated with the two Hb variants originated by different defects. Hb Rogliano showed an intrinsic instability of the tetramer due to anomalous intra- and inter-chain interactions suggesting that the variant chain is normally synthesized and complexed with AHSP but rapidly degraded because it is unable to form the alpha1beta1 dimers. On the contrary in the case of Hb Policoro two different molecular mechanisms were shown: the reduction of the variant mRNA level by an unclear mechanism and the protein instability due to impairment of AHSP interaction. These data highlighted that multiple approaches, including mRNA quantification, are needed to properly identify the mechanisms leading to the alpha-thalassemia defect. Elucidation of the specific mechanism leads to the definition of a given phenotype providing important guidance for the diagnosis of unstable variants. PMID- 25730316 TI - Potential small guide RNAs for tRNase ZL from human plasma, peripheral blood mononuclear cells, and cultured cell lines. AB - Several pieces of evidence suggest that small RNA degradation products together with tRNase ZL appear to form another layer of the whole gene regulatory network. The degraded RNA such as a 5'-half-tRNA and an rRNA fragment function as small guide RNA (sgRNA) to guide the enzyme to target RNA. We were curious whether there exist RNAs in plasma that can function as sgRNAs for tRNase ZL, whether these RNAs are working as signaling molecules between cells to fulfill physiological roles, and whether there are any differences in plasma sgRNA species and levels between normal and pathological conditions. Here, we analyzed small plasma RNAs from three healthy persons and three multiple myeloma patients for potential sgRNAs by deep sequencing. We also examined small RNAs from peripheral blood mononuclear cells (PBMC) of three healthy persons and three myeloma patients and from various cultured human cell lines for sgRNAs. We found that read-number distribution patterns of plasma and PBMC RNAs differ between persons in the range of 5-40 nt and that there are many RNA species that exist significantly more or less abundantly in the plasma or PBMC of the myeloma patients than those of the healthy persons. Furthermore, we found that there are many potential sgRNAs in the 5-40-nt RNAs and that, among them, a 31-nt RNA fragment derived from 94-nt Y4-RNA, which can function as a 5'-half-tRNA-type sgRNA, is overwhelmingly abundant in the plasma of 2/3 of the examinees. These observations suggest that the gene regulatory network via tRNase ZL and sgRNA may be extended intercellularly. PMID- 25730317 TI - Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress. AB - OBJECTIVE: Mitochondrial dysfunction and oxidative stress-mediated apoptosis plays an important role in various neurodegenerative diseases including Huntington's disease, Parkinson's disease (PD) and Alzheimer's disease (AD). 1 Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the most widely used neurotoxin mimics the symptoms of PD by inhibiting mitochondrial complex I that stimulates excessive intracellular reactive oxygen species (ROS) and finally leads to mitochondrial-dependent apoptosis. Lutein, a carotenoid of xanthophyll family, is found abundantly in leafy green vegetables such as spinach, kale and in egg yolk, animal fat and human eye retinal macula. Increasing evidence indicates that lutein has offers benefits against neuronal damages during diabetic retinopathy, ischemia and AD by virtue of its mitochondrial protective, antioxidant and anti-apoptotic properties. METHODS: Male C57BL/6 mice (23-26 g) were randomized and grouped in to Control, MPTP, and Lutein treated groups. RESULTS: Lutein significantly reversed the loss of nigral dopaminergic neurons by increasing the striatal dopamine level in mice. Moreover, lutein-ameliorated MPTP induced mitochondrial dysfunction, oxidative stress and motor abnormalities. In addition, lutein repressed the MPTP-induced neuronal damage/apoptosis by inhibiting the activation of pro-apoptotic markers (Bax, caspases-3, 8 and 9) and enhancing anti-apoptotic marker (Bcl-2) expressions. DISCUSSION: Our current results revealed that lutein possessed protection on dopaminergic neurons by enhancing antioxidant defense and diminishing mitochondrial dysfunction and apoptotic death, suggesting the potential benefits of lutein for PD treatment. PMID- 25730318 TI - Shock treatment: using immersive digital realism to restage and re-examine milgram's 'obedience to authority' research. AB - Attempts to revisit Milgram's 'Obedience to Authority' (OtA) paradigm present serious ethical challenges. In recent years new paradigms have been developed to circumvent these challenges but none involve using Milgram's own procedures and asking naive participants to deliver the maximum level of shock. This was achieved in the present research by using Immersive Digital Realism (IDR) to revisit the OtA paradigm. IDR is a dramatic method that involves a director collaborating with professional actors to develop characters, the strategic withholding of contextual information, and immersion in a real-world environment. 14 actors took part in an IDR study in which they were assigned to conditions that restaged Milgrams's New Baseline ('Coronary') condition and four other variants. Post-experimental interviews also assessed participants' identification with Experimenter and Learner. Participants' behaviour closely resembled that observed in Milgram's original research. In particular, this was evidenced by (a) all being willing to administer shocks greater than 150 volts, (b) near-universal refusal to continue after being told by the Experimenter that "you have no other choice, you must continue" (Milgram's fourth prod and the one most resembling an order), and (c) a strong correlation between the maximum level of shock that participants administered and the mean maximum shock delivered in the corresponding variant in Milgram's own research. Consistent with an engaged follower account, relative identification with the Experimenter (vs. the Learner) was also a good predictor of the maximum shock that participants administered. PMID- 25730319 TI - Adipose-derived mesenchymal stem cell administration does not improve corneal graft survival outcome. AB - The effect of local and systemic injections of mesenchymal stem cells derived from adipose tissue (AD-MSC) into rabbit models of corneal allograft rejection with either normal-risk or high-risk vascularized corneal beds was investigated. The models we present in this study are more similar to human corneal transplants than previously reported murine models. Our aim was to prevent transplant rejection and increase the length of graft survival. In the normal-risk transplant model, in contrast to our expectations, the injection of AD-MSC into the graft junction during surgery resulted in the induction of increased signs of inflammation such as corneal edema with increased thickness, and a higher level of infiltration of leukocytes. This process led to a lower survival of the graft compared with the sham-treated corneal transplants. In the high-risk transplant model, in which immune ocular privilege was undermined by the induction of neovascularization prior to graft surgery, we found the use of systemic rabbit AD MSCs prior to surgery, during surgery, and at various time points after surgery resulted in a shorter survival of the graft compared with the non-treated corneal grafts. Based on our results, local or systemic treatment with AD-MSCs to prevent corneal rejection in rabbit corneal models at normal or high risk of rejection does not increase survival but rather can increase inflammation and neovascularization and break the innate ocular immune privilege. This result can be partially explained by the immunomarkers, lack of immunosuppressive ability and immunophenotypical secretion molecules characterization of AD-MSC used in this study. Parameters including the risk of rejection, the inflammatory/vascularization environment, the cell source, the time of injection, the immunosuppression, the number of cells, and the mode of delivery must be established before translating the possible benefits of the use of MSCs in corneal transplants to clinical practice. PMID- 25730320 TI - The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA). AB - The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is responsible for transporting calcium (Ca(2+)) from the cytosol into the lumen of the sarcoplasmic reticulum (SR) following muscular contraction. The Ca(2+) sequestering activity of SERCA facilitates muscular relaxation in both cardiac and skeletal muscle. There are more than 10 distinct isoforms of SERCA expressed in different tissues. SERCA2a is the primary isoform expressed in cardiac tissue, whereas SERCA1a is the predominant isoform expressed in fast-twitch skeletal muscle. The Ca(2+) sequestering activity of SERCA is regulated at the level of protein content and is further modified by the endogenous proteins phospholamban (PLN) and sarcolipin (SLN). Additionally, several novel mechanisms, including post-translational modifications and microRNAs (miRNAs) are emerging as integral regulators of Ca(2+) transport activity. These regulatory mechanisms are clinically relevant, as dysregulated SERCA function has been implicated in the pathology of several disease states, including heart failure. Currently, several clinical trials are underway that utilize novel therapeutic approaches to restore SERCA2a activity in humans. The purpose of this review is to examine the regulatory mechanisms of the SERCA pump, with a particular emphasis on the influence of exercise in preventing the pathological conditions associated with impaired SERCA function. PMID- 25730323 TI - Characterization of collagen from haddock skin and wound healing properties of its hydrolysates. AB - Collagen, one of the most abundant structural proteins found in vertebrates, has been extensively used for biomedical applications. The objectives of this study were to isolate and characterize acid-soluble collagen (ASC) from haddock (Melanogrammus aeglefinus) skins and to investigate the biological function of ASC hydrolysates in wound healing. Amino acid composition, SDS-PAGE and FTIR suggested that the ASC is most likely type I collagen with well-maintained helical structures. Both the denaturation and shrinkage temperatures of ASC isolated from haddock skins were lower than those of mammalian collagens. The average molecular weights of hydrolysates decreased with the increase in HCl concentration as well as hydrolysis times. ASC and hydrolysates with more molecules (53.8 kDa) decreased the bleeding and clotting times and promoted order 2 vessel formation effectively. All the experimental groups, including the ASC group and its hydrolysate groups, could accelerate epithelialization and shorten the wound healing time of mice. The ASC from haddock skin could therefore serve as an alternative collagen for skin wound healing. PMID- 25730322 TI - Systemic inflammation predicts all-cause mortality: a glasgow inflammation outcome study. AB - INTRODUCTION: Markers of the systemic inflammatory response, including C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score), as well as neutrophil, lymphocyte and platelet counts have been shown to be prognostic of survival in patients with cancer. The aim of the present study was to examine the prognostic relationship between these markers of the systemic inflammatory response and all-cause, cancer, cardiovascular and cerebrovascular mortality in a large incidentally sampled cohort. METHODS: Patients (n = 160 481) who had an incidental blood sample taken between 2000 and 2008 were studied for the prognostic value of C-reactive protein (>10mg/l, albumin (>35mg/l), neutrophil (>7.5*109/l) lymphocyte and platelet counts. Also, patients (n = 52 091) sampled following the introduction of high sensitivity C-reactive protein (>3mg/l) measurements were studied. A combination of these markers, to make cumulative inflammation-based scores, were investigated. RESULTS: In all patients (n = 160 481) C-reactive protein (>10mg/l) (HR 2.71, p<0.001), albumin (>35mg/l) (HR 3.68, p<0.001) and neutrophil counts (HR 2.18, p<0.001) were independently predictive of all-cause mortality. These associations were also observed in cancer, cardiovascular and cerebrovascular mortality before and after the introduction of high sensitivity C-reactive protein measurements (>3mg/l) (n = 52 091). A combination of high sensitivity C-reactive protein (>3mg/l), albumin and neutrophil count predicted all-cause (HR 7.37, p<0.001, AUC 0.723), cancer (HR 9.32, p<0.001, AUC 0.731), cardiovascular (HR 4.03, p<0.001, AUC 0.650) and cerebrovascular (HR 3.10, p<0.001, AUC 0.623) mortality. CONCLUSION: The results of the present study showed that an inflammation-based prognostic score, combining high sensitivity C-reactive protein, albumin and neutrophil count is prognostic of all-cause mortality. PMID- 25730321 TI - Assessment of the concentrations of various advanced glycation end-products in beverages and foods that are commonly consumed in Japan. AB - Dietary consumption has recently been identified as a major environmental source of pro-inflammatory advanced glycation end-products (AGEs) in humans. It is disputed whether dietary AGEs represent a risk to human health. Nepsilon (carboxymethyl)lysine (CML), a representative AGE compound found in food, has been suggested to make a significant contribution to circulating CML levels. However, recent studies have found that the dietary intake of AGEs is not associated with plasma CML concentrations. We have shown that the serum levels of glyceraldehyde-derived AGEs (Glycer-AGEs), but not hemoglobin A1c, glucose derived AGEs (Glu-AGEs), or CML, could be used as biomarkers for predicting the progression of atherosclerosis and future cardiovascular events. We also detected the production/accumulation of Glycer-AGEs in normal rats administered Glu-AGE rich beverages. Therefore, we assessed the concentrations of various AGEs in a total of 1,650 beverages and foods that are commonly consumed in Japan. The concentrations of four kinds of AGEs (Glu-AGEs, fructose-derived AGEs (Fru-AGEs), CML, and Glycer-AGEs) were measured with competitive enzyme-linked immunosorbent assays involving immunoaffinity-purified specific antibodies. The results of the latter assays indicated that Glu-AGEs and Fru-AGEs (especially Glu-AGEs), but not CML or Glycer-AGEs, are present at appreciable levels in beverages and foods that are commonly consumed by Japanese. Glu-AGEs, Fru-AGEs, CML, and Glycer-AGEs exhibited concentrations of >=85%, 2-12%, <3%, and trace amounts in the examined beverages and >=82%, 5-15%, <3%, and trace amounts in the tested foods, respectively. The results of the present study indicate that some lactic acid bacteria beverages, carbonated drinks, sugar-sweetened fruit drinks, sports drinks, mixed fruit juices, confectionery (snacks), dried fruits, cakes, cereals, and prepared foods contain markedly higher Glu-AGE levels than other classes of beverages and foods. We provide useful data on the concentrations of various AGEs, especially Glu-AGEs, in commonly consumed beverages and foods. PMID- 25730324 TI - Palladium-catalyzed glycosylation: novel synthetic approach to diverse N heterocyclic glycosides. AB - An efficient and highly stereoselective method for the construction of N heterocyclic glycosides is reported. This method is based on a palladium catalyzed allylation which proceeded to provide N-heterocyclic glycosyl compounds in good-to-excellent yields with beta- or alpha-selectivity. Various N nucleophiles were examined for this reaction and selected N-glycosyl isatin substrates were further elaborated to bis-indole sugars which have potential as antiproliferative drugs. PMID- 25730325 TI - Risk stratification of prostate cancer in the modern era. AB - PURPOSE OF REVIEW: Novel tools have become available to the practicing urologist in recent years that endeavor to improve on commonly utilized prostate cancer (PCa) risk-stratification techniques. In this review, we provide an overview of these modalities in the context of active surveillance. RECENT FINDINGS: Multiparametric MRI (MP-MRI) has a rapidly growing body of evidence that suggests it provides the necessary sensitivity and negative predictive value to rule out clinically significant disease. MRI-guided targeted biopsy has the potential to improve detection of clinically significant cancers and for rebiopsy of patients with continued suspicion for PCa. Prostate-specific antigen isoforms and Prostate Health Index outperform PSA alone and improve risk stratification when combined with the established criteria, but need further prospective studies using template and MRI-targeted biopsies. Urinary biomarkers tend to fall short in predicting adverse pathology when used alone, but improve risk stratification when used in conjunction and with the established criteria. Finally, tissue biomarkers and gene assays allow patient-specific molecular and genetic characterization of cancer phenotype, showing significant promise in predicting adverse pathology, and in some cases have already been incorporated into and altered clinical practice. SUMMARY: These novel modalities show remarkable promise in improving the risk stratification of patients with PCa, and as the body of evidence grows will likely become incorporated into major oncologic guidelines and standard urologic practice. Further prospective clinical studies are needed, as well as analysis of cost-effectiveness. PMID- 25730326 TI - Disease-specific and patient-reported outcomes under active surveillance. AB - PURPOSE OF REVIEW: To give insight into literature from the past 12-18 months, reporting on disease-specific and patient-reported outcomes of men under active surveillance for prostate cancer. RECENT FINDINGS: From recently published established active surveillance cohorts, we learnt that medium and long-term follow-up outcome data provide favorable evidence for the feasibility and safety of active surveillance. The mortality rates reported are consistent with expected mortality in favorable-risk patients who were managed with initial radical therapy. More definite conclusions on the safety of active surveillance can only be drawn on the basis of randomized controlled trial data. With respect to quality of life, men on active surveillance seem to do well, also with respect to urinary and erectile function. Further research on this subject is, however, warranted. SUMMARY: Prostate cancer-specific mortality under active surveillance is very low. The combination of disease-specific and patient-reported outcomes indicates that active surveillance is feasible. This is also reflected in smaller, population-based studies which confirm the acceptance of active surveillance in clinical practice. PMID- 25730328 TI - Active surveillance for favorable risk prostate cancer. PMID- 25730327 TI - Should Gleason 6 be labeled as cancer? AB - PUPOSE OF REVIEW: The review covers arguments for and against removing the label of 'cancer' in Gleason score 6 prostate tumors. RECENT FINDINGS: While there are a number of factors that determine whether men elect active surveillance, the most powerful predictor remains the Gleason score. Gleason grading remains a robust and powerful predictor of outcome in patients with prostate cancer. A pure Gleason score 6 (GS6) tumor is exceedingly unlikely to cause harm in the near term, and there have been discussions regarding whether the term cancer should still be applied. In this review, we update the largely clinico-pathological arguments that have led to the suggestion to remove the cancer label from GS6 tumors, and we provide counter arguments on the basis of practical matters of needle biopsy sampling, classical histopathology, and molecular biology findings. SUMMARY: The implications are that by retaining the label of cancer and implementing the recently proposed concept of prognostic groups, with patients harboring GS6 tumors placed into the lowest category, there is still a strong rationale in support of the choice of active surveillance or watchful waiting for most patients with GS6 lesions. PMID- 25730329 TI - Ethane as a cleaner transportation fuel. PMID- 25730330 TI - Speech perception in older hearing impaired listeners: benefits of perceptual training. AB - Hearing aids (HAs) only partially restore the ability of older hearing impaired (OHI) listeners to understand speech in noise, due in large part to persistent deficits in consonant identification. Here, we investigated whether adaptive perceptual training would improve consonant-identification in noise in sixteen aided OHI listeners who underwent 40 hours of computer-based training in their homes. Listeners identified 20 onset and 20 coda consonants in 9,600 consonant vowel-consonant (CVC) syllables containing different vowels (/alpha/, /i/, or /u/) and spoken by four different talkers. Consonants were presented at three consonant-specific signal-to-noise ratios (SNRs) spanning a 12 dB range. Noise levels were adjusted over training sessions based on d' measures. Listeners were tested before and after training to measure (1) changes in consonant identification thresholds using syllables spoken by familiar and unfamiliar talkers, and (2) sentence reception thresholds (SeRTs) using two different sentence tests. Consonant-identification thresholds improved gradually during training. Laboratory tests of d' thresholds showed an average improvement of 9.1 dB, with 94% of listeners showing statistically significant training benefit. Training normalized consonant confusions and improved the thresholds of some consonants into the normal range. Benefits were equivalent for onset and coda consonants, syllables containing different vowels, and syllables presented at different SNRs. Greater training benefits were found for hard-to-identify consonants and for consonants spoken by familiar than unfamiliar talkers. SeRTs, tested with simple sentences, showed less elevation than consonant-identification thresholds prior to training and failed to show significant training benefit, although SeRT improvements did correlate with improvements in consonant thresholds. We argue that the lack of SeRT improvement reflects the dominant role of top-down semantic processing in processing simple sentences and that greater transfer of benefit would be evident in the comprehension of more unpredictable speech material. PMID- 25730331 TI - Measuring coping in parents of children with disabilities: a rasch model approach. AB - BACKGROUND: Parents of a child with disability must cope with greater demands than those living with a healthy child. Coping refers to a person's cognitive or behavioral efforts to manage the demands of a stressful situation. The Coping Health Inventory for Parents (CHIP) is a well-recognized measure of coping among parents of chronically ill children and assesses different coping patterns using its three subscales. The purpose of this study was to provide further insights into the psychometric properties of the CHIP subscales in a sample of parents of children with disabilities. METHODS: In this cross-sectional study, 220 parents (mean age, 33.4 years; 85% mothers) caring for a child with disability enrolled in special schools as well as in mainstream schools completed the 45-item CHIP. Rasch analysis was applied to the CHIP data and the psychometric performance of each of the three subscales was tested. Subscale revision was performed in the context of Rasch analysis statistics. RESULTS: Response categories were not used as intended, necessitating combining categories, thereby reducing the number from 4 to 3. The subscale - 'maintaining social support' satisfied all the Rasch model expectations. Four item misfit the Rasch model in the subscale -maintaining family integration', but their deletion resulted in a 15-item scale with items that fit the Rasch model well. The remaining subscale - 'understanding the healthcare situation' lacked adequate measurement precision (<2.0 logits). CONCLUSIONS: The current Rasch analyses add to the evidence of measurement properties of the CHIP and show that the two of its subscales (one original and the other revised) have good psychometric properties and work well to measure coping patterns in parents of children with disabilities. However the third subscale is limited by its inadequate measurement precision and requires more items. PMID- 25730332 TI - Performance of bedside diagnostic ultrasound in an Ebola isolation unit: the Emory University Hospital experience. AB - OBJECTIVE: Individuals with Ebola virus disease, a contagious and potentially lethal infection, are now being treated in specialized units in the United States. We describe Emory University's initial experience, current operating procedures, and ongoing planning with diagnostic ultrasound in the isolation unit. CONCLUSION: Ultrasound use has been limited to date. Future planning considerations include deciding what types of ultrasound studies will be performed, which personnel will acquire the images, and which ultrasound machine will be used. PMID- 25730333 TI - Nasal chondroma presenting as hypertelorism. AB - PURPOSE: To report a rare case of nasal chondroma presenting as hypertelorism. CASE REPORT: We report a case of a 16-year-old boy with a large calcified mass arising from the posterior nasal cavity presenting as hypertelorism. Surgical excision was done, and the histopathological examination revealed a chondroma. The hypertelorism resolved postoperatively. CONCLUSIONS: Nasal chondroma may also present innocuously as hypertelorism as in this case. PMID- 25730334 TI - Auto-avulsion and resolution of corneal pterygium. AB - PURPOSE: Corneal pterygium is a frequently encountered ocular condition in clinical practice. The lesion presents as a fibrous, winged-like growth that typically manifests on the nasal aspect of the conjunctiva and cornea. Pterygia can be surgically removed by excision when they cause significant discomfort, visual impairment, or poor cosmesis. However, the recurrence rate after excision remains high without adjunctive therapy. We present an exceedingly rare case of resolution of a pterygium by auto-avulsion followed by subsequent recurrence of the lesion. CASE REPORT: A 63-year-old Asian man presented to the clinic with pain and foreign body sensation. Anterior segment evaluation revealed a large corneal epithelial defect with an adjacent area of loose conjunctival tissue. Ocular history included a pterygium in the same area of the defect. Subsequent follow-up revealed a regrowth of the pterygium at the exact location. CONCLUSIONS: Strong tension imposed on the cornea by a pterygium could result in auto-avulsion of the lesion. The resulting corneal defect can then be treated accordingly. Recurrent pterygium is possible without adjunctive therapy, such as those seen with bare sclera excision. PMID- 25730335 TI - Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and Preservatives. AB - PURPOSE: To evaluate the prevalence of ocular surface disease (OSD) in glaucoma and nonglaucoma subjects using different clinical tests and to determine the effect of number of antiglaucoma medications and preservatives on OSD. METHODS: This is a cross-sectional, case-comparison study at the Eye Clinic of the University of Malaya Medical Centre, Malaysia, between June 2012 and January 2013. Glaucoma subjects (n = 105) using topical antiglaucoma medications were compared with control subjects (n = 102) who were not on any topical medications. The presence of OSD was assessed using the tear film breakup time (TBUT) test, corneal staining, Schirmer test, and Ocular Surface Disease Index (OSDI) questionnaire grading. RESULTS: The prevalence of OSD varied from 37 to 91% in the glaucoma group, depending on the type of clinical test. More subjects in the glaucoma group had corneal staining (63% vs. 36%, p = 0.004), abnormal Schirmer tests (39% vs. 25%, p = 0.049), and moderate OSDI symptoms (17% vs. 7%, p = 0.028). The percentage with abnormal TBUT increased with higher numbers of topical medications and was high with both benzalkonium chloride-containing and preservative-free eye drops (90% and 94%, respectively, both p < 0.001). Benzalkonium chloride was associated with a nearly three times higher odds ratio of showing abnormal OSDI. CONCLUSIONS: Ocular surface disease is common in those using topical antiglaucoma medications. Abnormal TBUT is associated with increasing number of eye drops and benzalkonium chloride-containing eye drops, although this also occurs with the use of preservative-free eye drops. PMID- 25730336 TI - Choroidal neovascularization associated with extensive macular atrophy and pseudodrusen. AB - PURPOSE: To describe a case of extensive macular atrophy and pseudodrusen complicated by bilateral choroidal neovascularization (CNV). METHODS: A 53-year old woman showed extensive macular atrophy at the posterior pole associated with disciform scar in the right eye and fibrotic juxtafoveal CNV in the left eye. RESULTS: The patient underwent a complete ophthalmological examination including fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography, showing a disciform scar at the posterior pole of the right eye and an extensive macular atrophy associated with a fibrotic juxtafoveal CNV. The patient was previously treated with four and seven intravitreal bevacizumab injections, respectively, in the right eye and in the left eye. Molecular analyses of the ABCA4 gene revealed the variant c.1268A=18 years with >=6-month pre- (baseline) and >=6-month post index (follow-up) data, retaining patients who died with <6 months of follow-up. Differences by site of service were analyzed by chi2 and t test (bevacizumab administrations, dose) and general linear model adjusted for demographic and clinical characteristics (all-cause healthcare costs). RESULTS: A total of 1687 mCRC (OFF: 1292; HOP: 395) and 1232 LC patients (OFF: 983; HOP: 249) were identified. Mean age was 61.3 years, 56.3% were male, and 78% were treated in OFF. Treatment in OFF declined from 2006 (84% of patients) to 2012 (61%). For OFF versus HOP, mean length of treatment (208.3 vs 191.0 days; P=.007), number of bevacizumab administrations per month (1.4 vs 1.1; P<.001), and mean weekly dose (eg, for 2012, 4.34 vs 3.11 mg/kg, P<.05) were higher in OFF. Adjusted monthly HOP costs (vs OFF) were higher by 37.8% for mCRC patients (cost ratio=1.378; 95% CI, 1.282-1.482) and 31.1% for LC patients (cost ratio=1.311; 95% CI, 1.204 1.427) CONCLUSIONS: Despite fewer administrations and lower weekly dose of bevacizumab in HOP, adjusted total costs were 31% to 38% higher for mCRC and LC patients treated in the HOP setting. PMID- 25730351 TI - Influence of hospital and nursing home quality on hospital readmissions. AB - OBJECTIVES: To determine whether the quality of the hospital and of the nursing home (NH) to which a patient was discharged were related to the likelihood of rehospitalization. STUDY DESIGN: Retrospective cohort study of 1,382,477 individual hospitalizations discharged to 15,356 NHs from 3683 hospitals between 2006 and 2008. METHODS: Data come from Medicare claims and enrollment records, Minimum Data Set, Online Survey Certification and Reporting Dataset, Hospital Compare, and the American Hospital Association Database. Cross-classified random effects models were used to test the association of hospital and NH quality measures and the likelihood of 30-day rehospitalization. RESULTS: Patients discharged from higher-quality hospitals (as indicated by higher scores on their accountability process measures and high nurse staffing levels) and patients who received care in higher-quality NHs (as indicated by high nurse staffing levels and lower deficiency scores) were less likely to be rehospitalized within 30 days. CONCLUSIONS: The passage of the Affordable Care Act changed the accountability of hospitals for patients' outcomes after discharge. This study highlights the joint accountability of hospitals and NHs for rehospitalization of patients. PMID- 25730352 TI - Care coordination measures of a family medicine residency as a model for hospital readmission reduction. AB - The processes of care coordination of patient transition from hospital to outpatient settings are an integral part of the Patient-Centered Medical Home. We report a cooperative initiative between our admission hospital and family medicine residency to analyze the discharge process using the Agency for Healthcare Research and Quality's Re-engineering Discharge initiative, focusing on efficient information transfer and communication with discharged patients to insure rapid follow-up in the clinic. Our project yielded markedly reduced readmission rates compared with both local hospital and national rates. PMID- 25730353 TI - Vacancy filling effect in thermoelectric NbO. AB - Using density functional theory, we have systematically explored the 1a and 1b vacancy filling in NbO (space group Pm-3m) with Nb and N, respectively, to design compounds with large Seebeck coefficients. The most dominating effect was identified for filling of 1b Wyckoff sites with N giving rise to a fivefold increase in the Seebeck coefficient. This may be understood based on the electronic structure. Nb d-nonmetal p hybridization induces quantum confinement and hence enables the enhancement of the Seebeck coefficient. This was validated by measuring the Seebeck coefficient of reactively sputtered thin films. At 800 degrees C these electrically conductive oxynitrides exhibit the Seebeck coefficient of -70 uV K(-1), which is the largest absolute value ever reported for these compounds. PMID- 25730368 TI - Chemical Composition of Different Botanical Origin Honeys Produced by Sicilian Black Honeybees (Apis mellifera ssp. sicula). AB - In 2008 a Slow Food Presidium was launched in Sicily (Italy) for an early warning of the risk of extinction of the Sicilian native breed of black honeybee (Apis mellifera L. ssp sicula). Today, the honey produced by these honeybees is the only Sicilian honey produced entirely by the black honeybees. In view of few available data regarding the chemical composition of A. mellifera ssp. sicula honeys, in the present investigation the chemical compositions of sulla honey (Hedysarum coronarium L.) and dill honey (Anethum graveolens L.) were studied with a multimethodological approach, which consists of HPLC-PDA-ESI-MSn and NMR spectroscopy. Moreover, three unifloral honeys (lemon honey (obtained from Citrus limon (L.) Osbeck), orange honey (Citrus arantium L.), and medlar honey (Eriobotrya japonica (Thunb.) Lindl)), with known phenol and polyphenol compositions, were studied with NMR spectroscopy to deepen the knowledge about sugar and amino acid compositions. PMID- 25730369 TI - Critical roles of specimen type and temperature before and during fixation in the detection of phosphoproteins in breast cancer tissues. AB - The most efficient approach for therapy selection to inhibit the deregulated kinases in cancer tissues is to measure their phosphorylation status prior to the treatment. The aim of our study was to evaluate the influence of pre-analytical parameters (cold ischemia time, temperature before and during tissue fixation, and sample type) on the levels of proteins and phosphoproteins in breast cancer tissues, focusing on the PI3 kinase/AKT pathway. The BALB-neuT mouse breast cancer model expressing HER2 and pAKT proteins and human biopsy and resection specimens were analyzed. By using quantitative reverse phase protein arrays (RPPA), 9 proteins and 16 phosphoproteins relevant to breast cancer biology were assessed. Cold temperatures before and during fixation resulted in a marked improvement in the preservation of the reactivity of biological markers (eg, ER, HER2) in general and, specifically, pHER2 and pAKT. Some phosphoproteins, eg, pHER2 and pAKT, were more sensitive to prolonged cold ischemia times than others (eg, pS6RP and pSTAT5). By comparing the phosphoprotein levels in core needle biopsies with those in resection specimens, we found a marked decrease in many phosphoproteins in the latter. Cold conditions can improve the preservation of proteins and phosphoproteins in breast cancer tissues. Biopsies <= 1 mm in size are the preferred sample type for assessing the activity of deregulated kinases for personalized cancer treatments because the phosphoprotein levels are better preserved compared with resection specimens. Each potential new (phospho)protein biomarker should be tested for its sensitivity to pre-analytical processing prior to the development of a diagnostic assay. PMID- 25730370 TI - Immunohistochemistry and mass spectrometry for highly multiplexed cellular molecular imaging. AB - The role of immunohistochemistry (IHC) in the management of cancer has expanded to provide improved diagnostic classification, as well as guidance on disease prognosis, therapy, and relapse. These new tasks require evaluation of an increasing number of protein targets; however, conventional multiplexing, usually achieved using serial tissue sections stained for a single analyte per slide, can exhaust small biopsy specimens, complicate slide-to-slide protein expression correlation, and leave insufficient material for additional molecular assays. A new approach, mass spectrometry immunohistochemistry (MSIHC), compatible with high levels of target multiplexing and suitable for use on formalin-fixed, paraffin-embedded samples can circumvent many of these issues. The strategy employs antibodies that are labeled with elemental mass tags, such as isotopically pure lanthanides not typically found in biological specimens, rather than with typical fluorophores or chromogens. The metal-labeled antibodies are then detected in tissue using lasers or ion beams to liberate the tags for subsequent mass spectrometry detection. Within a given multiplexed IHC panel, the metal labels are selected so that their respective masses do not overlap. More than 30 antibodies have been imaged simultaneously, and up to 100 antibodies could potentially be detected at once if the full available mass spectrum is deployed. MSIHC has a number of advantages over conventional IHC techniques. Background due to autofluorescence is absent and the dynamic range is 10(5), exceeding immunofluorescence and chromogenic IHC by 100-fold and 1000-fold, respectively. Detection of labeled primary antibodies improves assay linearity over both chromogenic and fluorescent IHC. Multiplexed mass-tagged antibodies incubated simultaneously with tissue do not appear to cross-interfere, and because the mass tags do not degrade, samples are stable indefinitely. The imaging resolution of multiplexed ion-beam imaging can be better than light microscopy. With appropriate instrumentation, MSIHC has the potential to transform research and clinical pathology practice. PMID- 25730371 TI - GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways. AB - Tumor-associated macrophages (TAMs) are known to be involved in the progression, angiogenesis, and motility of various cancers. We previously reported the association between an increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study the roles of TAMs in ESCC, we first exposed peripheral blood monocyte (PBMo)-derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of the expression of the M2 macrophage marker CD204 and the protumorigenic factors interleukin (IL) 10, VEGFA, and MMPs. Next, we compared gene expression profiles between PBMo derived macrophages stimulated with or without TECM by cDNA microarray and focused on growth differentiation factor 15 (GDF15) among the highly expressed genes including IL-6, IL-8, and CXCL1. Our immunohistochemical study of 70 surgically resected ESCCs revealed that GDF15 was present not only in cancer cells but also in macrophages. The high expression of GDF15 in the ESCCs was significantly correlated with several more malignant phenotypes including vessel invasion, lymph node metastasis, and clinical stages. Patients with high GDF15 expression showed significantly poorer disease-free survival (P=0.011) and overall survival (P=0.041). We also found that recombinant human GDF15 promotes cell proliferation and the phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in the tumor microenvironment and is associated with aberrant growth and a poor prognosis in human ESCC. PMID- 25730372 TI - SV2B is essential for the integrity of the glomerular filtration barrier. AB - The glomerular visceral epithelial cell (podocyte) is characterized as a specialized structure of the interdigitating foot processes, covering the outer side of the glomerular basement membrane (GBM). The neighboring foot processes are connected by a slit diaphragm, which is a key structure regulating the barrier function of the glomerular capillary wall to prevent proteinuria. We have previously reported that synaptic vesicle protein 2 B (SV2B) is expressed in the podocyte and that the expression is clearly decreased in nephrotic models. However, the precise function of SV2B in the podocyte is unclear. To investigate the role of SV2B in maintaining the podocyte function and to better understand the function of the neuron-like vesicle expressing SV2B in the podocyte, we analyzed them with SV2B knockout (KO) mice. An increase in the amount of proteinuria, effacement of the foot process of the podocyte, and alterations of the GBM were detected in SV2B KO mice. It was also found that the expression of CD2AP, nephrin, and NEPH1, the functional molecules of the slit diaphragm, and laminin, a critical component of the GBM, is clearly altered in SV2B KO mice. Synaptotagmin and neurexin, which have a role in the synaptic vesicle docking in neurons, are downregulated in the kidney cortex of SV2B KO mice. We have previously reported that neurexin interacts with CD2AP, and the present study shows that SV2B interacts with CD2AP. These findings suggest that the SV2B neurexin complex is involved in the formation and maintenance of the slit diaphragm. In addition, SV2B is densely expressed close to the cell surface in the presumptive podocyte in the early stage of glomerulogenesis. These results suggest that SV2B has an essential role in the formation and maintenance of the glomerular capillary wall. PMID- 25730373 TI - Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis. AB - Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4 deficient F344/DuCrl/Crlj rats diabetic by injection of streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in streptozotocin induced diabetic rats. Compared with control rats at 9 and 11 weeks old, body weight and heart rates were significantly lower, while fasting blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of body weight, fasting blood glucose and lipid parameters between the two diabetic rat strains. AGEs, 8-hydroxy-2' deoxyguanosine (8-OHdG) and nitrotyrosine levels in the kidney, renal gene expression of RAGE and intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and albumin, and the ratio of renal to body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1 diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing diabetic nephropathy. PMID- 25730375 TI - Synthesis and indole coupling reactions of azetidine and oxetane sulfinate salts. AB - Azetidine and oxetane sulfinate salts are easily prepared from commercially available 3-iodoheterocycle precursors in a three-step sequence. They undergo smooth coupling reactions thereby providing an expedient route for the introduction of these four-membered heterocycles into indoles. PMID- 25730374 TI - Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies: first experiences. AB - OBJECTIVE: This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. PATIENTS AND METHODS: This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n = 36), unclassified generalized epilepsy (n = 12), Lennox-Gastaut syndrome (n = 5), West syndrome (n = 3), and Dravet syndrome (n = 2). RESULTS: The response rate (>= 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n = 16) and behavioral changes (n = 14). DISCUSSION: PER seems to be effective also in children and adolescents with pharmaco-refractory epilepsies. Tolerability was acceptable. PMID- 25730376 TI - Protein kinase Snf1 is involved in the proper regulation of the unfolded protein response in Saccharomyces cerevisiae. AB - Glc7 is the only catalytic subunit of the protein phosphatase type 1 in the yeast S. cerevisiae and, together with its regulatory subunits, is involved in many essential processes. Analysis of the non-essential mutants in the regulatory subunits of Glc7 revealed that the lack of Reg1, and no other subunit, causes hypersensitivity to unfolded protein response (UPR)-inducers, which was concomitant with an augmented UPR element-dependent transcriptional response. The Glc7-Reg1 complex takes part in the regulation of the yeast AMP-activated serine/threonine protein kinase Snf1 in response to glucose. We demonstrate in the present study that the observed phenotypes of reg1 mutant cells are attributable to the inappropriate activation of Snf1. Indeed, growth in the presence of limited concentrations of glucose, where Snf1 is active, or expression of active forms of Snf1 in a wild-type strain increased the sensitivity to the UPR-inducer tunicamycin. Furthermore, reg1 mutant cells showed a sustained HAC1 mRNA splicing and KAR2 mRNA levels during the recovery phase of the UPR, and dysregulation of the Ire1-oligomeric equilibrium. Finally, overexpression of protein phosphatases Ptc2 and Ptc3 alleviated the growth defect of reg1 cells under endoplasmic reticulum (ER) stress conditions. Altogether, our results reveal that Snf1 plays an important role in the attenuation of the UPR, as well as identifying the protein kinase and its effectors as possible pharmacological targets for human diseases that are associated with insufficient UPR activation. PMID- 25730377 TI - Measurement of Radiation Exposure When Using the Mini C-Arm to Reduce Pediatric Upper Extremity Fractures. AB - BACKGROUND: Previous literature has underreported radiation exposure with the use of mini C-arm during pediatric forearm fracture reductions. The purpose of this study is to report an accurate amount of radiation exposure during fracture reductions using a mini C-arm that records the amount of kilovolts, milliamps, and the number of seconds of foot pedal use. METHODS: Eighty-six consecutive pediatric patients undergoing upper extremity fracture reduction in the emergency department were studied. The orthopaedic resident, either a PGY2 or PGY3, performed a manipulative reduction and casting of the fracture with use of the mini C-arm. Postreduction, in cast, anteroposterior and lateral images from the mini C-arm were saved to the computerized radiology system. The mini C-arm recorded the amount of kilovolts, milliamps, and the number of seconds that the foot pedal was used for each reduction. A radiology physicist (S.K.) calculated the amount of millirem (mR) exposure for each reduction from these data. RESULTS: The resident using the mini C-arm and the fracture pattern affected the amount of radiation exposure. The average mini C-arm mR exposure for distal radius fractures was 63 mR; forearm 109 mR; elbow 53 mR; and hand 69 mR. For comparison, conventional anteroposterior/lateral forearm radiographs emit an average of 20 mR. Less-experienced PGY2 residents had a higher mR exposure per reduction compared with PGY3 residents. CONCLUSIONS: Radiation exposure when using the mini C-arm for reduction of pediatric fractures has been underestimated in previous literature. Radiation from the mini C-arm exceeded that from conventional radiographs in most cases. We recommend that residents receive training about the use of the mini C-arm before its utilization as an aid to reduce pediatric fractures in the emergency department. PMID- 25730378 TI - A Predictive Risk Index for 30-day Readmissions Following Surgical Treatment of Pediatric Scoliosis. AB - BACKGROUND: Pediatric scoliosis often requires operative treatment, yet few studies have examined readmission rates in this patient population. The purpose of this study is to examine the incidence, reasons, and independent risk factors for 30-day unplanned readmissions following scoliosis surgery. METHODS: A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement-Pediatric database from 2012 to 2013 was performed. Patients undergoing spinal arthrodesis for progressive infantile scoliosis, idiopathic scoliosis, or scoliosis due to other medical conditions were identified and divided between 2 groups: patients with unplanned 30-day readmissions (Readmitted) and patients with no unplanned readmissions (Non-Readmitted). Multivariate logistic regression models were created to determine independent risk factors for readmissions. RESULTS: A total of 3482 children were identified, of which 120 (3.4%) had an unplanned readmission. A majority of patients had a readmission due to a surgical site complication regardless of scoliosis etiology. Risk factors for readmission included obesity (P<0.001) and posterior fusion of 13 or more vertebrae (P=0.029) for idiopathic scoliosis, impaired cognition (P=0.009) for progressive infantile scoliosis, and pelvic fixation (P=0.025) and American Society of Anesthesiologist >=3 (P=0.048) for scoliosis due to other conditions. CONCLUSIONS: We present 30-day readmissions risk factors based on independent patient and procedural risk factors. This may be useful in the clinical management of patients following scoliosis surgery, specifically for the role of preoperative and predischarge risk stratification. PMID- 25730379 TI - VEPTR Implantation After Age 3 is Associated With Similar Radiographic Outcomes With Fewer Complications. AB - BACKGROUND: The purpose of this study was to analyze the risks and benefits of early vertical expandable prosthetic titanium rib (VEPTR) implantation (below 3 y of age) compared with delayed intervention (3 to 6 y of age). Early intervention with milder deformity may make device implantation easier and may facilitate symmetric chest and pulmonary development. However, later intervention may decrease the number of lengthenings required, and implant anchor points and bone quality may be better in older patients. METHODS: A multicenter prospective database of patients treated with the VEPTR device was retrospectively reviewed. A total of 71 patients with minimum 5-year follow-up were included. Thirty-seven patients had VEPTR surgery below 3 years of age (group 1), and 34 patients had surgery between 3 and 6 years of age (group 2). Radiographs from the preoperative, immediate postoperative, and most recent follow-up visits were reviewed to determine coronal plane deformity and change in T1-T12 height over time. Complications were analyzed using a nonparametric mean cumulative function for the number of complications per subject over time. RESULTS: Patients in both groups had similar diagnoses, ASA scores (P=0.22), and number of lengthenings (10+/-4 in both groups, P=0.40). Preoperative and most recent major Cobb angles were not significantly different between the 2 groups [66+/-22 and 60+/-20 degrees (group 1) vs. 63+/-19 and 57+/-23 degrees (group 2), respectively] (P=0.38). The change in T1-T12 was significantly correlated with the number of lengthenings (P<0.001); however, there was no difference between age groups (P=0.55). There were 118 complications in 33 subjects in group 1 and there were 69 complications in 28 subjects in group 2. The number of complications per lengthening was significantly different between the 2 age groups (P<0.001). Subjects in group 2 had 41% fewer complications per lengthening compared with subjects in group 1 (P<0.001). CONCLUSIONS: VEPTR treatment resulted in similar deformity control and thoracic growth in both age groups with lower complication rates in the older population. The rate of complications was similar between the 2 groups for the first 2 years postimplantation, but after 2 years, the rate of complications increased over time faster for the younger group compared with the older group. LEVEL OF EVIDENCE: Level III-retrospective chart and radiographic review. PMID- 25730380 TI - Eccentric Capitellar Ossification Limits the Utility of the Radiocapitellar Line in Young Children. AB - BACKGROUND: The radiocapitellar line (RCL) has long been used for the radiographic evaluation of elbow alignment. In children, the capitellar ossific nucleus serves as a proxy for the entire capitellum, but this substitution has not been verified. Using magnetic resonance imaging (MRI), we sought to understand how maturation of the ossific nucleus of the capitellum affects the utility of RCL throughout skeletal maturation of the elbow. METHODS: The RCL was drawn on coronal and sagittal MRIs in 82 children (43 boys, 39 girls; age range, 1 to 13 y) with at least 3 patients in each 1-year interval age group. The perpendicular distance of the RCL from the center of both the cartilaginous capitellum and the capitellar ossific nucleus was measured relative to its total width, and a percent offset for each measurement was calculated. Logarithmic regression analysis was performed to analyze the effect of age and sex on percent offset. RESULTS: The RCL reliably intersected with the central third of the cartilaginous capitellum at all ages in both planes. Although the RCL intersected with the ossified capitellum in all but 3 measurements, it intersected with the central third of the ossified capitellum less often in younger children in both sagittal (B=0.47, P<0.001) and coronal (B=0.31, P=0.002) planes. Percent offset decreased significantly with age in a logarithmic manner in both sagittal (r=0.57, P<0.001) and coronal (r=-0.47, P<0.001) planes. 95% confidence intervals predict that the sagittal plane RCL will accurately intersect the central third of the ossified capitellum by age 10 years in girls and age 11 years in boys but not in the coronal plane. CONCLUSIONS: Eccentric ossification of the capitellum explains RCL variability in young children. The RCL does not reliably intersect the central third of the ossified capitellum until ages 10 years in girls and 11 years in boys in the sagittal plane. The RCL should be used within its limitations in skeletally immature children and should be combined with advanced imaging if necessary. PMID- 25730381 TI - Osteonecrosis After Femoral Neck Fractures in Children and Adolescents: Analysis of Risk Factors. AB - BACKGROUND: The most serious complication of femoral neck fractures in children and adolescents is osteonecrosis. Although a number of factors have been implicated in the development of osteonecrosis, no specific cause-and-effect relationship has been determined. The primary purpose of this study was to determine the prevalence of osteonecrosis in children and adolescents after femoral neck fractures and to identify risk factors for its development. METHODS: This retrospective review identified 70 patients between the ages of 1.3 and 18.1 years who were treated for a femoral neck fracture between 2000 and 2011 at a single level I pediatric trauma center and followed until clinical and radiographic union. Demographic information, injury event details, type of surgical treatment, associated injuries, time from injury to treatment, and postoperative alignment were recorded from chart and radiographic review. The primary outcome was the presence of osteonecrosis, which was determined by review of available imaging. Multivariable logistic regression analysis tested age, time to treatment, type of fixation, mechanism of injury, postoperative alignment, and capsular decompression as possible risk factors for the development of osteonecrosis. RESULTS: Osteonecrosis occurred in 20 (29%) of the 70 patients. The median time to diagnosis of osteonecrosis was 7.8 months. Multivariable predictors of osteonecrosis included fracture displacement (P=0.01) and fracture location (P=0.02). Patient age, type of fixation, mechanism of injury, capsular decompression, postoperative alignment, and performance of reduction were not predictive of osteonecrosis after femoral neck fracture. Finally, time to treatment also was found to be a positive predictor of osteonecrosis (P=0.004), with osteonecrosis more likely in patients treated in less than 24 hours, but this finding is likely due to confounding because injury severity was closely linked to time to treatment. CONCLUSIONS: Regardless of the treatment, the prevalence of osteonecrosis after femoral neck fractures remains high. Recognizing factors that are predictive of the development of osteonecrosis can help surgeons counsel patients and families appropriately about the risk of this complication. PMID- 25730382 TI - A half millimeter thick coplanar flexible battery with wireless recharging capability. AB - Most of the existing flexible lithium ion batteries (LIBs) adopt the conventional cofacial cell configuration where anode, separator, and cathode are sequentially stacked and so have difficulty in the integration with emerging thin LIB applications, such as smart cards and medical patches. In order to overcome this shortcoming, herein, we report a coplanar cell structure in which anodes and cathodes are interdigitatedly positioned on the same plane. The coplanar electrode design brings advantages of enhanced bending tolerance and capability of increasing the cell voltage by in series-connection of multiple single-cells in addition to its suitability for the thickness reduction. On the basis of these structural benefits, we develop a coplanar flexible LIB that delivers 7.4 V with an entire cell thickness below 0.5 mm while preserving stable electrochemical performance throughout 5000 (un)bending cycles (bending radius = 5 mm). Also, even the pouch case serves as barriers between anodes and cathodes to prevent Li dendrite growth and short-circuit formation while saving the thickness. Furthermore, for convenient practical use wireless charging via inductive electromagnetic energy transfer and solar cell integration is demonstrated. PMID- 25730383 TI - Determination of selenium in serum in the presence of gadolinium with ICP-QQQ-MS. AB - Gadolinium (Gd)-based magnetic resonance imaging (MRI) contrasting agents interfere with the determination of selenium (Se) when analysed by single quadrupole inductively coupled plasma-mass spectrometry (ICP-MS). This paper demonstrates that an ICP-triple quadrupole-MS (ICP-QQQ-MS) with oxygen mass shift overcomes Gd(++) interference on Se(+) and mitigates typically encountered matrix and spectral based interferences. Normal human serum was diluted in a solution containing isopropanol, EDTA, NH4OH and Triton X-100. Samples were unspiked (control) serum; serum spiked with 0.127 MUmol L(-1) Se or 127 MUmol L(-1) Gd; and serum spiked with both 0.127 MUmol L(-1) Se and 127 MUmol L(-1) Gd. Consideration of collision/reaction gases and conditions for interference mitigation included helium (He); a 'low' and 'high' hydrogen (H2) flow, and oxygen (O2). The instrument tune for O2 was optimised for effective elimination of interferences via a mass shift reaction of Se(+) to SeO(+). The ICP-QQQ-MS was capable of detecting trace (>9.34 nmol L(-1)) levels of Se in serum in the presence of Gd in our simulated post-MRI serum sample. The multi-tune capabilities of the ICP-QQQ-MS may be adapted to eliminate other specific isobaric interferences that cause false positive results in other analyses where the analyte is confounded by doubly charged and/or polyatomic species. PMID- 25730384 TI - Self-reactivated mesostructured Ca-Al-O composite for enhanced high-temperature CO2 capture and carbonation/calcination cycles performance. AB - In this study, highly efficient high-temperature CO2 sorbents of calcium aluminate (Ca-Al-O) mesostructured composite were synthesized using presynthesized mesoporous alumina (MA) as a porous matrix to react with calcium nitrate through a microwave-assisted process. Upon annealing at 600 degrees C, a highly stable mesoporous structure composed of poorly crystalline Ca12Al14O33 phase and the CaO matrix was obtained. The Ca-Al-O mesostructured sorbents with a Ca(2+)/Al(3+) ratio of 5:1 exhibit an enhanced increasing CO2 absorption kinetics in the CO2 capture capacity from 37.2 wt % to 48.3 wt % without apparent degradation with increasing carbonation/calcination cycling up to 50 at 700 degrees C due to the strong self-reactivation effect of the mesoporous Ca-Al-O microstructure. Remarkable improvements in the CaO-CaCO3 conversion attained from the mesostructured Ca-Al-O composite can be explained using the concept combined with available mesoporous structure and Ca12Al14O33 phase content. However, a high Ca(2+)/Al(3+) =8:1 Ca-Al-O composite causes degradation because the pores become blocked and partial sintering induces CaO agglomeration. PMID- 25730385 TI - Memory outcomes following cognitive interventions in children with neurological deficits: A review with a focus on under-studied populations. AB - Given the primary role of memory in children's learning and well-being, the aim of this review was to examine the outcomes of memory remediation interventions in children with neurological deficits as a function of the affected memory system and intervention method. Fifty-seven studies that evaluated the outcome of memory interventions in children were identified. Thirty-four studies met the inclusion criteria, and were included in a systematic review. Diverse rehabilitation methods for improving explicit and implicit memory in children were reviewed. The analysis indicates that teaching restoration strategies may improve, and result in the generalisation of, semantic memory and working memory performance in children older than 7 years with mild to moderate memory deficits. Factors such as longer protocols, emotional support, and personal feedback contribute to intervention efficacy. In addition, the use of compensation aids seems to be highly effective in prospective memory tasks. Finally, the review unveiled a lack of studies with young children and the absence of group interventions. These findings point to the importance of future evidence-based intervention protocols in these areas. PMID- 25730387 TI - Inorganic mercury sequestration by a poly(ethylene imine) dendrimer in aqueous solution. AB - The interaction of the G-2 poly(ethylene imine) dendrimer L, derived from ammonia as initiating core, with Hg(II) and HgCl42- was studied in aqueous solution by means of potentiometric (pH-metric) measurements. Speciation of these complex systems showed that L is able to form a wide variety of complexes including 1:1, 2:1, 3:1 and 3:2 metal-to-ligand species, of different protonation states, as well as the anion complexes [(H7L)HgCl4]5+ and [(H8L)HgCl4]6+. The stability of the metal complexes is very high, making L an excellent sequestering agent for Hg(II), over a large pH range, and a promising ligand for the preparation of functionalized activated carbons to be employed in the remediation and the prevention of environmental problems. PMID- 25730386 TI - Determinants of baseline seroreactivity to human papillomavirus type 16 in the Ludwig-McGill cohort study. AB - BACKGROUND: Immunity plays an important role in controlling human papillomavirus (HPV) infection and associated lesions. Unlike infections caused by other viruses, natural HPV infection does not always result in a protective antibody response. Therefore, HPV antibodies are also considered markers of cumulative exposure. The aim of this study was to identify determinants of HPV16 seroreactivity at enrollment among women from the Ludwig-McGill cohort, a natural history study of HPV infection and risk of cervical neoplasia. METHODS: HPV16 serology was assessed by ELISA for L1 and L2 capsid antigens, while HPV typing and viral load measurements were performed by PCR-based methods. The associations were analyzed by unconditional logistic regression. RESULTS: Of 2049 subjects, 425 (20.7%) were strongly seropositive for HPV16. In multivariate analysis, seroreactivity was positively correlated with age, lifetime number of sexual partners, frequency of sex, and HPV16 viral load, and negatively associated with duration of smoking. CONCLUSIONS: HPV16 seroreactivity is determined by factors that reflect viral exposure. PMID- 25730388 TI - Lectins with potential for anti-cancer therapy. AB - This article reviews lectins of animal and plant origin that induce apoptosis and autophagy of cancer cells and hence possess the potential of being developed into anticancer drugs. Apoptosis-inducing lectins encompass galectins, C-type lectins, annexins, Haliotis discus discus lectin, Polygonatum odoratum lectin, mistletoe lectin, and concanavalin A, fucose-binding Dicentrarchus labrax lectin, and Strongylocentrotus purpuratus lectin, Polygonatum odoratum lectin, and mistletoe lectin, Polygonatum odoratum lectin, autophagy inducing lectins include annexins and Polygonatum odoratum lectin. PMID- 25730389 TI - An efficient synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and thiones catalyzed by a novel Bronsted acidic ionic liquid under solvent-free conditions. AB - We report here an efficient and green method for Biginelli condensation reaction of aldehydes, beta-ketoesters and urea or thiourea catalyzed by Bronsted acidic ionic liquid [Btto][p-TSA] under solvent-free conditions. Compared to the classical Biginelli reaction conditions, the present method has the advantages of giving good yields, short reaction times, near room temperature conditions and the avoidance of the use of organic solvents and metal catalyst. PMID- 25730390 TI - Synthesis, central nervous system activity and structure-activity relationships of novel 1-(1-Alkyl-4-aryl-4,5-dihydro-1H-imidazo)-3-substituted urea derivatives. AB - A series of 10 novel urea derivatives has been synthesized and evaluated for their central nervous system activity. Compounds 3a-3h were prepared in the reaction between the respective 1-alkyl-4-aryl-4,5-dihydro-1H-imidazol-2-amines 1a and 1b and appropriate benzyl-, phenethyl-isocyanate or ethyl 4 isocyanatobenzoate and ethyl isocyanatoacetate 2 in dichloromethane. Derivatives 4c and 4g resulted from the conversion of 3c and 3g into the respective amides due to action of an aqueous ammonia solution. The results obtained in this study, based on literature data suggest a possible involvement of serotonin system and/or the opioid system in the effects of tested compounds, and especially in the effect of compound 3h. The best activity of compound 3h may be primarily attributed to its favourable ADMET properties, i.e., higher lipophilicity (related to lower polar surface area and greater molecular surface, volume and mass than for other compounds) and good blood-brain permeation. This compound has also the greatest polarizability and ovality. The HOMO and LUMO energies do not seem to be directly related to activity. PMID- 25730391 TI - The physician-scientist workforce and board certification. PMID- 25730392 TI - Atomic origin of ultrafast resistance switching in nanoscale electrometallization cells. AB - Nanoscale resistance-switching cells that operate via the electrochemical formation and disruption of metallic filaments that bridge two electrodes are among the most promising devices for post-CMOS electronics. Despite their importance, the mechanisms that govern their remarkable properties are not fully understood, especially for nanoscale devices operating at ultrafast rates, limiting our ability to assess the ultimate performance and scalability of this technology. We present the first atomistic simulations of the operation of conductive bridging cells using reactive molecular dynamics with a charge equilibration method extended to describe electrochemical reactions. The simulations predict the ultrafast switching observed in these devices, with timescales ranging from hundreds of picoseconds to a few nanoseconds for devices consisting of Cu active electrodes and amorphous silica dielectrics and with dimensions corresponding to their scaling limit (cross-sections below 10 nm). We find that single-atom-chain bridges often form during device operation but that they are metastable, with lifetimes below a nanosecond. The formation of stable filaments involves the aggregation of ions into small metallic clusters, followed by a progressive chemical reduction as they become connected to the cathode. Contrary to observations in larger cells, the nanoscale conductive bridges often lack crystalline order. An atomic-level mechanistic understanding of the switching process provides guidelines for materials optimization for such applications and the quantitative predictions over an ensemble of devices provide insight into their ultimate scaling and performance. PMID- 25730393 TI - Solid friction between soft filaments. AB - Any macroscopic deformation of a filamentous bundle is necessarily accompanied by local sliding and/or stretching of the constituent filaments. Yet the nature of the sliding friction between two aligned filaments interacting through multiple contacts remains largely unexplored. Here, by directly measuring the sliding forces between two bundled F-actin filaments, we show that these frictional forces are unexpectedly large, scale logarithmically with sliding velocity as in solid-like friction, and exhibit complex dependence on the filaments' overlap length. We also show that a reduction of the frictional force by orders of magnitude, associated with a transition from solid-like friction to Stokes's drag, can be induced by coating F-actin with polymeric brushes. Furthermore, we observe similar transitions in filamentous microtubules and bacterial flagella. Our findings demonstrate how altering a filament's elasticity, structure and interactions can be used to engineer interfilament friction and thus tune the properties of fibrous composite materials. PMID- 25730394 TI - High-precision realization of robust quantum anomalous Hall state in a hard ferromagnetic topological insulator. AB - The discovery of the quantum Hall (QH) effect led to the realization of a topological electronic state with dissipationless currents circulating in one direction along the edge of a two-dimensional electron layer under a strong magnetic field. The quantum anomalous Hall (QAH) effect shares a similar physical phenomenon to that of the QH effect, whereas its physical origin relies on the intrinsic spin-orbit coupling and ferromagnetism. Here, we report the experimental observation of the QAH state in V-doped (Bi,Sb)2Te3 films with the zero-field longitudinal resistance down to 0.00013 +/- 0.00007h/e(2) (~3.35 +/- 1.76 Omega), Hall conductance reaching 0.9998 +/- 0.0006e(2)/h and the Hall angle becoming as high as 89.993 degrees +/- 0.004 degrees at T = 25 mK. A further advantage of this system comes from the fact that it is a hard ferromagnet with a large coercive field (Hc > 1.0 T) and a relative high Curie temperature. This realization of a robust QAH state in hard ferromagnetic topological insulators (FMTIs) is a major step towards dissipationless electronic applications in the absence of external fields. PMID- 25730395 TI - Universal helimagnon and skyrmion excitations in metallic, semiconducting and insulating chiral magnets. AB - Nearly seven decades of research on microwave excitations of magnetic materials have led to a wide range of applications in electronics. The recent discovery of topological spin solitons in chiral magnets, so-called skyrmions, promises high frequency devices that exploit the exceptional emergent electrodynamics of these compounds. Therefore, an accurate and unified quantitative account of their resonant response is key. Here, we report all-electrical spectroscopy of the collective spin excitations in the metallic, semiconducting and insulating chiral magnets MnSi, Fe1-xCoxSi and Cu2OSeO3, respectively, using broadband coplanar waveguides. By taking into account dipolar interactions, we achieve a precise quantitative modelling across the entire magnetic phase diagrams using two material-specific parameters that quantify the chiral and the critical field energy. The universal behaviour sets the stage for purpose-designed applications based on the resonant response of chiral magnets with tailored electric conductivity and an unprecedented freedom for an integration with electronics. PMID- 25730396 TI - Effect of hydrostatic pressure on gas solubilization in micelles. AB - Molecular dynamics simulations of anionic sodium decylsulfate and nonionic pentaethylene glycol monodecyl ether micelles in water have been performed to examine the impact of hydrostatic pressure on argon solubilization as a function of pressure. The potential-of-mean force between the micelles and argon demonstrates that nonpolar gases are attracted to the interiors of both micelles. The affinity of argon for micelle interiors, however, decreases with increasing pressure as a result of the comparatively higher molar volume of argon inside assemblies. We evaluate solubility enhancement coefficients, which describe the drop in the solute chemical potential as a function of the micellized surfactant concentration, to quantify the impact of micellization on gas solubilization. While argon is similarly attracted to the hydrophobic cores of both micelles, the gas is more effectively sequestered within nonionic micelles compared with anionic micelles as a result of salting out by charged head groups and accompanying counterions. The solubility enhancement coefficients of both micelles decrease with increasing pressure, reflecting the changing forces observed in the potentials-of-mean force. An analytical liquid drop model is proposed to describe the pressure dependence of argon solubilization within micelles that captures the simulation solubility enhancement coefficients after fitting an effective micelle radius for each surfactant. PMID- 25730397 TI - Creutzfeldt-Jakob Disease with a prion protein gene codon 180 mutation presenting asymmetric cortical high-intensity on magnetic resonance imaging. AB - Here we report a genetically confirmed case of Creutzfeldt-Jakob disease with a prion protein gene codon 180 mutation presenting atypical magnetic resonance imaging findings. The present case exhibited an acute onset and lateralized neurologic signs, and progressive cognitive impairment. No myoclonus or periodic synchronous discharges on electroencephalography were observed. Diffusion weighted images revealed areas of high signal intensity in the right frontal and temporal cortices at onset that extended to the whole cortex and basal ganglia of the right cerebral hemisphere at 3 months. Although the cerebrospinal fluid (CSF) was initially negative for neuron specific enolase, tau protein, 14-3-3 protein, and abnormal prion protein, the CSF was positive for these brain-derived proteins at 3 months after onset. PMID- 25730398 TI - Exploratory analysis of urinary tract infection using a GC-APCI-MS platform. AB - Urinary tract infection (UTI) is among the most common bacterial infections worldwide. The understanding of the physiological mechanisms affected by UTI may need modern integrative '-omics' technologies, and metabolomics in particular. Here we present the first GC-APCI-MS-based explorative metabolomics study of UTI, using MS and FID detectors simultaneously. This provides high quality mass spectral data as well as semi-quantitative information demonstrating the feasibility of the GC-APCI-MS platform for non-targeted approaches. The work is part of a bigger project aiming at providing a comprehensive overview of UTI induced changes in urine. Taking advantage of a fully clinically characterized cohort that offers the possibility of both case-control and longitudinal modelling, we can define UTI-induced change as a list of urinary metabolites which distinguish E. coli UTI patients from the subjects with no signs of an active infection. The list of molecular descriptors includes compounds related to bacterial activity such as lactic acid and lactose while other molecules show an association with the physiological status (inositol, citric acid). PMID- 25730399 TI - Effect of acid-catalyzed formation rates of benzimidazole-linked polymers on porosity and selective CO2 capture from gas mixtures. AB - Benzimidazole-linked polymers (BILPs) are emerging candidates for gas storage and separation applications; however, their current synthetic methods offer limited control over textural properties which are vital for their multifaceted use. In this study, we investigate the impact of acid-catalyzed formation rates of the imidazole units on the porosity levels of BILPs and subsequent effects on CO2 and CH4 binding affinities and selective uptake of CO2 over CH4 and N2. Treatment of 3,3'-Diaminobenzidine tetrahydrochloride hydrate with 1,2,4,5-tetrakis(4 formylphenyl)benzene and 1,3,5-(4-formylphenyl)-benzene in anhydrous DMF afforded porous BILP-15 (448 m(2) g(-1)) and BILP-16 (435 m(2) g(-1)), respectively. Alternatively, the same polymers were prepared from the neutral 3,3' Diaminobenzidine and catalytic amounts of aqueous HCl. The resulting polymers denoted BILP-15(AC) and BILP-16(AC) exhibited optimal surface areas; 862 m(2) g( 1) and 643 m(2) g(-1), respectively, only when 2 equiv of HCl (0.22 M) was used. In contrast, the CO2 binding affinity (Qst) dropped from 33.0 to 28.9 kJ mol(-1) for BILP-15 and from 32.0 to 31.6 kJ mol(-1) for BILP-16. According to initial slope calculations at 273 K/298 K, a notable change in CO2/N2 selectivity was observed for BILP-15(AC) (61/50) compared to BILP-15 (83/63). Similarly, ideal adsorbed solution theory (IAST) calculations also show the higher specific surface area of BILP-15(AC) and BILP-16(AC) compromises their CO2/N2 selectivity. PMID- 25730400 TI - Three new mononuclear tri-spin lanthanide-nitronyl nitroxide radical compounds: syntheses, structures and magnetic properties. AB - Based on the nitronyl nitroxide radical, 2-(4-(methoxycarbonyl)phenyl)-4,4,5,5 tetramethylimidazolin-1-oxyl-3-oxide (1, NITPhCOOMe), and three mononuclear tri spin compounds [Ln(hfac)3(NITPhCOOMe)2] (Ln = Gd (2), Tb (3), Dy (4); hfac = hexafluoroacetylacetonate) are successfully synthesized and fully characterized. Compounds 2 and 4 are isostructural and crystallize in the C2/c space group, while compound 3 crystallizes in the P21/c space group. For compounds 2-4, the central metal ions are all eight-coordinate in distorted triangular dodecahedral LnO8 coordination geometry (D(2d) symmetry) completed by three bischelate hfac(-) ligands and two monodentate radicals. Magnetic studies show that radical 1 undertakes the transition from the paramagnetic state to 3D antiferromagnetic ordering at 4.2 K. In addition, compound 3 exhibits field-induced single-molecule magnet (SMM) behavior. PMID- 25730401 TI - Blood pressure control and cognitive impairment--why low is not always better. PMID- 25730402 TI - Divorced mothers' coparental boundary maintenance after parents repartner. AB - When divorced parents remarry or cohabit with new partners, it is challenging to maintain functional postdivorce coparenting systems. In this grounded theory study of 19 divorced mothers, we examined the processes by which they maintained boundaries around coparental relationships after 1 or both coparents had repartnered. Mothers saw themselves as captains of the coparenting team, making decisions about who should play what roles in parenting their children. They viewed themselves as having primary responsibility for their children, and they saw their children's fathers as important coparenting partners. Mothers used a variety of strategies to preserve boundaries around the coparental subsystem when either they or their ex-husbands repartnered. Stepparents became more active participants in coparenting when: (a) mothers perceived them to be adequate caregivers, (b) biological parents were able to cooperatively coparent, (c) mothers perceived the fathers as good parents and responsible fathers, and (d) mothers felt secure as the primary parents. When all 4 conditions were present, mothers were likely to expand the coparental subsystem to include new partners. If any of these conditions were not present, mothers resisted including stepparents as part of the child rearing team. The findings from this study highlight how coparental roles in a nonclinical sample of families develop and change; mothers often modify coparenting boundaries over time to include stepparents. PMID- 25730403 TI - Dynamic changes in parent affect and adolescent cardiac vagal regulation: a real time analysis. AB - The current study explored the role of parents' negative and positive affect in adolescent respiratory sinus arrhythmia (RSA) reactivity during a parent adolescent conflict discussion task and the moderating effects of adolescent sex and age. Questionnaire data were collected from 206 adolescents (10-18 years of age; M = 13.37 years) and their primary caregivers (83.3% biological mothers). Electrocardiogram and respiration data were collected from adolescents, and RSA variables were computed. Parent affect was coded during the conflict discussion task. Multilevel modeling was used to distinguish the between- and within individual effects of parent affect on adolescent RSA. Results indicated that observed within-parent-teen dyad anger was negatively associated with adolescent RSA, controlling for previous-minute RSA level, particularly among adolescents 13 years and older. In addition, observed between-dyad positive affect was positively linked to RSA for both boys and girls when previous-minute RSA level was controlled. Within-dyad positive affect was positively related to girl's RSA only. These findings suggest that expressions of positive affect may be related to better vagal regulation (RSA increases), whereas expressions of anger may be related to poor vagal regulation (RSA decreases) during social engagement. PMID- 25730404 TI - Getting the most out of family data with the R package fSRM. AB - Family research aims to explore family processes, but is often limited to the examination of unidirectional processes. As the behavior of 1 person has consequences that go beyond that individual, family functioning should be investigated in its full complexity. The social relations model (SRM; Kenny & La Voie, 1984) is a conceptual and analytical model that can disentangle family data from a round-robin design at 3 different levels: the individual level (actor and partner effects), the dyadic level (relationship effects), and the family level (family effect). Its statistical complexity may however be a hurdle for family researchers. The user-friendly R package fSRM performs almost automatically those rather complex SRM analyses and introduces new possibilities for assessing differences between SRM means and between SRM variances, both within and between groups of families. Using family data on negative processes, different type of research questions are formulated and corresponding analyses with fSRM are presented. PMID- 25730405 TI - Caregiving burden and uplifts: a contradiction or a protective partnership for the quality of life of parents and their children with asthma? AB - Parental caregiving in the context of pediatric chronic conditions is a multifaceted experience that encompasses negative (burdens) and positive dimensions (uplifts), which may support risk and protective processes that influence family adaptation. This study aimed to examine the caregiving experience of parents caring for a child with asthma and the moderating role of caregiving uplifts on the associations between caregiving burden and quality of life (QoL) of parents and their children. Participants were 180 dyads of children/adolescents with asthma between 8 and 18 years of age and one of their parents. The parents reported on caregiving burden and uplifts and on their QoL, and the children/adolescents completed a self-report measure of generic QoL. Results showed that although parents of children with intermittent asthma and parents of younger children presented higher levels of caregiving burden, noncontrolled asthma was the only clinical variable representing a significant risk factor for decreased QoL in children. Significant negative and positive associations were found between burden dimensions and QoL and between caregiving uplifts and QoL, respectively, in parents and children. Additionally, caregiving uplifts moderated the negative link between relationship burden and parents' QoL. These results suggest that, far from being contradictory, caregiving uplifts may co-occur with high levels of burden and may constitute a protective factor against the deleterious effect of the caregiving burden on parents' QoL and a resource that directly contributes to children's QoL. This risk-resistance approach to family caregiving may contribute to operationalizing strength-based interventions in the context of pediatric asthma. PMID- 25730406 TI - Parental knowledge of adolescent activities: links with parental attachment style and adolescent substance use. AB - Parents' knowledge of their adolescents' whereabouts and activities is a robust predictor of adolescent risk behavior, including the use of drugs and alcohol. Surprisingly few studies have attempted to identify parental characteristics that are associated with the degree of parental knowledge. The present study is the first to examine how parental attachment style relates to mother, father, and adolescent reports of parental knowledge. Further, we used structural equation modeling to test the associations among parents' attachment styles, reports of parental knowledge, and adolescents' alcohol and marijuana use. Participants included 203 adolescents (M age = 14.02, SD = .91) living in 2-parent households and their parent(s). As predicted, mothers' and fathers' insecure attachment styles were negatively associated with self-reported and adolescent-reported parental knowledge, and all 3 reports of parental knowledge were negatively related to adolescent substance use. Mothers' and fathers' attachment styles were unrelated to adolescent substance use. However, evidence emerged for indirect effects of parental attachment style on adolescent substance use through reports of parental knowledge. Implications for prevention efforts and the importance of multiple reporters within the family are discussed. PMID- 25730407 TI - Music therapy as grief therapy for adults with mental illness and complicated grief: a pilot study. AB - This randomized, controlled, mixed-methods pilot study examined the effectiveness and experiences of grief-specific music therapy, in addition to standard care, with adults (N=10) who have complicated grief (CG) and mental illness, as compared to standard care alone. The study tested Worden's (2009) theories of grief therapy as well as a new grief-specific music therapy intervention, based on Shear, Frank, Houck, and Reynolds' (2005) imaginal dialogue intervention and Austin's (2008) method of vocal psychotherapy. Results demonstrated that participants in the experimental group had a greater decrease of grief symptoms, as measured by the ICG-R, as compared with the control group. PMID- 25730408 TI - Jenny Pronczuk de Garbino: a global champion for children's health. PMID- 25730409 TI - Stellate ganglion local anesthetic blockade and neurolysis for the treatment of refractory ventricular fibrillation. AB - Electrical storm (ES) is a syndrome characterized by recurrent ventricular fibrillation or tachycardia. It is a major clinical challenge and is often unresponsive to conventional drug therapy; instead, its treatment requires multiple attempts at electrical defibrillation. Sympathetic hyperactivity is an important modulator of ventricular arrhythmias, including ES. We report a case of ES treated safely and effectively with pharmacologic sympathectomy involving diagnostic continuous stellate ganglion blockade with local anesthetic followed by therapeutic neurolysis. This technique reduced ES in a patient for whom conservative medical and interventional procedures were ineffective. PMID- 25730410 TI - General anesthesia for adults with mitochondrial myopathy. AB - We report the case of a 59-year-old woman with mitochondrial myopathy who underwent elective laparoscopic cholecystectomy and hemorrhoidectomy, and we review the literature discussing general anesthesia for adults with mitochondrial myopathy. Our management technique avoids neuromuscular-blocking drugs and uses a modified awake intubation method not previously described in such patients. We hope to improve patient safety by discussing evidence-based anesthetic concerns and complications specific to these uncommon patients and aid practitioners in devising a suitable anesthetic plan. PMID- 25730411 TI - Retrograde type A aortic dissection after thoracoabdominal aneurysm repair: early diagnosis with intraoperative transesophageal echocardiography. AB - Retrograde type A aortic dissection that arises immediately after open replacement of the thoracoabdominal aorta is a rare and potentially lethal complication that has only been reported twice previously. A 74-year-old man with a history of expanding Crawford type I thoracoabdominal aortic aneurysm presented for open surgical repair. The intraoperative course was unremarkable. However, intraoperative transesophageal echocardiography after the repair revealed type A aortic dissection extending up to the sinotubular junction. Subsequently, emergent aortic arch repair was performed under deep hypothermic circulatory arrest. Early diagnosis with transesophageal echocardiography and optimal cerebral protection were instrumental in the successful outcome of this repair. PMID- 25730412 TI - Polyethylene glycols (PEG) and related structures: overlooked allergens in the perioperative setting. AB - We describe hypersensitivity to polyethylene glycols (PEGs), with cross reactivity to a structural analog, polysorbate 80, in a 69-year-old patient with perioperative anaphylaxis and subsequent, severe anaphylactic reactions to unrelated medical products. PEGs and PEG analogs are prevalent in the perioperative setting, contained in a wide range of products seldom suspected of causing hypersensitivity reactions and thus rarely documented in surgical/anesthetic records. We suggest routine testing for PEGs after perioperative anaphylaxis because exposure to these polymers often is significant. Comprehensive brand name documentation on the anesthetic chart of all product exposures is central to identifying the responsible allergen. PMID- 25730413 TI - Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health. AB - Periconceptional environment may influence embryo development, ultimately affecting adult health. Here, we review the rodent model of maternal low-protein diet specifically during the preimplantation period (Emb-LPD) with normal nutrition during subsequent gestation and postnatally. This model, studied mainly in the mouse, leads to cardiovascular, metabolic and behavioural disease in adult offspring, with females more susceptible. We evaluate the sequence of events from diet administration that may lead to adult disease. Emb-LPD changes maternal serum and/or uterine fluid metabolite composition, notably with reduced insulin and branched-chain amino acids. This is sensed by blastocysts through reduced mammalian target of rapamycin complex 1 signalling. Embryos respond by permanently changing the pattern of development of their extra-embryonic lineages, trophectoderm and primitive endoderm, to enhance maternal nutrient retrieval during subsequent gestation. These compensatory changes include stimulation in proliferation, endocytosis and cellular motility, and epigenetic mechanisms underlying them are being identified. Collectively, these responses act to protect fetal growth and likely contribute to offspring competitive fitness. However, the resulting growth adversely affects long-term health because perinatal weight positively correlates with adult disease risk. We argue that periconception environmental responses reflect developmental plasticity and 'decisions' made by embryos to optimise their own development, but with lasting consequences. PMID- 25730414 TI - Metal hybrid nanoparticles for catalytic organic and photochemical transformations. AB - In order to understand heterogeneous catalytic reactions, model catalysts such as a single crystalline surface have been widely studied for many decades. However, catalytic systems that actually advance the reactions are three-dimensional and commonly have multiple components including active metal nanoparticles and metal oxide supports. On the other hand, as nanochemistry has rapidly been developed and been applied to various fields, many researchers have begun to discuss the impact of nanochemistry on heterogeneous catalysis. Metal hybrid nanoparticles bearing multiple components are structurally very close to the actual catalysts, and their uniform and controllable morphology is suitable for investigating the relationship between the structure and the catalytic properties in detail. In this Account, we introduce four typical structures of metal hybrid nanoparticles that can be used to conduct catalytic organic and photochemical reactions. Metal@silica (or metal oxide) yolk-shell nanoparticles, in which metal cores exist in internal voids surrounded by thin silica (or metal oxide) shells, exhibited extremely high thermal and chemical stability due to the geometrical protection of the silica layers against the metal cores. The morphology of the metal cores and the pore density of the hollow shells were precisely adjusted to optimize the reaction activity and diffusion rates of the reactants. Metal@metal oxide core-shell nanoparticles and inverted structures, where the cores supported the shells serving an active surface, exhibited high activity with no diffusion barriers for the reactants and products. These nanostructures were used as effective catalysts for various organic and gas-phase reactions, including hydrogen transfer, Suzuki coupling, and steam methane reforming. In contrast to the yolk- and core-shell structures, an asymmetric arrangement of distinct domains generated acentric dumbbells and tipped rods. A large domain of each component added multiple functions, such as magnetism and light absorption, to the catalytic properties. In particular, metal-semiconductor hybrid nanostructures could behave as effective visible photocatalysts for hydrogen evolution and CO oxidation reactions. Resulting from the large surface area and high local concentration of the reactants, a double-shell hollow structure showed reaction activities higher than those of filled nanoparticles. The introduction of plasmonic Au probes into the Pt-CdS double-shell hollow particles facilitated the monitoring of photocatalytic hydrogen generation that occurred on an individual particle surface by single particle measurements. Further development of catalysis research using well-defined metal hybrid nanocatalysts with various in situ spectroscopic tools provides a means of maximizing catalytic performances until they are comparable to or better than those of homogeneous catalysts, and this would have possibly useful implications for industrial applications. PMID- 25730416 TI - Examining the relationship between cue-induced craving and actual smoking. AB - Smoking cue-reactivity studies have consistently demonstrated heightened self report craving, as well as moderate autonomic reactivity, among smokers exposed to salient drug-related cues. However, significantly fewer studies have examined whether exposure to smoking cues affects smokers' actual smoking, or examined the predictive relationship between cue-induced craving and smoking behavior. Using our well-tested pictorial cues in a cue-reactivity paradigm, we investigated the impact of smoking-related cues relative to neutral cues on subjective craving and smoking behavior (assessed via CReSS; Plowshare Technologies, Baltimore, MD) measures of latency to smoke, puff volume, and number of puffs). Further, we examined the predictive value of cue-induced craving on subsequent smoking behavior. Sixty nondeprived daily smokers completed 2 experimental sessions involving exposure to either smoking-related or neutral pictorial cues. Following initial exposure to cues, smokers rated their craving and were then allowed to smoke freely if they chose to during a subsequent 6-min cue exposure period. Result showed that exposure to smoking cues relative to neutral predicted significantly greater craving and increases in smoking behavior. Likewise, the magnitude of the difference in cue-induced craving when exposed to smoking cues relative to neutral cues (i.e., the cue-reactivity effect) was highly predictive of shorter latency to smoke, as well as increased number of puffs and puff volume. PMID- 25730415 TI - Effects of tryptophan depletion and a simulated alcohol binge on impulsivity. AB - Researchers have suggested binge drinkers experience disproportionate increases in impulsivity during the initial period of drinking, leading to a loss of control over further drinking, and that serotonergic mechanisms may underlie such effects. We examined the effects of a simulated alcohol binge and tryptophan depletion on 3 types of impulsivity-response initiation (immediate memory task [IMT]), response inhibition (GoStop task), and delay discounting (single key impulsivity paradigm [SKIP])-and tested whether observed effects were related to real-world binging. Adults (N = 179) with diverse drinking histories completed a within-subject crossover design over 4 experimental days. Each day, participants underwent 1 of 4 test conditions: tryptophan depletion/alcohol, tryptophan depletion/placebo, tryptophan-balanced control/alcohol, or tryptophan-balanced control/placebo. The simulated binge involved consuming 0.3 g/kg of alcohol at 5, 6, and 7 hr after consuming the tryptophan-depletion/balanced mixture. Impulsivity was measured before and after each drink. Relative to the placebo beverage condition, when alcohol was consumed, impulsive responding was increased at moderate and high levels of intoxication on the IMT and the GoStop but only at high levels of intoxication on the SKIP. Tryptophan depletion had no effect on impulsivity. Effects of alcohol and tryptophan manipulations on impulsivity were unrelated to patterns of binge drinking outside the laboratory. The effects of alcohol consumption on impulsivity depend on the component of impulsivity and the dose of alcohol consumed. Such effects do not appear to be a result of reduced serotonin synthesis. In addition, real-world binge drinking behaviors were unrelated to behavioral changes observed in the laboratory. PMID- 25730417 TI - Does impulsiveness moderate response to financial incentives for smoking cessation among pregnant and newly postpartum women? AB - We examined whether impulsiveness moderates response to financial incentives for cessation among pregnant smokers. Participants were randomized to receive financial incentives delivered contingent on smoking abstinence or to a control condition wherein incentives were delivered independent of smoking status. The study was conducted in two steps: First, we examined associations between baseline impulsiveness and abstinence at late pregnancy and 24-weeks-postpartum as part of a planned prospective study of this topic using data from a recently completed, randomized controlled clinical trial (N = 118). Next, to increase statistical power, we conducted a second analysis collapsing results across that recent trial and two prior trials involving the same study conditions (N = 236). Impulsivity was assessed using a delay discounting (DD) of hypothetical monetary rewards task in all three trials and Barratt Impulsiveness Scale (BIS) in the most recent trial. Neither DD nor BIS predicted smoking status in the single or combined trials. Receiving abstinence-contingent incentives, lower baseline smoking rate, and a history of quit attempts prepregnancy predicted greater odds of antepartum abstinence across the single and combined trials. No variable predicted postpartum abstinence across the single and combined trials, although a history of antepartum quit attempts and receiving abstinence-contingent incentives predicted in the single and combined trials, respectively. Overall, this study provides no evidence that impulsiveness as assessed by DD or BIS moderates response to this treatment approach while underscoring a substantial association of smoking rate and prior quit attempts with abstinence across the contingent incentives and control treatment conditions. PMID- 25730419 TI - Intramolecular rearrangement of alpha-azidoperoxides: an efficient synthesis of tert-butyl esters. AB - An unprecedented intramolecular rearrangement of alpha-azidoperoxides, promoted by simple organic base to provide tert-butyl esters, has been presented. Further, a one-pot methodology consisting of in situ generation of the alpha azidoperoxides from corresponding aldehydes followed by base-promoted rearrangement to obtain the desired ester has also been executed. Relevant mechanistic studies, to provide the proof for intramolecular alkoxy transfer, are investigated. PMID- 25730418 TI - Alcohol-related and negatively valenced cues increase motor and oculomotor disinhibition in social drinkers. AB - Our aim in the present study was to investigate the psychological mechanisms that underlie the disinhibiting effects of alcohol cues in social drinkers by contrasting motor and oculomotor inhibition after exposure to alcohol-related, emotional, and neutral pictures. We conducted 2 studies in which social drinkers completed modified stop-signal (laboratory) and antisaccade (online) tasks in which positive, negative, alcohol-related, and neutral pictures were embedded. We measured cue-specific disinhibition in each task, and investigated whether sex and drinking status moderated the effects of pictures on disinhibition. Across both studies, comparable increases in disinhibition were observed in response to both alcohol and negatively valenced pictures, relative to both positive and neutral pictures. These differences in disinhibition could not be explained by differences between picture sets in arousal or valence ratings. There was no clear evidence of moderation by sex or drinking status. Secondary analyses demonstrated that alcohol-specific disinhibition was not reliably associated with individual differences in alcohol consumption or craving. These results suggest that the disinhibiting properties of alcohol-related cues cannot be attributed solely to their valence or arousing properties, and that alcohol cues may have unique disinhibiting properties. PMID- 25730420 TI - Geniposide protects against acute alcohol-induced liver injury in mice via up regulating the expression of the main antioxidant enzymes. AB - Geniposide (GP) is one of main compounds in Gardenia jasminoides Ellis, with both medicinal and nutritional value. This study was designed to determine, for the first time, how GP from G. jasminoides protects against acute alcohol-induced liver injury, and the underlying mechanisms. Mice were orally administered alcohol (6.0 g/kg body mass) 2 h after intragastric administration of GP and bifendate, every day for 7 continuous days. Six hours after the alcohol was administered, levels of serum alanine/aspartate transaminase (ALT/AST), hepatic lipid peroxidation (LPO), glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), copper- and zinc-containing superoxide dismutase (CuZn-SOD), and catalase (CAT), and mRNA expression of CuZn-SOD and CAT were assayed. The results demonstrated that GP (20.0, 40.0, or 80 mg/kg) significantly reversed the excessive, alcohol-induced elevation in both serum ALT/AST and hepatic LPO levels. Moreover, hepatic GSH, GST, GPx, CuZn-SOD, and CAT levels were all decreased in the alcohol-treated mice, whereas treatment with GP reversed these decreases. Further analysis indicated that hepatic mRNA expression of CuZn-SOD and CAT in the alcohol-treated mice was significantly down-regulated, whereas GP up-regulated such decreases. Taken together, this study shows that GP protects against acute alcohol-induced liver injury via up-regulating the expression of the main antioxidant enzymes, and thus ameliorates alcohol-induced oxidative stress injury in the liver. PMID- 25730421 TI - Discovery of core biotic stress responsive genes in Arabidopsis by weighted gene co-expression network analysis. AB - Intricate signal networks and transcriptional regulators translate the recognition of pathogens into defense responses. In this study, we carried out a gene co-expression analysis of all currently publicly available microarray data, which were generated in experiments that studied the interaction of the model plant Arabidopsis thaliana with microbial pathogens. This work was conducted to identify (i) modules of functionally related co-expressed genes that are differentially expressed in response to multiple biotic stresses, and (ii) hub genes that may function as core regulators of disease responses. Using Weighted Gene Co-expression Network Analysis (WGCNA) we constructed an undirected network leveraging a rich curated expression dataset comprising 272 microarrays that involved microbial infections of Arabidopsis plants with a wide array of fungal and bacterial pathogens with biotrophic, hemibiotrophic, and necrotrophic lifestyles. WGCNA produced a network with scale-free and small-world properties composed of 205 distinct clusters of co-expressed genes. Modules of functionally related co-expressed genes that are differentially regulated in response to multiple pathogens were identified by integrating differential gene expression testing with functional enrichment analyses of gene ontology terms, known disease associated genes, transcriptional regulators, and cis-regulatory elements. The significance of functional enrichments was validated by comparisons with randomly generated networks. Network topology was then analyzed to identify intra- and inter-modular gene hubs. Based on high connectivity, and centrality in meta modules that are clearly enriched in defense responses, we propose a list of 66 target genes for reverse genetic experiments to further dissect the Arabidopsis immune system. Our results show that statistical-based data trimming prior to network analysis allows the integration of expression datasets generated by different groups, under different experimental conditions and biological systems, into a functionally meaningful co-expression network. PMID- 25730422 TI - Oxidative damage of U937 human leukemic cells caused by hydroxyl radical results in singlet oxygen formation. AB - The exposure of human cells to oxidative stress leads to the oxidation of biomolecules such as lipids, proteins and nuclei acids. In this study, the oxidation of lipids, proteins and DNA was studied after the addition of hydrogen peroxide and Fenton reagent to cell suspension containing human leukemic monocyte lymphoma cell line U937. EPR spin-trapping data showed that the addition of hydrogen peroxide to the cell suspension formed hydroxyl radical via Fenton reaction mediated by endogenous metals. The malondialdehyde HPLC analysis showed no lipid peroxidation after the addition of hydrogen peroxide, whereas the Fenton reagent caused significant lipid peroxidation. The formation of protein carbonyls monitored by dot blot immunoassay and the DNA fragmentation measured by comet assay occurred after the addition of both hydrogen peroxide and Fenton reagent. Oxidative damage of biomolecules leads to the formation of singlet oxygen as conformed by EPR spin-trapping spectroscopy and the green fluorescence of singlet oxygen sensor green detected by confocal laser scanning microscopy. It is proposed here that singlet oxygen is formed by the decomposition of high-energy intermediates such as dioxetane or tetroxide formed by oxidative damage of biomolecules. PMID- 25730424 TI - Chitosan finishing nonwoven textiles loaded with silver and iodide for antibacterial wound dressing applications. AB - Polyethylene terephtalate (PET) and Polypropylene (PP) textiles are widely used in biomedical application such as wound dressings and implants. The aim of this work was to develop an antibacterial chitosan (CHT) coating activated by silver or by iodine. Chitosan was immobilized onto PET and PP supports using citric acid (CTR) as a crosslinking agent through a pad-dry-cure textile finishing process. Interestingly, depending on the CHT/CTR molar ratio, two different systems were obtained: rich in cationic ammonium groups when the CTR concentration was 1%w/v, and rich in anionic carboxylate groups when the CTR concentration was 10%w/v. As a consequence, such samples could be selectively loaded with iodine and silver nitrate, respectively.Both types of coatings were analyzed using SEM and FTIR, their sorption capacities were evaluated toward iodide/iodate anions (I(-)/IO3( )) and the silver cations (Ag(+)) were evaluated using elemental analysis. Finally, in vitro evaluations were carried out to evaluate the cytocompatibility on the epithelial cell line. The silver loaded textile reported a stronger antibacterial effect against E.coli (5 log10 reduction) than toward S. aureus (3 log10) while the antibacterial effect of the iodide loaded textiles was limited to 1 log10 to 2 log10 on both strains. PMID- 25730423 TI - Aided and unaided speech perception by older hearing impaired listeners. AB - The most common complaint of older hearing impaired (OHI) listeners is difficulty understanding speech in the presence of noise. However, tests of consonant identification and sentence reception threshold (SeRT) provide different perspectives on the magnitude of impairment. Here we quantified speech perception difficulties in 24 OHI listeners in unaided and aided conditions by analyzing (1) consonant-identification thresholds and consonant confusions for 20 onset and 20 coda consonants in consonant-vowel-consonant (CVC) syllables presented at consonant-specific signal-to-noise (SNR) levels, and (2) SeRTs obtained with the Quick Speech in Noise Test (QSIN) and the Hearing in Noise Test (HINT). Compared to older normal hearing (ONH) listeners, nearly all unaided OHI listeners showed abnormal consonant-identification thresholds, abnormal consonant confusions, and reduced psychometric function slopes. Average elevations in consonant identification thresholds exceeded 35 dB, correlated strongly with impairments in mid-frequency hearing, and were greater for hard-to-identify consonants. Advanced digital hearing aids (HAs) improved average consonant-identification thresholds by more than 17 dB, with significant HA benefit seen in 83% of OHI listeners. HAs partially normalized consonant-identification thresholds, reduced abnormal consonant confusions, and increased the slope of psychometric functions. Unaided OHI listeners showed much smaller elevations in SeRTs (mean 6.9 dB) than in consonant-identification thresholds and SeRTs in unaided listening conditions correlated strongly (r = 0.91) with identification thresholds of easily identified consonants. HAs produced minimal SeRT benefit (2.0 dB), with only 38% of OHI listeners showing significant improvement. HA benefit on SeRTs was accurately predicted (r = 0.86) by HA benefit on easily identified consonants. Consonant-identification tests can accurately predict sentence processing deficits and HA benefit in OHI listeners. PMID- 25730425 TI - Characterization of Bronsted acid-base complexes by 19F DOSY. AB - A (19)F DOSY protocol for the determination of formula weights for acid-base complexes in solution has been developed. (19)F internal standards were chosen and were used to evaluate the formula weights of complexes in solution using simple diffusion coefficient (D)-formula weight (FW) analysis. This method has potential applications in characterization of reactive intermediates in catalytic asymmetric reactions. PMID- 25730426 TI - Do symptoms of pelvic floor disorders bias maternal recall of obstetrical events up to 10 years after delivery? AB - OBJECTIVES: The aim of this prospective study was to investigate whether symptoms of incontinence and prolapse bias maternal recall of obstetrical events up to 10 years after delivery. METHODS: In this secondary analysis of data gathered from the Mothers' Outcomes After Delivery study, we compared obstetrical medical records with maternal recall of delivery events. We calculated the agreement between maternal recall and the medical record across 1821 deliveries from 1011 participants for events including macrosomia, mode of delivery, prolonged second of labor, episiotomy, spontaneous laceration, anal sphincter laceration, and operative delivery. Women with symptomatic pelvic floor disorders were identified through administration of the Epidemiology of Prolapse and Incontinence Questionnaire or a clinical history of therapy for a pelvic floor disorder. We determined whether agreement between maternal recall and the medical record differed for those with or without symptoms using the medical record as a criterion standard. RESULTS: Agreement between maternal recall and the medical record was excellent for macrosomia and forceps deliveries (kappa > 0.8), fair to good for episiotomy (kappa = 0.61) and anal sphincter laceration (kappa = 0.57), and poor for spontaneous perineal laceration (kappa = 0.41). Symptomatic pelvic floor disorders did not impact maternal recall of macrosomia, prolonged second stage, episiotomy, spontaneous laceration, or operative delivery. However, recall of anal sphincter lacerations was biased by symptoms of pelvic floor disorders. Specifically, symptomatic women were significantly more likely to report a history of anal sphincter laceration, regardless of whether a sphincter laceration was documented (P = 0.025). CONCLUSIONS: Maternal recall of anal sphincter laceration may be biased by symptomatic pelvic floor disorders. In research based on maternal recall of obstetrical events, this could strengthen the apparent association between sphincter laceration and pelvic floor disorders. PMID- 25730427 TI - Effective treatment of dyssynergic defecation using sacral neuromodulation in a patient with cerebral palsy. AB - BACKGROUND: Dyssynergic defecation is a complex bowel problem that leads to chronic constipation and abdominal pain. Management is often challenging owing to the incoordination of multiple pelvic floor muscles involved in normal defecation. CASE: We report a case of dyssynergic defecatory dysfunction in a patient with cerebral palsy treated with sacral neuromodulation. At presentation, Sitz marker study and magnetic resonance defecography showed evidence of chronic functional constipation. Anorectal manometry, rectal anal inhibitory reflex, and rectal sensation study showed intact reflex and decreased first sensation of lower canal at 50 mL. After stage 2 of InterStim implant placement, bowel habits improved to once- to twice-daily soft solid bowel movements from no regular solid bowel movements. Fecal incontinence improved from daily liquid and small solid loss to no stool leakage. CONCLUSIONS: In patients with systemic medical problems contributing to defecatory dysfunction and bowel incontinence, such as cerebral palsy, sacral neuromodulation was found to provide significant relief of bowel symptoms in addition to associated abdominal pain. As a result of intervention, the patient reported significant improvement in quality of life and less limitations due to dyssynergic defecation. PMID- 25730428 TI - A novel approach to recurrent vaginal vault prolapse in a patient with mullerian agenesis. AB - BACKGROUND: Vaginal agenesis is a congenital disorder affecting 1 in 4000 to 1 in 10,000 females. Lack of normal vaginal support structures may lead these patients to develop prolapse of the distal rudimentary vagina. Presently, there is no consensus regarding the best surgical option. However, the goal of surgery is to restore normal anatomy and establish normal sexual function. CASE: We report the case of a 28-year-old woman with mullerian agenesis, diagnosed at age 19 years, who presented with complaints of dyspareunia and vaginal eversion. One year before presentation to our practice, the patient underwent an anterior and posterior repair with mesh and a transobturator sling. After careful evaluation, the patient underwent excision of mesh and a second procedure to elongate and suspend her vagina. Her vaginal length was extended from 4 to 8 cm. CONCLUSIONS: Prolapse of the neovagina in mullerian agenesis is a rare event; it can occur after nonsurgical or surgical treatments. Although there have been reported cases of abdominal or laparoscopic sacrocolpopexy to correct vaginal vault prolapse in these patients, there is a scarcity of information addressing the vault suspension in cases lacking healthy vaginal tissue. Our case shows how successful anatomical functional correction can be achieved with a simpler technique using an allograft to achieve a normal vaginal length in combination with a sacrocolpopexy. PMID- 25730429 TI - Ultrasound Evaluation of Midurethral Sling Position and Correlation to Physical Examination and Patient Symptoms. AB - OBJECTIVE: The primary objective was to evaluate the position and angle variation between 3 different midurethral slings (MUSs) using 3-dimensional ultrasound (US) technology. The secondary objective was to compare differences in findings on physical examination and symptoms of incontinence and sexual dysfunction between subjects. METHODS: This was a cross-sectional study of 61 subjects who had undergone MUS placement without concomitant anterior or apical compartment prolapse surgery (21 retropubic [RP], 19 out-to-in transobturator [TOT], 21 in-to out transobturator [TVT-O]). Subjects completed validated questionnaires (Sandvik Incontinence Severity Index, Urogenital Distress Inventory 6) and underwent a pelvic examination and standardized 2-dimensional and 3-dimensional ultrasonography evaluation. RESULTS: On translabial US, the median RP sling angle was 108.2 degrees (72.6-135.9), significantly more acute than the angle of TOT and TVT-O slings (119.3 degrees [72.3-140.4, P = 0.02] and 118.5 degrees [99.0 154.7, P = 0.004]). There was no difference in the sling angles between the TOT and TVT-O slings (P = 0.86). No difference was noted in the position of the sling along the urethra (P = 0.82). The TOT sling was more often palpable (57.8%, P = 0.02) compared with the RP or TVT-O groups.Fifteen patients (4 RP, 5 TOT, 6 TVT O) reported discomfort during intercourse that they attributed to the MUS. Three of 19 TOT subjects reported that their partner experienced pain with intercourse because of the sling. However, sexual function and urinary symptoms were not statistically different between the 3 groups. CONCLUSIONS: On 3-dimensional US, RP sling angle was found to be significantly more acute than the angles of the TOT and TVT-O slings, and there was no difference between the 2 transobturator slings. The TOT sling was more often palpable on examination, but this finding did not correlate with increased pain on palpation. PMID- 25730430 TI - Reproducibility of intra-abdominal pressure measured during physical activities via a wireless vaginal transducer. AB - AIMS: In the urodynamics laboratory setting, a wireless pressure transducer, developed to facilitate research exploring intra-abdominal pressure (IAP) and pelvic floor disorders, was highly accurate. We aimed to study reproducibility of IAP measured using this transducer in women during activities performed in an exercise science laboratory. METHODS: Fifty-seven women (mean +/- SD, age 30.4 +/ 9.3 years; body mass index, 22.4 +/- 2.68 kg/m) completed 2 standardized activity sessions using the same transducer at least 3 days apart. Pressure data for 31 activities were transmitted wirelessly to a base station and analyzed for mean net maximal IAP, area under the curve, and first moment of the area. Activities included typical exercises, lifting 13.6 to 18.2 kg, and simulated household tasks. Analysis for test-retest reliability included Bland-Altman plots with absolute limits of agreement, Wilcoxon signed rank tests to assess significant differences between sessions, intraclass correlations, and kappa statistics to assess intersession agreement in highest versus other quintiles of maximal IAP. RESULTS: Few activities exhibited significant differences between sessions in maximal IAP, or in area under the curve and first moment of the area values. For 13 activities, the agreement between repeat measures of maximal IAP was better than +/-10 cm H20; for 20 activities, better than +/-15 cm H20. The absolute limits of agreement increased with mean IAP. The highest quintile of IAP demonstrated fair/substantial agreement between sessions in 25 of 30 activities. CONCLUSIONS: Reproducibility of IAP depends on the activity undertaken. Interventions geared toward lowering IAP should account for this, maximize efforts to improve IAP reproducibility. PMID- 25730431 TI - Internet Use Among Urogynecology Patients in North Carolina. AB - OBJECTIVES: Given limited information regarding digital technology use among patients, we sought to evaluate Internet use among younger (<65 years) as compared to older (>=65 years) women and to assess factors associated with Internet use. METHODS: We administered an anonymous questionnaire on digital technology use to English-speaking women who presented to our Urogynecology practice during a 1-month period. The questionnaire assessed the following sociodemographics: age, race, education, income, and insurance status. For our primary outcome, we assessed Internet use among younger versus older women. We also conducted a logistic regression analysis to evaluate the association of age with Internet use, while adjusting for potential confounders. RESULTS: A total of 556 women presented during the study period. Among these women, 506 completed the survey, for a 91% response rate. There were 282 (55.7%) younger women and 222 (43.9%) older women. Most of the younger and older cohorts were white (77% vs 86.5%, P = 0.02). Younger women were more educated (79.8% vs 59.5% >= college education; P < 0.0001) and had a higher income (58.3% vs 39.8% >= $50,000; P < 0.0001). For our primary outcome, younger women were significantly more likely to use the Internet (93.8% vs 66.3%, P < 0.001). In a logistic regression model which adjusted for age, race, education, and income, younger women remained significantly more likely to use the Internet (odds ratio, 6.6; 95% CI, 3.4 13.0). CONCLUSIONS: Although women younger than 65 years reported greater Internet use when compared to women 65 years or older, most of older women also used the Internet. PMID- 25730432 TI - Physician Attitudes Toward Urinary Incontinence Identification. AB - Urinary incontinence (UI) is a prevalent condition. Urinary incontinence impacts health, quality of life, and financial resources. Most barriers research is evaluated from the patient perspective. Research from physician perspective is needed to determine how best to address UI barriers. OBJECTIVE: This study aimed to elucidate physician barriers to UI identification and treatment. METHODS: After institutional review board waiver, we surveyed 78 NorthShore University HealthSystem primary care physicians. The survey was designed to assess physician comfort, familiarity with UI, and current practice patterns. RESULTS: Fifty-five (71%) of the 78 physicians completed the survey. Most indicated that they clearly understood UI and that UI was a common problem in their practice. Fifty-six percent of the physicians were very comfortable inquiring about UI. Only 19% of the physicians were very comfortable diagnosing UI and 11% of the physicians were very comfortable treating UI. Fifty-nine percent of the physicians agreed that differentiating the different types of UI is difficult and 69% of the physicians believed that managing UI is difficult. However, only 26% of the physicians agreed that managing UI takes too much time. Overall, 65% of the physicians would like to diagnose and treat UI more in their practices. The most common barriers listed were (1) "not familiar with algorithm available for treatment," (2) "no good screening tool," and (3) "uncomfortable with diagnosis and treatment." CONCLUSIONS: We initially thought that time would be the biggest barrier to care for UI, but we identified discomfort with diagnosis and treatment as barriers. The most common barrier was the lack of an accessible algorithm. Attention to physician education implementation of a screening tool algorithm for treatment of UI could improve UI identification. PMID- 25730433 TI - Urinary Incontinence Due to Urethral Coitus in a Multiparous Woman. AB - Urethral coitus in women with a normal vagina and introitus has very rarely been reported. We report the case of a 48-year-old gravida 5, para 5 woman with a history of urethral coitus complaining of urinary incontinence. To the best of our knowledge, our patient is the fifth reported case of urethral coitus with normal genitalia, and it might be accepted as the first reported case of urethral coitus in a multiparous woman. PMID- 25730434 TI - Uretero-Uterine Fistula: Delayed Presentation After Ureteral Reimplantation for Vesicoureteral Reflux. AB - Primary cyclic hematuria occurring with the onset of menstruation can be a presenting symptom of a fistula between the Mullerian structures (uterus/cervix/upper vagina) and the urinary tract. When occurring, these fistulas are most often vesicovaginal connections caused by congenital Mullerian anomalies. We present a case of a fistula occurring between a bicornuate uterus and the ureteral stump that had been ligated at the time of ureteral reimplantation during childhood. The presenting symptom was cyclic hematuria beginning at the age of 14 years with the onset of menarche. Cystoscopy and retrograde pyelogram showed a fistula connecting the ureteral stump (which had been ligated at the time of ureteral reimplantation) to the small horn of the bicornuate uterus. Computed tomographic scan showed bilateral single orthotopic kidneys and collecting systems. The patient underwent successful transvaginal and transvesical surgical repair of the fistula, with complete resolution of her cyclic hematuria. We review genitourinary embryology in discussion of this unusual case. PMID- 25730435 TI - Cost utility analysis of urethral bulking agents versus midurethral sling in stress urinary incontinence. AB - OBJECTIVE: The aim of this study was to determine the cost utility of urethral bulking agents (BA) compared with midurethral slings (MUS) in the treatment of stress urinary incontinence (SUI) in patients without urethral hypermobility. METHODS: A decision tree was constructed to compare the cost utility of urethral BA versus MUS in the setting of SUI without urethral hypermobility. Probability estimates for success, failure, and complications were obtained from the published literature. Immediate-term, short-term, and longer-term complications were accounted for over a 1-year time horizon in the model. One-way and 2-way sensitivity analyses and Monte Carlo simulations were performed to assess the robustness of our results. RESULTS: Our model demonstrated that MUS cost $436,465 more than BA for every 100 women treated in 1 year. Using MUS compared with BA leads to an incremental cost-effectiveness ratio of $70,400 per utility gained. Assuming a willingness to pay of $50,000, this makes MUS not cost-effective as a first-line treatment in many situations. When MUS costs less than $5132, it becomes a cost-effective first-line treatment, and when it costs less than $2035, it is cost saving. CONCLUSIONS: Bulking agents are more cost-effective than MUS over a 1-year time horizon in the treatment of SUI in patients without urethral hypermobility. In women who lack urethral hypermobility, BA remain a cost effective option in this patient population. PMID- 25730436 TI - Complexity and confusion in female pelvic medicine and reconstructive surgery: creating a paradigm for increasing patient understanding and assessment. PMID- 25730437 TI - Levatorplasty for Symptomatic Posterior Prolapse due to Recurrent Malignant Ascites. AB - BACKGROUND: Although infrequently described, massive ascites due to malignancy contributes to symptomatic pelvic organ prolapse. CASE: A 73-year-old woman with recurrent ovarian cancer and massive ascites underwent a levatorplasty for repair of posterior prolapse after failing conservative management. CONCLUSIONS: Management of patient with cancer with prolapse is complex. Patients with cancer with ascites also have pelvic organ prolapse, in addition to other, better described sequelae of increased intra-abdominal pressure. These patients should be treated specifically for prolapse, with therapy, including type of surgery, chosen with special consideration of their underlying disease. PMID- 25730438 TI - Practice patterns regarding management of rectovaginal fistulae: a multicenter review from the Fellows' Pelvic Research Network. AB - OBJECTIVES: Rectovaginal fistulae (RVFs) are often debilitating and there are no established treatment algorithms. We sought to describe current diagnosis and management strategies for RVFs across the United States. METHODS: This institutional review board-approved multicenter retrospective study included 12 sites. Cases were identified using International Classification of Diseases, Ninth Revision codes during a 5-year period. Demographics, management, and outcomes of RVF treatment were collected. RESULTS: Three hundred forty-two charts were identified; 176 (52%) met criteria for inclusion. The mean (SD) age was 45 (17) years. Medical history included hypertension (21%), cancer (17%), Crohn disease (11%), and diabetes (7%). Rectovaginal fistulae were often associated with obstetric trauma (42%), infection/inflammation (24%), and cancer (11%). Overall, most RVFs were primary (94%), small (0.5-1.5 cm; 49%), transsphincteric (31%), and diagnosed via vaginal and rectal (60%) examination. Eighteen percent (32/176) were initially managed conservatively for a median duration of 56 days (interquartile range, 29-168) and 66% (21/32) of these resolved. Almost half (45%) of RVFs treated expectantly were tiny (<0.5 cm). Eighty-two percent (144/176) of subjects were initially managed surgically and 81% (117/144) resolved. Procedures included simple fistulectomy with or without Martius graft (59%), transsphincteric repair (23%), transverse transperineal repair (10%), and open techniques (8%), and 87% of these procedures were performed by urogynecologists. CONCLUSIONS: In this large retrospective review, most primary RVFs were treated surgically, with a success rate of more than 80%. Two thirds of RVFs managed conservatively resolved spontaneously, and most of these were tiny (<0.5 cm). These success rates can be used in counseling to help our patients make informed decisions about their treatment options. PMID- 25730439 TI - Conformational difference in human IgG2 disulfide isoforms revealed by hydrogen/deuterium exchange mass spectrometry. AB - Both recombinant and natural human IgG2 antibodies have several different disulfide bond isoforms, which possess different global structures, thermal stabilities, and biological activities. A detailed mapping of the structural difference among IgG2 disulfide isoforms, however, has not been established. In this work, we employed hydrogen/deuterium exchange mass spectrometry to study the conformation of three major IgG2 disulfide isoforms known as IgG2-B, IgG2-A1, and IgG2-A2 in two recombinant human IgG2 monoclonal antibodies. By comparing the protection factors between amino acid residues in isoforms B and A1 (the classical form), we successfully identified several local regions in which the IgG2-B isoform showed more solvent protection than the IgG2-A1 isoform. On the basis of three-dimensional structural models of IgG2, these identified regions were located on the Fab domains, close to the hinge, centered on the side where the two Fab arms faced each other in spatial proximity. We speculated that in the more solvent-protected B isoform, the two Fab arms were brought into contact by the nonclassical disulfide bonds, resulting in a more compact global structure. Loss of Fab domain flexibility in IgG2-B could limit its ability to access cell surface epitopes, leading to reduced antigen binding potency. The A2 isoform was previously found to have disulfide linkages similar to those of the classical A1 isoform, but with different biophysical behaviors. Our data indicated that, compared to IgG2-A1, IgG2-A2 had less solvent protection in some heavy-chain Fab regions close the hinge, suggesting that the A2 isoform had more flexible Fab domains. PMID- 25730440 TI - Correlations of Physical Activity, Body Mass Index, Shift Duty, and Selected Eating Habits among Nurses in Riyadh, Saudi Arabia. AB - Nurses are the largest group of direct health providers and can serve as role models for their patients. In this cross sectional study we assessed the relationship among physical activity and barriers, shift duty, elevated BMI, and selected eating habits among 362 non-Saudi female nurses in Riyadh, Saudi Arabia. Results showed that 46.7% were either overweight or obese. Marital status, shift duty, education level, and BMI were significant predictors of physical activity. Weather was the most frequently reported barrier to physical activity (88.3%), followed by a lack of transportation (82.6%), and a lack of time (81.3%). Nurses who worked shift duty had significantly (p = 0.004) higher BMIs compared with day shift nurses. Nurses who rarely ate breakfast (p = 0.004) and meals (p = 0.001) and often eat fast food (p = 0.001) were more likely to be overweight or obese. Nurses should be encouraged for a better healthy lifestyles. PMID- 25730441 TI - Pivotal roles of ILCs in hepatic diseases. AB - Innate lymphoid cells (ILCs) are involved in the development of mucosal associated lymphoid tissues and serve as a rapid and early source of the effector cytokines that are typically associated with the T helper cell subsets in response to pathogen-induced changes in the microenvironment. Recent research has implicated ILCs as potential contributing factors to the spectrum of inflammation related hepatic diseases, particularly hepatitis, fibrosis and carcinoma. In this review, we summarize the current knowledge on the roles of ILCs in these hepatic pathogeneses, providing insights into the underlying cellular and signaling mechanisms to help guide the future research to elucidate the ILCs' characters under normal and diseased conditions and provide interventional targets with therapeutic potential. PMID- 25730442 TI - The role of lipid droplets and adipocytes in cancer. Raman imaging of cell cultures: MCF10A, MCF7, and MDA-MB-231 compared to adipocytes in cancerous human breast tissue. AB - We have studied live non-malignant (MCF10A), mildly malignant (MCF7) and malignant (MDA-MB-231) breast cancer cells and human breast cancer tissue. We demonstrate the first application of Raman imaging and spectroscopy in diagnosing the role of lipid droplets in cell line cultures that closely mimic an in vivo environment of various stages in human breast cancer tissue. We have analyzed the composition of the lipid droplets in non-malignant and malignant human breast epithelial cell lines and discussed the potential of lipid droplets as a prognostic marker in breast cancer. To identify any difference in the lipid droplet-associated biochemistry and to correlate it with different stages of breast cancer, the PCA method was employed. The chemical composition of lipids and proteins, both in the cell line models and in human breast tissue has been analyzed. The paper shows the alterations in lipid metabolism that have been reported in cancer, at both the cellular and tissue levels, and discusses how they contribute to the different aspects of tumourigenesis. PMID- 25730443 TI - Interaction of arginine, lysine, and guanidine with surface residues of lysozyme: implication to protein stability. AB - Additives are widely used to suppress aggregation of therapeutic proteins. However, the molecular mechanisms of effect of additives to stabilize proteins are still unclear. To understand this, we herein perform molecular dynamics simulations of lysozyme in the presence of three commonly used additives: arginine, lysine, and guanidine. These additives have different effects on stability of proteins and have different structures with some similarities; arginine and lysine have aliphatic side chain, while arginine has a guanidinium group. We analyze atomic contact frequencies to study the interactions of the additives with individual residues of lysozyme. Contact coefficient, quantified from contact frequencies, is helpful in analyzing the interactions with the guanidine groups as well as aliphatic side chains of arginine and lysine. Strong preference for contacts to the additives (over water) is seen for the acidic followed by polar and the aromatic residues. Further analysis suggests that the hydration layer around the protein surface is depleted more in the presence of arginine, followed by lysine and guanidine. Molecular dynamics simulations also reveal that the internal dynamics of protein, as indicated by the lifetimes of the hydrogen bonds within the protein, changes depending on the additives. Particularly, we note that the side-chain hydrogen-bonding patterns within the protein differ with the additives, with several side-chain hydrogen bonds missing in the presence of guanidine. These results collectively indicate that the aliphatic chain of arginine and lysine plays a critical role in the stabilization of the protein. PMID- 25730444 TI - Dual-Energy MDCT for Imaging the Renal Mass. AB - OBJECTIVE: The purpose of this article is to provide the reader with a comprehensive overview of dual-energy MDCT applications for imaging renal masses. CONCLUSION: Dual-energy MDCT has the potential to substantially improve the ability of radiologists to diagnose renal masses compared with conventional MDCT, potentially streamlining patients' clinical management. PMID- 25730445 TI - Intraoperative Electrophysiologic Variations Caused by the Scalar Position of Cochlear Implant Electrodes. AB - OBJECTIVE: The position of cochlear implant (CI) electrodes in the cochlea is fundamental for the interaction between the implant and the neurons of the spiral ganglion. The scalar position of the electrode in the cochlea is assumed to be an important parameter for the clinical outcome. In our study, the intraoperative electrophysiologic characteristics in dependence of the position of CI electrodes in the scala tympani or in the scala vestibuli after scalar change should be determined. MATERIALS AND METHODS: The intraoperative impedances and neural response telemetry (NRT) data of 23 patients implanted with a Nucleus Advance Contour (Cochlear Pty, Sydney, Australia) electrode were recorded. One CI surgeon and two radiologists evaluated the electrode array's position independently radiologically by flat-panel tomography. Results from 17 patients with the electrode positioned in the scala tympani and six patients with the electrode changing intraoperatively from the tympanic into the vestibular scala were retrospectively analyzed. RESULTS: We found a statistically significant difference with an NRT threshold-based ratio for the groups. An estimation of the (radiologically confirmed) scalar position based on the NRT ratio was possible retrospectively. CONCLUSION: The evaluation of specific intraoperative electrophysiologic data allowed separating between a regular and an irregular (i.e., scalar changing) position of CI electrodes. This noninvasive methodology can support the postoperative radiologic evaluation of the CI electrode array position. PMID- 25730446 TI - Treatment of chronically infected open mastoid cavities with medical honey: a randomized controlled trial. AB - OBJECTIVE: To investigate the efficacy of medical honey as topical treatment of chronically discharging open mastoid cavities in comparison with conventional eardrops. STUDY DESIGN: Single-center, prospective, randomized controlled, double dose trial of 12 weeks. PATIENTS AND INTERVENTION: Twenty-eight patients diagnosed as having a chronically discharging open mastoid cavity underwent medical honey gel (intervention) or conventional eardrops (control) treatment. Treatment interventions were repeated after 4 weeks. MAIN OUTCOME MEASURES: Visual analogue scale of ear complaints, cavity inflammation, and bacterial infection. RESULTS: Most patients had a cavity with localized granulation. After treatment, inflammation score decreased in both groups (p < 0.05), with more pronounced inflammation-free cavities in the honey group. Honey treatment resulted in less discomfort (p < 0.001) and otorrhea (p < 0.001), even after correction for additional medication use (p < 0.05, p < 0.01). This decrease was not seen in the control group. Pain and itching did not change on treatment. Most cavities were infected with Pseudomonas species and Staphylococcus aureus. After treatment, a 23% increase of negative culture was seen with honey compared with 30% in the control group (nonsignificant). No serious adverse reactions were found. CONCLUSION: Medical honey gel is a safe alternative treatment option for patients with a chronically discharging open mastoid cavity and beneficial in reducing discomfort, otorrhea, and inflammation with a bactericidal effect. PMID- 25730447 TI - Mental Health and Subjective Well-being of Individuals With Meniere's: Cross sectional Analysis in the UK Biobank. AB - HYPOTHESIS: Meniere's disease significantly impacts on an individual's mental health and subjective well-being (SWB). BACKGROUND: Meniere's disease is an unpredictable illness that impacts on mental health. The symptom triad of vertigo, tinnitus, and hearing loss all contribute to the disabling nature of the condition. To date, limited research has investigated the mental health and SWB impact of Meniere's disease. METHODS: We investigated the mental health and SWB of 1,376 Meniere's sufferers in the UK Biobank and compared this to over 500,000 controls. Participants in the Biobank were asked 38 questions pertaining to mental health and SWB. We utilized crude and adjusted linear and logistic regression to investigate the association between Meniere's and mental health and SWB. We also investigated how mental health and SWB might be related to length of diagnosis to see whether people might adapt to Meniere's over time. RESULTS: Meniere's was associated with increased frequency of depression, tiredness, tenseness, and unenthusiasm in the 2 weeks before recruitment. Meniere's was associated with longer periods of depression than controls (10.2 wk [95% CI: 5.2 15.2 wk]). Reduced health satisfaction was associated with Meniere's, but in other aspects of life (general happiness, work, family, friends, financial), individuals with Meniere's were as happy as controls. Mental health and SWB in individuals diagnosed for longer was better than in those who were recently diagnosed suggesting at least partial adaptation. DISCUSSION: This is the largest population study investigating the mental health impact of Meniere's. Our findings suggest that Meniere's adversely impacts on mental health, an individual's emotional state, and their life satisfaction. However, our findings raise the importance of supporting social relations for people with Meniere's and that although a cure is not currently available, we can still learn much about the adaptation strategies developed by long-term sufferers to help individuals with new diagnoses. PMID- 25730448 TI - Comparison of audiologic results and patient satisfaction for two osseointegrated bone conduction devices: results of a prospective study. AB - OBJECTIVE: Osseointegrated bone conduction (BC) devices are an important rehabilitation option for patients with mixed or conductive hearing loss or single-sided deafness. The development of new devices is ongoing and requires evaluation of the performance of new hearing aids. Here, we compared the audiologic outcome and subjective benefit of two different designs of osseointegrated implant systems from different manufacturers. STUDY DESIGN: Prospective, experimental, monocentric, crossover study performed at the Medical University Hannover, Germany. PATIENTS AND INTERVENTIONS: Eleven patients, already implanted with an adequate abutment, tested each device in daily life situations sequentially for a period of 3 weeks. MAIN OUTCOME MEASURES: Bone conduction, word recognition in quiet (Freiburg monosyllable test, L50%), and speech reception thresholds in noise (Oldenburg Sentence Test) were measured unaided and aided with the devices after each test period. The subjective benefit was assessed by the Abbreviated Profile of Hearing Aid Benefit; the Speech, Spatial and Qualities of Hearing Scale-Comparative questionnaire; and a self developed handling questionnaire. RESULTS: Audiologic results indicate a slightly better performance of the BCB. However, subjective benefit and patient satisfaction and preference evaluated with questionnaires were higher with the BCP than with the BCB. CONCLUSION: Amplification-wise, both devices are suitable treatments for hearing-impaired patients. Nevertheless, audiometric tests do not reflect subjective benefit and patients' satisfaction, and both options should be tested to provide each patient with the best possible hearing solution. The study further elucidates the importance and necessity of questionnaires in the process of evaluating the hearing benefit of hearing devices. PMID- 25730449 TI - Reduced Cochlear Implant Performance After the Use of Growth Hormone With Regain of Function After Cessation of Growth Hormone Therapy. AB - OBJECTIVE: To assess whether recombinant growth factor (hGH) therapy has an effect on cochlear implant (CI) performance. PATIENTS: Two pediatric CI recipients (S1, S2) who underwent treatment with hGH for short stature were identified for review. S1 has bilateral labyrinthine dysplasia and received implants at ages 10 months (right) and 4 years 3 months (left). S2 was diagnosed with severe to progressive sensorineural hearing loss bilaterally and received a CI at age 9 years 10 months (left). INTERVENTION(S): Case series. MAIN OUTCOME MEASURE(S): Cochlear implant, hGH, and speech perception data were collected. Phonetically Balanced Kindergarten (PBK) and Consonant Nucleus Consonant (CNC) word recognition scores were reviewed to assess auditory perception. Electrode impedances, threshold levels, and comfort levels were also reviewed. RESULTS: After 4 months of hGH, word recognition scores for S1 were observed to decrease from 90 to 72% (right) and were stable at 40% (left). Despite troubleshooting, performance continued to decline bilaterally to 52% (right) and 28% (left), and the decision was made to discontinue hGH. One month after cessation of hGH, word recognition scores began improving to 74% (right) and 68% (left). Word recognition scores for S2 were observed to have decreased from 92% the previous year to 82% after taking hGH for 2 months. Given both our previous experience with S1 and discussions with S2's parents, hGH was discontinued after 10 months of therapy. Two months after cessation of hGH, S2's word recognition had improved to 86% (left). CONCLUSIONS: Our case studies illustrate that implanted children undergoing treatment with hGH may experience a decrease in speech perception, which recovers after the cessation of treatment. Since hGH use has become more prevalent in recent years, it is important to inquire whether children undergoing, or who have undergone, implantation are receiving hGH so that they may be appropriately monitored. PMID- 25730450 TI - Reply to Dong-Hee Lee's Letter to the Editor RE: Yang F, Zhao Y, An P, et al. Longitudinal Results of Intratympanic Injection of Budesonide for Otitis Media With Effusion in Children Over 12 Years and Adults. Otol Neurotol 2014;35;629-34. PMID- 25730451 TI - Transcutaneous Bone-anchored Hearing Aids Versus Percutaneous Ones: Multicenter Comparative Clinical Study. AB - OBJECTIVE: The aim of this study is to compare the clinical audiological outcomes as well as patient satisfaction of bone-anchored, hearing aid surgery between the percutaneous Dermalock and the transcutaneous Attract systems. STUDY DESIGN AND METHODS: This is a multicenter, retrospective clinical study. The patients who underwent Baha Dermalock and Baha Attract surgery were analyzed for hearing results, surgical complications, and postoperative follow-up specifications for both systems. Speech reception thresholds and bone conduction thresholds with and without aided conditions were evaluated. Patient satisfactions were also determined for both groups by Glasgow Benefit Inventory questionnaire. RESULTS: Both of the groups had some minor complications such as skin irritations around the abutment and skin erythema over the magnet. Both of the groups benefit from the devices audiologically; however, when the groups were compared, better results were observed in the percutaneous, bone-conduction group. CONCLUSION: We can confirm that both transcutaneous and percutaneous techniques are effective in the rehabilitation of conductive hearing loss when conventional hearing aids cannot be used. However, both of the systems have some advantages and limitations in terms of audiological and surgical perspectives. PMID- 25730452 TI - Practical Repair Method for Unilateral Cleft Lips: Straight-Line Advanced Release Technique. AB - BACKGROUND: Straight-line closure repair of unilateral cleft lips was first introduced in the 1840s, and since then, many different techniques have been attempted for cleft repair. However, these methods have several disadvantages and are difficult to adopt. In this study, we describe our novel technique, known as Straight-Line Advanced Release Technique (StART), and its application in treating several cases of unilateral cleft lip. METHODS: The preoperative design of the surgical method is drawn on the skin, the vermilion, and the oral mucosa. A total of 13 points are marked (points 0-12). The A flap, B flap, triangular flap, M (medial mucosal) flap, and L (lateral mucosal) flap are designed. After completion of the preoperative marking, the wide dissection is performed to separate the orbicularis oris muscle completely from the abnormally inserted bony structure and the enveloped skin-mucosal flap. The freed orbicularis oris muscle is then reconstructed with full width. After all planes of the lip wound are closed, a straight vertical skin suture line is achieved without any unnecessary transverse scar. RESULTS: Unilateral cleft lip repair using StART was conducted in 145 patients between 1993 and 2012. Cases of microform cleft lip were excluded. A total of 21 patients (14%) required a secondary operation on the lip after the first unilateral cheiloplasty. In all patients, satisfactory surgical outcomes were obtained with an indistinct straight-lined scar and a well-aligned lip contour. CONCLUSIONS: To acquire a natural and balanced shape in unilateral cleft lip repair, we recommend the novel StART. PMID- 25730453 TI - Comparison of combination therapy (steroid, calcium channel blocker, and interferon) with steroid monotherapy for treating human hypertrophic scars in an animal model. AB - BACKGROUND: Hypertrophic scar (HSc) treatment continues to be a clinical challenge. OBJECTIVE: To evaluate the efficacy of a combined regimen of calcium channel blocker (verapamil), steroid, and interferon in treating HSc. MATERIALS AND METHODS: Ten excised human HSc fragments obtained from surgically treated burn patients were divided into 3 groups: A (no drug), B (steroid, 0.05 mL), and C (verapamil, steroid, and interferon, 0.016 mL each). These specimens were implanted on the backs of nude mice after treatment with intralesional injections of drugs and observed for 4 weeks. Fibroblast proliferation, scar weights, hematoxylin-eosin (HE) staining, fibroblast activity using the fibroblast populated collagen lattice (FPCL) method, and the quantity of collagen were determined to evaluate the efficacy of the treatments. Data were analyzed using analysis of variance. RESULTS: All the implants were removed from animal body 4 weeks later for study. For the fibroblasts activity study, another 10 days of cell culture was done. The viability and proliferation of HSc fibroblasts in group C mice were significantly decreased at 10 days after explantation. The fibroblast numbers in the 3 groups were as follows: (A) 16.6*105; (B) 1.5*105; and (C) 0.4*105 (P<0.05). At 4 weeks after implantation, group C showed the significantly least amount of type I collagen (A, 0.12 MUg/mL; B, 0.07 MUg/mL; C, 0.055 MUg/mL; P<0.05). In the nonimplanted scars, the collagen in group C was 0.4 MUg/mL, less than that in groups B (0.6 MUg/mL) and A (1.7 MUg/mL; P<0.05). Significant differences were observed in reduction of scar weight among the 3 groups (A, 85%; B, 82.3%; C, 78.6%; P<0.05). The combination therapy group, that is, group C, significant inhibition of FPCL contraction and delayed contraction of burn scar fibroblasts compared with the other groups. The FPCL contraction rate at 4 weeks in groups A, B, and C was 15.4%, 65%, and 73.4% of the original size, respectively (P<0.05). CONCLUSIONS: Combined intralesional injection of steroid, verapamil, and interferon exhibits significant therapeutic efficacy than does a single high dose of steroid in the treatment of hypertrophic burn scars. PMID- 25730454 TI - Serum salusin-beta levels are associated with the presence and severity of coronary artery disease. AB - OBJECTIVES: We sought to assess whether serum salusin-beta levels are correlated with the presence and severity of coronary artery disease (CAD). METHODS: We measured serum salusin-beta levels in 278 consecutive patients undergoing coronary angiography (CAG) for the evaluation of CAD and in 126 healthy controls. Serum salusin-beta levels were measured by enzyme-linked immunosorbent assay. The severity of CAD was assessed by angiographic coronary atherosclerosis index score system. RESULTS: Serum salusin-beta levels were significantly higher in patients undergoing CAG (n = 278) than those in healthy controls (n = 126) (3.81 +/- 0.99 vs 4.34 +/- 1.40 nmol/L, P < 0.01). In patients undergoing CAG, patients with CAD (n = 160) had significantly higher serum salusin-beta levels compared to patients without CAD (n = 118) (4.65 +/- 1.44 vs 3.94 +/- 1.23 nmol/L, P < 0.01). Multivariate logistic regression analysis revealed that serum salusin-beta levels were independently associated with the presence of CAD (odds ratio, 1.439; 95% confidence interval, 1.176-1.760; P < 0.01). Serum salusin-beta levels were positively correlated with the coronary atherosclerosis index score (r = 0.316, P < 0.001). CONCLUSIONS: Serum salusin-beta levels were associated with the presence and severity of CAD. Salusin-beta in serum might serve as a potential biomarker for reflecting the development and progression of CAD. Therapeutic treatment by inhibiting salusin-beta interaction to prevent CAD warrants further investigation. PMID- 25730455 TI - Diagnosis of vitamin B12 deficiency in patients with myeloproliferative disorders. AB - BACKGROUND: Myeloproliferative disorders are characterized by proliferation of 1 or more lineage of hematologic cells. Rapid proliferation of cells may lead to depletion of vitamin B12, which may be falsely elevated by conventional assays in these disorders. We evaluated vitamin B12 status with conventional vitamin B12 assay and levels of serum methylmalonic acid (MMA), serum holotranscobalamin (holoTC), and plasma homocysteine in myeloproliferative disorders. METHODS: In 58 patients who had myeloproliferative disorders and normal serum creatinine levels, we measured levels of vitamin B12, MMA, holoTC, and homocysteine. Correlations were evaluated between these tests, with MMA as the reference standard for vitamin B12 deficiency. RESULTS: Prevalence of vitamin B12 deficiency was 69%, despite high serum vitamin B12 levels. Levels of holoTC of 40.6 pmol/L or less and homocysteine of greater than 14 mol/L were the best cutoff levels with sensitivity values of 75% and 70%, specificity values of 80% and 68%, and positive predictive values of 88% and 80%. Logistic regression showed that cutoff values of holoTC of 40.6 pmol/L or less and homocysteine of greater than 14 mol/L resulted in odds ratio 15.5 for low versus high holoTC, and odds ratio 5.4 for high versus low homocysteine, to confirm vitamin B12 deficiency. CONCLUSIONS: Patients who had myeloproliferative disorders had a high prevalence of vitamin B12 deficiency, despite high serum vitamin B12 levels. Therefore, vitamin B12 status should be evaluated in patients with myeloproliferative disorders. Holotranscobalamin level may be the best initial test and may replace vitamin B12 assay to accompany MMA and homocysteine levels. PMID- 25730457 TI - The coexistence of seven sympatric fulvettas in Ailao Mountains, Ejia Town, Yunnan Province. AB - The coexistence of ecologically similar species sharing sympatric areas is a central issue of community ecology. Niche differentiation is required at least in one dimension to avoid competitive exclusion. From 2012-2014, by adopting the methods of mist-nets and point counts to evaluate spatial niche partitioning and morphological differentiations, we explored the coexistence mechanisms of seven sympatric fulvettas in Ailao Mountains, Ejia town, Yunnan Province, China. The microhabitats of these seven fulvettas were significantly different in elevation, roost site height and vegetation coverage, indicating a spatial niche segregation in different levels. Approximately, 90.30% of the samples were correctly classified by linear discriminant analysis (LDA) with correct rates at 91.20% 100%, except the White-browed fulvetta (Alcippe vinipectus) (65.4%) and the Streak-throated fulvetta (A. cinereiceps) (74.6%). The seven fulvettas were classified into four guilds based on their specific morphological characters, suggesting that the species in each guild use their unique feeding ways to realize resource partitioning in the overlapped areas. These finding indicate that through multi-dimensional spatial niche segregation and divergence in resource utilizing, the inter-specific competition among these seven fulvettas is minimized, whereas, coexistence is promoted. PMID- 25730458 TI - Age-related habitat selection by brown forest skinks (Sphenomorphus indicus). AB - In reptiles, habitat selection is the process whereby suitable habitat is selected that optimizes physiological functions and behavioral performance. Here, we used the brown forest skink (Sphenomorphus indicus) as a model animal and examined whether the frequency of active individuals, environmental temperature, illumination of activity area, and habitat type vary with different age classes. We surveyed the number of active individuals and measured environmental variables at Baiyunshan Mountain in Lishui, Zhejiang, China. We found no difference in the activity frequency of adult and juvenile S. indicus; the activity pattern of active individuals was bimodal. The mean environmental temperature selected by adults was higher than that selected by juveniles. The environmental temperature of active areas measured at 0900-1000 h and 1100-1200 h was higher than at 1400 1500 h; illumination of the active area at 1000-1200 h was also higher than at 1400 h-1600 h. The number of active individuals, the environmental temperature and illumination of activity areas showed pairwise positive correlation. There was a difference in habitat type between juveniles and adults whereby juveniles prefer rock habitats. We predict that active S. indicus select optimal habitats with different environmental temperatures and types to reach the physiological needs particular to their age classes. PMID- 25730456 TI - Genomic organization and evolution of ruminant lysozyme c genes. AB - Ruminant stomach lysozyme is a long established model of adaptive gene evolution. Evolution of stomach lysozyme function required changes in the site of expression of the lysozyme c gene and changes in the enzymatic properties of the enzyme. In ruminant mammals, these changes were associated with a change in the size of the lysozyme c gene family. The recent release of near complete genome sequences from several ruminant species allows a more complete examination of the evolution and diversification of the lysozyme c gene family. Here we characterize the size of the lysozyme c gene family in extant ruminants and demonstrate that their pecoran ruminant ancestor had a family of at least 10 lysozyme c genes, which included at least two pseudogenes. Evolutionary analysis of the ruminant lysozyme c gene sequences demonstrate that each of the four exons of the lysozyme c gene has a unique evolutionary history, indicating that they participated independently in concerted evolution. These analyses also show that episodic changes in the evolutionary constraints on the protein sequences occurred, with lysozyme c genes expressed in the abomasum of the stomach of extant ruminant species showing the greatest levels of selective constraints. PMID- 25730459 TI - Microsatellite analysis of genetic diversity and population structure of freshwater mussel (Lamprotula leai). AB - Lamprotula leai is one of the most commercially important freshwater pearl mussels in China, but there is limited data on its genetic diversity and population structure. In the present study, 119 individuals from four major geographical populations were investigated using 15 microsatellite loci identified via cross-species amplification. A total of 114 alleles were detected, with an average of 7.6 alleles per locus (range: 2 to 21). Among the four stocks, those from Hung-tse Lake and Poyang Lake had the lowest (0.412) and highest (0.455) observed heterozygosity respectively. The polymorphism information content (PIC) ranged from 0.374 to 0.927 (mean: 0.907). AMOVA showed that 12.56% and 44.68% genetic variances were among populations and within individuals, respectively. Pairwise Fst ranged from 0.073 to 0.146, indicating medium genetic differentiation among the populations. In aggregate, our results suggest that inbreeding is a crucial factor accounting for deviations from Hardy-Weinberg equilibrium at 12 loci. Moreover, the genetic distance among four stocks ranged from 0.192 to 0.890. Poyang Lake and Hung-tse Lake were clustered together, joined with Dongting Lake and Anqing Lake. Given that specimens from Hung-tse Lake showed the highest average allele richness, expected heterozygosity and PIC, this location may be the source of the highest quality germplasm resources and the stock from this area may be the best for future breeding efforts. PMID- 25730460 TI - Hydrophilic/hydrophobic characters of antimicrobial peptides derived from animals and their effects on multidrug resistant clinical isolates. AB - Multidrug resistant (MDR) pathogen infections are serious threats to hospitalized patients because of the limited therapeutic options. A novel group of antibiotic candidates, antimicrobial peptides (AMPs), have recently shown powerful activities against both Gram-negative and Gram-positive bacteria. Unfortunately, the viability of using these AMPs in clinical settings remains to be seen, since most still need to be evaluated prior to clinical trials and not all of AMPs are potent against MDR clinical isolates. To find a connection between the characteristics of several of these AMPs and their effects against MDR pathogens, we selected 14 AMPs of animal origin with typical structures and evaluated their in vitro activities against clinical strains of extensive drug-resistant Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, extended spectrum beta-lactamase-producing Pseudomonas aeruginosa and extended spectrum beta-lactamase-producing Escherichia coli. Our results showed that these peptides' hydrophilic/hydrophobic characteristics, rather than their secondary structures, may explain their antibacterial effects on these clinical isolates. Peptides that are amphipathic along the longitudinal direction seemed to be effective against Gram-negative pathogens, while peptides with hydrophilic terminals separated by a hydrophobic intermediate section appeared to be effective against both Gram-negative and Gram-positive pathogens. Among these, cathelicidin-BF was found to inhibit all of the Gram-negative pathogens tested at dosages of no more than 16 mg/L, killing a pandrug-resistant A. baumannii strain within 2 h at 4*MICs and 4 h at 2*MICs. Tachyplesin III was also found capable of inhibiting all Gram-negative and Gram-positive pathogens tested at no more than 16 mg/L, and similarly killed the same A. baumannii strain within 4 h at 4*MICs and 2*MICs. These results suggest that both cathelicidin-BF and tachyplesin III are likely viable targets for the development of AMPs for clinical uses. PMID- 25730461 TI - Effects of senescence on the expression of BDNF and TrkB receptor in the lateral geniculate nucleus of cats. AB - To explore the neural mechanisms mediating aging-related visual function declines, we compared the expressions of brain-derived neurotrophic factor (BDNF) and its high affinity receptor-tyrosine kinase B (TrkB) between young and old adult cats. Nissl staining was used to display neurons in each layer of the lateral geniculate nucleus (LGN). The BDNF- and TrkB receptor-immunoreactive neurons were labeled immunohistochemically, observed under optical microscope and photographed. Their neuronal density and immunoreactive intensity were measured. Results showed that the mean density of the Nissl stained neurons in each LGN layer were comparable between old and young adult cats, and their BDNF and TrkB proteins were widely expressed in all LGN layers. However, compared with young adult cats, both the density and optical absorbance intensity of BDNF- and TrkB immunoreactive cells in each LGN layer in old cats were significantly decreased. These findings indicate that the decreased expressions of BDNF and TrkB proteins in the LGN may be an important factor inducing the compromised inhibition in the central visual nucleus and the functional visual decline in senescent individuals. PMID- 25730462 TI - Effects of alcohol on H3K9 acetylation in mouse pre-implantation embryos. AB - It is well known that excessive long-term alcohol consumption is harmful, especially in pregnant women. In the present study, the Kunming white mouse was used as an animal model and indirect immunofluorescence was performed to analyze the toxic effects of alcohol on early pre-implantation embryos. H3K9 acetylation immunofluorescence could not be detected in MII oocytes. H3K9 acetylation levels in the treatment group were higher than in the control group during the morula stage, and contrary to results during the blastocyst stage. Other stages showed no obvious differences for in vivo embryos. For in vitro embryos, almost no difference was found between the two experimental groups across all stages, and both groups showed increasing H3K9 acetylation levels (except at the 2-cell stage). This study shows that H3K9 acetylation levels in early pre-implantation embryos are notably impacted by excessive alcohol ingestion by females. These data are the first step in understanding the epigenetic mechanism of alcohol toxicity in early pre-implantation mouse embryos. PMID- 25730463 TI - Update on the distribution range of the white-browed crake (Porzana cinerea): a new record from mainland China. AB - Since 1980, the white-browed crake (Porzana cinerea) has been experiencing an expansion from south of the Isthmus of Kra, northward to China. Recently, this species was observed in several locations throughout Southwest China, including Ningming and Baise, Guangxi (2012, 2013), and Xichang, Sichuan (2013). These sightings are the first distribution record of this species in mainland China, suggesting that the white-browed crake is following a natural species dispersal northward into mainland China from Southeast Asia. PMID- 25730464 TI - Evaluating the effect of habitat diversity on the species-area relationship using land-bridge islands in Thousand Island Lake, China. PMID- 25730468 TI - Outcomes of a diabetes education program for registered nurses caring for individuals with diabetes. AB - BACKGROUND: Nurses from various setting lack sufficient knowledge about diabetes and diabetes management. Better understand of evidence-based practices by nurses who are involved in caring for hospitalized individuals with diabetes can positively influence care outcomes. METHOD: A pretest design was used to evaluate the effectiveness of a diabetes education program for RNs working voluntarily participated. A 1-day education program was developed and delivered to the participating nurses. Knowledge regarding diabetes was tested before and after the education program. RESULTS: a significant difference was noted in the modified diabetes basic knowledge mean test scores before and after implementation of the education program (t[128] = 17.95, P < 0.001). CONCLUSIONS: The diabetes education program had a positive on nurses' knowledge. This finding has implications for developing diabetes education content within nursing curricula, as well as continuing education courses for practicing nurses. PMID- 25730467 TI - Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus. AB - RATIONALE: Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV specific serum neutralizing antibodies, which are associated with reduced RSV related hospitalization rates in observational studies but may not actually prevent infection. OBJECTIVES: To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. METHODS: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity. MEASUREMENTS AND MAIN RESULTS: Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered. CONCLUSIONS: This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone. PMID- 25730469 TI - A novel alkaline hemicellulosic heteroxylan isolated from alfalfa (Medicago sativa L.) stem and its thermal and anti-inflammatory properties. AB - A novel hemicellulosic polysaccharide (ACAP) was purified from the cold alkali extraction of alfalfa stems and characterized as a heteroxylan with a weight average molecular weight of 7.94 * 10(3) kDa and a radius of 58 nm. Structural analysis indicated that ACAP consisted of a 1,4-linked beta-D-Xylp backbone with 4-O-MeGlcpA and T-L-Araf substitutions at O-2 and O-3 positions, respectively. Transmission electron microscopy (TEM) examination revealed the entangled chain morphology of ACAP molecules. The evaluation of thermal degradation property revealed a primary decomposition temperature range of 238.8-314.0 degrees C with an apparent activation energy (Ea) and a pre-exponential factor (A) of 220.0 kJ/mol and 2.81 * 10(24)/s, respectively. ACAP also showed significant inhibitory activities on IL-1beta, IL-6, and COX-2 gene expressions in cultured RAW 264.7 mouse macrophage cells. These results suggested the potential utilization of ACAP in functional foods and dietary supplement products. PMID- 25730470 TI - Association of the choline acetyltransferase gene with responsiveness to acetylcholinesterase inhibitors in Alzheimer's disease. AB - INTRODUCTION: The response to acetylcholinesterase inhibitors (AChEIs) of Alzheimer's disease (AD) patients varies depending on the genetic characteristics of the patient. We have examined the association of response to AChEIs and genetic polymorphisms in AD patients. METHODS: 158 patients with AD underwent treatment with AChEIs, and the therapeutic effect was assessed with the Korean version of the Mini Mental State Examination (K-MMSE). The association of 25 SNPs located in 3 genes (CHAT, CHT and ACHE) with changes in the K-MMSE score was analyzed. RESULTS: The response to AChEIs in AD patients was significantly associated with 2 SNPs on the intronic region of CHAT rs2177370 (uncorrected P=0.0025, FDR controlled P=0.026) and rs3793790 (uncorrected P=0.0024, FDR controlled P=0.026). CONCLUSION: The results of our study confirmed again that genetic polymorphism of CHAT has an influence on drug response in AD. PMID- 25730471 TI - Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. AB - Excessive accumulation of white adipose tissue (WAT) is the defining characteristic of obesity. WAT mass is composed primarily of mature adipocytes, which are generated through the proliferation and differentiation of adipocyte precursors (APs). Although the production of new adipocytes contributes to WAT growth in obesity, little is known about the cellular and molecular mechanisms underlying adipogenesis in vivo. Here, we show that high-fat diet feeding in mice rapidly and transiently induces proliferation of APs within WAT to produce new adipocytes. Importantly, the activation of adipogenesis is specific to the perigonadal visceral depot in male mice, consistent with the patterns of obesogenic WAT growth observed in humans. Furthermore, we find that in multiple models of obesity, the activation of APs is dependent on the phosphoinositide 3 kinase (PI3K)-AKT2 pathway; however, the development of WAT does not require AKT2. These data indicate that developmental and obesogenic adipogenesis are regulated through distinct molecular mechanisms. PMID- 25730473 TI - A sensitive whole-cell biosensor for the simultaneous detection of a broad spectrum of toxic heavy metal ions. AB - Bacterial biosensors are simple, cost-effective and efficient analytical tools for detecting bioavailable heavy metals in the environment. This work presents the design, construction and calibration of a novel whole-cell fluorescent biosensory device that, simultaneously and with high sensitivity, reports the presence of toxic mercury, lead, cadmium and/or gold ions in aqueous samples. This bio-reporter can be easily applied as an immediate alerting tool for detecting the presence of harmful pollutants in drinking water. PMID- 25730472 TI - EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival. AB - Expansion and remodelling of the mammary epithelium requires a tight balance between cellular proliferation, differentiation and death. To explore cell survival versus cell death decisions in this organ, we deleted the pro-survival gene Mcl-1 in the mammary epithelium. Mcl-1 was found to be essential at multiple developmental stages including morphogenesis in puberty and alveologenesis in pregnancy. Moreover, Mcl-1-deficient basal cells were virtually devoid of repopulating activity, suggesting that this gene is required for stem cell function. Profound upregulation of the Mcl-1 protein was evident in alveolar cells at the switch to lactation, and Mcl-1 deficiency impaired lactation. Interestingly, EGF was identified as one of the most highly upregulated genes on lactogenesis and inhibition of EGF or mTOR signalling markedly impaired lactation, with concomitant decreases in Mcl-1 and phosphorylated ribosomal protein S6. These data demonstrate that Mcl-1 is essential for mammopoiesis and identify EGF as a critical trigger of Mcl-1 translation to ensure survival of milk-producing alveolar cells. PMID- 25730474 TI - Extraction of saponins and toxicological profile of Teucrium stocksianum boiss extracts collected from District Swat, Pakistan. AB - BACKGROUND: The current era is facing challenges in the management of neoplasia and weeds control. The currently available anti-cancer and herbicidal drugs are associated with some serious side effects. Therefore numerous researchers are trying to discover and develop plant based alternative particularly for the rational management of cancer and weed control. Teucrium stocksianum possess antioxidant and analgesic activities. The current study was designed to evaluate crude saponins (CS), methanolic extract and sub-fractions of T. stocksianum for cytotoxic and phytotoxic potentials. CS, methanolic extract and sub-fractions were extracted from powdered plant material using different solvents. Cytotoxic potential of the extracts at a dose of 10, 100 and 1000 MUg/ml were evaluated against Brine shrimp's nauplii. Phytotoxic assay also performed at the same concentration against Lemna minor. Etoposide and Paraquat were used as positive controls in cytotoxic and phytotoxic assays respectively. RESULTS: The percent yield of crude saponins was (5%). CS demonstrated tremendous brine shrimp lethality showing < 10 MUg/ml LC50. The n-hexane (HF) and chloroform fractions (CF) demonstrated excellent cytotoxicity with 80 and 55 MUg/ml LC50 respectively. Whereas the methanolic extract (TSME), ethyl acetate (EAF) and aqueous fractions (AF) revealed moderate cytotoxicity showing 620, 860 and 1000 MUg/ml LC50 values respectively. In phytotoxic assay profound inhibition was displayed by HF (96.67%) and TSME (95.56%, 30 MUg/ml LC50) against the growth of Lemna minor at 1000 MUg/ml respectively. Both CF and EAF demonstrated profound phytoxicity (93.33%) respectively at highest concentration (1000 MUg/ml), while AF and CS demonstrated weak phytotoxicity with 1350 and 710 MUg/ml LC50 values respectively. CONCLUSION: Cytotoxicity and phytotoxicity assays indicated that the crude saponins, n-hexane and chloroform fractions of T. stocksianum could play a vital role in the treatment of neoplasia and as potential natural herbicides. Therefore these sub-fractions are recommended for further investigation with the aim to isolate novel anti-cancer and herbicidal compounds. PMID- 25730475 TI - Weak antilocalization effect of topological crystalline insulator Pb(1-x)Sn(x)Te nanowires with tunable composition and distinct {100} facets. AB - Pb(1-x)Sn(x)Te is a unique topological crystalline insulator (TCI) that undergoes a topological phase transition from topological trivial insulator to TCI with the change of Sn content and temperature. Meanwhile, the surface states properties of Pb(1-x)Sn(x)Te are strongly dependent on crystallographic plane orientation. In this work, we first reported controllable synthesis of rectangular prismatic Pb(x)Sn(1-x)Te nanowires by vapor deposition method. Rectangular prismatic Pb(x)Sn(1-x)Te nanowires exhibits distinct {100} surfaces. Furthermore, The Sn composition of Pb(1-x)Sn(x)Te nanowires can be continuously controlled from 0 to 1. Low temperature magnetotransport shows that PbTe nanowire exhibits weak localization (WL) effect, whereas Pb0.5Sn0.5Te and Pb0.2Sn0.8Te nanowires display pronounced weak antilocalization (WAL) effect. This transition is explained by the topological phase transform of Pb(1-x)Sn(x)Te from trivial to nontrivial insulator with Sn content (x) exceeding 0.38. Pb(x)Sn(1-x)Te nanowires synthesized in this work lay a foundation for probing spin-correlated electron transport and show great potentials for future applications of tunable spintronic devices. PMID- 25730476 TI - siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. AB - Asialoglycoprotein receptor (ASGPR) mediated delivery of triantennary N acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) to hepatocytes is a promising paradigm for RNAi therapeutics. Robust and durable gene silencing upon subcutaneous administration at therapeutically acceptable dose levels resulted in the advancement of GalNAc-conjugated oligonucleotide based drugs into preclinical and clinical developments. To systematically evaluate the effect of display and positioning of the GalNAc moiety within the siRNA duplex on ASGPR binding and RNAi activity, nucleotides carrying monovalent GalNAc were designed. Evaluation of clustered and dispersed incorporation of GalNAc units to the sense (S) strand indicated that sugar proximity is critical for ASGPR recognition, and location of the clustered ligand impacts the intrinsic potency of the siRNA. An array of nucleosidic GalNAc monomers resembling a trivalent ligand at or near the 3' end of the S strand retained in vitro and in vivo siRNA activity, similar to the parent conjugate design. This work demonstrates the utility of simple, nucleotide-based, cost-effective siRNA-GalNAc conjugation strategies. PMID- 25730477 TI - The blind spot in high-dose tigecycline pharmacokinetics in critically ill patients: membrane adsorption during continuous extracorporeal treatment. PMID- 25730478 TI - Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis. AB - The microcirculation during sepsis fails due to capillary plugging involving microthrombosis. We demonstrated that intravenous injection of ascorbate reduces this plugging, but the mechanism of this beneficial effect remains unclear. We hypothesize that ascorbate inhibits the release of the antifibrinolytic plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and platelets during sepsis. Microvascular endothelial cells and platelets were isolated from mice. Cells were cultured and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFalpha), or thrombin (agents of sepsis), with/without ascorbate for 1-24 h. PAI-1 mRNA was determined by quantitative PCR. PAI-1 protein release into the culture medium was measured by ELISA. In platelets, PAI 1 release was measured after LPS, TNFalpha, or thrombin stimulation, with/without ascorbate. In endothelial cells, LPS and TNFalpha increased PAI-1 mRNA after 6-24 h, but no increase in PAI-1 release was observed; ascorbate did not affect these responses. In platelets, thrombin, but not LPS or TNFalpha, increased PAI-1 release; ascorbate inhibited this increase at low extracellular pH. In unstimulated endothelial cells and platelets, PAI-1 is released into the extracellular space. Thrombin increases this release from platelets; ascorbate inhibits it pH-dependently. The data suggest that ascorbate promotes fibrinolysis in the microvasculature under acidotic conditions in sepsis. PMID- 25730479 TI - Development of an NDIR CO2 sensor-based system for assessing soil toxicity using substrate-induced respiration. AB - The eco-toxicological indicators used to evaluate soil quality complement the physico-chemical criteria employed in contaminated site remediation, but their cost, time, sophisticated analytical methods and in-situ inapplicability pose a major challenge to rapidly detect and map the extent of soil contamination. This paper describes a sensor-based approach for measuring potential (substrate induced) microbial respiration in diesel-contaminated and non-contaminated soil and hence, indirectly evaluates their microbial activity. A simple CO2 sensing system was developed using an inexpensive non-dispersive infrared (NDIR) CO2 sensor and was successfully deployed to differentiate the control and diesel contaminated soils in terms of CO2 emission after glucose addition. Also, the sensor system distinguished glucose-induced CO2 emission from sterile and control soil samples (p <= 0.0001). Significant effects of diesel contamination (p <= 0.0001) and soil type (p <= 0.0001) on glucose-induced CO2 emission were also found. The developed sensing system can provide in-situ evaluation of soil microbial activity, an indicator of soil quality. The system can be a promising tool for the initial screening of contaminated environmental sites to create high spatial density maps at a relatively low cost. PMID- 25730480 TI - Development of a hydrogen gas sensor using a double SAW resonator system at room temperature. AB - A double SAW resonator system was developed as a novel method for gas sensing applications. The proposed system was investigated for hydrogen sensing. Commercial Surface Acoustic Wave (SAW) resonators with resonance frequencies of 433.92 MHz and 433.42 MHz were employed in the double SAW resonator system configuration. The advantages of using this configuration include its ability for remote measurements, and insensitivity to vibrations and other external disturbances. The sensitive layer is composed of functionalized multiwalled carbon nanotubes and polyaniline nanofibers which were deposited on pre-patterned platinum metal electrodes fabricated on a piezoelectric substrate. This was mounted into the DSAWR circuit and connected in parallel. The sensor response was measured as the difference between the resonance frequencies of the SAW resonators, which is a measure of the gas concentration. The sensor showed good response towards hydrogen with a minimum detection limit of 1%. PMID- 25730481 TI - Design and test of a low-cost RGB sensor for online measurement of microalgae concentration within a photo-bioreactor. AB - In this study, a low-cost RGB sensor is developed to measure online the microalgae concentration within a photo-bioreactor. Two commercially available devices, i.e., a spectrophotometer for offline measurements and an immersed probe for online measurements, are used for calibration and comparison purposes. Furthermore, the potential of such a sensor for estimating other variables is illustrated with the design of an extended Luenberger observer. PMID- 25730482 TI - Refrigerated fruit storage monitoring combining two different wireless sensing technologies: RFID and WSN. AB - Every day, millions of tons of temperature-sensitive goods are produced, transported, stored or distributed worldwide, thus making their temperature and humidity control essential. Quality control and monitoring of goods during the cold chain is an increasing concern for producers, suppliers, logistic decision makers and consumers. In this paper we present the results of a combination of RFID and WSN devices in a set of studies performed in three commercial wholesale chambers of 1848 m3 with different set points and products. Up to 90 semi-passive RFID temperature loggers were installed simultaneously together with seven motes, during one week in each chamber. 3D temperature mapping charts were obtained and also the psychrometric data model from ASABE was implemented for the calculation of enthalpy changes and the absolute water content of air. Thus thank to the feedback of data, between RFID and WSN it is possible to estimate energy consumption in the cold room, water loss from the products and detect any condensation over the stored commodities. PMID- 25730483 TI - Role of edge inclination in an optical microdisk resonator for label-free sensing. AB - In this paper, we report on the measurement and modeling of enhanced optical refractometric sensors based on whispering gallery modes. The devices under test are optical microresonators made of silicon nitride on silicon oxide, which differ in their sidewall inclination angle. In our approach, these microresonators are vertically coupled to a buried waveguide with the aim of creating integrated and cost-effective devices. Device modeling shows that the optimization of the device is a delicate balance of the resonance quality factor and evanescent field overlap with the surrounding environment to analyze. By numerical simulations, we show that the microdisk thickness is critical to yield a high figure of merit for the sensor and that edge inclination should be kept as high as possible. We also show that bulk-sensing figures of merit as high as 1600 RIU(-1) (refractive index unit) are feasible. PMID- 25730484 TI - Calculation of the electronic parameters of an Al/DNA/p-Si Schottky barrier diode influenced by alpha radiation. AB - Many types of materials such as inorganic semiconductors have been employed as detectors for nuclear radiation, the importance of which has increased significantly due to recent nuclear catastrophes. Despite the many advantages of this type of materials, the ability to measure direct cellular or biological responses to radiation might improve detector sensitivity. In this context, semiconducting organic materials such as deoxyribonucleic acid or DNA have been studied in recent years. This was established by studying the varying electronic properties of DNA-metal or semiconductor junctions when exposed to radiation. In this work, we investigated the electronics of aluminium (Al)/DNA/silicon (Si) rectifying junctions using their current-voltage (I-V) characteristics when exposed to alpha radiation. Diode parameters such as ideality factor, barrier height and series resistance were determined for different irradiation times. The observed results show significant changes with exposure time or total dosage received. An increased deviation from ideal diode conditions (7.2 to 18.0) was observed when they were bombarded with alpha particles for up to 40 min. Using the conventional technique, barrier height values were observed to generally increase after 2, 6, 10, 20 and 30 min of radiation. The same trend was seen in the values of the series resistance (0.5889-1.423 Omega for 2-8 min). These changes in the electronic properties of the DNA/Si junctions could therefore be utilized in the construction of sensitive alpha particle detectors. PMID- 25730485 TI - An automated field phenotyping pipeline for application in grapevine research. AB - Due to its perennial nature and size, the acquisition of phenotypic data in grapevine research is almost exclusively restricted to the field and done by visual estimation. This kind of evaluation procedure is limited by time, cost and the subjectivity of records. As a consequence, objectivity, automation and more precision of phenotypic data evaluation are needed to increase the number of samples, manage grapevine repositories, enable genetic research of new phenotypic traits and, therefore, increase the efficiency in plant research. In the present study, an automated field phenotyping pipeline was setup and applied in a plot of genetic resources. The application of the PHENObot allows image acquisition from at least 250 individual grapevines per hour directly in the field without user interaction. Data management is handled by a database (IMAGEdata). The automatic image analysis tool BIVcolor (Berries in Vineyards-color) permitted the collection of precise phenotypic data of two important fruit traits, berry size and color, within a large set of plants. The application of the PHENObot represents an automated tool for high-throughput sampling of image data in the field. The automated analysis of these images facilitates the generation of objective and precise phenotypic data on a larger scale. PMID- 25730486 TI - The past, present and future of cyber-physical systems: a focus on models. AB - This paper is about better engineering of cyber-physical systems (CPSs) through better models. Deterministic models have historically proven extremely useful and arguably form the kingpin of the industrial revolution and the digital and information technology revolutions. Key deterministic models that have proven successful include differential equations, synchronous digital logic and single threaded imperative programs. Cyber-physical systems, however, combine these models in such a way that determinism is not preserved. Two projects show that deterministic CPS models with faithful physical realizations are possible and practical. The first project is PRET, which shows that the timing precision of synchronous digital logic can be practically made available at the software level of abstraction. The second project is Ptides (programming temporally-integrated distributed embedded systems), which shows that deterministic models for distributed cyber-physical systems have practical faithful realizations. These projects are existence proofs that deterministic CPS models are possible and practical. PMID- 25730487 TI - Electropolymerized molecularly imprinted polypyrrole film for sensing of clofibric acid. AB - Piezoelectric quartz crystals and analogous gold substrates were electrochemically coated with molecularly imprinted polypyrrole films for pulsed amperometric detection (PAD) of clofibric acid, a metabolite of clofibrate. Cyclic voltammetry data obtained during polymerization and deposited weight estimations revealed a decrease of the polymerization rate with increasing clofibric acid concentration. XPS measurements indicated that clofibric acid could be removed after imprinting with an aqueous ethanol solution, which was further optimized by using PAD. Zeta potential and contact angle measurements revealed differences between molecularly imprinted (MIP) and non-imprinted polymer (NIP) layers. Binding experiments with clofibric acid and other substances showed a pronounced selectivity of the MIP for clofibric acid vs. carbamazepine, but the response of MIP and NIP to 2,4-dichlorophenoxyacetic acid was higher than that for clofibric acid. A smooth surface, revealed by AFM measurements, with roughness of 6-8 nm for imprinted and non-imprinted layers, might be a reason for an excessively low density of specific binding sites for clofibric acid. Furthermore, the decreased polymerization rate in the presence of clofibric acid might not result in well-defined polymer structures, which could be the reason for the lower sensitivity. PMID- 25730488 TI - State innovation model initiative: a state-led approach to accelerating health care system transformation. PMID- 25730489 TI - Exposure to airborne asbestos in thermal power plants in Mongolia. AB - BACKGROUND: Coal-fired thermal power plants (TPPs) in Mongolia use various types of asbestos-containing materials (ACMs) in thermal insulation of piping systems, furnaces, and other products. OBJECTIVE: To investigate the occupational exposure of insulation workers to airborne asbestos in Mongolian power plants. METHODS: Forty-seven air samples were collected from four power plants in Mongolia during the progress of insulation work. The samples were analyzed by phase contrast microscopy (PCM) and transmission electron microscopy (TEM). RESULTS: The average phase contrast microscopy equivalent (PCME) asbestos fiber concentration was 0.93 f/cm(3). Sixteen of the 41 personal and one of the area samples exceeded the United States Occupational Safety and Health Administration (US OSHA) short-term exposure limit of 1.0 f/cm(3). If it is assumed that the short-term samples collected are representative of full-shift exposure, then the exposures are approximately 10 times higher than the US OSHA 8-hour permissible exposure limit of 0.1 f/cm(3). CONCLUSION: Power plant insulation workers are exposed to airborne asbestos at concentrations that exceed the US OSHA Permissible Exposure Limit. Action to mitigate the risks should be taken in Mongolia. PMID- 25730490 TI - Highly efficient Cas9-mediated transcriptional programming. AB - The RNA-guided nuclease Cas9 can be reengineered as a programmable transcription factor. However, modest levels of gene activation have limited potential applications. We describe an improved transcriptional regulator obtained through the rational design of a tripartite activator, VP64-p65-Rta (VPR), fused to nuclease-null Cas9. We demonstrate its utility in activating endogenous coding and noncoding genes, targeting several genes simultaneously and stimulating neuronal differentiation of human induced pluripotent stem cells (iPSCs). PMID- 25730491 TI - Genome sequence-independent identification of RNA editing sites. AB - RNA editing generates post-transcriptional sequence changes that can be deduced from RNA-seq data, but detection typically requires matched genomic sequence or multiple related expression data sets. We developed the GIREMI tool (genome independent identification of RNA editing by mutual information; https://www.ibp.ucla.edu/research/xiao/GIREMI.html) to predict adenosine-to inosine editing accurately and sensitively from a single RNA-seq data set of modest sequencing depth. Using GIREMI on existing data, we observed tissue specific and evolutionary patterns in editing sites in the human population. PMID- 25730493 TI - High-throughput RNA profiling via up-front sample parallelization. AB - We describe a method called modular, early-tagged amplification (META) RNA profiling that can quantify a broad panel of microRNAs or mRNAs simultaneously across many samples and requires far less sequence depth than existing digital profiling technologies. The method assigns quantitative tags during reverse transcription to permit up-front sample pooling before competitive amplification and deep sequencing. This simple, scalable and inexpensive approach improves the practicality of large-scale gene expression studies. PMID- 25730492 TI - Simultaneous generation of many RNA-seq libraries in a single reaction. AB - Although RNA-seq is a powerful tool, the considerable time and cost associated with library construction has limited its utilization for various applications. RNAtag-Seq, an approach to generate multiple RNA-seq libraries in a single reaction, lowers time and cost per sample, and it produces data on prokaryotic and eukaryotic samples that are comparable to those generated by traditional strand-specific RNA-seq approaches. PMID- 25730494 TI - Association between cationic liposomes and low molecular weight hyaluronic acid. AB - This work presents a study of the association between low molecular weight hyaluronic acid (16 kDa HA) and cationic liposomes composed of egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). The cationic liposome/HA complexes were evaluated to determine their mesoscopic structure, average size, zeta potential, and morphology as a function of the amount of HA in the system. Small angle X-ray scattering results revealed that neighboring cationic liposomes either stick together after a partial coating of low concentration HA or disperse completely in excess of HA, but they never assemble as multilamellar vesicles. Cryo-transmission electron microscopy images confirm the existence of unilamellar vesicles and large aggregates of unilamellar vesicles for HA fractions up to 80% (w/w). High concentrations of HA (> 20% w/w) proved to be efficient for coating extruded liposomes, leading to particle complexes with sizes in the nanoscale range and a negative zeta potential. PMID- 25730496 TI - Planarization, fusion, and strain of carbon-bridged phenylenevinylene oligomers enhance pi-electron and charge conjugation: a dissectional vibrational Raman study. AB - We have used Raman spectroscopy to study the molecular and electronic structures of the radical cations and dications of carbon-bridged oligo(para phenylenevinylene)s (COPVn, n = 1-6) possessing consecutive fused pentagons and hexagons, up to 19, along with COPV derivatives having electron-donating and withdrawing groups. This study was made possible by the outstanding stability of the charged states of COPVs. We could untangle the effects of pi-conjugation in the planar structure on the Raman frequency by distinguishing it from other structural effects, such as strain in the vinylene groups shared by the two pentagons. The analyses showed that the radical cations have benzo-quinoidal structures confined in the center of the molecule, as well as benzo-aromatic rings at the terminal sites. In contrast, dications of COPVn longer than n = 3 exhibit a biradicaloid character because of the recovery of aromaticity in the central rings and quinoidal rings at the terminal positions. These biradicaloids favor a singlet nature in their ground electronic states because of the double spin polarization. The introduction of electron-donating and -withdrawing groups on the termini of a COPV core affords, upon oxidation or reduction, a fully delocalized class III mixed valence system because of the high degree of conjugation of the COPV platform, which favors extensive charge delocalization. PMID- 25730495 TI - Exogenous salicylic acid improves photosynthesis and growth through increase in ascorbate-glutathione metabolism and S assimilation in mustard under salt stress. AB - Ascorbate (AsA)-glutathione (GSH) cycle metabolism has been regarded as the most important defense mechanism for the resistance of plants under stress. In this study the influence of salicylic acid (SA) was studied on ascorbate-glutathione pathway, S-assimilation, photosynthesis and growth of mustard (Brassica juncea L.) plants subjected to 100 mM NaCl. Treatment of SA (0.5 mM) alleviated the negative effects of salt stress and improved photosynthesis and growth through increase in enzymes of ascorbate-glutathione pathway which suggest that SA may participate in the redox balance under salt stress. The increase in leaf sulfur content through higher activity of ATP sulfurylase (ATPS) and serine acetyl transferase (SAT) by SA application was associated with the increased accumulation of glutathione (GSH) and lower levels of oxidative stress. These effects of SA were substantiated by the findings that application of SA-analog, 2,6, dichloro-isonicotinic acid (INA) and 1 mM GSH treatment produced similar results on rubisco, photosynthesis and growth of plants establishing that SA application alleviates the salt-induced decrease in photosynthesis mainly through inducing the enzyme activity of ascorbate-glutathione pathway and increased GSH production. Thus, SA/GSH could be a promising tool for alleviation of salt stress in mustard plants. PMID- 25730497 TI - Scientists raise alarms about fast tracking of transoceanic canal through Nicaragua. AB - Seeking economic growth and job creation to tackle the nation's extreme poverty, the Nicaraguan government awarded a concession to build an interoceanic canal and associated projects to a recently formed Hong Kong based company with no track record or related expertise. This concession was awarded without a bidding process and in advance of any feasibility, socio-economic or environmental impact assessments; construction has begun without this information. The 278 km long interoceanic canal project may result in significant environmental and social impairments. Of particular concern are damage to Lake Cocibolca, a unique freshwater tropical lake and Central America's main freshwater reservoir; damage to regional biodiversity and ecosystems; and socio-economic impacts. Concerned about the possibly irreparable damage to the environment and to native communities, conservationists and the scientific community at large are urging the Nicaraguan government to devise and reveal an action plan to address and mitigate the possible negative repercussions of this interoceanic canal and associated projects. Critical research needs for preparation of a comprehensive benefit-cost analysis for this megaproject are presented. PMID- 25730498 TI - PCR-CTPP design for enzyme-free SNP genotyping using memetic algorithm. AB - In recent years, many single nucleotide polymorphisms (SNPs) have been successfully genotyped by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). However, computation experiments of feasible CTPP primers are still challenging. The melting temperatures between four primers must be within a very narrow range, and many primer constraints need to be conformed to. PCR-CTPP is a simple, time- and cost-effective SNP genotyping method applied in molecular biology and biomedical fields. In this study, an MA (memetic algorithm)-based method is proposed to enable the design of feasible CTPP primer sets. Overall, 288 SNPs which exclude the deletion/insertion polymorphisms (DIPs) and multi nucleotide polymorphisms (MNPs) in the SLC6A4 gene were tested in silico. The results were compared with a GA (genetic algorithm)-based method and indicate that the proposed method provides more feasible CTPP primers than the GA-based method. The MA-based CTPP primer design method provides critical melting temperatures and all kinds of evaluation of the common primer constraints. It could conceivably assist biologists and other researchers in obtaining feasible CTTP primer sets. The MA-CTPP algorithm is implemented in JAVA and a user friendly input interface is freely available at http://bio.kuas.edu.tw/ma-ctpp/. PMID- 25730499 TI - Constructing query-driven dynamic machine learning model with application to protein-ligand binding sites prediction. AB - We are facing an era with annotated biological data rapidly and continuously generated. How to effectively incorporate new annotated data into the learning step is crucial for enhancing the performance of a bioinformatics prediction model. Although machine-learning-based methods have been extensively used for dealing with various biological problems, existing approaches usually train static prediction models based on fixed training datasets. The static approaches are found having several disadvantages such as low scalability and impractical when training dataset is huge. In view of this, we propose a dynamic learning framework for constructing query-driven prediction models. The key difference between the proposed framework and the existing approaches is that the training set for the machine learning algorithm of the proposed framework is dynamically generated according to the query input, as opposed to training a general model regardless of queries in traditional static methods. Accordingly, a query-driven predictor based on the smaller set of data specifically selected from the entire annotated base dataset will be applied on the query. The new way for constructing the dynamic model enables us capable of updating the annotated base dataset flexibly and using the most relevant core subset as the training set makes the constructed model having better generalization ability on the query, showing "part could be better than all" phenomenon. According to the new framework, we have implemented a dynamic protein-ligand binding sites predictor called OSML (On site model for ligand binding sites prediction). Computer experiments on 10 different ligand types of three hierarchically organized levels show that OSML outperforms most existing predictors. The results indicate that the current dynamic framework is a promising future direction for bridging the gap between the rapidly accumulated annotated biological data and the effective machine learning-based predictors. OSML web server and datasets are freely available at: http://www.csbio.sjtu.edu.cn/bioinf/OSML/ for academic use. PMID- 25730500 TI - Probing electronic and vibrational dynamics in molecules by time-resolved photoelectron, Auger-electron, and X-ray photon scattering spectroscopy. AB - We present a unified description for time-resolved electron and photon scattering spectroscopies from molecules prepared in nonstationary states. Signals are expressed in terms of superoperator Green's functions and a systematic procedure for treating various degrees of freedom consistently at different levels of theory is developed. The standard Fermi Golden Rule expressions for photoelectron spectra, which are limited to broad, slowly-varying signals, are obtained as a limiting case of our more general theory that applies to broader parameter regimes. PMID- 25730501 TI - Helical jump motions of poly(L-lactic acid) chains in the alpha phase as revealed by solid-state NMR. AB - The molecular dynamics of Poly(L-lactic Acid) (PLLA) chains in the alpha phase was investigated by Solid-State NMR spectroscopy. (13)C high-resolution NMR clearly indicates that the crystalline signals split into 2, 3, and 4 signals for the CH3, CH and CO groups, respectively at 25 degrees C, while the amorphous signals give a broad component at the bottom of the crystalline signals. (13)C NMR spectra show that the crystalline line shape changes with increasing temperatures well above the glass transition temperature (Tg) and imply the presence of the molecular dynamics in the crystalline region. Comparisons of the evolution-time dependence of CODEX data and simulation results based on reorientation of chemical shift anisotropy (CSA) indicate that the chains in the alpha phase perform helical jump motions in the slow dynamic range at temperatures above 115 degrees C. The mixing-time dependence of the CODEX data yields an activation energy of Ea of (95 +/- 8) kJ/mol for the helical jump motions. Moreover, two-dimensional exchange NMR with highly resolved signals for the CO group provides cross peaks among four well resolved signals due to the helical jumps. Comparison of 2D buildup curves of the cross peaks and calculated data determines that helical jump motions prefer largely uncorrelated random back and-forth motions between the neighboring sites, possibly enabling large-scale chain diffusion in the crystalline regions. PMID- 25730502 TI - Implications of the new atrial fibrillation guideline. PMID- 25730503 TI - Measuring teamwork in primary care: Triangulation of qualitative and quantitative data. AB - This article describes the triangulation of qualitative dimensions, reflecting high functioning teams, with the results of standardized teamwork measures. The study used a mixed methods design using qualitative and quantitative approaches to assess teamwork in 19 Family Health Teams in Ontario, Canada. This article describes dimensions from the qualitative phase using grounded theory to explore the issues and challenges to teamwork. Two quantitative measures were used in the study, the Team Climate Inventory (TCI) and the Providing Effective Resources and Knowledge (PERK) scale. For the triangulation analysis, the mean scores of these measures were compared with the qualitatively derived ratings for the dimensions. The final sample for the qualitative component was 107 participants. The qualitative analysis identified 9 dimensions related to high team functioning such as common philosophy, scope of practice, conflict resolution, change management, leadership, and team evolution. From these dimensions, teams were categorized numerically as high, moderate, or low functioning. Three hundred seventeen team members completed the survey measures. Mean site scores for the TCI and PERK were 3.87 and 3.88, respectively (of 5). The TCI was associated will all dimensions except for team location, space allocation, and executive director leadership. The PERK was associated with all dimensions except team location. Data triangulation provided qualitative and quantitative evidence of what constitutes teamwork. Leadership was pivotal in forging a common philosophy and encouraging team collaboration. Teams used conflict resolution strategies and adapted to the changes they encountered. These dimensions advanced the team's evolution toward a high functioning team. PMID- 25730504 TI - Panel management, team culture, and worklife experience. AB - Burnout and professional dissatisfaction are threats to the primary care workforce. We investigated the relationship between panel management capability, team culture, cynicism, and perceived "do-ability" of primary care among primary care providers (PCPs) and staff in primary care practices. We surveyed 326 PCPs and 142 staff members in 10 county-administered, 6 university-run, and 3 Veterans Affairs primary care clinics in a large urban area in 2013. Predictor variables included capability for performing panel management and perception of team culture. Outcome variables included 2 work experience measures--the Maslach Burnout Inventory cynicism scale and a 1-item measure of the "do-ability" of primary care this year compared with last year. Generalized Estimation Equation (GEE) models were used to account for clustering at the clinic level. Greater panel management capability and higher team culture were associated with lower cynicism among PCPs and staff and higher reported "do-ability" of primary care among PCPs. Panel management capability and team culture interacted to predict the 2 work experience outcomes. Among PCPs and staff reporting high team culture, there was little association between panel management capability and the outcomes, which were uniformly positive. However, there was a strong relationship between greater panel management capability and improved work experience outcomes for PCPs and staff reporting low team culture. Team-based processes of care such as panel management may be an important strategy to protect against cynicism and dissatisfaction in primary care, particularly in settings that are still working to improve their team culture. PMID- 25730505 TI - Factors influencing consumers' attitudinal and behavioral responses to direct-to consumer and over-the-counter drug advertising. AB - Using a model developed from the research literature, the authors compared consumers' attitudinal and behavioral responses to direct-to-consumer prescription drug advertising (DCTA) and over-the-counter nonprescription drug advertising (OTCA) of drugs. Adults 18 years of age and older who had taken any prescription drugs in the past 6 months completed online survey questionnaires. Variables measured included demographics (age, gender, race, education, and income), health-related characteristics (health status, prescription and over-the counter drug use, health consciousness, and involvement with prescription or over the-counter drugs), perceived amount of attention and exposure to DTCA and OTCA, attitudinal outcomes (skepticism toward DTCA/OTCA and attitude toward DTCA/OTCA), and behavioral outcomes triggered by DTCA and OTCA. The findings indicate that exposure to drug advertising is one of the most significant predictors of attitudinal and behavioral outcomes. Some audience factors such as health status, involvement with drugs, health consciousness, drug use, income, and age also were differentially associated with consumer responses to drug advertising. PMID- 25730506 TI - Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. AB - OBJECTIVES: CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin methatrexate/ifusamide, etoposide, cytarabine) chemotherapy is commonly used to treat Burkitt lymphoma and in the HIV-negative population. Rituximab is often added with suggested survival benefits. Concerns over increased toxicity in an already immunocompromized population have prevented its routine addition in people living with HIV (PLWH). This study evaluated the effect on treatment related toxicity and efficacy of adding rituximab to CODOX-M/IVAC chemotherapy in PLWH. DESIGN: Retrospective review of 91 PLWH (74 men) with Burkitt lymphoma treated in five London centers between 2003 and 2013. All patients received combination antiretroviral therapy. RESULTS: Forty-nine patients received CODOX M/IVAC and 42 rituximab (R)-CODOX-M/R-IVAC. The addition of rituximab did not confer any significant increase in grade 3/4 toxicities including infections, mucositis, diarrhea, renal impairment, and tumor lysis syndrome. There was no significant difference in toxic deaths between groups (P = 0.14). The 2-year overall survival (OS) was greater for patients receiving rituximab {2-year OS 72% [95% confidence interval (CI) 0.22-0.92, hazard ratio 0.46] vs. 55% [95% CI 1.1 4.5, hazard ratio 2.2]; log-rank P = 0.04}. Similarly, the 2-year progression free survival (PFS) was greater in the rituximab cohort [2-year PFS 81% (95% CI 0.21-0.99, hazard ratio 0.46) vs. 55% (95% CI 1.0-4.8, hazard ratio 2.2); log rank P = 0.04]. CONCLUSION: Our multicenter analysis is the largest to date in this population and showed that the addition of rituximab to CODOX-M/IVAC chemotherapy confers no increase in toxicity and results in significantly improved OS and PFS in PLWH with Burkitt lymphoma who receive concomitant combination antiretroviral therapy. PMID- 25730507 TI - Viremic control and viral coreceptor usage in two HIV-1-infected persons homozygous for CCR5 Delta32. AB - OBJECTIVES: To determine viral and immune factors involved in transmission and control of HIV-1 infection in persons without functional CCR5. DESIGN: Understanding transmission and control of HIV-1 in persons homozygous for CCR5(Delta32) is important given efforts to develop HIV-1 curative therapies aimed at modifying or disrupting CCR5 expression. METHODS: We identified two HIV infected CCR5(Delta32/Delta32) individuals among a cohort of patients with spontaneous control of HIV-1 infection without antiretroviral therapy and determined coreceptor usage of the infecting viruses. We assessed genetic evolution of full-length HIV-1 envelope sequences by single-genome analysis from one participant and his sexual partner, and explored HIV-1 immune responses and HIV-1 mutations following virologic escape and disease progression. RESULTS: Both participants experienced viremia of less than 4000 RNA copies/ml with preserved CD4(+) T-cell counts off antiretroviral therapy for at least 3.3 and 4.6 years after diagnosis, respectively. One participant had phenotypic evidence of X4 virus, had no known favorable human leukocyte antigen alleles, and appeared to be infected by minority X4 virus from a pool that predominately used CCR5 for entry. The second participant had virus that was unable to use CXCR4 for entry in phenotypic assay but was able to engage alternative viral coreceptors (e.g., CXCR6) in vitro. CONCLUSION: Our study demonstrates that individuals may be infected by minority X4 viruses from a population that predominately uses CCR5 for entry, and that viruses may bypass traditional HIV-1 coreceptors (CCR5 and CXCR4) completely by engaging alternative coreceptors to establish and propagate HIV-1 infection. PMID- 25730508 TI - State-level structural sexual stigma and HIV prevention in a national online sample of HIV-uninfected MSM in the United States. AB - BACKGROUND: Stigmatizing social environments (of which 'structural stigma' is one component) negatively affect health-related outcomes. However, few studies have examined structural stigma related to sexual minority status as a risk factor for HIV outcomes among MSM. METHODS: In August 2013, members of a large MSM social and sexual networking site in the United States completed a survey about HIV prevention practices. A previously validated composite index provided values for state-level structural stigma, including density of same-sex couples, proportion of public high schools with Gay-Straight Alliances, state laws protecting sexual minorities, and public opinion toward homosexuality. Multivariable logistic generalized estimating equations assessed the relationship between structural stigma and condomless anal intercourse, use and awareness of antiretroviral-based HIV-prevention strategies (i.e. pre and postexposure prophylaxis, or PEP and PrEP), and comfort discussing male-male sex with primary care providers. RESULTS: Among the 4098 HIV-uninfected MSM, lower state-level structural stigma was associated with decreased odds of condomless anal intercourse [adjusted odds ratio (aOR) 0.97 per one unit increase in structural stigma score, 95% confidence interval (CI) 0.94-0.99], increased odds of awareness of PEP (aOR 1.06, 95% CI 1.02-1.09), and PrEP (aOR 1.06, 95% CI 1.02-1.10), having taken PEP (aOR 1.15, 95% CI 1.05-1.26) and PrEP (aOR 1.21, 95% CI 1.01-1.44), and comfort discussing male-male sex with providers (aOR 1.08, 95% CI 1.05-1.11), after adjusting for social and state-level confounders. CONCLUSION: MSM living in more stigmatizing environments had decreased use of antiretroviral-based HIV-prevention strategies compared to those in less stigmatizing environments. Legal reforms protecting sexual minorities should be evaluated as structural interventions that could reduce HIV risk among MSM. PMID- 25730509 TI - Early antiretroviral therapy with raltegravir generates sustained reductions in HIV reservoirs but not lower T-cell activation levels. AB - OBJECTIVE: The initiation of antiretroviral therapy (ART) during primary infection may offer clinical benefits for HIV-infected individuals by reducing HIV DNA reservoir size and chronic T-cell activation. Current evidence for the advantages of early ART, however, are mostly derived from cross-sectional studies, with the long-term benefits yet to be ascertained. DESIGN/METHODS: We conducted an open-label, nonrandomized study, monitoring for 3 years: plasma viral load (pVL), T-cell phenotypes, and peripheral CD4(+) T-cell associated total, integrated and 2-long terminal repeat HIV DNA species. The study included 16 treatment-naive individuals initiating ART with raltegravir and Truvada during either primary (PHI, n = 8) or chronic (CHI, n = 8) HIV infection. RESULTS: ART initiated during PHI compared with CHI generated significant reductions of peripheral CD4(+) T-cell HIV DNA reservoirs that were sustained for 3 years of therapy. Median log10 HIV DNA copies/10(6) CD4(+) T cells at the final visit: total; CHI = 3.23 > PHI = 2.72, P < 0.01; integrated; CHI = 2.64 > PHI = 1.77, P < 0.01. Similar trends were observed for pVL, however, did not reach significance: log10 HIV RNA copies/ml plasma at the final visit: CHI = 1.3 >= PHI = 0.39, P = 0.08. Both cohorts displayed similar and elevated levels of CD38/HLA DR coexpression on CD4(+) and CD8(+) T cells relative to uninfected healthy controls. CONCLUSION: The reduction in HIV DNA reservoirs generated by the early initiation of ART was sustained for 3 years of therapy. Although the PHI cohort trended to lower levels of pVL, and pVL was associated with CD8(+) T-cell activation, no differences in T-cell activation were observed between the PHI and CHI groups. PMID- 25730510 TI - HIV-infection impact on clinical-biological features and outcome of diffuse large B-cell lymphoma treated with R-CHOP in the combination antiretroviral therapy era. AB - OBJECTIVE: Since the introduction of combination antiretroviral therapy (cART) patients with HIV-related diffuse large B-cell lymphoma (DLBCL) show better control of immunosuppression, which may have an impact on the characteristics and prognosis of the disease. We aimed to compare the clinical presentation and prognosis of patients with HIV-related and HIV-unrelated DLBCL treated with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) in the cART era. METHODS AND DESIGN: Eighty-one HIV-infected patients included in a Spanish multicentre trial were compared with 84 HIV-uninfected patients diagnosed in a Spanish institution in the same period all treated with R-CHOP. RESULTS: HIV infected patients had a worse performance status, more frequent B-symptoms, and higher Ann-Arbor stages than HIV-uninfected patients, with similar frequency of extranodal involvement. The complete response (CR) rate of patients with high tumor burden was not different in HIV-infected and HIV-uninfected patients. Patients with HIV-related DLBCL showed a worse overall survival (OS) (5-year OS: 56 vs. 74%) but a similar disease-free survival (DFS) (5-year DFS: 84 vs. 73%). In the subgroup of patients with high tumor, the results regarding survival were similar to the whole series. Previous AIDS-defining illness was the strongest negative prognostic factor for OS in HIV-infected patients. CONCLUSION: In the cART era, HIV-related DLBCL still presents more aggressive features than HIV unrelated DLBCL, and has a worse OS despite having a similar DFS. Prevention of HIV-related complications is essential to achieve outcomes comparable with HIV uninfected patients with DLBCL. PMID- 25730511 TI - Let's talk about sex: gender norms and sexual health in English schools. AB - The sexual health of young people in England is an urgent public health concern. While interventions to address young people's sexual health have focussed on knowledge, skills and contraception access, amazingly none in the UK has explicitly addressed the effects of the social hierarchies of gender and gendered behavioural ideals that shape young people's sexual expectations, attitudes and behaviour. The lack of attention to gender is a persistent gap in health research, practice and policy. A rigorous evaluation of such an intervention package would go some way to building an evidence base for challenging gender norms, which appear to be strongly associated with adverse sexual health outcomes. PMID- 25730512 TI - Targeted crystal growth of rare Earth intermetallics with synergistic magnetic and electrical properties: structural complexity to simplicity. AB - The single-crystal growth of extended solids is an active area of solid-state chemistry driven by the discovery of new physical phenomena. Although many solid state compounds have been discovered over the last several decades, single crystal growth of these materials in particular enables the determination of physical properties with respect to crystallographic orientation and the determination of properties without possible secondary inclusions. The synthesis and discovery of new classes of materials is necessary to drive the science forward, in particular materials properties such as superconductivity, magnetism, thermoelectrics, and magnetocalorics. Our research is focused on structural characterization and determination of physical properties of intermetallics, culminating in an understanding of the structure-property relationships of single crystalline phases. We have prepared and studied compounds with layered motifs, three-dimensional magnetic compounds exhibiting anisotropic magnetic and transport behavior, and complex crystal structures leading to intrinsically low lattice thermal conductivity. In this Account, we present the structural characteristics and properties that are important for understanding the magnetic properties of rare earth transition metal intermetallics grown with group 13 and 14 metals. We present phases adopting the HoCoGa5 structure type and the homologous series. We also discuss the insertion of transition metals into the cuboctahedra of the AuCu3 structure type, leading to the synthetic strategy of selecting binaries to relate to ternary intermetallics adopting the Y4PdGa12 structure type. We provide examples of compounds adopting the ThMn12, NaZn13, SmZn11, CeCr2Al20, Ho6Mo4Al43, CeRu2Al10, and CeRu4Al16-x structure types grown with main-group-rich self-flux methods. We also discuss the phase stability of three related crystal structures containing atoms in similar chemical environments: ThMn12, CaCr2Al10, and YbFe2Al10. In addition to dimensionality and chemical environment, complexity is also important in materials design. From relatively common and well-studied intermetallic structure types, we present our motivation to work with complex stannides adopting the Dy117Co57Sn112 structure type for thermoelectric applications and describe a strategy for the design of new magnetic intermetallics with low lattice thermal conductivity. Our quest to grow single crystals of rare-earth-rich complex stannides possessing low lattice thermal conductivity led us to discover the new structure type Ln30Ru4+xSn31-y (Ln = Gd, Dy), thus allowing the correlation of primitive volumes with lattice thermal conductivities. We highlight the observation that Ln30Ru4+xSn31-y gives rise to highly anisotropic magnetic and transport behavior, which is unexpected, illustrating the need to measure properties on single crystals. PMID- 25730513 TI - "Opening the curtains": How do voice hearers make sense of their voices? AB - OBJECTIVE: The current study sought to explore how, if at all, people construct an understanding of the origin and maintenance of their experience of hearing voices. METHOD: A social constructionist grounded theory method was adopted throughout the research process. Eight voice hearers, who were distressed by this experience, were recruited and interviewed. RESULTS: Three overarching descriptive categories were constructed regarding participants' understanding of the development and maintenance of hearing voices; search for meaning, view of self, and framework for understanding voices. The "essence" of the developing grounded theory was that individuals actively searched for meaning of their voices through different frameworks, but the relative "success" of this pursuit, and potential usefulness of an understanding, is influenced by the individual's perceptions of agency, stigma, and hope(lessness). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This research illustrates how voice hearers actively searched for meaning in relation to their voices and the challenges they encountered during this process. One clinical implication from this study emphasizes the potential role of psychological formulation in generating a shared understanding of the voices. Future research is warranted to explore voice hearers from a wider range of cultural, religious, and spiritual backgrounds. PMID- 25730514 TI - From loss to loneliness: The relationship between bereavement and depressive symptoms. AB - Spousal bereavement can cause a rise in depressive symptoms. This study empirically evaluates 2 competing explanations concerning how this causal effect is brought about: (a) a traditional latent variable explanation, in which loss triggers depression which then leads to symptoms; and (b) a novel network explanation, in which bereavement directly affects particular depression symptoms which then activate other symptoms. We used data from the Changing Lives of Older Couples (CLOC) study and compared depressive symptomatology, assessed via the 11 item Center for Epidemiologic Studies Depression Scale (CES-D), among those who lost their partner (N = 241) with a still-married control group (N = 274). We modeled the effect of partner loss on depressive symptoms either as an indirect effect through a latent variable, or as a direct effect in a network constructed through a causal search algorithm. Compared to the control group, widow(er)s' scores were significantly higher for symptoms of loneliness, sadness, depressed mood, and appetite loss, and significantly lower for happiness and enjoyed life. The effect of partner loss on these symptoms was not mediated by a latent variable. The network model indicated that bereavement mainly affected loneliness, which in turn activated other depressive symptoms. The direct effects of spousal loss on particular symptoms are inconsistent with the predictions of latent variable models, but can be explained from a network perspective. The findings support a growing body of literature showing that specific adverse life events differentially affect depressive symptomatology, and suggest that future studies should examine interventions that directly target such symptoms. PMID- 25730515 TI - The structure of personality pathology: Both general ('g') and specific ('s') factors? AB - Recent editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5; American Psychiatric Association, 2013) conceptualize personality disorders (PDs) as categorical constructs, but high PD co-occurrence suggests underlying latent dimensions. Moreover, several borderline PD criteria resemble Criterion A of the new DSM-5 Section III general criteria for personality pathology (i.e., self and interpersonal dysfunction). We evaluated a bifactor model of PD pathology in which a general factor and several specific factors of personality pathology (PD 'g' and 's' factors, respectively) account for the covariance among PD criteria. In particular, we examined the extent to which the borderline PD criteria would load exclusively onto the g-factor versus on both the g- and one or more s-factors. A large (N = 966) sample of inpatients were interviewed for six DSM-IV (American Psychiatric Association, 1994) PDs using the (Structured Clinical Interview for Personality Disorders (SCID-II; First, Spitzer, Gibbon, Williams, & Benjamin, 1994) with no skip-outs. We ran a series of confirmatory, exploratory, and bifactor exploratory factor analyses on the rated PD criteria. The confirmatory analysis largely replicated the DSM PDs, but with high factor correlations. The "standard" exploratory analysis replicated four of the DSM PDs fairly well, but nearly half the criteria cross-loaded. In the bifactor analysis, borderline PD criteria loaded only on the general factor; the remaining PDs loaded either on both the general and a specific factor or largely only on a specific factor. Results are interpreted in the context of several possibilities to define the nature of the general factor. PMID- 25730516 TI - Rumination but not distraction increases eating-related symptoms in anorexia and bulimia nervosa. AB - Recent models of eating disorders emphasize the importance of ruminative thinking in the occurrence of unhealthy eating behavior. Hence, the aim of the current study was to examine the influence of induced rumination and distraction on the desire to engage in eating-related symptoms in anorexia (AN) and bulimia nervosa (BN). After a sadness induction, either a ruminative or distractive emotion regulation style was encouraged in women with AN (n = 38), BN (n = 37), and non eating disordered controls (CG; n = 36). At baseline and after the emotion regulation induction feelings of sadness, desire to abstain from eating (DTA) and desire to binge (DTB) were assessed. Main results reveal that rumination led to a significant increase of DTA in the AN group and of DTB in patients with BN. In the CG, DTA significantly decreased after distraction. Although there were significant increases in subjective sadness in the rumination condition, no changes were found in the distraction condition. The results suggest that rumination in response to sadness has a detrimental effect on eating-related symptoms in eating disorders. PMID- 25730517 TI - "The modal suicide decedent did not consume alcohol just prior to the time of death: An analysis with implications for understanding suicidal behavior": Correction to Anestis et al. (2014). AB - Reports an error in "The modal suicide decedent did not consume alcohol just prior to the time of death: An analysis with implications for understanding suicidal behavior" by Michael D. Anestis, Thomas Joiner, Jetta E. Hanson and Peter M. Gutierrez (Journal of Abnormal Psychology, 2014[Nov], Vol 123[4], 835 840). The institutional affiliation in the byline for Jetta E. Hanson was incorrectly listed as Military Suicide Research Consortium, Tallahassee, Florida. Jetta E. Hanson's correct institutional affiliation is provided in the erratum. PMID- 25730518 TI - Controlled reperfusion for different durations in the treatment of ischemia reperfusion injury of the rat ovary: evaluation of biochemical features, molecular gene expression, and histopathology. AB - High numbers of proinflammatory cells (PMNLs), which are carried by the blood to ischemic tissue during reperfusion, are considered responsible for inducing the inflammatory response that occurs in ischemia-reperfusion (I/R) injury. Our objective was to determine the controlled reperfusion (CR) interval duration (CRID) that would minimize the injury caused by the PMNLs that infiltrate ischemic tissue. Animal groups were divided into the following groups: Sham group, ovarian I/R group (OIR), and ovarian ischemia controlled-reperfusion groups OICR-1, OICR-2, OICR-3, OICR-4, OICR-5, OICR-6, which had their ovarian artery opened and then closed for 10, 8, 6, 4, 2, or 1 s, respectively. The results show that the COX-2 activity and the gene expression decreased while the COX-1 activity and the gene expression were found to be increased in parallel to the shortening of the period in CRID. From the histopathological examinations, the findings of hemorrhage, edema, congested vascular structures, degenerated cells, and migration and adhesion of PMNLs were scaled as follows: Sham group < OICR-6 < OICR-5 < OICR-4 < OICR-3 < OICR-2 < OICR-1. The results from the histopathological assessments were consistent with the molecular and biochemical findings. In conclusion, our findings suggest that increased COX-2 activity plays a role in I/R injury of the rat ovary, and that controlled reperfusion for 3, 2, or 1 s following 2 h of ischemia may attenuate the effects of I/R injury. PMID- 25730520 TI - Nitric oxide reduction to ammonia by TiO2 electrons in colloid solution via consecutive one-electron transfer steps. AB - The reaction mechanism of nitric oxide (NO) reduction by excess electrons on TiO2 nanoparticles (e(TiO2)(-)) has been studied under anaerobic conditions. TiO2 was loaded with 10-130 electrons per particle using gamma-irradiation of acidic TiO2 colloid solutions containing 2-propanol. The study is based on time-resolved kinetics and reactants and products analysis. The reduction of NO by e(TiO2)(-) is interpreted in terms of competition between a reaction path leading to formation of NH3 and a path leading to N2O and N2. The proposed mechanism involves consecutive one-electron transfers of NO, and its reduction intermediates HNO, NH2O(*), and NH2OH. The results show that e(TiO2)(-) does not reduce N2O and N2. Second-order rate constants of e(TiO2)(-) reactions with NO (740 +/- 30 M(-1) s(-1)) and NH2OH (270 +/- 30 M(-1) s(-1)) have been determined employing the rapid-mixing stopped-flow technique and that with HNO (>1.3 * 10(6) M(-1) s(-1)) was derived from fitting the kinetic traces to the suggested reaction mechanism, which is discussed in detail. PMID- 25730519 TI - Relationship-level analysis of drug users' anticipated changes in risk behavior following HIV vaccination. AB - Formative research into the behavioral factors surrounding HIV vaccine uptake is becoming increasingly important as progress is made in HIV vaccine development. Given that the first vaccines on the market are likely to be partially effective, risk compensation (i.e., increased risk behavior following vaccination) may present a concern. This study characterized the relationships in which HIV vaccine-related risk compensation is most likely to occur using dyadic data collected from people who use drugs, a high-risk group markedly underrepresented in extant literature. Data were collected from 433 drug users enrolled in a longitudinal study in the USA. Respondents were asked to provide the first name and last initial of individuals with whom they had injected drugs and/or had sex during the past six months. For each partner, respondents reported their likelihood of increasing risk behavior if they and/or their partner received an HIV vaccine. Using generalized linear mixed models, relationship-level correlates to risk compensation were examined. In bivariate analysis, risk compensation was more likely to occur between partners who have known each other for a shorter time (odds ratio [OR]=0.95, 95% confidence interval [CI]: 0.90-0.99, p=0.028) and between those who inject drugs and have sex together (OR=2.52, CI: 1.05-6.04, p=0.039). In relationships involving risk compensation, 37% involved partners who had known each other for a year or less compared to only 13% of relationships not involving risk compensation. Adjusting for other variables, duration (OR: 0.95, CI: 0.90-1.00, p=0.033) was associated with risk compensation intent. These analyses suggest that risk compensation may be more likely to occur in less established relationships and between partners engaging in more than one type of risk behavior. These data provide further support for the need to expand measures of risk compensation in HIV vaccine preparedness studies to assess not only if people will change their behavior, but also with whom. PMID- 25730521 TI - Gender differences in clinical trials of binge eating disorder: An analysis of aggregated data. AB - OBJECTIVE: The aim of the study was to examine gender differences in baseline and outcome variables in clinical trials for binge eating disorder (BED). METHOD: Data from 11 randomized controlled psychosocial treatment studies were aggregated (N = 1,325: 208 male, 1,117 female). Baseline and outcome symptoms were assessed via the interview and questionnaire versions of the Eating Disorder Examination (EDE). Multilevel analyses were conducted investigating gender differences at baseline and posttreatment, defined as EDE scores, objective binge episode (OBE) reduction, and OBE remission at termination. RESULTS: Few males from low socioeconomic status or minority groups participated in the outcome studies. Males reported significantly lower EDE global, shape, weight, and eating concerns at baseline. No main effects of gender were found in treatment outcome scores when controlling for baseline differences; however, baseline EDE global score (which showed gender differences at baseline) and OBEs directly predicted outcome for both males and females. A significant interaction between gender, treatment length, and shape/weight concerns indicated that males with lower shape/weight concerns achieved OBE remission in shorter treatments, whereas men with high shape/weight concerns and women with either high or low shape/weight concerns were more likely to achieve OBE remission in treatments of longer duration. CONCLUSIONS: These results suggest BED treatment studies must improve their recruitment of men and appeal to men with lower shape/weight concerns. Additionally, longer term treatments, although more efficacious for women and men with more severe shape/weight concerns, may not be necessary for men with low shape/weight concerns. (PsycINFO Database Record PMID- 25730522 TI - Defining and characterizing differences in college alcohol intervention efficacy: A growth mixture modeling application. AB - OBJECTIVE: While college alcohol misuse remains a pervasive issue, individual level interventions are among the most efficacious methodologies to reduce alcohol-related harms. Growth mixture modeling (GMM) was used as an exploratory moderation analysis to determine how many types of college drinkers exist with regard to intervention efficacy over a 12-month period. METHOD: Data from 3 randomized controlled trials were combined to yield a sample of 1,040 volunteer and mandated college students who were given 1 of 3 interventions: a brief motivational intervention, Alcohol Edu for Sanctions, or Alcohol 101 Plus. Participants were assessed at baseline, and 1, 6, and 12 months postintervention. RESULTS: Through the examination of heavy drinking behaviors, piecewise GMM identified 6 subpopulations of drinkers. Most of the sample (76%) was lighter drinkers who demonstrated a strong intervention response, but returned to baseline behaviors over the subsequent 12 months. In contrast, 11% of the sample reported no significant change over the 12-month period. Four minority subpopulations were also identified. In sum, 82% of the sample responded to intervention, but 84% of the sample reported intervention decay over the subsequent 12 months. Female gender, being an, upperclassmen, beginning drinking later in life, not engaging in drinking games, and lower norms predicted a greater likelihood of responding to intervention. CONCLUSION: Individual-level interventions are successful at effecting change in most college students, but these effects tend to decay to baseline behaviors by 12 months. These results suggest intervention efforts need to find ways to engage freshmen men and those who play drinking games. (PsycINFO Database Record PMID- 25730523 TI - Asymmetric total synthesis of (+)-dragmacidin D reveals unexpected stereocomplexity. AB - The first asymmetric total synthesis of the bis-indole marine alkaloid (+) dragmacidin D (1) has been achieved. This synthesis revises an earlier configurational assignment based on biosynthetic considerations and assigns an R absolute configuration to (+)-1. The current studies reveal that natural dragmacidin D is isolated as either a racemate or a scalemic mixture (39% ee). PMID- 25730524 TI - Surface modification of silicone tubes by functional carboxyl and amine, but not peroxide groups followed by collagen immobilization improves endothelial cell stability and functionality. AB - Surface modification by functional groups promotes endothelialization in biohybrid artificial lungs, but whether it affects endothelial cell stability under fluid shear stress, and the release of anti-thrombotic factors, e.g. nitric oxide (NO), is unknown. We aimed to test whether surface-modified silicone tubes containing different functional groups, but similar wettability, improve collagen immobilization, endothelialization, cell stability and cell-mediated NO-release. Peroxide, carboxyl, and amine-groups increased collagen immobilization (41-76%). Only amine-groups increased ultimate tensile strength (2-fold). Peroxide and amine enhanced (1.5-2.5 fold), but carboxyl-groups decreased (2.9-fold) endothelial cell number after 6 d. After collagen immobilization, cell numbers were enhanced by all group-modifications (2.8-3.8 fold). Cells were stable under 1 h-fluid shear stress on amine, but not carboxyl or peroxide-group-modified silicone (>50% cell detachment), while cells were also stable on carboxyl-group modified silicone with immobilized collagen. NO-release was increased by peroxide and amine (1.1-1.7 fold), but decreased by carboxyl-group-modification (9.8 fold), while it increased by all group-modifications after collagen immobilization (1.8-2.8 fold). Only the amine-group-modification changed silicone stiffness and transparency. In conclusion, silicone-surface modification of blood contacting parts of artificial lungs with carboxyl and amine, but not peroxide groups followed by collagen immobilization allows the formation of a stable functional endothelial cell layer. Amine-group-modification seems undesirable since it affected silicone's physical properties. PMID- 25730527 TI - Global perspectives on nutritional knowledge, eating behavior, household food security, and hunger. PMID- 25730526 TI - An Independently folding RNA G-quadruplex domain directly recruits the 40S ribosomal subunit. AB - In this study, we report that a 17-nucleotide independently folding RNA G quadruplex (GQ) domain within the 294-nucleotide human VEGF IRES A interacts with the 40S ribosomal subunit. Footprinting and structure mapping analyses indicate that the RNA GQ forms independently and interacts directly with the 40S ribosomal subunit in the absence of other protein factors. Moreover, a filter binding assay in conjunction with enzymatic footprinting clearly established that the GQ forming domain singularly dictates the binding affinity and also the function of internal ribosomal entry site (IRES) A. The deletion of the GQ domain abrogates the binding of the 40S ribosomal subunit to the IRES, which impairs cap independent translation initiation. The findings provide a unique and defined role for a noncanonical RNA structure in cap-independent translation initiation by cellular IRESs. The GQ structure when present in an IRES acts as an essential element in contrast to their generally accepted inhibitory role in translation. The results of this study explain the hitherto unknown mechanistic necessity of the GQ structure in IRES function. PMID- 25730525 TI - Switching from risperidone long-acting injectable to paliperidone long-acting injectable or oral antipsychotics: analysis of a Medicaid claims database. AB - This report examines relapse risk following a switch from risperidone long-acting injectable (RLAI) to another long-acting injectable antipsychotic [paliperidone palmitate (PP)] versus a switch to oral antipsychotics (APs). Truven Health's MarketScan Multistate Medicaid Database compared relapses following switches from RLAI. New user cohorts for these two groups were created on the basis of first incidence of exposure to the 'switched to' drug. Groups were balanced using 1:1 propensity score matching. Time-to-event analysis assessed schizophrenia-related hospital/emergency department visits. A total of 188 patients switched from RLAI to PP, and 131 patients switched from RLAI to oral AP. Propensity score-matched cohort included 109 patients who switched to PP and 109 patients who switched to an oral AP. Patients who switched from RLAI to PP had fewer events (26 vs. 32), longer time to an event (mean 70 vs. 47 days), and lower risk of relapse (hazard ratio, 0.54; 95% confidence interval, 0.32-0.92; P=0.024) compared with those who switched from RLAI to oral AP. Switching from RLAI to PP may be associated with a lower risk for relapse and longer duration of therapy compared with switching to oral AP. Given the limitations of observational studies, these results should be confirmed by other prospective evaluations. PMID- 25730528 TI - Evaluation of Dietary Supplement Contamination by Xenobiotic and Essential Elements Using Microwave-Enhanced Sample Digestion and Inductively Coupled Plasma Mass Spectrometry. AB - Dietary supplements were analyzed by evaluating the elemental content in six widely consumed products manufactured by four well-known companies. The elements included the neurotoxic and carcinogenic elements cadmium, mercury, aluminum, lead, arsenic, and antimony, as well as the essential elements zinc, selenium, chromium, iron, and copper, which were often not listed as ingredients on the product labels. Contamination from either xenobiotic or essential elements was found in all samples analyzed. The samples were prepared using US Environmental Protection Agency (EPA) Method 3052, microwave-enhanced digestion. The resulting digests were analyzed by Inductively Coupled Plasma-Mass Spectrometry based on EPA Method 6020B. The analytical protocols were validated by analyzing a multivitamin standard reference material, the National Institute of Standards and Technology Standard Reference Material 3280. The application of EPA standard methods demonstrated their utility in making accurate and precise measurements in complex matrices with multiple ingredients and excipients. In the future, the use of these methods could provide a uniform quality assurance protocol that can be implemented along with other industry guidelines to improve the production of dietary supplements. PMID- 25730534 TI - How to write a journal article for PSN. AB - Are you considering writing a journal article for Plastic Surgical Nursing? This official journal of the American Society of Plastic Surgical Nurses presents the latest advances in plastic and reconstructive surgical nursing practice. The journal features clinical articles covering a wide variety of surgical and nonsurgical procedures. Patient education techniques and research findings are also included, as well as articles discussing the ethical issues and trends in this expanding clinical nursing specialty. This is a perfect forum to share your knowledge with others in the plastic surgery field, resulting in improved patient care. The editorial board is established and available to assist you in the writing process. It is important to know that you do not have to be an academic scholar to write an article; instead, you have information that you would like to share. This article is intended to provide key points to follow to make sure that writing your article is a positive experience. PMID- 25730530 TI - Model of interactive clinical supervision in acute care environments. Balancing patient care and teaching. AB - RATIONALE: Progressive trainee autonomy is considered essential for clinical learning, but potentially harmful for patients. How clinical supervisors and medical trainees establish progressive levels of autonomy in acute care environments without compromising patient safety is largely unknown. OBJECTIVES: To explore how bedside interactions among supervisors and trainees relate to trainee involvement in patient care and to clinical oversight. METHODS: We conducted a qualitative study based on constructivist grounded theory methodology. We used participant observation for our data collection. We observed the overt teaching interactions among trainees and staff physicians in the critical care units of two university-affiliated hospitals during 74 acute care episodes. Our analysis led to the elaboration of a theoretical model of clinical supervision. MEASUREMENTS AND MAIN RESULTS: A model of interactive clinical supervision is proposed on the basis of three themes: engaging without enactment, sharing care with support, and caring independently with feedback. Each theme regroups different teaching interactions. Engaging in monologues and dialogues about patient care and facilitating hands-off care provision involved progressive levels of trainee involvement without risk for patients. Facilitating hands-on provision of care and providing support-in-action encouraged further trainee involvement with limited risks for patients. Providing feedback-on-action created additional learning opportunities based on trainee independent involvement in clinical activities. CONCLUSIONS: Engaging in teaching interactions during acute care episodes allows trainees to exercise progressive autonomy and supervisors to provide adequate clinical oversight. Our model of interactive clinical supervision can inform faculty development initiatives. Learning outcomes resulting from different levels of trainee autonomy should be further explored. PMID- 25730535 TI - An evidence-based practice case study: white coat hypertension. AB - White coat hypertension, also referred to as isolated clinical hypertension, is a condition in which blood pressure rises in the medical setting due to anxiety. White coat hypertension causes no more than 15 mmHg increase in systolic blood pressure or 7 mmHg increase in diastolic blood pressure in normotensive patients, and these increases in blood pressures should return to baseline within 3 visits to the medical provider. In this case, a 77-year-old white man presented to preoperative testing, with a blood pressure of 265/101 mmHg, claiming to have white coat hypertension. This case discusses the interventions implemented for this particular patient and the misdiagnosis and misperceptions of white coat hypertension by both clinicians and patients. This article also addresses recommendations for diagnosis, treatment options, and follow-up for patients with true white coat hypertension. PMID- 25730532 TI - Evidence-based practice (EBP). PMID- 25730529 TI - Extracts of Leptadenia hastata Leaf, a Famine Food and Traditional Remedy for Furuncles, Suppress Inflammation in Murine Models. AB - The effects of the methanol extract (LHE), hexane (LHHF), ethylacetate (LHEF) and methanol (LHMF) fractions of leaf of Leptadenia hastata on acute and chronic inflammation were studied. Furthermore, the effects of LHE on acetic acid induced increase in vascular permeability, carrageenan induced leucocyte migration and membrane stability were evaluated. The LHE and fractions were also subjected to phytochemical analysis. The LHE, LHEF and LHMF significantly (p < 0.05) suppressed topical ear edema, systemic paw edema, global edematous response to formaldehyde arthritis and granuloma tissue growth. The LHE suppressed acetic acid induced vascular permeability and carrageenan-induced leucocyte migration, and also stabilized the erythrocyte membrane. An acute toxicity test in mice established an oral LD50 > 5 g/kg for LHE. The LHEF elicited the greatest inhibition, suggesting that the observed anti-inflammatory effects may be attributable to the flavonoids abundant in the fraction. These findings demonstrate that the effectiveness of L. hastata leaf in the treatment of furuncles may largely derive from anti-inflammatory activities mediated through inhibition of both increase in vascular permeability and leucocyte migration, and stabilization of cell membranes. PMID- 25730536 TI - Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. AB - BACKGROUND: The ever-expanding range of dermal filler products for aesthetic soft tissue augmentation is of benefit for patients and physicians, but as indications and the number of procedures performed increase, the number of complications will likely also increase. OBJECTIVE: To describe potential adverse events associated with dermal fillers and to provide structured and clear guidance on their treatment and avoidance. METHODS: Reports of dermal filler complications in the medical literature were reviewed and, based on the publications retrieved and the authors' extensive experience, recommendations for avoiding and managing complications are provided. RESULTS: Different dermal fillers have widely varying properties, associated risks, and injection requirements. All dermal fillers have the potential to cause complications. Most are related to volume and technique, though some are associated with the material itself. The majority of adverse reactions are mild and transient, such as bruising and trauma-related edema. Serious adverse events are rare, and most are avoidable with proper planning and technique. CONCLUSION: For optimum outcomes, aesthetic physicians should have a detailed understanding of facial anatomy; the individual characteristics of available fillers; their indications, contraindications, benefits, and drawbacks; and ways to prevent and avoid potential complications. PMID- 25730538 TI - Sample policies for your policy and procedure manual. AB - A policy and procedure manual is a tool to set guidelines and expectations based on the mission and vision of an office. If a manual is not available to set guidelines, the employees may make their own decisions to solve problems, which can often result in confusion, inconsistencies, and mistakes. A well-written policy manual will also benefit the staff by providing them with a quick resource for decision-making. This will increase the quality of service by reducing the risk of potential mistakes that can be made in a busy practice. PMID- 25730537 TI - Aesthetic self-esteem. AB - The concept of aesthetic self-esteem was explored for utilization in the medical spa environment. The aims and purposes of the analysis were outlined. The literature review identified various uses of the self-esteem concept as well as published definitions of the word. Defining attributes were also explored and examined, including positive and negative connotations of self-esteem. Two tools were utilized to help aesthetic nurse specialists assess patients for self-esteem and assess for a possible mental illness that may present as low self-esteem. A culturally sensitive theoretical definition of self-esteem was constructed to fit the needs and environment of medical spas. A model case of this definition, as well as a borderline and contrary case, was presented. Antecedents and consequences, as well as empirical referents of the concept, were explored. PMID- 25730539 TI - "Skin facts" to optimize aesthetic outcomes. AB - Aesthetic providers need to be well versed in the anatomy and intricacies of the skin. This foundational skin knowledge is critical in assessing clients' aged skin during the aesthetic consultation. A sound understanding of the skin is also a prerequisite to any facial rejuvenation procedure. This article provides the aesthetic provider with the basics of skin anatomy and how the skin changes over time. PMID- 25730540 TI - A prospective randomized trial comparing silver sulfadiazine cream with a water soluble polyantimicrobial gel in partial-thickness burn wounds. AB - The lipid base of silver sulfadiazine (SSD) makes removal of the product painful for the patient and difficult for the physician to accurately assess particularly in partial-thickness burn injuries. As an alternative, a water-soluble antimicrobial gel is used at the University of Virginia. We present a prospective, randomized comparison of these two therapies using pain with dressing changes and time to perform dressing changes as our primary endpoints. Adult inpatients with partial-thickness burn wounds were randomized to begin therapy with either SSD cream or the water-soluble burn wound gel (BWG), and then therapies were alternated daily. Pain assessments, time to complete dressing care, total narcotic medication administered, and the number of personnel required for dressing changes were recorded. Eight patients were enrolled resulting in 13 pairs (26 points) of data comparison between the two therapies. Four of the eight enrolled patients (50%) refused to continue receiving SSD because of pain associated with dressing changes and voluntarily withdrew from the study. The amount of time to perform dressing changes was an average of 79 nurse-minutes longer for SSD. A 6.08 greater morphine equivalent was delivered to those having BWG removed.A water-soluble polyantimicrobial gel was superior to SSD in the parameters measured as exhibited by our patient dropout rate and differential time to perform dressing care. Limiting the time to perform dressing care will reduce the cumulative pain experience, improve patient satisfaction, and reduce the resources to deliver care. PMID- 25730544 TI - Metabolic disorders associated with the use of targeted cancer therapies. AB - PURPOSE OF REVIEW: The everyday use of targeted therapies, whose mechanisms of action differ from the conventional cytotoxic agents, also causes the emergence of new toxicities as metabolic disorders about which little is known. We propose a systematic literature review of the incidence and physiopathology of targeted therapies-induced metabolic disorders and provide some management guidance. RECENT FINDINGS: In recent decades, significant breakthroughs in molecular oncology and immunology have been made. The administration of targeted therapies and immunotherapy has been associated with metabolic toxicities such as endocrine disorders, dyslipidemia, induced diabetes, and electrolytic disorders. Current data show that metabolic disorders are becoming increasingly common, but rarely life threatening and often reversible with prompt therapeutic intervention. SUMMARY: In the era of targeted therapies, medical oncologists should know the symptoms, carefully monitor patients for potential metabolic disorders, and manage these emerging side-effects with the help of endocrinologists and other medical specialists. PMID- 25730543 TI - Safety Profile of 5-Aminolevulinic Acid as a Surgical Adjunct in Clinical Practice: A Review of 207 Cases From 2008 to 2013. AB - BACKGROUND: 5-Aminolevulinic acid (5-ALA) is used for brain tumor identification during surgery through fluorescence. Its use is linked to side effects such as photodermatosis, anemia, or plaquetopenia. Many institutions take very strict precautions to prevent them. Our hospital's protocol mandates avoidance of direct sunlight during the first 24 hours only. METHODS: Retrospective cohort observational study of 207 consecutive patients who underwent 5-ALA-guided brain tumor resection between 2008 and 2013, and compared with a control group of 53 patients without 5-ALA. RESULTS: No skin reaction was reported. No difference was found in hemoglobin or platelet level comparisons at different points in time. There was no difference in trends within groups. Mean duration of surgery was longer in the 5-ALA group; the subgroup of patients undergoing their first surgery had a positive correlation with lower hemoglobin levels. In postoperative magnetic resonance imaging, patients in the 5-ALA group had a lower percentage of residual bleeding (19% of all patients; 17.9% in 5-ALA group and 22.7% in non-ALA [P=0.04]). Eight patients in the 5-ALA group required blood transfusion (3.9%), compared with 2 in the control group (3.8%). Four patients in the 5-ALA group required reintervention in the first 48 hours due to bleeding, although none had platelets <150,000/mL. CONCLUSIONS: Significant side effects appear to be uncommon. Blood count changes are likely multifactorial; surgical time may account for it partially, whereas 5-ALA role is not clear and may not be significant. PMID- 25730545 TI - Recovery of cerebral blood flow following sports-related concussion. AB - IMPORTANCE: Animal models suggest that reduced cerebral blood flow (CBF) is one of the most enduring physiological deficits following concussion. Despite this, longitudinal studies documenting serial changes in regional CBF following human concussion have yet to be performed. OBJECTIVE: To longitudinally assess the recovery of CBF in a carefully selected sample of collegiate athletes and compare time course of CBF recovery with that of cognitive and behavioral symptoms. DESIGN, SETTING, AND PARTICIPANTS: A cohort of collegiate football athletes (N = 44) participated in this mixed longitudinal and cross-sectional study at a private research institute specializing in neuroimaging between March 2012 and December 2013. Serial imaging occurred approximately 1 day, 1 week, and 1 month postconcussion for a subset of participants (n = 17). All athletes reported no premorbid mood disorders, anxiety disorders, substance abuse, or alcohol abuse. MAIN OUTCOMES AND MEASURES: Arterial spin labeling magnetic resonance imaging was used to collect voxelwise relative CBF at each visit. Neuropsychiatric evaluations and a brief cognitive screen were also performed at all 3 points. Clinicians trained in sports medicine provided an independent measure of real world concussion outcome (ie, number of days withheld from competition). RESULTS: The results indicated both cognitive (simple reaction time) and neuropsychiatric symptoms at 1 day postinjury that resolved at either 1 week (cognitive; P < .005) or 1 month (neuropsychiatric; P < .005) postinjury. Imaging data suggested both cross-sectional (ie, healthy vs concussed athletes; P < .05) and longitudinal (1 day and 1 week vs 1 month postinjury; P < .001) evidence of CBF recovery in the right insular and superior temporal cortex. Importantly, CBF in the dorsal midinsular cortex was both decreased at 1 month postconcussion in slower-to recover athletes (t11 = 3.45; P = .005) and was inversely related to the magnitude of initial psychiatric symptoms (Hamilton Depression Scale: r = -0.64, P = .02; Hamilton Anxiety Scale: r = -0.56, P = .046), suggesting a potential prognostic indication for CBF as a biomarker. CONCLUSIONS AND RELEVANCE: To our knowledge, these results provide the first prospective evidence of reduced CBF in human concussion and subsequent recovery. The resolution of CBF abnormalities closely mirrors previous reports from the animal literature and show real-world validity for predicting outcome following concussion. PMID- 25730547 TI - The DosR Regulon Modulates Adaptive Immunity and Is Essential for Mycobacterium tuberculosis Persistence. AB - RATIONALE: Hypoxia promotes dormancy by causing physiologic changes to actively replicating Mycobacterium tuberculosis. DosR controls the response of M. tuberculosis to hypoxia. OBJECTIVES: To understand DosR's contribution in the persistence of M. tuberculosis, we compared the phenotype of various DosR regulon mutants and a complemented strain to M. tuberculosis in macaques, which faithfully model M. tuberculosis infection. METHODS: We measured clinical and microbiologic correlates of infection with M. tuberculosis relative to mutant/complemented strains in the DosR regulon, studied lung pathology and hypoxia, and compared immune responses in lung using transcriptomics and flow cytometry. MEASUREMENTS AND MAIN RESULTS: Despite being able to replicate initially, mutants in DosR regulon failed to persist or cause disease. On the contrary, M. tuberculosis and a complemented strain were able to establish infection and tuberculosis. The attenuation of pathogenesis in animals infected with the mutants coincided with the appearance of a Th1 response and organization of hypoxic lesions wherein M. tuberculosis expressed dosR. The lungs of animals infected with the mutants (but not the complemented strain) exhibited early transcriptional signatures of T-cell recruitment, activation, and proliferation associated with an increase of T cells expressing homing and proliferation markers. CONCLUSIONS: Delayed adaptive responses, a hallmark of M. tuberculosis infection, not only lead to persistence but also interfere with the development of effective antituberculosis vaccines. The DosR regulon therefore modulates both the magnitude and the timing of adaptive immune responses in response to hypoxia in vivo, resulting in persistent infection. Hence, DosR regulates key aspects of the M. tuberculosis life cycle and limits lung pathology. PMID- 25730548 TI - An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins. AB - The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3 diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds. PMID- 25730550 TI - Identification and characterization of the aroma-impact components of Thai fish sauce. AB - Comprehensive analysis of the potent odorants in Thai premium fish sauce samples was accomplished by use of complementary volatile isolation methods combined with gas chromatography-olfactometry (GC-O) and GC-mass spectrometry. Odorants of intermediate and low volatility were determined by direct solvent extraction/solvent-assisted flavor evaporation (DSE-SAFE) and aroma extract dilution analysis (AEDA). Meanwhile, static headspace dilution analysis (SHDA) and headspace solid-phase microextraction (H-SPME) were used to determine the highly volatile odorants. Results of AEDA indicated the importance (log3FD factor>=6) of five acidic odorants (butanoic acid, 3-methylbutanoic acid, 4 hydroxy-2,5-dimethyl-3(2H)-furanone, 4-hydroxy-2-ethyl-5-methyl-3(2H)-furanone, and 2-phenylacetic acid) and four neutral/basic odorants (3-methylbutanal, (Z) 1,5-octadien-3-one, phenylacetaldehyde, and o-aminoacetophone). Results of SHDA indicated the predominant (log3FD factors>=5) headspace odorants were methanethiol, 2-methylpropanal, 2-methylbutanal, 3-methylbutanal, dimethyl trisulfide, 3-(methylthio)propanal, and butanoic acid. Concentrations for 21 odorants were determined by stable isotope dilution analysis (SIDA), and their odor-activity values (OAVs) were calculated. Among these, methanethiol, 2 methylpropanal, 3-methylbutanal, dimethyl trisulfide, 3-(methylthio)propanal, and butanoic acid had the highest OAVs (>500). Results of aroma recombination and omission studies revealed the importance of acids, aldehydes, and sulfur containing compounds to the overall aroma of the Thai fish sauce. PMID- 25730549 TI - The structure of SpnF, a standalone enzyme that catalyzes [4 + 2] cycloaddition. AB - In the biosynthetic pathway of the spinosyn insecticides, the tailoring enzyme SpnF performs a [4 + 2] cycloaddition on a 22-membered macrolactone to forge an embedded cyclohexene ring. To learn more about this reaction, which could potentially proceed through a Diels-Alder mechanism, we determined the 1.50-A resolution crystal structure of SpnF bound to S-adenosylhomocysteine. This sets the stage for advanced experimental and computational studies to determine the precise mechanism of SpnF-mediated cyclization. PMID- 25730552 TI - A three-state nanofluidic field effect switch. AB - We report a three-state nanofluidic field effect switch in an asymmetrically gated device with a forward (positive), off (zero), and a reverse (negative) current state for tunable control of ionic transport by systematically controlling the gate potential. The embedded gate electrode allows for modulation of the ionic current through the 16 nm deep channels as a function of electrolyte concentration and gate electrode location for a fixed streamwise potential. PMID- 25730553 TI - Coronary computed tomography angiography for the assessment of acute chest pain in the emergency department: evidence, guidelines, and tips for implementation. AB - Acute chest pain is an important clinical challenge and a major reason for presentation to the emergency department. Although multiple imaging techniques are available to assess such patients, considerable interest has focused on the use of coronary computed tomography (CT) angiography. Three recent multicenter trials have demonstrated the value of coronary CT angiography (CCTA) to diagnose patients with acute coronary syndrome (ACS) rapidly and accurately. Guidelines developed on the basis of these and other studies suggest that CCTA is optimally used in patients with low to intermediate risk for ACS. A related protocol, the triple rule-out scan, may be valuable if overlapping symptoms occur, particularly between those of ACS and pulmonary embolism. In developing a program to perform CCTA in the emergency room, it is important to work closely with emergency physicians and cardiologists to maximize appropriate use of this technique and to develop appropriate protocols that minimize radiation dose. Ongoing efforts to improve existing capabilities of CCTA include better characterization of coronary plaque and the use of CT fractional flow reserve and perfusion techniques. PMID- 25730554 TI - Diffuse Parenchymal Abnormalities in Acutely Dyspneic Patients: A Pattern-based Approach. AB - Acute dyspnea is a common presenting complaint in the Emergency Room. Evaluation with chest radiography is vital for initial assessment and may reveal diffuse parenchymal abnormalities that require further assessment with computed tomography (CT). The aim of this review is to outline a pattern-based approach for the analysis of diffuse pulmonary abnormalities in an acutely dyspneic patient with emphasis on CT appearances. Specific disease entities may be differentiated by their distribution in the lungs and by their radiologic findings. Recognition of the predominant finding and its distribution can generate an appropriate differential diagnosis that is further refined by the presence or absence of ancillary findings. Incorporation of the clinical history, laboratory data, and prior studies narrows the differential diagnosis, indicates the optimum modality for further evaluation, and, in some situations, provides important prognostic data. PMID- 25730555 TI - Prevalence of Venoatrial Compression by Lymphadenopathy in Sarcoidosis. AB - PURPOSE: The purpose of the study was to evaluate the prevalence of compressive lymphadenopathy on pulmonary veins (PV) and left atrium (LA) in patients with sarcoidosis. MATERIALS AND METHODS: A total of 101 consecutive patients underwent a chest computed tomography angiographic examination with specific analysis of: (a) 3 nodal stations (ie, 7, 8, and 9 stations) for detection of LA compression; (b) 2 nodal stations (ie, 10 and 11 right and left stations) for detection of PV compression. RESULTS: Lymphadenopathy was present in 64 patients (64/101; 63.4%) with computed tomography features of venoatrial compression in 17 patients (17/101; 16.8%). This subgroup included 10 patients with LA compression alone (10/64; 15.6%), 6 patients with PV compression alone (6/64; 9.4%), and 1 patient with both (1/64; 1.5%). The mean diameter of enlarged lymph nodes compressing the LA and PVs was 3.18 +/- 0.73 cm (range: 2.1 to 4.4 cm) and 1.9 +/- 0.45 cm (range: 1 to 2.9 cm), respectively. PV compression was depicted in a total of 7 patients (7/101; 6.9%), observed as a unilateral (n = 5) or bilateral (n = 2) finding, with a mean number of 3.0 PVs compressed per patient (range: 1 to 7). A total of 10 venous sections showed features of compression, at the level of a lobar confluence (n = 6) or individual segmental veins (V6; n = 4), with a mean reduction in the venous cross-sectional area of 51.09% +/- 12.85% (median: 50.06%). Nonfibrotic lung infiltration associated with sarcoidosis was observed in 88.2% of patients with compressive lymphadenopathy (15/17). CONCLUSIONS: The prevalence of venoatrial compression in sarcoidosis is 16.8% in the studied population. PMID- 25730556 TI - Tuning the electronic and phosphorescence properties of blue-emitting iridium(III) complexes through different cyclometalated ligand substituents: a theoretical investigation. AB - The geometric and electronic structures, phosphorescence properties and the organic light-emitting diode (OLED) performance of a series of Ir(III) complexes based on bis[(4,6-di-fluorophenyl)-pyridinato-N,C2']picolinate (FIrpic) were investigated by using density functional theory/time-dependent density functional theory (DFT/TD-DFT), including Ir(III)bis[2-(2,4-difluorophenyl)-4-(tert butyl)pyridinato-N,C2']picolinate (1a), Ir(III)bis[2-(2,4-difluorophenyl)-4-(n heptyl)pyridinato-N,C2']picolinate (2a), Ir(III)bis[2-(2,4-difluorophenyl)-4-(3 ethylheptyl)pyridinato-N,C2']picolinate (3a), Ir(III)bis[2-(2,4-difluorophenyl)-4 (2,4,6-trimethylphenyl)pyridinato-N,C2']picolinate (5a), and Ir(III)bis[2-(2,4 difluoro-3-(2,4,6-trimethylphenyl)phenyl)-pyridinato-N,C2'] picolinate (5b). To explore the influence of the substituted positions on the optical and electronic properties of the Ir(III) complexes, seven other new complexes were designed by introducing the substituted groups on the difluorophenyl rings or pyridine rings. After introducing the phenyl substituted groups on the pyridine or difluorophenyl rings of cyclometalated ligands, the HOMO-LUMO energy gap is decreased. Thus, the absorption spectra of 4a and 4b undergo a red-shifting, especially for 4a, and have a stronger absorption strength that will be beneficial to improving their quantum yields, which is proved by the further evaluation of the radiative (k(r)) and non-radiative (k(nr)) rate constants. The combinations of a larger (3)MLCT (3)MC energy gap, smaller DeltaE(S1-T1), and higher contribution of (3)MLCT in the emission process result in the higher quantum yields for complexes 4a and 4b. Besides, the designed complexes 4a and 4b are considered to be potential candidates as blue-emitting materials with better equilibrium between the hole transport (lambda(hole)) and electron transport (lambda(electron)). PMID- 25730557 TI - Cognitive abilities required in time judgment depending on the temporal tasks used: A comparison of children and adults. AB - The aim of this study was to examine age-related differences in time judgments during childhood as a function of the temporal task used. Children aged 5 and 8 years, as well as adults, were submitted to 3 temporal tasks (bisection, generalization and reproduction) with short (0.4/0.8 s) and long durations (8/16 s). Furthermore, their cognitive capacities in terms of working memory, attentional control, and processing speed were assessed by a wide battery of neuropsychological tests. The results showed that the age-related differences in time judgment were greater in the reproduction task than in the temporal discrimination tasks. This task was indeed more demanding in terms of working memory and information processing speed. In addition, the bisection task appeared to be easier for children than the generalization task, whereas these 2 tasks were similar for the adults, although the generalization task required more attention to be paid to the processing of durations. Our study thus demonstrates that it is important to understand the different cognitive processes involved in time judgment as a function of the temporal tasks used before venturing to draw conclusions about the development of time perception capabilities. PMID- 25730562 TI - "Less is more" and the house of god: was the fat man right again? PMID- 25730563 TI - Teaching the diagnostic and healing qualities of story. PMID- 25730559 TI - The A, B, Cs of herpesvirus capsids. AB - Assembly of herpesvirus nucleocapsids shares significant similarities with the assembly of tailed dsDNA bacteriophages; however, important differences exist. A unique feature of herpesviruses is the presence of different mature capsid forms in the host cell nucleus during infection. These capsid forms, referred to as A-, B-, and C-capsids, represent empty capsids, scaffold containing capsids and viral DNA containing capsids, respectively. The C-capsids are the closest in form to those encapsidated into mature virions and are considered precursors to infectious virus. The evidence supporting A- and B-capsids as either abortive forms or assembly intermediates has been lacking. Interaction of specific capsid forms with viral tegument proteins has been proposed to be a mechanism for quality control at the point of nuclear egress of mature particles. Here, we will review the available literature on these capsid forms and present data to debate whether A- and B-capsids play an important or an extraneous role in the herpesvirus life cycle. PMID- 25730564 TI - Increased left ventricular trabeculation does not necessarily equate to left ventricular noncompaction in athletes. PMID- 25730565 TI - Intermittent bolus or continuous infusion of proton pump inhibitors for ulcer bleeding? PMID- 25730566 TI - Using Medicare data to understand health care value: measures of incremental cost and effectiveness are both needed to estimate value. PMID- 25730567 TI - Using medicare data to understand health care value--reply. PMID- 25730568 TI - Antidepressant dose and risk of deliberate self-harm: is it the dose or the indication? PMID- 25730569 TI - Advancing medical professionalism and the choosing wisely campaign. PMID- 25730570 TI - Antidepressant dose and risk of deliberate self-harm--reply. PMID- 25730571 TI - Treatment of borderline elevated thyrotropin levels. PMID- 25730572 TI - Advancing medical professionalism and the choosing wisely campaign--reply. PMID- 25730573 TI - Treatment of borderline elevated thyrotropin levels. PMID- 25730574 TI - Treatment of borderline elevated thyrotropin levels--reply. PMID- 25730575 TI - Access to primary care in England. PMID- 25730576 TI - Access to primary care in England--reply. PMID- 25730577 TI - Television watching and effects on food intake: distress vs eustress. PMID- 25730578 TI - Television watching and effects on food intake--reply. PMID- 25730579 TI - Mortality trends in diabetes mellitus. PMID- 25730580 TI - Error in author's name. PMID- 25730581 TI - Error in figure. PMID- 25730582 TI - Mortality trends in diabetes mellitus--reply. PMID- 25730583 TI - Molecular engineering of nonmetallic biosensors for CEST MRI. AB - Recent advancements in molecular and synthetic biology, combined with synthetic chemistry and biotechnology, have opened up new opportunities to engineer novel platforms that can monitor complex biological processes with various noninvasive imaging modalities. After decades of using gadolinium- or iron-based metallic sensors for MRI, the recently developed chemical exchange saturation transfer (CEST) contrast mechanism has created an opportunity for rational design, in silico, of nonmetallic biosensors for MRI. These biomolecules are either naturally occurring compounds (amino acids, sugars, nucleosides, native proteins) or can be artificially engineered (synthetic probes or recombinant proteins). They can be administered either as exogenous agents or can be genetically (over)expressed. Moreover, they can be precisely engineered to achieve the desired biochemical properties for fine tuning optimized imaging schemes. The availability of these agents marks the dawn of a new scientific era for molecular and cellular MRI. PMID- 25730584 TI - Does Resilience Mediate Carer Distress After Head and Neck Cancer? AB - BACKGROUND: Caring for patients with head and neck cancer (HNC) can have significant negative psychological and practical impact; however, some carers seem able to cope effectively. Little research has investigated this resilience among carers. OBJECTIVE: The objective of this study was to investigate the resilience levels among carers of patients with HNC. METHODS: Carers (n = 51) from 2 cancer services in New South Wales completed the Resilience Scale (RS), the Head and Neck Information Needs Questionnaire, and the Hospital Anxiety and Depression Scale. Hospital Anxiety and Depression Scale cutoff scores (>8) were used to classify carers with clinically significant levels of anxiety or depression. RESULTS: The majority of carers (67% [34/51]) reported moderately high to high resilience. Rates of anxiety and depression among carers were 27.4% and 9.8%, respectively. Higher resilience scores were significantly correlated with lower anxiety and depression scores, as well as increasing age. Resilience Scale scores were independent of the severity of the HNC. There were no significant correlations between RS scores and Head and Neck Information Needs Questionnaire scores. Finally, increasing RS scores were associated with a decreasing probability of possible anxiety or depression. CONCLUSIONS: These results indicate that higher resilience in carers of HNC patients was associated with lower levels of psychological distress. Further investigation into the relationship between resilience and carer psychological wellbeing is warranted. IMPLICATIONS FOR PRACTICE: If further evidence supports the findings of this study, then investigating ways to build resilience will be an important clinical option for reducing carer morbidity associated with anxiety and depression. The RS could be used to assess resilience levels among carers of HNC patients. PMID- 25730585 TI - Farsi Version of the Mammography Self-efficacy Scale for Iranian Women. AB - BACKGROUND: Self-efficacy is a crucial factor in adopting mammography behavior. A reliable and valid instrument is necessary to measure self-efficacy among Iranian women. OBJECTIVE: The aim of this study is to translate the original version of Champion's Mammography Self-efficacy Scale into Farsi and then to estimate the Farsi version's reliability and validity. METHODS: In a cross-sectional study, 200 women 40 years or older who were referred to health centers in Iran were invited to complete the related questionnaires during an interview. Cronbach's alpha coefficients and item-total correlations were measured to evaluate the reliability of the scales. Content and face validities were evaluated using the opinions of a panel of experts, and construct validity was estimated through applying confirmatory factor analysis. Logistic regression and chi tests were used to estimate theoretical relationships. RESULTS: In terms of reliability, the internal consistency alpha was .904 and the test-retest reliability correlation over a 4-week period was 0.624. With regard to the confirmatory factor analysis, the proportion of chi to degrees of freedom was 0.394, giving a P value of .852 and a root-mean-square error of approximation less than 0.001 with confidence intervals of less than 0.001 and 0.018, with a comparative fit index of 1, normed fit index of 0.999, relative fit index of 0.993, and incremental fit index of 1. CONCLUSION: The items that form the self-efficacy measurement scale in the Farsi version are highly reliable and valid. IMPLICATIONS FOR PRACTICE: Healthcare professionals and nursing health communities may apply the instrument to determine women's self-efficacy and to plan appropriate educational interventions, aiming at promoting women's mammography behavior. PMID- 25730586 TI - Caring for Family Members Older Than 50 Years of Turkish and Northwest African Descent: The Meaning of Caregiving. AB - BACKGROUND: The first generation of immigrants to Belgium from Turkey and Northwest Africa are aging and at risk for developing cancer. Family members play an important role in both illness and old age. OBJECTIVE: The objective of this study was to gain insight into experiences and perceptions of families with Turkish or Northwest African backgrounds who were caring for cancer patients older than 50 years in Flanders, Belgium. METHODS: A qualitative research design with elements of constructivist grounded theory was used. Twenty-eight loosely structured interviews were conducted. Three researchers were involved in data analysis (researcher triangulation), and 6 conversations took place with experts. RESULTS: Cancer appeared to be a family matter. Caregiving had a strong moral meaning for all participants, particularly for children providing care to a parent. Caregiving could be described as "guiding": family members led the patient through, or familiarized the patient with, the healthcare system. There were strong differences in the extent to which family members believed they should provide care, as well as the kind of professional care considered desirable. CONCLUSIONS: Despite shared values of the importance of family and family caregiving, concrete ideas about caregiving differed considerably. The findings imply that shared cultural or religious normative values do not predict day-to-day care practices. IMPLICATIONS FOR PRACTICE: This study provides new insights into the moral and practical meaning of caregiving, which will help professionals understand the roles adopted by family members. Furthermore, individualized approaches to care appear to be essential, because concrete ideas about informal caregiving differ strongly despite shared values. PMID- 25730587 TI - Evaluation of the Impact of Human Papillomavirus DNA Self-sampling on the Uptake of Cervical Cancer Screening. AB - BACKGROUND: The rate of uptake of the Papanicolaou (Pap) smear is generally low. Its causal relationship with human papillomavirus (HPV) DNA allows HPV DNA self sampling to be used as an alternative screening tool for cervical cancer. OBJECTIVES: This study explored the acceptability of HPV DNA self-sampling and its impact on the rate of compliance with cervical cancer screening. METHODS: A crossover randomized clinical trial was conducted in community-based clinics. Participants were allocated to 1 of the following 2 arms: arm 1: self-sampling before a Pap smear; and arm 2: a Pap smear before self-sampling. After completing the 2 screening methods, participants in each arm took part in face-to-face interviews using standardized, structured questionnaire. RESULTS: The participants accepted both self-sampling (7.7/10) and a Pap smear (7.8/10) for cervical cancer screening. However, participants without previous experience of Pap smears or who had more than 2 sexual partners preferred self-sampling (P < .05). The participants expressed overall positive feelings toward self-sampling, and there was good agreement in HPV detection between the 2 screening methods (kappa = 0.65). We estimate that the introduction of HPV DNA self-sampling could increase the future rate of uptake of cervical cancer screening by 6.5% and would entail lower costs. CONCLUSION: Human papillomavirus DNA self-sampling could be an alternative screening method to increase the coverage of cervical cancer screening. IMPLICATIONS FOR PRACTICE: Human papillomavirus DNA self-sampling could overcome the barriers raised by Pap smears and enhance the coverage of cervical cancer screening. Promotional publicity and education are essential. PMID- 25730588 TI - Ankle Dorsiflexion in Childhood Cancer Patients: A Review of the Literature. AB - BACKGROUND: Improved treatment protocols necessary for survival in pediatric oncology are associated with the development of serious late effects. Of particular importance, especially with regard to physical activity, may be ankle dorsiflexion (DF). OBJECTIVE: This review summarizes the results of observational and exercise intervention studies exploring ankle DF-range of motion (DF-ROM) and/or ankle DF strength in pediatric oncology. METHODS: PUBMED, Medline, Cochrane library, and SportDiscus were searched by 2 researchers using predefined search terms. The reference lists of included papers and Google scholar were then searched to that ensure all appropriate articles were included. RESULTS: Twelve studies were identified and were observational (n = 8), providing information regarding the status of DF-ROM and/or DF strength, or intervention studies (n = 4) using exercise as a strategy to improve DF function. All observational studies reported some degree of impairment in ankle DF. Two intervention studies found a positive effect of exercise on ankle DF-ROM. CONCLUSION: The preliminary results suggest that pediatric cancer patients and survivors suffer from limitations in ankle DF with interventions varying in efficacy. IMPLICATION FOR PRACTICE: It is hoped that this review will enhance the recognition of the limited ankle DF function in pediatric oncology and initiate further research programs focused on targeting and evaluating ankle DF. PMID- 25730589 TI - Effects of Nei-Guan (P6) Acupressure Wristband: On Nausea, Vomiting, and Retching in Women After Thyroidectomy. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) after thyroidectomy is a common health problem in the recovery room. OBJECTIVE: The aim of this study is to examine the effect of the Nei-Guan (P6) acupressure wristband for PONV among patients undergoing thyroidectomy. METHODS: Sixty Korean female participants were assigned to 1 of 3 groups (n = 20 each). The control group received usual care without the wristband. The placebo group received usual nursing care plus a wristband at the non-P6 site. The treatment group received usual care plus a wristband at the P6 acupoint 30 minutes before anesthesia; the wristband was removed before leaving the recovery room. Data were collected at 3 periods: in the recovery room and at 6 and 24 hours after surgery. RESULTS: The nausea scores of the treatment group were significantly lower than the scores of the placebo or control groups in the recovery room (F = 6.229, P = .044). There were no significant differences in vomiting or retching among the groups. CONCLUSIONS: The P6 stimulation with wristband suppressed nausea right after thyroidectomy in the recovery room but did not suppress subsequent vomiting or retching. IMPLICATION FOR PRACTICE: The findings indicate that P6 acupressure has the short term effect of relieving nausea but not vomiting and retching. Use of P6 wristband holds promise and suggests the need for further testing in a larger randomized clinical trial. Identifying other acupoints is recommended to achieve successful management of PONV. PMID- 25730590 TI - Predictors for Weight Loss in Head and Neck Cancer Patients Undergoing Radiotherapy: A Systematic Review. AB - BACKGROUND: Head and neck cancer patients are at high risk of weight loss because of their disease process and the treatment of their disease. Recognition of predictors for weight loss may be able to give proactive or reactive nutritional treatment to patients at risk. OBJECTIVE: The aim of this study is to identify the independent risk factors for head and neck cancer patients developing weight loss undergoing radiotherapy. METHODS: A comprehensive literature search was performed on January 2014. Articles reporting studies of the predictors for weight loss in head and neck cancer patients undergoing radiotherapy were included. These studies were published between 1982 and 2014. Study quality was assessed using a modified quality assessment tool that was designed previously for an observational study. The effects of studies were combined with the study quality score using a best-evidence synthesis model. RESULTS: Twenty-two observational studies involving 6159 patients were included. There was strong evidence for 3 predictors, including advanced tumor stage, a higher body mass index before treatment, and the use of concurrent chemoradiotherapy. We also identified 8 moderate evidence predictors and 30 limited evidence predictors. CONCLUSION: The scientific literature to date indicates that patients with advanced tumor stage, or a higher body mass index before treatment, or the use of concurrent chemotherapy are at high risk to have weight loss during radiotherapy. IMPLICATIONS FOR PRACTICE: These data provide evidence to guide healthcare professionals in admitting patients who will have weight loss and choosing an optimal prophylactic strategy. PMID- 25730591 TI - A Good Time to Dance? A Mixed-Methods Approach of the Effects of Dance Movement Therapy for Breast Cancer Patients During and After Radiotherapy. AB - BACKGROUND: Dance movement therapy (DMT) is premised on an interconnected body and mind. It has known benefits for cancer patients' physical and psychological health and quality of life. OBJECTIVE: To offer greater insight into a previous randomized controlled trial, the present study qualitatively explored the beneficial elements of DMT over the course of radiotherapy. To better understand the uniqueness of DMT intervention for patients receiving radiotherapy, the study statistically compared them with patients who received DMT after treatment completion. METHODS: Participants were randomized into radiotherapy and postradiotherapy control groups. The radiotherapy group received DMT (6 sessions at 90 minutes each) as they were undergoing radiotherapy. The postradiotherapy group was provided with the same DMT intervention at 1 to 2 months after completing radiotherapy. RESULTS: One hundred and four participants identified 5 main benefit categories. Dance movement therapy helped them (1) cope with cancer, treatment, and physical symptoms; (2) improve mental well-being, attention, and appreciation for the self and body; (3) improve total functioning; (4) bridge back to a normal and better life; and (5) participate in shared positive experiences. The radiotherapy group reported categories 1 and 2 more prominently than did the postradiotherapy group. CONCLUSIONS: The findings reinforced the benefits of DMT while adding the new perspective that delivering DMT intervention throughout cancer treatment can have different and even additional benefits for patients. IMPLICATIONS FOR PRACTICE: The pleasure of dancing and the psychological and physical relief from DMT help patients cope with daily radiation treatments. This could decrease treatment dropout rates when administered in clinical settings. PMID- 25730592 TI - Symptom-Management Self-efficacy Mediates the Effects of Symptom Distress on the Quality of Life Among Taiwanese Oncology Outpatients With Breast Cancer. AB - BACKGROUND: Theory has suggested that self-efficacy plays an important role in facilitating health behaviors and, in turn, promoting healthy outcomes. However, limited research has focused on the mechanisms through which symptom-management self-efficacy acts as a mediator between symptom distress and quality of life (QOL) for patients with breast cancer who have undergone chemotherapy. OBJECTIVE: The purpose of this study is to examine the association between symptom distress and QOL among Taiwanese oncology outpatients with breast cancer and proposed symptom-management self-efficacy as a mediator between symptom distress and QOL. METHODS: This cross-sectional study included 201 oncology outpatients in 1 teaching hospital in the Taipei area of Taiwan. The research instruments included the Symptom-Management Self-Efficacy Scale-Breast Cancer, the symptom distress scale, and the European Organization for Research and Treatment of Cancer Quality of Life Group Questionnaire. Bootstrapping was used to statistically assess the possible mediating effects of self-efficacy on QOL. RESULTS: Symptom-management self-efficacy mediated the association between symptom distress and global QOL (indirect effect, -6.33; 95% confidence interval [CI], -9.63 to -3.74), functional QOL (indirect effect, -4.47; 95% CI, -7.05 to -2.36), and symptom QOL (indirect effect, 2.59; 95% CI, 1.07-4.83). All of the 95% CIs were significant. The lower symptom distress that patients experienced was indirectly associated with better QOL through higher self-efficacy. CONCLUSIONS: Symptom management self-efficacy may be a crucial mechanism through which symptom distress influences patients' QOL. IMPLICATIONS: Clinicians may incorporate strategies focused on improving patients' self-efficacy in relation to managing their symptoms caused by chemotherapy to improve patients' QOL. PMID- 25730593 TI - Palliative Cancer Patients' Experiences of Participating in a Lifestyle Intervention Study While Receiving Chemotherapy. AB - BACKGROUND: Lifestyle interventions have promise in terms of their potential health benefits and as an empowerment tool for cancer patients. Nevertheless, documentation of palliative cancer patients experiences of participating in lifestyle interventions remains poor. OBJECTIVE: The objective of this study was to explore how palliative cancer patients experience participation in a feasibility study focusing on multiple lifestyle interventions (physical, nutritional, smoking cessation, and stress management) while receiving chemotherapy. METHODS: This was a qualitative design with semistructured interviews of 9 palliative cancer patients 3 to 4 months after inclusion to the lifestyle intervention. Data were analyzed according to a qualitative content analysis within a hermeneutic approach. RESULTS: Three main themes emerged: (1) adopting a healthier lifestyle, (2) taking on a more active role, and (3) boosting confidence. Participation made some participants feel guilty when they were not able to reach their own lifestyle goals. CONCLUSIONS: Participation in lifestyle interventions is valued by palliative cancer patients and may strengthen their coping abilities. However, some of the participants also expressed feelings of guilt and inadequacy. Thus, the organizational aspects of interventions need to be considered carefully to minimize the possibility of causing increased strain on the participants, who already experience the burden of coping with their disease. IMPLICATIONS FOR PRACTICE: This study provides a unique insight into the palliative cancer patients experiences of participating in a trial focusing on multiple lifestyle interventions while receiving chemotherapy. The results may provide guidance for healthcare professionals in their efforts to help palliative cancer patients adopt a healthier lifestyle and to help patients increase their coping abilities. PMID- 25730594 TI - Tobacco Cessation Practices and Attitudes Among Nurses in the Czech Republic. AB - BACKGROUND: Tobacco is the leading cause of cancer in the Czech Republic. More than one-third of the population older than 15 years smokes, including many nurses. Most smokers want to quit, but the extent of nurses' involvement in tobacco cessation is unknown. OBJECTIVE: The purposes of this study are to describe the frequency of nurses' interventions in helping smokers quit, examine their attitudes and skills, and explore the relationship of nurses' smoking status to level of intervention. METHODS: A convenience sample of nurses in the Czech Republic completed a survey about their frequency of interventions according to the 5As for tobacco dependence treatment (i.e., ask, advise, assess, assist, arrange), their attitudes and perceived skills, and their smoking status (never, former, current). RESULTS: A total of 157 nurses completed the survey; 26% "always" or "usually" assisted patients with smoking cessation. Few (22%) reported that nurses could play an important role in helping patients quit, and 65% rated their ability to help smokers quit as "fair/poor." Nurse who smoked (30%) were less likely to consistently assess smoking status or arrange for follow-up support. CONCLUSION: Few nurses in the Czech Republic consistently provide smoking cessation support to patients, have the skills to do so, or view this role as an important part of their role. IMPLICATIONS FOR PRACTICE: To reduce tobacco-related cancers in the Czech Republic, capacity-building efforts are needed to enhance nurses' skills and confidence in providing smoking cessation interventions. Support is also need to help nurses who smoke quit. PMID- 25730595 TI - A Review of Psychoeducational Interventions to Improve Sexual Functioning, Quality of Life, and Psychological Outcomes in Gynecological Cancer Patients. AB - BACKGROUND: Psychoeducational interventions are recommended for use with clinical gynecological cancer patients to improve their patient care outcomes. However, the evidence of their effectiveness is far from conclusive. OBJECTIVE: The objective of this study was to identify the best available research evidence related to the effects of psychoeducational interventions on sexual functioning, quality of life, and psychological outcomes in gynecological cancer patients. METHODS: A systematic search was conducted to identify English and Chinese articles from the inception of the databases to April 2012 and included 13 English databases and 7 Chinese databases. Gray literature or unpublished studies were also searched. RESULTS: A total of 11 studies involving 975 gynecological cancer patients were included in the review. Meta-analysis results for 4 comparable studies indicated that psychoeducational interventions were effective in treating depressive symptoms among gynecological cancer patients (standardized mean difference = -0.80; 95% confidence interval, -1.05 to -0.54), whereas information provision significantly improved the mental aspect of quality of life (standardized mean difference = -0.41; 95% confidence interval, -0.74 to -0.08). With regard to sexual functioning, psychoeducational interventions appeared to have benefits in improving the sexual life of patients. CONCLUSIONS: Findings confirm the effectiveness of psychoeducational interventions on depressive symptoms and mental aspect of the quality of life in gynecological cancer patients. IMPLICATIONS FOR PRACTICE: The authors discuss the implications of review findings for the effective design of psychoeducational interventions including components, provider, provision time frame, and duration for clinical practice, as well as psychoeducational intervention research. PMID- 25730596 TI - The Effect on Bone Outcomes of Adding Exercise to Supplements for Osteopenic Breast Cancer Survivors: A Pilot Randomized Controlled Trial. AB - BACKGROUND: Cancer treatment-induced bone loss is an important long-term effect in breast cancer survivors, but evidence regarding lifestyle interventions for preventing cancer treatment-induced bone loss is lacking. OBJECTIVE: The aim of this study was to investigate the feasibility, safety, and effects of a 6-month combined home-based exercise and calcium and vitamin D supplements (EX + SUPP) intervention compared with calcium and vitamin D supplements alone (SUPP) on bone health of osteopenic breast cancer survivors. METHODS: In this pilot randomized controlled trial, we enrolled 43 women with breast cancer who were diagnosed as osteopenic through bone mineral density screening. Women were randomly assigned to the EX + SUPP group (n = 23) or the SUPP group (n = 20). RESULTS: The rates of participant retention (90.7%) and of counseling calls delivered to the EX + SUPP group (90.3%) were high. The average exercise adherence rate was 69.5% for weight bearing exercise and 48.5% for resistance exercise. The EX + SUPP group reported no injuries or adverse events. Despite positive findings of adherence and safety, no significant group differences were observed for bone mineral density, bone turnover marker, or physical performance. CONCLUSIONS: A home-based exercise program for bone health among osteopenic breast cancer survivors is feasible and safe. There was no significant additive effect of exercise on bone outcomes under the conditions studied, however, suggesting the need for a larger trial. IMPLICATIONS FOR PRACTICE: Effective exercise intervention may require more intensive components such as higher loading forces and longer duration for improving bone health among this population. PMID- 25730597 TI - Transitions in Symptom Cluster Subgroups Among Men Undergoing Prostate Cancer Radiation Therapy. AB - BACKGROUND: Prostate cancer is a common type of cancer worldwide and in the United States. However, little information has been reported on the symptoms of men over time who receive radiation therapy. OBJECTIVE: The objectives of this study were to identify subgroups of men at pre- and post-radiation therapy on general and treatment-related symptoms and to determine transitions in subgroup membership over time. METHODS: Men (n = 84) receiving radiation therapy completed questionnaires on fatigue, insomnia, pain, depression, anxiety, and sexual, urinary, and bowel problems at pretreatment and posttreatment. Latent class analysis identified subgroups. One-way analyses of variance determined subgroups differed on symptoms, participant characteristics, and quality of life. Latent transition analysis examined subgroup transitions over time. RESULTS: At pretreatment, 4 subgroups were identified: resilient group, with little to no symptom reporting; adjusted group, with moderately high treatment-related symptoms, low insomnia, depression, and anxiety; distressed group, consistently high on most symptoms; and emerging group, with moderately high fatigue, depression, and anxiety with few treatment-related symptoms. At posttreatment, similar results were seen in groups to those at pretreatment: resilient, adjusted. and distressed groups with an impacted group having high pain, insomnia, depression, and urinary and bowel symptoms. Quality of life and participant characteristics further distinguished groups at pretreatment and posttreatment. Income level predicted a transition in group membership. CONCLUSIONS: Men can be classified into distinctly different subgroups over time. IMPLICATIONS FOR PRACTICE: Assessment and intervention with men in subgroups such as distressed and emerging before and during treatment may lessen potential for remaining distressed or moving into impacted group where symptom severity is high at posttreatment. Interventions to reduce multiple symptoms are vitally needed. PMID- 25730599 TI - Silver nanoplate-decorated copper wire for the on-site microextraction and detection of perchlorate using a portable Raman spectrometer. AB - Perchlorate, which causes health concerns because of its effects on the thyroid function, is highly soluble and mobile in the environment. In this study, diethyldithiocarbamate (DDTC)-modified silver nanoplates were fabricated on a copper wire to perform the on-site microextraction and detection of perchlorate. This fiber could be inserted into water or soil to extract perchlorate through electrostatic interaction and then can be detected by a portable Raman spectrometer, owing to its surface-enhanced Raman (SERS) activity. A relatively stable vibrational mode (delta(HCH)(CH3), (CH2)) of DDTC at 1273 cm(-1) was used as an internal standard, which was negligibly influenced by the absorption of ClO4(-). The DDTC-modified Ag/Cu fiber showed high uniformity, good reusability and temporal stability under continuous laser radiation each with an RSD lower than 10%. The qualitative and quantitative detection of perchlorate were also realized. A log-log plot of the normalized SERS intensity against perchlorate concentration showed a good linear relationship. The fiber could be also directly inserted into the perchlorate-polluted soil, and the perchlorate could thereby be detected on site. The detection limit in soil reached 0.081 ppm, which was much lower than the EPA-published safety standard. The recovery of the detection was 105% and comparable with the ion chromatography. This hyphenated method of microextraction with direct SERS detection may find potential application for direct pollutant detection free from complex sample pretreatment. PMID- 25730598 TI - Using Data to Strengthen Ambulatory Oncology Nursing Practice. AB - BACKGROUND: Efforts to measure quality of care do not capture the unique aspects of ambulatory oncology settings. To retain nurses, ensure a safe practice environment, and encourage behaviors that support high-quality care, there is a need to identify factors associated with job satisfaction and turnover with measures that reflect the ambulatory setting. OBJECTIVE: The objective of this study was to examine the patterns and correlates of the work environment for nurses and nurse practitioners working in a National Cancer Institute-designated Comprehensive Cancer Center. METHODS: Web-based questionnaires were disseminated to employees with a registered nurse license in ambulatory settings and related support services and included 3 affiliated satellite locations. Participants completed the Practice Environment Scale of the Nursing Work Index, revised for ambulatory oncology settings, the Safety Organizing Scale, and items to assess job satisfaction, perceived quality of care, and intention to leave their current position. Logistic and linear regression models were used to examine factors associated with these outcomes. RESULTS: From 403 individuals, 319 (79.2%) participated. The majority of respondents endorsed excellent quality of care (57.7%), job satisfaction (69.3%), and intention to stay in current position (77.4%). Endorsement of favorable collegial nurse-physician relationships was significantly associated with all 3 outcomes and increased performance of safety organizing behaviors. Nurses reported variations in practice environments and safety organizing behaviors across units. CONCLUSIONS: Work environment assessments are useful to retain experienced nurses and support the delivery of high-quality patient care. IMPLICATIONS FOR PRACTICE: Routine assessment of the work environment for registered nurses and advanced practice nurses is feasible and informative. PMID- 25730600 TI - Assessing occupational exposure to sea lamprey pesticides. AB - BACKGROUND: Sea lampreys are parasitic fish found in lakes of the United States and Canada. Sea lamprey is controlled through manual application of the pesticides 3-trifluoromethyl-4-nitrophenol (TFM) and Bayluscide(TM) into streams and tributaries. 3-Trifluoromethyl-4-nitrophenol may cause irritation and central nervous system depression and Bayluscide may cause irritation, dermatitis, blisters, cracking, edema, and allergic skin reactions. OBJECTIVES: To assess occupational exposures to sea lamprey pesticides. METHODS: We developed a wipe method for evaluating surface and skin contamination with these pesticides. This method was field tested at a biological field station and at a pesticide river application. We also evaluated exposures using control banding tools. RESULTS: We verified TFM surface contamination at the biological station. At the river application, we found surfaces and worker's skin contaminated with pesticides. CONCLUSION: We recommended minimizing exposures by implementing engineering controls and improved use of personal protective equipment. PMID- 25730601 TI - Spin-orbit-torque engineering via oxygen manipulation. AB - Spin transfer torques allow the electrical manipulation of magnetization at room temperature, which is desirable in spintronic devices such as spin transfer torque memories. When combined with spin-orbit coupling, they give rise to spin orbit torques, which are a more powerful tool for controlling magnetization and can enrich device functionalities. The engineering of spin-orbit torques, based mostly on the spin Hall effect, is being intensely pursued. Here, we report that the oxidation of spin-orbit-torque devices triggers a new mechanism of spin-orbit torque, which is about two times stronger than that based on the spin Hall effect. We thus introduce a way to engineer spin-orbit torques via oxygen manipulation. Combined with electrical gating of the oxygen level, our findings may also pave the way towards reconfigurable logic devices. PMID- 25730602 TI - A Patient-centered Approach to Evaluate the Information Needs of Women With Ductal Carcinoma In Situ. AB - OBJECTIVE: To evaluate the information needs of ductal carcinoma in situ (DCIS) patients. METHODS: Four focus groups involving 24 previously treated DCIS patients were conducted to develop a comprehensive list of questions they felt were important to have answered at the time of diagnosis. Using a survey, a separate group of patients treated for DCIS then rated the importance of having each of these questions addressed before treatment decision making. Response options were "essential," "desired," "not important," "no opinion," and "avoid." For each essential/desired question, respondents specified how addressing it would help them: "understand," "decide," "plan," "not sure," or "other." RESULTS: Focus group participants generated 117 questions used in the survey. Fifty-seven patients completed the survey (55% response rate). Respondents rated a median of 66 questions as essential. The most commonly cited reason for rating a question essential was to "understand," followed by to "decide." The top questions women deemed essential to help them understand were disease specific, whereas the top questions deemed essential to help women decide were predominantly treatment specific, pertaining to available options, recurrence and survival outcomes, and timelines to decide and start treatment. CONCLUSIONS: DCIS patients want a large number of questions answered, mostly for understanding, and also for deciding and planning. A core set of questions that most patients consider essential for decision making has been formulated and may be used in the clinical setting and in research to develop educational resources and decision-making tools specific to DCIS. PMID- 25730603 TI - Favorable Outcome of Hurthle Cell Carcinoma of the Thyroid Treated With Total Thyroidectomy, Radioiodine, and Selective Use of External-Beam Radiotherapy. AB - OBJECTIVES: There is controversy about the prognosis of Hurthle cell carcinoma of the thyroid. The purpose of this project is to report the outcome of a well defined group of patients treated at a single institution in the modern era. METHODS: Sixteen patients met the following inclusion criteria: Treatment with curative intent at our institution between January 1, 1997, and December 31, 2010. Primary treatment with total thyroidectomy with or without neck dissection. Age >18 years at the time of thyroidectomy. Confirmation by a pathologist of the diagnosis of a primary Hurthle cell carcinoma of the thyroid based on >=75% Hurthle cells with extension through the tumor capsule. No areas of poorly differentiated (insular) or undifferentiated (anaplastic) carcinoma. Stage T1-3, NX-1b, M0. All patients received radioiodine immediately after thyroidectomy (remnant ablation, n=14) or as adjuvant for a recurrence (n=2). External-beam radiotherapy to the neck as adjuvant therapy after thyroidectomy was used in 2 patients and after resection of a neck recurrence in 1 patient. RESULTS: Five year actuarial rates with a median 6 years of follow up on surviving patients were as follows:Overall and cancer-specific survival: 92% (1 death from Hurthle cell carcinoma). Relapse-free survival (no visible tumor and unstimulated thyroglobulin <=1.0): 65%. CONCLUSIONS: Our experience suggests that the outcome of Hurthle cell carcinoma of the thyroid is favorable in adults with stage T1-3 NX-1b M0 disease who are managed with total thyroidectomy, radioiodine, and-in selected cases-external-beam radiotherapy. We do not have the ability to compare our results to other management strategies. PMID- 25730604 TI - Radiotherapy for Brain Metastases From Renal Cell Carcinoma in the Targeted Therapy Era: The University of Rochester Experience. AB - OBJECTIVES: Radiotherapy remains the standard approach for brain metastases from renal cell carcinoma (RCC). Kinase inhibitors (KI) have become standard of care for metastatic RCC. They also increase the radiosensitivity of various tumor types in preclinical models. Data are lacking regarding the effect of KIs among RCC patients undergoing radiotherapy for brain metastases. We report our experience of radiotherapy for brain metastatic RCC in the era of targeted therapy and analyzed effects of concurrent KI therapy. METHODS: We retrospectively analyzed 25 consecutive patients who received radiotherapy for brain metastases from RCC with whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both. Kaplan-Meier rates of overall survival (OS) and brain progression-free survival (BPFS) were calculated and univariate analyses performed. RESULTS: Lower diagnosis-specific graded prognostic assessment (DS GPA) score and multiple intracranial metastases were associated with decreased OS and BPFS on univariate analysis; DS-GPA is also a prognostic factor on multivariate analysis. There was no significant difference in OS or BPFS for SRS compared with WBRT or WBRT and SRS combined. The concurrent use of KI was not associated with any change in OS or BPFS. CONCLUSIONS: This hypothesis-generating analysis suggests among patients with brain metastatic RCC treated with the most current therapies, those selected to undergo SRS did not experience significantly different survival or control outcomes than those selected to undergo WBRT. From our experience to date, limited in patient numbers, there seems to be neither harm nor benefit in using concurrent KI therapy during radiotherapy. Given that most patients progress systemically, we would recommend considering KI use during brain radiotherapy in these patients. PMID- 25730605 TI - Coordination-based molecular assemblies as electrochromic materials: ultra-high switching stability and coloration efficiencies. AB - We demonstrate high-performance electrochromic assemblies that exhibit a practical combination of low-voltage operation and efficient electrochromic switching as well as long-term thermal and redox stability (1.12 * 10(5) cycles). Our molecular assemblies can be integrated into a solid-state configuration. Furthermore, we also show how the molecular structure of the chromophores correlates with the materials' growth and function. The coloration efficiencies of our assemblies are higher than those of inorganic materials and many conducting polymers, in addition to offering an alternative fabrication approach. PMID- 25730606 TI - Effect of the 2014 atrial fibrillation guideline revisions on the proportion of patients recommended for oral anticoagulation. PMID- 25730607 TI - Contact electrification and energy harvesting using periodically contacted and squeezed water droplets. AB - We investigate the contact electrification occurring when a small water droplet resting on a metal electrode is brought periodically in contact with a hydrophobic film of fluorinated ethylene propylene. It is found that the maximum current increases with the drop volume according to a power law. The time scale for the contact current to develop is consistent with that required for a droplet to spread and is, therefore, longer than the time required to form the electric double layer. Adding salt into the water does reduce the contact current but not entirely, which suggests that any remaining water layer cannot entirely neutralize the charges developed upon contact. With an average power of 0.7 MUW and a peak power near 5 MUW at a frequency of 5 Hz, a 200 MUL droplet of pure water can be used to light up a light-emitting diode. PMID- 25730608 TI - Enhanced ALP activity of MG63 cells cultured on hydroxyapatite-poly(ethylene glycol) hydrogel composites prepared using EDTA-OH. AB - In order to obtain a hydroxyapatite (HAp)-poly(ethylene glycol) (PEG) composite, tetra amine-terminated PEG was crosslinked using disuccinimidyl tartrate to obtain a PEG hydrogel. Using two kinds of chelators with different stability constants for Ca ion (N-(2-hydroxyethyl) ethylenediamine-N,N',N'-triacetic acid (EDTA-OH, 8.14), and ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA, 10.96)), calcium phosphate was deposited within PEG hydrogels by heating the chelator containing calcium phosphate solution at 90 degrees C. X-ray diffraction analysis showed that the deposited calcium phosphate was HAp. The crystallinity of the HAp deposited using EDTA-OH was low compared with that obtained using EDTA, but the amount of HAp deposited within the PEG hydrogel using EDTA-OH was higher than that deposited using EDTA. Significantly more human osteoblast-like MG-63 cells adhered on the HAp-PEG composite prepared using EDTA-OH than on the HAp-PEG composites prepared using EDTA. Furthermore, the alkaline phosphatase activity of MG-63 cultured on the HAp-PEG composite prepared using EDTA-OH was four times higher than that on the HAp-PEG composite prepared using EDTA. Therefore, the HAp-PEG composite prepared using EDTA-OH has potential as a bone substitute material. PMID- 25730609 TI - Occurrence, fate, behavior and ecotoxicological state of phthalates in different environmental matrices. AB - Because of their large and widespread application, phthalates or phthalic acid esters (PAEs) are ubiquitous in all the environmental compartements. They have been widely detected throughout the worldwide environment. Indoor air where people spend 65-90% of their time is also highly contaminated by various PAEs released from plastics, consumer products as well as ambient suspended particulate matter. Because of their widespread application, PAEs are the most common chemicals that humans are in contact with daily. Based on various exposure mechanisms, including the ingestion of food, drinking water, dust/soil, air inhalation and dermal exposure the daily intake of PAEs may reach values as high as 70 MUg/kg/day. PAEs are involved in endocrine disrupting effects, namely, upon reproductive physiology in different species of fish and mammals. They also present a variety of additional toxic effects for many other species including terrestrial and aquatic fauna and flora. Therefore, their presence in the environment has attracted considerable attention due to their potential impacts on ecosystem functioning and on public health. This paper is a synthesis of the extensive literature data on behavior, transport, fate and ecotoxicological state of PAEs in environmental matrices: air, water, sediment, sludge, wastewater, soil, and biota. First, the origins and physicochemical properties of PAEs that control the behavior, transport and fate in the environment are reviewed. Second, the compilation of data on transport and fate, adverse environmental and human health effects, legislation, restrictions, and ecotoxicological state of the environment based on PAEs is presented. PMID- 25730610 TI - Moderated mediation of the relationships between masculinity ideology, outcome expectations, and energy drink use. AB - OBJECTIVE: The consumption of energy drinks is a growing health-risk behavior for young men in the United States. The present study investigated the relationship between masculinity ideology, outcome expectations, energy drink use, and sleep disturbances. METHOD: The authors recruited 467 adult males from universities and the Internet who provided data on their endorsement of traditional masculinity ideology, outcome expectations for use of energy drinks, use of energy drinks, and sleep disturbances. A theoretical model positing moderated mediation was tested using structural equation modeling and conditional process modeling. RESULTS: The results supported the hypothesized model in which endorsement of traditional masculinity ideology was linked with increased outcome expectations for benefits of energy drinks, which in turn was linked with increased energy drink consumption, and which finally was linked with greater sleep disturbance symptoms. The relationship between masculinity ideology and energy drink outcome expectations was moderated by age (significant for younger men but not for older men), and the relationship between energy drink outcome expectations and energy drink use was moderated by race (significant for White men but not for racial minority men). CONCLUSION: The present study adds to the literature on potential negative health implications of the endorsement of traditional masculinity ideology by offering a link between predictors of energy drink use (masculinity ideology, outcome expectations) and health outcomes of energy drink use (e.g., sleep disturbance). PMID- 25730611 TI - Dyadic coping within couples dealing with breast cancer: A longitudinal, population-based study. AB - OBJECTIVE: The way couples deal with stressors is likely to influence their adjustment after breast cancer diagnosis. Based on the systemic-transactional model, this study examined whether the supportive, delegated and negative dyadic coping provided by patients and partners and their common dyadic coping as a couple were associated with change in relationship quality and depressive symptoms over time. METHOD: Women with breast cancer and their male partners (N = 538 couples) participated in a longitudinal study (Time 1, <= 4 months after surgery; Time 2, 5 months later). Dyadic coping was assessed using the Dyadic Coping Inventory (Bodenmann, 2008). The Center for Epidemiologic Studies Depression Scale (Radloff, 1977) and the Relationship Ladder (Kuijer, Buunk, De Jong, Ybema, & Sanderman, 2004) measured depressive symptoms and relationship quality, respectively. RESULTS: Negative dyadic coping was adversely associated with both patients' and partners' outcomes. The more patients rated the couple as engaging in common dyadic coping, the higher relationship quality and the fewer depressive symptoms both patients and partners experienced. Patients experienced more depressive symptoms the more delegated coping (i.e., taking over tasks) they provided to the partner. Partners experienced fewer depressive symptoms the more delegated coping they provided to the patient, but more depressive symptoms the more supportive coping the patient provided to them. CONCLUSION: This study has contributed to disentangling how dyadic coping behaviors influence couples' adjustment. Interventions may focus on reducing negative dyadic coping and strengthening common dyadic coping, and be attentive to the different effects of dyadic coping on patients and partners. PMID- 25730612 TI - Routine intra-operative trans-oesophageal echocardiography yields better outcomes in surgical repair of CHD. AB - OBJECTIVES: Trans-oesophageal echocardiographic imaging is valuable in the pre- and post-operative evaluation of children and adults with CHD; however, the frequency by which trans-oesophageal echocardiography guides the intra-operative course of patients is unknown. METHODS: We retrospectively reviewed 1748 intra operative trans-oesophageal echocardiograms performed between 1 October, 2005 and 31 December, 2010, and found 99 cases (5.7%) that required return to bypass, based in part upon the intra-operative echocardiographic findings. RESULTS: The diagnoses most commonly requiring further repair and subsequent imaging were mitral valve disease (20.9%), tricuspid valve disease (16.0%), atrioventricular canal defects (12.0%), and pulmonary valve disease (14.1%). The vast majority of those requiring immediate return to bypass benefited by avoiding subsequent operations and longer lengths of hospital stay. A total of 14 patients (0.8%) who received routine imaging required further surgical repair within 1 week, usually due to disease that developed over ensuing days. Patients who had second post operative trans-oesophageal echocardiograms in the operating room rarely required re-operations, confirming the benefit of routine intra-operative imaging. CONCLUSIONS: This study represents a large single institutional review of intra operative trans-oesophageal echocardiography, and confirms its applicability in the surgical repair of patients with CHD. Routine imaging accurately identifies patients requiring further intervention, does not confer additional risk of mortality or prolonged length of hospital stay, and prevents subsequent operations and associated sequelae in a substantial subset of patients. This study demonstrates the utility of echocardiography in intra-operative monitoring of surgical repair and highlights patients who are most likely to require return to bypass, as well as the co-morbidities of such manipulations. PMID- 25730613 TI - Synergistic rate boosting of collagen fibrillogenesis in heterogeneous mixtures of crowding agents. AB - The competition for access to space that arises between macromolecules is the basis of the macromolecular crowding phenomenon, known to modulate biochemical reactions in subtle ways. Crowding is a highly conserved physiological condition in and around cells in metazoans, and originates from a mixture of heterogeneous biomolecules. Here, using collagen fibrillogenesis as an experimental test platform and ideas from the theory of nonideal solutions, we show that an entropy based synergy is created by a mixture of two different populations of artificial crowders, providing small crowders with extra volume occupancy when in the vicinity of bigger crowders. We present the physiological mechanism by which synergistic effects maximize volume exclusion with the minimum amount of heterogeneous crowders, demonstrating how the evolutionarily optimized crowded conditions found in vivo can be reproduced effectively in vitro. PMID- 25730614 TI - Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study. AB - The hypothalamic pituitary adrenal axis and dopamine have a key role in transition from alcohol social use to addiction. The medial prefrontal cortex was shown to modulate dopaminergic activity and cortisol releasing factor (CRF) release in hypothalamic and extra-hypothalamic systems. The recent advancements in non-invasive neurostimulation technologies has enabled stimulation of deeper brain regions using H-coil transcranial magnetic stimulation (TMS) in humans. This randomized double-blind placebo-controlled pilot study aims to evaluate H coil efficacy in stimulating the medial prefrontal cortex. Cortisolemia and prolactinemia were evaluated as effectiveness markers. Alcohol intake and craving were considered as secondary outcomes. Eighteen alcoholics were recruited and randomized into 2 homogeneous groups: 9 in the real stimulation group and 9 in the sham stimulation group. Repetitive TMS (rTMS) was administered through a magnetic stimulator over 10 sessions at 20 Hz, directed to the medial prefrontal cortex. rTMS significantly reduced blood cortisol levels and decreased prolactinemia, thus suggesting dopamine increase. Craving visual analogic scale (VAS) in treated patients decreased, as well as mean number of alcoholic drinks/day and drinks on days of maximum alcohol intake (DMAI). In the sham group there was no significant effect observed on cortisolemia, prolactinemia, mean number of alcoholic drinks/day, or drinks/DMAI. Thus, deep rTMS could be considered a potential new treatment for alcoholism. PMID- 25730615 TI - Intravitreal injections and endophthalmitis. PMID- 25730616 TI - Uveitis in human immunodeficiency virus-infected individuals. PMID- 25730617 TI - Biological response modifiers in the treatment of noninfectious uveitis. PMID- 25730618 TI - Advances in tuberculosis-associated uveitis. PMID- 25730619 TI - Drug-induced uveitis. PMID- 25730620 TI - Vitreoretinal surgery in uveitis. PMID- 25730621 TI - The enigma of autoimmune retinopathy. PMID- 25730622 TI - Quality-of-life metrics in pediatric uveitis. PMID- 25730623 TI - Emerging causes of viral-associated uveitis. PMID- 25730625 TI - Preface: advances in the management of uveitis part I. PMID- 25730626 TI - Base-stabilized nitrilium ions as convenient imine synthons. AB - A simple and efficient methodology is presented for the synthesis of a wide range of substituted imines. It is based on stabilizing readily available, but thermally labile, N-alkylnitrilium triflates with pyridine or DMAP to moderately air-stable adducts. These base-stabilized imine synthons react conveniently with phosphorus- and nitrogen-based nucleophiles to amidines and phosphaamidines. PMID- 25730627 TI - Concept mapping: A supervision strategy for introducing case conceptualization skills to novice therapists. AB - Case conceptualization, a term synonymous with case formulation, is an essential psychotherapy skill. Novice therapists enter into the practice of psychotherapy with limited case conceptualization skills. Hence, an important goal when supervising novice therapists is to effectively teach these skills. Concept mapping facilitates case conceptualization skills through the process of methodically creating graphic representations of clients' problems and dynamic relationships between these problems. This article introduces a highly structured and practical 4-stage approach to supervision that effectively introduces case formulation skills to novice therapists using concept mapping. It is assumed that concept maps, when shared with clients, function as an intervention to facilitate insight and change. PMID- 25730628 TI - The impact of gambling advertising: Problem gamblers report stronger impacts on involvement, knowledge, and awareness than recreational gamblers. AB - Although there is a general lack of empirical evidence that advertising influences gambling participation, the regulation of gambling advertising is hotly debated among academic researchers, treatment specialists, lobby groups, regulators, and policymakers. This study contributes to the ongoing debate by investigating perceived impacts of gambling advertising in a sample of gamblers drawn from the general population in Norway (n = 6,034). Three dimensions of advertising impacts were identified, representing perceived impacts on (a) gambling-related attitudes, interest, and behavior ("involvement"); (b) knowledge about gambling options and providers ("knowledge"); and (c) the degree to which people are aware of gambling advertising ("awareness"). Overall, impacts were strongest for the knowledge dimension, and, for all 3 dimensions, the impact increased with level of advertising exposure. Those identified as problem gamblers in the sample (n = 57) reported advertising impacts concerning involvement more than recreational gamblers, and this finding was not attributable to differences in advertising exposure. Additionally, younger gamblers reported stronger impacts on involvement and knowledge but were less likely to agree that they were aware of gambling advertising than older gamblers. Male gamblers were more likely than female gamblers to report stronger impacts on both involvement and knowledge. These findings are discussed with regard to existing research on gambling advertising as well as their implications for future research and policy-making. (PsycINFO Database Record PMID- 25730629 TI - How do impulsivity traits influence problem gambling through gambling motives? The role of perceived gambling risk/benefits. AB - Although substantial research suggests that motivations have been found to mediate the relationships between impulsivity traits and various forms of substance use, no studies have examined how gambling motives may mediate the relationships between impulsivity traits and problem gambling. The primary purpose of this study was to test an integrative model linking impulsivity traits and gambling problems, evaluating the mediating effects of gambling motives. Participants were 594 students (73% male; age, M = 19.92 years; SD = 2.91) enrolled in public high schools or universities. Young people who tend to act rashly in response to extremely positive moods showed higher enhancement and coping motives, which in turn were positively related to gambling problems. Individuals with higher levels of sensation seeking were more likely to have higher levels of enhancement motives, which in turn were also positively related to gambling problems. The model was examined in several groups, separately for the level of perceived gambling risk/benefits (lower perceived gambling risk, higher perceived gambling risk, lower perceived gambling benefits, and higher perceived gambling benefits). There were significant differences between these groups for this division. These findings suggest that prevention and/or treatment strategies might need to consider the model's variables, including impulsivity traits and gambling motives, in accordance with individual levels of perceived gambling risk/benefits. PMID- 25730630 TI - Examining temptation to drink from an existential perspective: Associations among temptation, purpose in life, and drinking outcomes. AB - Temptation to drink (TTD), defined as the degree to which one feels compelled to drink in the presence of internal or external alcohol-related cues, has been shown to predict alcohol-treatment outcomes among individuals with alcohol-use disorders (AUDs). Research examining TTD from an existential perspective is lacking and little is known about how existential issues such as purpose in life (PIL) relate to TTD, which is surprising given the role of existential issues in many treatments and mutual help approaches for AUDs. In the current study, we examined the longitudinal associations in a sample of 1726 among TTD, PIL, and drinking outcomes using data from Project MATCH (1997, 1998). Parallel process latent growth curve analyses indicated that PIL and TTD were significantly associated across time, such that higher initial levels of PIL and increases in PIL over time were associated with lower initial levels of TTD and decreases in TTD over time. Higher initial levels of TTD, lower initial levels of PIL, increases in TTD, and decreases in PIL were significantly associated with greater intensity and frequency of drinking and greater drinking-related consequences at the 15-month follow-up. Accordingly, TTD and PIL may be important constructs for clinicians to consider throughout the course of treatment. Future studies should examine if and how various kinds of treatments for AUDs are associated with increases in PIL, and whether these increases are related to decreased TTD and reduced drinking. PMID- 25730632 TI - Effects of DL-2-hydroxy-4-(methylthio) butanoic acid on broilers at different dietary inclusion rates. AB - 1. A growth experiment was conducted to determine the effectiveness of liquid analogue, DL-2-hydroxy-4-(methylthio) butanoic acid (HMTBA), compared to powder DL-methionine (DLM), in commercial maize-soybean-meal broiler diets similar to those commonly used in China, on feed conversion ratio (FCR), growth performance and European Production Index (EPI) of broilers. 2. A 4 * 2 + 1 factorial arrangement of treatments was used in which HMTBA or DLM was fed at 4 concentrations (low, medium, high and very-high inclusion rates) of supplementation at 100% equivalence on an equimolar basis. Negative control diets were commercial starter, grower and finisher feeds with no added methionine. A total of 1008 commercial-type Arbor Acres 1-d-old chicks were randomly distributed into 9 groups, with 8 replicates of 14 (7 male + 7 female) birds per treatment. 3. The body weight gain of the control group was significantly lower than that of the others in the starter period but did not show any differences during the other periods. The FCR of the control group was higher than that of the others except for those with HMTBA in the grower period. It was also observed that the FCR dropped as the supplemented concentration of methionine was increased regardless of the source. Some of the treatment groups produced a better breast yield than the control. The EPI between the two products did not show any significant difference. 4. In conclusion, both of the methionine sources were equally effective in ameliorating the effects of a dietary deficiency of total sulphur amino acids. PMID- 25730633 TI - Statistical Electronic Structure Calibration Study of the CCSD(T*)-F12b Method for Atomization Energies. AB - In the explicitly correlated CCSD(T)-F12b coupled cluster method only the singles and doubles component of the energy benefits from inclusion of terms involving the interelectronic distance. Consequently, only that component exhibits accelerated convergence with respect to the 1-particle basis set. The smaller perturbative triples component converges at the same rate as the corresponding piece in standard CCSD(T). With the alternative CCSD(T*)-F12b method the triples correlation energy is scaled up by the ratio of explicitly correlated to standard second-order perturbation theory correlation energies in an attempt to better approximate the basis set limit. An extensive and diverse 212 molecule collection of reference total atomization energies, developed with large basis sets (up to aug-cc-pV9Z in some cases) and standard CCSD(T), was used to calibrate the performance of CCSD(T*). Scaling of the (T) energy led to improved results relative to raw F12b values but only provided a statistical advantage over previously proposed complete basis set extrapolation techniques for the smallest basis sets. With larger sets, scaling (T) produced noticeably poorer results, sometimes by a factor of 2. In agreement with earlier studies, basis set extrapolated CCSD(T)-F12b was found to exhibit a systematic bias toward overestimating reference atomization energies with an error that increases with the magnitude of the valence correlation energy. PMID- 25730631 TI - Whole genome sequencing in clinical and public health microbiology. AB - Genomics and whole genome sequencing (WGS) have the capacity to greatly enhance knowledge and understanding of infectious diseases and clinical microbiology.The growth and availability of bench-top WGS analysers has facilitated the feasibility of genomics in clinical and public health microbiology.Given current resource and infrastructure limitations, WGS is most applicable to use in public health laboratories, reference laboratories, and hospital infection control affiliated laboratories.As WGS represents the pinnacle for strain characterisation and epidemiological analyses, it is likely to replace traditional typing methods, resistance gene detection and other sequence-based investigations (e.g., 16S rDNA PCR) in the near future.Although genomic technologies are rapidly evolving, widespread implementation in clinical and public health microbiology laboratories is limited by the need for effective semi automated pipelines, standardised quality control and data interpretation, bioinformatics expertise, and infrastructure. PMID- 25730634 TI - The context of collecting family health history: examining definitions of family and family communication about health among African American women. AB - Public health initiatives encourage the public to discuss and record family health history information, which can inform prevention and screening for a variety of conditions. Most research on family health history discussion and collection, however, has predominantly involved White participants and has not considered lay definitions of family or family communication patterns about health. This qualitative study of 32 African American women-16 with a history of cancer-analyzed participants' definitions of family, family communication about health, and collection of family health history information. Family was defined by biological relatedness, social ties, interactions, and proximity. Several participants noted using different definitions of family for different purposes (e.g., biomedical vs. social). Health discussions took place between and within generations and were influenced by structural relationships (e.g., sister) and characteristics of family members (e.g., trustworthiness). Participants described managing tensions between sharing health information and protecting privacy, especially related to generational differences in sharing information, fear of familial conflict or gossip, and denial (sometimes described as refusal to "own" or "claim" a disease). Few participants reported that anyone in their family kept formal family health history records. Results suggest family health history initiatives should address family tensions and communication patterns that affect discussion and collection of family health history information. PMID- 25730635 TI - Regulating the architectures of hydrogen-bonded frameworks through topological enforcement. AB - The role of conformational flexibility in topological enforcement of several crystalline materials based on hydrogen-bonded two-dimensional guanidinium sulfonate (GS) networks is demonstrated by using a series of organopolysulfonates that prompt the formation of either lamellar or cylindrical architectures. Whereas flexible organopolysulfonate linkers decorated with flexible arms self assemble into lamellar architectures, rigid organopolysulfonates linkers enforce the formation of hydrogen-bonded cylinders with intercylinder spacing governed by the size of the linker. Specifically, hexagonal cylindrical structures generated from trisulfonates with three-fold molecular symmetry are the topological equivalent of the cylindrical hexagonal phases reported previously for guanidinium organomonosulfonate inclusion compounds, but neighboring cylinders are now connected through covalent nodes provided by the trisulfonates rather than dispersive interactions between the arene rings of the organomonosulfonates. Organopolysulfonates with moderate conformational freedom, however, can generate both lamellar and cylindrical structures, depending on the guest molecules encapsulated by the host framework. These observations illustrate that the crystal architecture (i.e., lamellar vs cylindrical) and the shape of GS cylinders can be regulated in a predictable way by the molecular symmetries and conformational constraints of the organopolysulfonates building blocks. PMID- 25730636 TI - Testosterone-to-oestradiol ratio is associated with female facial attractiveness. AB - The relationship between facial shape and attractiveness has been extensively studied, yet few studies have investigated the underlying biological factors of an attractive face. Many researchers have proposed a link between female attractiveness and sex hormones, but there is little empirical evidence in support of this assumption. In the present study we investigated the relationship between circulating sex hormones and attractiveness. We created prototypes by separately averaging photographs of 15 women with high and low levels of testosterone, oestradiol, and testosterone-to-oestradiol ratio levels, respectively. An independent set of facial images was then shape transformed toward these prototypes. We paired the resulting images in such a way that one face depicted a female with high hormone level and the other one with a low hormone level. Fifty participants were asked to choose the more attractive face of each pair. We found that low testosterone-to-oestradiol ratio and low testosterone were positively associated with female facial attractiveness. There was no preference for faces with high oestradiol levels. In an additional experiment with 36 participants we confirmed that a low testosterone-to oestradiol ratio plays a larger role than low testosterone alone. These results provide empirical evidence that an attractive female face is shaped by interacting effects of testosterone and oestradiol. PMID- 25730637 TI - The effect of selective attention and a stimulus prefix on the output order of immediate free recall of short and long lists. AB - Participants tend to initiate immediate free recall (IFR) of short lists of words with the first word in the list (Serial Position 1 [SP1]) and then proceed in forward serial order. Two potential explanations for this finding were examined: that the first items have increased selective attention (Experiment 1A and 1B) and enhanced temporal distinctiveness (Experiment 2) relative to subsequent list items. In Experiments 1A and 1B, participants were presented with lists of colored words for IFR. The experimental group was told that some trials would contain a red word and that when this occurred, they should output this word first in recall before recalling as many other words as they could. This instruction was designed to shift attention away from SP1 and toward the red item. The control group participants received identical stimuli but were unaware of the importance of the colored words and had no output order constraints. The overall recall of SP1 was not greatly affected in either experiment. In Experiment 2, participants were presented with lists containing between 2 and 12 words. Half of the trials contained a triple word stimulus prefix. For short lists in IFR, the overall recall of SP1 and the tendency to initiate recall with SP1 were reduced but far from eliminated by the stimulus prefix. We argue that our findings may be explained within a grouping interpretation in which the tendency to initiate recall with the first to-be-remembered item may reflect participants' tendency to output the first word in a highly salient participant determined group. PMID- 25730638 TI - Individual differences in working memory capacity and attentional control. AB - Visual working memory (WM) has a very limited online capacity making it considerably important to control the gating of encoding into WM. Recent studies have suggested that attention control is of importance in doing so, especially the time needed to disengage. However, the disengagement mechanism operates on a later stage of processing after the initial selection of information has already been initiated. We assume that individual differences in WM capacity are also driven by individual variations in the voluntary engagement of attention. In 2 experiments we investigated whether individuals with high- and low-WM capacity differ in the efficiency and speed of this attention control process. We realised different versions of the task in which different amounts of attention control were necessary, a more automatically triggered allocation of attention and a voluntary initiation of attention engagement, respectively. We further manipulated the time course to look for differences in the latency of attention control. The results revealed that participants with low-WM capacity were less effective to exhibit voluntary attention control processes and they were also slower in doing so compared with high-WM capacity individuals. However, this effect seems to be partly moderated by the ability to update the current task set. If the trial structure did not require task set updating smaller individual differences involving WM capacity could be found. PMID- 25730639 TI - Not so fast! Talker variability in serial recall at standard presentation rates. AB - In serial recall tasks, presenting items in alternating female and male voices impairs performance relative to the single-voice presentation. This phenomenon, termed the talker-variability effect (TVE), was recently reexamined by Hughes, Marsh, and Jones (2009, 2011), who used the effect as confirmatory evidence for their perceptual-gestural account of serial recall performance. Despite the authors' claim of generalisability, the serial recall paradigm employed did not reflect the standard parameters more generally adopted in verbal short-term memory research. Specifically, the presentation rate of the stimuli was almost 3 times that typically used. We sought to determine if the TVE, as observed by Hughes et al., was generalisable to the standard serial recall task by directly comparing recall performance in talker-variable conditions at fast and slow stimulus presentation rates. Experiment 1 employed a systematic replication of the foundational study undertaken by Hughes et al. (2009). Utilising a novel stimulus set, Experiment 2 provided a subsequent test of the generalisability of the TVE, examining the influence of item properties. Both experiments showed a robust TVE at the atypical fast presentation rate; however, for the slower item presentation, the TVE was unreliable. Furthermore, error analysis suggests that item recall also contributes to the TVE, contrary to the current explanation proposed by Hughes et al. (2009, 2011). The challenge of the present data to the perceptual-gestural account of the TVE is explored. Alternative accounts that focus on the resource cost of categorical speech perception in the context of talker variability are posited. PMID- 25730640 TI - Redintegration, task difficulty, and immediate serial recall tasks. AB - While current theoretical models remain somewhat inconclusive in their explanation of short-term memory (STM), many theories suggest at least a contribution of long-term memory (LTM) to the short-term system. A number of researchers refer to this process as redintegration (e.g., Schweickert, 1993). Under short-term recall conditions, the current study investigated the effects of redintegration and task difficulty in order to extend research conducted by Neale and Tehan (2007). Thirty participants in Experiment 1 and 26 participants in Experiment 2 completed a serial recall task in which retention interval, presentation rate, and articulatory suppression were used to modify task difficulty. Redintegration was examined by manipulating the characteristics of the to-be-remembered items; lexicality in Experiment 1 and wordlikeness in Experiment 2. Responses were scored based on correct-in-position recall, item scoring, and order accuracy scoring. In line with the Neale and Tehan results, as the difficulty of the task increased so did the effects of redintegration. This was evident in that the advantage for words in Experiment 1 and wordlikeness in Experiment 2 decreased as task difficulty increased. This relationship was observed for item but not order memory, and findings were discussed in relation to the theory of redintegration. PMID- 25730641 TI - Positional uncertainty in the Brown-Peterson paradigm. AB - Since McGeoch's (1932) influential article, no accounts of long-term memory have invoked decay as a cause of forgetting. In contrast, multiple accounts of short term memory (STM) invoke decay, with many appealing to results from the Brown Peterson paradigm as offering support. Two experiments are reported that used a standard Brown-Peterson task but which scored the data in 2 ways. With traditional scoring (was the entire 3-letter consonant trigram recalled?) performance decreased with increasing delay. With immediate serial recall scoring (e.g., was the first letter recalled first, was the second letter recalled second?), standard position error gradients (Experiment 1), and protrusion gradients (Experiment 2) were observed. That is, when the first letter of the consonant trigram was not recalled first, it was more likely to be recalled second than last. In addition, if a letter from a previous list was mistakenly recalled in a later list, it most likely retained its original position. The presence of such gradients is inconsistent with claims of decay but is predicted by SIMPLE, a local distinctiveness model of memory. Moreover, the presence of such gradients is consistent with the claim that forgetting in the Brown-Peterson paradigm follows the same principles observed in other memory tasks. PMID- 25730642 TI - Working memory for meaningless manual gestures. AB - Effects on working memory performance relating to item similarity have been linked to prior categorisation of representations in long-term memory. However, there is evidence from gesture processing that this link may not be obligatory. The present study investigated whether working memory for incidentally generated meaningless manual gestures is influenced by formational similarity and whether this effect is modulated by working-memory load. Results showed that formational similarity did lower performance, demonstrating that similarity effects are not dependent on prior categorisation. However, this effect was only found when working-memory load was low, supporting a flexible resource allocation model according to which it is the quality rather than quantity of working memory representations that determines performance. This interpretation is in line with proposals suggesting language modality specific allocation of resources in working memory. PMID- 25730643 TI - Learning multiple lists at the same time in the Hebb repetition effect. AB - In short-term ordered recall, when 1 list of items is repeated over the course of the experiment, recall performance typically improves. This is known as the Hebb repetition effect (Hebb, 1961). In the present study, we contrasted the typical condition involving a single repeated sequence with concurrent learning of 2 repeated sequences. Participants performed a spatial recall task, in which sequences of 7 dots were presented in each trial. For a given participant, the location of the dots were the same for all trials. Presentation order of dots varied randomly, except for 1 or 2 particular series that were repeated every 4 trials. Results revealed a significant learning slope for both the single and dual list conditions and learning was as efficient in both conditions. The findings provide further evidence in support of models linking the Hebb repetition effect to word-form learning. PMID- 25730644 TI - [Learning virtual routes: what does verbal coding do in working memory?]. AB - Two experiments were run to complete our understanding of the role of verbal and visuospatial encoding in the construction of a spatial model from visual input. In experiment 1 a dual task paradigm was applied to young adults who learned a route in a virtual environment and then performed a series of nonverbal tasks to assess spatial knowledge. Results indicated that landmark knowledge as asserted by the visual recognition of landmarks was not impaired by any of the concurrent task. Route knowledge, assessed by recognition of directions, was impaired both by a tapping task and a concurrent articulation task. Interestingly, the pattern was modulated when no landmarks were available to perform the direction task. A second experiment was designed to explore the role of verbal coding on the construction of landmark and route knowledge. A lexical-decision task was used as a verbal-semantic dual task, and a tone decision task as a nonsemantic auditory task. Results show that these new concurrent tasks impaired differently landmark knowledge and route knowledge. Results can be interpreted as showing that the coding of route knowledge could be grounded on both a coding of the sequence of events and on a semantic coding of information. These findings also point on some limits of Baddeley's working memory model. PMID- 25730645 TI - Memory as a hologram: an analysis of learning and recall. AB - We present a holographic theory of human memory. According to the theory, a subject's vocabulary resides in a dynamic distributed representation-a hologram. Studying or recalling a word alters both the existing representation of that word in the hologram and all words associated with it. Recall is always prompted by a recall cue (either a start instruction or the word just recalled). Order of report is a joint function of the item and associative information residing in the hologram at the time the report is made. We apply the model to archival data involving simple free recall, learning in multitrial free recall, simple serial recall, and learning in multitrial serial recall. The model captures accuracy and order of report in both free and serial recall. It also captures learning and subjective organisation in multitrial free recall. We offer the model as an alternative to the short- and long-term account of memory postulated in the modal model. PMID- 25730646 TI - Exposure to di-2-ethylhexyl phthalate, di-n-butyl phthalate and bisphenol A through infant formulas. AB - Phthalates and bisphenol A (BPA) are ubiquitous contaminants identified as endocrine disruptors. Phthalates are worldwide used as plasticizers, in particular to improve the mechanical properties of polymers such as polyvinyl chloride. Because they are not chemically bound to the polymer, they tend to leach out with time and use. Di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DnBP) are the two most common phthalates. BPA is an estrogenic compound used to manufacture polycarbonate containers for food and drink, including baby bottles. It can migrate from container into foods, especially at elevated temperatures. Diet is a predominant source of exposure for phthalates and BPA, especially for infants. The aim of this study was to test the presence of DEHP, DnBP, and BPA in infant formulas. DEHP, DnBP, and BPA concentrations were measured in 22 liquid and 28 powder milks by gas chromatography with flame ionization detection and high performance liquid chromatography with fluorimetric detection, respectively. DEHP concentrations in our samples were between 0.005 and 5.088 MUg/g (median 0.906 MUg/g), DnBP concentrations were between 0.008 and 1.297 MUg/g (median 0.053 MUg/g), and BPA concentrations were between 0.003 and 0.375 MUg/g (median 0.015 MUg/g). Concentrations of the investigated contaminants in liquid and powder milks were not significantly different, even though samples were packed in different types of containers. These data point out potential hazards for infants fed with baby formulas. Contamination seems more related to the production of formulas than to a release from containers. PMID- 25730647 TI - Muscle-bone interactions during fracture healing. AB - Although it is generally accepted that the rate and strength of fracture healing is intimately linked to the integrity of surrounding soft tissues, the contribution of muscle has largely been viewed as a vascular supply for oxygen and nutrient exchange. However, more is becoming known about the cellular and paracrine contributions of muscle to the fracture healing process. Research has shown that muscle is capable of supplying osteoprogenitor cells in cases where the periosteum is insufficient, and the muscular osteoprogenitors possess similar osteogenic potential to those derived from the periosteum. Muscle's secrotome includes proteins capable of inhibiting or enhancing osteogenesis and myogenesis following musculoskeletal injury and can be garnered for therapeutic use in patients with traumatic musculoskeletal injuries. In this review, we will highlight the current knowledge on muscle-bone interaction in the context of fracture healing as well as concisely present the current models to study such interactions. PMID- 25730648 TI - Analysis of the independent power of age-related, anthropometric and mechanical factors as determinants of the structure of radius and tibia in normal adults. A pQCT study. AB - To compare the independent influence of mechanical and non-mechanical factors on bone features, multiple regression analyses were performed between pQCT indicators of radius and tibia bone mass, mineralization, design and strength as determined variables, and age or time since menopause (TMP), body mass, bone length and regional muscles' areas as selected determinant factors, in Caucasian, physically active, untrained healthy men and pre- and post-menopausal women. In men and pre-menopausal women, the strongest influences were exerted by muscle area on radial features and by both muscle area and bone length on the tibia. Only for women, was body mass a significant factor for tibia traits. In men and pre-menopausal women, mass/design/strength indicators depended more strongly on the selected determinants than the cortical vBMD did (p<0.01-0.001 vs n.s.), regardless of age. However, TMP was an additional factor for both bones (p<0.01 0.001). The selected mechanical factors (muscle size, bone lengths) were more relevant than age/TMP or body weight to the development of allometrically-related bone properties (mass/design/strength), yet not to bone tissue 'quality' (cortical vBMD), suggesting a determinant, rather than determined role for cortical stiffness. While the mechanical impacts of muscles and bone levers on bone structure were comparable in men and pre-menopausal women, TMP exerted a stronger impact than allometric or mechanical factors on bone properties, including cortical vBMD. PMID- 25730649 TI - Effects of whole-body vibration on acute bone turnover marker responses to resistance exercise in young men. AB - OBJECTIVE: We investigated acute bone turnover marker (BTM) responses to high intensity resistance exercise with and without whole-body vibration (WBV) in young men (n=10). METHODS: In this randomized crossover study, subjects performed 2 protocols separated by 2-week wash out periods: 1) resistance exercise only (RE) (3 sets 10 repetitions 80% 1RM for 9 exercises); and 2) WBV + RE (side alternating vibration platform 5 intermittent, 1-minute bouts 20 Hz, 3.38 mm peak to-peak displacement followed by RE). Fasting morning blood draws were taken before RE or WBV (PRE), immediately post RE (IP), and 30 minutes post RE (30P). WBV + RE also had a blood draw after the WBV exposure (POST WBV). Blood samples were analyzed for lactate, hematocrit, bone-specific alkaline phosphatase (Bone ALP, U/L), C-terminal telopeptide of type I collagen (CTX-I, ng/mL) and tartrate resistant acid phosphatase 5b (TRAP5b, U/L). RESULTS: Lactate, hematocrit, and Bone ALP significantly increased (p<0.05) IP for both protocols. Bone resorption markers did not change during RE only. CTX-I significantly decreased POST WBV. TRAP5b increased POST WBV, then significantly decreased at 30P. CONCLUSIONS: Generally, BTM changes to RE only were not significant when adjusted for hemoconcentration. The WBV stimulus altered bone resorption marker but not bone formation marker responses. PMID- 25730650 TI - Lower-extremity muscle atrophy and fat infiltration after chronic spinal cord injury. AB - BACKGROUND: Atrophy and fatty-infiltration of lower-extremity muscle after spinal cord injury (SCI) predisposes individuals to metabolic disease and related mortality. OBJECTIVES: To determine the magnitude of atrophy and fatty infiltration of lower-extremity muscles and related factors in a group of individuals with chronic SCI and diverse impairment. METHODS: Muscle cross sectional area and density were calculated from peripheral quantitative computed tomography scans of the 66% site of the calf of 70 participants with chronic SCI [50 male, mean age 49 (standard deviation 12) years, C2-T12, AIS A-D] and matched controls. Regression models for muscle area and density were formed using 16 potential correlates selected a priori. RESULTS: Participants with motor-complete SCI had ~ 32% lower muscle area, and ~ 43% lower muscle density values relative to controls. Participants with motor-incomplete SCI had muscle area and density values that were both ~ 14% lower than controls. Body mass (+), tetraplegia (+), motor function (+), spasticity (+), vigorous physical activity (+), wheelchair use (-), age (-), and waist circumference (-) were associated with muscle size and/or density in best-fit regression models. CONCLUSIONS: There are modifiable factors related to muscle size, body composition, and activity level that may offer therapeutic targets for preserving metabolic health after chronic SCI. PMID- 25730651 TI - Comparison between quantitative X-ray imaging, dual energy X-ray absorptiometry and microCT in the assessment of bone mineral density in disuse-induced bone loss. AB - OBJECTIVES: We recently introduced a new methodology called quantitative X-ray imaging (qXRI) to investigate bone mineral density in isolated rodent bones. The aims of the present study were to compare DXA and microCT with qXRI in a rat model of disuse osteoporosis. METHODS: Fourteen Copenhagen rats were injected with a single dose of botulinum toxin (BTX - 2 UI) in the right Mus quadriceps femoris. The left hindlimb serves as control. Areal BMD and vBMD were determined with a Hologic Discovery-W device and a Skyscan 1172 microcomputed tomograph (microCT). Absorbing material density (AMD) was determined on digitized X-ray images obtained with a Faxitron M020 device. RESULTS: All three methods highlighted significant lower values for aBMD, vBMD and AMD in trabecular and cortical bone in the BTX-injected side. In trabecular bone, aBMD, vBMD and AMD were significantly correlated with BV/TV. In cortical bone, only aBMD and vBMD were significantly correlated with cortical bone mass On the other hand, only AMD was significantly correlated with the mechanical parameters bending strength and bending modulus. CONCLUSIONS: qXRI is a rapid and cheap method to assess trabecular bone mass in isolated rodent bones and can be used as a surrogate for the densitometry of small animals. PMID- 25730652 TI - Acute effects of superimposed electromyostimulation during cycling on myokines and markers of muscle damage. AB - OBJECTIVES: The purpose of the present study was to evaluate the effects of superimposed electromyostimulation (E) during cycling on myokines and markers of muscle damage, as E might be a useful tool to induce a high local stimulus to skeletal muscle during endurance training without performing high external workloads. METHODS: 13 subjects participated in three experimental trials each lasting 60 min in a randomized order. 1) Cycling (C), 2) Cycling with superimposed E (C+E) and 3) E. Interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), creatine kinase (CK) and myoglobin were determined before (pre) and 0', 30', 60', 240' and 24h after each intervention. RESULTS: Only C+E caused significant increases in levels of CK and myoglobin. BDNF and IL-6 significantly increased after C and C+E, however increases for IL-6 were significantly higher after C+E compared to C. CONCLUSION: The present study showed that superimposed E during cycling might be a useful tool to induce a high local stimulus to skeletal muscle even when performing low to moderate external workloads. This effect might be due the activation of additional muscle fibers and mild eccentric work due to the concomitant activation of agonist and antagonist. However the higher load to skeletal muscle has to be taken into account. PMID- 25730653 TI - Effects of five days of bed rest with intermittent centrifugation on neurovestibular function. AB - OBJECTIVES: We tested whether intermittent short-radius centrifugation was effective for mitigating alteration in balance and gait following bed rest. METHODS: Ten male subjects were exposed to 5 days of 6 degrees head-down tilt bed rest with: (a) no countermeasure; (b) daily 1-g centrifugation for a continuous 30-min period; and (c) daily 1-g centrifugation for six periods of 5 min. During and after the bed rest, subjects were asked to scale the severity of neurovestibular symptoms that followed centrifugation or 80 degrees head-up tilt. Following the bed rest, equilibrium scores were derived from anterior posterior sway while standing on a foam pad with the eyes open or closed while making pitch head movements, and gait was evaluated by grading subjects' performance during various locomotion tasks. RESULTS: At the beginning of bed rest, one single 30-min period of centrifugation induced more severe neurovestibular symptoms than six periods of 5-min centrifugation. After bed rest, although equilibrium scores and gait performance were not significantly altered, subjects felt less neurovestibular dysfunction with orthostatic stress when centrifugation was used. CONCLUSION: Centrifugation was effective at reducing the severity of neurovestibular symptoms after bed rest, but this decrease was not different between one or multiple daily sessions. PMID- 25730654 TI - Bone and cartilage characteristics in postmenopausal women with mild knee radiographic osteoarthritis and those without radiographic osteoarthritis. AB - OBJECTIVES: To evaluate the association between radiographically-assessed knee osteoarthritis and femoral neck bone characteristics in women with mild knee radiographic osteoarthritis and those without radiographic osteoarthritis. METHODS: Ninety postmenopausal women (mean age [SD], 58 [4] years; height, 163 [6] cm; weight, 71 [11] kg) participated in this cross-sectional study. The severity of radiographic knee osteoarthritis was defined using Kellgren-Lawrence grades 0=normal (n=12), 1=doubtful (n=25) or 2=minimal (n=53). Femoral neck bone mineral content (BMC), section modulus (Z), and cross-sectional area (CSA) were measured with DXA. The biochemical composition of ipsilateral knee cartilage was estimated using quantitative MRI measures, T2 mapping and dGEMRIC. The associations between radiographic knee osteoarthritis grades and bone and cartilage characteristics were analyzed using generalized linear models. RESULTS: Age-, height-, and weight-adjusted femoral neck BMC (p for linearity=0.019), Z (p for linearity=0.033), and CSA (p for linearity=0.019) increased significantly with higher knee osteoarthritis grades. There was no linear relationship between osteoarthritis grades and knee cartilage indices. CONCLUSIONS: Increased DXA assessed hip bone strength is related to knee osteoarthritis severity. These results are hypothesis driven that there is an inverse relationship between osteoarthritis and osteoporosis. However, MRI assessed measures of cartilage do not discriminate mild radiographic osteoarthritis severity. PMID- 25730655 TI - Prolonged occupational activity and 6-year changes in postural sway in elderly women. AB - OBJECTIVES: Prolonged occupational work such as farm work has been reported to adversely affect mobility in elderly women. The purpose of this study was to investigate possible relationships between prolonged occupational work and 6-year changes in postural sway in elderly women. METHODS: Subjects were 392 women aged >= 69 years who participated in a 6-year follow-up examination of the Muramatsu Cohort Study. Handgrip strength and postural sway, measured as gravity-center velocity (cm/s), were evaluated at baseline and 6-year follow-up. Interviews were conducted to determine the time spent on moderate occupational activity (3-5 metabolic equivalents) such as farm work. Activity levels were defined as: 1, no activity; 2, 'short' (>0, <= 17.75 h/wk); and 3, 'long' ( >= 17.75 h/wk). RESULTS: At baseline, mean values for age, handgrip strength, and postural sway were 73.3 years (SD 3.7), 20.3 kg (SD 4.1), and 2.0 cm/s (SD 0.8), respectively, and 32.5% of participants engaged in occupational activity. The change in postural sway was significantly greater in the long-activity group (median, 35.0 h/wk) than the no-activity group (0.56 vs. 0.27 cm/s, P=0.021). CONCLUSIONS: Prolonged occupational work may be detrimental to the control of body balance. Accordingly, elderly individuals are not recommended to engage in prolonged occupational activity. PMID- 25730656 TI - Activated leukocyte cell adhesion molecule (ALCAM or CD166) modulates bone phenotype and hematopoiesis. AB - Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166), is expressed on osteoblasts (OB) and hematopoietic stem cells (HSC) residing in the hematopoietic niche, and may have important regulatory roles in bone formation. Because HSC numbers are reduced 77% in CD166(-/-) mice, we hypothesized that changes in bone phenotype and consequently the endosteal niche may partially be responsible for this alteration. Therefore, we investigated bone phenotype and OB function in CD166(-/-) mice. Although osteoclastic measures were not affected by loss of CD166, CD166(-/-) mice exhibited a modest increase in trabecular bone fraction (42%), and increases in osteoid deposition (72%), OB number (60%), and bone formation rate (152%). Cortical bone geometry was altered in CD166(-/-) mice resulting in up to 81% and 49% increases in stiffness and ultimate force, respectively. CD166(-/-) OB displayed elevated alkaline phosphatase (ALP) activity and mineralization, and increased mRNA expression of Fra 1, ALP, and osteocalcin. Overall, CD166(-/-) mice displayed modestly elevated trabecular bone volume fraction with increased OB numbers and deposition of osteoid, and increased OB differentiation in vitro, possibly suggesting more mature OB are secreting more osteoid. This may explain the decline in HSC number in vivo because immature OB are mainly responsible for hematopoiesis enhancing activity. PMID- 25730657 TI - Relationship between innervation zone width and mean muscle fiber conduction velocity during a sustained isometric contraction. AB - OBJECTIVES: To examine the relationship between the biceps brachii muscle innervation zone (IZ) width and the mean muscle fiber conduction velocity (MFCV) during a sustained isometric contraction. METHODS: Fifteen healthy men performed a sustained isometric elbow flexion exercise at their 60% maximal voluntary contraction (MVC) until they could not maintain the target force. Mean MFCV was estimated through multichannel surface electromyographic recordings from a linear electrode array. Before exercise, IZ width was quantified. Separate non parametric one-way analyses of variance (ANOVAs) were used to examine whether there was a difference in each mean MFCV variable among groups with different IZ width. In addition, separate bivariate correlations were also performed to examine the relationships between the IZ width and the mean MFCV variables during the fatiguing exercise. RESULTS: There was a significant difference in the percent decline of mean MFCV (%DeltaMFCV) among groups with different IZ width (chi(2) (3)=11.571, p=0.009). In addition, there was also a significant positive relationship between the IZ width and the %DeltaMFCV (Kendall's tau= 0.807; p<0.001). CONCLUSIONS: We believe that such relationship is likely influenced by both muscle fiber size and the muscle fiber type composition. PMID- 25730658 TI - The impact of weight classification on safety: timing steps to adapt to external constraints. AB - OBJECTIVES: The purpose of the current study was to evaluate how weight classification influences safety by examining adults' ability to meet a timing constraint: walking to the pace of an audio metronome. METHODS: With a cross sectional design, walking parameters were collected as 55 adults with normal (n=30) and overweight (n=25) body mass index scores walked to slow, normal, and fast audio metronome paces. RESULTS: Between group comparisons showed that at the fast pace, those with overweight body mass index (BMI) had longer double limb support and stance times and slower cadences than the normal weight group (all ps<0.05). Examinations of participants' ability to meet the metronome paces revealed that participants who were overweight had higher cadences at the slow and fast paces (all ps<0.05). CONCLUSIONS: Findings suggest that those with overweight BMI alter their gait to maintain biomechanical stability. Understanding how excess weight influences gait adaptation can inform interventions to improve safety for individuals with obesity. PMID- 25730659 TI - Recurrent finger swelling. PMID- 25730660 TI - Serial-position effects on a free-recall task in bilinguals. AB - In this study, we examined mechanisms that underlie free-recall performance in bilinguals' first language (L1) and second language (L2) through the prism of serial-position effects. On free-recall tasks, a typical pattern of performance follows a U-shaped serial-position curve, where items from the beginning of the list (the primacy effect) and items from the end of the list (the recency effect) are recalled with higher accuracy than items from the middle of the list. The present study contrasted serial-position effects on the free-recall task in Korean-English bilinguals' L1 vs. L2 and examined the relationship between an independent working memory (WM) measure and serial-position effects in bilinguals' two languages. Results revealed stronger pre-recency (primacy and middle) effects in L1 than in L2, but similar recency effects in the two languages. A close association was observed between WM and recall performance in the pre-recency region in the L1 but not in the L2. Together, these findings suggest that linguistic knowledge constrains free-recall performance in bilinguals, but only in the pre-recency region. PMID- 25730663 TI - Home Modifications and Ways of Living Well. AB - People living with a disability or illness and health care professionals often have different perspectives on what needs to be done, and why, in order to create a life they can recognize as good. Focusing on home modifications, I explore the enactment of diverging perspectives on the desired good. I show how one couple living with the effects of motor neuron disease in Wales tried to create a way of living. Drawing from a narrative-based study, I explore what happens when there is an interaction of different perspectives of what is considered to be a desirable outcome. I argue that the construction of some expectations as needs, and others as desires, serves to subjugate people to certain technologies. These technologies are those deemed necessary, following a neo-liberal language of cost effectiveness where desires can be seen as liabilities. PMID- 25730661 TI - A randomized trial comparing didactics, demonstration, and simulation for teaching teamwork to medical residents. AB - RATIONALE: Effective teamwork is fundamental to the management of medical emergencies, and yet the best method to teach teamwork skills to trainees remains unknown. OBJECTIVES: In a cohort of incoming internal medicine interns, we tested the hypothesis that expert demonstration of teamwork principles and participation in high-fidelity simulation would each result in objectively assessed teamwork behavior superior to traditional didactics. METHODS: This was a randomized, controlled, parallel-group trial comparing three teamwork teaching modalities for incoming internal medicine interns. Participants in a single-day orientation at the Vanderbilt University Center for Experiential Learning and Assessment were randomized 1:1:1 to didactic, demonstration-based, or simulation-based instruction and then evaluated in their management of a simulated crisis by five independent, blinded observers using the Teamwork Behavioral Rater score. Clinical performance was assessed using the American Heart Association Advanced Cardiac Life Support algorithm and a novel "Recognize, Respond, Reassess" score. MEASUREMENTS AND MAIN RESULTS: Participants randomized to didactics (n = 18), demonstration (n = 17), and simulation (n = 17) were similar at baseline. The primary outcome of average overall Teamwork Behavioral Rater score for those who received demonstration-based training was similar to simulation participation (4.40 +/- 1.15 vs. 4.10 +/- 0.95, P = 0.917) and significantly higher than didactic instruction (4.40 +/- 1.15 vs. 3.10 +/- 0.51, P = 0.045). Clinical performance scores were similar between the three groups and correlated only weakly with teamwork behavior (coefficient of determination [Rs(2)] = 0.267, P < 0.001). CONCLUSIONS: Among incoming internal medicine interns, teamwork training by expert demonstration resulted in similar teamwork behavior to participation in high-fidelity simulation and was more effective than traditional didactics. Clinical performance was largely independent of teamwork behavior and did not differ between training modalities. PMID- 25730664 TI - Ethics, morality, and conflicting interests: how questionable professional integrity in some scientists supports global corporate influence in public health. AB - Clinical and public health research, education, and medical practice are vulnerable to influence by corporate interests driven by the for-profit motive. Developments over the last 10 years have shown that transparency and self reporting of corporate ties do not always mitigate bias. In this article, we provide examples of how sound scientific reasoning and evidence-gathering are undermined through compromised scientific enquiry resulting in misleading science, decision-making, and policy intervention. Various medical disciplines provide reference literature essential for informing public, environmental, and occupational health policy. Published literature impacts clinical and laboratory methods, the validity of respective clinical guidelines, and the development and implementation of public health regulations. Said literature is also used in expert testimony related to resolving tort actions on work-related illnesses and environmental risks. We call for increased sensitivity, full transparency, and the implementation of effective ethical and professional praxis rules at all relevant regulatory levels to rout out inappropriate corporate influence in science. This is needed because influencing the integrity of scientists who engage in such activities cannot be depended upon. PMID- 25730665 TI - Novel methods and technologies for 21st-century clinical trials: a review. AB - IMPORTANCE: New technologies are rapidly reshaping health care. However, their effect on drug development to date generally has been limited. OBJECTIVES: To evaluate disease modeling and simulation, alternative study design, novel objective measures, virtual research visits, and enhanced participant engagement and to examine their potential effects as methods and tools on clinical trials. EVIDENCE REVIEW: We conducted a systematic search of relevant terms on PubMed (disease modeling and clinical trials; adaptive design, clinical trials, and neurology; Internet, clinical trials, and neurology; and telemedicine, clinical trials, and neurology), references of previous publications, and our files. The search encompassed articles published from January 1, 2000, through November 30, 2014, and produced 7976 articles, of which 22 were determined to be relevant and are included in this review. FINDINGS: Few of these new methods and technologies have been applied to neurology clinical trials. Clinical outcomes, including cognitive and stroke outcomes, increasingly are captured remotely. Other therapeutic areas have successfully implemented many of these tools and technologies, including web-enabled clinical trials. CONCLUSIONS AND RELEVANCE: Increased use of new tools and approaches in future clinical trials can enhance the design, improve the assessment, and engage participants in the evaluation of novel therapies for neurologic disorders. PMID- 25730666 TI - Synthesis of activated carbon-based amino phosphonic acid chelating resin and its adsorption properties for Ce(III) removal. AB - This work aims to investigate the adsorption of Ce(III) onto chelating resin based on activated carbon (CRAC). The CRAC adsorbent was prepared from activated carbon (AC) followed by oxidation, silane coupling, ammoniation and phosphorylation, and characterized by Fourier transform-infrared spectrometry, nitrogen adsorption measurements and scanning electron microscopy. The effects of solution pH, adsorbent dosage and contact time were studied by batch technique. Langmuir and Freundlich isotherms were used to describe the adsorption behaviour of Ce(III) by CRAC, and the results showed that the adsorption behaviour well fitted the Langmuir model. The maximum uptake capacity (qmax) calculated by using the Langmuir equation for cerium ions was found to be 94.34 mg/g. A comparison of the kinetic models and the overall experimental data was best fitted with the type 1 pseudo second-order kinetic model. The calculated thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ) showed that the adsorption for Ce(III) was feasible, spontaneous and exothermic at 25-45 degrees C. The CRAC showed an excellent adsorptive selectivity towards Ce(III). Moreover, more than 82% of Ce(III) adsorbed onto CRAC could be desorbed with HCl and could be used several times. PMID- 25730668 TI - GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. AB - The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid beta-peptide (Abeta) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid beta-peptide (Abeta) pathology, reduced Abeta clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo neuronal dysfunction and degeneration. PMID- 25730669 TI - Anxious individuals have difficulty learning the causal statistics of aversive environments. AB - Statistical regularities in the causal structure of the environment enable us to predict the probable outcomes of our actions. Environments differ in the extent to which action-outcome contingencies are stable or volatile. Difficulty in being able to use this information to optimally update outcome predictions might contribute to the decision-making difficulties seen in anxiety. We tested this using an aversive learning task manipulating environmental volatility. Human participants low in trait anxiety matched updating of their outcome predictions to the volatility of the current environment, as predicted by a Bayesian model. Individuals with high trait anxiety showed less ability to adjust updating of outcome expectancies between stable and volatile environments. This was linked to reduced sensitivity of the pupil dilatory response to volatility, potentially indicative of altered norepinephrinergic responsivity to changes in this aspect of environmental information. PMID- 25730671 TI - Attention alters orientation processing in the human lateral geniculate nucleus. AB - Orientation selectivity is a cornerstone property of vision, commonly believed to emerge in the primary visual cortex. We found that reliable orientation information could be detected even earlier, in the human lateral geniculate nucleus, and that attentional feedback selectively altered these orientation responses. This attentional modulation may allow the visual system to modify incoming feature-specific signals at the earliest possible processing site. PMID- 25730670 TI - Mitochondrial control by DRP1 in brain tumor initiating cells. AB - Brain tumor initiating cells (BTICs) co-opt the neuronal high affinity glucose transporter, GLUT3, to withstand metabolic stress. We investigated another mechanism critical to brain metabolism, mitochondrial morphology, in BTICs. BTIC mitochondria were fragmented relative to non-BTIC tumor cell mitochondria, suggesting that BTICs increase mitochondrial fission. The essential mediator of mitochondrial fission, dynamin-related protein 1 (DRP1), showed activating phosphorylation in BTICs and inhibitory phosphorylation in non-BTIC tumor cells. Targeting DRP1 using RNA interference or pharmacologic inhibition induced BTIC apoptosis and inhibited tumor growth. Downstream, DRP1 activity regulated the essential metabolic stress sensor, AMP-activated protein kinase (AMPK), and targeting AMPK rescued the effects of DRP1 disruption. Cyclin-dependent kinase 5 (CDK5) phosphorylated DRP1 to increase its activity in BTICs, whereas Ca(2+) calmodulin-dependent protein kinase 2 (CAMK2) inhibited DRP1 in non-BTIC tumor cells, suggesting that tumor cell differentiation induces a regulatory switch in mitochondrial morphology. DRP1 activation correlated with poor prognosis in glioblastoma, suggesting that mitochondrial dynamics may represent a therapeutic target for BTICs. PMID- 25730673 TI - Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone. AB - We analyzed the progeny of individual neural stem cells (NSCs) of the mouse adult subependymal zone (SEZ) in vivo and found a markedly fast lineage amplification, as well as limited NSC self-renewal and exhaustion in a few weeks. We further unraveled the mechanisms of neuronal subtype generation, finding that a higher proportion of NSCs were dedicated to generate deep granule cells in the olfactory bulb and that larger clones were produced by these NSCs. PMID- 25730672 TI - Internally organized mechanisms of the head direction sense. AB - The head-direction (HD) system functions as a compass, with member neurons robustly increasing their firing rates when the animal's head points in a specific direction. HD neurons may be driven by peripheral sensors or, as computational models postulate, internally generated (attractor) mechanisms. We addressed the contributions of stimulus-driven and internally generated activity by recording ensembles of HD neurons in the antero-dorsal thalamic nucleus and the post-subiculum of mice by comparing their activity in various brain states. The temporal correlation structure of HD neurons was preserved during sleep, characterized by a 60 degrees -wide correlated neuronal firing (activity packet), both within and across these two brain structures. During rapid eye movement sleep, the spontaneous drift of the activity packet was similar to that observed during waking and accelerated tenfold during slow-wave sleep. These findings demonstrate that peripheral inputs impinge on an internally organized network, which provides amplification and enhanced precision of the HD signal. PMID- 25730674 TI - Silencing sounds off. AB - Silent chromatin in budding yeast is propagated from one generation to the next, even though 'silenced' genes are occasionally expressed. PMID- 25730675 TI - The timing of discharge from the intensive care unit and subsequent mortality. A prospective, multicenter study. AB - RATIONALE: Previous studies suggested an association between after-hours intensive care unit (ICU) discharge and increased hospital mortality. Their retrospective design and lack of correction for patient factors present at the time of discharge make this association problematic. OBJECTIVES: To determine factors independently associated with mortality after ICU discharge. METHODS: This was a prospective, multicenter, binational observational study involving 40 ICUs in Australia and New Zealand. Participants were consecutive adult patients discharged alive from the ICU between September 2009 and February 2010. MEASUREMENTS AND MAIN RESULTS: We studied 10,211 patients discharged alive from the ICU. Median age was 63 years (interquartile range, 49-74), 6,224 (61%) were male, 5,707 (56%) required mechanical ventilation, and their median Acute Physiology and Chronic Health Evaluation III risk of death was 9% (interquartile range, 3-25%). A total of 8,539 (83.6%) patients were discharged in-hours (06:00 18:00) and 1,672 (16.4%) after-hours (18:00-06:00). Of these, 408 (4.8%) and 124 (7.4%), respectively, subsequently died in hospital (P < 0.001). After risk adjustment for markers of illness severity at time of ICU discharge including limitations of medical therapy (LOMT) orders, the time of discharge was no longer a significant predictor of mortality. The presence of a LOMT order was the strongest predictor of death (odds ratio, 35.4; 95% confidence interval, 27.5 45.6). CONCLUSIONS: In this large, prospective, multicenter, binational observational study, we found that patient status at ICU discharge, particularly the presence of LOMT orders, was the chief predictor of hospital survival. In contrast to previous studies, the timing of discharge did not have an independent association with mortality. PMID- 25730676 TI - Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model. AB - 1,25 Dihydroxyvitamin D3 (1,25D) is a hormone produced from vitamin D through two hydroxylating steps catalyzed successively in the liver by the vitamin D 25 hydroxylase Cyp2R1 and in the kidney by the 25-hydroxyvitamin D3 1alpha hydroxylase Cyp27B1. 1,25D behaves like a steroid hormone. It regulates gene transcription by interacting with a nuclear receptor named vitamin D receptor (VDR) for the vitamin D receptor. Although the role of vitamin D is historically related to rickets, its physiological function largely encompasses bone tissues. Accumulating evidence has indicated that 1,25D can also be considered a neurosteroid. For example, both VDR and CYP27B1 are expressed in brain cells. Similarly, the neuroprotective and anti-inflammatory potential of 1,25D in nervous tissue has been shown experimentally. The regulation of Cyp27B1, which catalyzes the last step of 1,25D synthesis, by the inflammatory cytokines tumor necrosis factor-alpha and interferon-gamma has been reported recently. However, the fate of Cyp2R1 that catalyzes the first enzymatic reaction of the vitamin D metabolism has not received attention. Using human brain pericytes, we studied the expression of CYP2R1 and VDR genes when these cells were challenged to an inflammatory stimulus. We found a significant upregulation of these two genes in human brain pericytes challenged with tumor necrosis factor-alpha and interferon gamma. These results suggest the existence of an autocrine/paracrine vitamin D system in the neurovascular unit. The function of this novel signaling system might be critical in the control of neuroinflammation and in brain pathologies. PMID- 25730677 TI - Cholinergic and endocannabinoid neuromodulatory effects overlap on neurons of the pedunculopontine nucleus of mice. AB - The pedunculopontine nucleus (PPN) is a part of the reticular activating system and one of the main sources of the cholinergic fibers in the midbrain, while it is also subject to cholinergic modulation. This nucleus is known to be a structure that controls sleep-wake cycles, arousal, and locomotion. Neurons of the PPN are targets of several neuromodulatory mechanisms, which elicit heterogeneous pharmacological responses including hyperpolarization and depolarization, whereas lack of response can also be observed. In agreement with previous findings, we found that PPN neurons respond to the muscarinic agonist carbachol in a heterogeneous manner: they were depolarized and showed increased firing rate, decreased firing frequency, and were hyperpolarized, or showed no response. The heterogeneity of the muscarinic activation was similar to our previous observations with type 1 cannabinoid (CB1) receptor agonists; therefore, we investigated whether muscarinic and endocannabinoid modulatory mechanisms elicit the same action on a certain neuron. To achieve this, whole-cell patch clamp experiments were conducted on midbrain slices containing the PPN. Carbachol was applied first and, after recording the changes in the membrane potential and the firing frequency and achieving washout, the CB1 receptor agonist arachidonyl 2'-chloroethylamide (ACEA) was applied. A marked but not full overlap was observed: all neurons depolarized by carbachol were depolarized by the CB1 receptor agonist ACEA, and all neurons lacking response to carbachol lacked response to ACEA as well. However, neurons hyperpolarized by carbachol were depolarized, hyperpolarized, or not affected by the ACEA. These results indicate that endocannabinoid and muscarinic modulatory effects involve similar mechanisms of action. PMID- 25730678 TI - Emotion and novelty processing in an implicit aesthetic experience of architectures: evidence from an event-related potential study. AB - The present study explored the implicit aesthetic processing of different architectures using an event-related potential method. Event-related potential data were acquired in a categorization task in which participants were asked to distinguish between two different categories of pictures of everyday life objects and the architectures as soon as possible. The architectural pictures included two categories: noted-architect-designed and ordinary architectures. A smaller P2 amplitude and a larger N2 amplitude were elicited by the master architects' works than those of ordinary architectures, which indicated that perceived positive emotion and novelty perception occurred in the aesthetic processing of architectures. Our results present two sensitive neural indicators, P2 and N2, to judge the delight and novelty qualities shown by the architecture, respectively. PMID- 25730679 TI - Electrocortical indices of attention correlate with the need for closure. AB - Need for closure (NFC), defined as a desire for a quick and unambiguous answer to a question and an aversion to uncertainty, usually leads to a more structured, persistent, and rigid cognitive style. We suggested that this cognitive characteristic could be related to differences in a simple sensory gating control mechanism as reflected in event-related potentials (N1 component). We expected that the higher an individual's NFC, the more attention he/she would allocate to the selected stimuli or the feature of the stimuli, which is manifested in an increased N1 component. We tested this assumption in two experiments where NFC was measured by a scale and event-related potentials were recorded during the Stroop task and the Visual Distractor task. In line with the hypotheses, we found that NFC was associated with amplified processing of stimuli at an early sensory stage, which was evidenced in an increased N1 component. We suggested that this early sensory gating mechanism protects high NFC individuals against anxiety producing uncertainty. PMID- 25730680 TI - Current treatments and preventive strategies for radiation retinopathy. AB - PURPOSE OF REVIEW: Radiation retinopathy remains a devastating cause of visual morbidity in patients undergoing radiation for globe, orbit, and head and neck malignancies. This review discusses the recent efforts of several authors to treat radiation retinopathy once it has developed and efforts to prevent its development with early aggressive management. RECENT FINDINGS: Intravitreal anti vascular endothelial growth factor agents and intravitreal steroid agents have been used to successfully treat radiation-induced macular edema and neovascular events secondary to radiation retinopathy. The visual outcomes, however, have varied. Recent work has been directed towards prevention of radiation retinopathy prior to its development. This has been done with preventive scatter laser and intravitreal bevacizumab therapy. Effective customization of radiation dose to the tumor has also reduced some collateral radiation damage. Preventive vitrectomy and silicone oil placement at the time of plaque brachytherapy may shield normal ocular structures from radiation injury. SUMMARY: Radiation retinopathy remains a major source of visual morbidity following radiotherapy for malignancies. Promising, albeit unproven, new therapies and preventive efforts may ameliorate the negative visual outcomes. PMID- 25730681 TI - The quest for a practical synthesis of morphine alkaloids and their derivatives by chemoenzymatic methods. AB - We became interested in approaches to morphine in the early 1990s following our immersion into the new program on the enzymatic dihydroxylation of aromatics. Larry Kwart, a former classmate of one of us at Rice University, who worked with our group at Virginia Tech in the mid-1980s, introduced to us the use of blocked mutants of Pseudomonas putida (Pp39D) for the production of arene-cis dihydrodiols. Larry had gained expertise in microbiology from a postdoctoral stay with David Gibson, who discovered this unique enzymatic transformation, and he helped us to establish a strong program in chemoenzymatic synthesis that continues to this day. Without his pioneering effort, none of our accomplishments in chemoenzymatic synthesis, including the various approaches to morphine, would have materialized. Here we trace the evolution of our approaches to morphine alkaloids and some commercial opiate-derived medicinal agents. The design features and chronology of our approaches are discussed in a way that allows the reader to appreciate a number of errors that were made in conception as well as in execution. Experience acquired from many failed or less-than-effective attempts has finally led to an "almost reasonable" total synthesis, the key concept being based on our very first but unsuccessful attempt more than two decades ago. The irony of this accomplishment has not been lost on us. Each section of this Account presents a summary of distinctly different approaches to morphine alkaloids. Each ends with a short and philosophical lesson that was (or should have been) learned in the process. We intend for this Account to offer more than the history of a search for the perfect design solution to a synthetic problem. In today's era of rapid and often careless publication of results, it should serve also as a reminder that the success and the integrity of synthetic ventures depends on perseverance, adjustment of strategy, improvements of previous attempts, and serious attention to the quality of experimental data. Although somewhat satisfied with our latest accomplishment in morphinan synthesis, we plan to improve our design in the hope that a six-step synthesis is no longer in the realm of fantasy. With more than 20 years of effort in this area, our continuing involvement may qualify as obsession. PMID- 25730682 TI - Extraction of pure spectral signatures and corresponding chemical maps from EPR imaging data sets: identifying defects on a CaF2 surface due to a laser beam exposure. AB - A calcium fluoride (CaF2) plate was exposed to pulsed laser irradiations inducing surface morphological and ionization changes on its surface. More precisely surface damages mainly correspond to intrinsic defects. Electron paramagnetic resonance (EPR) hyperspectral imaging is a powerful technique able to characterize the defects formed on the CaF2 surface. Indeed, EPR hyperspectral images provide spatial and spectral information about the sample studied. In fact, these images possess a great potential to obtain accurate and reliable knowledge about the chemical composition and the distribution of the component due to the presence of the spatial aspect. However, the complexity of such hyperspectral data sets imposes the use of advanced chemometric tools to extract valuable information on the considered physicochemical system. Therefore, Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) is proposed to identify and locate the different constituents in the images. The originality of this work is that it reports on the application of MCR-ALS, for the first time, on electron paramagnetic resonance (EPR) imaging data sets that will furnish the distribution maps and the spectral signatures of all components present in the sample. The results show the identification of different intrinsic defects on a CaF2 sample from the sole information in the raw image measurements and, therefore, confirm the potential of this methodology and the important role of spatial information contained in the image. PMID- 25730683 TI - Measuring postural sway in sitting: a new segmental approach. AB - Global measures of trunk sway are traditionally used even though the trunk comprises a multiple number of segments. The authors' aim was to measure the seated sway of typically developing children using a multisegment approach. Twenty typically developing children divided into 2 groups, older and younger than 10 years old, participated in this study. The children sat unsupported for 30 s while their posture and sway were quantified using stereophotogrammetry. The tendency in both age groups was to sit with a backward tilted pelvis and a kyphotic trunk. The sitting position was most varied in the younger group. Marker sway amplitude and velocity in sitting were age dependent, with reduced sway amplitude and velocity with increased age for all segments. Anteroposterior intersegmental angular sway was not age dependent. The difference in marker sway in the anteroposterior direction for the younger group appeared to result from an equally stable trunk supported on a less stable pelvis. Mediolateral marker sway and intersegmental angular sway showed a clearer age dependency. Trunk postural control does not appear to differ between children older and younger than 10 years old, but sagittal plane pelvic stability can explain the increased sway reported in younger children. PMID- 25730687 TI - Don'T forget palliative patients. PMID- 25730686 TI - Neonate with choking. PMID- 25730688 TI - Don'T forget palliative patients--reply. PMID- 25730689 TI - The American board of pediatrics should close up shop. PMID- 25730690 TI - Reducing rate of fertility multiples requires policy changes. PMID- 25730691 TI - Physical activity and depression: type of exercise matters. PMID- 25730692 TI - The American board of pediatrics should close up shop--reply. PMID- 25730693 TI - Physical activity and depression: type of exercise matters--reply. PMID- 25730694 TI - Common questions about neonatal jaundice. PMID- 25730696 TI - Systematic growth monitoring for the early detection of celiac disease in children. AB - IMPORTANCE: Growth-monitoring programs in children aim to achieve the early detection of disorders that affect growth. Celiac disease (CD) is underdiagnosed in the pediatric population in which the presenting features often include faltering linear growth, short stature, or poor weight gain. OBJECTIVES: To develop new evidence-based cutoffs for screening for growth disorders and to evaluate the performance of these cutoffs among children with CD measured regularly in a nationwide growth screening program. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal retrospective study that included longitudinal growth data of healthy children (the reference population) from primary health care and children with CD (the cases) from primary health care and 3 university hospital outpatient clinics in Finland (Kuopio University Hospital, Tampere University Hospital, and Helsinki University Hospital) from January 1, 1994, to April 9, 2009. Children of the reference population were between 0 and 20 years of age and children with CD were between 1 and 16 years of age. In the reference population of 51,332 healthy children, 5 age-specific and sex-specific growth screening parameters (height standard deviation score and body mass index standard deviation score distance from the population mean, distance from target height, change in height standard deviation score, and change in body mass index standard deviation score) were developed. Performance of these parameters and their combination was evaluated in 177 children with CD by analyzing longitudinal growth data from birth until diagnosis of CD. MAIN OUTCOME AND MEASURE: The screening accuracy for detecting abnormal growth in children with CD, assessed using receiver operating characteristics analysis expressed as the area under the curve. RESULTS: Celiac disease was detected with good accuracy (area under the curve [95% CI] = 0.88 [0.84-0.93] for girls and 0.84 [0.77-0.91] for boys) when screening was performed using the combination of all 5 growth-screening parameters. When the specificity of the screening was set at 90%, growth was already abnormal in 57% of the girls with CD and 48% of the boys with CD 2 years prior to diagnosis. CONCLUSIONS AND RELEVANCE: Prior to diagnosis, growth faltered in most children with CD. These children could have been detected several years earlier by a well-established growth-monitoring program. Acceptable screening accuracy can be achieved for CD via the use of several growth monitoring parameters in combination, preferably using computerized screening algorithms that are integrated into an electronic health record system. PMID- 25730697 TI - Electronic cigarette sales to minors via the internet. AB - IMPORTANCE: Electronic cigarettes (e-cigarettes) entered the US market in 2007 and, with little regulatory oversight, grew into a $2-billion-a-year industry by 2013. The Centers for Disease Control and Prevention has reported a trend of increasing e-cigarette use among teens, with use rates doubling from 2011 to 2012. While several studies have documented that teens can and do buy cigarettes online, to our knowledge, no studies have yet examined age verification among Internet tobacco vendors selling e-cigarettes. OBJECTIVE: To estimate the extent to which minors can successfully purchase e-cigarettes online and assess compliance with North Carolina's 2013 e-cigarette age-verification law. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study conducted from February 2014 to June 2014, 11 nonsmoking minors aged 14 to 17 years made supervised e cigarette purchase attempts from 98 Internet e-cigarette vendors. Purchase attempts were made at the University of North Carolina Internet Tobacco Vendors Study project offices using credit cards. MAIN OUTCOME AND MEASURE: Rate at which minors can successfully purchase e-cigarettes on the Internet. RESULTS: Minors successfully received deliveries of e-cigarettes from 76.5% of purchase attempts, with no attempts by delivery companies to verify their ages at delivery and 95% of delivered orders simply left at the door. All delivered packages came from shipping companies that, according to company policy or federal regulation, do not ship cigarettes to consumers. Of the total orders, 18 failed for reasons unrelated to age verification. Only 5 of the remaining 80 youth purchase attempts were rejected owing to age verification, resulting in a youth buy rate of 93.7%. None of the vendors complied with North Carolina's e-cigarette age-verification law. CONCLUSIONS AND RELEVANCE: Minors are easily able to purchase e-cigarettes from the Internet because of an absence of age-verification measures used by Internet e-cigarette vendors. Federal law should require and enforce rigorous age verification for all e-cigarette sales as with the federal PACT (Prevent All Cigarette Trafficking) Act's requirements for age verification in Internet cigarette sales. PMID- 25730698 TI - Plasmonic nanostructured metal-oxide-semiconductor reflection modulators. AB - We propose a plasmonic surface that produces an electrically controlled reflectance as a high-speed intensity modulator. The device is conceived as a metal-oxide-semiconductor capacitor on silicon with its metal structured as a thin patch bearing a contiguous nanoscale grating. The metal structure serves multiple functions as a driving electrode and as a grating coupler for perpendicularly incident p-polarized light to surface plasmons supported by the patch. Modulation is produced by charging and discharging the capacitor and exploiting the carrier refraction effect in silicon along with the high sensitivity of strongly confined surface plasmons to index perturbations. The area of the modulator is set by the area of the incident beam, leading to a very compact device for a strongly focused beam (~2.5 MUm in diameter). Theoretically, the modulator can operate over a broad electrical bandwidth (tens of gigahertz) with a modulation depth of 3 to 6%, a loss of 3 to 4 dB, and an optical bandwidth of about 50 nm. About 1000 modulators can be integrated over a 50 mm(2) area producing an aggregate electro-optic modulation rate in excess of 1 Tb/s. We demonstrate experimentally modulators operating at telecommunications wavelengths, fabricated as nanostructured Au/HfO2/p-Si capacitors. The modulators break conceptually from waveguide-based devices and belong to the same class of devices as surface photodetectors and vertical cavity surface-emitting lasers. PMID- 25730699 TI - The usefulness of diagnostic testing in the initial evaluation of chronic kidney disease. PMID- 25730700 TI - Antimicrobials: Resistance is costly for Candida. PMID- 25730705 TI - Iron catalysed Negishi cross-coupling using simple ethyl-monophosphines. AB - Monophosphines prepared by iron catalysed hydrophosphination have been used as pro-ligands in iron catalysed Negishi cross-coupling of alkyl bromides and diphenyl zinc reagents. The cross-coupling has been investigated with monophosphines with varying electronic properties and we find the simplest, unsubstituted phosphine to offer the optimum reaction conditions (both in terms of yield of diarylmethane product and cost-effectiveness of the phosphine). In situ catalyst generation from monophosphine and FeCl2 was used in catalysis; however, preparation of a discrete homonuclear iron complex was also achieved and this four-coordinate iron-phosphine complex was isolated and used in catalysis. PMID- 25730703 TI - Parasite biology: The antisense antigen switch. PMID- 25730701 TI - Ecology and exploration of the rare biosphere. AB - The profound influence of microorganisms on human life and global biogeochemical cycles underlines the value of studying the biogeography of microorganisms, exploring microbial genomes and expanding our understanding of most microbial species on Earth: that is, those present at low relative abundance. The detection and subsequent analysis of low-abundance microbial populations-the 'rare biosphere'-have demonstrated the persistence, population dynamics, dispersion and predation of these microbial species. We discuss the ecology of rare microbial populations, and highlight molecular and computational methods for targeting taxonomic 'blind spots' within the rare biosphere of complex microbial communities. PMID- 25730706 TI - Theodora (Theo) Colborn: 1927-2014. PMID- 25730702 TI - The many projected futures of dengue. AB - Dengue is a vector-borne disease that causes a substantial public health burden within its expanding range. Several modelling studies have attempted to predict the future global distribution of dengue. However, the resulting projections are difficult to compare and are sometimes contradictory because the models differ in their approach, in the quality of the disease data that they use and in the choice of variables that drive disease distribution. In this Review, we compare the main approaches that have been used to model the future global distribution of dengue and propose a set of minimum criteria for future projections that, by analogy, are applicable to other vector-borne diseases. PMID- 25730707 TI - A quantitative assay for reductive metabolism of a pesticide in fish using electrochemistry coupled with liquid chromatography tandem mass spectrometry. AB - This is the first study to use electrochemistry to generate a nitro reduction metabolite as a standard for a liquid chromatography-mass spectrometry-based quantitative assay. This approach is further used to quantify 3-trifluoromethyl-4 nitrophenol (TFM) reductive metabolism. TFM is a widely used pesticide for the population control of sea lamprey (Petromyzon marinus), an invasive species of the Laurentian Great Lakes. Three animal models, sea lamprey, lake sturgeon (Acipenser fulvescens), and rainbow trout (Oncorhynchus mykiss), were selected to evaluate TFM reductive metabolism because they have been known to show differential susceptibilities to TFM toxicity. Amino-TFM (aTFM; 3-trifluoromethyl 4-aminophenol) was the only reductive metabolite identified through liquid chromatography-high-resolution mass spectrometry screening of liver extracts incubated with TFM and was targeted for electrochemical synthesis. After synthesis and purification, aTFM was used to develop a quantitative assay of the reductive metabolism of TFM through liquid chromatography and tandem mass spectrometry. The concentrations of aTFM were measured from TFM-treated cellular fractions, including cytosolic, nuclear, membrane, and mitochondrial protein extracts. Sea lamprey extracts produced the highest concentrations (500 ng/mL) of aTFM. In addition, sea lamprey and sturgeon cytosolic extracts showed concentrations of aTFM substantially higher than those of rainbow trout. However, other fractions of lake sturgeon extracts tend to show aTFM concentrations similar to those of rainbow trout but not with sea lamprey. These data suggest that the level of reductive metabolism of TFM may be associated with the sensitivities of the animals to this particular pesticide. PMID- 25730709 TI - Futurescapes: evidence expectations in the USA for comparative effectiveness research for drugs in 2020. AB - AIM: Explore key factors influencing future expectations for the production of evidence from comparative effectiveness research for drugs in the USA in 2020 and construct three plausible future scenarios. MATERIALS & METHODS: Semistructured key informant interviews and three rounds of modified Delphi with systematic scenario-building methods. RESULTS & CONCLUSION: Most influential key factors were: health delivery system integration; electronic health record development; exploitation of very large databases and mixed data sources; and proactive patient engagement in research. The scenario deemed most likely entailed uneven development of large integrated health systems with pockets of increased provider risk for patient care, enhanced data collection systems, changing incentives to do comparative effectiveness research and new opportunities for evidence generation partnerships. PMID- 25730710 TI - Pulse Electron Double Resonance Detected Multinuclear NMR Spectra of Distant and Low Sensitivity Nuclei and Its Application to the Structure of Mn(II) Centers in Organisms. AB - The ability to characterize the structure of metal centers beyond their primary ligands is important to understanding their chemistry. High-magnetic-field pulsed electron double resonance detected NMR (ELDOR-NMR) is shown to be a very sensitive approach to measuring the multinuclear NMR spectra of the nuclei surrounding Mn(II) ions. Resolved spectra of intact organisms with resonances arising from (55)Mn, (31)P, (1)H, (39)K, (35)Cl, (23)Na, and (14)N nuclei surrounding Mn(2+) centers were obtained. Naturally abundant cellular (13)C could be routinely measured as well. The amplitudes of the (14)N and (2)H ELDOR-NMR spectra were found to be linearly dependent on the number of nuclei in the ligand sphere. The evolution of the Mn(II) ELDOR-NMR spectra as a function of excitation time was found to be best described by a saturation phenomenon rather than a coherently driven process. Mn(II) ELDOR-NMR revealed details about not only the immediate ligands to the Mn(II) ions but also more distant nuclei, providing a view of their extended structures. This will be important for understanding the speciation and chemistry of the manganese complexes as well as other metals found in organisms. PMID- 25730708 TI - Minireview: translocator protein (TSPO) and steroidogenesis: a reappraisal. AB - The 18-kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a transmembrane protein in the outer mitochondrial membrane. TSPO has long been described as being indispensable for mitochondrial cholesterol import that is essential for steroid hormone production. In contrast to this initial proposition, recent experiments reexamining TSPO function have demonstrated that it is not involved in steroidogenesis. This fundamental change has forced a reexamination of the functional interpretations made for TSPO that broadly impacts both basic and clinical research across multiple fields. In this minireview, we recapitulate the key studies from 25 years of TSPO research and concurrently examine their limitations that perhaps led towards the incorrect association of TSPO and steroid hormone production. Although this shift in understanding raises new questions regarding the molecular function of TSPO, these recent developments are poised to have a significant positive impact for research progress in steroid endocrinology. PMID- 25730711 TI - Modelling resistance and reactance with heterogeneous airway narrowing in mild to severe asthma. AB - Ventilation heterogeneity is an important marker of small airway dysfunction in asthma. The frequency dependence of respiratory system resistance (Rrs) from oscillometry is used as a measure of this heterogeneity. However, this has not been quantitatively assessed or compared with other outcomes from oscillometry, including respiratory system reactance (Xrs) and the associated elastance (Ers). Here, we used a multibranch model of the human lung, including an upper airway shunt, to match previously reported respiratory mechanics in mild to severe asthma. We imposed heterogeneity by narrowing a proportion of the peripheral airways to account for patient Ers at 5 Hz, and then narrowed central airways to account for the remaining Rrs at 18 Hz. The model required >75% of the small airways to be occluded to reproduce severe asthma. While the model produced frequency dependence in Rrs, it was upward-shifted below 5 Hz compared with in vivo results, indicating that other factors, including more distributed airway narrowing or central airway wall compliance, are required. However, Ers quantitatively reflected the imposed heterogeneity better than the frequency dependence of Rrs, independent of the frequency range for the estimation, and thus was a more robust measure of small-airway function. Thus, Ers appears to have greater potential as a clinical measure of early small-airway disease in asthma. PMID- 25730712 TI - Honoring Newman L. Stephens: a legacy of science and success. PMID- 25730714 TI - Chemoenzymatic dynamic kinetic resolution: a powerful tool for the preparation of enantiomerically pure alcohols and amines. AB - Chemoenzymatic dynamic kinetic resolution (DKR) constitutes a convenient and efficient method to access enantiomerically pure alcohol and amine derivatives. This Perspective highlights the work carried out within this field during the past two decades and pinpoints important avenues for future research. First, the Perspective will summarize the more developed area of alcohol DKR, by delineating the way from the earliest proof-of-concept protocols to the current state-of-the art systems that allows for the highly efficient and selective preparation of a wide range of enantiomerically pure alcohol derivatives. Thereafter, the Perspective will focus on the more challenging DKR of amines, by presenting the currently available homogeneous and heterogeneous methods and their respective limitations. In these two parts, significant attention will be dedicated to the design of efficient racemization methods as an important means of developing milder DKR protocols. In the final part of the Perspective, a brief overview of the research that has been devoted toward improving enzymes as biocatalysts is presented. PMID- 25730715 TI - Cancer control falls squarely within the province of the psychological sciences. AB - Against the background of cancer as a contemporary public health challenge, this article presents a selective overview of psychological science contributions to cancer control research, practice, and policy. Initial contributions were circumscribed to awareness campaigns and the assessment of emotional responses to diagnosis and treatment. As evidence linking certain behaviors to cancer risk and outcomes accumulated, psychology emerged as a "hub science" in the Nation's cancer control program. Despite substantial accomplishments, new societal trends further challenge our ability to reduce risk, incidence, and deaths from cancer and enhance quality of life for cancer survivors. Evidence generated from psychological research conducted within each cell of Pasteur's quadrant continues to be relevant and necessary for effective 21st-century approaches to cancer prevention and control at the individual, clinical, and population levels. PMID- 25730716 TI - Fostering multiple healthy lifestyle behaviors for primary prevention of cancer. AB - The odds of developing cancer are increased by specific lifestyle behaviors (tobacco use, excess energy and alcohol intakes, low fruit and vegetable intake, physical inactivity, risky sexual behaviors, and inadequate sun protection) that are established risk factors for developing cancer. These behaviors are largely absent in childhood, emerge and tend to cluster over the life span, and show an increased prevalence among those disadvantaged by low education, low income, or minority status. Even though these risk behaviors are modifiable, few are diminishing in the population over time. We review the prevalence and population distribution of these behaviors and apply an ecological model to describe effective or promising healthy lifestyle interventions targeted to the individual, the sociocultural context, or environmental and policy influences. We suggest that implementing multiple health behavior change interventions across these levels could substantially reduce the prevalence of cancer and the burden it places on the public and the health care system. We note important still unresolved questions about which behaviors can be intervened upon simultaneously in order to maximize positive behavioral synergies, minimize negative ones, and effectively engage underserved populations. We conclude that interprofessional collaboration is needed to appropriately determine and convey the value of primary prevention of cancer and other chronic diseases. PMID- 25730717 TI - Health psychology and translational genomic research: bringing innovation to cancer-related behavioral interventions. AB - The past decade has witnessed rapid advances in human genome sequencing technology and in the understanding of the role of genetic and epigenetic alterations in cancer development. These advances have raised hopes that such knowledge could lead to improvements in behavioral risk reduction interventions, tailored screening recommendations, and treatment matching that together could accelerate the war on cancer. Despite this optimism, translation of genomic discovery for clinical and public health applications has moved relatively slowly. To date, health psychologists and the behavioral sciences generally have played a very limited role in translation research. In this report we discuss what we mean by genomic translational research and consider the social forces that have slowed translational research, including normative assumptions that translation research must occur downstream of basic science, thus relegating health psychology and other behavioral sciences to a distal role. We then outline two broad priority areas in cancer prevention, detection, and treatment where evidence will be needed to guide evaluation and implementation of personalized genomics: (a) effective communication, to broaden dissemination of genomic discovery, including patient-provider communication and familial communication, and (b) the need to improve the motivational impact of behavior change interventions, including those aimed at altering lifestyle choices and those focusing on decision making regarding targeted cancer treatments and chemopreventive adherence. We further discuss the role that health psychologists can play in interdisciplinary teams to shape translational research priorities and to evaluate the utility of emerging genomic discoveries for cancer prevention and control. PMID- 25730719 TI - Screening for prevention and early diagnosis of cancer. AB - The poor outcomes for cancers diagnosed at an advanced stage have been the driver behind research into techniques to detect disease before symptoms are manifest. For cervical and colorectal cancer, detection and treatment of "precancers" can prevent the development of cancer, a form of primary prevention. For other cancers-breast, prostate, lung, and ovarian-screening is a form of secondary prevention, aiming to improve outcomes through earlier diagnosis. International and national expert organizations regularly assess the balance of benefits and harms of screening technologies, issuing clinical guidelines for population-wide implementation. Psychological research has made important contributions to this process, assessing the psychological costs and benefits of possible screening outcomes (e.g., the impact of false positive results) and public tolerance of overdiagnosis. Cervical, colorectal, and breast screening are currently recommended, and prostate, lung, and ovarian screening are under active review. Once technologies and guidelines are in place, delivery of screening is implemented according to the health care system of the country, with invitation systems and provider recommendations playing a key role. Behavioral scientists can then investigate how individuals make screening decisions, assessing the impact of knowledge, perceived cancer risk, worry, and normative beliefs about screening, and this information can be used to develop strategies to promote screening uptake. This article describes current cancer screening options, discusses behavioral research designed to reduce underscreening and minimize inequalities, and considers the issues that are being raised by informed decision making and the development of risk-stratified approaches to screening. PMID- 25730720 TI - Tertiary prevention in cancer care: understanding and addressing the psychological dimensions of cancer during the active treatment period. AB - Tertiary prevention refers to care aimed at reducing morbidity and disability in people diagnosed with, and being treated for, disease. This article focuses on psychological aspects of tertiary prevention during the active phase of cancer treatment. Research in this area gained momentum in the 1970s, a time that coincides with changing public attitudes about discussing cancer and the origins of health psychology and behavioral medicine as fields of study. Over the past 40 years, much has been learned about the psychological impact of cancer and the beneficial effects of psychological interventions on patients' mental and physical well-being. The amount of research in this area necessitates a selective, rather than comprehensive, review approach. The focus here is on issues that affect a large proportion of people with cancer and for which research has generated an in-depth understanding. Accordingly, the article summarizes findings regarding the prevalence, etiology, and contributing factors, and the clinical management of, two of the most common psychological reactions to cancer diagnosis and treatment (i.e., depression and anxiety) and two of the most common physical symptoms related to cancer and its treatment (i.e., fatigue and pain). The review also summarizes emerging lines of research on psychological reactions to recurrent and second cancers, and on cancer diagnosis and treatment as a "teachable moment" for promoting health behavior change. Finally, important future directions are identified, including the need to adopt a team science approach to tertiary care and to better translate findings from intervention research into clinical practice. PMID- 25730718 TI - Decision making and cancer. AB - We review decision making along the cancer continuum in the contemporary context of informed and shared decision making in which patients are encouraged to take a more active role in their health care. We discuss challenges to achieving informed and shared decision making, including cognitive limitations and emotional factors, but argue that understanding the mechanisms of decision making offers hope for improving decision support. Theoretical approaches to decision making that explain cognition, emotion, and their interaction are described, including classical psychophysical approaches, dual-process approaches that focus on conflicts between emotion versus cognition (or reason), and modern integrative approaches such as fuzzy-trace theory. In contrast to the earlier emphasis on rote use of numerical detail, modern approaches emphasize understanding the bottom-line gist of options (which encompasses emotion and other influences on meaning) and retrieving relevant social and moral values to apply to those gist representations. Finally, research on interventions to support better decision making in clinical settings is reviewed, drawing out implications for future research on decision making and cancer. PMID- 25730721 TI - The integration of psychology in pediatric oncology research and practice: collaboration to improve care and outcomes for children and families. AB - Childhood cancers are life-threatening diseases that are universally distressing and potentially traumatic for children and their families at diagnosis, during treatment, and beyond. Dramatic improvements in survival have occurred as a result of increasingly aggressive multimodal therapies delivered in the context of clinical research trials. Nonetheless, cancers remain a leading cause of death in children, and their treatments have short- and long-term impacts on health and well-being. For over 35 years, pediatric psychologists have partnered with pediatric oncology teams to make many contributions to our understanding of the impact of cancer and its treatment on children and families and have played prominent roles in providing an understanding of treatment-related late effects and in improving quality of life. After discussing the incidence of cancer in children, its causes, and the treatment approaches to it in pediatric oncology, we present seven key contributions of psychologists to collaborative and integrated care in pediatric cancer: managing procedural pain, nausea, and other symptoms; understanding and reducing neuropsychological effects; treating children in the context of their families and other systems (social ecology); applying a developmental perspective; identifying competence and vulnerability; integrating psychological knowledge into decision making and other clinical care issues; and facilitating the transition to palliative care and bereavement. We conclude with a discussion of the current status of integrating knowledge from psychological research into practice in pediatric cancer. PMID- 25730722 TI - Life after diagnosis and treatment of cancer in adulthood: contributions from psychosocial oncology research. AB - The number of individuals living with a history of cancer is estimated at 13.7 million in the United States and is expected to rise with the aging of the population. With expanding attention to the psychosocial and physical consequences of surviving illness, psychological science and evidence-based practice are making important contributions to addressing the pressing needs of cancer survivors. Research is demonstrating that adults diagnosed with cancer evidence generally positive psychosocial adjustment over time; however, a subset is at risk for compromised psychological and physical health stemming from long term or late effects of cancer and its treatment. In this article, we characterize survivorship after medical treatment completion during the periods of reentry, early survivorship, and long-term survivorship. We describe the major psychosocial and physical sequelae facing adults during those periods, highlight promising posttreatment psychosocial and behavioral interventions, and offer recommendations for future research and evidence-based practice. PMID- 25730723 TI - Health-related quality of life measurement in oncology: advances and opportunities. AB - The concept of health-related quality of life has a long history in the field of oncology treatment and research. We present a brief history of how the concept has evolved in oncology and the sentinel events in that process. We then focus on advances in measurement science as applied to health-related quality of life measures and argue that a compelling new set of measurement tools is now available, including brief, generic measures with good psychometric qualities (exemplified by the new PROMIS measures and the possibility of a common metric spanning all diseases). The last section of the paper turns to emerging opportunities for these measures, including in clinical trials, healthcare reform, and regulatory deliberations. Our conclusion is that health-related quality of life is more important today than it has ever been, and that the time has come for an even wider adoption of the new measures. PMID- 25730725 TI - Cancer communication and informatics research across the cancer continuum. AB - Over the past decade, dramatic changes brought about by a rapid diffusion of Internet technologies, cellular telephones, mobile devices, personal digital assistants, electronic health records, and data visualization have helped to create a revolution in health communication. To understand the implications of this communication revolution for cancer care, the National Cancer Institute launched an ambitious set of research priorities under its "extraordinary opportunities" program. We present an overview of some of the relevant behavioral research being conducted within the perspective of this extraordinary opportunity in cancer communication research. We begin by tracing the implications of this research for behavioral scientists across the continuum of cancer care from primary prevention (e.g., tobacco control, diet, exercise, sun protection, and immunization against human papilloma virus), to secondary prevention (e.g., screening for polyps, lesions, and early stage neoplasms), to diagnosis and treatment, posttreatment survivorship, and end of life. Along each point of the continuum, we describe a natural evolution of knowledge from studies on the traditional role of media to research on the changing role of new media and informatics, and we carefully highlight the role that psychological research has played in improving communication- and health-related outcomes along the way. We conclude with an appeal to psychologists of many different backgrounds to join with biomedical researchers, engineers, clinical practitioners, and others to accelerate progress against cancer. PMID- 25730726 TI - An implementation science perspective on psychological science and cancer: what is known and opportunities for research, policy, and practice. AB - We discuss the role of implementation science in cancer and summarize the need for this perspective. Following a summary of key implementation science principles and lessons learned, we review the literature on implementation of cancer prevention and control activities across the continuum from prevention to palliative care. We identified 10 unique relevant reviews, four of which were specific to cancer. Multicomponent implementation strategies were found to be superior to single-component interventions, but it was not possible to draw conclusions about specific strategies or the range of conditions across which strategies were effective. Particular gaps identified include the need for more studies of health policies and reports of cost, cost-effectiveness, and resources required. Following this review, we summarize the types of evidence needed to make research findings more actionable and discuss emerging implementation science opportunities for psychological research on cancer prevention and control. These include innovative study designs (i.e., rapid learning designs, simulation modeling, comparative effectiveness, pragmatic studies, mixed-methods research) and measurement science (i.e., development of context-relevant measures; practical, longitudinal measures to gauge improvement; cost effectiveness data; and harmonized patient report data). We conclude by identifying a few grand challenges for psychologists that if successfully addressed would accelerate integration of evidence into cancer practice and policy more consistently and rapidly. PMID- 25730727 TI - Risks and opportunities for psychology's contribution to the war on cancer. AB - This special issue of American Psychologist reviews a broad, diverse, and growing research literature that has established the discipline as an essential source of evidence concerning cancer prevention and control. Nevertheless, the history of psychological science that is intended to inform cancer control suggests a number of risks going forward that could attenuate the impact of this work. Fortunately, the field also faces new opportunities to contribute more substantially, especially if psychologists engage the broader biomedical and public health communities through rigorous, relevant, multilevel research that is informed by current knowledge of the disease and its treatment, the skills required to participate in large-scale trans-disciplinary team science, and an appreciation of the economic, organizational, and policy context of cancer control at the local and national levels. PMID- 25730724 TI - Biobehavioral approaches to cancer progression and survival: Mechanisms and interventions. AB - Over the last decade, there have been groundbreaking strides in our understanding of the multiple biological pathways by which psychosocial and behavioral factors can affect cancer progression. It is now clear that biobehavioral factors not only affect cellular immunity but both directly and indirectly modulate fundamental processes in cancer growth, including inflammation, angiogenesis, invasion, and metastasis. There is also an emerging understanding of how psychological and behavioral factors used in interventions can impact these physiological processes. This review outlines our current understanding of the physiological mechanisms by which psychological, social, and behavioral processes can affect cancer progression. The intervention literature is discussed, along with recommendations for future research to move the field of biobehavioral oncology forward. PMID- 25730729 TI - Increased neurocognitive intra-individual variability is associated with declines in medication adherence in HIV-infected adults. AB - OBJECTIVE: There is cross-sectional evidence that neurocognitive intra-individual variability (IIV), or dispersion, is elevated in human immunodeficiency virus (HIV) disease and is associated with declines in activities of daily living, including medication adherence. METHODS: This longitudinal study extends this literature by examining whether increased neurocognitive IIV in HIV-positive persons over time predicts declines in medication adherence above and beyond changes in mean level of performance over a 6-month observation. RESULTS: After controlling for drug use, declines in mean performance, and changes in depressive symptoms, results confirmed that increases in IIV were associated with overall poorer antiretroviral medication adherence. HIV-positive individuals with the greatest increases in dispersion demonstrated marked reductions in adherence by the third month that exceeded what was observed in less variable individuals. CONCLUSIONS: Our results indicate that increases in dispersion are associated with poorer declines in medication adherence in HIV disease, which may have implications for the early detection and remediation of suboptimal antiretroviral adherence. PMID- 25730730 TI - Beating their chests: University students with ADHD demonstrate greater attentional abilities on an inattentional blindness paradigm. AB - OBJECTIVE: Adults diagnosed with attentional deficit disorder (ADHD) are easily distracted in many tasks. Yet ADHD performance on inattentional blindness (IB) tasks has not been examined. Such investigation may aid in discriminating between 3 ADHD models: the neurological model, the perceptual load theory, and the "hunter versus farmer" hypothesis. METHOD: Distractibility was assessed in ADHD and non-ADHD college students using the MOXO task that involves detection of a single attended stimulus that repeatedly appears in the same place and in the well-known IB "gorilla" video which involves tracking of a stimulus moving at a fast pace in a dynamic, complex manner. RESULTS: ADHD college students showed increased distractibility in the MOXO task. By contrast, they performed better than controls in the attended channel of the IB task, while they were also better at noticing the unattended stimuli and thus exhibiting little-to-no inattentional blindness. CONCLUSIONS: As no attentional tradeoffs were evident in the IB task, it appears that the results are most consistent with the "hunter versus farmer" hypothesis, which postulates that ADHD individuals have an alternative cognitive style which is less equipped to deal with detection of repeated stimuli while comprising advantages in the tracking of stimuli moving in a fast dynamic manner. PMID- 25730728 TI - The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery. AB - This review covers the initial discovery of the marine actinomycete genus Salinispora through its development as a model for natural product research. A focus is placed on the novel chemical structures reported with reference to their biological activities and the synthetic and biosynthetic studies they have inspired. The time line of discoveries progresses from more traditional bioassay guided approaches through the application of genome mining and genetic engineering techniques that target the products of specific biosynthetic gene clusters. This overview exemplifies the extraordinary biosynthetic diversity that can emanate from a narrowly defined genus and supports future efforts to explore marine taxa in the search for novel natural products. PMID- 25730734 TI - Sources of interference in item and associative recognition memory. AB - A powerful theoretical framework for exploring recognition memory is the global matching framework, in which a cue's memory strength reflects the similarity of the retrieval cues being matched against the contents of memory simultaneously. Contributions at retrieval can be categorized as matches and mismatches to the item and context cues, including the self match (match on item and context), item noise (match on context, mismatch on item), context noise (match on item, mismatch on context), and background noise (mismatch on item and context). We present a model that directly parameterizes the matches and mismatches to the item and context cues, which enables estimation of the magnitude of each interference contribution (item noise, context noise, and background noise). The model was fit within a hierarchical Bayesian framework to 10 recognition memory datasets that use manipulations of strength, list length, list strength, word frequency, study-test delay, and stimulus class in item and associative recognition. Estimates of the model parameters revealed at most a small contribution of item noise that varies by stimulus class, with virtually no item noise for single words and scenes. Despite the unpopularity of background noise in recognition memory models, background noise estimates dominated at retrieval across nearly all stimulus classes with the exception of high frequency words, which exhibited equivalent levels of context noise and background noise. These parameter estimates suggest that the majority of interference in recognition memory stems from experiences acquired before the learning episode. PMID- 25730732 TI - Probabilistic category learning in developmental dyslexia: Evidence from feedback and paired-associate weather prediction tasks. AB - OBJECTIVE: Developmental dyslexia is presumed to arise from specific phonological impairments. However, an emerging theoretical framework suggests that phonological impairments may be symptoms stemming from an underlying dysfunction of procedural learning. METHOD: We tested procedural learning in adults with dyslexia (n = 15) and matched-controls (n = 15) using 2 versions of the weather prediction task: feedback (FB) and paired-associate (PA). In the FB-based task, participants learned associations between cues and outcomes initially by guessing and subsequently through feedback indicating the correctness of response. In the PA-based learning task, participants viewed the cue and its associated outcome simultaneously without overt response or feedback. In both versions, participants trained across 150 trials. Learning was assessed in a subsequent test without presentation of the outcome, or corrective feedback. RESULTS: The dyslexia group exhibited impaired learning compared with the control group on both the FB and PA versions of the weather prediction task. CONCLUSIONS: The results indicate that the ability to learn by feedback is not selectively impaired in dyslexia. Rather it seems that the probabilistic nature of the task, shared by the FB and PA versions of the weather prediction task, hampers learning in those with dyslexia. Results are discussed in light of procedural learning impairments among participants with dyslexia. PMID- 25730731 TI - Habitual prospective memory in HIV disease. AB - OBJECTIVE: HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM). However, most PM research in HIV has used single-event tasks as opposed to habitual PM paradigms, which may be more relevant to clinical populations for whom many health-care behaviors must be performed both frequently and routinely. METHOD: For the current study, we examined habitual PM and its associations with real-world functioning outcomes in 36 HIV+ individuals with HAND (HAND+), 70 HIV+ individuals without HAND (HAND-), and 115 HIV- individuals. The ongoing task consisted of 24 1-min Stroop trial blocks in which the emotive and cognitive load was manipulated. The habitual PM task required participants to press the spacebar once per block, but only after 20 s had elapsed. RESULTS: A series of MANOVAs covarying for relevant clinicodemographic factors revealed a main effect of study group on habitual PM, such that the HAND+ cohort made significantly more repetition errors than the HIV and HAND- groups, particularly during early trial blocks. There was no main effect of ongoing task demands, nor was there an interaction between HAND group and task demands. Within the entire HIV+ sample, poorer habitual PM was associated with deficits in learning and dysfunction in real-world outcomes, including medication nonadherence and failures on a naturalistic health-care task. CONCLUSION: Findings indicate that HAND may be associated with deficient internal source monitoring or temporal discrimination for habitual PM output that may play a critical role in real-world functioning, including HIV disease management. PMID- 25730733 TI - Blood pressure interacts with APOE epsilon4 to predict memory performance in a midlife sample. AB - OBJECTIVE: Elevated blood pressure and the Apolipoprotein epsilon4 allele (APOE epsilon4) are independent risk factors for Alzheimer's disease. We sought to determine whether the combined presence of the APOE epsilon4 allele and elevated blood pressure is associated with lower cognitive performance in cognitively healthy middle-aged adults. METHODS: A total of 975 participants aged 30-54 (mean age = 44.47) were genotyped for APOE. Cardiometabolic risk factors including blood pressure, lipids, and glucose were assessed and cognitive function was measured using the Trail Making Test and the Visual Reproduction and Logical Memory subtests from the Wechsler Memory Scale. RESULTS: Multivariable regression analysis showed that the association between APOE epsilon4 and episodic memory performance varied as a function of systolic blood pressure (SBP), such that elevated SBP was predictive of poorer episodic memory performance only in APOE epsilon4 carriers (beta = -.092; t = -2.614; p = .009). Notably, this association was apparent at prehypertensive levels (>=130 mmHg), even after adjusting for physical activity, depression, smoking, and other cardiometabolic risk factors. CONCLUSIONS: The joint presence of APOE epsilon4 and elevated SBP, even at prehypertensive levels, is associated with lower cognitive performance in healthy, middle-aged adults. Results of this study suggest that the combination of APOE epsilon4 and elevated SBP may synergistically compromise memory function well before the appearance of clinically significant impairments. Interventions targeting blood pressure control in APOE epsilon4 carriers during midlife should be studied as a possible means to reduce the risk of cognitive decline in genetically susceptible samples. PMID- 25730735 TI - Turn-on fluorescent sensing of glutathione S-transferase at near-infrared region based on FRET between gold nanoclusters and gold nanorods. AB - A fluorescence resonance energy transfer (FRET) method based on gold nanoclusters capped glutathione (AuNCs@GSH) and amine-terminated gold nanorods (AuNRs) is designed for turn-on and near-infrared region (NIR) sensing of glutathione S transferase (GST). The absorption band of AuNRs is tuned carefully to maximize the spectra overlap and enhance the efficiency of FRET. The FRET from multiple AuNCs to single AuNR quenches about 70% fluorescence emission of AuNCs. After GST is added, the strong specific interaction of GSH-GST can replace the AuNCs@GSH from AuNRs, FRET based on electrostatic interaction between AuNCs@GSH and AuNRs is switched off. Thus, emission enhancement of AuNCs@GSH is observed. The fluorescent enhancement is linearly with the increasing GST concentration over the range of 2-100 nM GST and the limit of detection for GST is about 1.5 nM. PMID- 25730736 TI - X-ray accelerated photo-oxidation of As(III) in solution. AB - We performed near edge X-ray absorption spectroscopy (XANES) measurements on the arsenic K-edge of As(III) in solution under acidic and basic conditions, after exposure of the solutions to air. Spectra were recorded for increasing exposure times to the X-rays used to perform absorption spectroscopy measurements. We did not find changes for the solution under acidic conditions, whereas we observed significant changes in the case of solution under alkaline conditions. To interpret these changes, we compared the obtained spectra with XANES spectra of As(III) and As(V) solutions under alkaline conditions, not exposed to air, and used as standards. Principal component fits using these standards indicate an accelerated conversion of As(III) to As(V) due to the exposure to X-rays. PMID- 25730737 TI - Diverticulum With Papillae: Does Position of Papilla Affect Technical Success? AB - BASIS AND PURPOSE: The presence of peripapillary diverticulum (PPD) can cause some biliary diseases, especially common bile duct stones, and also, literally, can change the technique of endoscopic retrograde cholangiopancreatography (ERCP) and affect the complication ratio of this procedure. In this study, we investigate the effect of localization and position of the papilla according to the diverticulum on the success of therapeutic ERCP procedures. MATERIALS AND METHODS: The study was conducted prospectively in the patients with naive papillae, who underwent ERCP for a period of 16 months. In all patients, the position of papillae according to the diverticulum (the periphery of the diverticulum is thought as the clock circumference, and the position of papillae is defined as the dials of clock), the success rate of biliary cannulation, total procedure time, overall treatment success rate of ERCP, and the complications are investigated. RESULTS: During this period, 222 (18.5%) of the 1205 enrolled patients who underwent ERCP had PPD. Of the patients with PPD, 123 (55.4%) were female and 99 (44.6%) were male, and the median age was 68.9+/-10.1 years. According to the position of the papilla by the diverticulum, 90 (40.5%) patients have it on 7 o'clock position, 64 (28.8%) patients have on 6 o'clock position, 63 (28.3%) patients have on 5 o'clock position, and 5 (2.3%) patients have on 1 o'clock position. In the cases of the papilla on 1 o'clock position according to the diverticulum, cannulation procedures were found to be more difficult than other patients (P<0.05). The presence of the diverticulum did not affect the success of therapeutic procedures and did not increase the ratio of complications. CONCLUSIONS: In the presence of PPD, additional cannulation techniques may be required for the procedure. Particularly, the aid of percutaneous techniques may be needed for the papilla on 1 o'clock position. PMID- 25730738 TI - The Learning Curve for Robotic Thyroidectomy Using a Bilateral Axillo-Breast Approach From the 100 Cases. AB - PURPOSE: The purpose of this study was to examine the learning curve for robotic thyroidectomy using a bilateral axillo-breast approach. METHODS: We examined the first 100 robotic thyroidectomies with central lymph node dissection due to papillary thyroid cancer between April 2010 and August 2011. We evaluated the clinical characteristics, operative time, pathologic data, and complications. RESULTS: Operative time was reduced significantly after 40 cases; therefore, the patients were divided into 2 groups: group A (1 to 40 cases) and group B (41 to 100 cases). The mean operative time in group A (232.6+/-10.0 min) was longer than that in group B (188.9+/-6.0 min) with statistical significance (P=0.001). Other data, including characteristics, drainage amount, hospital stay, retrieved lymph nodes, thyroglobulin, and complications, were not different between the 2 groups. The learning curves with lobectomy and total thyroidectomy were reached at the same time. CONCLUSIONS: The learning curve for robotic thyroidectomy with central lymph node dissection using bilateral axillo-breast approach was 40 cases for beginner surgeons. Robotic total thyroidectomy was performed effectively and safely after experience with 40 cases, as with lobectomy. PMID- 25730739 TI - Analysis of Hand Size and Ergonomics of Instruments in Pediatric Minimally Invasive Surgery. AB - Moving from the study conducted in 2004 on adult surgeons we want to analyze the ergonomics applied in pediatric minimally invasive surgery. An online survey was conducted among the members of the European Paediatric Surgeons' Association that included 14 questions pertaining to demographic, surgical glove size, double glove use, prior hand surgery, and the ease or difficulty in using different types of laparoscopic instruments. A total of 138 pediatric surgeons completed the survey. The difficulty score (DS) was similar between the 3.5- and 5-mm instruments. Other specialized instruments such as Ligasure, Ultracision, Clip applicators, endobags, and staplers were found to have higher DS. The needle holder was the only instrument that is part of the normal 5-mm operating sets, which was found to have a higher DS. Our survey found increased DS with the endobag and stapler, but this was not significant. Also prior hand surgery or double glove use was not associated with difficulty in usage of minimally invasive instruments when compared with normal hands in this survey. PMID- 25730740 TI - Systemic Acute-phase Response in Laparoscopic and Open Ileal Pouch Anal Anastomosis in Patients With Ulcerative Colitis: A Case-matched Comparative Study. AB - AIM: The current trial was designed to study and compare the postoperative outcomes and systemic acute responses between patients undergoing laparoscopic ileal pouch anal anastomosis (LAP-IPAA) and open IPAA for ulcerative colitis. METHODS: The clinical records of patients who underwent 89 restorative proctocolectomy procedures with IPAA were reviewed. After determining which patients underwent LAP-IPAA versus open IPAA, an equivalent number of controls matched for age and ulcerative colitis severity were selected. RESULTS: Twenty of 22 patients who underwent laparoscopic surgery met the inclusion criteria. Patients who underwent LAP-IPAA had significantly shorter times to first walking (P=0.021) and food intake (P=0.0003). The LAP-IPAA group had significantly lower interleukin-6 and interleukin-1ra levels soon after surgery (P=0.011 and P=0.0076). The LAP-IPAA group had significantly lower C-reactive protein levels on postoperative day 1 (P=0.0027). CONCLUSIONS: LAP-IPAA is a less-invasive operative procedure than open IPAA with respect to the postoperative systemic inflammatory response and postoperative recovery. PMID- 25730741 TI - Laparoscopic Right Colon Resection With Transvaginal Extraction: A Systematic Review of 90 Cases. AB - BACKGROUND: Natural orifice specimen extraction is a laparoscopic technique that reduces the procedure's invasiveness. OBJECTIVE: We aimed to examine all the available data for the transvaginal extraction of laparoscopic right-sided colonic resections. DATA SOURCES: A systematic search was conducted using PubMed/MEDLINE, Cochrane, Google Scholar, EBSCO, clinicaltrials.gov, and congress abstract databases. STUDY SELECTION: All case-control series, case series, and case reports were included, irrespective of age, region, race, obesity, comorbidities, or history of previous surgery. No restrictions were made in terms of language, country, or journal. MAIN OUTCOME MEASURES: Patient selection criteria and results of the cumulative data. RESULTS: The search identified 10 studies including 90 cases. Most patients were elderly (mean, 65.9; range, 29 to 87 y) and had comorbid diseases (96%). 33.8% had a history of abdominopelvic surgery. The mean body mass index was 25.7 kg/m (range, 18 to 50 kg/m). Most patients (83%) had malign or premalign (14%) diseases and required regular or extended right hemicolectomies (99%). The mean operating time and blood loss ranges were 193 (140 to 471) minutes and 62.4 (0 to 300) mL, respectively. Overall, morbidities were seen in 18 patients (20%), and 3 of them were related to the transvaginal extraction. There were no abdominal wound related early or late complications. When compared with laparoscopic colon resections with transabdominal extraction, the procedure seems to result in decreased postoperative pain and length of hospital stay. LIMITATIONS: There are a limited number of comparative studies and an absence of randomized studies. CONCLUSIONS: Laparoscopic resection and transvaginal specimen extraction is a promising technique for some right-sided colon pathologies. For patient selection, an accessible vaginal port (patient acceptance and a vagina that is not narrow) and an en-mass lesion of <=8 cm were necessary. Malignancy, previous abdominopelvic surgery, obesity, and old age were not considered as contraindications. PMID- 25730742 TI - Scientific uncertainty as a moderator of the relationship between descriptive norm and intentions to engage in cancer risk-reducing behaviors. AB - This study examined motivational factors underlying six behaviors with varying levels of scientific uncertainty with regard to their effectiveness in reducing cancer risk. Making use of considerable within-subjects variation, the authors examined the moderating role of the degree of scientific uncertainty about the effectiveness of cancer risk-reducing behaviors in shaping relationships between constructs in the Integrative Model of Behavioral Prediction (Fishbein & Yzer, 2003 ). Using cross-sectional data (n = 601), the descriptive norm-intention relationship was stronger for scientifically uncertain behaviors such as avoiding BPA plastics and using a hands-free mobile phone headset than for established behaviors (e.g., avoiding smoking, fruit and vegetable intake, exercise, and applying sunscreen). This pattern was partially explained by the mediating role of injunctive norms between descriptive norm and intentions, as predicted by the extended Theory of Normative Social Behavior (Rimal, 2008 ). For behaviors more clearly established as an effective means to reduce the risk of cancer, self efficacy was significantly more predictive of intentions to perform such behaviors. The authors discuss practical implications of these findings and theoretical insights into better understanding the role of normative components in the adaptation of risk-reduction behaviors. PMID- 25730743 TI - Errata. PMID- 25730744 TI - Associations between seasonal sleep change and indoor tanning. AB - Identification of risk factors for indoor tanning may ultimately aid the development of better indoor tanning prevention strategies, which is pertinent given the association between indoor tanning and skin cancer. This study aimed to examine the relationship between seasonal sleep change and indoor tanning. Female tanners (N=139) completed self-report measures including items relating to seasonal sleep changes, seasonal affective disorder (SAD), reasons for tanning, tanning during the winter months, and the Tanning Pathology Scale (TAPS), which measures problematic tanning motives and symptoms of tanning dependence. It was hypothesized that seasonal sleep change and SAD would be associated with greater indoor tanning during the winter, more tanning to improve mood and to relax, and higher scores on the TAPS. Findings indicated that more seasonal sleep change was associated with tanning to improve mood and higher scores on the TAPS. Similarly, the presence of SAD was related to tanning to improve mood, tanning to relax, and more problematic tanning. PMID- 25730745 TI - Bifactor analysis of the mental health continuum-short form (MHC-SF). AB - This report examined the factor structure of the Mental Health Continuum-Short Form (MHC-SF) using bifactor analysis to evaluate a general well-being factor and the three group factors that correspond with emotional, social, and psychological well-being. Using a sample of 902 South African psychology students (M age=21.1 yr., SD=2.7), the MHC-SF was examined using confirmatory factor models, (1) a one factor model conceptualizing well-being as unidimensional, (2) a correlated three factor model corresponding with Keyes' model, and (3) a bifactor solution with a general well-being factor and three orthogonalized group factors. The bifactor solution fitted the best and evidenced a strong general well-being factor and three comparatively weak residualized group factors. These findings contribute to the literature by facilitating an examination of the strength of a general well being factor as contrasted with the multidimensional components of emotional, social, and psychological well-being and advance a case for the interpretation of both the general and multidimensional components. The results inform considerations regarding the employ of the scale in statistical procedures such as multiple regression analysis and structural equation modeling. PMID- 25730746 TI - Socially desirable responding in Chinese university students: denial and enhancement? AB - This study examined the Balanced Inventory of Desirable Responding (BIDR) with one-, two-, three-, and four-dimensional models and tested the BIDR's discriminant validity with personality variables. A confirmatory and exploratory factor analysis of responses from 600 Chinese university students (314 men, 282 women, 4 missing; M age=20.0 yr.) provided results indicating that the four factor model fit the data best; i.e., self-deception and impression management split into denial and enhancement. The Denial and Enhancement subscales with personality variables show significant differences, confirming the four-factor model. The cultural differences as a possible reason for the split were discussed. PMID- 25730747 TI - Exploratory examination of the relationship between acculturation and personal growth among Korean immigrants. AB - Korean immigrants are motivated to accept new cultural perspectives and/or transform their own cultural values into those of their new country. During this acculturation process, they encounter cultural differences, make adaptations, and thus may experience positive changes in social relationships, coping resources, personal strength, and cultural knowledge. The purpose of this study was to investigate the relationship between the dimensions of acculturation and personal growth. The results indicated that two dimensions of acculturation (e.g., self control and collectivism), age, and length of stay were predictors of personal growth that involves social relationships, personal resources, life philosophy, and coping skills. This study suggests that high scores on two acculturation dimensions indicated lower acculturation, which predicts personal growth. PMID- 25730748 TI - Children left behind in romania: anxiety and predictor variables. AB - Children left behind while their parents immigrate or travel for employment are becoming a widespread phenomenon for economic reasons, creating potentially stressful and inadequate developmental support for a substantial portion of some countries' working class populations. This study assessed the emotional status and coping skills of two matched samples of 163 Romanian children left behind and 163 comparable children living with their parents. The State-Trait Anxiety Inventory for Children, the Anger Expression Scale for Children, the Short Mood and Feelings Questionnaire, and the Children's Coping Strategies Checklist were utilized. Higher anxiety and depression were observed in left-behind children compared to the control group living with parents. Hierarchical multiple regression supported the relevance of coping strategies, controlled for sociodemographic characteristics, to help explain anxiety in left-behind children. Strategies to promote psychological health and general well being are discussed. PMID- 25730749 TI - Self-acceptance mediates the relationship between mindfulness and perceived stress. AB - Previous research has shown that the effects of mindfulness-based interventions and increased trait mindfulness are associated with reduced stress. Further research is needed to understand the mechanisms by which mindfulness-based interventions exert their beneficial effect on decreased stress. The purpose of the present study was to examine the role of self-acceptance in the relationship between trait mindfulness and perceived stress among a sample of 132 students from Beijing, China. Results revealed that self-acceptance was found to partially mediate the relationship between mindfulness and stress. Limitations, clinical implications, and directions for future research are identified. PMID- 25730750 TI - Psychometric properties of the Physical Self-Concept Questionnaire with Mexican university students. AB - This study analyzes, in a sample of Mexican students, the factor structure of the Physical Self-Concept Questionnaire of Goni, Ruiz de Azua, and Rodriguez (2006), which assesses physical ability, physical fitness, attractiveness, strength, general physical self-concept, and global self-concept. A representative sample of 1,466 Mexican university physical education students was selected (754 men, 712 women; M age=20.6 yr., SD=2.0). Confirmatory factor analysis showed a two factor structure (motor competency and physical attractiveness). The two-factor structure, regarding statistical and substantive criteria, had good fit indices. Results of the factor analyses carried out with the sub-samples indicated a strong stability and evidence for the factor structure obtained. The findings support the use of this questionnaire to measure physical self-concept in Mexican university students. Future studies should replicate these findings in other populations. PMID- 25730751 TI - Personalized medicine for effective Alzheimer disease treatment. PMID- 25730752 TI - A comparison of mouse parvovirus 1 infection in BALB/c and C57BL/6 mice: susceptibility, replication, shedding, and seroconversion. AB - This study characterized the effects of challenge with a field isolate of mouse parvovirus 1 (MPV1e) in C57BL/6NCrl (B6) and BALB/cAnNCrl (C) mice. We found that C mice were more susceptible to MPV1e infection than were B6 mice; ID50 were 50 to 100 times higher after gavage and 10-fold higher after intraperitoneal injection in B6 as compared with C mice. To evaluate the host strain effect on the pathogenesis of MPV1e, B6 and C mice were inoculated by gavage. Feces and tissues, including mesenteric lymph nodes (MLN), ileum, spleen and blood, were collected for analysis by quantitative PCR (qPCR) to assess infection and fecal shedding and by RT-qPCR to evaluate replication. Peak levels of MPV1e shedding, infection, and replication were on average 3.4, 4.3, and 6.2 times higher, respectively, in C than in B6 mice. Peaks occurred between 3 and 10 d after inoculation in C mice but between 5 and 14 d in B6 mice. Multiplexed fluorometric immunoassays detected seroconversion in 2 of 3 C mice at 7 d after inoculation and in all 3 B6 mice at 10 d. By 56 d after inoculation, viral replication was no longer detectable, and fecal shedding was very low; infection persisted in ileum, spleen, and MLN, with levels higher in C than B6 mice and highest in MLN. Therefore, the lower susceptibility of B6 mice, as compared with C mice, to MPV1e infection was associated with lower levels of infection, replication, and shedding and delayed seroconversion. PMID- 25730753 TI - Pathogenicity of Helicobacter ganmani in mice susceptible and resistant to infection with H. hepaticus. AB - Helicobacter spp. are some of the most prevalent bacterial contaminants of laboratory mice. Although abundant data regarding the diseases associated with H. hepaticus infection are available, little is known about the pathogenicity of H. ganmani, which was first isolated in 2001 from the intestines of laboratory mice. The objective of this study was to evaluate the host response to H. ganmani colonization in H. hepaticus disease-resistant C57BL/6 and disease-susceptible A/J and IL10-deficient mice. Mice were inoculated with H. ganmani, H. hepaticus, or Brucella broth. Cecal lesion scores, cecal gene expression, and Helicobacter load were measured at 4 and 90 d after inoculation. At both time points, mice inoculated with H. ganmani had similar or significantly more copies of cecum associated Helicobacter DNA than did mice inoculated with H. hepaticus. When compared with those of sham-inoculated control mice, cecal lesion scores at 4 and 90 d after inoculation were not significantly greater in H. ganmani-inoculated A/J, C57BL/6, or IL10-deficient mice. Analysis of cecal gene expression demonstrated that H. ganmani infection failed to cause significant elevations of IFNgamma in A/J, C57BL/6, or IL10-deficient mice. However, in IL10-deficient mice, H. ganmani infection was associated with a significant increase in the expression of the proinflammatory cytokine IL12/23p40. Although H. ganmani infection in this study failed to induce the typhlitis that is the hallmark of H. hepaticus infection, infection with H. ganmani was associated with alterations in inflammatory cytokines in IL10-deficient mice. PMID- 25730754 TI - Pathology, organ distribution, and immune response after single and repeated intravenous injection of rats with clinical-grade parvovirus H1. AB - Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID- 25730755 TI - Bioavailability, biodistribution, and CNS toxicity of clinical-grade parvovirus H1 after intravenous and intracerebral injection in rats. AB - The autonomous parvovirus H1 (H1PV) is transmitted in rodent populations. The natural host is the rat, in which H1PV infection is pathogenic only in fetuses and newborns. H1PV infection of human cancer cells leads to strong oncolytic effects in preclinical models. In preparation for a clinical trial of H1PV injection in patients with malignant brain tumors, H1PV had to be prepared to Good Manufacturing Practice standards, including extensive toxicology testing in rats. Because the trial involves direct intracerebral injection of H1PV into the tumor and around the resection cavity, possible toxicity to CNS tissue had to be investigated. In addition, quantitative blood levels and the tissue distribution of H1PV after single intracerebral or intravenous injection were measured. Direct injection of H1PV into rat brain at 3 dose levels (maximum, 7.96 * 107 pfu) did not cause any macroscopic or histologic pathology. Furthermore, H1PV infection of the brain did not alter central or autonomous nervous system function. H1PV DNA was detected in almost all organs at 6 h, 48 h, and 14 d after intravenous and intracerebral injection, with the highest levels in liver and spleen. H1PV concentrations in most organs were similar after intravenous and intracerebral injection, indicating high permeability of the blood-brain barrier for this small virus. The current results demonstrate wide organ distribution of H1PV after intravenous or intracerebral injection, confirm that H1PV is nonpathogenic in adult rats even after direct injection into the brain, and form the basis for the ongoing ParvOryx01 clinical trial. PMID- 25730756 TI - Four-point bending as a method for quantitatively evaluating spinal arthrodesis in a rat model. AB - The most common method of evaluating the success (or failure) of rat spinal fusion procedures is manual palpation testing. Whereas manual palpation provides only a subjective binary answer (fused or not fused) regarding the success of a fusion surgery, mechanical testing can provide more quantitative data by assessing variations in strength among treatment groups. We here describe a mechanical testing method to quantitatively assess single-level spinal fusion in a rat model, to improve on the binary and subjective nature of manual palpation as an end point for fusion-related studies. We tested explanted lumbar segments from Sprague-Dawley rat spines after single-level posterolateral fusion procedures at L4-L5. Segments were classified as 'not fused,' 'restricted motion,' or 'fused' by using manual palpation testing. After thorough dissection and potting of the spine, 4-point bending in flexion then was applied to the L4 L5 motion segment, and stiffness was measured as the slope of the moment displacement curve. Results demonstrated statistically significant differences in stiffness among all groups, which were consistent with preliminary grading according to manual palpation. In addition, the 4-point bending results provided quantitative information regarding the quality of the bony union formed and therefore enabled the comparison of fused specimens. Our results demonstrate that 4-point bending is a simple, reliable, and effective way to describe and compare results among rat spines after fusion surgery. PMID- 25730757 TI - Infestation of research zebra finch colony with 2 novel mite species. AB - A zebra finch (Taeniopygia guttata) housed in a neuroscience laboratory was observed to have numerous feather mites. Subsequently, similar mites were found on other birds in the animal facility and research space. The most abundant mite was a novel, undescribed species in the genus Neocheyletiella. Whereas known Neocheyletiella mites have previously been characterized as skin parasites of various birds worldwide, the species on the zebra finches is unique because it lives and builds nests in the feathers. Infrequent specimens of a 'true' feather mite, a new species of Megninialges, were present also. Although multiple treatments using a pyrethrin spray were effective in eradicating the mites, topical ivermectin later was found to be more efficacious, better tolerated by the birds, and less labor intensive. This case highlights the general dearth of information regarding ectoparasites in zebra finches, even though these are the most frequently used songbirds in biomedical research. The mite epizootic also underscores the diverse pathogens possible in zebra finches that arrive from outside sources and why ongoing health monitoring of finch colonies is warranted. PMID- 25730758 TI - Comparison of isoflurane and alpha-chloralose in an anesthetized swine model of acute pulmonary embolism producing right ventricular dysfunction. AB - Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and alpha-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received alpha-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO2, end-tidal CO2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given alpha-chloralose compared with isoflurane exhibited a lower heart rate (63 +/- 10 compared with 116 +/- 15 bpm) and peripheral arterial pressure (52 +/- 12 compared with 61 +/- 12 mm Hg); higher SpO2 (98% +/- 3% compared with 95% +/- 1%), end-tidal CO2 (35 +/- 4 compared with 32 +/- 5), and systolic blood pressure (121 +/- 8 compared with 104 +/- 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 +/- 0.50 compared with 1.23 +/- 0.19) and troponin I mean values (0.09 +/- 0.07 ng/mL compared with 0.09 +/- 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for alpha-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with alpha-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of alpha-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE. PMID- 25730759 TI - Use of genome-wide heterospecific single-nucleotide polymorphisms to estimate linkage disequilibrium in rhesus and cynomolgus macaques. AB - Rhesus and cynomolgus macaques are frequently used in biomedical research, and the availability of their reference genomes now provides for their use in genome wide association studies. However, little is known about linkage disequilibrium (LD) in their genomes, which can affect the design and success of such studies. Here we studied LD by using 1781 conserved single-nucleotide polymorphisms (SNPs) in 183 rhesus macaques (Macaca mulatta), including 97 purebred Chinese and 86 purebred Indian animals, and 96 cynomolgus macaques (M. fascicularis fascicularis). Correlation between loci pairs decayed to 0.02 at 1146.83, 2197.92, and 3955.83 kb for Chinese rhesus, Indian rhesus, and cynomolgus macaques, respectively. Differences between the observed heterozygosity and minor allele frequency (MAF) of pairs of these 3 taxa were highly statistically significant. These 3 nonhuman primate taxa have significantly different genetic diversities (heterozygosity and MAF) and rates of LD decay. Our study confirms a much lower rate of LD decay in Indian than in Chinese rhesus macaques relative to that previously reported. In contrast, the especially low rate of LD decay in cynomolgus macaques suggests the particular usefulness of this species in genome wide association studies. Although conserved markers, such as those used here, are required for valid LD comparisons among taxa, LD can be assessed with less bias by using species-specific markers, because conserved SNPs may be ancestral and therefore not informative for LD. PMID- 25730760 TI - Detection and quantification of male-specific fetal DNA in the serum of pregnant cynomolgus monkeys (Macaca fascicularis). AB - Because of their developmental similarities to humans, nonhuman primates are often used as a model to study fetal development for potential clinical applications in humans. The detection of fetal DNA in maternal plasma or serum offers a source of fetal genetic material for prenatal diagnosis. However, no such data have been reported for cynomolgus monkeys (Macaca fascicularis), an important model in biomedical research. We have developed a specific, highly sensitive PCR system for detecting and quantifying male-specific fetal DNA in pregnant cynomolgus monkeys. We used multiplex quantitative real-time PCR to analyze cell-free DNA in maternal blood serum obtained from 46 pregnant monkeys at gestational weeks 5, 12, and 22. The presence of SRY gene and DYS14 Y chromosomal sequences was determined in 28 monkeys with male-bearing pregnancies. According to confirmation of fetal sex at birth, the probe and primers for detecting the Y chromosomal regions at each time point revealed 100% specificity of the PCR test and no false-positive or false-negative results. Increased levels of the SRY-specific sequences (mean, 4706 copies/mL serum DNA; range, 1731 to 12,625) and DYS14-specific sequences (mean, 54,814 copies/mL serum DNA; range, 4175-131,250 copies) were detected at week 22. The SRY- and DYS14-specific probes appear to be an effective combination of markers in a multiplex PCR system. To our knowledge, this report is the first to describe the detection of cell-free DNA in cynomolgus monkeys. PMID- 25730761 TI - Development of a cerebrospinal fluid lateral reservoir model in rhesus monkeys (Macaca mulatta). AB - Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult male rhesus monkeys were utilized in this study. Pre-surgical MRI was performed to determine the coordinates of the lateral ventricle and location of choroid plexus (CP). The coordinates were determined to avoid the CP and major blood vessels. The predetermined coordinates were 100% accurate, according to MRI validation. The LR system functioned successfully in 67% of cases for 221 d, and 44% remain functional at 426 to 510 d postoperatively. Compared with established models, our LR model markedly reduced postoperative complications and recovery time. Development of the LR model was successful in rhesus macaques and is a useful alternative to the FR and LP methods of CSF collection from nonhuman primates. PMID- 25730762 TI - Technology, Biopolitics, Rationalities and Choices: Recent Studies of Reproduction. AB - New synergies across anthropology, science and technology studies (STS), legal studies and sociology, bring fresh theoretical perspectives to the study of reproduction. Recent works on reproduction trace some of the changing rationalities: from the tactics of feminist self-help health movements in 1970s and 1980s in the US, to the commercialized experience of pregnancy and the various configurations, policies and legalities addressing globalized genetic and assisted reproductive technologies. Reproductive decision-making is deeply entangled with neoliberalism, welfare reforms, racial and geographic disparities, economic stratification and cultural rationalities to produce inequalities. Studies of reproduction remain central to basic anthropological questions: what it means to be human, what constitutes life, how we live our lives, and how societies value particular lives. PMID- 25730764 TI - Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance. AB - Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals. PMID- 25730763 TI - Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. AB - Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases. PMID- 25730765 TI - The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. AB - Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 * 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL. PMID- 25730768 TI - Ventilator associated pneumonia in the ICU: where has it gone? AB - PURPOSE OF REVIEW: To highlight the clinical importance of ventilator-associated pneumonia (VAP) in an era of escalating antimicrobial resistance. RECENT FINDINGS: VAP continues to be an important infection in the critically ill. The development of rapid microbiologic diagnostics and new antimicrobial agents offer opportunities for improved treatment strategies for VAP balancing the need to treat effectively in a timely manner and antimicrobial stewardship. Additionally, the new surveillance definitions for assessing the quality of care in critically ill patients (ventilator-associated events, ventilator-associated conditions, and infection-related ventilator-associated conditions) do not appear to be adequate surrogates for the identification of VAP. SUMMARY: Clinicians caring for critically ill patients should be aware of the importance of correctly treating VAP. As new diagnostic technologies and antimicrobials become available for VAP, their incorporation into routine patient management should occur in a way that optimizes patient outcomes wherein minimizing further emergence of antimicrobial resistance. PMID- 25730766 TI - The genome and transcriptome of the zoonotic hookworm Ancylostoma ceylanicum identify infection-specific gene families. AB - Hookworms infect over 400 million people, stunting and impoverishing them. Sequencing hookworm genomes and finding which genes they express during infection should help in devising new drugs or vaccines against hookworms. Unlike other hookworms, Ancylostoma ceylanicum infects both humans and other mammals, providing a laboratory model for hookworm disease. We determined an A. ceylanicum genome sequence of 313 Mb, with transcriptomic data throughout infection showing expression of 30,738 genes. Approximately 900 genes were upregulated during early infection in vivo, including ASPRs, a cryptic subfamily of activation-associated secreted proteins (ASPs). Genes downregulated during early infection included ion channels and G protein-coupled receptors; this downregulation was observed in both parasitic and free-living nematodes. Later, at the onset of heavy blood feeding, C-lectin genes were upregulated along with genes for secreted clade V proteins (SCVPs), encoding a previously undescribed protein family. These findings provide new drug and vaccine targets and should help elucidate hookworm pathogenesis. PMID- 25730772 TI - Radiation Exposure: Optimizing Image Quality or Image Utility? PMID- 25730767 TI - Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. AB - Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin. PMID- 25730773 TI - A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity. AB - In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl(-) channels and phospholipid scramblases. ANO10 augments volume-regulated Cl(-) currents (IHypo) in Xenopus oocytes, HEK293 cells, lymphocytes and macrophages and controls volume regulation by enhancing regulatory volume decrease (RVD). ANO10 supports migration of macrophages and phagocytosis of spirochetes. The R263H variant is inhibitory on IHypo, RVD and intracellular Ca(2+) signals, which may delay spirochete clearance, thereby sensitizing adaptive immunity. Our data demonstrate for the first time that ANO10 has a central role in innate immune defense against Borrelia infection. PMID- 25730775 TI - Effects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs. AB - IMPORTANCE: The prognostic role of high blood pressure and the aggressiveness of blood pressure lowering in dementia are not well characterized. OBJECTIVE: To assess whether office blood pressure, ambulatory blood pressure monitoring, or the use of antihypertensive drugs (AHDs) predict the progression of cognitive decline in patients with overt dementia and mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS: Cohort study between June 1, 2009, and December 31, 2012, with a median 9-month follow-up of patients with dementia and MCI in 2 outpatient memory clinics. MAIN OUTCOMES AND MEASURES: Cognitive decline, defined as a Mini-Mental State Examination (MMSE) score change between baseline and follow-up. RESULTS: We analyzed 172 patients, with a mean (SD) age of 79 (5) years and a mean (SD) MMSE score of 22.1 (4.4). Among them, 68.0% had dementia, 32.0% had MCI, and 69.8% were being treated with AHDs. Patients in the lowest tertile of daytime systolic blood pressure (SBP) (<= 128 mm Hg) showed a greater MMSE score change (mean [SD], -2.8 [3.8]) compared with patients in the intermediate tertile (129-144 mm Hg) (mean [SD], -0.7 [2.5]; P = .002) and patients in the highest tertile (>= 145 mm Hg) (mean [SD], -0.7 [3.7]; P = .003). The association was significant in the dementia and MCI subgroups only among patients treated with AHDs. In a multivariable model that included age, baseline MMSE score, and vascular comorbidity score, the interaction term between low daytime SBP tertile and AHD treatment was independently associated with a greater cognitive decline in both subgroups. The association between office SBP and MMSE score change was weaker. Other ambulatory blood pressure monitoring variables were not associated with MMSE score change. CONCLUSIONS AND RELEVANCE: Low daytime SBP was independently associated with a greater progression of cognitive decline in older patients with dementia and MCI among those treated with AHDs. Excessive SBP lowering may be harmful for older patients with cognitive impairment. Ambulatory blood pressure monitoring can be useful to help avoid high blood pressure overtreatment in this population. PMID- 25730774 TI - Acute Hepatic Insulin Resistance Contributes to Hyperglycemia in Rats Following Myocardial Infarction. AB - Although hyperglycemia is common in patients with acute myocardial infarction (MI), the underlying mechanisms are largely unknown. Insulin signaling plays a key role in the regulation of glucose homeostasis. In this study, we test the hypothesis that rapid alteration of insulin signaling pathways could be a potential contributor to acute hyperglycemia after MI. Male rats were used to produce MI by ligation of the left anterior descending coronary artery. Plasma glucose and insulin levels were significantly higher in MI rats than those in controls. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) was reduced significantly in the liver tissue of MI rats compared with controls, followed by decreased attachment of phosphatidylinositol 3-kinase (PI3K) p85 subunit with IRS1 and Akt phosphorylation. However, insulin stimulated signaling was not altered significantly in skeletal muscle after MI. The relative mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase were slightly higher in the liver tissue of MI rats than those in controls. Rosiglitazone (ROSI) markedly restored hepatic insulin signaling, inhibited gluconeogenesis and reduced plasma glucose levels in MI rats. Insulin resistance develops rapidly in liver but not skeletal muscle after MI, which contributes to acute hyperglycemia. Therapy aimed at potentiating hepatic insulin signaling may be beneficial for MI-induced hyperglycemia. PMID- 25730776 TI - Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs. AB - MicroRNAs (miRNAs) play a major part in the post-transcriptional regulation of gene expression. Mammalian miRNA biogenesis begins with cotranscriptional cleavage of RNA polymerase II (Pol II) transcripts by the Microprocessor complex. Although most miRNAs are located within introns of protein-coding transcripts, a substantial minority of miRNAs originate from long noncoding (lnc) RNAs, for which transcript processing is largely uncharacterized. We show, by detailed characterization of liver-specific lnc-pri-miR-122 and genome-wide analysis in human cell lines, that most lncRNA transcripts containing miRNAs (lnc-pri-miRNAs) do not use the canonical cleavage-and-polyadenylation pathway but instead use Microprocessor cleavage to terminate transcription. Microprocessor inactivation leads to extensive transcriptional readthrough of lnc-pri-miRNA and transcriptional interference with downstream genes. Consequently we define a new RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells. PMID- 25730777 TI - A specialized molecular motion opens the Hv1 voltage-gated proton channel. AB - The Hv1 proton channel is unique among voltage-gated channels for containing the pore and gate within its voltage-sensing domain. Pore opening has been proposed to include assembly of the selectivity filter between an arginine (R3) of segment S4 and an aspartate (D1) of segment S1. We determined whether gating involves motion of S1, using Ciona intestinalis Hv1. We found that channel opening is concomitant with solution access to the pore-lining face of S1, from the cytoplasm to deep inside the pore. Voltage- and patch-clamp fluorometry showed that this involves a motion of S1 relative to its surroundings. S1 motion and the S4 motion that precedes it are each influenced by residues on the other helix, thus suggesting a dynamic interaction between S1 and S4. Our findings suggest that the S1 of Hv1 has specialized to function as part of the channel's gate. PMID- 25730779 TI - Cardiotonic and vasoconstriction effects of aqueous methanolic extract of Paspalidium flavidum L. AB - The cardiovascular activity of aqueous methanolic extract of Paspalidium flavidum L. was evaluated on isolated rabbit heart and aorta. Heart rates, force of contraction and perfusion pressure were assessed in the presence of different concentrations of extract and adrenaline by using Langendorff's technique. Moreover, the vasoconstriction effects were studied in rabbit aorta using isolated organ bath. The results indicated that the extract (1ng-100 MU g/ml) exhibited a significant increase in heart rate, contractility and perfusion pressure of isolated rabbit's heart; with a maximum effect at 1ng/ml, which was comparable to adrenaline (1 MU g/ml). Similarly, adrenaline at doses from 1-10 MU g/ml produced a significant dose dependant increase in all the cardiac parameters. The cardiotonic effects of the extract were significantly blocked by propranolol (10(-5)M) while an increase in perfusion pressure was completely antagonized by verapamil (10(-6)M). Activity of cardiac marker enzymes was also significantly raised in the perfusate of isolated heart pretreated with the extract. In rabbit aorta, the extract exhibited a dose dependent vasoconstriction effect however it did not increase the tone of aorta when pre-treated with verapamil (10(-6)M). It is conceivable therefore; that the cardiotonic and vasoconstriction effects of the extract might be due to its agonistic actions on beta-receptors and Ca(+2) channels. PMID- 25730778 TI - Small-RNA loading licenses Argonaute for assembly into a transcriptional silencing complex. AB - Argonautes and their small-RNA cofactors form the core effectors of ancient and diverse gene-silencing mechanisms whose roles include regulation of gene expression and defense against foreign genetic elements. Although Argonautes generally act within multisubunit complexes, what governs their assembly into these machineries is not well defined. Here, we show that loading of small RNAs onto Argonaute is a checkpoint for Argonaute's association with conserved GW protein components of silencing complexes. We demonstrate that the Argonaute small interfering RNA chaperone (ARC) complex mediates loading of small RNAs onto Ago1 in Schizosaccharomyces pombe and that deletion of its subunits, or mutations in Ago1 that prevent small-RNA loading, abolish the assembly of the GW protein containing RNA-induced transcriptional silencing (RITS) complex. Our studies uncover a mechanism that ensures that Argonaute loading precedes RITS assembly and thereby averts the formation of inert and potentially deleterious complexes. PMID- 25730780 TI - Study of the effect of inorganic and organic complexes of arsenic metal on the status of GSH in T. cells and B. cells of blood. AB - Arsenic is a major threat to large part of the population due to its carcinogenic nature. The toxicity of Arsenic varies with its chemical form and oxidation states. Glutathione (GSH), a major intra-cellular tripeptide plays a major role in arsenic detoxification. The present study was designed to provide insight into the extent of changes in GSH level by inorganic arsenic in the form of Arsenic trioxide (ATO) and organic arsenic in the form of nitro benzene arsenic acid (NBA). Lymphocytes (T.cells and B.cells) were investigated for determination of change in GSH metabolic status caused by arsenic. The depletion of GSH level positively correlated with increasing arsenic concentration and time of incubation. The decline in GSH level was consistent with increasing pH and physiological temperature. Our findings show that changes in GSH status produced by Arsenic could be due to adduct (As-(SG)3) formation. This change in GSH metabolic status provides information regarding mechanism of toxicity of inorganic and organic arsenicals. These findings are important for the rational design of antidote for the prevention of arsenic induced toxicity. PMID- 25730781 TI - Phenolic composition and antioxidant activity of the different extracts from Thymus longicaulis C Presl. subsp. longicaulis var. longicaulis and T. longicaulis C. Presl. subsp. longicaulis var. subisophyllus growing in Turkey. AB - The objectives of the present study were to investigate the phenolic composition and in vitro antioxidant capacities of the infusions and different extracts of two Thymus taxa: Thymus longicaulis C. Presl. subsp. longicaulis var. longicaulis and Thymus longicaulis C. Presl. subsp. longicaulis var. subisophyllus (Lamiaceae). The quantitative estimation of total flavonoid, flavonoland phenolic contents of the studied extracts were performed by spectrophotometrical method; the aluminum chloride the aluminum chloride+Na acetate and Folin-Ciocalteau methods, respectively. The determination of phenolic acids in the studied species was achieved by using a modified reverse phase-High Pressure Liquid Chromatography method adopting an internal standard. Antioxidant activities of the extracts were determined by three test systems namely, radical scavenging on DPPH, beta-carotene bleaching and Rancimat methods. The results were compared to those of BHT as synthetic antioxidant. Ethyl acetate extracts were found to be rich as a source of phenolics. In addition, the main phenolic acid of the extracts identified by HPLC-DAD was rosmarinic acid. Also, the infusions containing especially water-soluble compounds were observed to exhibit lower antioxidant capacities than those of the methanol and ethyl acetate extracts. Our results indicated that ethyl acetate fraction of studied Thymus taxa can be used as antioxidant in food and medicinal preparations. In addition, the present study revealed that the infusions of these plants exhibit lower activity in contrast to general believes in which aqueous extracts, as in the case of herbal teas, have high antioxidant activity. PMID- 25730782 TI - Assessing of oxidative stress related parameters in diabetes mellitus type 2: cause excessive damaging to DNA and enhanced homocysteine in diabetic patients. AB - Oxidative stress and reactive oxygen species (ROS) have been documented subsist to the pathogenesis of many diseases including diabetes mellitus. The strength of both parameters could be estimated by measuring oxidative stress marker thiobarbituric acid reactive substances (TBARS), its related parameters and the antioxidants glutathione peroxidase and superoxide dismutase (SOD) in plasma of DM patients. Lipid peroxidation was measured as TBARS and presented as malondialdehyde, total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (Tg), the antioxidants (vitamin A (beta-carotene), vitamin E, vitamin C, glutathione peroxidase (GPx) and superoxide dismutase) levels. The results showed that these parameters, commonly, were declined appreciably in diabetic individuals as compared to the healthy individuals. In most cases, age and gender were appeared to involve in having greater values of diabetes marker. Further, increased level of lipid peroxidation and random behaviour of antioxidant potential also associated with Diabetes. For that reason these biomarkers might be of great important to diagnosis DNA damages of diabetic patients. PMID- 25730783 TI - Comparative evaluation of Nigella sativa (Kalonji) and simvastatin for the treatment of hyperlipidemia and in the induction of hepatotoxicity. AB - Hyperlipidemia is a major risk factor for incidence of coronary artery disease. Simvastatin is a synthetic lipid lowering drug and Nigella sativa seeds found helpful in controlling hyperlipidemia. The study performed to evaluate the efficacy of Nigella sativa in comparison to simvastatin to treat hyperlipidemia. Thirty Sprague Dawley rats fed on an ad libitum diet for 02 weeks, on cholesterol diet for 08 weeks. Then group II treated with simvastatin and group III with Nigella sativa for 06 weeks. Blood samples analyzed for serum cholesterol, serum triglycerides, HDL-C, LDL-C & serum ALT. The results evident that Nigella sativa (kalonji) and simvastatin showed significant improvement in the lipid profile of rats in respective groups after treatment. The p value <0.05 of group II and III documented that Nigella sativa (kalonji) affect the lipid profile in the same way as of simvastatin. However, ALT levels significantly raised in group II treated with simvastatin compared to group III. Nigella sativa and simvastatin showed comparable effects in the treatment of hyperlipidemia. Nigella sativa showed protective role in terms of hepatic dysfunction and can be used as a cholesterol lowering agent. PMID- 25730784 TI - Comparative anti-glycation and alpha-glucosidase inhibition studies of microbial transformed compounds of dydrogesterone. AB - Anti-glycation and alpha-glucosidase inhibition activities of microbial transformed compounds of dydrogesterone (1); 20R-hydroxy-9beta,10alphaa-pregna 4,6-diene-3-one (2), 17beta-hydroxy-9beta,10alpha-androsta-4,6-diene-3-one (3) and 9beta,10alpha-androsta-4,6-diene-3,17-dione (4) were evaluated. Compounds 1 and 4 showed potent alpha-glucosidase inhibitory activities, while 2 and 3 were found to be weak inhibitors, whereas anti-glycation activities of 1-4 were not observed. PMID- 25730785 TI - Antibacterial, cytotoxicity and anticoagulant activities from Hypnea esperi and Caulerpa prolifera marine algae. AB - Extracts from 2 algal species (Hypnea esperi and Caulerpa prolifera) from Suez Canal region, Egypt were screened for the production of antibacterial compounds against some pathogenic bacteria. The bacteria tested included Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, Aeromonas hydrophila, Bacillus subtilis and Staphylococcus aureus. Algal species displayed antibacterial activity. The methanolic extracts showed variable response by producing various zones of inhibition against studied bacteria. The tested Gram-negative bacteria were less affected by studied algal extracts than Gram-positive bacteria. We determined some biopotentials properties such as cytotoxicity and anticoagulant activity of most potent algal active extracts. The secondary metabolites of only Hypnea esperi algal extract effectively prevented the blood clotting to the extent of 120 seconds. Minimum inhibitory concentration (MIC) indicated that all potent tested algal extract C inhibits Bacillus subtilis and Staphylococcus aureus. Minimum bactericidal concentration (MBC) was between 1 and 1.4mg/ml. The algal isolates from Egypt have been found showing promising results against infectious bacteria instead of some synthetic antibiotics. PMID- 25730786 TI - In vitro antioxidant activity of methanolic extracts of various parts of Leptadenia pyrotechnica (Forssk.) Decne. AB - Leptadenia pyrotechnica is a desert plant and its unripe fruits are cooked as a vegetable. Besides, this plant is also used for treating various ailments by the dwellers, yet very little is known about its free radical scavenging activity. Methanolic extracts of aerial parts and roots of this plant were evaluated for their free radical scavenging activity through 2,2' diphenyl-1-picrylhydrazyl (DPPH*) scavenging, hydrogen peroxide scavenging and reducing power assays. Results revealed that there is strong free-radical scavenging activity lying in both parts comparable with synthetic antioxidant i.e. Butylated Hydroxy Anisole (BHA). The activity was found increased in a concentration-dependent manner. Root extracts showed significant DPPH* and hydrogen peroxide scavenging activity, whereas highest electron donating capacity was observed in aerial parts extracts (O.D. of 2.38) at a concentration of 100MUg/ml. This research work will be helpful in the discovery of novel antioxidants from L. pyrotechnica that may replace synthetic antioxidants. PMID- 25730787 TI - Influence of formulation technique on acrylate methacrylate copolymer modified paracetamol matrix tablets. AB - This work was designed to evaluate the influence of various methods such as dry granulation (DG), wet granulation (using the polymer in an ethanolic solution (WGO) or aqueous dispersion (WGA) and solid dispersion (SD) techniques, on properties of paracetamol matrix tablets prepared using varying concentrations of acrylate methacrylate copolymer. Tablet properties were investigated using official and unofficial standards. Drug dissolution profile assessed at pH 1.2 was studied spectrophotometrically at lambda(max) of 245 nm. With the use of various kinetic models, the release mechanism of the drug was analyzed. The parameters, maximum amount of drug release (m(infinity)) at time t(infinity) were obtained, m(infinity) was >= 91.36 %, while t(infinity) was >= 4.5 h. The release rate constant (k) for DG tablets was 15.61 h(sup>-1(/sup>, while, WGO, WGA and SD tablets were 12.90, 11.03 and 10.75 h(-1) respectively. The matrix tablets, which exhibited marked retardation in drug release displayed a Higuchi square root of time model (R(2) > 0.98). The mechanism through which the drug was released was governed by Fickian diffusion release (n values < 0.5). The performance of the drug was affected by the formulation technique in the order of SD > WGO > WGA > DG. PMID- 25730788 TI - Clinical evaluation of herbal coded formulation Cran-off to Urixin in the treatment of urinary tract infection. AB - Urinary Tract Infections are the largest group of infections after the respiratory tract infections. In 85% of the cases the causative organism is E. Coli. A clinical trial was conducted to evaluate the efficacy of coded herbal formulation "Cranoff" (Test drug) for the treatment of Urinary tract infection comparing with Urixin (Control). One hundred and thirty patients suffering from Urinary tract infection from both groups (Males: 45, mean age: 34+/-14 and females: 85, mean age: 33+/-13 year, range: 15-55) were enrolled in the trial and divided in to two groups according to treatment regimens. Cranoff (Test drug) 500mg two capsules and Urixin (Pipemidic Acid Trihydrate JP15) (Control) 400mg capsules twice daily were prescribed for 2-3 weeks. Urinary tract infection was improved in 23 (35.38%) patients out of 65 patients by the use of Cranoff (Test drug), and in 15 (23.07%) patients out of 65 by the use of Urixin (Control drug). Furthermore, there was a significant improvement in Urinary tract infection associated clinical features as compared to Urixin. It is concluded that Cranoff possesses a therapeutic value for the improvement of urinary tract infection and its associated symptoms as compared to Urixin. PMID- 25730789 TI - Optimization and partial characterization of bacteriocin produced by Lactobacillus bulgaricus -TLBFT06 isolated from Dahi. AB - Lactobacillus bulgaricus is one of the predominant lactic acid bacteria of dahi, conferring technological and functional attributes. In the present study thirty dahi samples were investigated for bacteriocin producing L. bulgaricus. Fourteen different isolates were obtained and five were scrutinized for antibacterial activities against food born pathogens. Amongst, a strain TLB06FT was found to have a wide array of antibacterial activities against Gram positive and negative bacteria was selected for further characterization. Growth media optimization for this strain revealed maximum bacteriocin production on MRS media supplemented with glucose (2%), sodium chloride (1%), Tween-80 (0.5%) and yeast extract (1 %). In addition, optimization of growth conditions revealed maximum bacteriocin production at pH 5.5 and temperature of 30-37 degrees C. Bacteriocin showed thermo stability at 90 degrees C and remained highly active in the pH range of 3.5-7.5, inactive by protein catalyzing enzymes and showed no change in activity (800AumL(-1)) when treated with organic solvents and surfactants. The obtained bacteriocin was purified to 1600AU mL(-1) by ammonium sulfate precipitation (80%) by using dialyzing tubing. In the same way, a single peak was obtained by RP-HPLC having antibacterial activity of 6400AU mL(-1). Thus, wild strains of L. bulgaricus have great potential for the production new and novel type of bacteriocins. PMID- 25730790 TI - Formulation and in vivo evaluation of diclofenac sodium sustained release matrix tablet: effect of compression force. AB - In the present study, Diclofenac Sodium (DS) matrix tablets were prepared by direct compression method under different compression forces (5, 10, 15 and 20 KN), using ethylcellulose as matrix forming material. The produced tablets were characterized on the foundation of satisfactory tablet properties such as hardness, friability, drug content, weight variations and in vitro drug release rate. Differential scanning calorimetry (DSC), Fourier Transform Infrared (FT-IR) spectroscopy and X-ray diffraction have been used to investigate any incompatibilities of the tablet's ingredients. Additionally, in vivo bioavailability has been investigated on beagle dogs. Data obtained revealed that, upon increasing compression force the in vitro drug release was sustained and the T(max) value was four hours (for formulations compressed at 15 and 20 kN) compared to the conventional voltarine((r)) 50 tablets (T(max) value of 2 hours). PMID- 25730791 TI - In vitro antibacterial activity of selected medicinal plants from lower Himalayas. AB - The present studies cover antibacterial activity of the crude methanolic extracts of 11 medicinal plants viz. Adhatoda vasica, Bauhenia variegate, Bombax ceiba, Carrisa opaca, Caryopteris grata, Debregeasia salicifolia, Lantana camara, Melia azedarach, Phyllanthus emblica, Pinus roxburghii and Olea ferruginea collected from lower Himalayas against two Gram positive (Staphylococcus aureus, Micrococcus luteus) and two Gram negative (Escherichia coli, Pseudomonas aureginosa) bacterial strains. The extracts were applied at four different concentrations (120 mg/mL, 90mg/mL, 60mg/mL and 30mg/mL) in dimethyl sulfoxide (DMSO) by using agar well diffusion method. Antibacterial activities against Staphylococcus aureus and Micrococcus luteus were observed formethanolic extracts of all the above mentioned plants. Greater antibacterial activity against Pseudomonas aeruginosa was only exhibited by Phyllanthus emblica, Pinus roxburghii, Debregeasia salicifolia and Lantana camara. Escherichia coli was highly resistant to all the plant extracts at all concentrations. It is inferred that methanolic crude extracts of the above mentioned plantsexhibitantibacterial activities against pathogenic bacteria, which proved the ethnobotanical importance of the selected plants that indigenous people use for cure against various diseases. PMID- 25730792 TI - Synthesis, antioxidant and anti-microbial properties of two organoselenium compounds. AB - The aim of this study is synthesis of two different series of organoselenium compounds and available in vitro antioxidant and antimicrobial properties of these synthetic compounds. The synthetic compounds were identified by (1)H-NMR (300 MHz), (13)C-NMR (75.5 MHz), FT-IR spectroscopic techniques and micro analysis. Antioxidant properties of two synthetic organoselenium compounds were determined by 1,1- diphenyl-2-picrylhydrazyl (DPPH) radical method, reducing power assay and beta-carotene bleaching method as in vitro. Antimicrobial effects of samples were assessed by the agar dilution procedure and using gram positive and gram-negative bacteria and yeast strains. Although 1,3-di-p methoxybenzylpyrimidine-2-selenone showed better antiradical activity in DPPH test and higher protective activity on beta-carotene, 1-isopropyl-3 methylbenzimidazole-2-selenone was found to be better in reducing power and antimicrobial activity. PMID- 25730793 TI - Spectrophotometric estimation of eflornithine hydrochloride by using ion-pair reagents. AB - Four newer, cost effective and sensitive ion-pair complex methods were estimated for the determination of eflornithine hydrochloride drug in pharmaceutical formulation. In these methods eflornithine hydrochloride react with bromocresol green (buffer of pH 4), bromophenol blue (buffer pH 4.5), methyl orange (buffer of pH 5.5) and bromothymol blue (buffer of pH 5) respectively. The chloroform was used for extraction of ion-pair complexes. The measurement of complexes was done at 413, 416, 417 and 425 nm respectively. Under the described conditions the proposed methods are linear over the concentration range of 3-18, 4-16, 6-30 and 2-12 MUg/ml and the coefficient of determination were >0.999 (n=6) with a relative standard deviation of <1% (n=6). The average recovery of the target compound is >100% with a limit of quantification (LOQ) of 20, 0.869, 2 and 4.167 MUg/ml and the limit of detection (LOD) 6.6, 0.287, 0.66 and 1.375 MUg/ml. The mechanism of the derivatization reaction is proposed and advantages of the proposed method are discussed. PMID- 25730794 TI - Report: complexation of beta-sitosterol with tris (dibenzylideneacetone) dipalladium and its anti-microbial activity. AB - beta-sitosterol is a naturally occurring plant sterol (phytosterol) present in many fruits and vegetables. Scientific research has proven that beta-sitosterol is helpful in maintaining the proper functioning of our body. Previously we described the complexation of beta-sitosterol with trace metals (Mahmood et al., 2013). Trace metals after the formation of complex unable to absorb in the body and hence eliminated out from the body thus reducing metal toxicity (Marsha, 1996). The present article describes the complexation of MU-sitosterol with Palladium (Pd) metal. Palladium is a toxic metal and due to polluted and hazardous environment traces of this metal can be transferred into the body, which is harmful for human health. Our aim is to make Pd-sterol complex so that this toxic metal (Pd) does not absorb in the body and hence excreted out from the body in the complex form. In order to form this complex MU-sitosterol (Ib) is reacted with Tris (dibenzylideneacetone) dipalladium or [Pd(2) (DBA)(3)] (Ia) in 2:1 ratio in an inert atmosphere and dimethylformamid (DMF) added as a solvent. The resulting complex [Pd(2) (DBA)(3).(beta-sitosterol) (Ic) was identified by various spectroscopic techniques such as IR, Mass and (1)H-NMR. This new organo metallic complex (Ic) also showed significant antibacterial and antifungal activity. The present work revealed that Pd-sterol complex does not only reduce metal toxicity but also helpful in minimizing bacterial and fungal infections present in the body. Our research also concluded that we must take plenty of fruits and vegetables in our diet so that natural plant sterol such as beta sitosterol can enhance our defense mechanism and maintain other functions of our body. PMID- 25730795 TI - Toxicological investigations of Aloe ferox Mill. extracts using Brine shrimp (Artemia salina L.) assay. AB - Cytotoxicity of the extracts of Aloe ferox using brine shrimp was evaluated. Effects of the extracts on hatchability and lethality of brine shrimps were reported in terms of minimum inhibitory concentration and LD(50) respectively. The hatching success was in the order: aqueous root extract (39.8%) >aqueous leaf (26.5%) >acetone leaf (13.7%) > ethanol leaf extracts (2.5%). Hatchability in incubations of ethanol and acetone extracts was found to be dose - dependent, with hatching success decreasing as the concentration of the extracts increased. The lethality of extracts was in the order: aqueous leaf extract (4.7%) >aqueous root extract (4.2%) >acetone leaf extract (3.5%) >ethanol root extract (2.6%) > ethanol leaf extract (1.8%) >acetone root extract (0.7%). Mean mortality of nauplii in the control was higher (6.7%) than that of all the extracts. Based on Meyer's index of toxicity, the acetone leaf extract with LD(50) >1.0mg/mL could be considered as non toxic, while the ethanol root extract (LD(50) <1.0mg/mL was significantly toxic to the brine shrimp. Since the extracts of A. ferox have consistently exhibited significant pharmaceutical properties in-vitro, the non toxic extracts could further be exploited for the development of plant-based pharmaceuticals. PMID- 25730796 TI - Report: trends in adherence to secondary prevention medications in post-acute coronary syndrome patients. AB - To evaluate patients' adherence to evidence-based therapies at an average of 2 years after discharge for Acute Coronary Syndrome (ACS) and to identify factors associated with non-adherence. This study was conducted at Hospital Pulau Pinang, Malaysia. A random sample of ACS patients (n=190) who had discharged on a regimen of secondary preventive medications were included and followed up over a three follow-up appointments at 8, 16, and 23 months post discharge. At each appointment, patients were interviewed and given Morisky questioner to complete in order to compare their level of adherence to the prescribed regimens across the three consecutive time periods. Majority of patients reported either medium or low adherence across the three time periods with only small portion reported high adherence. Furthermore, there was a significant downward trend in the level of adherence to cardio protective medications during the study period (p<0.001). This study also identified 6 factors-age, gender, employment status, ACS subtype, number of co morbidities and number of prescription medications per day that may influence Patients' adherence to their medications. Our findings suggest that long-term adherence to secondary prevention therapies among patients with ACS in Malaysia is sub optimal and influenced by many demographic, social as well as clinical factors. PMID- 25730797 TI - Review: approaches to develop PLGA based in situ gelling system with low initial burst. AB - In situ gelling systems have gained much interest owing to their successful application in the preparation of controlled drug delivery and tissue engineering. The commonly used polymer for these systems is the biocompatible and biodegradable polymer of Poly (lactic-co-glycolic acid) (PLGA) that is available in the market as implants, microparticles and in situ implant. A polymeric solution is prepared by mixing the polymer with a biocompatible solvent which may be water miscible such as N-methyl pyrrolidone (NMP), 2-pyrrolidone and Dimethyl sulfoxide (DMSO) or partially water miscible solvents such as triacetin, benzyl benzoate, ethyl acetate, triethyl citrate and benzyl alcohol. Upon injection of this polymeric solution into buffer or physiological fluid, the system solidifies and the administered drug releases in a controlled manner. The major drawback of these systems is their high initial burst that characterized by release of a noticeable amount of the administered drug during the first release stage that usually results in drug toxicity and tissue irritation. This review focuses on presenting the different strategies utilized to decrease the initial burst from PLGA in situ gelling system. PMID- 25730798 TI - An extract of Perilla stem inhibits Src homology phosphatase-1 (SHP)-1 and influences insulin signaling. AB - Protein tyrosine phosphatases (PTPs) are enzymes that catalyze protein tyrosine dephosphorylation of which Src homology phosphatase-1 (SHP-1) is one of the best validated, a widely distributed intracellular tyrosine phosphatase that contains two SH2 domains. Down regulation of SHP-1 tyrosine phosphatases was significantly increased sensitivity to insulin in insulin signaling pathway. Through in vitro enzymatic reaction kinetics experiment, we found that the extract of Perilla stem was a potential inhibitor to deltaSHP-1, the catalytic domain of SHP-1 protein tyrosine phosphatase, and its IC(50) was 4ug/ml, and was more sensitive towards SHP-1than other PTPs, which indicated that SHP-1 might be a target of the extract of Perilla stem. It can strengthened the level of tyrosine phosphorylation of insulin receptor (IR) and extracellular signal-regulated protein kinase (ERK) in HepG2 cells, and then activated the insulin signaling pathway through inhibiting the protein phosphorylation of SHP-1. These results demonstrated that the extract of Perilla stem could play an important role for diabetes treatment through inhibiting the level of SHP-1 in insulin signaling pathway. PMID- 25730799 TI - Antiproliferative xanthone derivatives from Calophyllum inophyllum and Calophyllum soulattri. AB - Structure-activity relationships of eleven xanthones were comparatively predicted for four cancer cell lines after the compounds were subjected to antiproliferative assay against B-lymphocyte cells (Raji), colon carcinoma cells (LS174T), human neuroblastoma cells (IMR-32) and skin carcinoma cells (SK-MEL 28). The eleven chemical constituents were obtained naturally from the stem bark of Calophyllum inophyllum and Calophyllum soulattri. Inophinnin (1) and inophinone (2) were isolated from Calophyllum inophyllum while soulattrin (3) and phylattrin (4) were found from Calophyllum soulattri. The other xanthones were from both Calophyllum sp. and they are pyranojacareubin (5), rheediaxanthone A (6), macluraxanthone (7), 4-hydroxyxanthone (8), caloxanthone C (9), brasixanthone B (10) and trapezifolixanthone (11). Compound 3 was found to be the most cytotoxic towards all the cancer cell lines with an IC50 value of 1.25MUg/mL while the simplest xanthone, compound 8 was inactive. PMID- 25730800 TI - Evaluation of antioxidant potential and HPLC based identification of phenolics in Polygonum amplexicaule extract and its fractions. AB - There is a growing interest for the plant-based medicines in pharmaceutical industry. Plant derived Antioxidants have gained huge importance regarding their medicinal value. The present study was designed to establish pharmaceutical value of Polygonum amplexicaule for their antioxidant activity using shoot, leaf and rhizome crude methanolic extract along with their n-butanolic, ethanolic, ethyl acetate and aqueous fractions. DPPH assay was used to assess antioxidants, which shows the maximum activity by crude methanolic extract of leaves (CMEL) having IC(50) 1.03 MUg/ml where all other fractions showed IC(50) in a range of 1.03 58.2 MUg/mL. The DNA plasmid protection assay showed that 10 ppm and 100 ppm concentrations of crude methanolic extracts (rhizome and leaf), aqueous fractions (shoot and leaf extract), n-butanolic fractions (shoot and leaf extract) and ethanolic fraction (rhizome extract) have DNA protection properties. TLC and HPLC based Identification of different antioxidants present in shoot, leaf and rhizome crude extracts and their fractions showed the presence of gallic acid, quercetin, catechin, caffeic acid, rutin, myricetin and kaempferol. This study suggested that this plant have high content of antioxidants, which needs to be investigated further for their medicinal and/cosmaceutical applications. PMID- 25730801 TI - Dimethyl 3, 3', 4, 4'-tetrahydroxy-delta-truxinate isolated from the leaves of Andrographis lineata.Wall. ex. Nees suppress adipogenesis in 3T3-L1 preadipocytes for type 2 diabetes. AB - The present investigation elucidates the isolation and characterization of bioactive compound from the ethanolic leaf extract of Andrographis lineata (EtALL) which suppress the differentiation of 3T3-L1 adipocytes. The ethanolic leaf extract was subjected to bioassay guided fractionation in 3T3-L1 cell lines. Five fractions were isolated from the EtALL extract by column chromatography. All the Fractions (I-V) along with EtALL were screened for adipogenesis activity (Oil Red-O staining).The fraction which showed maximum adipogenesis activity was purified by thin layer chromatography. The bioactive Fraction IV was found to have maximum adipogenic (96.83%) activity and the activity was comparable to Rosiglitazone. The spectroscopic data analysis reveals that, the isolated bioactive compound was Dimethyl 3, 3', 4, 4'-tetrahydroxy-delta-truxinate (DTdeltaT), a combination of truxillic and truxinic acid derivative. DTdeltaT showed insulin mimicking (131.2%), sensitizing (810.02%) and adipogenic activity (80.23%). Hence our present study concluded that, Dimethyl 3, 3', 4, 4' tetrahydroxy-delta-truxinate isolated from the ethanolic leaf extract of Andrographis lineata stimulates glucose uptake, potentiates insulin-stimulated glucose in 3T3-L1 adipocytes without increasing adiposity. PMID- 25730802 TI - Antimicrobial salicylaldehyde Schiff bases: synthesis, characterization and evaluation. AB - As the pathogens soon develop resistance to the existing antibiotics, the demand for new and more effective anti-microbial agents is a continuous phenomenon. In this paper we are reporting synthesis and spectral data of eight Schiff bases of salicylaldehyde with different amines, and evaluation of their anti-microbial activities against different bacterial strains. The bases were synthesized by reflux method, and their structures were determined based FT-IR, (1)H-NMR, (13)C NMR and Mass spectrometric data. The Schiff bases synthesized included 2-{[(Z)-(2 hydroxyphenyl) methylidene] amino}benzoicacid (SB1), 4-{[(Z)-(2-hydroxyphenyl) methylidene] amino} benzoic acid (SB2),2-[(naphthalene-2-ylimino)methyl] phenol(SB3),2-2'-[benzene-1,4-diylbis(nitrilomethylylidene)]diphenol (SB4), 2-2' [benzene-1,2-diylbis (nitrile-(E)-methylylidene)]diphenol (SB5), 2-[(2 phenylhydrazineylidene)methyl]phenol (SB6), 2-2'-[ethene-1,2 diylbis(iminomethanediyl)]diphenol (SB7) and 2-[(Z)-(phenylimino)methyl]phenol (SB8). The anti-microbial activities of synthesized Schiff bases were determined in terms of zones of inhibition and minimum inhibitory concentrations (MICs). All the bases showed moderate to good activities against all the tested microorganisms. The MICs of most compounds were 100-200betag/mL against different microorganisms. However, it was 50betag/mL for SB1 against P. aeruginosa (1), SB3 against P. aurantiaca, P. aeruginosa (1), E. coli (2), S. typhi (2) and C. freundii, SB4against E. coli (2), S. typhi (1) and S. maltophilia, SB5 against K. pneumoniae and S. typhi (2), SB6 against P. aeruginosa (3) and C. freundii, SB7 against E. cloacae and A. lipoferum, and SB8 against E. coli (2). Considerably active bases may prove to be potential candidates for future antibiotic drugs. PMID- 25730803 TI - Broad spectrum anti-microbial compounds producing bacteria from coast of Qingdao bays. AB - Anti-microbial resistance burden and hazard associated with chemical treatment of infections demanded for new anti-microbial natural products. Marine associated microorganisms are the enormous source of bioactive compounds. In this study we have isolated 272 marine bacteria among them 136 (50%) were antagonistic to at least one of the four pathogenic strains Listeria monocytogenes, Vibrio cholerae, E. coli and S. aureus. Only two strains exhibited antibacterial activity against all four test strains, which were identified by 16S rDNA sequencing as Bacillus sp. DK1-SA11 and Vibrio sp. DK6-SH8. Marine isolate DK1-SA11 has potential to resist boiling temperature and pH 2-12. Furthermore cell free extract (CFE) inhibited all test organisms including superbug MRSA and pathogenic yeast Candida albicans. Marine isolate Bacillus sp. DK1-SA11 could be a potential combatant for the battle of drugs and bugs. PMID- 25730804 TI - The combination of zinc and glibenclamide limits cardiovascular complications in diabetic rats via multiple mechanisms. AB - Cardiovascular complications have become a major cause of mortality for diabetic patients. Glibenclamide is an effective hypoglycemic agent, but failed to alleviate diabetic complications. This study aimed to evaluate whether the addition of zinc to glibenclamide could mitigate such complications. Diabetes was induced using streptozotocin (60 mg/kg, i.p.). Cardiovascular complications were detected by the significant rise of cardiac enzymes, serum lipids, myocardial oxidative stress and cardiac levels of tumor necrosis factor-alpha (TNF-alpha, a marker for inflammation) as well as massive histological changes in the heart wall in diabetic control compared to non-diabetic group. Levels of serum nitric oxide and cardiac vascular endothelial growth factor (VEGF, an angiogenic marker) were lower in diabetic rats. Addition of zinc sulfate (30mg/kg) to glibenclamide (600betag/kg) resulted in significant improvement in cardiac biomarkers, oxidative status and serum lipids. Highly significant reduction in cardiac TNF alpha (P<0.001), in addition to significant rise in nitric oxide (P< 0.05) and VEGF (P<0.01) were observed. Cellular infiltration and myocardial edema were ameliorated. These results suggest that a combined treatment of zinc and glibenclamide might be a potential therapy for preventing the risk of cardiovascular complications and reducing the mortality rate among diabetic patients. PMID- 25730805 TI - Ethambutol-Cobalt (II) ions complexation spectral characteristics and applications for quantitative analysis. AB - Ethambutol (EMB) has no significant absorption characteristics beyond 200 nm due to its aliphatic saturated nature. Thus, direct EMB determination in the UV range is not feasible due to its very low molar absorptivity and must requiring a derivatization reaction. Since EMB can act as a chelating agent that disrupts one of several metal-containing enzyme systems in the nucleic acid structure of mycobacteria. This chelating property can be used for quantitative analysis of EMB by formation of UV-Vis absorbing metal complexes. The study in this work describes simple, accurate and sensitive spectrophotometric procedure for the determination of EMB in its pure form and in pharmaceutical formulations. The method depends on the interaction of EMB with cobalt (II) ions in presence of ammonia solution (4 N). The absorbance was measured either at 250, 348 or 521 nm respectively. All parameters affecting the reaction were carefully studied and optimized. Beers-Lamberts law was obeyed within the concentration ranges 5-25, 40 240 and 100-700 MUg ml-1 for the three studied wavelengths respectively. The developed method was validated according to the ICH guidelines and applied to pharmaceutical formulation analysis with good recovery ranges. The results were compared to those obtained by an official method and found satisfactorily matched and no significant differences were found within the 95% confidence level. The proposed procedures were suitable for simple routine work and quality control analysis of EMB. PMID- 25730806 TI - Effect of methanolic extract of Asparagus racemosus Willd. on lipopolysaccharide induced-oxidative stress in rats. AB - Lipopolysaccharide (LPS) induced oxidative stress and impairment of normal physiological function generally categorized by increased anxiety and reduced mobility. Therefore, the present study was to find out the effect Methanolic extract of Asparagus racemosus (MEAR ) in lipopolysaccharide (LPS)-induced oxidative stress in rats . LPS-induced oxidative stress in rats was measured by locomotor activity by photoactometer test, anxiety with elevated plus maze test and also studied the oxidative stress markers, nitric oxide and cytokines. The obtained data shows that LPS markedly exhausted (p<0.001) brain- reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) significantly increased (p<0.001) the level of malondialdehyde (MDA), nitric oxide and the activity of cytokines in the brain. MEAR supplementation resulted in normalization of brain GSH and CAT and SOD and decreases in the levels of MDA with reduction of nitric oxide and cytokines in the brain. The action of the extract at dose of 200 mg/kg was almost similar to the standard drug, quercetin (100mg/kg, p.o.). These present study conclude that MEAR administration significantly (P<0.05) reduced LPS- induced oxidative-stress and intensely suggest that Asparagus racemosus Willd. is a functionally newer type of cerebroprotective agent. PMID- 25730807 TI - Pharmacological rational of dry ripe fruit of Aegle marmelos L. as an anti nociceptive agent in different painful conditions. AB - The aim of study is to investigate central and peripheral analgesic effects of methanolic extract of dry ripe fruit of Aegle marmelos Linn. Corea (Am. Cr) by two methods, tail flick test and acetic acid induced writhing test at 100, 250 and 500mg/kg doses in animal models. Analgesic activity against tail flick test revealed that Am. Cr induced significant increase in latency period in dose dependent manner i.e. 65.38% at 100mg/kg, 395.37% at 250mg/kg (p<0.01) and 459.25% at 500mg/kg (p<0.01) body weight at 1hr after drug delivery while at 2hr effect decreased i.e. 61.53% at 100mg/kg, 161.11% (p<0.01) at 250mg/kg and 165.74% (p<0.01) at 500mg/kg but interestingly again there is an elongation in latency period at 3hr i.e. 106.15% at 100mg/kg dose, 251.85% (p<0.01) at 250mg/kg and 293.51% (p<0.05) at 500mg/kg respectively. The standard drug Diclofenac sodium at the dose of 5mg/kg continuously increased the latency period but less significantly as compared to the test substance i.e. 79.43%, 113.08% and 222.42% (p<0.05) respectively. Acetic acid induced writhing test produced highest significant activity at the dose of 100mg/kg i.e. 89.83% (p<0.01) as compared to Diclofenic sodium (standard drug) at a dose of 5mg/kg body weight i.e 63.63% (p<0.01). It is concluded that dry ripe fruit of A. marmelos possesses significant dual analgesic activities i.e. central and peripheral. PMID- 25730808 TI - Anticonvulsant and neuroprotective effects of the Acacia tortilis growing in KSA. AB - In different region of Saudi Arabia Acacia tortilis (Fabaceae) is present but still the medicinal properties of Acacia tortilis have not been studied. However, in Zimbabwe different species of Acacia are already used for the treatment of convulsions and dizziness. In the present study, the anticonvulsant and neuroprotective effects of the Acacia tortilis, were evaluated by using different paradigms. For extraction, the leaves of acacia were blended with distilled water at 40 degrees C and filtered. Two different doses of the extracts (400 and 800mg/kg) were administered in the mice once orally (p.o.) and after 30 min occurrence of seizures (strychnine at the dose of 1mg/kg, i.m.) were monitored. In the present work, acute toxicity and neurotoxicity of the extracts were also assessed by inducing hypoxic stress. The Acacia tortilis leaves AAq (400 and 800 mg/kg) produced a dose dependent increase in time of onset of seizures (197.8+/ 32.4 and 338.2+/-40.6 respectively) when compared with its respective control (184.0+/-13.8sec). The anticonvulsant effect after administration of AAq (800mg/kg: 338.2+/-40.6 sec) was more pronounced than diazepam (290.6+/-1.38 sec). The high dose (800mg/kg) of AAq administered orally prolonged the onset of convulsion and latencies for death following hypoxic stress. The present study suggested that Acacia have anticonvulsant property and may probably be affecting the inhibitory mechanism of glycine. It is also concluded that chemical constituent of acacia might act on BZD or 5-HT(1A) receptor and decrease the oxidative brain membrane damage process induced by psychological/hypoxic stress. Further experiments will be required to identify the active molecules (s) and their mechanism (s) of action. PMID- 25730809 TI - A plausible mechanism of biosorption in dual symbioses by vesicular-arbuscular mycorrhizal in plants. AB - Dual symbioses of vesicular-arbuscular mycorrhizal (VAM) fungi with growth of Momordica charantia were elucidated in terms of plausible mechanism of biosorption in this article. The experiment was conducted in green house and mixed inoculum of the VAM fungi was used in the three replicates. Results demonstrated that the starch contents were the main source of C for the VAM to builds their hyphae. The increased plant height and leaves surface area were explained in relation with an increase in the photosynthetic rates to produce rapid sugar contents for the survival of plants. A decreased in protein, and amino acid contents and increased proline and protease activity in VAM plants suggested that these contents were the main bio-indicators of the plants under biotic stress. The decline in protein may be due to the degradation of these contents, which later on converted into dextrose where it can easily be absorbed by for the period of symbioses. A mechanism of C chemisorption in relation with physiology and morphology of plant was discussed. PMID- 25730810 TI - Comparative effects of metformin and pioglitazone on lipid profile of rabbits. AB - This is the initial part of study in which the effects of two oral hypoglycemic drugs metformin and pioglitazone were studied on lipid profile of rabbits. White rabbits of both sexes were equally divided in to three groups each comprising of seven animals. Control group was given distilled water 2m1/kg, animals of group II were given metformin in the dose of 22mg/kg and animals of group III received pioglitazone in the dose of 0.5mg/kg. Serum concentration of cholesterol, very low-density lipoprotein (VLDL), triglycerides (TGs), low density lipoprotein (LDL) and high density lipoprotein (HDL) were measured after 8 week of oral dosing. Results shows that after 8 weeks animals received metformin did not reveal any significant change in lipid profile, but animals received pioglitazone showed significant (P<0.05) decrease in lipid profile, the decrease in cholesterol, LDL, VLDL and triglycerides is favorable however decrease in HDL is troublesome and warrant further investigations. PMID- 25730811 TI - Intravenous lidocaine suppresses dexamethasone-induced perineal pruritus during anesthesia induction: a randomized controlled, double blind study. AB - Previous studies have found that intravenous dexamethasone may produce perineal pruritus in some patients when administered as premedicant in the preoperative period. This randomized controlled, double-blind study evaluated the efficacy of pretreatment of lidocaine on the incidence and severity of dexamethasone-induced perineal pruritus. 400 patients were enrolled in this study and allocated randomly into four groups (n=100, in each). Then, patients received intravenously anesthesia induction as the following sequence of medications: injecting 0.9% sodium chloride (placebo) 10 mL in group I, lidocaine 0.5mg/kg in group II, lidocaine 1mg/kg in group III, and lidocaine 1.5mg/kg in group IV, 1 minute later, injecting 10mg dexamethasone in all groups. The severity of perineal pruritus was graded based on the VAS as none (VAS 0), mild (VAS 1-3), moderate (4 6), or severe (VAS 7 to 10), and recorded the occurrence, the severity and the duration of perineal pruritus. Occurrence of perineal pruritus was significantly reduced in group III and group IV (8%, 9% vs 40% and 33% in Groups I and II, respectively, p<0.05). The incidence of perineal pruritus of females was higher than males in groups I and II (P<0.05). The duration of perineal pruritus was shorter in group IV compared to groups I, II and III (p<0.05). We conclude that pretreatment 1mg/kg or 1.5mg/kg lidocaine may effectively reduce the incidence of perineal pruritus. PMID- 25730812 TI - Nigella sativa fixed and essential oil improves antioxidant status through modulation of antioxidant enzymes and immunity. AB - The onset of 21st century witnessed the awareness among the masses regarding the diet-health linkages. The researchers attempted to explore traditional products/plants were in the domain of pharmacy and nutrition focussing on their health benefits. In the present research intervention, we investigate the role of Nigella sativa fixed oil (NSFO) and essential oil (NSEO) in improving antioxidant status and modulation of enzymes. The National Institute of Health (NIH) provided us 30 Sprague Dawley rats that were equally placed in three groups. The groups were fed on their respective diets (56 days) two experimental diets i.e. D2 (NSFO @ 4.0%) and D3 (NSEO @ 0.30%) and control. The indices pertaining to antioxidant status, antioxidant enzymes, and parameters pertaining to immunity were evaluated at 4 weeks interval. The experimental diets (NSFO@ 4.0% & NSEO@ 0.30%) modulated the activities of antioxidant enzymes i.e., catalase (CAT), superoxide dismutase (SOD), glutathione transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx), positively. Indices of antioxidant status like tocopherols and glutathione were in linear relationship with that of GPx, GR and GST (P<0.01). Myeloperoxidase activities were in negative correlation with GST (P<0.01) but positive correlation with some other parameters. In the nutshell, the fixed and essential oil of Nigella sativa are effective in improving the indices pertaining to antioxidant status, however, the immune boosting potential needs further clarification. However, authors are of the view that there is need to explore the molecular targets of Nigella sativa fixed and essential oils. Findings from such studies would be useful to validate this instant study for health promoting potential against diabetes mellitus and cardiovascular disorders. PMID- 25730813 TI - Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus. AB - Cytotoxic and antiviral potential of ivermectin and ribavirin was evaluated. Cytotoxicity was checked on chick primary fibroblast cell line through MTT assay. Antiviral potential was determined against Newcastle disease virus on 9-day old chicken embryos. Six different concentrations (200, 100, 50, 25, 12.5 and 6.25MUg/ml) of both the drugs were evaluated. The 100MUg/ml concentration of ivermectin and higher were cytotoxic. The 25MUg/ml concentration of ribavirin and higher were cytotoxic. Comparison of ivermectin and ribavirin showed that ivermectin was safe at 50MUg/ml and lower concentrations. Ribavirin was protective for cell at 12.5MUg/ml and 6.25MUg/ml only. Comparison of antiviral activity indicated that ivermectin has strong antiviral potential at 100MUg/ml and higher but same concentrations were cytotoxic. Ribavirin showed strong antiviral potential at all concentrations. PMID- 25730814 TI - Rhodamine-123: a p-glycoprotein marker complex with sodium lauryl sulfate. AB - Aim of this study was to investigate the role of sodium lauryl sulfate (SLS) as P glycoprotein inhibitor. The everted rat gut sac model was used to study in-vitro mucosal to serosal transport of Rhodamine-123 (Rho-123). Surprisingly, SLS decreases the serosal absorption of Rho-123 at all investigated concentrations. Investigation reveals complex formation between Rhodamine-123 and sodium lauryl sulfate. Interaction profile of SLS & Rho-123 was studied at variable SLS concentrations. The SLS concentration higher than critical micelle concentration (CMC) increases the solubility of Rho-123 but could not help in serosal absorption, on the contrary the absorption of Rho-123 decreased. Rho-123 and SLS form pink color complex at sub-CMC. The SLS concentrations below CMC decrease the solubility of Rho-123. For further studies, Rho-123 & SLS complex was prepared by using solvent evaporation technique and characterized by using differential scanning calorimeter (DSC). Thermal analysis also proved the formation of complex between SLS & Rho-123. The P values were found to be significant (<0.05) except group comprising 0.0001% SLS, and that is because 0.0001% SLS is seems to be very low to affect the solubility or complexation of Rho-123. PMID- 25730815 TI - Dengue fever: natural management. AB - Dengue fever is caused by the mosquito-borne dengue virus (DENV) serotypes 1-4, and is the most common arboviral infection of humans in subtropical and tropical regions of the world. Dengue virus infections can present with a spacious range of clinical signs, from a mild feverish illness to a life-threatening shock syndrome. Till now, there is no approved vaccine or drug against this virus. Therefore, there is an urgent need of development of alternative solutions for dengue. Several plant species have been reported with anti-dengue activity. Many herbal/natural drugs, most of which are commonly used as nutritional components, have been used as antiviral, larvicidal, mosquitocidal and mosquito repellents that may be used against dengue. The objective of this review article was to provide current approaches for the treatment and management/prevention of dengue fever by targeting viral proteins involved in replication cycle of the virus and different developmental stages of mosquito. PMID- 25730816 TI - Substrate controlled divergence in polyketide synthase catalysis. AB - Biochemical characterization of polyketide synthases (PKSs) has relied on synthetic substrates functionalized as electrophilic esters to acylate the enzyme and initiate the catalytic cycle. In these efforts, N-acetylcysteamine thioesters have typically been employed for in vitro studies of full PKS modules as well as excised domains. However, substrate engineering approaches to control the catalytic cycle of a full PKS module harboring multiple domains remain underexplored. This study examines a series of alternatively activated native hexaketide substrates on the catalytic outcome of PikAIV, the sixth and final module of the pikromycin (Pik) pathway. We demonstrate the ability to control product formation with greater than 10:1 selectivity for either full module catalysis, leading to a 14-membered macrolactone, or direct cyclization to a 12 membered ring. This outcome was achieved through modifying the type of hexaketide ester employed, demonstrating the utility of substrate engineering in PKS functional studies and biocatalysis. PMID- 25730817 TI - Correction to Beus, Dhanani, and McCord (2014). AB - Reports an error in "A meta-analysis of personality and workplace safety: Addressing unanswered questions" by Jeremy M. Beus, Lindsay Y. Dhanani and Mallory A. McCord (Journal of Applied Psychology, Advance online publication. September 22, 2014. http://dx.doi.org/10.1037/a0037916). Table 3 contained formatting errors. Minus signs used to indicate negative statistical estimates within the table were inadvertently changed to m-dashes. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2014-39088-001.) The purpose of this meta-analysis was to address unanswered questions regarding the associations between personality and workplace safety by (a) clarifying the magnitude and meaning of these associations with both broad and facet-level personality traits, (b) delineating how personality is associated with workplace safety, and (c) testing the relative importance of personality in comparison to perceptions of the social context of safety (i.e., safety climate) in predicting safety-related behavior. Our results revealed that whereas agreeableness and conscientiousness were negatively associated with unsafe behaviors, extraversion and neuroticism were positively associated with them. Of these traits, agreeableness accounted for the largest proportion of explained variance in safety-related behavior and openness to experience was unrelated. At the facet level, sensation seeking, altruism, anger, and impulsiveness were all meaningfully associated with safety-related behavior, though sensation seeking was the only facet that demonstrated a stronger relationship than its parent trait (i.e., extraversion). In addition, meta analytic path modeling supported the theoretical expectation that personality's associations with accidents are mediated by safety-related behavior. Finally, although safety climate perceptions accounted for the majority of explained variance in safety-related behavior, personality traits (i.e., agreeableness, conscientiousness, neuroticism) still accounted for a unique and substantive proportion of the explained variance. Taken together, these results substantiate the value of considering personality traits as key correlates of workplace safety. PMID- 25730818 TI - miR-155 is associated with the leukemogenic potential of the class IV granulocyte colony-stimulating factor receptor in CD34+ progenitor cells. AB - Granulocyte colony-stimulating factor (G-CSF) is a major regulator of granulopoiesis on engagement with the G-CSF receptor (G-CSFR). The truncated, alternatively spliced, class IV G-CSFR (G-CSFRIV) has been associated with defective differentiation and relapse risk in pediatric acute myeloid leukemia (AML) patients. However, the detailed biological properties of G-CSFRIV in human CD34(+) hematopoietic stem and progenitor cells (HSPCs) and the potential leukemogenic mechanism of this receptor remain poorly understood. In the present study, we observed that G-CSFRIV-overexpressing (G-CSFRIV(+)) HSPCs demonstrated an enhanced proliferative and survival capacity on G-CSF stimulation. Cell cycle analyses showed a higher frequency of G-CSFRIV(+) cells in the S and G2/M phase. Also, apoptosis rates were significantly lower in G-CSFRIV(+) HSPCs. These findings were shown to be associated with a sustained Stat5 activation and elevated miR-155 expression. In addition, G-CSF showed to further induce G-CSFRIV and miR-155 expression of peripheral blood mononuclear cells isolated from AML patients. A Stat5 pharmacological inhibitor or ribonucleic acid (RNA) interference-mediated silencing of the expression of miR-155 abrogated the aberrant proliferative capacity of the G-CSFRIV(+) HSPCs. Hence, the dysregulation of Stat5/miR-155 pathway in the G-CSFRIV(+) HSPCs supports their leukemogenic potential. Specific miRNA silencing or the inhibition of Stat5 associated pathways might contribute to preventing the risk of leukemogenesis in G-CSFRIV(+) HSPCs. This study may promote the development of a personalized effective antileukemia therapy, in particular for the patients exhibiting higher expression levels of G-CSFRIV, and further highlights the necessity of pre screening the patients for G-CSFR isoforms expression patterns before G-CSF administration. PMID- 25730819 TI - Prevention of groin injuries in sports: a systematic review with meta-analysis of randomised controlled trials. AB - BACKGROUND/AIM: Groin injuries are common in football and ice hockey, and previous groin injury is a strong risk factor for future groin injuries, which calls for primary prevention. The aim of this systematic review was to evaluate the effect of specific groin-injury prevention programmes in sports. METHODS: A comprehensive search was performed in May 2014 yielding 1747 potentially relevant references. Two independent assessors evaluated randomised controlled trials for inclusion, extracted data and performed quality assessments using Cochrane's risk of bias tool. Quantitative analyses were performed in Review Manager 5.3. RESULTS: Seven trials were included: six on football players (four male and two female populations) and one on male handball players. In total there were 4191 participants with a total of 157 injuries. The primary analysis, including all participants, did not show a significant reduction in the number of groin injuries after completing a groin injury prevention programme (relative risk (RR) 0.81; 95% CI 0.60 to 1.09). Subgroup analysis based on type of sports, gender and type of prevention programme showed similar non-significant estimates with RR ranging from 0.48 to 0.81. CONCLUSION: Meta-analysis revealed a potential clinically meaningful groin injury reduction of 19%, even though no statistical significant reduction in sport-related groin injuries could be documented. TRIAL REGISTRATION: PROSPERO registration ID CRD42014009614. PMID- 25730820 TI - Improving Myoelectric Control for Amputees through Transcranial Direct Current Stimulation. AB - Most prosthetic myoelectric control studies have shown good performance for unimpaired subjects. However, performance is generally unacceptable for amputees. The primary problem is the poor quality of electromyography (EMG) signals of amputees compared with healthy individuals. To improve clinical performance of myoelectric control, this study explored transcranial direct current stimulation (tDCS) to modulate brain activity and enhance EMG quality. We tested six unilateral transradial amputees by applying active and sham anodal tDCS separately on two different days. Surface EMG signals were acquired from the affected and intact sides for 11 hand and wrist motions in the pre-tDCS and post tDCS sessions. Autoregression coefficients and linear discriminant analysis classifiers were used to process the EMG data for pattern recognition of the 11 motions. For the affected side, active anodal tDCS significantly reduced the average classification error rate (CER) by 10.1%, while sham tDCS had no such effect. For the intact side, the average CER did not change on the day of sham tDCS but increased on the day of active tDCS. These results demonstrated that tDCS could modulate brain function and improve EMG-based classification performance for amputees. It has great potential in dramatically reducing the length of learning process of amputees for effectively using myoelectrically controlled multifunctional prostheses. PMID- 25730821 TI - Matching Pursuit-Based Time-Variant Bispectral Analysis and its Application to Biomedical Signals. AB - OBJECTIVE: Principle aim of this study is to investigate the performance of a matching pursuit (MP)-based bispectral analysis in the detection and quantification of quadratic phase couplings (QPC) in biomedical signals. Nonlinear approaches such as time-variant bispectral analysis are able to provide information about phase relations between oscillatory signal components. METHODS: Time-variant QPC analysis is commonly performed using Gabor transform (GT) or Morlet wavelet transform (MWT), and is affected by either constant or frequency dependent time-frequency resolution (TFR). The matched Gabor transform (MGT), which emerges from the incorporation of GT into MP, can overcome this obstacle by providing a complex time-frequency plane with an individually tailored TFR for each transient oscillatory component. QPC analysis was performed by MGT, and MWT was used as the state-of-the-art method for comparison. RESULTS: Results were demonstrated using simulated data, which present the general case of QPC, and biomedical benchmark data with a priori knowledge about specific signal components. HRV of children during temporal lobe epilepsy and EEG during burst interburst pattern of neonates during quiet sleep were used for the biomedical signal analysis to investigate the two main areas of biomedical signal analysis: The cardiovascular-cardiorespiratory system and neurophysiological brain activities, respectively. Simulations were able to show the applicability and reliability of the MGT for bispectral analysis. HRV and EEG analysis demonstrate the general validity of the MGT for QPC detection by quantifying statistically significant time patterns of QPC. CONCLUSION AND SIGNIFICANCE: Results confirm that MGT-based bispectral analysis provides significant benefits for the analysis of QPC in biomedical signals. PMID- 25730822 TI - The Palm-Sized Cryoprobe System Based on Refrigerant Expansion and Boiling and Its Application to an Animal Model of Epilepsy. AB - GOAL: The purpose of this study is to propose the palm-sized cryoprobe system based on a new concept and to suggest that the freezing technique could be used for treatment of epilepsy. METHODS: We propose herein a cryoprobe system based on the boiling effect that uses a specific refrigerants with a boiling point higher than that of liquid nitrogen yet low enough to result in cell necrosis. To evaluate and verify the effectiveness of the proposed system, cooling characteristics are investigated in agar. In addition, the system is applied to a Wistar rat brain-model, in which the epileptic activities are induced in advance by a potent epileptogenic substance. RESULTS: The design concept yielded the following benefits: 1) the selected refrigerant promotes sealing in the tank; 2) the tank can be made as compact as possible, limited only by the volume required for the refrigerant; 3) because the tank and probe units can be separated by a nonconducting, flexible, and high-pressure tube, the tank unit can be manipulated without disturbing the probe tip with mechanical vibrations and electrical noise. Although the agar experiments, we verified that the proposed system can uniquely and reproducibly create an ice ball. Moreover, in the rat experiments in vivo, it was confirmed that penicillin G-induced epileptic activities disappeared on freezing with the proposed system. CONCLUSIONS: The palm-sized system has desired characteristics and can apply for an animal model of epilepsy. SIGNIFICANCE: Results of in vivo experiments suggest that cryosurgery may be an effective treatment for epilepsy. PMID- 25730823 TI - A Stimulus Artifact Removal Technique for SEMG Signal Processing During Functional Electrical Stimulation. AB - GOAL: The purpose of this study was to design a method for extracting the volitional EMG from recorded surface electromyography (EMG), contaminated by functional electrical stimulation (FES) artifact. METHODS: Considering that the FES artifact emerges periodically with rather large amplitude in nonstationary EMG, we designed an adaptive-matched filter (AMF) via genetic algorithm (GA) optimization. Both the simulated and real data from seven subjects were processed, using the GA-AMF filter and comb filter, respectively. To test the filtering effect on the EMG, contaminated with FES artifact of different current intensities, the contaminated EMG was simulated by combining the simulation artifact and clean EMG with various FES artifacts to clean EMG ratios. RESULTS: The results show that, in simulation test, compared to the EMG filtered by comb filter, the simulated EMG (p < 0.05), filtered by using GA-AMF, had significantly higher correlation coefficient, higher signal to noise ratio, and lower normalized root mean square error, whereas the real EMG (p < 0.05), filtered by using GA-AMF had higher power reduction than that filtered by using comb filter. The results indicate that GA-AMF can effectively remove FES artifact from the EMG of the stimulated muscle and its adjacent muscle, and the GA-AMF filter performed better than did the comb filter. CONCLUSION: All these results demonstrate that the GA-AMF filter is capable of extracting volitional EMG from the stimulated muscle and adjacent muscles. SIGNIFICANCE: GA-AMF could provide technical support for improving EMG feedback control of FES rehabilitation system. PMID- 25730824 TI - Denoising of Contrast-Enhanced Ultrasound Cine Sequences Based on a Multiplicative Model. AB - BACKGROUND: Speckle noise is an inherent characteristic of dynamic contrast enhanced ultrasound (DCEUS) movies and ultrasound images in general. Speckle noise considerably reduces the quality of these images and limits their clinical use. Currently, temporal compounding and maximum intensity persistence (MIP) are among the most widely accepted processing methods enabling the visualization of vasculature using DCEUS. GOAL: A different approach has been used in this study, in order to improve the noise removal, while enabling the investigation of CEUS dynamics. METHODS: A multiplicative model for the formation of DCEUS speckled images is adopted and the log-transformed cines are processed. A preprocessing step was performed, locally removing low value outliers. Due to the fast-changing spatial distribution of microbubbles inside the vasculature, the noise in consecutive DCEUS frames is independent, facilitating its removal by temporal denoising. Noise reduction is efficiently achieved by wavelet denoising, in which the signal's wavelet coefficients are thresholded and small-value noise-related coefficients are discarded. The main advantage of using wavelet denoising in the present context is its ability to estimate ultrasound contrast agents' (UCA) concentration over time adaptively, without assuming a model or predefining the signal's degree of smoothness. The performance of wavelet denoising was compared against MIP, temporal compounding, and Log-normal model fitting. RESULTS: Phantom experiments showed improved SNR, using wavelet denoising over a wide range of UCA concentrations (MicroMarker, 0.001-1%). In the in vivo tests, improved noise removal was achieved, reflected by a significantly lower coefficient of variation in homogeneous vascular regions (p < 0.01). PMID- 25730825 TI - 3D Microendoscopic Electrical Impedance Tomography for Margin Assessment During Robot-Assisted Laparoscopic Prostatectomy. AB - Radially configured microendoscopic electrical impedance probes intended for intraoperative surgical margin assessment during robot-assisted laparoscopic prostatectomy (RALP) were examined through simulation, bench-top experimentation, and ex vivo tissue studies. Three probe designs with 8, 9, and 17 electrodes, respectively, were analyzed through finite element method based simulations. One mm diameter spherical inclusions ( sigmainclusion = 1 S/m) are positioned at various locations within a hemispherical background ( sigmabackground = 0.1 S/m) of radius 5 mm. An 8-electrode configuration is not able to localize the inclusion at these positions while 9 and 17-electrode configurations are able to accurately reconstruct the inclusion at maximum depth of 1 mm and 3 mm, respectively. All three probe designs were constructed and evaluated using saline phantoms and ex vivo porcine and human prostate tissues. The 17-electrode probe performed best in saline phantom studies, accurately reconstructing high contrast, 1-mm-diameter metal cylindrical inclusions in a saline bath ( sigmasaline = 0.1 S/m) with a position and area error of 0.46 mm and 0.84 mm2, respectively. Additionally, the 17-electrode probe was able to adequately distinguish cancerous from benign tissues in three ex vivo human prostates. Simulations, bench-top saline experiments, and ex vivo tissue sampling suggest that for intraoperative surgical margin assessment during RALP, the 17-electrode probe (as compared to an 8 and 9 electrode probe) will be necessary to provide sufficient accuracy and sensitivity. PMID- 25730826 TI - A Unified Sparse Recovery and Inference Framework for Functional Diffuse Optical Tomography Using Random Effect Model. AB - Diffuse optical tomography (DOT) is a non-invasive imaging technique to reconstruct optical properties of biological tissues using near-infrared light, and it has been successfully used to measure functional brain activities via changes in cerebral blood volume and cerebral blood oxygenation. However, DOT presents a severely ill-posed inverse problem, so various types of regularization should be incorporated to overcome low spatial resolution and lack of depth sensitivity. Another limitation of the conventional DOT reconstruction methods is that an inference step is separately performed after the reconstruction, so complicated interaction between reconstruction and regularization is difficult to analyze. To overcome these technical difficulties, we propose a unified sparse recovery framework using a random effect model whose termination criterion is determined by the statistical inference. Both numerical and experimental results confirm that the proposed method outperforms the conventional approaches. PMID- 25730827 TI - Assessment of the Tongue-Drive System Using a Computer, a Smartphone, and a Powered-Wheelchair by People With Tetraplegia. AB - Tongue-Drive System (TDS) is a wireless and wearable assistive technology that enables people with severe disabilities to control their computers, wheelchairs, and smartphones using voluntary tongue motion. To evaluate the efficacy of the TDS, several experiments were conducted, in which the performance of nine able bodied (AB) participants using a mouse, a keypad, and the TDS, as well as a cohort of 11 participants with tetraplegia (TP) using the TDS, were observed and compared. Experiments included the Fitts' law tapping, wheelchair driving, phone dialing, and weight-shifting tasks over five to six consecutive sessions. All participants received a tongue piercing, wore a magnetic tongue stud, and completed the trials as evaluable participants. Although AB participants were already familiar with the keypad, throughputs of their tapping tasks using the keypad were only 1.4 times better than those using the TDS. The completion times of wheelchair driving task using the TDS for AB and TP participants were between 157 s and 180 s with three different control strategies. Participants with TP completed phone-dialing and weight-shifting tasks in 81.9 s and 71.5 s, respectively, using tongue motions. Results showed statistically significant improvement or trending to improvement in performance status over the sessions. Most of the learning occurred between the first and second sessions, but trends did suggest that more practice would lead to increased improvement in performance using the TDS. PMID- 25730828 TI - An Information-Based Learning Approach to Dual Control. AB - Dual control aims to concurrently learn and control an unknown system. However, actively learning the system conflicts directly with any given control objective for it will disturb the system during exploration. This paper presents a receding horizon approach to dual control, where a multiobjective optimization problem is solved repeatedly and subject to constraints representing system dynamics. Balancing a standard finite-horizon control objective, a knowledge gain objective is defined to explicitly quantify the information acquired when learning the system dynamics. Measures from information theory, such as entropy-based uncertainty, Fisher information, and relative entropy, are studied and used to quantify the knowledge gained as a result of the control actions. The resulting iterative framework is applied to Markov decision processes and discrete-time nonlinear systems. Thus, the broad applicability and usefulness of the presented approach is demonstrated in diverse problem settings. The framework is illustrated with multiple numerical examples. PMID- 25730829 TI - An Interval-Valued Neural Network Approach for Uncertainty Quantification in Short-Term Wind Speed Prediction. AB - We consider the task of performing prediction with neural networks (NNs) on the basis of uncertain input data expressed in the form of intervals. We aim at quantifying the uncertainty in the prediction arising from both the input data and the prediction model. A multilayer perceptron NN is trained to map interval valued input data onto interval outputs, representing the prediction intervals (PIs) of the real target values. The NN training is performed by nondominated sorting genetic algorithm-II, so that the PIs are optimized both in terms of accuracy (coverage probability) and dimension (width). Demonstration of the proposed method is given in two case studies: 1) a synthetic case study, in which the data have been generated with a 5-min time frequency from an autoregressive moving average model with either Gaussian or Chi-squared innovation distribution and 2) a real case study, in which experimental data consist of wind speed measurements with a time step of 1 h. Comparisons are given with a crisp (single valued) approach. The results show that the crisp approach is less reliable than the interval-valued input approach in terms of capturing the variability in input. PMID- 25730830 TI - Multiple actor-critic structures for continuous-time optimal control using input output data. AB - In industrial process control, there may be multiple performance objectives, depending on salient features of the input-output data. Aiming at this situation, this paper proposes multiple actor-critic structures to obtain the optimal control via input-output data for unknown nonlinear systems. The shunting inhibitory artificial neural network (SIANN) is used to classify the input-output data into one of several categories. Different performance measure functions may be defined for disparate categories. The approximate dynamic programming algorithm, which contains model module, critic network, and action network, is used to establish the optimal control in each category. A recurrent neural network (RNN) model is used to reconstruct the unknown system dynamics using input-output data. NNs are used to approximate the critic and action networks, respectively. It is proven that the model error and the closed unknown system are uniformly ultimately bounded. Simulation results demonstrate the performance of the proposed optimal control scheme for the unknown nonlinear system. PMID- 25730831 TI - Robust Multitask Multiview Tracking in Videos. AB - Various sparse-representation-based methods have been proposed to solve tracking problems, and most of them employ least squares (LSs) criteria to learn the sparse representation. In many tracking scenarios, traditional LS-based methods may not perform well owing to the presence of heavy-tailed noise. In this paper, we present a tracking approach using an approximate least absolute deviation (LAD)-based multitask multiview sparse learning method to enjoy robustness of LAD and take advantage of multiple types of visual features, such as intensity, color, and texture. The proposed method is integrated in a particle filter framework, where learning the sparse representation for each view of the single particle is regarded as an individual task. The underlying relationship between tasks across different views and different particles is jointly exploited in a unified robust multitask formulation based on LAD. In addition, to capture the frequently emerging outlier tasks, we decompose the representation matrix to two collaborative components that enable a more robust and accurate approximation. We show that the proposed formulation can be effectively approximated by Nesterov's smoothing method and efficiently solved using the accelerated proximal gradient method. The presented tracker is implemented using four types of features and is tested on numerous synthetic sequences and real-world video sequences, including the CVPR2013 tracking benchmark and ALOV++ data set. Both the qualitative and quantitative results demonstrate the superior performance of the proposed approach compared with several state-of-the-art trackers. PMID- 25730832 TI - Hinfinity State Estimation for Discrete-Time Delayed Systems of the Neural Network Type With Multiple Missing Measurements. AB - This paper investigates the Hinfinity state estimation problem for a class of discrete-time nonlinear systems of the neural network type with random time varying delays and multiple missing measurements. These nonlinear systems include recurrent neural networks, complex network systems, Lur'e systems, and so on which can be described by a unified model consisting of a linear dynamic system and a static nonlinear operator. The missing phenomenon commonly existing in measurements is assumed to occur randomly by introducing mutually individual random variables satisfying certain kind of probability distribution. Throughout this paper, first a Luenberger-like estimator based on the imperfect output data is constructed to obtain the immeasurable system states. Then, by virtue of Lyapunov stability theory and stochastic method, the Hinfinity performance of the estimation error dynamical system (augmented system) is analyzed. Based on the analysis, the Hinfinity estimator gains are deduced such that the augmented system is globally mean square stable. In this paper, both the variation range and distribution probability of the time delay are incorporated into the control laws, which allows us to not only have more accurate models of the real physical systems, but also obtain less conservative results. Finally, three illustrative examples are provided to validate the proposed control laws. PMID- 25730833 TI - Bidirectional Active Learning: A Two-Way Exploration Into Unlabeled and Labeled Data Set. AB - In practical machine learning applications, human instruction is indispensable for model construction. To utilize the precious labeling effort effectively, active learning queries the user with selective sampling in an interactive way. Traditional active learning techniques merely focus on the unlabeled data set under a unidirectional exploration framework and suffer from model deterioration in the presence of noise. To address this problem, this paper proposes a novel bidirectional active learning algorithm that explores into both unlabeled and labeled data sets simultaneously in a two-way process. For the acquisition of new knowledge, forward learning queries the most informative instances from unlabeled data set. For the introspection of learned knowledge, backward learning detects the most suspiciously unreliable instances within the labeled data set. Under the two-way exploration framework, the generalization ability of the learning model can be greatly improved, which is demonstrated by the encouraging experimental results. PMID- 25730834 TI - RSTFC: A Novel Algorithm for Spatio-Temporal Filtering and Classification of Single-Trial EEG. AB - Learning optimal spatio-temporal filters is a key to feature extraction for single-trial electroencephalogram (EEG) classification. The challenges are controlling the complexity of the learning algorithm so as to alleviate the curse of dimensionality and attaining computational efficiency to facilitate online applications, e.g., brain-computer interfaces (BCIs). To tackle these barriers, this paper presents a novel algorithm, termed regularized spatio-temporal filtering and classification (RSTFC), for single-trial EEG classification. RSTFC consists of two modules. In the feature extraction module, an l2 -regularized algorithm is developed for supervised spatio-temporal filtering of the EEG signals. Unlike the existing supervised spatio-temporal filter optimization algorithms, the developed algorithm can simultaneously optimize spatial and high order temporal filters in an eigenvalue decomposition framework and thus be implemented highly efficiently. In the classification module, a convex optimization algorithm for sparse Fisher linear discriminant analysis is proposed for simultaneous feature selection and classification of the typically high dimensional spatio-temporally filtered signals. The effectiveness of RSTFC is demonstrated by comparing it with several state-of-the-arts methods on three brain-computer interface (BCI) competition data sets collected from 17 subjects. Results indicate that RSTFC yields significantly higher classification accuracies than the competing methods. This paper also discusses the advantage of optimizing channel-specific temporal filters over optimizing a temporal filter common to all channels. PMID- 25730835 TI - Performance Analysis of Network Model to Identify Healthy and Cancerous Colon Genes. AB - Modeling of cancerous and healthy Homo Sapiens colon gene using electrical network is proposed to study their behavior. In this paper, the individual amino acid models are designed using hydropathy index of amino acid side chain. The phase and magnitude responses of genes are examined to screen out cancer from healthy genes. The performance of proposed modeling technique is judged using various performance measurement metrics such as accuracy, sensitivity, specificity, etc. The network model performance is increased with frequency, which is analyzed using the receiver operating characteristic curve. The accuracy of the model is tested on colon genes and achieved maximum 97% at 10-MHz frequency. PMID- 25730836 TI - Learning Flexible Graph-Based Semi-Supervised Embedding. AB - This paper introduces a graph-based semi-supervised embedding method as well as its kernelized version for generic classification and recognition tasks. The aim is to combine the merits of flexible manifold embedding and nonlinear graph-based embedding for semi-supervised learning. The proposed linear method will be flexible since it estimates a nonlinear manifold that is the closest one to a linear embedding. The proposed kernelized method will also be flexible since it estimates a kernel-based embedding that is the closest to a nonlinear manifold. In both proposed methods, the nonlinear manifold and the mapping (linear transform for the linear method and the kernel multipliers for the kernelized method) are simultaneously estimated, which overcomes the shortcomings of a cascaded estimation. The dimension of the final embedding obtained by the two proposed methods is not limited to the number of classes. They can be used by any kind of classifiers once the data are embedded into the new subspaces. Unlike nonlinear dimensionality reduction approaches, which suffer from out-of-sample problem, our proposed methods have an obvious advantage that the learnt subspace has a direct out-of-sample extension to novel samples, and are thus easily generalized to the entire high-dimensional input space. We provide extensive experiments on seven public databases in order to study the performance of the proposed methods. These experiments demonstrate much improvement over the state of-the-art algorithms that are based on label propagation or graph-based semi supervised embedding. PMID- 25730837 TI - MOD* Lite: An Incremental Path Planning Algorithm Taking Care of Multiple Objectives. AB - The need for determining a path from an initial location to a target one is a crucial task in many applications, such as virtual simulations, robotics, and computer games. Almost all of the existing algorithms are designed to find optimal or suboptimal solutions considering only a single objective, namely path length. However, in many real life application path length is not the sole criteria for optimization, there are more than one criteria to be optimized that cannot be transformed to each other. In this paper, we introduce a novel multiobjective incremental algorithm, multiobjective D* lite (MOD* lite) built upon a well-known path planning algorithm, D* lite. A number of experiments are designed to compare the solution quality and execution time requirements of MOD* lite with the multiobjective A* algorithm, an alternative genetic algorithm we developed multiobjective genetic path planning and the strength Pareto evolutionary algorithm. PMID- 25730838 TI - Block-Row Sparse Multiview Multilabel Learning for Image Classification. AB - In image analysis, the images are often represented by multiple visual features (also known as multiview features), that aim to better interpret them for achieving remarkable performance of the learning. Since the processes of feature extraction on each view are separated, the multiple visual features of images may include overlap, noise, and redundancy. Thus, learning with all the derived views of the data could decrease the effectiveness. To address this, this paper simultaneously conducts a hierarchical feature selection and a multiview multilabel (MVML) learning for multiview image classification, via embedding a proposed a new block-row regularizer into the MVML framework. The block-row regularizer concatenating a Frobenius norm (F-norm) regularizer and an l(2,1) norm regularizer is designed to conduct a hierarchical feature selection, in which the F-norm regularizer is used to conduct a high-level feature selection for selecting the informative views (i.e., discarding the uninformative views) and the l(2,1)-norm regularizer is then used to conduct a low-level feature selection on the informative views. The rationale of the use of a block-row regularizer is to avoid the issue of the over-fitting (via the block-row regularizer), to remove redundant views and to preserve the natural group structures of data (via the F-norm regularizer), and to remove noisy features (the l(2,1)-norm regularizer), respectively. We further devise a computationally efficient algorithm to optimize the derived objective function and also theoretically prove the convergence of the proposed optimization method. Finally, the results on real image datasets show that the proposed method outperforms two baseline algorithms and three state-of-the-art algorithms in terms of classification performance. PMID- 25730839 TI - Semi-Supervised Text Classification With Universum Learning. AB - Universum, a collection of nonexamples that do not belong to any class of interest, has become a new research topic in machine learning. This paper devises a semi-supervised learning with Universum algorithm based on boosting technique, and focuses on situations where only a few labeled examples are available. We also show that the training error of AdaBoost with Universum is bounded by the product of normalization factor, and the training error drops exponentially fast when each weak classifier is slightly better than random guessing. Finally, the experiments use four data sets with several combinations. Experimental results indicate that the proposed algorithm can benefit from Universum examples and outperform several alternative methods, particularly when insufficient labeled examples are available. When the number of labeled examples is insufficient to estimate the parameters of classification functions, the Universum can be used to approximate the prior distribution of the classification functions. The experimental results can be explained using the concept of Universum introduced by Vapnik, that is, Universum examples implicitly specify a prior distribution on the set of classification functions. PMID- 25730840 TI - Two-Stage Learning to Predict Human Eye Fixations via SDAEs. AB - Saliency detection models aiming to quantitatively predict human eye-attended locations in the visual field have been receiving increasing research interest in recent years. Unlike traditional methods that rely on hand-designed features and contrast inference mechanisms, this paper proposes a novel framework to learn saliency detection models from raw image data using deep networks. The proposed framework mainly consists of two learning stages. At the first learning stage, we develop a stacked denoising autoencoder (SDAE) model to learn robust, representative features from raw image data under an unsupervised manner. The second learning stage aims to jointly learn optimal mechanisms to capture the intrinsic mutual patterns as the feature contrast and to integrate them for final saliency prediction. Given the input of pairs of a center patch and its surrounding patches represented by the features learned at the first stage, a SDAE network is trained under the supervision of eye fixation labels, which achieves both contrast inference and contrast integration simultaneously. Experiments on three publically available eye tracking benchmarks and the comparisons with 16 state-of-the-art approaches demonstrate the effectiveness of the proposed framework. PMID- 25730841 TI - Hand-me-down hazard: flame retardants in discarded foam products. PMID- 25730842 TI - Diversity outbred: a new generation of mouse model. PMID- 25730843 TI - Air pollution and ASDs: homing in on an environmental risk factor. PMID- 25730844 TI - Comparing models: DBP effects in rat and human germ cells. PMID- 25730845 TI - Roadmap for children's health: controlling diverse environmental exposures in Latin America. PMID- 25730846 TI - Stress and telomere shortening among central Indian conservation refugees. AB - Research links psychosocial stress to premature telomere shortening and accelerated human aging; however, this association has only been demonstrated in so-called "WEIRD" societies (Western, educated, industrialized, rich, and democratic), where stress is typically lower and life expectancies longer. By contrast, we examine stress and telomere shortening in a non-Western setting among a highly stressed population with overall lower life expectancies: poor indigenous people--the Sahariya--who were displaced (between 1998 and 2002) from their ancestral homes in a central Indian wildlife sanctuary. In this setting, we examined adult populations in two representative villages, one relocated to accommodate the introduction of Asiatic lions into the sanctuary (n = 24 individuals), and the other newly isolated in the sanctuary buffer zone after their previous neighbors were moved (n = 22). Our research strategy combined physical stress measures via the salivary analytes cortisol and alpha-amylase with self-assessments of psychosomatic stress, ethnographic observations, and telomere length assessment [telomere-fluorescence in situ hybridization (TEL FISH) coupled with 3D imaging of buccal cell nuclei], providing high-resolution data amenable to multilevel statistical analysis. Consistent with expectations, we found significant associations between each of our stress measures--the two salivary analytes and the psychosomatic symptom survey--and telomere length, after adjusting for relevant behavioral, health, and demographic traits. As the first study (to our knowledge) to link stress to telomere length in a non-WEIRD population, our research strengthens the case for stress-induced telomere shortening as a pancultural biomarker of compromised health and aging. PMID- 25730847 TI - Joint control of terrestrial gross primary productivity by plant phenology and physiology. AB - Terrestrial gross primary productivity (GPP) varies greatly over time and space. A better understanding of this variability is necessary for more accurate predictions of the future climate-carbon cycle feedback. Recent studies have suggested that variability in GPP is driven by a broad range of biotic and abiotic factors operating mainly through changes in vegetation phenology and physiological processes. However, it is still unclear how plant phenology and physiology can be integrated to explain the spatiotemporal variability of terrestrial GPP. Based on analyses of eddy-covariance and satellite-derived data, we decomposed annual terrestrial GPP into the length of the CO2 uptake period (CUP) and the seasonal maximal capacity of CO2 uptake (GPPmax). The product of CUP and GPPmax explained >90% of the temporal GPP variability in most areas of North America during 2000-2010 and the spatial GPP variation among globally distributed eddy flux tower sites. It also explained GPP response to the European heatwave in 2003 (r(2) = 0.90) and GPP recovery after a fire disturbance in South Dakota (r(2) = 0.88). Additional analysis of the eddy-covariance flux data shows that the interbiome variation in annual GPP is better explained by that in GPPmax than CUP. These findings indicate that terrestrial GPP is jointly controlled by ecosystem-level plant phenology and photosynthetic capacity, and greater understanding of GPPmax and CUP responses to environmental and biological variations will, thus, improve predictions of GPP over time and space. PMID- 25730848 TI - SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. AB - Neutrophils cast neutrophil extracellular traps (NETs) to defend the host against invading pathogens. Although effective against microbial pathogens, a growing body of literature now suggests that NETs have negative impacts on many inflammatory and autoimmune diseases. Identifying mechanisms that regulate the process termed "NETosis" is important for treating these diseases. Although two major types of NETosis have been described to date, mechanisms regulating these forms of cell death are not clearly established. NADPH oxidase 2 (NOX2) generates large amounts of reactive oxygen species (ROS), which is essential for NOX dependent NETosis. However, major regulators of NOX-independent NETosis are largely unknown. Here we show that calcium activated NOX-independent NETosis is fast and mediated by a calcium-activated small conductance potassium (SK) channel member SK3 and mitochondrial ROS. Although mitochondrial ROS is needed for NOX independent NETosis, it is not important for NOX-dependent NETosis. We further demonstrate that the activation of the calcium-activated potassium channel is sufficient to induce NOX-independent NETosis. Unlike NOX-dependent NETosis, NOX independent NETosis is accompanied by a substantially lower level of activation of ERK and moderate level of activation of Akt, whereas the activation of p38 is similar in both pathways. ERK activation is essential for the NOX-dependent pathway, whereas its activation is not essential for the NOX-independent pathway. Despite the differential activation, both NOX-dependent and -independent NETosis require Akt activity. Collectively, this study highlights key differences in these two major NETosis pathways and provides an insight into previously unknown mechanisms for NOX-independent NETosis. PMID- 25730849 TI - beta-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. AB - Recent studies have demonstrated that beta-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how beta catenin exerts its functions remains incompletely understood. Here we report that activation of beta-catenin in DCs inhibits cross-priming of CD8(+) T cells by up regulating mTOR-dependent IL-10, suggesting blocking beta-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-beta-catenin(-/-) (CD11c-specific deletion of beta-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-beta-catenin(-/-) mice were deficient in generating CD8(+) T cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by beta-catenin(-/-) DCs. Deletion of beta-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8(+) T cells, suggesting that beta-catenin in DCs plays a positive role in CD8(+) T-cell maintenance postclonal expansion through IL-10. Thus, our study has not only identified mTOR/IL-10 as a previously unidentified mechanism for beta-catenin-dependent inhibition of cross-priming, but also uncovered an unexpected positive role that beta-catenin plays in maintenance of CD8(+) T cells. Despite beta-catenin's opposite functions in regulating CD8(+) T-cell responses, selectively blocking beta-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8(+) T-cell immunity and improved antitumor efficacy, suggesting manipulating beta-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy. PMID- 25730850 TI - Redefining the role of Broca's area in speech. AB - For over a century neuroscientists have debated the dynamics by which human cortical language networks allow words to be spoken. Although it is widely accepted that Broca's area in the left inferior frontal gyrus plays an important role in this process, it was not possible, until recently, to detail the timing of its recruitment relative to other language areas, nor how it interacts with these areas during word production. Using direct cortical surface recordings in neurosurgical patients, we studied the evolution of activity in cortical neuronal populations, as well as the Granger causal interactions between them. We found that, during the cued production of words, a temporal cascade of neural activity proceeds from sensory representations of words in temporal cortex to their corresponding articulatory gestures in motor cortex. Broca's area mediates this cascade through reciprocal interactions with temporal and frontal motor regions. Contrary to classic notions of the role of Broca's area in speech, while motor cortex is activated during spoken responses, Broca's area is surprisingly silent. Moreover, when novel strings of articulatory gestures must be produced in response to nonword stimuli, neural activity is enhanced in Broca's area, but not in motor cortex. These unique data provide evidence that Broca's area coordinates the transformation of information across large-scale cortical networks involved in spoken word production. In this role, Broca's area formulates an appropriate articulatory code to be implemented by motor cortex. PMID- 25730851 TI - Inference of seasonal and pandemic influenza transmission dynamics. AB - The inference of key infectious disease epidemiological parameters is critical for characterizing disease spread and devising prevention and containment measures. The recent emergence of surveillance records mined from big data such as health-related online queries and social media, as well as model inference methods, permits the development of new methodologies for more comprehensive estimation of these parameters. We use such data in conjunction with Bayesian inference methods to study the transmission dynamics of influenza. We simultaneously estimate key epidemiological parameters, including population susceptibility, the basic reproductive number, attack rate, and infectious period, for 115 cities during the 2003-2004 through 2012-2013 seasons, including the 2009 pandemic. These estimates discriminate key differences in the epidemiological characteristics of these outbreaks across 10 y, as well as spatial variations of influenza transmission dynamics among subpopulations in the United States. In addition, the inference methods appear to compensate for observational biases and underreporting inherent in the surveillance data. PMID- 25730852 TI - Evidence and implications of higher-order scaling in the environmental variation of animal population growth. AB - Environmental stochasticity is an important concept in population dynamics, providing a quantitative model of the extrinsic fluctuations driving population abundances. It is typically formulated as a stochastic perturbation to the maximum reproductive rate, leading to a population variance that scales quadratically with abundance. However, environmental fluctuations may also drive changes in the strength of density dependence. Very few studies have examined the consequences of this alternative model formulation while even fewer have tested which model better describes fluctuations in animal populations. Here we use data from the Global Population Dynamics Database to determine the statistical support for this alternative environmental variance model in 165 animal populations and test whether these models can capture known population-environment interactions in two well-studied ungulates. Our results suggest that variation in the density dependence is common and leads to a higher-order scaling of the population variance. This scaling will often stabilize populations although dynamics may also be destabilized under certain conditions. We conclude that higher-order environmental variation is a potentially ubiquitous and consequential property of animal populations. Our results suggest that extinction risk estimates may often be overestimated when not properly taking into account how environmental fluctuations affect population parameters. PMID- 25730853 TI - Parameter-free methods distinguish Wnt pathway models and guide design of experiments. AB - The canonical Wnt signaling pathway, mediated by beta-catenin, is crucially involved in development, adult stem cell tissue maintenance, and a host of diseases including cancer. We analyze existing mathematical models of Wnt and compare them to a new Wnt signaling model that targets spatial localization; our aim is to distinguish between the models and distill biological insight from them. Using Bayesian methods we infer parameters for each model from mammalian Wnt signaling data and find that all models can fit this time course. We appeal to algebraic methods (concepts from chemical reaction network theory and matroid theory) to analyze the models without recourse to specific parameter values. These approaches provide insight into aspects of Wnt regulation: the new model, via control of shuttling and degradation parameters, permits multiple stable steady states corresponding to stem-like vs. committed cell states in the differentiation hierarchy. Our analysis also identifies groups of variables that should be measured to fully characterize and discriminate between competing models, and thus serves as a guide for performing minimal experiments for model comparison. PMID- 25730854 TI - Cells as liquid motors: mechanosensitivity emerges from collective dynamics of actomyosin cortex. AB - Living cells adapt and respond actively to the mechanical properties of their environment. In addition to biochemical mechanotransduction, evidence exists for a myosin-dependent purely mechanical sensitivity to the stiffness of the surroundings at the scale of the whole cell. Using a minimal model of the dynamics of actomyosin cortex, we show that the interplay of myosin power strokes with the rapidly remodeling actin network results in a regulation of force and cell shape that adapts to the stiffness of the environment. Instantaneous changes of the environment stiffness are found to trigger an intrinsic mechanical response of the actomyosin cortex. Cortical retrograde flow resulting from actin polymerization at the edges is shown to be modulated by the stress resulting from myosin contractility, which in turn, regulates the cell length in a force dependent manner. The model describes the maximum force that cells can exert and the maximum speed at which they can contract, which are measured experimentally. These limiting cases are found to be associated with energy dissipation phenomena, which are of the same nature as those taking place during the contraction of a whole muscle. This similarity explains the fact that single nonmuscle cell and whole-muscle contraction both follow a Hill-like force velocity relationship. PMID- 25730855 TI - Focus on the success of others leads to selfish behavior. AB - It has often been argued that the spectacular cognitive capacities of humans are the result of selection for the ability to gather, process, and use information about other people. Recent studies show that humans strongly and consistently differ in what type of social information they are interested in. Although some individuals mainly attend to what the majority is doing (frequency-based learning), others focus on the success that their peers achieve with their behavior (success-based learning). Here, we show that such differences in social learning have important consequences for the outcome of social interactions. We report on a decision-making experiment in which individuals were first classified as frequency- and success-based learners and subsequently grouped according to their learning strategy. When confronted with a social dilemma situation, groups of frequency-based learners cooperated considerably more than groups of success based learners. A detailed analysis of the decision-making process reveals that these differences in cooperation are a direct result of the differences in information use. Our results show that individual differences in social learning strategies are crucial for understanding social behavior. PMID- 25730856 TI - Persistent and widespread occurrence of bioactive quinone pigments during post Paleozoic crinoid diversification. AB - Secondary metabolites often play an important role in the adaptation of organisms to their environment. However, little is known about the secondary metabolites of ancient organisms and their evolutionary history. Chemical analysis of exceptionally well-preserved colored fossil crinoids and modern crinoids from the deep sea suggests that bioactive polycyclic quinones related to hypericin were, and still are, globally widespread in post-Paleozoic crinoids. The discovery of hypericinoid pigments both in fossil and in present-day representatives of the order Isocrinida indicates that the pigments remained almost unchanged since the Mesozoic, also suggesting that the original color of hypericinoid-containing ancient crinoids may have been analogous to that of their modern relatives. The persistent and widespread occurrence, spatially as well as taxonomically, of hypericinoid pigments in various orders during the adaptive radiation of post Paleozoic crinoids suggests a general functional importance of the pigments, contributing to the evolutionary success of the Crinoidea. PMID- 25730857 TI - Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex. AB - Mitogen-activated protein kinases (MAPKs) bind and activate their downstream kinase substrates, MAPK-activated protein kinases (MAPKAPKs). Notably, extracellular signal regulated kinase 2 (ERK2) phosphorylates ribosomal S6 kinase 1 (RSK1), which promotes cellular growth. Here, we determined the crystal structure of an RSK1 construct in complex with its activator kinase. The structure captures the kinase-kinase complex in a precatalytic state where the activation loop of the downstream kinase (RSK1) faces the enzyme's (ERK2) catalytic site. Molecular dynamics simulation was used to show how this heterodimer could shift into a signaling-competent state. This structural analysis combined with biochemical and cellular studies on MAPK->MAPKAPK signaling showed that the interaction between the MAPK binding linear motif (residing in a disordered kinase domain extension) and the ERK2 "docking" groove plays the major role in making an encounter complex. This interaction holds kinase domains proximal as they "readjust," whereas generic kinase domain surface contacts bring them into a catalytically competent state. PMID- 25730858 TI - Hunger promotes acquisition of nonfood objects. AB - Hunger motivates people to consume food, for which finding and acquiring food is a prerequisite. We test whether the acquisition component spills over to nonfood objects: Are hungry people more likely to acquire objects that cannot satisfy their hunger? Five laboratory and field studies show that hunger increases the accessibility of acquisition-related concepts and the intention to acquire not only food but also nonfood objects. Moreover, people act on this intention and acquire more nonfood objects (e.g., binder clips) when they are hungry, both when these items are freely available and when they must be paid for. However, hunger does not influence how much they like nonfood objects. We conclude that a basic biologically based motivation can affect substantively unrelated behaviors that cannot satisfy the motivation. This presumably occurs because hunger renders acquisition-related concepts and behaviors more accessible, which influences decisions in situations to which they can be applied. PMID- 25730859 TI - Discovery of multiple hidden allosteric sites by combining Markov state models and experiments. AB - The discovery of drug-like molecules that bind pockets in proteins that are not present in crystallographic structures yet exert allosteric control over activity has generated great interest in designing pharmaceuticals that exploit allosteric effects. However, there have only been a small number of successes, so the therapeutic potential of these pockets--called hidden allosteric sites--remains unclear. One challenge for assessing their utility is that rational drug design approaches require foreknowledge of the target site, but most hidden allosteric sites are only discovered when a small molecule is found to stabilize them. We present a means of decoupling the identification of hidden allosteric sites from the discovery of drugs that bind them by drawing on new developments in Markov state modeling that provide unprecedented access to microsecond- to millisecond timescale fluctuations of a protein's structure. Visualizing these fluctuations allows us to identify potential hidden allosteric sites, which we then test via thiol labeling experiments. Application of these methods reveals multiple hidden allosteric sites in an important antibiotic target--TEM-1 beta-lactamase. This result supports the hypothesis that there are many as yet undiscovered hidden allosteric sites and suggests our methodology can identify such sites, providing a starting point for future drug design efforts. More generally, our results demonstrate the power of using Markov state models to guide experiments. PMID- 25730860 TI - Allosteric and hyperekplexic mutant phenotypes investigated on an alpha1 glycine receptor transmembrane structure. AB - The glycine receptor (GlyR) is a pentameric ligand-gated ion channel (pLGIC) mediating inhibitory transmission in the nervous system. Its transmembrane domain (TMD) is the target of allosteric modulators such as general anesthetics and ethanol and is a major locus for hyperekplexic congenital mutations altering the allosteric transitions of activation or desensitization. We previously showed that the TMD of the human alpha1GlyR could be fused to the extracellular domain of GLIC, a bacterial pLGIC, to form a functional chimera called Lily. Here, we overexpress Lily in Schneider 2 insect cells and solve its structure by X-ray crystallography at 3.5 A resolution. The TMD of the alpha1GlyR adopts a closed channel conformation involving a single ring of hydrophobic residues at the center of the pore. Electrophysiological recordings show that the phenotypes of key allosteric mutations of the alpha1GlyR, scattered all along the pore, are qualitatively preserved in this chimera, including those that confer decreased sensitivity to agonists, constitutive activity, decreased activation kinetics, or increased desensitization kinetics. Combined structural and functional data indicate a pore-opening mechanism for the alpha1GlyR, suggesting a structural explanation for the effect of some key hyperekplexic allosteric mutations. The first X-ray structure of the TMD of the alpha1GlyR solved here using GLIC as a scaffold paves the way for mechanistic investigation and design of allosteric modulators of a human receptor. PMID- 25730861 TI - Late Pleistocene age and archaeological context for the hominin calvaria from GvJm-22 (Lukenya Hill, Kenya). AB - Kenya National Museums Lukenya Hill Hominid 1 (KNM-LH 1) is a Homo sapiens partial calvaria from site GvJm-22 at Lukenya Hill, Kenya, associated with Later Stone Age (LSA) archaeological deposits. KNM-LH 1 is securely dated to the Late Pleistocene, and samples a time and region important for understanding the origins of modern human diversity. A revised chronology based on 26 accelerator mass spectrometry radiocarbon dates on ostrich eggshells indicates an age range of 23,576-22,887 y B.P. for KNM-LH 1, confirming prior attribution to the Last Glacial Maximum. Additional dates extend the maximum age for archaeological deposits at GvJm-22 to >46,000 y B.P. (>46 kya). These dates are consistent with new analyses identifying both Middle Stone Age and LSA lithic technologies at the site, making GvJm-22 a rare eastern African record of major human behavioral shifts during the Late Pleistocene. Comparative morphometric analyses of the KNM LH 1 cranium document the temporal and spatial complexity of early modern human morphological variability. Features of cranial shape distinguish KNM-LH 1 and other Middle and Late Pleistocene African fossils from crania of recent Africans and samples from Holocene LSA and European Upper Paleolithic sites. PMID- 25730863 TI - Conductance enlargement in picoscale electroburnt graphene nanojunctions. AB - Provided the electrical properties of electroburnt graphene junctions can be understood and controlled, they have the potential to underpin the development of a wide range of future sub-10-nm electrical devices. We examine both theoretically and experimentally the electrical conductance of electroburnt graphene junctions at the last stages of nanogap formation. We account for the appearance of a counterintuitive increase in electrical conductance just before the gap forms. This is a manifestation of room-temperature quantum interference and arises from a combination of the semimetallic band structure of graphene and a cross-over from electrodes with multiple-path connectivity to single-path connectivity just before breaking. Therefore, our results suggest that conductance enlargement before junction rupture is a signal of the formation of electroburnt junctions, with a picoscale current path formed from a single sp(2) bond. PMID- 25730862 TI - In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. AB - NAD is an essential metabolite that exists in NAD(+) or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD(+)/NADH redox state and modulating cellular signaling processes through the activity of the NAD(+)-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high field MR scanner and is capable of noninvasively assessing NAD(+) and NADH contents and the NAD(+)/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD(+), total NAD contents, and NAD(+)/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ. PMID- 25730864 TI - Interplay among nucleosomal DNA, histone tails, and corepressor CoREST underlies LSD1-mediated H3 demethylation. AB - With its noncatalytic domains, DNA-binding regions, and a catalytic core targeting the histone tails, LSD1-CoREST (lysine-specific demethylase 1; REST corepressor) is an ideal model system to study the interplay between DNA binding and histone modification in nucleosome recognition. To this end, we covalently associated LSD1-CoREST to semisynthetic nucleosomal particles. This enabled biochemical and biophysical characterizations of nucleosome binding and structural elucidation by small-angle X-ray scattering, which was extensively validated through binding assays and site-directed mutagenesis of functional interfaces. Our results suggest that LSD1-CoREST functions as an ergonomic clamp that induces the detachment of the H3 histone tail from the nucleosomal DNA to make it available for capture by the enzyme active site. The key notion emerging from these studies is the inherently competitive nature of the binding interactions because nucleosome tails, chromatin modifiers, transcription factors, and DNA represent sites for multiple and often mutually exclusive interactions. PMID- 25730865 TI - Transcription factor interaction with COMPASS-like complex regulates histone H3K4 trimethylation for specific gene expression in plants. AB - Accumulation of unfolded or misfolded proteins causes endoplasmic reticulum (ER) stress, which activates a set of ER membrane-associated transcription factors for protein homeostasis regulation. Previous genome-wide chromatin immunoprecipitation analysis shows a strong correlation between histone H3K4 trimethylation (H3K4me3) and active gene expression. However, how the histone modification complex is specifically and timely recruited to the active promoters remains unknown. Using ER stress responsive gene expression as a model system, we demonstrate that sequence-specific transcription factors interact with COMPASS like components and affect H3K4me3 formation at specific target sites in Arabidopsis. Gene profiling analysis reveals that membrane-associated basic leucine zipper (bZIP) transcription factors bZIP28 and bZIP60 regulate most of the ER stress responsive genes. Loss-of-functions of bZIP28 and bZIP60 impair the occupancy of H3K4me3 on promoter regions of ER stress responsive genes. Further, in vitro pull-down assays and in vivo bimolecular fluorescence complementation (BiFC) experiments show that bZIP28 and bZIP60 interact with Ash2 and WDR5a, both of which are core COMPASS-like components. Knockdown expression of either Ash2 or WDR5a decreased the expression of several ER stress responsive genes. The COMPASS like complex is known to interact with histone methyltransferase to facilitate preinitiation complex (PIC) assembly and generate H3K4me3 during transcription elongation. Thus, our data shows that the ER stress stimulus causes the formation of PIC and deposition of H3K4me3 mark at specific promoters through the interaction between transcription factor and COMPASS-like components. PMID- 25730866 TI - In vitro reconstitution of indolmycin biosynthesis reveals the molecular basis of oxazolinone assembly. AB - The bacterial tryptophanyl-tRNA synthetase inhibitor indolmycin features a unique oxazolinone heterocycle whose biogenetic origins have remained obscure for over 50 years. Here we identify and characterize the indolmycin biosynthetic pathway, using systematic in vivo gene inactivation, in vitro biochemical assays, and total enzymatic synthesis. Our work reveals that a phenylacetate-CoA ligase-like enzyme Ind3 catalyzes an unusual ATP-dependent condensation of indolmycenic acid and dehydroarginine, driving oxazolinone ring assembly. We find that Ind6, which also has chaperone-like properties, acts as a gatekeeper to direct the outcome of this reaction. With Ind6 present, the normal pathway ensues. Without Ind6, the pathway derails to an unusual shunt product. Our work reveals the complete pathway for indolmycin formation and sets the stage for using genetic and chemoenzymatic methods to generate indolmycin derivatives as potential therapeutic agents. PMID- 25730867 TI - Dendritic cell SIRT1-HIF1alpha axis programs the differentiation of CD4+ T cells through IL-12 and TGF-beta1. AB - The differentiation of naive CD4(+) T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3(+) regulatory T cells (T(reg) cells). Genetic deletion of SIRT1 in DCs restrained the generation of T(reg) cells while driving TH1 development, resulting in an enhanced T-cell mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1alpha)-dependent pathway, orchestrating the reciprocal TH1 and T(reg) lineage commitment through DC-derived IL-12 and TGF-beta1. Our studies implicates a DC-based SIRT1-HIF1alpha metabolic checkpoint in controlling T-cell lineage specification. PMID- 25730869 TI - Moth tails divert bat attack: evolution of acoustic deflection. AB - Adaptations to divert the attacks of visually guided predators have evolved repeatedly in animals. Using high-speed infrared videography, we show that luna moths (Actias luna) generate an acoustic diversion with spinning hindwing tails to deflect echolocating bat attacks away from their body and toward these nonessential appendages. We pit luna moths against big brown bats (Eptesicus fuscus) and demonstrate a survival advantage of ~ 47% for moths with tails versus those that had their tails removed. The benefit of hindwing tails is equivalent to the advantage conferred to moths by bat-detecting ears. Moth tails lured bat attacks to these wing regions during 55% of interactions between bats and intact luna moths. We analyzed flight kinematics of moths with and without hindwing tails and suggest that tails have a minimal role in flight performance. Using a robust phylogeny, we find that long spatulate tails have independently evolved four times in saturniid moths, further supporting the selective advantage of this anti-bat strategy. Diversionary tactics are perhaps more common than appreciated in predator-prey interactions. Our finding suggests that focusing on the sensory ecologies of key predators will reveal such countermeasures in prey. PMID- 25730868 TI - Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression. AB - HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4(+) T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8(+) T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4(+) T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions. PMID- 25730870 TI - Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: relevance to trypanosome lysis. AB - Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species including Trypanosoma brucei brucei, but not the human-infective pathogens T. brucei rhodesiense and T. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to an increased ion permeability of the plasma membrane. Here we demonstrate that nanogram quantities of full-length recombinant APOL1 induce ideally cation selective macroscopic conductances in planar lipid bilayers. The conductances were highly sensitive to pH: their induction required acidic pH (pH 5.3), but their magnitude could be increased 3,000-fold upon alkalinization of the milieu (pK(a) = 7.1). We show that this phenomenon can be attributed to the association of APOL1 with the bilayer at acidic pH, followed by the opening of APOL1-induced cation-selective channels upon pH neutralization. Furthermore, the conductance increase at neutral pH (but not membrane association at acidic pH) was prevented by the interaction of APOL1 with the serum resistance-associated protein, which is produced by T. brucei rhodesiense and prevents trypanosome lysis by APOL1. These data are consistent with a model of lysis that involves endocytic recycling of APOL1 and the formation of cation-selective channels, at neutral pH, in the parasite plasma membrane. PMID- 25730871 TI - Floral organ abscission is regulated by a positive feedback loop. AB - Abscission is the process by which plants shed unwanted organs, either as part of a natural developmental program or in response to environmental stimuli. Studies in Arabidopsis thaliana have elucidated a number of the genetic components that regulate abscission of floral organs, including a pair of related receptor-like protein kinases, HAESA and HAESA-like 2 (HAE/HSL2) that regulate a MAP kinase cascade that is required for abscission. HAE is transcriptionally up-regulated in the floral abscission zone just before cell separation. Here, we identify AGAMOUS like 15 (AGL15; a MADS-domain transcription factor) as a putative regulator of HAE expression. Overexpression of AGL15 results in decreased expression of HAE as well as a delayed abscission phenotype. Chromatin immunoprecipitation experiments indicate that AGL15 binds the HAE promoter in floral receptacles. AGL15 is then differentially phosphorylated through development in floral receptacles in a MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4/5-dependent manner. MAP kinase phosphorylation of AGL15 is necessary for full HAE expression, thus completing a positive feedback loop controlling HAE expression. Together, the network components in this positive feedback loop constitute an emergent property that regulates the large dynamic range of gene expression (27-fold increase in HAE) observed in flowers when the abscission program is initiated. This study helps define the mechanisms and regulatory networks involved in a receptor-mediated signaling pathway that controls floral organ abscission. PMID- 25730873 TI - Capillary-bridge-derived particles with negative Gaussian curvature. AB - We report the preparation of millimeter-scale particles by thermal polymerization of liquid monomer capillary bridges to form catenoid-shaped particles that exhibit negative Gaussian curvature. The shape of the capillary bridges and resulting particles can be finely tuned using several addressable parameters: (i) the shape, size, and orientation of lithographic pinning features on the spanned surfaces; (ii) the distance between opposing support surfaces; and (iii) the lateral displacement (shear) of opposing features. The catenoid-shaped particles exhibit controllable optical properties as a result of their concave menisci, the shape of which can be easily manipulated. The particles self assemble in the presence of a condensing liquid (water) to form reversible neck-to-neck pairs and less reversible end-to-end aggregates. We argue that this approach could be scaled down to micrometer dimensions by fabricating an array of micrometer-scale particles. We also argue, with a discussion of dynamic wetting, that these particles will exhibit interesting anisotropic adhesive properties. PMID- 25730872 TI - Epigenetic control of intestinal barrier function and inflammation in zebrafish. AB - The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset. PMID- 25730874 TI - Mutant IDH is sufficient to initiate enchondromatosis in mice. AB - Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1 R132Q mutation. These mutations harbored enzymatic activity to catalyze alpha ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas. PMID- 25730875 TI - A new type of half-quantum circulation in a macroscopic polariton spinor ring condensate. AB - We report the observation of coherent circulation in a macroscopic Bose-Einstein condensate of polaritons in a ring geometry. Because they are spinor condensates, half-quanta are allowed in where there is a phase rotation of pi in connection with a polarization vector rotation of pi around a closed path. This half-quantum behavior is clearly seen in the experimental observations of the polarization rotation around the ring. In our ring geometry, the half-quantum state that we see is one in which the handedness of the spin flips from one side of the ring to the other side in addition to the rotation of the linear polarization component; such a state is allowed in a ring geometry but will not occur in a simply connected geometry. This state is lower in energy than a half-quantum state with no change of the spin direction and corresponds to a superposition of two different elementary half-quantum states. The direction of circulation of the flow around the ring fluctuates randomly between clockwise and counterclockwise from one shot to the next; this fluctuation corresponds to spontaneous breaking of time-reversal symmetry in the system. This type of macroscopic polariton ring condensate allows for the possibility of direct control of the circulation to excite higher quantized states and the creation of Josephson junction tunneling barriers. PMID- 25730876 TI - ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis. AB - Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross coupling between stress and hormone-sensitive pathways. PMID- 25730877 TI - Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance. AB - Cell stress is implicated in triggering bouts of systemic inflammation in patients with autoinflammatory disorders. Blood monocytes from patients affected by NLRP3-mediated cryopyrin-associated periodic syndromes (CAPS) release greater amounts of IL-1beta than monocytes from unaffected subjects. Here we show that stress lowers the threshold of activation; blood monocytes from CAPS patients maintain the high levels of secreted IL-1beta (fivefold) and IL-18 (10-fold) when stimulated with 1,000-fold less LPS than that required for full IL-1beta secretion in control subjects. Unexpectedly, IL-1alpha secretion is increased 10 fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1beta but may also involve IL-1alpha. In CAPS monocytes, LPS induces the externalization of copious amounts of ATP (10-fold), which drive IL-1beta, IL-18, and IL-1alpha release via activation of the P2X purinoceptor 7. This enhanced ATP release appears to be the link between cell stress and increased cytokine secretion in CAPS. In the later phase after LPS stimulation, CAPS monocytes undergo oxidative stress, which impairs production of the anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Remarkably, IL-1Ra secretion is fully restored by treatment with antioxidants. In two patients with the same NLRP3 mutation, but different disease severity, monocytes from the mildly affected patient exhibited more efficient redox response, lower ATP secretion, and more balanced cytokine production. Thus, the robustness of the individual antioxidant response increases the tolerance to stress and reduces the negative effect of the disease. Pharmacologic block of P2X purinoceptor 7 and improved stress tolerance may represent novel treatment strategies in stress-associated inflammatory diseases. PMID- 25730878 TI - APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation. AB - Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B(del)), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B(del) individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B(del) breast cancers, which seems to be related to hypermutation arising in A3B(del) carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B(del) require additional study, these findings nominate the A3B(del) polymorphism as a potential predictor for cancer immunotherapy. PMID- 25730880 TI - Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. AB - Monoclonal antibodies can block cellular interactions that negatively regulate T cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK. PMID- 25730879 TI - Rare variants in neuronal excitability genes influence risk for bipolar disorder. AB - We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. PMID- 25730881 TI - Electron crystallography of ultrathin 3D protein crystals: atomic model with charges. AB - Membrane proteins and macromolecular complexes often yield crystals too small or too thin for even the modern synchrotron X-ray beam. Electron crystallography could provide a powerful means for structure determination with such undersized crystals, as protein atoms diffract electrons four to five orders of magnitude more strongly than they do X-rays. Furthermore, as electron crystallography yields Coulomb potential maps rather than electron density maps, it could provide a unique method to visualize the charged states of amino acid residues and metals. Here we describe an attempt to develop a methodology for electron crystallography of ultrathin (only a few layers thick) 3D protein crystals and present the Coulomb potential maps at 3.4-A and 3.2-A resolution, respectively, obtained from Ca(2+)-ATPase and catalase crystals. These maps demonstrate that it is indeed possible to build atomic models from such crystals and even to determine the charged states of amino acid residues in the Ca(2+)-binding sites of Ca(2+)-ATPase and that of the iron atom in the heme in catalase. PMID- 25730882 TI - Profile of Eric Betzig, Stefan Hell, and W. E. Moerner, 2014 Nobel Laureates in Chemistry. PMID- 25730883 TI - Dissecting the role of the gamma-subunit in the rotary-chemical coupling and torque generation of F1-ATPase. AB - Unraveling the molecular nature of the conversion of chemical energy (ATP hydrolysis in the alpha/beta-subunits) to mechanical energy and torque (rotation of the gamma-subunit) in F1-ATPase is very challenging. A major part of the challenge involves understanding the rotary-chemical coupling by a nonphenomenological structure-energy description, while accounting for the observed torque generated on the gamma-subunit and its change due to mutation of this unit. Here we extend our previous study that used a coarse-grained model of the F1-ATPase to generate a structure-based free energy landscape of the rotary chemical process. Our quantitative analysis of the landscape reproduced the observed torque for the wild-type enzyme. In doing so, we found that there are several possibilities of torque generation from landscapes with various shapes and demonstrated that a downhill slope along the chemical coordinate could still result in negligible torque, due to ineffective coupling of the chemistry to the gamma-subunit rotation. We then explored the relationship between the functionality and the underlying sequence through systematic examination of the effect of various parts of the gamma-subunit on free energy surfaces of F1 ATPase. Furthermore, by constructing several types of gamma-deletion systems and calculating the corresponding torque generation, we gained previously unknown insights into the molecular nature of the F1-ATPase rotary motor. Significantly, our results are in excellent agreement with recent experimental findings and indicate that the rotary-chemical coupling is primarily established through electrostatic effects, although specific contacts through gamma-ionizable residue side chains are not essential for establishing the basic features of the coupling. PMID- 25730884 TI - Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis. AB - Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release. PMID- 25730885 TI - Insect capa neuropeptides impact desiccation and cold tolerance. AB - The success of insects is linked to their impressive tolerance to environmental stress, but little is known about how such responses are mediated by the neuroendocrine system. Here we show that the capability (capa) neuropeptide gene is a desiccation- and cold stress-responsive gene in diverse dipteran species. Using targeted in vivo gene silencing, physiological manipulations, stress tolerance assays, and rationally designed neuropeptide analogs, we demonstrate that the Drosophila melanogaster capa neuropeptide gene and its encoded peptides alter desiccation and cold tolerance. Knockdown of the capa gene increases desiccation tolerance but lengthens chill coma recovery time, and injection of capa peptide analogs can reverse both phenotypes. Immunohistochemical staining suggests that capa accumulates in the capa-expressing Va neurons during desiccation and nonlethal cold stress but is not released until recovery from each stress. Our results also suggest that regulation of cellular ion and water homeostasis mediated by capa peptide signaling in the insect Malpighian (renal) tubules is a key physiological mechanism during recovery from desiccation and cold stress. This work augments our understanding of how stress tolerance is mediated by neuroendocrine signaling and illustrates the use of rationally designed peptide analogs as agents for disrupting protective stress tolerance. PMID- 25730888 TI - Development and validation of the multidimensional motivational climate observation system. AB - This article outlines the development and validation of the Multidimensional Motivational Climate Observation System (MMCOS). Drawing from an integration of the dimensions of the social environment emphasized within achievement goal theory and self-determination theory (as assumed within Duda's [2013] conceptualization of "empowering" and "disempowering" climates), the MMCOS was developed to enable an objective assessment of the coach-created motivational environment in sport. Study 1 supported the initial validity and reliability of the newly developed observation system. Study 2 further examined the interobserver reliability and factorial structure of the MMCOS. Study 3 explored the predictive validity of the observational system in relation to athletes' reported basic psychological need satisfaction. Overall, the results of these studies provide preliminary support for the inter- and intraobserver reliability, as well as factorial and predictive validity of the MMCOS. Suggestions for the use of this observational system in future research in sport are provided. PMID- 25730886 TI - Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion. AB - Mitochondrial DNA (mtDNA) is essential for mitochondrial and cellular function. In Saccharomyces cerevisiae, mtDNA is organized in nucleoprotein structures termed nucleoids, which are distributed throughout the mitochondrial network and are faithfully inherited during the cell cycle. How the cell distributes and inherits mtDNA is incompletely understood although an involvement of mitochondrial fission and fusion has been suggested. We developed a LacO-LacI system to noninvasively image mtDNA dynamics in living cells. Using this system, we found that nucleoids are nonrandomly spaced within the mitochondrial network and observed the spatiotemporal events involved in mtDNA inheritance. Surprisingly, cells deficient in mitochondrial fusion and fission distributed and inherited mtDNA normally, pointing to alternative pathways involved in these processes. We identified such a mechanism, where we observed fission-independent, but F-actin-dependent, tip generation that was linked to the positioning of mtDNA to the newly generated tip. Although mitochondrial fusion and fission were dispensable for mtDNA distribution and inheritance, we show through a combination of genetics and next-generation sequencing that their absence leads to an accumulation of mitochondrial genomes harboring deleterious structural variations that cluster at the origins of mtDNA replication, thus revealing crucial roles for mitochondrial fusion and fission in maintaining the integrity of the mitochondrial genome. PMID- 25730889 TI - Transformational leadership and task cohesion in sport: the mediating role of inside sacrifice. AB - In this cross-sectional study, we examined a mediational model whereby transformational leadership is related to task cohesion via sacrifice. Participants were 381 American (Mage = 19.87 years, SD = 1.41) Division I university athletes (188 males, 193 females) who competed in a variety of sports. Participants completed measures of coach transformational leadership, personal and teammate inside sacrifice, and task cohesion. After conducting multilevel mediation analysis, we found that both personal and teammate inside sacrifice significantly mediated the relationships between transformational leadership behaviors and task cohesion. However, there were differential patterns of these relationships for male and female athletes. Interpretation of the results highlights that coaches should endeavor to display transformational leadership behaviors as they are related to personal and teammate inside sacrifices and task cohesion. PMID- 25730890 TI - Toward an integrative model of doping use: an empirical study with adolescent athletes. AB - The present study assessed adolescent athletes' intentions toward doping by using an integrative theoretical model. Overall, 650 adolescent athletes from team and individual sports completed an anonymous structured questionnaire including demographic information, social desirability, achievement goals, motivational regulations, sportspersonship orientations, social cognitive variables, and anticipated regret. Hierarchical regression analysis showed that the integrative model predicted 57.2% of the variance in doping intentions. Social cognitive variables and anticipated regret directly predicted doping intentions. Anticipated regret added 3% incremental variance on top of other predictors. Multiple mediation analyses showed that the effects of achievement goals on intentions were mediated by self-efficacy beliefs, whereas the effects of sportspersonship were mediated by attitudes and anticipated regret. The present study confirmed the dual structure of an integrative model of doping intentions and further highlighted the role of anticipated regret in the study of adolescent doping use. PMID- 25730891 TI - Applying generalizability theory to examine the antecedents of perceived coach support. AB - Although social support is integral to the coaching process, there is only a limited understanding of the antecedents of perceived coach support. We applied generalizability theory to examine perceived coach support and its antecedents at perceiver, provider, and relational levels of analysis. Two studies were conducted in which athletes rated the degree to which they identified with a selection of coaches, and the personality, competency, and supportiveness of those coaches. Univariate analyses demonstrated that the relational component accounted for a significant amount of variance in perceived coach support in both studies. Multivariate analyses demonstrated that when athletes perceive specific coaches to be highly agreeable, competent, and individuals with whom they share a common identity, they also perceive these same coaches to be particularly supportive in comparison with other coaches. PMID- 25730892 TI - Going to the gym or to the movies?: situated decisions as a functional link connecting automatic and reflective evaluations of exercise with exercising behavior. AB - The goal of the present paper is to propose a model for the study of automatic cognition and affect in exercise. We have chosen a dual-system approach to social information processing to investigate the hypothesis that situated decisions between behavioral alternatives form a functional link between automatic and reflective evaluations and the time spent on exercise. A new questionnaire is introduced to operationalize this link. A reaction-time-based evaluative priming task was used to test participants' automatic evaluations. Affective and cognitive reflective evaluations, as well as exercising time, were requested via self-report. Path analyses suggest that the affective reflective (beta = .71) and the automatic evaluation (beta = .15) independently explain situated decisions, which, in turn (beta = .60) explain time spent on exercise. Our findings highlight the concept of contextualized decisions. They can serve as a starting point from which the so far seldom investigations of automatic cognition and affect in exercise can be integrated with multitudinous results from studies on reflective psychological determinants of health behavior. PMID- 25730893 TI - The use of patterns to disguise environmental cues during an anticipatory judgment task. AB - A number of novel manipulations to the design of playing uniforms were used to try to disguise the actions of penalty takers in soccer. Skilled and less-skilled soccer goalkeepers were required to anticipate penalty kick outcome while their opponent wore one of three different uniform designs that were intended to disguise the availability of potentially key information from the hip region. Variations of shapes/patterns were designed to conceal the actual alignment of the hips. Three occlusion points were used in the test film: -160 ms, -80 ms before, and at foot-ball contact. Skilled individuals reported higher accuracy scores than their less-skilled counterparts (p < .05). There were no performance decrements for the less-skilled group across the different uniform conditions (p > .05); however, the skilled group decreased their accuracy on the experimental conditions compared with the control (p < .05). Findings highlight the potential benefits of designing playing uniforms that facilitate disguise in sport. PMID- 25730894 TI - Who takes risks in high-risk sport?: the role of alexithymia. AB - People who have difficulty identifying and describing their emotions are more likely to seek out the experience of emotions in the high-risk domain. This is because the high-risk domain provides the experience of more easily identifiable emotions (e.g., fear). However, the continued search for intense emotion may lead such individuals to take further risks within this domain, which, in turn, would lead to a greater likelihood of experiencing accidents. Across three studies, we provide the first evidence in support of this view. In Study 1 (n = 762), alexithymia was associated with greater risk taking and a greater propensity to experience accidents and close calls. In Study 2 (n = 332) and Study 3 (n = 356), additional bootstrapped mediation models confirmed these relationships. The predictive role of alexithymia remained significant when controlling for sensation seeking (Study 1) and anhedonia (Study 2 and Study 3). We discuss the practical implications of the present model as they pertain to minimizing accidents and close calls in the high-risk domain. PMID- 25730895 TI - Habit strength moderates the effects of daily action planning prompts on physical activity but not sedentary behavior. AB - This study was designed to examine the moderating influence of habit strength on daily action planning effects on physical activity and sedentary behavior. A 2 by 2 design was used with experimental factors corresponding to action planning interventions for (a) engaging in physical activity and (b) limiting or interrupting sedentary behavior. At the end of each day for 1 week, university students (n = 195) completed (a) a questionnaire about their behavior during the day and behavioral intentions for the following day and (b) a planning intervention(s) corresponding to their randomly assigned experimental condition. Action planning increased physical activity in those with weak habits but decreased physical activity in those with strong habits compared with those who did not create action plans. Action planning did not impact sedentary behavior. Action planning was a useful behavior change technique for increasing physical activity in people with weak habits, but may be iatrogenic for those with strong habits. PMID- 25730896 TI - The effect of long-term administered CRAC channels blocker on the functions of respiratory epithelium in guinea pig allergic asthma model. AB - Previously, therapeutic potency of CRAC channels blocker was evidenced as a significant decrease in airway smooth muscle hyperreactivity, antitussive and anti-inflammatory effects. The major role of the respiratory epithelium in asthma pathogenesis was highlighted only recently and CRAC channels were proposed as the most significant route of Ca2+ entry into epithelial cells. The aim of the study was to analyse the impact of long-term administered CRAC channels blocker on airway epithelium, e.g. cytokine production and ciliary beat frequency (CBF) using an animal model of allergic asthma. Ovalbumin-induced allergic airway inflammation of guinea pigs was followed by long-term (14 days lasted) therapy by CRAC blocker (3-fluoropyridine-4-carboxylic acid, FPCA). The influence of long term therapy on cytokines (IL-4, IL-5 and IL-13) in BALF and in plasma, immunohistochemical staining of pulmonary tissue (c-Fos positivity) and CBF in vitro were used for analysis. Decrease in cytokine levels and in c-Fos positivity confirmed an anti-inflammatory effect of long-term administered FPCA. Cytokine levels in BALF and distribution of c-Fos positivity suggested that FPCA was a more potent inhibitor of respiratory epithelium secretory functions than budesonide. FPCA and budesonide reduced CBF only insignificantly. All findings supported CRAC channels as promising target in the new strategy of antiasthmatic treatment. PMID- 25730897 TI - Protective effect of allicin against glycidamide-induced toxicity in male and female mice. AB - Acrylamide is known to be a neurotoxic, genotoxic, and carcinogenic compound. Glycidamide has a close relationship to the toxic mechanism of acrylamide. In order to explore the toxic mechanism of acrylamide, we further discussed the effects of oral administration of allicin on glycidamide-induced toxicity by determining the hematological parameters like AST, ALT, LDH, BUN, creatinine, ROS, and 8-OHdG, and biochemical parameters such as MDA, MPO, SOD, GST and GSH in the kidney, liver, brain and lung of male and female mice for the first time. We found that the same dose of glycidamide had more toxic effects and damage effects to the mice compared to the previous study of acrylamide. It could markedly increase the level of AST, ALT, LDH, BUN, ROS, 8-OHdG, MDA, MPO while decrease the SOD, GST and GSH. However, our data showed the oral administered allicin with a concentration of 5, 10, and 20 mg/kg b.w./day could significantly decrease the damage indexes of AST, ALT, LDH, BUN, ROS, 8-OHdG, MDA, and MPO, while increase the antioxidant indicators of SOD, GST and GSH. Thus allicin could be used as an effective dietary supplement for the chemoprevention of glycidamide genotoxicity internally, and to prevent the tissue damage and toxicity induced by glycidamide. PMID- 25730898 TI - Molecular pharmacology of antihistamines in inhibition of oxidative burst of professional phagocytes. AB - Antihistamines of the H1and H3/H4groups interfere with oxidative burst of human professional phagocytes in vitro. In the concentration of 10 MUM, H1antihistamines of the 1st and 2nd generation inhibited oxidative burst of human neutrophils in the rank order of potency: dithiaden > loratadine > brompheniramine > chlorpheniramine > pheniramine. Of the H1antihistamines, the most effective was dithiaden in suppressing oxidative burst of whole human blood and dose-dependently the chemiluminescence of isolated neutrophils at extra- and intracellular level. Inhibition of free oxygen radical generation in isolated neutrophils by dithiaden resulted from the inhibition of protein kinase C activation. The potentiation of recombinant caspase-3 by dithiaden is supportive of the antiinflammatory effect of dithiaden and suggestive of increasing the apoptosis of professional phagocytes. Of the H3/H4antihistamines, the most effective was JNJ7777120 in decreasing chemiluminescence in whole blood and also at extra- and intracellular sites of isolated neutrophils. JNJ 10191584 and thioperamide were less effective and the latter significantly potentiated free oxygen radical generation intracellularly. The results demonstrated that, compared with the H3/H4antihistamines investigated, H1antihistamines were much more potent in inhibiting free oxygen radical generation in human professional phagocytes. This finding should be taken into account therapeutically. PMID- 25730899 TI - The action of stress hormones on the structure and function of erythrocyte membrane. AB - The action of a mixture of hormones (cortisol and adrenaline) on erythrocyte membrane during their binding was investigated. Changes in the membrane structure were elucidated by atomic force microscopy; microviscosity of the lipid bilayer and changes in the activity of Na(+),K(+)-ATPase at different concentrations of the hormones in erythrocyte suspension were estimated by the fluorescence method. Cortisol and adrenaline were shown to compete for the binding sites. A hormone that managed to bind nonspecifically to the membrane hindered the binding of another hormone. In a mixture of these hormones, cortisol won a competition for the binding sites; therewith, microviscosity of the membranes increased by 25%, which corresponds to a change in microviscosity produced by the action of cortisol alone. The competitive relationships affected also the Na(+),K(+)-ATPase activity, which was indicated by appearance of the second maximum of enzyme activity. It is assumed that an increase in microviscosity of erythrocyte membrane first raises the Na(+),K(+)-ATPase activity due to a growth of the maximum energy of membrane phonons, and then decreases the activity due to hindering of conformational transitions in the enzyme molecule. PMID- 25730900 TI - Structure and binding efficiency relations of QB site inhibitors of photosynthetic reaction centres. AB - Many herbicides employed in agriculture and also some antibiotics bind to a specific site of the reaction centre protein (RC) blocking the photosynthetic electron transport. Crystal structures showed that all these compounds bind at the secondary ubiquinone (QB) site albeit to slightly different places. Different herbicide molecules have different binding affinities (evaluated as inhibition constants, KI, and binding enthalpy values, DeltaHbind). The action of inhibitors depends on the following parameters: (i) herbicide molecular structure; (ii) interactions between herbicide and quinone binding site; (iii) protein environment. In our investigations KI and DeltaHbind were determined for several inhibitors. Bound herbicide structures were optimized and their intramolecular charge distributions were calculated. Experimental and calculated data were compared to those available from databank crystal structures. We can state that the herbicide inhibition efficiency depends on steric and electronic, i.e. geometry of binding with the protein and molecular charge distribution, respectively. Apolar bulky groups on N-7 atom of the inhibitor molecule (like t buthyl in terbutryn) are preferable for establishing stronger interactions with QB site, while such substituents are not recommended on N-8. The N-4,7,8 nitrogen atoms maintain a larger electron density so that more effective H-bonds are formed between the inhibitor and the surrounding amino acids of the protein. PMID- 25730901 TI - Bee venom inhibits growth of human cervical tumors in mice. AB - We studied whether bee venom (BV) inhibits cervical tumor growth through enhancement of death receptor (DR) expressions and inactivation of nuclear factor kappa B (NF-kappaB) in mice. In vivo study showed that BV (1 mg/kg) inhibited tumor growth. Similar inhibitory effects of BV on cancer growth in primary human cervical cancer cells were also found. BV (1-5 MUg/ml) also inhibited the growth of cancer cells, Ca Ski and C33Aby the induction of apoptotic cell death in a dose dependent manner. Agreed with cancer cell growth inhibition, expression of death receptors; FAS, DR3 and DR6, and DR downstream pro-apoptotic proteins including caspase-3 and Bax was concomitantly increased, but the NF-kappaB activity and the expression of Bcl-2 were inhibited by treatment with BV in tumor mice, human cancer cell and human tumor samples as well as cultured cancer cells. In addition, deletion of FAS, DR3 and DR6 by small interfering RNA significantly reversed BV-induced cell growth inhibitory effects as well as NF-kappaB inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-kappaB pathway. PMID- 25730902 TI - Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis. AB - Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between the different stages of tumor evolution in this patient emphasizes the importance of molecular profiling of metastatic tissue directing molecularly targeted therapy at recurrence. PMID- 25730903 TI - Identifying the determinants of response to MDM2 inhibition. AB - Previous reports have provided evidence that p53 mutation is a strong negative predictor of response to MDM2 inhibitors. However, this correlation is not absolute, as many p53Mutant cell lines have been reported to respond to MDM2 inhibition, while many p53WT cell lines have been shown not to respond. To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies. However, upon extensive curation of this panel, these apparent exceptions could be eliminated, revealing a perfect correlation between p53 mutational status and MDM2 inhibitor responsiveness. It has been suggested that the MDM2-amplified subset of p53WT tumors might be particularly sensitive to MDM2 inhibition. To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification. Applying this cutoff resulted in a pan cancer MDM2 amplification rate far lower than previously published. PMID- 25730904 TI - Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling. AB - O-glycosylation is a common protein modification. Aberrant O-glycosylation is associated with many cancers. GALNT1 is a GalNAc-transferase that initiates protein O-glycosylation. We found that GALNT1 is frequently up-regulated in hepatocellular carcinoma (HCC) and is associated with poor patient survival. Overexpression of GALNT1 increased and knockdown decreased HCC cell migration and invasion. Knockdown of GALNT1 inhibited EGF-induced migration and invasion. Knockdown of GALNT1 decreased EGFR activation and increased EGFR degradation, by decreasing EGFR O-glycosylation. This study demonstrates that down-regulation of GALNT1 is sufficient to suppress malignant phenotype of HCC cells by decreasing EGFR signaling. Thus, GALNT1 is a potential target in HCC. PMID- 25730905 TI - Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase. AB - Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase. PMID- 25730906 TI - Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer. AB - Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs. 13%, p = 0.024), progression-free survival (61% vs. 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs. 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice. PMID- 25730907 TI - Inhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR. AB - The epidermal growth factor receptor (EGFR) is a therapeutic target (oncotarget) in NSCLC. Using in vitro EGFR kinase activity system, we identified a novel small molecule, WB-308, as an inhibitor of EGFR. WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis. Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model). WB-308 impaired the phosphorylation of EGFR, AKT, and ERK1/2 protein. WB 308 was less cytotoxic than Gefitinib. Our study suggests that WB-308 is a novel EGFR-TKI and may be considered to substitute for Gefitinib in clinical therapy for NSCLC. PMID- 25730909 TI - [Cohort study]. PMID- 25730910 TI - [Immunotherapy with allergen]. PMID- 25730908 TI - Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. AB - Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox) inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma. PMID- 25730911 TI - A clinical minute: new management strategy for the treatment of deep partial thickness burns. PMID- 25730912 TI - [Children and adults with fever and exanthema]. AB - Patients with fever and rash/exanthema generally are "small emergencies", rarely needing emergency transport or intensive care in a hospital. Low experience of most parents and doctors (who never have seen Measles, Rubella or Varicella) result in non-necessary extensive laboratory tests (e.g. PCR in Meales), while looking for Koplik-Sport is even not mentioned in official guidelines. "Red flags" such as Petechia, Erysipela, necrotizing faszilitis or severe allergic reaction warrant, that "fever and exanthema" remains a permanent challenge for doctors on duty. PMID- 25730913 TI - Building a sustainable positive reputation for the Nigerian medical association]. PMID- 25730914 TI - Research sheds new light on deadly bat fungus. PMID- 25730915 TI - Academics lead group to advise government on antimicrobial resistance. PMID- 25730916 TI - Supports anesthesia for veterinary dental cleanings. PMID- 25730917 TI - Lead ammunition. PMID- 25730918 TI - Lead ammunition. PMID- 25730919 TI - Lead ammunition. PMID- 25730920 TI - Schedules of controlled substances: removal of naloxegol from control. Final rule. AB - With the issuance of this final rule, the Administrator of the Drug Enforcement Administration removes naloxegol ((5[alpha],6[alpha])-17-allyl-6-((20-hydroxy 3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol) and its salts from the schedules of the Controlled Substances Act (CSA). This scheduling action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. Prior to the effective date of this rule, naloxegol was a schedule II controlled substance because it can be derived from opium alkaloids. This action removes the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled substances, on persons who handle (manufacture, distribute, reverse distribute, dispense, conduct research, import, export, or conduct chemical analysis) or propose to handle naloxegol. PMID- 25730921 TI - International Conference on Harmonisation; S10 Photosafety Evaluation of Pharmaceuticals; guidance for industry; availability. Notice. AB - The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled "S10 Photosafety Evaluation of Pharmaceuticals.'' The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance outlines details on when photosafety testing is warranted and on possible assessment strategies; it should be read in conjunction with the ICH M3(R2) guidance, section XIV(14) Photosafety Testing. The purpose of the guidance is to recommend international standards for photosafety assessment and to harmonize such assessments that support human clinical trials and marketing authorization for pharmaceuticals. This guidance finalizes the draft guidance issued on February 4, 2013. PMID- 25730922 TI - Effective date of requirement for premarket approval for automated external defibrillator systems. Final rule. AB - The Food and Drug Administration (FDA or the Agency) is issuing a final order to require the filing of premarket approval applications (PMA) for automated external defibrillator (AED) systems, which consist of an AED and those AED accessories necessary for the AED to detect and interpret an electrocardiogram and deliver an electrical shock (e.g., pad electrodes, batteries, adapters, and hardware keys for pediatric use). PMID- 25730923 TI - Closed-circuit escape respirators; extension of transition period. Interim final rule. AB - In March 2012, the Department of Health and Human Services (HHS) published a final rule establishing new standards for the certification of closed-circuit escape respirators (CCERs) by the National Institute for Occupational Safety and Health (NIOSH) within the Centers for Disease Control and Prevention (CDC). The new standards were designed to take effect over a 3-year transition period. HHS has determined that extending the concluding date for the transition is necessary to allow sufficient time for respirator manufacturers to meet the demands of the mining, maritime, railroad, and other industries. Pursuant to this interim final rule, NIOSH will extend the phase-in period until 6 months after the date that the first approval is granted to certain CCER models. PMID- 25730924 TI - Schedules of controlled substances: temporary placement of three synthetic cannabinoids into schedule I. Final order. AB - The Administrator of the Drug Enforcement Administration is issuing this final order to temporarily schedule three synthetic cannabinoids (SCs) into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act (CSA). The substances are: (1) N-(1-amino-3-methyl-1-oxobutan-2-yl)-1 (cyclohexylmethyl)-1H-indazole-3-carboxamide ("AB-CHMINACA''); (2) N-(1-amino-3 methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide ("AB-PINACA''); and (3) [1-(5-fluoropentyl)-1H-indazol-3-yl](naphthalen-1-yl)methanone ("THJ-2201''). This action is based on a finding by the Administrator that the placement of these synthetic cannabinoids and their optical, positional, and geometric isomers, salts, and salts of isomers into schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, import, export, engage in research, or possess), or propose to handle these SCs. PMID- 25730925 TI - State Long-Term Care Ombudsman programs. Final rule. AB - The Administration on Aging (AoA) of the Administration for Community Living (ACL) within the Department of Health and Human Services (HHS) is issuing this final rule in order to implement provisions of the Older Americans Act (the Act) regarding States' Long-Term Care Ombudsman programs (Ombudsman programs). Since its creation in the 1970s, the functions of the Nursing Home Ombudsman program (later, changed to Long-Term Care Ombudsman program) have been delineated in the Act; however, regulations have not been promulgated specifically focused on States' implementation of this program. In the absence of regulation, there has been significant variation in the interpretation and implementation of these provisions among States. HHS expects that a number of States may need to update their statutes, regulations, policies, procedures and/or practices in order to operate the Ombudsman program consistent with Federal law and this final rule. PMID- 25730926 TI - [Individual approaches to monitoring and predicting rehabilitation recovery of stroke patients]. AB - The article based on the results of our own research shows the importance of the development of objective options for the individual forecast to recovery of stroke patients, and control of the rehabilitation process. MATERIAL AND METHODS: We examined 44 patients with stroke and 35 healthy volunteers as a control group. All patients and healthy volunteers underwent a neurological examination, neurophysiological testing, and extended neuropsychological survey. We evaluated the results of rehabilitation depending on the data obtained in the survey. The study had found that cognitive impairment reaching moderate severity can be regarded as a poor prognostic factor for recovery of hand function. The clear direct relationship was shown between the impaired hand (with decreased strength and agility) and severity of frontal-subcortical dysfunction, and visual-spatial disorders. We found that elongated latent periods of auditory evoked potentials, P300 latency prolongation (beyond the age norm) were inherent mainly for patients with moderate cognitive impairment with postural disorders and high risk of falls. These patients, according to our data, had almost no improvement of motor functions versus patients who had moderate cognitive impairment, in which the parameters of evoked potentials of the brain were within the age norm. CONCLUSION: Evoked potentials of the brain in conjunction with the results of the extended neuropsychological testing may be an objective indicator for prediction and possibly control of the dynamics of recovery of cognitive and motor functions in the rehabilitation of stroke patients. PMID- 25730927 TI - [The effectiveness of early rehabilitation of the patients presenting with ischemic stroke]. AB - In this paper we evaluate the clinical effectiveness of rehabilitation of 92 patients who survived after acute ischemic stroke and received the combined treatment with the use of transcranial magnetic stimulation (the study group, n=32). The first control group (n=30) included the patients given transcranial magnetic stimulation in the function of placebo (n=30) and the second control group was comprised of the patients who received low-frequency magnetic therapy (n=30). The course of transcranial magnetic stimulation (TMS) resulted in the significant regression of the locomotor deficiency in the patients of the study group compared with those in both control groups (chi2>3,8). In addition, a significant decrease in anxiety and depression was documented in the patients of the study group. Dynamics of these characteristics in the patients of the control groups group was significantly less pronounced (chi2>3,8). The well apparent improvement of the cognitive function evaluated with the help of the MMSE test was observed in the patients of the study group and control group 2, but this effect of transcranial magnetic stimulation was significantly more pronounced than that of low-frequency magnetic therapy (chi2>3,8). Transcranial magnetic stimulation significantly normalized cerebral hemodynamics on the side of the stroke-affected hemisphere and improved the daily activities of the patients. Studying the long-term results within 6 months after the onset of rehabilitation in the hospital environment, most patients rated their health with improving. The evaluation of long-term results of the treatment during the 6 month rehabilitation period demonstrated that the majority of the patients reported the marked improvement of their health status. PMID- 25730928 TI - [The combined application of enhanced external counterpulsation for the rehabilitation of the patients presenting with coronary heart disease]. AB - We have studied the influence of enhanced external counterpulsation (EECP) applied in the combination with gaseous carbon dioxide baths and infrared laser therapy on the dynamics of clinical and functional abnormalities in the patients presenting with coronary heart disease (CHD) including those after surgical myocardial revascularization. The study was conducted on 40 patients of whom 20 suffered from chronic coronary heart disease and FC II-III angina of effort and the remaining 20 ones presented with coronary artery disease following myocardial revascularization (including 5 patients six months after coronary bypass grafting (CBG) and 15 ones three months after translumbar angioplasty (TLAP) in the combination with stenting of the coronary arteries). The study demonstrated that EECP in the combination with gaseous carbon dioxide baths and infrared laser therapy produced anti-ischemic and antianginal effects, stimulated myocardial contractility, contributed to economization of the cardiac activity, increased exercise tolerance, myocardial and coronary reserves. These changes resulted in the improvement of both the psychological status and the quality of life of the patients. PMID- 25730929 TI - [The role of enteral oxygen-therapy in the correction of functional disturbances in the autonomic nervous system of the children presenting with chronic diseases of the respiratory organs]. AB - BACKGROUND: Vegetative dysfunction is observed in 60-90% of the children presenting with chronic respiratory diseases. Its timely identification and correction increases the effectiveness of the combined rehabilitative treatment of such patients. MATERIAL AND METHODS: The vegetative regulation was dynamically evaluated by the analysis of the heart rate variability in 95 patients presenting with bronchial asthma and chronic nonspecific lung diseases. The age of the patients varied from 7 to 16 years. Sixty children received the combined treatment including enteral oxygen therapy, the control group was comprised of 35 patients. RESULTS: The enteral oxygen therapy eliminated the vegetative disbalance in 80.0% of the children with bronchial asthma and in 88,0% of those suffering from chronic nonspecific lung diseases. The results of the spectral analysis of heart rate variability indicate that the total spectrum power (TSP) was significantly increased in the patients of the study group. This effect was accompanied by the restructuring of wave frequency ranges pointing out to the enhancement of the activity of the sympathetic-adrenal system. The integral index of adaptive reserves (AR) increased from 2.0+/-0,6 to 4.7+/-0,6 points (p<0.001) under the influence of enteral oxygen therapy; this parameter remained practically unaltered in the patients of the control group where it varied from 1.7+/-0,8 to 2.0+/-0,9 points (p>0.05). More manifest pronounced positive dynamics was observed in the patients presenting with initial vagotonia and the severe or moderate form of the disease. CONCLUSION: The present study has demonstrated the favourable influence of enteral oxygen therapy on the vegetative regulation mechanisms and the adaptive potential of the organism. Analysis of the heart rate variability may be a screening method for the evaluation of the effectiveness of the proposed therapeutic modality. PMID- 25730930 TI - [The economic analysis of the total cost of rehabilitation of the patients suffering from coronary heart disease]. AB - OBJECTIVE: To report the results of analysis of the economic efficiency of physical rehabilitation of the patients surviving after myocardial infarction with the use of physical exercises. MATERIAL AND METHODS: The study included 110 patients (mean age 58,3+/-9,8 years) who were randomized into two groups: the group where the patients were treated with the use of physical training (n=53) and the control group (n=57). The physical training included natural walking over the level ground at a speed corresponding to 60% of the maximum heart rate achieved during the initial 6 minute of the walking test. RESULTS: The results of the analysis indicate that the cost of the full course of medicamental therapy for the patients of the control group was 790.043,83 rubles higher than that for the patients treated with the use of physical exercises. The expenses for the instrumental and laboratory studies in the former group proved to be 142.776,8 rubles higher than in the latter. CONCLUSION: The inclusion of controlled physical exercises in the program in the rehabilitative treatment of the patients surviving after myocardial infarction makes it possible to achieve a higher quality of their life with the more favourable cost-benefit ratio compared with use of medicamental therapy alone. PMID- 25730931 TI - [Our experience with the application of the speleotherapeutic treatment based at the state healthcare facility "Republican Speleotherapeutic Hospital"]. AB - The non-medicamental therapeutic modalities find an increasingly wider application for the rehabilitation and maintenance of the health status in man. Speleotherapy is one of such methods. The Republican Speleotherapeutic Hospital of Belarus exploits the underground speleocomplex in which over 42,000 petients with respiratory diseases and allergic pathologies were given the required treatment. The clinical effectiveness of speleotherapy is estimated at 97.3%. Remission persists for 7.0+/-0.4 months on the average within one year after a course of speleotherapy. Repeated courses are followed by even longer periods of remission (up to 2.5-3 years). It is concluded that speleotherapy is the highly efficient method for the rehabilitation of the patients presenting with respiratory diseases and allergic pathologies. PMID- 25730932 TI - [The medical and psychological support for the child athletes during different periods of the training cycle]. AB - OBJECTIVE: To study dynamics of the indicators of the hormonal and psychological status as well as psychological features of significance for the sportive performance under conditions of rehabilitative treatment during training and post training periods in the child athlete engaged in rhythmic gymnastics. MATERIAL AND METHODS: The study included 42 child athletes at the age from 8 to 15 years engaged in rhythmic gymnastics. The children of the study group (group 1, n=17) received the combined restorative treatment under conditions of regular training while those comprising group 2 group (n=25) were given a similar treatment in the absence of the training load. All athletes underwent clinical and laboratory examination before and after the treatment for the assessment of their psychological status. RESULTS: The study has demonstrated that additional physical activities were responsible for the development of negative changes in the hormonal and psychological spheres of the child athletes. As a result, they experienced the impairment of certain qualities significant for their sportive performance. CONCLUSION: The rehabilitative measures during different periods of the training cycle promote normalization of all parameters of the hormonal, psychological, and physical status of the child athletes; moreover, they improve the adaptive capacity of the children. PMID- 25730933 TI - [Potentiation of the effect of peloid balneotherapy during the treatment of non specific pains in the lower back]. AB - The natural factors of the "Kluchi" resort are successfully used for the medical rehabilitation of the patients suffering from nonspecific pain in the lower back for a long time. The present comprehensive study of the painful psychovegetative status and the level of blood serotonin included 78 patients presenting with lumbar dorsopathy. After the course of the treatment based at the "Kluchi" health resort, the most significant improvement in the patient's condition was documented in the case of the combination of peloid balneotherapy with magnetic laser therapy and application of efthidermum MPE to the lumbar region. PMID- 25730934 TI - [The influence of pulsed low-intensity laser radiation of the red (635 nm) and infrared (904 nm) spectra on the human mesenchymal stem cells in vitro]. AB - INTRODUCTION: Mesenchymal stem cells (MSC) have for a long time been an object of investigation with a view to elucidating the prospects for their application in clinical medicine and cosmetology. One of the approaches to the non-specific regulation of the activity of these cells at the stage of preliminary in vitro combination is the treatment with low-intensity laser radiation (LILR). The objective of the present study was to evaluate the possibility of using pulsed LILR of the infrared and red spectra for this purpose. MATERIAL AND METHODS: We used the 4th passage adhesive MSC cultures based at the umbilical tissue of a donor who gave the informed consent to participate in the study. The source of illumination was a Lazmik-VLOK laser therapeutic apparatus (RU No RZN 2014/1410 dated 06.02.2014) with the matrix laser infrared radiation heads (wavelength 904 nm, light pulse length 108 ns, frequency 1500 Hz). The apparatus was operated either in the multi-frequency Lazmik regime [Moskvin S.V., 2014] with mean power density 0.05 and 0.14 mW/cm2 and the red spectrum (wavelength 635 nm, light pulse length 144 ns, frequency 1500 Hz) or in the multi-frequency Lazmik regime [Moskvin S.V., 2014] with mean power density 0.03 and 0.12. The exposition was 5 min in both regimes. CONCLUSION: The study has demonstrated that neither the morphological structure nor the viability of mesenchymal stem cells changed under the influence of energy and time parameters used in experiments. The number of cells was shown to slightly increase in comparison with control. The most pronounced effect was documented after illumination with pulse infrared (904 nm) LILR in the multi-frequency Lazmik regime. The maximum effect was observed during a period between days 1 and 3 of cultivation. PMID- 25730935 TI - [The determination of molecular sulphur in Matsesta mineral water and its analog Novonukutskaya mineral water]. AB - The method of microcolumn reversed phase high performance liquid chromatography (rp-HPLC) was employed to determine the content of elemental sulphur in mineral waters. The study envisaged the analysis of the samples of sulphide-containing mineral waters Novonukutskaya and Matsesta obtained by the solid phase extraction technique. Based on these data, the authors discuss the origin and the circulation of sulphur in the hydrogen sulphide sources. The elution conditions selected in this study ensured the high-resolution separation of the octasulphur peak from the peaks of allotropic components of the extract whereas the two-wave detection technique allowed to identify the peaks of molecular sulphur. PMID- 25730936 TI - [The targeted transport of the medicinal substances and the therapeutic physical factors]. AB - The present review describes the existing systems for the directed transport of the medicines to the target organs. The article presents the data on the use of the protein vectors, nanoparticles, artificial and natural containers for the targeted delivery of the pharmaceutical products. The potential applications of the physical factors for the directed transport of medicinal substances are considered. PMID- 25730937 TI - [Certain molecular effects of physical exercises]. AB - According to the current concept, therapeutic physical exercises provide a simple and efficacious tool for reducing the risk of development of cardiovascular diseases and their complications. The main beneficial effects of regular physical training include positive dynamics of atherogenesis and angiogenesis, improved rheological properties of blood, decreased left ventricular myocardial hypertrophy and re-modeling. The present review is focused on some of the modern views of the molecular mechanisms underlying the influence of therapeutic physical exercises on the above processes with special reference to the activation of nitrous oxide production, regulation of the functions of the progenitor cells, and stimulation of the resident stem cells in the myocardium. PMID- 25730938 TI - [The Karachi health resort: synthesis of science and practice]. AB - This article is devoted to the history of one of the oldest Siberian health resorts known as "The Karachi Lake". It describes the stages of its development, the scientific component of the system of spa-and-resort therapy and medico social rehabilitation of the patients. The detailed analysis of the mechanisms underlying the beneficial action of the natural therapeutic factors, cooperation with the leading research institutions, and the formation of the modern scientific and technical basis have strengthened the position of the resort on the market of the medical, health-promoting, and recreational services due to the development of the new activities in this field. PMID- 25730939 TI - [Knowledge of the management of dental trauma in southern Hungary]. AB - The aim of the study was to evaluate the knowledge of dental trauma management in the southern part of Hungary among parents, teachers, medical doctors and dentists. A cross-sectional study was performed among the mentioned groups, with a structured questionnaire. The participants consisted of 275 people, most of them were parents (185), the other groups were smaller (30-30). 73.62% of parents recognised that the maxillary incisor of a 9-year-old girl is probably a permanent tooth. In case of the coronal fracture of this tooth 65.03% responded correctly. The correct response rate for the management of an avulsed tooth was only 39.26%, but in case of loss of consciousness 92.64% would act correctly. The Chi-square test indicated that there was a significant association between the correct recognition of the type of incisor and higher education (p < 0.01), and the number of seen TDIs. The 76.7% of the parents was not satisfied with his knowledge about TDLs, and 74.9% was interested in more information. In our study the parents performed generally better compared to other studies, but compared to the other three groups their results were worse. The knowledge of the teachers and the doctors was almost equivalent. The dentist had the best results. The level of knowledge of dental trauma management was inadequate among parents, but the teachers and doctors should improve their knowledge too. We suggest that it's necessary to start educational campaigns among groups that could be the primary caregivers of traumatic dental injuries. PMID- 25730940 TI - [Clinical examination of the gingival effects of three glass ionomer restorative materials (GC Fuji IX GP, GC Fuji IX GP EXTRA es GC EQUIA)]. AB - The restoration of cervical abrasions, erosions or cervical carious lesions is still challenging because of their unpredictable adhesion and possible negative effects on the marginal plaque accumulation. The impact of three different glass ionomer cements (GIC) on the marginal gingiva and root sensitivity was studied. Furthermore, it was investigated in details, whether or not a recently developed light curing varnish (GC Coat - EQUIA) had any additional effect on the gingival tissue. A total number of 30 non-smokers with healthy gingiva having at least one cervical supra/paragingival abrasion/erosion/abfraction defects were enrolled in the present study. The cervical defects were randomly restored by using one of the three GIC and the gingival parameters were recorded and evaluated at baseline, 6 weeks and 6 months. According to our results root sensitivity were substantially decreased in all the three groups. Plaque scores were also reduced in all groups with the greatest improvement at the sites where the new varnish were applied. Although this improvement was not reflected by the gingival parameters, such as bleeding on probing and crevicular fluid flow, since both were slightly increased in the varnish group. However, neither the intra-group, nor the intergroup differences reached statistical significance. Consequently, the three investigated GIC did not significantly affect the gingival health, therefore they might serve as alternative for the treatment of such cervical lesions. Nevertheless, the new light cure varnish-coated GIC did not seem to be either clinically or statistical significantly more favorable. PMID- 25730941 TI - [The simultaneous appearance and treatment of diffuse maxilla and mandible cyst with autotransplantatum. Case report]. AB - The authors have observed 3 simultaneously but independently occurring cysts in the mandible and the maxilla at a 45 years old male patient. A plum sized follicular cyst around the non erupted maxillary # 23 canine and a bean sized follicular cyst around the mandibular # 33 tooth in residual retention and also an infectious, diffuse root cyst developed around the # 35 retained root was found in the mandibular corpus. The surgical extraction of the # 23, 33 residual retention canines, the # 35 retained root and the excision of the cysts were performed in intubation narcosis by two medical teams. For the filling up of the cyst cavities cortical cancellous bone blocks and particulated trabecular bone grafts were used harvested from the coxa. In the case of the infectious mandibular cyst the author's have also used local antibiotic perfusion. This complex therapy resulted in a successful recruitment within a short period of time. PMID- 25730943 TI - [In memoriam Professor Sol Silverman]. PMID- 25730942 TI - [Allergies to dental materials and effectiveness of treatment in the north eastern region of Hungary]. AB - The recognition and treatment of allergy is a great challenge for all fields of medicine. The high prevalence of allergic reactions to dental materials and the related financial burden of their treatment make investigation of this disease very important. Our investigation was carried out on patients assigned to our outpatient department for dental allergy test between 1996 and 1998. We determined the distribution of gender and age among the allergic patients in the examined population. We also studied the prevalence of allergic reactions to different dental allergens and the distribution of dental allergens. In a follow up study we determined the proportion of those patients, who were retreated in conformity with the results of epicutan tests and we followed up the positive effects of these treatments. We have found that dental allergy occurred five times more frequently in women (84%) than in men (16%) and the most affected age group was between 20 to 39 and 40-49 years (31%). Seventy-five percent of the patients suffered from a combination of metal and polymer allergy. The most frequent metal allergen was TEGDMA (triethylene glycol dimethacrylate) (49.7%). The suggested treatment plan was carried out in 63% of the allergic patients. The applied treatment was successful in 48% of these cases. We experienced that 48% of these patients got rid of their earlier signs and symptoms. PMID- 25730944 TI - [Investigation of a new treatment outcome index for tuberculosis]. AB - PURPOSE: To investigate a new treatment outcome index that may be useful in the Japanese tuberculosis surveillance system. OBJECTIVE AND METHOD: For sputum smear positive primary tuberculosis patients, we estimated (a) treatment completion rates at the end of the next year of registration, and (b) treatment completion rates within 1 year from starting treatment in cases in which >= 1 year of treatment are indicated. For (a), we estimated treatment completion rates for newly registered cases during 2009 in the Japanese tuberculosis surveillance system, specifically at Fukujuji Hospital, which has a highly specialized tuberculosis treatment unit. For (b), we estimated the above-mentioned cases as well as those of "A" Public Health Center. RESULT: (a): The treatment completion rate at the end of the next year of registration was estimated to be 88.7% for newly registered cases during 2009 in the Japanese tuberculosis surveillance system. Among 66 jurisdictions, the highest and lowest completion rates were 100% and 58.3%, respectively, with a standard deviation of 6.7%. For Fukujuji Hospital cases, the completion rate was 93.1%. (b): The treatment completion rate within 1 year from the start of treatment was estimated to be 76.4% for newly registered cases during 2009 in the Japanese tuberculosis surveillance system. Among 66 jurisdictions, the highest and lowest completion rates were 90.9% and 44.1%, respectively, with a standard deviation of 8.8%. For Fukujuji Hospital and "A" Public Health Center cases, the completion rates were 91.1% and 80.0%, respectively. CONCLUSION: As a new treatment outcome index, treatment completion rates within 1 year might be more accurate than the treatment completion rate at the end of the next year of registration. PMID- 25730945 TI - [A case of pulmonary Mycobacterium kansasii infection with pleural effusion, distinguished from pulmonary tuberculosis]. AB - A case of pulmonary Mycobacterium kansasii infection with pleural effusion is very rare. We report a case of pulmonary Mycobacterium kansasii infection with pleural effusion, distinguished from pulmonary tuberculosis. A 44-year-old man presented to a clinic with a productive cough, sputum, and loss of appetite for several months. Chest X-ray and chest computed tomography (CT) showed right pleural effusion, centrilobular nodules and infiltrative shadows with cavities in the bilateral lung fields. The direct smear examination showed positive acid-fast bacilli (Gaffky 5). He was referred to our hospital for suspected recurrent pulmonary tuberculosis. We started anti-tuberculosis drugs because pulmonary tuberculosis complicated with pleurisy was first suspected from the findings of high ADA level (78.6 IU/l) of the effusion and positive result of interferon gamma release assay (QuantiFERON TB-2G). But Mycobacterium tuberculosis and M. avium complex was not identified by the polymerase chain reaction method and the culture of the sputum was negative. At a later date, Mycobacterium kansasii was detected by sputum culture. The patient was diagnosed as pulmonary Mycobacterium kansasii infection and treatment with anti-tuberculosis drugs including RFP resulted in a good clinical response. This case was a rare case of pulmonary Mycobacterium kansasii infection with pleural effusion, distinguished from pulmonary tuberculosis. PMID- 25730946 TI - [The evaluation of the utility of QuantiFERON TB-Gold In-Tube; QFT-GIT]. AB - Four years has passed since QuantiFERON TB-Gold In-Tube (QFT-GIT), the third generation test, has replaced QuantiFERON-Gold in Japan. The QFT-GIT test detects interferon-gamma (IFN-gamma), which is released from lymphocytes present in blood after exposure to the M. tuberculosis complex antigens ESAT-6, CFP-10 and TB7.7. These proteins are absent from all Bacille-Calmette-Guerin (BCG) strains and from most non-tuberculosis mycobacteria, resulting in fewer false positive reactions as seen with the tuberculin skin test (TST). We had various experiences with QFT GIT during these four years. So, we discussed the usefulness and its limitation of QFT-GIT as follows: 1. Development of the principle of QuantiFERON-GIT: Nobuyuki HARADA (Research Institute of Immune Diagnosis (RIID)). QuantiFERON (QFT) was originated from diagnostic system for bovine in Australia. Although the first generation of QFT, in which PPD had been used as stimulating antigens, was approved in USA, its diagnostic value was not recognized in Japan where most of Japanese are vaccinated with BCG. By combining M. tuberculosis-specific antigens with QFT system, the second generation of QFT, QFT-Gold, was developed, and approved in Japan in 2005. QFT-Gold was soon incorporated in several guidelines such as contact investigations and nosocomial infection measures. Now, QFT-Gold was superseded by the improved QFT-Gold, the current QFT-GIT. However, since QFT GIT may contain unstable factors including blood volume and shaking methods of blood collection tubes, development of the more improved version is strongly expected. 2. Evaluating the result of QFT-GIT in patients treated with dialysis and immunosuppressive agents: Hidetoshi IGARI (National Hospital Organization Chiba-East National Hospital) The effectiveness of QuantiFERON TB-Gold In-Tube was analyzed in the patients with chronic kidney disease (CKD) and rheumatoid arthritis (RA). QFT positive was 7% and 11% respectively, and indeterminate was 5% and 2% respectively. QFT positive was 2% in hemodialysis patients, significantly lower than that of CKD. QFT positive after biological drug was administered was 8% in RA patients, significantly lower than 15% of RA without biological drug. The rate of latent tuberculosis patients in CKD was as well as health care workers (HCWs) of 8% of QFT positive. On the other hand that of RA might be higher than HCWs. Hemodialysis and biological drug administration might attenuate QFT result with lower rate of positive. The rate of indeterminate was less than 5%. This results was improved in compared with former generation QFT. 3. QFT in Vietnam: Naoto KEICHO (Research Institute of Tuberculosis, JATA). We have promoted collaborative research on tuberculosis with Vietnamese institutes since 2002. NCGM-BMH Medical Collaboration Center plays an important role in the clinical research projects. We report 1) quality assessment of QFT for tuberculosis infection, 2) prevalence and risk factors for tuberculosis infection among hospital workers, and 3) analysis of factors lowering sensitivity of QFT for active tuberculosis. We also discuss significance of QFT in developing countries. 4. Comparison of diagnostic performances using QFT Gold and Gold In Tube in patients with active tuberculosis: Tetsuya YAGI (Department of Infectious Diseases, Center of National University Hospital for Infection Control, Nagoya University Hospital). The goal of this study was to assess the diagnostic performances of QFT-GIT compared with QFT-Gold in patients with active tuberculosis in Nagoya University Hospital, in Japan. The sensitivity of QFT-Gold was 87.2%, the specificity of that was 77.5%. The sensitivity of QFT-GIT was 88.8%, specificity 73.2%. The performance of QFT-GIT was the same as that of QFT Gold. The QFT-GIT tended to show higher concentration values of IFN-gamma than that of QFT-Gold especially in patients with extra pulmonary tuberculosis, smear positive pulmonary tuberculosis, both lung lesion and using immunosuppressive medications. 5. Simultaneous and longitudinal comparison between QFT Gold and Gold In-Tube among health care workers; Tomoshige MATSUMOTO (Department of Clinical Laboratory Medicine, Osaka Anti-Tuberculosis Association Osaka Hospital. ex-Osaka Prefectural Medical Center for Respiratory and Allergic Diseases). The aim of this study was to compare the indeterminate rates between QFT-GIT and QFT Gold tests. And to make longitudinal comparison by QFT-Gold assay to the same HCW. We collected blood samples by simultaneously QFT-Gold and QFT-GIT from 120 staff members in the institute who participated in this prospective comparison study. Moreover, the latest QFT-Gold test was longitudinally compared for the same 55 staff members who have received QFT-Gold before. The statistically significant difference was observed in the results of indeterminate rate between QFT-Gold and QFT-GIT using the same blood samples. It is concluded that QFT-Gold and QFT-GIT are different assays therefore it is difficult to compare QFT-Gold with QFT-GIT data on the same level. Concerning the follow-up test of the 55 people by QFT-Gold, 5 turned from positive to negative and 4 turned from indeterminate to negative. From this analysis, QFT-Gold positive subjects in the previous time have not been always positive. 6. Interpreting QFT "equivocal" results: Kenji MATSUMOTO (Osaka City Public Health Office). The participants were examined QFT-GIT test after two months to four months from last contact of smear positive tuberculosis cases in contact investigations. We enrolled 79 contacts whose tests of QFT-GIT were equivocal results. The second QFT-GIT results were 42 negative (53.2%), 28 equivocal (35.4%) and nine positive (11.4%). 64% of the second QFT-GIT tests result in negative or positive among the first QFT-GIT equivocal contacts. When the second QFT-GIT tests were positive, it is highly probable that the contacts were infected tuberculosis and we adequately could treat latent tuberculosis infected contacts. PMID- 25730947 TI - [Experience of rapid drug desensitization therapy in the treatment of mycobacterial disease]. AB - BACKGROUND: Drugs for tuberculosis and non-tuberculosis mycobacterial diseases are limited. In particular, no new drugs for non-tuberculosis mycobacterial disease have been developed in recent years. Antimycobacterial drugs have many adverse reactions, for which drug desensitization therapy has been used. PURPOSE: Rapid drug desensitization (RDD) therapy, including antituberculosis drugs and clarithromycin, has been implemented in many regions in Europe and the United States. We investigated the validity of RDD therapy in Japan. PATIENTS AND METHOD: We report our experience with RDD therapy in 13 patients who developed severe drug allergy to antimycobacterial treatment. The desensitization protocol reported by Holland and Cernandas was adapted. RESULT: The underlying diseases were 7 cases of pulmonary Mycobacterium avium complex disease and 6 cases of pulmonary tuberculosis. Isoniazid was readministered in 2 (100%) of 2 patients; rifampicin, in 8 (67.7%) of 12 patients; ethambutol, in 4 (67.7%) of 6 patients; and clarithromycin, in 2 (100%) of 2 patients. CONCLUSION: In Japan, the desensitization therapy recommended by the Treatment Committee of the Japanese Society for Tuberculosis have been implemented generally. We think RDD therapy is effective and safe as the other desensitization therapy. We will continue to investigate the efficiency of RDD therapy in patients who had discontinued antimycobacterial treatment because of the drug allergic reaction. PMID- 25730948 TI - [Association between smoking and tuberculosis infection]. AB - PURPOSE: Several reports show smoking as a risk factor of tuberculosis (TB) infection, especially in prisoners, emigrants, the homeless, or people in areas where TB is endemic. These reports mostly used the tuberculin test to detect TB. However, there is no report evaluating smoking as a risk factor of TB infection among people coming into contact with TB with the use of the Interferon-Gamma Release Assays (IGRA) test. MATERIAL & METHOD: We compared TB infection in smokers and non-smokers who came into contact with TB infection by using the IGRA test. We retrospectively collected information about people coming into contact with TB who visited the Daiichi Dispensary from July 1, 2011 to June 30, 2012. They were divided into 2 groups (IGRA positive or negative) and smoking (present/past or never). RESULT: Out of 390 subjects who came into contact with TB examined, 229 were male and 161 were female. The mean age was 39.0 years, 98 were present smokers, 69 were past smokers, and 223 were never-smokers. There were 19 IGRA-positive and 371 IGRA-negative subjects. The IGRA positive rate was 4.9%. Out of 19 IGRA-positive subjects, 13 were smokers or ever-smoker (68.4%). Out of 371 IGRA-negative subjects, 154 cases were smoker or ever-smoker (41.5%). Smoking experience (present and past) was statistically significant in the IGRA positive group. There were no significant differences in sex, age, drinking habits, and level of contact. Multivariate analysis showed smoking was only one independent risk factor for being IGRA-positive (odds ratio 3.06, 95% confidence interval: 1.14-8.21, p = 0.027). DISCUSSION: Our results suggest that smoking experience in subjects coming into contact with TB is a risk factor for TB infection. TB cases in smokers are reported to be more severe and have delayed detection of disease. They are also more likely to infect those who come in contact with them. If TB source cases and their contacts are both smokers and co exist in a narrow and limited area, the contacts might be at higher risk of exposure to TB-contaminated air than non-smokers. PMID- 25730949 TI - [A case of antitubercular drug-induced toxic epidermal necrosis in a systemic lupus erythematosus patient during treatment for pulmonary tuberculosis]. AB - A 48-year-old woman, who had been suffering from systemic lupus erythematosus for one year and receiving steroid therapy, was admitted to our hospital because of pulmonary tuberculosis. The tuberculosis was treated with INH, RFP, EB, and PZA after having doubled the dose of steroid, but terminated three weeks later due to the appearance of erythema exsudativum multiforme. Treatment was resumed with PZA, SM, and LVFX after resolution of the eruption. However, the addition of INH to the regimen provoked a recurrence of the eruption, which progressed rapidly to toxic epidermal necrolysis (TEN). Steroid pulse therapy stopped progression of the TEN, and treatment for tuberculosis was resumed. Although the choice of drug was rendered difficult by other adverse reactions, the patient was able to complete her tuberculosis treatment with RFP, EB, and TH. INH was most likely to be the offending agent in this case. Eruptions induced by antitubercular drugs are often seen, but there are few reports of severe toxic epidermal necrolysis. PMID- 25730950 TI - [Considerations on uses of newly developed anti-tuberculosis drugs for multi-drug resistant tuberculosis]. AB - We, group of tuberculosis experts, made discussions over how to improve the quality of treatment of multidrug resistant tuberculosis using a newly developed anti-tuberculosis drug, and at the same time, how to prevent the disadvantages of the treated patients and also that of persons who would be infected with newly produced drug-resistant bacilli, by preventing the emergence of resistance to the new drug. A series of proposals are made. PMID- 25730951 TI - [Importance of monitoring the drug dosage and treatment duration for the management of tuberculosis patients at public health centers]. AB - PURPOSE: On the basis of actual field data, we investigated the importance of monitoring the drug dosage and treatment duration for the supportive care of patients with tuberculosis who were being treated at public health centers. PATIENTS & METHODS: Data of the drug dosage of principal anti-tuberculosis drugs and the treatment duration for the registered patients with tuberculosis at the Shinjuku-ku Public Health Center were analyzed. RESULTS: The actual dosage of rifampicin and isoniazid according to the "recommended" dosage was administered to 57.3% (67/117) and 82.0% (114/139), respectively, patients with tuberculosis registered at the Shinjuku-ku Public Health Center. In contrast, in patients with tuberculosis who were treated at a highly specialized tuberculosis hospital, the rates were 81.0% (98/121) and 93.5% (86/92), respectively; for both drugs, the rates were significantly higher in this hospital than in the Shinjuku-ku Public Health Center. For the treatment duration, of 92 patients registered at the Shinjuku-ku Public Health Center who could have completed standard treatment in the standard duration, the actual treatment durations were shorter than the standard duration in 15.2% of the patients (14/92; -32 to -1 days), and longer than the standard duration in 77.2% (71/92; 2 to 146 days); the total superfluous treatment days for the latter 71 patients were 1,877 days. The treatment durations were more than 2 weeks shorter or longer than the standard duration for 31 patients, and in 71.0% (22/31) of these patients, no specific reason could be determined as to why the treatment durations were not standard. CONCLUSION: In a significant number of patients, the drug dosage and treatment duration were not according to the standard values. By using this data about the management of the drug dosage and treatment duration for the supportive care of patients with tuberculosis treated at public health centers, we may improve quality of the provided supportive care. PMID- 25730952 TI - [Development of eosinophilic pneumonia in a patient with latent tuberculosis infection resulting from isoniazid]. AB - We report a 37-year-old patient with latent tuberculosis infection who received isoniazid (INH) antituberculosis chemoprophylaxis. However, he developed fever and productive cough 3 weeks after treatment. Chest radiography and computed tomography showed bilateral infiltrative shadows in upper fields. Bronchoalveolar lavage fluid revealed a high proportion of eosinophils, and histological examination of biopsied lung tissue showed interstitial thickening with eosinocyte infiltration. Based on these findings, the patient was diagnosed with drug-induced eosinophilic pneumonia. His febrile condition and dry cough resolved after discontinuation of INH. Chest X-rays showed improvement of infiltrative shadows. This case report highlights the potential for INH-induced pneumonitis during the course of antituberculosis chemoprophylaxis. PMID- 25730953 TI - [A young case of pulmonary tuberculosis with atypical tumor shadow on chest computed tomography and its difficulty in diagnosis]. AB - BACKGROUND: Diagnosis of pulmonary tuberculosis is usually made by diagnostic imaging such as chest X-ray or computed tomography (CT), and sputum test including smear and polymerase chain reaction (PCR) test. However there is difficulty in making diagnose when atypical imaging and negative sputum test are presented, followed by diagnostic delay. CASE: A 26-year-old man from Philippines consulted other clinic because of dry cough and was pointed out mass shadow in right upper lung field in his chest CT. He visited our office because of positive interferon gamma release assay, but repeated sputum test could not find tuberculosis. Bleeding from mass lesion failed to perform biopsy by bronchoscope, and we failed to find tuberculosis by smear and PCR test from bronchial brushing and wash. Transthoracic needle biopsy from his mass lesion revealed multiple non caseous granuloma, and lead to make a decision about starting medication. Four weeks later sputum culture from his first visit revealed positive, and diagnosis of tuberculosis was made. DISCUSSION: For avoiding therapy delay it is important to perform invasive diagnostic procedure including histological examination and clinical decision of starting medication, when conservative diagnostic procedure such as sputum test or diagnostic imaging present atypical finding for diagnosing tuberculosis. PMID- 25730955 TI - Is your staffing ratio appropriate for your case management model? AB - Case managers may be working longer hours and have more responsibilities to help their hospital comply with health care reform initiatives, but before rushing to the C-suite to ask for more staff, case management directors should take a hard look at the roles and responsibilities of the department, experts say. They recommend: Look at your staffing ratio and determine if it is appropriate for your case management model and if it is in line with staffing ratios at similar hospitals with similar models. Make a list of all the tasks that case managers are asked to do and break out those that don't affect outcomes or cost of care and those that don't require licensure. Get these assigned to other employees. Before you approach management to ask for more staff, do your homework and have hard data to back up your request. Consider hiring case management extenders to take over clerical tasks and free up case managers to work at the top of their licenses. PMID- 25730954 TI - [Tuberculosis annual report 2012--(3). Case finding and condition of tuberculosis on diagnosis]. AB - Tuberculosis (TB) case findings from 2012 nationwide TB surveillance data in Japan were reviewed for diagnosis delay, proportion of far-advanced cavitary lesions, coexisting human immunodeficiency virus (HIV) infection and diabetes mellitus (DM), and drug susceptibility'testing (DST). Among 21,283 new TB cases in 2012, 82.4% were detected when patients sought medical attention for TB symptoms or visited medical facilities for other chief complaints. Among 16,432 patients with pulmonary TB, 25.8% had only respiratory symptoms, 31.7% had both respiratory and non-respiratory symptoms, 16.7% had only non-respiratory symptoms, and 0.6% had unknown symptoms. The rest (25.2%) were asymptomatic. The proportion of patient and doctor delays among 12,197 symptomatic pulmonary TB cases was analyzed. A large proportion--approximately 25-30%--of patients aged 35 64 years with symptomatic pulmonary TB exhibited a patient delay of 2 months. Like patient delay, the proportion of patients with a total delay (i.e., the sum of the patient and doctor delays) of >= 3 months decreased after 55 years of age. Moreover, the proportion of patients aged >= 65 years with a doctor delay of >= 1 month was higher than patients aged < 65 years. A large proportion--approximately 30%--of patients with symptomatic smear-positive TB were < 60 years of age with a total delay of >= 3 months due to longer patient delays. Meanwhile, the proportion of patients-approximately 15%--with a doctor delay >= 1 month was relatively stable across all age groups. The proportion of patients with pulmonary TB with advanced lung cavities increased from 1.5% in 1975 to approximately 2% and remained stable from 1985 to 2007. From 2007 to 2012, 366 patients with HIV infection had newly notified TB, 314 (85.8%) and 52 (14.2%) men and women, respectively, including 76 (20.8%) non-Japanese patients. Newly notified TB cases with DM comprised 14.3% (3,036/ 21,283) of the total cases in 2012 : 16.4% (2,127/12,988) of men and 11.0% (909/8,295) of women. The surveillance system obtained DST results for 8,347 (74.1%) of 11,261 culture positive pulmonary TB cases in 2012. Among previously untreated cases, the proportions of patients with multi-drug resistant TB, any isoniazid resistance, and any rifampicin resistance were 0.5%, 4.0%, and 0.6%, respectively; the proportions in previously treated cases were 4.0%, 12.1%, and 4.7%, respectively. The proportions in previously untreated cases have remained stable for 6 years (2007-2012). PMID- 25730956 TI - Have data ready to back up your need for more staff, experts say. PMID- 25730957 TI - CM extenders can free up licensed staff to do what they do best. PMID- 25730958 TI - CM-physician alignment cuts length of stay. AB - When Sentara Healthcare enacted a pilot project in which a care coordinator was assigned to a hospitalist group and followed patients throughout the hospital stay, the average length of stay for patients in the program dropped by one day. One care coordinator was assigned to two to three hospitalists and had a caseload of 20 to 23 patients with pneumonia, sepsis, or heart failure and other patients determined to be at high risk. Care coordinators meet with hospitalists each morning to review patients likely to be discharged that day, meet again during multidisciplinary rounds, and communicate constantly during the day. Other initiatives include providing box lunches for patients discharged around noon and establishing a team of discharge facilitators in a central location to send referrals to post-acute providers and set up transportation. PMID- 25730959 TI - Case management insider. C-suite executives: the final frontier for hospital case management. AB - In order to sit at the table with your organization's leadership and make credible arguments and a sound business case for the resources you may need tomove your department forward, remember that you need to be as well versed as you possibly can be. Anecdotal thoughts and opinions will not get you the resources you need. Best practice information will be a much better tool for making the case and having it stick. With the changes that have been imposed by CMS and other regulatory bodies, the time has never been better for case management. Case management is one of the solutions to meeting the challenges to today's health care environment! PMID- 25730960 TI - An extra day in the hospital may prevent readmissions, reduce mortality. AB - When researchers at Columbia Business School reviewed Medicare records, they concluded that an extra day in the hospital decreases the readmission rate and mortality risk for some patients. They examined the charts of more than 6.6 million Medicare patients who were hospitalized for pneumonia, heart failure, or heart attack. They concluded that one more day in the hospital cuts the risk of readmission for heart failure patients by 7%. The extra day lowered the mortality rate for pneumonia and heart attack patients. PMID- 25730961 TI - Hospital's wellness program cuts health care costs by more than $5 million in five years. PMID- 25730962 TI - [The phosphorylation state of transducin beta-subunits]. AB - The supposition that nucleoside diphosphate kinase is the enzyme that phosphorylates transducin beta-subunits on one of the histidine residues (His 266) has been analyzed. It stands the reason that 1) this enzyme is multifunctional and plays in particular the role of protein histidine kinase; and 2) the phosphorylated beta-subunit of transducin may activate transducin via the mechanism of transphosphorylation. Nevertheless, in our experiments, in which different forms of transducin preparations were incubated with alpha- and beta isoforms of recombinant rat NDP kinase in the presence of [gamma32P]ATP or [gamma32P]GTP (specific activity of about 1 Ci/mmol) followed by separation of proteins by electrophoresis and-gel radio-autography, the phosphorylation of the transducin beta-subunit wasn't succeeded to be found. The negative result of our experiments most likely implies that the major part of transducin beta-subunits in the preparations has already been phosphorylated via a process that takes place in vivo. PMID- 25730963 TI - [Interaction of C60 fullerene-polyvinylpyrrolidone complex and brain Abeta(1-42) peptide in vitro]. AB - Using a spectrophotometric method changes occurring in solution containing brain Abeta(1-42)-peptide, fullerene C60, and polyvinylpyrrolidone were analyzed. Using the Bent-French method relative binding constants of fullerene C60 with Abeta(1 42)-peptide and polyvinylpyrrolidone with Abeta(1-42)- peptide were determined. These data suggest that Abeta(1-42)-peptide interacting with the C60 fullerene polyvinylpyrrolidone complex partially displaces polyvinylpyrrolidone and generates a new three molecular compound. PMID- 25730964 TI - [The influence of small doses of exogenic nitrite on oxidative modifications of water-soluble proteins of rat cardiac and skeletal muscle]. AB - The influence of small doses of exogenic nitrite on reversible and irreversible oxidative modifications of water-soluble proteins of rat cardiac and skeletal muscle was studied with the aid of redox 2D-electrophoresis and colorimetric determination of protein carbonyl group, correspondingly. To explain the absence of significant changes under hypoxia induced by nitrite the known hypothesis about nitrite inhibition of some sites of mitochondrial electron transporting chain decreasing free radical quantity was discussed. PMID- 25730965 TI - [Activation of bovine retinal rod outer segment cGMP-specific phosphodiesterase by the transducin-GTP complex in a physiologically significant range of free calcium ion concentrations]. AB - The kinetic behavior of cGMP-specific phosphodiesterase in a totally bleached bovine retinal rod outer segment suspension was studied by the pH-metric method at high and low concentrations of free calcium ions (~ 100 MUM and 10 nM, respectively). The phosphodiesterase was activated by low GTP concentrations (about 1-2 MUM) that were comparable with the concentration of G-protein transducin, its GTP-binding alpha-subunit was the intrinsic activator of photoreceptor phosphodiesterase. The results allow the suggestion that besides the earlier described system of RGS proteins, participating in the acceleration of GTP hydrolysis, rod outer segments also contain an additional Ca(2+)-dependent mechanism to inactivate so called "free transducin", i.e. active transducin that has not managed to interact with phosphodiesterase during the time, restricted by duration of photoreceptor response. PMID- 25730966 TI - [Impact of biologically important anions on reactive oxygen species formation in water under the effect of non-ionizing physical agents]. AB - The influence of biologically relevant anions (succinate, acetate, citrate, chloride, bicarbonate, hydroorthophosphate, dihydroorthophosphate, nitrite, nitrate) on the formation of hydrogen peroxide and hydroxyl radicals in water was studied under the effect of non-ionizing radiation: heat, laser light with a wavelength of 632.8 nm, corresponding to the maximum absorption of molecular oxygen, and electromagnetic radiation of extremely high frequencies. It has been established that various anions may both inhibit the formation of reactive oxygen species and increase it. Bicarbonate and sulfate anions included in the biological fluids' and medicinal mineral waters have significant, but opposite effects on reactive oxygen species production. Different molecular mechanisms of reactive oxygen species formation are considered under the action of the investigated physical factors involving these anions, which may influence the biological processes by signal-regulatory manner and provide a healing effect in physical therapy. PMID- 25730967 TI - [Functional interactions of Na,K-ATPase with molecular environment]. AB - The present review covers the analysis of research in the field of intermolecular interactions of Na,K-ATPase which underlie novel cellular regulatory mechanisms. The capability of Na,K-ATPase to form multimolecular regulatory complexes and take part as a scaffolding protein in formation of cell functional and signaling microcompartments is considered. Particular attention is directed to membrane lipid microdomains (rafts, caveolae). Mechanisms of signaling and neuroprotective functions of Na,K-ATPase as well as the involvement of endogenous cardiotonic steroids in their realization are discussed. This review demonstrates novel data on functional interactions of Na,K-ATPase with neurotransmitter receptors and other proteins involved in regulation of synaptic transmission. PMID- 25730968 TI - [Microtubular disrupter nocodazole and vesicular transport inhibitor brefeldin A attenuate the glutoxim effect on Na+ transport in frog skin]. AB - Using the voltage-clamp technique, a possible role of microtubules and vesicular transport in the effect of pharmacological analogue of oxidized glutathione, drug glutoxim, on Na+ transport in the frog Rana temporaria skin was investigated. It was shown for the first time that the disrupter of microtubules nocodazole or inhibitor of vesicular transport brefeldin A similarly modulate (completely inhibit) the stimulatory effect of glutoxim on Na+ transport. The data suggest the involvement of reorganization of microtubules and vesicular transport in the regulatory effect of glutoxim on Na+ transport. . PMID- 25730969 TI - [A role for calreticulin in functioning of mitochondrial ATP-dependent potassium channel]. AB - Homology of the amino acid sequence of the mitochondrial potassium-transporting protein (MW 57kDa), having the properties of a channel subunit of the mitochondrial ATP-dependent potassium channel, and calreticulin (MW 55kDa) was detected by MALDI-TOF-TOF analysis method. Inhibitory analysis of ATP-dependent potassium transport in mitochondria with polyclonal antibodies to calreticulin was carried out. A dose-dependent inhibition of potassium transport in mitochondria by these antibodies was shown. The maximum value of inhibition was 55-60%. Based on these data it is hypothesized that at least two types of ATP sensitive potassium channels are localized in mitochdndrial membrane. It is expected that the type of mitochondrial ATP-dependent potassium channel, which includes homologous calreticulin protein is localized mainly at mitochondrial and reticulum membrane contact sites. PMID- 25730970 TI - [The influence of spermine on Ca(2+)-dependent permeability transition in mitochondria and liposomes induced by palmitic and alpha,Omega-hexadecanedioic acids]. AB - The effect of spermine on Ca(2+)-dependent permeability transition in mitochondria and liposomes induced by palmitic and alpha,Omega-hexadecanedioic acid was studied. It has been shown that spermine inhibited the cyclosporin A insensitive mitochondrial swelling induced by palmitic acid and Ca2+ and alpha,Omega-hexadecanedioic acid and Ca2+. 100 MUM spermine did not influence the mitochondrial respiration in state V2 and the respiration stimulated by palmitic acid, alpha,Omega-hexadecanedioic acid and Ca2+. Pre-incubation of liposomes with 100 MUM spermine resulted in the inhibition of palmitic acid/Ca(2+)- and alpha,Omega-hexadecanedioic acid/Ca(2+)-induced release of the fluorescent dye sulforhodamine B from liposomes. At the same time, spermine added to fatty acids contained membranes of liposomes stimulated Ca(2+)-dependent release of sulforhodamine B from liposomes. It was shown that an addition of spermine to liposomes resulted in a significant increase in z-potential of liposomal membranes (from -39.8 mV to -18.6 mV). A possible mechanism of spermine influence on palmitic acid/Ca(2+)- and alpha,Omega-hexadecanedioic acid/Ca(2+)-induced permeability transition in mitochondria and liposomes is discussed. PMID- 25730971 TI - [Redox-dependent ferric oxide nanoparticles loaded with doxorubicin and their influence on the functions of mitochondria]. AB - The spectral, fluorescent and functional properties of ferric oxide and ferric hydroxide nanoparticles loaded with doxorubicin and stabilized with citric acid or lysine were studied in comparison with free doxorubicin. Their effect on the opening of calcium-induced mitochondrial pore and the possibility of the controlled release of doxorubicin under the influence of redox stimuli were investigated. The data show that the effect of nanoparticles on mitochondria depends on the type of a stabilizer. The spectral and fluorescence methods used allow us to estimate the presence or absence of free doxorubicin in solution of nanoparticles and the:concentration of bound doxorubicin. It is shown that the dithiotreitol and glutathione increase the amplitude of absorption and fluorescence of doxorubicin during incubation with nanoparticles. It is assumed that this effect may be associated with the reduction of the oxidized iron by thiols with subsequent release of doxorubicin. PMID- 25730972 TI - [Arp2/3 complex is involved in the effect of glutoxim and molixan on intracellular Ca2+ concentration in macrophages]. AB - The involvement of Arp2/3 complex, which causes actin filament branching, in the effect of drugs glutoxim and molixan was investigated. Using Fura-2AM microfluorimetry it was shown for the first time that Arp2/3 complex inhibitor CK 0944666 almost completely prevents the increase in intracellular Ca2+ concentration, induced by glutoxim or molixan in macrophages. The data suggest the involvement of Arp2/3 complex in the glutoxim and molixan effect on the Ca2+ signalling processes in macrophages. PMID- 25730973 TI - [Reorganization of actin cytoskeleton in the initial stage of transendothelial migration of bone marrow multipotent mesenchymal stromal cells]. AB - The analysis of actin cytoskeleton reorganization in rat bone marrow multipotent mesenchymal stromal cells after one hour adhesion to a monolayer of endothelial cell line EA.hy 926 allowed us to identify three types of cells interacting with the endothelial cells. Approximately half of multipotent mesenchymal stromal cells retained a rounded shape, most of them contained large round actin aggregates, had irregular borders and contacted with the surface of the endothelial cells by microvilli or protrusions similar to small lamellae. Almost all other cells were surrounded by narrow lamellae along the entire perimeter. In addition, a small amount.of elongated flattened cells that contacting with endothelial cells by means of focal contacts was observed. Microenvironmental factors such as proinflammatory cytokine tumor necrosis factor alpha or plasma proteins affected the ratio of stromal cell types, with different types of organization of the actin cytoskeleton in multipotent mesenchymal stromal cells population. PMID- 25730974 TI - [Simultaneous opposite axonal currents in neural process. Retraction hypothesis]. AB - Bidirectional axonal current of organelles and molecules in the nerve fibers was demonstrated using radioautography, the horseradish peroxidase and in virology. However, the mechanism of this phenomenon and regulation of the currents direction in axoplasm still remain not entirely understood. In this article we used the model of living single neurons of mollusk isolated with fragment of neural process at its different levels. It was proved that the axoplasm has a mechanical tone, which is realized in the form of retraction up to complete axoplasm invagination in the neuron soma. The geometry changing of the living axon was treated as its transport neuroplasm mass. It turned out that the direction of axoplasm mass depends on the location of its adhesion sites. It is always simultaneous and bidirectional opposite, as it is the case with contractile muscle fibers. PMID- 25730975 TI - [Specific molecular and morphological changes in cardiomyocytes of hibernating ground squirrels in different periods of annual cycle]. AB - Structural and molecular changes in cardiomyocytes of hibernating ground squirrels in different periods of the annual cycle were analyzed by means of electron microscopy and polymerase chain reaction. Morphological analysis showed an increase in relative area of sarcoplasmic reticulum in cardiac muscle of ground squirrels preparing to torpor compared to active summer animals. The size of sarcoplasmic reticulum in cardiomyocytes of torpid animals was reliably less than in any other condition of ground squirrels in the annual cycle. The results of molecular analysis showed the decrease in sarcoplasmic reticulum Ca(2+)-ATPase gene (SERCA2a) expression .at all stages of hibernation process and also in periods of autumn activity compared to control mRNA level in active summer animals. The revealed season changes in structure of sarcoplasmic reticulum and sarcoplasmic reticulum Ca(2+)-ATPase gene expression are discussed in regard to adaptation of ground squirrels to hibernation. PMID- 25730976 TI - [Involvement of phosphatidylinositol-4,5-bisphosphate binding proteins in the generation of contractile oscillations in the Physarum polycephalum plasmodium]. AB - Using the Physarum polycephalum, plasmodium, a giant amoeboid cell with the strongly pronounced auto-oscillatory mode of motility, which exhibits regularities of motile behavior common with those of tissue cells and has the same signal systems, the possibility of the participation of phosphatidylinositol 4,5-bisphosphate in the regulation of the contractile activity has been studied. The effect of neomycin as a substrate inhibitor of phospholipase C, which binds with high affinity to phosphatidylinositol-4,5-bisphosphate in the membrane, on force oscillations generated by plasmodial strands under isometric conditions and after the addition of the protein kinase C inhibitors staurosporine, UCN-01, and Ro-318220, separatelyand in combination with the calmodulin inhibitor calmidazolium has been examined. It has been shown that neomycin at pH 7.0 and concentrations of 0.1-5.0 mM stops contractile oscillations for 10-30 min but then they begin to gradually restore; the oscillation period at the initial stage of the restoration is.shorter than it was earlier and then increases due to the elongation of the contraction phase. Analysis of data obtained is in favor of the assumption that the plasmodial membrane contains MARCKS-like proteins and protein kinase C-controlled pools of phosphatidylinositol-4,5-bisphosphate, which can participate in the generation of auto-oscillations observed in the plasmodium. PMID- 25730977 TI - [The effect of uridine on the endurance of animals with different resistance to physical stress: the role of mitochondrial ATP-dependent potassium channel]. AB - The effect of a metabolic precursor of natural activator of mitochondrial ATP dependent potassium channel (mitochondrial K+(ATP))--uridine on animal's endurance to physical stress was studied. The endurance was determined by recording the time period during which the rat loaded with a plummet of 20% of body weight can swim until physical exhaustion at 32 degrees C. It was found that highly resistant animals swam until exhaustion for 7.40 +/- 0.35 min, whereas low resistant rats hold out 2.07 +/- 0.10 min only. The injection of uridine influenced the swimming time of the animals, increasing it twofold in low resistant rats. The effect of uridine was decreased by injection of inhibitors of mitochondrial K+(ATP) channel. It was found that the injection of uridine into low resistant rats increased the rate of potassium transport in mitochondria isolated from liver of these rats, and inhibitors of the channel prevent the channel activating effect of uridine. The role of mitochondrial K+(ATP) cannel in the formation of animal's resistance to physical stress and protection of tissues from hypoxia is discussed. PMID- 25730978 TI - [Nonspecific effect of Na+/K(+)-ATPase inhibition with strophanthin or under hypothermia in rat heart]. AB - Electron probe microanalysis was applied to study the kinetics of changes in potassium and sodium concentration in muscle cells of isolated heart from Wistar rat during experimental ischemia. Hypoxic perfusion without glucose was shown to evoke the potassium deficiency and sodium accumulation in cardiac myocells. Short term action (10 min) of strophanthin (0.1 mM/l) recovered Na/K balance in ischemic myocells. Hypothermic perfusion exhibited the opportunity to conserve the cytoplasmic elemental contents in the state corresponding to the beginning of low temperature (4 degrees C) operation. PMID- 25730979 TI - [A simple kinetic model of myocardium contraction: calcium-mechanics coupling]. AB - A kinetic model of cardiac muscle contraction is suggested. It is based on our earlier simplified model of the kinetics of the actin-myosin interaction. We examined the kinetics of formation of calcium-troponin complexes that open the binding sites-on actin for myosin heads. The model also takes into account the cooperativity of this process and the influence of myosin heads on it. It was shown that with proper choice of its parameters the model appropriately describes the dependence of myocardium activation.on sarcomeres length that underlies the Frank-Starling law of the heart. The model fits both steady state experiments on myocardial specimens with permeable membrane and twitch contractions of intact cardiac muscle. It also describes well the myocardium load-dependent relaxation. PMID- 25730980 TI - [Inotropic effect of a new probiotic product on myocardial contractility. Comparison with diazoxide]. AB - The inotropic effect of a new probiotic product on myocardial contractility of the frog Rana ridibunda and the effect of probiotic product on the rat cardiac mitochondria swelling were studied. In both cases, the comparison with known cardioprotector diazoxide was done. Probiotic product and diazoxide were shown to cause a dual effect on the maximum force induced by the muscle sample during spontaneous atrial contraction. Addition of agents caused a negative impact, while washing out exerted a positive inotropic effect. At the same time probiotic product has virtually no effect on the amplitude of contraction induced by electrical stimulation of the ventricle fragments. Probiotic product decreases both proton passive permeability in the inner mitochondrial membrane, and potassium active transport in mitochondria caused by activation of K(+)-uniporter of cardiomyocytes. A possible mechanism of action of probiotic product is discussed. PMID- 25730981 TI - [Comparison of force and shortening velocity in fast and slow rabbit muscle fibers at different temperatures]. AB - The temperature dependence of force, maximal shortening velocity and power of maximally activated single permeabilized fibers from fast and slow muscles of the rabbit were recorded in a temperature range from 10 to 35 degrees C with 5 degrees C step. It was found that temperature dependence of force of both types of fibers is identical. Averaged maximal shortening velocity in the slow fibers, unlike the fast fibers, had no statistically significant temperature dependence that is not in agreement with the data obtained on intact rat muscle fibers and in an in vitro motility assay. However maximal shortening velocity in each individual slow fiber did depend on temperature. The temperature dependence of power of the slow fibers was lower than that of the fast ones. Because of large data scattering the average temperature dependence of power of the slow fibers was significantly lower than that in individual slow fibers. PMID- 25730982 TI - [Modeling of disturbances in electrical and mechanical function of cardiomyocytes under acute ischemia]. AB - The effect of acute myocardial ischemia on the electrical and mechanical function of cardiomyocytes was studied in the framework of a mathematical model of a single cardiomyocyte. Acute ischemia consequences were simulated via a combination of two factors--a reduction of intracellular ATP concentration and an increase in extracellular potassium concentration, which affect the kinetics of ATP-sensitive potassium current and other potassium currents. In accord with experimental data, ischemic models produce action potential shortening and diastolic depolarization, which reduce contractile, ability of cardiomyocytes, Utilizing a 'difference-current integral' approach, we assessed quantitative contribution of ionic currents to changes in the action potential generation during ischemic injuries. It has been shown that an increase in the amplitude of inward rectifier potassium current I(K1) with increased extracellular potassium concentration has most essential contribution to the changes in the action potential duration under ischemia. PMID- 25730983 TI - [Desmin content and transversal stiffness of the left ventricle mouse cardiomyocytes and skeletal muscle fibers after a 30-day space flight on board "BION-M1" biosatellite]. AB - The aim of this study was to determine the transversal stiffness of the cortical cytoskeleton and the cytoskeletal protein desmin content in the left ventricle cardiomyocytes, fibers of the mouse soleus and tibialis anterior muscle after a 30-day space flight on board the "BION-M1" biosatellite (Russia, 2013). The dissection was made after 13-16.5 h after landing. The transversal stiffness was measured in relaxed and calcium activated state by, atomic force microscopy. The desmin content was estimated by western blotting, and the expression level of desmin-coding gene was detected using real-time PCR. The results indicate that, the transversal stiffness of the left ventricle cardiomyocytes and fibers of the soleus muscle in relaxed and activated states did not differ from the control. The transversal stiffness of the tibialis muscle fibers in relaxed and activated state was increased in the mice group after space flight. At the same time, in all types of studied tissues the desmin content and the expression level of desmin-coding gene did not differ from the control level. PMID- 25730984 TI - [Effect of vibrostimulation of foot and supporting afferentation on functional state of shin muscles in rats during hindlimb unloading]. AB - The goal of this work was to study the influence of daily 3-hr vibrostimulation of the supporting zones of the foot and 3-hr of usual locomotion on the functional state of the soleus, gastrocnemius, and tibial anterior muscles in rats after 7 and 14 days of hindlimb unloading. After 7 days of unloading the soleus weight decreased, while the weight of gastrocnemius and tibial anterior remained unchanged. After 14 days of hindlimb unloading a weight reduction was observed in all studied muscles. Vibrostimulation of the foot and supporting afferentation prevented the loss of weight in gastrocnemius and tibial anterior during the first week of unloading and reduced the negative effect of hindlimb unloading in 14 days. Our results demonstrate that the amplitude of the M response after 7 days of hindlimb unloading was decreased predominantly in soleus as compared to gastrocnemius and tibial anterior. By the 14 day we observed restoration of the amplitude of the M-response in gastrocnemius and tibial anterior, and the increased amplitude of the M-response in soleus. Different techniques for foot stimulation in rats during hindlimb unloading demonstrated the positive effect in regard to M-response restoration--the amplitude of the M response was increased in all studied muscles. Thus, our results demonstrate that foot vibrostimulation or supporting afferentation can completely prevent atrophy caused by hindlimb unloading in gastrocnemius and tibial anterior and decrease atrophy in soleus in rats. PMID- 25730985 TI - [Quantitative analysis of connective tissue matrix structure during myocardial remodeling]. AB - A new approach is proposed to quantify a contribution of connective tissue matrix to the myocardial structure. Also we introduced a new morphometrical criterion to estimate mean thickness of connective tissue fibers by histological section of isolated myocardial samples. The approach allows of correlating structural and functional changes in cardiac tissue by myocardium remodeling during pathology, age-related changes. PMID- 25730986 TI - [Computer simulation for localization and extensiveness of myocardial ischemia]. AB - Features of genesis of the electrocardiosignal in conditions of the myocardial ischemia under changing localization and extensiveness of the ischemia foci, as well as an impact of this process on the repolarization parameters of the electrocardiosignal were investigated using a system for 3D simulation of the heart electrical activity. The model of the ventricles of the heart is a cellular automaton with the matrix about of 10(5) elements of the "Myocardium", "His", and "Purkinje" types and with prescribed rules of their interaction. In process of the study a developed earlier method of segmentation of the modeled ventricles was used. For estimating the contribution of the "ischemic" segments to the total signal of different leads of the electrocardiograms the previously suggested method of the partial curves was used. The ischemia foci were simulated by changing the characteristics of the transmembrane action potential in selected areas of the ventricles, such as the resting potential, transmembrane action potential amplitude, duration of the plateau phase, and the steepness of the final phase of rapid repolarization in accordance with literature data. Electrocardiosignals generated by the model were processed to obtain previously selected parameters, characterizing repolarization process. The influence of size and localization of the myocardial ischemia on the parameters obtained are examined, as well-as some hypotheses about their relation with an electrophysiological state of the heart muscle are discussed. PMID- 25730987 TI - [Parameters of cardiac muscle repolarization on the electrocardiogram when changing anatomical and electric position of the heart]. AB - While discussing the diagnostic value of the single channel electrocardiogram a set of theoretical considerations emerges inevitably, one of the most important among them is the question about dependence of the electrocardiogram parameters from the direction of electrical axis of heart. In other words, changes in what of electrocardiogram parameters are in fact liable to reflect pathological processes in myocardium, and what ones are determined by extracardiac factors, primarily by anatomic characteristics of patients. It is arguable that while analyzing electrocardiogram it is necessary to orient to such physiologically based informative indexes as ST segment displacement. Also, symmetry of the T wave shape is an important parameter which is independent of patients anatomic features. The results obtained are of interest for theoretical and applied aspects of the biophysics of the cardiac electric field. PMID- 25730988 TI - [Effect of local hypothermia on H- and M-responses after spinal cord contusion in dogs]. AB - In this study we investigated a motor-neuronal functional state based on H- and M responses from m. quadratus plantae in dogs before and after experimental spinal cord contusion with and without following local intraoperative hypothermia. H- and M-responses from m. quadratus plantae were recorded during stimulation of the tibial nerve and results were compared between the groups. Our results demonstrate that local hypothermia applied after spinal cord contusion reduces amplitude of both M- and H-responses and also H(max)/M(max) ratio that may indicate depression of motorneurons excitability. After spinal cord contusion without following hypothermia the excitability of the spinal motorneurons during post-traumatic period, in opposite, was significantly increased. These results support a conclusion that intraoperative hypothermia after spinal cord contusion can delay development of functional excitability of the motoneurons and protect from further changes in H- and M-responses. PMID- 25730989 TI - [Main mechanisms of rhabdomyolysis-caused kidney injury and their correction by organospecific peptides]. AB - The influence of the organospecific peptides--kidney tripeptides T-31 and T-35, pineal tetrapeptide epitalon on the main mechanisms of kidney injury caused by experimental rhabdomyolysis--toxic injury of tubular cells, development of oxidative stress and energetic misbalance, leading to significant disturbances of the functional state of kidneys and development of acute kidney failure was studied. The renoprotective effect of oligopeptides realized by impact on all of the indicated mechanisms of kidney injury and confirmed by correlation between them was estimated. PMID- 25730990 TI - [Renoprotective effects of statins under the conditions of acute renal failure, caused by rhabdomyolysis]. AB - The experiment on white rats was targeted at the examination of influence of statins (atorvastatin, lovastatin, simvastatin) under the conditions of acute renal failure, caused by rhabdomyolysis. Renoprotective effects of statins were demonstrated by reduction of hyperazotemia and proteinuria and improvement of renal excretory function, which correlated with antioxidant properties of drugs. PMID- 25730991 TI - [The influence of acute hypoxia on motility of rats in the open field test under the conditions of an altered photoperiod]. AB - The influence of acute hypoxia on the motility of rats under the conditions of an altered photoperiod in the open field test was studied. Thus, keeping the animals in constant darkness after the modeling of acute hypoxia leads to the depression of locomotive and exploratory components of the behavior. At the same time the animals that were kept under the conditions of constant light show a change in the correlation between the components of motility after the action of hypoxia. PMID- 25730992 TI - [Artefacts of confocal microscopy]. AB - Typical artefacts caused by using confocal fluorescent microscopy while studying living cells are considered. The role of light scattering, mobility, staining, local concentrations, etc. is discussed. PMID- 25730993 TI - Vocal therapy of hyperkinetic dysphonia. AB - INTRODUCTION: Hyperkinetic (hyperfunctional) dysphonia is a common pathology. The disorder is often found in vocal professionals faced with high vocal requirements. OBJECTIVE: The objective of this study was to evaluate the effects of vocal therapy on voice condition characterized by hyperkinetic dysphonia with prenodular lesions and soft nodules. METHODS: The study included 100 adult patients and 27 children aged 4-16 years with prenodular lesions and soft nodules. A subjective acoustic analysis using the GIRBAS scale was performed prior to and after vocal therapy. Twenty adult patients and 10 children underwent objective acoustic analysis including several acoustic parameters. Pathological vocal qualities (hoarse, harsh and breathy voice) were also obtained by computer analysis. RESULTS: The subjective acoustic analysis revealed a significant (p<0.01) reduction in all dysphonia parameters after vocal treatment in adults and children. After treatment, all levels of dysphonia were lowered in 85% (85/100) of adult patients and 29% (29/100) had a normal voice. Before vocal therapy 9 children had severe, 13 had moderate and 8 slight dysphonia. After vocal therapy only 1 child had severe dysphonia, 7 had moderate, 10 had slight levels of dysphonia and 9 were without voice disorder. The objective acoustic analysis in adults revealed a significant improvement (p<=0.025) in all dysphonia parameters except SD FO and jitter %. In children, the acoustic parameters SD FO, jitter % and NNE (normal noise energy) were significantly improved (p=0.003 0.03). Pathological voice qualities were also improved in adults and children (p<0.05). CONCLUSION: Vocal therapy effectively improves the voice in hyperkinetic dysphonia with prenodular lesions and soft nodules in both adults and children, affectinq diverse acoustic parameters. PMID- 25730994 TI - Frequency and quality of root canal fillings in an adult Serbian population. AB - INTRODUCTION: Estimation of frequency and quality of root canal fillings is the way to evaluate endodontic treatment needs and success/failure rates of performed endodontic procedures. OBJECTIVE: The aim of this study was to determine the frequency and quality of root canal fillings and the frequency of apical periodontitis on endodontically treated teeth in a group of adult patients from Serbia. METHODS: In order to analyze the presence and quality of root canal fillings and the frequency of periapical radiolucencies on endodontically treated teeth, 3526 teeth were examined on orthopantomograms of 153 adult patients. RESULTS: Overall, 12.5% of examined teeth were root filled, and 51.8% of them had radiographic signs of apical periodontitis. The analysis of root fillings quality revealed the presence of more inadequate ones (55.9%). The frequency of apical periodontitis was significantly higher in teeth with inadequate than in those having adequate root canal obturation (72.2% and 25.9%, respectively). CONCLUSION: The frequency of apical periodontitis on root-filled teeth in this group of patients was high, indicating a low success rate of performed endodotic procedures and high endodontic retreatment needs. PMID- 25730995 TI - Eugenol-based temporary luting cement possesses antioxidative properties. AB - INTRODUCTION: Antioxidants protect against reactive oxygen species and expose beneficial anti-inflammatory activity when in contact with biological tissues. Dental materials that are used as temporary luting on fixed dental restorations are often in contact with injured gingival tissue, hence they should contain anti inflammatory characteristics that are essential after prosthetic procedures preceding cementation of final restauration. OBJECTIVE: The aim of this study was to investigate the antioxidant effect through the oxidation inhibition (OI) of mixed dental cement for temporary luting or their liquid component. METHODS: Eight study groups were prepared each by ten samples: 1) ex tempore preparation of zinc-oxide eugenol paste (Kariofil Z Galenika, Serbia), 2) Viko Temp paste (Galenika, Serbia), 3) Temp Bond NE paste (Kerr, Germany), 4) ScutaBond (ESPE, Germany), 5) Cp-CAP paste (Germany, Lege Artis) and oil component of 6) Kariofil Z, 7) Viko Temp and 8) Cp-CAP. The samples were subjected to spectrophotometer to measure OI 2,2'-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) (ABTS) using Randox kit, United Kingdom. The control samples were pure ascorbic acid (1% w/v). RESULTS: High values of OI exposed materials (groups 1, 5, 6, 7, 8) with content of eugenol (or its derivates) in the range of 100-88.8% were statistically more significant than the values of non-eugenol substances (groups 2, 3, 4) with the range of 8.2-43.5%. CONCLUSION: Eugenol containing temporary fixation materials show significant antioxidative properties and therefore they may be used in those clinical situations where surrounding gingival tissue is injured during restorative procedure. PMID- 25730996 TI - Surgical treatment results of carpal tunnel syndrome in patients with and without type 2 diabetes mellitus. AB - INTRODUCTION: Carpal tunnel syndrome (CTS) is the most commonly seen peripheral nerve compression syndrome and CTS surgery is the most common surgery done for peripheral nerve compression syndromes. Type 2 diabetes mellitus (DM) is a systemic disease with a component of peripheral neuropathy. OBJECTIVE: We aimed to investigate the effects of type 2 DM on functional results in type 2 DM patients who underwent carpal tunnel surgery. METHODS: The study included 39 patients with carpal tunnel syndrome which was confirmed by electromyography. Twenty-one patients did not have DM, 18 patients had type 2 DM that were treated for DM and had regulated blood glucose levels. Assessments were done with the Boston scale. All operations were done by the same surgical team using the same surgical technique. Functional and symptomatic scores between the two groups were compared with the Mann-Whitney U test which is the non-parametric version of the Student's t test, and 95% confidence interval p<0.05, which is considered as statistically significant. RESULTS: In patients with type 2 DM, preoperative mean Symptom Severity Score was 3.6+/-0.35 (2.9 to 4.2) in the last control mean Symptom Severity Score was 1.2+/-0.16 (1.0-1.7), and preoperative mean functional status score was 3.3+/-0.56 (2.3 to 4.5) and in the last control mean functional status score was 1.3+/-0.36 (1.0 to 2.4).The patients without DM, preoperative mean Symptom Severity Score was 3.5+/-0.45 (2.8 to 4.2) in the last control mean Symptom Severity Score was 1.2+/-0.19 (1.0 to 1.6), and preoperative functional status score was 3.2+/-0.47 (2.4 to 4.6) in the last control mean functional status score was 1.3+/-0.35 (1.0 to 2.5). There was no statistically significant difference between the two groups. CONCLUSION: Type 2 DM patients with regulated blood glucose levels can be operated without additional procedure during and after surgery for carpal tunnel syndrome like in carpal tunnel syndrome patients without DM. PMID- 25730997 TI - [Parapneumonic effusions: features, diagnostics and treatment options]. AB - INTRODUCTION: Parapneumonic effusions, as a complication of inflammatory processes in the lungs, usually have a good course, but they sometimes progress into pulmonary empyema, thus becoming a significant clinical problem. OBJECTIVE: To review clinical and radiological features, as well as diagnostic and therapeutic options in parapneumonic effusions. METHODS: The analysis included 130 patients with parapneumonic effusions hospitalized at the General Pulmonology Clinic of the Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica during 2013. RESULTS: Of 385 patients with pneumonia, 130 (33.8%) had parapneumonic effusion, 78 (60.0%) of whom were males. Most patients (361; 27.7%) were 60-69 years of age. The most common symptoms included fever (92; 70.8%) and cough (91; 70.0%). Hypertension was the most common comorbidity registered in 81 (62.3%) patients, and chronic obstructive pulmonary disease present in 33 (25.4%) patients. Pleural puncture was performed in 62 (47.7%) patients. Macroscopically, effusion was clear in most cases (31; 50.0%), and cytologically the mixed type was most frequently established (26; 41.9%). Bronchoscopy was performed in 52 (40.0%) patients, and video-assisted thoracoscopy in 9 (6.9%) patients. Empyema signs were registered in 13 (10.0%) patients; in all a thoracic drainage with administration of intrapleural streptokinase was performed. CONCLUSION: Patients with a parapneumonic effusion have the symptoms of acute respiratory infection and frequent concomitant diseases. Further diagnostic and therapeutic treatment depends on pleural fluid features and chest CT finding. PMID- 25730998 TI - Cost-effectiveness analysis of different types of labor for singleton pregnancy: real life data. AB - INTRODUCTION: Views on the conduct of labor have changed over time, and a significant difference exists in relation to obstetric centers. OBJECTIVE: To assess cost, clinical outcomes and cost-effectiveness of different types of labor in singleton pregnancies. METHODS: A decision model was used to compare vaginal labor, induced labor and planned cesarean section. All data were taken from the Book of Labor from the University Hospital for Gynecology and Obstetrics "Narodni Front", Belgrade, Serbia for labors conducted during one month period in 2011. Successful delivery (i.e. labor that began up to 42 gestation weeks, without maternal mortality and the newborn Apgar scores greater than or equal to seven in the fifth minute of life) was considered as the outcome of the cost effectiveness analysis. To test the robustness of this definition probabilistic sensitivity analysis was performed. RESULTS: From a total of 667 births, vaginal labor was conducted in 98 cases, induced vaginal in 442, while planned cesarean section was performed 127 times. Emergency cesarean section as a complication was much higher in the vaginal labor cohort compared to the induced vaginal cohort (OR=17.374; 95% CI: 8.522 to 35.418; p<0.001). The least costly type of labor was induced vaginal labor: average cost 461 euro, with an effectiveness of 98.17%. Both, vaginal and planned cesarean labor were dominated by the induced labor. The results were robust. CONCLUSION: Elective induction of labor was associated with the lowest cost compared to other types of labor, with favorable maternal and neonatal outcomes. PMID- 25730999 TI - Adequate weight gain in pregnancy: an analysis of its determinants in a cross sectional study. AB - INTRODUCTION: Prenatal care is considered an important tool for promoting a healthy lifestyle, but has not been studied as a predictor for maternal weight gain during pregnancy, especially in Romania, where evidence about pregnancy and nutrition is scarce. OBJECTIVE: This study has aimed to explore the relationship between pre-gestational body mass index (BMI), adequacy of prenatal care and weight gain during pregnancy. METHODS: We carried a cross-sectional study on a sample of 400 pregnant women admitted at the "Cuza Voda" Obstetrics and Gynecology Hospital in Iasi. Information regarding demographic characteristics, number of prenatal visits, date of the initial hospital record, nutritional education during pregnancy were registered throughout a questionnaire filled out by means of a direct interview. The anthropometric indicators analyzed were the pre-gestational BMI and the pregnancy weight gain. Data on caloric intake were obtained using a food frequency questionnaire. RESULTS: Weight gain within the limits of the Institute of Medicine recommendations was noticed at 44.35% of the women who declared that they received nutritional advice compared to 40.7% of those who did not receive advice regarding diet during pregnancy. Overweight (53.1%) and obese women (66.7%) had a larger weight gain than those with a normal pre-pregnancy BMI (29.8%) (p<0.001). The variables that were identified with an effect on weight gain in this sample of pregnant women were: inadequate prenatal care, pre-gestational BMI and energy intake. CONCLUSION: Identifying the pre gestational BMI and diet changes as predictors of weight gain underline the importance of an individualized prenatal care. PMID- 25731000 TI - Experience with lamivudine treatment for severe acute hepatitis B. AB - INTRODUCTION: Experience with lamivudine treatment for acute severe hepatitis B is limited. Fulminant hepatitis develops in 1% of immunocompetent patients with acute hepatitis B. OBJECTIVE: The aim of this study was to evaluate the efficacy of lamivudine in the treatment of severe acute hepatitis B (SAHB) in immunocompetent adult patients. METHODS: Between January 2006 and May 2013 at the Clinic for Infectious Diseases Banja Luka, 13 patients with SAHB were treated with lamivudine at a dose of 100 mg per day. All 13 patients fulfilled at least two of three default criteria: 1. hepatic encephalopathy; 2. total bilirubin greater than 210 MUmol/L; and 3. severe coagulopathy (international normalized ratio--INR >=1.5 or prothrombin time--PT <40%). The criteria were defined according to the experiences reported in the study of Schmilovitz-Weiss et al. "Lamivudine treatment for severe acute hepatitis B". Nine patients had a rapid rise in the total bilirubin and decrease of alanine aminotransferase level, which escalated risk for development of fulminant hepatitis. RESULTS: Within 1-6 months, HBsAg was undetectable in 12 of 13 examined patients. Protective anti HBsAg developed in 10 of them during 2-14 months. Two patients did not develop protective antibodies, but the result of the analysis of PCR HBV DNA was repeatedly negative. Corticosteroids were shortly used in two patients. One patient died four days after starting the therapy. Lamivudine treatment was well tolerated by all patients. CONCLUSION: Early treatment with lamivudine can reduce the risk of progression to fulminant hepatitis in patients with SAHB. PMID- 25731001 TI - Identification of Campylobacter species isolates with phenotypic methods and polymerase chain reaction. AB - INTRODUCTION: Campylobacter jejuni (C. jejuni) and Campylobacter coli (C. coli) are the most common bacterial causes of enterocolitis in humans. However, identification of the species level is not always possible using standard biochemical tests. OBJECTIVE: Therefore, the goal of this study was to identify these microorganisms by both phenotyping and polymerase chain reaction (PCR) technique. METHODS: A total of 153 species of thermophilic campylobacters were examined with standard biochemical tests and PCR technique to prove hipO genes of C. jejuni and asp genes of C. coli. RESULTS: Standard biochemical tests enabled the speciation of 121 strains of C. jejuni, while application of PCR detected 126 C. jejuni strains. CONCLUSION: PCR technique allowed not only identification of hippurate-positive C. jejuni, but also hipurat-negative strains of C. jejuni which otherwise would be detected as C. coli if only biochemical tests were applied. PMID- 25731002 TI - Spinal metastasis of medulloblastoma in adults: a case report. AB - INTRODUCTION: Medulloblastoma is a primitive neuro-ectodermal malignant tumor most commonly seen in childhood and rarely and uncommonly in adult age. Treatment consists of surgery followed by radiotherapy. In the case of a relapse there is no overall accepted treatment. Tumor metastasis can be seen along the neural axis, lymph nodes, soft tissues, bones and distant organs. CASE OUTLINE: In this paper we present a 45-year-old female patient with a thoraco-spinal extramedullary metastatic medulloblastoma and progressive neurological deterioration seen 11 months after the first operation and description of magnetic resonance and intraoperative finding. CONCLUSION: Although rare, the presence of metastasis is a poor prognostic factor. The treatment options for patients with metastases are limited and their prognosis continues to remain poor. PMID- 25731003 TI - Retinal detachment in the eye with the choroidal coloboma. AB - INTRODUCTION: Choroidal coloboma is a congenital defect caused by an inadequate closure of embryonic fissure. About 40% of the eyes with the choroidal coloboma (CHC) develop the retinal detachment (RD). It is extremely difficult to manage these cases due to the lack of pigmentation at the site of choroidal coloboma. OUTLINE OF CASES: This is a case series of five patients with CHC and RD who were successfully operated using one of two different surgical techniques: pars plana vitrectomy (PPV)+silicone oil internal tamponade and/or scleral buckle with encircling band with laser photocoagulation (SB+EB+LPC) around the coloboma. The purpose of this paper is to present how to successfully handle patients with CHC, who have concurrent retinal detachment in the same eye and to compare two different techniques and indications for the predominant use of one of them in a specific case. CONCLUSION: Both surgical techniques can be applied with equal success in the operation of retinal detachment in eyes with the chorioidal coloboma. Which one will be used depends only of the posterior segment of eye findings. We use scleral buckling in cases with RD accompanied by CHC when the peripheral break is evident and there are no breaks in the coloboma itself. We also perform, 2-3 days after surgery, laser burns around the coloboma, which is our modification of this technique. In all other cases it is indicated to perform PPV+silicon oil internal tamponade. PMID- 25731004 TI - Pedunculated obstructive lipoma of the ileocecal valve: a case report. AB - INTRODUCTION: Colonic lipomas are relatively common but they rarely progress to complete acute obstruction. CASE OUTLINE: We report a case of a 67-year-old woman with acute intestinal obstruction caused by a large pedunculated lipoma of the ileocecal valve. Preoperatively, the patient presented acutely with clinical and radiographic signs of small intestine ileus. A right hemicolectomy with subsequent terminolateral ileocolostomy was performed.The histopathological examination revealed a benign lipoma of the ileocecal valve which telescoped into the cecum and caused ileocolonic intussusception. The postoperative course was uneventful and the patient was free of symptoms during a 12-month follow-up period. CONCLUSION: Since these benign tumors are frequently revealed by laparotomy and the definitive diagnosis is made on the basis of histopathological examination, we can conclude that extensive resections of the large intestine are justified in cases with acute clinical presentation. PMID- 25731005 TI - Dysfunctional ectopic thyroid gland: a case report. AB - INTRODUCTION: Lingual thyroid gland is a rare anomaly of thyroid gland development, occurring more frequently in females. If it causes local symptomatology such as dysphagia, dysphonia or dyspnea it is diagnosed in childhood, however, if it is asymptomatic it is usually diagnosed in adulthood. CASE OUTLINE: We present a 23-year-old female patient in whom we diagnosed lingual thyroid gland coincidentally during diagnostic procedures of a concomitant disease. The application of 131I scintigraphy showed an oval field of intensive accumulation of radio markers in the zone of medial face line, around tongue base, with the absence of thyroid gland in its physiological position. Functional testing proved primary hypothyroidism and we started the application of substitution therapy. The application of levothyroxine resulted in reaching euthyroid state and the reduction of thyroid gland size. CONCLUSION: We present a very rare anomaly of the thyroid gland, and so far there have been no clear attitudes about further treatment. The general condition of the patient, age, the size of ectopic thyroid gland and the existence of local symptomatology or complications represent the factors that have influence on the choice of treatment method. PMID- 25731006 TI - Low estriol levels in the maternal marker screen as a predictor of X-linked adrenal hypoplasia congenita: case report. AB - INTRODUCTION: X-linked adrenal hypoplasia congenita (AHC) is a rare cause of adrenocortical insufficiency. Early postnatal diagnosis may prevent severe hypoglycemia, Addisonian crises and death. Low maternal estriol (E3) levels in the second trimester of pregnancy could indicate the possibility that the fetus suffers from a disorder that causes adrenal insufficiency. Suspicion is based on the fact that E3 originates from dehydroepiandrosterone (DHEA) synthesized in the fetal adrenals. In case of adrenal insufficiency, the impaired production of fetal DHEA leads to a subsequent reduction of E3 concentrations in maternal serum. There are only a few reports of AHC suspected prenatally due to low maternal E3 levels. CASE OUTLINE: We describe two brothers with adrenal insufficiency due to AHC. The older brother was admitted to the hospital at the age of 33 days due to failure to thrive, vomiting, and dehydration. Genetic analysis revealed a hemizygous mutation in DAX-1 gene, thus confirming the diagnosis of ACH. The same mutation was detected in his mother. In the second pregnancy, E3 concentrations were determined from maternal serum. Estriol levels during the second trimester were extremely low suggesting the diagnosis of AHC. The diagnosis was confirmed during the neonatal period by genetic testing, and replacement therapy was started at the age of 10 days. This boy never experienced an adverse episode such as hypoglycemia or adrenal crises. CONCLUSION: Since determination of E3 is a simple, sensitive, noninvasive and cheap method, its use as an obligatory prenatal screening test should be accepted as a standard practice in Serbia. PMID- 25731007 TI - Oligomeganephronia: case report and literature review. AB - INTRODUCTION: Oligomeganephronia (OMN) is one of rare congenital kidney disease. The number of nephrons reduces and the volume of glomerulus increases. The incidence of OMN is uncertain because it is difficult to diagnose. There are no any special clinical manifestations of OMN. Renal pathology is the only way to diagnose OMN, so missed diagnosis always happens without renal pathology. CASE OUTLINE: A 26-year-old male was diagnosed OMN associated with proteinuria and increased serum creatinine. The size of both kidneys on ultrasound was smaller than normal. Pathological features involved a reduced number of greatly enlarged glomeruli indicating OMN. CONCLUSION: OMN is a rare disease and it has been rarely reported. The exact mechanism is not clear. The diagnosis mainly depends on pathological findings. For patients with OMN, proteinuria and renal dysfunction are often the main cause to visit a doctor. Early diagnosis is important. PMID- 25731008 TI - Case report of acute vitamin D intoxication in an infant. AB - INTRODUCTION: Vitamin D intoxication represents a rare and potentially serious pathological condition caused by the excess of calcium and phosphorus. We are presenting an infant with vitamin D intoxication due to excessive daily administration, as well as therapeutic procedures that prevented its adverse effects. CASE OUTLINE: A 1.5-month-old female infant, born at term, exclusively breastfed and without any complaints and abnormalities of physical findings, was observed due to the data that during the preceding month, by her mother's mistake, she had received about 200,000 IU of vitamin D3. Laboratory analyses showed a high serum level of 25(OH)D (>400 nmol/L) and calcium (2.72 mmol/L), lowered PTH (6.6 pg/ml) and high urinary calcium/creatinine ratio (1.6), while other findings, including urotract ultrasonography image, were within normal limits. Treatment based on the discontinuation of vitamin D administration, infant's forced water intake, as well as the application of 2-month prednisolone and 4-month phenobarbitone and furosemide, resulted in complete normalization of the laboratory indicators of vitamin D overdose, as well as the prevention of its adverse effects. CONCLUSION: By timely recognition and adequate treatment, including triple therapy with prednisolone, phenobarbitone and furosemide, adverse effects of acute vitamin D intoxication can be prevented. PMID- 25731009 TI - [Inflammatory mechanisms in nasal polyposis]. AB - Nasal polyposis is a chronic inflammatory disease of the nasal and paranasal sinuses mucosa, characterized by prolapse of edematous mucosa, most commonly from the area of anterior ethmoid. The mean histological characteristics are proliferation of pseudostratified respiratory epithelium, thickening of the basement membrane, focal fibrosis and eosinophilic and lymphocytic infiltration of the lamina propria. Although etiology is unknown, two hypotheses are dominant among the scientists: "hypothesis of staphylococcal superantigens" and "hypothesis of immune barrier dysfunction". Although we have not yet achieved a full understanding of the precise mechanisms underlying the pathogenesis of this disease, it is known that nasal polyposis is associated with intensive chronic inflammation, followed by dysregulation of chemotaxis, migration, activation and function of eosinophils. A great number of cytokines, chemokines, and adhesion molecules are involved in the regulation of these complex mechanisms. After activation, eosinophils produce and release enzymes, which can lead to the damage of mucosa and tissue remodeling. Hyperactive eosinophils release a new amount of chemokines and cytokines, attracting new eosinophils into the site of inflammation, and may cause the persistence of chronic inflammation. PMID- 25731010 TI - [Congestive heart failure in patients with chronic kidney disease]. AB - Cardiovascular disorders are the most frequent cause of death (46-60%) among patients with advanced chronic renal failure (CRF), and on dialysis treatment. Uremic cardiomyopathy is the basic pathophysiologic substrate, whereas ischemic heart disease (IHD) and anemia are the most important contributing factors. Associated with well-know risk factors and specific disorders for terminal kidney failure and dialysis, the aforementioned factors instigate congestive heart failure (CHF). Suspected CHF is based on the anamnesis, clinical examination and ECG, while it is confirmed and defined more precisely on the basis of echocardiography and radiology examination. Biohumoral data (BNP, NT-proBNP) are not sufficiently reliable because of specific volemic fluctuation and reduced natural clearance. Therapy approach is similar to the one for the general population: ACEI, ARBs, beta-blockers, inotropic drugs and diuretics. Hypervolemia and most of the related symptoms can be kept under control effectively by the isolated or ultrafiltation, in conjunction with dialysis, during the standard bicarbonate hemodialysis or hemodiafiltration. In the same respect peritoneal dialysis is efficient for the control of hypervolemia symptoms, mainly during the first years of its application and in case of the lower NYHA class (II degrees /III degrees ). In general, heart support therapy, surgical interventions of the myocardium and valve replacement are rarely used in patients on dialysis, whereas revascularization procedures are beneficial for associated IHD. In selected cases the application of cardiac resynchronization and/or implantation of a cardioverter defibrillator are advisable. PMID- 25731011 TI - The renin-angiotensin system and its blockers. AB - Research on the renin-angiotensin system (RAS) has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE) metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS) and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well. PMID- 25731012 TI - [Inadequate burials as an important factor in plague epidemic amongst Serbs in the Habsburg monarchy by the end of the 18th century: a historical analysis]. AB - Analysis of the archaic customs of burying the deceased in Srem, primarily amongst Serbs, in the second half of the 18th century is the essential part of the paper that aims at clarifying the consequences of this negative habit onto the spreading of plague epidemic. The Austrian Empire tried to stop and prevent the epidemic with an array of legal norms, but in practice, these orders were often not upheld. Serbian Metropolitans Pavle Nenadovic and Stefan Stratimirovic insisted on eradicating superstition and retrograde, often uncivilized actions in burial rituals, and they partially succeeded. The example of plague in Irig and the surroundings in 1795-1796 explicitly shows the hazardous effects of the inadequate attitude towards the deceased as one of the factors in spreading the epidemic. Using primary archives, and published sources, with adequate literature, authors depict this complex historical process. PMID- 25731013 TI - [Contribution of pharmacists to the development of healthcare culture in Vranje by the end of the 19th century and in the first half of the 20th century]. AB - INTRODUCTION: Healthcare enlightenment and healthcare culture in Vranje and its region were under Turkish influence until the liberation in 1878, when the organisation of education, schooling and healthcare were initiated in the Vranje region OBJECTIVE: The aims of this study were to shed light on the beginning of the development of pharmaceutical personnel, and their contribution to healthcare culture development in Vranje and its region, with a focus on healthcare legislation and its impact on pharmaceutical service availability, and the analysis of pharmaceutical personnel development within the healthcare services. METHODS: We used the methods of documentation analysis and the desk analysis of the secondary information. RESULTS: At the beginning of the 19th century healthcare services in Vranje were still inexistent. After the liberation from the Turks, Naum's medical office with pharmacy was opened in Vranje. Although it did not comply with regulations, it presented the only formal source of supply of medications and sanitary material, and as such it gave its contribution to healthcare service at that time in Vranje. Mr ph. Stevan Varjacic, 1st class pharmacy assistant, worked at a temporary hospital from 1880 until January 1881, suppling with medications soldiers and residents of Vranje. The development of pharmaceutical schooling began in 1883, when a pharmacy was opened by the pharmacist Velimir Karic according to the Law on Healthcare Organisation and People's Healthcare Maintenance. By the end of the 1930s there were ten civilian healthcare institutions in Vranje, even three of which were pharmacies. By the end of 1948, they were nationalized, and were renamed the City National Pharmacy of Vranje. CONCLUSION: By the end of the 10th century, passing of the legislation on the regulations of pharmaceutical industry within healthcare services had an impact on Vranje that resulted in opening pharmacies with educated pharmaceutical personnel. Pharmacy owners changed, and the quality and continuity of medical supplies was always secured. PMID- 25731015 TI - [What is the role of otolaryngologists in deglutition practice?--A survey for medical practitioners in different fields]. AB - The advent of a super aging society is causing a rapid increase in the number of patients with dysphagia, and, in response, the use of percutaneous endoscopic gastrostomy (PEG) has become markedly widespread over the past decade. As the result of its rapid spread, PEG is controversial both ethically and economically, and, in the revision of medical treatment fees for 2014, the preoperative deglutition usability test of all cases is fixed for the full amount request requirements of gastrostomy. Thus, the demands on dysphagia practice are rising. Therefore, we conducted a survey of the dysphagia practice of otolaryngologists, doctors, and speech therapists in charge of dysphagia practice in hospitals, home medical care clinics, and dental offices in Itabashi-ku, Tokyo, and we considered the role of otolaryngologists in dysphagia practice. According to the survey, the roles that are expected of otolaryngologists in dysphagia practice are the evaluation of swallowing function using videoendoscopic examination of swallowing in over 50% of home medical care clinics and dental offices. On the other hand, surgical treatment is expected of otolaryngologists in over half in the hospital group. A total of 64% of the home care clinic group and 47% of the dental group did not coordinate with otolaryngologists in dysphagia practice because there are no otolaryngologists to consult. The home care clinic group indicated a demand of the swallowing function test in short-term admission or home practice. In the survey of departments of otolaryngology in hospitals or otolaryngology clinics, 40% of these institutions evaluate deglutition, while the other institutions did not perform evaluations because of the lack of human resources or deficient facilities. The otolaryngologist specializes in the laryngopharynx where aspiration occurs, and not only diagnoses local organic disease, but also directs the patient to a doctor in an appropriate department on the basis of understanding the patient's background diseases. We conclude that organized participation and leadership in this region are urgent tasks of otolaryngologist. PMID- 25731014 TI - [Subjective evaluation of cochlear implants through a questionnaire survey in 100 long term adult cochlear implant users]. AB - The satisfaction level is one of the important parameters to evaluate the effectiveness of cochlear implant (CI) in adult CI users. The purpose of this study is to investigate what factor improves the satisfaction level in adult CI users. Questionnaires were used to evaluate the items concerning the satisfaction level. One hundred patients who underwent cochlear implant placement at or over the age of 20 years were enrolled in this study. All patients had an experience of at least 5 years of CI use. To evaluate the effect of CI, questionnaire items were answered about the common communicative methods, listening under various situations, points of dissatisfaction, useful level, anxiety level without CI, satisfaction level, and the duration of CI usage. Sixty two percent of the patients were satisfied with the effect of CI and 80% felt that their CI was useful. Their listening results tended to be better in quieter environments or conversation in small groups. Furthermore, listening was related to the useful and satisfaction levels. Therefore, the better they could hear, the more they were satisfied with their CI, and appreciated its usefulness. The frequency of using CI as a communicative method (application level of CI) was statistically related to useful level, but no statistical relationship was seen between the application level of CI and anxiety level or satisfaction levels. These results suggest that other factors such as psychological status might affect the satisfaction level in addition to the CI application level. We concluded that it was necessary for us to understand the listening level before CI surgery in order to predict the postoperative course and to give an appropriate explanation to the patients. PMID- 25731016 TI - [An endoscopic transnasal transsphenoidal biopsy for pituitary gland Langerhans cell histiocytosis in a child: a case report]. AB - Endoscopic transnasal transsphenoidal surgery is gaining wide acceptance as the first-line treatment of pituitary tumors in adults, as this procedure is minimally invasive and associated with good outcomes. On the other hand, conventional transcranial and sublabial approaches are chosen for infants as their small anatomical structures pose some difficulty. This study reports on the case of a 5-year-old boy who had a Langerhans cell histiocytosis appearing in the sella. The biopsy was performed using the endoscopic transnasal transsphenoidal approach, and the patient has not exhibited any post-operative complications. Although the patient was a fairly young child, the endoscopic transnasal transsphenoidal approach resulted in fewer complications as compared to the transcranial and translabial approaches. Otolaryngologists, therefore, should view this approach more positively. The indication for pediatric skull base diseases can be expected to expand to include endoscopic transnasal surgery. PMID- 25731017 TI - [Four cases of extracranial trigeminal benign neurogenic tumors]. AB - Extracranial trigeminal schwannomas are rare tumors accounting for about 10% of all trigeminal schwannomas. We report herein on four cases of extracranial trigeminal benign neurogenic tumors. The patients were aged between 39 and 75 years; they consisted of one male and three females. The origins of the schwannomas consisted of the maxillary nerve in two cases and the mandibular nerve in two cases. All cases were surgically treated using a transmaxillary approach in three cases, and a combination of the transcervical-parotid approach with a midline mandibulotomy in one case. In two cases, the schwannomas located in the pterygopalatine fossa were removed using a transmaxillary approach with the endoscope and the surgical microscope. Two patients underwent selective intravascular embolization of the feeding artery to reduce intraoperative bleeding, and they were less invasively treated via the transmaxillary approach. PMID- 25731018 TI - [Parotidectomy for parotid gland tumor using a retrograde approach from the peripheral branches of the facial nerve]. AB - There are two techniques for excising a parotid gland tumor. The first technique is the anterograde approach, and the second is the retrograde approach. Although the anterograde approach has generally been adopted, the retrograde approach may be useful depending on the identification and dissection of the facial nerve and the localization of the tumor. We reviewed 35 patients who were surgically treated with a parotidectomy using the retrograde approach between 2002 and 2012 at Tenri Hospital. We also reviewed the clinical records for evidence of temporary or definitive injury to the facial nerve. In cases where the identification of the main nerve trunk was expected to be difficult, the parotidectomy was performed using the retrograde approach guided by the mandibular branch. In cases where a tumor was located in the marginal region of the parotid gland, the retrograde approach was guided by the mandibular branch or the zygomatic branch. Of the 35 patients, 17 underwent the retrograde approach guided by the mandibular branch and 18 underwent this approach guided by the zygomatic branch. The mean surgical time and amount of bleeding using the retrograde approach were 70.7 minutes and 33.9 g, respectively. Two of the 35 patients in the retrograde group exhibited a temporary facial deficit. PMID- 25731019 TI - [The virulence factors of Mycobacterium tuberculosis: genetic control, new conceptions]. AB - The problem of Mycobacterium tuberculosis virulence, together with drug resistance, is becoming key for the design of drugs with a new mechanism of action and the production of modern concepts and tuberculosis treatment schemes. The review describes gene complexes and their products, including mycolic acids and global regulatory systems at the level of transcriptional, translational, and post-translational modification, etc. The criteria for selection of virulence/pathogenicity factors that might be used for comparative genomic analysis of strains differing in the degree of virulence were recommended. The experimental approaches and test systems for an adequate estimation of the virulence degree of different strains of M. tuberculosis were analyzed. PMID- 25731020 TI - [Inheritable changes in miRNAs expression in HeLa cells after X-ray and mitomycin C treatment]. AB - We identified 40 miRNAs with inherited aberrant expression by multiple parallel sequencing of human HeLa cells irradiated with X rays and mitomycin C. Twenty-two miRNAs were repressed and 15 miRNAs were induced after radiation and mytomycin C treatment. The expression of three miRNAs (miR-10b-5p, miR-148a-3p, and miR-340 5p) decreased after X-ray exposure and increased after mitomycin C treatment. The spectrum of aberrantly expressed miRNAs after X-ray and mitomycin C treatment is different, except for three miRNAs (mir-100-5p, miR-99b-5p, miR-501-3p), which showed the inherited decreased expression after both mutagens. It has been ascertained that for five miRNAs (miR-21-3p, miR-182-5p, miR-19b-3p, miR-30a-3p, and miR-30e-3p) with increased inherited expression, the targets are well described tumor suppressor genes. For 9 miRNAs (miR-99b-5p, miR-148a-3p, miR-365a 3p, miR-193a-3p, miR-100-5p, miR-99a-5p, miR-29b-3p, miR-340-5p, and miR-23b-3p) with reduced inherited expression, the targets are oncogenes. The obtained results provide further support of the idea that induced epigenetic changes in the genome should be considered when assessing the long-term genetic effects of ionizing radiation and chemical compounds. PMID- 25731021 TI - [Estradiol inducible and flower-specific expression of ARGOS and ARGOS-LIKE genes in transgenic tobacco plants]. AB - Transgenic tobacco plants expressing Arabidopsis thaliana ARGOS and ARGOS-LIKE genes under the control of the chalcone synthase promoter of Petunia hybrid L., as well as the estradiol inducible XVE system, have been obtained. The part of transgenic plants with flower-specific expression of the target genes was characterized by increased flower size, caused by an increase in cell size and quantity in the case of the ARGOS gene and by a stimulation of cell growth via stretching in the case of the ARGOS-LIKE gene. An enhanced expression level of the NtEXPA1, NtEXPA4 genes encoding expansins, NtEXGT gene encoding endo xyloglucan transferase, and the AINTEGUMENTA-like gene was detected in the flowers of transgenic tobacco plants. In the case of inducible expression of ARGOS and ARGOS-LIKE genes, an increase in leaf, stem and flower size was revealed in several lines of transgenic plants as compared to control. Expression of the ARGOS gene also affected cell number and size in this case, while the ARGOS-LIKE gene mainly influenced cell size via stretching. Inducible expression of the ARGOS gene in flowers mainly provided an enhanced containment of AINTEGUMENTA-like mRNA, while ARGOS-LIKE gene expression resulted in the activation of NtEXPA1 and NtEXGT genes. PMID- 25731023 TI - [Phylogenetic relations of Salix L. subg. Salix species (Salicaceae) according to sequencing data of intergenic spacers of chloroplasic genomes and ITS rDNA]. AB - A phylogenetic analysis based on a comparison of nucleotide sequences of six regions from cpDNA and ITS rDNA (petN-psbM, trnD-trnT, trnC-petN, psaA-ycf3, petG trnP, and rpoB-trnC) allowed for elucidating the relationship among species and sections belonging to the Salix subgenus and, more generally, to the Salix genus, as well as revealing the relations of the Chosenia genus. The definition of the subgenera of Pleuradenia (including the Urbanianea genus and the Chosenia genus), Salix (without the Triandrae section), Triandrae, and Longifoliae is essentially consistent with current classification schemes of the Salix genus. The previously defined genera of Chosenia and Toisusu (Urbanianea) are not only joined with the Salix genus but are also closely related between themselves. The Protitea subgenus only corresponds to the American species of the Humboldtianae section (S. humboldtiana, S. amygdaloides, S. gooddingii). The relationship of S. chaenomeloides, which is a nomenclatural type of this subgenus, as well as the relationship of the Wilsonia section, remains unresolved. The Humboldtianae section should be interpreted more narrowly, apparently, separating the Acmophillae and Tetraspermae sections from it. The monotypic American Floridanae section is related to the Salix, Salicaster, Tetraspermae, and Wilsonia. PMID- 25731022 TI - [Mitotic behavior of centromeres in meiosis as the fertility restoration mechanism in wheat-rye amphihaploids]. AB - The regulation of chromosomal behavior in meiosis in partly fertile wheat-rye amphihaploids was studied using the centromere specific probes pAWRC1 and Ae. tauschii pAet6-09. Comparative analysis of the probe localization patterns in mitosis, normal meiosis in wheat Triticum aestivum L. and rye Secale cereale L., and meiosis in amphihaploids was performed. The differences in the structure of centromeres in monopolar- and bipolar- oriented chromosomes were revealed. Single dense hybridization signals were observed in the diplotene and the metaphase of the first meiotic division, while hybridization signals appeared as stretched bands with diffuse structure located across the centromere region in mitosis and the second round of meiotic division. Based upon the obtained data, we used the corresponding centromere-specific probes as a tool for the analysis of chromosomal behavior in meiosis in amphihaploids. In meiocytes with three types of chromosome behavior (reductional, equational plus reductional, and equational), dense point-like hybridization signals for the pAet6-09 probe were observed for univalents with the reductional division type and stretched bands with diffuse structure for those with the equational division type. Thus, pAet6 09 probe localization patterns suggest some structural and functional specificities of centromeres in the meiosis in wheat-rye amphihaploids that reflect special regulation of chromosomal behavior during equational division. Meiocytes with true mitotic division were also observed in anthers predominantly containing meiocytes with chromosomes undergoing equational division. PMID- 25731024 TI - [Allozyme variability and the population genetic structure of the mice Apodemus agrarius, Mus musculus, and Sylvaemus uralensis (Rodenita, Muridae) in Western Siberia]. AB - Of the three mouse species inhabiting Western Siberia, the striped field mouse is characterized by the highest level of genetic variation, a uniform distribution of polymorphism indicators, lower values of genetic differentiation, and higher values of gene flow, as compared to the house mouse and pygmy wood mouse. The house mouse populations have abrupt changes in the parameters of protein polymorphism in different localities. This is due to the considerable spatial dissociation of the cities of Siberia and the differing histories of their settlement. Inhabitation of an urban area leads to the partitioning of striped wood mouse populations into groups that considerably differ in allele frequencies and genetic variation indices. These changes are not related to the degree of urbanization and are determined by genetic drift. Some characteristics of these groups, like reduced variability, heterozygote deficit, and deviation from the Hardy-Weinberg equilibrium, limit their adaptive potential and make them dependent on the populations of inter-settlement territories. PMID- 25731025 TI - [The effects of prolonged selection for behavior on the stress response and Activity of the reproductive system of male Brown rats (Rattus norvegicus)]. AB - Two Norway rat (Rattus norvegicus) populations contrasting in behavior have been raised at the Institute of Cytology and Genetics, Novosibirsk, Russia with long term selection for the absence or enhancement of an aggressive response towards humans. They are designated as tame and aggressive, respectively. In this work we investigated the effects of the selection on behavior, stress responsiveness, and fertility in males of the 78th generation. It is shown that the difference between the strains in their response to humans remains the same as in previous generations. However, the differences in stress response and maturation age contradict earlier data. For the first time, we note a higher glucocorticoid mediated response to restriction stress and retarded sexual maturation in tame rats compared to aggressive ones, according to morphometric indices of gonads and testosterone levels. It is conceivable that the change in selection effects is determined by the disjunction of the directions of selection for behavior and the modification of the stress response. This study is the first to characterize males recently (six or seven generations of propagation in captivity) caught in the wild with regard to the indices under consideration and used as a control group. Wild rats have the highest stress response and rate of sexual maturation as compared to those selected. PMID- 25731026 TI - [The evolution of microsatellite loci in salmonid fishes]. AB - In ten species of salmonid fishes, sequences of five microsatellite loci were determined. Considerable differences in the structure of the same microsatellites in different species were found. It was demonstrated that the evolution of microsatellites was a complex process, including changes in the copy number, point mutations, and extended deletions and insertions, leading either to the formation of microsatellites or to their loss. PMID- 25731027 TI - [The polymorphism of DNA repair genes XPD, XRCC1, OGG1, and ERCC6, life expectancy, and the inclination to smoke]. AB - The polymorphism of excision repair genes XPD Asp312Asn, XRCC1 Arg399Gln, OGG1 Ser326Cys, and ERCC6 Met1097Val was analyzed by PCR-RFLP in 370 representatives of the Belarusian population of average, old, and elderly ages. Correlation analysis showed that the frequencies of wild-type homozygous combinations significantly increase with age in the group of subjects over 70 years old in the case of the interaction of two genes, XPD 312 and XRCC1399, or three genes, XPD312, XRCC1399, and ERCC6 1097. In a subgroup of the long-lived, this relationship is manifested in case of a pairwise interaction of gene XPD 312 with XRCC1 399 or ERCC6 1097, as well as an interaction of three genes, XPD 312, XRCC1 399, and ERCC6 1097. The data suggest that the optimum activity of repair processes may favor longevity. It is shown that the frequency of the Asp/Asp genotype is reduced, and the frequency of the Asn allele of the XPD 312 gene is increased in the subgroup of smokers as compared with nonsmokers, which apparently indicates an association of this gene polymorphism with an inclination to smoke. The problem requires further study. PMID- 25731028 TI - [Somatic genome variations in vascular tissues and peripheral blood leukocytes in patients with atherosclerosis]. AB - The first data on the existence of multiple genomic rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity, in vascular tissues and peripheral blood leukocytes from patients with atherosclerosis, are presented. Compared to internal mammary arteries and peripheral blood leukocytes, right coronary arteries in the atherosclerotic plaque area presented with a higher CNV length and number of genes located in their vicinity. In each of the patients, 6-16% of CNVs were common to the three types of tissues examined. Therefore, most of the copy number variations in the tissues affected by atherosclerosis (from 68 to 91% in each of the patients) were of somatic origin. The gains in 3p21.31 (CACNA2D2), 7q32.1 (FLNC), 19p13.3 (C19orf29, PIP5K1C), and 21q22.3 (COL6A1) were detected in vascular tissues but not in peripheral blood leukocytes. Moreover, the gain in 7p15.2 (SKAP2), detected in the patients with atherosclerosis, did not overlap with any CNV regions currently reported in The Database of Genomic Variants. The loss of heterozygosity in 12 out of 13 chromosomal regions was copy neutral and covered tumor suppressor genes (SFRP1, CEBPD, RB1CC1, DIRAS3, TUSC3, and ZDHHC2). PMID- 25731029 TI - [Modelling of selection acting upon the pleioptropic locus in an asynchronous population]. AB - We created and examined a mathematical model describing the size and genetic composition dynamics in a population with two age classes, where the survival of both zygotes and adult individuals is determined by one pleioptropic locus. Even under present limitations, as the outside effects of a complex multigenic system are reduced to the case of single locus, our model demonstrates a wide range of different evolutionary scenarios for possible changes in the population dynamics. An increase in the reproductive potential and survival is accompanied by a transition from stable to oscillating population numbers. However, the evolutionary growth of these parameters may be nonmonotonic and may fluctuate significantly. In the case of antagonistic pleioptropy, an increase in one of these parameters usually leads to a predictable decrease in the other. This, in turn, may even stabilize the numbers and genetic compositions of the age groups. We demonstrated that selection acting on later stages of the life cycle is accompanied by destabilization of the Hardy-Weinberg equilibriums that link allele and genotype frequencies. We obtained a balance ratio, which allowed us to compare the combined fitness of the genotypes and to demonstrate that selection leads to the exclusion of the least adapted genotypes. Initial conditionsmay in some cases determine the genetic composition and pattern of population size dynamics. PMID- 25731030 TI - [Phylogenetic relations between frit fly groups from the genus Meromyza based on genetic and morphological analysis]. AB - Phylogenetic relations between groups of frit fly species from the genus Meromyza were studied on the mtDNA COI locus and on the morphology of the male reproductive apparatus. Branching of the phylogenetic tree constructed by the Neighbor-Joining method unites sequences of samples from species of the genus Meromyza in five clusters with high support. It was demonstrated that joining of species in a certain cluster corresponds to uniformity of morphological traits of male parameres. PMID- 25731031 TI - [Genetic passportization and identification of Siberian cranes (Grus leucogeranus Pallas) in captivity]. AB - The genetic diversity of the founders of an artificial population of the Siberian crane Grus leucogeranus Pallas (rare species of cranes) was characterized using 10 microsatellite loci. It was established that the allelic diversity (on average, 5.9 alleles per locus) and genic (H(o) = 0.739) diversity of the Siberian crane is rather high and comparable with the estimations for natural populations of different crane species. Genetic passportization of the birds (119 individuals) from the register of the Siberian crane International Studbook was carried out at the initial stage. The efficiency of genetic passportization for individual identification, identification of the origin, paternity analysis, and exclusion of inbreeding was demonstrated in Siberian cranes under natural mating and artificial insemination. Cases of natural reproduction in pairs of Siberian cranes imprinted to the human and continuous storage of spermatozoa in the female reproductive ducts were registered. PMID- 25731032 TI - [Secondary fungal metabolites (mycotoxins) in lichens of different taxonomic groups]. AB - Secondary fungal metabolites (mycotoxins) in 22 lichen species of the families Parmeliaceae, Nephromataceae, Umbilicariaceae, Ramalinaceae, Cladoniaceae, Peltigeraceae, and Teloschistaceae were identified determined by enzyme immunoassay enzyme-linked immunosorbent assay. The following mycotoxins were identified found in these lichens in a broad concentration range with a frequency of 70-100%: sterigmatocystin (7-2090 ng/g), alternariol (20-6460 ng/g), and emodin (45-94500 ng/g). Mycophenolic acid frequently occurred in 19 lichen species; citrinin, in 17 species; diacetoxyscirpenol, in 11 species; cyclopiazonic acid, in 10 species; and zearalenone, in 9 species. PR toxin was regularly detected in three lichen species; deoxynivalenol, fumonisins, and ochratoxin A, in two species; and T-2 toxin and ergot alkaloids, in one species. Aflatoxin B1 was detected in only six species with a frequency of 2-42%, whereas roridin A was identified present in 10% of Hypogymnia physodes samples. PMID- 25731033 TI - [Characteristics of the new plasmid, pMTB1, from the metagenome of the microbial community of underground thermal waters of Western Siberia]. AB - A new circular 4935-bp long plasmid pMTB1 has been identified in sequences of the metagenome. The nucleotide sequence of pMTB1 is highly similar to that of plasmids, pME2001 and pME2200, from the methanogenic archaeon Methanothermobacter marburgensis. One of six putative protein-coding genes encodes a protein containing helix-turn-helix and ATP/GTP-binding motifs and, probably, functioning as a replication initiator protein. Homologs of other genes have been found only in the plasmids of M. marburgensis, but their functions are unknown. Comparison of the complete nucleotide sequences of the plasmids pMTB1, pME2001, and pME2200 has revealed that they have a common origin but differ from each other by the presence of several inserts flanked by nearly perfect direct repeats within regions not essential for replication. PMID- 25731034 TI - [Number, viability, and diversity of the filterable forms of prokaryotes in sphagnous high-moor peat]. AB - The number, potential viability, and taxonomic diversity (at the level of phylum) of the filterable forms of prokaryotes (FFP) are estimated in the main genetic horizons of high-moor peat. It was shown that the number of FFP reached 500 million cells in 1 g, i.e., up to 5% of the general size bacteria. The portion of viable cells among FFP (93-98%) was higher than that for the general size bacteria (60-68%). FISH-analysis (fluorescence in situ hybridization) showed that FFP contained the same phylogenetic groups as the population of general size bacteria (domain Archea and phylum Actinobacteria, Cytophaga, and Proteobacteria of the domain Bacteria). PMID- 25731035 TI - [Ecophysiological Characteristics of actinomycetes of desert soils of Mongolia]. AB - It is shown that the actinomycete complex in steppe-desert light brown salty soil of desert steppes of Mongolia is represented by the genera Streptomyces and Micromonospora. The species diversity of the genus Streptomyces, which dominates the complex, decreases with increasing osmolarity of the medium. The influence of environmental factors--temperature and osmolarity of medium--on the development of metabolically active members of the phylum Actinobacteria in the domain Bacteria of the prokaryotic microbial soil community was established. The proportion of metabolically active bacteria belonging to Actinobacteria increases with increasing osmolarity and incubation temperature of soil. The dominance of the filamentous metabolically active members of the phylum Actinobacteria over the unicellular organisms was shown. The halotolerant actinomycetes isolated from the steppe-desert soils were alkalotolerant, xerophilic, and thermotolerant and exhibited antimicrobial activity with respect to Gram-positive bacteria and actinomycetes. PMID- 25731036 TI - [Effect of stress conditions on the activity and isozyme composition of peroxidase of vacuoles and tissue extract of red beet roots]. AB - Changes in the enzymatic activity of phenol-dependent peroxidase (PO) of vacuoles and tissue extract of red beet (Beta vulgaris L.) roots in different phases of plant development and in hyperosmotic stress and pathogen infection were found. The highest activity was observed during root growth and the lowest PO activity occurred in dormancy, respectively. Activation of the enzyme was observed in infected roots. The isozyme composition of PO was characterized by lability, and the number of cationic isoforms varied significantly. The optimum pH of the enzyme changed depending on the growth phase and stressor, tending to shift towards low values at rest and in hyperosmotic stress. The shift in the optimum pH coincided with the appearance of additional cationic PO isoforms. PMID- 25731037 TI - [Fatty acid composition of lipids of vegetative organs of Nigella at different levels of environment salinization]. AB - A comparative study of the tolerance of two species of medicinal plants of the genus Nigella (N. damascene L. and N. sativa L.) to salt stress was performed. It is shown that growing of plants in the presence of 70 or 110 mM NaCl suppressed the growth and accumulation of dry weight of leaves and roots in both species studied and that this suppression was more pronounced at the higher NaCl concentration. It is established that the salt stress leads to the accumulation of proline in leaves and to a change in the fatty acids composition of lipids in the vegetative parts of plants. It is noted that N. sativa has a higher salt tolerance (70-100 mM NaCl) than N. damascena. It is found that the removal of NaCI from the culture medium and subsequent cultivation of plants exposed to salt stress in a salt-free medium led to a gradual recovery of both Nigella species studied. N. sativa plants showed a high ability for recovery (regeneration) after a strong salt stress. PMID- 25731038 TI - [Localization of prostaglandin E2, gamma-aminobutyric acid, and other potential immunomodulators in the plerocercoid Diphyllobothrium dendriticum (Cestoda)]. AB - For the first time, the potential immunomodulators prostaglandin E2 and gamma aminobutyric acid (GABA) have been revealed in the plerocercoid Diphyllobothrium dendriticum, which is a parasite in the tissues and abdominal cavity of the Baikal omul Coregonus migratorius. The localization of immunomodulators in parasite tissues was compared with the location of typical markers of the nervous system (serotonin (5-HT) and FMRF-amide) and a marker of microtubules (alpha tubulin). Prostaglandin E2 was revealed in the cells that are immunoreactive to alpha-tubulin and are situated in the cortical parenchyma outside the central nervous system (CNS). It is supposed that prostaglandin E2 is produced by the frontal glands and is carried out onto the tegument surface through specialized ducts. Immunoreaction to GABA was revealed in the central and peripheral nervous systems. GABA-ergic neurosomes, the neurites of which form a net on the surface of muscle layers and in the subtegument, were revealed in the cerebral ganglion and main nerve cords. The morphological characteristics for the identification of serotoninergic neurons in the CNS were described. PMID- 25731039 TI - [Role of microbiocenosis of the gastrointestinal tract in the nutrition of grouse]. AB - In order to assess the role of the microbiocenosis of the digestive tract of herbivorous birds in transforming poor forage, the activity of cellulolytic enzymes in all departments of the gastrointestinal tract of the black grouse (Lyrurus tetrix) and Western capercaillie (Tetrao urogallus) was studied. The functional diversity of microbial communities of different departments was also investigated. In both species of birds, nitrogenase and cellobiohydrolase activities were discovered in the digestive tract, with the maximum observed in the cecum. PMID- 25731041 TI - [Insecticidal and immunosuppressive effect of ascomycete Cordyceps militaris on the larvae of the Colorado potato beetle Leptinotarsa decemlineata]. AB - The immunosuppressive and insecticidal activity of cultures of the entomopathogenic fungus Cordyceps militaris on the larvae of the Colorado potato beetle Leptinotarsa decemlineata has been established for the first time. It was found that the peroral effect of the fungal culture resulted in dose-dependent decrease in survival, delayed in development time and molting, decreases in the total hemocyt counts, increased activity of phenoloxidases in the hemolymph, and reduced activity of the enzyme in the cuticle, as well as increased sensitivity of larvae to the fungus Beauveria bassiana at the level of the synergistic effect. PMID- 25731040 TI - [Bioaccumulation of silver and gold nanoparticles in organs and tissues of rats by neutron activation analysis]. AB - Bioaccumulation of silver (Ag) and gold (Au) nanoparticles (NPs) with mean sizes of 6 nm and 35 nm, respectively, has been studied after their intragastric administration to rats at a dose of 100 MUg/kg of body weight for 28 or 14 days. The organs and tissues (liver, kidney, spleen, heart, gonads brain, and blood) were subjected to thermal neutron activation, and, then, the activity of the 110mAg and 198Au isotopes generated was measured. The NPs of both metals were detected in all biological samples studied, the highest specific weight and content of Ag NP being found in the liver, and those of Au being found in kidneys of animals. The content of Ag NPs detected in the brain was 66.4 +/- 5.6 ng (36 ng/g tissue), no more than 7% ofthese NPs being localized in the lumen of brain blood vessels. The content of Ag and Au NPs found in organs and tissues of rats could be regarded as nonhazardous (nontoxic) in accordance with the known literature data. PMID- 25731042 TI - [Postglacial migration and phenogeography of populations of the Scots pine (Pinus sylvestris L.) in the northeast of the Russian Plain]. AB - The history, distribution routes, and phenogeographic structure of the Scots pine (Pinus sylvestris L.) in the northeast of the Russian Plain were studied on the basis of paleogeographic data and results of our own phenotypic and allozyme genetic studies. It is assumed that, after the maximum Dnieper glaciation, P. sylvestris populations could successfully distribute to the northwest and north from the refugia of the South and Middle Urals as a result of seed dispersal by Belaya, Ufa, Chusovaya rivers (in Holocene, by Severnaya Dvina, Mezen', and Pechora rivers). On the basis of the hypothesis of "migration complexes" and the theory of hydrochory for coniferous species, a scheme of formation of a population structure of the Scots pine in the northeast of the Russian Plain is proposed. PMID- 25731043 TI - [Does the comparator method has a future in diagnosing large bivalves (Bivalvia: Unionida)?]. AB - It is shown that the contours of the frontal sections of valves in shells of different size of the same species run through different parts of the valve. A new modification of the comparator method is proposed, which allows studying the shape of the maximum convex contour of the cross-section of the shell. PMID- 25731044 TI - [Update on multifocal intraocular lenses' development]. PMID- 25731045 TI - [Clinical results of tinted aspheric multifocal toric intraocular lens (SND1T3, SND1T4, SND1T5, SND1T6) for eyes following cataract extraction]. AB - PURPOSE: The efficacy and safety of tinted aspheric multifocal toric intraocular lens (IOL) (SND1T3, SND1T4, SND1T5, SND1T6 : Alcon) were evaluated in 130 eyes of 65 patients following cataract removal. METHODS: Visual acuities (VAs) at distance, near (40 cm) and intermediate (50 cm, 1 m), IOL rotation, contrast sensitivity, spectacle usage and glare/halo were examined up to 1 year postoperatively. RESULTS: The mean bilateral uncorrected distance VA was -0.04 +/ 0.10 logMAR, near VA was 0.00 +/- 0.11 logMAR, intermediate VA at 50 cm was 0.00 +/- 0.11 logMAR, intermediate VA at 1 m was 0.11 +/- 0.15 logMAR. IOL rotation was 5.73 +/- 4.36 degrees, photopic contrast sensitivities were within normal range, and 76.9% of the patients did not require any spectacles. None of the patients complained of either serious glare or halo. CONCLUSION: The multifocal toric IOL provides better VA from distance to near at 40 cm. PMID- 25731046 TI - [Ultrasound biomicroscopy in infants with congenital corneal opacity and its correlations with clinical diagnosis and intraocular pressure]. AB - PURPOSE: Ultrasound biomicroscopy (UBM) can be used to investigate the appearance of the anterior chamber in infants with congenital corneal opacity. This study investigated the association between the UBM-obtained clinical imaging of anterior chamber morphology and the clinical diagnosis in infants with congenital corneal opacity. SUBJECTS AND METHODS: This study involved 19 eyes of 10 consecutive infants with congenital corneal opacity, 13 eyes with Peters anomaly (PA, 7 cases) and 6 eye with sclerocornea (SC, 3 cases), recruited at the Kyoto Prefectural University of Medicine, Kyoto, Japan between September 2001 and January 2009. In each subject eye, UBM findings were compared with the clinical diagnosis based on slit-lamp findings and intraocular pressure (IOP). RESULTS: UBM findings revealed partial angle closure in 10 PA eyes and in 5 SC eyes, absence of Descemet's membrane in 13 eyes and 6 eyes, and funicular fiber from the iris in 12 eyes and 6 eyes. All 6 eyes with SC showed normal IOP, while 9 eyes with PA were diagnosed as glaucoma. CONCLUSION: Similarities in UBM appearance were observed between PA and SC. PA had a higher incidence of glaucoma; however, there was no relation between IOP and the UBM images. PMID- 25731047 TI - [Why do you want to be a pain clinician?]. PMID- 25731048 TI - [Postoperative cognitive dysfunction: Preface and Comments]. AB - Postoperative cognitive dysfunction (POCD) has been highlighted over a decade. Although perioperative stroke is obvious central nervous system pathology, POCD is often subtle and unrecognized. No consensus on the definition for POCD has been reached. POCD may be attributed to preoperative, surgical, anesthetic, or adverse perioperative events. POCD often occurs frequently in elderly patients even after minor surgical procedures. POCD may last years after surgery and may impair the patient's social activity including premature departure from the workforce. Although neuroinflammation is suggested as an important predisposing factor, our knowledge on other predisposing factors is limited and effective preventive measure is unknown. PMID- 25731049 TI - [Overview and assessment of cognitive function in interpreting postoperative cognitive dysfunction]. AB - The most important point for evaluation of the post-operative cognitive dysfunction is that we understand "cognitive function". First we described the definition of the "cognitive function" and second, outlined each function (dysfunction) and introduced the main assessment methods from the view point of neuropsychology. Cognitive function (dysfunction) described in this paper includes consciousness (confusional state, disturbance of consciousness), generalized attention (disorder of generalized attention), memory (amnesia), orientation (disorientation), executive function (dysexecutive syndrome), social cognition (social cognitive impairment), language (aphasia), cognition (agnosia), behavior (apraxia), directed attention (unilateral spatial neglect), and construction (constructional disorder). PMID- 25731050 TI - [Effects of anesthetics on the higher brain function]. AB - Number of surgeries for the elderly is increasing year by year. Postoperative cognitive dysfunction, POCD, and delirium are typical failure's of higher brain function after surgery. The mechanism of POCD and delirium has been suggested to be associated with inflammation, but its details are unknown. Alzheimer's disease leads to derangement in cognitive function. The number of patients with Alzheimer's disease is expected to increase rapidly. There is a possibility that inhalation anesthesia exacerbates the pathology of patients with impaired higher brain function such as Alzheimer's disease. On the other hand, the another suspect, that propofol is safe. However, it should be recognized that these results became clear by basic research. Further clinical study is required. PMID- 25731051 TI - [Pathophysiology and mechanisms of postoperative cognitive dysfunction]. AB - Postoperative cognitive impairment is a recognized clinical phenomenon. Previously, such clinical findings were called "adverse cerebral effects of anesthesia on old people". POCD is transient disturbance that can affect patients of any age but is more common in elderly people. Its relevance with the immediate post-operative phase was made clear. The aging of the population and new developments in medicine both lead to the increasing number of elderly patietnts undergoing extensive surgery. Mechanism of POCD is considered to be due to the inflammatory response and Ca2+ dysregulation of the brain. For the diagnosis of POCD, pscychometric tests are applied. Risk factors for POCD are aging, extensive invasive operations, intra and postoperative complications, and anesthetics. To reduce POCD, it is necessary to provide preoperative screening and cognitive training, minimally invasive surgery, the use of short-acting agents, meticulous anesthetic technique to prevent perioperative disturbances of homeostasis and organ ischemia, tight volume balance, and EEG monitoring. PMID- 25731052 TI - [Development of postoperative cognitive dysfunction following major vascular surgery]. AB - The development of postoperative cognitive dysfunction (POCD) is a devastating complication, leading to a poor postoperative quality of life. Even though the number of patients undergoing major vascular surgery has increased, the development of POCD has not been well evaluated in these patients compared with patients undergoing coronary artery bypass graft surgery (CABG). According to previous reports, more patients undergoing major vascular surgery by deep circulatory arrest or retrograde cerebral perfusion, and an equal or even larger number of patients undergoing surgery by selective cerebral perfusion, seem to develop POCD when compared with patients after CABG. However, only a small numbers of patients have been assessed and the timing of evaluating POCD has varied in previous studies. Well-organized studies with a sufficient number of cases and systematic post-operative evaluation of POCD are necessary. PMID- 25731053 TI - [Postoperative cognitive dysfunction in off-pump versus on-pump coronary artery bypass surgery]. AB - Patients referred for coronary artery bypass grafting (CABG) are older and more likely to have extensive vascular diseases than those referred for such procedures in the past. Undiagnosed cerebral small vessel diseases (SVD), such as lacunar infarctions or white matter lesions, and dementia are common. Postoperative cognitive dysfunction (POCD) remains a major concern in these elderly patients. POCD is caused by cerebral emboli, hypoperfusion, and inflammation attributed largely to the use of cardiopulmonary bypass. Off-pump CABG is a surgical strategy proposed to decrease the risk of POCD. Although some researchers have found that off-pump CABG is associated with improved cognitive outcome in the early postoperative period, many studies have shown no difference at any time points. Consequently, efforts to reduce the incidence of POCD are focusing on patient-related rather than procedure-related factors. Surgical procedures could exacerbate neuroinflammation and accelerate cognitive dysfunction, especially in patients with SVD and dementia. Mild cognitive impairment may serve as a surrogate marker for underlying SVD or dementia. Preoperative cerebrovascular evaluation, such as MRI, MRA, or cervical ultrasound, and cognitive screening may be effective to identify high-risk patients, making it possible to individualize surgical approaches aimed at reducing POCD. PMID- 25731054 TI - [Postoperative cognitive dysfunction after non-cardiac surgery]. AB - Postoperative cognitive dysfunction (POCD) is seen not only after cardiac surgery but also after non-cardiac surgery. POCD leads to decreased quality of life and increased mortality. Various reports describe the occurrence and risk factor of POCD in adopting different neuropsychological tests and different follow-up periods. POCD is highly associated with age or inflammation in the central nerve system. Anti-inflammatory strategies including dexmedetomidine, statin or minocycline in the perioperative period may reduce incidence of POCD. PMID- 25731055 TI - [Airway management in children with vallecular cyst: review of 25 cases--can we predict difficult intubation?]. AB - BACKGROUND: Vallecular cysts frequently cause difficult intubation due to poor glottic visualization during direct laryngoscopy. The appropriate way of airway management and predictive factors of difficult intubation are unknown. METHODS: We reviewed anesthetic induction and airway management in 25 cases of vallecular cysts for the past 11 years. We collected the following data of 24 cases in 20 children who were intubated under direct laryngoscopy: age (month), height (cm), weight (kg), cyst-diameter (mm), cyst-diameter to patient-height ratio, and clinical symptoms. These data were compared between difficult intubation group (group A) and easy or slightly difficult intubation group (group B). RESULTS: In the majority of cases, anesthesia was induced with spontaneous ventilation maintained. Group A and B consisted of 6 and 18 cases, respectively. All cases of group A required assistive devices such as stylets or tube introducers. Cyst diameter to patient-height ratios were significantly higher in group A than in group B (0.26 vs. 0.18, P = 0.03). CONCLUSIONS: Because children with vallecular cysts have a risk of difficult airway, we need to prepare for difficult airway management. The cyst-diameter to patient-height ratio could be useful as a predictor of difficult intubation. PMID- 25731056 TI - [Epidural anesthesia at the L1-2 interspaces enables ambulation after cesarean delivery within less than 3 hours 30 minutes--a new perspective in the use of epidural anesthesia in cesarean deliveries]. AB - BACKGROUND: In cesarean deliveries, it is important to prevent deep vein thrombosis in the lower limbs as this can result in pulmonary embolisms. Taking post-operative analgesia into account it is preferable to use an anesthesia method that allows early ambulation of patients. It is therefore necessary to use epidural anesthesia as a sole anesthesia method for cesarean deliveries. METHODS: In an analysis of 633 cesarean delivery patients who had been administered only epidural anesthesia, we investigated and compared the time to ambulation and cessation of continuous epidural infusion in groups that had received epidural puncture either at L1-2 or L2-3 space. RESULTS: The postoperative time to ambulation in the L1-2 puncture group was 189.9 +/- 56.1 minutes. Postoperative analgesia administered via continuous epidural infusion of local anesthetic was discontinued due to remaining paralysis in 2.5% of the L1-2 puncture group, which was significantly lower than the L2- 3 puncture group (7.6%). CONCLUSIONS: Our findings showed that it is possible to utilize only epidural anesthesia for cesarean deliveries. Using lumbar epidural anesthesia with L1-2 puncture reduced a postoperative time to ambulation to less than 3 hours 10 minutes. PMID- 25731057 TI - [Evaluation of postoperative pain intensity after ear, nose, and throat surgery- the effect of intraoperative fentanyl use]. AB - BACKGROUND: This study was designed to determine postoperative pain levels after ear, nose, and throat (ENT) surgery, and also to examine whether intraoperative fentanyl use during ENT surgery enhances the quality of postoperative pain control. METHODS: The distribution of pain scores and rescue analgesic requirements among 198 patients undergoing ENT surgery were examined. Multivariate logistic regression analysis was performed to identify independent factors associated with moderate to severe postoperative pain (maximal pain score >= 5 on the numerical rating scale) and postoperative nausea and vomiting (PONV). RESULTS: 27.8% of patients experienced moderate to severe postoperative pain after ENT surgery. The distribution of postoperative pain levels was similar among procedures performed on different anatomical regions. Intraoperative fentanyl use was not associated with moderate to severe postoperative pain (adjusted odds ratio (95% confidence interval) :1.03 (0.51-2.13))]. On the other hand, intraoperative fentanyl use was independently associated with PONV [3.10 (1.25-8.92); P = 0.0138]. CONCLUSIONS: Prevalence of moderate to severe postoperative pain after ENT surgery was approximately 28%. Intraoperative fentanyl use was not associated with a decreased incidence of moderate to severe postoperative pain, but was significantly associated with PONV. PMID- 25731058 TI - [Anesthetic management for nasal foreign body removal in children]. AB - Migration of a foreign body into the nasal cavity accidentally occurred in three children aged 2 yr. All procedures for removal were performed under general anesthesia. Two patients underwent slow anesthetic induction with sevoflurane and their tracheas were intubated under spontaneous breathing without neuromuscular blocking agents. One patient underwent rapid sequence induction with cricoid pressure to prevent aspiration. Anesthetic courses of the three patients were stable, and the foreign bodies were successfully removed without any complications. Since a nasal foreign body can cause occurrence of its aspiration into the trachea due to crying or reduction of muscle tone, special attention should be paid for safe management of the airway and/or anesthesia throughout the procedure. PMID- 25731059 TI - [Anesthetic management of a patient with Trousseau's syndrome and ovarian cancer who underwent gynecological surgery]. AB - Trousseau's syndrome, a complex paraneoplastic disease, is characterized by the occurrence of thromboembolic disorders such as brain infarctions in patients with malignant neoplasms. We report the case of a 46-year-old woman with ovarian cancer who had suffered cerebral infarctions and presented with left hemiplegia, aphasia, and atypical genital bleeding. She suffered multiple right brain infarctions, a pulmonary embolism, a right renal infarction with bilateral hydronephrosis and deep venous thromboses and exhibited increased D-dimer and fibrinogen levels and so was administered heparin (10,000 U x day(-1)). She had no other underlying diseases such as coagulopathy, cardiovascular disease, collagen disease, or angiitis. Therefore, we were able to diagnose her with Trousseau's syndrome. She was scheduled to undergo total abdominal hysterectomy with bilateral oophorectomy, pelvic lymphadenectomies, and omentectomy. Preoperatively, an inferior vena cava filter was temporarily installed to prevent the development of further pulmonary thromboses. General anesthesia was uneventfully maintained by inhalation of oxygen, air, and sevoflurane and the continuous infusion of remifentanil whilst regional cerebral oxygen saturation and transesophageal echocardiography monitoring were performed. Postoperatively, she received heparin-based anticoagulant therapy (10,000 U x day(-1)) and did not exhibit bleeding diathesis or thrombosis. It is of great importance that anesthesiologists are aware of the thromboembolic status of patients with malignant neoplasms, especially those with gynecological tumors. PMID- 25731060 TI - [A comparison of patient-controlled epidural analgesia and intravenous fentanyl analgesia for laparoscopic ovarian cystectomy]. AB - BACKGROUND: Laparoscopic ovarian cystectomy (LOC) can be performed in conjunction with patient-controlled epidural analgesia (PCEA) or intravenous fentanyl analgesia (IFA). Therefore, we evaluated the postoperative pain associated with both analgesia methods. METHODS: We retrospectively evaluated the postoperative pain associated with PCEA and IEA. We calculated the combined remifentanil and fentanyl effect-site concentrations (ESC) in 43 patients at 1-2 hours after operations involving PCEA (n = 24, group E) or IFA (n = 19, group F). We also evaluated the supplementary analgesics required and the incidences of decreased respiratory rate and desaturation. RESULTS: The patients' backgrounds were similar in both groups. The ESC was below 1.0 ng x ml(-1) in group E and 1.0-2.0 ng x ml(-1) in group F. In group E, five patients received supplementary local bolus injections, one received an NSAID, and one received a morphine injection, while four received NSAIDs and one received a morphine injection in group F. Thus, supplementary analgesics used for 7/24 patients in group E and 5/19 patients in group F (P = 1.000). No complications were noted in either group. CONCLUSIONS: Both PCEA and IFA regimens can effectively manage postoperative pain with relatively low amounts of supplementary analgesics. PMID- 25731061 TI - [Succesful management of esophageal banding and gastrostomy for esophageal atresia in a trisomy 18 child with complex cardiac malformation]. AB - Trisomy 18 is one of the congenital disorders caused by a chromosomal abnormality. Ninety percent of fetuses with trisomy 18 have various other malformations. The present patient had heart failure due to a complex cardiac malformation and a Gross C type esophageal atresia. Before the esophageal banding, ventilation of the lungs was impossible and respiratory condition was unstable. Considering that direction of the shunt can easily change by hyperventilation and high oxygen concentration, we employed the lowest oxygen concentration and ventilation as possible. In the present case, it was necessary to provide respiratory care for both esophageal atresia and complex cardiac malformation. PMID- 25731062 TI - [A case of obstruction in the left internal jugular vein which both ultrasound prescan and chest computed tomography could not detect before the insertion of a pulmonary artery catheter]. AB - In a 54-year-old man, at the time of anesthesia administration during the Bentall re-operation, a preoperative ultrasound scan showed right internal jugular vein thrombosis before insertion of a pulmonary artery catheter into the right internal jugular vein. Therefore, we performed the insertion after confirming that the left internal jugular vein was safe via a preoperative ultrasound and chest computed tomography (CT). Although we could insert the catheter sheath, contrast imaging revealed that the pulmonary artery catheter had advanced no further than approximately 15 cm into the left internal jugular vein. Similar advancement was noted when inserting the pulmonary artery catheter under fluroscopic guidance. This indicated an obstruction in the confluence of the left internal jugular vein and the brachiocephalic vein. A postoperative chest contrast CT showed thrombosis in the confluence of the left internal jugular vein and the brachiocephalic vein. Considering that the chest CT scan was performed 2 months before the surgery, it is necessary to perform imaging again before surgery. PMID- 25731063 TI - [A case of ventricular tachycardia that was probably caused by coronary artery spasm induced by pericardial manipulation]. AB - We present a case of ventricular tachycardia (VT) that was probably caused by coronary artery spasm. A 74-year-old man was scheduled to undergo right lower lobectomy for lung cancer. Although he had never suffered from any episodes of ischemic heart disease, he had several risk factors for coronary artery disease (CAD); i. e., a history of smoking, a low high-density lipoprotein cholesterol level, and diabetes mellitus type 2. Anesthesia for one-lung ventilation was maintained by inhalation of sevoflurane (1-1.5%), the continuous intravenous infusion of remifentanil (0.1-0.15 MUg x kg(-1) x min(-1)), and the intermittent administration of epidural (T4-5) 2% mepivacaine (4 ml) and 0.75% ropivacaine (5 ml). During manipulation of the pericardium, the patient's systolic blood pressure suddenly increased to 200 mmHg, followed by an ST elevation on his electrocardiogram. Despite the immediate infusion of nitroglycerin (1 mg), he developed non-sustained VT, lasting for about 30 seconds. Then, diltiazem (0.5 MUg x kg(-1) x min(-1)) was continuously administered, and the infusion rate of remifentanil was increased to 0.3 MUg x kg(-1) x min(-1). The patient recovered smoothly from anesthesia and his postoperative course was uneventful. Anesthesiologists should be aware of the possibility of coronary artery spasms induced by sudden modulation of the autonomic nervous system, particularly in patients who are at high risk of CAD. PMID- 25731064 TI - [Three cases of perioperative anaphylaxis identified by using skin-prick tests]. AB - We encountered three cases of perioperative anaphylaxis identified by using skin prick tests. [Case 1] A 43-year-old woman was scheduled to undergo elective laparoscopic subtotal gastrectomy under general anesthesia for gastric tumor. However, the procedure was cancelled because of anaphylaxis that was noted at the beginning of the surgery. We performed a skin-prick test and observed a positive reaction with ro- curonium. [Case 2] A 79-year-old man underwent laparoscopic colon resection under general anesthesia for colon cancer. Anaphylaxis was noted at the end of surgery. We performed a skin-prick test and observed a positive reaction with sugammadex. [Case 3] A 44-year-old woman underwent myomectomy under general anesthesia for a uterine fibroid. Anaphylaxis was noted approximately 10 minutes after the beginning of surgery. We performed a skin-prick test and noted a positive reaction with latex. It is difficult to identify the reason for anaphylaxis during surgery under general anesthesia because various agents may be responsible for the anaphylactic reaction. Anaphylaxis during surgery is a rare but life-threatening event and it is important to identify the causative agent for anaphylaxis. PMID- 25731065 TI - [Postoperative takotsubo cardiomyopathy caused by an ectopic paraganglinoma after gastric submucosal tumor resection]. AB - We encountered an 80-year-old woman with an ectopic paraganglioma of the bladder who developed takotsubo cardiomyopathy after gastric submucosal resection performed for an unrelated tumor. Preoperative blood pressure control was not necessary despite the presence of the noradrenaline-producing paraganglioma However, the patient developed severe intraoperative hypotension, and thereafter manifested takotsubo cardiomyopathy after the operation. Perioperative stress and catecholamine production by the bladder paraganglioma were considered to have induced the takotsubo cardiomyopathy. In retrospect, considering the influence of potential catecholamine release from the paraganglioma, we should probably have scheduled preferential treatment of the bladder paraganglioma and strictly monitored the perioperative hemodynamics. PMID- 25731066 TI - [A case report: perioperative management of adenotonsillectomy in a morbidly obese patient with severe obstructive sleep apnea syndrome]. AB - A male patient in his thirties was scheduled to undergo adenotonsillectomy due to dyspnea from bilateral tonsillar hypertrophy. He was morbidly obese (body mass index 56 kg x m(-2)) with severe obstructive sleep apnea syndrome (OSAS), and thus was evaluated with extreme risk for difficult ventilation and intubation. We planned awake intubation via video-assisted laryngoscopy and fiberoptic bronchoscopy under dexmedetomidine sedation, and the intubation was successfully performed. After adenotonsillectomy, upper airway obstruction due to hemorrhage and oropharyngeal swelling can be life-threatening requiring emergent airway management. Thus for postoperative airway management, due to the possibility of "cannot intubate, cannot ventilate" (CICV) and presumed difficult tracheotomy, we scheduled to perform tracheotomy during adenotonsillectomy, right after anesthetic induction and awake intubation. On postoperative day 1, he started walking with no need of sedative drugs. On day 4, after confirmation of minimal oropharyngeal swelling, tracheal cannulae was removed, and no further complications were observed in his postoperative course. We conclude that careful preoperative evaluation of the airway, retention of spontaneous breathing via awake intubation, and preventive tracheotomy for postoperative airway management are important points in perioperative management of a morbidly obese patient with severe obstructive sleep apnea syndrome. PMID- 25731067 TI - 3D silver nanoparticles decorated zinc oxide/silicon heterostructured nanomace arrays as high-performance surface-enhanced Raman scattering substrates. AB - Three-dimensional (3D) hierarchical nanostructures have been considered as one of the most promising surface-enhanced Raman spectroscopy (SERS) substrates because of the ordered arrangement of high-density hotspots along the third dimension direction. Herein, we reported a unique 3D nanostructure for SERS detection based on silver nanoparticles (AgNPs) decorated zinc oxide/silicon (ZnO/Si) heterostructured nanomace arrays. They were prepared by two steps: (1) Si nanoneedles were grafted onto ZnO nanorod arrays via a catalyst-assisted vapor liquid-solid (VLS) growth mechanism. (2) AgNPs were rapidly immobilized on the surface of nanomaces by a facile galvanic displacement reaction. The fabricated substrates were employed to detect rhodamine 6G (R6G) with a detection limit down to 10(-16) M, and exhibited a high-enhanced performance (enhancement factor (EF) as high as 8.7 * 10(7)). To illustrate the potential value of the prepared substrates, the different concentrations of melamine aqueous solution (from 10( 4) to 10(-10) M) were detected, and a quantitative relationship between the SERS spectrum intensity and the melamine concentration had been established. In addition, the measure of melamine residual in pure milk was carried out successfully, and the results indicated that the prepared 3D nanomace substrates had great potential in food inspection, environment protection, and a few other technologically important fields. PMID- 25731068 TI - The analysis of colored acrylic, cotton, and wool textile fibers using micro Raman spectroscopy. Part 2: comparison with the traditional methods of fiber examination. AB - In the second part of this survey, the ability of micro-Raman spectroscopy to discriminate 180 fiber samples of blue, black, and red cottons, wools, and acrylics was compared to that gathered with the traditional methods for the examination of textile fibers in a forensic context (including light microscopy methods, UV-vis microspectrophotometry and thin-layer chromatography). This study shows that the Raman technique plays a complementary and useful role to obtain further discriminations after the application of light microscopy methods and UV vis microspectrophotometry and assure the nondestructive nature of the analytical sequence. These additional discriminations were observed despite the lower discriminating powers of Raman data considered individually, compared to those of light microscopy and UV-vis MSP. This study also confirms that an instrument equipped with several laser lines is necessary for an efficient use as applied to the examination of textile fibers in a forensic setting. PMID- 25731069 TI - Effect of time and duration of untreated psychosis on cognitive and social functioning in Chinese patients with first-episode schizophrenia: A 1-year study. AB - BACKGROUND: Duration of untreated psychosis (DUP) is believed to exert a deleterious effect on cognitive and social function. However, to date, results remain inconclusive. AIMS: To investigate the effect of time and DUP on cognitive and social functioning in first-episode schizophrenia (FES) subjects in Shanghai, China. METHODS: FES patients were subjected to a comprehensive neuropsychological battery, the Personal and Social Performance scale (PSP) and the Positive and Negative Symptoms Scale (PANSS) at baseline, 6 month and 1 year. DUP was defined as the time from onset of first psychotic symptoms to first contact made with psychiatric services. RESULTS: Though the rate of non-completers in our observational study was relatively high (40%), we did not find any significant differences between the completers and non-completers (P-values > 0.05). Significant impairments in verbal learning and memory and executive function were noted over the course of 1 year. Meanwhile, social function improved significantly over the course of 1 year. Although, DUP did not share any significant relationship with cognitive or social function the effect estimate (range: - 0.03 to 0.02) of an increase of 1 month in DUP was clinically non negligible in this study. CONCLUSIONS: In Chinese FES patients, the longitudinal course of cognitive function tends to worsen in verbal learning and memory, executive function and motor speed, while that of social function tends to improve. DUP was not found to be associated with cognitive or social deterioration in Chinese FES. PMID- 25731070 TI - Prevalence and correlates of functional dependence among maintenance dialysis patients. AB - Functional dependence is an important determinant of longevity and quality of life. The purpose of the current study was to determine the prevalence and correlates of functional dependence among patients with end-stage renal disease (ESRD) receiving maintenance dialysis. We enrolled 148 participants with ESRD from five clinics. Functional status, as measured by basic and instrumental activities of daily living (ADL, IADL), was ascertained by validated questionnaires. Functional dependence was defined as needing assistance in at least one of seven IADLs or at least one of four ADLs. Demographic characteristics, chronic health conditions, anthropometric measurements, and laboratories were assessed by a combination of self-report and chart review. Cognitive function was assessed with a neurocognitive battery, and depressive symptoms were assessed by questionnaire. Mean age of the sample was 56.2 +/- 14.6 years. Eighty-seven participants (58.8%) demonstrated dependence in ADLs or IADLs, 70 (47.2%) exhibited IADL dependence alone, and 17 (11.5%) exhibited combined IADL and ADL dependence. In a multivariable-adjusted model, stroke, cognitive impairment, and higher systolic blood pressure were independent correlates of functional dependence. We found no significant association between demographic characteristics, chronic health conditions, depressive symptoms or laboratory measurements, and functional dependence. Impairment in executive function was more strongly associated with functional dependence than memory impairment. Functional dependence is common among ESRD patients and independently associated with stroke, systolic blood pressure, and executive function impairment. PMID- 25731071 TI - Pancreatic neuroendocrine tumors in von Hippel-Lindau disease. PMID- 25731072 TI - Drug survival of cyclosporine in the treatment of hand eczema: a multicentre, daily use study. AB - BACKGROUND: Hand eczema is a common condition; it is often chronic and can be difficult to treat. Cyclosporine is used off-label to treat severe hand eczema; however, the evidence for this treatment is scarce. OBJECTIVE: To examine the drug survival of cyclosporine in a daily practice cohort of patients with chronic hand eczema. METHODS: This retrospective daily use study included hand eczema patients who were treated with cyclosporine between 01-06-1999 and 01-06-2014 in two Dutch university hospitals. Patient and treatment characteristics were retrospectively collected from medical charts. First treatment episodes were analysed by means of Kaplan-Meier drug survival curves. Possible determinants of drug survival were analysed by Cox regression models. Treatment effectiveness was analysed with a retrospective physician's global assessment. RESULTS: A total of 102 patients were treated with cyclosporine. The median drug survival rate was 0.86 years (10.3 months). The overall drug survival rate after 6 months, 1, 2 and 3 years were 61.7%, 45.2%, 18.6% and 13.9% respectively. Main reasons for discontinuation were adverse events, especially early in treatment, and ineffectiveness. After 3 months, a good response to treatment was recorded in 62.9% of the patients. CONCLUSION: Cyclosporine had a median drug survival of 10.3 months. Especially patients with recurrent vesicular hand eczema showed a good treatment response. PMID- 25731073 TI - Improving patient knowledge and safe use of opioids: a randomized controlled trial. AB - OBJECTIVES: The use of opioid analgesics in the United States has significantly increased in recent years. However, there is minimal consensus on what discharge counseling should accompany these high-risk prescriptions and large variations in what is done in practice. The objective of this study was to evaluate the effect of a dual-modality (written and spoken) literacy-appropriate educational strategy on patients' knowledge of and safe use of opioid analgesics. METHODS: This was a prospective, randomized controlled trial. Consecutive discharged patients at an urban academic ED (>88,000 visits) with new prescriptions for hydrocodone acetaminophen were enrolled. Patients were randomized to receive either usual care or the educational intervention. The educational intervention was a one-page information sheet about hydrocodone-acetaminophen, which was both given to the patients and read aloud by the research assistant (nonblinded). Follow-up phone calls were conducted 4 to 7 days after the visit to assess patient knowledge about the medication and self-report of activities associated with safety of use (e.g., double-dipping with acetaminophen, storage, use with alcohol or while driving). RESULTS: A total of 274 patients were enrolled; 210 completed follow-up (110 usual care and 100 intervention). No significant differences in baseline characteristics emerged between the study arms; 42% were male, and 51% were white, with a median age of 43 years. Half of patients had non-back pain orthopedic injuries (49.5%). On follow-up, overall knowledge was poor, with only 28% able to name both active ingredients in the medication. The intervention group had better knowledge of precautions related to taking additional acetaminophen (usual care 18.2%, 95% confidence interval [CI] = 10.9% to 25.5% vs. intervention 38%, 95% CI = 28.3% to 47.7%; difference = 27.6, 95% CI of difference = 21.5 to 33.7) and knowledge of side effects (usual care median = 1, interquartile range [IQR] 0 to 2 vs. intervention median = 2, IQR = 1 to 2; p < 0.0001). Additionally, those who received the intervention were less likely to have reported driving within 6 hours after taking hydrocodone (usual care 13.6%, 95% CI = 7.2% to 20% vs. intervention 3%, 95% CI = -0.3% to 6.3%; difference = 10.6, 95% CI of difference = 3.4 to 17.9). There was no difference between groups related to knowledge about drinking alcohol while taking hydrocodone (overall 18.1%) or knowledge that the opioid could be addictive (overall 72.4%). CONCLUSIONS: This simple strategy improved several, but not all, aspects of patient knowledge and resulted in fewer patients in the intervention arm driving while taking hydrocodone. Integration of a patient education document into conversations about opioids holds promise for improving patient knowledge about these high-risk medications. PMID- 25731074 TI - Effect of calcination conditions on porous reduced titanium oxides and oxynitrides via a preceramic polymer route. AB - A preceramic polymer route from Ti-based inorganic-organic hybrid networks provides electroconductive N-doped reduced titanium oxides (TinO2n-1) and titanium oxynitrides (TiOxNy) with a monolithic shape as well as well-defined porous structures. This methodology demonstrates an advantageously lower temperature of the crystal phase transition compared to the reduction of TiO2 by carbon or hydrogen. In this study, the effect of calcination conditions on various features of the products has been explored by adopting three different atmospheric conditions and varying the calcination temperature. The detailed crystallographic and elemental analyses disclose the distinguished difference in the phase transition behavior with respect to the calcination atmosphere. The correlation between the crystallization and nitridation behaviors, porous properties, and electric conductivities in the final products is discussed. PMID- 25731076 TI - Assessment of racial and sex disparities in open femoral fractures. AB - BACKGROUND: Open femoral fractures are common; however, many factors may affect treatment protocol. We aim to assess any racial/ethnic or sex disparities associated with the definitive fixation of open femoral fractures. METHODS: ICD-9 codes from the National Trauma Data Bank (2007 to 2010) for patients greater than or equal to 18 years with open femoral fractures who underwent operative management at level I or II trauma centers were identified and analyzed. RESULTS: Of the 9,406 cases, the majority were White (61%), men (73%), and aged between 25 and 44 years (41%). The odds of definitive fixation after hospital day 2 (odds ratio [OR] .96, 95% confidence interval [CI] .82 to 1.09, P = .53) or any complication (OR .96, 95% CI .79 to 1.15, P = .69) were not associated with race/ethnicity. Men were 17% less likely to have surgery after hospital day 2 (OR .83, 95% CI .78 to .96, P < .001), and 18% more likely to have a complication (OR 1.18, 95% CI 1.03 to 1.35, P = .02). CONCLUSIONS: There are no racial/ethnic disparities associated with the timing of definitive fixation. Men are more likely to undergo fixation earlier than women; however, they are more likely to have a complication. Fixation within the first 2 hospital days may decrease complications. PMID- 25731075 TI - CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. AB - Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one of the major limitations in the use of triptans. However their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question of where is the target site(s) for antimigraine action. The gepants are small molecules that can partially pass the blood-brain barrier (BBB) and therefore, might have effects in the CNS. However, antibodies are large molecules and have limited possibility to pass the BBB, thus effectively excluding them from having a major site of action within the CNS. It is suggested that the antimigraine site should reside in areas not limited by the BBB such as intra- and extracranial vessels, dural mast cells and the trigeminal system. In order to clarify this topic and surrounding questions, it is important to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB. PMID- 25731077 TI - Caregiving and 5-HTTLPR Genotype Predict Adolescent Physiological Stress Reactivity: Confirmatory Tests of Gene * Environment Interactions. AB - A theory-driven confirmatory approach comparing diathesis-stress and differential susceptibility models of Gene * Environment (G * E) interactions was applied to examine whether 5-HTTLPR genotype moderated the effect of early maternal caregiving on autonomic nervous system (ANS) stress reactivity in 113 adolescents aged 13-17 years. Findings supported a differential susceptibility, rather than diathesis-stress, framework. Carriers of one or more 5-HTTLPR short alleles (SS/SL carriers) reporting higher quality caregiving exhibited approach ANS responses to a speech task, whereas those reporting lower quality caregiving exhibited withdrawal ANS responses. Carriers of two 5-HTTLPR long alleles (LL carriers) were unaffected by caregiving. Findings suggest that 5-HTTLPR genotype and early caregiving in interaction are associated with ANS stress reactivity in adolescents in a "for better and for worse" fashion, and they demonstrate the promise of confirmatory methods for testing G * E interactions. PMID- 25731078 TI - Modulating the serotonin system in the treatment of major depressive disorder ERRATUM. PMID- 25731079 TI - Towards the integration and development of a cross-European research network and infrastructure: the DEterminants of DIet and Physical ACtivity (DEDIPAC) Knowledge Hub. AB - To address major societal challenges and enhance cooperation in research across Europe, the European Commission has initiated and facilitated 'joint programming'. Joint programming is a process by which Member States engage in defining, developing and implementing a common strategic research agenda, based on a shared vision of how to address major societal challenges that no Member State is capable of resolving independently. Setting up a Joint Programming Initiative (JPI) should also contribute to avoiding unnecessary overlap and repetition of research, and enable and enhance the development and use of standardised research methods, procedures and data management. The Determinants of Diet and Physical Activity (DEDIPAC) Knowledge Hub (KH) is the first act of the European JPI 'A Healthy Diet for a Healthy Life'. The objective of DEDIPAC is to contribute to improving understanding of the determinants of dietary, physical activity and sedentary behaviours. DEDIPAC KH is a multi-disciplinary consortium of 46 consortia and organisations supported by joint programming grants from 12 countries across Europe. The work is divided into three thematic areas: (I) assessment and harmonisation of methods for future research, surveillance and monitoring, and for evaluation of interventions and policies; (II) determinants of dietary, physical activity and sedentary behaviours across the life course and in vulnerable groups; and (III) evaluation and benchmarking of public health and policy interventions aimed at improving dietary, physical activity and sedentary behaviours. In the first three years, DEDIPAC KH will organise, develop, share and harmonise expertise, methods, measures, data and other infrastructure. This should further European research and improve the broad multi-disciplinary approach needed to study the interactions between multilevel determinants in influencing dietary, physical activity and sedentary behaviours. Insights will be translated into more effective interventions and policies for the promotion of healthier behaviours and more effective monitoring and evaluation of the impacts of such interventions. PMID- 25731081 TI - Functional characterization of three (GH13) branching enzymes involved in cyanobacterial starch biosynthesis from Cyanobacterium sp. NBRC 102756. AB - Starch and glycogen are widespread storage polysaccharides in bacteria, plants, and animals. Recently, some cyanobacteria were found to accumulate water insoluble alpha-glucan similar to amylopectin rather than glycogen, the latter of which is more commonly produced in these organisms. The amylopectin-producing species including Cyanobacterium sp. NBRC 102756 invariably have three branching enzyme (BE) homologs, BE1, BE2, and BE3, all belonging to the glycoside hydrolase family 13. Multiple BE isoforms in prokaryotes have not been previously studied. In the present work, we carried out functional characterization of these enzymes expressed in Escherichia coli. The recombinant enzymes were all active, although the specific activity of BE3 was much lower than those of BE1 and BE2. After the incubation of the enzymes with amylopectin or amylose, the reaction products were analyzed by fluorophore-assisted carbohydrate capillary electrophoresis method. BE1 and BE2 showed similar chain-length preference to BEIIb isoform of rice (Oryza sativa L.), while the catalytic specificity of BE3 was similar to that of rice BEI. These results indicate that starch-producing cyanobacteria have both type-I BE (BE3) and type-II BEs (BE1 and BE2) in terms of chain-length preferences, as is the case of plants. All BE isoforms were active against phosphorylase limit dextrin, in which outer branches had been uniformly diminished to 4 glucose residues. Based on its catalytic properties, BE3 was assumed to have a role to transfer the glucan chain bearing branch(es) to give rise to a newly growing unit, or cluster as observed in amylopectin molecule. PMID- 25731080 TI - Moonlighting O-acetylserine sulfhydrylase: New functions for an old protein. AB - O-acetylserine sulfhydrylase A (CysK) is the pyridoxal 5'-phosphate-dependent enzyme that catalyzes the final reaction of cysteine biosynthesis in bacteria. CysK was initially identified in a complex with serine acetyltransferase (CysE), which catalyzes the penultimate reaction in the synthetic pathway. This "cysteine synthase" complex is stabilized by insertion of the CysE C-terminus into the active-site of CysK. Remarkably, the CysK/CysE binding interaction is conserved in most bacterial and plant systems. For the past 40years, CysK was thought to function exclusively in cysteine biosynthesis, but recent studies have revealed a repertoire of additional "moonlighting" activities for this enzyme. CysK and its paralogs influence transcription in both Gram-positive bacteria and the nematode Caenorhabditis elegans. CysK also activates an antibacterial nuclease toxin produced by uropathogenic Escherichia coli. Intriguingly, each moonlighting activity requires a binding partner that invariably mimics the C-terminus of CysE to interact with the CysK active site. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio applications. PMID- 25731082 TI - Conserved C272/278 in b domain regulate the function of PDI-P5 to make lysozymes trypsin-resistant forms via significant intermolecular disulfide cross-linking. AB - Protein disulfide isomerase-P5 (P5) is thought to have important functions as an oxidoreductase, however, molecular functions of P5 have not been fully elucidated. We have reported that P5 has insulin reductase activity and inhibits lysozyme refolding by formation of lysozyme multimers with hypermolecular mass inactivated by intermolecular disulfides (hyLYS) in oxidative refolding of reduced denatured lysozyme. To explore the role of each domain of P5, we investigated the effects of domain deletion and Cys-Ala mutants of P5 on insulin reduction and the oxidative refolding of the lysozyme. The mutants of catalytic cysteines, C36/39A, C171/174A, and C36/39/171/174A inhibited the lysozyme refolding almost similarly to P5, and even b domain without catalytic cysteines showed moderate inhibitory effect, suggesting that the b domain played a key role in the inhibition. Western blotting analysis of the refolding products indicated that the catalytic cysteines in both the a and a' domains cross-linked lysozyme comparably to form hyLYS resistant to trypsin, in which b domain was suggested to capture lysozyme for the significant sulfhydryl oxidation. The mutant of the conserved cysteines in b domain, C272/278A, did not form hyLYS, however, showed predominant reductase activity, implying that P5 functioned as a potent sulfhydryl oxidase and a predominant reductase depending on the circumstance around C272/278. These results provide new insight into the molecular basis of P5 function. PMID- 25731083 TI - Characterisation of the Manduca sexta sperm proteome: Genetic novelty underlying sperm composition in Lepidoptera. AB - The application of mass spectrometry based proteomics to sperm biology has greatly accelerated progress in understanding the molecular composition and function of spermatozoa. To date, these approaches have been largely restricted to model organisms, all of which produce a single sperm morph capable of oocyte fertilisation. Here we apply high-throughput mass spectrometry proteomic analysis to characterise sperm composition in Manduca sexta, the tobacco hornworm moth, which produce heteromorphic sperm, including one fertilisation competent (eupyrene) and one incompetent (apyrene) sperm type. This resulted in the high confidence identification of 896 proteins from a co-mixed sample of both sperm types, of which 167 are encoded by genes with strict one-to-one orthology in Drosophila melanogaster. Importantly, over half (55.1%) of these orthologous proteins have previously been identified in the D. melanogaster sperm proteome and exhibit significant conservation in quantitative protein abundance in sperm between the two species. Despite the complex nature of gene expression across spermatogenic stages, a significant correlation was also observed between sperm protein abundance and testis gene expression. Lepidopteran-specific sperm proteins (e.g., proteins with no homology to proteins in non-Lepidopteran taxa) were present in significantly greater abundance on average than those with homology outside the Lepidoptera. Given the disproportionate production of apyrene sperm (96% of all mature sperm in Manduca) relative to eupyrene sperm, these evolutionarily novel and highly abundant proteins are candidates for possessing apyrene-specific functions. Lastly, comparative genomic analyses of testis-expressed, ovary-expressed and sperm genes identified a concentration of novel sperm proteins shared amongst Lepidoptera of potential relevance to the evolutionary origin of heteromorphic spermatogenesis. As the first published Lepidopteran sperm proteome, this whole-cell proteomic characterisation will facilitate future evolutionary genetic and developmental studies of heteromorphic sperm production and parasperm function. Furthermore, the analyses presented here provide useful annotation information regarding sex-biased gene expression, novel Lepidopteran genes and gene function in the male gamete to complement the newly sequenced and annotated Manduca genome. PMID- 25731085 TI - Growth in literacy, cognition, and working memory in English language learners. AB - This cohort sequential study explored the components of working memory that underlie English reading and language acquisition in elementary school children whose first language is Spanish. To this end, children (N=410) in Grades 1, 2, and 3 at Wave 1 were administered a battery of cognitive (short-term memory [STM], working memory [WM], rapid naming, phonological processing, and random letter and number generation), vocabulary, and reading measures in both Spanish and English. These same measures were administered 1 and 2 years later. The results showed that (a) a three-factor structure (phonological STM, visual spatial WM, and verbal WM) captured the data within both language systems, (b) growth in both the executive and STM storage components was uniquely related to growth in second language (L2) reading and language acquisition, and (c) the contribution of growth in the executive component of WM to growth in L2 processing was independent of growth in storage, phonological knowledge, inhibition, and rapid naming speed. The results suggested that growth in the phonological storage system does not supersede growth of the executive component of WM as a major contributor to growth in children's L2 reading and language. PMID- 25731086 TI - Application of reverse dot blot hybridization to simultaneous detection and identification of harmful algae. AB - Warning and monitoring projects of harmful algal blooms require simple and rapid methods for simultaneous and accurate detection and identification of causative algae present in the environmental samples. Here, reverse dot blot hybridization (RDBH) was employed to simultaneously detect several harmful algae by using five representative bloom-forming microalgae along the Chinese coast. A set of specific probes for RDBH were developed by PCR, cloning, and sequencing of the internal transcribed spacer (ITS), alignment analysis, and probe design. Each probe was oligo (dT)-tailed and spotted onto positively charged nylon membrane to make up a low-density oligonucleotide array. Universal primers designed within the conserved regions were used to amplify the ITS sequences by using genomic DNA of target as templates. The digoxigenin (Dig)-labeled PCR products were denatured and then hybridized to the oligonucleotide array. The array produced a unique hybridization pattern for each target species differentiating them from each other. The preparations of oligonucleotide array and hybridization conditions were optimized. The developed RDBH demonstrated a detection limit up to 10 cells. The detection performance of RDBH was relatively stable and not affected by non target species and the fixation time of target species over at least 30 days. The RDBH could recover all the target species from the simulated field samples and target species confirmed by the subsequent microscopy examination in the environmental samples. These results indicate that RDBH can be a new technical platform for parallel discrimination of harmful algae and is promising for environmental monitoring of these microorganisms. PMID- 25731087 TI - Distinguishing anthropogenic and natural sources of trace elements in soils undergoing recent 10-year rapid urbanization: a case of Donggang, Eastern China. AB - A total of 59 samples consisting of 45 topsoils samples and 14 subsoils samples were collected from urban soils of Donggang and were analyzed for soil properties and 12 trace elements. The mean contents of As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Se, V, and Zn in topsoils were 5.76, 0.20, 9.88, 44.82, 17.69, 0.05, 578.96, 19.98, 28.38, 0.21, 58.88, and 58.32 mg kg(-1), respectively. The mean enrichment factor results suggested that Hg, Cd, Pb, Cu, Se, and Zn were enriched in topsoils compared with subsoils. Spatial distribution maps of trace elements indicated that Hg, Cd, Pb, Cu, Se, and Zn had similar patterns, with the highest values in the industrial region. There were no significant associations displayed between spatial distributions of As, Co, Cr, Mn, Ni, and V and the industrial region. Through correlation analysis, stepwise regression analysis, and redundancy analysis, three main sources of 12 trace elements were identified. Cd, Hg, and Se originated from industrial emissions and coal combustion, and As, Co, Cr, Mn, Ni, and V had a lithogenic origin. The combination of human activities and natural sources contributed to the contents of Cu, Pb, and Zn, and the human activities included industrial and traffic emissions. PMID- 25731088 TI - Chronic exposures to low and high concentrations of ibuprofen elicit different gene response patterns in a euryhaline fish. AB - Ibuprofen is one of the most commonly detected pharmaceuticals in wastewater effluent; however, the effects of ibuprofen on aquatic organisms are poorly understood. This study presents the transcriptome-wide response of the inland silverside, Menidia beryllina, to chronic exposure to ibuprofen. At the lowest exposure concentration (0.0115 mg/L), we detected a downregulation of many genes involved in skeletal development, aerobic respiration, and immune function. At the highest exposure concentration (1.15 mg/L), we detected increased expression of regulatory genes in the arachidonic acid metabolism pathway and several immune genes involved in an inflammatory response. Additionally, there was differential expression of genes involved in oxidative stress responses and a downregulation of genes involved in osmoregulation. This study provides useful information for monitoring the effects of this common wastewater effluent contaminant in the environment and for the generation of biomarkers of exposure to ibuprofen that may be transferable to other fish species. PMID- 25731089 TI - Reduction of mercury (II) by humic substances--influence of pH, salinity of aquatic system. AB - This study demonstrates that under abiotic dark conditions in aquatic system, humic substances are not only capable of converting Hg(II) to Hg(0) but also able to bind Hg(II) ion. The degree of Hg(II) reduction is significantly influenced by the ratio of -COOH/-OH groups and the sulfur content in the HS, revealing a strong competition between complexation and reduction of Hg(II). This study suggests that abiotic and dark Hg(II) reduction depends on the pH and salinity of aqueous medium. At lower pH (~ 4.0) and lower salinity (<= 5.0 PSU), the reduction of Hg(II) to elemental mercury (Hg(0)) was comparatively rapid. Higher COOH/-OH ratios in HS, favors dark abiotic reduction of Hg(II) as did a lower sulfur (S) content of HS. This study provided a rigorously controlled experimental design that showed that dark abiotic Hg(II) reduction by HS can potentially be important in the aquatic environment and is independent of the photochemical reduction observed in both fresh water and sea water. PMID- 25731090 TI - All-optical broadband ultrasonography of single cells. AB - Cell mechanics play a key role in several fundamental biological processes, such as migration, proliferation, differentiation and tissue morphogenesis. In addition, many diseased conditions of the cell are correlated with altered cell mechanics, as in the case of cancer progression. For this there is much interest in methods that can map mechanical properties with a sub-cell resolution. Here, we demonstrate an inverted pulsed opto-acoustic microscope (iPOM) that operates in the 10 to 100 GHz range. These frequencies allow mapping quantitatively cell structures as thin as 10 nm and resolving the fibrillar details of cells. Using this non-invasive all-optical system, we produce high-resolution images based on mechanical properties as the contrast mechanisms, and we can observe the stiffness and adhesion of single migrating stem cells. The technique should allow transferring the diagnostic and imaging abilities of ultrasonic imaging to the single-cell scale, thus opening new avenues for cell biology and biomaterial sciences. PMID- 25731091 TI - Preparation of hydrocarbon/fluorocarbon double-chain phospholipid polymer brusheson polyurethane films by ATRP. AB - To fabricate artificial biomembrane mimicking cell surfaces, hydrocarbon/fluorocarbon double-chain phospholipid macromonomer was grafted on polyurethane (PU) film surfaces by surface-initiated atom transfer radical polymerization (SI-ATRP). The surface structures of modified PU film surfaces were characterized by X-ray photoelectron spectroscopy (XPS) and water contact angle measurement. The results indicate that initiator densities on these polymer film surfaces have a significant impact on graft polymerization of this fluorocarbon phospholipid macromonomer. The phospholipid polymer brushes grafted on PU film surfaces could self-assemble into biomimetic membranes under water environment, as demonstrated by liquid/liquid static contact angle measurement, atomic force spectroscopy (AFM), and attenuated total reflectance Fourier transform infrared (ATR-FTIR). These biomimetic membranes could maintain water within them as the "surrounding" water. Such would be favorable condition for the preservation of native conformational state of proteins and cell membranes. This work provides a new approach to fabricate biomimetic membranes on biomaterials surfaces. PMID- 25731092 TI - In vitro degradation behavior and cytocompatibility of biodegradable AZ31 alloy with PEO/HT composite coating. AB - Biodegradable magnesium-based implants have attracted much attention recently in orthopedic applications because of their good mechanical properties and biocompatibility. However, their rapid degradation in vivo will not only reduce their mechanical strength, but also induce some side effects, such as local alkalization and gas cavity, which may lead to a failure of the implant. In this work, a hydroxyapatite (HA) layer was prepared on plasma electrolytic oxidization (PEO) coating by hydrothermal treatment (HT) to fabricate a PEO/HT composite coating on biodegradable AZ31 alloy. The in vitro degradation behaviors of all samples were evaluated in simulated body fluid (SBF) and their surface cytocompatibility was also investigated by evaluating the adhesion and proliferation of osteoblast cells (MC3T3-E1). The results showed that the HA layer consisted of a dense inner layer and a needle-like outer layer, which successfully sealed the PEO coating. The in vitro degradation tests showed that the PEO/HT composite coating improved the corrosion resistance of AZ31 alloy in SBF, presenting nearly no severe local alkalization and hydrogen evolution. The lasting corrosion resistance of the PEO/HT composite coating may attribute to the new hydroxyapatite formation during the degradation process. Moreover, compared with AZ31 alloy and PEO coating, PEO/HT composite coating was more suitable for cells adhesion and proliferation, indicating improved surface cytocompatibility. The results show that the PEO/HT composite coating is promising as protective coating on biodegradable magnesium-based implants to enhance their corrosion resistance as well as improve their surface cytocompatibility for orthopedic applications. PMID- 25731093 TI - Crystallographic structure of Ni-Co coating on the affinity adsorption of histidine-tagged protein. AB - The principle of immobilized metal affinity chromatography (IMAC) has been recently implemented for protein microarrays for the study of protein abundance and function. Ni-Co film fabricated by electrodeposition is a novel microarray surface in an alloy type for immobilizing histidine-tagged proteins based on IMAC. In this paper, the effects of crystallographic structures and surface properties of Ni-Co coatings, with and without the annealing process, on the immobilization of histidine-tagged proteins were systematically investigated. The experimental results reveal that the stronger hcp texture, due to a higher Co content, results in better affinity adsorption for histidine-tagged biotin. Nevertheless, the allotropic phase transformation from hcp to fcc, due to the annealing process, leads to the decrease of affinity adsorption. The wettability property and the surface roughness of Ni-Co coating are, however, not important factors. Obviously, the crystallographic structure of Ni-Co coating is the dominant factor for the specific affinity adsorption of histidine-tagged protein. PMID- 25731094 TI - AFM in peak force mode applied to worn siloxane-hydrogel contact lenses. AB - The objective of this work is to apply Atomic Force Microscopy in Peak Force mode to obtain topographic characteristics (mean roughness, root-mean-square roughness, skewness and kurtosis) and mechanical characteristics (adhesion, elastic modulus) of Siloxane-Hydrogel Soft Contact Lenses (CLs) of two different materials, Lotrafilcon B of Air Optix (AO) and Asmofilcon A of PremiO (P), after use (worn CLs). Thus, the results obtained with both materials will be compared, as well as the changes produced by the wear at a nanoscopic level. The results show significant changes in the topographic and mechanical characteristics of the CLs, at a nanoscopic level, due to wear. The AO CL show values of the topographic parameters lower than those of the P CL after wear, which correlates with a better comfort qualification given to the former by the wearers. A significant correlation has also been obtained between the adhesion values found after the use of the CLs with tear quality tests, both break-up-time and Schirmer. PMID- 25731095 TI - Development of a diagnostic polymersome system for potential imaging delivery. AB - In order to enhance visualization of soft tissues, a dual-imaging diagnostic polymersome system featured with highly hydrated multilamellar wall structure capable of simultaneously embedding a hydrophobic near-infrared fluorophore, Cy5.5, and a paramagnetic probe, gadolinium (Gd(III)) cations was developed. The polymersomes were obtained from the self-assembly of lipid-containing copolymer, poly(acrylic acid-co-distearin acrylate), in aqueous solution. The Cy5.5 and Gd(III) species were loaded into polymersomes via hydrophobic association (loading efficiency of Cy5.5 ca 74%) and electrostatic complexation (Gd(III) 83%), respectively. The Cy5.5/Gd(III)-loaded polymersomes (CGLPs) have shown excellent payload confinement, reduced dilution effect on assembly dissociation and decreased protein/salt-induced colloidal aggregation. Owing to the highly hydrated structure of vesicular membrane, the superior contrast enhancement of CGLPs in magnetic resonance (MR) imaging was obtained as a result of prolonged rotational correlation time of Gd(III) cations and fast water exchange from Gd(III) to bulk solution. The CGLPs exhibit a 15-fold higher longitudinal relaxivity value (ca 60 mM(-1) s(-1)) than that (4 mM(-1) s(-1)) of the commercial contrast agent, Magnevist, in phosphate buffered saline. The in vivo characterization demonstrates that CGLPs exhibit a signal-to-noise ratio in T1 weighted MR image contrast similar to that of Magnevist, yet with a Gd dose 5 fold lower. An excellent contrast in NIR imaging at tumor site was attained following the intravenous injection of GGLPs into Tramp-C1 tumor-bearing mice (C57BL/6). Along with their non-toxicity at the dose used, these results demonstrate the great potential of the CGLPs as an advanced diagnostic nanodevice. PMID- 25731096 TI - Development of novel mesoporous nanomatrix-supported lipid bilayers for oral sustained delivery of the water-insoluble drug, lovastatin. AB - The purpose of this study was to investigate the effect of a core/shell structured nanocomposite, mesoporous nanomatrix-supported lipid bilayer (MN-SLB), as an oral drug nanocarrier, on the dissolution behavior and in vivo absorption of a water-insoluble drug, lovastatin (LOV). The formulation strategy was based on the use of drug-loaded mesoporous silica as the core for the fusion of liposomes. Field emission scanning electron microscopy (FESEM), cryogenic transmission electron microscopy (Cryo-TEM) and nitrogen adsorption were used to systematically characterize the drug carrier and drug-loaded MN-SLB formulation, confirming the successful inclusion of LOV into the nano-pores of MN-SLB. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) confirmed that the incorporated drug in the carrier was in an amorphous state. An in vitro dissolution study showed that LOV-loaded MN-SLB exhibited a sustained drug release behavior. Compared with the LOV-loaded mesoporous silica particles, LOV loaded MN-SLB markedly suppressed the burst release. Furthermore, the pharmacokinetics and relative bioavailability of the LOV-loaded MN-SLB formulation was studied in beagle dogs after oral administration and using a commercially available immediate release formulation (Sandoz Lovastatin(r)) as a reference. It was found that the relative bioavailability of LOV and LOV beta hydroxy acid (LOVA) for the LOV-loaded MN-SLB formulation was 207.2% and 192.1%, respectively. In addition, MN-SLB exhibited negligible toxicity against Caco-2 and HT-29 cells in cytotoxicity assays. The results of this study indicate that the MN-SLB nanocomposite is a promising candidate as a novel oral drug delivery nanovehicle for controlling the dissolution rate and improving the oral absorption of water-insoluble drugs. PMID- 25731097 TI - A facile one-pot synthesis of starch functionalized graphene as nano-carrier for pH sensitive and starch-mediated drug delivery. AB - A fast, green and facile method was developed to prepare starch functionalized graphene nanosheets (starch-GNS) via the reduction of exfoliated graphene oxides by soluble starch, which acted both as a reductant and as a functionalization reagent for capping graphene nanosheets to prevent aggregation. The as-prepared starch-GNS exhibited good biocompatibility, which was deemed crucial for the biomedical application of graphene. Cellular toxicity tests suggested that the starch-GNS was nontoxic to SW-620 cells even at the relatively concentration of 200 MUg mL(-1). After the loading of the commonly used anticancer drug hydroxycamptothecin (HCPT) via physisorption on starch-GNS, the HCPT@starch-GNS composite exhibited a high drug loading capacity and was therefore used for cellular imaging and drug delivery studies. Through the nonspecific endocytosis effect, the HCPT@starch-GNS composite was encapsulated into cytoplasm by SW-620 cancer cells. With the double action of an acid microenvironment and the diastase in SW-620 cells, the HCPT@starch-GNS composite showed high toxicity to the SW-620 cells and experienced a pH sensitive as well as a starch-mediated in vitro sustained release process, which had the potential advantage of improving therapeutic efficacy. Therefore, the starch-GNS composite could be used as an ideal nano-carrier for drug delivery and offered a new avenue for broadening the application of graphene in biomedicine. PMID- 25731098 TI - Trading polymeric microspheres: exchanging DNA molecules via microsphere interaction. AB - A new class of artificial molecular transport system is constructed by polymeric microspheres. The microspheres are prepared by self-assembly of poly(ethylene glycol)-block-poly(3-dimethyl(methacryloyloxyethyl)ammonium propane sulfonate), PEG-b-PDMAPS, by intermolecular dipole-dipole interaction of sulfobetaine side chains in water. Below the upper critical solution temperature (UCST) of PEG-b PDMAPS, the microspheres (~1MUm) interact with other microspheres by partial and transit fusion. In order to apply the interaction between microspheres, a 3' TAMRA-labeled single-stranded DNA oligomer (ssDNA) is encapsulated into a PEG-b PDMAPS microsphere by thermal treatment. The exchange of ssDNA between microspheres is confirmed by fluorescence resonance energy transfer (FRET) quenching derived from double-stranded formation with complementary 5'-BHQ-2 labeled ssDNA encapsulated in PEG-b-PDMAPS microspheres. The exchange rate of ssDNA is controllable by tuning the composition of the polymer. The contact dependent transport of molecules can be applied in the areas of microreactors, sensor devices, etc. PMID- 25731099 TI - Programming cell fate on bio-functionalized silicon. AB - Controlling the growth of cells on the surface of silicon without an additive layer or topographical modification is unexplored. This research article delineates the discovery of unique properties of a bio-functionalized silicon substrate, programmed to repel or control cells, generated by ultrafast femtosecond pulse interaction with silicon. Remarkably, bio-functionalization in any shape or size without change in topology or morphology is observed indicating only sub-surface phase transformations. Material characterization reveals the presence of a unique mixture of phases of SiO2 and Si. Consequently, these variations in phase alter the physicochemical characteristics on the surface of silicon resulting in its bio-functionalization. The culture of mouse embryonic fibroblasts shows unique adhesion characteristics on these bio-functionalized silicon surfaces that include cell controlling, cell trapping, and cell shaping. Furthermore, the directionality of fibroblasts is restrained parallel to bio functionalized zones as evidenced by changes in cytoskeleton. The controlling of proliferation, migration and adhesion of cells is attributed to unique phase bio functionalization. This method presents considerable promise in a myriad of applications such as tissue engineering, MEMS, and lab-on-a-chip devices. PMID- 25731100 TI - Electrospun poly(L-lactic acid-co-E-caprolactone) fibers loaded with heparin and vascular endothelial growth factor to improve blood compatibility and endothelial progenitor cell proliferation. AB - Emulsion electrospinning is a convenient and promising method for incorporating proteins and drugs into nanofiber scaffolds. The aim of this study was to fabricate a nanofiber scaffold for anticoagulation and rapid endothelialization. For this purpose, we encapsulated heparin and vascular endothelial growth factor (VEGF) into the core of poly(L-lactic acid-co-E-caprolactone) (P(LLA-CL)) core shell nanofibers via emulsion electrospinning. The fiber morphology, core-shell structure and hydrophilicity of the nanofiber mats were analyzed by scanning electron microscopy, transmission electron microscopy and water contact angle. The blood compatibility was measured by hemolysis and anticoagulation testing. A CCK-8 assay was performed to study the promotion of endothelial progenitor cell (EPC) growth and was complemented by immunofluorescent staining and SEM. Our study demonstrates that heparin and VEGF can be incorporated into P(LLA-CL) nanofibers via emulsion. The released heparin performed well as an anticoagulant, and the released VEGF promoted EPC growth on the fiber scaffolds. These results imply that electrospun P(LLA-CL) nanofibers containing heparin and VEGF have great potential in the development of vascular grafts in cases where antithrombogenicity and accelerated endothelialization are desirable. PMID- 25731101 TI - Effects of irradiation and pH on fluorescence properties and flocculation of extracellular polymeric substances from the cyanobacterium Chroococcus minutus. AB - Microbial extracellular polymeric substances (EPS) may flocculate or be decomposed when environmental factors change, which significantly influences nutrient cycling and transport of heavy metals. However, little information is available on the stability of EPS in natural environments. Fluorescence and flocculation properties of EPS from Chroococcus minutus under different irradiation and pH conditions were studied. Two aromatic protein-like fluorescence peaks and one tyrosine protein-like peak were identified from the excitation-emission-matrix (EEM) fluorescence spectra of EPS. UVB (ultraviolet B) and solar irradiation increased the fluorescence intensity of all the three peaks while UVC (ultraviolet C) irradiation had little effect. EPS formed unstable flocs after exposure to UV (ultraviolet) irradiation and formed stable flocs under solar irradiation. EPS were prone to flocculation under highly acidic conditions and minimal fluorescence of peaks was observed. The fluorophores in EPS were relatively stable under neutral and alkaline conditions. These findings are helpful for understanding the behavior of EPS in aquatic environments and their role in biogeochemical cycles of the elements. PMID- 25731102 TI - Cationic liposomes evoke proinflammatory mediator release and neutrophil extracellular traps (NETs) toward human neutrophils. AB - Cationic liposomes are widely used as nanocarriers for therapeutic and diagnostic purposes. The cationic components of liposomes can induce inflammatory responses. This study examined the effect of cationic liposomes on human neutrophil activation. Cetyltrimethylammonium bromide (CTAB) or soyaethyl morpholinium ethosulfate (SME) was incorporated into liposomes as the cationic additive. The liposomes' cytotoxicity and their induction of proinflammatory mediators, intracellular calcium, and neutrophil extracellular traps (NETs) were investigated. The interaction of the liposomes with the plasma membrane triggered the stimulation of neutrophils. CTAB liposomes induced complete leakage of lactate dehydrogenase (LDH) at all concentrations tested, whereas SME liposomes released LDH in a concentration-dependent manner. CTAB liposomes proved to more effectively activate neutrophils compared with SME liposomes, as indicated by increased superoxide anion and elastase levels. Calcium influx increased 9-fold after treatment with CTAB liposomes. This influx was not changed by SME liposomes compared with the untreated control. Scanning electron microscopy (SEM) and immunofluorescence images indicated the presence of NETs after treatment with cationic liposomes. NETs could be quickly formed, within minutes, after CTAB liposomal treatment. In contrast to this result, NET formation was slowly and gradually increased by SME liposomes, within 4h. Based on the data presented here, it is important to consider the toxicity of cationic liposomes during administration in the body. This is the first report providing evidence of NET production induced by cationic liposomes. PMID- 25731103 TI - Performance comparison of LUR and OK in PM2.5 concentration mapping: a multidimensional perspective. AB - Methods of Land Use Regression (LUR) modeling and Ordinary Kriging (OK) interpolation have been widely used to offset the shortcomings of PM2.5 data observed at sparse monitoring sites. However, traditional point-based performance evaluation strategy for these methods remains stagnant, which could cause unreasonable mapping results. To address this challenge, this study employs 'information entropy', an area-based statistic, along with traditional point based statistics (e.g. error rate, RMSE) to evaluate the performance of LUR model and OK interpolation in mapping PM2.5 concentrations in Houston from a multidimensional perspective. The point-based validation reveals significant differences between LUR and OK at different test sites despite the similar end result accuracy (e.g. error rate 6.13% vs. 7.01%). Meanwhile, the area-based validation demonstrates that the PM2.5 concentrations simulated by the LUR model exhibits more detailed variations than those interpolated by the OK method (i.e. information entropy, 7.79 vs. 3.63). Results suggest that LUR modeling could better refine the spatial distribution scenario of PM2.5 concentrations compared to OK interpolation. The significance of this study primarily lies in promoting the integration of point- and area-based statistics for model performance evaluation in air pollution mapping. PMID- 25731126 TI - Suicidal Kronlein shot with a home manufactured firearm. PMID- 25731127 TI - First report of a mermithid nematode infecting the invasive Megacopta cribraria (Hemiptera: Plataspidae) in the United States. AB - Megacopta cribraria (Hemiptera: Plataspidae) has become a pest of soybean, Glycine max (L.), in the United States. While several natural enemies of M. cribraria have been reported, our study is the first to report nematodes beneath the pleural membranes in the abdominal cavities of adults. Morphological and molecular analyses suggest this nematode belongs to the family Mermithidae. This first report of a nematode infection in M. cribraria adds to the current inventory of enemies attacking this insect. Our observations provide a basis for future research to examine the impact of nematodes on M. cribraria mortality and to investigate their capacity to reduce populations. PMID- 25731128 TI - The neural correlates of volitional attention: A combined fMRI and ERP study. AB - Studies of visual-spatial attention typically use instructional cues to direct attention to a relevant location, but in everyday vision, attention is often focused volitionally, in the absence of external signals. Although investigations of cued attention comprise hundreds of behavioral and physiological studies, remarkably few studies of voluntary attention have addressed the challenging question of how spatial attention is initiated and controlled in the absence of external instructions, which we refer to as willed attention. To explore this question, we employed a trial-by-trial spatial attention task using electroencephalography and functional magnetic resonance imaging (fMRI). The fMRI results reveal a unique network of brain regions for willed attention that includes the anterior cingulate cortex, left middle frontal gyrus (MFG), and the left and right anterior insula (AI). We also observed two event-related potentials (ERPs) associated with willed attention; one with a frontal distribution occurring 250-350 ms postdecision cue onset (EWAC: Early Willed Attention Component), and another occurring between 400 and 800 ms postdecision cue onset (WAC: Willed Attention Component). In addition, each ERP component uniquely correlated across subjects with different willed attention-specific sites of BOLD activation. The EWAC was correlated with the willed attention specific left AI and left MFG activations and the later WAC was correlated only with left AI. These results offer a comprehensive and novel view of the electrophysiological and anatomical profile of willed attention and further illustrate the relationship between scalp-recorded ERPs and the BOLD response. PMID- 25731129 TI - The role of urban food policy in preventing diet-related non-communicable diseases in Cape Town and New York. AB - OBJECTIVES: Cities are important settings for production and prevention of non communicable diseases. This article proposes a conceptual framework for identification of opportunities to prevent diet-related non-communicable diseases in cities. It compares two cities, Cape Town in South Africa and New York City in the United States, to illustrate municipal, regional, national and global influences in three policy domains that influence NCDs: product formulation, shaping retail environments and institutional food practices, domains in which each city has taken action. STUDY DESIGN: Comparative case study. METHODS: Critical analysis of selected published studies and government and non governmental reports on food policies and systems in Cape Town and New York City. RESULTS: While Cape Town and New York City differ in governance, history and culture, both have food systems that make unhealthy food more available in low income than higher income neighborhoods; cope with food environments in which unhealthy food is increasingly ubiquitous; and have political economies dominated by business and financial sectors. New York City has more authority and resources to take on local influences on food environments but neither city has made progress in addressing deeper social determinants of diet-related NCDs including income inequality, child poverty and the disproportionate political influence of wealthy elites. CONCLUSIONS: Through their intimate connections with the daily lives of their residents, municipal governments have the potential to shape environments that promote health. Identifying the specific opportunities to prevent diet-related NCDs in a particular city requires intersectoral and multilevel analyses of the full range of influences on food environments. PMID- 25731130 TI - Information search behaviour, understanding and use of nutrition labeling by residents of Madrid, Spain. AB - OBJETIVES: To describe the information search behaviour, comprehension level, and use of nutritional labeling by consumers according to sociodemographic characteristics. STUDY DESIGN: Cross-sectional study of consumers recruited in five stores of the main supermarket chains in Madrid: a random sample of 299 consumers (response rate: 80.6%). METHODS: Interviewers collected information about the information search behaviour, comprehension, and use of nutritional labeling using a questionnaire designed for this purpose. Analyses examined the frequency of the variables of interest. Differences were tested using the Chi square statistic. RESULTS: In this sample, 38.8% of consumers regularly read the nutritional labeling before making a purchase (45% of women vs 30% in men; P = 0.03) and the most common reason reported was choosing healthier products (81.3%). The proportion of people who were interested in additives and fats was the higher, (55% and 50%, respectively). Lack of time (38.9%), lack of interest (27.1%), and reading difficulties (18.1%) were the most common reasons given for not reading labels. Over half (52.4%) of consumers reported completely understanding the nutritional information on labels and 20.5% reported using such information for dietary planning. CONCLUSIONS: Reported information search behaviour, comprehension, and use of nutritional labeling were relatively high among consumers of the study, and their main goal was picking healthier products. However, not only are there still barriers to reading the information, but also the information most relevant to health is not always read or understood. Thus, interventions to increase nutritional labeling comprehension and use are required in order to facilitate the making of healthier choices by consumers. PMID- 25731131 TI - NFAT transcription factors regulate survival, proliferation, migration, and differentiation of neural precursor cells. AB - The study of factors that regulate the survival, proliferation, and differentiation of neural precursor cells (NPCs) is essential to understand neural development as well as brain regeneration. The Nuclear Factor of Activated T Cells (NFAT) is a family of transcription factors that can affect these processes besides playing key roles during development, such as stimulating axonal growth in neurons, maturation of immune system cells, heart valve formation, and differentiation of skeletal muscle and bone. Interestingly, NFAT signaling can also promote cell differentiation in adults, participating in tissue regeneration. The goal of the present study is to evaluate the expression of NFAT isoforms in NPCs, and to investigate its possible role in NPC survival, proliferation, migration, and differentiation. Our findings indicate that NFAT proteins are active not only in neurogenic brain regions such as hippocampus and subventricular zone (SVZ), but also in cultured NPCs. The inhibition of NFAT activation with the peptide VIVIT reduced neurosphere size and cell density in NPC cultures by decreasing proliferation and increasing cell death. VIVIT also decreased NPC migration and differentiation of astrocytes and neurons from NPCs. In addition, we identified NFATc3 as a predominant NFAT isoform in NPC cultures, finding that a constitutively-active form of NFATc3 expressed by adenoviral infection reduces NPC proliferation, stimulates migration, and is a potent inducer of NPC differentiation into astrocytes and neurons. In summary, our work uncovers active roles for NFAT signaling in NPC survival, proliferation and differentiation, and highlights its therapeutic potential for tissue regeneration. PMID- 25731132 TI - Design and feasibility of a memory intervention with focus on self-management for cognitive impairment in epilepsy. AB - The aim of this study was to assess the feasibility of a self-management intervention targeting cognitive dysfunction to improve quality of life and reduce memory-related disability in adults with epilepsy. The intervention incorporates (1) education on cognitive function in epilepsy, (2) self-awareness training, (3) compensatory strategies, and (4) application of these strategies in day-to-day life using problem-solving therapy. In addition to the behavioral modification, formal working memory training was conducted by utilizing a commercially available program in a subgroup of patients. Our findings suggest that a self-management intervention targeting cognitive dysfunction was feasible for delivery to a rural population with epilepsy, with 13 of 16 enrolled participants completing the 8-session program. Qualitative data indicate high satisfaction and subjective improvement in cognitive functioning in day-to-day life. These findings provide support for further evaluation of the efficacy of this intervention through a randomized controlled trial. PMID- 25731133 TI - Ezetimibe plus moderate-dose simvastatin after acute coronary syndrome: what are we IMPROVEing on? AB - The recent IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is the first study to demonstrate a significant benefit of another medication (ezetimibe) on top of statin therapy in patients who have recently experienced an acute coronary syndrome. Despite the fact that ezetimibe led to positive results on the primary endpoint, the clinical benefit translated to real life practice is only modest at best. However, this is the first major trial to demonstrate a significant benefit of a lipid medication in addition to statins. We explore the strengths and weaknesses of IMPROVE-IT in the context of current day acute coronary syndrome practice, where high-dose statins now are prescribed widely. PMID- 25731134 TI - Electronic Cigarettes-A Narrative Review for Clinicians. AB - Electronic cigarettes (e-cigarettes) were introduced into the US market in 2007 and have quickly become a popular source of nicotine for many patients. They are designed to simulate smoking by heating a nicotine-containing solution producing an aerosol that the user inhales. The short- and long-term effects of e-cigarette use are still unclear, but their use is increasing. Some acute effects of e cigarettes on heart rate, blood pressure, and airway resistance are reported. Although there are some reports of improved cessation in a subset of users, there are also studies reporting decreased cessation in dual users of regular and e cigarettes. Additionally, there is no current regulation of these devices, and this allows virtually anyone with a form of online payment to obtain them. PMID- 25731135 TI - Why do so many Americans oppose the Affordable Care Act? AB - The Patient Protection and Affordable Care Act (ACA) was passed by a Democratic Congress and signed into law by a Democratic president in 2010. Republican congressmen, governors, and Republican candidates have consistently opposed the ACA and have vowed to repeal it. Polls have consistently shown that it is supported by <50% of Americans. The most important goal of the ACA is to improve the health of Americans by increasing the number covered by health insurance. In the first year of its implementation, more than 10 million citizens gained health insurance. The percentage of Americans without health insurance decreased from 18% in July 2013 to 13.4% in June 2014. In addition, the ACA has eliminated many of the negative features of private insurance such as the denial of coverage for those with "prior conditions." The benefits of Medicare have been enhanced to decrease the cost of prescription drugs and to eliminate co-pays for preventive services. Despite these positive changes, a near majority of Americans still oppose the ACA, even though they approve of most of its features. They oppose the mandate that all Americans must have health insurance (the individual mandate), and they oppose a government role in health care. Yet Medicare, a mandatory insurance for seniors administered by the federal government since 1965, is overwhelmingly approved by the American public. The opposition to a government role in health care is based on the fact that that the vast majority of our citizens do not trust their government. Republicans are much less trusting of the federal government and much less supportive of a government role in health care than Democrats. The overwhelmingly negative TV ads against the ACA by the Republican candidates in the elections of 2012 and 2014 have had a major impact on Americans' views of the ACA. More than 60% of Americans have stated that most of what they know about the ACA came from watching TV. Opposition to a government role in health care and to mandatory health insurance makes it unlikely that the US will be able to insure that all of its citizens have ongoing access to health care in the near future. PMID- 25731136 TI - Gender differences in salary of internal medicine residency directors: a national survey. AB - OBJECTIVES: Whether salary disparities exist between men and women in medical education leadership roles is not known. The study objective was to determine whether salary disparities exist between male and female Internal Medicine residency program directors, and if so, to identify factors associated with the disparities and explore historical trends. METHODS: The annual Association of Program Directors in Internal Medicine (APDIM) survey in August 2012 included items to assess the salary and demographic characteristics of program directors, which were merged with publically available program data. To assess historical trends, we used similarly obtained survey data from 2008 to 2011. The study included program directors of 370 APDIM member programs, representing 95.6% of the 387 accredited Internal Medicine training programs in the United States and Puerto Rico. Of the 370 APDIM member programs, 241 (65.1%) completed the survey, of whom 169 (70.1%) were men and 72 (29.9%) were women. Program directors' total annual salary, measured in $25,000 increments, ranged from $75,000 or less to more than $400,000. Historical trends of mode salary by gender from 2008 to 2012 were assessed. RESULTS: The mode salary was $200,000 to 225,000 for men and $175,000 to $200,000 for women (P = .0005). After controlling for academic rank, career in general internal medicine, and program director age, the distribution of salary remained different by gender (P = .004). Historical trends show that the difference in mode salary has persisted since 2008. CONCLUSIONS: Leaders in academic medical centers, residency and fellowship directors, and all faculty in medical education need to be aware that salary disparities cited decades ago persist in this sample of medical educators. Closing the gender gap will require continued advocacy for measuring and reporting salary gaps, and changing the culture of academic medical centers. PMID- 25731137 TI - Obstructive sleep apnea: a new preventive and therapeutic target for stroke: a new kid on the block. AB - Stroke is the second leading cause of death worldwide and a major cause of mental and physical impairment. Numerous studies have identified risk factors for stroke, including hypertension, atrial fibrillation, diabetes, and smoking. However, even after considering these well-recognized risk factors, there is substantial variation in stroke rates and stroke-related outcomes. There is emerging evidence that obstructive sleep apnea increases the risk of stroke independently of traditional risk factors. Obstructive sleep apnea is present in the majority of patients with stroke and contributes to persistent neurologic impairment. Early recognition and treatment of obstructive sleep apnea during the post-stroke period lead to better neurologic outcome. Healthcare providers should be aware of the strong association of obstructive sleep apnea as a risk factor for stroke and its effect on neurologic recovery. The presence of hypertension and diabetes-the 2 most common comorbid conditions in obstructive sleep apnea should prompt diagnostic workup for and treatment of obstructive sleep apnea as a way of primary and secondary prevention of stroke. PMID- 25731138 TI - Irritable bowel syndrome: modern concepts and management options. AB - Irritable bowel syndrome is the most common functional gastrointestinal disorder, manifesting as abdominal pain/discomfort and altered bowel function. Despite affecting as many as 20% of adults, a lack of understanding of etiopathogenesis and evaluation strategies results in diagnostic uncertainty, and in turn frustration of both the physician and the patient. This review summarizes the current literature on the diagnosis and management of irritable bowel syndrome, with attention to evidence-based approaches. A 4-step treatment strategy that has been used successfully in our tertiary referral practice is presented and should lead to successful therapeutic outcomes in the majority of patients with irritable bowel syndrome. PMID- 25731139 TI - Ebola Virus Disease: A Perspective for the United States. AB - Ebola virus caused an epidemic of unprecedented extension in West Africa. There was concern that the outbreak would not be controlled for a prolonged period of time. Two cases of infected returning travelers have been reported in the US. One of the cases has been associated with secondary transmission and other infected subjects have been repatriated for treatment. This article reviews the etiology, pathogenesis, transmission, clinical manifestations, diagnosis, treatment, and prevention of the disease with emphasis on the identification and management in the US. PMID- 25731140 TI - Assessment of hypertensive patients' self-care agency after counseling training of nurses. AB - PURPOSE: The aim of the study was to assess hypertensive patients' self-care agency and any correlation with the patient's lifestyle changes and the nurse's degree of patient centeredness after counseling training. DATA SOURCES: Nurses in the intervention group (IG; n = 19) working at nurse-led clinics at health centers were trained in patient centeredness (motivational interviewing) and the stages of change model and included 137 patients. Nurses in the control group (CG; n = 14) included 51 patients. The Exercise of Self-Care Agency (ESCA) instrument was used. There was a significant difference from baseline to the 2 year follow-up in the ESCA score (IG, p = .0001). An increase in ESCA score was correlated with an increased level of physical activity after 2 years (IG, p = .0001; CG, p = .040). CONCLUSIONS: The counseling training gave an increase in the patients' self-care agency scores, which was significantly correlated with increased physical activity. IMPLICATIONS FOR PRACTICE: In clinical practice it is important for nurses to be patient centered in their counseling to affect patients' self-care agency in a positive direction. PMID- 25731142 TI - Plasmonic circular dichroism in side-by-side oligomers of gold nanorods: the influence of chiral molecule location and interparticle distance. AB - Chiral metal nanostructures, which exhibit plasmonic circular dichroism (PCD), have great potential for the development of chiral sensors and devices. Previously, we developed a method for fabricating chiral gold-nanorod oligomers: the nanorods are linked by achiral molecules, while chiral molecules (e.g.l- or d cysteine) on the Au surface exert a directional twisting force on the oligomers and thereby generate a PCD signal. In this paper, we investigate how the location of chiral molecules and the interparticle distance affect the PCD of the oligomers. Cysteine at the ends of the nanorods and those on the side were found to induce PCD with opposite signs. When we increased the interparticle distance, the PCD signal was weakened; in particular, cysteine at the ends lost the twisting effect. Besides introducing the twisting force at the Au surface, chiral molecules in the hydrophobic surfactant bilayer and those adsorbed outside the surfactants can also twist the oligomers and generate PCD signals. These findings not only provide guidelines to the manipulation of PCD signals, but also serve as a more elaborate platform for studying the nanoscale interactions between nanoparticles. PMID- 25731141 TI - Coupled Simulation of Hemodynamics and Vascular Growth and Remodeling in a Subject-Specific Geometry. AB - A computational framework to couple vascular growth and remodeling (G&R) with blood flow simulation in a 3D patient-specific geometry is presented. Hyperelastic and anisotropic properties are considered for the vessel wall material and a constrained mixture model is used to represent multiple constituents in the vessel wall, which was modeled as a membrane. The coupled simulation is divided into two time scales-a longer time scale for G&R and a shorter time scale for fluid dynamics simulation. G&R is simulated to evolve the boundary of the fluid domain, and fluid simulation is in turn used to generate wall shear stress and transmural pressure data that regulates G&R. To minimize required computation cost, the fluid dynamics are only simulated when G&R causes significant vascular geometric change. For demonstration, this coupled model was used to study the influence of stress-mediated growth parameters, and blood flow mechanics, on the behavior of the vascular tissue growth in a model of the infrarenal aorta derived from medical image data. PMID- 25731143 TI - Synthesis and Properties of Star HPMA Copolymer Nanocarriers Synthesised by RAFT Polymerisation Designed for Selective Anticancer Drug Delivery and Imaging. AB - High-molecular-weight star polymer drug nanocarriers intended for the treatment and/or visualisation of solid tumours were synthesised, and their physico chemical and preliminary in vitro biological properties were determined. The water-soluble star polymer carriers were prepared by the grafting of poly(amido amine) (PAMAM) dendrimers by hetero-telechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, synthesised by the controlled radical Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation. The well-defined star copolymers with Mw values ranging from 2 . 10(5) to 6 . 10(5) showing a low dispersity (approximately 1.2) were prepared in a high yield. A model anticancer drug, doxorubicin, was bound to the star polymer through a hydrazone bond, enabling the pH-controlled drug release in the target tumour tissue. The activated polymer arm ends of the star copolymer carrier enable a one-point attachment for the targeting ligands and/or a labelling moiety. In this study, the model TAMRA fluorescent dye was used to prove the feasibility of the polymer carrier visualisation by optical imaging in vitro. The tailor-made structure of the star polymer carriers should facilitate the synthesis of targeted polymer drug conjugates, even polymer theranostics, for simultaneous tumour drug delivery and imaging. PMID- 25731144 TI - [Revision arthroplasty : Histopathological diagnostics in periprosthetic joint infections]. AB - BACKGROUND: Histopathological differences in synovia and synovial-like interface membrane (SLIM) patterns can be used to differentiate periprosthetic particle induced reactions, bacterial infections (bacterial synovitis and osteomyelitis), mechanical-induced tissue alterations, adverse reactions to implant material, and arthrofibrosis (SLIM consensus classification). AIM: Because of differences in treatment the diagnosis of a bacterial implant infection is very important. Histopathological tests and scoring systems are important diagnostic tools in identifying deep implant infections in patients with unclear clinical history as well as radiographic and laboratory studies. RESULTS: Modern enzyme PCR-based methods, histochemical- and immune-histopathological techniques (CD3,CD15, CD68) are useful in identifying specific and nonspecific infections, as well as differentiating postsurgical changes from recurrent infections in patients with a spacer. In all histopathological scoring systems for bacterial infection, quantifying the number of neutrophil granulocytes in a defined number of high power fields is crucial. DISCUSSION: Neutrophil granulocytes can be detected through histochemical methods and more specifically by immune-histopathological techniques and by various quantification systems (histopathological scores) leading to the diagnosis of bacterial peri-implant infection. One important function of histopathology, apart from diagnosing infection, is to rule out other mechanisms of implant failure, such as tumor infiltrations, particle-induced reactions, and adverse reactions to implant materials. PMID- 25731145 TI - [No weakening of the muscles with body brace ]. PMID- 25731146 TI - Electrodeposition of palladium and reduced graphene oxide nanocomposites on foam nickel electrode for electrocatalytic hydrodechlorination of 4-chlorophenol. AB - A high-performance palladium (Pd) and reduced graphene oxide (RGO) composite electrode was prepared on foam-nickel (foam-Ni) via two-step electrodeposition processes. The scanning electron microscopic (SEM) observation showed that the obtained Pd/RGO/foam-Ni composite electrode displayed a uniform and compact morphology. The X-ray diffraction (XRD) and X-ray photoelectron spectroscopic (XPS) analysis confirmed the successful deposition of Pd and RGO on nickel substrate. The cyclic voltammetric (CV) measurements indicated that the presence of RGO greatly enhanced the active surface area of Pd particles deposited on foam Ni. The as-deposited Pd/RGO/foam-Ni electrode was applied to electrocatalytic hydrodechlorination (ECH) of 4-chlorophenol (4-CP). Various factors influencing the dechlorination of 4-CP such as dechlorination current, initial concentration of 4-CP, Na2SO4 concentration and initial pH were systematically investigated. The thermodynamic analysis showed that the dechlorination reaction of 4-CP at different temperatures followed the first-order kinetics and the activation energy for 4-CP dechlorination on Pd/RGO/foam-Ni electrode was calculated to be 51.96 kJ mol(-1). Under the optimum conditions, the dechlorination efficiency of 4-CP could reach 100% after 60-min ECH treatment. Moreover, the prepared Pd/RGO/foam-Ni composite electrode showed good stability for recycling utilization in ECH of 4-CP. PMID- 25731147 TI - Photodegradation mechanism of sulfonamides with excited triplet state dissolved organic matter: a case of sulfadiazine with 4-carboxybenzophenone as a proxy. AB - Excited triplet states of dissolved organic matter ((3)DOM*) are important players for photodegradation sulfonamide antibiotics (SAs) in sunlit natural waters. However, the triplet-mediated reaction mechanism was poorly understood. In this study, we investigated the reaction adopting sulfadiazine as a representative SA and 4-carboxybenzophenone (CBBP)as a proxy of DOM. Results showed that the excited triplet state of CBBP ((3)CBBP*) is responsible for the photodegradation of sulfadiazine. The reaction of (3)CBBP* with substructure model compounds verified there are two reaction sites (amino-or sulfonyl-N atoms) of sulfadiazine. Density functional theory calculations were performed, which unveiled that electrons transfer from the N reaction sites to the carbonyl oxygen atom of (3)CBBP* moiety, followed by proton transfers, leading to the formation of sulfadiazine radicals. Laser flash photolysis experiments were performed to confirm the mechanism. Thus, this study identified that the photodegradation mechanism of SAs initiated by (3)DOM*, which is important for understanding the photochemical fate, predicting the photoproducts, and assessing the ecological risks of SAs in the aquatic environment. PMID- 25731148 TI - Influence of coagulation mechanisms on the residual aluminum--the roles of coagulant species and MW of organic matter. AB - Aluminum (Al) based coagulants are widely used in coagulation process to enhance the removal of turbidity and dissolved substances in the drinking water treatment. However, it raised more concerns due to the increase of residual aluminum in treated water, which can cause even more issues. In this study, the effects of organic matter molecular weight and coagulants species on the concentration and aluminum distribution in residual aluminum were investigated. The residual aluminum concentration decreases as the organic matter (OM) molecular weight (MW) rises. Charge neutralization mechanism was found to be the most important factor that determines the residual aluminum concentration directly. Basically, higher Ala percentage leads to lower residual Al concentration at acidic conditions, and Alb/Alc plays an important role in controlling the residual Al concentration at neutral and alkaline condition. The flocs structures formed by charge neutralization mechanism will be more compact for the mid and high MW OM, and fractal dimension (Df) was important to reflect the dissolved residual aluminum rather than the flocs size. The total dissolved residual aluminum concentration of Al13 and Al30 was mainly contributed by the fractions with low and/or high MW, especially by the fraction with MW range of 0 1 kDa. PMID- 25731149 TI - Spurious alternative impact factors: The scale of the problem from an academic perspective. AB - The recent explosion in the number of predatory journals has led to the appearance of questionable websites providing fake or spurious impact factors, which are analyzed and discussed here. We believe that academic associations, universities, and research funding bodies must take action to stop these questionable practices. PMID- 25731150 TI - Postpartum depression and timing of spousal military deployment relative to pregnancy and delivery. AB - OBJECTIVE: This study aimed to determine the relationship between spousal deployment and postpartum depression diagnosis among U.S. military wives, accounting for the timing of deployment with respect to pregnancy and delivery. METHODS: A retrospective cohort study was conducted to evaluate the association between spousal deployment and postpartum depression among pregnant wives of active-duty service members. Electronic medical records for 161,454 births occurring between 2004 and 2009 were used to define postpartum depression. Three non-mutually exclusive exposure variables were created to categorize deployments as occurring before, during, or after the infant's delivery. A multivariable logistic regression model mutually adjusted for these exposure variables was fitted, producing an odds ratio for each of the three timing categories. RESULTS: A modest significant association was detected only in those whose husbands deployed in pregnancy and returned after delivery (i.e., deployed during delivery) [odds ratio (OR) 1.10, 95 % confidence interval (CI) 1.04-1.15]. An interactive effect between preexisting depression or anxiety and deployment during delivery was also detected in the data (OR 1.13, 95 % CI 1.07-1.20 for those without a preexisting diagnosis; OR 0.87, 95 % CI 0.80-0.95 for those with a preexisting diagnosis). CONCLUSION: Health care providers should continue to be aware of spousal deployment as a military-unique stressor in this population and rigorously screen for potential symptoms of postpartum depression, especially among those whose husbands are absent at delivery. PMID- 25731151 TI - Prognostic value of preoperative Ca125 and Tag72 serum levels and their correlation to disease relapse and survival in endometrial cancer. AB - OBJECTIVE: To evaluate preoperative serum levels of Ca125 and Tag72-4 tumour markers and investigate if abnormal levels correlate to mortality and disease free survival. METHOD: Retrospective observational study of a cohort of 282 women (mean age 62.3, SD 10.5 years) with primary endometrial cancer included all consecutive cases treated in a tertiary Gynaecological oncology Center. Excluded cases with other cancer or previous cancer treatment, major abdominal pathology or inflammation, endometriosis. Preoperative serum Tag72 and Ca125 levels were determined and evaluated in relation to disease-free survival (DFS) and disease specific overall survival (DOS). RESULTS: Raised Ca125 correlates to worse overall disease-specific survival (66.1 vs 87.8 months, p = 0.021) and Tag72 correlates to shorter disease-free survival (69.2 vs 67.3 months, p = 0.021) and higher recurrence rate (13.5 vs 6 %, p = 0.021). When both Ca125 and Tag72 are abnormal DFS and DOS are worse. 93.3 % (72.3 months) vs 82.4 %, (61.3 months) p = 0.018 and 96.3 % (74.8 months) vs 88.2 %, (65.9 months) p = 0.021, respectively. CONCLUSION: This study enhances the value of preoperative tumour markers and their prognostic value. Ca125 and Tag72 appear to be good predictors of poor prognosis in patients with endometrial cancer. PMID- 25731152 TI - 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with polycystic ovary syndrome in Chinese patients: a meta-analysis. AB - PURPOSE: To date, case-control studies on the association between a single nucleotide polymorphism (SNP) in the plasminogen activator inhibitor-1 (PAI-1) gene and polycystic ovary syndrome (PCOS) have provided controversial results. METHODS: The electronic databases PubMed, Embase, Web of Science, and CNKI (China National Knowledge Infrastructure) were searched for studies to include in the present meta-analysis. RESULTS: The fixed effects and random effects models showed that the 4G allele was associated with a risk of PCOS compared with the 5G allele in Chinese patients (OR = 2.05; 95 % CI = 1.56-2.69), but not in Caucasian patients (OR = 1.05; 95 % CI = 0.81-1.37). The contrast of homozygotes and the recessive and dominant models produced the same pattern of results as the allele contrast. CONCLUSION: Our pooled data suggest evidence for a major role of PAI-1 gene 4G/5G polymorphism in the pathogenesis of PCOS among Chinese patients. PMID- 25731153 TI - WITHDRAWN: Anticonvulsants for cocaine dependence. PMID- 25731154 TI - Reactivities of vinyl azides and their recent applications in nitrogen heterocycle synthesis. AB - Nitrogen heterocycles are abundant in natural products and pharmaceuticals. An emerging interest among synthetic chemists is to apply vinyl azides as a pivotal three-atom synthon for the construction of structurally complex and diverse N heterocyclic skeletons. The unique features of the azide group connected to an alkene moiety permit vinyl azides to function as electrophiles, nucleophiles, or radical acceptors; their access to diverse reaction pathways provides great opportunities to generate highly reactive intermediates with often unusual or unconventional reactivities. This tutorial review will systematically illustrate the reactivities of vinyl azides and describe recent breakthroughs in the development of new transformations that create N-heterocycles. PMID- 25731155 TI - Baseline caries risk assessment as a predictor of caries incidence. AB - Few studies have evaluated clinical outcomes following caries risk assessment in large datasets that reflect risk assessments performed during routine practice. OBJECTIVES: From clinical records, compare 18-month caries incidence according to baseline caries risk designation. METHODS: For this retrospective cohort study, data were collected from electronic records of non-edentulous adult patients who completed an oral examination and caries risk assessment (CRA) at a university instructional clinic from 2007 to 2012 (N=18,004 baseline patients). The primary outcome was the number of new decayed/restored teeth from the initial CRA to the ensuing oral examination, through June 30, 2013 (N=4468 patients with follow-up). We obtained doubly-robust estimates for 18-month caries increment by baseline CRA category (low, moderate, high, extreme), adjusted for patient characteristics (age, sex, payer type, race/ethnicity, number of teeth), provider type, and calendar year. RESULTS: Adjusted mean decayed, restored tooth (DFT) increment from baseline to follow-up was greater with each rising category of baseline caries risk, from low (0.94), moderate (1.26), high (1.79), to extreme (3.26). The percentage of patients with any newly affected teeth (DFT increment>0) was similar among low-risk and moderate-risk patients (cumulative incidence ratio, RR: 1.01; 95% confidence interval, CI: 0.83, 1.23), but was increased relative to low-risk patients among high-risk (RR: 1.28; 95% CI: 1.10, 1.52), and extreme risk patients (RR: 1.52; 95% CI: 1.23, 1.87). CONCLUSIONS: These results lend evidence that baseline caries risk predicts future caries in this setting, supporting the use of caries risk assessment to identify candidate patients for more intensive preventive therapy. CLINICAL SIGNIFICANCE: Identification of patients at greater risk for future caries helps clinicians to plan appropriate personalized care. In this study, a multifactorial approach to caries risk assessment effectively stratified patients into groups of higher or lower caries propensity. Dentists can apply risk assessment in practice antecedent to patient tailored caries management. PMID- 25731157 TI - Influence of dental restorations and mastication loadings on dentine fatigue behaviour: Image-based modelling approach. AB - OBJECTIVES: The aim of this study was to use Finite Element Analysis (FEA) to estimate the influence of various mastication loads and different tooth treatments (composite restoration and endodontic treatment) on dentine fatigue. The analysis of fatigue behaviour of human dentine in intact and composite restored teeth with root-canal-treatment using FEA and fatigue theory was performed. METHODS: Dentine fatigue behaviour was analysed in three virtual models: intact, composite-restored and endodontically-treated tooth. Volumetric change during the polymerization of composite was modelled by thermal expansion in a heat transfer analysis. Low and high shrinkage stresses were obtained by varying the linear shrinkage of composite. Mastication forces were applied occlusally with the load of 100, 150 and 200N. Assuming one million cycles, Fatigue Failure Index (FFI) was determined using Goodman's criterion while residual fatigue lifetime assessment was performed using Paris-power law. RESULTS: The analysis of the Goodman diagram gave both maximal allowed crack size and maximal number of cycles for the given stress ratio. The size of cracks was measured on virtual models. For the given conditions, fatigue-failure is not likely to happen neither in the intact tooth nor in treated teeth with low shrinkage stress. In the cases of high shrinkage stress, crack length was much larger than the maximal allowed crack and failure occurred with 150 and 200N loads. The maximal allowed crack size was slightly lower in the tooth with root canal treatment which induced somewhat higher FFI than in the case of tooth with only composite restoration. CONCLUSIONS: Main factors that lead to dentine fatigue are levels of occlusal load and polymerization stress. However, root canal treatment has small influence on dentine fatigue. CLINICAL SIGNIFICANCE: The methodology proposed in this study provides a new insight into the fatigue behaviour of teeth after dental treatments. Furthermore, it estimates maximal allowed crack size and maximal number of cycles for a specific case. PMID- 25731156 TI - Incorporation of bactericidal poly-acrylic acid modified copper iodide particles into adhesive resins. AB - OBJECTIVES: This study aimed to investigate incorporation of polyacrylic acid (PAA) coated copper iodide (CuI) nanoparticles into dental adhesives, and to evaluate for the first time, their antibacterial properties, bond strength and cytotoxicity. METHODS: PAA-CuI nanoparticles were synthesized and incorporated into commercially available adhesives Optibond XTR (1.0mg/ml) and XP Bond (0.5 and 1.0mg/ml). The antibacterial properties of experimental and control specimens were evaluated (n=8), after ageing for 18h or 1 year, against Streptococcus mutans (1*10(8)cells/ml). Bond strength to human dentine of the control and experimental adhesives was evaluated by shear bond strength (n=10). For cytotoxicity evaluation, HGF cells were cultured with gingival fibroblast media and exposed to control and experimental adhesive blends (n=3). An MTT cell viability assay was used to assess cell metabolic function. A one-way analysis of variance followed by Tukey's test was used for data analysis. RESULTS: Significantly greater antibacterial properties were demonstrated for PAA-CuI containing adhesives after ageing for 18h or 1 year relative to all control groups. A reduction in Streptococcus mutans viable cell count of 99.99%, 99.99% and 79.65% was shown for XP Bond - 0.5mg/ml, XP Bond - 1.0mg/ml and Optibond XTR 1.0mg/ml PAA-CuI after ageing for 18h, and 99.99% for both XP Bond - 0.5mg/ml and XP Bond - 1.0mg/ml PAA-CuI after ageing for 1 year. No significant variations in shear bond strength or cytotoxicity were detected between the experimental resins and their corresponding controls. CONCLUSIONS: PAA-CuI nanoparticles are an effective additive to adhesive blends as it renders them antibacterial without adversely affecting their bond strength or cytotoxicity. CLINICAL SIGNIFICANCE: The incorporation of PAA-coated copper iodide particles into adhesive resins renders the adhesive antibacterial to S. mutans for at least 1 year in vitro. This may prevent or delay bacterial invasion and the consequent development of caries lesions if the adhesive interface becomes defective. PMID- 25731158 TI - BLV-CoCoMo-qPCR-2: improvements to the BLV-CoCoMo-qPCR assay for bovine leukemia virus by reducing primer degeneracy and constructing an optimal standard curve. AB - Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis, which is the most common neoplastic disease of cattle. Because BLV infection can remain clinically silent, the proviral load is an important index for estimating disease progression. CoCoMo-qPCR, an assay developed to estimate BLV proviral load, allows the highly sensitive detection of BLV originating in different countries. Here, we developed a modified version of the CoCoMo-qPCR assay, the "BLV-CoCoMo-qPCR-2" assay, which uses optimized degenerate primers. We also constructed a new plasmid standard. Finally, we used both assays to examine DNA samples from BLV-infected cattle and compared the results. PMID- 25731159 TI - A gp130-Src-YAP module links inflammation to epithelial regeneration. AB - Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. PMID- 25731161 TI - Nuclear architecture dictates HIV-1 integration site selection. AB - Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome. However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. Once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle. PMID- 25731162 TI - Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. AB - The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases. PMID- 25731163 TI - Evolution: Fitness tracking for adapting populations. PMID- 25731164 TI - Pathogen-secreted proteases activate a novel plant immune pathway. AB - Mitogen-activated protein kinase (MAPK) cascades play central roles in innate immune signalling networks in plants and animals. In plants, however, the molecular mechanisms of how signal perception is transduced to MAPK activation remain elusive. Here we report that pathogen-secreted proteases activate a previously unknown signalling pathway in Arabidopsis thaliana involving the Galpha, Gbeta, and Ggamma subunits of heterotrimeric G-protein complexes, which function upstream of an MAPK cascade. In this pathway, receptor for activated C kinase 1 (RACK1) functions as a novel scaffold that binds to the Gbeta subunit as well as to all three tiers of the MAPK cascade, thereby linking upstream G protein signalling to downstream activation of an MAPK cascade. The protease-G protein-RACK1-MAPK cascade modules identified in these studies are distinct from previously described plant immune signalling pathways such as that elicited by bacterial flagellin, in which G proteins function downstream of or in parallel to an MAPK cascade without the involvement of the RACK1 scaffolding protein. The discovery of the new protease-mediated immune signalling pathway described here was facilitated by the use of the broad host range, opportunistic bacterial pathogen Pseudomonas aeruginosa. The ability of P. aeruginosa to infect both plants and animals makes it an excellent model to identify novel immunoregulatory strategies that account for its niche adaptation to diverse host tissues and immune systems. PMID- 25731165 TI - Observational determination of surface radiative forcing by CO2 from 2000 to 2010. AB - The climatic impact of CO2 and other greenhouse gases is usually quantified in terms of radiative forcing, calculated as the difference between estimates of the Earth's radiation field from pre-industrial and present-day concentrations of these gases. Radiative transfer models calculate that the increase in CO2 since 1750 corresponds to a global annual-mean radiative forcing at the tropopause of 1.82 +/- 0.19 W m(-2) (ref. 2). However, despite widespread scientific discussion and modelling of the climate impacts of well-mixed greenhouse gases, there is little direct observational evidence of the radiative impact of increasing atmospheric CO2. Here we present observationally based evidence of clear-sky CO2 surface radiative forcing that is directly attributable to the increase, between 2000 and 2010, of 22 parts per million atmospheric CO2. The time series of this forcing at the two locations-the Southern Great Plains and the North Slope of Alaska-are derived from Atmospheric Emitted Radiance Interferometer spectra together with ancillary measurements and thoroughly corroborated radiative transfer calculations. The time series both show statistically significant trends of 0.2 W m(-2) per decade (with respective uncertainties of +/-0.06 W m(-2) per decade and +/-0.07 W m(-2) per decade) and have seasonal ranges of 0.1-0.2 W m( 2). This is approximately ten per cent of the trend in downwelling longwave radiation. These results confirm theoretical predictions of the atmospheric greenhouse effect due to anthropogenic emissions, and provide empirical evidence of how rising CO2 levels, mediated by temporal variations due to photosynthesis and respiration, are affecting the surface energy balance. PMID- 25731166 TI - Massive migration from the steppe was a source for Indo-European languages in Europe. AB - We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of Western and Far Eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000-year old Siberian. By ~6,000-5,000 years ago, farmers throughout much of Europe had more hunter-gatherer ancestry than their predecessors, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but also from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~75% of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for a steppe origin of at least some of the Indo-European languages of Europe. PMID- 25731167 TI - Decrease in CO2 efflux from northern hardwater lakes with increasing atmospheric warming. AB - Boreal lakes are biogeochemical hotspots that alter carbon fluxes by sequestering particulate organic carbon in sediments and by oxidizing terrestrial dissolved organic matter to carbon dioxide (CO2) or methane through microbial processes. At present, such dilute lakes release ~1.4 petagrams of carbon annually to the atmosphere, and this carbon efflux may increase in the future in response to elevated temperatures and increased hydrological delivery of mineralizable dissolved organic matter to lakes. Much less is known about the potential effects of climate changes on carbon fluxes from carbonate-rich hardwater and saline lakes that account for about 20 per cent of inland water surface area. Here we show that atmospheric warming may reduce CO2 emissions from hardwater lakes. We analyse decadal records of meteorological variability, CO2 fluxes and water chemistry to investigate the processes affecting variations in pH and carbon exchange in hydrologically diverse lakes of central North America. We find that the lakes have shifted progressively from being substantial CO2 sources in the mid-1990s to sequestering CO2 by 2010, with a steady increase in annual mean pH. We attribute the observed changes in pH and CO2 uptake to an atmospheric-warming induced decline in ice cover in spring that decreases CO2 accumulation under ice, increases spring and summer pH, and enhances the chemical uptake of CO2 in hardwater lakes. Our study suggests that rising temperatures do not invariably increase CO2 emissions from aquatic ecosystems. PMID- 25731168 TI - Polyploidy can drive rapid adaptation in yeast. AB - Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood. Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations. For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability. The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms and can promote tumorigenesis in mammalian cells. Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology. Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation. PMID- 25731170 TI - Cell signalling: Disarming Wnt. PMID- 25731169 TI - Quantitative evolutionary dynamics using high-resolution lineage tracking. AB - Evolution of large asexual cell populations underlies ~30% of deaths worldwide, including those caused by bacteria, fungi, parasites, and cancer. However, the dynamics underlying these evolutionary processes remain poorly understood because they involve many competing beneficial lineages, most of which never rise above extremely low frequencies in the population. To observe these normally hidden evolutionary dynamics, we constructed a sequencing-based ultra high-resolution lineage tracking system in Saccharomyces cerevisiae that allowed us to monitor the relative frequencies of ~500,000 lineages simultaneously. In contrast to some expectations, we found that the spectrum of fitness effects of beneficial mutations is neither exponential nor monotonic. Early adaptation is a predictable consequence of this spectrum and is strikingly reproducible, but the initial small-effect mutations are soon outcompeted by rarer large-effect mutations that result in variability between replicates. These results suggest that early evolutionary dynamics may be deterministic for a period of time before stochastic effects become important. PMID- 25731171 TI - A dusty, normal galaxy in the epoch of reionization. AB - Candidates for the modest galaxies that formed most of the stars in the early Universe, at redshifts z > 7, have been found in large numbers with extremely deep restframe-ultraviolet imaging. But it has proved difficult for existing spectrographs to characterize them using their ultraviolet light. The detailed properties of these galaxies could be measured from dust and cool gas emission at far-infrared wavelengths if the galaxies have become sufficiently enriched in dust and metals. So far, however, the most distant galaxy discovered via its ultraviolet emission and subsequently detected in dust emission is only at z = 3.2 (ref. 5), and recent results have cast doubt on whether dust and molecules can be found in typical galaxies at z >= 7. Here we report thermal dust emission from an archetypal early Universe star-forming galaxy, A1689-zD1. We detect its stellar continuum in spectroscopy and determine its redshift to be z = 7.5 +/- 0.2 from a spectroscopic detection of the Lyman-alpha break. A1689-zD1 is representative of the star-forming population during the epoch of reionization, with a total star-formation rate of about 12 solar masses per year. The galaxy is highly evolved: it has a large stellar mass and is heavily enriched in dust, with a dust-to-gas ratio close to that of the Milky Way. Dusty, evolved galaxies are thus present among the fainter star-forming population at z > 7. PMID- 25731172 TI - A motor cortex circuit for motor planning and movement. AB - Activity in motor cortex predicts specific movements seconds before they occur, but how this preparatory activity relates to upcoming movements is obscure. We dissected the conversion of preparatory activity to movement within a structured motor cortex circuit. An anterior lateral region of the mouse cortex (a possible homologue of premotor cortex in primates) contains equal proportions of intermingled neurons predicting ipsi- or contralateral movements, yet unilateral inactivation of this cortical region during movement planning disrupts contralateral movements. Using cell-type-specific electrophysiology, cellular imaging and optogenetic perturbation, we show that layer 5 neurons projecting within the cortex have unbiased laterality. Activity with a contralateral population bias arises specifically in layer 5 neurons projecting to the brainstem, and only late during movement planning. These results reveal the transformation of distributed preparatory activity into movement commands within hierarchically organized cortical circuits. PMID- 25731173 TI - Selective corticostriatal plasticity during acquisition of an auditory discrimination task. AB - Perceptual decisions are based on the activity of sensory cortical neurons, but how organisms learn to transform this activity into appropriate actions remains unknown. Projections from the auditory cortex to the auditory striatum carry information that drives decisions in an auditory frequency discrimination task. To assess the role of these projections in learning, we developed a channelrhodopsin-2-based assay to probe selectively for synaptic plasticity associated with corticostriatal neurons representing different frequencies. Here we report that learning this auditory discrimination preferentially potentiates corticostriatal synapses from neurons representing either high or low frequencies, depending on reward contingencies. We observe frequency-dependent corticostriatal potentiation in vivo over the course of training, and in vitro in striatal brain slices. Our findings suggest a model in which the corticostriatal synapses made by neurons tuned to different features of the sound are selectively potentiated to enable the learned transformation of sound into action. PMID- 25731174 TI - Erratum: A new antibiotic kills pathogens without detectable resistance. PMID- 25731175 TI - Notum deacylates Wnt proteins to suppress signalling activity. AB - Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase. PMID- 25731178 TI - Advances in the Development of Site-Specific Antibody-Drug Conjugation. AB - Antibody-drug conjugates (ADCs) showed strong anticancer efficacy in the clinic. However, the current conventional technologies generate conjugates with undefined attachment sites and heterogeneous profiles containing different sub-populations, leading to potential off-target toxicity. In order to reduce the variability and heterogeneity associated with the ADCs generated using conventional technologies, several site-specific antibody-drug conjugation strategies were developed for the next generation of ADCs. These strategies include cysteine-targeted conjugation by engineering a free cysteine into the antibody or by placing a thiol bridge on cysteines in hinge disulfides. Glutamine-targeted conjugation was also demonstrated by coupling the drug-linker to glutamine residues through an engineered glutamine tag or a native glutamine, as well as an additionally introduced glutamine residue in aglycosylated antibody mutant using microbial transglutaminase. The site-specific conjugation of drug-linker to antibody carbohydrates was developed either through metabolic engineering or a chemo enzymatic approach. Other amino acids, such as unnatural amino acids or amino acid derivatives introduced through protein engineering, have also been shown to be efficient targets for site-specific conjugation. The sitespecific ADCs with homogeneous profiles and well-defined conjugation sites were obtained using these second generation ADC methods and showed potent in vitro cytotoxicity and strong in vivo antitumor activity. These results suggest that newly developed site specific conjugation technologies can potentially be applied in producing the next generation ADC for cancer treatment in the clinic with high therapeutic index. PMID- 25731176 TI - The nuclear encoded subunits gamma, delta and epsilon from the shrimp mitochondrial F1-ATP synthase, and their transcriptional response during hypoxia. AB - The mitochondrial FOF1 ATP synthase produces ATP in a reaction coupled to an electrochemical proton gradient generated by the electron transfer chain. The enzyme also hydrolyzes ATP according to the energy requirements of the organism. Shrimp need to overcome low oxygen concentrations in water and other energetic stressors, which in turn lead to mitochondrial responses. The aim of this study was to characterize the full-length cDNA sequences of three subunits that form the central stalk of the F1 catalytic domain of the ATP synthase of the white shrimp Litopenaeus vannamei and their deduced proteins. The effect of hypoxia on shrimp was also evaluated by measuring changes in the mRNA amounts of these subunits. The cDNA sequences of the nucleus-encoded ATPgamma, ATPdelta and ATPepsilon subunits are 1382, 477 and 277 bp long, respectively. The three deduced amino acid sequences exhibited highly conserved regions when compared to homologous sequences, and specific substitutions found in shrimp subunits are discussed through an homology structural model of F1 ATP-synthase that included the five deduced proteins, which confirm their functional structures and specific characteristics from the cognate complex of ATP synthases. Genes expression was evaluated during hypoxia-reoxygenation, and resulted in a generalized down regulation of the F1 subunits and no coordinated changes were detected among these five subunits. The reduced mRNA levels suggest a mitochondrial response to an oxidative stress event, similar to that observed at ischemia-reperfusion in mammals. This model analysis and responses to hypoxia-reoxygenation may help to better understand additional mitochondrial adaptive mechanisms. PMID- 25731177 TI - Cancer chemoprevention by natural carotenoids as an efficient strategy. AB - The use of specific compounds to suppress the growth of tumors or reverse carcinogenesis is defined as chemoprevention. Natural products have been known as one of the most important resources of anticancer agents. Among them, carotenoids are lipophilic molecules accumulating in lipophilic compartments including lipoproteins and/or membranes. Various carotenoids were used as major phytonutrients to inhibit the development of tumors in vitro and in vivo. They have shown different functions such as scavenging free radicals, inhibition of angiogenesis, prevention of cell propagation, and apoptosis induction in lung, colon, breast and prostate. Regarding these roles, most carotenoids possess anti oxidant properties. However, their therapeutic use is problematic due to the lack of solubility of carotenoids in water. Hence, recent studies have been focused on uncommon carotenoids soluble in water because of their glycosylated form, such as crocin(s) extracted from saffron. These structures with their cytotoxicity effects on human cancer cells are suggested as the most suitable compounds for cancer treatment. Herein, we summarize different functions of carotenoids for suppressing tumor growth. PMID- 25731179 TI - Complementary and alternative medicine for childhood asthma: an overview of evidence and patents. AB - Asthma is a prevalent childhood atopic disease associated with significant impairment of quality of life. Management relies on avoidance of triggers such as food and aeroallergens, the use of inhaled bronchodilators/corticosteroids and anti-allergic or immune-modulating therapies. Inhaled corticosteroids (ICSs) and bronchodilators have been the mainstay of treatment. In China as well as throughout Asia, myths and misconceptions on western medicine and corticosteroids are prevalent and result in non-adherence of treatment. A wide variety of complementary and alternative medicines (CAM) are available. Some of these have undergone extensive clinical trials and have been documented to have some therapeutic effects on asthma. Nevertheless, the majority of these treatment modalities is not efficacious and may even be detrimental. This article overviews the evidence for the clinical efficacy of all major CAM modalities. Despite CAM modalities are extensively used by the patients with asthma, very few CAM patents are available. This article also discusses recent patents pertinent to asthma. Only a few patents on herbal medicine for asthma have been evaluated but therapeutic efficacy is not substantially documented. Parents seeking CAM for asthma must consult qualified registered practitioners before using it. PMID- 25731181 TI - Hotspots of immune response to tumours can predict breast cancer progression, study shows. PMID- 25731180 TI - Screening and brief intervention for substance misuse: Does it reduce aggression and HIV-related risk behaviours? AB - PURPOSE: To explore whether reducing substance misuse through a brief motivational intervention also reduces aggression and HIV risk behaviours. METHODS: Participants were enrolled in a randomized controlled trial in primary care if they screened positive for substance misuse. Substance misuse was assessed using the Alcohol, Smoking and Substance Involvement Screening Test; aggression, using a modified version of the Explicit Aggression Scale; and HIV risk, through a count of common risk behaviours. The intervention was received on the day of the baseline interview, with a 3-month follow-up. RESULTS: Participants who received the intervention were significantly more likely to reduce their alcohol use than those who did not; no effect was identified for other substances. In addition, participants who reduced substance misuse (whether as an effect of the intervention or not) also reduced aggression but not HIV risk behaviours. CONCLUSIONS: Reducing substance misuse through any means reduces aggression; other interventions are needed for HIV risk reduction. PMID- 25731182 TI - Cohort and Gender Differences in Psychosocial Adjustment to Later-Life Widowhood. AB - OBJECTIVES: Despite the large body of literature on bereavement, little is known about the impact of sociohistorical context on individual reactions to spousal loss. This study examines the effect of marital status, time period and gender on physical and mental health, and whether reported difficulties following spousal loss differ at 2 distinctive time periods. METHOD: Two cohorts of older bereaved persons (n = 753) in Switzerland, surveyed in 1979 and 2011, were compared regarding their reports of difficulties related to marital loss. The bereaved spouses were also compared with a group of married contemporaries (n = 1,517) regarding subjective health and depressive symptoms. RESULTS: Marital status and gender each have independent effects on subjective health and depressive symptoms. The effects of widowhood on subjective health differed significantly at both time points. Widowed individuals in 2011, especially women, reported fewer social and financial difficulties than their counterparts in 1979. However, the effect of widowhood on depressive symptoms and psychological difficulties did not differ significantly across time points. DISCUSSION: Social changes in the late 20th century may be protective for older adults' physical, social, and financial well-being in the face of spousal loss, yet these changes do not alleviate widow(er)s' psychological distress. PMID- 25731183 TI - The Influence of Hyperactivity, Impulsivity, and Attention Problems on Social Functioning in Adolescents and Young Adults With Fragile X Syndrome. AB - OBJECTIVE: Individuals with fragile X syndrome (FXS) present primarily with cognitive and social deficits in addition to symptoms of ADHD. The relationship between symptoms of ADHD, cognitive functioning, and social skills has never been explicitly studied. METHOD: Here, we analyzed both longitudinal (n = 70; Time 1: ages 6-18; Time 2: ages 15-26) and cross-sectional (n = 73; Time 2 only) data using hierarchical linear regression to assess how global intellectual functioning (IQ) and symptoms of ADHD influence social functioning in individuals with FXS. RESULTS: We found that ADHD symptoms at Times 1 and 2 consistently predict social functioning in both males and females with FXS at Time 2. CONCLUSION: Our results suggest that addressing ADHD symptoms in childhood may have positive, long-term effects on the social functioning of adolescents and young adults with FXS. PMID- 25731184 TI - Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody. AB - Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT 806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indium-labeled version of ABT-806, [(111)In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII-expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity. PMID- 25731186 TI - The NICE recommendation for drug-coated balloons and its global impact. AB - OBJECTIVES: The clinical efficacy and safety of drug-coated balloon (DCB) angioplasty in patients with coronary in-stent restenosis (ISR) has been demonstrated. The objective of this article is to provide comparative cost efficacy data for DCB angioplasty in various countries based on the original methodology of the Medical Technologies Evaluation Programme (MTEP) at the National Institute for Health and Clinical Excellence (NICE) in 2010. STUDY DESIGN: Published and unpublished Health Technology Assessment (HTA) reports were evaluated for comparison in selected countries. Furthermore, a systematic review of economic evaluations of DCB angioplasty versus standard treatments (uncoated balloon angioplasty or drug-eluting stent implantations) was conducted. METHODS: National cost efficacy data were evaluated using Markov state transition models which were adapted to fit each country's device and procedure related costs. The clinical input for adverse events was defined with two relevant trials for in stent restenosis of bare metal stents (BMS-ISR) and of drug-eluting stents (DES ISR). RESULTS: In the UK, Germany, Switzerland, South Africa, Japan and Brazil, DCB angioplasty is cost-effective when compared with drug-eluting stents to treat either BMS-ISR or DES-ISR. CONCLUSIONS: DCB angioplasty ought to be the preferred treatment option for patients with BMS-ISR and DES-ISR from the payers' point of view. PMID- 25731185 TI - Endomyocardial biopsy-integrating electrode at the bioptome tip. AB - BACKGROUND: The addition of electroanatomic mapping to a standard echo-guided endomyocardial biopsy could identify areas of abnormal pathology and increase the diagnostic yield of the procedure. METHODS AND RESULTS: In this demonstration of a novel technique, a 45-year-old woman with clinical suspicion for cardiac sarcoidosis underwent right ventricular bipolar electroanatomical mapping with identification of areas of signal fractionation and low voltage. A bioptome, configured to record an electrogram from the tip, was then visualized on the three-dimensional electroanatomic mapping (3DEAM) system, and directed to these areas. The biopsy was assisted by the use of a steerable introducer sheath, and by recording unipolar and extended bipolar signals from the bioptome tip. A prominent change in the signal was detected by the electrode at the bioptome tip when the jaws closed on the endomyocardial tissue. Patient tolerated the procedure without complications, and the biopsied samples were appropriate for pathological analysis. CONCLUSIONS: Using existing technology, the 3DEAM, which integrates unipolar and bipolar signal from the bioptome tip, is feasible, and can be safely added to a standard echocardiographically guided endomyocardial biopsy. Future studies should investigate whether such a technique could increase the safety and diagnostic yield of endomyocardial biopsies in patients with suspected cardiomyopathies. PMID- 25731187 TI - Behavioral and hormonal pattern of repeat breeder cows around estrus. AB - Repeat breeder (RB) cows were compared with normal (CTRL) ones with respect to behavioral estrus intensity, endocrine patterns and concentrations of plasma estradiol, progesterone and LH around estrus, and ovulation timing. A total of 27 and 31 cycles in 12 RB and 18 CTRL cows, respectively, were synchronized by means of the Ovsynch protocol followed by a single PG injection after 7 days. Behavioral estrus and ovulation were observed in 81.5 and 83.8% of the synchronized cycles in the RB and CTRL cows respectively. The RB and CTRL groups had similar estrus durations of 21.4 and 19.6 h respectively, but estrus was more intense in the RB, as indicated by numerically higher overall activity indexes and higher peak neck activity. The interval from PG injection to estrus onset (considered as proestrus) was 8.2 h shorter in RB than in CTRL cows, at 47.9 and 56.1 h respectively (P<0.007), but the average preovulatory follicle size was similar. The estradiol concentration at peak was numerically higher (21%) and the AUC tended to be higher in the RB cows than in the CTRL cows. LH secretion during the period from 18 to 3 h before the LH peak was also lower in RB than in CTRL cows: 2.5 and 4.6 ng/ml respectively (P<0.01). In conclusion, the behavioral estrus was more intense in the RB cows; nevertheless, short proestrus and subdued LH concentrations before the LH peak, which could impair oocyte competence and development, were first reported in RB cows. PMID- 25731188 TI - Effects of the mycotoxin deoxynivalenol on steroidogenesis and apoptosis in granulosa cells. AB - Mycotoxins can reduce fertility and development in livestock, notably in pigs and poultry, although the effect of most mycotoxins on reproductive function in cattle has not been established. One major mycotoxin, deoxynivalenol (DON), not only targets immune cells and activates the ribotoxic stress response (RSR) involving MAPK activation, but also inhibits oocyte maturation in pigs. In this study, we determined the effect of DON on bovine granulosa cell function using a serum-free culture system. Addition of DON inhibited estradiol and progesterone secretion, and reduced levels of mRNA encoding estrogenic (CYP19A1) but not progestogenic (CYP11A1 and STAR) proteins. Cell apoptosis was increased by DON, which also increased FASLG mRNA levels. The mechanism of action of DON was assessed by western blotting and PCR experiments. Addition of DON rapidly and transiently increased phosphorylation of MAPK3/1, and resulted in a more prolonged phosphorylation of MAPK14 (p38) and MAPK8 (JNK). Activation of these pathways by DON resulted in time- and dose-dependent increases in abundance of mRNA encoding the transcription factors FOS, FOSL1, EGR1, and EGR3. We conclude that DON is deleterious to granulosa cell function and acts through a RSR pathway. PMID- 25731189 TI - Protein expression of HER2, 3, 4 in gastric cancer: correlation with clinical features and survival. AB - BACKGROUND AND AIMS: Despite significant improvements in targeted therapies for patients with advanced gastric cancer (GC), the prognosis of those patients remains poor. This study explores the expression and clinicopathological significance of human epidermal growth factor receptor 2, 3 and 4 (HER2, HER3, HER4) in GC, in order to find more prognostic biomarkers of GC and putative targets of therapy. METHODS: Immunohistochemistry was performed for HER2, HER3 and HER4 in 498 patients with GC using tissue microarray. Correlations between the receptor expression and clinicopathological features, as well as prognosis of the patients were statistically analysed. RESULTS: The high expression rates of HER2, HER3 and HER4 proteins in the patients were 8.6% (43/498), 20.7% (103/498) and 13.3% (66/498), respectively. High expression of HER2 and HER3 was correlated with proximal GC of the cardia (p<0.05). High expression of HER3 was associated with the tumour depth, tumour node metastasis (TNM) stage and lymph node metastasis (p<0.05). High expression of HER4 was associated with TNM stage (p<0.05) only. According to a regression model, high expression of HER3 was significantly associated with patients' poor survival (p=0.004). High expression rates of HER2, HER3 and HER4 were correlated with each other, but they were all associated merely with histologically intestinal-type adenocarcinoma of GC (p<0.05). CONCLUSIONS: HER3 is correlated with the malignant biological behaviour of GC. Expression of HER3 is a significant predictor of poor survival in GC. Therefore, the development of HER3-targeted agents may provide new possibilities in the treatment of GC. PMID- 25731190 TI - Receptor for hyaluronic acid-mediated motility (RHAMM, CD168) expression is prognostically important in both nodal negative and nodal positive large cell lung cancer. AB - OBJECTIVE: Despite advances in therapy, lung cancer is still the leading cause of cancer-related mortality in the world. Further prognostic tools are warranted for risk-adapted therapeutic decisions. We analysed a cohort of primary surgically treated non-small cell lung cancers (NSCLCs) to determine the prognostic role of CD44 and associated molecules (receptor for hyaluronic acid-mediated motility (RHAMM), CD95, osteopontin (OPN), P-glycoprotein (P-gp) and caspase 3 (Casp3)). CD44 is a cell adhesion molecule. While the standard form (CD44s) is ubiquitously expressed, its variant isoforms are claimed to play an important role in invasion and metastasis in various cancers. METHODS: Three-hundred and eighty-three primary surgically resected NSCLC specimens were brought into a standardised tissue microarray platform. Immunohistochemistry for CD44, CD95, RHAMM, OPN, P-gp and Casp3 was performed. The clinical correlation was made with known histopathological, phenotypical and genotypical variables; clinical data were available for a postoperative follow-up period of up to 15 years. RESULTS: RHAMM expression in the subgroup of large cell carcinomas (LCC) was associated with inferior survival (p=0.000223). Median overall survival was 92 versus 18 months for RHAMM-negative and positive patients, respectively. This survival difference remained significant in both nodal negative and positive patients (pN0: p=0.013 and pN>=1: p=0.007, respectively). P-gp expression was associated with inferior survival in adenocarcinomas (ACA; p=0.013) and appeared to be a postsurgical Union International Contre le Cancer (pUICC)- stage and gender-independent prognostic factor, irrespective of adjuvant chemotherapy, in the multivariable analysis; considering nodal status, this survival difference applied to pN0 cancers (p=0.026). CONCLUSIONS: Analysis of RHAMM expression is a valuable predictor of survival in LCC. RHAMM-positive patients may benefit from a targeted therapy even in early nodal negative stages. Expression of P-gp identifies a subset of pN0 ACA patients with poor outcome independent of stage, gender and adjuvant chemotherapy. PMID- 25731191 TI - Evaluation of different lactation curve models fitted for milk viscosity recorded by an automated on-line California Mastitis Test. AB - Laboratory somatic cell count (LSCC) records are usually recorded monthly and provide an important information source for breeding and herd management. Daily milk viscosity detection in composite milking (expressed as drain time) with an automated on-line California Mastitis Test (CMT) could serve immediately as an early predictor of udder diseases and might be used as a selection criterion to improve udder health. The aim of the present study was to clarify the relationship between the well-established LSCS and the new trait,'drain time', and to estimate their correlations to important production traits. Data were recorded on the dairy research farm Karkendamm in Germany. Viscosity sensors were installed on every fourth milking stall in the rotary parlour to measure daily drain time records. Weekly LSCC and milk composition data were available. Two data sets were created containing records of 187,692 milkings from 320 cows (D1) and 25,887 drain time records from 311 cows (D2). Different fixed effect models, describing the log-transformed drain time (logDT), were fitted to achieve applicable models for further analysis. Lactation curves were modelled with standard parametric functions (Ali and Schaeffer, Legendre polynomials of second and third degree) of days in milk (DIM). Random regression models were further applied to estimate the correlations between cow effects between logDT and LSCS with further important production traits. LogDT and LSCS were strongest correlated in mid-lactation (r = 0.78). Correlations between logDT and production traits were low to medium. Highest correlations were reached in late lactation between logDT and milk yield (r = -0.31), between logDT and protein content (r = 0.30) and in early as well as in late lactation between logDT and lactose content (r = -0.28). The results of the present study show that the drain time could be used as a new trait for daily mastitis control. PMID- 25731192 TI - Do ictal EEG characteristics predict treatment outcomes in schizophrenic patients undergoing electroconvulsive therapy? AB - OBJECTIVE: The aim of this study is to investigate the relationship between features of electroencephalography (EEG), including seizure time, energy threshold level and post-ictal suppression time, and clinical variables, including treatment outcomes and side-effects, among schizophrenia inpatients undergoing electroconvulsive therapy (ECT). METHOD: This is a naturalistic follow up study on schizophrenia patients, diagnosed using DSM-IV-TR criteria, treated by a psychosis inpatient service. All participants completed the Brief Psychiatric Rating Scale (BPRS), the Global Assessment of Functioning (GAF) scale, the Frontal Assessment Battery (FAB) and a Data Collection Form. Assessments were made before treatment, during ECT and after treatment. FINDINGS: Statistically significant improvements in both clinical and cognitive outcome were noted after ECT in all patients. Predictors of improvement were sought by evaluating electrophysiological variables measured at three time points (after the third, fifth and seventh ECT sessions). Logistic regression analysis showed that clinical outcome/improvement did not differ by seizure duration, threshold energy level or post-ictal suppression time. DISCUSSION AND CONCLUSION: We found that ictal EEG parameters measured at several ECT sessions did not predict clinical recovery/outcomes. This may be because our centre defensively engages in "very specific patient selection" when ECT is contemplated. ECT does not cause short-term cognitive functional impairment and indeed improves cognition, because symptoms of the schizophrenic episode are alleviated. PMID- 25731193 TI - A novel approach to normal responder patient with repeated implantation failures- a case report. AB - We describe a case of normal responder patients with repeated implantation failure who was offered the combination of the ultrashort GnRH-ag/ GnRH-ant COH protocol, followed by endometrial injury and a subsequent natural cycle frozen thawed embryos transfer. The patient conceived following the natural FET cycle that was supported by luteal daily progesterone, with the additional single injection of HCG and GnRH-agonist, on day of ET and 4 days later, respectively. This combined approach seems to be a valuable tool in the armamentarium for treating normal responder patients with repeated implantation failures and should be further examined in large randomized controlled trials. PMID- 25731194 TI - Contributing to the professional literature must be a 2-way street. PMID- 25731195 TI - Girls and boys gambling with health and well-being in Finland. AB - BACKGROUND: The aim of this study was to examine the associations among gambling frequency, health status, health risk behavior, and sexual risk-taking among eighth and ninth grade boys and girls (N = 101,167). METHODS: Data were obtained from the nationwide School Health Promotion Study conducted in Finland 2010 and 2011. Outcome measures were adolescents' health and sexual behavior. Associations with gambling frequency were studied separately for boys and girls using polychotomous logistic regression models where grade level was adjusted. RESULTS: Approximately 62% of adolescents had gambled during the previous year. Gambling was more common among boys than girls in both grade levels. Gambling frequency was associated with several health and sexual risk-taking indicators such as signs of school burnout, staying up late, and having more than 1 sexual partner. Those who gambled the most had a higher risk for poorer health and taking health risks. Girls and those who had gambled on a weekly basis were the most vulnerable groups. CONCLUSIONS: It would be beneficial to raise teacher, parent, and adolescent awareness of the wide range of negative health outcomes and risks associated with gambling. PMID- 25731196 TI - A national assessment of colleges and university school health education methods courses. AB - BACKGROUND: Across the United States, school health education programs provide a wide variety of knowledge and skills to their students. There are currently no guidelines for school health methods courses. METHODS: Using a 2-wave mailing followed by a third wave e-mail reminder, a final population of 226 university school health methods instructors at school health preparation programs were surveyed. RESULTS: A total of 138 completed surveys (61%) were returned. The topics taught in school health education methods courses emphasized the most included aligning objectives, instruction, and assessment (79%); development of lesson plans (73%); teaching methods that engage learners (72%); and application of the National Health Education Standards and performance indicators (69%). The content taught and how the instructors assessed their students differed statistically by 1 or more of the following: whether they had a health education degree, had experience teaching in the public schools, and if their program was accredited. CONCLUSIONS: This study provides information regarding what school health methods instructors across the United States are teaching in their classes. Using this information as a baseline can serve as a guide for preservice faculty teaching a school health methods course. PMID- 25731197 TI - Food-based science curriculum yields gains in nutrition knowledge. AB - BACKGROUND: Students may be receiving less than an average of 4 hours of nutrition instruction per year. Integrating nutrition with other subject areas such as science may increase exposure to nutrition education, while supporting existing academics. METHODS: During the 2009-2010 school year, researchers implemented the Food, Math, and Science Teaching Enhancement Resource (FoodMASTER) Intermediate (FMI) curriculum in 18 fourth-grade classrooms, whereas 16 classrooms served as comparison. FMI is a hands-on, integrative curriculum for children in grades 3-5 that uses food as a tool to teach mathematics and science. Researchers developed a 28-item multiple-choice questionnaire to assess students' nutrition knowledge in 6 content areas. Students were evaluated at baseline and post-intervention. Data were analyzed using independent t tests. Analysis of covariance was employed to control for differences at baseline when assessing the effectiveness of the FMI curriculum to increase nutrition knowledge. RESULTS: A significant improvement was observed in total nutrition knowledge at post intervention (adjusting for baseline) between groups (F [1] = 128.95; p < .01) and in all content areas post-intervention. CONCLUSIONS: Findings from this study suggest teachers were successfully able to integrate science and nutrition to meet multiple academic standards. More specifically, results showed implementation of the integrative FMI curriculum effectively improved fourth graders' nutrition knowledge compared with students not exposed to FMI. PMID- 25731198 TI - Absenteeism, educational plans, and anxiety among children with incontinence and their parents. AB - BACKGROUND: Children with incontinence have more absenteeism, poorer academic performance, and potential social difficulties during the school years. These children and their parents are at risk for illness-related anxiety. Whereas educational plans are designed to remediate educational, medical, and social emotional barriers at school, little research has explored the relationship among absenteeism, educational plans, and anxiety for this population. METHODS: Eighty three families provided demographic information and completed either the Revised Children's Manifest Anxiety Scale Second Edition (RCMAS-2) or the Adult Manifest Anxiety Scale (AMAS-A). A multiple regression analysis was conducted to determine the relationships among these variables. RESULTS: Children with chronic illness resulting in incontinence had greater than expected rates of absenteeism. A high level of absenteeism was a significant predictor of parental anxiety, but not child anxiety. Over one third reported having no plan in place to support the child's needs at school. However, when a plan was present, it had no impact on child or parental anxiety. CONCLUSIONS: Absenteeism contributes to familial anxiety and educational difficulties. Despite the potential for educational plans to support these children at school, these plans are underutilized for children with incontinence. This population requires more attention to their academic and social-emotional well-being at school. PMID- 25731199 TI - One size (never) fits all: segment differences observed following a school-based alcohol social marketing program. AB - BACKGROUND: According to commercial marketing theory, a market orientation leads to improved performance. Drawing on the social marketing principles of segmentation and audience research, the current study seeks to identify segments to examine responses to a school-based alcohol social marketing program. METHODS: A sample of 371 year 10 students (aged: 14-16 years; 51.4% boys) participated in a prospective (pre-post) multisite alcohol social marketing program. Game On: Know Alcohol (GO:KA) program included 6, student-centered, and interactive lessons to teach adolescents about alcohol and strategies to abstain or moderate drinking. A repeated measures design was used. Baseline demographics, drinking attitudes, drinking intentions, and alcohol knowledge were cluster analyzed to identify segments. Change on key program outcome measures and satisfaction with program components were assessed by segment. RESULTS: Three segments were identified; (1) Skeptics, (2) Risky Males, (3) Good Females. Segments 2 and 3 showed greatest change in drinking attitudes and intentions. Good Females reported highest satisfaction with all program components and Skeptics lowest program satisfaction with all program components. CONCLUSION: Three segments, each differing on psychographic and demographic variables, exhibited different change patterns following participation in GO:KA. Post hoc analysis identified that satisfaction with program components differed by segment offering opportunities for further research. PMID- 25731200 TI - Coordinated school health and the contribution of a district wellness coordinator. AB - BACKGROUND: A San Francisco Bay Area school health initiative was established in fall 2010 to improve wellness programs in 4 local school districts using the Coordinated School Health (CSH) model. This study examines the role of district wide wellness coordinators and the ways in which they contribute to intentional coordination of health and wellness programs and activities in their school districts. METHODS: This study included 8 schools across 4 school districts. Researchers conducted semistructured interviews and focus groups with district and school staff, students, parents, wellness committee members, and wellness coordinators in 2012 to examine a range of perspectives about the coordination of school health and wellness. RESULTS: District wellness coordinators' efforts were linked to an increase in (1) awareness of health and wellness, (2) integration of wellness activities within and across schools and districts, and (3) leveraged resources. CONCLUSIONS: Wellness coordinators are critical to successful CSH efforts. Through intentional and strategic collaboration with key stakeholders, wellness coordinators advance CSH goals of integrating health and wellness programs within and across school districts, reaching more students equitably and leveraging resources. PMID- 25731202 TI - Resolution of hidradenitis suppurativa after weight loss by dietary measures, especially on frictional locations. PMID- 25731201 TI - School- and family-level socioeconomic status and health behaviors: multilevel analysis of a national survey in wales, United Kingdom. AB - BACKGROUND: Interventions to address inequalities in adolescent health behaviors often target children from less affluent families, or schools in poorer areas. Few studies have examined whether school- or family-level affluence predicts health behaviors independently, or in combination. METHODS: This article reports secondary analysis of the Welsh Health Behavior in School-aged Children (HBSC) survey. Mixed-effects logistic regression models test associations of school and family socioeconomic status (SES) with smoking, fruit and vegetable consumption, alcohol consumption, and physical activity. RESULTS: Higher family SES was associated with healthier behaviors, except in relation to alcohol consumption. For all behaviors except physical activity, school-level SES was independently associated with healthier behaviors. In higher SES schools, a stronger association of family SES with health behavior was observed, particularly in relation to smoking and physical activity. CONCLUSIONS: School and family SES may exert independent and combined influences upon adolescent health behaviors. Targeting interventions toward deprived schools may fail to address substantial inequalities within more affluent schools. Targeting deprived families may fail to address behaviors of children from affluent families, attending more deprived schools. Identifying universal health improvement interventions which have greater effects among children from poorer backgrounds may be a more effective means of reducing inequalities. PMID- 25731204 TI - Neurogenic rosacea: an uncommon and poorly recognized entity? PMID- 25731203 TI - An unusual cause of postdialysis dyspnea: Percutaneous endovascular management. AB - Vascular access through femoral vein is commonly used for hemodialysis treatment in patients with end-stage renal disease. Consequently, iatrogenic complications, such as femoral arteriovenous fistula, are increasingly being reported in these patients. Percutaneous endovascular management of such iatrogenic arteriovenous fistulas with stent graft placement is a minimally invasive technique with decreased morbidity and hospital stay compared with surgical repair. Here, we report a case with postcatheterization arteriovenous fistula between superficial femoral artery and femoral vein which was successfully managed with a placement of a self-expanding stent graft. PMID- 25731205 TI - HPV-negative head and neck squamous cell carcinomas: how can we use the tumor protein signature? PMID- 25731206 TI - Low level of the X-linked ribosomal protein S4 in human urothelial carcinomas is associated with a poor prognosis. AB - AIM: We determined whether the Y-box binding protein-1 (YB-1) and its binding partner, the X-linked ribosomal protein S4 (RPS4X), are associated with clinical outcome in bladder cancer. MATERIALS & METHODS: A population of 167 patients with muscle-invasive bladder tumor without evidence of metastasis at time of cystectomy was analyzed retrospectively. YB-1 and RPS4X expressions were evaluated immunohistochemically in tumors and analyzed for association with clinical variables and survival. RESULTS: Kaplan-Meier and multivariate Cox regression analyses indicated that low expression of RPS4X was associated with a higher risk of death or disease recurrence. In contrast, YB-1 was not significantly associated with either recurrence-free or overall survival. CONCLUSION: Low RPS4X expression is associated with poor disease-specific and recurrence-free survival in bladder cancer. PMID- 25731207 TI - Platelet-to-lymphocyte ratio is a marker of poor prognosis in patients with diabetes mellitus and ST-elevation myocardial infarction. AB - AIM: Platelet-to-lymphocyte ratio (PLR) has emerged as a strong marker of worse outcomes. We determined the association between PLR and clinical outcomes in patients with diabetes mellitus and ST-elevation myocardial infarction. METHODS: Five hundred and twenty three patients were enrolled. Low PLR (group 1, n = 349) was defined as <= 124 and high PLR (group 2, n = 174) as >124. RESULTS: In hospital and 1-year mortality was higher in group 2. Receiver operating characteristic analysis revealed moderate diagnostic value in predicting in hospital (PLR cut-off >155) and long-term (PLR cut-off >146) death. PLR remained an independent risk factor of early and late mortality. CONCLUSION: PLR proved to have good prognostic value for in-hospital and late mortality. PLR cut-off value for predicting in-hospital mortality was higher to that predicting late mortality. PLR remained an independent risk factor early and late mortality. PMID- 25731208 TI - Advanced glycation end-products as long-term predictors of death and reinfarction after an acute coronary syndrome. AB - AIM: We evaluated the prognostic value of plasmatic fluorescent advanced glycation end-products (AGE) to predict long-term death and reinfarction in patients with acute coronary syndrome (ACS). MATERIALS & METHODS: A unicenter registry comprising a prospective cohort of 210 ACS patients (47.4% ST-segment elevation myocardial infarction) followed up during 3.1 +/- 0.9 years were carried out. RESULTS: Cardiovascular death ratio was 5.7% and 23 patients suffered reinfarction (11.0%). The hazard ratio of the multivariate analysis with respect to death and reinfarction for AGE adjusted by GRACE risk score was 1.011 (1.006-1.016), p < 0.001. CONCLUSION: Fluorescent AGE plasma levels were an independent predictor of death and reinfarction in the long-term follow-up of patients with ACS. PMID- 25731209 TI - Peripheral and placental biomarkers in women with placental malaria: a systematic review. AB - Placental malaria (PM) causes significant morbidity in mothers and infants. Diagnosis of PM during pregnancy is however problematic due to placental sequestration of parasites. Host biomarkers may therefore be used as a diagnostic method. In this systematic review most studies focused on inflammatory markers. A trend was observed for increased IL-10 and TNF-alpha in PM positives. These markers are however unspecific, thus a combination of multiple biomarkers involved in different pathophysiological pathways of PM is indicated. Of interest are inflammatory markers (TNF-R2, CXCL-13), markers of lipid metabolism (APO-B), angiogenesis (sFlt-1) and hormones (estradiol). As the majority of published studies tested biomarker levels only at delivery, more longitudinal cohort studies will be necessary to detect biomarkers during pregnancy that can predict PM. PMID- 25731210 TI - miRNAs as prognostic and therapeutic tools in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and is the fifth leading cause of cancer deaths in women. Developing adjuvant therapy to circumvent drug resistance represents an important aspect of current initiatives to improve survival in women with advanced EOC. A regulatory molecule that can act on multiple genes associated with a chemoresistant phenotype will be the ideal target for the development of therapeutics to overcome resistance and miRNAs constitute promising tools in this regard. In this review, we discuss the emerging role of miRNAs in regulating EOC phenotype with a focus on prognostic and therapeutic importance of miRNAs and the possibility of miRNA modulation as a tool to improve efficacy of chemotherapy in EOC. PMID- 25731211 TI - Mining the granule proteome: a potential source of endocrine biomarkers. AB - Proteomics of secretory granules is an emerging strategy for identifying secreted proteins, including potentially novel candidate biomarkers and peptide hormones. In addition, proteomics can provide information about the abundance, localization and structure (post-translational modification) of granule proteins and peptides. Analytical strategies within this research line include so-called 'subtractive proteomics', 'peptidomics' and granule purification by the use of multiple gradient centrifugations. Here we review the literature, and describe the challenges and opportunities in proteomics of secretory granules. PMID- 25731212 TI - Biomarkers of multiorgan injury in neonatal encephalopathy. AB - Neonatal encephalopathy (NE) is a major contributor to neurodevelopmental deficits including cerebral palsy in term and near-term infants. The long-term neurodevelopmental outcome is difficult to predict with certainty in first few days of life. Multiorgan involvement is common but not part of the diagnostic criteria for NE. The most frequently involved organs are the heart, liver, kidneys and hematological system. Cerebral and organ involvement is associated with the release of organ specific biomarkers in cerebrospinal fluid, urine and blood. These biomarkers may have a role in the assessment of the severity of asphyxia and long-term outcome in neonates with NE. PMID- 25731213 TI - Biomarker approaches in major depressive disorder evaluated in the context of current hypotheses. AB - Major depressive disorder is a heterogeneous disorder, mostly diagnosed on the basis of symptomatic criteria alone. It would be of great help when specific biomarkers for various subtypes and symptom clusters of depression become available to assist in diagnosis and subtyping of depression, and to enable monitoring and prognosis of treatment response. However, currently known biomarkers do not reach sufficient sensitivity and specificity, and often the relation to underlying pathophysiology is unclear. In this review, we evaluate various biomarker approaches in terms of scientific merit and clinical applicability. Finally, we discuss how combined biomarker approaches in both preclinical and clinical studies can help to make the connection between the clinical manifestations of depression and the underlying pathophysiology. PMID- 25731214 TI - The Reliability and Validity of the Clinical Perfectionism Questionnaire in Eating Disorder and Community Samples. AB - BACKGROUND: Clinical perfectionism is a risk and maintaining factor for anxiety disorders, depression and eating disorders. AIMS: The aim was to examine the psychometric properties of the 12-item Clinical Perfectionism Questionnaire (CPQ). METHOD: The research involved two samples. Study 1 comprised a nonclinical sample (n = 206) recruited via the internet. Study 2 comprised individuals in treatment for an eating disorder (n = 129) and a community sample (n = 80). RESULTS: Study 1 factor analysis results indicated a two-factor structure. The CPQ had strong correlations with measures of perfectionism and psychopathology, acceptable internal consistency, and discriminative and incremental validity. The results of Study 2 suggested the same two-factor structure, acceptable internal consistency, and construct validity, with the CPQ discriminating between the eating disorder and control groups. Readability was assessed as a US grade 4 reading level (student age range 9-10 years). CONCLUSIONS: The findings provide evidence for the reliability and validity of the CPQ in a clinical eating disorder and two separate community samples. Although further research is required the CPQ has promising evidence as a reliable and valid measure of clinical perfectionism. PMID- 25731215 TI - Arterial puncture using insulin needle is less painful than with standard needle: a randomized crossover study. AB - OBJECTIVES: Arterial punctures are important procedures performed by emergency physicians in the assessment of ill patients. However, arterial punctures are painful and can create anxiety and needle phobia in patients. The pain score of radial arterial punctures were compared between the insulin needle and the standard 23-gauge hypodermic needle. METHODS: In a randomized controlled crossover design, healthy volunteers were recruited to undergo bilateral radial arterial punctures. They were assigned to receive either the insulin or the standard needle as the first puncture, using blocked randomization. The primary outcome was the pain score measured on a 100-mm visual analogue scale (VAS) for pain, and secondary outcomes were rate of hemolysis, mean potassium values, and procedural complications immediately and 24 hours postprocedure. RESULTS: Fifty healthy volunteers were included in the study. The mean (+/-standard deviation) VAS score in punctures with the insulin needle was lower than the standard needle (23 +/- 22 mm vs. 39 +/- 24 mm; mean difference = -15 mm; 95% confidence interval = -22 mm to -7 mm; p < 0.001). The rates of hemolysis and mean potassium value were greater in samples obtained using the insulin needle compared to the standard needle (31.3% vs. 11.6%, p = 0.035; and 4.6 +/-0.7 mmol/L vs. 4.2 +/-0.5 mmol/L, p = 0.002). Procedural complications were lower in punctures with the insulin needle both immediately postprocedure (0% vs. 24%; p < 0.001) and at 24 hours postprocedure (5.4% vs. 34.2%; p = 0.007). CONCLUSIONS: Arterial punctures using insulin needles cause less pain and fewer procedural complications compared to standard needles. However, due to the higher rate of hemolysis, its use should be limited to conditions that do not require a concurrent potassium value in the same blood sample. PMID- 25731216 TI - Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients. AB - There are currently no data to support the suggestion that the dose of therapeutic immunoglobulin (Ig) should be capped in obese patients for pharmacokinetic (PK), safety and economic reasons. We compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically equivalent lean patient across a range of indications, including primary antibody deficiency or autoimmune peripheral neuropathy. Comprehensive matching was carried out using ongoing research databases at two centres in which the dose of Ig was based on clinical outcome, whether infection prevention or documented clinical neurological stability. The IgG trough or steady state levels, IgG increments and Ig efficiencies at times of clinical stability were compared between the obese and lean cohorts and within the matched pairs. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight adjusted dose compared with the lean patients. However at an individual patient level there were significant exceptions to this correlation, and upon sub-group analysis no significant difference was found between obese and lean patients receiving replacement therapy. Across all dose regimens a high body mass index (BMI) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate. PMID- 25731217 TI - [Intraperitoneal chemotherapy with CDDP for patients with peritoneal recurrent gastric cancer following surgical intervention]. AB - We evaluated the efficacy of intraperitoneal chemotherapy with cisplatin (CDDP) for peritoneal recurrent gastric cancer following surgical intervention. Twelve patients were enrolled. The combination systemic chemotherapy was S-1 or S-1 plus paclitaxel (S-1+PTX). PTX was administered intravenously at 80 mg/m2 on day S-1 and 15. S-1 was administered at 80 mg/ m2/ day for 7 consecutive days, followed by 7 days of rest, and the cycle was repeated. CDDP was administered intraperitoneally at 40 mg/body on day 8. This treatment was repeated every 4 weeks until disease progression was diagnosed. The survival time(ST)and time to treatment failure(TTF)were estimated. The surgical interventions were gastrectomy in 3 patients, colostomy in 8 patients, and enterostomy in 1 patient. Overall, the median TTF and ST were 294 days and 455 days, respectively. When stratified by surgical method and combination chemotherapy, the median TTF and ST were not statistically significant. However, when stratified by performance status (PS), the median TTF was 352 days for patients with PS 0 and 218 days for those with PS 1, 2 (p=0.0029), whereas the median ST was 553 days for patients with PS 0 and 331 days for those with PS 1, 2 (p=0.0198). In conclusion, the data suggest that intraperitoneal CDDP chemotherapy with systemic chemotherapy is effective for the treatment of extensive peritoneal recurrent gastric cancer, especially in patients with good PS. PMID- 25731218 TI - [Surgical treatment outcomes of multimodality therapy for locally recurrent rectal cancer]. AB - The aim of this study was to clarify the status of multimodality therapy for locally recurrent rectal cancer. Between 2000 and 2012, 27 patients with locally recurrent rectal cancer underwent surgical resection. We examined 18 patients treated with preoperative chemo-radiotherapy (CRT group) and 9 patients treated with surgery alone (surgical group). The rate of R0 - resection was 89% in the CRT group and 78% in the surgical group. The mean operative durations for the CRT and surgical groups were 323 min and 289 min, respectively. The mean amount of bleeding was 1,462 g for the CRT group and 2,846 g for the surgical group. There was no significant difference in the rate of postoperative complications between both groups (CRT group: 78%, surgical group: 78%). Regarding local recurrences, the recurrence rate of the CRT group was 28%, whereas that of the surgical group was 67%. The 3-year and 5-year overall survival rates of the CRT group were 71%and 44%, respectively, whereas those of the surgical group were 58% and 22%, respectively. These results showed that CRT treatment was associated with an improvement in prognosis. Preoperative CRT and surgical resection should be the standard treatment for patients with local recurrence. PMID- 25731219 TI - [A review of stereotactic radiotherapy (SRT) for lung metastasis of colon cancer]. AB - We retrospectively analyzed the efficacy of stereotactic radiotherapy (SRT) for lung metastasis of colon cancer, with particular emphasis on local tumor control. Seven patients with 8 lesions underwent SRT for lung metastasis of colon cancer in our institution between February 2012 and February 2014. We judged the curative effect of SRT on the basis of tumor shrinkage observed on computed tomography (CT) scans. All lung metastases decreased in size, and local recurrence was not observed. SRT is a technique involving three-dimensional radiation, which decreases radiation exposure to neighboring normal tissues. The 2-year local tumor control rate for lung metastasis of colon cancer with SRT is 77.9%, and the 2-year survival rate is 53.7%. Our results, in which all patients achieved local control, suggest that SRT is a minimally aggressive treatment option for lung metastasis of colon cancer in cases where a pneumonectomy is difficult to perform. In the future, results from long-term studies are needed to validate our findings. PMID- 25731220 TI - [Evaluated cases of M1a (non-regional) and recurrent lymph node metastases obtained long-term survival by additional local treatment]. AB - According to the 2014 guidelines for the treatment of Stage IV colorectal cancer, surgical therapy is recommended if R0 resection is possible by resecting both distant metastases and the primary tumor. However, there was no clear evidence regarding the treatment of non-regional lymph node metastases and recurrent lymph node metastases. Thus, we evaluated cases of non-regional lymph node metastases and recurrent lymph node metastases at our hospital from 2005 to the present date. The 5-year overall survival (OS) rate was 50.0%. There was no significant difference in the survival rate between synchronous and metachronous metastases. The survival rate increased significantly in cases that received additional local treatment compared to that in cases that did not receive additional treatment (p=0.013). Multivariate analysis based on the 5-year OS rate of 50.0% revealed a statistically significant difference only in disease free interval (DFI). Although no predictive factor for OS was identified, DFI was considered to be a critical factor. Performing chemotherapy during the perioperative period and determining the appropriate timing of resection based on the response to the chemotherapy and presence/absence of metastases in other organs are expected to increase the survival rate. PMID- 25731221 TI - [Re-resection for recurrent intrahepatic cholangiocarcinoma]. AB - INTRODUCTION: The benefits of re-resection for recurrent intrahepatic cholangiocarcinoma (IHC) are unknown. PATIENTS AND METHODS: We evaluated the comparative efficacy of different treatment schema for recurrent IHC following curative resection. RESULTS: Among 46 patients, 26 underwent R0 resection, while 20 underwent R1 resection. There were 13 cases of recurrence in R1 patients (65%), and 19 in R0 patients (61%). Recurrent IHC cases were divided into 3 groups based on the treatment received after recurrence: re-resection (n=5), chemotherapy (n=13), and best supportive care (BSC) (n=8). Survival times were evaluated for each group; median survival times (MSTs) after recurrence were 26, 14, and 4 months for the re-resection, chemotherapy, and BSC groups, respectively (p=0.030). Next, we examined the patients who only had intrahepatic recurrence; MSTs after recurrence for re-resection, chemotherapy, and BSC groups were 26, 14, and 5 months, respectively (p=0.0018). CONCLUSION: In recurrent IHC, survival time improves with re-resection or chemotherapy, when compared to BSC. In patients with intrahepatic recurrence only, re-resection is especially effective in prolonging survival. PMID- 25731222 TI - [Novel approach to laparoscopy and endoscopy cooperative surgery (LECS) in gastric submucosal tumors near the esophago-gastric junction]. AB - BACKGROUND AND PURPOSE: Laparoscopy and endoscopy cooperative surgery (LECS) for gastric submucosal tumors is an excellent surgical procedure that enables prevention of excessive resection and deformity of the stomach. This procedure may be more useful for gastric submucosal tumors near the esophagogastric (EG) junction and the pylorus. We present a novel approach to LECS for gastric submucosal tumors near the EG junction. PATIENTS: From 2010 to 2013, seven consecutive patients underwent LECS for gastric submocosal tumors near the EG junction. Novel approach: Our novel approach to LECS involved (1) minimizing the resection of the stomach wall by using endoscopic mucosal resection for all types of submucosal tumor, (2) selecting the best anastomotic axis in order to avoid deformity of the stomach, (3) using hand sewing if anastomotic complications might occur and (4) sometimes combining anti-reflux surgery with LECS for tumors extremely close to the EG junction. RESULTS: No patient had any anastomotic complications or reflux esophagitis. CONCLUSIONS: LECS is safe and useful for gastric submucosal tumors near the EG junction. PMID- 25731223 TI - [Intraoperative complications and short-term outcomes of total laparoscopic distal gastrectomy (TLDG) for gastric cancer]. AB - In recent years there has been an increase in the number of laparoscopic surgeries for gastric cancer, with over 8,000 cases reported nationwide in 2012. To date, we have performed 420 total laparoscopic distal gastrectomy (TLDG) procedures. In all cases, the mean operative time was 304 minutes, intraoperative bleeding was at 52 g, 30 lymph nodes were dissected, and the length of postoperative hospital stay was 10.6 days, on average. We experienced 5 intraoperative complications and 13 postoperative complications. Of 4 patients, there were 2 cases of postoperative recurrence in liver metastases, 1 case of metastatic lung tumor, and 1 case of peritoneal metastasis. Based on surgical outcomes, TLDG is a safe and feasible procedure for gastric cancer. PMID- 25731224 TI - [Comparison of early clinical outcomes between laparoscopic total gastrectomy and open total gastrectomy for early-stage gastric cancer]. AB - BACKGROUND/AIMS: Recently, laparoscopic distal gastrectomy has become one of the standard therapies for early gastric cancer. However, there are still some obstacles in performing laparoscopic total gastrectomy (LTG) as a standard therapy due to the difficulties in surgical techniques. We have performed LTG for patients with early gastric cancer in the upper portion of the stomach since 2010. In this study, we compared early clinical outcomes of LTG with those of open total gastrectomy (OTG) for patients with cT1N0 gastric cancer. METHODOLOGY: We reviewed 69 patients who had gastric cancer of cStage IA between January 2010 and December 2013. We performed a comparative study of short-term clinical outcomes, quantity of dissected lymph nodes, and in-hospital costs between patients undergoing LTG (n=34) and those undergoing OTG (n=35). RESULTS: The clinical characteristics of patients were well matched in the LTG and OTG groups. The median operating time was significantly longer for the LTG group (p<.0001). The estimated blood loss was significantly reduced in the LTG group (p< 0.0001). The postoperative morbidity rate was 14.7% in the LTG group and 14.2% in the OTG group with no significant difference. There were no differences in the total cost for hospital stay between the LTG and OTG groups. CONCLUSIONS: We were able to perform LTG safely and successfully for early gastric cancer in our institute. The total cost of the treatment was almost the same between LTG and OTG. We conclude that LTG is a potential alternative in the management of early gastric cancer. PMID- 25731225 TI - [Lymphadenectomy performed along the left recurrent laryngeal nerve after anterior detachment of the esophagus via thoracoscopic esophagectomy in the prone position under artificial pneumothorax]. AB - Thoracoscopic esophagectomy was performed in the prone position under artificial pneumothorax and did not affect the surgical area during lung ventilation; tracheal mobility was also improved. Lymphadenectomy around the left recurrent laryngeal nerve was performed by separating the left main bronchus and trachea between the esophagus and pericardium before detaching the dorsal side of the esophagus. PMID- 25731226 TI - [Outcomes of laparoscopic surgery after preoperative metallic stent placement for obstructive colorectal cancer]. AB - AIM: To assess the outcomes of preoperative colonic stent placement for obstructive colorectal cancer. PATIENTS AND METHODS: A total of 30 patients with colorectal cancer were treated after preoperative colonic metallic stent placement between July 2012 and March 2014. We reviewed their medical records to assess the usefulness of stent placement and the clinical course. The effects of various clinicopathological variables on post-operative complications were analyzed statistically. RESULTS: Stent insertion was effective in 93% of the 30 patients with obstructive colorectal cancer. Preoperative colonoscopy or enema for proximal colonic survey was possible in 70% of the patients after stent placement; colonic lesions requiring simultaneous resection were noted in 5 patients (24%). The mean interval between stent insertion and operation was 19 days, and 23%of the patients underwent laparoscopic surgery. Statistical analysis revealed that the occurrence of complications was associated with laparoscopic surgery and the amount of operative blood loss. CONCLUSION: Preoperative stent placement in patients with obstructive colorectal cancer is feasible and laparoscopic surgery can be selected after stent placement. PMID- 25731227 TI - [Endoscopic stenting for patients with malignant colorectal obstruction in our hospital]. AB - In January 2012, the Wall Flex Colonic Stent (Boston Scientific) for treating patients with malignant colorectal obstruction was included in the National Health Insurance (NHI) price list in Japan, and since July 2012, our hospital has placed this stent in 22 patients(as bridge-to-surgery [BTS] in 14 patients and as palliative treatment in 8 patients). The subjects included 13 men and 9 women, aged 27-94 years. The placement sites were the ileocecal lesion in 1 patient, the ascending colon in 1 patient, the transverse colon in 3 patients, the descending colon in 6 patients, the sigmoid colon in 4 patients, and the rectum in 7 patients. Stent placement was successful in all 22 patients (100%). The primary endpoint was improvement in scores on the ColoRectal Obstruction Scoring System (CROSS). The mean CROSS score before stenting was 1.18. The mean CROSS score after stenting was 3.71. Only 1 patient showed no change in the CROSS score(before versus after stenting). The rate of clinical efficacy was 95.4%. One patient experienced restenosis, an accidental event, requiring re-stenting after 3 days. There was 1 case of stent migration, which occurred 32 days after stenting. Colonic stent placement, as BTS and palliative treatment, is effective in improving the quality of life (QOL) of patients. PMID- 25731228 TI - Prophylactic laparoscopic lateral pelvic lymph node dissection for lower rectal cancer: remarking on the vesicohypogastric fascia. AB - OBJECTIVE: To introduce the prophylactic laparoscopic lateral pelvic lymph node dissection performing by remarking the vesicohypogastric fascia following total mesorectal excision for patients with advanced lower rectal cancer without radiological evidence of lymph node involvement. SURGICAL METHOD: We set 5 ports for conventional laparoscopic rectal surgery. During the prophylactic laparoscopic lateral pelvic lymph node dissection, we retrieved the lymph nodes from the internal iliac area and obturator area. We recognized the pelvic nerve plexus, vesicohypogastric fascia (including internal iliac vessels), and parietal fascia (psoas muscle fascia, pubic bone and internal obturator muscle fascia) as the dissection borders from internal to external. Of note, the vesicohypogastric fascia can be recognized under magnified clear vision, and can be preserved by precise dissection, resulting in reduced hemorrhage from the internal iliac vessels and complications such as urinary dysfunction. CONCLUSION: Prophylactic laparoscopic lateral pelvic lymph node dissection after remarking on the vesicohypogastric fascia may contribute to a less invasive surgery compared with conventional laparoscopic lateral pelvic lymph node dissection. PMID- 25731229 TI - [Evaluation of laparoscopic hepatectomy for hepatocellular carcinoma with cirrhosis]. AB - Laparoscopic hepatectomy has been reported as a safe and effective approach for the treatment of hepatocellular carcinoma ( HCC). However, few studies have reported survival outcomes after laparoscopic hepatectomy in HCC patients with cirrhosis. In the present study, we evaluated the surgical outcomes and disease free survival in these cases. Between June 2010 and March 2013, 35 HCC patients with cirrhosis underwent laparoscopic hepatectomy. Operative variables for laparoscopic vs open hepatectomy were as follows: operative times, 268.3 vs 183.3 minutes (p=0.0043); blood loss volume, 151.0 vs 1,106.1 g (p<.001); 1-year disease-free survival rate, 73.1 vs 71.6%; and 2-year disease-free survival rate, 39.9% vs 28.6% (p=0.568), respectively. Laparoscopic hepatectomy is feasible and safe in selected patients with liver cirrhosis, with similar outcomes in disease free survival when compared with open hepatectomy. PMID- 25731230 TI - [A novel technique of laparoscopic hepatectomy]. AB - We report a novel technique of laparoscopic hepatectomy (lap-HT) performed at our hospital and the outcomes.Lap -HT was performed in 90 cases at our hospital, including 38 cases of anatomical resection of the liver.After mobilization of the right lobe with the patient in the half-lateral position, we resected the liver tissue using cavitron ultrasonic surgical aspirator (CUSA) and AquamantysTM Bipolar(r).This surgical instrument is useful for laparoscopic anatomical resection of the liver because it is based on vessel sealing technology.In the 90 cases in which lap-HT was performed, the mean duration of surgery and mean blood loss were 332.9 minutes and 381 mL, respectively. The mean duration of hospitalization after surgery was 12.1 days, and postoperative complications were noted in 5 cases(5.6%). Comparison of the clinical factors and short-term performance of the surgery between liver cirrhosis patients who underwent open hepatectomy and lap-HT revealed that blood loss was significantly lower and the hospital stay duration was significantly shorter in patients who underwent lap HT. Our findings suggest that laparoscopic anatomical resection of the liver can be safely performed using this novel technique and surgical instrument. PMID- 25731231 TI - [Useful device for hepatectomy in patients with a surgical history of bile duct GI tract anastomosis at the porta hepatis]. AB - We experienced three hepatectomies in patients with a history of bile duct gastrointestinal (GI) tract anastomosis at the porta hepatis. Patient 1 had a history of pancreaticoduodenectomy for bile duct cancer. Because the third liver metastasis of cecal cancer postoperatively invaded the right kidney, after 5 courses of FOLFOX we performed partial resection of the liver (S6) and the right kidney using microwave pre-coagulation and a cavitron ultrasonic surgical aspirator (CUSA) without the Pringle method. Patient 2 had a history of splenectomy for congenital spherocytosis, cholecystectomy, choledocholithotomy, and bile duct duodenal anastomosis for hepatolithiasis. Partial (S5) liver resection was performed to treat hepatocellular carcinoma. Patient 3 had a history of bile duct resection and choledochojejunostomy for congenital cystic dilatation of the common bile duct. She had repeated episodes of cholangitis in the year following surgery. Extended liver segmental (S4) resection was performed to treat intrahepatic bile duct carcinoma. Bile duct jejunum anastomosis was performed, and the portal vein and the hepatic artery in the porta hepatis were exfoliated. Hepatectomy was performed using the Pringle method and a CUSA. Surgical procedures using various devices are necessary for hepatectomy in patients with a history of bile duct-GI tract anastomosis at the porta hepatis. PMID- 25731232 TI - [Clinical benefit of thoracoscopic approach for liver tumors located under the diaphragm]. AB - It is important to ensure restricted operation fields and operation maneuvers in the surgical resection of liver tumors located under the diaphragm, especially those near the hepatic vein and IVC. Here we describe resection and ablation using thoracoscopy for tumors under the diaphragm after preoperative three dimensional (3D) simulation. METHOD: Preoperative 3D images were reformatted preoperatively using a 3D software tool (Virtual Place; AZE, Japan). These images simulate the thoracoscopic view on the surface of the diaphragm, enabling us to confirm the tumor location and choose optimal port position. RESULT: We performed thoracoscopic surgery in 5 patients (4 with HCC and 1 with a metastatic tumor) after the simulation. In all cases, we were able to safely confirm the tumor locations and perform the surgeries. CONCLUSION: Preoperative 3D simulation makes it easy to determine the optimal port position for the thoracoscope and confirm the tumor location. The approach through the diaphragm using thoracoscpy is useful since it does not require liver mobilization. PMID- 25731233 TI - [Intra-arterial infusion of IA-call(r) combined with oral anticancer drugs for recurrent hepatocellular carcinoma after liver resection]. AB - Continuous hepatic artery infusion chemotherapy for hepatocellular carcinoma (HCC) refractory to trans-arterial chemoembolization ( TACE) sometimes adversely affects the quality of life (QOL) of patients. Herein, we report a one-shot intraarterial infusion of cisplatin powder (IA-call(r)) combined with oral anticancer drugs for recurrent HCC refractory to TACE after liver resection.From July 2013, 4 patients who were diagnosed with recurrent HCC refractory to TACE after liver resection were treated with IA-call(r) infusions at 1-2 month intervals.Encapsulated tegafur-uracil (UFT-E) or sorafenib were administered sequentially.On average, IA-call(r) was administered 3.6 times per patient at a mean dosage of 93 mg per treatment. UFT-E was combined with the IA-call(r) infusion for 3 patients, and a sorafenib combination was used for 1 patient.In terms of the therapeutic effects of these regimens, we observed complete response (CR) in 1 patient, partial response (PR) in 2 patients, and progressive disease (PD) in 1 patient(response rate: 75%). Therefore, one-shot intra-arterial infusion of IAcall (r) combined with oral anticancer drugs is an effective therapy for recurrent HCC while maintaining patients' QOL. PMID- 25731234 TI - [Short-term adjuvant hepatic arterial infusion chemotherapy after hepatic resection for hepatocellular carcinoma with macrovascular invasion]. AB - BACKGROUND: Prognosis of patients with hepatocellular carcinoma (HCC) with macrovascular invasion is extremely poor even after hepatic resection. Herein, the efficacy of short-term adjuvant hepatic arterial infusion chemotherapy (HAI) for HCC with macrovascular invasion has been studied. PATIENTS AND METHODS: From 1997 to 2013, 39 patients with HCC (BVp3, Vv3, or B3) undergoing hepatic resection were enrolled(group A: adjuvant HAI, n=21, group B: hepatectomy alone, n=18). RESULTS: Clinical and demographic characteristics were similar in the 2 groups. Five-year disease-free survival (DFS) rates were 31.0% and 6.2% in group A and group B, respectively (p=0.008). In multivariate analysis for DFS, adjuvant HAI was the only independent prognostic factor (hazard ratio: 0.44, p=0.04). In group A, the intrahepatic recurrence rate was significantly lower (33% vs 72%, p=0.01) compared to group B, but rates of extrahepatic recurrence were similar in the 2 groups (19% vs 22%). The rate of overall survival was marginally higher in group A compared to group B (51% vs 19%, respectively, p= 0.06). CONCLUSION: Short-term adjuvant HAI after hepatic resection may significantly improve DFS for HCC patients with macrovascular invasion. PMID- 25731235 TI - [A case of curative resection after downsizing chemotherapy in initially unresectable locally advanced intrahepatic cholangiocarcinoma]. AB - This case report describes an 83-year-old man with intrahepatic cholangiocarcinoma who was referred by a local hospital. Abdominal computed tomography (CT) showed a large tumor in hepatic segments 4, 5, and 8 involving the right hepatic vein and inferior vena cava, which is normally indicative of an unresectable locally advanced tumor. After systemic chemotherapy with gemcitabine and cisplatin, the observed decrease in the level of tumor marker suggested that the cancer was responding to treatment, while radiological findings showed the main tumor shrunk without the presence of distant metastases. Thus, hepatic left trisectionectomy with bile duct resection was performed after portal vein embolization. Pathological examination revealed negative margins (R0). Eighteen months after surgery, the patient is free of disease and shows no signs of recurrence. An initially unresectable, locally advanced biliary tract cancer may be down sized by chemotherapy, which makes radical resection possible, at least in a proportion of patients. This approach provides longer survival and may have a potential for disease eradication as a new multidisciplinary approach for patients with unresectable locally advanced biliary tract cancer. PMID- 25731236 TI - [A case of initially unresectable pancreatic cancer with arterial invasion successfully resected after chemotherapy]. AB - A 63-year-old man was diagnosed with pancreatic head cancer, and an operation was planned at his previous hospital. However, resection was not possible because of invasion of the superior mesenteric artery, and gemcitabine-based chemotherapy was administered for the tumor for 2 years. Imaging examinations after chemotherapy were unable to detect the tumor at the pancreatic head or the arterial invasion. The patient was subsequently referred to our hospital for surgery. Upon laparotomy, the tumor was judged to be resectable, and a pancreaticoduodenectomy was performed. Pathological examination indicated the presence of cancer cells in the resected specimens. The patient underwent adjuvant chemotherapy and is currently alive without recurrence. This case highlights the importance of ongoing follow-up in patients with locally advanced pancreatic cancer so that tumor resectability can be evaluated during chemotherapy. PMID- 25731237 TI - [Successful treatment of advanced gallbladder cancer involving the extrahepatic bile duct with neoadjuvant chemoradiation therapy - a case report]. AB - A 57-year-old man with jaundice was diagnosed as having advanced gallbladder cancer involving the extrahepatic bile duct.We initiated neoadjuvant chemoradiation therapy with 3-dimensional conformal irradiation (2 Gy * 25 Fr/5 weeks)and gemcitabine (1,000 mg/m2) on days 1, 8, and 15, every 28 days for 3 courses. After percutaneous transhepatic portal vein embolization (PTPE), we performed right hepatectomy with extrahepatic bile duct resection. A follow-up examination 5 years after the operation showed no evidence of recurrence. Therefore, neoadjuvant chemoradiation therapy has the potential to improve the prognosis of patients with advanced gallbladder cancer involving the extrahepatic bile duct. PMID- 25731238 TI - [A case of postoperative recurrent hilar cholangiocarcinoma in the lower bile duct treated with pancreatoduodenectomy]. AB - When surgery is selected to treat postoperative recurrent hilar cholangiocarcinoma in the intrapancreatic bile duct, attention should be paid to the following: 1 ) technical resectability of the lesion, 2) reconstruction, and 3) high risk of complications. Eight cases, including the present case, of pancreatoduodenectomy (PD) for postoperative recurrent hilar cholangiocarcinoma in the intrapancreatic bile duct have been reported thus far. In October 2009, a 73-year-old man noticed that his stools were gray and visited a physician. He was diagnosed with cholangiocarcinoma on close examination and underwent left hepatic and caudate lobectomy in January 2010. After the surgery, he was treated with TS 1 (80 mg) and followed up at the outpatient clinic of our hospital. In July 2013, he was diagnosed with cancer of the lower bile duct and was admitted for surgery. The first and second pathological findings were carcinoma of the bile duct and papillary adenocarcinoma, respectively. The findings from the immunostaining were also inconsistent. The histopathological examination result suggested multicentric recurrence. The surgery was highly invasive, increasing the patient's risk of complications, in addition to the presence of postoperative adhesion. Therefore, surgery may be an important option for cases of localized recurrence but not for multicentric recurrence. PMID- 25731239 TI - [A case of synchronous cancer of the gall bladder, common bile duct, and the papilla of vater]. AB - A 58-year-old man was diagnosed with liver dysfunction during a health exam and subsequently visited a doctor. Abdominal ultrasonography revealed space-occupying lesions in the gall bladder and bile duct, and he was hospitalized for further examination and treatment. Computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and magnetic resonance cholangiopancreatography (MRCP) revealed double cancer of the gall bladder and bile duct with pancreaticobiliary maljunction (PBM), and we performed a pancreatoduodenectomy. Pathological examination revealed gall bladder and bile duct cancer, and severe dysplasia of the papilla of Vater. We diagnosed synchronous triple cancer because none of the cancers had continuity or vascular invasion. Each cancer was at Stage I, and the patient has survived for 2 years and 6 months without recurrence and no additional treatment. PBM is a mutation of the junction of the pancreatic and bile ducts outside of the duodenal wall, and is a known complication of biliary tract cancer due to the reflux of pancreatic juice and bile. Because K-ras and p53 gene mutations occur in the biliary tract mucosal epithelium, PBM increases the risk of developing multicentric cancer. It is important to consider the existence of double cancer when biliary tract cancer is detected in a PBM patient. PMID- 25731240 TI - [Hepatic inferior vena cava resection and vascular prosthesis reconstruction for locally advanced intrahepatic cholangiocarcinoma - a case report]. AB - A 61-year-old woman was referred to our hospital because of jaundice and general itching. Computed tomography (CT) scan demonstrated that the tumor was located in the caudate lobe of the liver with hilar invasion and involved the hepatic inferior vena cava (IVC) and the right renal artery and vein. The patient was diagnosed with locally advanced intrahepatic cholangiocarcinoma, for which she underwent right hemihepatectomy with right caudate lobectomy, portal vein resection, hepatic IVC resection, extrahepatic bile duct resection, and right nephrectomy. IVC was reconstructed using vascular prosthesis by expanded polytetrafluoroethylene (ePTFE)-ringed graft. The patient's postoperative course was uneventful. The patient was treated with gemcitabine for postoperative chemotherapy, and 3 years after the operation, she died due to recurrence resulting from peritoneal dissemination. Although the thrombosis-related vascular prosthesis obstruction had occurred 2 years after the operation, no clinical symptom were noted, such as lower leg edema or renal dysfunction, during the postoperative course. Hepatic IVC prosthesis reconstruction for locally advanced cancer with extensive IVC invasion can be a useful surgical procedure for improving the resection rate and maintaining quality of life (QOL) in such cases. PMID- 25731241 TI - [A case of advanced gallbladder cancer with mediastinum lymph node metastasis successfully treated with multimodality therapy]. AB - A 69 -year-old female with advanced gallbladder cancer underwent cholecystectomy, S4a/S5 segmentectomy of the liver, and resection of the extra-hepatic bile duct in October 2005. Adjuvant chemotherapy consisted of gemcitabine (GEM) and tegafururacil (UFT) administered consecutively. Four years after surgery, computed tomography revealed a single enlarged lymph node in the mediastinum, along with 18F-fluorodeoxyglucose accumulation and increased carcinoembryonic antigen (CEA) levels. Therefore, the mediastinal lymph node was considered to be a metastasis and GEM was readministered. Although the patient was treated with GEM for 1 year, the accumulation of 18F-fluorodeoxyglucose in the lymph node remained elevated. No other distant metastases were detected. Abronchoscopic biopsy histologically confirmed mucinous adenocarcinoma in the lymph node. Thus, the mediastinal lymph node was resected. Post-surgery, there was no evidence of recurrence during the 30-month follow up period without chemotherapy. Herein, we report a successful case of surgical treatment for solitary mediastinal lymph node metastasis of gallbladder cancer and review the relevant literature. PMID- 25731242 TI - [A long term survival case of hilar cholangiocarcinoma with multiple metastases treated with chemotherapy and operation]. AB - A 40-year-old woman presenting with hilar cholangiocarcinoma and multiple liver metastases was admitted to our hospital. Initially, she underwent an extended right hepatectomy, 1 segmentectomy, and partial resection of the liver. After adjuvant chemotherapy with gemcitabine (1,000 mg/m2 days 1, 8, and 15, of a 28 day cycle), multiple liver metastases (1 lesion in S2 and 2 lesions in S4) were detected by computed tomography (CT). As a result of the impaired response to gemcitabine, the chemotherapy regimen was changed to include combined chemotherapy with gemcitabine (1,000 mg/m2 days 1 and 8, of a 21-day cycle), and S-1 (120 mg/body/day days 1 through 14). After 5 courses of combined chemotherapy, the liver metastases reduced in size; subsequently, a left internal sectionectomy and radiofrequency ablation were performed. Thereafter, the patient continued to receive adjuvant chemotherapy with S-1 for an additional 3 years; she is alive, without recurrence, 5 years after the initial operation. We propose that aggressive surgery should be considered for patients presenting with chemotherapy-responsive cholangiocarcinoma with multiple metastases. PMID- 25731243 TI - [A successful case with TS-1+CDDP chemotherapy for recurrent gastric cancer]. AB - A 64-year-old woman underwent cholecystectomy for treatment of cholecystolithiasis in January 2005. Pathological examination rendered a diagnosis of gallbladder carcinoma. Wedge resection of the liver and dissection of the lymph nodes was performed. No tumor cells in either the liver nodule or lymph nodes were found during pathological examination. At 4 years after surgery, paraaortic lymph node recurrence was confirmed by computed tomography (CT). Gemcitabine was administered once weekly for the first 3 weeks in a monthly cycle, but the tumor continued to increase in size. Gemcitabine was then switched to TS-1, after which it was changed to cisplatin because of continued tumor growth. After 35 courses of chemotherapy, CT showed the disappearance of the paraaortic lymph node, and the patient achieved a complete response. She is currently free of disease at 9 years after surgery. PMID- 25731244 TI - [Prophylactic portal vein stenting in a patient with local recurrence of cholangiocarcinoma without clinical symptoms of portal vein stenosis - a case report]. AB - A 70-year-old man was diagnosed with local recurrence 1 and half years after pancreatoduodenectomy for extrahepatic cholangiocarcinoma. Progression of the recurrent tumor involved the portal vein, even though the patient had received chemotherapy (gemcitabine). Although no clinical symptoms caused by portal venous stenosis were found at the time, we performed percutaneous transhepatic portal vein stenting to avoid interrupting chemotherapy. Eighteen months after this procedure, the patency of the portal vein stent was well maintained, and the patient was treated with S-1 chemotherapy continuously without any symptoms related to portal venous stenosis reported. Prophylactic portal vein stenting without clinical symptoms of portal vein stenosis is a useful procedure, not only for palliative care but for improving the prognosis of patients with cholangiocarcinoma by continuous chemotherapy. PMID- 25731245 TI - [Portal vein stenting as a bridge to chemotherapy for perihilar cancer with portal vein stenosis - a case report]. AB - The stenting strategy for portal vein stenosis in cases with unresectable hilar malignancies reduces portal hypertension and maintains portal vein blood flow. This not only improves quality of life, but also leads to aggressive therapy with anticancer agents. A 65-year-old woman presented with painless jaundice 8 months after left hemihepatectomy with lymph node dissection for intrahepatic cholangiocellular carcinoma. Seven months after biliary stenting for bile duct stenosis, progressing pancytopenia and ascites were noted. Imaging studies revealed portal vein stenosis by the tumor at the hepatic hilum. Percutaneous transhepatic portal vein stent placement was performed, and pancytopenia and ascites improved immediately thereafter. Chemotherapy for recurrence of intrahepatic cholangiocellular carcinoma at the hepatic hilum has been initiated, and the patient has been alive 15 months since. PMID- 25731246 TI - [Long-term survivor of unresectable bile duct cancer complicated with sclerosing cholangitis treated with chemotherapy]. AB - A 70-year-old woman was admitted to a near by hospital with complaints of epigastric pain and fever. Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) revealed stenosis of the hilar bile duct and multiple stenoses in the intrahepatic bile duct; bile cytological analysis indicated adenocarcinoma. The levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were within normal limits. It was very difficult to evaluate the extent of tumor invasion; therefore, we concluded that the tumor was unresectable. The patient underwent systemic chemotherapy with gemcitabine. After 5 years, she developed obstructive jaundice and cholangitis. The patient underwent endoscopic retrograde biliary drainage (ERBD), with 3 incidents of cholangitis recurrence. Although systemic chemotherapy with gemcitabine was performed for a long time, she died 6 years after the initiation of chemotherapy. Gemcitabine was administered 140 times in total, with a total dose of 203.744 g. PMID- 25731247 TI - [A case of recurrent duodenal gastrointestinal stromal tumor resistant to imatinib and sunitinib, successfully treated with regorafenib]. AB - Regorafenib is a novel, orally administered multi-kinase inhibitor that has recently been approved for the treatment of recurrent gastrointestinal stromal tumor (GIST). We report a case of successful treatment of recurrent duodenal GIST, which was found to be resistant to imatinib and sunitinib, with regorafenib. A 62-year-old woman underwent a pancreatoduodenectomy for duodenal GIST; after 2 years, a computed tomography (CT) scan detected liver metastases. The patient received imatinib for 6 years, and underwent 2 hepatectomies. Subsequently, she received sunitinib for 10 months; however, CT scans revealed the presence of multiple vertebral metastases. She underwent a laminectomy for the palliative treatment of the vertebral metastases. Upon immunohistochemical examination, the recurrent tumor stained positive for c-kit, confirming the diagnosis for GIST. Consequently, the patient received regorafenib; although the treatment controlled the liver metastases, the vertebral metastases were found to have progressed. She survived for 9 years and 5 months after the initial surgical resection. Regorafenib might be beneficial in the treatment of recurrent GISTs that prove to be resistant to imatinib and sunitinib. PMID- 25731248 TI - [A case of postpancreaticoduodenectomy local recurrence successfully treated with extended resection]. AB - A 68 -year-old man underwent a pancreaticoduodenectomy after being diagnosed with primary duodenal cancer. The postoperative pathological diagnosis was tub2, SE, ly1, v1, panc3, pn+, N0. Although adjuvant chemotherapy was administered, local recurrence in the portal region was detected 18 months later. The recurrent tumor pressed against the region of the bile duct anastomosis, which caused obstructive jaundice. After serum bilirubin levels were reduced, resection of the recurrent tumors was performed. This required resection of the transverse colon, parts of the portal vein, and the inferior vena cava. The bile duct anastomotic region, which had been infiltrated by the tumor, was excised and rebuilt. The postoperative pathological diagnosis was tub2. The patient continued to receive adjuvant chemotherapy and showed no signs of recurrence 9 months after surgery. Extended resection for local recurrences of primary duodenal cancer may be an effective means of disease control. PMID- 25731249 TI - [Usefulness of the retrograde intraduodenal drainage tube for severe duodenum related complications of gastrectomy for gastric cancer]. AB - No ideal or generally accepted treatment strategy has been established for severe duodenum-related complications of gastrectomy for gastric cancer. Between 1997 and 2012, we successfully treated 5 patients with such complications using the retrograde intraduodenal drainage tube. Of the patients, 3 had anastomotic leakage of the duodenal stump, 1 had an intestinal injury, and 1 had the afferent loop syndrome. None of the patients experienced any further adverse events related to the procedure. This retrograde intraduodenal drainage technique was safe and effective, and may be considered as an optimal treatment strategy for severe duodenum-related complications of gastrectomy for gastric cancer. PMID- 25731250 TI - [A case of gastric outlet obstruction and rectal obstruction due to metastases from breast cancer treated by gastroduodenal and colon stenting]. AB - Malignant bowel obstruction often causes oral intake difficulties and decreases quality of life. In Japan, gastroduodenal stenting for malignant gastric outlet obstruction has been covered by health insurance since 2010, while colon stenting has been covered since 2012. Both approaches are useful treatments for malignant bowel obstruction. Here we report the case of a woman with gastric outlet obstruction and rectal obstruction due to breast cancer metastases who was able to eat solid food after duodenal and colon stenting. When choosing whether to perform endoscopic stenting or surgical intervention such as gastrojejunostomy, ileostomy, and colostomy for treating malignant bowel obstruction, it is important to assess the patient's general condition and prognosis as well as the obstruction position. PMID- 25731251 TI - [Significance of preoperative radiotherapy and lateral lymph node dissection for locally advanced rectal cancer - a comparative study involving different hospitals]. AB - The aim of this study was to compare the results between lateral lymph node dissection (LLND) alone, and preoperative radiotherapy (preRT) followed by LLND, for the treatment of locally advanced rectal cancer. This study assessed 44 consecutive patients with lower rectal cancer (clinical Stages II and III) without lateral lymph node metastasis by preoperative imaging at two hospitals. Twenty-five patients at one hospital received preoperative short-course radiation therapy (total 25 Gy) followed by a curative LLND operation (preRT group), and 19 patients at another hospital underwent a curative operation by LLND alone (non preRT group). The 5-year locoregional relapse-free survival, disease-free survival, and overall survival rates were not different between the preRT and non preRT groups. Although three patients in each group had lateral lymph node metastases, none developed pelvic sidewall recurrence. This study suggests that preRT followed by curative surgery with LLND for lower rectal cancers without lateral lymph node metastasis before surgery would not improve survival and local control rates. PMID- 25731252 TI - [A case of pathological complete response to lt. Lateral lymph node metastasis from lower rectal cancer by S-1 combined neoadjuvant chemoradiotherapy]. AB - A 54-year-old man presented with an enlarged left (lt) lateral lymph node (LLN), which was detected by magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET-CT). Endoscopic examination of the colon revealed the presence of a type 1 tumor, 20mm in diameter, in the lower rectum; the tumor was diagnosed as a well-differentiated adenocarcinoma (tub1). The patient received combined neoadjuvant chemoradiotherapy (nCRT)with S- 1 for treatment of the rectal cancer and LLN metastasis (MP, T2N3M0, Stage IIIb). S-1 was administered orally at a dose of 120 mg/day on days 1-14, and 22-35; a total dose of 45 Gy was delivered (1.8 Gy/day, for 25 days). Upon nCRT, there was a remarkable reduction in the tumor size, the primary tumor receded, and the LLN decreased from 16 mm to 8 mm in diameter. The maximum standardized uptake value (SUVmax) also decreased from 3.8 to 1.9 on PET-CT. Six weeks after nCRT, ultralow anterior resection and bilateral lymph node dissections were performed. Histopathological examination showed a partial presence of cancer cells in the scarred primary tumor; however, no viable cancer cells were observed in the lt. LLN. PMID- 25731253 TI - [A case of locally advanced rectal carcinoma treated with preoperative chemoradiotherapy resulting in pathologically complete response]. AB - An 84-year-old woman presented with the chief complaint of melena. Colonoscopy revealed a type 2 tumor that circumferentially occupied the lumen of the lower rectum about 6 cm from the anal verge. A biopsy specimen was obtained from the tumor and the patient was diagnosed with moderately differentiated adenocarcinoma. Computed tomography revealed that the rectal cancer had invaded the marginal fatty tissue, accompanied by several regional lymph node metastases with no distant metastasis. On the basis of this evidence, the tumor was staged as cT4a, cN2b, cM0 according to the TNM Classification of Malignant Tumors (7th Edition, UICC). Preoperative radiotherapy combined with an oral chemopreventive agent (RT 1.8 Gy * 25 frames; total 45 Gy, S-1 80 mg/day) was administered with trivial adverse effects. Laparoscopy-assisted low anterior resection with Japanese D3 dissection was performed successfully. The patient is doing well without recurrence after 14 months of surgery. Histological examination revealed that both the primary lesion and regional lymph nodes had no residual cancer; that is, the histological effect of the preoperative chemoradiotherapy was a pathologically complete response (pCR). PMID- 25731254 TI - [Efficiency of pre-operative chemoradiotherapy in treating a case of advanced rectal cancer]. AB - There is insufficient evidence for the pre-operative use of chemoradiotherapy (CRT) in treatment of advanced rectal cancers, and its efficiency and safety are unclear. However, it has recently been suggested that a new class of carcinostatic agents are more effective during preoperative CRT. Under the National Comprehensive Cancer Network (NCCN) guidelines, 5-FU and capecitabine have been recommended as the standard drugs for use during combination chemoradiotherapy. The Japanese Society for Cancer of Colon and Rectum (JSCCR) guidelines for 2014 also recommend the use of both drugs during preoperative CRT. We report a case of rectal cancer, which was successfully treated with radical resection and neoadjuvant chemoradiotherapy. PMID- 25731256 TI - [Surgical resection after chemotherapy for advanced rectal cancer - report of a case]. AB - Herein, we present a case of advanced rectal cancer surgically resected after chemotherapy. A 65-year-old woman presented with anal pain, and rectal cancer extending beyond the anus was diagnosed. The primary tumor was a well differentiated adenocarcinoma with a KRAS mutation. Computed tomography revealed cancer invasion into the vagina and sacral and coccygeal bones, and cancer metastases to the bilateral inguinal lymph nodes and the left lung. Sigmoid colostomy and subcutaneous venous port insertion were performed. The patient was treated with modified oxaliplatin, leucovorin, and 5- fluorouracil (FOLFOX6) plus bevacizumab. She showed a partial response according to the Response Evaluation Criteria in Solid Tumors after 13 courses of chemotherapy. The primary tumor was then resected via posterior pelvic exenteration, bilateral inguinal lymphadenectomy, and sacral/coccygeal resection. Histological examination of the resected specimens revealed moderately differentiated adenocarcinoma with vaginal invasion. Metastasis to a right inguinal lymph node was observed. The pathological stage was ypT4bN0M1b, ypStage IV according to the tumor-node metastasis system of the eighth edition of the Japanese Classification of Colorectal Carcinoma. The pathological response grade of the tumor after chemotherapy was determined to be Grade 1b. PMID- 25731255 TI - [A case of pathological complete response with neoadjuvant XELOX chemotherapy for locally advanced rectal cancer]. AB - A 70-year-old man presenting with melena was referred to our clinic. A clinical examination revealed a bulky tumor in the lower rectum. After ileostomy, 4 courses of capecitabine plus oxaliplatin (XELOX) therapy were administered as neoadjuvant chemotherapy. Computed tomography (CT) revealed significant reduction of the tumor. Laparoscopic super-low anterior resection with lateral lymph node dissection was performed. The pathological examination revealed no residual cancer cells, and a diagnosis of pathological complete response was made. The patient has been disease-free for 1 year after the operation. Neoadjuvant chemotherapy with XELOX might be promising for patients with locally advanced rectal cancer. PMID- 25731257 TI - [Self-expandable metallic stent therapy for obstructive colon cancer]. AB - Patients with colon cancer who present with stenosis are treated with emergency surgery. Colostomy or Hartmann's operation are commonly performed, but are associated with an increased risk of complications such as anastomotic leakage, which reduce the quality of life of the patient. In our patient, emergency surgery was avoided by metallic stent placement. Metallic stents can be an effective bridge to surgery in colon cancer patients with ileal symptoms. PMID- 25731258 TI - [Study of stent placement period and stent-related complications in metastatic and obstructive colorectal cancer patients who received palliative chemotherapy after stent placement]. AB - PURPOSE: To examine the complications and determine the detention period in obstructive colorectal cancer patients who received chemotherapy after placement of a stent in the colon. PATIENTS AND METHODS: Seven out of 16 patients with colon cancer received chemotherapy in our hospital after stent placement as palliative therapy. RESULTS: No complications such as perforation, restenosis, deviation, or bleeding were noted. Stent insertion after median 224 stenting period was (66-397) days. CONCLUSION: Systemic chemotherapy after stenting is associated with an increased risk of perforation or deviations, but no complications were noted in this study. More cases are needed to determine the optimal detention period. PMID- 25731259 TI - [Transnasal and transanal tube decompression versus self-expanding metallic stent as a bridge to surgery for obstructive colorectal cancer]. AB - PURPOSE: The aim of this study was to compare the efficacy between the use of transnasal and transanal tube decompression and self-expanding metallic stents (SEMS) as a bridge to surgery for obstructive colorectal cancer. MATERIALS: Of a total of 42 patients with obstructive colorectal cancer, 29 were managed with transnasal or transanal tubes and 13 were managed by SEMS. RESULTS: The management duration to surgery in the stent group was longer than that in the tube group (18 vs 11 days; p<.05). More patients in the stent group could be discharged and take food or liquid normally. There was no difference in overall complications including anastomotic leakage, surgical side effects, or primary anastomosis. Perforation occurred in 2 patients in the tube group, while stent migration occurred in 1 patient in the stent group. There was no difference in complications between 2 groups. CONCLUSIONS: SEMS as a bridge to surgery for obstructive colorectal cancer could improve patients' quality of life during the preoperative period. Evaluations of the complications during decompression are needed for both methods. PMID- 25731260 TI - [Combination of self-expandable metallic stent insertion and laparoscopic surgery as a less invasive treatment of obstructive left-sided colon cancer]. AB - The purpose of this study was to evaluate the outcome of treating obstructive left-sided colon cancer with a combination of self-expandable metallic stent (SEMS) insertion and laparoscopic surgery. Ten patients were included in this study. Two patients had obstructive transverse colon cancer, and eight had obstructive sigmoid colon cancer. The patients had a SEMS inserted preoperatively as a bridge to surgery. Efficient decompression was achieved in all the patients, without any complications. Normal oral intake was possible until the laparoscopic, or laparoscope-assisted, one-stage radical operation. The SEMS insertion did not affect the surgical maneuver or laparoscopic operation at all. None of the patients developed any postoperative complications. After surgery, five patients were diagnosed with Stage II disease and three patients were diagnosed with Stage IIIA disease. The remaining two patients had distant metastasis (para-aortic lymph node and liver) and were diagnosed with Stage IV disease. Chemotherapy was administered to the two patients with Stage IV disease after a comparatively early recovery from a less invasive surgical procedure. SEMS insertion appears to be an effective, less invasive decompression method. When used in combination with laparoscopic surgery, SEMS insertion appears to be a safe and less invasive method of treating obstructive left-sided colon cancer. PMID- 25731261 TI - [Examination of the usefulness of the self-expanding metallic stent for ileus due to colorectal cancer]. AB - Ileus due to colon cancer often develops from a timing and the method of the operation and perioperative care, comparing with ordinary cases. The use of self expanding metallic stent (SEMS) was first authorized by insurance and became available nationwide in Japan in 2012. Insertion of SEMS for ileus due to colorectal cancer is useful as a bridge to surgery (BTS) approach and releases stenosis as palliative care. Here we report 5 successful cases of anastomosis performed during a laparoscopic operation for ileus due to colorectal cancer after BTS using SEMS. Successful SEMS insertion for colon cancer ileus enables observation of the proximal side. Because the decompression efficiency with SEMS is high, laparoscopic surgery becomes possible. SEMS insertion as a BTS is useful for ileus due to colorectal cancer. PMID- 25731262 TI - [Large bowel malignant obstruction treated with SEMS placement as a bridge to surgery procedure]. AB - We treated 5 cases of preoperative decompression using the self-expandable metallic stent (SEMS) against obstructive left side colon cancer since October 2013. The obstruction site was the descending colon in one patient, sigmoid colon in 2, rectal-sigmoid colon in 1, and rectum in 1. Colonic stent placements were successful in all cases. Oral intake started an average of 3.7 days after SEMS placement. All patients underwent radical surgery an average of 17.2 days after SEMS placement. Two patients waited for surgery while out of the hospital. All patients underwent colonoscopy. One patient had advanced colon cancer. Our findings show that SEMS placement can treat obstructive left-sided colon cancer. PMID- 25731263 TI - [A bridge to surgery for colon cancer obstruction in a very elderly patient - a case report]. AB - A 94-year-old woman with a distended abdomen was transferred to our hospital.Based on the enhanced abdominal computed tomographic (CT) finding, she was diagnosed with colonic obstruction due to sigmoid cancer. Colonoscopy was performed to make definitive and qualitative diagnoses, and to release the stenosis using a self-expanding metallic stent (SEMS). The SEMS was inserted without complication.On the fifth day after the decompression, the patient underwent laparoscope-assisted sigmoidectomy with lymph node resection.Despite the colon obstruction, a primary anastomosis was performed.The operation time was 163 min, and 3 mL of blood was lost.The patient was discharged without complications. We describe the case of a bridge to surgery in a very elderly patient. A bridge to surgery can be an effective option for the treatment of colon obstruction in non-elderly and very elderly patients. PMID- 25731264 TI - [Detection of lateral lymph node metastasis by PET/CT]. AB - PURPOSE: There appears to be no gold standard concerning preoperative imaging studies in patients with locally advanced lower rectal cancer. In the present study, we evaluated whether it would be appropriate to diagnose metastases of the lateral lymph node by positron emission tomography/computed tomography (PET/CT). PATIENTS AND METHODS: From 1997 to 2014, 45 patients with locally advanced lower rectal cancer underwent curative surgery and lateral lymph node dissection without neoadjuvant chemotherapy in our institute. Preoperative PET/CT analysis was performed; a total of 180 regions (45 lt. internal iliac, 45 rt. Internal iliac, 45 lt. obturator, 45 rt. obturator)were evaluated. RESULTS: Lateral lymph node metastasis was detected in ten cases, present in thirteen regions overall. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of predicting metastasis were 23.1%, 98.8%, 60.0%, 94.3%, and 93.3%, respectively, upon PET/CT. CONCLUSIONS: Our results indicate that PET/CT diagnosis alone was not suitable for detecting lateral lymph node metastasis, since the sensitivity was low when compared with the high rate of accuracy. PMID- 25731265 TI - [Detection of hepatic lymph node involvement by PET/CT in colorectal cancer patients with liver metastasis]. AB - We investigated the clinical significance of hepatic lymph node (HN) metastasis in 50 patients with colorectal cancer metastases to the liver. Patients underwent preoperative positron emission tomography/computed tomography (PET/CT), and subsequently, resection of colorectal liver metastases with HN dissection from 2007 to 2013. In the present study, we evaluated whether PET/CT screening would be beneficial in diagnosing the HN metastases. Our results indicate that 2 histo- logically confirmed HN metastases were detected during preoperative PET/CT screening for 50 patients, of which only 1 patient received a positive diagnosis prior to surgery. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of predicting metastasis were 50%, 100%, 100%, 98%, and 98%, respectively. We conclude that PET/ CT screening is not feasible for detecting HN metastasis. PMID- 25731266 TI - [False-positive local recurrences on FDG-PET/CT due to postoperative infection - a case report]. AB - Although 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a powerful tool for detecting the recurrence of colorectal cancer, FDG uptake is not tumor specific. Herein, we report a case of a 65-year- old man who underwent emergency colectomy for perforation of colon cancer. FDG PET/CT after surgery showed 2 tumors that were difficult to differentiate from peritoneal metastases with invasion to the spleen. Splenectomy was performed, and the histopathology revealed that the tumors in fact were abscesses. This is a clinically thought-provoking case that showed the difficulty of the differential diagnosis between early recurrence after emergent surgery of colorectal cancer and the postoperative changes. PMID- 25731267 TI - [Tumor-infiltrating lymphocytes can be used to screen for lynch syndrome - a case report]. AB - Lynch syndrome is an inherited syndrome associated with the development of colorectal and various other cancers. A 65- year-old male underwent a laparoscopic-assisted right hemi-colectomy for ascending colon cancer (cStage II). Histologically, his tumor was diagnosed as a poorly differentiated adenocarcinoma. Lymphocytic reactions, such as tumor-infiltrating lymphocytes (TIL), and Crohn's-like reactions, were observed. Genetic testing revealed the presence of a pathogenic mutation in the MLH1. In the Lynch syndrome, the most frequently observed findings include the accumulation of mutations, and an early onset of familial colon cancer. Although the case presented here did not show the typical clinical findings of Lynch syndrome, histological examination of the lymphocytic reactions proved useful for screening for Lynch syndrome. Herein, we establish the important role of the pathologist in alerting the clinician to the possibility of Lynch syndrome when the findings of TIL and Crohn's-like reactions are detected. PMID- 25731268 TI - [The usefulness of intraoperative Doppler echo and laparoscopic echo in laparoscopic colectomy]. AB - Laparoscopic surgery has been increasingly performed in colon cancer patients; it has also been adapted for cases of advanced colorectal cancer. While performing an operation for rectosigmoid colon cancer, preservation of the left colic artery and prompt and accurate detection of the branch of the left colic artery from the inferior mesenteric artery is important. Detecting the left colon arterial bifurcation takes time, especially because of the presence of mesenteric fat, which is observed in many cases. In addition, in cases in which preoperative enhanced computed tomography (CT) cannot be performed, the surgery is sometimes performed without knowing the traveling vessel. As palpation is impossible, it is impossible to tactile running of the arteries as laparotomy in laparoscopic surgery. With endoscopic echo or Doppler echo, real-time identification of the blood vessels during surgery is possible without being invasive. It would be in laparoscopic surgery impossible palpation, and the combined use of intraoperative echo in ensuring the safety to be useful. PMID- 25731269 TI - [Radiosensitizing effect of 5-aminolevulinic acid (5-ALA ) in Colon cancer]. AB - 5-aminolevulinic acid (5-ALA) is widely used in clinical practice because it shows tumor-selective accumulation of protoporphyrin IX, a fluorescent substance and a metabolite of 5-ALA. In addition, some studies have reported that 5-ALA increases the radiation sensitivity of glioma and melanoma. In this study, we investigated the radiosensitization effect of 5-ALA on colon cancer. Mice implanted with the human colon cancer cell line HT29 were administered 5-ALA and subsequently X-ray irradiated. These mice were compared with those not administered 5-ALA. Following multiple irradiations, the tumor volume of the 5 ALA group was significantly lower than that of the non-5-ALA group (day 5: p value=0.0489, day 8: p value= 0.0318, day 12: p value=0.0394). Tumor growth was inhibited by multiple irradiations in the 5-ALA group compared with the non-5-ALA group. These results suggest that 5-ALA also exhibits a radiosensitization effect on colon cancer. PMID- 25731270 TI - [Curative dissection of paraaortic lymph node metastases after operation for ascending colon cancer]. AB - In October 2007, a 69-year-old woman underwent right hemicolectomy and D3 lymph node dissection for the treatment of adenocarcinoma (type 2, por2]tub2, pSS, pN3, fStage IIIb). Serum carcinoembryonic antigen (CEA) concentration was 152.8 ng/mL preoperation, but returned to normal after the operation. Adjuvant chemotherapy using 450 mg/day UFT-E was added. Computed tomography (CT) examination revealed a swollen paraaortic lymph node 3 months after the operation, while serum CEA concentration had increased to 92.7 ng/mL. After the chemotherapy was changed to FOLFOX, the paraaortic lymph node shrank and serum CEA concentration decreased. However, after 6 courses, serum CEA concentration increased again and bevacizumab FOLFIRI therapy was initiated. After 3 courses of bevacizumab-FOLFIRI were not effective, paraaortic lymph node dissection was performed in February 2009. Pathological examination of the resected specimen showed metastatic adenocarcinoma. At present, the patient is alive without any signs of recurrence. Although the effectiveness of chemotherapy for paraaortic lymph node metastasis of colorectal cancer has been described, complete cure has not been reported. Thus, surgical resection has the potential to cure solitary recurrence of paraaortic lymph node metastasis, and therefore, should be considered in the treatment of such cases. PMID- 25731271 TI - [A case of lymph node recurrence occurring nine years after surgery for sigmoid colon cancer]. AB - A 64-year-old man underwent sigmoidectomy for sigmoid colon cancer 9 years ago. We attempted to discontinue surveillance, as the postoperative course was event free for 5 years; however, we continued the follow-up on the patient's request. Nine years after the operation, elevation of the serum carcinoembryonic antigen (CEA) level was detected, and positron emission tomography-computed tomography (PET-CT) showed a 35-mm mass with an abnormal signal (SUVmax 18.6 Bq/ mL). We performed an abdominal CT and magnetic resonance imaging and found the mass invading the sigmoid colon. We suspected lymph node recurrence of the sigmoid colon cancer and considered curative surgery to be appropriate as there were no other signs of recurrence. We therefore excised the tumor by sigmoidectomy. A histopathological examination revealed metastatic adenocarcinoma in the lymph node. One year after the second operation, there was no evidence of recurrence on imaging and the levels of tumor markers were within the normal limits. Few reports have documented recurrence over 5 years after surgery. We herein describe our case and report the characteristics of a recurrent lesion and also suggest a protocol for surveillance, taking into consideration the previous literature. PMID- 25731272 TI - [Resection of a left obturator lymph node recurrence five years five months after surgery for rectal cancer]. AB - A 62-year-old man with lower rectal cancer underwent abdominoperineal resection and dissection of the lateral pelvic lymph nodes. The cancer was staged at pT3pN0cM0, pStage II and did not show recurrence. Two years later, the patient had dysphagia and was diagnosed with esophageal cancer based on upper gastrointestinal endoscopy. Positron emission tomography-computed tomography (PET/CT) performed to detect distant metastasis revealed fluorodeoxyglucose (FDG) uptake in the left obturator lymph nodes, indicating rectal cancer recurrence. The patient received radiation therapy (60.4 Gy) for the recurrence. A PET/CT scan obtained 2 years 6 months after the initial rectal cancer resection revealed no FDG uptake. Uraciltegafur plus Leucovorin (UFT+LV) was started and continued for 6 months, but tumor enlargement was noted. Treatment was changed to LV, 5 fluorouracil, and irinotecan (FOLFIRI), but after 4 courses, the patient's carcinoembryonic antigen (CEA) levels rose. The patient then received 4 courses of bevacizumab plus FOLFIRI. A CT scan revealed tumor shrinkage, so the patient received 4 more courses of this regimen. Five years postoperatively, the patient's CEA levels rose again. A PET/CT scan 4 months later revealed FDG uptake in the left obturator lymph nodes, indicative of rectal cancer recurrence. One month later, the lymph nodes were resected. The patient was subsequently recurrence free. Tumor marker measurement and PET/CT helped to assess the patient's condition. When cancer recurs in the lateral pelvic lymph nodes with no involvement of the pelvis and R0 resection is possible, resection should be considered if the patient is capable of undergoing surgery. PMID- 25731273 TI - [A case of long-term survival after lateral pelvic lymph node dissection for recurrence as skip metastasis of rectal cancer]. AB - Herein, we present a case of long-term survival after lateral pelvic lymph node dissection for recurrence in the form of skip metastasis of rectal cancer. A 63 year-old man underwent abdominoperineal resection without lateral pelvic lymph node dissection for advanced lower rectal cancer. The histological diagnosis was type 2, 85 * 50 mm, tub1, pT4a, ly0, v1, pPM0, pDM0 and pN0, pStage II (Japanese Classification of Colorectal Carcinoma, 8th edition). Six months after surgery, enhanced computed tomography showed right obturator lymph node metastasis. We performed lateral pelvic lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma in the right obturator lymph node. The lymph node metastasis was diagnosed as a skip metastasis of the rectal cancer. The patient has had no recurrence for 9 years after resection of the lateral pelvic lymph node. PMID- 25731274 TI - [A case of simultaneous laparoscopic resection of colorectal cancer and a synchronous liver metastasis]. AB - A 39-year-old woman was referred to our hospital with a history of fecal occult blood.She was diagnosed with advanced sigmoid colon cancer.A colonoscopy indicated a stenosis, and an enhanced abdominal computed tomography (CT) scan revealed liver metastasis.The patient was operated on for a total of 337 minutes, and an estimated 35 mL of blood was lost. This is the shortest operating time and lowest amount of blood loss of which we are aware.Although an intra-abdominal abscess occurred, the patient recovered well and was discharged on postoperative day 25.Herein, we describe the case of a patient who underwent simultaneous laparoscopic resection of sigmoid colon cancer and a synchronous liver metastasis.We also review the efficacy of simultaneous laparoscopic resection of colorectal cancer and synchronous liver metastasis in this report. PMID- 25731275 TI - [A case of colonoscopy release of intussusception due to sigmoid colon cancer]. AB - A 53-year-old woman with recurrent abdominal pain was referred to our hospital. Based on the enhanced abdominal computed tomographic (CT) finding, she was diagnosed with intussusception of the sigmoid colon. Colonoscopy was performed to release the intussusception, and a lead point lesion was detected. An advanced cancer was found in the rectum, which could be pushed back into the sigmoid colon easily using pressurized air. A more-advanced colon cancer was also detected on the oral side of the lesion. The patient was diagnosed with double cancer of the sigmoid colon and was treated with laparoscopic sigmoidectomy with lymph node resection (D3). Preliminary reduction by colonoscopy prior to surgery is an effective option in cases of adult intussusception. Colonoscopy can be used to perform definitive and qualitative diagnoses. PMID- 25731276 TI - [A case of appendiceal intussusception induced by appendiceal carcinoma]. AB - A 26-year-old man was admitted to hospital because of lower quadrant pain. Colonoscopy showed a polypoid lesion (0- Ip: protruded, pedunculated)in the cecum. Endoscopic biopsy revealed a tubular adenoma with severe atypia. Laparoscopy- assisted ileocecal resection was performed, as the diameter of the tumor made colonoscopic treatment difficult. Appendiceal intussusceptions were found in the excised specimen. The tumor was mucosal in origin. The patient remained cancer-free after the surgery. PMID- 25731277 TI - [A case report of the use of laparoscopic surgery to remove an adrenal tumor following resection of sigmoid colon cancer]. AB - A 58-year-old woman underwent sigmoidectomy and partial cystectomy for sigmoid colon cancer following colostomy. The final staging of the tumor was T3, N1, tub2, M0, fStage IIIa. She received 6 courses of CapeOX (oxaliplatin 130mg/m2, capecitabine 200mg/m2) as adjuvant chemotherapy, which was discontinued because of severe general fatigue. At the same time, an increase in the levels of serum carcinoembryonic antigen (CEA) was detected and abdominal computed tomography (CT) revealed an expanded adrenal mass. Since whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) showed no evidence of multiple organ metastases except for the right adrenal tumor, a solitary adrenal metastasis from sigmoid colon cancer was strongly suspected. Hence, colostomy closure and laparoscopic adrenalectomy were concurrently performed. Histological examination revealed non-functional adrenal adenoma. Therefore, laparoscopic surgery was a reasonable choice even in this complex case. PMID- 25731278 TI - [Laparoscopic total colectomy (TPC) for familial adenomatous polyposis - a case report]. AB - A 30-year-old man was admitted with anemia. Colonoscopy showed diffuse small polyps in the colon, 1 cancer in the sigmoid colon, and 2 cancers in the rectum. He was diagnosed with familial adenomatous polyposis (FAP). Total colectomy was conducted laparoscopically through 5 trocars, and a total proctocolectomy (TPC ) was performed. The operating time was 9 hours and 30 minutes, and intraoperative blood loss was 20 g. On the 1st postoperative day, he started oral intake. On the 14th postoperative day, he was discharged from our hospital. We thus consider laparoscopic resection to be a very useful technique for FAP. PMID- 25731279 TI - [The feasibility of reduced port surgery for sigmoid colon and rectal (Rs) cancer]. AB - Laparoscopic surgery for colorectal cancer has the advantage of being less invasive and delivering better cosmetic appearance. Although single-incision laparoscopic surgery produces excellent cosmetic results, it is considered very difficult to perform. We performed reduced port surgery (single-incision plus one or 2 ports) on 42 patients in our institute. The operation time, number of dissected lymph nodes, morbidity rates, and length of hospital stay after the operation were not inferior to those in conventional laparoscopic surgery. The estimated blood loss in reduced port surgery was less than in conventional laparoscopic surgery. In conclusion, the procedure of reduced port surgery should be further standardized to make it safer and more feasible, and to provide a favorable cosmetic result for selected patients. PMID- 25731280 TI - [A case of reduced port surgery after laparoscopic-assisted colectomy]. AB - A 52-year-old woman was admitted to our hospital because of melena and right abdominal pain. Detailed gastrointestinal examination revealed ascending colon cancer. She underwent laparoscopic-assisted right hemicolectomy and D3 lymphadenectomy using 5 ports. After surgery, the patient refused adjuvant chemotherapy. Outpatient follow-up was periodically performed and included blood examination and imaging studies, but she refused colonoscopy. Four and a half years after the initial operation, stool was positive for occult blood. Following colon examination, descending colon cancer was diagnosed. Therefore, the patient underwent colectomy and D3 lymphadenectomy by double incision laparoscopic surgery (DILS) using the glove method. There were no adhesions in the operation field; therefore, laparoscopic surgery was effortless. Because there were almost no adhesions following the first laparoscopic surgery, the second laparoscopic surgery for metachronous colon cancer was possible. PMID- 25731281 TI - [Single-port laparoscopic stoma creation for fecal diversion - experience of ten consecutive patients]. AB - PURPOSE: In the present study, we aimed to describe the surgical results of single-port laparoscopic stoma creation in our institution. METHODS: We examined the safety of the surgical procedure and short-term results in 10 consecutive patients who underwent single-port laparoscopic stoma creation at our hospital between April 2011 and July 2013. RESULTS: The median age of the patients was 60.5 (range, 31-75) years. Five patients were men, and 5 were women. There were 5 cases of colorectal cancer, 2 each of extramammary Paget's disease and uterine cancer, and one of perineal neurofibroma. Eight surgeries were performed for bowel obstruction or stenosis, and two surgeries were performed for other reasons. The median operative time was 59.5 (range, 40-91) min, blood loss volume was 0 (range, 0-10) mL, postoperative duration before commencement of oral intake was 2.5 (range, 1-4) days, and duration of postoperative hospital stay was 11(range, 5-19) days. No short-term complications were noted after the surgery. CONCLUSION: Single-port laparoscopic stoma creation appears to be feasible in terms of safety and short-term surgical results, and may improve the quality of life of patients requiring fecal diversion. PMID- 25731282 TI - [Two case reports with hepatic metastases of colorectal cancer treated with radiofrequency ablation, raising the possibility of local control in the liver]. AB - Only hepatic metastasectomy has been shown to have a therapeutic effect for hepatic metastases of colorectal cancer if the primary tumor can be removed radically according to the 2014 guidelines of the Japanese Society for Cancer of the Colon and Rectum. However, only a few patients with hepatic metastases are candidates for metastasectomy due to tumor factors other than the hepatic metastases. Furthermore, hepatic metastasectomy is frequently judged to be impossible in older patients due to underlying diseases and surgical tolerability. In such cases, therefore, treatment is often difficult. Herein, we report 2 patients with hepatic metastases of colorectal cancer treated with radiofrequency ablation, raising the possibility of local control in the liver. PMID- 25731283 TI - [A case of hepatic metastases from colorectal cancer in a long-term survivor undergoing local combined modality therapy for repeated local recurrences]. AB - Herein, we report of a long-term survivor who underwent local combined modality therapy for local hepatic recurrences detected 10 years after initial surgery for colorectal cancer and 7 years after metachronous liver metastasis. In the third year after surgery for colorectal cancer, a solitary liver metastasis was detected, and curative surgical resection was performed. However, because local recurrence developed 3 years later, curative resection was repeated. When local recurrence developed again 1.5 years later, the patient declined surgery and systemic chemotherapy, and radiofrequency ablation was performed. However, because of the development of another local recurrence 6 months later, hepatic arterial infusion chemotherapy was initiated. This therapy has been continued for 1.5 years to date, with successful local disease control and no adverse events. Although surgical resection is the first choice for resectable liver metastases of colorectal cancer, thermocoagulation and hepatic arterial infusion chemotherapy can also be valid options for patients who are inoperable or refuse surgery as well as for those who are not suitable for or refuse systemic chemotherapy. Notwithstanding, the guidelines for the treatment of colorectal cancer (2014 edition) now include the following statement: thermocoagulation is not recommended as an alternative to surgical resection. Hepatic arterial infusion chemotherapy appears to be a promising treatment strategy associated with antitumor effects with few adverse events. It is also relatively less expensive than systemic chemotherapy. PMID- 25731284 TI - [Learning experiences of colorectal ESD in a community general hospital]. AB - Learning how to perform colorectal endoscopic submucosal dissection (ESD) is considered difficult because of different factors including the thin colorectal wall, poor fixation, numerous folds and flexures, and changing conditions over time. A surgeon with experience in performing 25 gastric ESDs began to perform colorectal ESD after fully communicating and consulting with the Department of Surgery and obtaining adequate informed consent. Herein, we examined the results of colorectal ESD performed for 57 lesions between July 2012 and September 2013. Moreover, we selected the first 10 cases (early-phase) and the last 10 cases (late-phase) from 33 colorectal ESD cases to compare the results between the early-phase and late-phase groups. For sites where it was difficult to perform colorectal ESD, it was possible to perform ESD by changing the detachment device, tip attachment, body position, and endoscope. As the surgeon gained experience in performing gastric ESD, the colorectal procedure in the late phase group could be performed with greater speed, and a rising learning curve was observed. An incidental event of delayed perforation occurred in 1 case, for which laparoscopic partial colectomy was performed immediately after the definitive diagnosis had been made. PMID- 25731285 TI - [A case of sigmoid colon cancer liver metastasis accompanied by multiple liver abscesses]. AB - We describe the case of a patient with sigmoid colon cancer liver metastasis accompanied by multiple liver abscesses. The 59-year-old female patient presented with a fever at a body temperature of 39.0 degrees C. On abdominal computed tomography (CT), multiple liver abscesses were detected, and percutaneous transhepatic abscess drainage (PTAD) was performed. The day after the PTAD, the patient's fever subsided and her inflammatory response abated. A lower gastrointestinal examination, performed to identify the origin of her symptoms, revealed a type 1 tumor in the sigmoid colon. A biopsy indicated a moderately differentiated adenocarcinoma. Prior to surgery, a second abdominal CT scan was performed, and a single liver metastasis was detected. Laparoscopic sigmoidectomy and partial liver resection were simultaneously performed. The histopathological diagnosis of the colon cancer was tub2, pN1, pH1, P0, ly1, v1, stage IV. To date, the patient remains free from hepatic abscess and colon cancer recurrence. Gastrointestinal examinations should be performed as early as possible to identify the cause of hepatic abscesses. Moreover, therapeutic decisions should only be made after imaging and examinations have been performed, which will be sufficient to identify the presence of liver metastases. PMID- 25731286 TI - [A case report of a splenic abscess due to colon cancer in splenic flexure infiltrating into spleen]. AB - An 80-year-old man was admitted to our hospital with fever and dizziness. He was diagnosed with splenic abscess and invasion of descending colon cancer by enhanced abdominal computed tomography. A type 2 colon cancer was also observed in the descending colon by colonoscopy. There was no distant metastasis. Therefore, he underwent left hemicolectomy with splenectomy. A histological diagnosis of mucinous adenocarcinoma was made. The pathological findings were pT4b, pN1, cM0, fStage IIIa. The patient was discharged on the ninth post operative day without any complications. We herein report a rare case of splenic abscess due to invasion of colon cancer and review 8 previous case reports. An en block resection including lymph node resection is recommended in such cases for curative resection. PMID- 25731287 TI - [Pancreaticoduodenectomy performed in a patient with transverse colon cancer associated with a duodenal fistula - a case report]. AB - A 71-year-old man with a positive fecal occult blood test was diagnosed with transverse colon cancer and referred to our hospital. Colonoscopy revealed type II transverse colon cancer with circumferential involvement. Contrast-enhanced computed tomography (CT)revealed a tumor with an unclear boundary in the pancreas. No metastases to the liver or lungs were detected, and there were no significantly enlarged regional lymph nodes. During open surgery, the tumor of the transverse colon was found to have formed a mass in the pancreatoduodenum, and it was difficult to separate them. As curative resection was considered possible, resections of both the pancreatoduodenum and transverse colon cancer were performed. Laboratory findings revealed fistula formation between the transverse colon cancer and the duodenum. The cancer was diagnosed as stageII, T4bN0M0, and R0 surgery was successfully performed. The patient was alive without recurrence 14- months after the surgery. Colorectal cancer is more likely to advance locally and directly invade the surrounding organs. However, fistula formation with the duodenum has rarely been reported, occurring at an estimated incidence of 0.1%. Such tumors are typically large; however, metastases rates to the lymph nodes are low. Histopathological examination of the resected specimen revealed a severe inflammatory adhesion, and fistula formation between the traverse colon and the duodenum. There was no evidence of invasion of the lymphatic system or blood vessels, which enabled us to perform a high curative surgery. We propose that it is important to consider high curative resection with positive lymph node dissection for cases of colorectal cancer associated with duodenal fistula formation. PMID- 25731288 TI - [A case of adenosquamous carcinoma of the sigmoid colon with inferior mesenteric vein thrombosis]. AB - A 63-year-old man who had been admitted to another institute with sepsis and renal failure was referred to our hospital after computed tomography (CT) findings showed thickening of the walls in the sigmoid colon and a defect in contrast enhancement in the portal and inferior mesenteric veins. Emergency sigmoid colon resection with D2 lymphadenectomy was performed after detection of perforation due to sigmoid colon cancer. The histopathological diagnosis was adenosquamous carcinoma, pSS, int, INF b, ly1, v0, pN2, pStage IIIband inferior mesenteric vein thrombosis. He was discharged on day 12, and we administered anticoagulant warfarin therapy. PMID- 25731289 TI - [A case of appendceal cancer with abdominal, intraabdominal, and retroperitoneal abscesses]. AB - A 65-year-old woman was admitted to our hospital owing to difficulty walking and an abdominal tumor in the right lower abdomen. An irregular mass with calcification was detected in her cecum, and abdominal, intraabdominal, and retroperitoneal abscess was detected by computed tomography(CT). An irregular mass was diagnosed as Group 5 adenocarcinoma by biopsy. After the inflammation improved by abscess drainage, we conducted ileocecal resection and fenestrated the abscess. Pathological analysis showed well-differentiated tubular adenocarcinoma: dimensions 20 * 20 mm, pSS, stroma: med, INF a, ly1, v0, pPM0 (70 mm), pDM0 (70 mm), pRM0 (8mm), LN(-): #201: (0/9), fStageII. Thepatie nts can now walk, and she remains in good health and has been recurrence-free 8 months after surgery. To our knowledge, colon cancer with an abdominal abscess is comparatively rare, and we discuss this in light of the literature. PMID- 25731290 TI - [Long-term outcomes and risk factors of lymph node metastases in invasive submucosal colorectal cancer]. AB - To evaluate the risk factors associated with lymph node(LN)metastases described in the Japanese Society for Cancer of Colon and Rectum (JSCCR) guidelines, we retrospectively analyzed 40 patients with submucosal invasive colorectal cancer who underwent surgical resection after endoscopic resection at Osaka Medical Center for Cancer and Cardiovascular Diseases between 2006 and 2008. We examined clinicopathological factors such as sex, age, tumor diameter, morphology, histological grade, submucosal invasion, lymphatic invasion, venous invasion, and LN metastasis and 5-year disease-free survival(DFS) and overall survival (OS). All patients had tubular adenocarcinoma. Ten patients had LN metastasis. Histological grade, tub2, and a positive vertical margin were significant risk factors. Submucosal invasion was greater than 1,000 um in patients with LN metastasis. There was no difference in clinicopathological factors between patients with colon cancer and those with rectal cancer, but LN metastasis occurred in 18.7% and 50.0% of colon cancer and rectal cancer patients, respectively. There were no recurrences or cancer-related deaths, although one patient died of other causes. In conclusion, patients who were treated according to the JSCCR guidelines had a favorable prognosis. PMID- 25731291 TI - [A case of adenosquamous carcinoma of the ascending colon]. AB - A 6 8-year-old man was admitted to our hospital with lower abdominal pain. Lower gastrointestinal endoscopy showed type 2 advanced cancer in the ascending colon. Histopathological examination after endoscopical biopsy revealed both moderately differentiated adenocarcinoma and well-differentiated squamous carcinoma. Subsequently, right hemicolectomy was performed. The tumor was 55 * 40 mm in size and was diagnosed as an adenosquamous carcinoma A, type 2, pSS, pN0, sH0, sP0, sM0, fStageII. Adenosquamous carcinoma is extremely rare, represents about 0.1% of all colorectal cancer, and usually has a poor prognosis. Thirty-one months after surgery, the patient is still in good health and displays no signs of recurrence. PMID- 25731292 TI - [A case of long-term survival in a patient with rectal cancer with virchow lymph node metastasis, liver metastases, and lung metastases]. AB - A 69-year-old man with advanced rectal cancer and liver metastases was treated with 2 courses of chemotherapy with irinotecan and S-1 followed by low anterior resection and partial hepatectomy. Chemotherapy with S-1 was then administered for 22 months. However, lung metastases developed, for which partial pneumonectomy was performed. Seven months later, computed tomography (CT) revealed swelling of the left supraclavicular lymph node. Despite chemotherapy with 5- fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX6); 5-fluorouracil, Leucovorin and irinotecan (FOLFIRI); and capecitabine plus bevacizumab, the lung metastases recurred and Virchow lymph node swelling was noted again. Accordingly, palliative therapy was administered. The patient died 3 years 1 month after Virchow lymph node resection. Herein, we describe a case of advanced rectal cancer, in which lung and Virchow lymph node metastases developed after liver metastasis. Surgical excision of the metastases resulted in long-term survival of 6 years following the first operation. PMID- 25731293 TI - [A case of curatively resected, locally advanced ascending colon cancer with ileal conduit invasion]. AB - A 71 -year-old man was referred to our hospital because of repeated bowel obstruction. He had previously undergone cystectomy with ileal conduit urinary diversion for the treatment of bladder cancer at the age of 28 years. Computed tomography revealed a mass in the ascending colon. Ileostomy was initially performed because of poor general condition that improved with postoperative nutrition management. Enema findings revealed ascending colon cancer and we therefore decided to perform curative surgery. Intraoperative findings revealed that the ascending colon cancer had invaded the ileal conduit. However, it was confirmed that the ureter-ileal conduit anastomosis and the mesentery of the ileal conduit could be preserved. We performed right colectomy and partial resection of the ileal conduit with curative intent. The pathological stage was pT4bpN0cM0, pStage II. There were no signs of recurrence 15 months after curative surgery. PMID- 25731294 TI - [A case of carcinoma arising in a diverticulum of the transverse colon]. AB - A 64 year-old woman presented with advanced, transverse colon cancer arising in the diverticulum. Tumor invasion extended beyond the serosa to the anal side of the colon. Anemia and fatigue progressed after 6 months of iron administration. The hemoglobin value was 5.3 g/dL and carcinoembryonic antigen (CEA) level was elevated to 44.2 ng/mL. A palpable and tender fist-sized mass was found in the right upper abdomen. Computed tomography (CT) revealed a low-density mass in the transverse colon invading beyond the serosa to the anal side of the colon. Right hemi-colectomy with lymph node dissection was performed. The resected specimen contained multiple diverticula including the one from which the tumor arose. Histological examination revealed a well-differentiated, tubular adenocarcinoma (UICC TNM T4bN0M0) arising in a transverse colon diverticulum. There has been no recurrence for 2 years. Colon cancer arising in a diverticulum may expand to the extra-serosa and easily invade to the adjacent organ. In such cases, malignancy should be considered. PMID- 25731295 TI - [A case of ascending colon signet-ring cell careinoma discovered after treatment for acute cholecystitis]. AB - A 81-year-old woman confined to full bed rest due to the effects of a stroke 7 years prior, was brought to our hospital with acute cholecystitis in late April 2013. After PTGBD, her condition improved and she was discharged in early June. However, she was urgently hospitalized at the beginning of August with melena and a fever. A detailed examination revealed aspiration pneumonia, which was resolved with a course of antibiotics. A colonoscopy, conducted to find the cause of the melena, revealed a circumferential type 2 tumor in the ascending colon, and a fiberscope was unable to pass through the stenosis. A biopsy confirmed a diagnosis of signet-ring cell carcinoma. Using abdominal computed tomography, thickening of the ascending colon wall, suggesting infiltration to the periphery, was visible. The adjacent lymph nodes were enlarged, but there were no clear signs of liver metastasis. Cancerous peritonitis was suspected due to the presence of ascitic fluid. Considering the overall condition of the patient, surgery was not performed, and colonic stent was not placed due to the proximity of the stenosis to the ileocecal valve. The patient's family chose best supportive care. The patient's condition worsened and she died 3 months after leaving the hospital. PMID- 25731296 TI - [A case of multifocal colon carcinoma and cholecystolithiasis in an elderly patient]. AB - An 83-year-old woman was admitted to our hospital because of general fatigue and symptoms of anemia. For 20 years, she had experienced right hypochondrial pain several times a year. Colonoscopic examination revealed a type 2 tumor at the ascending colon. The biopsy specimen was a Group 5 and type 0-IIa polyp at the transverse colon. The endoscopic mucosal resection (EMR) specimen was a well differentiated adenocarcinoma(Stage pSM [2mm], ly0, v0). An apple core lesion in the cecum was detected by enema. Abdominal computed tomography demonstrated cholecystolithiasis and no metastasis or distant metastases. Therefore, a diagnosis of multifocal colon carcinoma and cholecystolithiasis was made. Expanding right hemicolectomy with cholecystectomy was performed. The patient was discharged without any complications. Subsequently, she underwent adjuvant chemotherapy for 6 months. At present, 1 year after surgery, the patient is still alive and has shown no signs of recurrence. PMID- 25731297 TI - [Malignant small bowel ileus due to recurrent colorectal cancer with peritoneal metastasis]. AB - PURPOSE: To investigate the clinical findings of patients who underwent surgery for small bowel obstruction following a previous operation for colorectal cancer. We assessed consecutive patients operated on for peritoneal metastasis with small bowel ileus. PATIENTS AND METHODS: We evaluated the clinical characteristics of 7 consecutive patients with malignant small bowel ileus due to recurrent colorectal cancer with peritoneal metastasis. RESULTS: 1) Primary cancer location: descending colon, 2 cases (28.6%); sigmoid colon, 1 case (14.3%); and rectum, 4 cases (57.1%). 2) Peritoneal dissemination grade: P2, 1 case (14.3%); and P3, 6 cases (85.7%). 3) Liver metastasis grade: H1, 1 case (14.3%); H2, 5 cases (71.4%); and H3, 1 case (14.3%). 4) Lymph node metastasis grade: N2, 1 case (14.3%); and N3, 6 cases (85.7%). 5) Extra-abdominal metastasis: multiple lung metastases were detected in 3 cases (42.9%). 6) Pathological type: moderately differentiated tubular adenocarcinoma (tub2), 3 cases (42.3%); poorly differentiated adenocarcinoma (por), 1 case (14.3%); and mucinous adenocarcinoma (muc), 3 cases (42.3%). The differentiated type (tub2) was more common than the undifferentiated types(por and muc). 7) Malignant small bowel stenosis and/or obstruction: there were 3 or more cases with stenosis and/or obstruction in jejunum and ileum. 8) OPERATIVE PROCEDURE: gastrostomy was performed in 2 cases (28.6%); nephrostomy was performed in 1 case (14.3%); gastrostomy with nephrostomy was performed in 1 case (14.3%); and probe laparotomy was performed in 3 cases (42.9%). 9) Survival time of patients with recurrent colorectal cancer, from readmission to death: 0.5-1 month, 3 cases (42.9%); 1-1.5 months, 3 cases (42.9%); and 1.5-3 months, 1 case (14.3%). All patients died in less than 3 months. CONCLUSIONS: The prognosis of the malignant small bowel ileus due to recurrent colorectal cancer with peritoneal metastasis is very bad. PMID- 25731298 TI - [Is PCI effective in predicting prognosis in the era of oxaliplatin-based chemotherapy in stage IV colorectal cancer with peritoneal dissemination ?]. AB - PURPOSE: Peritoneal dissemination is expected to be present in P1, P2, and P3 according to the 8th edition of colon cancer handling convention. The peritoneal carcinomatosis index (PCI) plays a central role in classification of peritoneal metastases. PATIENTS AND METHODS: Peritoneal dissemination was examined during surgery in patients with colon cancer and peritoneal metastasis undergoing treatment with oxaliplatin-based chemotherapy. RESULTS: Correlation between PCI and P1, P2, and P3 was found. Moreover, using a PCI cut-off value of 6 for peritoneal dissemination, there was a significant difference in survival. CONCLUSION: Positive correlation was found between PCI and P classification of colon cancer. Regardless of the presence metastases to other organs, there is a possibility that PCI is effective in predicting prognosis of patients with peritoneal dissemination- positive colon cancer. PMID- 25731299 TI - [A case of juvenile colon cancer with peritoneal dissemination treated effectively by use of resection and chemotherapy]. AB - A 37 -year-old man experienced abdominal pain and vomiting. Computed tomography showed massive ascites and obstruction of the colon by a tumor at the left colic flexure. The tumor was classified as advanced Borrmann type 3 on the basis of a colonoscopy. Palliative resection of the colon and colostomy on the oral side were performed. Operative findings showed massive peritoneal dissemination of the tumor. We administered palliative chemotherapy consisting of capecitabine/oxaliplatin (XELOX) and bevacizumab. After 4 courses of chemotherapy, the primary and disseminated tumors and ascites had disappeared, and tumor marker expression levels were within normal range. Palliative resection and subsequent chemotherapy was effective for this young patient with very advanced colon cancer that had disseminated and caused obstruction. PMID- 25731300 TI - [A case of recurrent sigmoid colon cancer with multiple peritoneal and liver metastases controlled effectively by resection]. AB - A 71 year -old man underwent sigmoid colectomy for sigmoid colon cancer. A solitary liver metastasis found on examination 8 months after the initial surgery was resected. One year after the second surgery, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and computed tomography (CT) revealed multiple peritoneal and liver metastases, and laparotomy was performed. All metastatic lesions were resectable or controllable. Eight peritoneal and 3 hepatic lesions were removed surgically and 1 hepatic lesion was treated with radiofrequency ablation. Eight months after the third surgery FDGPET and CT examination again revealed recurrence of liver and peritoneal metastases. Chemotherapy was ineffective and metastases progressed and resulted in death 26 months after the third surgery (39 months after the initial recurrence). We suggest that aggressive resection for multiple peritoneal and liver metastases can be an effective therapy for selected patients with recurrent colon cancer. PMID- 25731301 TI - [A case of postoperative colon cancer with peritoneal dissemination in which a long-term response was achieved using panitumumab maintenance therapy]. AB - A 66-year-old man underwent a sigmoidectomy for advanced sigmoid colon cancer. The pathological examination revealed that the tumor was T3, N0, M0, and KRAS wild type. Fifteen months after surgery, the patient was hospitalized with stenosis of the anastomosis due to recurrent disease that had disseminated to the peritoneum, and which was unresectable. After transverse colostomy, the patient received 8 courses of mFOLFOX6+panitumumab (Pmab), and 39 courses of infusional 5 fluorouracil (5-FU) + Leucovorin (LV)+ Pmab. A partial remission (PR) was maintained for 27 months. The utility of maintenance therapy with an anti epidermal growth factor receptor (EGFR) antibody-based regime has not previously been demonstrated. In this case, a long PR was achieved using infusional 5 FU+LV+Pmab, suggesting that this is a useful maintenance therapy following mFOLFOX6 + Pmab. However, the side effects resulting from Pmab treatment reduced the patient's quality of life (QOL). We suggest that Pmab maintenance therapy can be established by controlling the side effects of the anti-EGFR antibody. PMID- 25731302 TI - [A case of colon cancer with multiple liver metastases showing a long-term response following first-line therapy]. AB - A 71-year-old man presented with sigmoid colon cancer and multiple unresectable liver metastases. As the sigmoid colon cancer caused anemia, we performed laparoscopic-assisted sigmoidectomy prior to the administration of systemic chemotherapy. Bevacizumab (Bv) plus modified Leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) was administered as first line therapy.At 3 months from the start of chemotherapy, computed tomography revealed that the size of the liver metastases reduced by 49.45%, as evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). The only adverse event observed was Grade 1 peripheral neuropathy after the eighth dose of oxaliplatin.As the progression of peripheral neuropathy was observed at the ninth dose of oxaliplatin, oxaliplatin was omitted from further therapy; the patient was converted to maintenance therapy with simplified biweekly Leucovorin and fluorouracil (sLV5FU2). Bv plus mFOLFOX6 followed by sLV5FU2 for first-line therapy was effective for disease management over 23 months, but a partial response (PR) was the best overall response achieved. PMID- 25731303 TI - [Two cases of intrapelvic recurrence after radical resection of rectal cancer, treated with carbon ion radiotherapy]. AB - We report two cases of intrapelvic recurrence after radical resection of rectal cancer, which were successfully treated with Carbon Ion Radiotherapy (C-ion RT). The first case is of a 71-year-old man who underwent abdominoperineal resection (APR) with D2 lymphadenectomy for rectal cancer in December 2010, followed by adjuvant chemotherapy with S-1 plus oxaliplatin. The patient was diagnosed with a recurrence on the left pelvic wall in August 2012, and underwent C-ion RT (73.6 Gray equivalent) for this lesion in October 2012. Three months after this treatment, the lesion had regressed significantly, as ascertained by computed tomography (CT). He remains alive with no signs of recurrence. The second case is of a 63-year-old man who underwent APR with D3 lymphadenectomy for rectal cancer, followed by adjuvant chemotherapy with uraciltegafur ( UFT). The patient was diagnosed with a recurrence on the right pelvic wall in January 2013, and underwent C-ion RT (73.6 Gray equivalent) for this lesion in March 2013. Three months after this treatment, the lesion reduced significantly, and the patient is alive with no signs of recurrence. Although the long-term outcomes need to be assessed, C-ion RT could be a safe and effective therapy. PMID- 25731304 TI - [Rectal cancer with local re-recurrence successfully treated by carbon ion radiotherapy]. AB - A 61 year-old male with rectal cancer underwent anterior resection with D2 lymph node dissection in August 2007. Carcinoembryonic antigen (CEA) level was 5.6 before the operation. Pathological findings were Rs, tub2">tub1, type 3, pSE, ly1, v2, pN1 (1/23), H0, P0, M0 , pStage IIIA. Adjuvant chemotherapy with tegafur uracil (UFT) 600 mg/Leucovorin (LV) 75 mg was administered for 1 year. A recurrence at a site of anastomosis developed and lower anterior resection was required in September 2010. CEA level was 5.4 before the operation. After 7 courses of capecitabine plus oxaliplatin (XELOX) treatment, the right #283 lymph node increased to 8 mm in October 2011 and the patient was diagnosed with a re recurrence of the original tumor (CEA level, 4.6). Carbon ion radiotherapy (73.6 Gy/16 Fr/4 weeks) was performed between November 28 and December 22, 2011. Although the right #283 lymph node had shrunk by January 2012, a single node in the S3 domain of the right lung was observed and became progressively larger, indicating a lung metastasis (CEA level, 5.4). The patient received carbon ion radiotherapy (60.0 Gy/4 Fr) for the lung metastasis between July 30 and August 2, 2012. No additional recurrences have been seen through February 2014. PMID- 25731305 TI - [Irradiation with carbon ions for locally recurrent rectal cancer]. AB - A female patient in her 70s underwent an abdominoperineal resection and bilateral lymph node dissection for advanced lower rectal cancer. The patient did not receive neoadjuvant therapy. In the Japanese classification of colorectal carcinoma (8th Edition), the tumor was a moderately differentiated type 2 adenocarcinoma, and was 4.5 cm in size. Histologically, the tumor was considered to be Stage IIIb (T3N0M0). She received no adjuvant chemotherapy. After 39 months, pelvic computed tomography (CT ) revealed a 29 mm tumor in the right pelvic wall. The patient declined surgery for recurrence so radiotherapy was planned. First, chemotherapy with mFOLFOX6 was administered for 4 courses to reduce tumor size. Consequently, irradiation with carbon ions was given to the site of recurrence at a total dose of 74 GyE in 37 fractions. There were no severe complications. Carcinoembryonic antigen (CEA) level decreased to the lower limit of the normal range from a maximum of 4.9, and no progression of the recurrent tumor was detected on CT for approximately 4 years. Systemic chemotherapy followed by irradiation with carbon ions may be effective for recurrent rectal cancer. PMID- 25731306 TI - [Complete response in a case of anastomotic recurrence of rectal cancer treated with S-1 monotherapy]. AB - A 63-year-old woman underwent a low anterior resection for rectal cancer in 2002.A n anastomotic recurrence was diagnosed in July 2011.S he rejected the possibility of colostomy as radical surgery.Chemotherapy consisting of capecitabine+ oxaliplatin (XELOX) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX6) + bevacizumab were not possible because of high costs. In view of the lower costs and the potential for ambulation, S-1 monotherapy was started. After 3 months, a reduction in the recurrent lesion was observed.After 19 months, the recurrent lesion revealed a scar, which was judged by biopsy to be Group 1.We had achieved a pathological complete response (CR).The standard treatment for recurrent colon cancer is surgical resection or multidrug chemotherapy. However, in view of a patient's quality of life (QOL), S-1 monotherapy may be considered as a potential therapy. PMID- 25731307 TI - [A case of colorectal cancer with pelvic recurrence treated by systemic chemotherapy and radiotherapy]. AB - A 63-year-old man who had a history of rectal cancer and was treated with low anterior resection in February 2006, presented with liver metastases in September 2007 and underwent right anterior sectionectomy of the liver. He developed a pelvic wall recurrence with buttock pain in September 2009. This was treated with conventional radiation therapy and Cyber- Knife. The buttock pain was relieved after CyberKnife treatment and the patient received systemic chemotherapy in the outpatient clinic. Subsequently, he developed a left sacral recurrence with buttock pain and gait disturbance in August 2013. Since the tumor was located close to the field previously subjected to radiotherapy, we opted for CyberKnife treatment again. Although the pain subsided, our patient died of lymphangitic carcinomatosis in April 2014, 7 years and 2 months after the surgery. In this case, CyberKnife was effective in treating pelvic recurrence with pain, and thus, may have a significant role to play in the multidisciplinary treatment of metastatic colorectal cancer. PMID- 25731308 TI - [Trans-anal resection for recurrence of a very low rectal anastomosis at the suture line after colorectal cancer surgery]. AB - When a relatively small anastomotic recurrence of colorectal cancer is detected in the low rectum, trans-anal resection (TAR) might be an option both for curative intent and for preservation of anal function. We report 3 such cases. Case No. 1: A 58-year-old woman presented with an anastomotic recurrence of sigmoid colon cancer. Low anterior resection(LAR)was performed. Two small recurrent nodules were detected at the suture line 1 year after LAR, which were successfully treated with TAR. The depth of the nodules indicated T2 cancer. The patient remained cancer free 5 years after TAR. Case No. 2: A 56-year-old man developed a severe anastomotic stenosis and an anastomotic recurrence 6 months after LAR for low rectal cancer. TAR was performed circumferentially to resect both the stricture and the recurrence. The depth of the nodule indicated T2 cancer. The patient was cancer free for 7 years after TAR. Case No. 3: A 54-year old man developed 2 small recurrent nodules at the suture line after LAR for low rectal cancer. TAR was performed. The depth of the nodule indicated T1 cancer. One of the nodules was not resected, which necessitated intersphincteric resection (ISR) 10 months later. In conclusion, in cases of a relatively small recurrence of low rectal anastomosis after colorectal cancer surgery, TAR is an effective treatment option. PMID- 25731309 TI - [Therapeutic strategy for perforated colorectal cancer]. AB - A total of 37 patients were surgically treated for a colorectal perforation between May 2006 and December 2013. The patients were divided into 2 groups: those with perforation due to colorectal cancer(colorectal cancer group, n=12) and those with perforation due to benign colorectal disease(non-colorectal cancer group, n=25). We examined the influence that onset near the perforation had on colorectal cancer clinical outcome. There was no significant difference in patient backgrounds between the two groups. In the colorectal cancer group, curative resections were performed in eight of the cases (67%), while there were 7 cases (58%) of regional lymph node dissection and all patients received a stoma without bowel anastomosis. In the colorectal cancer group, 1 patient (8%) died of a pulmonary embolism after surgery, whereas 2 patients (8.3%) in the non colorectal cancer group died of sepsis after surgery. Nine of those patients (75%) received adjuvant chemotherapy. Four patients survived without recurrence. Prompt judgment of the disease severity and selection of optical surgical procedures including tumor resection and regional lymph node dissection is important for colorectal cancer perforation, and an adjuvant setting for the purpose of the long-term survival is necessary. PMID- 25731310 TI - [Clinical outcome of 13 patients with perforated colorectal cancer]. AB - We investigated the clinicopathological findings of 13 patients with perforated colorectal cancer. In 6 patients, the primary region affected by the cancer was the sigmoid or rectosigmoid colon, and 9 out of 13 patients had perforations at the location of the tumor itself. The Hartmann operation was performed in 5 patients, and D2 or D3 lymph node dissection was performed in 6 patients. The final stages of the 13 patients were as follows: 1 patient with stage II cancer, 5 patients with stage III cancer, and 7 patients with stage IV cancer. Postoperative death occurred in 1 patient. Five out of 7 patients with curative operations had recurrences; 2 patients had peritoneal disseminations, 2 patients had lung metastases, and 1 patient had paraaortic lymph node metastases. Even if patients underwent a curative operation, a high frequency of recurrence, especially of peritoneal dissemination, was observed. Therefore, we conclude that a careful follow-up is required. PMID- 25731311 TI - [A case of intractable fistula after low anterior resection repaired by transsacral direct suture]. AB - We report a case of an intractable fistula repaired by transsacral direct suture. A 65-year-old man underwent low anterior resection for rectal cancer. He subsequently underwent ileostomy due to anastomosis leakage. The fistula of the anastomosis persisted 3 months after surgery. He underwent surgery to repair the fistula using a transsacral approach. After removing the coccyx, the fistula in the postrectal space was exposed directly. The presence of the fistula was confirmed by an air leak test and was closed by direct suture. After 33 days, the patient underwent ileostomy closure. PMID- 25731312 TI - [A case of a villous tumor of the rectum with electrolyte depletion syndrome]. AB - We report a case of a villous tumor of the rectum with electrolyte depletion syndrome (EDS). A 76-year-old woman developed general fatigue, and on investigation, we found a large laterally spreading tumor of the rectum using bowel enema and colon fiber. Pathologically, the biopsy specimen was graded Group 4. We intended to perform a laparoscopy-assisted low anterior resection in the patient. However, the operation was interrupted by a short-run type of ventricular premature contraction (VPC) due to EDS-induced hypokalemia. After treating the hypokalemia, low anterior resection or laparotomy was performed. The tumor was 19 * 13 cm in size and occupied the circumference of the rectum. Histological examination revealed well differentiated tubular adenocarcinomas with tubulovillous adenoma. Pathological staging was pTis, pN0, M0, stage 0 according to the Japanese Classification of Colorectal Carcinoma (8th edition). It is now 6 months after the operation and hypokalemia has not recurred in the patient. PMID- 25731313 TI - [Protein-losing gastroenteropathy in a case of colon cancer]. AB - A 74-year-old man was admitted with primary complaints of appetite loss, abdominal swelling, and pedal edema. Laboratory data revealed the presence of anemia and hypoalbuminemia. Barium enema and colonofiberscopy demonstrated an advanced cancer in the transverse colon. Albumin scintigraphy revealed high uptake by the tumor in the transverse colon. Preoperative administration of albumin did not improve hypoalbuminemia. Serum protein and albumin levels improved immediately after resection of the tumor. Therefore, in the presence of hypoalbuminemia due to leakage from the tumor, it is important to operate promptly, without waiting to correct the hypoalbuminemia. PMID- 25731314 TI - [A case of neoadjuvant chemotherapy for locally advanced rectal cancer, which had a invasion into the vagina followed by curative resection]. AB - A-64-years-old woman with locally advanced rectal cancer, which had invaded the vagina, was referred to our hospital. She was administered neoadjuvant chemotherapy to reduce the tumor size. After 4 courses of chemotherapy consisting of folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6), an enhanced computed tomography (CT) scan and magnetic resonance imaging (MRI) indicated marked tumor shrinkage. We performed a laparoscopically assisted low anterior resection, which included total mesorectal resection, resection of the vaginal posterior wall, and right lateral lymph node resection. The chemotherapy prevented us from having to create a permanent colostomy. The efficacy of the neoadjuvant chemotherapy was Grade 1b. We experienced a case of neoadjuvant chemotherapy followed by curative resection. PMID- 25731315 TI - [Preoperative chemotherapy enabled radical resection of tumors in a patient with multiple liver metastases]. AB - The patient was a 61-year-old man with a prominent epigastric mass and dull pain. Sigmoid colon cancer and multiple hepatic metastases were diagnosed upon examination. The liver metastases were adjacent to the right hepatic artery and the portal vein; therefore, the patient received preoperative bevacizumab+XELOX (capecitabine plus oxaliplatin) chemotherapy. After 6 courses of chemotherapy, a sufficient partial response (PR) was achieved to secure a surgical margin during radical resection of the tumors. The patient is alive, without recurrence, 10 months after surgery. This report highlights the importance of securing a surgical margin during conversion therapy and reviews evidence from previous literature reports. PMID- 25731316 TI - [A case of stage IV rectal cancer successfully resected after chemotherapy (mFOLFOX6 plus panitumumab)]. AB - A 6 6-year-old woman with hematochezia was admitted to our hospital. A colonoscopy detected KRAS wild-type rectal cancer. An abdominal computed tomography (CT) scan revealed a liver metastasis, and invasion to the uterus was suspected. The patient underwent a laparotomy, and intraoperative cytology and peritoneal dissemination proved positive. The tumor had invaded the uterus. We administered chemotherapy consisting of 5-fluorouracil, Leucovorin, and oxaliplatin(mFOL FOX6)plus panitumumab. A CT scan and colonoscopy performed after 10 courses of chemotherapy indicated remarkable tumor regression. An abdominal CT scan did not detect any liver metastases, and we performed a laparoscopic low anterior resection. In the second operation, peritoneal dissemination and washing cytology were negative. The pathological diagnosis of the surgically resected specimen was ypStageII. The patient is recurrence-free 7 months after surgery. PMID- 25731317 TI - [Efficacy of oxaliplatin-based adjuvant chemotherapy in stage II and III colorectal cancer with perforation]. AB - This retrospective study evaluated the efficiency of oxaliplatin-based (Oxa based) adjuvant chemotherapy for colorectal cancer with perforation. The study included 38 patients who underwent surgery for perforation associated with StageII and III colorectal cancer between April 1998 and March 2013. Patients with operative mortality were excluded from the study. The numbers of patients with StageII and III disease were 26 and 12, respectively. Adjuvant chemotherapy was received by 16 patients (62%) in the Stage II group. Seven patients (54%) in the Stage III group received adjuvant chemotherapy, of which 6 received Oxa-based adjuvant chemotherapy. The median relative dose intensity(range)of oxaliplatin was 83.3 (28.8- 100)%. Grade 3 adverse events were reported in 2 cases. The 3 year overall survival rates in the StageII and III groups were 60% and 79%, respectively. There was no significant difference in overall survival between the groups (p=0.28). Patients who received adjuvant chemotherapy had a 2.3-fold greater 3-year overall survival rate than those who did not receive adjuvant chemotherapy (80% vs 35%, p=0.01). The 3-year overall survival rates were 100% in patients who received Oxabased adjuvant chemotherapy (n=6), and 76%in patients who received adjuvant chemotherapy without oxaliplatin (n=17), with no significant difference between the groups (p=0.24). The Oxa-based adjuvant chemotherapy was tolerated equally well in Stage II and III colorectal cancer patients with or without perforation. Further studies are needed to compare the effect of oxaliplatin with other adjuvant chemotherapies. PMID- 25731318 TI - [Adjuvant chemotherapy with capecitabine for colon cancer - a case series]. AB - We examined the treatment condition; adverse events, especially hand-foot syndrome (HFS); and prognosis in 65 patients with colon cancer who received adjuvant chemotherapy with capecitabine. The treatment completion rate was 75.4%; however, only 15.4% of patients completed treatment without dose reduction or treatment interruption. HFS occurred in 78.5% of all cases. The 3-year relapse free survival rate was 73.8% for all cases, 80.8% for treatment-completed cases, and 51.1% for treatment-discontinued cases; however, there were no differences in relapse-free survival rates for cases that required dose reduction or treatment interruption. We conclude that adjuvant chemotherapy with capecitabine is effective in colon cancer and that completing treatment (even with dose reduction or dose interruption) improves prognosis. PMID- 25731319 TI - [A case report of complete pathological response of a locally advanced rectal cancer after long term chemotherapy]. AB - A-39-year-old man presented to a nearby clinic owing to long-term diarrhea and painful defecation. He was diagnosed with a well-differentiated tubular adenocarcinoma of the rectosigmoid and underwent a laparotomy at another hospital. At surgery, the tumor was seen to deeply invade into the urinary bladder with the presence of intra-abdominal abscess. Loop sigmoid colostomy was performed due to possible invasion into the pelvic wall and peritoneal dissemination. The patient was referred to the our hospital for systemic chemotherapy. After 32 courses of FOLFIRI, 10 courses of CapeOX + Bmab, and 34 courses of LV5FU2 + Bmab, radiographic examination revealed complete response (CR) of the rectal tumor, and low anterior resection of the rectum was carried out. Since pathological examination showed no viable cancer cells in any specimen, the patient was considered to have achieved a CR from a pathological standpoint. PMID- 25731320 TI - [A case of long-term survival following chemotherapy after laparoscopic resection of sigmoid colon cancer with multiple liver metastases]. AB - We report a rare case of long -term survival after laparoscopic resection of sigmoid colon cancer with multiple liver metastases, followed by 5-fluorouracil Leucovorin irinotecan with bevacizumab (FOLFIRI+Bev) chemotherapy. A 61-year-old woman was referred to our hospital with a principal complaint of bloody stools. She was diagnosed with sigmoid colon cancer by colonoscopy and multiple liver metastases by ultrasonography. In October 2008, we performed laparoscopic resection of the sigmoid colon cancer with multiple liver metastases, followed by 4 courses of modified 5-fluorouracil Leucovorin oxaliplatin ( mFOLFOX6) chemotherapy. In February 2009, abdominal ultrasonography showed progressive disease, and as a result the patient was administered 73 courses of FOLFIRI +Bev chemotherapy. As of March 2014, the patient has survived for more than 5 years following treatment, but still has liver metastases. The possibility of resecting multiple liver metastases from colorectal cancer should be considered, and in some cases, chemotherapy may enhance survival. PMID- 25731321 TI - [A case of liver metastasis from sigmoid colon cancer treated effectively by second-line chemotherapy]. AB - A case of successful chemotherapy for a metachronous liver metastasis following resection for sigmoid colon cancer is presented. A 51-year-old man underwent sigmoidectomy, ileocecal resection, and descending colon colostomy for sigmoid colon cancer with ileum invasion. Six courses of FOLFOX4 were performed as adjuvant chemotherapy. One year after sigmoidectomy, a liver metastasis was detected on computed tomography (CT) examination. Chemotherapy with FOLFOX+bevacizumab was restarted. Three courses were administered, but hepatic dysfunction occurred after the second and third courses, and FOLFOX was discontinued. Subsequent chemotherapy was reinitiated with FOLFIRI+bevacizumab. After 9 courses, the carcinoembryonic antigen level was normalized and appeared to be decreased by imaging studies. Upon the patient's request, only oral S-1 was administered. After 2 courses, CT revealed that the diameter of the tumor had increased by 2 cm. Therefore, right lobectomy of the liver, colostomy closure, and anastomosis were performed. During these procedures, a nodule was found in the omentum and was removed. Rapid intra-operative diagnosis revealed peritoneal dissemination. The pathological diagnosis was liver metastasis of sigmoid colon cancer, with necrosis and fibrosis seen in approximately one-half of specimens. The surgical margins were negative. Neither metastatic cancer nor dissemination were found in the resected greater omentum. PMID- 25731322 TI - [A case of rectal cancer with brain metastasis successfully treated with combined modality therapy - a case report]. AB - The authors report their experience in a patient with brain metastasis from rectal cancer who has survived without recurrence after multidisciplinary treatment. A 60-year-old man presented to the Department of Neurosurgery with the primary complaint of spasm of the left side of the face. Examination revealed a tumor 2 cm in diameter in the right frontal lobe. The tumor was suspected to be metastatic, and brain metastasis from rectal cancer was diagnosed. The brain tumor was removed by a neurosurgeon, and the patient was transferred to the Department of Surgery. Removal of the primary lesion in the rectum was attempted, but only colostomy could be performed due to extensive anterior invasion. Postoperatively, 5 courses of capecitabine and oxaliplatin (XELOX) + bevacizumab were administered. The rectal tumor shrank in size, while another mass, suspected to be a lung metastasis, remained unchanged. Therefore, a second surgery on the rectum was scheduled, and abdominoperineal resection of the rectum and lateral lymphadenectomy were performed. Postoperatively, 4 courses of XE LOX therapy were administered. The patient is currently alive without recurrence at 1 year after surgery. Treatment (including timing) for brain metastasis from rectal cancer has not been established and prognosis is poor. However, multidisciplinary treatment may provide the possibility of cure. PMID- 25731323 TI - [A case of desmoid tumor and advanced sigmoid colon cancer with liver metastasis in familial adenomatous polyposis (FAP)]. AB - We report on a 30-year-old man with familial adenomatous polyposis (FAP ) who developed advanced sigmoid colon cancer with desmoid tumors. The patient initially presented with melena. FAP advanced sigmoid colon cancer was diagnosed following a laparoscopy-assisted proctocolectomy in 2007. A computed tomography (CT) scan, conducted 7 months later, revealed a tumor around the branch of the common iliac artery. We diagnosed sigmoid colon cancer recurrence and attempted treatment by surgical removal. However, there were many smooth tumors within the patient's abdomen, which were diagnosed as desmoid tumors using rapid intraoperative pathological diagnosis. Although the patient was administered a COX-2 inhibitor and tamoxifen after surgery, the tumor grew. Dacarbazine (DTIC) and doxorubicin (DOX) were subsequently administered to the patient, and after 4 courses, the tumor was reduced by 60% and stable disease (SD) was achieved. In 2009, a CT scan indicated sigmoid colon cancer recurrence in the liver. The patient underwent a left hepatic lobectomy by laparoscopy-assisted surgery. To date, 4 years and 6 months after surgery, we have been unable to find new disease or desmoid tumor growth. PMID- 25731324 TI - [Effect of chemotherapy on the inoperable or recurrent colorectal cancers in patients with lynch syndrome]. AB - We examined the clinicopathological features of 4 patients with Lynch syndrome (including those with strongly suspected Lynch syndrome) who had undergone chemotherapy as part of the treatment for colon cancer. The study population included 3 men and 1 woman. The median age at diagnosis was 72 years (range, 24 40 years). Two patients relapsed and 2 patients had Stage IV cancer. All the patients had primary right-sided colon cancer. On histopathological examination, well differentiated adenocarcinoma, moderately differentiated adenocarcinoma, and poorly differentiated adenocarcinoma were observed in 1, 2, and 1 patients, respectively. Components of mucinous adenocarcinoma or poorly differentiated adenocarcinoma were observed in all patients. Microsatellite instability (MSI) testing revealed high MSI (MSI-H) in all patients. Immunostaining results indicated loss of expression of the MSH2/MSH6 proteins at the tumor site in all patients. With regard to chemotherapy, a 5-fluorouracil-based regimen was selected as the first-line of therapy. Although 1 patient experienced long-term survival (alive at 48 months after surgery), the other 3 patients died of cancer within 9 months. The median overall survival was 8.5 months. Active assessment and accumulation of such cases is essential for the establishment of appropriate and effective treatments for colon cancer in patients with Lynch syndrome. PMID- 25731325 TI - [A case of metastatic colorectal cancer that reduced in size after re-challenging with an anti-EGFR monoclonal antibody]. AB - A 58-year-old woman was confirmed as having multiple liver metastases after undergoing a high anterior resection for a sigmoid colon tumor. She was administered bevacizumab+FOLFOX as the first regimen and bevacizumab+FOLFIRI and S-1 and irinotecan (IRIS)therapy as the second regimen. During this treatment she also underwent hepatectomy 3 times and radiofrequency ablation once. She was administered panitumumab+irinotecan as the third regimen and, due to the presence of multiple pulmonary metastases, was subsequently considered to have had a partial response (PR). Because she subsequently developed progressive disease (PD), she received the fourth regimen as part of a clinical trial (TAS102) in another hospital. Cetuximab+irinotecan was administered as the fifth regimen after PD and the tumor was found to have reduced in size by 23%upon computed tomography (CT) 2 months later. Although stable disease (SD) was achieved, she was subsequently administered regorafenib for 8 months as a sixth regimen after the disease progressed a second time. In some cases of KRAS wild type metastatic colorectal cancer, re-challenging with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody seems to be an effective strategy for reducing tumor mass. PMID- 25731326 TI - [Cetuximab improved the poor performance status of a colorectal cancer patient]. AB - A 60-year-old man with unresectable colon cancer required treatment for hydronephrosis, acute cholecystitis, and obstructive jaundice before chemotherapy. His performance status (PS) gradually deteriorated to PS 4. Cetuximab monotherapy was initiated instead of intensive chemotherapy. His general condition improved and mFOLFOX7 therapy was then continued in addition to cetuximab. A computed tomography (CT) scan after 6 months of chemotherapy revealed a partial response (PR). Cetuximab monotherapy may contribute to the treatment of patients with a poor PS. PMID- 25731327 TI - [A case of sigmoid colon cancer with abdominal wall abscess]. AB - A 63-year-old man was admitted for an abdominal mass. Computed tomography revealed an abscess (21 * 20 cm) in the abdominal wall and a tumor in the sigmoid colon. Thus, cancer of the sigmoid colon complicated by an abscess of the abdominal wall was diagnosed. The abscess was drained and transverse colostomy was performed with curative intent. After the intervention, chemotherapy (XELOX*3) was administered. Three months later, sigmoidectomy was performed and the stoma was closed. Macroscopic and microscopic examination of the resected specimen detected no remnants of cancer. In patients with advanced colon cancer and abdominal wall involvement, a two-stage operation and preoperative chemotherapy may be considered essential when curative resection is performed. PMID- 25731328 TI - [The case of a patient who experienced perforation related to sigmoid colon cancer, was bearing a hepatic metastasis, and who underwent radical resection for advanced colon cancer after a salvage operation for pan-peritonitis and chemotherapy]. AB - Colorectal cancer associated perforation initially develops as pan-peritonitis but easily progresses to septic shock, which can be fatal. As such, it can be hard for patients to recover from this pathological condition. A 79-year-old man who was suffering from pan-peritonitis due to sigmoid colon cancer-associated perforation and also had a metastatic hepatic lesion was admitted to our hospital. He underwent an emergency operation in October 2012. Due to hemodynamic instability, peritoneal lavage and drainage, and stomal formation were performed during the operation. Polymyxin-B direct hemoperfusion (PMXDHP) and continuous hemodiafiltration (CHDF) were performed for septic shock and acute renal failure, respectively. The patient was administered 5 courses of chemotherapy consisting of capecitabine, oxaliplatin, and bevacizumab (Cape+L-OHP +Beva) with no severe adverse reactions; the primary colonic and metastatic hepatic lesions showed a good response to the chemotherapy. A radical resection for the sigmoid colon cancer, including a partial hepatic resection for the metastatic lesion, was performed in May 2013. Surveillance examinations have indicated that the patient is recurrence-free 13 months after radical resection. PMID- 25731329 TI - [A case of descending colon cancer with multiple liver metastases effectively treated with capecitabine/oxaliplatin (CapeOX) and bevacizumab]. AB - A 57-year-old woman was referred to our hospital because of descending colon cancer with multiple liver metastases. Abdominal magneticresonanc e imaging (MRI) revealed 13 liver metastases across the lobes. We started combination che- motherapy with capecitabine/oxaliplatin (CapeOX) and bevacizumab. After 9 courses of the treatment, the number and size of the liver metastases were remarkably reduced on MRI. Left colectomy and partial hepatectomy were performed. Histopathological examination revealed no residual cancer cells in the colon but revealed a few cancer cells in 4 of 7 resected liver specimens. At 11 postoperative months, 1 liver metastasis reappeared, for which we performed laparoscopy-assisted partial hepatectomy. At 21 months after the second operation, the patient was well without any signs of recurrence. Thus, the combination chemotherapy with CapeOX and bevacizumab allowed for the successful resection of the tumor and metastasis in our patient who initially had unresectable colon cancer and multiple liver metastases. PMID- 25731330 TI - [A case of recurrent colon cancer with improvement in prognosis and cancer pain after surgical intervention]. AB - We report a case of recurrent colon cancer with improvement in prognosis and cancer pain after surgical intervention. A 47-year-old man underwent an emergency Hartmann procedure for colon obstruction from descending colon cancer. Histopathological findings confirmed adenocarcinoma (moderate to poor), pT4apN0cM0, pStage II, and Cur A. In October 2009, abdominal computed tomography examination detected a solitary intraperitoneal recurrent lesion. Multi-agent chemotherapy ( mFOLFOX6)was administered. A fentanyl patch was also placed for relieving cancer pain, but was removed 4 months later because the pain disappeared. From June 2010, multi-agent chemotherapy with FOLFIRI was replaced with bevacizumab because of the increase in recurrent lesion size. In August 2011, the recurrent lesion involving the abdominal wall, left side of the colon, iliopsoas muscle, and left side of the ureter was resected and the left ureter was reconstructed. No fentanyl patch was prescribed at this time. In October 2012, tumor relapse was detected along with lung metastasis, and multi-agent chemotherapy ( FOLFIRI+bevacizumab) was resumed. In January 2013, the cancer pain recurred, and a fentanyl patch was placed again. Since then, the fentanyl dosage has been gradually increased. In August 2013, the tumor in the abdominal wall was resected to manage the patients' pain in the left lower side of the abdomen. Histopathology revealed a tumor in the lymph nodes. In November 2013, multi-agent chemotherapy with FOLFIRI+cetuximab was initiated, but was ineffective. In January 2014, regorafenib was prescribed. The patient has survived for more than 6 years after the primary surgery. We conclude that a therapeutic strategy that combines surgical interventions and multi-agent chemotherapy needs to be considered for improving prognosis and cancer pain in recurrent colon cancer. PMID- 25731331 TI - [A case of rectal cancer with multiple liver metastases successfully treated by repeated hepatectomy]. AB - A 61-year-old man was diagnosed with rectal cancer with multiple liver metastases in December 2009, and low anterior resection of the rectum was performed. Postoperative adjuvant chemotherapy with 6 courses of oxaliplatin, Leucovorin, and 5-FU (FOLFOX4) and bevacizumab was initiated, followed by 5 courses of fluorouracil, Leucovorin, and irinotecan (FOLFIRI) and bevacizumab. Right posterior segment (S6, S7) hepatectomy with enucleation of S2, S3 and S5 was performed, and chemotherapy with FOLFOX4 (11 courses) was administered. New metastases in the S5 segment were observed in August 2011 and right hepatic lobectomy was performed. The patient then underwent 8 courses of adjuvant chemotherapy with FOLFOX4. However, left hepatic lobe lateral segment and caudate lobe metastases then appeared. Subsequent repeated chemotherapy with FOLFIRI plus cetuximab (3 courses) and irinotecan plus cetuximab was interrupted in August 2013 owing to adverse events resulting in rapid growth of hepatic metastases. The patient underwent hepatic left lateral segmentectomy and left caudate lobectomy. The postoperative course was uneventful and the patient has currently survived 4 years and 7 months after the initial surgery. PMID- 25731332 TI - [Surgical curative resection after chemotherapy and portal vein embolization for multiple liver metastases of rectal cancer - report of a case]. AB - A 34 -year-old woman presenting with bloody stools was diagnosed with a rectal tumor. Computed tomography (CT) revealed multiple liver masses in Couinaud segments IV, V, and VII. The lesions were diagnosed as multiple liver metastases from rectal cancer. Right trisegmentectomy of the liver was considered the optimal treatment option for curative resection; however, liver volumetric examination using CT estimated that the remnant liver volume after right trisegmentectomy would be only 24.6% of the total liver volume. Therefore, she underwent resection of the primary lesion followed by systemic chemotherapy for multiple liver metastases. She showed a partial response, according to the Response Evaluation Criteria in Solid Tumors, after 5 courses of capecitabine/oxaliplatin plus bevacizumab. Embolization of the right branch of the portal vein was performed to increase liver volume. Asubsequent liver volumetric examination with CT estimated that the remnant liver volume after right trisegmentectomy would be 38.4% of the total liver volume. Therefore, she underwent right trisegmentectomy of the liver for curative resection of the liver metastases. She had had no signs of recurrence at 3 years and 6 months after initial surgery. PMID- 25731333 TI - [A case of rectal cancer treated with aggressive surgery for liver and anal metastases]. AB - A 64-year-old man underwent laparoscopic surgery for rectal cancer and lateral lymph node dissection. The histopathological findings indicated adenocarcinoma (moderate>well), pA, pN3(4/25No 263 1/1), pM0, Stage IIIb. After the surgery, he received 12 courses of adjuvant chemotherapy with modified 5-fluorouracil Leucovorin oxaliplatin (mFOLFOX6). Liver metastasis( S8)was present, and open hepatectomy was performed 1 year after the first surgery. Three months after the second surgery, the carcinoembryonic antigen (CEA) level increased and chemotherapy TS-1 was started. However, the CEA level continued to increase, and positron emission tomography-computed tomography revealed peritoneal dissemination, and multiple lymph node, bone, and local metastases(in the liver and rectum). Accordingly, 11 courses of chemotherapy with 5- fluorouracil Leucovorin irinotecan (FOLFIRI) and bevacizumab was administered. The patient recently experienced anal bleeding during each bowel evacuation, which developed owing to the recurrence of the cancer in the anus. To improve his quality of life, the anal tumor was excised 2 years 6 months after the first surgery. Chemotherapy with FOLFIRI and bevacizumab was restarted. The CEA level stopped increasing. We think that the anal surgery did not affect our patient's prognosis but helped improve his quality of life. PMID- 25731334 TI - [Transurethral resection of a intravesical recurrence of a tumor after resection of sigmoid colon cancer]. AB - A 66-year-old man presented to the urology clinic with hematuria. Cystoscopy with biopsy was performed for suspected bladder cancer, and a pathological diagnosis of adenocarcinoma was made. Colonoscopy revealed sigmoid colon cancer, and he was referred to our hospital. Computed tomography (CT) and magnetic resonance imaging (MRI) showed sigmoid colon cancer with urinary bladder invasion. Sigmoidectomy with lymph node dissection and partial cystectomy were performed under laparotomy. The pathological diagnosis was moderately differentiated adenocarcinoma: T4b (bladder), N1, M0, and the bladder margin was negative. Four months after surgery, CT revealed a small mass in the bladder. Cystoscopy showed a papillary pedunculated tumor at the bladder trigone, and a transurethral resection was performed. Pathological examination revealed a moderately differentiated adenocarcinoma, similar to the prior sigmoid colon cancer, which was diagnosed as an intravesical recurrence of the tumor. More than 8 years after the transurethral resection, the patient has shown no signs of recurrence. PMID- 25731335 TI - [A case of metastatic gastric cancer originating from transverse colon cancer]. AB - Metastatic gastric cancer is uncommon, and metastasis of colorectal cancer to the stomach is extremely rare. We report a case of metastatic gastric cancer that originated from transverse colon cancer. A 52-year-old woman underwent a left hemicolectomy and D3 lymph node dissection based on a diagnosis of transverse colon cancer. The pathology results were as follows: mucinous adenocarcinoma, type 2, 6 * 11 cm, ss, ly1 v1, pm (-), dm (-), n1 (+), P0, H0, M0, Stage IIIa. The patient received XELOX as postoperative adjuvant therapy for 6 months. One year and 3 months after the left hemicolectomy, gastroscopy revealed a submucosal tumor in the lower body of the stomach and an incipient cancer in the cardia of the stomach, and a colonoscopy revealed an incipient cancer in the transverse colon. An endoscopic ultrasonography fine needle aspiration biopsy of the submucosal tumor in the lower body of the stomach was performed. Histology showed that this tumor was a mucinous adenocarcinoma similar to the primary transverse colon cancer, which led to a diagnosis of metastatic gastric cancer originating from transverse colon cancer. Distant metastasis was not detected. Endoscopic submucosal dissection of the incipient gastric cancer was performed, as were distal gastrectomy and partial colectomy. Peritoneal dissemination and para aortic lymph node recurrence were detected 7 months after the second surgery. PMID- 25731336 TI - [A case of long-term survival in rectal cancer with late lung and kidney metastases treated with combined multimodality therapy]. AB - A 59-year-old man was diagnosed with rectal cancer and a low anterior resection was performed. Bilateral lung metastases appeared 4 years and 4 months after the primary surgery. The lung metastases were resected and FOLFOX6 neoadjuvant chemotherapy was administered. An abdominal computed tomography (CT) scan 7 years and 11 months after the primary surgery revealed bilateral multiple lung metastases, a left renal tumor, and swelling in the surrounding lymph node. A left nephrectomy and lymph node dissection were performed. A diagnosis of renal tumor from rectal cancer metastasis was made. For the lung metastases, chemotherapy (sLV/5FU2+Bmab) was administered in 26 courses and stable disease was achieved. It is important to combine adequate surgical resection and systemic chemotherapy for long survival. PMID- 25731337 TI - [Successful resection of recurrent lesions in a patient with ovarian torsion diagnosed with rectal cancer]. AB - We report the successful resection of recurrent tumors, including brain metastasis, in a patient with StageIV rectal cancer. A 29-year-old female patient was admitted with lower abdominal pain to the gynecological department in April 2005. The patient underwent emergency surgery following the diagnosis of left ovarian torsion. She was transferred to the Department of Surgery with suspected rectal cancer based on a pathological diagnosis of a Krukenberg's tumor. She underwent surgery for local advanced cancer using high anterior resection, hysterectomy, right oophorectomy, partial ileal resection, and appendectomy. In September 2007, she underwent very low anterior resection for an anastomotic recurrence. The patient then received 6 courses of modified 5-fluorouracil Leucovorin oxaliplatin (mFOLFOX6) as adjuvant chemotherapy. In March 2009, left paresis was observed. She underwent tumor resection and g-knife radiosurgery for brain metastasis in the right temporal lobe. In December 2009, metastasis in the right rectal muscle was resected following diagnosis by computed tomography (CT). In September 2013, she underwent further surgical resection of a tumor recurrence in the right rectal muscle. The pathological diagnosis of each resected tumor was metastatic rectal cancer. The patient has been disease-free since the last operation. PMID- 25731338 TI - [A case of palliative resection resulting in improvement in quality of life in a patient with colon cancer and simultaneous ovarian metastasis]. AB - A 72-year-old woman was admitted for investigation of lower abdominal bloating and melena. She was diagnosed with rectal cancer with ascites, multiple liver metastases, and large bilateral ovarian metastases. The patient underwent bilateral oophorectomy for the ovarian tumors and a Hartmann procedure for rectal cancer. The ovarian lesions were diagnosed as ovarian metastasis of colorectal cancer by histological analysis. Ascites and lower abdominal bloating resolved after the intervention. At 11 months after surgery, the patient is alive and well. Ovarian metastasis from colorectal cancer is relatively rare and associated with poor prognosis. Radical intervention is generally not possible in the presence of metastases, but in the present case, the ovarian tumors were large. It is often difficult to determine the optimal type of invasive surgery, although excision of the lesion may provide palliative relief. In this case, the patient's quality of life improved following palliative resection of the primary colon cancer and ovarian metastases. PMID- 25731339 TI - [Laparoscopic surgery for primary resection of StageIV colorectal cancer]. AB - BACKGROUND: The outcomes of laparoscopic surgery for primary tumors of symptomatic Stage IV colorectal cancer have not been clarified.This study aimed to review the outcomes of colorectal resection in patients with symptomatic StageIV colorectal cancer, treated either by laparoscopic colorectal resection (LAC), or by open colorectal resection (OC). METHODS AND RESULTS: A total of 69 patients were included, of which 55 patients underwent LAC.The proportion of patients with ileus was higher in the OC group than in the LAC group.The conversion rate of patients receiving LAC was 13% (7 cases).No operative mortality was observed in either group.The operation time was shorter, postoperative complication rate was lower, and postoperative hospital stay was significantly shorter in the LAC group.Median survival times in the LAC and OC groups were 26.3 months and 26.8 months, respectively. CONCLUSION: Although the short-term outcome of LAC for symptomatic Stage IV colorectal cancer was favorable, the long-term outcomes were similar in both groups.A safe and minimally invasive surgical procedure is needed for the treatment of Stage IV colorectal patients. PMID- 25731340 TI - [A case of laparoscopic surgery for a rectal carcinoid after ALTA therapy for an internal hemorrhoid]. AB - We report a case of laparoscopic surgery for a rectal carcinoid after aluminum potassium and tannic acid (ALTA) therapy for an internal hemorrhoid. A 66-year old man was admitted to our hospital because of bleeding during defecation. He was diagnosed via anoscopy with Goligher grade II internal hemorrhoids. Examination via colonoscopy revealed 2 yellowish submucosal tumors in the lower rectum that were 5mm and 10mm in diameter. A rectal carcinoid tumor was diagnosed based on histopathology. Abdominal computed tomography demonstrated no metastases to the liver or lymph nodes. First, we performed ALTA therapy for the internal hemorrhoids. Two weeks later, we performed laparoscopic-assisted low anterior resection (D2) for the rectal carcinoid. The patient was discharged without complications and has not experienced recurrence during the 2 years of follow-up care. PMID- 25731341 TI - [Two cases of rectal NET excised by laparoscopic surgery]. AB - Even if grade 1 neuroendocrine tumors (NET) have low malignant potential, they may still be associated with lymph node metastasis. While the World Health Organization (WHO) classification requires determination of the grade of malignancy and presence of metastasis, it is also useful to evaluate tumor diameter, extent of invasion, and histological characteristics(cell variant, nuclear atypia, and ductal invasion). The authors present 2 cases of rectal NET excised by laparoscopic surgery. Considerations for surgical indications in rectal NET are made based on these case reports. PMID- 25731342 TI - [A case of rapidly progressing treatment-resistant colorectal neuroendocrine carcinoma]. AB - We performed primary lesion resection in a 48-year-old man diagnosed with sigmoid colon cancer showing multiple liver metastases and extensive lymph node metastases. Endocrine cell carcinoma was diagnosed from an excised specimen. In the early postoperative period, orbital metastases and thoracic spine metastasis were detected, while the multiple liver metastases and lymph node metastases worsened markedly. We administered radiotherapy for the orbital and thoracic spine metastases, but it was ineffective. Treatment with anticancer agents was also ineffective. The patient died 56 days after the operation. PMID- 25731343 TI - [A case of mixed adenoneuroendocrine carcinoma of the transverse colon]. AB - A 7 1-year-old man presented to our hospital with constipation and abdominal pain. Computed tomography of the abdomen and colonoscopy revealed advanced cancer of the transverse colon. The biopsy specimen indicated a highly differentiated adenocarcinoma. The patient underwent extended right hemicolectomy with regional lymph node dissection. Pathological examination showed a neuroendocrine carcinoma (NEC) with concurrent adenocarcinoma of the transverse colon and regional lymph node metastases of the NEC and adenocarcinoma. The histopathological examination confirmed a diagnosis of mixed adenoneuroendocrine carcinoma (MANEC) in accordance with the 2010 WHO Classification of Tumors of the Digestive System. Liver and lung metastases were identified 8 months after the surgery. We administered chemotherapy including 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX) plus bevacizumab, with limited therapeutic effect, as the disease progressed despite treatment. The patient chose best supportive care 13 months after the surgery. Several studies have reported that most patients with adenoendocrine cell carcinoma, including MANEC, experience relapse within 1 year after surgery, and few patients remain disease-free for long periods after surgery. The optimal strategy for the management of MANEC is variable owing to its rarity; only 2 cases of MANEC in the colon, including the present case, have been reported in Japan. It is thus important to gather more evidence on this disease and its management. PMID- 25731344 TI - [Four resections of metachronous liver metastases and lateral lymph node metastases of a rectal carcinoid tumor - a case report]. AB - The authors present a case of rectal carcinoid tumor with lateral lymph node metastases and liver metastases that was successfully treated by 4 resections. A 70-year-old man was diagnosed with a rectal carcinoid tumor (20 mm in diameter) with submucosal (SM) invasion. Radical resection was performed at 25 months, 38 months, and 57 months, when abdominal computed tomography (CT) revealed metachronous liver metastases of the rectal carcinoid tumor. At 50 months, metachronous lateral lymph node metastases were also revealed. Three hepatectomies and a laparoscopic lateral lymph node dissection were performed. The patient is currently free of disease at 25 months after the last intervention. PMID- 25731345 TI - [A case of resection of pancreatic head lymph node metastasis of rectal carcinoid]. AB - An 80-year-old woman was treated with low anterior resection and D3 lymph node dissection for rectal carcinoid in August 2007. Pathological diagnosis was a tumor 23 * 22 mm in size with muscularis propria invasion, ly1, v0, n1 (No. 251[1/12]). Partial hepatectomy was performed for liver metastasis in March 2010 and September 2011. In June 2013, an isolated tumor of 17 mm in diameter was detected between the inferior vena cava and the stomach using abdominal ultrasonography. The tumor was diagnosed as pancreatic head lymph node metastasis using abdominal enhanced computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), and positron emission tomography (PET); fluorodeoxyglucose (FDG) uptake was noted at the site of the tumor, but not at other parts of the body. Curative resection was the chosen treatment option. Open surgery was performed in September 2013, and a tumor 30 mm in diameter located at the ventral side of the inferior vena cava, lateral side of the portal vein, and cranial side of duodenum was resected. No surrounding tissue infiltration was found. Pathological analysis of the resected specimen indicated lymph node metastasis of the rectal carcinoid. The patient has been disease free for 9 months after surgery. PMID- 25731346 TI - [A case of advanced rectal cancer with irinotecan (CPT-11)-induced delayed emesis]. AB - A 64 -year-old woman was referred to our hospital with a diagnosis of advanced rectal cancer with metastases to the left supraclavicular lymph nodes and paraaortic lymph nodes. Alow anterior resection was performed because of the symptoms of ileus. Subsequently, chemotherapy consisting of XELOX with bevacizumab was initiated as the first-line regimen, over 6 courses. Asecond line regimen of FOLFIRI with bevacizumab was selected due to multiple lung metastases and the progression to both left supraclavicular and paraaortic lymph nodes. During the first 3 courses, the patient had no harmful side effects. Although the patient received adequate prophylactic antiemetic therapy and supportive treatment, grade 4 delayed emesis induced by irinotecan (CPT-11) occurred at 7 days after the fourth course of FOLFIRI chemotherapy. The patient was given total parenteral nutrition, after which she recovered substantially from the emesis. Delayed emesis is occasionally seen with irinotecan therapy and can be efficiently managed with adequate prophylactic antiemetic therapy. However, delayed emesis occurring one week after administration is rarely observed. Delayed emesis and subsequent therapy affect the quality of life (QOL) of the patient and subsequent therapy therefore, adequate attention and prompt management are required for delayed emesis. PMID- 25731347 TI - [A case of metastatic rectal cancer with fulminant hepatitis caused by XELOX therapy]. AB - We report a case of fulminant hepatitis that was caused by XELOX therapy administered for metastatic rectal cancer. A 69- year-old man with metastatic rectal cancer received 4 courses XELOX therapy. He was subsequently admitted to our hospital with general fatigue. Shenzhen flapping and altered consciousness were noticed on the fifth day of hospitalization. A liver biopsy was subsequently performed. The patient was diagnosed with liver failure due to sinusoidal obstruction syndrome caused by oxaliplatin. This case provides valuable information as there are only a few reports of fulminant hepatitis caused by oxaliplatin. PMID- 25731348 TI - [A case of erythema multiforme induced by regorafenib therapy for metastatic colon cancer]. AB - A 47-year-old woman underwent colectomy for advanced colon cancer and thereafter received regorafenib therapy as fourth-line chemotherapy. On treatment day 12, the patient developed erythema multiforme (EM) induced by the regorafenib therapy. Immediately after regorafenib was withdrawn, the patient was treated with oral bepotastine and steroid ointment, which relieved the EM without progressing to Stevens-Johnson syndrome (SJS). Regorafenib is used for third- or fourth-line chemotherapy. Progression of regorafenib-induced EM to SJS may cause critical dysfunction among patients. Before administering regorafenib therapy, the patient should be made aware of this potential adverse effect and be advised to withdraw the treatment and visit the hospital immediately if symptoms of EM are observed. PMID- 25731349 TI - [A case of cardiopulmonary arrest due to hypersensitivity reaction to oxaliplatin for multiple liver and lung metastases of colon cancer]. AB - A 69-year-old man underwent right hemicolectomy and D3 lymphadenectomy for transverse colon cancer in 2009. Under the postoperative pathological diagnosis of Stage IIIb (pT3pN2cM0) cancer, he was given 8 courses of adjuvant chemotherapy with capecitabine. After the chemotherapy, in April 2013, we detected recurrence of the multiple liver and lung metastases; thus, we administered modified 5 fluorouracil, Leucovorin, oxaliplatin (mFOLFOX6) and bevacizumab. Six courses of oxaliplatin infusion were completed uneventfully. However, 3 min after starting the seventh infusion courses, the patient experienced cardiopulmonary arrest. We immediately performed cardiopulmonary resuscitation. The patient's anaphylaxis symptoms resolved after treatment with intravenous epinephrine. He was discharged 3 days after the event with no further complications. Clinicians should be aware that oxaliplatin-induced anaphylactic shock often occurs during the eighth infusion cycle and that this severe hypersensitivity reaction is difficult to predict and prevent. PMID- 25731350 TI - [A case of rectal GIST treated by perineal partial rectal resection using laparoscopic surgery]. AB - A 60-year-old man presented to our hospital with melena. A submucosal tumor (24 mm) was found via magnetic resonance imaging between the prostate and the rectum (Rb). A gastrointestinal stromal tumor (GIST) that displaced the prostate ventrally was diagnosed via histopathology. Preoperative imatinib treatment was initiated to reduce the tumor size and prevent extensive surgery. Approximately 33% of the tumor was reduced using chemotherapy. First, laparoscopic rectal dissection and mobilization were performed reaching the pelvic floor. Then, we performed perineal partial rectal resection. There has been no recurrence. PMID- 25731351 TI - [A case of rectal gastrointestinal stromal tumor (GIST) locally resected after long-term chemotherapy with imatinib mesylate]. AB - We report a case of gastrointestinal stromal tumor (GIST) locally resected after long-term chemotherapy with imatinib mesylate. A 78-year-old woman was diagnosed with GIST in the lower rectum on screening colonoscopy for anemia. The tumor was 7 cm in diameter, and the anal sphincter was considered to be difficult to preserve due to the extent of the tumor. The patient refused surgery, so she was administered imatinib mesylate chemotherapy. The medication was continued for 5 years without any major adverse events, and the status of the tumor was stable. Five years later, she underwent transanal local resection for anal prolapse and incarceration of the tumor. Pathological findings revealed a 7 cm sized high-risk GIST. The long-term stable status of the tumor was maintained, and the anal function was preserved by the local resection. PMID- 25731352 TI - [Treatment outcome in nine cases of anal squamous cell carcinoma]. AB - We reviewed the clinical records of 9 patients with anal squamous cell carcinoma (SCC) chiefly to evaluate the effectiveness of chemoradiotherapy (CRT). Surgery was performed in 1 patient; radiotherapy (RT), in 2; and CRT, in 6. RT consisted of 40 Gy delivered to the pelvic and bilateral inguinal lesions, and a perianal booster dose of 20 Gy in fractions of 2.0 Gy/day, 5 days a week. 5-fluorouraci (l 750 mg/m2, administered through a 24-h continuous infusion for 5 days) and mitomycin C (10 mg/m2, administered as a single bolus infusion)were administered 3 times every 4 weeks as standard chemotherapy. One patient with a T3 tumor received oral TS-1 during RT because of advanced age. In the CRT group, 1 patient had a T1 tumor, another had a T3 tumor, and the others had a T2 tumor. Grade 2 adverse effects occurred in 3 patients, and grade 3 adverse effects occurred in 1 patient. Nevertheless, CRT was completed in all of the 6 patients. All the patients had complete response after CRT for the anal lesion. Two patients, one of whom had a T3 tumor treated with oral S-1, had recurrence of the anal lesion. The 2 patients (T2 and T3) who underwent RT and needed surgery because of residual tumor died of recurrent disease. The patient with a T4 tumor who underwent abdominoperineal resection also died of recurrent disease. CRT is considered a safe and effective treatment option to improve prognosis in anal SCC. PMID- 25731353 TI - [Three cases of anal squamous cell carcinoma treated with chemoradiotherapy]. AB - We reviewed the clinical records of 3 patients with anal squamous cell carcinoma treated with chemoradiotherapy (CRT). Case 1: The patient was diagnosed with StageI (T1N0M0) and treated with cisplatin (CDDP)+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. She achieved partial response(PR), and underwent a salvage surgery. Seven months after the surgery, she died from other comorbidities. Case 2: The patient was diagnosed with Stage I (T1N0M0) and treated with CDDP+5-FU+radiation. Chemotherapy was discontinued after the second course because of adverse effects. He achieved PR, and underwent a salvage surgery. Three years and 7 months after the surgery, he died from other comorbidities. Case 3: The patient was diagnosed with Stage IIIB (T4N1M0) and treated with MMC+S-1+radiation. Chemotherapy was discontinued after the first course because of adverse effects. She achieved complete response (CR) and is still surviving without cancer recurrence. We conclude that CRT is an effective treatment for anal squamous cell carcinoma. PMID- 25731354 TI - [Squamous cell carcinoma of the anal canal showing complete response after concurrent chemoradiotherapy and S-1 plus mitomycin C - a case report]. AB - The patient was a 65-year-old man who underwent colonoscopy for melena. Following a biopsy, the patient was diagnosed with anal canal squamous cell carcinoma. A computed tomography (CT) scan revealed metastasis to the regional lymph nodes. The proposed treatment regimen comprised radiotherapy combined with S-1 and mitomycin C (MMC). Dur- ing radiotherapy (59.6 Gy in 32 fractions), 10mg/m2 MMC was administered, as an intravenous bolus injection, on days 1 and 29. S-1 was administered orally, at a dose of 80 mg/m2, on days 1-14 and 29-42. No serious adverse events were observed during chemoradiotherapy; the observed adverse events were leukemia (Grade 2), diarrhea (Grade 1), anorexia (Grade 1), and radiation dermatitis (Grade 1). After 8 weeks of treatment, no tumors, only scar tissue could be detected by using colonoscopy, and a CT scan revealed a remarkable reduction in regional lymph node metastases. The patient achieved a complete response. PMID- 25731355 TI - [A case of adenocarcinoma of the anal canal in which palliation was achieved by chemoradiotherapy]. AB - An 82-year-old man who complained of constipation, anal pain, and bleeding was diagnosed with internal hemorrhoid in another hospital 6 months previously. At the time of our consultation, a tumor was observed in the anal canal. Computed tomography (CT) imaging revealed that the tumor extended to the front of the coccyx with abscess formation. Histological examination of biopsy specimens confirmed a diagnosis of adenocarcinoma. Since the patient refused to undergo surgery, we recommended chemoradiotherapy for relieving pain. A total of 60 Gy of irradiation was administered to the lesser pelvis, and chemotherapy was initiated with S-1 at a dose of 8 0mg/day for 14 consecutive days followed by 7 days of rest. Subsequently, tumor reduction was seen and the pain was controlled. The patient showed improvement in activities of daily living (ADL). Currently, the patient continues to receive S-1 therapy. We conclude that chemoradiotherapy is useful as a palliative therapy in anal mucinous carcinoma. PMID- 25731356 TI - [Local excision of T1b anal canal cancer - a case report]. AB - We performed transanal local excision of anal canal cancer in a 51-year-old man. The tumor was detected as an Isp polyp(7 mm)on the dentate line, by colonofiberscopic examination. Pathological findings indicated adenocarcinoma(T1b). The patient desired preservation of anal function, and hence refused abodominoperineal rectal transection with lymph node dissection. We obtained informed consent for recurrence, and observed the patient rigorously. No recurrence or metastasis has been detected 3 years and 3 months after tumor excision. We propose that transanal local excision might be a treatment option for early stage cancer of the anal canal. PMID- 25731357 TI - Mucinous adenocarcinoma associated with a chronic perianal fistula - a review of cases from a single institution. AB - PURPOSE: The purpose of this study was to evaluate the clinicopathological features of mucinous adenocarcinoma associated with perianal fistulas (MAF), to assess the importance of preoperative MRI analysis, and to determine the optimal surgery. METHODS: We performed a retrospective analysis of the data from seven patients with MAF treated at our hospital between 2000 and 2013, and herein discuss the importance of preoperative magnetic resonance imaging (MRI) and of radical surgery. RESULTS: The male to female ratio was 5:2, and the mean age of the patients was 63 years old (28-70). The median duration of chronic fistulation was 16 years (5-40). The tumor extension was classified as II+III+IV in five patients and as II+III in 2 patients according to the Sumikoshi classification, as determned by pelvic MRI. The performed surgeries were 3 abdominoperineal resections with sacral resection and 4 pelvic exenterations with sacral resection. Two local recurrences developed in patients with R1 resection, and 1 distant metastasis occurred in 1 patient with R0 resection. CONCLUSION: For patients with MAF, a curative surgical resection is the only definitive treatment that can be expected to provide a good prognosis. The application of the Sumikoshi classification using MRI may provide a precise assessment of the extension of MAF, which can allow the appropriate surgery to be selected for the patients with MAF. PMID- 25731358 TI - [A case report of metastatic anal fistula cancer treated with neoadjuvant chemotherapy]. AB - A 69-year-old man with perianal pain was diagnosed with an anal fistula and a rectal tumor by magnetic resonance imaging and pulmonary tuberculosis by computed tomography. A colonoscopy confirmed the presence of a circular mass in the rectum 6 cm from the anal verge. Histological examination revealed a moderately differentiated adenocarcinoma. Initially, seton drainage was used to improve the perianal pain. After 2 months of anti-tuberculosis therapy, the patient underwent low anterior resection for the rectal cancer. Six months after surgery, a perianal tumor was detected at the postoperative site of the anal fistula. Biopsy of the tumor revealed adenocarcinoma. Because the histological appearance of the second tumor was identical to the rectal cancer, it was diagnosed as a metastatic anal fistula cancer. The tumor shrunk after 3 courses of neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX) plus bevacizumab and there was no evidence of distant metastasis. Local resection of the anal fistula cancer was performed. Six months postoperatively, the patient is doing well and shows no sign of recurrence. PMID- 25731359 TI - [A case of primary carcinoma associated with anal fistula]. AB - A 47-year-old man with no history of anal fistula was admitted to our hospital with a complaint of perianal pain. Computed tomography (CT) imaging revealed perianal abscess. Incision and drainage were performed under spinal anesthesia. Ten months after drainage, magnetic resonance imaging revealed anal fistula on the left side of the anus. Subsequently, core-out and seton procedures were performed for ischiorectalis type III anal fistula. Pathological examination of the resected specimen of anal fistula revealed a moderately differentiated adenocarcinoma, leading to the diagnosis of carcinoma associated with anal fistula. No distant metastases or enlarged lymph nodes were observed on positron emission tomography (PET)/CT. We performed abdominoperineal resection with wide resection of ischiorectalis fat tissue. The pathology results were tub2, A, ly0, v0, n0, PM0, DM0, RM0, H0, P0, M0, Stage II. Negative pressure wound therapy was performed for perineum deficiency, after which rapid wound healing was observed. Left inguinal lymph node recurrence was detected 8 months after surgery, for which radiotherapy was administered. Distant metastasis was detected 11 months after surgery. The patient died 21 months after surgery. PMID- 25731360 TI - [Laparoscopic abdominoperineal resection after preoperative chemoradiotherapy for advanced carcinoma associated with anal fistula]. AB - The patient was a 71-year-old man who was diagnosed with anal fistula 50 years previously. He complained of mucous and bloody stools. He was diagnosed with a carcinoma associated with anal fistula after biopsy. Image examination showed that the tumor was filled with mucinous substances and that it had invaded the levator ani muscle, with left external iliac and left inguinal lymph node metastases. Therefore, preoperative chemoradiotherapy for locally advanced cancer was administered. After chemoradiotherapy, the tumor and metastatic lymph nodes reduced in size. We performed laparoscopic abdominoperineal resection. Histopathologically, the tumor was revealed as a mucinous adenocarcinoma, but no cancer cells were present on the surgical margin. This case suggested that preoperative chemoradiotherapy could be effective for locally advanced carcinoma associated with anal fistula. PMID- 25731361 TI - [A difficult diagnosis of asynchronous both side breast cancers]. AB - A 53-years-old woman was diagnosed with left breast cancer (T2N0M0, Stage IIA) and underwent breast conserving surgery and axillaryly mph nodes resection. She was administered 2 courses of chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil (CMF) and received a total of 50 Gy of radiation therapy as adjuvant therapy. Ultrasonography of the right breast, performed 2 years after the first operation, detected a tumor 7 mm in diameter. A core needle biopsy of the tumor was performed. The pathological diagnosis was fibroadenoma. The patient's whole body was checked for metastatic legions, but none were found. Right axillary lymph node swelling was detected 9 years after her first operation, and a surgical biopsy was performed. Frozen section analysis indicated that it was metastasis from the breast cancer. A further surgical biopsy was performed on the right breast mass. Frozen section analysis indicated the tumor was invasive ductal carcinoma within a fibroadenoma. Breast conserving surgeryand axillaryly mph node dissection were performed for the right breast cancer. The final permanent pathological diagnosis of the right breast was invasive ductal carcinoma within fibroadenoma ( T2N1M0, Stage IIB), negative for estrogen receptor, negative for progesterone receptor, and negative for epidermal growth factor receptor 2(ErbB-2). The patient was administered 3 courses of chemotherapy consisting of taxotere and cyclophosphamide (TC) and received a total of 50 Gy of radiation therapy. The patient is alive without metastases 3 years after the second surgery. PMID- 25731362 TI - [A case of locally recurrent breast cancer difficult to differentiate from nodular fasciitis]. AB - Breast-conserving surgery was performed on a 78-year-old woman for left breast cancer 5 years previously (invasive ductal carcinoma, T1cN2M0, stage IIIA, ER[+], PR[-], HER2[-]). Chemotherapy, radiotherapy, and hormonal therapy were administered. A left subclavian tumor was detected, and an excisional biopsy was performed. Histological examination showed spindle cells, different from primary breast cancer histology, and nodular fasciitis was diagnosed negative cytokeratin and vimentin immunostaining results. After 12 months, a mass had developed in the same region, and reoperation was performed for resection. Similar spindle cells were observed, but they tested positive for cytokeratin. Carcinoma was diagnosed and thought to be locally recurrent breast cancer. Despite postoperative chemotherapy, the patient experienced bone and lung metastasis and a third local recurrence. She died 13 months following the last surgery. Recurrent breast cancer sometimes displays different histology from the initial cancer, and mimics stromal tumors in certain cases. PMID- 25731363 TI - [A case of squamous cell lung carcinoma that was difficult to distinguish from squamous cell carcinoma of the breast]. AB - A 74 -year-old man was hospitalized for chest pain. Chest computed tomography showed a 4 * 8 cm-sized tumor pressing on the left pectoralis major muscle. Subsequent imaging showed progression of the tumor along with rib erosion and intrapleural invasion. The patient was admitted to our hospital for a follow-up examination of the tumor. Bronchoscopy results were normal. Ultrasound-guided percutaneous needle biopsy was performed. Histopathology indicated squamous cell carcinoma on the basis of the presence of keratin pearls. We therefore diagnosed the patient with squamous cell lung carcinoma fStage IIb (T3N0M0) and subsequently administered chemoradiotherapy owing to the inoperable status of the lesion. We report a case of squamous cell lung carcinoma that was difficult to differentiate from squamous cell carcinoma of the breast, along with a review of the literature. PMID- 25731364 TI - [Clinical experience with a handheld vacuum-assisted biopsy system (VACORA(r) )for mammary lesions]. AB - We evaluated the usefulness and safety of a handheld vacuum-assisted biopsy system (VACORA(r)) in 253 lesions suspected to be malignant. Biopsy samples were successfully obtained from 252 lesions, and no complications occurred that required other treatments during or after the biopsy. The definitive diagnosis rate using VACORA / (r)was 89.3% (226/253). For 27 lesions, biopsy using Mammotome(r)or open biopsy was performed because a diagnosis could not be made with the VACORA(r) system, despite a category 4 result on ultrasonography. The lesions that were diagnosed as benign using the VACORA(r) system did not manifest malignant features during the observation period (1-36 months). We considered the VACORA(r) biopsy system as an effective technique that has both convenience and high diagnostic accuracy. PMID- 25731365 TI - [Success rate of breast conserving surgery for different breast cancer screening methods]. AB - We evaluated the significance of the success rate of breast conserving surgery in patients with breast cancer discovered by using different screening methods. Patients underwent either population-based screening (group A) or opportunistic screening(group B). We retrospectively investigated patients who visited our hospital in 2012. A total of 552 patients visited our hospital for breast cancer screening. Thirty-five percent of these patients were diagnosed with breast cancer based on the histopathological results. The rate of breast cancer discovery was significantly higher in group B than in group A. The rate of discovery of early clinical stage breast cancer was also higher in group B than in group A. The rate of total breast conserving surgery for breast cancer screening cases was 54.4%. The rate of breast conserving surgery was higher in group B than in group A. Group A patients only underwent mammography, while 80.1% of group B patients underwent mammography plus ultrasonography. These results suggest that adding ultrasonography to breast cancer screening is useful for detection of early breast cancer. PMID- 25731366 TI - [Immediate breast reconstruction for breast cancer]. AB - We performed immediate breast reconstruction after nipple-sparing mastectomy or skin-sparing mastectomy and evaluated the reconstruction procedure, cosmesis, and complications. Among the 30 patients included in the study, 6 received latissimus dorsi flaps, 1 received a transverse rectus abdominis myocutaneous flap, 7 received deep inferior epigastric perforator flaps, 1 received an implant, and 15 received tissue expanders. In addition, the results were excellent in 25 patients, good in 3 patients, and poor in 2 patients. As the number of patients with breast cancer is increasing, the demand for breast reconstruction will increase. Therefore, it is essential to choose an appropriate method of breast reconstruction for each case. PMID- 25731367 TI - [A case of cardiac tamponade due to pericarditis carcinomatosa of breast cancer successfully treated via pericardiocentesis and systemic chemo-endocrine therapy]. AB - We report a case of lung and bone metastases of right advanced breast cancer in a 33-year-old woman. Her breast cancer (T4bN1M1, StageIV)was resected in December 2003 (mastectomy [BT] plus axillary lymph node dissection [AX]) after local arterial infusion therapy and subsequent systemic chemo-endocrine therapy was initiated and continued. In June 2007, a computed tomography (CT) scan revealed cardiac tamponade due to pericarditis carcinomatosa. Pericardiocentesis was performed, and the bloody effusion was drained immediately. Subsequently, the sysytemic chemo-endocrine therapy was modified. In 2009, multiple cerebellar metastases were discovered and treated via whole brain irradiation. In 2010, multiple liver metastases appeared, and they were treated by intravenous (IV) administration of nab-paclitaxel. In 2011, superior vena cava syndrome appeared gradually, and it was treated via venous metallic stenting. In 2012, epidural spinal cord compression appeared gradually, and it was treated via irradiation. In November 2012, the patient died because of lymphangitis carcinomatosa; her prognosis was good, as it was approximately 5 years after the pericardiocentesis. PMID- 25731368 TI - [The case of a long-surviving patient with breast cancer and brain metastases treated using multidisciplinary therapy]. AB - We present the case of a 55-year-old-woman who was diagnosed with left breast cancer, and underwent a left mastectomy and left axillary lymph node resection. The histopathological examination indicated scirrhous carcinoma and lesser papillotubular carcinoma[estrogen receptor-negative (ER-), progesterone receptor negative(PgR-), and human epidermal growth factor receptor 2-positive, grade 3 (HER2, 3+)] with lymph node metastases. Adjuvant chemotherapy consisting of epirubicin and cyclophosphamide (EC) followed by paclitaxel was administered. During the therapy, the patient noticed a mass on her left chest wall. It was diagnosed as a locally recurrent tumor. A computed tomography (CT) scan indicated supraclavicular lymph node metastasis. The patient underwent radiotherapy and was administered chemotherapy with TS-1 and trastuzumab. Brain metastases were found 24 months postoperatively, and the patient underwent surgery and wholebrain radiotherapy. After these, systemic capecitabine and trastuzumab chemotherapy was administered. The therapy was subsequently changed to capecitabine and lapatinib. There have been no subsequent metastatic tumors, and good control has been achieved for a long time after the detection of brain metastases. PMID- 25731369 TI - [A case of stromal sarcoma with multiple local recurrences]. AB - A 53-year-old woman presented with a right breast lump identified approximately 6 months previously on palpation. Because the lump gradually increased in size, she initially visited a general practitioner who referred her to our hospital. Mammography and breast ultrasonography revealed a lesion in the right breast. Biopsy indicated a case of stromal sarcoma. Three months later, another lesion was detected, and simple mastectomy was performed. A recurrent lesion was detected after 1 month, and lumpectomy was performed. Another mass developed 1 month later, and extirpation was performed. After 1 month, another mass was detected, and extirpation was performed again. The stump was negative for lesions and recurrences. A thorough examination did not reveal metastasis to remote organs. There are no established therapies for stromal sarcoma. Surgical excision is undoubtedly indicated, as observed in this patient who showed multiple recurrent lesions despite the surgeries performed. PMID- 25731370 TI - [Using skin graft for local control in stage IV breast cancer to improve quality of life]. AB - A 59-year-old woman was hospitalized in June 2012 for Stage IV bilateral breast cancer, axillary lymph-node metastasis, metastatic lung tumor, metastatic bone tumor, right carcinomatous pleuritis, and right-eye choroidal metastasis. Treatment for improvement of symptoms included steroids, continuous subcutaneous infusion of morphine hydrochloride, and thoracic drainage. Chemotherapy with zoledronic acid+TC therapy was administered, with only a small residual primary lesion of the right breast. Interstitial pneumonia caused by the chemotherapy occurred and the volume occupied, it was continued treatment is difficult. In October 2013, she experienced right axillary lymph node metastases, and progress of the right breast cancer, with pain and bleeding from the right breast tumor. Therefore, for the purpose of improving quality of life, Bt+Ax was administered in October 2013, but since the resected part of the right breast included an approximately 10 cm dermal infiltration, a preserved subcutaneous vascular network (PSVN) skin graft was performed using healthy skin. The patient recovered well, the pain and bleeding disappeared, and the patient was discharged following surgery. PSVN skin graft for the purpose of local control was useful in this case. PMID- 25731371 TI - [Two cases of dural metastasis of breast cancer]. AB - The first case of dural metastasis occurred in a 60s years old woman, who presented with bone metastasis to the right breast. Nine months later, disorientation and left hemiplegia developed, the right coronal bone metastasis enlarged, and dural metastases were detected close to the tumor, as observed by using cranial magnetic resonance imaging (MRI). Whole brain radiation and chemotherapy(weekly paclitaxel)were administered. The right coronal bone metastasis reduced remarkably, and the dural metastases almost disappeared, as observed on a cranial MRI scan. The second case of dural metastasis occurred in a 50s years old woman who presented with multiple bone metastases. Extensive bone metastases to the skull and dural metastases to the side of the head were observed on cranial MRI scans. Subsequently, the patient experienced a severe headache, and whole brain radiation and pharmacotherapy with anastrozole and trastuzumab were administered. Cranial MRI revealed that the skull bone metastasis reduced and the dural metastases almost disappeared. We report that radiotherapy and pharmacotherapy were effective in these 2 cases of dural metastases of breast cancer. PMID- 25731372 TI - [Two cases of radiotherapy-induced sarcoma after breast cancer surgery]. AB - We report 2 cases of radiotherapy-induced sarcoma of the residual breast after breast cancer surgery. In 1 case, the patient was a 64-year-old woman. She underwent breast-conserving surgery and axillary lymph node dissection followed by irradiation to the residual breast in July 2001. A 1.1 * 1.0-cm tumor was noted in the residual breast 7 years 5 months after radiotherapy. An excisional biopsy was performed, and a histological diagnosis of angiosarcoma was made. She died of lung and peritoneal metastases 3 years 2 months after the diagnosis. In the other case, the patient was also 64 years old. She underwent breast conserving surgery and sentinel lymph node biopsy followed by irradiation to the residual breast in October 2006. A 5.7 * 3.9-cm induration was noted in the residual breast 3 years 5 months after radiotherapy. A core needle biopsy was performed, and a histological diagnosis of sarcoma was made. Mastectomy was performed, and the histological diagnosis was malignant fibrous histiocytoma. She died of chest wall and intrapleural tumor recurrence 3 months after the mastectomy. Although radiotherapy-induced sarcoma is rare, early detection of the tumor in the irradiation area is important, as radiotherapy is often performed for breast cancer patients. PMID- 25731373 TI - [Usefulness of reductive surgery for elderly advanced breast cancer with bone metastases - a case report]. AB - We report the case of an elderly, advanced breast cancer patient with multiple bone metastases. Breast reduction surgery was useful for this patient. The patient was an 81-year-old woman who had a breast lump. A core needle biopsy for breast cancer led to a diagnosis of invasive ductal carcinoma. The mucinous carcinoma was estrogen receptor (ER) nd progesterone receptor (PgR) positive and HER2/neu negative. Due to patient complications, it was not possible to treat with chemotherapy. The patient was administrated aromatase inhibitors (AI) and zoledronic acid hydrate. However, the AI treatment was not effective, and so she was administered toremifene. Toremifene treatment was effective for 6 months, after which she received fulvestrant. Fulvestrant treatment maintained stable disease (SD)for 14 months. After 14 months of fulvestrant treatment, serum concentrations of the tumor markers CA15-3, CEA, and BCA225 increased. We therefore decided to perform surgical breast reduction surgery. The pathological diagnosis from the surgically resected specimen was mucinous carcinoma, positive for ER and HER2, and negative for PgR. After surgery, serum concentrations of the tumor markers decreased. Following surgery, the patient was administrated lapatinib plus denosumab plus fulvestrant. The patient remains well, without bone metastases, 2 years and 6 months after surgery. PMID- 25731374 TI - [A case of hyoid bone metastasis from breast cancer]. AB - A 69-year-old woman had undergone breast conserving surgery and axillary lymph node dissection for left breast cancer 10 years previously. The tumor was positive for estrogen receptor (ER) and progesterone receptor (PgR), and negative for human epidermal growth factor receptor-2 (HER2). Adjuvant tamoxifen and radiation therapy were administered to the conserved breast for 5 years. The patient detected a painless neck mass 1 year previously. Computed tomography (CT) revealed a hyoid bone mass, and fine needle aspiration cytology indicated a diagnosis of adenocarcinoma. Positron emission tomography combined with CT (PET CT) revealed masses in the pelvis, spine, hyoid bone, and cervical lymph node. For definitive diagnosis, excisional biopsy of the hyoid bone was performed. Immunohistostaining revealed that the cells were CK7 (+), CK20(-), mammaglobin (+), GCDFP-15 (+), ER (+), PgR (+), and HER2 (-). The final diagnosis was multiple bone metastasis(hyoid, pelvis, spine)as well as cervical lymph node metastasis from breast cancer. After diagnosis, the patient was treated with anastrozole and denosumab, and she achieved a partial response. She has experienced progression free survival for 12 months. Metastasis to the hyoid bone is uncommon for breast cancer. We report a case in which hormone therapy was effective after it was selected based on the results of excisional biopsy. PMID- 25731375 TI - [Analysis of axillary recurrence after breast reconstruction]. AB - In recent years, breast reconstruction is being increasingly performed. Axillary resection is the standard treatment for axillary recurrence after a negative sentinel node (SN) biopsy. Appropriate treatment in the event of a negative SN artifact poses a problem. Case 1: A3 9-year-old woman with right breast cancer underwent Bt+SN (negative)+TE, IMP. Approximately 8 years postoperatively, axillary lymph node recurrence was diagnosed. Axillary resection was performed, and the reconstructed breast was preserved. Case 2: A4 0-year-old woman with right breast cancer underwent Bt+SN (negative)+TE, IMP. Approximately 8 years postoperatively, axillary lymph node recurrence was diagnosed. Axillary resection was performed, and the reconstructed breast was preserved. Case 3: A5 7-year-old woman with right breast cancer underwent Bt+SN (negative)+ TE, IMP. Because the metastatic lymph node was near the reconstructed breast, axillary resection and removal of the reconstructed breast was performed. It is expected that the incidence of axillary lymph node recurrence after breast reconstruction will increase in the future. For axillary lymph node recurrence, surgical resection needs to be performed to achieve a complete recovery. Therefore, it may be necessary to perform surgery without preserving the reconstructed breast. PMID- 25731376 TI - [The synergistic effect of local microwave hyperthermia and chemotherapy for advanced or recurrent breast cancer]. AB - The purpose of our study was to test the efficacy and toxicity of hyperthermia in conjunction with chemotherapy for breast cancer. Between 2009 and 2014, 6 patients diagnosed with breast carcinoma were selected for this retrospective study. Patients received standard chemotherapy (AC followed by paclitaxel ) in combination with hyperthermia. The hyperthermia device employed microwave heating with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. Following hyperthermia therapy, 4 patients had a partial response to treatment and the toxicity was mild, consisting of Grade 1 acute skin toxicity. Therefore, hyperthermia combined with chemotherapy for breast cancer seems to be effective and generally tolerable. A larger patient cohort is needed to confirm these results. PMID- 25731377 TI - [Locoregional recurrence of HER2-positive breast cancer - treatment after complete remission and long-term clinical benefits]. AB - We report 7 cases of locoregional recurrence in human epidermal growth factor receptor 2 (HER2)-positive breast cancer that we treated. An early complete response (CR) and long-term response was achieved in 5 cases. There were 4 HER2- subtype and 3 Luminal HER2-type cases. Metastasis and recurrence were detected in the residual breast tissue and the supraclavicular, axillary, and parasternal lymph nodes. Chemotherapy consisting of trastuzumab was administered as first line treatment. A CR was observed 3-4 months after the initiation of therapy in 4 cases, and the time to progression was 27.6- 65.8 months. After achieving a CR, 3 patients terminated treatment and 2 patients continued to take trastuzumab. However, due to adverse effects associated with the chemotherapy, 1 patient changed to endocrine therapy. A second, long-term, CR was achieved in 2 relapsed CR patients by re-challenging with the same chemotherapy regimen. Two patients did not achieve CR and died due to distant metastases. For a better quality of life, it is advisable to continue treatment after a clinical CR for solitary or more complex locoregional recurrences. Following the first-line therapy and a so called chemoholiday, the patient's disease can be re-challenged using the previously sensitive regimen with careful observation. PMID- 25731379 TI - [The case of a giant malignant phyllodes tumor of the breast]. AB - A 75-year-old female patient complained of a mass in her left breast 2 years ago. The patient experienced a rapid enlargement of the mass 2 months later and visited our hospital. A computed tomography (CT) scan indicated a 25-cm tumor with infiltration of the left breast skin. Pectoral muscle invasion was considered. Swelling of the axillary lymph node and remote metastases were not found. A needle biopsy indicated a phyllodes tumor. A pectoral muscle-preserving mastectomy was undertaken. The tumor weighed 7.1 kg. Pathological examination indicated hyperplasia of the stroma and part of the epithelium, which had invaded the skin layer and fatty tissue. The pathological diagnosis was a malignant phyllodes tumor. This paper reports the case of a giant malignant phyllodes tumor. PMID- 25731378 TI - [A case of malignant phyllodes tumor after surgery for breast cancer]. AB - A 63-year-old woman underwent breast-conserving resection and axillary lymph node dissection for bilateral breast cancer in December 2008. Histopathological diagnosis for the right breast cancer was t=1.3 cm, n=1/29, estrogen receptor (ER) (+), progesterone receptor (PgR) (+), human epidermal growth factor receptor 2(HER2) (-), and that for the left breast cancer was t=1.8 cm, n=9/28, ER (+), PgR (+), and HER2 (-). She was administered adjuvant chemotherapy (4 courses of fluorouracil, epirubicin, and cyclophosphamide [FEC 100] and 4 courses of docetaxel[DTX], 75 mg/m2), letrozole, and bilateral radiation therapy for the remaining breast tissue. She noticed a mass in the left breast in December 2013. Fine-needle aspiration cytology and core-needle biopsy indicated a malignant phyllodes tumor or stromal sarcoma. Positron emission tomography-computed tomography (PET-CT) revealed the accumulation of fluorodeoxyglucose (FDG) only in the mass. The tumor enlarged rapidly to more than 5 cm during the pre-operative period. In January 2014, the patient underwent left mastectomy. The histopathological diagnosis was malignant phyllodes tumor in the left breast, with a tumor diameter of 7 cm, and negative margins. Presently, 6 months after the operation, the patient is alive without recurrence. PMID- 25731380 TI - [A case of spindle cell carcinoma of the breast]. AB - The patient was a 53-year-old woman in whom ultrasonography of the breast revealed a lobular mass, 14 mm in diameter, in the right AB region. Spindle cells were obtained on fine-needle aspiration biopsy, but it was not possible to diagnose whether the tumor was benign or malignant. Contrast-enhanced magnetic resonance imaging showed a mass with a cystic component that was darkly stained in the early phase. Needle biopsy showed a dense proliferation of atypical spindle cells with no distinct epithelial-like arrangement. The differential diagnosis included mesenchymal malignant tumors such as fibrosarcoma, some phyllodes tumors, and epithelial tumors with sarcomatoid differentiation. Immunostaining revealed that the tumor was cytokeratin (AE1/AE3)-negative, partially CAM 5.2-positive, p63-positive, S100-negative, SMA-positive, partially vimentin-positive, with a Ki-67 index of 80% and negativity for ER, PgR, and HER2. Spindle-cell carcinoma was thus diagnosed. A partial right mastectomy with sentinel lymph-node biopsy was performed. Immunostaining of the resected specimen confirmed spindle cell carcinoma. The General Rules for Clinical and Pathological Recording of Breast Cancer classify spindle cell carcinoma as a special type of invasive cancer with a sarcomatoid structure, consisting of spindle-shaped cancer cells. This type of carcinoma is extremely rare, accounting for less than 1% of all breast cancers. PMID- 25731382 TI - [A case of malignant melanoma metastasis to the mammary gland]. AB - Herein, we report a rare case of malignant melanoma metastasis to the mammary gland. A 76-year-old woman had a tumor resection performed for primary malignant melanoma of the epipharynx. The patient subsequently underwent local and lymph node recurrence, for which she received heavy ion radiotherapy and lymph node dissection, respectively. The patient was referred to our hospital for a problem with her right breast. Computed tomography and magnetic resonance imaging showed a mammary tumor and multiple subcutaneous tumors. A biopsy was performed, which proved positive for S100 and Melan A staining, and the diagnosis of malignant melanoma was confirmed. Partial mastectomy was performed; and S100, HMB45, and Melan A positivity was confirmed based on immunohistological findings. The diagnosis was malignant melanoma metastasis to the mammary gland. Malignant melanoma commonly metastasizes to the liver, mediastinum, mediastinal glands, lung, and brain; and metastasis to the mammary gland is rare. To our knowledge, only 2 cases have previously been reported in the Japanese literature. PMID- 25731381 TI - [A case report of matrix-producing carcinoma of the breast]. AB - A 43 -year-old woman with a palpable mass in the right breast consulted a neighborhood doctor. She was diagnosed with right breast cancer after core needle biopsy, and she was referred to our hospital. Mammography revealed an indistinct mass with calcification in the lower outer quadrant of the right breast. Ultrasonography revealed a hypoechoic mass with a high echo spot. Magnetic resonance imaging (MRI) revealed a high intensity tumor with peripheral enhancement. The patient underwent mastectomy with sentinel lymph node(SN) biopsy and axillary lymph node dissection. Histologically, the tumor was composed of a solid-tubular carcinoma with a centrally located metaplastic cartilaginous element. There was an abrupt transition between these components, without intervening spindle cells or osteoclastic cells. Subtyping via immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) demonstrated that the tumor was triple negative (TN). The histological diagnosis was matrix-producing carcinoma (MPC). Adjuvant chemotherapy was administered, and she has been recurrence-free. MPC has unique features, such as emphasis of the peripheral zone of the tumor by using contrast enhanced-computed tomography (CT) and gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) MRI. Most cases of MPC that have been reported were TN. The 5 year survival rate for MPC is poorer than that for breast cancer. In Japan, 7 cases of MPC recurrence have been reported within 2.5 years, suggesting that careful follow-up is necessary for 2-3 years after surgery. PMID- 25731383 TI - [Four cases of malignant primary breast lymphoma]. AB - Primary malignant lymphoma of the breast (PBL) is comparatively rare in Japan.Herein, the authors present report 4 cases of PBL. All patients had the primary finding of a palpable left breast mass.Malignant lymphoma was strongly suspected by core needle biopsy, and final diagnosis was made on surgical specimens. All cases were diffuse large B-cell lymphoma and were treated with targeted chemotherapy with R-CHOP. Only 1 of the 4 patients needed multidisciplinary therapy due to advanced age.Whenever PBL is suspected, targeted therapy should be considered. PMID- 25731384 TI - [A case of parathyroid adenoma with oxyphil cells]. AB - A 56-year-old woman who was undergoing dialysis for renal failure that occurred 4 years previously was identified with hypercalcemia and high levels of intact parathyroid hormone (iPTH), as observed on blood analysis results. Blood analysis also indicated high levels of Ca (12.7 mg/dL) and parathyroid hormone (PTH 1,280 ng/mL). Secondary hyperparathyroidism was suspected to be the cause of hypercalcemia. Cervical neck ultrasonography revealed a 13-* 4-mm hypoechoic mass in the lower left pole of the thyroid gland. Tc-99 metaiodobenzylguanidine (MIBG )imaging revealed aberrant accumulation at the lower region of the left accessory thyroid. Cervical neck computed tomography revealed a 12-mm mass at the inferior pole of the left thyroid gland. Considering the above observations, a diagnosis of lower left parathyroid adenoma was made. Lumpectomy was performed, and the final pathology report indicated oxyphilic adenoma. Chief cells are often observed in parathyroid adenoma, but, to our knowledge, this is the first case of a parathyroid adenoma with oxyphil cells. PMID- 25731385 TI - [Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer]. AB - Nanoparticle albumin-bound paclitaxel (nab-PTX, Abraxane(r)) does not require premedication, and it can be used for patients with alcohol intolerance. We administered nab-PTX to 31 patients with breast cancer between October 2010 and April 2013. Eighteen patients had progressive, recurring breast cancers and 13 patients had locally advanced operable breast cancers. The treatment schedules were 175 or 260 mg/m2 every 3 weeks (q3w). No patient experienced an allergic reaction. Grade 1-3 sensory neuropathies were observed in 20 patients; however, no patient experienced grade 4 neuropathy. In patients with locally advanced, operable breast cancer, 1 patient treated with 175 mg/m2 q3w had a partial response (PR), while of the patients treated with 260 mg/m2 q3w, 10 patients showed a PR, and 1 patient had stable disease (SD). Of the patients with progressive, recurring breast cancer, 2 patients showed a PR and 4 patients had SD when treated with 175 mg/m2 q3w, whereas 1 patient displayed a PR and 1 patient had SD when treated with 260 mg/m2 q3w. Our investigation suggests that nab-PTX is well tolerated, even by patients with advanced breast cancer. PMID- 25731386 TI - [Eribulin chemotherapy after taxane treatment in advanced metastatic breast cancer]. AB - Clinical outcomes, including adverse events, in 52 advanced breast cancer patients treated with eribulin chemotherapy after taxane treatment (TX) were analyzed to confirm the effectiveness and safety of this treatment.The objective response rate (ORR) in patients was 34.6% (TX group 31.6%, non-TX group 36.4%). There were no significant differences in overall survival, time to treatment failure, or progression-free between three TX and non-TX groups. Further, adverse events did not differ between groups expression of neutropenia of Grade 3 or more. On the other hand, the number of patients with sensory peripheral neuropathy of Grade 1 or more was significantly more in the TX group than in the non-TX group. Eribulin chemotherapy was effective for the treatment of advanced breast cancer regardless of a history of taxane treatment.In addition, sensory peripheral neuropathy is a possible complication that can occur in advanced breast cancer patients treated with eribulin chemotherapy with taxane treatment history. PMID- 25731387 TI - [A complete response following treatment with Paclitaxel and bevacizumab for metastatic breast cancer]. AB - A 60-year-old woman with left breast cancer underwent partial mastectomy and sentinel lymph node biopsy. Pathological examination revealed an invasive ductal carcinoma that was ER (+), PgR (-), HER2 (-), and node positive (1/1). She received adjuvant chemotherapy with doxorubicin and cyclophosphamide (AC), followed by weekly paclitaxel (PTX). After receiving radiation therapy, she was administered an aromatase inhibitor for 5 years. Six months after completion of therapy, she found a hard lymph node in the left infraclavicular area. Fine needle aspiration cytology of the lymph node indicated metastatic breast cancer. Fulvestrant was administered but disease progression was observed after 3 months. Systemic chemotherapy with PTX and bevacizumab (Bev) was begun. After 3 cycles of chemotherapy, computed tomography (CT) scan revealed a complete response (CR). After 6 cycles of chemotherapy, the CR has been maintained. PMID- 25731388 TI - [A case of bone marrow carcinomatosis with disseminated intravascular coagulation arising from breast cancer successfully treated with paclitaxel plus bevacizumab]. AB - We report a case of bone marrow carcinomatosis with disseminated intravascular coagulation (DIC) originating from metastatic breast cancer that was treated with paclitaxel plus bevacizumab. A woman in her 30s was diagnosed with bone marrow carcinomatosis arising from metastatic breast cancer 2 years previously. Pathologically, estrogen receptor (ER) and progesterone receptor(PgR) / -positive and human epidermal growth factor receptor 2(HER2/neu)-negative scirrhous carcinoma was diagnosed. She improved after treatment with paclitaxel plus bevacizumab and zoledronic acid. Subsequently, she was treated with hormonal therapy(tamoxifen plus luteinizing-hormone-releasing hormone [LH-RH]agonist) for 7 months. Because progressive bone metastasis was identified and tumor markers increased, the patient was administered paclitaxel plus bevacizumab again. Fifteen days after chemotherapy was initiated, DIC developed. Chemotherapy was continued without decreasing the dose, and recombinant human soluble thrombomodulin (rTM) was added. The DIC resolved in 5 days. After 6 courses of paclitaxel plus bevacizumab, improvement of tumor markers and bone metastasis was observed. Paclitaxel plus bevacizumab can be effective for treatment of bone marrow carcinomatosis with DIC originating from metastatic breast cancer. PMID- 25731389 TI - [Long-term control of stage IV breast and gastric cancer with combination therapy of S-1 and paclitaxel]. AB - We here describe a case of Stage IV breast and gastric cancer in which S 1/paclitaxel therapy was effective in maintaining the patient's QOL. A 50-year old woman visited our hospital with complaints of her right breast tumor and right brachialgia. She was diagnosed with breast cancer with multiple bone metastases including cervical vertebrae. Accordingly, local radiation therapy and tamoxifen(TAM)administration was started immediately. Gastrointestinal endoscopy revealed gastric cancer, but laparotomy disclosed the gastric cancer was unresectable. At that time, the complaints of pain, nausea, and fatigue had increased and S-1/paclitaxel therapy was started immediately. The treatment reduced the size of the lesions in the breast and stomach and improved the QOL without serious adverse events. We have been maintaining partial response(PR)in this patient for 28 months. PMID- 25731390 TI - [Two cases of esophageal variceal rupture associated with chemotherapy for liver metastasis of breast cancer]. AB - A morphological change resembling liver cirrhosis called pseudocirrhosis may be observed following chemotherapy for liver metastasis of breast cancer. Pseudocirrhosis is hypothesized to be caused by retraction of the hepatic capsule along with tumor shrinkage and subsequent scar formation around the metastatic lesion, as a response to the infiltrating tumor or chemotherapy-induced hepatic injury. The progression of cirrhotic changes may result in portal hypertension and esophageal varices. We managed two cases of esophageal variceal rupture during chemotherapy for breast cancer with liver metastasis. Hemostasis was successfully achieved by the endoscopic variceal ligation technique in both cases. We conclude that clinicians should be aware of the risk of pseudocirrhosis during chemotherapy for liver metastasis, and a periodic endoscopic follow-up is recommended along with appropriate management of esophageal varices. PMID- 25731391 TI - [Synchronous and ipsilateral invasive ductal carcinoma of the breast occurring near a phyllodes tumor - a case report]. AB - We report 2 cases of invasive ductal carcinoma of the breast occurring near a phyllodes tumor. The first case was ofa 58- year-old woman who had a tumor in her right breast and visited our hospital. Following a core needle biopsy (CNB), a malignant phyllodes tumor was diagnosed. We performed a lumpectomy for the phyllodes tumor, with 1.5-cm surgical margins. Pathological diagnosis of the resected specimen confirmed the malignant phyllodes tumor. A ductal carcinoma in situ (DCIS) was also discovered near the phyllodes tumor. The second case was of another 58-year-old woman who had a big tumor in her right breast and visited our hospital. CNB resulted in pathological diagnosis ofa benign phyllodes tumor. The tumor was removed by a lumpectomy with 1.5-cm surgical margins. The pathological diagnosis from the resected specimen was borderline phyllodes tumor with invasive ductal carcinoma in the proximity. In both cases, DCIS could not have been diagnosed preoperatively. PMID- 25731392 TI - [A case of locally advanced breast cancer that responded to preoperative chemotherapy]. AB - A 51-year-old woman presented with a huge tumor in the left breast. The tumor occupied the whole breast, accompanied with a 10-cm wide red discoloration of the skin, subsequently followed by a massive axillary lymph node metastasis. The patient was diagnosed with locally advanced breast cancer, graded as T4cN2aM0, StageIIIB. After preoperative chemotherapy, even though the tumor could not be observed on a CT scan, it was assumed to persist in the skin as discoloration was observed. Bt+Ax+Mj+Mi(level 1+2) and a full-thickness skin graft transplantation were performed. Pathological findings revealed a benign remnant of the active cancer in the skin. Four months after the operation, local recurrence was observed in the skin of the chest wall. Therefore, radiotherapy was performed. PMID- 25731393 TI - [Sentinel lymph node biopsy in male breast cancer - a case report]. AB - We report a case of breast cancer in a man who underwent sentinel lymph node biopsy (SLNB). The patient, a 66-year-old man, observed a tumor under his left areola. The elastic hard tumor had a clear border. Ultrasonography revealed a hypoechoic tumor, approximately 18 mm in diameter, in the left subareolar and outer upper region. On fine needle aspiration cytology (FNAC), the tumor was diagnosed as a ductal carcinoma. The patient underwent a mastectomy (Bt) and an axillaryly mph node dissection(Ax)after the SLNB. The SLNB was performed with the blue dye alone. Based on histopathological observations, estrogen receptor (ER)- and progesterone receptor (PgR)-positive invasive micropapillary carcinoma was diagnosed. The human epidermal growth factor receptor 2(HER2) score was 1+, and Ki-67 labeling index was 30%. Lymph node metastasis was not seen in SLNB (0/1) and Ax (0/13). Postoperatively, the patient received oral tamoxifen therapy. There was no evidence of recurrence during the 9-month follow-up. In this case, computed tomographic (CT) lymphography (CTLG) and SLNB were performed successfully, without incident. We recommend SLNB in cases of male breast cancer with clinically negative nodes. PMID- 25731394 TI - [Identification of the primary lesion in a patient with concomitant breast and kidney cancer following fracture of the femur]. AB - A 61-year-old woman was diagnosed with breast cancer [T3N3cM0: Stage IIIC, estrogen receptor [ER] (+), progesterone receptor [PgR] (+), human epidermal growth factor receptor 2[HER2] (-)]at the time of initial presentation. Following diagnosis, combined modality therapy including hormone therapy and chemotherapy were initiated, but hemorrhage from the primary lesion and bone metastases were observed. Priority was given to treatment of the breast cancer, and chemotherapy was administered, after which, right mastectomy and axillary lymph node sampling were performed to assess local disease control. In addition, concurrent right kidney enucleation was performed for a renal lesion. The renal neoplasm was diagnosed as T1aN0M0, Stage I. After this intervention, treatment of the breast cancer was continued, but pain of the right femoral region developed, and bone metastasis was diagnosed on close inspection. The bone metastasis was considered to derive from the breast cancer. During hospitalization, the patient fell and broke her right femur. Open reduction and internal fixation was performed immediately, and bone metastasis of kidney cancer was diagnosed via perioperative cytodiagnosis. Pulmonary metastasis, local recurrence, and metastasis to the shoulder blade have been detected. The metastases are considered to derive from the breast cancer, for which treatment has been continued. In the case of concomitant cancers, biopsy for metastatic foci can be considered essential, whenever it can be performed safely. PMID- 25731395 TI - [Synchronous male bladder cancer and breast cancer - a case report]. AB - A 74-year-old man complained of blood in his urine over a 1-week period beginning in early October 2013, and was examined in the urology department of our hospital. A thorough examination revealed bladder cancer, and surgery was planned after two cycles of preoperative gemcitabine plus cisplatin chemotherapy. A chest computed tomography (CT) performed to evaluate the response to chemotherapy revealed a mass in the right breast. The patient had previously complained about the same site, and mammography and ultrasonography had suggested the possibility of a malignant mammary gland tumor. The results of aspiration cytology were Class V, and based on that finding, a diagnosis of cancer of the right breast was made. In February 2014, we performed a mastectomy, while preserving the pectoral muscles, along with sentinel node biopsy, total cystectomy, urethrectomy, pelvic lymph node dissection, and ureteroileal anastomosis. The histopathological diagnosis of the right breast tumor was invasive ductal carcinoma[scirrhous carcinoma, ly (+), v (-), g (+), f (+), s (+), nuclear grade 1=atypia 2+mitosis 1, EIC (-), ICT (-), NCAT (-)]. A micrometastatic tumor measuring approximately 1mm was observed in the sentinel lymph node. The breast disease was classified as pT1N1mi(sn)M0, Stage IIA, and the tumor was ER (+), PgR (+), HER2/neu (2+), and FISH (-). The bladder cancer was diagnosed as urothelial carcinoma, non papillary, invasive G2>G3, pT2a; no pelvic lymph node metastases were detected, and it was classified as pT2aN0M0, Stage II. Synchronous male breast cancer and bladder cancer is a very rare condition, and we report the case with a review of the literature. PMID- 25731396 TI - [Determination of treatment strategies for a 43-year-old single woman with Stage IV breast cancer]. AB - The patient was a 43-year-old single woman. Her family history included schizophrenia in her mother and manic-depression in her father. Remicade(r) (infliximab) had been administered for 3 years to treat rheumatoid arthritis. The patient initially presented to our hospital with dyspnea. Computed tomography revealed left-sided breast cancer associated with multiple bone tumors and multiple pulmonary nodules. A poorly mobile mass with an ulcer was found in left breast. Core-needle biopsy and fluorescent in situ hybridization (FISH)revealed an invasive ductal carcinoma that was positive for estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2, 2 +). The clinical diagnosis was Stage IV T4bN3M1 cancer (metastases to the lungs, liver, and bone). Because of the presence of bone metastasis, the patient was admitted and she received complete bed rest as supportive therapy. However, the patient decided to receive treatment on an outpatient basis after carefully discussing the following points: 1) treatment of pulmonary metastasis with dyspnea should receive priority; 2) anticancer agents not causing nausea were required; 3) the risk of bone fractures as a complication (spinal cord injury); 4) how she wanted to spend the limited time available with her family; and 5) how the patient wanted to. PMID- 25731397 TI - [Total pharyngolaryngoesophagectomy with free jejunal transfer for a patient who previously underwent distal esophagectomy with gastric tube reconstruction via a posterior mediastinal route]. AB - The patient in this case study was a 71-year-old male who underwent distal esophagectomy with gastric tube reconstruction via a posterior mediastinal route for esophageal cancer 12 years previously. An endoscopy revealed a hypopharyngeal tumor in the right piriform fossa, and the histopathological diagnosis, based on a biopsy sample, was squamous cell carcinoma. Preoperative angiography of the right gastroepiploic artery revealed poor blood flow in the remnant esophagus. First, the adhesion of the gastric tube to the surrounding tissue was dissected via a right thoracotomy. Then, the gastric tube was raised using a cervical approach, and total pharyngolaryngoesophagectomy with free jejunal transfer was performed. The patient was discharged 28 days after the operation without complications. We report a patient with hypopharyngeal cancer who had previously undergone distal esophagectomy with gastric tube reconstruction via a posterior mediastinal route upon whom we successfully performed a total pharyngolaryngoesophagectomy with free jejunal transfer. In such a case, it is important to carefully decide the surgical approach in order to prevent anastomotic leakage. PMID- 25731398 TI - [Self-expanding antireflux stents for malignant esophageal stenosis - a report of three cases]. AB - Use of a standard open stent or self-expanding metal stent for patients with malignant dysphagia is associated with a risk of gastroesophageal reflux especially when placed across the esophagogastric junction. We report 3 cases of malignant esophageal stenosis treated with a long cover-type Niti-STM stent with an antireflux mechanism. Case 1: A 87-year-old man presented with dysphagia due to esophageal cancer at the middle thoracic esophagus. Two months after surgery using a standard open stent, the dysphagia relapsed because of tissue overgrowth. Case 2: A 73-year-old woman presented with lung cancer and severe dysphagia due to enlarged mediastinal lymph nodes. Case 3: A 66-year-old man presented with dysphagia due to esophageal cancer at the lower thoracic esophagus. All 3 patients received an antireflux stent across the esophagogastric junction. In cases 1 and 2, dysphagia was relieved immediately without complications. In case 3, the patient experienced severe reflux and chest pain associated with stent placement and could not ingest any solid food. We conclude that the antireflux stent may be useful for palliation in patients with severe malignant esophageal obstruction; however, patients should be informed about the risk of failure to prevent reflux. PMID- 25731399 TI - [High BMI does not influence short- and long-term outcomes of patients with esophageal cancer treated with esophagectomy]. AB - The aim of this study was to clarify the influence of a high body mass index (BMI) on short- and long-term outcomes of patients after esophagectomy for cancer. PATIENTS AND METHODS: A total of 164 patients with a BM >= 18.5 who underwent esophagectomy for cancer from July 2008 through March 2013 were enrolled. Patients were divided into 2 groups according to BMI: BMI<5 (normal BMI group) and BM >= 25 (high BMI group). Further, the short- and long-term outcomes after esophagectomy were retrospectively analyzed. RESULTS: The median BMI was 21.6. The high BMI group (n=26) had significantly more histological adenocarcinomas than the normal BMI group (p=0.003). Other clinicopathological factors such as the type of surgery performed, R0 resections, and perioperative complications, were not influenced by the BMI. There were no significant differences between the 2 groups in the 3-year disease-free rates and 3-year overall survival rates. CONCLUSIONS: Esophagectomy for patients with a high BMI is acceptable based on the similar short- and long-term outcomes when compared with normal BMI patients. PMID- 25731400 TI - [Continuous dissection of the posterior mediastinal and abdominal lymph nodes using a laparoscopic transhiatal approach for esophageal cancer]. AB - We began performing laparoscopic transhiatal esophagectomies in patients with esophageal cancer in 2009. By June 2014, 172 patients had undergone this procedure. The main advantage of this method was that the dissection of the posterior mediastinal and abdominal lymph nodes(LNs)could be performed continuously under a magnified videoscopic view. An abdominal wall sealing device was placed in the upper abdomen, and 4 ports were inserted. The esophageal hiatus was opened, and carbon dioxide was introduced into the mediastinum. The posterior plane of the pericardium was separated and extended, and the anterior side of each posterior mediastinal LN was separated. The thoracic aorta's adventitia was exposed, and the posterior sides of the LNs were then separated. While lifting the LNs like a membrane, they were resected along the border of the left mediastinal pleura. Subsequently, dissection of the posterior mediastinal LNs was extended towards the caudal side from the crural diaphragm to the celiac artery. Thus, the LNs along the celiac and left gastric artery were dissected en bloc from the left side. Our surgical procedure allowed good views during surgery, and the continuous dissection of the posterior mediastinal and abdominal LNs was performed safely. PMID- 25731401 TI - [Esophagectomy after endoscopic submucosal dissection (ESD)]. AB - Herein, we report 9 patients who underwent esophagectomy after endoscopic submucosal dissection (ESD) between April 2003 and December 2013. All patients were men, with a mean age of 65 years. En bloc ESD was performed, and no complications arose in any patient. The mean surgical time of esophagectomy was 323 minutes, and mean blood loss was 295 mL. Postoperative complications were present in 5 patients(anastomotic leakage in 3, pulmonary complications in 2, and recurrent laryngeal nerve palsy in 1). In a patient diagnosed with pT1b-SM1 disease after ESD, a residual tumor(pT1a-MM, N0) was detected after esophagectomy. In another patient diagnosed with pT1b-SM2 disease, lymph node metastasis was detected after esophagectomy. In all patients, curative resection was performed, and no recurrences have been observed to date. This highlights the importance of additional esophagectomy after ESD for patients with pT1b disease. Esophagectomy after ESD can be considered a valid treatment because it provides high curative rates with acceptable safety. PMID- 25731402 TI - [Analysis of thoracic esophageal squamous cell carcinoma with single lymph node metastasis]. AB - BACKGROUND: We studied cases with single lymph node metastasis from thoracic esophageal squamous cell carcinoma. METHODS: We reviewed the site of nodal metastasis in 73 cases with a single metastatic site. RESULTS: The lymph node metastases of the upper thoracic cases were located in the cervical, superior mediastinal, middle mediastinal, lower mediastinal, and abdominal lymph nodes in 5, 10, 3, 0, and 0 cases, respectively. The lymph node metastases of the middle thoracic cases were located in the cervical, superior mediastinal, middle mediastinal, lower mediastinal, and abdominal lymph nodes in 1, 18, 6, 0, and 11 cases, respectively. The depth of tumor in the middle thoracic case that had metastasis in a cervical lymph node was T1b, and the location of the metastatic lymph node was number 104 L. The lymph node metastases of the lower thoracic cases were located in the cervical, superior mediastinal, middle mediastinal, lower mediastinal, and abdominal lymph nodes in 0, 2, 2, 4, and 11 cases, respectively. The depth of tumor in the lower thoracic cases with metastasis in a superior mediastinal lymph node was T1b and T4. CONCLUSION: Even in superficial thoracic esophageal squamous cell carcinoma cases, distant metastasis was observed at an early stage. Therefore, the range of lymph node dissection should be decided carefully in these cases. PMID- 25731403 TI - [A case of salvage surgery for gastric wall recurrence of esophageal cancer after chemoradiotherapy]. AB - The patient was a 69-year-old man. He underwent chemoradiotherapy for advanced esophageal cancer, and achieved a complete response. However, 16 months after chemoradiotherapy, lymph nodes metastases were detected along the celiac artery. He underwent chemotherapy followed by radiotherapy. Positron emission tomography (PET)-computed tomography (CT) at 3 months after radiotherapy showed new uptake of fluorodeoxyglucose (FDG) at the cardiac region of the stomach. Endoscopy revealed a tumor that was diagnosed as squamous cell carcinoma by biopsy. Under the diagnosis of gastric intramural recurrence of esophageal cancer, he was referred to our hospital. Proximal gastrectomy and resection of lymph nodes along the celiac artery were performed. The patient is alive without recurrence 1 year after surgery. Metachronous gastric intramural recurrence of esophageal cancer is very rare. We report this case with a review of the literature. PMID- 25731404 TI - [Long-term survival of a patient with esophageal cancer with brain metastasis after multidisciplinary therapy - a case report]. AB - A 70-year-old woman was admitted for difficulty in swallowing. Esophageal cancer (MtLt, type 3, T4N3M0, cStage IVa) was diagnosed in May 2010. The cancer was unresectable, and chemoradiotherapy (CRT) with TS-1 was initiated in June 2010, and a partial response (PR) was observed. After CRT, TS-1 was continued, but a brain metastasis was detected owing to the development of right hemiplegia in April 2012. Craniotomy and tumorectomy were performed, and the right hemiplegia improved. Pathological examination of the brain tumor indicated squamous cell carcinoma. Because of a recurrence of brain metastasis, a gamma knife procedure was performed in May 2012. Subsequently, several recurrences of brain metastases were diagnosed, and a total of 7 gamma knife procedures were performed up to January 2014. Although systemic chemotherapy (5-fluorouracil and cisplatin [FP], 5 courses)was administered, the patient showed progressive lung metastases in February 2013. The chemotherapy regimen was changed from FP to docetaxel (TXT), but the lung metastases continued to progress up to June 2013. The patient died in March 2014. Patients with esophageal cancer and metastases to the brain have poor prognosis, but the present patient survived approximately 2 years after first diagnosis of metastases to the brain after multidisciplinary therapy. PMID- 25731405 TI - [Treatment outcomes of patients with cervical lymph node recurrence after esophagectomy for esophageal cancer]. AB - Herein, we report the treatment outcomes of patients with limited cervical lymph node recurrence after esophagectomy for esophageal cancer. Between April 2010 and December 2013, 8 patients with cervical lymph nodes recurrence were diagnosed and treated in our department. All patients were detected with recurrent disease by using positron emission tomography computed tomography(PET-CT), and among these, 5 patients had solitary node recurrence. Initial treatments were irradiation therapy in 5 patients and lymphadenectomy in 3 patients. Four of 5 patients underwent irradiation therapy and lymphadenectomy. Four of 5 patients with solitary node recurrence are still alive without relapse of disease. In conclusion, PET-CT can be useful for early detection of recurrent disease after esophagectomy. Appropriate therapy for patients with solitary cervical lymph node recurrence is associated with long-term survival after recurrence. PMID- 25731406 TI - [A case of esophageal cancer with lung metastases successfully resected after chemotherapy]. AB - Herein, we report a case of esophageal cancer with lung metastases that was successfully resected after chemotherapy. A 61-year-old man was diagnosed with a middle thoracic esophageal squamous cell carcinoma showing lung metastases. The clinical Stage diagnosis was T4NxM1, Stage IVb. After systemic chemotherapy with 1 course of cisplatin/5-fluorouracil (CDDP/5-FU)and 3 courses of nedaplatin/5-FU (CDGP/5-FU), lung metastases could not be detected by using computed tomography (CT). We added 2 courses of CDGP/5-FU, followed by 3 courses of docetaxel. The patient underwent esophagectomy and was alive without recurrence for 6 months after surgery. PMID- 25731407 TI - [A long-term survivor of cT4 esophageal carcinoma treated via a multimodal approach - a case report]. AB - The patient was a 53-year-old man whose chief complaint was dysphagia. Pretreatment examination revealed 2 types of locally advanced esophageal squamous cell carcinoma at the middle to lower thoracic esophagus. A computed tomography (CT) scan showed a bulky primary tumor suspicious of aortic invasion and cardiac lymph node metastasis. The pretreatment diagnosis was cT4N2M0, cStageIVa. After induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (CDDP) (the FP regimen) according to the JCOG9907 regimen, subtotal esophagectomy and 2-field lymphadenectomy with retrosternal stomach roll reconstruction were performed. Intraoperatively, the primary tumor showed extensive and firm adhesion to the aortic wall. The postoperative diagnosis was pT4N0M0, pStageIII, RM1. Postoperative chemoradiotherapy (65 Gy+FP) was performed for the residual tumor at the aortic wall. The patient is alive without recurrences 4 years and 6 months after the esophagectomy. Downstaging of the tumor with induction chemotherapy and effective local control with surgery and postoperative chemoradiotherapy may have contributed to the patient's long-term survival. For multimodal treatment of cT4 esophageal cancer, an effective combination of chemotherapy, surgery, and chemoradiotherapy is essential to improve the treatment outcome. PMID- 25731408 TI - [A case of advanced esophageal cancer with direct bronchial invasion successfully treated by multidisciplinary therapy]. AB - A 66-year-old man with advanced esophageal cancer (staging Mt, 6.0 cm, cT3N0M0, cStage II) was administered neoadjuvant chemotherapy (NAC: 5-fluorouracil and cisplatin). As the tumor continued to grow after one course of NAC, video assisted thoracoscopic surgery(VATS) was used to perform an esophagectomy along with 3-field lymph node dissection and retrosternal route reconstruction using a gastric tube. The second course of NAC was not administered. Intraoperative findings showed the direct invasion of the primary esophageal cancer into the membranous portion of the left bronchus. The maximum possible tumor tissue was resected and removed. The tumor tissue was exposed extensively to the surface of the esophageal adventitia and a residual tumor at the surface of the left bronchus was suspected. It was diagnosed as CT-pT4 (left bronchus), N0, M0, CT pStage III. Subsequently, we administered chemoradiotherapy consisting of weekly low-dose docetaxel with radiation for the residual tumor (60 Gy/30 Fr). The patient is still alive 40 months after surgery without any signs of recurrence. PMID- 25731409 TI - [Stage IV small cell esophageal carcinoma that responded to various chemotherapeutic regimens with relative longevity - a case report]. AB - Small cell carcinoma of the esophagus is reported to be both rare and aggressive, and is commonly associated with a short post-diagnosis survival period. We report a case of Stage IV small cell carcinoma of the esophagus involving a relatively long survival period of 2 years. The patient was a 70-year-old man with a chief complaint of epigastric discomfort. Upper gastrointestinal endoscopy by a local physician showed a protruding tumor at the mid-thoracic esophagus. Tumor biopsy revealed small cell carcinoma. Chest-abdominal computed tomography revealed multiple liver metastases, and swelling of a number of regional lymph nodes. The diagnosis was cT3N4M1, cStage IVb esophageal small cell carcinoma. According to the regimen used for lung small cell carcinoma, we administered CDDP/CPT-11. After administration of four courses, the primary lesion, liver metastases, and lymph node metastases significantly reduced, indicating a partial response. However, after completion of eight courses, liver metastasis and lymph node swelling recurred. The patient subsequently received other therapeutic regimens such as CBDCA/VP-16, AMR, NGT, and CDGP/5-FU. However, the tumor gradually progressed, and the patient died approximately 2 years after the first treatment. PMID- 25731410 TI - [Long-term survival of a patient with esophageal metastasis from breast cancer treated with esophagectomy]. AB - Esophageal metastasis from breast cancer is rarely observed. We encountered a case of long-term survival after esophageal metastasis from breast cancer that was treated with esophagectomy. A 79-year-old woman developed dysphagia 26 years after radical mastectomy. Endoscopic examination revealed stenosis at the mid thoracic esophagus. An esophageal biopsy led to a diagnosis of undifferentiated cancer. A computed tomography (CT) scan revealed a massive tumor in the esophagus, but no distant metastases. Esophagectomy was performed with the suspicion of primary or metastatic esophageal cancer. Histopathologically, the excised tumor was an adenocarcinoma, which had histopathological features similar to that of the breast cancer. Accordingly, the adenocarcinoma was diagnosed as esophageal metastasis of the breast cancer. The patient is still alive 8 years after the esophagectomy. PMID- 25731411 TI - [Carcinosarcoma of the esophagus - a case report]. AB - The patient was a 79-year-old male complaining of fever, loss of appetite, cough, and a feeling of obstruction when swallowing. He was diagnosed with pneumonia and admitted as an emergency case the same day. Because an esophagus space-occupying lesion was observed on chest computed tomography(CT), in addition to evidence of pneumonia, an upper gastrointestinal endoscopy was performed. A tumor, protruding into the lumen of the esophagus, was seen in the midesophagus, 25-30 cm from the incisors. Because of the narrow lumen, only a fine caliber fiber could be passed. Biopsy results indicated only necrotic tissue, and a repeat biopsy was performed, with similar histological findings. No esophagobronchial fistulas were observed during bronchoscopy. We therefore diagnosed the patient with aspiration pneumonia, secondary to esophageal narrowing by a tumor. A preoperative diagnosis of cancer could not be made, and no distant organ metastasis was detected, but surgery was indicated because of the narrowing of the esophagus, regardless of the possibility of cancer. After the pneumonia improved, total thoracic esophagectomy was performed through a right thoracolaparotomy, plus a 3- region cervico-thoraco-abdominal lymph node dissection. Pathological examination of the surgical specimen revealed autolysis of the superficial layer with progression to necrosis and associated inflammation. The majority of the tumor was composed of spindle-shaped atypical cells, but because a very small transitional area between squamous cell carcinoma and sarcoma was noted, a diagnosis of carcinosarcoma was made. Depth of invasion was sm3, and no regional lymph node metastasis was detected. The patient's disease was classified as pT1b(sm3)N0M0, StageI. No definite diagnosis was made preoperatively. Although carcinosarcoma of the esophagus is rare, the endoscopic findings are characteristic. We report this case with a review of the literature. PMID- 25731412 TI - Clinical analysis of esophageal cancer patients with a history of metachronous primary cancer. AB - Esophageal cancer (EC) is often associated with multiple primary cancers, and the frequency of EC in patients with a history of metachronous primary cancers (HMPC) was reported as 7.8%. The clinical characteristics of these cases have not yet been elucidated in detail. Therefore, we analyzed 36 EC patients with HMPC among 370 cases that underwent curative resection in our hospital between 1996 and 2013. The most frequent HMPC was gastric cancer (36.1%). The group with HMPC was significantly older than the group without HMPC, whereas no significant differences were observed in other background factors. The stomach was used for reconstruction more frequently reconstructed in the group without HMPC (p<.05). No significant differences were observed in surgical complications between the 2 groups (p=0.283). The 5-year overall survival rates were similar between the groups. The safety of surgery for and prognosis of EC patients with HMPC were similar to those of EC patients without HMPC; therefore, curative surgery should be considered for EC patients with HMPC. PMID- 25731413 TI - [A case of metachronous triple cancer treated with a multimodal approach including surgical resection]. AB - We report a patient with metachronous triple cancer of the hypopharynx, esophagus, and tongue. A 37-year-old man with hypopharyngeal cancer underwent hypopharyngolaryngectomy and cervical lymphadenectomy in 1999. Submental lymphadenectomy following adjuvant radiotherapy was performed for lymph node recurrence in 2000. The patient then underwent esophagectomy for esophageal cancer in 2004. Subsequently, the patient underwent 2 partial resections and 1 subtotal resection of the tongue for tongue cancer in 2005, 2007, and 2008, respectively. The pathological findings for each cancer were squamous cell carcinoma. Two rounds of radiotherapy were performed for bone metastasis of the esophageal cancer and for the local recurrence of the tongue cancer. A total of 7 lines of chemotherapy, including superselective arterial infusion chemotherapy, were administered to treat the recurrences. The patient died in 2013, but he showed long-term survival of 13 years from the first operation owing to the multimodality treatment. PMID- 25731414 TI - [Six synchronous primary cancers - a case report]. AB - A 60-year-old man presenting with dysphagia was referred to our hospital with a diagnosis of esophageal cancer and gastric cancer. Upper gastrointestinal endoscopy revealed type 2 tumors in the upper thoracic esophagus and in the lesser curvature of the angular incisure, and elevated lesions in the duodenum and in the transverse colon. Laryngoscopy revealed erosion of the right vocal cord. Computed tomography (CT) of the chest revealed a nodule in the middle lobe of the right lung. Laryngomicro surgery was performed for the right vocal cord erosion, and it was diagnosed as carcinoma in situ. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) were performed for the lesions in the duodenum and in the transverse colon, respectively; the lesions were diagnosed as adenocarcinoma in adenoma. After 2 courses of neoadjuvant chemotherapy with the 5-fluorouracil (5-FU), cisplatin, and Adriamycin (FAP) regimen, subtotal esophagectomy with reconstruction of the pedunculated jejunum through the antethoracic route, total gastrectomy, and resection were performed on the right middle lobe of lung. Pathological examination revealed esophageal cancer (fT4N0M0, fStageIII), gastric cancer (ypT3N0M0, pStageIIA), and primary pulmonary adenocarcinoma (pT1bN1M0, pStageIIA). After surgery, the patient was treated with chemoradiotherapy (60 Gy, with 2 courses of 5-FU plus cisplatin [FP]), and 6 months after the operation, he was in good health without recurrence. PMID- 25731415 TI - [Occurrence of squamous cell lung carcinoma in the irradiated field after radiotherapy for breast cancer]. AB - Radiotherapy for breast cancer reduces the incidence of disease recurrence and breast cancer mortality.However, it has also been associated with an increased risk of developing secondary cancers in exposed sites.Recently, we observed a 64 year-old woman who developed squamous cell lung carcinoma in the field irradiated with a total dose of 55 Gy after conservative breast surgery for left breast cancer 16 years previously.The patient underwent left upper lobectomy combined with chest wall resection.She had no recurrence of the breast cancer for 16 years.The secondary lung cancer tumor was of a different histological type than the primary breast cancer, and it appeared in the irradiated field.In conclusion, we regarded her lung cancer as a radiation-induced cancer, although it is difficult to clearly define radiation-induced cancer.In addition, the patient 's lung cancer may not only be a result of the late effect of irradiation, but might also be due to her smoking habit. PMID- 25731416 TI - Photodynamic therapy for multiple central type lung cancer - a case report. AB - In case of central type lung cancer, it happens that tumors tend to grow at many foci of bronchial tree, sometimes simultaneously and sometimes not. And these patients with such abnormalities often suffer from pulmonary emphysema or chronic bronchitis because of heavy smoking habits. So it is important to choose the treatment which preserve the pulmonary function in these cases. Today among several kinds of treatments, photodynamic therapy (PDT) is the definite method to maintain lung function. We report here a case of multiple central type lung cancer treated successfully by PDT. PMID- 25731417 TI - [Improvement in quality of life by endobronchial electrocautery using snare in a patient with advanced non-small cell lung cancer]. AB - Endobronchial electrocautery using a polypectomy snare may serve as a useful tool for treating patients with airway obstructing polypoid tumors. An 84-year-old man was admitted to our hospital because of an abnormal shadow observed on chest radiography. He was diagnosed with advanced squamous cell carcinoma, located in the right lower lobe of the lung along with metastatic lesions and obstructive pneumonia. He declined systemic chemotherapy because of his age. Endobronchial electrocautery using a polypectomy snare was performed to treat the obstructive pneumonia. The patient's quality of life improved after polypectomy. This was due to an improvement in malaise and a spontaneous decrease in the size of the hepatic metastasis tumor. PMID- 25731418 TI - [Advanced lung cancer with recurrence of liver and tracheal metastases responsive to multimodality therapy - a case report]. AB - We report a case of advanced lung cancer with recurrence of liver and tracheal metastases that were responsive to multimodality therapy. The patient was a 77 year-old man who suffered from advanced lung cancer with chronic obstructive pulmonary disease (COPD) and alcohol-induced liver cirrhosis. The primary lung cancer was surgically resected. Eight months after resection of the primary lung cancer, a solitary liver tumor appeared and hepatic resection was performed. Histological findings showed that both the primary lung tumor and the solitary liver tumor were squamous cell carcinoma (SCC). Subsequently, he developed a recurrence in his trachea 8 months after hepatic resection. Radiotherapy, endobronchial argon plasma coagulation (APC), and systemic chemotherapy were administered. The tracheal tumor remained stable without any liver metastasis for 25 months. PMID- 25731419 TI - [Post-recurrence survival after surgical resection of non-small cell lung cancer with local recurrence]. AB - We retrospectively evaluated the clinical outcomes of 192 consecutive patients with local recurrence after complete resection of non-small cell lung cancer NSCLC). The initial local recurrent site was the resection stump in 5 patients the chest wall in 3 patients, mediastinum in 1 patient, and diaphragm in 1 patient), and the hilar and/or mediastinal lymph node (HMLN) in 17 patients. The sites of distant metastasis were the lungs in 10 patients, pleura in 4 patients, brain in 7 patients, liver in 5 patients, bone in 4 patients, and other sites in 4 patients. Treatments after initial recurrence included surgery in 2 patients, radiotherapy in 5 patients, chemotherapy in 9 patients, and chemo-radiotherapy in 5 patients. Only 1 patient received supportive care. The response to radiotherapy was a complete response (R) in 1 patient, partial response (PR) in 5 patients, stable disease (SD )in 3 patients, and progressive disease (PD )in 1 patient. The best response of all lines of chemotherapy was CR in 3 patients, PR in 4 patients, SD in 3 patients, and PD in 4 patients. The median post-recurrence survival (PRS) time with local recurrence was better than that with distant metastasis (23 vs 14 months); however, the best PRS was obtained in patients with recurrence in the lungs (29 months). A CR for more than 2 years was obtained in 1 patient after surgery, in 1 patient after radiotherapy, and in 2 patients after chemotherapy. Although local recurrence of resected NSCLC can be potentially controlled by using local treatments - such as surgery and radiotherapy - or systemic chemotherapy, curative aggressive treatment should be considered when required. PMID- 25731420 TI - [Long-term survival following resection of primary rectal cancer metachronous metastases and salvage surgeries for relapsed lesions after stereotactic body radiotherapy for lung metastases - a case report]. AB - A 66-year-old man underwent abdominoperineal resection for rectal cancer in 2003, followed by liver resection for a solitary liver metastasis in 2005. In 2006, the patient underwent abdominal para-aortic lymph node dissection, which was performed concurrently with partial resections of 3 metastases in the right lung. New metastatic lesions were subsequently diagnosed in S8 of the right lung and S1+2 of the left lung. The patient underwent stereotactic body radiotherapy (SBRT) for both lesions. However, the lesions relapsed and salvage surgeries were subsequently performed. These included a partial resection in 2009 for the lesion in the right lung and an upper division segmentectomy in 2010 for the lesion in the left lung. Currently, 11 years after resection of the primary rectal cancer, the patient is asymptomatic, without any signs of recurrence. In this report, we describe the use of SBRT for the treatment of colorectal cancer pulmonary metastases, and the use of salvage surgery for relapsed lesions. PMID- 25731421 TI - [Three cases of resected pulmonary metastasis from colorectal cancer after preoperative chemotherapy]. AB - We describe three cases of resected pulmonary metastasis from postoperative colorectal cancer after preoperative 5-fluorouracil, Leucovorin, oxaliplatin (FOLFOX) chemotherapy. The first case is a 38-year-old man who underwent low anterior resection for rectal cancer in 2003. Subsequently, left lung metastasis occurred in February 2009. FOLFOX chemotherapy was administered, resulting in a partial response (PR) of tumor size. Post-chemotherapy, segmental resection of he S1+2 segments of the left lung was performed in May 2009. A pathological diagnosis of Grade 1b was made. The patient remained recurrence-free 5 years post surgery. The second case is a 68-year-old man who underwent left half colon resection for descending colon cancer with left lung metastasis in March 2006. FOLFOX chemotherapy was administered, with a PR of lung metastasis size. Post chemotherapy, a segmental resection of the S4 segment of the left lung was performed in September 2006. A pathological diagnosis of Grade 1b was made. The patient was alive 8 years post-surgery. The third case is a 64-year-old man who underwent low anterior resection for rectal cancer in November 2007. A year later, bilateral lung metastases were detected. FOLFOX+bevacizumab was administered, with a stable disease effect on tumor size. Post-chemotherapy, partial resection of both lungs was performed in March and April 2010. A pathological diagnosis of Grade 1a was made. The patient was recurrence-free at the 4-year follow up. We believe that preoperative FOLFOX chemotherapy may be effective in treating lung metastasis from colon cancer. PMID- 25731422 TI - [A case of hepatic resection after chemotherapy for metastatic colon cancer of the liver with invasion of the inferior vena cava and hepatic vein]. AB - A 61-year-old man presented with lower abdominal pain. Further examination revealed descending colon cancer and multiple liver metastases (S1, S2, and S5). The largest metastatic lesion in S1 showed massive invasion to the inferior vena cava (IVC) and was considered unresectable. Resection of the primary colon cancer was performed in January 2011, followed by several types of systemic chemotherapy(12 courses of capecitabine plus oxaliplatin [XELOX] + bevacizumab[Response Evaluation Criteria In Solid Tumors{RECIST}: PD], 5 courses of folinic acid, fluorouracil, and irinotecan [FOLFIRI] + bevacizumab[RECIST: SD], and 13 courses of FOLFIRI+ panitumumab). After these regimens, the lesions in S1 and S2 substantially decreased in size (RECIST: PR), and the lesion in S5 was no longer visible. The extent of invasion to the IVC significantly reduced, and liver resection(extended left lobectomy)and partial IVC resection were performed in November 2013 without reconstruction of the IVC by using a vascular prosthesis. The patient was discharged uneventfully on postoperative day 16, and administration of tegafur-uracil-Leucovorin (UFT/UZEL) was initiated. After 4 months, a recurrent lesion was found in S5, and partial liver resection was performed. In addition, FOLFIRI+panitumumab was reinitiated for the multiple lung metastases. The patient is alive without progression of disease 3 years and 4 months after colectomy. PMID- 25731423 TI - [Hepatic resection for local recurrence after radiofrequency ablation therapy for colorectal liver metastases]. AB - Patients who underwent hepatic resection of locally recurrent tumors after radiofrequency ablation(RFA)for colorectal liver metastases (CRLM) were retrospectively investigated. Among 12 patients who underwent RFA as first-line treatment for CRLM, 7 experienced local recurrence, 5 of whom (6 nodules) underwent hepatic resection. The mean diameter (range) of the tumors was 9.5(5 16) mm, and they were located at S2, S7 (adjacent to the right hepatic vein), S5/6 (between the root of the anterior and the posterior Glisson's pedicle), S1r (right paracaval portion), S6, and S3. No local recurrence was observed after hepatic resection. In conclusion, hepatic resection must be the initial therapeutic strategy for CRLM, and the indication for RFA must be considered carefully. PMID- 25731424 TI - [Five-year-survival in a case of large synchronous liver metastases from colon cancer treated with local (operation, HAI, RFA, and TAE) and systemic combined therapy]. AB - A 58-year-old woman was suffering from abdominal pain due to large liver metastases(LM)and lung metastasis from sigmoid colon cancer. After laparoscopic sigmoidectomy, three 6 g/wk high dose hepatic arterial infusions(HDHAI)of5 - fluorouracil (5-FU) were administered and the tumor decreased in size. Unfortunately, the patient had an infectious pseudoaneurysm at the site of puncture. She was given a drainage and femoro-femoral(F-F)bypass. At last, a hepatectomy, radiofrequency ablation(RFA), and catheter insertion from gastroepiploic artery, were performed successfully. Subsequently, she received a half HDHAI and several systemic chemotherapy drugs. However, residual liver metastases developed thrice and we operated on all of them. Finally, when the hepatic arterial infusion(HAI)catheter became unavailable, we only continued the systemic therapy (Erbitux+FOLFIRI). However, inoperable residual liver metastases(maximum 13 cm in size)occurred. We chose to administer hepatic transarterial embolization(TAE)therapy 3 times. From the second time, we performed TAE from the right subphrenic artery and in the third time, we added 1 day HAI therapy. Finally, the tumor size decreased(maximum 9 cm). The patient is still an outpatient 5 years after the first HDHAI. PMID- 25731425 TI - [Report of a successful case of multidisciplinary therapy for a patient with lung and liver metastasis from rectal adenocarcinoma]. AB - A strategy of multidisciplinary therapy is considered necessary for the longer survival of a patient diagnosed with advanced colorectal cancer. We report a successful multi-disciplinary therapy case of a 70's-year-old male who received pulmonary resection for metastatic lung cancer twice after primary resection for rectal cancer. Solitary metastatic liver cancer with portal vein tumor thrombus (PVTT) was diagnosed 5 years and 4 months after primary surgery. Although systemic chemotherapy was started immediately, disease control was poor and local pulmonary recurrence appeared. Although intrahepatic metastasis was considered the most important prognostic factor, radiation therapy against PVTT (50 Gy) was initially performed to control disease. After verifying that no new recurrent lesions had arisen during radiation therapy, a third pulmonary resection (in the left upper remnant lobectomy)was performed. Hepatectomy(in the right lobectomy)was then performed for curative purposes. Pathological efficacy of radiation therapy to PVTT was revealed as GradeIb according to Evans' classification. In accordance with the patient's request, no adjuvant treatment was planned. Seven years after primary resection no sign of recurrence is evident. Radiation therapy is suggested to be most useful for disease control and patient selection. PMID- 25731426 TI - [A case of resection of a metastatic liver tumor that recurred after particle beam therapy]. AB - Recently, the indications for particle beam therapy have been expanded to include metastatic liver tumors. However, its adverse effects on the treated liver are unclear, and the possibility of local recurrence after treatment should not be ignored. A 65-year-old man with advanced rectal carcinoma underwent low anterior resection. Resectable metastatic liver tumors were detected after adjuvant chemotherapy; however, he opted to undergo particle beam therapy. Nine months after treatment, a local recurrence was detected around the treated area, and central bisegmentectomy of the liver was performed as a salvage operation. The operation was technically complicated owing to severe adhesions and inflammatory changes in the liver parenchyma around the treated area. Pathological examination revealed advanced liver fibrosis at the treated area, in contrast with normal parenchyma in the untreated area. Although the procedure requires advanced surgical techniques, salvage surgery is a feasible option for recurrent liver tumors after particle beam therapy. PMID- 25731427 TI - [A case report of hepatectomy for liver metastasis of colon cancer after heavy particle radiotherapy]. AB - A 51-year-old female patient was admitted to our hospital with a diagnosis of sigmoid colon cancer, and a sigmoidectomy and D3 lymphadenectomy was performed. The tumor was a moderately differentiated tubular adenocarcinoma (pT3N0M0, pStage II). No adjuvant therapy was administered. An abdominal computed tomography (CT) performed 11 months after the sigmoidectomy revealed a hepatic metastasis. The patient chose to undergo carbon ion radiotherapy (53.0 GyE/1 Fr). However, a second CT performed 10 months later indicated regrowth of the hepatic metastasis. A partial liver resection was performed, and severe deformity was observed in the irradiated region of the liver. The borderline between the tumor and surrounding tissue was not clearly discriminated. Histopathological examinations indicated increased numbers of fibrous cells in the irradiated region. To perform hepatic resection safely for liver metastasis of colorectal cancer following heavy particle radiotherapy, it is necessary to accurately determine the resection line before and during surgery. When feasible, resection of the whole irradiated area should be considered. PMID- 25731428 TI - [A case of combined hepatocellular and cholangiocarcinoma with right-sided ligamentum teres hepatis treated via extended left hepatic lobetectomy]. AB - A 78-year-old man presented with fever and jaundice. Computed tomography (CT) revealed a hepatocellular carcinoma in the hepatic left lobe as well as right sided ligamentum teres (RSLT). Extended left hepatic lobetectomy was performed without division at the left Glissonian root in order to preserve the Glissonian branch at segment 8. No complications occurred during the post-operative course of 13 days. Pathologically, the tumor was diagnosed as a combined hepatocellular and cholangiocarcinoma. Additional congenital variations can exist in RSLT frequently; therefore, we must take care when performing hepatobiliary surgeries. Recently, advanced imaging modalities, such as multi-detector rowcomputed tomography (CT) and magnetic resonance imaging(MRI), help us obtain virtual images of vascular architecture and to plan the operative procedure. PMID- 25731429 TI - [A case of intrahepatic cholangiocarcinoma difficult to distinguish from metastatic liver cancer]. AB - A 65-year-old woman presented to our department with a liver tumor. She had undergone subtotal colectomy and total hysterectomy for hereditary nonpolyposis colorectal cancer and uterine cancer 14 years prior to diagnosis. An abdominal CT scan revealed a ring-enhancing tumor with portal vein tumor thrombus on the left lobe. With a preoperative diagnosis of intrahepatic cholangiocarcinoma, combined hepatocellular and cholangiocarcinoma, or metastatic liver cancer; we performed an extended left hepatic lobectomy. The histopathological examination showed adenocarcinoma of the liver. The histopathological findings of the liver tumor resembled that of the previous uterine cancer. Immunohistochemical testing was positive for CK7 and negative for CK20, CDX2, PgR, vimentin, and CA125. However, PgR, vimentin, and CA125 were positively stained in the uterine cancer. Based on these findings, the final diagnosis of the liver tumor was primary intrahepatic cholangiocarcinoma. PMID- 25731430 TI - [A case of curatively resected advanced intrahepatic cholangiocellular carcinoma through effective response to neoadjuvant chemotherapy]. AB - A 67-year-old-man came to our hospital for further evaluation of a liver tumor detected by abdominal ultrasonography at another hospital. Abdominal computed tomography showed a tumor (8 cm in diameter)in the left lobe of the liver, with invasion of the left and middle hepatic veins, and multiple lymph node metastases. Liver biopsy examination revealed intrahepatic cholangiocellular carcinoma (cStage IVB). Therefore, chemotherapy with gemcitabine(GEM)was administered. The hepatic tumor and multiple lymph nodes were reduced in size after eight courses of GEM chemotherapy. In May 2013, we performed an extended left hepatectomy with biliary tract reconstruction and extended lymph node dissection. The histological diagnosis was intrahepatic cholangiocellular carcinoma, pT3N0H0P0M (-), fStage III. The patient's postoperative recovery was good, and 1 month after surgery, the patient received 6 course of postoperative adjuvant GEM chemotherapy. No serious adverse events occurred during the postoperative adjuvant therapy period. The patient is alive without recurrence 14 months after surgery and 23 months after diagnosis. PMID- 25731431 TI - [A case of curatively resected intrahepatic cholangiocarcinoma with hepatic artery and portal vein reconstruction]. AB - We report a case of curatively resected intrahepatic cholangiocarcinoma (ICC) with hepatic artery (HA) and portal vein (PV) reconstruction. A 25-year-old man was diagnosed with ICC. Computed tomography (CT) showed that the tumor had invaded the left and common hepatic duct, the right and left HA, and the main branch of the PV. Because the posterior HA was tumor free, we performed a left trisegmentectomy, PV and HA resection and reconstruction, and a hepatocholangiojejunostomy. Pathological examination revealed a tumor classification of T3, N1, M0, Stage IVB. The patient was discharged on postoperative day 59 and gemcitabine (1,000 mg/m2) was administered as adjuvant chemotherapy. However, abdominal CT revealed peritoneal metastasis 8 months after the surgery. A gemcitabine, cisplatin, and TS-1 (GCS) regimen was selected as treatment, and the patient is alive 13 months after surgery. PMID- 25731432 TI - [A case of intrahepatic cholangiocarcinoma with peritoneal dissemination treated successfully with surgical resection and adjuvant chemotherapy]. AB - A 72-year-old woman was diagnosed with liver dysfunction during a medical examination. An abdominal computed tomography (CT) scan showed multiple nodules in the left lobe, anterior segment, andposterior segment of the liver, leading to a diagnosis of intrahepatic cholangiocarcinoma (ICC). Extended left lobectomy and partial hepatectomy in the anterior and posterior segment with lymph node dissection was performed. At the time of the operation, small nodules on the peritoneum near the stomach were resected; these nodules were diagnosed as peritoneal disseminations of ICC. The histopathological diagnosis was moderately differentiated tubular adenocarcinoma (T4N0M1, Stage IVB). Adjuvant chemotherapy with S-1 was administered for 18 months. Thirty months after the operation, multiple lung metastases were detected by using CT, and chemotherapy with gemcitabine was initiated. Thirty-six months after chemotherapy with gemcitabine, the patient is alive and at home despite her lung metastases, which grew slightly in size. Herein, we report a long-term survival case of ICC with peritoneal dissemination that was successfully treated with surgical resection and adjuvant chemotherapy. PMID- 25731433 TI - [Two cases of resectable adrenal metastases from hepatocellular carcinoma]. AB - The first case is a 72-year-old man who underwent(palliative)anterior segmentectomy for multiple hepatocellular carcinoma tumors with a maximum diameter of 10 cm at the age of 70 years. The hepatic lesion was well controlled for some time by trans-catheter arterial chemoembolization (TACE). However, left adrenalectomy was performed 17 months after surgery when metastasis to the left adrenal gland was found. The postoperative course was uneventful and he has not experienced recurrence for 7 months. The second case is a 69-year-old man who underwent TACE at the age of 68 years because of multiple hepatocellular carcinoma tumors with a maximum diameter of 15 mm. The hepatic lesion was well controlled for some time. However, a left adrenalectomy was performed at the age of 70 years when metastasis to the left adrenal gland was found. The postoperative course was uneventful and he has not experienced recurrence for 5 months. We investigated 157 additional cases of adrenal metastasis of hepatocellular cancer. Treatments for adrenal metastases included surgical resection, artery embolization, and ethanol injection therapy, but long-term survival was most commonly observed when surgical resection was used. When the primary tumor that metastasized to the adrenal gland was controllable and no other metastases were observed, active resection was indicated. PMID- 25731434 TI - [Three cases of surgical resection of peritoneal recurrence of hepatocellular carcinoma following hepatectomy]. AB - Surgical treatment of peritoneal recurrence (PR) of hepatocellular carcinoma (HCC) is still controversial. We report herein 3 cases of PR treated by surgical resection. Firstly, a 55-year-old woman presented with recurrences in the peritoneum and mediastinal lymph nodes 12 months after hepatectomy for ruptured HCC. After the administration of sorafenib, the mediastinal lesions shrank and the PRs were resected. There has been no recurrence 20 months after PR resection. The second case was of a 56-year-old man with recurrences in the remnant liver and the peritoneum 41 months after hepatectomy for ruptured HCC. The remnant liver lesions were controlled by transcatheter arterial chemoembolization (TACE), and the PRs were resected twice. However, multiple bone and lung metastases developed and the patient died of HCC 73 months after peritoneal resection. In the third case, a 63-year-old man had recurrences in the remnant liver and the peritoneum 78 months after hepatectomy. Remnant liver lesions were controlled by radiofrequency ablation (RFA) and TACE, and PRs were resected. However, the hepatic lesions had progressed and he died 102 months after initial hepatectomy. Based on our observations, patients with PRs who have no other distant metastases and whose intrahepatic lesions are controllable and PRs are completely resectable may have relatively long-term survival. Surgical treatment of PR may also improve the quality of life and prognosis. PMID- 25731435 TI - [Experiences of laparoscopic repeat hepatectomy for recurrent hepatic cancer after open hepatectomy]. AB - We report 3 cases of recurrent hepatic cancer in patients who underwent laparoscopic repeat hepatectomy (LRH). Case 1: A 70-year-old female with ascending colon cancer and liver metastases underwent open right colectomy followed by open S5 resection. Seven months later, the patient experienced a recurrence in the lateral segment and underwent laparoscopy-assisted ( L-A) partial resection. The adhesiolysis around the left liver was performed through a 7-cm upper median incision. Partial resection of the lateral segment was performed by hand-assisted laparoscopic surgery (HALS) using a median incision. Case 2: A 63-year-old female with metachronous liver metastases from rectal cancer underwent open S4a and S5 resection. Nineteen months later, she experienced a recurrence in S4b and underwent an L-A S4b resection. Adhesiolysis around the previous hepatic transection was performed through a small upper median incision. Mobilization of the liver was performed by HALS. A hepatic transection of S4b was also performed in the upper median incision. Case 3: An 80 year-old female with hepatocellular carcinoma (HCC) recurrence in the lateral segment after open S4 resection underwent L-A lateral segmentectomy. An adhesiolysis, mobilization of the liver, and a hepatic transection were performed by HALS and hybrid technique as described in case 2. In a patient with a history of open hepatectomy, LRH may be extensively indicated by utilizing HALS or a hybrid procedure. PMID- 25731436 TI - [Improvement of the viscosity and the intrahepatic distribution of miriplatin lipiodol suspension]. AB - The effects of warming or emulsification with the water-soluble contrast medium, Iomeron (IOM), on reducing the viscosity of miriplatin-lipiodol (MPT-LPD) suspension were studied. Reduction in the viscosity of MPT-LPD suspension was ob- served upon increasing the temperature. Although the O/W MPT-LPD emulsion with a low ratio of MPT-LPD to IOM reduced the viscosity, the effect was lesser than that achieved with the warming treatment. Radiographic images of the liver obtained after administration of the emulsion into the rat portal vein showed that warming resulted in improved intrahepatic distribution of the formulation, which was dependent on the reduction of viscosity. Emulsification also led to better intrahepatic distribution, but this distribution did not depend on the viscosity of the formulation. The MPT-LPD emulsion showed different distribution properties from the MPT-LPD suspension, and it was difficult to estimate the intrahepatic distribution property from the viscosity of the emulsion. Thus, we suggest that emulsification and warming of MPT-LPD are effective methods for improving the intrahepatic distribution of the MPT formulation. PMID- 25731437 TI - [Basic studies on the lipiodolization of miriplatin in combination with CDDP]. AB - Platinum release and initial hepatic toxicity of a formulation containing both miriplatin (MPT) and cisplatin (CDDP), prepared to improve the weak initial effect of MPT-Lipiodol (LPD) suspension, were evaluated. No difference in platinum release from CDDP was found between CDDP-LPD and MPT.CDDP-LPD, which suggested that platinum release was not affected by the viscosity of MPT-LPD. On the day following administration into rat portal vein, drugs suspended in LPD increased liver function values, and these values returned to the previous levels 3 days after administration. Both the CDDP-LPD and MPT. CDDP-LPD groups showed higher liver function values than the MPT-LPD group, and there was little difference in liver function values between the CDDP-LPD and MPT.CDDP-LPD groups. Thus, MPT.CDDP-LPD retains the characteristics of MPTLPD and CDDP-LPD without reducing the effects of either drug or enhancing their side effects. PMID- 25731438 TI - [Long-term survival in a patient receiving multidisciplinary therapy for hepatocellular carcinoma with left iliac bone metastasis]. AB - The patient was a 79-year-old man diagnosed with a single 9.3-cm hepatocellular carcinoma (HCC) in the medial segment of the liver, and left iliac bone metastasis. Initially, the patient was treated with a hepatic arterial infusion of low-dose FP (cisplatin/5-fluorouracil) at another hospital. Here, the patient received particle therapy for the left iliac bone metastasis at a total dose of 52.8 Gy in 4 fractions. Subsequently, he underwent medial segmentectomy of the liver to treat the primary HCC. Eleven months later, the first intrahepatic recurrence occurred, and the tumor was treated with percutaneous radiofrequency ablation (RFA). A second intrahepatic recurrence was detected 39 months later, which was also treated with percutaneous RFA. The patient remains well, with no evidence of tumor recurrence. PMID- 25731439 TI - [Successful treatment of metastatic hepatocellular carcinoma with sorafenib combined with transcatheter arterial chemoembolization/hepatic arterial infusion chemotherapy]. AB - We report the long-term survival of a patient with metastatic hepatocellular carcinoma (HCC), successfully treated with transcatheter arterial chemoembolization (TACE)/hepatic arterial infusion chemotherapy (HAIC) combined with long-term administration of sorafenib. A 74-year-old man underwent hepatectomy for a huge hepatocellular carcinoma, measuring 19 * 13 cm. Multiple intrahepatic HCCs that recurred 5 months post-surgery were treated with TACE. After 3 cycles of TACE, however, sorafenib was administered to treat progressive disease. Six months after sorafenib treatment, TACE combined with sorafenib was administered for treatment of refractory intrahepatic lesions. Following further disease progression, TACE was replaced by up to 11 rounds of HAIC. We report successfully treatment of refractory metastatic HCC with sorafenib for more than 30 months along with a review of the literature. PMID- 25731440 TI - [Clinical evaluation of the risk factors for liver abscess after TACE or RFA]. AB - Radiofrequency ablation(RFA)and transcatheter arterial chemoembolization (TACE) are widely enforced as a standard combined therapy for liver cancer. Liver abscess occurs occasionally as a complication. This clinical study was conducted to determine risk factors for liver abscess. We investigated the clinical background of 10 cases complicated by liver abscess in 957 cases of patients who underwent TACE or RFA for liver cancer at Minoh City Hospital between April 2002 and March 2012. Risk factors for liver abscess were analyzed statistically in comparison to a control group without liver abscess. Diabetes and a history of biliary tract organic disease were statistically significant independent risk factors determined by multivariate analysis. We consider patients with a history of biliary tract organic disease, or who have a potential biliary tract infection, and diabetes, to be susceptible to infection. A case presenting with diabetes and a history of biliary tract disease is in a high-risk group, so treatment with TACE or RFA for such cases should be considered carefully. PMID- 25731441 TI - [A case of resected liver metastasis from rectal cancer with bile duct stricture after radiofrequency ablation]. AB - The patient was a 66-year-old woman who had undergone low anterior resection for rectal cancer. Although she received adjuvant chemotherapy after the surgery, a 1.5 cm hepatic metastasis was observed in segments 4/8. Radiofrequency ablation ( RFA) was performed for the metastatic tumor. Approximately 1 month after RFA, a local recurrence was identified together with intrahepatic bile duct dilation in the right lobe of the liver. Extended right hepatic lobectomy and left intrahepatic cholangiojejunostomy were performed to remove the tumor. Histopathological examination of the resected specimen showed a liver metastasis from the rectal cancer with stricture of the bile duct although the bile duct was not involved in the tumor. This suggested that the bile duct stricture was caused by RFA and not by the recurrent tumor. Currently, the patient is alive with no recurrence 14 months after the surgery. This case suggests the importance of salvage surgery for recurrent tumors after RFA therapy, especially in the case of RFA-related complications in conjunction with the tumor. PMID- 25731442 TI - [Postoperative cholangitis of balloon-occluded transarterial chemoembolization (B TACE) for hepatocellular carcinoma]. AB - In 35 patients who underwent balloon-occluded transarterial chemoembolization (B TACE) for hepatocellular carcinoma (HCC) since January 2013, 5 patients (14%) had postoperative cholangitis, 1 of whom required drainage of a liver abscess. Four of these patients(80%)were treated with cisplatin (CDDP)-epirubicin (EPI) Lipiodol (Lp) emulsion, and 1 was treated with EPI-Lp emulsion.The balloon was located and inflated at the lobar level (C: conventional)in 3 patients (60%) and at the subsegmental or more distal level (SS: superselective) in 2 patients (40%). Chemical vascular damage was considered to cause the cholangitis.We conclude that it is necessary to determine the optimal drug for B-TACE to reduce vascular damage. Miriplatin may be useful because of its lower vascular damage compared with CDDP-Lp and EPI-Lp. PMID- 25731443 TI - [A case of partial hepatectomy and gastrectomy for hepatocellular carcinoma with direct invasion to the stomach]. AB - An 81-year-old man treated with chronic hepatitis C virus (HCV)-related hepatitis and hepatocellular carcinoma (HCC) was diagnosed in 2010 with HCC recurrence (subclass S2) on computed tomography (CT). He refused surgery and was followed up without treatment. In 2012, he was admitted to our hospital because of hematemesis. Gastrointestinal endoscopy revealed a large tumor in the upper gastric corpus, and pathological examination of the tumor revealed HCC; hence, we diagnosed the patient with direct HCC invasion to the stomach. Although active bleeding from the tumor was controlled, he experienced repeated episodes of hematemesis, and the tumor increased in size. Therefore, partial hepatectomy and gastrectomy were performed. It was confirmed that the tumor invaded the stomach wall. Although surgery was effective for gastrointestinal bleeding caused by HCC invasion, the patient died 12 months after surgery because of multiple liver metastases and exacerbated liver failure. PMID- 25731444 TI - [A case of advanced hepatocellular carcinoma successfully treated by liver resection after complete response induced by sorafenib administration]. AB - A 50-year-old man presented to our hospital with the chief complaint of right hypochondriac pain and a palpable tumor. Advanced hepatocellular carcinoma (HCC) and chronic hepatitis B infection were diagnosed and treated by twice-repeated transcatheterarterial chemoembolization (TACE) followed by administration of entecavir. Two months after the last TACE, alpha-fetoprotein(AFP)and protein induced by vitamin K absence or antagonistII (PIVKA-II) levels had elevated, and multiple small early enhancing nodules were detected on computed tomography(CT)scan. Based on his age and liver function (Child-Pugh score A5), a full dose of sorafenib (800 mg/day) was administered. The sorafenib dose was decreased after one month to 400mg/day because of hand-foot syndrome. Following sorafenib administration, the lesions shrank markedly, and complete response (CR) according to modified Response Evaluation Criteria In Solid Tumors(mRECIST)was achieved within 4 months. Six months after sorafenib treatment was begun, recurrent HCC was detected in segment 6, near the previously treated lesion. The decreased size of the main tumor and normalization of AFP levels allowed curative surgical resection. The patient was discharged 5 days after surgery and is currently treated with a half dose of sorafenib. Thirteen months after surgery, a small early enhancing lesion is visible on postoperative CT scan, but AFP and PIVKA-II levels are still keeping in a normal range. This case demonstrates that if sorafenib treatment is effective, then subsequent surgical treatment can be reconsidered in patients with advanced HCC responding to this combined therapy. PMID- 25731445 TI - [A case of HCC with portal vein thrombosis treated with multidisciplinary treatment combined with preoperative SBRT and radical resection]. AB - A 70s man with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) (Vp-HCC) in the main trunk (Vp4) was referred to our hospital. He was negative for hepatitis C virus (HCV) and hepatitis B virus (HBV), and his liver function was well preserved. The main tumor was in the right lobe and exceeded 10 cm in diameter. There were no intrahepatic metastases to the left lobe. The patient underwent stereotactic body radiation therapy (SBRT) (48 Gy/4 fractions) to the area of the PVTT. Six days after SBRT, the patient underwent right lobectomy for removal of PVTT. The postoperative course was uneventful, and low-dose 5-fluorouracil and cisplatin(FP)intra-arterial chemotherapy was administered for 3 months. Histopathological findings for the tumor indicated a poorly differentiated HCC, vp4, with moderate to severe tumor necrosis or degeneration in the area that received SBRT. Tumor markers (alpha-fetoprotein [AFP], proteins induced by vitamin K absence [PIVKA-II]) decreased within the normal range, and there was no apparent HCC recurrence 6 months after the hepatectomy. Multidisciplinary treatment combined with preoperative SBRT and radical resection for Vp-HCC was feasible and effective in this case. PMID- 25731446 TI - [Long-term survival in a case of advanced hepatocellular carcinoma with tumor thrombus in the portal vein and the right atrium (vp4,vv3 ) treated successfully with multidisciplinary therapies]. AB - The prognosis for hepatocellular carcinoma (HCC) with severe vascular invasion is dismal. Surgery alone is not enough to control recurrence. Here, we report long term survival in a case of HCC with tumor thrombus in the portal vein and right atrium, which was successfully treated through multidisciplinary therapies including surgery. The patient, a 74-year-old man, had undergone several rounds of local ablation and transarterial chemoembolization for HCC recurrence, in another hospital. He was referred to us for recurrent HCC with vascular invasion in July 2011. An abdominal computed tomography (CT) revealed a mass lesion(4 cm in diameter)in the left hepatic lobe. It also detected a tumor thrombus in the main trunk of the portal vein (Vp4), and in the right atrium (Vv3). Consequently, the patient underwent an extended left lobectomy and removal of the tumor thrombus in the portal vein and right atrium. Subsequently, fluorouracil (FU) arterial infusion and interferon therapy (FAIT) was initiated, and followed with sorafenib administration. However, multiple recurrent lesions were found in the liver, lungs, and lymph nodes. The dose of sorafenib was increased and maintained for 10 months. So far, the patient has been alive for 35 months after the operation. PMID- 25731447 TI - [A case report of surgical treatment for hepatocellular carcinoma with a Hugely swollen lymph node that showed high FDG uptake]. AB - A 74-year-old man with chronic hepatitis C was diagnosed with liver tumors. Contrast-enhanced computed tomography (CT) and ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) revealed hepatocellular carcinomas(HCC) in segments 8 (S8)and 5/8 (S5/8), and detected a lymph node (LN) swelling of 75 mm diameter in the posterior aspect of the pancreatic head. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG PET) was positive for the swollen LN (SUVmax 12.3), but negative for the intrahepatic HCCs. The alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) values were elevated, and soluble interleukin 2 receptor levels were also increased (1,440 U/mL). Based on a diagnosis of HCCs with either LN metastasis, or with malignant lymphoma, partial hepatectomy (S8 and S5/8), lymphadenectomy (#13LN), and cholecystectomy were performed. Histopathological examination indicated well differentiated HCC in S5/8, and moderately to poorly differentiated HCC in S8, while poorly differentiated HCC was detected in the LN. Therefore, the final diagnosis was HCCs with metastasis to #13LN originating from the HCC in S8. At present, the patient is alive without further extrahepatic recurrence. The extent of FDG accumulation is related to the degree of differentiation of the HCC; furthermore, there are discrepancies between the FDG uptake in intrahepatic and extrahepatic lesions. PMID- 25731448 TI - [A case of surgical resection for liver metastasis of gastric cancer with portal vein tumor thrombus]. AB - A 58-year-old man presented with anorexia and weight loss in April 2010. Endoscopic examination revealed a type 3 tumor extending from the gastric cardia to the antrum. Preoperative imaging showed liver metastasis (S8; 2 cm) and direct invasion of the cancer into the pancreas. We administered 4 courses of chemotherapy (DCS) for the unresectable tumor; the impact of the therapy was partial response (PR). We performed total gastrectomy, D2 dissection, splenectomy, distal pancreatectomy, and partial hepatectomy (S8) in April 2011. The patient was treated with 8 courses of adjuvant chemotherapy with S-1. In April 2012, abdominal computed tomography (CT) revealed a solitary recurrent lesion in the liver (S2). After 7 courses of chemotherapy(weekly paclitaxel), abdominal CT and magnetic resonance imaging (MRI) revealed a tumor thrombus in the portal vein extending from P2 to the umbilical portion (UP). We performed left hepatectomy and cholecystectomy due to the absence of new lesions. Histopathological findings revealed that the poorly differentiated adenocarcinoma had metastasized to the liver. Abdominal CT revealed the presence of multiple recurrent metastases in the liver, 4 months after the surgery. The patient died 27 months after the initial surgery and 7 months after the last operation. PMID- 25731449 TI - [Two cases of neuroendocrine tumors of the pancreas with multiple liver metastases treated by use of degradable starch microspheres and octreotide]. AB - The first case involved a 38-year-old man who received a pancreaticoduodenectomy and hepatectomy for a pancreatic neuroendocrine tumor (pNET) with multiple liver metastases. A recurrent tumor was detected in his liver 3 months after surgery. The second case involved a 61-year-old woman who received a distal pancreatectomy for a pNET. Multiple liver metastases were detected 29 months later. Both patients received a combined therapy consisting of trans-catheter arterial chemoembolization (TACE) with degradable starch microspheres (DSM) and octreotide. The combined therapy prolonged progression-free survival in both cases. Although only 2 cases were evaluated in this study, multimodal treatment consisting of TACE with DSM and octreotide effectively controlled liver metastasis of pNET in both cases. PMID- 25731450 TI - [A long-term survivor of a rectal carcinoid treated by use of repeat TACE for multiple intrahepatic recurrences after liver resection and MCT]. AB - A woman between 50 and 60 years of age was diagnosed with a rectal carcinoid tumor and synchronal multiple liver metastases. We performed a transanal local resection of the rectal tumor, which was 10mm in diameter. During surgery, ultrasonography revealed 8 hypoechoic masses in the liver, and we performed a partial hepatectomy (S5/6, S8) and administered microwave coagulation therapy. Thirty-seven months after surgery, abdominal computed tomography revealed multiple low-density tumors in the bilateral lobe of the liver. We diagnosed these tumors as a recurrence of the liver metastases of the rectal carcinoid and performed trans-arterial chemo-embolization (TACE). After repeated TACE treatments, the liver metastases were controlled favorably. The patient is alive more than 50 months after diagnosis of the recurrent liver metastases. TACE appears to be effective for treating non-resectable multiple liver metastases of rectal carcinoids. PMID- 25731451 TI - [Mixed adenoneuroendocrine carcinoma with multiple liver metastases successfully treated by cetuximab/CPT-11 chemotherapy followed by curative resection - a case report]. AB - A 73-year-old man underwent laparoscopy-assisted partial resection of the rectum to treat rectal cancer diagnosed in September 2011 at a previous hospital. Lymph node dissection was not performed and the vertical margin was positive. When multiple liver tumors were detected 10 months later, the patient was referred to our hospital. A computed tomography (CT) scan revealed local recurrence of the rectal cancer, lymph node metastasis, and 9 liver metastases, which had a maximum diameter of 10 cm, and where curative resection would have been difficult. The rectal cancer expressed epidermal growth factor receptor (EGFR) and wild type K ras gene, and we initiated cetuximab/irinotecan (CPT-11) chemotherapy. After 2 courses of chemotherapy, the liver tumors had markedly decreased in size and anterior resection of the rectum with regional lymph node dissection was performed. The pathological diagnosis of the rectal tumor was mixed adenoneuroendocrine carcinoma ( MANEC). Extended right hepatectomy was performed four months later. The liver tumors were also diagnosed as metastases of MANEC of the rectum. The therapeutic efficacy of chemotherapy was assessed as Grade 1b. The patient is alive without recurrence 34 months since the initial rectal surgery and 15 months after the liver resection. Thus, an anti-EGFR antibody agent might be effective against MANEC of the colon and rectum. PMID- 25731452 TI - [An inflammatory pseudotumor of the liver mimicking a metastatic lesion of gallbladder cancer - a case report]. AB - An inflammatory pseudotumor (IPT) of the liver is a rare benign disorder.As its characteristics based on computer tomography and magnetic resonance imaging findings are still unclear, it is difficult to distinguish IPT from malignant diseases of the liver.Herein, we report a case of IPT of the liver concurrent with advanced gallbladder cancer, which we could not diagnose preoperatively.First, we performed lateral segmentectomy of the liver.Second, a radical operation for gallbladder cancer was performed after confirming that the hepatic tumor was IPT via intraoperative pathological diagnosis.Therefore, modalities less invasive than surgical resection should be innovated, even though surgical resection is accurate. PMID- 25731453 TI - [Treatment of repeat TACE plus S-1 for multiple intrahepatic recurrence of hepatoma and gastric cancer]. AB - We report here an experience treating a patient who developed gastric cancer at the same time as a multifocal intrahepatic recurrence of hepatocellular carcinoma (HCC). The patient was a 76-year-old woman who underwent partial liver resection after diagnosis of HCC in August 2008. Histopathological examination revealed moderately differentiated hepatocellular carcinoma and stage III pathology. Six months following surgery, an upper gastrointestinal endoscopy revealed a typeIIa+IIc gastric tumor in the angle of the stomach, which was pathologically diagnosed as adenocarcinoma(por2/sig) in the biopsy. Simultaneously, abdominal CT scan revealed multifocal intrahepatic recurrence of HCC, so Lip-TACE as performed. Eight days after TACE, S-1 (80 mg/body) was initiated. About one month after TACE, abdominal CT scan revealed multiple new hepat- ic lesions. The patient was repeatedly treated with a combination of Lip-TACE on day 1 and S-1 80 mg/body/day, administered on days 8 to 35 for 28 days, followed by a 7 day interval as 1 course. After 5 courses of medication of S-1, liver function had deteriorated and thrombocytopenia occurred. Although there was no progression of gastric cancer, medication of S-1 was discontinued. Lip-TACE was performed nine times. About one year after the initial TACE, the patient was admitted to our hospital in order to control ascites, 3 days after admission, she suffered a cerebral infarction and died 3 days later. PMID- 25731454 TI - [A case of Carboplatin and pemetrexed combination chemotherapy for synchronous double cancers of hepatocellular carcinoma and primary lung cancer]. AB - A 78-year-old man presented to our hospital with lung abnormality on his chest radiograph. Computed tomography (CT) showed a mass and obstructive pneumonia in the right upper lobe of the lung. The mass was diagnosed as a pulmonary adenocarcinoma with a bronchoscopy (cT4N2M0, Stage IIIB). CT also revealed multiple hepatic tumors, which were diagnosed as hepatocellular carcinoma (HCC) by dynamic CT and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging(EOB-MRI). First, we treated the lung cancer with a combination of cisplatin and pemetrexed (PEM), but it caused renal dysfunction. Carboplatin (CBDCA) and PEM combination chemotherapy was administered, and not only the lung cancer but also the HCCs decreased in size. There are few reports of synchronous double cancers of HCC and primary lung cancer, and the treatment is not established. We report that platinum-containing anticancer drugs such as CBDCA may be effective against synchronous double cancers of HCC and lung cancer. PMID- 25731455 TI - [A resected case of pancreatic carcinoma associated with multiple intrahepatic recurrence of hepatocellular carcinoma]. AB - A 7 1-year-old man, diagnosed with hepatocellular carcinoma (HCC), underwent lateral segmentectomy of the liver and partial hepatectomies. Ten months after the hepatic resections, computed tomography imaging of the abdomen revealed a pancreatic tumor and multiple liver metastases of HCC. The patient underwent transcatheter arterial chemoembolization three times to manage the HCC. Subsequently, he underwent distal pancreatic resection. Although it was a non curative surgery, the postoperative course was uneventful; he was free from cancer pain, and his diabetes improved. At the 7-month follow-up after the pancreatectomy, the patients' course remained uneventful. There have been no reports of resected cases of pancreatic carcinoma that developed during the treatment of multiple intrahepatic recurrence of HCC. In cases wherein recurrence of HCC is well controlled, aggressive treatment for pancreatic cancer can be considered. PMID- 25731456 TI - [A case of resectable lung metastasis one year six months after surgery for pancreatic cancer]. AB - The patient was a 68-year-old man who underwent pylorus-preserving pancreaticoduodenectomy for cancer of the pancreatic head in March 2012. Pre operative chest computed tomography (CT) revealed a scar-like shade approximately 1.5 cm in length in the right middle lobe of the lung, but an active metastasis was not suspected. Adjuvant S-1 was initiated in June the same year at 100 mg/day and reduced to 50 mg/day in October because of neutropenia. The internal structure of the right middle lobe was observed to be uneven on a CT scan obtained in July 2013, and the shading increased to approximately 3 cm in length along with spicula. Brushing and transbronchial lung biopsy(TBLB)were performed. No other distant organ metastases were detected on a whole body search. Diagnosis was between a solitary lung metastasis of pancreatic cancer or cT2N0M0, StageIB primary lung cancer. The right middle lobe of the lung was resected via thoracoscopy along with lymph node dissection in September 2013. Histological examination revealed that the lesion was a well differentiated adenocarcinoma, with negative immunostaining for thyroid transcription factor-1(TTF-1) and Napsin A, and positive staining for cytokeratin (CK)7 and CK20, consistent with a solitary lung metastasis of pancreatic cancer. This report documents a rare case of pancreatic cancer with a solitary, resectable lung metastasis without involvement of other organs. PMID- 25731457 TI - [A case of a patient who underwent resection of the remnant pancreatic cancer following a distal pancreatectomy for invasive ductal carcinoma]. AB - Herein, we report the case of a patient who underwent resection of the remnant pancreas for pancreatic cancer following a distal pancreatectomy for invasive ductal carcinoma. An 81-year-old woman underwent a distal pancreatectomy. The tumor was found to be pancreatic cancer. The tumor was histologically diagnosed as a poorly differentiated tubular adenocarcinoma (Stage I). An abdominal computed tomography (CT) performed 17 months later revealed a 13 mm tumor in the remnant pancreatic head. A remnant pancreatectomy was performed. The histological diagnosis was a moderately differentiated tubular adenocarcinoma (StageIII). Remnant pancreatic cancer is rare following a pancreatectomy for invasive ductal carcinoma. The course of remnant pancreatic cancer can be followed with imaging. Long-term follow-up of patients who have undergone a pancreatectomyis, therefore, essential. PMID- 25731458 TI - [A case of two re-resections for peritoneal recurrence of pancreatic cancer]. AB - A 63-year-old man underwent subtotal stomach-preserving pancreaticoduodenectomy and intraoperative radiation therapy for pancreatic head cancer (Stage IVa, JPS). Subsequently, he received adjuvant chemotherapy including gemcitabine (GEM). A peritoneal recurrence appeared adjacent to the right colon and the lower pole of the right kidney. He received chemotherapy including S-1 and GEM+S-1. Since the recurrent lesions were localized, he underwent resection for the recurrence lesions 2 years and 9 months after surgery. The resection was R1, and re recurrence appeared in the lower pole of the right kidney. After chemotherapy and chemoradiotherapy, he underwent re-resection for the recurrence 4 years and 3 months after the first surgery. Three months after re-resection, multiple liver metastases appeared in the bilateral lobes. Reoperation can be one of the multidisciplinary management options for local recurrence of pancreatic cancer under specific conditions. PMID- 25731459 TI - [A case of curative resected pancreatic cancer coincident with a retroperitoneal abscess]. AB - A 64-year-old man presented with a chief complaint of abdominal pain. An abdominal computed tomography (CT) scan showed a mass 30-mm in diameter at the splenic flexure, and we diagnosed a retroperitoneal abscess. Conservative therapy was successful, and the patient was discharged. However, 1 month later, he again experienced abdominal pain. To reassess the abscess, contrast-enhanced abdominal CT was performed. In addition to the retroperitoneal abscess, the CT scan showed an approximate 30-mm mass in the head of the pancreas with no contrast uptake. The abscess was also detected by endoscopic retrograde pancreatography. We suspected but could not confirm pancreatic cancer. Two months later, the patient developed obstructive jaundice. At this time, we diagnosed pancreatic cancer, and subtotal stomach-preserving pancreaticoduodenectomy was performed. The histopathologic diagnosis was pancreatic cancer, T4, N0, M0, Stage IVa. The postoperative course was favorable, and the patient received postoperative adjuvant chemotherapy. He remains alive without recurrence 15 months after surgery. PMID- 25731460 TI - [Multidisciplinary therapy for recurrent pancreatic cancer]. AB - We report 2 cases of pancreatic cancer with distant organ metastasis. Case 1: A 67-year-old man with pancreatic cancer (T3N0M0, Stage III) underwent pancreaticoduodenectomy (PD). A follow-up computed tomography (CT) scan performed 48 months after the primary resection detected two masses in his right lung, which were treated by stereotactic body radiotherapy ( SBRT). Twenty-three months after SBRT, the patient is alive. Case 2: A 54-year-old woman with pancreatic cancer (T3N1M0, Stage III) underwent PD. A follow-up CT scan performed 12 months after the primary resection detected 3 masses in her liver, which were treated by SBRT. The patient died because of lymph node metastasis of the pancreatic cancer 32 months after SRT. PMID- 25731461 TI - [Analysis of portal vein resection during pancreaticoduodenectomy in patients with pancreatic cancer]. AB - The feasibility of portal vein resection (PVR) during pancreaticoduodenectomy (PD) for cancer of the pancreatic head is controversial. We retrospectively evaluate the surgical results and prognosis of 26 patients with pancreatic cancer who received PD with PVR (PVR group, n=14) or without PVR (non-PVR group, n=12). The operation time was significantly greater in the PVR group, with a mean time of 13.6 +/- 2.4 minutes. There were no differences between the PVR and non-PVR groups in the incidence of complications or the number of days in hospital. In the PVR group, 7 patients were histopathologically diagnosed with portal vein invasion (PV), but there was no difference in the postoperative survival between PV negative and positive patients. PVR during PD appears to be a safe and feasible treatment for appropriate stage pancreatic cancer patients receiving adjuvant chemotherapy. PMID- 25731462 TI - [A case of adjuvant surgery for a patient with initially unresectable locally advanced pancreatic cancer (LAPC) with a favorable response to S-1 chemotherapy]. AB - A 67-year-old man was admitted to our hospital with a complaint of epigastric discomfort. A 29-mm hypovascular tumor was detected in the head of the pancreas by abdominal computed tomography imaging. As the superior mesenteric artery (SMA) was also involved, we diagnosed the tumor as unresectable pancreatic cancer. With S-1 chemotherapy, a radiological partial response was seen. After 4 courses of chemotherapy, a subtotal-stomach-preserving-pancreatoduodenectomy with dissection of the nerve plexus surrounding the SMA was performed. Although the tissue surrounding the SMA was hard, invasion of the SMA was not detected. Microscopic investigation revealed a few moderately differentiated adenocarcinoma cells in the fibrous tissue and the nerve fibers of pancreas. No cancer cells were found at the edges of the surgical specimen. The patient underwent R0 resection and a pathological evaluation showed Grade III tumor according to the Evans classification. After surgery, S-1 was interrupted because of diarrhea and local recurrence appeared 4 months postoperatively. For improving the prognosis of patients with pancreatic cancers, surgical intervention is often performed in patients with initially unresectable pancreatic cancers who have "long-term" favorable responses to chemotherapy or chemoradiotherapy. However, because of the possibility of relatively good prognosis with nonsurgical treatment for such patients and also the demerits of surgical stress, it is important to carefully consider the adjuvant surgery option. PMID- 25731463 TI - [A case of radical resection for pancreatic head cancer with peritoneal dissemination treated with combination chemotherapy]. AB - A 69-year-old man underwent surgery for pancreatic head cancer. During surgery, a few tubercles were found in the bursa omentalis, which were diagnosed pathologically as peritoneal dissemination. Curative resection was impossible, and exploratory laparotomy was completed. After surgery, 17 cycles of S 1/gemcitabine combination chemotherapy were administered for 1 year. Significant changes were not observed in the primary tumor on computed tomography (CT) scan, but the uptake of fluorodeoxyglucose (FDG) in the tumor decreased on positron emission tomography combined with CT(PET/CT), suggesting a decrease in tumor activity. Although imaging modalities could not identify distant or peritoneal metastases, levels of serological tumor markers increased at this time. Therefore, a second exploratory laparotomy was performed 13 months after the initial surgery. The nodules in the bursa omentalis had disappeared, and the patient underwent a pancreatoduodenectomy with common hepatic artery resection. Histopathological findings revealed mucinous carcinoma of the pancreas. The postoperative diagnosis was pT3, pN2, M0, Stage IVa. PMID- 25731464 TI - [A case of pancreatic cancer with distant metastasis successfully resected after neoadjuvant chemotherapy with a combination of S-1 and gemcitabine]. AB - The patient was a 70-year-old man with a chief complaint of cough.After careful examination, he was diagnosed with pancreatic body cancer with metastasis to the liver and right pleura and with early gastric cancer.He was treated with S-1 and gemcitabine combination chemotherapy.After completing 3 courses, the distant metastasis could no longer be observed. After completing 4 courses, the tumor marker level in the serum was normalized.The pancreatic lesion was restricted by the end of 10 courses, and the pancreas body and tail were resected.After additional chemotherapy with S-1, he was switched to weekly paclitaxel therapy because of peritoneal dissemination.The patient survived for 15 months after surgery.In cases of unresectable pancreatic cancer with distant metastasis, it may be possible to consider the surgical option when chemotherapy is effective. PMID- 25731465 TI - [A case of locally advanced pancreatic cancer successfully resected after gemcitabine+S-1 therapy]. AB - A 6 1-year-old man who was admitted to our hospital because of obstructive jaundice. He was diagnosed with locally advanced cancer of the pancreatic head on computed tomography. Gemcitabine (1,000 mg/m2 on days 8 and 15, every 21 days) + S-1 (6 0 mg/m2 on day 1-15, every 21 days) chemotherapy was administered because the tumor had invaded the common hepatic artery and portal vein. The tumor was reduced following 9 months of chemotherapy. Thus, subtotal stomach- preserving pancreaticoduodenectomy (SSPPD)was performed. The histopathological findings indicated no invasion of the cancer into the surrounding tissues. No recurrence has occurred 7 months after surgery. Neoadjuvant chemotherapy is important for effective treatment of locally advanced pancreatic cancer. PMID- 25731466 TI - [Long-term survival following postoperative combined modality therapy for pancreatic cancer]. AB - A 69-year-old woman with back pain underwent distal pancreatectomy with left adrenectomy for advanced pancreatic cancer pathologically diagnosed as poorly differentiated invasive ductal carcinoma with retroperitoneal and perineural invasion, pT3N0M0, Stage III. The patient received adjuvant chemotherapy with S-1 for 6 months. However, 3 years after surgery, computed tomography (CT) revealed para-aorticlymph node (LN) recurrence. Treatment with gemcitabine (GEM) was begun and continued for 3 years. Following progression of the LN recurrence 5 and half years after surgery, administration of radiotherapy reduced diarrhea and back pain. Supportive care combined with radio-frequency ablation(RFA)was provided for multiple liver metastasis 5 years 7 months after surgery. The patient died due to gastrointestinal hemorrhage 6 years after surgery. We report long-term postoperative survival of a patient with recurrent pancreatic cancer following combined modality therapy. PMID- 25731467 TI - [A case of pancreatic cancer with local recurrence and liver metastases eight years after surgery]. AB - Here we report a rare case of late recurrence of pancreatic cancer 8 years after surgery. A woman in her mid-fifties was hospitalized for examination of epigastralgia. Computed tomography (CT) revealed a 4 cm nodule at the pancreatic head with suspected invasion of the superior mesenteric vein. She underwent pancreaticoduodenectomy with wedge resection of superior mesenteric vein and intraoperative radiation therapy. Pathological findings showed moderately differentiated tubular adenocarcinoma and T3N1M0, Stage IIB according to The Union for International Cancer Control (UICC) TNM classification. As adjuvant chemotherapy, 56 courses of gemcitabine (GEM) were administered in 3.5 years. Because of long-term use of GEM, common terminology criteria for adverse events (CTCAE) Grade 3 anemia occurred, and chemotherapy was discontinued. Tumor markers were evaluated every month and CT scans were taken every 6 months for 5 years. Subsequently, CT was performed annually. The patient was hospitalized for high grade fever, 8.5 years after surgery. CT, magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT) detected local recurrence with liver metastases. GEM was administered again, but was ineffective. The patient died 9 years after surgery. In conclusion, even if long term survival is achieved in pancreatic cancer, follow-ups should not be stopped. PMID- 25731468 TI - [A case of resection for a huge pancreatic acinar cell carcinoma with tumor thrombus in the portal vein]. AB - A 6 3-year-old man with a huge pancreatic tumor was referred to our hospital. Abdominal computed tomography revealed a heterogeneously enhanced encapsulated mass, 14 cm in diameter, in the pancreas head. The tumor thrombus extended to the bifurcation of the portal vein. The tumor, which had invaded the descending duodenum, was diagnosed as a probable case of acinar cell carcinoma, based on the biopsy results. Prior to resection, we prepared an ileocecal vein-umbilical vein bypass. Initially, we planned to perform a pancreatoduodenectomy, however, a total pancreatectomy had to be performed due to the atrophy of the residual pancreas tail. Since the tumor thrombus was visible, floating up from the portal vein wall at the upper level of pancreas, we dissected the portal vein at this level. The thrombus was extracted after securing the main tract and both (right and left) branches of the portal vein with vessel tape. About 5 cm of portal vein was resected and reconstructed. Since patients who undergo resection of acinar cell carcinoma have a better prognosis and long-term survival is often reported for cases of resected tumor thrombus of the portal vein, it is advisable to resect acinar cell carcinomas even in cases as advanced as reported here. PMID- 25731469 TI - [A case of main-duct IPMN with multicentric invasive carcinoma]. AB - Intraductal papillary mucinous neoplasm (IPMN) of the pancreas often contains multifocal lesions, and total pancreatectomy is sometimes needed for curative resection. We report here our experience with a case of IPMN with multiple invasive carcinoma foci that was successfully treated with total pancreatectomy. A 66-year-old man had jaundice, and a computed tomography (CT) scan revealed a hypovascular mass in the pancreas head in conjunction with calcification and dilation of the entire main pancreatic duct. He was diagnosed with pancreas head cancer and chronic pancreatitis, and a pancreaticoduodenectomy was planned. Intraoperative pathological examination revealed papillary growth of high grade dysplasia in the main and branch duct epithelium and perineural invasion of the atypical glands. After 2 additional resections, we performed a total pancreatectomy. Pathological findings showed that the pancreas head tumor was an invasive carcinoma derived from main-duct IPMN of the pancreas. It was a mucinous carcinoma with calcification. Moreover, we found other multiple, discontinuous invasive foci in the body and tail of the pancreas which were undetectable by preoperative imaging. This case was highly suggestive for preoperative diagnosis for pancreas tumor and developmental pattern of main-duct IPMN. PMID- 25731470 TI - [A patient with invasive carcinoma derived from IPMN who achieved long-term survival despite lymph node metastasis]. AB - A woman in her 70s was referred for examination of liver dysfunction. A cystic lesion with irregular contrast was observed at the pancreas head. The bile and pancreatic ducts were obstructed by the lesion. Part of the branch of the pancreatic duct at the pancreas head, continuous with the main pancreatic duct, was observed to be extended by using pancreatography. Pancreaticoduodenectomy was performed, and a diagnosis of invasive carcinoma from an intraductal papillary mucinous neoplasm (IPMN) was made. Postoperative pathological diagnosis showed 16b1 inter-node metastasis. Liver and lung metastases were also detected after surgery; nevertheless, long-term survival was achieved for 5 years and 2 months by using various treatment modalities. PMID- 25731471 TI - [A case report of hepatic arterial infusion chemotherapy and RFA for liver metastasis from pancreatic cancer]. AB - A 71-year-old female patient was administered 2 courses of neoadjuvant chemotherapy (GS therapy) for pancreatic body cancer, and underwent pancreatic body and tail resection. She was diagnosed as having T3N0M0, Stage III disease, and adjuvant chemotherapy with gemcitabine was started. However, a solitary 9 mm liver metastasis was found using CT imaging 3 months after the operation. We started hepatic arterial infusion chemotherapy (GEM+5-FU), with additional treatment using RFA after 5 courses, and a CR was achieved. The HAI regimens were changed to GEM+S-1 and a further 18 courses were administered. After HAI, adjuvant chemotherapy (S-1) was continued, but 2 further liver metastases were found. The patient was still alive 4 years after surgery and continued to undergo radiation chemotherapy. PMID- 25731472 TI - [A case of portal vein stenting for portal vein stenosis due to pancreatic cancer recurrence after pancreatoduodenectomy]. AB - We report a case of portal vein stenosis due to pancreatic cancer recurrence that was successfully treated with intravenous stent implantation. The patient was a 70-year-old man who had undergone a subtotal stomach-preserving pancreatoduodenectomy with the modified Child method for pancreatic cancer. He was readmitted due to melena, dorsal pain, and severe ascites 8 months after the operation. Computed tomography (CT) findings revealed that pancreatic cancer recurrence had narrowed the portal vein. Neither gastrointestinal nor colon endoscopy could locate the source of gastrointestinal bleeding. Bleeding from the varices increased, and a hepatopetal collateral was considered to be the cause. We therefore placed an intravenous stent at the site of portal vein stenosis, by the transileocolic portal vein. After the stent placement, no further gastrointestinal hemorrhagic episodes occurred. PMID- 25731473 TI - [A case of pancreatic pseudocyst associated with pancreatic cancer successfully treated with endoscopic pseudocyst drainage, which allowed continuation of chemotherapy]. AB - We report a case of pancreatic pseudocyst associated with pancreatic cancer that was successfully treated with endoscopic pseudocyst drainage, which allowed continuation of chemotherapy. A 74-year-old woman complaining of jaundice was diagnosed with locally advanced cancer in the head of the pancreas, and she underwent chemotherapy with gemcitabine. One month later, she was admitted to our hospital for severe epigastralgia, and she diagnosed with a pancreatic pseudocyst that was 14 cm in diameter. Endoscopic ultrasonography-guided pseudocyst drainage was successfully performed. The amylase concentration of pseudocyst fluid was 13,320 U/L, and bacterial culture was negative. The epigastralgia soon resolved, but 1 week later, the size of the pseudocyst was 12 cm in diameter. Endoscopic retrograde pancreatography revealed communication of the pancreatic duct with the pseudocyst. A pancreatic stent was placed. The patient again underwent chemotherapy for 3 months, without major complications. The pseudocyst was no longer visible 3 months after stent placement. The patient died of pancreatic cancer with peritonitis carcinomatosa, 6 months after the initial diagnosis. PMID- 25731474 TI - [Hassab's operation for left-sided portal hypertension after pancreatoduodenectomy]. AB - Here, we report a case of Hassab's operation for left-sided portal hypertension after pancreatoduodenectomy. A 69-year old man underwent pancreatoduodenectomy for pancreatic cancer in 2006 in which the splenic vein was ligated near the portal vein and then divided. The patient suffered repeated episodes of anemia between 2010 and 2013. However, we could not identify the bleeding site at that time. In 2011, local recurrence was detected. Disease progression occurred despite chemotherapy treatment, which was then discontinued. The left-sided portal hypertension gradually progressed, and the collateral vessels became dilated. In 2014, he was examined in our department for gastrointestinal bleeding. An upper gastrointestinal endoscopy revealed bleeding from gastric varices. Gastrointestinal bleeding ceased after endoscopic injection sclerotherapy ( EIS) was performed; however, the bleeding recurred. Balloon retrograde transvenous occlusion (BRTO) could not be performed because blood flow was not detected within the gastro-renal shunt. An emergency surgery was performed. Surgical splenectomy and devascularization (Hassab's operation) were performed. After surgery, the gastric body varices and gastrointestinal anastomosis disappeared and the bleeding did not occur. He is currently receiving outpatient treatment. PMID- 25731475 TI - [An analysis of cases with malignant pyloroduodenal obstruction from unresectable pancreatic cancer who underwent palliative gastrojejunostomy]. AB - The aims of this study were to examine the effectiveness of palliative gastrojejunostomy in terms of the postoperative food intake and hospital stay in patients with advanced pancreatic cancer. Retrospective data from 17 consecutive patients who underwent gastrojejunostomy from 2008 to 2013 in Toho University Omori Medical Center were analyzed. In our analysis, patients without peritoneal dissemination and distant metastasis were associated with poor oral intake and patients with lower neutrophil to lymphocyte ratio (NLR) were associated with rate of discharge. PMID- 25731476 TI - [Laparoscopic hemi-double stapling and reduced-port laparoscopic distal gastrectomy for gastric cancer]. AB - INTRODUCTION: The hemi-double stapling method (HDS) is typically used for extracorporeal Billroth-I anastomosis. We used HDS for reduced-port surgery. Laparoscopic HDS is used for intracorporeal Billroth-I anastomosis after laparoscopic distal gastrectomy. We performed reduced-port laparoscopic distal gastrectomy for gastric cancer. METHODS: Reduced-port laparoscopic distal gastrectomy was performed using the multi-trocar method with 5mm and 3mm ports. Laparoscopic HDS was performed using an umbilical incision and a left upper abdominal incision. A total of 17 patients underwent reduced-port laparoscopic distal gastrectomy. A D1+or D1 lymph node dissection was performed, and laparoscopic HDS was used for reconstruction. RESULTS: The patients had no short term complications. CONCLUSIONS: Laparoscopic HDS and reduced-port laparoscopic distal gastrectomy are safe and feasible procedures. PMID- 25731477 TI - [Usefulness of laparoscopy endoscopy cooperative surgery for gastric gastrointestinal stromal tumor]. AB - BACKGROUND: Laparoscopy endoscopy cooperative surgery (LECS) for gastrointestinal stromal tumors (GIST) is an established technique for safe tumor resection, with lesser surgical margin than laparoscopic wedge resection (WR). We report the usefulness of LECS for GIST compared with WR. METHOD: Between 2008 and 2012, 8 patients with GIST underwent LECS and 11 patients underwent laparoscopic WR. Intraoperative blood loss, surgical margin, and operation time were compared between LECS and WR. RESULTS: Patients undergoing LECS had significantly less surgical margin compared with those undergoing WR (mean 5.6mm versus 28.0 mm, p<.05). The difference in operation time between LECS and WR (214 min versus 112min)was also significant. Intraoperative blood loss was very little and not significantly different between both groups. CONCLUSION: LECS for GIST was a safe procedure with lesser surgical margins. PMID- 25731478 TI - [An assessment of liver metastasis resection in gastric cancer]. AB - We assessed cases of gastric cancer in which liver metastases had been resected in our hospital. Liver resection was performed in 359 cases of metastatic cancer beginning in April 2003 when we initiated aggressive liver resection in conjunction with standard therapy. Of the 359 cases, 137 included metastatic liver cancer. The most common primary lesion was colorectal cancer, accounting for 101 cases, followed by gastric cancer with 21 cases. Here, we report on 14 cases of gastric cancer following exclusion of a single case of gastric endocrine tumor. The mean overall recurrence-free survival time after the initial liver resection was 8 months. However, mean survival time was prolonged to 45 months by subsequent chemotherapy and repeat hepatectomy. The 3-year survival rate was 64.2%, and the 5-year survival rate was 34.4%. Multivariate analysis identified total gastrectomy and multiple lesions as significant unfavorable prognostic factors. At our hospital, we consider a primary lesion that has been curatively resected, the absence of distant metastasis, and all liver metastases capable of being safely resected to be the indications for surgery. We have performed standard surgery and D2 lymph node dissection to treat primary gastric cancer lesions and have not observed any local lymph node recurrences. However, recurrence in the remnant liver occurred in more than 70% of the cases. We conclude that performing aggressive resection and postoperative chemotherapy according to the regimen for unresectable gastric cancer contributes to prolonging the survival time. PMID- 25731479 TI - [Clinical significance of ascites on preoperative MDCT in patients with advanced gastric cancer]. AB - In advanced gastric cancer patients, preoperative multi detector row computed tomography (MDCT) often reveals abnormal ascites, which can indicate the possibility of peritoneal metastasis. The aim of this study was to clarify the clinical significance of preoperative ascites revealed by MDCT in gastric cancer patients. The study included a total of 183 advanced gastric cancer patients who underwent consecutive surgical procedures from February 2008 to November 2011. The results indicate that the presence of ascites on MDCT is significantly correlated with peritoneal metastasis (p<.005), pathological T4 (p< 0.005), R1-R2 (p<.01), and a positive diagnosis of peritoneal washing cytology(p<.05). Multivariate analysis indicated that the presence of ascites on MDCT was an independent prognostic factor (hazard ratio[HR]2.6). In conclusion, the presence of ascites on preoperative MDCT is strongly associated with peritoneal metastasis, and might indicate the need for diagnostic laparoscopy to evaluate Stage IV factors and select the best treatment strategy. PMID- 25731480 TI - [The role of staging laparoscopy in clinical stage III/IV gastric cancer]. AB - We investigated the significance of staging laparoscopy (SL) for clinical Stage III/IVgastric cancer.SL was performed in 60 patients with clinical Stages III/IV gastric cancer.Pre -SL Stages were T3/4a/4b in 3/49/8 patients, N1/2/3 in 14/21/25, M0/ 1 in 38/22, and IIIA/IIIB/IIIC/IV in 16/13/9/22 patients, respectively.After SL, 11 patients were downstaged from T4a to T3, and 3 patients were downstaged from T4b to T4a.Moreover, 14 patients of P0 were identified as P1 or CY1, and 1 patient of H0 was identified as H1 after SL.As a result, post-SL Stages were IIB/IIIA/IIIB/IIIC/IV in 3/17/9/2/29 patients, respectively. In Stage III patients, staging was changed in 17 patients (44.7%) and the treatment strategies were changed in 9 patients (23.7%).In Stage IV cases, none of the patients changed staging and treatment strategies after SL.In conclusion, SL is useful for accurate staging and determining the treatment strategies in Stage III gastric cancer; however, re-evaluation is needed for the indication of SL in Stage IV gastric cancer. PMID- 25731481 TI - [Treatment strategy for patients with CY1 gastric cancer using subgroup analyses]. AB - BACKGROUND AND AIMS: Recent advances in anti-cancer drug treatments enable us to improve prognosis in Stage IV gastric cancer. In particular, in recent reports patients with only cytology positive (CY1) non-curative factors have comparatively better prognosis than others. This study was designed to evaluate our outcomes, to allow identification of CY1 gastric cancer patients and to investigate new treatment strategies. PATIENTS AND METHODS: Between 2000 and 2008, 336 patients underwent peritoneal washing cytology for gastric cancer intra operatively. Of these, 35 patients (10.4%) were diagnosed with CY1 gastric cancer. RESULTS: 1 ) In all CY1 gastric cancers, 1-year, 3-year, and 5-year survival rates were 49%, 11%, and 5.7%, respectively. Clinical factors such as number of non-curative factors (p=0.008) and gastrectomy (p=0.001)were significantly related to poor prognosis. 2 ) The number of CY1 patients with only CY1 non-curative factors (Group C) and multiple non-curative factors (Group CM)were 14 and 21, respectively. The number of CY1 patients with gastrectomy and without gastrectomy were 30 (MST 366 days, Group C: 14 Group CM: 16) and 5 (MST: 88 days, Group CM: 5), respectively. 3 ) In CY1 patients with gastrectomy, patients treated with S-1 based chemotherapy had better prognosis in both Group C and Group CM. 4 ) 8 CY1 patients with neoadjuvant chemotherapy (NAC) followed by gastrectomy (MST 501 days, 1-year survival rate 62.5%) tended to have better prognosis than those without NAC (MST 132 days, 1-year survival rate 25.0% (p= 0.055). CONCLUSIONS: Gastrectomy, number of non-curative factor, S-1 based chemotherapy and NAC were keys to improving prognosis by subgroup analyses in CY1 gastric cancer. PMID- 25731482 TI - [Clinical Impact of adjuvant chemotherapy in patients with T1N2/3 Gastric cancer]. AB - The ACTS-GC trial showed the efficacy of S-1 adjuvant chemotherapy in patients with pathological Stage II/III gastric cancer who had undergone D2 gastrectomy; however, T1 patients were excluded from this trial.In this study, we compared the prognosis of T1N2/3 gastric cancer with the outcomes of ACTS-GC.From 2000 to 2009, out of 480 patients with resected T1 gastric cancer, 27 patients(5.6%) were pN2/3.Six patients received S-1 adjuvant chemotherapy (group S), whereas 21 patients did not(group N).The 3-year overall survival rates of T1N0/1 and T1N2/3 were 91.7% and 71.3%, respectively. Among T1N2/3 gastric cancer patients, the 3 year survival rate and relapse-free survival rate were 100%/100% in group S and 72.7%/71.1% in group N, respectively. The prognosis of group N was poorer than that of the surgery-alone group in Stage II of ACTS-GC.Furthermore, 5 patients (23.8%) of group N had recurrences; the primary sites of recurrences were lymph nodes in 4 cases, and lymph nodes and liver in 1 case.The prognosis of T1N2/3 gastric cancer is poor; we should, therefore, consider evaluating the efficacy of adjuvant chemotherapy in T1N2/3 gastric cancer patients. PMID- 25731483 TI - [Treatment of type four gastric cancer in our institution]. AB - Since 2011, we have performed routine staging laparoscopy on 7 patients presenting with type 4 gastric cancer at our department. After staging laparoscopy, the patients received neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS). After the completion of 2 courses of chemotherapy, radical gastrectomy with D2 gastrectomy or greater was performed, followed by postoperative adjuvant chemotherapy with S-1 for 1 year. In the present study, we evaluate the outcomes of the treatment strategies for the type 4 gastric cancer patients treated at our institution. Staging laparoscopy and peritoneal lavage cytology revealed that none of the patients had peritoneal metastasis, while peritoneal cytology detected carcinoma cells in 3 patients. Grade 3 or greater neutropenia developed in 3 patients, and Grade 3 or greater nonhematological toxicity developed in 3 patients after neoadjuvant chemotherapy. The disease control rate was 100% and all patients underwent radical gastrectomy. Of the 3 patients who had positive peritoneal cytology on staging laparoscopy, 2 patients had no peritoneal cancer cells at the time of gastrectomy. Six patients underwent R0 surgery after DCS chemotherapy, and the response rate was 57.1%. The median survival time was 540 days. Four patients experienced peritoneal recurrence, and 1 developed lymph node recurrence. Our therapeutic strategy for type 4 gastric cancer contributed to prolonged survival; however, it is necessary to develop better strategies that can prevent or control the peritoneal recurrence. PMID- 25731484 TI - [Generational changes in clinicopathological characteristics of younger patients with gastric carcinoma]. AB - The present study investigated generational changes in the clinicopathological characteristics of younger patients with gastric carcinoma (GC). The medical records of 1,420 patients who had undergone gastrectomy for GC between 1997 and 2012 were reviewed retrospectively. The patients were divided into 2 groups based on age, with 49 patients below the age of 40 and 1,371 patients above the age of 40. Moreover, the clincopathological features of the 49 patients below the age of 40 were compared with age-matched GC patients who had undergone gastrectomy from 1985 to 1996. Younger GC patients group had a higher number of women and a higher incidence of undifferentiated GC, although there was no prognostic significance between the 2 groups. Comparison of three-generational younger GC patient groups (1985-1996, 1997-2002, and 2003-2012) demonstrated no difference in survival curve between the 3 groups, although a higher incidence of undifferentiated GC was observed with time. Furthermore, in younger patients with undifferentiated GC, the last generational group (2003-2012) had a tendency towards an improved prognosis in the early postoperative period. This study demonstrated that there was no prognostic significance between GC patients below the age of 40 and over the age of 40. Chemotherapy might contribute to improved prognosis in younger GC patients. PMID- 25731485 TI - [Chemotherapy for gastric cancer patients over 75 years of age]. AB - PURPOSE: The efficacy of chemotherapy for advanced or recurrent gastric cancer in patients who were aged over 75 years was investigated. MATERIALS AND METHODS: Progression free survival (PFS) and overall survival (OS) of advanced gastric cancer patients who received first-line chemotherapy with TS-1 plus cisplatin or TS-1 in our hospital from 2009 to 2013 were determined. The patients were divided into two groups: H and L. H group patients were aged over 75 years, and L group patients were aged less than 75 years. RESULTS: Median PFS and median OS of patients in the H and L groups who received TS-1 plus cisplatin chemotherapy were not significantly different. PFS was 77[range, 13-211] days and 139[range, 53 211]days for the H and L groups, respectively(p=0.141), while OS was 523[range, 22-1,030] days and 402 [range, 322-623] days, respectively (p=0.620). Similarly, median PFS and median OS of patients who received TS-1 chemotherapy were not significantly different between the H and L groups. PFS was 103[range, 51 156]days and 152.5[range, 85-278]days for the H and L groups, respectively (p=0.230), while OS was 414 [range, 224-714]days and 605[range, 452-1,077] days, respectively ( p=0.1337). CONCLUSION: PFS and OS were not significantly different in younger patients with advanced gastric cancer who received TS-1 plus cisplatin or TS-1 chemotherapy compared to that in similarly treated elderly patients with advanced gastric cancer. PMID- 25731486 TI - [Nanoparticle albumin-bound Paclitaxel for unresectable or recurrent gastric cancer]. AB - The efficacy and safety of nanoparticle albumin-bound paclitaxel(nab paclitaxel)administered every 3 weeks for unresectable or recurrent gastric cancer was evaluated retrospectively. Nab-paclitaxel was intravenously administered at 260 mg/ m2 on day 1 of each 21-day course without anti-allergic premedication until disease progression or discontinuation. Nine patients received nab-paclitaxel. The overall response rate was 11.1%, and the disease control rate was 55.6%. Grade 3/4 toxicities included neutropenia(44.4%), leukopenia(33.3%), and peripheral sensory neuropathy (33.3%). It is important to manage both neutropenia and peripheral neuropathy. Although only few cases were analyzed, therapeutic effect can be obtained even with the starting dose of 180 mg/m2 suggesting management of toxicities will be feasible. In view of the toxicities observed, a reduced starting dose of 180 mg/m2 should be considered in the case of poor performance status patients. Nab-paclitaxel is a promising drug because of its convenience and may replace weekly paclitaxel for unresectable or recurrent gastric cancer. PMID- 25731487 TI - [A case report of distal gastrectomy with thrombectomy after NAC for Gastric cancer]. AB - This is a case report of gastric cancer with a tumor embolus in the portal vein of a 76-year-old male. Both computed tomography (CT) and upper gastrointestinal endoscopy were performed. The diagnosis was gastric cancer with an accompanying tumor embolus in the portal vein, specifically in the superior mesenteric vein. After neoadjuvant chemotherapy, a distal gastrectomy, and thrombectomy were performed. Upon pathological examination, the main tumor was diagnosed as adenocarcinoma, and the embolus was confirmed to extend from the main tumor into the superior mesenteric vein. Upon immunostaining examination, neither the embolus nor main tumor expressed alpha-fetoprotein (AFP), but both expressed carcinoembryonic antigen (CEA). Gastric cancer with a tumor embolus in the portal vein is considered an incurable disease. However, with no other non-curative factor than portal vein embolus, it is possible that gastrectomy with thrombectomy can result in a good prognosis. On the other hand, it is extremely difficult to improve the prognosis of gastric cancer with both tumor embolus in the portal vein and liver metastasis. PMID- 25731488 TI - [A case of gastric cancer with solitary metachronous adrenal metastasis]. AB - A 61 -year-old man underwent total gastrectomy with distal pancreatectomy and D2 lymphadenectomy for gastric cancer. The final diagnosis was UM, Post-Gre-Less, Type 3, 12 * 9 cm, T4b (SI), N3b (31/99), H0, P0, CY0, M0, tub2, ly3, v3, Stage IIIC, R0. Fifteen months after the operation, abdominal computed tomography showed a left adrenal tumor measuring 2.5 cm in diameter. Because it was a solitary tumor, we performed tumor resection, confirming adrenal metastasis that was negative for human epidermal growth factor receptor type 2 (HER2). Subsequently, the patient was treated with a chemotherapy regimen consisting of S 1 plus cisplatin. Because he developed left adrenal metastasis 6 months after tumor resection, we initiated chemotherapy with docetaxel plus irinotecan. Left adrenalectomy was performed owing to the tumor increasing to 3.6 cm despite chemotherapy. The patient is currently alive 50 months after the initial operation, without any signs of disease recurrence. For patients with solitary adrenal metastasis from gastric cancer, surgical resection in addition to chemotherapy might be the preferred choice of treatment. PMID- 25731489 TI - [Gastric cancer arising from gastric polyps in gardner syndrome - a case report]. AB - The patient was a 48-year-old woman who was diagnosed with early gastric cancer during a long-term follow-up period for Gardner syndrome. Subtotal colectomy for colon leiomyoma was performed when the patient was 22 years old. Partial resection of the ileum was performed for ileum leiomyoma at the age of 27. Total resection of the remaining colon with ileostomy was performed for a pelvic desmoid tumor at the age of 40. In addition, resection of a desmoid tumor of the abdominal wall was performed 8 times in the 25 years since the first operation. During the follow-up for gastric polyps associated with Gardner syndrome, gastric cancer was detected from biopsy specimens of a wide range of the fundus polyps. Endoscopic resection was considered not to be applicable because of the extensive nature of the lesion. Total gastrectomy was also considered not to be applicable because of concerns about short bowel syndrome due to intestinal reconstruction. Therefore, proximal gastrectomy with esophagogastric anastomosis was performed. The pathological diagnosis was 0-IIa, 70 * 44 mm, tub1, m, ly0, v0, n0, PM (-), DM (-), stageIA. The postoperative course was uneventful, and the patient was discharged on postoperative day (POD) 16. We speculate that long-term survival of patients with Gardner syndrome without severe short bowel syndrome might result in carcinogenesis of gastric polyps. PMID- 25731490 TI - [A case of gastric cancer developed after pylorus-preserving gastrectomy in a patient with lynch syndrome]. AB - Lynch syndrome is an inherited autosomal dominant disorder caused by germ-line mutation of mismatch repair genes, in which a malignant tumor develops at a young age in the colon, endometrium, stomach, or other tissues. A 54-year-old patient with gastric cancer received pylorus-preserving gastrectomy, and a genetic examination confirmed a pathological variation of the MLH1 gene. Five years after surgery, an upper gastrointestinal endoscopy revealed a residual 0 -IIa+IIc gastric tumor approximately 2 cm in size extending from the anastomotic site to the lesser curvature side of the stomach. The remaining stomach was completely removed. The final diagnosis was T1b (SM) N1M0, StageIB gastric cancer. Microsatellite instability was positive, and we attributed the cancer to Lynch syndrome. In Lynch syndrome, the risk of multicentric gastric cancer is higher than normal, and for the initial therapy, preventive total gastrectomy should be considered as an option. PMID- 25731491 TI - [A case report of gastric cancer consisting predominantly of undifferentiated carcinoma]. AB - We encountered a rare case of gastric cancer consisting predominantly of undifferentiated carcinoma.The patient was a 64-year-old man who underwent various tests because of symptoms of dysphagia in September 2012.We found a subcircumferential type II tumor at the gastroesophageal junction.A total gastrectomy, splenectomy, and Rouxen-Y reconstruction were performed.Adhesiotomy was also performed for the ileus on postoperative day (POD)2.The patient subsequently experienced septic shock with disseminated intravascular coagulation (DIC) and acute kidney failure due to complications of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and MRSA colitis.As a consequence, the patient required respiratory management and continuous hemodiafiltration (CHDF). In addition, the patient experienced hemorrhage from the Roux-en-Y-anastomotic site in the contact with the ileus tube during treatment for septicemia on POD14, which was resolved with endoscopic treatment.Moreover, a cholecystectomy was performed on POD52 for gangrenous cholecystitis.The patient's progress was satisfactory.The pathology results revealed an undifferentiated carcinoma with the following characteristics: pT4a (SE), ly1, v0, pPM1, pDM0, type 2, 80 * 75 mm, UE, Less.In addition, immunostaining results revealed a tumor consisting of at least 90% of undifferentiated carcinoma tissue.Four months after surgery, local recurrence at the site of the esophagojejunostomy, disseminated recurrence around the left kidney, and metastases in the left adrenal gland appeared. The partial response (PR) was maintained by treatment with CPT-11+ cisplatin (CDDP) + trastuzumab.However, left adrenalectomy was performed 1 year and 4 months after the initial surgery was performed for metastasis to the left adrenal gland that started 10 months after surgery.One year and 10 months after the initial surgery, the patient continues to receive treatment with trastuzumab and has not exhibited signs of recurrence. PMID- 25731492 TI - [A case of an adenocarcinoma in a duplication cyst of the esophagogastric junction]. AB - Duplication cysts of the esophagogastric junction are an extremely rare disease entity. Computed tomography showed a cystic lesion in the wall of the esophagogastric junction ofa 75-year-old man. The cystic tumor gradually increased in size from 40 mm to 60 mm in diameter within 6 months. On the basis of magnetic resonance cholangiopancreatography and positron emission tomography, it was described as a cystic pathological alteration enclosing a solid lesion. The pre-operative diagnosis was a gastrointestinal stromal tumor in the stomach cardia, and we performed proximal gastrectomy under laparotomy. Histological findings showed gastric mucosa in the internal mucosa of the cyst and an adenocarcinoma inside the cyst. We diagnosed the cystic tumor as a duplication cyst of the esophagogastric junction with adenocarcinoma. It is important to carefully choose the procedure to be used for resection of cystic tumors adjacent to the alimentary canal. PMID- 25731493 TI - [A case of gastric small cell carcinoma with liver and lymph node metastases responding to CPT-11 plus CDDP chemotherapy]. AB - We report a case of gastric small cell carcinoma with liver and lymph node metastases responding to CPT-11 plus cisplatin (CDDP) chemotherapy. The patient was a 77-year-old woman with advanced gastric cancer, clinically diagnosed as P0H1M1CY0T4aN3. The immunostaining and pathological analysis of a biopsied specimen obtained during a gastrointestinal tract endoscopy indicated small cell carcinoma of the stomach. The patient received the following chemotherapy treatments: 11 courses of CPT-11 plus CDDP, 8 courses of docetaxel plus S-1, and 2 courses of paclitaxel. The patient is alive 2 years after the first chemotherapy treatment. We conclude that the combination of chemotherapy used was effective for treating the patient's small cell carcinoma of the stomach, which is considered to have a poor prognosis. PMID- 25731494 TI - [A case report of advanced gastric cancer with bulky lymph node metastases successfully treated with induction chemotherapy followed by curative resection]. AB - The patient was a 74-year-old woman with advanced gastric cancer in the greater curvature of the antrum and lesser curvature of the angle.Abdominal computed tomography revealed bulky lymph node metastases of No. 3, 8a, and 11p.She was diagnosed with clinical Stage IIIA gastric cancer (cT3N2M0) and underwent surgery.Laparotomy findings revealed invasion of bulky lymph nodes to the common hepatic artery and pancreas.Since radical resection was not feasible, exploratory laparotomy was performed.After the surgery, she received 1 course of S-1 monotherapy and 3 courses of S-1/cisplatin (CDDP) therapy.The therapeutic response, as assessed by imaging studies, was partial for the primary lesions and complete for the enlarged lymph nodes.Distal gastrectomy and D2 lymph node dissection were performed.Histopathological findings showed no evidence of lymph node involvement, allowing the patient to undergo radical surgery.The patient received postoperative adjuvant chemotherapy with S-1.She is alive 11 months after the surgery, with no evidence of recurrence.Induction chemotherapy appears to be a promising option for advanced gastric cancer with significant lymph node involvement. PMID- 25731495 TI - [Two cases of advanced gastric cancer achieved pathological complete response by preoperative chemotherapy with S-1 plus weekly low-dose CDDP]. AB - We report 2 cases of resectable advanced gastric cancer who achieved pathological complete response by preoperative chemotherapy with S-1 plus weekly low-dose cisplatin (CDDP). S-1 (80 mg/m2)was administered consecutively for 21 days followed by 14 days' rest, with CDDP (25mg/m2) injected on days 1, 8, and 21. Case 1: A man in his 70s diagnosed with cStage III gastric cancer with lymph node metastases received 2 courses of preoperative chemotherapy with S-1 plus weekly low-dose CDDP followed by total gastrectomy with D2 lymph node dissection. Case 2: A man in his 60s diagnosed with cStage III gastric cancer with lymph node metastases received 4 courses of preoperative chemotherapy with S-1 plus weekly low-dose CDDP followed by total gastrectomy with D2 lymph-node dissection. In both cases, postoperative pathological examination revealed no cancer cells in the resected stomach and lymph nodes. The therapeutic effect of preoperative chemotherapy was assessed as Grade 3. With this regimen, we accomplished preoperative chemotherapy successfully without inpatient care. This regimen can be a promising option as preoperative chemotherapy for advanced gastric cancer. PMID- 25731496 TI - [Pathological complete response in a case of advanced gastric cancer after neoadjuvant chemotherapy]. AB - A 6 2-year-old man with advanced gastric cancer was referred to our hospital. A gastroscopy revealed a type 3 tumor invading the esophagus in the lesser curvature of the stomach cardia. We diagnosed the tumor as cStageIIIB(T4bN1M0) gastric cancer. For the best chance of a pathological complete response, we selected neoadjuvant chemotherapy (NAC) with S-1+CDDP (SP therapy). A total gastrectomy with lymph node dissection was performed after 2 courses of SP therapy. Pathological evaluation of the resected stomach and lymph nodes indicated an absence of cancerous cells, confirming a pathological complete response (pCR). The patient has been followed up for 4 months without evidence of recurrence. PMID- 25731497 TI - [A case of HER2-positive esophagogastric junction cancer treated by using a neoadjuvant chemotherapy regimen consisting of trastuzumab]. AB - The case herein pertains to a 78-year-old man, who was referred to our department and in whom esophagogastric junctional cancer, triggering weight loss, was indicated. A 0.75 xx circumferential Type 3 lesion was observed in the esophagogastric junction via upper gastrointestinal endoscopy, and a biopsy revealed a moderately differentiated adenocarcinoma with overexpression of human epidermal growth factor type 2 (HER2). Contrast-enhanced computed tomography (CT) showed multiple enlarged lymph nodes on the lesser curvature of the stomach. The preoperative diagnosis was T4a (SE) N2M0, Stage IIIB esophagogastric adenocarcinoma. Four courses of preoperative chemotherapy consisting of capecitabine plus cisplatin and trastuzumab were administered. The primary lesion showed cicatrization after chemotherapy, and enlarged lymph nodes were not visible on a CT scan. Total gastrectomy, splenectomy, and D2 lymph node dissection were performed. Only a small amount (approximately 5 mm) of the primary lesion remained beneath the abdominal and esophageal mucosa, and the treatment effectiveness was Grade 2. The final diagnosis was T1b (SM) N0M0, Stage IA esophagogastric adenocarcinoma. Survival with no recurrence was confirmed 6 months after surgery. These findings suggest that inclusion of trastuzumab in preoperative chemotherapy regimens improves the degree of curability of HER2 positive esophagogastric junction cancers. PMID- 25731498 TI - [A case report of neuroendocrine carcinoma of the stomach with liver metastases curatively resected after neoadjuvant chemotherapy]. AB - The patient was a 73-year-old male with advanced gastric cancer in the lesser curvature of the antrum.Abdominal computed tomography revealed multiple liver metastases(S5, S8).He was diagnosed with clinical Stage IV gastric cancer (cT3N0M1H1).He received 3 courses of combined neoadjuvant chemotherapy with capecitabine, cisplatin, and trastuzumab because immunostaining indicated the tumor was human epidermal growth factor receptor 2(HER2)-positive.The therapeutic response, as assessed by imaging studies, was partial for the primary lesions and stable for liver metastases.Distal gastrectomy, D2 lymph node dissection, and S5 extended subsegmentectomy of the liver were performed.Histopathological findings indicated that both the primary tumor and liver metastases were neuroendocrine carcinoma.The patient declined post-operative adjuvant chemotherapy and he is alive 6 months after the surgery with no evidence of recurrence.Surgery with neoadjuvant chemotherapy appears to be a promising option for advanced gastric cancer with liver metastases. PMID- 25731499 TI - [A case of advanced gastric cancer with liver metastasis involving curative surgery after neoadjuvant chemotherapy]. AB - A 77-year-old-woman, whose chief complaint was anemia, was referred to our hospital and diagnosed with advanced gastric cancer with liver metastasis and lymph node metastasis.Gastrointestinal endoscopy showed a tumor on the lesser curvature of the gastric corpus.Histologically, biopsy specimens indicated adenocarcinoma with genetic amplification of human epidermal growth factor receptor type 2.Computed tomography and magnetic resonance imaging showed lymph node metastasis and liver metastasis.The patient received a total gastrectomy and a partial liver resection after combination chemotherapy consisting of capecitabine, cisplatin, and trastuzumab.Histopathological examination of a resected specimen showed a minute residual cancer nest at the subserosa of the stomach and lymph node metastasis, but no liver metastasis. This combined modality therapy can be considered an effective treatment for gastric cancer with liver metastasis, and we hope that it will be established as a standard therapy. PMID- 25731500 TI - [Examination of outcomes after conversion surgery for Stage IVGastric cancer in our hospital]. AB - PURPOSE: We examined the outcomes of conversion surgery (CS) for Stage IV gastric cancer performed in our hospital. OBJECTIVE AND METHOD: We retrospectively examined the outcomes of 5 Stage IV gastric cancer patients, for whom surgical excision was possible and CS was performed after induction chemotherapy between January 2010 and December 2013. RESULTS: The median age of the patients who underwent CS was 62 years, and non-recovering factors were as follows: M1 (LYM) for 3 patients, H1 for 1 patient, and P1 for 1 patient. For all patients, the induction chemotherapy regimen consisted only of TS-1+cisplatin (CDDP). Using diagnostic imaging to determine treatment effect, we found that 2 patients showed a partial response(PR)as a result of the induction chemotherapy. As a result of CS, R0 surgery could be enforced to 3 cases and postoperative complications accepted neither. Ef-grade which of the histopathological judging of the chemotherapy were 1a: 4 cases, 2: 1 case. After adjuvant chemotherapy treatment in 3 patients, the median survival time (MST) of the CS patients was 22.5 months. In contrast, the MST of non-CS patients, who received treatments other than CS, was 4 months. These results indicate that the MST for CS patients was substantially longer compared to patients who did not receive CS (p=0.046). CONCLUSION: Although CS in response to Stage IV gastric cancer fully needed to examine selection of a case, the timing of operation introduction, etc. to be successful, a possibility of contributing to a prognosis improvement in a multidisciplinary treatment was suggested. PMID- 25731501 TI - [A case of HER2-positive advanced gastric cancer with extensive lymph node metastasis treated via chemotherapy with a trastuzumab-containing regimen followed by conversion surgery]. AB - A 62-year-old man presented with type 3 gastric cancer (tub1, HER2 positive) in the cardia, with 10-cm direct invasion into the lower esophagus, and extensive lymph node metastasis (Virchow and paraaortic nodes). Trastuzumab (Her), in the XP regimen (capecitabine and cisplatin [CDDP] plus Her; Xeloda(r): 2,000 mg/m2 on day 1-14, CDDP: 80 mg/m2 on day 1, Her: 8(6) mg/kg on day 1), was administered every 3 weeks and repeated for 6 courses. After administering 6 courses of the XP plus Her regimen, without severe adverse events in the patient, computed tomography (CT) revealed shrinkage of both the main tumor and the metastatic sites, by 51%. Esophagectomy and proximal gastrectomy with 3-field lymphadenectomy and gastric tube reconstruction was performed via right thoracotomy and laparotomy (R0). However, Grade 3 pneumonia occurred postoperatively, and the patient was discharged on day 67 after surgery. After treatment, the tumor was histologically evaluated as Grade 1b gastric cancer, and remnant cancer cells also expressed HER2. The patient was too frail to receive adjuvant chemotherapy, and he died of pneumonia 11 months after surgery, without obvious relapse. Perioperative chemotherapy with a regimen containing Her has a possible role in treating advanced HER2-positive gastric cancer. Multiple invasive conversion surgeries might decrease the feasibility of adjuvant chemotherapy and worsen the prognosis. PMID- 25731502 TI - [A case of advanced gastric cancer successfully treated with second-line chemotherapy followed by curative conversion gastrectomy]. AB - We report a case of advanced gastric cancer that was successfully treated with second-line chemotherapy followed by curative conversion gastrectomy. The patient was a 71-year-old man. Endoscopic examination revealed a type 3 gastric cancer in the lower third of the stomach. Abdominal computed tomography (CT) revealed multiple lymph node metastases and metastasis to the peritoneal cavity. The clinical diagnosis was cT4N3aP1H0M1(LYM), cStage IV. The patient was treated with S-1 (80 mg/m2 on days 1-28, every 6 weeks [q6w]) in November 2009. Temporarily, both the size of the primary lesion and the swelling of the lymph nodes were markedly reduced. However, after 10 courses of chemotherapy, the primary lesion was found to be enlarged again. The patient was then treated with S-1(80 mg/m2, on days 1-14, every 6 weeks [q3w]) plus CPT- 11 (150 mg/m2 on day 1, q3w) as the second-line chemotherapy. After 8 courses, an abdominal CT showed no peritoneal or lymph node metastases, but gastric endoscopy revealed the presence of a residual primary lesion. After staging laparoscopy, distal gastrectomy with D2 lymphadenectomy was performed. The histological diagnosis was ypT3 (SS) N1M0, Stage IIB. Analysis of the histological features of the primary tumor and peritoneal metastases resulted in their classifications as Grade 1a and Grade 3, respectively. After surgery, there were no serious adverse events. The patient has been in good health without recurrence for over 3 years after surgery. PMID- 25731503 TI - [A case of curative surgery for HER2-positive gastric cancer after chemotherapy using paclitaxel combined with trastuzumab]. AB - A 74-year-old man was diagnosed with unresectable HER2-positive gastric cancer due to metastases to distant lymph nodes. Paclitaxel combined with trastuzumab was administered as third-line chemotherapy. After 4 courses of therapy, the metastases to distant lymph nodes disappeared with no evidence of progressive disease. Downstaging by chemotherapy made curative treatment feasible and he underwent distal gastrectomy. The patient has been free from recurrent disease 13 months after surgery. PMID- 25731504 TI - [Curative resection for Stage IV advanced gastric cancer that responded to combination chemotherapy with docetaxel, cisplatin, and S-1]. AB - A 50-year-old man was diagnosed with advanced gastric cancer(Borrmann type 3)accompanied with N3.Staging laparoscopy revealed invasion to the transverse mesocolon and positive cytology from peritoneal washing (CY1). After the patient underwent gastrojejunostomy, we administered DCS combination chemotherapy consisting of docetaxel (40 mg/m2 intravenously on day 1), cisplatin(60 mg/m2 intravenously on day 1), and S-1 (orally 80 mg/m2 on days 1 to 14).Four courses of this treatment were provided every 4 weeks, and it resulted in a partial response (PR).We performed curative distal gastrectomy with transverse mesocolon resection and D2 plus 14v lymph node dissection. Cytological analysis of the samples obtained after peritoneal washing showed negative results.Histopathologically, no variable cancer cells remained in the primary lesion, but a few degenerated cancer cells remained in one of the lymph nodes.Pathological features were classified as Grade 3 for the primary lesion and Grade 2 for the lymph node lesions.S -1 and S-1/cisplatin were administered as adjuvant chemotherapy.One year and 6 months after surgery, the patient is alive and free of disease. PMID- 25731505 TI - [Two cases of Stage IV Gastric cancer responding to chemotherapy and leading to pathological complete response]. AB - Case 1: A 76-year-old man presented with advanced gastric cancer in the esophagogastric junction with para-aortic lymph node metastasis (HER2 positive cT4N1M1 [LYM], cStage IV). After 3 courses of chemotherapy consisting of S 1+docetaxel +trastuzumab were completed, we performed surgery. No cancer cells were revealed during histopathological examination, indicating pathological complete response (pCR). At present, 12 months after treatment, the patient is well, with no signs of recurrence. Case 2: A 74-year-old man presented with advanced gastric cancer with peritoneal metastasis (cT4b[Panc] N1M1[P], cStage IV). After 2 courses of chemotherapy consisting of S-1+CDDP were completed, we performed surgery. Histopathological examination revealed no cancer cells, indicating pCR. At present, 13 months after treatment, the patient is incident free, with no signs of recurrence. PMID- 25731506 TI - [A case of advanced gastric cancer successfully treated with trastuzumab, capecitabine, and Cisplatin therapy followed by curative resection]. AB - We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23 year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S 1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1. PMID- 25731507 TI - [Significance of surgical resection of local recurrence after gastrectomy for gastric carcinoma - report of two cases]. AB - We report on 2 patients with gastric carcinoma who underwent surgical resection for local recurrence after gastrectomy. Patient 1 was admitted to our hospital because of left-upper abdominal pain caused by local recurrence with abdominal wall invasion. He had undergone distal gastrectomy for gastric cancer 2 years and 4 months previously. Surgical resection of the tumor involving the stomach jejunum anastomosis region with partial hepatectomy and colectomy was performed. The patient was subsequently discharged without symptoms. A re-recurrence requiring ileocolic bypass then occurred. In spite of chemotherapy and radiotherapy, he died 6 months after the re-recurrence. Patient 2 was admitted to our hospital because of ileus by transverse colon obstruction. He had undergone total gastrectomy for gastric cancer 6 years and 7 months previously and received chemotherapy for local recurrence 4 years after the first surgery. Resection of the local recurrence involving the right transverse colon and the gallbladder was performed at that time. He was discharged without symptoms. He exhibited re recurrence in the right-upper abdomen 2 months after the second operation. Surgical resection for local recurrence is useful for the improvement of quality of life (QOL) in appropriate cases, but the re-recurrence risk is high because of low curability in these cases. PMID- 25731508 TI - [A case of locoregional recurrence of gastric carcinoma that was treated using pancreaticoduodenectomy]. AB - A 71-year-old man underwent distal gastrectomy for gastric cancer in November 2011. The corresponding pathological diagnosis was of well differentiated adenocarcinoma, pT4a(SE), N1(2/15), H0, P0,M0, pStage IIIA. TS-1 was administered as an adjuvant therapy for one year from the second month after the operation. During the 16th month after the operation, we found an elevated tumor marker level and locoregional recurrence near the pancreas head and the abdominal wall upon computed tomography. We could not find any other suspected tumor recurrence using positron-emission tomography and computed tomography. We performed a pancreaticoduodenectomy and transverse colon merger resection in June 2013. Although the tumor marker was again found to be elevated during the second month after the metastasectomy, chemotherapy was continued because obstructive jaundice and gastrointestinal obstruction were prevented by the operation. PMID- 25731509 TI - [A case of surgery for stenosis of the colon from recurrent gastric cancer]. AB - In June 2010, a 67-year-old man presented with advanced gastric cancer. He underwent 2 courses of combination chemo- therapy with S-1/CDDP. After chemotherapy, total gastrectomy was performed (pT4aN3aM0, Stage IIIC). Although he underwent S-1 chemotherapy, colon tumors recurred 22 months after the operation. Colonoscopy revealed the presence of type 2 advanced cancer in the ascending colon, and type IIa early cancer in the transverse colon, which were diagnosed as either primary colon cancers or recurrent gastric cancers upon pathological examination. In October 2012, resection of the right side of the colon was performed in order to prevent malignant bowel obstruction. Pathological examination of the resected specimen identified recurrent gastric cancers. After the surgery, he is currently undergoing S-1 chemotherapy and has no sign of recurrent tumors. PMID- 25731510 TI - [Two cases of afferent loop syndrome caused by obstruction at the jejuno jejunostomy site in the Roux-en-Y loop that were successfully treated by endoscopic balloon dilatation]. AB - We report 2 rare cases of afferent loop syndrome caused by obstruction at the jejuno-jejunostomy site in the Roux-en-Y loop after total gastrectomy, which was successfully treated by endoscopic balloon dilatation of the anastomotic stenosis. Case 1: A 62-year-old woman presented with malaise and lower abdominal distension 6 months after laparoscopy-assisted total gastrectomy with Roux-en-Y reconstruction. She was diagnosed with afferent loop syndrome; CT imaging indicated marked dilatation of the afferent loop, with membranous obstruction at the jejuno-jejunostomy site in the Roux-en-Y loop. Although almost complete occlusion was noted at the jejuno-jejunostomy site, the obstruction was successfully relieved by endoscopic balloon dilation using TandemTM XL Triple Lumen ERCP Cannula (Boston Scientific)(r). Case 2: A 70-year-old man presented with malaise and lower abdominal distension 3 years after laparoscopy-assisted total gastrectomy with Roux-en-Y reconstruction. He was diagnosed with afferent loop syndrome; CT imaging indicated complete obstruction at the jejuno jejunostomy site in the Roux-en-Y loop. As in case 1, the obstruction was successfully treated by endoscopic balloon dilatation of the occluded anastomosis. PMID- 25731511 TI - [Effectiveness of chemoradiotherapy for a patient with local recurrence of advanced gastric cancer followed by curable gastrectomy]. AB - We report here the effectiveness of chemoradiotherapy for a patient with local recurrence followed by curable gastrectomy. A 57-year-old man presented with a history of total gastrectomy with distal pancreatectomy and splenectomy, D2 lymphadenectomy, and Roux-en-Y reconstruction for advanced gastric cancer arising from the cardia. Esophageal intramural metastasis and lymph node metastasis around the right recurrent nerve were detected by chest-abdominal computed tomography and gastrointestinal endoscopy 27 months after the initial gastrectomy. Stable disease was achieved following 7 courses of chemotherapy using S-1 plus CDDP. Concurrent chemoradiotherapy including administration of S-1 and radiation of total 50 Gy (2 Gy/25 Fr) was selected for local tumor control. The patient was not able to eat solid food because of esophageal stenosis from regrowth of intramural metastasis of the esophagus 60 months after the chemotherapy. A WallFlexTM Duodenal Stent was placed to improve the dysphagia 67 months after chemotherapy. The patient died from recurrence of gastric cancer 69 months after completion of the initial chemotherapy and 2 months after the stent insertion. PMID- 25731512 TI - [Three cases of endoscopic gastroduodenal stenting for gastric outlet obstruction caused by unresectable gastric cancer]. AB - Gastroduodenal stenting for gastric outlet obstruction (GOO) caused by malignant disease has been covered by health insurance in Japan since April 2010. We have inserted WallFlexTM duodenal stents (WDS) in 3 patients with GOO caused by unresectable advanced gastric cancer. WDS placement was successful with no complications in all cases. Mean treatment time was 44.7 (35-50) minutes, and mean survival time after WDS placement was 34.7 (19-51) days. Oral food intake was improved in all patients but 1. Enteroparalysis due to peritoneal metastasis supposedly voided WDS placement in 1 patient. WDS placement for GOO caused by advanced gastric cancer is expected to be a safe and effective palliative treatment but sometimes yields no benefit in the patient with peritoneal metastasis. PMID- 25731513 TI - [Palliation of gastric cancer-related jejunum stricture with a self-expandable metal stent - a case report with review of the literature]. AB - Prospective randomized controlled studies have indicated that endoscopic placement of self-expandable metal stents (SEMSs)is an effective treatment option for patients with malignant gastric outlet obstruction (GOO). We report a case of effective palliation of gastric cancer-related jejunum stricture with a SEMS. A7 7-year-old woman, who had previously undergone partial remnant gastrectomy and Roux-en-Y reconstruction, was diagnosed with abdominal recurrence of gastric cancer. After a 4 month observation period, which the patient opted for with informed consent, recurrent vomiting and loss of appetite ensued. Computed tomography (CT) and upper gastrointestinal series (UGI) examinations revealed a single intestinal stenosis caused by a recurrent tumor. Endoscopic placement of a SEMS palliated this intestinal obstruction, and her oral intake improved (GOOSS score improved from 0 to 3). Upper gastrointestinal series verified that the SEMS maintained its lumen 3 months after the procedure. Endoscopic treatment with a SEMS can be more effective for malignant intestinal stenosis caused by abdominal recurrence of gastric cancer, especially when it is difficult to laparotomy adhesion derived previous operation or peritonitis carcinomatosa. Further studies may be needed to clarify the clinical benefits of stent placement for patients with abdominal recurrence of gastric cancer. PMID- 25731514 TI - [Efficacy of endoscopic gastroduodenal stenting for unresectable gastric cancer with gastric outlet obstruction]. AB - METHODS: We performed endoscopic gastroduodenal stenting for gastric outlet obstruction (GOO) caused by unresectable gastric cancer in 15 patients. We compared the clinical outcomes of the stent placement procedure with those of a gastrojejunostomy performed in 32 patients. RESULTS: Stent placement was performed safely without complications, and the median number of days until oral food intake could be resumed and the median number of days spent in the hospital was 2 and 15 days, respectively. The GOO score improved in 13 patients (87%); however, re-interventions were necessary for 7 patients due to stent obstruction caused by tumor growth. No differences between the stenting and gastrojejunostomy groups were found for the rate of improvement in GOO score, the duration until oral food intake could be resumed, or the overall survival rate. Patients in the stenting group had significantly fewer complications and shorter hospital stay. However, more re-interventions were required for patients of the stenting group compared to patients of the gastrojejunostomy group. CONCLUSION: Endoscopic gastroduodenal stenting can be performed safely and is beneficial for the improvement of oral food intake. PMID- 25731515 TI - [A case of gastric cancer with liver metastases achieving a clinical complete response after S-1 plus CDDP therapy]. AB - We report a case of gastric carcinoma with metastasis to the liver responding to surgery and chemotherapy.The patient was a 74-year-old man with gastric cancer, clinically diagnosed as P0H0M0T3N0.We initially planned to perform an open distal gastrectomy.However, intraoperative findings revealed metastatic tumors in the liver.Therefore, the patient underwent a D1 distal gastrectomy.After surgery, the patient received the following chemotherapy regimens: 1 course of S-1 and 8 courses of a S-1 and cisplatin (CDDP) combination.After 8 courses of S-1 plus CDDP treatment, liver metastases could not be detected by computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET). The patient was assessed to have a clinical complete response.Fifty months after surgery, the patient is alive without recurrence. PMID- 25731516 TI - [A case of advanced gastric cancer with portal vein thrombus leading to liver metastases]. AB - A 68-year-old man presenting with anorexia was admitted to our hospital; he was diagnosed with pyloric stenosis arising from a type 3 tumor in the antrum of the stomach. Pathological examination revealed a poorly differentiated adenocarcinoma; immunohistochemical staining tested positive for alpha fetoprotein(AFP), and negative for human epidermal growth factor receptor 2(HER2). Abdominal computed tomography (CT) showed a portal vein thrombus and enlarged lymph nodes. Since the clinical finding was Stage IV(T4aN3M1), curative surgery was ruled out. Following stent placement for food intake, TS-1 plus cisplatin (CDDP) neoadjuvant chemotherapy was initiated. TS-1(80 mg/m2 / day) was administered orally for 2 weeks followed by a drug-free 1-week period, and CDDP (60 mg/m2) was administered intravenously on day-1 as 1 course. After 5 courses of this regimen, lymph nodes were reduced in size and the portal vein thrombus disappeared. However, grade 4 thrombocytopenia was observed, and the treatment schedule was modified to include several other chemotherapies. Two years after the initiation of chemotherapy, liver metastasis was detected via elevated AFP. The patient died 27 months after initial treatment. Although the prognosis for gastric cancer with portal vein thrombus is very poor, it is possible to prolong survival with multimodality therapy. PMID- 25731517 TI - [A case of Stage IV gastric cancer was successfully treated with multi combination chemotherapy with S-1]. AB - Stage IV gastric cancer has poor prognosis, and median survival time (MST) is reported to range from 6 to 13 months. We report a case of long-term survival in a Stage IV gastric cancer patient who was successfully treated with multi combination chemotherapy with S-1. A 73-year-old woman presenting with gastric cancer with pyloric stenosis and peritoneal dissemination at the sigmoid colon underwent distal gastrectomy with D2 lymphadenectomy and sigmoidectomy. She received adjuvant chemotherapy with S-1 and CDDP after surgery. During the twelfth administration of S-1 and CDDP, she developed an anaphylactic reaction against CDDP; therefore, only S-1 was administered for the next 6 courses. Thirty one months postgastrectomy, a left ovarian metastasis (about 4 cm) was detected by computed tomography. Two courses of S-1 and CPT-11 were administered; however, the ovarian metastasis grew to twice its initial size. She underwent hysterectomy and bilateral ovariectomy. The pathological diagnosis was metastatic tumors in the uterus and ovary(Krukenberg tumor). After the second surgery, S-1 and docetaxel therapy was initiated. A metastasis (S2, 5mm diameter) appeared in the right lung around 65 months after the gastrectomy. The patient received a total of 28 courses, up until 69 months post-gastrectomy. At present, she hopes to finish the chemotherapy and is consulting a palliative care facility. At 80 months post-gastrectomy, she has no symptoms because the lung metastasis exhibits slow growth (15 mm diameter), and is maintaining her quality of life (QOL). PMID- 25731518 TI - [A case of advanced HER2- positive gastric cancer with a partial response to molecular targeted chemotherapy (S-1+CDDP+Trastuzumab)]. AB - A 61-year-old man was referred to our hospital because of gastric pain and weight loss.Upper gastrointestinal endoscopy revealed a superficial depressed (Type 3) tumor with pyloric stenosis.The tumor was diagnosed as tubular adenocarcinoma by pathological examination.Abdominal computed tomography showed enlarged paraaortic and No. 8a lymph nodes.The patient underwent distal gastrectomy (D0)and Roux-en-Y reconstruction.After surgery, chemotherapy combined with molecular targeted therapy (S-1+cisplatin[CDDP]+trastuzumab), based on overexpression of the HER2 protein in the primary tumor as assessed by immunostaining, was administered.After the molecular targeted chemotherapy, the carcinoembryonic antigen (CEA )levels decreased to the normal range and the enlarged lymph nodes were remarkably decreased in size. The patient is currently alive without progressive disease. PMID- 25731519 TI - [A case of AFP-producing esophagogastric junction cancer with liver metastases with a good response to chemotherapy]. AB - A 62-year-old man was diagnosed with esophagogastric junction cancer following esophagogastroduodenoscopy in response to hematemesis. Although liver metastasis was detected during surgery, a total gastrectomy and lower esophagus resection for local control was performed. Alpha-fetoprotein(AFP)-producing tumor with hepatoid adenocarcinoma was diagnosed on the basis of the pathological examination. Serum AFP levels remained high postoperatively and multiple liver metastases were detected on computed tomography imaging. After 6 courses of chemotherapy with S-1 and cisplatin (CDDP), a significant reduction in the size of the liver metastases and a decrease of serum AFP levels were achieved. Postoperative 2-year tumor control using S-1 single agent chemotherapy was obtained. AFP-producing esophagogastric junction cancer has a poor prognosis. This case raises the possibility that long-term survival can be obtained by combining surgery for local control with systemic chemotherapy. PMID- 25731520 TI - [A case of metachronous liver metastasis from gastric cancer successfully treated with hepatectomy]. AB - The use of hepatectomy for the treatment of liver metastasis from gastric cancer has been controversial. We report a case of metachronous liver metastasis from gastric cancer, which we successfully treated with hepatectomy. A 59-year-old man underwent laparoscopy-assisted total gastrectomy with D1 plus lymphadenectomy for gastric cancer. The histopathological findings revealed that the tumor was a well differentiated tubular adenocarcinoma, T2(MP), N1(#1 2/3), M0, fStage II, according to the 14th edition of the Japanese Classification of Gastric Carcinoma. TS-1 was administered as adjuvant chemo- therapy for 1 year after the operation. About 5 years after the gastrectomy, a recurrent tumor was detected in S5/8-7 of the liver. Although chemotherapy with TS-1 plus Lentinan was administered, the liver tumor increased in size. Percutaneous transhepatic portal embolization was performed to improve liver function followed by resection of the right lobe of the liver. Paclitaxel plus doxifluridine (5'-DFUR) was administered for 6 months as adjuvant chemotherapy. No recurrence was observed for 17 months after hepatectomy. PMID- 25731521 TI - [A case of metastatic liver tumor arising from gastric cancer resected after second-line chemotherapy]. AB - A man in his 60s was diagnosed with gastric cancer and underwent distal gastrectomy and D2 lymph node dissection. The histological diagnosis was adenocarcinoma (T3, N1, StageIIB). He was treated with S-1 as adjuvant chemotherapy for 1 year. One year and 2 months after gastrectomy, a computed tomography (CT) scan revealed liver metastasis (S8, 38 mm). The patient was diagnosed with liver metastasis(refractory to S-1), and administered combination chemotherapy with irinotecan and cisplatin. After 4 courses of treatment, a CT scan detected a progressive liver tumor (55 mm). Combination chemotherapy with docetaxel and S-1 was selected as second-line chemotherapy. After 6 courses of treatment, the tumor size reduced to 40 mm in diameter, and no other metastasis was detected. Nine months after the diagnosis of liver metastasis, partial resection of the liver (S8) was performed. A pathological diagnosis of metastatic adenocarcinoma was determined, and the pathological therapeutic effect was rated as Grade 1b. Combination chemotherapy with docetaxel and S-1 was found to be effective, and was thus administrated after the operation. There have been no signs of recurrence for 6 months after the operation. Surgery with perioperative chemotherapy can be an effective treatment for liver metastasis from gastric cancer. PMID- 25731522 TI - [A case of gastric cancer showing response to first-line XP regimen after lymph node recurrence during the administration of S-1 as postoperative adjuvant chemotherapy]. AB - We report on a patient who underwent total gastrectomy with D2 lymph node dissection for metastatic gastric cancer. We administered S-1 at 60 mg/m2 as postoperative adjuvant chemotherapy. Six months after surgery, recurrence was detected in the para-aortic lymph node. As a first-line treatment for the recurrent cancer, the patient underwent capecitabine/CDDP therapy(capecitabine 1,800 mg/m2, CDDP 60 mg/m2). A significant reduction in the recurrent lymph nodes was observed by CT after 6 months of administration, resulting in 24 months of progression-free survival. S-1/CDDP therapy is recommended as a first-line chemotherapy for recurrent gastric carcinoma in the Japanese gastric cancer treatment guidelines. Likewise, single agent S-1 administration is recommended as postoperative adjuvant chemotherapy for advanced gastric cancer patients. However, in cases of recurrence after S-1 therapy, there is insufficient evidence on the efficacy of S-1/CDDP; thus, the type of administration and time to recurrence could be considered for optimization. We identified a case of gastric cancer showing response to first-line capecitabine/CDDP therapy after lymph node recurrence following the administration of S-1 as postoperative adjuvant chemotherapy. Since capecitabine and S-1 differ in their mechanisms of action and as predictive factors for therapeutic effect, capecitabine may be an efficient option in cases of S-1 failure. The present case suggests that capecitabine/CDDP therapy may be an effective treatment for S-1 pretreated patients with advanced or metastatic gastric cancer. PMID- 25731523 TI - [A case of successful treatment of peritoneal dissemination from gastric cancer with S-1/DOC chemotherapy]. AB - A 66-year-old man underwent a curative operation for advanced gastric cancer (T4aN0M0, Stage IIB). A gastric cancer recurrence with paraaortic lymph node (PALN) metastasis was diagnosed fifteen months after the operation. Systemic chemotherapy was initiated, using a regimen of S-1/CDDP. After 7 courses, abdominal computed tomography (CT) examination indicated the regression of PALN swelling. However, peritoneal dissemination was detected in the neighborhood of the right kidney. S-1/docetaxel (S-1/DOC) was selected as the second-line chemotherapy. After 3 courses, the peritoneal dissemination could not be detected. Five years since the curative operation, the patient has been doing well, with no signs of recurrence. In summary, we successfully treated a case of peritoneal dissemination from gastric cancer with S-1/DOC chemo- therapy. PMID- 25731524 TI - [A case of early gastric cancer completely responding to adjuvant chemotherapy for advanced colon cancer]. AB - A 70-year-old man was referred to our hospital with ascending colon cancer (cT3N1M0, Stage IIIa), which was found during examinations following a positive fecal occult blood test. The patient was also diagnosed with early gastric cancer (cT1a, N0, M0, Stage IA)during a preoperative gastroscopy examination. A laparoscopically assisted right colectomy and D3 lymphadenectomy was performed for the ascending colon cancer. The postoperative pathological diagnosis was Stage IIIb (pT3N2), he was administered in combination with capecitabine plus oxaliplatin (CapeOX) as adjuvant chemotherapy before the treatment for the colon cancer. After 6 months of adjuvant chemotherapy, we were unable to detect any gastric lesions at the same location using gastroscopy, and so diagnosed a clinical complete response. A follow-up gastroscopy 6 months later showed the same findings. The patient has had no recurrence of gastric cancer for 18 months after the initial operation. He will continue to be followed up closely using gastroscopy. In this case, CapeOX as adjuvant chemotherapy for advanced colon cancer was also effective for early gastric cancer. PMID- 25731525 TI - [A case report of scirrhous gastric cancer with peritoneal dissemination treated effectively with various chemotherapy regimens after laparoscopic distal subtotal gastrectomy]. AB - We report a 44-year-old male patient who was diagnosed with scirrhous gastric cancer with peritoneal dissemination using laparoscopy. The patient underwent a non-curative resection with laparoscopic distal subtotal gastrectomy. In addition, we placed a port into the patient's abdomen for intraperitoneal chemotherapy administration. Postoperatively, we administered capecitabine (per os)+ paclitaxel (intraperitoneally) and, after 2 cycles, the oral anticancer agent 5-FU was given. The patient died of peritonitis carcinomatosa 25 months after the operation. The combined therapies contributed to improve the quality of life, specifically oral ingestion, for 2 years. PMID- 25731526 TI - [Usefulness of FDG-PET for superficial esophageal squamous cell carcinoma]. AB - We investigated the usefulness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for superficial esophageal squamous cell carcinoma after resection via endoscopic submucosal dissection (ESD). Our case study included 37 patients and 49 tumors resected via ESD in our hospital between January 2012 and December 2013. Histopathological diagnosis confirmed squamous cell carcinoma in all cases. Tumors located near the esophago cardiac junction were excluded. We investigated retrospectively whether the standardized uptake value (SUV) obtained by using FDG-PET could be the criterion to decide whether to perform ESD. At first, the tumor was examined via endoscopy. If tumor depth (T status)was less than cSM1, we performed ESD. When the tumor depth was less than pSM1, no infiltration of the vessel or lymph duct was observed, and the surgical margin was free; therefore, we did not perform any further therapy. On the other hand, we measured the SUV obtained via FDG-PET. The cut-off value was set as 3.0 based on the correlation between the SUV and tumor depth. We investigated if SUV<.0 could be the criterion for further therapy after ESD. In our results, the sensitivity was 95%, specificity was 67%, and accuracy was 90%. The SUV also helped to identify the malignancy of the superficial esophageal cancer and could help to decide whether ESD should be undertaken. PMID- 25731527 TI - [A case of mediastinal recurrence of esophageal cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration]. AB - A 63-year-old man was admitted to our hospital for treatment of cervical esophageal cancer and hepatocellular carcinoma. He had undergone subtotal esophagectomy for esophageal cancer and partial hepatectomy for hepatocellular carcinoma after preoperative chemotherapy and transcatheter arterial embolization (TAE). Histologically, esophageal cancer was diagnosed as pT3, pN2, M0, pStage III. Five months after surgery, a 2.2 cm tumor with abnormal uptake of fluorodeoxyglucose (FDG) was found in the upper mediastinum by positron emission tomography-computed tomography (PET-CT). To obtain a definitive diagnosis, we performed endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) on the mediastinal tumor. A tumefactive mucosal lesion was present in the main bronchus and the presence of a tumor was confirmed by ultrasonography. We diagnosed the lesion as a mediastinal recurrence of the primary esophageal cancer because squamous cell carcinoma was observed upon cytological examination. Chemoradiotherapy was performed for the mediastinal recurrence. EBUS-TBNA was useful for the diagnosis of metastases and recurrence of esophageal cancer in the mediastinum. PMID- 25731528 TI - [A case of pneumatosis cystoides intestinalis after neoadjuvant chemotherapy for esophageal cancer]. AB - A man in his 60s was diagnosed with esophageal cancer (T3, N0, StageII) and treated with 5-fluorouracil and cisplatin as neoadjuvant chemotherapy (NAC). On day 18 of the second NAC course, the patient developed febrile neutropenia, and a computed tomography (CT) scan showed pneumatosis cystoides intestinalis (PCI) of the ascending and transverse colon, free air around the ascending colon, thickening of the gallbladder wall, pleural effusion, and ascites. Because there were no signs of peritoneal irritation and intestinal perforation was ruled out, conservative treatment was selected. Seven days after PCI was diagnosed, CT showed improvement in PCI and the free air had disappeared, and 26 days after the diagnosis, a subtotal esophagectomy was performed. Observation of the abdomen did not show a thickened wall or stenosis of the ascending or transverse colon. PCI could be treated conservatively, even with free air in the abdominal cavity, by comprehensively assessing not only the imaging but also the physical findings. We were able to perform radical resection of the esophageal cancer without excessive treatment for PCI. PMID- 25731529 TI - [Pulmonary embolism in esophageal cancer patients receiving neoadjuvant chemotherapy with CDDP and 5-FU]. AB - We report our experience with 2 male patients (71 and 74 years old, respectively) with advanced esophageal cancer who exhibited pulmonary embolism during treatment with neoadjuvant chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5- FU). The patients had no symptoms associated with pulmonary embolism. The pulmonary emboli were incidentally detected on computed tomography performed to assess the effect of chemotherapy. It was found that the pulmonary emboli were associated with the central venous catheter-associated thrombi. The pulmonary emboli were effectively treated with heparin in both patients. A recent meta-analysis showed that the risk of chemotherapy-associated venous thromboembolism was increased by 1.67-fold when CDDP was included in the chemotherapy regimen. The increased risk was proposed to be associated with CDDP-mediated endothelial cell injury, platelet activation, increased levels of coagulation factors, or renal damage. The pulmonary embolism in our cases may be ascribed to the central venous catheterization and the treatment with CDDP. A possible occurrence of venous thromboembolism should be kept in mind when CDDP is used, particularly with central venous catheterization, for the treatment of esophageal cancer. PMID- 25731530 TI - [A case of ARDS after esophagectomy treated with low-dose steroid therapy]. AB - A 48-year-old woman was found to have an esophageal cancer, and after preoperative chemotherapy with cisplatin (CDDP)/5-fluorouracil (5-FU), radical subtotal esophagectomy was performed. On the fifth day after surgery, her respiratory condition suddenly worsened and a chest radiograph showed low permeability in both lung fields, leading to a diagnosis of acute respiratory distress syndrome (ARDS) and intubation for mechanical ventilation. Since clinical examination did not detect signs of infection on the seventh day, we began administering hydrocortisone at a dose of 300 mg. Her inflammatory response and respiratory condition improved by the next day and the dose of hydrocortisone was gradually reduced. The patient was extubated on the 13th day, administration of steroids was halted on the 22nd day, and she was discharged from the hospital on the 26th day. ARDS remains a refractory disease and no drug has proven to be effective in randomized controlled trials. The use of steroids for ARDS management remains controversial. Our present case suggests that low-dose steroids from an early stage in uninfected ARDS patients may improve prognosis. PMID- 25731531 TI - [Evaluation of combination chemotherapy with docetaxel and nedaplatin in patients with advanced or recurrent esophageal cancer]. AB - BACKGROUND: There is no standard regimen after failure of 5-fluorouracil and cisplatin-based first-line chemotherapy in patients with advanced or recurrent esophageal cancer. The feasibility of combination chemotherapy with docetaxel (DOC) and nedaplatin (CDGP) for these patients was retrospectively evaluated. METHODS: Patients received DOC (30 mg/m2 intra- venously) and CDGP (30-40 mg/m2 intravenously) on days 1 and 15 of each 4-week period. The efficacy and toxicity of combination chemotherapy with DOC and CDGP in 13 patients was analyzed. RESULTS: The patients received a median of 2 cycles of treatment(range, 1-23). The response and disease control rates were 8% and 54%, respectively. Grade 3 or 4 hematological toxicities were neutropenia, anemia, and thrombocytopenia, observed in 4(31%), 11(15%), and 2 patients (15%), respectively. Non hematological toxicity, anorexia, was detected in only 1 patient(8%). No treatment-related death was observed. The median progression-free survival and overall survival were 3.2 and 11.6 months, respectively. CONCLUSIONS: Combination chemotherapy with DOC and CDGP is considered a feasible regimen for refractory esophageal cancer. PMID- 25731532 TI - [Heavy ion radiotherapy for recurrence of an esophageal primary malignant melanoma]. AB - A 55-year-old man, with a prior diagnosis of primary malignant melanoma of the esophagus, had undergone esophagectomy 6 years prior. During the postoperative follow-up, a flat tumor with black pigmentation, about 2 cm in diameter, was detected during upper gastrointestinal endoscopy. A pathological examination of the biopsy specimen showed a recurrent malignant melanoma. He underwent heavy ion radiotherapy for the tumor, and it disappeared after 6 months. Subsequently, a mediastinal lymph node metastasis was detected a year after radiotherapy. He received heavy ion radiotherapy for that tumor, and it was reduced in size a year after radiotherapy. At present, the patient is alive, 13 years after the initial radiotherapy. Although malignant melanoma is generally considered to be a radioresistant cancer, heavy ion radiotherapy led to a favorable outcome. This is the first reported case of heavy ion radiotherapy for treating the recurrence of a primary malignant melanoma of the esophagus. PMID- 25731533 TI - [Evaluation of esophageal cancer treatment for patients aged over 80 years]. AB - We examined the effectiveness of chemoradiotherapy for esophageal cancer patients aged 80 years or older, 9 of whom were treated after 2010. Treatment consisted of cisplatin 35 mg/m2 (day 1 and 29) and 5-FU 350 mg/m2 (days 1-4 and 29- 32) combined with 50.4 Gy radiotherapy (1.8 Gy/day, 5 days/week, days 1-42). We administered 50% of the normal dose of chemotherapy. Median survival was 387 days, and there were 6 PRs, 1 SD, and 2 PDs. The toxicities related to the chemoradiotherapy were manageable (7 patients had toxicities worse than Grade 2, of whom 6 died and 3 were alive at the time of reporting). This treatment may be effective and safe for elderly esophageal cancer patients. PMID- 25731534 TI - [An examination of the utility of high-precise radiation therapies for the recurrence of postoperative esophageal cancer]. AB - We analyzed 16 cases (23 therapeutic sites) of post-operative recurrence of esophageal cancers that were treated with high-precise radiation therapies.The recurrence sites were cervical lymph nodes (5 cases), superior mediastinal lymph nodes (5 cases), posterior mediastinal lymph nodes (3 cases), regional lymph nodes with anastomosis (2 cases), abdominal paraaortic lymph node (3 cases), and regions with hematogenous metastasis (5 cases: liver, lung, spleen, and dissemination to the diaphragm bottom).By recurrence number, 10 cases presented with a single lesion, and 6 cases had multiple lesions.The effect of the treatment was complete response (CR) in all cases, and 6 cases maintained CR.The median of the overall survival after radiotherapy was 562 (132-1,231) days.Analysis of the prognostic factors for the overall survival from a recurrence revealed that the metastatic number (single) (p=0.003), and the metastatic pattern(hematogenous metastasis) (p= 0.004), significantly improved prognosis.We conclude that radiotherapy is an option to extend prognosis in some recurrence cases. PMID- 25731535 TI - [Salvage gastrectomy and radiotherapy for R-CHOP-refractory gastric malignant lymphoma]. AB - A man in his seventies presented with a stomach abnormality that was revealed upon physical examination.Following workup, he was diagnosed with gastric diffuse large B-cell lymphoma (DLBCL)StageII1 (Lugano staging system for gastrointestinal lymphoma) with low risk as defined by the International Prognostic Index criteria.The entire stomach showed an intense, abnormal FDG uptake by FDG-PET evaluation.He was treated with rituximab plus CHOP (R-CHOP).The patient's body weight decreased by 12 kg during the treatment period.Post -treatment evaluation by gastroscopy and FDG-PET following 5 courses of R-CHOP therapy revealed a residual lesion in the stomach.Total gastrectomy was performed for R-CHOP refractory gastric DLBCL.The pathological diagnosis was DLBCL, and the pathological therapeutic effect was Grade 1a.Lymphoma cells were detected at the duodenal margin of the resected specimen, and an FDG-PET scan showed abnormal FDG uptake in the duodenal stump necessitating salvage chemotherapy (DeVIC therapy)and radiotherapy.The patient's body weight increased by 5 kg after gastrectomy and there were no signs of relapse for 14 months after the operation.Salvage therapy including gastrectomy may be effective for chemotherapy resistant gastric DLBCL. PMID- 25731537 TI - [Pathological complete response in a large gastric GIST that became resectable after neoadjuvant chemotherapy with imatinib mesylate]. AB - We report a case of a large gastric gastrointestinal stromal tumor (GIST), which became resectable and achieved pathological complete response after neoadjuvant chemotherapy with imatinib mesylate. A 59-year-old man presented with left hypochondrial pain. Abdominal computed tomography (CT) revealed gastric GIST invading the spleen and the diaphragm. Administration of imatinib mesylate was initiated as neoadjuvant chemotherapy. Six months after neoadjuvant chemotherapy with imatinib mesylate, abdominal CT revealed a reduction in tumor size. We judged the tumor resectable and performed partial gastrectomy and splenectomy. Histologically, number of myofibroblasts increased, but no viable tumor cells were observed. Pathological complete response was obtained. PMID- 25731536 TI - [A case of giant gastric GIST with multiple hepatic metastases with long-term survival after multimodal therapy]. AB - A male patient in his 40s presented with abdominal pain and mass palpitation. He was diagnosed with a submucosal gastric tumor and referred to our clinic. Computed topography (CT) scan revealed a large gastric tumor and multiple hepatic metastases. He was diagnosed with unresectable gastrointestinal stromal tumor (GIST) and began imatinib treatment. However, 2 weeks later, the patient developed a high fever and abdominal pain. Tumor necrosis and abscess formation was observed on the CT scan. We performed emergency surgery, which comprised partial gastrectomy, distal pancreatectomy, and splenectomy, combined with radiofrequency ablation (RFA) for the hepatic metastases. Subsequently, he continued imatinib therapy. However, a new lesion developed in the liver and was diagnosed as imatinib-resistant disease. The new lesion was treated with RFA. Eight years after the treatment, a new lesion occurred in the liver, which was difficult to excise owing to the location. Accordingly, a right-hepatic lobectomy was performed. Currently, he is alive and continues on imatinib therapy. PMID- 25731538 TI - [A case of an elderly patient with recurrent GIST, which was effectively treated with low-dose imatinib mesylate]. AB - The recommended dose of imatinib for recurrent gastrointestinal stromal tumors (GIST) is 400mg/day. However, adverse effects limit the use of the standard dose in elderly patients. We report a case of an elderly patient with recurrent GIST, where long-term control of the disease was achieved with low-dose imatinib therapy. An 86-year-old man presenting with tarry stool was admitted to the hospital; upper GI endoscopy revealed a gastric submucosal tumor of the stomach at the posterior wall of the cardia. Partial gastrectomy was performed laparoscopically. The submucosal lesion was histopathologically diagnosed as malignant GIST. Administration of imatinib was initiated 17 months after surgery because of recurrence of GIST. The initial dose of imatinib was 400mg/day, which was later adjusted to 200mg or 300 mg/day because of adverse effects. Though imatinib was withdrawn several times due to strong side effects, the disease was well controlled for 6 years after surgery. PMID- 25731539 TI - [A case of resection margin involvement gastric carcinoma that relapsed late after additional gastrectomy]. AB - We report a case of a patient with resection margin involvement gastric carcinoma that recurred 5.5 years after additional resection. A 64-year-old man underwent distal gastrectomy for advanced gastric carcinoma (sig+por2, pSE, pN0, pStage IIB) in January 2008. A total gastrectomy was performed 2 months after the initial gastrectomy because of proximal resection line involvement, and curative resection was obtained. Adjuvant chemotherapy with S-1 was completed, and follow up surveillance was finished 5 years after the additional surgery. In November 2013, the patient experienced bouts of vomiting, and a computed tomography (CT) scan showed an abdominal abscess that had spread to the liver and communicated with the intestine. Despite abscess drainage and antibiotic therapy, infection control was difficult and the patient died 20 days after hospitalization. An autopsy showed the recurrence lesions had diffusely spread to the peritoneum and was also disseminated around the Roux-Y jejunum. These findings suggest that peritoneal recurrence might lead to penetration of the intestine and abscess formation. PMID- 25731540 TI - [A case of long-term survival of advanced gastric cancer with schnitzler metastasis effectively treated with combination chemotherapy]. AB - A 66-year-old woman was diagnosed with unresectable advanced gastric cancer with Schnitzler metastasis in January 2012. She was treated with combination chemotherapy comprising S-1 and docetaxel (DTX). However, in January 2013, after 13 courses of treatment, a computed tomography (CT) indicated peritoneal dissemination growth. The chemotherapy regimen was changed to a combination of S 1 and irinotecan (CPT-11), but after a single course of treatment the patient complained of stomachaches and vomiting. The patient developed ileus from the stenosis of the rectum, and a transanal ileus tube was used to decompress the bowel tract. Due to the patient's poor general condition, a metallic stent was inserted, and she could resume eating. Thereafter, we changed the chemotherapy regimen to weekly paclitaxel (PTX). However, 1 year and 4 months after starting treatment she died of regrowth of the peritoneal disseminating lesions. We recommend a combination of chemotherapy and metallic stent placement to improve quality of life and long-term survival. PMID- 25731541 TI - [A case of remnant gastric cancer seven years after initial diagnosis]. AB - A 79-year-old woman was admitted with cholangitis caused by a common bile duct stone (CBDS), and the CBDS was removed by endoscopic sphincterotomy (EST). The patient had undergone distal gastrectomy for gastric cancer located in the lower body of the stomach in 2006. A flat, elevated lesion of the cardiac region was noted in the preoperative examination; however, this lesion was not treated because there was no clear evidence of malignancy upon histopathological examination of the biopsy specimen. Following esophagogastroduodenoscopy in 2013, the macroscopic findings had changed to infiltrative cancer. The lesion was considered to be a submucosal(sm)cancer, and the patient underwent simultaneous cholecystectomy and remnant gastrectomy. The histopathological examination of the surgical specimens revealed a well differentiated tubular adenocarcinoma, type 0 IIb+0-IIa, tub1>tub2, pT1b1, ly0, v0, n0. PMID- 25731542 TI - [Ten-year survival of a patient with advanced gastric cancer with no. 16 lymph node metastases after total gastrectomy and paraaortic lymphadenectomy]. AB - When no other non-curative treatment options are available, R0 resection can be achieved with paraaortic lymphadenectomy for patients with advanced gastric cancer with No.16 lymph node metastases. Herein, we report of a patient who underwent R0 resection for gastric cancer with No.16 lymph node metastases and who achieved long-term survival. PMID- 25731543 TI - [A case of gastric cancer with multiple liver metastases that was successfully treated by chemotherapy]. AB - A man in his 60s received SP (S-1+CDDP) therapy for gastric cancer with multiple liver metastases. After completion of 3 courses, liver metastases had reduced significantly, and the paraaortic lymph nodes, which had swelled previously, had reduced in size. Furthermore, the serum carcinoembryonic antigen (CEA) level had also improved to the standard value from 814.3 ng/mL. The patient was able to discontinue the opioid he had needed for pain control. The chemotherapy was continued for 18 courses, with the dose reduced at the time of the adverse events along the way. By completion of the 18 courses, we recognized regrowth of the primary lesion and a rise in the serum CEA over the standard value. There was no sign of the regrowth of liver metastases and distant lymph nodes according to examinations for enhanced computed tomography (CT) and 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) CT.The patient received distal gastrectomy. The CEA level decreased in standard value or less after surgery and we believed the cancer was limited to the primary stomach lesion. PMID- 25731544 TI - [A case of metastatic colon carcinoma following curative resection for advanced gastric cancer associated with metastases to the liver and gallbladder]. AB - A 55-year-old man suffering from gastric cancer associated with metastases to the lymph node, gallbladder, and liver was administered chemotherapy with S-1 and cisplatin. Before initiation of therapy, the primary tumor, lymph node metastases, and liver metastases showed fluorodeoxyglucose (FDG) accumulation by positron emission tomography (PET). After 1 course of chemotherapy, the patient received curative surgical treatment including distal gastrectomy, partial hepatectomy, cholecystectomy, and lymph node dissection. The final pathological finding was moderately differentiated adenocarcinoma, T4b(SI), N3a(10/20), P0, CY0, pH1, pM1, Stage IV. Five months after surgery, the serum carcinoembryonic antigen (CEA) level was found to be increasing and PET examination identified an FDG-accumulating nodule in the ascending colon. Colonoscopy identified a submucosal tumor diagnosed as a metastasis from the gastric cancer. Right colectomy was performed 7 months after the first surgery resulting in a curative resection. In each surgery, PET examination indicated that no other distant metastases existed, and curative resection would be possible. Furthermore, although solitary metastatic colorectal lesions are rare, PET examination revealed them accurately. Thus, FDG-PET is very useful for identifying metastases in patients with gastric cancer. PMID- 25731545 TI - [Poor outcome of a patient with early double cancers of the stomach and sigmoid colon in which liver metastases were detected postoperatively]. AB - A 63-year-old man underwent laparoscopic-assisted distal gastrectomy (LADG) and laparoscopic assisted colectomy (LAC) simultaneously for double cancers of the gastric antrum and sigmoid colon in August 2012. Both cancers, considered to be at an early-Stage, were pathologically diagnosed as tub1, sm, and n0. The patient was observed but no adjuvant chemotherapy was administered. A follow-up computed tomography (CT) in December 2012 detected a 15 mm tumor mass in the lateral segment of the liver and another 5mm mass in the S4. Liver metastasis of the sigmoid colon cancer was suspected, and 6 courses of BEV+mFOLFOX6 were administered. The metastatic tumor in the lateral segment showed stable disease (SD) and the S4 tumor showed a complete response (CR). Thereafter, the lateral hepatic segment was partially resected in March 2013. Pathological examinations led to a diagnosis of stomach cancer liver metastasis, and the patient was given oral TS-1. During the first course of treatment, a CT showed new tumor masses in the lateral segment of the liver and S4. Treatment was changed to TS-1+CDDP in mid-May. However, after completion of the first course of treatment, the patient experienced exacerbation of the liver metastases, pulmonary metastasis, and inflammation of the intrahepatic bile ducts. The patient was hospitalized in mid June to receive inpatient care, but died in early July. PMID- 25731546 TI - [A case of recurrent gastric cancer successfully treated with TS-1+CDDP chemotherapy]. AB - A 74-year-old woman underwent distal gastrectomy and D1+ alpha dissection for the treatment of gastric cancer (pT2a, pN2, H0, P0, M0, Stage IIIA) in February 2008. She was treated with adjuvant postoperative chemotherapy consisting of TS-1. However, 32 months after the operation, paraaortic lymph node recurrence was confirmed by computed tomography (CT). She was treated with combined TS-1 and cisplatin chemotherapy. After 14 courses, CT revealed that the paraaortic lymph node metastasis had disappeared, and a complete response was attained. The patient is currently disease-free, 6 years after the operation. PMID- 25731547 TI - [The case of a solitary pulmonary tumor which could be diagnosed as early gastric cancer recurrence by detailed pathological examinations]. AB - We report the case of a solitary pulmonary tumor, which was diagnosed as recurrent early gastric cancer by detailed pathological examinations. A 59-year old man initially underwent total gastrectomy for gastric adenocarcinoma located at the esophago-gastric junction. A pathological examination indicated a papillary adenocarcinoma (pap ) that had invaded the submucosal layer (sm2), but had not metastasized to the regional lymph nodes (n0). The final diagnosis was P0H0M0T1bN0, Stage IA. Chest computed tomography (CT) 30 months after primary surgery indicated a solitary tumor with a diameter of 9 mm at S3 of the left lung. A positron emission tomography (PET)-CT scan showed an accumulation of 18F fluordeoxy-glucose (FDG18) at the same location. Lung cancer was suspected and the patient was given a left upper lobectomy. The resected tumor was diagnosed as gastric cancer metastatic adenocarcinoma by permanent pathological examination. The tumors showed similar histology and immuno histochemical findings for CK7, CK20, TTF-1, SP-A, CDX-2, and HER2 . Early gastric cancer is an almost curable disease and recurrence is very rare. We report the details of this case and review the literature. PMID- 25731548 TI - [A case of locoregional recurrence after gastric cancer surgery, which was treated with XPT regimen chemotherapy]. AB - Based on the results of the trastuzumab for gastric cancer (ToGA) trial, the regimen of Xeloda/5-FU+CDDP+trastuzu- mab (XPT/FPT) has become the standard of care for treatment of HER2-positive unresectable or recurrent gastric cancers. In our hospital, the percentage of HER2-positive gastric cancer patients is 16.7%; we present a case of recurrence 26 months after gastric cancer surgery. A 67-year old man presented with locoregional lymph node recurrence, with swelling in a paraaortic lymph node. 18F-fluorodeoxy glucose positron emission tomography (FDG PET) examination revealed abnormal accumulation in these lymph nodes. He was treated with a regimen of XPT chemotherapy because of the HER2-positive status of his gastric cancer. After 8 courses, the lymph nodes had shrunk and FDG-PET examination revealed no abnormal accumulation. Imaging revealed the presence of interstitial pneumonia, and the adverse events of venous thromboembolism, and grade 3 hand-foot syndrome were detected; as a result, chemotherapy was suspended. The XPT regimen may be an effective treatment for HER2-positive unresectable or recurrent gastric cancers. HER2 status should be the key determinant in the strategy for the treatment of unresectable and recurrent gastric cancers in the future. PMID- 25731549 TI - [A case of gastric cancer with portal vein tumor thrombosis]. AB - We present a case of gastric cancer with portal vein tumor thrombosis. A 77-year old man visited our hospital because of epigastric pain. Esophagogastroduodenoscopy and computed tomography (CT) revealed advanced gastric cancer. Total gastrectomy was performed. During surgery, peritoneal dissemination was found. Histopathological diagnosis was Stage IV gastric cancer (por2, T4aN3M1) with massive vascular invasion. He was treated with a chemotherapy regimen of S-1 plus docetaxel for approximately 2 years after which the regimen was changed to S-1 monotherapy. Six months later, CT revealed portal vein tumor thrombosis (PVTT) without progression of peritoneal dissemination. The metastatic route of PVTT was believed to be hematogenous because neither liver nor lymph node metastasis was detected. The regimen was shifted to CPT- 11 plus cisplatin therapy since the effects of the treatment was evaluated as progressive. The patient was alive with stable disease after 5 courses of chemotherapy. PVTT should be taken into consideration as a possible type of recurrence when the tumor is associated with massive vascular invasion, although gastric cancer with PVTT is rare. PMID- 25731550 TI - [A case report of residual gastric cancer 15 years after pancreatoduodenectomy with modified child's reconstruction]. AB - A 75-year-old man underwent pancreatoduodenectomy for pancreatic cancer. He had presented with epigastralgia in June 2008. Gastrointestinal endoscopy revealed type 2 gastric cancer in the cardiac area. Enhanced abdominal CT scanning confirmed an enhanced mass in the cardiac area. Gastrectomy with Roux-en-Y reconstruction was performed for residual gastric cancer. Histopathological findings revealed, pT3(SS), pN0, pH0, pP0, pStageIIA. Single-agent TS-1 therapy was chosen as adjuvant chemotherapy but was changed to TS-1+CDDP because of CT detected recurrence 3 months after the second operation. After a 6 month course of chemotherapy, complete reduction of the tumor was obtained. PMID- 25731551 TI - [A case of an elderly patient who underwent single-incision laparoscopic surgery for small intestine cancer]. AB - An 81-year-old man presented with chief complaints of abdominal pain and vomiting. Intestinal obstruction was found at the time of admission to a local hospital in October 2011. Conservative treatment provided symptomatic relief; however, he was readmitted with similar symptoms in December 2011. Small intestinal wall thickening was detected by abdominal and pelvic computed tomography, and he was referred to our hospital. Small-bowel endoscopy revealed an elevated subcircumferential tumor in the jejunum. Biopsy revealed well to moderately differentiated adenocarcinoma diagnosed as jejunal cancer, which caused narrowing of the jejunum. Single-incision laparoscopy-assisted small-bowel resection was performed. The intraoperative findings were a tumor with inflammatory changes in the jejunum and enlarged surrounding lymph nodes. We performed regional lymph node dissection. Histopathological analysis showed moderately differentiated small-intestinal tubular adenocarcinoma and 2 of 5 lymph nodes positive for metastatic cancer cells. After an uneventful postoperative course, he was discharged on day 7. He preferred not to undergo postoperative adjuvant chemotherapy and quickly recovered his activities of daily living postoperatively. He stayed home until he developed abdominal distention resulting from peritoneal recurrence 1 year and 6 months postoperatively and died 1 month later. PMID- 25731552 TI - [A case of small bowel cancer with positive peritoneal cytology and five-year recurrence-free survival]. AB - Small bowel cancer is frequently detected at an advanced stage and its prognosis is poor. We report on a patient with small bowel cancer with positive peritoneal cytology who survived for 5 years without recurrence after surgery.The case involved a 73-year-old woman who had undergone partial resection of the small intestine and lymphadenectomy for a small bowel tumor with obstruction. Pathological examination confirmed papillary adenocarcinoma with partial serosal invasion. Ascites cytology indicated a class V tumor. Adjuvant chemotherapy with TS-1 was administered for 20 months, and the patient has survived without evidence of disease for over 5 years.In this case, it is possible that TS-1 chemotherapy was effective for prevention against small bowel cancer recurrence.Furthermore , peritoneal cytology in patients with small bowel cancer should be evaluated as a predictor of prognosis. PMID- 25731553 TI - [A case of long-term survival of small intestinal adenocarcinoma treated by resection and chemotherapy]. AB - A 60-year-old man had visited our hospital a few times due to vomiting since July 2008. In January 2009, because he was no longer able to eat, he was hospitalized to receive close examination. Single balloon enteroscopy revealed jejunal adenocarcinoma. After examination of the whole body, as there was no distant metastasis, jejunum partial resection was performed in February 2009. One dissemination nodule was recognized on the serosa near the main tumor. We obtained the final pathological diagnosis as Stage IV. From April 2009, adjuvant chemotherapy with combination of oxaliplatin, 5-fluorouracil and Leucovorin (mFOLFOX6) was performed 8 times. In April 2009, a small metastatic lesion appeared in the upper lobe of the right lung. We started administering combination of irinotecan, 5-fluorouracil and Leucovorin (FOLFIRI) from January 2010, but stopped because of side effects after the second cycle. Administration of capecitabine was started in March 2010. The metastatic lesion had diminished for a time but was found to be enlarged in March 2011. Thus, a partial right lung resection was performed in April 2012. After lung resection, systemic chemotherapy was not performed. The patient remains alive without a recurrence 3 years after lung resection and over 5 years after detection of the small intestinal adenocarcinoma. PMID- 25731554 TI - [A case of fixing an anastomotic site to the abdominal wall out of the abdominal cavity for a small intestinal perforation during chemotherapy]. AB - A 53-year-old man presented with a continuous high fever and was diagnosed with diffuse large B-cell lymphoma with metastasis to the lung, spleen, and mesenterium. He was treated with cyclophosphamide and prednisolone followed by administration of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy 20 days later. Two days after initiation of CHOP therapy, the patient complained of severe abdominal pain. Perforative peritonitis was diagnosed using abdominal computed tomography. A perforation of the small intestine approximately 160 cm distal to the Treitz ligament was uncovered during emergency laparotomy. The risk of leakage was considered too high for anastomosis of the small intestine to be performed. Further, construction of an intestinal stoma could result in a high-output syndrome that could lead to difficulty in resuming chemotherapy. Based on these considerations, we fixed the anastomotic region to the abdominal wall using a technique similar to construction of an intestinal stoma. Post-operative anastomotic leakage did not occur. Nine days later, a perineal hernia was noted near the anastomotic site and a second operation was performed. The anastomotic site was placed back into the abdominal cavity during this operation. CHOP therapy was resumed 16 days after the first operation. PMID- 25731555 TI - [A case of small intestinal lymphoma with ileus requiring surgery during chemotherapy]. AB - Perforation, bleeding, and ileus are known complications of small intestinal lymphoma and can occur either at diagnosis or during the course of treatment. Surgery is an important component in the management of these gastrointestinal complications. However, there is no consensus regarding the indications for and timing of surgery in small intestinal lymphoma. We herein present our experience with a case of small intestinal lymphoma with ileus that required surgery during chemotherapy. A 69-year-old man developed abdominal pain. Computed tomography revealed lower right jaw lymphadenopathy, small intestinal wall thickening, and mesenteric lymphadenopathy. Malignant lymphoma (diffuse large B-cell type) was diagnosed on the basis of a lower jaw lymph node biopsy. The patient was initially administered chemotherapy. After the third cycle of chemotherapy, the patient developed small intestinal obstruction detected upon abdominal computed tomography. Because a stricture persisted despite medical treatment, we performed partial resection of the small intestine. The postoperative course was good, and the patient rapidly resumed chemotherapy. Currently, 6 months after the surgery, the patient is alive without any progression of the lymphoma. A multidisciplinary treatment strategy, including surgery, is desirable to achieve a safe but radical cure for small intestinal lymphoma. PMID- 25731556 TI - [A case of multiple intestinal lymphomas accompanied by rapid growth of cutaneous infiltration after surgery]. AB - We report a case of multiple intestinal lymphomas accompanied by rapid growth of cutaneous infiltration after surgery. An 86-year-old woman visited our hospital complaining of lower abdominal pain. Multiple tumors in the sigmoidal and ascending colon were detected by using colonoscopy and computed tomography; therefore, we performed surgery. Postoperative pathological examination identified the sigmoidal colon tumor as an adenocarcinoma and the ascending colon tumor as a B cell lymphoma. The tumors in the ileum and the ileal diverticulum, which were simultaneously excised, were also diagnosed as B-cell lymphomas. After surgery, rapid appearance of multiple light purple nodules on the skin of the right thigh was observed. Histological examination of biopsied skin nodules led to a diagnosis of B-cell lymphoma, similar to the previously removed tumors. Although radiotherapy and chemotherapy were administered to the dermatological lesion that reached an advanced stage, the disease condition was progressive. The patient was transferred to another hospital to receive medical treatment 3 months postoperatively. We consider these dermatological lesions to be dermal infiltration of B-cell lymphomas originating from tumors in the intestinal tract. PMID- 25731557 TI - [A case of synchronous triple cancer treated with multidisciplinary therapy - cancers in the middle part of the extrahepatic bile duct, the pancreas head, and the supraglottis]. AB - An 83-year-old man was admitted to our institution for the purpose of investigation of hoarseness in January 2014. He was diagnosed with cancer in the supraglottis via biopsy while undergoing laryngeal microsurgery. Positron emission tomography (PET)evaluation for tumor staging revealed two hot spots, 1 in the hepatoduodenal ligament and 1 in the pancreas head. Accordingly, the patient was diagnosed with synchronous double cancer in the middle bile duct and the pancreas head. The treatment of the bile duct cancer and pancreatic cancer was performed prior to that of the supraglottic cancer. Curative pancreatoduodenectomy was performed, and the postoperative course was uneventful. Three weeks after the surgery, chemoradiotherapy for the supraglottic lesion was initiated. The tumor almost disappeared 2 months after the start of chemoradiotherapy, as observed by using a laryngoscope. Multidisciplinary therapy based on the therapeutic guidelines for each of the cancers was beneficial for the patient. PMID- 25731558 TI - [A case of adenocarcinoma occurring in the bladder mucosa after a surgical operation for colovesical fistula]. AB - We report a case of adenocarcinoma occurring in the bladder mucosa 6 years after a surgical operation for colovesical fistula due to colonic diverticulitis of the sigmoid colon. The patient was a 76-year-old woman who had undergone a sigmoidectomy and ligation of the colovesical fistula at the age of 70 years. She presented with a complaint of gross hematuria. Cystoscopy and computed tomography revealed bladder cancer at the site of the original colovesical fistula surgery. She underwent transurethral resection of the bladder tumor. Histopathological findings revealed intestinal adenocarcinoma in the urinary bladder. A radical partial cystectomy was subsequently performed because of a positive and involved margin. This tumor may have originated from the bladder mucosa and then replaced by intestinal metaplastic cells that originated from the same initiating event. PMID- 25731559 TI - [Mesenteric recurrence of leiomyosarcoma of the kidney seven years after the first operation - a case report]. AB - A 60-year-old woman presented to our hospital with a pelvic tumor detected by using computed tomography at the Department of Urology of another hospital. Her medical history indicated that she had undergone left nephrectomy and left hemicolectomy for a tumor of the left kidney 7 years previously. Leiomyosarcoma of the left kidney was diagnosed on the basis of the histopathological examination at the previous hospital. Recurrence of leiomyosarcoma was suspected, and a second operation was performed. A mesenteric tumor was detected. Leiomyosarcoma recurrence was diagnosed on the basis of another histopathological examination. The patient remains free of disease and recurrence 3 years after the second operation. Primary leiomyosarcoma of the kidney is a rare disease, even among renal tumors. The prognosis of leiomyosarcoma of the kidney is poor because of frequent metastasis and recurrence. Radical resection is the preferred first choice for treatment, but recurrence still occurs frequently. In our case, the mesenteric recurrence was detected 7 years after the first operation. There have been no previous reports of mesenteric recurrence of leiomyosarcoma of the kidney. Although histopathological and immunohistochemical examinations indicated a poor prognosis, the patient is alive and there are no signs of recurrence 3 years after the second operation. PMID- 25731560 TI - [Two cases of giant retroperitoneal liposarcoma]. AB - The first patient was of a 71-year-old woman who was examined for abdominal protuberance. Computed tomography (CT) and magnetic resonanc e imaging(MRI)revealed a giant tumor almost occupying the entire abdomen. En-bloc resection was performed. The tumor was 30 cm in size and weighed 6,500 g. The histological diagnosis was a well-differentiated liposarcoma. The second patient was a 72-year-old woman who visited our hospital after she had been diagnosed with an abdominal tumor by her family doctor. CT and MRI revealed a massive tumor involving various components. The tumor had invaded the left ureter and descending colon; therefore, we performed tumorectomy, left nephrectomy, and descending colectomy. The histopathological findings indicated a well differentiated, myxoid, pleomorphic liposarcoma. The tumor recurred 4, 5, and 7 years after the first operation. By the fourth operation, the histological subtype of the tumor had changed to a dedifferentiated type. PMID- 25731562 TI - [No recurrent case of the combination of surgical management with chemotherapy]. AB - A 61-year-old man consulted a nearby doctor with the chief complaint of lassitude in June 2010. Blood tests revealed a hemoglobin level of 3.7 g/dL. The observation of significant anemia resulted in a full medical workup. On computed tomography (CT) findings, a large mass (17 * 10 cm in diameter) was found in the abdominal region. The lumen was distended with accumulation of air and fluid. In addition, I continued with a bladder wall, but did not recognize the abnormality that was apparent to a bladder lumen. There was no evidence of ileus. A diagnosis of appendix cancer or sarcoma was made preoperatively. During surgery, the bladder was observed to have some permeation, but the bladder wall contained a lesion of small intestinal origin with only slight permeation. The neighboring small intestine was surrounded by the tumor, with 3 sites of penetration. Histopathologic diagnosis indicated a high-risk gastrointestinal stromal tumor (GIST) with mitotic figures (44/50 high power fields). In accordance with the recommended guidelines, imatinib was administered for 1 year. Two sites of recurrences were observed by CT after discontinuing imatinib. A second operation was performed without increase because of the absence other lesions. Separate lesions in the sigmoid colon and jejunum were removed surgically. The tumor in the sigmoid colon was a lesion with high denaturation for mesenchymal system tumor such as GISTs by pathologic diagnosis. The lesion in the small mesentery was a suture granuloma. In this case, the combination of surgical management with chemotherapy resulted in good quality of life with no recurrence despite the presence of a high-risk GIST. PMID- 25731561 TI - [A case of small intestinal gastrointestinal stromal tumor (GIST) with peritoneal dissemination, treated effectively with molecular target drug after operation]. AB - A 54-year-old man, presenting with sudden onset of abdominal pain, was admitted to our hospital. Blood examination revealed high white blood cell counts and elevated C-reactive protein (CRP) levels. Ultrasonography and computed tomography detected a 12 cm mass in the lower abdomen, some ascites, and multiple small nodules spread through the abdomen. The preoperative diagnosis of the tumor was either a gastrointestinal stromal tumor (GIST) or a possible lymphoma. The 12 cm tumor and greater omentum with multiple nodules were resected. Upon pathological examination, the tumor was diagnosed as a GIST, and appeared KIT positive by immunostaining. After the operation, imatinib was administered; however, psoriasis vulgaris developed within 5 months. As the next line of therapy, sunitinib treatment was initiated; however, since peripheral nerve disorder developed, sunitinib dose was halved and maintained. Two years after the operation, the patient is still alive. Small intestinal GISTs, which make up only 20-30% of all GISTs, are considered to be more malignant than others. We report a rare case of GIST with peritoneal metastases originating from the small intestine, which was treated effectively with molecular target drugs. PMID- 25731563 TI - [A case of recurrent gastrointestinal stromal tumor progressing after interruption of long-term imatinib therapy]. AB - A 62-year-old man presented to our hospital with multiple liver metastases of gastric gastrointestinal stromal tumor (GIST) in 2002.T he patient had undergone imatinib treatment for liver metastases as a participant in a clinical trial, and he had achieved complete response (CR) for 89 months.However, imatinib treatment was disrupted at the request of the patient. Progression of liver metastases was observed 18 months later.Imatinib treatment was reinitiated, and a partial response was obtained.Twenty -five months later, progression of disease was observed in segment 7 of the liver on an abdominal computed tomography (CT) scan. Partial imatinib-resistance was diagnosed, and partial resection of the lesion in S7 of the liver was performed in 2013. Imatinib therapy was continued after surgical intervention, and no progression has been detected for 10 months. Despite the beneficial effects of imatinib in patients with advanced GISTs, almost all patients have been reported to develop disease progression when imatinib is interrupted, even in lesions showing radiographic improvement.In the present case, after treatment with imatinib for 7 years, progression of liver metastases was observed upon discontinuation of therapy. Moreover, progression after disruption of imatinib may lead to the emergence of drug-resistant clones. We reported a case of recurrent GIST progressed after interruption of long-term imatinib therapy, which has been reported few times previously. PMID- 25731564 TI - [A case of extragastrointestinal stromal tumor with peritoneal dissemination]. AB - Here, we present the case of a 60-year-old man in whom abdominal computed tomography showed a solid abdominal tumor (11 cm in diameter) in the pelvic space, with widely disseminated nodular lesions. Emergency surgery was performed following the rapid onset of intense abdominal pain. Peritoneal disseminations were widespread and the tumor was confirmed to be in the pelvic space. The tumor was not connected to any segment of the intestinal tract but rather to the retroperitoneum. Immunohistochemical staining was positive for c-kit (exon 11 mutation) and CD34 but negative for S-100 protein. Careful postoperative examination did not reveal any lesions in the upper or lower alimentary tract. On the basis of these findings we diagnosed the tumor as an extragastrointestinal stromal tumor (EGIST) originating from the retroperitoneum. After surgery, intravenous infusion of imatinib was started at a full dose of 400mg/day; however, owing to strong adverse effects, the dose was reduced to 200mg/day. Despite halving the dose, the patient has remained lesion-free according to computed tomography for 36 months after the operation. Low-dose imatinib chemotherapy remained efficacious in controlling progression in this case. PMID- 25731565 TI - Hyperthermia in the treatment of recurrent abdominal desmoid tumor. AB - The most suitable management of recurrent abdominal desmoid tumor is still unclear. A case of recurrent huge abdominal desmoid tumor successfully treated by hyperthermia therapy is described. A 63-year-old man was operated upon for desmoid tumor in the retroperitoneum involving pancreas, posterior wall of the stomach and transverse mesocolon in 2007. In 2008, the tumor recurred and could not be resected because of the patient refused the operation. Several therapies using tamoxifen, anastrozole, imatinib mesylate and radiotherapy were all ineffective. The tumor grew bigger and bigger during a treatment period. Finally, hyperthermia treatment was applied to the tumor. The size of the recurrent desmoid tumor reduced 75% by hyperthermia treatment for 46-month. Base on this experience, we recommend hyperthermia as the treatment for patients with recurrent abdominal desmoid tumor that several therapeutic strategies did not achieve a remarkable response. PMID- 25731566 TI - [A case of malignant peritoneal mesothelioma without deletion of p16]. AB - The patient was a man in his 60s with a history of 2 operations for the treatment of malignant neurogenic tumors. Partial resection of the stomach and liver was performed in December 2006, followed by chemotherapy with adriamycin and interferon; resection of a recurrent tumor in the left subphrenic space was performed in December 2007. In June 2011, recurrent tumors were detected in the lesser curvature of the stomach body and left inferior quadrant of the abdomen (12 mm [SUVmax 7.9] and 23 mm [SUVmax 10.5], respectively)by using 18F fluorodeoxyglucose-positron emission tomography (FDG-PET). The tumors resected in August 2011 were diagnosed as malignant peritoneal mesothelioma on immunohistochemical analysis. In February 2013, FDG-PETrevealed a 20-mm tumor of in the mesentery with a SUVmax of 7.6, and the tumor was resected. This secondary tumor had the same features of the previously resected malignant mesothelioma. Fluorescence in situ hybridization revealed no deletion of the p16 gene, and the patient had had no other recurrence during follow-up. Malignant peritoneal mesothelioma is a rare disease, accounting for 10% of all malignant mesothelioma cases, with low rates of p16 gene deletion compared with malignant pleural mesothelioma. Previous studies have reported that the lack of p16 deletion is associated with better prognosis in malignant pleural mesothelioma. Herein, we report of a patient diagnosed with malignant peritoneal mesothelioma, without deletion of the p16 gene, who survived for over 2 years and 10 months after initial diagnosis of malignant mesothelioma. PMID- 25731567 TI - [A case of primary peritoneal carcinoma successfully treated using Paclitaxel and Carboplatin chemotherapy]. AB - BACKGROUND: A standard treatment for primary peritoneal carcinoma has not been established to date. We describe a case in which this cancer was successfully treated by use of paclitaxel and carboplatin chemotherapy. CASE: An 80-year-old woman who presented with abdominal distension and right upper abdominal pain was diagnosed with massive ascites and an omentum tumor via abdominal computed tomography and magnetic resonance imaging (MRI); her ovaries were normal-sized. Serum levels of the tumor marker CA125 were above normal (170 U/mL), and aspiration cytology showed the presence of adenocarcinoma cells. Despite several examinations, the primary tumor was not detected. The patient underwent exploratory laparotomy and was diagnosed with primary peritoneal carcinoma. She received combination chemotherapy consisting of paclitaxel and carboplatin. Serum CA125 levels returned to normal, and an MRI showed no evidence ofa tumor. CONCLUSION: Paclitaxel and carboplatin combination chemotherapy is effective for treatment of primary peritoneal adenocarcinomas. PMID- 25731568 TI - [A case of solitary fibrous tumor from the greater omentum resected via laparoscopic surgery]. AB - Solitary fibrous tumor (SFT) are relatively rare neoplasms that usually arise in the thoracic cavity in adults. Although many cases of extrathoracic SFT have been recently reported, SFT from the omentum is rare. A 32-year-old woman consulted a gynecologist complaining of irregular vaginal bleeding. Magnetic resonance imaging (MRI) revealed a tumor in the omentum, and the patient was admitted to our department. The patient underwent laparoscopic tumorectomy. The tumor size was 48 * 35 * 30 mm, and grayish-white nodules were observed. Histological examination showed hyperplastic spindle-shaped tumor cells with a pattern-less arrangement. Immunohistochemical staining showed the tumor was positive for CD34 and bcl-2, slightly positive for alpha smooth muscle actin(a-SMA), and negative for S-100 and c-kit. Accordingly, a diagnosis of SFT was made. The patient has not shown any recurrence 12 months after surgery. Most SFTs are benign, although there are some reports of recurring tumors. There are no clear guidelines for the treatment of SFT because of its rarity. Therefore, close long-term follow-up should be performed. PMID- 25731569 TI - Pharmacokinetics of docetaxel during hyperthermic intraperitoneal chemotherapy for peritoneal metastasis. AB - The purpose of this manuscript is to report the pharmacokinetics of docetaxel during hyperthermic intraperitoneal chemotherapy (HIPEC) after peritonectomy. MATERIALS AND METHODS: Eleven patients with peritoneal metastasis (PM) underwent peritonectomies combined with 40 min of HIPEC with 40 mg/body of docetaxel. The pharmacokinetics of docetaxel were studied by using high-performance liquid chromatography. RESULTS: The docetaxel concentration at the start of HIPEC (0 min) was 9.084 +/- 0.972 mg/L. The concentration gradually decreased to 5.599 +/- 0.458 mg/L 40 min after HIPEC. In contrast, serum docetaxel levels increased during HIPEC, reaching a maximum level of 0.1334 +/- 0.0726 mg/L at 40 min. The clearance (CLp) was 3.164 +/- 1.383 L/hr, and the area under the curve (AUC) ratio was 95.12 +/- 87.32. The AUC ratio of less-extensive peritonectomies was significantly higher than that of extended peritonectomies. The docetaxel concentration in the tumor tissue increased at 40 min (4.45 mg/gr). The apparent permeability (Papp, 40 min) was 1.47 +/- 0.67 mm/40 min. No severe adverse effects were observed after HIPEC. CONCLUSION: From these results, 40 mg is a safe dose for docetaxel combined with HIPEC, and the locoregional intensity of docetaxel is enough to control PM less than 1.47 mm in diameter. PMID- 25731570 TI - [Fibrin glue injection therapy with diluted thrombin for complicated postoperative fistulas following digestive surgery]. AB - Fibrin glue injection is used for treating postoperative digestive fistulas; however, this method is not always successful, especially in cases of complicated fistulas. Generally, the fibrin glue coagulates immediately after application before it reaches the end of the fistulas. Based on the results of an in vitro study of tensile strength and coagulation time, we utilized fibrin glue injection therapy with diluted thrombin solution (* 30) for treating refractory postoperative complicated fistulas in 23 cancer patients. In 20 of these patients, the fistulas were successfully closed after an average of 2.0 treatment cycles. This simple method of fibrin glue injection with diluted thrombin is useful for treating complicated postoperative digestive fistulas. PMID- 25731571 TI - [Effect of recombinant human soluble thrombomodulin in patients with solid carcinoma with DIC]. AB - There are only a few reports in the literature about the effect of recombinant human soluble thrombomodulin (rTM) in patients with solid carcinoma with disseminated intravascular coagulation (DIC). A retrospective study of 40 patients with solid carcinoma with DIC was performed between February 2009 and April 2013. The withdrawal rate was 32.5% (13/40 patients), and the 28-day survival rate was 40.0% (16/40 patients). Patients with successful withdrawal of DIC had significantly better outcomes (p<.001). Therapy with rTM is one of the treatment options for patients with solid carcinoma with DIC. PMID- 25731572 TI - [Four cases of bevacizumab-related gastrointestinal perforation]. AB - We report 4 cases of gastrointestinal perforation associated with systemic administration of bevacizumab. Case 1: A 51- year-old man with colorectal cancer (CRC) received mFOLFOX+bevacizumab (Bev). A small intestinal perforation occurred 7 days after Bev administration (Bev-a) and was successfully treated with omental packing. Case 2: A 50-year-old woman with CRC received capecitabine+Bev. A small intestinal perforation was detected 5 days after Bev-a, and was successfully treated with primary suture and an omental flap. Case 3: A 74-year-old man with CRC received CapeOX+Bev. A duodenal perforation occurred on the same day as Bev a, but could be treated conservatively. Case 4: A 57-year-old man with lung cancer received DTX+Bev. A small intestinal perforation occurred 13 days after Bev-a, but this could be managed with primary suture and an omental flap. The gastrointestinal perforation presented with mild abdominal pain and was detected within 14 days after Bev-a in each of these 4 cases. Three patients were successfully treated with only minimal surgical procedures and 1 patient could be managed with conservative treatment for a perforated duodenal ulcer. PMID- 25731573 TI - [Thyroid carcinoma diagnosed by pathology during surgery]. AB - We describe the pathological diagnosis of 4 resected cases of thyroid carcinoma made during surgery in comparison to that for 6 benign thyroid tumors. Preoperative computed tomography scanning and ultrasonography revealed 1 case of simple nodules, 3 cases of multiple nodules, 3 cases of solid cystic nodules, and 3 cases of calcification. Cytological examination of fine needle aspirates revealed 1 case to be Class II and 3 cases to be Class III. The diagnosis, which was made during the operation procedure on the basis of the frozen section and final operative methods, was papillary adenocarcinoma in 2 cases (total thyroidectomy + D1 and subtotal thyroidectomy+D1) and suspected papillary adenocarcinoma in 2 cases (hemithyroidectomy+ D1 and lobectomy of the thyroid+D1). The final pathological diagnosis of the 4 cases was papillary adenocarcinoma (pStage I: 3 cases, pStage II: 1 case). In the 6 cases of benign thyroid tumor, preoperative examinations revealed variegated tumor findings, and cytological examination of fine needle aspirates revealed 1 case to be ClassII and 5 cases to be ClassIII. Pathological diagnosis of the frozen sections of the 6 benign samples indicated 1 case of suspected malignancy and 5 cases of benign tumor. In all 10 cases, the pathological diagnosis based on frozen sections (with a sensitivity of 4/4 and specificity of 5/6) was more accurate than that established with preoperative imaging and cytological examination, and is therefore effective for the decision-making process when selecting the operative method. PMID- 25731574 TI - [A case of anaplastic thyroid carcinoma with surgical treatment]. AB - We describe a case of a 52-year-old man who presented with a neck tumor. Ultrasonography and a neck computed tomography (CT) scan revealed a large, 6-cm mass in the left thyroid lobe. Analysis of cytological specimens obtained from the mass indicated the tumor was classIV (indicative of anaplastic carcinoma). In addition, chest CT revealed multiple small nodules in the lung, which we suspected were metastases from the primary thyroid carcinoma. To relieve pressure symptoms in the neck, we performed left hemithyroidectomy and lymph node dissection. Six months after surgery, a chest CT scan revealed enlargement of a nodule in the left lung. CT-guided biopsy of the left lung mass indicated a histopathological diagnosis of metastasis from anaplastic carcinoma. Four cycles of paclitaxel chemotherapy suppressed enlargement of the lung tumor. The patient's general condition gradually deteriorated; however, and he died 15 months after surgery. Anaplastic carcinoma of the thyroid is generally considered to be one of the most aggressive cancers encountered in humans. In this case, surgical intervention led to improved clinical symptoms and prognosis. PMID- 25731575 TI - [A case of inflammatory myofibroblastic tumor with repeated recurrence and metastasis]. AB - A 37-year-old woman presented with an asymptomatic pulmonary nodule. A pulmonary S8 segmentectomy was performed. Recurrence and metastasis were noted every 6 months after surgery; repeat surgeries were performed at 18, 24, and 36 months. On histopathological examination, the tumor showed spindle cell proliferation with infiltration of various inflammatory cells, and was diagnosed as inflammatory myofibroblastic tumor (IMT). An IMT is defined as a tumor of intermediate biological potential, which may sometimes metastasize. It is necessary to note the potential for metastasis in the future, especially in cases with anaplastic lymphoma kinase (ALK)-negative immunohistological staining, where the tumor grade can be high. PMID- 25731576 TI - [Multiple extracranial metastases from meningioma treated with surgical resection - a case report]. AB - A 73-year-old woman underwent a craniotomy for an atypical meningioma in 1993, and underwent re-excision for local recurrence 4 years later. In 2008, a chest X ray film revealed 2 nodules in the right lung. A wedge resection of S2 and a middle lobectomy of the right lung were performed. Pathological findings indicated that the 2 tumors originated from the intracranial meningioma resected in 1993. In 2013, a computed tomography (CT) scan demonstrated hypervascular masses in the liver (S4), pancreatic body, and lower portion of the right kidney. She underwent partial hepatectomy, distal pancreatectomy, and partial nephrectomy, and the final diagnosis was hepatic, pancreatic, and renal metastases from meningioma. After 10 months, a transcatheter arterial embolization (TAE) was performed for hepatic recurrence (S5). She is presently doing well, 5 months after TAE, without any signs of recurrence. PMID- 25731577 TI - [A case report of laparoscopy-assisted low anterior resection after hepatectomy]. AB - A 72-year-old man was admitted to our hospital because of anal discomfort. A detailed gastrointestinal examination revealed both left cholangiocellular carcinoma and rectal cancer. We performed endoscopic mucosal resection (EMR) for the rectal cancer. Pathological findings suggested the possibility of residual cancer after EMR. The cholangiocellular carcinoma was thought to be of greater influence on the patient's prognosis than the rectal cancer. We performed left hepatectomy and caudate lobectomy. Two months after the initial surgery, we performed laparoscopy-assisted low anterior resection and D2 lymphadenectomy. Laparoscopic surgery could proceed since no adhesions were observed. Two-stage surgery can be an effective strategy for avoiding excessive surgical stress when removing 2 cancer types. PMID- 25731578 TI - [Four cases of operations for malignant disease in elderly patients]. AB - The management of elderly patients with malignant disease is determined by their condition, complications, and living environment. Sometimes it is difficult to judge surgical indications for elderly patients. We report 4 cases of patients, 80 years or older, who underwent an operation for malignancy. In the first case we performed a bile duct excision for bile duct cancer, and in the second case we performed distal pancreatectomy for pancreatic cancer. Both operations were non curative, and the patients were alive and maintained quality of life for 12 months after the operation. In the third non-curative operation, we performed total gastrectomy for remnant gastric cancer. The patient died of cancer 4 months after the surgery. In the fourth case we performed pancreaticoduodenectomy for bile duct cancer; it was a curative operation. The patient was in very good condition 4 months post-operation, but died suddenly due to acute myocardial infarction. In operations treating malignancy in elderly patients, it is important for the patients and their families to fully understand the significance of the operations. PMID- 25731579 TI - Determination of total antioxidant capacity of milk by CUPRAC and ABTS methods with separate characterisation of milk protein fractions. AB - Most milk-applied antioxidant assays in literature are based on the isolation and quantification of individual antioxidative compounds, whereas total antioxidant capacity (TAC) gives a more holistic picture due to cooperative action of antioxidants. Recently, the cupric reducing antioxidant capacity (CUPRAC) method has been modified to measure the antioxidant capacities of thiol-containing proteins, where the classical ammonium acetate buffer - that may otherwise precipitate proteins- was replaced with concentrated urea buffer (able to expose embedded thiol groups of proteins to oxidative attack) adjusted to pH 7.0. Thus, antioxidant capacity of milk was investigated with two competing TAC assays, namely CUPRAC and ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid))/persulphate, because only these assays were capable of evaluating protein contribution to the observed TAC value. As milk fat caused turbidity, experiments were carried out with skim milk or defatted milk samples. To determine TAC, modified CUPRAC method was applied to whole milk, separated and redissolved protein fractions, and the remaining liquid phase after necessary operations. Both TAC methods were investigated for their dilution sensitivity and antioxidant power assessment of separate milk fractions such as casein and whey. Proteins like beta-lactoglobulin and casein (but not simple thiols) exhibited enhanced CUPRAC reactivity with surfactant (SDS) addition. Addition of milk protein fractions to whole skim milk produced significant 'negative-biased' deviations (up to -26% relative standard error) from TAC absorbance additivity in the application of the ABTS method, as opposed to that of the CUPRAC method less affected by chemical deviations from Beer's law thereby producing much smaller deviations from additivity (i.e. the property of additivity is valid when the measured TAC of a mixture is equal to the sum of individual antioxidant capacities of its constituents). PMID- 25731580 TI - Psychiatric emergency services in Copenhagen 2012: A 27-year psychiatric and demographic follow-up study. AB - BACKGROUND: Since the first publication of the psychiatric emergency units (PEUs) in Copenhagen 1985, outpatient facilities have undergone considerable changes. Our aim is to examine how these changes have influenced the activities in the PEUs in the same catchment area. METHODS: We conducted a follow-up study to describe this development in the past 27 years by comparing 1985 variables with same measures in 2012. A random sample of all visits every 10 days in 2012 to three PEUs in Copenhagen were registered and compared with data collected, using the same study design in 1985. MAIN RESULTS: The number of visits has decreased significantly from 367 visits/year/10,000 inhabitants in 1985 to 225 in 2012. Apart from a considerable number (15.6%) of visitors with non-Danish background, the demographic variables have not changed significantly since 1985. Compared with 1985, the diagnostic distribution among the 2012 visitors shows an increased frequency of affective disorders and neurotic and stress disorders, while schizophrenia spectrum and personality disorders show almost the same frequencies in 1985 and 2012. Rates of alcoholism and organic mental disorders show a minor reduction during the 27-year follow-up period. In 1985, 20.7% of the visits ended up without any referrals, compared with 4.8% in 2012. The rate of acute admissions into a psychiatric ward was 60.8% in 2012 compared with 35.65% in 1985. CONCLUSION: The extension of the psychiatric outpatients' facilities since 1985 has reduced the number of visits in the PEUs considerably. The results have shown a change of diagnostic distribution and more severe conditions requiring acute admissions for emergency treatment. Close collaboration with the patients' families, GPs, social authorities and specialized psychiatric outpatient clinics is emphasized. PMID- 25731581 TI - Evaluation of the effects of nonlinear frequency compression on speech recognition and sound quality for adults with mild to moderate hearing loss. AB - OBJECTIVE: While potentially improving audibility for listeners with considerable high frequency hearing loss, the effects of implementing nonlinear frequency compression (NFC) for listeners with moderate high frequency hearing loss are unclear. The purpose of this study was to investigate the effects of activating NFC for listeners who are not traditionally considered candidates for this technology. DESIGN: Participants wore study hearing aids with NFC activated for a 3-4 week trial period. After the trial period, they were tested with NFC and with conventional processing on measures of consonant discrimination threshold in quiet, consonant recognition in quiet, sentence recognition in noise, and acceptableness of sound quality of speech and music. STUDY SAMPLE: Seventeen adult listeners with symmetrical, mild to moderate sensorineural hearing loss participated. Better ear, high frequency pure-tone averages (4, 6, and 8 kHz) were 60 dB HL or better. RESULTS: Activating NFC resulted in lower (better) thresholds for discrimination of /s/, whose spectral center was 9 kHz. There were no other significant effects of NFC compared to conventional processing. CONCLUSION: These data suggest that the benefits, and detriments, of activating NFC may be limited for this population. PMID- 25731582 TI - Evaluation of wideband frequency responses and non-linear frequency compression for children with mild to moderate high-frequency hearing loss. AB - OBJECTIVE: To evaluate wideband amplification and non-linear frequency compression (NLFC) as a means to improve speech recognition for children with mild/moderate hearing loss. DESIGN: Randomized within-subject design with repeated measures across test conditions. STUDY SAMPLE: Eleven children with mild to moderate hearing loss were evaluated with: (1) Phonak BTE without NLFC, (2) Phonak BTE with NLFC, and (3) Oticon BTE with wideband response extending to 8000 Hz. RESULTS: Use of NLFC provided better detection and recognition of high frequency stimuli (e.g. /sh/ and /s/). No difference in performance between conditions was observed for speech recognition when measured with the University of Western Ontario (UWO) plurals test and the UWO distinctive features difference test. Finally, there were no differences between conditions on the BKB-SIN test. CONCLUSIONS: Children with mild to moderate hearing loss have good access to high frequency phonemes presented at fixed levels (e.g. 50 to 60 dBA) with both wideband and NLFC technology. Similarly, sentence recognition in noise was similar with wideband and NLFC. Adaptive test procedures that probe performance at lower input levels showed small but significant improvements in the detection and recognition of the phonemes /s/ and /sh/ with NLFC condition when compared to the NLFC Off and wideband conditions. PMID- 25731583 TI - Reappraisal of shunt surgery for extrahepatic portal vein obstruction in adults: Report of a single-center case series. AB - AIM: Extrahepatic portal venous obstruction (EHPVO) is a relatively rare disease in adults. The clinical significance of shunt surgery for EHPVO in adult cases remains unclear. METHODS: We retrospectively analyzed the patient characteristics and the results of shunt surgery in 13 adult cases of EHPVO treated between March 1995 and March 2013 at a tertiary care hospital in Switzerland. The indication for shunt surgery was recurrent bleeding after endoscopic treatment. To update the outcomes of shunt surgery in adult cases of EHPVO, we performed a systematic review of published work to examine this issue. RESULTS: The mean age of the 13 patients in the present case series was 41.8 years (range, 20-68), and the mean follow-up duration after surgery was 4.4 years (range, 1-16). The types of shunt surgery performed were mesocaval shunt (n = 8), portacaval shunt (n = 2), splenorenal shunt (n = 1) and mesorenal shunt (n = 2). Two patients (15%) developed postoperative rebleeding, which was successfully treated by endoscopic treatment. None of the patients developed postoperative hepatic encephalopathy. No operative-related deaths occurred in this series. Six studies, including our own, were identified in the published work. The overall mortality rate was 0 3.7%, and no cases of encephalopathy were observed. The rebleeding rate ranged 2.5-23%. CONCLUSION: Shunt surgery for EHPVO in adults after the failure of endoscopic treatment is feasible, with acceptable outcomes at specialized centers. This surgical procedure should always be taken into consideration when managing adult cases of EHPVO. PMID- 25731585 TI - Systemic antihistamines--a common outside the guidelines therapeutic strategy in hand eczema management. AB - BACKGROUND: Hand eczema (HE) is the most common skin disease affecting hands. Although the current treatment guidelines do not recommend use of systemic antihistamines as routine therapy, they seem to be widely used by physicians handling with this problem. OBJECTIVE: The aim of the study was to investigate the attitude to prescribe systemic antihistamines in HE. MATERIAL AND METHODS: A 10-item questionnaire was distributed among physicians participating in regional dermatological conferences. 127 valid questionnaires were analysed. RESULTS: A total of 127 physicians participated in the survey. 124 (97.6%) responders prescribe antihistamines in HE and 16 (12.6%) subjects declared routine use of oral antihistamines in the HE management. Significantly more dermatologists than other specialists used antihistamines in the treatment of HE accompanying atopic dermatitis (77.8% vs. 54.5%, P < 0.01) and dermatologists significantly more commonly used antihistamines in HE due to their anti-inflammatory properties (40.3% vs. 20.0%, P = 0.02). Regarding the type of eczema, antihistamines were prescribed most frequently in acute allergic HE (n = 92, 72.4%) and in HE accompanying atopic dermatitis (n = 86, 67.7%). CONCLUSIONS: Despite the lack of the large, randomized, controlled studies on the effectiveness of the systemic antihistamines in the treatment of HE, this type of therapy seems to be prevalently used among the physicians. PMID- 25731584 TI - Morphometric and histological parameters in veins of diabetic patients undergoing brachiocephalic fistula placement. AB - Diabetic patients with end-stage renal failure have higher rates of arteriovenous failures when compared with nondiabetics. The aim was to compare differences in indicators of vascular remodeling and endothelial dysfunction in veins of patients with or without diabetes at the time of surgical placement. In this prospective observational trial, vein samples were collected from patients when a brachiocephalic fistula was created. Morphometric measurements and extent of fibrosis were determined using Image J software. Histological analysis, for the presence of myofibroblasts and level of endothelial nitric oxide synthase, was performed by immunohistochemical staining and scored in semi-quantitative manner. Asymmetric dimethylarginine was determined at the time of access placement. Comparison of diabetics and nondiabetics was performed using Wilcoxon rank sum and Fisher's exact tests. Eighteen patients were included; 10 were diabetics. There was a significant difference in the measurement of vein area between groups, with diabetic vein samples having larger luminal area of average 832,001.18 MUm(2) (317,582.17-3,695,670.36, P = 0.04). The maximal intimal to medial thickness ratio was higher in diabetic vein samples (0.71 vs. 0.24, P = 0.03) along with statistically significant higher maximal intimal thickness (312.12 vs. 115.14 MUm, P = 0.03). There is a significant difference in vascular wall remodeling between diabetics and nondiabetics at the level of the cephalic vein at the time of brachiocephalic placement. The unexpected finding of significantly larger luminal area in diabetic veins could be a major factor positively affecting brachiocephalic outcomes in otherwise impaired remodeling in this patient population. PMID- 25731586 TI - 'One physical system': Tansley's ecosystem as Earth's critical zone. AB - Integrative concepts of the biosphere, ecosystem, biogeocenosis and, recently, Earth's critical zone embrace scientific disciplines that link matter, energy and organisms in a systems-level understanding of our remarkable planet. Here, we assert the congruence of Tansley's (1935) venerable ecosystem concept of 'one physical system' with Earth science's critical zone. Ecosystems and critical zones are congruent across spatial-temporal scales from vegetation-clad weathering profiles and hillslopes, small catchments, landscapes, river basins, continents, to Earth's whole terrestrial surface. What may be less obvious is congruence in the vertical dimension. We use ecosystem metabolism to argue that full accounting of photosynthetically fixed carbon includes respiratory CO2 and carbonic acid that propagate to the base of the critical zone itself. Although a small fraction of respiration, the downward diffusion of CO2 helps determine rates of soil formation and, ultimately, ecosystem evolution and resilience. Because life in the upper portions of terrestrial ecosystems significantly affects biogeochemistry throughout weathering profiles, the lower boundaries of most terrestrial ecosystems have been demarcated at depths too shallow to permit a complete understanding of ecosystem structure and function. Opportunities abound to explore connections between upper and lower components of critical-zone ecosystems, between soils and streams in watersheds, and between plant-derived CO2 and deep microbial communities and mineral weathering. PMID- 25731587 TI - Hydration thermodynamics of the proton conducting oxygen-deficient perovskite series BaTi1-xMxO3-x/2 with M = In or Sc. AB - This article establishes the effect of structure and composition on water uptake and the hydration and proton transport properties of the oxygen-deficient perovskite series BaTi1-x(In,Sc)xO3-x/2, with 0.2 <= x <= 0.7. The equilibrium water uptake is determined by thermogravimetry, while combining thermogravimetry with differential scanning calorimetry allows for direct determination of the materials' hydration thermodynamics. Proton and oxide ion transport properties are characterized by means of ac impedance measurements up to 1000 degrees C. In general, the hydration thermodynamics of the scandates are more favorable than that of the indates and are also affected by changes in crystal structure throughout the series. The more favorable hydration thermodynamics of cubic scandates increase their proton conductivity at higher temperatures compared to their indate counterparts. In contrast to the BaTi1-xInxO3-x/2 series, the BaTi1 xScxO3-x/2 (0.5 <= x <= 0.7) materials retain their cubic structures upon full saturation by protons and show no signs of chemical instability upon exposure to 1 atm H2O(g) down to 100 degrees C. The BaTi1-xScxO3-x/2 materials with 0.5 <= x <= 0.7 may therefore find application in, for instance, steam electrolysis or similar processes involving high water vapor pressures. PMID- 25731588 TI - Effect of Lonicera japonica extract on Mycoplasma gallisepticum in naturally infected broiler flocks. AB - 1. In this study, the effect of chlorogenic acid extract from Lonicera japonica Thunb. on Mycoplasma gallisepticum infections and the performance of broiler flocks was investigated. 2. A total of 360 Ross-308 broiler chicks taken from M. gallisepticum seropositive flocks were divided equally into three groups designated as control (nothing administered), antibiotic (Tylosin tartrate given for the first 3 d and d 20-22) and test group (chlorogenic acid extract given twice a day on d 16 and 22). 3. Broiler performance analysis, serological tests (slide agglutination), molecular identification (polymerase chain reaction) and histopathological examination were performed to detect M. gallisepticum. 4. The results show that chlorogenic acid not only increases live body weight but is also an alternative treatment option in M. gallisepticum-infected broiler flocks. PMID- 25731589 TI - Synthesis and in vitro Evaluation of Polymeric Prodrug of Ibuprofen with Amino Acid Spacer. AB - The present work is an agreement with simple and efficient method of improving the therapeutic efficacy of ibuprofen by masking its acidic moiety. It aims to reduce gastrointestinal side effects by controlling the rate, duration and site of release. This is achieved by synthesis and evaluation of polymeric prodrug of ibuprofen with natural polymer sodium alginate. The synthesis was supported by N protected serine as spacer due to chemical incompatibility of drug and polymer. Synthesized prodrug was characterized for confirmation of said structures. The in vitro dissolution profile of ibuprofen-alginate prodrug showed that the release of the drug is significantly higher in case of pH 7.2 buffer as compared to ibuprofen, which might be due to ester group adjacent to drug get hydrolyzed. The hydrolysis was found to be with faster rate in alkaline media than that of in acidic media. PMID- 25731590 TI - Comparison of the Structure and Biological Activities of Wild-type and Mutant Liver-targeting Peptide Modified Recombinant Human Endostatin (rES-CSP) in Human Hepatocellular Carcinoma HepG2 Cells. AB - A missense mutation of Aspartic to Asparagine acid in 113 position of liver targeting peptide CSP I-plus modified rEndostatin (rES-CSP) happened unexpectedly results in the changes of protein secondary structure and a reduced bioactivity. With the aim to clarify the structure-function relationships featuring the fuse protein rES-CSP, the three-dimensional structural models of wild-type and mutant D113NrES-CSP were constructed by template-based modeling approach. To evaluate the effect of the single mutation on rES-CSP stability, the molecular dynamic simulation was used to reveal the structural and dynamic characteristics. Analysis on the bioactivity were conducted using a number of validated in vitro assays including proliferation, migration, cell cycle and apoptosis in HepG2 cells. Results showed that the mutant rES-CSP reduce the stability and loss of function, and the wild-type rES-CSP could both bind to the normal liver cells Chang's and the hepatoma cells HepG2 but significantly higher than non-targeted rEndostatin. rESCSP could inhibit the proliferation of hepatoma cells in a dose dependent manner, and increase the proportion of G1 phase, reduce the proportion of S phase, promote the apoptosis on hepatoma cells. These results make a further complement of the mechanisms by which the fuse protein rES-CSP would provide a feasible and convenient approach to produce liver-targeting drugs for treatment of the liver disease. PMID- 25731591 TI - In Silico Identification of Novel APRIL Peptide Antagonists and Binding Insights by Molecular Modeling and Immunosorbent Assays. AB - The "A proliferation inducing ligand" protein (APRIL) is a cytokine over expressed in many transformed and tumoral cells acting onto two distinct receptors of the Tumoral Necrosis Factor B cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). We herein describe, through a detailed computational approach, the molecular interactions between TACI and its ligands APRIL and another structurally similar protein called B-cell activating factor (BAFF) by means of molecular dynamics. Dynamical analysis suggests R84 and D85 residues from TACI as possible mutation candidates, yielding increased affinity between TACI and APRIL. The association of computational simulations, site directed mutagenesis and peptide design could be a powerful tool, driving to better in vitro experiments. Our results contribute to the elucidation of APRIL signaling and help clarify the effects of blocking interaction between APRIL and its receptors through the use of particular peptides. PMID- 25731592 TI - Isolation and characterization of an aspartic protease from Salpichroa origanifolia fruits. AB - This report describes the purification of an aspartic protease (salpichroin) from ripe fruits of Salpichroa origanifolia (Solanaceae) starting with precipitation using organic solvents and anionexchange chromatography with 32.1% recovery and 13.4-fold purification. SDS-PAGE and zymograms of this enzyme showed a single band corresponding to an apparent molecular mass of approximately 32 kDa. The biochemical and kinetic characterization of the pure enzyme showed an acidic behavior with an optimal pH value around 3.0-4.5 with hemoglobin and 5.5-6.0 with casein. Salpichroin activity was inhibited by pepstatin but not by phenylmethylsulfonyl fluoride, E-64, EDTA or 1,10-phenanthroline, thus suggesting an aspartic protease behavior. Salpichroin hydrolyzed natural substrates, such as casein and hemoglobin, with high specific activity. Kinetic studies conducted with the synthetic peptide H-Pro- Thr-Glu-Phe-p-(NO2)-Phe-Arg-Leu-OH showed lower affinity (Km 494 uM) than other representative aspartic proteases. By investigating the cleavage of oxidized insulin beta-chain to establish the hydrolytic specificity of salpichroin, we found six cleavage sites on the substrate of peptide bonds similar to those of chymosin. MALDI-TOF/TOF-MS of the tryptic ingel digest of salpichroin showed that the isolated protease shared homologous sequences with other plant proteases of the A1 aspartic protease family. This is the first report concerning the isolation and biochemical characterization of an aspartic protease isolated from Salpichroa origanifolia fruits. PMID- 25731593 TI - Iodinated contrast prior to thrombolysis was not associated with worse intracranial hemorrhage. AB - OBJECTIVES: The objective was to assess relative incidence of clinical adverse effects between patients receiving, and not receiving, iodinated contrast prior to thrombolysis. METHODS: This was a retrospective registry review of patients presenting to the emergency department treated with recombinant tissue-type plasminogen activator (rt-PA) for acute ischemic stroke between 2004 and 2012. The authors compared the occurrence of all grades of intracranial hemorrhage (ICH), symptomatic intracranial hemorrhage (sICH), and in-hospital deaths between patients undergoing computed tomographic angiography (CTA) prior to thrombolysis and those who did not. RESULTS: A total of 1,014 patients were available for analysis meeting inclusion criteria. A total of 473 patients underwent CTA prior to rt-PA administration. Baseline characteristics were generally similar across groups, excepting fewer signs of acute infarct and old stroke in the CTA group (28.8% vs. 8.5% and 9.9% vs. 3.7%, respectively) and creatinine. Adverse event outcomes were not consistently distributed across the groups. Patients in the CTA group had a similar incidence of any ICH (11.0% vs. 8.1%, p = 0.120), but fewer type II parenchymal hemorrhages (2.1% vs. 4.6%, p = 0.025) and fewer in-hospital deaths (7.2% vs. 12.6%, p = 0.005). CONCLUSIONS: No consistent harms were observed in association with intravenous iodinated contrast prior to rt-PA administration. It is reasonable to continue CTA prior to thrombolysis as clinically indicated. PMID- 25731594 TI - Dravet syndrome in Sweden. PMID- 25731595 TI - Iodine deficiency during pregnancy: a national cross-sectional survey in Latvia. AB - OBJECTIVE: Low iodine intake during pregnancy may cause thyroid dysfunction, which results in inadequate fetal brain development. In the absence of a universal salt iodization programme, we conducted a nationwide survey of iodine deficiency in pregnant women in Latvia. DESIGN: A countrywide twenty-cluster survey, with at least twenty women per cluster. Participants completed a questionnaire on dietary habits concerning iodine intake (n 739). Thyroid function (thyroid-stimulating hormone, free thyroxine and thyroperoxidase antibodies) was measured (n 550). Urinary iodine was measured using the ammonium persulfate method (n 696). SETTING: The survey was performed in all regions of Latvia during the spring and autumn seasons in 2013. SUBJECTS: Pregnant women (n 829). RESULTS: The median creatinine (Cr)-standardized urinary iodine concentration (UIC) was 80.8 (interquartile range (IQR) 46.1-130.6) ug/g Cr or 69.4 (IQR 53.9-92.6) ug/l during pregnancy, and 81% of pregnant women had UIC levels below the WHO recommended range of 150-250 ug/g Cr. The UIC was lowest during the first trimester of pregnancy, 56.0 (IQR 36.4-100.6) ug/g Cr, reaching higher concentrations of 87.5 (IQR 46.4-141.7) ug/g Cr and 86.9 (IQR 53.8-140.6) ug/g Cr in the second and third trimesters, respectively. Women taking supplements containing >=150 ug iodine (6.8% of respondents) had non significantly higher UIC than did women without supplementation (96.2 v. 80.3 ug/g Cr, respectively, P=NS). Thyroperoxidase antibody concentration did not correlate significantly with UIC: Spearman's rho=-0.012, P=0.78. CONCLUSIONS: The median UIC indicates iodine deficiency in pregnant women in Latvia. Iodine supplementation (150 ug daily) and regular UIC monitoring should be suggested to overcome iodine deficiency and to reach the recommended levels without inducing autoimmune processes. PMID- 25731596 TI - Discrete {Gd(III)4M} (M = Gd(III) or Co(II)) pentanuclear complexes: a new class of metal-organophosphate molecular coolers. AB - The first examples of homo- and hetero-polymetallic organophosphates of gadolinium are reported. Magnetic measurements reveal a higher magnetic entropy change for the isotropic {Gd(III)5} complex (25.8 J kg(-1) K(-1)) as compared to the heterometallic {Gd(III)4Co(II)} complex (20.3 J kg(-1) K(-1)), which is attributable to a change in magnetic coupling as estimated from DFT calculations. PMID- 25731597 TI - Replacement of the CysA7-CysB7 disulfide bond with a 1,2,3-triazole linker causes unfolding in insulin glargine. AB - Two analogues of insulin glargine containing a 1,4-disubstituted 1,2,3-triazole group in place of the CysA7-CysB7 disulfide bond were prepared using CuAAC click chemistry to efficiently join the peptide chains. The resulting insulin analogues were analysed by circular dichroism spectroscopy to assess whether this modification compromised the folding pattern of the native form. Investigations, including an in vivo murine study, revealed that these analogues were not biologically active and that the structures were significantly unfolded, an outcome which suggests that maintaining a precise inter-chain distance is critical to the structure of the insulin hormone. PMID- 25731598 TI - Neck dissection: cause and effect. AB - OBJECTIVE: This study aimed to evaluate changes in neck dissection procedures over time in a tertiary university hospital to determine their influence on residency training. METHODS: Neck dissections performed in a recent decade (2003 2012) were retrospectively analysed and compared with those of an earlier decade (1981-1990). RESULTS: Nowadays, neck dissections are most frequently performed for thyroid (2003-2012 vs 1981-1990: 60.7 per cent vs 25 per cent, p = 0.002) and less often for epithelial malignancies (23.2 per cent vs 53.5 per cent, p = 0.002). Compared with dissections for thyroid spread, more dissections for epithelial malignancies are extensive (epithelial vs thyroid malignancies, 66 per cent vs 4.9 per cent) and more are performed after chemoradiation failures (25.6 per cent vs 0 per cent). CONCLUSION: This study demonstrates changes in neck dissection procedures over time. There is an increasing preference for conservative treatment for epithelial cancers. In addition, there is a large increase in both the diagnosis and surgical treatment of thyroid cancer. This shift may have a great effect on residents' learning curves and on their ability to achieve competency in performing neck dissections. PMID- 25731600 TI - Characterizing the severe asthma population in the United States: claims-based analysis of three treatment cohorts in the year prior to treatment escalation. AB - OBJECTIVES: Little is known about the disposition of severe patients prior to treatment escalation. To classify patients by treatment step using pharmacy data and describe their economic and healthcare utilization, insurance status, and sociodemographic characteristics in the year prior to escalation to Global Initiative for Asthma (GINA) steps 4 and 5. METHODS: This was a retrospective claims cohort study of asthma patients (age 12-75 years) newly initiated on "stable therapy" (three consecutive months of therapy) with omalizumab, high intensity corticosteroids (HICS; >=1000 ug/d inhaled fluticasone equivalent or oral prednisone), or high-dose inhaled corticosteroid (HDICS; >=500-<1000 ug/d fluticasone equivalent) from 2002 to 2011. Other asthma treatments were compared as a reference. RESULTS: Of 25,297 patients, 856 initiated omalizumab, 6926 initiated HICS, and 11,445 initiated HDICS. In the year prior to treatment escalation to omalizumab, HICS, and HDICS, respectively, individuals had high annual mean medical expenditures ($14,071, $12,030, and $7570), utilization (27 outpatient and 10 specialty care visits; 19 outpatient and three specialty; 15 outpatient and two specialty), asthma-related prescription drugs (11.74, 7.8, and 5.17) and chronic comorbidities (2.68, 2.67, and 2.19). Prior to omalizumab treatment, patients were more likely to be salaried, full-time employees with commercial PPO/POS insurance. CONCLUSIONS: Prior to escalating treatment to GINA steps 4 and 5, individuals experienced significant annual medical expenditures, healthcare resource utilization and polypharmacy burden, which may reflect poorly controlled asthma and the need to escalate treatment. Medical claims data and utilization-based measures may be helpful in classifying individuals by GINA treatment step. PMID- 25731601 TI - Metal-free oxidative decarbonylative coupling of aromatic aldehydes with arenes: direct access to biaryls. AB - A metal-free oxidative decarbonylative coupling of aromatic aldehydes with electron-rich or electron-deficient arenes to produce biaryl compounds was developed. This novel coupling was proposed to proceed via a non-chain radical homolytic aromatic substitution (HAS) type mechanism, based on the substrate scope, ortho-regioselectivity, radical trapping experiments and DFT calculation studies. With the ready availability of aromatic aldehydes and arenes, metal-free conditions should make this coupling attractive for the biaryl synthesis. PMID- 25731599 TI - The late positive potential indexes a role for emotion during learning of trust from eye-gaze cues. AB - Gaze direction perception triggers rapid visuospatial orienting to the location observed by others. When this is congruent with the location of a target, reaction times are faster than when incongruent. Functional magnetic resonance imaging studies suggest that the non-joint attention induced by incongruent cues are experienced as more emotionally negative and this could relate to less favorable trust judgments of the faces when gaze-cues are contingent with identity. Here, we provide further support for these findings using time-resolved event-related potentials. In addition to replicating the effects of identity contingent gaze-cues on reaction times and trust judgments, we discovered that the emotion-related late positive potential increased across blocks to incongruent compared to congruent faces before, during and after the gaze-cue, suggesting both learning and retrieval of emotion states associated with the face. We also discovered that the face-recognition-related N250 component appeared to localize to sources in anterior temporal areas. Our findings provide unique electrophysiological evidence for the role of emotion in learning trust from gaze-cues, suggesting that the retrieval of face evaluations during interaction may take around 1000 ms and that the N250 originates from anterior temporal face patches. PMID- 25731602 TI - Obesity, psoriasis, and microbiota: an unexplored dangerous connection? PMID- 25731603 TI - Solution self-assembly of block copolymers containing a branched hydrophilic block into inverse bicontinuous cubic mesophases. AB - Solution self-assembly of amphiphilic block copolymers into inverse bicontinuous cubic mesophases is an emerging strategy for directly creating highly ordered triply periodic porous polymer nanostructures with large pore networks and desired surface functionalities. Although there have been recent reports on the formation of highly ordered triply periodic minimal surfaces of self-assembled block copolymer bilayers, the structural requirements for block copolymers in order to facilitate the preferential formation of such inverse mesophases in solution have not been fully investigated. In this study, we synthesized a series of model block copolymers, namely, branched poly(ethylene glycol)-block polystyrene (bPEG-PS), to investigate the effect of the architecture of the block copolymers on their solution self-assembly into inverse mesophases consisting of the block copolymer bilayer. On the basis of the results, we suggest that the branched architecture of the hydrophilic block is a crucial structural requirement for the preferential self-assembly of the resulting block copolymers into inverse bicontinuous cubic phases. The internal crystalline lattice of the inverse bicontinuous cubic structure can be controlled via coassembly of branched and linear block copolymers. The results presented here provide design criteria for amphiphilic block copolymers to allow the formation of inverse bicontinuous cubic mesophases in solution. This may contribute to the direct synthesis of well defined porous polymers with desired crystalline order in the porous networks and surface functionalities. PMID- 25731604 TI - Two-dimensional HYSCORE spectroscopy of superoxidized manganese catalase: a model for the oxygen-evolving complex of photosystem II. AB - The solar water-splitting protein complex, photosystem II (PSII), catalyzes one of the most energetically demanding reactions in Nature by using light energy to drive a catalyst capable of oxidizing water. The water oxidation reaction takes place at the tetra-nuclear manganese calcium-oxo (Mn4Ca-oxo) cluster at the heart of the oxygen-evolving complex (OEC) of PSII. Previous studies have determined the magnetic interactions between the paramagnetic Mn4Ca-oxo cluster and its environment in the S2 state of the OEC. The assignments for the electron-nuclear magnetic interactions that were observed in these studies were facilitated by the use of synthetic dimanganese di-MU-oxo complexes. However, there is an immense need to understand the effects of the protein environment on the coordination geometry of the Mn4Ca-oxo cluster in the OEC of PSII. In the present study, we use a proteinaceous model system to examine the protein ligands that are coordinated to the dimanganese catalytic center of manganese catalase from Lactobacillus plantarum. We utilize two-dimensional hyperfine sublevel correlation (2D HYSCORE) spectroscopy to detect the weak magnetic interactions of the paramagnetic dinuclear manganese catalytic center of superoxidized manganese catalase with the nitrogen and proton atoms of the surrounding protein environment. We obtain a complete set of hyperfine interaction parameters for the protons of a water molecule that is directly coordinated to the dinuclear manganese center. We also obtain a complete set of hyperfine and quadrupolar interaction parameters for two histidine ligands as well as a coordinated azide ligand, in azide-treated superoxidized manganese catalase. On the basis of the values of the hyperfine interaction parameters of the dimanganese model, manganese catalase, and those of the S2 state of the OEC of PSII, for the first time, we discuss the impact of a proteinaceous environment on the coordination geometry of multinuclear manganese clusters. PMID- 25731605 TI - A microfluidic live cell assay to study anthrax toxin induced cell lethality assisted by conditioned medium. AB - It is technically challenging to investigate the function of secreted protein in real time by supply of conditioned medium that contains secreted protein of interest. The internalization of anthrax toxin is facilitated by a secreted protein Dickkopf-1 (DKK1) and its receptor, and eventually leads to cell lethality. To monitor the dynamic interplay between these components in live cells, we use an integrated microfluidic device to perform the cell viability assays with real-time controlled culture microenvironment in parallel. Conditioned medium, which contains the secreted proteins from specific cell lines, can be continuously pumped towards the cells that exposed to toxin. The exogenous DKK1 secreted from distant cells is able to rescue the sensitivity to toxin for those DKK1-knocked-down cells. This high-throughput assay allows us to precisely quantify the dynamic interaction between key components that cause cell death, and provide independent evidence of the function of DKK1 in the complex process of anthrax toxin internalization. PMID- 25731606 TI - Detecting local heterogeneity and ionization ability in the head group region of different lipidic phases using modified fluorescent probes. AB - Local heterogeneity in lipid self-assembly is important for executing the cellular membrane functions. In this work, we chemically modified 2-(2' hydroxyphenyl)benzoxazole (HBO) and attached a C8 alkyl chain in two different locations to probe the microscopic environment of four lipidic phases of dodecyl beta-maltoside. The fluorescence change in HBO and the new probes (HBO-1 and HBO 2) shows that in all phases (micellar, hexagonal, cubic and lamellar) three HBO tautomeric species (solvated syn-enol, anionic, and closed syn-keto) are stable. The formation of multi tautomers reflects the heterogeneity of the lipidic phases. The results indicate that HBO and HBO-1 reside in a similar location within the head group region, whereas HBO-2 is slightly pushed away from the sugar-dominated area. The stability of the solvated syn-enol tautomer is due to the formation of a hydrogen bond between the OH group of the HBO moiety and an adjacent oxygen atom of a sugar unit. The detected HBO anions was proposed to be a consequence of this solvation effect where a hydrogen ion abstraction by the sugar units is enhanced. Our results point to a degree of local heterogeneity and ionization ability in the head group region as a consequence of the sugar amphoterism. PMID- 25731607 TI - Inactivation of viruses in platelet and plasma products using a riboflavin-and-UV based photochemical treatment. AB - BACKGROUND: Multilayered blood safety programs reduce the risk of transfusion transmitted diseases; however, there remains a risk of window period transmission of screened viruses and transmission of unscreened and emerging viruses from asymptomatic donors. To reduce this risk, a riboflavin-and-UV-light-based pathogen reduction process was evaluated against eight viral agents. STUDY DESIGN AND METHODS: Riboflavin and UV light was evaluated against the following eight viral agents: encephalomyocarditis virus (EMC), hepatitis A virus (HAV), hepatitis C virus (HCV), influenza A (FLUAV), La Crosse virus (LACV), pseudorabies virus (PRV), sindbis virus (SINV), and vesicular stomatitis virus (VSV). Before treatment, a sample was removed to determine the product's initial viral load. After treatment the product's viral load was reevaluated and the log reduction was calculated. RESULTS: Virus reduction after treatment with riboflavin and UV light is equivalent in platelet (PLT) and plasma units, as demonstrated by a 3.2-log reduction of EMC in plasma, PLTs, and PLT additive solution containing 35% plasma. Additionally, the following viral reductions values were observed: HAV 1.8 log, HCV at least 4.1 log, FLUAV at least 5.0 log, LACV at least 3.5 log, PRV 2.5 log, SINV 3.2 log, and VSV at least 6.3 log. CONCLUSIONS: The results observed in this study suggest that treating PLT and plasma products with a riboflavin-and-UV-light-based pathogen reduction process could potentially eliminate window period transmission of screened viruses and greatly reduce the risk of transfusion transmission of unscreened viruses. PMID- 25731608 TI - A quantum circuit rule for interference effects in single-molecule electrical junctions. AB - A quantum circuit rule for combining quantum interference effects in the conductive properties of oligo(phenyleneethynylene) (OPE)-type molecules possessing three aromatic rings was investigated both experimentally and theoretically. Molecules were of the type X-Y-X, where X represents pyridyl anchors with para (p), meta (m) or ortho (o) connectivities and Y represents a phenyl ring with p and m connectivities. The conductances GXmX (GXpX) of molecules of the form X-m-X (X-p-X), with meta (para) connections in the central ring, were predominantly lower (higher), irrespective of the meta, para or ortho nature of the anchor groups X, demonstrating that conductance is dominated by the nature of quantum interference in the central ring Y. The single-molecule conductances were found to satisfy the quantum circuit rule Gppp/Gpmp=Gmpm/Gmmm. This demonstrates that the contribution to the conductance from the central ring is independent of the para versus meta nature of the anchor groups. PMID- 25731609 TI - Many metals make the cut: quaternary rare-earth germanides RE4M2InGe4 (M = Fe, Co, Ni, Ru, Rh, Ir) and RE4RhInGe4 derived from excision of slabs in RE2InGe2. AB - The formation of quaternary rare-earth (RE) germanides containing transition metals (M's) from groups 6 to 10 was investigated through arc-melting and annealing reactions at 800 degrees C; about 50 new compounds were obtained. These include several new series of quaternary germanides RE4M2InGe4 (M = Fe, Co, Ru, Rh, Ir), previously known only for M = Mn and Ni; additional members of RE4Ni2InGe4 extended to other RE substituents; and a different but closely related series RE4RhInGe4. Detailed crystal structures were determined by single crystal X-ray diffraction studies for 20 compounds. Monoclinic structures in space group C2/m are adopted by RE4M2InGe4 (Ho4Ni2InGe4-type, a = 15.1-16.5 A, b = 4.1-4.4 A, c = 6.9-7.3 A, beta = 106.2-108.6 degrees ) and RE4RhInGe4 (own type, a = 20.0-20.2 A, b = 4.2-4.3 A, c = 10.1-10.2 A, beta = 105.0-105.3 degrees ). Both structures contain frameworks built from MGe4 tetrahedra, InGe4 square planes, and Ge2 dimers, delimiting tunnels occupied by RE atoms. These structures can also be derived by cutting slabs along different directions from the more symmetrical RE2InGe2 structure. Although the Ge2 dimers are relatively invariant, the InGe4 square planes can undergo distortion to form two sets of short versus long In-Ge distances. This distortion results from a competition between M-Ge bonding in the MGe4 tetrahedra and In-Ge bonding in the InGe4 square planes. PMID- 25731610 TI - A prospective, randomized trial of intravenous hydroxocobalamin versus whole blood transfusion compared to no treatment for Class III hemorrhagic shock resuscitation in a prehospital swine model. AB - OBJECTIVES: The objective was to compare systolic blood pressure (sBP) over time in swine that have had 30% of their blood volume removed (Class III shock) and treated with intravenous (IV) whole blood or IV hydroxocobalamin, compared to nontreated control animals. METHODS: Thirty swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged a total of 20 mL/kg over a 20-minute period. Five minutes after hemorrhage, animals were randomly assigned to receive 150 mg/kg IV hydroxocobalamin solubilized in 180 mL of saline, 500 mL of whole blood, or no treatment. Animals were monitored for 60 minutes thereafter. A sample size of 10 animals per group was determined based on a power of 80% and an alpha of 0.05 to detect an effect size of at least a 0.25 difference (>1 standard deviation) in mean sBP between groups. sBP values were analyzed using repeated-measures analysis of variance (RANOVA). Secondary outcome data were analyzed using repeated-measures multivariate analysis of variance (RMANOVA). RESULTS: There were no significant differences between hemodynamic parameters of IV hydroxocobalamin versus whole blood versus control group at baseline (MANOVA; Wilks' lambda; p = 0.868) or immediately posthemorrhage (mean sBP = 47 mm Hg vs. 41 mm Hg vs. 37 mm Hg; mean arterial pressure = 39 mm Hg vs. 28 mm Hg vs. 34 mm Hg; mean serum lactate = 1.2 mmol/L vs. 1.4 mmol/L vs. 1.4 mmol/L; MANOVA; Wilks' lambda; p = 0.348). The outcome RANOVA model detected a significant difference by time between groups (p < 0.001). Specifically, 10 minutes after treatment, treated animals showed a significant increase in mean sBP compared to nontreated animals (mean sBP = 76.3 mm Hg vs. 85.7 mm Hg vs. 51.1 mm Hg; p < 0.001). RMANOVA modeling of the secondary data detected a significant difference in mean arterial pressure, heart rate, and serum lactate (p < 0.001). Similar to sBP, 10 minutes after treatment, treated animals showed a significant increase in mean arterial pressure compared to nontreated animals (mean arterial pressure = 67.7 mm Hg vs. 61.4 mm Hg vs. 40.5 mm Hg). By 10 minutes, mean heart rate was significantly slower in treated animals compared to nontreated animals (mean heart rate = 97.3 beats/min vs. 95.2 beats/min vs. 129.5 beats/min; p < 0.05). Serum lactate, an early predictor of shock, continued to rise in the control group, whereas it did not in treated animals. Thirty minutes after treatment, serum lactate values of treated animals were significantly lower compared to nontreated animals (p < 0.05). This trend continued throughout the 60 minute observation period such that 60-minute values for lactate were 1.4 mmol/L versus 1.1 mmol/L versus 3.8 mmol/L. IV hydroxocobalamin produced a statistically significant increase in systemic vascular resistance compared to control, but not whole blood, with a concomitant decrease in cardiac output. CONCLUSIONS: Intravenous hydroxocobalamin was more effective than no treatment and as effective as whole blood transfusion, in reversing hypotension and inhibiting rises in serum lactate in this prehospital, controlled, Class III swine hemorrhage model. PMID- 25731611 TI - Light and laser therapies for the treatment of sebaceous gland hyperplasia a review of the literature. AB - Sebaceous gland hyperplasia (SGH) is a benign cutaneous condition that presents primarily on the face and increases with UVB exposure and ageing. These lesions are a common cosmetic concern but are difficult to treat, as the entire sebaceous gland needs to be destroyed to prevent recurrence. Traditional methods of treatment include: cryosurgery, electrodessication, curettage, shave excision and topical trichloroacetic acid. These methods have an increased risk of skin discoloration and scarring to the area of treatment that may lead to inferior cosmetic outcomes. Alternatively, oral isotretinoin can treat SGH, but is a known teratogen in pregnancy and has high relapse rates with discontinuation. A systematic review of the literature was performed to look at photodynamic therapy (PDT) and laser treatment for SGH. According to the results of this study, PDT, lasers and combinations of the two treatments were found to offer alternatives to the more conventional techniques with better outcomes. In particular, the use of wavelength-specific laser for the sebaceous gland of 1720 nm were found to have better outcomes and provide minimal damage to surrounding tissues. Additionally, combination PDT with aminolevulinic acid and pre-treatment with carbon dioxide laser ablation or pulse-dyed laser offered higher cure rates over stand-alone laser or PDT treatments in a shorter number of sessions with similar transient side-effects. However, further large-scale prospective studies with adequate follow-up are required to confirm these findings and those for sebaceous gland specific lasers. PMID- 25731612 TI - Trunk control for reaching: growing into or out of dysfunction? PMID- 25731613 TI - FtsZ1/FtsZ2 Turnover in Chloroplasts and the Role of ARC3. AB - Chloroplast division requires filamentation temperature-sensitive Z (FtsZ), a tubulin-like GTPase of cyanobacterial endosymbiotic origin. Plants and algae possess two distinct FtsZ protein families, FtsZ1 and FtsZ2 that co-assemble into a ring (Z-ring) at the division site. Z-ring assembly and disassembly and division site positioning is controlled by both positive and negative factors via their specific interactions with FtsZ1 and FtsZ2. Here we present the in planta analysis of Arabidopsis FtsZ1 and FtsZ2 turnover in the context of a native chloroplast division machinery. Fluorescence recovery after photobleaching analysis was conducted using fluorescently tagged FtsZ at wild-type (WT)-like levels. Rapid photobleaching, low signal-to-noise ratio, and phototropic movements of chloroplasts were overcome by (i) using progressive intervals in time-lapse imaging, (ii) analyzing epidermal rather than stromal chloroplasts, and (iii) employing image stack alignment during postprocessing. In plants of WT background, fluorescence recovery half-times averaged 117 and 325 s for FtsZ1 and FtsZ2, respectively. In plants lacking ARC3, the key negative regulator of FtsZ assembly, the turnover was threefold slower. The findings are discussed in the context of previous results conducted in a heterologous system. PMID- 25731614 TI - Patients with complex regional pain syndrome overestimate applied force in observed hand actions. AB - BACKGROUND: Movement accuracy is ensured by interaction between motor, somatosensory, and visual systems. In complex regional pain syndrome (CRPS), this interaction is disturbed. To explore CRPS patients' visual perception of actions, we investigated how these patients evaluate the applied force in observed hand actions of another person. METHODS: Nineteen patients suffering from unilateral upper-limb CRPS and 19 healthy control subjects viewed six different videos of left- and right-hand actions. They were asked to evaluate the applied force in each hand action, as well as their subjective sensations of unpleasantness and pain during the observation. RESULTS: The patients overestimated the force applied in the videos: the ratings were two times as large as in the control subjects for actions performed with the hand corresponding to the patients' affected hand, and 1.5 times as large for actions corresponding to their healthy hand. The control subjects considered the stimuli neutral and painless, whereas the patients rated them unpleasant. Moreover, the patients felt increased pain during viewing actions performed with the hand corresponding to their affected side. The overestimation of force was related to the elicited unpleasantness and pain, but not to the patients' muscle strength. CONCLUSIONS: We propose that the overestimation of force is explained both by the pain elicited by the observation and by the abnormal sensorimotor integration that is associated with perception of increased effort. This visually elicited unpleasantness and painfulness may promote avoidance of viewing own actions, further impairing the patients' motor performance. PMID- 25731615 TI - GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. AB - Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18 month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. PMID- 25731616 TI - Meta-analysis of gene expression profiles indicates genes in spliceosome pathway are up-regulated in hepatocellular carcinoma (HCC). AB - Hepatocellular carcinoma (HCC) is among the commonest kind of malignant tumors, which accounts for more than 500,000 cases of newly diagnosed cancer annually. Many microarray studies for identifying differentially expressed genes (DEGs) in HCC have been conducted, but results have varied across different studies. Here, we performed a meta-analysis of publicly available microarray Gene Expression Omnibus datasets, which covers five independent studies, containing 753 HCC samples and 638 non-tumor liver samples. We identified 192 DEGs that were consistently up-regulated in HCC vs. normal liver tissue. For the 192 up regulated genes, we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis. To our surprise, besides several cell growth-related pathways, spliceosome pathway was also up-regulated in HCC. For further exploring the relationship between spliceosome pathway and HCC, we investigated the expression data of spliceosome pathway genes in 15 independent studies in Nextbio database ( https://www.nextbio.com/b/nextbioCorp.nb ). It was found that many genes of spliceosome pathway such as HSPA1A, SNRPE, SF3B2, SF3B4 and TRA2A genes which we identified to be up-regulated in our meta-analysis were generally overexpressed in HCC. At last, using real-time PCR, we also found that BUD31, SF3B2, SF3B4, SNRPE, SPINK1, TPA2A and HSPA1A genes are significantly up-regulated in clinical HCC samples when compared to the corresponding non-tumorous liver tissues. Our study for the first time indicates that many genes of spliceosome pathway are up regulated in HCC. This finding might put new insights for people's understanding about the relationship of spliceosome pathway and HCC. PMID- 25731617 TI - Wnt signaling regulates the stemness of lung cancer stem cells and its inhibitors exert anticancer effect on lung cancer SPC-A1 cells. AB - Wnt signaling plays an important role in regulating the activity of cancer stem cells (CSCs) in a variety of cancers. In this study, we explored the role of Wnt signaling in the lung cancer stem cells (LCSCs). LCSCs were obtained by sphere culture, for which human lung adenocarcinoma cell line SPC-A1 was treated with IGF, EGF and FGF-10. The stemness of LCSCs was confirmed by immunofluorescence, and pathway analysis was performed by functional genome screening and RT-PCR. The relationship between the identified signaling pathway and the expression of the stemness genes was explored by agonist/antagonist assay. Moreover, the effects of different signaling molecule inhibitors on sphere formation, cell viability and colony formation were also analyzed. The results showed that LCSCs were successfully generated as they expressed pluripotent stem cell markers Nanog and Oct 4, and lung distal epithelial markers CCSP and SP-C, by which the phenotype characterization of stem cells can be confirmed. The involvement of Wnt pathway in LCSCs was identified by functional genome screening and verified by RT-PCR. The expression of Wnt signaling components was closely related to the expression of the Nanog and Oct 4. Furthermore, targeting Wnt signaling pathway by using different signaling molecule inhibitors can exert anticancer effects. In conclusion, Wnt signaling pathway is involved in the stemness regulation of LCSCs and might be considered as a potential therapeutic target in lung adenocarcinoma. PMID- 25731618 TI - Wnt2 protein plays a role in the progression of pancreatic cancer promoted by pancreatic stellate cells. AB - This study aimed to investigate the expression of Wnt2 protein in pancreatic cancer tissues and pancreatic stellate cells (PSCs), and determine its effect on the biological functions of pancreatic cancer cells. Immunohistochemistry was used to study the expression pattern of Wnt2 in pancreatic cancer tissues. The relationship between Wnt2 protein expression level and patient prognosis was analyzed. PSCs were isolated and cultured. The expression of Wnt2 in activated PSCs was investigated using Western blot and immunofluorescence. We also analyzed the effect of Wnt2 recombinant protein and stellate cell culture supernatant on the Wnt/beta-catenin signaling pathway, as well as the effect of Wnt2 recombinant protein on the biological functions of pancreatic cancer cells. The expression of Wnt2 in interstitial cells of pancreatic cancer was correlated with the prognosis of pancreatic cancer. Wnt2 protein was expressed in activated PSCs. Both stellate cell culture supernatant and Wnt2 recombinant protein could activate the classic Wnt/beta-catenin signaling pathway. Wnt2 protein enhanced the migration, invasion, and metastasis of pancreatic cancer cells. These results suggested that Wnt2 protein secreted by PSCs promoted the progression of pancreatic cancer by activating the classic Wnt/beta-catenin signaling pathway. PMID- 25731619 TI - Down-expression pattern of Ku70 and p53 coexisted in colorectal cancer. AB - To address the relationship of altered expression of double-strand break repair proteins Ku70 and p53 in clinical colorectal cancer (CRC), we examined the expression pattern of Ku70 and p53 by using fluorescent immunohistochemistry and real-time PCR assays in CRC and pericancerous samples from 152 Chinese patients. The results showed that down-expression pattern of both Ku70 and p53 coexisted in the CRC samples with significant correlating rate (R (2) = 0.9103; P < 0.001), and the down-expression of Ku70 and p53 was significantly associated with the advanced tumor node metastasis stage (Ku70: HR 3.453 in recurrence and 4.182 in survival, P < 0.001; P53: HR 3.114 in recurrence and 4.113 in survival, P < 0.001). The down-regulated Ku70 and p53 were associated with poor disease-free survival. Loss of Ku70 and p53 expression might serve as a biomarker of poor prognosis in CRC patients. PMID- 25731620 TI - Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer's disease. AB - Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD). The main endogenous antioxidant, glutathione (GSH), has been shown to decline with ageing and in several age related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteine. However, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacy to elevate depleted GSH levels in several in vivo and in vitro models of disease. It has been suggested that the decline in GSH levels in AD, may be associated with down regulation of GSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulated by non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor gamma-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves as a crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH, and the administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD. PMID- 25731621 TI - Identification of novel quantitative traits-associated susceptibility loci for APOE epsilon 4 non-carriers of Alzheimer's disease. AB - APOE epsilon4 allele is a major risk factor in Late-Onset Alzheimer's Disease (AD). Distinct phenotypes that depend on the APOE epsilon4 status have been demonstrated. The genetic etiology of APOE epsilon4 non-carriers is still elusive. Thus we investigated the genetic components of AD that is independent of APOE epsilon4 by combining genome association analysis with quantitative trait analyses in non-Hispanic Caucasian participants in the Alzheimer' s Disease Neuroimaging Initiative (ADNI) cohort. Five top susceptible single nucleotide polymorphisms (SNPs) in three loci in ZNF827, KDM2B and NANP were initially identified in APOE epsilon4 non-carriers and four of these SNPs were confirmed in mild cognitive impairment. These SNPs and one nominally significant SNP are located in three haplotype blocks. Quantitative trait analyses of these haplotype blocks demonstrated that the haplotype block in ZNF827 was associated with CSF Abeta42 level, and the haplotype block in KDM2B with CSF p-tau181p and p tau181p/Abeta42 ratio. The haplotype block between NANP and NINL was associated with brain atrophy. Moreover, these SNPs took additive effects on AD incidence and demonstrated the interaction with APOE epsilon4 status. Therefore, we conclude that these novel loci are associated with AD in APOE epsilon4 non carriers. This study indicates the distinct genetic risk genes for AD non carrying APOE epsilon4 and provides new insight into the molecular mechanisms of AD. PMID- 25731623 TI - Stroke suggests increased risk of dementia. AB - BACKGROUND: Stroke is a major cause of disability in the elderly and considerably increases the risk of dementia, which is another important source of disability. This population-based study aimed to examine the risk of dementia in patients with stroke compared with non-stroke cases with similar comorbidities. METHODS: Using the Taiwan National Health Insurance databank covering the period 2001 2007, this retrospective cohort study evaluated the risk of dementia in 10,884 patients with first stroke who had no history of dementia. In this study, we performed a 1:5 case-control matched analysis, in which cases were matched to controls based on their estimated propensity scores, which were estimated with demographics and associated risk factors. This approach reduced selection bias. Cox proportional hazards regression analysis was then used to estimate the risk of dementia in stroke patients. RESULTS: During the 5-year follow-up period, 1,487 (13.74%) stroke and 1,402 (2.59%) non-stroke patients suffered dementia. Stroke was independently associated with a 6.09 (95% confidence interval [CI], 5.66 to 6.55) times greater risk of dementia 5 years after stroke. Older age was associated with a higher incidence of dementia after stroke. Each stroke type had different impacts on the occurrence of dementia. The hazard ratio of dementia among hemorrhagic stroke patients was much higher than those of ischemic stroke and controls. CONCLUSION: The findings of this study suggest that stroke confers an increased risk of dementia, especially in the elderly and in patients with hemorrhagic stroke. We advocate the need for close observation and enhanced health education programs to benefit patients with stroke. PMID- 25731622 TI - Amyloid beta accumulation assessed with 11C-Pittsburgh compound B PET and postmortem neuropathology. AB - 11C-Pittsburgh compound B (PiB) uptake in PET images is frequently used to analyze beta amyloid (Abeta) deposition in living individuals, but its correlation with histologically determined Abeta has not been examined. Six individuals with dementia underwent PiB-PET imaging, and their brains were analyzed neuropathologically (mean interval between imaging and death: 816 days; PiB positive:negative, 3:3; male:female, 3:3; mean age: 84.0 years). PiB uptake (reported as standardized uptake value ratio [SUVR]) was analyzed in 11 cortical regions and 10 subcortical grey matter areas and compared with the Abeta load (% area [the percentage of total area positive for Abeta] and number of neuritic plaques) seen with immunohistochemical staining with an anti-Abeta 11-28 antibody. Two PiB-positive subjects had abundant neuritic plaques and were diagnosed with Alzheimer's disease (AD). SUVR and % area were strongly correlated in the cortical regions of these subjects (subject 1: r = 0.65, p = 0.03; subject 2: r = 0.80, p = 0.003). The other PiBpositive subject (subject 3) showed focal PiB uptake. In subject 3 and the 3 PiB-negative subjects (subjects 4-6), there was no correlation between regional SUVR and % area or neuritic plaques. PiB uptake was not correlated with Abeta deposition in subcortical regions. High PiB positivity in the cerebral cortex suggests the presence of substantial Abeta deposition and neuritic plaques associated with the pathologic changes of AD. Our results suggest that high cortical SUVR is a reliable marker of AD. Subcortical PiB positivity must be interpreted more carefully. PMID- 25731624 TI - Disrupted functional connectivity related to differential degeneration of the cingulum bundle in mild cognitive impairment patients. AB - Previous studies have demonstrated that Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) exhibited anatomical and functional abnormalities in the anterior cingulate cortex (ACC) and accumulating evidence supported the hypothesis that changes in the ACC predict the progression from aMCI to AD. In this study, we aimed to explore how the two functional and structural heterogeneous sub-regions of ACC, namely the dorsal ACC (dACC) and the ventral ACC (vACC), changed in aMCI and whether the structural connectivity affects the functional connectivity between the two ACC subregions. To investigate this hypothesis, we studied resting-state fMRI and DTI images in a group of 24 aMCIs and 29 healthy controls. The dACC exhibited a significantly increased functional connectivity in the Salience Network (SN) and a decreased functional connectivity with the vACC in aMCI. The DTI results showed that the bilateral cingulum fibers were the most damaged tracts in aMCI and that the fractional anisotrophy of the left anterior cingulum was significantly correlated with the functional connectivity between the two ACC sub-regions. In conclusion, this study revealed the pathological changes in the intrinsic functional connectivity of the ACC within SN, as well as the connectivity between the dACC and vACC in aMCI. Our study also revealed that disrupted white matter integrity of the anterior regions of the cingulum was associated with the alterations in subregional connectivity in the ACC. PMID- 25731626 TI - Anatomical correlates of the neuropsychiatric symptoms in Alzheimer's disease. AB - The current study aimed to assess the relationship between the neuropsychiatric symptoms in Alzheimer's disease (AD) and the regional grey matter (GM) volume using voxel based morphometry (VBM). Data of 85 AD patients, 208 subjects with mild cognitive impairment (MCI), and 131 healthy controls were selected from the Alzheimer's Disease Neuroimaging Initiative. Individual VBM models across the entire sample for each items of the Neuropsychiatric Inventory Questionnaire as variables of interest were specified with four nuisance covariates, including age, sex, total intracranial volume (TIV), and Mini-Mental State Examination (MMSE) score. Agitation was related to the GM atrophy in the left inferior frontal/insula and bilateral retrosplenial cortices. Aberrant motor behavior (AMB) was related to the GM reductions in the right basal ganglia. The VBM models were recalculated by specifying three nuisance covariates (age, sex, TIV), and by excluding voxels related to AD severity by applying a MMSE mask. This procedure confirmed the first results, and additionally revealed associations between depression and GM atrophy in the left middle frontal cortex, between agitation and the GM atrophy in the left middle frontal cortex, and between AMB and GM reduction in the right inferior frontal cortex. Hierarchical multiple regression analyses using extracted mean GM value in these additional regions confirmed these associations. Finally, VBM analyses within a subgroup (85 AD patients and 41 MCI converters) largely confirmed the results. Our results suggest that specific patterns of GM atrophy within AD related neurodegeneration predispose to certain neuropsychiatric symptoms, suggesting distinct neurobiological mechanisms. PMID- 25731625 TI - Genetic markers in biological fluids for aging-related major neurocognitive disorder. AB - Aging-related major neurocognitive disorder (NCD), formerly named dementia, comprises of the different acquired diseases whose primary deficit is impairment in cognitive functions such as complex attention, executive function, learning and memory, language, perceptual/motor skills, and social cognition, and that are related to specific brain regions and/or networks. According to its etiology, the most common subtypes of major NCDs are due to Alzheimer' s disease (AD), vascular disease (VaD), Lewy body disease (LBD), and frontotemporal lobar degeneration (FTLD). These pathologies are frequently present in mixed forms, i.e., AD plus VaD or AD plus LBD, thus diagnosed as due to multiple etiologies. In this paper, the definitions, criteria, pathologies, subtypes and genetic markers for the most common age-related major NCD subtypes are summarized. The current diagnostic criteria consider cognitive decline leading to major NCD or dementia as a progressive degenerative process with an underlying neuropathology that begins before the manifestation of symptoms. Biomarkers associated with this asymptomatic phase are being developed as accurate risk factor and biomarker assessments are fundamental to provide timely treatment since no treatments to prevent or cure NCD yet exist. Biological fluid assessment represents a safer, cheaper and less invasive method compared to contrast imaging studies to predict NCD appearance. Genetic factors particularly have a key role not only in predicting development of the disease but also the age of onset as well as the presentation of comorbidities that may contribute to the disease pathology and trigger synergistic mechanisms which may, in turn, accelerate the neurodegenerative process and its resultant behavioral and functional disorders. PMID- 25731627 TI - Buccal cell cytokeratin 14 identifies mild cognitive impairment and Alzheimer' s disease in the AIBL study of aging. AB - Previous studies have suggested that mild cognitive impairment (MCI) may be reflective of the early stages of neurodegenerative disorders such as Alzheimer's disease (AD). The hypothesis was that cytokeratin (CK) 14 expression can be used as a biomarker in isolated buccal mucosa to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Visual assessment of buccal cell CK14 expression was carried out using immunofluorescence techniques. The frequency of basal buccal cells expressing CK14 was significantly lower in the MCI (P=0.0002) and AD (P<0.05) groups compared with the control group. Receiver-operating characteristic (ROC) curves were carried out for CK14 expression and yielded an area under the curve (AUC) of 0.899 for the MCI (P<0.0001) group and 0.772 for the AD (P=0.004) group. When the CK14 expression data were combined with plasma homocysteine concentration, the AUC was further improved to 0.932 and 0.788 for the MCI (P=0.0001) and AD (P=0.004) groups, respectively. APOE epsilon4 carriers in the control group had 21% lower CK14 expression compared with control non APOE epsilon4 carriers, however this difference was not statistically significant. The changes in the buccal cell CK14 expression observed in this pilot study could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD. These promising results need to be replicated in a larger subset of the AIBL cohort and in cohorts of other neurodegenerative disorders to determine changes specific to AD. PMID- 25731628 TI - Clinical relevance of apolipoprotein E genotyping based on a family history of Alzheimer's disease. AB - Having a family history of Alzheimer' s disease (AD) may potentiate cumulative risk associated with phenotypic expression of the epsilon-4 allele of the apolipoprotein E (APOE) gene. In this study, we compared the genotype distribution and allele frequencies of APOE epsilon-2 (rs7412) and epsilon -4 (rs429358) in 537 South African individuals participating in a chronic disease screening program, in order to establish whether AD family history modulates the expression of their dyslipidemic effects. Significant differences in the genotype distribution for APOE epsilon-2 (p=0.034) as well as APOE epsilon-4 (p=0.038) were found between study participants with (n=67) and without (n=470) a family history of AD. LDL cholesterol levels were inversely associated with physical activity in the study group with a positive family history of AD (p<0.001) but not in those with a negative family history of AD (p=0.257). Similar to its existing use in the diagnosis of monogenic dyslipidemias such as familial hypercholesterolemia, clinical inquiry regarding family history was identified as an important determinant of eligibility for APOE genotyping performed in the context of chronic disease risk management. To our knowledge, this is the first study to demonstrate the modulating influence of AD family history on expression of a dyslipidemic phenotype associated with the APOE epsilon-4 allele. Our findings provide the scientific rationale supporting a novel clinical application for APOE genotyping as a means of identifying a genetic subgroup of dyslipidemic patients set to derive the greatest benefit from early lifestyle-based interventions aimed at decreasing cumulative risk for cardiovascular disease and prevention of AD later in life. PMID- 25731629 TI - Vanutide cridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer's disease: results from two phase 2 studies. AB - OBJECTIVE: Multiple lines of evidence indicate that pathological accumulation of amyloid beta (Abeta) peptide in the brain is linked to the pathophysiology of Alzheimer's disease (AD). Removal of Abeta from the brain by binding to anti Abeta specific antibodies is under active investigation. Vaccination with a full length Abeta42 peptide (AN1792) successfully elicited anti-Abeta antibodies in human subjects with AD, but was associated with meningoencephalitis. To avoid this safety issue, an aminoterminal Abeta1-7 peptide conjugate, vanutide cridificar (ACC-001), was designed and is currently in clinical development. This report describes two phase 2 multiple ascending-dose studies in Japanese subjects with mild to moderate AD. Safety and immunogenicity evaluation were the primary and secondary objectives, respectively. METHODS: ACC-001 was administered to three cohorts of subjects at doses of 3, 10, or 30 MUg, with or without a QS-21 adjuvant in Study 1, and with a QS-21 adjuvant in Study 2; control groups consisted of QS-21 alone (both studies) and phosphate-buffered saline (Study 1 only). RESULTS: A variety of treatment-emergent adverse events (TEAEs) were reported from most subjects during the studies; most of these were mild or moderate in intensity. Three subjects withdrew from the study because of an adverse event (in Study 2). The most common treatment-associated TEAE was injection site reactions. No deaths were observed in either study. All doses of ACC-001 + QS-21 elicited high, sustained anti-Abeta antibody titers; QS-21 was necessary for this effect. CONCLUSION: These data will provide valuable information on further investigation of anti-Abeta vaccine therapy for AD. PMID- 25731630 TI - Technical and practical issues for tidal breathing measurements of nasal nitric oxide in children. AB - To promote early screening of patients with suspected Primary Ciliary Dyskinesia (PCD), nasal nitric oxide (nNO) measurements during tidal breathing (TB) have been developed for children unable to ensure velum closure (VC) during breath hold or expiration against resistance. To investigate technical and practical issues related to TB-nNO methods in children referred for suspected or asserted PCD, we recorded, in a prospective multicenter study, TB-nNO (calculated as the mean of 5 peaks, 10 or 30 sec during tidal breathing) and VC-nNO when available. We studied 142 children (PCD diagnosis asserted in 47, excluded in 39). Nasal NO values were significantly different according to methods, VC-nNO being higher than TB-nNO (TB-nNO 5 peaks higher than mean of 10 or 30 sec). Specificity (90 94%) and sensitivity (86-97%) were similar between TB-nNO and VC-nNO methods. Age was more correlated with VC-nNO than with TB-nNO. TB-nNO could differ between the two nostrils by more than 10% (or 10 ppb when nNO absolute value lower 100 ppb) in 32-43% of the tested children, according to the different tidal breathing values, and was reproducible in the long term but influenced by ambient NO. Despite TB-nNO values being lower than VC-nNO, TB-nNO was found to be as discriminant for PCD, and probably more discriminant in children less than 8 years old, as the VC method. These results were obtained using the chemiluminescence technique which allows an easier assessment of relevant factors such as nasal permeability and ambient NO than the electrochemical technique. PMID- 25731631 TI - Plant polysaccharides initiate underground crosstalk with bacilli by inducing synthesis of the immunogenic lipopeptide surfactin. AB - Some plant-associated bacteria such as Bacillus sp. can protect their host from pathogen ingress and this biocontrol activity correlates with their potential to form multiple antibiotics upon in vitro growth. However, our knowledge on antibiotic production by soil bacilli evolving on roots in natural conditions is still limited. In this work, antibiome imaging first revealed that the lipopeptide surfactin is the main bacterial ingredient produced in planta within the first hours of interaction with root tissues. We further demonstrated that surfactin synthesis is specifically stimulated upon perception of plant cell wall polymers such as xylan or arabinogalactan, leading to fast accumulation of micromolar amounts in the root environment. At such concentrations, the lipopeptide may not only favour the ecological fitness of the producing strain in term of root colonization, but also triggers systemic resistance in the host plant. This surfactin-induced immunity primes the plant to better resist further pathogen ingress, and involves only limited expression of defence-related molecular events and does not provoke seedling growth inhibition. By contrast with the strong response mounted upon perception of pathogens, this strongly attenuated defensive reaction induced by surfactin in plant tissues should help Bacillus to be tolerated as saprophytic partner by its host. PMID- 25731632 TI - Analysis of the coplanarity of functional pairs of semicircular canals using three-dimensional images reconstructed from temporal bone magnetic resonance imaging. AB - OBJECTIVES: This study was conducted to investigate the angles and orientation of semicircular canals, and the coplanarity of functional canal pairs. METHODS: Fluid signals in semicircular canals were reconstructed with three-dimensional reconstruction software using 20 temporal bone magnetic resonance images of normal subjects. The angles between each pair of semicircular canals were measured. RESULTS: The mean angles between the anterior and horizontal semicircular canal plane, the horizontal and posterior semicircular canal plane, and the anterior and posterior semicircular canal plane were 83.7 degrees , 82.5 degrees and 88.4 degrees , respectively. Pairs of contralateral synergistic canal planes were formed 15.1 degrees between the right and left horizontal semicircular canal planes, 21.2 degrees between the right anterior and left posterior semicircular canal, and 21.7 degrees between the left anterior and right posterior semicircular canal. CONCLUSION: Each semicircular canal makes an almost right angle with other canals, but synergistically acting functional canal pairs of both ears do not lie in exactly the same plane. PMID- 25731633 TI - Impact of follow-up consultations for ICU survivors on post-ICU syndrome: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the impact of routine follow-up consultations versus standard of care for intensive care unit (ICU) survivors. METHODS: Systematic literature review from five databases (Cochrane CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL), reference lists, citation tracking, and ongoing/unpublished trials. Randomized controlled trials investigating post-ICU consultations in adults with outcomes such as quality of life (QOL), anxiety, depression, posttraumatic stress disorder (PTSD), physical ability, cognitive function, and return to work were included. Two reviewers extracted data and assessed quality independently. The mean differences, risk ratios, and 95 % confidence intervals were calculated depending on outcome measures. RESULTS: From 1544 citations, five trials were included (855 patients). The overall risk of bias was low in two trials, unclear in two trials, and high in one trial. The overall quality of evidence was low. The trials assessed follow-up interventions defined as consultations informing survivors about their ICU stay. One trial found no effect on QOL. Pooling data from two trials (n = 374) showed a protective effect on risk of new onset PTSD at 3-6 months after ICU (risk ratio 0.49, 95 % CI 0.26-0.95). There was no effect on other outcomes. CONCLUSIONS: The evidence indicates that follow-up consultations might reduce symptoms of PTSD at 3-6 months after ICU discharge in ICU survivors, but without affecting QOL and other outcomes investigated. This review highlights that planning of future RCTs should aim to standardize interventions and outcome measures to allow for comparisons across studies. PMID- 25731635 TI - Severe preeclampsia: what's new in intensive care? AB - Preeclampsia remains an important cause of avoidable maternal morbidity and mortality. Publication of guidelines and monitoring adherence to life-saving therapies should be prioritized. Prediction of fluid responsiveness requires individual hemodynamic investigation. Future studies are required to determine the optimal early warning system and monitoring tools for providing early and non invasive hemodynamic assessment. PMID- 25731634 TI - Outcome of acute mesenteric ischemia in the intensive care unit: a retrospective, multicenter study of 780 cases. AB - BACKGROUND: In the intensive care unit (ICU), the outcomes of patients with acute mesenteric ischemia (AMI) are poorly documented. This study aimed to determine the risk factors for death in ICU patients with AMI. METHODS: A retrospective, observational, non-interventional, multicenter study was conducted in 43 ICUs of 38 public institutions in France. From January 2008 to December 2013, all adult patients with a diagnosis of AMI during their hospitalization in ICU were included in a database. The diagnosis was confirmed by at least one of three procedures (computed tomography scan, gastrointestinal endoscopy, or upon surgery). To determine factors associated with ICU death, we established a logistic regression model. Recursive partitioning analysis was applied to construct a decision tree regarding risk factors and their interactions most critical to determining outcomes. RESULTS: The death rate of the 780 included patients was 58 %. Being older, having a higher sequential organ failure assessment (SOFA) severity score at diagnosis, and a plasma lactate concentration over 2.7 mmol/l at diagnosis were independent risk factors of ICU mortality. In contrast, having a prior history of peripheral vascular disease or an initial surgical treatment were independent protective factors against ICU mortality. Using age and SOFA severity score, we established an ICU mortality score at diagnosis based on the cutoffs provided by recursive partitioning analysis. Probability of survival was statistically different (p < 0.001) between patients with a score from 0 to 2 and those with a score of 3 and 4. CONCLUSION: Acute mesenteric ischemia in ICU patients was associated with a 58 % ICU death rate. Age and SOFA severity score at diagnosis were risk factors for mortality. Plasma lactate concentration over 2.7 mmol/l was also an independent risk factor, but values in the normal range did not exclude the diagnosis of AMI. PMID- 25731636 TI - Reverse triggering in a patient with ARDS. PMID- 25731637 TI - Chronotypes, night shifts and intensive care. PMID- 25731638 TI - Early thrombus formation on a pulmonary artery catheter. PMID- 25731640 TI - Extrinsic apoptotic pathways, anti-TNF-alpha therapy and cancer progression: more and more clinical data support this critical relationship? PMID- 25731639 TI - Acyclic cucurbit[n]uril-type molecular containers: influence of glycoluril oligomer length on their function as solubilizing agents. AB - We present the synthesis of a series of six new glycoluril derived molecular clips and acyclic CB[n]-type molecular containers (1-3) that all feature SO3(-) solubilizing groups but differ in the number of glycoluril rings between the two terminal dialkoxyaromatic sidewalls. We report the X-ray crystal structure of 3b which shows that its dialkoxynaphthalene sidewalls actively define a hydrophobic cavity with high potential to engage in pi-pi interactions with insoluble aromatic guests. Compounds 1-3 possess very good solubility characteristics (>=38 mM) and undergo only very weak self-association (Ks < 92 M(-1)) in water. The weak self-association is attributed to unfavorable SO3(-)...SO3(-) electrostatic interactions in the putative dimers 12-42. Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, beta-estradiol, and ziprasidone). We find that the containers 3a and 3b which feature three glycoluril rings between the terminal dialkoxy-o-xylylene and dialkoxynaphthalene sidewalls are less efficient solubilizing agents than 4a and 4b because of their smaller hydrophobic cavities. Containers 1 and 2 behave as molecular clip type receptors and therefore possess the ability to bind to and thereby solubilize aromatic drugs like camptothecin, ziprasidone, and PBS-1086. PMID- 25731641 TI - Determination of sparstolonin B by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry: application to pharmacokinetic study of sparstolonin B in rat plasma. AB - Sparstolonin B (SsnB), a spontaneous isocoumarin compound isolated from the tuber of Scirpus yagara Ohwi. (Cyperaceae), possesses potent anti-inflammatory and antitumor activity. In the present study, a rapid and simple UHPLC/MS/MS method for determination of SsnB in rat plasma was developed and validated. Plasma samples were pretreated by liquid-liquid extraction with ethyl acetate containing rhein as an internal standard and separated on a C18 column at 35 degrees C, with a gradient mobile phase consisting of acetonitrile and water containing 0.2% (v/v) formic acid within 2.1 min. MS/MS detection was accomplished in multiple reaction monitoring mode with negative electrospray ionization. The precursor product ion transitions were m/z 266.9 [M-H](-) -> m/z 211.0 for SsnB and m/z 283.2 [M-H](-) -> m/z 239.0 for IS. The intra- and inter-day precision (RSD) was <8.98% and the accuracy (RE) ranged from -7.40 to 4.50%. The extraction recoveries ranged from 96.28 to 97.30%. The pharmacokinetic parameters were calculated using Win Nonlin53 software. The absolute bioavailability of SsnB was estimated to be 6.98%. The proposed method was successfully applied to a pharmacokinetic study of SsnB in rats after intravenous administration with a dose of 0.5 mg/kg and oral administration at a dose of 5 mg/kg. PMID- 25731642 TI - Complications of sclerotherapy for 75 head and neck venous malformations. AB - Sclerotherapy is one treatment option for head and neck venous malformations (VMs). Evaluation of complication risks is, however, essential to improve its safety. We aimed to systematically report sclerotherapy complications by means of the Clavien-Dindo classification and to distinguish factors predisposing to complications. We identified our institution's head and neck VM patients who received sclerotherapy between 1 January 2007 and 31 August 2013, analyzed patient reports retrospectively, and applied to them the Clavien-Dindo classification. Our 75 VM patients underwent a total of 150 sclerotherapy sessions. The most common sclerosants were 3 % sodium tetradecyl sulfate and polidocanol. Complications occurred in 13 patients (17.3 %) and in 15 sessions (10.0 %); 3 complications required extensive postprocedural treatment and caused permanent morbidity, whereas 12 received conservative treatment. Patients with sclerotherapy complications underwent more treatments (p = 0.009) and more often needed further surgery (p = 0.007). We thus consider sclerotherapy a relatively safe treatment modality for head and neck VMs. To avoid complications, evaluation of VM characteristics and optimal treatment technique in a multidisciplinary team is vital. PMID- 25731643 TI - The effect of duration of nasal obstruction on mean platelet volume in patients with marked nasal septal deviation. AB - Nasal obstruction is a common cause of marked nasal septal deviation. It is related strongly with hypoxia. Hypoxic conditions increase mean platelet volume levels. This study aimed to investigate the effect of age on mean platelet volume in patients with marked nasal septal deviation. We made a retrospective study of patients with marked nasal septal deviation between January 2012 and May 2014. The patients were divided into four groups according to duration of nasal obstruction (less than 10, 10-20, 20-30 and more than 30 years). The groups were compared with each other in terms of mean platelet volume, platelet distribution width, platelet count in preoperative hemogram. This study was performed on 356 male and 139 female patients. Mean age was 33.9 +/- 12.3 years. It was determined that the platelet count, mean platelet volume did not constitute statistically significant difference between groups (p > 0.05). Nevertheless, it was determined that as the duration of nasal obstruction elongated the mean platelet volume value increased and platelet count values decreased. Mean values of platelet distribution width constituted statistically significant difference between all groups (p = 0.026). Patients with marked nasal septum deviation should be subjected to surgery as soon as possible because of the increase in mean platelet volume and platelet distribution width values which are related to increase in the risk of cardiopulmonary complications of nasal obstruction. PMID- 25731644 TI - Identifying chemical functionalization on individual carbon nanotubes and graphene by local vibrational fingerprinting. AB - Chemical functionalization of carbon nanotubes (CNTs) and graphene allows for fine-tuning their physical and chemical properties to realize fascinating new fundamental phenomena as well as exotic applications. A primary challenge in such endeavors is the need to identify the chemical nature of attached functionalities at a single-nano-object level in a spatially resolved manner. Here we report the vibrational fingerprinting of functional groups that are attached to individual CNTs and graphene flakes. In order to achieve this, we decorate noncovalently functionalized CNTs and graphene with nanoparticles, which leads to the appearance of Raman peaks that can be correlated with the vibrational modes characteristic of the functional groups with diffraction-limited spatial resolution. The presented strategy is generic enough to be extended to other chemical modification routes on a range of nanostructures and hence will allow for rapid characterization of chemical modification of individual (semi)conducting nanostructures. PMID- 25731646 TI - A study on the human pancreaticobiliary duct system and ampulla region with their clinical considerations. AB - INTRODUCTION: The purpose of this study is to present the variations of the pancreatic duct system and hepatopancreatic ampulla so that an awareness of these variations may help in surgical planning and prevention of ductal injury. METHODS: Forty human pancreatic specimens were used to study the duct pattern of the pancreas and the formation and mode of termination of the pancreatic ducts. Also, the patency of the main pancreatic ducts, length of the hepatopancreatic ampulla, and length of the main pancreatic duct were measured. RESULTS: The main pancreatic duct was patent in 37 out of 40 specimens, 2 specimens showed the embryonic type of the duct system, and one had the duct obliterated at its duodenal end. The mode of termination of the main pancreatic and common pancreatic ducts was divided into four types. Seventy-five percent specimens belonged to type I, followed by type II in 22.5 % and type III in 2.5 % of specimens. The length of the main pancreatic duct ranged from 11 to 21.2 cm, the average being 17.3 cm, and the length of the hepatopancreatic ampulla varied from 1 to 10 mm (1 to 2 mm-5 %, 3 to 8 mm-55 %, and more than 8 mm in 15 % of specimens), and it was absent in 25 %. CONCLUSION: Awareness of these anomalies may help in surgical planning and prevention of undue ductal injury. PMID- 25731647 TI - Immunohistochemical study of MUC1, MUC2 and MUC5AC in colorectal carcinoma and review of literature. AB - BACKGROUND: A hallmark of colorectal carcinomas is their ability to secrete mucus. Aberrant expression of mucins and alterations in their glycosylation are associated with the development and progression of malignant diseases. Therefore, mucins can be used as markers of malignancy. Tumor-associated mucins are also used as immunotargets in the treatment of cancer. The present work aimed to study the patterns of expression of MUC1, MUC2 and MUC5AC in colorectal carcinoma using immunohistochemistry and their relationship with site, histological differentiation and stage. METHODS: Fifty cases of colorectal carcinoma were chosen for the study. The histopathology slides were reviewed and blocks were retrieved. Using manual method, tissue microarray blocks were prepared. Immunostaining for MUC1, MUC2 and MUC5AC was performed on slides cut from the tissue microarray block. RESULTS: We found that MUC1 expression was upregulated to 39 %, MUC2 expression was downregulated to 43 % and MUC5AC was aberrantly expressed in 24 % of colorectal cancer (CRC). There was a significant correlation between MUC1 positivity and tumor differentiation. As the grade increased from well to moderately differentiated, MUC1 expression increased from 1 1 % to 55 % (p-value 0.01). There was a statistically significant difference between MUC5AC positivity and grade of tumor (p-value 0.006). The percentage of cases showing MUC5AC expression increased as the stage of disease progressed from 1 to 4. However, there was no significant difference in MUC5AC positivity and stage of CRC (p-value 0.77). CONCLUSION: We do not find any correlation between tumor stage or site and MUC1, MUC2 or MUC5AC expression. MUC1and MUC5AC expression showed significant correlation with tumor grade. PMID- 25731648 TI - Frontier innovations for control of sarcomas. PMID- 25731650 TI - The clinical outcomes of unplanned pregnancy in severely obese women. AB - OBJECTIVE: The objective of this study was to compare the clinical outcomes of unplanned pregnancies among severely obese women with those of planned pregnancies. METHODS: This prospective cohort study included severely obese women (Body Mass Index [BMI] >= 40.0 kg/m(2)) who delivered a baby weighing >= 500 g over 5 years 2009-2013 in a large university hospital. Maternal weight and height were measured and BMI was calculated at the first prenatal visit. RESULTS: Of the 650 women, the mean BMI was 43.8 kg/m(2), mean age was 31.6 years, and 30.0% (n = 195) were nulliparous. Prenatal complications including gestational diabetes mellitus (GDM), hypertensive and thromboembolic disorders occurred in 56.6% (n = 368). Compared with planned pregnancies (58.2%, n = 378), those that were unplanned (41.8%, n = 272) were associated with increased prepregnancy risk factors including essential hypertension (4.0% versus 1.6%, p = 0.03) and depression (6.6% versus 3.2%, p = 0.03). Unplanned pregnancy was associated with a higher macrosomia rate (birthweight > 4.5 kg) compared with planned pregnancies (p = 0.03). This was not explained by a higher GDM rate in unplanned pregnancies. Compared with planned pregnancies, unplanned pregnancies were not associated with increased adverse fetomaternal outcomes. CONCLUSION: Despite increased prepregnancy risk factors, in severely obese women, unplanned pregnancies were not associated with increased prenatal complications or adverse pregnancy outcomes compared with planned pregnancies. PMID- 25731649 TI - Obesity in pregnancy: what's next? Long-term cardiovascular morbidity in a follow up period of more than a decade. AB - OBJECTIVE: To investigate whether obesity during pregnancy poses a risk for subsequent maternal long-term cardiovascular morbidity, after controlling for diabetes and hypertensive disorders. STUDY DESIGN: Data were analyzed from consecutive pregnant women who delivered between 1988 and 1999, and were followed up until 2010. Long-term cardiovascular morbidity was compared among women with and without obesity in pregnancy (maternal pre-pregnancy body mass index (BMI) of 30 kg/m(2) or more). Kaplan-Meier survival curves were used to compare cumulative incidence of cardiovascular hospitalizations. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for long-term cardiovascular hospitalizations. RESULTS: During the study period 46 688 women met the inclusion criteria, 1221 (2.6%) had a BMI >=30 kg/m(2). During a follow-up period of more than 10 years, patients with obesity had higher rates of simple cardiovascular events and total number of cardiovascular hospitalizations. These complications tended to occur at a shorter interval (mean 4871 days +/- 950 versus 5060 days +/- 1140; p = 0.001). In a Cox proportional hazards model that adjusted for diabetes mellitus, preeclampsia and maternal age, obesity was independently associated with cardiovascular hospitalizations (adjusted HR 2.6, 95% CI 2.0-3.4). CONCLUSION: Obesity during pregnancy is an independent risk factor for long-term cardiovascular morbidity, and these complications tend to occur earlier. Pregnancy should be considered as a window of opportunity to predict future health problems and as an opportunity to promote women's health. Obese parturients might benefit from cardiovascular risk screening that could lead to early detection and secondary prevention of cardiovascular morbidity. PMID- 25731651 TI - Analysis of etiology, chromosome and prognosis for small left heart system development in 69 fetuses. AB - OBJECTIVE: To provide a basis for evaluating the prognosis of small left heart system development in fetuses, we analyzed its related factors. METHODS: The fetal echocardiogram was performed in 3859 pregnant women, and then small left heart system development was identified in 69 fetuses. The data of prenatal and postnatal echocardiograms, postnatal cardiac surgical treatment, chromosome and autopsy after induced labor were analyzed in the 69 fetuses. RESULTS: Except 1320 cases losing follow-up, 2539 cases had complete data. Among the 2539 cases, small left heart system development was identified in 69 fetuses. Of the 69 fetuses, 12 had hypoplastic left heart syndrome, 20 premature closure of foramen ovale, 13 total anomalous pulmonary venous drainage, 2 common pulmonary vein lumen atresia, 21 aortic coarctation or interruption and 1 right pulmonary hypoplasia. Among the 69 fetuses, chromosome abnormality was found in 7. CONCLUSION: There are many etiological factors causing small left heart system development. The prognosis is poor in the fetuses with hypoplastic left heart syndrome, common pulmonary vein lumen atresia, pulmonary hypoplasia, other malformations or/and chromosome abnormality. Fetal echocardiography combined with chromosome examination can provide important bases for making diagnosis and evaluating the prognosis regarding small left heart system development. PMID- 25731652 TI - Three-dimensional ultrasonographic placental volume in gestational diabetes mellitus. AB - OBJECTIVES: We aimed to evaluate the placental volume and placental mean gray value in gestational diabetes mellitus (GDM) and healthy placentas using three dimensional (3D) ultrasound and Virtual Organ Computer-aided AnaLysis (VOCAL). METHODS: This case-control prospective study consisted of 39 singleton pregnancies complicated by GDM and 42 healthy singleton pregnancies matched for gestational age, maternal age and parity. Placental volume and placental volumetric mean gray values were evaluated. The placental volume (cm(3)) was analyzed using the VOCAL imaging analysis program and 3D histogram was used to calculate the volumetric mean gray value (%). RESULTS: Placental volume was significantly larger in GDM (411.59 +/- 170.82 versus 343.86 +/- 128.94 cm(3); p = 0.046). There was no significant difference in mean gray value between GDM and healthy placentas (36.65 +/- 7.02 versus 38.71 +/- 7.91, respectively; p = 0.277). Placental volume was significantly correlated with gestational week (r = 0.219, p = 0.035) and parity (r = 0.228, p = 0.048). There was negative significant relation between placental volume and umbilical artery systolic/diastolic ratio, pulsatility index and resistance index (r = -0.278, p = 0.007; r = -0.315, p = 0.002; r = -0.322, p = 0.001, respectively). CONCLUSIONS: Placental volume increases significantly in GDM, whereas mean gray values do not alter significantly. These data may reflect the placental changes in GDM placentas that may help to understand the pathophysiology better. PMID- 25731653 TI - Is umbilical cord milking always an advantage? AB - OBJECTIVE: The role of cord milking as an alternative to delayed cord clamping is an area that requires more research. Purpose of this clinical trial was to investigate the impact of umbilical cord milking on the absolute neutrophil counts (ANCs) and the neutropenia frequency of preterm infants. METHODS: Fifty eight pregnant women were randomly assigned to one of the umbilical cord milking and control groups. A total of 54 preterm infants (gestational age <= 32 weeks) were enrolled into the study. The umbilical cords of 25 infants were clamped immediately after birth, and in 29 infants, umbilical cord milking was performed first. RESULTS: The ANCs were statistically significantly lower in the cord milking group compared with the control group on days 1, 3 and 7. The frequency of neutropenia was higher in the cord milking group compared with the control group. CONCLUSION: In our study, ANCs were lower in the cord milking group and the frequency of neutropenia was higher. Umbilical cord milking plays a role on the ANCs of preterm infants. PMID- 25731654 TI - Risk factors for spontaneous preterm delivery after arrested episode of preterm labor. AB - INTRODUCTION: We aimed to identify specific risk factors for spontaneous preterm delivery (PTD) among women with arrested preterm labor (PTL). METHOD: A retrospective study of women admitted due to imminent PTL and intact membranes, which did not progress to PTD within 24 h from admission. Eligibility was limited to singleton gestations at 24 + 0/7-33 + 6/7 weeks of gestations with no known chromosomal or structural anomalies. All women were treated with corticosteroids and tocolysis. Comparison was made between those who delivered at <37 + 0/7 weeks of gestation (study group) to women who delivered at >=37 + 0/7 weeks of gestation (controls). RESULTS: Overall, 301 women were recruited, of which 85 (28.2%) delivered before 37 + 0/7 weeks and 216 (71.8%) delivered at term. Advanced cervical dilatation was found to be an independent risk factor for PTD [for women with no past PTD: adjusted odds ratio (aOR) 1.66, 95% CI: 1.06-2.61 for each 1 cm dilatation; for women with past PTD: aOR 2.81, 95% CI: 1.02-7.73 for each 1 cm dilatation]. Among women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission (OR: 1.20, 95% CI: 1.09-1.32 for each earlier week) and short cervical length (OR: 1.04, 95% CI: 1.01-1.08 for each decrease of 1 mm in cervical length). CONCLUSION: Advanced cervical dilatation, earlier gestational age at the episode of arrested PTL, and short cervical length are specific risk factors for PTD in women with arrested PTL. These findings may assist in counseling women and direct further investigation. PMID- 25731655 TI - Risk factors for acute postpartum urinary retention after vaginal delivery: focus on episiotomy direction. AB - OBJECTIVE: This study aimed to investigate the independent factors for acute postpartum urinary retention (APUR) after vaginal delivery. METHODS: From January 2008 to December 2013, 98 patients with APUR after vaginal delivery without instrument use were compared with 108 control patients matched by age and medical history. Multivariate logistic regression analysis was performed to identify independent risk factors for APUR. Predictive accuracy for the multivariate model was assessed using the derived area under a receiver operating characteristics curve. RESULTS: Among maternal previous partial history, mean live birth history was lower in the APUR group (0.12 versus 0.31, p = 0.017). Regional anesthesia use (76.5% versus 60.2%, p = 0.036), mediolateral episiotomy (63.3% versus 31.5%, p < 0.001) and labor time were significantly higher in the APUR group. Multivariate logistic regression analysis showed that mediolateral episiotomy, labor time and the presence of regional anesthesia were independent contributing factors for the development of APUR. This model's predictive accuracy for APUR was 73.1%. CONCLUSION: Prolonged labor time, regional anesthesia and mediolateral episiotomy were independent factors for APUR. Therefore, we considered median episiotomy to be the best approach during vaginal delivery avoiding APUR. PMID- 25731656 TI - Social media messaging in pregnancy: comparing content of Text4baby to content of free smart phone applications of pregnancy. AB - OBJECTIVE: Text4baby is the only free text-message program for pregnancy available. Our objective was to determine whether content differed between Text4baby and popular pregnancy smart phone applications (apps). METHODS: Researchers enrolled in Text4baby in 2012 and downloaded the four most-popular free pregnancy smart phone apps in July 2013; content was re-extracted in February 2014. Messages were assigned thematic codes. Two researchers coded messages independently before reviewing all the codes jointly to ensure consistency. Logistic regression modeling determined statistical differences between Text4baby and smart phone apps. RESULTS: About 1399 messages were delivered. Of these, 333 messages had content related to more than one theme and were coded as such, resulting in 1820 codes analyzed. Compared to smart phone apps, Text4baby was significantly more likely to have content regarding Postpartum Planning, Seeking Care, Recruitment and Prevention and significantly less likely to mention Normal Pregnancy Symptoms. No messaging program included content regarding postpartum contraception. CONCLUSIONS: To improve content without increasing text message number, Text4baby could replace messages on recruitment with messages regarding normal pregnancy symptoms, fetal development and postpartum contraception. PMID- 25731657 TI - Carbetocin versus oxytocin for prevention of postpartum hemorrhage after vaginal delivery in high risk women. AB - OBJECTIVE: To compare effectiveness and tolerability of carbetocin versus oxytocin in prevention of postpartum hemorrhage (PPH) after vaginal delivery. METHODS: A prospective double-blinded randomized study conducted on 200 pregnant women randomized into two groups: Group 1 (100 women) received single 100 MUg IM dose of carbetocin and Group 2 received of 5 IU oxytocin IM. Both groups received their drug after fetal and before placental delivery. RESULTS: There was a statistically significant difference between the two study groups regarding amount of bleeding (337.73 +/- 118.77 versus 378 +/- 143.2), occurrence of PPH (4 versus 16%), need for other uterotonics (23 versus 37%) and hemoglobin difference between before and after delivery (0.55 +/- 0.35 versus 0.96 +/- 0.62) (all being lower in carbetocin group) and measured hemoglobin 24 h after delivery (being higher in carbetocin group); however, there was no significant difference between the two study groups regarding occurrence of major PPH and the need for blood transfusion. Women in carbetocin group showed a statistically significant lower systolic and diastolic blood pressure immediately after delivery and at 30 and 60 min than women in oxytocin group. There was no significant difference between the two study groups regarding occurrence of nausea, vomiting, flushing, dizziness, headache, shivering, metallic taste, dyspnea, palpitation and itching. Women in carbetocin group experienced tachycardia more than women in oxytocin group. CONCLUSIONS: Carbitocin is a better alternative to traditional oxytocin in prevention of PPH after vaginal delivery with minimal hemodynamic changes and similar side effects. PMID- 25731658 TI - Decreased hazard of necrotizing enterocolitis in preterm neonates receiving red cell transfusions. AB - BACKGROUND AND OBJECTIVES: Many observational studies reporting a temporal association between red cell transfusions (RBCTs) and necrotizing enterocolitis (NEC) in preterm infants fail to take into account RBCTs in infants without NEC. The objective of this study was to investigate the association between RBCTs and NEC in an analytical retrospective cohort study with minimization of selection and measurement bias and controlling for clinical covariates. METHODS: Inborn preterm infants [23-32 weeks gestational age (GA)] without major congenital anomalies were eligible. Association of RBCT and modified Bell's Stage >=2A NEC was explored using bivariate analyses and verified using multivariable Cox regression. RESULTS: Of 627 eligible infants, 305 neither received RBCT nor developed NEC and 12 developed NEC prior to RBCT. Of 310 infants with RBCT, 27 developed NEC. Compared to infants without NEC, infants with NEC received significantly lower number of RBCTs before diagnosis of NEC (p = 0.000). On multivariable Cox regression controlling for clinical covariates, dichotomous RBCT exposure was associated with 60% reduced hazard for NEC. CONCLUSIONS: RBCT exposure was associated with decreased hazards for NEC in preterm infants in this study; factors previously reported to be associated with NEC remained statistically significant predictors. PMID- 25731659 TI - HIV Among Indigenous peoples: A Review of the Literature on HIV-Related Behaviour Since the Beginning of the Epidemic. AB - From the early days of the HIV epidemic, Indigenous peoples were identified as a population group that experiences social and economic determinants-including colonialism and racism-that increase exposure to HIV. There are now substantial disparities in HIV rates between Indigenous and non-Indigenous peoples in some countries. We conducted a comprehensive literature review to assess the evidence on HIV-related behaviors and determinants in four countries-Australia, Canada, New Zealand and the United States-in which Indigenous peoples share important features of colonization and marginalization. We identified 107 articles over more than 20 years. The review highlights the determinants of HIV-related behaviors including domestic violence, stigma and discrimination, and injecting drug use. Many of the factors associated with HIV risk also contribute to mistrust of health services, which in turn contributes to poor HIV and health outcomes among Indigenous peoples. PMID- 25731661 TI - Providing ART to HIV Seropositive Persons Who Use Drugs: Progress in New York City, Prospects for "Ending the Epidemic". AB - New York City has experienced the largest HIV epidemic among persons who use psychoactive drugs. We examined progress in placing HIV seropositive persons who inject drugs (PWID) and HIV seropositive non-injecting drug users (NIDU) onto antiretroviral treatment (ART) in New York City over the last 15 years. We recruited 3511 PWID and 3543 NIDU from persons voluntarily entering drug detoxification and methadone maintenance treatment programs in New York City from 2001 to 2014. HIV prevalence declined significantly among both PWID and NIDU. The percentage who reported receiving ART increased significantly, from approximately 50 % (2001-2005) to approximately 75 % (2012-2014). There were no racial/ethnic disparities in the percentages of HIV seropositive persons who were on ART. Continued improvement in ART uptake and TasP and maintenance of other prevention and care services should lead to an "End of the AIDS Epidemic" for persons who use heroin and cocaine in New York City. PMID- 25731663 TI - Inspections of radiocesium concentration levels in rice from Fukushima Prefecture after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - We summarize the inspections of radiocesium concentration levels in rice produced in Fukushima Prefecture, Japan, for 3 years from the nuclear accident in 2011. In 2011, three types of verifications, preliminary survey, main inspection, and emergency survey, revealed that rice with radiocesium concentration levels over 500 Bq/kg (the provisional regulation level until March 2012 in Japan) was identified in the areas north and west of the Fukushima nuclear power plant. The internal exposure of an average adult eating rice grown in the area north of the nuclear plant was estimated as 0.05 mSv/year. In 2012, Fukushima Prefecture authorities decided to investigate the radiocesium concentration levels in all rice using custom-made belt conveyor testers. Notably, rice with radiocesium concentration levels over 100 Bq/kg (the new standard since April 2012 in Japan) were detected in only 71 and 28 bags out of the total 10,338,000 in 2012 and 11,001,000 in 2013, respectively. We considered that there were almost no rice exceeding 100 Bq/kg produced in Fukushima Prefecture after 3 years from the nuclear accident, and the safety of Fukushima's rice were ensured because of the investigation of all rice. PMID- 25731664 TI - [Physico-chemical and toxicological profile of gadolinium chelates as contrast agents for magnetic resonance imaging]. AB - Gadolinium chelates (GC) are contrast agents widely used to facilitate or to enable diagnosis using magnetic resonance imaging (MRI). From a regulatory viewpoint, GC are drugs. GC have largely contributed to the success of MRI, which has become a major component of clinician's diagnostic armamentarium. GC are not metabolised and are excreted by the kidneys. They distribute into the extracellular compartment. Because of its high intrinsic toxicity, gadolinium must be administered as a chelate. GC can be classified according to two key molecular features: (a) nature of the chelating moiety: either macrocyclic molecules in which gadolinium is caged in the pre-organized cavity of the ligand, or linear, open-chain molecules, (b) ionicity: Gd chelates can be ionic (meglumine or sodium salts) or non-ionic. The thermodynamic and kinetic stabilities of the various GCs differ according to these structural characteristics. The kinetic stability of macrocyclic GCs is much higher than that of linear GCs and the thermodynamic stability of ionic GCs is generally higher than that of non-ionic GC, thus leading to a lower risk of gadolinium dissociation. This class of drugs has enjoyed an excellent reputation in terms of safety for a long time, until a causal link with a recently-described serious disease, nephrogenic systemic fibrosis (NSF), was evidenced. It is acknowledged that the vast majority of NSF cases are related to the administration of some linear CG in renally-impaired patients. Health authorities, worldwide, released recommendations which drastically reduced the occurrence of new cases. PMID- 25731660 TI - Physical Activity is Associated with Better Neurocognitive and Everyday Functioning Among Older Adults with HIV Disease. AB - We examined the association between physical activity (PA), neurocognitive impairment (NCI), and instrumental activities of daily living (IADLs) among older HIV+ persons. One hundred older HIV+ adults completed the International Physical Activity Questionnaire, a neurocognitive battery, and IADL scale. Higher levels of moderate PA were associated with lower odds of NCI (p = 0.01), even when covariates were modeled. The association between moderate PA and NCI was driven by executive function (p = 0.04). Higher levels of moderate PA were also associated with lower odds of IADL Dependence (p = 0.03), although this fell to a trend (p = 0.08) when including covariates. Follow-up analysis showed those with both NCI and IADL Dependence had lower moderate PA than those with neither (p = 0.03). While these cross-sectional findings suggest PA is associated with better neurocognitive and everyday functioning in older HIV+ adults, longitudinal studies utilizing objective PA methods are needed to evaluate directionality and mechanisms. PMID- 25731666 TI - Interaction of Zn(2+) ions with single-stranded polyU and polyC in neutral solutions. AB - Effect of Zn(2+) ions on the conformation of single-stranded polynucleotides polyU and polyC in a wide temperature range at pH 7 was studied by differential UV spectroscopy and by thermal denaturation. The atoms coordinating Zn(2+) ions were determined (O4 and N3 in polyU and N3 in polyC). A three-dimensional phase diagram and its two-dimensional components were constructed for a polyC-Zn(2+) system. The phase diagram revealed a region in which ordered single-stranded structures, stabilized by Zn(2+)-mediated cross-links involving N3 atom of cytosine, are formed. The phase diagram also demonstrated that the behavior of the polyC-Zn(2+) system is similar to the effect of retrograde condensation observed in some binary solutions of simple liquids. A dependence of Zn(2+)-polyC binding constant on the metal ion concentration was obtained. The reason why zinc induced transition of the sequences with adenine-uracil (AU) base pairs from A form geometry to a metallized m-form requires higher pH compared to the sequences comprised of guanine-cytosine (GC) base pairs is explained. This information can be useful for the development of possible technological applications based on m DNA. PMID- 25731665 TI - Differential effects of self-reported lifetime marijuana use on interleukin-1 alpha and tumor necrosis factor in African American adults. AB - It is unknown how lifetime marijuana use affects different proinflammatory cytokines. The purpose of the current study is to explore potential differential effects of lifetime marijuana use on interleukin-1 alpha (IL-1alpha) and tumor necrosis factor (TNF) in a community based sample. Participants included 168 African American adults (51 % female, median age = 47 years). Upon study entry, blood was drawn and the participants completed questions regarding illicit drug use history whose answers were used to create three groups: lifetime non-drug users (n = 77), lifetime marijuana only users (n = 46) and lifetime marijuana and other drug users (n = 45). In the presence of demographic and physiological covariates, non-drug users were approximately two times more likely (AOR 2.73, CI 1.18, 6.31; p = .03) to have higher TNF levels than marijuana only users. Drug use was not associated with IL-1alpha. The influence of marijuana may be selective in nature, potentially localizing around innate immunity and the induction of cellular death. PMID- 25731667 TI - Endocytic pathway mediates refractoriness of insect Bactrocera dorsalis to RNA interference. AB - RNA interference (RNAi) is a powerful and convenient tool for sequence-specific gene silencing, and it is triggered by double-stranded RNA (dsRNA). RNAi can be easily achieved in many eukaryotes by either injecting or feeding dsRNAs. This mechanism has demonstrated its potential in fundamental research on genetics, medicine and agriculture. However, the possibility that insects might develop refractoriness to RNAi remains unexplored. In this study, we report that the oriental fruit fly, Bactrocera dorsalis, became refractory to RNAi using orally administered dsRNA targeting endogenous genes. Furthermore, refractoriness to RNAi is not gene-specific, and its duration depends on the dsRNA concentration. RNAi blockage requires the endocytic pathway. Fluorescence microscopy indicated that in RNAi refractory flies, dsRNA uptake is blocked. Genes involved in the entry of dsRNAs into cells, including chc, cog3, light and others, are down regulated in RNAi refractory flies. Increasing the endocytic capacity by improving F-actin polymerization disrupts RNAi refractoriness after both primary and secondary dsRNA exposures. Our results demonstrate that an insect can become refractory to RNAi by preventing the entry of dsRNA into its cells. PMID- 25731668 TI - Hypotensive transfusion reactions in the era of prestorage leukoreduction. AB - BACKGROUND: Clinical characteristics of hypotensive transfusion reactions (HyTRs) have not been evaluated in the context of universal prestorage leukoreduction. STUDY DESIGN AND METHODS: A retrospective review of medical records of patients with HyTRs during the years 2011 and 2012 was performed at two academic medical institutions. RESULTS: Thirty-five patients with 35 HyTRs were identified, with an incidence of 1.33 per 10,000 transfusions. Red blood cells (RBCs) were implicated in 21 (60.0%) reactions and platelets (PLTs) and plasma (PL) in 11 (31.4%) and three (8.6%), respectively. The HyTR rate per blood component was 0.019% for PLTs, 0.015% for RBCs, and 0.006% for PL. Mean patient age was 65 years (range, 2 months-87 years), five (14.3%) were pediatric (<18 years), and 20 (57.1%) were male. The most frequent clinical settings associated with HyTRs were cardiac surgery (n=13; 37.1%), hematology-oncology diseases (n=11; 31.4%), and general surgery (n=7; 20.0%). Extracorporeal circuits were used within 24 hours before the reaction in 16 patients (45.7%), including nine patients on cardiopulmonary bypass, four on dialysis or continuous venous-venous hemodialysis, and three on extracorporeal membrane oxygenation. Four patients (11.4%) received an angiotensin-converting enzyme inhibitor within 24 hours before the HyTR. Seventeen patients (48.6%) responded to stopping the transfusion and supportive treatment. Thirteen patients (37.1%) had severe reactions. No HyTR resulted in death. CONCLUSION: In the absence of bedside leukoreduction filters, several medical situations are associated with HyTRs. The pathophysiology of HyTRs is yet to be defined. The US hemovigilance system allows for standardization of transfusion reactions, which facilitates their classification and study. PMID- 25731669 TI - A sublimation heat engine. AB - Heat engines are based on the physical realization of a thermodynamic cycle, most famously the liquid-vapour Rankine cycle used for steam engines. Here we present a sublimation heat engine, which can convert temperature differences into mechanical work via the Leidenfrost effect. Through controlled experiments, quantified by a hydrodynamic model, we show that levitating dry-ice blocks rotate on hot turbine-like surfaces at a rate controlled by the turbine geometry, temperature difference and solid material properties. The rotational motion of the dry-ice loads is converted into electric power by coupling to a magnetic coil system. We extend our concept to liquid loads, generalizing the realization of the new engine to both sublimation and the instantaneous vapourization of liquids. Our results support the feasibility of low-friction in situ energy harvesting from both liquids and ices. Our concept is potentially relevant in challenging situations such as deep drilling, outer space exploration or micro mechanical manipulation. PMID- 25731670 TI - miR-630 overexpression in hepatocellular carcinoma tissues is positively correlated with alpha-fetoprotein. AB - BACKGROUND: MicroRNA-630 (miR-630) has been shown to be involved in various human malignancies. However, its role in hepatocellular carcinoma (HCC) remains unknown. MATERIAL AND METHODS: TaqMan qRT-PCR assay was performed to detect the expression of miR-630 in 42 pairs of HCC tissues and corresponding noncancerous hepatocellular tissues, and its correlations with clinicopathologic features and serum alpha-fetoprotein (AFP) level of patients were analyzed. RESULTS: The present study found that miR-630 expression was significantly increased in HCC tissues and cells compared with their normal counterparts. miR-630 expression level did not significantly chang at stage I but was markedly increased at advanced TNM stage (stage II~III). In addition, the increased expression of miR 630 in tissues of HCC appeared in patients who exhibited elevated serum levels of AFP (>25 ng/ml), but not in those with normal AFP levels (<=25 ng/ml). The miR 630 expression in carcinoma tissues revealed a positive correlation with the levels of serum alpha-fetoprotein (AFP; R2=0.768). CONCLUSIONS: These results suggest that miR-630 is associated with tumor progression of hepatocellular carcinoma and may be a potential prognosis indicator. PMID- 25731671 TI - Long-term outcome in men and women after CABG; results from the IMAGINE trial. AB - BACKGROUND: The aim of this study is to determine sex differences in long-term outcome after coronary artery bypass grafting (CABG). METHODS: The international randomized controlled IMAGINE study included 2553 consecutive patients with a left ventricular ejection fraction of >40% who underwent isolated CABG. Median follow-up was 32 months (IQR 17-42 months). The composite endpoint comprised of death, myocardial infarction (MI), cerebrovascular event, angina, revascularization and congestive heart failure. Cox regression analysis was used to examine sex differences in outcome post-CABG. RESULTS: Of the 2553 patients, 2229 were men and 324 (13%) were women. Women were older and more often reported diabetes and hypertension. Smoking and impaired renal function were more prevalent in men. Women experienced a higher event rate during follow-up (composite endpoint 18% vs 12%; P = 0.007). Cox regression showed an increased risk of the composite endpoint in women after adjustment for age (HR 1.48 (95% CI: 1.11-1.97)) which was non-significant after additional adjustment for other confounders (HR 1.26 (95% CI: 0.92-1.72)). CONCLUSION: Women have a worse long term outcome after CABG than men in univariate analysis. However, after adjusting for potential confounders female sex became a non-significant predictor for prognosis, possibly due to the small sample size of women. Definite answers regarding sex-differences in long-term outcome after CABG should come from future pooling of studies comprising a larger number of women. PMID- 25731672 TI - Endodontic management of immature teeth with spontaneous apical closure and periapical lesions: case series and review of the literature. AB - Spontaneous apical closure in non-vital immature teeth has been rarely encountered and outcome of non-surgical endodontic treatment of related teeth associated with periapical lesions has not yet been adequately elucidated. The aim of this article was to report endodontic management of spontaneous apical closure of infected untreated immature teeth with periapical lesions and to review previously proposed mechanisms for the development of spontaneous hard tissue barrier. Three patients were referred at different time intervals to the endodontic clinic for treatment of their maxillary anterior incisors with acute or chronic apical periodontitis. Dental histories indicated that related teeth had been subjected to trauma approximately 12-18 years previously. Radiographically, the involved teeth exhibited incomplete root formation with spontaneous apical closure and were associated with an apical radiolucency. After biomechanical preparation, calcium hydroxide paste was applied and was changed once or twice within 3 months. All canals were then filled with gutta-percha and AH Plus and the follow-up period was 16-50 months; both clinical and radiographic examinations revealed adequate function, the absence of clinical symptoms and significant healing of the periapical radiolucency. PMID- 25731673 TI - Targeted Lipidomics Studies Reveal that Linolenic Acid Promotes Cotton Fiber Elongation by Activating Phosphatidylinositol and Phosphatidylinositol Monophosphate Biosynthesis. AB - The membrane lipids from fast-elongating wild-type cotton (Gossypium hirsutum) fibers at 10 days post-anthesis, wild-type ovules with fiber cells removed, and ovules from the fuzzless-lintless mutant harvested at the same age, were extracted, separated, and quantified. Fiber cells contained significantly higher amounts of phosphatidylinositol (PI) than both ovule samples with PI 34:3 being the most predominant species. The genes encoding fatty acid desaturases (Delta(15)GhFAD), PI synthase (PIS) and PI kinase (PIK) were expressed in a fiber preferential manner. Further analysis of phosphatidylinositol monophosphate (PIP) indicated that elongating fibers contained four- to five-fold higher amounts of PIP 34:3 than the ovules. Exogenously applied linolenic acid (C18:3), soybean L alpha-PI, and PIPs containing PIP 34:3 promoted significant fiber growth, whereas a liver PI lacking the C18:3 moiety, linoleic acid, and PIP 36:2 were completely ineffective. The growth inhibitory effects of carbenoxolone, 5-hydroxytryptamine, and wortmannin were reverted by C18:3, PI, or PIP, respectively, suggesting that PIP signaling is essential for fiber cell growth. Furthermore, cotton plants expressing virus-induced gene-silencing constructs that specifically suppressed GhDelta(15)FAD, GhPIS, or GhPIK expression, resulted in significantly short fibered phenotypes. Our data provide the basis for in-depth studies on the roles of PI and PIP in mediating cotton fiber growth. PMID- 25731675 TI - The dangerous outcomes of blood transfusion to thalassemia patients in Pakistan. PMID- 25731674 TI - Use of the surgical safety checklist to improve communication and reduce complications. AB - Existing evidence suggests that communication failures are common in the operating room, and that they lead to increased complications, including infections. Use of a surgical safety checklist may prevent communication failures and reduce complications. Initial data from the World Health Organization Surgical Safety Checklist (WHO SSC) demonstrated significant reductions in both morbidity and mortality with checklist implementation. A growing body of literature points out that while the physical act of "checking the box" may not necessarily prevent all adverse events, the checklist is a scaffold on which attitudes toward teamwork and communication can be encouraged and improved. Recent evidence reinforces the fact the compliance with the checklist is critical for the effects on patient safety to be realized. PMID- 25731676 TI - Switching a 2D Co(II) layer to a 3D Co7-cluster-based metal-organic framework: syntheses, crystal structures, and magnetic properties. AB - Two 2D layered coordination networks with formulas of {[Co(TPA)Cl](H2O)2.5}n (1) and {[Co(TPA)(MU2-OH)](H2O)2}n (2) (HTPA = 4-(1,2,4-triazol-4-yl)phenylacetic acid) were solvothermally synthesized and fully characterized. Interesting 1D Co(2+)-Cl or Co(2+)-MU2-OH chain structures were observed. By carefully adjusting the reaction conditions, a new 3D metal-organic framework (MOF) with a formula of {[Co7(TPA)6(MU3-OH)4(MU2-OH)2(H2O)4](TPA)2(DMF)3(H2O)3}n (3) was obtained. MOF 3 is built from Co7 clusters and fully deprotonated TPA ligands, which display a cubic pcu topology. Factors that influence the structures of the three TPA-based complexes, as well as their magnetic properties, were investigated in detail. The heptanuclear-Co(II)-cluster-based MOF 3 shows interesting magnetization dynamics at low temperature. PMID- 25731677 TI - Behaviour of transplanted tumours and role of matching in rejection. AB - BACKGROUND: Tumour transfer/development is one of the more serious risks associated with transplantation. The behaviour of a tumour can be unpredictable in immunosuppressed recipients. We report a highly sensitive method to monitor tumour behaviour in real time in a rodent tumour transplant model. This paper also explores the effect of MHC matching on tumour growth among control and immunosuppressed hosts. METHODS: Luciferase expressing Wistar rat kidney tumour cells were transplanted into either Wistar or Lewis recipients which mimic a well and poorly matched combination to assess the effects of MHC matching on transplanted tumour cells. Experimental groups included controls with no immunosuppression and animals immunosuppressed with cyclosporine. The latter group was further divided into a continuous treatment group which received four weeks of immunosuppression and a treatment withdrawal group where immunosuppression was stopped after two weeks to assess the effects of rejection on tumour growth. RESULTS: All the tumour cells were rejected in the control animals that received no immunosuppression, within 2 weeks among well-matched combination and within one week in the poorly matched combination (p 0.001). The transplanted tumour cells continued to grow in both well-matched and poorly matched groups who were treated with cyclosporine, but growth was significantly faster in the well-matched combination (p 0.033). After treatment withdrawal the tumour cells were rejected in all the animals of the poorly matched group compared to 50% in well matched animals within the four-week study period (p 0.039). CONCLUSION: In the absence of immunosuppression the hosts reject the transplanted tumour cells, and the anti-tumour response is stronger when there is a greater mismatch in MHC with the recipient. In the presence of cyclosporine immunosuppression the tumour continues to grow, however, after withdrawal of the immunosuppression, tumour clearance is quicker in the poorly matched background. This data supports the idea of expansion of the donor pool by using kidneys after ex vivo resection of small renal tumours and that these organs should be transplanted into a less well-matched HLA recipient. We hypothesise that should a tumour recurrence occur a poorly matched recipient could clear the tumour through withdrawal of immunosuppression. PMID- 25731678 TI - HLA class I associations with EBV+ post-transplant lymphoproliferative disorder. AB - Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous individuals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation. PMID- 25731679 TI - Profiles of children's arithmetic fact development: a model-based clustering approach. AB - The current longitudinal study tried to capture profiles of individual differences in children's arithmetic fact development. We used a model-based clustering approach to delineate profiles of arithmetic fact development based on empirically derived differences in parameters of arithmetic fact mastery repeatedly assessed at the start of three subsequent school years: third, fourth, and fifth grades. This cluster analysis revealed three profiles in a random sample-slow and variable (n = 8), average (n = 24), and efficient (n = 20)-that were marked by differences in children's development in arithmetic fact mastery from third grade to fifth grade. These profiles did not differ in terms of age, sex, socioeconomic status, or intellectual ability. In addition, we explored whether these profiles varied in cognitive skills that have been associated with individual differences in single-digit arithmetic. The three profiles differed in nonsymbolic and symbolic numerical magnitude processing as well as phonological processing, but not in digit naming or working memory. After also controlling for cluster differences in general mathematics achievement and reading ability, only differences in symbolic numerical magnitude processing remained significant. Taken together, our longitudinal data reveal that symbolic numerical magnitude processing represents an important variable that contributes to individual variability in children's acquisition of arithmetic facts. PMID- 25731680 TI - DHEA replacement for postmenopausal women: placebo or panacea? AB - In adults, dehydroepiandrosterone (DHEA) is the most abundant steroid found in serum and its levels fall with age. It can be converted into androgens and estrogens by peripheral tissues. Thus it may be considered to be a pro-hormone. Many websites are promoting oral DHEA as an anti-aging tonic and in some countries it is sold as a supplement. Recent clinical trials of oral DHEA and reviews of those trials have failed to show any health benefits for postmenopausal women. However, there may be a role for vaginal DHEA. PMID- 25731681 TI - In reply. PMID- 25731682 TI - ROS generated during early reperfusion contribute to intermittent hypobaric hypoxia-afforded cardioprotection against postischemia-induced Ca(2+) overload and contractile dysfunction via the JAK2/STAT3 pathway. AB - Moderate enhanced reactive oxygen species (ROS) during early reperfusion trigger the cardioprotection against ischemia/reperfusion (I/R) injury, while the mechanism is largely unknown. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) contributes to the cardioprotection but whether it is activated by ROS and how it regulates Ca(2+) homeostasis remain unclear. Here we investigated whether the ROS generated during early reperfusion protect the heart/cardiomyocyte against I/R-induced Ca(2+) overload and contractile dysfunction via the activation of JAK2/STAT3 signaling pathway by using a cardioprotective model of intermittent hypobaric hypoxia (IHH) preconditioning. IHH improved the postischemic recovery of myocardial contractile performance in isolated rat I/R hearts as well as Ca(2+) homeostasis and cell contraction in simulated I/R cardiomyocytes. Meanwhile, IHH enhanced I/R increased STAT3 phosphorylation at tyrosine 705 in the nucleus and reversed I/R suppressed STAT3 phosphorylation at serine 727 in the nucleus and mitochondria during reperfusion. Moreover, IHH improved I/R-suppressed sarcoplasmic reticulum (SR) Ca(2+)-ATPase 2 (SERCA2) activity, enhanced I/R-increased Bcl-2 expression, and promoted the co-localization and interaction of Bcl-2 with SERCA2 during reperfusion. These effects were abolished by scavenging ROS with N-(2 mercaptopropionyl)-glycine (2-MPG) and/or by inhibiting JAK2 with AG490 during the early reperfusion. Furthermore, IHH-improved postischemic SERCA2 activity and Ca(2+) homeostasis as well as cell contraction were reversed after Bcl-2 knockdown by short hairpin RNA. In addition, the reversal of the I/R-suppressed mitochondrial membrane potential by IHH was abolished by 2-MPG and AG490. These results indicate that during early reperfusion the ROS/JAK2/STAT3 pathways play a crucial role in (i) the IHH-maintained intracellular Ca(2+) homeostasis via the improvement of postischemic SERCA2 activity through the increase of SR Bcl-2 and its interaction with SERCA2; and (ii) the IHH-improved mitochondrial function. PMID- 25731684 TI - Resilience and recovery: the effect of triclosan exposure timing during development, on the structure and function of river biofilm communities. AB - Triclosan (TCS) is a ubiquitous antibacterial agent found in soaps, scrubs, and consumer products. There is limited information on hazardous effects of TCS in the environment. Here, rotating annular reactors were used to cultivate river biofilm communities exposed to 1.8 MUg l(-1) TCS with the timing and duration of exposure and recovery during development varied. Two major treatment regimens were employed: (i) biofilm development for 2, 4 or 6 weeks prior to TCS exposure and (ii) exposure of biofilms to TCS for 2, 4 or 6 weeks followed by recovery. Biofilms not exposed to TCS were used as a reference condition. Communities cultivated without and then exposed to TCS all exhibited reductions in algal biomass and significant (p<0.05) reductions in cyanobacterial biomass. No significant effects were observed on bacterial biomass. CLSM imaging of biofilms at 8 weeks revealed unique endpoints in terms of community architecture. Community composition was altered by any exposure to TCS, as indicated by significant shifts in denaturing gradient gel electrophoresis fingerprints and exopolymer composition relative to the reference. Bacterial, algal and cyanobacterial components initially exposed to TCS were significantly different from those TCS-free at time zero. Pigment analyses suggested that significant changes in composition of algal and cyanobacterial populations occurred with TCS exposure. Bacterial thymidine incorporation rates were reduced by TCS exposure and carbon utilization spectra shifted in terms substrate metabolism. Direct counts of protozoans indicated that TCS was suppressive, whereas micrometazoan populations were, in some instances, stimulated. These results indicate that even a relatively brief exposure of a river biofilm community to relatively low levels of TCS alters both the trajectory and final community structure. Although some evidence of recovery was observed, removal of TCS did not result in a return to the unexposed reference condition. PMID- 25731683 TI - Oxidative stress and metabolic responses to copper in freshwater- and seawater acclimated killifish, Fundulus heteroclitus. AB - In freshwater (FW), many of the main mechanisms of copper (Cu) toxicity have been characterized; however, toxicity mechanisms in seawater (SW) are less well understood. We investigated the effects of salinity on Cu-induced oxidative stress and metabolic responses in adult killifish, Fundulus heteroclitus. We exposed FW and SW-acclimated killifish to either low Cu (LC, 50 MUg/L) or high Cu (HC, 200 MUg/L) for 96 h and compared them to controls (CTRL) under the same salinities without added Cu. Cu exerted minimal influence on tissue ion levels in either FW or SW. Salinity generally protected against Cu bioaccumulation in the gills and liver, but not in the carcass. Hematocrit (Hct) and hemoglobin (Hb) levels were increased by LC and HC in both FW and SW, and blood lactate was reduced in FW-killifish exposed to LC and HC. Rates of oxygen consumption were similar across treatments. Salinity reduced Cu load in gill, liver and intestine at LC but only in the gills at HC. In general, Cu increased gill, liver, and intestine catalase (CAT) activity, while superoxide dismutase (SOD) either decreased or remained unchanged depending on tissue-type. These changes did not directly correlate with levels of protein carbonyls, used as an index of oxidative stress. Cu-induced changes in carbohydrate metabolic enzymes were low across tissues and the effect of salinity was variable. Thus, while salinity clearly protects against Cu bioaccumulation in some tissues, it is unclear whether salinity protects against Cu-induced oxidative stress and metabolic responses. PMID- 25731685 TI - Dynamics of sub-lethal effects of nano-CuO on the microalga Chlamydomonas reinhardtii during short-term exposure. AB - Though nano-CuO has been classified as toxic toward aquatic microorganisms and its use in various applications is expected to increase in near future, its ecotoxicity is currently poorly understood. The aim of this study was to investigate the mechanisms of nano-CuO toxicity based on the paradigm of oxidative stress, the dynamics of response over 24h, and the modulating effect of exposure conditions on toxicity and responses. To this end, the model microalga Chlamydomonas reinhardtii was exposed to 10mgL(-1) nano-CuO in five different exposure media, including two different growth media, two Good's buffers, and natural lake water. The measured endpoints included cell growth, morphological aspect, chlorophyll autofluorescence, oxidative stress, and membrane permeabilization. The results suggest that agglomerated nano-CuO is toxic and that exposure media are decisive in whether or not particles or free Cu ions are the main mediators of toxicity. A significant particle effect was only observed in the Good's buffer 3-(N-morpholino) propanesulfonic acid. However, nano-CuO particles especially influenced the dynamics of response early in exposure, between 0h and 5h, suggesting that an adaptation to particle stress may occur or that particles modify the bioavailability of the free Cu ions in early exposure. PMID- 25731686 TI - Targeting the spindle assembly checkpoint for breast cancer treatment. AB - Breast cancer is the most common malignancy in women worldwide and the second leading cause of cancer deaths after lung cancer. As in other malignancies, aneuploidy is a common feature of breast cancer and influences its behavior. Aneuploidy has been linked to inappropriate activity of the spindle assembly checkpoint (SAC), a surveillance mechanism that, in normal cells, prevents anaphase onset until correct alignment of all chromosomes at the metaphase is achieved. Interestingly, the widely used anti-microtubule drugs, vinca alkaloids and taxanes, kill cancer cells through chronic arrest in mitosis as a consequence of chronic SAC activation. Deregulated SAC has been reported in breast cancer in many reports and presents an attractive therapeutic strategy. We present here a review of the current knowledge on the SAC defects and the underlying molecular mechanisms in breast cancer, and discuss the potential of SAC components as targets for breast cancer therapies. PMID- 25731687 TI - Complete Freund's adjuvant-induced reduction of exploratory activity in a novel environment as an objective nociceptive endpoint for sub-acute inflammatory pain model in rats. AB - BACKGROUND: Hind paw injection of complete Freund's adjuvant (CFA) is a commonly used sub-acute inflammatory pain model in rodents with typical subjective endpoint measurements of paw withdrawal to thermal or mechanical stimuli. METHODS: Here, we assessed CFA-induced reduction of exploratory activity in a novel environment (CRANE) as an objective nociceptive endpoint in rats. CFA (50%) was subcutaneously injected into the plantar aspect of the hind paw either unilaterally or bilaterally (150 MUL/paw). Exploratory activity was recorded using an automated locomotor activity system. RESULTS: Bilateral CFA injection reduced exploratory activity 4-48 h following injection, compared to sham controls. Unilateral CFA injection produced less reduction of exploratory activity, compared to bilateral injection. Effects of orally dosed standard analgesics on CRANE were examined 48 h following bilateral CFA injection. Diclofenac treatment produced dose-related reversal of CRANE at 0.03-1.0 mg/kg with a plateau effect observed at higher doses (up to 30 mg/kg). Ibuprofen also produced dose-related reversal CRANE at 0.3-3.0 mg/kg with a plateau effect at higher doses (up to 60 mg/kg). Similarly, celecoxib produced dose-related reversal CRANE at 3-10 mg/kg, but not 30 mg/kg. Gabapentin (up to 100 mg/kg) and duloxetine (up to 30 mg/kg) produced no reversal of CRANE. CONCLUSIONS: The results presented here demonstrate that CRANE provides an objective assessment of pain behaviours for sub-acute inflammatory pain in rats. The pharmacological profile of standard analgesics supports that CRANE model may potentially be used to identify novel analgesic agents for the treatment of sub-acute inflammatory pain. PMID- 25731688 TI - Postural correction reduces hip pain in adult with acetabular dysplasia: A case report. AB - Developmental dysplasia of the hip is often diagnosed in infancy, but less severe cases of acetabular dysplasia are being detected in young active adults. The purpose of this case report is to present a non-surgical intervention for a 31 year-old female with mild acetabular dysplasia and an anterior acetabular labral tear. The patient presented with right anterior hip and groin pain, and she stood with the trunk swayed posterior to the pelvis (swayback posture). The hip pain was reproduced with the anterior impingement test. During gait, the patient maintained the swayback posture and reported 6/10 hip pain. Following correction of the patient's posture, the patient's pain rating was reduced to a 2/10 while walking. The patient was instructed to maintain the improved posture. At the 1 year follow-up, she demonstrated significantly improved posture in standing and walking. She had returned to recreational running and was generally pain-free. The patient demonstrated improvement on self-reported questionnaires for pain, function, and activity. These findings suggest that alteration of posture can have an immediate and lasting effect on hip pain in persons with structural abnormality and labral pathology. PMID- 25731689 TI - QCT-based failure analysis of proximal femurs under various loading orientations. AB - In this paper, the variations of the failure strength and pattern of human proximal femur with loading orientation were analysed using a novel quantitative computed tomography (QCT)-based linear finite element (FE) method. The QCT images of 4 fresh-frozen femurs were directly converted into voxel-based finite element models for the analyses of the failure loads and patterns. A new geometrical reference system was used for the alignment of the mechanical loads on the femoral head. A new method was used for recognition and assortment of the high risk elements using a strain energy-based measure. The FE results were validated with the experimental results of the same specimens and the results of similar case studies reported in the literature. The validated models were used for the computational investigation of the failure loads and patterns under 15 different loading conditions. A consistent variation of the failure loads and patterns was found for the 60 different analysed cases. Finally, it was shown that the proposed procedure can be used as a reliable tool for the failure analysis of proximal femurs, e.g. identification of the relevant loading directions for specific failure patterns, or determination of the loading conditions under which the proximal femurs are failure-prone. PMID- 25731690 TI - Vaginal progesterone for the prevention of preterm birth in twin gestations: a randomized placebo-controlled double-blind study. AB - OBJECTIVE: The purpose of this study was to investigate the use of vaginal progesterone for the prevention of preterm delivery in twin pregnancies. STUDY DESIGN: We conducted a prospective, randomized, double-blind, placebo-controlled trial that involved 390 naturally conceived twin pregnancies among mothers with no history of preterm delivery who were receiving antenatal care at a single center. Women with twin pregnancies between 18 and 21 weeks and 6 days' gestation were assigned randomly to daily vaginal progesterone (200 mg) or placebo ovules until 34 weeks and 6 days' gestation. The primary outcome was the difference in mean gestational age at delivery; the secondary outcomes were the rate of spontaneous delivery at <34 weeks' gestation and the rate of neonatal composite morbidity and mortality in the treatment and nontreatment groups. RESULTS: The baseline characteristics were similar in both groups. The final analysis included 189 women in the progesterone group and 191 in the placebo group. No difference (P = .095) in the mean gestational age at delivery was observed between progesterone (35.08 +/- 3.19 [SD]) and placebo groups (35.55 +/- 2.85). The incidence of spontaneous delivery at <34 weeks' gestation was 18.5% in the progesterone group and 14.6% in the placebo group (odds ratio, 1.32; 95% confidence interval, 0.24-2.37). No difference in the composite neonatal morbidity and mortality was observed between the progesterone (15.5%) and placebo (15.9%) groups (odds ratio, 1.01; 95% confidence interval, 0.58-1.75). CONCLUSION: In nonselected twin pregnancies, vaginal progesterone administration does not prevent preterm delivery and does not reduce neonatal morbidity and death. PMID- 25731691 TI - How much platinum passes the placental barrier? Analysis of platinum applications in 21 patients with cervical cancer during pregnancy. AB - OBJECTIVE: Cervical cancer is the most common solid cancer diagnosed in pregnancy. Platinum is an active drug in the treatment of patients with cervical cancer. In the second and third trimesters, platinum is used to prevent cancer progression until fetal maturity is reached. However, knowledge about the transplacental passage of platinum is very limited. STUDY DESIGN: Between May 2008 and June 2014, platinum-based neoadjuvant chemotherapy was applied to 21 consecutive patients with cervical cancer diagnosed in their second trimester. At the time of delivery by cesarean delivery, synchronous samples from maternal blood, umbilical cord blood, and amniotic fluid were taken and analyzed for platinum concentrations. RESULTS: The mean week of gestation at cancer diagnosis was 17 (13-23). On average 3 (range, 2-4) cycles of chemotherapy were applied. Cesarean deliveries were carried out between 30.4 and 36.5 weeks of gestation. Twenty-two healthy babies without renal, hepatic, auditory, or hematopoietic impairment were delivered. Platinum concentrations in umbilical cord blood and amniotic fluid were 23-65% and 11-42% of the maternal blood, respectively. CONCLUSION: This series on in vivo measurement of platinum concentrations in the fetomaternal compartment observed that because of consistently lower platinum values in the fetoplacental unit, a placental filtration mechanism of platinum may be assumed. PMID- 25731692 TI - Prevention and management of postpartum hemorrhage: a comparison of 4 national guidelines. AB - OBJECTIVE: The purpose of this study was to compare 4 national guidelines for the prevention and management of postpartum hemorrhage (PPH). STUDY DESIGN: We performed a descriptive analysis of guidelines from the American College of Obstetrician and Gynecologists practice bulletin, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, the Royal College of Obstetrician and Gynaecologists (RCOG), and the Society of Obstetricians and Gynaecologists of Canada on PPH to determine differences, if any, with regard to definitions, risk factors, prevention, treatment, and resuscitation. RESULTS: PPH was defined differently in all 4 guidelines. Risk factors that were emphasized in the guidelines conferred a high risk of catastrophic bleeding (eg, previous cesarean delivery and placenta previa). All organizations, except the American College of Obstetrician and Gynecologists, recommended active management of the third stage of labor for primary prevention of PPH in all vaginal deliveries. Oxytocin was recommended universally as the medication of choice for PPH prevention in vaginal deliveries. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists and RCOG recommended development of a massive transfusion protocol to manage PPH resuscitation. Recommendations for nonsurgical treatment strategies such as uterine packing and balloon tamponade varied across all guidelines. All organizations recommended transfer to a tertiary care facility for suspicion of abnormal placentation. Specific indications for hysterectomy were not available in any guideline, with RCOG recommending hysterectomy "sooner rather than later" with the assistance of a second consultant. CONCLUSION: Substantial variation exists in PPH prevention and management guidelines among 4 national organizations that highlights the need for better evidence and more consistent synthesis of the available evidence with regard to a leading cause of maternal death. PMID- 25731693 TI - Discordance in fetal biometry and Doppler are independent predictors of the risk of perinatal loss in twin pregnancies. AB - OBJECTIVE: Impaired fetal growth might be better evaluated in twin pregnancies by assessing the intertwin discordance rather than the individual fetal size. The aim of this study was to investigate the prediction of perinatal loss in twin pregnancy using discordance in fetal biometry and Doppler. STUDY DESIGN: This was a retrospective cohort study in a tertiary referral center. The estimated fetal weight (EFW), umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR), and their discordance recorded at the last ultrasound assessment before delivery or demise of one or both fetuses were converted into centiles or multiples of the median (MoM). The discordance was calculated as the larger value-smaller value/larger value. A logistic regression analysis was performed to identify, and adjust for, potential confounders. The predictive accuracy was assessed using receiver-operating characteristic curve analysis. RESULTS: The analysis included 620 (464 dichorionic diamniotic and 156 monochorionic diamniotic) twin pregnancies (1240 fetuses). Perinatal loss of one or both fetuses complicated 16 pregnancies (2.6%). The combination of EFW discordance and CPR discordance had the best predictive performance (area under the curve, 0.96; 95% confidence interval, 0.92 1.00) for perinatal mortality. The detection rate, false-positive rate, positive likelihood ratio, and negative likelihood ratio were 87.5%, 6.7%, 13.08, and 0.13, respectively. The EFW centile, EFW below the 10th centile (small for gestational age), UA PI discordance, MCA PI discordance, and MCA PI MoM were significantly associated with the risk of perinatal loss on univariate analysis, but these associations became nonsignificant after adjusting for other confounders (P = .097, P = .090, P = .687, P = .360, and P = .074, respectively). The UA PI MoM, CPR MoM, EFW discordance, and CPR discordance were all independent predictors of the risk of perinatal loss, even after adjusting for potential confounders (P = .022, P = .002, P < .001, and P = .010, respectively). CONCLUSION: EFW discordance and CPR discordance are independent predictors of the risk of perinatal loss in twin pregnancies. Their combination could identify the majority of twin pregnancies at risk of perinatal loss. These findings highlight the importance of discordance in Doppler indices of fetal hypoxia, as well as fetal size, in assessing the risk of perinatal mortality. PMID- 25731695 TI - Posterior axilla sling traction for shoulder dystocia: case review and a new method of shoulder rotation with the sling. AB - OBJECTIVE: The purpose of this study was to report on all cases in which posterior axilla sling traction (PAST) has been used to deliver cases of intractable shoulder dystocia and to describe a new method of shoulder rotation with the sling. STUDY DESIGN: A record of all published and known cases was collected that included information on preliminary obstetric techniques that were used and how the PAST technique was performed. Maternal outcomes that included maternal injury and length of hospital stay and fetal outcomes, which included birthweight, Apgar scores, nerve injuries, fractures, hospital stay, and outcome, were documented. RESULTS: We have recorded 19 cases where PAST has been used. In 5 cases, the babies had died in utero. Ten were assisted deliveries. PAST was successful in 18 cases. In one case, it was partially successful because it enabled delivery of the posterior shoulder with digital axillary traction. The most commonly used material was suction tubing. Once the posterior shoulder was delivered, the shoulder dystocia was resolved in all cases. Time from insertion to delivery was <3 minutes when recorded. The birthweights of the infants varied from 3200-4800 g. Posterior arm humerus fractures occurred in 3 cases. There was one case of a permanent Erb's palsy and 4 cases of transient Erb's palsies. None were of the posterior arm. During this review, we found that, when direct delivery of the posterior shoulder was difficult because of very severe impaction, the sling could be used to rotate the shoulders easily through 180 degrees assisted by counter pressure on the back of the anterior shoulder. This new method was used in 5 cases and may reduce fetal trauma further during difficult shoulder delivery. CONCLUSION: This review confirms that PAST can be a lifesaving technique when all another techniques for shoulder dystocia fail. Advantages are that it is easy to use (even by someone who has not seen it used previously), that the sling material is readily available, and that it is inserted quickly with 2 fingers. This is the first report of its use to rotate the posterior shoulder to the anterior position for delivery. PMID- 25731694 TI - Identification of early transcriptome signatures in placenta exposed to insulin and obesity. AB - OBJECTIVE: The purpose of this study was to investigate the effects of insulin on human placental transcriptome and biological processes in first-trimester pregnancy. STUDY DESIGN: Maternal plasma and placenta villous tissue were obtained at the time of voluntary termination of pregnancy (7-12 weeks) from 17 lean (body mass index, 20.9+/-1.5 kg/m2) and 18 obese (body mass index, 33.5+/ 2.6 kg/m2) women. Trophoblast cells were immediately isolated for in vitro treatment with insulin or vehicle. Patterns of global gene expression were analyzed using genome microarray profiling after hybridization to Human Gene 1.1 ST and real time reverse transcription-polymerase chain reaction. RESULTS: The global trophoblast transcriptome was qualitatively separated in insulin-treated vs untreated trophoblasts of lean women. The number of insulin-sensitive genes detected in the trophoblasts of lean women was 2875 (P<.001). Maternal obesity reduced the number of insulin-sensitive genes recovered by 30-fold. Insulin significantly impaired several gene networks regulating cell cycle and cholesterol homeostasis but did not modify pathways related to glucose transport. Obesity associated with high insulin and insulin resistance, but not maternal hyperinsulinemia alone, impaired the global gene profiling of early gestation placenta, highlighting mitochondrial dysfunction and decreased energy metabolism. CONCLUSION: We report for the first time that human trophoblast cells are highly sensitive to insulin regulation in early gestation. Maternal obesity associated with insulin resistance programs the placental transcriptome toward refractoriness to insulin with potential adverse consequences for placental structure and function. PMID- 25731697 TI - Does paying for performance in primary care save lives? PMID- 25731696 TI - Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. AB - The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll-like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR-induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti-inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN-sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. PMID- 25731698 TI - Fluoride dose-response of human and bovine enamel artificial caries lesions under pH-cycling conditions. AB - OBJECTIVES: This laboratory study aimed to (a) compare the fluoride dose-response of different caries lesions created in human and bovine enamel (HE/BE) under pH cycling conditions and (b) investigate the suitability of Knoop and Vickers surface microhardness (K-SMH/V-SMH) in comparison to transverse microradiography (TMR) to investigate lesion de- and remineralization. MATERIALS AND METHODS: Caries lesions were formed using three different protocols (Carbopol, hydroxyethylcellulose-HEC, methylcellulose-MeC) and assigned to 24 groups using V SMH, based on a 2 (enamel types) * 3 (lesion types) * 4 (fluoride concentrations used during pH-cycling-simulating 0/250/1100/2800 ppm F as sodium fluoride dentifrices) factorial design. Changes in mineral content and structural integrity of lesions were determined before and after pH-cycling. Data were analyzed using three-way ANOVA. RESULTS: BE was more prone to demineralization than HE. Both enamel types showed similar responses to fluoride with BE showing more remineralization (as change in integrated mineral loss and lesion depth reduction), although differences between tissues were already present at lesion baseline. Carbopol and MeC lesions responded well to fluoride, whereas HEC lesions were almost inert. K- and V-SMH correlated well with each other and with the integrated mineral loss data, although better correlations were found for HE than for BE and for MeC than for Carbopol lesions. Hardness data for HEC lesions correlated only with surface zone mineral density data. CONCLUSION: BE is a suitable surrogate for HE under pH-cycling conditions. CLINICAL RELEVANCE: The in vitro modeling of dental caries is complex and requires knowledge of lesion behavior, analytical techniques, and employed hard tissues. PMID- 25731699 TI - MiR-1247-5p is overexpressed in castration resistant prostate cancer and targets MYCBP2. AB - BACKGROUND: Recently, there has been increasing attention on the role of microRNAs (miRNAs) in cancer development. Several expression profiling studies have provided evidence of aberrant expression of miRNAs in prostate cancer and have highlighted the potential use of specific miRNA expression signatures as prognostic or predictive markers. Here we report an expression analysis of miR 1247-5p, miR-1249, miR-1269a, miR-1271-5p, miR-1290, miR-1291, and miR-1299. METHODS: qRT-PCR was performed to validate the differential expression of miRNAs in clinical samples, and the effect of miR-1247-5p was studied in prostate cancer cell lines transiently transfected with a miR-1247-5p mimic. The expression of miR-1247-5p's putative target MYCBP2 was evaluated by qRT-PCR and Western blotting, and the interaction of the miRNA with the target gene was assessed using a luciferase assay. RESULTS: We found a significant up-regulation of miR 1247-5p in castration-resistant prostate cancer (CRPC) samples compared to non malignant prostate. The expression of miR-1247-5p was subsequently studied in prostate cancer (PC) cell lines where an up-regulation of miR-1247-5p was observed in the androgen-independent PC-3 model. Target prediction analysis for miR-1247-5p performed online revealed that MYCBP2 (myc-binding protein 2) was a high-scoring potential target. Functional studies in vitro performed using PC-3 and LNCaP models confirmed the down-regulation of MYCBP2 at the mRNA and protein levels, and a luciferase assay showed interaction between the miRNA and target gene. CONCLUSION: miR-1247-5p is overexpressed in CRPC and targets MYCBP2. PMID- 25731700 TI - EMF radiation at 2450 MHz triggers changes in the morphology and expression of heat shock proteins and glucocorticoid receptors in rat thymus. AB - AIMS: Electromagnetic fields (EMFs) can act as inducers or mediators of stress response through the production of heat shock proteins (HSPs) that modulate immune response and thymus functions. In this study, we analyzed cellular stress levels in rat thymus after exposure of the rats to a 2.45 GHz radio frequency (RF) using an experimental diathermic model in a Gigahertz Transverse Electromagnetic (GTEM) chamber. MAIN METHODS: In this experiment, we used H&E staining, the ELISA test and immunohistochemistry to examine Hsp70 and Hsp90 expression in the thymus and glucocorticoid receptors (GR) of 64 female Sprague Dawley rats exposed individually to 2.45 GHz (at 0, 1.5, 3.0 or 12.0 W power). The 1 g averaged peak and mean SAR values in the thymus and whole body of each rat to ensure that sub-thermal levels of radiation were being reached. KEY FINDINGS: The thymus tissue presented several morphological changes, including increased distribution of blood vessels along with the appearance of red blood cells and hemorrhagic reticuloepithelial cells. Levels of Hsp90 decreased in the thymus when animals were exposed to the highest power level (12 W), but only one group did not show recovery after 24 h. Hsp70 presented no significant modifications in any of the groups. The glucocorticoid receptors presented greater immunomarking on the thymic cortex in exposed animals. SIGNIFICANCE: Our results indicate that non-ionizing sub-thermal radiation causes changes in the endothelial permeability and vascularization of the thymus, and is a tissue modulating agent for Hsp90 and GR. PMID- 25731701 TI - Molecular characterization of hepatitis C virus genotype 6 subtypes in Thai blood donors. AB - BACKGROUND: Hepatitis C virus (HCV) genotype is important for identifying effective antiviral therapy, evaluating pathogenic severity, and tracking transmission routes. In Thailand, HCV genotypes 3 and 1 are the most common. We have previously demonstrated an increasing appearance of genotype 6 in HCV infections in Thailand. However, only limited epidemiological data on genotype 6 in Thailand are available. This study aimed to characterize HCV genotype 6 among apparently healthy Thai blood donors. METHODS: In total, 240 blood samples were collected from Phitsanulok Regional Blood Center, Phitsanulok, Thailand. RNA was reverse transcribed and amplified by the nested polymerase chain reaction. HCV genotyping was performed by direct sequencing and phylogenetic tree analysis of core sequences. Amino acid polymorphism of various subtypes of HCV genotype 6 was investigated. RESULTS: Of the 240 samples, 192 were successfully sequenced for the core region and 84 were determined to be of HCV genotype 6 by phylogenetic analysis. The most prevalent HCV-6 subtypes were 6f > 6n > 6c > 6i. Amino acid sequences of the partial core region among these four subtypes differed by one to seven residues. CONCLUSION: For HCV-6, the subtype 6f was commonly found in Thai blood donors. Comparison of core protein from various HCV-6 subtypes showed substantial polymorphisms, which may form the basis of future studies using samples from patients with clear HCV histories. This feature can be applied to therapies tailored to particular genotype variants. PMID- 25731702 TI - Mycobacterium abscessus pneumonia in a South Pacific islander. PMID- 25731703 TI - Bidirectional Photoinduced Electron Transfer in Ruthenium(II)-Tris-bipyridyl Modified PpcA, a Multi-heme c-Type Cytochrome from Geobacter sulfurreducens. AB - PpcA, a tri-heme cytochrome c7 from Geobacter sulfurreducens, was investigated as a model for photosensitizer-initiated electron transfer within a multi-heme "molecular wire" protein architecture. Escherichia coli expression of PpcA was found to be tolerant of cysteine site-directed mutagenesis, demonstrated by the successful expression of natively folded proteins bearing cysteine mutations at a series of sites selected to vary characteristically with respect to the three CXXCH- heme binding domains. The introduced cysteines readily reacted with Ru(II) (2,2'-bpy)2(4-bromomethyl-4'-methyl-2,2'-bipyridine) to form covalently linked constructs that support both photo-oxidative and photo-reductive quenching of the photosensitizer excited state, depending upon the initial heme redox state. Excited-state electron-transfer times were found to vary from 6 * 10(-12) to 4 * 10(-8) s, correlated with the distance and pathways for electron transfer. The fastest rate is more than 10(3)-fold faster than previously reported for photosensitizer-redox protein constructs using amino acid residue linking. Clear evidence for inter-heme electron transfer within the multi-heme protein is not detected within the lifetimes of the charge-separated states. These results demonstrate an opportunity to develop multi-heme c-cytochromes for investigation of electron transfer in protein "molecular wires" and to serve as frameworks for metalloprotein designs that support multiple-electron-transfer redox chemistry. PMID- 25731704 TI - Editors' note. PMID- 25731706 TI - [Radiology in the 21(st) century: The SERAM's vision]. PMID- 25731707 TI - [Angioedema of the small bowel secondary to treatment with angiotensin converting enzyme inhibitor]. PMID- 25731708 TI - Connexin 43 and ERK regulate tension-induced signal transduction in human periodontal ligament fibroblasts. AB - Periodontal ligament (PDL) fibroblasts play an important role in preserving periodontal homeostasis and transmitting mechanical signals to alveolar bone. Connexin 43 (Cx43), a gap junction protein, is essential for bone homeostasis and regulates bone remodeling. However, the function of Cx43 in human PDL fibroblast regulated bone remodeling has not yet been elucidated. In this study, human PDL fibroblasts were exposed to cyclic mechanical tension with a maximum 5% elongation for different durations. We then examined the expression of signaling molecules related to osteogenesis and osteoclastogenesis at both the mRNA and protein levels as well as the activity of extracellular signal-regulated kinase (ERK) in human PDL fibroblasts after loading. We found that mechanical tension increased Cx43, which further upregulated osteogenic (e.g., RUNX2, Osterix, and OPG) and down-regulated osteoclastogenic (e.g., RANKL) signaling molecules. Suppressing Cx43 gene (Gja1) by siRNA inhibited the increase in osteogenesis related molecules but enhanced RANKL expression. Similar to Cx43, activated ERK1/2 was also enhanced by mechanical tension and suppressed by Cx43 siRNA. Inhibition of ERK1/2 signaling using PD98059 reduced the tension-regulated increase in osteogenesis-related molecules but enhanced that of osteoclastogenesis-related ones. These findings suggest that cyclic tension may involve into the osteogenic or osteoclastogenetic differentiation potential of human PDL fibroblasts via the Cx43-ERK1/2 signaling pathway. PMID- 25731709 TI - Male obesity is associated with changed spermatozoa Cox4i1 mRNA level and altered seminal vesicle fluid composition in a mouse model. AB - The rate of obesity among men of reproductive age has tripled in the last three decades. Previously, we demonstrated that paternal obesity resulted in impaired preimplantation developmental kinetics, compromised post-compaction metabolism and decreased blastocyst cell number when embryos were generated in vivo. Subsequently, using in vitro fertilization we found embryos of obese males to have altered metabolism before compaction, reduced inner cell mass cell number and retarded fetal development--the difference between these two studies being the method of embryo generation and the presence or absence of seminal plasma, respectively. Here, we hypothesize that both sperm and seminal plasma are affected by obesity, compromising embryogenesis and pregnancy health in a cumulative manner. Epididymal sperm and seminal vesicle fluid were collected from normal and obese C57BL/6 mice. RNA and DNA were extracted from spermatozoa for qPCR and global methylation analysis, respectively. Proteomic (Luminex) and metabolomic (GC-MS) techniques were employed to analyse the composition of seminal vesicle fluid. Nuclear encoded cytochrome c oxidase subunit IV isoform 1 (Cox4i1) of the terminal enzyme in the mitochondrial respiratory chain demonstrated significantly increased RNA levels in the sperm of obese males (P< 0.05). Quantitative seminal plasma analysis identified significant changes in levels of the hormones insulin, leptin and estradiol between normal and obese males (P < 0.05). Further, the metabolite composition of seminal vesicle fluid was significantly affected by obesity. Consequently, this study has determined that obesity affects both sperm and seminal plasma composition. The interaction between sperm and seminal plasma warrants further analysis. PMID- 25731710 TI - "Coming to a Strange Land": The West African Migrant Women's Establishment of Home and Family in a New Culture Within Australia. AB - PURPOSE: Migrating and establishing a new life in another culture can have diverse health effects especially for women. This article explores the struggles and social adjustment issues that might constitute negatively to the health of West African migrant women living in Australia. DESIGN: Qualitative storytelling. Audiotaped voluntary stories from 20 West African migrant women living in Sydney, Australia were transcribed and analyzed. FINDINGS: Three themes are presented for discussion: (1) But it is different here: life in a new country; (2) I have to do it all by myself: communal versus individual living; and (3) They don't listen to parents: perceived threats to the family unit. CONCLUSION/IMPLICATION FOR PRACTICE: The demand for and the importance of nurses and midwives in supporting migrant families is demonstrated by findings suggesting that social adjustment into the Australian culture has a significant impact on both the nuclear and extended family unit of women. PMID- 25731711 TI - Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations. AB - Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876). PMID- 25731712 TI - ER egress of invariant chain isoform p35 requires direct binding to MHCII molecules and is inhibited by the NleA virulence factor of enterohaemorrhagic Escherichia coli. AB - Four invariant chain (Ii) isoforms assist the folding and trafficking of human MHC class II (MHCIIs). The main isoforms, Iip33 and Iip35, assemble in the ER into homo- and/or hetero-trimers. The sequential binding of up to three MHCII alphabeta heterodimers to Ii trimers results in the formation of pentamers, heptamers and nonamers. MHCIIs are required to overcome the p35-encoded di arginine (RxR) ER retention motif and to allow anterograde trafficking of the complex. Here, we show that inactivation of the RxR motif requires a direct cis interaction between p35 and the MHCII, precluding ER egress of some unsaturated Ii trimers. Interestingly, as opposed to MHCII/p33 complexes, those including p35 remained in the ER when co-expressed with the NleA protein of enterohaemorrhagic Escherichia coli. Taken together, our results demonstrate that p35 influences distinctively MHCII/Ii assembly and trafficking. PMID- 25731713 TI - Clinical significance of granulation tissue after transoral laser microsurgery for glottic cancer. AB - BACKGROUND: Granulation tissue after transoral laser microsurgery can make it difficult to distinguish between normal healing and tumour recurrence. MATERIALS AND METHODS: We carried out a retrospective analysis of 316 consecutive glottic carcinomas (Tis-T3). Presence of granulation tissue at one and six months was correlated with demographic and clinical data, tumour and surgical characteristics, and tumour relapse. RESULTS: Granulation tissue appeared in 53.8 per cent of patients at month 1, resolving spontaneously in 41.8 per cent. Revision surgery was performed in 60.1 per cent and was effective in 41.1 per cent. At month 6, 14.9 per cent of patients presented with granulation tissue. In 74.5 per cent the tissue was surgically removed and was positive for malignancy in 62.9 per cent. Tumour relapse presented in 29.4 per cent with granulation tissue at month 1 and in 61.7 per cent at month 6 (p = 0.000). Granulation tissue at month 1 correlated with thyroid cartilage exposure and continued smoking. At month 6, granulation tissue correlated with thyroid cartilage exposure, the affected surgical margins and diabetes. CONCLUSION: Granulation tissue after transoral laser microsurgery is frequent. When it persists at six months, revision surgery is formally recommended. PMID- 25731714 TI - A Kazal-type inhibitor is modulated by Trypanosoma cruzi to control microbiota inside the anterior midgut of Rhodnius prolixus. AB - The triatomine insect, Rhodnius prolixus, is a vector of Trypanosoma cruzi, a protozoan parasite that causes Chagas disease. The parasite must overcome immune response and microbiota to develop inside the midgut of triatomines. In this study, we expressed, purified and characterized a Kazal-type inhibitor from the midgut of R. prolixus, named RpTI, which may be involved in microbiota - T. cruzi interactions. The qPCR showed that the RpTI transcript was primarily expressed in tissues from the intestinal tract and that it was upregulated in the anterior midgut after T. cruzi infection. A 315-bp cDNA fragment encoding the mature protein was cloned into the pPIC9 vector and expressed in Pichia pastoris system. Recombinant RpTI (rRpTI) was purified on a trypsin-Sepharose column and had a molecular mass of 11.5 kDa as determined by SDS-PAGE analysis. This protein inhibited trypsin (Ki = 0.42 nM), whereas serine proteases from the coagulation cascade were not inhibited. Moreover, trypanocidal assays revealed that rRpTI did not interfere in the viability of T. cruzi trypomastigotes. The RpTI transcript was also knocked down by RNA interference prior to infection of R. prolixus with T. cruzi. The amount of T. cruzi in the anterior midgut was significantly lower in RpTI knockdown insects compared to the non-silenced groups. We also verified that the bacterial load is higher in the anterior midgut of silenced and infected R. prolixus compared to non-silenced and infected insects. Our results suggest that T. cruzi infection increases the expression of RpTI to mediate microbiota modulation and is important for parasite immediately after infection with R. prolixus. PMID- 25731715 TI - Contemporary occupational therapy: Our occupational therapy models are essential to occupation centred practice. PMID- 25731716 TI - Mechanically durable, superoleophobic coatings prepared by layer-by-layer technique for anti-smudge and oil-water separation. AB - Superoleophobic surfaces are of interest for anti-fouling, self-cleaning, anti smudge, low-drag, anti-fog, and oil-water separation applications. Current bioinspired surfaces are of limited use due to a lack of mechanical durability. A so-called layer-by-layer approach, involving charged species with electrostatic interactions between layers, can provide the flexibility needed to improve adhesion to the substrate while providing a low surface tension coating at the air interface. In this work, a polyelectrolyte binder, SiO2 nanoparticles, and a fluorosurfactant are spray deposited separately to create a durable, superoleophobic coating. Polydiallyldimethylammonium chloride (PDDA) polyelectrolyte was complexed with a fluorosurfactant layer (FL), which provides oil repellency while being hydrophilic. This oleophobic/superhydrophilic behavior was enhanced through the use of roughening with SiO2 particles resulting in a superoleophobic coating with hexadecane contact angles exceeding 155 degrees and tilt angles of less than 4 degrees . The coating is also superhydrophilic, which is desirable for oil-water separation applications. The durability of these coatings was examined through the use of micro- and macrowear experiments. These coatings currently display characteristics of transparency. Fabrication of these coatings via the layer-by-layer technique results in superoleophobic surfaces displaying improved durability compared to existing work where either the durability or the oil-repellency is compromised. PMID- 25731717 TI - Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation. AB - Aptamer nanomedicine, including therapeutic aptamers and aptamer nanocomplexes, is beginning to fulfill its potential in both clinical trials and preclinical studies. Especially in oncology, aptamer nanomedicine may perform better than conventional or antibody-based chemotherapeutics due to specificity compared to the former and stability compared to the latter. Many proof-of-concept studies on applying aptamers to drug delivery, gene therapy, and cancer imaging have shown promising efficacy and impressive safety in vivo toward translation. Yet, there remains ample room for improvement and critical barriers to be addressed. In this review, we will first introduce the recent progress in clinical trials of aptamer nanomedicine, followed by a discussion of the barriers at the design and in vivo application stages. We will then highlight recent advances and engineering strategies proposed to tackle these barriers. Aptamer cancer nanomedicine has the potential to address one of the most important healthcare issues of the society. PMID- 25731718 TI - Mammographic tumour appearance and triple-negative breast cancer associated with long-term prognosis of breast cancer death: a Swedish Cohort Study. AB - BACKGROUND: Numerous studies have paid attention to the role of the triple negative marker in the prognosis of breast cancer, but very few studies have combined mammographic phenotypes with the triple-negative marker to assess their relevance to the long-term prognosis of breast cancer. The current study aims to assess the respective contributions of both mammographic tumour appearance and the triple-negative marker, and their possible interactions, on the long-term survival of breast cancer, taking into account the prognostic factors already established. METHODS: A retrospective cohort of 498 breast cancer patients was enrolled at Falun Central Hospital, Sweden, between 1996 and 1998, and information on immunohistochemical markers and histological tumour distribution in these patients was collected. This cohort - together with prior information on conventional tumour attributes and mammographic tumour features from 1968 to 1995 - was formed by the Bayesian method and was followed over time until the end of 2011. RESULTS: After considering tumour attributes, histological tumour distribution, and triple-negative cancer, two mammographic tumour features - casting type (adjusted hazard ratio, aHR=3.47, 2.21-5.53) and architectural distortion (aHR=4.43, 2.02-9.50) - had poorer survival compared to other types (stellate, circular, crushed-stone-like, and powdery mass). Triple-negative status conferred an independent 1.95-fold (1.06-3.52) higher risk for death from breast cancer than non-triple-negative status. Stratified by mammographic tumour features, the impact of triple-negative status on the prognosis of breast cancer was statistically significantly greater for the casting and architecturally distorted types (aHR=5.40, 1.40-20.59) but was not statistically significant for other types of mammographic appearance (aHR=1.75, 0.75-4.21). Stratified by the triple-negative feature, the effect of casting type and architectural distortion versus other tumour types on the risk of breast cancer death was statistically significant not only among triple-negative breast cancers (aHR=9.67, 2.74-29.54) but also among non-triple-negative cancers (aHR=4.11, 1.88-8.68). CONCLUSION: In addition to demonstrating mammographic appearance and the triple-negative feature as two independent prognostic factors, the most novel finding of this study is that the triple-negative feature played a more important role among breast tumours with the mammographic appearance of casting and architectural distortion than among tumours with other types of mammographic appearance. The risk stratification of long-term prognosis of breast cancer in the light of multi attribute information in chronological order (mammographic tumour appearance first and then the triple-negative test) may aid clinicians in developing a customised schedule of surveillance and in optimising treatment and adjuvant therapy. PMID- 25731719 TI - A complete mitochondrial genome of Dazu Black goat. AB - Dazu Black goat is an indigenous goat genetic resource in Southwest of China. Here, we describe its complete mitochondrial genome sequence. The mitogenome is 16,641 bp in length, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and a control region. As in other mammals, most mitochondrial genes are encoded on the heavy strand, except for ND6 and eight tRNA genes, which are encoded on the light strand. Its overall base composition is A: 33.5%, T: 27.3%, C: 26.1% and G: 13.1%. The complete mitogenome of the indigenous goat could provide important data to further explore the taxonomic status of the subspecies and also provide a starting point for further phylogenetic studies. PMID- 25731720 TI - Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients. AB - Tumor necrosis factor-alpha (TNF)-alpha inhibitors are licensed for patients with severe refractory psoriasis and psoriatic arthritis. However, TNF-alpha inhibitors have also been used off-label for various recalcitrant mucocutaneous diseases. This study aimed to evaluate the efficacy and safety of TNF-alpha inhibitors used for off-label dermatological indications. We retrospectively evaluated patient records of 118 patients treated off-label with TNF-alpha inhibitors in a dermatological university department. Patients presented with severe aphthous stomatitis/genital aphthous lesions (26), chronic urticaria (25), hidradenitis suppurativa (29), acne conglobata (11), dissecting cellulitis of the scalp (two), orofacial granulomatosis (four), sarcoidosis (four), granuloma annulare (two), granulomatous rosacea (one), granuloma faciale (one), subcorneal pustulosis (one), pyoderma gangrenosum (four), Sweet's syndrome (four), Well's syndrome (one), benign familial pemphigus (one), lichen planus (one), and folliculitis decalvans (one). A significant number of these patients went into remission during therapy with TNF-alpha inhibitors. A total of 11 patients (9%) experienced severe adverse effects during therapy. Off-label therapy with TNF alpha inhibitors may be considered for selected patients with severe recalcitrant mucocutaneous diseases. The risk of severe adverse effects signals that a thorough benefit-risk assessment should be performed before initiating off-label treatment with TNF-alpha inhibitors for these conditions. PMID- 25731721 TI - Creating a gold standard surgical procedure: the development and implementation of TVT : Ulf Ulmsten Memorial Lecture 2014. PMID- 25731722 TI - Transvaginal repair of stage III-IV cystocele using a lightweight mesh: safety and 36-month outcome. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the 36-month safety and efficacy of a lightweight polypropylene mesh used for the transvaginal repair of stage III-IV cystocele. METHODS: A multicenter prospective cohort study was performed. Preoperative assessment included an interview and evaluation with the Pelvic Organ Prolapse Quantification (POP-Q) system. Inclusion criteria were stage III-IV cystocele and no contraindications for mesh use. A lightweight (28 g/m(2)) four-arm transobturator polypropylene mesh was used for the study. Pre- and postoperative symptoms and quality of life were assessed using the Urinary Symptoms Measurement (MHU), Pelvic Floor Distress Inventory (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7), and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). The main endpoint was mesh safety. Secondary endpoints were anatomic (Ba point <= -1) and functional success. RESULTS: In all, 111 patients with a mean age of 67 +/- 9 years (range 47-89) were included in the study, and 94 (84.7%) were included in the analysis. Two intraoperative complications occurred (one bladder and one rectal injury, 2.2%). Medium-term analysis of 79 patients (84%) after 36 months showed a satisfaction rate of 98.7% (78/79), a mesh contraction rate of 5.1% (4/78), only one case of vaginal mesh exposure (1.3%), no cases of chronic pelvic pain, and a postoperative dyspareunia rate of 2.8% (1/36). The anatomic success rate of cystocele repair was 75/79 (94.9%) and a highly significant improvement was noted for symptoms and on quality of life questionnaires. Overall, 7/79 patients (8.9%) were reoperated, including 1 for hemorrhage, 1 for vaginal mesh exposure, 3 for stress urinary incontinence, and 2 for cystocele recurrence (2.5%). CONCLUSION: Transvaginal cystocele repair using a lightweight transobturator polypropylene mesh was safe and efficient in the medium term. Long-term data and comparative studies are needed. PMID- 25731724 TI - Engineering Biological Approaches for Detection of Toxic Compounds: A New Microbial Biosensor Based on the Pseudomonas putida TtgR Repressor. AB - Environmental contamination by toxic organic compounds and antimicrobials is one of the causes for the recent surge of multidrug-resistant pathogenic bacteria. Monitoring contamination is therefore the first step in containment of antimicrobial resistance and requires the development of simple, sensitive, and quantitative tools that detect a broad spectrum of toxic compounds. In this study, we have engineered a new microbial biosensor based on the ttgR-regulated promoter that controls expression of the TtgABC extrusion efflux pump of Pseudomonas putida, coupled to a gfp reporter. The system was introduced in P. putida DOT-T1E, a strain characterized by its ability to survive in the presence of high concentrations of diverse toxic organic compounds. This whole-cell biosensor is capable to detect a wide range of structurally diverse antibiotics, as well as compounds such as toluene or flavonoids. PMID- 25731725 TI - Surface chemistry and serum type both determine the nanoparticle-protein corona. AB - The protein corona that forms around nanoparticles in vivo is a critical factor that affects their physiological response. The potential to manipulate nanoparticle characteristics such that either proteins advantageous for delivery are recruited and/or detrimental proteins are avoided offers exciting possibilities for improving drug delivery. In this work, we used nanoliquid chromatography tandem mass spectrometry to characterize the corona of five lipid formulations after incubation in mouse and human plasma with the hope of providing data that may contribute to a better understanding of the role played by both the nanoparticle properties and the physiological environment in recruiting specific proteins to the corona. Notably, we showed that minor changes in the lipid composition might critically affect the protein corona composition demonstrating that the surface chemistry and arrangement of lipid functional groups are key players that regulate the liposome-protein interactions. Notably, we provided evidence that the protein corona that forms around liposomes is strongly affected by the physiological environment, i.e., the serum type. These results are likely to suggest that the translation of novel pharmaceutical formulations from animal models to the clinic must be evaluated on a case-by-case basis. BIOLOGICAL SIGNIFICANCE: In the present work nanoliquid chromatography tandem mass spectrometry was used to characterize the protein corona of five different liposome formulations after exposure to mouse and human plasma. The modern proteomic methods employed have clarified that the arrangement of lipid functional groups is a key player that regulates the liposome-protein interactions. We also clarified that the protein corona enrichment and complexity depend on the serum type. Our results suggest that the translational of novel pharmaceutical formulations from animal models to the clinic must be evaluated on a case-by-case basis. PMID- 25731726 TI - Goos-Hanchen effect in epsilon-near-zero metamaterials. AB - Light reflection and refraction at an interface between two homogeneous media is analytically described by Snell's law. For a beam with a finite waist, it turns out that the reflected wave experiences a lateral displacement from its position predicted by geometric optics. Such Goos-Hanchen (G-H) effect has been extensively investigated among all kinds of optical media, such as dielectrics, metals, photonic crystals and metamaterials. As a fundamental physics phenomenon, the G-H effect has been extended to acoustics and quantum mechanics. Here we report the unusual G-H effect in zero index metamaterials. We show that when linearly polarized light is obliquely incident from air to epsilon-near-zero metamaterials, no G-H effect could be observed for p polarized light. While for s polarization, the G-H shift is a constant value for any incident angle. PMID- 25731727 TI - An integrative review of facilitators and barriers influencing collaboration and teamwork between general practitioners and nurses working in general practice. AB - AIM: To identify facilitators and barriers influencing collaboration and teamwork between general practitioners and nurses working in general (family) practice. BACKGROUND: Internationally, a shortage of doctors entering and remaining in general practice and an increasing burden of chronic disease has diversified the nurse's role in this setting. Despite a well-established general practice nursing workforce, little attention has been paid to the ways doctors and nurses collaborate in this setting. DESIGN: Integrative literature review. DATA SOURCES: CINAHL, Scopus, Web of Life, Cochrane Library, Joanna Briggs Institute Library of Systematic Reviews and Trove (dissertation and theses) were searched for papers published between 2000 and May 2014. REVIEW METHODS: This review was informed by the approach of Whittemore and Knafl (2005). All included papers were assessed for methodological quality. Findings were extracted, critically examined and grouped into themes. RESULTS: Eleven papers met the inclusion criteria. Thematic analysis revealed three themes common to the facilitators of and barriers to collaboration and teamwork between GPs in general practice: (1) roles and responsibilities; (2) respect, trust and communication; and (3) hierarchy, education and liability. CONCLUSION: This integrative review has provided insight into issues around role definition, communication and organizational constraints which influence the way nurses and general practitioners collaborate in a team environment. Future research should investigate in more detail the ways doctors and nurses work together in general practice and the impact of collaboration on nursing leadership and staff retention. PMID- 25731728 TI - Upregulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma. AB - Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8%, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC. PMID- 25731729 TI - Bevacizumab in combination with anticancer drugs for previously treated advanced non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases. Patients with NSCLC often have an advanced disease at the time of diagnosis, with a 1-year survival rate about 10-15% under the best support treatment. As therapeutic methods for lung cancer developed rapidly in recent years, the prognosis of stage IIIB or IV NSCLC also improve to a large extend. Bevacizumab is a monoclonal antibody against VEGFR which inhibits abnormal vascular growth in malignant tumors. In October 2006, bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for first-line use in advanced NSCLC. For patients with advanced NSCLC who failed in previously platinum-based chemotherapy, bevacizumab also showed enhancing efficacy to antitumor drugs recommended by the latest NCCN guideline. This review intends to present the recent progress and prospects of bevacizumab in second- or third-line treatment for patients with refractory NSCLC. PMID- 25731730 TI - MiR-221/222 promote human glioma cell invasion and angiogenesis by targeting TIMP2. AB - miR-221/222 are two highly homologous microRNAs that are frequently upregulated in solid tumors. However, the effects of miR-221/222 in malignant gliomas have not been investigated thoroughly. In this study, we found that miR-221/222 were significantly upregulated in human glioma samples and glioma cell lines. Both gain- and loss-of-function studies showed that miR-221/222 regulate cell proliferation, the cell cycle and apoptosis, in addition to, invasion, metastasis, and angiogenesis in glioma cell lines. Subsequent investigations revealed that TIMP2 is a direct target of miR-221/222, and overexpression of TIMP2 reduced the miR-221/222-mediated invasion, metastasis, and angiogenesis of glioma cells. Taken together, our results suggest that the suppression of miR 221/222 may be a feasible approach for inhibiting the malignant behaviors of glioma. PMID- 25731731 TI - CEA serum level as early predictive marker of outcome during EGFR-TKI therapy in advanced NSCLC patients. AB - Considering the role of carcinoembryonic antigen (CEA) serum levels as potential useful predictive marker during chemotherapy treatment, we studied its applicability in advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). Our retrospective cohort consists of 79 patients (33 EGFR mutated and 46 EGFR wild type or unknown) affected by advanced NSCLC, for whom CEA serum values at the beginning of TKI therapy and after the first month of treatment were available, regardless of treatment line. Baseline CEA value, percentage of CEA reduction after 1 month, and percentage of patients with >=20 % CEA decrease after 1 month (CEA response) were correlated with disease control rate (DCR), progression-free (PFS), and overall (OS) survival, according to EGFR mutational status. Median baseline CEA levels were significantly higher in EGFR mutated (40.9 ng/ml; interquartile range (IQR) 8.9-197.6) than in wild-type cases (6.2 ng/ml; IQR 2.8-12.8; p = 0.003). Both percentage reduction in CEA levels (-10.7 vs. +13.4 %) and percentage of cases with CEA response (42 vs. 20 %) were significantly higher in mutated vs. wild-type/unknown patients (p = 0.007 and p = 0.027, respectively). In wild-type/unknown patients, CEA response was significantly correlated with DCR (p = 0.001) and resulted as a significant predictor of PFS both in univariate (p = 0.002) and in multivariate analyses (hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.11-0.66; p = 0.004); only a trend was found for OS prediction (p = 0.082). In EGFR-mutated group, CEA reduction did not show any correlation either with PFS or OS. CEA response after 1 month of EGFR-TKI therapy could be a useful marker, worthy to further studies, as early predictor of treatment outcome in EGFR wild-type/unknown unselected NSCLC cases for which no molecular predictor is yet available. PMID- 25731732 TI - MiR-124 inhibits cell proliferation in breast cancer through downregulation of CDK4. AB - Studies have shown that microRNAs (miRNAs) are involved in the malignant progression of human cancer. However, little is known about the potential role of miRNAs in breast carcinogenesis. miR-124 expression in breast cancer tissue was measured by quantitative real-time PCR (qRT-PCR). Target prediction algorithms and luciferase reporter gene assays were used to investigate the target of miR 124. Breast cancer cells growth was regulated by overexpression or knockdown miR 124. At the end of the study, tumor-bearing mice were tested to confirm the function of miR-124 in breast cancer. In this study, we demonstrated that the expression of miR-124 was significantly downregulated in breast cancer tissues compared with matched adjacent non-neoplastic tissues. We identified and confirmed that cyclin-dependent kinase 4 (CDK4) was a direct target of miR-124. Overexpression of miR-124 suppressed CDK4 protein expression and attenuated cell viability, proliferation, and cell cycle progression in MCF-7 and MDA-MB-435S breast cancer cells in vitro. Overexpression of CDK4 partially rescued the inhibitory effect of miR-124 in the breast cancer cells. Moreover, we found that miR-124 overexpression effectively repressed tumor growth in xenograft animal experiments. Our results demonstrate that miR-124 functions as a growth suppressive miRNA and plays an important role in inhibiting tumorigenesis by targeting CDK4. PMID- 25731733 TI - The platelet-to-lymphocyte ratio predicts poor survival in patients with huge hepatocellular carcinoma that received transarterial chemoembolization. AB - Inflammation is particularly strong in huge hepatocellular carcinoma (HCC). However, it is unclear whether the platelet-to-lymphocyte ratio (PLR), as an inflammatory-related marker, can predict survival of patients with huge HCC. In this study, we enrolled 291 patients with huge HCC (diameter over 10 cm) who were undergoing repeated transarterial chemoembolization (TACE) at our institute. The baseline PLR was calculated from complete serum blood counts before the first chemoembolization. We found that a baseline PLR cutoff value over 150 best predicted huge HCC survival. The 12, 24, and 36 months survival rates in the high PLR group (22.6, 8.1, and 4.1 %, respectively) were significantly lower than in the low PLR group (35.6, 22.4, and 14 %, respectively). Thus, a significant difference was found in overall survival (log-rank test, p < 0.0001). Univariate analyses indicated a high PLR (p < 0.0001) was predictor of poor survival, and multivariate Cox analyses further showed that a high PLR (p = 0.002) was an independent factor that predicted worse survival. In conclusion, for patients with huge HCC, a high baseline PLR is a useful predictor of poor survival in patients undergoing chemoembolization. Additional anti-inflammatory or anti platelet treatments, in combination with TACE, may improve survival in HCC patients with high PLR. PMID- 25731734 TI - Anti-huCD20 antibody therapy for antibody-mediated rejection of renal allografts in a mouse model. AB - We have reported that B6.CCR5(-/-) mice reject renal allografts with high serum donor-specific antibody (DSA) titers and marked C4d deposition in grafts, features consistent with antibody-mediated rejection (AMR). B6.huCD20/CCR5(-/-) mice, where human CD20 expression is restricted to B cells, rejected A/J renal allografts by day 26 posttransplant with DSA first detected in serum on day 5 posttransplant and increased thereafter. Recipient treatment with anti-huCD20 mAb prior to the transplant and weekly up to 7 weeks posttransplant promoted long term allograft survival (>100 days) with low DSA titers. To investigate the effect of B cell depletion at the time serum DSA was first detected, recipients were treated with anti-huCD20 mAb on days 5, 8, and 12 posttransplant. This regimen significantly reduced DSA titers and graft inflammation on day 15 posttransplant and prolonged allograft survival >60 days. However, DSA returned to the titers observed in control treated recipients by day 30 posttransplant and histological analyses on day 60 posttransplant indicated severe interstitial fibrosis. These results indicate that anti-huCD20 mAb had the greatest effect as a prophylactic treatment and that the distinct kinetics of DSA responses accounts for acute renal allograft failure versus the development of fibrosis. PMID- 25731735 TI - Aging of the lungs in asymptomatic lifelong nonsmokers: findings on HRCT. AB - PURPOSE: To report lung parenchymal findings on high-resolution computed tomography (HRCT) in a population of asymptomatic, never-smoker urban dwellers aged 65 years and older. MATERIALS AND METHODS: After institutional approval, asymptomatic older patients from the Geriatrics Outpatient Clinic aged 65 years and older (older group) and healthy volunteers aged 30-50 years (younger group) were invited to participate in the study. Asymptomatic, never-smoker subjects considered free of relevant disease after spirometry and echocardiography underwent chest HRCT. Three researchers reviewed every scan, noting the absence/presence and distribution of pre-specified parenchymal findings. Statistical comparisons between groups were performed using appropriate tests with the aid of software. RESULTS: Forty-seven older and 24 younger subjects were included in this analysis. A higher proportion of women and a longer history of urban dwelling were present in the older group. Parenchymal findings were more prevalent in the older group (78.7 vs. 25% in the younger group; p < 0.001). Parenchymal bands (59.6 vs. 25%; p = 0.007), ground-glass opacities (25.5 vs. 0%; p = 0.006), and septal lines (21.3 vs. 0%; p = 0.013) were more prevalent in the elderly. When only subjects aged 75 years and older were considered as the older group, micronodules, reticular opacities, cysts, and bronchiectases (19.1 vs. 0 % for all comparisons; p = 0.04) were also more frequently found among the elderly. CONCLUSION: Parenchymal bands, ground-glass opacities, septal lines, bronchiectasis, micronodules, reticular opacities, and lung cysts were more prevalent among the elderly. PMID- 25731736 TI - Long-term effects of a 12-week exercise training program on clinical outcomes in idiopathic pulmonary fibrosis. AB - PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, lung disease, with few therapeutic options. Data are limited with respect to the long term effect of exercise training (ET) in IPF. This study sought to evaluate the long-term effects of a 12-week ET program on clinical outcomes in IPF patients. METHODS: Thirty-four IPF patients were randomly allocated to ET or control groups. ET group participated in a 12-week supervised exercise program, while the control group continued with regular medical treatment alone. Exercise capacity, 30 s-chair-stand test for leg strength, dyspnea, and Saint George's Respiratory Questionnaire (SGRQ) for quality of life (QOL) were assessed at baseline and re evaluated at 11 months from baseline. In addition, at 30-month time point from baseline, the impact of the 12-week intervention was analyzed with respect to survival and cardio-respiratory-related hospitalizations. RESULTS: Thirty-two patients completed the 12-week intervention and 28 patients (14 in each group) were re-evaluated. At 11-month follow-up, no significant differences between the groups and time effect were demonstrated for most outcomes. ET group showed preserved values at the baseline level while the control group showed a trend of deterioration. Only the 30 s-chair-stand test (mean difference 3 stands, p = 0.01) and SGRQ (mean difference -6 units, p = 0.037) were significantly different between the groups. At 30 months, the survival analysis showed three deaths, eight hospitalizations occurred in the control group versus one death, one lung transplantation and seven hospitalizations in the ET group, with no significant differences between groups. CONCLUSIONS: At 11-month follow-up, the 12-week ET program showed clinical outcomes were preserved at baseline levels with some maintenance of improvements in leg strength and QOL in the ET group. The control group showed a trend of deterioration in the outcomes. At 30 months, the 12-week ET program did not show benefits in prognosis although the study was underpowered to detect such differences. We suggest including ET as a long-term continued treatment and as a core component of pulmonary rehabilitation programs for IPF patients. PMID- 25731737 TI - Investigation on the performance of a viscoelastic dielectric elastomer membrane generator. AB - Dielectric elastomer generators (DEGs), as a recent transduction technology, harvest electrical energy by scavenging mechanical energy from diverse sources. Their performance is affected by various material properties and failure modes of the dielectric elastomers. This work presents a theoretical analysis on the performance of a dielectric elastomer membrane generator under equi-biaxial loading conditions. By comparing our simulation results with the experimental observations existing in the literature, this work considers the fatigue life of DE-based devices under cyclic loading for the first time. From the simulation results, it is concluded that the efficiency of the DEG can be improved by raising the deforming rate and the prescribed maximum stretch ratio, and applying an appropriate bias voltage. However, the fatigue life expectancy compromises the efficiency improvement of the DEG. With the consideration of the fatigue life, applying an appropriate bias voltage appears to be a more desirable way to improve the DEG performance. The general framework developed in this work is expected to provide an increased understanding on the energy harvesting mechanisms of the DEGs and benefit their optimal design. PMID- 25731739 TI - Arenimonas taoyuanensis sp. nov., a novel bacterium isolated from rice-field soil in China. AB - A Gram-stain negative, aerobic, rod-shaped bacterial strain, YN2-31A(T), was isolated from rice-field soil, Taoyuan Village, Yunnan province of China. The bacterium was observed to grow at 20-45 degrees C (optimum 28 degrees C), at pH 5.0-10.0 (optimum 7.0), and in the presence of 0-2% (w/v) NaCl (optimum 0-1%). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain YN2 31A(T) is most closely related to Arenimonas daejeonensis DSM 18060(T) (96.1%), Arenimonas malthae DSM 21305(T) (95.9%), Arenimonas donghaensis DSM 18148(T) (95.1%), Arenimonas composti DSM 18010(T) (94.8%) and Arenimonas maotaiensis JCM 19710(T) (94.8%). The major cellular fatty acids (>10%) were found to be iso C(18:1) omega9c, iso-C(15:0), Sum In Feature 3 (C(16:1) omega7c/C(16:1) omega6c), and C(16:0). The major ubiquinone was identified as Q-8 and the major cellular polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and unidentified phospholipids. The genomic DNA G+C content was determined to be 72.3 mol%. The results of the phylogenetic, genetic, phenotypic and chemotaxonomic analyses suggest that strain YN2-31A(T) represents a novel species of the genus Arenimonas, for which the name Arenimonas taoyuanensis sp. nov. is proposed. The type strain is YN2-31A(T) (=DSM 26777(T) = CCTCC AB2012964(T)). PMID- 25731740 TI - Comparison of the behaviour of Brettanomyces bruxellensis strain LAMAP L2480 growing in authentic and synthetic wines. AB - Brettanomyces bruxellensis is the main microorganism responsible for the production of off-flavours in wine. Studies have been carried out in synthetic cultures using p-coumaric acid for the production of vinyl and ethylphenols. The results obtained have been extrapolated to authentic wine, but there is no evidence that this correlation will be correct. We studied the behaviour of B. bruxellensis native strain LAMAP L2480 in authentic wine and in a synthetic medium with a chemical composition similar to the authentic wine used in this study (basal synthetic wine + pH, ethanol and hydroxycinnamic acid concentrations of commercial wine). In some assays, B. bruxellensis has been studied using media containing 100 mg L(-1) p-coumaric acid, so we also used the same concentration added to the authentic and synthetic wines. The microorganism showed better growth in authentic wine, regardless of the presence of p-coumaric acid. In the case of synthetic wine, the addition of p-coumaric acid caused a delay in yeast growth and an increase in the production of volatile phenols. The coumarate decarboxylase activity did not show any difference regardless of the media and the presence of p-coumaric acid. Vinylphenol reductase showed higher activity when a higher concentration of p-coumaric acid was added in synthetic wine, but no change was observed in authentic wine. PMID- 25731738 TI - Mechanobiology of the meniscus. AB - The meniscus plays a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Importantly, growing evidence indicates that the mechanobiologic response of meniscal cells plays a critical role in the physiologic, pathologic, and repair responses of the meniscus. Here we review experimental and theoretical studies that have begun to directly measure the biomechanical effects of joint loading on the meniscus under physiologic and pathologic conditions, showing that the menisci are exposed to high contact stresses, resulting in a complex and nonuniform stress-strain environment within the tissue. By combining microscale measurements of the mechanical properties of meniscal cells and their pericellular and extracellular matrix regions, theoretical and experimental models indicate that the cells in the meniscus are exposed to a complex and inhomogeneous environment of stress, strain, fluid pressure, fluid flow, and a variety of physicochemical factors. Studies across a range of culture systems from isolated cells to tissues have revealed that the biological response of meniscal cells is directly influenced by physical factors, such as tension, compression, and hydrostatic pressure. In addition, these studies have provided new insights into the mechanotransduction mechanisms by which physical signals are converted into metabolic or pro/anti-inflammatory responses. Taken together, these in vivo and in vitro studies show that mechanical factors play an important role in the health, degeneration, and regeneration of the meniscus. A more thorough understanding of the mechanobiologic responses of the meniscus will hopefully lead to therapeutic approaches to prevent degeneration and enhance repair of the meniscus. PMID- 25731742 TI - Li-ion battery shut-off at high temperature caused by polymer phase separation in responsive electrolytes. AB - For the purpose of realizing inherently safe high-power Li-ion batteries, a model Li4Ti5O12/LiFePO4 rechargeable battery is investigated using the thermally responsive polymer, poly(benzyl methacrylate), in an ionic liquid. At high temperature, battery operation is inhibited as a result of increased internal resistance caused by polymer and ionic liquid phase separation. Li-ion concentration is shown to affect the phase transition temperature and the extent to which batteries are deactivated. PMID- 25731741 TI - Concurrent chemoradiotherapy with vinorelbine plus split-dose cisplatin may be an option in inoperable stage III non-small cell lung cancer: a single-center experience. AB - BACKGROUND: Concurrent chemoradiotherapy is the current standard treatment for inoperable stage III non-small cell lung cancer (NSCLC). In this study we aimed to investigate the efficacy and toxicity of CCRT with split dose of cisplatin (30 mg/m2) and vinorelbine (20 mg/m2) in patients with inoperable stage III NSCLC followed in our oncology clinic. MATERIAL AND METHODS: Medical records of 97 patients with inoperable stage III NSCLC treated with concurrent chemoradiotherapy with cisplatin-vinorelbine were retrospectively analyzed. Cisplatin (30 mg/m2) and vinorelbine (20 mg/m2) were administered on days 1, 8, 22, and 29 during radiotherapy. Two cycles of consolidation chemotherapy were given. All patient data, including pathological, clinical, radiological, biochemical, and hematological data, were assessed retrospectively using our database system. RESULTS: Our study included 97 unresectable stage III NSCLC patients who were treated with CCRT. Median age was 58 years old (range 39-75) and 87 (89.7%) of the patients were men. ECOG performance score was 0-1 in 93 patients (95.9%). Squamous histology, the most common histology, was diagnosed in 46 patients (47.4%). Median follow-up time was 23.8 months. Median progression free survival (PFS) and median overall survival time (OS) were 10.3 months and 17.8 months, respectively. Objective response rate and clinical benefit rate were 75.3% and 83.5%, respectively. Distant and local relapse rate were 57.1% and 42.9%, respectively. Hematological and non-hematological grade 3-4 toxicities were seen in 13 (13.4%) and 16 (16.5%) patients, respectively. Six (6.1%) patients died due to toxicity. CONCLUSIONS: The results of this study suggest that split-dose cisplatin may offer fewer grade III-IV toxicities without sacrificing efficacy and could be an option in patients with inoperable stage III NSCLC during CCRT. Similar to past studies, despite high response rate during CCRT, distant relapse is the major parameter that influences patient survival in long-term in NSCLC. PMID- 25731743 TI - Human disease phenotypes associated with mutations in TREX1. AB - Considering that it is a single exon gene encoding a 314 amino acid protein, the genotype-phenotype landscape of TREX1 is remarkably complex. Here we briefly describe the human diseases so-far associated with mutations in TREX1, which include Aicardi-Goutieres syndrome, familial chilblain lupus, systemic lupus erythematosus and retinal vasculopathy with cerebral leukodystrophy. PMID- 25731745 TI - In vivo time-sequential histological study focused on melanocytes: suggestion of golden time for intervention to prevent post-laser pigmentary changes. AB - BACKGROUND: Post-inflammatory pigmentary changes after laser treatments are challenging adverse effect. OBJECTIVE: To suggest an ideal time period with regard to intervention to prevent post-laser pigmentary changes, an in vivo time sequential histological study focused on melanocytes was performed. METHODS: The back skin of four volunteers was irradiated with Q-switched alexandrite laser (QSAL). In one subject (subject 4), topical corticosteroid was applied onto the irradiated skin from the time of irradiation to day 28. In all subjects, time sequential skin biopsies were performed at baseline, an immediate time after irradiation, day 2, day 7, and day 28. Histological and immunohistochemical analyses were conducted. RESULTS: Q-switched alexandrite laser led to the successful removal of pigments and most melanocytes from the epidermis in all subjects. At day 28, there was increased epidermal pigmentation in the skin of the subjects 1-3. It was noted that numerous activated melanocytes appeared on day 7, continued to be observed until day 28. However, in the subject 4, the melanocyte activation and post-laser pigmentary changes were not observed. CONCLUSION: In regard to intervene melanocyte activation, at least 1 week after laser treatment is suggested as a 'golden' time period to prevent pigmentary changes. PMID- 25731744 TI - FAAH genetic variation enhances fronto-amygdala function in mouse and human. AB - Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human. PMID- 25731746 TI - Insulin resistance in Alzheimer disease: Is heme oxygenase-1 an Achille's heel? AB - Insulin resistance, clinically defined as the inability of insulin to increase glucose uptake and utilization, has been found to be associated with the progression of Alzheimer disease (AD). Indeed, postmortem AD brain shows all the signs of insulin resistance including: (i) reduced brain insulin receptor (IR) sensitivity, (ii) hypophosphorylation of the insulin receptor and downstream second messengers such as IRS-1, and (iii) attenuated insulin and insulin growth factor (IGF)-1 receptor expression. However, the exact mechanisms driving insulin resistance have not been completely elucidated. Quite recently, the levels of the peripheral inducible isoform of heme oxygenase (HO-1), a well-known protein up regulated during cell stress response, were proposed to be among the strongest positive predictors of metabolic disease, including insulin resistance. Because our group previously reported on levels, activation state and oxidative stress induced post-translational modifications of HO-1 in AD brain and our ongoing studies to better elucidate the role of HO-1 in insulin resistance-associated AD pathology, the aim of this review is to provide reader with a critical analysis on new aspects of the interplay between HO-1 and insulin resistance and on how the available lines of evidence could be useful for further comprehension of processes in AD brain. PMID- 25731747 TI - Cortical alterations in a model for absence epilepsy and febrile seizures: in vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation. AB - Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures. Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting. Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms. PMID- 25731748 TI - Enhanced corticosteroid signaling alters synaptic plasticity in the dentate gyrus in mice lacking the fragile X mental retardation protein. AB - The fragile X mental retardation protein (FMRP) is an important regulator of protein translation, and a lack of FMRP expression leads to a cognitive disorder known as fragile X syndrome (FXS). Clinical symptoms characterizing FXS include learning impairments and heightened anxiety in response to stressful situations. Here, we report that, in response to acute stress, mice lacking FMRP show a faster elevation of corticosterone and a more immediate impairment in N-methyl-d aspartate receptor (NMDAR) dependent long-term potentiation (LTP) in the dentate gyrus (DG). These stress-induced LTP impairments were rescued by administering the glucocorticoid receptor (GR) antagonist RU38486. Administration of RU38486 also enhanced LTP in Fmr1(-/y) mice in the absence of acute stress to wild-type levels, and this enhancement was blocked by application of the NMDAR antagonist 2 amino-5-phosphonopentanoic acid. These results suggest that a loss of FMPR results in enhanced GR signaling that may adversely affect NMDAR dependent synaptic plasticity in the DG. PMID- 25731749 TI - Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson's disease. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 contains functional GTPase and kinase domains. The most common G2019S mutation enhances the kinase activity of LRRK2 in vitro whereas G2019S LRRK2 expression in cultured neurons induces toxicity in a kinase-dependent manner. These observations suggest a potential role for kinase activity in LRRK2-associated PD. We have recently developed a novel rodent model of PD with progressive neurodegeneration induced by the adenoviral-mediated expression of G2019S LRRK2. In the present study, we further characterize this LRRK2 model and determine the contribution of kinase activity to LRRK2-mediated neurodegeneration. Recombinant human adenoviral vectors were employed to deliver human wild-type, G2019S or kinase-inactive G2019S/D1994N LRRK2 to the rat striatum. LRRK2-dependent pathology was assessed in the striatum, a region where LRRK2 protein is normally enriched in the mammalian brain. Human LRRK2 variants are robustly expressed throughout the rat striatum. Expression of G2019S LRRK2 selectively induces the accumulation of neuronal ubiquitin-positive inclusions accompanied by neurite degeneration and the altered distribution of axonal phosphorylated neurofilaments. Importantly, the introduction of a kinase-inactive mutation (G2019S/D1994N) completely ameliorates the pathological effects of G2019S LRRK2 in the striatum supporting a kinase activity-dependent mechanism for this PD-associated mutation. Collectively, our study further elucidates the pathological effects of the G2019S mutation in the mammalian brain and supports the development of kinase inhibitors as a potential therapeutic approach for treating LRRK2-associated PD. This adenoviral rodent model provides an important tool for elucidating the molecular basis of LRRK2 mediated neurodegeneration. PMID- 25731750 TI - Conformation of BCL-XL upon Membrane Integration. AB - BCL-XL is an anti-apoptotic BCL-2 family protein found both in the cytosol and bound to intracellular membranes. Structural studies of BCL-XL have advanced by deleting its hydrophobic C-terminus and adding detergents to enhance solubility. However, since the C-terminus is essential for function and detergents strongly affect structure and activity, the molecular mechanisms controlling intracellular localization and cytoprotective activity are incompletely understood. Here we describe the conformations and ligand binding activities of water-soluble and membrane-bound BCL-XL, with its complete C-terminus, in detergent-free environments. We show that the C-terminus interacts with a conserved surface groove in the water-soluble state of the protein and inserts across the phospholipid bilayer in the membrane-bound state. Contrary to current models, membrane binding does not induce a conformational change in the soluble domain and both states bind a known ligand with affinities that are modulated by the specific state of the protein. PMID- 25731752 TI - Host resistance and pathogen infectivity in host populations with varying connectivity. AB - Theory predicts that hosts and pathogens will evolve higher resistance and aggressiveness in systems where populations are spatially connected than in situations in which populations are isolated and dispersal is more local. In a large cross-inoculation experiment we surveyed patterns of host resistance and pathogen infectivity in anther-smut diseased Viscaria alpina populations from three contrasting areas where populations range from continuous, through patchy but spatially connected to highly isolated demes. In agreement with theory, isolated populations of V. alpina were more susceptible on average than either patchily distributed or continuous populations. While increased dispersal in connected systems increases disease spread, it may also increase host gene flow and the potential for greater host resistance to evolve. In the Viscaria Microbotryum system, pathogen infectivity mirrored patterns of host resistance with strains from the isolated populations being the least infective and strains from the more resistant continuous populations being the most infective on average, suggesting that high resistance selects for high infectivity. To our knowledge this study is the first to characterize the impacts of varying spatial connectivity on patterns of host resistance and pathogen infectivity in a natural system. PMID- 25731753 TI - Diverse roles of jasmonates and ethylene in abiotic stress tolerance. AB - Jasmonates (JAs) and ethylene (ET), often acting cooperatively, play essential roles in regulating plant defense against pests and pathogens. Recent research reviewed here has revealed mechanistic new insights into the mode of action of these hormones in plant abiotic stress tolerance. During cold stress, JAs and ET differentially regulate the C-repeat binding factor (CBF) pathway. Major JA and ET signaling hubs such as JAZ proteins, CTR1, MYC2, components of the mediator complex, EIN2, EIN3, and several members of the AP2/ERF transcription factor gene family all have complex regulatory roles during abiotic stress adaptation. Better understanding the roles of these phytohormones in plant abiotic stress tolerance will contribute to the development of crop plants tolerant to a wide range of stressful environments. PMID- 25731754 TI - Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review. AB - Ecstasy or 3,4-methylenedioxymethamphetamine (MDMA) is a popular drug of abuse. In the animal studies MDMA has been shown to have deleterious effects on the serotonergic neurotransmitter system. Understanding the adverse effects of MDMA on human brain function is of considerable importance owing to the rising number of MDMA users. Various neuroimaging studies have investigated the structural, chemical and functional differences in the brain integrity of chronic MDMA users. Various neurocognitive domains like working memory, episodic memory, semantic memory, visual stimulation, motor function and impulsivity have been compared between chronic MDMA users and nonusers using fMRI. The fMRI studies remain much more sensitive in studying the neurological deficits associated with chronic MDMA use as compared to the cognitive studies alone and therefore they serve as a prelude in our understanding of MDMA induced neurotoxicity. However they still face certain limitations contributing to inconsistency in the results and further research is needed before we can draw definitive conclusions regarding the neurotoxic effects of MDMA. PMID- 25731751 TI - A roadmap for interpreting (13)C metabolite labeling patterns from cells. AB - Measuring intracellular metabolism has increasingly led to important insights in biomedical research. (13)C tracer analysis, although less information-rich than quantitative (13)C flux analysis that requires computational data integration, has been established as a time-efficient method to unravel relative pathway activities, qualitative changes in pathway contributions, and nutrient contributions. Here, we review selected key issues in interpreting (13)C metabolite labeling patterns, with the goal of drawing accurate conclusions from steady state and dynamic stable isotopic tracer experiments. PMID- 25731755 TI - Rare case of truncus arteriosus with anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) and unilateral left pulmonary artery agenesis. AB - The incidence of congenital heart disease (CHD) is 2.4-3.8/1000 live births. Up to 70.7 % of all cases of CHD are reported to be benign; complex heart anomalies are extremely rare. Our case is extremely rare, as we report three very rare findings-truncus arteriosus, anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA), and unilateral left pulmonary artery agenesis-in a single patient. Congenital complex cardiac abnormalities are very rare, and two dimensional echocardiography screening should be supported by cardiac computed tomography (CT). We report a case of truncus arteriosus associated with ARCAPA and left pulmonary artery agenesis diagnosed by cardiac computed tomography; we believe that such an unusual case with all three of these entities has never been reported before. PMID- 25731756 TI - Fluorescent dye incorporation causes weakened gene association and intracellular aggregate formation in nonviral carriers. AB - BACKGROUND: The successful application of nonviral gene transfer technologies requires both improved understanding and control with respect to intracellular trafficking and release. However, the intracellular space is highly complex and hence well-defined, stable structures are necessary to probe the stages of the delivery pathway. Fluorescent labeling is a regularly used approach to monitor nonviral delivery and release, yet few studies investigate the effects of label incorporation on the structure and activity of gene-containing vehicles. METHODS: In the present study, the impacts of label incorporation on the assembly and gene transfer capacity of DNA polyplexes were determined through the utilization of a model DNA-polyethylenimine (PEI) delivery system. PEI was fluorescently labeled with the Oregon Green(r) dye prior to polyplex formation and delivery to CHO-K1 cells. RESULTS: The present study provides evidence showing that routine labeling strategies for polyplexes weakened DNA binding affinity, produced large quantities of extracellular structures and significantly increased intracellular polyplex aggregation. Additionally, cellular internalization studies showed that increased labeling fractions led to reductions in polyplex uptake as a result of weakened complexation. CONCLUSIONS: These results not only provide insight into the assembly of these structures, but also help to identify labeling strategies sufficient to preserve activity at the same time as enabling detailed studies of trafficking and disassembly. PMID- 25731757 TI - Antimicrobial ruthenium complex coating on the surface of titanium alloy. High efficiency anticorrosion protection of ruthenium complex. AB - A ruthenium complex was prepared and structurally characterized using various techniques. Antibacterial and antifungal activities of ruthenium complex were evaluated. High significant antimicrobial activity against Escherichia coli, Staphylococcus aureus and Candida albicans was recorded. Minor cytotoxicity records were reported at the highest concentration level using MTT assay. The influence of Cu(II), Cr(III), Fe(III) and Ru(III) metal ions of salen Schiff base on the corrosion resistance of Ti-alloy in 0.5M HCl was studied. In vitro corrosion resistance was investigated using electrochemical impedance spectroscopy (EIS) measurements and confirmed by surface examination via scanning electron microscope (SEM) technique. Both impedance and phase angle maximum (theta(max)) values were at maximum in the case of the ruthenium complex with promising antibacterial and antifungal activities. The surface film created by the ruthenium complex was highly resistant against attack or deterioration by bacteria. The EIS study showed high impedance values for the ruthenium complex with increasing exposure time up to 8 days. SEM images showed uniform distribution and adsorption of Ru(III) ions on Ti-alloy surface. The ruthenium complex, as a model of organic-inorganic hybrid complex, offered new prospects with desired properties in industrial and medical applications. PMID- 25731758 TI - Embedding electronic decision-support tools for suspected cancer in primary care: a qualitative study of GPs' experiences. AB - AIM: The purpose of this evaluation was to obtain views from general practitioners (GPs) who piloted the electronic risk assessment tools (eRATs) for suspected lung or colorectal cancer. We wanted to find out whether GPs were able to integrate these tools into their everyday practice. We were also keen to identify facilitators and barriers to their more widespread use. BACKGROUND: Cancer remains one of UK's biggest health problems, in terms of morbidity and mortality. Comparative European data show that five-year survival figures for many cancers are lower in the United Kingdom than in comparable European countries. eRATs are intended to aid recognition of symptoms of lung and colorectal cancers in patients aged 40 years and over. METHODS: This was a qualitative study; telephone interviews were conducted with 23 GPs who piloted the eRATs. A systematic qualitative analysis was applied to the data. The normalisation process model was used after data collection. This theory-driven conceptual framework was used to examine the operationalisation of this intervention in Primary Care. FINDINGS: Electronic decision-support tools appear to be useful additions to the resources available to GPs in order to assist them with recognizing potential cancer symptoms. However, the tools need to be refined in order to integrate them into GP practice. The tools raised GPs' awareness about cancer because of the prompt facility of the software, although this also raised the potential of 'prompt fatigue'. GPs constantly receive alerts via their clinical system, particularly related to the Quality and Outcomes Framework. The integration of eRATs into routine practice could be engendered by improvement to the training packages that accompany them, and by its delivery via a platform compatible with all GP clinical systems. PMID- 25731759 TI - A monophasic solution for isolation of RNA devoid of polymerase chain reaction detectable genomic DNA contamination. AB - Commercially available reagents and published protocols are widely used for RNA isolation. However, genomic DNA contamination in isolated RNA is a potential problem. Here we describe a simple, inexpensive method for eliminating genomic DNA contamination beyond the level of PCR-based detection through reduction of the guanidine thiocyanate concentration (1.5M) in a single monophasic solution based on Chomczynski-Sacchi reagents. The new method can be used to isolate small and large RNA species of high quality and can be completed within an hour. PMID- 25731760 TI - A reflection on the measurement of the burnout syndrome. PMID- 25731761 TI - Drosophila PS2 and PS3 integrins play distinct roles in retinal photoreceptors glia interactions. AB - Cellular migration and differentiation are important developmental processes that require dynamic cellular adhesion. Integrins are heterodimeric transmembrane receptors that play key roles in adhesion plasticity. Here, we explore the developing visual system of Drosophila to study the roles of integrin heterodimers in glia development. Our data show that alphaPS2 is essential for retinal glia migration from the brain into the eye disc and that glial cells have a role in the maintenance of the fenestrated membrane (Laminin-rich ECM layer) in the disc. Interestingly, the absence of glial cells in the eye disc did not affect the targeting of retinal axons to the optic stalk. In contrast, alphaPS3 is not required for retinal glia migration, but together with Talin, it functions in glial cells to allow photoreceptor axons to target the optic stalk. Thus, we present evidence that alphaPS2 and alphaPS3 integrin have different and specific functions in the development of retinal glia. PMID- 25731762 TI - Blood and lymphatic vessel formation. AB - Blood and lymphatic vessels deliver oxygen and nutrients, remove waste and CO2, and regulate interstitial pressure in tissues and organs. These vessels begin life early in embryogenesis using transcription factors and signaling pathways that regulate differentiation, morphogenesis, and proliferation. Here we describe how these vessels develop in the mouse embryo, and the signals that are important to their development. PMID- 25731764 TI - Dosage compensation in mammals. AB - Many organisms show major chromosomal differences between sexes. In mammals, females have two copies of a large, gene-rich chromosome, the X, whereas males have one X and a small, gene-poor Y. The imbalance in expression of several hundred genes is lethal if not dealt with by dosage compensation. The male-female difference is addressed by silencing of genes on one female X early in development. However, both males and females now have only one active X chromosome. This is compensated by twofold up-regulation of genes on the active X. This complex system continues to provide important insights into mechanisms of epigenetic regulation. PMID- 25731767 TI - The evidence base for new drugs. PMID- 25731763 TI - Cell biology of mitotic recombination. AB - Homologous recombination provides high-fidelity DNA repair throughout all domains of life. Live cell fluorescence microscopy offers the opportunity to image individual recombination events in real time providing insight into the in vivo biochemistry of the involved proteins and DNA molecules as well as the cellular organization of the process of homologous recombination. Herein we review the cell biological aspects of mitotic homologous recombination with a focus on Saccharomyces cerevisiae and mammalian cells, but will also draw on findings from other experimental systems. Key topics of this review include the stoichiometry and dynamics of recombination complexes in vivo, the choreography of assembly and disassembly of recombination proteins at sites of DNA damage, the mobilization of damaged DNA during homology search, and the functional compartmentalization of the nucleus with respect to capacity of homologous recombination. PMID- 25731765 TI - Conscious and unconscious memory systems. AB - The idea that memory is not a single mental faculty has a long and interesting history but became a topic of experimental and biologic inquiry only in the mid 20th century. It is now clear that there are different kinds of memory, which are supported by different brain systems. One major distinction can be drawn between working memory and long-term memory. Long-term memory can be separated into declarative (explicit) memory and a collection of nondeclarative (implicit) forms of memory that include habits, skills, priming, and simple forms of conditioning. These memory systems depend variously on the hippocampus and related structures in the parahippocampal gyrus, as well as on the amygdala, the striatum, cerebellum, and the neocortex. This work recounts the discovery of declarative and nondeclarative memory and then describes the nature of declarative memory, working memory, nondeclarative memory, and the relationship between memory systems. PMID- 25731766 TI - Mismatch repair during homologous and homeologous recombination. AB - Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for generating genetic diversity during sexual reproduction. HR is initiated in meiosis by numerous programmed DNA double-strand breaks (DSBs; several hundred in mammals). A characteristic feature of HR is the exchange of DNA strands, which results in the formation of heteroduplex DNA. Mismatched nucleotides arise in heteroduplex DNA because the participating parental chromosomes contain nonidentical sequences. These mismatched nucleotides may be processed by MMR, resulting in nonreciprocal exchange of genetic information (gene conversion). MMR and HR also play prominent roles in mitotic cells during genome duplication; MMR rectifies polymerase misincorporation errors, whereas HR contributes to replication fork maintenance, as well as the repair of spontaneous DSBs and genotoxic lesions that affect both DNA strands. MMR suppresses HR when the heteroduplex DNA contains excessive mismatched nucleotides, termed homeologous recombination. The regulation of homeologous recombination by MMR ensures the accuracy of DSB repair and significantly contributes to species barriers during sexual reproduction. This review discusses the history, genetics, biochemistry, biophysics, and the current state of studies on the role of MMR in homologous and homeologous recombination from bacteria to humans. PMID- 25731768 TI - Rheumatoid arthritis and the prevalence of diabetic retinopathy. AB - OBJECTIVE: RA increases vascular disease and angiogenesis, yet a 1964 Lancet report paradoxically linked RA to lower diabetic retinopathy. Our objective was to examine RA as a risk factor for diabetic retinopathy compared with other vascular risk factors. METHODS: This cohort study compared the prevalence of diabetic retinopathy in diabetes patients with and without RA in a 5% Medicare sample. We analysed the impact of RA on the prevalence of diabetic retinopathy using multivariate logistic regression calculating adjusted rate ratios (ARRs) controlling for sociodemographics, co-morbidity and health utilization. Sensitivity analysis examined eye exam rates. RESULTS: Among 256 331 Medicare diabetes patients, 5572 (2%) had RA. Diabetic retinopathy was less prevalent in patients with RA compared with those without RA (13.7% vs 16.1%, P <= 0.01). Compared with patients without RA, the adjusted model demonstrated that patients with diabetes and RA were 28% less likely to have diabetic retinopathy and 4% more likely to receive an eye exam [ARR 0.72 (95% CI 0.67, 0.77), ARR 1.04 (95% CI 1.02, 1.06)]. CONCLUSION: Findings support the 1964 paradox observing decreased diabetic retinopathy in patients with RA. These findings pose new questions regarding whether RA physiology or treatments protect against diabetic retinopathy and how intraocular factors vary in contrast to adverse vascular changes elsewhere. PMID- 25731769 TI - Predictive value of Doppler ultrasound-detected synovitis in relation to failed tapering of biologic therapy in patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate the predictive value of synovitis detected by Doppler US in relation to failed tapering of biologic therapy (BT) in RA patients in sustained clinical remission. METHODS: A total of 77 RA patients (52 women, 25 men) in sustained clinical remission, treated with a stable dosage of BT were prospectively recruited. BT was tapered according to an agreed strategy implemented in clinical practice (i.e. increasing the interval between doses for s.c. BT and reducing the dose for i.v. BT). BT tapering failure was assessed at 6 and 12 months. Doppler US investigation of 42 joints for the presence and grade (0-3) of B-mode synovial hypertrophy and synovial power Doppler signal (i.e. Doppler synovitis) was performed at baseline by a rheumatologist blinded to clinical and laboratory data. Hand and foot radiographs were obtained at baseline and at 12-month follow-up. RESULTS: Of the 77 patients, 46 (59.7%) were on s.c. BT and 31 (40.3%) on i.v. BT. At 12 months, 35 patients (45.5%) presented BT tapering failure, 23 of them (29.9% of all patients) in the first 6 months of BT tapering. In logistic regression analysis, the baseline DAS28 and the global score of Doppler synovitis were identified as independent predictors of BT tapering failure at 12 and 6 months. The presence of Doppler synovitis was the strongest predictor for BT tapering failure. No patient showed radiographic progression. CONCLUSION: Our results suggest that the presence of Doppler detected synovitis may predict BT tapering failure in RA patients in sustained clinical remission. PMID- 25731770 TI - Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis. AB - OBJECTIVE: IL-35 is the most recently identified member of the IL-12 family. It consists of EBV-induced gene 3 (EBI3) and IL-12alpha chain p35. We investigated whether IL-35 enhances the in vitro immunosuppressive function of peripheral blood isolated from patients with RA. METHODS: Peripheral blood was harvested from 17 active and 10 inactive RA patients and IL-35 concentrations were quantified using an ELISA. An expression vector containing IL-35 with a FLAG tag at the carboxyl-terminus was constructed by covalently linking EBI3 and IL 12alpha (p35). The function of IL-35 was then evaluated in a suppression assay using T cells isolated from human RA patients with CD2, CD3 and CD28 antibodies. RESULTS: Serum IL-35 levels and the number of Treg were decreased significantly in patients with active RA. There was a significant correlation between serum IL 35 and the 28-joint DAS with ESR (DAS28-ESR) in patients with active RA. IL-35 treatment enhanced the regulatory function, suppressing the levels of inflammatory cytokines such as IL-17 and IFN-gamma and the cellular growth of effector T cells stimulated by conjugation with CD2, CD3 and CD28. CONCLUSION: These data revealed that IL-35 might suppress T cell activation during the peripheral immune responses of RA. Therefore our data suggest that IL-35 might have multiple therapeutic targets. PMID- 25731771 TI - Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer. AB - BACKGROUND: 3beta-hydroxysteroid dehydrogenase type 1 (3betaHSD1), which is a rate-limiting enzyme that catalyzes the conversion of adrenal-derived steroid dehydroepiandrosterone to dihydrotestosterone (DHT), may be a promising target for treating castration-resistant prostate cancer (CRPC). METHODS: From 2004 to 2011, a total of 103 consecutive patients presenting with advanced prostate cancer were included in this study. All patients were treated with surgical castration as androgen-deprivation therapy (ADT). Germline DNA was extracted from archived tissue from each patient and sequenced. PSA half-time (representing rate to PSA nadir after ADT), the incidence of, and time to CRPC occurrence, and cause specific mortality rates were determined during the 3-10 years follow-up. The perioperative data and postoperative outcomes are compared. The patients were retrospectively analyzed for survival time. RESULTS: Of the 103 patient samples analyzed, 18 harbored a heterozygous variant (1245C) HSD3B1 gene, while 85 patients were homozygous wild-type (1245A) for HSD3B1. The two groups were homogenous for age, PSA, Gleason and metastases rate preoperatively. The incidence of CRPC observed in the variant group was significantly higher than that of wild-type group (100% vs. 64.7%, respectively; P = 0.003). Despite this higher incidence of CRPC, there were no significant differences in time to develop CRPC, or in cause-specific mortality. Further, neither PSA half-time, nor time to biochemical recurrence were different between the variant and wild-type groups. CONCLUSION: Prostate cancer patients who harbored the heterozygous variant HSD3B1 (1245C) are more likely to develop to CRPC, but do not have shorter time to biochemical recurrence, shorter survival time or higher mortality risk. PMID- 25731773 TI - HIV-1 gag: an emerging target for antiretroviral therapy. AB - The advances made in the treatment of HIV-1 infection represent a major success of modern biomedical research, prolonging healthy life and reducing virus transmission. There remain, however, many challenges relating primarily to side effects of long-term therapy and the ever-present danger of the emergence of drug resistant strains. To counter these threats, there is a continuing need for new and better drugs, ideally targeting multiple independent steps in the HIV-1 replication cycle. The most successful current drugs target the viral enzymes: protease (PR), reverse transcriptase (RT), and integrase (IN). In this review, we outline the advances made in targeting the Gag protein and its mature products, particularly capsid and nucleocapsid, and highlight possible targets for future pharmacological intervention. PMID- 25731772 TI - Targeting HIV transcription: the quest for a functional cure. AB - Antiretroviral therapy (ART) potently suppresses HIV-1 replication, but the virus persists in quiescent infected CD4(+)T cells as a latent integrated provirus, and patients must indefinitely remain on therapy. If ART is terminated, these integrated proviruses can reactivate, driving new rounds of infection. A functional cure for HIV requires eliminating low-level ongoing viral replication that persists in certain tissue sanctuaries and preventing viral reactivation. The HIV Tat protein plays an essential role in HIV transcription by recruiting the kinase activity of the P-TEFb complex to the viral mRNA's stem-bulge-loop structure, TAR, activating transcriptional elongation. Because the Tat-mediated transactivation cascade is critical for robust HIV replication, the Tat/TAR/P TEFb complex is one of the most attractive targets for drug development. Importantly, compounds that interfere with transcription could impair viral reactivation, low-level ongoing replication, and replenishment of the latent reservoir, thereby reducing the size of the latent reservoir pool. Here, we discuss the potential importance of transcriptional inhibitors in the treatment of latent HIV-1 disease and review recent findings on targeting Tat, TAR, and P TEFb individually or as part of a complex. Finally, we discuss the impact of extracellular Tat in HIV-associated neurocognitive disorders and cancers. PMID- 25731775 TI - Tripeptide-copper complex GHK-Cu (II) transiently improved healing outcome in a rat model of ACL reconstruction. AB - After anterior cruciate ligament reconstruction (ACLR), the biological healing of the graft is a rate-limiting step which can contribute to graft failure. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu) is a well known activator of tissue remodeling. We investigated whether GHK-Cu can improve graft healing following ACLR. Seventy-two rats underwent unilateral ACLR were randomized to saline, 0.3 or 3 mg/ml GHK-Cu groups (n = 24). Post-operational intra-articular injections were given from week 2, once a week, for 4 weeks. Gait analysis was performed pre-injury and at harvesting time. At 6 or 12 weeks post operation, knee specimens were harvested for knee laxity test, graft pull-out test, and histology. At 6 weeks post-ACLR, GHK-Cu groups resulted in a smaller side-to-side difference in knee laxity as compared to the saline group (p = 0.009), but there was no significant difference at 12 weeks post-operation. The graft complex in the 0.3 mg/ml GHK-Cu group had higher stiffness than saline group at 6 weeks post-operation (p = 0.026), but there was no significant difference in ultimate load, gait parameters, and histological scores among treatment groups. All grafts failed mid-substance during pull-out test. Intra articular supplementation with a bioactive small molecule GHK-Cu improved graft healing following ACLR in rat, but the beneficial effects could not last as treatment discontinued. PMID- 25731774 TI - Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor in adults, with a dismal prognosis. Treatment is hampered by GBM's unique biology, including differential cell response to therapy. Although several mitochondrial abnormalities have been identified, how mitochondrial DNA (mtDNA) mutations contribute to GBM biology and therapeutic response remains poorly described. We sought to determine the spectrum of functional complex III and IV mtDNA mutations in GBM. METHODS: The complete mitochondrial genomes of 10 GBM cell lines were obtained using next-generation sequencing and combined with another set obtained from 32 GBM tissues. Three-dimensional structural mapping and analysis of all the nonsynonymous mutations identified in complex III and IV proteins was then performed to investigate functional importance. RESULTS: Over 200 mutations were identified in the mtDNAs, including a significant proportion with very low mutational loads. Twenty-five were nonsynonymous mutations in complex III and IV, 9 of which were predicted to be functional and affect mitochondrial respiratory chain activity. Most of the functional candidates were GBM specific and not found in the general population, and 2 were present in the germ-line. Patient-specific maps reveal that 43% of tumors carry at least one functional candidate. CONCLUSIONS: We reveal that the spectrum of GBM-associated mtDNA mutations is wider than previously thought, as well as novel structural-functional links between specific mtDNA mutations, abnormal mitochondria, and the biology of GBM. These results could provide tangible new prognostic indicators as well as targets with which to guide the development of patient-specific mitochondrially mediated chemotherapeutic approaches. PMID- 25731776 TI - The Electronic Structure of Amorphous Carbon Nanodots. AB - We have studied hydrogen-passivated amorphous carbon nanostructures with semiempirical molecular orbital theory in order to provide an understanding of the factors that affect their electronic properties. Amorphous structures were first constructed using periodic calculations in a melt/quench protocol. Pure periodic amorphous carbon structures and their counterparts doped with nitrogen and/or oxygen feature large electronic band gaps. Surprisingly, descriptors such as the elemental composition and the number of sp(3)-atoms only influence the electronic structure weakly. Instead, the exact topology of the sp(2)-network in terms of effective conjugation defines the band gap. Amorphous carbon nanodots of different structures and sizes were cut out of the periodic structures. Our calculations predict the occurrence of localized electronic surface states, which give rise to interesting effects such as amphoteric reactivity and predicted optical band gaps in the near-UV/visible range. Optical and electronic gaps display a dependence on particle size similar to that of inorganic colloidal quantum dots. PMID- 25731777 TI - Meditation Interventions for Chronic Disease Populations: A Systematic Review. AB - The rapidly growing body of research regarding the use of meditation interventions in chronic disease presents an opportunity to compare outcomes based on intervention content. For this review, meditation interventions were described as those interventions delivered to persons with chronic disease where sitting meditation was the main or only content of the intervention with or without the addition of mindful movement. This systematic review identified 45 individual research studies that examined meditations effect on levels of anxiety, depression, and chronic disease symptoms in persons with chronic disease. Individual studies were assessed based on interventional content, the consistency with which interventions were applied, and the research quality. This study identified seven categories of meditation interventions based on the meditation skills and mindful movement practices that were included in the intervention. Overall, half of the interventions had clearly defined and specific meditation interventions (25/45) and half of the studies were conducted using randomized control trials (24/45). PMID- 25731778 TI - Determinants of breast reconstruction outcome: How important is volume symmetry? AB - Breast reconstruction has established psychosocial benefit compared to mastectomy alone. Evaluation of determinants of breast reconstruction outcome has previously been limited by lack of high quality, condition-specific, patient-reported outcomes measures. The BREAST-Q is such a measure and is well suited to comparison against objective measurements of reconstructed breasts such as volume and volume symmetry. A cohort of patients who had undergone breast reconstruction over a 14 year period underwent assessment of their breast reconstructions using a 3D laser scanning technique and at the same time completed the BREAST-Q patient reported outcomes measure. The objective data derived from the 3D laser scans were then compared to the quantitative data from the patient-reported outcomes measure. Internal comparisons between domains of the BREAST-Q were also examined. 119 patients completed the study. No correlation was found between objectively measured post-operative volume symmetry and patient reported satisfaction with breasts. Examination of a specific question of the BREAST-Q established that patients did notice if they had breast asymmetry but that this did not translate into dissatisfaction with the breasts overall. Patients who had second stage surgery to correct asymmetry, however, did have a statistically significant increase in satisfaction with breasts between pre and post-symmetrization measures. The strongest correlation for a high level of satisfaction with the reconstructed breast(s) was high level of satisfaction with pre-operative information given. Although symmetrization procedures are valuable for increasing satisfaction with breasts, breast volume symmetry is not a major determinant of outcome in breast reconstruction. The breast reconstruction 'process' is more important in determining patients' post-operative well-being and satisfaction with their overall outcome than the actual final 'product' of their reconstruction. PMID- 25731779 TI - The RET oncogene in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for greater than 80% of cases. Surgical resection, with or without postoperative radioiodine therapy, remains the standard of care for patients with PTC, and the prognosis is generally excellent with appropriate treatment. Despite this, significant numbers of patients will not respond to maximal surgical and medical therapy and ultimately will die from the disease. This mortality reflects an incomplete understanding of the oncogenic mechanisms that initiate, drive, and promote PTC. Nonetheless, significant insights into the pathologic subcellular events underlying PTC have been discovered over the last 2 decades, and this remains an area of significant research interest. Chromosomal rearrangements resulting in the expression of fusion proteins that involve the rearranged during transfection (RET) proto-oncogene were the first oncogenic events to be identified in PTC. Members of this fusion protein family (the RET/PTC family) appear to play an oncogenic role in approximately 20% of PTCs. Herein, the authors review the current understanding of the clinicopathologic role of RET/PTC fusion proteins in PTC development and progression and the molecular mechanisms by which RET/PTCs exert their oncogenic effects on the thyroid epithelium. PMID- 25731780 TI - Prognostic value of poorly differentiated clusters in the primary tumor in patients undergoing hepatectomy for colorectal liver metastasis. AB - BACKGROUND: This study aimed to determine the prognostic value of a novel grading system based on the histologic assessment of poorly differentiated clusters (PDCs) in the primary lesions in patients with hepatectomy for colorectal liver metastasis (CRLM). Preoperative survival predictors for CRLM are required to determine candidates for perioperative chemotherapy who would otherwise have a poor prognosis. METHODS: In total, 411 consecutive patients undergoing curative resection of primary colorectal cancers and metastatic liver lesions at 2 institutions were enrolled. Cancer clusters comprising >= 5 cancer cells, lacking a gland-like structure, were defined as PDCs and quantifiably graded. RESULTS: According to PDCs, 65, 127, and 219 patients were classified as being grades (G)1, G2, and G3, respectively. PDCs were associated with T and N stages and tumor budding in primary tumor, extrahepatic disease, and serum CEA levels (P <= .0001-.045), but not with the number and size of liver metastasis. PDC grade significantly influenced recurrence rate in extrahepatic sites, including the lung and peritoneum (P < .0001). The 2-year disease-free survival after hepatectomy was 64.6%, 38.8%, and 22.4% in G1, G2, and G3, respectively. Based on multivariate analysis, PDC grade was selected as an independent prognostic factor together with other conventional factors such as extrahepatic disease and the number of liver metastasis. CONCLUSION: PDC grade in primary lesions is a novel potent prognostic indicator in CRLM independent of the anatomic extent of disease. Notably, PDC grade can bias survival rates in clinical studies targeting perioperative chemotherapy in CRLM. PMID- 25731781 TI - Stapled versus handsewn intestinal anastomosis in emergency laparotomy: a systemic review and meta-analysis. AB - BACKGROUND: The optimal technique for gastrointestinal anastomosis remains controversial in emergency laparotomy. The aim of this meta-analysis was to compare outcomes of stapled versus handsewn anastomosis after emergency bowel resection. METHODS: A systematic review was performed for studies comparing outcomes after emergency laparotomy using stapled versus handsewn anastomosis until July 2014 (PROSPERO registry number: CRD42013006183). The primary endpoint was anastomotic failure, a composite measure of leak, abscess and fistula. Odds ratio (OR; with 95% CI) and weighted mean differences were calculated using meta analytical techniques. Subgroup analysis was conducted for trauma surgery (TS) and emergency general surgery (EGS) cohorts. Risk of bias for each study was calculated using the Newcastle-Ottawa scale for cohort studies, and Cochrane Collaboration's tool for randomized trials. RESULTS: The final analysis included 7 studies of 1,120 patients, with a total of 1,205 anastomoses. There were 5 TS studies and 2 EGS studies. There were no differences in anastomotic failure between handsewn and stapled techniques on an individual anastomosis level (OR, 1.53; 95% CI, 0.97-2.43; P = .070), or on an individual patient level (OR, 1.44; 95% CI, 0.92-2.25; P = .110). There were no differences in the individual rates of anastomotic leak, abscess, fistulae, or postoperative deaths between techniques. Subgroup analysis of EGS and TS studies demonstrated no superior operative technique. CONCLUSION: Available evidence is sparse and at high risk of bias, and neither stapling nor handsewing is justifiably favored in emergency laparotomy. Surgeons might therefore select the technique of their own choice with caution owing to unresolved uncertainty. PMID- 25731782 TI - Extending the value of the National Surgical Quality Improvement Program claims dataset to study long-term outcomes: Rate of repeat ventral hernia repair. AB - BACKGROUND: Existing large clinical registries capture short-term follow-up. Yet, there are many important long-term outcomes in surgery, such as recurrence of a ventral hernia after ventral hernia repair. The goal of the current study was to conduct an exploratory analysis to determine whether the rates, timing, and risk factors for ventral hernia re-repair in claims data linked to registry data were consistent with the known clinical literature. STUDY DESIGN: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and Medicare inpatient claims linked data set from 2005 to 2008 was queried to identify ventral hernia re-repairs after index ventral hernia repairs. Survival analysis was used to examine the ventral hernia re-repair rate over time and to quantify the relationship with clinical variables. RESULTS: Of 3,730 index ventral hernia repairs identified in ACS-NSQIP, 247 patients (6.6%) underwent re repair of a ventral hernia during the study period (2005-2008) in the Medicare claims data. ACS-NSQIP clinical variables that were associated with the ventral hernia re-repair rate in Medicare claims data 1 year after index ventral hernia repair were being a smoker (hazard ratio [HR] = 1.70, P = .02), body mass index (HR = 1.16, P = .04), and postoperative superficial surgical-site infection (HR = 2.88, P < .001). CONCLUSION: Long-term rate and timing of ventral hernia re repair obtained from claims data were an underestimate compared with clinical studies. Yet, several known clinical risk factors for recurrence in the clinical registry were associated with the re-repair rate in claims data at one year. It may be possible to study certain long-term outcomes using selected reoperation rates using the technique of linked clinical registry-claims data, with an understanding that event rates are conservative estimates. PMID- 25731783 TI - Predictors of surgical complications: A systematic review. AB - BACKGROUND: Operative complications occur more frequently, often are more preventable, and their consequences can be more severe than other types of complications. Controversy exists regarding how best to identify and predict operative complications. Several studies on predictive factors for operative complications focused on a specific predictor for a specific outcome. To develop a reliable tool to identify patients with operative complications, insight in predictive factors for operative complications is required. PATIENTS AND METHODS: We searched all publications addressing predictive factors for the development of operative complications in adult patients admitted to the gastrointestinal, vascular, or general surgery departments. Data were extracted regarding study design, patient characteristics, operative specialty, types of operative procedures, types of complications, possible predictors, and associated complication risk increase (expressed as an odds ratio; OR). RESULTS: The final set of 30 articles yielded a total of 53 predictive factors studied in various settings, operative specialties, and disorders. To focus our analysis we selected the 25 most robust and clinically applicable factors (ie, appearing in 3 or more studies). These factors were then categorized into 4 different groups: Patient related factors, Co-morbidities, Laboratory values, and Surgery-related factors. The most predictive factors for morbidity in these groups were body mass index (ORs from 1.80 to 6.30), age (1.02-4.62 years), American Society of Anesthesiologists classification (1.77-7.10), dyspnea (1.23-1.30), serum creatinine (1.39-2.14), emergency surgery (1.50-2.54), and functional status (1.36-4.07). CONCLUSION: This review presents a set of factors predictive of operative complications for general surgery departments. These easily retrievable factors can and should be validated in the specific patient populations of each hospital. PMID- 25731785 TI - Reducing recurrence in non-muscle-invasive bladder cancer using photodynamic diagnosis and immediate post-transurethral resection of the bladder chemoprophylaxis. AB - OBJECTIVE: The aim of this study was to evaluate the effect of fluorescence cystoscopy and immediate post-transurethral resection of the bladder (TURB) chemoprophylaxis on the risk of recurrence of non-muscle-invasive bladder cancer (NMIBC) under routine clinical conditions. MATERIALS AND METHODS: Fluorescence cystoscopy using hexyl-aminolevulinate and post-TURB chemoprophylaxis using mitomycin C were simultaneously introduced in an effort to reduce the recurrence of NMIBC. In total, 190 consecutive patients were enrolled over a 2 year period and followed as the intervention group; 216 patients treated over a 2 year period before introduction served as controls. An intention-to-treat analysis was performed with baseline control. RESULTS: The recurrence risk was reduced by 41% (hazard ratio 0.59, 95% confidence interval 0.45-0.78) (intention-to-treat analysis). Median recurrence-free survival was extended from 13.6 months to 36.8 months. Every third follow-up TURB was avoided. Patients with low-risk tumors and patients with primary as well as recurrent disease benefited from the treatment. CONCLUSIONS: Fluorescence cystoscopy and immediate post-TURB chemoprophylaxis effectively reduced the recurrence risk and numbers of follow-up procedures under clinical routine conditions. PMID- 25731786 TI - Sinonasal outcomes following endoscopic anterior skull base surgery with nasoseptal flap reconstruction: a prospective study. AB - OBJECTIVE: To assess nasal morbidity resulting from nasoseptal flap use in the repair of skull base defects in endoscopic anterior skull base surgery. METHODS: Thirty-six patients awaiting endoscopic anterior skull base surgery were prospectively recruited. A nasoseptal flap was used for reconstruction in all cases. Patients were assessed pre-operatively and 90 days post-operatively via the Sino-Nasal Outcome Test 20 questionnaire and visual analogue scales for nasal obstruction, pain, secretions and smell; endoscopic examination findings and mucociliary clearance times were also recorded. RESULTS: Sino-Nasal Outcome Test 20 questionnaire data and visual analogue scale scores for pain, smell and secretions showed no significant differences between pre- and post-operative outcomes, with visual analogue scale scores for nasal obstruction actually showing a significant improvement (p = 0.0007). A significant deterioration for both flap and non-flap sides was demonstrated post-operatively on endoscopic examination (p = 0.002 and p = 0.02 respectively). CONCLUSION: Whilst elevation of a nasoseptal flap in endoscopic surgery of the anterior skull base engendered significant clinical deterioration on examination post-operatively, quality of life outcomes showed that no such deterioration was subjectively experienced by the patient. In fact, there was significant nasal airway improvement following nasoseptal flap reconstruction. PMID- 25731784 TI - Oncolytic adenovirus expressing interferon alpha in a syngeneic Syrian hamster model for the treatment of pancreatic cancer. AB - BACKGROUND: The addition of interferon (IFN) alpha to adjuvant chemoradiotherapy regimens resulted in remarkable improvements in survival for pancreatic cancer patients. However, systemic toxicities and insufficient levels of IFN at the tumor sites have limited its widespread adoption in treatment schemes. We have previously developed an IFN-expressing conditionally replicative oncolytic adenovirus and demonstrated its therapeutic effects both in vitro and in vivo. Here, the same vectors were tested in a syngeneic and immunocompetent Syrian hamster model to better understand the roles of adenoviral replication and of the pleiotropic effects of IFN on pancreatic tumor growth suppression. METHODS: Oncolytic adenoviruses expressing human or hamster IFN were designed and generated. Viral vectors were tested in vitro to determine qualitative and quantitative cell viability, cyclooxygenase 2 (Cox2) promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with 1 intratumoral dose of virus. Similarly, 1 intraperitoneal dose of virus was used to prolong survival in a carcinomatosis model. RESULTS: All cell lines tested demonstrated Cox2 promoter activity. The oncolytic potential of a replication competent adenovirus expressing the IFN cytokine was clearly demonstrated. These viruses resulted in significant tumor growth suppression and survival increases compared with controls in a hamster model. CONCLUSION: The profound therapeutic potential of an IFN-expressing oncolytic adenovirus for the treatment of pancreatic cancer was demonstrated in a syngeneic Syrian hamster model. These results strongly suggest the potential application of our viruses as part of combination regimens with other therapeutics. PMID- 25731787 TI - Media and public reactions toward vaccination during the 'hepatitis B vaccine crisis' in China. AB - BACKGROUND: Public disputations affected vaccine confidence and vaccine rates particularly when adverse events occur. The vigorous development of Internet in China provides an opportunity to observe public reaction and sentiment toward vaccination when Kangtai Hepatitis B vaccine crisis happened and evolved to a widespread debate on the internet from December 12, 2013 to January 3, 2014. METHODS: This study conducted Internet surveillance by examining three daily indicators including the daily number of relevant online news article, Sina Weibo posts and Baidu search index during the crisis. We also analyzed the sentiments of relevant original microblog posts collected from Sina Weibo platform in the crisis. RESULTS: A total of 17 infant deaths were reported to associated with Hepatitis B vaccination. Three major waves of high media and public attention were detected. The daily indicators reached their peaks in the second wave after the relevant vaccine was suspended by the authority (from December 20 to December 29, 2013) with 23,200 daily online news reports, 34,018 Sina Weibo posts and 17,832 Baidu search indices. There were significant correlations between the daily amount of online news, Weibo posts, and Baidu searches (p<.001). The contents analysis suggested 1343 out of 1608 (83.5%) original Weibo posts expressed negative sentiment with almost 90% in the second wave. CONCLUSION: This study found the Kangtai vaccine crisis raised great public attention and negative sentiment toward vaccinations on the internet in China. Policy change such as suspension of the suspected vaccine might trigger even greater reaction and more negative sentiment. The government should provide ways to address emerging public concerns after policy change to avoid misinformation and misunderstanding during such a vaccine crisis. PMID- 25731788 TI - Acceptability of using standing orders to deliver human papillomavirus vaccines in the outpatient obstetrician/gynecologist setting. AB - OBJECTIVE: Standing orders, an effective method for increasing vaccination, are not widely used for HPV vaccine. This is especially so among obstetrician/gynecologists (Ob/Gyns) - the specialty many women use as their primary care provider. We sought to understand the acceptability of using standing orders for HPV vaccination among a sample of women attending outpatient Ob/Gyn clinics. STUDY DESIGN: From February to April 2014, an on-line survey was administered to a convenience sample of 400 women aged 15-26 recruited from 9 Ob/Gyn practices in Colorado. The survey identified attitudes about standing orders for HPV vaccination, demographics and prior experience with HPV vaccines. RESULTS: The response rate was 44%. Receipt of prior HPV vaccine doses was reported by 67% of respondents. Approximately half (53%) were comfortable with the idea of standing orders for HPV vaccination at Ob/Gyn clinics among women generally, but only 40% of the 154 women not initially opposed to HPV vaccination indicated they would personally feel comfortable receiving HPV vaccines offered under a standing order policy. General and personal acceptance of standing orders for HPV vaccination was significantly higher among women who reported receiving HPV vaccine doses previously, but not by any demographic or experiential variables. Acceptability of standing orders for HPV vaccines was higher for series completion than initiation (88% vs. 70%, p<0.001) and was more commonly supported for adult patients (79%) than for adolescents (43%). Acceptability of standing orders increased if the patient was first told that the provider 'strongly recommended the vaccine', even for a majority (52%) of those who generally were not comfortable receiving the vaccine using standing orders. CONCLUSIONS: Because standing orders for HPV vaccine are generally acceptable to women attending Ob/Gyn clinics, to increase vaccination uptake among adults Ob/Gyn providers may want to consider adoption of standing orders for HPV vaccine, at least for series completion. PMID- 25731789 TI - Human papillomavirus vaccine uptake in boys and girls in a school-based vaccine delivery program in Prince Edward Island, Canada. AB - BACKGROUND: In 2013, Prince Edward Island was the first province to introduce HPV vaccine universally to grade six boys in a school-based program. Because uptake rates in boys are unknown in this type of vaccination program, uptake of HPV vaccination in boys was measured and compared with uptake rates in girls and then analyzed with factors such as county, urban-rural location of the school, and school board to identify where the vaccine program could be improved. METHODS: HPV vaccination records from the provincial childhood immunization registry in PEI were merged with Department of Education data containing all grade six girls and boys in PEI. Vaccine uptakes between years and between sexes were compared using two sample tests of proportions. Logistic regression modeling which accounted for the hierarchical nature of the data was used to analyze associations between factors and uptake rates. RESULTS: Although uptake was high in boys and girls, a significantly greater proportion of girls (85%) received all three doses of the HPV vaccine compared to boys (79%; p=0.004). The odds of grade six girls being fully vaccinated for HPV were 1.5 times greater than of grade six boys, and the odds of students in the English Language School Board receiving all three doses were more than twice as great as the odds of French Language School Board students. CONCLUSIONS: HPV vaccination for boys in PEI has had a successful launch, almost reaching the Canadian Immunization Committee recommendations of >80% for the early years of a program. PEI has a highly organized Public Health Nursing program that is involved in all childhood and school-based vaccinations in PEI and in this context very high coverage rates were obtained. Areas to target for improving uptake include the boys and the students in the French Language School Board. PMID- 25731790 TI - Rubella susceptibility in pregnant women and results of a postpartum immunization strategy in Catalonia, Spain. AB - BACKGROUND: Elimination of congenital rubella syndrome depends not only on effective childhood immunization but also on the identification and immunization of rubella susceptible women. We assessed rubella susceptibility among pregnant women and evaluated the adherence and response to postpartum immunization with measles, mumps and rubella (MMR) vaccine. METHODS: Cross-sectional study of women who gave birth at the Hospital Clinic de Barcelona (Spain) between January 2008 and December 2013. Antenatal serological screening for rubella was performed in all women during pregnancy. In rubella-susceptible women, two doses of MMR vaccine were recommended following birth. We evaluated rubella serological response to MMR vaccination in mothers who complied with the recommendations. RESULTS: A total of 22,681 pregnant women were included in the study. The mean age was 32.3 years (SD 5.6), and 73.6% were primipara. The proportion of immigrants ranged from 43.4% in 2010 to 38.5% in 2012. The proportion of women susceptible to rubella was 5.9% (1328). Susceptibility to rubella declined with increasing maternal age. Immigrant pregnant women were more susceptible to rubella (7.6%) than women born in Spain (4.6%). Multivariate analyses showed that younger age (<=19 years) aOR 1.7 (95% CI 1.1-2.5), primiparas aOR 1.3 (95% CI 1.1 1.5) and immigrant women aOR 1.6 (95% CI 1.4-1.8) were more likely to be susceptible. The second dose of MMR vaccine was received by 57.2% (718/1256) of rubella-susceptible women, with the highest proportion being immigrant women compared with women born in Spain. After vaccination, all women showed rubella immunity. CONCLUSIONS: The higher rubella susceptibility found in the three youngest age groups and in immigrant women highlights the relevance of antenatal screening, in order to ensure identification and postpartum immunization. The postpartum immunization strategy is an opportunity to protect women of childbearing age and consequently prevent occurrence of CRS, and to increase vaccination coverage against rubella and other vaccine-preventable diseases. PMID- 25731793 TI - Surgical Treatment of Spinal Dural Arteriovenous Fistula: Management and Long Term Outcome in a Single-Center Series. AB - OBJECTIVE: To perform a retrospective chart review of surgically treated patients with spinal dural arteriovenous fistula (SDAVF), a rare disease but the most common vascular malformation of the spine, focusing on clinical characteristics and functional outcome during long-term follow-up. METHODS: Between June 1990 and April 2012, 29 patients with SDAVFs were treated surgically in a single institution. Patient characteristics, time from onset of symptoms to treatment, radiologic features, treatment-related complications, and functional outcome were analyzed. Outcome was assessed according to the Aminoff-Logue scale during follow up. Results of magnetic resonance imaging scans performed during long-term follow up were correlated with functional outcome. RESULTS: There were 3 female (10%) and 26 male (90%) patients with SDAVFs treated surgically. Mean age was 61 years +/- 11. Location of the fistula was at the thoracic level in 20 patients (69%), at the lumbar level in 8 patients (28%), and at the sacral level in 1 patient (3%). Mean postoperative Aminoff-Logue scale scores regarding gait and micturition improved after treatment compared with preoperatively (P = 0.02; P = 0.03). After surgical treatment, 22 patients (76%) achieved improvement in neurologic symptoms. In 6 patients (21%), neurologic status was the same as preoperatively. In 1 patient (3%), neurologic status worsened. Medullary signal alteration of diagnostic magnetic resonance imaging scans did not correlate with functional outcome (P = 0.2). Mean follow-up time was 63 months +/- 55. All SDAVFs were treated in a single session without recurrence during the long-term follow-up period. CONCLUSIONS: Surgical treatment of SDAVFs is safe and effective and leads to an improvement of neurologic symptoms in most patients. Surgical treatment of SDAVFs also provides long-term stability. PMID- 25731792 TI - Transition From Microscopic to Endoscopic Transsphenoidal Surgery for Nonfunctional Pituitary Adenomas. AB - OBJECTIVE: At our institution, a total of 320 patients were operated on between 2000 and 2010 for a newly diagnosed pituitary adenoma. In an attempt to improve quality of tumor resection, the transsphenoidal microscopic technique was replaced by the endoscopic technique in June 2008. This retrospective single center study compares the outcomes after microscopic (n = 144) and endoscopic (n = 41) tumor surgery of all patients operated on for a nonfunctional pituitary adenoma. METHODS: Tumor size and location, Knosp grade, prevalence of anterior hypopituitarism, diabetes insipidus, visual acuity/fields, complication rates, and operation time were compared between the groups. RESULTS: At the 3-month follow-up, hypopituitarism had improved in 7% of patients in the microscopic group and in 9% in the endoscopic group, and had further impaired in 13% and 9%, respectively. At the 3-month follow-up magnetic resonance imaging, a total tumor removal was achieved in 45% versus 56% of patients, respectively (P = not significant [NS]). Visual fields had normalized or improved in 90% versus 88% of patients, respectively (P = NS). Postoperative cerebrospinal fluid leak occurred in 3.5% versus 2.4% (P = NS), and diabetes insipidus (transient or permanent) in 7.6% versus 4.9% (P = NS) of cases, respectively. Larger tumor size (P < 0.0005) and endoscopic technique (P = 0.03) were independent predictors of increased mean operative time. CONCLUSIONS: Initial results with the endoscopic technique were statistically similar to those achieved with the microscopic technique. However, there was a trend toward improved outcomes and fewer complications in the endoscopic group. PMID- 25731794 TI - Acute Traumatic Brain Injury: Mortality in the Elderly. AB - OBJECTIVE: Despite recent progress, prognosis for the elderly (defined as aged >=70 years) afflicted by traumatic brain injury (TBI) is unfavorable and surgical intervention remains controversial. Research during the past decade on the mortality rates or prognostic factors for survival in the elderly is limited. METHODS: We analyzed 97 patients aged >=70 years who were treated surgically for closed TBI at our neurosurgical unit between January 1, 2003 and December 31, 2012. In addition, we analyzed 22 patients aged >=70 years who had sustained a closed TBI and on whom no neurosurgical intervention was performed. Outcome in both groups was measured as 30-, 90- and 180-day mortality. RESULTS: Surgically treated patients: median age, 76 years' 30-day overall mortality rate, 36%. Higher mortality was seen with lower level of consciousness, high energy trauma, one pupil fixed and dilated, and more extensive intracranial pathology. Presence of warfarin, more advanced age, or degree of midline shift were not associated with worsened outcome. Patients not treated neurosurgically: median age. 81.5 years; 30-day overall mortality rate, 23%. Mortality for patients with Glasgow coma scale (GCS) 10-15 was 6%, GCS 6-9 67%, and GCS 3-5 100%. CONCLUSIONS: Selected patients aged >=70 years can benefit from surgical intervention for closed TBI. Level of consciousness, radiologic type of injury, mechanism of injury, and pupil abnormalities should be carefully evaluated. There also seems to exist a group of patients in whom surgical intervention offers little benefit, as mortality rate is low without surgical intervention. PMID- 25731796 TI - Sellar Floor Reconstruction with the Medpor Implant Versus Autologous Bone After Transnasal Transsphenoidal Surgery: Outcome in 200 Consecutive Patients. AB - OBJECTIVE: The Medpor porous polyethylene implant provides benefits to perform sellar floor reconstruction when indicated. This material has been used for cranioplasty and reconstruction of skull base defects and facial fractures. We present the most extensive use of this implant for sellar floor reconstruction and document the safety and benefits provided by this unique implant. METHODS: The medical charts for 200 consecutive patients undergoing endonasal transsphenoidal surgery from April 2008 through December 2011 were reviewed. Material used for sellar floor reconstruction, pathologic diagnosis, immediate inpatient complications, and long-term complications were documented and analyzed. Outpatient follow-up was documented for a minimum of 1-year duration, extending in some patients up to 5 years. RESULTS: Of the 200 consecutive patients, 136 received sellar floor cranioplasty using the Medpor implant. Postoperative complications included 6 complaints of sinus irritation or drainage, 1 postoperative cerebrospinal fluid leak requiring operative re exploration, 1 event of tension pneumocephalus requiring operative decompression, 1 case of aseptic meningitis, 1 subdural hematoma, and 1 case of epistaxis. The incidence of these complications did not differ from the autologous nasal bone group in a statistically significant manner. CONCLUSIONS: Sellar floor reconstruction remains an important part of transsphenoidal surgery to prevent postoperative complications. Various autologous and synthetic options are available to reconstruct the sellar floor, and the Medpor implant is a safe and effective option. The complication rate after surgery is equivalent to or less frequent than other methods of reconstruction and the implant is readily incorporated into host tissue after implantation, minimizing infectious risk. PMID- 25731795 TI - Evaluation of Effect of Weekend Admission on the Prevalence of Hospital-Acquired Conditions in Patients Receiving Cervical Fusions. AB - BACKGROUND: Hospital-acquired conditions (HACs) are defined by the Centers for Medicaid and Medicare Services (CMS) as preventable adverse events that do not qualify for reimbursement of resulting hospital costs. HACs have been employed as a metric for quality of patient care. Patients undergoing cervical spine fusions are at risk for occurrence of HACs because of limited mobility and potential extended hospital length of stay (LOS). Previous studies have not evaluated the contribution of weekend admission on the rate of HACs in this patient population. We abstracted data from the Nationwide Inpatient Sample to evaluate rate of HACs as a function of weekend admission among patients admitted for cervical fusions. METHODS: Patients undergoing anterior and posterior cervical fusions were identified from the 2002-2010 Nationwide Inpatient Sample database. HACs as defined by the CMS were collected via International Classification of Diseases, Ninth Revision, Clinical Modification codes. Multivariate analysis, including adjustment for demographics, disease severity, admission acuity, and admission source, was used to evaluate the effect of weekend admission on HAC occurrence, prolonged LOS, and higher inpatient costs. RESULTS: During the period 2002-2010, 1,404,181 admissions for cervical fusion were identified. HACs occurred at a frequency of 4.6%. After multivariate adjustment for demographics, disease severity, and urgency of admission, weekend admissions were associated with a 56% increased risk of HAC occurrence compared with weekday admissions (relative risk = 1.56, 95% confidence interval = 1.51, 1.62, P < 0.01). HAC occurrence was independently associated with prolonged LOS and higher inpatient costs (P < 0.05). CONCLUSIONS: Patients undergoing cervical fusions who are admitted on weekends have an increased rate of HACs. HACs were associated with increases in LOS and hospital costs. Further study is warranted to evaluate disparities and potential improvement among weekend admissions. PMID- 25731797 TI - Microsurgical Treatment of Previously Coiled Intracranial Aneurysms: Systematic Review of the Literature. AB - OBJECTIVE: To assess indications, complications, clinical outcomes, and technical nuances of microsurgical treatment of previously coiled intracranial aneurysms. METHODS: A systematic review of the literature was performed using PubMed/MEDLINE and EMBASE databases from January 1990 to December 2013. English-language articles reporting on microsurgical treatment of previously coiled intracranial aneurysms were included. Articles that involved embolization materials other than coils were excluded. Data on aneurysm characteristics, indications for surgery, techniques, complications, angiographic obliteration rates, and clinical outcomes were collected. RESULTS: The literature review identified 29 articles reporting on microsurgical clipping of 375 previously coiled aneurysms. Of the aneurysms, 68% were small (<10 mm). Indications for clipping included the presence of a neck remnant (48%) and new aneurysmal growth (45%). Rebleeding before clipping was reported in 6% of cases. Coil extraction was performed in 13% of cases. The median time from initial coiling to clipping was 7 months. The angiographic cure rate was 93%, with morbidity and mortality of 9.8% and 3.6%, respectively. CONCLUSIONS: Microsurgical clipping of previously coiled aneurysms can result in high obliteration rates with relatively low morbidity and mortality in select cases. Considerations for microsurgical strategies include the presence of sufficient aneurysmal tissue for clip placement and the potential need for temporary occlusion or flow arrest. Coil extraction is not needed in most cases. PMID- 25731798 TI - Computational Fluid Dynamics and Intracranial Aneurysms: Higher Mathematics Meets Complex Biology. PMID- 25731799 TI - The Role of Radiation Therapy in Gross Totally Resected Meningiomas. PMID- 25731800 TI - Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. AB - This study examined outcomes beyond 1 year in eculizumab-treated (EC) positive crossmatch kidney transplants (+XMKTx) compared to a historical control group. +XMKTx received desensitization with either plasma exchange (PE) alone (N = 48) or PE and EC (N = 30). EC, given for at least 1 month, was continued in the setting of persistently high DSA (B flow cytometric crossmatch [BFXM] >200) including: 4 weeks (n = 14); 9 weeks (n = 6), 6 months (n = 2), and 12 months (n = 8). All patients had at least 2 years follow-up. The incidence of acute clinical ABMR was lower in the EC group than controls (6.7% vs. 43.8% p < 0.01). Death-censored allograft survival was similar between groups. Chronic ABMR was the main cause of graft loss. On 1-year protocol biopsies, no differences were noted between EC and controls including: cg score >0, 26.7% versus 31.9% (p = 0.62), ptc score >= 2, 60.0% versus 60.0% (p = 1.00), or C4d + , 33.8% versus 13.5% (p = 0.08). A persistently high BFXM in EC-treated patients was associated with cg score >0 at 1 year, while EC appeared to protect against cg if the BFXM remained low. We conclude that despite decreasing acute clinical ABMR rates, EC treatment does not prevent chronic ABMR in recipients with persistently high BFXM after +XMKTx. PMID- 25731801 TI - Dopamine: an old target in a new therapy. AB - Dopamine, a molecule of joy and emotions, plays vital role in regulation cancer growth and tumor angiogenesis. Dopamine secrets from neural cells in brain and peripheral cells as well. Peripheral dopamine is associated with tumorigenic events. Recent publication [Sarkar et al. Int. J. Cancer: doi: 10.1002/ijc.29414 , 2014] suggests that dopamine can be an ideal substitute as an anti-vascular endothelial growth factor A (VEGF-A) agent for the treatment tumor angiogenesis as dopamine is less expensive, minimum side-effect and more sensitive than other drugs. The studies also found that dopamine prevent the 5FU-induced neutropenia in tumor-bearing mice. Collectively, these pre-clinical studies claim that dopamine could be a novel therapy for managing cancer growth and chemotherapy related disorder. PMID- 25731802 TI - An effective biphase system accelerates hesperidinase-catalyzed conversion of rutin to isoquercitrin. AB - Isoquercitrin is a rare, natural ingredient with several biological activities that is a key precursor for the synthesis of enzymatically modified isoquercitrin (EMIQ). The enzymatic production of isoquercitrin from rutin catalyzed by hesperidinase is feasible; however, the bioprocess is hindered by low substrate concentration and a long reaction time. Thus, a novel biphase system consisting of [Bmim][BF4]:glycine-sodium hydroxide (pH 9) (10:90, v/v) and glyceryl triacetate (1:1, v/v) was initially established for isoquercitrin production. The biotransformation product was identified using liquid chromatography-mass spectrometry, and the bonding mechanism of the enzyme and substrate was inferred using circular dichroism spectra and kinetic parameters. The highest rutin conversion of 99.5% and isoquercitrin yield of 93.9% were obtained after 3 h. The reaction route is environmentally benign and mild, and the biphase system could be reused. The substrate concentration was increased 2.6-fold, the reaction time was reduced to three tenths the original time. The three-dimensional structure of hesperidinase was changed in the biphase system, which alpha-helix and random content were reduced and beta-sheet content was increased. Thus, the developed biphase system can effectively strengthen the hesperidinase-catalyzed synthesis of isoquercitrin with high yield. PMID- 25731803 TI - 4DCT Simulation With Synchronized Contrast Injection in Liver SBRT Patients. AB - BACKGROUND/PURPOSE: Delivering stereotactic body radiotherapy for liver metastases remains a challenge because of respiratory motion and poor visibility without intravenous contrast. The purpose of this article is to describe a novel and simple computed tomography (CT) simulation process of integrating timed intravenous contrast that could overcome the uncertainty of target delineation. METHODS AND RESULTS: The simulation involves two 4-dimensional CT (4DCT) scans. The first scan only encompasses the immediate region of the tumor and surrounding tissue, which reduces the 4DCT scan time so that it can be optimally timed with intravenous contrast injection. The second 4DCT scan covers a larger volume and is used as the primary CT data set for dose calculation, as well as patient setup verification on the treatment unit. The combination of the two 4DCT scans allows us to optimally visualize liver metastases over all phases of the breathing cycle while simultaneously acquiring a long enough 4DCT data set that is suitable for planning and patient setup verification. CONCLUSION: This simulation technique allows for a better target definition when treating liver metastases, without being invasive. PMID- 25731804 TI - Decision Trees Predicting Tumor Shrinkage for Head and Neck Cancer: Implications for Adaptive Radiotherapy. AB - OBJECTIVE: To develop decision trees predicting for tumor volume reduction in patients with head and neck (H&N) cancer using pretreatment clinical and pathological parameters. METHODS: Forty-eight patients treated with definitive concurrent chemoradiotherapy for squamous cell carcinoma of the nasopharynx, oropharynx, oral cavity, or hypopharynx were retrospectively analyzed. These patients were rescanned at a median dose of 37.8 Gy and replanned to account for anatomical changes. The percentages of gross tumor volume (GTV) change from initial to rescan computed tomography (CT; %GTVDelta) were calculated. Two decision trees were generated to correlate %GTVDelta in primary and nodal volumes with 14 characteristics including age, gender, Karnofsky performance status (KPS), site, human papilloma virus (HPV) status, tumor grade, primary tumor growth pattern (endophytic/exophytic), tumor/nodal/group stages, chemotherapy regimen, and primary, nodal, and total GTV volumes in the initial CT scan. The C4.5 Decision Tree induction algorithm was implemented. RESULTS: The median %GTVDelta for primary, nodal, and total GTVs was 26.8%, 43.0%, and 31.2%, respectively. Type of chemotherapy, age, primary tumor growth pattern, site, KPS, and HPV status were the most predictive parameters for primary %GTVDelta decision tree, whereas for nodal %GTVDelta, KPS, site, age, primary tumor growth pattern, initial primary GTV, and total GTV volumes were predictive. Both decision trees had an accuracy of 88%. CONCLUSIONS: There can be significant changes in primary and nodal tumor volumes during the course of H&N chemoradiotherapy. Considering the proposed decision trees, radiation oncologists can select patients predicted to have high %GTVDelta, who would theoretically gain the most benefit from adaptive radiotherapy, in order to better use limited clinical resources. PMID- 25731805 TI - Flow enhancement of water-based nanoparticle dispersion through microscale sedimentary rocks. AB - Understanding and controlling fluids flow at the microscale is a matter of growing scientific and technological interest. Flow enhancements of water-based nanoparticle dispersions through microscale porous media are investigated through twelve hydrophilic sedimentary rocks with pore-throat radius between 1.2 and 10 MUm, which are quantitatively explained with a simple model with slip length correction for Darcy flow. Both as wetting phase, water exhibited no-slip Darcy flow in all cores; however, flow enhancement of nanoparticle dispersions can be up to 5.7 times larger than that of water, and it increases with the decreasing of pore-throat radius. The experimental data reveals characteristic slip lengths are of order 500 and 1000 nm for 3M(r) and HNPs-1 nanoparticles, respectively, independent of the lithology or nanoparticle concentration or shear rate. Meanwhile, the phenomenon of flow degradation is observed for HNPs-2 nanoparticles. These results explore the feasible application of using nanoparticle dispersions to control flow at the microscale. PMID- 25731806 TI - A partnership development process assessment scale for public health nurses in Japan. AB - OBJECTIVE: The objective of this study was to develop and test a Partnership Development Process Assessment (PDPA) scale for content and construct validity and internal consistency reliability. This is needed to document and evaluate community health partnership development processes between public health nurses and community-based organizations in Japan. DESIGN: The study was conducted in three phases. Ten semi-structured interviews were conducted to generate items for a new scale. Thirty items were generated and reviewed by an expert panel for content validity and item refinement. A national postal survey of public health nurses was conducted to determine the scale's internal structure, evaluate its reliability, and explore its construct and criterion validity. MEASURES: Validity and reliability testing of the PDPA scale using a content validity index and analysis of correlations with an existing scale were performed. RESULTS: Twenty six items were selected and grouped into four factors: activities to share roles to manage community health issues, platform activities to support partnerships, activities to evaluate partnership practices, and activities to share information regarding community health issues. After factor analysis, 23 items were retained. CONCLUSION: The PDPA scale is a valid and reliable instrument for public health nurses to assess partnership development activities. PMID- 25731807 TI - Dietary patterns and risk of hip fractures in postmenopausal women and men over 50 years. AB - We followed 74,540 postmenopausal women and 35,451 men above age 50 for up to 30 years. Neither the prudent pattern, characterized by higher intakes of whole grains, fruits, and vegetables, nor the Western pattern, characterized by higher intakes of red/processed meats, and refined grains were associated with hip fracture risk. INTRODUCTION: We examined the association between predominant dietary patterns and risk of hip fractures in postmenopausal women and men over 50 years. METHODS: We used data from 74,540 women in the Nurses' Health Study followed between 1980 and 2010, and 35,451 men from the Health Professionals Follow-up Study followed between 1986 and 2012 for this analysis. Health and lifestyle information was assessed every 2 years. Diet was assessed approximately every 4 years with a food frequency questionnaire. Two major dietary patterns were previously derived using principal component analysis. The prudent pattern is characterized by higher intakes of fruits, vegetables, whole grains, and poultry, and the Western pattern is characterized by higher intakes of red and processed meats, sweets, and refined grains. We computed relative risks (RR) for hip fracture by dietary pattern scores using Cox proportional hazards models, adjusting for potential confounders. RESULTS: During follow-up, there were 1891 hip fractures in women and 596 in men. No association was observed between the prudent or Western pattern and risk of hip fractures in either men or women. We also did not find an association among lean (body mass index (BMI) <25) or overweight (BMI >=25) individuals or among those with higher or lower levels of physical activity. CONCLUSION: Neither the prudent nor the Western dietary pattern was associated with risk of hip fractures in postmenopausal women or men over 50 years of age. PMID- 25731809 TI - Consecutive Mechanism in the Diffusion of D2O on a NaCl(100) Bilayer. AB - The motion of D2O monomers is investigated on a NaCl(100) bilayer on Ag(111) between 42.3 and 52.3 K by scanning tunneling microscopy. The diffusion distance histogram reveals a squared diffusion lattice that agrees with the primitive unit cell of the (100) surface. From the Arrhenius dependence, we derive the diffusion energy, the pre-exponential factor, and the attempt frequency. The mechanism of the motion is identified by comparison of the experimental results to theoretical calculations. Via low temperature adsorption site determination in connection with density functional theory, we reveal an influence of the metallic support onto the intermediate state of the diffusive motion. PMID- 25731808 TI - Serum uric acid is associated with quantitative ultrasound parameters in men: data from the Camargo cohort. AB - This study analyzes the association between serum uric acid levels and heel quantitative ultrasound (QUS) parameters in men aged 50 or more from the Camargo cohort. We found that higher serum uric acid levels are positively associated with all QUS measurements, suggesting a better bone quality in men with elevated serum uric acid values. INTRODUCTION: Higher serum uric acid concentrations have been associated with higher bone mineral density and lower prevalence of fractures. However, there are no studies that have assessed the bone quality properties in Caucasians. Therefore, we have analyzed the association between quantitative ultrasound (QUS) and serum uric acid levels in adult men from a population-based cohort. METHODS: A total of 868 men older than 50 were recruited from a larger cohort (Camargo Cohort) after excluding those with any known condition or drug treatment with a possible influence on bone metabolism, or those with a previous diagnosis of gout or taking hipouricemic agents. Bone turnover markers (PINP and CTX), 25OH-vitamin D and PTH levels were measured by electrochemiluminiscence. BMD was determined by DXA, and heel QUS with a gel coupled device. RESULTS: Lumbar, femoral neck and total hip BMD was significantly higher in men with higher serum uric acid levels. QUS parameters were also significantly higher in men with high uric acid levels than those with lower values, and increased continuously across quartiles after adjustment for confounding variables. In multiple regression analysis, serum uric acid was significantly associated with all QUS parameters. Finally, men with serum acid levels above median showed higher values in all the QUS parameters than men with lower values. CONCLUSIONS: Higher serum uric acid levels in men older than 50 years are positively associated with QUS parameters. These data might suggest a better bone quality in men with elevated serum uric acid values. PMID- 25731810 TI - On the capability of in-situ exposure in an environmental scanning electron microscope for investigating the atmospheric corrosion of magnesium. AB - The feasibility of environmental scanning electron microscope (ESEM) in studying the atmospheric corrosion behavior of 99.97% Mg was investigated. For reference, ex-situ exposure was performed. A model system was designed by spraying few salt particles on the metal surface and further promoting the corrosion process using platinum (Pt) deposition in the form of 1*1*1 um(3) dots around the salt particles to create strong artificial cathodic sites. The results showed that the electron beam play a significant role in the corrosion process of scanned regions. This was attributed to the irradiation damage occurring on the metal surface during the ESEM in-situ experiment. After achieving to a reliable process route, in a successful attempt, the morphology and composition of the corrosion products formed in-situ in the ESEM were in agreement with those of the sample exposed ex-situ. PMID- 25731811 TI - Effects of single and double bonds in linkers on colorimetric and fluorescent sensing properties of polyving akohol grafting rhodamine hydrazides. AB - Two rhodamine derivatives, N-mono-maleic acid amide-N'-rhodamine B hydrazide (MRBH) and N-mono-succinic acid amide-N'-rhodamine 6G hydrazide (SR6GH), were synthesized by amidation with maleic anhydride (MAH), succinic anhydride (SAH) and rhodamine B hydrazide, rhodamine 6G hydrazide, which were identified by FTIR, (1)H NMR and elemental analysis. Two water-soluble fluorescent materials (PVA MRBH and PVA-SR6GH) were prepared via esterification reaction with N-mono-maleic acyl chloride amide-N'-rhodamine B hydrazide (MRBHCl) or N-mono-maleic acyl chloride amide-N'-rhodamine 6G hydrazide (SR6GHCl) and poly(vinyl alcohol) (PVA) in DMSO solution. The sensing behaviors of PVA-MRBH and PVA-SR6GH were explored by recording the fluorescence spectra in completely aqueous solution. Upon the addition of Cu(2+) and Fe(3+) ions to the aqueous solution of PVA-MRBH, visual color change from rose pink to amaranth and orange for Cu(2+) and Fe(3+) ions, respectively, and fluorescence quenching were observed. Titration of Cu(2+), Fe(3+), Cr(3+) or Hg(2+) into the aqueous solution of PVA-SR6GH, although they induced fluorescence enhancement, only Fe(3+) made the color changing from colorless to yellow. Moreover, other metal ions did not induce obvious changes to color and the fluorescence spectra. PMID- 25731812 TI - A capillary based chemiluminscent multi-target immunoassay. AB - Renewed interest in capillary format immunoassays has lead to increasingly costly and complex approaches to preparation and readout. This study describes a simple multi-target method based on a capillary platform using horseradish peroxidase (HRP) labelled IgG to visualize an antibody antigen complex. When goat-anti-human IgG was employed as the probe and human IgG as target, the system allowed detection of target to less than 1 ng/mL using a standard detection approach. The capillaries were read visually or with a commercial grade CCD camera. Multi target detection was demonstrated using a model system of rat-anti-mouse, goat anti-human and mouse-anti-rat IgG. These probes were encoded to different locations in the capillary, providing a simple inexpensive approach to achieve multi-target assays. PMID- 25731813 TI - Construction of an off-on fluorescence system based on carbon dots for trace pyrophosphate sensing. AB - A novel and simple fluorescence Off-On system is proposed for selective pyrophosphate (PPi) sensing in an aqueous solution. The method is constructed based on the strong blue emission of carbon dots (CDs) owing to its outstanding photoluminescence and easy synthesis, which has shown exciting potential in analytical and biological field. The fluorescence of CDs can be remarkably quenched by some transition metal ions such as Cu(2+), Ni(2+), Mn(2+) and Co(2+) due to the coordination reaction between metal ions and the carboxylic groups on the surface of CDs. When PPi was introduced to CDs-metal ion system the fluorescence of CDs was recovered regularly. The increment of fluorescence intensity was proportional with the concentration of PPi in the range of 1-200 MUM and correspondingly the limit of detection was calculated as 0.32 MUM according to the recommendation of IUPAC as 3.29 S B/m. The possible mechanism was discussed for the detection of PPi and the quenching reaction between CDs and metal ions. Furthermore, the proposed system was successfully used to monitor the content of PPi in water samples from artificial wetland. PMID- 25731814 TI - Optical characterization of normal, benign, and malignant thyroid tissue: a pilot study. AB - Fine-needle aspiration cytology is the standard technique to diagnose thyroid pathologies. However, this method has a high percentage of inconclusive and false negative results for benign and malignant lesions. Hence, it is important to search for a new method to assist medical evaluation during these surgical procedures. The use of time-resolved fluorescence techniques to detect biochemical composition and tissue structure alterations could help to develop a portable, minimally invasive, and non-destructive method to assist medical evaluation. In this study, we investigated 17 human thyroid samples by absorbance, fluorescence, excitation, and time-resolved fluorescence measurements. This initial investigation has demonstrated that thyroid fluorescence originates from many endogenous fluorophores and culminates in several bands. The fluorescence lifetimes of benign and malignant lesions were significantly different, as attested by analysis of variance using Tukey test with individual confidence level of 98.06%. Our results suggest that fluorescence lifetimes of benign and malignant lesions can potentially assist diagnosis. After further investigations, fluorescence methods could become a tool for the surgeon to identify differences between normal and pathological thyroid tissues. PMID- 25731815 TI - Novel pyridinium inner salt dye and its complexes: synthesis, crystal structures and photophysical properties. AB - Two novel metal complexes, namely [Tb2(L)6(H2O)4].(NO3)6.L2.(H2O)18 (1) and [Hg(L)Cl2]n (2), were obtained by the reaction of D-pi-A (D = donor, pi = conjugated spacer, A = acceptor) type pyridinium inner salt dye, trans-4-[(p-N,N dimethylamino)styryl]-N-(2-propanoic-acid) pyridinium (L) with corresponding metal salts. Single crystal X-ray diffraction analyses reveal that compound 1 possesses dinuclear motif in which two Tb(III) ions are linked by four carboxylate groups while complex 2 exhibits 1D chain structure based on Hg(II) ions bridged by carboxylate groups. The linear and non-linear optical properties of complexes 1 and 2 have been studied. Both 1 and 2 exhibit intense single photon excited fluorescence (SPEF) and two-photon excited fluorescence (TPEF) in the red range. Results show that the replacement of central ions from Hg(2+) to Tb(3+) influence the two-photon absorption cross-section significantly through increasing the density of the chromophore. However, the peak positions of two photon excited fluorescence are only slightly affected. Compared with L molecule, complex 1 shows enhanced two-photon absorption cross-section and decreased fluorescent lifetime. PMID- 25731816 TI - Investigation of femtosecond collisional ionization rates in a solid-density aluminium plasma. AB - The rate at which atoms and ions within a plasma are further ionized by collisions with the free electrons is a fundamental parameter that dictates the dynamics of plasma systems at intermediate and high densities. While collision rates are well known experimentally in a few dilute systems, similar measurements for nonideal plasmas at densities approaching or exceeding those of solids remain elusive. Here we describe a spectroscopic method to study collision rates in solid-density aluminium plasmas created and diagnosed using the Linac Coherent light Source free-electron X-ray laser, tuned to specific interaction pathways around the absorption edges of ionic charge states. We estimate the rate of collisional ionization in solid-density aluminium plasmas at temperatures ~30 eV to be several times higher than that predicted by standard semiempirical models. PMID- 25731817 TI - Corneal biomechanics in steroid induced ocular hypertension. AB - AIM: This study aims to investigate the corneal biomechanical properties of steroid sensitive refractive surgery patients and to compare these with those patients that did not have steroid induced ocular hypertension after refractive surgery. MATERIAL AND METHODS: This retrospective study in a tertiary care center involved 48 eyes with steroid induced ocular hypertension (Group I) and 61 eyes of age and sex matched refractive patients who used topical steroids for the same duration as group I without developing ocular hypertension (group II). All patients had preoperative ophthalmological examination, pachymetry and postoperative corneal hysteresis (CH) and resistance factor (CRF) measurements by ocular response analyser. The preoperative CH and CRF measurements of the two groups were compared. RESULTS: The mean CH was statistically lower in group I (6.89+/-1.62) as compared to group II (7.80+/-1.30) (p=0.001). The CRF was higher in group I (7.68+/-2.26) as compared to group II (7.66+/-1.72) but the difference was not statistically significant (p=0.96). The preoperative spherical refractive error (r=0.43, p=0.00) and postoperative corneal thickness (r=0.58, p=0.001) were moderately correlated with CH. CONCLUSIONS: A statistically significant decrease in CH in subjects with steroid induced ocular hypertension is found. Previous studies have revealed an association of low CH with risk of glaucomatous damage of optic nerve. This may imply risk of optic disc damage in this ocular hypertension group if not recognized and treated properly. However the results should be confirmed with larger sample sizes. PMID- 25731818 TI - Can retinoscopy keep up in keratoconus diagnosis? AB - PURPOSE: To evaluate the diagnostic potential of retinoscopy in comparison with Amsler-grading, Pentacam and Ocular Response Analyzer (ORA) in classifying keratoconus stages. METHODS: Clinical examination, retinoscopy, Pentacam and ORA were performed in 126 patients. Data of Amsler, retinoscopy, topographic keratoconus classification (TKC) of Pentacam and keratoconus match probability (KMP) of ORA were analyzed. Each of these four classification techniques quotes keratoconus into stage 0 (normal) to 4 (severe). Descriptive analysis and cross tables were used to compare the different devices. RESULTS: For retinoscopy the distribution in the five keratoconus grades normal/suspect/mild/moderate/severe (in numbers) was 34/33/34/17/8. For Amsler it was 37/36/35/12/4, for TKC 38/17/34/31/4, for KMP 32/34/32/15/9. The cross tables show large classification differences of all devices. Overall, classification of retinoscopy and Amsler/TKC/KMP is congruent in 51.6%/36.3%/39.8% of the cases. Of all eyes, Amsler was congruent with TKC/KMP in 54.0%/48.4%, and TKC and KMP were congruent in 53.3%. In a binary decision (normal vs. any stage of mild/moderate/severe) matching between retinoscopy and Amsler/TKC/KMP was 98.6%/88.8%/82.4%. Sensitivity/specificity for retinoscopy and Amsler, TKC, KMP was 98.8%/94.0%, 84.4%/100% and 80.0%/79.1%. CONCLUSIONS: The congruence of keratoconus classification was very poor of all the techniques tested in our study. This applies to objective measures such as TKC, KMP as well as clinical classification techniques such as Amsler and retinoscopy. Compared to TKC and KMP, retinoscopy underestimates keratoconus stages. In contrast, the performance of binary decisions (normal vs. keratoconus) shows a high sensitivity and specificity. Retinoscopy, however, showed a clear clinical use in confirming the diagnosis of keratoconus. PMID- 25731819 TI - Synthesis, structure, and Hg(2+)-ion-sensing properties of stable calixazasmaragdyrins. AB - The first stable calixazasmaragdyrins containing two meso-sp(2) and one meso sp(3) carbon atoms were synthesized by [3 + 2] condensation of 2,2'-(1 methylethylidene)bis(pyrrole) and 5,10-diaryltripyrromethane under trifluoroacetic acid catalyzed conditions. The macrocycles were confirmed by high resolution mass spectrometry, and the molecular structures were deduced by detailed 1D and 2D NMR spectroscopy. The single-crystal structural analysis showed the highly strained and distorted nature of a calixazasmaragdyrin macrocycle. The presence of the one meso-sp(3) carbon center induces sufficient flexibility into the macrocycle, which, in turn, helps with the stability of the calixazasmaragdyrin macrocycle. The calixazasmargdyrins showed one broad absorption band at ~425 nm and an ill-defined band at ~685 nm. The electrochemical studies revealed that the calixazasmaragdyrins are not stable under redox conditions. Because the calixazasmargdyrin macrocycle possesses five pyrrole rings with three ionizable inner NH protons, we investigated anion and cation sensing properties of calixazasmargdyrins. Our studies revealed that the calixazasmaragdyrins do not show any sensing behavior toward anions but exhibited specific sensing behavior toward Hg(2+) ions as verified by spectral and electrochemical studies. PMID- 25731820 TI - Self-assembling dual component nanoparticles with endosomal escape capability. AB - This study reports a novel nanoparticle system with simple and modular one-step assembly, which can respond intelligently to biologically relevant variations in pH. Importantly, these particles also show the ability to induce escape from the endosomal/lysosomal compartments of the cell, which is integral to the design of efficient polymeric delivery systems. The nanoparticles were formed by the nanoprecipitation of pH-responsive poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) and poly(2-(diethylamino)ethyl methacrylate)-b-poly(ethylene glycol) (PDEAEMA-b-PEG). Rhodamine B octadecyl ester perchlorate was successfully encapsulated within the hydrophobic core of the nanoparticle upon nanoprecipitation into PBS at pH 8. These particles disassembled when the pH was reduced below 6.8 at 37 degrees C. Cellular experiments showed the successful uptake of the nanoparticles into the endosomal/lysosomal compartments of 3T3 fibroblast cells. The ability to induce escape from the endosomes was demonstrated by the use of calcein, a membrane-impermeable fluorophore. The modular nature of these particles combined with promising endosomal escape capabilities make these dual component PDEAEMA nanoparticles useful for drug and gene delivery applications. PMID- 25731821 TI - Driving forces for drug loading in drug carriers. AB - The loading capacity of a drug carrier is determined essentially by intermolecular interactions between drugs and carrier materials. In this review, the process of drug loading is described in detail based on the differences in the driving force for drug incorporation, including hydrophobic interaction, electrostatic interaction, hydrogen bonding, Pi-Pi stacking and van der Waals force. Modifying drug-loading sites of carrier materials with interacting groups aiming at tailoring drug-carrier interactions is reviewed by highlighting its importance for improving in vitro properties such as the loading capacity, release behaviour and stability. Other factors affecting drug loading, methods employed to predict the encapsulation capacity and the techniques to verify intermolecular interactions are also discussed to inform the readers of all-sided information on drug-loading processes and theories. The drug carriers can be designed more reasonably with the better understanding of the nature and interacting mechanism of intermolecular interactions. PMID- 25731822 TI - NELF knockout is associated with impaired pubertal development and subfertility. AB - Puberty and reproduction require proper signaling of the hypothalamic-pituitary gonadal axis controlled by gonadotropin-releasing hormone (GnRH) neurons, which arise in the olfactory placode region and migrate along olfactory axons to the hypothalamus. Factors adversely affecting GnRH neuron specification, migration, and function lead to delayed puberty and infertility. Nasal embryonic luteinizing hormone-releasing factor (NELF) is a predominantly nuclear protein. NELF mutations have been demonstrated in patients with hypogonadotropic hypogonadism, but biallelic mutations are rare and heterozygous NELF mutations typically co exist with mutations in another gene. Our previous studies in immortalized GnRH neurons supported a role for NELF in GnRH neuron migration. To better understand the physiology of NELF, a homozygous Nelf knockout (KO) mouse model was generated. Our findings indicate that female Nelf KO mice have delayed vaginal opening but no delay in time to first estrus, decreased uterine weight, and reduced GnRH neuron number. In contrast, male mice were normal at puberty. Both sexes of mice had impaired fertility manifested as reduced mean litter size. These data support that NELF has important reproductive functions. The milder than expected phenotype of KO mice also recapitulates the human phenotype since heterozygous NELF mutations usually require an additional mutation in a second gene to result in hypogonadotropic hypogonadism. PMID- 25731824 TI - Characterization of ovatoxin-h, a new ovatoxin analog, and evaluation of chromatographic columns for ovatoxin analysis and purification. AB - The presence of Ostreopsis cf. ovata on the Mediterranean coast represents a serious concern to human health due to production of toxins - putative palytoxin and ovatoxins (ovatoxin-a, -b, -c, -d, -e, -f and -g). However, purified ovatoxins are not widely available and their toxicities are still unknown. In the present study, we report on HR LC-MS/MS analysis of a French O. cf. ovata strain (IFR-OST-0.3V) collected at Villefranche-sur-Mer (France) during a bloom in 2011. Investigation of this strain of O. cf. ovata cultivated in our laboratory by ultra-high performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC-HRMS) confirmed the production of ovatoxins-a to -e and revealed the presence of a new ovatoxin analog, named ovatoxin-h. O. cf. ovata extracts were pre-purified by Sephadex LH-20 to obtain a concentrated fraction of ovatoxins (OVTXs). This method provided a recovery of about 85% of OVTXs and a cleanup efficiency of 93%. Different stationary phases were tested with this fraction of interest to elucidate the structure of the new OVTX congener and to obtain purified ovatoxins. Eight reversed phase sorbents were evaluated for their capacity to separate and purify ovatoxins. Among them Kinetex C18, Kinetex PFP and Uptisphere C18-TF allowed for best separations almost achieving baseline resolution. Kinetex C18 is able to sufficiently separate these toxins, allowing us to identify the toxins present in the extract purified by Sephadex LH-20, and to partly elucidate the structure of the new ovatoxin congener. This toxin possesses one oxygen atom less and two hydrogens more than ovatoxin-a. Investigations using liquid chromatography coupled to high resolution tandem mass spectrometry suggest that the part of the molecule where ovatoxin-h differs from ovatoxin-a is situated between C42 and C49. Uptisphere C18-TF was proposed as a first step preparative chromatography as it is able to separate a higher number of ovatoxins (especially ovatoxin-d and ovatoxin-e) and because it separates ovatoxins from unknown compounds, identified using full scan single quadrupole mass spectrometry. After pre-purification with Sephadex LH-20, purification and separation of individual ovatoxins was attempted using an Uptisphere C18-TF column. During recovery of purified toxins, problems of stability of OVTXs were observed, leading us to investigate experimental conditions responsible for this degradation. PMID- 25731825 TI - Quantitative liquid chromatography-electrospray ionization-mass spectrometry analysis of amine-containing metabolites derivatized with cyanuric chloride and methylamine isotopologues. AB - Electrospray ionization (ESI) is the most useful interface for mass spectrometry associated with liquid chromatography (LC). However, analyses of polar metabolites become a challenge because the high polarity impairs the separation of metabolites in reversed-phase liquid chromatography and ionization of metabolites by ESI. In this article, we have used cyanuric chloride to couple the amine-containing molecules with methylamine and found that both resolution on LC chromatogram and ionization by ESI are greatly improved. Derivatives would be obtained in 2-h coupling reactions, and then resolved by LC-ESI-MS in 15 min for each sample. Most amino acids can be quantified with linear range from 1 nM to 1 MUM and with an R(2) above 0.979. Although reversed-phase chromatography is suitable for resolving the derivatives, phenyl columns with methanol elution provide optimal separation and signal intensity. Moreover, most structural isomers are well separated following cyanuric chloride and methylamine derivatization. Instead of synthesizing a stable isotope-labeled cyanuric chloride, we can take advantage of using commercially available methyl-d3-amine for a novel stable isotope-coded derivatization method. Each metabolite can be directly quantified by the peak intensity ratio of each derivative isotopologue pair in a single LC-MS analysis. The coupling reactions are relatively easy and accessible to most investigators to generate multiple stable isotope-labeled derivatives of amine-containing compounds for a differential metabolomic analysis. PMID- 25731823 TI - The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis. AB - The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date. PMID- 25731826 TI - False-Positive PET/CT After Cyanoacrylate Sealing of a Pancreaticojejunostomy. AB - In 2013, a 68-year-old male had a pancreaticoduodenectomy for pancreatic cancer. The pancreaticojejunostomy was sealed with cyanoacrylate (Dermabond) to prevent postoperative pancreatic fistula. Local recurrence of malignancy at the anastomosis was suspected 18 months later in PET/CT. Surgical revision was performed and anastomosis resected. However, histology showed no tumor recurrence, but strong inflammation and foreign-body reaction towards Dermabond. The sealant caused false-positive PET/CT findings, so its use in oncologic surgery should be abandoned. PMID- 25731827 TI - The Added Value of Partial Stomach-partitioning to a Conventional Gastrojejunostomy in the Treatment of Gastric Outlet Obstruction. AB - INTRODUCTION: Poor results have been reported after conventional gastrojejunostomy (CGJ) as palliative surgical bypass treatment of gastric outlet obstruction (GOO). Partial stomach-partitioning gastrojejunostomy (PSPGJ) has been introduced as an alternative surgical treatment of GOO to reduce the risk of postoperative delayed gastric emptying (DGE). AIM: The aim was to study PSPGJ as an alternative to CGJ in the treatment of GOO, with respect to DGE. PATIENTS AND METHODS: A retrospective cohort study was completed in all patients who underwent a bypass of the duodenum via PSPGJ or CGJ due to GOO. Cases where concomitant biliary or bariatric procedures were performed were excluded. RESULTS: Twenty four patients met the inclusion criteria for the study; ten cases underwent PSPGJ and 14 CGJ. The incidence of DGE grade B-C was significantly lower in the PSPGJ group (0 %) compared with the CGJ group (42.9 %, p = 0.024). Oral nutrition only was recorded more often at follow-up in the PSPGJ group (9/9, 100 %) than in the CGJ group (4/13, 30.8 %) (p = 0.002). CONCLUSION: PSPGJ seems to be followed by a lower rate of DGE compared to CGJ. PMID- 25731828 TI - Adherence to Guidelines for Adjuvant Imatinib Therapy for GIST: A Multi institutional Analysis. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Adjuvant imatinib therapy improves recurrence-free and overall survival following surgery for patients with high-risk GIST; however, the factors associated with use of adjuvant imatinib therapy are unclear, and adherence to adjuvant imatinib has not been investigated. We sought to determine the clinicopathologic predictors of therapy with adjuvant imatinib following surgical resection for GIST and to determine the utilization of adjuvant imatinib in patients who underwent surgical resection of primary GIST in 2009 or later as recommended by National Comprehensive Cancer network (NCCN) guidelines. METHODS: A multi-institutional cohort including 171 patients who underwent surgery for primary GIST at seven high-volume cancer centers in the USA and Canada between January 2009-December 2012 was used in this study. Receipt of adjuvant imatinib therapy was ascertained, and factors associated with imatinib therapy were analyzed. RESULTS: Following surgery for primary GIST, tumor size (<5.0 cm: ref; 5.0-9.9 cm: odds ratio (OR) 2.36, 95 % confidence interval (CI) 0.74-7.55; >10.0 cm: OR 9.15, 95 % CI 2.28-36.75; p = 0.007), mitotic rate (<=5/50 mitoses per 50 high powered field [HPF]: ref; 6 10/50 HPF: OR 24.91, 95 % CI 3.64-170.35; >10/50 HPF: OR 5.80, 95 % CI 3.64 170.35; p < 0.001), and neoadjuvant therapy (OR 9.52; 95 % CI 2.51-36.14; p = 0.001) were associated with receipt of adjuvant imatinib therapy. Overall, 75 % of patients received appropriate treatment, 23 % of patients were undertreated, and 2 % of patients were overtreated as compared to NCCN guidelines. Adjuvant imatinib therapy was administered in only 53 % of patients for which the NCCN guidelines recommended adjuvant therapy. CONCLUSION: The clinicopathologic factors associated with use of adjuvant imatinib therapy in patients following resection of primary GIST are consistent with established risk factors for recurrence. Adjuvant imatinib therapy remains underutilized in patients with intermediate and high-risk GIST and in patients who receive neoadjuvant therapy. Barriers to adjuvant imatinib therapy in this group of patients needs to be further explored. PMID- 25731829 TI - The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to alpha-synuclein inclusions. AB - Multiple system atrophy (MSA) exhibits widespread astrogliosis together with alpha-synuclein (alpha-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained "skinned" three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n=75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to the GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r<25MUm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r>25MUm), with a reciprocal linear correlation (m, 90MUm(2)) between mean process length and radial distance to the nearest GCI (R(2), 0.7). In primary cell culture studies, alpha-syn addition caused ERK dependent activation of rat astrocytes and perinuclear alpha-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Activated astrocytes were also observed in close proximity to alpha-syn deposits in a unilateral rotenone-lesion mouse model. Moreover, unilateral injection of MSA tissue-derived alpha-syn into the mouse medial forebrain bundle resulted in widespread neuroinflammation in the alpha-syn-injected, but not sham-injected hemisphere. Taken together, our data suggests that the action of localized concentrations of alpha-syn may underlie both astrocyte and oligodendrocyte MSA pathological features. PMID- 25731830 TI - Response to Feng Tian et al.: mTOR mediates the cross-talk of macrophage polarization and autophagy in atherosclerosis. PMID- 25731831 TI - A fourth form of left ventricular involvement in takotsubo cardiomyopathy. PMID- 25731832 TI - VERP in Brugada syndrome - Very effective risk predictor? PMID- 25731833 TI - Neonatal hypertrophic cardiomyopathy caused by double mutation in RAS pathway genes. PMID- 25731834 TI - Fluoroscopic integration of the cardiac computed tomography as a guide for transseptal puncture during atrial fibrillation ablation: A feasibility study. PMID- 25731835 TI - Heart rate control in patients with left ventricular systolic dysfunction and heart failure. PMID- 25731836 TI - Takotsubo cardiomyopathy in a young woman with coronary hypoplasia detected at CT scan. PMID- 25731837 TI - Protection of intravenous HMGB1 on myocardial ischemia reperfusion injury. PMID- 25731838 TI - Transesophageal echocardiograpy in patients with persistent atrial fibrillation undergoing electrical cardioversion on new oral anticoagulants: A multi center registry. PMID- 25731839 TI - Aortic root surgery improves long-term survival after acute type A aortic dissection. AB - OBJECTIVE: Our objective was to analyze the long term survival of patient operated on for acute type A aortic dissection. METHODS: Between 1990 and 2010, 226 patients underwent emergency surgical operation for acute type A aortic dissection. We have followed the long-term outcomes. RESULTS: 144 patients were operated on with a supracommissural replacement of the ascending aorta (SCR) and 82 with an aortic root surgery (ARS, including 77 Bentall procedures and 5 Tirone David operations). Aortic cross-clamp was longer in ARS group (150.8 vs. 103.6 min, p<0.0001). Overall in-hospital mortality was lower in ARS group (20% vs. 34%, p 0.03). Median follow-up was 11.6 years. 10-year survival was higher in ARS group (85.7% vs. 65.9%, p 0.03) and 10-year freedom from aortic root reoperation was significantly lower in ARS group (93.4% vs. 82.9%, p 0.02). In a multivariate analysis aortic root surgery was an independent protective factor for proximal reoperations OR 0.393, CI 95% [0.206-0.748], p=0.005. CONCLUSIONS: Our study suggests that complete aortic root replacement in type A aortic dissection does not burden short-term outcomes, improves long-term survivals and decreases the rate of late reoperation. Whether this approach has to be preferred in younger patient has to be demonstrated in further studies. PMID- 25731841 TI - Antiarrhythmic properties of atrial pacing - Alternative sites or better pharmacotherapy or both? PMID- 25731840 TI - Long-term outcomes associated with prolonged PR interval in the general Japanese population. PMID- 25731842 TI - A case of cardio-pulmonary arrest caused by anomalous origin of left main coronary artery from right sinus of valsalva. PMID- 25731844 TI - Treatment of refractory enterovirus effusive-constrictive pericarditis with corticosteroids. PMID- 25731843 TI - Metabolic exercise data combined with cardiac and kidney indexes: MECKI score. Predictive role in cardiopulmonary exercise testing with low respiratory exchange ratio in heart failure. PMID- 25731845 TI - Absence of a sustained blood pressure lowering effect of once daily remote ischemic conditioning sessions in a normotensive/prehypertensive subject. PMID- 25731846 TI - Delayed myocardial recovery in peripartum cardiomyopathy. PMID- 25731847 TI - Letter in response to cardioprotection with melatonin in the acute myocardial infarction: Awaiting results of MARIA trial? PMID- 25731848 TI - Impact of asymmetrical dilatation of the left atrium on the long-term success after catheter ablation of atrial fibrillation. PMID- 25731849 TI - Female gender and atrial fibrillation: An association with worse prognosis and outcomes. PMID- 25731850 TI - Inhibition of the malate-aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion. AB - Altered secretion of insulin as well as glucagon has been implicated in the pathogenesis of Type 2 diabetes (T2D), but the mechanisms controlling glucagon secretion from alpha-cells largely remain unresolved. Therefore, we studied the regulation of glucagon secretion from alphaTC1-6 (alphaTC1 clone 6) cells and compared it with insulin release from INS-1 832/13 cells. We found that INS-1 832/13 and alphaTC1-6 cells respectively secreted insulin and glucagon concentration-dependently in response to glucose. In contrast, tight coupling of glycolytic and mitochondrial metabolism was observed only in INS-1 832/13 cells. Although glycolytic metabolism was similar in the two cell lines, TCA (tricarboxylic acid) cycle metabolism, respiration and ATP levels were less glucose-responsive in alphaTC1-6 cells. Inhibition of the malate-aspartate shuttle, using phenyl succinate (PhS), abolished glucose-provoked ATP production and hormone secretion from alphaTC1-6 but not INS-1 832/13 cells. Blocking the malate-aspartate shuttle increased levels of glycerol 3-phosphate only in INS-1 832/13 cells. Accordingly, relative expression of constituents in the glycerol phosphate shuttle compared with malate-aspartate shuttle was lower in alphaTC1-6 cells. Our data suggest that the glycerol phosphate shuttle augments the malate aspartate shuttle in INS-1 832/13 but not alphaTC1-6 cells. These results were confirmed in mouse islets, where PhS abrogated secretion of glucagon but not insulin. Furthermore, expression of the rate-limiting enzyme of the glycerol phosphate shuttle was higher in sorted primary beta- than in alpha-cells. Thus, suppressed glycerol phosphate shuttle activity in the alpha-cell may prevent a high rate of glycolysis and consequently glucagon secretion in response to glucose. Accordingly, pyruvate- and lactate-elicited glucagon secretion remains unaffected since their signalling is independent of mitochondrial shuttles. PMID- 25731851 TI - Nucleosome adaptability conferred by sequence and structural variations in histone H2A-H2B dimers. AB - Nucleosome variability is essential for their functions in compacting the chromatin structure and regulation of transcription, replication and cell reprogramming. The DNA molecule in nucleosomes is wrapped around an octamer composed of four types of core histones (H3, H4, H2A, H2B). Nucleosomes represent dynamic entities and may change their conformation, stability and binding properties by employing different sets of histone variants or by becoming post translationally modified. There are many variants of histones H2A and H2B. Specific H2A and H2B variants may preferentially associate with each other resulting in different combinations of variants and leading to the increased combinatorial complexity of nucleosomes. In addition, the H2A-H2B dimer can be recognized and substituted by chaperones/remodelers as a distinct unit, can assemble independently and is stable during nucleosome unwinding. In this review we discuss how sequence and structural variations in H2A-H2B dimers may provide necessary complexity and confer the nucleosome functional variability. PMID- 25731853 TI - Combined musculoskeletal pain in the upper and lower body: associations with occupational mechanical and psychosocial exposures. AB - PURPOSE: Pain in more than one site is common in working populations. We aimed to characterise combined pain (pain in the upper and lower body) and to evaluate whether the prevalence of combined pain is positively related to combined occupational mechanical exposures to the upper and lower body and to high psychosocial job strain. METHODS: This cross-sectional study was based on questionnaire data from the Musculoskeletal Research Database at the Danish Ramazzini Centre. The study included 14,081 men and 20,173 women. Occupational exposures were assessed by job exposure matrices. We analysed the prevalence of pain limited to the upper body, pain limited to the lower body, and combined pain in relation to occupational exposures using Poisson regression. RESULTS: During the last year, 23.2 % of the men and 33.9 % of the women reported combined pain, which was characterised by somatisation, illness worrying, and low SF-36 scores. For men, the adjusted prevalence ratio for combined pain was 1.51 [95 % confidence interval (95 % CI) 1.40-1.64] in relation to exposures limited to the upper body and 2.24 (95 % CI 2.11-2.39) in relation to combined exposures. For women, the corresponding adjusted prevalence ratios were 1.56 (95 % CI 1.50-1.63) and 1.55 (95 % CI 1.50-1.61). High job strain was related to pain among men, only. CONCLUSION: Combined pain may in part be explained by local effects of occupational mechanical exposures acting at more than one site. PMID- 25731852 TI - Association of perceived job insecurity with ischemic heart disease and antihypertensive medication in the Danish Work Environment Cohort Study 1990 2010. AB - PURPOSE: To determine the effect of job insecurity based on repeated measurements on ischemic heart disease (IHD) and on antihypertensive medication. METHODS: The study population consists of 12,559 employees aged 18-59 years of the Danish Work Environment Cohort Study. With an open cohort design, data from up to four representative waves were linked to four registers. Poisson regression with time dependent covariates was used to estimate the rate ratio (RR) with confidence interval (CI) of perceived job insecurity associated with first-time IHD hospitalization or mortality 1991-2010 (n = 561 cases) and incident dispensing of prescribed antihypertensive medications 1996-2010 (n = 2,402 cases). RESULTS: Participants with perceived job insecurity filled more antihypertensive prescriptions (age-, gender-, and calendar year-adjusted RR 1.23, 95 % CI 1.12 1.33) and had a borderline significant higher IHD incidence (RR 1.23, 95 % CI 0.98-1.55). In a subanalysis, the risk of antihypertensive medication dispensed was only significant among employees with worries about both unemployment and poor reemployment opportunities. After explorative stratifications by age, gender, and occupational status, perceived job insecurity was associated with more dispensing of antihypertensive medications to participants less than 50 years of age. CONCLUSIONS: In a country with high social security and active labor market policy, employees with the feeling of an insecure job have a modestly increased risk to fill an antihypertensive prescription. Further studies on health risks of job insecurity should consider improved exposure assessment, earlier outcomes such as medication in order to increase statistical power, and identification of vulnerable population groups. PMID- 25731854 TI - Modeling the mechanisms of biological GTP hydrolysis. AB - Enzymes that hydrolyze GTP are currently in the spotlight, due to their molecular switch mechanism that controls many cellular processes. One of the best-known classes of these enzymes are small GTPases such as members of the Ras superfamily, which catalyze the hydrolysis of the gamma-phosphate bond in GTP. In addition, the availability of an increasing number of crystal structures of translational GTPases such as EF-Tu and EF-G have made it possible to probe the molecular details of GTP hydrolysis on the ribosome. However, despite a wealth of biochemical, structural and computational data, the way in which GTP hydrolysis is activated and regulated is still a controversial topic and well-designed simulations can play an important role in resolving and rationalizing the experimental data. In this review, we discuss the contributions of computational biology to our understanding of GTP hydrolysis on the ribosome and in small GTPases. PMID- 25731856 TI - Regulation by heat shock protein 22 (HSPB8) of transforming growth factor-alpha induced ovary cancer cell migration. AB - Accumulating evidence suggests that heat shock proteins (HSPs) are implicated in progression of cancer. HSP22 (HSPB8), a small HSP, is recognized to be ubiquitously expressed in various tissues. However, the expression and the role of HSP22 in ovarian cancer remain to be clarified. In the present study, we investigated the involvement of HSP22 in transforming growth factor (TGF)-alpha induced migration of ovarian cancer cells. The expression of HSP22 was detected in a serous ovarian cancer cell line, SKOV3.ip1. The migration was reduced by down-regulation of HSP22 expression. The TGF-alpha-induced migration was reduced by SB203580 (a p38 MAP kinase inhibitor), SP600125 (a SAPK/JNK inhibitor) and Y27632 (a Rho-kinase inhibitor). However, down-regulation of HSP22 had little effect on the TGF-alpha-induced phosphorylation of p38 MAP kinase, SAPK/JNK and MYPT, a target protein of Rho-kinase. The HSP22 expression was further analyzed in 20 resected specimens of human ovarian serous carcinoma. The expression of HSP22 was detected in all the twenty tissues (8.24-109.22 pg/mg protein), and the cases with highly expression of HSP22 showed a tendency to acquire the progressive ability. Our results strongly suggest that HSP22 acts as a positive regulator in TGF-alpha-induced migration of ovarian cancer cells, subsequently directing ovarian cancer toward progression. PMID- 25731855 TI - Myeloperoxidase scavenges peroxynitrite: A novel anti-inflammatory action of the heme enzyme. AB - Peroxynitrite, a potent pro-inflammatory and cytotoxic species, interacts with a variety of heme containing proteins. We addressed the question whether (i) the interaction of myeloperoxidase (MPO, an enzyme generating hypochlorous acid from hydrogen peroxide and chloride ions) with peroxynitrite affects the clearance of peroxynitrite, and (ii) if peroxynitrite could modulate the chlorinating activity of MPO. Our results show that this interaction promotes the decomposition of the highly reactive pro-inflammatory oxidant, whereby MPO Compound II (but not Compound I) is formed. The efficiency of MPO to remove peroxynitrite was enhanced by L-tyrosine, nitrite and (-)-epicatechin, substances known to reduce Compound II with high reaction rate. Next, peroxynitrite (added as reagent) diminished the chlorinating activity of MPO in the presence of hydrogen peroxide. Alternatively, SIN-1, a peroxynitrite donor, reduced hypochlorous acid formation by MPO, as measured by aminophenyl fluorescein oxidation (time kinetics) and taurine chloramine formation (end point measurement). At inflammatory loci, scavenging of peroxynitrite by MPO may overcome the uncontrolled peroxynitrite decomposition and formation of reactive species, which lead to cell/tissue damage. PMID- 25731857 TI - Mutagenesis of triad determinants of rat Alox15 alters the specificity of fatty acid and phospholipid oxygenation. AB - Among lipoxygenases ALOX15 orthologs are somewhat peculiar because of their capability of oxygenating polyenoic fatty acids even if they are incorporated in complex lipid-protein assemblies. ALOX15 orthologs of different species have been characterized before, but little is known about the corresponding rat enzyme. Since rats are frequently employed as models in biomedical research we expressed rat Alox15 as recombinant protein in pro- and eukaryotic expression systems and characterized the enzyme with respect to its enzymatic properties. The enzyme oxygenated free arachidonic acid mainly to 12S-HpETE with 15S-HpETE only contributing 10% to the product mixture. Multiple directed mutagenesis studies indicated applicability of the triad concept with particular importance of Leu353 and Ile593 as specificity determinants. Ala404Gly exchange induced subtle alterations in enantioselectivity suggesting partial applicability of the Coffa/Brash concept. Wildtype rat Alox15 and its 15-lipoxygenating Leu353Phe mutant are capable of oxygenating ester lipids of biomembranes and high-density lipoproteins. For the wildtype enzyme 13S-HODE and 12S-HETE were identified as major oxygenation products but for the Leu353Phe mutant 13S-HODE and 15S-HETE prevailed. These data indicate for the first time that mutagenesis of triad determinants modifies the reaction specificity of ALOX15 orthologs with free fatty acids and complex ester lipids in a similar way. PMID- 25731858 TI - Safety and efficacy of the EPICTM nitinol vascular stent system for the treatment of lesions located in the superficial femoral artery: prospective and multicentric trial. AB - BACKGROUND: The aim of this study was to evaluate the short and mid-term safety and efficacy of the EPICTM nitinol vascular stent system for the treatment of lesions located in the superficial femoral artery (SFA). METHODS: From October 2010 to June 2012, 83 subjects were enrolled in a prospective, multicenter, non randomized study designed to demonstrate that the EPIC nitinol vascular stent system for SFA lesions is non-inferior to the published patency rates found in literature. Inclusion criteria were stenosis or occlusion of the SFA or SFA and proximal popliteal artery, with total length from 4 to 11 cm and amenable for treatment with a single stent, in patients with a score from 2 to 5 on Rutherford classification. The primary endpoint was primary patency rate at 12 months as determined by Duplex ultrasound. The secondary endpoints evaluated were: initial arteriographic success, primary patency rate at 6 months, major adverse event rate at one year and technical success. Follow-up with a complete clinical and physical exam, including ABI and Duplex ultrasound was performed at 6 and 12 months. RESULTS: Most patients (56.6%) were men and the mean age was 68.59 (33.1 99.15) years. 25.3% of the total population had intermittent claudication and 73.5% presented with critical limb ischemia. Most lesions were total occlusions (75.9%) and the mean lesion length was 71.16 mm. Contralateral femoral access was performed in 26.5%cases, and ipsilateral femoral approach was used for the remaining 73.5% patients. Technical and arteriographic success was obtained in all 83 (100.00%) patients. Duplex controlled primary patency rate at 6 and 12 months was 95.8% and 76.1%, respectively. The freedom from target lesion revascularization rate was 98.7% and 92.6% at 6 and 12 months, respectively. No stent fractures were observed in this study. Major adverse event rate at 1 year (clinically driven TLR, major amputation, and all-cause mortality) was 15.7%: two target lesion revascularizations (2.4%), one major amputation (1.2%) and ten deaths not related to the procedure (12%). CONCLUSIONS: In conclusion, this study demonstrates the safety and efficacy of the EPICTM Nitinol Vascular Stent System for the treatment of SFA lesions. PMID- 25731859 TI - Endovascular treatment of true and false aneurysms in hemodialysis access. AB - Formation of true and false aneurysms in vascular access for hemodialysis is a complication associated with an immediate or chronic threat to the patient, which jeopardizes access function for further dialysis. Although open surgical repair remains the established treatment of choice, during the last decade, endovascular procedures, largely utilizing stent grafts, have emerged as a viable option for treatment in emergencies as well as for elective cases. Here, basic concepts in vascular access aneurysm management are recapitulated and strategies for endovascular treatment of these complications discussed. PMID- 25731860 TI - Coccygeal pad associated with neurosyphilis. PMID- 25731861 TI - Meeting the psychological needs of community-living stroke patients and carers: a study of third sector provision. AB - PURPOSE: To elucidate how community stroke staff in a major third sector organisation experienced their role and understood and responded to clients' psychological needs. METHOD: In stage 1, three focus groups of 28 staff in total were recorded, transcribed and analysed using inductive thematic analysis. Themes were authenticated by new staff groups. In stage 2, these themes informed the construction of a questionnaire delivered through the organisation's intranet by "Survey Monkey". RESULTS: Five themes emerged from the focus groups: background and context; perceptions of clients' psychological issues; approaches to meeting psychological needs; the experience of working with psychological needs and sources of support; aspirations for future development. Four themes were used in constructing the questionnaire. Responses from 144 staff with diverse qualifications and experience were received; over half encountered 16 (of 35) psychological issues at least once per week. Stroke survivors' needs predominated over carers' needs. Skills used to address psychological problems were identified, also training and support needs and future aspirations. Support needs included information, training and access to specialist consultants. CONCLUSIONS: Psychological issues were central in the work of third sector community stroke staff; psychological skills were routinely used. Attention to means of supporting and developing these skills is required. IMPLICATIONS FOR REHABILITATION: Service leaders and commissioners should be aware that third sector community stroke staff frequently deal with a diverse range of psychological issues and perceive psychological care as central. Service leaders should consider providing training in assessment and management of mood and cognition, risk assessment and management and basic counselling. Staff should be provided with access to specialist consultation and better information about psychological aspects of referrals. There is uncertainty about key methods for supporting the delivery of psychological care (supervision, mentoring and peer support) which requires consideration. PMID- 25731862 TI - Predicting a change in the order of spring phenology in temperate forests. AB - The rise in spring temperatures over the past half-century has led to advances in the phenology of many nontropical plants and animals. As species and populations differ in their phenological responses to temperature, an increase in temperatures has the potential to alter timing-dependent species interactions. One species-interaction that may be affected is the competition for light in deciduous forests, where early vernal species have a narrow window of opportunity for growth before late spring species cast shade. Here we consider the Marsham phenology time series of first leafing dates of thirteen tree species and flowering dates of one ground flora species, which spans two centuries. The exceptional length of this time series permits a rare comparison of the statistical support for parameter-rich regression and mechanistic thermal sensitivity phenology models. While mechanistic models perform best in the majority of cases, both they and the regression models provide remarkably consistent insights into the relative sensitivity of each species to forcing and chilling effects. All species are sensitive to spring forcing, but we also find that vernal and northern European species are responsive to cold temperatures in the previous autumn. Whether this sensitivity reflects a chilling requirement or a delaying of dormancy remains to be tested. We then apply the models to projected future temperature data under a fossil fuel intensive emissions scenario and predict that while some species will advance substantially others will advance by less and may even be delayed due to a rise in autumn and winter temperatures. Considering the projected responses of all fourteen species, we anticipate a change in the order of spring events, which may lead to changes in competitive advantage for light with potential implications for the composition of temperate forests. PMID- 25731863 TI - Excited state conformational dynamics in carotenoids: dark intermediates and excitation energy transfer. AB - A consideration of the excited state potential energy surfaces of carotenoids develops a new hypothesis for the nature of the conformational motions that follow optical preparation of the S2 (1(1)Bu(+)) state. After an initial displacement from the Franck-Condon geometry along bond length alternation coordinates, it is suggested that carotenoids pass over a transition-state barrier leading to twisted conformations. This hypothesis leads to assignments for several dark intermediate states encountered in femtosecond spectroscopic studies. The Sx state is assigned to the structure reached upon the onset of torsional motions near the transition state barrier that divides planar and twisted structures on the S2 state potential energy surface. The X state, detected recently in two-dimensional electronic spectra, corresponds to a twisted structure well past the barrier and approaching the S2 state torsional minimum. Lastly, the S(*) state is assigned to a low lying S1 state structure with intramolecular charge transfer character (ICT) and a pyramidal conformation. It follows that the bent and twisted structures of carotenoids that are found in photosynthetic light-harvesting proteins yield excited-state structures that favor the development of an ICT character and optimized energy transfer yields to (bacterio)chlorophyll acceptors. PMID- 25731865 TI - Prisoners at ultra-high-risk for psychosis: a cross-sectional study. AB - BACKGROUND: The definition of ultra-high risk (UHR) for psychosis was derived from community-based help-seeking populations. Prisoners have high rates of psychosis and other severe mental health (MH) problems. They also have high rates of risk factors for psychiatric morbidity and yet they are among the populations who are less likely to seek help in the community. Despite a policy of equivalence of care for individuals in prison there are no early intervention services for psychosis in prisons in the UK. This was a study exploring feasibility of introducing such a service into a local London prison. This paper discusses the differences in MH profile of prisoners who met criteria for at-risk mental state compared with those who did not. METHOD: A two-stage procedure was used. Participants in a local London prison were routinely screened in the first week of arrival in prison with the Prodrome Questionnaire - Brief Version (PQ-B; Loewy et al. 2011). Those that screened positive as well as a small sample of those who screened negative underwent a further semi-structured assessment to see whether they met criteria for UHR state. Data on self-harm and suicide attempt, family psychiatric history, and anxiety and depression was also collected. RESULTS: A total of 891 prisoners were screened, 44% of whom screened positive. A total of 354 underwent second stage assessment, 60 of whom had screened negative. Four groups were identified: those that had no MH problems, a group experiencing First Episode Psychosis, those at UHR of psychosis and a group with other MH problems. The UHR state and Psychotic groups had very similar MH profiles of symptoms and distress. Prisoners with no MH problems were at the other end of the spectrum with few symptoms and little distress. The Other group fell in between this group and the psychotic spectrum group in terms of symptomology and distress. CONCLUSIONS: This study is the first to examine risk for psychosis in an adult male prison population. We identified a broad spectrum of MH disorder for which there is little current service provision in prisons. Screening early in the custodial process has the potential to identify unmet MH need and has implications for keeping individuals safe in custody. A long-term strategic approach is required to address MH need in prisons. PMID- 25731864 TI - Optimizing diagnostic imaging in the emergency department. AB - While emergency diagnostic imaging use has increased significantly, there is a lack of evidence for corresponding improvements in patient outcomes. Optimizing emergency department (ED) diagnostic imaging has the potential to improve the quality, safety, and outcomes of ED patients, but to date, there have not been any coordinated efforts to further our evidence-based knowledge in this area. The objective of this article is to discuss six aspects of diagnostic imaging to provide background information on the underlying framework for the 2015 Academic Emergency Medicine consensus conference, "Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization." The consensus conference aims to generate a high priority research agenda for emergency diagnostic imaging that will inform the design of future investigations. The six components herein will serve as the group topics for the conference: 1) patient-centered outcomes research; 2) clinical decision rules; 3) training, education, and competency; 4) knowledge translation and barriers to image optimization; 5) use of administrative data; and 6) comparative effectiveness research: alternatives to traditional CT use. PMID- 25731866 TI - Connexin43 hemichannels mediate secondary cellular damage spread from the trauma zone to distal zones in astrocyte monolayers. AB - The mechanism of secondary damage spread after brain trauma remains unsolved. In this work, we redirected the attention to astrocytic communication pathways. Using an in vitro trauma model that consists of a scratch injury applied to an astrocyte monolayer, we found a significant and transient induction of connexin43 (Cx43) hemichannel activity in regions distal from the injury, which was maximal ~1 h after scratch. Two connexin hemichannel blockers, La(3+) and the peptide Gap26, abolished the increased activity, which was also absent in Cx43 KO astrocytes. In addition, the scratch-induced increase of hemichannel activity was prevented by inhibition of P2 purinergic receptors. Changes in hemichannel activity took place with a particular spatial distribution, with cells located at ~17 mm away from the scratch presenting the highest activity (dye uptake). In contrast, the functional state of gap junction channels (dye coupling) was not significantly affected. Cx43 hemichannel activity was also enhanced by the acute extracellular application of 60 mM K(+) . The increase in hemichannel activity was associated with an increment in apoptotic cells at 24 h after scratch that was totally prevented by Gap26 peptide. These findings suggest that Cx43 hemichannels could be a new approach to prevent or reduce the secondary cell damage of brain trauma. PMID- 25731867 TI - Development and Optimization of Solid Self Nanoemulsifying Drug Delivery (S SNEDDS) Using D-Optimal Design for Improvement of Oral Bioavailability of Amiodarone Hydrochloride. AB - The solid-self nanoemulsifying drug delivery system (S-SNEDDS) of Amiodarone hydrochloride (AH) was prepared and evaluated. AH exhibits poor aqueous solubility (0.3-0.5 mg/ml) and therefore variable oral bioavailability. Capmul MCM, Cremophor RH-40 and Propylene glycol were identified as oil, surfactant and co-surfactant for preparing L-SNEDDS. D-optimal design was used to optimize the amount of components in liquid self nanoemulsifying drug delivery system (L SNEDDS). Optimized AH-L-SNEDDS having 15.8 nm globule size and 99.5 %transmittance was then adsorbed on Neusilin US2 to form solid self nanoemulsifying drug delivery system (AH-SSNEDDS). AH loaded L-SNEDDS and S SNEDDS were characterized for various physicochemical properties and solid state properties. In vitro dissolution, ex vivo drug release study and In vivo study were performed for pure AH, AH-LSNEDDS and AH-S-SNEDDS. Both AH loaded L-SNEDDS and S-SNEDDS showed more than 95% drug release in 20 min during drug release studies. In vivo study revealed that release of AH from S-SNEDDS was 2.26 times and LSNEDDS was 1.83 times higher than that from suspension when given to rabbits (p < 0.01). The optimized S-SNEDDS was found to be stable and its shelf life was found to be 2.2 years. S-SNEDDS could serve as a potential drug delivery system for AH. PMID- 25731868 TI - QbD-Oriented Development of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) of Valsartan with Improved Biopharmaceutical Performance. AB - The objectives of the present studies were to develop the systematically optimized selfnanoemulsifying drug delivery systems (SNEDDS) of valsartan employing the holistic QbD approach. The quality profile target product (QTPP) was defined and critical quality attributes (CQAs) earmarked. Preformulation studies including the equilibrium solubility and pseudoternary phase titration studies facilitated the selection of suitable lipids and emulgents for formulation of SNEDDS. Risk assessment and factor screening studies facilitated the selection of Lauroglycol FCC and Capmul MCM L8 (i.e., lipid), Tween 40 and Tween 80 (i.e., emulgent) as the critical material attributes (CMAs) for SNEDDS prepared using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). A central composite design (CCD) was employed for systematic optimization of SNEDDS, taking globule size (Dnm), drug release in 10 min (Q10min) and amount permeated in 45 min (%Perm45min) as the CQAs. Design space was generated using apt mathematical models to embark upon the optimized formulations and validation of the QbD. In situ SPIP studies revealed significant improvement in the absorptivity and permeability parameters of SNEDDS owing to the inhibition of P gp/MRP2 efflux vis-a-vis the conventional marketed formulation and pure drug. In vivo pharmacokinetic studies corroborated marked enhancement in the oral bioavailability drug from SNEDDS vis-a-vis the marketed formulation. Establishment of various levels of in vitro/in vivo correlations (IVIVC) indicated excellent goodness of fit between the in vitro drug release data with the in vivo absorption parameters. In a nutshell, the present studies report successful QbD-based development of MCT and LCT-SNEDDS of valsartan with improved biopharmaceutical performance. PMID- 25731869 TI - Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps. AB - OBJECTIVE: The serrated neoplasia pathway accounts for up to 30% of all sporadic colorectal cancers (CRCs). Sessile serrated adenomas/polyps (SSA/Ps) with cytological dysplasia (SSA/P-D) are a high-risk serrated CRC precursor with little existing data. We aimed to describe the clinical and endoscopic predictors of SSA/P-D and high grade dysplasia (HGD) or cancer. DESIGN: Prospective multicentre data of SSA/Ps >=20 mm referred for treatment by endoscopic mucosal resection (September 2008-July 2013) were analysed. Imaging and lesion assessment was standardised. Histological findings were correlated with clinical and endoscopic findings. RESULTS: 268 SSA/Ps were found in 207/1546 patients (13.4%). SSA/P-D comprised 32.4% of SSA/Ps >=20 mm. Cancer occurred in 3.9%. On multivariable analysis, SSA/P-D was associated with increasing age (OR=1.69 per decade; 95% CI (1.19 to 2.40), p0.004) and increasing lesion size (OR=1.90 per 10 mm; 95% CI (1.30 to 2.78), p0.001), an 'adenomatous' pit pattern (Kudo III, IV or V) (OR=3.98; 95% CI (1.94 to 8.15), p<0.001) and any 0-Is component within a SSA/P (OR=3.10; 95% CI (1.19 to 8.12) p0.021). Conventional type dysplasia was more likely to exhibit an adenomatous pit pattern than serrated dysplasia. HGD or cancer was present in 7.2% and on multivariable analysis, was associated with increasing age (OR=2.0 per decade; 95% CI 1.13 to 3.56) p0.017) and any Paris 0 Is component (OR=10.2; 95% CI 3.18 to 32.4, p<0.001). CONCLUSIONS: Simple assessment tools allow endoscopists to predict SSA/P-D or HGD/cancer in SSA/Ps >=20 mm. Correct prediction is limited by failure to recognise SSA/P-D which may mimic conventional adenoma. Understanding the concept of SSA/P-D and the pitfalls of SSA/P assessment may improve detection, recognition and resection and potentially reduce interval cancer. TRIAL REGISTRATION NUMBER: NCT01368289. PMID- 25731870 TI - Genetic variation and gastric cancer risk: a field synopsis and meta-analysis. AB - BACKGROUND: Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available. METHODS: We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative). RESULTS: Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110). CONCLUSIONS: We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes. PMID- 25731871 TI - Deep resequencing of 131 Crohn's disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants. AB - OBJECTIVE: Genome wide association studies (GWAS) and meta-analyses for Crohn's disease (CD) have not fully explained the heritability of CD, suggesting that additional loci are yet to be found and that the known loci may contain high effect rare risk variants that have thus far gone undetected by GWAS. While the cost of deep sequencing remains too high to analyse many samples, targeted sequencing of pooled DNA samples allows the efficient and cost effective capture of all variations in a target region. DESIGN: We performed pooled sequencing in 500 Korean CD cases and 1000 controls to evaluate the coding exon and 5' and 3' untranslated regions of 131 CD associated genes. The identified genetic variants were validated using genotyping in an independent set of 500 CD cases and 1000 controls. RESULTS: Pooled sequencing identified 30 common/low single nucleotide variants (SNVs) in 12 genes and 3 rare SNVs in 3 genes. Our results confirmed a significant association of CD with the following previously reported risk loci: rs3810936 in TNFSF15 (OR=1.83, p<2.2*10(-16)), rs76418789 in IL23R (OR=0.47, p=1.14*10(-8)) and rs2241880 in ATG16L1 (OR=1.30, p=5.28*10(-6)). In addition, novel loci were identified in TNFSF8 (rs3181374, OR=1.53, p=1.03*10(-14)), BTNL2 (rs28362680, OR=1.47, p=9.67*10(-11)), HLA-DQA2 (rs3208181, OR=1.36, p=4.66*10( 6)), STAT3 (rs1053004, OR=1.29, p=2.07*10(-5)), NFKBIA (rs2273650, OR=0.80, p=3.93*10(-4)), NKX2-3 (rs888208, OR=0.82, p=6.37*10(-4)) and DNAH12 (rs4462937, OR=1.13, p=3.17*10(-2)). A novel rare SNV, rs200735402 in CARD9, was shown to have a protective effect (OR=0.09, p=5.28*10(-5)). CONCLUSIONS: Our deep resequencing of 131 CD associated genes confirmed 3 reported risk loci and identified 8 novel risk loci for CD in Koreans, providing new insights into the genetic architecture of CD. PMID- 25731873 TI - Controversy on the time to progression of pancreatic ductal adenocarcinoma. PMID- 25731872 TI - Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. AB - OBJECTIVE: In alcoholic hepatitis (AH), development of targeted therapies is crucial and requires improved knowledge of cellular and molecular drivers in liver dysfunction. The unique opportunity of using explanted livers from patients with AH having undergone salvage liver transplantation allowed to perform more in depth molecular translational studies. DESIGN: We studied liver explants from patients with AH submitted to salvage transplantation (n=16), from patients with alcoholic cirrhosis without AH (n=12) and fragments of normal livers (n=16). Hepatic cytokine content was quantified. Hepatocyte function and proliferation and the presence of hepatic progenitor cells (HPCs) were evaluated by immunohistochemistry, western blot or quantitative PCR. Mitochondrial morphology was evaluated by electron microscopy. RESULTS: Livers from patients with AH showed decreased cytokine levels involved in liver regeneration (tumour necrosis factor alpha and interleukin-6), as well as a virtual absence of markers of hepatocyte proliferation compared with alcoholic cirrhosis and normal livers. Electron microscopy revealed obvious mitochondrial abnormalities in AH hepatocytes. Importantly, livers from patients with AH showed substantial accumulation of HPCs that, unexpectedly, differentiate only into biliary cells. AH livers predominantly express laminin (extracellular matrix protein favouring cholangiocyte differentiation); consequently, HPC expansion is inefficient at yielding mature hepatocytes. CONCLUSIONS: AH not responding to medical therapy is associated with lack of expression of cytokines involved in liver regeneration and profound mitochondrial damage along with lack of proliferative hepatocytes. Expansion of HPCs is inefficient to yield mature hepatocytes. Manoeuvres aimed at promoting differentiation of HPCs into mature hepatocytes should be tested in AH. PMID- 25731875 TI - Epidemiology of work-related traumatic brain injury: a systematic review. AB - OBJECTIVE: This systematic review aimed to describe the burden and risk factors of work-related traumatic brain injury (wrTBI) and evaluate methodological quality of existing literature on wrTBI. METHODS: A search of electronic databases (MEDLINE, EMBASE, PsycINFO, and CINAHL) was conducted to identify articles published between 1980 and 2013 using a combination of terms for work, TBI, and epidemiology, without geographical limitations. RESULTS: Ninety-eight studies were included in this review, of which 24 specifically focused on wrTBI. In general, male workers, those in the youngest and oldest age groups, and those working in the primary (e.g., agriculture, forestry, mining) or construction industries were more likely to sustain wrTBI, with falls being the most common mechanism of injury. CONCLUSIONS: This review identified workers at highest risk of wrTBI, with implications for prevention efforts. Future research of better methodological quality is needed to provide a more complete picture of the epidemiology of wrTBI. PMID- 25731874 TI - Multimodality endoscopic eradication for neoplastic Barrett oesophagus: results of an European multicentre study (EURO-II). AB - OBJECTIVE: Focal endoscopic resection (ER) followed by radiofrequency ablation (RFA) safely and effectively eradicates Barrett's oesophagus (BO) containing high grade dysplasia (HGD) and/or early cancer (EC) in smaller studies with limited follow-up. Herein, we report long-term outcomes of combined ER and RFA for BO (HGD and/or EC) from a single-arm multicentre interventional study. DESIGN: In 13 European centres, patients with BO <= 12 cm with HGD and/or EC on 2 separate endoscopies were eligible for inclusion. Visible lesions (<2 cm length; <50% circumference) were removed with ER, followed by serial RFA every 3 months (max 5 sessions). Follow-up endoscopy was scheduled at 6 months after the first negative post-treatment endoscopic control and annually thereafter. OUTCOMES: complete eradication of neoplasia (CE-neo) and intestinal metaplasia (CE-IM); durability of CE-neo and CE-IM (once achieved) during follow-up. Biopsy and resection specimens underwent centralised pathology review. RESULTS: 132 patients with median BO length C3M6 were included. After entry-ER in 119 patients (90%) and a median of 3 RFA (IQR 3-4) treatments, CE-neo was achieved in 121/132 (92%) and CE IM in 115/132 patients (87%), per intention-to-treat analysis. Per-protocol analysis, CE-neo and CE-IM were achieved in 98% and 93%, respectively. After a median of 27 months following the first negative post-treatment endoscopic control, neoplasia and IM recurred in 4% and 8%, respectively. Mild-to-moderate adverse events occurred in 25 patients (19%); all managed conservatively or endoscopically. CONCLUSIONS: In patients with early Barrett's neoplasia, intensive multimodality endotherapy consisting of ER combined with RFA is safe and highly effective, and the treatment effect appears to be durable during mid term follow-up. TRIAL REGISTRATION NUMBER: NTR 1211, http://www.trialregister.nl. PMID- 25731876 TI - Expression of the myostatin gene in the adductor muscle of the Pacific lion-paw scallop Nodipecten subnodosus in association with growth and environmental conditions. AB - The cDNA sequence of the myostatin gene in the Pacific lion-paw Nodipecten subnodosus (Ns-mstn) was characterized, and the temporal expression during grow out was analyzed for the first time in a scallop. Ns-mstn encodes a 459-amino acid protein in which two propeptide proteolytic sites were identified, the previously recognized (RSKR) and a second one at position 266-269 aa (RRKR). The alternative furin cleavage site could be related with post-translational processing, or it could be a tissue-specific mechanism for signaling activity. The Ns-mstn transcript was located by in situ hybridization in sarcomeres and around the nucleus of muscle fibers. The temporal expression analysis by qPCR in the adductor muscle showed that Ns-mstn expression was significantly different (P < 0.05) between months during the grow-out period, increasing largely during the summer months when both biomass and muscle weight did not increase or even decreased; muscle fiber size and number were found to decrease significantly. Exogenous and endogenous factors such as high temperature and low food availability, as well as gametogenesis and reproduction, can be associated with the growth pattern and Ns-mstn expression changes. Our results indicate that MSTN is involved in adductor muscle growth regulation in N. subnodosus as it occurs in vertebrate skeletal muscle although Ns-mstn expression in non-muscle organs/tissues suggests additional functions. PMID- 25731877 TI - Studies of conformational changes of an arginine-binding protein from Thermotoga maritima in the presence and absence of ligand via molecular dynamics simulations with the coarse-grained UNRES force field. AB - The arginine-binding protein (ArgBP) from the hyperthermophilic eubacterium Thermotoga maritima (TmArgBP) is responsible for arginine transport through the bacterial cell membrane. The protein binds a single molecule of L-arginine, which results in conformational changes due to hinge bending. Thereby, TmArgBP acquires one of two possible conformations: open (without the presence of the arginine ligand) and closed (in the presence of the arginine ligand). Here we report a molecular dynamics study of the influence of the presence or absence of the ligand on the dynamics of TmArgBP, using the coarse-grained UNRES force field. The results of our studies indicate that binding of the arginine ligand promotes a closed conformation, which agrees with experimental data. However, the sensitivity of the TmArgBP conformation to the presence of arginine decreases and the protein becomes more flexible with increasing temperature, which might be related to the functionality of this protein in the thermophilic organism T. maritima. PMID- 25731878 TI - Does single-electron chalcogen bond exist? Some theoretical insights. AB - Ab initio calculations have been carried out to investigate the sigma-hole interaction in XHY...CH3 and XHY...CH2CH3 complexes, where X = F, Cl, Br and Y = S, Se. This interaction, termed "single-electron chalcogen bond interaction" was analyzed in terms of geometric, interaction energies and electronic features of the complexes. This interaction is a weak one, with an interaction energy that varies from a minimum of -1.7 kcal mol(-1) for BrHS...CH3 to -6.0 kcal mol(-1) for FHSe...CH2CH3 at the CCSD(T)/aug-cc-pVTZ level of theory. Energy decomposition analysis indicated that the dominant attraction energy originates in the electrostatic term which is larger for the Se complexes than for the S counterparts. However, the attractive polarization and dispersion components also make an important contribution to the interaction energy for the single-electron chalcogen bond interactions. PMID- 25731879 TI - Quality of healthcare services provided in disaster shelters: An integrative literature review. AB - BACKGROUND: Globally, shelters are a resource to promote critical health and safety in disasters, particularly for vulnerable populations (e.g., children, elderly, chronically ill). This study examines the nature and quality of healthcare services rendered in disaster and emergency shelters. OBJECTIVES: To determine based upon systematic and accurate measurement the scope and quality of health care services rendered in disaster shelters and to describe the health outcomes experienced by shelter residents. METHODS: An integrative review of English-language literature pertaining to the assessment, evaluation, and systematic measurement of healthcare quality and client outcomes in disaster and emergency shelters was undertaken. Articles were identified using a structured search strategy of six databases and indexing services (PubMed, CINAHL, EMBase, Scopus, Web of Science, and Google Scholar). RESULTS: Limited literature exists pertaining specifically to metrics for quality of health care in acute disaster and emergency shelters, and the literature that does exist is predominately U.S. based. Analysis of the existing evidence suggests that nurse staffing levels and staff preparedness, access to medications/medication management, infection control, referrals, communication, and mental health may be important concepts related to quality of disaster health care services. CONCLUSIONS: A small number of population-based and smaller, ad hoc outcomes-based evaluation efforts exist; however the existing literature regarding systematic outcomes-based quality assessment of disaster sheltering healthcare services is notably sparse. PMID- 25731880 TI - Methylation status of HPV16 E2-binding sites classifies subtypes of HPV associated oropharyngeal cancers. AB - BACKGROUND: The human papillomavirus (HPV) E2 protein is a transcriptional repressor of the oncogenes E6/E7 and loss of E2 function is considered a key step in carcinogenesis. Integration of HPV into the host genome may disrupt the E2 gene. Furthermore, methylation of CpG dinucleotides in E2-binding sites (E2BSs) in the HPV upstream regulatory region may interfere with transcriptional repression of E6 and E7 by E2. The authors hypothesized that the CpG methylation status of E2BS identifies subtypes of HPV type 16 (HPV16)-associated oropharyngeal squamous cell cancers (OPSCC) in association with E2 gene integrity and viral integration. METHODS: Methylation of 10 CpG dinucleotides within the upstream regulatory region, encompassing E2BSs 1, 2, 3, and 4, was quantitatively analyzed by bisulfite pyrosequencing in 57 HPV16-associated OPSCC cases. E2 status was analyzed by gene amplification and quantitative real-time reverse transcriptase-polymerase chain reaction. Viral integration was determined by integration-specific polymerase chain reaction methods. RESULTS: Three subgroups with differential methylation at E2BS3 and E2BS 4 were identified: 1) complete methylation (>80%) associated with the presence of integrated HPV genomes with an intact E2 gene; 2) intermediate methylation levels (20%-80%) with predominantly episomal HPV genomes with intact E2; and 3) no methylation (<20%) with a disrupted E2 gene. Patients with high methylation levels tended to have a worse 5 year overall survival compared with patients with intermediate methylation (hazard ratio, 3.23; 95% confidence interval, 1.13-9.24 [P = .06]). CONCLUSIONS: Methylation of E2BS3 and E2BS4 in OPSCC is associated with E2 integrity and viral physical status. It might explain deregulated viral oncogene expression in the presence of E2. The prognostic significance of E2BS methylation for patients with HPV-associated OPSCC needs to be analyzed further. PMID- 25731882 TI - Shape Amphiphiles in 2-D: Assembly of 1-D Stripes and Control of Their Surface Density. AB - The morphology of monolayers assembled from mixtures of a shape-amphiphilic molecule, {33,19} = 1-((hentriaconta-14,16-diyn-1-yloxy)methyl)-5 ((heptadecyloxy)methyl)anthracene, and a symmetric molecule, {192}, at the solution-HOPG interface depends strongly on the components' solution concentrations and sample annealing history. The kinked alkadiyne side chain, {33}, packs optimally only with antiparallel aligned, {33} side chains. Thus, optimal packing of {33} side chains should assemble "{33} stripes" consisting of two adjacent {33,19} columns with interdigitated {33} chains. The aliphatic {19} side chain of {33,19} can pack with antiparallel aligned {19} side chains from {192} or from {33,19}. Thus, {33} stripes can incorporate as "guests" within {192} "host" monolayers. The composition and morphology of monolayers formed by drop casting solutions of {33,19} and {192} at 19 degrees C are dominated by assembly kinetics. Short {33} strips are immersed haphazardly in monolayers comprised mostly of {192}. Thermal annealing promotes fuller expression of {33,19}'s shape amphiphilicity and assembly of thermodynamically determined monolayers incorporating 1-D {33} stripes within a 2-D matrix of {192}. Larger solution mole fractions of {192} yield annealed monolayers with nearly constant {33} strip lengths, decreased {33} strip density, and increased {33} strip spacing. PMID- 25731881 TI - Assessment and management of behavioral and psychological symptoms of dementia. AB - Behavioral and psychological symptoms of dementia include agitation, depression, apathy, repetitive questioning, psychosis, aggression, sleep problems, wandering, and a variety of inappropriate behaviors. One or more of these symptoms will affect nearly all people with dementia over the course of their illness. These symptoms are among the most complex, stressful, and costly aspects of care, and they lead to a myriad of poor patient health outcomes, healthcare problems, and income loss for family care givers. The causes include neurobiologically related disease factors; unmet needs; care giver factors; environmental triggers; and interactions of individual, care giver, and environmental factors. The complexity of these symptoms means that there is no "one size fits all solution," and approaches tailored to the patient and the care giver are needed. Non pharmacologic approaches should be used first line, although several exceptions are discussed. Non-pharmacologic approaches with the strongest evidence base involve family care giver interventions. Regarding pharmacologic treatments, antipsychotics have the strongest evidence base, although the risk to benefit ratio is a concern. An approach to integrating non-pharmacologic and pharmacologic treatments is described. Finally, the paradigm shift needed to fully institute tailored treatments for people and families dealing with these symptoms in the community is discussed. PMID- 25731883 TI - Longitudinal evaluation of local muscle conditions in a rat model of gastrocnemius muscle injury using an in vivo imaging system. AB - This study aimed to evaluate the time course of local changes during the acute phase of gastrocnemius muscle strain, in a rat model, using an in vivo imaging system. Thirty-eight, 8-week-old Sprague-Dawley male rats were used in our study. Experimental injury of the right gastrocnemius muscle was achieved using the drop mass method. After inducing muscle injury, a liposomally formulated indocyanine green derivative (LP-iDOPE, 7 mg/kg) was injected intraperitoneally. We evaluated the muscle injuries using in vivo imaging, histological examinations, and enzyme linked immunosorbent assays. The fluorescence peaked approximately 18 h after the injury, and decreased thereafter. Histological examinations revealed that repair of the injured tissue occurred between 18 and 24 h after injury. Quantitative analyses for various cytokines demonstrated significant elevations of interleukin 6 and tumor necrosis factor-alpha at 3 and 18 h post-injury, respectively. The time course of fluorescence intensity, measured using in vivo imaging, demonstrated that the changes in cytokine levels and histopathologic characteristics were consistent. Specifically, these changes reached peaked 18 h post-injury, followed by trends toward recovery. PMID- 25731885 TI - Cognitive Effort and Schizophrenia Modulate Large-Scale Functional Brain Connectivity. AB - Schizophrenia (SZ) is characterized by cognitive dysfunction and disorganized thought, in addition to hallucinations and delusions, and is regarded a disorder of brain connectivity. Recent efforts have been made to characterize the underlying brain network organization and interactions. However, to which degree connectivity alterations in SZ vary across different levels of cognitive effort is unknown. Utilizing independent component analysis (ICA) and methods for delineating functional connectivity measures from functional magnetic resonance imaging (fMRI) data, we investigated the effects of cognitive effort, SZ and their interactions on between-network functional connectivity during 2 levels of cognitive load in a large and well-characterized sample of SZ patients (n = 99) and healthy individuals (n = 143). Cognitive load influenced a majority of the functional connections, including but not limited to fronto-parietal and default mode networks, reflecting both decreases and increases in between-network synchronization. Reduced connectivity in SZ was identified in 2 large-scale functional connections across load conditions, with a particular involvement of an insular network. The results document an important role of interactions between insular, default-mode, and visual networks in SZ pathophysiology. The interplay between brain networks was robustly modulated by cognitive effort, but the reduced functional connectivity in SZ, primarily related to an insular network, was independent of cognitive load, indicating a relatively general brain network-level dysfunction. PMID- 25731884 TI - Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. AB - BACKGROUND: Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cyclic adenosine monophosphate signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect. METHODS: A variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current, while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance. RESULTS: Immunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased HCN channel current, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation. CONCLUSIONS: These findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses. PMID- 25731886 TI - Mediators of the association between low socioeconomic status and chronic kidney disease in the United States. AB - Using data collected from 9,823 participants in the 2007-2008 and 2009-2010 cycles of the National Health and Nutrition Examination Survey, we formally investigated potentially modifiable factors linking low socioeconomic status (SES) to chronic kidney disease (CKD) for their presence and magnitude of mediation. SES was defined using the poverty income ratio. The main outcome was CKD, defined as estimated glomerular filtration rate <60 mL/minute/1.73 m(2) (using the Chronic Kidney Disease Epidemiology Collaboration equation) and/or urinary albumin:creatinine ratio >=30 mg/g. In mediation analyses, we tested the contributions of health-related behaviors (smoking, alcohol intake, diet, physical activity, and sedentary time), comorbid conditions (diabetes, hypertension, obesity, abdominal obesity, and hypercholesterolemia), and access to health care (health insurance and routine health-care visits) to this association. Except for sedentary time and diet, all examined health-related behaviors, comorbid conditions, and factors related to health-care access mediated the low SES-CKD association and contributed 20%, 32%, and 11%, respectively, to this association. In race/ethnicity-specific analyses, identified mediators tended to explain more of the association between low SES and CKD in non-Hispanic blacks than in other racial/ethnic groups. In conclusion, potentially modifiable factors like health-related behaviors, comorbid conditions, and health-care access contribute substantially to the association between low SES and CKD in the United States, especially among non-Hispanic blacks. PMID- 25731887 TI - The contribution of genomic research to explaining racial disparities in cardiovascular disease: a systematic review. AB - After nearly a decade of genome-wide association studies, no assessment has yet been made of their contribution toward an explanation of the most prominent racial health disparities observed at the population level. We examined populations of African and European ancestry and focused on cardiovascular diseases, which are collectively the largest contributor to the racial mortality gap. We conducted a systematic search for review articles and meta-analyses published in 2007-2013 in which genetic data from both populations were available. We identified 68 articles relevant to this question; however, few reported significant associations in both racial groups, with just 3 variants meeting study-specific significance criteria. For most outcomes, there were too few estimates for quantitative summarization, but when summarization was possible, racial group did not contribute to heterogeneity. Most associations reported from genome-wide searches were small, difficult to replicate, and in no consistent direction that favored one racial group or another. Although the substantial investment in this technology might have produced clinical advances, it has thus far made little or no contribution to our understanding of population level racial health disparities in cardiovascular disease. PMID- 25731888 TI - Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a Childhood Leukemia International Consortium study. AB - The associations between childhood acute lymphoblastic leukemia (ALL) and several proxies of early stimulation of the immune system, that is, day-care center attendance, birth order, maternally reported common infections in infancy, and breastfeeding, were investigated by using data from 11 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2010). The sample included 7,399 ALL cases and 11,181 controls aged 2-14 years. The data were collected by questionnaires administered to the parents. Pooled odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Day-care center attendance in the first year of life was associated with a reduced risk of ALL (odds ratio = 0.77, 95% confidence interval: 0.71, 0.84), with a marked inverse trend with earlier age at start (P < 0.0001). An inverse association was also observed with breastfeeding duration of 6 months or more (odds ratio = 0.86, 95% confidence interval: 0.79, 0.94). No significant relationship with a history of common infections in infancy was observed even though the odds ratio was less than 1 for more than 3 infections. The findings of this large pooled analysis reinforce the hypothesis that day-care center attendance in infancy and prolonged breastfeeding are associated with a decreased risk of ALL. PMID- 25731889 TI - Dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin and diabetes mellitus: a meta-analysis. AB - We systematically evaluated studies published through May 2014 in which investigators assessed the dose-response relationship between serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the occurrence of diabetes mellitus (DM), and we investigated the extent and sources of interstudy heterogeneity. The dose-response relationship between serum TCDD and DM across studies was examined using 2 dependent variables: an exposure level-specific proportion of persons with DM and a corresponding natural log-transformed ratio measure of the association between TCDD and DM. Regression slopes for each dependent variable were obtained for each study and included in a random-effects meta-analysis. Sensitivity analyses were used to assess the influence of inclusion and exclusion decisions, and sources of heterogeneity were explored using meta-regression models and a series of subanalyses. None of the summary estimates in the main models or in the sensitivity analyses indicated a statistically significant association. We found a pronounced dichotomy: a positive dose-response in cross-sectional studies of populations with low-level TCDD exposures (serum concentrations <10 pg/g lipid) and heterogeneous, but on balance null, results for prospective studies of persons with high prediagnosis TCDD body burdens. Considering the discrepancy of results for low current versus high past TCDD levels, the available data do not indicate that increasing TCDD exposure is associated with an increased risk of DM. PMID- 25731891 TI - Peri-Incisional Botulinum Toxin for Chronic Postcraniotomy Headache After Traumatic Brain Injury: A Case Series. AB - Botulinum neurotoxin (BoNT) has been used successfully to treat primary headache syndromes, but there are no published data on its use for chronic postcraniotomy headache. Botulinum neurotoxin type A (BoNT-A) (4:1 dilution) was injected at a dose of 15-50 units into peri-incisional sites of the scalp in 3 patients who had undergone craniotomy remotely for traumatic epidural hematoma. All patients reported reductions in headache lasting at least 2.5 months. Repeat injections were performed in all cases with favorable outcomes. There were no complications. Peri-incisional BoNT-A appears to be a potentially valuable tool in the chronic management of post craniotomy headache after traumatic brain injury. PMID- 25731892 TI - Complement inhibition in HLA-incompatible kidney transplants: persisting antibody mediated injury despite marked decrease of clinical ABMR. PMID- 25731894 TI - Distance-dependent patterns of molecular divergences in Tuatara mitogenomes. AB - Population genetic models predict that populations that are geographically close to each other are expected to be genetically more similar to each other compared to those that are widely separate. However the patterns of relationships between geographic distance and molecular divergences at neutral and constrained regions of the genome are unclear. We attempted to clarify this relationship by sequencing complete mitochondrial genomes of the relic species Tuatara (Sphenodon punctatus) from ten offshore islands of New Zealand. We observed a positive relationship that showed a proportional increase in the neutral diversity at synonymous sites (dS), with increasing geographical distance. In contrast we showed that diversity at evolutionarily constrained sites (dC) was elevated in the case of comparisons involving closely located populations. Conversely diversity was reduced in the case of comparisons between distantly located populations. These patterns were confirmed by a significant negative relationship between the ratio of dC/dS and geographic distance. The observed high dC/dS could be explained by the abundance of deleterious mutations in comparisons involving closely located populations, due to the recent population divergence times. Since distantly related populations were separated over long periods of time, deleterious mutations might have been removed by purifying selection. PMID- 25731893 TI - Cumulus cells accelerate oocyte aging by releasing soluble Fas ligand in mice. AB - Although previous studies have suggested that cumulus cells (CCs) accelerate oocyte aging by secreting soluble and heat-sensitive paracrine factors, the factors involved are not well characterized. Because Fas-mediated apoptosis represents a major pathway in induction of apoptosis in various cells, we proposed that CCs facilitate oocyte aging by releasing soluble Fas ligand (sFasL). In this study, we reported that when the aging of freshly ovulated mouse oocytes were studied in vitro, both the apoptotic rates of CCs and the amount of CCs produced sFasL increased significantly with the culture time. We found that oocytes expressed stable levels of Fas receptors up to 24 h of in vitro aging. Moreover, culture of cumulus-denuded oocytes in CCs-conditioned CZB medium (CM), in CZB supplemented with recombinant sFasL, or in CM containing sFasL neutralizing antibodies all showed that sFasL impaired the developmental potential of the oocytes whereas facilitating activation and fragmentation of aging oocytes. Furthermore, CCs from the FasL-defective gld mice did not accelerate oocyte aging due to the lack of functional FasL. In conclusion, we propose that CCs surrounding aging oocytes released sFasL in an apoptosis-related manner, and the released sFasL accelerated oocyte aging by binding to Fas receptors. PMID- 25731895 TI - Creating Effective Media Messaging for Rural Smoke-free Policy. AB - OBJECTIVES: Objectives were to (1) explore perceived effectiveness of existing smoke-free print advertisements in rural communities and (2) generate message content, characteristics, and media delivery channels that resonate with residents. DESIGN AND SAMPLE: Qualitative methods design. Thirty-nine rural adults recruited by community partners. MEASURES: Content analysis of findings from individuals in four focus groups who participated in general discussion and reviewed eight print ads related to secondhand smoke (SHS) and smoke-free policy. RESULTS: Six content themes were identified: smoking/SHS dangers, worker health, analogies, economic impact, rights, and nostalgia. Seven message characteristics were recognized: short/to the point, large enough to read, graphic images, poignant stories, statistics/charts/graphs, message sender, and messages targeting different groups. Four media delivery channels were considered most effective: local media, technology, billboard messages, and print materials. CONCLUSIONS: Seeking input from key informants is essential to reaching rural residents. Use of analogies in media messaging is a distinct contribution to the literature on effective smoke-free campaigns. Other findings support previous studies of effective messaging and delivery channels. Further research is needed to examine effectiveness of themes related to message content in smoke-free ads and delivery strategies. Effective media messaging can lead to policy change in rural communities to reduce exposure to SHS. PMID- 25731896 TI - Zinc for Acute Diarrhea and Amoxicillin for Pneumonia, Do They Work? : Delivered at the AIIMS, IJP Excellence Award for the year 2013 on 7th September 2014. AB - Acute diarrhea and pneumonia are the two largest killers of under-five children in the world. Zinc, used in management of acute diarrhea and Amoxicillin, used in community acquired pneumonia, feature in the list of 13 Life Saving Commodities for Women's and Children Health by the UN Commission. Zinc has caught wide scientific attention for the conceptual promise it has to offer for prevention, control and treatment of acute diarrhea. This presentation focuses on author's research on the mechanisms by which zinc might contribute to the pathogenesis of acute diarrhea and the degree of success achieved in diarrhea control and treatment by zinc supplementation including its impact on mortality. However, emerging evidence in terms of controlled studies in humans beckons a more complete understanding of the mechanistic basis for zinc supplementation. Current evidence indicates that studies specifically addressing the variability in response to zinc supplementation need to be undertaken to better comprehend these mechanisms. Similarly, the author presented her research that examined the role of oral amoxicillin in community management of severe pneumonia in children and the need to assess its universal efficacy in all children with severe pneumonia. PMID- 25731897 TI - Nebulized Magnesium Sulfate in Acute Bronchiolitis: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the efficacy of nebulized magnesium sulfate as a bronchodilator in infants hospitalized with acute bronchiolitis. METHODS: This three-center double masked randomized clinical trial comprised 120 children with moderate to severe bronchiolitis. They were randomly assigned into two groups: the first group was treated with nebulized magnesium sulfate (40 mg/kg) and nebulized epinephrine (0.1 ml/kg) and the second group (control) was treated with nebulized epinephrine (0.1 ml/kg). The primary outcome was the length of hospital stay. The use of oxygen, temperature, oxygen saturation (SPO2), pulse rate (PR), respiratory rate (RR) and respiratory distress assessment instrument (RDAI) score were measured in the beginning of the study and during hospitalization. RESULTS: The mean (SD) age of 120 infants was 5.1(+/- 2.6) mo and 60% were boys. The length of hospital stay was not different between the two groups (P > 0.01). Use of oxygen supplementation, SPO2 and vital signs were similar in the two groups. Improvement in RDAI score was significantly better in infants treated with nebulized magnesium sulfate than in the other group (P 0.01). CONCLUSIONS: Thus, in infants with acute bronchiolitis, the effect of nebulized magnesium sulfate is comparable to nebulized epinephrine. However nebulized magnesium sulfate can improve the clinical score so it may have additive effect to reduce symptoms during hospitalization. PMID- 25731899 TI - A practical way to resolve ambiguities in wavefront reconstructions by the transport of intensity equation. AB - The transport of intensity equation (TIE) provides a very straight forward way to computationally reconstruct wavefronts from measurements of the intensity and the derivative of this intensity along the optical axis of the system. However, solving the TIE requires knowledge of boundary conditions which cannot easily be obtained experimentally. The solution one obtains is therefore not guaranteed to be accurate. In addition, noise and systematic measurement errors can very easily lead to low-frequency artefacts. In this paper we solve the TIE by the finite element method (FEM). The flexibility of this approach allows us to define additional boundary conditions (e.g. a flat phase in areas where there is no object) that lead to a correct solution of the TIE, even in the presence of noise. PMID- 25731898 TI - The dependence of quorum sensing in Serratia marcescens JG on the transcription of luxS gene. AB - Bacteria communicate with one another using chemical signal molecules. This phenomenon termed quorum sensing enables the bacteria to monitor the environment for other bacteria and to alter behavior on a population-wide scale in response to cell density. Serratia marcescens JG, a quorum sensing bacterium, can secrete a furanosyl borate diester autoinducer (AI-2) in the exponential phase of growth. In this study, to further investigate the regulation of AI-2 production in S. marcescens JG, the pfs and luxS promoter fusions to an operon luxCDABE reporter were constructed in a low-copy-number vector pBR322K, which allows an examination of transcription of the genes in the pathway for signal synthesis. The results show that the luxS expression is constitutive, and the transcription of luxS is tightly correlated with AI-2 production in S. marcescens JG because the peaks of AI-2 production and transcriptional level of luxS appear at the same time point. The close relation of the profiles of luxS transcription and AI-2 production was also confirmed with real-time PCR technology. These results support the hypothesis that the quorum sensing in S. marcescens JG is luxS dependent. PMID- 25731900 TI - Spin-torque-induced dynamics at fine-split frequencies in nano-oscillators with two stacked vortices. AB - The gyrotropic rotation around the equilibrium position constitutes the fundamental excitation of magnetic vortices in nanostructures. The frequency of this mode varies with material and sample geometry, but is independent of the vortex handedness and its core direction. Here, we demonstrate that this degeneracy is lifted in a spin-torque oscillator containing two vortices stacked on top of each other. When driven by spin-polarized currents, such devices exhibit a set of dynamic modes with discretely split frequencies, each corresponding to a specific combination of vorticities and relative core polarities. The fine splitting occurs even in the absence of external fields, demonstrating that such devices can function as zero-field, multi-channel, nano oscillators for communication technologies. It also facilitates the detection of the relative core polarization and allows for the eight non-degenerate configurations to be distinguished electrically, which may enable the design of multi-state memory devices based on double-vortex nanopillars. PMID- 25731901 TI - Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers. AB - N-Acetylcysteine (NAC) could be included in protocols designed for the treatment of lead toxicity. Therefore, in this study, we decided to investigate the influence of NAC administration on homocysteine (Hcy) levels, oxidative damage to proteins, and the levels of iron (Fe), transferrin (TRF), and haptoglobin (HPG) in lead (Pb)-exposed workers. The examined population (n = 171) was composed of male employees who worked with Pb. They were randomized into four groups. Workers who were not administered any antioxidants, drugs, vitamins, or dietary supplements were classified as the reference group (n = 49). The remaining three groups consisted of workers who were treated orally with NAC at three different doses (1 * 200, 2 * 200, or 2 * 400 mg) for 12 weeks. After the treatment, blood Pb levels significantly decreased in the groups receiving NAC compared with the reference group. The protein concentration was not affected by NAC administration. In contrast, Hcy levels significantly decreased or showed a strong tendency toward lower values depending on the NAC dose. Levels of the protein carbonyl groups were significantly decreased in all of the groups receiving NAC. Conversely, glutamate dehydrogenase activity was significantly elevated in all of the groups receiving NAC, while the level of protein thiol groups was significantly elevated only in the group receiving 200 mg of NAC. Treatment with NAC did not significantly affect Fe and TRF levels, whereas HPG levels showed a tendency toward lower values. Treatment with NAC normalized the level of Hcy and decreased oxidative stress as measured by the protein carbonyl content; this effect occurred in a dose-dependent manner. Moreover, small doses of NAC elevated the levels of protein thiol groups. Therefore, NAC could be introduced as an alternative therapy for chronic Pb toxicity in humans. PMID- 25731902 TI - Arctic observers: Richard King, monogenism and the historicisation of Inuit through travel narratives. AB - In 1848 the ethnologist, surgeon and Arctic explorer Richard King (1810-1876) published a three-part series on Inuit in the Journal of the Ethnological Society of London. This series provided a detailed history of Inuit from the eleventh century to the early nineteenth century. It incorporated a mixture of King's personal observations from his experience travelling to the Arctic as a member of George Back's expedition (1833-1835), and the testimonies of other contemporary and historical actors who had written on the subject. The aim was to historicise Inuit through the use of travel reports and show persistent features among the race. King was a monogenist and his sensitive recasting of Inuit was influenced by his participation in a research community actively engaged in humanitarian and abolitionist causes. The physician and ethnologist Thomas Hodgkin (1798-1866) argued that King's research on Inuit was one of the best ethnological approaches to emulate and that it set the standard for the nascent discipline. If we are to take seriously Hodgkin's claim, we should look at how King constructed his depiction of Inuit. There is much to be gained by investigating the practices of nineteenth-century ethnologists because it strengthens our knowledge of the discipline's past and shows how modern understandings of races were formed. PMID- 25731904 TI - Semantic grasping escapes Weber's law. AB - According to Weber's law, the just noticeable difference between stimuli increases proportionally with stimulus magnitude, suggesting that perception becomes more variable when a stimulus becomes larger. Surprisingly, this basic psychophysical principle appears to be violated in grasping because the variability of grasping movements does not increase with object size. This dissociation between perception and grasping has been interpreted either as evidence for different neuronal processing of real-time visual size information [Ganel, T., Chajut, E., Algom, D. (2008a). Current Biology, 18(14), R599-R601], or for the idea that grasping ignores stimulus size and is based on position information only [Smeets, J. B. J., and Brenner, E. (2008). Current Biology, 18(23), R1089-R1090]. Both accounts assume that it is the processing of visual information that leads to the absence of Weber's law in grasping. We show that even if neither visual nor any real-time sensory information about the stimulus is presented (but only abstract, semantic information about its size), grasping does not follow Weber's law. This indicates that other mechanisms must be responsible for the unexpected behavior of grasping. PMID- 25731903 TI - Cortical regions involved in semantic processing investigated by repetitive navigated transcranial magnetic stimulation and object naming. AB - BACKGROUND: Knowledge about the cortical representation of semantic processing is mainly derived from functional magnetic resonance imaging (fMRI) or direct cortical stimulation (DCS) studies. Because DCS is regarded as the gold standard in terms of language mapping but can only be used during awake surgery due to its invasive character, repetitive navigated transcranial magnetic stimulation (rTMS) a non-invasive modality that uses a similar technique as DCS-seems highly feasible for use in the investigation of semantic processing in the healthy human brain. METHODS: A total number of 100 (50 left-hemispheric and 50 right hemispheric) rTMS-based language mappings were performed in 50 purely right handed, healthy volunteers during an object-naming task. All rTMS-induced semantic naming errors were then counted and evaluated systematically. Furthermore, since the distribution of stimulations within both hemispheres varied between individuals and cortical regions stimulated, all elicited errors were standardized and subsequently related to their cortical sites by projecting the mapping results into the cortical parcellation system (CPS). RESULTS: Overall, the most left-hemispheric semantic errors were observed after targeting the rTMS to the posterior middle frontal gyrus (pMFG; standardized error rate: 7.30/00), anterior supramarginal gyrus (aSMG; 5.60/00), and ventral postcentral gyrus (vPoG; 5.00/00). In contrast to that, the highest right-hemispheric error rates occurred after stimulation of the posterior superior temporal gyrus (pSTG; 12.40/00), middle superior temporal gyrus (mSTG; 6.20/00), and anterior supramarginal gyrus (aSMG; 6.20/00). CONCLUSIONS: Although error rates were low, the rTMS-based approach of investigating semantic processing during object naming shows convincing results compared to the current literature. Therefore, rTMS seems a valuable, safe, and reliable tool for the investigation of semantic processing within the healthy human brain. PMID- 25731905 TI - Methods for Ensuring High Quality of Coding of Cause of Death. The Mortality Register to Follow Southern Urals Populations Exposed to Radiation. AB - BACKGROUND: To follow up populations exposed to several radiation accidents in the Southern Urals, a cause-of-death registry was established at the Urals Center capturing deaths in the Chelyabinsk, Kurgan and Sverdlovsk region since 1950. OBJECTIVES: When registering deaths over such a long time period, quality measures need to be in place to maintain quality and reduce the impact of individual coders as well as quality changes in death certificates. METHODS: To ensure the uniformity of coding, a method for semi-automatic coding was developed, which is described here. Briefly, the method is based on a dynamic thesaurus, database-supported coding and parallel coding by two different individuals. RESULTS: A comparison of the proposed method for organizing the coding process with the common procedure of coding showed good agreement, with, at the end of the coding process, 70 - 90% agreement for the three-digit ICD -9 rubrics. CONCLUSIONS: The semi-automatic method ensures a sufficiently high quality of coding by at the same time providing an opportunity to reduce the labor intensity inherent in the creation of large-volume cause-of-death registries. PMID- 25731906 TI - Theoretical predictions of novel superconducting phases of BaGe3 stable at atmospheric and high pressures. AB - A series of new superconducting binary silicides and germanides have recently been synthesized under high-pressure high-temperature conditions. A representative member of this group, BaGe3, was theoretically investigated using evolutionary structure searches coupled with structural analogies in the pressure range from 1 atm to 250 GPa, where three new phases were discovered. At 1 atm, in addition to the synthesized P63/mmc phase, we predicted two new phases, I4/mmm and Amm2, to be dynamically stable. The Amm2 structure comprises Ge clusters and triangular prisms intercalated with Ba and Ge atoms, a unique structural motif unknown to this group. The I4/mmm structure has been previously synthesized in binary silicides and is calculated to be thermodynamically stable in BaGe3 between 15.6 and 35.4 GPa. Above 35.4 GPa, two new phases of P6m2 and R3m symmetry become the global minima and remain so up to the highest pressure considered. These two phases have very similar enthalpies, and both feature layers of double Kagome nets of Ge intercalated with Ba-Ge layers. The predicted phases are suggested to be metallic with itinerant electrons and to be potentially superconducting from the considerable electron-phonon coupling strength. Density functional perturbation calculations combined with the Allen Dynes-modified McMillan formula were used to estimate the superconducting critical temperatures (Tc) for these new phases, which, with slight pressure variations, are comparable to the experimental Tc measured for the P63/mmc phase. PMID- 25731908 TI - Penile Dysmorphic Disorder: Development of a Screening Scale. AB - Penile dysmorphic disorder (PDD) is shorthand for men diagnosed with body dysmorphic disorder, in whom the size or shape of the penis is their main, if not their exclusive, preoccupation causing significant shame or handicap. There are no specific measures for identifying men with PDD compared to men who are anxious about the size of their penis but do not have PDD. Such a measure might be helpful for treatment planning, reducing unrealistic expectations, and measuring outcome after any psychological or physical intervention. Our aim was, therefore, to validate a specific measure, termed the Cosmetic Procedure Screening Scale for PDD (COPS-P). Eighty-one male participants were divided into three groups: a PDD group (n = 21), a small penis anxiety group (n = 37), and a control group (n = 23). All participants completed the COPS-P as well as standardized measures of depression, anxiety, social phobia, body image, quality of life, and erectile function. Penis size was also measured. The final COPS-P was based on nine items. The scale had good internal reliability and significant convergent validity with measures of related constructs. It discriminated between the PDD group, the small penis anxiety group, and the control group. This is the first study to develop a scale able to discriminate between those with PDD and men anxious about their size who did not have PDD. Clinicians and researchers may use the scale as part of an assessment for men presenting with anxiety about penis size and as an audit or outcome measure after any intervention for this population. PMID- 25731907 TI - Combined cognitive and parent training interventions for adolescents with ADHD and their mothers: A randomized controlled trial. AB - This study examined the individual and combined effects of two nonpharmacological treatments for attention deficit/hyperactivity disorder (ADHD): Cogmed working memory training (CWMT) for adolescents and behavioral parent training (BPT) for mothers. Ninety-one adolescents (ages 11-15) and their mothers were randomized to one of four CWMT and BPT treatment and active control (placebo) group combinations of 5-week interventions. At pre- and posttest, mothers and teachers completed rating forms, and adolescents completed neuropsychological measures of working memory (WM). Individual intervention effects showed that treatment CWMT significantly improved WM spans, whereas there were no significant differences for treatment or control BPT on reports of parent-related outcomes. Combined treatment effects indicated an overall pattern of greatest improvements for the control CWMT/treatment BPT group, as compared to the other three groups, on adolescent WM deficit, behavioral regulation problems, and global executive deficit. Most significant effects for outcomes were main effects of improvements over time. A combination of CWMT and BPT did not result in increased treatment gains. However, potential effects of combined treatment may have been masked by greater perceived benefits arising from lack of struggle in the nonadaptive, CWMT active control condition. Future combined intervention research should focus on specific, theoretically driven WM deficits among individuals with ADHD, should include possible adaptations to the standard CWMT program, should examine effectiveness of cognitive treatments combined with contextual interventions and should utilize appropriate control groups to fully understand the unique and combined effects of interventions. PMID- 25731909 TI - The Putative Son's Attractiveness Alters the Perceived Attractiveness of the Putative Father. AB - A body of literature has investigated female mate choice in the pre-mating context (pre-mating sexual selection). Humans, however, are long-living mammals forming pair-bonds which sequentially produce offspring. Post-mating evaluations of a partner's attractiveness may thus significantly influence the reproductive success of men and women. I tested herein the theory that the attractiveness of putative sons provides extra information about the genetic quality of fathers, thereby influencing fathers' attractiveness across three studies. As predicted, facially attractive boys were more frequently attributed to attractive putative fathers and vice versa (Study 1). Furthermore, priming with an attractive putative son increased the attractiveness of the putative father with the reverse being true for unattractive putative sons. When putative fathers were presented as stepfathers, the effect of the boy's attractiveness on the stepfather's attractiveness was lower and less consistent (Study 2). This suggests that the presence of an attractive boy has the strongest effect on the perceived attractiveness of putative fathers rather than on non-fathers. The generalized effect of priming with beautiful non-human objects also exists, but its effect is much weaker compared with the effects of putative biological sons (Study 3). Overall, this study highlighted the importance of post-mating sexual selection in humans and suggests that the heritable attractive traits of men are also evaluated by females after mating and/or may be used by females in mate poaching. PMID- 25731910 TI - Mice and rats differ with respect to activity-dependent slowing of conduction velocity in the saphenous peripheral nerve. AB - We assess in mice, the electrophysiological criteria developed in humans and rats in vivo for unmyelinated (C) fibre differentiation into sub-classes, derived from the activity-induced latency increase ("slowing") in response to electrical stimulation during 6 min at 0.25 Hz followed by 3 min at 2 Hz. Fibres are considered nociceptors if they show more than 10% slowing at 2 Hz; nociceptors are further divided into mechanosensitive ("polymodal") and mechanoinsensitive ("silent") ones according to a latency shift of less and more than 1% during the first minute at 0.25 Hz, respectively. Sympathetic postganglionics are recognised by 2-10% slowing at 2 Hz; units slowing less than 2% at 2 Hz remain uncategorised. For assessment of these criteria, we also developed a novel in vivo technique for recording of peripheral single-fibres in the mouse. We compared the theoretical slowing-rate discriminator criteria with experimental data obtained from mice in vivo/in vitro and rats in vitro. Out of 69 cutaneous mouse C-fibres in vitro and 19 in vivo, only 38 (67%) and 9 (47%) met the above 1% criterion, respectively; sympathetics were not identified. In contrast, out of 20 rats nerve fibres in vitro, 19 (95%) met this criterion. We conclude that (A) our novel electrophysiological technique is a practical method for examining mouse cutaneous single-fibres in vivo and (B) the published criterion for identifying silent nociceptors in rats and humans is not applicable in mice. PMID- 25731911 TI - 2015 ASMS "Emerging Investigators" focus section. PMID- 25731912 TI - Dynamic anchoring transitions at aqueous-liquid crystal interfaces induced by specific and non-specific binding of vesicles to proteins. AB - This paper reports on the dynamics of continuous anchoring transitions at interfaces formed between nematic liquid crystals (LCs, 4'-pentyl-4-cyanobiphenyl (5CB)) and immiscible aqueous phases that are induced by either non-specific or specific interactions between phospholipid vesicles and proteins adsorbed at the LC interfaces. By analyzing the dynamic response of LCs to non-specific adsorption of lipids onto bovine serum albumin (BSA)-decorated LC interfaces, we provide evidence that the LC anchoring transitions are slower than diffusion controlled accumulation of lipid at the interface, consistent with the hypothesis that the LC transition involves lateral reorganization of proteins and lipids at the interface. Significantly, optical measurements of the tilt angle of the LC as a function of the amount of lipid captured at the interface were found to be quantitatively consistent with theoretical predictions of LC anchoring directed by nanoscopic domains of molecules that cause planar (protein) and homeotropic (lipid) anchoring of the LC. Finally, specific binding interactions between the antibody-decorated LC interfaces and vesicles (through antibody-antigen recognition) greatly accelerated the continuous LC anchoring transitions, with dynamics that were measured to scale with the logarithm of the ligand composition of the vesicles (over four orders of magnitude). The latter dynamics were found to be strongly influenced by addition of synthetic surfactants, consistent with our proposal that the rate-limiting step underlying the response of the LC was the transfer of lipids from captured vesicles into the protein-decorated LC interface. Overall, the results presented in this paper provide quantitative insight into the origin of continuous anchoring transitions triggered by vesicles at protein-decorated LC interfaces and, more broadly, guidance for the design of stimuli-responsive LC systems. PMID- 25731913 TI - Studying bubble-particle interactions by zeta potential distribution analysis. AB - Over a decade ago, Xu and Masliyah pioneered an approach to characterize the interactions between particles in dynamic environments of multicomponent systems by measuring zeta potential distributions of individual components and their mixtures. Using a Zetaphoremeter, the measured zeta potential distributions of individual components and their mixtures were used to determine the conditions of preferential attachment in multicomponent particle suspensions. The technique has been applied to study the attachment of nano-sized silica and alumina particles to sub-micron size bubbles in solutions with and without the addition of surface active agents (SDS, DAH and DF250). The degree of attachment between gas bubbles and particles is shown to be a function of the interaction energy governed by the dispersion, electrostatic double layer and hydrophobic forces. Under certain chemical conditions, the attachment of nano-particles to sub-micron size bubbles is shown to be enhanced by in-situ gas nucleation induced by hydrodynamic cavitation for the weakly interacting systems, where mixing of the two individual components results in negligible attachment. Preferential interaction in complex tertiary particle systems demonstrated strong attachment between micron-sized alumina and gas bubbles, with little attachment between micron-sized alumina and silica, possibly due to instability of the aggregates in the shear flow environment. PMID- 25731915 TI - Hospitalists and primary care. PMID- 25731914 TI - Malaria and immunity during pregnancy and postpartum: a tale of two species. AB - It is well established that pregnant women are at an increased risk of Plasmodium falciparum infection when compared to non-pregnant individuals and limited epidemiological data suggest Plasmodium vivax risk also increases with pregnancy. The risk of P. falciparum declines with successive pregnancies due to the acquisition of immunity to pregnancy-specific P. falciparum variants. However, despite similar declines in P. vivax risk with successive pregnancies, there is a paucity of evidence P. vivax-specific immunity. Cross-species immunity, as well as immunological and physiological changes that occur during pregnancy may influence the susceptibility to both P. vivax and P. falciparum. The period following delivery, the postpartum period, is relatively understudied and available epidemiological data suggests that it may also be a period of increased risk of infection to Plasmodium spp. Here we review the literature and directly compare and contrast the epidemiology, clinical pathogenesis and immunological features of P. vivax and P. falciparum in pregnancy, with a particular focus on studies performed in areas co-endemic for both species. Furthermore, we review the intriguing epidemiology literature of both P. falciparum and P. vivax postpartum and relate observations to the growing literature pertaining to malaria immunology in the postpartum period. PMID- 25731917 TI - Capsule Commentary on Jackson et al., The Quality of Written Feedback by Attendings of Internal Medicine Residents. PMID- 25731916 TI - Factors Underlying Quality Problems with Alcohol Screening Prompted by a Clinical Reminder in Primary Care: A Multi-site Qualitative Study. AB - BACKGROUND: Population-based alcohol screening is recommended in primary care, and increasingly incentivized by policies, yet is challenging to implement. The U.S. Veterans Health Administration (VA) achieved high rates of screening using a national performance measure and associated electronic clinical reminder to prompt and facilitate screening and document results. However, the sensitivity of alcohol screening for identifying unhealthy alcohol use is low in VA clinics. OBJECTIVE: We aimed to understand factors that might contribute to low sensitivity of alcohol screening. DESIGN: This was an observational, qualitative study. PARTICIPANTS: Participants included clinical staff responsible for conducting alcohol screening and nine independently managed primary care clinics of a single VA medical center in the Northwestern U.S. APPROACH: Four researchers observed clinical staff as they conducted alcohol screening. Observers took handwritten notes, which were transcribed and coded iteratively. Template analysis identified a priori and emergent themes. KEY RESULTS: We observed 72 instances of alcohol screening conducted by 31 participating staff. Observations confirmed known challenges to implementation of care using clinical reminders, including workflow and flexibility limitations. Three themes specific to alcohol screening emerged. First, most observed screening was conducted verbally, guided by the clinical reminder, although some variability in approaches to screening (e.g., paper-based or laminate-based screening) was observed. Second, specific verbal screening practices that might contribute to low sensitivity of clinical screening were identified, including conducting non-verbatim screening and making inferences, assumptions, and/or suggestions to input responses. Third, staff introduced and adapted screening questions to enhance patient comfort. CONCLUSIONS: This qualitative study in nine clinics found that implementation of alcohol screening facilitated by a clinical reminder resulted primarily in verbal screening in which questions were not asked vertbatim and were otherwise adapted. Non-verbal approaches to screening, or patient self-administration, may enhance validity and standardization of screening while simultaneously addressing limitations of the clinical reminder and issues related to perceived discomfort. PMID- 25731918 TI - Syntenin is involved in the bacteria clearance response of kuruma shrimp (Marsupenaeus japonicus). AB - Syntenin is a multifunctional cytosolic adaptor protein that contributes to cell migration, proliferation, attachment, and apoptosis, as well as immune response to virus, in vertebrates. However, the functions of syntenin in the antibacterial response of invertebrates remain unclear. In this study, we identified a syntenin like gene (MjSyn) from the kuruma shrimp (Marsupenaeus japonicus) and detected its function in the antibacterial immunity of shrimp. The full-length MjSyn was 1223 bp with a 963 bp open reading frame that encodes 320 amino acids. The deduced MjSyn proteins contained two atypical PDZ domains (sequence repeat that was first reported in the postsynaptic density protein or PSD-95, DlgA, and ZO-1 protein), an N-terminal domain, and a C-terminal domain. Reverse transcription (RT)-PCR results showed that MjSyn was expressed in all tested tissues. Quantitative real-time PCR analysis revealed that MjSyn transcripts in the hemocyte, gill, and intestine were significantly induced at various time points after infection with Staphylococcus aureus and Vibrio anguillarum. The knockdown of the expression of MjSyn by RNA interference resulted in a significant decrease in the phagocytic ability and increased bacteria number in vivo of shrimp. Moreover, the expression of MjCnx, a cytoplasma and membrane location lectin chaperone protein, was inhibited in the MjSyn-knocked down shrimp, which indicated a possible calnexin-related way. Thus, the MjSyn participates in the bacterial clearance response of kuruma shrimp, thereby providing new insight into the function of this kind of important adaptor protein. PMID- 25731919 TI - Molecular characterization and expression analysis of eleven interferon regulatory factors in half-smooth tongue sole, Cynoglossus semilaevis. AB - Interferon regulatory factors (IRFs) act as transcription mediators in virus-, bacteria-, and interferon (IFN)-induced signaling pathways and play diverse functions in antimicrobial defense, immune modulation, hematopoietic differentiation, and cell apoptosis. In this study, we described for the first time eleven IRFs (IRF1, IRF1L, IRF2X1, IRF3, IRF4a, IRF4b, IRF5, IRF6, IRF7, IRF8, and IRF9) from half-smooth tongue sole (Cynoglossus semilaevis) and examined their tissue distributions and expression patterns under different conditions. The deduced protein sequences of these IRFs (except IRF1) share high identities (71.8-86.6%) with other corresponding IRFs in other teleosts, whereas the sequence identity of IRF1 with the corresponding IRF1 in other teleosts is only 58.1%. A conserved N-terminal DNA binding domain (DBD), which is characterized by a winged type helix-loop-helix motif with four to six tryptophan repeats, is present in all IRFs. Another conserved IRF associated domain (IAD), which mediates the interactions in the C-terminal part of the protein, is present in all IRFs except IRF1 and IRF2X1, which instead contain the IAD2 domain. Several special domains also were found, including a serine-rich domain (SRD) in IRF3, IRF4a, IRF4b, and IRF7; a proline-rich domain (PRD) in IRF9; nuclear localization signals (NLSs) in IRF5, IRF8, and IRF9; and a virus activated domain (VAD) in IRF5. Quantitative real time RT-PCR (qRT-PCR) analysis showed that expression of all IRFs occurred in multiple tissues. IRF1, IRF2X1, IRF4a, IRF5, IRF7, and IRF8 exhibited relatively high levels of expression in immune organs, whereas the other five IRFs displayed high levels of expression in non-immune organs. Infection with extracellular and intracellular bacterial pathogens and virus upregulated the expression of IRFs in a manner that depended on tissue type, pathogen, and infection stage. Specifically, IRF1 and IRF2X1 were highly induced by bacterial and viral pathogens; IRF1L and IRF6 responded mainly to extracellular and intracellular bacterial pathogens; IRF3, IRF5, IRF7, IRF8, and IRF9 were markedly induced by intracellular bacterial pathogen and virus; IRF4a and IRF4b were mainly induced by virus and intracellular bacterial pathogen respectively. These results indicate that the IRFs of C. semilaevis can be categorized into several groups which exhibit different expression patterns in response to the infection of different microbial pathogens. These results provide new insights into the roles of teleost IRFs in antimicrobial immunity. PMID- 25731920 TI - Characterization and expression analyses of five interferon regulatory factor transcripts (Irf4a, Irf4b, Irf7, Irf8, Irf10) in Atlantic cod (Gadus morhua). AB - The interferon regulatory factor (IRF) family of genes encodes a group of transcription factors that have important roles not only in regulating the expression of Type I interferons (IFNs) and other genes in the IFN pathway, but also in growth, development and the regulation of oncogenesis. In this study, several IRF family members (Irf4a, Irf4b, Irf7, Irf8, Irf10) in Atlantic cod (Gadus morhua) were characterized at the cDNA and putative amino acid levels, allowing for phylogenetic analysis of these proteins in teleost fish, as well as the development of gene-specific primers used in RT-PCR and quantitative PCR (QPCR) analyses. Two Atlantic cod Irf10 splice variants were identified and their presence confirmed by sequencing of the Irf10 genomic region. RT-PCR showed that Irf7, Irf8 and both Irf10 transcripts were expressed in all 15 cod tissues tested, while Irf4a and Irf4b were absent in some tissues. QPCR analysis of spleen expression expanded upon this, and upon previous work. All IRF transcripts in the study were responsive to stimulation by the viral mimic poly(I:C), and all except Irf4a were responsive to exposure to formalin-killed Aeromonas salmonicida (ASAL). These IRF genes, thus, are likely important in the cod immune response to both viral and bacterial infections. Increased temperature (10 degrees C to 16 degrees C) was also observed to modulate the antibacterial responses of all IRF transcripts, and the antiviral responses of Irf4b and Irf10-v2. This research supports earlier studies which reported that elevated temperature modulates the expression of many immune genes in Atlantic cod. PMID- 25731921 TI - Screening of candidate genes encoding proteins expressed in pectoral fins of fugu Takifugu rubripes, in relation to habitat site of parasitic copepod Caligus fugu, using suppression subtractive hybridization. AB - Caligus fugu is a parasitic copepod specific to the tetraodontid genus Takifugu including the commercially important Takifugu rubripes. Despite the rapid accumulation of knowledge on other aspects of its biology, the host and settlement-site recognition mechanisms of this parasite are not yet well understood. Since the infective copepodid stage shows preferential site selection in attaching to the fins, we considered it likely that the copepodid recognizes chemical cues released or leaking from the fins, and/or transmembrane protein present on the fins. To isolate molecules potentially related to attachment site specificity, we applied suppression subtractive hybridization (SSH) PCR by identifying genes expressed more highly in pectoral fins of T. rubripes than in the body surface skin. We sequenced plasmid DNA from 392 clones in a SSH library. The number of non-redundant sequences was 276, which included 135 sequences located on 117 annotated genes and 141 located in positions where no genes had been annotated. We characterized those annotated genes on the basis of gene ontology terms, and found that 46 of the identified genes encode secreted proteins, enzymes or membrane proteins. Among them nine showed higher expression in the pectoral fins than in the skin. These could be candidate genes for involvement in behavioral mechanisms related to the site specificity shown by the infective copepodids of C. fugu. PMID- 25731922 TI - Is there a missing link? Effects of root herbivory on plant-pollinator interactions and reproductive output in a monocarpic species. AB - Herbivores can have a major influence on plant fitness. The direct impact of herbivory on plant reproductive output has long been studied, and recently also indirect effects of herbivory on plant traits and pollinator attraction have received increasing attention. However, the link between these direct and indirect effects has seldom been studied. In this study, we investigated effects of root herbivory on plant and floral traits, pollination success and reproductive outcome in the monocarpic perennial Cynoglossum officinale. We exposed 119 C. officinale plants to a range of root herbivore damage by its specialist herbivore Mogulones cruciger. We assessed the effect of herbivory on several plant traits, pollinator foraging behaviour and reproductive output, and to elucidate the link between these last two we also quantified pollen deposition and pollen tube growth and applied a pollination experiment to test whether seed set was pollen-limited. Larval root herbivory induced significant changes in plant traits and had a negative impact on pollinator visitation. Infested plants were reduced in size, had fewer flowers and received fewer pollinator visits at plant and flower level than non-infested plants. Also, seed set was negatively affected by root herbivory, but this could not be attributed to pollen limitation since neither stigmatic pollen loads and pollen tube growth nor the results of the hand-pollination experiment differed between infested and non-infested plants. Our observations demonstrate that although herbivory may induce significant changes in flowering behaviour and resulting plant-pollinator interactions, it does not necessarily translate into higher rates of pollen limitation. The observed reductions in reproductive output following infection can mainly be attributed to higher resource limitation compared to non-infested plants. PMID- 25731923 TI - Breaking up of prolonged sitting over three days sustains, but does not enhance, lowering of postprandial plasma glucose and insulin in overweight and obese adults. AB - To compare the cumulative (3-day) effect of prolonged sitting on metabolic responses during a mixed meal tolerance test (MTT), with sitting that is regularly interrupted with brief bouts of light-intensity walking. Overweight/obese adults (n=19) were recruited for a randomized, 3-day, outpatient, cross-over trial involving: (1) 7-h days of uninterrupted sitting (SIT); and (2) 7-h days of sitting with light-intensity activity breaks [BREAKS; 2-min of treadmill walking (3.2 km/h) every 20 min (total: 17 breaks/day)]. On days 1 and 3, participants underwent a MTT (75 g of carbohydrate, 50 g of fat) and the incremental area under the curve (iAUC) was calculated from hourly blood samples. Generalized estimating equation (GEE) models were adjusted for gender, body mass index (BMI), energy intake, treatment order and pre-prandial values to determine effects of time, condition and time * condition. The glucose iAUC was 1.3 +/- 0.5 and 1.5 +/- 0.5 mmol.h.l(-1) (mean differences +/- S.E.M.) higher in SIT compared with BREAKS on days 1 and 3 respectively (condition effect: P=0.001), with no effect of time (P=0.48) or time * condition (P=0.8). The insulin iAUC was also higher on both days in SIT (day 1: ?151 +/- 73, day 3: ?91 +/- 73 pmol.h.l(-1), P=0.01), with no effect of time (P=0.52) or time * condition (P=0.71). There was no between-treatment difference in triglycerides (triacylglycerols) iAUC. There were significant between-condition effects but no temporal change in metabolic responses to MTT, indicating that breaking up of sitting over 3 days sustains, but does not enhance, the lowering of postprandial glucose and insulin. PMID- 25731924 TI - Modelling and kinetics studies of a corn-rape blend combustion in an oxy-fuel atmosphere. AB - A kinetic oxy-combustion study of a previously optimized lignocellulose blend is proposed. Kinetic and diffusion control mechanism are considered. The proposed correlations fit properly with the experimental results and diffusion effects are identified as be important enough to be taken into account. Afterwards, with the results obtained in the kinetic study, a detailed consecutive and parallel kinetic scheme is proposed for modelling the oxy-combustion of the blend. A discussion of the temperature and concentration profiles are included. Variation of products final distribution is considered. Smaller particles than 0.001 m are proposed for reducing temperature and concentration profiles and obtaining a good final product distribution. CO2-char reaction is identified as one of the most important step to be optimized for obtaining the lowest final residue. In this study, char is mainly oxidised at 950 K and this situation is attributed to an optimized blending of the bioresidues. PMID- 25731925 TI - Reverse engineering of biochar. AB - This study underpins quantitative relationships that account for the combined effects that starting biomass and peak pyrolysis temperature have on physico chemical properties of biochar. Meta-data was assembled from published data of diverse biochar samples (n=102) to (i) obtain networks of intercorrelated properties and (ii) derive models that predict biochar properties. Assembled correlation networks provide a qualitative overview of the combinations of biochar properties likely to occur in a sample. Generalized Linear Models are constructed to account for situations of varying complexity, including: dependence of biochar properties on single or multiple predictor variables, where dependence on multiple variables can have additive and/or interactive effects; non-linear relation between the response and predictors; and non-Gaussian data distributions. The web-tool Biochar Engineering implements the derived models to maximize their utility and distribution. Provided examples illustrate the practical use of the networks, models and web-tool to engineer biochars with prescribed properties desirable for hypothetical scenarios. PMID- 25731926 TI - Enzymatic biodiesel synthesis from yeast oil using immobilized recombinant Rhizopus oryzae lipase. AB - The recombinant Rhizopus oryzae lipase (1-3 positional selective), immobilized on Relizyme OD403, has been applied to the production of biodiesel using single cell oil from Candida sp. LEB-M3 growing on glycerol from biodiesel process. The composition of microbial oil is quite similar in terms of saponifiable lipids than olive oil, although with a higher amount of saturated fatty acids. The reaction was carried out in a solvent system, and n-hexane showed the best performance in terms of yield and easy recovery. The strategy selected for acyl acceptor addition was a stepwise methanol addition using crude and neutralized single cell oil, olive oil and oleic acid as substrates. A FAMEs yield of 40.6% was obtained with microbial oils lower than olive oil 54.3%. Finally in terms of stability, only a lost about 30% after 6 reutilizations were achieved. PMID- 25731927 TI - Low-load resistance training promotes muscular adaptation regardless of vascular occlusion, load, or volume. AB - PURPOSE: This study investigates the impact of two different intensities and different volumes of low-load resistance training (LLRT) with and without blood flow restriction on the adaptation of muscle strength and size. METHODS: The sample was divided into five groups: one set of 20 % of one repetition maximum (1RM), three sets of 20 % of 1RM, one set of 50 % of 1RM, three sets of 50 % of 1RM, or control. LLRT was performed with (OC) or without (NOC) vascular occlusion, which was selected randomly for each subject. The maximal muscle strength (leg extension; 1RM) and the cross-sectional area (quadriceps; CSA) were assessed at baseline and after 8 weeks of LLRT. RESULTS: 1RM performance was increased in both groups after 8 weeks of training: OC (1 * 50 % = 20.6 %; 3 * 50 % = 20.9 %; 1 * 20 % = 26.6 %; 3 * 20 % = 21.6 %) and NOC (1 * 50 % = 18.6 %; 3 * 50 % = 26.8 %; 1 * 20 % = 18.5 %; 3 * 20 % = 21.6 %; 3 * 20 % = 24.7 %) compared with the control group (-1.7 %). Additionally, the CSA was increased in both groups: OC (1 * 50 % = 2.4 %; 3 * 50 % = 3.8 %; 1 * 20 % = 4.6 %; 3 * 20 % = 4.8 %) and NOC (1 * 50 % = 2.4 %; 3 * 50 % = 1.5 %; 1 * 20 % = 4.3 %; 3 * 20 % = 3.8 %) compared with the control group (-0.7 %). There were no significant differences between the OC and NOC groups. CONCLUSION: We conclude that 8 weeks of LLRT until failure in novice young lifters, regardless of occlusion, load or volume, produces similar magnitudes of muscular hypertrophy and strength. PMID- 25731928 TI - Short-arm human centrifugation with 0.4g at eye and 0.75g at heart level provides similar cerebrovascular and cardiovascular responses to standing. AB - BACKGROUND AND PURPOSE: Orthostatic intolerance continues to be a problem with astronauts upon return to Earth as a result of cerebral and cardiovascular adaptations to weightlessness. We tested the hypothesis that artificial gravity from a short-arm human centrifuge (SAHC) could provide cerebral and cardiovascular stimuli similar to upright posture and thereby serve as a suitable countermeasure. METHODS: We compared cardiovascular and cerebrovascular responses before, during, and after exposure to hyper-G with that of standing in healthy young participants. The head was positioned such that the middle cerebral artery (MCA) was 0.46 m from the center of rotation. Two levels of hyper-G that provided 1g and 2g at foot level were investigated. Continuous blood pressure, heart rate, calf blood volume, MCA mean blood flow velocity (MFV) and end-tidal CO2 were measured. RESULTS: Blood pressure at the level of the MCA (BP-MCA) and MFV was reduced during stand and at 2g. The relationship between MFV and BP-MCA at 2g was different from supine and similar to standing, while 1g centrifugation was not different from supine. The cardiovascular system was also not different from supine at 1g but was similarly challenged in 2g compared to stand. CONCLUSIONS: Our data suggest that short-arm centrifugation 2g at the feet, with the head offset 0.5 m from the center, provides similar cardiovascular and cerebral responses to standing. This supports the hypothesis that passive 2g SAHC exposure at the feet could be used as a countermeasure for in-flight cardiovascular and cerebrovascular deconditioning. PMID- 25731929 TI - Why Definitions Matter: Stalking Victimization in the United States. AB - Although there is a growing understanding of stalking victimization, it remains difficult to define, and characterizations of the phenomenon vary within the literature. As such, research is needed to understand how variations in the definition of stalking may change who is defined as a victim and thereby limit the generalizability of findings across previous studies. The focus of this study is the inclusion or exclusion of subjective and reasonable measures of fear for 1,430 victims identified by the 2006 Supplemental Victimization Survey. Results suggest that the definition of stalking is important, and prior research has potentially excluded stalking victims due to restrictive operationalizations. Victims who report different types of fear appear to be similar to each other in some respects but differ in others, particularly with regard for gender representation, suggesting some definitions of stalking may be gendered and under represent male stalking victims. Finally, using complex stratified survey weights, the impact of these varying operationalizations is examined. Using the same data but different definitions resulted in estimates of just over 1 to 5.3 million persons who are stalked in the United States each year. PMID- 25731930 TI - Correlates of Female-Perpetrated Intimate Partner Violence in Kano, Northern Nigeria. AB - Women are by no means the exclusive victims of intimate partner violence (IPV). This study assessed the lifetime prevalence and predictors of female-perpetrated IPV among public servants in Kano, Nigeria. Using a descriptive cross-sectional design and systematic sampling, pre-tested structured self-administered questionnaires were used to assess prevalence, types, and predictors of IPV among 302 married men. The lifetime prevalence of IPV was 66.8% (n = 177; 95% confidence interval [CI] = [60.7, 72.4]). Of surveyed men who have ever experienced violence, 78.0% (n = 138), 81.4% (n = 144), and 16.4% (n = 29) encountered physical assault, psychological aggression, and sexual coercion, respectively. After controlling for confounders, having >=5 children, adjusted odds ratio (aOR) [95% CI] = 3.93 [1.16, 13.29], p = .027, and childhood experience of violence, aOR [95% CI] = 0.14 [0.05, 0.39], p = .0001, remained significant predictors of female-perpetrated IPV. In conclusion, female perpetrated IPV is prevalent in northern Nigeria. Addressing IPV will require comprehensive violence prevention measures, including counseling and support for victims and exposed children. PMID- 25731931 TI - Individual Community-Based Treatment of Offenders With Mental Illness: Relationship to Recidivism. AB - This study explores the effectiveness of psychological intervention at reducing the risk of recidivism among a group of high-risk, high-need offenders housed in a Community Correctional Centre (CCC) operated by the Correctional Service of Canada (CSC). File reviews on 136 male federal offenders living in a CCC in a large metropolitan area were included in the present investigation. Previous research on this sample by our team indicated that the majority of this sample met diagnostic criteria for a variety of psychiatric conditions. Data on the number of individual counseling sessions received and progress in treatment were collected from official file information for the purpose of the present investigation. After accounting for actuarially assessed risk, moderate doses of treatment were found to be associated with 7.7 times less likelihood of recidivism, and high doses of treatment were found to be associated with 11.6 times less likelihood of recidivism, when compared with offenders who received no treatment or were only assessed for treatment. These results are discussed in the context of correctional models of offender risk assessment and rehabilitation. It is notable that a very simple measure of global mental health treatment attendance, with no consideration of such factors as responsiveness, added considerable incremental predictive validity to the results after having statistically accounted for actuarially assessed risk of recidivism. PMID- 25731932 TI - The efficacy of percutaneous transluminal angioplasty treatment for the patients with arteriovenous fistula dysfunction. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and outcomes of three different percutaneous transluminal angioplasty (PTA) approaches in the treatment of patients with arteriovenous fistula (AVF) dysfunction. METHODS: A retrospective review was performed in a total of 183 patients with AVF dysfunction treated with 3 different PTA approaches (transarterial, transvenous and combination) in our hospital from October 2006 to October 2012. Technical and clinical success rate, complications and vessel patency were assessed. RESULTS: The mean length of pretreatment stenosis segment was 2.0+/-1.4 cm (range 0.5-6.8 cm), and the mean length of stenosis segment was shortest in transvenous group. The technical success rates using transarterial and transvenous approach were 80.4% (P<0.01) and 87.8% (P<0.01), respectively, compared to 32.4% of combination approach. Moreover, the clinical success rates using transarterial and transvenous approach were 92.8% and 95.9% (P<0.01), respectively, comparing to 54.1% of combination approach. Moreover, significant difference was found on the presence of vasospasm among the three groups (P<0.01). In addition, a higher primary patency rate was also achieved by using transarterial (P<0.01) and transvenous approach (P<0.01) compared to combination approach. CONCLUSIONS: Transarterial and transvenous PTA is more efficient than combination PTA for the patients with dysfunctional AVF. A high technical and clinical success rate could be achieved by using both approaches. Limited number of complications and high rate of primary patency were found in the patients. PMID- 25731933 TI - New Ways of Using Well Construction Reports for Hydrostratigraphic Analyses. AB - Hydrostratigraphic models require subsurface data. Those data can be gleaned from Well Construction Reports (WCRs) if the reports are properly reviewed and processed. In the United States, WCRs or similar documents are generally required to be submitted to a state agency. The quality of those reports varies considerably and depends on the water well contractor's level of geologic knowledge. Nevertheless, these types of reports are usually the largest available subsurface data set. We present two examples from Wisconsin, each of which had approximately 2000 WCRs, to demonstrate a variety of new applications of WCRs including obtaining information about the depositional environment; selecting sites to perform surface geophysical measurements; and creating three-dimensional hydrostratigraphic models for groundwater modeling. PMID- 25731934 TI - The use of insulin detemir during pregnancy: a safety evaluation. AB - INTRODUCTION: Diabetes during pregnancy causes both fetal and maternal complications. Insulin is the most effective pharmacological treatment for controlling hyperglycemia during gestation and can limit adverse outcomes. Insulin detemir (IDet), a novel basal insulin, has already been used for this indication for several years. It was reclassified in 2012 by the FDA from category C to category B for the treatment of pregnant women with diabetes. AREAS COVERED: This article reviews published data regarding the use of IDet during pregnancy. We discuss pharmacokinetic and pharmacodynamic qualities of IDet and potential advantages for its use during pregnancy. EXPERT OPINION: IDet is a viable option for the management of diabetes during pregnancy. Though data is limited, its safety and efficacy is probably comparable to human insulin, and in some aspects superior to it. More data, specifically for IDet in pregnancies complicated by gestational diabetes (GDM) or type 2 diabetes, is needed. PMID- 25731935 TI - Rapid adjustment of bird community compositions to local climatic variations and its functional consequences. AB - The local spatial congruence between climate changes and community changes has rarely been studied over large areas. We proposed one of the first comprehensive frameworks tracking local changes in community composition related to climate changes. First, we investigated whether and how 12 years of changes in the local composition of bird communities were related to local climate variations. Then, we tested the consequences of this climate-induced adjustment of communities on Grinnellian (habitat-related) and Eltonian (function-related) homogenization. A standardized protocol monitoring spatial and temporal trends of birds over France from 2001 to 2012 was used. For each plot and each year, we used the spring temperature and the spring precipitations and calculated three indices reflecting the thermal niche, the habitat specialization, and the functional originality of the species within a community. We then used a moving-window approach to estimate the spatial distribution of the temporal trends in each of these indices and their congruency with local climatic variations. Temperature fluctuations and community dynamics were found to be highly variable in space, but their variations were finely congruent. More interestingly, the community adjustment to temperature variations was nonmonotonous. Instead, unexplained fluctuations in community composition were observed up to a certain threshold of climate change intensity, above which a change in community composition was observed. This shift corresponded to a significant decrease in the relative abundance of habitat specialists and functionally original species within communities, regardless of the direction of temperature change. The investigation of variations in climate and community responses appears to be a central step toward a better understanding of climate change effects on biodiversity. Our results suggest a fine-scale and short-term adjustment of community composition to temperature changes. Moreover, significant temperature variations seem to be responsible for both the Grinnellian and Eltonian aspects of functional homogenization. PMID- 25731936 TI - Instrumented gait analysis for an objective pre-/postassessment of tap test in normal pressure hydrocephalus. AB - OBJECTIVE: To present an objective method to evaluate gait improvements after a tap test in idiopathic normal pressure hydrocephalus (INPH). DESIGN: Retrospective analysis of gait data. SETTING: Public tertiary care center, day hospital. The gait analysis was performed before and 2 to 4 hours after the tap test. PARTICIPANTS: Participants included patients with INPH (n=60) and age- and sex-matched controls (n=50; used to obtain reference intervals). From an initial referred sample of 79 patients (N=79), we excluded those unable to walk without walking aids (n=9) and those with incomplete (pre-/posttap test) gait data (n=10). Thirteen out of 60 patients were shunted and then reappraised after 6 months. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mahalanobis distance from controls, before and after the tap test. Eleven gait parameters were combined in a single quantitative score. Walking velocity was also evaluated because it is frequently used in tap test assessment. RESULTS: Patients were classified into 2 groups: tap test responders (n=22, 9 of them were shunted) and not suitable for shunt (n=38, 4 of them were shunted). In the tap test responders group, 9 out of 9 patients improved after shunt. In the not suitable for shunt group, 3 out of 4 patients did not improve. Gait velocity increased after the tap test in 53% of responders and in 37% of patients not suitable for shunt. CONCLUSIONS: The new method is applicable to clinical practice and allows for selecting tap test responders in an objective way, quantifying the improvements. Our results suggest that gait velocity alone is not sufficient to reliably assess tap test effects. PMID- 25731937 TI - Prevalence of fatigue, pain, and affective disorders in adults with duchenne muscular dystrophy and their associations with quality of life. AB - OBJECTIVES: To assess the prevalence of fatigue, pain, anxiety, and depression in adults with Duchenne muscular dystrophy (DMD), and to analyze their relationship with health-related quality of life. DESIGN: Cross-sectional study. SETTING: Home of participants. PARTICIPANTS: Adults (N=80) with DMD. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fatigue was assessed with the Fatigue Severity Scale; pain with 1 item of the Medical Outcomes Study 36-Item Short-Form Health Survey and by interview; and anxiety and depression by using the Hospital Anxiety and Depression Scale. Health-related quality of life was assessed using the World Health Organization Quality of Life Scale-Brief Version. Associations between these conditions and quality of life were assessed by means of univariate and multivariate logistic regression analyses. RESULTS: Symptoms of fatigue (40.5%), pain (73.4%), anxiety (24%), and depression (19%) were frequently found. Individuals often had multiple conditions. Fatigue was related to overall quality of life and to the quality-of-life domains of physical health and environment; anxiety was related to the psychological domain. CONCLUSIONS: Fatigue, pain, anxiety, and depression, potentially treatable symptoms, occur frequently in adults with DMD and significantly influence health-related quality of life. PMID- 25731938 TI - Influence of circadian rhythms on the temporal features of motor imagery for older adult inpatients. AB - OBJECTIVE: To examine the circadian modulation on motor imagery quality for older adult inpatients to determine the best time of day to use motor imagery in rehabilitation activities. DESIGN: Time series posttest only. SETTING: Inpatient rehabilitation center. PARTICIPANTS: Participants included older adult inpatients (N=34) who were hospitalized for diverse geriatric or neurogeriatric reasons. They were able to sit without assistance, manipulate objects, and walk 10m in <30 seconds without technical help or with a walking stick. INTERVENTION: None. MAIN OUTCOME MEASURES: The executed and imagined durations of writing and walking movements were recorded 7 times a day (9:15 am-4:45 pm), at times compatible with the hours of rehabilitation activities. Motor imagery quality was evaluated by computing the isochrony index (ie, absolute difference between the average duration of executed and imagined actions) for each trial and each inpatient. The cosinor method was used to analyze the time series for circadian rhythmicity. RESULTS: Imagined movements duration and isochrony index exhibited circadian modulations, whereas no such rhythmic changes appeared for executed movements. Motor imagery quality was better late in the morning, at approximately 10:18 am and 12:10 pm for writing and walking, respectively. CONCLUSIONS: Cognitive and sensorimotor aspects of motor behaviors differed among the older adults. The temporal features of motor imagery showed a clear circadian variation. From a practical perspective, this study offers information on an effective schedule for motor imagery in rehabilitation activities with older adult inpatients. PMID- 25731939 TI - Impact of fetal growth and preterm birth on the retinal microvasculature in mid adulthood. AB - OBJECTIVE: We hypothesized that preterm birth and being born SGA would be associated with changes in retinal microvascular architecture and that these changes would be more marked among those born preterm. We further hypothesized that these microvascular changes would correlate with early markers of CVD in mid adulthood. METHODS: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish University cities. Retinal microvascular architecture of participants born preterm, born at term and SGA and a control group born at term and AGA were compared (aged 34-49 years). RESULTS: In participants born preterm, arteriolar tortuosity (*10(2)) was higher-means (standard error), 0.06 (0.01) versus 0.04 (0.01), p = 0.001, arteriolar length (pixels) were greater-644.9 (35.9) versus 591.7 (33.5), p = 0.007 and arteriolar diameters (pixels) were narrower-19.9 (0.4) versus 20.3 (0.3), p = 0.034 compared to participants born AGA, after adjustment. In participants born SGA, only arteriolar tortuosity was higher-0.05 (0.01) versus 0.04 (0.01), p = 0.074 compared to participants born AGA. CONCLUSION: This study demonstrated that being born SGA and in particular preterm birth are associated with changes in retinal microvascular architecture. The prenatal and immediate postnatal environment may contribute to the mechanisms. PMID- 25731941 TI - From demyelination to remyelination: the road toward therapies for spinal cord injury. AB - Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation. PMID- 25731940 TI - Functions that protect Escherichia coli from DNA-protein crosslinks. AB - Pathways for tolerating and repairing DNA-protein crosslinks (DPCs) are poorly defined. We used transposon mutagenesis and candidate gene approaches to identify DPC-hypersensitive Escherichia coli mutants. DPCs were induced by azacytidine (aza-C) treatment in cells overexpressing cytosine methyltransferase; hypersensitivity was verified to depend on methyltransferase expression. We isolated hypersensitive mutants that were uncovered in previous studies (recA, recBC, recG, and uvrD), hypersensitive mutants that apparently activate phage Mu Gam expression, and novel hypersensitive mutants in genes involved in DNA metabolism, cell division, and tRNA modification (dinG, ftsK, xerD, dnaJ, hflC, miaA, mnmE, mnmG, and ssrA). Inactivation of SbcCD, which can cleave DNA at protein-DNA complexes, did not cause hypersensitivity. We previously showed that tmRNA pathway defects cause aza-C hypersensitivity, implying that DPCs block coupled transcription/translation complexes. Here, we show that mutants in tRNA modification functions miaA, mnmE and mnmG cause defects in aza-C-induced tmRNA tagging, explaining their hypersensitivity. In order for tmRNA to access a stalled ribosome, the mRNA must be cleaved or released from RNA polymerase. Mutational inactivation of functions involved in mRNA processing and RNA polymerase elongation/release (RNase II, RNaseD, RNase PH, RNase LS, Rep, HepA, GreA, GreB) did not cause aza-C hypersensitivity; the mechanism of tmRNA access remains unclear. PMID- 25731943 TI - Psychosocial factors at work and occupational injuries: A prospective study of the general working population in Norway. AB - BACKGROUND: We examined the effects of psychosocial stressors at work on subsequent injuries, taking into account organizational and mechanical working conditions. METHODS: Randomly drawn from the general population, the cohort comprised respondents with an active employee relationship in 2006 and 2009 (n = 6,745). OUTCOME MEASURE: "Have you, over the past 12 months, afflicted injuries that were caused by an accident at work, and resulting in time off work after the day of the accident?". RESULTS: High job strain (Odds ratio [OR] 2.31; 95% confidence interval [CI] 1.16-4.57), high role conflict (OR 3.01; 95% CI 1.70 5.31), and high emotional demands (OR 1.96; 95% CI 1.15-3.35) predicted injury at follow up (P < 0.01). The population risk attributable to each of these factors ranged from 11% to 14%. CONCLUSIONS: Excess risk of occupational injuries was attributable to job strain, role conflict, and emotional demands. These factors are potentially amenable to preventive measures. PMID- 25731946 TI - Module based training improves and sustains surgical skills: a randomised controlled trial. AB - PURPOSE: Traditional surgical training is challenged by factors such as patient safety issues, economic considerations and lack of exposure to surgical procedures due to short working hours. A module-based clinical training model promotes rapidly acquired and persistent surgical skills. METHODS: A randomised controlled trial concerning supervised hernia repair in eight training hospitals in Denmark was performed. The participants were 18 registrars [Post graduate year (PGY) 3 or more] in their first year of surgical specialist training. The intervention consisted of different modules with a skills-lab course followed by 20 supervised Lichtenstein hernia repairs. Operative performance was video recorded and blindly rated by two consultants using a previously validated skills rating scale (8-40 points). Outcome measures were change in the ratings of operative skills and operative time. RESULTS: In the intervention group (n = 10) the average rating of operative skills before intervention was 22.5 (20.6-24.3) and after 26.2 (23.5-28.8), p = 0.044. At follow-up after 1 year, rating was 26.9 (23.4-30.4), p = 0.019. In the conventionally trained group average rating was 23.4 (19.4-27.3) at start and 21.7 (17.3-26.1) at end, p = 0.51. At start no difference was detected between the two groups, p = 0.59; by 1 year the difference was statistically significant favouring intervention, p = 0.044. Operative time showed similar results in favour of the intervention. CONCLUSIONS: A module-based training model in Lichtenstein hernia repair was preferable in both short and long-term compared with standard clinical training. The model will probably be applicable to other surgical training procedures. PMID- 25731947 TI - Results of prosthetic mesh repair in the emergency management of the acutely incarcerated and/or strangulated groin hernias: a 10-year study. AB - PURPOSE: The aim of this prospective study was to present a 10-year experience with the use of prosthetic mesh repair in the management of the acutely incarcerated and/or strangulated groin hernias. METHODS: Patients with acutely incarcerated and/or strangulated groin hernias were treated by emergency repair of the hernia using a Prolene mesh. The presence of non-viable intestine necessitating resection-anastomosis of the bowel was not considered a contraindication to the use of mesh. RESULTS: The present study included 234 patients. Their age ranged from 16 to 85 years with a mean of 55.9 +/- 17.7 years. The hernia was indirect inguinal in 201 patients (85.9%), direct inguinal in 5 patients 5 (2.1%), hernia of canal of nuck in 13 patients (5.6%) and femoral in 15 patients (6.4%). Thirty patients (12.8%) had recurrent hernias. Resection anastomosis of non-viable small intestine was performed in 32 patients (13.7%). There were 5 perioperative mortalities (2.1%). Complications were encountered in 41 patients (17.5%) and included wound infection in 14 patients (6%), scrotal hematoma in 9 patients (3.8%), chest infection in 8 patients (3.4%), deep vein thrombosis in 2 patients (0.9%), transient deterioration of liver function in 11 patients (4.7%) and mesh infection in 1 patient (0.5%). Follow-up duration ranged from 6 to 120 months with a mean of 62.5 +/- 35.3 months. Two recurrences (0.9%) were encountered throughout the study period. CONCLUSIONS: The use of prosthetic mesh repair in the emergency management of the acutely incarcerated and/or strangulated groin hernias is safe. The presence of non-viable intestine cannot be regarded as a contraindication for prosthetic repair. PMID- 25731948 TI - Impact of varicocele on biological markers of gonadal function. AB - PURPOSE: The aim of this study is to evaluate the potential effect of varicocele in the hormonal and clinical profile of adolescents. METHODS: Twenty adolescents at Tanner stage 4-5 with left varicocele were studied and compared with a control group of 20 healthy adolescents. All patients underwent ultrasonographic testicular volumetry as well as hormonal evaluation of inhibin B, testosterone, baseline and gonadotropin-releasing hormone stimulated, follicle-stimulating hormone as well as luteinizing hormone. Statistical analysis was performed using the student's t test with p value <0.05 taken as statistical significant. RESULTS: Patients with varicocele showed reduced levels of inhibin B compared to controls and a significant reduction in the testicular volume on the affected side. The response of luteinizing hormone to gonadotropin-releasing hormone stimulation was significantly higher in the varicocele group compared to the control group. Furthermore a significant inverse relationship of inhibin B compared to follicle-stimulating hormone was noted. CONCLUSION: Serum inhibin B levels could represent a useful marker of Sertoli cell damage caused by varicocele. PMID- 25731949 TI - Late mesh sepsis: how late is late? PMID- 25731950 TI - The etiology of indirect inguinal hernia in adults: congenital, acquired or both? PMID- 25731951 TI - Oral manifestations in AIDS. PMID- 25731952 TI - Laryngeal amyloidosis presenting as false vocal fold bulging: clinical and therapeutic aspects. PMID- 25731954 TI - Exploring reaction pathways for O-GlcNAc transferase catalysis. A string method study. AB - The inverting O-GlcNAc glycosyltransferase (OGT) is an important post-translation enzyme, which catalyzes the transfer of N-acetylglucosamine from UDP-N acetylglucosamine (UDP-GlcNAc) to the hydroxyl group of the Ser/Thr of cytoplasmic, nuclear, and mitochondrial proteins. In the past, three different catalytic bases were proposed for the reaction: His498, alpha-phosphate, and Asp554. In this study, we used hybrid quantum mechanics/molecular mechanics (QM/MM) Car-Parrinello molecular dynamics to investigate reaction paths using alpha-phosphate and Asp554 as the catalytic bases. The string method was used to calculate the free-energy reaction profiles of the tested mechanisms. During the investigations, an additional mechanism was observed. In this mechanism, a proton is transferred to alpha-phosphate via a water molecule. Our calculations show that the mechanism with alpha-phosphate acting as the base is favorable. This reaction has a rate-limiting free-energy barrier of 23.5 kcal/mol, whereas reactions utilizing Asp554 and water-assisted alpha-phosphate have barriers of 41.7 and 40.9 kcal/mol, respectively. Our simulations provide a new insight into the catalysis of OGT and may thus guide rational drug design of transition-state analogue inhibitors with potential therapeutic use. PMID- 25731953 TI - Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. AB - BACKGROUND: Evidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25 hydroxyvitamin D (25(OH)D) and common variations in key vitamin D-related genes with fatal PCa. METHODS: In a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single nucleotide polymorphisms (SNPs) in 7 vitamin D-related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor alpha) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls. RESULTS: No statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend = .22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002. CONCLUSIONS: Statistically significant associations were not observed for either 25(OH)D or vitamin D-related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration. PMID- 25731955 TI - Assessment of functional and behavioral changes sensitive to painful disc degeneration. AB - The development of an in vivo rodent discogenic pain model can provide insight into mechanisms for painful disc degeneration. Painful disc degeneration in rodents can be inferred by examining responses to external stimuli, observing pain-related behaviors, and measuring functional performance. This study compared the sensitivity of multiple pain and functional assessment methods to disc disruption for identifying the parameters sensitive to painful disc degeneration in rats. Disc degeneration was induced in rats by annular injury with saline injection. The severity of disc degeneration, pain sensitivity, and functional performance were compared to sham and naive control rats. Saline injection induced disc degeneration with decreased disc height and MRI signal intensity as well as more fibrous nucleus pulposus, disorganized annular lamellae and decreased proteoglycan. Rats also demonstrated increased painful behaviors including decreased hindpaw mechanical and thermal sensitivities, increased grooming, and altered gait patterns with hindpaw mechanical hyperalgesia and duration of grooming tests being most sensitive. This is the first study to compare sensitivities of different pain assessment methods in an in vivo rat model of disc degeneration. Hindpaw mechanical sensitivity and duration of grooming were the most sensitive parameters to surgically induced degenerative changes and overall results were suggestive of disc degeneration associated pain. PMID- 25731956 TI - Production of new amilorides as potent inhibitors of mitochondrial respiratory complex I. AB - Amilorides, well-known inhibitors of Na(+)/H(+) antiporters, have also shown to inhibit bacterial and mitochondrial NADH-quinone oxidoreductase (complex I). Since the membrane subunits ND2, ND4, and ND5 of bovine mitochondrial complex I are homologous to Na(+)/H(+) antiporters, amilorides have been thought to bind to any or all of the antiporter-like subunits; however, there is no direct experimental evidence in support of this notion. Photoaffinity labeling is a powerful technique to identify the binding site of amilorides in bovine complex I. Commercially available amilorides such as 5-(N-ethyl-N-isopropyl)amiloride are not suitable as design templates to synthesize photoreactive amilorides because of their low binding affinities to bovine complex I. Thereby, we attempted to modify the structures of commercially available amilorides in order to obtain more potent derivatives. We successfully produced two photoreactive amilorides (PRA1 and PRA2) with a photolabile azido group at opposite ends of the molecule. PMID- 25731957 TI - Virus-associated small satellite RNAs and viroids display similarities in their replication strategies. AB - Since the discovery of non-coding, small, highly structured, satellite RNAs (satRNAs) and viroids as subviral pathogens of plants , have been of great interest to molecular biologists as possible living fossils of pre-cellular evolution in an RNA world. Despite extensive studies performed in the last four decades, there is still mystery surrounding the origin and evolutionary relationship between these subviral pathogens. Recent technical advances revealed some commonly shared replication features between these two subviral pathogens. In this review, we discuss our current perception of replication and evolutionary origin of these petite RNA pathogens. PMID- 25731958 TI - Virus hunting. AB - Viral diagnosis and discovery are receiving increasing emphasis with the recognition of their importance in addressing the challenges of emerging infectious and chronic diseases, and the advent of antiviral drugs with which to reduce the morbidity and mortality of viral infections. Here we review the status of the field including the use of molecular, proteomic and immunological assays for viral detection, social media platforms for surveillance, and public health investments that may enable enhanced situational awareness and insights into the origins of zoonotic viral diseases. PMID- 25731960 TI - Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. AB - Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or osteomalacia and tooth loss, and sometimes to craniosynostosis and calcium crystal arthropathies. HPP's remarkably broad-ranging expressivity spans stillbirth from profound skeletal hypomineralization to adult-onset dental problems or arthropathies without bone disease, which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred, usually missense, TNSALP mutations. For clinical purposes, this expressivity has been codified according to absence or presence of skeletal disease and then patient age at presentation and diagnosis. Pediatric patients are reported principally with "odonto", "childhood", "infantile", or "perinatal" HPP. However, this nosology has not been tested using a cohort of patients, and the ranges of the clinical and laboratory findings have not been defined and contrasted among these patient groups. To evaluate the extant nosology for HPP in children, we assessed our 25 years experience with 173 pediatric HPP patients. Data were exclusively from inpatient studies. The childhood form of HPP was further designated "mild" or "severe". Here, we focused on demographic, clinical, and dual-energy X-ray absorptiometry parameters compared to data from healthy American children. The 173-patient cohort comprised 64 individuals with odonto HPP, 38 with mild childhood HPP, 58 with severe childhood HPP, and 13 with infantile HPP. None was a survivor of perinatal HPP. TNSALP analysis revealed a mutation(s) in all 105 probands tested. Thirteen mutations were unique. Most patients represented autosomal dominant inheritance of HPP. Mutant allele dosage generally indicated the disorder's severity. Gender discordance was found for severe childhood HPP; 42 boys versus 16 girls (p=0.006), perhaps reflecting parental concern about stature and strength. Key disease parameters (e.g., height, weight, numbers of teeth lost prematurely, grip strength, spine and hip bone mineral density) were increasingly compromised as HPP was designated more severe. Although data overlapped successively between the four patient groups, body size (height and weight) differed significantly. Thus, our expanded nosology for HPP in children organizes the disorder's broad-ranging expressivity and should improve understanding of HPP presentation, natural history, complications, and prognosis. PMID- 25731961 TI - High-throughput screens in mammalian cells using the CRISPR-Cas9 system. AB - As a powerful genome-editing tool, the clustered regularly interspaced short palindromic repeats (CRISPR)-clustered regularly interspaced short palindromic repeats-associated protein 9 (Cas9) system has been quickly developed into a large-scale function-based screening strategy in mammalian cells. This new type of genetic library is constructed through the lentiviral delivery of single-guide RNA collections that direct Cas9 or inactive dead Cas9 fused with effectors to interrogate gene function or regulate gene transcription in targeted cells. Compared with RNA interference screening, the CRISPR-Cas9 system demonstrates much higher levels of effectiveness and reliability with respect to both loss-of function and gain-of-function screening. Unlike the RNA interference strategy, a CRISPR-Cas9 library can target both protein-coding sequences and regulatory elements, including promoters, enhancers and elements transcribing microRNAs and long noncoding RNAs. This powerful genetic tool will undoubtedly accelerate the mechanistic discovery of various biological processes. In this mini review, we summarize the general procedure of CRISPR-Cas9 library mediated functional screening, system optimization strategies and applications of this new genetic toolkit. PMID- 25731962 TI - Two-component dipolar Bose-Einstein condensate in concentrically coupled annular traps. AB - Dipolar Bosonic atoms confined in external potentials open up new avenues for quantum-state manipulation and will contribute to the design and exploration of novel functional materials. Here we investigate the ground-state and rotational properties of a rotating two-component dipolar Bose-Einstein condensate, which consists of both dipolar bosonic atoms with magnetic dipole moments aligned vertically to the condensate and one without dipole moments, confined in concentrically coupled annular traps. For the nonrotational case, it is found that the tunable dipolar interaction can be used to control the location of each component between the inner and outer rings, and to induce the desired ground state phase. Under finite rotation, it is shown that there exists a critical value of rotational frequency for the nondipolar case, above which vortex state can form at the trap center, and the related vortex structures depend strongly on the rotational frequency. For the dipolar case, it is found that various ground state phases and the related vortex structures, such as polygonal vortex clusters and vortex necklaces, can be obtained via a proper choice of the dipolar interaction and rotational frequency. Finally, we also study and discuss the formation process of such vortex structures. PMID- 25731963 TI - The electronic structure of metal oxide/organo metal halide perovskite junctions in perovskite based solar cells. AB - Cross-sections of a hole-conductor-free CH3NH3PbI3 perovskite solar cell were characterized with Kelvin probe force microscopy. A depletion region width of about 45 nm was determined from the measured potential profiles at the interface between CH3NH3PbI3 and nanocrystalline TiO2, whereas a negligible depletion was measured at the CH3NH3PbI3/Al2O3 interface. A complete solar cell can be realized with the CH3NH3PbI3 that functions both as light harvester and hole conductor in combination with a metal oxide. The band diagrams were estimated from the measured potential profile at the interfaces, and are critical findings for a better understanding and further improvement of perovskite based solar cells. PMID- 25731964 TI - Exercise behavior and patient-reported outcomes in women with early breast cancer receiving locoregional radiation therapy. AB - PURPOSE: Radiation therapy is associated with acute treatment-related complications that can lead to decreased quality of life (QOL). Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes, and acute radiation therapy toxicities. METHODS AND MATERIALS: Women receiving curative breast radiation therapy were enrolled. Each patient completed an exercise behavior/QOL survey before or during the first week of treatment and again during the last week of treatment. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Measurements to evaluate upper extremity lymphedema and shoulder range of motion were completed. Skin toxicity was assessed weekly. Patient-reported outcomes were measured using standardized questionnaires. RESULTS: Forty-five patients were enrolled. Mean patient age was 54 (range, 28-73) years. Mean METs in the exercise cohort (>=9 METs/wk) was 21 per week (range, 11-38, n = 14); 3 per week (range, 0-8, n = 25) in the nonexercise cohort (<9 METs/wk). Women in the exercise cohort showed improvements in treatment-induced quality of life and fatigue (not significant) despite more extensive surgical, medical, and radiation treatment. No differences in treatment related toxicities, pain, or sleep scores were noted. Lymphedema was mild (<3 cm) in the entire patient cohort. CONCLUSIONS: The vast majority of current exercise oncology literature implicates physical activity as an independent predictor of QOL in cancer patients. Our study noted similar trends, but they were not statistically significant. This may be due to our finding that patient-reported outcomes with radiation therapy are relatively high compared with other treatment modalities and remain stable throughout treatment. Thus, it may be that radiation therapy has a limited impact on QOL in breast cancer patients. Exercise may be best used as a targeted therapy in patients at high risk for poor QOL or radiation-related toxicities at baseline. PMID- 25731965 TI - Incidence and predictors of severe acute esophagitis and subsequent esophageal stricture in patients treated with accelerated hyperfractionated chemoradiation for limited-stage small cell lung cancer. AB - PURPOSE: Clinical and dosimetric predictors of severe (grade 3 or greater) acute esophageal toxicity and subsequent esophageal dilation were explored in patients with limited-stage small cell lung cancer treated with accelerated hyperfractionated chemoradiation. METHODS AND MATERIALS: A total of 130 patients were identified who were treated to 45 Gy in 1.5-Gy twice-daily fractions with concurrent platinum-based chemotherapy between 2000 and 2009. Data on clinical, disease-related, and treatment-related variables were collected. Patients with percutaneous endoscopic gastrostomy tube insertion or intravenous hydration because of poor oral intake were designated as having acute grade 3 esophagitis. Univariate and multivariate analyses that associated treatment characteristics with esophagitis were assessed via logistic regression, and optimal cut points were identified with recursive partitioning analysis. RESULTS: Twenty-five patients developed severe acute esophagitis, at a rate of 26% (18/69) in patients treated with earlier 3-dimensional conformal radiation therapy techniques and 11.5% (7/61) in patients treated with intensity modulated radiation therapy techniques and omission of elective nodal irradiation. The incidence of esophageal stricture was 6% overall (8 of 128 eligible) but 26% (6/23) among those who experienced prior grade 3 acute esophagitis and 2% (2/105) among those with acute esophagitis less than or equal to grade 2. Significant multivariate predictors of acute esophagitis were mean dose and volume of esophagus receiving at least 5% to 35% of the prescribed dose (V5 to V40). Patients with V5 >= 74% had a 44.4% risk of severe acute esophagitis (12/27) versus 12.6% (13/103) among those with V5 < 74%. V45 was the only dosimetric predictor for esophageal stricture, with 13.7% of patients in whom V45 was >=37.5% requiring subsequent dilation. CONCLUSIONS: Modern radiation techniques are associated with a lower frequency of severe acute esophagitis than previous paradigms. The proportion of esophagus receiving low- to moderate-range doses (mean, V5 through V40) predicts acute esophagitis, whereas the proportion of esophagus that receives high doses (V45) predicts the development of esophageal stricture that requires dilation. Patients who develop grade 3 acute esophagitis are at significant risk for subsequent esophageal stricture, whereas those with acute esophagitis of grade 2 or less display minimal risk. PMID- 25731966 TI - The Calling. PMID- 25731968 TI - Most common cause of death in England and Wales in 2013 was heart disease in men and dementia in women. PMID- 25731967 TI - Improving Physical Activity in Hispanics with Diabetes and their Families. AB - OBJECTIVE: This study examined changes in physical activity among Hispanics with diabetes and their families who received an 8-week diabetes self-management intervention. DESIGN: A quasi-experimental design was used to conduct a secondary analysis of physical activity data from two intervention studies that used the same protocols and measures. SAMPLE: A total of 65 patients and 66 family members participated in the studies. MEASURES: Physical activity was measured with the International Physical Activity Questionnaire (IPAQ) and pedometers. Self-report of physical activity was collected pre- and postintervention, and pedometer data for the 8 weeks of the intervention period. INTERVENTION: The interventions consisted of 8 weeks of educational sessions. RESULTS: IPAQ walking Metabolic Equivalent of Task (MET)-minutes per week significantly increased for patients (p < .001) and family members (p < .001) from pre- to postintervention as did moderate activity MET-minutes/week for family members (p = .004). Based on pedometer steps, the percentage of sedentary patients declined from 38% to 17% over the intervention record; differences in pedometer steps over time were not significant for patients (p = .803) or family members (p = .144). CONCLUSIONS: Pedometers are a cost effective and user-friendly method of measuring physical activity. Pedometers can also serve as a motivator to help increase physical activity among Hispanics with diabetes and their family members. PMID- 25731969 TI - Different selection pressures give rise to distinct ethnic phenomena : a functionalist framework with illustrations from the Peruvian Altiplano. AB - Many accounts of ethnic phenomena imply that processes such as stereotyping, essentialism, ethnocentrism, and intergroup hostility stem from a unitary adaptation for reasoning about groups. This is partly justified by the phenomena's co-occurrence in correlational studies. Here we argue that these behaviors are better modeled as functionally independent adaptations that arose in response to different selection pressures throughout human evolution. As such, different mechanisms may be triggered by different group boundaries within a single society. We illustrate this functionalist framework using ethnographic work from the Quechua-Aymara language boundary in the Peruvian Altiplano. We show that different group boundaries motivate different ethnic phenomena. For example, people have strong stereotypes about socioeconomic categories, which are not cooperative units, whereas they hold fewer stereotypes about communities, which are the primary focus of cooperative activity. We also show that, despite the cross-cultural importance of ethnolinguistic boundaries, the Quechua-Aymara linguistic distinction does not strongly motivate any of these intergroup processes. PMID- 25731970 TI - Association of XRCC1 polymorphisms with arsenic methylation. AB - The associations of four single nucleotide polymorphisms (p.Arg194Trp, p.Arg280His, p.Pro206Pro, and p.Arg399Gln) in X-ray repair cross-complementing group 1 with urinary arsenic metabolites and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were investigated in a Vietnamese population (n = 100). Individuals with genotype AA in p.Pro206Pro showed significantly higher urinary monomethylarsonic acid (MMA(V)) and lower dimethylarsinic acid (DMA(V))/MMA(V) ratio than genotype AG. As for p.Arg399Gln, both Arg/Arg homozygous subjects and Arg/Gln heterozygous individuals showed a significantly higher urinary inorganic As percentage and lower 8-OHdG concentrations than Gln/Gln homozygous. Our results suggested that Arg399Gln is a functional SNP that may be related to DNA repair activity. PMID- 25731971 TI - Indium oxide (In2O3) nanoparticles induce progressive lung injury distinct from lung injuries by copper oxide (CuO) and nickel oxide (NiO) nanoparticles. AB - Indium is an essential element in the manufacture of liquid crystal displays and other electronic devices, and several forms of indium compounds have been developed, including nanopowders, films, nanowires, and indium metal complexes. Although there are several reports on lung injury caused by indium-containing compounds, the toxicity of nanoscale indium oxide (In2O3) particles has not been reported. Here, we compared lung injury induced by a single exposure to In2O3 nanoparticles (NPs) to that caused by benchmark high-toxicity nickel oxide (NiO) and copper oxide (CuO) NPs. In2O3 NPs at doses of 7.5, 30, and 90 cm(2)/rat (50, 200, and 600 ug/rat) were administered to 6-week-old female Wistar rats via pharyngeal aspiration, and lung inflammation was evaluated 1, 3, 14, and 28 days after treatment. Neutrophilic inflammation was observed on day 1 and worsened until day 28, and severe pulmonary alveolar proteinosis (PAP) was observed on post-aspiration days 14 and 28. In contrast, pharyngeal aspiration of NiO NPs showed severe neutrophilic inflammation on day 1 and lymphocytic inflammation with PAP on day 28. Pharyngeal aspiration of CuO NPs showed severe neutrophilic inflammation on day 1, but symptoms were completely resolved after 14 days and no PAP was observed. The dose of In2O3 NPs that produced progressive neutrophilic inflammation and PAP was much less than the doses of other toxic particles that produced this effect, including crystalline silica and NiO NPs. These results suggest that occupational exposure to In2O3 NPs can cause severe lung injury. PMID- 25731972 TI - Functional characterization of botulinum neurotoxin serotype H as a hybrid of known serotypes F and A (BoNT F/A). AB - A unique strain of Clostridium botulinum (IBCA10-7060) was recently discovered which produces two toxins: botulinum neurotoxin (BoNT) serotype B and a novel BoNT reported as serotype H. Previous molecular assessment showed that the light chain (LC) of the novel BoNT most resembled the bont of the light chain of known subtype F5, while the C-terminus of the heavy chain (HC) most resembled the binding domain of serotype A. We evaluated the functionality of both toxins produced in culture by first incorporating an immunoaffinity step using monoclonal antibodies to purify BoNT from culture supernatants and tested each immune-captured neurotoxin with full-length substrates vesicle-associated membrane protein 2 (VAMP-2), synaptosomal-associated protein 25 (SNAP-25), syntaxin, and shortened peptides representing the substrates. The BoNT/B produced by this strain behaved as a typical BoNT/B, having immunoaffinity for anti-B monoclonal antibodies and cleaving both full length VAMP-2 and a peptide based on the sequence of VAMP-2 in the expected location. As expected, there was no activity toward SNAP-25 or syntaxin. The novel BoNT demonstrated immunoaffinity for anti-A monoclonal antibodies but did not cleave SNAP-25 as expected for BoNT/A. Instead, the novel BoNT cleaved VAMP-2 and VAMP-2-based peptides in the same location as BoNT/F5. This is the first discovery of a single botulinum neurotoxin with BoNT/A antigenicity and BoNT/F light chain function. This work suggests that the newly reported serotype H may actually be a hybrid of previously known BoNT serotype A and serotype F, specifically subtype F5. PMID- 25731974 TI - Prevalence of and Risk Factors for Dislocation Arthropathy: Radiological Long term Outcome of Arthroscopic Bankart Repair in 100 Shoulders at an Average 13 Year Follow-up. AB - BACKGROUND: Glenohumeral osteoarthritis is a well-documented, long-term complication of open stabilization procedures. However, there is a lack of knowledge about long-term radiographic outcome after arthroscopic Bankart procedures. HYPOTHESIS: Glenohumeral osteoarthritis will develop less frequently in arthroscopic Bankart repair compared with open repairs reported in the literature. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The inclusion criteria for this study were (1) all-arthroscopic Bankart repair for a (2) symptomatic anteroinferior shoulder instability and (3) a minimum follow-up of 10 years. True anteroposterior and lateral radiographs were obtained to evaluate the prevalence and grade of osteoarthritis according to the Samilson classification. Patients were assessed by the Constant score and examined for passive external rotation deficits. RESULTS: Of 165 shoulders that fulfilled the inclusion criteria, 100 were available for evaluation. The median Constant score at an average+/-SD 156.2+/-18.5 months after Bankart repair was 94 (range, 46 100). Twenty-one shoulders (21%) sustained a recurrent dislocation. Overall, 31% of shoulders showed no evidence of glenohumeral osteoarthritis; 41% showed mild, 16% moderate, and 12% severe degenerative changes. Osteoarthritis did not correlate with Constant score results (P=.427). The grade of osteoarthritis was significantly associated with the number of preoperative dislocations (P=.016), age at initial dislocation (P=.005) and at surgery (P=.002), and the number of anchors used (P=.001), whereas time from initial dislocation to surgery (P=.854) and external rotation deficit at 0 degrees and 90 degrees of abduction (P=.104 and .348, respectively) showed no significant correlation. Recurrent dislocation did not affect the presence or grade of osteoarthritis (P=.796 and .665, respectively). CONCLUSION: At an average 13 years after arthroscopic Bankart repair, osteoarthritic changes are a common finding and, overall, are comparable with reports in the literature regarding open procedures as well as nonoperative treatment. The extent of trauma sustained during preoperative dislocations and the age of the patient seem to be more relevant for long-term dislocation arthropathy than the kind of treatment. Accordingly, the study hypothesis must be rejected. Avoiding preoperative dislocations is more important for the prevention of osteoarthritis than short-term treatment. The number of anchors used was found to be a predictor for long-term development of osteoarthritis. PMID- 25731975 TI - Use of QR and EAN-13 codes by older patients taking multiple medications for a safer use of medication. AB - BACKGROUND: Older persons following a prolonged complex drug regimen often make mistakes when taking their medication. Currently, the widespread use of tablets and smartphones has encouraged the development of applications to support self management of medication. OBJECTIVE: The aim of this study was to design, develop and assess an app that transforms medication-associated ean-13 (barcodes) and Quick Response codes (QR) into verbal instructions, to enable safer use of medication by the elderly patients taking multiple medications. METHODS: Meetings were held in which participated a total of 61 patients. RESULTS: The results showed that patients appreciated the application and found it useful for safer use of medicines. CONCLUSIONS: The study results support the use of such technology to increase patient safety taking multiple medications safety. PMID- 25731976 TI - Dysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae. AB - Cadmium is a transition metal ion that is highly toxic in biological systems. Although relatively rare in the Earth's crust, anthropogenic release of cadmium since industrialization has increased biogeochemical cycling and the abundance of the ion in the biosphere. Despite this, the molecular basis of its toxicity remains unclear. Here we combine metal-accumulation assays, high-resolution structural data and biochemical analyses to show that cadmium toxicity, in Streptococcus pneumoniae, occurs via perturbation of first row transition metal ion homeostasis. We show that cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress. Despite this, high cellular concentrations of cadmium (~17 mM) are tolerated, with negligible impact on growth or sensitivity to oxidative stress, when manganese and glutathione are abundant. Collectively, this work provides insight into the molecular basis of cadmium toxicity in prokaryotes, and the connection between cadmium accumulation and oxidative stress. PMID- 25731977 TI - Pituitary CRH-binding protein and stress in female mice. AB - The CRH-binding protein (CRH-BP) binds CRH with very high affinity and inhibits CRH-mediated ACTH release from anterior pituitary cells in vitro, suggesting that the CRH-BP functions as a negative regulator of CRH activity. Our previous studies have demonstrated sexually dimorphic expression of CRH-BP in the murine pituitary. Basal CRH-BP expression is higher in the female pituitary, where CRH BP mRNA is detected in multiple anterior pituitary cell types. In this study, we examined stress-induced changes in CRH-BP mRNA and protein expression in mouse pituitary and assessed the in vivo role of CRH-BP in modulating the stress response. Pituitary CRH-BP mRNA was greater than 200-fold more abundant in females than males, and restraint stress increased pituitary CRH-BP mRNA by 11.8 fold in females and 3.2-fold in males as assessed by qRT-PCR. In females, restraint stress increased CRH-BP mRNA levels not only in POMC-expressing cells, but also in PRL-expressing cells. The increase in female pituitary CRH-BP mRNA following stress resulted in significant increases in CRH-BP protein 4-6h after a 30-minute restraint stress as detected by [(125)I]-CRH:CRH-BP cross-linking analyses. Based on this temporal profile, the physiological role of CRH-BP was assessed using a stressor of longer duration. In lipopolysaccharide (LPS) stress studies, female CRH-BP-deficient mice showed elevated levels of stress-induced corticosterone release as compared to wild-type littermates. These studies demonstrate a role for the pituitary CRH-BP in attenuating the HPA response to stress in female mice. PMID- 25731978 TI - Get the right balance--lessons learned from the first Ebola infected patient in Dallas. PMID- 25731979 TI - The role of executive functions in social impairment in Autism Spectrum Disorder. AB - Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by socio-communicative impairments. Executive dysfunction may explain some key characteristics of ASD, both social and nonsocial hallmarks. Limited research exists exploring the relations between executive function and social impairment in ASD and few studies have used a comparison control group. Thus, the objective of the present study was to investigate the relations between executive functioning using the Behavioral Rating Inventory of Executive Functioning (BRIEF), social impairment as measured by the Social Responsiveness Scale (SRS), and overall autistic symptomology as measured by the Autism Diagnostic Observation Schedule (ADOS) in children and adolescents with and without ASD. Seventy children and adolescents diagnosed with ASD and 71 typically developing controls were included in this study. Findings showed that behavioral regulation executive processes (i.e., inhibition, shifting, and emotional control) predicted social function in all children. However, metacognitive executive processes (i.e., initiation, working memory, planning, organization, and monitoring) predicted social function only in children with ASD and not in typically developing children. Our findings suggest a distinct metacognitive executive function-social symptom link in ASD that is not present in the typical population. Understanding components of executive functioning that contribute to the autistic symptomology, particularly in the socio-communicative domain, is crucial for developing effective interventions that target key executive processes as well as underlying behavioral symptoms. PMID- 25731980 TI - Rhodamine B-conjugated encrypted vipericidin nonapeptide is a potent toxin to zebrafish and associated with in vitro cytotoxicity. AB - BACKGROUND: Animal venoms contain a diverse array of proteins and enzymes that are toxic toward various physiological systems. However, there are also some practical medicinal uses for these toxins including use as anti-bacterial and anti-tumor agents. METHODS: In this study, we identified a nine-residue cryptic oligopeptide, KRFKKFFKK (EVP50) that is repeatedly encoded in tandem within vipericidin sequences. RESULTS: EVP50 displayed in vivo potent lethal toxicity to zebrafish larvae (LD50=6 MUM) when the peptide's N-terminus was chemically conjugated to rhodamine B (RhoB). In vitro, RhoB-conjugated EVP50 (RhoB-EVP50) exhibited a concentration-dependent cytotoxic effect toward MCF-7 and MDA-MB-231 breast cancer cells. In MCF-7 cells, the RhoB-EVP50 nonapeptide accumulated inside the cells within minutes. In the cytoplasm, the RhoB-EVP50 induced extracellular calcium influx and intracellular calcium release. Membrane budding was also observed after incubation with micromolar concentrations of the fluorescent EVP50 conjugate. CONCLUSIONS: The conjugate's interference with calcium homeostasis, its intracellular accumulation and its induced membrane dysfunction (budding and vacuolization) seem to act in concert to disrupt the cell circuitry. Contrastively, unconjugated EVP50 peptide did not display neither toxic nor cytotoxic activities in our in vivo and in vitro models. GENERAL SIGNIFICANCE: The synergic mechanism of toxicity was restricted to the structurally modified encrypted vipericidin nonapeptide. PMID- 25731981 TI - Action mechanism of 6, 6'-dihydroxythiobinupharidine from Nuphar japonicum, which showed anti-MRSA and anti-VRE activities. AB - BACKGROUND: Multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE), cause serious infections at clinical sites, for which the development of new drugs is necessary. We screened candidates for new antibiotics and investigated its action mechanism. METHODS: An antimicrobial compound was isolated from an extract of Nuphar japonicum. Its chemical structure was determined by NMR, MS, and optical rotation. We measured its minimum inhibitory concentration (MIC) using the microdilution method. The effects of the compound on DNA gyrase and DNA topoisomerase IV were investigated with DNA supercoiling, decatenation, and cleavage assay. RESULTS: We isolated and identified 6,6' dihydroxythiobinupharidine as the antimicrobial compound. The MIC of this compound was 1-4 MUg/mL against various MRSA and VRE strains. We also demonstrated that this compound inhibited DNA topoisomerase IV (IC50 was 10-15 MUM), but not DNA gyrase in S. aureus, both of which are known to be the targets of quinolone antibiotics and necessary for DNA replication. However, this compound only exhibited slight cross-resistance to norfloxacin-resistant S. aureus, which indicated that DTBN might inhibit other targets besides topoisomerase IV. These results suggest that 6,6'-dihydroxythiobinupharidine may be a potent candidate or seed for novel antibacterial agents. CONCLUSIONS: DTBN from N. japonicum showed anti-MRSA and anti-VRE activities. DTBN might be involved in the inhibition of DNA topoisomerase IV. GENERAL SIGNIFICANCE: DTBN might be useful as a seed compound. The information on the inhibition mechanism of DTBN will be useful for the modification of DTBN towards developing novel anti MRSA and anti-VRE drug. PMID- 25731982 TI - Multi-functional liposomes showing radiofrequency-triggered release and magnetic resonance imaging for tumor multi-mechanism therapy. AB - Recently, nanoplatforms with multiple functions, such as tumor-targeting drug carriers, MRI, optical imaging, thermal therapy etc., have become popular in the field of cancer research. The present study reports a novel multi-functional liposome for cancer theranostics. A dual targeted drug delivery with radiofrequency-triggered drug release and imaging based on the magnetic field influence was used advantageously for tumor multi-mechanism therapy. In this system, the surface of fullerene (C60) was decorated with iron oxide nanoparticles, and PEGylation formed a hybrid nanosystem (C60-Fe3O4-PEG2000). Thermosensitive liposomes (dipalmitoylphosphatidylcholine, DPPC) with DSPE PEG2000-folate wrapped up the hybrid nanosystem and docetaxel (DTX), which were designed to combine features of biological and physical (magnetic) drug targeting for fullerene radiofrequency-triggered drug release. The magnetic liposomes not only served as powerful tumor diagnostic magnetic resonance imaging (MRI) contrast agents, but also as powerful agents for photothermal ablation of tumors. Furthermore, a remarkable thermal therapy combined chemotherapy multi-functional liposome nanoplatform converted radiofrequency energy into thermal energy to release drugs from thermosensitive liposomes, which was also observed during both in vitro and in vivo treatment. The multi-functional liposomes also could selectively kill cancer cells in highly localized regions via their excellent active tumor targeting and magnetic targeted abilities. PMID- 25731983 TI - The influence of multiple temporal memories in the peak-interval procedure. AB - Memories for when an event has occurred are used to anticipate future occurrences of the event, but what happens when the event is equally likely to occur at two different times? In this study, one group of rats was always reinforced at 21 s on the peak-interval procedure (21-only group), whereas another group of rats was reinforced at either 8 or 21 s, which varied daily (8-21 group). At the beginning of each session, the behavior of the 8-21 group largely lacked temporal control, but by the end of the session, temporal control was reestablished. When both groups were reinforced at 21 s, the patterns of responding were indistinguishable after subjects in the 8-21 group had experienced 13 reinforcement trials. Finally, the reinforcement times of previous sessions affected the 8-21 group, such that subjects were biased depending on the reinforcement time of the prior session. These results show that when the reinforcement time is initially ambiguous, rats respond in a way that combines their expectations of both possibilities; then they incrementally adjust their responding as they receive more information, but still information from prior sessions biases their initial expectation for the reinforcement time. Combined, these results imply that rats are sensitive to the age of encoded temporal memories in an environment in which the reinforcement time is variable. How these results inform the scalar expectancy theory, the currently accepted model of interval-timing behavior, is discussed. PMID- 25731984 TI - Immunohistochemical labelling of cytokines in calves infected experimentally with Mycoplasma bovis. AB - To gain further insight into the pathogenesis of Mycoplasma bovis-associated pneumonia, cytokine expression in different pulmonary compartments was examined. The expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-4 and interferon (IFN)-gamma was examined immunohistochemically in the lung of 10 calves infected experimentally with M. bovis. M. bovis antigen was located in respiratory epithelial cells and within inflammatory cells in the airway lumina. Immunolabelling for TNF-alpha, IL-4 and IFN-gamma was usually associated with inflammation, particularly in macrophages and lymphocytes in hyperplastic bronchus-associated lymphoid tissue (BALT), in thickened alveolar septa and in the bronchoalveolar exudate of infected animals. In M. bovis infection, macrophage and lymphocyte activation results in expression of a number of cytokines capable of inducing lung lesions and hyperplasia of the BALT. The cytokines examined likely play a role in pulmonary defence against M. bovis infection. PMID- 25731985 TI - Differences between chimpanzee and baboon gastrointestinal parasite communities. AB - Cross-species infection among humans, chimpanzees (Pan troglodytes) and baboons (Papio spp.) is potentially a significant public health issue in Africa, and of concern in the conservation of P. troglodytes. However, to date, no statistical comparisons have been made between the prevalence, richness and composition of parasite communities in sympatric populations of baboons and P. troglodytes. We compared parasite communities in sympatric P. troglodytes and Papio papio living in a wilderness site, in the Republic of Senegal, West Africa. We asked whether, in the absence of humans, there are significant differences between these hosts in their interactions with gastrointestinal parasites. We tested whether host, location, or time of collection accounted for variation in prevalence, richness and community composition, and compared prevalence across six studies. We concluded that, despite being closely related, there are significant differences between these two hosts with respect to their parasite communities. At our study site, prevalence of Balantidium, Trichuris and Watsonius was higher in P. papio. Papio papio harboured more parasites per host, and we found evidence of a positive association between Trichuris and Balantidium in P. troglodytes but not P. papio. PMID- 25731986 TI - In or out? Barriers and facilitators to refugee-background young people accessing mental health services. AB - Refugee young people have been identified as a group with high risk for mental health problems, due to their experience of trauma, forced migration, and stressors associated with settlement. A high prevalence of mental health problems is reported in this group, however some research suggests refugee young people have low rates of mental health service access. There is little information available on barriers and facilitators to mental service delivery for this group. Using data from 15 focus groups and five key informant interviews with a total of 115 service providers from 12 agencies in Melbourne, Australia, this paper explores barriers and facilitators to engaging young people from refugee backgrounds with mental health services. Eight key themes emerged: cultural concepts of mental health, illness, and treatment; service accessibility; trust; working with interpreters; engaging family and community; the style and approach of mental health providers; advocacy; and continuity of care. PMID- 25731988 TI - Gestalt perception is associated with reduced parietal beta oscillations. AB - The ability to perceive composite objects as a whole is fundamental for visual perception in a complex and cluttered natural environment. This ability may be mediated by increased communication between neural representations of distinct object elements, and has been linked to increased synchronization of oscillatory brain activity in the gamma band. Previous studies of perceptual grouping either guided attention between local and global aspects of a given stimulus or manipulated its physical properties to achieve grouped and ungrouped perceptual conditions. In contrast to those studies, we fully matched the physical properties underlying global and local percepts using a bistable stimulus that causes the viewer to perceive either local motion of multiple elements or global motion of two illusory shapes without any external change. To test the synchronization hypothesis we recorded brain activity with EEG, while human participants viewed the stimulus and reported changes in their perception. In contrast to previous findings we show that power of the beta-band was lower during perception of global Gestalt than during that of local elements. Source localization places these differences in the posterior parietal cortex, overlapping with a site previously associated with both attention and Gestalt perception. These findings reveal a role of parietal beta-band activity in internally, rather than externally or attention-driven processes of Gestalt perception. They also add to the growing evidence for shared neural substrates of attention and Gestalt perception, both being linked to parietal cortex. PMID- 25731987 TI - Cerebral angiography, blood flow and vascular reactivity in progressive hypertension. AB - Chronic hypertension alters cerebral vascular morphology, cerebral blood flow (CBF), cerebrovascular reactivity, and increses susceptibility to neurological disorders. This study evaluated: i) the lumen diameters of major cerebral and downstream arteries using magnetic resonance angiography, ii) basal CBF, and iii) cerebrovascular reactivity to hypercapnia of multiple brain regions using arterial-spin-labeling technique in spontaneously hypertensive rats (SHR) at different stages. Comparisons were made with age-matched normotensive Wistar Kyoto (WKY) rats. In 10-week SHR, lumen diameter started to reduce, basal CBF, and hypercapnic CBF response were higher from elevated arterial blood pressure, but there was no evidence of stenosis, compared to age-matched WKY. In 20-week SHR, lumen diameter remained reduced, CBF returned toward normal from vasoconstriction, hypercapnic CBF response reversed and became smaller, but without apparent stenosis. In 40-week SHR, lumen diameter remained reduced and basal CBF further decreased, resulting in larger differences compared to WKY. There was significant stenosis in main supplying cerebral vessels. Hypercapnic CBF response further decreased, with some animals showing negative hypercapnic CBF responses in some brain regions, indicative of compromised cerebrovascular reserve. The territory with negative hypercapnia CBF responses corresponded with the severity of stenosis in arteries that supplied those territories. We also found enlargement of downstream vessels and formation of collateral vessels as compensatory responses to stenosis of upstream vessels. The middle cerebral and azygos arteries were amongst the most susceptible to hypertension-induced changes. Multimodal MRI provides clinically relevant data that might be useful to characterize disease pathogenesis, stage disease progression, and monitor treatment effects in hypertension. PMID- 25731989 TI - Robust regression for large-scale neuroimaging studies. AB - Multi-subject datasets used in neuroimaging group studies have a complex structure, as they exhibit non-stationary statistical properties across regions and display various artifacts. While studies with small sample sizes can rarely be shown to deviate from standard hypotheses (such as the normality of the residuals) due to the poor sensitivity of normality tests with low degrees of freedom, large-scale studies (e.g. >100 subjects) exhibit more obvious deviations from these hypotheses and call for more refined models for statistical inference. Here, we demonstrate the benefits of robust regression as a tool for analyzing large neuroimaging cohorts. First, we use an analytic test based on robust parameter estimates; based on simulations, this procedure is shown to provide an accurate statistical control without resorting to permutations. Second, we show that robust regression yields more detections than standard algorithms using as an example an imaging genetics study with 392 subjects. Third, we show that robust regression can avoid false positives in a large-scale analysis of brain behavior relationships with over 1500 subjects. Finally we embed robust regression in the Randomized Parcellation Based Inference (RPBI) method and demonstrate that this combination further improves the sensitivity of tests carried out across the whole brain. Altogether, our results show that robust procedures provide important advantages in large-scale neuroimaging group studies. PMID- 25731990 TI - Cerebral maturation in the early preterm period-A magnetization transfer and diffusion tensor imaging study using voxel-based analysis. AB - The magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) correlates of early brain development were examined in cohort of 18 very preterm neonates (27-31 gestational weeks) presenting with normal radiological findings scanned within 2weeks after birth (28-32 gestational weeks). A combination of non linear image registration, tissue segmentation, and voxel-wise regression was used to map the age dependent changes in MTR and DTI-derived parameters in 3D across the brain based on the cross-sectional in vivo preterm data. The regression coefficient maps obtained differed between brain regions and between the different quantitative MRI indices. Significant linear increases as well as decreases in MTR and DTI-derived parameters were observed throughout the preterm brain. In particular, the lamination pattern in the cerebral wall was evident on parametric and regression coefficient maps. The frontal white matter area (subplate and intermediate zone) demonstrated a linear decrease in MTR. While the intermediate zone showed an unexpected decrease in fractional anisotropy (FA) with age, with this decrease (and the increase in mean diffusivity (MD)) driven primarily by an increase in radial diffusivity (RD) values, the subplate showed no change in FA (and an increase in MD). The latter was the result of a concomitant similar increase in axial diffusivity (AD) and RD values. Interpreting the in vivo results in terms of available histological data, we present a biophysical model that describes the relation between various microstructural changes measured by complementary quantitative methods available on clinical scanners and a range of maturational processes in brain tissue. PMID- 25731991 TI - Fast quantitative susceptibility mapping using 3D EPI and total generalized variation. AB - Quantitative susceptibility mapping (QSM) allows new insights into tissue composition and organization by assessing its magnetic property. Previous QSM studies have already demonstrated that magnetic susceptibility is highly sensitive to myelin density and fiber orientation as well as to para- and diamagnetic trace elements. Image resolution in QSM with current approaches is limited by the long acquisition time of 3D scans and the need for high signal to noise ratio (SNR) to solve the dipole inversion problem. We here propose a new total-generalized-variation (TGV) based method for QSM reconstruction, which incorporates individual steps of phase unwrapping, background field removal and dipole inversion in a single iteration, thus yielding a robust solution to the reconstruction problem. This approach has beneficial characteristics for low SNR data, allowing for phase data to be rapidly acquired with a 3D echo planar imaging (EPI) sequence. The proposed method was evaluated with a numerical phantom and in vivo at 3 and 7 T. Compared to total variation (TV), TGV-QSM enforced higher order smoothness which yielded solutions closer to the ground truth and prevented stair-casing artifacts. The acquisition time for images with 1mm isotropic resolution and whole brain coverage was 10s on a clinical 3 Tesla scanner. In conclusion, 3D EPI acquisition combined with single-step TGV reconstruction yields reliable QSM images of the entire brain with 1mm isotropic resolution in seconds. The short acquisition time combined with the robust reconstruction may enable new QSM applications in less compliant populations, clinical susceptibility tensor imaging, and functional resting state examinations. PMID- 25731992 TI - EEG imaging of toddlers during dyadic turn-taking: Mu-rhythm modulation while producing or observing social actions. AB - Contemporary active-EEG and EEG-imaging methods show particular promise for studying the development of action planning and social-action representation in infancy and early childhood. Action-related mu suppression was measured in eleven 3-year-old children and their mothers during a 'live,' largely unscripted social interaction. High-density EEG was recorded from children and synchronized with motion-captured records of children's and mothers' hand actions, and with video recordings. Independent Component Analysis (ICA) was used to separate brain and non-brain source signals in toddlers' EEG records. EEG source dynamics were compared across three kinds of epochs: toddlers' own actions (execution), mothers' actions (observation), and between-turn intervals (no action). Mu (6 9Hz) power was suppressed in left and right somatomotor cortex during both action execution and observation, as reflected by independent components of individual children's EEG data. These mu rhythm components were accompanied by beta-harmonic (~16Hz) suppression, similar to findings from adults. The toddlers' power spectrum and scalp density projections provide converging evidence of adult-like mu-suppression features. Mu-suppression components' source locations were modeled using an age-specific 4-layer forward head model. Putative sources clustered around somatosensory cortex, near the hand/arm region. The results demonstrate that action-locked, event-related EEG dynamics can be measured, and source resolved, from toddlers during social interactions with relatively unrestricted social behaviors. PMID- 25731993 TI - Gaussian process classification of Alzheimer's disease and mild cognitive impairment from resting-state fMRI. AB - Multivariate pattern analysis and statistical machine learning techniques are attracting increasing interest from the neuroimaging community. Researchers and clinicians are also increasingly interested in the study of functional connectivity patterns of brains at rest and how these relations might change in conditions like Alzheimer's disease or clinical depression. In this study we investigate the efficacy of a specific multivariate statistical machine learning technique to perform patient stratification from functional-connectivity patterns of brains at rest. Whilst the majority of previous approaches to this problem have employed support vector machines (SVMs) we investigate the performance of Bayesian Gaussian process logistic regression (GP-LR) models with linear and non linear covariance functions. GP-LR models can be interpreted as a Bayesian probabilistic analogue to kernel SVM classifiers. However, GP-LR methods confer a number of benefits over kernel SVMs. Whilst SVMs only return a binary class label prediction, GP-LR, being a probabilistic model, provides a principled estimate of the probability of class membership. Class probability estimates are a measure of the confidence the model has in its predictions, such a confidence score may be extremely useful in the clinical setting. Additionally, if miss-classification costs are not symmetric, thresholds can be set to achieve either strong specificity or sensitivity scores. Since GP-LR models are Bayesian, computationally expensive cross-validation hyper-parameter grid-search methods can be avoided. We apply these methods to a sample of 77 subjects; 27 with a diagnosis of probable AD, 50 with a diagnosis of a-MCI and a control sample of 39. All subjects underwent a MRI examination at 3T to obtain a 7minute and 20second resting state scan. Our results support the hypothesis that GP-LR models can be effective at performing patient stratification: the implemented model achieves 75% accuracy disambiguating healthy subjects from subjects with amnesic mild cognitive impairment and 97% accuracy disambiguating amnesic mild cognitive impairment subjects from those with Alzheimer's disease, accuracies are estimated using a held-out test set. Both results are significant at the 1% level. PMID- 25731994 TI - A multicontrast approach for comprehensive imaging of substantia nigra. AB - We characterize the contrast behavior of substantia nigra (SN) in both magnetization transfer (MT) imaging, which is believed to be sensitive to neuromelanin (NM), and susceptibility weighted imaging (SWI). Images were acquired with a MT prepared dual echo gradient echo sequence. The first echo was taken as the MT contrast image and the second was used to generate the SWI image. SN volumes were segmented from these two types of images using a thresholding method. The spatial and signal characteristics of the extracted SWI and MT volumes were compared. Both images showed the presence of SN but the volumes of the SN identified in the two are spatially incongruent. The MT volume was more caudal than the SWI volume and with only a 12% overlap between the two volumes. Considering the SN volumes in each hemisphere separately, the average distances between the centers of mass of the volumes from the two types images are 5.1+/ 1.1mm and 4.1+/-1.2mm, respectively. The frequency offsets (homodyne filtered phase/echo time) for the volumes derived from MT (NM) images and SWI images are 0.09+/-0.32radians/s and -1.12+/-0.57radians/s (p<0.0001), respectively. The MT contrasts for the two volumes are 0.16+/-0.02 and 0.10+/-0.03 (p<0.001), respectively. Our results indicate that the two contrasts are sensitive to different portions of the SN, with MT seeing the more caudal portion of the SN than SWI, likely due to variations of NM and iron content in the SN. Despite the small overlap, these regions are complementary. Our results provide a new understanding of the contrast behavior of the SN in the two imaging approaches commonly used to image it and indicate that using both may yield a more comprehensive visualization of the SN. PMID- 25731995 TI - Motivation by potential gains and losses affects control processes via different mechanisms in the attentional network. AB - Attentional control in demanding cognitive tasks can be improved by manipulating the motivational state. Motivation to obtain gains and motivation to avoid losses both usually result in faster reaction times and stronger activation in relevant brain areas such as the prefrontal cortex, but little is known about differences in the underlying neurocognitive mechanisms of these types of motivation in an attentional control context. In the present functional magnetic resonance imaging (fMRI) study, we tested whether potential gain and loss as motivating incentives lead to overlapping or distinct neural effects in the attentional network, and whether one of these conditions is more effective than the other. A Flanker task with word stimuli as targets and distracters was performed by 115 healthy participants. Using a mixed blocked and event-related design allowed us to investigate transient and sustained motivation-related effects. Participants could either gain money (potential gain) or avoid losing money (potential loss) in different task blocks. Participants showed a congruency effect with increased reaction times for incongruent compared to congruent trials. Potential gain led to generally faster responses compared to the neutral condition and to stronger improvements than potential loss. Potential loss also led to shorter response times compared to the neutral condition, but participants improved mainly during incongruent and not during congruent trials. The event-related fMRI data revealed a main effect of congruency with increased activity in the left inferior frontal gyrus (IFG) and inferior frontal junction area (IFJ), the pre-supplementary motor area (pre-SMA), bilateral insula, intraparietal sulcus (IPS) and visual word form area (VWFA). While potential gain led to increased activity in a cluster of the IFJ and the VWFA only during incongruent trials, potential loss was linked to activity increases in these regions during incongruent and congruent trials. The block analysis revealed greater activity in gain and loss blocks compared to the neutral condition in most of these regions but no differences in the direct comparison of gain and loss blocks. These findings show that potential monetary gain and loss rely on different mechanisms: Gain was more effective in reducing the reaction time compared to potential loss. Brain data indicate that in the gain context attentional control is executed specifically in incongruent trials, whereas the loss context induces an unspecific increase of attentional control. These findings extend previous studies by providing evidence for diverging neural mechanisms for the effects of different types of motivation on attentional control, specifying the underlying activity patterns in task- and stimulus related regions. PMID- 25731996 TI - Differences between target and non-target probe processing--combined evidence from fMRI, EEG and fMRI-constrained source analysis. AB - Previous studies reported heterogeneous findings in working memory tasks when examining differences between correct recognition (targets) and correct rejection (non-targets). In the present study, twenty human participants completed a delayed match-to-sample task in two separate functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) sessions. Targets and non-target items were presented at different within-trial positions. We used fMRI constrained source analysis to investigate the spatio-temporal neuronal dynamics of probe processing. Probe type-related differences were modulated by position in the trial or by the ratio of target stimuli to non-target stimuli at different trial positions. fMRI-constrained source analysis revealed a temporal pattern of source activities starting in occipital and temporal brain regions, followed by a simultaneous engagement of parietal and frontal brain regions and a later activity of a source in pre-SMA (supplementary motor area). Source activities demonstrated a specific involvement of left fusiform gyrus in the non-target condition compared to the target condition that might be associated with mental imagination of the target stimulus during non-target probe processing. Source activities, furthermore, showed the anterior cingulate to be particularly involved in target processing compared to non-target processing before response execution and the pre-SMA before and during response execution. These brain areas appear to be activated in different stages of conflict managing operations due to a lower stimulus frequency of target trials compared to non-target trials at different target positions in the present design. PMID- 25731997 TI - Functional brain networks underlying detection and integration of disconfirmatory evidence. AB - Processing evidence that disconfirms a prior interpretation is a fundamental aspect of belief revision, and has clear social and clinical relevance. This complex cognitive process requires (at minimum) an alerting stage and an integration stage, and in the current functional magnetic resonance imaging (fMRI) study, we used multivariate analysis methodology on two datasets in an attempt to separate these sequentially-activated cognitive stages and link them to distinct functional brain networks. Thirty-nine healthy participants completed one of two versions of an evidence integration experiment involving rating two consecutive animal images, both of which consisted of two intact images of animal faces morphed together at different ratios (e.g., 70/30 bird/dolphin followed by 10/90 bird/dolphin). The two versions of the experiment differed primarily in terms of stimulus presentation and timing, which facilitated functional interpretation of brain networks based on differences in the hemodynamic response shapes between versions. The data were analyzed using constrained principal component analysis for fMRI (fMRI-CPCA), which allows distinct, simultaneously active task-based networks to be separated, and these were interpreted using both temporal (task-based hemodynamic response shapes) and spatial (dominant brain regions) information. Three networks showed increased activity during integration of disconfirmatory relative to confirmatory evidence: (1) a network involved in alerting to the requirement to revise an interpretation, identified as the salience network (dorsal anterior cingulate cortex and bilateral insula); (2) a sensorimotor response-related network (pre- and post-central gyri, supplementary motor area, and thalamus); and (3) an integration network involving rostral prefrontal, orbitofrontal and posterior parietal cortex. These three networks were staggered in their peak activity (alerting, responding, then integrating), but at certain time points (e.g., 17s after trial onset) the hemodynamic responses associated with all three networks were simultaneously active. These findings highlight distinct cognitive processes and corresponding functional brain networks underlying stages of disconfirmatory evidence integration, and demonstrate the power of multivariate and multi-experiment methodology in cognitive neuroscience. PMID- 25731998 TI - Improving reliability of subject-level resting-state fMRI parcellation with shrinkage estimators. AB - A recent interest in resting state functional magnetic resonance imaging (rsfMRI) lies in subdividing the human brain into anatomically and functionally distinct regions of interest. For example, brain parcellation is often a necessary step for defining the network nodes used in connectivity studies. While inference has traditionally been performed on group-level data, there is a growing interest in parcellating single subject data. However, this is difficult due to the inherent low signal-to-noise ratio of rsfMRI data, combined with typically short scan lengths. A large number of brain parcellation approaches employ clustering, which begins with a measure of similarity or distance between voxels. The goal of this work is to improve the reproducibility of single-subject parcellation using shrinkage-based estimators of such measures, allowing the noisy subject-specific estimator to "borrow strength" in a principled manner from a larger population of subjects. We present several empirical Bayes shrinkage estimators and outline methods for shrinkage when multiple scans are not available for each subject. We perform shrinkage on raw inter-voxel correlation estimates and use both raw and shrinkage estimates to produce parcellations by performing clustering on the voxels. While we employ a standard spectral clustering approach, our proposed method is agnostic to the choice of clustering method and can be used as a pre processing step for any clustering algorithm. Using two datasets - a simulated dataset where the true parcellation is known and is subject-specific and a test retest dataset consisting of two 7-minute resting-state fMRI scans from 20 subjects - we show that parcellations produced from shrinkage correlation estimates have higher reliability and validity than those produced from raw correlation estimates. Application to test-retest data shows that using shrinkage estimators increases the reproducibility of subject-specific parcellations of the motor cortex by up to 30%. PMID- 25731999 TI - Prediction of brain maturity based on cortical thickness at different spatial resolutions. AB - Several studies using magnetic resonance imaging (MRI) scans have shown developmental trajectories of cortical thickness. Cognitive milestones happen concurrently with these structural changes, and a delay in such changes has been implicated in developmental disorders such as attention-deficit/hyperactivity disorder (ADHD). Accurate estimation of individuals' brain maturity, therefore, is critical in establishing a baseline for normal brain development against which neurodevelopmental disorders can be assessed. In this study, cortical thickness derived from structural magnetic resonance imaging (MRI) scans of a large longitudinal dataset of normally growing children and adolescents (n=308), were used to build a highly accurate predictive model for estimating chronological age (cross-validated correlation up to R=0.84). Unlike previous studies which used kernelized approach in building prediction models, we used an elastic net penalized linear regression model capable of producing a spatially sparse, yet accurate predictive model of chronological age. Upon investigating different scales of cortical parcellation from 78 to 10,240 brain parcels, we observed that the accuracy in estimated age improved with increased spatial scale of brain parcellation, with the best estimations obtained for spatial resolutions consisting of 2560 and 10,240 brain parcels. The top predictors of brain maturity were found in highly localized sensorimotor and association areas. The results of our study demonstrate that cortical thickness can be used to estimate individuals' brain maturity with high accuracy, and the estimated ages relate to functional and behavioural measures, underscoring the relevance and scope of the study in the understanding of biological maturity. PMID- 25732000 TI - Genetic variability and fumonisin production by Fusarium proliferatum isolated from durum wheat grains in Argentina. AB - Fusarium proliferatum is a member of the Fusarium fujikuroi species complex (FFSC) involved in the maize ear rot together with Fusarium verticillioides, which is a very closely related species. Recently, different studies have detected natural fumonisin contamination in wheat kernels and most of them have shown that the main species isolated was F. proliferatum. Fusarium strains obtained from freshly harvested durum wheat samples (2008 to 2011 harvest seasons) from Argentina were characterized through a phylogenetic analysis based on translation elongation factor-1 alpha (EF-1alpha) and calmodulin (CaM) genes, determination of mating type alleles, and evaluation of fumonisin production capability. The strains were identified as F. proliferatum (72%), F. verticillioides (24%) and other Fusarium species. The ratio of mating type alleles (MAT-1 and MAT-2) obtained for both main populations suggests possible occurrence of sexual reproduction in the wheat fields, although this seems more frequent in F. proliferatum. Phylogenetic analysis revealed greater nucleotide variability in F. proliferatum strains than in F. verticillioides, however this was not related to origin, host or harvest year. The fumonisin-producing ability was detected in 92% of the strains isolated from durum wheat grains. These results indicate that F. proliferatum and F. verticillioides, among the fumonisin producing species, frequently contaminate durum wheat grains in Argentina, presenting a high risk for human and animal health. PMID- 25732001 TI - Decontamination method using heat and relative humidity for radish seeds achieves a 7-log reduction of Escherichia coli O157:H7 without affecting product quality. AB - We developed a novel decontamination method to inactivate Escherichia coli O157:H7 on radish seeds without adversely affecting seed germination or product quality. The use of heat (55, 60, and 65 degrees C) combined with relative humidity (RH; 25, 45, 65, 85, and 100%) for 24h was evaluated for effective microbial reduction and preservation of seed germination rates. A significant two way interaction of heat and RH was observed for both microbial reduction and germination rate (P<0.0001). Increases in heat and RH were associated with corresponding reductions in E. coli O157:H7 and in germination rate (P<0.05). The order of lethality for the different treatments was generally as follows: no treatment <55 degrees C/25-65% RH ?60 degrees C/25-45% RH ?65 degrees C/25% RH <55 degrees C/85% RH =60 degrees C/65% RH <55 degrees C/100% RH =60 degrees C/85-100% RH =65 degrees C/45-100% RH. The most effective condition, 65 degrees C/45% RH, completely inactivated E. coli O157:H7 on the seeds (7.0 log CFU/g reduction) and had no significant effect on the germination rate (85.4%; P>0.05) or product quality. The method uses only heat and relative humidity without chemicals, and is thus applicable as a general decontamination procedure in spout producing plants where the use of growth chambers is the norm. PMID- 25732002 TI - Architectural and biochemical changes in embryonic tissues of maize under cadmium toxicity. AB - Heavy metals greatly alter plant morphology and architecture, however detailed mechanisms of such changes are not fully explored. Two experiments were conducted to investigate the influence of cadmium (CdCl2 . 2.5H2 O) on some germination, morphological, biochemical and histological characteristics of developing embryonic tissue of maize. In the first experiment, maize seeds were germinated in increasing levels of CdCl2 (200-2000 MUm) in sand and measurements were taken of changes in germination and seedling development attributes. Based on these parameters, 1000 MUM CdCl2 was chosen for detailed biochemical and histological measurements. In the second experiment, seeds were germinated in Petri dishes and supplied with 0 (control) or 1000 MUM CdCl2 (Cd-treated). Radicle, plumule, coleoptile and coleorhiza were measured for biochemical and histological changes. The highest amount of Cd was in the coleorhiza and radicle. Free proline, soluble sugars, anthocyanin, soluble phenolics, ascorbic acid, H2 O2 and MDA were significantly higher in coleorhizae, followed by the coleoptile, radicle and plumule. Although the radicle and coleorhiza were relatively poor targets of Cd than the other tissues, Cd stress reduced cortical cell size and vascular tissues, and deformed xylem and phloem parenchyma in all plant parts. In conclusion, the main reason for reduced germination was the influence of Cd on architecture of the coleorhiza and coleoptile, which was the result of oxidative stress and other physiological changes taking place in these tissues. PMID- 25732003 TI - Genes for a series of proteins that are involved in glucose catabolism are upregulated by the Hik8-cascade in Synechocystis sp. PCC 6803. AB - MAIN CONCLUSION: In summary, we could show the involvement of a Hik8-cascade in the expression of genes involved in the glycolytic and OPP pathways induced by GPL, and another signal pathway under photosynthetic conditions in Synechocystis . The Hik8-cascade under GPL conditions may regulate glucose degradation to produce some energy and carbon compounds. This cascade might be important for the supply of organic materials such as amino acids and nucleotides through enhancement of the rates of the glycolysis and OPP pathways. Histidine kinase Hik8 upregulates the expression of one of the important glycolytic genes, fbaA, via sll1330 under heterotrophic growth conditions (i.e., in the presence of glucose with an indispensable short period of light) in Synechocystis sp. PCC 6803. In this study, expression of the genes for the glycolytic and OPP pathways was investigated using the wild type, and disruption mutants of Hik8 and sll1330, to determine whether or not the Hik8-involving signal transduction system generally regulates glucose catabolism. In the wild type, all the genes for the glycolytic and OPP pathways were upregulated under the same conditions as for fbaA. Analyses of the disruption mutants suggested that the signal transduction system involving Hik8 and Sll1330 plays a key role in the upregulation of genes such as pfkA, pgmB, and glk, and also that Hik8 induces genes including gap1 and pgk independently of Sll1330. This complicated signal transduction cascade, designated as the Hik8-cascade, occurs under heterotrophic growth with light pulses. In addition, a disruption mutant of a putative histidine kinase, sll1334, exhibited growth and gene expression patterns that suggested it to be a negative regulator in the cascade. Possible histidine kinases and response regulators as candidates for other components in the cascade are discussed. PMID- 25732004 TI - Effects of nanosecond pulse electric fields on cellular elasticity. AB - We investigated the effects of a single 60 nanosecond pulsed electric field (nsPEF) of low (15 kV/cm) and high (60 kV/cm) field strengths on cellular morphology and membrane elasticity in Jurkat cells using fluorescent microscopy and atomic force microscopy (AFM). We performed force displacement measurements on cells using AFM and calculated the Young's modulus for membrane elasticity. Differential effects were observed depending upon pulsing conditions. We found that a single nsPEF of low field strength did not induce any apparent cytoskeletal breakdown and had minor morphological changes. Interestingly, force measurements and calculation of Young's modulus showed a significant decrease in membrane elasticity. A single nsPEF of high field strength induced stark morphological changes due to disruption of the actin cytoskeleton and a marked decrease in elasticity likely caused by irreversible membrane damage. We suggest that the cellular morphology is mainly dependent on stabilization by the actin cytoskeleton, while the elasticity changes are partially dependent on the cytoskeletal integrity. PMID- 25732005 TI - Magnesium: looking for a role in anesthesia. PMID- 25732006 TI - Yap7 is a transcriptional repressor of nitric oxide oxidase in yeasts, which arose from neofunctionalization after whole genome duplication. AB - Flavohemoglobins are the main detoxifiers of nitric oxide (NO) in bacteria and fungi and are induced in response to nitrosative stress. In fungi, the flavohemoglobin encoding gene YHB1 is positively regulated by transcription factors which are activated upon NO exposure. In this study, we show that in the model yeast Saccharomyces cerevisiae and in the human pathogen Candida glabrata, the transcription factor Yap7 constitutively represses YHB1 by binding its promoter. Consequently, YAP7 deletion conferred high NO resistance to the cells. Co-immunoprecipitation experiments and mutant analyses indicated that Yap7 represses YHB1 by recruiting the transcriptional repressor Tup1. In S. cerevisiae, YHB1 repression also involves interaction of Yap7 with the Hap2/3/5 complex through a conserved Hap4-like-bZIP domain, but this interaction has been lost in C. glabrata. The evolutionary origin of this regulation was investigated by functional analyses of Yap7 and of its paralogue Yap5 in different yeast species. These analyses indicated that the negative regulation of YHB1 by Yap7 arose by neofunctionalization after the whole genome duplication which led to the C. glabrata and S. cerevisiae extant species. This work describes a new aspect of the regulation of fungal nitric oxidase and provides detailed insights into its functioning and evolution. PMID- 25732007 TI - Effects of the Ten Percent Cap in Medicare Home Health Care on Treatment Intensity and Patient Discharge Status. AB - OBJECTIVE: To estimate the effect of the 10 percent cap introduced to Medicare home health care on treatment intensity and patient discharge status. DATA SOURCES: Medicare Denominator, Medicare Home Health Claims, and Medicare Provider of Services Files from 2008 through 2010. STUDY DESIGN: We used agency-level variation in the proportion of outlier payments prior to the implementation of the 10 percent cap to identify how home health agencies adjusted the number of home health visits and patient discharge status under the new law. PRINCIPAL FINDINGS: Under the 10 percent cap, agencies dramatically decreased the number of service visits. Agencies also dropped relatively healthy patients and sent sicker patients to nursing homes. CONCLUSIONS: The drastic reduction in the number of service visits and discontinuation of relatively healthy patients from home health care suggest that the 10 percent cap improved the efficiency of home health services as intended. However, the 10 percent cap increased other types of health care expenditures by pushing sicker patients to use more expensive health services. PMID- 25732008 TI - Improving Molecular Genetic Test Utilization through Order Restriction, Test Review, and Guidance. AB - The ordering of molecular genetic tests by health providers not well trained in genetics may have a variety of untoward effects. These include the selection of inappropriate tests, the ordering of panels when the assessment of individual or fewer genes would be more appropriate, inaccurate result interpretation and inappropriate patient guidance, and significant unwarranted cost expenditure. We sought to improve the utilization of molecular genetic tests by requiring providers without specialty training in genetics to use genetic counselors and molecular genetic pathologists to assist in test selection. We used a genetic and genomic test review process wherein the laboratory-based genetic counselor performed the preanalytic assessment of test orders and test triage. Test indication and clinical findings were evaluated against the test panel composition, methods, and test limitations under the supervision of the molecular genetic pathologist. These test utilization management efforts resulted in a decrease in genetic test ordering and a gross cost savings of $1,531,913 since the inception of these programs in September 2011 through December 2013. The combination of limiting the availability of complex genetic tests and providing guidance regarding appropriate test strategies is an effective way to improve genetic tests, contributing to judicious use of limited health care resources. PMID- 25732010 TI - Genomic sciences for developmentalists: a merge of science and practice. AB - The etiological forces of development have been a central question for the developmental sciences (however defined) since their crystallization as a distinct branch of scientific inquiry. Although the history of these sciences contains examples of extreme positions capitalizing on either the predominance of the genome (i.e., the accumulation of genetic factors driving development) or the environmentome (i.e., the accumulation of environmental factors driving development), the moderate view of development as the emergence of a person from a particular genome and within a specific context has settled into the driver's seat and is disputed no longer. Yet, although there is a converging theoretical perspective, a gap between this perspective and practice remains. In other words, society needs to translate this position into praxis. This opinion exemplifies the current state of corresponding knowledge in the developmental sciences, with a particular emphasis on the understanding of the role of the genome in child and adolescent development, and offers a set of comments on how this translation is being shaped by the newest technologies in the genomic sciences. PMID- 25732009 TI - Safety and tolerability of 5-grass pollen tablet sublingual immunotherapy: pooled analysis and clinical review. AB - INTRODUCTION: The 5-grass pollen tablet (Oralair(r), Stallergenes, Antony, France) is a once-daily preseasonal and coseasonal sublingual immunotherapy (SLIT) that is effective in controlling the symptoms of allergic rhinoconjunctivitis and in reducing the need for symptomatic medication. AREAS COVERED: The body of safety data gathered from the 5-grass pollen tablet clinical development program, post-approval studies, and more than 6 years of real-life experience demonstrates the safety and tolerability profile of the 5-grass pollen tablet across all age groups. Adverse events (AEs) are generally mild or moderate in severity, and rarely lead to treatment discontinuation. AEs also tend to decline in frequency and severity over time and with repeated treatment. The most frequent treatment-emergent AEs are local-site oropharyngeal reactions (e.g., oral pruritus, throat irritation, tongue pruritus, mouth edema, ear pruritus), which are consistent with the sublingual route of administration. EXPERT OPINION: The first dose of the 5-grass pollen tablet should be administered under the supervision of an experienced physician, to allow for optimal monitoring and timely management of AEs, should they occur. The 5-grass pollen tablet can be administered at home after the first dose, and patients and carers should be educated on how to manage adverse reactions, unplanned treatment interruptions and situations in which SLIT should be withheld. PMID- 25732011 TI - Utilizing biopsychosocial and strengths-based approaches within the field of child health: what we know and where we can grow. AB - We continue to increase our understanding of the experiences and settings that contribute to positive developmental outcomes in childhood, and those that confer greater risk. Although the mechanisms by which the risk and protective factors affect developmental outcomes need to be further elucidated through research, converging findings from the field of child health (spanning both physical and mental health) indicate that a biopsychosocial approach is useful. Here, we examine the evidence that early experiences confer both risk and protective processes on biopsychosocial development in childhood, and touch on some implications for the life course. Although this interdisciplinary field of research has already garnered substantial attention, here we aim to highlight the opportunity to use a strengths-based approach with the biopsychosocial model, with particular focus on children who experience prolonged stress. We close with consideration for future directions with an emphasis on policy and practice in clinical and educational settings to improve well-being in these early stages of the life course. PMID- 25732012 TI - Challenges for an interdisciplinary consideration of cognitive training. AB - Whether fluid cognitive functions are malleable has been a topic of ongoing debate for at least the past 100 years. Ever-evolving technology has led to new and diverse fields of investigation entering this debate. There are significant advantages to be gained by integrating different scientific paradigms, but there are also significant challenges. Cross-paradigm differences in levels of analysis, nomenclature, and expectations of training outcomes complicate interpretation of training results. It is argued that further investigations of (a) cross-paradigm intricacies and (b) strategy versus process training, particularly with spatial abilities, are needed. PMID- 25732013 TI - Edutainment, games, and the future of education in a digital world. AB - Since the development of educational television in the 1960s, there has been a growing interest in incorporating features of entertainment in informal and formal education. Reviewing the literature on edutainment and games, we will discuss the limits of the current state of research and propose research questions investigating broad issues linked to the adoption of games for education. PMID- 25732014 TI - Bilingualism: research and policy. AB - Bilingualism, commonplace throughout the world, is not well accepted or supported in many parts of the United States. Education policies and practices regarding bilingualism are often based on myths and attitudes rather than facts, despite scientific evidence on both the disadvantages and advantages of bilingualism. Based on a brief overview of this evidence, I assert that we should embrace more informed policies and practice. Researchers should also work toward new and more complex research approaches to delve more deeply into how the brain organizes and reorganizes with language learning. Despite the continuing need for more research, we know enough to put in place (and study) informed policies and practices that can benefit all children. Now is the time for evidence-based practice, evidence-based policies, and integrative research on bilingualism and education. PMID- 25732015 TI - The utility of neuroimaging studies for informing educational practice and policy in reading disorders. AB - Educational neuroscience is an emerging scientific field that brings together researchers from neuroscience, psychology, and education to explore the neurocognitive processes underlying educational practice and theory. In this brief article, we take reading disorder (RD, also known as developmental dyslexia) as an example, and explore trends in neuroimaging research, which may have future implications for educational practice and policy. Specifically, we present two examples that have been central to research efforts in our laboratory: (a) utilizing multimodal neuroimaging to optimize criteria to diagnose RD, and (b) identifying neuroimaging markers that predict future academic outcomes. Such research is faced with important challenges, and rigorous validation is necessary before any claims of the widespread practical utility of neuroimaging can be made. Nevertheless, we contend that neuroimaging studies offer opportunities for providing critical information that could lead to advancing theory of reading and RD. This could in turn lead to better diagnostic criteria and more accurate and earlier identification of RD. PMID- 25732016 TI - New directions for the study of within-individual variability in development: the power of "N = 1". AB - This article provides an introduction to the idiographic approach ("N = 1" research) in developmental psychology and an overview of methodological and statistical techniques employed to address the study of within-individual variability in development. Through a popularization of the idiographic approach and associated statistical techniques, but also through technical advances in the apparatus used to produce single-case intensive longitudinal data, the "power" of "N = 1" is becoming increasingly tangible and may challenge, or supplement, established paradigms in nomothetic (group-level) developmental psychology. PMID- 25732017 TI - Challenges of adolescent psychology in the European identity context. AB - In Europe, the question of identity and youth civic engagement constitutes a challenge both for the European Union (EU) and for research on adolescent psychology. In this article, we discuss the European historical context and the current initiatives from the EU that aim to encourage civic engagement among young people. Then, we suggest some research directions in youth civic engagement and identity formation, which could contribute to the facilitation of the initiative drawn by the EU. These directions include (a) understanding the role and the dynamics of the sense of belonging to the different levels of social communities into sociocultural contexts (such as continental, national), and (b) the development of civic engagement during adolescence integrating the various components of civic engagement and identity formation processes. Finally, (c) the specificities of sociocultural contexts and the diversity of multifaceted identity with regard to cultural, social, and ethnic groups should be taken into account. PMID- 25732018 TI - Anger and globalization among young people in India. AB - This article addresses the challenges faced by youth in developing countries. Using India as an example of a fast-globalizing country, this article highlights the experience and challenges faced by adolescents and emerging adults as they search for their interpersonal and professional identities. The difficulties of defining identity in the context of rapid globalization where people are exposed to diverse cultural forces that may conflict with each other are particularly salient when dealing with anger. Anger frequently results from thwarted wants and needs. In globalizing developing economies, young people often face inequitable access and opportunities that may be cause for distress-anger and depression. However, the skills to deal with anger are frequently culturally determined and may not be effective in situations where multiple cultural rules are operational. For example, India being a collectivist culture traditionally encourages the suppression of anger. However, situations and rules of conduct in a global economic order require the assertive expression of anger and the confrontation of conflict. Research that is methodologically and culturally appropriate is needed in exploring these issues and ameliorating distress associated with inequity, conflicts, and challenges. PMID- 25732019 TI - Classroom research and child and adolescent development in South America. AB - The article reviews recent classroom research developed in South America related to child and adolescent development. We review work about three themes: ethnicity, school climate and violence, and the learning process. The few studies found on ethnicity and classroom experiences told a story of invisibility, if not exclusion and discrimination. Research on violence suggests that, although there are variations within countries, school climate is an area of concern. Intervention work, still limited, is necessary considering the incidence of violence in the classrooms. Research on learning showed that most classrooms adhere to a very conventional pedagogy. There is a need to advance on international comparisons across all themes. Similarly, there is a need to go beyond the description of classroom dynamics to test educational interventions that may shed light on ways to improve educational performance, to decrease school violence, and to promote diversity within the classroom. Notwithstanding its limitations, the research here reviewed provides clear evidence of the relevant role that classroom experiences play in human development. In addition to their essential role in schooling, classrooms are the settings where processes related to peer relations, identity formation, and socioemotional development unfold. PMID- 25732020 TI - Adverse environments and children's creativity development: transforming the notion of "success in adversity" in China. AB - China has been undergoing great social change due to its new focus on urbanization and globalization. Such change has had a tremendous adverse impact on the living conditions of millions of young children, simultaneously generating new interest in children's creativity development. The intersection of these two issues has important implications for China's future as it brings together one of China's core cultural values-"success in adversity"-the importance of creativity, and very real social and economic needs. "Success in adversity" reflects the strongly held belief that individuals who suffer adverse environments can rise to excellence and success through persistence, effort, and creativity. In this article, we briefly explore the historical sources of this belief and how it is closely related to the Chinese conception of creativity. We then present some studies on the creativity of some of China's migrant children. Findings show that while migrant children as a group may not generally exhibit higher creativity than their urban peers as hypothesized, indications of resilience and creative potential suggest that the notion of success in adversity may contribute to the positive development of China's migrant children more substantially when it is informed by research and augmented by research-supported policy. PMID- 25732021 TI - Seeing the trees within the forest: addressing the needs of children without parental care in the Russian Federation. AB - In this essay, we comment on the dominant practice in high-resource societies of placing children without biological parental care (CwoBPC) into substitution families, and the promotion of this solution as evidence-based and state of the art. As the Russian Federation has formulated and is now addressing in matching legislation, it possibly overestimated the role of substitution families and underestimated the importance of specialized institutions in addressing the CwoBPC issue. Although we do not question the overall benefit of placing all CwoBPC in adequate family settings, we question the specifics of its realization in particular societies, including that of modern Russia. We argue for the importance of a mixed model, in which informed and supervised family placements are combined with high-quality family-environment institutional settings as the most appropriate model for middle- and, perhaps, even high-resource societies, especially for young children and children with disabilities. Diversifying placements based on the individual needs of each CwoBPC, especially children with special needs, is what is best for these children. PMID- 25732022 TI - Cultural considerations in the treatment of mental illness among sexually abused children and adolescents: the case of Bali, Indonesia. AB - Childhood and adolescence sexual abuse can have long-lasting and devastating effects on personal and interpersonal growth and development. Sexually abused children tend to exhibit higher rates of poor school performance, aggressive behavior, PTSD (posttraumatic stress disorder), or depressive symptomatology, as well as social and relational deficits (e.g., age-inappropriate sexual behaviors). The trauma following such abuse can further affect neurodevelopment and physiology, aggravating mental or physical problems in adulthood. Early symptom recognition and appropriate interventional applications are important factors in successfully treating or even preventing the development of mental disorders in such cohorts. A central element of effective treatment is the selection of treatment targets. Cultural considerations are rarely or peripherally considered in sexual abuse treatment strategies. Western-trained psychiatrists and clinical psychologists tend to overlook or underestimate such factors in cross-cultural settings, resulting in interventional efforts that may interfere with traditional approaches to healing, and potentially contributing to a transgenerational cycle of trauma. By using Bali (Indonesia) as a focal culture, in this article we discuss the effects of cultural elements and showcase their potential contribution and systematic implementation into a holistic and sensitive interventional model for the treatment of mental illness in childhood and adolescence sexual traumatization. PMID- 25732023 TI - Commentary-child and adolescent development in the focus of emerging developmental science. AB - In this brief essay, I comment on the constellation of papers published in the current issue. I argue that it represents the new beginning of the new era for the journal, driven by several considerations. Among these, three are key. First, the collection of articles in this issue is explicitly concerned with the multivariate and multidisciplinary nature of development and developmental science. Second, they explicate this point by providing an overview of several cross-disciplinary methodological approaches and the ways they can be used to study development. Finally, a common thread among the papers appearing in this issue is to attempt to relate and integrate research, practice, and policy in child and adolescent development. PMID- 25732024 TI - Commentary-a united front: using the range of psychological variance in cutting edge practice and emerging research. AB - Psychological and behavioral variance can be explained by differences in the environment, and between and within individuals. Almost 60 years ago, Cronbach (1957) called for converging investigations into all three sources as important for the development of accurate science and useful applications in the real world. Yet rifts among researchers tackling these various sources still exist. The articles in this issue, for example, differ greatly in terms of content, methodological approaches, and the sources of variance being addressed. On the basis of these articles, this commentary seeks to reignite Cronbach's call as an important step for psychological research to progress as a unified and useful science. PMID- 25732025 TI - Commentary-of quadrants and fish scales: reflections on new directions in research in child and adolescent development. AB - In this article, I reflect on how ways of reporting research as well as reviewing and commenting on submitted manuscripts could take new directions to promote progress in the discipline of developmental science. I argue for (a) attitudinal openness toward migratory impulses in relation to Stokes's quadrant model of science, (b) the relinquishment of an unproductive sense of problem ownership in authors, reviewers, and commentators, (c) active attempts to fill intra- and interdisciplinary gaps rather than solely focusing on strengthening existing islets of disciplinary expertise, (d) a strategic diversification of expertise in the selection of reviewers and commentators, (e) adopting a communication style that can be described as deferential transgressions, and (f) promoting attempts for transdisciplinary replications. (c) 2015 Wiley Periodicals, Inc. PMID- 25732026 TI - Heat-activated liposome targeting to streptavidin-coated surfaces. AB - There is a great need of improved anticancer drugs and corresponding drug carriers. In particular, liposomal drug carriers with heat-activated release and targeting functions are being developed for combined hyperthermia and chemotherapy treatments of tumors. The aim of this study is to demonstrate the heat-activation of liposome targeting to biotinylated surfaces, in model experiments where streptavidin is used as a pretargeting protein. The design of the heat-activated liposomes is based on liposomes assembled in an asymmetric structure and with a defined phase transition temperature. Asymmetry between the inside and the outside of the liposome membrane was generated through the enzymatic action of phospholipase D, where lipid head groups in the outer membrane leaflet, i.e. exposed to the enzyme, were hydrolyzed. The enzymatically treated and purified liposomes did not bind to streptavidin-modified surfaces. When activation heat was applied, starting from 22 degrees C, binding of the liposomes occurred once the temperature approached 33+/-0.5 degrees C. Moreover, it was observed that the asymmetric structure remained stable for at least 2 weeks. These results show the potential of asymmetric liposomes for the targeted binding to cell membranes in response to (external) temperature stimulus. By using pretargeting proteins, this approach can be further developed for personalized medicine, where tumor-specific antibodies can be selected for the conjugation of pretargeting agents. PMID- 25732027 TI - Geometrical effects of phospholipid olefinic bonds on the structure and dynamics of membranes: A molecular dynamics study. AB - The trans isomers of fatty acids are found in human adipose tissue. These isomers have been linked with deleterious health effects (e.g., coronary artery disease). In this study, we performed molecular dynamics simulations to investigate the structures and dynamic properties of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphatidylcholine (POPC) and 1-palmitoyl-2-elaidoyl sn-glycero-3 phosphatidylcholine (PEPC) lipid bilayers. The geometry of the olefinic bond and membrane packing effects significantly influenced the conformations and dynamics of the two C-C single bonds adjacent to the olefinic bond. For the PEPC lipid, the two C-C single bonds adjacent to the olefinic bond adopted mainly nonplanar skew-trans and planar cis-trans motifs; although the cis conformation featured relatively strong steric repulsion, it was stabilized through membrane packing because its planar structure is more suitable for membrane packing. Moreover, membrane packing effects stabilized the planar transition state for conformational conversion to a greater extent than they did with the nonplanar transition state, thereby affecting the dynamics of conformational conversion. The rotational motions of the first neighboring C-C single bonds were much faster than those of typical saturated C-C single bonds; in contrast, the rotational motions of the second neighboring C-C single bonds were significantly slower than those of typical saturated torsion angles. The packing of PEPC lipids is superior to that of POPC lipids, leading to a smaller area per lipid, a higher order parameter and a smaller diffusion coefficient. The distinct properties of POPC and PEPC lipids result in PEPC lipids forming microdomains within a POPC matrix. PMID- 25732028 TI - De novo design of transmembrane helix-helix interactions and measurement of stability in a biological membrane. AB - Membrane proteins regulate a large number of cellular functions, and have great potential as tools for manipulation of biological systems. Developing these tools requires a robust and quantitative understanding of membrane protein folding and interactions within the bilayer. With this in mind, we have designed a series of proteins to probe the net thermodynamic contribution of well-known sequence motifs to transmembrane helix-helix association in a biological membrane. The proteins were designed from first principles (de novo) using current knowledge about membrane insertion and stabilizing interaction motifs. A simple poly-Leu "scaffold" was decorated with individual helix interaction motifs (G-XXX-G, polar residues, heptad repeat) to create transmembrane helix-helix interactions of increasing strength. The GALLEX assay, an in vivo assay for measurement of transmembrane helix self-association, was combined with computational methods to characterize the relative strength and mode of interaction for each sequence. In addition, the apparent free energy contribution (DeltaDeltaGapp) of each motif to transmembrane helix self-association was measured in a biological membrane, results that are the first of their kind for these de novo designed sequences, and suggest that the free energy barrier to overcoming weak association is quite small (<1.4 kcal mol(-1)) in a natural membrane. By quantifying and rationalizing the contribution of key motifs to transmembrane helix association, our work offers a route to direct the design of novel sequences for use in biotechnology or synthetic biology (e.g. molecular switches) and to predict the effects of sequence modification in known transmembrane domains (for control of cellular processes). PMID- 25732029 TI - Evaluation of an antigen-capture EIA for the diagnosis of hepatitis E virus infection. AB - An enzyme immunoassay (EIA) has been developed for hepatitis E virus (HEV) antigen (HEV-Ag) detection and marketed in China. This study aimed to evaluate the sensitivity of the assay and assess the value of HEV-Ag detection in the diagnosis of HEV infection in comparison with HEV RNA detection. Using serial dilutions of a genotype 4 HEV strain, significant correlation was found between the EIA (S/CO) and HEV RNA (IU/mL) concentration in the range 10(3.5) to 10(0.5) IU/mL HEV RNA, the Pearson correlation coefficient r approached 0.97. The EIA detection limit was 54.6 IU/mL, compared to 24 IU/mL for HEV RNA using real-time RT-PCR. In clinical samples from hepatitis E patients, the HEV-Ag and HEV RNA positivity rates were 55.6% (65/117) and 60.7% (71/117) in sera and 76.7% (56/73) and 84.9% (62/73) in stools, and the concordance of these two markers was 77.8% in sera and 80.8% in stools. In serum samples, the HEV-Ag positivity rate and the concordance between HEV-Ag and HEV RNA were inversely proportional to the presence of anti-HEV antibody. The presence of anti-HEV IgG could reduce the S/CO of the HEV-Ag EIA. These results reveal a significant correlation between the detection of HEV-Ag and HEV RNA. The sensitivity of the HEV-Ag EIA was lower than real-time RT-PCR but could be higher than conventional nested RT-PCR. Therefore, the detection of HEV-Ag in serum and faeces is valuable for the diagnosis and prognosis of HEV infection in developing regions where real-time RT-PCR is not available. PMID- 25732030 TI - Diagnosis and management of diabetes and the relationship of dglucose to kidney function. AB - This article reviews different glycemic parameters and is aimed to clarify the most dependable glycemic parameter that predicts renal preservation. Glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) are the most commonly ordered tests for the diagnosis of diabetes and are also used to indicate prevention of microvascular complications associated with diabetes. Some experts have concluded that HbA1c remains the only test that can predict microvascular complications but HbA1c is misleading with anemia. Other experts have reported that elevation of 2 hour postprandial glucose (2hPPG) or postprandial hyperglycemia is critical for the development of diabetic complications Measurement of parameters under fasting conditions is convenient in both clinical and research settings and are used to establish clinical guidelines for diabetes management and for rating efficacy of management. Despite the use of these diagnostic markers and a plethora of oral antidiabetic agents to treat diabetes, diabetic complications namely; cardiovascular disorders (CVD), end stage renal disease (ESRD) and amputation are on the rise. Although affirmative data on many of the complications are not available, the United States Renal Data System on ESRD is a testimonial to poor diabetes care. We have innovated dglucose (2hPPG-FBG) and found that dglucose relates significantly to renal function change measured by serum creatinine levels or estimated glomerular filtration rate. Our current study on dglucose confirms our previous finding and validates the importance of dglucose to aid in the management of diabetes and prevents diabetic complications. In conclusion, the new finding in this study is dglucose (2h-postprandial glucose-Fasting glucose) which convincingly relates to renal function changes. Since dglucose is a product of 2hPP glucose, keeping 2hPPG under tight control with intensive insulin therapy is fundamentally important. Further blood pressure control avoiding the use of renin-angiotensin inhibitor therapy is additive to renal protection in diabetes. PMID- 25732031 TI - A novel antidiabetic therapy: free fatty acid receptors as potential drug target. AB - Excessive dietary intake of fat is strongly involved in the development of type 2 diabetes (T2D). Free fatty acids (FFAs), which are provided from dietary fat, are not only important nutrients, but also act as signaling molecules and stimulate key biological functions. Recent physiological and pharmacological studies have shown that several G-protein coupled receptors, such as FFAR1-4, are receptors for FFAs. FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids (SCFAs). These FFA receptors (FFARs) mediate various physiological functions, depending on the carbon chain length of the FFAs and the ligand specificity of the FFARs. Functional analyses have revealed that FFARs mediate important metabolic functions, such as peptide hormone secretion and inflammation, and thereby contribute to energy homeostasis. Since imbalances in energy homeostasis lead to metabolic disorders, such as obesity and T2D, FFARs are considered to be key therapeutic targets in these diseases. In particular, recent studies have shown that the administration of selective agonists of FFAR1 and FFAR4 improved glucose metabolism and ameliorated systemic metabolic disorders. Furthermore, the biological functions of SCFAs in anti-inflammation and energy metabolism are linked with the activation of FFAR2 and FFAR3. Hence, in this review, we summarize the physiological functions of FFARs and discuss the potential of selective ligands of FFARs for development as drugs to treat metabolic disorders, such as T2D and obesity. PMID- 25732033 TI - Simultaneous determination of phenylurea herbicides in yam by capillary electrophoresis with electrochemiluminescence detection. AB - A method of capillary electrophoresis (CE) coupled with electrochemiluminescence (ECL) detection has been applied to detect three major phenylurea herbicides (monuron, monolinuron and diuron) simultaneously. The effects of yam sample preparation, injection voltage and time, detection potential, detection buffer concentration and pH, Ru(bpy)3(2+) concentration, separation buffer type, separation buffer pH and concentration, separation voltage were investigated in detail. Under optimum conditions, a good baseline separation and highly sensitive detection for monuron, monolinuron and diuron were achieved. The ECL intensity (I) was in proportion to three analytes concentration (rho) in the range of 0.1 10,000 MUg/L for monuron (r>=0.9993), 0.1-18,000 MUg/L for monolinuron (r>=0.9995) and 0.1-20,000 MUg/L for diuron (r>=0.9997). The detection limits for monuron, monolinuron and diuron were 0.05, 0.04 and 0.01 MUg/L (S/N=3), respectively. The developed method was successfully applied for the analysis of monuron, monolinuron and diuron residues in yam simultaneously. The average recoveries are in the ranges of 90.0-99.2% with relative standard deviations less than 3.2%. The limits of detection of the proposed method were 0.010 MUg/kg for monuron, 0.008 MUg/kg for monolinuron and diuron in yam. PMID- 25732032 TI - Outcome of patients admitted with acute coronary syndrome on palliative treatment: insights from the nationwide AMIS Plus Registry 1997-2014. AB - OBJECTIVE: Compliance with guidelines is increasingly used to benchmark the quality of hospital care, however, very little is known on patients admitted with acute coronary syndromes (ACS) and treated palliatively. This study aimed to evaluate the baseline characteristics and outcomes of these patients. DESIGN: Prospective cohort study. SETTING: Eighty-two Swiss hospitals enrolled patients from 1997 to 2014. PARTICIPANTS: All patients with ACS enrolled in the AMIS Plus registry (n=45,091) were analysed according to three treatment groups: palliative treatment, defined as use of aspirin and analgesics only and no reperfusion; conservative treatment, defined as any treatment including antithrombotics or anticoagulants, heparins, P2Y12 inhibitors, GPIIb/IIIa but no pharmacological or mechanical reperfusion; and reperfusion treatment (thrombolysis and/or percutaneous coronary intervention during initial hospitalisation). The primary outcome measure was in-hospital mortality and the secondary measure was 1-year mortality. RESULTS: Of the patients, 1485 (3.3%) were palliatively treated, 11,119 (24.7%) were conservatively treated and 32,487 (72.0%) underwent reperfusion therapy. In 1997, 6% of all patients were treated palliatively and this continuously decreased to 2% in 2013. Baseline characteristics of palliative patients differed in comparison with conservatively treated and reperfusion patients in age, gender and comorbidities (all p<0.001). These patients had more in-hospital complications such as postadmission onset of cardiogenic shock (15.6% vs 5.2%; p<0.001), stroke (1.8% vs 0.8%; p=0.001) and a higher in-hospital mortality (25.8% vs 5.6%; p<0.001).The subgroup of patients followed 1 year after discharge (n=8316) had a higher rate of reinfarction (9.2% vs 3.4%; p=0.003) and mortality (14.0% vs 3.5%; p<0.001). CONCLUSIONS: Patients with ACS treated palliatively were older, sicker, with more heart failure at admission and very high in-hospital mortality. While refraining from more active therapy may often constitute the most humane and appropriate approach, we think it is important to also evaluate these patients and include them in registries and outcome evaluations. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT01 305 785. PMID- 25732034 TI - Prevention of hepatitis B. AB - Hepatitis B virus (HBV) causes life-threatening liver disease. It is transmitted through a horizontal route or a mother-to-infant route, and the latter is the major route in endemic areas. Prevention of HBV infection by immunization is the best way to eliminate HBV-related diseases. The HBV vaccine is the first human vaccine using a viral antigen from infected persons, which is safe and effective. Either passive immunization by hepatitis B immunoglobulin (HBIG) or active immunization by HBV vaccine is effective, and a combination of both yields the best efficacy in preventing HBV infection. The impact of universal HBV immunization is huge, with 90%-95% effectiveness in preventing chronic HBV infection. It is the first cancer preventive vaccine with a protective efficacy against hepatocellular carcinoma (HCC) of ~ 70%. Nevertheless, further effort is still needed to avoid vaccine failure and to increase the global coverage rate. PMID- 25732037 TI - The scent of a handshake. AB - Sniffing our hand after a handshake may allow us to detect chemical signals produced by others. PMID- 25732035 TI - Role of astrocytes in epilepsy. AB - Astrocytes express ion channels, transmitter receptors, and transporters and, thus, are endowed with the machinery to sense and respond to neuronal activity. Recent studies have implicated that astrocytes play important roles in physiology, but these cells also emerge as crucial actors in epilepsy. Astrocytes are abundantly coupled through gap junctions allowing them to redistribute elevated K(+) and transmitter concentrations from sites of enhanced neuronal activity. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial K(+) and water channels. In addition, malfunction of glutamate transporters and the astrocytic glutamate-converting enzyme, glutamine synthetase, has been observed in epileptic tissue. These findings suggest that dysfunctional astrocytes are crucial players in epilepsy and should be considered as promising targets for new therapeutic strategies. PMID- 25732036 TI - Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area. AB - To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing <=10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time. PMID- 25732038 TI - Fighting an old disease with next-generation sequencing. AB - Whole genome sequencing has revealed that most cases of tuberculosis in a high incidence setting in Malawi were caused by just one lineage of the bacterium responsible for the disease. PMID- 25732039 TI - A social chemosignaling function for human handshaking. AB - Social chemosignaling is a part of human behavior, but how chemosignals transfer from one individual to another is unknown. In turn, humans greet each other with handshakes, but the functional antecedents of this behavior remain unclear. To ask whether handshakes are used to sample conspecific social chemosignals, we covertly filmed 271 subjects within a structured greeting event either with or without a handshake. We found that humans often sniff their own hands, and selectively increase this behavior after handshake. After handshakes within gender, subjects increased sniffing of their own right shaking hand by more than 100%. In contrast, after handshakes across gender, subjects increased sniffing of their own left non-shaking hand by more than 100%. Tainting participants with unnoticed odors significantly altered the effects, thus verifying their olfactory nature. Thus, handshaking may functionally serve active yet subliminal social chemosignaling, which likely plays a large role in ongoing human behavior. PMID- 25732040 TI - Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro evolution of a double-minute chromosome. AB - BACKGROUND: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. METHODS: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. RESULTS: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. CONCLUSION: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success. PMID- 25732041 TI - Examining cultural, social, and self-related aspects of stigma in relation to sexual assault and trauma symptoms. AB - The current study investigated a model explaining sexual assault victims' severity of trauma symptoms that incorporated multiple stigma constructs. Integrating the sexual assault literature with the stigma literature, this study sought to better understand trauma-related outcomes of sexual assault by examining three levels of stigma-cultural, social, and self. Results showed self stigma was significantly and positively related to trauma symptom severity. Thus, results revealed that the internalized aspect of stigma served as a mechanism in the relation between sexual assault severity and increased levels of trauma symptom severity, highlighting the importance of assessing self-stigma in women reporting sexual assault experiences. PMID- 25732042 TI - A novel strategy to synthesize well-defined PS brushes on silica particles by combination of lithium-iodine exchange (LIE) and surface-initiated living anionic polymerization (SI-LAP). AB - Core-shell hybrid particles, possessing a hard core of silica particles (SiPs) and a soft shell of brushlike polystyrene (PS), were successfully prepared by the combination of lithium-iodine exchange (LIE) and surface-initiated living anionic polymerization (SI-LAP). The molecular weight, graft density and brush thicknesses of the PS brushes were controllable. PMID- 25732043 TI - Empathic Embarrassment Accuracy in Autism Spectrum Disorder. AB - Empathic accuracy refers to the ability of perceivers to accurately share the emotions of protagonists. Using a novel task assessing embarrassment, the current study sought to compare levels of empathic embarrassment accuracy among individuals with autism spectrum disorders (ASD) with those of matched controls. To assess empathic embarrassment accuracy, we compared the level of embarrassment experienced by protagonists to the embarrassment felt by participants while watching the protagonists. The results show that while the embarrassment ratings of participants and protagonists were highly matched among controls, individuals with ASD failed to exhibit this matching effect. Furthermore, individuals with ASD rated their embarrassment higher than controls when viewing themselves and protagonists on film, but not while performing the task itself. These findings suggest that individuals with ASD tend to have higher ratings of empathic embarrassment, perhaps due to difficulties in emotion regulation that may account for their impaired empathic accuracy and aberrant social behavior. PMID- 25732045 TI - Solvent-free liquid crystals and liquids based on genetically engineered supercharged polypeptides with high elasticity. AB - A series of solvent-free elastin-like polypeptide liquid crystals and liquids are developed by electrostatic complexation of supercharged elastin-like polypeptides with surfactants. The smectic mesophases exhibit a high elasticity and the values can be easily tuned by varying the alkyl chain lengths of the surfactants or the lengths of the elastin-like polypeptides. PMID- 25732044 TI - Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria. AB - This prospective trial investigated the population pharmacokinetics of piperaquine given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard 3-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three-compartment model with first-order absorption described the data well. Age had a statistically significant effect (P < 0.005) on clearance/bioavailability in a model that accounts for allometric scaling. Simulations demonstrated that higher doses in all children, but especially in those with lower weight for age, are required for adequate piperaquine exposure, although safety and tolerance will need to be established. These findings support other evidence that both weight- and age specific guidelines for piperaquine dosing in children are urgently needed. PMID- 25732046 TI - [Parental death in childhood: the state of theoretical knowledge and clinical challenges in the future]. AB - Although children's psychological adaptation to parental cancer is a wide field for psycho-oncological research, few empirical studies target children bereavement specifically following parental cancer. In this paper, our purpose is to make a state of art about literature concerning parental death. Literature dealing with grief concerns psychopathological consequences of parental loss and most recently post-traumatic growth. Although references about support programs have emerged, few of these programs have been scientifically evaluated. This review underlines that more studies are needed with prospective quantitative and qualitative studies, in order to describe more precisely children bereavement process and long term effects of bereavement. Psychological support for other family members and evaluation of support programs seem to be critical to improve children adaptation to parental death. PMID- 25732047 TI - [Respecting patient's end of life wishes: feasibility study of an information on surrogate and advance directives]. AB - This prospective interventional study aims to show the feasibility and impact of information procedure on surrogate and advance directives (AD), for patients with incurable lung or gastrointestinal cancer. The intervention consisted of two semi structured interviews. The first included: collection of preferences for prognostic information and involvement in decision-making, initial assessment of knowledge, information and surrogate and DA. The second assessed the impact of the first interview on knowledge, surrogate designation and DA writing, the assessment procedure by the patient and assessment of anxiety generated. Among 77 eligible patients, 23 (30 %) were included, 6/29 (21 %) refused to participate, 20/23 (87 %) completed both interviews. Patients not included had a higher 4 month death rate than included ones (39 % vs. 4 %, P=0.002). Patients included had high expectations of information and appreciated it be delivered early, by someone not involved in their care. The study shows the feasibility of the procedure and its impact on the use of surrogate and DA by patients, however, revealing the complexity of approaching end-of-life wills and the importance of a process of anticipated discussion. PMID- 25732048 TI - [Elderly patients with glioblastoma: state of the art]. AB - The incidence of glioblastoma increases with age, with a median age, at diagnosis, of 65 years. Indeed, the optimization of standard of care of elderly glioblastoma patients in an aging population in Western countries becomes crucial. The age remains the main prognostic factor of glioblastoma. Survival among elderly patients is significantly less than among younger patients. The median survival of elderly glioblastoma patients is generally inferior to 6 months. More aggressive tumor behavior, less aggressive treatments, increased toxicity of therapies and more unfavorable clinical factors and comorbidities could explain a higher severity of the disease in the elderly. The balance between treatment efficacy and quality of life is a major focus because of the shorter life expectancy of patients. The standard of care of glioblastoma in elderly patients remains controversial. Large optimal resection, when achievable, should be preferred to biopsy. Survival is longer after adjuvant radiotherapy, either normofractionated over 6-weeks course or hypofractionated over 3-weeks course, for patients with good clinical status. Hypofractionation is often preferred because of shorter procedure. Chemotherapy alone with temozolomide can be proposed to patients with methylated MGMT promoter. A phase III randomized study, testing short-course adjuvant radiotherapy with or without temozolomide in elderly patients with good clinical status, is ongoing. PMID- 25732049 TI - Time's up! Involvement of metamemory knowledge, executive functions, and time monitoring in children's prospective memory performance. AB - This study examined time-based prospective memory (PM) in children and explored the possible involvement of metamemory knowledge and executive functions in the use of an appropriate time-monitoring strategy depending on the ongoing task's difficulty. Specifically, a sample of 72 typically developing children aged 4, 6, and 9 years old were given an original PM paradigm composed of both an ongoing procedural activity and a PM task. Half of the participants (expert group) were trained in the ongoing activity before the prospective test. As expected, results show that time monitoring had a positive effect on children's PM performance. Furthermore, mediation analyses reveal that strategic time monitoring was predicted by metamemory knowledge in the expert group but only by executive functions in the novice group. Overall, these findings provide interesting avenues to explain how metamemory knowledge, strategy use, and executive functions interact to improve PM performance during childhood. PMID- 25732050 TI - How to engage small retail businesses in workplace violence prevention: Perspectives from small businesses and influential organizations. AB - BACKGROUND: Small retail businesses experience high robbery and violent crime rates leading to injury and death. Workplace violence prevention programs (WVPP) based on Crime Prevention Through Environmental Design reduce this risk, but low small business participation limits their effectiveness. Recent dissemination models of occupational safety and health information recommend collaborating with an intermediary organization to engage small businesses. METHODS: Qualitative interviews with 70 small business operators and 32 representatives of organizations with small business influence were conducted to identify factors and recommendations for improving dissemination of a WVPP. RESULTS: Both study groups recommended promoting WVPPs through personal contacts but differed on other promotion methods and the type of influential groups to target. Small business operators indicated few connections to formal business networks. CONCLUSIONS: Dissemination of WVPPs to small businesses may require models inclusive of influential individuals (e.g., respected business owners) as intermediaries to reach small businesses with few formal connections. PMID- 25732051 TI - Trans-splicing repair of mutant p53 suppresses the growth of hepatocellular carcinoma cells in vitro and in vivo. AB - Reactivation of wild-type p53 (wt-p53) function is an attractive therapeutic approach to p53-defective cancers. An ideal p53-based gene therapy should restore wt-p53 production and reduces mutant p53 transcripts simultaneously. In this study, we described an alternative strategy named as trans-splicing that repaired mutant p53 transcripts in hepatocellular carcinoma (HCC) cells. The plasmids which encoded a pre-trans-splicing molecule (PTM) targeting intron 6 of p53 were constructed and then transfected into HCC cells carrying p53 mutation. Phenotypic changes of HCC cells induced by p53-PTM were analyzed through cell cycle, cell apoptosis and the expression of p53 downstream target genes. Spliceosome mediated RNA trans-splicing (SMaRT) reduced mutant p53 transcripts and produced functional wt-p53 protein after the delivery of p53-PTM plasmids, which resulted in phenotype correction of HCC cells. In tumor xenografts established by p53-mutated HCC cells, adenovirus encoding p53-PTM induced cell cycle arrest and apoptosis and then blocked the growth of tumors in mice. Collectively, our results demonstrated for the first time that mutant p53 transcripts were functionally corrected in p53-defective HCC cells and xenografts using trans-splicing, which indicated the feasibility of using trans-splicing to repair p53 mutation in p53 defective cancers. PMID- 25732052 TI - Delayed exercise promotes remodeling in sub-rupture fatigue damaged tendons. AB - Tendinopathy is a common musculoskeletal injury whose treatment is limited by ineffective therapeutic interventions. Previously we have shown that tendons ineffectively repair early sub-rupture fatigue damage. In contrast, physiological exercise has been shown to promote remodeling of healthy tendons but its utility as a therapeutic to promote repair of fatigue damaged tendons remains unknown. Therefore, the objective of this study was to assess the utility of exercise initiated 1 and 14 days after onset of fatigue damage to promote structural repair in fatigue damaged tendons. We hypothesized that exercise initiated 14 days after fatigue loading would promote remodeling as indicated by a decrease in area of collagen matrix damage, increased procollagen I and decorin, while decreasing proteins indicative of tendinopathy. Rats engaged in 6-week exercise for 30 min/day or 60 min/day starting 1 or 14 days after fatigue loading. Initiating exercise 1-day after onset of fatigue injury led to exacerbation of matrix damage, particularly at the tendon insertion. Initiating exercise 14 days after onset of fatigue injury led to remodeling of damaged regions in the midsubstance and collagen synthesis at the insertion. Physiological exercise applied after the initial biological response to injury has dampened can potentially promote remodeling of damaged tendons. PMID- 25732053 TI - Progressive supranuclear palsy: what do we know about it? AB - Progressive supranuclear palsy (PSP) is a progressive tauopathy characterized by supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, axial rigidity, frontal lobe dysfunction, and dementia. The typical pathology includes neuronal loss, gliosis and microtubule-associated protein tau (MAPT)-positive inclusions in neurons and glial cells, primarily in basal ganglia, brainstem and cerebellum. The pathogenesis of PSP is not yet completely understood; however, there are several hypotheses. This article reviews the present knowledge about PSP, and the concepts underlying mitochondrial dysfunction, lipoperoxidation, and gene mutations. The clinical features of PSP are also discussed; these include vertical gaze palsy, pseudobulbar palsy, aphasia, dysarthria, axial rigidity, and neuropsychiatric symptoms, such as amnesia, irritability, loss of interest, and dementia. In terms of diagnosis, there is considerable interest in neuroimaging for detecting PSP; therefore, neuroimaging techniques such as magnetic resonance imaging (MRI) and [18F]- fluorodeoxyglucose positron-emission tomography (FDG PET) are reviewed. A definitive diagnosis of PSP depends on pathology, and the introduction of new clinical subtypes challenges presents the widely adopted diagnosis criteria. PSP treatments such as serotonin antagonists, alpha2 receptor antagonists, and coenzyme Q10 are also discussed. There is no curative therapy for PSP; all of the available treatments are palliative. PMID- 25732054 TI - Confined helium on Lagrange meshes. AB - The Lagrange-mesh method has the simplicity of a calculation on a mesh and can have the accuracy of a variational method. It is applied to the study of a confined helium atom. Two types of confinement are considered. Soft confinements by potentials are studied in perimetric coordinates. Hard confinement in impenetrable spherical cavities is studied in a system of rescaled perimetric coordinates varying in [0,1] intervals. Energies and mean values of the distances between electrons and between an electron and the helium nucleus are calculated. A high accuracy of 11 to 15 significant figures is obtained with small computing times. Pressures acting on the confined atom are also computed. For sphere radii smaller than 1, their relative accuracies are better than 10(-10). For larger radii up to 10, they progressively decrease to 10(-3), still improving the best literature results. PMID- 25732055 TI - Fitting Procedures for Novel Gene-by-Measured Environment Interaction Models in Behavior Genetic Designs. AB - For quantitative behavior genetic (e.g., twin) studies, Purcell proposed a novel model for testing gene-by-measured environment (GxM) interactions while accounting for gene-by-environment correlation. Rathouz et al. expanded this model into a broader class of non-linear biometric models for quantifying and testing such interactions. In this work, we propose a novel factorization of the likelihood for this class of models, and adopt numerical integration techniques to achieve model estimation, especially for those without close-form likelihood. The validity of our procedures is established through numerical simulation studies. The new procedures are illustrated in a twin study analysis of the moderating effect of birth weight on the genetic influences on childhood anxiety. A second example is given in an online appendix. Both the extant GxM models and the new non-linear models critically assume normality of all structural components, which implies continuous, but not normal, manifest response variables. PMID- 25732056 TI - A high molecular mass zinc transporter MTP12 forms a functional heteromeric complex with MTP5 in the Golgi in Arabidopsis thaliana. AB - Zinc (Zn) is an essential micronutrient required for plant growth and development. In Arabidopsis thaliana, several families of Zn transporters engaged in Zn import, export and intracellular compartmentalization play important roles in Zn homeostasis. We describe a novel Zn transporter, A. thaliana metal tolerance protein 12 (AtMTP12), which belongs to the cation diffusion facilitator family. AtMTP12 is predicted to consist of 798 amino acids and have 14 transmembrane segments. The expression of AtMTP12 in suspension-cultured cells was not affected by Zn deficiency or excess. Heterologous expression in a mutant of budding yeast (Saccharomyces cerevisiae) that lacks Msc2p, an orthologue of AtMTP12, revealed that AtMTP12 complements the growth phenotype of the msc2 mutant when AtMTP5t1, one of the splicing variants of AtMTP5, is coexpressed. Transient expression of AtMTP12-fused green fluorescent protein in A. thaliana mesophyll protoplasts demonstrated that AtMTP12 is localized to the Golgi apparatus. Moreover, AtMTP12 and AtMTP5t1 interact in the Golgi, as determined by a bimolecular fluorescence complementation assay. These results suggest that AtMTP12 forms a functional complex with AtMTP5t1 to transport Zn into the Golgi. DATABASE: Nucleotide sequence data for full-length of AtMTP12 is available in the DDBJ/EMBL/GenBank database under accession number AB986563. PMID- 25732057 TI - Interactions between osteopontin and vascular endothelial growth factor: Implications for cancer. AB - For this comprehensive review, 257 publications with the keywords "osteopontin" or "OPN" and "vascular endothelial growth factor" or "VEGF" in PubMed were screened (time frame from year 1996 to year 2014). 37 articles were excluded because they were not focused on the interactions between these molecules, and papers relevant for transformation-related phenomena were selected. Osteopontin (OPN) and vascular endothelial growth factor (VEGF) are characterized by a convergence in function for regulating cell motility and angiogenesis, the response to hypoxia, and apoptosis. Often, they are co-expressed or one molecule induces the other, however, in some settings OPN-associated pathways and VEGF associated pathways are distinct. Their relationships affect the pathogenesis in cancer, where they contribute to progression and angiogenesis and serve as markers for poor prognosis. The inhibition of OPN may reduce VEGF levels and suppress tumor progression. In vascular pathologies, these two cytokines mediate remodeling, but may also perpetuate inflammation and narrowing of the arteries. OPN and VEGF are elevated and contribute to vascularization in inflammatory diseases. PMID- 25732058 TI - Insulating state in tetralayers reveals an even-odd interaction effect in multilayer graphene. AB - Close to charge neutrality, the electronic properties of graphene and its multilayers are sensitive to electron-electron interactions. In bilayers, for instance, interactions are predicted to open a gap between valence and conduction bands, turning the system into an insulator. In mono and (Bernal-stacked) trilayers, which remain conducting at low temperature, interactions do not have equally drastic consequences. It is expected that interaction effects become weaker for thicker multilayers, whose behaviour should converge to that of graphite. Here we show that this expectation does not correspond to reality by revealing the occurrence of an insulating state close to charge neutrality in Bernal-stacked tetralayer graphene. The phenomenology-incompatible with the behaviour expected from the single-particle band structure-resembles that observed in bilayers, but the insulating state in tetralayers is visible at higher temperature. We explain our findings, and the systematic even-odd effect of interactions in Bernal-stacked layers of different thickness that emerges from experiments, in terms of a generalization of the interaction-driven, symmetry broken states proposed for bilayers. PMID- 25732059 TI - Vision maintenance and retinal apoptosis reduction in RCS rats with Okayama University-type retinal prosthesis (OURePTM) implantation. AB - Photoelectric dye-coupled polyethylene film, designated Okayama University-type retinal prosthesis or OURePTM, generates light-evoked surface electric potentials and stimulates neurons. In this study, the vision was assessed by behavior tests in aged hereditary retinal dystrophic RCS rats with OURePTM, retinal apoptosis and electroretinographic responses were measured in dystrophic eyes with OURePTM. The dye-coupled films, or plain films as a control, were implanted in subretinal space of RCS rats. On behavior tests, RCS rats with dye-coupled films, implanted at the old age of 14 weeks, showed the larger number of head-turning, consistent with clockwise and anticlockwise rotation of a surrounding black-and-white striped drum, compared with rats with plain films, under the dim (50 lux) and bright (150 lux) conditions in the observation period until the age of 22 weeks (n = 5, P < 0.05, repeated-measure ANOVA). The number of apoptotic cells in retinal sections at the site of dye-coupled film implantation was significantly smaller, compared with the other retinal sites, neighboring the film, or opposite to the film, 5 months after film implantation at the age of 6 weeks (P = 0.0021, Friedman test). The dystrophic eyes of RCS rats with dye-coupled films showed positive responses to maximal light stimulus at a significantly higher rate, compared with the eyes with no treatment (P < 0.05, Chi-square test). Electroretinograms in normal eyes of Wistar rats with dye-coupled or plain films showed significantly decreased amplitudes (n = 14, P < 0.05, repeated-measure ANOVA). In conclusions, vision was maintained in RCS rats with dye-coupled films implanted at the old age. The dystrophic eyes with dye-coupled films showed electroretinographic responses. Five-month film implantation caused no additional retinal changes. PMID- 25732061 TI - Vacuum nanohole array embedded phosphorescent organic light emitting diodes. AB - Light extraction from organic light-emitting diodes that utilize phosphorescent materials has an internal efficiency of 100% but is limited by an external quantum efficiency (EQE) of 30%. In this study, extremely high-efficiency organic light emitting diodes (OLEDs) with an EQE of greater than 50% and low roll-off were produced by inserting a vacuum nanohole array (VNHA) into phosphorescent OLEDs (PhOLEDs). The resultant extraction enhancement was quantified in terms of EQE by comparing experimentally measured results with those produced from optical modeling analysis, which assumes the near-perfect electric characteristics of the device. A comparison of the experimental data and optical modeling results indicated that the VNHA extracts the entire waveguide loss into the air. The EQE obtained in this study is the highest value obtained to date for bottom-emitting OLEDs. PMID- 25732060 TI - Large-scale identification of core-fucosylated glycopeptide sites in pancreatic cancer serum using mass spectrometry. AB - Glycosylation has significant effects on protein function and cell metastasis, which are important in cancer progression. It is of great interest to identify site-specific glycosylation in search of potential cancer biomarkers. However, the abundance of glycopeptides is low compared to that of nonglycopeptides after trypsin digestion of serum samples, and the mass spectrometric signals of glycopeptides are often masked by coeluting nonglycopeptides due to low ionization efficiency. Selective enrichment of glycopeptides from complex serum samples is essential for mass spectrometry (MS)-based analysis. Herein, a strategy has been optimized using LCA enrichment to improve the identification of core-fucosylation (CF) sites in serum of pancreatic cancer patients. The optimized strategy was then applied to analyze CF glycopeptide sites in 13 sets of serum samples from pancreatic cancer, chronic pancreatitis, healthy controls, and a standard reference. In total, 630 core-fucosylation sites were identified from 322 CF proteins in pancreatic cancer patient serum using an Orbitrap Elite mass spectrometer. Further data analysis revealed that 8 CF peptides exhibited a significant difference between pancreatic cancer and other controls, which may be potential diagnostic biomarkers for pancreatic cancer. PMID- 25732062 TI - Carotid Arterial Stiffness in Patients with Congenital Heart Disease-Related Pulmonary Hypertension Assessed with Radio Frequency Data Technique. AB - BACKGROUND: It has been well known that pulmonary hypertension (PH) caused by congenital heart disease (CHD) leads to reduced flexibility of the small pulmonary arteries, due to hemodynamic changes in the pulmonary circulation and alterations of the vasoactive profile. However, whether CHD-related PH affects the elasticity of the systemic arteries, such as the common carotid artery (CCA), has not been fully investigated. The purpose of this study was to explore the CCA stiffness in patients with CHD-related PH using the radio frequency data technique. METHODS: Forty patients with CHD were included. They were divided into PH and non-PH (NPH) groups by the right heart catheter-determined or regurgitation velocity-determined mean pulmonary arterial pressure (mPAP). MyLabTwice (Esaote, Genoa, Italy) ultrasound machine equipped with automatic quality intima-media thickness (QIMT) and quality arterial stiffness (QAS) capabilities was used to measure the left common carotid arterial (CCA) intima media thickness and arterial stiffness parameters. RESULTS: The results have shown that the left CCA internal diameter, pulse wave velocity, arterial wall tension, and local diastolic pressure were increased in the CHD-related PH group compared with the CHD-related NPH group (all P < 0.05). The left CCA internal diameter negatively and significantly correlated with the mean PAP. CONCLUSIONS: Common carotid artery diameter and stiffness increase in patients with CHD related pulmonary hypertension. QIMT and QAS ultrasound techniques may provide a comprehensive assessment of the CCA remodeling. PMID- 25732063 TI - Biogeography of the intestinal mucosal and lumenal microbiome in the rhesus macaque. AB - The gut microbiome is widely studied by fecal sampling, but the extent to which stool reflects the commensal composition at intestinal sites is poorly understood. We investigated this relationship in rhesus macaques by 16S sequencing feces and paired lumenal and mucosal samples from ten sites distal to the jejunum. Stool composition correlated highly with the colonic lumen and mucosa and moderately with the distal small intestine. The mucosal microbiota varied most based on location and was enriched in oxygen-tolerant taxa (e.g., Helicobacter and Treponema), while the lumenal microbiota showed inter-individual variation and obligate anaerobe enrichment (e.g., Firmicutes). This mucosal and lumenal community variability corresponded to functional differences, such as nutrient availability. Additionally, Helicobacter, Faecalibacterium, and Lactobacillus levels in stool were highly predictive of their abundance at most other gut sites. These results quantify the composition and biogeographic relationships between gut microbial communities in macaques and support fecal sampling for translational studies. PMID- 25732064 TI - Structure and function of the bacterial root microbiota in wild and domesticated barley. AB - The microbial communities inhabiting the root interior of healthy plants, as well as the rhizosphere, which consists of soil particles firmly attached to roots, engage in symbiotic associations with their host. To investigate the structural and functional diversification among these communities, we employed a combination of 16S rRNA gene profiling and shotgun metagenome analysis of the microbiota associated with wild and domesticated accessions of barley (Hordeum vulgare). Bacterial families Comamonadaceae, Flavobacteriaceae, and Rhizobiaceae dominate the barley root-enriched microbiota. Host genotype has a small, but significant, effect on the diversity of root-associated bacterial communities, possibly representing a footprint of barley domestication. Traits related to pathogenesis, secretion, phage interactions, and nutrient mobilization are enriched in the barley root-associated microbiota. Strikingly, protein families assigned to these same traits showed evidence of positive selection. Our results indicate that the combined action of microbe-microbe and host-microbe interactions drives microbiota differentiation at the root-soil interface. PMID- 25732066 TI - A case report and literature review of chronic graft-versus-host disease manifesting as polymyositis. AB - Polymyositis (PM) is a rare but documented manifestation of chronic graft-versus host disease (cGvHD) post allogeneic hematopoietic cell transplantation (HCT). We present the case of a 70-year-old male patient who developed severe cGvHD-related PM 3 years after undergoing allogeneic HCT for acute myeloid leukemia. The patient responded to steroids and was maintained long-term with hydroxychloroquine as a steroid-sparing agent. We review the literature concerning the diagnosis and treatment of PM as cGvHD as well as the differentiation of this manifestation from other forms of PM. PMID- 25732065 TI - A genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite. AB - The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission. PMID- 25732067 TI - Sickle cell in Latin America and the United States [corrected]. AB - Latin Americans are an underappreciated population affected by sickle cell disease (SCD). Sickle trait and SCD exist throughout Latin America and U.S. Latino communities. We describe the epidemiology and genetic heterogeneity of SCD among Latin Americans, and fetal hemoglobin expression. National population-based newborn screening for SCD is limited to Brazil, Costa Rica, and the U.S. Available and extrapolated data suggest that over 6,000 annual births and 100,000 150,000 Latin Americans are affected by SCD. This comprehensive review highlights the substantial numbers and population distribution of SCD and sickle trait in Latin America, and where national newborn screening programs for SCD exist. PMID- 25732068 TI - Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice. AB - The combination of depression and anorexia may influence morbidity and progressive physical disability in the elderly. Gender differences exist in hypothalamic-pituitary-adrenal axis activation following stress exposure. The objective of this study was to investigate gender differences in feeding behavior under novelty stress in aged mice. Food intake measurement, immunohistochemical assessment, and mRNA expression analysis were conducted to investigate the role of serotonin 2C receptor (5-HT(2C)R) and its relationship with ghrelin in stress induced suppression of feeding behavior in aged mice. After exposure to novelty stress, a 21-fold increase in plasma corticosterone and remarkable suppression of food intake were observed in aged male mice. Furthermore, a 5-HT(2C)R agonist suppressed food intake in aged male mice. Novelty stress induced a 7-fold increase in 5-HT(2C)R and c-Fos co-expressing cells in the paraventricular nucleus of the hypothalamus in aged male mice but caused no change in aged female mice. Plasma acylated ghrelin levels decreased in stressed aged male mice and administration of the 5-HT(2C)R antagonist inhibited this decrease. The 5-HT(2C)R antagonist also reversed the suppression of food intake in estrogen receptor alpha agonist-treated aged male mice. Therefore, conspicuously suppressed feeding behavior in novelty stress-exposed aged male mice may be mediated by 5-HT(2C)R hypersensitivity, leading to hypoghrelinemia. The hypersensitivity may partly be due to estrogen receptor activation in aged male mice. PMID- 25732069 TI - Phylogeny of world stag beetles (Coleoptera: Lucanidae) reveals a Gondwanan origin of Darwin's stag beetle. AB - Stag beetles (family Lucanidae Latreille, 1804) are one of the earliest branching lineages of scarab beetles that are characterized by the striking development of the male mandibles. Despite stag beetles' popularity among traditional taxonomists and amateur collectors, there has been almost no study of lucanid relationships and evolution. Entomologists, including Jeannel (1942), have long recognized resemblance between the austral stag beetles of the tribes Chiasognathini, Colophonini, Lamprimini, Pholidotini, Rhyssonotini, and Streptocerini, but this hypothesis of their close relationship across the continents has never been tested. To gain further insight into lucanid phylogeny and biogeography, we reconstructed the first molecular phylogeny of world stag beetles using DNA sequences from mitochondrial 16S rDNA, nuclear 18S and 28S rDNA, and the nuclear protein-coding (NPC) gene wingless for 93 lucanid species representing all extant subfamilies and 24 out of the 27 tribes, together with 14 representative samples of other early branching scarabaeoid families and two staphyliniform beetle families as outgroups. Both Bayesian inference (BI) and maximum likelihood inference (MLI) strongly supported the monophyly of Lucanidae sensu lato that includes Diphyllostomatidae. Within Lucanidae sensu stricto, the subfamilies Lucaninae and Lampriminae appeared monophyletic under both methods of phylogenetic inferences; however, Aesalinae and Syndesinae were found to be polyphyletic. A time-calibrated phylogeny based on five fossil data estimated the origin of crown group Lucanidae as circa 160 million years ago (MYA). Divergence between the Neotropical and Australasian groups of the Chiasognathini was estimated to be circa 47MYA, with the South African Colophonini branching off from the ancient Chiasognathini lineage around 87MYA. Another Gondwanan relationship was recovered between the Australasian Eucarteria and the Neotropical Casignetus, which diverged circa 58MYA. Lastly, as Jeannel's hypothesis predicted, divergence within Lampriminae between the Australasian Lamprima and the Neotropical Streptocerus was estimated to be circa 37MYA. The split of these lineages were generally concordant with the pattern of continental break-up of the super-continent Gondwana, and our biogeographic reconstructions based on the dispersal-extinction-cladogenesis model (DEC) corroborate our view that the divergences in these austral lineages were caused by vicariance events following the Gondwanan break-up. In addition, the phylogenetic position and geographic origin of the Hawaiian genus Apterocyclus was revealed for the first time. Overall, our results provide the framework toward studying lucanid relationships and divergence time estimates, which allowed for more accurate biogeographic explanations and discussions on ancestral lucanids and the evolutionary origin of the enlarged male mandibles. PMID- 25732070 TI - Repeated range expansions and inter-/postglacial recolonization routes of Sargentodoxa cuneata (Oliv.) Rehd. et Wils. (Lardizabalaceae) in subtropical China revealed by chloroplast phylogeography. AB - Most plant phylogeographic studies in subtropical China have stressed the importance of multiple refugia and limited admixture among refugia. Little attention has been paid to range expansion and recolonization routes in this region. In this study, we implemented a phylogeographic survey on Sargentodoxa cuneata, a widespread woody deciduous climber in subtropical China to determine if it conforms to the expansion-contraction (EC) model during the Pleistocene. Sequence variation of two chloroplast intergenic spacers (IGSs) in 369 individuals from 54 populations of S. cuneata was examined. Twenty-six chloroplast haplotypes were recovered. One of these (H5) occurred across the range of S. cuneata and was absent from only 13 populations. Sixteen of the 26 haplotypes were connected to H5 by one mutation and displayed a star-like pattern in the haplotype network. All chloroplast haplotypes clustered into two lineages (A and B) in a Bayesian tree, and most haplotypes (18 out of 26) originated during the mid-Pleistocene (0.63-1.07Ma). Demographic analyses detected a recent range expansion that occurred at 95.98ka (CI: 61.7-112.53ka) for Lineage A. The genetic signature of an ancient range expansion after the Middle Pleistocene Transition (MPT) was also evident. Three recolonization routes were identified in subtropical China. The results suggest that temperate plants in subtropical China may conform to the EC model to some extent. However, the genetic signature from multiple historical processes may complicate the phylogeographic patterns of organisms in the region due to the mild Pleistocene climate. This study provides a new perspective for understanding the evolutionary history of temperate plants in subtropical China. PMID- 25732071 TI - Synthesis of novel 17-(5'-iodo)triazolyl-3-methoxyestrane epimers via Cu(I) catalyzed azide-alkyne cycloadditon, and an evaluation of their cytotoxic activity in vitro. AB - The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of 3-methoxyestrane 17alpha- and 17beta-azide epimers (3 and 5) with different terminal alkynes afforded novel 1,4-substituted triazolyl derivatives (8a-f and 11a-f). If the Ph3P in the classical CuAAC process was replaced by Et3N, the formation of small quantities of 5-iodotriazoles (9a-f and 11a-f) was observed. For the preparation of 5-iodo-1,2,3-triazoles (9a-f and 11a-f), an improved method was developed, directly from steroidal azides and terminal alkynes, in reactions mediated by CuI and ICl as iodinating agents. The antiproliferative activities of the structurally related triazoles were determined in vitro with the microculture tetrazolium assay on six malignant human cell lines of gynecological origin (HeLa, A2780, MCF7, MDA-MB-231, MDA-MB-361 and T47D). X-ray analysis revealed the presence of the iodo substituent on the 1,2,3-triazole ring. PMID- 25732073 TI - A web-based institutional DICOM distribution system with the integration of the Clinical Trial Processor (CTP). AB - To develop and test a fast and easy rule-based web-environment with optional de identification of imaging data to facilitate data distribution within a hospital environment. A web interface was built using Hypertext Preprocessor (PHP), an open source scripting language for web development, and Java with SQL Server to handle the database. The system allows for the selection of patient data and for de-identifying these when necessary. Using the services provided by the RSNA Clinical Trial Processor (CTP), the selected images were pushed to the appropriate services using a protocol based on the module created for the associated task. Five pipelines, each performing a different task, were set up in the server. In a 75 month period, more than 2,000,000 images are transferred and de-identified in a proper manner while 20,000,000 images are moved from one node to another without de-identification. While maintaining a high level of security and stability, the proposed system is easy to setup, it integrate well with our clinical and research practice and it provides a fast and accurate vendor-neutral process of transferring, de-identifying, and storing DICOM images. Its ability to run different de-identification processes in parallel pipelines is a major advantage in both clinical and research setting. PMID- 25732072 TI - Characterizing and differentiating task-based and resting state fMRI signals via two-stage sparse representations. AB - A relatively underexplored question in fMRI is whether there are intrinsic differences in terms of signal composition patterns that can effectively characterize and differentiate task-based or resting state fMRI (tfMRI or rsfMRI) signals. In this paper, we propose a novel two-stage sparse representation framework to examine the fundamental difference between tfMRI and rsfMRI signals. Specifically, in the first stage, the whole-brain tfMRI or rsfMRI signals of each subject were composed into a big data matrix, which was then factorized into a subject-specific dictionary matrix and a weight coefficient matrix for sparse representation. In the second stage, all of the dictionary matrices from both tfMRI/rsfMRI data across multiple subjects were composed into another big data matrix, which was further sparsely represented by a cross-subjects common dictionary and a weight matrix. This framework has been applied on the recently publicly released Human Connectome Project (HCP) fMRI data and experimental results revealed that there are distinctive and descriptive atoms in the cross subjects common dictionary that can effectively characterize and differentiate tfMRI and rsfMRI signals, achieving 100% classification accuracy. Moreover, our methods and results can be meaningfully interpreted, e.g., the well-known default mode network (DMN) activities can be recovered from the very noisy and heterogeneous aggregated big-data of tfMRI and rsfMRI signals across all subjects in HCP Q1 release. PMID- 25732074 TI - Mutual information analysis of sleep EEG in detecting psycho-physiological insomnia. AB - The primary goal of this study is to state the clear changes in functional brain connectivity during all night sleep in psycho-physiological insomnia (PPI). The secondary goal is to investigate the usefulness of Mutual Information (MI) analysis in estimating cortical sleep EEG arousals for detection of PPI. For these purposes, healthy controls and patients were compared to each other with respect to both linear (Pearson correlation coefficient and coherence) and nonlinear quantifiers (MI) in addition to phase locking quantification for six sleep stages (stage.1-4, rem, wake) by means of interhemispheric dependency between two central sleep EEG derivations. In test, each connectivity estimation calculated for each couple of epoches (C3-A2 and C4-A1) was identified by the vector norm of estimation. Then, patients and controls were classified by using 10 different types of data mining classifiers for five error criteria such as accuracy, root mean squared error, sensitivity, specificity and precision. High performance in a classification through a measure will validate high contribution of that measure to detecting PPI. The MI was found to be the best method in detecting PPI. In particular, the patients had lower MI, higher PCC for all sleep stages. In other words, the lower sleep EEG synchronization suffering from PPI was observed. These results probably stand for the loss of neurons that then contribute to less complex dynamical processing within the neural networks in sleep disorders an the functional central brain connectivity is nonlinear during night sleep. In conclusion, the level of cortical hemispheric connectivity is strongly associated with sleep disorder. Thus, cortical communication quantified in all existence sleep stages might be a potential marker for sleep disorder induced by PPI. PMID- 25732075 TI - An obstructive sleep apnea detection approach using kernel density classification based on single-lead electrocardiogram. AB - Obstructive sleep apnea (OSA) is a common sleep disorder that often remains undiagnosed, leading to an increased risk of developing cardiovascular diseases. Polysomnogram (PSG) is currently used as a golden standard for screening OSA. However, because it is time consuming, expensive and causes discomfort, alternative techniques based on a reduced set of physiological signals are proposed to solve this problem. This study proposes a convenient non-parametric kernel density-based approach for detection of OSA using single-lead electrocardiogram (ECG) recordings. Selected physiologically interpretable features are extracted from segmented RR intervals, which are obtained from ECG signals. These features are fed into the kernel density classifier to detect apnea event and bandwidths for density of each class (normal or apnea) are automatically chosen through an iterative bandwidth selection algorithm. To validate the proposed approach, RR intervals are extracted from ECG signals of 35 subjects obtained from a sleep apnea database ( http://physionet.org/cgi bin/atm/ATM ). The results indicate that the kernel density classifier, with two features for apnea event detection, achieves a mean accuracy of 82.07 %, with mean sensitivity of 83.23 % and mean specificity of 80.24 %. Compared with other existing methods, the proposed kernel density approach achieves a comparably good performance but by using fewer features without significantly losing discriminant power, which indicates that it could be widely used for home-based screening or diagnosis of OSA. PMID- 25732076 TI - An anesthesia medication cost scorecard--concepts for individualized feedback. AB - There is a growing emphasis on both cost containment and better quality health care. The creation of better methods for alerting providers and their departments to the costs associated with patient care is one tool for improving efficiency. Since anesthetic medications used in the OR setting are one easily monitored factor contributing to OR costs, anesthetic cost report cards can be used to assess the cost and, potentially the quality of care provided by each practitioner. An ongoing challenge is the identification of the most effective strategies to control costs, promote cost awareness and at the same time maximize quality. To test the scorecard concept, we utilized existing informatics systems to gather and analyze drug costs for anesthesia providers in the OR. Drug costs were analyzed by medication class for each provider. Individual anesthesiologist's anesthetic costs were collected and compared to the average costs of the overall group and individual trends over time were noted. We presented drug usage data in an electronic report card format. Real-time individual reports can be provided to anesthesiologists to allow for anesthetic cost feedback. Data provided can include number of cases, average case time, total anesthetic medication costs, and average anesthetic cost per case. Also included can be subcategories of pre-medication, antibiotics, hypnotics, local anesthetics, neuromuscular blocking drugs, analgesics, vasopressors, beta blockers, anti-emetics, volatile anesthetics, and reversal agents. The concept of anesthetic cost report card should be further developed for individual feedback, and could include many other dimensions. Such a report card can be utilized to encourage lower anesthetic costs, quality improvement among anesthesia providers, and for cost containment in the operating room. PMID- 25732077 TI - Free blood donation mobile applications. AB - Blood donation (BD) is a noble act and mobile applications (apps) can help increase awareness about it. This paper analyzes and assesses the characteristics of free apps for BD as regards features and functionality. A search in Google Play, Apple Apps store, Blackberry App World and Windows Mobile App store was carried out to select 169 free BD apps from the 188 apps identified. The results presented in this paper show that the majority of the apps selected have been developed for the Android operating system. Moreover, most of the apps selected are available to help users search for donors. Few of the apps could not be installed and/or accessed. Of those that could be installed: half of them do not require any kind of authentication; a few of them are available in more than one language; half of them have a geographical restriction; around 60 % of them do not notify the user of BD events and requests; one, which is available for Android and iOS, can connect with a laboratory; around 45 % of them allow users to share information via social networks, and the majority of them do not provide BD recommendations. These results are used as a basis to provide app developers with certain recommendations. There is a need for better BD apps with more features in order to increase the number of volunteer donors. PMID- 25732078 TI - Perceptions of physicians about knowledge sharing barriers in Turkish health care system. AB - This study was based on knowledge sharing barriers about attitudes of physicians in Turkish health care system. The present study aims to determine whether the knowledge sharing barriers about attitudes of physicians vary depending on gender, position, departments at hospitals, and hospital ownership status. This study was planned and conducted on physicians at one public hospital, one university hospital, and one private hospital in Turkey. 209 physicians were reached for data collection. The study was conducted in June-September 2014. The questionnaire (developed by A. Riege, (J. Knowl. Manag. 9(3):18-35, 2005)), five point Likert-type scale including 39 items having the potential of the physicians' knowledge- sharing attitudes and behaviors, was used in the study for data collection. Descriptive statistics, reliability analysis, student t test and ANOVA were used for data analysis. According to results of this study, there was medium level of knowledge sharing barriers within hospitals. In general, physicians had perceptions about the lowest level individual barriers, intermediate level organizational barriers and the highest level technological barriers perceptions, respectively. This study revealed that some knowledge sharing barriers about attitudes of physicians were significantly difference according to hospital ownership status, gender, position and departments. Most evidence medical decisions and evidence based practice depend on experience and knowledge of existing options and knowledge sharing in health care organizations. Physicians are knowledge and information-intensive and principal professional group in health care context. PMID- 25732079 TI - Shape and texture based novel features for automated juxtapleural nodule detection in lung CTs. AB - Lung cancer is one of the types of cancer with highest mortality rate in the world. In case of early detection and diagnosis, the survival rate of patients significantly increases. In this study, a novel method and system that provides automatic detection of juxtapleural nodule pattern have been developed from cross sectional images of lung CT (Computerized Tomography). Shape-based and both shape and texture based 7 features are contributed to the literature for lung nodules. System that we developed consists of six main stages called preprocessing, lung segmentation, detection of nodule candidate regions, feature extraction, feature selection (with five feature ranking criteria) and classification. LIDC dataset containing cross-sectional images of lung CT has been utilized, 1410 nodule candidate regions and 40 features have been extracted from 138 cross-sectional images for 24 patients. Experimental results for 10 classifiers are obtained and presented. Adding our derived features to known 33 features has increased nodule recognition performance from 0.9639 to 0.9679 AUC value on generalized linear model regression (GLMR) for 22 selected features and being reached one of the most successful results in the literature. PMID- 25732080 TI - Metadata from data: identifying holidays from anesthesia data. AB - The increasingly large databases available to researchers necessitate high quality metadata that is not always available. We describe a method for generating this metadata independently. Cluster analysis and expectation maximization were used to separate days into holidays/weekends and regular workdays using anesthesia data from Vanderbilt University Medical Center from 2004 to 2014. This classification was then used to describe differences between the two sets of days over time. We evaluated 3802 days and correctly categorized 3797 based on anesthesia case time (representing an error rate of 0.13%). Use of other metrics for categorization, such as billed anesthesia hours and number of anesthesia cases per day, led to similar results. Analysis of the two categories showed that surgical volume increased more quickly with time for non-holidays than holidays (p < 0.001). We were able to successfully generate metadata from data by distinguishing holidays based on anesthesia data. This data can then be used for economic analysis and scheduling purposes. It is possible that the method can be expanded to similar bimodal and multimodal variables. PMID- 25732081 TI - Robust ECC-based authenticated key agreement scheme with privacy protection for Telecare medicine information systems. AB - To protect the transmission of the sensitive medical data, a secure and efficient authenticated key agreement scheme should be deployed when the healthcare delivery session is established via Telecare Medicine Information Systems (TMIS) over the unsecure public network. Recently, Islam and Khan proposed an authenticated key agreement scheme using elliptic curve cryptography for TMIS. They claimed that their proposed scheme is provably secure against various attacks in random oracle model and enjoys some good properties such as user anonymity. In this paper, however, we point out that any legal but malicious patient can reveal other user's identity. Consequently, their scheme suffers from server spoofing attack and off-line password guessing attack. Moreover, if the malicious patient performs the same time of the registration as other users, she can further launch the impersonation attack, man-in-the-middle attack, modification attack, replay attack, and strong replay attack successfully. To eliminate these weaknesses, we propose an improved ECC-based authenticated key agreement scheme. Security analysis demonstrates that the proposed scheme can resist various attacks and enables the patient to enjoy the remote healthcare services with privacy protection. Through the performance evaluation, we show that the proposed scheme achieves a desired balance between security and performance in comparisons with other related schemes. PMID- 25732082 TI - Overview of recent trans-institutional health network projects in Japan and Germany. AB - Worldwide populations are aging and countries have to prepare for the effects of demographic change in health care. Health information exchange (HIE), which is the process of moving patient information across health care providers electronically, can help overcome health data fragmentation and open opportunities to improve patient care in terms of quality, economy and efficiency. Since Japan and Germany are among the first countries strongly impacted by demographic changes of aging populations, we report on current developments about health information systems carrying out HIE based on case studies in both countries. Four projects that address the improvement of HIE within a defined region have been selected and investigated: the German project of the Lower Saxony Bank of Health and the Japanese projects Chiba ITnet, Nagasaki AjisaiNet and the National Disaster and Backup System of Japan. The project descriptions are based on relevant English publications, on-site visits and interviews with developers and users. The projects are introduced in terms of their basic architecture and implementation, their present status and future objectives. The projects' developments are still in progress and all have to cope with significant challenges before they will be able to provide a fully working trans-institutional health network solution. PMID- 25732083 TI - A security framework for nationwide health information exchange based on telehealth strategy. AB - This study focuses on the situation of health information exchange (HIE) in the context of a nationwide network. It aims to create a security framework that can be implemented to ensure the safe transmission of health information across the boundaries of care providers in Malaysia and other countries. First, a critique of the major elements of nationwide health information networks is presented from the perspective of security, along with such topics as the importance of HIE, issues, and main approaches. Second, a systematic evaluation is conducted on the security solutions that can be utilized in the proposed nationwide network. Finally, a secure framework for health information transmission is proposed within a central cloud-based model, which is compatible with the Malaysian telehealth strategy. The outcome of this analysis indicates that a complete security framework for a global structure of HIE is yet to be defined and implemented. Our proposed framework represents such an endeavor and suggests specific techniques to achieve this goal. PMID- 25732084 TI - Classification of hemodynamic responses associated with force and speed imagery for a brain-computer interface. AB - Functional near-infrared spectroscopy (fNIRS) is an emerging optical technique, which can assess brain activities associated with tasks. In this study, six participants were asked to perform three imageries of hand clenching associated with force and speed, respectively. Joint mutual information (JMI) criterion was used to extract the optimal features of hemodynamic responses. And extreme learning machine (ELM) was employed to be the classifier. ELM solved the major bottleneck of feedforward neural networks in learning speed, this classifier was easily implemented and less sensitive to specified parameters. The 2-class fNIRS BCI system was firstly built with an average accuracy of 76.7%, when all force and speed tasks were categorized as one class, respectively. The multi-class systems based on different levels of force and speed attempted to be investigated, the accuracies were moderate. This study provided a novel paradigm for establishing fNIRS-BCI system, and provided a possibility to produce more degrees of freedom in BCI system. PMID- 25732085 TI - Oxidative stress induces phosphorylation of neuronal NOS in cardiomyocytes through AMP-activated protein kinase (AMPK). AB - Neuronal nitric oxide synthase (nNOS) plays a critical role in regulating cardiomyocyte function. nNOS was reported to decrease superoxide production in the myocardium by inhibiting the function of xanthine oxidoreductase. However, the effect of oxidative stress on nNOS in cardiomyocytes has not been determined. We report here that brief exposure of HL-1 cardiomyocytes to hydrogen peroxide (H2O2) induces phosphorylation of nNOS at serine 1412. This increase in phosphorylation was concomitant with increased nitric oxide (NO) production. Prolonged exposure to the oxidant, however, resulted in decreased expression of the protein. H2O2 treatment for short periods also stimulated phosphorylation of AKT and AMPK. H2O2-induced phosphorylation of nNOS was reduced when AMPK activity was inhibited by compound C, suggesting that AMPK is a mediator of oxidative stress-induced phosphorylation of nNOS. However, inhibition of AKT activity by the pan AKT inhibitor, AKTi, had no effect on nNOS phosphorylation caused by H2O2. These data demonstrate the novel regulation of nNOS phosphorylation and expression by oxidative stress. PMID- 25732086 TI - Cross-talk between angiotensin-II and toll-like receptor 4 triggers a synergetic inflammatory response in rat mesangial cells under high glucose conditions. AB - Toll-like Receptor 4 (TLR4) may play an important role in the pathogenesis of diabetic nephropathy (DN). In this study, We observed the TLR4 signal and the release of inflammation factors after angiotensin II (Ang II) stimulation in rat mesangial cells (MCs) under high glucose conditions, this revealed the innate immune mechanism of injury by Ang II in DN. Our data showed that TLR4 and MyD88 were up-regulated significantly in high glucose and AngII-induced MCs; meanwhile, NF-kappaB as well as MCP-1, IL-6 were also highly expressed. In cells that were transfected with TLR4 SiRNA,the parameters were greatly inhibited; similar effects were detected in cells that were treated with Irbesartan. We concluded that Ang II synergized with high glucose in the release of pro-inflammatory factors mainly through the upregulation of TLR4 signaling in MCs, Cross-talk between Ang II and TLR4 contributed to the MC inflammatory injury under high glucose conditions. PMID- 25732087 TI - Secreted pyruvate kinase M2 facilitates cell migration via PI3K/Akt and Wnt/beta catenin pathway in colon cancer cells. AB - Pyruvate Kinase M2 (PKM2) is a key glycolytic enzyme, which highly expressed in tumor cells, and plays a pivotal role in the growth, survival and metabolism reprogramming of cancer cells. Besides the location of cytoplasm as a glycolytic enzyme and the location of nucleus as a protein kinase, extracellular PKM2 is present in serum and feces of tumor patients. However, little is known about the secretion of PKM2 and its significance in the progression of colon cancer. Here we demonstrated that PKM2 could be secreted from colon cancer cells, and purified PKM2 protein mimicing the secreted PKM2 was able to promote colon cancer cell migration. Moreover, PI3K/Akt and Wnt/beta-catenin signaling were involved in secreted PKM2 induced colon cancer cell migration. The results reveal critical roles of secreted PKM2 in the progression of colon cancer, and indicate that PKM2 may be a therapeutic target for colon cancer. PMID- 25732088 TI - VHL negatively regulates SARS coronavirus replication by modulating nsp16 ubiquitination and stability. AB - Eukaryotic cellular and most viral RNAs carry a 5'-terminal cap structure, a 5' 5' triphosphate linkage between the 5' end of the RNA and a guanosine nucleotide (cap-0). SARS coronavirus (SARS-CoV) nonstructural protein nsp16 functions as a methyltransferase, to methylate mRNA cap-0 structure at the ribose 2'-O position of the first nucleotide to form cap-1 structures. However, whether there is interplay between nsp16 and host proteins was not yet clear. In this report, we identified several potential cellular nsp16-interacting proteins from a human thymus cDNA library by yeast two-hybrid screening. VHL, one of these proteins, was proven to interact with nsp16 both in vitro and in vivo. Further studies showed that VHL can inhibit SARS-CoV replication by regulating nsp16 ubiquitination and promoting its degradation. Our results have revealed the role of cellular VHL in the regulation of SARS-CoV replication. PMID- 25732089 TI - The ameliorative effects of a hypnotic bromvalerylurea in sepsis. AB - Sepsis is a severe pathologic event, frequently causing death in critically ill patients. However, there are no approved drugs to treat sepsis, despite clinical trials of many agents that have distinct targets. Therefore, a novel effective treatment should be developed based on the pathogenesis of sepsis. We recently observed that an old hypnotic drug, bromvalerylurea (BU) suppressed expression of many kinds of pro- and anti-inflammatory mediators in LPS- or interferon-gamma activated alveolar and peritoneal macrophages (AMs and PMs). Taken the anti inflammatory effects of BU on macrophages, we challenged it to septic rats that had been subjected to cecum-ligation and puncture (CLP). BU was subcutaneously administered to septic rats twice per day. Seven days after CLP treatment, 85% of septic rats administrated vehicle had died, whereas administration of BU reduce the rate to 50%. Septic rats showed symptoms of multi-organ failure; respiratory, circulatory and renal system failures as revealed by histopathological analyses, blood gas test and others. BU ameliorated these symptoms. BU also prevented elevated serum-IL-6 level as well as IL-6 mRNA expression in septic rats. Collectively, BU might be a novel agent to ameliorate sepsis by preventing the onset of MOF. PMID- 25732090 TI - The role of the partner and relationship satisfaction on treatment outcome in patients with chronic fatigue syndrome. AB - BACKGROUND: Cognitive behaviour therapy (CBT) for chronic fatigue syndrome (CFS) leads to a significant decrease in CFS-related symptoms and disability. The primary objective of this study was to explore whether partners' solicitous responses and patients' and partners' perceived relationship satisfaction had an effect on treatment outcome. METHOD: The treatment outcome of a cohort of 204 consecutively referred patients treated with CBT was analysed. At baseline, CFS patients completed the Maudsley Marital Questionnaire. The Checklist Individual Strength subscale Fatigue and the Sickness Impact Profile total scores completed by CFS patients post-treatment were used as measures of clinically significant improvement. Partners completed the Family Response Questionnaire, the Maudsley Marital Questionnaire, the Brief Illness Perception Questionnaire, and the Causal Attribution List. Logistic regression analyses were performed with clinically significant improvement in fatigue and disability as dependent variables and scores on questionnaires at baseline as predictors. RESULTS: Solicitous responses of the partner were associated with less clinically significant improvement in fatigue and disability. Partners more often reported solicitous responses when they perceived CFS as a severe condition. Patients' relationship dissatisfaction was negatively associated with clinically significant improvement in fatigue. CONCLUSIONS: Partners' solicitous responses and illness perceptions at the start of the therapy can negatively affect the outcome of CBT for CFS. We emphasize the importance of addressing this in therapy. PMID- 25732091 TI - Emerging drug for diarrhea predominant irritable bowel syndrome. AB - INTRODUCTION: Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders with a 9 - 23% prevalence estimated in the general population. Patients can be subdivided into those who tend to have predominant diarrhea (IBS-D) or predominant constipation (IBS-C). Total annual productivity loss related to IBS in US is estimated at $205 million, with a significant impairment of health-related quality of life. A gold standard for the treatment of IBS is not established. Symptoms might improve with the use of few drugs and behavioral therapy, however, data concerning efficacy, safety and tolerability are limited. Therefore, development and validation of new therapies targeting at the molecular level are widely awaited. AREAS COVERED: We will specifically describe in this review Phase II and Phase III trials, with specific focus on treatment of IBS-D patients. Unfortunately, it is difficult to draw definite conclusions from Phase II and Phase III trials, because of the known high placebo effect. EXPERT OPINION: Drugs active on opioid receptor subtypes and neurokinin (NK) receptors seem to be the most promising, but substantial progress of information in this field is still needed. The achievement of more insights on the pathogenesis of IBS could surely better drive and target the therapy, but still strong efforts are awaited. PMID- 25732092 TI - Simultaneous determination of sulfonamides and metabolites in manure samples by one-step ultrasound/microwave-assisted solid-liquid-solid dispersive extraction and liquid chromatography-mass spectrometry. AB - An in-line matrix cleanup method was used for the simultaneous extraction of 15 sulfonamides and two metabolites from manure samples. The ultrasound/microwave assisted extraction (UMAE) combined with solid-liquid-solid dispersive extraction (SLSDE) procedure provides a simple sample preparation approach for the processing of manure samples, in which the extraction and cleanup are integrated into one step. Ultrasonic irradiation power, extraction temperature, extraction time, and extraction solvent, which could influence the UMAE efficiency, were investigated. C18 was used as the adsorbent to reduce the effects of interfering components during the extraction procedure. The extracts were concentrated, and the analytes were analyzed by liquid chromatography-tandem mass spectrometry (LC MS/MS) without any further cleanup. The isotopically labeled compounds sulfamethoxazole-d 4, sulfamethazine-d 4, sulfamonomethoxine-d 4, and sulfadimethoxine-d 6 were selected as internal standards to minimize the matrix effect in this method. The recoveries of the antibiotics tested ranged from 71 to 118 % at the three spiking levels examined (20, 200, and 500 MUg . kg(-1)). The limits of detections were 1.2-3.6 MUg . kg(-1) and the limits of quantification were 4.0-12.3 MUg . kg(-1) for the sulfonamides and their metabolites. The applicability of the method was demonstrated by analyzing 30 commercial manure samples. The results indicated that UMAE-SLSDE combined with LC-MS/MS is a simple, rapid, and environmentally friendly method for the analysis of sulfonamides and their metabolites in manure, and it could provide the basis for a risk assessment of the antibiotics in agricultural environments. PMID- 25732093 TI - An approach for identification and determination of arsenic species in the extract of kelp. AB - The National Institute of Standards and Technology is developing a kelp powder standard reference material (SRM) in support of dietary supplement measurements. Edible seaweeds such as kelp and laver consumed as diet or dietary supplement contain tens of mg/kg arsenic. The speciation information of arsenic in the seaweed should be provided because the total arsenic alone does not fully address the safety issue of the dietary supplement as the value assignment is originally intended. The inability to avail all arsenic species for value assignment measurements prevented the certification of arsenic species in the candidate SRM; however, approximately 70 % of total arsenic extracted with a 1:1 volume fraction of methanol:water mixture allowed arsenic speciation values to be assigned to a procedure-defined extract, which may be used for method validation in research to improve upon current extraction and measurement practices. Arsenic species in kelp and laver were identified using electrospray ionization ion trap time of flight mass spectrometry (ESI-IT-TOF). Arsenosugars As(328), As(482), and As(392) were found in the kelp candidate SRM while As(328) and As(482) were found in GBW 08521, a certified reference material (CRM) of laver produced by the National Institute of Metrology of China (NIM). A discovery that the digests of kelp and laver contained only dimethylarsinic acid led to the conclusion that the seaweeds did not contain detectible levels of arsenobetaine, arsenocholine or trimethylarsine oxide that could overlap with the peaks of arsenosugars in the separation. The mean +/- s of (5.68 +/- 0.28) mg/kg and (13.43 +/- 0.31) mg/kg found for As(482) and As(392) in kelp, respectively, using instrumental neutron activation analysis (INAA) demonstrated that value assignment measurement of arsenosugars was possible without arsenosugar calibration standards. PMID- 25732094 TI - A rational model of function learning. AB - Theories of how people learn relationships between continuous variables have tended to focus on two possibilities: one, that people are estimating explicit functions, or two that they are performing associative learning supported by similarity. We provide a rational analysis of function learning, drawing on work on regression in machine learning and statistics. Using the equivalence of Bayesian linear regression and Gaussian processes, which provide a probabilistic basis for similarity-based function learning, we show that learning explicit rules and using similarity can be seen as two views of one solution to this problem. We use this insight to define a rational model of human function learning that combines the strengths of both approaches and accounts for a wide variety of experimental results. PMID- 25732095 TI - Choose to move: The motivational impact of autonomy support on motor learning. AB - Numerous studies in the motor learning domain have demonstrated learning advantages of self-controlled practice relative to yoked conditions. In separate lines of evidence in the social-psychological literature, findings show that providing participants with task-relevant autonomy support or minor incidental choices can result in superior outcomes when compared with conditions that thwart autonomy or do not offer choice. We hypothesized that motor learning could be enhanced by providing learners with choices - even if those choices are unrelated to task performance. In Experiment 1, two groups of participants practiced a golf putting task. While one group (the choice group) was able to select the color of golf balls (white, yellow, or orange) to be used in each upcoming block of 10 trials, participants in the second group (the yoked group) were provided with the same colored golf balls their choice-group counterparts had chosen. The results of a 24-h delayed retention test indicated significantly greater putting accuracy for the choice compared with the yoked group. Experiment 2 went one step further by asking choice group participants for their preferences regarding two issues unrelated to the practice task (balancing on a stabilometer): (1) which of two subsequent tasks (coincident timing or hand dynamometry) they wanted to perform and (2) which of two prints of paintings by Renoir they thought the investigator should hang on the laboratory wall. Yoked group participants were simply informed about which task they would perform afterwards and of which painting the experimenter would put on the wall. Balance learning was significantly more effective in the choice group on a retention test. Thus, self-controlled practice conditions can influence motor learning without providing task-relevant information, content, or strategic learning advantages. Self-controlled effects in motor learning may be motivational in nature, attributable to satisfaction of fundamental autonomy needs. PMID- 25732097 TI - Radiation shielding design of BNCT treatment room for D-T neutron source. AB - Recent studies have shown that D-T neutron generator can be used as a proper neutron source for Boron Neutron Capture Therapy (BNCT) of deep-seated brain tumors. In this paper, radiation shielding calculations have been conducted based on the computational method for designing a BNCT treatment room for a recent proposed D-T neutron source. By using the MCNP-4C code, the geometry of the treatment room has been designed and optimized in such a way that the equivalent dose rate out of the treatment room to be less than 0.5MUSv/h for uncontrolled areas. The treatment room contains walls, monitoring window, maze and entrance door. According to the radiation protection viewpoint, dose rate results of out of the proposed room showed that using D-T neutron source for BNCT is safe. PMID- 25732096 TI - The proteome of human cytomegalovirus virions and dense bodies is conserved across different strains. AB - The morphogenesis of human cytomegalovirus (HCMV) particles is incompletely understood. Analysis of the protein composition of HCMV virions and subviral dense bodies (DBs) by mass spectrometry provides valuable information to increase our knowledge about viral morphogenesis. Here we addressed the viral proteome of virions and DBs from two fibroblast-passaged isolates and the widely used endotheliotropic TB4-BAC40 strain of HCMV. The results show a striking concordance of the particle proteomes of different strains. One surprising finding was that only low levels of gpUL128-131A were found in TB40-BAC4 virions. These three proteins, together with gH and gL, form a protein complex that is critical for the endothelial cell tropism of that strain. This indicates that either few molecules of that complex per virion or a small fraction of pentamer positive virions suffice to retain the tropism. Furthermore, using a pp65 deficient variant of TB40-BAC4, we confirm our previous finding that the major tegument protein serves as a scaffold to support the upload of a fraction of the outer tegument proteins into particles. The results demonstrate that HCMV particle morphogenesis is an orchestrated process that leads to the formation of particles with a largely strain-independent protein composition. PMID- 25732098 TI - Computerized Q wave dimensions in athletes and hypertrophic cardiomyopathy patients. AB - BACKGROUND: There is controversy regarding Q wave criteria for assessing risk for hypertrophic cardiomyopathy (HCM) in young athletes. METHODS: The 12-lead ECGs from Preparticipation screening in healthy athletes and patients with HCM were studied retrospectively. All 12 leads were measured using the same automated ECG analysis program. RESULTS: There were a total of 225 HCM patients and 1124 athletes with 12-lead electrocardiograms available for analysis. Athletes were on average 20 years of age, 65% were male and 24% were African-American. Patients with HCM were on average 51 years of age, 56% were male and 5.8% were African American. Q waves by either amplitude, duration or area criteria were more prevalent in males than females, in lateral leads than inferior and in HCM patients than athletes. The most striking difference in Q waves between the groups was in Limb lead I and in the females. Tall, skinny Q waves were rare in athletes and had the highest prevalence of only 3.7% in male HCM patients. CONCLUSION: Q waves are more common in males compared to females and in patients with HCM compared to athletes. Q waves of 30 ms or more in limb lead I appear to offer the greatest discriminatory value for separating patients with HCM from athletes. PMID- 25732099 TI - Can we protect from malignant arrhythmias by modulation of cardiac cell-to-cell coupling? AB - Defects in intercellular coupling in the heart play a key role in the initiation and persistence of malignant arrhythmias. Such disorders result from abnormal expression and distribution of connexins, the major constituents of cardiac gap junction channels. The alterations of myocardial connexin are well established as a consistent feature of both human and animal heart disease and aging. Following these facts, the modulation of connexin mediated intercellular coupling is suggested as a new antiarrhythmic approach. This review provides recent data supporting this concept. It can be challenging for the development of new antiarrhythmic drugs. Moreover, findings point out the implication of some endogenous compounds in protection from life-threatening arrhythmias via preservation of myocardial connexin. PMID- 25732101 TI - Genetic associations in PLEKHA7 and COL11A1 with primary angle closure glaucoma: a meta-analysis. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) rs11024102 in PLEKHA7 and rs3753841 in COL11A1 were identified to be associated with primary angle closure glaucoma (PACG) by a recent large genome-wide association study. This present study is to evaluate the association of PLEKHA7 rs11024102 and COL11A1 rs3753841 with PACG. DESIGN: A systematic review and meta-analysis. PARTICIPANTS: A total of 25 271 subjects (4895 PACG patients and 20 376 controls) in different ethnicities were tested for PLEKHA7 rs11024102 and COL11A1 rs3753841. METHODS: A comprehensive literature search was conducted on studies published up to July 2014. Summary odds ratios (ORs) and 95% confidence intervals were analysed. Publication bias of the included articles was evaluated using funnel plots and Egger's test. MAIN OUTCOME MEASURES: OR for the effects of PLEKHA7 rs11024102 and COL11A1 rs3753841 on PACG risk. RESULTS: Four eligible articles were included in this study for meta-analysis. The overall result showed that SNPs rs11024102 and rs3753841 were statistically associated with PACG (P < 0.001) in fixed-effects model. Stratified analyses showed that the association of PLEKHA7 rs11024102 and COL11A1 rs3753841 with PACG was statistically significant in Asian population (including South Indian cohort) (P < 0.001). In Caucasian population, significant association of COL11A1 rs3753841 with PACG was detected (P = 0.004), but PLEKHA7 rs11024102 did not show any association with PACG (P = 0.140). CONCLUSIONS: This meta-analysis suggests that PLEKHA7 rs11024102 is associated with PACG in Asian population and COL11A1 rs3753841 has a genetic association with the development of PACG both in Caucasian and Asian populations. PMID- 25732100 TI - The endosomal sorting complex required for transport machinery influences haem uptake and capsule elaboration in Cryptococcus neoformans. AB - Iron availability is a key determinant of virulence in the pathogenic fungus Cryptococcus neoformans. Previous work revealed that the ESCRT (endosomal sorting complex required for transport) protein Vps23 functions in iron acquisition, capsule formation and virulence. Here, we further characterized the ESCRT machinery to demonstrate that defects in the ESCRT-II and III complexes caused reduced capsule attachment, impaired growth on haem and resistance to non-iron metalloprotoporphyrins. The ESCRT mutants shared several phenotypes with a mutant lacking the pH-response regulator Rim101, and in other fungi, the ESCRT machinery is known to activate Rim101 via proteolytic cleavage. We therefore expressed a truncated and activated version of Rim101 in the ESCRT mutants and found that this allele restored capsule formation but not growth on haem, thus suggesting a Rim101-independent contribution to haem uptake. We also demonstrated that the ESCRT machinery acts downstream of the cAMP/protein kinase A pathway to influence capsule elaboration. Defects in the ESCRT components also attenuated virulence in macrophage survival assays and a mouse model of cryptococcosis to a greater extent than reported for loss of Rim101. Overall, these results indicate that the ESCRT complexes function in capsule elaboration, haem uptake and virulence via Rim101-dependent and independent mechanisms. PMID- 25732102 TI - Use of thyroid hormones in relation to pregnancy: a Danish nationwide cohort study. AB - OBJECTIVE: To determine the rate of exposure of pregnant women to levothyroxine and to assess changes in these rates before, during and after pregnancy. DESIGN: Register-based cohort study. SETTING: Danish nationwide registers. POPULATION: All women having a live birth in Denmark between 1 January 1997 and 31 December 2010 (n = 912 342). METHODS: All pregnant women in the study period were identified from the Danish Medical Birth Register. Exposed women were identified from the Danish National Prescription Register, based on redemption of levothyroxine prescriptions before, during or after pregnancy. MAIN OUTCOME MEASURES: The rate of pregnant women redeeming levothyroxine prescriptions and maternal characteristics. RESULTS: We identified a fourfold increase in levothyroxine prescription redemption during the study period, from 0.34% in 1997 to 1.39% by 2010. A mean of 0.79% of our cohort received levothyroxine. Most of the women who were using levothyroxine before pregnancy continued the therapy during their pregnancy, but 9.4% stopped redeeming their prescriptions. Overall, 0.28% of our cohort received a levothyroxine prescription for the first time within 9 months after pregnancy. CONCLUSIONS: Fewer women than expected received levothyroxine treatment during pregnancy even though a fourfold increase was observed during the study period. Furthermore, one of 10 discontinued treatments during pregnancy. These findings all indicate that too few women are treated for hypothyroidism during pregnancy. Further research is needed to determine whether hypothyroid pregnant women are suboptimally treated and the possible consequences for the mother and fetus. PMID- 25732103 TI - Is the concept of the death drive still useful in the clinical field? PMID- 25732104 TI - Management of bisphosphonate-related osteonecrosis of the jaw: a literature review. AB - Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non-bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high-dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate-related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen. PMID- 25732105 TI - The effects of anodal-tDCS on cross-limb transfer in older adults. AB - OBJECTIVE: Age-related neurodegeneration may interfere with the ability to respond to cross-limb transfer, whereby bilateral performance improvements accompany unilateral practice. We investigated whether transcranial direct current stimulation (tDCS) would facilitate this phenomena in older adults. METHODS: 12 young and 12 older adults underwent unilateral visuomotor tracking (VT), with anodal or sham-tDCS over the ipsilateral motor cortex. Transcranial magnetic stimulation (TMS) assessed motor evoked potentials (MEPs) and short interval intracortical inhibition (SICI). Performance was quantified through a VT error. Variables were assessed bilaterally at baseline and post-intervention. RESULTS: The trained limb improved performance, facilitated MEPs and released SICI in both age groups. In the untrained limb, VT improved in young for both sham and anodal-tDCS conditions, but only following anodal-tDCS for the older adults. MEPs increased in all conditions, except the older adult's receiving sham. SICI was released in both tDCS conditions for young and old. CONCLUSION: Following a VT task, older adults still display use-dependent plasticity. Although no significant age-related differences between the outcome measures, older adults exhibited significant cross-limb transfer of performance following anodal-tDCS, which was otherwise absent following motor practice alone. SIGNIFICANCE: These findings provide clinical implications for conditions restricting the use of one limb, such as stroke. PMID- 25732106 TI - Vasculitis associated with connective tissue diseases. AB - Vasculitis in connective tissue disease (CTD) is quite rare, it is reported in approximately 10% of patients with CTD; systemic lupus erythematosus (SLE) shows the highest association rate. Vessels of any size may be involved, but mainly small vessels vasculitis is reported. At present the classification of these vasculitis is unsatisfactory. According to the 2012 revised International Chapel Hill Consensus Conference, vasculitides secondary to CTD are a well identified entity and are classified under the category of "vasculitis associated with systemic disease". However only lupus vasculitis and rheumatoid vasculitis are explicitly listed, while the remaining are generically included under the heading "others". Petechiae, purpura, gangrene and ulcers are the most frequent cutaneous manifestations that should investigated in order to rule out potentially dangerous systemic involvement, especially if cryoglobulinemic or necrotizing vasculitis are suspected. This review will focus on the cutaneous involvement in CTD associated vasculitis. PMID- 25732107 TI - Clinical Pathway for Thyroidectomy. AB - Clinical pathways are care plans applicable to patient care procedures that present variations in practice and a predictable clinical course. They are designed not as a substitute for clinical judgment, but rather as a means to improve the effectiveness and efficiency of the procedures. This clinical pathway is the result of a collaborative work of the Sections of Endocrine Surgery and Quality Management of the Spanish Association of Surgeons. It attempts to provide a framework for standardizing the performance of thyroidectomy, the most frequently performed operation in endocrine surgery. Along with the usual documents of clinical pathways (temporary matrix, variance tracking and information sheets, assessment indicators and a satisfaction questionnaire) it includes a review of the scientific evidence around different aspects of pre, intra and postoperative management. Among others, antibiotic and antithrombotic prophylaxis, preoperative preparation in hyperthyroidism, intraoperative neuromonitoring and systems for obtaining hemostasis are included, along with management of postoperative hypocalcemia. PMID- 25732108 TI - Anti-inflammatory Strategies to Prevent Diabetic Cardiovascular Disease. AB - Diabetes is a proinflammatory state and inflammation is crucial in the genesis of vascular complications. While there are many anti-inflammatory strategies, most of which have been shown to reduce inflammation in diabetes, there is sparse data on reduction in cardiovascular events (CVEs). To date, the only anti-inflammatory strategies that have been shown to reduce CVE in diabetes include statins, angiotensin receptor blockers, metformin, and pioglitazone. We also discuss the role of novel emerging therapies. PMID- 25732109 TI - Well-differentiated hepatocellular neoplasm of uncertain malignant potential- reply. PMID- 25732111 TI - Cell interaction with graphene microsheets: near-orthogonal cutting versus parallel attachment. AB - Recent experiments indicate that graphene microsheets can either undergo a near orthogonal cutting or a parallel attachment mode of interaction with cell membranes. Here we perform a theoretical analysis to characterize the deformed membrane microstructure and investigate how these two interaction modes are influenced by the splay, tilt, compression, tension, bending and adhesion energies of the membrane. Our analysis indicates that, driven by the membrane splay and tension energies, a two-dimensional microsheet such as graphene would adopt a near-perpendicular configuration with respect to the membrane in the transmembrane penetration mode, whereas the membrane bending and tension energies would lead to parallel attachment in the absence of cross membrane penetration. These interaction modes may have broad implications in applications involving drug delivery, cell encapsulation and protection, and the measurement of the dynamic cell response. PMID- 25732110 TI - ORAOV1 overexpression in esophageal squamous cell carcinoma and esophageal dysplasia: a possible biomarker of progression and poor prognosis in esophageal carcinoma. AB - Oral cancer overexpressed 1 (ORAOV1) has been reported to exhibit high amplification levels in esophageal squamous cell cancer (ESCC) and in premalignant lesions. However, ORAOV1 protein expression levels in ESCC and esophageal squamous intraepithelial neoplasia (ESIN) have not yet been reported. We have explored the relationship of ORAOV1 protein expression with ESCC and ESIN by immunohistochemically analyzing tissue microarrays containing esophageal samples from patients with various clinical features and prognoses. The percentage of ESCC, high-grade ESIN (HGESIN), low-grade ESIN (LGESIN), and nontumoral control patients overexpressing ORAOV1 were 70.63% (101/143), 77.36% (41/53), 48.96% (47/96), and 5.79% (7/121), respectively. ORAOV1 overexpression also appears to be significantly higher in ESCC, HGESIN, and LGESIN than in the controls (all P < .001), and the levels observed for ESCC and HGESIN were also significantly higher than that in LGESIN (both P = .001). These results corresponded to high sensitivity and specificity values in ESCC, HGESIN, and LGESIN tissues. Furthermore, the increased expression of ORAOV1 is significantly associated with lymph node metastasis (P = .001) and an advanced TNM stage (III + IV) (P = .014), and patients with ORAOV1 overexpression experienced shorter overall survival time compared with those with lower ORAOV1 (chi(2) = 11.505, P = .001). This study provides the first evidence of ORAOV1 overexpression in ESCC and ESIN and demonstrates a potential role in tumor progression and metastasis. ORAOV1 overexpression could, therefore, be used as a novel biomarker of poor prognosis in patients with ESCC. PMID- 25732121 TI - One-step surface modification of polyurethane using affinity binding peptides for enhanced fouling resistance. AB - Affinity binding peptides were examined for surface fabrication of synthetic polymeric materials. Peptides possessing strong binding affinities toward polyurethane (PU) were discovered via biopanning of M13 phage peptide library. The apparent binding constant (K(app)) was as high as 2.68 * 10(9) M(-1) with surface peptide density exceeded 1.8 MUg/cm(2). Structural analysis showed that the ideal peptide had a high content (75%) of H-donor amino acid residues, and that intensified hydrogen bond interaction was the key driving force for the highly stable binding of peptides on PU. PU treated with such affinity peptides promises applications as low-fouling materials, as peptides increased its wettability and substantially reduced protein adsorption and cell adhesion. These results demonstrated a facile but highly efficient one-step strategy for surface property modification of polymeric materials for biotechnological applications. PMID- 25732123 TI - All that glisters is not gold - Staphylococcus aureus and innate immunity. PMID- 25732122 TI - Learning language in autism: maternal linguistic input contributes to later vocabulary. AB - It is well established that children with typical development (TYP) exposed to more maternal linguistic input develop larger vocabularies. We know relatively little about the linguistic environment available to children with autism spectrum disorders (ASD), and whether input contributes to their later vocabulary. Children with ASD or TYP and their mothers from English and French speaking families engaged in a 10 min free-play interaction. To compare input, children were matched on language ability, sex, and maternal education (ASD n = 20, TYP n = 20). Input was transcribed, and the number of word tokens and types, lexical diversity (D), mean length of utterances (MLU), and number of utterances were calculated. We then examined the relationship between input and children's spoken vocabulary 6 months later in a larger sample (ASD: n = 19, 50-85 months; TYP: n = 44, 25-58 months). No significant group differences were found on the five input features. A hierarchical multiple regression model demonstrated input MLU significantly and positively contributed to spoken vocabulary 6 months later in both groups, over and above initial language levels. No significant difference was found between groups in the slope between input MLU and later vocabulary. Our findings reveal children with ASD and TYP of similar language levels are exposed to similar maternal linguistic environments regarding number of word tokens and types, D, MLU, and number of utterances. Importantly, linguistic input accounted for later vocabulary growth in children with ASD. PMID- 25732124 TI - Coumarin-BODIPY hybrids by heteroatom linkage: versatile, tunable and photostable dye lasers for UV irradiation. AB - Linking amino and hydroxycoumarins to BODIPYs through the amino or hydroxyl group lets the easy construction of unprecedented photostable coumarin-BODIPY hybrids with broadened and enhanced absorption in the UV spectral region, and outstanding wavelength-tunable laser action within the green-to-red spectral region (~520-680 nm). These laser dyes allow the generation of a valuable tunable UV (~260-350 nm) laser source by frequency doubling, which is essential to study accurately the photochemistry of biological molecules under solar irradiation. The tunability is achieved by selecting the substitution pattern of the hybrid. Key factors are the linking heteroatom (nitrogen vs. oxygen), the number of coumarin units joined to the BODIPY framework and the involved linking positions. PMID- 25732125 TI - WNT-1 inducible signaling pathway protein-1 enhances growth and tumorigenesis in human breast cancer. AB - WNT1 inducible signaling pathway protein 1 (WISP1) plays a key role in many cellular functions in a highly tissue-specific manner; however the role of WISP1 in breast cancer is still poorly understood. Here, we demonstrate that WISP1 acts as an oncogene in human breast cancer. We demonstrated that human breast cancer tissues had higher WISP1 mRNA expression than normal breast tissues and that treatment of recombinant WISP1 enhanced breast cancer cell proliferation. Further, ectopic expression of WISP1 increased the growth of breast cancer cells in vitro and in vivo. WISP1 transfection also induced epithelial-mesenchymal transition (EMT) in MCF-7 cells, leading to higher migration and invasion. During this EMT-inducing process, E-cadherin was repressed and N-cadherin, snail, and beta-catenin were upregulated. Filamentous actin (F-actin) remodeling and polarization were also observed after WISP1 transfection into MCF-7 cells. Moreover, forced overexpression of WISP1 blocked the expression of NDRG1, a breast cancer tumor suppressor gene. Our study provides novel evidence that WISP1 modulated NDRG1 gene expression is dependent on a DNA fragment (-128 to +46) located within the human NDRG1 promoter. Thus, we concluded that WISP1 is a human breast cancer oncogene and is a potential therapeutic target. PMID- 25732126 TI - Temporal profile of inflammatory response to fracture and hemorrhagic shock: Proposal of a novel long-term survival murine multiple trauma model. AB - Hemorrhagic shock (hS) interacts with the posttraumatic immune response and fracture healing in multiple trauma. Due to the lack of a long-term survival multiple trauma animal models, no standardized analysis of fracture healing referring the impact of multiple trauma on fracture healing was performed. We propose a new long-term survival (21 days) murine multiple trauma model combining hS (microsurgical cannulation of carotid artery, withdrawl of blood and continuously blood pressure measurement), femoral (osteotomy/external fixation) and tibial fracture (3-point bending technique/antegrade nail). The posttraumatic immune response was measured via IL-6, sIL-6R ELISA. The hS was investigated via macrohemodynamics, blood gas analysis, wet-dry lung ration and histologic analysis of the shock organs. We proposed a new murine long-term survival (21 days) multiple trauma model mimicking clinical relevant injury patterns and previously published human posttraumatic immune response. Based on blood gas analysis and histologic analysis of shock organs we characterized and standardized our murine multiple trauma model. Furthermore, we revealed hemorrhagic shock as a causative factor that triggers sIL-6R formation underscoring the fundamental pathophysiologic role of the transsignaling mechanism in multiple trauma. PMID- 25732127 TI - A robust smart window: reversibly switching from high transparency to angle independent structural color display. AB - A smart window is fabricated from a composite consisting of elastomeric poly(dimethylsiloxane) embedded with a thin layer of quasi-amorphous silica nanoparticles. The smart window can be switched from the initial highly transparent state to opaqueness and displays angle-independent structural color via mechanical stretching. The switchable optical property can be fully recovered after 1000 stretching/releasing cycles. PMID- 25732128 TI - Faecal calprotectin as a marker for oesophago-gastric cancer. AB - BACKGROUND: Faecal calprotectin has been shown to be useful as a non-invasive screening test to differentiate functional from organic bowel disease, and it has been noted to be elevated in colorectal cancer. The aim of this study was to describe concentrations of faecal calprotectin in patients with oesophago-gastric cancer and investigate any potential discriminatory power of the test. PATIENTS: Faecal calprotectin was measured in samples from 39 patients with known oesophago gastric cancer and in 191 samples from control subjects. RESULTS: The median calprotectin concentration was < 20 ug/g (range < 20-421 ug/g) in control subjects and 97 ug/g (range < 20-940 ug/g) in patients with oesophago-gastric cancer (P < 0.001). A receiver operating characteristic curve gave an area under the ROC curve of 0.84 and a sensitivity of 76.9% (95% CI: 63.7-90.1%) and specificity of 88.0% (95% CI: 83.3-92.6%) at a cutoff of 50 ug/g. CONCLUSION: Faecal calprotectin is elevated in patients with cancer of the upper gastrointestinal tract. This study suggests that calprotectin may be promising in discriminating cancer patients from controls, but further work is required to explore any potential role of faecal calprotectin in screening for, or diagnosis of, oesophago-gastric cancer. PMID- 25732129 TI - Sucrose non-fermenting AMPK related kinase/Pentraxin 3 and DNA damage axis: a gateway to cardiovascular disease in systemic lupus erythematosus among Egyptian patients. AB - BACKGROUND: Systemic lupus erythematosus is a chronic multisystemic autoimmune disease characterized by chronic inflammatory processes and failure of immune regulatory mechanisms. Systemic lupus erythematosus is associated with increased risk for cardiovascular disease. In view of immunometabolic derangements of systemic lupus erythematosus, we investigated the roles of sucrose non-fermenting AMPK related kinase, Pentraxin 3, and DNA damage in the pathogenesis of systemic lupus erythematosus complicated with cardiovascular disease. METHODS: Forty systemic lupus erythematosus women with cardiovascular disease (systemic lupus erythematosus cases), 40 systemic lupus erythematosus women without cardiovascular disease, and 40 healthy controls were enrolled in this study. Demographic and clinical data were recorded. Plasma concentrations of sucrose non fermenting AMPK related kinase and Pentraxin 3 were immunoassayed. Carotid intima media thickness, atherogenic, and DNA damage indices were also assessed. RESULTS: Plasma sucrose non-fermenting AMPK related kinase and Pentraxin 3 concentrations were increased in systemic lupus erythematosus cases with cardiovascular disease compared to systemic lupus erythematosus controls and healthy controls (P < 0.0001). In systemic lupus erythematosus cases, there was a positive correlation between sucrose non-fermenting AMPK related kinase and Pentraxin 3 (r = 0.57, P < 0.002). CONCLUSIONS: These data highlight a novel role of sucrose non-fermenting AMPK related kinase/Pentraxin 3 axis in systemic lupus erythematosus pathogenesis. Sucrose non-fermenting AMPK related kinase/Pentraxin 3 combined role in immunometabolic signaling and DNA damage response is proposed to accelerate cardiovascular complications in systemic lupus erythematosus patients. PMID- 25732130 TI - Rapidly rule out acute myocardial infarction by combining copeptin and heart-type fatty acid-binding protein with cardiac troponin. AB - BACKGROUND: The rapid exclusion of acute myocardial infarction in patients with chest pain can reduce the length of hospital admission, prevent unnecessary diagnostic work-up and reduce the burden on our health-care systems. The combined use of biomarkers that are associated with different pathophysiological aspects of acute myocardial infarction could improve the early diagnostic assessment of patients presenting with chest pain. METHODS: We measured cardiac troponin I, copeptin and heart-type fatty acid-binding protein concentrations in 584 patients who presented to the emergency department with acute chest pain. The diagnostic performances for the diagnosis of acute myocardial infarction and NSTEMI were calculated for the individual markers and their combinations. Separate calculations were made for patients presenting to the emergency department <3 h, 3-6 h and 6-12 h after chest pain onset. RESULTS: For ruling out acute myocardial infarction, the net predictive values (95% CI) of cardiac troponin I, copeptin and heart-type fatty acid-binding protein were 90.4% (87.3-92.9), 84% (79.8-87.6) and 87% (83.5-90), respectively. Combining the three biomarkers resulted in a net predictive value of 95.8% (92.8-97.8). The improvement was most pronounced in the early presenters (<3 h) where the combined net predictive value was 92.9% (87.3 96.5) compared to 84.6% (79.4-88.9) for cardiac troponin I alone. The area under the receiver operating characteristic for the triple biomarker combination increased significantly (P < 0.05) compared to that of cardiac troponin I alone (0.880 [0.833-0.928] vs. 0.840 [0.781-0.898], respectively). CONCLUSIONS: Combining copeptin, heart-type fatty acid-binding protein and cardiac troponin I measurements improves the diagnostic performance in patients presenting with chest pain. Importantly, in patients who present early (<3 h) after chest pain onset, the combination improves the diagnostic performance compared to the standard cardiac troponin I measurement alone. PMID- 25732131 TI - A laboratory investigation of interactions between denitrifying anaerobic methane oxidation (DAMO) and anammox processes in anoxic environments. AB - This study investigates interactions between recently identified denitrifying anaerobic methane oxidation (DAMO) and anaerobic ammonium oxidation (anammox) processes in controlled anoxic laboratory reactors. Two reactors were seeded with the same inocula containing DAMO organisms Candidatus Methanoperedens nitroreducens and Candidatus Methylomirabilis oxyfera, and anammox organism Candidatus Kuenenia stuttgartiensis. Both were fed with ammonium and methane, but one was also fed with nitrate and the other with nitrite, providing anoxic environments with different electron acceptors. After steady state reached in several months, the DAMO process became solely/primarily responsible for nitrate reduction while the anammox process became solely responsible for nitrite reduction in both reactors. 16S rRNA gene amplicon sequencing showed that the nitrate-driven DAMO organism M. nitroreducens dominated both the nitrate-fed (~70%) and the nitrite-fed (~26%) reactors, while the nitrite-driven DAMO organism M. oxyfera disappeared in both communities. The elimination of M. oxyfera from both reactors was likely the results of this organism being outcompeted by anammox bacteria for nitrite. K. stuttgartiensis was detected at relatively low levels (1-3%) in both reactors. PMID- 25732132 TI - Understanding commercial truck drivers' decision-makin process concerning distracted driving. AB - A concurrent mixed methods design was used to explore personal and workplace factors, informed by the Theory of Planned Behavior, that affect truck drivers' decision-making about distracted driving on the job. Qualitative data were collected via semi-structured interviews with experts in truck safety and distracted driving, and quantitative data were collected via online survey of truck drivers in the United States. Findings from the interviews illustrated how drivers perceived distractions and the importance of supervisors enforcing organizational distracted driving policies. Survey results found that behavioral intentions were most important in regards to texting and crash and near-crash outcomes, while perceived norms from management best described the correlation between dispatch device use and negative crash-related outcomes. By using a mixed methods design, rather than two separate studies, these findings revealed nuanced differences into the influence of supervisors on distracted driving. PMID- 25732133 TI - An exposure based study of crash and injury rates in a cohort of transport and recreational cyclists in New South Wales, Australia. AB - This paper examines self-reported prospectively collected data from 2038 adult transport and recreational cyclists from New South Wales (Australia) to determine exposure-based incident crash and injury rates. During 25,971 days of cycling, 198 crashes were reported, comprising approximately equal numbers of falls and collisions. The overall crash rate was 0.290 (95% CI, 0.264-0.319) per 1000km or 6.06 (95% CI, 5.52-6.65) per 1000h of travel. The rate of crashes causing any injury (self-treated, or medically attended without overnight hospital stay) was 0.148 (95% CI, 0.133-0.164) per 1000km or 3.09 (95% CI, 2.79-3.43) per 1000h of travel. The rate of crashes causing a medically attended injury (without overnight hospital stay) was 0.023 (95% CI, 0.020-0.027) per 1000km or 0.49 (95% CI, 0.43-0.56) per 1000h of travel. No injuries requiring an overnight stay in hospital were reported on days meeting the inclusion criteria. After adjustment for exposure in hours, or for the risks associated with different infrastructure utilisation, the rates of crashes and medically attended injuries were found to be greater for females than males, less experienced than more experienced cyclists, and for those who rode mainly for transport rather than mainly for recreation. Comparison of estimated crash and injury rates on different infrastructure types were limited by the small number of events, however findings suggest that the separation of cyclists from motorised traffic is by itself not sufficient to ensure safe cycling. PMID- 25732135 TI - Lateral regulation of synaptic transmission by astrocytes. AB - Fifteen years ago the concept of the "tripartite synapse" was proposed to conceptualize the functional view that astrocytes are integral elements of synapses. The signaling exchange between astrocytes and neurons within the tripartite synapse results in the synaptic regulation of synaptic transmission and plasticity through an autocrine form of communication. However, recent evidence indicates that the astrocyte synaptic regulation is not restricted to the active tripartite synapse but can be manifested through astrocyte signaling at synapses relatively distant from active synapses, a process termed lateral astrocyte synaptic regulation. This phenomenon resembles the classical heterosynaptic modulation but is mechanistically different because it involves astrocytes and its properties critically depend on the morphological and functional features of astrocytes. Therefore, the functional concept of the tripartite synapse as a fundamental unit must be expanded to include the interaction between tripartite synapses. Through lateral synaptic regulation, astrocytes serve as an active processing bridge for synaptic interaction and crosstalk between synapses with no direct neuronal connectivity, supporting the idea that neural network function results from the coordinated activity of astrocytes and neurons. PMID- 25732134 TI - Most highly expressed protein-coding genes have a single dominant isoform. AB - Although eukaryotic cells express a wide range of alternatively spliced transcripts, it is not clear whether genes tend to express a range of transcripts simultaneously across cells, or produce dominant isoforms in a manner that is either tissue-specific or regardless of tissue. To date, large-scale investigations into the pattern of transcript expression across distinct tissues have produced contradictory results. Here, we attempt to determine whether genes express a dominant splice variant at the protein level. We interrogate peptides from eight large-scale human proteomics experiments and databases and find that there is a single dominant protein isoform, irrespective of tissue or cell type, for the vast majority of the protein-coding genes in these experiments, in partial agreement with the conclusions from the most recent large-scale RNAseq study. Remarkably, the dominant isoforms from the experimental proteomics analyses coincided overwhelmingly with the reference isoforms selected by two completely orthogonal sources, the consensus coding sequence variants, which are agreed upon by separate manual genome curation teams, and the principal isoforms from the APPRIS database, predicted automatically from the conservation of protein sequence, structure, and function. PMID- 25732136 TI - Developmental changes in the flotillin-1 expression pattern of the rat visual cortex. AB - Ocular dominance plasticity is activity dependent, changes in response to eye competition, and is transitory during developmental stages. Lipid rafts have modulatory functions in cellular, physiological, and behavioral processes. Although many of these modulatory roles are mediated by flotillin-1, a lipid raft associated protein, the ontogenetic changes in the cellular and subcellular distribution patterns of flotillin-1 are unclear. I investigated the developmental pattern of the distribution of flotillin-1 in the rat visual cortex with immunohistochemistry at both light and electron microscopic levels. An affinity-purified anti-flotillin-1 antibody reacted with a single band of about 40-50 kDa in total proteins prepared from the rat visual cortex. Flotillin-1 levels transiently increased on postnatal days 21-35. Flotillin-1 immunoreactivity at 3 weeks of age was broadly distributed though all visual cortical layers, but it exhibited a relatively higher density in layers II/III and V/VI. Flotillin-1 immunoreactivity at 3 months of age was significantly decreased compared with that at 3 weeks of age. Strong flotillin-1 immunoreactivity was observed in both neuronal perikarya and processes at 3 weeks of age. Double-labeling experiments with anti-microtubule-associated protein 2, anti-neurofilament, anti-synaptophysin, anti-vesicular glutamate transporter 1, anti-vesicular glutamate transporter 2, anti-glial fibrillary acidic protein, and flotillin-1 mainly labeled the somata of excitatory neurons and corticocortical synapses. Some flotillin-1 was distributed in excitatory neuron axons, thalamocortical synapses, astrocytes, oligodendrocytes, and microglial cells. Immunoelectron microscopy revealed numerous regions of flotillin-1 immunoreactivity near the rough endoplasmic reticulum in neurons and presynaptic regions at 3 weeks of age. These findings illustrate early developmental changes in the cellular and subcellular localization of flotillin-1 protein in the rat visual cortex. Moreover, the ultrastructural distribution of flotillin-1 immunoreactivity suggested that flotillin-1 was transported mainly into presynaptic terminals where it exerts effects at the presynaptic sites of excitatory and inhibitory neurons. PMID- 25732137 TI - Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety- and depression-like behaviors. AB - Mood disorders are a severe health burden but molecular mechanisms underlying mood dysfunction remain poorly understood. Here, we show that wild-type p53 induced phosphatase 1 (Wip1) negatively responds to the stress-induced negative mood-related behaviors. Specifically, we show that Wip1 protein but not its mRNA level was downregulated in the hippocampus but not in the neocortex after 4 weeks of chronic unpredictable mild stress (CUMS) in mice. Moreover, the CUMS responsive WIP1 downregulation in the hippocampus was restored by chronic treatment of fluoxetine (i.p. 20 mg/kg) along with the CUMS procedure. In addition, Wip1 knockout mice displayed decreased exploratory behaviors as well as increased anxiety-like and depression-like behaviors in mice without impaired motor activities under the non-CUMS condition. Furthermore, the Wip1 deficiency responsive anxiety-like but not depression-like behaviors were further elevated in mice under CUMS. Although limitations like male-alone sampling and multiply behavioral testing exist, the present study suggests a potential protective function of Wip1 in mood stabilization. PMID- 25732138 TI - Glutamate receptor and transporter modifications in rat organotypic hippocampal slice cultures exposed to oxygen-glucose deprivation: the contribution of cyclooxygenase-2. AB - Meloxicam is a non-steroidal anti-inflammatory drug which has been reported to lessen the ischemic transcriptional effects in some of the glutamatergic system genes as well as to decrease the infarct volume in in vivo assays. In this study, we show how the presence of meloxicam decreases cell mortality in assays of oxygen-glucose deprivation (OGD) in rat organotypic hippocampal slices culture. Mortality was measured using propidium iodide. Transcript levels of some glutamatergic system genes, including vesicular and membrane glutamate transporters (VGLUT1, VGLUT2, GLAST-1A, GLT-1, and EAAC-1) and some glutamatergic receptor subunits (NMDA receptor, GluN1, GluN2A and GluN2B subunits and AMPA receptor, GluA1 and GluA2 subunits) were measured by real-time PCR (qPCR). The transcription of vesicular glutamate transporters and glutamatergic receptor subunits, but not membrane glutamate transporters, was modified by the presence of meloxicam. The study demonstrates the neuroprotective role of meloxicam in organotypic hippocampal slice cultures and shows how meloxicam is able to selectively increase or decrease the OGD-induced changes in the expression of the different glutamatergic system genes studied here. We suggest that the neuroprotective role of meloxicam could be due to a modification in the balance of the expression of some glutamatergic receptor subunits, leading to a different stoichiometry of receptors such as NMDA or AMPA. Thus, meloxicam would decrease the excitotoxicity induced by OGD. PMID- 25732139 TI - Effects of galanin subchronic treatment on memory and muscarinic receptors. AB - The cholinergic pathways, which originate in the basal forebrain and are responsible for the control of different cognitive processes including learning and memory, are also regulated by some neuropeptides. One of these neuropeptides, galanin (GAL), is involved in both neurotrophic and neuroprotective actions. The present study has evaluated in rats the effects on cognition induced by a subchronic treatment with GAL by analyzing the passive avoidance response, and the modulation of muscarinic cholinergic receptor densities and activities. [(3)H]-N-methyl-scopolamine, [(3)H]-oxotremorine, and [(3)H]-pirenzepine were used to quantify the density of muscarinic receptors (MRs) and the stimulation of the binding of guanosine 5'-(gamma-[(35)S]thio)triphosphate by the muscarinic agonist, carbachol, to determine their functionality. Some cognitive deficits that were induced by the administration of artificial cerebrospinal fluid (aCSF) (i.c.v. aCSF 2 MUl/min, once a day for 6 days) were not observed in the animals also treated with GAL (i.c.v. 1.5 mmol in aCSF, 2 MUl/min, once a day for 6 days). GAL modulates the changes in M1 and M2 MR densities observed in the rats treated with aCSF, and also increased their activity mediated by G(i/o) proteins in specific areas of the dorsal and ventral hippocampus. The subchronic administration of the vehicle was also accompanied by an increased number of positive fibers and cells for GAL around the cortical tract of the cannula used, but that was not the case in GAL-treated rats. In addition, the increase of GAL receptor density in the ventral hippocampus and entorhinal cortex in the aCSF group was avoided when GAL was administered. The number of acetylcholinesterase (AChE)-positive neurons was decreased in the nucleus basalis of Meynert of both GAL- and aCSF-treated animals. In summary, GAL improves memory-related abilities probably through the modulation of MR density and/or efficacy in hippocampal areas. PMID- 25732141 TI - Third-generation beta-adrenoceptor antagonists in the treatment of hypertension and heart failure. AB - Hypertensive treatment with beta-adrenoceptor antagonists (BAAs) has been successfully applied for four decades. These drugs have a beneficial effect on the health of the patients by both decreasing number of deaths and improving morbidity. Nevertheless, the BAAs differ in pharmacological properties. They have different lipophilicity, different adrenoceptor selectivity and/or varying additional abilities in cardiac tissue and periphery vasculature hereby exceeding their known receptor-blocking effects. Nebivolol shows nitric oxide-mediated vasodilating properties that improve arterial rigidity. Carvedilol has anti oxidative and antiproliferative effects, which exert a beneficial effect on patients with chronic congestive heart failure (CHF). These findings suggest that the true potential of the third-generation BAAs and their value in the treatment of CHF, hypertension and following cardiovascular events has yet to be acknowledged. This MiniReview provides an overview of the third-generation BAAs and their effects on the vasculature of hypertensive patients and patients with CHF. Additionally, BAAs that potentially can be used in different patient groups are discussed. PMID- 25732140 TI - Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex. AB - In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the structure and activity of pyramidal neurons and decreases the number of oligodendroglial progenitors in the medial prefrontal cortex (mPFC). In this study, adult Wistar rats were exposed to seven weeks of CIE and were withdrawn from CIE for 21 days (protracted abstinence; PA). Tissue enriched in the mPFC was processed for Western blot analysis and Golgi-Cox staining to investigate the long-lasting effects of CIE on the structure of mPFC neurons and the levels of myelin-associated proteins. PA increased dendritic arborization within apical dendrites of pyramidal neurons. These changes occurred concurrently with hypophosphorylation of the N-methyl-d-aspartate (NMDA) receptor 2B (NR2B) at Tyr-1472. PA increased myelin basic protein (MBP) levels which occurred concurrently with hypophosphorylation of the premyelinating oligodendrocyte bHLH transcription factor Olig2 in the mPFC. Given that PA is associated with increased sensitivity to stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and stress alters oligodendrocyte expression as a function of glucocorticoid receptor (GR) activation, the levels of total GR and phosphorylated GR were also evaluated. PA produced hypophosphorylation of the GR at Ser-232 without affecting expression of total protein. These findings demonstrate persistent and compensatory effects of ethanol in the mPFC long after cessation of CIE, including enhanced myelin production and impaired GR function. Collectively, these results suggest a novel relationship between oligodendrocytes and GR in the mPFC, in which stress may alter frontal cortex function in alcohol dependent subjects by promoting hypermyelination, thereby altering the cellular composition and white matter structure in the mPFC. PMID- 25732142 TI - Common isolation of New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae in a large surgical hospital in Vietnam. AB - This study sought to monitor the presence of carbapenem-resistant Enterobacteriaceae (CRE) and the proportion New Delhi metallo-beta-lactamase 1 (NDM-1)-producing bacteria between August 2010 and December 2012 in a surgical hospital in Vietnam. We identified 47 CRE strains from a total of 4,096 Enterobacteriaceae isolates (1.1 %) that were NDM-1-positive from 45 patients admitted to 11 different departments, with the majority being from the urology department. The NDM-1 gene was found in seven different species. Genotyping revealed limited clonality of NDM-1-positive isolates. Most of the isolates carried the NDM-1 gene on a plasmid and 17.8 % (8/45) of those were readily transferable. We found five patients at admission and one patient at discharge with NDM-1-positive bacteria in their stool. From 200 screening environmental hospital samples, five were confirmed to be NDM-1-positive and included Acinetobacter species (n = 3) and Enterobacter aerogenes (n = 2). The results reveal that NDM-1-producing Enterobacteriaceae are commonly isolated in patients admitted to a Vietnamese surgical hospital and are also detected in the hospital environment. PMID- 25732143 TI - The postimplantation electrocardiogram predicts clinical response to cardiac resynchronization therapy. AB - BACKGROUND: Biventricular (BiV) pacing for cardiac resynchronization therapy (CRT) is intended to improve left ventricular function by coordinating systolic activity of the septum and free walls. Optimal resynchronization should be manifested by 12-lead electrocardiogram (ECG) patterns consistent with resynchronized activation, a tall (>=4 mm) R wave in V1, and predominant negative deflection in lead I (RV1SI). We investigated whether the presence or absence of RV1SI predicts heart failure outcomes within 1 year of CRT implant. METHODS: Two independent physicians reviewed the paced ECG of 213 patients post-CRT device implantation with disputes resolved by a third reviewer. The primary end points of all-cause death, unplanned hospitalization, left ventricular assist device implant, or transplant within a 1-year follow-up were blindly adjudicated according to standard definitions. Groups were compared via Kaplan-Meier estimates and Cox proportional hazards models to determine association with event free survival. RESULTS: Among CRT patients postimplantation, 56 (26.3%) exhibited the RV1SI pattern on ECG. Patients with the RV1SI pattern were significantly less likely to achieve the primary end point as compared to patients without the RV1SI pattern (33.9% vs 52.2%; Log Rank P = 0.022). This difference was driven by a significantly lower risk for unplanned hospitalization among patients with the RV1SI pattern (hazard ratio = 0.510; confidence interval [0.298, 0.876]). The predictive value remained after adjustment for potential confounders (P = 0.004). CONCLUSIONS: The 12-lead ECG postimplantation predicts clinical outcomes of BiV pacing. Such prediction may be useful in predicting the need for alternative or advanced heart failure therapies. Further study into ECG patterns may help to prospectively guide CRT. PMID- 25732144 TI - Molecular magnetic switch for a metallofullerene. AB - The endohedral fullerenes lead to well-protected internal species by the fullerene cages, and even highly reactive radicals can be stabilized. However, the manipulation of the magnetic properties of these radicals from outside remains challenging. Here we report a system of a paramagnetic metallofullerene Sc3C2@C80 connected to a nitroxide radical, to achieve the remote control of the magnetic properties of the metallofullerene. The remote nitroxide group serves as a magnetic switch for the electronic spin resonance (ESR) signals of Sc3C2@C80 via spin-spin interactions. Briefly, the nitroxide radical group can 'switch off' the ESR signals of the Sc3C2@C80 moiety. Moreover, the strength of spin-spin interactions between Sc3C2@C80 and the nitroxide group can be manipulated by changing the distance between these two spin centres. In addition, the ESR signals of the Sc3C2@C80 moiety can be switched on at low temperatures through weakened spin-lattice interactions. PMID- 25732145 TI - Interatrial Dyssynchrony May Contribute to Heart Failure Symptoms in Patients with Preserved Ejection Fraction. AB - PURPOSE: Heart failure (HF) with preserved ejection fraction (HFPEF) is the most prevalent type of HF in nonhospitalized patients, but its pathophysiology remains poorly understood. The aim of our study was to assess the existence of interatrial dyssynchrony (IAD), a potentially treatable condition, in the development of HF symptoms. METHODS: Consecutive patients with new onset of shortening of breath, referred for suspected HF, were screened. In all cases, a transthoracic echocardiography, ECG, and determination of plasma BNP level were performed at initial consultation. Patients were diagnosed according to current guidelines. Patients with HF and reduced ejection fraction were excluded. Later, the time from P-wave onset on the ECG to peak negative strain (atrial contraction) was determined using speckle tracking echocardiography; the time difference between both atria (ms) was used as an index of IAD. RESULTS: Sixty six patients were included. Mean age was 74 +/- 8 years (74% female, 77% hypertensive). HFPEF patients (n = 32) showed an increased IAD as compared to subjects with non-HF (n = 34; interatrial time difference 72.7 +/- 27 vs. 28 +/- 7 ms, P < 0.001). IAD showed a significant correlation with BNP levels, diastolic pattern, and echocardiographic parameters indicative of elevated LV filling pressures. LA function assessed by LA strain rate was not significantly different between HPPEF patients with and without IAD > 60 ms. CONCLUSIONS: We showed that IAD was present at initial stages of symptomatic HFPEF. It might be an important mechanism involved in the development of symptoms in HFPEF and a potential target amenable to be treated with device therapy. PMID- 25732146 TI - Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy. AB - Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies. PMID- 25732147 TI - Decoupling of N-acetyl-aspartate and glutamate within the dorsolateral prefrontal cortex in schizophrenia. AB - Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([(1)H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [(1)H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease. PMID- 25732148 TI - Imaging genetics and psychiatric disorders. AB - Imaging genetics is an integrated research method that uses neuroimaging and genetics to assess the impact of genetic variation on brain function and structure. Imaging genetics is both a tool for the discovery of risk genes for psychiatric disorders and a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative and mechanistic aspects of brain function implicated in psychiatric disease. Early studies of imaging genetics included association analyses between brain morphology and single nucleotide polymorphisms whose function is well known, such as catechol Omethyltransferase (COMT) and brain-derived neurotrophic factor (BDNF). GWAS of psychiatric disorders have identified genes with unknown functions, such as ZNF804A, and imaging genetics has been used to investigate clues of the biological function of these genes. The difficulty in replicating the findings of studies with small sample sizes has motivated the creation of largescale collaborative consortiums, such as ENIGMA, CHARGE and IMAGEN, to collect thousands of images. In a genome-wide association study, the ENIGMA consortium successfully identified common variants in the genome associated with hippocampal volume at 12q24, and the CHARGE consortium replicated this finding. The new era of imaging genetics has just begun, and the next challenge we face is the discovery of small effect size signals from large data sets obtained from genetics and neuroimaging. New methods and technologies for data reduction with appropriate statistical thresholds, such as polygenic analysis and parallel independent component analysis (ICA), are warranted. Future advances in imaging genetics will aid in the discovery of genes and provide mechanistic insight into psychiatric disorders. PMID- 25732150 TI - Neurogenesis and sensorimotor gating: bridging a microphenotype and an endophenotype. AB - Human genetic data on psychiatric disorders repeatedly demonstrate the involvement of various genes that are associated with neural development and neurogenesis. Neurogenesis is a biological process that is critical in brain development and continues throughout life. Neurogenesis is a multi-step process starting from the division of neural stem cells/progenitor cells, leading to self renewal and simultaneously to the production of lineage-committed cells, including neurons and glial cells. Minor defects in the neurogenesis process, such as production of fewer new neurons and malformation of neural circuits, could represent phenotypes of psychiatric disorders at molecular and cellular levels in animal models (here termed as "microphenotypes"). However, microphenotypes are not easily used as biomarkers. We have focused on a physiological condition, sensorimotor gating deficits, that can be scored by a prepulse inhibition (PPI) test. Impaired PPI is considered to be one of the compelling endophenotypes (biological markers) of mental disorders such as schizophrenia, autism, and other neurodevelopmental disorders. Because the neural circuit for PPI involves the hippocampus, a unique brain region where neurogenesis occurs postnatally, we hypothesize that an impairment of preadolescent neurogenesis is critical for the onset of sensorimotor gating defects. To test this hypothesis, we investigated a critical period of neurogenesis that can affect PPI. In this paradigm, we introduced an enriched environment to restore neurogenesis, thereby recovering PPI deficits in mice. We noted impairments in the maturation of newborn neurons in the hippocampal dentate gyrus (DG) and GABAergic neurons in the hippocampus, which could be considered as microphenotypes associated with PPI defects. More precise genetically controlled neurogenesis models (with precise time points or periods) are needed to be studied in further investigation to support our hypothesis. PMID- 25732151 TI - Impaired DNA damage repair as a common feature of neurodegenerative diseases and psychiatric disorders. AB - Impaired DNA damage repair is a common pathological endophenotype of some types of neurodegenerative diseases, intellectual disabilities, and psychiatric diseases. Dysfunctional DNA repair and DNA damage, including DNA double-stranded breaks, are linked to transcriptional dysfunction and abnormal DNA methylation. Impaired DNA repair in neural stem cells leads to microcephaly or cerebellar ataxia. Furthermore, DNA repair defects and DNA damage in mature neurons lead to progressive cognitive impairment, which might be a common feature of Alzheimer's disease, Huntington's disease, and other polyglutamine diseases. Oxidative DNA damage and altered DNA repair gene expression are observed in GABAergic neurons in schizophrenia. These findings indicate that impaired DNA repair is a common pathological endophenotype of neurological diseases, and that DNA damage might lead to diverse disease symptoms dependent on timing and the affected cell type. PMID- 25732152 TI - How does pain induce negative emotion? Role of the bed nucleus of the stria terminalis in pain-induced place aversion. AB - Pain consists of sensory-discriminative and negative-affective components. Neuronal mechanisms for the sensory component of pain have been investigated extensively. On the other hand, neuronal mechanisms for the affective component of pain remain to be investigated. Recent behavioral studies have revealed the brain regions and neuronal mechanisms involved in the affective component of pain. Glutamatergic transmission within the anterior cingulate cortex and basolateral amygdaloid nucleus plays a critical role in pain-induced aversion. Noradrenaline and corticotropin-releasing factor (CRF) within the ventral and dorsolateral parts of the bed nucleus of the stria terminalis (BNST), respectively, play important roles in paininduced aversion. Electrophysiological studies have revealed that both noradrenaline and CRF activate type II BNST neurons, which may inhibit the BNST output neurons. A recent histochemical study showed that most VTA-projecting BNST output neurons are GABAergic neurons, which preferentially make synaptic contact with VTA GABAergic neurons. Therefore, activation of VTA-projecting BNST output neurons should increase the neuronal excitability of VTA dopaminergic (DAergic) neurons through increased inhibitory input to VTA GABAergic neurons, which negatively regulate VTA DAergic neurons. Pain-induced release of noradrenaline and CRF within the BNST may activate type II BNST neurons, which could suppress VTA-projecting BNST output neurons, thereby attenuating the excitatory influence to the VTA DAergic neurons. Recent optogenetic studies suggest that the suppression of VTA DAergic neurons is sufficient to induce place aversion. Pain-induced place aversion may be due to the suppression of VTA DAergic neurons via the processing of nociceptive information within the BNST. PMID- 25732154 TI - Microphenotypes of mental disorders: a systematic approach to study disease mechanisms. PMID- 25732153 TI - Microendophenotypes of psychiatric disorders: phenotypes of psychiatric disorders at the level of molecular dynamics, synapses, neurons, and neural circuits. AB - Psychiatric disorders are caused not only by genetic factors but also by complicated factors such as environmental ones. Moreover, environmental factors are rarely quantitated as biological and biochemical indicators, making it extremely difficult to understand the pathological conditions of psychiatric disorders as well as their underlying pathogenic mechanisms. Additionally, we have actually no other option but to perform biological studies on postmortem human brains that display features of psychiatric disorders, thereby resulting in a lack of experimental materials to characterize the basic biology of these disorders. From these backgrounds, animal, tissue, or cell models that can be used in basic research are indispensable to understand biologically the pathogenic mechanisms of psychiatric disorders. In this review, we discuss the importance of microendophenotypes of psychiatric disorders, i.e., phenotypes at the level of molecular dynamics, neurons, synapses, and neural circuits, as targets of basic research on these disorders. PMID- 25732149 TI - Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. AB - Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis. PMID- 25732155 TI - Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. AB - PURPOSE: Both presence of minimal residual disease (MRD) and achievement of complete remission (CR) with incomplete platelet recovery (CRp) rather than CR after induction therapy predict relapse in acute myeloid leukemia (AML). These results suggest a correlation between response (peripheral count recovery) and MRD at the time of morphologic remission. Here we examine this hypothesis and whether MRD and response provide independent prognostic information after accounting for other relevant covariates. PATIENTS AND METHODS: We retrospectively analyzed data from 245 adults with AML who achieved CR, CRp, or CR with incomplete blood count recovery (CRi) after induction therapy. Bone marrow samples were collected on or closest to the first date of blood count recovery, and MRD was determined by 10-color multiparameter flow cytometry. RESULTS: The 71.0% of patients who achieved CR had MRD less frequently and had lower levels of MRD than the 19.6% of patients achieving CRp and 9.4% achieving CRi. Although pretreatment covariates such as cytogenetics, monosomal karyotype, relapsed or refractory rather than newly diagnosed AML, and FLT3 internal tandem duplication were associated with relapse, their prognostic effect was much lower once MRD and response were taken into account, the univariable statistical effect of which was not materially affected by inclusion of pretreatment covariates. CONCLUSION: Our data indicate that post-therapy parameters including MRD status and response are important independent prognostic factors for outcome in patients with AML achieving remission. MRD status and type of response (CR v CRp or CRi) should play important, and perhaps dominant, roles in planning postinduction therapy. PMID- 25732156 TI - Awareness of breast density and its impact on breast cancer detection and risk. AB - PURPOSE: Legislation mandating disclosure of breast density (BD) information has passed in 21 states; however, actual awareness of BD and knowledge of its impact on breast cancer detection and risk are unknown. METHODS: We conducted a national cross-sectional survey administered in English and Spanish using a probability based sample of screening-age women, with oversampling of Connecticut, the only state with BD legislation in effect for > 1 year before the survey. RESULTS: Of 2,311 women surveyed, 65% responded. Overall, 58% of women had heard of BD, 49% knew that BD affects breast cancer detection, and 53% knew that BD affects cancer risk. After multivariable adjustment, increased BD awareness was associated with white non-Hispanic race/ethnicity (Hispanic v white non-Hispanic: odds ratio [OR], 0.23; P < .001), household income (OR, 1.07 per category increase; P < .001), education (OR, 1.19 per category increase; P < .001), diagnostic evaluation after a mammogram (OR, 2.64; P < .001), and postmenopausal hormone therapy (OR, 1.69; P = .002). Knowledge of the masking effect of BD was associated with higher household income (OR, 1.10; P < .001), education (OR, 1.22; P = .01), prior breast biopsy (OR, 2.16; P < .001), and residing in Connecticut (Connecticut v other states: OR, 3.82; P = .003). Connecticut residents were also more likely to have discussed their BD with a health care provider (67% v 43% for residents of other US states; P = .001). CONCLUSION: Disparities in BD awareness and knowledge exist by race/ethnicity, education, and income. BD legislation seems to be effective in increasing knowledge of BD impact on breast cancer detection. These findings support continued and targeted efforts to improve BD awareness and knowledge among women eligible for screening mammography. PMID- 25732157 TI - Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. AB - PURPOSE: Three small retrospective studies have suggested that patients undergoing continuous androgen deprivation (CAD) have superior survival and time to progression if lower castrate levels of testosterone (< 0.7 nmol/L) are achieved. Evidence from prospective large studies has been lacking. PATIENTS AND METHODS: The PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery plus radiation therapy to CAD or intermittent androgen deprivation. The relationship between testosterone levels in the first year and cause-specific survival (CSS) and time to androgen independent progression in men in the CAD arm was evaluated using Cox regression. RESULTS: There was a significant difference in CSS (P = .015) and time to hormone resistance (P = .02) among those who had first-year minimum nadir testosterone <= 0.7, > 0.7 to <= 1.7, and >= 1.7 nmol/L. Patients with first-year nadir testosterone consistently > 0.7 nmol/L had significantly higher risks of dying as a result of disease (0.7 to 1.7 nmol/L: hazard ratio [HR], 2.08; 95% CI, 1.28 to 3.38; > 1.7 nmol/L: HR, 2.93; 95% CI, 0.70 to 12.30) and developing hormone resistance (0.7 to 1.7 nmol/L: HR, 1.62; 95% CI, 1.20 to 2.18; >= 1.7 nmol/L: HR, 1.90; 95% CI, 0.77 to 4.70). Maximum testosterone >= 1.7 nmol/L predicted for a higher risk of dying as a result of disease (P = .02). CONCLUSION: Low nadir serum testosterone (ie, < 0.7 mmol/L) within the first year of androgen deprivation therapy correlates with improved CSS and duration of response to androgen deprivation in men being treated for biochemical failure undergoing CAD. PMID- 25732158 TI - User beware: we need more science and less art when measuring financial toxicity in oncology. PMID- 25732159 TI - A bag of chips. PMID- 25732160 TI - Does a Picture Make a Difference? Ultrasound Guidance in the Management of the Axilla After Neoadjuvant Chemotherapy. PMID- 25732161 TI - Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505. AB - PURPOSE: In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS: Eligible patients had metastatic or recurrent cervical cancer and had <= one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS: Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION: TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents. PMID- 25732162 TI - Reply to m.j. Mourits et Al. PMID- 25732164 TI - In assessing surrogate clinical trial end points: drug safety is a requisite. PMID- 25732163 TI - Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance). AB - PURPOSE: To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC). PATIENTS AND METHODS: The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m(2) or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m(2) per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with alpha = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67. RESULTS: One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks). CONCLUSION: Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC. PMID- 25732166 TI - Reply to C. Twelves et Al. PMID- 25732165 TI - Phase III open-label randomized study of cytarabine in combination with amonafide L-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia. AB - PURPOSE: Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML. PATIENTS AND METHODS: Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m(2) continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m(2) IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m(2) IV over 30 minutes once per day on days 1 to 3 (D + C arm). RESULTS: The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively. CONCLUSION: Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML. PMID- 25732167 TI - Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. AB - PURPOSE: Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent. METHODS: By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models. RESULTS: From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort. CONCLUSION: Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD. PMID- 25732168 TI - Recognizing the place of trials with treatment of physician's choice as the control arm. PMID- 25732169 TI - Reply to J.A. de Souza et al. PMID- 25732170 TI - Nomograms Predicting Progression-Free Survival, Overall Survival, and Pelvic Recurrence in Locally Advanced Cervical Cancer Developed From an Analysis of Identifiable Prognostic Factors in Patients From NRG Oncology/Gynecologic Oncology Group Randomized Trials of Chemoradiotherapy. AB - PURPOSE: To evaluate the prognostic factors in locally advanced cervical cancer limited to the pelvis and develop nomograms for 2-year progression-free survival (PFS), 5-year overall survival (OS), and pelvic recurrence. PATIENTS AND METHODS: We retrospectively reviewed 2,042 patients with locally advanced cervical carcinoma enrolled onto Gynecologic Oncology Group clinical trials of concurrent cisplatin-based chemotherapy and radiotherapy. Nomograms for 2-year PFS, five year OS, and pelvic recurrence were created as visualizations of Cox proportional hazards regression models. The models were validated by bootstrap-corrected, relatively unbiased estimates of discrimination and calibration. RESULTS: Multivariable analysis identified prognostic factors including histology, race/ethnicity, performance status, tumor size, International Federation of Gynecology and Obstetrics stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy. PFS, OS, and pelvic recurrence nomograms had bootstrap-corrected concordance indices of 0.62, 0.64, and 0.73, respectively, and were well calibrated. CONCLUSION: Prognostic factors were used to develop nomograms for 2-year PFS, 5-year OS, and pelvic recurrence for locally advanced cervical cancer clinically limited to the pelvis treated with concurrent cisplatin-based chemotherapy and radiotherapy. These nomograms can be used to better estimate individual and collective outcomes. PMID- 25732171 TI - Does degree of androgen suppression matter in hormone-sensitive prostate cancer? PMID- 25732172 TI - Pathologic findings at risk-reducing surgery. PMID- 25732173 TI - Reply to T.j. Herzog et Al. PMID- 25732174 TI - Cardiac troponin testing in idiopathic inflammatory myopathies and systemic sclerosis-spectrum disorders: biomarkers to distinguish between primary cardiac involvement and low-grade skeletal muscle disease activity. AB - Primary cardiac involvement, an under-recognised manifestation of the idiopathic inflammatory myopathies (IIM) and systemic sclerosis (SSc)-spectrum disorders, is associated with significant mortality. Within these two conditions, traditional skeletal muscle enzyme testing may not effectively distinguish between skeletal and cardiac muscle involvement, especially in patients with subclinical cardiac disease. Accurate biomarkers are thus required to screen for cardiac disease, to better inform both therapeutic decision-making and treatment response. The widespread uptake of cardiac troponin testing has revolutionised the management of acute coronary syndromes. While cardiac troponin I (cTnI) appears specific to the myocardium, cardiac troponin T (cTnT) is also expressed by skeletal muscle, including regenerating skeletal muscle tissue. There is increasing interest about the role of cardiac troponins as a putative biomarker of primary cardiac involvement in IIM and SSc-spectrum disorders. Herewith we discuss subclinical cardiac disease in IIM and SSc-spectrum disorders, the respective roles of cTnI and cTnT testing, and the re-expression of cTnT within regenerating skeletal muscle tissue. There remains wide variation in access to cardiac troponin testing nationally and internationally. We propose two pragmatic clinical pathways using cardiac troponins, preferably measuring concomitant cTnT followed by confirmatory (cardiac) cTnI to screen patients for subclinical cardiac disease and/or low grade skeletal muscle disease activity, and also an agenda for future research. PMID- 25732175 TI - Paracetamol: not as safe as we thought? A systematic literature review of observational studies. AB - OBJECTIVES: We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. METHODS: We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. RESULTS: Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose-response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose-response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose-response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose response with one reporting an increasing OR of >=30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). DISCUSSION: Given the observational nature of the data, channelling bias may have had an important impact. However, the dose-response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses. PMID- 25732177 TI - Expression of Autophagy-Related Proteins in the Spinal Cord of Pembroke Welsh Corgi Dogs With Canine Degenerative Myelopathy. AB - Canine degenerative myelopathy (DM) is a progressive neurodegenerative disease frequently found in Pembroke Welsh Corgi (PWC) dogs, and it has clinical and pathologic similarities to human amyotrophic lateral sclerosis. Autophagy is a major intracellular protein degradation system. Abnormalities of autophagy- resulting in cell death through mechanisms called type II programmed cell death- have recently been reported to occur in various neurodegenerative diseases, including amyotrophic lateral sclerosis. Thus, the distribution and expression levels of proteins involved in autophagy were examined in the spinal cords of 8 PWC dogs suffering from DM with superoxide dismutase mutation, 5 non-DM PWC dogs, and 6 Beagle dogs without neurologic signs. There was no significant difference in the ratio of neurons with microtubule-associated protein light chain 3 (LC3) positive somata relative to those that were LC3 negative among the 3 groups, whereas the number of LC3-positive neurites was significantly increased in DM dogs. Punctate LC3 immunoreactivity did not colocalize with a lysosome marker, LAMP2 (lysosome-associated membrane protein 2). NBR1 (neighbor of BRCA gene 1) was localized mostly in reactive astrocytes, whereas there were p62 (p62/A170/SQSTM1)-positive foci in the neuropil of the spinal cord of DM dogs. Western blotting revealed in DM dogs the decreased expression of Beclin1 and Atg16 L, which are molecules involved in formation of the isolation membrane. These findings suggest that altered autophagosome degradation may result in LC3 and p62 accumulation in the DM spinal cord, whereas the early stage of membrane formation is likely to be downregulated. PMID- 25732176 TI - F344/NTac Rats Chronically Exposed to Bromodichloroacetic Acid Develop Mammary Adenocarcinomas With Mixed Luminal/Basal Phenotype and Tgfbeta Dysregulation. AB - Breast cancer is the most common cancer and the second-leading cause of cancer mortality in women in the United States. A recent 2-year National Toxicology Program carcinogenicity study showed an increased incidence of proliferative mammary lesions (hyperplasia, fibroadenoma, adenocarcinoma) in F344/NTac rats exposed to bromodichloroacetic acid (BDCA), a disinfection by-product in finished drinking water with widespread human exposure. We hypothesized that the increase in mammary tumors observed in BDCA-exposed F344/NTac rats may be due to underlying molecular changes relevant for human breast cancer. The objective of the study was to compare (1) gene and protein expression and (2) mutation spectra of relevant human breast cancer genes between normal untreated mammary gland and mammary tumors from control and BDCA-exposed animals to identify molecular changes relevant for human cancer. Histologically, adenocarcinomas from control and BDCA-exposed animals were morphologically very similar, were estrogen/progesterone receptor positive, and displayed a mixed luminal/basal phenotype. Gene expression analysis showed a positive trend in the number of genes associated with human breast cancer, with proportionally more genes represented in the BDCA-treated tumor group. Additionally, a 5-gene signature representing possible Tgfbeta pathway activation in BDCA-treated adenocarcinomas was observed, suggesting that this pathway may be involved in the increased incidence of mammary tumors in BDCA-exposed animals. PMID- 25732178 TI - A comparison of bleeding efficiency, microbiological quality and lipid oxidation in goats subjected to conscious halal slaughter and slaughter following minimal anesthesia. AB - The study assessed the effect of conscious halal slaughter and slaughter following minimal anesthesia on bleeding efficiency of goats and keeping quality of goat meat. Ten Boer cross bucks were divided into two groups and subjected to either halal slaughter without stunning (HS) or minimal anesthesia prior to slaughter (AS). The blood lost during exsanguination was measured. Residual blood was further quantified by determination of hemoglobin and myoglobin content in longissimus lumborum muscle. Storage stability of the meat was evaluated by microbiological analysis and lipid oxidation. Blood loss at exsanguination, residual hemoglobin and lipid oxidation were not significantly different (p>0.05) between HS and AS. Lactic acid bacteria was the only microbe that was significantly elevated after 24h of storage at 4 degrees C in the AS group. In conclusion, slaughtering goats under minimal anesthesia or fully conscious did not affect bleeding efficiency and keeping quality of goat meat. PMID- 25732179 TI - The effect of retail packaging method on objective and consumer assessment of beef quality traits. AB - This study evaluated the effect of 7days of modified atmosphere packaging (MAP: 80% O2, 20% CO2) or skin packaging (no oxygen) of beef M. longissimus steaks after 1 or 7days of ageing in vacuum on objective and sensory meat quality traits and degradation of desmin. Shear force was negatively affected by MAP after both 1 and 7days of ageing in vacuum (P<0.005). Sensory evaluation of grilled steaks revealed significantly negative effects of MAP on sensory traits, resulting in an overall decrease of 8 points in the Meat Standards Australia (MSA) eating quality score (MQ4). Desmin degradation was not affected by packaging method, suggesting that the toughening effect of high-oxygen MAP is not due to inhibition of postmortem proteolysis. The results of this study and others suggest that packaging method should be incorporated as a variable in the MSA grading system. Further research to quantify the impact of oxidative cross-linking of proteins on tenderness appears warranted. PMID- 25732180 TI - Fanconi anemia (FA) and crosslinker sensitivity: Re-appraising the origins of FA definition. AB - The commonly accepted definition of Fanconi anemia (FA) relying on DNA repair deficiency is submitted to a critical review starting from the early reports pointing to mitomycin C bioactivation and to the toxicity mechanisms of diepoxybutane and a group of nitrogen mustards causing DNA crosslinks in FA cells. A critical analysis of the literature prompts revisiting the FA phenotype and crosslinker sensitivity in terms of an oxidative stress (OS) background, redox-related anomalies of FA (FANC) proteins, and mitochondrial dysfunction. This re-appraisal of FA basic defect might lead to innovative approaches both in elucidating FA phenotypes and in clinical management. PMID- 25732181 TI - Characterization of dermal plates from armored catfish Pterygoplichthys pardalis reveals sandwich-like nanocomposite structure. AB - Dermal plates from armored catfish are bony structures that cover their body. In this paper we characterized structural, chemical, and nanomechanical properties of the dermal plates from the Amazonian fish Pterygoplichthys pardalis. Analysis of the morphology of the plates using scanning electron microscopy (SEM) revealed that the dermal plates have a sandwich-like structure composed of an inner porous matrix surrounded by two external dense layers. This is different from the plywood-like laminated structure of elasmoid fish scales but similar to the structure of osteoderms found in the dermal armour of some reptiles and mammals. Chemical analysis performed using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results revealed similarities between the composition of P. pardalis plates and the elasmoid fish scales of Arapaima gigas. Reduced moduli of P. pardalis plates measured using nanoindentation were also consistent with reported values for A. gigas scales, but further revealed that the dermal plate is an anisotropic and heterogeneous material, similar to many other fish scales and osteoderms. It is postulated that the sandwich-like structure of the dermal plates provides a lightweight and tough protective layer. PMID- 25732182 TI - Neuronal amyloid-beta accumulation within cholinergic basal forebrain in ageing and Alzheimer's disease. AB - The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer's disease, are not fully understood. Because age is the primary risk factor for Alzheimer's disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid beta accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer's disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-beta1-42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer's disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-beta antibodies confirmed accumulation of high concentration of amyloid-beta in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-beta content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-beta42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer's disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-beta accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer's disease. Selective intraneuronal amyloid-beta accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease. PMID- 25732183 TI - Ictal SPECT in patients with rapid eye movement sleep behaviour disorder. AB - Rapid eye movement sleep behaviour disorder is a rapid eye movement parasomnia clinically characterized by acting out dreams due to disinhibition of muscle tone in rapid eye movement sleep. Up to 80-90% of the patients with rapid eye movement sleep behaviour disorder develop neurodegenerative disorders within 10-15 years after symptom onset. The disorder is reported in 45-60% of all narcoleptic patients. Whether rapid eye movement sleep behaviour disorder is also a predictor for neurodegeneration in narcolepsy is not known. Although the pathophysiology causing the disinhibition of muscle tone in rapid eye movement sleep behaviour disorder has been studied extensively in animals, little is known about the mechanisms in humans. Most of the human data are from imaging or post-mortem studies. Recent studies show altered functional connectivity between substantia nigra and striatum in patients with rapid eye movement sleep behaviour disorder. We were interested to study which regions are activated in rapid eye movement sleep behaviour disorder during actual episodes by performing ictal single photon emission tomography. We studied one patient with idiopathic rapid eye movement sleep behaviour disorder, one with Parkinson's disease and rapid eye movement sleep behaviour disorder, and two patients with narcolepsy and rapid eye movement sleep behaviour disorder. All patients underwent extended video polysomnography. The tracer was injected after at least 10 s of consecutive rapid eye movement sleep and 10 s of disinhibited muscle tone accompanied by movements registered by an experienced sleep technician. Ictal single photon emission tomography displayed the same activation in the bilateral premotor areas, the interhemispheric cleft, the periaqueductal area, the dorsal and ventral pons and the anterior lobe of the cerebellum in all patients. Our study shows that in patients with Parkinson's disease and rapid eye movement sleep behaviour disorder in contrast to wakefulness-the neural activity generating movement during episodes of rapid eye movement sleep behaviour disorder bypasses the basal ganglia, a mechanism that is shared by patients with idiopathic rapid eye movement sleep behaviour disorder and narcolepsy patients with rapid eye movement sleep behaviour disorder. PMID- 25732184 TI - Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain. AB - Oligomeric forms of alpha-synuclein are emerging as key mediators of pathogenesis in Parkinson's disease. Our understanding of the exact contribution of alpha synuclein oligomers to disease is limited by the lack of a technique for their specific detection. We describe a novel method, the alpha-synuclein proximity ligation assay, which specifically recognizes alpha-synuclein oligomers. In a blinded study with post-mortem brain tissue from patients with Parkinson's disease (n = 8, age range 73-92 years, four males and four females) and age- and sex-matched controls (n = 8), we show that the alpha-synuclein proximity ligation assay reveals previously unrecognized pathology in the form of extensive diffuse deposition of alpha-synuclein oligomers. These oligomers are often localized, in the absence of Lewy bodies, to neuroanatomical regions mildly affected in Parkinson's disease. Diffuse alpha-synuclein proximity ligation assay signal is significantly more abundant in patients compared to controls in regions including the cingulate cortex (1.6-fold increase) and the reticular formation of the medulla (6.5-fold increase). In addition, the alpha-synuclein proximity ligation assay labels very early perikaryal aggregates in morphologically intact neurons that may precede the development of classical Parkinson's disease lesions, such as pale bodies or Lewy bodies. Furthermore, the alpha-synuclein proximity ligation assay preferentially detects early-stage, loosely compacted lesions such as pale bodies in patient tissue, whereas Lewy bodies, considered heavily compacted late lesions are only very exceptionally stained. The alpha-synuclein proximity ligation assay preferentially labels alpha-synuclein oligomers produced in vitro compared to monomers and fibrils, while stained oligomers in human brain display a distinct intermediate proteinase K resistance, suggesting the detection of a conformer that is different from both physiological, presynaptic alpha synuclein (proteinase K-sensitive) and highly aggregated alpha-synuclein within Lewy bodies (proteinase K-resistant). These disease-associated conformers represent previously undetected Parkinson's disease pathology uncovered by the alpha-synuclein proximity ligation assay. PMID- 25732185 TI - Loss of anterior cruciate ligament integrity and the development of radiographic knee osteoarthritis: a sub-study of the osteoarthritis initiative. AB - INTRODUCTION: The aim of this study was to determine whether loss of ACL integrity in an older cohort precedes the onset of radiographic OA (ROA). METHODS: Participants in this nested case-control study were selected from the Osteoarthritis Initiative (OAI) study who had risk factors for OA development but did not have ROA (Kellgren-Lawrence grading (KLG) of 0 or 1) in both knees at baseline. The MRIs were assessed for the presence of ACL tears. Case knees were defined by the development of ROA on knee radiographs between the 12 and 48 month visits. Their radiographs were assessed at P0 (time of onset of radiographic knee OA), 1 year prior to P0 (P-1) and at baseline. Controls were selected from amongst those who did not develop incident ROA and were matched to cases. RESULTS: 355 persons who developed ROA were matched to 355 controls. No relationship between loss of ACL integrity and incident ROA was found at any assessment time point. Odds ratios (OR) for baseline, 1 year prior to incident ROA (P1) and at point of occurrence of incident ROA (P0) were 2.00 (0.66-6.06), 2.5 (0.76-8.24) and 2.75 (0.85-8.88) respectively. A significant risk of incident ROA was found in participants who had a history of knee injury with an OR of 1.51 (1.05-2.16). CONCLUSION: Loss of ACL integrity does not confer a significantly increased risk of incident ROA in an older adult cohort. In contrast, a history of knee injury was associated with an increased risk of incident ROA. PMID- 25732186 TI - Adaptive behaviour and multiple equilibrium states in a predator-prey model. AB - There is evidence that multiple stable equilibrium states are possible in real life ecological systems. Phenomenological mathematical models which exhibit such properties can be constructed rather straightforwardly. For instance, for a predator-prey system this result can be achieved through the use of non-monotonic functional response for the predator. However, while formal formulation of such a model is not a problem, the biological justification for such functional responses and models is usually inconclusive. In this note, we explore a conjecture that a multitude of equilibrium states can be caused by an adaptation of animal behaviour to changes of environmental conditions. In order to verify this hypothesis, we consider a simple predator-prey model, which is a straightforward extension of the classic Lotka-Volterra predator-prey model. In this model, we made an intuitively transparent assumption that the prey can change a mode of behaviour in response to the pressure of predation, choosing either "safe" of "risky" (or "business as usual") behaviour. In order to avoid a situation where one of the modes gives an absolute advantage, we introduce the concept of the "cost of a policy" into the model. A simple conceptual two dimensional predator-prey model, which is minimal with this property, and is not relying on odd functional responses, higher dimensionality or behaviour change for the predator, exhibits two stable co-existing equilibrium states with basins of attraction separated by a separatrix of a saddle point. PMID- 25732187 TI - Transgastric band removal. A different approach. PMID- 25732188 TI - Sustainability of State-Level Substance Abuse Prevention Infrastructure After the Completion of the SPF SIG. AB - Recent national substance abuse prevention efforts that have been disseminated at the state level have provided fertile ground for addressing the dearth of systematic research on state-level substance abuse prevention infrastructure. The Strategic Prevention Framework State Incentive Grant Program (SPF SIG), a national public health initiative sponsored by the US Substance Abuse and Mental Health Services Administration and its Center for Substance Abuse Prevention, is one such effort, providing an opportunity to examine state-level substance abuse prevention infrastructure across the country. The aims of the SPF SIG initiative include reducing substance abuse and its related problems, as well as enhancing state and local prevention infrastructure and capacity. In this article, we describe the status of state-level substance abuse prevention infrastructure and capacity 1 year after the first 26 funded states ended their projects, based on follow-up interviews with state prevention decision-makers. We found that, in five of the six prevention domains we measured, prevention infrastructure capacity increased during the 12-month period after the grants ended. The evidence for further SPF capacity development even after the conclusion of the grants suggests that states recognized the benefits of using the SPF and took deliberate steps to sustain and enhance the integration of this framework into their state prevention systems. In addition, the findings suggest that state agencies and organizations can benefit from time-limited resources aimed at increasing their capacity and that such efforts can have a lasting impact on measures of state prevention system capacity. PMID- 25732189 TI - The (mal) adaptive value of mid-adolescent dating relationship labels. AB - The aim of this study was to explore adolescent dating relationships through the prism of high school girls' narratives. We probed the contexts and meanings associated with different forms of dating to better understand the developmental significance of romantic relationships during adolescence. Cross-sectional, in depth semi-structured interviews were conducted with 20 high school females. The analytic approach was phenomenological and grounded in the narratives rather than based on an a priori theoretical framework. Interviews were digitally recorded, transcribed verbatim by research staff and entered into ATLAS.ti 6, a qualitative data-management software package, prior to analysis. Teen relationships were found to vary along a Dis-Continuum from casual hookups to "official" boyfriend/girlfriend. There was a lack of consensus, and much ambiguity, as to the substantive meaning of different relationships. Labeling dating relationships seem to facilitate acquisition of important developmental needs such as identity, affiliation, and status, while attempting to manage cognitive dissonance and emotional disappointments. Findings underscore the confusion and complexity surrounding contemporary adolescent dating. Adolescent girls are using language and social media to assist them in meeting developmental goals. Sometimes their dating labels are adaptive, other times they are a cause of stress, or concealment of unmet needs and thwarted desires. Programs focused on positive youth development need to resonate with the realities of teens' lives and more fully acknowledge the complicated dynamics of teen dating relationships and how they are formalized, publicized and negotiated. PMID- 25732190 TI - Hyperhexosemia-Induced Retinal Vascular Pathology in a Novel Primate Model of Diabetic Retinopathy. AB - The paucity of animal models exhibiting full pathology of diabetic retinopathy (DR) has impeded understanding of the pathogenesis of DR and the development of therapeutic interventions. Here, we investigated whether hyperhexosemic marmosets (Callithrix jacchus) develop characteristic retinal vascular lesions including macular edema (ME), a leading cause of vision loss in DR. Marmosets maintained on 30% galactose (gal)-rich diet for 2 years were monitored for retinal vascular permeability, development of ME, and morphological characteristics including acellular capillaries (AC) and pericyte loss (PL), vessel tortuosity, and capillary basement membrane (BM) thickness. Excess vascular permeability, increased number of AC and PL, vascular BM thickening, and increased vessel tortuosity were observed in the retinas of gal-fed marmosets. Optical coherence tomography (OCT) images revealed significant thickening of the retinal foveal and the juxtafoveal area, and histological analysis showed incipient microaneurysms in retinas of gal-fed marmosets. Findings from this study indicate that hyperhexosemia can trigger retinal vascular changes similar to those seen in human DR including ME and microaneurysms. The striking similarities between the marmoset retina and the human retina, and the exceptionally small size of the monkey, offer significant advantages to this primate model of DR. PMID- 25732191 TI - Inactivation of Protein Tyrosine Phosphatases Enhances Interferon Signaling in Pancreatic Islets. AB - Type 1 diabetes (T1D) is the result of an autoimmune assault against the insulin producing pancreatic beta-cells, where chronic local inflammation (insulitis) leads to beta-cell destruction. T cells and macrophages infiltrate into islets early in T1D pathogenesis. These immune cells secrete cytokines that lead to the production of reactive oxygen species (ROS) and T-cell invasion and activation. Cytokine-signaling pathways are very tightly regulated by protein tyrosine phosphatases (PTPs) to prevent excessive activation. Here, we demonstrate that pancreata from NOD mice with islet infiltration have enhanced oxidation/inactivation of PTPs and STAT1 signaling compared with NOD mice that do not have insulitis. Inactivation of PTPs with sodium orthovanadate in human and rodent islets and beta-cells leads to increased activation of interferon signaling and chemokine production mediated by STAT1 phosphorylation. Furthermore, this exacerbated STAT1 activation-induced cell death in islets was prevented by overexpression of the suppressor of cytokine signaling-1 or inactivation of the BH3-only protein Bim. Together our data provide a mechanism by which PTP inactivation induces signaling in pancreatic islets that results in increased expression of inflammatory genes and exacerbated insulitis. PMID- 25732192 TI - Adenylyl Cyclase Type 5 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance. AB - Adenylyl cyclase type 5 knockout (AC5KO) mice have increased longevity and share a similar phenotype with calorie-restricted wild-type (WT) mice. To determine the in vivo metabolic properties of AC5 deficiency, we compared the effects of standard diet (SD) and high-fat diet (HFD) on obesity, energy balance, glucose regulation, and insulin sensitivity. AC5KO mice on SD had reduced body weight and adiposity compared with WT mice. Blood cholesterol and triglyceride levels were also significantly reduced in AC5KO mice. Indirect calorimetry demonstrated increased oxygen consumption, respiratory exchange ratio, and energy expenditure in AC5KO compared with WT mice on both SD and HFD. AC5KO mice also displayed improved glucose tolerance and increased whole-body insulin sensitivity, accompanied by decreased liver glycogen stores. Euglycemic-hyperinsulinemic clamp studies confirmed the marked improvement of glucose homeostasis and insulin sensitivity in AC5KO mice primarily through increased insulin sensitivity in skeletal muscle. Moreover, the genes involved in mitochondrial biogenesis and function were significantly increased in AC5KO skeletal muscle. These data demonstrate that deficiency of AC5 protects against obesity, glucose intolerance, and insulin resistance, supporting AC5 as a potential novel therapeutic target for treatment of obesity and diabetes. PMID- 25732193 TI - The development of the causative construction in Persian child language. AB - The acquisition of systematic patterns and exceptions in different languages can be readily examined using the causative construction. Persian allows four types of causative structures, including one productive multiword structure (i.e. the light verb construction). In this study, we examine the development of all four structures in Persian child speech between the ages of 1;11 and 6;7, in correspondence with their caregivers' speech. We define developmental stages based on dendrograms derived from variability clustering (Gries & Stoll, 2009). These stages are further substantiated by qualitative data, including overgeneralization errors and alternating structures. We find that Persian speaking children learn to exploit two (i.e. lexical and light verb construction causatives) of the four constructions. They go from relying on lexical causatives to forming progressively constrained templates for the more complex light verb construction. This first study of the development of Persian causatives supports a usage-based account of verb-by-verb learning in child language development. PMID- 25732194 TI - Dependency of 2-methoxyestradiol-induced mitochondrial apoptosis on mitotic spindle network impairment and prometaphase arrest in human Jurkat T cells. AB - The present study sought to determine the correlation between 2-methoxyestradiol (2-MeO-E2)-induced cell cycle arrest and 2-MeO-E2-induced apoptosis. Exposure of Jurkat T cell clone (JT/Neo) to 2-MeO-E2 (0.5-1.0 MUM) caused G2/M arrest, Bak activation, Deltapsim loss, caspase-9 and -3 activation, PARP cleavage, intracellular ROS accumulation, and apoptotic DNA fragmentation, whereas none of these events except for G2/M arrest were induced in Jurkat T cells overexpressing Bcl-2 (JT/Bcl-2). Under these conditions, Cdk1 phosphorylation at Thr-161 and dephosphorylation at Tyr-15, up-regulation of cyclin B1 expression, histone H1 phosphorylation, Cdc25C phosphorylation at Thr-48, Bcl-2 phosphorylation at Thr 56 and Ser-70, Mcl-1 phosphorylation at Ser-159/Thr-163, and Bim phosphorylation were detected irrespective of Bcl-2 overexpression. Concomitant treatment of JT/Neo cells with 2-MeO-E2 and the G1/S blocking agent aphidicolin resulted in G1/S arrest and abrogation of all apoptotic events, including Cdk1 activation, phosphorylation of Bcl-2, Mcl-1 and Bim, and ROS accumulation. The 2-MeO-E2 induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by a Cdk1 inhibitor, but not by an Aurora A kinase (AURKA), Aurora B kinase (AURKB), JNK, or p38 MAPK inhibitor. Immunofluorescence microscopic analysis revealed that 2-MeO-E2-induced mitotic arrest was caused by mitotic spindle network impairment and prometaphase arrest. Whereas 10-20 MUM 2 MeO-E2 reduced the proportion of intracellular polymeric tubulin to monomeric tubulin, 0.5-5.0 MUM 2-MeO-E2 increased it. These results demonstrate that the apoptogenic effect of 2-MeO-E2 (0.5-1.0 MUM) was attributable to mitotic spindle defect-mediated prometaphase arrest, Cdk1 activation, phosphorylation of Bcl-2, Mcl-1, and Bim, and activation of Bak and mitochondria-dependent caspase cascade. PMID- 25732195 TI - Analysis of protein kinase C theta inhibitors for the control of HIV-1 replication in human CD4+ T cells reveals an effect on retrotranscription in addition to viral transcription. AB - HIV-1 infection cannot be cured due to reservoirs formed early after infection. Decreasing the massive CD4+ T cell activation that occurs at the beginning of the disease would delay reservoir seeding, providing a better prognosis for patients. CD4+ T cell activation is mediated by protein kinase C (PKC) theta (theta), which is involved in T-cell proliferation, as well as NF-kappaB, NF-AT, and AP-1 activation. We found that PKCtheta activity increased viral replication, but also that HIV-1 induced higher activation of PKCtheta in infected CD4+ T cells, creating a feedback loop. Therefore, specific inhibition of PKCtheta activity could contribute to control HIV-1 replication. We tested the efficacy of seven PKCtheta specific inhibitors to control HIV-1 replication in CD4+ T cells and selected two of the more potent and safer: CGX1079 and CGX0471. They reduced PKCtheta phosphorylation at T538 and its translocation to the plasma membrane, which correlated with decreased HIV-1 retrotranscription through partial inhibition of SAMHD1 antiviral activity, rendering lower proviral integration. CGX1079 and CGX0471 also interfered with viral transcription, which would reduce the production of new virions, as well as the subsequent spread and infection of new targets that would increase the reservoir size. CGX1079 and CGX0471 did not completely abrogate T-cell functions such as proliferation and CD8-mediated release of IFN-gamma in PBMCs from HIV-infected patients, thereby avoiding general immunosuppresion. Consequently, using PKCtheta inhibitors as adjuvant of antiretroviral therapy in recently infected patients would decrease the pool of activated CD4+ T cells, thwarting proviral integration and reducing the reservoir size. PMID- 25732196 TI - Electron microscopic observation of selective excitation of conformational change of a single organic molecule. AB - Atomic resolution transmission electron microscopic observations at different electron acceleration voltages enabled us to observe visually the energy relaxation process of one conformer into another via rotation of various parts of the molecule. Cross-correlation analysis of sequential transmission electron microscopy (TEM) images or of the difference between experimental and simulated TEM images has been utilized for investigation of the conformational mobility and for structure identification of conformers. PMID- 25732197 TI - Pharmacokinetics of crizotinib in NSCLC patients. AB - INTRODUCTION: For a subpopulation of NSCLC patients genetic rearrangement of the anaplastic lymphoma kinase (ALK) was found as driver mutation, which can be targeted by the selective inhibitor crizotinib. AREAS COVERED: This article presents an overview of the clinical studies that provided the characterization of the pharmacokinetic parameters for the administration of crizotinib to cancer patients and the factors influencing the clinical profiles of this drug. EXPERT OPINION: Crizotinib is administered orally as a capsule and clinical studies indicated 250 mg crizotinib BID continuously as the maximal tolerated dose in cancer patients. Bioavailability is ~ 40% and pharmacokinetic parameters are influenced by food only to a minor degree. This dose of the drug corresponds to a significant inhibition of the mutated ALK, retards tumor growth and achieves clinical responses in the majority of patients. Crizotinib lactam is the single metabolite with minor inhibitory activity for the ALK fusion protein. Metabolization is executed mainly by CYP3A4/5 and is modulated by other drugs interacting with this cytochrome oxidase. Despite the one-fits-all approach in administration of crizotinib at a fixed dose the pharmacokinetic parameters indicate a stable steady state upon continuous administration, which achieves sufficient inhibition of the ALK drug target. PMID- 25732198 TI - A DSC and FTIR spectroscopic study of the effects of the epimeric cholestan-3-ols and cholestan-3-one on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine bilayer membranes: Comparison with their 5 cholesten analogs. AB - We present the results of a comparative differential calorimetric and Fourier transform infrared spectroscopic study of the effect of cholesterol and five analogs on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine bilayer membranes. These sterols/steroids differ in both the nature and stereochemistry of the polar head group at C3 (beta-OH, alpha-OH or C=O) and in the presence or absence of a double bond in ring B. In both the Delta(5) and saturated sterols/steroid series, the concentration of these compounds required to abolish the DPPC pretransition, inversely related to their relative ability to disorder gel state DPPC bilayers, decreases in the order beta-OH > alpha-OH > C=O. However, in the saturated series, these concentrations are much more similar, regardless of polar head group chemical structure. Similarly, the residual enthalpy of the DPPC main phase transition at 50 mol% sterol/steroid, inversely related to the miscibility of these compounds in fluid DPPC bilayers, also increases in the order beta-OH > alpha-OH > C=O, but this effect is again attenuated in the saturated series. Moreover, replacement of the double bond at C5 with a saturated linkage also reduces sterol/steroid solubility in all cases. Interestingly, the C5 double bond has no effect on DPPC hydrocarbon chain ordering in the betaOH sterol pair, considerably increases ordering in the alphaOH pair, and considerably reduces ordering in the C=O pair. Moreover, the ability of these compounds to order the DPPC hydrocarbon chains decreases in the order beta-OH > alpha-OH > C=O in the Delta(5) series of compounds, but in the order beta-OH > C=O > alpha-OH in the saturated series. Our results indicate that the effects of the presence or absence of a double bond at C5 of ring B on the thermotropic phase behavior and organization of DPPC bilayers are influenced by the nature and stereochemistry of the polar group present at C3 and vice versa. Nevertheless, the characteristic effects of sterols/steroids on fluid lipid bilayers are optimal when an OH group rather than C=O group is present at C3, and when this OH group is in the equatorial (beta) orientation. Moreover, the presence of a single double bond specifically at C5 is required to maximize sterol solubility in fluid DPPC bilayers, which is probably its primary function in natural sterols. PMID- 25732199 TI - Infarction in the pars libera of the column of fornix including pre (cholinergic) and post (circuit of Papez fiber tracts)-commissural fibers causes "basal forebrain" amnesia. PMID- 25732200 TI - Low C-reactive protein values at admission predict mortality in patients with severe community-acquired pneumonia caused by Streptococcus pneumoniae that require intensive care management. AB - PURPOSE: To identify risk factors associated with mortality in patients with severe community-acquired pneumonia (CAP) caused by S. pneumoniae who require intensive care unit (ICU) management, and to assess the prognostic values of these risk factors at the time of admission. METHODS: Retrospective analysis of all consecutive patients with CAP caused by S. pneumoniae who were admitted to the 32-bed medico-surgical ICU of a community and referral university hospital between 2002 and 2011. Univariate and multivariate analyses were performed on variables available at admission. RESULTS: Among the 77 adult patients with severe CAP caused by S. pneumoniae who required ICU management, 12 patients died (observed mortality rate 15.6%). Univariate analysis indicated that septic shock and low C-reactive protein (CRP) values at admission were associated with an increased risk of death. In a multivariate model, after adjustment for age and gender, septic shock [odds ratio (OR), confidence interval 95%; 4.96, 1.11-22.25; p = 0.036], and CRP (OR 0.99, 0.98-0.99 p = 0.034) remained significantly associated with death. Finally, we assessed the discriminative ability of CRP to predict mortality by computing its receiver operating characteristic curve. The CRP value cut-off for the best sensitivity and specificity was 169.5 mg/L to predict hospital mortality with an area under the curve of 0.72 (0.55-0.89). CONCLUSIONS: The mortality of patients with S. pneumoniae CAP requiring ICU management was much lower than predicted by severity scores. The presence of septic shock and a CRP value at admission <169.5 mg/L predicted a fatal outcome. PMID- 25732201 TI - Functional analyses and prognostic significance of SFRP1 expression in bladder cancer. AB - PURPOSE: We previously showed that the Wnt-signaling antagonist SFRP1 (secreted frizzled-related protein 1) is a promising marker in bladder cancer. The aim of this study was to validate the prognostic role and analyze the functional significance of SFRP1. METHODS: Four bladder cancer cell lines (RT112, RT4, J82 and BFTC905) and one urothelial cell line (UROtsa) were used for functional characterization of SFRP1 expression. Effects on viability, proliferation and wound healing were investigated, and canonical Wnt-pathway activity as well as Wnt-signaling target gene expression was analyzed. Additionally, tissue micro arrays from two different bladder tumor cohorts were evaluated for SFRP1 expression, and associations with survival and histopathological parameters were analyzed. RESULTS: The cell lines RT112, RT4, J82 and UROtsa showed SFRP1 expression. In BFTC905, SFRP1 expression was inhibited by promoter hypermethylation. Wnt-pathway activity was absent in all cell lines and independent from SFRP1 expression. RT112 and BFTC905 were used for further functional characterization. SFRP1 overexpression resulted in decreased viability and migration in BFTC905 cells. Knockdown of SFRP1 expression in RT112 cells resulted only in marginal effects. In bladder tumors, SFRP1 expression was associated with lower tumor grade, but not with progression in patients with papillary bladder cancer. SFRP1 expressing papillary bladder cancer tumors also demonstrated a tendency to longer overall survival. CONCLUSIONS: SFRP1 is reducing malignant potential of BFTC905 cells, but not by regulation of canonical Wnt-signaling pathway. Other pathways, like non-canonical Wnt or the MAPK pathway, could be activated via SFRP1-expression loss. In bladder tumors, SFRP1 has the potential to predict outcome for a subset of papillary bladder tumors. PMID- 25732202 TI - ArsH is an organoarsenical oxidase that confers resistance to trivalent forms of the herbicide monosodium methylarsenate and the poultry growth promoter roxarsone. AB - Environmental organoarsenicals are produced by microorganisms and are introduced anthropogenically as herbicides and antimicrobial growth promoters for poultry and swine. Nearly every prokaryote has an ars (arsenic resistance) operon, and some have an arsH gene encoding an atypical flavodoxin. The role of ArsH in arsenic resistance has been unclear. Here we demonstrate that ArsH is an organoarsenical oxidase that detoxifies trivalent methylated and aromatic arsenicals by oxidation to pentavalent species. Escherichia coli, which does not have an arsH gene, is very sensitive to the trivalent forms of the herbicide monosodium methylarsenate [MSMA or MAs(V)] and antimicrobial growth promoter roxarsone [Rox(V)], as well as to phenylarsenite [PhAs(III), also called phenylarsine oxide or PAO]. Pseudomonas putida has two chromosomally encoded arsH genes and is highly resistant to the trivalent forms of these organoarsenicals. A derivative of P. putida with both arsH genes deleted is sensitive to MAs(III), PhAs(III) or Rox(III). P. putida arsH expressed in E. coli conferred resistance to each trivalent organoarsenical. Cells expressing PpArsH oxidized the trivalent organoarsenicals. PpArsH was purified, and the enzyme in vitro similarly oxidized the trivalent organoarsenicals. These results suggest that ArsH catalyzes a novel biotransformation that confers resistance to environmental methylated and aromatic arsenicals. PMID- 25732203 TI - 'First, do no harm': managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer. AB - Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non-metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research. PMID- 25732204 TI - Transvaginal sonographic evaluation of cervical length in the second trimester of asymptomatic singleton pregnancies, and the risk of preterm delivery. AB - OBJECTIVE: To evaluate cervical length in asymptomatic women with singleton pregnancies in the second trimester by means of transvaginal ultrasonography, and to examine the relation between cervical length and spontaneous preterm delivery. DESIGN: Observational, prospective study. SETTING: A university hospital and a county hospital in Western Sweden. POPULATION: A total of 2122 asymptomatic women with live singleton pregnancies without fetal anomalies. METHODS: Cervical length was measured at between 16 and 23 weeks of gestation by means of transvaginal ultrasonography. Data were analysed using logistic regression analysis. MAIN OUTCOME MEASURES: Cervical length in relation to spontaneous preterm delivery <34 weeks (primary outcome) and <37 weeks of gestation (secondary outcome). RESULTS: Eleven women had a cervical length of <=25 mm (0.5%) and 73 women had a cervical length of <=30 mm (3.4%). Spontaneous preterm delivery at <34 weeks occurred in 22/2061 women (1.1%) and at <37 weeks in 87/2061 women (4.2%). There was a significant association between cervical length and spontaneous preterm delivery at <34 weeks (odds ratio 1.78; 95% confidence interval 1.19-2.65 for a decrease of cervical length by 5 mm) but no significant association at <37 weeks. CONCLUSIONS: The rate of short cervical length of <=25 mm was lower than expected. The study confirmed the increased risk of spontaneous preterm delivery in women with a short cervix, although the analysis was based on only a few cases. In Sweden, a larger study is needed to evaluate the prevalence of short cervical length and the possible association with preterm delivery before universal screening can be recommended. PMID- 25732205 TI - In hot and cold water: differential life-history traits are key to success in contrasting thermal deep-sea environments. AB - Few species of reptant decapod crustaceans thrive in the cold-stenothermal waters of the Southern Ocean. However, abundant populations of a new species of anomuran crab, Kiwa tyleri, occur at hydrothermal vent fields on the East Scotia Ridge. As a result of local thermal conditions at the vents, these crabs are not restricted by the physiological limits that otherwise exclude reptant decapods south of the polar front. We reveal the adult life history of this species by piecing together variation in microdistribution, body size frequency, sex ratio, and ovarian and embryonic development, which indicates a pattern in the distribution of female Kiwaidae in relation to their reproductive development. High-density 'Kiwa' assemblages observed in close proximity to sources of vent fluids are constrained by the thermal limit of elevated temperatures and the availability of resources for chemosynthetic nutrition. Although adult Kiwaidae depend on epibiotic chemosynthetic bacteria for nutrition, females move offsite after extrusion of their eggs to protect brooding embryos from the chemically harsh, thermally fluctuating vent environment. Consequently, brooding females in the periphery of the vent field are in turn restricted by low-temperature physiological boundaries of the deep-water Southern Ocean environment. Females have a high reproductive investment in few, large, yolky eggs, facilitating full lecithotrophy, with the release of larvae prolonged, and asynchronous. After embryos are released, larvae are reliant on locating isolated active areas of hydrothermal flow in order to settle and survive as chemosynthetic adults. Where the cold water restricts the ability of all adult stages to migrate over long distances, these low temperatures may facilitate the larvae in the location of vent sites by extending the larval development period through hypometabolism. These differential life history adaptations to contrasting thermal environments lead to a disjunct life history among males and females of K. tyleri, which is key to their success in the Southern Ocean vent environment. We highlight the complexity in understanding the importance of life-history biology, in combination with environmental, ecological and physiological factors contributing to the overall global distribution of vent-endemic species. PMID- 25732206 TI - Sequence modifications and heterologous expression of eukaryotic cytochromes P450 in Escherichia coli. AB - The development of a heterologous expression system is often a principal step in biochemical and biotechnological studies on cytochromes P450 (P450s). However, heterologous expression of eukaryotic membrane-bound P450s in Escherichia coli is still a trial-and-error process because theoretical and systematical experimental procedures have not yet been established. In this study, we generated a series of chimeric variants of fungal P450s by replacing their N-terminal domains with the N-terminal domains of other P450s and explored their potentials for heterologous expression in E. coli. Large-scale screening demonstrated that a number of fungal P450s could be expressed when their N-terminal amino acid sequences were replaced with the corresponding domain of CYP5144C1, even when the expression of the non chimeric sequence was unpromising. Furthermore, a comprehensive screening resulted in the identification of 64 different types of chimeric partners whose N terminal domains could potentially be used to increase the expression levels of various P450s. These findings will help to elaborate experimental strategies for high-level heterologous expression of a variety of eukaryotic membrane-bound P450s in E. coli. PMID- 25732207 TI - Biosynthesis of poly(3-hydroxybutyrate-co-3-hydroxyalkanoates) by recombinant Escherichia coli from glucose. AB - The polyhydroxyalkanoate (PHA) copolymers consisting of short-chain-length (scl) and medium-chain-length (mcl) monomers have various properties ranging from stiff to flexible depending on the molar fraction of the monomer compositions. It has been reported that PhaG, which is first known as a (R)-3-hydroxyacyl-acyl carrier protein (ACP)-CoA transferase, actually functions as a 3-hydroxyacyl-ACP thioesterase, and the product of PP0763 gene from Pseudomonas putida KT2440 has a (R)-3-hydroxyacyl (3HA)-CoA ligase activity (Wang et al., Appl. Environ. Microbiol., 78, 519-527, 2012). In this study, we found a new (R)-3HA-CoA ligase (the product of PA3924 gene) from Pseudomonas aeruginosa PAO. The PA3924 gene was coexpressed with PHA synthase 1 gene (phaC1Ps) and phaGPs gene from Pseudomonas sp. 61-3, and beta-ketothiolase gene (phbARe) and acetoacetyl-CoA reductase gene (phbBRe) from Ralstonia eutropha in Escherichia coli LS5218 at 25 degrees C. As a result, the copolymer containing 94.6 mol% 3-hydroxybutyrate (3HB) and 5.4 mol% mcl-3-hydroxyalkanoates (3HA) consisting of C8, C10, C12 and C14 was synthesized by recombinant E. coli LS5218 from glucose as the sole carbon source. The concentration of P(3HB-co-3HA) (scl-co-mcl-PHA) synthesized by the recombinant E. coli LS5218 harboring phaC1Ps, phaGPs, phbABRe and the PA3924 genes was approximately 7-fold higher than that of the recombinant LS5218 harboring phaC1Ps, phaGPs, phbABRe and the PP0763 genes. The number-average molecular weight of the P(3HB-co-5.4% 3HA) copolymer was 233 * 10(3), which was relatively high molecular weight. In addition, the physical and the mechanical properties of the copolymer were demonstrated to improve the brittleness of P(3HB) homopolymer. PMID- 25732209 TI - Association of low 25-hydroxyvitamin D levels with the frailty syndrome in an aged population: results from the KORA-age Augsburg study. AB - OBJECTIVES: Older adults often suffer from vitamin D deficiency and from the frailty syndrome charac-terized by different physical limitations, complicating independent everyday life. Previous studies have suggested a relationship between vitamin D status and the frailty syndrome, but results have been partly inconsistent, particularly regarding the shape of the association. Therefore, our aim was to further assess the association of 25-hydroxyvitamin D (25(OH)D) serum levels and frailty in older participants. DESIGN: Cross-sectional population based study. PARTICIPANTS: The study population included 478 men and 462 women of the KORA (COoperative health research in the Region of Augsburg)-Age study born before 1944 examined in 2009. MEASUREMENTS: Classification of participants into different frailty states was performed according to the following criteria: weight loss, exhaustion, physical inactivity, slowness, and weakness. PARTICIPANTS who met 1-2 or >= 3 of the 5 criteria were classified as prefrail or frail, respectively. Total 25(OH)D was measured in non-fasting serum samples with an enhanced chemiluminescence immunoassay. Sequential logistic regression models adjusted for age, sex, season, lifestyle factors, diseases and biomarkers including parathyroid hormone (PTH) were calculated. RESULTS: High levels of 25(OH)D were inversely associated with being prefrail (N=351) or frail (N=38) in the model adjusted for age, sex, season and lifestyle factors. Compared to levels <15 ng/ml, odds ratios (ORs) (95% confidence intervals (CIs) were 0.52 (0.34 0.78) for levels of 15-<20 ng/ml, 0.55 (0.37-0.81) for levels of 20-<30 ng/ml and 0.32 (0.21-0.51) for levels >= 30 ng/ml. Additional adjustment for potential mediators including PTH only slightly attenuated these associations. For single frailty-components, significantly decreased ORs were found for exhaustion, physical inactivity and slowness comparing 25(OH)D levels >= 30 ng/ml with levels <15 ng/ml. CONCLUSION: Subjects with 25(OH)D serum levels >= 15 ng/ml were less frequently prefrail or frail. PMID- 25732208 TI - Frailty and nutrition: searching for evidence. AB - Frailty is a geriatric syndrome that predicts disability, morbidity and mortality in the elderly. Poor nutritional status is one of the main risk factors for frailty. Macronutrients and micronutrients deficiencies are associated with frailty. Recent studies suggest that improving nutritional status for macronutrients and micronutrients may reduce the risk of frailty. Specific diets such as the Mediterranean diet rich in anti-oxidants, is currently investigated in the prevention of frailty. The aim of this paper is to summarize the current body of knowledge on the relations between nutrition and frailty, and provide recommendations for future nutritional research on the field of frailty. PMID- 25732210 TI - Dietary intake of energy, nutrients and water in elderly people living at home or in nursing home. AB - OBJECTIVES: There is a lack of detailed information on dietary intake in elderly people at an individual level, which is crucial for improvement of nutritional support. The aim of this study was to investigate the dietary intake in elderly people in two types of living situations. DESIGN: Observational study, analysing prospective data. SETTING: The dietary intake was studied in elderly people living at home or in nursing home, in different cities of Sweden. PARTICIPANTS: A total of 264 elderly people (mean age 84) participated in the observational study. MEASUREMENTS: Dietary intake was measured using weighed food records and food diaries, comparing females and males. The observed dietary intake was related to Recommended intake and Lower intake level. RESULTS: All dietary intake and patient characteristic variables showed large individual differences (ranges). We found no significant differences (p>0.05) between those living at home and nursing home residents regarding the average intake of energy, protein and water when expressed as total intake per kg of body weight. A very low daily intake of energy (<20 kcal/kg body weight/day) was observed in 16% of the participants. For vitamin D and iron, 19% and 15%, respectively, had intakes below the Lower intake level. There was no correlation between intake of energy, protein or water and resident characteristics such as age, autonomy, morbidity, nutritional state or cognition. CONCLUSIONS: The large individual differences (ranges) in energy, nutrients and water show that the use of mean values when analysing dietary intake data from elderly people is misleading. From a clinical perspective it is more important to consider the individual intake of energy, nutrients and water. Ageism is intrinsic in the realm of 'averageology'. PMID- 25732211 TI - Cognitive frailty: what is still missing? AB - In recent years, the complex relationship between frailty and cognitive functioning has been increasingly investigated. Accordingly, the concept of "cognitive frailty" was recently proposed to describe a clinical condition characterized by the simultaneous occurrence of both physical frailty and cognitive impairment, in absence of overt dementia diagnosis or underlying neurological conditions. This novel construct has several elements of novelty and may delineate a promising target for preventive and therapeutic actions against age-related conditions. In the present paper we discuss the main issues that are still limiting the clinical and research implementation of the cognitive frailty construct. In particular, a) how to operationalize its definition; b) the supporting epidemiological data; and c) the underlying clinical and biological characteristics constitute points that need to be addressed and clarified. PMID- 25732212 TI - Cognitive aspects of frailty: mechanisms behind the link between frailty and cognitive impairment. AB - Whereas physical impairment is the main hallmark of frailty, evidence suggests that other dimensions, such as psychological, cognitive and social factors also contribute to this multidimensional condition. Cognition is now considered a relevant domain of frailty. Cognitive and physical frailty interact: cognitive problems and dementia are more prevalent in physically frail individuals, and those with cognitive impairment are more prone to become frail. Disentangling the relationship between cognition and frailty may lead to new intervention strategies for the prevention and treatment of both conditions. Both frailty and cognitive decline share common potential mechanisms. This review examines the relationship between frailty and cognitive decline and explores the role of vascular changes, hormones, vitamin D, inflammation, insulin resistance, and nutrition in the development of physical frailty and cognitive problems, as potential underlying mechanisms behind this link. Dual tasking studies may be a useful way to explore and understand the relation between cognitive and physical frailty. Further studies are needed to elucidate this complex relation to improve the outcomes of frailty. PMID- 25732213 TI - A cross sectional study of the association between walnut consumption and cognitive function among adult US populations represented in NHANES. AB - OBJECTIVE: To examine the association between walnut consumption and measures of cognitive function in the US population. DESIGN: Nationally representative cross sectional study using 24 hour dietary recalls of intakes to assess walnut and other nut consumption as compared to the group reporting no nut consumption. SETTING: 1988-1994 and 1999-2002 rounds of the National Health and Nutrition Examination Survey (NHANES). POPULATION: Representative weighted sample of US adults 20 to 90 years of age. MAIN OUTCOME MEASURE: The Neurobehavioral Evaluation System 2 (NES2), consisting of simple reaction time (SRTT), symbol digit substitution (SDST), the single digit learning (SDLT), Story Recall (SRT) and digit-symbol substitution (DSST) tests. RESULTS: Adults 20-59 years old reporting walnut consumption of an average of 10.3 g/d required 16.4ms less time to respond on the SRTT, P=0.03, and 0.39s less for the SDST, P=0.01. SDLT scores were also significantly lower by 2.38s (P=0.05). Similar results were obtained when tertiles of walnut consumption were examined in trend analyses. Significantly better outcomes were noted in all cognitive test scores among those with higher walnut consumption (P < 0.01). Among adults 60 years and older, walnut consumers averaged 13.1 g/d, scored 7.1 percentile points higher, P=0.03 on the SRT and 7.3 percentile points higher on the DSST, P=0.05. Here also trend analyses indicate significant improvements in all cognitive test scores (P < 0.01) except for SRTT (P = 0.06) in the fully adjusted models. CONCLUSION: These significant, positive associations between walnut consumption and cognitive functions among all adults, regardless of age, gender or ethnicity suggest that daily walnut intake may be a simple beneficial dietary behavior. PMID- 25732214 TI - Effects of local hypothermia on neuronal cell apoptosis after intracerebral hemorrhage in rats. AB - OBJECTIVES: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that is characterized by significant morbidity and mortality. Thus far, there is no effective treatment option for spontaneous ICH. In this study, we aimed to investigate the effects of local hypothermia on brain injuries after ICH. MEASUREMENTS: Bacterial collagenase was used to induce ICH stroke in male Wistar rats. We assessed the effects of normothermia and 4 hours of local hypothermia (~33.2 degrees C) initiated 1 hour after collagenase infusion on the neurological outcomes and brain water content at 1 and 3 days after ICH. The pathological changes of neuronal ultrastructure were examined with transmission electron microscopy. Furthermore, the expression levels of apoptotic molecules and matrix metalloproteinases-9 (MMP-9) were determined using western blotting and immunohistochemical staining. Results :Local hypothermia tends to reduce neurological deficits compared with the normothermic group at day 3 after ICH. Transmission electron microscopy reveals that local hypothermia significantly improves the ultrastructural outcomes at 1 and 3 days after ICH. In addition, local hypothermia markedly reduces edema formation and the expression levels of MMP-9 and apoptotic signal. CONCLUSION: These data suggest that local hypothermia induces a reduction in the brain edema and partly reduces neurological deficits along with marked inhibitory effects on MMP-9 and cell apoptosis after ICH. PMID- 25732215 TI - Effects of guar gum ingestion on postprandial blood pressure in older adults. AB - OBJECTIVES: The aim of this study was to investigate the effects of guar gum on postprandial blood pressure in older people. DESIGN: A randomized, double-blind, placebo-controlled, cross-over design. SETTING: Community senior centers in B city, South Korea. PARTICIPANTS: Twenty-two older female adults aged 67 to 88 with postprandial hypotension. INTERVENTION: The participants were randomly assigned to guar gum (semi-fluid food with 9 gram) or placebo intervention during the first treatment phase. After a washout period of 1 week, the two interventions were switched to the other in the second treatment phase. MEASUREMENTS: Blood pressure was measured during both phases before having a meal and every 15 minutes during 120 minutes after a meal with automated sphygmomanometer. RESULTS: Change in systolic blood pressure (SBP) over time was significantly different between guar gum and placebo groups (F=4.07, p=0.001). Compared with placebo group, guar gum group had significantly low prevalence of postprandial hypotension (PPH) (guar gum group=18.2% vs. placebo group=72.7%; chi2 =13.20, p<0.001). It also had significant difference in change of diastolic blood pressure (DBP) over time between guar gum and placebo groups (F=2.49, p=0.027). CONCLUSION: This findings show that guar gum could be effective on postprandial drops in blood pressure in older female adults. PMID- 25732216 TI - Mediterranean diet and cognitive function: the SUN project. AB - OBJECTIVE: Our aim was to evaluate the association between adherence to the Mediterranean Diet (MedDiet) and cognitive function in 823 participants (62 +/- 6 years at baseline) from a Spanish prospective cohort (SUN project). METHOD: A validated 136-item food frequency questionnaire was used to assess the adherence to the MedDiet at baseline. The 10-point (0 to 9) MedDiet Score was used to categorize adherence to MedDiet. Cognitive function was assessed twice at follow up with a mean follow-up time between exposure and outcome assessment of 6 and 8y using the Telephone Interview of Cognitive Status-modified (TICS-m, range 0 to 54 points). ANCOVA models were used to assess the association between adherence to the MedDiet and cognitive decline. RESULTS: In the multivariable-adjusted analysis of 2-year changes, a higher cognitive decline was observed among participants with low or moderate baseline adherence to the MedDiet than among those with better adherence (adjusted difference = -0.56 points in TICS-m, 95% CI = -0.99 to -0.13). CONCLUSION: A higher adherence to the MedDiet might be associated with better cognitive function. However, observed differences were of small magnitude and further studies are needed to confirm this finding. PMID- 25732218 TI - Comparative outcomes of total parenteral nutrition use in patients aged greater or less than 80 years of age. AB - OBJECTIVES: Total-parenteral-nutrition (TPN) can act as a bridge to enteral nutrition. The current study aims to explore the outcomes of TPN use in older adults which are at present poorly defined. DESIGN, SETTING AND PARTICIPANTS: Data on 172 patients who received TPN between January-December 2011 were prospectively recorded and examined. RESULTS: Mean age was 62.7 +/- 16.8 years (12.8% >= 80 years). Those >= 80 years were less often male (31.8% Vs 57.3%, P=0.038) and had no history of hepatic dysfunction (0.0% Vs 16.7%, P=0.025). In those >= 80 years the indication was more often suspected ileus (40.9% Vs 13.3%, P=0.004). Patients >= 80 years developed hypertriglyceridaemia less frequently (7.7% Vs 36.2%, P=0.031). There was no difference in the duration of TPN administration, the rate of TPN line sepsis, serum electrolyte derangement or glycaemic control. Change in serum albumin over the course of treatment did not differ (>= 80 Vs <80 years, -0.28 +/- 0.62 mg/dL Vs -2.00 +/- 1.57 mg/dL, P=0.323). CONCLUSIONS: These data suggest TPN use is safe in patients aged >= 80 years and advanced age alone should not preclude TPN use. PMID- 25732217 TI - Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review. AB - A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer's disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD. PMID- 25732220 TI - Comparisons of sarcopenia prevalence based on different diagnostic criteria in Chinese older adults. AB - The study aimed to describe the prevalence of sarcopenia and discussed the applicability of different diagnostic criteria in Chinese older adults. 286 Chinese adults (136 men and 150 women) aged 60-88 were recruited. The prevalence of sarcopenia were calculated using different diagnostic criteria. Physical functioning was compared in sarcopenic and non-sarcopenic older adults. Compared with the standard of EWGSOP (European Working Group on Sarcopenia in Older People), the prevalence of sarcopenia was higher when the IWGS (International Working Group on Sarcopenia) standard was applied (Men: 7.4% vs. 0.8%; Women: 4.7% vs. 0%). If the AWGS (Aisa Working Group on Sarcopenia) standard was applied, the prevalence was 5.9% in men and 0.7% in women. In conclusion, the prevalence of sarcopenia in Chinese older adults ranged from 0% to around 10% when the diagnostic criteria of IGWS, EWGSOP and AGWS were applied. Further studies are still needed to investigate appropriate diagnostic criterion of sarcopenia for Chinese population. PMID- 25732219 TI - Considerations in selection of diet assessment methods for examining the effect of nutrition on cognition. AB - Older adults are the most rapidly growing age group in the United States, and it is estimated that 22.2 % of U.S. adults over 71 years of age have cognitive impairments without dementia and 13.9% have dementia. Cognitive impairment is associated with reduced quality of life, increased risk of hospitalization, inability to live independently, and increased health care costs; therefore, identification of modifiable risk factors for prevention and delay of cognitive decline is of increasing importance. There is a growing body of research and interest in the relationship between diet and cognitive function. Epidemiologic studies suggest that cognitive function may be improved and cognitive decline prevented as a function of a particular nutrient, food group or dietary pattern; however, results from these trials have failed to be replicated in randomized controlled trials. One possible reason for the equivocality of findings in the diet and cognitive function literature may be the methodological issues and limitations in the assessment of dietary patterns and nutritional intake. Self reported dietary data can be biased by many factors such as age, gender, socioeconomic status, and education; yet, there is limited research on the impact of cognitive function on the integrity of self-reported dietary data. Cognitive function itself may bias diet assessment methods, subsequently obscuring the evaluation of the nutrition-cognition relationship. The present review summarizes methodological validation studies that provide insight into potential errors of diet assessment methods due to cognitive function, identifies research gaps and provides recommendations for improving diet assessment accuracy in studies of individuals with cognitive impairments. PMID- 25732221 TI - Physical function decline and degradation of postural sway dynamics in asymptomatic sedentary postmenopausal women. AB - BACKGROUND: Postural control is an important aspect of physical functioning. OBJECTIVE: To determine whether postural sway complexity could discriminate asymptomatic sedentary postmenopausal women with normal or subnormal physical function from those with lower physical function. DESIGN: Cross-sectional study. SETTING: Department of Geriatrics, University Hospital of Montpellier. PARTICIPANTS: 126 community-dwelling women aged 55 to 76 recruited though public meetings aimed at promoting physical activity in postmenopausal women. MEASUREMENTS: Women were asked to stand still on a force platform, either with eyes open (EO) or eyes closed (EC). Physical function was estimated using the Six Minute Walking Distance (6MWD) test, expressed as a percentage of the predicted 6MWD (%-pred 6MWD) based on age, gender, body height, and weight. In addition to traditional stabilometric measures, dynamical measures (percentage of determinism of recurrence quantification analysis [DETRQA], sample entropy [SampEn] and complexity index of multiscale entropy [CIMSE]) were used to quantify the complexity of center of pressure (COP) time series (DETRQA: predictability, SampEn: regularity, CIMSE: multiscale regularity). RESULTS: None of the traditional stabilometric measures differentiated women with lower (%-pred 6MWD <= 85.5%) from those with subnormal or normal (%-pred 6MWD > 85.5%) physical function. Conversely, women with lower physical function showed lower SampEn values in the AP direction in both EO and EC conditions, as well as lower SampEn and higher DETRQA values in the ML direction in EC condition. No significant difference in the CIMSE values was found between the two groups. CONCLUSION: Lower physical function was found to be associated with lower postural sway complexity (higher regularity and predictability) in asymptomatic sedentary postmenopausal women, especially in the absence of vision. Future work is needed to determine whether a decrease in postural sway complexity could predict future decline in physical function in these women. PMID- 25732222 TI - Compliance of nursing home residents with a nutrient- and energy-dense oral nutritional supplement determines effects on nutritional status. AB - OBJECTIVES: Administration of oral nutritional supplements (ONS) is an effective strategy to treat and avoid malnutrition, a persisting issue in nursing homes. However, little is known about compliance in the NH population. This study aimed to analyse the effects of compliance of NH residents with a low-volume, nutrient- and energy-dense ONS on nutritional status and to identify residents' characteristics associated with compliance. DESIGN AND SETTING: Randomized, controlled trial in nursing homes. PARTICIPANTS AND INTERVENTION: 87 nursing home residents (87 +/- 6y, 91% female) with malnutrition or at risk of malnutrition were randomly allocated to an intervention group (IG) receiving 2 x 125 ml ONS (2.4 kcal/ml)/d for 12 weeks, or the control group (CG) with usual care. MEASUREMENTS: ONS intake was recorded daily and compliance calculated. Low and high compliance were defined as <= 30% and >= 80% of provided ONS actually consumed, respectively. Body weight (BW), BMI, upper-arm (UAC) and calf circumference (CC) and MNA-SF were assessed at baseline and after 12 weeks. Associations between compliance and changes of nutritional parameters and residents' characteristics were analysed. RESULTS: Compliance was high in 35.7% and low in 28.6% of the IG (n=42). BW change was significantly higher in subjects with high compliance (median +3.0 (interquartile range +2.1;+3.8) kg, n=15) than in those with low compliance (-0.2 (-2.2;+1.6) kg, n=12) and CG (-0.1 (-1.2; +0.6) kg, n=35; p<0.001), and significantly correlated with compliance in IG (r=0.691; p<0.001). Significant differences and correlations were also identified for BMI, UAC and MNA-SF. High compliance was more often observed in residents with malnutrition (66.7 vs. 27.3%) and chewing difficulties (77.8 vs. 24.2%) than in those without these conditions. Low compliance was more prevalent in residents who were immobile (45.0 vs. 13.6%), depressed (33.3 vs. 6.7%) or had gastrointestinal complaints (50.0 vs. 17.9%) (all p<0.05). CONCLUSIONS: A high compliance of nursing home residents with a low volume, nutrient- and energy dense ONS was related to a significantly improved nutritional status in comparison to low compliance and therefore enhanced the effectiveness of ONS. A higher compliance may be achieved by consideration of different residents' characteristics. PMID- 25732223 TI - Addressing the bias problem in the assessment of the quality of life of patients with dementia: determinants of the accuracy and precision of the proxy ratings. AB - OBJECTIVES: We aimed to examine the discrepancy between patients and caregivers' ratings of quality of life in terms of accuracy and precision, and identify factors associated with it, in order to facilitate the use of this scale as dementia progresses. DESIGN: Cross-sectional analytic study. SETTING: Day care centres. PARTICIPANTS: Community-living patients with Alzheimer's disease in early or moderate stage and their principal caregivers. MEASUREMENTS: PARTICIPANTS rated patients' quality of life using DEMQOL. The discrepancy was assessed using the individual difference score and the residuals for each domain of DEMQOL. The scores on Mini-Mental State Examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Clinical Insight Rating Scale, Cumulative Illness Rating Scale, Health Utilities Index Mark 3 and Zarit Burden Interview were considered as possible predictors of the discrepancy. RESULTS: A total of 276 subjects participated in the study (138 patients with Alzheimer's disease and their caregivers). Discrepancy measured by individual difference score was lower than that measured by the residuals. Burden and mood-related symptoms explained the positive differences and residuals, while pain, self-perceived depression and cognition determined the negative ones. CONCLUSIONS: Differences exist between patients and caregivers' perceptions about subjective states. The evaluations of each informant seem to be influenced by their own emotional state and the inner experience of the effects of the disease. Caregivers' ratings on DEMQOL could be useful to monitor the efficacy of any treatment whenever burden is low and patients have no great physical or emotional suffering. PMID- 25732224 TI - Efficacy of transurethral prostate enucleation by bipolar system for patients with benign prostatic hyperplasia. AB - BACKGROUND: The aim of this paper was to evaluate the efficacies and safety of transurethral prostate enucleation by bipolar system (TUEB) for the patients with benign prostatic hyperplasia (BPH). METHODS: We prospectively evaluated clinical outcomes of TUEB in 55 patients with BPH from July 2005 to January 2011. Mean ages of the patients were 69.2 years. International Prostate Symptom Score (IPSS), IPSS-quality of life (IPSS-QOL) were assessed before and 12 months after surgery. Serum PSA, maximal flow rate (MFR), and post-void residual (PVR) were also evaluated before and 6 and 12 months after surgery. RESULTS: The median prostate volumes and resection volumes were 64.1 g (interquartile range [IQR]: 48 87) and 34.4 g (25-60.2), respectively. The median operation time was 138.0 min (100.2-169.2). Total IPSS scores and IPSS-QOL were significantly improved (from 24 [17-31] to 5 [2-8] points, and from 6 [5-6] to 2 [1-2] points, both P<0.001). MFR and PVR were significantly improved 6 and 12 months after TUEB (from 6.2 [3.9 8.3] to 15.1 [10.5-20.9], and 14.6 [10.2-20.5] mL/s, P<0.0001, and from 151.5 [81.5-284.7] to 16.5 [0-30.5], and 6.0 [0-41.0] mL, P<0.0001, respectively). Serum PSA also significantly decreased, 6 and 12 months (from 7.5 [4.7-9.8] to 1.1 [0.5-1.5], and 0.6 [0.3-1.9] ng/mL, P<0.0001). Although hemoglobin decreased after operation, no case experienced blood transfusion. Three episodes of urinary tract infections, 14 cases of mild stress urinary incontinence, 2 cases of urinary retention were occurred transiently with recovery within 1 month after surgery. CONCLUSIONS: We identified favorable efficacy and safety of TUEB. TUEB appears to be another possibility in the treatment of BPH. PMID- 25732225 TI - Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. AB - BACKGROUND: The aim of this study was to retrospectively analyze the pathological outcomes of patients meeting the Prostate Cancer Research International Active Surveillance (PRIAS) criteria who had undergone radical prostatectomy (RP). METHODS: Out of 2014 patients recruited for minimally invasive RP between 2008 and 2014 in 7 centers, 226 (11.2%) met the modified PRIAS criteria (clinical stage T1c/T2, PSA<10 ng/mL, 1-2 positive biopsy cores and Gleason Score<6). RESULTS: At pathological evaluation, Gleason Score upgrade was reported in 47.3% of patients; 74 (32.7%), 10 (4.4%), 9 (3.9%) patients showed RP Gleason sum 7, 8 and 9, respectively. Upstaging was reported in 135 patients (59.7%). Twelve (5.3%) and 4 (1.7%) patients had T3a and T3b pathological stage respectively. CONCLUSIONS: Notwithstanding the PRIAS criteria can identify some PCa patients as low-risk, at pathological evaluation some of them harbored intermediate- or high risk disease. According to our data, patients eligible for AS should be carefully counseled about possible disease understaging. PMID- 25732227 TI - Metabolic rewiring of pancreatic ductal adenocarcinoma: New routes to follow within the maze. AB - Pancreatic ductal adenocarcinoma (PDAC) is a debilitating and almost universally fatal malignancy. Despite advances in understanding of the oncogenetics of the disease, very few clinical benefits have been shown. One of the main characteristics of PDAC is the tumor architecture where tumor cells are surrounded by a firm desmoplasia. By reducing vascularization, thus both oxygen and nutrients delivery to the tumor, this stroma causes the appearance of hypoxic zones driving metabolic adaptation in surviving tumor cells in order to cope with challenging conditions. This metabolic reprogramming promoted by environmental constraints enhances PDAC aggressiveness. In this review, we provide a brief overview of previous works regarding the importance of glucose and glutamine addiction of PDAC cells. In particular we aim to highlight the need for exploring the impact of metabolites other than glucose and glutamine, such as non-essential amino acids and oncometabolites, to find new treatments. We also discuss the need for progress in methodology for metabolites detection. The overall purpose of our review is to emphasize the need to look beyond what is currently known, with a focus on amino acid availability, in order to improve our understanding of PDAC biology. PMID- 25732226 TI - MicroRNA-30c-2-3p negatively regulates NF-kappaB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer. AB - Nuclear Factor kappa B (NF-kappaB) signaling is frequently deregulated in a variety of cancers and is constitutively active in estrogen receptor negative (ER ) breast cancer subtypes. These molecular subtypes of breast cancer are associated with poor overall survival. We focused on mechanisms of NF-kappaB regulation by microRNAs (miRNAs), which regulate eukaryotic gene expression at the post-transcriptional level. In a previous genome-wide miRNA screen, we had identified miR-30c-2-3p as one of the strongest negative regulators of NF-kappaB signaling. Here we have uncovered the underlying molecular mechanisms and its consequences in breast cancer. In vitro results show that miR-30c-2-3p directly targets both TNFRSF1A-associated via death domain (TRADD), an adaptor protein of the TNFR/NF-kappaB signaling pathway, and the cell cycle protein Cyclin E1 (CCNE1). Ectopic expression of miR-30c-2-3p downregulated essential cytokines IL8, IL6, CXCL1, and reduced cell proliferation as well as invasion in MDA-MB-231 breast cancer cells. RNA interference (RNAi) induced silencing of TRADD phenocopied the effects on invasion and cytokine expression caused by miR-30c-2 3p, while inhibition of CCNE1 phenocopied the effects on cell proliferation. We further confirmed the tumor suppressive role of this miRNA using a dataset of 781 breast tumors, where higher expression was associated with better survival in breast cancer patients. In summary we have elucidated the mechanism by which miR 30c-2-3p negatively regulates NF-kappaB signaling and cell cycle progression in breast cancer. PMID- 25732228 TI - Detection and characterization of nanoparticles in suspension at low concentrations using the X-ray total scattering pair distribution function technique. AB - Difference atomic pair distribution function methods have been applied to detect and characterize nanoparticles suspended in a solvent at very dilute concentrations. We specifically consider nanoparticles of a pharmaceutical compound in aqueous solution using X-ray PDF methods, a challenging case due to the low atomic number of the nanoparticle species. The nanoparticles were unambiguously detected at the level of 0.25 wt%. Even at these low concentrations the signals were highly reproducible, allowing for reliable detection and quantitative analysis of the nanoparticle structure. PMID- 25732231 TI - Endoscopic vidian neurectomy: a prospective case series. AB - BACKGROUND: Chronic refractory vasomotor rhinitis (VMR) is a debilitating condition that causes significant impairment of quality of life. The purpose of this study is to investigate the efficacy and potential side effects of endoscopic vidian neurectomy as treatment for patients with VMR. METHODS: This study was a prospective, intent-to-follow case series. Inclusion criteria were as follows: (1) patients with debilitating VMR refractory to medical therapy and with significant impact on quality of life; (2) negative allergy history and skin testing; and (3) negative computed tomography (CT) scan to rule out skull-base defect or cerebrospinal fluid (CSF) fistula. Patients underwent bilateral vidian neurectomy via a pterygomaxillary approach. Prior to surgery all patients underwent formal ophthalmologic testing to quantify preoperative ocular and lacrimal function. Ophthalmologic testing was repeated postoperatively at approximately 3 months. Patients also completed surveys regarding rhinologic outcomes including the Sinusitis Symptom Questionnaire (SSQ) and the 22-item Sino Nasal Outcome Test (SNOT-22) at the following time points: preoperatively, and 1 week, 4 weeks, 12 weeks, 6 months, 1 year, and 2 years postsurgery. Descriptive statistics and analysis of variance (ANOVA) were undertaken. RESULTS: Eleven patients (22 sides) underwent bilateral vidian neurectomy with pathologic confirmation of nerve section in all cases. Average follow-up was 19.4 months. Statistically and clinically significant improvement was measured for both the SSQ and the SNOT-22 and compared with the patients' baseline scores (p < 0.0001). Subscores for rhinorrhea and nasal congestions were also statistically significantly improved (p < 0.05). No incidence of permanent or measureable dry eye has been reported. CONCLUSION: The data suggests that vidian neurectomy is an effective, safe, and definitive treatment for most patients with VMR refractory to medical treatment. PMID- 25732229 TI - The clinical significance of negative flow cytometry immunophenotypic results in a morphologically scored positive bone marrow in patients following treatment for acute myeloid leukemia. AB - In a patient with acute myeloid leukemia (AML) following therapy, finding >=5% bone marrow (BM) blasts is highly concerning for residual/relapsed disease. Over an 18-month period, we performed multicolor flow cytometry immunophenotyping (MFC) for AML minimal residual disease on >4,000 BM samples, and identified 41 patients who had >=5% myeloblasts by morphology but negative by MFC. At the time of a negative MFC study, an abnormal cytogenetic study converted to negative in 14 patients and remained positive at a low level (2.5-9.5%) by fluorescence in situ hybridization in 3 (14%), of the latter, abnormalities subsequently disappeared in the repeated BM in 2 patients. Positive pretreatment mutations, including FLT3, NPM1, IDH1, CEBPA, became negative in all 10 patients tested. Of the seven patients with favorable cytogenetics, PML/RARA, CBFB-MYH11 or RUNX1 RUNX1T1 fusion transcripts were detected at various levels in six patients but all patients remained in complete remission. With no additional chemotherapy given, 39 patients had BM repeated (median 2 weeks, range <1-21), and all cases showed <5% BM blasts and a continuously negative MFC. In the end of follow-up (median 10 months, range 1-22), 13 patients experienced relapse, 12/13 showing clonal cytogenetic evolution/switch and 11 demonstrating major immunophenotypic shifts. We conclude that MFC is useful in identifying a regenerating BM sample with >=5% BM blasts that would otherwise be scored as positive using standard morphologic examination. We believe this conclusion is supported by the changes in molecular cytogenetic status and the patient clinical follow-up data. PMID- 25732232 TI - Religion-related stigma and discrimination experienced by lesbian, gay, bisexual and transgender students at a South African rural-based university. AB - This paper reports on the stigma and discrimination experienced by lesbian, gay, bisexual and transgender students at a rural university in South Africa. Twenty lesbian, gay, bisexual and transgender students recruited through snowball sampling participated in this study. Interpretative Phenomenological Analysis was used as a framework for data analysis. Findings indicate that religion-related stigma and discrimination are common at a rural-based university in South Africa. Lesbian, gay, bisexual and transgender students are typically ascribed a range of labels, including 'sinners', 'devils' and 'demon possessed'. They are also exposed to a number of discriminatory acts, such as the denial of financial and healthcare services and threats of and/or actual rape. Study participants reported attempts to convert lesbian, gay, bisexual and transgender students' sexual orientation which involved the use of intervention in the form of prayers. Derogatory labelling and associated discriminatory acts, for example the threat of rape, led many students to conceal their sexual identity, not attend specific classes, terminate their studies and even attempt suicide. Universities should develop policies to promote greater social inclusion and the acceptance of lesbian, gay, bisexual and transgender students. Policies should also specify the steps or approaches to be taken in addressing discriminatory practices. PMID- 25732233 TI - Complex transition metal hydrides incorporating ionic hydrogen: thermal decomposition pathway of Na2Mg2FeH8 and Na2Mg2RuH8. AB - Complex transition metal hydrides have potential technological application as hydrogen storage materials, smart windows and sensors. Recent exploration of these materials has revealed that the incorporation of anionic hydrogen into these systems expands the potential number of viable complexes, while varying the countercation allows for optimisation of their thermodynamic stability. In this study, the optimised synthesis of Na2Mg2TH8 (T = Fe, Ru) has been achieved and their thermal decomposition properties studied by ex situ Powder X-ray Diffraction, Gas Chromatography and Pressure-Composition Isotherm measurements. The temperature and pathway of decomposition of these isostructural compounds differs considerably, with Na2Mg2FeH8 proceeding via NaMgH3 in a three-step process, while Na2Mg2RuH8 decomposes via Mg2RuH4 in a two-step process. The first desorption maxima of Na2Mg2FeH8 occurs at ca. 400 degrees C, while Na2Mg2RuH8 has its first maxima at 420 degrees C. The enthalpy and entropy of desorption for Na2Mg2TH8 (T = Fe, Ru) has been established by PCI measurements, with the DeltaHdes for Na2Mg2FeH8 being 94.5 kJ mol(-1) H2 and 125 kJ mol(-1) H2 for Na2Mg2RuH8. PMID- 25732234 TI - Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. AB - Advancing age is characterized by functional and phenotypic alterations in the distribution of circulating T-cell subsets, some of which are exacerbated by a latent infection with the persistent herpesvirus, cytomegalovirus (CMV). The influence of age, sex and CMV-infection on T-cell subpopulations in the peripheral blood remains incompletely understood. Here, T cells from 157 participants of the Berlin Aging Study II (BASE-II) were characterized at 21-34 (n = 59) and 62-85 (n = 98) years of age. We found that the frequency of naive CD8(+) T cells was significantly lower in the older group than in the young, and was different in men and women. Elderly men had a significantly lower proportion of naive CD8(+) T cells than younger men, regardless of their CMV-status, but in older women, this was seen only in the CMV-seropositive group. Reciprocally, older men had a higher proportion of late-differentiated, potentially "senescent" CD57(+) T cells. Thus, T-cell senescence may be more pronounced in older men than women. Within the CD4(+) population, in the elderly of both sexes there was a significantly higher proportion of late-differentiated TEMRA cells (T effector memory cells re-expressing CD45RA), but these were present exclusively in CMV positive subjects. Finally, for the first time, we examined the so-called TSCM cell (T-stem cell-like memory) subpopulations in both CD4(+) and CD8(+) subsets and found that neither CMV-seropositivity nor age or sex affected their frequencies. This study confirms significant cross-sectional age-associated differences of T-cell subset distribution in a representative German urban population and emphasizes the impact of both sex and CMV-infection on T-cell naive and memory phenotypes, but unaffected frequencies of T-stem cell-like memory cells. PMID- 25732235 TI - Protein phosphorylation detection using dual-mode field-effect devices and nanoplasmonic sensors. AB - Phosphorylation by kinases is an important post-translational modification of proteins. It is a critical control for the regulation of vital cellular activities, and its dysregulation is implicated in several diseases. A common drug discovery approach involves, therefore, time-consuming screenings of large libraries of candidate compounds to identify novel inhibitors of protein kinases. In this work, we propose a novel method that combines localized surface plasmon resonance (LSPR) and electrolyte insulator semiconductor (EIS)-based proton detection for the rapid identification of novel protein kinase inhibitors. In particular, the selective detection of thiophosphorylated proteins by LSPR is achieved by changing their resonance properties via a pre-binding with gold nanoparticles. In parallel, the EIS field-effect structure allows the real-time electrochemical monitoring of the protein phosphorylation by detecting the release of protons associated with the kinases activity. This innovative combination of both field-effect and nanoplasmonic sensing makes the detection of protein phosphorylation more reliable and effective. As a result, the screening of protein kinase inhibitors becomes more rapid, sensitive, robust and cost effective. PMID- 25732236 TI - The Antiinflammatory Properties of Humic Substances: A Mini Review. AB - Humic substances are effective in the suppression of delayed type hypersensitivity, rat paw oedema, a graft-versus-host reaction and contact hypersensitivity in rats. They reduce the C-reactive protein levels of patients suffering from osteoarthritis of the knee and the wheel and flare reaction of patients suffering from hay fever. They have also been described as cardioprotective and pro-angiogenic. Toxicity studies have indicated that potassium humate is safe in humans up to a daily dosage of 1 g/kg, whereas fulvic acid is safe in humans up to a daily dosage of 1.8 g per adult. The antiinflammatory action of potassium humate can be contributed to the inhibition of the release of inflammatory-related cytokines, an adhesion molecule, oxidants and components of the complement system. PMID- 25732237 TI - Disentangling the impacts of outcome valence and outcome frequency on the post error slowing. AB - Post-error slowing (PES) reflects efficient outcome monitoring, manifested as slower reaction time after errors. Cognitive control account assumes that PES depends on error information, whereas orienting account posits that it depends on error frequency. This raises the question how the outcome valence and outcome frequency separably influence the generation of PES. To address this issue, we varied the probability of observation errors (50/50 and 20/80, correct/error) the "partner" committed by employing an observation-execution task and investigated the corresponding behavioral and neural effects. On each trial, participants first viewed the outcome of a flanker-run that was supposedly performed by a 'partner', and then performed a flanker-run themselves afterwards. We observed PES in the two error rate conditions. However, electroencephalographic data suggested error-related potentials (oERN and oPe) and rhythmic oscillation associated with attentional process (alpha band) were respectively sensitive to outcome valence and outcome frequency. Importantly, oERN amplitude was positively correlated with PES. Taken together, these findings support the assumption of the cognitive control account, suggesting that outcome valence and outcome frequency are both involved in PES. Moreover, the generation of PES is indexed by oERN, whereas the modulation of PES size could be reflected on the alpha band. PMID- 25732238 TI - Reduced satellite cell number in situ in muscular contractures from children with cerebral palsy. AB - Satellite cells (SC) are quiescent adult muscle stem cells critical for postnatal development. Children with cerebral palsy have impaired muscular growth and develop contractures. While flow cytometry previously demonstrated a reduced SC population, extracellular matrix abnormalities may influence the cell isolation methods used, systematically isolating fewer cells from CP muscle and creating a biased result. Consequently, the purpose of this study was to use immunohistochemistry on serial muscle sections to quantify SC in situ. Serial cross-sections from human gracilis muscle biopsies (n = 11) were labeled with fluorescent antibodies for Pax7 (SC transcriptional marker), laminin (basal lamina), and 4',6-diamidino-2-phenylindole (nuclei). Fluorescence microscopy under high magnification was used to identify SC based on labeling and location. Mean SC/100 myofibers was reduced by ~70% (p < 0.001) in children with CP (2.89 +/- 0.39) compared to TD children (8.77 +/- 0.79). Furthermore, SC distribution across fields was different (p < 0.05) with increased percentage of SC in fields being solitary cells (p < 0.01) in children with CP. Quantification of SC number in situ, without any other tissue manipulation confirms children with spastic CP have a reduced number. This stem cell loss may, in part, explain impaired muscle growth and apparent decreased responsiveness of CP muscle to exercise. PMID- 25732239 TI - N-acetylcysteine prevents rotenone-induced Parkinson's disease in rat: An investigation into the interaction of parkin and Drp1 proteins. AB - There are convincing evidences that oxidative stress has an important role in both the initiation and progression of Parkinson's disease. N-acetylcysteine (NAC) is shown to have antioxidant properties via fortifying glutathione which is one of the main endogenous antioxidant systems. Therefore our study was aimed to evaluate the effect of NAC in management of Parkinson's disease. To this aim, male Wistar rats (10-12 months) received rotenone 2.5mg/kg/48 h intraperitoneally (ip) to induce a Parkinson's disease model. Pretreatment with NAC (25 and 50mg/kg/48 h ip) was administered 1h before the rotenone injection. Three behavioral tests (rotarod, rearing and bar tests) were performed for motor function assessment. Dopamine levels of dopaminergic areas in rat brain including substantia nigra (SN) and striatum (ST) were assessed using high performance liquid chromatography analysis to measure the loss of dopamine. Western blot analysis was also done for parkin and Drp1 (dynamin related protein-1) proteins quantification in SN and ST. Our results indicated that NAC significantly ameliorated the rotenone-induced motor dysfunction and dopamine loss. Furthermore, NAC was able to prevent the rotenone-induced changes in parkin and Drp1 levels in the both studied areas. In conclusion we found that NAC delayed the Parkinson's disease induction by rotenone and this effect might be related to its proved antioxidant effect. PMID- 25732240 TI - Design, Synthesis and in vivo Evaluation of Novel C-Aryl Glucosides as Potent Sodium-Dependent Glucose Cotransporters Inhibitors for the Treatment of Diabetes. AB - A series of novel C-aryl glucosides with substituents at the 3'-position or cyclization at 3', 4'-positions of the distal aryl ring were designed and synthesized, which might decrease the oxidative metabolism of dapagliflozin. Preliminary evaluation for hypoglycemic effect and the risk of hypoglycemia were carried out both in normal and in streptozotocin-induced diabetic mice. Among the synthesized compounds, compound 19a exerted potency-similarity with dapagliflozin and triggered the hypoglycemic effect in a dose-dependent manner. Besides, compound 19a, even at the high dose of 10 mg/kg, revealed a low risk of hypoglycemia. In further studies, 19a exhibited sustained antihyperglycemic effect without particular side-effects in 30-day chronic diabetic mice studies. Moreover, histological changes in the pancreas of diabetic mice indicated 19a might protect pancreatic beta-cell from apoptosis by reducing the damage of glucotoxicity. All of these results demonstrated that compound 19a, with excellent in vivo pharmacological activity and safety profile, was considered to be a promising drug candidate for the treatment of diabetes mellitus. PMID- 25732241 TI - Impact of acute coronary syndromes on survival of dialysis patients following surgical or percutaneous coronary revascularization in the United States. AB - AIMS: We sought to evaluate survival of dialysis (chronic kidney disease (CKD) stage 5D) patients undergoing coronary revascularization procedures in the context of acute coronary syndrome (ACS) compared with absence of ACS. METHODS AND RESULTS: CKD 5D patients undergoing coronary revascularization, 2004-2009 (n = 23,033), were identified from the United States Renal Data System. Long-term survival was estimated by the Kaplan-Meier method and independent predictors of mortality using a comorbidity-adjusted Cox proportional hazards model. Among ACS patients (n = 12,473; 54%), revascularization procedures were coronary artery bypass grafting (CABG, n = 2910), drug-eluting stents (DESs, n = 6566), and bare metal stents (BMSs, n = 2997). All-cause survival rates following these procedures, respectively, were: in-hospital 90%, 96%, 93%; one-year: 66%, 67%, 58%; two-year: 53%, 48%, 43%. Among non-ACS patients (n = 10,560; 46%), procedures were CABG (n = 3268), DESs (n = 5278), and BMSs (n = 2014). Survival rates following these procedures, respectively, were: in-hospital 94%, 99%, 98%; one year: 73%, 77%, 70%; two year: 61%, 59%, 55%. DESs (versus CABG) independently predicted mortality among ACS (hazard ratio 1.08; 95% confidence interval 1.02-1.15) but not non-ACS patients (1.01, 0.95-1.07); BMSs (versus CABG) independently predicted mortality among ACS (1.30, 1.21-1.38) and non-ACS (1.13, 1.05-1.22) patients. CONCLUSIONS: Among CKD 5D patients, survival was lower for ACS versus non-ACS indications following all revascularization strategies. CABG (versus DESs) was associated with higher long-term survival in the context of ACS; in the absence of ACS, long-term survival was similar after CABG or DESs. BMSs were consistently associated with worse outcomes. PMID- 25732243 TI - Sharing without caring? Respect for moral others compensates for low sympathy in children's sharing. AB - We examined links between sharing, respect for moral others, and sympathy in an ethnically diverse sample of 7- and 15-year-olds (N = 146). Sharing was assessed through children's allocation of resources in the dictator game. Children reported their respect towards hypothetical characters performing moral acts. Sympathy was evaluated via caregiver and child reports. Respect and caregiver reported sympathy interacted in predicting sharing: Higher levels of respect were associated with higher levels of sharing for children with low, but not medium or high, levels of sympathy. The motivational components of other-oriented respect may compensate for low levels of sympathetic concern in the promotion of sharing. PMID- 25732242 TI - Assessment of the effect of laser irradiations at different wavelengths (660, 810, 980, and 1064 nm) on autophagy in a rat model of mucositis. AB - It is known that high-dose radiation has an effect on tissue healing, but tissue healing does not occur when low dose radiation is applied. To clarify this issue, we compare the treatment success of low dose radiation with programmed cell death mechanisms on wounded tissue. In this study, we aimed to investigate the interactions of low and high-dose radiation using an autophagic mechanism. We included 35 adult Wistar-Albino rats in this study. All animals were injected with 100 mg/kg of 5-fluorouracil (5-FU) on the first day and 65 mg/kg of 5-FU on the third day. The tips of 18-gauge needles were used to develop a superficial scratching on the left cheek pouch mucosa by dragging in a linear movement on third and fifth days. After mucositis formation was clinically detected, animals were divided into five groups (n = 7). Different wavelengths of laser irradiations (1064 nm, Fidelis Plus, Fotona, Slovenia; 980 nm, FOX laser, A.R.C., Germany; 810 nm, Fotona XD, Fotona, Slovenia; 660 nm, HELBO, Medizintechnik GmbH, Wels, Austria) were performed on four groups once daily for 4 days. The laser irradiation was not performed on the control group. To get the tissue from the left cheek at the end of fourth day from all animals, oval excisional biopsy was performed. Molecular analysis assessments of pathological and normal tissue taken were performed. For this purpose, the expression analysis of autophagy genes was performed. The results were evaluated by normalization and statistics analysis. We found that Ulk1, Beclin1, and Atg5 expression levels were increased in the rats when the Nd:YAG laser was applied. This increase showed that a 1064-nm laser is needed to activate the autophagic mechanism. However, in the diode applications, we found that Beclin1, Atg10, Atg5, and Atg7 expressions numerically decreased. Atg5 is responsible for the elongation of autophagosome. Becn1 is a control gene in the control mechanism of autophagy. The reduction of the expression of these genes leads us to think that it may depend on the effect of drug (5-FU) used to form model. Expressions of therapeutic genes increase to ensure hemostasis, but in our study, expressions were found to decrease. More detailed studies are needed. PMID- 25732244 TI - Snake trajectories in ultraclean graphene p-n junctions. AB - Snake states are trajectories of charge carriers curving back and forth along an interface. There are two types of snake states, formed by either inverting the magnetic field direction or the charge carrier type at an interface. The former has been demonstrated in GaAs-AlGaAs heterostructures, whereas the latter has become conceivable only with the advance of ballistic graphene where a gap-less p n interface governed by Klein tunnelling can be formed. Such snake states were hidden in previous experiments due to limited sample quality. Here we report on magneto-conductance oscillations due to snake states in a ballistic suspended graphene p-n junction, which occur already at a very small magnetic field of 20 mT. The visibility of 30% is enabled by Klein collimation. Our finding is firmly supported by quantum transport simulations. We demonstrate the high tunability of the device and operate it in different magnetic field regimes. PMID- 25732246 TI - Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence. AB - The purpose of this work is to use simulated trials to study how pilot trials can be implemented in relation to bioequivalence testing, and how the use of the information obtained at the pilot stage can influence the overall chance of showing bioequivalence (power) or the chance of approving a truly bioinequivalent product (type I error). The work also covers the use of repeat pivotal trials since the difference between a pilot trial followed by a pivotal trial and a pivotal trial followed by a repeat trial is mainly a question of whether a conclusion of bioequivalence can be allowed after the first trial. Repeating a pivotal trial after a failed trial involves dual or serial testing of the bioequivalence null hypothesis, and the paper illustrates how this may inflate the type I error up to almost 10%. Hence, it is questioned if such practice is in the interest of patients. Tables for power, type I error, and sample sizes are provided for a total of six different decision trees which allow the developer to use either the observed geometric mean ratio (GMR) from the first or trial or to assume that the GMR is 0.95. In cases when the true GMR can be controlled so as not to deviate more from unity than 0.95, sequential design methods ad modum Potvin may be superior to pilot trials. The tables provide a quantitative basis for choosing between sequential designs and pivotal trials preceded by pilot trials. PMID- 25732245 TI - Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. AB - Autologous transplantation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility, and safety of iPSC-derived dopamine neurons in non-human primate models will be an important step in clinical development of cell therapy. Here, we analyzed cynomolgus monkey (CM) iPSC-derived midbrain dopamine neurons for up to 2 years following autologous transplantation in a Parkinson's disease (PD) model. In one animal, with the most successful protocol, we found that unilateral engraftment of CM-iPSCs could provide a gradual onset of functional motor improvement contralateral to the side of dopamine neuron transplantation, and increased motor activity, without a need for immunosuppression. Postmortem analyses demonstrated robust survival of midbrain-like dopaminergic neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD. PMID- 25732247 TI - Re-induction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL): Phase II results from Children's Oncology Group (COG) study ADVL04P2. AB - BACKGROUND: Given the success of immunotherapeutic approaches in hematologic malignancies, the COG designed a phase I/II study to determine whether the addition of epratuzumab (anti-CD22) to an established chemotherapy platform improves rates of second remission (CR2) in pediatric patients with B lymphoblastic leukemia (B-ALL) and early bone marrow relapse. PROCEDURE: Therapy consisted of three established blocks of re-induction chemotherapy. Epratuzumab (360 mg/m(2)/dose) was combined with chemotherapy on weekly * 4 (B1) and twice weekly * 4 [eight doses] (B2) schedules during the first re-induction block. Remission rates and minimal residual disease (MRD) status were compared to historical rates observed with the identical chemotherapy platform alone. RESULTS: CR2 was achieved in 65 and 66%, of the evaluable B1 (n = 54) and B2 patients (n = 60), respectively; unchanged from that observed historically without epratuzumab. Rates of MRD negativity (<0.01%) were 31% in B1 (P = 0.4128) and 39% in B2 patients (P = 0.1731), compared to 25% in historical controls. The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re-induction chemotherapy platform regimen alone. CONCLUSIONS: Epratuzumab was well tolerated in combination with re-induction chemotherapy. While CR2 rates were not improved compared to historical controls treated with chemotherapy alone, there was a non-significant trend towards improvement in MRD response with the addition of epratuzumab (twice weekly for eight doses) to re-induction chemotherapy. PMID- 25732248 TI - Tri-allelic pattern of short tandem repeats identifies the murderer among identical twins and suggests an embryonic mutational origin. AB - Monozygotic twins can be co-identified by genotyping of short tandem repeats (STRs); however, for distinguishing them, STR genotyping is ineffective, especially in the case of murder. Here, a rarely occurring tri-allelic pattern in the vWA locus (16, 18, 19) was identified only in the DNA of one identical twin, which could help to exonerate the innocent twin in a murder charge. This mutation was defined as primary through genotyping of the family and could be detected in blood, buccal and semen samples from the individual; however, two alternative allele-balanced di-allelic patterns (16, 18 or 16, 19) were detected in hair root sheath cells. Such a kind of segregation indicates a one-step mutation occurs in cell mitosis, which is after embryonic zygote formation and during the early development of the individual after the division of the blastocyte. Sequencing revealed the insertion between the allele 18 and 19 is a repeat unit of TAGA/TCTA (plus/minus strand), which belongs to "AGAT/ATCT"-based core repeats identified from all tri-allelic pattern reports recorded in the STR base and a detailed model was proposed for STR repeat length variation caused by false priming during DNA synthesis. Our model illustrates the possible origination of allele-balanced and unbalanced tri-allelic pattern, clarifies that the genotypes of parent-child mismatches, aberrant di-allelic patterns, and type 1 or 2 tri-allelic patterns should be considered as independent, but interconnected forms of STR mutation. PMID- 25732250 TI - Effects of mineralocorticoid receptor stimulation via fludrocortisone on memory in women with borderline personality disorder. AB - In a previous study, we found that in contrast to healthy controls, hydrocortisone administration had enhancing effects on memory in patients with borderline personality disorder (BPD). Because hydrocortisone acts on glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), it is unclear which receptor mediated these effects. The aim of the current study was to test whether more selective MR stimulation with fludrocortisone improves memory in BPD. In a placebo-controlled, randomized, within-subject, cross-over study, 39 medication-free women with BPD and 39 healthy women received placebo or 0.4mg fludrocortisone prior to cognitive testing. We measured verbal memory, visuospatial memory, and working memory. We found a significant group by fludrocortisone interaction on verbal memory and visuospatial memory. In both tests patients with BPD, but not healthy women, had impaired memory performance after fludrocortisone compared to placebo. In contrast, working memory was improved after fludrocortisone compared to placebo in both groups. Contrary to our hypothesis, we found impairing effects of MR stimulation on hippocampus mediated verbal memory and visuospatial memory in BPD but not in healthy controls. In contrast, working memory, which depends more on the prefrontal cortex, was improved after MR stimulation across groups. Future studies should systematically disentangle beneficial and adverse effects of MR stimulation in health and disease. PMID- 25732249 TI - Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation. AB - The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6h/d/21d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype. PMID- 25732251 TI - Nap sleep preserves associative but not item memory performance. AB - Many studies have shown that sleep improves memory performance, and that even short naps during the day are beneficial. Certain physiological components of sleep such as spindles and slow-wave-sleep are thought to be particularly important for memory consolidation. The aim of this experiment was to reveal the role of naps for hippocampus-dependent associative memory (AM) and hippocampus independent item memory (IM) alongside their corresponding ERP old/new effects. Participants learnt single words and word-pairs before performing an IM- and an AM-test (baseline). One group was subsequently allowed to nap (~90min) while the other watched DVDs (control group). Afterwards, both groups performed a final IM- and AM-test for the learned stimuli (posttest). IM performance decreased for both groups, while AM performance decreased for the control group but remained constant for the nap group, consistent with predictions concerning the selective impact of napping on hippocampus-dependent recognition. Putative ERP correlates of familiarity and recollection were observed in the IM posttest, whereas only the later recollection-related effect was present in the AM test. Notably, none of these effects varied with group. Positive correlations were observed between spindle density during slow-wave-sleep and AM posttest performance as well as between spindle density during non-REM sleep and AM baseline performance, showing that successful learning and retrieval both before and after sleep relates to spindle density during nap sleep. Together, these results speak for a selective beneficial impact of naps on hippocampus-dependent memories. PMID- 25732252 TI - Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio). AB - DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5nM TCDD for 1h from 4 to 5h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2, and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns. PMID- 25732253 TI - Aetiology of arthritis in hospitalised children: an observational study. AB - BACKGROUND AND OBJECTIVE: Arthritis in children has many causes and includes septic and viral arthritis, reactive arthritis and juvenile idiopathic arthritis (JIA). We aimed to describe the different types of arthritis among children hospitalised for a first episode of arthritis. DESIGN: Retrospective, descriptive case series study. SETTING: A French tertiary care centre. PATIENTS: Children under 16 years of age hospitalised for an arthritis episode between 1 January 2008 and 31 December 2009. MAIN OUTCOME MEASURES: Demographic and clinical features were compared with chi(2) or Fisher's exact tests and non-parametric tests. RESULTS: 173 children were hospitalised for a first episode of arthritis during the study period, with a male/female ratio of 1.14. The most frequent cause of hospitalisation was septic arthritis (43.4% of cases, 69.3% of which were due to Kingella kingae and 10.7% to Staphylococcus aureus). JIA was responsible for 8.1% of cases and arthritis without any definitive diagnosis for 40.4%. Median age at diagnosis was 2.7 years (IQR 0.3-14.6) and was lower in the septic arthritis group (1.5 years; 1.1-3.4) than in the JIA group (4.7 years; 2.5 10.9) (p<0.01). Septic arthritis involved a single joint in 97.3% of cases, while JIA involved four joints in 14.3% of cases and two to four joints in 28.6% of cases (p<0.01). CONCLUSIONS: Septic arthritis was the most frequent cause of arthritis in hospitalised children. Despite the increasing application of microbiological molecular methods to synovial fluid analysis, further measures are required to improve the diagnosis of arthritis of unknown cause. PMID- 25732254 TI - Pheochromocytoma presenting as hyperglycemic hyperosmolar syndrome and unusual fever. PMID- 25732255 TI - Sarsaparilla (Smilax Glabra Rhizome) Extract Inhibits Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy via Redox-Dependent ERK1/2 Pathway. AB - Cancer is still the major cause of death across the world. Regular approaches cannot effectively solve the emerging problems, including drug/radiation resistance, side effects, and therapeutic ineffectiveness. Natural dietary supplements have shown effectiveness in the prevention and treatment of cancer. Sarsaparilla (Smilax Glabra Rhizome) has growth-inhibitory effects on several cancer cell lines in vitro and in vivo, with little toxicity on normal cells. However, the mechanism underlying its function remains elusive. In the present study, we examined the anticancer activity of the supernatant of the water soluble extract (SW) from sarsaparilla. Liquid chromatography/mass spectrometry ion trap-time-of-flight (LC/MS-IT-TOF) analysis identified flavonoids, alkaloids, and phenylpropanoids as the major bioactive components of SW. SW was shown to markedly inhibit the growth of a broad spectrum of cancer cell lines in the in vitro and in vivo assays. S phase arrest, autophagy, or/and apoptosis were partly responsible for SW-induced growth inhibition. Results of microarray analysis and validation by quantitative RT-PCR indicated the involvement of oxidative stress and the MAPK1 pathway in SW-treated cells. We further found that SW destroyed intracellular-reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and supplement with N-acetylcysteine (NAC) or glutathione (GSH) significantly antagonized SW-induced S phase arrest, apoptosis, and autophagy. In addition, SW induced GSH/GSSG imbalance activated the ERK1/2 pathway, which contributed to SW induced S phase arrest, apoptosis, autophagy, and resultant growth-inhibitory effect. Together, our results provide a molecular basis for sarsaparilla as an anticancer agent. PMID- 25732256 TI - Trichomonas vaginalis infection among Iranian general population of women: a systematic review and meta-analysis. AB - Trichomonas vaginalis (T. vaginalis) is one of the main causes of vaginitis, prostatitis, and cervicitis all over the world. Little information is available regarding the burden of T. vaginalis infection in Iranian women. This systematic review and meta-analysis were carried out to determine the prevalence of T. vaginalis among general population of Iranian women. Data were systematically collected from 1992 to 2012 in Iran on such electronic databases as PubMed, Google Scholar, Science Direct, Scopus, Web of Science, Magiran, Irandoc, Iran medex, Scientific Information Database (SID), Global Health, and LILACS. Additionally, abstracts of national scientific congresses and dissertations were included. A total of 30 articles attempted to examine 70,373 individuals and reported the prevalence of trichomoniasis from different regions of Iran. The overall prevalence rate of trichomoniasis in Iran was estimated to be 8% (95% confidence interval (CI) = 0.07 to 0.09) with the maximum 38.8% (95% CI = 0.036 to 0.042) and the minimum 0.009% (95% CI = 0.008 to 0.010), respectively. Also, it was found that the prevalence in Central provinces is higher than other ones. In all studies, the average of age was 24.5 with the maximum and the minimum of 45 and 22.5 years old, respectively. The present review revealed that infection rate is relatively high among Iranian women, and risk factors such as hygienic situation, behavior and local culture, poor socioeconomic condition, feeble moral considerations, and increase in marriage age must be considered in the management of controlling programs. PMID- 25732257 TI - Characterization of the dynamics in the protonic conductor CsH2PO4 by 17O solid state NMR spectroscopy and first-principles calculations: correlating phosphate and protonic motion. AB - (17)O NMR spectroscopy combined with first-principles calculations was employed to understand the local structure and dynamics of the phosphate ions and protons in the paraelectric phase of the proton conductor CsH2PO4. For the room temperature structure, the results confirm that one proton (H1) is localized in an asymmetric H-bond (between O1 donor and O2 acceptor oxygen atoms), whereas the H2 proton undergoes rapid exchange between two sites in a hydrogen bond with a symmetric double potential well at a rate >=10(7) Hz. Variable-temperature (17)O NMR spectra recorded from 22 to 214 degrees C were interpreted by considering different models for the rotation of the phosphate anions. At least two distinct rate constants for rotations about four pseudo C3 axes of the phosphate ion were required in order to achieve good agreement with the experimental data. An activation energy of 0.21 +/- 0.06 eV was observed for rotation about the P-O1 axis, with a higher activation energy of 0.50 +/- 0.07 eV being obtained for rotation about the P-O2, P-O3(d), and P-O3(a) axes, with the superscripts denoting, respectively, dynamic donor and acceptor oxygen atoms of the H-bond. The higher activation energy of the second process is most likely associated with the cost of breaking an O1-H1 bond. The activation energy of this process is slightly lower than that obtained from the (1)H exchange process (0.70 +/- 0.07 eV) (Kim, G.; Blanc, F.; Hu, Y.-Y.; Grey, C. P. J. Phys. Chem. C 2013, 117, 6504 6515) associated with the translational motion of the protons. The relationship between proton jumps and phosphate rotation was analyzed in detail by considering uncorrelated motion, motion of individual PO4 ions and the four connected/H bonded protons, and concerted motions of adjacent phosphate units, mediated by proton hops. We conclude that, while phosphate rotations aid proton motion, not all phosphate rotations result in proton jumps. PMID- 25732258 TI - Dimeric chlorite dismutase from the nitrogen-fixing cyanobacterium Cyanothece sp. PCC7425. AB - It is demonstrated that cyanobacteria (both azotrophic and non-azotrophic) contain heme b oxidoreductases that can convert chlorite to chloride and molecular oxygen (incorrectly denominated chlorite 'dismutase', Cld). Beside the water-splitting manganese complex of photosystem II, this metalloenzyme is the second known enzyme that catalyses the formation of a covalent oxygen-oxygen bond. All cyanobacterial Clds have a truncated N-terminus and are dimeric (i.e. clade 2) proteins. As model protein, Cld from Cyanothece sp. PCC7425 (CCld) was recombinantly produced in Escherichia coli and shown to efficiently degrade chlorite with an activity optimum at pH 5.0 [kcat 1144 +/- 23.8 s(-1), KM 162 +/- 10.0 MUM, catalytic efficiency (7.1 +/- 0.6) * 10(6) M(-1) s(-1)]. The resting ferric high-spin axially symmetric heme enzyme has a standard reduction potential of the Fe(III)/Fe(II) couple of -126 +/- 1.9 mV at pH 7.0. Cyanide mediates the formation of a low-spin complex with k(on) = (1.6 +/- 0.1) * 10(5) M(-1) s(-1) and k(off) = 1.4 +/- 2.9 s(-1) (KD ~ 8.6 MUM). Both, thermal and chemical unfolding follows a non-two-state unfolding pathway with the first transition being related to the release of the prosthetic group. The obtained data are discussed with respect to known structure-function relationships of Clds. We ask for the physiological substrate and putative function of these O2 -producing proteins in (nitrogen-fixing) cyanobacteria. PMID- 25732259 TI - Metagenomic assessment of the potential microbial nitrogen pathways in the rhizosphere of a mediterranean forest after a wildfire. AB - Wildfires are frequent in the forests of the Mediterranean Basin and have greatly influenced this ecosystem. Changes to the physical and chemical properties of the soil, due to fire and post-fire conditions, result in alterations of both the bacterial communities and the nitrogen cycle. We explored the effects of a holm oak forest wildfire on the rhizospheric bacterial communities involved in the nitrogen cycle. Metagenomic data of the genes involved in the nitrogen cycle showed that both the undisturbed and burned rhizospheres had a conservative nitrogen cycle with a larger number of sequences related to the nitrogen incorporation pathways and a lower number for nitrogen output. However, the burned rhizosphere showed a statistically significant increase in the number of sequences for nitrogen incorporation (allantoin utilization and nitrogen fixation) and a significantly lower number of sequences for denitrification and dissimilatory nitrite reductase subsystems, possibly in order to compensate for nitrogen loss from the soil after burning. The genetic potential for nitrogen incorporation into the ecosystem was assessed through the diversity of the nitrogenase reductase enzyme, which is encoded by the nifH gene. We found that nifH gene diversity and richness were lower in burned than in undisturbed rhizospheric soils. The structure of the bacterial communities involved in the nitrogen cycle showed a statistically significant increase of Actinobacteria and Firmicutes phyla after the wildfire. Both approaches showed the important role of gram-positive bacteria in the ecosystem after a wildfire. PMID- 25732260 TI - Involvement of NFkappaB signaling in mediating the effects of GRK5 on neural stem cells. AB - Nuclear factor kappaB (NFkappaB) signaling plays ubiquitous roles in inflammation, immune response and neurogenesis. G protein-coupled receptor kinase 5 (GRK5) can protect neurons from degeneration. GRK5 also mediates tumor necrosis factor-alpha (TNFalpha)-induced NFkappaB signaling through the phosphorylation of IkappaBalpha. Here, we show that NFkappaB signaling is involved in neural stem cell (NSC) differentiation. The IkappaBalpha/p65 pathway was activated by phorbol myristate acetate (PMA), a stimulator of protein kinase C (PKC). Once the NFkappaB was activated, the initial stage of neural differentiation was induced, with an increased level of GRK5 in NSCs. This finding was reversed in response to the NFkappaB inhibitor N-acetyl cysteine (NAC). To evaluate the effect of GRK5 NFkappaB signaling crosstalk on NSC neurogenesis and apoptosis, GRK5 was knocked down by siRNAs in cell culture. SiRNAs against GRK5 not only impaired neural differentiation and axogenesis, but also induced apoptosis of NSC. GRK5 knockdown affected the transcription of NFkappaB, phosphorylation of the liver kinase B1 (LKB1) and the activity of caspase 3, thereby modulated neurogenesis and apoptosis. Taken together, our findings reveal a novel function of GRK5 in neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases. PMID- 25732261 TI - Viral vector mediated expression of mutant huntingtin in the dorsal raphe produces disease-related neuropathology but not depressive-like behaviors in wildtype mice. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the HTT gene (mHTT) encoding the protein huntingtin. An expansion in the gene's CAG repeat length renders a misfolded, dysfunctional protein with an abnormally long glutamine (Q) stretch at the N terminus that often incorporates into inclusion bodies and leads to neurodegeneration in many regions of the brain. HD is characterized by motor and cognitive decline as well as mood disorders, with depression being particularly common. Approximately 40% of the HD population suffers from depressive symptoms. Because these symptoms often manifest a decade or more prior to the knowledge that the person is at risk for the disease, a portion of the early depression in HD appears to be a consequence of the pathology arising from expression of the mutant gene. While the depression in HD patients is often treated with serotonin agonists, there is scant experimental evidence that the depression in HD responds well to these serotonin treatments or in a similar manner to how non-HD depression tends to respond. Additionally, at very early sub-threshold depression levels, abnormal changes in several neuronal populations are already detectable in HD patients, suggesting that a variety of brain structures may be involved. Taken together, the serotonin system is a viable candidate. However, at present there is limited evidence of the precise nuclei or circuits that play a role in HD depression. With this in mind, the current study was designed to control for the widespread brain neuropathology that occurs in HD and in transgenic mouse models of HD and focuses specifically on the influence of the midbrain dorsal raphe nucleus (DRN). The DRN provides the majority of the serotonin to the forebrain and exhibits cell loss in non-HD depression. Therefore, we employed a viral vector delivery system to investigate whether the over-expression of mHTT in the DRN's ventral sub-nuclei alone is sufficient to produce depressive-like behaviors. Wildtype mice were injected with an adeno-associated virus (AAV2/1) encoding HTT containing either a pathogenic (N171-82Q) or control (N171-16Q) CAG repeat length into the ventral DRN and depressive-like behaviors and motor behaviors were assessed for 12 weeks post surgery. Quantitative PCR and immunohistochemistry (IHC) verified positive transduction in the ventral aspects of the DRN, including the ventral sub-nucleus (DRv) and interfascicular sub-nucleus (DRif). IHC demonstrated microgliosis in and around the injection site and mHTT-positive inclusions in serotonin-producing neurons and a small percentage of astrocytes in animals injected with N171-82Q compared to controls. Moreover, N171-82Q injected mice showed a 75% reduction in cells that stained positive for the serotonin synthesis enzyme, tryptophan hydroxylase-2 (TPH2) compared to controls (p<0.05). Despite mHTT-mediated pathology in the DRv and DRif, no significant changes in depressive-like behavior were detected. Consequently, we conclude that 12 weeks of N171-82Q expression in the ventral sub-nuclei of the DRN of wildtype mice causes characteristic disease related cellular neuropathology but is not sufficient to elicit depressive-like behaviors. Ongoing studies are investigating whether a larger injection volume that transfects a larger percentage of the DRN and/or a longer time course of mHTT expression might elicit depressive-like behaviors. Moreover, mHTT expression in other regions of the brain, such as the hippocampal dentate gyrus and/or the frontal cortex might be necessary to elicit HD depression. Together, these results may prove helpful in addressing which therapeutic and/or pharmacological strategies might be most efficacious when treating depressive symptomology in patients suffering from HD. PMID- 25732262 TI - A dietary supplement improves facial photoaging and skin sebum, hydration and tonicity modulating serum fibronectin, neutrophil elastase 2, hyaluronic acid and carbonylated proteins. AB - BACKGROUND AND AIMS: Excessive exposure to the sun can cause severe photoaging as early as the second decade of life resulting in a loss of physiological elastic fiber functions. We designed a first study to assess differences in facial skin pH, sebum, elasticity, hydration and tonicity and serum levels of fibronectin, elastin, neutrophil elastase 2, hyaluronic acid and carbonylated proteins between patients affected by facial photoaging and healthy controls. In a second study we tested the hypothesis that a dietary supplement would improve facial photoaging, also promoting changes in the above mentioned skin and serum parameters. METHODS: In the first study we enrolled 30 women [age: 47.5 +/- 1.6 years (mean +/- standard error of the mean)] affected by moderate facial photoaging (4 cm <= Visual Analogue Scale (VAS)<7 cm) and 30 healthy women [age: 45.9 +/- 1.6 years (mean +/- standard error of the mean)]. In the second study we enrolled a cohort of 30 women [age: 43.6 +/- 1.2 years (mean +/- standard error of the mean)], affected by moderate (n = 22) and severe (VAS >= 7 cm; n = 8) facial photoaging, who were randomized to receive a pharmaceutical formulation (VISCODERM Pearls; IBSA FARMACEUTICI ITALIA Srl, Lodi, Italy) containing Pycnogenol, collagen, coenzyme Q10, low-molecular-weight hyaluronic acid, chondroitin sulfate and glucosamine sulfate (n = 15) or placebo (n = 15). Dietary supplement and placebo were administered 2 times a day for 4 weeks. Facial photoaging was assessed by VAS in the first cohort of patients affected by facial photoaging and healthy controls and, at baseline and 2 weeks after the end of treatment, in the second cohort of patients who underwent treatment with VISCODERM Pearls and placebo. Skin Tester was used to analyze differences in facial skin parameters between patients affected by facial photoaging and healthy controls. Skin Tester was also used to assess the effect of VISCODERM Pearls on facial skin parameters and compared with placebo 2 weeks after the end of treatment. Serum levels of fibronectin, elastin, neutrophil elastase 2, hyaluronic acid and carbonylated proteins were measured by enzyme-linked immunosorbent assay in the first cohort of patients affected by facial photoaging and healthy controls and, at baseline and 2 weeks after the end of treatment, in the second cohort of patients who underwent treatment with VISCODERM Pearls and placebo. RESULTS: VAS photoaging score was higher in patients affected by photoaging, if compared with healthy controls (p < 0.0001). pH and sebum were increased in patients affected by photoaging, if compared with healthy controls (both p < 0.0001), while elasticity, hydration and tonicity were decreased in patients affected by photoaging, if compared with healthy controls (all p < 0.0001). Serum fibronectin and hyaluronic acid concentrations were lower in patients affected by photoaging, if compared with healthy controls (both p < 0.0001). Serum neutrophil elastase 2, elastin and carbonylated protein concentrations were higher in patients affected by photoaging, if compared with healthy controls (p < 0.01, p < 0.01 and p < 0.0001, respectively). Dietary supplement administration resulted in an improvement in VAS photoaging score, if compared with placebo (p < 0.0001), as observed 2 weeks after the end of treatment. Facial sebum, hydration and tonicity were increased in the active treatment group vs. placebo (p < 0.0001, p < 0.0001 and p < 0.05, respectively) 2 weeks after the end of treatment. Serum fibronectin and hyaluronic acid concentrations were increased in the dietary supplement group, if compared with placebo (p < 0.01 and p < 0.001) 2 weeks after the end of treatment, while no statistical difference in serum elastin concentration was observed between the two groups. Serum neutrophil elastase 2 and carbonylated protein concentrations were decreased in the dietary supplement group 2 weeks after the end of treatment, if compared with placebo (p < 0.001 and p < 0.0001). CONCLUSIONS: We found significantly increased serum levels of neutrophil elastase 2, elastin and carbonylated proteins and decreased levels of hyaluronic acid and fibronectin in patients affected by facial photoaging, if compared with healthy controls. These findings coupled with a significant decrease in skin hydration, tonicity and elasticity and increased skin pH and sebum. Treatment with the dietary supplement VISCODERM Pearls significantly improved VAS photoaging score and skin hydration, sebum and tonicity 2 weeks after the end of a 4-week treatment period in patients affected by moderate to severe facial photoaging. These findings coupled with a significant increase in serum fibronectin and hyaluronic acid and a decrease in serum carbonylated proteins and neutrophil elastase 2 in the active treatment group, if compared with placebo. Our findings suggest that VISCODERM Pearls is effective for treatment of facial photoaging but further studies in larger cohorts of patients are required. PMID- 25732264 TI - Pemetrexed and gemcitabine versus carboplatin and gemcitabine in non-small cell lung cancer: a randomized noninferiority phase II study in one center. AB - BACKGROUND: The standard treatment for non-small cell lung cancer (NSCLC) stages IIIb and IV is a platinum compound combined with a third-generation cytotoxic agent. We decided to conduct a phase II study to assess whether the platinum compound could be replaced with pemetrexed with similar results and without an increase in side effects. METHODS: Consecutive eligible patients were randomized to either the standard arm of gemcitabine plus carboplatin (GC) or the experimental arm of gemcitabine plus pemetrexed (GP). RESULTS: Fifty evaluable patients were enrolled in the GC arm, and 44 received GP. There were 10 partial responses in the GC arm and 16 in the GP arm. With GC, mean survival was 9 months compared with 15 months with GP. The side effects were similar in both groups. CONCLUSION: Pemetrexed can replace platinum compounds in the first-line treatment of stage IIIb and IV NSCLC without increasing the side effects. A trend toward better survival was observed in the patients receiving pemetrexed instead of a platinum compound, and this should be studied further. PMID- 25732263 TI - Systematic literature review and network meta-analysis comparing bone-targeted agents for the prevention of skeletal-related events in cancer patients with bone metastasis. AB - BACKGROUND: Complications from skeletal-related events (SREs) constitute a challenge in the care of cancer patients with bone metastasis (BM). OBJECTIVES: This study evaluated the comparative effectiveness of pamidronate, ibandronate, zoledronate, and denosumab in reducing the morbidity of SREs in cancer patients with BM. METHODS: Medline (1948 to January 2014), Embase (1980 to January 2014), the Cochrane Library (2014 issue 1), and Web of Science with Conference Proceedings (1970 to January 2014) were searched. Only randomized controlled trials assessing denosumab, bisphosphonates, or placebo in cancer patients with BM were included. The primary outcomes were SREs and SREs by type. The network meta-analysis (NMA) was performed with a random-effects Bayesian model. RESULTS: The NMA included 14 trials with 10,192 patients. Denosumab was superior to placebo in reducing the risk of SREs (odds ratio [OR]: 0.49; 95% confidence interval [CI]: 0.31-0.75), followed by zoledronate (OR: 0.57; 95% CI: 0.41-0.77) and pamidronate (OR: 0.55; 95% CI: 0.41-0.72). Ibandronate compared with placebo could not reduce the risk of SREs. Denosumab was superior to placebo in reducing the risk of pathologic fractures (OR: 0.50; 95% CI: 0.32-0.79), followed by zoledronate (OR: 0.61; 95% CI: 0.43-0.86). Denosumab was superior to placebo in reducing the risk of radiation (OR: 0.51; 95% CI: 0.35-0.75), followed by pamidronate (OR: 0.67; 95% CI: 0.52-0.86) and zoledronate (OR: 0.70; 95% CI: 0.52 0.96). CONCLUSION: This NMA showed that denosumab, zoledronate, and pamidronate were generally effective in preventing SREs in cancer patients with BM. Denosumab and zoledronate were also associated with reductions in the risk of pathologic fractures and radiation compared with placebo. Denosumab was shown to be the most effective of the bone-targeted agents. PMID- 25732266 TI - Authors' reply: pharmacokinetic and pharmacodynamic drug interactions between antiretrovirals and oral contraceptives. PMID- 25732265 TI - Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials. AB - BACKGROUND: Randomized clinical trials (RCT) that evaluated the addition of lapatinib to trastuzumab plus neoadjuvant chemotherapy (NAC) in patients with HER2-positive, operable breast cancer revealed a questionable improvement in pathologic complete response (pCR) rate. We performed a meta-analysis of prospective RCTs that examined the effect of adding lapatinib to trastuzumab and NAC on pCR rate. METHODS: PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs that compared lapatinib plus trastuzumab and NAC with trastuzumab in combination with NAC and that included pCR as the primary outcome. Our main objective was to estimate the effect of adding lapatinib to trastuzumab plus NAC on pCR rate, defined as no residual invasive cancer in breast and axillary lymph nodes. RESULTS: In total, 1,017 patients with early stage breast cancer from 5 trials were included. Four trials examined the addition of lapatinib to trastuzumab plus NAC; this resulted in statistically significant improvement in pCR, defined as no residual carcinoma in breast and lymph nodes. The pCR rate was 55.76% and 38.36% in the lapatinib plus trastuzumab and the trastuzumab plus NAC arms, respectively (odds ratio [OR]: 1.94; 95% confidence interval [CI]: 1.44-2.60). In three trials, the rates of pCR, defined as no residual invasive carcinoma in breast only, for the lapatinib plus trastuzumab and trastuzumab-alone groups were 55.01% and 40.70%, respectively, also resulting in significant improvement (OR: 1.78; 95% CI: 1.27-2.50). CONCLUSION: The addition of lapatinib to trastuzumab in combination with neoadjuvant chemotherapy significantly improves pCR rates in patients with HER2 positive breast cancer. PMID- 25732267 TI - Advances in pharmacotherapy for treating female sexual dysfunction. AB - INTRODUCTION: 'Female sexual dysfunction' (FSD) is an umbrella term comprising a range of common disorders, including hypoactive sexual desire, reduced subjective and/or physical genital arousal (poor sensation, vasocongestion, lubrication), sexual pain and inability to achieve orgasm/satisfaction, which are multidimensional by nature and often coexisting. Psychological and contextual factors have a significant influence on organic components of sexual response and behavior and a tailored medical approach to sexual symptoms is inevitably limited. AREAS COVERED: The paper reports the most recent advances in pharmacotherapy for women taking into account the biopsychosocial model. Hormone therapy, including estrogens, testosterone, tibolone and dehydroepiandrosterone, are discussed in term of efficacy and safety in postmenopausal women both for female sexual interest/arousal disorder (FSIAD) and genito-pelvic pain/penetration disorder. Ospemifene, a selective estrogen receptor modulator, approved to treat dyspareunia at menopause, is also discussed. Data on psychoactive agents for treatment of FSIAD in premenopausal women are discussed, including the potential use of on-demand combined hormonal (testosterone) and non hormonal (buspirone or sildenafil) treatments to address possible neurophysiological profiles of women. EXPERT OPINION: We are still waiting for an approved pharmacotherapy for FSD. This is not the result of gender inequality in sexual medicine, but it reflects the need of balancing benefits and risks in order to provide effective and safe treatments to women of any age. PMID- 25732268 TI - Compassionate access anti-tumour necrosis factor-alpha therapy for ulcerative colitis in Australia: the benefits to patients. AB - BACKGROUND: The efficacy of infliximab has been demonstrated in patients with both acute severe and moderate-severe ulcerative colitis (UC). However, there is a need for 'real-life data' to ensure that conclusions from trial settings are applicable in usual care. We therefore examined the national experience of anti tumour necrosis factor-alpha (TNF-alpha) therapy in UC. METHODS: Case notes review of patients with UC who had received compassionate access (CA) anti-TNF alpha therapy from prospectively maintained inflammatory bowel disease databases of six Australian adult teaching hospitals. RESULTS: Patients either received drug for acute severe UC (ASUC) failing steroids (n = 29) or for medically refractory UC (MRUC) (n = 35). In ASUC, the treating physicians judged that anti TNF-alpha therapy was successful in 20/29 patients (69%); in these cases, anti TNF-alpha was able to be discontinued (after 1-3 infusions in 19/20 responders) as clinical remission was achieved. Consistent with this perceived benefit, only 7/29 (24%) subsequently underwent colectomy during a median follow up of 12 months (interquartile range (IQR) 5-16). Eight of the 35 patients with MRUC (23%) required colectomy during a median follow up of 28 months (IQR 11-43). The majority of these patients (20/35 or 57%) had anti-TNF-alpha therapy for >=4 months, whereas, 27/29 (93%) of ASUC patients had CA for <=3 months. CONCLUSIONS: These data show an excellent overall benefit for anti-TNF-alpha therapy in both ASUC and MRUC. In particular, only short-duration anti-TNF-alpha was required in ASUC. These real-life data thus support the clinical trial data and should lead to broader use of this therapy in UC. PMID- 25732269 TI - The perennial problem of variability in adenosine triphosphate (ATP) tests for hygiene monitoring within healthcare settings. AB - OBJECTIVE: To investigate the reliability of commercial ATP bioluminometers and to document precision and variability measurements using known and quantitated standard materials. METHODS: Four commercially branded ATP bioluminometers and their consumables were subjected to a series of controlled studies with quantitated materials in multiple repetitions of dilution series. The individual dilutions were applied directly to ATP swabs. To assess precision and reproducibility, each dilution step was tested in triplicate or quadruplicate and the RLU reading from each test point was recorded. Results across the multiple dilution series were normalized using the coefficient of variation. RESULTS: The results for pure ATP and bacterial ATP from suspensions of Staphylococcus epidermidis and Pseudomonas aeruginosa are presented graphically. The data indicate that precision and reproducibility are poor across all brands tested. Standard deviation was as high as 50% of the mean for all brands, and in the field users are not provided any indication of this level of imprecision. CONCLUSIONS: The variability of commercial ATP bioluminometers and their consumables is unacceptably high with the current technical configuration. The advantage of speed of response is undermined by instrument imprecision expressed in the numerical scale of relative light units (RLU). PMID- 25732270 TI - "Because I was sick": seriously ill veterans' perspectives on reason for 30-day readmissions. AB - OBJECTIVES: To determine the perspectives of seriously ill individuals on reasons for 30-day hospital readmission. DESIGN: A prospective qualitative study was conducted employing individual interviews conducted at bedside. SETTING: Department of Veterans Affairs Greater Los Angeles Healthcare System. PARTICIPANTS: Seriously ill individuals with heart failure or cancer receiving inpatient palliative care and readmitted to the hospital within 30 days of hospital discharge were recruited to participate. Nine were interviewed. MEASUREMENTS: A semistructured interview protocol was used to elicit participant perspectives on readmission causes. RESULTS: All participants were male and had a mean age of 70.1+/-9.5. Participants were ethnically diverse (three African Americans, three Caucasians, three Hispanic or mixed ethnic background). Six lived alone, and four did not have caregiver support. Qualitative analysis of transcripts revealed three themes relating to reasons for hospital readmission: lack of caregiver support and motivation to provide self-care, acceptance of condition and desire for aggressive care, and access to care and poor quality of care. CONCLUSION: Participants identified potentially avoidable reasons for hospital readmission as well as causes that require rethinking regarding how community support is targeted and delivered. Participant preference for aggressive care, inability to provide self-care, and lack of caregiver support suggest the need for new and innovative mechanisms to support seriously ill community-dwelling individuals. PMID- 25732271 TI - Duodenum-preserving total and partial pancreatic head resection for benign tumors -systematic review and meta-analysis. AB - BACKGROUND: Potential benefits of local extirpation of benign pancreatic head tumors are tissue conservation of pancreas, stomach, duodenum and common bile duct (CBD) and maintenance of pancreatic functions. METHODS: Medline/PubMed, Embase and Cochrane Library databases were searched to identify studies applying duodenum-preserving total or partial pancreatic-head resection (DPPHRt/p) and reporting short- and long-term outcomes. Twenty-four studies, including 416 patients who underwent DPPHRt/p, were identified for systematic analysis. The meta-analysis was based on 10 prospective controlled and 4 retrospective controlled cohort studies, comparing 293 DPPHRt/p resections with 372 pancreato duodenectomies (PD). RESULTS, SYSTEMATIC ANALYSIS: Of 416 patients, 75.7% underwent total and 24.3% partial head resection, while 47.1% included segmentectomy of duodenum and CBD. The most common pathology was cystic neoplasm (65.8%) and endocrine tumors (13.4%). The frequencies of severe postoperative complications of 8.8%, pancreatic fistula of 19.2%, re-operation of 1.7% and hospital mortality of 0.48%, indicate a low level of early post-operative complications. META-ANALYSIS: DPPHRt/p significantly preserved the level of exocrine (IV = -0.67, 95% CI -0.98 to -0.35, p = 0.0001) and endocrine (IV = 18.20, fixed, 95% CI -0.92 to 25.48, p = 0.0001) pancreatic functions compared to PD when the pre- and postoperative functional status in both groups are analyzed. There were no significant differences between DPPHRt/p and PD in frequency of pancreatic fistula, delayed gastric emptying or hospital mortality. CONCLUSION: DPPHRt/p for benign neoplasms and neuro-endocrine tumors of the pancreatic head is associated with a low level of early-postoperative complications and a better conservation of exocrine and endocrine functions. PMID- 25732272 TI - Shared locations of TB cases: places of acquisition or transmission of infection? PMID- 25732273 TI - Effects of exercise amount and intensity on abdominal obesity and glucose tolerance in obese adults: a randomized trial. AB - BACKGROUND: Exercise reduces obesity and related glucose tolerance, but whether increasing exercise intensity offers additional benefit at fixed exercise amounts is unknown. OBJECTIVE: To determine the separate effects of exercise amount and intensity on abdominal obesity and glucose tolerance. DESIGN: 24-week, single center, parallel-group trial from 2009 to 2013. (ClinicalTrials.gov: NCT00955071). SETTING: Kingston, Ontario, Canada. PARTICIPANTS: 300 abdominally obese adults. INTERVENTION: Control (no exercise) (n = 75) or 5 weekly sessions of low-amount, low-intensity exercise (LALI) (180 and 300 kcal/session for women and men, respectively, at 50% of maximum oxygen consumption [Vo2peak]) (n = 73); high-amount, low-intensity exercise (HALI) (360 and 600 kcal/session, respectively, at 50% of Vo2peak) (n = 76); or high-amount, high-intensity exercise (HAHI) (360 and 600 kcal/session, respectively, at 75% of Vo2peak) (n = 76). Daily unsupervised physical activity and sedentary time were measured by accelerometer. MEASUREMENTS: Waist circumference and 2-hour glucose level (primary outcomes) and cardiorespiratory fitness and measures of insulin action (secondary measurements). RESULTS: 217 participants (72.3%) completed the intervention. Mean exercise time in minutes per session was 31 (SD, 4.4) for LALI, 58 (SD, 7.6) for HALI, and 40 (SD, 6.2) for HAHI. Daily unsupervised physical activity and sedentary time did not change in any exercise group versus control (P > 0.33). After adjustment for age and sex in a linear mixed model, reductions in waist circumference were greater in the LALI (-3.9 cm [95% CI, -5.6 to -2.3 cm]; P < 0.001), HALI (-4.6 cm [CI, -6.2 to -3.0 cm]; P < 0.001), and HAHI (-4.6 cm [CI, -6.3 to -2.9 cm]; P < 0.001) groups than the control group but did not differ among the exercise groups (P > 0.43). After adjustment for covariates, reductions in 2-hour glucose level were greater in the HAHI group ( 0.7 mmol/L [-12.5 mg/dL] [CI, -1.3 to -0.1 mmol/L {-23.5 to -1.5 mg/dL}]; P = 0.027) than the control group but did not differ for the LALI or HALI group versus the control group (P > 0.159). Weight loss was greater in all exercise groups than the control group (P < 0.001); however, reduction in body weight did not differ among the exercise groups (P > 0.182). LIMITATION: The clinical importance of reducing 2-hour glucose level in nondiabetic adults remains undetermined. CONCLUSION: Fixed amounts of exercise independent of exercise intensity resulted in similar reductions in abdominal obesity. Reduction in 2 hour glucose level was restricted to high-intensity exercise. PMID- 25732274 TI - Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. AB - BACKGROUND: The negative health effects of cigarette smoking and HIV infection are synergistic. OBJECTIVE: To compare the prevalence of current cigarette smoking and smoking cessation between adults with HIV receiving medical care and adults in the general population. DESIGN: Nationally representative cross sectional surveys. SETTING: United States. PATIENTS: 4217 adults with HIV who participated in the Medical Monitoring Project and 27 731 U.S. adults who participated in the National Health Interview Survey in 2009. MEASUREMENTS: The main exposure was cigarette smoking. The outcome measures were weighted prevalence of cigarette smoking and quit ratio (ratio of former smokers to the sum of former and current smokers). RESULTS: Of the estimated 419 945 adults with HIV receiving medical care, 42.4% (95% CI, 39.7% to 45.1%) were current cigarette smokers, 20.3% (CI, 18.6% to 22.1%) were former smokers, and 37.3% (CI, 34.9% to 39.6%) had never smoked. Compared with the U.S. adult population, in which an estimated 20.6% of adults smoked cigarettes in 2009, adults with HIV were nearly twice as likely to smoke (adjusted prevalence difference, 17.0 percentage points [CI, 14.0 to 20.1 percentage points]) but were less likely to quit smoking (quit ratio, 32.4% vs. 51.7%). Among adults with HIV, factors independently associated with greater smoking prevalence were older age, non-Hispanic white or non Hispanic black race, lower educational level, poverty, homelessness, incarceration, substance use, binge alcohol use, depression, and not achieving a suppressed HIV viral load. LIMITATION: Cross-sectional design with some generalizability limitations. CONCLUSION: Adults with HIV were more likely to smoke and less likely to quit smoking than the general adult population. Tobacco screening and cessation strategies are important considerations as part of routine HIV care. PMID- 25732276 TI - The state of research funding from the National Institutes of Health for criminal justice health research. AB - BACKGROUND: Over 20 million Americans are currently or have been incarcerated. Most are from medically underserved populations; 1 in 3 African American men and 1 in 6 Latino men born in 2001 are projected to go to prison during their lifetime. The amount of funding from the National Institutes of Health (NIH) to understand and improve the health of persons involved with the criminal justice system is unknown. OBJECTIVE: To describe NIH funding for research on the health and health care needs of criminal justice-involved persons. DESIGN: Review of NIH grants (2008-2012) in the RePORT (Research Portfolio Online Reporting Tools) database. SETTING: U.S. criminal justice system. PATIENTS: Criminal justice involved persons participating in NIH-funded clinical research. MEASUREMENTS: NIH research and training grants awarded, by number, type, research area, institute or center, and dollar amount. RESULTS: Of more than 250 000 NIH-funded grants, 180 (<0.1%) focused on criminal justice health research. The 3 most common foci were substance use or HIV (64%), mental health (11%), and juvenile health (8%). The National Institute on Drug Abuse and the National Institute of Mental Health funded 78% of all grants. In 2012, the NIH invested $40.9 million in criminal justice health research, or 1.5% of the $2.7 billion health disparities budget for that year. LIMITATION: NIH-supported research that did not explicitly include current or former prisoners but may have relevance to criminal justice health was not included. CONCLUSION: Federal funding for research focused on understanding and improving the health of criminal justice-involved persons is small, even compared with the NIH's overall investment in health disparities research. The NIH is well-positioned to transform the care of current and former prisoners by investing in this critical yet overlooked research area. PMID- 25732277 TI - Relationships between Medicare Advantage contract characteristics and quality-of care ratings: an observational analysis of Medicare Advantage star ratings. AB - BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) publishes star ratings on Medicare Advantage (MA) contracts to measure plan quality of care with implications for reimbursement and bonuses. OBJECTIVE: To investigate whether MA contract characteristics are associated with quality of care through the Medicare plan star ratings. DESIGN: Retrospective study of MA star ratings in 2010. Unadjusted and adjusted multivariable linear regression models assessed the relationship between 5-star rating summary scores and plan characteristics. SETTING: CMS MA contracts nationally. PARTICIPANTS: 409 (71%) of a total of 575 MA contracts, covering 10.56 million Medicare beneficiaries (90% of the MA population) in the United States in 2010. MEASUREMENTS: The MA quality ratings summary score (stars range from 1 to 5) is a quality measure based on 36 indicators related to processes of care, health outcomes, access to care, and beneficiary satisfaction. RESULTS: Nonprofit, larger, and older MA contracts were more likely to receive higher star ratings. Star ratings ranged from 2 to 5. Nonprofit contracts received an average 0.55 (95% CI, 0.42 to 0.67) higher star ratings than for-profit contracts (P < 0.001) after controls were set for contract characteristics. LIMITATION: The study focused on persons aged 65 years or older covered by MA. CONCLUSION: In 2010, nonprofit MA contracts received significantly higher star ratings than for-profit contracts. When comparing health plans in the future, the CMS should give increasing attention to for profit plans with lower quality ratings and consider developing programs to assist newer and smaller plans in improving their care for Medicare beneficiaries. PRIMARY FUNDING SOURCE: None. PMID- 25732278 TI - Risk assessment and prevention of pressure ulcers: a clinical practice guideline from the American College of Physicians. AB - DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations based on the comparative effectiveness of risk assessment scales and preventive interventions for pressure ulcers. METHODS: This guideline is based on published literature on this topic that was identified by using MEDLINE (1946 through February 2014), CINAHL (1998 through February 2014), the Cochrane Library, clinical trials registries, and reference lists. Searches were limited to English-language publications. The outcomes evaluated for this guideline include pressure ulcer incidence and severity, resource use, diagnostic accuracy, measures of risk, and harms. This guideline grades the quality of evidence and strength of recommendations by using ACP's clinical practice guidelines grading system. The target audience for this guideline includes all clinicians, and the target patient population is patients at risk for pressure ulcers. RECOMMENDATION 1: ACP recommends that clinicians should perform a risk assessment to identify patients who are at risk of developing pressure ulcers. (Grade: weak recommendation, low quality evidence). RECOMMENDATION 2: ACP recommends that clinicians should choose advanced static mattresses or advanced static overlays in patients who are at an increased risk of developing pressure ulcers. (Grade: strong recommendation, moderate-quality evidence). RECOMMENDATION 3: ACP recommends against using alternating-air mattresses or alternating-air overlays in patients who are at an increased risk of developing pressure ulcers. (Grade: weak recommendation, moderate-quality evidence). PMID- 25732279 TI - Treatment of pressure ulcers: a clinical practice guideline from the American College of Physicians. AB - DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations based on the comparative effectiveness of treatments of pressure ulcers. METHODS: This guideline is based on published literature on this topic that was identified by using MEDLINE, EMBASE, CINAHL, EBM Reviews, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and the Health Technology Assessment database through February 2014. Searches were limited to English-language publications. The outcomes evaluated for this guideline include complete wound healing, wound size (surface area, volume, and depth) reduction, pain, prevention of sepsis, prevention of osteomyelitis, recurrence rate, and harms of treatment (including but not limited to pain, dermatologic complications, bleeding, and infection). This guideline grades the quality of evidence and strength of recommendations by using ACP's clinical practice guidelines grading system. The target audience for this guideline includes all clinicians, and the target patient population is patients with pressure ulcers. RECOMMENDATION 1: ACP recommends that clinicians use protein or amino acid supplementation in patients with pressure ulcers to reduce wound size. (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 2: ACP recommends that clinicians use hydrocolloid or foam dressings in patients with pressure ulcers to reduce wound size. (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 3: ACP recommends that clinicians use electrical stimulation as adjunctive therapy in patients with pressure ulcers to accelerate wound healing. (Grade: weak recommendation, moderate-quality evidence). PMID- 25732280 TI - Major concepts of health care economics. AB - This article applies major economic concepts, such as supply, demand, monopoly, monopsony, adverse selection, and moral hazard, to central features of U.S. health care. These illustrations help explain some of the principal problems of health policy-high cost and the uninsured-and why solutions are difficult to obtain. PMID- 25732282 TI - Celebrating the ACP centennial: from the Annals archive. PMID- 25732283 TI - Endurance exercise: more pain, more metabolic gain. PMID- 25732284 TI - Pressure ulcer prevention and management: a dire need for good science. PMID- 25732285 TI - Healing the enemy: the personal narrative of an Israeli surgeon. PMID- 25732286 TI - Effects of low-carbohydrate and low-fat diets. PMID- 25732287 TI - Effects of low-carbohydrate and low-fat diets. PMID- 25732288 TI - Effects of low-carbohydrate and low-fat diets. PMID- 25732289 TI - Effects of low-carbohydrate and low-fat diets. PMID- 25732291 TI - Effects of low-carbohydrate and low-fat diets. PMID- 25732292 TI - Treatment of latent tuberculosis infection. PMID- 25732294 TI - Treatment of latent tuberculosis infection. PMID- 25732295 TI - Treatment of latent tuberculosis infection. PMID- 25732296 TI - The association between confidence and accuracy among users of a mobile web platform for medical education. PMID- 25732297 TI - Progress and challenges in electronic health record adoption: findings from a national survey of physicians. PMID- 25732298 TI - Summaries for patients.Effect of higher-intensity exercise on weight loss and waist circumference. PMID- 25732299 TI - Summaries for patients. Risk assessment and prevention of pressure ulcers. PMID- 25732300 TI - Summaries for patients. Treatment of pressure ulcers. PMID- 25732301 TI - In the clinic. Type 2 diabetes. AB - This issue provides a clinical overview of Type 2 Diabetes focusing on prevention, diagnosis, treatment, practice improvement, and patient information. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including ACP Smart Medicine and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from ACP Smart Medicine and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult http://smartmedicine.acponline.org, http://mksap.acponline.org, and other resources referenced in each issue of In the Clinic. PMID- 25732302 TI - Trophic cascades from wolves to grizzly bears or changing abundance of bears and alternate foods? AB - This is a Forum article commenting on: Ripple, W. J., Beschta, R. L., Fortin, J. K., & Robbins, C. T. (2014) Trophic cascades from wolves to grizzly bears in Yellowstone. Journal of Animal Ecology, 83, 223-233. Comparisons Ripple et al. (2014) used to demonstrate increased fruit availability and consumption by grizzly bears post-wolf reintroduction are flawed and tenuous at best. Importantly, a more parsimonious (than trophic cascades) hypothesis, not sufficiently considered by Ripple et al., exists and is better supported by available data I review. PMID- 25732303 TI - Epithelial NAIPs protect against colonic tumorigenesis. AB - NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6(Delta/Delta)), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6(Delta/Delta) mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6(Delta/Delta) mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6(Delta/Delta) mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6(Delta/Delta) mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis. PMID- 25732304 TI - Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. AB - Failure of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to kill target cells by perforin (Prf)/granzyme (Gzm)-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, Prf deficient infants suffer a fatal "cytokine storm" resulting from macrophage overactivation, but the link to failed target cell death is not understood. We show that prolonged target cell survival greatly amplifies the quanta of inflammatory cytokines secreted by CTLs/NK cells and that interferon-gamma (IFN gamma) directly invokes the activation and secondary overproduction of proinflammatory IL-6 from naive macrophages. Furthermore, using live cell microscopy to visualize hundreds of synapses formed between wild-type, Prf-null, or GzmA/B-null CTLs/NK cells and their targets in real time, we show that hypersecretion of IL-2, TNF, IFN-gamma, and various chemokines is linked to failed disengagement of Prf- or Gzm-deficient lymphocytes from their targets, with mean synapse time increased fivefold, from ~8 to >40 min. Surprisingly, the signal for detachment arose from the dying target cell and was caspase dependent, as delaying target cell death with various forms of caspase blockade also prevented their disengagement from fully competent CTLs/NK cells and caused cytokine hypersecretion. Our findings provide the cellular mechanism through which failed killing by lymphocytes causes systemic inflammation involving recruitment and activation of myeloid cells. PMID- 25732305 TI - TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. AB - Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics. PMID- 25732307 TI - Electrogenerated chemiluminescence biosensing for the detection of prostate PC-3 cancer cells incorporating antibody as capture probe and ruthenium complex labelled wheat germ agglutinin as signal probe. AB - A highly selective and sensitive electrogenerated chemiluminescence (ECL) biosensor for the detection of prostate PC-3 cancer cells was designed using a prostate specific antibody as a capture probe and ruthenium complex-labelled wheat germ agglutinin as a signal probe. The ECL biosensor was fabricated by covalently immobilising the capture probe on a graphene oxide-coated glassy carbon electrode. Target PC-3 cells were selectively captured on the surface of the biosensor, and then, the signal probe was bound with the captured PC-3 cells to form a sandwich. In the presence of tripropylamine, the ECL intensity of the sandwich biosensor was logarithmically directly proportion to the concentration of PC-3 cells over a range from 7.0*10(2) to 3.0*10(4) cells mL(-1), with a detection limit of 2.6*10(2) cells mL(-1). The ECL biosensor was also applied to detect prostate specific antigen with a detection limit of 0.1 ng mL(-1). The high selectivity of the biosensor was demonstrated in comparison with that of a lectin-based biosensor. The strategy developed in this study may be a promising approach and could be extended to the design of ECL biosensors for highly sensitive and selective detection of other cancer-related cells or cancer biomarkers using different probes. PMID- 25732306 TI - Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. AB - Pancreatic cancer has an extremely high mortality rate due to its aggressive metastatic nature. Resolving the underlying mechanisms will be crucial for treatment. Here, we found that overexpression of IL-17B receptor (IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients. Consistently, results from ex vivo experiments further validated that IL-17RB and its ligand, IL-17B, plays an essential role in pancreatic cancer metastasis and malignancy. Signals from IL-17B-IL-17RB activated CCL20/CXCL1/IL-8/TFF1 chemokine expressions via the ERK1/2 pathway to promote cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival at distant organs. Treatment with a newly derived monoclonal antibody against IL-17RB blocked tumor metastasis and promoted survival in a mouse xenograft model. These findings not only illustrate a key mechanism underlying the highly aggressive characteristics of pancreatic cancer but also provide a practical approach to tackle this disease. PMID- 25732308 TI - Determination of detergent and dispensant additives in gasoline by ring-oven and near infrared hypespectral imaging. AB - A method using the ring-oven technique for pre-concentration in filter paper discs and near infrared hyperspectral imaging is proposed to identify four detergent and dispersant additives, and to determine their concentration in gasoline. Different approaches were used to select the best image data processing in order to gather the relevant spectral information. This was attained by selecting the pixels of the region of interest (ROI), using a pre-calculated threshold value of the PCA scores arranged as histograms, to select the spectra set; summing up the selected spectra to achieve representativeness; and compensating for the superimposed filter paper spectral information, also supported by scores histograms for each individual sample. The best classification model was achieved using linear discriminant analysis and genetic algorithm (LDA/GA), whose correct classification rate in the external validation set was 92%. Previous classification of the type of additive present in the gasoline is necessary to define the PLS model required for its quantitative determination. Considering that two of the additives studied present high spectral similarity, a PLS regression model was constructed to predict their content in gasoline, while two additional models were used for the remaining additives. The results for the external validation of these regression models showed a mean percentage error of prediction varying from 5 to 15%. PMID- 25732309 TI - Polybutylene terephthalate-nickel oxide nanocomposite as a fiber coating. AB - A highly efficient polybutylene terephthalate (PBT)-based nanocomposite containing nickel oxide nanoparticles was synthesized by electrospinning technique and used as a fiber coating for solid phase microextraction. The influential morphological parameters and capability of the prepared nanocomposite including the NiO content, the coating time, the PBT concentration and applied voltage were considered for optimization. The applicability of the synthesized fiber coating was examined by headspace solid phase micro extraction and gas chromatography mass spectrometry detection of some volatile organic compounds in aqueous samples. Among the synthesized nanocomposites and pristine PBT nanofibers, the fiber coating with 14% of NiO nanoparticles doping level exhibited the highest extraction efficiency. In addition, important parameters influencing the extraction/desorption process were investigated and optimized. The detection limits were less than 5 ng L(-1) using the selected ion monitoring mode. The inter-day and intra-day precisions of the developed method under optimized conditions were below 11%. The method showed a linearity in the range of 10-1000 ng L(-1) with the correlation coefficient greater than 0.9987. The optimized method was applied to the sampling of some volatile organic compounds from real water samples. The developed method is convenient, rapid, simple, easy and inexpensive and offers high sensitivity and sufficient reproducibility. PMID- 25732310 TI - Multi-analyte high performance liquid chromatography coupled to high resolution tandem mass spectrometry method for control of pesticide residues, mycotoxins, and pyrrolizidine alkaloids. AB - A new reliable and highly sensitive method based on high performance liquid chromatographic (HPLC) separation and high resolution tandem mass spectrometric detection (HRMS/MS) has been developed and validated for determination of 323 pesticide residues, 55 mycotoxins, and 11 plant toxins represented by pyrrolizidine alkaloids. The method was validated for three matrices, leek, wheat, and tea differing in nature/amount of co-extracts that may cause various matrix effects. For target analytes isolation, optimized QuEChERS-based (quick, easy, cheap, effective, rugged, and safe) extraction procedure was employed. Spectral HRMS/MS library has been established providing an entire spectrum of fragment ions for each analyte, which allows unbiased identification and confirmation of target compounds. The limits of quantification (LOQs) of target analytes were below 10 MUg kg(-1) for 82%, 81%, and 61% for matrices leek, wheat, and tea, respectively. Recoveries were in the acceptable range (70-120%) according to SANCO/12571/2013 for most of target analytes, except for highly polar 'masked' mycotoxin deoxynivalenol-3-glucoside with recoveries 35%, 47%, and 42% for matrices leek, wheat, and tea, respectively. The linearities of calibration curves expressed as coefficients of determination were in the range of 0.9661-1.000, and repeatabilities expressed as relative standard deviations (RSDs) at LOQs lied in the range of 0.25-13.51%. The trueness of the method was verified using several certified reference materials (CRMs) and proficiency test samples. PMID- 25732311 TI - Optofluidic microsystem with quasi-3 dimensional gold plasmonic nanostructure arrays for online sensitive and reproducible SERS detection. AB - Practical applications of chemical and biological detections through surface enhanced Raman scattering (SERS) require high reproducibility, sensitivity, and efficiency, along with low-cost, straightforward fabrication. In this work, we integrated a poly-(dimethylsiloxane) (PDMS) chip with quasi-3D gold plasmonic nanostructure arrays (Q3D-PNAs), which serve as SERS-active substrates, into an optofluidic microsystem for online sensitive and reproducible SERS detections. The Q3D-PNA PDMS chip was fabricated through soft lithography to ensure both precision and low-cost fabrication. The optimal dimension of the Q3D-PNA in PDMS was designed using finite-difference time-domain (FDTD) electromagnetic simulations with a simulated enhancement factor (EF) of 1.6*10(6). The real-time monitoring capability of the SERS-based optofluidic microsystem was investigated by kinetic on/off experiments through alternatively flowing Rhodamine 6G (R6G) and ethanol in the microfluidic channel. A switch-off time of ~2 min at a flow rate of 0.3 mL min(-1) was demonstrated. When applied to the detection of low concentration malathion, the SERS-based optofluidic microsystem with Q3D-PNAs showed high reproducibility, significantly improved efficiency and higher detection sensitivity via increasing the flow rate. The optofluidic microsystem presented in this paper offers a simple and low-cost approach for online, label free chemical and biological analysis and sensing with high sensitivity, reproducibility, efficiency, and molecular specificity. PMID- 25732312 TI - Synergistic improvement of gas sensing performance by micro-gravimetrically extracted kinetic/thermodynamic parameters. AB - A novel method is explored for comprehensive design/optimization of organophosphorus sensing material, which is loaded on mass-type microcantilever sensor. Conventionally, by directly observing the gas sensing response, it is difficult to build quantitative relationship with the intrinsic structure of the material. To break through this difficulty, resonant cantilever is employed as gravimetric tool to implement molecule adsorption experiment. Based on the sensing data, key kinetic/thermodynamic parameters of the material to the molecule, including adsorption heat -DeltaH degrees , adsorption/desorption rate constants Ka and Kd, active-site number per unit mass N' and surface coverage theta, can be quantitatively extracted according to physical-chemistry theories. With gaseous DMMP (simulant of organophosphorus agents) as sensing target, the optimization route for three sensing materials is successfully demonstrated. Firstly, a hyper-branched polymer is evaluated. Though suffering low sensitivity due to insufficient N', the bis(4-hydroxyphenyl)-hexafluoropropane (BHPF) sensing group exhibits satisfactory reproducibility due to appropriate -DeltaH degrees . To achieve more sensing-sites, KIT-5 mesoporous-silica with higher surface-area is assessed, resulting in good sensitivity but too high -DeltaH degrees that brings poor repeatability. After comprehensive consideration, the confirmed BHPF sensing-group is grafted on the KIT-5 carrier to form an optimized DMMP sensing nanomaterial. Experimental results indicate that, featuring appropriate kinetic/thermodynamic parameters of -DeltaH degrees , Ka, Kd, N' and theta, the BHPF-functionalized KIT-5 mesoporous silica exhibits synergistic improvement among reproducibility, sensitivity and response/recovery speed. The optimized material shows complete signal recovery, 55% sensitivity improvement than the hyper-branched polymer and 2~3 folds faster response/recovery speed than the KIT 5 mesoporous silica. PMID- 25732313 TI - High-precision measurements of seawater Pb isotope compositions by double spike thermal ionization mass spectrometry. AB - A new method for the determination of seawater Pb isotope compositions and concentrations was developed, which combines and optimizes previously published protocols for the separation and isotopic analysis of this element. For isotopic analysis, the procedure involves initial separation of Pb from 1 to 2L of seawater by co-precipitation with Mg hydroxide and further purification by a two stage anion exchange procedure. The Pb isotope measurements are subsequently carried out by thermal ionization mass spectrometry using a (207)Pb-(204)Pb double spike for correction of instrumental mass fractionation. These methods are associated with a total procedural Pb blank of 28+/-21 pg (1sd) and typical Pb recoveries of 40-60%. The Pb concentrations are determined by isotope dilution (ID) on 50 mL of seawater, using a simplified version of above methods. Analyses of multiple aliquots of six seawater samples yield a reproducibility of about +/ 1 to +/-10% (1sd) for Pb concentrations of between 7 and 50 pmol/kg, where precision was primarily limited by the uncertainty of the blank correction (12+/ 4 pg; 1sd). For the Pb isotope analyses, typical reproducibilities (+/-2sd) of 700-1500 ppm and 1000-2000 ppm were achieved for (207)Pb/(206)Pb, (208)Pb/(206)Pb and (206)Pb/(204)Pb, (207)Pb/(204)Pb, (208)Pb/(204)Pb, respectively. These results are superior to literature data that were obtained using plasma source mass spectrometry and they are at least a factor of five more precise for ratios involving the minor (204)Pb isotope. Both Pb concentration and isotope data, furthermore, show good agreement with published results for two seawater intercomparison samples of the GEOTRACES program. Finally, the new methods were applied to a seawater depth profile from the eastern South Atlantic. Both Pb contents and isotope compositions display a smooth evolution with depth, and no obvious outliers. Compared to previous Pb isotope data for seawater, the (206)Pb/(204)Pb ratios are well correlated with (207)Pb/(206)Pb, underlining the significant improvement achieved in the measurement of the minor (204)Pb isotope. PMID- 25732314 TI - New approach for sensitive photothermal detection of C60 and C70 fullerenes on micro-thin-layer chromatographic plates. AB - In this paper the pulse thermovision (photothermal) detection and quantification methods of C60 and C70 fullerenes are presented. Quantification results are compared with optical and fluorescence measurements. Target components were separated under isothermal conditions (30 degrees C) on micro-TLC plates (RP18WF254S) using n-hexane as the mobile phase. The principle of described analytical protocol is based on sensitive measurement of the temperature contrast generated within TLC stationary phase and fullerenes spots after white light pulse excitation. It has been demonstrated that observed temperature contrast is mainly driven by the optical properties of fullerenes (UV-vis absorption spectra). Contrary to the commonly applied optical reflection or transmission techniques the proposed thermovision method involves dissipated light. The results of presented experimental work have revealed that both types of quantitative measurements provide similar outcome despite the key differences in the signal origin. However, it has been found that thermovision method was characterized by smaller value of LOD, particularly for C60 molecule. We demonstrated that application of correlation technique to post-acquisition analysis of the sequence of temperature contrast images significantly increase detection limits of fullerenes, even in comparison to fluorescence quenching detection mode. Moreover, the thermal contrast images and particularly, computed correlation image, allow detection of stationary phase layer nonuniformities, including changes in the adsorbent thickness and thermal conductivity. Therefore, invented pulsed thermovision methodology can be additionally used for fast quality screening of home made and commercially available TLC plates. PMID- 25732315 TI - A high performance system to study the influence of temperature in on-line solid phase extraction capillary electrophoresis. AB - A novel high performance system to control the temperature of the microcartridge in on-line solid phase extraction capillary electrophoresis (SPE-CE) is introduced. The mini-device consists in a thermostatic bath that fits inside of the cassette of any commercial CE instrument, while its temperature is controlled from an external circuit of liquid connecting three different water baths. The circuits are controlled from a switchboard connected to an array of electrovalves that allow to rapidly alternate the water circulation through the mini thermostatic-bath between temperatures from 5 to 90 degrees C. The combination of the mini-device and the forced-air thermostatization system of the commercial CE instrument allows to optimize independently the temperature of the sample loading, the clean-up, the analyte elution and the electrophoretic separation steps. The system is used to study the effect of temperature on the C18-SPE-CE analysis of the opioid peptides, Dynorphin A (Dyn A), Endomorphin1 (END) and Met enkephalin (MET), in both standard solutions and in spiked plasma samples. Extraction recoveries demonstrated to depend, with a non-monotonous trend, on the microcartridge temperature during the sample loading and became maximum at 60 degrees C. Results prove the potential of temperature control to further enhance sensitivity in SPE-CE when analytes are thermally stable. PMID- 25732316 TI - Two dimensional separations of human urinary protein digest using a droplet interfaced platform. AB - For highly complex mixtures, coelution is a common phenomenon in chromatography. A great deal of resolution is hidden in coelution, and lost due to inevitable molecular diffusion during sample transfer. The molecular diffusion may lead to band broadening and remix of separated peaks, which cause degradation of achievable resolution. In this study, we introduced droplet microfluidics as a high performance sample transfer tool in two dimensional nanoflow liquid chromatography-capillary electrophoresis separation of a human urine sample. The fine fractionation capability and sampling completeness enabled by the droplet interface demonstrated the 2D system's usefulness in high-resolution mapping of real world biological samples. PMID- 25732317 TI - Somatotype and stress hormone levels in young soccer players. AB - AIM: The relationship between somatotype and cortisol and adrenocorticotropic (ACTH) hormone concentrations at rest or after exercise in adolescent soccer players at different time points throughout a soccer season is not understood. Therefore, the aim of this study was to examine the relationship between somatotype and cortisol and ACTH concentrations at rest and after exercise in adolescent soccer players at different time points during a soccer season. METHODS: During the first 4 months of the soccer season, 47 soccer players (between 15-17 years of age) were tested at three different time points including at baseline, after 6 weeks, and at the end of 4 months. Testing included anaerobic threshold (AnT, km/h) and maximal speed of running (Max, km/h) were measured with Conconi protocol on treadmill. Before and after a maximal exercise Test, plasma levels of cortisol (ug/dL) and ACTH (pg/ml) were assessed by chemiluminometry enzyme amplificated method. Heath-Carter anthropometric somatotype model was used to determine 13 elements of somatotype. Descriptive statistics and multiple regression were used for statistical analysis (P<0.05). RESULTS: Body composition and AnT were not significantly different between each time point of testing. The mesomorph-ectomorph (N.=21), balanced mesomorph (N.=8) and balanced ectomorph (N.=7) were the most frequent somatotypes. There were significant decrements of cortisol plasma levels (at rest 33.4%; after test 27.46%), with insignificant changes of ACTH plasma levels, after 6 weeks of preparation phase and after finishing of half season, at rest and after maximal treadmill test. There were significant correlation between ACTH levels at rest (R=0.44; P<0.01) and some somatotypes (mesomorph endomorph, central and balanced endomorph) and ACTH levels after maximal exercise test (R=0.36; P<0.05) and balanced ectomorph and endomorph mesomorph. There were significant correlation between cortisol levels after maximal exercise test at the beginning of training process (R=0.59; P<0.01) and some somatotypes (mesomorph ectomorph, mesomorph endomorph, balanced endomorph and endomorph mesomorph) and after the finishing of training process (R=0.62; P<0.01) and some somatotypes (central, balanced ectomorph and mesomorph ectomorph). CONCLUSION: The significant decreases of cortisol plasma levels during soccer training process could indicate a stagnation of training process, accordingly with insignificant changes of AnT. The significant correlations of some somatotypes with stress hormonal responses could only suggest that the somatotype characteristics of young soccer players could be of interest in process of selection and planning of soccer training process with an essential need for more studies. PMID- 25732318 TI - Effects of intra-set rest on the ability to repeat work at maximal isometric strength. AB - BACKGROUND: The aim of this paper was to analyze how the rest between interval repetitions in intra-set training (at maximal isometric loads) could affect the ability to repeat maximal contractions in subjects with different levels of performance and different experience in strength development work. METHODS: Twenty subjects were divided randomly into two different groups depending on their sport characteristics: ten subjects were trained in strength development work (Group Strenght--23.1+/-4.6 years; 172.0+/-5.3 cm; 79.9+/-12.1 kg; 2175.6+/ 490.8 N; 46.9+/-4.9 mL/kg.min), and ten subjects were trained in endurance work (Group Endurance--21.3+/-4.5 years; 172.4+/-4.1 cm; 60.0+/-4.6 kg; 815.5+/-206.5 N; 67.4+/-4.9 mL/kg.min). To assess the ability to repeat maximal efforts, 20 repetitions of 5 seconds were performed in a half-squat position, with 1 minute of rest between repetitions. RESULTS: For both groups, four different phases were observed in the Interval Maximal Force test during the 20-repetition assessment: potentiation, maintenance, moderate loss, and significant loss. For the GE, the loss in maximum strength capacity began in the fourth repetition (GS4th: 3.4%, ns, Effect Size: 0.09 vs. GE3th: 1.6%; ns; ES: 0.06) and reached a statistically significant value in the twelfth repetition (GS12th: 12.7%, P=0.03, ES: 0.35 vs. GE7th: 12.5%; P=0.01; ES: 0.49). The number of repetitions at which the strength began to decrease depended on the subject's sport characteristic and performance level. CONCLUSIONS: This study shows how an appropriate intra-set rest inclusion can significantly increase the work performed in every set without changing the muscle contraction characteristics, thus delaying muscle fatigue and maintaining the desired training objective. PMID- 25732319 TI - Muscle synergies during incremental rowing VO2max test of collegiate rowers and untrained subjects. AB - BACKGROUND: The purpose of this study was to evaluate the muscle synergies during incremental rowing VO2 max Test of collegiate rowers and untrained subjects. As a power endurance sport, high aerobic capacity was one of the determinants of rowing performance. The modulation of muscle recruitment patterns following specific physiological demands was an indication of the robustness of muscle synergies composition which was overlooked in previous studies. METHODS: Ten male collegiate rowers and physically active untrained subjects were recruited. Muscle synergies were extracted from 16 rowing-specific muscles using Principal Component Analysis with varimax rotation. Incremental rowing VO2 max Test was performed on slides ergometer (SE). Rowing performance and physiological variables were analyzed. RESULTS: Rowers exerted greater power output, more energy expenditure and better rowing economy compared to untrained subjects. Rowers preferred to row slower with longer strokes compared to the untrained subjects. Three muscle synergies with high indices of similarity of waveform patterns were extracted in both groups. Significant association was found between muscle synergies and rowing economy. CONCLUSIONS: The findings of this study showed that muscle synergies were robust during aerobic-dominant activity for collegiate rowers and untrained subjects. Rowers and coaches could utilize the findings by emphasizing on muscle coordination training, which may enhance the rowing economy. PMID- 25732320 TI - Re: Incidental abdominopelvic findings on expanded field-of-view lumbar spinal MRI: frequency, clinical importance, and concordance in interpretation by neuroimaging and body imaging radiologists. PMID- 25732321 TI - Development of a modified artificial insemination technique combining penile vibration stimulation and the swim-up method in the common marmoset. AB - The common marmoset, Callithrix jacchus, is used as a New World monkey species in biomedical studies because of its small body size and good reproduction in captivity. A modified artificial insemination technique was developed in this species to encourage breeding of lines carrying interesting genes and traits. Fresh semen was collected by penile vibratory stimulation. Medium containing highly motile sperm was inseminated into the uterus using a catheter. Seven females were inseminated using freshly prepared sperm from different males every day for 3 days including the expected ovulation day. As a result, four females conceived, and three females delivered six offspring in total (two singletons and one quadruplet). The paternity of the newborns was determined using microsatellite markers to accurately pinpoint the timing of insemination and ovulation. It is expected that our artificial insemination protocol can be effectively used to establish marmoset lines and genetically manage marmoset colonies. PMID- 25732322 TI - Consensus on the management of advanced medullary thyroid carcinoma on behalf of the Working Group of Thyroid Cancer of the Spanish Society of Endocrinology (SEEN) and the Spanish Task Force Group for Orphan and Infrequent Tumors (GETHI). AB - BACKGROUND: In Spain medullary thyroid carcinoma (MTC) would not exceed 80 new cases per year and less than half of them would be good candidates for systemic treatment with novel agents. METHODS: Relevant literature was reviewed, including PubMed searches supplemented with additional articles. RESULTS: The consensus summarizes the clinical outcomes in terms of activity and toxicity of each of the available drugs. A brief summary of the minimum requirements in terms of follow up and genetic counseling around MTC is also included. CONCLUSIONS: Only those patients with objective imaging progression in the last 12-14 months with large volume of disease are clear candidates to start systemic treatment. However, those patients with low disease volume should be considered for 'wait and see' strategy until symptoms of the disease appear. Multidisciplinary approach for the management of MTC patient is mandatory nowadays. PMID- 25732323 TI - [Pituitary apoplexy in a pregnant woman with cystic microprolactinoma]. PMID- 25732324 TI - Central pontine myelinolysis-induced mania: A case study. PMID- 25732326 TI - Participation after acquired brain injury: Associations with everyday technology and activities in daily life. AB - BACKGROUND: The development of the information society has led to increased use of everyday technology and changed the conditions for participation. Enabling participation in everyday life situations is an important rehabilitation goal after acquired brain injury (ABI). Identifying factors associated with individuals' experienced participation and problems therein is therefore essential. OBJECTIVE: This study aimed at exploring the relationship between perceived difficulty in everyday technology use, perceived ability in the activities of daily living (ADL), and perceived participation, and participation problems in persons with ABI. METHODS: Eighty-one persons with ABI participated in the study and were assessed by the Impact on Participation and Autonomy questionnaire, the Everyday Technology Use Questionnaire, and the ADL taxonomy. RESULTS: Findings showed that the combined model of difficulty in everyday technology (ET) use, ADL ability, and the interaction between them explained both participation in various domains of everyday life, and also overall level of perceived participation and the perceived problems. CONCLUSIONS: The findings underscore the importance of evaluating individuals' ability in both ET use and ADL after ABI to increase the probability of explaining these persons' participation in desired everyday life situations and, also, for rehabilitation design. PMID- 25732325 TI - Serotonin and insulin-like peptides modulate leucokinin-producing neurons that affect feeding and water homeostasis in Drosophila. AB - Metabolic homeostasis and water balance is maintained by tight hormonal and neuronal regulation. In Drosophila, insulin-like peptides (DILPs) are key regulators of metabolism, and the neuropeptide leucokinin (LK) is a diuretic hormone that also modulates feeding. However, it is not known whether LK and DILPs act together to regulate feeding and water homeostasis. Because LK neurons express the insulin receptor (dInR), we tested functional links between DILP and LK signaling in feeding and water balance. Thus, we performed constitutive and conditional manipulations of activity in LK neurons and insulin-producing cells (IPCs) in adult flies and monitored food intake, responses to desiccation, and peptide expression levels. We also measured in vivo changes in LK and DILP levels in neurons in response to desiccation and drinking. Our data show that activated LK cells stimulate diuresis in vivo, and that LK and IPC signaling affect food intake in opposite directions. Overexpression of the dInR in LK neurons decreases the LK peptide levels, but only caused a subtle decrease in feeding, and had no effect on water balance. Next we demonstrated that LK neurons express the serotonin receptor 5-HT1B . Knockdown of this receptor in LK neurons diminished LK expression, increased desiccation resistance, and diminished food intake. Live calcium imaging indicates that serotonin inhibits spontaneous activity in abdominal LK neurons. Our results suggest that serotonin via 5-HT1B diminishes activity in the LK neurons and thereby modulates functions regulated by LK peptide, but the action of the dInR in these neurons remains less clear. PMID- 25732327 TI - Outcome of patients with multiple myeloma and hypotension during high-dose chemotherapy. PMID- 25732328 TI - Mesoscale mechanics of twisting carbon nanotube yarns. AB - Fabricating continuous macroscopic carbon nanotube (CNT) yarns with mechanical properties close to individual CNTs remains a major challenge. Spinning CNT fibers and ribbons for enhancing the weak interactions between the nanotubes is a simple and efficient method for fabricating high-strength and tough continuous yarns. Here we investigate the mesoscale mechanics of twisting CNT yarns using full atomistic and coarse grained molecular dynamics simulations, considering concurrent mechanisms at multiple length-scales. To investigate the mechanical response of such a complex structure without losing insights into the molecular mechanism, we applied a multiscale strategy. The full atomistic results are used for training a coarse grained model for studying larger systems consisting of several CNTs. The mesoscopic model parameters are updated as a function of the twist angle, based on the full atomistic results, in order to incorporate the atomistic scale deformation mechanisms in larger scale simulations. By bridging across two length scales, our model is capable of accurately predicting the mechanical behavior of twisted yarns while the atomistic level deformations in individual nanotubes are integrated into the model by updating the parameters. Our results focused on studying a bundle of close packed nanotubes provide novel mechanistic insights into the spinning of CNTs. Our simulations reveal how twisting a bundle of CNTs improves the shear interaction between the nanotubes up to a certain level due to increasing the interaction surface. Furthermore, twisting the bundle weakens the intertube interactions due to excessive deformation in the cross sections of individual CNTs in the bundle. PMID- 25732329 TI - Odontogenic sinusitis: a case series studying diagnosis and management. AB - BACKGROUND: Odontogenic sinusitis is a well-recognized, but understudied form of sinusitis. Odontogenic sinusitis requires unique diagnostic criteria and a treatment regimen that differs from non-odontogenic sinusitis. The purpose of this article is to present a case series of patients with odontogenic sinusitis in order to clarify key disease characteristics and management techniques. METHODS: Retrospective case series of 55 patients with odontogenic sinusitis. Each patient underwent chart and imaging review to analyze demographic factors, diagnostic criteria, clinical course, and management. RESULTS: Fifty-five patients were identified retrospectively. Forty-four were diagnosed at initial visit. Twenty-eight (64%) of these patients were diagnosed by computed tomography (CT) scan showing dental pathology, 11 (25%) by known temporal relationship to a dental procedure, and 5 (11%) by presentation with oral-antral fistula. Only 65% of radiology reports for all patients mentioned dental pathology. Overall, 21 (38%) patients had disease resolution. Of these, 7 (33%) resolved with endoscopic sinus surgery (ESS) alone, 7 (33%) resolved with concurrent ESS and dental surgery, 2 (10%) resolved with dental surgery alone, 2 (10%) resolved with ESS after failing dental surgery, 2 (10%) resolved with medical management alone, and 1 (5%) resolved with medical management after failing dental surgery. Forty-six (84%) patients had unilateral odontogenic sinusitis. The Lund-Mackay score for all patients was (mean +/- standard deviation [SD]) 4.0 +/- 3.2. CONCLUSION: Odontogenic sinusitis is often misdiagnosed. Radiology reports commonly do not mention dental pathology. Management of odontogenic sinusitis needs to be tailored to each individual patient and involves varying combinations of medical management, dental surgery, and ESS. PMID- 25732330 TI - Sex, health and the technological imagination. PMID- 25732331 TI - Ovulation monitoring and reproductive heterosex: living the conceptive imperative? AB - Using biosensors, or devices that provide biological information to users about their own bodies, to map ovulation and time intercourse is a practice of rising significance in economically privileged countries. Based on an ethnographic study of ovulation biosensing, this paper explores the contradictions between device manufacturers' figurations of reproductive heterosex as a natural and pleasurable experience facilitated by fertility monitoring technology, and heterosexual women users' accounts of the pleasures and difficulties of ovulation monitoring and associated sexual encounters. Drawing on Science and Technology Studies and the concept of 'script', we examine the frameworks of action defined by makers of ovulation biosensors and how these are accepted, refused or remade by users. Within the scientific romance configured by manufacturers, reproductive heterosex emerges as exciting and fun, whilst the hard, 'technical' work of conception is done by ovulation technologies. Yet ovulation monitoring is described by many heterosexual women users as an exciting and yet anxiety-producing practice through which they come to know their bodies differently, often through online discussions with other women. Living a 'conceptive imperative', women engaging with ovulation sensing reconfigure their reproductive embodiment and shift their relationship to male partners in ways that reveal heterosexual 'baby-making' as a complex and nuanced practice worthy of critical engagement. PMID- 25732332 TI - A procedure to find thermodynamic equilibrium constants for CO2 and CH4 adsorption on activated carbon. AB - Thermodynamic equilibrium for adsorption means that the chemical potential of gas and adsorbed phase are equal. A precise knowledge of the chemical potential is, however, often lacking, because the activity coefficient of the adsorbate is not known. Adsorption isotherms are therefore commonly fitted to ideal models such as the Langmuir, Sips or Henry models. We propose here a new procedure to find the activity coefficient and the equilibrium constant for adsorption which uses the thermodynamic factor. Instead of fitting the data to a model, we calculate the thermodynamic factor and use this to find first the activity coefficient. We show, using published molecular simulation data, how this procedure gives the thermodynamic equilibrium constant and enthalpies of adsorption for CO2(g) on graphite. We also use published experimental data to find similar thermodynamic properties of CO2(g) and of CH4(g) adsorbed on activated carbon. The procedure gives a higher accuracy in the determination of enthalpies of adsorption than ideal models do. PMID- 25732333 TI - Chromosome architecture and segregation in prokaryotic cells. PMID- 25732334 TI - Dynamic organization: chromosome domains in Escherichia coli. AB - Bacteria are small and their chromosomes are several orders of magnitude longer than the cell size. The chromosome is consequently compacted into a structure known as the nucleoid. Zooming into the nucleoid of the model organism Escherichia coli reveals additional layers of organization: the chromosomal domains. These domains are much more than simple compaction devices. Essential cellular processes such as chromosome segregation, gene regulation and DNA replication are dependent on the domain organization of the chromosome. Here, we provide an overview of discoveries about micro- and macrodomains in E. coli and discuss potential routes to be taken in future research. PMID- 25732335 TI - Function of nucleoid-associated proteins in chromosome structuring and transcriptional regulation. AB - Nucleoid-associated proteins typically are abundant, low-molecular-mass polypeptides that bind DNA and alter its shape and its ability to participate in transactions such as transcription. Some can bind RNA and influence the gene expression profile of the cell at a posttranscriptional level. They also have the potential to model and remodel the structure of the nucleoid, contributing to chromosome packaging within the cell. Some nucleoid-associated proteins have been implicated in the facilitation of chromosome evolution through their ability to silence transcription, allowing new genes to be integrated into the nucleoid both physically and in a regulatory sense. The dynamic composition of the population of nucleoid-associated proteins in model bacteria such as Escherichia coli and Salmonella enterica links nucleoid structure and the global regulation of gene expression, enhancing microbial competitive fitness and survival in complex environments. PMID- 25732336 TI - Order from the order: how a spatiotemporal genetic program is encoded in a 2-D genetic map of the bacterial chromosome. AB - In this article, we sketch out a holistic methodology used for exploring how the genetic program is encoded in a 2-D genetic map of a bacterial chromosome. We argue that the major problem resides in the conceptual integration of the two logically distinct types of information encoded in the chiral double-helical DNA polymer. This integration is accomplished by mapping the genetic function on the genomic sequence organisation and therefore is potentially applicable to any chromosome. The vast generalisation achieved by this approach necessarily ignores exquisite details, yet it is fundamental in providing comprehensive methodology for exploring the role of the DNA sequence organisation in harnessing genetic information and sustaining biological order. PMID- 25732337 TI - Genomic looping: a key principle of chromatin organization. AB - The effective volume occupied by the genomes of all forms of life far exceeds that of the cells in which they are contained. Therefore, all organisms have developed mechanisms for compactly folding and functionally organizing their genetic material. Through recent advances in fluorescent microscopy and 3C-based technologies, we finally have a first glimpse into the complex mechanisms governing the 3-D folding of genomes. A key feature of genome organization in all domains of life is the formation of DNA loops. Here, we describe the main players in DNA organization with a focus on DNA-bridging proteins. Specifically, we discuss the properties of the bacterial DNA-bridging protein H-NS. Via two different modes of binding to DNA, this protein is a key driver of bacterial genome organization and provides a link between 3-D organization and transcription regulation. Importantly, H-NS function is modulated in response to environmental cues, which are translated into adapted gene expression patterns. We delve into the mechanisms underlying DNA looping and explore the complex and subtle modulation of these diverse, yet difficult-to-study, structures. DNA looping is universal and a conserved mechanism of genome organization throughout all domains of life. PMID- 25732338 TI - Chromosome segregation in Vibrio cholerae. AB - The study of chromosome segregation is currently one of the most exciting research frontiers in cell biology. In this review, we discuss our current knowledge of the chromosome segregation process in Vibrio cholerae, based primarily on findings from fluorescence microscopy experiments. This bacterium is of special interest because of its eukaryotic feature of having a divided genome, a feature shared with 10% of known bacteria. We also discuss how the segregation mechanisms of V. cholerae compare with those in other bacteria, and highlight some of the remaining questions regarding the process of bacterial chromosome segregation. PMID- 25732340 TI - Structural maintenance of chromosome complex in bacteria. AB - In all organisms, from eukaryotes to prokaryotes, the chromosome is highly compacted and organized. Chromosome condensation is essential in all cells and ranges from 1,000- to more than 10,000-fold between bacterial and eukaryotic cells. Replication and transcription occur in parallel with chromosome segregation in bacteria. Structural maintenance of chromosome proteins play a key role in chromosome compaction and segregation, their coordination with the cell cycle, and in various other chromosome dynamics, including DNA repair. In spite of their essential nature in almost all organisms, their function at a molecular level is only slowly beginning to emerge. PMID- 25732341 TI - The FtsK family of DNA translocases finds the ends of circles. AB - A global view of bacterial chromosome choreography during the cell cycle is emerging, highlighting as a next challenge the description of the molecular mechanisms and factors involved. Here, we review one such factor, the FtsK family of DNA translocases. FtsK is a powerful and fast translocase that reads chromosome polarity. It couples segregation of the chromosome with cell division and controls the last steps of segregation in time and space. The second model protein of the family SpoIIIE acts in the transfer of the Bacillus subtilis chromosome during sporulation. This review focuses on the molecular mechanisms used by FtsK and SpoIIIE to segregate chromosomes with emphasis on the latest advances and open questions. PMID- 25732339 TI - MukBEF, a chromosomal organizer. AB - Global folding of bacterial chromosome requires the activity of condensins. These highly conserved proteins are involved in various aspects of higher-order chromatin dynamics in a diverse range of organisms. Two distinct superfamilies of condensins have been identified in bacteria. The SMC-ScpAB proteins bear significant homology to eukaryotic condensins and cohesins and are found in most of the presently sequenced bacteria. This review focuses on the MukBEF/MksBEF superfamily, which is broadly distributed across diverse bacteria and is characterized by low sequence conservation. The prototypical member of this superfamily, the Escherichia coli condensin MukBEF, continues to provide critical insights into the mechanism of the proteins. MukBEF acts as a complex molecular machine that assists in chromosome segregation and global organization. The review focuses on the mechanistic analysis of DNA organization by MukBEF with emphasis on its involvement in the formation of chromatin scaffold and plausible other roles in chromosome segregation. PMID- 25732342 TI - Polyploidy in archaea and bacteria: about desiccation resistance, giant cell size, long-term survival, enforcement by a eukaryotic host and additional aspects. AB - During recent years, it has become clear that many species of archaea and bacteria are polyploid and contain more than 10 copies of their chromosome. In this contribution, eight examples are discussed to highlight different aspects of polyploidy in prokaryotes. The species discussed are the bacteria Azotobacter vinelandii, Deinococcus radiodurans, Sinorhizobium meliloti, and Epulopiscium as well as the archaea Methanocaldococcus jannaschii, Methanococcus maripaludis, Haloferax volcanii, and haloarchaeal isolates from salt deposits. The topics include possible laboratory artifacts, resistance against double-strand breaks, long-term survival, relaxation of DNA segregation and septum formation, enforced polyploidy by a eukaryotic host, genome equalization by gene conversion, and the nongenetic usage of genomic DNA as a phosphate storage polymer. Together, the selected topics give an overview of the biodiversity of polyploidy in archaea and bacteria. PMID- 25732343 TI - Archaeal chromosome biology. AB - Knowledge of the chromosome biology of archaeal species has grown considerably in the last 15 years, since the publication of the first full archaeal genome sequences. A number of model organisms have been studied, revealing a striking variety of mechanisms and modes of genome duplication and segregation. While clear sequence relationships between archaeal and eukaryotic replication proteins are well known, some archaea also seem to possess organizational parameters for replication and segregation that reveal further striking parallels to eukaryotes. PMID- 25732345 TI - Second primary malignancies in Waldenstrom's macroglobulinemia: a US population based study. PMID- 25732344 TI - The African American Women and Mass Media (AAMM) campaign in Georgia: quantifying community response to a CDC pilot campaign. AB - PURPOSE: To evaluate whether a culturally appropriate campaign using "Black radio" and print media increased awareness and utilization of local mammography screening services provided by the Centers for Disease Control and Prevention's National Breast and Cervical Cancer Early Detection Program among African American women. METHODS: The evaluation used a quasi-experimental design involving data collection during and after campaign implementation in two intervention sites in GA (Savannah with radio and print media and Macon with radio only) and one comparison site (Columbus, GA). We used descriptive statistics to compare mammography uptake for African American women during the initial months of the campaign (8/08-1/09) with the latter months (2/09-8/09) and a post-campaign (9/09-12/09) period in each of the study sites. Comparisons of monthly mammogram uptake between cities were performed with multinomial logistic regression. We assumed a p value <0.05 to be significant. RESULTS: We observed an increase of 46 and 20 % in Savannah and Macon, respectively, from the initial period of the campaign to the later period. However, the increase did not persist in the post-campaign period. Analysis comparing monthly mammogram uptake in Savannah and Macon with Columbus showed a significant increase in uptake from the first to the second period in Savannah only (OR 1.269, 95 % CI (1.005-1.602), p = 0.0449). CONCLUSIONS: Dissemination of health promotion messages via a culturally appropriate, multicomponent campaign using Black radio and print media was effective in increasing mammogram uptake in Savannah among low-income, African American women. Additional research is needed to quantify the relative contribution of campaign radio, print media, and community components to sustain increased mammography uptake. PMID- 25732346 TI - Applications of magnetic surface imprinted materials for solid phase extraction of levofloxacin in serum samples. AB - In this work, molecularly imprinted magnetic carbon nanotubes (MCNTs@MIPs) was prepared with surface imprinting technique for extraction of levofloxacin in serum samples. The preparation of molecularly imprinted polymers (MIPs) used levofloxacin as template, methacrylic acid as functional monomer, and ethylene glycol dimethacrylate as cross-linker, and the magnetic carbon nanotubes (MCNTs) was synthesized by solvothermal method. The prepared polymers not only can be separated and collected easily by an external magnetic, but also exhibited high specific surface area and high selectivity to template molecules. Kinetic adsorption and static adsorption capacity investigations indicated that the synthesized MCNTs@MIPs had excellent recognition towards levofloxacin. Furthermore, magnetic solid phase extraction (MSPE) using the prepared MCNTs@MIPs as sorbent was then investigated, and an efficient sample cleanup was obtained with recoveries ranged from 78.7 +/- 4.8 % to 83.4 +/- 4.1%. In addition, several parameters, including the pH of samples, the amount of MCNTs@MIPs, the adsorption and desorption times, and the eluent, were investigated to obtain optimal extraction efficiency. Under the optimal extraction conditions, the stability of the polymer was also evaluated, and the average recovery reduced less than 7.6% after 5 cycles. MCNTs@MIPs successfully applied in the preconcentration and determination of levofloxacin in serum sample suggested that the MSPE method based on the novel polymers could be a promising alternative for selective and efficient extraction of trace amounts of pharmaceutical substances in bio-matrix samples. PMID- 25732348 TI - C2 rs547154 polymorphism and polypoidal choroidal vasculopathy susceptibility: a meta-analysis. AB - Previous studies have indicated the association between C2 rs547154 polymorphism and polypoidal choroidal vasculopathy (PCV) risk, while the results are controversial and inconsistent. Herein, we perform a meta-analysis to gain a precise estimation of the association using 5 eligible studies involving 4076 subjects, of which 1220 were PCV cases, 1073 were age-related macular degeneration (AMD) cases and 1783 were controls. Allelic frequencies of C2 rs547154 polymorphism between PCV and AMD were also compared. Both crude and adjusted odds ratios (OR) with their 95% confidence interval (CI) were included to assess the strength of the association. The pooled OR in random-effect model for allele T versus G was 0.64 (95% CI, 0.52-0.80; p < 0.0001), for genotype TG versus GG was 0.65 (95% CI, 0.52-0.83; p, 0.0004), and for genotype TT + TG versus GG was 0.64 (95% CI, 0.51-0.80; p, 0.0002). No difference in allelic frequency was observed between PCV and AMD (OR, 0.86; 95% CI, 0.64-1.16; p, 0.32). Sensitivity analysis proved the robustness of our data. No significant ethnic divergence was suggested by subgroup analysis, and no publication bias was detected via Egger's test. In conclusion, our data indicate that C2 rs547154 polymorphism plays a protective role in the development of PCV. PMID- 25732347 TI - Crystal structure of Gib2, a signal-transducing protein scaffold associated with ribosomes in Cryptococcus neoformans. AB - The atypical Gbeta-like/RACK1 Gib2 protein promotes cAMP signalling that plays a central role in regulating the virulence of Cryptococcus neoformans. Gib2 contains a seven-bladed beta transducin structure and is emerging as a scaffold protein interconnecting signalling pathways through interactions with various protein partners. Here, we present the crystal structure of Gib2 at a 2.2-A resolution. The structure allows us to analyse the association between Gib2 and the ribosome, as well as to identify the Gib2 amino acid residues involved in ribosome binding. Our studies not only suggest that Gib2 has a role in protein translation but also present Gib2 as a physical link at the crossroads of various regulatory pathways important for the growth and virulence of C. neoformans. PMID- 25732349 TI - Comparison of healing process in open osteotomy model and open fracture model: Delayed healing of osteotomies after intramedullary screw fixation. AB - Murine osteotomy and fracture models have become the standard to study molecular mechanisms of bone healing. Because there is little information whether the healing of osteotomies differs from that of fractures, we herein studied in mice the healing of femur osteotomies compared to femur fractures. Twenty CD-1 mice underwent a standardized open femur osteotomy. Another 20 mice received a standardized open femur fracture. Stabilization was performed by an intramedullary screw. Bone healing was studied by micro-CT, biomechanical, histomorphometric and protein expression analyses. Osteotomies revealed a significantly lower biomechanical stiffness compared to fractures. Micro-CT showed a reduced bone/tissue volume within the callus of the osteotomies. Histomorphometric analyses demonstrated also a significantly lower amount of osseous tissue in the callus of osteotomies (26% and 88% after 2 and 5 weeks) compared to fractures (50% and 100%). This was associated with a delayed remodeling. Western blot analyses demonstrated comparable BMP-2 and BMP-4 expression, but higher levels of collagen-2, CYR61 and VEGF after osteotomy. Therefore, we conclude that open femur osteotomies in mice show a markedly delayed healing when stabilized less rigidly with an intramedullary screw. This should be considered when choosing a model for studying the mechanisms of bone healing in mice. PMID- 25732350 TI - A comprehensive scientific overview of Garcinia cambogia. AB - The fruit rind of Garcinia gummi-gutta, commonly known as Garcinia cambogia (syn.), is extensively used traditionally as a flavourant in fish curries due to its sharp sour taste. Additional ethnobotanical uses include its use as a digestive and a traditional remedy to treat bowel complaints, intestinal parasites and rheumatism. This small fruit, reminiscent of a pumpkin in appearance, is currently most popularly used and widely advertised as a weight loss supplement. Studies have shown that the extracts as well as (-) hydroxycitric acid (HCA), a main organic acid component of the fruit rind, exhibited anti-obesity activity including reduced food intake and body fat gain by regulating the serotonin levels related to satiety, increased fat oxidation and decreased de novo lipogenesis. HCA is a potent inhibitor of adenosine triphosphate-citrate lyase, a catalyst for the conversion process of citrate to acetyl-coenzyme A, which plays a key role in fatty acid, cholesterol and triglycerides syntheses. The crude extract or constituents from the plant also exerted hypolipidaemic, antidiabetic, anti-inflammatory, anticancer, anthelmintic, anticholinesterase and hepatoprotective activities in in vitro and in vivo models. Phytochemical studies of various plant parts revealed the presence of mainly xanthones (e.g. carbogiol) and benzophenones (e.g. garcinol) together with organic acids (e.g. HCA) and amino acids (e.g. gamma aminobutyric acid). Currently, a large number of G. cambogia/HCA dietary supplements for weight management are being sold although the possible toxicity associated with the regular use of these supplements has raised concerns. In most cases, complaints have been related to multicomponent formulations and at this stage G. cambogia has not been confirmed as the potentially toxic culprit. This review presents a scientific overview of G. cambogia with reference to relevant botanical aspects, ethnobotanical uses, phytochemistry and biological activity as well as toxicity. PMID- 25732351 TI - Antimicrobial and cytotoxic constituents from native Cameroonian medicinal plant Hypericum riparium. AB - Bioassay guided fractionation of Hypericum riparium leaves extract has resulted in the isolation and characterization of three new compounds namely chipericumin E (1), hyperenone C (3), and hyperixanthone (5), together with twenty known compounds. Their structures were elucidated based on comprehensive interpretation of spectroscopic and spectrometric data. Compounds 1-4, and 6-8 displayed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cytotoxic effects on the human gastric cell line BGC-823 with IC50 values ranging from 6.54 to 18.50MUM. PMID- 25732352 TI - Elemental carbon and polycyclic aromatic compounds in a 150-year sediment core from Lake Qinghai, Tibetan Plateau, China: influence of regional and local sources and transport pathways. AB - Elemental carbon (EC) and polycyclic aromatic compounds (PACs) are potential proxies for the reconstruction of change in human activities and the origin of air masses in historic times. In this study, the historic deposition of char and soot (the two subtypes of EC) and PACs in a 150-year sediment core from different topographic subbasins of Lake Qinghai on the Qinghai Tibetan Plateau (QTP) were reconstructed. The objective was to explore how the variations in the concentrations of EC and PACs, in the ratios of char to soot and of oxygenated polycyclic aromatic hydrocarbons (OPAHs) to parent PAHs, and in the composition of the PAC mixtures reflect historical changes in climate and human activity and the origin of air masses arriving at the QTP. The deposition fluxes of soot in the different subbasins were similar, averaging 0.18 (range of 0.15-0.25) and 0.16 (0.13-0.23) g m(-2) year(-1), respectively, but they varied for char (averaging 0.11 and 0.22 g m(-2) year(-1), respectively), suggesting ubiquitous atmospheric deposition of soot and local river inputs of char. The different vertical distributions of the char/soot ratios in the different subbasins can be interpreted in terms of the different transport mechanisms of char and soot. An abrupt increase in soot concentrations since 1980 coincides with results from the QTP ice cores that were interpreted to be indicative of soot transport from South Asia. Similar concentration patterns of PAHs with soot and 9,10 anthraquinone/anthracene (9,10-AQ/ANT) ratios all >2.0 suggest regional PAC sources. Increasing PAH/soot ratios and decreasing 9,10-AQ/ANT ratios since the beginning of the 1970s indicate increasing local emissions. The historical trends of these diagnostic ratios indicate an increase in the fossil-fuel contribution since the beginning of the 1970s. The increase of perylene concentrations with increasing core depth and the ratio of perylene to its penta-aromatic isomers indicate that perylene originates mainly from in situ biogenic diagenesis. We demonstrate that the concentrations of EC, char, soot, and PACs in sediments can be used to reconstruct local, regional, and remote sources and transport pathways of pollutants to the QTP. PMID- 25732353 TI - Optimization of Combinatory Nicking Endonucleases for Accurate Identification of Nucleic Acids in Low Abundance. AB - Nucleic acid biomarkers embody inherent importance for differentiating disease causing organisms or environmental pathogens. Identifying unknown nucleic acids in low abundance remains extremely challenging. Previously, we reported a method to identify complementary DNA (cDNA) molecules based on sequence-specific topographical labels measured by atomic force microscopy (AFM). However, the accuracy is limited because only one type of nicking endonuclease was used as the labeling agent. Here we investigate how accuracy is improved using multiple types of nicking endonucleases in combinations. The numerical experiments created cDNA molecules incorporating measurement error or labeling defects, which were later compared with the 29,563 human messenger RNA (mRNA) transcript database with ideal labels. After comparison, the unknown cDNA molecule was identified as the transcript with the highest matching score. Thus, the accuracy was determined by the rate of true positives. We found that the accuracy is positively proportional to the label number. Compared with cases using single nicking endonuclease, which has an average accuracy of 51.2% +/- 34.4%, the average accuracy was improved to 97.1% +/- 5.6% using an optimized combination of NtBsmAI + NtBstNBI + NtAlwI. This improved accuracy is applicable to more than 85% of human mRNA transcripts. Together, our study suggests an optimization strategy for identifying nucleic acids in low abundance using the AFM-based method, with implications for diseases diagnosis, pathogen identification, and forensics at the single molecule level. PMID- 25732354 TI - Electrochemical Detection in Stacked Paper Networks. AB - Paper-based electrochemical biosensors are a promising technology that enables rapid, quantitative measurements on an inexpensive platform. However, the control of liquids in paper networks is generally limited to a single sample delivery step. Here, we propose a simple method to automate the loading and delivery of liquid samples to sensing electrodes on paper networks by stacking multiple layers of paper. Using these stacked paper devices (SPDs), we demonstrate a unique strategy to fully immerse planar electrodes by aqueous liquids via capillary flow. Amperometric measurements of xanthine oxidase revealed that electrochemical sensors on four-layer SPDs generated detection signals up to 75% higher compared with those on single-layer paper devices. Furthermore, measurements could be performed with minimal user involvement and completed within 30 min. Due to its simplicity, enhanced automation, and capability for quantitative measurements, stacked paper electrochemical biosensors can be useful tools for point-of-care testing in resource-limited settings. PMID- 25732355 TI - Ischemic colitis: spectrum of CT findings, sites of involvement and severity. AB - To summarize the frequency of findings on IV contrast, enhanced computer tomography (CT) in 335 patients with pathologically proven ischemic colitis (IC) determine the most frequent locations and patterns of involvement and establish the correlation of these findings with the severity of IC. 231 patients were excluded for not having a concomitant CT or for having underlying comorbidities. 104 cases were analyzed. Scans were evaluated for abnormal wall enhancement (AE), bowel wall thickening (BWT), bowel dilatation (DIL), mesenteric fat stranding (FS), venous engorgement (VE), pericolonic free fluid (FF), and pneumatosis (PN) and portomesenteric venous gas. Segmental versus pancolonic involvement was noted. Severity was determined by histopathology criteria. Data obtained are as follows: female to male incidence, 69 % (70) vs. 31 % (34); average age, 64.5; and positive CT, 102/104 (98.1 %). The most frequent findings include FS (88 %), BWT (88 %), and AE (82 %) regardless of severity of involvement. Statistically significant increased risk ratio and likelihood of severe ischemia for PN, DIL, and FF individually. BWT, DIL, FS, FF, VE, and PN together have a probability for severe IC of 91.8 %. A correlation between fewer findings and milder IC was found (R (2) = 0.6771). The most frequently involved segments: descending (64 %) and sigmoid colon (54 %). Splenic flexure (SF) was infrequently involved (n = 8, 7.84 %). Females had two times higher incidence of IC. The most frequent CT findings in IC are FS, BWT, and AE regardless of the severity. PN is suggestive of severe IC. Segmental involvement is the predominant pattern. The distal colon is more frequently involved. SF contrary to the conventional literature is not disproportionately involved in IC. PMID- 25732356 TI - Ruptured intracranial aneurysm during pregnancy with false-negative computed tomography angiography findings: a case report. AB - A 34-year-old female was admitted at 34 weeks of gestation with sudden onset of a severe headache accompanied by vomiting. Neurological examination revealed neck rigidity, and computed tomography (CT) of the brain revealed a subarachnoid hemorrhage (SAH). Although the hemorrhage was located primarily in the left Sylvian fissure, computed tomography angiography (CTA) performed immediately after CT did not reveal any obvious vascular abnormalities such as an intracranial aneurysm. An emergency cesarean section was performed, and a healthy infant was delivered. Cerebral digital subtraction angiography (DSA) was performed the day following surgery, which revealed a saccular aneurysm measuring 4.3 mm * 2.4 mm in the left middle cerebral artery. Left craniotomy and clipping of the aneurysm were performed. The clot around the aneurysm was relatively solid. This case report is of significance given that initial CTA was negative for SAH during pregnancy, suggesting the requirement for immediate DSA or another CTA in such cases. There are many previous reports on false-negative CTA findings or disappearance and reappearance of aneurysms in SAH patients, and various biophysical and dynamic parameters are suggested to cause such phenomena. However, there are no reports on similar occurrences during pregnancy. Although the precise cause remains unclear, multiple factors associated with homeostasis during pregnancy were possibly associated with the transient disappearance in this patient. PMID- 25732357 TI - Use of bacteriocin-producing, probiotic strain Enterococcus faecium AL41 to control intestinal microbiota in farm ostriches. AB - Probiotic enterococci can produce bacteriocins. Enterococcus faecium AL41 is an Enterocin M-producing, probiotic strain which has previously shown beneficial effect in broiler chickens. In this study, it was used to control intestinal microbiota in farm ostriches in a 42-day experiment with an experimental group (EG, 40 ostriches) and a control group (CG, 46). In addition to feed mixture, the ostriches in EG received Ent. faecium AL41 (10(9) CFU ml(-1); by rifampicin marked variant) 400 MUl per animal per day in their drinking water for 21 days. Sampling was carried out at the start of the experiment (at day 0/1), at day 21 (after 21 days of AL41 application) and at day 42 (21 days after AL41 cessation). Faeces (mixture, n = 6) were treated using the standard microbiological dilution method and cultivated on selective media (ISO). The highest count of AL41 was found at day 42. Its identity was confirmed with PCR and Maldi-Tof. The ostriches were free of Salmonella and Campylobacter cells. At day 21, antimicrobial effect was demonstrated by significant reduction in coagulase-positive and negative staphylococci in EG compared to CG (P < 0.001) and coliforms, Enterobacteria and Pseudomonas-like bacteria (P < 0.001). We conclude that AL41 can be used to control intestinal microbiota in farm ostriches. Significance and impact of the study: Ostriches are excellent for high intensity farming in a wide range of climates, requiring only limited space and giving high yields per hectare. They are reared mainly for their meat. Although adult birds possess quite good immunity, young birds can be threatened by spoilage bacteria, especially when they are transferred from the nests to the farm area. Based on our previous results related to the beneficial effect of bacteriocin-producing, probiotic strain Enterococcus faecium AL41 in poultry or rabbits, we decided to test its ability to control intestinal microbiota in farming ostriches which has never been tested previously. PMID- 25732358 TI - Hypertension: Arteriovenous anastomosis--next panacea for hypertension? PMID- 25732359 TI - Atrial fibrillation: Migraine improvement after AF ablation. PMID- 25732360 TI - Antiplatelet therapy: Vorapaxar in diabetes and MI. PMID- 25732361 TI - Device therapy: High-zone programming of ICDs reduces inappropriate shocks. PMID- 25732362 TI - Bedtime-related jerks in the upper limbs associated with restless arms syndrome. PMID- 25732363 TI - Fatty acid 2-hydroxylase deficiency: clinical features and brain iron accumulation. PMID- 25732364 TI - Prehospital stroke scales in urban environments: a systematic review. PMID- 25732365 TI - Peripheral pulse measurement after ischemic stroke: a feasibility study. PMID- 25732366 TI - Defining the clinical course of multiple sclerosis: the 2013 revisions. PMID- 25732367 TI - Physical activity attenuates age-related biomarker alterations in preclinical AD. PMID- 25732368 TI - Clinical reasoning: a 35-year-old man with 2 episodes of meningoencephalitis associated with flu-like illnesses. PMID- 25732369 TI - Teaching NeuroImages: Unilateral agenesis of internal carotid artery with ophthalmic artery from opposite side. PMID- 25732370 TI - Teaching NeuroImages: Idiopathic hypertrophic spinal pachymeningitis mimicking epidural lymphoma. PMID- 25732371 TI - Far Space Remapping by Tool Use: A rTMS Study Over the Right Posterior Parietal Cortex. AB - BACKGROUND: In previous studies, rTMS has been successfully employed to interfere with the right posterior parietal cortex (rPPC) inducing neglect-like behavior in healthy subjects. Several studies have shown that the use of tools can modulate the boundaries between near and far space: indeed when far space is reached by the stick, far space can be remapped as near. OBJECTIVE: The aim of the present study was to investigate whether once that rTMS on the rPPC has selectively induced neglect-like bias in the near space (but not in the far space), neglect can appears also in the far space when the subjects used a tool to perform the task. METHODS: Fifteen right-handed healthy subjects executed a line length judgment task in two different spatial positions (60 cm: near space and 120 cm: far space), with or without rPPC on-line rTMS. In the far space condition, subjects performed the perceptual task while holding or not a tool. RESULTS: During rTMS, visuospatial performance significantly shifted toward right when the task was performed in the near space and in the far space when the tool was used. No significant effect was found when rTMS was delivered in the far space condition without tool use. CONCLUSIONS: Our results demonstrate that the application of rTMS on rPPC, specifically affect the representation of near space because it caused neglect both when the subjects acted in the near space and when they acted in a far space that was remapped as near by the use of a tool. PMID- 25732372 TI - The Stabilization of Amorphous Zopiclone in an Amorphous Solid Dispersion. AB - Zopiclone is a poorly soluble psychotherapeutic agent. The aim of this study was to prepare and characterize an amorphous form of zopiclone as well as the characterization and performance of a stable amorphous solid dispersion. The amorphous form was prepared by the well-known method of quench-cooling of the melt. The solid dispersion was prepared by a solvent evaporation method of zopiclone, polyvinylpyrrolidone-25 (PVP-25), and methanol, followed by freeze drying. The physico-chemical properties and stability of amorphous zopiclone and the solid dispersion was studied using differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray diffractometry (XRD), solubility, and dissolution studies. The zopiclone amorphous solid-state form was determined to be a fragile glass; it was concluded that the stability of the amorphous form is influenced by both temperature and water. Exposure of amorphous zopiclone to moisture results in rapid transformation of the amorphous form to the crystalline dihydrated form. In comparison, the amorphous solid dispersion proved to be more stable with increased aqueous solubility. PMID- 25732374 TI - Reply to: Colon LB, Perissinotti A, Santarosa M, Marini BL. Pharmacokinetic and clinical considerations for monitoring asparaginase activity levels during pegaspargase therapy. PMID- 25732373 TI - Sublingual Diffusion of Epinephrine Microcrystals from Rapidly Disintegrating Tablets for the Potential First-Aid Treatment of Anaphylaxis: In Vitro and Ex Vivo Study. AB - For the first-aid treatment of anaphylaxis, epinephrine (Epi) 0.3 mg intramuscular (IM) injection in the thigh is the drug of choice. Epi auto injectors are widely recommended for anaphylaxis treatment in community settings but not necessarily carried or used as prescribed when anaphylaxis occurs. We therefore developed rapidly disintegrating sublingual tablets (RDSTs) as an alternative noninvasive dosage form. Our objective in this study was to evaluate the effect of reducing Epi particle size on its in vitro and ex vivo diffusion, with the goal of enhancing Epi sublingual absorption from Epi RDSTs. Epi particle size was reduced by top-bottom technique using a microfluidizer for one pass at 30,000 Psi. The micronized Epi crystals (Epi-MC) were characterized using Zetasizer, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Epi RDSTs were formulated and manufactured using our previously developed method. In vitro and ex vivo diffusion of Epi 10, 20, and 40 mg RDSTs and Epi-MC 10 and 20 mg RDSTs (n = 4) were evaluated using Franz cells. Epi 10 mg solution was used as a control. Mean (+/-standard deviation (SD)) Epi particle size was successfully reduced from 131.8 +/- 10.5 to 2.5 +/- 0.4 MUm. Cumulative Epi diffused and influx from 40 mg Epi RDSTs and 20 mg Epi-MC RDSTs were not significantly different from each other in vitro and ex vivo (p > 0.05). Also, Epi permeability from 20 mg Epi-MC RDSTs was significantly higher than from the rest (p < 0.05). Epi-MC RDSTs improved Epi diffusion twofold and might have the potential to reduce the Epi dose needed in RDSTs by 50%. PMID- 25732375 TI - Influence of the Comprehensive Unit-based Safety Program in ICUs: Evidence From the Keystone ICU Project. AB - Using data from the Keystone ICU project, this study examined whether the intensive care units (ICUs) that implemented the Comprehensive Unit-based Safety Program (CUSP) would have greater improvement in safety climate, team progress barriers, and central line-associated bloodstream infections (CLABSIs) than ICUs not implementing CUSP. The study population consisted of 103 ICUs; 60 ICUs (58%) used CUSP, with 6 of them later discontinuing CUSP, and 17 ICUs (16.5%) never used CUSP. The researchers could not determine CUSP use status for the remaining 26 ICUs because of missing data. The use of CUSP was associated with improved safety climate, job satisfaction, and working conditions after a 2-year period, as measured by the Safety Attitudes Questionnaire. Study results on barriers and CLABSIs are inconclusive. This study demonstrated that unit-based, formalized processes targeting cultural improvements in teamwork, communication, self identification of hazards, and hazard mitigation can improve several aspects of patient safety climate in ICUs. PMID- 25732376 TI - Maintenance of Certification, Medicare Quality Reporting, and Quality of Diabetes Care. AB - Aligning maintenance of certification with quality reporting may ease reporting burden, but the impact on quality is uncertain. This study compared changes in quality measures from American Board of Family Medicine Performance in Practice Modules (PPMs), Physician Quality Reporting System (PQRS), and a combined PQRS/PPM for diabetes between 2008 and 2012. Physicians completed 7264 diabetes PPMs, 297 only reported PQRS measures 2 or more times, and 675 completed a combination project, representing more than 200 000 patients. After adjustment, PQRS and PQRS/PPM projects were associated with greater blood pressure and cholesterol control improvement than PPM only (P < .05). PPM-only projects had greater improvement than PQRS-only projects on 4 of 6 process measures and greater hemoglobin A1c improvement (P < .05) but were only better on 2 process measures and on hemoglobin A1c control than PQRS/PPM projects. These findings identify differences between quality reporting and quality improvement, suggesting reason to align the 2 programs. PMID- 25732379 TI - Omega-3 fatty acids and stress-induced changes to mood and cognition in healthy individuals. AB - Omega-3 fatty acid (n-3 PUFA) intake is associated with improved mood and cognition, but randomized controlled trials addressing the causal nature of such relationships are less clear, especially in healthy, young adults. Stress is one potential mechanism by which n-3 PUFAs may influence mood. Thus the present aim is to evaluate the influence of n-3 PUFA supplementation on stress-induced changes to mood, cognition, and physiological stress markers in healthy, young adults. Using a double-blind, placebo-controlled design, 72 young adults were randomized to receive 2800mg/day fish oil (n=36, 23 females) or olive oil control (n=36, 22 females) for 35days. Subjects completed measures of mood and cognition before supplementation, and two times after supplementation: following an acute stressor or non-stressful control task. The stress induction was effective in that the stressor impaired mood, including augmenting feelings of tension, anger, confusion and anxiety, reduced accuracy on a cognitive task measuring attentional control and the ability to regulate emotion, and increased salivary cortisol and pro-inflammatory cytokine interleukin-1beta (IL-1beta). Rated anger and confusion increased with stress in the olive oil group, but remained stable in the fish oil group. However, fish oil had no further effects on mood, cognitive function, cortisol, or IL-1beta. Fish oil exerted few effects in stressful and non stressful situations, consistent with findings showing little influence of n-3 PUFA supplementation on mood and cognition in young, healthy individuals. Potential target populations who would more likely benefit from increased n-3 PUFA intake are discussed. PMID- 25732377 TI - By the sound of it. An ERP investigation of human action sound processing in 7 month-old infants. AB - Recent evidence suggests that human adults perceive human action sounds as a distinct category from human vocalizations, environmental, and mechanical sounds, activating different neural networks (Engel et al., 2009; Lewis et al., 2011). Yet, little is known about the development of such specialization. Using event related potentials (ERP), this study investigated neural correlates of 7-month olds' processing of human action (HA) sounds in comparison to human vocalizations (HV), environmental (ENV), and mechanical (MEC) sounds. Relative to the other categories, HA sounds led to increased positive amplitudes between 470 and 570ms post-stimulus onset at left anterior temporal locations, while HV led to increased negative amplitudes at the more posterior temporal locations in both hemispheres. Collectively, human produced sounds (HA+HV) led to significantly different response profiles compared to non-living sound sources (ENV+MEC) at parietal and frontal locations in both hemispheres. Overall, by 7 months of age human action sounds are being differentially processed in the brain, consistent with a dichotomy for processing living versus non-living things. This provides novel evidence regarding the typical categorical processing of socially relevant sounds. PMID- 25732380 TI - Evidence for homoploid speciation in Phytophthora alni supports taxonomic reclassification in this species complex. AB - Alder decline has been a problem along European watercourses since the early 1990s. Hybridization was identified as the main cause of this emerging disease. Indeed, the causal agent, a soil-borne pathogen named Phytophthora alni subsp. alni (Paa) is the result of interspecific hybridization between two taxa, Phytophthora alni subsp. multiformis (Pam) and Phytophthora alni subsp. uniformis (Pau), initially identified as subspecies of Paa. The aim of this work was to characterize the ploidy level within the P. alni complex that is presently poorly understood. For that, we used two complementary approaches for a set of 31 isolates of Paa, Pam and Pau: (i) quantification of allele copy number of three single-copy nuclear genes using allele-specific real-time PCR and (ii) comparison of the genome size estimated by flow cytometry. Relative quantification of alleles of the three single-copy genes showed that the copy number of a given allele in Paa was systematically half that of its parents Pau or Pam. Moreover, DNA content estimated by flow cytometry in Paa was equal to half the sum of those in Pam and Pau. Our results therefore suggest that the hybrid Paa is an allotriploid species, containing half of the genome of each of its parents Pam and Pau, which in turn are considered to be allotetraploid and diploid, respectively. Paa thus results from a homoploid speciation process. Based on published data and on results from this study, a new formal taxonomic name is proposed for the three taxa Paa, Pam and Pau which are raised to species status and renamed P. *alni, P. *multiformis and P. uniformis, respectively. PMID- 25732381 TI - Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach. AB - Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan into host cells. NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-kappaB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure. We previously demonstrated that the H. pylori cag(+) strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF kappaB, inflammation, and cancer. Coculture of H. pylori strain 7.13 or its pgdA( ) isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-kappaB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-kappaB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA(-) mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, preactivation of NOD1 before bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared with noncancer samples harvested from the same patients. These results indicate that peptidoglycan deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche. PMID- 25732382 TI - Host age is a systemic regulator of gene expression impacting cancer progression. AB - Aging is the major determinant of cancer incidence, which, in turn, is likely dictated in large part by processes that influence the progression of early subclinical (occult) cancers. However, there is little understanding of how aging informs changes in aggregate host signaling that favor cancer progression. In this study, we provide direct evidence that aging can serve as an organizing axis to define cancer progression-modulating processes. As a model system to explore this concept, we employed adolescent (68 days), young adult (143 days), middle aged (551 days), and old (736 days) C57BL/6 mice as syngeneic hosts for engraftment of Lewis lung cancer to identify signaling and functional processes varying with host age. Older hosts exhibited dysregulated angiogenesis, metabolism, and apoptosis, all of which are associated with cancer progression. TGFbeta1, a central player in these systemic processes, was downregulated consistently in older hosts. Our findings directly supported the conclusion of a strong host age dependence in determining the host tumor control dynamic. Furthermore, our results offer initial mechanism-based insights into how aging modulates tumor progression in ways that may be actionable for therapy or prevention. PMID- 25732384 TI - Emotion Word Processing: Effects of Word Type and Valence in Spanish-English Bilinguals. AB - Previous studies comparing emotion and emotion-laden word processing have used various cognitive tasks, including an Affective Simon Task (Altarriba and Basnight-Brown in Int J Billing 15(3):310-328, 2011), lexical decision task (LDT; Kazanas and Altarriba in Am J Psychol, in press), and rapid serial visual processing (Knickerbocker and Altarriba in Vis Cogn 21(5):599-627, 2013). Each of these studies has found significant differences in emotion and emotion-laden word processing. The current study investigated this word type distinction using a bilingual sample, to assess emotion and emotion-laden word processing in a bilingual's two languages. Sixty Spanish-English bilinguals performed a masked LDT with positive and negative emotion and emotion-laden word pairs, in either Spanish or English. Overall, the four-way interaction of relatedness, word type, valence, and language was significant. Response times (RTs) to emotion words were significantly faster than RTs to emotion-laden words, but only in English. These results indicate that the emotion/emotion-laden word type distinction may be the most robust in a person's dominant language. PMID- 25732383 TI - Do rice suspension-cultured cells treated with abscisic acid mimic developing seeds? AB - Starch synthesis is activated in the endosperm during seed development and also in rice suspension cells cultured with abscisic acid. In the anticipation that the mechanisms of starch synthesis are similar between the endosperm and the suspension cells cultured with abscisic acid, expression of genes involved in starch synthesis was evaluated in the suspension cells after abscisic acid treatment. However, it was found that the regulatory mechanism of starch synthesis in the suspension cells cultured with abscisic acid was different from that in developing seeds. Expression analyses of genes involved in oil bodies, which accumulate in the embryo and aleurone layer, and seed storage proteins, which accumulate mainly in the endosperm, showed that the former were activated in the suspension cells cultured with abscisic acid, but the latter were not. Master regulators for embryogenesis, OsVP1 (homologue of AtABI3) and OsLFL1 (homologue of AtFUS3 or AtLFL2), were expressed in the suspension cells at levels comparable to those in the embryo. From these results, it is suggested that interactions between regulators and abscisic acid control the synthesis of phytic acid and oil bodies in the cultured cells and embryo. We suggest that the system of suspension cells cultured with abscisic acid helps to reveal the mechanisms of phytic acid and oil body synthesis in embryo. PMID- 25732385 TI - Transpiration and water-use efficiency in mixed-species forests versus monocultures: effects of tree size, stand density and season. AB - Mixtures can be more productive than monocultures and may therefore use more water, which may make them more susceptible to droughts. The species interactions that influence growth, transpiration and water-use efficiency (WUE, tree growth per unit transpiration) within a given mixture vary with intra- and inter-annual climatic variability, stand density and tree size, but these effects remain poorly quantified. These relationships were examined in mixtures and monocultures of Eucalyptus globulus Labill. and Acacia mearnsii de Wildeman. Growth and transpiration were measured between ages 14 and 15 years. All E. globulus trees in mixture that were growing faster than similar sized trees in monocultures had higher WUE, while trees with similar growth rates had similar WUE. By the age of 14 years A. mearnsii trees were beginning to senesce and there were no longer any relationships between tree size and growth or WUE. The relationship between transpiration and tree size did not differ between treatments for either species, so stand-level increases in transpiration simply reflected the larger mean tree size in mixtures. Increasing neighbourhood basal area increased the complementarity effect on E. globulus growth and transpiration. The complementarity effect also varied throughout the year, but this was not related to the climatic seasonality. This study shows that stand-level responses can be the net effect of a much wider range of individual tree-level responses, but at both levels, if growth has not increased for a given species, it appears unlikely that there will be differences in transpiration or WUE for that species. Growth data may provide a useful initial indication of whether mixtures have higher transpiration or WUE, and which species and tree sizes contribute to this effect. PMID- 25732386 TI - Variations between the photosynthetic properties of elite and landrace Chinese rice cultivars revealed by simultaneous measurements of 820 nm transmission signal and chlorophyll a fluorescence induction. AB - The difference between the photosynthetic properties of elite and landrace Chinese rice cultivars was studied, using chlorophyll a fluorescence induction (mostly a monitor of Photosystem II activity) and I820 transmission signal (mostly a monitor of Photosystem I activity) to identify potential photosynthetic features differentiating these two groups, which show different degrees of artificial selection and grain yields. A higher fluorescence (related to PSII) IP rise phase and a lower P700(+) (related to PSI) accumulation were observed in the elite cultivars as compared to the landraces. Using these data, together with simulation data from a kinetic model of fluorescence induction, we show that the high IP rise phase and the low P700(+) accumulation can be a result of transient block on electron transfer and traffic jam on the electron acceptor side of PSI under a high [NADPH]/[NADP(+)] ratio. Considering that the ferredoxin NADP(+) reductase (FNR) transcript levels of XS134 (a representative elite cultivars) remains unaffected during the first few minutes of light/dark transition compared to Q4145 (a representative landrace cultivars), which shows a strong decline during the same time range, we propose that the FNR of elite cultivars may take more time to be inactivated in darkness. During this time the FNR enzyme can continue to reduce NADP(+) molecules, leading to initially high [NADPH]/[NADP(+)] ratio during OJIP transient. These data suggested a potential artificial selection of FNR during the breeding process of these examined elite rice cultivars. PMID- 25732387 TI - Rectal cancer: the evolving role of adjuvant radiotherapy. PMID- 25732388 TI - Getting young surgeons interested in rural practice still vexes us: but should it? PMID- 25732389 TI - Radical cystectomy in Australia. PMID- 25732390 TI - Complete clinical response to neoadjuvant chemoradiotherapy for rectal cancer: an Australasian perspective. PMID- 25732391 TI - Re: palliative bypass for small bowel carcinoid with mesenteric mass and vascular encasement. PMID- 25732392 TI - Response to re: palliative bypass for small bowel carcinoid with mesenteric mass and vascular encasement. PMID- 25732393 TI - Response to re: rapid progression of perianal abscess into Fournier's gangrene. PMID- 25732394 TI - Re: rapid progression of perianal abscess into Fournier's gangrene. PMID- 25732395 TI - Triplication of ureter with ureterocoele and renal calculi. PMID- 25732396 TI - Mesenteric epidermoid cyst presenting with right iliac fossa pain. PMID- 25732397 TI - Health professionals' provision of lifestyle advice in the oncology context in the United Kingdom. AB - A healthy lifestyle following a cancer diagnosis is linked with better long-term outcomes. Health professionals can play an important role in promoting healthy lifestyles after cancer, but little is known about the factors that influence whether or not they give lifestyle advice. We conducted an online survey to examine levels of, and predictors of, health professionals' provision of lifestyle advice to cancer patients in the United Kingdom. The survey included questions on awareness of lifestyle guidelines for cancer survivors, current practices with regard to giving advice on smoking, diet, exercise, weight and alcohol, and perceived barriers to giving advice. Nurses, surgeons and physicians (N=460) responded to the survey. Many (36%) were not aware of any lifestyle guidelines for cancer survivors, but 87% reported giving some lifestyle advice; although this was lower for individual behaviours and often to <50% of patients. Respondents who were aware of lifestyle guidelines were more likely to give lifestyle advice on all behaviours (all OR's>1.76, all P's<0.05). Not believing lifestyle would affect outcomes was associated with lower odds of giving lifestyle advice (all OR's<0.48, all P's<0.05). Improved survivorship education for health professionals may increase the number of patients receiving lifestyle advice, and improve their long-term outcomes. PMID- 25732398 TI - Effect of a new longitudinal interprofessional geriatric medicine educational track on knowledge and attitude of medical students: a controlled cohort study. AB - A new interprofessional geriatric medicine curriculum was recently introduced at a large undergraduate Asian medical school. A longitudinal controlled interventional cohort study was conducted to evaluate the effect of the new curriculum on the knowledge and attitudes of medical students. The medical students under the new curriculum formed the intervention cohort, and those under the former curriculum formed the control cohort. To test knowledge, the University of California at Los Angeles (UCLA) geriatrics knowledge test (GKT) was used in Year 2 and the University of Michigan GKT in Year 5. Geriatrics attitudes were evaluated using the UCLA geriatrics attitudes test in Years 2 and 5. Not surprisingly, geriatrics knowledge at the end of Year 5 of medical school was enhanced to a greater degree in the intervention cohort than the control cohort, although improvements in geriatrics attitudes in each cohort were of similar magnitude by the end of Year 5, suggesting that factors other than a formal geriatrics curriculum influenced the improvements in geriatrics attitudes. This article is one of few published on the effectiveness of geriatrics curricular innovations using validated knowledge and attitude outcomes in a longitudinal controlled study design and will be useful to other medical institutions seeking to improve the geriatrics knowledge and attitudes of their students. PMID- 25732399 TI - Micro-computed Tomographic Analysis of Mandibular Second Molars with C-shaped Root Canals. AB - INTRODUCTION: The goal of the present study was to evaluate the morphometric aspects of the internal anatomy of the root canal system of mandibular second molars with C-shaped canals. METHODS: Fifty-two extracted second mandibular molars with C-shaped canals, fused roots, and radicular grooves were selected from a Brazilian population. The samples were scanned with a micro-computed tomographic scanner at a voxel size of 19.6 MUm. The root canal cross sections were recorded as C1, C2, C3, and C4 root canal configurations according to the modified Melton classification. Morphometric parameters, including the major and minor diameters of the root canals, the aspect ratio, the roundness, and the tridimensional configuration (merging, symmetric, and asymmetric), were evaluated. RESULTS: The 3-dimensional reconstruction images of the teeth indicated an even distribution within the sample. The analysis of the prevalence of the different cross-sectional configurations of the C-shaped molars revealed that these were predominantly of the C4 and C3 configurations (1 mm from the apex) and the C1 and C2 configurations in the cervical third. According to the morphometric parameters, the C1 and the distal aspect of the C2 configurations exhibited the lowest roundness values and higher values for the area, major diameter, and aspect ratio in the apical third. CONCLUSIONS: Mandibular molars with C-shaped root canals exhibited similar distributions of symmetric, asymmetric, and merging type canals. The C1 configuration and the distal aspect of the C2 configuration exhibited the highest area values, low roundness values, and large apical diameters. PMID- 25732400 TI - Differential diagnoses for persistent pain after root canal treatment: a study in the National Dental Practice-based Research Network. AB - INTRODUCTION: Pain present 6 months after root canal treatment (RCT) may be of odontogenic or nonodontogenic origin. This is important because treatments and prognoses are different; therefore, the aim of this study was to provide specific diagnoses of patients reporting pain 6 months after receiving initial orthograde RCT. METHODS: We enrolled patients from the Midwest region of an existing prospective observational study of pain after RCT. Pain at 6 months was defined as >=1 day of pain and average pain intensity of at least 1 of 10 over the preceding month. An endodontist and an orofacial pain practitioner independently performed clinical evaluations, which included periapical and cone-beam computed tomographic radiographs, to determine diagnoses. RESULTS: Thirty-eight of the 354 eligible patients in the geographic area (11%) met the pain criteria, with 19 (50%) consenting to be clinically evaluated. As the sole reason for pain, 7 patients (37%) were given odontogenic diagnoses (4 involving the RCT tooth and 3 involving an adjacent tooth). Eight patients (42%) were given nonodontogenic pain diagnoses (7 from referred temporomandibular disorder pain and 1 from persistent dentoalveolar pain disorder). Two patients (11%) had both odontogenic and nonodontogenic diagnoses, whereas 2 (11%) no longer fit the pain criteria at the time of the clinical evaluation. CONCLUSIONS: Patients reporting "tooth" pain 6 months after RCT had a nonodontogenic pain diagnosis accounting for some of this pain, with temporomandibular disorder being the most frequent nonodontogenic diagnosis. Dentists should have the necessary knowledge to differentiate between these diagnoses to adequately manage their patients. PMID- 25732401 TI - Acetaminophen: old drug, new issues. AB - INTRODUCTION: The purpose of this review was to discuss new issues related to safety, labeling, dosing, and a better understanding of the analgesic effect of acetaminophen. METHODS: The MEDLINE, Embase, Cochrane, and PubMed databases were searched. Additionally, the bibliography of all relevant articles and textbooks were manually searched. Two reviewers independently selected the relevant articles. RESULTS: Concerns about acetaminophen overdose and related liver failure have led the US Food and Drug Administration to mandate new labeling on acetaminophen packaging. In addition, large-scale epidemiologic studies increasingly report evidence for second-generation adverse effects of acetaminophen. Prenatal exposure to acetaminophen is associated with neurodevelopmental and behavioral disorders. Recent studies also suggest that acetaminophen is a hormone disrupter (ie, it interferes with sex and thyroid hormone function essential for normal brain development) and thus may not be considered a safe drug during pregnancy. Finally, emerging evidence suggests that although the predominant mechanism by which acetaminophen exerts its therapeutic effect is by inhibition of cyclooxygenase, multiple other mechanisms also contribute to its analgesic effect. CONCLUSIONS: Available evidence suggests that indiscriminate usage of this drug is not warranted. and its administration to a pregnant patient should be considered with great caution. PMID- 25732402 TI - Color changes of teeth after treatment with various mineral trioxide aggregate based materials: an ex vivo study. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) materials have been used for many years as a pulp therapy material. The most widely used product, ProRoot MTA (Dentsply, Tulsa, OK), has a major drawback in that it causes tooth discoloration. Alternatives have recently been developed such as ENDOCEM Zr (MARUCHI, Wonju, Korea) and RetroMTA (BioMTA, Seoul, Korea). The purpose of this study was to compare the discoloration of these various MTA-based materials. METHODS: Discoloration of discs prepared from 4 different MTA-based materials (ProRoot MTA, MTA Angelus [Angelus, Londrina, PR, Brazil], ENDOCEM Zr, and RetroMTA) were observed at 15 and 30 minutes after exposure to light at an intensity of 1000 mA/cm(2). In a tooth model, 12 premolars were used per each group to retrofill the pulp chamber with MTA-based materials. The degree of discoloration was measured over a 16-week period using a digital spectrophotometer. RESULTS: Distinct color changes were observed for discs made from ProRoot MTA and MTA Angelus, but no clear change was observed for those made from either ENDOCEM Zr or RetroMTA. In the tooth model, more distinct, time dependent color changes were observed for teeth filled with ProRoot MTA and MTA Angelus than for those filled with ENDOCEM Zr and RetroMTA. CONCLUSIONS: Less discoloration was observed with ENDOCEM Zr and RetroMTA (which contain zirconium oxide) than with ProRoot MTA and MTA Angelus (which contain bismuth oxide) in both of the test models used. PMID- 25732403 TI - Endodontic Treatment of an Anomalous Anterior Tooth with the Aid of a 3 dimensional Printed Physical Tooth Model. AB - Endodontic treatment of tooth formation anomalies is a challenge to clinicians and as such requires a complete understanding of the aberrant root canal anatomy followed by careful root canal disinfection and obturation. Here, we report the use of a 3-dimensional (3D) printed physical tooth model including internal root canal structures for the endodontic treatment of a challenging tooth anomaly. A 12-year-old boy was referred for endodontic treatment of tooth #8. The tooth showed class II mobility with swelling and a sinus tract in the buccal mucosa and periapical radiolucency. The tooth presented a very narrow structure between the crown and root by distal concavity and a severely dilacerated root. Moreover, a perforation site with bleeding and another ditching site were identified around the cervical area in the access cavity. A translucent physical tooth model carrying the information on internal root canal structures was built through a 3 step process: data acquisition by cone-beam computed tomographic scanning, virtual modeling by image processing, and manufacturing by 3D printing. A custom made guide jig was then fabricated to achieve a safe and precise working path to the root canal. Endodontic procedures including access cavity preparation were performed using the physical tooth model and the guide jig. At the 7-month follow up, the endodontically treated tooth showed complete periapical healing with no clinical signs and symptoms. This case report describes a novel method of endodontic treatment of an anomalous maxillary central incisor with the aid of a physical tooth model and a custom-made guide jig via 3D printing technique. PMID- 25732404 TI - Epigallocatechin gallate (EGCG) suppresses lipopolysaccharide-induced Toll-like receptor 4 (TLR4) activity via 67 kDa laminin receptor (67LR) in 3T3-L1 adipocytes. AB - Obesity-related insulin resistance is associated with chronic systemic low-grade inflammation, and toll-like receptor 4 (TLR4) regulates inflammation. We investigated the pathways involved in epigallocatechin gallate (EGCG) modulation of insulin and TLR4 signaling in adipocytes. Inflammation was induced in adipocytes by lipopolysaccharide (LPS). An antibody against the 67 kDa laminin receptor (67LR, to which EGCG exclusively binds) was used to examine the effect of EGCG on TLR4 signaling, and a TLR4/MD-2 antibody was used to inhibit TLR4 activity and to determine the insulin sensitivity of differentiated 3T3-L1 adipocytes. We found that EGCG dose-dependently inhibited LPS stimulation of adipocyte inflammation by reducing inflammatory mediator and cytokine levels (IKKbeta, p-NF-kappaB, TNF-alpha, and IL-6). Pretreatment with the 67LR antibody prevented EGCG inhibition of inflammatory cytokines, decreased glucose transporter isoform 4 (GLUT4) expression, and inhibited insulin-stimulated glucose uptake. TLR4 inhibition attenuated inflammatory cytokine levels and increased glucose uptake by reversing GLUT4 levels. These data suggest that EGCG suppresses TLR4 signaling in LPS-stimulated adipocytes via 67LR and attenuates insulin-stimulated glucose uptake associated with decreased GLUT4 expression. PMID- 25732405 TI - Brinzolamide/brimonidine: a review of its use in patients with open-angle glaucoma or ocular hypertension. AB - Brinzolamide 1 %/brimonidine 0.2 % ophthalmic suspension (Simbrinza((r))) is a fixed-combination of a carbonic anhydrase inhibitor and an alpha2-adrenergic receptor agonist that is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension in both the USA and EU (with the EU indication restricted to patients for whom monotherapy provides insufficient IOP reduction). In phase III randomized trials, both three-times-daily and twice-daily administration of brinzolamide/brimonidine provided significantly greater IOP-lowering efficacy over 3-6 months than either of its individual components alone, and twice-daily brinzolamide/brimonidine was noninferior to concomitant administration of brinzolamide plus brimonidine over 6 months in this regard. Brinzolamide/brimonidine was generally well tolerated, with a tolerability profile that was consistent with its individual components and with no unexpected safety findings. Therefore, brinzolamide/brimonidine is an effective treatment option for patients with open-angle glaucoma or ocular hypertension, providing a convenient alternative for those patients who require multiple IOP-lowering medications. Brinzolamide/brimonidine is the first available fixed-combination that does not contain timolol, and maybe particularly suited to patients with comorbidities that restrict treatment with beta adrenergic receptor antagonists. PMID- 25732406 TI - Prediction of esophageal varices in cirrhotic patients with apparent diffusion coefficient of the spleen. AB - PURPOSE: To predict esophageal varices in cirrhotic patients with apparent diffusion coefficient (ADC) of the spleen and to correlate the ADC with clinical and laboratory biomarkers of esophageal varices. MATERIALS AND METHODS: This study was conducted upon 40 patients (28 male, 12 female; age ranged 19-45 years; mean age = 33 years) with biopsy-proven cirrhotic liver. Twenty age- and sex matched healthy volunteers were included as a control group. Patients with varices (n = 15) and without varices (n = 25) and volunteers underwent echo planar diffusion-weighted MR imaging of the abdomen with b factors of 0, 400, and 800 s/mm(2). The ADC maps of the abdomen were reconstructed. The ADC values of the spleen were calculated and correlated with the Child score, platelet count, and prothrombin time. RESULTS: The mean ADC value of the spleen in cirrhotic patients (1.34 +/- 0.05 * 10(-3) mm(2)/s) was significantly different (P = 0.001) from that of volunteers (0.87 +/- 0.04 * 10(-3) mm(2)/s). The ADC of the spleen in cirrhotic patients with varices (1.49 +/- 0.05 * 10(-3) mm(2)/s) was significantly different (P = 0.001) from that of patients without varices (1.11 +/- 0.06 * 10(-3) mm(2)/s). The cut-off ADC value of the spleen used for prediction of cirrhosis and varices was 1.15 and 1.29 * 10(-3) mm(2)/s with areas under the curve were 0.872 and 0.889, respectively. The ADC value of the spleen was correlated with the splenic volume (r = 0.862; P = 0.001), Child score (r = 0.742; P = 0.001), platelet count (r = -0.698; P = 0.01), and prothrombin time (r = 0.684; P = 0.01). CONCLUSION: The ADC value of the spleen can predict esophageal varices in cirrhotic patients and is well correlated with the clinical and laboratory biomarkers of esophageal varices. PMID- 25732407 TI - Wolves trigger a trophic cascade to berries as alternative food for grizzly bears. AB - This is a Forum article in response to: Barber-Meyer, S. (2015) Trophic cascades from wolves to grizzly bears or changing abundance of bears and alternate foods? Journal of Animal Ecology, 83, doi: 10.1111/1365-2656.12338. We used multiple data sets and study areas as well as several lines of evidence to investigate potential trophic linkages in Yellowstone National Park. Our results suggest that a trophic cascade from wolves to elk to berry production to berry consumption by grizzly bears may now be underway in the Park. PMID- 25732408 TI - What are the Consequences of Volume Expansion in Chronic Dialysis Patients?: Defining and Measuring Fluid Overload in Hemodialysis Patients. PMID- 25732409 TI - Identification of methicillin-susceptible or methicillin-resistant Staphylococcus aureus carrier status preoperatively using polymerase chain reaction in patients undergoing elective surgery with hardware implantation. AB - We compared bedside polymerase chain reaction to culture for identifying Staphylococcus aureus in patients about to undergo surgery with hardware implantation. Patients were screened for S. aureus carrier status at the preoperative clinic and on the day of surgery. The sensitivity, specificity, positive and negative predictive values, and accuracy were calculated. PMID- 25732410 TI - Current approaches to device implantation in pediatric and congenital heart disease patients. AB - The pediatric ventricular assist device (VAD) has recently shown substantial improvements in survival as a bridge to heart transplant for patients with end stage heart failure. Since that time, its use has become much more frequent. With increasing utilization, additional questions have arisen including patient selection, timing of VAD implantation and device selection. These challenges are amplified by the uniqueness of each patient, the recent abundance of literature surrounding VAD use as well as the technological advancements in the devices themselves. Ideal strategies for device placement must be sought, for not only improved patient care, but also for optimal resource utilization. Here, we review the most relevant literature to highlight some of the challenges facing the heart failure specialist, and any physician, who will care for a child with a VAD. PMID- 25732411 TI - Characterisation of a Babesia orientalis apical membrane antigen, and comparison of its orthologues among selected apicomplexans. AB - In the present study, we identified and characterised the complete coding sequence of Babesia orientalis apical membrane antigen 1 (designated Bo-ama1); it is 1803bp in length and encodes a polypeptide of 601 amino acids (aa). The Bo-ama 1 gene product (Bo-AMA1) is predicted to be 67kDa in size and contains a signal peptide. Mature Bo-AMA1 is predicted to have one transmembrane region and a short cytoplasmic tail (C-terminal domain). The extracellular part of Bo-AMA1 has three functional domains (DI, DII and DIII) with 14 conserved cysteine residues. A Bo AMA1 fragment containing all three of these domains (designated Bo-AMA1 DI/II/III) was cloned into the plasmid vector pET-28a and expressed as a recombinant (His-fusion) protein of 53kDa. Antibodies in the serum from a B. orientalis-infected water buffalo specifically recognised this protein in immunoblotting analysis. Rabbit antibodies raised against the recombinant protein were able to detect native Bo-AMA1 (67kDa) from erythrocytes of B. orientalis infected water buffalo. Bo-AMA1 is a new member of the AMA1 family and might be a good antigen for the specific detection of antibodies produced in B. orientalis infected cattle. This protein is likely to play critical roles during host cell adherence and invasion by B. orientalis, as the AMA1s reported in other organisms such as Plasmodium falciparum and Toxoplasma gondii. Further research is required to explore the biological functions of this protein and to determine whether its immunisation can induce protective effects in water buffalo against B. orientalis infection. PMID- 25732412 TI - Examining the psychometric properties of the Yale-Brown Obsessive-Compulsive Scale in a sample of compulsive pornography users. AB - OBJECTIVE: The current study evaluated several psychometric properties of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (Goodman et al., 1989) adapted for compulsive sexual behavior (CSB) in a sample of 103 men seeking treatment at a private and a public university clinic in the United States. METHOD: Measures of mental health functioning were collected from patients on two separate appointments: the initial screening and the follow-up appointment. RESULTS: All patients reported using pornography compulsively, and approximately half of the sample also reported a history of having frequent anonymous sex with strangers. Results found that the adapted Y-BOCS had good internal consistency reliability, moderate mean inter-item correlations, and good test-retest reliability. Results from a multiple regression analysis also found that affect dysregulation (depression and anxiety), particularly among single, impaired men, was significantly associated with more severe sexual obsessive and compulsive features. Approximately 94% of the sample met criteria for at least one psychiatric disorder, and 57% of men met criteria for two or more psychiatric disorders. CONCLUSIONS: Findings from the current study suggest the CSB-Y-BOCS is a reliable measure of obsessive and compulsive symptoms associated with CSB, and clinicians and researchers could use this scale to aid in the assessment and treatment of problematic sexual behaviors. PMID- 25732413 TI - Cloninger's temperament and character traits in medical students of Korea with problem eating behaviors. AB - BACKGROUND AND OBJECTIVE: The personality profiles of patients with eating disorder have been extensively investigated, but those of people in the general population with eating behavior problems need to be evaluated to assess the relationship between personality, health behavior and level of overall well-being in non-clinical samples. DESIGN: Temperament and character traits, reasons for over-eating, and the negative influence of functional dyspepsia on quality of life were measured by the Temperament and Character Inventory (TCI), Dutch Eating Behavior Questionnaire (DEBQ), and Functional Dyspepsia Quality of Life (FDQOL) inventory, respectively, in 199 Korean medical students. The associations among TCI, FDQOL, DEBQ and body mass index (BMI) were examined by correlational analysis. Multiple regression analysis was carried out to measure how well personality (TCI) accounted for patterns of overeating (DEBQ) and impaired quality of life from functional dyspepsia (FDQOL). RESULTS: Individual differences in personality (especially harm-avoidance, self-transcendence, and self-directedness) were weakly associated with overeating and impaired quality of life from functional dyspepsia. Gender, social desirability and body mass index also played important roles in predicting eating behavior problems in the nonclinical population. DISCUSSION AND CONCLUSION: We found that the personality traits observed in clinical patients with eating disorders are also found in people with eating behavior problems in the nonclinical population of Korea. The ways that personality traits affect eating behaviors were discussed along with recommendations for future studies in light of the limitations of available data. PMID- 25732414 TI - How do gastroenterologists assess overall activity of eosinophilic esophagitis in adult patients? AB - OBJECTIVES: There is no "gold standard" for assessing disease activity in patients with eosinophilic esophagitis (EoE). We aimed to compare physicians' judgment of EoE activity with patients' judgment of symptom severity. We also aimed to examine the relative contribution of symptoms as well as endoscopic and histologic findings in shaping physicians' judgment of EoE activity. METHODS: Six gastroenterologists (all EoE experts) assessed EoE-associated symptoms in adult patients. Patients completed a symptom instrument and provided global assessment of EoE symptom severity (PatGA) (Likert scale: 0 (inactive) to 10 (most active)). Following esophagogastroduodenoscopy with biopsy sampling, gastroenterologists provided a global assessment of EoE activity (PhysGA) (Likert scale from 0 to 10) based on patient history and endoscopic and histologic findings. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms and endoscopic and histologic findings explain variations in PhysGA. RESULTS: A total of 149 EoE patients were prospectively included (71.8% male, median age at inclusion 38 years, 71.8% with concomitant allergies). A moderate positive correlation between PhysGA and PatGA (rho=0.442, P<0.001) was observed and the mean difference in the Bland-Altman plot was 1.77. Variations in severity of endoscopic findings, symptoms, and histologic findings alone explained 53%, 49%, and 30%, of the variability in PhysGA, respectively. Together, these findings explained 75% of variability in PhysGA. CONCLUSIONS: Gastroenterologists rate EoE activity mainly on the basis of endoscopic findings and symptoms and, to a lesser extent, on histologic findings. PMID- 25732415 TI - Impact of retroflexion vs. second forward view examination of the right colon on adenoma detection: a comparison study. AB - OBJECTIVES: Although screening colonoscopy is effective in preventing distal colon cancers, effectiveness in preventing right-sided colon cancers is less clear. Previous studies have reported that retroflexion in the right colon improves adenoma detection. We aimed to determine whether a second withdrawal from the right colon in retroflexion vs. forward view alone leads to the detection of additional adenomas. METHODS: Patients undergoing screening or surveillance colonoscopy were invited to participate in a parallel, randomized, controlled trial at two centers. After cecal intubation, the colonoscope was withdrawn to the hepatic flexure, all visualized polyps removed, and endoscopist confidence recorded on a 5-point Likert scale. Patients were randomized to a second exam of the proximal colon in forward (FV) or retroflexion view (RV), and adenoma detection rates (ADRs) compared. Logistic regression analysis was used to evaluate predictors of identifying adenomas on the second withdrawal from the proximal colon. RESULTS: A total of 850 patients (mean age 59.1+/-8.3 years, 59% female) were randomly assigned to FV (N=400) or RV (N=450). Retroflexion was successful in 93.5%. The ADR (46% FV and 47% RV) and numbers of adenomas per patient (0.9+/-1.4 FV and 1.1+/-2.1 RV) were similar (P=0.75 for both). At least one additional adenoma was detected on second withdrawal in similar proportions (10.5% FV and 7.5% RV, P=0.13). Predictors of identifying adenomas on the second withdrawal included older age (odds ratio (OR)=1.04, 95% confidence interval (CI)=1.01-1.08), adenomas seen on initial withdrawal (OR=2.8, 95% CI=1.7-4.7), and low endoscopist confidence in quality of first examination of the right colon (OR=4.8, 95% CI=1.9-12.1). There were no adverse events. CONCLUSIONS: Retroflexion in the right colon can be safely achieved in the majority of patients undergoing colonoscopy for colorectal cancer screening. Reexamination of the right colon in either retroflexed or forward view yielded similar, incremental ADRs. A second exam of the right colon should be strongly considered in patients who have adenomas discovered in the right colon, particularly when endoscopist confidence in the quality of initial examination is low. PMID- 25732416 TI - Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis. AB - OBJECTIVES: It has been suggested that colonization with C. difficile protects from infection. Nevertheless, the association between carriage of toxinogenic strains and ensuing C. difficile infections (CDIs) has not been studied. METHODS: We searched PubMed and EMBASE databases up to 20 June 2014, using the term "difficile". Our primary outcomes of interest included the prevalence of isolation of toxinogenic C. difficile or its toxins from asymptomatic patients on hospital admission through stool or rectal swab testing and the risk of ensuing infection among colonized and noncolonized patients. Data on previous hospitalization, antibiotic, and proton pump inhibitor (PPI) use and prior CDIs among colonized and noncolonized patients were also extracted. RESULTS: Nineteen out of 26,081 studies on 8,725 patients were included. The pooled prevalence of toxinogenic C. difficile colonization was 8.1% (95% confidence interval (CI) 5.7 11.1%), with an increasing trend over time (P=0.003), and 10.0% (95% CI 7.1 13.4%) among North American studies. Patients colonized upon hospital admission had a 5.9 times higher risk of subsequent CDIs compared with noncolonized patients (relative risk (RR) 5.86; 95% CI 4.21-8.16). The risk of CDI for colonized patients was 21.8% (95% CI 7.9-40.1%), which was significantly higher than that of noncolonized patients (3.4%; 95% CI 1.5-6.0%; P=0.03), with an attributable risk of 18.4%. History of hospitalization during the previous 3 months was associated with a higher risk of colonization (RR 1.63; 95% CI 1.13 2.34), as opposed to previous antibiotic (RR 1.07; 95% CI 0.75-1.53) and PPI use (RR 1.44; 95% CI 0.94-2.23), as well as history of CDI (RR 1.45; 95% CI 0.66 3.18) that had no impact. CONCLUSIONS: Over 8% of admitted patients are carriers of toxinogenic C. difficile with an almost 6 times higher risk of infection. These findings update current knowledge regarding the contribution of colonization in CDI epidemiology and stress the importance of preventive measures toward colonized patients. PMID- 25732417 TI - A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. AB - OBJECTIVES: The aim of this study was to assess the long-term prognosis, efficacy, and safety of combination therapy using ursodeoxycholic acid (UDCA) and bezafibrate (BF) for primary biliary cirrhosis (PBC) patients exhibiting dyslipidemia. METHODS: We performed a prospective, randomized, controlled, multicenter study to compare the long-term clinical results between combination therapy and UDCA monotherapy for patients refractory to UDCA monotherapy. Twenty seven consecutive PBC patients were enrolled. RESULTS: The median treatment period in the UDCA and UDCA+BF groups was 107 and 110 months, respectively. The serum alkaline phosphatase (ALP) levels and the Mayo risk score in the combination therapy group (mean 290 IU/l and 0.91, respectively) were significantly lower than those in the UDCA monotherapy group (mean 461 IU/l and 1.42, respectively) at 8 years after the beginning of the study (P<0.05). The serum creatinine levels in the combination therapy group (mean 0.94 mg/dl) were significantly higher than those in the UDCA monotherapy group (mean 0.56 mg/dl) at 8 years after the beginning of the study (P<0.05). However, the survival rate was not significantly different between the groups. We observed dose reduction or discontinuation of the administration of BF, but not UDCA, due to renal dysfunction or muscle pain. CONCLUSIONS: Long-term combination therapy significantly improved the serum ALP levels and the Mayo risk score. However, the survival rate was not significantly different between the groups. In addition, long-term combination therapy significantly increased the serum creatinine levels. We should pay close attention to adverse events during this long-term combination therapy. PMID- 25732418 TI - Plasma cathepsin D levels: a novel tool to predict pediatric hepatic inflammation. AB - OBJECTIVES: Nonalcoholic steatohepatitis (NASH) is the most severe form of a hepatic condition known as nonalcoholic fatty liver disease (NAFLD). NASH is histologically characterized by hepatic fat accumulation, inflammation, and ballooning, and eventually coupled with fibrosis that, in turn, may progress to end-stage liver disease even in young individuals. Hence, there is a critical need for specific noninvasive markers to predict hepatic inflammation at an early age. We investigated whether plasma levels of cathepsin D (CatD), a lysosomal protease, correlated with the severity of liver inflammation in pediatric NAFLD. METHODS: Liver biopsies from children (n=96) with NAFLD were histologically evaluated according to the criteria of Kleiner (NAFLD activity score) and the Brunt's criteria. At the time of liver biopsy, blood was taken and levels of CatD, alanine aminotransferase (ALT), and cytokeratin-18 (CK-18) were measured in plasma. RESULTS: Plasma CatD levels were significantly lower in subjects with liver inflammation compared with steatotic subjects. Furthermore, we found that CatD levels were gradually reduced and corresponded with increasing severity of liver inflammation, steatosis, hepatocellular ballooning, and NAFLD activity score. CatD levels correlated with pediatric NAFLD disease progression better than ALT and CK-18. In particular, CatD showed a high diagnostic accuracy (area under receiver operating characteristic curve (ROC-AUC): 0.94) for the differentiation between steatosis and hepatic inflammation, and reached almost the maximum accuracy (ROC-AUC: 0.998) upon the addition of CK-18. CONCLUSIONS: Plasma CatD holds a high diagnostic value to distinguish pediatric patients with hepatic inflammation from children with steatosis. PMID- 25732420 TI - Compartmentalization of the chick cerebellar cortex based on the link between the striped expression pattern of aldolase C and the topographic olivocerebellar projection. AB - The avian cerebellum is organized into multiple longitudinal stripes defined by expression profiles of aldolase C (zebrin II) in Purkinje cells. The relationship between the aldolase C striped pattern and the olivocerebellar projection pattern is crucial in understanding cerebellar functional compartmentalization. We identified all aldolase C stripes across all lobules with the serial section alignment analysis method and then looked at this relationship by anterograde and retrograde labeling of olivocerebellar axons in the chick cerebellum. Aldolase C stripes were generally consistent and continuous from lobule I through VII and to the medial part of lobules VIII-IXb. The dorsal and ventral lamellas (DL, VL) of the inferior olive projected to the stripes in these areas with a simple mediolateral topographic relation. A few aldolase C stripes appeared at the lateral edge of lobules VI-VIII. Several more stripes were added in the lateral parts of lobules IXa-IXb and IXc-X. The medial column (MC) of the inferior olive projected to the stripes in lobules VIII-X, including the added lateral stripes, with a complex topographic relation. Sharp boundaries between aldolase C-positive and -negative stripes often accompanied a gap in the Purkinje cell layer and bordered topographically distinct groups of axons. Although the compartmental organization of the chick cerebellum is comparable to that of the mammalian cerebellum, several significant differences in the organization suggest partly separate evolutionary lineages of the mammalian and avian cerebella. We propose that rostral lobules may be evolved by rostral extension of medial stripes from caudal lobules in the avian cerebellum. PMID- 25732419 TI - A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is viewed as a diagnosis of exclusion by most providers. The aim of our study was to perform a systematic review and meta-analysis to evaluate the utility of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin, and fecal lactoferrin to distinguish between patients with IBS and inflammatory bowel disease (IBD) and healthy controls (HCs). METHODS: A systematic online database search was performed. Included studies were prospective, adult, diagnostic cohort studies with any of the four tests. The means and s.d. values of biomarker logarithms were estimated based on studies that gave medians and either confidence intervals for the median, interquartile ranges, or ranges. We used a Naive Bayes approach to estimate the probability of being a HC, having IBS, or having IBD based on the biomarker values. RESULTS: Systematic review identified 1,252 citations. After cross-referencing medical subject headings, detailed evaluation identified 140 potentially relevant journal articles/abstracts for CRP, ESR, calprotectin, and lactoferrin of which 4, 4, 8, and 2 fulfilled our inclusion criteria, respectively. None of the biomarkers reliably distinguished between IBS and healthy controls. At a CRP level of <=0.5 or calprotectin level of <=40 MUg/g, there was a <=1% probability of having IBD. Individual analysis of ESR and lactoferrin had little clinical utility. CONCLUSION: CRP and calprotectin of <=0.5 or 40, respectively, essentially excludes IBD in patients with IBS symptoms. The addition of CRP and calprotectin to symptom-based criteria may improve the confident diagnosis of IBS. PMID- 25732421 TI - Calibration transfer employing univariate correction and robust regression. AB - This paper proposes a new method for calibration transfer, which was specifically designed to work with isolated variables, rather than the full spectrum or spectral windows. For this purpose, a univariate procedure is initially employed to correct the spectral measurements of the secondary instrument, given a set of transfer samples. A robust regression technique is then used to obtain a model with low sensitivity with respect to the univariate correction residuals. The proposed method is employed in two case studies involving near infrared spectrometric determination of specific mass, research octane number and naphthenes in gasoline, and moisture and oil in corn. In both cases, better calibration transfer results were obtained in comparison with piecewise direct standardization (PDS). The proposed method should be of a particular value for use with application-targeted instruments that monitor only a small set of spectral variables. PMID- 25732422 TI - A green deep eutectic solvent-based aqueous two-phase system for protein extracting. AB - As a new type of green solvent, deep eutectic solvent (DES) has been applied for the extraction of proteins with an aqueous two-phase system (ATPS) in this work. Four kinds of choline chloride (ChCl)-based DESs were synthesized to extract bovine serum albumin (BSA), and ChCl-glycerol was selected as the suitable extraction solvent. Single factor experiments have been done to investigate the effects of the extraction process, including the amount of DES, the concentration of salt, the mass of protein, the shaking time, the temperature and PH value. Experimental results show 98.16% of the BSA could be extracted into the DES-rich phase in a single-step extraction under the optimized conditions. A high extraction efficiency of 94.36% was achieved, while the conditions were applied to the extraction of trypsin (Try). Precision, repeatability and stability experiments were studied and the relative standard deviations (RSD) of the extraction efficiency were 0.4246% (n=3), 1.6057% (n=3) and 1.6132% (n=3), respectively. Conformation of BSA was not changed during the extraction process according to the investigation of UV-vis spectra, FT-IR spectra and CD spectra of BSA. The conductivity, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to explore the mechanism of the extraction. It turned out that the formation of DES-protein aggregates play a significant role in the separation process. All the results suggest that ChCl-based DES-ATPS are supposed to have the potential to provide new possibilities in the separation of proteins. PMID- 25732423 TI - A matrix-induced ion suppression method to normalize concentration in urinary metabolomics studies using flow injection analysis electrospray ionization mass spectrometry. AB - Normalizing the total urine concentration is important for minimizing bias in urinary metabolomics analysis comparisons. In this study, we report a matrix induced ion suppression (MIIS)-based method to normalize concentration using flow injection analysis coupled with electrospray ionization mass spectrometry (FIA ESI-MS). An ion suppression indicator (ISI) was spiked into urine samples, and the intensity of the extracted ion chromatogram (EIC) for ISI in a urine matrix was subtracted by the EIC for a blank solution and used to calculate the extent to which the signal was reduced by the urine matrix. A series dilution of pooled urine samples was used to correlate the urine concentration and level of ion suppression for ISI. A regression equation was used to estimate the relative concentration of unknown urine samples. The MIIS method was validated for linearity, precision and accuracy. We obtained a good correlation using a quadratic regression model for 1- to 32-fold urine dilutions (R(2)=0.998). The reproducibility (n=4) and intermediate precision (n=3) were below 5% RSD, and the accuracy ranged from 97.15% to 102.10%. The established method was used to estimate the relative concentrations of 16 urine samples, and the results were compared with commonly used normalization methods. Pearson's correlation test was used to demonstrate that the MIIS method correlated highly with the creatinine and osmolarity methods; the correlation coefficients were 0.93 and 0.99, respectively. We successfully applied this method to a urinary metabolomics study on breast cancer. This study demonstrated the MIIS method is simple, accurate and can contribute to data integrity in urinary metabolomics studies. PMID- 25732424 TI - A novel method of liquid chromatography-tandem mass spectrometry combined with chemical derivatization for the determination of ribonucleosides in urine. AB - Ribonucleosides are the end products of RNA metabolism. These metabolites, especially the modified ribonucleosides, have been extensively evaluated as cancer-related biomarkers. However, the determination of urinary ribonucleosides is still a challenge due to their low abundance, high polarity and serious matrix interferences in urine samples. In this study, a derivatization method based on a chemical reaction between ribonucleosides and acetone to form acetonides was developed for the determination of urinary ribonucleosides. The derivative products, acetonides, were detected by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The methodological evaluation was performed by quantifying four nucleosides for linear range, average recovery, precision, accuracy and stability. The validated procedures were applied to screen modified ribonucleosides in urine samples. Improvement of separation and enhancement of sensitivity were obtained in the analysis. To identify ribonucleosides, inexpensive isotope labeling acetone (acetone-d6) and label-free acetone were applied to form ordinary and deuterated acetonides, respectively. The two groups of samples were separated with orthogonal partial least squares (OPLS). The ordinary and deuterated pairs of acetonides were symmetrically distributed in the S-plot for easy and visual signal identification. After structural confirmation, a total of 56 ribonucleosides were detected, 52 of which were modified ribonucleosides. The application of derivatization, deuterium-labeling and multivariate statistical analysis offers a new option for selective detection of ribonucleosides in biological samples. PMID- 25732425 TI - Rapid monitoring of intermediate states and mass balance of nitrogen during denitrification by means of cavity enhanced Raman multi-gas sensing. AB - The comprehensive investigation of changes in N cycling has been challenging so far due to difficulties with measuring gases such as N2 and N2O simultaneously. In this study we introduce cavity enhanced Raman gas spectroscopy as a new analytical methodology for tracing the stepwise reduction of (15)N-labelled nitrate by the denitrifying bacteria Pseudomonas stutzeri. The unique capabilities of Raman multi-gas analysis enabled real-time, continuous, and non consumptive quantification of the relevant gases ((14)N2, (14)N2O, O2, and CO2) and to trace the fate of (15)N-labeled nitrate substrate ((15)N2, (15)N2O) added to a P. stutzeri culture with one single measurement. Using this new methodology, we could quantify the kinetics of the formation and degradation for all gaseous compounds (educts and products) and thus study the reaction orders. The gas quantification was complemented with the analysis of nitrate and nitrite concentrations for the online monitoring of the total nitrogen element budget. The simultaneous quantification of all gases also enabled the contactless and sterile online acquisition of the pH changes in the P. stutzeri culture by the stoichiometry of the redox reactions during denitrification and the CO2 bicarbonate equilibrium. Continuous pH monitoring - without the need to insert an electrode into solution - elucidated e.g. an increase in the slope of the pH value coinciding with an accumulation of nitrite, which in turn led to a temporary accumulation of N2O, due to an inhibition of nitrous oxide reductase. Cavity enhanced Raman gas spectroscopy has a high potential for the assessment of denitrification processes and can contribute substantially to our understanding of nitrogen cycling in both natural and agricultural systems. PMID- 25732426 TI - Lateral flow devices for nucleic acid analysis exploiting quantum dots as reporters. AB - There is a growing interest in the development of biosensors in the form of simple lateral flow devices that enable visual detection of nucleic acid sequences while eliminating several steps required for pipetting, incubation and washing out the excess of reactants. In this work, we present the first dipstick type nucleic acid biosensors based on quantum dots (QDs) as reporters. The biosensors enable sequence confirmation of the target DNA by hybridization and simple visual detection of the emitted fluorescence under a UV lamp. The 'diagnostic' membrane of the biosensor contains a test zone (TZ) and a control zone (CZ). The CZ always fluoresces in order to confirm the proper function of the biosensor. Fluorescence is emitted from the TZ, only when the specific nucleic acid sequence is present. We have developed two general types of QD-based nucleic acid biosensors, namely, Type I and Type II, in which the TZ consists of either immobilized streptavidin (Type I) or immobilized oligodeoxynucleotides (Type II). The control zone consists of immobilized biotinylated albumin. No purification steps are required prior to the application of the DNA sample on the strip. The QD-based nucleic acid biosensors performed accurately and reproducibly when applied to (a) the visual detection of PCR amplification products and (b) visual genotyping of single nucleotide polymorphisms (SNPs) in human genomic DNA from clinical samples. As low as 1.5 fmol of double-stranded DNA were clearly detected by naked eye and the dynamic range extended to 200 fmol. The %CV were estimated to be 4.3-8.2. PMID- 25732427 TI - Pyrene-based chemosens or detects picric acid upto attogram level through aggregation enhanced excimer emission. AB - A pyrene-based small molecular weight probe, exhibiting aggregation enhanced excimer emission has been synthesized. The crystalline emissive form detects 2,4,6-trinitrophenol (picric acid) at parts-per-billion concentration in solution and as low as 0.46 attogram in direct contact mode, operating predominantly in a static quenching mechanism, proposed on the basis of steady state and life-time fluorescence measurements. PMID- 25732428 TI - A single cataluminescence sensor based on spectral array and its use in the identification of vinegars. AB - The discrimination of complex mixtures, especially those with very similar compositions, remains a challenging part of chemical analysis. In this paper, a single cataluminescence (CTL) sensor constructed using MgO nanomaterials in a closed reaction cell (CRC) was used to identify vinegars. It may provide an archetype of this type of highly multicomponent system. By scanning the CTL spectra, which were distributed in 15 wavelengths during the reaction period, the spectral array patterns of the vinegars were obtained. These functioned as their fingerprints. The CTL signals of the array were then normalized and identified through linear discrimination analysis (LDA). Nine types and eight brands of vinegars and an additional series of artificial samples were tested; the new technique was found to distinguish between them very well. This single sensor demonstrated excellent promise for analysis of complex mixtures in real-world applications and may provide a novel method for identifying very similar complex analytes. PMID- 25732430 TI - Capillary electrophoresis study on phase of mixed micelles and its role in transport phenomena of particles. AB - In the present work comprehensive studies on electrophoretic effects induced by a phase of mixed micelles, that migrates surrounded with background electrolyte (BGE) and is denoted as the BGE/segment of mixed micelles/BGE system, were undertaken using capillary electrophoresis coupled with contactless conductivity or UV-vis detector. It was established that mixed micelles under electrophoresis are subject of evolution in terms of mobility, peak area and presence of sub zones enforced by the composition of micellar phase, segment length and applied voltage. Established features allowed us to explain the electrophoretic behavior of nanoparticles in the system BGE/sample containing nanocrystals/segment of mixed micelles/BGE and it was postulated that a pseudomicellar state of nanoparticles can be useful term in analyzing the migration phenomena of nanoparticles within micellar environment. In contrast to the previous works, where transport of nanocrystals (NCs) within micellar segment or between two micellar segments was analyzed, the present work is focused on the transport of NCs from sample of NCs dispersed in BGE to phase of mixed micelles, i.e., to rear boundary between micellar zone and BGE. Based on these results, systematic studies on transport efficiency for nanoparticles in the system BGE/sample containing nanocrystals/segment of mixed micelles/BGE show that the system assures efficient transport of nanoparticles from BGE based sample to micellar phase and their efficient preconcentration at the micellar segment/BGE rear boundary. PMID- 25732429 TI - A facile approach for synthesizing molecularly imprinted graphene for ultrasensitive and selective electrochemical detecting 4-nitrophenol. AB - In this work, a novel and convenient strategy was developed to prepare molecularly imprinted polymers (MIPs) on the surface of graphene sheet. In this route, vinyl group functionalized graphene (GR/NVC) was first prepared by immobilizing 4-vinylcarbazole onto the surface of graphene via pi-pi interaction. The subsequent grafting copolymerization of methacrylic acid and ethylene glycol dimethacrylate in the presence of 4-nitrophenol (4-NP, template molecule) was carried out at GR/NVC surface, leading to the formation of GR/MIPs composite. The GR/MIPs composite was characterized by FTIR, fluorescence, TGA, SEM and AFM, and was used to fabricate electrochemical sensor for the detection of 4-NP. The electrochemical behavior of GR/MIPs sensor for 4-NP was investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The effects of the preparation conditions, such as concentration of the NVC and template, the solution pH, and incubation time, were also optimized. Under optimized conditions, the DPV current response of GR/MIPs sensor was nearly 12 times than that of the GR/NIPs sensor. It also should be noted that as compared to traditional MIP, shorter response time and much higher current response were demonstrated. In addition, the GR/MIPs sensor could recognize 4-NP from its structural analogs, indicating the excellent selectivity of the GR/MIPs sensor. The peak current is linearly proportional to the concentration of 4-NP ranging from 0.01 MUM to 100 MUM and 200 MUM to 1000 MUM with a significantly low detection limit of 5 nM, a wider response range and lower detection limits as compared to most of the previously reported electrochemical sensors for 4-NP. Furthermore, the GR/MIPs sensor exhibits good stability with adequate reproducibility and has been successfully used to determine 4-NP in water samples. PMID- 25732431 TI - A warning threshold for monitoring tuberculosis surveillance data: an alternative to hidden Markov model. AB - OBJECTIVES: Although hidden Markov model (HMM) is known as a powerful tool for the detection of epidemics based on the historical data, the frequent use of such a model poses some limitation especially when decision-making is required for new observations. This study was aimed to address a warning threshold for monitoring the weekly incidences of tuberculosis as an alternative to HMM. METHODS: We extracted the weekly counts of newly diagnosed patients with sputum smear positive pulmonary TB from 2005 to 2011 nationwide. To detect unexpected incidences of the disease, two approaches: Serfling and HMM, were applied in presence/absence of linear, seasonal and autoregressive components. Models were subsequently evaluated in terms of goodness of fit, and their results were compared in detection of the disease phases. Then, multiple hypothetical thresholds were constructed based on the estimate of models and the optimal one was revealed through ROC curve analysis. RESULTS: Findings from both adjusted R square (R~2) and Bayesian information criterion (BIC) presented a higher goodness of fit for periodic autoregressive HMM (BIC = -1323.6; R~2=0.74) than other models. According to ROC analysis, better values for both Youden's index and area under curve (0. 96 and 0. 98 respectively) were obtained by the threshold based on the estimate of periodic autoregressive model. CONCLUSIONS: As the optimal threshold presented in this study is simple in concept and has no limitation in practice, especially for monitoring new observations, we would recommend such a threshold to be used for monitoring of TB incidence data in the surveillance system. PMID- 25732432 TI - Impact of new oral anticoagulants on gastrointestinal bleeding in atrial fibrillation: A meta-analysis of interventional trials. AB - BACKGROUND: New oral anticoagulants represent an alternative to standard therapy with vitamin K antagonists but data regarding gastrointestinal bleeding are still unclear. AIMS: To investigate if new oral anticoagulants are associated with an enhanced risk of gastrointestinal bleeding vs warfarin in patients with atrial fibrillation. METHODS: Meta-analysis of phase three randomized controlled trials to compare the incidence of gastrointestinal bleeding in atrial fibrillation patients treated with new oral anticoagulants (apixaban, dabigatran, edoxaban and rivaroxaban) vs warfarin. RESULTS: Four studies including 71,302 patients were selected. Compared with warfarin, new oral anticoagulants significantly increased gastrointestinal bleeding (RR: 1.23; 95% CI 1.03-1.46; p=0.01). Rivaroxaban (RR: 1.46; 95% CI 1.2-1.8; p<0.001) and high dosages of edoxaban (RR: 1.22; 95% CI 1.01-1.47; p=0.038) and dabigatran (RR: 1.50; 95% CI 1.20-1.88; p<0.001) significantly increased gastrointestinal bleeding while a null effect was detected with apixaban. CONCLUSIONS: This meta-analysis suggests that rivaroxaban and high dosages of dabigatran and edoxaban should be avoided in patients at high risk of gastrointestinal bleeding. PMID- 25732433 TI - Role of bilirubin in digestive proteases inactivation in the lower intestine. PMID- 25732434 TI - Serum tests, liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension. AB - BACKGROUND: The diagnostic performance of biochemical scores and artificial neural network models for portal hypertension and cirrhosis is not well established. AIMS: To assess diagnostic accuracy of six serum scores, artificial neural networks and liver stiffness measured by transient elastography, for diagnosing cirrhosis, clinically significant portal hypertension and oesophageal varices. METHODS: 202 consecutive compensated patients requiring liver biopsy and hepatic venous pressure gradient measurement were included. Several serum tests (alone and combined into scores) and liver stiffness were measured. Artificial neural networks containing or not liver stiffness as input variable were also created. RESULTS: The best non-invasive method for diagnosing cirrhosis, portal hypertension and oesophageal varices was liver stiffness (C-statistics=0.93, 0.94, and 0.90, respectively). Among serum tests/scores the best for diagnosing cirrhosis and portal hypertension and oesophageal varices were, respectively, Fibrosis-4, and Lok score. Artificial neural networks including liver stiffness had high diagnostic performance for cirrhosis, portal hypertension and oesophageal varices (accuracy>80%), but were not statistically superior to liver stiffness alone. CONCLUSIONS: Liver stiffness was the best non-invasive method to assess the presence of cirrhosis, portal hypertension and oesophageal varices. The use of artificial neural networks integrating different non-invasive tests did not increase the diagnostic accuracy of liver stiffness alone. PMID- 25732435 TI - A convenient method for palladium-catalyzed reductive deuteration of organic substrates using deuterated hypophosphite in D2O. AB - A convenient method for the deuteration of organic substrates using deuterated hypophosphite as the deuterium source was investigated. Transfer deuteration of organic substrates, such as aromatic halides, alkenes, alkynes, epoxides, and O benzyl derivatives, in the presence of palladium on carbon in deuterium oxide proceeded efficiently to give the corresponding deuterated products in excellent yields with high deuterium contents. PMID- 25732436 TI - Linking genetics to ARDS pathogenesis: the role of the platelet. PMID- 25732437 TI - COPD in heart failure: are there long-term implications following acute heart failure hospitalization? PMID- 25732438 TI - Should they stay or should they go?: Identification of low-risk patients with acute pulmonary embolism who can be safely treated outside of the hospital. PMID- 25732439 TI - Management of alveolar-pleural fistula: a complex medical and surgical problem. PMID- 25732441 TI - Point: Should nurse practitioners perform transbronchial biopsies? Yes. PMID- 25732442 TI - Counterpoint: Should nurse practitioners perform transbronchial biopsies? No. PMID- 25732443 TI - Rebuttal from Ms Blumenthal. PMID- 25732444 TI - Rebuttal from Drs Pastis and Strange. PMID- 25732445 TI - Evolution in reimbursement for sleep studies and sleep centers. AB - Because of the rapid increase in the volume and costs of polysomnography and other sleep medicine diagnostic services, the Centers for Medicare & Medicaid Services (CMS) recently commissioned the Office of Inspector General (OIG) to review claims submitted for these services. The OIG found numerous cases of inappropriate payment for submitted claims and recommended significant changes in the CMS auditing process for polysomnography claims review. Additionally, a local Medicare Administrative Contractor released the most specific rules and regulations to date regarding billing and payment for sleep medicine services. These regulations specify covered diagnoses for submitted claims for both facility-based polysomnograms and unattended home sleep tests (HSTs) and list noncovered diagnoses that cannot be used to document medical necessity for such studies. The proposed rules specify minimum credentials for technologists performing polysomnograms and HSTs, mandate education prior to application of HST devices, demand a follow-up visit to discuss results after studies, and elaborate new requirements for physicians interpreting these studies. Providers of sleep medicine services must be prepared to provide documentation of diagnoses and indications when submitting claims for sleep services, and they can expect to be required to produce evidence of accreditation of the physicians and technologists providing services and the credentials of the sleep center. These changes will dramatically affect sleep medicine practitioners who order sleep studies and positive airway pressure therapies. Successful sleep medicine centers and sleep physicians alike will need to develop strategies to meet these new challenges. PMID- 25732446 TI - Bronchoconstriction and airway biology: potential impact and therapeutic opportunities. AB - Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. PMID- 25732447 TI - Aspiration-related pulmonary syndromes. AB - Aspiration of foreign matter into the airways and lungs can cause a wide spectrum of pulmonary disorders with various presentations. The type of syndrome resulting from aspiration depends on the quantity and nature of the aspirated material, the chronicity, and the host responses. Aspiration is most likely to occur in subjects with a decreased level of consciousness, compromised airway defense mechanisms, dysphagia, gastroesophageal reflux, and recurrent vomiting. These aspiration-related syndromes can be categorized into airway disorders, including vocal cord dysfunction, large airway obstruction with a foreign body, bronchiectasis, bronchoconstriction, and diffuse aspiration bronchiolitis, or parenchymal disorders, including aspiration pneumonitis, aspiration pneumonia, and exogenous lipoid pneumonia. In idiopathic pulmonary fibrosis, aspiration has been implicated in disease progression and acute exacerbation. Aspiration may increase the risk of bronchiolitis obliterans syndrome in patients who have undergone a lung transplant. Accumulating evidence suggests that a causative role for aspiration is often unsuspected in patients presenting with aspiration related pulmonary diseases; thus, many cases go undiagnosed. Herein, we discuss the broadening spectrum of these pulmonary syndromes with a focus on presenting features and diagnostic aspects. PMID- 25732449 TI - Acute right ventricular dysfunction: real-time management with echocardiography. AB - In critically ill patients, the right ventricle is susceptible to dysfunction due to increased afterload, decreased contractility, or alterations in preload. With the increased use of point-of-care ultrasonography and a decline in the use of pulmonary artery catheters, echocardiography can be the ideal tool for evaluation and to guide hemodynamic and respiratory therapy. We review the epidemiology of right ventricular failure in critically ill patients; echocardiographic parameters for evaluating the right ventricle; and the impact of mechanical ventilation, fluid therapy, and vasoactive infusions on the right ventricle. Finally, we summarize the principles of management in the context of right ventricular dysfunction and provide recommendations for echocardiography-guided management. PMID- 25732448 TI - Ethics and policy issues for stem cell research and pulmonary medicine. AB - Stem cell research and related initiatives in regenerative medicine, cell-based therapy, and tissue engineering have generated considerable scientific and public interest. Researchers are applying stem cell technologies to chest medicine in a variety of ways: using stem cells as models for drug discovery, testing stem cell based therapies for conditions as diverse as COPD and cystic fibrosis, and producing functional lung and tracheal tissue for physiologic modeling and potential transplantation. Although significant scientific obstacles remain, it is likely that stem cell-based regenerative medicine will have a significant clinical impact in chest medicine. However, stem cell research has also generated substantial controversy, posing a variety of ethical and regulatory challenges for research and clinical practice. Some of the most prominent ethical questions related to the use of stem cell technologies in chest medicine include (1) implications for donors, (2) scientific prerequisites for clinical testing and use, (3) stem cell tourism, (4) innovation and clinical use of emerging stem cell based interventions, (5) responsible translation of stem cell-based therapies to clinical use, and (6) appropriate and equitable access to emerging therapies. Having a sense of these issues should help to put emerging scientific advances into appropriate context and to ensure the responsible clinical translation of promising therapeutics. PMID- 25732450 TI - OSA and pulmonary hypertension: time for a new look. AB - OSA is a common yet underdiagnosed disorder encountered in everyday practice. The disease is a unique physiologic stressor that contributes to the development or progression of many other disorders, particularly cardiovascular conditions. The pulmonary circulation is specifically affected by the intermittent hypoxic apneas associated with OSA. The general consensus has been that OSA is associated with pulmonary hypertension (PH), but only in a minority of OSA patients and generally of a mild degree. Consequently, there has been no sense of urgency to screen for either condition when evaluating the other. In this review, we explore available evidence describing the interaction between OSA and PH and seek to better understand underlying pathophysiology. We describe certain groups of patients who have a particular preponderance of OSA and PH. Failure to recognize the mutual additive effects of these disorders can lead to suboptimal patient outcomes. Among patients with PH and OSA, CPAP, the mainstay treatment for OSA, may ameliorate pulmonary pressure elevations, but has not been studied adequately. Conversely, among patients with OSA, PH significantly limits functional capacity and potentially shortens survival; yet, there is no routine screening for PH in patients with OSA. We think it is time to study the interaction between OSA and PH more carefully to identify high-risk subgroups. These would be screened for the presence of combined disorders, facilitating earlier institution of therapy and improving outcomes. PMID- 25732451 TI - A teenager presents with fulminant hepatic failure and acute hemolytic anemia. AB - A teenager was admitted to an outside hospital ED following an episode of melena. He had been complaining of intermittent abdominal pain, nausea, malaise, and easy fatigability for 2 months, with significant worsening of symptoms 2 weeks prior to this episode. He had no significant medical, surgical, or family history. On presentation at the outside ED, he was found to be profoundly icteric and encephalopathic. Initial laboratories suggested anemia, acute kidney injury, and acute liver failure, leading to a presumptive diagnosis of acute fulminant liver failure necessitating transfer to our institution. PMID- 25732452 TI - Silibinin: where is the ethical conundrum? PMID- 25732453 TI - Response. PMID- 25732454 TI - Can procalcitonin and chest echography be used to diagnose ventilator-associated pneumonia? PMID- 25732455 TI - Response. PMID- 25732456 TI - A new score based on procalcitonin and chest echography for diagnosis of ventilator-associated pneumonia: when? How? For whom? PMID- 25732457 TI - Response. PMID- 25732458 TI - Parabasalids in respiratory secretions and lung diseases. PMID- 25732459 TI - Response. PMID- 25732460 TI - Correlation of pulmonary artery dimensions between endobronchial ultrasound and CT scan. PMID- 25732461 TI - Tapias score for predicting recurrences in resected solitary fibrous tumor of the pleura: controversial points and future perspectives emerging from an external validation. PMID- 25732462 TI - Response. PMID- 25732463 TI - Late gadolinium enhancement in sarcoidosis: ventricular wall stress should not be overlooked. PMID- 25732464 TI - Response. PMID- 25732465 TI - Safety considerations regarding noninvasive positive pressure ventilation following esophagectomy. PMID- 25732466 TI - Response. PMID- 25732467 TI - Endosonographic staging for N1 disease. PMID- 25732468 TI - Response. PMID- 25732469 TI - Pleural plaques and their effect on lung function: conclusions based on insufficient power to reject the null. PMID- 25732470 TI - Response. PMID- 25732471 TI - Pleural plaques and their effect on lung function: Libby amphibole: pleural fibrosis and its consequences. PMID- 25732472 TI - Response. PMID- 25732473 TI - Controlling asthma by breathing techniques: role of anxiety. PMID- 25732474 TI - Hybrid DynaCT scan-guided localization single-port lobectomy. [corrected]. AB - Small pulmonary lesions can be difficult to locate intraoperatively. Preoperative CT scan-guided localization, for example with hookwire, is a popular method to help localize such lesions. However, the delay between CT scan localization with hookwire and surgery can lead to risks of pneumothorax and wire dislodgement. We describe a 56-year-old woman who underwent DynaCT-guided hookwire localization of a ground-glass opacity in the hybrid operating room followed immediately by single-port video-assisted thoracic surgery lobectomy. The advantages, disadvantages, and special considerations in adopting this approach are discussed. PMID- 25732475 TI - Improved clinical and radiographic outcomes after treatment with ivacaftor in a young adult with cystic fibrosis with the P67L CFTR mutation. AB - The underlying cause of cystic fibrosis (CF) is the loss of epithelial chloride and bicarbonate transport due to mutations in the CF transmembrane conductance regulator (CFTR) gene encoding the CFTR protein. Ivacaftor is a gene-specific CFTR potentiator that augments in vivo chloride transport in CFTR mutations affecting channel gating. Originally approved for the G511D CFTR mutation, ivacaftor is now approved for eight additional alleles exhibiting gating defects and has also been tested in R117H, a CFTR mutation with residual function that exhibits abnormal gating. P67L is a class 4 conductance (nongating) mutation exhibiting residual CFTR function. We report marked clinical improvement, normalization of spirometry, and dramatic reduction in radiographic structural airway changes after > 1 year of treatment with ivacaftor in a young adult with the compound heterozygous genotype P67L/F508del CFTR. The case suggests that ivacaftor may have a potential benefit for patients with CF with nongating mutations. PMID- 25732476 TI - A 42-year-old man presenting with progressive shortness of breath and severe hypoxemia. PMID- 25732477 TI - A 51-year-old man with seizures and progressive behavioral changes. AB - A 51-year-old man was admitted for evaluation of new-onset generalized seizures in the context of progressive and significant behavioral change. His medical history was only notable for previous outbreaks of genital herpes. He took no medications. He had occasional social alcohol use and no illicit drug use but was a 35-pack-year current smoker. The patient had no relevant occupational exposure history but had recently traveled to Panama. Initially, the patient's significant other noticed a progressive flattening of his affect. The patient then started to experience episodes of "passing out" that led to injuries prompting ED visits. He was prescribed antiseizure medications and scheduled for an outpatient workup. However, with progressive gait instability, lethargy, and an increase in frequency of generalized seizures, the patient was admitted for treatment of suspected viral encephalitis. Despite initiation of antimicrobial and antiviral therapy, the patient's level of alertness continued to decline, ultimately leading to intubation for airway protection. PMID- 25732478 TI - A 62-year-old man with skin rash and an abnormal chest radiograph. AB - A 62-year-old man developed a scalp rash 2 months ago, followed by bilateral eyelid swelling. The nonpruritic rash then spread to involve most of his skin. He also had fatigue, muscle weakness, mild muscle soreness with activity, and dysphagia for solid foods for the last 3 weeks. He had no other symptoms. He had a 50 pack-year history of smoking and drank two to three shots of alcohol daily. PMID- 25732479 TI - A 55-year-old man with a small right lung and a right-sided heart. AB - A healthy 55-year-old man without known medical problems presented for a routine physical examination and was found to have an abnormal ECG. He denied chest pain, dyspnea, palpitations, dizziness, or syncopal episodes. He also denied orthopnea, paroxysmal nocturnal dyspnea, and lower-extremity edema. His exercise capacity had been excellent. He was a lifelong nonsmoker and never had lung problems. PMID- 25732480 TI - Chemically doped three-dimensional porous graphene monoliths for high-performance flexible field emitters. AB - Despite the recent progress in the fabrication of field emitters based on graphene nanosheets, their morphological and electrical properties, which affect their degree of field enhancement as well as the electron tunnelling barrier height, should be controlled to allow for better field-emission properties. Here we report a method that allows the synthesis of graphene-based emitters with a high field-enhancement factor and a low work function. The method involves forming monolithic three-dimensional (3D) graphene structures by freeze-drying of a highly concentrated graphene paste and subsequent work-function engineering by chemical doping. Graphene structures with vertically aligned edges were successfully fabricated by the freeze-drying process. Furthermore, their number density could be controlled by varying the composition of the graphene paste. Al- and Au-doped 3D graphene emitters were fabricated by introducing the corresponding dopant solutions into the graphene sheets. The resulting field emission characteristics of the resulting emitters are discussed. The synthesized 3D graphene emitters were highly flexible, maintaining their field-emission properties even when bent at large angles. This is attributed to the high crystallinity and emitter density and good chemical stability of the 3D graphene emitters, as well as to the strong interactions between the 3D graphene emitters and the substrate. PMID- 25732481 TI - Cellular proliferation and angiogenesis in nasal polyps of young adult and geriatric patients. AB - BACKGROUND: Cellular proliferation and angiogenesis are associated with pathophysiology of nasal polyposis (NP). In a previous report, we showed that patient age is a predictive factor of surgical outcomes among patients with chronic rhinosinusitis and NP, and that geriatric patients exhibit better outcomes than pediatric and adult patients. We postulated that better outcomes in the geriatric population may be secondary to decreased proliferation and angiogenesis within polyps. Therefore, we evaluated the cellular proliferation and angiogenesis in young adult and geriatric patients with NP. This was a prospective case-control study. METHODS: Twenty patients were divided into 2 groups according to age (20 to 30 years vs >=65 years of age). NP tissues were sampled during endoscopic sinus surgery and processed for immunohistochemistry. Cellular proliferation was evaluated with proliferating cell nuclear antigen and Ki67, and angiogenesis was assessed with vascular endothelial growth factor. We also compared objective surgical outcomes using endoscopy scores. RESULTS: Immunohistochemical analysis revealed significantly higher expression and positive reactivity of proliferating cell nuclear antigen and Ki67 in the polyps of young adults than in those of geriatric patients, whereas the expression of vascular endothelial growth factor was similar between the 2 groups. Endoscopy scores were better in the geriatric group. CONCLUSION: Geriatric patients have a lower cellular proliferative ability than young adults, and angiogenesis does not significantly differ between the 2 age groups. Cellular proliferation seems to be the cause of the different surgical outcomes between the 2 age groups, whereas angiogenesis has no significant influence on the postoperative course. PMID- 25732482 TI - Obtaining edaphic biostimulants/biofertilizers from different sewage sludges. Effects on soil biological properties. AB - We studied the influence of six edaphic biostimulants/biofertilizers (BSs) manufactured by the pH-stat method from different sewage sludge (SS): SS1 (an anaerobic mature sludge, one year old), SS2 (an aerobic young sludge, without maturation) and SS3 (an aerobic mature sludge, four months old), not previously autoclaved (A) and autoclaved (B), by analysing their effects on soil biological properties. Soil enzymatic activities were measured at 1, 3, 5, 7, 15, 30 and 60 days of the incubation period, whereas the 16S rDNA-DGGE profiles were determined at 0, 5 and 60 days. The enzymatic activities were significantly stimulated. The highest stimulation was found in the B2 treatment followed by B3, A2, A3, B1 and A1 treatments. Increasing the number of lower molecular weight proteins in the BS enhances the stimulation of soil enzymatic activities. The application of BS caused at 5 days of the incubation period temporal variations in the soil bacterial community structure. PMID- 25732483 TI - Slow magnetic relaxation in a lanthanide helix chain compound [Dy(HNA)(NA)2(NO3)]n (HNA = nicotinic acid). AB - A helix chain Dy(3+) compound, [Dy(HNA)(NA)2(NO3)]n (1, HNA = nicotinic acid), was synthesized under solvothermal conditions and fully characterized. The absolute configurations of the enantiomers in P61 and P65 space groups are characterized by single crystal X-ray diffraction and circular dichroism (CD). Magnetic studies reveal that compound 1 exhibits ferromagnetic interaction and slow magnetic relaxation at low temperatures with the energy barrier of 37 K under 900 Oe dc field. PMID- 25732484 TI - How valuable is information? PMID- 25732485 TI - The Affordable Care Act returns to the US Supreme Court. PMID- 25732486 TI - Medicare's Bundled Payment initiative: most hospitals are focused on a few high volume conditions. AB - The Bundled Payments for Care Improvement initiative is a federally funded innovation model mandated by the Affordable Care Act. It is designed to help transition Medicare away from fee-for-service payments and toward bundling a single payment for an episode of acute care in a hospital and related postacute care in an appropriate setting. While results from the initiative will not be available for several years, current data can help provide critical early insights. However, little is known about the participating organizations and how they are focusing their efforts. We identified participating hospitals and used national Medicare claims data to assess their characteristics and previous spending patterns. These hospitals are mostly large, nonprofit, teaching hospitals in the Northeast, and they have selectively enrolled in the bundled payment initiative covering patient conditions with high clinical volumes. We found no significant differences in episode-based spending between participating and nonparticipating hospitals. Postacute care explains the largest variation in overall episode-based spending, signaling an opportunity to align incentives across providers. However, the focus on a few selected clinical conditions and the high degree of integration that already exists between enrolled hospitals and postacute care providers may limit the generalizability of bundled payment across the Medicare system. PMID- 25732487 TI - English National Health Service's savings plan may have helped reduce the use of three 'low-value' procedures. AB - The pressure to contain health expenditures is unprecedented. In England a flattening of the health budget but increasing demand led the National Health Service (NHS) to seek reductions in health expenditures of 17 percent over four years. The spending cuts were to be achieved through improvements in service quality and efficiency, including reducing the use of ineffective, overused, or inappropriate procedures. However, the NHS left it to the local commissioning (or funding) organizations, known as primary care trusts, to determine what steps to take to reduce spending. To assess whether the initiative had an impact, we examined six low-value procedures: spinal surgery for lower back pain, myringotomy to relieve eardrum pressure, inguinal hernia repair, cataract removal, primary hip replacement, and hysterectomy for heavy menstrual bleeding. We found significant reductions in three of the six procedures-cataract removal, hysterectomy, and myringotomy-in the program's first year, compared to prior years' trends. However, changes in the rates of all examined procedures varied widely across commissioning organizations. Our findings highlight some of the challenges of making major budget cuts in health care. Reducing ineffective spending remains a significant opportunity for the US health care system, and the English experience may hold valuable lessons. PMID- 25732488 TI - New analysis reexamines the value of cancer care in the United States compared to Western Europe. AB - Despite sharp increases in spending on cancer treatment since 1970 in the United States compared to Western Europe, US cancer mortality rates have decreased only modestly. This has raised questions about the additional value of US cancer care derived from this additional spending. We calculated the number of US cancer deaths averted, compared to the situation in Western Europe, between 1982 and 2010 for twelve cancer types. We also assessed the value of US cancer care, compared to that in Western Europe, by estimating the ratio of additional spending on cancer to the number of quality-adjusted life-years saved. Compared to Western Europe, for three of the four costliest US cancers-breast, colorectal, and prostate-there were approximately 67,000, 265,000, and 60,000 averted US deaths, respectively, and for lung cancer there were roughly 1,120,000 excess deaths in the study period. The ratio of incremental cost to quality-adjusted life-years saved equaled $402,000 for breast cancer, $110,000 for colorectal cancer, and $1,979,000 for prostate cancer-amounts that exceed most accepted thresholds for cost-effective medical care. The United States lost quality adjusted life-years despite additional spending for lung cancer: -$19,000 per quality-adjusted life-year saved. Our results suggest that cancer care in the United States may provide less value than corresponding cancer care in Western Europe for many leading cancers. PMID- 25732489 TI - Safety-net hospitals more likely than other hospitals to fare poorly under Medicare's value-based purchasing. AB - Medicare's value-based purchasing (VBP) program potentially puts safety-net hospitals at a financial disadvantage compared to other hospitals. In 2014, the second year of the program, patient mortality measures were added to the VBP program's algorithm for assigning penalties and rewards. We examined whether the inclusion of mortality measures in the second year of the program had a disproportionate impact on safety-net hospitals nationally. We found that safety net hospitals were more likely than other hospitals to be penalized under the VBP program as a result of their poorer performance on process and patient experience scores. In 2014, 63 percent of safety-net hospitals versus 51 percent of all other sample hospitals received payment rate reductions under the program. However, safety-net hospitals' performance on mortality measures was comparable to that of other hospitals, with an average VBP survival score of thirty-two versus thirty-one among other hospitals. Although safety-net hospitals are still more likely than other hospitals to fare poorly under the VBP program, increasing the weight given to mortality in the VBP payment algorithm would reduce this disadvantage. PMID- 25732490 TI - In Tanzania, the many costs of pay-for-performance leave open to debate whether the strategy is cost-effective. AB - Pay-for-performance programs in health care are widespread in low- and middle income countries. However, there are no studies of these programs' costs or cost effectiveness. We conducted a cost-effectiveness analysis of a pay-for performance pilot program in Tanzania and modeled costs of its national expansion. We reviewed project accounts and reports, interviewed key stakeholders, and derived outcomes from a controlled before-and-after study. In 2012 US dollars, the financial cost of the pay-for-performance pilot was $1.2 million, and the economic cost was $2.3 million. The incremental cost per additional facility-based birth ranged from $540 to $907 in the pilot and from $94 to $261 for a national program. In a low-income setting, the costs of managing the program and generating and verifying performance data were substantial. Pay-for-performance programs can stimulate the generation and use of health information by health workers and managers for strategic planning purposes, but the time involved could divert attention from service delivery. Pay for-performance programs may become more cost-effective when integrated into routine systems over time. PMID- 25732491 TI - Reference-based benefit design changes consumers' choices and employers' payments for ambulatory surgery. AB - Some employers are using reference-based benefit (RBB) designs, also known as "reference-based pricing," to encourage patients to select lower-price ambulatory surgery centers instead of expensive hospital outpatient departments. This article analyzes the impact of such benefit designs for cataract removal surgery from the period 2009-13, using data on 2,347 surgical patients covered by the California Public Employees Retirement System (CalPERS), in comparison to 14,867 patients enrolled in non-CalPERS Anthem Blue Cross plans, which are not covered by RBB. After adjusting for changes in patient case-mix and other factors, the shift to RBB was associated with an increase in ambulatory surgery center use by 8.6 percentage points compared to trends among Anthem enrollees. Total employer and employee payments per procedure, after adjusting for changes in case-mix severity and market factors, declined by 19.7 percent compared with Anthem enrollees not subject to RBB. Consumer cost-sharing requirements increased for CalPERS patients who continued to use hospital outpatient departments but who were not exempted from RBB because of geographic or clinical factors. Reference based benefits for cataract surgery saved CalPERS $1.3 million in the two years after implementation. PMID- 25732492 TI - National hospital ratings systems share few common scores and may generate confusion instead of clarity. AB - Attempts to assess the quality and safety of hospitals have proliferated, including a growing number of consumer-directed hospital rating systems. However, relatively little is known about what these rating systems reveal. To better understand differences in hospital ratings, we compared four national rating systems. We designated "high" and "low" performers for each rating system and examined the overlap among rating systems and how hospital characteristics corresponded with performance on each. No hospital was rated as a high performer by all four national rating systems. Only 10 percent of the 844 hospitals rated as a high performer by one rating system were rated as a high performer by any of the other rating systems. The lack of agreement among the national hospital rating systems is likely explained by the fact that each system uses its own rating methods, has a different focus to its ratings, and stresses different measures of performance. PMID- 25732493 TI - When patient activation levels change, health outcomes and costs change, too. AB - Patient engagement has become a major focus of health reform. However, there is limited evidence showing that increases in patient engagement are associated with improved health outcomes or lower costs. We examined the extent to which a single assessment of engagement, the Patient Activation Measure, was associated with health outcomes and costs over time, and whether changes in assessed activation were related to expected changes in outcomes and costs. We used data on adult primary care patients from a single large health care system where the Patient Activation Measure is routinely used. We found that results indicating higher activation in 2010 were associated with nine out of thirteen better health outcomes-including better clinical indicators, more healthy behaviors, and greater use of women's preventive screening tests-as well as with lower costs two years later. Changes in activation level were associated with changes in over half of the health outcomes examined, as well as costs, in the expected directions. These findings suggest that efforts to increase patient activation may help achieve key goals of health reform and that further research is warranted to examine whether the observed associations are causal. PMID- 25732494 TI - Mandatory disclaimers on dietary supplements do not reliably communicate the intended issues. AB - Some efforts by the government to regulate the promotional statements of pharmaceutical manufacturers have recently been found unconstitutional under the First Amendment, which has been interpreted to protect commercial as well as personal speech. As an alternative means of protecting patients from unreliable marketing claims, courts have proposed that the Food and Drug Administration could add disclaimers to promotional messages that discuss off-label, or unapproved, uses. We conducted a systematic review of studies of the disclaimers currently required for dietary supplements, to assess how well disclaimers inform consumers' health choices. A few small studies reported a modest impact of disclaimers on consumers' attitudes about dietary supplements, but larger and more rigorous studies generally revealed that many consumers were unaware of a disclaimer or reported that it did not affect their perceptions of a product. The available evidence indicates that replacing government restrictions on pharmaceutical marketing with potentially ineffective disclaimers will be an inadequate way of informing patients about the efficacy and safety of drugs, and it risks returning the United States to a previous era when inappropriate marketing claims about prescription drugs proliferated and contributed to the inappropriate use of those products. PMID- 25732495 TI - Medicaid beneficiaries in california reported less positive experiences when assigned to a managed care plan. AB - In 2011 California began transitioning approximately 340,000 seniors and people with disabilities from Medicaid fee-for-service (FFS) to Medicaid managed care plans. When beneficiaries did not actively choose a managed care plan, the state assigned them to one using an algorithm based on their previous FFS primary and specialty care use. When no clear link could be established, beneficiaries were assigned by default to a managed care plan based on weighted randomization. In this article we report the results of a telephone survey of 1,521 seniors and people with disabilities enrolled in Medi-Cal (California Medicaid) and who were recently transitioned to a managed care plan. We found that 48 percent chose their own plan, 11 percent were assigned to a plan by algorithm, and 41 percent were assigned to a plan by default. People in the latter two categories reported being similarly less positive about their experiences compared to beneficiaries who actively chose a plan. Many states in addition to California are implementing mandatory transitions of Medicaid-only beneficiaries to managed care plans. Our results highlight the importance of encouraging beneficiaries to actively choose their health plan; when beneficiaries do not choose, states should employ robust intelligent assignment algorithms. PMID- 25732496 TI - Use of intelligent assignment to Medicare Part D plans for people with schizophrenia could produce substantial savings. AB - Medicare insures about half of the people in the United States diagnosed with schizophrenia. More than 90 percent of these beneficiaries are eligible for a low income subsidy for their Part D prescription drug benefit, and the great majority of them are randomly assigned to a stand-alone drug plan. We simulated savings from replacing random assignment with an "intelligent assignment" algorithm that would assign beneficiaries to the least expensive plan in 2010 based on their drug usage in the previous year. Doing so generated projected annual drug savings of $379 per dual-eligible (those enrolled in both Medicaid and Medicare) beneficiary with a low-income subsidy; $404 per non-dual eligible with the subsidy; and $604 per beneficiary for those without the subsidy who chose their own plans. This translates into savings of $466 per beneficiary with schizophrenia. Intelligent assignment could have saved about $150 million for Medicare and beneficiaries with schizophrenia combined in 2010. We recommend that Medicare use intelligent assignment as the default approach for all beneficiaries with schizophrenia who receive a low-income subsidy, and consider it as an option for all Part D beneficiaries, regardless of their income. PMID- 25732497 TI - Collectively bargained health plans: more comprehensive, less cost sharing than employer plans. AB - National statistics on the cost and provisions of collectively bargained health plans show them to have similar single premiums, but lower family premiums, compared to employer-based plans not subject to collective bargaining. Union members contribute 4 percent and 6 percent of the cost of their premiums for single and family coverage, respectively, versus 18 percent and 29 percent for workers in employer-based plans. Cost sharing in collectively bargained plans is considerably less than in employer-based plans; coverage for prescription drugs is similar. PMID- 25732498 TI - Comparing employer-sponsored and federal exchange plans: wide variations in cost sharing for prescription drugs. AB - Just under seven million Americans acquired private insurance through the new health insurance exchanges, or Marketplaces, in 2014. The exchange plans are required to cover essential health benefits, including prescription drugs. However, the generosity of prescription drug coverage in the plans has not been well described. Our primary objective was to examine the variability in drug coverage in the exchanges across plan types (health maintenance organization or preferred provider organization) and metal tiers (bronze, silver, gold, and platinum). Our secondary objective was to compare the exchange coverage to employer-sponsored coverage. Analyzing prescription drug benefit design data for the federally facilitated exchanges, we found wide variation in enrollees' out-of pocket costs for generic, preferred brand-name, nonpreferred brand-name, and specialty drugs, not only across metal tiers but also within those tiers across plan types. Compared to employer-sponsored plans, exchange plans generally had lower premiums but provided less generous drug coverage. However, for low-income enrollees who are eligible for cost-sharing subsidies, the exchange plans may be more comparable to employer-based coverage. Policies and programs to assist consumers in matching their prescription drug needs with a plan's benefit design may improve the financial protection for the newly insured. PMID- 25732499 TI - Despite the spread of health information exchange, there is little evidence of its impact on cost, use, and quality of care. AB - Health information exchange (HIE), which is the transfer of electronic information such as laboratory results, clinical summaries, and medication lists, is believed to boost efficiency, reduce health care costs, and improve outcomes for patients. Stimulated by federal financial incentives, about two-thirds of hospitals and almost half of physician practices are now engaged in some type of HIE with outside organizations. To determine how HIE has affected such health care measures as cost, service use, and quality, we identified twenty-seven scientific studies, extracted selected characteristics from each, and meta analyzed these characteristics for trends. Overall, 57 percent of published analyses reported some benefit from HIE. However, articles employing study designs having strong internal validity, such as randomized controlled trials or quasi-experiments, were significantly less likely than others to associate HIE with benefits. Among six articles with strong internal validity, one study reported paradoxical negative effects, three studies found no effect, and two studies reported that HIE led to benefits. Furthermore, these two studies had narrower focuses than the others. Overall, little generalizable evidence currently exists regarding benefits attributable to HIE. PMID- 25732500 TI - Most primary care physicians are aware of prescription drug monitoring programs, but many find the data difficult to access. AB - State prescription drug monitoring programs are common tools intended to reduce prescription drug abuse and diversion, or the nonmedical use of a prescribed drug. The success of these programs depends largely upon physicians' awareness and use of them. We conducted a nationally representative mail survey of 1,000 practicing primary care physicians in 2014 to characterize their attitudes toward and awareness and use of prescription drug monitoring programs. A total of 420 eligible physicians (adjusted response rate: 58 percent) returned completed surveys. Among all physicians surveyed, 72 percent were aware of their state's prescription drug monitoring program, and 53 percent reported using one of the programs. We identified several barriers that may prevent greater use of the programs, including the time-consuming nature of information retrieval and the lack of an intuitive format for data provided by the programs. These results suggest that the majority of US primary care physicians are aware of and use prescription drug monitoring programs at least on occasion, although many did not access these programs routinely. To increase the use of the programs in clinical practice, states should consider implementing legal mandates, investing in prescriber education and outreach, and taking measures to enhance ease of access to and use of the programs. PMID- 25732501 TI - Compulsory licensing often did not produce lower prices for antiretrovirals compared to international procurement. AB - Compulsory licensing has been widely suggested as a legal mechanism for bypassing patents to introduce lower-cost generic antiretrovirals for HIV/AIDS in developing countries. Previous studies found that compulsory licensing can reduce procurement prices for drugs, but it is unknown how the resulting prices compare to procurements through the Global Fund to Fight AIDS, Tuberculosis, and Malaria; UNICEF; and other international channels. For this study we systematically constructed a case-study database of compulsory licensing activity for antiretrovirals and compared compulsory license prices to those in the World Health Organization's (WHO's) Global Price Reporting Mechanism and the Global Fund's Price and Quality Reporting Tool. Thirty compulsory license cases were analyzed with 673 comparable procurements from WHO and Global Fund data. Compulsory license prices exceeded the median international procurement prices in nineteen of the thirty case studies, often with a price gap of more than 25 percent. Compulsory licensing often delivered suboptimal value when compared to the alternative of international procurement, especially when used by low-income countries to manufacture medicines locally. There is an ongoing need for multilateral and charitable actors to work collectively with governments and medicine suppliers on policy options. PMID- 25732502 TI - Reflections on the 20th anniversary of Taiwan's single-payer National Health Insurance System. AB - On its twentieth anniversary, Taiwan's National Health Insurance (NHI) stands out as a high-performing single-payer national health insurance system that provides universal health coverage to Taiwan's 23.4 million residents based on egalitarian ethical principles. The system has encountered myriad challenges over the years, including serious financial deficits. Taiwan's government managed those crises through successive policy adjustments and reforms. Taiwan's NHI continues to enjoy high public satisfaction and delivers affordable modern health care to all Taiwanese without the waiting times in single-payer systems such as those in England and Canada. It faces challenges, including balancing the system's budget, improving the quality of health care, and achieving greater cost-effectiveness. However, Taiwan's experience with the NHI shows that a single-payer approach can work and control health care costs effectively. There are lessons for the United States in how to expand coverage rapidly, manage incremental adjustments to the health system, and achieve freedom of choice. PMID- 25732503 TI - Necessary steps: how health care fails older patients, and how it can be done better. AB - A chance meeting between an octogenarian and a geriatrician shows how the US health system focuses on medical care at the expense of older adults' well-being. PMID- 25732504 TI - Long-term services and supports: what foundations are funding. PMID- 25732506 TI - Patient-centered medical homes in Louisiana. PMID- 25732507 TI - Medical homes in Louisiana: the authors reply. PMID- 25732508 TI - Transformational change for radiology. PMID- 25732509 TI - Errata. PMID- 25732510 TI - Erratum. PMID- 25732511 TI - Erratum to: K(+) Channels Expression in Hypertension After Arterial Injury, and Effect of Selective Kv1.3 Blockade with PAP-1 on Intimal Hyperplasia Formation. PMID- 25732512 TI - Epidemiological associations between posttraumatic stress disorder and incarceration in the National Survey of American Life. AB - BACKGROUND: In spite of an elevated prevalence of trauma histories among prisoners, there has been little research examining the relationship between incarceration and posttraumatic stress disorder (PTSD); this is especially true for Black Americans. AIMS: To examine relationships between PTSD and incarceration in a nationally representative sample of Black Americans. METHODS: We conducted analysis of data from the National Survey of American Life sample of 5008 Black American adults in the USA. Multivariate logistic regression analyses controlling for demographic factors including age, gender, home region and education were conducted to examine whether incarceration status was independently associated with PTSD. RESULTS: Incarceration was significantly associated with trauma exposure, PTSD in the 12 months prior to interview and lifetime PTSD, even while controlling for demographic covariates. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Incarceration, trauma exposure and PTSD share a significant number of risk factors and co-vary frequently in some populations, including the one of Black Americans investigated in this study. Interventions that can reduce shared risk factors for incarceration and PTSD and/or facilitate successful treatment of the established condition have the potential to make a large positive impact among incarcerated and formerly incarcerated people. PMID- 25732513 TI - MiRNA-320 in the human follicular fluid is associated with embryo quality in vivo and affects mouse embryonic development in vitro. AB - Previous work from our laboratory demonstrated the existence of miRNAs in human follicular fluid. In the current study, we have sought to identify miRNAs that might affect oocyte/embryo quality in patients undergoing intracytoplasmic sperm injection and to investigate their roles in in vitro fertilization outcomes in mouse oocytes. 53 samples were classified as Group 1 (high quality) if the day-3 embryos had seven and more cells or as Group 2 (low quality) if the embryos had six and fewer cells. TaqMan Human microRNAs cards and qRT-PCR were performed to verify differently expressed miRNAs. The function of the corresponding miRNA was investigated in mouse oocytes by injecting them with miRNA-inhibitor oligonucleotides. We found that hsa-miR-320a and hsa-miR-197 had significantly higher expression levels in the Group 1 follicular fluids than in Group 2 (p = 0.0073 and p = 0.008, respectively). Knockdown of mmu-miR-320 in mouse oocytes strongly decreased the proportions of MII oocytes that developed into two-cell and blastocyst stage embryos (p = 0.0048 and p = 0.0069, respectively). Wnt signaling pathway components had abnormal expression level in miR-320 inhibitor injected oocytes. This study provides the first evidence that miRNAs in human follicular fluid are indicative of and can influence embryo quality. PMID- 25732514 TI - Enzymatic production of defined chitosan oligomers with a specific pattern of acetylation using a combination of chitin oligosaccharide deacetylases. AB - Chitin and chitosan oligomers have diverse biological activities with potentially valuable applications in fields like medicine, cosmetics, or agriculture. These properties may depend not only on the degrees of polymerization and acetylation, but also on a specific pattern of acetylation (PA) that cannot be controlled when the oligomers are produced by chemical hydrolysis. To determine the influence of the PA on the biological activities, defined chitosan oligomers in sufficient amounts are needed. Chitosan oligomers with specific PA can be produced by enzymatic deacetylation of chitin oligomers, but the diversity is limited by the low number of chitin deacetylases available. We have produced specific chitosan oligomers which are deacetylated at the first two units starting from the non reducing end by the combined use of two different chitin deacetylases, namely NodB from Rhizobium sp. GRH2 that deacetylates the first unit and COD from Vibrio cholerae that deacetylates the second unit starting from the non-reducing end. Both chitin deacetylases accept the product of each other resulting in production of chitosan oligomers with a novel and defined PA. When extended to further chitin deacetylases, this approach has the potential to yield a large range of novel chitosan oligomers with a fully defined architecture. PMID- 25732515 TI - Attenuation of cartilage pathogenesis in post-traumatic osteoarthritis (PTOA) in mice by blocking the stromal derived factor 1 receptor (CXCR4) with the specific inhibitor, AMD3100. AB - SDF-1 was found to infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity after joint trauma. In this study, we tested the hypothesis that interference of the SDF-1/CXCR4 signaling pathway via AMD3100 can attenuate pathogenesis in a mouse model of PTOA. We also tested the predictive and confirmatory power of fluorescence molecular tomography (FMT) for cartilage assessment. AMD3100 was continuously delivered via mini-osmotic pumps. The extent of cartilage damage after AMD3100 or PBS treatment was assessed by histological analysis 2 months after PTOA was induced by surgical destabilization of the medial meniscus (DMM). Biochemical markers of PTOA were assessed via immunohistochemistry and in vivo fluorescence molecular tomography (FMT). Regression analysis was used to validate the predictive power of FMT measurements. Safranin-O staining revealed significant PTOA damage in the DMM/PBS mice, while the DMM/AMD3100 treated mice showed a significantly reduced response with minimal pathology. Immunohistochemistry showed that AMD3100 treatment markedly reduced typical PTOA marker expression in chondrocytes. FMT measurements showed decreased cathepsins and MMP activity in knee joints after treatment. The results demonstrate that AMD3100 treatment attenuates PTOA. AMD3100 may provide a viable and expedient option for PTOA therapy given the drug's FDA approval and well-known safety profile. PMID- 25732516 TI - Genome-wide analysis reveals the differential regulations of mRNAs and miRNAs in Dorset and Small Tail Han sheep muscles. AB - Sheep are highly diverse species raised for meat and other agricultural products. The aim of the present study was to investigate the genetic regulators that could control muscle growth and development in different sheep breeds. The study showed that the differentially expressed genes are involved in various cellular activities, such as metabolic cascades, catalytic function and signaling pathway. Many signaling molecules are also found to be differentially expressed, suggesting important roles of signaling pathways contributing to genetic diversity and sheep development. Analysis of miRNAs suggested important roles of miRNAs in controlling muscle differences. This study provided a genome-wide resolution of mRNA and miRNA regulations in muscles from Dorset and Han sheep. PMID- 25732517 TI - Oxidative stress and its association with TNF-alpha-308 G/C and IL-1alpha-889 C/T gene polymorphisms in patients with diabetes and diabetic nephropathy. AB - Diabetic nephropathy is one of the major complications of type 2 diabetes and it is currently the leading cause of end-stage renal disease. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species might be a primary source. This study was conducted in four groups in West Indian population: control (235), type 2 diabetes (DM) (214), nephropathy with diabetes (DN) (188) and nephropathy without diabetes (NDN) (196). Oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), superoxide dismutase and catalase were measured in all the groups. TNF-alpha-308 G/C and IL-1alpha-889 C/T polymorphisms were analyzed using PCR-RFLP method. Correlations between genotype frequency and the level of oxidative stress markers were examined. MDA was significantly increased in the patient group in comparison to control group. GSH and SOD were significantly decreased in the patient group in comparison to control group. There was no significant difference observed in genotype frequency of TNF-alpha in the patient group compared with control group. IL-1alpha-889 C/T polymorphism may be associated with diabetic nephropathy. Moreover there was no association of TNF-alpha-308 G/C polymorphism with diabetic nephropathy in West Indian population. The higher serum levels of oxidative stress markers in diabetic patients with nephropathy suggest the possible role of oxidative stress. PMID- 25732518 TI - Diabetes: New treatment approach for T1DM. PMID- 25732519 TI - Chylomicronaemia--current diagnosis and future therapies. AB - This Review discusses new developments in understanding the basis of chylomicronaemia--a challenging metabolic disorder for which there is an unmet clinical need. Chylomicronaemia presents in two distinct primary forms. The first form is very rare monogenic early-onset chylomicronaemia, which presents in childhood or adolescence and is often caused by homozygous mutations in the gene encoding lipoprotein lipase (LPL), its cofactors apolipoprotein C-II or apolipoprotein A-V, the LPL chaperone lipase maturation factor 1 or glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1. The second form, polygenic late-onset chylomicronaemia, which is caused by an accumulation of several genetic variants, can be exacerbated by secondary factors, such as poor diet, obesity, alcohol intake and uncontrolled type 1 or type 2 diabetes mellitus, and is more common than early-onset chylomicronaemia. Both forms of chylomicronaemia are associated with an increased risk of life threatening pancreatitis; the polygenic form might also be associated with an increased risk of cardiovascular disease. Treatment of chylomicronaemia focuses on restriction of dietary fat and control of secondary factors, as available pharmacological therapies are only minimally effective. Emerging therapies that might prove more effective than existing agents include LPL gene therapy, inhibition of microsomal triglyceride transfer protein and diacylglycerol O acyltransferase 1, and interference with the production and secretion of apoC-III and angiopoietin-like protein 3. PMID- 25732521 TI - Diabetes. Genetically engineered Lactobacilli reprogram intestinal cells to secrete insulin and ameliorate hyperglycaemia. PMID- 25732520 TI - MicroRNA regulatory networks in human adipose tissue and obesity. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and, therefore, biological processes in different tissues. A major function of miRNAs in adipose tissue is to stimulate or inhibit the differentiation of adipocytes, and to regulate specific metabolic and endocrine functions. Numerous miRNAs are present in human adipose tissue; however, the expression of only a few is altered in individuals with obesity and type 2 diabetes mellitus or are differentially expressed in various adipose depots. In humans, obesity is associated with chronic low-grade inflammation that is regulated by signal transduction networks, in which miRNAs, either directly or indirectly (through regulatory elements such as transcription factors), influence the expression and secretion of inflammatory proteins. In addition to their diverse effects on signalling, miRNAs and transcription factors can interact to amplify the inflammatory effect. Although additional miRNA signal networks in human adipose tissue are not yet known, similar regulatory circuits have been described in brown adipose tissue in mice. miRNAs can also be secreted from fat cells into the circulation and serve as markers of disturbed adipose tissue function. Given their role in regulating transcriptional networks, miRNAs in adipose tissue might offer tangible targets for treating metabolic disorders. PMID- 25732523 TI - Duodenal duplication cyst extending into the posterior mediastinum. AB - INTRODUCTION: Duodenal duplication is a rare congenital malformation. Although more frequent in childhood, it is rarely observed in adulthood. Preoperative diagnosis can be difficult. PRESENTATION OF CASE: We report a case of 42 year-old woman with duodenal duplication cyst situated in the posterior mediastinum, who was misdiagnosed even after a primary surgery. Detailed diagnostic workup and a second operation was done. DISCUSSION: This article discusses the incidence of duodenal duplications, their types and clinical presentations, the radiologic and diagnostic features with different therapeutic options. CONCLUSION: Duodenal and the other intestinal duplication cysts should be considered in the differential diagnosis of oral contrast enhanced intrathoracic lesions in thorocoabdominal computerised tomography imaging. PMID- 25732524 TI - "An unusual presentation of colonic mucormycosis mimicking carcinoma colon- a surgeon's perspective". AB - INTRODUCTION: Mucormycosis caused by order mucorales, an ubiquitous saprophytic mold found in soil and organic matter worldwide, is a rare but invasive opportunistic fungal infection. Gastrointestinal mucormycosis is the most uncommon clinical presentation being particularly rare, accounted for 4-7% of all cases. PRESENTATION OF CASE: We report an unusual presentation of mucormycosis of ascending colon that was simulating carcinoma colon. DISCUSSION: GI mucormycosis most commonly involves the stomach (57.5%), followed by the colon (32.3%) and the ileum (6.9%). Initial presentations may be abdominal pain and distension, fever, and diarrhoea. Colonic mucormycosis presenting as a mass with altered bowel habit, melena and abdominal pain in our case is extremely difficult to differentiate it from carcinoma colon. A definitive diagnosis of mucormycosis is almost always ascertained by histopathological evidence of fungal invasion of tissue. CONCLUSION: Knowing these unusual presentations of this disease, surgeon need to maintain a high index of suspicion and perform timely and appropriate diagnostic evaluation to improve patient outcome. Prompt diagnosis, reversal of predisposing conditions, and aggressive surgical debridement remain cornerstones of therapy for this deadly disease. PMID- 25732522 TI - Diagnosis of cerebral vasospasm and risk of delayed cerebral ischemia related to aneurysmal subarachnoid haemorrhage: an overview of available tools. AB - In the first weeks following aneurysmal subarachnoid haemorrhage, cerebrovascular alterations may impact the outcome significantly. Diagnosis of cerebral vasospasm and detection of alterations at risk of delayed cerebral ischemia are key targets to be monitored in the post-acute phase. Available tools include clinical monitoring, as well as studies that can detect possible arterial narrowing, alterations of perfusion, metabolism and neurophysiology. Each technique is able to investigate possible vascular impairment and has different advantages and limits. All available techniques have been described. Among these, the most practical have been selected and compared for their peculiar characteristics. Based on this analysis, a flowchart to monitor these patients is finally proposed. PMID- 25732525 TI - The association between risk factors and time of onset for thrombocytopenia in Japanese patients receiving linezolid therapy: a retrospective analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Linezolid (LZD) is an oxazolidinone antibiotic that is active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The major adverse effect related to its use in humans is reversible myelosuppression, which mostly manifests as thrombocytopenia. This retrospective study was conducted to identify risk factors that might contribute towards the development of thrombocytopenia due to intravenous administration of LZD. METHOD: Patients who were administered LZD between January 2008 and March 2013 were included. Thrombocytopenia was defined as a decrease in platelet count of >=10 * 10(4) cell/MUL from baseline or of >=30%. RESULTS: A total of 47 patients were included in this study. These patients were divided into two groups: 22 patients (46.8%) were assigned to a non thrombocytopenia group and 25 patients (53.2%) to a thrombocytopenia group. Multivariate logistic regression analysis revealed significant intergroup differences in duration of LZD treatment [odds ratio (OR) = 1.278; 95% confidence interval (CI) = 1.068-1.529; P = 0.007] and white blood cell (WBC) count (>12000 cells/MUL; OR = 10.399; 95% CI = 1.667-64.882; P = 0.012). WHAT IS NEW AND CONCLUSIONS: This finding suggests that duration of LZD treatment and WBC count (>12000 cells/MUL) are risk factors associated with thrombocytopenia resulting from LZD administration. PMID- 25732526 TI - Prefrontal cortex and sensory cortices during working memory: quantity and quality. AB - The activity in sensory cortices and the prefrontal cortex (PFC) throughout the delay interval of working memory (WM) tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in sensory cortices is fine-tuned to sensory information and forms the neural basis of the precision of WM storage, while the delay activity in the PFC appears to represent behavioral goals and filters out irrelevant distractions, forming the neural basis of the quantity of task-relevant information in WM. The PFC and sensory cortices interact through different frequency bands of neuronal oscillation (theta, alpha, and gamma) to fulfill goal-directed behaviors. PMID- 25732528 TI - Ca(2+) signaling initiated by canonical transient receptor potential channels in dendritic development. AB - The spatial patterns of dendritic structures diverge in different types of neurons as adaptations to their unique functions. Although different intracellular mechanisms underlying dendritic morphogenesis have been suggested, it is evident that the elevation in intracellular Ca(2+) levels plays a major role in the process. Canonical transient receptor potential (TRPC) channels, known to be non-selective Ca(2+)-permeable cation channels, act as environmental detectors to sense and transduce extracellular signals into different intracellular responses, including the regulation of dendritic growth, via Ca(2+) influx. Here, we review recent advances in the understanding of Ca(2+) signaling, especially signals mediated by Ca(2+) influx via TRPC channels, and the underlying molecular events in dendritic development. PMID- 25732527 TI - Hypothalamic-pituitary-adrenal axis function during perinatal depression. AB - Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol pro-inflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11beta-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby. PMID- 25732530 TI - Changes in desmin expression in patients with cardiac diastolic dysfunction and preserved or reduced ejection fraction. AB - PURPOSE: Desmin regulates function of mitochondria, T-tubular system and cytosolic Ca(2+) transients. We investigated whether desmin remodeling correlates with diastolic dysfunction and whether progressive desmin abnormalities are accompanied by increasing diastolic dysfunction stages. PATIENTS AND METHODS: Eighty five patients with idiopathic dilated cardiomyopathy and suspected myocarditis without confirmed cardiac tissue inflammation in histopathology assays were included and divided into groups: with preserved EF and reduced EF. After echocardiographic analysis of diastolic dysfunction we identified 2 preserved EF subgroups (normal diastolic function (NDF) and impaired relaxation (IR)) and 3 reduced EF subgroups (NDF, IR, and pseudonormalization). Patients with preserved EF and NDF formed the control group. Tissue desmin staining revealed 4 types of desmin expression: I - normal, with regular pattern of cross section, IIA - increased with regular pattern, IIB - increased, with irregular pattern and presence of aggregates, III - decreased/lack desmin. RESULTS: Desmin I was observed only in patients with NDF n=8 (100%) in preserved EF and reduced EF, desmin IIA in NDF n=8 (33%) in preserved EF and n=5 (33%) in reduced EF and IR n=16 (66%) in preserved EF and n=10 (66%) in reduced EF. Desmin IIB and III were observed in patients with reduced EF and diastolic dysfunction: IR and pseudonormalization n=9 (39%) and n=2 (29%); n=14 (61%) and n=5 (71%), respectively. Desmin was found to be an independent predictor of diastolic function parameters beta=-0.63, R(2)=0.52 for E'; beta=0.54, R(2)=0.42 for E/E'. CONCLUSIONS: Increasing desmin abnormalities were correlated with diastolic dysfunction progression. Desmin expression represents a novel factor contributing or paralleling the development of diastolic dysfunction. PMID- 25732529 TI - Abnormal circumferential strain measured by echocardiography is present in patients with Shwachman-Diamond syndrome despite normal shortening fraction. AB - BACKGROUND: Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure and exocrine pancreatic dysfunction. Heart failure has been described in patients with SDS. Circumferential strain (epsilon(cc)) is a measure of cardiac performance that may identify dysfunction when standard measures are normal. PROCEDURES: Patients with SDS were identified and the echocardiographic database queried. Cardiac anatomy and function were recorded, and epsilon(cc) was measured retrospectively. RESULTS: From 1995-2013, 27 patients with biallelic SBDS mutations confirming the diagnosis of SDS were identified at our institution: 14 had at least one echocardiogram available; 10 underwent HSCT, with echocardiograms available in nine. Ejection fraction (EF) was normal in all 14 patients evaluated; however, epsilon(cc) was decreased in 4/12 studies prior to HSCT. In two patients, epsilon(cc) was abnormal both before and after HSCT, in one, epsilon(cc) changed from normal to abnormal after HSCT, and in one, epsilon(cc) was normal after HSCT despite being abnormal prior. Echocardiogram reports were also available for six patients in the North American SDS registry, all with normal EF. CONCLUSIONS: While EF was normal in all patients with SDS, epsilon(cc) was abnormal in 33% prior to HSCT and 33% of those who had undergone HSCT. This suggests that SDS is associated with systolic dysfunction. Further studies are needed to define the incidence of dysfunction in this group and the progression to heart failure. PMID- 25732531 TI - Metamorphopsia before and after full-thickness macular hole surgery. AB - PURPOSE: We quantified the degree and dynamics of metamorphopsia changes in patients subjected to full-thickness macular hole surgery. MATERIAL/METHODS: This prospective interventional case series included 10 eyes of 10 patients with full thickness macular hole (mean age 66.2+/-6.0 years). The patients underwent a complete ophthalmological examination including SD-OCT. The severity of metamorphopsia (expressed as M-score) was evaluated with M-CHARTS. 20-gauge pars plana vitrectomy with trypan blue staining, internal limiting membrane peeling and 20% sulphur hexafluoride tamponade was performed. Time course of metamorphopsia changes and their relation to best corrected visual acuity (BCVA) and OCT parameters were assessed. RESULTS: Significant but not total M-score decrease was observed one month postoperatively (0.72+/-0.44 vs. 0.50+/-0.36, z= 2.207, p=0.0353, power=0.26, pre- vs. post-op), with subsequent stabilization (0.41+/-0.41 three months and 0.37+/-0.44 six months post-op). The differences between M-score one month, three months and six months postoperatively were not significant. Baseline M-score correlated significantly with postoperative values at three follow-ups (rho=0.853, 0.715, 0.847; p<0.05 for all; power=0.94, 0.58, 0.79). Baseline M-score did not correlate with macular hole dimensions (including basis p=0.154, minimal diameter p=0.051 or height of the border p=0.700). No correlation between M-score and the following parameters was found either pre- or postoperatively: BCVA, central foveal thickness, central subfield macular thickness and central subfield macular volume. CONCLUSIONS: In patients with successfully operated full-thickness macular hole, M-score decreased as early as one month postoperatively and was stable afterwards. The baseline M-score was a prognostic factor for the postoperative M-score. M-score turned out to be independent from BCVA and macular hole dimensions. PMID- 25732533 TI - Loss of floral repressor function adapts rice to higher latitudes in Europe. AB - The capacity to discriminate variations in day length allows plants to align flowering with the most favourable season of the year. This capacity has been altered by artificial selection when cultivated varieties became adapted to environments different from those of initial domestication. Rice flowering is promoted by short days when HEADING DATE 1 (Hd1) and EARLY HEADING DATE 1 (Ehd1) induce the expression of florigenic proteins encoded by HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1). Repressors of flowering antagonize such induction under long days, maintaining vegetative growth and delaying flowering. To what extent artificial selection of long day repressor loci has contributed to expand rice cultivation to Europe is currently unclear. This study demonstrates that European varieties activate both Hd3a and RFT1 expression regardless of day length and their induction is caused by loss-of-function mutations at major long day floral repressors. However, their contribution to flowering time control varies between locations. Pyramiding of mutations is frequently observed in European germplasm, but single mutations are sufficient to adapt rice to flower at higher latitudes. Expression of Ehd1 is increased in varieties showing reduced or null Hd1 expression under natural long days, as well as in single hd1 mutants in isogenic backgrounds. These data indicate that loss of repressor genes has been a key strategy to expand rice cultivation to Europe, and that Ehd1 is a central node integrating floral repressive signals. PMID- 25732535 TI - Nitric oxide: a multifaceted regulator of the nitrogen-fixing symbiosis. AB - The specific interaction between legumes and Rhizobium-type bacteria leads to the establishment of a symbiotic relationship characterized by the formation of new differentiated organs named nodules, which provide a niche for bacterial nitrogen (N2) fixation. In the nodules, bacteria differentiate into bacteroids with the ability to fix atmospheric N2 via nitrogenase activity. As nitrogenase is strongly inhibited by oxygen, N2 fixation is made possible by the microaerophilic conditions prevailing in the nodules. Increasing evidence has shown the presence of NO during symbiosis, from early interaction steps between the plant and the bacterial partners to N2-fixing and senescence steps in mature nodules. Both the plant and the bacterial partners participate in NO synthesis. NO was found to be required for the optimal establishment of the symbiotic interaction. Transcriptomic analysis at an early stage of the symbiosis showed that NO is potentially involved in the repression of plant defence reactions, favouring the establishment of the plant-microbe interaction. In mature nodules, NO was shown to inhibit N2 fixation, but it was also demonstrated to have a regulatory role in nitrogen metabolism, to play a beneficial metabolic function for the maintenance of the energy status under hypoxic conditions, and to trigger nodule senescence. The present review provides an overview of NO sources and multifaceted effects from the early steps of the interaction to the senescence of the nodule, and presents several approaches which appear to be particularly promising in deciphering the roles of NO in N2-fixing symbioses. PMID- 25732534 TI - A wheat ABC transporter contributes to both grain formation and mycotoxin tolerance. AB - The mycotoxin deoxynivalenol (DON) acts as a disease virulence factor for Fusarium fungi, and tolerance of DON enhances wheat resistance to Fusarium head blight (FHB) disease. Two variants of an ATP-binding cassette (ABC) family C transporter gene were cloned from DON-treated wheat mRNA, namely TaABCC3.1 and TaABCC3.2. These represent two of three putative genes identified on chromosomes 3A, 3B, and 3D of the wheat genome sequence. Variant TaABCC3.1 represents the DON responsive transcript previously associated with DON resistance in wheat. PCR based mapping and in silico sequence analyses located TaABCC3.1 to the short arm of wheat chromosome 3B (not within the FHB resistance quantitative trait locus Fhb1). In silico analyses of microarray data indicated that TaABCC3 genes are expressed in reproductive tissue and roots, and in response to the DON producer Fusarium graminearum. Gene expression studies showed that TaABCC3.1 is activated as part of the early host response to DON and in response to the FHB defence hormone jasmonic acid. Virus-induced gene silencing (VIGS) confirmed that TaABCC3 genes contributed to DON tolerance. VIGS was performed using two independent viral construct applications: one specifically targeted TaABCC3.1 for silencing, while the other targeted this gene and the chromosome 3A homeologue. In both instances, VIGS resulted in more toxin-induced discoloration of spikelets, compared with the DON effects in non-silenced spikelets at 14 d after toxin treatment (>=2.2-fold increase, P<0.05). Silencing by both VIGS constructs enhanced head ripening, and especially so in DON-treated heads. VIGS of TaABCC3 genes also reduced the grain number by more than 28% (P<0.05), both with and without DON treatment, and the effects were greater for the construct that targeted the two homeologues. Hence, DON-responsive TaABCC3 genes warrant further study to determine their potential as disease resistance breeding targets and their function in grain formation and ripening. PMID- 25732536 TI - Arabidopsis C3H14 and C3H15 have overlapping roles in the regulation of secondary wall thickening and anther development. AB - Plant tandem CCCH zinc finger (TZF) proteins play diverse roles in developmental and adaptive processes. Arabidopsis C3H14 has been shown to act as a potential regulator of secondary wall biosynthesis. However, there is lack of direct evidence to support its functions in Arabidopsis. It is demonstrated here that C3H14 and its homologue C3H15 redundantly regulate secondary wall formation and that they additionally function in anther development. Plants with double, but not single, T-DNA mutants for C3H14 or C3H15 have few pollen grains and thinner stem secondary walls than the wild type. Plants homozygous for c3h14 and heterozygous for c3h15 [c3h14 c3h15(+/-)] have slightly thinner secondary walls than plants heterozygous for c3h14 and homozygous for c3h15 [c3h14(+/-) c3h15], and c3h14(+/-) c3h15 have lower fertility. Overexpression of C3H14 or C3H15 led to increased secondary wall thickness in stems and the ectopic deposition of secondary walls in various tissues, but did not affect anther morphology. Transcript profiles from the C3H14/15 overexpression and c3h14 c3h15 plants revealed marked changes in the expression of many genes associated with cell wall metabolism and pollen formation. Subcellular localization and biochemical analyses suggest that C3H14/15 might function at both the transcriptional and post-transcriptional levels. PMID- 25732537 TI - Identification of cleavage sites and substrate proteins for two mitochondrial intermediate peptidases in Arabidopsis thaliana. AB - Most mitochondrial proteins contain an N-terminal targeting signal that is removed by specific proteases following import. In plant mitochondria, only mitochondrial processing peptidase (MPP) has been characterized to date. Therefore, we sought to determine the substrates and cleavage sites of the Arabidopsis thaliana homologues to the yeast Icp55 and Oct1 proteins, using the newly developed ChaFRADIC method for N-terminal protein sequencing. We identified 88 and seven putative substrates for Arabidopsis ICP55 and OCT1, respectively. It was determined that the Arabidopsis ICP55 contains an almost identical cleavage site to that of Icp55 from yeast. However, it can also remove a far greater range of amino acids. The OCT1 substrates from Arabidopsis displayed no consensus cleavage motif, and do not contain the classical -10R motif identified in other eukaryotes. Arabidopsis OCT1 can also cleave presequences independently, without the prior cleavage of MPP. It was concluded that while both OCT1 and ICP55 were probably acquired early on in the evolution of mitochondria, their substrate profiles and cleavage sites have either remained very similar or diverged completely. PMID- 25732538 TI - Examining communication- and media-based recreational sedentary behaviors among Canadian youth: results from the COMPASS study. AB - OBJECTIVES: To examine the prevalence of different communication- and media-based sedentary behaviors and examine how they are associated with modifiable risk behaviors and key demographic correlates among a large sample of youth. METHODS: Data from 23,031 grade 9 to grade 12 students in Year 1 (2012-2013) of the COMPASS study (Canada) were used to examine the prevalence of sedentary behaviors by gender and by grade. The between-school variance in sedentary behaviors was calculated and models were developed to examine how modifiable risk factors and demographic correlates were associated with sedentary behaviors. RESULTS: Youth averaged 494 (+/- 313) min/day of sedentary behavior and 96.7% of the sample exceeded the sedentary behavior guidelines of no more than 2h per day. Significant between-school random variation in the sedentary behaviors was identified. Substance use, weight status, ethnicity, and gender were the main predictors of the sedentary behaviors examined. CONCLUSIONS: The vast majority of youth in the COMPASS sample are considered highly sedentary. The evidence clearly suggests we need to develop more effective methods of intervening, that school based programming is warranted, and that gender-specific programming may be required. PMID- 25732539 TI - Vitamin D as an adjunctive therapy in asthma. Part 1: A review of potential mechanisms. AB - Vitamin D deficiency (VDD) is highly prevalent worldwide. The classical role for vitamin D is to regulate calcium absorption form the gastrointestinal tract and influence bone health. Recently vitamin D receptors and vitamin D metabolic enzymes have been discovered in numerous sites systemically supporting diverse extra-skeletal roles of vitamin D, for example in asthmatic disease. Further, VDD and asthma share several common risk factors including high latitude, winter season, industrialization, poor diet, obesity, and dark skin pigmentation. Vitamin D has been demonstrated to possess potent immunomodulatory effects, including effects on T cells and B cells as well as increasing production of antimicrobial peptides (e.g. cathelicidin). This immunomodulation may lead to asthma specific clinical benefits in terms of decreased bacterial/viral infections, altered airway smooth muscle-remodeling and -function as well as modulation of response to standard anti-asthma therapy (e.g. glucocorticoids and immunotherapy). Thus, vitamin D and its deficiency have a number of biological effects that are potentially important in altering the course of disease pathogenesis and severity in asthma. The purpose of this first of a two-part review is to review potential mechanisms whereby altering vitamin D status may influence asthmatic disease. PMID- 25732540 TI - Spatially resolved in situ determination of reaction progress using microfluidic systems and FT-IR spectroscopy as a tool for biocatalytic process development. AB - A concept for the determination of concentrations in microchannels using FT-IR spectroscopy in transmission is presented. The fundamental idea of spatially resolved measurements along several measuring points was implemented in a single channel microreactor. Compared to existing microreactor setups for the analysis of fast chemical reactions or mixing processes, the presented concept enables longer residence times at appropriate resolution. Once steady-state conditions were reached in the reactor, mid-infrared spectra were collected at different locations. Information throughout the considered conversion range is available, which is of great importance to analyze inhibitory effects, next to the kinetic constants (vmax and KM). Therefore, this technology enables a rapid screening of (bio-)catalysts, substrate specificity and process conditions. In particular, the analysis of real substrates instead of model substrates and the possibility to follow side reactions and follow-up reactions during enzymatic catalysis open a broad field of application. PMID- 25732541 TI - Enhanced Aspergillus ficuum phytase production in fed-batch and continuous fermentations in the presence of talcum microparticles. AB - This study aimed to enhance Aspergillus ficuum phytase production in fed-batch and continuous fermentations with addition of talcum microparticles. Phytase activity almost doubled in fed-batch and continuous fermentations by addition of 15 g/l of talcum compared to the control. Effect of talcum on fungal morphology was also shown that addition of talcum provided smaller fungal pellets and more homogenized fermentation broth compared to the control. Average fungal pellet radius decreased from 500 to 100 um by addition of 15 g/l of talcum in the bioreactors. Also, 15 g/l talcum addition increased phytase productivity and optimum dilution rate in the continuous fermentations from 0.293 to 0.621 U/ml/h and from 0.09 to 0.1/h, respectively, compared to control. PMID- 25732542 TI - Identification and bioinformatics analysis of miRNAs involved in bovine skeletal muscle satellite cell myogenic differentiation. AB - MicroRNAs (miRNAs) are short non-coding RNA molecules that perform post transcriptional repression of target genes by binding to 3' untranslated regions, and involved in the regulation of many biological processes. Some studies indicate that miRNAs are mechanistically involved in the muscle growth and differentiation. However, little is known about miRNAs expression patterns during the process of bovine skeletal muscle satellite cell myogenic differentiated into myotubes. To investigate the mechanisms of miRNAs-mediated regulation during this process, we performed a miRNAs microarray to detect 783 bovine miRNAs in bovine skeletal muscle satellite cell myogenic differentiation, and the results were further confirmed by a quantitative real-time RT-PCR assay. We observed that the expression of 15 miRNAs was significantly different between bovine skeletal muscle satellite cells and differentiated myotubes, in which twelve were significantly up-regulated and three were down-regulated in myotubes. Furthermore, using bioinformatics methods, the targets of differentially expressed miRNAs were predicted, and were further subjected to gene ontology (GO) and KEGG analysis. A total of 3077 potential target genes were produced, and the highly enriched GOs and KEGG pathways showed that these genes together formed a regulatory network that involved in cell proliferation, cell differentiation, and multiple biological molecular signaling processes. Taken together, the results of the current study suggested the potential regulating roles of these differentially expressed miRNAs in bovine myogenic differentiation. PMID- 25732543 TI - An evaluation of cancer survivorship activities across national comprehensive cancer control programs. AB - INTRODUCTION: Centers for Disease Control and Prevention's (CDC) National Comprehensive Cancer Control Program (NCCCP) funds states, the District of Columbia, tribal organizations, territories, and jurisdictions across the USA develop and implement jurisdiction-specific comprehensive cancer control (CCC) plans. The objective of this study was to analyze NCCCP action plan data for incorporation and appropriateness of cancer survivorship-specific goals and objectives. METHODS: In August 2013, NCCCP action plans maintained within CDC's Chronic Disease Management Information System (CDMIS) from years 2010 to 2013 were reviewed to assess the inclusion of cancer survivorship objectives. We used the CDMIS search engine to identify "survivorship" within each plan and calculated the proportion of programs that incorporate cancer survivorship related content during the study period and in each individual year. Cancer survivorship objectives were then categorized by compatibility with nationally accepted, recommended strategies from the report A National Action Plan for Cancer Survivorship: Advancing Public Health Strategies (NAP). RESULTS: From 2010 to 2013, 94% (n = 65) of NCCCP action plans contained survivorship content in at least 1 year during the time period and 38% (n = 26) of all NCCCP action plans addressed cancer survivorship every year during the study period. Nearly 64% (n = 44) of NCCCP action plans included cancer survivorship objectives recommended in NAP. CONCLUSION: Nearly all NCCCP action plans addressed cancer survivorship from 2010 to 2013, and most programs implemented recommended cancer survivorship efforts during the time period. IMPLICATIONS FOR CANCER SURVIVORS: NCCCP grantees can improve cancer survivorship support by incorporating recommended efforts within each year of their plans. PMID- 25732545 TI - NICE guidance on sipuleucel-T for asymptomatic or minimally symptomatic metastatic hormone-relapsed prostate cancer. PMID- 25732544 TI - Similar sponge-associated bacteria can be acquired via both vertical and horizontal transmission. AB - Marine sponges host diverse communities of microorganisms that are often vertically transmitted from mother to oocyte or embryo. Horizontal transmission has often been proposed to co-occur in marine sponges, but the mechanism is poorly understood. To assess the impact of the mode of transmission on the microbial assemblages of sponges, we analysed the microbiota in sympatric sponges that have previously been reported to acquire bacteria via either vertical (Corticium candelabrum and Crambe crambe) or horizontal transmission (Petrosia ficiformis). The comparative study was performed by polymerase chain reaction denaturing gradient gel electrophoresis and pyrosequencing of barcoded PCR amplified 16S rRNA gene fragments. We found that P. ficiformis and C. candelabrum each harbour their own species-specific bacteria, but they are similar to other high-microbial-abundance sponges, while the low-microbial-abundance sponge C. crambe hosts microbiota of a very different phylogenetic signature. In addition, nearly 50% of the reads obtained from P. ficiformis were most closely related to bacteria that were previously reported to be vertically transmitted in other sponges and comprised vertical-horizontal transmission phylogenetic clusters (VHT clusters). Therefore, our results provide evidence for the hypothesis that similar sponge-associated bacteria can be acquired via both vertical and horizontal transmission. PMID- 25732546 TI - NICE guidance on axitinib for treating advanced renal cell carcinoma after failure of prior systemic treatment. PMID- 25732547 TI - Temperature-sensitive fitness cost of insecticide resistance in Chinese populations of the diamondback moth Plutella xylostella. AB - Alleles conferring a higher adaptive value in one environment may have a detrimental impact on fitness in another environment. Alleles conferring resistance to pesticides and drugs provide textbook examples of this trade-off as, in addition to conferring resistance to these molecules, they frequently decrease fitness in pesticide/drug-free environments. We show here that resistance to chlorpyrifos, an organophosphate (OP), in Chinese populations of the diamondback moth, Plutella xylostella, is conferred by two mutations of ace1 the gene encoding the acetylcholinesterase enzyme targeted by OPs - affecting the amino acid sequence of the corresponding protein. These mutations were always linked, consistent with the segregation of a single resistance allele, ace1R, carrying both mutations, in the populations studied. We monitored the frequency of ace1R (by genotyping more than 20 000 adults) and the level of resistance (through bioassays on more than 50 000 individuals) over several generations. We found that the ace1R resistance allele was costly in the absence of insecticide and that this cost was likely recessive. This fitness costs involved a decrease in fecundity: females from resistant strains laid 20% fewer eggs, on average, than females from susceptible strains. Finally, we found that the fitness costs associated with the ace1R allele were greater at high temperatures. At least two life history traits were involved: longevity and fecundity. The relative longevity of resistant individuals was affected only at high temperatures and the relative fecundity of resistant females - which was already affected at temperatures optimal for development - decreased further at high temperatures. The implications of these findings for resistance management are discussed. PMID- 25732548 TI - Pharmacist calls to older adults with cognitive difficulties after discharge in a Tertiary Veterans Administration Medical Center: a quality improvement program. AB - OBJECTIVES: To evaluate the effect of the Pharmacological Intervention in Late Life (PILL) Service, which provides pharmacist telephone follow-up after discharge of older adults from the hospital, on postdischarge acute care utilization. DESIGN: Retrospective, secondary data analysis of a quality improvement project from 2010 to 2012. SETTING: Tertiary Veterans Affairs hospital. PARTICIPANTS: Participants were inpatients aged 65 and older with delirium risk or prescribed a dementia medication (N=501, mean age 79.5+/-8.0; 98% male). MEASUREMENTS: PILL Service pharmacist telephone follow-up included a medication review and reconciliation within 5 days after hospital discharge. The time of the pharmacist call was examined in relation to the outcomes of emergency and urgent care encounters, readmissions, and mortality within 60 days. RESULTS: The average number of discharge medications was 14.8+/-5.7 with 2.8+/-2.2 medication changes and 1.4+/-1.8 discrepancies between medication order and instruction. After adjustment for age, number of medication changes, and number of discrepancies, every additional 5 minutes of pharmacist call was associated with a 15% reduction in 60-day readmission (adjusted odds ratio (OR)=0.85, 95% confidence interval (95% CI)=0.75-0.97) but was not associated with emergency or urgent care encounters (adjusted OR=1.03, 95% CI=0.91-1.17) or mortality (adjusted OR=0.84, 95% CI=0.58-1.20). CONCLUSION: Pharmacist-led medication review, reconciliation, and telephone calls after hospital discharge were associated with fewer 60-day hospital readmissions in this quality improvement program. PMID- 25732549 TI - The advancement of human serum albumin-based molecular probes for molecular imaging. AB - Human serum albumin (HSA) is an abundant protein in blood and tissue fluids and has been used as a carrier for drug delivery. HSA can improve the pharmacokinetic profiles of drugs, such as extending the blood half-life of existing drugs and reducing toxic side effects. At the same time, more and more molecular imaging probes conjugated or fused with HSA have been studied to achieve higher specificity and better pharmacokinetic performance. These molecular probes can be attached to HSA covalently or non-covalently. They can also be fused with HSA as a fusion protein or coupled with HSA in vivo. Importantly, HSA conjugated probes have been applied to many imaging modalities such as the single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography (PET) and optical imaging alone or in combination with more than one modality. Besides in vivo molecular imaging, HSA conjugated probes can be used for molecular therapeutics, image-guided therapy, such as photodynamic imaging and photodynamic therapy (PDI/PDT). Some potential problems also need to be considered when using of HSA based probe strategy which are discussed in detail in the paper. Overall, HSA based probe design represents a very useful and powerful strategy for developing more molecular probes for theranostics of diseases. PMID- 25732550 TI - Recombinant human serum albumin fusion proteins and novel applications in drug delivery and therapy. AB - Fusion proteins have been well-studied and widely applied in biopharmaceutics. Albumin fusion proteins are simple to construct, easy to purify, and stable to formulate. One main application of fusion protein is to extend the plasma half life of therapeutic proteins and peptides. Albiglutide for diabetes treatment is the first albumin fusion protein drug approved by FDA. Balugrastim and other albumin fusion proteins have been evaluated in clinical trials. Taking advantage of the physiological functions of albumin, albumin fusion proteins can also been applied to act on an essential intracellular target and carry fatty acid-modified drugs. This novel approach makes it possible to co-deliver two different types of drug to one tumor cell for synergistic cytotoxicity. PMID- 25732551 TI - Molecular imaging and targeted drug delivery using albumin-based nanoparticles. AB - Albumin has been used as a popular material for carrying imaging probes and/or drugs to provide efficient biomedical imaging and therapy. It is considered as an ideal material for in vivo applications, because albumin is naturally abundant in serum to show non-toxicity and non-immunogenicity. In addition, based on the convenience of chemical modifications, it is widely used for the delivery of diverse molecules including chemicals, proteins/peptides, and oligonucleotides. Albumin nanoparticles carrying these molecules have shown improved pharmacokinetic properties by providing longer circulation time and more disease specific accumulation, and they are emerging as a promising carrier system for in vivo imaging and therapy. Constant efforts to improve the properties of albumin nanoparticles have led to a great progress in medical application, and recent examples of market approval and success are brightening the prospect of albumin based nanocarrier formulations in the future. This article will summarize the developments in albumin nanocarriers for biomedical imaging and targeted drug delivery. This review will give an account of the different applications of albumin carriers with examples of some recent innovative works. PMID- 25732552 TI - Recent advances on the development of pharmacotherapeutic agents on the basis of human serum albumin. AB - Human serum albumin (HSA), a major transport protein component in blood plasma, has been reported recently to play many important roles in pharmacotherapeutics development. Owing to its promising intrinsic binding capability of drug molecules, HSA offers favorable characteristics and can be directly used as its monomeric formula or can be fabricated into protein based nanoparticle platforms to realize the effective delivery of therapeutic molecules into targeted diseases areas. In addition, HSA can also serve as a protein stabilizer or environment responsive moieties to hybridize with the functional materials including polymers or inorganic nanoparticles through the covalent reactions or electrostatic interactions, and can thus greatly alter the relevant biological distribution and pharmacokinetic behavior to improve their therapeutic efficacy. By right, extensive studies have been conducted to develop HSA-conjugated pharmacotherapeutic agents toward effective in vitro and in vivo diseases diagnosis and treatment. The current review gives an in-detail account of the latest progresses of HSA-based carriers as functional protein materials, mainly with respect to its conjugation types, formulation aspects, and importantly their promising applications towards enhanced drug delivery and medical diagnosis. PMID- 25732553 TI - Review: modifications of human serum albumin and their binding effect. AB - Human serum albumin (HSA) regulates the transport and availability of numerous chemical compounds and molecules in the blood vascular system. While previous HSA research has found that HSA interacts with specific varieties of ligands, new research efforts aim to expand HSA's ability to interact with more different drugs in order to improve the delivery of various pharmacological drugs. This review will cover fatty acid chain and posttranslational modifications of HSA that potentially modulate how HSA interacts with various pharmacological drugs, including glycation, cysteinylation, S-nitrosylation, S-transnitrosation and S guanylation. PMID- 25732554 TI - Evaluation of interactions between platinum-/ruthenium-based anticancer agents and human serum albumin: development of HSA carrier for metal-based drugs. AB - To date, many potent metal-based anticancer drugs have been developed and many drug delivery systems have been exploited to improve the targeting and decrease the side effects of anticancer drugs. Human serum albumin (HSA) binding contributes significantly to the discovery of new drug candidates because binding of drugs to HSA strongly influences their pharmacokinetic behaviour. Moreover, HSA is widely used in the clinical setting as a drug delivery system due to its potential for improving targeting while decreasing the side effects of drugs. This review not only provides a brief outline of the properties of HSA carriers but also provides an overview of the binding and anticancer characteristics of platinum-/ruthenium-based anticancer drugs to HSA that may guide the rational designing and development of metal-based drugs and HSA-based carriers for clinical applications. PMID- 25732555 TI - Drugs modulate allosterically heme-Fe-recognition by human serum albumin and heme fe-mediated reactivity. AB - Human serum albumin (HSA) represents an important determinant of plasma oncotic pressure and a relevant factor that modulates fluid distribution between the body compartments. Moreover, HSA (i) represents the depot and transporter of several compounds, both endogenous and exogenous, (ii) affects the pharmacokinetics of many drugs, (iii) regulates chemical modifications of some ligands, (iv) shows (pseudo-)enzymatic properties, (v) inactivates some toxic compounds, and (vi) displays anti-oxidant properties. HSA binding and (pseudo-)enzymatic properties are regulated competitively, allosterically, and by covalent modifications. While competitive inhibition of HSA binding properties is evident, allosteric mechanisms and covalent modifications affecting HSA reactivity are less clear. In several pathological conditions in which free heme-Fe levels increase, the buffering capacity of plasma hemopexin is overwhelmed and most of heme-Fe binds to the fatty acid site 1 of HSA. HSA-heme-Fe displays globin-like properties; in turn, heme-Fe modulates competitively and allosterically HSA binding and reactivity properties. Remarkably, heme-Fe-mediated HSA properties are time dependent, representing a case for "chronosteric effects". Here, we review the drug-based modulation of (i) heme-Fe-recognition by HSA and (ii) heme-Fe-mediated reactivity. PMID- 25732556 TI - Structure and enzymatic activities of human serum albumin. AB - Human serum albumin (HSA) is the most abundant protein in plasma, and plays multiple roles in physiology, including as a carrier protein for endogenous and exogenous compounds. Recent studies provide new evidences to support the enzymatic activities of HSA and new molecular insights for such activities. Here, the structural features and enzymatic characteristics of HSA are reviewed. PMID- 25732557 TI - Studies on drug-human serum albumin binding: the current state of the matter. AB - Human serum albumin (HSA) is the major plasma protein with vital functions acting as depot and career for many endogenous (fatty acids, bilirubin, etc.) and exogenous substances (drugs, nutrients, etc.) in the blood. Binding to HSA controls the free, active concentration of the drug and may affect considerably the overall pharmacodynamic and pharmacokinetic profile. Studies on drug - protein binding are important from both theoretical and practical point of view as they allow better understanding of the processes underlying drug disposition and elimination and the effect of several pathological states or co-administered drugs on drug delivery and efficacy. The present review focuses on the current state of drug - HSA binding studies. The major functions and consequences of drug - protein binding are described. The X-ray structure of HSA is discussed focusing on the location and the architecture of the primary drug and fatty acids binding sites. Some of the most commonly used methods for drug - HSA binding assay are presented together with examples for their application. The most extensive studied topics in the area are discussed including quantitative characterization of drug - HSA complexation, identification of the binding sites, stereoselectivity of drug - HSA interactions, and thermodynamic characterization of the binding process. A short section is devoted to in silico prediction of drug - HSA binding as an important step in drug design and development. PMID- 25732558 TI - Dynamics of bacterial communities before and after distribution in a full-scale drinking water network. AB - Understanding the biological stability of drinking water distribution systems is imperative in the framework of process control and risk management. The objective of this research was to examine the dynamics of the bacterial community during drinking water distribution at high temporal resolution. Water samples (156 in total) were collected over short time-scales (minutes/hours/days) from the outlet of a treatment plant and a location in its corresponding distribution network. The drinking water is treated by biofiltration and disinfectant residuals are absent during distribution. The community was analyzed by 16S rRNA gene pyrosequencing and flow cytometry as well as conventional, culture-based methods. Despite a random dramatic event (detected with pyrosequencing and flow cytometry but not with plate counts), the bacterial community profile at the two locations did not vary significantly over time. A diverse core microbiome was shared between the two locations (58-65% of the taxa and 86-91% of the sequences) and found to be dependent on the treatment strategy. The bacterial community structure changed during distribution, with greater richness detected in the network and phyla such as Acidobacteria and Gemmatimonadetes becoming abundant. The rare taxa displayed the highest dynamicity, causing the major change during water distribution. This change did not have hygienic implications and is contingent on the sensitivity of the applied methods. The concept of biological stability therefore needs to be revised. Biostability is generally desired in drinking water guidelines but may be difficult to achieve in large-scale complex distribution systems that are inherently dynamic. PMID- 25732559 TI - Bis(MU-oxo) versus mono(MU-oxo)dicopper cores in a zeolite for converting methane to methanol: an in situ XAS and DFT investigation. AB - Dicopper species have been identified as the active sites in converting methane to methanol in Cu-zeolites. To understand the formation of these copper cores in mordenite, we used in situ time-resolved X-ray absorption spectroscopy during heat treatment. Significant dehydration enabled the reduction of the copper cores, after which molecular oxygen was cleaved. The activated oxygen bridged two copper atoms to make the reactive precursor for the activation of methane. Even though the active bridging oxygen was detected, the XAS data were unable to distinguish a bis(MU-oxo)dicopper core from a mono(MU-oxo)dicopper core since XAS measures the average structure of the total copper population and the sample contains a mixture of copper species. We therefore used DFT calculations to understand the energetics of the formation of the active copper species and found that if a copper dimer exists in a zeolite, the mono(MU-oxo)dicopper species is an energetically plausible structure. This is in contrast to molecular dicopper cores where the bis(MU-oxo)dicopper core is preferentially formed. PMID- 25732560 TI - 3-Nitroasterric Acid Derivatives from an Antarctic Sponge-Derived Pseudogymnoascus sp. Fungus. AB - Four new nitroasterric acid derivatives, pseudogymnoascins A-C (1-3) and 3 nitroasterric acid (4), along with the two known compounds questin and pyriculamide, were obtained from the cultures of a Pseudogymnoascus sp. fungus isolated from an Antarctic marine sponge belonging to the genus Hymeniacidon. The structures of the new compounds were determined by extensive NMR and MS analyses. These compounds are the first nitro derivatives of the known fungal metabolite asterric acid. Several asterric acid derivatives isolated from other fungal strains have shown antibacterial and antifungal activities. However, the new compounds described in this work were inactive against a panel of bacteria and fungi (MIC > 64 MUg/mL). PMID- 25732561 TI - Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study. AB - INTRODUCTION: The prevalence of liver steatosis is particularly high in subjects with signs of the metabolic syndrome, and current therapeutic guidelines mostly rely on lifestyle changes alone, which rarely achieve significant objective improvements. In the present study, we evaluated the possibility of monitoring objective improvements in these subjects, before and after a dietary regimen. METHODS: Overall, 78 subjects with metabolic syndrome and ultrasound confirmation of liver steatosis were included in an open, controlled study; all of these subjects were treated for 90 days with the standard regimen of diet and exercise. One group of 43 subjects (Group A) also received a Eurosil 85((r))-based nutraceutical (silymarin + vitamin E) as a dietary adjunct, whereas the remaining 35 subjects (Group B) represented the control group. Changes from baseline values were recorded in biometric, biochemical, and ultrasound data. For assessments and monitoring of liver steatosis, two indexes were utilised-Hepatic Steatosis Index (HSI) and Lipid Accumulation Product (LAP) index. RESULTS: The absolute changes from baseline were significantly higher in Group A in biometric parameters (reduction of abdominal circumference, Body Mass Index, ultrasound measurement of right liver lobe) and in both the HSI and LAP indexes. Both treatments were well tolerated. CONCLUSION: The results observed suggest that the use of a Eurosil 85((r))-based nutraceutical as a dietary adjunct with antioxidant properties potentially favours the efficacy of the dietary regimen alone and may possibly improve the subjects' motivation to sustain such lifestyle changes over time. PMID- 25732562 TI - Double origin and early bifurcation of the anterior inferior cerebellar artery diagnosed by CT angiography. AB - Due to the technical improvements, anatomical variations of the small arteries, those were previously reported on cadaveric series, can also be evaluated on CT angiography. Absence of the anterior inferior cerebellar artery (AICA) is the most common variation of the AICA. Duplication and fenestration of the AICA can be rarely seen. In this report, two new variations, early bifurcation and double origin of the AICA, were described on CT angiography. PMID- 25732563 TI - The 'surprise' question may improve the accuracy of GPs in identifying death in patients with advanced stage IV solid-cell cancer. PMID- 25732564 TI - Learning what is in the "secret sauce" of MI that is essential for teaching busy clinicians. PMID- 25732565 TI - Spirometry remains an unfulfilled right for children with asthma. PMID- 25732566 TI - Reply: To PMID 25175496. PMID- 25732567 TI - Test-Retest Reliability and Stability of the Nicotine Metabolite Ratio Among Treatment-Seeking Smokers. AB - INTRODUCTION: The nicotine metabolite ratio (NMR), the ratio of 3-hydroxycotinine to cotinine, is a biomarker used in smoking cessation research, with several retrospective studies suggesting that NMR predicts treatment outcome. To be maximally useful in tailoring treatment, estimates of NMR should be stable over time. The present study is the first to examine the short-term test-retest reliability of NMR among treatment-seeking smokers. METHODS: Blood NMR was assessed at two time points, approximately 2-3 weeks apart and prior to intervention, among 72 healthy adult smokers (49% female; 35% non-White) enrolled in a cessation trial (http://ClinicalTrials.gov ID: NCT01314001). RESULTS: Mean NMR was stable from Time-1 to Time-2, with no significant change between assessments; test-retest reliability for NMR values was excellent (ICC[2,1] = 0.87). Test-retest reliability remained acceptable to high when NMR was categorized, as in recent clinical trials. Classification of participants as slow (quartile 1, NMR <= 0.24) or normal/fast NMR (quartiles 2-4, NMR >= 0.25) was consistent from Time-1 to Time-2 for 96% of participants (kappa = 0.89). Though classification of participants into NMR quartiles was less consistent from Time-1 to Time-2 (67% agreement; weighted kappa = 0.73), all reclassifications occurred between adjacent quartiles. CONCLUSIONS: Overall, these data support the use of a single NMR assessment for association studies with smoking phenotypes and in smokers seeking to quit, and they encourage large-scale efforts to determine optimal NMR cutpoints for tailoring treatment selection. PMID- 25732568 TI - Impact of Medicare's Hospital-Acquired Condition policy on infections in safety net and non-safety net hospitals. AB - BACKGROUND: Policymakers may wish to align healthcare payment and quality of care while minimizing unintended consequences, particularly for safety net hospitals. OBJECTIVE: To determine whether the 2008 Centers for Medicare and Medicaid Services Hospital-Acquired Conditions policy had a differential impact on targeted healthcare-associated infection rates in safety net compared with non safety net hospitals. DESIGN: Interrupted time-series design. SETTING AND PARTICIPANTS: Nonfederal acute care hospitals that reported central line associated bloodstream infection and ventilator-associated pneumonia rates to the Centers for Disease Control and Prevention's National Health Safety Network from July 1, 2007, through December 31, 2013. RESULTS: We did not observe changes in the slope of targeted infection rates in the postpolicy period compared with the prepolicy period for either safety net (postpolicy vs prepolicy ratio, 0.96 [95% CI, 0.84-1.09]) or non-safety net (0.99 [0.90-1.10]) hospitals. Controlling for prepolicy secular trends, we did not detect differences in an immediate change at the time of the policy between safety net and non-safety net hospitals (P for 2 way interaction, .87). CONCLUSIONS: The Centers for Medicare and Medicaid Services Hospital-Acquired Conditions policy did not have an impact, either positive or negative, on already declining rates of central line-associated bloodstream infection in safety net or non-safety net hospitals. Continued evaluations of the broad impact of payment policies on safety net hospitals will remain important as the use of financial incentives and penalties continues to expand in the United States. PMID- 25732569 TI - Stem cells and differentiation--a synoptic review of patents granted since 2009. AB - INTRODUCTION: Innovations in human pluripotent stem cell research and their application in therapeutics have seen a giant leap in the past decade. Patent applications related to human pluripotent stem cell generation, culture and differentiation show an ever-increasing trend worldwide with hundreds of patents being applied for every year. With the turn of the second decade in stem cell patenting, a review of the latest patents issued will be significant. AREAS COVERED: The growing need in healthcare sector has revolutionized stem cell application in clinical therapeutics by extending in unprecedented dimensions. With the potential of being able to differentiate into any desired adult cell lineage, human pluripotent stem cells find a wide range of applicability in clinical as well as cosmetic therapy. Moreover, the recent innovation of isolating a disease-specific pluripotent stem cell has opened new horizons to stem cell application in cell therapy. This review gives an overview of significant international patents granted on innovations in human pluripotent stem cell differentiation methodologies between 2009 and 2014. EXPERT OPINION: The discovery of human pluripotent stem cells and their immense potential in clinical therapeutics has increasingly channeled scientific research in their orientation. Although being widely used to fathom human physiology, the trend in stem cell application is slowly shifting toward disease-modeling, drug safety evaluation and toxicity-testing. And in order to probe those unexplored realms of stem cell applications, a unified approach from the scientific community is imperative. PMID- 25732570 TI - Potential public sector cost-savings from over-the-counter access to oral contraceptives. AB - OBJECTIVE: This study estimates how making oral contraceptive pills (OCPs) available without a prescription may affect contraceptive use, unintended pregnancies and associated contraceptive and pregnancy costs among low-income women. STUDY DESIGN: Based on published figures, we estimate two scenarios [low over-the-counter (OTC) use and high OTC use] of the proportion of low-income women likely to switch to an OTC pill and predict adoption of OCPs according to the out-of-pocket costs per pill pack. We then estimate cost-savings of each scenario by comparing the total public sector cost of providing OCPs OTC and medical care for unintended pregnancy. RESULTS: Twenty-one percent of low-income women at risk for unintended pregnancy are very likely to use OCPs if they were available without a prescription. Women's use of OTC OCPs varies widely by the out-of-pocket pill pack cost. In a scenario assuming no out-of-pocket costs for the over-the counter pill, an additional 11-21% of low-income women will use the pill, resulting in a 20-36% decrease in the number of women using no method or a method less effective than the pill, and a 7-25% decrease in the number of unintended pregnancies, depending on the level of use and any effect on contraceptive failure rates. CONCLUSIONS: If out-of-pocket costs for such pills are low, OTC access could have a significant effect on use of effective contraceptives and unintended pregnancy. Public health plans may reduce expenditures on pregnancy and contraceptive healthcare services by covering oral contraceptives as an OTC product. IMPLICATIONS: Interest in OTC access to oral contraceptives is high. Removing the prescription barrier, particularly if pill packs are available at low or zero out-of-pocket cost, could increase the use of effective methods of contraception and reduce unintended pregnancy and healthcare costs for contraceptive and pregnancy care. PMID- 25732571 TI - Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice. AB - AIM: Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo. METHODS: The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg.kg(-1).d(-1) for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis. RESULTS: Yhhu981 (12.5-25 MUmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1alpha and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice. CONCLUSION: Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK. PMID- 25732572 TI - Association of positively selected eIF3a polymorphisms with toxicity of platinum based chemotherapy in NSCLC patients. AB - AIM: Eukaryotic translation initiation factor 3 subunit A (eIF3a) plays critical roles in regulating the initiation of protein translation, and eIF3a is highly expressed in lung cancer. In this study, we investigated the association of the positively selected SNPs of eIF3a with the response to and toxicity of platinum based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). METHODS: SNP data for eIF3a locus were downloaded from HapMap database. For each SNP, haplotype, LD profile and population differentiation were analyzed. The long range haplotype (LRH) test was employed to identify positively selected SNPs of eIF3a. A total of 325 NSCLC patients were enrolled and genotyped for these SNPs. RESULTS: Five positively selected (rs1409314, rs4752219, rs4752220, rs7091672 and rs10510050) and 5 non-positively selected SNPs (rs10886342, rs11198804, rs2275112, rs10787899 and rs4752269) were identified in the LRH test. However, none of them was correlated with the platinum-based chemotherapy response. In contrast, 4 of the positively selected SNPs (rs1409314, rs4752219, rs4752220 and rs7091672) were significantly correlated with the toxicities tested (neutropenia, anemia, thrombocytopenia, emesis and hepatotoxicity). In addition, rs10510050 was significantly correlated with thrombocytopenia, emesis and hepatotoxicity. None of the 5 non-positively selected SNPs was correlated with the 5 toxicities. CONCLUSION: The positively selected SNPs of eIF3a are significantly correlated with platinum-based chemotherapy toxicities in Chinese NSCLC patients. PMID- 25732573 TI - An unusual infection outbreak in rats held in a human hospital research laboratory. AB - Most animal hazards in laboratories are widely recognized. These, together with zoonoses and other possible insults, are subject to the establishment of guidelines for the operation and maintenance of such facilities. Most of the infectious diseases described among laboratory animals are related to the inadequate implementation of preventive and quality control policies. These included surgical, respiratory and intestinal tract infections, and typically spread between animals. This report is about an outbreak of nosocomial bacterial infection in rats held in the research laboratory of a human hospital. Symptoms of general infection were runny nose and sneezing, excessive lachrymation, dyspnea, loss of appetite, limited activity and disheveled fur, which appeared in two rats initially, and spread to another 60. A common characteristic physical finding observed later was a lump under the skin, with subsequent ulceration. Mortality was 70%. Blood cultures were sterile. Accurate diagnosis was possible only after examination of tissue sampled from the diseased and dead rats. Histology showed an excessive proliferative and inflammatory reaction. Bacteriology analysis revealed the presence of three types of hospital-borne bacteria: enterococcus, coagulase-negative staphylococci and Acinetobacter radioresistens, with common sensitivity to ciprofloxacin and ceftazidime. Empiric antibiotic therapy was switched to a bacteriology-based regimen. Complete recovery was achieved among the diseased rats that survived the previous antibiotic therapy. This is the first written description of a nosocomial infection of laboratory animals caused by bacteria borne in a human hospital. Medical staff-to-animal transmission is suggested. A high index of suspicion and prompt diagnostic evaluation are essential for successful management, and preventive guidelines concerning such events need to be established. PMID- 25732574 TI - Gender differences in a mouse model of chemotherapy-induced neuropathic pain. AB - Chemotherapy-induced neuropathic pain is one of the major problems for cancer patients. Although paclitaxel and cisplatin are widely used in women, most laboratory studies of chemotherapy-induced neuropathic pain have been conducted on male animals. The current study examined the gender differences in chemotherapy-induced neuropathic pain in mice. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (2 mg/kg) for five consecutive days and cisplatin (1 mg/kg) for seven consecutive days. Cold allodynia was evaluated by measuring the paw withdrawal frequency and duration of paw licking in mice; however, mechanical allodynia was assessed by von Frey filaments. Neuropathic pain began to manifest after a few days (P < 0.001). Cold allodynia was more robust in female mice (P < 0.001) treated with paclitaxel, while no differences were observed between the two genders in the manifestation of paclitaxel-induced mechanical allodynia. Interestingly, no gender differences were observed in cisplatin-induced cold and mechanical allodynia tests. In conclusion, gender differences play a major role in neuropathic pain induced by paclitaxel. The differences between male and female animals should be considered in future studies and the findings should be generalized to humans with caution. PMID- 25732575 TI - Percutaneously inserted long-term central venous catheters in pigs of different sizes. AB - Pigs are used for long-term biomedical experiments requiring repeated injections, infusions and collections of blood samples. Thus, it is necessary for vascular catheters to be indwelling to avoid undue stress to the animals and the use of restraints. We propose a refined model of percutaneous insertion of long-term central venous catheters to minimize the surgical trauma and postoperative complications associated with catheter insertion. Different sizes of needles (18 Ga versus 21 Ga) for initial puncture of the veins were compared. In conventional pigs weighing less than 30 kg, catheter insertion may be facilitated by using a microintroducer set with a 21 Ga needle. In pigs weighing 50 kg, a standard 18 Ga needle may be preferable. PMID- 25732576 TI - A portable system for studying discrete-trial group choice. AB - Whether groups of people or animals behave optimally in relation to resources is an issue of interest to psychology, ecology, and economics. In behavioral ecology, the simplest model of optimal group choice is the ideal free distribution (IFD). The IFD model has been tested in humans with discrete or continuous inputs and through manual or automated procedures (e.g., Kraft, Baum, & Burge, 2002; Madden, Peden, & Yamagushi, 2002). Manual procedures tend to be time consuming, however, whereas automated procedures typically require access to a computer network. In this article, we describe a new automated system for discrete-trial tests of the IFD model. Our protocol involves a single computer connected to a digital projector (for stimulus presentation) and a network of gamepads (for registering choices). The system is comparatively inexpensive, easy to install, easy to transport, and it permits the automated collection of group data in minimal time. We show that the data generated through this protocol are comparable to those previously reported in the IFD literature. PMID- 25732577 TI - Proteomic analysis reveals the mechanisms of Mycena dendrobii promoting transplantation survival and growth of tissue culture seedlings of Dendrobium officinale. AB - AIMS: Dendrobium officinale is an important traditional Chinese medicinal herb. Its seedlings generally show low survival and growth when transferred from in vitro tissue culture to a greenhouse or field environment. In this study, the effect of Mycena dendrobii on the survival and growth of D. officinale tissue culture seedlings and the mechanisms involved was explored. METHODS AND RESULTS: Mycena dendrobii were applied underneath the roots of D. officinale tissue culture seedlings. The seedling survival and growth were analysed. The root proteins induced by M. dendrobii were identified using two-dimensional (2-D) electrophoresis and matrix-assisted laser desorption/ionization time-of-flight MS (MALDI-TOF-MS). Mycena dendrobii treatment significantly enhanced survival and growth of D. officinale seedlings. Forty-one proteins induced by M. dendrobii were identified. Among them, 10 were involved in defence and stress response, two were involved in the formation of root or mycorrhizae, and three were related to the biosynthesis of bioactive constituents. CONCLUSIONS: These results suggest that enhancing stress tolerance and promoting new root formation induced by M. dendrobii may improve the survival and growth of D. officinale tissue culture seedlings. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides a foundation for future use of M. dendrobii in the large-scale cultivation of Dendrobiums. PMID- 25732578 TI - Photodiode array to charged aerosol detector response ratio enables comprehensive quantitative monitoring of basic drugs in blood by ultra-high performance liquid chromatography. AB - Quantitative screening for a broad range of drugs in blood is regularly required to assess drug abuse and poisoning within analytical toxicology. Mass spectrometry-based procedures suffer from the large amount of work required to maintain quantitative calibration in extensive multi-compound methods. In this study, a quantitative drug screening method for blood samples was developed based on ultra-high performance liquid chromatography with two consecutive detectors: a photodiode array detector and a corona charged aerosol detector (UHPLC-DAD-CAD). The 2.1 mm * 150 mm UHPLC column contained a high-strength silica C18 bonded phase material with a particle size of 1.8 MUm, and the mobile phase consisted of methanol/0.1% trifluoroacetic acid in gradient mode. Identification was based on retention time, UV spectrum and the response ratio from the two detectors. Using historic calibration over a one-month period, the median precision (RSD) of retention times was 0.04% and the median accuracy (bias) of quantification 6.75%. The median precision of the detector response ratio over two orders of magnitude was 12%. The applicable linear ranges were generally 0.05-5 mg L(-1). The method was validated for 161 compounds, including antipsychotics, antidepressants, antihistamines, opioid analgesics, and adrenergic beta blocking drugs, among others. The main novelty of the method was the proven utility of the response ratio of DAD to CAD, which provided the additional identification efficiency required. Unlike with mass spectrometry, the high stability of identification and quantification allowed the use of facile historic calibration. PMID- 25732579 TI - Polyhydroxyalkanoate granules quantification in mixed microbial cultures using image analysis: Sudan Black B versus Nile Blue A staining. AB - Polyhydroxyalkanoates (PHA) can be produced and intracellularly accumulated as inclusions by mixed microbial cultures (MMC) for bioplastic production and in enhanced biological phosphorus removal (EBPR) systems. Classical methods for PHA quantification use a digestion step prior to chromatography analysis, rendering them labor intensive and time-consuming. The present work investigates the use of two quantitative image analysis (QIA) procedures specifically developed for PHA inclusions identification and quantification. MMC obtained from an EBPR system were visualized by bright-field and fluorescence microscopy for PHA inclusions detection, upon Sudan Black B (SBB) and Nile Blue A (NBA) staining, respectively. The captured color images were processed by QIA techniques and the image analysis data were further treated using multivariate statistical analysis. Partial least squares (PLS) regression coefficients of 0.90 and 0.86 were obtained between QIA parameters and PHA concentrations using SBB and NBA, respectively. It was found that both staining procedures might be seen as alternative methodologies to classical PHA determination. PMID- 25732580 TI - Molecularly imprinted coated graphene oxide solid-phase extraction monolithic capillary column for selective extraction and sensitive determination of phloxine B in coffee bean. AB - A method was developed to sensitively determine phloxine B in coffee bean by molecularly imprinted polymers (MIPs) coated graphene oxide (GO) solid-phase extraction (GO-MISPE) coupled with high-performance liquid chromatography and laser-induced fluorescence detection (HPLC-LIF). The GO-MISPE capillary monolithic column was prepared by water-bath in situ polymerization, using GO as supporting material, phloxine B, methacrylic acid (MAA), and ethylene dimethacrylate (EDMA) as template, functional monomer, and cross-linker, respectively. The properties of the homemade GO-MISPE capillary monolithic column, including capacity and specificity, were investigated under optimized conditions. The GO-MIPs were characterized by scanning electron microscopy (SEM) and Fourier transform-infrared spectroscopy (FT-IR). The mean recoveries of phloxine B in coffee bean ranged from 89.5% to 91.4% and the intra-day and inter day relative standard deviation (RSD) values all ranged from 3.6% to 4.7%. Good linearity was obtained over 0.001-2.0 MUg mL(-1) (r=0.9995) with the detection limit (S/N=3) of 0.075 ng mL(-1). Under the selected conditions, enrichment factors of over 90-fold were obtained and extraction on the monolithic column effectively cleaned up the coffee bean matrix. The results demonstrated that the proposed GO-MISPE HPLC-LIF method can be applied to sensitively determine phloxine B in coffee bean. PMID- 25732581 TI - Fabric phase sorptive extraction: a new sorptive microextraction technique for the determination of non-steroidal anti-inflammatory drugs from environmental water samples. AB - Fabric phase sorptive extraction (FPSE) is a new, yet very promising member of the sorbent-based sorptive microextraction family. It has simultaneously improved both the extraction sensitivity and the speed of the extraction by incorporating high volume of sol-gel hybrid inorganic-organic sorbents into permeable fabric substrates. The advantages of FPSE have been investigated for the determination of four non-steroidal anti-inflammatory drugs, ibuprofen, naproxen, ketoprofen and diclofenac, in environmental water samples in combination with gas chromatography-mass spectrometry. Initially, the significance of several parameters affecting FPSE: sorbent chemistry, matrix pH and ionic strength were investigated using a mixed level factorial design (3(1)*2(2)). Then, other important parameters e.g., sample volume, extraction kinetics, desorption time and volume were also carefully studied and optimized. Due to the high sorbent loading on the FPSE substrate in the form of ultra-thin coating and the open geometry of the microextraction device, higher mass transfer of the target analytes occurs at a faster rate, leading to high enrichment factors in a relatively short period of time (equilibrium times: 45-100 min). Under optimal operational conditions, the limits of detection (S/N=3) were found to be in the range of 0.8 ng L(-1) to 5 ng L(-1). The enrichment factors ranged from 162 to 418 with absolute extraction efficiencies varied from 27 to 70%, and a good trueness (82-116% relative recoveries) indicating that the proposed method can be readily deployed to routine environmental pollution monitoring. The proposed method was successfully applied to the analysis of target analytes in two influent and effluent samples from a wastewater treatment plant and two river water samples in Spain. PMID- 25732582 TI - A new strategy to determine the protein mutation site using matrix-assisted laser desorption ionization in-source decay: derivatization by ionic liquid. AB - Matrix-assisted laser desorption ionization (MALDI) time-of-flight mass spectrometry (TOF-MS) can be considered as state of the art in the field of proteins and peptides analysis. In this work, we have designed an ionic liquid derivative strategy to obtain abundant fragment ions in MALDI in-source decay (ISD) and used the analysis of angiogenin with mutation in the fortieth (K40I) as an instance. Firstly, we have synthesized two types of ionic liquids, 3-allyl-4 methyl-1H-imidazol-3-ium and 4-methyl-3-(pent-4-yn-1-yl)-1H-imidazol-3-ium. Then in the light-catalyzed reaction, the alkenyl ionic liquid can open the disulfide bond of K40I protein and add to the thiol. And the derived protein can process in source decay under the effect of ionic liquid group to produce c-z type ions. Additionally this fragmentation is potentiated to support widely range of fragment ions which can cover the location of mutation. Our results have supplied a new top-down method about how to analyze the mutation or even post translational modification of proteins in MALDI mass spectrometry. PMID- 25732583 TI - Ion mobility spectrometric analysis of vaporous chemical warfare agents by the instrument with corona discharge ionization ammonia dopant ambient temperature operation. AB - The ion mobility behavior of nineteen chemical warfare agents (7 nerve gases, 5 blister agents, 2 lachrymators, 2 blood agents, 3 choking agents) and related compounds including simulants (8 agents) and organic solvents (39) was comparably investigated by the ion mobility spectrometry instrument utilizing weak electric field linear drift tube with corona discharge ionization, ammonia doping, purified inner air drift flow circulation operated at ambient temperature and pressure. Three alkyl methylphosphonofluoridates, tabun, and four organophosphorus simulants gave the intense characteristic positive monomer derived ion peaks and small dimer-derived ion peaks, and the later ion peaks were increased with the vapor concentrations. VX, RVX and tabun gave both characteristic positive monomer-derived ions and degradation product ions. Nitrogen mustards gave the intense characteristic positive ion peaks, and in addition distinctive negative ion peak appeared from HN3. Mustard gas, lewisite 1, o-chlorobenzylidenemalononitrile and 2-mercaptoethanol gave the characteristic negative ion peaks. Methylphosphonyl difluoride, 2-chloroacetophenone and 1,4 thioxane gave the characteristic ion peaks both in the positive and negative ion mode. 2-Chloroethylethylsulfide and allylisothiocyanate gave weak ion peaks. The marker ion peaks derived from two blood agents and three choking agents were very close to the reactant ion peak in negative ion mode and the respective reduced ion mobility was fluctuated. The reduced ion mobility of the CWA monomer-derived peaks were positively correlated with molecular masses among structurally similar agents such as G-type nerve gases and organophosphorus simulants; V-type nerve gases and nitrogen mustards. The slope values of the calibration plots of the peak heights of the characteristic marker ions versus the vapor concentrations are related to the detection sensitivity, and within chemical warfare agents examined the slope values for sarin, soman, tabun and nitrogen mustards were higher. Some CWA simulants and organic solvents gave the ion peaks eluting at the similar positions of the CWAs, resulting in false positive alarms. PMID- 25732584 TI - In situ fabrication of cleavable peptide arrays on polydimethylsiloxane and applications for kinase activity assays. AB - Polydimethylsiloxane (PDMS) is widely used for microfabrication and bioanalysis; however, its surface functionalization is limited due to the lack of active functional groups and incompatibility with many solvents. We presented a novel approach for in situ fabrication of cleavable peptide arrays on polydimethylsiloxane (PDMS) viatert-butyloxycarbonyl (t-Boc)/trifluoroacetic acid (TFA) chemistry using gold nanoparticles (AuNPs) as the anchor and a disulfide/amine terminated hetero-polyethylene glycol as the cleavable linker. The method was fine tuned to use reagents compatible with the PDMS. Using 5-mer pentapeptide, Trp5, as a model, step-by-step covalent coupling during the reaction cycles was monitored by Attenuated total reflectance-Fourier transform infrared spectrometer (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), or atomic force microscopy (AFM), and further confirmed by mass spectrometry (MS) detection of the cleaved peptides. Using such a method, heptapeptides of the PKA substrate, LRRASLG (Kemptide), and its point mutated analogs were fabricated in an array format for comparative studies of cAMP-dependent protein kinase (PKA) activity. Based on on-chip detection, Kemptide sequence exhibited the highest phosphorylation activity, which was detected to a 1.5-time lesser extent for the point mutated sequence (LRRGSLG) containing the recognition motif (RRXS), and was nearly undetectable for another point mutated sequence (LRLASLG) that lacked the recognition motif. These results indicate that the reported fabrication method is able to yield highly specific peptide sequences on PDMS, leading to a highly motif-sensitive enzyme activity assay. PMID- 25732585 TI - A colourimetric sensor for the simultaneous determination of oxidative status and antioxidant activity on the same membrane: N,N-dimethyl-p-phenylene diamine (DMPD) on Nafion. AB - A colourimetric sensor capable of simultaneously measuring oxidative status (OS) in terms of the hazard produced by reactive oxygen species (ROS) and antioxidant activity (AOA) in regard to ROS-scavenging ability of antioxidant compounds was developed. The coloured cationic semi-quinone derivatives, caused by ROS oxidative degradation of N,N-dimethyl-p-phenylene diamine hydrochloride (DMPD) in pH 5.7 acetate-buffered medium, were formed in solution and immobilized on a perfluorosulfonate-based Nafion membrane. ROS, namely hydroxyl (.OH) and superoxide (O2(.-)) radicals, were produced by Fenton/UV and xanthine/xanthine oxidase methods, respectively. The pink-coloured, (+)-charged chromophore (referred to as DMPD-quinone or DMPDQ), resulting from the reaction between DMPD and ROS, could be completely retained on the solid membrane sensor by electrostatic interaction with the anionic sulfonate groups of Nafion. After equilibration, the Nafion membrane surface was homogeneously coloured enabling an absorbance measurement at 514 nm, while the aqueous phase completely lacked colour. Antioxidants, when present, caused an absorbance decrease on the membrane due to their ROS scavenging action, giving rise to less DMPDQ production. The absorbance decrease on the sensor was linearly dependent on antioxidant concentration over a reasonable concentration range, enabling the simultaneous determination of OS and AOA-against ROS. The proposed antioxidant sensing method was tested in synthetic and real antioxidant mixtures, and validated against standard antioxidant capacity assays (i.e. ABTS and CUPRAC) for a variety of polyphenolic and antioxidant compounds. The dynamic linear ranges of antioxidants with the DMPD sensor in protection against hydroxyl and superoxide radicals generally varied within the micromolar to a few tens of micromolar concentration interval over one order-of-magnitude. Choosing three representative compounds in the high (epigallocatechin gallate), medium (quercetin) and low (p-coumaric acid) molar absorptivity range, the detection limits ranged within the concentration intervals of 0.2-0.9 MUM, 0.3-0.8 MUM, and 4-14 MUM, respectively, depending on the radical scavenged. PMID- 25732586 TI - A rapid and simple approach for glycoform analysis. AB - Fast glycoform analysis is important for quality control of glycoproteins that account for over 40% of the approved biopharmaceuticals. Herein, we realized an Au nanoparticle-based lectin affinity chromatography (LAC) using simple standard laboratory equipment for fast glycoform analysis. Pisum sativum agglutinin (PA), a lectin derived from P. sativum, was covalently conjugated to Au nanoparticles via naturally formed carboxylic groups onto the surface of Au nanoparticles and amino groups of PA. Each model glycoprotein was separated into several fractions including the unbound, weakly bound, modestly bound, and strongly bound glycoforms based on affinity strength of the glycoform toward PA. A single run of Au nanoparticle-based LAC was finished within 18 min, which could be further decreased by centrifuging the mixture of the PA functionalized Au nanoparticles and the glycoproteins at a higher speed. To our knowledge, we are the first to use Au nanoparticles as LAC matrix. PMID- 25732587 TI - Utilization of magnetic nanobeads for analyzing haptoglobin in human plasma as a marker of Alzheimer's disease by capillary electrophoretic immunoassay with laser induced fluorescence detection. AB - Alzheimer's disease (AD) is a neurodegenerative disorder resulting from an impaired cholinergic function with loss of cognitive activity in the brain. Haptoglobin is a useful biomarker for AD analysis. Compared to the conventional enzyme-linked immunosorbent assay for haptoglobin analysis, the proposed immunoassay procedure reduces sample analysis time by approximately 55 min. Therefore, immunoassay was coupled with capillary electrophoresis (CE) to determine haptoglobin concentrations indirectly by using magnetic nanobeads (MBs) as a support and laser-induced fluorescence detection. In human plasma sample, the haptoglobin was immobilized on the MBs and reacted with the purified anti haptoglobin antibody. The optimum separation time for the analyte was shorter than 6 min at 25 degrees C with a fused-silica capillary column of 40.2 cm * 50 MUm ID (effective length 30 cm) and a run buffer containing 25 mM phosphate (pH 8.0) with 0.01% poly(ethylene oxide) (PEO). When using Atto 495 NHS ester as an internal standard (IS) (250.0 ng mL(-1)), the linear range of the proposed method for indirect determination of haptoglobin was 0.2-3.0 mg mL(-1). The method was further used to monitor the course of AD in patients with behavioral and psychological symptoms of dementia (BPSD). PMID- 25732588 TI - Organic solvent and temperature-enhanced ion chromatography-high resolution mass spectrometry for the determination of low molecular weight organic and inorganic anions. AB - There has recently been increased interest in coupling ion chromatography (IC) to high resolution mass spectrometry (HRMS) to enable highly sensitive and selective analysis. Herein, the first comprehensive study focusing on the direct coupling of suppressed IC to HRMS without the need for post-suppressor organic solvent modification is presented. Chromatographic selectivity and added HRMS sensitivity offered by organic solvent-modified IC eluents on a modern hyper-crosslinked polymeric anion-exchange resin (IonPac AS18) are shown using isocratic eluents containing 5-50 mM hydroxide with 0-80% methanol or acetonitrile for a range of low molecular weight anions (<165 Da). Comprehensive experiments on IC thermodynamics over a temperature range between 20-45 degrees C with the eluent containing up to 60% of acetonitrile or methanol revealed markedly different retention behaviour and selectivity for the selected analytes on the same polymer based ion-exchange resin. Optimised sensitivity with HRMS was achieved with as low as 30-40% organic eluent content. Analytical performance characteristics are presented and compared with other IC-MS based works. This study also presents the first application of IC-HRMS to forensic detection of trace low-order anionic explosive residues in latent human fingermarks. PMID- 25732589 TI - Arabidopsis NIP3;1 Plays an Important Role in Arsenic Uptake and Root-to-Shoot Translocation under Arsenite Stress Conditions. AB - In Arabidopsis, the nodulin 26-like intrinsic protein (NIP) subfamily of aquaporin proteins consists of nine members, five of which (NIP1;1, NIP1;2, NIP5;1, NIP6;1, and NIP7;1) were previously identified to be permeable to arsenite. However, the roles of NIPs in the root-to-shoot translocation of arsenite in plants remain poorly understood. In this study, using reverse genetic strategies, Arabidopsis NIP3;1 was identified to play an important role in both the arsenic uptake and root-to-shoot distribution under arsenite stress conditions. The nip3;1 loss-of-function mutants displayed obvious improvements in arsenite tolerance for aboveground growth and accumulated less arsenic in shoots than those of the wild-type plants, whereas the nip3;1 nip1;1 double mutant showed strong arsenite tolerance and improved growth of both roots and shoots under arsenite stress conditions. A promoter-beta-glucuronidase analysis revealed that NIP3;1 was expressed almost exclusively in roots (with the exception of the root tips), and heterologous expression in the yeast Saccharomyces cerevisiae demonstrated that NIP3;1 was able to mediate arsenite transport. Taken together, our results suggest that NIP3;1 is involved in arsenite uptake and root-to-shoot translocation in Arabidopsis, probably as a passive and bidirectional arsenite transporter. PMID- 25732590 TI - Ethylene signaling in rice and Arabidopsis: conserved and diverged aspects. AB - Ethylene as a gas phytohormone plays significant roles in the whole life cycle of plants, ranging from growth and development to stress responses. A linear ethylene signaling pathway has been established in the dicotyledonous model plant Arabidopsis. However, the ethylene signaling mechanism in monocotyledonous plants such as rice is largely unclear. In this review, we compare the ethylene response phenotypes of dark-grown seedlings of Arabidopsis, rice, and other monocotyledonous plants (maize, wheat, sorghum, and Brachypodium distachyon) and pinpoint that rice has a distinct phenotype of root inhibition but coleoptile promotion in etiolated seedlings upon ethylene treatment. We further summarize the homologous genes of Arabidopsis ethylene signaling components in these monocotyledonous plants and discuss recent progress. Although conserved in most aspects, ethylene signaling in rice has evolved new features compared with that in Arabidopsis. These analyses provide novel insights into the understanding of ethylene signaling in the dicotyledonous Arabidopsis and monocotyledonous plants, particularly rice. Further characterization of rice ethylene-responsive mutants and their corresponding genes will help us better understand the whole picture of ethylene signaling mechanisms in plants. PMID- 25732592 TI - Ultrathin high efficiency photodetectors based on subwavelength grating and near field enhanced absorption. AB - Optical absorbers, comprising a thin semiconductor layer placed between two transparent ones in close proximity to a subwavelength grating, are considered. With no back mirror, these structures only mimic the resonant cavity enhanced photodetector, being an order of magnitude thinner. It is argued that the grating can assist the light confinement by near field microcavity resonance rather than by far field mirroring. Tolerant designs to attain nearly 100% optical absorption at a predefined wavelength are demonstrated, and the near-field enhancement of the absorption is confirmed. The results obtained indicate that the proposed near field enhanced photodetectors meet the combined challenges of significantly increasing the efficiency and reducing the complexity and size of the entire device as compared to the resonant cavity enhanced photodetectors, which may be useful for integrated multi-detector arrays. PMID- 25732591 TI - Comparative analyses of lysophosphatidic acid receptor-mediated signaling. AB - Lysophosphatidic acid (LPA) is a bioactive lipid mediator that activates G protein-coupled LPA receptors to exert fundamental cellular functions. Six LPA receptor genes have been identified in vertebrates and are classified into two subfamilies, the endothelial differentiation genes (edg) and the non-edg family. Studies using genetically engineered mice, frogs, and zebrafish have demonstrated that LPA receptor-mediated signaling has biological, developmental, and pathophysiological functions. Computational analyses have also identified several amino acids (aa) critical for LPA recognition by human LPA receptors. This review focuses on the evolutionary aspects of LPA receptor-mediated signaling by comparing the aa sequences of vertebrate LPA receptors and LPA-producing enzymes; it also summarizes the LPA receptor-dependent effects commonly observed in mouse, frog, and fish. PMID- 25732593 TI - Cell-free DNA screening for fetal aneuploidy as a clinical service. AB - Non-invasive prenatal testing (NIPT) through the analysis of cell free (cf)DNA is revolutionizing prenatal screening for fetal aneuploidy. Current methods used in clinical practice include shotgun massively parallel sequencing (s-MPS); targeted (t-MPS); and an approach that takes advantage of single nucleotide polymorphism (SNP) differences between mother and fetus. Efficacy of cfDNA testing for the common autosomal trisomies far exceeds that of conventional screening. Depending on the methodology used, reasons for discordancy between cfDNA results and fetal karyotype can include true fetal mosaicism, confined placental mosaicism, presence of a maternal karyotype abnormality, insufficient counting due to low fetal fraction, and a vanishing twin. Among the possible cfDNA strategies a Primary test has the highest performance but is expensive, while a Contingent cfDNA test can achieve high performance at a relatively low cost. Practicalities to be considered in the provision of testing include pretest counseling about the scope and accuracy of the testing, the interpretation of results when there is a low fetal fraction and follow-up studies for positive test results. The role of first trimester nuchal translucency measurement and conventional biochemical testing needs to be reassessed in the context of the use of cfDNA. PMID- 25732595 TI - Effects of ultrasonic disintegration of excess sludge obtained in disintegrators of different constructions. AB - The ultrasonic disintegration of excess sludge is placed after the mechanical thickening but before the digestion tanks in order to intensify the process of sludge stabilization. The effects obtained directly after ultrasonic disintegration depend on many factors and can be grouped in two main categories: factors affecting the quality of sludge and those associated with the construction of disintegrators and its parameters. The ultrasonic disintegration research was carried out using three types of structural solutions of disintegrators. Two of them, that is, WK-2000 ultrasonic generator (P = 400 W) working with a thin sonotrode and WK-2010 ultrasonic generator (P = 100-1000 W) working with a new type construction emitter lens sonotrode, were compared with the influence of a washer with a flat emitter. The investigations have shown that in the same sludge, using the same value of volumetric energy, the resulting effect depends on the construction of the ultrasonic disintegrator, that is, design of the head and the ratio between the field of the emitter and the field of the chamber in sonicated medium. PMID- 25732596 TI - Magnetophoresis 'meets' viscoelasticity: deterministic separation of magnetic particles in a modular microfluidic device. AB - The deflection of magnetic beads in a microfluidic channel through magnetophoresis can be improved if the particles are somehow focused along the same streamline in the device. We design and fabricate a microfluidic device made of two modules, each one performing a unit operation. A suspension of magnetic beads in a viscoelastic medium is fed to the first module, which is a straight rectangular-shaped channel. Here, the magnetic particles are focused by exploiting fluid viscoelasticity. Such a channel is one inlet of the second module, which is a H-shaped channel, where a buffer stream is injected in the second inlet. A permanent magnet is used to displace the magnetic beads from the original to the buffer stream. Experiments with a Newtonian suspending fluid, where no focusing occurs, are carried out for comparison. When viscoelastic focusing and magnetophoresis are combined, magnetic particles can be deterministically separated from the original streamflow to the buffer, thus leading to a high deflection efficiency (up to ~96%) in a wide range of flow rates. The effect of the focusing length on the deflection of particles is also investigated. Finally, the proposed modular device is tested to separate magnetic and non-magnetic beads. PMID- 25732594 TI - Knee Instability and Basic and Advanced Function Decline in Knee Osteoarthritis. AB - OBJECTIVE: Manifestations of instability in knee osteoarthritis (OA) include low overall knee confidence, low confidence that the knees will not buckle, buckling, and excessive motion during gait. Confidence and buckling may particularly influence activity choices, contributing to events leading to disability. Buckling is more likely to affect advanced than basic functional tasks. In this prospective longitudinal study, we tested the hypothesis that overall knee confidence, buckling confidence, buckling, and frontal plane motion during gait are associated with advanced 2-year function outcomes in persons with knee OA. METHODS: Persons with knee OA were queried about overall knee confidence (higher score = worse confidence), buckling confidence, and knee buckling, and underwent quantitative gait analysis to quantify varus-valgus excursion and angular velocity. Physical function was assessed using the Late-Life Function and Disability Instrument Basic and Advanced Lower Extremity Domain scores. Logistic regression was used to evaluate the relationship between baseline instability measures and baseline-to-2-year function outcome, adjusting for potential confounders. RESULTS: The sample was comprised of 212 persons (mean age 64.6 years, 76.9% women). Buckling was significantly associated with poor advanced function outcome (adjusted odds ratio [OR] 2.08, 95% confidence interval [95% CI] 1.03-4.20) but not basic function outcome. Overall knee confidence was significantly associated with advanced outcome (adjusted OR 1.65, 95% CI 1.01 2.70), while associations between buckling confidence and both outcomes approached significance. Neither varus-valgus excursion nor angular velocity during gait was associated with either outcome. CONCLUSION: Knee buckling and low knee confidence were each associated with poor 2-year advanced function outcomes. Current treatment does not address these modifiable factors; interventions to address them may improve outcome in knee OA. PMID- 25732597 TI - Deletion of Nrf2 Exacerbates Oxidative Stress After Traumatic Brain Injury in Mice. AB - Traumatic brain injury (TBI) is a worldwide public health and medical problem. Oxidative stress is recognized as an important contributing factor in the pathogenesis of TBI. The present study was designed to explore the anti-oxidative effect of Nuclear factor erythroid 2-related factor 2 (Nrf2) on brain damage induced by traumatic injury in a mouse model. Moderate weight-drop impact head injury was induced in adult male mice. The mice were randomly divided into four groups: Nrf2(+/+) sham-operation, Nrf2(-/-) sham-operation, Nrf2(+/+) TBI, and Nrf2(-/-) TBI group. Neurological scores were evaluated 24 h after TBI, followed by collection of the brain specimens. Brain edema was detected by the wet-dry ratio method. The expression of NOX2 protein in the brain specimen was investigated using Western Blot analysis and immunohistochemical staining. In addition, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were evaluated in the brain tissues. Twenty-four hours after TBI, our results showed Nrf2(+/+) TBI mice have more severe neurological deficits and brain edema than Nrf2(+/+) sham group. On the other hand, the Nrf2(-/-) TBI mice were found to have significantly increased neurological deficits and brain edema, compared to Nrf2(+/+) TBI mice (P < 0.05). At the same time, we found that the expression of NOX2 protein, MDA level were significantly increased in Nrf2(-/-) mice, while SOD activity was considerably decreased after TBI compared to Nrf2(+/+) mice (P < 0.05). We demonstrated that deletion of Nrf2 exacerbates brain injury after TBI in mice, suggesting that Nrf2 may play an important role in protecting brain injury after TBI, possibly by modulating oxidative stress. PMID- 25732598 TI - A practical topological insulator saturable absorber for mode-locked fiber laser. AB - A novel saturable absorber (SA) was fabricated by coating the topological insulator (TI) film on microfiber using pulsed laser deposition (PLD) method. The TISA device had an insertion loss of ~1.25 dB, a saturable intensity of 26.7 MW/cm(2), a modulation depth of ~5.7%, and a nonsaturable loss of 20.5%. Upon employing this SA device, we established a passively mode-locked EDFL and achieved nearly free-chirped soliton pulse with 286 fs of pulse duration and >73 dB of signal to noise ratio (SNR). This result clearly evidences that the PLD is an effective scheme for practical SA device fabrication. PMID- 25732599 TI - Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. AB - Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes. PMID- 25732600 TI - Fatal autoimmunity results from the conditional deletion of Snai2 and Snai3. AB - Transcriptional regulation of gene expression is a key component of orchestrating proper immune cell development and function. One strategy for maintaining these transcriptional programs has been the evolution of transcription factor families with members possessing overlapping functions. Using the germ line deletion of Snai2 combined with the hematopoietic specific deletion of Snai3, we report that these factors function redundantly to preserve the development of B and T cells. Such animals display severe lymphopenia, alopecia and dermatitis as well as profound autoimmunity manifested by the production of high levels of autoantibodies as early as 3 weeks of age and die by 30 days after birth. Autoantibodies included both IgM and IgG isotypes and were reactive against cytoplasmic and membranous components. A regulatory T cell defect contributed to the autoimmune response in that adoptive transfer of wild type regulatory T cells alleviated symptoms of autoimmunity. Additionally, transplantation of Snai2/Snai3 double deficient bone marrow into Snai2 sufficient Rag2(-/-) recipients resulted in autoantibody generation. The results demonstrated that appropriate expression of Snai2 and Snai3 in cells of hematopoietic derivation plays an important role in development and maintenance of immune tolerance. PMID- 25732602 TI - Granulocytic subset of myeloid derived suppressor cells in rats with mammary carcinoma. AB - Limited knowledge is available on myeloid derived suppressor cells (MDSCs) of rat origin. We examined the myeloid cells from peripheral blood, bone marrow and spleens of healthy and mammary tumor bearing rats employing a novel immunophenotyping strategy with CD172a, HIS48, and Rp-1 antibodies. We addressed rat granulocytes by Rp-1 positivity and used HIS48 in discrimination of two mononuclear cell subsets. An expansion of granulocyte numbers was detected in peripheral blood and spleens of mammary tumor-bearing animals. The purified granulocytes were able to impair antigen-specific helper T-cell proliferation, and therefore nominated as granulocytic MDSCs of this rat tumor model. HIS48(+) mononuclear cell numbers were also increased in the blood and spleens of mammary tumor bearing rats with a lower MHC class II positivity. Despite the lack of an antigen specific suppression of CD4(+) T cells, HIS48(+) monocytes resemble monocytic MDSCs with their inflammatory phenotype. Together, these results provide evidence for the existence and phenotypic characterization of a granulocytic MDSC subset in a rat model of mammary carcinoma. PMID- 25732603 TI - Reconstruction of the lateral malleolus and calcaneus region using free thoracodorsal artery perforator flaps. AB - Reconstruction of the lateral malleolus or calcaneus region is challenging because of poor vascularity, minimal presence of soft tissue, and difficulties with flap positioning during and after the operation. In many cases, local flaps are limited in terms of size, durability, and vascularity. Free tissue transfer can be useful for complicated wounds. We report here on the results of the reconstruction in this region using free thoracodorsal artery perforator flaps. Between October 2010 and October 2013, 16 cases of lateral malleolus or calcaneus defects were reconstructed using free thoracodorsal artery perforator flaps. The defects varied from 2 * 5 cm(2) to 12 * 16 cm(2), and the flaps from 3 * 5 cm(2) to 10 * 15 cm(2). Two cases were reconstructed using chimeric-pattern flaps. Only the superficial adipose layers were harvested for all the flaps, without further thinning or debulking process. Five cases with complications occurred, including three cases of partial necrosis of the flap and two cases of venous congestion caused by thrombosis and compression of the venous pedicle, and one flap was totally lost. The mean follow-up duration was 11.8 months. All the patients were able to wear shoes. All but one were able to walk. The thoracodorsal artery perforator flap can be made super-thin, allowing patients to wear shoes, and it can be harvested in a chimeric-pattern for complex defects. Therefore, it may represent a viable alternative choice for the reconstruction of the lateral malleolus and calcaneus region. PMID- 25732601 TI - Generation, cryopreservation, function and in vivo persistence of ex vivo expanded cynomolgus monkey regulatory T cells. AB - We expanded flow-sorted Foxp3(+) cynomolgus monkey regulatory T cells (Treg) >1000-fold after three rounds of stimulation with anti-CD3 mAb-loaded artificial antigen-presenting cells, rapamycin (first round only) and IL-2. The expanded Treg maintained their expression of Treg signature markers, CD25, CD27, CD39, Foxp3, Helios, and CTLA-4, as well as CXCR3, which plays an important role in T cell migration to sites of inflammation. In contrast to expanded effector T cells (Teff), expanded Treg produced minimal IFN-gamma and IL-17 and no IL-2 and potently suppressed Teff proliferation. Following cryopreservation, thawed Treg were less viable than their freshly-expanded counterparts, although no significant changes in phenotype or suppressive ability were observed. Additional rounds of stimulation/expansion restored maximal viability. Furthermore, adoptively-transferred autologous Treg expanded from cryopreserved second round stocks and labeled with CFSE or VPD450 were detected in blood and secondary lymphoid tissues of normal or immunosuppressed recipients at least two months after their systemic infusion. PMID- 25732604 TI - Appraisal of within- and between-laboratory reproducibility of non-radioisotopic local lymph node assay using flow cytometry, LLNA:BrdU-FCM: comparison of OECD TG429 performance standard and statistical evaluation. AB - Mouse local lymph node assay (LLNA, OECD TG429) is an alternative test replacing conventional guinea pig tests (OECD TG406) for the skin sensitization test but the use of a radioisotopic agent, (3)H-thymidine, deters its active dissemination. New non-radioisotopic LLNA, LLNA:BrdU-FCM employs a non radioisotopic analog, 5-bromo-2'-deoxyuridine (BrdU) and flow cytometry. For an analogous method, OECD TG429 performance standard (PS) advises that two reference compounds be tested repeatedly and ECt(threshold) values obtained must fall within acceptable ranges to prove within- and between-laboratory reproducibility. However, this criteria is somewhat arbitrary and sample size of ECt is less than 5, raising concerns about insufficient reliability. Here, we explored various statistical methods to evaluate the reproducibility of LLNA:BrdU-FCM with stimulation index (SI), the raw data for ECt calculation, produced from 3 laboratories. Descriptive statistics along with graphical representation of SI was presented. For inferential statistics, parametric and non-parametric methods were applied to test the reproducibility of SI of a concurrent positive control and the robustness of results were investigated. Descriptive statistics and graphical representation of SI alone could illustrate the within- and between laboratory reproducibility. Inferential statistics employing parametric and nonparametric methods drew similar conclusion. While all labs passed within- and between-laboratory reproducibility criteria given by OECD TG429 PS based on ECt values, statistical evaluation based on SI values showed that only two labs succeeded in achieving within-laboratory reproducibility. For those two labs that satisfied the within-lab reproducibility, between-laboratory reproducibility could be also attained based on inferential as well as descriptive statistics. PMID- 25732605 TI - METAXA2: improved identification and taxonomic classification of small and large subunit rRNA in metagenomic data. AB - The ribosomal rRNA genes are widely used as genetic markers for taxonomic identification of microbes. Particularly the small subunit (SSU; 16S/18S) rRNA gene is frequently used for species- or genus-level identification, but also the large subunit (LSU; 23S/28S) rRNA gene is employed in taxonomic assignment. The METAXA software tool is a popular utility for extracting partial rRNA sequences from large sequencing data sets and assigning them to an archaeal, bacterial, nuclear eukaryote, mitochondrial or chloroplast origin. This study describes a comprehensive update to METAXA - METAXA2 - that extends the capabilities of the tool, introducing support for the LSU rRNA gene, a greatly improved classifier allowing classification down to genus or species level, as well as enhanced support for short-read (100 bp) and paired-end sequences, among other changes. The performance of METAXA2 was compared to other commonly used taxonomic classifiers, showing that METAXA2 often outperforms previous methods in terms of making correct predictions while maintaining a low misclassification rate. METAXA2 is freely available from http://microbiology.se/software/metaxa2/. PMID- 25732606 TI - Cluster-randomized trial of a German leisure-based alcohol peer education measure. AB - Because of scarce research, the effectiveness of substance abuse prevention in leisure settings remains unclear. In this study, we evaluated the effectiveness of a peer-led educational prevention measure with adolescent groups in unstructured leisure settings, which is a component of the complex German nationwide 'Na Toll!' campaign. Using a cluster-randomized two-group post-test only design, we tested whether the measure influenced component-specific goals, namely risk and protective factors of alcohol use such as risk perception, group communication and resistance self-efficacy. The sample consisted of 738 adolescents aged 12-20 years who were recruited at recreational locations and completed an online questionnaire 1 week after the peer education or recruitment event. Sixty-three percent of the sample participated in the 3-month follow-up assessment. Data analysis revealed post-test effects on risk perception, perceived norm of alcohol communication in the peer group and resistance self efficacy. Follow-up effects were not observed, with the exception of a significant effect on risk perception. In conclusion, the peer-led education measure in leisure settings might have supported the adolescents in this study to perceive alcohol-related risks, to feel accepted to talk about alcohol problems with their friends and to be more assertive in resisting alcohol use in the short term. PMID- 25732607 TI - "Tail" tuning of iron(II) spin crossover temperature by 100 K. AB - Two new Rdpt ligands featuring long "tails", padpt (N-4H-1,2,4-triazole-3,5-di(2 pyridyl)palmitamide) and hpdpt (4-(4-heptadecafluoroctylphenyl)-3,5-bis(2 pyridyl)-4H-1,2,4-triazole), were made and reacted with [Fe(II)(py)4(NCS)2] to give pinkish-red [Fe(II)(padpt)2(SCN)2] (1) and purple-red [Fe(II)(hpdpt)2(SCN)2] (2) as solvent-free crystals. Magnetic measurements reveal that both 1 and 2 exhibit complete and reproducible spin crossovers, with a far lower T1/2 for the amide-alkyl tailed 1 (182 K) than for the fluorocarbon tailed 2 (248 K), which in turn is far lower than the T1/2 of 290 K previously reported for the nonamide alkyl tailed analogue [Fe(II)(C16dpt)2(SCN)2].(2)/3H2O (3). Structure determinations for 1 and 2 in both the high spin (HS) and low spin (LS) states confirm the expected trans-NCS conformation and reveal that (a) the "tails" interdigitate and (b) the LS forms are less distorted than the HS forms (Sigma = 58-70 degrees vs 47-54 degrees ). DSC and Raman spectroscopy confirmed the high tail-dependence of the SCO events in 1 and 2, as well as in 3, with the Raman data giving T1/2 values of 190, 243, and 285 K, respectively. Bright orange single crystals of the solvatomorph [Fe(II)(hpdpt)2(SCN)2].MeOH.H2O (2solv) were also structurally and magnetically characterized and, in contrast to 2, found to remain HS down to 4 K, providing further evidence of the huge impact of crystal packing on SCO. Both 1 and 2 form stable Langmuir films at an air-water interface, a single layer of which can be transferred to a solid support. PMID- 25732608 TI - Efficacy and safety of acetylcysteine in "non-acetaminophen" acute liver failure: A meta-analysis of prospective clinical trials. AB - BACKGROUND: Acute liver failure (ALF) is a rare but highly mortal condition without liver transplantation (LT). N-acetylcysteine (NAC), a glutathione precursor that detoxifies the reactive metabolite of acetaminophen and replenishes hepatic glutathione stores, is a highly effective drug for the prevention of ALF caused by acetaminophen. However, therapeutic use of NAC in non acetaminophen-induced ALF (NAI-ALF) including alcohol intoxication, hepatitis virus infection, or drug and toxin-related hepatotoxicity is still inconclusive. The aim of this article is using meta-analysis method to analyze recent prospective clinical trials for the safety and efficacy of NAC in patients with ALF not caused by acetaminophen poisoning. METHODS: Prospective clinical trials comparing efficacy and safety between NAC and control in the treatment of NAI-ALF were identified by searching Pubmed (2000-2014) and EMBASE (2000-2014) using the search terms acetylcysteine or NAC and NAI-ALF. The primary outcome was overall survival. Secondary outcomes included liver transplantation-free survival, post transplantation survival, length of ICU and hospital stays, and the relationship with coma grade. The safety profiles were also analyzed. RESULTS: Four clinical trials were selected for meta-analysis. A total of 331 patients receiving treatment with NAC (oral or intravenously) and 285 patients in control group were included for meta-analysis. No statistical difference was identified between NAC group and control group for overall survival [236/331 (71%) vs 191/285 (67%); 95% CI 1.16 (0.81-1.67); P=0.42]. However, there were significant differences between NAC group and control group regarding the survival with native liver [112/273 (41%) vs 68/226 (30%); 95% CI 1.61 (1.11-2.34); P=0.01] and post-transplantation survival [78/91 (85.7%) vs 50/70 (71.4%); 95% CI 2.44 (1.11-5.37); P=0.03]. The identified side effects of NAC included nausea, vomiting, and diarrhea or constipation. Rarely, it could cause rashes, fever, headache, drowsiness, low blood pressure, and elevated serum transaminase levels in a patient with cystic fibrosis. At the dose used for acetaminophen toxicity, acetylcysteine does not have hepatotoxic effects. CONCLUSION: NAC is safe for NAI-ALF. It can prolong patients' survival with native liver without transplantation and survival after transplantation, but it cannot improve the overall survival. PMID- 25732609 TI - Treatment outcomes of external-beam radiotherapy for squamous cell carcinoma of the base of the tongue. AB - PURPOSE: To evaluate definitive external-beam radiotherapy (EBRT) for patients with base of the tongue (BOT) cancers. METHODS: We reviewed results for 26 patients with BOT cancers who were treated with EBRT. Clinical stages T1, T2, T3, and T4a were observed for 10, 7, 4, and 5 patients, respectively, and stages N0, N1, N2a, N2b, N2c, and N3 were observed for 4, 2, 5, 6, 8, and 1 patients, respectively. More than half of the patients (n = 19) were stage IVA. Standard total delivered doses were 70 Gy to primary tumors and cervical lymph node (CLN) metastases and 40-46 Gy to elective nodal regions. Eleven patients with advanced loco-regional disease received concurrent or neoadjuvant chemotherapy. Four T3 patients and one T2 patient received 2 or 3 cycles of concurrent intra-arterial cisplatin with EBRT (RADPLAT). RESULTS: Three-year overall survival was 69 % (95 % CI 47-83 %), with a median follow-up period of 33 months. Three-year local control was 100, 86, 100, and 20 % for T1, T2, T3, and T4 patients, respectively. Three-year regional control was 100 % for N0, N1, and N2a, 83 % for N2b, 75 % for N2c, and 0 % for N3 patients. Treatment failed for 7 patients. All 5 patients undergoing RADPLAT achieved complete responses and did not develop local recurrence. CONCLUSIONS: We achieved favorable outcomes for patients with T1-T3 BOT cancers by use of definitive EBRT with or without chemotherapy. PMID- 25732610 TI - Metagenomics: Urban microbiome. PMID- 25732611 TI - The effects of chromatin organization on variation in mutation rates in the genome. AB - The variation in local rates of mutations can affect both the evolution of genes and their function in normal and cancer cells. Deciphering the molecular determinants of this variation will be aided by the elucidation of distinct types of mutations, as they differ in regional preferences and in associations with genomic features. Chromatin organization contributes to regional variation in mutation rates, but its contribution differs among mutation types. In both germline and somatic mutations, base substitutions are more abundant in regions of closed chromatin, perhaps reflecting error accumulation late in replication. By contrast, a distinctive mutational state with very high levels of insertions and deletions (indels) and substitutions is enriched in regions of open chromatin. These associations indicate an intricate interplay between the nucleotide sequence of DNA and its dynamic packaging into chromatin, and have important implications for current biomedical research. This Review focuses on recent studies showing associations between chromatin state and mutation rates, including pairwise and multivariate investigations of germline and somatic (particularly cancer) mutations. PMID- 25732613 TI - Quality evaluation and pattern recognition analyses of marker compounds from five medicinal drugs of Rutaceae family by HPLC/PDA. AB - To establish a standard of quality control and to identify different origins for the Rutaceae family [Citri Unshiu Peel (CU), Citri Unshiu Immature Peel (CI), Ponciri Immature Fructus (PI), Aurantii Immature Fructus (AI), and Aurantii Fructus (AU)], 13 standards including rutin (1), narirutin (2), naringin (3), hesperidin (4), neohesperidin (5), neoponcirin (6), poncirin (7), naringenin (8), isosinensetin (9), sinensetin (10), nobiletin (11), heptamethoxyflavone (12), and tangeretin (13) were determined by high performance liquid chromatography (HPLC)/photo-diode array (PDA) analysis. A YMC ODS C18 (250 * 4.6 mm, 5 um) column was used and the ratio of mobile phases of water (A) and acetonitrile (B) delivered to the column for gradient elution was applied. This method was fully validated with respect to linearity, accuracy, precision, stability, and robustness. The HPLC/PDA method was applied successfully to quantify 13 major compounds in the extracts of CU, CI, PI, AI, and AU. The pattern recognition analysis combined with LC chromatographic data was performed by repeated analysis of 27 reference samples in the above five Rutaceae oriental medicinal drugs. The established HPLC method was rapid and reliable for quantitative analysis and quality control of multiple components in five Rutaceae species with different origins. PMID- 25732614 TI - An ethical framework for responding to drug shortages in pediatric oncology. AB - The frequency of drug shortages has increased considerably over the last decade. Important ethical issues arise whenever the supply of an effective drug is insufficient to meet demand. Using the ethical principles of beneficence, non maleficence, and justice, institutions can guide prioritization of drug distribution before a shortage occurs to avoid unfair and unethical distribution of resources. This analysis will give a historical context for drug shortages, identify, and explore the central ethical concerns raised by drug shortages, and propose an ethical framework for addressing them in the context of pediatric oncology. PMID- 25732612 TI - Rett syndrome: a complex disorder with simple roots. AB - Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Two decades of research have fostered the view that MeCP2 is a multifunctional chromatin protein that integrates diverse aspects of neuronal biology. More recently, studies have focused on specific RTT-associated mutations within the protein. This work has yielded molecular insights into the critical functions of MeCP2 that promise to simplify our understanding of RTT pathology. PMID- 25732615 TI - Sclerosing stromal tumor of the ovary treated with 2-incision total laparoscopic cystectomy. AB - Sclerosing stromal tumor (SST) is an extremely rare benign tumor of the ovary that is derived from the sex cord stroma [1,2] and occurs in young women [3-11]. Preoperative diagnosis of the tumor is difficult as it often mimics a malignant tumor. Oophorectomy is usually performed in many cases of young women [3], and diagnosis of SST is made based on post-operative pathological examination. Laparoscopic surgery is seldom performed in SST cases. Here, we report a case of SST of the ovary in an 18-year-old girl who was diagnosed by preoperative imaging and underwent laparoscopic cystectomy. Accurate preoperative imaging helped to perform minimally invasive surgery for SST. PMID- 25732616 TI - Colonic metastases from small cell carcinoma of the lung presenting with an acute abdomen: A case report. AB - INTRODUCTION: Colonic metastases are rare, and usually secondary from malignant tumours of the stomach, breast, ovarian, cervix, kidney, lung, prostate, or skin. Around one third are asymptomatic or found only at autopsy. CASE REPORT: A middle aged male smoker, who had a small cell carcinoma of the lung diagnosed two years previously and treated with radiotherapy and chemotherapy, was admitted to the emergency room with intense abdominal pain and constipation. With the suspicion of an acute appendicitis he was submitted to surgery. At laparotomy he was found to have a normal appendix but two hard colonic lesions: a mobile one in the right colon and the other fixing the sigmoid colon to the sacrum. A right hemicolectomy and a sigmoid loop colostomy were performed. Pathology showed those lesions to be colonic metastases from small cell carcinoma of the lung. DISCUSSION: Colonic secondaries are most frequently diagnosed in patients who have had a known primary tumour, and may present with bowel obstruction, lower gastrointestinal haemorrhage, gastrointestinal fistula, or intestinal perforation. Presentation with acute abdomen is rare, and survival is usually limited. CONCLUSION: Colonic metastatic disease should be considered in any patient presenting with an acute abdomen and past history of lung malignancy. PMID- 25732617 TI - The repurposed social brain. AB - Human social intelligence depends on a diverse array of perceptual, cognitive, and motivational capacities. Some of these capacities depend on neural systems that may have evolved through modification of ancestral systems with non-social or more limited social functions (evolutionary repurposing). Social intelligence, in turn, enables new forms of repurposing within the lifetime of an individual (cultural and instrumental repurposing), which entail innovating over and exploiting pre-existing circuitry to meet problems our brains did not evolve to solve. Considering these repurposing processes can provide insight into the computations that brain regions contribute to social information processing, generate testable predictions that usefully constrain social neuroscience theory, and reveal biologically imposed constraints on cultural inventions and our ability to respond beneficially to contemporary challenges. PMID- 25732618 TI - Distinctive green recovery of silver species from modified cellulose: mechanism and spectroscopic studies. AB - The present study aimed to recover precious silver in order to identify the adsorption coupled reduction pathways that determine this process. A combination technique of adsorption and nanocrystallization was used to investigate the recovery of silver species from taurine-cellulose (T-DAC) samples. The non synthetic route of nanocrystallization yielded spherical zero-valent silver sized ~ 18 nm. Rate-controlling steps were modeled by adsorption parameters by the best fit of Langmuir capacity (55 mg/g), pseudo-second order curves, and exothermic chemical reactions. The T-DAC was an excellent sorbing phase for the treatment of silver-polluted waters over a broad range of pH (2.1-10.1) and varying ionic strengths (8.5-850 mM, as NaCl), which are the conditions often encountered in industrial and mining effluents. A good recovery of silver (40-65%) was also obtained in the presence of Cd(II), Co(II), Cr(VI), Ni(II), and As(V) at lower or equivalent concentrations with Ag(I), either from individually added metals or from all metal ions mixed together. Desorption was compared with a series of five eluents including complexing agents. In these experiments acidified thiourea yielded 86% desorption of Ag(I). Aqueous silver reduced to metallic silver on the surface of the T-DAC samples, which was confirmed by X-ray photo electron spectroscopy. PMID- 25732619 TI - Optimisation of high-pressure ultrasonic-assisted extraction and antioxidant capacity of polysaccharides from the rhizome of Ligusticum chuanxiong. AB - High-pressure ultrasound-assisted extraction was used to extract polysaccharides from the Ligusticum chuanxiong rhizomes. Three independent variables, namely, extraction temperature (X1), ultrasonic power (X2) and extraction time (X3) were investigated. Response surface methodology was performed based on the results of single-factor tests. Experimental data were fitted to a second-order polynomial equation using multiple regression analysis, and results were examined using appropriate statistical methods. The optimal conditions were as follows: extraction temperature of 85 degrees C, ultrasonic power of 187 W and extraction time of 29 min. Under these conditions, the experimental yield of polysaccharides was 5.33%, which is close to the predicted yield of 5.41%. The extracted and purified polysaccharides showed excellent antioxidative effects on 2,2-diphenyl-1 picryl-hydrazy, hydroxyl and superoxide radicals in vitro. PMID- 25732620 TI - Erratum to: The Influence of Food Texture and Liquid Consistency Modification on Swallowing Physiology and Function: A Systematic Review. AB - Erratum to: Dysphagia DOI 10.1007/s00455-014-9578-x. In the original version of this article, Fig. 1 was published incorrectly. The corrected figure is given below. PMID- 25732621 TI - A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma. AB - Solid tumors arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumor-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumors. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase inhibitor nilotinib as a therapeutic option for the management of pediatric gliomas. We have utilized two independent pediatric high-grade glioma cell lines with either high platelet derived growth factor receptor alpha (PDGFRalpha) or high PDGFRbeta expression in in vitro assays to investigate the specific downstream effects of nilotinib treatment. Using in vitro cell-based assays we show that nilotinib inhibits PDGF BB-dependent activation of PDGFRalpha. We further show that nilotinib is able to decrease cell proliferation and anchorage-independent growth via suppression of AKT and ERK1/2 signaling pathways. Our results suggest that nilotinib may be effective for management of a PDGFRalpha-dependent group of pediatric gliomas. PMID- 25732622 TI - Lipoprotein(a)-clinical aspects and future challenges. AB - Lipoprotein(a) (Lp(a)) was first described by K. Berg and is known for more than 50 years. It is an interesting particle and combines the atherogenic properties of low-density lipoprotein (LDL)-cholesterol as well as the thrombogenic properties of plasminogen inactivation. However, due to technical problems and publication of negative trials the potential role of Lp(a) in atherosclerosis was severely underestimated. In recent years our understanding of the function and importance of Lp(a) improved. Interventional trials with niacin failed to demonstrate any benefit of lowering Lp(a); however, several studies confirmed the residual cardiovascular disease (CVD) risk of elevated Lp(a). LDL/Lp(a) apheresis is able to lower Lp(a) and some new drugs under development should help us to lower Lp(a) in the near future. It will be important to follow this with hard endpoint trials. Until then most clinicians recommend the use of an aggressive LDL-lowering approach in patients with high Lp(a). Since most of these patients with high Lp(a) might have manifested atherosclerosis anyway, we would also consider the use of acetylsalicylic acid. PMID- 25732624 TI - Engineering lipid overproduction in the oleaginous yeast Yarrowia lipolytica. AB - Conversion of carbohydrates to lipids at high yield and productivity is essential for cost-effective production of renewable biodiesel. Although some microorganisms can convert sugars to oils, conversion yields and rates are typically low due primarily to allosteric inhibition of the lipid biosynthetic pathway by saturated fatty acids. By reverse engineering the mammalian cellular obese phenotypes, we identified the delta-9 stearoyl-CoA desaturase (SCD) as a rate limiting step and target for the metabolic engineering of the lipid synthesis pathway in Yarrowia lipolytica. Simultaneous overexpression of SCD, Acetyl-CoA carboxylase (ACC1), and Diacylglyceride acyl-transferase (DGA1) in Y. lipolytica yielded an engineered strain exhibiting highly desirable phenotypes of fast cell growth and lipid overproduction including high carbon to lipid conversion yield (84.7% of theoretical maximal yield), high lipid titers (~55g/L), enhanced tolerance to glucose and cellulose-derived sugars. Moreover, the engineered strain featured a three-fold growth advantage over the wild type strain. As a result, a maximal lipid productivity of ~1g/L/h is obtained during the stationary phase. Furthermore, we showed that the engineered yeast required cytoskeleton remodeling in eliciting the obesity phenotype. Altogether, our work describes the development of a microbial catalyst with the highest reported lipid yield, titer and productivity to date. This is an important step towards the development of an efficient and cost-effective process for biodiesel production from renewable resources. PMID- 25732623 TI - Futile cycling increases sensitivity toward oxidative stress in Escherichia coli. AB - Reactive oxygen species (ROS) are toxic molecules utilized by the immune system to combat invading pathogens. Recent evidence suggests that inefficiencies in ATP production or usage can lead to increased endogenous ROS production and sensitivity to oxidative stress in bacteria. With this as inspiration, and knowledge that ATP is required for a number of DNA repair mechanisms, we hypothesized that futile cycling would be an effective way to increase sensitivity to oxidative stress. We developed a mixed integer linear optimization framework to identify experimentally-tractable futile cycles, and confirmed metabolic modeling predictions that futile cycling depresses growth rate, and increases both O2 consumption and ROS production per biomass generated. Further, intracellular ATP was decreased and sensitivity to oxidative stress increased in all actively cycling strains compared to their catalytically inactive controls. This research establishes a fundamental connection between ATP metabolism, endogenous ROS production, and tolerance toward oxidative stress in bacteria. PMID- 25732625 TI - Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial. AB - AIM: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. METHODS: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. RESULTS: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 +/- 0.5, 6.9 +/- 0.6 and -10.9 +/- 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 +/- 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib. CONCLUSIONS: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss. PMID- 25732626 TI - Sublineages of Mycobacterium tuberculosis Beijing genotype strains and unfavorable outcomes of anti-tuberculosis treatment. AB - The influence of Mycobacterium tuberculosis (MTB) lineages/sublineages on unfavorable tuberculosis (TB) treatment outcomes is poorly understood. We investigated the effects of Beijing genotype sublineages and other factors contributing to treatment outcome. Patients newly diagnosed with sputum smear positive and culture-positive TB in Hanoi, Vietnam, participated in the study. After receiving anti-TB treatment, they were intensively followed up for the next 16 months. MTB isolates collected before treatment were subjected to drug susceptibility testing, and further analyzed to determine MTB (sub) lineages and their clonal similarities. Of 430 patients, 17 had treatment failure and 30 had TB recurrence. Rifampicin resistance was associated with treatment failure {adjusted odds ratio = 6.64 [95% confidence interval (CI), 1.48-29.73]}. The modern Beijing genotype was significantly associated with recurrent TB within 16 months [adjusted hazard ratio = 3.29 (95% CI, 1.17-9.27)], particularly after adjustment for the relevant antibiotic resistance. Human immunodeficiency virus coinfection and severity on chest radiographs were not significantly associated with unfavorable outcomes. Our findings provide further understanding of the influence of MTB strains on unfavorable treatment outcomes. Multiple risk factors should be considered for the optimal management of TB. PMID- 25732627 TI - ESX/type VII secretion systems of mycobacteria: Insights into evolution, pathogenicity and protection. AB - Pathogenesis of Mycobacterium tuberculosis depends on the secretion of key virulence factors, such as the 6 kDa early secreted antigenic target ESAT-6 (EsxA) and its protein partner, the 10 kDa culture filtrate protein CFP-10 (EsxB), via the ESX-1 secretion system. ESX-1 represents the prototype system of the recently named type VII secretion systems that exist in a range of actinobacteria. The M. tuberculosis genome harbours a total of five gene clusters potentially coding for type VII secretion systems, designated ESX-1 - ESX-5, with ESX-4 being the most ancient system from which other ESX systems seem to have evolved by gene duplication and gene insertion events. The five ESX systems show similarity in gene content and gene order but differ in function. ESX-1 and ESX-5 are both crucial virulence determinants of M. tuberculosis, but with different mechanisms. While ESX-1 is implicated in the lysis of the host cell phagosomes, ESX-5 is involved in secretion of the mycobacteria specific PE and PPE proteins and cell wall stability. Research on type VII secretion systems has thus become a large and competitive research topic that is tightly linked to studies of host pathogen interaction of pathogenic mycobacteria. Insights into this matter are of relevance for redrawing the patho-evolution of M. tuberculosis, which might help improving current strategies for prevention, diagnostics and therapy of tuberculosis as well as elucidating the virulence mechanisms employed by this important human pathogen. PMID- 25732628 TI - Population structure and dispersal of the coral-excavating sponge Cliona delitrix. AB - Some excavating sponges of the genus Cliona compete with live reef corals, often killing and bioeroding entire colonies. Important aspects affecting distribution of these species, such as dispersal capability and population structure, remain largely unknown. Thus, the aim of this study was to determine levels of genetic connectivity and dispersal of Cliona delitrix across the Greater Caribbean (Caribbean Sea, Bahamas and Florida), to understand current patterns and possible future trends in their distribution and effects on coral reefs. Using ten species specific microsatellite markers, we found high levels of genetic differentiation between six genetically distinct populations: one in the Atlantic (Florida Bahamas), one specific to Florida and four in the South Caribbean Sea. In Florida, two independent breeding populations are likely separated by depth. Gene flow and ecological dispersal occur among other populations in the Florida reef tract, and between some Florida locations and the Bahamas. Similarly, gene flow occurs between populations in the South Caribbean Sea, but appears restricted between the Caribbean Sea and the Atlantic (Florida-Bahamas). Dispersal of C. delitrix was farther than expected for a marine sponge and favoured in areas where currents are strong enough to transport sponge eggs or larvae over longer distances. Our results support the influence of ocean current patterns on genetic connectivity, and constitute a baseline to monitor future C. delitrix trends under climate change. PMID- 25732630 TI - Was NAP5 'NICE' enough; where next for depth of anaesthesia monitors? PMID- 25732629 TI - Salivary diagnostics using a portable point-of-service platform: a review. AB - Clinical diagnostics can be improved by faster and more accessible disease detection. Our laboratory has developed a point-of-service (POS) device capable of rapid, sensitive, automated, and multiplexed biomarker detection that uses human saliva instead of other biofluids. Here, we review the technology that led to the development of this POS device. This POS technology can advance clinical diagnostics by saving time because of faster diagnosis, saving money because of a shorter hospital stay, and ultimately improving clinical care. PMID- 25732631 TI - Occurrence and dry deposition of organophosphate esters in atmospheric particles over the northern South China Sea. AB - Nine organophosphate esters (OPEs) in airborne particles were measured during a cruise campaign over the northern South China Sea (SCS) from September to October 2013. The concentration of the total OPEs (?OPEs) was 47.1-160.9 pg m(-3), which are lower than previous measurements in marine atmosphere environments. Higher OPE concentrations were observed in terrestrially influenced samples, suggesting that OPE concentrations were significantly influenced by air mass transport. Chlorinated OPEs were the dominant OPEs, accounting for 65.8-83.7% of the ?OPEs. Tris-(2-chloroethyl) phosphate (TCEP) was the predominant OPE compound in the samples (45.0+/-12.1%), followed by tris-(1-chloro-2-propyl) phosphates (TCPPs) (28.8+/-8.9%). Dry particle-bound deposition fluxes ranged from 8.2 to 27.8 ng m( 2) d(-1) for the ?OPEs. Moreover, the dry deposition input of the ?OPEs was estimated to be 4.98 ton y(-1) in 2013 in a vast area of northern SCS. About half of the input was found to relate to air masses originating from China. PMID- 25732632 TI - Novel methods for measuring air-water interfacial area in unsaturated porous media. AB - Interfacial partitioning tracer tests (IPTT) are used to measure air-water interfacial area for unsaturated porous media. The standard IPTT method involves conducting tests wherein an aqueous surfactant solution is introduced into a packed column under unsaturated flow conditions. Surfactant-induced drainage has been observed to occur for this method in some cases, which can complicate data analysis and impart uncertainty to the measured values. Two novel alternative approaches for conducting IPTTs are presented herein that are designed in part to prevent surfactant-induced drainage. The two methods are termed the dual surfactant IPTT (IPTT-DS) and the residual-air IPTT (IPTT-RA). The two methods were used to measure air-water interfacial areas for two natural porous media. System monitoring during the tests revealed no measurable surfactant-induced drainage. The measured interfacial areas compared well to those obtained with the standard IPTT method conducted in such a manner that surfactant-induced drainage was prevented. PMID- 25732633 TI - Mercury methylation in sediments of a Brazilian mangrove under different vegetation covers and salinities. AB - The presence and formation of methylmercury (MMHg), a highly toxic form of Hg, in mangrove ecosystems is poorly studied. Therefore the aim of this study was to evaluate mercury methylation potentials in sediment, litter and root samples (Avicennia shaueriana and Spartina alterniflora) from different regions of a mangrove ecosystem, as well as the influence of salinity on methylation. Sediment was sampled under different depths and in mangrove regions with different plant covers and salinities. All samples were incubated with (203)Hg and MM(203)Hg was extracted and measured by liquid scintillation. MMHg was formed in all samples and sites tested including plant roots and litter. Higher Hg methylation was found in the superficial fraction of sediments (0.47-7.82%). Infralittoral sandy sediment had low MMHg formation (0.44-1.61%). Sediment under Rhizophora mangle had lower MMHg formation (0.018-2.23%) than under A. shaueriana (0.2-4.63%) and Laguncularia racemosa (0.08-7.82). MMHg formation in sediment tended to increase with salinity but the differences were not significant. Therefore, MMHg formation occurs in different sites of mangrove ecosystems and may be an important threat that requires further study. PMID- 25732634 TI - Measles-mumps-rubella-varicella combination vaccine (ProQuad): a guide to its use in children in the E.U. AB - In the EU, the live attenuated, tetravalent measles-mumps-rubella-varicella vaccine ProQuad is indicated for simultaneous vaccination against measles, mumps, rubella and varicella in individuals from 12 months of age using a two-dose schedule and may be used in infants from 9 months of age to conform with a national vaccination schedule, outbreak situations or travel to a region with a high prevalence of measles. Clinical data in young children indicates that vaccination with ProQuad is as immunogenic as the component vaccines, provides long-term protection against these potentially serious childhood infections and has an acceptable safety profile. Combining the viral strains of the measles mumps-rubella vaccine M-M-RVAXPRO and the varicella vaccine Varivax in ProQuad reduces the complexity of vaccination schedules, thereby potentially improving vaccination coverage and the timeliness of vaccination. PMID- 25732635 TI - Prognostic value of ERCC1, RRM1, and TS proteins in patients with resected non small cell lung cancer. AB - PURPOSE: Recent clinical trials showed that expression of excision repair cross complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) proteins was able to predict the effects of non-small cell lung cancer (NSCLC) to chemotherapy. However, it remains unknown whether the adjuvant chemotherapy based on expression of the three proteins has survival significance in Chinese NSCLC patients. METHODS: We investigated 128 Chinese patients receiving chemotherapy after tumor resection for expression of these proteins using immunohistochemistry. Based on protein expression, patients were assigned to two groups for different adjuvant chemotherapy regimes. The disease free survival (DFS) data were collected and analyzed using Kaplan-Meier curves and Cox models. RESULTS: We found that DFS of these patients with carboplatin and a third-generation agent (gemcitabine or pemetrexed) stratified by protein expression showed no statistical difference between individual treatment versus non-individuation treatment analyzed using Kaplan-Meier method (P = 0.143, median 23.9 vs. 30.8 months). Furthermore, the multivariate analysis showed that histology and tumor stages were independent predictors for DFS in these patients. CONCLUSIONS: The results suggest that chemotherapy based on ERCC1, RRM1, and TS expression did not have significant impact on DFS of patients with resection of NSCLC. PMID- 25732636 TI - Pituitary tumors. AB - Pituitary tumors are commonly encountered intracranial neoplasms that are invariably benign. Classic oncogene mutations are not encountered in these tumors, and disrupted cell cycle control and growth factor signaling likely contribute to pathogenesis and natural history. They have unique clinical features that are determined by the secreted hormone gene product. PMID- 25732637 TI - A prognostic clinicopathologic classification of pituitary endocrine tumors. AB - Pituitary endocrine tumors are considered as benign. However, clinical and pathological data favor their consideration as more than an endocrinological disease. Using data from a retrospective case-control study of 410 patients, with 8 years of follow-up, the authors have validated a new clinicopathologic classification of pituitary tumors. This classification is based on tumor size, immunohistochemical type, and grade based on the assessment of invasion and proliferation, and it provides a prognostic value for predicting postoperative disease-free outcome or recurrence/progression status. This classification aids the identification of patients presenting with pituitary tumors that have a high risk of recurrence and enable construction of personalized therapies. PMID- 25732638 TI - Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. AB - The most frequent conditions that are associated with inherited/familial pituitary adenomas are familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 1 (MEN1), which together account for up to 5% of pituitary adenomas. One important genetic cause of FIPA are inactivating mutations or deletions in the aryl hydrocarbon receptor interacting protein (AIP) gene. FIPA is the most frequent clinical presentation of AIP mutations. This article traces the current state of knowledge regarding the clinical features of FIPA and the particular genetic, pathologic, and clinical characteristics of pituitary adenomas due to AIP mutations. PMID- 25732639 TI - Pitfalls of insulin-like growth factor-i and growth hormone assays. AB - Accurate measurement of growth hormone (GH) and insulin-like growth factor-I (IGF I) are the key to correct diagnosis of acromegaly and GH deficiency. Unfortunately, there is much variation involved when these hormones are measured at different sites and using different assay methods. There is an ongoing global effort to standardize the measurement process to obtain more comparable results in the future. This review discusses common pitfalls in the measurement of GH and IGF-I and guides laboratories in their analyses of these hormones. PMID- 25732640 TI - Pharmacotherapy for acromegaly: future role for pasireotide? AB - Somatostatin receptor ligands (octreotide and lanreotide) are currently first line pharmacotherapy for patients with acromegaly in whom surgery fails to control the disease or cannot be considered. The efficacy of a new pan somatostatin receptor ligand, pasireotide, has been investigated as a potential treatment of acromegaly. Several clinical trials showed disease-remission with pasireotide in one-third of patients and some octreotide-resistant patients were responsive to pasireotide. Pasireotide can likely be used for patients with suboptimal response or resistance to treatment with the approved maximal doses of octreotide long-acting release (LAR) or lanreotide Autogel; however, the development or exacerbation of diabetes mellitus is of concern. PMID- 25732641 TI - Cushing syndrome: update on testing. AB - Endogenous hypercortisolism (Cushing syndrome) is one of the most enigmatic diseases in clinical medicine. The diagnosis and differential diagnosis of Cushing syndrome depend on proper laboratory evaluation. In this review, an update is provided on selected critical issues in the diagnosis and differential diagnosis of Cushing syndrome: the use of late-night salivary cortisol in initial diagnosis and for postoperative surveillance, and the use of prolactin measurement to improve the performance of inferior petrosal sinus sampling to distinguish Cushing disease from ectopic adrenocorticotropic hormone (ACTH) syndrome during differential diagnosis of ACTH-dependent Cushing syndrome. PMID- 25732642 TI - Medical treatment of Cushing disease: new targets, new hope. AB - This article provides an update on current medical therapies for the treatment of Cushing disease. This information will be of value in determining patients' suitability for certain medical treatments. An approach of combining drugs from the same or different classes could potentially increase the number of patients in whom Cushing can be controlled while minimizing adverse effects, although larger studies are needed. Successful clinical management of patients with Cushing disease remains a challenge. PMID- 25732643 TI - Prolactinomas. AB - Identifying the correct cause of hyperprolactinemia is crucial for treatment. Prolactinoma is the most common pathologic cause of hyperprolactinemia. Dopamine agonists are efficacious in about 80% to 90% of patients with prolactinoma, leading to reduction of serum prolactin levels and tumor dimensions. Neurosurgery, mainly by the transsphenoidal route, is indicated in cases of intolerant and resistant dopamine agonists. Radiotherapy is rarely used because of its side effects and low efficacy. The alkylating agent temozolomide showed efficacy for treatment of aggressive and resistant prolactinomas. Other approaches, such as thyrosine kinase inhibitors, are currently being tested and could be an additional tool for these troublesome tumors. PMID- 25732644 TI - Silent pituitary adenomas. AB - Pituitary adenomas are frequently silent. Among silent adenomas, some are clinically silent but can be detected on the basis of the excessive secretion of hormonal products, whereas others are totally silent and cannot be detected by hormonal measurements. Treatment of a silent pituitary adenoma depends on its size and extent. Silent adenomas that are associated with neurologic compromise should be treated by surgery. Postoperative radiation therapy may be used to prevent or treat recurrences. Only occasional silent pituitary adenomas respond to treatment with dopamine agonists or somatostatin analogs. PMID- 25732645 TI - Cabergoline use for pituitary tumors and valvular disorders. AB - Cabergoline (CAB) is widely used for the medical treatment of pituitary tumors, particularly those associated with hormone hypersecretion. Whether treatment with CAB is associated with an increased risk of clinically relevant cardiac valve disease in patients with pituitary tumors is still debated. In most studies, CAB has been found not associated with an increased risk of significant valvulopathy, and no correlation has been shown between valvular abnormalities and CAB duration or cumulative dose. This review provides an overview of the studies reporting on the outcome of CAB in terms of cardiac valve disease in patients with pituitary tumors. PMID- 25732646 TI - Invasive, atypical and aggressive pituitary adenomas and carcinomas. AB - Aggressive pituitary adenomas have a high risk of recurrence, a lack of therapeutic response, and resistance to conventional treatment. So far, no satisfactory biomarkers are available for predicting their behavior. Some specific pituitary adenoma histotypes are more prone to follow an aggressive behavior. Pituitary carcinomas are rare and show cerebrospinal and/or systemic metastasis. They have worse prognosis than aggressive adenomas, and radiation is of limited use in their treatment. PMID- 25732647 TI - Outcomes of endoscopic transsphenoidal pituitary surgery. AB - Since the 1990s, endoscopic transsphenoidal surgery for pituitary adenomas has increased in popularity. Outcomes of endoscopic surgery for clinically secretory adenomas are favorable, and results for nonfunctional tumors reveal high rates of complete resection, improvements in vision, and low rates of complications. This article discusses some of the recent studies reporting outcomes from endoscopic series for Cushing disease, acromegaly, prolactin-secreting tumors, and nonfunctioning macroadenomas. PMID- 25732648 TI - Efficacy and complications of pituitary irradiation. AB - Radiation therapy is widely used in the management of intracranial (including sellar and parasellar) and systemic disorders. Although in many cases the irradiation aims to prevent the growth or regrowth and to control the hormonal hypersecretion of a pituitary tumor, in many others it adversely affects the hypothalamo-pituitary function simply because this area receives significant doses of radiation delivered for non-hypothalamo-pituitary disorders. The main long-term complications include hypopituitarism, optic neuropathy, cerebrovascular morbidity, and second brain tumors. Radiation technique and schedule are important determinants of these adverse effects. PMID- 25732649 TI - Hypopituitarism: growth hormone and corticotropin deficiency. AB - This article presents an overview of adult growth hormone deficiency (AGHD) and corticotropin deficiency (central adrenal failure, CAI). Both conditions can result from various ailments affecting the hypothalamus or pituitary gland (most frequently a tumor in the area or its treatment). Clinical manifestations are subtle in AGHD but potentially life-threatening in CAI. The diagnosis needs dynamic testing in most cases. Treatment of AGHD is recommended in patients with documented severe deficiency, and treatment of CAI is mandatory in all cases. Despite significant progress in replacement hormonal therapy, more physiologic treatments and more reliable indicators of treatment adequacy are still needed. PMID- 25732650 TI - Hypophysitis. AB - In this article, an overview is presented of hypophysitis in terms of current clinical and experimental findings, with discussion of the anatomic and histopathologic classification of primary hypophysitis and factors associated with secondary hypophysitis. In addition, discusses the pathophysiology, clinical features, management, and prognosis associated with this disease are discussed. PMID- 25732651 TI - Hypopituitarism after traumatic brain injury. AB - The prevalence of hypopituitarism after traumatic brain (TBI) injury is widely variable in the literature; a meta-analysis determined a pooled prevalence of anterior hypopituitarism of 27.5%. Growth hormone deficiency is the most prevalent hormone insufficiency after TBI; however, the prevalence of each type of pituitary deficiency is influenced by the assays used for diagnosis, severity of head trauma, and time of evaluation. Recent studies have demonstrated improvement in cognitive function and cognitive quality of life with substitution therapy in GH-deficient patients after TBI. PMID- 25732652 TI - Health-related quality of life in pituitary diseases. AB - In the last 15 years, worse health-related quality of life (QoL) has been reported in patients with pituitary diseases compared with healthy individuals. Different QoL questionnaires have shown incomplete physical and psychological recovery after therapy. Residual impairments often affect QoL even long-term after successful treatment of pituitary adenomas. In this article, knowledge of factors that affect QoL in pituitary diseases is reviewed. The focus is on 5 pituitary diseases: Cushing syndrome, acromegaly, prolactinomas, nonfunctioning pituitary adenomas, and hypopituitarism. PMID- 25732653 TI - Pituitary diseases and bone. AB - Pituitary hormones have direct and indirect effects on bone remodeling, and skeletal fragility is a frequent complication of pituitary diseases. Fragility fractures may occur in many patients with prolactinomas, acromegaly, Cushing disease, and hypopituitarism. As in other forms of secondary osteoporosis, pituitary diseases generally affect bone quality more than bone quantity, and fractures may occur even in the presence of normal or low-normal bone mineral density, making difficult the prediction of fractures in these settings. Treatment of excess and defective pituitary hormone generally improves skeletal health, although some patients remain at high risk for fractures, necessitating treatment with bone-active drugs. PMID- 25732654 TI - Pituitary tumor management in pregnancy. AB - The improved management of pituitary adenomas has led to an increasing number of pregnancies in patients harboring pituitary adenomas. Therefore, adequate management of pregnant women with pituitary adenomas is of growing importance. Because pregnancy produces several physiologic changes to the endocrine system, especially to the pituitary gland, endocrinologists must be knowledgeable and skilled to effectively manage pregnant women with pituitary adenomas and to guarantee the wellbeing of the fetus. PMID- 25732655 TI - Pituitary apoplexy. AB - Pituitary apoplexy (PA) is a rare clinical syndrome caused by sudden hemorrhaging and/or infarction of the pituitary gland, generally within a pituitary adenoma. The main symptom is sudden-onset severe headache, associated with visual disorders or ocular palsy. Corticotropic deficiency may be life-threatening if left untreated. Computed tomography (CT) or MRI confirms the diagnosis by revealing a pituitary tumor with hemorrhagic and/or necrotic components. PA used to be considered a neurosurgical emergency but a conservative approach is increasingly used in selected patients, as it yields similar outcomes. Glucocorticoid treatment must always be started immediately after onset. PMID- 25732656 TI - Pituitary disorders. PMID- 25732657 TI - Updates and highlights in pituitary medicine. PMID- 25732658 TI - Recent advancements in carbon nanofiber and carbon nanotube applications in drug delivery and tissue engineering. AB - Since the discovery and synthesis of carbon nanotubes (CNTs) and carbon nanofibers (CNFs) over a decade ago, researchers have envisioned and discovered new potential applications for these materials. CNTs and CNFs have rapidly become a platform technology for a variety of uses, including biomedical applications due to their mechanical, electrical, thermal, optical and structural properties. CNTs and CNFs are also advantageous due to their ability to be produced in many different shapes and sizes. Since their discovery, of the many imaginable applications, CNTs and CNFs have gained a significant amount of attention and therapeutic potential in tissue engineering and drug delivery applications. In recent years, CNTs and CNFs have made significant contributions in designing new strategies for, delivery of pharmaceuticals, genes and molecular probes into cells, stem cell therapies and assisting in tissue regeneration. Furthermore, it is widely expressed that these materials will significantly contribute to the next generation of health care technologies in treating diseases and contributing to tissue growth. Hence, this review seeks to explore the recent advancements, current status and limitations of CNTs and CNFs for drug delivery and tissue engineering applications. PMID- 25732659 TI - Implication of nanofibers in oral drug delivery. AB - Nanofibers has gained significant prominence in recent years due to its wide applications in medicinal pharmacy, textile, tissue engineering and in various drug delivery system. In oral drug delivery system (DDS), nanofibers can be delivered as Nanofiber scaffolds, electrosponge nanofibers as oral fast delivery system, multilayered nanofiber loaded mashes, surface modified cross-linked electrospun nanofibers. Nanofibers are of 50- 1000 nm size fibres having large surface area, high porosity, small pore size, low density. Various approaches for formulation of nanofibers are molecular assembly, thermally induced phase separation, electrospining. Most commonly used by using electrospining polymer nanofibres with different range can be produced collective usage of electro spinning with pharmaceutical polymers offers novel tactics for developing drug delivery system (DDS). Different polymers used in preparation of nanofibers include biodegradable hydrophilic polymers, hydrophobic polymers and amphiphilic polymers. Electrospun nanofibers are often used to load insoluble drugs for enhancing their dissolution properties due to their high surface area per unit mass. Besides the water insoluble drugs freely water soluble sodium can also spun into the fibers. The most commonly polymers used for nanofibers are gelatin, dextran, nylon, polystyrene, polyacrylonitrile, polycarbonate, polyimides, poly vinyl alchol, polybenzimidazole. Delivery systems reviewed rely on temporal control, changes in pH along the GIT, the action of local enzymes to trigger drug release, and changes in intraluminal pressure. Dissolution of enteric polymer coatings due to a change in local pH and reduction of azo-bonds to release an active agent are both used in commercially marketed products. In vitro and in vivo studies have demonstrated that the release rates of drugs from these nanofiber formulations are enhanced compared to those from original drug substance. This review is focused on the different type of polymers used, different used in the preparation of nanofibers, cytotoxicity studies and application of nanofiber by using oral drug delivery. PMID- 25732660 TI - Nanofibers based tissue engineering and drug delivery approaches for myocardial regeneration. AB - Human heart has endogenous regenerative capability; however, the intrinsic repair mechanism is not sufficient to overcome the impact placed by adverse pathological conditions, such as myocardial infarction (MI). In such circumstances, the damaged tissue initiates a series of remodeling process which results in the deterioration of structural, functional, and mechanical properties of the myocardium. To address such adverse conditions, clinical approaches ranging from surgical interventions, pharmaceutical drugs, and device implantation are administered which have played significant role in reducing the mortality rate. However, these approaches do not replace the lost cardiomyocytes, or restore the degraded structure-function relationship of the myocardium. In this aspect, cell based therapy has gained substantial interest as a potential clinical approach for myocardial regeneration; however this method is impeded by lower graft retention and poor cell viability. To overcome these limitations, biomaterials are being developed as "trojan horses", i.e., vehicles for homing and deploying cells, and as matrices for delivering specific biological, mechanical, and chemical cues intended for tissue regeneration. Similarly, several candidate drugs, potent synthetic and biological molecules, and advanced drug delivery systems are being examined to provide exogenous cues in a controlled fashion to the diseased myocardium. In this article, we review biomaterials-based drug delivery systems for myocardial regeneration, specifically on the applications of hydrogels, microgels, nanoparticles, and nanofibers in the field. The prime focus of the article is on nanofibers-based drug delivery systems that is gaining considerable attention as a biomimetic pharmacological approach. We highlight literature on fabrication methods of self-assembling and electrospun nanofibers, drug incorporation methods and release kinetics, and in vitro and in vivo outcomes from nanofiber-based drug delivery systems in cardiac regeneration. PMID- 25732661 TI - Controlled Bioactive Molecules Delivery Strategies for Tendon and Ligament Tissue Engineering using Polymeric Nanofibers. AB - The interest in polymeric nanofibers has escalated over the past decade given its promise as tissue engineering scaffolds that can mimic the nanoscale structure of the native extracellular matrix. With functionalization of the polymeric nanofibers using bioactive molecules, localized signaling moieties can be established for the attached cells, to stimulate desired biological effects and direct cellular or tissue response. The inherently high surface area per unit mass of polymeric nanofibers can enhance cell adhesion, bioactive molecules loading and release efficiencies, and mass transfer properties. In this review article, the application of polymeric nanofibers for controlled bioactive molecules delivery will be discussed, with a focus on tendon and ligament tissue engineering. Various polymeric materials of different mechanical and degradation properties will be presented along with the nanofiber fabrication techniques explored. The bioactive molecules of interest for tendon and ligament tissue engineering, including growth factors and small molecules, will also be reviewed and compared in terms of their nanofiber incorporation strategies and release profiles. This article will also highlight and compare various innovative strategies to control the release of bioactive molecules spatiotemporally and explore an emerging tissue engineering strategy involving controlled multiple bioactive molecules sequential release. Finally, the review article concludes with challenges and future trends in the innovation and development of bioactive molecules delivery using polymeric nanofibers for tendon and ligament tissue engineering. PMID- 25732662 TI - Scaffold-based Drug Delivery for Cartilage Tissue Regeneration. AB - Regenerative engineering is an advanced field comprising the collective benefit of biodegradable polymers with cells and tissue inducing factors. Current method of replacing the defective organ is through transplantation, but is limited due to immune rejection and availability. As a solution, new polymeric biomaterial based three-dimensional (3D) scaffolds in combination with cells and inducing factors were aroused to fulfil the existing demands. These scaffolds apply material science, biomedical technology and translational medicine to develop functional tissue engineering constructs. Presence of small molecules and growth factors guides the cell phenotypes to specific organ development. The 3D scaffold thus could also be favorably used as carriers for various types of drugs and genes, with the release profile fine-tuned by modulation of the scaffold's morphology, porosity, and composition. An increasing trend was observed in recent years toward the combination of scaffolds and growth factors to fabricate a bioactive system, which not only provide a biomimetic biodegradable physical support for tissue growth but also explores biological signals to modulate tissue regeneration. In this review, along with general aspects of tissue engineering, we also discuss the importance of various scaffold architectures like nanofibers, hydrogels, beads, meshes, microspheres etc. in combination with specific drugs, growth factors and small molecules for cartilage regeneration. Growth factors may be incorporated into scaffolds by direct blending, physical adsorption, drop casting, surface grafting, covalent bonding, chemical immobilization, coaxial electrospinning, microparticle incorporation etc. This offers new possibilities for the development of biomimetic scaffolds that are endowed with a hierarchical architecture and sophisticated release kinetics of the growth factors. This review portrait the fundamentals of tissue engineering with emphasis on the role of inducing factors in scaffold based cartilage tissue regeneration. PMID- 25732663 TI - Immobilization and Application of Electrospun Nanofiber Scaffold-based Growth Factor in Bone Tissue Engineering. AB - Electrospun nanofibers have been extensively used in growth factor delivery and regenerative medicine due to many advantages including large surface area to volume ratio, high porosity, excellent loading capacity, ease of access and cost effectiveness. Their relatively large surface area is helpful for cell adhesion and growth factor loading, while storage and release of growth factor are essential to guide cellular behaviors and tissue formation and organization. In bone tissue engineering, growth factors are expected to transmit signals that stimulate cellular proliferation, migration, differentiation, metabolism, apoptosis and extracellular matrix (ECM) deposition. Bolus administration is not always an effective method for the delivery of growth factors because of their rapid diffusion from the target site and quick deactivation. Therefore, the integration of controlled release strategy within electrospun nanofibers can provide protection for growth factors against in vivo degradation, and can manipulate desired signal at an effective level with extended duration in local microenvironment to support tissue regeneration and repair which normally takes a much longer time. In this review, we provide an overview of growth factor delivery using biomimetic electrospun nanofiber scaffolds in bone tissue engineering. It begins with a brief introduction of different kinds of polymers that were used in electrospinning and their applications in bone tissue engineering. The review further focuses on the nanofiber-based growth factor delivery and summarizes the strategies of growth factors loading on the nanofiber scaffolds for bone tissue engineering applications. The perspectives on future challenges in this area are also pointed out. PMID- 25732664 TI - Drug-incorporated electrospun fibers efficiently prevent postoperative adhesion. AB - Postoperative adhesion (POA) is a serious event that always causes chronic pain and functional obstruction. Up to now, a variety of matrices prepared by diverse technologies have been employed as the physical barriers to prevent POA. Among them, the electrospun fibers of biodegradable polymers exhibit more obvious advantages, such as large surface area, high porosity, and excellent anti adhesion efficiency. However, the pure electrospun fibers for anti-adhesion cannot effectively regulate the cellular behaviors, and tissue inflammation and healing. In recent years, the polymeric electrospun fibers loaded with various drugs, such as antimicrobial agents, antiinflammatory drugs, and healing accelerators, have been developed. The advanced anti-adhesion fibers play a more efficient role in the field of anti-adhesion, which can efficiently prevent POA and infection, tamp down inflammation, and promote the recovery of tissue function after surgery. This review highlights the recent development of anti adhesion electrospun fibers loaded with various drugs, and presents the possible prospects. PMID- 25732666 TI - Nanofibers based antibacterial drug design, delivery and applications. AB - Infections caused by microorganisms like bacteria, fungi, etc. are the main obstacle in healing processes. Conventional antibacterial administration routes can be listed as oral, intravenous/intramuscular, topical and inhalation. These kinds of drug administrations are faced with critical vital issues such as; more rapid delivery of the drug than intended which can result in bacterial resistance, dose related systemic toxicity, tissue irritation and finally delayed healing process that need to be tackled. Recently, studies have been focused on new drug delivery systems, overcoming resistance and toxicological problems and finally localizing the molecules at the site of action in a proper dose. In this regard, many nanotechnological approaches such as nanoparticulate therapeutic systems have been developed to address accompanying problems mentioned above. Among them, drug loaded electrospun nanofibers propose main advantages like controlled drug delivery, high drug loading capacity, high encapsulation efficiency, simultaneous delivery of multiple drugs, ease of production and cost effectiveness for pharmaceutical and biomedical applications. Therefore, some particular attention has been devoted to the design of electrospun nanofibers as promising antibacterial drug carrier systems. A variety of antibacterials e.g., biocides, antibiotics, quaternary ammonium salts, triclosan, metallic nanoparticles (silver, titanium dioxide, and zinc oxide) and antibacterial polymers (chitosan, polyethyleneimine, etc.) have been impregnated by various techniques into nanofibers that exhibit strong antibacterial activity in standard assays. This review highlights the design and delivery of antibacterial drug loaded nanofibers with particular focus on their function in the fields of drug delivery, wound healing, tissue engineering, cosmetics and other biomedical applications. PMID- 25732665 TI - Smart electrospun nanofibers for controlled drug release: recent advances and new perspectives. AB - In biological systems, chemical molecules or ions often release upon certain conditions, at a specific location, and over a desired period of time. Electrospun nanofibers that undergo alterations in the physicochemical characteristics corresponding to environmental changes have gained considerable interest for various applications. Inspired by biological systems, therapeutic molecules have been integrated with these smart electrospun nanofibers, presenting activation-modulated or feedback-regulated control of drug release. Compared to other materials like smart hydrogels, environment-responsive nanofiber-based drug delivery systems are relatively new but possess incomparable advantages due to their greater permeability, which allows shorter response time and more precise control over the release rate. In this article, we review the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. We also illustrate several typical examples in specific applications. We conclude this article with a discussion on perspectives and future possibilities in this field. PMID- 25732667 TI - Anti-cancer cytotoxic effects of multiwalled carbon nanotubes. AB - Recent research has opened new alternatives to traditional chemotherapy treatments using nanomaterials as cytotoxic agents. Anti-cancer nanomedicines do not require specific target sites on key proteins or genes to kill cancer cells and have radically different mechanisms to interact with the living matter. Among 1D nanomaterials, multiwalled carbon nanotubes (MWCNTs) have the intrinsic ability to bind tubulin and interfere with microtubule dynamics, mimicking the effect of traditional cytotoxic microtubule-binding agents such as paclitaxel (taxol(r)). Here, we review the cytotoxic properties of MWCNTs and show a direct pro-apoptotic effect of these nanomaterials in vitro in different cancer cell lines and tumor cells obtained from surgical specimens. Understanding the bio synthetic relationship between MWCNTs and microtubules could serve to improve these nanomaterials to be used as broad spectrum antineoplastic agents in combination to traditional microtubule-binding treatments, thus avoiding drug resistance mechanisms in cancer cells. PMID- 25732668 TI - Hoarding and emotional reactivity: the link between negative emotional reactions and hoarding symptomatology. AB - Hoarding disorder (HD) is characterized by difficulty discarding, clutter, and frequently excessive acquiring. Theories have pointed to intense negative emotional reactions (e.g., sadness) as one factor that may play a critical role in HD's etiology. Preliminary work with an analogue sample indicated that more intense negative emotions following emotional films were linked with greater hoarding symptoms. Symptom provocation imaging studies with HD patients have also found evidence for excessive activation in brain regions implicated in processing emotions. The current study utilized a sample with self-reported serious hoarding difficulties to examine how hoarding symptoms related to both general and hoarding-related emotional reactivity, taking into account the specificity of these relationships. We also examined how two cognitive factors, fear of decision making and confidence in memory, modified this relationship. 628 participants with self-identified hoarding difficulties completed questionnaires about general emotional reactivity, depression, anxiety, decision-making, and confidence in memory. To assess hoarding-related emotional reactivity, participants reported their emotional reactions when imagining discarding various items. Heightened general emotional reactivity and more intense emotional reactions to imagined discarding were associated with both difficulty discarding and acquisition, but not clutter, controlling for age, gender, and co-occurring mood and anxiety symptoms. Fear of decision-making and confidence in memory interacted with general emotional reactivity to predict hoarding symptoms. These findings provide support for cognitive-behavioral models of hoarding. Experimental research should be conducted to discover whether emotional reactivity increases vulnerability for HD. Future work should also examine whether emotional reactivity should be targeted in interventions for hoarding. PMID- 25732669 TI - The risk of post-operative complications in psoriasis and psoriatic arthritis patients on biologic therapy undergoing surgical procedures. AB - BACKGROUND: There is limited evidence as to whether biologic therapy should be stopped or continued in patients with psoriasis and/or psoriatic arthritis (PsA) who are undergoing surgical procedures. Current guidelines of care recommend a planned break from biologic therapy in those undergoing major surgical procedures. OBJECTIVE: To audit current practice of managing biologic therapy peri-operatively in a tertiary referral psoriasis clinic against guidelines of care and to investigate the effects of continuing/stopping biologic therapy in psoriasis and PsA patients. METHODS: A retrospective audit of psoriasis and PsA patients who had a surgical procedure whilst on biologic therapy. A proforma was used to collect information on the biologics used, whether they were stopped peri operatively and whether patients developed post-operative complications and/or disease flare. RESULTS: A total of 42 patients who had 77 procedures were identified. Procedures ranged from skin surgery to orthopaedic and cardiothoracic surgery. Biologic therapy was continued in the majority of procedures (76%). There was no significant difference in post-operative risk of infection and delayed wound healing between those patients who continued and those who stopped biologic therapy, including those undergoing major surgery. Interrupting biologic therapy peri-operatively was associated with a significant (P = 0.003) risk of flare of psoriasis or PsA. CONCLUSION: Continuing biologic therapy in psoriasis and PsA patients peri-operatively did not increase the risk of post-operative complications. Interrupting biologic therapy peri-operatively significantly increased the risk of disease flare. This study is limited by cohort size and requires replication, ideally in a prospective randomized controlled manner. PMID- 25732670 TI - Bortezomib plus dexamethasone results in a late organ response in primary heavy chain amyloidosis without a hematologic response. PMID- 25732671 TI - Cancer care in Jordan. AB - Cancer is the second leading cause of death in Jordan after cardiovascular diseases. Due to increase in life expectancy and prolonged exposure to risk factors, cancer mortality and morbidity are expected to increase as the young population ages. This increase will constitute a challenging burden on healthcare systems in Jordan and many other neighboring countries. Planning is key to managing the expected rise in the demand for cancer care, and this will require public health initiatives to guarantee access to quality cancer care. Over the past decade, cancer care in Jordan has witnessed remarkable improvement through access to advanced diagnostics and therapeutics. In this review, we address the history of cancer care in Jordan, including cancer statistics, infrastructure, workforce as well as cancer care outcomes. We also discuss many of the challenges that we face and offer suggestions for the improvement of cancer management in Jordan and the region. PMID- 25732672 TI - Non-NMDAR neuronal Ca(2+)-permeable channels in delayed neuronal death and as potential therapeutic targets for ischemic brain damage. AB - INTRODUCTION: Transient cerebral ischemia represents the most common cause of complex chronic disability in adults due to delayed neuronal death as a result of aberrant post-ischemic increases in the [Ca(2+)]c and [Zn(2+)]c. A number of Ca(2+)-permeable channels are engaged in transient ischemia-induced neuronal death. AREAS COVERED: In this review, the authors discuss the GluA2-lacking AMPARs, acid-sensing ion channel 1a, melastatin-related transient receptor potential 2 (TRPM2), TRPM7 and store-operated Ca(2+) channels expressed in ischemia-vulnerable neurons, and focus on the studies using in vitro and in vivo models of transient ischemia that supports a significant role for these channels in inducing increases in the [Ca(2+)]c and/or [Zn(2+)]c and delayed neuronal death, and their potential as therapeutic targets. EXPERT OPINION: Non-NMDAR Ca(2+)-permeable channels are important mechanisms mediating delayed neuronal death and cognitive dysfunctions after transient ischemia. Identification of such Ca(2+)-permeable channels significantly improves our understanding of the molecular events leading to ischemic brain damage and provides promising novel targets for post-ischemic therapeutics treating ischemic brain damage. PMID- 25732673 TI - High counts of carbapenemase-producing Enterobacteriaceae in hospital sewage. PMID- 25732674 TI - The experience of regret and the self-relevant emotions in autism spectrum disorders: a reply to Nicolle et al. PMID- 25732675 TI - CT angiography and magnetic resonance angiography findings after surgical and interventional radiology treatment of peripheral arterial obstructive disease. AB - In the last years, technical innovations in the field of CT angiography (CTA) and magnetic resonance angiography (MRA) have allowed accurate and highly detailed evaluation of peripheral vascular pathologies. This has dramatically changed the diagnostic approach in treatment planning of peripheral arterial obstructive disease and also enabling early identification of treatment failure or treatment related complications after surgical or endovascular procedures. Although Doppler Ultrasound is the first-line imaging modality during follow-up after treatment, its role is currently diminishing in importance mostly because of the proliferation of high-end CT and MR scanners capable of fast, reproducible, and highly reliable vascular imaging. The aim of this study is to review the various surgical and endovascular procedures for peripheral arterial obstructive disease and to provide CTA and MRA samples of common and uncommon complications related to treatment. PMID- 25732676 TI - Left atrial drainage of the great cardiac vein. AB - Coronary venous anomaly is a less studied and rarely encountered subject in contrast to the coronary arterial system. In this article, we present 2 cases of anomalous great cardiac veins that drain into the left atrium individually. PMID- 25732678 TI - The right atrium, a forgotten cardiac chamber: An updated review of multimodality imaging. AB - Despite several limitations, two-dimensional echocardiography (2DE) is the standard method for assessing the right atrium (RA) in everyday clinical routine. Cardiac magnetic resonance remains the current "gold standard" for RA visualization and volume quantification. The development of 2DE-derived strain imaging has enabled assessing RA deformation and phasic function in various pathologic conditions. Three-dimensional echocardiography was demonstrated to be more accurate and reproducible than 2DE for cardiac chamber quantification, while also allowing the evaluation of RA phasic function without geometric assumption. The purpose of this review is to summarize currently available data about RA anatomy, phasic function, and mechanics acquired by different imaging modalities. PMID- 25732677 TI - Heparanase activates the syndecan-syntenin-ALIX exosome pathway. AB - Exosomes are secreted vesicles of endosomal origin involved in signaling processes. We recently showed that the syndecan heparan sulfate proteoglycans control the biogenesis of exosomes through their interaction with syntenin-1 and the endosomal-sorting complex required for transport accessory component ALIX. Here we investigated the role of heparanase, the only mammalian enzyme able to cleave heparan sulfate internally, in the syndecan-syntenin-ALIX exosome biogenesis pathway. We show that heparanase stimulates the exosomal secretion of syntenin-1, syndecan and certain other exosomal cargo, such as CD63, in a concentration-dependent manner. In contrast, exosomal CD9, CD81 and flotillin-1 are not affected. Conversely, reduction of endogenous heparanase reduces the secretion of syntenin-1-containing exosomes. The ability of heparanase to stimulate exosome production depends on syntenin-1 and ALIX. Syndecans, but not glypicans, support exosome biogenesis in heparanase-exposed cells. Finally, heparanase stimulates intraluminal budding of syndecan and syntenin-1 in endosomes, depending on the syntenin-ALIX interaction. Taken together, our findings identify heparanase as a modulator of the syndecan-syntenin-ALIX pathway, fostering endosomal membrane budding and the biogenesis of exosomes by trimming the heparan sulfate chains on syndecans. In addition, our data suggest that this mechanism controls the selection of specific cargo to exosomes. PMID- 25732679 TI - An under-recognized influenza epidemic identified by rapid influenza testing, southern Sri Lanka, 2013. AB - Influenza accounts for a large burden of acute respiratory tract infections in high-income countries; data from lower-income settings are limited due to lack of confirmatory testing. Consecutive outpatients presenting to the largest tertiary care hospital in southern Sri Lanka were surveyed for influenza-like illness (ILI), defined as acute onset of fever >= 38.0 degrees C and cough. Patients were administered a questionnaire and nasal/nasopharyngeal sampling for rapid influenza A/B testing. We enrolled 311 patients with ILI from March to November 2013: 170 (54.7%) children and 172 (55.3%) males. Approximately half (147, 47.3%) tested positive for influenza, but 253 (81.4%) were prescribed antibiotics. On bivariable analysis, symptoms associated with influenza included pain with breathing (P < 0.001), headache (P = 0.005), fatigue (P = 0.003), arthralgias (P = 0.003), and myalgias (P = 0.006) in children and pain with breathing (P = 0.01), vomiting (P = 0.03), and arthralgias (P = 0.03) in adults. Our final clinical predictive models had low sensitivity and fair specificity-50.0% (95% CI: 38.6-61.4%) and 83.2% (95% CI: 73.4-90.0%), respectively, in children and 52.2% (95% CI: 39.9-64.2%) and 81.4% (95% CI: 70.0-89.4%), respectively, in adults. Our study confirms the ability of rapid influenza testing to identify an influenza epidemic in a setting in which testing is not routinely available. PMID- 25732680 TI - A review of mosquitoes associated with Rift Valley fever virus in Madagascar. AB - Rift Valley fever (RVF) is a viral zoonotic disease occurring throughout Africa, the Arabian Peninsula, and Madagascar. The disease is caused by a Phlebovirus (RVF virus [RVFV]) transmitted to vertebrate hosts through the bite of infected mosquitoes. In Madagascar, the first RVFV circulation was reported in 1979 based on detection in mosquitoes but without epidemic episode. Subsequently, two outbreaks occurred: the first along the east coast and in the central highlands in 1990 and 1991 and the most recent along the northern and eastern coasts and in the central highlands in 2008 and 2009. Despite the presence of 24 mosquitoes species potentially associated with RVFV transmission in Madagascar, little associated entomological information is available. In this review, we list the RVFV vector, Culex antennatus, as well as other taxa as candidate vector species. We discuss risk factors from an entomological perspective for the re-emergence of RVF in Madagascar. PMID- 25732681 TI - Geographic variation of female genital mutilation and legal enforcement in sub Saharan Africa: a case study of Senegal. AB - This paper draws on household data to examine the prevalence of female genital mutilation (FGM) in Senegal and the effectiveness of the country's anti-FGM law in dealing with actual breaches and providing protection to the victims. The 2010 2011 Senegal Demographic Health Survey and Multiple Indicators Cluster Survey (SDHS-MICS) covers 14,228 women and their daughters. Logistic regression was used to investigate the geographic distribution of FGM across regions. For the enforceability of anti-FGM, desk research was used. Overall prevalence among women and daughters was 28.1% and 6.2%, respectively. Significant factors were sociodemographics, ethnicity, and region. This analysis shows both advantages and vulnerabilities of the anti-FGM law in relation to the issue of enforcement. It indicates that the law falls short of offering adequate protection to potential victims. FGM is a cultural and social norm imbedded predominantly in rural settings and as such, drives resistance to jettisoning FGM. Legislation has been one of the driving forces behind the eradication of the practice. PMID- 25732682 TI - Identifying the most sensitive and specific sign and symptom combinations for cholera: results from an analysis of laboratory-based surveillance data from Haiti, 2012-2013. AB - Since October 2010, over 700,000 cholera cases have been reported in Haiti. We used data from laboratory-based surveillance for diarrhea in Haiti to evaluate the sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of the cholera case definitions recommended by the World Health Organization (WHO). From April 2012 to May 2013, we tested 1,878 samples from hospitalized patients with acute watery diarrhea; 1,178 (62.7%) yielded Vibrio cholerae O1. The sensitivity and specificity of the WHO case definition for cholera in an epidemic setting were 91.3% and 43.1%, respectively, and the PPV and NPV were 72.8% and 74.8%, respectively. The WHO case definition for cholera in an area where cholera is not known to be present had lower sensitivity (63.1%) and NPV (55.1%) but higher specificity (74.2%) and PPV (80.0%). When laboratory diagnostic testing is not immediately available, clinicians can evaluate signs and symptoms to more accurately identify cholera patients. PMID- 25732683 TI - The prevalence of Blastocystis hominis and other protozoan parasites in soldiers returning from peacekeeping missions. AB - Blastocystis hominis is a common intestinal parasite found in humans living in poor sanitary conditions, living in tropical and subtropical climates, exposed to infected animals, or consuming contaminated food or water. The aim of this study was to determine the prevalence of B. hominis in Polish military personnel returning from peacekeeping missions in Iraq and Afghanistan. In total, 1,826 stool samples were examined. Gastrointestinal parasites were detected in 17% of the soldiers. The examined stool samples most frequently contained vacuolar forms of B. hominis (15.3%) and cysts of Entamoeba coli (1.0%) or Giardia lamblia (0.7%). In 97.1% of stool samples from infected soldiers, we observed less than five developmental forms of B. hominis in the field of view (40*). The parasite infections in soldiers were diagnosed in the autumn and the spring. There was no statistical correlation between age and B. hominis infection. Our results show that peacekeeping missions in countries with tropical or subtropical climates could be associated with risk for parasitic diseases, including blastocystosis. PMID- 25732684 TI - Spectrum of outpatient illness in a school-based cohort in Haiti, with a focus on diarrheal pathogens. AB - Currently, there are only limited data available on rates of major diagnostic categories of illnesses among Haitian children. We have established a cohort of 1,245 students attending schools run by the Christianville Foundation in the Gressier/Leogane region of Haiti, for whom our group provides primary medical care. Among 1,357 clinic visits during the 2012-2013 academic year, the main disease categories (with rates per 1,000 child years of observation) included acute respiratory infection (ARI) (385.6 cases/1,000 child years of observation), gastrointestinal complaints (277.8 cases/1,000 child years), febrile illness (235.0 cases/1,000 child years), and skin infections (151.7 cases/1,000 child years). The most common diarrheal pathogen was enteroaggregative Escherichia coli (present in 17% of children with diarrhea); Vibrio cholerae O1 and norovirus were the next most common. Our data highlight the importance of better defining etiologies for ARI and febrile illnesses and continuing problems of diarrheal illness in this region, including mild cases of cholera, which would not have been diagnosed without laboratory screening. PMID- 25732685 TI - Maji: a new tool to prevent overhydration of children receiving intravenous fluid therapy in low-resource settings. AB - We designed and evaluated the accuracy and usability of a device to regulate the volume of fluid dispensed during intravenous drip therapy. The mechanical system was developed in response to a pressing need articulated by clinicians in pediatric wards throughout sub-Saharan Africa, who require a tool to prevent overhydration in children receiving intravenous fluid in settings that lack burettes or electronic infusion pumps. The device is compatible with most intravenous bags and limits the volume dispensed to a preset amount that can be adjusted in 50 mL increments. Laboratory accuracy over a range of clinically relevant flow rates, initial bag volumes, and target volumes was within 12.0 mL of the target volume. The ease of use is "excellent," with a mean system usability score of 84.4 out of 100. Use of the device limits the volume of fluid dispensed during intravenous therapy and could potentially reduce the morbidity and mortality associated with overhydration in children receiving intravenous therapy. PMID- 25732686 TI - The NHS Health Check programme: insights from a qualitative study of patients. AB - OBJECTIVE: To provide an insight into the process of patients receiving Health Checks and to determine the extent to which patients were supported to reduce the risks of developing cardiovascular disease through behaviour change. METHODS: Semi-structured qualitative interviews were undertaken with 45 patients about their initial experiences of undertaking a Health Check. They were followed up 1 year later to assess whether the behavioural changes reported after the Health Check had been maintained. RESULTS: Patients expressed a need for individualized support in order to stay motivated and to adopt long-term diet and lifestyle changes. CONCLUSIONS: Those involved in the delivery of the programme need to adopt a consistent approach in terms of explaining the purpose of the Health Check, communicating risk and consider the challenges and the barriers that influence behaviour change. PMID- 25732687 TI - On-chip graphene oxide aptasensor for multiple protein detection. AB - The versatility of an on-chip graphene oxide (GO) aptasensor was successfully confirmed by the detection of three different proteins, namely, thrombin (TB), prostate specific antigen (PSA), and hemagglutinin (HA), simply by changing the aptamers but with the sensor composition remaining the same. The results indicate that both DNA and RNA aptamers immobilized on the GO surface are sufficiently active to realize an on-chip aptasensor. Molecular selectivity and concentration dependence were investigated in relation to TB and PSA detection by using a dual, triple, and quintuple microchannel configuration. The multiple target detection of TB and PSA on a single chip was also demonstrated by using a 2*3 linear-array GO aptasensor. This work enables us to apply this sensor to the development of a multicomponent analysis system for a wide variety of targets by choosing appropriate aptamers. PMID- 25732688 TI - Fourier transform infrared imaging and microscopy studies of Pinus radiata pulps regarding the simultaneous saccharification and fermentation process. AB - The distribution and chemical patterns of lignocellulosic components at microscopic scale and their effect on the simultaneous saccharification and fermentation process (SSF) in the production of bioethanol from Pinus radiata pulps were analyzed by the application of diverse microscopical techniques, including scanning electronic microscopy (SEM), confocal laser scanning microscopy (CLSM) and attenuated total reflectance (ATR) - Fourier transform infrared microspectroscopy. This last technique was accompanied with multivariate methods, including principal component analysis (PCA) and multivariate curve resolution with alternating least squares (MCR-ALS) to evaluate the distribution patterns and to generate pure spectra of the lignocellulosic components of fibers. The results indicate that the information obtained by the techniques is complementary (ultrastructure, confocality and chemical characterization) and that the distribution of components affects the SSF yield, identifying lignin coalescence droplets as a characteristic factor to increase the SSF yield. Therefore, multivariate analysis of the infrared spectra enabled the in situ identification of the cellulose, lignin and lignin-carbohydrates arrangements. These techniques could be used to investigate the lignocellulosic components distribution and consequently their recalcitrance in many applications where minimal sample manipulation and microscale chemical information is required. PMID- 25732689 TI - Determination of mercury species by the diffusive gradient in thin film technique and liquid chromatography--atomic fluorescence spectrometry after microwave extraction. AB - A diffusive gradient in thin films technique (DGT) was combined with liquid chromatography (LC) and cold vapor atomic fluorescence spectrometry (CV-AFS) for the simultaneous quantification of four mercury species (Hg(2+), CH3Hg(+), C2H5Hg(+), and C6H5Hg(+)). After diffusion through an agarose diffusive layer, the mercury species were accumulated in resin gels containing thiol functionalized ion-exchange resins (Duolite GT73, and Ambersep GT74). A microwave assisted extraction (MAE) in the presence of 6M HCl and 5 M HCl (55 degrees C, 15 min) was used for isolation of mercury species from Ambersep and Duolite resin gels, respectively. The extraction efficiency was higher than 95.0% (RSD 3.5%). The mercury species were separated with a mobile phase containing 6.2% methanol+0.05% 2-mercaptoethanol+0.02 M ammonium acetate with a stepwise increase of methanol content up to 80% in the 16th min on a Zorbax C18 reverse phase column. The LODs of DGT-MAE-LC-CV-AFS method were 38 ng L(-1) for CH3Hg(+), 13 ng L(-1) for Hg(2+), 34 ng L(-1) for C2H5Hg(+) and 30 ng L(-1) for C6H5Hg(+) for 24 h DGT accumulation at 25 degrees C. PMID- 25732690 TI - Effectively designed molecularly imprinted polymers for selective isolation of the antidiabetic drug metformin and its transformation product guanylurea from aqueous media. AB - In the present study, two novel molecularly imprinted polymers (MIPs) with remarkable recognition properties for metformin and its transformation product, guanylurea, have been prepared for their selective, enrichment, isolation and removal from aqueous media. The prepared adsorbents were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and swelling experiments. The performance of the prepared MIPs was evaluated by various parameters including the influence of pH, contact time, temperature and initial compound concentration. The effects on the adsorption behavior of the removal process parameters were studied and the equilibrium data were fitted by the Langmuir and Freundlich models. Due to the imprinting effect, adsorption performance of MIPs was always superior to its corresponding NIP (non-imprinted polymer), with maximum adsorption capacity ~80 mg g(-1) for both MIPs. Stability and reusability of the MIPs up to the 5th cycle meant that they could be applied repeatedly without losing substantial removal ability. In the next step, the prepared MIP nanoparticles were evaluated as sorbents in a dispersive solid phase extraction (D-SPE) configuration for selective enrichment and determination of metformin and guanylurea in different aqueous matrices. Under the working extraction conditions, the D-SPE method showed good linearity in the range of 50 1000 ng L(-1), repeatability of the extractions (RSD 2.1-5.1%, n=3), and low limits of detection (1.5-3.4 ng L(-1)). The expanded uncertainty of the data obtained was estimated following a bottom-up approach. The proposed method combined the advantages of MIPs and D-SPE, and it could become an alternative tool for analyzing the residues of METF and its transformation product GUA in complex water matrices, such as wastewaters. PMID- 25732691 TI - Determination of 13 endocrine disrupting chemicals in sediments by gas chromatography-mass spectrometry using subcritical water extraction coupled with dispersed liquid-liquid microextraction and derivatization. AB - In this study, a sample pretreatment method was developed for the determination of 13 endocrine disrupting chemicals (EDCs) in sediment samples based on the combination of subcritical water extraction (SWE) and dispersed liquid-liquid microextraction (DLLME). The subcritical water that provided by accelerated solvent extractor (ASE) was the sample solution (water) for the following DLLME and the soluble organic modifier that spiked in the subcritical water was also used as the disperser solvent for DLLME in succession. Thus, several important parameters that affected both SWE and DLLME were investigated, such as the extraction solvent for DLLME (chlorobenzene), extraction time for DLLME (30s), selection of organic modifier for SWE (acetone), volume of organic modifier (10%) and extraction temperature for SWE (150 degrees C). In addition, good chromatographic behavior was achieved for GC-MS after derivatisation by using N,O bis(trimethylsilyl) trifluoroacetamide (BSTFA). As a result, proposed method sensitive and reliable with the limits of detection (LODs) ranging from 0.006 ng g(-1) (BPA) to 0.639 ng g(-1) (19-norethisterone) and the relative standard deviations (RSDs) between 1.5% (E2) and 15.0% (DES). Moreover, the proposed method was compared with direct ASE extraction that reported previously, and the results showed that SWE-DLLME was more promising with recoveries ranging from 42.3% (dienestrol) to 131.3% (4,5alpha-dihydrotestosterone), except for diethylstilbestrol (15.0%) and nonylphenols (29.8%). The proposed method was then successfully applied to determine 13 EDCs sediment of Humen outlet of the Pearl River, 12 of target compounds could be detected, and 10 could be quantitative analysis with the total concentration being 39.6 ng g(-1), and which indicated that the sediment of Humen outlet was heavily contaminated by EDCs. PMID- 25732692 TI - Comprehensive characterization of natural organic matter by MALDI- and ESI Fourier transform ion cyclotron resonance mass spectrometry. AB - Natural organic matter (NOM) is a complex and non-uniform mixture of organic compounds which plays an important role in environmental processes. Due to the complexity, it is challenging to obtain fully detailed structural information about NOM. Although Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) has been demonstrated to be a powerful tool for providing molecular information about NOM, multiple ionization methods are needed for comprehensive characterization of NOM at the molecular level considering the ionizing selectivity of different ionization methods. This paper reports the first use of matrix assisted laser desorption/ionization (MALDI) method coupled with FT-ICR-MS for molecular characterization of NOM within a mass range of 200-800 Da. The mass spectral data obtained by MALDI were systematically compared with data generated by electrospray ionization (ESI). It showed that complementary molecular information about NOM which could not be detected by ESI, were provided by MALDI. More unsaturated and aromatic constituents of NOM with lower O/C ratio (O/C ratio<0.5) were preferentially ionized in MALDI negative mode, whereas more polar constituents of NOM with higher O/C ratio were preferentially ionized in ESI negative mode. Molecular anions of NOM appearing at even m/z in MALDI negative ion mode were detected. The results show that NOM molecules with aromatic structures, moderate O/C ratio (0.7>O/C ratio>0.25) and lower H/C ratio were liable to form molecular anions at even m/z, whereas those with higher H/C ratio are more likely to form deprotonated ions at odd m/z. It is speculated that almost half of the NOM molecules identified by MALDI may be aromatic or condensed aromatic compounds with special groups which are liable to absorb electron from other molecules to generate free radical anions during MALDI ionization. PMID- 25732693 TI - Quantitative analysis of N-glycans from human alfa-acid-glycoprotein using stable isotope labeling and zwitterionic hydrophilic interaction capillary liquid chromatography electrospray mass spectrometry as tool for pancreatic disease diagnosis. AB - In this work we demonstrate the potential of glycan reductive isotope labeling (GRIL) using [(12)C]- and [(13)C]-coded aniline and zwitterionic hydrophilic interaction capillary liquid chromatography electrospray mass spectrometry (MUZIC HILIC-ESI-MS) for relative quantitation of glycosylation variants in selected glycoproteins present in samples from cancer patients. Human alpha1-acid glycoprotein (hAGP) is an acute phase serum glycoprotein whose glycosylation has been described to be altered in cancer and chronic inflammation. However, it is not clear yet whether some particular glycans in hAGP can be used as biomarker for differentiating between these two pathologies. In this work, hAGP was isolated by immunoaffinity chromatography (IAC) from serum samples of healthy individuals and from those suffering chronic pancreatitis and different stages of pancreatic cancer, respectively. After de-N-glycosylation, relative quantitation of the hAGP glycans was carried out using stable isotope labeling and MUZIC-HILIC ESI-MS analysis. First, protein denaturing conditions prior to PNGase F digestion were optimized to achieve quantitative digestion yields, and the reproducibility of the established methodology was evaluated with standard hAGP. Then, the proposed method was applied to the analysis of the clinical samples (control vs. pathological). Pancreatic cancer samples clearly showed an increase in the abundance of fucosylated glycans as the stage of the disease increases and this was unlike to samples from chronic pancreatitis. The results gained here indicate the mentioned glycan in hAGP as a candidate structure worth to be corroborated by an extended study including more clinical cases; especially those with chronic pancreatitis and initial stages of pancreatic cancer. Importantly, the results demonstrate that the presented methodology combining an enrichment of a target protein by IAC with isotope coded relative quantitation of N-glycans can be successfully used for targeted glycomics studies. The methodology is assumed being suitable as well for other such studies aimed at finding novel cancer associated glycoprotein biomarkers. PMID- 25732694 TI - One-pot electrochemical synthesis of functionalized fluorescent carbon dots and their selective sensing for mercury ion. AB - We propose a simple, economical, and one-pot method to synthesize water-soluble functionalized fluorescent carbon dots (C-Dots) through electrochemical carbonization of sodium citrate and urea. The as-prepared C-Dots have good photostability and exhibit a high quantum yield of 11.9%. The sizes of the C-Dots are mainly distributed in the range of 1.0-3.5 nm with an average size of 2.4 nm. It has been further used as a novel label-free sensing probe for selective detection of Hg(2+) ions with detection limit as low as 3.3 nM. The detection linear range is 0.01-10 MUM. The as-prepared C-Dots are also successfully applied for the determination of Hg(2+) in real water samples. PMID- 25732695 TI - Highly selective and sensitive paper-based colorimetric sensor using thiosulfate catalytic etching of silver nanoplates for trace determination of copper ions. AB - A novel, highly selective and sensitive paper-based colorimetric sensor for trace determination of copper (Cu(2+)) ions was developed. The measurement is based on the catalytic etching of silver nanoplates (AgNPls) by thiosulfate (S2O3(2-)). Upon the addition of Cu(2+) to the ammonium buffer at pH 11, the absorption peak intensity of AuNPls/S2O3(2-) at 522 nm decreased and the pinkish violet AuNPls became clear in color as visible to the naked eye. This assay provides highly sensitive and selective detection of Cu(2+) over other metal ions (K(+), Cr(3+), Cd(2+), Zn(2+), As(3+), Mn(2+), Co(2+), Pb(2+), Al(3+), Ni(2+), Fe(3+), Mg(2+), Hg(2+) and Bi(3+)). A paper-based colorimetric sensor was then developed for the simple and rapid determination of Cu(2+) using the catalytic etching of AgNPls. Under optimized conditions, the modified AgNPls coated at the test zone of the devices immediately changes in color in the presence of Cu(2+). The limit of detection (LOD) was found to be 1.0 ng mL(-1) by visual detection. For semi quantitative measurement with image processing, the method detected Cu(2+) in the range of 0.5-200 ng mL(-1)(R(2)=0.9974) with an LOD of 0.3 ng mL(-1). The proposed method was successfully applied to detect Cu(2+) in the wide range of real samples including water, food, and blood. The results were in good agreement according to a paired t-test with results from inductively coupled plasma-optical emission spectrometry (ICP-OES). PMID- 25732696 TI - A sensitive fluorescence turn-on assay of bleomycin and nuclease using WS2 nanosheet as an effective sensing platform. AB - As an important antitumor drug, bleomycin (BLM) is widely used in the treatment of a variety of cancers. In addition, nucleases play a crucial role in DNA replication, recombination and repair which are associated with cancer development. Thus, the development of BLM and nuclease detection methods is of great significance in cancer therapy and related biological mechanism research. Here, a WS2 nanosheet-based turn-on fluorescent sensing platform for simple, fast and sensitive detection of BLM and nuclease was reported. WS2 nanosheet exhibits different affinity toward ssDNA with different length and excellent fluorescence quenching ability. A fluorescein (FAM)-labeled long ssDNA could be adsorbed on the surface of WS2 nanosheet and the fluorescence was therefore quenched. In the presence of BLM.Fe(II) or S1 nuclease (a ssDNA-specific nuclease which was used as a model enzyme), an irreversible scission of long ssDNA was underwent through the BLM-induced oxidation cleavage or S1 nuclease-induced enzymatic hydrolysis. Short FAM-linked oligonucleotide fragments which could not be adsorbed on the nanosheet surface were then produced, resulting in a weak fluorescence quenching after mixing WS2 nanosheets. Thus, the fluorescence signal was restored. The proposed sensor displays a wide linear range and a high sensitivity with a detection limit of 0.3 nM for BLM and 0.01 U mL(-1) for S1 nuclease. It also exhibits a good performance in complex biological samples. This method not only provides a strategy for BLM or S1 nuclease assay but also offers a potential application in biomedical and clinical study. PMID- 25732697 TI - Ultrasensitive analysis of lysergic acid diethylamide and its C-8 isomer in hair by capillary zone electrophoresis in combination with a stacking technique and laser induced fluorescence detection. AB - This article deals with the development and validation of a novel capillary zone electrophoresis (CZE) with laser induced fluorescence detection method for the analysis of lysergic acid diethylamide (LSD) and its isomer iso-LSD in hair samples. The separation of both analytes has been achieved in less than 13 min in a 72-cm effective length capillary with 75-MUm internal diameter. As running buffer 25 mM citrate, pH 6.0 has been employed and separation temperature and voltage of 20 degrees C and 13 kV respectively, were applied. Field amplified sample injection (FASI) has been employed for on-line sample preconcentration, using ultrapure water containing 117 MUM H3PO4 as optimum injection medium. Injection voltage and time have been optimized by means of experimental design, obtaining values of 7 kV and 15s, respectively. Methylergonovine has been employed as internal standard in order to compensate irreproducibility from electrokinetic injection. The analytical method has been applied to hair samples, previous extraction of the target analytes by ultrasound assisted solid-liquid extraction at 40 degrees C for 2.5 h, employing acetonitrile as extracting solvent. Linear responses were found for LSD and iso-LSD in matrix-matched calibrations from around 0.400 up to 50.0 pg mg(-1). LODs (3 S/N) in the order of 0.100 pg mg(-1) were calculated for both analytes, obtaining satisfactory recovery percentages for this kind of sample. PMID- 25732698 TI - Recombinant bacille Calmette-Guerin coexpressing Ag85b, CFP10, and interleukin-12 elicits effective protection against Mycobacterium tuberculosis. AB - BACKGROUND: The tuberculosis (TB) pandemic remains a leading cause of human morbidity and mortality, despite widespread use of the only licensed anti-TB vaccine, bacille Calmette-Guerin (BCG). The protective efficacy of BCG in preventing pulmonary TB is highly variable; therefore, an effective new vaccine is urgently required. METHODS: In the present study, we assessed the ability of novel recombinant BCG vaccine (rBCG) against Mycobacterium tuberculosis by using modern immunological methods. RESULTS: Enzyme-linked immunospot assays demonstrated that the rBCG vaccine, which coexpresses two mycobacterial antigens (Ag85B and CFP10) and human interleukin (IL)-12 (rBCG2) elicits greater interferon-gamma (IFN-gamma) release in the mouse lung and spleen, compared to the parental BCG. In addition, rBCG2 triggers a Th1-polarized response. Our results also showed that rBCG2 vaccination significantly limits M. tuberculosis H37Rv multiplication in macrophages. The rBCG2 vaccine surprisingly induces significantly higher tumor necrosis factor-alpha (TNF-alpha) production by peripheral blood mononuclear cells that were exposed to a nonmycobacterial stimulus, compared to the parental BCG. CONCLUSION: In this study, we demonstrated that the novel rBCG2 vaccine may be a promising candidate vaccine against M. tuberculosis infection. PMID- 25732699 TI - Honey: A realistic antimicrobial for disorders of the skin. AB - Resistance of pathogenic microorganisms to antibiotics is a serious global health concern. In this review, research investigating the antimicrobial properties of honeys from around the world against skin relevant microbes is evaluated. A plethora of in vitro studies have revealed that honeys from all over the world have potent microbicidal activity against dermatologically important microbes. Moreover, in vitro studies have shown that honey can reduce microbial pathogenicity as well as reverse antimicrobial resistance. Studies investigating the antimicrobial properties of honey in vivo have been more controversial. It is evident that innovative research is required to exploit the antimicrobial properties of honey for clinical use and to determine the efficacy of honey in the treatment of a range of skin disorders with a microbiological etiology. PMID- 25732700 TI - Toxicity of fluoride to aquatic species and evaluation of toxicity modifying factors. AB - The present study was performed to investigate the toxicity of fluoride to a variety of freshwater aquatic organisms and to establish whether water quality variables contribute substantively to modifying its toxicity. Water hardness, chloride, and alkalinity were tested as possible toxicity modifying factors for fluoride using acute toxicity tests with Hyalella azteca and Oncorhynchus mykiss. Chloride appeared to be the major toxicity modifying factor for fluoride in these acute toxicity tests. The chronic toxicity of fluoride was evaluated with a variety of species, including 3 fish (Pimephales promelas, O. mykiss, and Salvelinus namaycush), 3 invertebrates (Ceriodaphnia dubia, H. azteca, and Chironomus dilutus), 1 plant (Lemna minor), and 1 alga (Pseudokirchneriella subcapitata). Hyalella azteca was the most sensitive species overall, and O. mykiss was the most sensitive species of fish. The role of chloride as a toxicity modifying factor was inconsistent between species in the chronic toxicity tests. PMID- 25732701 TI - In situ synthesis of luminescent carbon nanoparticles toward target bioimaging. AB - This paper describes the in situ synthesis of single fluorescence carbon nanoparticles (FCNs) for target bioimaging applications derived from biocompatible hyaluronic acid (HA) without using common conjugation processes. FCNs formed via the dehydration of hyaluronic acid, which were obtained by carbonizing HA, and partially carbonized HA fluorescence carbon nanoparticles (HA FCNs), formed by a lower degree of carbonization, show good aqueous solubility, small particle size (<20 nm) and different fluorescence intensities with a red shift. After confirming the cytotoxicity of HA-FCNs and FCNs, we carried out in vitro and in vivo bioimaging studies where HA-FCNs themselves functioned as single particle triggers in target imaging. The converted nanocrystal carbon particles from HA provide outstanding features for in vitro and in vivo new targeted delivery and diagnostic tools. PMID- 25732702 TI - Is synaesthesia a dominantly female trait? AB - Synaesthesia is a familial condition that gives rise to unusual secondary percepts. We present a large-scale prevalence study which informs our ideas on whether the condition is more prevalent in men or women. A number of studies over the last 20 years have suggested the condition is found more commonly in women, with up to six times more female synaesthetes than male. Other studies attributed this female bias to merely a recruitment confound: women synaesthetes may be more likely to self-refer for study. We offer two pieces of evidence that there is no extreme female bias in synaesthesia: first we re-analyse previous reports of very large female biases to show again that they likely arose from self-referral or other methodological issues. Second, we present the largest published prevalence study to date on grapheme->colour synaesthesia in which our prevalence (1.39% of the population) replicates our earlier estimates (and in which we demonstrate no strong female bias even with sufficient power to detect such a difference. PMID- 25732703 TI - Socioeconomic inequalities show remarkably poor association with health and disease in Southern Croatia. AB - OBJECTIVES: This study aimed at investigating the association of socioeconomic status and health outcomes in populations of the two remote Croatian islands and one coastal city. METHODS: Medical history and survey information were used to create 33 variables that were analysed using logistic regression. The population from the island of Vis was followed up and mortality data were used to calculate hazard ratios using Cox regression. RESULTS: Socioeconomic inequalities were poorly associated with health and disease indices. In the matrix of 33 outcome variables and 13 socioeconomic predictor classes, only 10 associations were significant at the level of P < 0.001. None of the associations was replicated across samples. We did not detect the association of any socioeconomic estimate with mortality data for the island of Vis. CONCLUSIONS: Homogenous island populations were expected to have greater levels of social homogeneity and consequently less expressed inequalities in health. The lack of stronger association in the urban population of Split is likely the result of the mechanisms that persisted from the former communist regime and high level of retained formal and informal social support. PMID- 25732704 TI - Cryopreservation of putative pre-pubertal bovine spermatogonial stem cells by slow freezing. AB - Development of techniques for the preservation of mammalian spermatogonial stem cells (SSCs) is a critical step in commercial application of SSC based technologies, including species preservation, amplification of agriculturally valuable germ lines, and human fertility preservations. The objective of this study was to develop an efficient cryopreservation protocol for preservation of bovine SSCs using a slow freezing technique. To maximize the efficiency of SSC cryopreservation, the effects of various methods (tissue vs. cell freezing) and cryoprotective agents (trehalose, sucrose, and polyethylene glycol [PEG]) were tested. Following thawing, cells were enriched for undifferentiated spermatogonia by differential plating and evaluated for recovery rate, proliferation capacity, and apoptosis. Additionally, putative stem cell activity was assessed using SSC xenotransplantation. The recovery rate, and proliferation capacity of undifferentiated spermatogonia were significantly greater for germ cells frozen using tissue freezing methods compared to cell freezing methods. Cryopreservation in the presence of 200 mM trehalose resulted in significantly greater recovery rate, proliferation capacity, and apoptosis of germ cells compared to control. Furthermore, cryopreservation using the tissue freezing method in the presence of 200 mM trehalose resulted in the production of colonies of donor-derived germ cells after xenotransplantation into recipient mouse testes, indicating putative stem cell function. Collectively, these data indicate that cryopreservation using tissue freezing methods in the presence of 200 mM trehalose is an efficient cryopreservation protocol for bovine SSCs. PMID- 25732705 TI - Importance of Contextual Factors When Measuring Work Outcome in Ankylosing Spondylitis: A Systematic Review by the OMERACT Worker Productivity Group. AB - OBJECTIVE: To review the literature on contextual factors (CoFas) and their relationship to work outcomes in individuals with ankylosing spondylitis (AS). METHODS: Articles that quantified the relationship between CoFas and employment status, sick leave, or presenteeism in individuals with AS were systematically identified. CoFas were classified into 5 domains for personal factors and 8 domains for environmental factors. We defined criteria for best-evidence synthesis for each CoFa domain based on the number of studies exploring that domain, and the quality of evidence of individual studies based on the risk of bias, adjustment of multivariable analyses for disease activity and physical function, and sample size. RESULTS: Twenty-five studies met our inclusion criteria: 20 addressed employment status, 6 examined sick leave, and 3 presenteeism. For employment, there was strong evidence for the role of age, moderate evidence for related skills/abilities, the absence of work accommodations, the nature of work and absence of workplace support, and poor evidence for the role of marital status. Evidence was insufficient for sex, education, and physical environment. For sick leave and presenteeism there were too few studies to perform a best-evidence synthesis for the role of CoFas. CONCLUSION: Using a newly proposed set of criteria for determining the best evidence of the association between CoFa domains and work outcome, the following factors emerged: age, related skills/abilities, work accommodations, nature of work, and workplace support. In addition to disease-related variables, these CoFa domains seem important to include when designing and interpreting studies on work outcomes. PMID- 25732706 TI - Identifying the threshold of iron deficiency in the central nervous system of the rat by the auditory brainstem response. AB - The deleterious effects of anemia on auditory nerve (AN) development have been well investigated; however, we have previously reported that significant functional consequences in the auditory brainstem response (ABR) can also occur as a consequence of marginal iron deficiency (ID). As the ABR has widespread clinical use, we evaluated the ability of this electrophysiological method to characterize the threshold of tissue ID in rats by examining the relationship between markers of tissue ID and severity of ABR latency defects. To generate various levels of ID, female Long-Evans rats were exposed to diets containing sufficient, borderline, or deficient iron (Fe) concentrations throughout gestation and offspring lifetime. We measured hematological indices of whole body iron stores in dams and offspring to assess the degree of ID. Progression of AN ID in the offspring was measured as ferritin protein levels at different times during postnatal development to complement ABR functional measurements. The severity of ABR deficits correlated with the level of Fe restriction in each diet. The sufficient Fe diet did not induce AN ID and consequently did not show an impaired ABR latency response. The borderline Fe diet, which depleted AN Fe stores but did not cause systemic anemia resulted in significantly increased ABR latency isolated to Peak I.The low Fe diet, which induced anemia and growth retardation, significantly increased ABR latencies of Peaks I to IV. Our findings indicate that changes in the ABR could be related to various degrees of ID experienced throughout development. PMID- 25732707 TI - Antitumor activity of a polypyridyl chelating ligand: in vitro and in vivo inhibition of glioma. AB - Glioblastoma multiforme is an extremely aggressive and invasive form of central nervous system tumor commonly treated with the chemotherapeutic drug Temozolomide. Unfortunately, even with treatment, the median survival time is less than 12 months. 2,9-Di-sec-butyl-1,10-phenanthroline (SBP), a phenanthroline based ligand originally developed to deliver gold-based anticancer drugs, has recently been shown to have significant antitumor activity in its own right. SBP is hypothesized to initiate tumor cell death via interaction with non-DNA targets, and considering most glioblastoma drugs kill tumors through DNA damage processes, SBP was tested as a potential novel drug candidate against glial-based tumors. In vitro studies demonstrated that SBP significantly inhibited the growth of rodent GL-26 and C6 glioma cells, as well as human U-87, and SW1088 glioblastomas/astrocytomas. Furthermore, using a syngeneic glioma model in mice, in vivo administration of SBP significantly reduced tumor volume and increased survival time. There was no significant toxicity toward nontumorigenic primary murine and human astrocytes in vitro, and limited toxicity was observed in ex vivo tissues obtained from noncancerous mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and recovery assays suggest that SBP induces apoptosis in gliomas. This exploratory study suggests SBP is effective in slowing the growth of tumorigenic cells in the brain while exhibiting limited toxicity to normal cells and tissues and should therefore be further investigated for its potential in glioblastoma treatment. PMID- 25732708 TI - Caspase-mediated apoptosis in the cochleae contributes to the early onset of hearing loss in A/J mice. AB - A/J and C57BL/6 J (B6) mice share a mutation in Cdh23 (ahl allele) and are characterized by age-related hearing loss. However, hearing loss occurs much earlier in A/J mice at about four weeks of age. Recent study has revealed that a mutation in citrate synthase (Cs) is one of the main contributors, but the mechanism is largely unknown. In the present study, we showed that A/J mice displayed more severe degeneration of hair cells, spiral ganglion neurons, and stria vascularis in the cochleae compared with B6 mice. Moreover, messenger RNA accumulation levels of caspase-3 and caspase-9 in the inner ears of A/J mice were significantly higher than those in B6 mice at 2 and 8 weeks of age. Immunohistochemistry localized caspase-3 expression mainly to the hair cells, spiral ganglion neurons, and stria vascularis in cochleae. In vitro transfection with Cs short hairpin RNA (shRNA) alone or cotransfection with Cs shRNA and Cdh23 shRNA significantly increased the levels of caspase-3 in an inner ear cell line (HEI-OC1). Finally, a pan-caspase inhibitor Z-VAD-FMK could preserve the hearing of A/J mice by lowering about 15 decibels of the sound pressure level for the auditory-evoked brainstem response thresholds. In conclusion, our results suggest that caspase-mediated apoptosis in the cochleae, which may be related to a Cs mutation, contributes to the early onset of hearing loss in A/J mice. PMID- 25732709 TI - Environmental implications of anaerobic digestion for manure management in dairy farms in Mexico: a life cycle perspective. AB - The environmental profile of milk production in Mexico was analysed for three manure management scenarios: fertilization (F), anaerobic digestion (AD) and enhanced anaerobic digestion (EAD). The study used the life cycle assessment (LCA) technique, considering a 'cradle-to-gate' approach. The assessment model was constructed using SimaPro LCA software, and the life cycle impact assessment was performed according to the ReCiPe method. Dairy farms with AD and EAD scenarios were found to exhibit, respectively, 12% and 27% less greenhouse gas emissions, 58% and 31% less terrestrial acidification, and 3% and 18% less freshwater eutrophication than the F scenario. A different trend was observed in the damage to resource availability indicator, as the F scenario presented 6% and 22% less damage than the EAD and AD scenarios, respectively. The magnitude of environmental damage from milk production in the three dairy manure management scenarios, using a general single score indicator, was 0.118, 0.107 and 0.081 Pt/L of milk for the F, AD and EAD scenarios, respectively. These results indicate that manure management systems with anaerobic digestion can improve the environmental profile of each litre of milk produced. PMID- 25732711 TI - Tribute to Emmet Keeffe. PMID- 25732712 TI - Primary Care Providers Report Challenges to Cirrhosis Management and Specialty Care Coordination. AB - BACKGROUND: Two-thirds of patients with cirrhosis do not receive guideline concordant liver care. Cirrhosis patients are less likely to receive recommended care when followed exclusively by primary care providers (PCPs), as opposed to specialty co-management. Little is known about how to optimize cirrhosis care delivered by PCPs. AIMS: We conducted a qualitative analysis to explore PCPs' attitudes and self-reported roles in caring for patients with cirrhosis. METHODS: We recruited PCPs from seven Veterans Affairs facilities in the Pacific Northwest via in-service trainings and direct email from March to October 2012 (n = 24). Trained staff administered structured telephone interviews covering: (1) general attitudes; (2) roles and practices; and (3) barriers and facilitators to cirrhosis management. Two trained, independent coders reviewed each interview transcript and thematically coded responses. RESULTS: Three overarching themes emerged in PCPs' perceptions of cirrhosis patients: the often overwhelming complexity of comorbid medical, psychiatric, and substance issues; the importance of patient self-management; and challenges surrounding specialty care involvement and co-management of cirrhosis. While PCPs felt they brought important skills to bear, such as empathy and care coordination, they strongly preferred to defer major cirrhosis management decisions to specialists. The most commonly reported barriers to care included patient behaviors, access issues, and conflicts with specialists. CONCLUSIONS: PCPs perceive Veterans with cirrhosis as having significant medical and psychosocial challenges. PCPs tend not to see their role as directing cirrhosis-related management decisions. Educational efforts directed at PCPs must foster PCP empowerment and improve comfort with managing cirrhosis. PMID- 25732713 TI - Hepatopulmonary Syndrome. AB - Hepatopulmonary syndrome (HPS) is a pulmonary complication observed in patients with chronic liver disease and/or portal hypertension, attributable to an intrapulmonary vascular dilatation that may induce severe hypoxemia. Microvascular dilation and angiogenesis in the lung have been identified as pathologic features that drive gas exchange abnormalities in experimental HPS. Pulse oximetry is a useful screening test for HPS, which can guide subsequent use of arterial blood gases. Contrast-enhanced echocardiography, perfusion lung scanning, and pulmonary arteriography are three currently used diagnostic imaging modalities that identify the presence of intrapulmonary vascular abnormalities. The presence of HPS increases mortality and impairs quality of life, but is reversible with liver transplantation. No medical therapy is established as effective for HPS. At the present time, liver transplantation is the only available treatment for HPS. PMID- 25732714 TI - HSPA4, the "Evil Chaperone" of the HSP Family, Delays Gastric Ulcer Healing. PMID- 25732715 TI - Association of Serotonin Transporter Promoter Polymorphism (5HTTLPR) with Microscopic Colitis and Ulcerative Colitis: Time to Be AsSERTive? PMID- 25732716 TI - GRG Profiles: Lawrence S. Friedman. PMID- 25732717 TI - Aspirin Has a Protective Effect Against Adverse Outcomes in Patients with Nonvariceal Upper Gastrointestinal Bleeding. AB - OBJECTIVE: To determine the effect of aspirin and anticoagulants on clinical outcomes and cause of in-hospital death in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). METHODS: Patients were identified from a tertiary center database that included all patients with UGIB. Clinical outcomes including (1) in-hospital mortality, (2) severe bleeding, (3) rebleeding, (4) in hospital complications, and (5) length of hospital stay were examined in patients taking (a) aspirin only, (b) anticoagulants only, and (c) no antithrombotics. RESULTS: Of 717 patients with NVUGIB, 56 % (402) were taking at least one antithrombotic agent. Seventy-eight (11 %) patients died in hospital, and 310 (43 %) had severe bleeding (BP < 90 mmHg, HR > 120 b/min, Hb < 7 g/dL on presentation, or transfusion of >3 units). On multivariate analysis, being on aspirin was protective against in-hospital mortality [OR 0.26 (0.13-0.53)], rebleeding [OR 0.31 (0.17-0.59)], and predictive of a shorter hospital stay (coefficient = -4.2 days; 95 % CI -8.7, 0.3). Similarly, being on nonaspirin antiplatelets was protective against in-hospital mortality (P = 0.03). However, being on anticoagulants was predictive of in-hospital complications [OR 2.0 (1.20 3.35)] and severe bleeding [OR 1.69 (1.02-2.82)]. Compared to those not taking any antithrombotics, patients who bled on aspirin were less likely to die in hospital of uncontrolled gastrointestinal bleeding (3.6 vs 0 %, P <= 0.01) and systemic cancer (4.9 vs 0 %, P <= 0.002), but equally likely to die of cardiovascular/thromboembolic disease, sepsis, and multiorgan failure. CONCLUSION: Patients who present with NVUGIB on aspirin had reduced in-hospital mortality and fewer adverse outcomes, while those on anticoagulants had increased in-hospital complications. PMID- 25732718 TI - Adalimumab Therapy Has a Beneficial Effect on Bone Metabolism in Patients with Crohn's Disease. AB - BACKGROUND: Infliximab has been shown to have beneficial effects on bone metabolism in patients with Crohn's disease (CD) although as yet the exact mechanisms have not been fully elucidated. AIM: To evaluate the impact of adalimumab therapy on bone metabolism using a combined in vivo and in vitro model. METHODS: Parathyroid hormone, vitamin D, bone formation markers, bone resorption marker, pro-inflammatory cytokines, anti-inflammatory cytokines, osteoprotegerin, and sRANKL were measured in control patients and pre- and post treatment with adalimumab in CD patients. The effect of control patients' and pre and post-treatment CD patients' sera on human osteoblasts (hFOB 1.19) in vitro cell viability and differentiation was also analyzed. RESULTS: There was a significant increase in bone formation markers osteocalcin (P < 0.05) and procollagen type 1 N-terminal propeptide (P < 0.01) at 1 and 3 months post treatment. Moreover, there was a sustained but not significant fall in serum CTx, a bone resorption marker. No significant change was seen over time with other parameters measured. Serum from CD patients pre-treated with adalimumab showed increased osteoblast viability compared with that of post-treated patients at 6 months (P = 0.002) and controls. However, post-adalimumab treatment sera at 6 months appeared to increase osteoblast differentiation (P = 0.001), which is likely to be important in new bone formation. CONCLUSIONS: This first study evaluating the role of adalimumab as a possible bone protector in Crohn's disease patients has shown that similar to infliximab, adalimumab has complex and potentially beneficial effects on bone metabolism. PMID- 25732719 TI - Safety of Non-anesthesia Provider-Administered Propofol (NAAP) Sedation in Advanced Gastrointestinal Endoscopic Procedures: Comparative Meta-Analysis of Pooled Results. AB - BACKGROUND AND AIMS: The aim of the study was to evaluate the safety of non anesthesia provider (NAAP)-administered propofol sedation for advanced endoscopic procedures with those of anesthesia provider (AAP). METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science databases were searched for prospective observational trials involving advanced endoscopic procedures. From a total of 519 publications, 26 were identified to meet inclusion criteria (10 AAPs and 16 NAAPs) and were analyzed. Data were analyzed for hypoxia rate, airway intervention rates, endoscopist, and patient satisfaction scores and total propofol administered. RESULTS: Total number of procedures in NAAP and AAP groups was 3018 and 2374, respectively. Pooled hypoxia (oxygen saturation less than 90 %) rates were 0.133 (95 % CI 0.117-0.152) and 0.143 (95 % CI 0.128-0.159) in NAAP and AAP, respectively. Similarly, pooled airway intervention rates were 0.035 (95 % CI 0.026-0.047) and 0.133 (95 % CI 0.118-0.150), respectively. Pooled patient satisfaction rate, pooled endoscopist satisfaction rate, and mean propofol administered dose for NAAP were 7.22 (95 % CI 7.17-7.27), 6.03 (95 % CI 5.94-6.11), and 251.44 mg (95 % CI 244.39-258.49) in that order compared with 9.82 (95 % CI 9.76-9.88), 9.06 (95 % CI 8.91-9.21), and 340.32 mg (95 % CI 327.30-353.33) for AAP. CONCLUSIONS: The safety of NAAP sedation compared favorably with AAP sedation in patients undergoing advanced endoscopic procedures. However, it came at the cost of decreased patient and endoscopist satisfaction. PMID- 25732720 TI - Stable semiconductor black phosphorus (BP)@titanium dioxide (TiO2) hybrid photocatalysts. AB - Over the past few decades, two-dimensional (2D) and layered materials have emerged as new fields. Due to the zero-band-gap nature of graphene and the low photocatalytic performance of MoS2, more advanced semiconducting 2D materials have been prompted. As a result, semiconductor black phosphorus (BP) is a derived cutting-edge post-graphene contender for nanoelectrical application, because of its direct-band-gap nature. For the first time, we report on robust BP@TiO2 hybrid photocatalysts offering enhanced photocatalytic performance under light irradiation in environmental and biomedical fields, with negligible affected on temperature and pH conditions, as compared with MoS2@TiO2 prepared by the identical synthesis method. Remarkably, in contrast to pure few layered BP, which, due to its intrinsic sensitivity to oxygen and humidity was readily dissolved after just several uses, the BP@TiO2 hybrid photocatalysts showed a ~92% photocatalytic activity after 15 runs. Thus, metal-oxide-stabilized BP photocatalysts can be practically applied as a promising alternative to graphene and MoS2. PMID- 25732722 TI - Shared decision making in senior medical students: results from a national survey. AB - PURPOSE: To explore perceptions and experiences of Peruvian medical students about observed, preferred, and feasible decision-making approaches. METHODS: We surveyed senior medical students from 19 teaching hospitals in 4 major cities in Peru. The self-administered questionnaire collected demographic information, current approach, exposure to role models for and training in shared decision making, and perceptions of the pertinence and feasibility of the different decision-making approaches in general as well as in challenging scenarios. RESULTS: A total of 327 senior medical students (51% female) were included. The mean age was 25 years. Among all respondents, 2% reported receiving both theoretical and practical training in shared decision making. While 46% of students identified their current decision-making approach as clinician-as perfect-agent, 50% of students identified their teachers with the paternalistic approach. Remarkably, 53% of students thought shared decision making should be the preferred approach and 50% considered it feasible in Peru. Among the 10 challenging scenarios, shared decision making reached a plurality (40%) in only one scenario (terminally ill patients). CONCLUSION: Despite limited exposure and training, Peruvian medical students aspire to practice shared decision making but their current attitude reflects the less participatory approaches they see role modeled by their teachers. PMID- 25732721 TI - Pre-activation of mesenchymal stem cells with TNF-alpha, IL-1beta and nitric oxide enhances its paracrine effects on radiation-induced intestinal injury. AB - Conditioned medium from mesenchymal stem cells (MSC-CM) may represent a promising alternative to MSCs transplantation, however, the low concentrations of growth factors in non-activated MSC-CM hamper its clinical application. Recent data indicated that the paracrine potential of MSCs could be enhanced by inflammatory factors. Herein, we pre-activated bone-marrow-derived MSCs under radiation induced inflammatory condition (MSC(IEC-6(IR))) and investigated the evidence and mechanism for the differential effects of MSC-CM(IEC-6(IR)) and non-activated MSC CM on radiation-induced intestinal injury (RIII). Systemic infusion of MSC-CM(IEC 6(IR)), but not non-activated MSC-CM, dramatically improved intestinal damage and survival of irradiated rats. Such benefits may involve the modulation of epithelial regeneration and inflammation, as indicated by the regeneration of intestinal epithelial/stem cells, the regulation of the pro-/anti-inflammatory cytokine balance. The mechanism for the superior paracrine efficacy of MSC(IEC 6(IR)) is related to a higher secretion of regenerative, immunomodulatory and trafficking molecules, including the pivotal factor IGF-1, induced by TNF-alpha, IL-1beta and nitric oxide partially via a heme oxygenase-1 dependent mechanism. Together, our findings suggest that pre-activation of MSCs with TNF-alpha, IL 1beta and nitric oxide enhances its paracine effects on RIII via a heme oxygenase 1 dependent mechanism, which may help us to maximize the paracrine potential of MSCs. PMID- 25732723 TI - Multistate Statistical Modeling: A Tool to Build a Lung Cancer Microsimulation Model That Includes Parameter Uncertainty and Patient Heterogeneity. AB - With the shift toward individualized treatment, cost-effectiveness models need to incorporate patient and tumor characteristics that may be relevant to treatment planning. In this study, we used multistate statistical modeling to inform a microsimulation model for cost-effectiveness analysis of individualized radiotherapy in lung cancer. The model tracks clinical events over time and takes patient and tumor features into account. Four clinical states were included in the model: alive without progression, local recurrence, metastasis, and death. Individual patients were simulated by repeatedly sampling a patient profile, consisting of patient and tumor characteristics. The transitioning of patients between the health states is governed by personalized time-dependent hazard rates, which were obtained from multistate statistical modeling (MSSM). The model simulations for both the individualized and conventional radiotherapy strategies demonstrated internal and external validity. Therefore, MSSM is a useful technique for obtaining the correlated individualized transition rates that are required for the quantification of a microsimulation model. Moreover, we have used the hazard ratios, their 95% confidence intervals, and their covariance to quantify the parameter uncertainty of the model in a correlated way. The obtained model will be used to evaluate the cost-effectiveness of individualized radiotherapy treatment planning, including the uncertainty of input parameters. We discuss the model-building process and the strengths and weaknesses of using MSSM in a microsimulation model for individualized radiotherapy in lung cancer. PMID- 25732724 TI - The pupil response reveals increased listening effort when it is difficult to focus attention. AB - Recent studies have shown that prior knowledge about where, when, and who is going to talk improves speech intelligibility. How related attentional processes affect cognitive processing load has not been investigated yet. In the current study, three experiments investigated how the pupil dilation response is affected by prior knowledge of target speech location, target speech onset, and who is going to talk. A total of 56 young adults with normal hearing participated. They had to reproduce a target sentence presented to one ear while ignoring a distracting sentence simultaneously presented to the other ear. The two sentences were independently masked by fluctuating noise. Target location (left or right ear), speech onset, and talker variability were manipulated in separate experiments by keeping these features either fixed during an entire block or randomized over trials. Pupil responses were recorded during listening and performance was scored after recall. The results showed an improvement in performance when the location of the target speech was fixed instead of randomized. Additionally, location uncertainty increased the pupil dilation response, which suggests that prior knowledge of location reduces cognitive load. Interestingly, the observed pupil responses for each condition were consistent with subjective reports of listening effort. We conclude that communicating in a dynamic environment like a cocktail party (where participants in competing conversations move unpredictably) requires substantial listening effort because of the demands placed on attentional processes. PMID- 25732725 TI - Function of Nogo-A/Nogo-A receptor in Alzheimer's disease. AB - Nogo-A is a protein inhibiting axonal regeneration, which is considered a major obstacle to nerve regeneration after injury in mammals. Rapid progress has been achieved in new physiopathological function of Nogo-A in Alzheimer's disease in the past decade. Recent research shows that through binding to Nogo-A receptor, Nogo-A plays an important role in Alzheimer's disease (AD) pathogenesis. Particularly, Nogo-A/Nogo-A receptors modulate the generation of amyloid beta protein (Abeta), which is thought to be a major cause of AD. This review describes the recent development of Nogo-A, Nogo-A receptor, and downstream signaling involved in AD and pharmacological basis of therapeutic drugs. We concluded the Nogo-A/Nogo-A receptor provide new insight into potential mechanisms and promising therapy strategies in AD. PMID- 25732726 TI - Probing highly luminescent europium-doped lanthanum orthophosphate nanorods for strategic applications. AB - Herein we have established a strategy for the synthesis of highly luminescent and biocompatible europium-doped lanthanum orthophosphate (La0.85PO4Eu0.15(3+)) nanorods. The structure and morphogenesis of these nanorods have been probed by XRD, SEM, and TEM/HRTEM techniques. The XRD result confirms that the as synthesized nanorods form in a monazite phase with a monoclinic crystal structure. Furthermore, the surface morphology shows that the synthesized nanorods have an average diameter of ~90 nm and length of ~2 MUm. The HRTEM images show clear lattice fringes that support the presence of better crystal quality and enhanced photoluminescence hypersensitive red emission at 610 nm ((5)D0-(7)F2) upon 394 nm wavelength excitation. Furthermore, time-resolved spectroscopy and an MTT assay of these luminescent nanorods demonstrate a photoluminescent decay time of milliseconds with nontoxic behavior. Hence, these obtained results suggest that the as-synthesized luminescent nanorods could be potentially used in invisible security ink and high-contrast bioimaging applications. PMID- 25732727 TI - Merkel cell carcinoma arising within a poroma: report of two cases. AB - Merkel cell carcinoma (MCC) has been reported in association with other types of cutaneous neoplasms within the same lesion, including squamous cell carcinoma, Bowen's disease, actinic keratosis, follicular cysts, trichoblastoma and lentigo maligna, among others. However, the association of MCC and sweat gland tumors has never been described in the literature. We report two unique cases of MCC that developed within cutaneous poromas. A 56-year-old male (Patient 1) and an 81-year old female (Patient 2) presented with nodules on the upper arm and lower back, respectively. Histopathologic study of both cases revealed a tumor in the dermis composed of poroid and cuticular cells intermingled with a proliferation of small round cells that showed characteristic histopathological and immunohistochemical features of MCC. In both cases, the two neoplasms were tightly admixed and distinct, suggesting that the MCC could have developed within a previously existing poroma. No morphological features of transition between the two tumors were seen. Neoplastic cells of MCC expressed immunoreactivity for chromogranin, synaptophysin, neuron-specific enolase, CAM 5.2 and cytokeratin 20, the last two markers showing the characteristic paranuclear dot-like pattern. In contrast, the poroma cells only expressed cytokeratin MNF116. Metastatic deposits were not identified in the regional lymph nodes or distantly. PMID- 25732728 TI - Type I IFNs and IL-18 regulate the antiviral response of primary human gammadelta T cells against dendritic cells infected with Dengue virus. AB - Little is known about the cellular mechanisms of innate immunity against dengue virus (DV) infection. Specifically, the gammadelta T cell response to DV has not been characterized in detail. In this article, we demonstrate that markers of activation, proliferation, and degranulation are upregulated on gammadelta T cells in PBMC isolated from individuals with acute dengue fever. Primary gammadelta T cells responded rapidly in vitro to autologous DV-infected dendritic cells by secreting IFN-gamma and upregulating CD107a. The anti-DV IFN-gamma response is regulated by type I IFN and IL-18 in a TCR-independent manner, and IFN-gamma secreting gammadelta T cells predominantly expressed IL-18Ralpha. Antagonizing the ATP-dependent P2X7 receptor pathway of inflammasome activation significantly inhibited the anti-DV IFN-gamma response of gammadelta T cells. Overnight priming with IL-18 produced effector gammadelta T cells with significantly increased ability to lyse autologous DV-infected dendritic cells. Monocytes were identified as accessory cells that augmented the anti-DV IFN-gamma response of gammadelta T cells. Lack of monocytes in culture is associated with lower IL-18 levels in culture supernatant and diminished production of IFN-gamma by gammadelta T cells, whereas addition of exogenous IL-18 restored the IFN-gamma response of gammadelta T cells in monocyte-depleted cocultures with DV-infected DC. Our results indicate that primary gammadelta T cells contribute to the immune response during DV infection by providing an early source of IFN-gamma, as well as by killing DV-infected cells, and suggest that monocytes participate as accessory cells that sense DV infection and amplify the cellular immune response against this virus in an IL-18-dependent manner. PMID- 25732729 TI - A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression. AB - The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood gammadelta Tau cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare gammadelta T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive gammadelta and alphabeta T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-gamma production following TCR stimulation of his "untouched" naive CD4(+) T cells. Biochemical analysis revealed that his gammadelta and alphabeta T cells carried an altered TCR complex with reduced amounts of the zeta-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric zeta protein. The diminished presence of CD247 and increased numbers of gammadelta T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good's syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive gammadelta and alphabeta T cells and an increased susceptibility to infections. PMID- 25732730 TI - Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes. AB - Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accumulation in the tissue. CD8(+) T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-gamma production by intraislet CD8(+) and CD4(+) T cells at the protein level with minimal effect on IFN-gamma mRNA. Sustained expression of IFN-gamma protein by effector T cells was dependent on common gamma-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8(+) T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis. PMID- 25732731 TI - Modeling the specific CD4+ T cell response against a tumor neoantigen. AB - The antitumor activity of CD4(+) T cells is increasingly acknowledged in both humans and mice. The involved mechanisms have been mostly studied using transplanted tumor mouse systems. In these models, many tumor cells die at the time of implantation leading to the release of Ag in an inflammatory context contrasting with the slow and nondestructive growth of early-stage human tumors. In this study, we show that the presentation of a MHC class II-restricted model Ag (male, DBY) released by dying tumor cells may last more than 4 wk. The duration of Ag presentation varies according to the way the cells are killed before implantation. To avoid this artifactual early priming of the host precluding the study of the interactions between the immune system and tumors at the steady state, we generated a cell line expressing the DBY Ag in an inducible manner. Ag expression can be efficiently induced in vivo several days after tumor implantation. We show that the Ag reaches the lymph node and activates naive CD4(+) T cells to proliferate and recirculate. We did not observe de novo induction of tumor-specific regulatory T cells. However, we observed Th1/Th17 effector cells in the tumor draining lymph node and tumors. Thus, when a neoantigen appears in established tumors, the immune system is not ignorant and naive CD4(+) T cells are not tolerized. This opens up the possibility of therapeutic vaccines improving the immune response toward tumor-specific neoantigens. PMID- 25732732 TI - FcMUR interacts and cooperates with the B cell receptor To promote B cell survival. AB - The IgM FcR (FcMUR) promotes B cell survival, but the molecular mechanism remains largely unknown. We show using FcMUR(-/-) and wild-type mice that FcMUR specifically enhanced B cell survival induced by BCR cross-linking with F(ab')2 anti-IgM Abs while having no effect on survival when the B cells were activated by CD40 ligation or LPS stimulation. FcMUR expression was markedly upregulated by anti-IgM stimulation, which may promote enhanced FcMUR signaling in these cells. Immunofluorescence and confocal microscopy analyses demonstrated that FcMUR colocalized with the BCR on the plasma membrane of primary B cells. Coimmunoprecipitation analysis further revealed that FcMUR physically interacted with the BCR complex. Because NF-kappaB plays a prominent role in B cell survival, we analyzed whether FcMUR was involved in BCR-triggered NF-kappaB activation. FcMUR did not affect BCR-triggered IkappaBalpha phosphorylation characteristic of the canonical NF-kappaB activation pathway but promoted the production of the noncanonical NF-kappaB pathway component p52. Consistent with the elevated p52 levels, FcMUR enhanced BCR-triggered expression of the antiapoptotic protein BCL-xL. Importantly, FcMUR stimulation alone in the absence of BCR signaling had no effect on either IkappaBalpha phosphorylation or the expression of p52 and BCL-xL. Therefore, FcMUR relied on the BCR signal to activate the noncanonical NF-kappaB pathway and enhance B cell survival. These results reveal a cross-talk downstream of FcMUR and BCR signaling and provide mechanistic insight into FcMUR-mediated enhancement of B cell survival after BCR stimulation. PMID- 25732733 TI - Transcription-dependent generation of a specialized chromatin structure at the TCRbeta locus. AB - V(D)J recombination assembles Ag receptor genes during lymphocyte development. Enhancers at AR loci are known to control V(D)J recombination at associated alleles, in part by increasing chromatin accessibility of the locus, to allow the recombination machinery to gain access to its chromosomal substrates. However, whether there is a specific mechanism to induce chromatin accessibility at AR loci is still unclear. In this article, we highlight a specialized epigenetic marking characterized by high and extended H3K4me3 levels throughout the Dbeta Jbeta-Cbeta gene segments. We show that extended H3K4 trimethylation at the Tcrb locus depends on RNA polymerase II (Pol II)-mediated transcription. Furthermore, we found that the genomic regions encompassing the two DJCbeta clusters are highly enriched for Ser(5)-phosphorylated Pol II and short-RNA transcripts, two hallmarks of transcription initiation and early transcription. Of interest, these features are shared with few other tissue-specific genes. We propose that the entire DJCbeta regions behave as transcription "initiation" platforms, therefore linking a specialized mechanism of Pol II transcription with extended H3K4 trimethylation and highly accessible Dbeta and Jbeta gene segments. PMID- 25732734 TI - WEE1 is a validated target of the microRNA miR-17-92 cluster in leukemia. AB - MicroRNAs are short single-stranded RNAs that regulate target gene expression by binding to complementary sites in the 3' untranslated region (UTR) of their mRNA targets. The polycistronic miR-17-92 cluster, which encodes miR-17, miR-18a, miR 19a, miR-20a, miR-19b, and miR-92a, was previously shown to be overexpressed in multiple types of cancer. In this study, target gene prediction algorithms were used to predict potential targets of the miR-17-92 cluster. WEE1, a kinase that inhibits cell cycle progression, was identified as a possible target of five of the six miRNAs in the cluster. Luciferase reporter assays were used to determine that miR-17, miR-20a, and miR-18a specifically target nucleotides 465-487 of the 3' UTR of WEE1, whereas miR-19a and miR-19b exert control on WEE1 by targeting nucleotides 1069-1091. A negative correlation was determined between endogenous miR-17 or miR-19a expression and endogenous WEE1 protein expression in the same panel of cell lines. We conclude that WEE1 is a valid target of the miR-17-92 cluster in leukemia. PMID- 25732735 TI - Erosion versus recurrence: is there a compromise using biologics for ventral rectopexy? PMID- 25732736 TI - Repair of complex parastomal hernias. AB - Development of parastomal hernias (PH) is very common after stoma formation and carries a risk of subsequent bowel incarceration, obstruction and strangulation. The management of PH remains a challenge for the colorectal surgeon, and there are currently no standardized guidelines for the treatment of PH. Even more difficult is the management of complex parastomal hernias (CPH). We conducted a review of the literature to identify recent developments in the treatment of CPH, including analysis of the use of synthetic and biologic mesh prostheses, method of mesh placement and surgical approach. PMID- 25732737 TI - Induced Stem Cells as a Novel Multiple Sclerosis Therapy. AB - Stem cell replacement is providing hope for many degenerative diseases that lack effective therapeutic methods including multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Transplantation of neural stem cells or mesenchymal stem cells is a potential therapy for MS thanks to their capacity for cell repopulation as well as for their immunomodulatory and neurotrophic properties. Induced pluripotent stem cell (iPSC), an emerging cell source in regenerative medicine, is also being tested for the treatment of MS. Remarkable improvement in mobility and robust remyelination have been observed after transplantation of iPSC-derived neural cells into demyelinated models. Direct reprogramming of somatic cells into induced neural cells, such as induced neural stem cells (iNSCs) and induced oligodendrocyte progenitor cells (iOPCs), without passing through the pluripotency stage, is an alternative for transplantation that has been proved effective in the congenital hypomyelination model. iPSC technology is rapidly progressing as efforts are being made to increase the efficiency of iPSC therapy and reduce its potential side effects. In this review, we discuss the recent advances in application of stem cells, with particular focus on induced stem/progenitor cells (iPSCs, iNSC, iOPCs), which are promising in the treatment of MS. PMID- 25732738 TI - PPARdelta modulates oxLDL-induced apoptosis of vascular smooth muscle cells through a TGF-beta/FAK signaling axis. AB - The peroxisome proliferator-activated receptor delta (PPARdelta) has been implicated in the modulation of vascular homeostasis. However, its roles in the apoptotic cell death of vascular smooth muscle cells (VSMCs) are poorly understood. Here, we demonstrate that PPARdelta modulates oxidized low-density lipoprotein (oxLDL)-induced apoptosis of VSMCs through the transforming growth factor-beta (TGF-beta) and focal adhesion kinase (FAK) signaling pathways. Activation of PPARdelta by GW501516, which is a specific ligand, significantly inhibited oxLDL-induced cell death and generation of reactive oxygen species in VSMCs. These inhibitory effects were significantly reversed in the presence of small interfering (si)RNA against PPARdelta, or by blockade of the TGF-beta or FAK signaling pathways. Furthermore, PPARdelta-mediated recovery of FAK phosphorylation suppressed by oxLDL was reversed by SB431542, a specific ALK5 receptor inhibitor, indicating that a TGF-beta/FAK signaling axis is involved in the action of PPARdelta. Among the protein kinases activated by oxLDL, p38 mitogen-activated protein kinase was suppressed by ligand-activated PPARdelta. In addition, oxLDL-induced expression and translocation of pro-apoptotic or anti apoptotic factors were markedly affected in the presence of GW501516. Those effects were reversed by PPARdelta siRNA, or inhibitors of TGF-beta or FAK, which also suggests that PPARdelta exerts its anti-apoptotic effect via a TGF-beta/FAK signaling axis. Taken together, these findings indicate that PPARdelta plays an important role in the pathophysiology of disease associated with apoptosis of VSMC, such as atherosclerosis and restanosis. PMID- 25732739 TI - Counts and sequences, observations that continue to change our understanding of viruses in nature. AB - The discovery of abundant viruses in the oceans and on land has ushered in a quarter century of groundbreaking advancements in our understanding of viruses within ecosystems. Two types of observations from environmental samples--direct counts of viral particles and viral metagenomic sequences--have been critical to these discoveries. Accurate direct counts have established ecosystem-scale trends in the impacts of viral infection on microbial host populations and have shown that viral communities within aquatic and soil environments respond to both short term and seasonal environmental change. Direct counts have been critical for estimating viral production rate, a measurement essential to quantifying the implications of viral infection for the biogeochemical cycling of nutrients within ecosystems. While direct counts have defined the magnitude of viral processes; shotgun sequences of environmental viral DNA--virome sequences--have enabled researchers to estimate the diversity and composition of natural viral communities. Virome-enabled studies have found the virioplankton to contain thousands of viral genotypes in communities where the most dominant viral population accounts for a small fraction of total abundance followed by a long tail of diverse populations. Detailed examination of long virome sequences has led to new understanding of genotype-to-phenotype connections within marine viruses and revealed that viruses carry metabolic genes that are important to maintaining cellular energy during viral replication. Increased access to long virome sequences will undoubtedly reveal more genetic secrets of viruses and enable us to build a genomics rulebook for predicting key biological and ecological features of unknown viruses. PMID- 25732740 TI - Microbial ecology in Hydra: why viruses matter. AB - While largely studied because of their harmful effects on human health, there is growing appreciation that viruses are also important members of the animal holobiont. This review highlights recent findings on viruses associated with Hydra and related Cnidaria. These early evolutionary diverging animals not only select their bacterial communities but also select for viral communities in a species-specific manner. The majority of the viruses associating with these animals are bacteriophages. We demonstrate that the animal host and its virome have evolved into a homeostatic, symbiotic relationship and propose that viruses are an important part of the Hydra holobiont by controlling the species-specific microbiome. We conclude that beneficial virus-bacterial-host interactions should be considered as an integral part of animal development and evolution. PMID- 25732741 TI - Against friend and foe: type 6 effectors in plant-associated bacteria. AB - Bacterial secretion systems play critical roles in communication with neighboring bacteria and in the modulation of host immune responses via the secretion of small proteins called effectors. Several secretion systems have been identified and these are denoted types I-VII. Of these, the type VI secretion system (T6SS) and its effectors were only recently elucidated. Most studies on the role and significance of the T6SS and its effectors have focused on human pathogens. In this review, type 6 effectors from plant-associated beneficial and pathogenic bacteria are discussed, including effectors from Agrobacterium tumefaciens, Dickeya dadanti, Rhizobium leguminosarum, Pectobacterium atroseptium, Ralstonia solanacearum, Pseudomonas syringae, Pseudomonas fluorescens, and Pseudomonas protegens. Type 6 effectors act in symbiosis, biofilm formation, virulence, and interbacterial competition. Understanding the impact of type 6 effectors on pathogenesis will contribute to the management of bacterial pathogens in crop plants by allowing the manipulation of intra and inter-specific interactions. PMID- 25732742 TI - Novel anti-platelet agents in acute coronary syndrome: mechanisms of action and opportunities to tailor therapy. AB - Dual anti-platelet therapy, most commonly aspirin and clopidogrel, has been the standard of care for over a decade in patients who have experienced acute coronary syndrome, particularly when treated with coronary stenting. However, residual risk in patients receiving dual anti-platelet therapy post-acute coronary syndrome raises an unmet need for alternative therapy to clopidogrel. Consequently, novel anti-platelets agents including the P2Y12 receptor antagonists, such as prasugrel and ticagrelor, have emerged. Furthermore, using new methods to assess genetic polymorphisms and functional phenotypic assessments of platelet reactivity may become important in the development of personalized medicine and in developing tailored approaches to individual treatment. While robust large-scale evidence for genotypic- and phenotypic-guided therapy in improving outcomes is currently lacking, tremendous interest from various stakeholders including researchers, funding agencies, and industry continues to spur research endeavors in this arena. Further investigation is required in this emerging field to potentially offer improved platelet inhibition that may optimize cardioprotection and minimize bleeding risk in patients with acute coronary syndrome. PMID- 25732743 TI - AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis. AB - AIP1 (ASK1-interacting protein-1; encoded by the DAB2IP gene), a signaling scaffolding protein, is abundantly expressed in vascular endothelial cells (EC). While it was initially discovered as an apoptosis signal-regulating kinase 1 (ASK1)-interacting protein, AIP1 broadly suppresses inflammatory responses triggered by cytokines and stresses such as TNF, LPS, VEGF, and endoplasmic reticulum (ER) stress in EC (therefore, AIP1 is an anti-inflammatory protein). Human genome-wide association study (GWAS) has identified DAB2IP gene variants conferring susceptibility to cardiovascular diseases. Consistently, a global or vascular EC-specific deletion of DAB2IP in mice strongly enhances inflammatory responses and exacerbates atherosclerosis and graft arteriosclerosis progression in mouse models. Mechanisms for AIP1 function and regulation associated with human cardiovascular diseases need further investigations. PMID- 25732744 TI - DNA methylation and application in forensic sciences. AB - DNA methylation of cytosine residues is a stable epigenetic alteration, beginning as early as foetal development in the uterus and continuously evolving throughout life. DNA methylation as well as other epigenetic modifications such as chromatin remodelling and histone modifications are indispensable in mammalian development. Methylation is to a large extent influenced by the ageing process, diets and lifestyle choices. Our understanding of this crucial modification may even contribute to the treatment and prevention of age-related illnesses in the very near future. Genome-wide methylation analysis using high throughput DNA technologies has discovered numerous differentially methylated regions (tDMRs) which differ in levels of methylation in various cell types and tissues. TDMRs have been useful in various applications, particularly medicine and forensic sciences. Forensic scientists are constantly seeking exciting and novel methods to aid in the reconstruction of crime scenes, and the analysis of tDMRs represents a new and reliable technique to identify biological fluids and tissues found at the scene of a violent act. Not only has research been able to unequivocally identify various fluids and tissues, but methods to determine the sex, age and phenotype of donors has been developed. New tDMRs in genes are being searched for consistently to serve as novel markers in forensic DNA analysis. PMID- 25732746 TI - Colonoscopy: Cold snaring diminutive polyps--the thinner the better! PMID- 25732747 TI - Identification of homogeneous and heterogeneous variables in pooled cohort studies. AB - Pooled analyses integrate data from multiple studies and achieve a larger sample size for enhanced statistical power. When heterogeneity exists in variables' effects on the outcome across studies, the simple pooling strategy fails to present a fair and complete picture of the effects of heterogeneous variables. Thus, it is important to investigate the homogeneous and heterogeneous structure of variables in pooled studies. In this article, we consider the pooled cohort studies with time-to-event outcomes and propose a penalized Cox partial likelihood approach with adaptively weighted composite penalties on variables' homogeneous and heterogeneous effects. We show that our method can characterize the variables as having heterogeneous, homogeneous, or null effects, and estimate non-zero effects. The results are readily extended to high-dimensional applications where the number of parameters is larger than the sample size. The proposed selection and estimation procedure can be implemented using the iterative shooting algorithm. We conduct extensive numerical studies to evaluate the performance of our proposed method and demonstrate it using a pooled analysis of gene expression in patients with ovarian cancer. PMID- 25732745 TI - Epidemiology and risk factors for IBD. AB - IBD, comprising Crohn's disease and ulcerative colitis, is a chronic immunologically mediated disease at the intersection of complex interactions between genetics, environment and gut microbiota. Established high-prevalence populations of IBD in North America and Europe experienced the steepest increase in incidence towards the second half of the twentieth century. Furthermore, populations previously considered 'low risk' (such as in Japan and India) are witnessing an increase in incidence. Potentially relevant environmental influences span the spectrum of life from mode of childbirth and early-life exposures (including breastfeeding and antibiotic exposure in infancy) to exposures later on in adulthood (including smoking, major life stressors, diet and lifestyle). Data support an association between smoking and Crohn's disease whereas smoking cessation, but not current smoking, is associated with an increased risk of ulcerative colitis. Dietary fibre (particularly fruits and vegetables), saturated fats, depression and impaired sleep, and low vitamin D levels have all been associated with incident IBD. Interventional studies assessing the effects of modifying these risk factors on natural history and patient outcomes are an important unmet need. In this Review, the changing epidemiology of IBD, mechanisms behind various environmental associations and interventional studies to modify risk factors and disease course are discussed. PMID- 25732748 TI - Heart rate is associated with progression of atrial fibrillation, independent of rhythm. AB - OBJECTIVE: Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described. METHODS: Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA2DS2VASc scores for identifying AF progression. RESULTS: Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12-24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS2 2.3+/-1.3 vs 2.1+/-1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64-80) vs 68(60-76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease <=80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA2DS2VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)). CONCLUSIONS: Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age. PMID- 25732749 TI - Where are the surgeons? A safety opportunity missed? PMID- 25732750 TI - Complications of cardiac catheterisation in children. PMID- 25732751 TI - Effects of remote ischaemic preconditioning on clinical outcomes after cardiac surgery. PMID- 25732752 TI - Coffee consumption and coronary artery calcium in young and middle-aged asymptomatic adults. AB - OBJECTIVE: To investigate the association between regular coffee consumption and the prevalence of coronary artery calcium (CAC) in a large sample of young and middle-aged asymptomatic men and women. METHODS: This cross-sectional study included 25 138 men and women (mean age 41.3 years) without clinically evident cardiovascular disease who underwent a health screening examination that included a validated food frequency questionnaire and a multidetector CT to determine CAC scores. We used robust Tobit regression analyses to estimate the CAC score ratios associated with different levels of coffee consumption compared with no coffee consumption and adjusted for potential confounders. RESULTS: The prevalence of detectable CAC (CAC score >0) was 13.4% (n=3364), including 11.3% prevalence for CAC scores 1-100 (n=2832), and 2.1% prevalence for CAC scores >100 (n=532). The mean +/-SD consumption of coffee was 1.8+/-1.5 cups/day. The multivariate adjusted CAC score ratios (95% CIs) comparing coffee drinkers of <1, 1-<3, 3-<5, and >=5 cups/day to non-coffee drinkers were 0.77 (0.49 to 1.19), 0.66 (0.43 to 1.02), 0.59 (0.38 to 0.93), and 0.81 (0.46 to 1.43), respectively (p for quadratic trend=0.02). The association was similar in subgroups defined by age, sex, smoking status, alcohol consumption, status of obesity, diabetes, hypertension, and hypercholesterolaemia. CONCLUSIONS: In this large sample of men and women apparently free of clinically evident cardiovascular disease, moderate coffee consumption was associated with a lower prevalence of subclinical coronary atherosclerosis. PMID- 25732754 TI - Yellow fever risk assessment in the Central African Republic. AB - Yellow fever still causes high burden in several areas of sub-Saharan Africa and Latin America. There are few well-designed epidemiological studies and limited data about yellow fever in Africa. Staples et al., in a recently published paper in Transactions of the Royal Society of Tropical Medicine & Hygiene, performed a nationwide study in the Central African Republic (CAR) assessing infection risk and the operational impact of preventive measures. The rapid assessment of human, non-human and mosquito data call attention to the potential risk of future yellow fever outbreaks in the CAR and elsewhere. The study reinforces the need for intensified applied and operational research to address problems and human capacity needs in the realm of neglected tropical diseases in the post-2015 agenda. PMID- 25732753 TI - Totally intracorporeal delta-shaped B-I anastomosis following laparoscopic distal gastrectomy using the Tri-StapleTM reloads on the manual Ultra handle: a prospective cohort study with historical controls. AB - BACKGROUND: A delta-shaped anastomosis in totally laparoscopic Billroth I gastrectomy could be performed easily and sufficiently using only laparoscopic linear staplers. However, the restricted maneuverability and severe blurring of these staplers along with their limited hemostability induced strain. In this study, we determined the feasibility and safety of performing delta-shaped anastomosis using the Endo GIATM Reloads with Tri-StapleTM Technology combined with Endo GIATM Ultra Universal stapler (Tri-Staple) with a particular focus on short-term surgical outcomes. METHODS: We performed a single-institutional prospective interventional study (UMIN 000008014). The Tri-Staple was prospectively used on 23 consecutive patients who underwent a curative totally laparoscopic Billroth I gastrectomy with delta-shaped anastomosis. These patients were matched with the 19 patients previously treated using the ENDOPATH((r)) ETS Articulating Linear Cutters (ETS) on clinical and demographic characteristics. RESULTS: There were no differences between the groups in anastomosis-related local complications, morbidity, non-anastomosis-related local complications, total systemic complications, and short-term outcomes with the exception of significantly reduced blood loss in the Tri-Staple group (ETS vs. Tri-Staple: 37 [10-306] vs. 15 [5-210] mL, p = 0.02). Intraoperative bleeding from the staple line was significantly reduced in the Tri-Staple group. The postoperative drain indwelling period (ETS vs. Tri-Staple, 6 [4-10] vs. 4 [2-43] days, p = 0.032), fasting period (5 [3-7] vs. 3 [3-24] days, p = 0.022), and hospital stay (14 [10 47] vs. 11 [6-58] days, p = 0.025) were significantly shorter in the Tri-Staple group. There was no mortality in this series. Acceleration assessed as indices of blurring of stapler tip might have a significant adverse influence on staple-line bleeding at stapling sites. CONCLUSION: Totally laparoscopic Billroth I distal gastrectomy using Tri-Staple was feasible and safe with favorable short-term surgical outcomes. Reduced blurring while stapling may be a novel endpoint which newly developed stapling devices should target. PMID- 25732755 TI - Prevalence of Chlamydia trachomatis infection in Samoan women aged 18 to 29 and assessment of possible risk factors: a community-based study. AB - BACKGROUND: Knowledge about genital Chlamydia trachomatis (CT) infections in the Pacific is limited. In this study we investigated CT infection in Samoan women. METHODS: We recruited women having unprotected sex aged 18 to 29 years from 41 Samoan villages. They completed a questionnaire and provided a urine sample for CT testing by PCR. Associations between CT infection and possible risk factors were explored using logistic regression. RESULTS: Altogether, 239 women were recruited; 86 (36.0%; weighted estimate of prevalence: 41.9%; 95% CI: 33.4-50.5%) were positive for CT infection. A higher proportion of women aged 18 to 24 were positive (54/145; 37.2%) than those aged 25 to 29 (32/94; 34.0%; p=0.20). Being single (OR 1.92; 95% CI: 1.02-3.63) and having two or more lifetime sexual partners (OR 3.02; 95% CI: 1.19-7.67) were associated with CT infection; 27.6% of those with one lifetime partner were positive. Participants who had a previous pregnancy were less likely to be positive (OR 0.49; 95% CI: 0.27-0.87). Primiparous and multiparous women were less likely to be positive than nulliparous women (OR 0.54; 95% CI: 0.30-0.99 and OR 0.46; 95% CI: 0.24-0.89, respectively). CONCLUSIONS: The prevalence of CT infection in these Samoan women is very high. Further studies, including investigating the prevalence of CT infection in men, and strategies for sustainable control are needed. PMID- 25732756 TI - The impact of friends on young adults' drinking over the course of the evening- an event-level analysis. AB - AIMS: To examine whether young adults' alcohol consumption during the course of an evening was affected by the number of friends present, and the interaction between participants' gender and number of friends present. DESIGN: Participants used the internet-based cellphone-optimized assessment technique (ICAT) to complete a series of cellphone questionnaires every Thursday, Friday and Saturday evening over five weekends. A multi-level growth curve model (hourly assessments, clustered within evenings, clustered within individuals) with time-invariant and time-varying covariates was estimated. SETTING: French-speaking Switzerland. PARTICIPANTS: A total of 183 young adults (53.0% female, mean age = 23.1) who completed 7205 questionnaires on 1441 evenings. MEASUREMENTS: Alcohol consumption and number of friends present assessed at 8 p.m., 9 p.m., 10 p.m., 11 p.m. and midnight. FINDINGS: Drinking pace accelerated notably over the course of the evening on Saturdays (b = 0.047; P < 0.01). Men consumed more alcohol than women, particularly at the beginning of the evening (b = 0.152; P < 0.05). However, this effect was no longer significant when the impact of friends was accounted for (b = 0.096; P = 0.139). The higher the number of friends present, the higher the number of drinks consumed at a given time during the course of the evening (b = 0.070; P < 0.001). Cross-level interaction effects indicated that this relationship was stronger for men than women (b = 0.027; P < 0.05). CONCLUSIONS: Among young adults in Switzerland, the number of friends present is associated positively with hourly drinking frequency during the course of weekend evenings. The impact of the drinking group size on alcohol use is stronger for men than women. PMID- 25732757 TI - Diabetes in Kearns-Sayre Syndrome: More Common than Anticipated. PMID- 25732758 TI - Pen needle preference in a population of Canadians with diabetes: results from a recent patient survey. AB - OBJECTIVE: To evaluate the safety and efficacy of insulin injections in patients using 8 mm 31 gauge vs. 5 mm 31 gauge pen needles, as determined by A1C results and to measure individual patient satisfaction and compare overall satisfaction regarding the use of the 2 needles. METHODS: The study was completed as a substudy of a single-site, open-label, randomized, 6-month comparative study consisting of 66 obese patients. Prior to the study, all individuals had treated their diabetes with either long-acting insulin glargine or insulin detemir. At the onset of the study, patients were randomized 1:1 to either insulin glargine or neutral protamine Hagedorn insulin. All patients used an 8 mm pen needle for the first 3 months and a 5 mm pen needle for the remaining 3 months. At the conclusion of the trial, patients completed a questionnaire regarding pen needle satisfaction. RESULTS: The 5 mm needle was preferred by 41.8% of study subjects, while the 8 mm needle was preferred by 27.9% of subjects. For other attributes (i.e. overall injection comfort, pain when inserting the needle into the skin and length of needle), the 5 mm needle scored higher than the 8 mm needle and higher also than the percentage of individuals who indicated no preference. CONCLUSIONS: In patients with insulin-treated type 2 diabetes with a mean single-injection volume dose of basal insulin of 50.2 units, the 5 mm needle was generally preferred over the 8 mm needle. The shorter needle was more comfortable and easier to use while being equally effective in delivering insulin. PMID- 25732759 TI - Treatment for diabetic foot ulcers complicated by major cardiac events. AB - OBJECTIVE: Diabetic foot ulcer (DFU) is a major complication in patients with diabetes mellitus and the leading cause of non-traumatic amputation in adults. Patients with DFU are usually fragile due to chronic diabetic comorbidities; therefore, tedious debridement and intervention procedures may not be well tolerated in patients with DFU. This study aimed to identify a casual relationship between in-hospital complications and treatment for limb-threatening DFUs. METHODS: From 2009 to 2011, 1130 consecutive patients who were admitted to the Diabetic Foot Care Center in Chang Gung Medical Center were surveyed. Rates of in-hospital mortality or events that lead to transfer to the intensive care unit (ICU) for various severe complications were retrospectively analyzed. RESULTS: Forty-seven patients (4.2%) experienced in-hospital complications (28 patients died). Major adverse cardiac events (MACE) (n=21, 44.7%) were the most common complications, followed by nosocomial infection (n=18, 38.3%). Previous myocardial infarction was a risk factor for MACE. The presentation of MACE was fulminant (eg, acute pulmonary edema, cardiogenic shock,cardiac arrest), and occurred within 10 days of admission or within 10 days following a major procedure in most cases. ST-T segment abnormality at rest was the most common presentation of electrocardiography for MACE. CONCLUSION: MACE should be prevented during treatment for limb-threatening DFU in high-risk patients. Acute stress might have caused MACE during the first 10 days after admission or a major procedure. PMID- 25732761 TI - Does using HbA1c inform diagnosis of diabetes in patients with coronary artery disease? PMID- 25732760 TI - Excitable Astrocytes: Ca(2+)- and cAMP-Regulated Exocytosis. AB - During neural activity, neurotransmitters released at synapses reach neighbouring cells, such as astrocytes. These get excited via numerous mechanisms, including the G protein coupled receptors that regulate the cytosolic concentration of second messengers, such as Ca(2+) and cAMP. The stimulation of these pathways leads to feedback modulation of neuronal activity and the activity of other cells by the release of diverse substances, gliosignals that include classical neurotransmitters such as glutamate, ATP, or neuropeptides. Gliosignal molecules are released from astrocytes through several distinct molecular mechanisms, for example, by diffusion through membrane channels, by translocation via plasmalemmal transporters, or by vesicular exocytosis. Vesicular release regulated by a stimulus-mediated increase in cytosolic second messengers involves a SNARE-dependent merger of the vesicle membrane with the plasmalemma. The coupling between the stimulus and vesicular secretion of gliosignals in astrocytes is not as tight as in neurones. This is considered an adaptation to regulate homeostatic processes in a slow time domain as is the case in the endocrine system (slower than the nervous system), hence glial functions constitute the gliocrine system. This article provides an overview of the mechanisms of excitability, involving Ca(2+) and cAMP, where the former mediates phasic signalling and the latter tonic signalling. The molecular, anatomic, and physiologic properties of the vesicular apparatus mediating the release of gliosignals is presented. PMID- 25732762 TI - Management of cardiogenic shock. AB - Cardiogenic shock (CS) remains the most common cause of death in patients with acute myocardial infarction although mortality could be reduced from formerly ~80% to 40-50%. In addition to percutaneous coronary intervention or coronary artery bypass grafting, catecholamines, fluids, intraaortic balloon pumping (IABP), and also active assist devices are widely used for CS management. However, there is only limited evidence for any of the above treatments except for early revascularization and the relative ineffectiveness of IABP. This updated review will therefore outline the management of CS complicating acute myocardial infarction with major focus on evidence-based revascularization techniques, intensive care unit treatment including ventilation, transfusion regimens, adjunctive medication, and mechanical support devices. PMID- 25732763 TI - Erratum: structural basis of AMPK regulation by adenine nucleotides and glycogen. PMID- 25732764 TI - Erratum: anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. PMID- 25732765 TI - Right ventricular function measures as biomarkers of diabetic cardiomyopathy. PMID- 25732766 TI - Response to the letter to the editor by Hammoudi et al. PMID- 25732768 TI - Contrast echo-underutilized? PMID- 25732770 TI - Synthesis, biological investigation and molecular docking study of N-malonyl-1,2 dihydroisoquinoline derivatives as brain specific and shelf-stable MAO inhibitors. AB - A group of N-malonyl-1,2-dihydroisoquinoline derivatives were synthesized and investigated as brain specific and shelf-stable MAO inhibitors. N-malonyl-1,2 dihydroisoquinoline redox carrier system was linked through amidic bond to 4 chloro and 4-nitrobenzylidenehydrazines (9a-b), as monoamine oxidase inhibitors (MAOIs), and beta-phenethylamine (14), as a model drug, to afford a novel group of N-malonyl-1,2-dihydroisoquinoline chemical delivery systems (DHIQCDSs) (13a-b and 18). These systems are expected to be stable against air oxidation due to the presence of the carbonyl group close to nitrogen of the dihydroisoquinoline. The synthesized DHIQCDS (18) was subjected to various chemical and biological investigations to evaluate its stability and prove its ability to cross the blood brain barrier and "lock-in" the brain. The in vitro chemical and enzymatic oxidation studies showed reasonable stability and adequate rate of conversion of DHIQCDS (18) to its corresponding quaternary metabolites. In vivo distribution study in rats revealed preferential concentration of the active moiety in the brain. Moreover, compounds (9a-b, 12a-b and 17) were screened for their in vitro MAO inhibitory activity compared to clorgyline as a reference compound. The inhibition profile was found to be competitive for both MAO-A and MAO-B isozymes with more selectivity toward MAO-A. Molecular docking study of compounds (9a-b, 12a-b and 17) and the suggested metabolites was carried out on both MAO-A and MAO B isozymes. Observation of the docked poses revealed many interactions with many residues previously reported to have an effect on the inhibition of MAO enzyme. PMID- 25732772 TI - Control of varicella in the post-vaccination era in Australia: a model-based assessment of catch-up and infant vaccination strategies for the future - CORRIGENDUM. PMID- 25732771 TI - Bifurcation and dynamics in a mathematical model of early atherosclerosis: How acute inflammation drives lesion development. AB - We present here a mathematical model describing the primary mechanisms that drive the early stages of atherosclerosis. This involves the interactions between modified low density lipoprotein (LDL), monocytes/macrophages, cytokines and foam cells. This model suggests that there is an initial inflammatory phase associated with atherosclerotic lesion development and a longer, quasi-static process of plaque development inside the arterial wall that follows the initial transient. We will show results that show how different LDL concentrations in the blood stream and different immune responses can affect the development of a plaque. Through numerical bifurcation analysis, we show the existence of a fold bifurcation when the flux of LDL from the blood is sufficiently high. By analysing the model presented in this paper, we gain a greater insight into this inflammatory response qualitatively and quantitatively. PMID- 25732773 TI - Linking perception and action by structure or process? Toward an integrative perspective. AB - Over the past decades cognitive neuroscience's renewed interest in action has intensified the search of principles explaining how the cognitive system links perception to action and vice versa. To date, at least two seemingly alternative approaches can be distinguished. Perception and action might be linked either by common representational structures, as assumed by the ideomotor approach, or by common attentional processes, as assumed by the attention approach. This article first reviews the evidence from different paradigms supporting each approach. It becomes clear that most studies selectively focus either on actions directed at goals outside the actors' perceptual range (supporting the ideomotor approach) or on actions directed at targets within the actors' perceptual range (supporting the attention approach). In a second step, I will try to reconcile both approaches by reviewing recent eye movement studies that abolish the classical combination of approach and goals under study. Demonstrating that both approaches cover target- as well as goal-directed actions, it is proposed that operations addressed in both conceptual frameworks interact with each other. PMID- 25732774 TI - Unveiling the charge migration mechanism in Na2O2: implications for sodium-air batteries. AB - Metal-air batteries have become promising candidates for modern energy storage due to their high theoretical energy density in comparison to other storage devices. The lower overpotential of Na compared with Li makes Na-air batteries more efficient in terms of battery lifetime. Additionally, the abundance of Na over Li is another advantage for Na batteries compared to Li batteries. Na2O2 is one of the main products of sodium-air battery reactions. The efficiency of air cells is always related to the charge transport mechanisms in the formed product. To unveil these diffusion mechanisms in one of the main products of the cell reaction Na-O2 we systematically investigate the mobility of charge carriers as well as the electronic structural properties of sodium peroxide. The framework of the density functional theory based on hybrid functional approach is used to study the mobility of charge carriers and intrinsic defects in Na2O2. Our calculations reveal that the formation of small electron and hole polarons is preferentially occurring over the delocalized state in the crystal structure of Na2O2. The migration of these small polarons displays activation energies of about 0.92 eV and 0.32 eV for the electron and hole polarons respectively, while the analysis of the charged sodium vacancy mobility reveals an activation energy of about 0.5 eV. These results suggest that the charge transport in sodium peroxide would mainly occur through the diffusion of hole polarons. PMID- 25732775 TI - A genetic interactome of the let-7 microRNA in C. elegans. AB - The heterochronic pathway controls temporal patterning during Caenorhabditis elegans larval development. The highly conserved let-7 microRNA (miRNA) plays a key role in this pathway, directing the larval-to-adult (L/A) transition. Hence, knowledge of the genetic interactome of let-7 has the potential to provide insight into both control of temporal cell fates and mechanisms of regulation and function of miRNAs. Here, we report the results of a genome-wide, RNAi-based screen for suppressors of let-7 mutant vulval bursting. The 201 genetic interaction partners of let-7 thus identified include genes that promote target silencing activity of let-7, seam cell differentiation, or both. We illustrate the suitability of our approach by uncovering the mitotic cyclin-dependent kinase CDK-1 as a downstream effector of let-7 that affects both seam cell proliferation and differentiation, and by identifying a core set of candidate modulators of let 7 activity, which includes all subunits of the condensin II complex. We propose that the genes identified in our screen thus constitute a valuable resource for studies of the heterochronic pathway and miRNAs. PMID- 25732777 TI - Software for analysing multifocal visual evoked potential signal latency progression. AB - BACKGROUND: This paper describes a new non-commercial software application (mfVEP(2)) developed to process multifocal visual-evoked-potential (mfVEP) signals in latency (monocular and interocular) progression studies. METHOD: The software performs analysis by cross-correlating signals from the same patients. The criteria applied by the software include best channels, signal window, cross correlation limits and signal-to-noise ratio (SNR). Software features include signal display comparing different tests and groups of sectors (quadrants, rings and hemispheres). RESULTS: The software's performance and capabilities are demonstrated on the results obtained from a patient with acute optic neuritis who underwent 9 follow-up mfVEP tests. Numerical values and graphics are presented and discussed for this case. CONCLUSIONS: The authors present a software application used to study progression in mfVEP signals. It is also useful in research projects designed to improve mfVEP techniques. This software makes it easier for users to manage the signals and allows them to choose various ways of selecting signals and representing results. PMID- 25732779 TI - The transverse musculo-cutaneous gracilis flap for breast reconstruction: How to avoid complications. AB - BACKGROUND: The transverse musculocutaneous gracilis (TMG) flap has become a common solution for breast reconstruction. However, the safe skin paddle limits are not yet understood. In this study, we attempted to address this issue based on our experiences with inferior and posterior skin paddle extension. METHODS: Forty-four breast reconstructions with TMG flaps performed between November 2010 and January 2014 were analyzed retrospectively. For the first 20 cases, the flap skin paddle was extended 3 cm posteriorly to the middle thigh (group 1). For the next 20 flaps (group 2), the posterior tip was limited to this line, whereas more fat was recruited inferiorly. In the four cases of group 3, the skin flap was extended posteriorly with a second vascular pedicle from the profunda artery perforator (PAP) flap. The weights and the dimensions of the flaps, operating durations, and postoperative complications of the entire series were analyzed. Groups 1 and 2 were statistically compared. RESULTS: Flap complications were statistically more frequent in group 1 compared with group 2 (45 vs. 0%, P = 0.0012); 40% posterior flap tip necrosis was observed in group 1. Conversely, donor site complications were statistically more frequent in group 2 than in group 1 (40 vs. 5%, P = 0.019) with 35% inner thigh dehiscence. In the TMG with extended PAP flap group, the operating duration was 77 min longer compared with the rest of the series with no donor site complications. In one case, limited necrosis occurred at the anterior skin tip. CONCLUSIONS: Harvesting the posterior portion of the TMG up to the middle of the posterior thigh may lead to partial flap necrosis. Extending subcutaneous fat removal under the inferior skin incision may increase the risk of donor site complications. Adding a second vascular pedicle from the PAP flap may improve posterior TMG tip perfusion at the expense of a longer operation. PMID- 25732778 TI - FPGA-based design and implementation of arterial pulse wave generator using piecewise Gaussian-cosine fitting. AB - Because arterial pulse waves contain vital information related to the condition of the cardiovascular system, considerable attention has been devoted to the study of pulse waves in recent years. Accurate acquisition is essential to investigate arterial pulse waves. However, at the stage of developing equipment for acquiring and analyzing arterial pulse waves, specific pulse signals may be unavailable for debugging and evaluating the system under development. To produce test signals that reflect specific physiological conditions, in this paper, an arterial pulse wave generator has been designed and implemented using a field programmable gate array (FPGA), which can produce the desired pulse waves according to the feature points set by users. To reconstruct a periodic pulse wave from the given feature points, a method known as piecewise Gaussian-cosine fitting is also proposed in this paper. Using a test database that contains four types of typical pulse waves with each type containing 25 pulse wave signals, the maximum residual error of each sampling point of the fitted pulse wave in comparison with the real pulse wave is within 8%. In addition, the function for adding baseline drift and three types of noises is integrated into the developed system because the baseline occasionally wanders, and noise needs to be added for testing the performance of the designed circuits and the analysis algorithms. The proposed arterial pulse wave generator can be considered as a special signal generator with a simple structure, low cost and compact size, which can also provide flexible solutions for many other related research purposes. PMID- 25732780 TI - Germanium nanocrystals as luminescent probes for rapid, sensitive and label-free detection of Fe3+ ions. AB - Luminescent water-soluble germanium nanocrystals (Ge NCs) have been developed as a fluorescent sensing platform for the highly selective and sensitive detection of Fe3+ via quenching of their strong blue luminescence, without the need for analyte-specific labelling groups. The amine-terminated Ge NCs were separated into two discrete size fractions with average diameters of 3.9+/-0.4 nm and 6.8+/ 1.8 nm using centrifugation. The smaller 3.9 nm NCs possessed a strong blue luminescence, with an average lifetime of 6.1 ns and a quantum yield (QY) of 21.5%, which is strongly influenced by solution pH. In contrast, 6.8 nm NCs exhibited a green luminescence with a longer lifetime of 7.8 ns and lower QY (6.2%) that is insensitive to pH. Sensitive detection of Fe3+ was successfully demonstrated, with a linear relationship between luminescence quenching and Fe3+ concentration observed from 0-800 MUM, with a limit of detection of 0.83 MUM. The Ge NCs show excellent selectivity toward Fe3+ ions, with no quenching of the fluorescence signal induced by the presence of Fe2+ ions, allowing for solution phase discrimination between ions of the same element with different formal charges. The luminescence quenching mechanism was confirmed by static and time resolved photoluminescence spectroscopies, while the applicability for this assay for detection of Fe3+ in real water samples was successfully demonstrated. PMID- 25732776 TI - A 190 base pair, TGF-beta responsive tooth and fin enhancer is required for stickleback Bmp6 expression. AB - The ligands of the Bone Morphogenetic Protein (BMP) family of developmental signaling molecules are often under the control of complex cis-regulatory modules and play diverse roles in vertebrate development and evolution. Here, we investigated the cis-regulatory control of stickleback Bmp6. We identified a 190bp enhancer ~2.5 kilobases 5' of the Bmp6 gene that recapitulates expression in developing teeth and fins, with a core 72bp sequence that is sufficient for both domains. By testing orthologous enhancers with varying degrees of sequence conservation from outgroup teleosts in transgenic reporter gene assays in sticklebacks and zebrafish, we found that the function of this regulatory element appears to have been conserved for over 250 million years of teleost evolution. We show that a predicted binding site for the TGFbeta effector Smad3 in this enhancer is required for enhancer function and that pharmacological inhibition of TGFbeta signaling abolishes enhancer activity and severely reduces endogenous Bmp6 expression. Finally, we used TALENs to disrupt the enhancer in vivo and find that Bmp6 expression is dramatically reduced in teeth and fins, suggesting this enhancer is necessary for expression of the Bmp6 locus. This work identifies a relatively short regulatory sequence that is required for expression in multiple tissues and, combined with previous work, suggests that shared regulatory networks control limb and tooth development. PMID- 25732781 TI - [Paediatric dermatology emergencies in a tertiary hospital]. AB - INTRODUCTION: In recent years, the increasing demand for dermatological consultations in the Emergency department has resulted in the publication of a variety of studies on this subject. However, most of them deal with the general population, without taking into account the changes in frequencies found in young children (ages 0-14). OBJECTIVES: To determine the frequency of various dermatological diagnoses made by the on-call paediatrician in the Emergency Department, and after referral to Paediatric Dermatology. MATERIAL AND METHODS: Firstly, a descriptive retrospective study was performed that included all patients aged between 0 and 14 years old who were seen after being referred to the emergency paediatric dermatologist by the on-call paediatrician from June 2010 to December 2013. Secondly, an analytical study was carried by calculating the kappa index calculus, in order to establish the diagnostic concordance between the emergency paediatrician and the paediatric dermatologist. RESULTS: A total of 861 patients, with a mean age of 4.5 years were included. More than half of the skin disorders analysed were eczema (27%) and infections (26%). The 5 main diagnoses were: atopic dermatitis (16%), acute prurigo simplex (5%), tinea (5%), pyogenic granuloma (4%), and molluscum contagiosum (4%). Additional tests were only required in 16% of the cases. The kappa index obtained was 0.206 (95% CI: 0.170-0.241). CONCLUSIONS: The dermatology consultations in the Emergency Department were shown to be frequent and mostly involved minor diseases. Collaboration between paediatricians and dermatologists resulted in a high treatment success rate, leading to a low percentage of additional tests required and a high rate of discharges. PMID- 25732782 TI - Urinary tract infections. PMID- 25732783 TI - Daily monitoring of temporal trajectories of suicidal ideation predict self injury: A novel application of patient progress monitoring. AB - OBJECTIVE: The interpersonal theory of suicide argues that suicidal ideation predicts self-injury. We hypothesized that distinct patterns of suicidal ideation could be identified and these ratings could allow early identification of self injury. METHOD: The sample consisted of 562 psychiatric inpatients who reported suicidal ideation. RESULTS: Latent growth class analysis identified five classes of change in suicidal ideation. Patients who displayed prolonged suicidal ideation could be identified with improved sensitivity (89.66%) and negative predictive power (94%), compared to a model based on routine ratings of suicidality at admission (sensitivity = 50%; negative predictive power = 74%). These patients had a fourfold increased risk of self-injury. CONCLUSIONS: Daily measurement of suicidal ideation may identify inpatients at risk and inform clinical decision-making. PMID- 25732784 TI - Chronic stress experience and burnout syndrome have appreciable influence on health-related quality of life in patients with psoriasis. AB - BACKGROUND: Psoriasis has a negative impact on health-related quality of life (HRQoL) and may favour mental comorbidity. OBJECTIVE: To investigate the contribution of chronic stress and burnout experience to HRQoL and how mental health influences the efficacy of an inpatient rehabilitation measure in psoriasis patients. METHODS: Eighty-four psoriasis patients taking part in a 3 week inpatient rehabilitation measure participated in the study. Severity of psoriasis was assessed with the Psoriasis Area and Severity Index (PASI) and by patients' self-evaluation at the beginning and end of treatment. The following aspects of mental health were explored using validated questionnaires. Symptoms of chronic stress and burnout experience: Trier Inventory for the Assessment of Chronic Stress (TICS) and Shirom Melamed Burnout Measure (SMBM). Symptoms of depression: depression scale of the Patient Health Questionnaire in the German version (PHQ-D). HRQoL: Dermatology Life Quality Index (DLQI) and Short Form Health Survey-8 (SF-8). RESULTS: Linear regression analyses revealed that chronic stress, burnout experience and perceived symptom severity but not clinician assessed severity of psoriasis had independent negative effects on HRQoL. Patients who achieved a PASI reduction of <75% at discharge from the rehabilitation measure had lower baseline QoL and showed more symptoms of depression, chronic stress and burnout than patients who achieved a PASI improvement of >=75. CONCLUSION: Chronic stress and burnout have appreciable influence on HRQoL and may adversely affect treatment success in psoriasis patients. Our data underscore the importance of a multidimensional approach in the management of psoriasis. PMID- 25732786 TI - Combining Voxel-based Lesion-symptom Mapping (VLSM) With A-tDCS Language Treatment: Predicting Outcome of Recovery in Nonfluent Chronic Aphasia. AB - BACKGROUND: Most of transcranial direct current stimulation (tDCS) studies in aphasia have already shown that significant changes in language performance could be improved by increased monitoring of the perilesional cortex in the left lesioned hemisphere with excitatory anodal tDCS (A-tDCS). However, no report to date has investigated which areas may be less predictable or may play a major role in the recovery from language impairment after brain stimulation. OBJECTIVE: We investigated the relationship between the localization of damage in the left hemisphere and the amount of language recovery after A-tDCS. METHODS: We conducted a Voxel-lesion mapping-symptom (VLSM) analysis on twenty non-fluent aphasics who underwent a language treatment in concomitance with left A-tDCS delivered over the left inferior frontal gyrus (IFG) and a sham condition. Significant changes in language performance before and after the two conditions were examined in three language tasks (picture description, noun and verb naming). RESULTS: VLSM analysis revealed that damage to distinct left hemispheric structures and, in particular, to the basal ganglia, the insula and the superior and inferior longitudinal fasciculi, resulted in lower responses to A-tDCS in all language measures. CONCLUSIONS: Beneficial effects after A-tDCS over the left IFG depend on the anatomical integrity of different left subcortical structures among which are the white matter language pathways. Future studies combining different approaches on larger samples of subjects will further elucidate our understanding of how the human brain responds to tDCS. PMID- 25732785 TI - Pairing Speech Sounds With Vagus Nerve Stimulation Drives Stimulus-specific Cortical Plasticity. AB - BACKGROUND: Individuals with communication disorders, such as aphasia, exhibit weak auditory cortex responses to speech sounds and language impairments. Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with tones or tone trains can enhance both the spectral and temporal processing of sounds in auditory cortex, and can be used to reverse pathological primary auditory cortex (A1) plasticity in a rodent model of chronic tinnitus. OBJECTIVE/HYPOTHESIS: We predicted that pairing VNS with speech sounds would strengthen the A1 response to the paired speech sounds. METHODS: The speech sounds 'rad' and 'lad' were paired with VNS three hundred times per day for twenty days. A1 responses to both paired and novel speech sounds were recorded 24 h after the last VNS pairing session in anesthetized rats. Response strength, latency and neurometric decoding were compared between VNS speech paired and control rats. RESULTS: Our results show that VNS paired with speech sounds strengthened the auditory cortex response to the paired sounds, but did not strengthen the amplitude of the response to novel speech sounds. Responses to the paired sounds were faster and less variable in VNS speech paired rats compared to control rats. Neural plasticity that was specific to the frequency, intensity, and temporal characteristics of the paired speech sounds resulted in enhanced neural detection. CONCLUSION: VNS speech sound pairing provides a novel method to enhance speech sound processing in the central auditory system. Delivery of VNS during speech therapy could improve outcomes in individuals with receptive language deficits. PMID- 25732787 TI - Development of PET probes for cancer imaging. AB - Positron emission tomography (PET) is one of the most rapidly growing areas of medical imaging for cancer research. The principal goal of PET imaging is to visualize, characterize, and measure biological processes at the molecular and cellular levels in living subjects using non-invasive procedures. Taking advantage of the traditional diagnostic imaging techniques, PET imaging introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer progression. As a key component of PET technique, an appropriate imaging probe must be able to specifically reach the target of interest in vivo while retaining in the target within reasonable time to be detected. Over the last decade, numerous target-specific PET probes have been developed and evaluated in preclinical and clinical studies. This review provides an overview of recent advances made in PET imaging of cancer biology with a focus on the best-studied biological targets. The trends in developing future PET imaging probes are also discussed. PMID- 25732788 TI - Small-molecule BET inhibitors in clinical and preclinical development and their therapeutic potential. AB - Lysine acetylation is a pivotal mechanism in chromatin processes and the regulation of gene transcription. The acetylated lysine residues of histones are exclusively recognized by bromodomains (BRDs) known as epigenetic reader. Proteins containing BRDs undergo a post-translational modification (PTM) with development of cellular signaling and disease biology. The bromo and extra terminal (BET) proteins are the second subfamily, which play important roles in cellular proliferation, cell cycle progression and chromatin compaction. Recently, a variety of small molecules have been reported to interact with the BET family proteins and accelerate the validation of BET proteins as druggable targets for treatment of cancers, inflammation and related diseases. In this review, we will summarize the small-molecule inhibitors in clinical and preclinical studies of the BET family bromodomains and their medicinal implications. PMID- 25732789 TI - Computational drug repositioning for cancer therapeutics. AB - Due to ever-increasing failure rates, high cost, unsatisfactory safety profile, and limited efficacy associated with anticancer drug development, the repositioning of established non-cancer drugs for new oncology indications has emerged as an increasingly attractive approach to addressing the unmet cancer related medical need. With the rapid development of bioinformatics, chemoinformatics as well as high-performance computing, drug repositioning is becoming more intentional than ever, and a significant surge of computational approaches has been well established to greatly facilitate drug repositioning for cancer treatment. In this review, we provide a brief overview of recent advances in the computational drug repositioning for anticancer applications with a specific emphasis on repositioning of non-cancer drugs by use of various computational approaches. PMID- 25732790 TI - Autophagy regulators as potential cancer therapeutic agents: a review. AB - Autophagy is an important basic metabolic mechanism by engulfing and degrading the unnecessary or dysfunctional cellular components within double-membered autolysosomes to maintain cellular homeostasis. Autophagy has sparkled great interest for its complicated functions in different stages of cancer, and is regarded as a potential target for anticancer therapy. As a suppressor pathway, autophagy prevents tumor initiation and as a survival pathway, autophagy contributes to tumor growth and progression by attenuating cellular metabolic stress and resisting therapeutic agents-induced cell death. Many autophagy regulators have been identified as potential cancer therapeutic agents and some cytotoxic anticancer drugs also induce autophagy. Combination regimen of autophagy regulators with other anticancer agent exhibits desirable efficacy and several protocols are underway in clinical trials. This review delineates the possible role of autophagy in anticancer therapy, and discusses reported potent autophagy regulators in cancer treatment. PMID- 25732791 TI - Membrane permeable lipophilic cations as mitochondrial directing groups. AB - The mitochondrion's negatively charged membrane potential has been well documented to drive the accumulation of membrane permeable delocalized lipophilic cations (DLC). DLC attachments to known bioactive compounds can direct organelle localization and improve drug exposure to targets within the mitochondria. Due to the mitochondria's essential function and its regulation of cell death, DLC targeted therapies are the focus of drug discovery projects altering cellular fate via mitochondrial targets. This review provides an update on recent developments for the two main applications of DLCs: cytoprotective therapies aimed at reducing oxidative stress and cytotoxic therapies aimed at initiating cell death for the treatment of various cancers. Both approaches have produced significant improvements using DLC conjugated compounds that include improved potency, pharmacokinetic properties, and the potential to overcome resistance mechanisms. PMID- 25732792 TI - Targeting Kruppel-like factor 5 (KLF5) for cancer therapy. AB - Kruppel-like factor 5 (KLF5) belongs to a family of zinc-finger-containing transcription factors which are involved in regulating expression of a wide range of genes, thereby affecting diverse cellular functions. The activities of KLF5 are regulated by multiple signaling pathways including Wnt, Ras, TGFbeta, Hippo, Notch, retinoid acid receptor, and hormone receptors. The expression of KLF5 is frequently abnormal in human cancers and the functions of KLF5 are context dependent. Accumulating evidence suggests that KLF5 represents a novel therapeutic target for cancer therapy. In this review, we discuss the potential biological functions of KLF5 associated with several key signaling pathways that are relevant to cancer as well as the involvement of KLF5 in various human cancers. We also describe the progress in the discovery and development of small molecules targeting KLF5 as potential therapeutics that may benefit cancer patients. The challenges and future research directions on the drug discovery of KLF5 ligands are also presented. PMID- 25732793 TI - Inhibition of the histone lysine methyltransferase EZH2 for the treatment of cancer. AB - In recent years, there has been an increased effort in the development of therapies which target an epigenetic mode of action. Among thes e efforts include progress in the development of inhibitors of EZH2 (Enhancer of Zeste Homolog 2), a key epigenetic target with strong disease implications to cancer. Over the last 3+ years, multiple reports describing small molecule inhibitors of EZH2 have been described, including those for chemical probes and drug candidates which have entered the clinic as first-in-class agents. Recent progress in this emerging area is presented in this review. PMID- 25732795 TI - Glucocorticoid Use in Patients With Systemic Lupus Erythematosus: Association Between Dose and Health Care Utilization and Costs. AB - OBJECTIVE: To investigate the determinants of health care utilization and costs with use of glucocorticoid (GC) drugs among adult systemic lupus erythematosus (SLE) patients. METHODS: This cross-sectional study analyzed established SLE patients identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes from a large US insurance claims database in 2007-2011. Five patient groups were defined by their oral GC use during a 1 year period: non-GC users, <60 days of GC use, and >=60 days of GC use in low dosage (<=7.5 mg/day), medium dosage (>7.5 to <=15 mg/day), or higher dosage (>15 mg/day). Annual health care utilization and costs were compared across these groups. Incremental costs of GC groups, calculated as the difference in total health care costs compared with those of the non-GC group, were estimated from multivariable regressions adjusting for demographic/clinical characteristics and stratified by concomitant immunosuppressant use. RESULTS: A total of 50,230 SLE patients were identified (52% non-GC users, 20% <60 days of GC use, and 10% low dose, 10% medium dose, and 8% higher dose of >=60 days of GC use). GC users had higher health care utilization and costs. Incremental costs were significant (all P < 0.01) for medium-dose ($5,319 and $6,913) and higher-dose ($12,517 and $15,019) GC groups, regardless of concomitant immunosuppressant use. The incremental costs for the low-dose GC group with concomitant immunosuppressants ($1,285; P = 0.04) were smaller than the incremental costs for the low-dose GC group without concomitant immunosuppressants ($2,514; P < 0.01). CONCLUSION: GC use, especially at higher doses, was associated with higher health care utilization and costs. Findings in users with concomitant immunosuppressants suggest that therapies with a GC-sparing effect may be associated with lower economic burden in SLE treatment. PMID- 25732794 TI - Influence of a chlor-alkali superfund site on mercury bioaccumulation in periphyton and low-trophic level fauna. AB - In Berlin, New Hampshire, USA, the Androscoggin River flows adjacent to a former chlor-alkali facility that is a US Environmental Protection Agency Superfund site and source of mercury (Hg) to the river. The present study was conducted to determine the fate and bioaccumulation of methylmercury (MeHg) to lower trophic level taxa in the river. Surface sediment directly adjacent to the source showed significantly elevated MeHg (10-40* increase, mean +/- standard deviation [SD]: 20.1 +/- 24.8 ng g(-1) dry wt) and total mercury (THg; 10-30* increase, mean +/- SD: 2045 +/- 2669 ng g(-1) dry wt) compared with all other reaches, with sediment THg and MeHg from downstream reaches elevated (3-7* on average) relative to the reference (THg mean +/- SD: 33.5 +/- 9.33 ng g(-1) dry wt; MeHg mean +/- SD: 0.52 +/- 0.21 ng g(-1) dry wt). Water column THg concentrations adjacent to the point source for both particulate (0.23 ng L(-1)) and dissolved (0.76 ng L(-1)) fractions were 5-fold higher than at the reference sites, and 2-fold to 5-fold higher than downstream. Methylmercury production potential of periphyton material was highest (2-9 ng g(-1) d(-1) dry wt) adjacent to the Superfund site; other reaches were close to or below reporting limits (0. 1 ng g(-1) d(-1) dry wt). Total Hg and MeHg bioaccumulation in fauna was variable across sites and taxa, with no clear spatial patterns downstream of the contamination source. Crayfish, mayflies, and shiners showed a weak positive relationship with porewater MeHg concentration. PMID- 25732796 TI - Violent video games and delinquent behavior in adolescents: A risk factor perspective. AB - Over the years, criminological research has identified a number of risk factors that contribute to the development of aggressive and delinquent behavior. Although studies have identified media violence in general and violent video gaming in particular as significant predictors of aggressive behavior, exposure to violent video games has been largely omitted from the risk factor literature on delinquent behavior. This cross-sectional study therefore investigates the relationship between violent video game play and adolescents' delinquent behavior using a risk factor approach. An online survey was completed by 3,372 Flemish adolescents, aged 12-18 years old. Data were analyzed by means of negative binomial regression modelling. Results indicated a significant contribution of violent video games in delinquent behavior over and beyond multiple known risk variables (peer delinquency, sensation seeking, prior victimization, and alienation). Moreover, the final model that incorporated the gaming genres proved to be significantly better than the model without the gaming genres. Results provided support for a cumulative and multiplicative risk model for delinquent behavior. Aggr. Behav. 41:267-279, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25732797 TI - Mass concentration and health risk assessment of heavy metals in size-segregated airborne particulate matter in Changsha. AB - This study was performed to investigate the concentration and the health risk of heavy metals (HMs: Zn, Pb, Cd, Ni, Fe, Mn, Cr and Cu) in size-segregated airborne particulate matter (APM). APM samples were collected into 9 size fractions (>9.0 MUm, 5.8-9.0 MUm, 4.7-5.8 MUm, 3.3-4.7 MUm, 2.1-3.3 MUm, 1.1-2.1 MUm, 0.7-1.1 MUm, 0.4-0.7 MUm, <0.4 MUm) by an 8 Stage Non-Viable Cascade Impactor in the campus of Hunan University in Changsha. And then 9 fractions of APM were analyzed for HMs by ICP-OES. The total size-segregated APM concentration in the campus of Hunan University ranged from 120.24 to 271.15 MUg/m(3), and the concentration of HMs in APM was in the range of 38.08-13955.14 ng/m(3). The health risk of HMs in APM was evaluated by hazard quotient (HQ) and hazard index (HI) and the results showed that dermal contact and ingestion of APM were the major exposure pathways to human health. The HI values of Cd, Mn, Pb and Cr for children and Cd, Mn and Pb for adults exhibited to be higher than 1 indicating that a non-carcinogenic health effect existed in the APM of the campus of Hunan University. The carcinogenic risks of Cd, Ni and Cr were all bellow the safe value. PMID- 25732798 TI - Black spots for aquatic and terrestrial ecosystems: impact of a perennial cormorant colony on the environment. AB - The global growth of populations of different cormorant species has raised concern on the consequences of their presence in the environment. This study examined the impact of a perennial colony (160 breeding pairs) of great cormorants on terrestrial and aquatic ecosystems. The deposition of bird originating nutrients within the area of colony, their accumulation in soils and the fluxed of chemical substances to a nearby lake were investigated. The impact of cormorants on terrestrial vegetation and microbial pollution of the lake were also studied. The soils beneath the colony were found to contain extremely high concentrations of nitrogen and phosphorus. The overgrowing vegetation was largely limited with nitrophilous and invasive species being more abundant. Increased loads of organic matter, nitrogen and phosphorus were also found in groundwater and particularly, surface runoff. The colony area delivered significant amounts of nutrients to the lake also when the birds were absent. The lake water near colony was also characterized by increased nutrient content and additionally higher number of faecal bacteria. The present results demonstrate the complexity through which the effect of cormorant colonies can be manifested simultaneously in terrestrial and aquatic ecosystem. PMID- 25732799 TI - N-(3-aminopropyl)subergorgamide, a new alkaloid from the gorgonian Paraplexaura sp. AB - A new alkaloid named N-(3-aminopropyl)subergorgamide (1), along with nine known nitrogen-containing compounds (2-10), was isolated from the organic extract of gorgonian Paraplexaura sp. collected from Zhanjiang in Naozhou Island, South China Sea. Their structures were established by detailed MS and NMR spectroscopic analyses, as well as by comparison with literature data. PMID- 25732800 TI - Central amygdalar nucleus treated with orexin neuropeptides evoke differing feeding and grooming responses in the hamster. AB - Interaction of the orexinergic (ORXergic) neuronal system with the excitatory (glutamate, l-Glu) or the inhibitory (GABA) neurosignaling complexes evokes major homeostatic physiological events. In this study, effects of the two ORXergic neuropeptides (ORX-A/B) on their receptor (ORX-2R) expression changes were correlated to feeding and grooming actions of the hibernating hamster (Mesocricetus auratus). Infusion of the central amygdala nucleus (CeA) with ORX-A caused hamsters to consume notable quantities of food, while ORX-B accounted for a moderate increase. Interestingly the latter neuropeptide was responsible for greater frequencies of grooming with respect to both controls and the hamsters treated with ORX-A. These distinct behavioral changes turned out to be even greater in the presence of l-Glu agonist (NMDA) while the alpha1 GABAA receptor agonist (zolpidem, Zol) greatly reduced ORX-A-dependent feeding bouts. Moreover, ORX-A+NMDA mainly promoted greater ORX-2R expression levels with respect to ORX-A treated hamsters while ORX-B+Zol was instead largely responsible for a down regulatory trend. Overall, these features point to CeA ORX-2R sites as key sensory limbic elements capable of regulating eating and grooming responses, which may provide useful insights regarding the type of molecular mechanism(s) operating during feeding bouts. PMID- 25732801 TI - High-resolution MRI vessel wall imaging in varicella zoster virus vasculopathy. AB - Contrast-enhanced vessel wall imaging high-resolution MRI (HRMR) has revealed vessel wall thickening and enhancement in multiple intracranial vasculopathies, including varicella zoster virus (VZV) vasculopathy. We retrospectively reviewed a database of patients with virologically-verified VZV vasculopathy, who underwent initial and follow-up HRMR between April 2011 and May 2014. Six patients were identified. Baseline demographic and clinical characteristics were collected, including stroke risk factors, history of VZV-related disorders, neurological presentation, course and antiviral treatment. Initial HRMR in patients with VZV vasculopathy demonstrated various patterns of stenosis, vessel wall thickening and enhancement, predominantly in terminal internal carotid artery segments and the M1 segment of the middle cerebral arteries. Follow-up HRMR showed improvement of stenosis, with reduced vessel wall thickening and enhancement at multiple times after treatment. HRMR has the potential to assist in diagnosis and treatment of VZV vasculopathy. PMID- 25732802 TI - Letter to the Editor on a paper by Hsiao C-T, Tsai P-C, Liao Y-C, Lee Y-C, Soong B-W. C9ORF72 repeat expansion is not a significant cause of late-onset cerebellar ataxia syndrome. J Neurol Sci 2014;347:322-324. PMID- 25732803 TI - Heterogeneity among patients with Parkinson's disease: cluster analysis and genetic association. AB - The clinical heterogeneity of Parkinson's disease (PD) reveals the presence of several PD subtypes. The objectives of this study were to identify PD subtypes using cluster analysis (CA) and to determine the association between the subtypes and the polymorphisms in LRRK2 (G2385R and R1628P) and GBA (L444P) genes. A k means CA of demographics, disease progression, motor and non-motor symptoms was performed from 1,510 Chinese PD patients from the Chinese National Consortium on Neurodegenerative Diseases. Pearson correlation analysis was performed to eliminate uninformative characteristics. Blood samples from 852 patients were obtained for genetic analysis of LRRK2 and GBA. Genotypic associations between various subtypes and genetic variants were examined using chi-square test. We identified four different subtypes: subtype 1 was non-tremor dominant (NTD, n=469; 31.1%); subtype 2 had a rapid disease progression with late onset (RDP-LO, n=67; 4.4%); subtype 3 had benign pure motor characteristics (BPM, n=778; 51.5%) without non-motor disturbances; and subtype 4 was tremor dominant with slow disease progression (TD-SP, n=196; 13.0%). Subtypes 1, 2, and 4 had similar mean age of onset. No associations were identified between polymorphisms in LRRK2 (R1628P) and GBA (L444P) genes and the four subtypes (P>0.05). PMID- 25732805 TI - The [U2(MU-S2)2Cl8](4-) anion: synthesis and characterization of the uranium double salt Cs5[U2(MU-S2)2Cl8]I. AB - Red plates of Cs5[U2(MU-S2)2Cl8]I were obtained in good yield from the reaction at 1173 K of U, GeI2 or SnI4, and S, with CsCl flux. The compound crystallizes in space group D2h25-Immm of the orthorhombic system in the Cs5[Nb2(MU-S2)2Cl8]Cl structure type. The centrosymmetric [U2(MU-S2)2Cl8]4- anion in the structure has mmm symmetry with the two U4+ atoms separated by 3.747(1) A. Each U atom is coordinated to four Cl atoms and four S atoms from two S22- groups in a square antiprismatic arrangement. The polarized absorbance spectra of Cs5[U2(MU S2)2Cl8]I display prominent optical anisotropy. Magnetic measurements are consistent with the modified Curie-Weiss law at high temperatures. The low temperature behavior may arise from antiferromagnetic coupling of the U4+ ions within the anion. PMID- 25732806 TI - Changes in antitoxic defense systems of the freshwater amphipod Gammarus pulex exposed to BDE-47 and BDE-99. AB - Polybrominated diphenyl ethers (PBDEs) are emerging pollutants widely distributed in aquatic environment. Although the bioaccumulation of this compound has been well studied, few studies have investigated their impacts on antitoxic systems of invertebrates, considering both genders. Here, we have evaluated the effects of BDE-47 and BDE-99 congeners on the antitoxic defence systems of the freshwater amphipod Gammarus pulex, and especially on the multixenobiotic resistance (MXR) activity, as well as the activities of two antitoxic enzymes, the glutathione-S transferase (GST) and the glutathione peroxidases (GPx). Results revealed that BDE-47 and BDE-99 have inhibited the MXR activity whatever the gammarid gender, which could lead to a reduction of the pollutant elimination from the organism. In addition, a gender-biased response and a congener-biased effect on the antitoxic enzymes activities were observed. Indeed, both BDE congener exposures increased the GST activity in males, whereas in females, only BDE-99 congener modified this activity by decreasing it. On the contrary, BDE exposures did not impact the GPx activity in females, while in males BDE-99 has increased it. Results of the present study highlight that a PBDE exposure at 0.1 ug L(-1) modify antitoxic enzymes activities differently according to gender, which could lead to a change in G. pulex sensitivity on the long term. Finally, this work confirms the ecotoxicological implication of gender in the pollutant toxicity assessment, in order to evaluate impact on populations. PMID- 25732807 TI - A quantum protective mechanism in photosynthesis. AB - Since the emergence of oxygenic photosynthesis, living systems have developed protective mechanisms against reactive oxygen species. During charge separation in photosynthetic reaction centres, triplet states can react with molecular oxygen generating destructive singlet oxygen. The triplet product yield in bacteria is observed to be reduced by weak magnetic fields. Reaction centres from plants' photosystem II share many features with bacterial reaction centres, including a high-spin iron whose function has remained obscure. To explain observations that the magnetic field effect is reduced by the iron, we propose that its fast-relaxing spin plays a protective role in photosynthesis by generating an effective magnetic field. We consider a simple model of the system, derive an analytical expression for the effective magnetic field and analyse the resulting triplet yield reduction. The protective mechanism is robust for realistic parameter ranges, constituting a clear example of a quantum effect playing a macroscopic role vital for life. PMID- 25732809 TI - Ancestral state reconstructions require biological evidence to test evolutionary hypotheses: A case study examining the evolution of reproductive mode in squamate reptiles. AB - To understand evolutionary transformations it is necessary to identify the character states of extinct ancestors. Ancestral character state reconstruction is inherently difficult because it requires an accurate phylogeny, character state data, and a statistical model of transition rates and is fundamentally constrained by missing data such as extinct taxa. We argue that model based ancestral character state reconstruction should be used to generate hypotheses but should not be considered an analytical endpoint. Using the evolution of viviparity and reversals to oviparity in squamates as a case study, we show how anatomical, physiological, and ecological data can be used to evaluate hypotheses about evolutionary transitions. The evolution of squamate viviparity requires changes to the timing of reproductive events and the successive loss of features responsible for building an eggshell. A reversal to oviparity requires that those lost traits re-evolve. We argue that the re-evolution of oviparity is inherently more difficult than the reverse. We outline how the inviability of intermediate phenotypes might present physiological barriers to reversals from viviparity to oviparity. Finally, we show that ecological data supports an oviparous ancestral state for squamates and multiple transitions to viviparity. In summary, we conclude that the first squamates were oviparous, that frequent transitions to viviparity have occurred, and that reversals to oviparity in viviparous lineages either have not occurred or are exceedingly rare. As this evidence supports conclusions that differ from previous ancestral state reconstructions, our paper highlights the importance of incorporating biological evidence to evaluate model generated hypotheses. PMID- 25732810 TI - Association Between Increased Vascular Nitric Oxide Bioavailability and Progression to Dengue Hemorrhagic Fever in Adults. AB - In a prospective longitudinal adult study, vascular nitric oxide bioavailability measured as reactive hyperemia index was significantly higher at enrollment in patients who developed dengue hemorrhagic fever (DHF) (n = 11), compared with the non-DHF group (n = 63) and those with other febrile illnesses (n = 25) (P = .01). After adjustment for age, fever day, and body mass index, enrollment reactive hyperemia index was associated with a 4-fold increased risk for DHF, and predicted DHF with an area under the receiver operating curve of 0.86. Increased vascular nitric oxide in dengue is associated with increased vascular permeability and impaired homeostasis and may have utility as a predictor of DHF. PMID- 25732811 TI - A Kunjin Replicon Virus-like Particle Vaccine Provides Protection Against Ebola Virus Infection in Nonhuman Primates. AB - The current unprecedented outbreak of Ebola virus (EBOV) disease in West Africa has demonstrated the urgent need for a vaccine. Here, we describe the evaluation of an EBOV vaccine candidate based on Kunjin replicon virus-like particles (KUN VLPs) encoding EBOV glycoprotein with a D637L mutation (GP/D637L) in nonhuman primates. Four African green monkeys (Cercopithecus aethiops) were injected subcutaneously with a dose of 10(9) KUN VLPs per animal twice with an interval of 4 weeks, and animals were challenged 3 weeks later intramuscularly with 600 plaque-forming units of Zaire EBOV. Three animals were completely protected against EBOV challenge, while one vaccinated animal and the control animal died from infection. We suggest that KUN VLPs encoding GP/D637L represent a viable EBOV vaccine candidate. PMID- 25732812 TI - Novel therapeutic targets in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease that leads to inflammation and destruction of synovial joints. Despite the broad spectrum of antirheumatic drugs, this heterogeneous disease is still not well controlled in up to 30% of patients. Here, we discuss two pathways that are regarded as interesting novel therapeutic targets in the field of rheumatology: the Janus kinase (JAK) pathway and the T helper-17 (Th17) pathway [including interleukin (IL)-17, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. We also review the therapy potential of biologicals and small-molecule inhibitors blocking these pathways. Advances in combination therapy in addition to progress in biomarker screening will help us to further achieve effective and personalized healthcare for patients with RA. PMID- 25732813 TI - Primary cutaneous cribriform carcinoma: report of six cases with clinicopathologic data and immunohistochemical profile. AB - BACKGROUND: Primary cutaneous cribriform carcinoma (PCCC) is a rare and under recognized variant of sweat gland carcinoma, characterized by anastomosing tubules and solid nests producing a sieve-like appearance. METHODS: Six cases of PCCC were clinically, histopathologically and immunophenotypically studied. RESULTS: All cases showed an unencapsulated, nodular dermal tumor composed of solid and cribriform nests, cords and tubules embedded within a desmoplastic stroma. Some tubules showed micropapillary projections reminiscent of tubular adenoma, and intraluminal thin bridges resembling adenomatoid tumor. One case showed a predominantly solid component. Only two cases showed very focal decapitation secretion. Tumor cells expressed CK7, CK5/6, EMA, CEA, S-100, BerEP4 and c-kit and were negative for cytokeratin 20, estrogen receptor/progesterone receptor (ER/PR), androgen receptor and GCDFP-15. Calponin, p63 and smooth muscle actin (SMA) showed absence of a myoepithelial layer. CONCLUSIONS: Contrary to the original reports, our series shows that PCCC may be predominantly solid with only a minor cribriform component, and expresses c-kit and S-100 which may potentially lead to the misdiagnosis of adenoid cystic carcinoma. Immunohistochemical stains may aid in distinction from tubular adenoma. Current data suggest a favorable outcome, as metastatic disease has not been reported to date. PMID- 25732814 TI - Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. AB - Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those >=90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age. PMID- 25732815 TI - STED nanoscopy reveals the ubiquity of subcortical cytoskeleton periodicity in living neurons. AB - In the axons of cultured hippocampal neurons, actin forms various structures, including bundles, patches (involved in the preservation of neuronal polarity), and a recently reported periodic ring-like structure. Nevertheless, the overlaying organization of actin in neurons and in the axon initial segment (AIS) is still unclear, due mainly to a lack of adequate imaging methods. By harnessing live-cell stimulated emission depletion (STED) nanoscopy and the fluorescent probe SiR-Actin, we show that the periodic subcortical actin structure is in fact present in both axons and dendrites. The periodic cytoskeleton organization is also found in the peripheral nervous system, specifically at the nodes of Ranvier. The actin patches in the AIS co-localize with pre-synaptic markers. Cytosolic actin organization strongly depends on the developmental stage and subcellular localization. Altogether, the results of this study reveal unique neuronal cytoskeletal features. PMID- 25732816 TI - Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism. AB - Aggregated alpha-synuclein inclusions are found where cell death occurs in several diseases, including Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. However, the relationship between inclusion formation and an individual cell's fate has been difficult to study with conventional techniques. We developed a system that allows for in vivo imaging of the same neurons over months. We show that intracerebral injection of preformed fibrils of recombinant alpha-synuclein can seed aggregation of transgenically expressed and endogenous alpha-synuclein in neurons. Somatic inclusions undergo a stage-like maturation, with progressive compaction coinciding with decreased soluble somatic and nuclear alpha-synuclein. Mature inclusions bear the post-translational hallmarks of human Lewy pathology. Long-term imaging of inclusion-bearing neurons and neighboring neurons without inclusions demonstrates selective degeneration of inclusion-bearing cells. Our results indicate that inclusion formation is tightly correlated with cellular toxicity and that seeding may be a pathologically relevant mechanism of progressive neurodegeneration in many synucleinopathies. PMID- 25732817 TI - A small-molecule screen for enhanced homing of systemically infused cells. AB - Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains) dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell based therapies. PMID- 25732818 TI - The mitochondrial calcium uniporter controls skeletal muscle trophism in vivo. AB - Muscle atrophy contributes to the poor prognosis of many pathophysiological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca(2+)], which control aerobic metabolism, cell death, and survival pathways. We investigated in vivo the effects of mitochondrial Ca(2+) homeostasis in skeletal muscle function and trophism by overexpressing or silencing the mitochondrial calcium uniporter (MCU). The results demonstrate that in both developing and adult muscles, MCU dependent mitochondrial Ca(2+) uptake has a marked trophic effect that does not depend on aerobic control but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1alpha4 and IGF1-Akt/PKB. In addition, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca(2+) dependent organelle-to-nucleus signaling route that links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in conditions of muscle loss. PMID- 25732819 TI - Identification of a family of fatty-acid-speciated sonic hedgehog proteins, whose members display differential biological properties. AB - Hedgehog (HH) proteins are proteolytically processed into a biologically active form that is covalently modified by cholesterol and palmitate. However, most studies of HH biogenesis have characterized protein from cells in which HH is overexpressed. We purified Sonic Hedgehog (SHH) from cells expressing physiologically relevant levels and showed that it was more potent than SHH isolated from overexpressing cells. Furthermore, the SHH in our preparations was modified with a diverse spectrum of fatty acids on its amino termini, and this spectrum of fatty acids varied dramatically depending on the growth conditions of the cells. The fatty acid composition of SHH affected its trafficking to lipid rafts as well as its potency. Our results suggest that HH proteins exist as a family of diverse lipid-speciated proteins that might be altered in different physiological and pathological contexts in order to regulate distinct properties of HH proteins. PMID- 25732820 TI - Human C6orf211 encodes Armt1, a protein carboxyl methyltransferase that targets PCNA and is linked to the DNA damage response. AB - Recent evidence supports the presence of an L-glutamyl methyltransferase(s) in eukaryotic cells, but this enzyme class has been defined only in certain prokaryotic species. Here, we characterize the human C6orf211 gene product as "acidic residue methyltransferase-1" (Armt1), an enzyme that specifically targets proliferating cell nuclear antigen (PCNA) in breast cancer cells, predominately methylating glutamate side chains. Armt1 homologs share structural similarities with the SAM-dependent methyltransferases, and negative regulation of activity by automethylation indicates a means for cellular control. Notably, shRNA-based knockdown of Armt1 expression in two breast cancer cell lines altered survival in response to genotoxic stress. Increased sensitivity to UV, adriamycin, and MMS was observed in SK-Br-3 cells, while in contrast, increased resistance to these agents was observed in MCF7 cells. Together, these results lay the foundation for defining the mechanism by which this post-translational modification operates in the DNA damage response (DDR). PMID- 25732821 TI - Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture. AB - Topological domains are key architectural building blocks of chromosomes, but their functional importance and evolutionary dynamics are not well defined. We performed comparative high-throughput chromosome conformation capture (Hi-C) in four mammals and characterized the conservation and divergence of chromosomal contact insulation and the resulting domain architectures within distantly related genomes. We show that the modular organization of chromosomes is robustly conserved in syntenic regions and that this is compatible with conservation of the binding landscape of the insulator protein CTCF. Specifically, conserved CTCF sites are co-localized with cohesin, are enriched at strong topological domain borders, and bind to DNA motifs with orientations that define the directionality of CTCF's long-range interactions. Conversely, divergent CTCF binding between species is correlated with divergence of internal domain structure, likely driven by local CTCF binding sequence changes, demonstrating how genome evolution can be linked to a continuous flux of local conformation changes. We also show that large-scale domains are reorganized during genome evolution as intact modules. PMID- 25732822 TI - Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP mediated p53 activation. AB - The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses. PMID- 25732823 TI - DBC1 functions as a tumor suppressor by regulating p53 stability. AB - DBC1 (deleted in breast cancer 1), also known as CCAR2 or KIAA1967, is an important negative regulator of SIRT1 and cellular stress response. Although the Dbc1 gene localizes at a region that is homozygously deleted in breast cancer, its role in tumorigenesis remains unclear. It has been suggested to be either a tumor suppressor or an oncogene. Therefore, the function of DBC1 in cancer needs to be further explored. Here, we report that Dbc1 knockout mice are tumor prone, suggesting that DBC1 functions as a tumor suppressor in vivo. Our data suggest that the increased tumor incidence in Dbc1 knockout mice is independent of Sirt1. Instead, we found that DBC1 loss results in less p53 protein in vitro and in vivo. DBC1 directly binds p53 and stabilizes it through competition with MDM2. These studies reveal that DBC1 plays an important role in tumor suppression through p53 regulation. PMID- 25732824 TI - Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation. AB - Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this change remain unclear. Here, we report that TGF-beta1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify downregulation of isocitrate dehydrogenase 3alpha (IDH3alpha) as a marker for this switch. Furthermore, miR-424 downregulates IDH3alpha during CAF formation. Downregulation of IDH3alpha decreases the effective level of alpha-ketoglutarate (alpha-KG) by reducing the ratio of alpha KG to fumarate and succinate, resulting in PHD2 inhibition and HIF-1alpha protein stabilization. The accumulation of HIF-1alpha, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2. CAFs from tumor samples exhibit low levels of IDH3alpha, and overexpression of IDH3alpha prevents transformation of fibroblasts into CAFs. Our studies reveal IDH3alpha to be a critical metabolic switch in CAFs. PMID- 25732825 TI - Wnt signaling regulates multipolar-to-bipolar transition of migrating neurons in the cerebral cortex. AB - The precise timing of pyramidal cell migration from the ventricular germinal zone to the cortical plate is essential for establishing cortical layers, and migration errors can lead to neurodevelopmental disorders underlying psychiatric and neurological diseases. Here, we report that Wnt canonical as well as non canonical signaling is active in pyramidal precursors during radial migration. We demonstrate using constitutive and conditional genetic strategies that transient downregulation of canonical Wnt/beta-catenin signaling during the multipolar stage plays a critical role in polarizing and orienting cells for radial migration. In addition, we show that reduced canonical Wnt signaling is triggered cell autonomously by time-dependent expression of Wnt5A and activation of non canonical signaling. We identify ephrin-B1 as a canonical Wnt-signaling-regulated target in control of the multipolar-to-bipolar switch. These findings highlight the critical role of Wnt signaling activity in neuronal positioning during cortical development. PMID- 25732826 TI - An organellar nalpha-acetyltransferase, naa60, acetylates cytosolic N termini of transmembrane proteins and maintains Golgi integrity. AB - N-terminal acetylation is a major and vital protein modification catalyzed by N terminal acetyltransferases (NATs). NatF, or Nalpha-acetyltransferase 60 (Naa60), was recently identified as a NAT in multicellular eukaryotes. Here, we find that Naa60 differs from all other known NATs by its Golgi localization. A new membrane topology assay named PROMPT and a selective membrane permeabilization assay established that Naa60 faces the cytosolic side of intracellular membranes. An Nt acetylome analysis of NAA60-knockdown cells revealed that Naa60, as opposed to other NATs, specifically acetylates transmembrane proteins and has a preference for N termini facing the cytosol. Moreover, NAA60 knockdown causes Golgi fragmentation, indicating an important role in the maintenance of the Golgi's structural integrity. This work identifies a NAT associated with membranous compartments and establishes N-terminal acetylation as a common modification among transmembrane proteins, a thus-far poorly characterized part of the N terminal acetylome. PMID- 25732827 TI - Fatty acid elongase 7 catalyzes lipidome remodeling essential for human cytomegalovirus replication. AB - Human cytomegalovirus (HCMV) infection rewires host-cell metabolism, upregulating flux from glucose into acetyl-CoA to feed fatty acid metabolism, with saturated very-long-chain fatty acids (VLFCAs) required for production of infectious virion progeny. The human genome encodes seven elongase enzymes (ELOVL) that extend long chain fatty acids into VLCFA. Here, we identify ELOVL7 as pivotal for HCMV infection. HCMV induces ELOVL7 by more than 150-fold. This induction is dependent on mTOR and SREBP-1. ELOVL7 knockdown or mTOR inhibition impairs HCMV-induced fatty acid elongation, HCMV particle release, and infectivity per particle. ELOVL7 overexpression enhances HCMV replication. During HCMV infection, mTOR activity is maintained by the viral protein pUL38. Expression of pUL38 is sufficient to induce ELOVL7, and pUL38-deficient virus is partially defective in ELOVL7 induction and fatty acid elongation. Thus, through its ability to modulate mTOR and SREBP-1, HCMV induces ELOVL7 to synthesize the saturated VLCFA required for efficient virus replication. PMID- 25732828 TI - Single-cell DNA methylome sequencing and bioinformatic inference of epigenomic cell-state dynamics. AB - Methods for single-cell genome and transcriptome sequencing have contributed to our understanding of cellular heterogeneity, whereas methods for single-cell epigenomics are much less established. Here, we describe a whole-genome bisulfite sequencing (WGBS) assay that enables DNA methylation mapping in very small cell populations (MUWGBS) and single cells (scWGBS). Our assay is optimized for profiling many samples at low coverage, and we describe a bioinformatic method that analyzes collections of single-cell methylomes to infer cell-state dynamics. Using these technological advances, we studied epigenomic cell-state dynamics in three in vitro models of cellular differentiation and pluripotency, where we observed characteristic patterns of epigenome remodeling and cell-to-cell heterogeneity. The described method enables single-cell analysis of DNA methylation in a broad range of biological systems, including embryonic development, stem cell differentiation, and cancer. It can also be used to establish composite methylomes that account for cell-to-cell heterogeneity in complex tissue samples. PMID- 25732829 TI - Cell-type phylogenetics and the origin of endometrial stromal cells. AB - A challenge of genome annotation is the identification of genes performing specific biological functions. Here, we propose a phylogenetic approach that utilizes RNA-seq data to infer the historical relationships among cell types and to trace the pattern of gene-expression changes on the tree. The hypothesis is that gene-expression changes coincidental with the origin of a cell type will be important for the function of the derived cell type. We apply this approach to the endometrial stromal cells (ESCs), which are critical for the initiation and maintenance of pregnancy. Our approach identified well-known regulators of ESCs, PGR and FOXO1, as well as genes not yet implicated in female fertility, including GATA2 and TFAP2C. Knockdown analysis confirmed that they are essential for ESC differentiation. We conclude that phylogenetic analysis of cell transcriptomes is a powerful tool for discovery of genes performing cell-type-specific functions. PMID- 25732830 TI - Plug-and-play genetic access to drosophila cell types using exchangeable exon cassettes. AB - Genetically encoded effectors are important tools for probing cellular function in living animals, but improved methods for directing their expression to specific cell types are required. Here, we introduce a simple, versatile method for achieving cell-type-specific expression of transgenes that leverages the untapped potential of "coding introns" (i.e., introns between coding exons). Our method couples the expression of a transgene to that of a native gene expressed in the cells of interest using intronically inserted "plug-and-play" cassettes (called "Trojan exons") that carry a splice acceptor site followed by the coding sequences of T2A peptide and an effector transgene. We demonstrate the efficacy of this approach in Drosophila using lines containing suitable MiMIC (Minos mediated integration cassette) transposons and a palette of Trojan exons capable of expressing a range of commonly used transcription factors. We also introduce an exchangeable, MiMIC-like Trojan exon construct that can be targeted to coding introns using the Crispr/Cas system. PMID- 25732831 TI - An inducible lentiviral guide RNA platform enables the identification of tumor essential genes and tumor-promoting mutations in vivo. AB - The CRISPR/Cas9 technology enables the introduction of genomic alterations into almost any organism; however, systems for efficient and inducible gene modification have been lacking, especially for deletion of essential genes. Here, we describe a drug-inducible small guide RNA (sgRNA) vector system allowing for ubiquitous and efficient gene deletion in murine and human cells. This system mediates the efficient, temporally controlled deletion of MCL-1, both in vitro and in vivo, in human Burkitt lymphoma cell lines that require this anti apoptotic BCL-2 protein for sustained survival and growth. Unexpectedly, repeated induction of the same sgRNA generated similar inactivating mutations in the human Mcl-1 gene due to low mutation variability exerted by the accompanying non homologous end-joining (NHEJ) process. Finally, we were able to generate hematopoietic cell compartment-restricted Trp53-knockout mice, leading to the identification of cancer-promoting mutants of this critical tumor suppressor. PMID- 25732832 TI - Frailty Screening in the Community Using the FRAIL Scale. AB - OBJECTIVES: To explore the feasibility of using the FRAIL scale in community screening of older Chinese people aged 65 years and older, followed by clinical validation by comprehensive geriatric assessment of those classified as pre-frail or frail. DESIGN: Two-phase study: screening of people aged 65 years and older by trained volunteers, followed by comprehensive geriatric assessment by multidisciplinary staff for those classified as pre-frail or frail. SETTING: Elderly Centers in the New Territories East Region of Hong Kong SAR China. PARTICIPANTS: A total of 816 members of elderly centers attending by themselves or accompanied by relatives. MEASUREMENTS: For phase 1, questionnaire (including demographic, lifestyle, chronic diseases) and screening tools were administered by trained volunteers. These consist of the FRAIL scale, SARC-F to screen for sarcopenia, and mild cognitive impairment using the abbreviated screening for mild cognitive impairment (Abbreviated Memory Inventory for the Chinese). Blood pressure, body mass index, and grip strength were recorded. For phase 2, comprehensive geriatric assessment include questionnaires assessing lifestyle domain (physical activity, nutritional status using the Mini-Nutritional Assessment-Short Form), the physical domain (number of diseases and number of drugs, activities of daily living and instrumental activities of daily living disabilities, geriatric syndromes, self-rated health, sleep quality), cognitive and psychological domain (Mini-Mental State Examination, Geriatric Depression Scale), and social domain (income, housing, living satisfaction, family support). RESULTS: The prevalence of pre-frailty and frailty were 52.4% and 12.5%, respectively. The prevalence for frailty increasing with age from 5.1% for those aged 65-69 years to 16.8% for those >=75, being greater in women compared with men (13.9% vs 4.2%). Of those who were pre-frail or frail (n = 529), 42.5% had sarcopenia and 60.7% had mild cognitive impairment. Among those who were frail (n = 102), sarcopenia and mild cognitive impairment were also frequently present: 12.8% had sarcopenia, 14.7% had mild cognitive impairment, 63.7% had both sarcopenia and mild cognitive impairment, and only 8.8% had neither. In phase 2, participants who were classified as pre-frail or frail (n = 529) were invited for further interviews; 255 participants (48.2%) returned. Compared with the pre frail group, those in the frail group were less physically active, had higher number of chronic diseases, were taking more medications (more were taking sleeping pills), reported more falls, rated their health as poor, had higher prevalence of depressive symptoms and mild cognitive impairment, had higher prevalence of sarcopenia, and a high number of activities of daily living and instrumental activities of daily living disabilities. CONCLUSION: The FRAIL scale may be used as the first step in a step care approach to detecting frailty in the community, allowing targeted intervention to potentially retard decline and future disability. PMID- 25732833 TI - Japanese public long-term care insured: preferences for future long-term care facilities, including relocation, waiting times, and individualized care. AB - OBJECTIVES: Expenditures on long-term care insurance (LTCI) in Japan have been increasing with the aging of the population, which has led to an increase in premiums. To optimize resource allocation, we aim to clarify the priorities of the functions of long-term care facilities from the viewpoint of future beneficiaries. DESIGN: The present study was conducted using a cross-sectional study design. SETTING/PARTICIPANTS: We conducted a mail-in survey targeting 2400 adults aged 50-65 in 8 cities in Japan, and 371 persons responded. MEASUREMENTS: Conjoint analysis was applied to measure participants' preferences for long-term care facility services. Participants read 1 of 2 vignettes of an 80-year-old person with either dementia or a fracture, and were asked to envision it as a possible future scenario for themselves. Participants then completed 8 or 9 tasks to select suitable long-term care facilities for the person described. The questionnaire also contained common questions on participants' personal profiles: age, gender, family situation, education, approximate yearly family income, experience as a family caregiver, dwelling status, present health status, and possibility of requiring long-term care services in the future. RESULTS: The results focused mainly on (1) possibilities of individual choice for daily schedules/meals; (2) availability of regular care staff; (3) room; (4) main daily interactions; (5) necessity of relocation associated with medical deterioration; 6) Waiting time; 7) distance from present residence; and (8) monthly fees. Necessity of relocation associated with medical deterioration was consistently given the greatest importance. Participants with experience as a family caregiver showed significantly greater preference for individualized care and communication. CONCLUSIONS: The option of avoiding relocation was highly valued by participants compared with private rooms and individualized care. The present situation of high demand for intensive care homes for the elderly, provoked by anxiety about future residence, will not change unless a robust system is built to support residents even when their health has deteriorated. Individualized care has been promoted by long-term care insurance policies, but further advances will require efforts to obtain the understanding of the insured. PMID- 25732834 TI - Structural stability and energetics of grain boundary triple junctions in face centered cubic materials. AB - We present a systematic study to elucidate the role of triple junctions (TJs) and their constituent grain boundaries on the structural stability of nanocrystalline materials. Using atomistic simulations along with the nudge elastic band calculations, we explored the atomic structural and thermodynamic properties of TJs in three different fcc materials. We found that the magnitude of excess energy at a TJ was directly related to the atomic density of the metal. Further, the vacancy binding and migration energetics in the vicinity of the TJ were examined as they play a crucial role in the structural stability of NC materials. The resolved line tension which takes into account the stress buildup at the TJ was found to be a good measure in predicting the vacancy binding tendency near the TJ. The activation energy for vacancy migration along the TJ was directly correlated with the measured excess energy. Finally, we show that the resistance for vacancy diffusion increased for TJs with larger excess stored energy and the defect mobility at some TJs is slower than their constituent GBs. Hence, our results have general implications on the diffusional process in NC materials and provide new insight into stabilizing NC materials with tailored TJs. PMID- 25732835 TI - Antileishmanial activity of standardized fractions of Stryphnodendron obovatum (Barbatimao) extract and constituent compounds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Stryphnodendron obovatum Benth. is a Brazilian tree used to treat skin ulceration, promote wound healing, and inhibit the growth of protozoa, including Trypanosoma and Leishmania species. Bioguided fractionation of the ethanol extract of S. obovatum stem bark was performed, and antileishmanial and antioxidant activities of the standardized fractions were analyzed. MATERIALS AND METHODS: Stationary-phase Leishmania amazonensis promastigotes, murine macrophages, and human red blood cells (RBCs) were exposed to plant extract, standardized fractions or isolated compounds for 48 h at 37 degrees C to evaluate their antiparasitic activity and cytotoxicity. The 2,2 diphenyl-1-picryl-hidrazyl assay was used to evaluate antioxidant activity. RESULTS: The S. obovatum extract and fractions showed antileishmanial and antioxidant activity; however, the organic fraction (OF) showed the best efficacy. We identified gallic acid, gallocatechin, epigallocatechin, catechin, and epigallocatechin gallate in the OF fraction. These compounds effectively inhibited L. amazonensis activity, with gallic acid, gallocatechin, and epigallocatechin gallate showing the highest selectivity. Furthermore, the evaluated compounds had no significant effect on murine macrophages and human RBCs. CONCLUSIONS: The compounds present in the S. obovatum plant bark ethanol extract may provide an alternative therapeutic approach for L. amazonensis treatment. PMID- 25732836 TI - Yokukansan, a traditional Japanese medicine, decreases head-twitch behaviors and serotonin 2A receptors in the prefrontal cortex of isolation-stressed mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan, a traditional Japanese (Kampo) medicine, has recently been used to treat the behavioral and psychological symptoms of dementia (BPSD), including aggressiveness, excitability, and hallucination. The present study was designed to investigate the mechanisms underlying the ameliorative effects of yokukansan on BPSD using animals exhibiting hallucination-like behaviors. For this purpose, we initially examined whether chronic isolation stress increases the frequency of hallucination in response to a psychedelic drug. Using this animal model, we next examined the effects of yokukansan on drug-induced hallucination-like behaviors. Finally, we examined the density and mRNA levels of serotonin 2A (5-HT2A) receptors. MATERIALS AND METHODS: Male mice were subjected to isolation stress for six weeks. Yokukansan was incorporated into food pellets, and administered to the mice for six weeks. In some experiments, yokukansan and each of seven constituent herbs were administered orally to the mice for the last two weeks during the six week period of isolation stress. A 5-HT2A receptor agonist, 2,5-dimethoxy-4 iodoamphetamine (DOI, 2.5mg/kg), was injected into the mice, and head-twitch behaviors were quantified. The binding sites of 5-HT2A receptors on the plasma membrane of the prefrontal cortex (PFC) were assessed by a receptor-binding assay using tritium-labeled ketanserin, and the density and affinity were calculated from a Scatchard plot. The level of mRNAs was measured by PCR analyses. RESULTS: Isolation stress enhanced the frequency of the DOI-induced head-twitch response, and yokukansan treatment by feeding significantly reduced this enhancement. Isolation stress significantly increased the 5-HT2A receptor density in the PFC, and yokukansan treatment by feeding as well as administration significantly down regulated this increase. Isolation stress and yokukansan did not affect the affinity. Among seven constituent herbs, Bupleurum Root, Uncaria Hook, Japanese Angelica Root, and Glycyrrhiza down-regulated the increase, but statistically not significant, in which their efficacies were over 50% relative to yokukansan. Neither isolation stress nor yokukansan affected mRNA levels of 5-HT2A receptors. CONCLUSION: Yokukansan attenuated drug-induced hallucination-like behaviors in isolated mice, which is suggested to be mediated by 5-HT2A receptor down regulation in the PFC. This mechanism may underlie the ameliorative effects of yokukansan on hallucination. PMID- 25732837 TI - An ethno botanical perspective of traditional medicinal plants from the Khattak tribe of Chonthra Karak, Pakistan. AB - ETHNO PHARMACOLOGICAL RELEVANCE: The present study was carried out with an aim to gather, evaluate and analyze the ethno botanical information of medicinal uses of the plant species possessed by the native Khattak tribe of the Chonthra, district Karak Pakistan. The region with poor documentation of traditional knowledge, preserving the local traditional knowledge, reporting new as well as rarely reported medicinal properties of medicinal plants, to be tested experimentally for validation. MATERIAL AND METHOD: The medicinal uses of existing plant species were documented by oral communication with 103 people, all over above 60 years of age, born and residing in Chonthra. Information was gathered by semi-structured interviews with further analysis by indices like Relative frequency citation RFC and Medicinal use value MUV. RESULTS: The study resulted with medicinal information on 66 plants species belonging to 34 families (using against 58 health related problems with 83 different preparations mainly administered orally and topical). The dominant families include Brasicaceae and Limiaceae. Withania coagulans and Pegnum harmala were the plant species quoted 100% by the informants with RFC values 1 each. The MUV were scattered between 1.24 and 0.03. The highest MUV were W. coagulans 1.24, Pegnum harmala 1.18, Fagonia cretica 1.14. This study for the first time include Nepeta lagopsis to the ethnobotanical wealth. CONCLUSIONS: This study was an extension to the ethnobotanical research conducted in Khyber Pakhtunkhwa (KPK) Pakistan. The target area being small and less number of plants with limited traditional knowledge can serve basis for further work focusing on rarely or non- reported plant species of pharmacological and phytochemical importance with active metabolite capable of broadening the sources of new drugs. PMID- 25732838 TI - In vitro relaxant and spasmolytic effects of essential oil of Pistacia integerrima Stewart ex Brandis Galls. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pistacia integerrima J.L. Stewart ex Brandis (Family: Anacardiaceae) galls are used in Indian ethnomedicine for its anti asthmatic, sedative and spasmolytic properties, however, there are no scientific studies demonstrating its spasmolytic activity. The present investigation deals with the evaluation of relaxant and spasmolytic activities of the essential oil isolated from the galls of Pistacia integerrima J.L. Stewart ex Brandis (EOPI). MATERIALS AND METHODS: In vitro pharmacological assays were carried out on rabbit jejunum spontaneous contractions, guinea pig ileum. The present investigation studied the relaxation of basal tone of isolated guinea pig ileum by possible involvement of NO, prostaglandins, membrane Na(+) channels, potassium channel, enteric nervous system, adrenoceptors, Ca(2+) channels. Additional studies were conducted for comparison of the relaxant effects of EOPI on CaCl2 induced contraction in calcium free tyrode solution, effect on nifedipine insensitive component of ACh-induced contraction and on the contractile machinery to intracellular [Ca(2+)] on isolated guinea pig ileum. RESULTS: EOPI at non relaxing dose potentiated the isoprenaline induced relaxation of rabbit jejunum. EOPI (50 ug/mL) exhibited 28% relaxation of basal tone of 60 mM K(+) induced contraction which is unaltered by preincubation with 0.5 mM hexamethonium, 0.5 uM Tetrodotoxin, 1 uM indomethacin, and 100 uM L-NG-Nitroarginine Methyl Ester (L NAME). EOPI inhibited Ca(2+) induced contraction of isolated guinea pig ileum in Ca(2+) free medium. EOPI (10 ug/ml) potentiated the reversal of a KCl-induced tonic contraction has been observed in Ca(2+) free medium. CONCLUSION: The present investigation reinforces the use of Pistacia integerrima Stewart ex Brandis as antispasmodic in folk medicine. Moreover, it is demonstrated the involvement of beta- adrenoceptors and calcium channels in this activity, but not the participation of nicotinic receptors, Na(+) channels, prostaglandins or nitric oxide. PMID- 25732839 TI - Multivariate sparse group lasso for the multivariate multiple linear regression with an arbitrary group structure. AB - We propose a multivariate sparse group lasso variable selection and estimation method for data with high-dimensional predictors as well as high-dimensional response variables. The method is carried out through a penalized multivariate multiple linear regression model with an arbitrary group structure for the regression coefficient matrix. It suits many biology studies well in detecting associations between multiple traits and multiple predictors, with each trait and each predictor embedded in some biological functional groups such as genes, pathways or brain regions. The method is able to effectively remove unimportant groups as well as unimportant individual coefficients within important groups, particularly for large p small n problems, and is flexible in handling various complex group structures such as overlapping or nested or multilevel hierarchical structures. The method is evaluated through extensive simulations with comparisons to the conventional lasso and group lasso methods, and is applied to an eQTL association study. PMID- 25732840 TI - FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen presenting cells in patients with multiple sclerosis. AB - OBJECTIVE: We aimed to clarify whether fingolimod has direct effects on antigen presenting cells in multiple sclerosis patients. METHODS: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. RESULTS: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFalpha, IL1-beta and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG specific transgenic T cells exhibiting reduced levels of TNFalpha and IFN-gamma but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. CONCLUSIONS: Our data indicate that fingolimod - apart from trapping lymphocytes in lymph nodes - exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells. PMID- 25732841 TI - Aquaporin-4: A novel diagnostic biomarker for seronegative neuromyelitis optica. PMID- 25732842 TI - Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis. AB - OBJECTIVE: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS. METHODS: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), alpha-sAPP and beta-sAPP; and Abeta38, Abeta40 and Abeta42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 +/- 6.4 years. RESULTS: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 - 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 - 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 - 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 - 20.83); p = 0.05). CONCLUSIONS: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL 40 and GFAP are independent prognostic markers for disability progression in MS. PMID- 25732843 TI - Sensitization pattern of inhalant allergens in children with asthma who are living different altitudes in Turkey. AB - Variability in children's allergic sensitization has been detected not only among different countries but also among cities within the same nation but yet different climatic areas. The aim of this study was to investigate the sensitization pattern of asthmatic children who lived in different altitude areas: the two largest Turkish cities, Istanbul (sea level) and Erzurum (high altitude). Five hundred and twelve asthmatic children (6-15 years old) from Istanbul (western Turkey, at sea level) and 609 from Erzurum (eastern Turkey, at an altitude of 1800 m) were included in the study. All participants underwent skin testing with common inhalant allergens, spirometry, total IgE level, and clinical examination. The positive sensitization ratio to aeroallergens in children with asthma living at sea level was statistically higher than that in children living in the high altitude group [p = 0.001, OR (odds ratio) 4.9 (confidence interval (CI) 3.67-6.459)]. However, pollen sensitization in asthmatic children living in high altitudes was significantly higher than that in children living at sea level [p = 0.00, OR 2.6 (CI 1.79-3.87)]. Children with asthma who live at high altitudes are characterized by higher pollen but lower mite sensitization rates than those living at sea level in Turkey. Different climatic conditions and altitudes may affect aeroallergen sensitization in children with asthma. PMID- 25732845 TI - Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. AB - PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment. PMID- 25732846 TI - Senescence versus apoptosis in chemotherapy. PMID- 25732847 TI - Monitoring of persistent organic pollutants in seawater of the Pearl River Estuary with rapid on-site active SPME sampling technique. AB - An on-site active solid-phase microextraction (SPME) sampling technique coupled with gas chromatography-mass spectrometry (GC-MS) for sampling and monitoring 16 polycyclic aromatic hydrocarbons (PAHs) and 8 organochlorine pesticides (OCPs) in seawater was developed. Laboratory experiments demonstrated that the sampling rate calibration method was practical and could be used for the quantification of on-site sampling. The proposed method was employed for field tests which covered large amounts of water samples in the Pearl River Estuary in rainy and dry seasons. The on-site SPME sampling method can avoid the contamination of sample, the losses of analytes during sample transportation, as well as the usage of solvent and time-consuming sample preparation process. Results indicated that the technique with the designed device can address the requirement of modern environment water analysis. In addition, the sources, bioaccumulation and potential risk to human of the PAHs and OCPs in seawater of the Pearl River Estuary were discussed. PMID- 25732849 TI - Erratum to: dynamics of cochlear synaptopathy after acoustic overexposure. PMID- 25732848 TI - Vascular complications in the diabetic pregnancy. AB - Long-standing hyperglycemia frequently leads to vasculopathy. Microvascular disease is characterized by retinopathy and nephropathy, while macrovascular involvement can affect coronary arteries. Diabetic autonomic neuropathy, when present, is generally associated with retinal and/or renal involvement. Early identification of these diabetic complications allows appropriate counseling and early treatment. Among women with diabetic vasculopathy, nephropathy, chronic hypertension, preeclampsia, preterm delivery, and fetal growth restriction are frequently observed. Furthermore, women with impaired renal function in early pregnancy have increased risk of long-term deterioration of glomerular filtration rate. Proliferative retinopathy can progress during pregnancy and 1 year after delivery, but long-term effects are not likely to occur. When coronary artery disease or gastroparesis diabeticorum are present, excessive maternal and fetal morbidity is observed. When modern management is synchronized with early medical care, favorable maternal and perinatal outcomes can be expected. PMID- 25732850 TI - Human FABP1 T94A variant enhances cholesterol uptake. AB - Although expression of the human liver fatty acid binding protein (FABP1) T94A variant alters serum lipoprotein cholesterol levels in human subjects, nothing is known whereby the variant elicits these effects. This issue was addressed by in vitro cholesterol binding assays using purified recombinant wild-type (WT) FABP1 T94T and T94A variant proteins and in cultured primary human hepatocytes expressing the FABP1 T94T (genotyped as TT) or T94A (genotyped as CC) proteins. The human FABP1 T94A variant protein had 3-fold higher cholesterol-binding affinity than the WT FABP1 T94T as shown by NBD-cholesterol fluorescence binding assays and by cholesterol isothermal titration microcalorimetry (ITC) binding assays. CC variant hepatocytes also exhibited 30% higher total FABP1 protein. HDL and LDL-mediated NBD-cholesterol uptake was faster in CC variant than TT WT human hepatocytes. VLDL-mediated uptake of NBD-cholesterol did not differ between CC and TT human hepatocytes. The increased HDL- and LDL-mediated NBD-cholesterol uptake was not associated with any significant change in mRNA levels of SCARB1, LDLR, CETP, and LCAT encoding the key proteins in lipoprotein cholesterol uptake. Thus, the increased HDL- and LDL-mediated NBD-cholesterol uptake by CC hepatocytes may be associated with higher affinity of T94A protein for cholesterol and/or increased total T94A protein level. PMID- 25732851 TI - Adipose triglyceride lipase is involved in the mobilization of triglyceride and retinoid stores of hepatic stellate cells. AB - Hepatic stellate cells (HSCs) store triglycerides (TGs) and retinyl ester (RE) in cytosolic lipid droplets. RE stores are degraded following retinoid starvation or in response to pathogenic stimuli resulting in HSC activation. At present, the major enzymes catalyzing lipid degradation in HSCs are unknown. In this study, we investigated whether adipose triglyceride lipase (ATGL) is involved in RE catabolism of HSCs. Additionally, we compared the effects of ATGL deficiency and hormone-sensitive lipase (HSL) deficiency, a known RE hydrolase (REH), on RE stores in liver and adipose tissue. We show that ATGL degrades RE even in the presence of TGs, implicating that these substrates compete for ATGL binding. REH activity was stimulated and inhibited by comparative gene identification-58 and G0/G1 switch gene-2, respectively, the physiological regulators of ATGL activity. In cultured primary murine HSCs, pharmacological inhibition of ATGL, but not HSL, increased RE accumulation. In mice globally lacking ATGL or HSL, RE contents in white adipose tissue were decreased or increased, respectively, while plasma retinol and liver RE levels remained unchanged. In conclusion, our study shows that ATGL acts as REH in HSCs promoting the degradation of RE stores in addition to its established function as TG lipase. HSL is the predominant REH in adipocytes but does not affect lipid mobilization in HSCs. PMID- 25732853 TI - Cholesterol sensing by the ABCG1 lipid transporter: Requirement of a CRAC motif in the final transmembrane domain. AB - The ATP-binding cassette (ABC) transporter, ABCG1, is a lipid exporter involved in removal of cholesterol from cells that has been investigated for its role in foam cells formation and atherosclerosis. The mechanism by which ABC lipid transporters bind and recognise their substrates is currently unknown. In this study, we identify a critical region in the final transmembrane domain of ABCG1, which is essential for its export function and stabilisation by cholesterol, a post-translational regulatory mechanism that we have recently identified as dependent on protein ubiquitination. This transmembrane region contains several Cholesterol Recognition/interaction Amino acid Consensus (CRAC) motifs, and its inverse CARC motifs. Mutational analyses identify one CRAC motif in particular with Y667 at its core, that is especially important for transport activity to HDL as well as stability of the protein in the presence of cholesterol. In addition, we present a model of how cholesterol docks to this CRAC motif in an energetically favourable manner. This study identifies for the first time how ABCG1 can interact with cholesterol via a functional CRAC domain, which provides the first insight into the substrate-transporter interaction of an ABC lipid exporter. PMID- 25732855 TI - Infection: Dysregulation of E. coli alpha-hemolysin alters UTI course. PMID- 25732858 TI - Kidney cancer: Orchestration of immune checkpoints has prognostic value in ccRCC. PMID- 25732860 TI - Kidney cancer: Surveillance not inferior in SRM. PMID- 25732852 TI - Polyphosphoinositide binding domains: Key to inositol lipid biology. AB - Polyphosphoinositides (PPIn) are an important family of phospholipids located on the cytoplasmic leaflet of eukaryotic cell membranes. Collectively, they are critical for the regulation of many aspects of membrane homeostasis and signaling, with notable relevance to human physiology and disease. This regulation is achieved through the selective interaction of these lipids with hundreds of cellular proteins, and thus the capability to study these localized interactions is crucial to understanding their functions. In this review, we discuss current knowledge of the principle types of PPIn-protein interactions, focusing on specific lipid-binding domains. We then discuss how these domains have been re-tasked by biologists as molecular probes for these lipids in living cells. Finally, we describe how the knowledge gained with these probes, when combined with other techniques, has led to the current view of the lipids' localization and function in eukaryotes, focusing mainly on animal cells. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25732861 TI - Retrospective study of the perioperative management and complications of ureteral obstruction in 37 cats. AB - OBJECTIVES: To describe perioperative management and complications, risk factors and mortality rates in cats anaesthetized for treatment of ureteral obstruction. STUDY DESIGN: Retrospective, clinical, cohort study. ANIMALS: Thirty-seven client owned cats anaesthetized for ureteral surgery. METHODS: Records with sufficient data for cats treated between March 2010 and March 2013 were examined for breed, age, gender, history, concurrent diseases, pre- and post-anaesthetic biochemical and haematological parameters, American Society of Anesthesiologists classification, anaesthetic protocol, surgical technique, surgeon, perioperative complications and mortality within 48 hours after extubation. Associations between risk factors and outcome variables were evaluated using univariable analysis. Odds ratios and 95% confidence intervals were calculated for significant parameters. Sensitivity and specificity using receiving operator characteristic curve analysis were calculated for creatinine, potassium level and standard base excess (SBE) to denote survival or non-survival. RESULTS: Preoperatively, all cats were azotaemic: mean+/-SD urea was 31.6 +/- 26.9 mmol L( 1) and median (range) creatinine was 562 MUmol L(-1) (95 MUmol L(-1) to off scale). Thirteen cats were hyperkalaemic (K+ 6.5 mmol L(-1)). Anaesthesia-related complications included bradycardia (n=8, 21.6%), hypotension (n=15, 40.5%) and hypothermia (n=32, 86.5%). Seven cats (18.9%) died postoperatively. Non-survivors were significantly (p=0.011) older (9.8+/-1.9 years) than survivors (6.4+/-3.1 years) and had higher potassium concentrations (p=0.040). Risk factors associated with mortality were ASA classes IV and V (p=0.022), emergency procedures (p=0.045) and bicarbonate administration (p=0.002). Non-survivors had higher creatinine concentrations (p=0.021) and lower SBE (p=0.030). CONCLUSION AND CLINICAL RELEVANCE: Intraoperative anaesthetic complications were common; increased age, poor health status, preoperative bicarbonate administration, hyperkalaemia and increased creatinine were associated with increased risk for death and can be used to predict risk for complications. PMID- 25732862 TI - Multiple aster formation is frequently observed in bovine oocytes retrieved from 1-day stored ovaries. AB - We have recently reported that multiple aster formation after in vitro fertilization (IVF) was one of the factors that negatively affected the developmental competence of vitrified-warmed bovine matured oocytes, and that short-term culture of the post-warm oocytes with an inhibitor of Rho-associated coiled-coil kinase (ROCK) suppressed the multiple aster formation and improved the blastocyst yield. The present study was conducted to investigate whether increased multiple aster formation following IVF was involved in impaired developmental competence of stored ovary-derived bovine oocytes. Oocytes retrieved from 1-day stored ovaries had lower developmental potential to day 8 blastocysts when compared with those from fresh ovaries (37 versus 63%). Immunostaining of alpha-tubulin 10 h post-IVF revealed that a higher incidence of multiple aster formation occurred in oocytes retrieved from stored ovaries than from fresh ovaries (31 versus 15%). Treatment of post-in vitro maturated (post IVM) oocytes with ROCK inhibitor for 2 h significantly suppressed the incidence of multiple aster formation (10 versus 32% in the control group). However, the suppression effect of ROCK inhibitor on multiple aster formation in IVM/IVF oocytes did not improve blastocyst yield from stored ovary-derived oocytes (41 versus 37% in the control group). These results suggested that the higher incidence of multiple aster formation by bovine ovary storage was not responsible for the decreased developmental competence of IVF oocytes. PMID- 25732863 TI - Molecular evidence that rough endoplasmic reticulum is the site of calreticulin translation in Petunia pollen tubes growing in vitro. AB - KEY MESSAGE: In germinating pollen grains and growing pollen tubes, CRT is translated on ER membrane-bound ribosomes in the regions where its activity is required for stabilization of tip-focused Ca (2+) gradient. Pollen tube growth requires coordination of signaling, exocytosis, and actin cytoskeletal organization. Many of these processes are thought to be controlled by finely tuned regulation of cytoplasmic Ca(2+) in discrete regions of the tube cytoplasm. Most notably, a mechanism must function to maintain a steep gradient of Ca(2+) that exists at the tip of growing pollen tube. Several pieces of evidence point to calreticulin (CRT) as a key Ca(2+)-binding/-buffering protein involved in pollen germination and pollen tube growth. We previously hypothesized that in germinating pollen and growing tubes, CRT is translated on the ribosomes associated with endoplasmic reticulum (ER) in the regions where its activity might be required. In this report, we have addressed this idea by identifying the sites where CRT mRNA, CRT protein, 18S rRNA, and rough ER are localized in Petunia pollen tubes. We observed all four components in the germinal aperture of pollen grains and in subapical regions of elongating tubes. These results seem to support our idea that CRT is translated on ER membrane-bound ribosomes during pollen germination and pollen tube growth. In elongated pollen tubes, we found CRT mainly localized in the subapical zone, where ER and Golgi stacks are abundant. In eukaryotic cells, these organelles serve as mobile intracellular stores of easily releasable Ca(2+), which can be buffered by proteins such as CRT. Therefore, we postulate that subapical-localized CRT is involved in pollen tube growth by maintaining the stable tip-focused Ca(2+) gradient and thus modulating local Ca(2+) concentration within the tube cytoplasm. PMID- 25732864 TI - A novel tacrine-dihydropyridine hybrid (-)SCR1693 induces tau dephosphorylation and inhibits Abeta generation in cells. AB - AChE inhibitors are the first choice for the treatment of Alzheimer's disease (AD), but they could only delay the progression of cognitive and behavioral dysfunction, and fail to reverse neuronal damage. Calcium channel blockers have been identified to have protective effect on neurons. Thus, therapy targeting both AChE and calcium channels is supposed to be more effective in AD treatment. In the present study, we explored the effect of a synthesized juxtaposition of an AChE inhibitor and a Calcium channel blocker (named (-)SCR1693) on tau phosphophorylation and Abeta generation. The results showed that: (1) Compared with higher concentrations, (-)SCR1693 incubation in low concentrations such as 0.4, 2, 4MUM for 24h did not affect the cell viability of HEK293/tau (HEK293 cells stably transfected with human tau40) and N2a/APP (N2a cells stably transfected with human APP) cells; (2) long-term treatment of cells with ( )SCR1693 (0.4, 2, 5MUM) (24h) induced tau dephosphorylation and reduced the total tau level in HEK293/tau cells. Short-term treatment (6h) also resulted in tau dephosphorylation, but did not reduce the total tau level; and (3) (-)SCR1693 (0.4, 2, 4MUM) incubation inhibited Abeta generation and release dramatically in N2a/APP cells. We conclude that the novel tacrine-dihydropyridine hybrid ( )SCR1693 in low concentrations could reduce total and phosphorylated tau levels, inhibit the generation and release of Abeta in cells. Thus, (-)SCR1693 may be a potential candidate for effectively treating AD. PMID- 25732865 TI - 5-Hydroxytryptamine does not reduce sympathetic nerve activity or neuroeffector function in the splanchnic circulation. AB - Infusion of 5-hydroxytryptamine (5-HT) in conscious rats results in a sustained (up to 30 days) fall in blood pressure. This is accompanied by an increase in splanchnic blood flow. Because the splanchnic circulation is regulated by the sympathetic nervous system, we hypothesized that 5-HT would: 1) directly reduce sympathetic nerve activity in the splanchnic region; and/or 2) inhibit sympathetic neuroeffector function in splanchnic blood vessels. Moreover, removal of the sympathetic innervation of the splanchnic circulation (celiac ganglionectomy) would reduce 5-HT-induced hypotension. In anaesthetized Sprague Dawley rats, mean blood pressure was reduced from 101+/-4 to 63+/-3mm Hg during slow infusion of 5-HT (25MUg/kg/min, i.v.). Pre- and postganglionic splanchnic sympathetic nerve activity were unaffected during 5-HT infusion. In superior mesenteric arterial rings prepared for electrical field stimulation, neither 5-HT (3, 10, 30nM), the 5-HT1B receptor agonist CP 93129 nor 5-HT1/7 receptor agonist 5-carboxamidotryptamine inhibited neurogenic contraction compared to vehicle. 5 HT did not inhibit neurogenic contraction in superior mesenteric venous rings. Finally, celiac ganglionectomy did not modify the magnitude of fall or time course of 5-HT-induced hypotension when compared to animals receiving sham ganglionectomy. We conclude it is unlikely 5-HT interacts with the sympathetic nervous system at the level of the splanchnic preganglionic or postganglionic nerve, as well as at the neuroeffector junction, to reduce blood pressure. These important studies allow us to rule out a direct interaction of 5-HT with the splanchnic sympathetic nervous system as a cause of the 5-HT-induced fall in blood pressure. PMID- 25732866 TI - Acute stress among adolescents and female rape victims measured by ASC-Kids: a pilot study. AB - BACKGROUND: Rape is considered a stressful trauma and often with durable consequences. How the aftermath of rape is for young adolescents' girls considering acute stress is an overlooked field and remains to be studied. AIMS: In this study, we wanted to investigate acute stress among adolescent victims of rape and the psychometric properties of the Acute Stress Checklist for Children (ASC-Kids). METHODS: A clinical sample (n = 79) of raped girls, 13-17 years old who had turned to a special rape victim unit for treatment, answered the ASC Kids. ASC-Kids was also given to a group of minor stressed, non-raped adolescents in the same age range (n = 154) together with the University of California at Los Angeles Post-traumatic Stress Disorder Reaction Index (UCLA PTSD RI), and the Sense of Coherence Scale 13 (SOC-13). RESULTS: The scores from the groups were compared and showed significant differences in mean values on all the diagnostic criteria of acute stress disorder. In the clinical group, 36.7% obtained full ASD criteria. ASC-Kids could discriminate well between groups. Cronbach's alpha was found to be excellent, and the correlation between the UCLA PTSD RI and ASC-Kids found to be good; both ASC-Kids and UCLA PTSD RI had a good and moderate negative correlation with SOC-13. CONCLUSION: Adolescent female rape victims were shown to have a very high level of acute stress, and the ASC-Kids was found to have sound psychometrics and can be a valuable screening instrument to support clinicians in their assessments of an indication of adolescents after potentially stressful events such as rape. PMID- 25732867 TI - A DFT study of the carboxymethyl-phosphatidylethanolamine formation from glyoxal and phosphatidylethanolamine surface. Comparison with the formation of N(epsilon) (carboxymethyl)lysine from glyoxal and L-lysine. AB - Mechanisms of the generation of carboxymethyl compounds Nepsilon (carboxymethyl)lysine (CML) and carboxymethyl-phosphatidylethanolamine (CM-PE) from the reactions between glyoxal and L-lysine, and glyoxal and phosphatidylethanolamine (PE) were studied using the DFT method at the PBE/DNP level of theory. In order to study the reaction with PE, a periodic model of the PE surface was built. The starting surface model includes two molecules of PE, a molecule of monohydrated form of glyoxal, and five water molecules as explicit solvent that form a hydrogen bond network, which are involved in the reactions by stabilizing reaction intermediates and transition states and as proton-transfer carriers, important in all steps of reactions. Both reactions take place in three steps, namely, (1) carbino-diol-amine formation; (2) dehydration; and (3) rearrangement into carboxymethyl final products. The rate-limiting step for the formation of CML/CM-PE was the dehydration stage. The comparison of both reactions in their equivalent stages showed a catalytic role of the PE surface; it is highlighted in the case of dehydration step where its relative free energy barrier had a value of 5.3 kcal mol(-1) lower than that obtained in the L-lysine glyoxal system. This study gives insights into the active role of the phospholipid surface in some chemical reactions that occur above it. Our results also give support to consider the pathway of formation of CML and CM-PE from the reactions between glyoxal and L-lysine, and glyoxal and PE as an alternative pathway for generation of these advanced glycation end-products (AGEs). PMID- 25732868 TI - Kisspeptin expression in mouse Leydig cells correlates with age. AB - BACKGROUND: Kisspeptin, encoded by the Kiss1 gene, has many forms including kisspeptin54, kisspeptin14, kisspeptin13, and kisspeptin10, and all these peptides have the same affinity to their receptor KISS1R encoded by the Kiss1r gene. The KISS1-KISS1R system was discovered in neurons, and many reports stress on their function in the brain. However, recent studies have shown that Kiss1 and Kiss1r are expressed in the testes. The goal of this study was to demonstrate the roles of Kiss1 and Kiss1r in testicular function, especially their steroidogenic activity. METHODS: Kisspeptin10 and the kisspeptin10 antagonist peptide234 were used to determine their effect on testosterone production. Moreover, expression of steroidogenic genes in mouse testes and their gonadosomatic index (weight of the testes divided by the total body weight) and also serum testosterone level were studied between the ages of 2 weeks and 15 weeks. RESULTS: Kisspeptin10 and peptide234 did not affect testosterone production in primary Leydig cells from adult mice. Kiss1 and Esr1 expression also increased during puberty. The peak gonadosomatic index occurred at 4 weeks of age, and serum testosterone levels plateaued after the age of 4 weeks. CONCLUSION: Our results suggest that kisspeptin10 does not affect steroidogenesis in adult Leydig cells, but its pattern of expression follows the stages of testicular development. Future studies should determine if kisspeptin regulates testicular development during puberty. PMID- 25732869 TI - Factors associated with health-related quality of life among injection drug users at methadone clinics in Taipei, Taiwan. AB - BACKGROUND: Health-related quality of life (HRQOL) is widely used as an indicator of health status. However, few studies have examined predictors of HRQOL among injection drug users (IDUs). We investigated factors associated with HRQOL among IDUs in Taiwan. METHODS: In this cross-sectional study, recruited IDUs completed an HRQOL-related interview at methadone clinics in Taipei during 2012-2013. Multiple linear regression was used to identify factors associated with HRQOL. RESULTS: Of 802 eligible participants, 85.4% were male; mean (SD) age was 44.7 (8.7) years. Mean scores for physical, psychological, social, and environmental HRQOL were 13.2, 11.8, 12.5, and 12.5, respectively. In multivariate analysis, social support was significantly associated with better HRQOL in all domains (beta = 0.56, 0.87, 0.83, and 0.64, respectively), while obtaining most income from temporary jobs or other noncriminal sources was significantly associated with worse HRQOL in all domains (beta = -1.00, -1.03, -1.15, and -1.22, respectively). Receiving methadone treatment was associated with good physical and psychological HRQOL (beta = 1.47 and 0.79, respectively), while history of drug overdose (beta = -0.40 and -0.53, respectively), history of cutaneous abscess (beta = -0.45 and -0.53, respectively), and human immunodeficiency virus (HIV) positivity (beta = -0.41 and -0.58, respectively) were associated with lower physical and psychological HRQOL. Male sex (beta = -0.64 and -0.70, respectively) and a greater number of incarcerations (beta = -0.11 and -0.12, respectively) were associated with poor social and environmental HRQOL. CONCLUSION: Poor HRQOL was associated with a number of factors among IDUs at methadone clinics in Taipei, Taiwan. To improve HRQOL in this population, future programs should focus on IDUs with a history of drug overdose. In addition, methadone programs and social support should be integrated to improve HRQOL among this socially marginalized population. PMID- 25732871 TI - Radical-based route to 2-(trifluoromethyl)-1,3,4-oxadiazoles and trifluoromethyl substituted polycyclic 1,2,4-triazoles and dihydrofurans. AB - O-Ethyl S-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl xanthate was readily prepared on a large scale and shown to undergo very efficient intermolecular radical additions to unactivated alkenes. The products were further elaborated by exploiting both radical and ionic processes to provide a variety of trifluoromethyl-substituted derivatives, including medicinally relevant triazoles. In particular, the application of a radical allylation on the initial adducts leads to structures that are able to undergo intramolecular [4 + 2] cycloaddition reactions. PMID- 25732872 TI - High reduction of interfacial charge recombination in colloidal quantum dot solar cells by metal oxide surface passivation. AB - Bulk heterojunction (BHJ) solar cells based on colloidal QDs and metal oxide nanowires (NWs) possess unique and outstanding advantages in enhancing light harvesting and charge collection in comparison to planar architectures. However, the high surface area of the NW structure often brings about a large amount of recombination (especially interfacial recombination) and limits the open-circuit voltage in BHJ solar cells. This problem is solved here by passivating the surface of the metal oxide component in PbS colloidal quantum dot solar cells (CQDSCs). By coating thin TiO2 layers onto ZnO-NW surfaces, the open-circuit voltage and power conversion efficiency have been improved by over 40% in PbS CQDSCs. Characterization by transient photovoltage decay and impedance spectroscopy indicated that the interfacial recombination was significantly reduced by the surface passivation strategy. An efficiency as high as 6.13% was achieved through the passivation approach and optimization for the length of the ZnO-NW arrays (device active area: 16 mm2). All solar cells were tested in air, and exhibited excellent air storage stability (without any performance decline over more than 130 days). This work highlights the significance of metal oxide passivation in achieving high performance BHJ solar cells. The charge recombination mechanism uncovered in this work could shed light on the further improvement of PbS CQDSCs and/or other types of solar cells. PMID- 25732870 TI - Galphaq controls rheumatoid arthritis via regulation of Th17 differentiation. AB - Galphaq, the alpha-subunit of Gq protein, is ubiquitously expressed in mammalian cells. It initially attracted attention for its physiological significance in cardiovascular system. In recent years, studies have also indicated the important roles of Galphaq in regulating immunity, supplying us a new insight into the mechanism of immune regulation. T helper type 17 (Th17) cells are potent inducers of tissue inflammation. Many studies have shown that Th17 cells are major effector cells in the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions such as rheumatoid arthritis (RA). One of our previous studies has shown that Galphaq negatively controls the disease activity of RA. However, how Galphaq controls the pathogenesis of autoimmune disease is not clear. Whether this effect is via the regulation of Th17 differentiation is still not known. We aimed to find out the role of Galphaq in control of Th17 differentiation. We investigated the relationship between Galphaq and Th17 in RA patients. We then investigated the mechanism of how Galphaq regulated Th17 differentiation by using Gnaq(-/-) mice. We observed that the expression of Galphaq was negatively associated with interleukin-17A expression in RA patients, indicating that Galphaq negatively controlled the differentiation of Th17 cells. By using Gnaq(-/-) mice, we demonstrated that Galphaq inhibited the differentiation of Th17 cell via regulating the activity of extracellular signal regulated kinase-1/2 to control the expression of STAT3 (signal transducer and activator of transcription 3) and RORalpha (RAR-related orphan receptor-alpha). These data suggest the possibility of targeting Galphaq to develop a novel therapeutic regimen for autoimmune disease. PMID- 25732873 TI - ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo. AB - Manganese (Mn) is an essential trace element found in many enzymes, however, excessive Mn-exposure can result in manganism which is similar to Parkinson's movement disorder. The mechanisms of manganism are not well-known. The present in vivo study was carried out to determine whether endoplasmic reticulum stress (ER stress) and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity. Sixty-four SD rats were randomly divided into four groups and were administered intraperitoneally with normal saline (NS, as control) or MnCl2 (7.5, 15 and 30 mg/kg body weight, respectively) for 4 weeks. We found that MnCl2 dose dependently accumulate in striatal. HE staining and TUNEL assay results indicated that MnCl2 induced striatal neurocytes apoptosis in both male and female rats. The alterations of ultrastructures showed that MnCl2 resulted in chromatin condensation, mitochondria and ER tumefaction in rat striatal neurocytes. Furthermore, MnCl2 increased the expressions of p-IRE-1, ATF-6alpha, PERK, GRP78, Sigma-1R, CHOP, Bim, Bax, caspase-12 and caspase-3, and decreased the expression of Bcl-2 in rat striatal neurocytes. In conclusion, MnCl2 could induce ER stress and ER stress-mediated apoptosis in rat striatal neurocytes, which might be one of the important mechanisms of Mn-induced neurotoxicity. PMID- 25732874 TI - New tools for the quantitative assessment of prodrug delivery and neurotoxicity. AB - Systemic off-target toxicities, including neurotoxicity, are prevalent side effects in cancer patients treated with a number of otherwise highly efficacious anticancer drugs. In the current study, we have: (1) developed a new analytical metric for the in vivo preclinical assessment of systemic toxicities/neurotoxicity of new drugs and delivery systems; and (2) evaluated, in mice, the in vivo efficacy and toxicity of a versatile and modular NanoDendron (ND) drug delivery and imaging platform that we recently developed. Our paclitaxel-carrying ND prodrug, ND(PXL), is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy. Using click chemistry, we combined ND(PXL) with a traceable beacon, ND(PB), yielding ND(PXL) ND(PB) that functions as a theranostic compound. In vivo fluorescence FRET imaging of this theranostic platform was used to confirm localized delivery to tumors and to assess the efficiency of drug delivery to tumors, achieving 25-30% activation in the tumors of an immunocompetent mouse model of breast cancer. In this model, ND-drug exhibited anti-tumor efficacy comparable to nab-paclitaxel, a clinical formulation. In addition, we combined neurobehavioral metrics of nociception and sensorimotor performance of individual mice to develop a novel composite toxicity score that reveals and quantifies peripheral neurotoxicity, a debilitating long-term systemic toxicity of paclitaxel therapy. Importantly, mice treated with nab-paclitaxel developed changes in behavioral metrics with significantly higher toxicity scores indicative of peripheral neuropathy, while mice treated with ND(PXL) showed no significant changes in behavioral responses or toxicity score. Our ND formulation was designed to be readily adaptable to incorporate different drugs, imaging modalities and/or targeting motifs. This formulation has significant potential for preclinical and clinical tools across multiple disease states. The studies presented here report a novel toxicity score for assessing peripheral neuropathy and demonstrate that our targeted, theranostic NDs are safe and effective, providing localized tumor delivery of a chemotherapeutic and with reduced common neurotoxic side-effects. PMID- 25732876 TI - Relationship representations and change in adolescents and emerging adults during psychodynamic psychotherapy. AB - OBJECTIVE: Two groups of clients at sequential developmental stages, adolescents and emerging adults, were compared regarding their presenting problems, psychological distress, and relationship representations over one year of psychotherapy. METHOD: Thirty adolescents aged 14-18 years and 30 emerging adults aged 22-28 years, with similar demographic background, completed outcome measures and interviews according to the Core Conflictual Relationship Theme (CCRT) method. RESULTS: The groups differed significantly in the presenting problems but did not differ in their initial levels of distress; their symptoms improved to a similar extent after one year of psychotherapy; differences between the groups in the representations of others were consistent with age-specific developmental challenges; levels of representations were associated with levels of symptoms at the end-point of treatment. CONCLUSION: Clinicians need to be attuned to the specific difficulties and challenges of these continuous yet distinct developmental stages. PMID- 25732875 TI - Increased behavioral economic demand and craving for alcohol following a laboratory alcohol challenge. AB - BACKGROUND AND AIMS: Although increases in subjective alcohol craving have been observed following moderate doses of alcohol (e.g. priming effects), the effects of alcohol consumption on behavioral economic demand for alcohol are largely unstudied. This study examined the effects of alcohol intoxication on alcohol demand and craving. DESIGN: A between-subjects design in which participants were randomly assigned to either an alcohol (n = 31), placebo (n = 29) or control (n = 25) condition. SETTING: A laboratory setting at the University of Missouri, USA. PARTICIPANTS: Eighty-five young adult moderate drinkers were recruited from the University of Missouri and surrounding community. MEASUREMENTS: Change in demand for alcohol across time was measured using three single items: alcohol consumption at no cost (i.e. intensity), maximum price paid for a single drink (i.e. breakpoint) and total amount spent on alcohol (i.e. Omax). Alcohol demand at baseline was also assessed using an alcohol purchase task (APT). Craving was assessed using a single visual analog scale item. FINDINGS: In the alcohol group compared with the combined non-alcohol groups, intensity, breakpoint and craving increased from baseline to the ascending limb and decreased thereafter (Ps < 0.05; Omax , P = 0.06). Change in craving following alcohol consumption was significantly associated with change in each of the demand indices (Ps < 0.0001). Finally, the demand single items were associated with corresponding indices from the APT (Ps < 0.05). CONCLUSIONS: Alcohol demand increases following intoxication, in terms of both the maximum amount people are willing to pay for one drink and the number of drinks people would consume if drinks were free. Behavioral economic measures of alcohol value can complement subjective craving as measures of moment-to-moment fluctuations in drinking motivation following intoxication. PMID- 25732877 TI - [Investigation of Pneumocystis jirovecii colonization in patients with pulmonary diseases]. AB - OBJECTIVE: The detection of Pneumocystis jirovecii or its DNA in respiratory samples from individuals who do not have signs or symptoms of pneumonia has been defined as colonization. In this study, we aimed to investigate the prevalence of P. jirovecii colonization in patients with various lung diseases. METHODS: Thirty patients who were followed-up and who had undergone bronchoscopy for diagnosis of different underlying diseases or pulmonary signs were included in the study. Bronchoalveolar lavage (BAL) fluids of these patients were analyzed with nPCR amplification of the mt-LSUrRNA gene of P. jirovecii. In addition to nPCR, giemsa, Gomori's methenamine silver (GMS), and indirect fluorescence antibody (IFA) staining assays were applied to all samples. RESULTS: P. jirovecii DNA was detected in 21 of 30 (70%) BAL samples by nPCR. However, P. jirovecii cysts were found in 1 of 21 nPCR-positive samples by giemsa and GMS. IFA assay showed six samples to be positive, but only four of them were found to be positive by nPCR. CONCLUSION: Result of our study showed that prevalence of P. jirovecii colonization is particularly high in patients with chronic pulmonary diseases, and nPCR was a good assay for evaluation of the colonization of P. jirovecii. PMID- 25732878 TI - Investigation of anti-Toxoplasma gondii antibodies in water buffaloes (Bubalus bubalis) in Samsun and Afyon provinces. AB - OBJECTIVE: The present study was conducted to investigate the seroprevalence of Toxoplasma gondii infection in water buffaloes. METHODS: The research was conducted on 131 water buffaloes from Samsun and Afyon provinces. Serum samples of buffaloes were tested for toxoplasmosis with the Sabin Feldman Dye Test (SFDT), using live tachyzoites and methylene-blue dye. RESULTS: 87.79% of buffaloes had anti-Toxoplasma gondii antibodies titered 1:16 and more. No statistically significant difference was observed between the age and gender of buffaloes with infection (p>0.05). CONCLUSION: These results show that toxoplasmosis is quite common in water buffaloes in the regions of study. PMID- 25732879 TI - [Retrospective evaluation of the results of female patients of childbearing age at a microbiology laboratory for screening Toxoplasma gondii in Kocaeli Derince]. AB - OBJECTIVE: The aim of the previous study was to retrospectively analyze the seropositive rate of Toxoplasma among women of childbearing age who were suspected to have toxoplasmosis at the Microbiology Laboratory of Kocaeli Derince Education and Research Hospital. METHODS: The presence of Toxoplasma antibodies (IgM, IgG) with Axsym commercial ELISA kits between January 2009 and February 2011 and the presence of Toxoplasma antibodies (IgM, IgG) with Architect commercial ELISA kit between February 2011 and June 2012 were investigated in a total of 943 sera from women included in the study. RESULTS: The seropositive rate of anti-Toxoplasma IgG and IgM in the study was 28.5% (N=741), 0.9% (N=898), respectively. Additionally, 10 samples (1.3%) were considered as border-line for IgG antibodies and 4 samples (0.4%) for IgM antibodies against T. gondii. CONCLUSION: In general, 70.2% of women in the study were seronegative for anti Toxoplasma IgG antibodies; it can be concluded that most of them were sensitive to a newly acquired infection, and that their babies were at risk of congenital toxoplasmosis in case of a possible pregnancy. In conclusion, the present study suggested that toxoplasmosis was still an emerging public health problem in study area, and particularly, women of reproductive age should be warned and informed about toxoplasmosis. PMID- 25732880 TI - [Seroprevalence rates of Toxoplasma gondii, rubella, cytomegalovirus, syphilis, and hepatitis B, seroprevalences rate in the pregnant population in Istanbul]. AB - OBJECTIVE: We retrospectively evaluated the rate of Toxoplasma gondii, rubella, syphilis, cytomegalovirus, and hepatitis B in Istanbul to compare these results with those of other literature and to contribute to the national screening program. METHODS: The study was conducted in 2011 with women in the first trimester of pregnancy, with ages ranging between 16 and 48 years, in Bakirkoy Training and Research Hospital's outpatient pregnancy clinic between January 2008 and January 2013. The mean age of pregnant women was 28.12+/-5.53, and the mean gravidity was 1.76+0.84.The seropositivities of T. gondii IgM and IgG, cytomegalovirus IgM and IgG, rubella IgM and IgG, VDRL (syphilis), HbsAg, anti HBsAg were evaluated by ELISA method and evaluated in relation with age and parity. RESULTS: The seropositivity rates were as follows: T. gondii IgM: 0.8%, T. gondii IgG: 31.4%, cytomegalovirus IgM: 0.8%, cytomegalovirus IgG: 99.3%, rubella IgM: 0.2%, rubella IgG: 95.7%, VDRL: 0%, HbsAg: 1.2%, and anti-HbsAg: 26.3%. Also, pregnant women with T. gondii IgG(+) were older than pregnant women with T. gondii IgG(-), and this was statistically significant (p<0.005). Pregnant women with anti-HbsAg(+) were older than pregnant women with anti-HbsAg IgG(-), and this was statistically significant (p<0.005). Also, pregnant women with anti HbsAg(+) had higher gravidity rates than pregnant women with anti-HbsAg(-), and this was statistically significant (p<0.005). CONCLUSION: To protect from perinatally transmitted diseases, vaccination programs against rubella and hepatitis B should be extended, and educational programs including the whole country should be arranged. Screening of high-risk pregnant women will be more appropriate when considering the financial charges of screening programs performed for early detection of perinatal infections and for protecting the fetus. PMID- 25732881 TI - [Knowledge levels about some ectoparasites in owners of dairy cattle enterprises in the Kars province of Turkey]. AB - OBJECTIVE: One of the most important problems in the livestock sector in Turkey is the failure to provide the desired yield increase in animal production. In dairy cattle enterprises owner's in Kars province in order to detect their knowledge level about recognition of some ectoparasites and protection methods from them. METHODS: In this study, a survey was conducted in 26 villages with a total of 92 producers in Kars province. RESULTS: Producers, participating in the study, are involved with livestock activity average 24.33 years, veterinary and vaccines--drug costs the average annual 161.42 TL for parasitic diseases, and the most common parasitic drug ivermectin was used with the oxfendazole-derived drugs. A total of 78.3% of producers expressed that there were lice, fleas, and ticks over animals, but only 59.8% of them gave the wrong answer to the question of "Lice, fleas, ticks, and mange. Is it a parasite?" The study also showed that among producers who have information about hypoderma infection, only 14.3% of them apply the vaccine /drug at the right time. CONCLUSION: As a result, producers in the region do not have enough knowledge about parasitic diseases, and irrational drug use was found to be common. PMID- 25732882 TI - [Morphological features of Bundleia spp. (Ciliophora: Entodiniomorphida: Buetschliidae) and ontogenesis in Bundleia Cunha and Muniz 1928]. AB - OBJECTIVE: The aim of this study was to investigate the morphological features of 7 endocommensal ciliates, B. (s. str.) postciliata, B. (s. str.) piriformis, B. (s. str.) nana, B. (C.) elongata, B. (C.) triangularis, B. (F.) dolichosoma, and B. (F.) inflata belonging to the genus Bundleia, which exist in the hindgut of 15 Rahvan horses and 15 racing horses living in the vicinity of Izmir and to investigate the ontogenesis in the Bundleia genus. METHODS: Specimens were obtained from 30 horses and were fixed with 10% formalin. The morphological features of the species were investigated with the pyridinated silver carbonate impregnation and silver nitrate impregnation techniques at the level of light microscopy. RESULTS: The morphological features of Bundleia spp. were found to be similar to the original descriptions, and it was detected that ontogenesis in the Bundleia genus exhibited suitability with other ciliate species in the Entodiniomorphida order. CONCLUSION: We conclude that the geographical variation and feeding habits of host animals are important for evaluating the biometric data of species. PMID- 25732883 TI - [Recommendations to researchers who will study lice (Phthiraptera) of wild birds (Aves) in Turkey]. AB - Lice (Antennata: Phthiraptera) fauna in Turkey is not a well-known field. A large number of lice species described up to date parasitize birds. Most bird species of nearly 500 species in Turkey have not been examined from the perspective of louse specimen. No louse was seen on some examined species, and that is why lice fauna on poultry have not been searched out well. This paper emphasizes on what researchers need to pay attention in the course of research, which features and knowledge they need to have, and which morphological criteria they need to examine during diagnosis of lice. PMID- 25732884 TI - Infection with Crenosoma striatum lungworm in Long-eared Hedgehog (Hemiechinus auritus) in Kerman province southeast of Iran. AB - Hedgehogs are distributed in different areas of Iran. Unfortunately, clinical and parasitological studies on parasites of hedgehogs are very few. Crenosoma striatum is a common lungworm in hedgehogs. C. striatum infection can cause weight loss, dry cough, bronchitis with ulcerous reactions based on secondary bacterial infections, pulmonary damage, thickening of the tracheal wall, and pulmonary emphysema up to cardiovascular failure. In this survey, six dead hedgehogs (Hemiechinus auritus) were investigated for lungworm infection. All the six hedgehogs had C. striatum infection in their lungs. PMID- 25732885 TI - [A case of malaria with uveitis, hyperglycemia, and rasha in a Turkish radiologist who went to Africa]. AB - Malaria is still an important health problem worldwide, particularly in Sub Saharan Africa. In Turkey, the most common type of malaria is Plasmodium vivax, and endemic regions are South-Eastern Anatolia and Cukurova. Due to globalization and tourism, travel-associated infection due to P. falciparum is also seen more frequently in Turkey. P. falciparum malaria can be highly fatal despite optimal antimalarial treatment. We present a case of falciparum malaria in a Turkish radiologist who went to Africa for occupational reasons and come back with malaria accompanied by uveitis, hyperglycemia, and purpuric rash. PMID- 25732886 TI - Anaphylactic shock due to unruptured hepatic hydatid cyst complicated by multiple intrahospital infections. AB - Anaphylactic shock due to unruptured hydatid cyst is a rare complication of hepatic echinococcosis. Here, we present an unusual case of unruptured hydatid cyst causing anaphylactic shock followed by appendicitis, ileus, and complicated by septic condition due to multiple intrahospital infections. Decision of the surgical cyst removal at the right moment and appropriate antimicrobial treatment are key factors for a positive outcome. PMID- 25732887 TI - Primary subcutaneous hydatid cyst over thoracic spine: a case report and review of the literature. AB - Hydatid disease is a public health problem in endemic areas. Although it is most commonly present in the liver and lung, it rarely affects other tissues. A 62 year-old female patient was admitted to our outpatient clinic with a palpable, moderately mobile mass over the thoracic spine. On MRI, a cystic lesion, hypointense and hyperintense on T1- and T2-weighted scans, respectively, was detected. During surgery, a well capsulated cyst was excised en bloc. On histological examination, a hydatid cyst was diagnosed. Her postoperative serological test was positive. Her whole body was scanned for any other organ involvement, but scans were all negative. She was treated with albendazol. After 3 months, the test result was negative, and there were no local or systemic recurrences. Primary subcutaneous tissue involvement is a rarely reported entity in the literature. To the best of our knowledge, this is the first case report of a primary subcutaneous hydatid cyst detected over the thoracic spine. PMID- 25732888 TI - [Is the agent of cutaneous leishmaniasis in Sanliurfa changing? First cases of Leishmania major]. AB - Today, almost 2 million new leishmaniasis cases are noted annually; 1.5 million of these are cutaneous (CL), and others are visceral leishmaniasis (VL). In Sanliurfa, CL cases caused by Leishmania tropica but not by other agents such as L. infantum and L. major. L. tropica is a unique parasite species in Sanliurfa and is the causative agent of anthroponotic CL (transmitted from human to vector to human). Our aim was to report 3 new CL cases due to L. major ( 2 autochthonous and 1 imported) identified in Sanliurfa. Lesion aspiration samples taken from patients were inoculated into NNN culture. Following successful isolation in NNN, promastigotes were obtained by mass culture using RPMI + 20% FCS medium. Parasites species were identified as L. major using ITS-1 PCR-RFLP analysis. This is the first report of autochthonous CL cases caused by L. major in Sanliurfa, and it is estimated that the number of such cases will increase in this region. Public health measures should be taken for L. major infections, while researchers should plan field studies to identify the vectors and reservoirs of L. major. PMID- 25732889 TI - Syndrome of inappropriate antidiuretic hormone associated with Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is a potentially fatal systemic disease in children caused by a tick- borne virus. Many different clinical and laboratory findings are seen in CCHF. We report here an atypical presentation of CCHF with hyponatremia. CCHF with electrolyte imbalance is not reported before. A 4-year old girl presented with fever, fatigue and unconsciousness with hyponatremia. Based on the clinical and epidemiological findings, virus infection was suspected. Hyponatremia is has never been reported in Crimean-Congo hemorrhagic fever (CCHF), as was observed in this case. The diagnosis was confirmed by detection of IgM antibody to CCHF virus and positive Real-Time PCR. We report the first case of imported CCHF presenting as hyponatremia. This electrolyte imbalance has never been reported before in CCHF in children, and the clinician should consider this entity in complications to explain unconsciousness. PMID- 25732890 TI - [Infestation of the human digestive system with beetle larvae (Coleoptera: Cantharidae): a case report]. AB - This study was conducted to report the digestive system infestation caused by the larvae of Coleoptera in a female pediatric patient. She was admitted to our hospital with the complaints of emergence of insect larvae from her vomit and feces, abdominal pain, inguinal pain, lack of appetite, hair loss, excessive cleaning behavior, extreme irritability, and distractibility. The larvae observed typically had the morphology of the larvae of insects related to the Cantharidae family in the Coleoptera order. For treatment, a single dose of albendazole (400 mg) was used. Consequently, in the present case, it was seen that the larvae of Coleoptera incidentally taken orally could continue to live for a period in the digestive tract of people, without losing vitality, and the larvae caused a variety of symptoms due to both their toxic agents and the possible irritation they caused. PMID- 25732891 TI - Clinical exacerbation developing during treatment of cutaneous leishmaniasis: an id reaction? PMID- 25732892 TI - A meta-analysis of heritability of cognitive aging: minding the "missing heritability" gap. AB - The etiologies underlying variation in adult cognitive performance and cognitive aging have enjoyed much attention in the literature, but much of that attention has focused on broad factors, principally general cognitive ability. The current review provides meta-analyses of age trends in heritability of specific cognitive abilities and considers the profile of genetic and environmental factors contributing to cognitive aging to address the 'missing heritability' issue. Our findings, based upon evaluating 27 reports in the literature, indicate that verbal ability demonstrated declining heritability, after about age 60, as did spatial ability and perceptual speed more modestly. Trends for general memory, working memory, and spatial ability generally indicated stability, or small increases in heritability in mid-life. Equivocal results were found for executive function. A second meta-analysis then considered the gap between twin-based versus SNP-based heritability derived from population-based GWAS studies. Specifically, we considered twin correlation ratios to agnostically re-evaluate biometrical models across age and by cognitive domain. Results modestly suggest that nonadditive genetic variance may become increasingly important with age, especially for verbal ability. If so, this would support arguments that lower SNP based heritability estimates result in part from uncaptured non-additive influences (e.g., dominance, gene-gene interactions), and possibly gene environment (GE) correlations. Moreover, consistent with longitudinal twin studies of aging, as rearing environment becomes a distal factor, increasing genetic variance may result in part from nonadditive genetic influences or possible GE correlations. Sensitivity to life course dynamics is crucial to understanding etiological contributions to adult cognitive performance and cognitive aging. PMID- 25732893 TI - Patterns of trophic niche divergence between invasive and native fishes in wild communities are predictable from mesocosm studies. AB - Ecological theory attempts to predict how impacts for native species arise from biological invasions. A fundamental question centres on the feeding interactions of invasive and native species: whether invasion will result in increased interspecific competition, which would result in negative consequences for the competing species, or trophic niche divergence, which would facilitate the invader's integration into the community and their coexistence with native species. Here, the feeding interactions of a highly invasive fish, topmouth gudgeon Pseudorasbora parva, with three native and functionally similar fishes were studied to determine whether patterns of either niche overlap or divergence detected in mesocosm experiments were apparent between the species at larger spatial scales. Using stable isotope analysis, their feeding relationships were assessed initially in the mesocosms (1000 L) and then in small ponds (<400 m(2) ) and large ponds (>600 m(2) ). In the mesocosms, a consistent pattern of trophic niche divergence was evident between the sympatric fishes, with niches shifting further apart in isotopic space than suggested in allopatry, revealing that sharing of food resources was limited. Sympatric P. parva also had a smaller niche than their allopatric populations. In eight small ponds where P. parva had coexisted for several years with at least one of the fish species used in the mesocosms, strong patterns of niche differentiation were also apparent, with P. parva always at a lower trophic position than the other fishes, as also occurred in the mesocosms. Where these fishes were sympatric within more complex fish communities in the large ponds, similar patterns were also apparent, with strong evidence of trophic niche differentiation. Aspects of the ecological impacts of P. parva invasion for native communities in larger ponds were consistent with those in the mesocosm experiments. Their invasion resulted in divergence in trophic niches, partly due to their reduced niche widths when in sympatry with other species, facilitating their coexistence in invaded ecosystems. Our study highlights the utility of controlled mesocosm studies for predicting the trophic relationships that can develop from introductions of non-native species into more complex ecosystems and at larger spatial scales. PMID- 25732894 TI - Neutrophilic urticarial dermatosis (NUD) indicating Cryopyrin-associated periodic syndrome associated with a novel mutation of the NLRP3 gene. PMID- 25732895 TI - Combination of a multimode antenna and TIAMO for traveling-wave imaging at 9.4 Tesla. AB - PURPOSE: To investigate the performance of a multimode antenna combined with time interleaved acquisition of modes (TIAMO) for improved (1)H image homogeneity as compared to conventional traveling-wave imaging in the human brain at 9.4 Tesla (T). METHODS: An adjustable three-port antenna was built to stimulate the propagation of three basic waveguide modes within a 9.4 T scanner bore. For TIAMO, two time-interleaved acquisitions using different linear combinations of these modes were optimized to achieve a homogeneous rooted sum-of-squares combination of their B1+ patterns ( B1,RSS+). The antenna's transmit and receive performance, as well as local specific absorption rate, were analyzed using experiments and numerical simulations. RESULTS: The optimized TIAMO B1,RSS+ combination was superior to radiofrequency shimming. Across the entire brain, it improved the homogeneity of the excitation field by a factor of two and its maximum-to-minimum ratio by almost a factor of five as compared to the circularly polarized mode. The two-fold increase in "virtual" receive channels enhanced the parallel imaging performance and enabled the use of higher acceleration factors. CONCLUSION: Despite the limited number of channels, a remote three-port antenna combined with TIAMO represents an easily implementable setup to achieve void-free (1)H images from the entire brain at 9.4 T, which can be used for anatomical localization and B0 shimming. PMID- 25732896 TI - [Feasability study of screening for malignant lesions in the oral cavity targeting tobacco users]. AB - INTRODUCTION: Oral cavity cancer is frequent. Prognosis of this cancer is closely linked to the development. Although the oral cavity is a potentially accessible site for examination, up to 50% of oral cancers are not detected until the disease is well advanced. PATIENTS AND METHOD: In a region where incidence rate is particularly high, local teams involved in screening, in epidemiological survey, in diagnosis and treatment of oral cancer performed a pilot feasibility study to improve strategy of early detection of oral cancer and premalignant lesion. Tobacco venders were solicited to distribute a flyer, which invite smokers to a free examination by general practitioner. General practitioners were invited to examine smokers, and to fill a predeterminate systematic oral cavity examination record during 3 months. They were asked to refer to a specialist if there was a potentially malignant disorder. RESULTS: The involvement of tobacco venders was rated as 67.3%. Ninety-three patients were included in 3 months. General practitioners referred 27% of the examinated patients. Among them, only 63.6% really saw a specialist, and a premalignant lesion was confirmed in 15.3%; further exams were carried out in 28.6%; a benign lesion was diagnosed in 57.1%. DISCUSSION/CONCLUSION: Original incentives for oral cavity screening were performed, based on multidisciplinary network. Nevertheless, it remains hardship to reach the targeted population and to maintain the patients in health system. PMID- 25732897 TI - Toxicological evaluation of clay minerals and derived nanocomposites: a review. AB - Clays and clay minerals are widely used in many facets of our society. This review addresses the main clays of each phyllosilicate groups, namely, kaolinite, montmorillonite (Mt) and sepiolite, placing special emphasis on Mt and kaolinite, which are the clays that are more frequently used in food packaging, one of the applications that are currently exhibiting higher development. The improvements in the composite materials obtained from clays and polymeric matrices are remarkable and well known, but the potential toxicological effects of unmodified or modified clay minerals and derived nanocomposites are currently being investigated with increased interest. In this sense, this work focused on a review of the published reports related to the analysis of the toxicological profile of commercial and novel modified clays and derived nanocomposites. An exhaustive review of the main in vitro and in vivo toxicological studies, antimicrobial activity assessments, and the human and environmental impacts of clays and derived nanocomposites was performed. From the analysis of the scientific literature different conclusions can be derived. Thus, in vitro studies suggest that clays in general induce cytotoxicity (with dependence on the clay, concentration, experimental system, etc.) with different underlying mechanisms such as necrosis/apoptosis, oxidative stress or genotoxicity. However, most of in vivo experiments performed in rodents showed no clear evidences of systemic toxicity even at doses of 5000mg/kg. Regarding to humans, pulmonary exposure is the most frequent, and although clays are usually mixed with other minerals, they have been reported to induce pneumoconiosis per se. Oral exposure is also common both intentionally and unintentionally. Although they do not show a high toxicity through this pathway, toxic effects could be induced due to the increased or reduced exposure to mineral elements. Finally, there are few studies about the effects of clay minerals on wildlife, with laboratory trials showing contradictory outcomes. Clay minerals have different applications in the environment, thus with a strict control of the concentrations used, they can provide beneficial uses. Despite the extensive number of reports available, there is also a need of systematic in vitro-in vivo extrapolation studies, with still scarce information on toxicity biomarkers such as inmunomodulatory effects or alteration of the genetic expression. In conclusion, a case by case toxicological evaluation is required taking into account that different clays have their own toxicological profiles, their modification can change this profile, and the potential increase of the human/environmental exposure to clay minerals due to their novel applications. PMID- 25732898 TI - Preparation of hybrid thiol-acrylate emulsion-templated porous polymers by interfacial copolymerization of high internal phase emulsions. AB - Emulsion-templated highly porous polymers (polyHIPEs), containing distinct regions differing in composition, morphology, and/or properties, are prepared by the simultaneous polymerization of two high internal phase emulsions (HIPEs) contained within the same mould. The HIPEs are placed together in the mould and subjected to thiol-acrylate photopolymerization. The resulting polyHIPE material is found to contain two distinct semicircular regions, reflecting the composition of each HIPE. The original interface between the two emulsions becomes a copolymerized band between 100 and 300 MUm wide, which is found to be mechanically robust. The separate polyHIPE layers are distinguished from one another by their differing average void diameter, chemical composition, and extent of contraction upon drying. PMID- 25732899 TI - Lewis-acid induced disaggregation of dimeric arylantimony oxides. AB - The previously known dimeric arylantimony oxides (Ph3SbO)2 and [2,6 (Me2NCH2)2C6H3SbO]2 were disaggregated by the Lewis acid B(C6F5)3 giving rise to the formation of the Lewis pair complexes Ph3SbOB(C6F5)3 and 2,6 (Me2NCH2)2C6H3SbOB(C6F5)3 having short bipolar single Sb-O bonds. PMID- 25732900 TI - New amino acid changes in drug resistance sites and HBsAg in hepatitis B virus genotype H. AB - Long-term treatment with retrotranscriptase (RT) inhibitors eventually leads to the development of drug resistance. Drug-related mutations occur naturally and these can be found in hepatitis B virus (HBV) carriers who have never received antiviral therapy. HBsAg are overlapped with RT domain, thus nucleot(s)ide analogues (NAs) resistance mutations and naturally-occurring mutations can cause amino acid changes in the HBsAg. Twenty-two patients with chronic hepatitis B were enrolled; three of them were previously treated with NAs and 19 were NAs naive treated. HBV reverse transcriptase region was sequenced; genotyping and analysis of missense mutations were performed in both RT domain and HBsAg. There was predominance of genotype H. Drug mutations were present in 18.2% of patients. Classical lamivudine resistance mutations (rtM204V/rtL180M) were present in one naive-treatment patient infected with genotype G. New amino acid changes were identified in drug resistance sites in HBV strains from patients infected with genotype H; rtQ215E was present in two naive-NAs treatment patients and rtI169M was identified in a patient previously treated with lamivudine. Mutations at sites rt169, rt204, and rt215 resulted in the Y161C, I195M, and C206W mutations at HBsAg. Also, new amino acid changes were identified in B-cell and T-cell epitopes and were more frequent in HBsAg compared to RT domain. In conclusion, new amino acid changes at antiviral resistance sites, B-cell and T-cell epitopes in HBV genotype H were identified in Mexican patients. PMID- 25732901 TI - Burden of Serious Infections in Adults With Systemic Lupus Erythematosus: A National Population-Based Study, 1996-2011. AB - OBJECTIVE: To compare rates of hospitalization for serious infections, trends in rates from 1996 to 2011, and in-hospital mortality between patients with systemic lupus erythematosus (SLE) and those without SLE in a national sample. METHODS: We analyzed hospitalizations for pneumonia, bacteremia/sepsis, urinary tract infections, skin infections, and opportunistic infections among adults in the Nationwide Inpatient Sample. We compared rates of hospitalization yearly among patients with SLE and the general population. We also computed odds ratios (ORs) for in-hospital mortality. RESULTS: In 1996, the estimated number of hospitalizations for pneumonia in patients with SLE was 4,382, followed by sepsis (2,305), skin infections (1,422), urinary tract infections (643), and opportunistic infections (370). Rates were much higher in patients with SLE than in those without SLE, with age-adjusted relative risks ranging from 5.7 (95% confidence interval [95% CI] 5.5-6.0) for pneumonia to 9.8 (95% CI 9.1-10.7) for urinary tract infection in 1996. Risks increased over time, so that by 2011, all relative risks exceeded 12.0. Overall risk of in-hospital mortality was higher in SLE only for opportunistic infections (adjusted OR 1.52 [95% CI 1.12-2.07]). However, in pneumonia and sepsis, mortality risks were higher in SLE among those who required mechanical ventilation. CONCLUSION: Hospitalization rates for serious infections in SLE increased substantially between 1996 and 2011, reaching over 12 times higher than in patients without SLE in 2011. Reasons for this acceleration are unclear. In-hospital mortality was higher among patients with SLE and opportunistic infections and those with pneumonia or sepsis who required mechanical ventilation. PMID- 25732902 TI - Diagnostic ability of EUS-FNA for pancreatic solid lesions with conventional 22 gauge needle using the slow pull technique: a prospective study. AB - OBJECTIVE: Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) using the slow pull technique (SP-FNA) has recently attracted attention as an effective tissue acquisition technique. However, efficacy of SP-FNA with a 22 gauge conventional needle remains unclear. The aim of this study is to evaluate the diagnostic ability of SP-FNA with a 22-gauge needle. MATERIAL AND METHODS: Patients with a pancreatic solid lesion were prospectively enrolled in this study. SP-FNA was performed at two needle passes with a 22-gauge needle. One dedicated pathologist evaluated the obtained samples in terms of quantity (Grade 0: scant; Grade 1: inadequate; Grade 2: adequate), quality (Grade 0: poor; Grade 1: moderate; Grade 2: good), and blood contamination (Grade 0: significant; Grade 1: moderate; Grade 2: low), and provided a pathological diagnosis. Additional EUS FNA was performed by applying suction (SA-FNA). The evaluation points were as follows: diagnostic accuracy of SP-FNA compared with that of SA-FNA, and the quantity, quality, and blood contamination level of SP-FNA-obtained samples. RESULTS: We enrolled 40 cases. The diagnostic accuracy of SP-FNA was 90% (36/40). There was no significant difference in the accuracy between SP-FNA and SA-FNA (90% vs. 90%, p = 1.000). The samples obtained using SP-FNA were assessed as Grade 2 for quantity in 29 cases (73%), quality in 31 (78%), and blood contamination in 25 (63%). CONCLUSIONS: Adequate, high-quality, and unsubstantially blood-contaminated samples could be obtained using SP-FNA. The diagnostic ability of SP-FNA was 90%, which appeared to be similar to that of SA FNA. PMID- 25732903 TI - [Right lobe hemihepatectomy as living donor : video article]. AB - The aim of this article is to demonstrate a right lobe hemihepatectomy to obtain a partial liver transplant for an adult organ recipient. Partial liver resection is carried out in the form of an ultrasound dissection of the parenchyma via a conventional (open) approach with a completely retained perfusion during the resection phase. The gall ducts are separated in the parenchymal phase and the peripheral segment of the middle hepatic vein is resected with the donor liver lobe. The surgical technique is demonstrated in detail with the help of a video of the operation that is available online. Furthermore, the advantages and disadvantages of the technique are discussed. PMID- 25732904 TI - Soluble sugar-based quinoline derivatives as new antioxidant modulators of metal induced amyloid aggregation. AB - Oxidative stress and protein aggregation have been demonstrated to be the major factors involved in neurodegenerative diseases. Metal ions play a pivotal role, acting as mediators of neurotoxicity either by favoring or redox cycling. Thus, they represent a promising and suitable therapeutic target for the treatment of neurodegenerative disorders. In particular, the development of bifunctional or multifunctional molecules, which have antiaggregant and metal chelating/antioxidant properties, may be considered as a valuable strategy for the treatment of neurodegeneration considering its multifactorial nature. Herein, we report the design and the characterization of four new multifunctional sugar appended 8-hydroxyquinolines focusing on the effects of the conjugation with trehalose, a nonreducing disaccharide involved in the protection of proteins and cells against environmental stresses. These glycoconjugates do not exhibit any antiproliferative activity against three human cell lines of different histological origin, unlike 8-hydroxyquinolines. The multiple properties of the new derivatives are highlighted, reporting their Cu(2+) and Zn(2+) binding ability, and antioxidant and antiaggregant capacities. In particular, these latter were determined by different assays, including the evaluation of their ability to modulate or even suppress the aggregation of Abeta1-40 and Abeta1-42 peptides induced by copper or zinc ions. PMID- 25732905 TI - A novel method of microwave heating mixed liquid-assisted regeneration of V2O5 WO3/TiO2 commercial SCR catalysts. AB - An experimental study on the regeneration of deactivated SCR catalysts was carried out using a microwave-assisted method containing three steps of washing with mixed liquid of ethanol and water, impregnating, and drying. After the regeneration treatment, NO conversion at 320 degrees C increased from 39 to 90% and vanadium content increased by 62.2%, which were much higher than those regenerated by the traditional method. The more impregnated vanadium was due to the fact that the rapid evaporation of mixed liquid inside the catalyst channels led to the enlargement of surface areas by creating more pores on the catalysts. Meanwhile, with the increasing concentrations of ethanol, the heating rate of the mixed liquid increased, and the volume after complete evaporation of the mixed liquid was gradually reduced. Since higher heating rate and lager volume after the liquid evaporation could help to create more pores, therefore, when the volume ratio of ethanol/mixed solution was 20%, the catalyst obtained the maximum specific surface area, which significantly increased to ca. 123% compared with the deactivated catalyst. In addition, the catalyst dried by microwave exhibited better catalytic activity than that dried in conventional oven. Therefore, this method showed great potential in industrial applications. PMID- 25732906 TI - Assessment of total and organic vanadium levels and their bioaccumulation in edible sea cucumbers: tissues distribution, inter-species-specific, locational differences and seasonal variations. AB - The objective of this study is to investigate the levels, inter-species-specific, locational differences and seasonal variations of vanadium in sea cucumbers and to validate further several potential factors controlling the distribution of metals in sea cucumbers. Vanadium levels were evaluated in samples of edible sea cucumbers and were demonstrated exhibit differences in different seasons, species and sampling sites. High vanadium concentrations were measured in the sea cucumbers, and all of the vanadium detected was in an organic form. Mean vanadium concentrations were considerably higher in the blood (sea cucumber) than in the other studied tissues. The highest concentration of vanadium (2.56 MUg g(-1)), as well as a higher degree of organic vanadium (85.5 %), was observed in the Holothuria scabra samples compared with all other samples. Vanadium levels in Apostichopus japonicus from Bohai Bay and Yellow Sea have marked seasonal variations. Average values of 1.09 MUg g(-1) of total vanadium and 0.79 MUg g(-1) of organic vanadium were obtained in various species of sea cucumbers. Significant positive correlations between vanadium in the seawater and V org in the sea cucumber (r = 81.67 %, p = 0.00), as well as between vanadium in the sediment and V org in the sea cucumber (r = 77.98 %, p = 0.00), were observed. Vanadium concentrations depend on the seasons (salinity, temperature), species, sampling sites and seawater environment (seawater, sediment). Given the adverse toxicological effects of inorganic vanadium and positive roles in controlling the development of diabetes in humans, a regular monitoring programme of vanadium content in edible sea cucumbers can be recommended. PMID- 25732907 TI - Establishing the characteristics of an effective pharmacogenetic test for clozapine-induced agranulocytosis. AB - Clozapine is the only evidence-based therapy for treatment-resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the agranulocytosis risk is low enough to alleviate monitoring requirements. Assuming a genotypic marker stratifies patients into a high-risk and a low-risk group, we explore the relationship between test sensitivity, group size and agranulocytosis risk. High sensitivity minimizes the agranulocytosis risk in the low-risk group and is essential for clinical utility, in particular in combination with a small high-risk group. PMID- 25732908 TI - Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. AB - Non-synonymous GRK4 variants, R65L, A142V and A486V, are associated with essential hypertension in diverse populations. This study replicated the association of GRK4 variants, including GRK4(142V), with human essential hypertension in a Japanese population (n=588; hypertensive, n=486 normotensive controls) and determined whether the presence of GRK4 variants predicted the blood pressure (BP) response to angiotensin receptor blockers (ARBs) in patients with essential hypertension. We analyzed 829 patients and compared the response to ARBs between individuals with no GRK4 variants (n=136) and those with variants at one or any of the three loci (n=693). Carriers of hGRK4(142V) had a greater decrease in systolic BP in response to ARBs than non-carrier hypertensive patients. By contrast, those with variants only at GRK4(486V) were less likely to achieve the BP goal in response to an ARB than those with no variants. These studies showed for the first time the association between GRK4(142V) and a larger decrease in BP with ARBs in hypertensive patients. PMID- 25732909 TI - Discordances in HER2 status between primary gastric cancer and corresponding metastatic sites. AB - OBJECTIVE: Determination of human epidermal growth factor receptor-2 status in advanced gastric cancer is important in clinical decision making. In the trastuzumab for GC trial, trastuzumab-based therapy demonstrated a significant overall survival benefit in patients with human epidermal growth factor receptor 2-positive advanced gastric cancer. Human epidermal growth factor receptor-2 discordance in gastric cancer primary and its metastases has been long debated. The aim of the study was to evaluate the rate of human epidermal growth factor receptor-2 discordance and its effect on treatment decisions in advanced gastric cancer. METHODS: A total of 74 patients with advanced gastric cancer were included in the study. Both immunohistochemical staining and dual-color silver in situ hybridization were performed in all patients to evaluate the human epidermal growth factor receptor-2 status of the primary lesion and paired metastasis. RESULTS: The assessment of human epidermal growth factor receptor-2 status with the immunohistochemical staining method and dual-color silver in situ hybridization revealed a discordance rate of 9.5 and 16.2%, respectively. However, this discordance was clinically meaningful in only one patient leading to a change in treatment decision. While this patient had a human epidermal growth factor receptor-2-negative status in primary tumor (immunohistochemical = 0, dual-color silver in situ hybridization = negative), the human epidermal growth factor receptor-2 status was positive for liver metastasis (immunohistochemical = 2+, dual-color silver in situ hybridization = positive). Trastuzumab was added to the chemotherapy regimen. CONCLUSIONS: In this study, we found a higher rate of human epidermal growth factor receptor-2 discordance between primary gastric tumor and metastatic lesions compared with the rates reported in previous studies. Detection of a human epidermal growth factor receptor-2-positive metastasis with a human epidermal growth factor receptor-2 negative primary tumor suggests that investigation of human epidermal growth factor receptor-2 is also required for the metastatic lesion and that trastuzumab could be administered in the case of a positive result. PMID- 25732912 TI - Antimicrobial resistance risk factors and characterisation of faecal E. coli isolated from healthy Labrador retrievers in the United Kingdom. AB - Antimicrobial resistant bacteria are increasingly detected from canine samples but few studies have examined commensal isolates in healthy community dogs. We aimed to characterise faecal Escherichia coli from 73 healthy non-veterinarian visiting and non-antimicrobial treated Labrador retrievers, recruited from dog shows in the North West United Kingdom between November 2010 and June 2011. Each enrolled dog provided one faecal sample for our study. E. coli were isolated from 72/73 (99%) faecal samples. Disc diffusion susceptibility tests were determined for a range of antimicrobials, including phenotypic extended-spectrum beta lactamase (ESBL) and AmpC-production. PCR assay detected phylogenetic groups and resistance genes (blaCTX-M, blaSHV, blaTEM, blaOXA, blaCIT, qnr), and conjugation experiments were performed to investigate potential transfer of mobile genetic elements. Multivariable logistic regression examined potential risk factors from owner-questionnaires for the presence of antimicrobial resistant faecal E. coli. Antimicrobial resistant, multi-drug resistant (>=3 antimicrobial classes; MDR) and AmpC-producing E. coli were detected in 63%, 30% and 16% of samples, respectively. ESBL-producing E. coli was detected from only one sample and conjugation experiments found that blaCTX-M and blaCIT were transferred from commensal E. coli to a recipient strain. Most isolates were phylogenetic groups B1 and A. Group B2 isolates were associated with lower prevalence of resistance to at least one antimicrobial (P<0.001) and MDR (P<0.001). Significant at P<0.003, was the consumption of raw meat for clavulanate-amoxicillin (OR: 9.57; 95% CI: 2.0-45.7) and third generation cephalosporin resistance (3GCR) (OR: 10.9; 95% CI: 2.2-54.0). AMR E. coli were surprisingly prevalent in this group of non antimicrobial treated and non-veterinarian-visiting dogs and consumption of raw meat was a significant risk factor for antimicrobial resistance. These findings are of concern due to the increasing popularity of raw-meat canine diets, and the potential for opportunistic infection, zoonotic transmission and transmission of antimicrobial resistant determinants from commensal isolates to potential pathogenic bacteria. PMID- 25732911 TI - Massive expansion and functional divergence of innate immune genes in a protostome. AB - The molecules that mediate innate immunity are encoded by relatively few genes and exhibit broad specificity. Detailed annotation of the Pacific oyster (Crassostrea gigas) genome, a protostome invertebrate, reveals large-scale duplication and divergence of multigene families encoding molecules that effect innate immunity. Transcriptome analyses indicate dynamic and orchestrated specific expression of numerous innate immune genes in response to experimental challenge with pathogens, including bacteria, and a pathogenic virus. Variable expression of individual members of the multigene families encoding these genes also occurs during different types of abiotic stress (environmentally-equivalent conditions of temperature, salinity and desiccation). Multiple families of immune genes are responsive in concert to certain biotic and abiotic challenges. Individual members of expanded families of immune genes are differentially expressed under both biotic challenge and abiotic stress conditions. Members of the same families of innate immune molecules also are transcribed in developmental stage- and tissue-specific manners. An integrated, highly complex innate immune system that exhibits remarkable discriminatory properties and responses to different pathogens as well as environmental stress has arisen through the adaptive recruitment of tandem duplicated genes. The co-adaptive evolution of stress and innate immune responses appears to have an ancient origin in phylogeny. PMID- 25732913 TI - Primary bone cancer in Leonbergers may be associated with a higher bodyweight during adolescence. AB - Weight-bearing stress may be a risk factor for both human and canine primary bone cancer. A cohort of Leonbergers (LB) was followed from birth to death and the cause of death recorded. We hypothesised that dogs dying due to primary bone cancer would be larger; measured by bodyweight (BW) and the circumference of the distal radius and ulna (CDRU) than those of the same breed that died of other causes. Information obtained from breeders, owners and veterinary surgeons were questionnaire-based. The dogs were examined by a veterinary surgeon at pre specified "observational ages" (3, 4, 6, 12, 18, and 24 m). Data were recorded, including BW and CDRU. The study population consisted of 196 LB, 9 of which died due to primary bone cancer (6 males, 3 females). Individual growth curves, showing BW and CDRU during the first 2 years of life, were made for these 9 dogs and compared to gender-specific mean values for LB that died from other causes. These curves showed that LB succumbing to primary bone cancer generally had a higher BW during the growth period than the remaining dogs, and that this difference appeared to be largest in the male LB. Male LB that developed primary bone cancer later in life also had a larger CDRU during most part of this period, as compared to those that did not develop this disease. Logistic regression showed a statistically significant effect of BW on the odds ratio of developing primary bone cancer at 12 m and 18 m and of CDRU at 18 m, and a Poisson regression verified consistency of these results. At these ages, an increase in BW of 1 kg yielded a nearly 20% higher risk of developing primary bone cancer, while a 1 cm larger CDRU was associated with a nearly 70% increased risk. These findings support that weight-bearing stress during the period of high proliferative activity in the long bones associated with growth may increase the risk of canine primary bone cancer. PMID- 25732914 TI - Molecular and serological in-herd prevalence of Anaplasma marginale infection in Texas cattle. AB - Bovine anaplasmosis is an infectious, non-contagious disease caused by the rickettsial pathogen Anaplasma marginale (A. marginale). The organism has a global distribution and infects erythrocytes, resulting in anemia, jaundice, fever, abortions and death. Once infected, animals remain carriers for life. The carrier status provides immunity to clinical disease, but is problematic if infected and naive cattle are comingled. Knowledge of infection prevalence and spatial distribution is important in disease management. The objective of this study was to assess A. marginale infection in-herd prevalence in Texas cattle using both molecular and serological methods. Blood samples from 11 cattle herds within Texas were collected and analyzed by reverse transcription quantitative real-time PCR (RT-qPCR) and a commercial competitive enzyme-linked immunosorbent assay (cELISA). Samples from experimentally infected animals were also analyzed and RT-qPCR detected A. marginale infection up to 15 days before cELISA, providing empirical data to support the interpretation of herd prevalence results. Herds with high prevalence were located in the north Texas Rolling Plains and west Trans-Pecos Desert, with RT-qPCR prevalence as high as 82% and cELISA prevalence as high as 88%. Overall prevalence was significantly higher in cattle in north and west Texas compared to cattle in east Texas (p<0.0001 for prevalence based on both RT-qPCR and cELISA). The overall RT-qPCR and cELISA results exhibited 90% agreement (kappa=0.79) and provide the first A. marginale infection prevalence study for Texas cattle using two diagnostic methods. Since cattle are the most important reservoir host for A. marginale and can serve as a source of infection for tick and mechanical transmission, information on infection prevalence is beneficial in the development of prevention and control strategies. PMID- 25732915 TI - Patient-matched instruments versus standard instrumentation in total knee arthroplasty: a prospective randomized study. AB - BACKGROUND: Optimal positioning of implants and restoration of neutral mechanical axis are two primary surgical goals in total knee arthroplasty (TKA). Despite modern instruments and improved surgical techniques, malalignment remains an important cause of early failure after TKA. The aim of this prospective randomized study was to compare the value of a new patient-matched instrument system (PMI) (Signature(TM); Biomet, Inc, Warsaw, Indiana) to that of standard TKA surgical instrumentation (STD) in terms of coronal mechanical alignment, time of operation and blood loss. PATIENTS AND METHODS: A total of 38 patients waiting for primary TKA were enrolled and randomized into two groups (19 PMI and 19 STD). Magnetic resonance imaging was performed in all patients in the PMI group, and specific instruments for the femur and tibia were designed preoperatively. All patients were operated on using the standard medial parapatellar approach with no use of tourniquet. Mechanical axis, time for the operation, and blood loss were evaluated. RESULTS: Patients in both groups had comparable age, body mass index, preoperative mechanical axis, Knee Society Score, and level of hemoglobin. Postoperative results showed that the PMI group fell significantly closer to neutral mechanical axis (STD: 2.7 +/- 1.7, PMI: 1.7 +/- 0.9; P = 0.013) with no outliers and a reduced time for the operation. There was no difference in the evaluation blood loss. CONCLUSIONS: The use of PMI can contribute in achieving better mechanical axis with reduction in outliers and decreased operation time. Due to small differences between PMI and standard instruments, additional research are needed to confirm these preliminary results, and to discover potential benefits and functional improvements in the long-term outcome. PMID- 25732916 TI - Lung cancer in pregnancy. AB - In the 26th week of gestation, a 29-year-old pregnant office employee was referred to the pulmonary department of Linz General Hospital (AKH) under the suspicion of tuberculosis. She complained of a cough with intermittent hemoptysis and pain in the thoracic spine from which she had been suffering the past 9 weeks. A plain chest X-ray showed a dense infiltrate on the right side and multiple smaller shadows in both lungs. Laboratory testing revealed anemia, leukocytosis, and an increase of C-reactive protein. All tests for tuberculosis were negative.A bronchoscopy was performed and biopsies were taken from the right upper and middle lobe. The histopathological examination found cells of an adenocarcinoma. A magnetic resonance imaging (MRI) revealed a large tumor and surrounding atelectasis were seen in the right upper and middle lobe, as well as multiple intrapulmonary metastases in both lungs. In addition, not only metastases in the thoracic spine (level Th2/3) but also at other osseous locations and multiple cerebral metastases were detected. The patient received one cycle of chemotherapy consisting of docetaxel and carboplatin (AUC5) in the 27th week of gestation. Additional radiotherapy was applied to the involved thoracic spine. Due to positive epidermal growth factor receptor mutation, therapy with gefitinib 250 mg/day was started 2 days after a Caesarean section (preceded by treatment for fetal lung maturation). A healthy girl was delivered in the 30th week of pregnancy. Staging with computed tomography (CT) after delivery revealed an unstable fracture of Th2 with compression of the spinal cord. Neurosurgery was performed, consisting of a ventral corporectomy of Th1-2 followed by an anterior and posterior osteosynthesis for stabilization. The patient was discharged without neurological deficits within 1 week. Subsequent treatment with gefitinib improved the performance status of the patient, and CT scans of the chest and an MRI of the brain showed the size of the tumor to be shrinking. Meanwhile, the infant developed appropriately for her age.After 14 months of the first diagnosis, the patient experienced neurological symptoms (aphasia, confusion) due to neoplastic meningeosis and cerebral venous sinus thrombosis together with local tumor progression in the lung. One course of chemotherapy, combining carboplatin/pemetrexed/bevacizumab, was given without clinical response. Despite best supportive care, the patient died 17 months after diagnosis in October 2013. PMID- 25732917 TI - Epidemiology of suicide in Austria during 2000-2010: potential years of life lost: time for the national suicide prevention program. AB - BACKGROUND: This article investigates suicide rates from 2000 to 2010 in Austria, a country with now average rates that had started to decline in the mid-80s. RESULTS: Rates declined in the observed period, to an average of 26.1 per 100,000 persons for men, 8.2 for women, and 16.9 in the general population. The decrease was found in all age-groups, but more marked in women, with a reduction by 26.3 % compared with the previous decade than in men (20.0 % reduction). Hanging still is the most common method, 49.1 % for men and 35.0 % for women, although also on the decline. Furthermore, person years of lost life were calculated, also reflecting a decrease from 40,702 years in 2000 to 29,883 in 2010. Altogether, 372,551 years of life were lost by suicide in Austria in the period 2000-2010, 277,998 years among men and 94,553 years among women. CONCLUSIONS: Concerning the still observed increase in old age-groups and the huge amount of lost life years, it is argued that implementation of the National Suicide Prevention Programme for Austria is strongly needed. PMID- 25732918 TI - Higher level of neuroticism in patients with problems with the sense of smell. AB - BACKGROUND: Recent research suggests an association between personality measures and olfactory performance. The question of whether one's personality changes has been the subject of debate in personality research. The goal of the present study was to investigate whether olfactory dysfunction would be associated with personality traits. STUDY DESIGN: A cross-sectional study was conducted by comparing a healthy control group and patients with olfactory dysfunction in terms of personality traits using the Big Five Plus One personality inventory. METHODS: A total of 17 normal controls with intact olfaction and 16 patients with olfactory dysfunction were included. All subjects included in the study were evaluated for olfactory dysfunction by means of the Sniffin' Sticks RESULTS: For the personality traits agreeableness, conscientiousness, extraversion, openness to new ideas and the additional dimension empathy no statistically significant difference was found, whereas a statistically significant difference (p = 0.03) between the control group and the patient group regarding neuroticism (emotional control) was detected. CONCLUSION: In conclusion, higher level of neuroticism is associated with patients with olfactory dysfunction. PMID- 25732919 TI - On the significance of electroconvulsive therapy in the treatment of severe mental diseases. AB - BACKGROUND: Quite a few patients with severe mental diseases do not respond sufficiently to psychopharmacology and psychotherapy. For some of these, electroconvulsive therapy (ECT) offers a promising alternative. Erroneously, the method is being perceived as old fashioned by the lay public, but also by many doctors. Therefore, this overview aims at all colleagues who in their role as multipliers, referring physicians or ECT specialists can reduce the likelihood of mental disease to become chronic. METHODS: During the last decades, numerous international medical societies including the Austrian and the German Association for Psychiatry (OGPP and DGPPN) have pointed to the importance of ECT as a modern medical intervention. Our overview is based on these guidelines and statements. Additionally selective literature searches have been conducted concerning some key aspects. RESULTS: Due to its excellent efficacy, ECT is an important option in the treatment of severe mental disease. Technological innovations and continued development in the psychiatric environment determined the evolution from the electroshock of the 1930s to the ECT of today. This process led to reduced side effects and a stronger patient-oriented praxis. CONCLUSIONS: ECT is a modern, highly effective and safe treatment of severe mental diseases with comparatively few side effects. The method should not be used as a last resort but in an evidence-based way. Patients should be informed timely and adequately about the therapeutic option. PMID- 25732920 TI - Vision problems in Down syndrome adults do not hamper communication, daily living skills and socialisation. AB - BACKGROUND: Down syndrome is the most commonly occurring chromosomal condition with a prevalence of 11.2-10000 life-births in Europe. The most important concern consists of various degrees of intellectual disability and sensory deficits. The overall prevalence of ophthalmologic abnormalities has been reported to be as high as 46-100%. Impairment of vision potentially hampers the capacity of learning and communication and thus of social integration. The aim of our study is to assess prospectively the occurrence of vision problems in patients with DS with special emphasis on adaptive behaviour and cognition. METHODS: Assessments included Hirschberg's corneal reflex method, eye alignment, cover test, Vineland Adaptive Behaviour Scales (VABS) for adaptive behaviour and Coloured Progressive Matrices (CPM) for cognitive abilities. RESULTS: We included prospectively 49 individuals from 19-52 years. Ophthalmologic problems were observed in 81.6% of our DS patients. The total number of visual disorders and symptoms was equally distributed with respect to ID-group and to levels of adaptive behaviour (p > 0.050). When comparing individuals matched for age, gender, cognitive skills and sociocultural background in a subset of individuals, vision problems did not decrease adaptive behaviour skills of our patients with visual disorders and daily living skills even fared better (p = 0.046). CONCLUSIONS: Effective early correction and intervention on visual-motor deficits seem to be important, but nevertheless personal autonomy is not seriously detained. PMID- 25732921 TI - Outcomes of pregnancy in patients with congenital erythrocytosis. PMID- 25732922 TI - Annular lichenoid dermatitis of youth: a separate entity or on the spectrum of mycosis fungoides? Case report and review of the literature. AB - Annular lichenoid dermatitis (ALDY) is a rare dermatosis that is most often seen in children and young adults and is characterized by annular patches with raised borders, most frequently on the trunk and the groin. A distinct lichenoid tissue reaction involving the base of the rete, resulting in squared-off rete ridges, helps to differentiate this from other lichenoid dermatoses and mycosis fungoides (MF). Herein, we report an additional case of this condition in a 7-year-boy, whose biopsy exhibited the typical quadrangular rete alteration and also contained distinct aggregates of CD8+ lymphocytes, Langerhans cells and colloid bodies within the involved rete. A literature review with emphasis on the clinical and histopathological differential diagnosis reveals additional clinical features of ALDY to potentially help differentiate this entity from annular presentations of mycosis fungoides. PMID- 25732924 TI - HarP: the EADC-ADNI Harmonized Protocol for manual hippocampal segmentation. A standard of reference from a global working group. PMID- 25732923 TI - Multimodal imaging in acute ischemic stroke. AB - OPINION STATEMENT: Recent years have seen the development of novel neuroimaging techniques whose roles in the management of acute stroke are sometimes confusing and controversial. This may be attributable in part to a focus on establishing simplified algorithms and terminology that omit consideration of the basic pathophysiology of cerebral ischemia and, consequently, of the full potential for optimizing patients' care based upon their individual imaging findings. This review begins by discussing cerebral hemodynamic physiology and of the effects of hemodynamic disturbances upon the brain. Particular attention will be paid to the hemodynamic measurements and markers of tissue injury that are provided by common clinical imaging techniques, with the goal of enabling greater confidence and flexibility in understanding the potential uses of these techniques in various clinical roles, which will be discussed in the remainder of the review. PMID- 25732925 TI - Improvement of renal diffusion-weighted magnetic resonance imaging with readout segmented echo-planar imaging at 3T. AB - PURPOSE: To assess the feasibility of a respiratory-gated implementation of readout-segmented SE-EPI (RESOLVE) for renal diffusion-weighted imaging (DWI) by comparison with single-shot SE-EPI (ss-EPI) in a phantom, healthy volunteers and chronic kidney disease (CKD) patients. MATERIALS AND METHODS: A fluid-filled phantom, 20 healthy volunteers and 10 CKD patients were scanned with the same parameters and coils on a 3T MR system with 3 DW sequences (b-values=0, 300, 500, 900s/mm(2)): a standard ss-EPI (Reference EPI), a ss-EPI with higher resolution, bandwidth and acceleration factor (HR-EPI) and RESOLVE with the same spatial resolution as HR-EPI but a segmentation of the readout into 5 shots. Geometric distortions, image blurring using a 'Canny' edge detection based measure, cortico medullary differentiation measured on b0 images and ADC quantification were compared between the 3 sequences using one-way analysis of variance (ANOVA) with post-hoc Bonferroni (p<0.05 was taken as statistically significant). RESULTS: RESOLVE reduced significantly geometric distortions and blurring and improved, in the volunteers and patients, the sharpness score by 56% on average in comparison to ss-EPI (p=0.02). In healthy volunteers, the cortico-medullary differentiation with RESOLVE was also possible on a wider range of b-values (p<0.02) with ADC values (in 10(-6)mm(2)/s) of 1994+/-246 in the cortex and 1762+/-238 in the medulla (p<0.001). In CKD patients, ADC values (in 10(-6)mm(2)/s) from the RESOLVE sequence were not different between the cortex (1755+/-145) and the medulla (1799+/-163, p=0.49). CONCLUSION: Despite a longer scan time, RESOLVE enhanced significantly the quality of renal diffusion-weighted images by improving the difference in SI and ADC between the renal cortex and medulla in healthy volunteers. In CKD patients, RESOLVE showed a disappearance of this cortico-medullary ADC difference. These improvements justify further clinical studies. PMID- 25732926 TI - Unusual angiogenic factor plays a role in lizard pregnancy but is not unique to viviparity. AB - Angiogenesis (blood vessel growth), a key process of mammalian pregnancy, facilitates gas exchange and nutrient transport between the mother and the embryo and is regulated by a suite of growth factors. Vascular endothelial growth factor (VEGF) is crucial to this process in pregnant mammals and potentially pregnant squamates (lizards and snakes), as we investigate here. VEGF111 , an unusual and potent angiogenic splice variant of VEGF, increases its expression during pregnancy in the uterus of a viviparous lizard, in parallel with similar increases in uterine angiogenesis during gestation. However, we also find that VEGF111 is expressed in oviparous skinks, and is not ubiquitous among viviparous skinks. Thus, different mechanisms of uterine angiogenesis during pregnancy may evolve concurrent with viviparity in different lizard lineages. PMID- 25732927 TI - Gene-gene interaction and RNA splicing profiles of MAP2K4 gene in rheumatoid arthritis. AB - We performed gene-gene interaction analysis, with HLA-DRB1 shared epitope (SE) alleles for 195 SNPs within immunologically important MAP2K, MAP3K and MAP4K gene families, in 2010 rheumatoid arthritis (RA) patients and 2280 healthy controls. We found a significant statistical interaction for rs10468473 with SE alleles in autoantibody-positive RA. Individuals heterozygous for rs10468473 demonstrated higher expression of total MAP2K4 mRNA in blood, compared to A-allele homozygous. We discovered a novel, putatively translated, "cassette exon" RNA splice form of MAP2K4, differentially expressed in peripheral blood mononuclear cells from 88 RA cases and controls. Within the group of RA patients, we observed a correlation of MAP2K4 isoform expression with carried SE alleles, autoantibody, and rheumatoid factor profiles. TNF-dependent modulation of isoform expression pattern was detected in the Jurkat cell line. Our data suggest a genetic interaction between MAP2K4 and HLA-DRB1, and the importance of rs10468473 and MAP2K4 splice variants in the development of autoantibody-positive RA. PMID- 25732928 TI - Computed high b-value diffusion-weighted imaging improves lesion contrast and conspicuity in prostate cancer. AB - BACKGROUND: To evaluate whether very high b-value computed diffusion-weighted imaging (cDWI) is able to provide better contrast between the foci of prostate cancer and background tissue than the standard apparent diffusion coefficient (ADC) map, and whether this improved contrast could be used to improve the tumor detection. METHODS: Very high b-value cDWI series up to b4000 were created for 14 patients with high-grade prostate cancer. Contrast-to-noise ratios (CNRs) and CNR to-ADC ratios were calculated. Three blinded readers also assessed the tumor conspicuity on a standard five-point scale. RESULTS: The tumor CNR increased with increasing b-values in all the patients up to a maximum average CNR of 75.1 for a b-value of 4000 (average CNR for the ADC maps: 10.0). CNR/ADC ratios were higher than 1 (indicating higher CNR than respective ADC) for cDWI of 1500 and higher, with a maximum of 6.5 for cDWI4000. The average subjective tumor conspicuity scores for cDWI2000, 3000 and 4000 were significantly higher than that of the ADC (4.0): 4.5 (P=0.018), 4.5 (P=0.017) and 4.6 (P=0.012). CONCLUSIONS: cDWI is able to provide better contrast between the foci of prostate cancer and background tissue compared with a standard ADC map. This resulted in improved subjective tumor conspicuity. PMID- 25732929 TI - Persistent drug shortages jeopardise patient safety in the USA. PMID- 25732930 TI - Questions about the article: 'Alfaxalone or ketamine-medetomidine in cats undergoing ovariohysterectomy: a comparison of intraoperative parameters and postoperative pain'. PMID- 25732931 TI - Hearing thresholds of swimming Pacific bluefin tuna Thunnus orientalis. AB - Pacific bluefin tuna (Thunnus orientalis) is a highly migratory, commercially valuable species potentially vulnerable to acoustic noise generated from human activities which could impact behavior and fitness. Although significant efforts have been made to understand hearing abilities of fishes, the large size and need to continuously swim for respiration have hindered investigations with tuna and other large pelagic species. In this study, Pacific bluefin tuna were trained to respond to a pure tone sound stimulus ranging 325-800 Hz and their hearing abilities quantified using a staircase psychophysical technique. Hearing was most sensitive from 400 to 500 Hz in terms of particle motion (radial acceleration -88 dB re 1 m s(-2); vertical acceleration -86 dB re 1 m s(-2)) and sound pressure (83 dB re 1 MUPa). Compared to yellowfin tuna (Thunnus albacares) and kawakawa (Euthynnus affinis), Pacific bluefin tuna has a similar bandwidth of hearing and best frequency, but greater sensitivity overall. Careful calibration of the sound stimulus and experimental tank environment, as well as the adoption of behavioral methodology, demonstrates an experimental approach highly effective for the study of large fish species in the laboratory. PMID- 25732932 TI - It might be time to let cooler heads prevail after mild traumatic brain injury or concussion. PMID- 25732933 TI - The morphology of the coronary sinus in patients with congenitally corrected transposition: implications for cardiac catheterisation and re-synchronisation therapy. AB - Patients with congenitally corrected transposition frequently benefit from re synchronisation therapy or ablation procedures. This is likely to require catheterisation of the coronary sinus. Its anatomy, however, is not always appreciated, despite being well-described. With this caveat in mind, we have evaluated its location and structure in hearts with congenitally corrected transposition in order to reinforce the guidance needed by the cardiac interventionist. We dissected and inspected the coronary sinus, the oblique vein of the left atrium, and the left-sided-circumflex venous channel in eight heart specimens with corrected transposition and eight controls, measuring the orifice and length of the sinus and the atrioventricular valves. In two-thirds of the malformed hearts, the sinus deviated from its anticipated course in the atrioventricular groove, ascending obliquely on the left atrial inferior wall to meet the left oblique vein. The maximal deviation coincided in all hearts with the point where the left oblique vein joined the left-sided-circumflex vein to form the coronary sinus. We describe a circumflex vein, rather than the great cardiac vein, as the latter venous channel is right-sided in the setting of corrected transposition. The length of the sinus correlated positively with the diameter of the tricuspid valve (p=0.02). Compared with controls, the left oblique vein in the malformed hearts joined the circumflex venous channel significantly closer to the mouth of the sinus. The unexpected course of the coronary sinus in corrected transposition and the naming of the cardiac veins have important implications for venous cannulation and interpretation of images. PMID- 25732934 TI - Polyglycolic acid microneedles modified with inkjet-deposited antifungal coatings. AB - In this study, the authors examined use of piezoelectric inkjet printing to apply an antifungal agent, voriconazole, to the surfaces of biodegradable polyglycolic acid microneedles. Polyglycolic acid microneedles with sharp tips (average tip radius = 25 +/- 3 MUm) were prepared using a combination of injection molding and drawing lithography. The elastic modulus (9.9 +/- 0.3 GPa) and hardness (588.2 +/ 33.8 MPa) values of the polyglycolic acid material were determined using nanoindentation and were found to be suitable for use in transdermal drug delivery devices. Voriconazole was deposited onto the polyglycolic acid microneedles by means of piezoelectric inkjet printing. It should be noted that voriconazole has poor solubility in water; however, it is readily soluble in many organic solvents. Optical imaging, scanning electron microscopy, energy dispersive x-ray spectrometry, and Fourier transform infrared spectroscopy were utilized to examine the microneedle geometries and inkjet-deposited surface coatings. Furthermore, an in vitro agar plating study was performed on the unmodified, vehicle-modified, and voriconazole-modified microneedles. Unlike the unmodified and vehicle-modified microneedles, the voriconazole-modified microneedles showed antifungal activity against Candida albicans. The unmodified, vehicle-modified, and voriconazole-modified microneedles did not show activity against Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus. The results indicate that piezoelectric inkjet printing may be useful for loading transdermal drug delivery devices such as polyglycolic acid microneedles with antifungal pharmacologic agents and other pharmacologic agents with poor solubility in aqueous solutions. PMID- 25732935 TI - Promoting organisational recovery after wrongdoing: is this next challenge for nurse leaders? PMID- 25732936 TI - The impact of a Web-based app (eBalance) in promoting healthy lifestyles: randomized controlled trial. AB - BACKGROUND: The use of Web-based apps to promote a healthy lifestyle is increasing, although most of these programs were not assessed using suitable epidemiological methods. We evaluated the effectiveness of a newly developed Web based app in promoting a healthy lifestyle and educating adults on such lifestyles. We also analyzed predictors for success in acquiring and maintaining a healthy lifestyle. OBJECTIVE: Our aim was to compare people receiving a new Web based app with people who got an introductory lecture alone on healthy lifestyle, weight change, nutritional knowledge, and physical activity, and to identify predictors of success for maintaining a healthy lifestyle. METHODS: Subjects were recruited from the community and were randomized into intervention and control groups. The intervention subjects received access to the app without any face-to face support; the control subjects continued their standard lifestyle. Measurements were taken by the researcher at baseline and after 14 weeks and included weight and waist circumference. Nutritional knowledge, diet quality, and physical activity duration were obtained using online questionnaires. The new Web based app was developed based on current US Department of Agriculture and Israel Ministry of Health recommendations for healthy lifestyle. The app provides tools for monitoring diet and physical activity while instructing and encouraging healthy diet and physical activity. RESULTS: Out of 99 subjects who were randomized into app and control groups, 85 participants (86%) completed the study, 56 in the intervention and 29 in the control group. The mean age was 47.9 (SD 12.3) years, and mean Body Mass Index was 26.2 (SD 3.9). Among the intervention group only, frequency of app use was 2.7 (SD 1.9) days/week. The mean change in physical activity was 63 (SD 20.8) minutes in the app group and 30 (SD 27.5) minutes in the control group (P=.02). The mean weight change was 1.44 (SD 0.4) kg in the app group and -0.128 (SD 0.36) kg in the control group (P=.03). Knowledge score increased significantly in the app group, 76 (SD 7.5) to 79 (SD 8.7) at the end of the study (P=.04) compared with the control group. Diet quality score also increased significantly at the end of the study, from 67 (SD 9.8) to 71 (SD 7.6; P<.001) in contrast to the control group. Success score (represents the success in maintaining healthy lifestyle) was higher among the app group (68%) compared with 36% in the control group (P<.001). The app frequency of use was significantly related to a higher success score (P<.001). CONCLUSIONS: We showed a positive impact of a newly developed Web-based app on lifestyle indicators during an intervention of 14 weeks. These results are promising in the app's potential to promote a healthy lifestyle, although larger and longer duration studies are needed to achieve more definitive conclusions. TRIAL REGISTRATION: Clinicaltrial.gov number: NCT01913496; http://www.clinicaltrials.gov/ct2/show/NCT01913496 (Archived by WebCite at http://www.webcitation.org/6WSTUEPuJ). PMID- 25732937 TI - Measuring beta-diversity with species abundance data. AB - In 2003, 24 presence-absence beta-diversity metrics were reviewed and a number of trade-offs and redundancies identified. We present a parallel investigation into the performance of abundance-based metrics of beta-diversity. beta-diversity is a multi-faceted concept, central to spatial ecology. There are multiple metrics available to quantify it: the choice of metric is an important decision. We test 16 conceptual properties and two sampling properties of a beta-diversity metric: metrics should be 1) independent of alpha-diversity and 2) cumulative along a gradient of species turnover. Similarity should be 3) probabilistic when assemblages are independently and identically distributed. Metrics should have 4) a minimum of zero and increase monotonically with the degree of 5) species turnover, 6) decoupling of species ranks and 7) evenness differences. However, complete species turnover should always generate greater values of beta than extreme 8) rank shifts or 9) evenness differences. Metrics should 10) have a fixed upper limit, 11) symmetry (betaA,B = betaB,A ), 12) double-zero asymmetry for double absences and double presences and 13) not decrease in a series of nested assemblages. Additionally, metrics should be independent of 14) species replication 15) the units of abundance and 16) differences in total abundance between sampling units. When samples are used to infer beta-diversity, metrics should be 1) independent of sample sizes and 2) independent of unequal sample sizes. We test 29 metrics for these properties and five 'personality' properties. Thirteen metrics were outperformed or equalled across all conceptual and sampling properties. Differences in sensitivity to species' abundance lead to a performance trade-off between sample size bias and the ability to detect turnover among rare species. In general, abundance-based metrics are substantially less biased in the face of undersampling, although the presence-absence metric, betasim , performed well overall. Only betaBaselga R turn , betaBaselga B-C turn and betasim measured purely species turnover and were independent of nestedness. Among the other metrics, sensitivity to nestedness varied >4-fold. Our results indicate large amounts of redundancy among existing beta-diversity metrics, whilst the estimation of unseen shared and unshared species is lacking and should be addressed in the design of new abundance-based metrics. PMID- 25732938 TI - Maternal socio-economic status based on occupation and autism spectrum disorders: a national case-control study. AB - BACKGROUND: The association between parental socio-economic status (SES) and autism spectrum disorders (ASD) has been studied in several countries, but the results have been contradictory. AIMS: The aim of this study was to examine the association between maternal SES and subtypes of ASD in Finland. METHODS: A national case-control study was conducted. Children born in 1991-2005 and diagnosed with ASD by the year 2007 were identified from the Finnish Hospital Discharge Register (FHDR). Their matched controls were selected from the Finnish Medical Birth Register (FMBR). There were 3468 cases and 13,868 controls. The information on maternal SES was collected from the FMBR and categorized into upper white-collar workers (referent), lower white-collar workers, blue-collar workers and "others", consisting of students, housewives and other groups with unknown SES. The statistical test used was conditional logistic regression. RESULTS: The likelihood of ASD was increased among offspring of mothers who belong to the group "others" (adjusted OR = 1.2, 95% CI 1.009-1.3). The likelihood of Asperger's syndrome was decreased among offspring of lower white collar workers (adjusted OR = 0.8, 95% CI 0.6-0.9) and blue-collar workers (adjusted OR = 0.6, 95% CI 0.5-0.7). The likelihood of pervasive developmental disorder not otherwise specified (PDD-NOS) was increased among offspring of blue collar workers (adjusted OR = 1.5, 1.2-1.9) and "others" (adjusted OR = 1.3, 1.1 1.7). No association was found between maternal SES and childhood autism. CONCLUSIONS: The association between maternal SES and ASD differs by ASD subtype. Socio-economic groups might differ from each other by risk factors for ASD subtypes or by their service use. PMID- 25732939 TI - Measles in Morocco: epidemiological profile and impact of vaccination strategy. AB - INTRODUCTION: Measles continues to persist as one of the leading causes of infant mortality due to preventable diseases through vaccination. This study aims to highlight measles in Morocco, and to present the vaccination strategy implemented to control and eliminate the disease in this country. METHODS: Throughout this study, and based on data from the Directorate of Epidemiology and Control of Diseases and those of the Directorate of Population, we present an overview on the epidemiological trends of measles from 1997 to 2012, while evoking the plans established by the Ministry of Health (MoH) for the control and elimination of this disease. RESULTS: The number of measles cases has decreased in Morocco between 1997 and 2012 (2574-720 reported cases per year) as a result of four important steps: first, increasing the routine vaccination coverage (73-94%); second, the introduction of the second dose of the combined vaccine against measles and rubella in schools (children aged 6 years) since 2003; third, the first catch-up campaign of vaccination in Morocco in 2008, for which coverage was highly satisfactory (96% and 100% for age groups 5-59 months and 5-14 years, respectively); and fourth, the organization of a mass vaccination campaign in 2013 that targeted children from aged 9 months to 19 years. CONCLUSION: The vaccination plan and the surveillance system executed in Morocco within the framework of the regional project implemented by the World Health Organization (WHO) to eliminate measles has given remarkable results regarding the reduction of measles cases and mortality due to this disease. According to the data from MoH and WHO, the number of reported and confirmed measles cases decreased drastically during 2014. However, these efforts are still unsatisfactory compared to the prospective of eliminating the disease by 2015. PMID- 25732940 TI - Chemistry in laser-induced plasmas: formation of M-C=C-Cl (M = Ag or Cu) and their characterization by rotational spectroscopy. AB - The new linear molecule Ag-C=C-Cl has been detected and fully characterized by means of rotational spectroscopy. It was synthesized by laser ablation of a silver rod in the presence of a gaseous sample containing a low concentration of CCl4 in argon, cooled to a rotational temperature approaching ~1-3 K through supersonic expansion, and analyzed by chirped-pulse, Fourier transform microwave spectroscopy. Six isotopologues were investigated, and for each the spectroscopic constants B0, D(J) and chi(aa)(Cl) were determined. The B0 values were interpreted to give the following bond lengths: r(Ag-C) = 2.015(14) A and r(C-Cl) = 1.635(6) A, with r(C=C) = 1.2219 A assumed from an ab initio calculation at the CCSD(T)/aug-cc-pV5Z level of theory. The Cu analogue Cu-C=C-Cl was similarly identified and characterized. PMID- 25732941 TI - [Introduction. Multiple sclerosis]. PMID- 25732942 TI - [Current description of multiple sclerosis]. AB - Multiple sclerosis is a multifocal demyelinating disease leading to progressive neurodegeneration caused by an autoimmune response in genetically predisposed individuals. In the last few years, the knowledge and management of this disease has been revolutionized by a series of findings. The present article reviews pathological features of the disease, in which cortical involvement is increasingly implicated, and aspects related to novel pathogenic mechanisms, such as the role of the microbiota in the genesis of multiple sclerosis, as well as recent contributions from the fields of epidemiology and genetics. Also reviewed are the latest diagnostic criteria, which currently allow a much earlier diagnosis, with clear therapeutic implications. PMID- 25732943 TI - [Multiple sclerosis: socioeconomic effects and impact on quality of life]. AB - Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that affects young adults. Survival is long, more than 35 years, and consequently the disease has a huge socioeconomic impact. The present article discusses the enormous difficulties of carrying out economic assessments in this field but also describes the advances made in research on this topic and the advantages of performing socioeconomic evaluations with increasingly sophisticated tools. We also discuss the need to quantify indirect and intangible costs to translate them into quality of life and subsequently into economic cost, expressed in euros in the case of Spain. The available data indicate that the enormous cost of the disease (1200 million euros per year) is due more to disability-related expenditure than to treatment, which-although expensive-does not represent more than 16-18% of the total expenditure (approximately 200 million euros per year). The increase represented by the cost of MS is not based on higher treatment expenditure but on an increase in the incidence and-especially-the prevalence of the disease. Above all, in the last few years, there has been a considerable rise in the percentage of patients with an indication for treatment. Reflection is therefore needed on the use of drug therapy in MS, since a saving in the most effective products seems to increase the overall cost of MS, while expenditure on these drugs represents a saving in the long-term. PMID- 25732944 TI - [Cormorbidity in multiple sclerosis and its therapeutic approach]. AB - Multiple sclerosis (MS) is a long-term chronic disease, in which intercurrent processes develop three times more frequently in affected individuals than in persons without MS. Knowledge of the comorbidity of MS, its definition and measurement (Charlson index) improves patient management. Acting on comorbid conditions delays the progression of disability, which is intimately linked to the number of concurrent processes and with health states and habits. Moreover, the presence of comorbidities delays the diagnosis of MS, which in turn delays the start of treatment. The main comorbidity found in MS includes other autoimmune diseases (thyroiditis, systemic lupus erythematosus, or pemphigus) but can also include general diseases, such as asthma or osteomuscular alterations, and, in particular, psychiatric disturbances. All these alterations should be evaluated with multidimensional scales (Disability Expectancy Table, DET), which allow more accurate determination of the patient's real clinical course and quality of life. These scales also allow identification of how MS, concurrent and intercurrent processes occurring during the clinical course, and the treatment provided affect patients with MS. An overall approach to patients' health status helps to improve quality of life. PMID- 25732945 TI - [Current therapy of multiple sclerosis]. AB - Since the introduction of interferon beta 1 b for the treatment of multiple sclerosis, there has been a progressive increase in the number of drugs available for this disease. Currently, 11 drugs have been approved in Spain, and their indications depend on specific clinical characteristics. The present article reviews these indications and also discusses other medications without official approval that have also been used in multiple sclerosis. PMID- 25732946 TI - [Oral treatments in multiple sclerosis]. AB - The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient' s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms. PMID- 25732947 TI - [Monoclonal antibodies for the treatment of multiple sclerosis]. AB - Until the mid 1990s, with the appearance of interferon beta and glatiramer acetate, there was no treatment for multiple sclerosis (MS). However, due to their moderate therapeutic potential in some patients, a broad search was continued to find new and more effective treatment strategies, largely concentrated on monoclonal antibodies (MOAB). Natalizumab, the first MOAB for the treatment of MS, was approved at the end of 2004, representing a major advance in the field of neuroimmunology. Today, there is broad experience with natalizumab and other MOAB (alemtuzumab, daclizumab, rituximab, ocrelizumab, ofatumumab and anti-lingo-1) that are pending commercialization or are under phase II or III of development with promising results. The present review analyzes the efficacy and safety results of all these drugs. PMID- 25732948 TI - [Special cases of multiple sclerosis]. AB - Multiple sclerosis is a chronic disease that usually occurs in young people and affects them for the rest of their lives. Patients and their families usually have a series of doubts and questions on everyday matters and all types of situations that occur during the distinct stages of life and which can influence the course of the disease. The aim of this review is to provide specific answers to these questions. PMID- 25732949 TI - [Treatment of multiple sclerosis symptoms and exacerbations]. AB - In the last few years, there has been an explosion of new drugs acting on the clinical course of multiple sclerosis (MS) but less attention has been paid to better knowledge of the symptoms of this disease and their pathogenesis and treatment, which is essential to improve patients' quality of life. Because many patients have numerous concurrent symptoms during their clinical course, their management is complex and consequently it is important to know which symptoms are a direct result of the degenerative lesions of MS. The present article describes all the therapeutic options available for spasticity and its associated pain, paroxystic symptoms, fatigue, genitourinary disorders and sexual dysfunction, tremor, ataxia, gait disorder and cognitive impairment, with special emphasis on novel treatments. The article also defines exacerbations, how to recognize them and the available treatments, mainly oral administration of high-dose methylprednisolone and plasmapheresis. PMID- 25732950 TI - [Future challenges in multiple sclerosis]. AB - Multiple sclerosis occurs in genetically susceptible individuals, in whom an unknown environmental factor triggers an immune response, giving rise to a chronic and disabling autoimmune disease. Currently, significant progress is being made in our knowledge of the frequency and distribution of multiple sclerosis and its risk factors, genetics, pathology, pathogenesis, diagnostic and prognostic markers, and treatment. This has radically changed patients' and clinicians' expectations of multiple sclerosis and has raised hope that there will soon be a way to control the disease. PMID- 25732951 TI - Quantitative assessment of the effect of purity on the properties of single wall carbon nanotubes. AB - We quantitatively demonstrate the importance of high purity for the application of single wall carbon nanotubes (SWCNTs), materials solely composed of one surface, by examining the effects of carbon impurities on the electrical, thermal, and mechanical properties of both as-grown SWCNT forests and processed buckypaper. While decreases in properties were expected, our results showed the extreme sensitivity of SWCNT properties to carbonaceous impurities either through scattering in the individual SWCNTs or an inhibition of the ability to form inter SWCNT junctions. Each property showed a nonlinear decrease (as high as 40%) with the addition of low levels of carbon impurities (~15 wt%), which demonstrates that purity is as important as the crystalline structure. PMID- 25732952 TI - Joint effect of ADARB1 gene, HTR2C gene and stressful life events on suicide attempt risk in patients with major psychiatric disorders. AB - OBJECTIVES: Adenosine to inosine RNA editing, serotonin 2C receptor (HTR2C), and stressful life events (SLEs) have all been implicated in suicidal behaviour. We examined the main and moderating effects of RNA editing (ADAR, ADARB1) and HTR2C genes, childhood trauma (CT), recent SLEs and psychiatric disorders as contributors to suicide attempt (SA) vulnerability. METHODS: Study included 165 suicide attempters and 188 suicide non-attempters, all diagnosed with one of major psychiatric disorders. CT and recent SLEs were assessed using Early Trauma Inventory-Self Report and List of Threatening Experiences Questionnaire, respectively. Selected ADAR and ADARB1 tag-variants, and HTR2C rs6318 were pre screened for association with SA, while generalized linear models and backward selection were applied to identify individual and interacting SA risk factors. RESULTS: ADARB1 rs9983925 and rs4819035 and HTR2C rs6318 were associated with SA. The best minimal model found emotional abuse, recent SLEs, rs9983925 and rs6318 as independent SA risk factors, and general traumas as a factor moderating the effect of psychiatric disorders and emotional abuse. CONCLUSIONS: SA vulnerability in psychiatric patients is related to the joint effect of ADARB1 and HTR2C variants, the existing mood disorder and the cumulative exposures to a various childhood and recent stressful experiences. PMID- 25732953 TI - Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism. AB - Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behavior in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioral test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioral disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity. PMID- 25732954 TI - AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: studies in cognitively poor middle-aged mice. AB - The present work describes, for the first time, the in vivo effects of the multitarget compound AVCRI104P3, a new anticholinesterasic drug with potent inhibitory effects on human AChE, human BuChE and BACE-1 activities as well as on the AChE-induced and self-induced Abeta aggregation. We characterized the behavioral effects of chronic treatment with AVCRI104P3 (0.6 MUmol kg(-1), i.p., 21 days) in a sample of middle aged (12-month-old) male 129/Sv*C57BL/6 mice with poor cognitive performance, as shown by the slow acquisition curves of saline treated animals. Besides, a comparative assessment of cognitive and non-cognitive actions was done using its in vitro equipotent doses of huprine X (0.12 MUmol kg( 1)), a huperzine A-tacrine hybrid. The screening assessed locomotor activity, anxiety-like behaviors, cognitive function and side effects. The results on the 'acquisition' of spatial learning and memory show that AVCRI104P3 exerted pro cognitive effects improving both short- and long-term processes, resulting in a fast and efficient acquisition of the place task in the Morris water maze. On the other hand, a removal test and a perceptual visual learning task indicated that both AChEIs improved short-term 'memory' as compared to saline treated mice. Both drugs elicited the same response in the corner test, but only AVCRI104P3 exhibited anxiolytic-like actions in the dark/light box test. These cognitive enhancement and anxiolytic-like effects demostrated herein using a sample of middle-aged animals and the lack of adverse effects, strongly encourage further studies on AVCRI104P3 as a promising multitarget therapeutic agent for the treatment of cholinergic dysfunction underlying natural aging and/or dementias. PMID- 25732955 TI - Time decay of object, place and temporal order memory in a paradigm assessing simultaneously episodic-like memory components in mice. AB - A common trait of numerous memory disorders is the impairment of episodic memory. Episodic memory is a delay-dependant memory, especially associating three components, the "what", "where" and "when" of a unique event. To investigate underlying mechanisms of such memory, several tests, mainly based on object exploration behaviour, have been set up in rodents. Recently, a three-trial object recognition task has been proposed to evaluate simultaneously the different components of episodic-like memory in rodents. However, to date, the time course of each memory component in this paradigm is not known. We characterised here the time course of memory decay in adult mice during the three trial object recognition task, with inter-trial interval (ITI) ranging from 1h to 4h. We found that, with 1h and 2h, but not 4h ITI, mice spent more time to explore the displaced "old object" relative to the displaced "recent object", reflecting memory for "what and when". Concomitantly, animals exhibited more exploration time for the displaced "old object" relative to the stationary "old object", reflecting memory for "what and where". These results provide strong evidence that mice establish an integrated memory for unique experience consisting of the "what", "where" and "when" that can persist until 2h ITI. PMID- 25732956 TI - Short-term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in hippocampus. AB - Hippocampus-dependent learning memory is sensitive to sleep deprivation (SD). Although the ionotropic glutamate receptors play a vital role in synaptic plasticity and learning and memory, however, whether the expression of these receptor subunits is modulated by sleep loss remains unclear. In the present study, western blotting was performed by probing with specific antibodies against the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1, GluA2, GluA3, and against the N-methyl-d-aspartate (NMDA) glutamate receptor subunits GluN1, GluN2A, GluN2B. In hippocampus, down regulation of surface GluA1 and GluN2A surface expression were observed in both SD groups. However, surface expression level of GluA2, GluA3, GluN1 and GluN2B was significantly up-regulated in 8h-SD rats when compared to the 4h-SD rats. In parallel with the complex changes in AMPA and NMDA receptor subunit expressions, we found the 8h-SD impaired rat spatial working memory in 30-s-delay T-maze task, whereas no impairment of spatial learning was observed in 4h-SD rats. These results indicate that sleep loss alters the relative expression levels of the AMPA and NMDA receptors, thus affects the synaptic strength and capacity for plasticity and partially contributes to spatial memory impairment. PMID- 25732957 TI - DNA driven self-assembly of micron-sized rods using DNA-grafted bacteriophage fd virions. AB - We have functionalized the sides of fd bacteriophage virions with oligonucleotides to induce DNA hybridization driven self-assembly of high aspect ratio filamentous particles. Potential impacts of this new structure range from an entirely new building block in DNA origami structures, inclusion of virions in DNA nanostructures and nanomachines, to a new means of adding thermotropic control to lyotropic liquid crystal systems. A protocol for producing the virions in bulk is reviewed. Thiolated oligonucleotides are attached to the viral capsid using a heterobifunctional chemical linker. A commonly used system is utilized, where a sticky, single-stranded DNA strand is connected to an inert double stranded spacer to increase inter-particle connectivity. Solutions of fd virions carrying complementary strands are mixed, annealed, and their aggregation is studied using dynamic light scattering (DLS), fluorescence microscopy, and atomic force microscopy (AFM). Aggregation is clearly observed on cooling, with some degree of local order, and is reversible when temperature is cycled through the DNA hybridization transition. PMID- 25732958 TI - Steady pulsed imaging and labeling scheme for noninvasive perfusion imaging. AB - PURPOSE: A steady pulsed imaging and labeling (SPIL) scheme is proposed to obtain high-resolution multislice perfusion images of mice brain using standard preclinical MRI equipment. THEORY AND METHODS: The SPIL scheme repeats a pulsed arterial spin labeling (PASL) module together with a short mixing time to extend the temporal duration of the generated PASL bolus to the total experimental time. Multislice image acquisition takes place during the mixing times. The mixing time is also used for magnetization recovery following image acquisition. The new scheme is able to yield multislice perfusion images rapidly. The perfusion kinetic curve can be measured by a multipulsed imaging and labeling (MPIL) scheme, i.e., acquiring single-slice ASL signals before reaching steady-state in the SPIL sequence. RESULTS: When applying the SPIL method to normal mice, and to mice with unilateral ischemia, high-resolution multislice (five slices) CBF images could be obtained in 8 min. Perfusion data from ischemic mice showed clear CBF reductions in ischemic regions. The SPIL method was also applied to postmortem mice, showing that the method is free from magnetization transfer confounds. CONCLUSION: The new SPIL scheme provides for robust measurement of CBF with multislice imaging capability in small animals. PMID- 25732959 TI - Study of human cytomegalovirus replication in body fluids, placental infection, and miscarriage during the first trimester of pregnancy. AB - Intrauterine infection caused by human cytomegalovirus (HCMV) can lead to embryo, fetal, and neonatal damage. The prevalence of HCMV replication in body fluids (blood, urine, and cervicovaginal secretion) was investigated, and its effects on HCMV vertical transmission and miscarriages in early pregnant women were evaluated. HCMV DNA in body fluids was detected in 1,064 early pregnant women (624 normal pregnancies and 440 miscarriages). There were 101 cases who were HCMV DNA positive in cervicovaginal secretion and the rates were 10.9% (48/440 cases) and 8.5% (53/624 cases) in miscarriages and normal pregnancies, respectively (P > 0.05). A total of 101 cases (63 and 38 cases with and without HCMV DNA in cervicovaginal secretion, respectively) were given HCMV DNA detection in placental villi/deciduas. There were five cases (7.9%; two normal pregnancies and three miscarriages) with HCMV DNA in placental villi/deciduas among the 63 cases with HCMV DNA in cervicovaginal secretion, whereas none of the other 38 cases were detected HCMV DNA positive in their placental villi/deciduas. The percentage of HCMV DNA in placental villi/deciduas was higher in miscarriage group (9.1% [3/33]) than that in the normal pregnancy group (6.7% [2/30]), but there was no statistical significance (P > 0.05). Two cases with a higher HCMV loads in cervicovaginal secretion and placental villi/deciduas had miscarriages. These findings suggest that HCMV replication in cervicovaginal secretion can involve in placental HCMV infection, and high HCMV DNA loads in cervicovaginal secretion and placental villi/deciduas are associated with miscarriage. PMID- 25732961 TI - The sandwich vertebral body sign in osteopetrosis. PMID- 25732960 TI - EGFR Targeted Theranostic Nanoemulsion for Image-Guided Ovarian Cancer Therapy. AB - PURPOSE: Platinum-based therapies are the first line treatments for most types of cancer including ovarian cancer. However, their use is associated with dose limiting toxicities and resistance. We report initial translational studies of a theranostic nanoemulsion loaded with a cisplatin derivative, myrisplatin and pro apoptotic agent, C6-ceramide. METHODS: The surface of the nanoemulsion is annotated with an endothelial growth factor receptor (EGFR) binding peptide to improve targeting ability and gadolinium to provide diagnostic capability for image-guided therapy of EGFR overexpressing ovarian cancers. A high shear microfludization process was employed to produce the formulation with particle size below 150 nm. RESULTS: Pharmacokinetic study showed a prolonged blood platinum and gadolinium levels with nanoemulsions in nu/nu mice. The theranostic nanoemulsions also exhibited less toxicity and enhanced the survival time of mice as compared to an equivalent cisplatin treatment. CONCLUSIONS: Magnetic resonance imaging (MRI) studies indicate the theranostic nanoemulsions were effective contrast agents and could be used to track accumulation in a tumor. The MRI study additionally indicate that significantly more EGFR-targeted theranostic nanoemulsion accumulated in a tumor than non-targeted nanoemulsuion providing the feasibility of using a targeted theranostic agent in conjunction with MRI to image disease loci and quantify the disease progression. PMID- 25732962 TI - Ablative fractional laser intensifies treatment outcome of scalp actinic keratoses with ingenol mebutate: a case report. PMID- 25732963 TI - Fidelity by design: Yoctoreactor and binder trap enrichment for small-molecule DNA-encoded libraries and drug discovery. AB - DNA-encoded small-molecule library (DEL) technology allows vast drug-like small molecule libraries to be efficiently synthesized in a combinatorial fashion and screened in a single tube method for binding, with an assay readout empowered by advances in next generation sequencing technology. This approach has increasingly been applied as a viable technology for the identification of small-molecule modulators to protein targets and as precursors to drugs in the past decade. Several strategies for producing and for screening DELs have been devised by both academic and industrial institutions. This review highlights some of the most significant and recent strategies along with important results. A special focus on the production of high fidelity DEL technologies with the ability to eliminate screening noise and false positives is included: using a DNA junction called the Yoctoreactor, building blocks (BBs) are spatially confined at the center of the junction facilitating both the chemical reaction between BBs and encoding of the synthetic route. A screening method, known as binder trap enrichment, permits DELs to be screened robustly in a homogeneous manner delivering clean data sets and potent hits for even the most challenging targets. PMID- 25732964 TI - Transcatheter arterial embolization for endoscopically unmanageable non-variceal upper gastrointestinal bleeding. AB - OBJECTIVE: Transcatheter arterial embolization (TAE) is a therapeutic option for endoscopically unmanageable upper gastrointestinal (GI) bleeding. We aimed to assess the efficacy and clinical outcomes of TAE for acute non-variceal upper GI bleeding and to identify predictors of recurrent bleeding within 30 days. MATERIALS AND METHODS: Visceral angiography was performed in 66 patients (42 men, 24 women; mean age, 60.3 +/- 12.7 years) who experienced acute non-variceal upper GI bleeding that failed to be controlled by endoscopy during a 7-year period. Clinical information was reviewed retrospectively. Outcomes included technical success rates, complications, and 30-day rebleeding and mortality rates. RESULTS: TAE was feasible in 59 patients. The technical success rate was 98%. Rebleeding within 30 days was observed in 47% after an initial TAE and was managed with re embolization in 8, by endoscopic intervention in 5, by surgery in 2, and by conservative care in 12 patients. The 30-day overall mortality rate was 42.4%. In the case of initial endoscopic hemostasis failure (n = 34), 31 patients underwent angiographic embolization, which was successful in 30 patients (96.8%). Rebleeding occurred in 15 patients (50%), mainly because of malignancy. Two factors were independent predictors of rebleeding within 30 days by multivariate analysis: coagulopathy (odds ratio [OR] = 4.37; 95% confidence interval [CI]: 1.25-15.29; p = 0.021) and embolization in >=2 territories (OR = 4.93; 95% CI: 1.43-17.04; p = 0.012). Catheterization-related complications included hepatic artery dissection and splenic embolization. CONCLUSION: TAE controlled acute non variceal upper GI bleeding effectively. TAE may be considered when endoscopic therapy is unavailable or unsuccessful. Correction of coagulopathy before TAE is recommended. PMID- 25732965 TI - Can we make stroke during cardiac surgery a never event? PMID- 25732966 TI - [Successful therapy of condylomata acuminata with ingenol mebutate]. AB - Condylomata acuminata (CA) are one of the most common sexually transmitted infections in the sexually active population. Due to the stigmatizing character of the disease and the high rate of relapse after therapy, CA may significantly affect patients' quality of life. Here, we report the case of successful treatment of multiple CA of the penis and scrotum in a 53-year-old man with ingenol mebutate gel. PMID- 25732967 TI - Propensity score analysis of outcomes following minimal access versus conventional aortic valve replacement. AB - OBJECTIVES: Minimal access aortic valve replacement has become routine in many institutions. Aim of this study was to compare the clinical outcomes between conventional and minimal access aortic valve replacement. METHODS: We retrospectively analysed the data of 2103 patients who underwent primary, isolated aortic valve replacement (AVR) in our institution between January 2001 and May 2012 with a minimal access AVR (MAAVR) via the upper partial ministernotomy approach (n = 936) or conventional AVR (CAVR) via the full sternotomy approach (n = 1167). After propensity score matching considering potential confounders [age, sex (female), weight, height, preoperative serum creatinine level, previous myocardial infarction, LV-EF and aortic valve pathology (isolated AS)], 585 matched patients were included in each group. RESULTS: Mean age (65 +/- 10.5 vs 65.7 +/- 11.5 years, P = 0.23), gender (females 37.2%, P = 0.9), aortic cross-clamp time (65.6 +/- 18.4 vs 64.3 +/- 19.8 min, P = 0.25) and postoperative blood loss [median (IQR) 400 (224-683) vs 400 (250-610) ml, P = 0.83) were similar in MAAVR and CAVR group. Thirty-day mortality was also not significantly different (1.5 vs 1.7%, P = 0.74, respectively). In contrast, CPB times were significantly longer in MAAVR (93.5 +/- 25 vs 88 +/- 28 min, P < 0.001). Intraoperative and postoperative autologous blood transfusions were significantly lower in MAAVR (927.2 +/- 425.6 vs 1036.4 +/- 599.6 ml, P < 0.001 and 170.2 +/- 47.6 vs 243.5 +/- 89.3 ml, P < 0.001, respectively). Intubation time was significantly shorter in MAAVR [median (IQR) 7 (5-11) vs 8 (6-14) h, P = 0.01). The incidence of renal insufficiency (creatinine >=1.5 mg/dl) and respiratory insufficiency (need for non-invasive ventilation, reintubation or tracheotomy) was significantly lower in MAAVR (9 vs 16%, P < 0.001 and 8.5 vs 11.8%, P = 0.03, respectively). CONCLUSIONS: In comparison with CAVR, our study shows that MAAVR is a safe and effective procedure associated with low mortality rate and good long-term survival rates. In addition to that, MAAVR was associated with shorter ventilation times, lower rate of autologous blood transfusion, as well as a lower rate of postoperative respiratory and renal insufficiency. Because of the superior cosmetic results, we therefore advocate MAAVR as the procedure of choice for primary isolated AVR. PMID- 25732968 TI - Hybrid versus open repair of aortic arch aneurysms: comparison of postoperative and mid-term outcomes with a propensity score-matching analysis. AB - OBJECTIVES: Operative strategies for repairing aortic arch aneurysms should be re evaluated following recent technical advances. METHODS: Of 364 patients who underwent aortic arch repair between 2002 and 2014, 58 were high-risk subjects who received isolated hybrid arch repair (HAR) via median sternotomy (type I n = 32, type II n = 1 and type III n = 25). During this period, excluding patients with type A dissection or extensive aneurysms, 124 patients received isolated open arch repair via median sternotomy. The patients in the HAR and open arch repair groups were compared. A propensity score-matching analysis was applied to adjust for baseline risk factors. RESULTS: The patients in the HAR group were older (77 years +/- 6 vs 69 +/- 9, P < 0.0001), exhibited a greater rate of malignancy (21 vs 4.8%, P = 0.0022) and had higher logistic EuroSCORE values (31 +/- 18 vs 20 +/- 15, P < 0.0001) than those in the open arch repair group. Following propensity score matching creating 38 matched pairs, the differences in preoperative risk diminished. Operative complications, including the mortality rate (2.6 vs 0%), were similar between the groups. Apart from the lower rates of cardiopulmonary bypass (CPB) and circulatory arrest, there was no apparent superiority of HAR with respect to patient recovery. The mean follow-up duration was 52.5 months, during which the rate of freedom from aortic events in the HAR and open arch repair groups was 79 and 99% at 24 months, respectively (P < 0.0001). CONCLUSIONS: HAR achieves equivalent short-term results to standard open arch repair, with a decreased need for CPB. However, considering the inferior mid term outcomes of this procedure, its indications should be limited to high-risk patients. PMID- 25732969 TI - Pulmonary embolism and thrombus-in-transit crossing a patent foramen ovale: comprehensive diagnosis using cardiac multislice computed tomography. PMID- 25732970 TI - Ascending aortic graft thrombosis from an endoluminal candida albicans infection. PMID- 25732971 TI - Surgical management of destructive aortic endocarditis: left ventricular outflow reconstruction with the Sorin Pericarbon Freedom stentless bioprosthesis?. AB - OBJECTIVES: The treatment of complicated aortic endocarditis with periannular abscesses and root disarrangement is a surgical challenge, and includes left ventricular outflow tract (LVOT) reconstruction with the patch technique or homograft implantation. The results of a simplified technique to reconstruct the LVOT in destructive endocarditis of either the aortic native valve or valve prosthesis with the Sorin Pericarbon Freedom stentless valve are reported. METHODS: Since August 2007, 40 patients with destructive endocarditis (mean age: 69 +/- 12, 75% males, European System for Cardiac Operative Risk Evaluation II (EuroSCORE II): 19 +/- 13, New York Heart Association (NYHA) class: >=3 in all cases) have undergone LVOT reconstruction with a Sorin Pericarbon Freedom stentless bioprosthesis. Seven patients (17.5%) were in septic or cardiogenic shock preoperatively, and 18 patients (45%) suffered from moderate or severe aortic regurgitation. Eleven patients (27.5%) experienced preoperative systemic embolizations. Thirty-six cases (90%) were valve redos and 9 patients (22.5%) had concomitant procedures. The mean follow-up was 26 +/- 25 months. RESULTS: One patient (2.5%) died early (<30 days) and another 3 patients never discharged died due to multiorgan failure and septic shock. Actuarial survival rate was 85 +/- 6% at 1 year, and 76 +/- 8% at 3 and 5 years, respectively. Twelve patients (30%) required pacemaker implantation because of atrioventricular block and 20 patients (50%) developed or showed a progression of renal failure. One patient (2.5%) had an endocarditis relapse, and 1 (2.5%) showed a mild paraprosthetic aortic leak. No patient needed reoperation. At the last echocardiographic evaluation, mean gradient, peak gradient and left ventricular ejection fraction were 7.9 +/- 5.0 mmHg, 15.1 +/- 7.2 mmHg and 63.3 +/- 9.3%, respectively. CONCLUSIONS: The Sorin Pericarbon Freedom stentless prosthesis, with the modified technique herein described, seems to be a good option in most of cases of destructive aortic valve endocarditis. It is promptly available in different sizes, easy to implant and, due to its pericardial inflow skirt, ideal for extensive reconstruction of the LVOT with good haemodynamic performance and low risk of relapse. PMID- 25732972 TI - The changing management of chylothorax in the modern era. AB - Initial conservative therapy is applied to all cases of chylothorax (CTx) with expected excellent outcomes. The indication for aggressive surgical treatment of early CTx remains uncertain and requires rigorous scientific scrutiny. Lymphangiography and lymphoscintigraphy are useful to localize the leak and assess thoracic duct patency as well as to differentiate partial from complete thoracic duct transection. The aetiology of the CTx, flow rate and patient condition dictate the preferred management. Octreotide/somatostatin and etilefrine therapy is highly efficacious in the conservative management of CTx. For patients in whom conservative management fails, those who are good surgical candidates, and those in whom the site of the leak is well identified, surgical repair and/or ligation using minimally invasive techniques is highly successful with limited adverse outcomes. Similarly, if the site of the chylous effusion cannot be well visualized, a thoracic duct ligation via video-assisted thoracic surgery is the gold standard approach. A pleuroperitoneal or less often a pleurovenous shunt is a final option and may be curative in some patients. PMID- 25732973 TI - False-positive axillary lymph node on positron emission tomography/computed tomography in a thymoma patient with a tattoo. PMID- 25732974 TI - Electrophysiological findings and long-term outcomes of percutaneous ablation of atrial arrhythmias after surgical ablation for atrial fibrillation?. AB - OBJECTIVES: Percutaneous ablation (PA) for relapsing atrial tachyarrhythmias after surgical ablation is an emerging therapy. The aim of this study is to report the electrophysiological findings and the procedural long-term outcomes of reablation, in this particular clinical setting. METHODS: We retrospectively analysed all patients who were readmitted to our centre for relapsing atrial arrhythmias after surgical ablation for atrial fibrillation (AF). RESULTS: From 2000 to 2011, 36 patients with previous surgical ablation of AF received additional percutaneous management. Seven patients had had biatrial Maze, 18 left atrial ablation lesion set and 11 pulmonary vein isolation. Energy sources involved were unipolar radiofrequency (RF) (n = 13), bipolar RF (n = 19), combined bipolar RF and cryoenergy (n = 2), cryoenergy (n = 1) and high intensity focused ultrasound (n = 1). The median time to reablation was 34 months (interquartile range: 10-66). The relapsing arrhythmias were left atrial tachycardia (n = 17), AF (n = 15), right atrial flutter (n = 2), right atrial tachycardia (n = 1) and biatrial atrial tachycardia (n = 1). Origin of re-entrant circuits was perimitral (n = 27), around pulmonary veins (PV) including posterior left atrium (n = 15) and cavotricuspid isthmus (n = 3). Twenty-seven (75%) patients had left isthmus catheter ablation and 11 (30%) reablation of PV. Eighteen out of the 27 perimitral circuits were in patients with previous left atrial Maze; in 17 patients the mitral line was performed with bipolar RF only, without the addition of cryoenergy. The importance of an appropriate energy source is also underlined by the prevalence of gaps in PV isolation that occurred for two-thirds of patients treated using unipolar RF only, which has been discontinued since 2001. Ten patients (27%) needed more than 1 PA for relapsing arrhythmia. At the last follow-up of 97 +/- 42 months, freedom from arrhythmias was 53% after single PAs and 67% after more than one procedure. No morbidity, mortality or strokes were recorded during the follow-up. CONCLUSIONS: Percutaneous treatment of highly symptomatic patients with unsuccessful previous surgical ablation is feasible, and relatively effective at the late follow-up. A multidisciplinary approach significantly improves the outcomes in these challenging patients. PMID- 25732976 TI - Thoracoscopic native lung pneumonectomy after single lung transplant: initial experience with 2 cases?. AB - Single lung transplants (SLTs) leave in place a diseased lung, a potential source of complications. Native lung pneumonectomy is occasionally indicated. We present 2 cases of native lung complications (NLCs) managed with video-assisted thoracoscopic surgery (VATS) pneumonectomy at our institution, a procedure never reported in this context before. Case 1 involves a 59-year old gentleman with refractory, invasive pulmonary aspergillosis of the native lung, 5 years after SLT for idiopathic pulmonary fibrosis. Case 2 involves a 66-year old gentleman with alpha-1 antitrypsin deficiency who developed severe haemoptysis and intraparenchymal haemorrhage in the native lung 12 years after SLT. A VATS pneumonectomy was performed in both cases because we believed it would facilitate wound healing and hasten recovery in immunosuppressed patients. Our short-term results align with this hypothesis. We conclude that VATS pneumonectomy is a feasible, adequate and safe procedure in this patient population; larger series are needed to draw definitive conclusions. PMID- 25732975 TI - Survival following lung resection in immunocompromised patients with pulmonary invasive fungal infection. AB - OBJECTIVES: Pulmonary invasive fungal infections (IFIs) are associated with high mortality in patients being treated for haematological malignancy. There is limited understanding of the role for surgical lung resection and outcomes in this patient population. METHODS: This is a retrospective cohort of 50 immunocompromised patients who underwent lung resection for IFI. Patient charts were reviewed for details on primary malignancy and treatment course, presentation and work-up of IFI, reasons for surgery, type of resection and outcomes including postoperative complications, mortality, disease relapse and survival. Analysis was also performed on two subgroups based on year of surgery from 1990-2000 and 2001-2014. RESULTS: The median age was 39 years (range: 5-64 years). Forty-seven patients (94%) had haematological malignancies and 38 (76%) underwent haematopoietic stem cell transplantation (HSCT). Surgical indications included haemoptysis, antifungal therapy failure and need for eradication before HSCT. The most common pathogen was Aspergillus in 34 patients (74%). Wedge resections were performed in 32 patients (64%), lobectomy in 9 (18%), segmentectomy in 2 (4%) and some combination of the 3 in 7 (14%) for locally extensive, multifocal disease. There were 9 (18%) minor and 14 (28%) major postoperative complications. Postoperative mortality at 30 days was 12% (n = 6). Acute respiratory distress syndrome was the most common cause of postoperative death. Overall 5-year survival was 19%. Patients who had surgery in the early period had a median survival of 24 months compared with 5 months for those who had surgery before 2001 (P = 0.046). At the time of death, 15 patients (30%) had probable or proven recurrent IFI. Causes of death were predominantly related to refractory malignancy, fungal lung disease or complications of graft versus host disease (GVHD). Patients who had positive preoperative bronchoscopy cultures had a trend towards worse survival compared with those with negative cultures (hazard ratio: 1.80, P = 0.087). CONCLUSIONS: Surgical resection of IFI in immunocompromised patients is associated with high perioperative mortality. Long term survival is limited by recurrent malignancy, persistent fungal infection and GVHD but has improved in recent years. Selection for surgical resection is difficult in this patient population, but should be carefully considered in those who are symptomatic, or have failed antifungal treatment. PMID- 25732977 TI - Fluctuations in serum ethanol concentration in the treatment of acute methanol poisoning: a prospective study of 21 patients. AB - OBJECTIVE: During the 2012 outbreak of mass methanol poisonings in the Czech Republic, ethanol, in the main, was used as an antidote. The complex pharmacokinetics of ethanol made it difficult to maintain the requisite 1000-1500 mg/L serum ethanol levels (S-EtOH). The aim of this study was to measure the fluctuations in S-EtOH during the treatment. METHODS: A prospective case series in 21 patients, median age 52 (27-79 years), 13 males and 8 females. Serum ethanol, methanol and formate were measured every 2-6 hours during the treatment. Follow-up clinical examination was carried out in 15/18 survivors. RESULTS: The majority of patients (17/21) were late presenters and on admission, almost half (10/21) had suffered a severe grade of intoxication according to the Poisoning Severity Score (PSS). The mean observation time was 90+/-20 h. The mean period of consistent maintenance of S-EtOH within the recommended therapeutic range lasted 28+/-7% of the total observation time. For 29+/-8% of the time, S-EtOH was >1500 mg/L with "peaks" of up to 3500 mg/L. For 44+/-10% of the observation time, S EtOH was <1000 mg/L. The mean duration of sub-therapeutic concentration of S-EtOH and toxic serum levels of methanol >200 mg/L or formate >20 mg/L lasted 20+/-10% and 18+/-11% of the time of observation, respectively. Complications occurred in 14 (67%) of cases including significant fluctuations of S-EtOH in 9; aspiration pneumonia in 3 and delirium tremens in 2 cases. Other complications included sepsis, bleeding, acidosis rebound, intolerance and set clotting. The outcomes were: 11 survivors free of health impairment, 7 with sequelae and 3 deaths. There was no significant difference in mean duration of sub-therapeutic and supra therapeutic concentrations of serum ethanol in patients who survived without sequelae and those with poor outcome (P > 0.05). CONCLUSION: Administration of ethanol according to the present guidelines of the AACT/EAPCCT is effective and relatively safe in the treatment of methanol poisoning during a mass outbreak(31). Physicians have to be most aware of fluctuations in serum ethanol at the end of short sessions of IHD and after changes in route from intravenous to oral. Rigorous monitoring of serum ethanol concentrations is pivotal for severely poisoned patients with PSS 3 and where there is suspected conversion of significant amounts of methanol to formic acid. PMID- 25732978 TI - Glucose concentrations in blood and tissue - a pilot study on variable time lag. AB - AIM: The aim of this pilot study was to acquire insight into the parameters of glycaemic control, especially, (1) the time delay (lag phase) between plasma and tissue glucose concentrations in relation to rise and fall in glucose levels and (2) the rate of glucose increase and decrease. METHODS: Four healthy people (HP), 4 people with type 1diabetes (DM1) and 4 with type 2 diabetes (DM2) underwent concurrent glucose measurements by means of (1) the continuous glucose monitoring system (CGMS-Medtronic), Medtronic-Minimed, CA, USA, calibrated by the glucometer Calla, Wellion, Austria, and, (2) the Beckman II analyser to measure glucose concentrations in venous plasma. Samples were taken on 4 consecutive days in the fasting state and 4 times after consumption of 50 g glucose. Carelink Personal, MS Excel, Maple and Mat lab were applied to plot the evolution of glucose concentration and analyse the results. The time difference between increase and decrease was calculated for HP, DM 1 and DM 2. RESULTS: In DM1and DM2, glucose tolerance testing (GTT) resulted in slower transport of glucose into subcutaneous tissue than in HP where the lag phase lasted up to 12 min. The maximum increase/decrease rates in DM1 and DM2 vs HP were 0.25 vs < 0.1 mmol/L/min. CONCLUSION: CGMS is shown to provide reliable plasma glucose concentrations provided the system is calibrated during a steady state. The analysis of glucose change rates improves understanding of metabolic processes better than standard GTT. PMID- 25732979 TI - CT-1 induces angiogenesis by regulating the ADMA/DDAH Pathway. AB - BACKGROUND: Cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is elevated in the serum of patients with ischemic and valvular heart disease. In this study, we hypothesized that CT-1 induces endothelial cell angiogenesis and that the ADMA/DDAH pathway plays an important role in the process. METHODS: pEGFP-N1-CTF1 GFP and pEGFP-N1 were constructed and used to transiently transfect to HUVECs, mediated by LipofectamineTM 2000. After transfection, the expression of CT-1 was examined by qRT-PCR and western blotting. Endothelial cell proliferation assay was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) method. Migration assay was performed using transwell, tube formation test was examined on Matrigel, eNOSmRNA expression was assayed by qRT PCR, DDAH I, DDAHII and VEGF expression were detected by western blotting, the level of ADMA and the activity of DDAH were measured by High Performance Liquid Chromatography, NOS activity and the concentration of NO were assayed by L-[3H] citrulline production from L-[3H]arginine. RESULTS: Overexpression of CT-1, increased endothelial cell proliferation, migration and formation of blood vessels, upregulated the expression of eNOSmRNA, DDAHI, DDAHII and VEGF, elevated the activity of DDAH and NOS, decreased the level of ADMA and promoted NO synthesis. In contrast, ADMA partially inhibited the effects of CT-1 induction. CONCLUSIONS: Overexpression of CT-1 increases cell proliferation, migration and formation of blood vessels. This result also suggests that CT-1 may regulate angiogenesis through the ADMA/DDAH pathway. PMID- 25732980 TI - Addition of Si-H and B-H bonds and redox reactivity involving low-coordinate nitrido-vanadium complexes. AB - In this study we enumerate the reactivity for two molecular vanadium nitrido complexes of [(nacnac)V=N(X)] formulation [nacnac = (Ar)NC(Me)CHC(Me)(Ar)(-), Ar = 2,6-(CHMe2)2C6H3); X(-) = OAr (1) and N(4-Me-C6H4)2 (Ntolyl2) (2)]. Density functional theory calculations and reactivity studies indicate the nitride motif to have nucleophilic character, but where the nitrogen atom can serve as a conduit for electron transfer, thus allowing the reduction of the vanadium(V) metal ion with concurrent oxidation of the incoming substrate. Silane, H2SiPh2, readily converts the nitride ligand in 1 into a primary silyl-amide functionality with concomitant two-electron reduction at the vanadium center to form the complex [(nacnac)V{N(H)SiHPh2}(OAr)] (3). Likewise, addition of the B-H bond in pinacolborane to the nitride moiety in 2 results in formation of the boryl-amide complex [(nacnac)V{N(H)B(pinacol)}(Ntolyl2)] (4). In addition to spectroscopic data, complexes 3 and 4 were also elucidated structurally by single-crystal X-ray diffraction analysis. One-electron reduction of 1 with 0.5% Na/Hg on a preparative scale allowed for the isolation and structural determination of an asymmetric bimolecular nitride radical anion complex having formula [Na]2[(nacnac)V(N)(OAr)]2 (5), in addition to room-temperature solution X-band electron paramagnetic resonance spectroscopic studies. PMID- 25732981 TI - Contamination and risk assessment of heavy metals in soils irrigated with biogas slurry: a case study of Taihu basin. AB - The accumulation of heavy metals in different soils resulting from irrigation with biogas slurry obtained from Taihu basin may create a potential public health risk. We quantified the concentration of heavy metals (Zn, Pb, Cu, Cr, As, and Cd.) in soils. Results indicated that the concentrations of Ni, Zn, Cd, and Pb in soil exceeded the maximum permitted levels set by Chinese Soil Environmental Quality Standard (GB15618-2008). The highest mean level in the soil was noted for Zn, followed by Zn, Pb, Cu, Cr, As, and Cd, while maximum geoaccumulation index (Igeo) was found for Cd in all soil samples which ranged from strongly polluted to extremely polluted. Pollution levels varied with metals and soil types. Moreover, the concentrations of Mn, Co, Ni, Cu, Zn, As, and Pb in soils showed significant correlations with OM; pH showed positive correlations with Cd, Cu, As, and Cr; pH and OM were the most important factors controlling the uptake of heavy metals by soils. Multivariate principal component analysis showed anthropogenic contributions of Zn, Pb, Cu, As, and Cd in the different kinds of soils. The target hazard quotient (HQ) values of six metals in soils were less than 1, which suggested that non-carcinogenic risks of metal exposure to soils were generally assumed to be safe. The assessment results of carcinogenic risks in soils showed higher risks than an acceptable range of 1E-06 to 1E-04 that would pose potential cancer risks to the farmers due to the work of leafy and root vegetables grown locally. PMID- 25732982 TI - Lead poisoning in Nile tilapia (Oreochromis niloticus): oxidant and antioxidant relationship. AB - Selenium and vitamin E are very effective antioxidant agents which play important roles in improving and development of aquaculture sector. This study was conducted to determine the protective and treatment effects of vitamin E and selenium against lead toxicity. Administration of both vitamin E and selenium ameliorated the adverse effects of lead acetate toxicity through significant increase in hemoglobin, packed cell volume, RBC count, WBC count, and lymphocytes compared to lead acetate-exposed groups especially after the 10th week. Also, it is revealed that severe decrease of total protein, calcium, phosphorous, and magnesium in lead acetate intoxicated group. On contrary, significant increase of blood parameters upon addition of vitamin E and selenium combined with/without lead. On the other hand, insignificant decreases of sAST, sALT, urea, and creatinine in group fed on vitamin E and selenium, while increase in lead acetate intoxicated group. Lead acetate caused increasing of lipid peroxidation level (malondialdehyde) and decreasing of superoxide dismutase activity and reduced glutathione level. From these results, it is concluded that exposure to lead acetate is considered as hepatotoxic environmental pollutant. Exposure to lead acetate induced significant effects on antioxidant status. Antioxidants (vitamin E and selenium) showed important roles to protect body against lipid peroxidation, which considered as the first step of cell membrane damage, in addition to the improvement of the endogenous antioxidant enzyme activities. PMID- 25732983 TI - Antibiotic and Diagnostic Discordance Between ED Physicians and Hospitalists for Pediatric Respiratory Illness. AB - BACKGROUND AND OBJECTIVE: Imperfect diagnostic tools make it difficult to know the extent to which a bacterial process is contributing to respiratory illness, complicating the decision to prescribe antibiotics. We sought to quantify diagnostic and antibiotic prescribing disagreements between emergency department (ED) and pediatric hospitalist physicians for children admitted with respiratory illness. METHODS: Manual chart review was used to identify testing, diagnostic, and antibiotic prescribing decisions for consecutive children admitted for respiratory illness in a winter (starting February 20, 2012) and a summer (starting August 20, 2012) season to a tertiary, freestanding children's hospital. Respiratory illness diagnoses were grouped into 3 categories: bacterial, viral, and asthma. RESULTS: A total of 181 children admitted for respiratory illness were studied. Diagnostic discordance was significant for all 3 types of respiratory illness but greatest for bacterial (P<.001). Antibiotic prescribing discordance was significant (P<.001), with pediatric hospitalists changing therapy for 93% of patients prescribed antibiotics in the ED, including stopping antibiotics altogether for 62% of patients. CONCLUSIONS: Significant diagnostic and antibiotic discordance between ED and pediatric hospitalist physicians exists for children admitted to the hospital for respiratory illness. PMID- 25732984 TI - Improved vitamin D supplementation in hospitalized breastfed infants through electronic order modification and targeted provider education. AB - OBJECTIVE: To examine effectiveness of an intervention promoting vitamin D supplementation in hospitalized breastfed infants. METHODS: Our urban tertiary care hospital instituted a 2-part intervention: brief education for providers on vitamin D guidelines and insertion of an opt-in order for vitamin D supplements into electronic admission order sets. Data downloads on admissions of patients aged <1 year were obtained. We excluded those not breastfed, with a dietary restriction, or admitted to intensive care. Intervention effects were compared from 6 months postintervention to the 6 same months 1 year earlier. We applied chi2 and logistic regression, including the patient as a random effect to adjust for repeated admissions. RESULTS: Data on 471 exclusively or partially breastfed admissions (441 infants) were analyzed (221 preintervention, 250 postintervention). Admission characteristics did not differ by period: 55.0% boys; 40.6% Medicaid; 63.7% hospitalized <=2 days; 72.0% on a general medical service; 16.6% received nutritionist consultation. In-hospital vitamin D prescribing rates significantly increased postintervention (19.5% vs 44.4%; P<.001). Postintervention admissions were more than twice as likely to receive vitamin D supplementation (adjusted odds ratio 2.3, 95% confidence interval 1.6 3.2). Other associated factors included vitamin D as a medication used before admission (adjusted odds ratio 14.3, 95% confidence interval 4.9-41.6), nutritionist consultation during admission, hospitalization>=3 days, and admission to a general medical service. Prescribing of vitamin D at discharge increased significantly (9.0% vs 19.6%; P<.001). CONCLUSIONS: Medical provider education and modification of electronic ordering templates significantly increased use of vitamin D supplementation in hospitalized breastfed infants. PMID- 25732985 TI - Improving resident handoffs for children transitioning from the intensive care unit. AB - BACKGROUND AND OBJECTIVE: Handoffs ensure patient safety during patient care transitions in the hospital setting. At our institution, verbal handoffs communicated by resident physicians are suggested practice for patients transferring from the PICU to the hospital medicine (HM) service. Despite their importance, these verbal handoffs occurred only 76% of the time before patient arrival on HM units. Our goal was to increase the completion rate of verbal handoffs to 100% within 5 months. METHODS: Baseline data were collected in a daily survey of HM residents. Interventions were developed and tested on small, incremental change cycles. Key interventions included education about the importance of handoffs, standardization of the handoff process, standardization of handoff documentation, and identification and mitigation of handoff documentation failures. We tracked handoff completion rates by using statistical control charts. After success with improving the completion rate of patient handoffs to the HM service, we applied our process to handoffs from the PICU to all inpatient services. RESULTS: Median completion of verbal patient handoff increased from 76% to 100% within 6 weeks, with improvement sustained for 15 months. Physician compliance with electronic medical record documentation increased from 58% to 94% within 8 months. After spreading to all patients transferring out of the PICU, documentation of patient handoffs increased from 76% to 94% in 5 months. CONCLUSIONS: A system using improvement science methods was successful in increasing the reliability of resident verbal patient handoffs. Consistent documentation and internal redundancy with checklists were associated with sustained improvement. PMID- 25732986 TI - Unplanned readmissions to acute care from a pediatric postacute care hospital: incidence, clinical reasons, and predictive factors. AB - OBJECTIVE: To identify the incidence, clinical reasons, and predictive factors for unplanned readmissions to acute care from a pediatric postacute care hospital. METHODS: A retrospective cohort analysis of all discharges between October 1, 2011, and September 30, 2013 (n=298), in 1 pediatric postacute care hospital was conducted. Descriptive statistics were used to summarize the incidence and assess the clinical reasons for all readmissions to an acute care hospital. Logistic regression was used to identify predictive factors of any unplanned readmission to an acute care hospital. RESULTS: Thirty percent of all postacute care hospital discharges were unplanned readmissions to an acute care hospital. The primary clinical reasons for unplanned readmissions to acute care were respiratory decompensation (54%) and infection (20%). Requiring invasive mechanical ventilation, being <1 year of age, and having a postacute care length of stay<30 days were the 3 predictive factors. CONCLUSIONS: This is the first study to examine readmission to acute care from a postacute care hospital and to identify age, length of stay, and dependence on mechanical ventilation as predictive factors. Understanding which children are likely to require an unplanned readmission may allow providers to develop strategies to minimize this occurrence. PMID- 25732987 TI - Intimate Partner Violence Programs in a Children's Hospital: Comprehensive Assessment Utilizing a Delphi Instrument. AB - OBJECTIVE: The purpose of this study was to conduct a baseline assessment of intimate partner violence (IPV) practices in a pediatric hospital system. METHODS: The Delphi Instrument for Hospital-based Domestic Violence Programs was used to assess the structure and components of the hospital system's IPV practices. Through key stakeholder interviews, we also assessed IPV practices in individual patient care areas. Qualitative analysis of interview data used a grounded theory approach. RESULTS: The hospital scored 17 of 100 points on the Delphi instrument assessment. Key areas of weakness identified by the Delphi instrument and interviews included lack of coordinated provider training and evaluation of IPV-related processes and no standards for IPV screening, safety assessment, and documentation. Most interviewees supported addressing IPV; all identified barriers to IPV screening at individual provider and institutional levels. Institutional barriers included lack of a standardized response to IPV disclosure, need for individualized screening protocols for different patient care settings, lack of standardized provider training, concerns about overextending social work resources, and lack of resources for hospital staff experiencing vicarious trauma. Individual barriers included concern that screening may harm physician-patient-family relationships and the perception that physicians are unwilling to address psychosocial issues. CONCLUSIONS: The Delphi Instrument for Hospital-based Domestic Violence Programs identified weaknesses and key areas for improvement in IPV practices. Deficiencies revealed by the Delphi instrument were affirmed by individual interview results. Institutional and individual provider level barriers must be addressed to optimize IPV practices in a pediatric hospital system. PMID- 25732988 TI - Variation in Procedural Sedation Practices Among Children's Hospitals. AB - BACKGROUND AND OBJECTIVE: Children often need procedural sedation for painful procedures. There are few data on type of provider, site of sedation, and agents used for procedural sedation in hospitals across the nation. The objective was to determine procedural sedation practices for hospitalized children outside the PICU and emergency department. METHODS: Surveys were sent to 89 pediatric hospitalist (PH) leaders in hospitals belonging to the Child Health Corporation of America or the National Association of Children's Hospitals and Related Institutions. RESULTS: We received responses from 56 PHs (63%), of whom 49 (55%) completed the survey. PHs provided sedation in 18 hospitals. Provider, setting, and agents used for procedural sedation varied. The primary providers of procedural sedation for abscess incision and drainage, renal biopsy, joint aspiration, computed tomography, and MRI were anesthesiologists. A significantly greater percentage of hospitals where PHs did not provide procedural sedation used the operating room for abscess incision and drainage compared with hospitals where PHs provided procedural sedation (63% vs 28%, respectively). Postoperative/abscess dressing change, vesicocystourethrogram, and >=1 painful procedure were performed without sedation in significantly greater percentage of hospitals where PHs did not provide procedural sedation compared with hospitals where PHs provided procedural sedation. CONCLUSIONS: There is variability in sedation practices in hospitals across the nation, which affects patient care and use of resources such as the operating room. In hospitals where PHs provide procedural sedation, there is less operating room use and fewer painful procedures for which no sedation is provided. PMID- 25732989 TI - Multicenter development, implementation, and patient safety impacts of a simulation-based module to teach handovers to pediatric residents. AB - OBJECTIVE: Teaching and evaluation of handovers are important requirements of graduate medical education (GME), but well-defined and effective methods have not been clearly established. Case-based computer simulations provide potential methods to teach, evaluate, and practice handovers. METHODS: Case-based computer simulation modules were developed. In these modules, trainees care for a virtual patient in a time-lapsed session, followed by real-time synthesis and handover of the clinical information to a partner who uses this information to continue caring for the same patient in a simulated night scenario, with an observer tallying included handover components. The process culminates with evaluator feedback and structured handover education. Surveys were used before and after module implementation to allow the interns to rate the quality of handover provided and record rapid responses and transfers to the ICU. RESULTS: Fifty-two pediatric and medicine/pediatric residents from 2 institutions participated in the modules. "Anticipatory guidance" elements of the handover were the most frequently excluded (missing at least 1 component in 77% of module handovers). There were no significant differences in the proportion of nights with rapid response calls (7.24% vs 12.79%, P=.052) or transfers to the ICU (7.76% vs 11.27%, P=.21) before and after module implementation. CONCLUSIONS: Case-based, computer-simulation modules are an easily implemented and generalizable mechanism for handover education and assessment. Although significant improvements in patient safety outcomes were not seen as a result of the educational module alone, novel techniques of this nature may supplement handover bundles that have been demonstrated to improve patient safety. PMID- 25732990 TI - A framework for reducing alarm fatigue on pediatric inpatient units. PMID- 25732991 TI - Buprenorphine ingestion in a 23-month-old boy. PMID- 25732992 TI - Call me? Maybe, stick me? Maybe not! PMID- 25732994 TI - Is L-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency? AB - BACKGROUND: 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCd) is an autosomal recessive disorder in the catabolism of leucine. In the present study, we investigated the current and prior medical condition of patients with 3-MCCd in the Faroe Islands and their carnitine levels in blood, urine and muscle tissue with and without L-carnitine supplementation to evaluate the current treatment strategy of not recommending L-carnitine supplementation to Faroese 3-MCCd patients. METHODS: Blood and urine samples and muscle biopsies were collected from patients at inclusion and at 3 months. Eight patients received L-carnitine supplementation when recruited; five did not. Included patients who received supplementation were asked to stop L-carnitine, the others were asked to initiate L-carnitine supplementation during the study. Symptoms were determined by review of hospital medical records and questionnaires answered at baseline and after the intervention. RESULTS: The prevalence of 3-MCCd in the Faroe Islands was 1:2,400, the highest reported worldwide. All patients were homozygous for the MCCC1 mutation c.1526delG. When not administered L-carnitine, the 3-MCCd patients (n = 13) had low plasma and muscle free carnitine levels, 6.9 (SD 1.4) MUmol/L and 785 (SD 301) nmol/g wet weight, respectively. L-Carnitine supplementation increased muscle and plasma carnitine levels to a low-normal range, 25.5 (SD 10.9) MUmol/L and 1,827 (SD 523) nmol/g wet weight, p < 0.01, respectively. Seven of the thirteen 3-MCCd subjects suffered from self-reported fatigue with some alleviation after L-carnitine supplementation. CONCLUSION: 3-MCCd is common in the Faroe Islands. Some symptomatic 3-MCCd patients may benefit biochemically and clinically from L-carnitine supplementation, a more general recommendation cannot be given. PMID- 25732993 TI - Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics. AB - Disrupted-in-schizophrenia-1 (DISC1) has emerged as a convincing susceptibility gene for multiple mental disorders, but its mechanistic link to the pathogenesis of schizophrenia related psychiatric conditions is yet to be further understood. Here, we showed that DISC1 localizes to the outer surface of the endoplasmic reticulum (ER). EXOC1, a subunit of the exocyst complex, interacted with DISC1 and affected its recruitment to inositol-1,4,5-trisphosphate receptor 1 (IP3R1). Notably, knockdown of DISC1 and EXOC1 elicited an exaggerated ER calcium response upon stimulation of IP3R agonists. Similar abnormal ER calcium responses were observed in hippocampal neurons from DISC1-deficient mutant mice. Moreover, perturbation of ER calcium dynamics upon DISC1 knockdown was effectively reversed by treatment with antipsychotic drugs, such as clozapine and haloperidol. These results collectively indicate that DISC1 is a regulatory factor in ER calcium dynamics, linking a perturbed intracellular calcium signaling and schizophrenia pathogenesis. PMID- 25732995 TI - Diet History Is a Reliable Predictor of Suboptimal Docosahexaenoic Acid Levels in Adult Patients with Phenylketonuria. AB - BACKGROUND: Omega-3 long-chain polyunsaturated fatty acids (n3LCPUFA) levels are reduced in phenylketonuria (PKU). Recent care guidelines recommend essential fatty acid status is monitored in patients with PKU but access to such testing is limited. We hypothesized that information obtained on diet history would identify PKU adults with suboptimal levels of n3LCPUFA. METHODS: A 12-month single site prospective study was completed including 35 adults (age 18-46) attending a clinic for adults with inborn errors of metabolism. Levels of n3LCPUFA were correlated with estimated intake using a published food frequency questionnaire. n3LCPUFA levels were tested at a commercial laboratory and values > one SD below the laboratory mean value were considered suboptimal. RESULTS: Mean levels of docosahexaenoic acid (DHA) were lower and levels of eicosapentaenoic acid (EPA) and alpha-linoleic acid (ALA) higher in subjects with PKU than in laboratory controls. n3LCPUFA levels correlated with estimated intake (p <0.002). Diet history had a positive predictive value of 93% and negative predictive value of 90% to identify subjects with suboptimal n3LCPUFA levels. CONCLUSIONS: Diet history is sufficient to predict adult subjects who may have low DHA levels and can be used to target testing or supplementation to those at risk. DHA levels are low despite high levels of ALA suggesting that supplementation, if indicated, should be with preformed DHA rather than with its precursors. PMID- 25732996 TI - Improvement in Bone Mineral Density and Architecture in a Patient with Gaucher Disease Using Teriparatide. AB - Gaucher disease is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme acid beta-glucosidase (glucocerebrosidase) due to mutations in the GBA gene. The most common form (type I) is associated with severe hematologic, visceral and bone disease. Disease-modifying treatments, such as enzyme replacement therapy and substrate reduction therapy, can improve the hematologic and visceral aspects of the disease but success with improving severe osteopenia, which can increase the risk of fractures, is limited. Our case involves a patient with complex disease affecting bone health including Gaucher disease (type I), Sjogren syndrome, rheumatoid arthritis and corticosteroid use who did not respond to long term use of bisphosphonates. We report an improvement in bone mineral density and bone architecture commensurate with a reduced incidence of fractures in whom we used teriparatide (human parathyroid hormone (PTH; 1-34) to treat severe osteopenia. We conclude that teriparatide should be considered for further studies as an agent to improve bone mineral density in patients with Gaucher disease. PMID- 25732997 TI - Two Novel Mutations in the SLC25A4 Gene in a Patient with Mitochondrial Myopathy. AB - In a 28-year-old male with a mild mitochondrial myopathy manifesting as exercise intolerance and early signs of cardiomyopathy without muscle weakness or ophthalmoplegia, we identified two novel mutations in the SLC25A4 gene: c.707G>C in exon 3 (p.(R236P)) and c.116_137del in exon 2 (p.(Q39Lfs*14)). Serum lactate levels at rest were elevated (12.7 mM). Both the patient's father and brother were heterozygous carriers of the c.707G>C mutation and were asymptomatic. The second mutation causes a 22 bp deletion leading to a frame shift likely giving rise to a premature stop codon and nonsense-mediated decay (NMD). The segregation of the mutations could not be tested directly as the mother had died before. However, indirect evidence from NMD experiments showed that the two mutations were situated on two different alleles in the patient. This case is unique compared to other previously reported patients with either progressive external ophthalmoplegia (PEO) or clear hypertrophic cardiomyopathy with exercise intolerance and/or muscle weakness carrying recessive mutations leading to a complete absence of the SLC25A4 protein. Most likely in our patient, although severely reduced, SLC25A4 is still partially present and functional. PMID- 25732998 TI - Girls with Seizures Due to the c.320A>G Variant in ALG13 Do Not Show Abnormal Glycosylation Pattern on Standard Testing. AB - A girl with early onset severe epilepsy, developmental delay, intellectual disability, visual maturation delays, and feeding problems was without a diagnosis despite an extensive genetic and metabolic evaluation. She initially manifested infantile spasms which responded to high-dose ACTH. Seizures seemed to resolve, but then at age 5, she developed complex partial seizures resistant to antiepileptics that responded to a ketogenic diet. Additional features included visual impairment, hypotonia, reflux, and severe feeding problems requiring a G tube. She was referred to the Geisinger Health System whole-genome sequencing clinical research program. A variant in the X-linked gene ALG13 (c.320A->G p. 107 N->S) was identified. Four additional girls from three published exome sequencing studies were found to have the identical c.320A>G variant in ALG13. All presented with early onset severe epilepsy and intellectual disability. Three of the five exhibited visual impairment and possible developmental regression. A boy with a variant in ALG13 presented with a severe congenital disorder of glycosylation type Is. Glycosylation studies in the case reported here were normal; none of the other girls reported in the literature have had glycosylation studies. X inactivation studies have not been done. The N107 residue and the surrounding region - MNNHQ - are highly conserved across species and are found in a presumed functional domain of this glycotransferase superfamily. The consistent clinical presentation of a severe phenotype in girls coupled with identical variants in an X-linked gene strongly suggests a critical position effect. Negative glycosylation studies in one individual suggest the possibility of a new mechanism requiring investigation. PMID- 25732999 TI - Monitoring of Therapy for Mucopolysaccharidosis Type I Using Dysmorphometric Facial Phenotypic Signatures. AB - There is a pattern of progressive facial dysmorphology in mucopolysaccharidosis type I (MPS I). Advances in 3D facial imaging have facilitated the development of tools, including dysmorphometrics, to objectively and precisely detect these facial phenotypes. Therefore, we investigated the application of dysmorphometrics as a noninvasive therapy-monitoring tool, by longitudinally scoring facial dysmorphology in a child with MPS I receiving enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). Both dysmorphometric measures showed a decreasing trend, and the greatest differences were found in the severity of facial discordance (Z-RMSE), displaying scores >3 SD higher than the mean at their peak, in comparison to Z-RSD scores that mostly fell within the normative range (maximum; 1.5 SD from the mean). In addition to the general trend of reduced facial dysmorphology with treatment, initial fluctuations were also evident that may have related to transient subcutaneous facial fluctuations, in the context of conditioning for bone marrow transplant. These findings support the potential of our approach as a sensitive, noninvasive, and rapid means of assessing treatment response or failure in clinical trials, and for established therapies, and would be applicable for other inherited disorders of metabolism. PMID- 25733000 TI - Dose response of pegfilgrastim in Japanese breast cancer patients receiving six cycles of docetaxel, doxorubicin, and cyclophosphamide therapy: a randomized controlled trial. AB - PURPOSE: A phase II, open-label, dose-finding, randomized study was performed to evaluate the recommended dose of pegfilgrastim in Japanese breast cancer patients. METHODS: Patients received 1.8, 3.6, or 6.0 mg of pegfilgrastim once per chemotherapy cycle for up to 6 cycles. Patients received docetaxel, doxorubicin, and cyclophosphamide (TAC) therapy followed by pegfilgrastim on the next day. RESULTS: Pegfilgrastim was administered to 87 women with stage II/III invasive breast carcinoma. The duration of grade 4 neutropenia in the first cycle, the primary endpoint, was 2.2 +/- 0.9 days, 1.5 +/- 0.9 days, and 1.4 +/- 0.7 days in the 1.8, 3.6, and 6.0 mg groups, respectively. This finding indicated that pegfilgrastim efficacy peaked at 3.6 mg. Pegfilgrastim doses up to 6.0 mg were considered safe. CONCLUSION: A 3.6-mg pegfilgrastim dose may be safe and effective for Japanese patients. A confirmatory study is required to establish safety and efficacy at this dose for intensive anti-cancer chemotherapy. PMID- 25733001 TI - Involvement of supportive care professionals in patient care in the last month of life. AB - BACKGROUND: In the last month of life, many patients suffer from multiple symptoms and problems. Professional supportive care involvement may help to alleviate patients' suffering and provide them with an optimal last phase of life. PURPOSE: We investigated how often palliative care consultants, pain specialists, psychological experts and spiritual caregivers are involved in caring for patients in the last month of life, and which factors are associated with their involvement. METHODS: Questionnaires were mailed to physicians who had attended the death of a patient from a stratified sample of 8496 deaths that had occurred in 2010 in the Netherlands. The response rate was 74 % (n = 6263). RESULTS: A palliative care team or consultant had been involved in the last month of life in 12 % of all patients for whom death was expected; this percentage was 3 % for pain specialists, 6 % for psychologists or psychiatrists and 13 % for spiritual caregivers. Involvement of palliative care or pain specialists was most common in younger patients, in patients with cancer and in patients who died at home. Involvement of psychological or spiritual caregivers was most common in older patients, in females, in patients with dementia and in patients who died in a nursing home. Involvement of supportive caregivers was also associated with the use of morphine and end-of-life decisions. CONCLUSION: Supportive care professionals are involved in end-of-life care in about a quarter of all non suddenly dying patients. Their involvement is related to the setting where patients die, to the patient's characteristics and to complex ethical decision making. PMID- 25733002 TI - Combined endoscopic-laparoscopic T-tube insertion for the treatment of staple line leak after sleeve gastrectomy: a simple and effective therapeutic option. AB - BACKGROUND: Management of staple-line leak after laparoscopic sleeve gastrectomy (LSG) remains controversial and matter of debate. Transforming a leak into a controlled fistula by insertion of a T-tube is a viable option. To minimize surgical dissection, and to facilitate identification of the leak site and insertion of the T-tube, we have developed a combined endoscopic-laparoscopic T tube (ELT-t) insertion technique. METHODS: Between February 2011 and June 2014, 7 patients presented with staple-line leak and were treated with ELT-t insertion. After laparoscopic dissection of the abscess cavity, a guidewire is passed endoscopically through the leak; a polypectomy snare is anchored to the guidewire and retrieved through the patient mouth. The long arm of a T-tube is eventually secured to the snare and pulled down through the leak. RESULTS: All patients were started on oral feeding with the T-tube in place. Serial water-soluble contrast swallows were performed to check for healing, and the T-tube was clamped as soon as no extravasation of contrast was demonstrated. The tube was removed either during the index admission or in the outpatient clinic. The residual fistula closed successfully after T-tube removal in all but one case with a "spiral shaped" sleeve and functional distal obstruction. This patient was treated with stent. Patients were discharged home after a mean postoperative hospital stay of 53.3 days (range: 15-87 days). CONCLUSION: In our experience, ELT-t is a valid alternative for the treatment of staple-line leak after LSG. It allows minimizing surgical dissection, and appears to be safe and effective. PMID- 25733003 TI - An innovative endoluminal rendezvous technique to restore gastrogastric continuity following extensive gastrointestinal loss from internal herniation after gastric bypass. PMID- 25733005 TI - Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. AB - This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. PMID- 25733006 TI - Towards real-time 3D ultrasound planning and personalized 3D printing for breast HDR brachytherapy treatment. AB - Two different end-to-end procedures were tested for real-time planning in breast HDR brachytherapy treatment. Both methods are using a 3D ultrasound (3DUS) system and a freehand catheter optimization algorithm. They were found fast and efficient. We demonstrated a proof-of-concept approach for personalized real-time guidance and planning to breast HDR brachytherapy treatments. PMID- 25733007 TI - The population benefit of radiotherapy for cervical cancer: local control and survival estimates for optimally utilized radiotherapy and chemoradiation. AB - PURPOSE: Population benefits of radiotherapy if evidence-based guidelines were routinely followed across the entire population are largely unknown. The aim of this study was to investigate population-based benefits for cervical cancer. METHODS: Overall survival (OS) and local control (LC) benefits were investigated. XRT benefit was defined as the absolute benefit of radiotherapy, over no treatment, for radical indications and defined as the benefit of adjuvant radiation over surgery alone for adjuvant indications. The concurrent chemoradiation (CRT) benefit was the incremental benefit of CRT over XRT. Australian population benefits were modeled using decision trees. Citation databases were systematically queried. Meta-analysis was performed if multiple sources of the same evidence level existed. Robustness of the model assumptions was tested through sensitivity analysis. RESULTS: 53% of all cervix patients had adjuvant or curative radiotherapy indications. 96% were for CRT. The estimated 5 year absolute benefits of optimally utilized radiotherapy alone were: LC: 31% (95% Confidence Interval 29%, 34%), OS: 17% (15%, 18%). These were over and above the contribution of other modalities to outcomes. The incremental 5-year absolute benefits of CRT were: LC 4% (2%, 5%), OS 3% (1%, 5%). In sensitivity analysis, the model was robust. CONCLUSIONS: Optimally utilized radiotherapy provides substantial population OS and LC benefits for cervical cancer. Chemoradiation provides a modest population benefit over XRT. The population-based model was robust. PMID- 25733008 TI - Melanocytic tumors with intraepidermal melanophages: a report of five cases with review of 231 archived cutaneous melanocytic tumors. AB - Dermal melanophages are frequently encountered in both benign melanocytic nevi and malignant melanoma. In contrast, intraepidermal melanophages (IEM) are under recognized in melanocytic lesions and their biologic significance is not understood. Herein, we report the clinical and histopathologic features of five melanocytic lesions featuring IEM encountered prospectively in our dermatopathology practice at the University of Chicago. Two hundred and thirty one (231) archived skin primary melanocytic proliferations were also investigated retrospectively in a de-identified, archival teaching set collection. Nineteen of 231 of the archived cases were positive for IEM. Among the total 24 IEM-positive cases (5 prospective and 19 archived cases), 13 were categorized as Spitz nevi (p < 0.0001) and 3 as atypical Spitz tumors (p = 0.0152). Fourteen of 24 cases with IEM also exhibited intracorneal melanocytes (p < 0.0001). IEM are evidently not rare, especially in spitzoid melanocytic neoplasms. IEM in our series were significantly correlated with intracorneal melanocytosis, possibly indicating an association between IEM and suprabasal melanocytosis and/or transepidermal elimination of melanocytes. PMID- 25733009 TI - The Chitranjan Ranawat Award: Running Subcuticular Closure Enables the Most Robust Perfusion After TKA: A Randomized Clinical Trial. AB - BACKGROUND: Maintaining robust perfusion is an important physiologic parameter in wound healing. The effect of different closure techniques on wound perfusion after total knee arthroplasty (TKA) has not been established previously and may have implications for wound healing. QUESTIONS/PURPOSES: We asked whether a running subcuticular, vertical mattress, or skin staple closure technique enables the most robust wound perfusion after TKA as measured by laser-assisted indocyanine green angiography (LA-ICGA) in patients without specific risk factors for wound healing complications. METHODS: Forty-five patients undergoing primary TKA without comorbidities known to impact wound healing and perfusion were prospectively randomized to receive superficial skin closure with one of the following techniques: (1) running subcuticular (3-0 monofilament); (2) vertical mattress (2-0 nylon); or (3) skin staples. Twenty procedures were performed by RTT, 15 by RJS, and 10 by FHS. All surgeons used an anterior skin incision over the medial third of the patella in combination with a median parapatellar arthrotomy. Perfusion was assessed with a LA-ICGA device and software system immediately after closure to quantify fluorescence. Twenty-seven points were assessed immediately after closure in the operating room in each patient (nine along the incision and nine pairs medial and lateral to the incision). Mean incision perfusion was determined from the nine points along the incision with higher values indicating greater blood flow. Mean perfusion impairment was determined by calculating the difference between the nine pairs of surrounding skin and the nine points along the incision with smaller values indicating less perfusion impairment. These parameters were compared with analysis of variance (ANOVA) and subsequent pairwise comparisons with an unadjusted analysis as well as a multivariate analysis that adjusted for age, sex, and body mass index. Patients were followed for a mean of 7 months after surgery (range, 3-12 months) for possible incision-related complications. No patents were lost to followup. RESULTS: Running subcuticular closure demonstrated the best overall perfusion. Mean incision perfusion in fluorescent units with SD was as follows: running subcuticular, 64 (16); vertical mattress, 32 (18); and staples, 19 (7) (ANOVA p < 0.001). The running subcuticular closure demonstrated the least impairment of perfusion among the closures compared. Mean perfusion impairment was as follows: running subcuticular, 21 (12); vertical mattress, 37 (24); and staples, 69 (27) (ANOVA p < 0.001). All Tukey-adjusted pairwise comparisons from both metrics likewise favored the subcuticular closure (p < 0.001) both before and after adjusting for age, sex, and body mass index. One patient in the vertical mattress cohort experienced a surgical site infection; no other wound-related complications were observed in this study. CONCLUSIONS: The method of closure can influence skin and soft tissue perfusion after TKA. Running subcuticular closure enables the most physiologic robust blood flow, which may improve wound healing. However, the clinical importance of these findings remains uncertain, because patients in this study were selected because they lacked risk factors for wound healing complications. Studies with this modality in specific patient populations at higher risk for wound complications will be necessary to quantify the clinical advantage of using running subcuticular closure. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 25733011 TI - Forest biorefinery: Potential of poplar phytochemicals as value-added co products. AB - The global forestry industry after experiencing a market downturn during the past decade has now aimed its vision towards the integrated biorefinery. New business models and strategies are constantly being explored to re-invent the global wood and pulp/paper industry through sustainable resource exploitation. The goal is to produce diversified, innovative and revenue generating product lines using on site bioresources (wood and tree residues). The most popular product lines are generally produced from wood fibers (biofuels, pulp/paper, biomaterials, and bio/chemicals). However, the bark and other tree residues like foliage that constitute forest wastes, still remain largely an underexploited resource from which extractives and phytochemicals can be harnessed as by-products (biopharmaceuticals, food additives and nutraceuticals, biopesticides, cosmetics). Commercially, Populus (poplar) tree species including hybrid varieties are cultivated as a fast growing bioenergy crop, but can also be utilized to produce bio-based chemicals. This review identifies and underlines the potential of natural products (phytochemicals) from Populus species that could lead to new business ventures in biorefineries and contribute to the bioeconomy. In brief, this review highlights the importance of by-products/co products in forest industries, methods that can be employed to extract and purify poplar phytochemicals, the potential pharmaceutical and other uses of >160 phytochemicals identified from poplar species - their chemical structures, properties and bioactivities, the challenges and limitations of utilizing poplar phytochemicals, and potential commercial opportunities. Finally, the overall discussion and conclusion are made considering the recent biotechnological advances in phytochemical research to indicate the areas for future commercial applications from poplar tree species. PMID- 25733010 TI - The effect of granulocyte-colony stimulating factor on rotator cuff healing after injury and repair. AB - BACKGROUND: The failure rate of tendon-bone healing after repair of rotator cuff tears remains high. A variety of biologic- and cell-based therapies aimed at improving rotator cuff healing have been investigated, and stem cell-based techniques have become increasingly more common. However, most studies have focused on the implantation of exogenous cells, which introduces higher risk and cost. We aimed to improve rotator cuff healing by inducing endogenous stem cell mobilization with systemic administration of granulocyte-colony stimulating factor (G-CSF). QUESTIONS/PURPOSES: We asked: (1) Does G-CSF administration increase local cellularity after acute rotator cuff repair? (2) Is there histologic evidence that G-CSF improved organization at the healing enthesis? (3) Does G-CSF administration improve biomechanical properties of the healing supraspinatus tendon-bone complex? (4) Are there micro-MRI-based observations indicating G-CSF-augmented tendon-bone healing? METHODS: After creation of full thickness supraspinatus tendon defects with immediate repair, 52 rats were randomized to control or G-CSF-treated groups. G-CSF was administered for 5 days after repair and rats were euthanized at 12 or 19 postoperative days. Shoulders were subjected to micro-MR imaging, stress relaxation, and load-to-failure as well as blinded histologic and histomorphometric analyses. RESULTS: G-CSF-treated animals had significantly higher cellularity composite scores at 12 and 19 days compared with both control (12 days: 7.40 +/- 1.14 [confidence interval {CI}, 5.98-8.81] versus 4.50 +/- 0.57 [CI, 3.58-5.41], p = 0.038; 19 days: 8.00 +/- 1.00 [CI, 6.75-9.24] versus 5.40 +/- 0.89 [CI, 4.28-6.51], p = 0.023) and normal animals (12 days: p = 0.029; 19 days: p = 0.019). There was no significant difference between G-CSF-treated animals or control animals in ultimate stress (MPa) and strain, modulus (MPa), or yield stress (MPa) and strain at either 12 days (p = 1.000, p = 0.104, p = 1.000, p = 0.909, and p = 0.483, respectively) or 19 days (p = 0.999, p = 0.964, p = 1.000, p = 0.988, and p = 0.904, respectively). There was no difference in MRI score between G-CSF and control animals at either 12 days (2.7 +/- 1.8 [CI, 1.08-4.24] versus 2.3 +/- 1.8 [CI, 0.49-4.17], p = 0.623) or 19 days (2.5 +/- 1.4 [CI, 1.05-3.94] versus 2.3 +/- 1.5 [CI, 0.75-3.91], p = 0.737). G-CSF-treated animals exhibited significantly lower relative bone volume compared with normal animals in the entire humeral head (24.89 +/- 3.80 [CI, 20.17-29.60) versus 32.50 +/- 2.38 [CI, 29.99-35.01], p = 0.009) and at the supraspinatus insertion (25.67 +/- 5.33 [CI, 19.04-32.29] versus 33.36 +/- 1.69 [CI, 31.58-35.14], p = 0.027) at 12 days. Further analysis did not reveal any additional significant relationships with respect to regional bone volume or trabecular thickness between groups and time points (p > 0.05). CLINICAL RELEVANCE: Postoperative stem cell mobilization agents may be an effective way to enhance rotator cuff repair. Future studies regarding the kinetics of mobilization, the homing capacity of mobilized cells to injured tissues, and the ability of homing cells to participate in regenerative pathways are necessary. PMID- 25733012 TI - Chloramphenicol significantly affects the pharmacokinetics of oral methadone in Greyhound dogs. AB - OBJECTIVE: To assess the effects of cytochrome P450 (CYP) inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) in various combinations on the pharmacokinetics of oral methadone in Greyhound dogs to determine the specific effects of the different inhibitors and if a clinically relevant interaction occurs. STUDY DESIGN: Non-randomized, sequential design. ANIMALS: Six healthy Greyhound dogs (three male, three female). METHODS: Canine CYP inhibitors (ketoconazole, chloramphenicol, trimethoprim, fluoxetine, cimetidine and medetomidine) were administered in varying combinations prior to the administration of oral methadone. Plasma was obtained from each dog to enable the determination of methadone and CYP inhibitor drug concentrations using liquid chromatography with either mass spectrometry or ultraviolet detection. RESULTS: Significant increases in the area under the curve (AUC) and maximum plasma concentrations (CMAX ) of methadone occurred in all groups administered chloramphenicol. The AUC (6 hours ng mL(-1)) and CMAX (6 ng mL(-1)) of methadone significantly increased to 541 hours ng mL(-1) and 47.8 ng mL(-1), respectively, when methadone was administered with chloramphenicol as a sole inhibitor. There were no significant effects of CYP inhibitors other than chloramphenicol on methadone pharmacokinetics, which suggests that chloramphenicol was primarily responsible for the pharmacokinetic interaction. CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated significant effects of chloramphenicol on the pharmacokinetics of oral methadone. Further studies should investigate the effects of chloramphenicol on methadone pharmacokinetics in multiple dog breeds and examine whether oral methadone would be an effective analgesic in dogs. In addition, the safety of chloramphenicol and its effects on the pharmacokinetics of parenteral methadone warrant assessment. PMID- 25733013 TI - Robust Skull-Stripping Segmentation Based on Irrational Mask for Magnetic Resonance Brain Images. AB - This paper proposes a new method for simple, efficient, and robust removal of the non-brain tissues in MR images based on an irrational mask for filtration within a binary morphological operation framework. The proposed skull-stripping segmentation is based on two irrational 3 * 3 and 5 * 5 masks, having the sum of its weights equal to the transcendental number pi value provided by the Gregory Leibniz infinite series. It allows maintaining a lower rate of useful pixel loss. The proposed method has been tested in two ways. First, it has been validated as a binary method by comparing and contrasting with Otsu's, Sauvola's, Niblack's, and Bernsen's binary methods. Secondly, its accuracy has been verified against three state-of-the-art skull-stripping methods: the graph cuts method, the method based on Chan-Vese active contour model, and the simplex mesh and histogram analysis skull stripping. The performance of the proposed method has been assessed using the Dice scores, overlap and extra fractions, and sensitivity and specificity as statistical methods. The gold standard has been provided by two neurologist experts. The proposed method has been tested and validated on 26 image series which contain 216 images from two publicly available databases: the Whole Brain Atlas and the Internet Brain Segmentation Repository that include a highly variable sample population (with reference to age, sex, healthy/diseased). The approach performs accurately on both standardized databases. The main advantage of the proposed method is its robustness and speed. PMID- 25733014 TI - The angulation of the septal structures impacts ventricular imbalance in atrioventricular septal defects with a common atrioventricular junction. AB - OBJECTIVE: Multiplanar re-formatting of full-volume three-dimensional echocardiography data sets offers new insights into the morphology of atrioventricular septal defects. We hypothesised that distortion of the alignment between the atrial and ventricular septums results in imbalanced venous return to the ventricles, with consequent proportional ventricular hypoplasia. METHODS: A single observer evaluated 31 patients, with a mean age of 52.09 months, standard deviation of 55, and with a range from 2 to 264 months, with atrioventricular septal defects, of whom 17 were boys. Ventricular imbalance, observed in nine patients, was determined by two-dimensional assessment, and confirmed at surgical inspection in selected cases when a univentricular strategy was undertaken. Offline analysis using multiplanar re-formatting was performed. A line was drawn though the length of the ventricular septum and a second line along the plane of the atrial septum, taking the angle between these two lines as the atrioventricular septal angle. We compared the angle between 22 patients with adequately sized ventricles, and those with ventricular imbalance undergoing univentricular repair. RESULTS: In the 22 patients undergoing biventricular repair, the septal angle was 0 in 14 patients; the other eight patients having angles ranging from 1 to 36, with a mean angle of 7.4 degrees , and standard deviation of 11.1 degrees .The mean angle in the nine patients with ventricle imbalance was 28.6 degrees , with a standard deviation of 3.04 degrees , and with a range from 26 to 35 degrees . Of those undergoing univentricular repair, two patients died, with angles of 26 and 30 degrees , respectively. CONCLUSIONS: The atrioventricular septal angle derived via multiplanar formatting gives important information regarding the degree of ventricular hypoplasia and imbalance. When this angle is above 25 degrees , patients are likely to have ventricular imbalance requiring univentricular repair. PMID- 25733015 TI - A reusable immobilization matrix for the biodegradation of phenol at 5000 mg/L. AB - Bacteria-mediated degradation of toxins has been reported as a practical technique for the innocuous removal of toxic organic compounds from water. Specifically, immobilized and pre-acclimatized Pseudomonas putida has been shown to clear low levels of contaminants (less than 2000 mg/L) from wastewater, wherein the bacteria consumes toxic aromatic compounds as the only source of carbon and energy. Here we report the preparation of a high-capacity composite adsorbent as an immobilization matrix for pre-acclimatized P. putida that is capable of complete degradation of 5000 mg/L of phenol within 80 hours. The composite adsorbent, a n-Butyl acrylate (BA)-resin evenly coated on polyester fiber (PF), can quickly reduce the phenol concentration to a level that is suitable for the immobilized bacteria to start the biodegradation process. Furthermore, the composite adsorbent (PF-BA) is regenerated during the biodegradation process without any additional manipulations, therefore it is reusable. As a whole, we provide a general strategy for more efficient biodegradation for phenol, which can be generalized to other water-soluble toxic organics removal for waste water treatment. PMID- 25733016 TI - Characteristics of idiopathic ventricular tachycardia originating above the pulmonary valve. AB - Panoptic studies of ventricular tachycardia (VT) originating above the pulmonary valve are scarce. The purpose of this study is to clarify the characteristic of idiopathic VT arising above pulmonary valve. We analyzed 15 consecutive patients with idiopathic VT that was successfully abolished by catheter ablation at the right ventricular outflow tract (RVOT-VT, n = 11) and above the pulmonary valve (PA-VT, n = 4). Incidence of syncope was higher in PA-VT than RVOT-VT (100 vs 27 %, P < 0.05) and polymorphic VT was also more prevalent in PA-VT (75 vs 0 %, P < 0.05). The coupling interval (315 +/- 29 vs 449 +/- 32 ms, mean +/- SE) at the onset of VT and minimum cycle length (CL) (192 +/- 13 vs 344 +/- 37 ms) during VT were shorter in PA-VT (both P < 0.05). Among 12-lead ECG parameters, only R-wave amplitude in lead II was different between groups (2.05 +/- 0.17 mV in PA-VT vs 1.44 +/- 0.05 mV in RVOT-VT, P < 0.005). At the successful ablation site, the activation time from the onset of QRS complex did not differ between groups (-37 +/- 3 vs -31 +/- 4, P = 0.405), whereas, the amplitude of intracardiac electrograms was significantly lower in PA-VT (0.83 +/- 0.38 mV vs 2.39 +/- 0.36 mV, P < 0.05). Although the number of patients in this study is limited, VT originating above the pulmonary valve demonstrated rapid excitation and often degenerated into polymorphic VT, suggesting its malignant electrophysiological characteristics. PMID- 25733017 TI - Generation of scaffoldless hyaline cartilaginous tissue from human iPSCs. AB - Defects in articular cartilage ultimately result in loss of joint function. Repairing cartilage defects requires cell sources. We developed an approach to generate scaffoldless hyaline cartilage from human induced pluripotent stem cells (hiPSCs). We initially generated an hiPSC line that specifically expressed GFP in cartilage when teratoma was formed. We optimized the culture conditions and found BMP2, transforming growth factor beta1 (TGF-beta1), and GDF5 critical for GFP expression and thus chondrogenic differentiation of the hiPSCs. The subsequent use of scaffoldless suspension culture contributed to purification, producing homogenous cartilaginous particles. Subcutaneous transplantation of the hiPSC derived particles generated hyaline cartilage that expressed type II collagen, but not type I collagen, in immunodeficiency mice. Transplantation of the particles into joint surface defects in immunodeficiency rats and immunosuppressed mini-pigs indicated that neocartilage survived and had potential for integration into native cartilage. The immunodeficiency mice and rats suffered from neither tumors nor ectopic tissue formation. The hiPSC-derived cartilaginous particles constitute a viable cell source for regenerating cartilage defects. PMID- 25733018 TI - Enhanced hematopoietic stem cell function mediates immune regeneration following sex steroid blockade. AB - Mechanisms underlying age-related defects within lymphoid-lineages remain poorly understood. We previously reported that sex steroid ablation (SSA) induced lymphoid rejuvenation and enhanced recovery from hematopoietic stem cell (HSC) transplantation (HSCT). We herein show that, mechanistically, SSA induces hematopoietic and lymphoid recovery by functionally enhancing both HSC self renewal and propensity for lymphoid differentiation through intrinsic molecular changes. Our transcriptome analysis revealed further hematopoietic support through rejuvenation of the bone marrow (BM) microenvironment, with upregulation of key hematopoietic factors and master regulatory factors associated with aging such as Foxo1. These studies provide important cellular and molecular insights into understanding how SSA-induced regeneration of the hematopoietic compartment can underpin recovery of the immune system following damaging cytoablative treatments. These findings support a short-term strategy for clinical use of SSA to enhance the production of lymphoid cells and HSC engraftment, leading to improved outcomes in adult patients undergoing HSCT and immune depletion in general. PMID- 25733020 TI - Structural phenotyping of stem cell-derived cardiomyocytes. AB - Structural phenotyping based on classical image feature detection has been adopted to elucidate the molecular mechanisms behind genetically or pharmacologically induced changes in cell morphology. Here, we developed a set of 11 metrics to capture the increasing sarcomere organization that occurs intracellularly during striated muscle cell development. To test our metrics, we analyzed the localization of the contractile protein alpha-actinin in a variety of primary and stem-cell derived cardiomyocytes. Further, we combined these metrics with data mining algorithms to unbiasedly score the phenotypic maturity of human-induced pluripotent stem cell-derived cardiomyocytes. PMID- 25733019 TI - CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation. AB - Embryonic stem cells (ESCs) have adopted an accelerated cell-cycle program with shortened gap phases and precocious expression of cell-cycle regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs). We examined the effect of CDK inhibition on the pathways regulating proliferation and survival of ESCs. We found that inhibiting cyclin-dependent kinase 1 (CDK1) leads to activation of the DNA damage response, nuclear p53 stabilization, activation of a subset of p53 target genes including NOXA, and negative regulation of the anti-apoptotic protein MCL1 in human and mouse ESCs, but not differentiated cells. We demonstrate that MCL1 is highly expressed in ESCs and loss of MCL1 leads to ESC death. Finally, we show that clinically relevant CDK1 inhibitors prevent formation of ESC-derived tumors and induce necrosis in established ESC-derived tumors. Our data demonstrate that ES cells are uniquely sensitive to CDK1 inhibition via a p53/NOXA/MCL1 pathway. PMID- 25733022 TI - The Discover artificial disc replacement versus fusion in cervical radiculopathy- a randomized controlled outcome trial with 2-year follow-up. AB - BACKGROUND CONTEXT: Several previous studies comparing artificial disc replacement (ADR) and fusion have been conducted with cautiously positive results in favor of ADR. This study is not, in contrast to most previous studies, an investigational device exemption study required by the Food and Drug Administration for approval to market the product in the United States. This study was partially funded with unrestricted institutional research grants by the company marketing the artificial disc used in this study. PURPOSE: To compare outcomes between the concepts of an artificial disc to treatment with anterior cervical decompression and fusion (ACDF) and to register complications associated to the two treatments during a follow-up time of 2 years. STUDY DESIGN/SETTING: This is a randomized controlled multicenter trial, including three spine centers in Sweden. PATIENT SAMPLE: The study included patients seeking care for cervical radiculopathy who fulfilled inclusion criteria. In total, 153 patients were included. OUTCOME MEASURES: Self-assessment with Neck Disability Index (NDI) as a primary outcome variable and EQ-5D and visual analog scale as secondary outcome variables. METHODS: Patients were randomly allocated to either treatment with the Depuy Discover artificial disc or fusion with iliac crest bone graft and plating. Randomization was blinded to both patient and caregivers until time for implantation. Adverse events, complications, and revision surgery were registered as well as loss of follow-up. RESULTS: Data were available in 137 (91%) of the included and initially treated patients. Both groups improved significantly after surgery. NDI changed from 63.1 to 39.8 in an intention-to-treat analysis. No statistically significant difference between the ADR and the ACDF groups could be demonstrated with NDI values of 39.1 and 40.1, respectively. Nor in secondary outcome measures (EQ-5D and visual analog scale) could any statistically significant differences be demonstrated between the groups. Nine patients in the ADR group and three in the fusion group underwent secondary surgery because of various reasons. Two patients in each group underwent secondary surgery because of adjacent segment pathology. Complication rates were not statistically significant between groups. CONCLUSIONS: Artificial disc replacement did not result in better outcome compared to fusion measured with NDI 2 years after surgery. PMID- 25733021 TI - Long-term expansion, enhanced chondrogenic potential, and suppression of endochondral ossification of adult human MSCs via WNT signaling modulation. AB - Mesenchymal stem cells (MSCs) are a potential source of chondrogenic cells for the treatment of cartilage disorders, but loss of chondrogenic potential during in vitro expansion and the propensity of cartilage to undergo hypertrophic maturation impede their therapeutic application. Here we report that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion of human bone marrow-derived MSCs. The cells retained their chondrogenic potential and other phenotypic and functional properties of multipotent MSCs, which were gradually lost in the absence of WNT3A. Moreover, we discovered that endogenous WNT signals are the main drivers of the hypertrophic maturation that follows chondrogenic differentiation. Inhibition of WNT signals during differentiation prevented calcification and maintained cartilage properties following implantation in a mouse model. By maintaining potency during expansion and preventing hypertrophic maturation following differentiation, the modulation of WNT signaling removes two major obstacles that impede the clinical application of MSCs in cartilage repair. PMID- 25733023 TI - The bone morphogenetic protein-2/7 heterodimer is a stronger inducer of bone regeneration than the individual homodimers in a rat spinal fusion model. AB - BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) are a group of dimeric growth factors that belong to the transforming growth factor super family and are capable of eliciting new bone formation. Previous studies have suggested that the coexpression of two different BMP genes in a cell can result in the production of BMP heterodimers that are more potent than homodimers. However, because of the difficulty in optimizing the level of BMP gene expression, the coexpression of two different BMP genes also produces BMP homodimers as a by-product. These homodimers could, in theory, interact with the heterodimers. PURPOSE: To elucidate the effects of a BMP-2/7 heterodimer, which were investigated in depth using purified BMP-2/7 heterodimers, BMP-2 homodimers, and BMP-7 homodimers in a rat spinal fusion model. METHODS: Bilateral posterolateral fusion at L4-L5 was performed in four different groups: control group animals were implanted with collagen carriers alone; BMP-7 group animals with collagen carriers+1 MUg of BMP 7 homodimer; BMP-2 group animals with collagen carriers+1 MUg of BMP-2 homodimer; and BMP-2/7 group animals with collagen carriers+1 MUg of the BMP-2/7 heterodimer. The following assessments were performed: bone microstructural analysis of the fusion mass and tissue volume (TV) with microcomputed tomography (micro-CT); fusion assessment with manual palpation testing and three-dimensional CT images; and bone histomorphometrical analysis of the fusion mass. RESULTS: The fusion scores, as determined by radiography, and the TV of the newly formed bone, as determined by micro-CT, were significantly higher in the BMP-2/7 heterodimer group than the other groups (p<.0001). The microstructural indices of the newly formed bone did not differ between the groups. Moreover, histologic analysis of the fused spines revealed that the formation of the trabecular bone bridging the transverse process was the highest in this group. CONCLUSIONS: This study demonstrated that BMP-2/7 heterodimer is a stronger inducer of bone regeneration than BMP-2 or -7 homodimers. The use of a purified BMP-2/7 heterodimer may represent an efficient alternative to the current clinical use of BMP-2 or -7 homodimers. Further studies as to the side effects of BMP-2/7 heterodimer are required. PMID- 25733024 TI - Oral vaccination of mice with Trichinella spiralis nudix hydrolase DNA vaccine delivered by attenuated Salmonella elicited protective immunity. AB - We have previously reported that Trichinella spiralis Nudix hydrolase (TsNd) bound to intestinal epithelial cells (IECs), and the vaccination of mice with recombinant TsNd protein (rTsNd) produced a partial protective immunity against challenge infection in mice. In this study, the full-length cDNA sequence of TsNd gene was cloned into the eukaryotic expression plasmid pcDNA3.1, and the recombinant TsNd DNA was transformed into attenuated Salmonella typhimurium strain ?cyaSL1344. Oral immunization of mice with TsNd/S. typhimurium elicited a significant local mucosal IgA response and a systemic Th1/Th2 immune response. Cytokine profiling also showed a significant increase in the Th1 (IFN-gamma, IL 2) and Th2 (IL-4, 10) responses in splenocytes of immunized mice upon stimulation with the rTsNd. The oral immunization of mice with TsNd/S. typhimurium displayed a statistically significant 73.32% reduction in adult worm burden and a 49.5% reduction in muscle larvae after challenge with T. spiralis muscle larvae, compared with PBS control group. Our results demonstrated that TsNd DNA delivered by attenuated live S. typhimurium elicited a local IgA response and a mixed Th1/Th2 immune response, and produced a partial protection against T. spiralis infection in mice. PMID- 25733025 TI - The course of PTSD in naturalistic long-term studies: high variability of outcomes. A systematic review. AB - BACKGROUND: With a lifetime prevalence of 8% posttraumatic stress disorder (PTSD) is one of the most common mental disorders; nevertheless, its longitudinal course is largely unknown. AIMS: Our aim was to conduct a systematic review summarizing available findings on the prospective, naturalistic long-term course of PTSD and its predictors. METHODS: Databases MEDLINE and PsycINFO were searched. Main selection criteria were: 1) naturalistic cohort study with a follow-up period of at least 3 years, 2) adult participants with observer-rated or probable PTSD at baseline. RESULTS: Twenty-four cohorts (25 studies) were retrieved (14 with observer-assessed, 10 with probable PTSD). In total, they comprised about 10,500 participants with PTSD at baseline that were included in the long-term follow ups. Studies investigating patient populations with observer-assessed PTSD found that between 18% and 50% of patients experienced a stable recovery within 3-7 years; the remaining subjects either facing a recurrent or a more chronic course. Outcomes of community studies and studies investigating probable PTSD varied considerably (remission rates 6-92%). Social factors (e.g. support) as well as comorbid physical or mental health problems seem to be salient predictors of PTSD long-term course and special focus should be laid on these factors in clinical settings. CONCLUSIONS: Included studies differed notably with regard to applied methodologies. The resulting large variability of findings is discussed. More standardized systematic follow-up research and more uniformed criteria for remission and chronicity are needed to gain a better insight into the long-term course of PTSD. PMID- 25733026 TI - A dynamic framework for the study of optimal birth intervals reveals the importance of sibling competition and mortality risks. AB - Human reproductive patterns have been well studied, but the mechanisms by which physiology, ecology and existing kin interact to affect the life history need quantification. Here, we create a model to investigate how age-specific interbirth intervals adapt to environmental and intrinsic mortality, and how birth patterns can be shaped by competition and help between siblings. The model provides a flexible framework for studying the processes underlying human reproductive scheduling. We developed a state-based optimality model to determine age-dependent and family-dependent sets of reproductive strategies, including the state of the mother and her offspring. We parameterized the model with realistic mortality curves derived from five human populations. Overall, optimal birth intervals increase until the age of 30 after which they remain relatively constant until the end of the reproductive lifespan. Offspring helping each other does not have much effect on birth intervals. Increasing infant and senescent mortality in different populations decreases interbirth intervals. We show that sibling competition and infant mortality interact to lengthen interbirth intervals. In lower-mortality populations, intense sibling competition pushes births further apart. Varying the adult risk of mortality alone has no effect on birth intervals between populations; competition between offspring drives the differences in birth intervals only when infant mortality is low. These results are relevant to understanding the demographic transition, because our model predicts that sibling competition becomes an important determinant of optimal interbirth intervals only when mortality is low, as in post-transition societies. We do not predict that these effects alone can select for menopause. PMID- 25733027 TI - Pharmacokinetics of the natural antibiotic negamycin. AB - 1. Negamycin exerts its antimicrobial activity by inhibiting bacterial protein synthesis and is efficacious in animal models of infection. In order to optimize negamycin exposure for therapeutic purposes, its pharmacokinetics in pre-clinical species were determined. 2. Negamycin has a dipeptide-like structure with logD7.4 < -1, causing low permeation into Caco-2 cells, low-oral bioavailability in rats of 6% and low-plasma protein binding of 10% in mouse, rat, dog and human plasma. Negamycin degradation rates in microsomes and hepatocytes predicted low-hepatic intrinsic clearance in pre-clinical species, which was confirmed in vivo where clearance varied between 3.4 and 11.5 mL/min/kg and virtually all negamycin was cleared unchanged renally. The similar behavior in multiple animal species allowed for the prediction of systemic clearance and volume of distribution in humans using multiple-scaling methods and physiological-based pharmacokinetic modeling and simulation. 3. Only 0.05-0.25% (mol/mol) of administered negamycin was recovered as 2-(1-methylhydrazinyl)acetic acid, a potential reactive metabolite, from rat and dog urine, respectively. 4. In summary, negamycin is a very polar molecule with low-plasma protein binding and low-oral bioavailability that is slowly and exclusively cleared into the urine. Its physicochemical properties make intravenous or intramuscular administration, or a derivative thereof, for therapeutic purposes most likely. PMID- 25733029 TI - In vitro and in vivo metabolism of CHF 6001, a selective phosphodiesterase (PDE4) inhibitor. AB - 1. The metabolism of CHF 6001, a novel PDE4 inhibitor, was determined in vitro in mouse, rat, dog, monkey and human microsomes and hepatocytes and in vivo in plasma, urine, feces and bile of rats after intravenous and intratracheal administration. 2. The behavior of CHF 6001 in microsomes and hepatocytes changed across species. CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the metabolism of CHF 6001 in human liver microsomes. 3. In the rat, CHF 6001 was found extensively metabolized in urine, feces and bile, but not in plasma, where CHF 6001 was the main compound present. The metabolite profiles were different in the four biological matrices from both qualitative and quantitative point of view. 4. CHF 6001 was metabolized through hydrolysis with the formation of the alcohol CHF 5956, loss of a chlorine atom, loss of the N oxide, hydroxylation, loss of the cyclopropylmethyl group in the alcohol moiety, conjugation with glucuronic acid, glutathione and cysteine-glycine. 5. The major metabolite present in the bile was isolated and characterized by nuclear magnetic resonance analysis. It derived from CHF 6001 through contraction of the pyridine N-oxide ring to N-hydroxy pyrrole and conjugation with glucuronic acid. PMID- 25733028 TI - Effect of various diets on the expression of phase-I drug-metabolizing enzymes in livers of mice. AB - 1. Previous studies have shown that diets can alter the metabolism of drugs; however, it is difficult to compare the effects of multiple diets on drug metabolism among different experimental settings. Phase-I-related genes play a major role in the biotransformation of pro-drugs and drugs. 2. In the current study, effects of nine diets on the mRNA expression of phase-I drug metabolizing enzymes in livers of mice were simultaneously investigated. Compared to the AIN 93M purified diet (control), 73 of the 132 critical phase-I drug-metabolizing genes were differentially regulated by at least one diet. Diet restriction produced the largest number of changed genes (51), followed by the atherogenic diet (27), high-fat diet (25), standard rodent chow (21), western diet (20), high fructose diet (5), EFA deficient diet (3) and low n-3 FA diet (1). The mRNAs of the Fmo family changed most, followed by Cyp2b and 4a subfamilies, as well as Por (from 1121- to 21-fold increase of theses mRNAs). There were 59 genes not altered by any of these diets. 3. The present results may improve the interpretation of studies with mice and aid in determining effective and safe doses for individuals with different nutritional diets. PMID- 25733030 TI - Predictability of plasma concentration-time curves in humans using single-species allometric scaling of chimeric mice with humanized liver. AB - 1. We used chimeric mice (PXB mice(r)), which were repopulated with human hepatocytes, to evaluate their predictabilities of human pharmacokinetics. 2. The relationships of total clearance (CLt) and the volume of distribution at steady state (Vdss) between that predicted from single-species allometric scaling (SSS) of PXB mice and the observed human values indicated good correlations for various drugs metabolized by cytochrome P450s (CYPs) and non-CYPs. 3. We examined the Dedrick plot with which the plasma concentration-time curves can exhibit superimposability using SSS of PXB mice for CLt and Vdss. The predicted plasma concentration-time curves using the complex Dedrick plot from PXB mice were generally superimposed with the observed human data. 4. However, the predicted curve of diazepam was not superimposable with the observed profile. Residual mouse hepatocytes in the livers of PXB mice may affect predictability of CLt of diazepam because significant discrepancy of in vitro intrinsic clearance in PXB mouse liver microsomes consisted of low and high replacement of human hepatocytes were observed. 5. The complex Dedrick plot with SSS from PXB mice is useful for predicting the plasma concentration-time curve in drug discovery, although there are some limitations. PMID- 25733031 TI - Gastric inflammatory fibroid polyp morphologically changed by Helicobacter pylori eradication. AB - A 60-year-old male presented to our hospital for further investigation of abnormal findings on an upper gastrointestinal series. Esophagogastroduodenoscopy demonstrated atrophic gastritis and a submucosal tumor (SMT) at the anterior wall of the antrum. The patient was positive for serum anti-Helicobacter pylori (H. pylori) antibody and H. pylori eradication therapy was performed. Five months later, the SMT showed a remarkable morphological change in that an ulcer had developed on its apex, and partial gastrectomy was performed. Pathological examination suggested an inflammatory fibroid polyp (IFP), and genetic analysis revealed no mutation in the platelet-derived growth factor receptor alpha gene. This case suggests that H. pylori infection plays an important role in the etiology of IFPs. PMID- 25733032 TI - Resources, key traits and the size of fungal epidemics in Daphnia populations. AB - Parasites can profoundly affect host populations and ecological communities. Thus, it remains critical to identify mechanisms that drive variation in epidemics. Resource availability can drive epidemics via traits of hosts and parasites that govern disease spread. Here, we map resource-trait-epidemic connections to explain variation in fungal outbreaks (Metschnikowia bicuspidata) in a zooplankton host (Daphnia dentifera) among lakes. We predicted epidemics would grow larger in lakes with more phytoplankton via three energetic mechanisms. First, resources should stimulate Daphnia reproduction, potentially elevating host density. Secondly, resources should boost body size of hosts, enhancing exposure to environmentally distributed propagules through size dependent feeding. Thirdly, resources should fuel parasite reproduction within hosts. To test these predictions, we sampled 12 natural epidemics and tracked edible algae, fungal infection prevalence, body size, fecundity and density of hosts, as well as within-host parasite loads. Epidemics grew larger in lakes with more algal resources. Structural equation modelling revealed that resource availability stimulated all three traits (host fecundity, host size and parasite load). However, only parasite load connected resources to epidemic size. Epidemics grew larger in more dense Daphnia populations, but host density was unrelated to host fecundity (thus breaking its link to resources). Thus, via energetic mechanisms, resource availability can stimulate key trait(s) governing epidemics in nature. A synthetic focus on resources and resource-trait links could yield powerful insights into epidemics. PMID- 25733033 TI - Acceptance factors of mobile apps for diabetes by patients aged 50 or older: a qualitative study. AB - BACKGROUND: Mobile apps for people with diabetes offer great potential to support therapy management, increase therapy adherence, and reduce the probability of the occurrence of accompanying and secondary diseases. However, they are rarely used by elderly patients due to a lack of acceptance. OBJECTIVE: We investigated the question "Which factors influence the acceptance of diabetes apps among patients aged 50 or older?" Particular emphasis was placed on the current use of mobile devices/apps, acceptance-promoting/-inhibiting factors, features of a helpful diabetes app, and contact persons for technical questions. This qualitative study was the third of three substudies investigating factors influencing acceptance of diabetes apps among patients aged 50 or older. METHODS: Guided interviews were chosen in order to get a comprehensive insight into the subjective perspective of elderly diabetes patients. At the end of each interview, the patients tested two existing diabetes apps to reveal obstacles in (first) use. RESULTS: Altogether, 32 patients with diabetes were interviewed. The mean age was 68.8 years (SD 8.2). Of 32 participants, 15 (47%) knew apps, however only 2 (6%) had already used a diabetes app within their therapy. The reasons reported for being against the use of apps were a lack of additional benefits (4/8, 50%) compared to current therapy management, a lack of interoperability with other devices/apps (1/8, 12%), and no joy of use (1/8, 12%). The app test revealed the following main difficulties in use: nonintuitive understanding of the functionality of the apps (26/29, 90%), nonintuitive understanding of the menu navigation/labeling (19/29, 66%), font sizes and representations that were too small (14/29, 48%), and difficulties in recognizing and pressing touch-sensitive areas (14/29, 48%). Furthermore, the patients felt the apps lacked individually important functions (11/29, 38%), or felt the functions that were offered were unnecessary for their own therapy needs (10/29, 34%). The most important contents of a helpful diabetes app were reported as the ability to add remarks to measured values (9/28, 32%), the definition of thresholds for blood glucose values and highlighting deviating values (7/28, 25%), and a reminder feature for measurement/medication (7/28, 25%). The most important contact persons for technical questions were family members (19/31, 61%). CONCLUSIONS: A lack of additional benefits and ease of use emerged as the key factors for the acceptance of diabetes apps among patients aged 50 or older. Furthermore, it has been shown that the needs of the investigated target group are highly heterogeneous due to varying previous knowledge, age, type of diabetes, and therapy. Therefore, a helpful diabetes app should be individually adaptable. Personal contact persons, especially during the initial phase of use, are of utmost importance to reduce the fear of data loss or erroneous data input, and to raise acceptance among this target group. PMID- 25733034 TI - In quest of a superhalogen supported covalent bond involving a noble gas atom. AB - The possibility of having neutral Xe-bound compounds mediated by some representative transition metal fluorides of general formula MX3 (where M=Ru, Os, Rh, Ir, Pd, Pt, Ag, Au and X=F) has been investigated through density functional theory based calculations. Nature of interaction between MX3 and Xe moieties has been characterized through detailed electron density, charge density and bond energy decomposition analyses. The feasibility of having compounds of general formula XeMX3 at 298 K has been predicted through thermodynamic considerations. The nature of interaction in between Xe and M atoms is partly covalent in nature and the orbital interaction is the dominant contributor toward these interactions as suggested by energy decomposition analysis. PMID- 25733035 TI - Risk of bleeding in patients undergoing percutaneous endoscopic gastrotrostomy tube insertion under antiplatelet therapy. PMID- 25733036 TI - Risk of bleeding in patients undergoing percutaneous endoscopic gastrotrostomy (PEG) tube insertion under antiplatelet therapy: a systematic review with a meta analysis. AB - BACKGROUND AND AIM: Patients undergoing percutaneous endoscopic gastrostomy (PEG) tube placement often are under antiplatelet therapy with a potential thromboembolic risk if these medications are discontinued. This systematic review aims to assess if maintaining aspirin and/or clopidogrel treatment increases the risk of bleeding following PEG placement. METHODS: A systematic search of the MEDLINE, EMBASE, and SCOPUS databases was developed for studies investigating the risk of bleeding in patients on antiplatelet therapy undergoing PEG tube insertion. Summary estimates, including 95 % confidence intervals (CI), were calculated. A fixed or random effects model was used depending on heterogeneity (I2). Publication bias risks were assessed by means of funnel plot analysis. RESULTS: Eleven studies with a total of 6,233 patients (among whom 3,665 were undergoing antiplatelet treatment), met the inclusion criteria and were included in the quantitative summary.Any PEG tube placement-related bleeding was found in 2.67 % (95 % CI 1.66 %, 3.91 %) of the entire population and in 2.7 % (95 % CI 1.5 %, 4.1 %) of patients not receiving antiplatelet therapy. Pooled relative risk (RR) for bleeding in patients under aspirin, when compared to controls, was 1.43 (95 % CI 0.89, 2.29; I2 = 0 %); pooled RR for clopidogrel was 1.21 (95 % CI 0.48, 3.04; I2 = 0 %) and for dual antiplatelet therapy, 2.13; (95 % CI 0.77,5.91; I2 = 47 %). No significant publication bias was evident for the different medications analyzed. CONCLUSION: Antiplatelet therapy was safe among patients undergoing PEG tube insertion. Future prospective and randomized studies with larger sample sizes are required to confirm the results of this study. PMID- 25733037 TI - A pharmacokinetic approach to model-guided design of infliximab schedules in ulcerative colitis patients. AB - BACKGROUND: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn's disease and ulcerative colitis, is administered at predefined interdose intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. AIMS: To explore optimal dosing strategies of infliximab in treatment-naive patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. METHODS: A population of 2,000 treatment-naive patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix interdose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. RESULTS: Strategies 2 6 reached trough levels statistically higher than strategy 1 (p < 0.05). Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 %) without reaching higher peak concentrations. CONCLUSIONS: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab naive patients with ulcerative colitis. PMID- 25733038 TI - Quality standards in 480 pancreatic resections: a prospective observational study. AB - Pancreatic resection is a standard procedure for the treatment of periampullary tumors. Morbidity and mortality are high, and quality standards are scarce in our setting. International classifications of complications (Clavien-Dindo) and those specific for pancreatectomies (ISGPS) allow adequate case comparisons. The goals of our work are to describe the morbidity and mortality of 480 pancreatectomies using the international classifications ISGPS and Clavien-Dindo to help establish a quality standard in our setting and to compare the results of CPD with reconstruction by pancreaticogastrostomy (1,55) versus 177 pancreaticojejunostomy). We report 480 resections including 337 duodenopancreatectomies, 116 distal pancreatectomies, 11 total pancreatectomies, 10 central pancreatectomies, and 6 enucleations. Results for duodenopancreatectomy include: 62 % morbidity (Clavien > or = III 25.9 %), 12.3 % reinterventions, and 3.3 % overall mortality. For reconstruction by pancreaticojejunostomy: 71.2 % morbidity (Clavien > or = III 34.4 %), 17.5 % reinterventions, and 3.3 % mortality. For reconstruction by pancreaticogastrostomy: 51 % morbidity (Clavien > or = III 15.4%), 6.4 % reinterventions, and 3.2 % mortality. Differences are significant except for mortality. We conclude that our series meets quality criteria as compared to other groups. Reconstruction with pancreaticogastrostomy significantly reduces complication number and severity, as well as pancreatic fistula and reintervention rates. PMID- 25733039 TI - Validity and reliability of the minimum basic data set in estimating nosocomial acute gastroenteritis caused by rotavirus. AB - INTRODUCTION: Rotavirus is the principal cause of nosocomial acute gastroenteritis (NAGE) under 5 years of age. The objectiveis to evaluate the validity and reliability of the minimum basic dataset (MBDS) in estimating the NAGE caused by rotavirus (NAGER) and to analyze any changes during the three years that the Rotarix(r) and Rotateq(r) vaccines were used in Spain. MATERIAL AND METHODS: A descriptive, retrospectivestudy was carried out in the University Hospital of Guadalajara(UHG) (Spain) between 2003-2009 using the MBDS, positive microbiological results for rotavirus (PMRs), and medical histories.Three methods of estimation were used: 1) An ICD-9-CM code 008.61 in the secondary diagnosis fields (DIAG2) of MBDS; 2) method 1 and/or PMRs with a current or recent hospitalization; and 3) the reference method or method 2 contrasted with patient medical histories. The validity of methods 1 and 2 was determined -sensitivity, specificity, predictive values and likelihood ratios (LRs)-, along with their agreement with method 3 (Kappa coefficient). In addition, the incidence rate ratio between the NAGER rate in 2007-2009 (commercialization period of both vaccines) was calculated with respect to 2003-2005 (precommercialization period). RESULTS: Method 1 identified 65 records with a DIAG2 of 008.61. Method 2 found 62 probable cases, and the reference method, 49 true cases. The sensitivity of the MBDS was 67 %,the positive predictive value was 51 %, and both negative LR (LR-) and reliability were moderate (LR- 0.33, Kappa coefficient 0.58). During 2007 2009, the NARGE decreased by 5 cases per 103 hospitalizations and by 9 per 104 days of hospitalization. Method 2 overestimated both the decline in incidence by 2 per 103 hospitalizations and the decreased risk per day of stay by 10 %. The MBDS found no differences between the two three-year periods, but, like method 2, showed an excellent level of diagnostic evidence (LR+ 67). CONCLUSION: The MBDS taken together with microbiological results, is more exact, safer and more reliable than the MBDS alone in estimating NAGER; and more useful in ruling out it. Nevertheless, the MBDS alone may be used to estimate and compare such disease in contexts with different prevalences. PMID- 25733040 TI - New trends in the management of diverticulitis and colonic diverticular disease. AB - Colonic diverticular disease is a chronic disorder presenting with a variety of abdominal symptoms and recurrent episodes of acute diverticulitis. It is close linked to age so its prevalence has risen notably during the last decades in western countries, increasing costs related to medical attention. Recently, several works have provided evidence to a series of measures that could improve the outcomes as well as reduce expenses associated to this process.The aim of the present review is to expose a view of the new trends in the management of diverticulitis and colonic diverticular disease, based on the highest clinical evidence available. PMID- 25733041 TI - Acral injury as first manifestation of a metastatic adenocarcinoma of the colon. PMID- 25733042 TI - Acute gastric volvulus: a case report. PMID- 25733043 TI - Ultrasound-guided percutaneous drainage and sclerotherapy in a patient with isolated autosomal dominant polycystic liver disease. AB - Isolated polycystic liver disease (IPLD) is a rare genetic condition characterized by the presence of multiple liver cysts with no association with polycystic kidney disease. Most patients are asymptomatic and acute complications (cyst torsion, bleeding, infection) are uncommon.Imaging techniques, including abdominal ultrasounds, computerized axial tomography, and magnetic resonance imaging, represent a vital diagnostic modality. They are also useful for therapy support in this disease. Below we report a peculiar case of a female patient recentlydiagnosed with IPLD who, having received treatment with ultrasoundguided percutaneous drainage and sclerotherapy for a giant liver cyst, showed symptom and laboratory improvement. PMID- 25733044 TI - Individualized exercise prescription in non-alcoholic steatohepatitis: a case report. AB - The effect of an individualized exercise programme on a non-alcoholic steatohepatitis case is presented. Before entering the programme the patient was treated with conventional recommendations on diet plus aerobic exercise during fourteen years, without major improvements of his analytical parameters.Two years after including him in a tailored exercise programme, aimed to fulfil the recommendations of the American College of Sports Medicine, his blood markers of liver dysfunction and cardiometabolic risk tended to improve. Consequently, our data support the idea that in non-alcoholic steatohepatitis the exercise-based therapeutic interventions should be individualized taking into account the cardio respiratory and muscular fitness of the patient, rather than using generic behavioural recommendations. PMID- 25733045 TI - [Argon: its use in gastroenterology]. PMID- 25733046 TI - Cholecystitis and duodenal fistula as EndoBarrier(r)-associated complications. Minimally invasive treatment. PMID- 25733047 TI - Eosinophilic gastroenteritis and bowel obstruction. Can surgery be avoided? PMID- 25733048 TI - Treatment with ribavirin of hepatitis E virus chronic infection in transplanted patients. PMID- 25733049 TI - Clinical presentation of anal duct adenocarcinoma as benign anal stenosis. PMID- 25733050 TI - Penicillamine induced pseudo-pseudoxanthoma elasticum in a patient with Wilson's disease, which role plays the hepatologist? PMID- 25733051 TI - Effect of hairpin loop structure on reactivity, sequence preference and adduct orientation of a DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumour agent. AB - The pyrrolobenzodiazepines (PBDs) are a family of covalent-binding DNA interactive minor-groove binding agents with a thermodynamic preference for binding to 5'-Pu-G-Pu-3' sequences (Pu = Purine) but a kinetic preference for 5' Py-G-Py-3' (Py = Pyrimidine). Using HPLC/MS methodology and a range of designed hairpin-forming oligonucleotides, the kinetics of reaction of a C8-bis-pyrrole pyrrolobenzodiazepine (PBD) conjugate (GWL-78, 2) with sixteen isomeric oligonucleotides has been evaluated, each containing a single PBD binding site in one of two locations. The PBD-binding base-pair triplets were designed to include every possible combination of A and T bases adjacent to the covalently-reacting guanine, with the set of hairpins consisting of isomeric pairs containing the same sequence in the hairpin stem but with either hexaethylene glycol (HEG) or TTT loops. The PBD 2 reacted most rapidly with TGT and TGA sequences, with the possibility that adducts might form in both the 3'- and 5'-directions with some sequences according to modelling studies. A faster reaction rate was observed for all hairpins containing the HEG loop except one (Seq 10) when the PBD binding triplets were located either near the loop or adjacent to the 5'-end. Modelling studies have suggested that this difference in reactivity could be due to the structural flexibility of the HEG loop allowing both A-ring-3' and A-ring-5' adducts to form, while a TTT loop should favour only A-ring-5' adducts due to steric considerations. These findings contrast with the results reported by Nguyen and Wilson for the interaction of non-covalent DNA-binding molecules with DNA hairpins, where the loop structure was found to have little effect on interaction in the main stem of the hairpin. PMID- 25733052 TI - MERS coronavirus envelope protein has a single transmembrane domain that forms pentameric ion channels. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly identified pathogen able of human transmission that causes a mortality of almost 40%. As in the case of SARS-CoV, MERS virus lacking E protein represents a potential vaccine. In both cases, abolishment of channel activity may be a contributor to the attenuation observed in E-deleted viruses. Herein, we report that purified MERS-CoV E protein, like SARS-CoV E protein, is almost fully alpha-helical, has a single alpha-helical transmembrane domain, and forms pentameric ion channels in lipid bilayers. Based on these similarities, and the proposed involvement of channel activity as virulence factor in SARS-CoV E protein, MERS-CoV E protein may constitute a potential drug target. PMID- 25733054 TI - Nanostructure enhanced ionic transport in fullerene reinforced solid polymer electrolytes. AB - Solid polymer electrolytes, such as polyethylene oxide (PEO) based systems, have the potential to replace liquid electrolytes in secondary lithium batteries with flexible, safe, and mechanically robust designs. Previously reported PEO nanocomposite electrolytes routinely use metal oxide nanoparticles that are often 5-10 nm in diameter or larger. The mechanism of those oxide particle-based polymer nanocomposite electrolytes is under debate and the ion transport performance of these systems is still to be improved. Herein we report a 6-fold ion conductivity enhancement in PEO/lithium bis(trifluoromethanesulfonyl) imide (LiTFSI)-based solid electrolytes upon the addition of fullerene derivatives. The observed conductivity improvement correlates with nanometer-scale fullerene crystallite formation, reduced crystallinities of both the (PEO)6:LiTFSI phase and pure PEO, as well as a significantly larger PEO free volume. This improved performance is further interpreted by enhanced decoupling between ion transport and polymer segmental motion, as well as optimized permittivity and conductivity in bulk and grain boundaries. This study suggests that nanoparticle induced morphological changes, in a system with fullerene nanoparticles and no Lewis acidic sites, play critical roles in their ion conductivity enhancement. The marriage of fullerene derivatives and solid polymer electrolytes opens up significant opportunities in designing next-generation solid polymer electrolytes with improved performance. PMID- 25733053 TI - Population structure of blueberry mosaic associated virus: Evidence of reassortment in geographically distinct isolates. AB - The population structure of blueberry mosaic associated virus (BlMaV), a putative member of the family Ophioviridae, was examined using 61 isolates collected from North America and Slovenia. The studied isolates displayed low diversity in the movement and nucleocapsid proteins and low ratios of non-synonymous to synonymous nucleotide substitutions, indicative of strong purifying selection. Phylogenetic analyses revealed grouping primarily based on geography with some isolates deviating from this rule. Phylogenetic incongruence in the two regions, coupled with detection of reassortment events, indicated the possible role of genetic exchange in the evolution of BlMaV. PMID- 25733055 TI - Sex differences in children with severe health conditions: Causes of admission and mortality in a Pediatric Intensive Care Unit. AB - OBJECTIVES: Based on the existing sex differences in mortality rates in children, we would like to explore whether girls and boys respond differently under severe health conditions, in terms of mortality and cause of admission. METHODS: We analyzed demographic characteristics (age and sex), causes of admission, clinical parameters, and mortality in a sample of 2,609 patients from a Pediatric Intensive Care Unit (PICU) in a children's hospital in Barcelona, Spain. RESULTS: PICU admittance was significantly higher in boys (57.5% vs. 42.5%) whereas PICU mortality was significantly higher in girls (4.9% vs. 3.3%). Female sex was a risk factor for PICU in-hospital mortality (OR = 1.55, P = 0.033), while increasing age had a protective effect (OR = 0.808, P = 0.021). In cases of PICU mortality, girls died from a broader range of causes and boys were more affected by respiratory and polytraumatic injuries. Boys were affected by polytraumatic injuries throughout the year, less frequently in winter, while girls showed a higher occurrence in holiday months. CONCLUSIONS: Although more boys were admitted to the PICU, a significantly higher number of girls died. Younger age and higher occurrence of nosocomial infection among girls could explain this finding. More frequent polytraumatic injuries in boys could reflect an increased exposure to risky activities and/or more careless behavior. PMID- 25733056 TI - Analysis of Side Effect Profile of Alopecia, Nail Changes, Peripheral Neuropathy, and Dysgeusia in Prostate Cancer Patients Treated With Docetaxel and Cabazitaxel. AB - INTRODUCTION: We hypothesized that the adverse event (AE) profile of cabazitaxel with regard to alopecia, nail changes, neuropathy, and dysgeusia differs from docetaxel. MATERIALS AND METHODS: Prospectively collected data on treatment emergent AEs (frequency and grade [G]) from clinical trial databases of docetaxel every 3 weeks (q3w) (in TAX327 and VENICE) and cabazitaxel q3w (in TROPIC) were analyzed. RESULTS: The frequency of new or worsening AEs (all G and G3-4) for 1301 patients was significantly less for alopecia, nail changes, neuropathy, and dysgeusia for cabazitaxel compared with docetaxel. CONCLUSION: Treatment with cabazitaxel might cause less alopecia, nail changes, neuropathy, and dysgeusia compared with docetaxel. PMID- 25733057 TI - Role of MicroRNAs in Prostate Cancer Pathogenesis. AB - Prostate cancer (PCa) remains the most commonly diagnosed malignant tumor in men, and is the second highest cause of cancer mortality after lung tumors in the United States. Accumulating research indicates that microRNAs (miRNAs) are increasingly being implicated in PCa. miRNAs are conserved small noncoding RNAs that control gene expression posttranscriptionally. Recent profiling research suggests that miRNAs are aberrantly expressed in PCa, and these have been implicated in the regulation of apoptosis, cell cycle, epithelial to mesenchymal transition, PCa stem cells, and androgen receptor pathway. All of these might provide the basis for new approaches for PCa. Here, we review current findings regarding miRNA research in PCa to provide a strong basis for future study aimed at promising contributions of miRNA in PCa. PMID- 25733058 TI - A Baffled Mind: A Mysterious Presentation of Small-Cell Carcinoma of the Bladder. PMID- 25733059 TI - Phlebovirus infections in Greece. AB - Sandfly fever viruses are endemic in the Mediterranean region causing to humans asymptomatic or mild infections to severe neurological syndromes. In order to investigate the epidemiology of phlebovirus infections in Greece, samples from 499 patients with acute febrile illness (50.2% accompanied by neurological symptoms) were tested during 2010-2014 by serological and molecular methods. Phlebovirus infection was detected in 40 (8%) patients, 25 of them presenting acute neurological infection. Most cases were observed in the summer, with a peak in August. Increased number of cases was observed in 2013, and three of them were observed in Athens. Toscana virus lineage C RNA was detected in one encephalitis case, while the serological results showed that most cases were caused by phleboviruses belonging to the sandfly fever Naples virus serocomplex. This study provided the first insight into the epidemiology of phleboviral disease in Greece. PMID- 25733060 TI - Might the Masson trichrome stain be considered a useful method for categorizing experimental tendon lesions? AB - Strain injuries of tendons are the most common orthopedic injuries in athletic subjects, be they equine or human. When the tendon is suddenly damaged, an acute inflammatory phase occurs whereas its repetitive overloading may cause chronic injuries. Currently the criteria used for grading injuries are general and subjective, and therefore a reliable grading method would be an improvement. The main purpose of this study was to assess qualitatively the histological pattern of Masson trichrome stain in healthy and injured tendons; indeed, the known "paradox" of Masson staining was used to create an evaluation for the matrix of tendons, following experimental lesions and natural repair processes. A statistically significant difference of aniline-staining between healthy and lesioned tendons was observed. Overall, we think that the Masson staining might be regarded as an informative tool in discerning the collagen spatial arrangement and therefore the histological characteristics of tendons. PMID- 25733061 TI - Helios Enhances Treg Cell Function in Cooperation With FoxP3. AB - OBJECTIVE: Helios+FoxP3+CD4+ (Helios+) Treg cells are believed to be involved in the regulation of various autoimmune diseases; however, the regulatory mechanisms underlying the development of Helios+ Treg cells remain uncertain. This study was undertaken to elucidate the regulatory mechanisms of Helios expression in CD4+ T cells and its roles in transforming growth factor beta (TGFbeta)-induced Treg cell function. METHODS: We examined the expression of Helios in CD4+ T cells in patients with rheumatoid arthritis by DNA microarray analysis before and after treatment with biologic agents. We also examined the effect of interleukin-6 (IL 6) and TGFbeta on Helios expression in CD4+ T cells in humans and mice. The effect of forced expression of Helios on murine induced Treg cell function was also examined. The role of FoxP3 in the induction and function of Helios was assessed by using CD4+ T cells from FoxP3-deficient scurfy mice. RESULTS: Tocilizumab, but not tumor necrosis factor (TNF) inhibitors or abatacept, increased Helios expression in CD4+ T cells in patients with a good response. IL 6 inhibited the TGFbeta-induced development of Helios+ induced Treg cells in both humans and mice. Both cell-intrinsic FoxP3 expression and TGFbeta signaling were required for Helios induction in murine induced Treg cells. The forced expression of Helios enhanced the expression of various Treg cell-related molecules and the suppressive function in murine induced Treg cells. Helios-mediated enhancement of the suppressive function of induced Treg cells was obvious in FoxP3-sufficient CD4+ T cells but not in FoxP3-deficient CD4+ T cells. CONCLUSION: Our findings indicate that Helios enhances induced Treg cell function in cooperation with FoxP3. PMID- 25733062 TI - Abatacept and Glomerular Diseases: The Open Road for the Second Signal as a New Target is Settled Down. AB - Glomerulopathy is the third most important cause of kidney disease. Proteinuria is the hallmark of glomerular damage, and a marker of progression of kidney disease, cardiovascular morbidity and mortality. Strategies to reduce proteinuria are partially successful, and despite proteinuria management, renal disease may still progress. Immunosuppression to treat glomerulopathies is nonspecific, partially effective and presents side-effects. It is critical to find safe drugs with specific podocyte molecular targets. Podocytes contain a complex array of proteins. Lymphocyte activation antigen B7-1 (CD80) is located on antigen presenting cells modulating CD4+ and CD8+ T cells by interacting with co stimulator CD28, a glycoprotein located on T-cells, or with cytotoxic T lymphocyte protein 4 (CTLA-4) co-inhibitor. Normally, podocytes do not express B7 1. However, certain glomerulopathies are associated with an increase on the surface of podocytes of B7-1, which reduces the ability of podocytes to attach to the surrounding glomerular basement membrane, favouring podocyturia and proteinuria. When the B7-1-CTLA-4 interaction takes place, the immune response is abrogated, while a B7-1-CD28 coupling leads to T cell activation. Abatacept binds to B7-1 by blocking the CD28 or potentiating the CTLA-4 signals. In B7-1 positive podocytes, abatacept may be a specific tool to decrease proteinuria. Selected patents are also briefly presented in this review. PMID- 25733063 TI - Synergistic effects of intrinsic cation disorder and electron-deficient substitution on ion and electron conductivity in La1-xSrxCo0.5Mn0.5O3-delta (x = 0, 0.5, and 0.75). AB - The effects of intrinsic cation disorder and electron-deficient substitution for La1-xSrxCo0.5Mn0.5O3-delta (LSCM, x = 0, 0.5, and 0.75) on oxygen vacancy formation, and their influence on the electrochemical properties, were revealed through a combination of computer simulation and experimental study. First principles calculations were first performed and found that the tendency of the oxygen vacancy formation energy was Mn(3+)-O*-Mn(4+) < Co(2+)-O*-Co(3+) < Co(2+) O*-Mn(4+), meaning that antisite defects not only facilitate the formation of oxygen vacancy but introduce the mixed-valent transition-metal pairs for high electrical conductivity. Detailed partial density of states (PDOS) analysis for Mn on Co sites (MnCo) and Co on Mn sites (CoMn) indicate that Co(2+) is prone to being Co(3+) while Mn(4+) is prone to being Mn(3+) when they are on antisites, respectively. Also it was found that the holes introduced by Sr tend to enter the Co sublattice for x = 0.5 and then the O sublattice when x = 0.75, which further promotes oxygen vacancy formation, and these results are confirmed by both the calculated PDOS results and charge-density difference. On the basis of microscopic predictions, we intentionally synthesized a series of pure LSCM compounds and carried out comprehensive characterization. The crystal structures and their stability were characterized via powder X-ray Rietveld refinements and in situ high-temperature X-ray diffraction. X-ray photoelectron spectroscopy testified to the mixed oxidation states of Co(2+)/Co(3+) and Mn(3+)/Mn(4+). The thermal expansion coefficients were found to match the Ce0.8Sm0.2O2-delta electrolyte well. The electrical conductivities were about 41.4, 140.5, and 204.2 S cm(-1) at doping levels of x = 0, 0.5, and 0.75, and the corresponding impedances were 0.041, 0.027, and 0.022 Omega cm(2) at 850 degrees C, respectively. All of the measured results testify that Sr-doped LaCo0.5Mn0.5O3 compounds are promising cathode materials for intermediate-temperature solid oxide fuel cells. PMID- 25733064 TI - Clinical pharmacy services that influence prescribing in the Western Pacific Region based on the FIP Basel Statements. AB - BACKGROUND: Clinical pharmacy services have been associated with decreased mortality rates, length of stay, medication errors, adverse drug reactions and total cost of care. Such services have recently been introduced to the Western Pacific Region (WPR), particularly in Asia. A survey to measure clinical pharmacy services that influence prescribing has been validated in the WPR and can be used to explore the implementation of such services. OBJECTIVE: To explore the implementation of clinical pharmacy services that influence prescribing in the WPR and the barriers and facilitators involved in their implementation. SETTING: Hospital pharmacies in the WPR. METHOD: Hospital pharmacy directors in the WPR were emailed a link to the validated survey. Surveys were available in English, Japanese, Chinese, Vietnamese, Lao, Khmer, French and Mongolian. MAIN OUTCOME MEASURE: (1) Percentage of hospitals offering clinical pharmacy services. (2) Percentage of in-patients receiving a medication history, review or discharge counselling by a pharmacist. RESULTS: In total, 726 responses were received from 31 countries and nations. Nearly all hospitals, 90.6 % (658/726), stated they provided clinical pharmacy services. On average 28 % of their clinical pharmacists attended medical rounds regularly. The median percentage of inpatients receiving a medication history and discharge counselling by a pharmacist was 40 and 30 % respectively. Higher internal facilitator factor scores significantly increased the likelihood of offering clinical services and having pharmacists attend medical rounds regularly. Internal facilitators included individual pharmacist traits and pharmacy departmental structure/resources. Higher environmental facilitator factor scores and having a higher percentage of pharmacists attend medical rounds regularly significantly increased the likelihood of inpatients receiving a medication history, a medication review and discharge counselling by a pharmacist. Environment facilitators included government support, patient and physician expectations. CONCLUSION: A large proportion of hospitals in the WPR have implemented clinical pharmacy services. Although internal facilitators were shown to be important for initiating such services, the addition of environmental facilitators and ward round participation by pharmacists allowed clinical services to be integrated throughout the hospitals. PMID- 25733065 TI - Building hospital pharmacy practice research capacity in Qatar: a cross-sectional survey of hospital pharmacists. AB - BACKGROUND: There is a need to systematically develop research capacity within pharmacy practice. Hamad Medical Corporation (HMC) is the principal non-profit health care provider in Qatar. Traditionally, pharmacists in Qatar have limited training related to research and lack direct experience of research processes. OBJECTIVES: To determine the interests, experience and confidence of hospital pharmacists employed by HMC, Qatar in relation to research, attitudes towards research, and facilitators and barriers. SETTING: Hospital pharmacy, Qatar. METHOD: A cross-sectional survey of all pharmacists (n = 401). Responses were analysed using descriptive and inferential statistics, and principal component analysis (PCA). MAIN OUTCOME MEASURES: Interests, experience and confidence in research; attitudes towards research; and facilitators and barriers to participation in research. RESULTS: The response rate was 53.1 % (n = 213). High levels of interest were expressed for all aspects of research, with respondents less experienced and less confident. Summary scores for items of interest were significantly higher than experience and confidence (p < 0.001). PCA identified four components: general attitudes towards research; confidence, motivation and resources; research culture; and support. While respondents were generally positive in response to all items, they were less sure of resources to conduct research, access to training and statistical support. They were also generally unsure of many aspects relating to research culture. Half (50.7 %, n = 108) had either never thought about being involved in research or taken no action. In multivariate binary logistic regression analysis, the significant factors were possessing postgraduate qualifications [odds ratio (OR) 3.48 (95 % CI 1.73-6.99), p < 0.001] and having more positive general attitudes to research [OR 3.24 (95 % CI 1.62-4.67), p = 0.001]. Almost all (89.7 %, n = 172) expressed interest in being involved in research training. CONCLUSION: HMC pharmacists expressed significantly higher levels of interest in research compared to experience and confidence. While general attitudes towards research were positive, there were some barriers relating to support (e.g. administration) and research culture. Positive attitudes towards research and possessing postgraduate qualifications were significant in relation to readiness to participate in research and research training. Findings are of key relevance when considering the aims of research capacity building of encouraging research, improving skills and identifying skills gaps. PMID- 25733067 TI - "One of the Most Uniform Races of the Entire World": Creole Eugenics and the Myth of Chilean Racial Homogeneity. AB - This article illuminates why Nicolas Palacios's 1904 monograph, Raza chilena: Libro escrito por un Chileno i para los Chilenos [Chilean Race: A Book Written by a Chilean for Chileans], is central to the creation of a myth of Chilean racial homogeneity at the turn of the twentieth century. Placing Palacios in the context of Latin American eugenic discourse, it demonstrates how he selected a specific racial origin story in order to accommodate his belief in racial hierarchy while also depicting race mixing in a positive light. Specifically, the article highlights how the myth of Chilean racial homogeneity elided the difference between the term "mestizo," which was applied to people of mixed racial heritage, and "white." I contend that Palacios sought to differentiate Chileans from other Latin Americans by emphasizing their racial distinctiveness. The article therefore highlights that Latin American eugenics was concerned with the creation of national narratives that historicized particular racial mixtures in order to reify and affirm national differences. As such, it connects to literature regarding the history of eugenics, race, nation, and the creation of whiteness. PMID- 25733066 TI - A fast algorithm for denoising magnitude diffusion-weighted images with rank and edge constraints. AB - PURPOSE: To accelerate denoising of magnitude diffusion-weighted images subject to joint rank and edge constraints. METHODS: We extend a previously proposed majorize-minimize method for statistical estimation that involves noncentral chi distributions to incorporate joint rank and edge constraints. A new algorithm is derived which decomposes the constrained noncentral chi denoising problem into a series of constrained Gaussian denoising problems each of which is then solved using an efficient alternating minimization scheme. RESULTS: The performance of the proposed algorithm has been evaluated using both simulated and experimental data. Results from simulations based on ex vivo data show that the new algorithm achieves about a factor of 10 speed up over the original Quasi-Newton-based algorithm. This improvement in computational efficiency enabled denoising of large datasets containing many diffusion-encoding directions. The denoising performance of the new efficient algorithm is found to be comparable to or even better than that of the original slow algorithm. For an in vivo high-resolution Q ball acquisition, comparison of fiber tracking results around hippocampus region before and after denoising will also be shown to demonstrate the denoising effects of the new algorithm. CONCLUSION: The optimization problem associated with denoising noncentral chi distributed diffusion-weighted images subject to joint rank and edge constraints can be solved efficiently using a majorize minimize-based algorithm. PMID- 25733069 TI - Lights, camera, action: high-throughput plant phenotyping is ready for a close up. AB - Anticipated population growth, shifting demographics, and environmental variability over the next century are expected to threaten global food security. In the face of these challenges, crop yield for food and fuel must be maintained and improved using fewer input resources. In recent years, genetic tools for profiling crop germplasm has benefited from rapid advances in DNA sequencing, and now similar advances are needed to improve the throughput of plant phenotyping. We highlight recent developments in high-throughput plant phenotyping using robotic-assisted imaging platforms and computer vision-assisted analysis tools. PMID- 25733068 TI - Adiponectin may mediate the association between omentin, circulating lipids and insulin sensitivity: results from the KORA F4 study. AB - OBJECTIVE: Reduced circulating omentin levels have been reported in obesity and type 2 diabetes, but data were mostly derived from univariate analyses in small study samples. This study aimed to investigate the relationship between omentin, abnormal glucose tolerance and related metabolic factors in a large population based cross-sectional study. DESIGN AND METHODS: Serum omentin was measured by ELISA in 1092 participants of the German KORA F4 survey (2006-2008). Associations between omentin serum levels, glucose tolerance (assessed with an oral glucose tolerance test) and diabetes-related factors were estimated using logistic and linear regression models respectively. RESULTS: Serum levels of omentin were not related to categories of glucose tolerance. However, serum omentin was positively associated with whole-body insulin sensitivity index (ISI (composite)) and HDL cholesterol and showed inverse associations with 2-h post-load glucose, fasting insulin, homeostasis model assessment-estimated insulin resistance, BMI and triglycerides (all P<=0.03 after adjustment for age, sex and lifestyle factors). Further adjustment for BMI and/or serum lipids attenuated the associations with parameters of glucose metabolism, whereas adjustment for serum adiponectin virtually abolished all aforementioned associations. In contrast, adjustment for omentin had no effect on the positive association between adiponectin levels and ISI (composite). CONCLUSIONS: The data from this large population-based cohort show that circulating omentin levels are associated with insulin sensitivity. Our observations further suggest that omentin acts via upregulation of adiponectin, which in turn affects lipid metabolism and thereby also indirectly enhances insulin sensitivity, but mechanistic studies are required to corroborate this hypothesis. PMID- 25733070 TI - Occult hepatitis B among patients with chronic renal failure on hemodialysis from a capital city in northeast Brazil. AB - Occult hepatitis B (OHB) is characterized by the presence of HBV-DNA in the absence of HBsAg in the serum of patients. Hemodialysis patients are at high risk for hepatitis B virus and there are few data on the prevalence of OHB in this population, mainly in Brazil. Thus, the aim of this study was to determine the prevalence of OHB in patients undergoing hemodialysis. A cross-sectional study was performed, including 301 patients on chronic hemodialysis at two dialysis centers in Sao Luis (Maranhao), northeast Brazil. Serological tests were performed for HBsAg, anti-HBc, anti-HBs, and anti-HCV using enzyme immunoassays (ELISA); HBV-DNA and HCV-RNA were studied by real-time PCR. The mean age was 49 +/- 15 years, and 128 (42%) were female. Serological tests confirmed that all samples were HBsAg negative. Anti-HBc was positive in 114 (38%) patients, anti HBc and anti-HBs were simultaneously positive in 104 (35%), and anti-HBc alone was positive in 10 (3%). Tests were negative for anti-HBc and anti-HBs in 55 patients (18%). Anti-HBs was the only positive marker in 132 (44%) patients. Anti HCV was positive in 15 (5%) patients with HCV-RNA present in 14 of them (93%). HBV-DNA was positive in seven cases (2.3%). There was no association of HBV-DNA with age, gender, time on dialysis, previous kidney transplant, or HBV serological pattern, but there was a positive correlation with the presence of anti-HCV (P < 0.001). OHB in chronic renal failure patients on hemodialysis appears to be a relevant finding, suggesting that studying HBV-DNA in this population using sensitive molecular tests should be a recommended course of action, especially in candidates for renal transplant. PMID- 25733071 TI - Projecting crop yield in northern high latitude area. AB - Changing climatic conditions on seasonal and longer time scales influence agricultural production. Improvement of soil and fertilizer is a strong factor in agricultural production, but agricultural production is influenced by climate conditions even in highly developed countries. It is valuable if fewer predictors make it possible to conduct future projections. Monthly temperature and precipitation, wintertime 500hPa geopotential height, and the previous year's yield are used as predictors to forecast spring wheat yield in advance. Canadian small agricultural divisions (SAD) are used for analysis. Each SAD is composed of a collection of Canadian Agricultural Regions (CAR) of similar weather and growing conditions. Spring wheat yields in each CAR are forecast from the following variables: (a) the previous year's yield, (b) earlier stages of the growing season's climate conditions and, (c) the previous year's wintertime northern hemisphere 500hPa geopotential height field. Arctic outflow events in the Okanagan Valley in Canada are associated with episodes of extremely low temperatures during wintertime. Principal component analysis (PCA) is applied for wintertime northern hemisphere 500hPa geopotential height anomalies. The spatial PCA mode1 is defined as Arctic Oscillation and it influences prevailing westerlies. The prevailing westerlies meanders and influences climatic conditions. The spatial similarity between wintertime top 5 Arctic outflow event year's composites of 500hPa geopotential height anomalies and mode 3's spatial pattern is found. Mode 3's spatial pattern looks like the Pacific/North American (PNA) pattern which describes the variation of atmospheric circulation pattern over the Pacific Ocean and North America. Climate conditions from April to June, May to July, mode 3's time coefficients, and previous year's yield are used for forecasting spring wheat yield in each SAD. Cross-validation procedure which generates eight sets of models for the eight validation periods is used. To show the reproducing projection between observed and calculated values, the root mean squared error for skill score (RMSE SS) with the persistence model serving as the reference model is used. The persistence model is used as a benchmark. The results show that SADs near USA border show better RMSE SS values and mode 3's time coefficients can be a useful predictor especially for inland province such as Manitoba. Among 27 Canadian Prairie's SADs with perfect yield data, 67% of Alberta's SADs, 86% of Manitoba's SADs, and 77% of Saskatchewan's SADs can get positive skill scores. In each SAD, future yield projection is calculated applying predictors in 2013 for the obtained eight sets of models and eight sets of forecasted values in 2013 are averaged and a near future projection result is obtained. Series of outputs including calculated forecasted yield value in each SAD is provided by smart phone application. A system for providing climatic condition for a point with a permission of Climatic Research Unit - University of East Anglia and for obtaining patent is proposed. There are several patented systems similar to the system proposed in this paper. However, these patents are different in essence. The system proposed in this paper consists of two parts. First part is to estimate equations using time series data. The second part is to acquire and apply latest climatic conditions for obtained equations and calculate future projection. If the procedure is refined and devices are originally developed, series of idea can be patented. For future work, crop index, Hokkaido is also introduced. PMID- 25733072 TI - Vulvar white sponge naevus in a girl. PMID- 25733073 TI - The utility of the DDAVP challenge test in children with low von Willebrand factor. PMID- 25733074 TI - Causes and costs for ED visits after pediatric adenotonsillectomy. AB - OBJECTIVE: (1) Review the reasons, timing, and costs for children presenting to the emergency department (ED) after adenotonsillectomy (T&A). STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: A standardized activity-based hospital accounting system was used to identify 437 children from an academic pediatric otolaryngology practice presenting to the ED after T&A from 2009 to 2012. The reason for presentation, timing after surgery, and facility costs were recorded. RESULTS: The study cohort represented 13.3% of the 3198 patients who underwent T&A during that time period. Overall, 133 (4.2%) presented for dehydration, 106 (3.3%) presented for post tonsillectomy hemorrhage, 65 (2.0%) for poorly controlled pain, 42 (1.3%) for fever, 29 (1.0%) for vomiting/nausea/GI discomfort, 22 (0.7%) for respiratory complications, and 12 (0.4%) for miscellaneous reasons related to the operation; 28 (0.8%) were unrelated to the T&A and excluded. Mean postoperative day at the time of ED presentation was 4.4 (95% CI, 4.1-4.7). The mean cost per patient presenting to the ED was $1420 (95% CI, $1104-$1737), the most costly subgroups being those presenting with respiratory complications ($2855; 95% CI, $1434 $4277), hemorrhage ($1502; 95% CI, $1216-$1787), and dehydration ($1372; 95% CI, $995-$1750). The least costly subgroup was acute postoperative pain ($781; 95% CI, $282-$1200). CONCLUSION: A significant portion of children present to the ED after T&A for poorly controlled pain, dehydration, or fever. The costs from these visits are significant. Accounting for these costs in the global care for pediatric T&A could assist in calculating appropriate reimbursement for bundled payments in this climate of health care reform. PMID- 25733075 TI - In silico analysis of RET variants in medullary thyroid cancer: from the computer to the bedside. AB - OBJECTIVE: The American Thyroid Association (ATA) medullary thyroid cancer (MTC) guidelines group RET variants, in the setting of familial medullary thyroid cancer and multiple endocrine neoplasia type 2, into 4 classes of severity based on epidemiological data. The aim of this study was to determine if genotype correlates with phenotype in RET missense mutations. STUDY DESIGN: In silico mutational tolerance prediction. SETTING: Academic research hospital. SUBJECTS AND METHODS: We analyzed all RET variants currently listed in the ATA guidelines for the management of MTC using 2 computer-based (in silico) mutation tolerance prediction approaches: PolyPhen-2 HumVar and PolyPhen-2 HumDiv. Our analysis also included 27 different RET single-nucleotide polymorphisms resulting in missense variants. RESULTS: There was a statistically significant difference in the overall HumDiv score between ATA groups A and B (P = .025) and a statistically significant different HumVar score between benign polymorphisms and ATA group A (P = .023). Overall, RET variants associated with a less aggressive clinical phenotype generally had a lower Hum Div/Var score. CONCLUSIONS: Polyphen-2 Hum Div/Var may provide additional clinical data to help distinguish benign from MEN2/familial medullary thyroid carcinoma-causing RET variants as well as less aggressive phenotypes (ATA A) from more aggressive ones (ATA B-C). In silico genetic analyses, with proper validation, may predict the phenotypic severity of RET variants, providing clinicians with a tool to aid clinical decision making in cases in which the RET variant is currently unknown or little epidemiological data are available. PMID- 25733076 TI - Ecotoxicity and genotoxicity of a binary combination of triclosan and carbendazim to Daphnia magna. AB - In the environment, chemical substances appear as complex mixtures and consequently organisms are exposed to a variety of chemicals from different sources (e.g. wastewater treatment plants, agriculture runoffs). When studying chemical mixtures, there are two conceptual models usually used to predict toxicity: the Independent Action (IA) and Concentration Addition (CA) models. However, deviations from these reference models can occur as synergism or antagonism, dose ratio or dose level dependency. The aim of the present study was to investigate the effects of triclosan and carbendazim, and their binary mixture to Daphnia magna. With this purpose, immobilisation, feeding inhibition, and reproduction were assessed as main ecotoxicity endpoints. In addition, in vivo genotoxicity of both chemicals was investigated using the comet assay. In the single exposure, carbendazim was more toxic to D. magna than triclosan. When daphnids were exposed to both single compounds, DNA damage was observed. Concerning mixture exposures, different endpoints followed different patterns of response, from additivity: IA model (feeding inhibition and reproduction data), to deviations that indicate interaction between chemicals inside the organism: dose level dependency (immobilisation data) and dose ratio dependency (DNA damage). This study showed that additivity does not rule the dose-effect relation in chemical mixtures of carbendazim and triclosan and interactions between both chemicals might induce generally higher toxicity than predicted based on single chemical exposures. PMID- 25733077 TI - Is mucosal healing more common than clinical remission in ulcerative colitis? - Is it the truth or only a myth coming from the studies? AB - BACKGROUND: The most important goals of the recent therapies of ulcerative colitis (UC) are to induce and maintain clinical remission and to achieve mucosal healing (MH). Rate of endoscopic remission has been shown to be higher than that of clinical remission in large trials like ULTRA and PURSUIT. The aim of our study was to evaluate the correlation between clinical and endoscopic disease activities of UC defined by activity scores. METHODS: Clinical and endoscopic activities were evaluated in 100 consecutive UC patients. Clinical activities were defined by two activity indices: the Rachmilewitz Activity Index (CAI) and the partial Mayo score. Colonoscopies and patient enrollments were performed by two experienced gastroenterologists and endoscopists. They graded the findings both according to the endoscopic part of the Rachmilewitz Endoscopic Activity Index (EI) and the Mayo endoscopic subscore. MH was defined as Mayo endoscopic subscore and EI of 0. Histological activity was scored by Riley score. RESULTS: Clinical and endoscopic activities showed strong correlations using both scoring systems (p = 0.0029 and p = 0.0001). Endoscopic disease activity also correlated with the histological activity (p >= 0.001). Significant correlation was shown between the clinical activity and MH (p = 0.0012 and p >= 0.001). No association was showed with the extension of the disease and clinical or endoscopic activity. CONCLUSION: Assessment of MH is very important for guiding therapy and for evaluation of remission in patients with UC. Our result showed good correlation between the clinical, endoscopic, and histological activities of UC focusing on the importance of evaluating the endoscopic activity of the patients. PMID- 25733079 TI - Microbial communities on flower surfaces act as signatures of pollinator visitation. AB - Microbes are easily dispersed from one place to another, and immigrant microbes might contain information about the environments from which they came. We hypothesized that part of the microbial community on a flower's surface is transferred there from insect body surfaces and that this community can provide information to identify potential pollinator insects of that plant. We collected insect samples from the field, and found that an insect individual harbored an average of 12.2 * 10(5) microbial cells on its surface. A laboratory experiment showed that the microbial community composition on a flower surface changed after contact with an insect, suggesting that microbes are transferred from the insect to the flower. Comparison of the microbial fingerprint approach and direct visual observation under field condition suggested that the microbial community on a flower surface could to some extent indicate the structure of plant-pollinator interactions. In conclusion, species-specific insect microbial communities specific to insect species can be transferred from an insect body to a flower surface, and these microbes can serve as a "fingerprint" of the insect species, especially for large-bodied insects. Dispersal of microbes is a ubiquitous phenomenon that has unexpected and novel applications in many fields and disciplines. PMID- 25733080 TI - A systematic review of the emotional, behavioural and cognitive features exhibited by school-aged children experiencing neglect or emotional abuse. AB - BACKGROUND: Interventions to minimize the long-term consequences of neglect or emotional abuse rely on prompt identification of these children. This systematic review of world literature (1947-2012) identifies features that children aged 5 14 years experiencing neglect or emotional abuse, as opposed to physical or sexual abuse, may exhibit. METHODS: Searching 18 databases, utilizing over 100 keywords, supplemented by hand searching, 13,210 articles were identified and 111 underwent full critical appraisal by two independent trained reviewers. RESULTS: The 30 included studies highlighted behavioural features (15 studies), externalizing features being the most prominent (8/9 studies) and internalizing features noted in 4/6 studies. Four studies identified attention deficit hyperactivity disorder (ADHD) associated features: impulsivity, inattention or hyperactivity. Child difficulties in initiating or developing friendships were noted in seven studies. Of 13 studies addressing emotional well-being, three highlighted low self-esteem, with a perception of external control (1), or depression (6) including suicidality (1). A negative internal working model of the mother increased the likelihood of depression (1). In assessing cognition or academic performance, lower general intelligence (3/4) and reduced literacy and numeracy (2) were reported, but no observable effect on memory (3). CONCLUSIONS: School-aged children presenting with poor academic performance, ADHD symptomatology or abnormal behaviours warrant assessment of neglect or emotional abuse as a potential underlying cause. PMID- 25733081 TI - Recovery from TBT pollution in English Channel environments: A problem solved? AB - Following recognition of effects in the 1980s, tributyltin (TBT) has been monitored at sites in the English Channel to evaluate the prognosis for biota - spanning the introduction of restrictions on TBT use on small boats and the recent phase-out on the global fleet. We describe how persistence and impact of TBT in clams Scrobicularia plana has changed during this period in Southampton Water and Poole Harbour. TBT contamination (and loss) in water, sediment and clams reflects the abundance and type of vessel activity: half-times in sediment (up to 8y in Poole, 33y in Southampton) are longest near commercial shipping. Recovery of clam populations - slowest in TBT-contaminated deposits - provides a useful biological measure of legislative efficacy in estuaries. On rocky shores, recovery from imposex in Nucella lapillus is evident at many sites but, near ports, is prolonged by shipping impacts, including sediment legacy, for example, in the Fal. PMID- 25733082 TI - UV-induced mutations in epidermal cells of mice defective in DNA polymerase eta and/or iota. AB - Xeroderma pigmentosum variant (XP-V) is a human rare inherited recessive disease, predisposed to sunlight-induced skin cancer, which is caused by deficiency in DNA polymerase eta (Poleta). Poleta catalyzes accurate translesion synthesis (TLS) past pyrimidine dimers, the most prominent UV-induced lesions. DNA polymerase iota (Poliota) is a paralog of Poleta that has been suggested to participate in TLS past UV-induced lesions, but its function in vivo remains uncertain. We have previously reported that Poleta-deficient and Poleta/Poliota double-deficient mice showed increased susceptibility to UV-induced carcinogenesis. Here, we investigated UV-induced mutation frequencies and spectra in the epidermal cells of Poleta- and/or Poliota-deficient mice. While Poleta-deficient mice showed significantly higher UV-induced mutation frequencies than wild-type mice, Poliota deficiency did not influence the frequencies in the presence of Poleta. Interestingly, the frequencies in Poleta/Poliota double-deficient mice were statistically lower than those in Poleta-deficient mice, although they were still higher than those of wild-type mice. Sequence analysis revealed that most of the UV-induced mutations in Poleta-deficient and Poleta/Poliota double-deficient mice were base substitutions at dipyrimidine sites. An increase in UV-induced mutations at both G:C and A:T pairs associated with Poleta deficiency suggests that Poleta contributes to accurate TLS past both thymine- and cytosine containing dimers in vivo. A significant decrease in G:C to A:T transition in Poleta/Poliota double-deficient mice when compared with Poleta-deficient mice suggests that Poliota is involved in error-prone TLS past cytosine-containing dimers when Poleta is inactivated. PMID- 25733083 TI - The study of the effect of guided imagery on pain, anxiety and some other hemodynamic factors in patients undergoing coronary angiography. AB - One of the most frequently used methods for the diagnosis and treatment of heart diseases is cardiac catheterization which increases the anxiety level in patients before surgery. In this random clinical study, 62 people undergoing coronary angiography were randomly assigned to experimental and control groups. The necessary data were collected through a hemodynamic variable sheet, the STAI anxiety questionnaire and a pain scale. The experimental group subjects were asked to listen to a Guided Imagery CD for 18 min. The mean level of anxiety for the Guided Imagery group after the intervention decreased significantly. The comparison of the means of hemodynamic parameters before and after the intervention showed a small decrease after the intervention, but this reduction was not statistically significant. Moreover, the means of pain as measured by pain scale showed that the control group had slower level of pain but, again, this difference was not statistically significant. PMID- 25733084 TI - Perthes disease in a 2-year-old child. AB - Perthes disease represents a transient interruption of the blood supply to the femoral head followed by collapse and subsequent remodelling. The majority of cases present between the ages of 4 and 10 years. We report the case of a child who developed a painful right-sided limp some days after his second birthday. The limp was initially interpreted as a transient synovitis of the hip. However, when the limp persisted, further investigations revealed that he had Perthes disease. PMID- 25733085 TI - Incidental diagnosis of liver tuberculosis in a patient with jaundice. AB - A 30-year-old afebrile woman presented with anorexia, yellowish discolouration of the sclera and bilateral pedal oedema. Blood investigations revealed severe anaemia, raised erythrocyte sedimentation rate and thrombocytopaenia. Liver function tests were abnormal with raised bilirubin, alanine transaminase and prothrombin time. Chest roentgenogram was negative for tuberculosis. Abdominal ultrasonography (USG) revealed coarsened echotexture of the liver with surface nodularity. Contrast-enhanced CT scan revealed heterogeneity with surface and parenchymal nodularity scattered throughout the liver parenchyma. USG-guided liver biopsy was performed, which showed changes in granulomatous hepatitis with positive Ziehl-Neelsen staining for acid-fast bacilli. The patient was started on antituberculous drugs. After completion of the antituberculous regimen, the patient made an uneventful recovery with normal range of aspartate aminotransferase, serum albumin and prothrombin time. In summary, isolated liver tuberculosis is rare and a high index of suspicion is required in a patient from an area where tuberculosis is endemic, after excluding other common diffuse liver pathologies. PMID- 25733086 TI - An unusual case of refractory wheeze. AB - A 37-year-old man presented with a history of episodic wheeze and breathlessness of 3 years' duration refractory to treatment. Physical examination revealed diffuse expiratory polyphonic rhonchi while the remainder of the examination including the cardiac examination was reported as normal. Pulmonary function testing revealed mild obstruction with bronchodilator reversibility. The patient was discharged on a 6-month course of antitubercular treatment (ATT) as bronchial brush cytology (obtained via bronchoscopy) was positive for acid-fast bacilli. The patient presented after completing 6 months of ATT with persistent symptoms, a loud S1 and a mid-diastolic murmur at the apex. High-resolution CT of the chest showed bilateral dependent ground glass opacities. An echocardiogram revealed a left atrial myxoma, and normal RV size and pressures. The patient underwent successful surgical removal of the same, and made a complete recovery. Refractory wheeze is a very unusual presentation of a left atrial myxoma. PMID- 25733087 TI - Carpal tunnel syndrome following an electrical injury in a child. AB - Carpal tunnel syndrome (CTS) is very rare in children and has been reported very infrequently in the literature. We present an unusual case of CTS in a 14-year old girl who developed this following an accidental electrical shock. As far as we are aware, this is the first case report of CTS in a child following electrical injury. This rare complication of electrical injury can easily be disregarded or misdiagnosed as neuropraxia, and this can delay appropriate treatment, as evidenced by this case. We propose that CTS should be considered when instigating initial medical care after an electrical injury, and that a referral to a hand surgeon should not be delayed, as these children need urgent surgical intervention to preserve hand function. PMID- 25733088 TI - Fatal multiple deer tick-borne infections in an elderly patient with advanced liver disease. AB - We present a case of a 66-year-old woman with decompensated alcoholic liver cirrhosis and poorly controlled non-insulin-dependent diabetes mellitus who was admitted with a 1 day history of altered mental status, high-grade fevers, worsening jaundice and generalised malaise with subsequent development of hypotension requiring intensive care. She was diagnosed with severe babesiosis with high-grade parasitaemia. She was also found to have Lyme disease coinfection. Despite aggressive therapeutic measures including appropriate antibiotics and multiple exchange blood transfusions, she developed septic shock and fulminant multiple organ failure with eventual demise. In this article, we highlight multiple tick-borne illnesses in a vulnerable host, in this case an elderly patient with liver cirrhosis, as risk factors for severe morbidity and potentially fatal outcomes. PMID- 25733089 TI - Rituximab-induced Takotsubo syndrome: more cardiotoxic than it appears? AB - Rituximab is used for treatment of multiple haematological cancers. Caution for use is advised in patients with significant cardiorespiratory disease due to known cases of exacerbations of angina and arrhythmias. However, its cardiotoxicity profile is not as well recognised as other monoclonal antibodies such as transtuzumab. We report a case of a 66-year-old man who developed Takotsubo's cardiomyopathy (TC) after an elective infusion of rituximab. This case is exceptional in that rituximab has not been linked to TC, and the vast majority of chemotherapy-linked and immunotherapy-linked TC reactions have occurred during initial infusions. We also discuss the different mechanisms which link TC to immunotherapy and chemotherapy, and propose that there may be a potential for risk-stratifying recipients of this frequently used immunotherapy prior to administering treatment. PMID- 25733090 TI - Acute postoperative inflammatory polyarthritis associated with a lone IgM cardiolipin antibody. AB - While the most recognised complication after joint surgery is septic arthritis, other forms of joint pathology may occur. We present a case of postoperative polyarthritis with high inflammatory markers, which responded to a course of prednisolone. The occurrence of high IgM cardiolipin antibodies that normalised with treatment suggests that this condition is a form of transient autoimmunity. PMID- 25733091 TI - De Garengeot's hernia: 40 years after Bassini inguinal hernioplasty. AB - De Garengeot's hernia (DGH) is a rare entity in which the vermiform appendix is located within the femoral hernia sac. Even though DGH is known to be more common in females, we report a case of a male patient having undergone Bassini-type inguinal hernia repair over 40 years ago. We present the preoperative diagnostic measures and an example of the surgical management of this rare entity. PMID- 25733092 TI - Cutaneous nocardiosis: an underdiagnosed pathogenic infection. PMID- 25733093 TI - Anaphylaxis after home-made quinoa dinner: hold the mustard. PMID- 25733094 TI - Acute suppurative parotitis caused by Streptococcus pneumoniae in an HIV-infected man. AB - We report a case of a 32-year-old man who presented with progressive unilateral parotid gland enlargement and subsequently tested positive for HIV. A CT scan of the neck performed with contrast showed a phlegmon in the region of the right parotid tail measuring approximately 2.5*2.4 cm. Cultures of the aspirated fluid grew Streptococcus pneumoniae and the S. pneumoniae urinary antigen test was also positive. The patient underwent surgical debridement and received antimicrobial therapy with complete resolution of the parotitis. Parotitis caused by S. pneumoniae is rare, and HIV infection should be suspected in any case of invasive pneumococcal disease. PMID- 25733095 TI - Primary hydatid cyst of the parotid gland. PMID- 25733096 TI - Pseudoabducens palsy mimicking myasthenia gravis. PMID- 25733097 TI - The diagnostic usefulness of 18F-fluorodoxyglucose-positron emission tomography/CT in SAPHO syndrome. PMID- 25733098 TI - Evaluation of early-stage hepatocellular carcinoma by magnetic resonance imaging with gadoxetic acid detects additional lesions and increases overall survival. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a high rate of intrahepatic recurrence after curative treatment, possibly because metastases are not always identified before treatment. Magnetic resonance (MR) imaging with a liver specific contrast agent, gadoxetic acid, can detect small HCCs with high levels of sensitivity. We investigated whether MR imaging with gadoxetic acid increases overall and recurrence-free survival of patients initially assessed by computed tomography (CT). METHODS: We performed a retrospective study of data from 700 patients diagnosed with a single-nodular HCC by dynamic 4-phase CT in Seoul, Korea, from January 2009 through December 2010. Of these patients, 323 underwent additional evaluation with gadoxetic acid-enhanced MR imaging (CT+MR group). The 377 patients who did not undergo MR imaging analysis are referred to as the CT group. RESULTS: The CT and CT+MR groups were comparable in most baseline characteristics (Child-Pugh class A, 93.1% vs 94.7%; and median size of the primary HCCs, 2.8 vs 2.6 cm, respectively). Seventy-four additional HCC nodules were detected in 53 (16.4%) of the patients who underwent MR evaluation after CT (CT+MR group). These detections increased the Barcelona Clinic Liver Cancer stages for 43 patients (13.3%) and modified their treatment plans. On multivariable analyses, the CT+MR group had a significantly lower rate of HCC recurrence (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.54-0.96) and lower overall mortality (HR, 0.65; 95% CI, 0.44-0.96) than the CT group. In an analysis of 285 pairs of patients matched on the basis of the propensity score, the CT+MR group had significantly lower overall mortality (HR, 0.66; 95% CI, 0.44 0.99). CONCLUSIONS: Among patients who underwent dynamic CT analysis of a single nodular HCC, additional evaluation by MR imaging with gadoxetic acid led to the detection of additional HCC nodules in 16% of patients, reduced the risk of disease recurrence, and decreased overall mortality. PMID- 25733099 TI - Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system. AB - BACKGROUND & AIMS: Medications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort. METHODS: We performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF. RESULTS: Among 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively. CONCLUSIONS: Drug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes. PMID- 25733100 TI - Biphasic effect of alcohol intake on the development of fatty liver disease. AB - BACKGROUND: Fatty liver is an important clinical feature not only in alcoholic and non-alcoholic fatty liver diseases, but in other chronic liver diseases as well. Our aim was to elucidate the effect and relationship between habitual alcohol intake and obesity in the development of fatty liver disease. METHODS: We enrolled 8,029 subjects undergoing abdominal ultrasonography with general medical examinations, and analyzed the factors associated with fatty liver based on daily alcohol intake, body mass index (BMI), and waist circumference. RESULTS: For fatty liver, BMI, waist circumference, total cholesterol, triglycerides, and fasting plasma glucose were significant and independent risk factors. Heavy alcohol intake (50 g/day) was a significant risk factor for fatty liver in women (odds ratio [OR], 3.35). Analysis based on the presence or absence of obesity revealed that moderate alcohol intake was a significant negative risk factor for fatty liver in both male and female obese (BMI >=25 kg/m(2)) subjects (OR, 0.74 for non-obese and 0.39 for obese patients, respectively). Heavy alcohol intake was also a significant negative risk factor in obese males (0.62). In contrast, heavy alcohol intake was a risk factor in non-obese males (OR, 1.29) and in all females (OR, 2.22 for non-obese and 6.6 for obese patients, respectively). CONCLUSIONS: The influence of alcohol intake on fatty liver differed depending on the level of alcohol consumption, gender, and the presence of obesity, and showed biphasic effects. PMID- 25733101 TI - Sleep disturbance and longitudinal risk of inflammation: Moderating influences of social integration and social isolation in the Coronary Artery Risk Development in Young Adults (CARDIA) study. AB - Both sleep disturbance and social isolation increase the risk for morbidity and mortality. Systemic inflammation is suspected as a potential mechanism of these associations. However, the complex relationships between sleep disturbance, social isolation, and inflammation have not been examined in a population-based longitudinal study. This study examined the longitudinal association between sleep disturbance and systemic inflammation, and the moderating effects of social isolation on this association. The CARDIA study is a population-based longitudinal study conducted in four US cities. Sleep disturbance - i.e., insomnia complaints and short sleep duration - was assessed in 2962 African American and White adults at baseline (2000-2001, ages 33-45years). Circulating C reactive protein (CRP) was measured at baseline and follow-up (2005-2006). Interleukin-6 (IL-6) and subjective and objective social isolation (i.e., feelings of social isolation and social network size) were measured at follow-up. Sleep disturbance was a significant predictor of inflammation five years later after full adjustment for covariates (adjusted betas: 0.048, P=0.012 for CRP; 0.047, P=0.017 for IL-6). Further adjustment for baseline CRP revealed that sleep disturbance also impacted the longitudinal change in CRP levels over five years (adjusted beta: 0.044, P=0.013). Subjective social isolation was a significant moderator of this association between sleep disturbance and CRP (adjusted beta 0.131, P=0.002). Sleep disturbance was associated with heightened systemic inflammation in a general population over a five-year follow-up, and this association was significantly stronger in those who reported feelings of social isolation. Clinical interventions targeting sleep disturbances may be a potential avenue for reducing inflammation, particularly in individuals who feel socially isolated. PMID- 25733102 TI - Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuroprotection after acute excitotoxicity. AB - Excitotoxic cell death is a crucial mechanism through which neurodegeneration occurs in numerous pathologies of the central nervous system (CNS), such as Alzheimer's disease, stroke and spinal cord injury. Toll-like receptors (TLRs) are strongly expressed on microglial cells and are key regulators of the innate immune response to neuronal damage. However, it is still unclear whether their stimulation is protective or harmful in excitotoxic contexts. In this study, we demonstrate that systemic administration of lipopolysaccharide (LPS) or Pam3CSK4 24h prior to an intrastriatal injection of kainic acid (KA) significantly protected cortical neurons in the acute phase of injury. Protection could not be detected with the TLR3 ligand poly-IC. Histological analyses revealed that microglia of LPS and Pam3CSK4 pre-conditioned group were primed to react to injury and exhibited a stronger expression of Tnf and Tlr2 mRNA. We also found that mice deficient for MyD88, a critical adaptor protein for most TLR, were more vulnerable than WT mice to KA-induced excitotoxicity at early (12h and 24h) and late (10days) time points. Finally, bone-marrow chimeric mice revealed that MyD88 signaling in CNS resident cells, but not in cells of hematopoietic origin, mediates the protective effect. This study unravels the potential of TLR2 and TLR4 agonists to induce a protective state of preconditioning against KA-mediated excitotoxicity and further highlights the beneficial role of cerebral MyD88 signaling in this context. PMID- 25733104 TI - Erratum. PMID- 25733106 TI - Medical protocols. PMID- 25733103 TI - The HIV-1 transgenic rat model of neuroHIV. AB - Despite the ability of current combination anti-retroviral therapy (cART) to limit the progression of HIV-1 to AIDS, HIV-positive individuals continue to experience neuroHIV in the form of HIV-associated neurological disorders (HAND), which can range from subtle to substantial neurocognitive impairment. NeuroHIV may also influence substance use, abuse, and dependence in HIV-positive individuals. Because of the nature of the virus, variables such as mental health co-morbidities make it difficult to study the interaction between HIV and substance abuse in human populations. Several rodent models have been developed in an attempt to study the transmission and pathogenesis of the HIV-1 virus. The HIV-1 transgenic (HIV-1Tg) rat is a reliable model of neuroHIV because it mimics the condition of HIV-infected patients on cART. Research using this model supports the hypothesis that the presence of HIV-1 viral proteins in the central nervous system increases the sensitivity and susceptibility of HIV-positive individuals to substance abuse. PMID- 25733105 TI - Myocardial viability as integral part of the diagnostic and therapeutic approach to ischemic heart failure. AB - Chronic heart failure is a major public-health problem with a high prevalence, complex treatment, and high mortality. A careful and comprehensive analysis is needed to provide optimal (and personalized) therapy to heart failure patients. The main 4 non-invasive imaging techniques (echocardiography, magnetic resonance imaging, multi-detector-computed tomography, and nuclear imaging) provide information on cardiovascular anatomy and function, which form the basis of the assessment of the pathophysiology underlying heart failure. The selection of imaging modalities depends on the information that is needed for the clinical management of the patients: (1) underlying etiology (ischemic vs non-ischemic); (2) in ischemic patients, need for revascularization should be evaluated (myocardial ischemia/viability?); (3) left ventricular function and shape assessment; (4) presence of significant secondary mitral regurgitation; (5) device therapy with cardiac resynchronization therapy and/or implantable cardiac defibrillator (risk of sudden cardiac death). This review is dedicated to assessment of myocardial viability, however "isolated assessment of myocardial viability" may be clinically not meaningful and should be considered among all those different variables. This complete information will enable personalized treatment of the patient with ischemic heart failure. PMID- 25733107 TI - An elderly man in cardiac arrest on a ski slope. PMID- 25733108 TI - Extracorporeal life support. PMID- 25733109 TI - Is that a defibrillator in your hangar? PMID- 25733110 TI - Sepsis and septic shock. PMID- 25733112 TI - Air medical resource management: our last line of defense. PMID- 25733113 TI - Preoxygenation reduces desaturation events and improves intubation success. AB - OBJECTIVE: Oxygen desaturation occurs frequently in the course of prehospital rapid sequence intubation (RSI) and is associated with increased morbidity and mortality. Preoxygenation with positive pressure ventilation by bag valve mask may delay the onset of desaturation. The purpose of this study was to evaluate implementation of a targeted preoxygenation protocol including the use of positive pressure ventilation on desaturation events and intubation success during air medical RSI. METHODS: The RSI air medical program airway training model was modified to target an oxygen saturation as measured by pulse oximetry value of >= 93% before initial laryngoscopy. A review of oxygen saturation as measured by pulse oximetry tracings was performed for 2 years before and 2 years after implementation of this protocol. The incidence of desaturation events and overall intubation success rates were compared before and after the intervention. RESULTS: One hundred fifty-five RSI procedures were evaluated over the study period. Desaturation events decreased from 58% in the 2 years before algorithm changes to 28% in the first year and 14% in the second year after implementation (P < .01). Intubation success rates increased from 89% to 98% (P < .01). There were no self-reports of aspiration events during the study period. CONCLUSION: A preoxygenation protocol dramatically reduced the incidence of desaturation events and increased intubation success without an increase in the number of reported aspiration events. PMID- 25733114 TI - Predictors of unfavorable thermal outcome during newborn emergency retrievals. AB - OBJECTIVE: Maintenance of normal body temperature is a challenge during transports. We aimed to identify predisposing factors for unfavorable thermal outcome during emergency retrievals of neonates. METHODS: Demographic data and clinical variables for transports performed over a 2-year period were extracted from the Newborn Emergency Transport Service (Victoria, Australia) database. Arrival temperatures outside normothermia (36.5 degrees -37.5 degrees C) were defined as an unfavorable outcome. RESULTS: Normothermia on arrival at the receiving hospital was achieved in 78% of 1,261 transports. The strongest predictor of unfavorable thermal outcome was an abnormal temperature at the start of the retrieval (odds ratio [OR] = 8.04; 95% confidence interval [CI], 5.91 10.95; P < .001) followed by very low weight on transport (< 1,500 g; OR = 2.49; 95% CI, 1.63-3.80; P < .001) and respiratory support (OR = 1.81; 95% CI, 1.29 2.54; P = .001). Medications (eg, inotropes and sedation/muscle relaxation) or central/peripheral venous/arterial lines were not significant predictors of outcome when temperature at retrieval start, weight at transport, and respiratory support were adjusted as cofactors. Mode of transport (road, fixed wing, or rotary wing aircraft) and outside temperature were not associated with thermal outcome. CONCLUSION: Abnormal temperature at the start of the retrieval, very low transport weight, and respiratory support were strong predictors of unfavorable thermal outcome during neonatal emergency transports. PMID- 25733115 TI - The Facilitator's Role in London's Air Ambulance's simulation "moulage" training. AB - OBJECTIVE: This research focused on the facilitator's role in the simulated patient training "moulages" used by London's Air Ambulance (LAA) for their team training. Facilitators are chosen based on their experience and expertise in the field. The aim of this research was to gain insight into the role of moulage facilitator. METHODS: An ethnographic approach was employed, using the notion of "progressive focusing." Overt observational fieldwork was performed, with the resulting field notes evaluated by content analysis. Semistructured interviews were then conducted with 8 facilitators selected by convenience sampling in order to gain an understanding of the role according to their perspective. RESULTS: The research revealed the role of the facilitator to be challenging and multifaceted. The moulage process appeared appropriate to its function, and the facilitation methods were largely in accordance with recommended practice outlined in educational literature. CONCLUSIONS: The London's Air Ambulance moulage facilitators have to prepare trainees for an intense and emotionally demanding job. Their methods are derived from experience, often with a subconscious application of sound educational practice. This research may help the team identify certain areas with scope for further refinement including feedback methods, fidelity, and reducing the burden of multitasking. PMID- 25733116 TI - Helicopter emergency medical services response times in norway: do they matter? AB - OBJECTIVE: The main objective of the Norwegian air ambulance service is to provide advanced emergency medicine to critically ill or severely injured patients. The government has defined a time frame of 45 minutes as the goal within which 90% of the population should be reached. The aims of this study were to document accurate flying times for rotor wing units to the scene and to determine the rates of acute primary missions in Norway. METHODS: We analyzed operational data from every acute primary mission from all air ambulance bases in Norway in 2011, focusing on the flying time taken to reach scene, the municipality requesting the flight, and the severity score data. RESULTS: A total of 5,805 acute primary missions were completed in Norway in 2011. The median flying time was 19 minutes (25%-75% percentiles: 13-28). The mean mission rate for the 17 bases was 7.5 (95% confidence interval, 7.4-7.8 per 10,000 inhabitants). The overall mean (standard deviation) National Committee on Aeronautics score for all missions was 4.07 (1.30). CONCLUSION: The government's expectation of serving the entire population via HEMS within 45 minutes appears to be achieved on a national level. However, vast differences remain in the flying times and rates between bases. PMID- 25733117 TI - Use of unmanned aerial vehicles for medical product transport. AB - Advances in technology and decreasing costs have led to an increased use of unmanned aerial vehicles (UAVs) by the military and civilian sectors. The use of UAVs in commerce is restricted by US Federal Aviation Administration (FAA) regulations, but the FAA is drafting new regulations that are expected to expand commercial applications. Currently, the transportation of medical goods in times of critical need is limited to wheeled motor vehicles and manned aircraft, options that can be costly and slow. This article explores the demand for, feasibility of, and risks associated with the use of UAVs to deliver medical products, including blood derivatives and pharmaceuticals, to hospitals, mass casualty scenes, and offshore vessels in times of critical demand. PMID- 25733118 TI - The lethargic diabetic: cerebral edema in pediatric patients in diabetic ketoacidosis. AB - Diabetic ketoacidosis (DKA) is the leading cause of hospitalizations for pediatric patients with diabetes mellitus. The most severe complication of DKA is cerebral edema that may lead to brain herniation. We present a case report that highlights the subclinical presentation of DKA-related cerebral edema in a pediatric patient and review the acute care management of suspected cerebral edema during transport. PMID- 25733119 TI - An instrument approach to airway management. AB - Aviation terminology and thought processes are commonly applied to medicine. We further propose the adaptation of instrument flight terminology to emergency airway management including the aviation approach plate visual aid and replacement of the term "failed airway" with "missed airway," PMID- 25733122 TI - Prediction of uterine dehiscence using ultrasonographic parameters of cesarean section scar in the nonpregnant uterus: a prospective observational study. AB - BACKGROUND: Every year 1.5 million cesarean section procedures are performed worldwide. As many women decide to get pregnant again, the population of pregnant women with a history of cesarean section is growing rapidly. For these women prediction of cesarean section scar performance is still a serious clinical problem. METHODS: Starting in 2005, the study included 308 nonpregnant women with a history of low transverse cesarean section. The following ultrasonographic parameters of the cesarean section scar in the nonpregnant uterus were assessed: the residual myometrial thickness (RMT) and the width (W) and the depth (D) of the triangular hypoechoic scar niche. During 8 years of follow-up, 41 of these women were referred to our department for delivery. In all cases, a repeat cesarean section was performed and the lower uterine segment was assessed. Two independent statistical methods namely the logit model and Decision Tree analysis were used to determine the relation between the appearance of the cesarean section scar in the nonpregnat state and the performance of the scar in the next pregnancy. RESULTS: The logit model revealed that the D/RMT ratio showed significant correlation with cesarean section scar dehiscence (P-value of 0.007). Specifically, a D/RMT ratio value greater than 1.3035 indicated that the likelihood of dehiscence was greater than 50%. The Decision Tree analysis revealed that a diagnosis of dehiscence versus non-dehiscence could be based solely on one criterion, a D/RMT ratio of at least 0.785. The sensitivity of this method was 71%, and the specificity was 94%. CONCLUSIONS: Assessment of the cesarean section scar in the nonpregant uterus can be used to predict the occurrence of scar dehiscence in the next pregnancy. PMID- 25733124 TI - A senile man with cystic lesion of liver and biliary obstruction. PMID- 25733125 TI - An unusual cause of abdominal pain. PMID- 25733123 TI - Characterization of Lipids and Proteins Associated to the Cell Wall of the Acapsular Mutant Cryptococcus neoformans Cap 67. AB - Cryptococcus neoformans is an opportunistic human pathogen that causes life threatening meningitis. In this fungus, the cell wall is exceptionally not the outermost structure due to the presence of a surrounding polysaccharide capsule, which has been highly studied. Considering that there is little information about C. neoformans cell wall composition, we aimed at describing proteins and lipids extractable from this organelle, using as model the acapsular mutant C. neoformans cap 67. Purified cell wall preparations were extracted with either chloroform/methanol or hot sodium dodecyl sulfate. Total lipids fractionated in silica gel 60 were analyzed by electrospray ionization tandem mass spectrometry (ESI-MS/MS), while trypsin digested proteins were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). We detected 25 phospholipid species among phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid. Two glycolipid species were identified as monohexosyl ceramides. We identified 192 noncovalently linked proteins belonging to different metabolic processes. Most proteins were classified as secretory, mainly via nonclassical mechanisms, suggesting a role for extracellular vesicles (EV) in transwall transportation. In concert with that, orthologs from 86% of these proteins have previously been reported both in fungal cell wall and/or in EV. The possible role of the presently described structures in fungal-host relationship is discussed. PMID- 25733126 TI - The role of endoscopy in the bariatric surgery patient. PMID- 25733127 TI - "Wet suction technique (WEST)": a novel way to enhance the quality of EUS-FNA aspirate. Results of a prospective, single-blind, randomized, controlled trial using a 22-gauge needle for EUS-FNA of solid lesions. AB - BACKGROUND: Contemporary EUS-guided FNA techniques involve the use of a needle, with an air column within the lumen, with or without suction. We describe a novel technique with an aim to improve the quality of the aspirate. OBJECTIVE: To compare a novel "wet suction" technique (WEST) with the conventional FNA technique (CFNAT) of EUS-guided FNA using a 22-gauge FNA needle. DESIGN: Prospective, single-blind, and randomized trial. SETTING: Two large tertiary-care hospitals. PATIENTS: All consecutive adult patients presenting for EUS with possible FNA of solid lesions were offered the chance to participate in the study. METHODS: All lesions were sampled with the same needle by using alternating techniques. Patients were randomized to the WEST versus the CFNAT for the first pass. If the first pass was made with the WEST, the second pass was made with the CFNAT, and subsequent passes were made in an alternating manner by using the same sequence. All FNAs were performed using 22-gauge needles. MAIN OUTCOME MEASUREMENTS: Specimen adequacy, cellularity, and blood contamination of EUS-guided FNA aspirates graded on a predefined scale. RESULTS: The WEST yielded significantly higher cellularity in a cell block compared with the CFNAT, with a mean cellularity score of 1.82+/-0.76 versus 1.45+/-0.768 (P<.0003). The WEST cell block resulted in a significantly better specimen adequacy of 85.5% versus 75.2% (P<.035). There was no difference in the amount of blood contamination between the 2 techniques. LIMITATIONS: Lack of cross check and grading by a second cytopathologist. CONCLUSION: The novel WEST resulted in significantly better cellularity and specimen adequacy in cell blocks of EUS-guided FNA aspirate of solid lesions than the CFNAT. PMID- 25733128 TI - Use of sleeve-customized self-expandable metal stents for the treatment of staple line leakage after laparoscopic sleeve gastrectomy. PMID- 25733129 TI - Levels of caffeine and its metabolites among U.S. smokers and nonsmokers. AB - Data from National Health and Nutrition Examination Survey for the years 2009 2010 were used to estimate the levels of caffeine and 14 of its metabolite among U.S. smokers and nonsmokers after adjustments were made for other factors that affect observed caffeine levels. In this study, when adjusted for daily caffeine intake, adjusted levels (AGM) of caffeine and its metabolites were not found to be statistically significantly different between smokers and nonsmokers. AGMs for caffeine and all of its metabolites were found to be statistically significantly higher (p < 0.01) among females aged >= 12 years than males. For caffeine, 1,3 dimethylxanthine, and 1,7-dimethylxanthine, those aged >= 20 years had statistically significantly higher (p < 0.01) AGM than those aged 12-19 years but the reverse was true for 7-methylxanthine and 3,7-dimethylxanthine (p <= 0.02). The order of the AGMs by race/ethnicity was non-Hispanic whites > Hispanics > non Hispanic blacks and most of the differences were statistically significant, at least between non-Hispanic whites and non-Hispanic blacks (p < 0.01). In general, there was a statistically significant positive association between the levels of caffeine and its metabolites and body mass index as well as daily caffeine intake. However, the levels of 7-methylxanthine were negatively associated with body mass index. PMID- 25733130 TI - Deferasirox-induced cytogenetic responses. AB - Deferasirox (commercially formulated as Exjade((r))) is one of the effective iron chelators used in treatment of iron overload diseases. In this study the effect of this substance for chromosome aberration, sister chromatid exchange and mitotic index was studied by in vitro (by using human peripheral lymphocytes) and in vivo (by using rat) analysis. Deferasirox increased the sister chromatid exchange frequency in all tested concentrations and periods in vitro. Also, in the presence of metabolic activator, the substance led to a statistically significant increase in the sister chromatid exchange frequencies only at high concentration. While in in vitro analysis the substance significantly increased abnormal cell percentages in all concentrations, in in vivo study the substance increased chromosome aberrations only in two concentrations at 12h treatment. In the cultured lymphocytes, deferasirox showed cytotoxicity by significantly reducing proliferation index and mitotic index values. While in the presence of metabolic activation it did not affect the proliferation index frequency, it had a stimulant effect on the mitotic index frequency. Deferasirox reduced significantly the mitotic index value in the bone marrow cells especially in high concentration and short treatment period (12h). PMID- 25733131 TI - Editorial: voltage-gated calcium 2.2 channels: therapeutic target for chronic arthritic pain? PMID- 25733132 TI - Rotating frame relaxation imaging of prostate cancer: Repeatability, cancer detection, and Gleason score prediction. AB - PURPOSE: To investigate relaxation along a fictitious field (RAFF) and continuous wave (cw) T1rho imaging of prostate cancer (PCa) in the terms of repeatability, PCa detection, and characterization. METHODS: Thirty-six patients (PSA 11.6 +/- 7.6 ng/mL, mean +/- standard deviation) with histologically confirmed PCa underwent two repeated 3T MR examinations using surface array coils before prostatectomy. Relaxation along fictitious field, cw T1rho, and T2 relaxation times (TRAFF, T1rhocw, T2) were measured and averaged over regions of interest placed in PCa, normal peripheral zone (PZ), and normal central gland (CG) positioned using whole-mount prostatectomy sections and anatomical T2-weighted images. Receiver operating characteristic curve analysis with area under the curve (AUC) was calculated to distinguish PCa from PZ/CG and PCa with Gleason score (GS) of 3+3 from GS of 3+4/>= 3+4. RESULTS: TRAFF and T1rhocw relaxation times were repeatable with coefficients of repeatability as a percentage of median value in the range of 7.8-23.2%. AUC (mean, 95% confidence interval) in the differentiation of PCa with GS of 3+3 from PCa with CS of >= 3+4 were 0.88 (0.72-0.99), 0.69 (0.46-0.90), and 0.68 (0.45-0.88), for TRAFF, T1rhocw, and T2, respectively. CONCLUSION: In quantitative region of interest based analysis, TRAFF outperformed T1rhocw and T2 in PCa detection and characterization. PMID- 25733133 TI - Organisational aspects and benchmarking of e-learning initiatives: a case study with South African community health workers. AB - South Africa desperately needs a comprehensive approach to fight HIV/AIDS. Education is crucial to reach this goal and Internet and e-learning could offer huge opportunities to broaden and deepen the knowledge basis. But due to the huge societal and digital divide between rich and poor areas, e-learning is difficult to realize in the townships. Community health workers often act as mediators and coaches for people seeking medical and personal help. They could give good advice regarding hygiene, nutrition, protection of family members in case of HIV/AIDS and finding legal ways to earn one's living if they were trained to do so. Therefore they need to have a broader general knowledge. Since learning opportunities in the townships are scarce, a system for e-learning has to be created in order to overcome the lack of experience with computers or the Internet and to enable them to implement a network of expertise. The article describes how the best international resources on basic medical knowledge, HIV/AIDS as well as on basic economic and entrepreneurial skills were benchmarked to be integrated into an e-learning system. After tests with community health workers, researchers developed recommendations on building a self-sustaining system for learning, including a network of expertise and best practice sharing. The article explains the opportunities and challenges for community health workers, which could provide information for other parts of the world with similar preconditions of rural poverty. PMID- 25733134 TI - Evaluation of the OPLS-AA force field for the study of structural and energetic aspects of molecular organic crystals. AB - Motivated by the need for reliable experimental data for the assessment of theoretical predictions, this work proposes a data set of enthalpies of sublimation determined for specific crystalline structures, for the validation of molecular force fields (FF). The selected data were used to explore the ability of the OPLS-AA parametrization to investigate the properties of solid materials in molecular dynamics simulations. Furthermore, several approaches to improve this parametrization were also considered. These modifications consisted in replacing the original FF atomic point charges (APC), by values calculated using quantum chemical methods, and by the implementation of a polarizable FF. The obtained results indicated that, in general, the best agreement between theoretical and experimental data is found when the OPLS-AA force field is used with the original APC or when these are replaced by ChelpG charges, computed at the MP2/aug-cc-pVDZ level of theory, for isolated molecules in the gaseous phase. If a good description of the energetic relations between the polymorphs of a compound is required then either the use of polarizable FF or the use of charges determined taking into account the vicinity of the molecules in the crystal (combining the ChelpG and MP2/cc-pVDZ methods) is recommended. Finally, it was concluded that density functional theory methods, like B3LYP or B3PW91, are not advisable for the evaluation of APC of organic compounds for molecular dynamic simulations. Instead, the MP2 method should be considered. PMID- 25733136 TI - How adhesion forms the early mammalian embryo. AB - The early mouse embryo is an excellent system to study how a small group of initially rounded cells start to change shape and establish the first forms of adhesion-based cell-cell interactions in mammals in vivo. In addition to its critical role in the structural integrity of the embryo, we discuss here how adhesion is important to regulate cell polarity and cell fate. Recent evidence suggests that adherens junctions participate in signaling pathways by localizing key proteins to subcellular microdomains. E-cadherin has been identified as the main player required for the establishment of adhesion but other mechanisms involving additional proteins or physical forces acting in the embryo may also contribute. Application of new technologies that enable high-resolution quantitative imaging of adhesion protein dynamics and measurements of biomechanical forces will provide a greater understanding of how adhesion patterns the early mammalian embryo. PMID- 25733137 TI - Regulation of cell adhesion and cell sorting at embryonic boundaries. AB - Embryonic boundaries are sharp delimitations that prevent intermingling between different cell populations. They are essential for the development of well organized structures and ultimately a functional organism. It has been long believed that this process was driven by global differences in cell adhesion strength, or expression of different types of adhesion molecules. The actual picture turns out to be quite different: Boundaries should be viewed as abrupt discontinuities, where cortical contractility is acutely upregulated in response to specific cell surface contact receptors which act as repulsive cues. Cell adhesion is also modulated along the interface, in different ways depending on the type of boundary, but in all cases the process is subordinated to the function of the cortical actomyosin cytoskeleton. PMID- 25733135 TI - Role of sGC-dependent NO signalling and myocardial infarction risk. AB - The NO/cGMP pathway plays an important role in many physiological functions and pathophysiological conditions. In the last few years, several genetic and functional studies pointed to an underestimated role of this pathway in the development of atherosclerosis. Indeed, several genetic variants of key enzymes modulating the generation of NO and cGMP have been strongly associated with coronary artery disease and myocardial infarction risk. In this review, we aim to place the genomic findings on components of the NO/cGMP pathway, namely endothelial nitric oxide synthase, soluble guanylyl cyclase and phosphodiesterase 5A, in context of preventive and therapeutic strategies for treating atherosclerosis and its sequelae. PMID- 25733138 TI - Active tension: the role of cadherin adhesion and signaling in generating junctional contractility. AB - In this chapter, we discuss the cell biology of contractility at cell-cell junctions. As discussed elsewhere in this volume, contractile forces play key roles in development and tissue homeostasis. Here, we review our understanding of the cellular mechanisms that functionally and physically link cadherin adhesion to the actomyosin contractile apparatus of the cell. Focusing on epithelia, we argue that E-cadherin junctions can be considered as active mechanical agents, which contribute to the assembly of actomyosin at the junctional cortex itself. This reflects cortical signaling, notably that regulated by the Rho GTPase, coordinated with actin regulation at junctions. The product, contractile tension at junctions, can then be regarded as an emergent property of a complex dynamical system that integrates adhesion with the cytoskeleton. PMID- 25733139 TI - Integration of cell-cell adhesion and contractile actomyosin activity during morphogenesis. AB - During embryonic development, cells become organized into complex tissues. Cells need to adhere and communicate with their immediate and remote neighbors to allow morphogenesis to take place in a coordinated way. Cell-cell adhesion, mediated by transmembrane adhesion receptors such as Cadherins and their intracellular interaction partners, is intimately linked to cell contractility that drives cell shape changes. Research in recent years has revealed that the contractile machinery responsible for cell shape changes, actomyosin, can in fact be organized into a number of different functional assemblies such as cortical junctional actomyosin, apical-medial actomyosin, supracellular actomyosin cables as well as basal actomyosin networks. During coordinated shape changes of a tissue, these assemblies have to be functionally and mechanically linked between cells through cell-cell junctions. Although many actin-binding proteins associated with adherens junctions have been identified, which specific factors are required for the linkage of particular actomyosin assemblies to junctions is not well understood. This review will summarize our current knowledge, based mainly on the in vivo study of morphogenesis in the fruit fly Drosophila melanogaster. PMID- 25733141 TI - Nectins and nectin-like molecules in development and disease. AB - Nectins and nectin-like molecules (Necls)/Cadms are Ca(2+)-independent immunoglobulin superfamily cell adhesion molecules, expressed in most cell types. Nectins mediate not only homotypic but also heterotypic cell-cell adhesion, in contrast to classic cadherins which participate only in homophilic adhesion. Nectins and Necls function in organogenesis of the eye, inner ear, tooth, and cerebral cortex and in a variety of developmental processes including spermatogenesis, axon guidance, synapse formation, and myelination. They are also involved in various diseases, such as viral infection, hereditary ectodermal dysplasia, Alzheimer's disease, autism spectrum disorder, and cancer. Thus, nectins and Necls are crucial for both physiology and pathology. This review summarizes recent advances in research on these cell adhesion molecules in development and pathogenesis. PMID- 25733142 TI - Anchors and signals: the diverse roles of integrins in development. AB - Integrins mediate cell adhesion by providing a link between the actin cytoskeleton and the extracellular matrix. As well as acting to anchor cells, integrin adhesions provide sensory input via mechanotransduction and synergism with signaling pathways, and provide the cell with the conditions necessary for differentiation in a permissive manner. In this review, we explore how integrins contribute to development, and what this tells us about how they work. From a signaling perspective, the influence of integrins on cell viability and fate is muted in a developmental context as compared to cell culture. Integrin phenotypes tend to arise from a failure of normally specified cells to create tissues properly, due to defective adhesion. The diversity of integrin functions in development shows how cell adhesion is continuously adjusted, both within and between animals, to fit developmental purpose. PMID- 25733143 TI - Epithelial-mesenchymal transitions: from cell plasticity to concept elasticity. AB - Epithelial-mesenchymal transition (EMT) is a developmental cellular process occurring during early embryo development, including gastrulation and neural crest cell migration. It can be broken down in distinct functional steps: (1) loss of baso-apical polarization characterized by cytoskeleton, tight junctions, and hemidesmosomes remodeling; (2) individualization of cells, including a decrease in cell-cell adhesion forces, (3) emergence of motility, and (4) invasive properties, including passing through the subepithelial basement membrane. These phases occur in an uninterrupted process, without requiring mitosis, in an order and with a degree of completion dictated by the microenvironment. The whole process reflects the activation of specific transcription factor families, called EMT transcription factors. Several mechanisms can combine to induce EMT. Some are reversible, involving growth factors and cytokines and/or environmental signals including extracellular matrix and local physical conditions. Others are irreversible, such as genomic alterations during carcinoma progression, along a selective and irreversible clonal drift. In carcinomas, these signals can converge to initiate a metastable phenotype. In this state, similarly to activated keratinocytes during re epithelialization, cells can initiate a cohort migration and engage into a transient and reversible EMT controlled by the local environment prior to efficient intravasation and metastasis. EMT transcription factors also participate in cancer progression by inducing apoptosis resistance and maintaining stem-like properties exposed in tumor recurrences. These properties, very important on a clinical point of view, are not intrinsically linked to EMT, but can share common pathways. PMID- 25733144 TI - Embryonic cell-cell adhesion: a key player in collective neural crest migration. AB - Cell migration is essential for morphogenesis, adult tissue remodeling, wound healing, and cancer cell migration. Cells can migrate as individuals or groups. When cells migrate in groups, cell-cell interactions are crucial in order to promote the coordinated behavior, essential for collective migration. Interestingly, recent evidence has shown that cell-cell interactions are also important for establishing and maintaining the directionality of these migratory events. We focus on neural crest cells, as they possess extraordinary migratory capabilities that allow them to migrate and colonize tissues all over the embryo. Neural crest cells undergo an epithelial-to-mesenchymal transition at the same time than perform directional collective migration. Cell-cell adhesion has been shown to be an important source of planar cell polarity and cell coordination during collective movement. We also review molecular mechanisms underlying cadherin turnover, showing how the modulation and dynamics of cell-cell adhesions are crucial in order to maintain tissue integrity and collective migration in vivo. We conclude that cell-cell adhesion during embryo development cannot be considered as simple passive resistance to force, but rather participates in signaling events that determine important cell behaviors required for cell migration. PMID- 25733145 TI - VE-cadherin in vascular development: a coordinator of cell signaling and tissue morphogenesis. AB - Blood and lymphatic vessels make up the vascular system of vertebrates and are lined by specialized endothelial cells. The connections between endothelial cells are formed by adhesion molecules and are essential to maintain cell-cell adhesion, cell-cell communication, and the integrity of our vascular tubes. One key adhesion molecule is the adherens junctional protein vascular endothelial cadherin (VE-cadherin). In addition to its role in endothelial adhesion, it is emerging that this protein is actively involved in modulating key cellular signaling cascades within endothelial cells and can control the behavior of endothelial cells during development and morphogenesis. We describe key studies that highlight VE-cadherin as a regulatory hub in endothelial cell signaling during angiogenesis, vessel morphogenesis, and vascular development. PMID- 25733140 TI - Nuclear signaling from cadherin adhesion complexes. AB - The arrival of multicellularity in evolution facilitated cell-cell signaling in conjunction with adhesion. As the ectodomains of cadherins interact with each other directly in trans (as well as in cis), spanning the plasma membrane and associating with multiple other entities, cadherins enable the transduction of "outside-in" or "inside-out" signals. We focus this review on signals that originate from the larger family of cadherins that are inwardly directed to the nucleus, and thus have roles in gene control or nuclear structure-function. The nature of cadherin complexes varies considerably depending on the type of cadherin and its context, and we will address some of these variables for classical cadherins versus other family members. Substantial but still fragmentary progress has been made in understanding the signaling mediators used by varied cadherin complexes to coordinate the state of cell-cell adhesion with gene expression. Evidence that cadherin intracellular binding partners also localize to the nucleus is a major point of interest. In some models, catenins show reduced binding to cadherin cytoplasmic tails favoring their engagement in gene control. When bound, cadherins may serve as stoichiometric competitors of nuclear signals. Cadherins also directly or indirectly affect numerous signaling pathways (e.g., Wnt, receptor tyrosine kinase, Hippo, NFkappaB, and JAK/STAT), enabling cell-cell contacts to touch upon multiple biological outcomes in embryonic development and tissue homeostasis. PMID- 25733146 TI - Adhesion in mammary development: novel roles for E-cadherin in individual and collective cell migration. AB - Epithelial tissues are essential for barrier function, secretion, and regulation of fluid transport. Their function requires cell polarity and cell-cell adhesion, mediated through intercellular junctions. Conversely, disruption of adhesion and polarity is thought to drive cancer progression. The mammary gland is an important model for cell adhesion due to its postnatal hormonally regulated development; ducts undergo branching morphogenesis in response to steroid hormones during puberty. These hormonal signals induce a transition from simple to stratified architecture, initiated by asymmetric luminal cell divisions. Ductal elongation is accomplished by this multilayered, low-polarity epithelium, and polarity is reestablished as elongation ceases. The requirement for cell adhesion has been tested in 3D culture and in vivo, using gene deletion, knockdown, and misexpression in both developmental and homeostatic contexts. Attention has focused on E-cadherin, the major classical cadherin in luminal epithelial cells. Classic studies revealed a requirement for E-cadherin during lactation, and E-cadherin loss is widely posited to promote metastasis. However, recent findings demonstrated a broader requirement for E-cadherin during branching morphogenesis and homeostasis and also, surprisingly, in epithelial dissemination. These studies suggest that long-standing models of the role of adhesion in epithelial biology need to be revisited. Advances in inducible gene expression and knockdown, CRISPR/Cas9 technology, and fluorescent labeling of genetically modified cells offer the opportunity to test the roles of diverse adhesion systems and to develop a mechanistic understanding of how cell adhesion regulates development and cancer. PMID- 25733147 TI - Cell adhesion in epidermal development and barrier formation. AB - Cell-cell adhesions are necessary for structural integrity and barrier formation of the epidermis. Here, we discuss insights from genetic and cell biological studies into the roles of individual cell-cell junctions and their composite proteins in regulating epidermal development and function. In addition to individual adhesive functions, we will discuss emerging ideas on mechanosensation/transduction of junctions in the epidermis, noncanonical roles for adhesion proteins, and crosstalk/interdependencies between the junctional systems. These studies have revealed that cell adhesion proteins are connected to many aspects of tissue physiology including growth control, differentiation, and inflammation. PMID- 25733149 TI - Cell-cell interactions driving kidney morphogenesis. AB - The mammalian kidney forms via cell-cell interactions between an epithelial outgrowth of the nephric duct and the surrounding nephrogenic mesenchyme. Initial morphogenetic events include ureteric bud branching to form the collecting duct (CD) tree and mesenchymal-to-epithelial transitions to form the nephrons, requiring reciprocal induction between adjacent mesenchyme and epithelial cells. Within the tips of the branching ureteric epithelium, cells respond to mesenchyme derived trophic factors by proliferation, migration, and mitosis-associated cell dispersal. Self-inhibition signals from one tip to another play a role in branch patterning. The position, survival, and fate of the nephrogenic mesenchyme are regulated by ECM and secreted signals from adjacent tip and stroma. Signals from the ureteric tip promote mesenchyme self-renewal and trigger nephron formation. Subsequent fusion to the CDs, nephron segmentation and maturation, and formation of a patent glomerular basement membrane also require specialized cell-cell interactions. Differential cadherin, laminin, nectin, and integrin expression, as well as intracellular kinesin and actin-mediated regulation of cell shape and adhesion, underlies these cell-cell interactions. Indeed, the capacity for the kidney to form via self-organization has now been established both via the recapitulation of expected morphogenetic interactions after complete dissociation and reassociation of cellular components during development as well as the in vitro formation of 3D kidney organoids from human pluripotent stem cells. As we understand more about how the many cell-cell interactions required for kidney formation operate, this enables the prospect of bioengineering replacement structures based on these self-organizing properties. PMID- 25733150 TI - Preface. Cellular adhesion in development and disease. PMID- 25733151 TI - Temporal and spatial distribution of young Brachyplatystoma spp. (Siluriformes: Pimelodidae) along the rapids stretch of the Madeira River (Brazil) before the construction of two hydroelectric dams. AB - Monthly (April 2009 to May 2010) bottom-trawl sampling for Brachyplatystoma species along the rapids stretch of the Madeira River in Brazil revealed that Brachyplatystoma rousseauxii larvae and juveniles were present in low abundances in all areas and during all hydrological periods. The presence of larvae and juveniles throughout the hydrological cycle suggests asynchronous spawning in the headwaters of the Madeira River. PMID- 25733153 TI - Distinct kinetics of molecular gelation in a confined space and its relation to the structure and property of thin gel films. AB - Thin films of molecular gels formed in a confined space have potential applications in transdermal delivery, artificial skin, molecular electronics, etc. The microstructures and properties of thin gel films can be significantly different from those of their bulk counterparts. However, so far a comprehensive understanding of the effects of spatial confinement on the molecular gelation kinetics, fiber network structure and related mechanical properties is still lacking. In this work, using rheological techniques, we investigated the effect of one-dimensional confinement on the formation kinetics of fiber networks in the molecular gelation process. Fractal analyses of the kinetic information in terms of an extended Dickinson model enabled us to describe quantitatively the distinct kinetic signature of molecular gelation. The structural features derived from gelation kinetics support well the fractal patterns of the fiber networks acquired by optical and electron microscopy. With the kinetics-structure correlation, we can gain an in-depth understanding of the confinement-induced differences in the structure and consequently the mechanical properties of a model molecular gelling system. Particularly, the confinement induced structural transition, from a three-dimensional, dense and compact spherulitic network composed of highly branched fibers to a quasi-two-dimensional sparse spherulitic network composed of less branched fibers and entangled fibrils at the boundary areas, renders a gel film to become less stiff but more ductile. Our study suggests here a new strategy of engineering the fiber network microstructure to achieve functional gel films with unusual but useful properties. PMID- 25733152 TI - Evaluation of 68Ga-labeled MG7 antibody: a targeted probe for PET/CT imaging of gastric cancer. AB - MG7-Ag, a specific gastric cancer-associated antigen, can be used to non invasively monitor gastric cancer by molecular imaging with positron emission tomography/computed tomography (PET/CT). In this study, we prepared and evaluated a (68)Ga-labeled MG7 antibody as a molecular probe for nanoPET/CT imaging of gastric cancer in a BGC-823 tumor xenografted mouse model. Macrocyclic chelator 1,4,7-triazacyclononane-N,N0,N00-triacetic acid (NOTA)-conjugated MG7 antibody was synthesized and radiolabeled with (68)Ga (t1/2 = 67.71 min). Then, (68)Ga NOTA-MG7 was tested using in vitro cytological studies, in vivo nanoPET/CT and Cerenkov imaging studies as well as ex vivo biodistribution and histology studies. The in vitro experiments demonstrated that (68)Ga-NOTA-MG7 has an excellent radiolabeling efficiency of approximately 99% without purification, and it is stable in serum after 120 min of incubation. Cell uptake and retention studies confirmed that (68)Ga-NOTA-MG7 has good binding affinity and tumor cell retention. For the nanoPET imaging study, the predominant uptake of (68)Ga-NOTA MG7 was visualized in tumor, liver and kidneys. The tumor uptake reached at its peak (2.53 +/- 0.28%ID/g) at 60 min pi. Cherenkov imaging also confirmed the specificity of tumor uptake. Moreover, the biodistribution results were consistent with the quantification data of nanoPET/CT imaging. Histologic analysis also demonstrated specific staining of BGC-823 tumor cell lines. PMID- 25733148 TI - Cadherin-based transsynaptic networks in establishing and modifying neural connectivity. AB - It is tacitly understood that cell adhesion molecules (CAMs) are critically important for the development of cells, circuits, and synapses in the brain. What is less clear is what CAMs continue to contribute to brain structure and function after the early period of development. Here, we focus on the cadherin family of CAMs to first briefly recap their multidimensional roles in neural development and then to highlight emerging data showing that with maturity, cadherins become largely dispensible for maintaining neuronal and synaptic structure, instead displaying new and narrower roles at mature synapses where they critically regulate dynamic aspects of synaptic signaling, structural plasticity, and cognitive function. At mature synapses, cadherins are an integral component of multiprotein networks, modifying synaptic signaling, morphology, and plasticity through collaborative interactions with other CAM family members as well as a variety of neurotransmitter receptors, scaffolding proteins, and other effector molecules. Such recognition of the ever-evolving functions of synaptic cadherins may yield insight into the pathophysiology of brain disorders in which cadherins have been implicated and that manifest at different times of life. PMID- 25733155 TI - The yin and yang of evasion and immune activation in HCC. AB - Current systemic treatment options for patients with hepatocellular carcinoma (HCC) are limited to sorafenib. With the recent FDA approval of the second PD1-PD L1 pathway inhibitor, immunotherapy has gained even more interest as a potential novel treatment option for patients with HCC. This is due not only because of the failure of other treatment approaches in the past, but also because immunological mechanisms have been shown to play an important role during tumor development, growth, and treatment. Here we present a review of immunological mechanisms in the liver relevant for tumor progression and treatment. We summarize our current knowledge on immune activating and immune suppressing mechanisms during tumor initiation, development, and treatment. We try to explain the paradox of how inflammatory responses in a setting of chronic infection promote tumor development, while the primary aim of immunotherapy is to activate immunity. Finally we summarize recent advances in addition to providing an outlook for the immunotherapy of HCC. PMID- 25733154 TI - Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids. AB - BACKGROUND & AIMS: Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. METHODS: Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. RESULTS: Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARalpha-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. CONCLUSIONS: AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. PMID- 25733156 TI - Hepatitis C virus-mediated Aurora B kinase inhibition modulates inflammatory pathway and viral infectivity. AB - BACKGROUND & AIMS: Chronic hepatitis C is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. DNA methylation and histone covalent modifications constitute crucial mechanisms of genomic instability in human disease, including liver fibrosis and hepatocellular carcinoma. The present work studies the consequences of HCV-induced histone modifications in early stages of infection. METHODS: Human primary hepatocytes and HuH7.5 cells were transiently transfected with the core protein of hepatitis C virus (HCV) genotypes 1a, 1b, and 2a. Infectious genotype 2a HCV in culture was also used. RESULTS: We show that HCV and core protein inhibit the phosphorylation of Serine 10 in histone 3. The inhibition is due to the direct interaction between HCV core and Aurora B kinase (AURKB) that results in a decrease of AURKB activity. HCV and core significantly downregulate NF-kappaB and COX-2 transcription, two proteins with anti-apoptotic and proliferative effects implicated in the control of the inflammatory response. AURKB depletion reduced HCV and core repression of NF kappaB and COX-2 gene transcription and AURKB overexpression reversed the viral effect. AURKB abrogation increased HCV specific infectivity which was decreased when AURKB was overexpressed. CONCLUSIONS: The core-mediated decrease of AURKB activity may play a role in the inflammatory pathway during the initial steps of viral infection, while ensuring HCV infectivity. PMID- 25733157 TI - The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. AB - BACKGROUND & AIMS: GS-9620 is an oral agonist of toll-like receptor 7, a pattern recognition receptor whose activation results in innate and adaptive immune stimulation. We evaluated the safety, pharmacokinetics, and pharmacodynamics of GS-9620 in patients with chronic hepatitis B. METHODS: In two double-blind, phase 1b trials of identical design, 49 treatment-naive and 51 virologically suppressed patients were randomized 5:1 to receive GS-9620 (at doses of 0.3mg, 1mg, 2mg, 4mg) or placebo as a single dose or as two doses seven days apart. Pharmacodynamic assessment included evaluation of peripheral mRNA expression of interferon-stimulated gene 15 (ISG15), serum interferon gamma-induced protein 10 and serum interferon (IFN)-alpha. RESULTS: Overall, 74% of patients were male and 75% were HBeAg negative at baseline. No subject discontinued treatment due to adverse events. Fifty-eight percent experienced ?1 adverse event, all of which were mild to moderate in severity. The most common adverse event was headache. No clinically significant changes in HBsAg or HBV DNA levels were observed. Overall, a transient dose-dependent induction of peripheral ISG15 gene expression was observed peaking within 48 hours of dosing followed by return to baseline levels within seven days. Higher GS-9620 dose, HBeAg positive status, and low HBsAg level at baseline were independently associated with greater probability of ISG15 response. Most patients (88%) did not show detectable levels of serum IFN-alpha at any time point. CONCLUSIONS: Oral GS-9620 was safe, well tolerated, and associated with induction of peripheral ISG15 production in the absence of significant systemic IFN-alpha levels or related symptoms. PMID- 25733158 TI - Adaptive Functioning in Autism Spectrum Disorder During the Transition to Adulthood. AB - There is a dearth of research regarding adaptive functioning during the transition to adulthood in autism spectrum disorder (ASD). Profiles on the Vineland Adaptive Behavior Scales, Second Edition were examined by age and intellectual ability in 75 participants with ASD (16-58 years). Results extend previous reports of a cognitive advantage over adaptive functioning in children by demonstrating a similar pattern in an older sample. Daily living skills were a relative strength compared to communication and socialization in adults, but not adolescents. In general, highest subdomain scores were observed in writing skills and lowest scores were observed in interpersonal skills. Regardless of cognitive ability, all standard scores were well below average, indicating a need for lifelong intervention that targets adaptive functioning. PMID- 25733159 TI - Attentional Learning Helps Language Acquisition Take Shape for Atypically Developing Children, Not Just Children with Autism Spectrum Disorders. AB - The shape bias-generalising labels to same shaped objects-has been linked to attentional learning or referential intent. We explore these origins in children with typical development (TD), autism spectrum disorders (ASD) and other developmental disorders (DD). In two conditions, a novel object was presented and either named or described. Children selected another from a shape, colour or texture match. TD children choose the shape match in both conditions, children with DD and 'high-verbal mental age' (VMA) children with ASD (language age > 4.6) did so in the name condition and 'low-VMA' children with ASD never showed the heuristic. Thus, the shape bias arises from attentional learning in atypically developing children and is delayed in ASD. PMID- 25733160 TI - Student Engagement in the Classroom: The Impact of Classroom, Teacher, and Student Factors. AB - Researchers have highlighted engagement as a critical component of effective interventions for students with autism spectrum disorder (ASD), yet there is limited research related to engagement in school-age children with ASD. This descriptive study was designed to examine joint engagement and its relationship with classroom factors and student characteristics. The sample included 25 elementary and middle school students with ASD. Mixed level modeling was used to examine relationships between joint engagement and classroom factors and student characteristics. Joint engagement was significantly related to group size, use of student-directed practices, autism severity, and expressive communication skills. These findings have important implications for educational policies and practices and future research related to engagement and effective interventions for students with ASD. PMID- 25733161 TI - X-ray crystallographic and kinetic investigations of 6-sulfamoyl-saccharin as a carbonic anhydrase inhibitor. AB - 6-Sulfamoyl-saccharin was investigated as an inhibitor of 11 alpha-carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, hCA I-XIV, and X-ray crystallographic data were obtained for its adduct with hCA II, the physiologically dominant isoform. This compound possesses two potential zinc binding groups, the primary sulfamoyl one and the secondary, acylatedsulfonamide. Saccharin itself binds to the Zn(II) ion from the CA active site coordinating with this last group, in deprotonated (SO2N(-)CO) form. Here we explain why 6 sulfamoyl-saccharin, unlike saccharin, binds to the metal ion from the hCA II active site by its primary sulfonamide moiety and not the secondary one as saccharin itself. Our study is useful for shedding new light to the structure based drug design of isoform-selective CA inhibitors of the sulfonamide type. PMID- 25733163 TI - Role of transcriptional regulation in the evolution of plant phenotype: A dynamic systems approach. AB - A growing body of evidence suggests that alterations in transcriptional regulation of genes involved in modulating development are an important part of phenotypic evolution, and this can be documented among species and within populations. While the effects of differential transcriptional regulation in organismal development have been preferentially studied in animal systems, this phenomenon has also been addressed in plants. In this review, we summarize evidence for cis-regulatory mutations, trans-regulatory changes and epigenetic modifications as molecular events underlying important phenotypic alterations, and thus shaping the evolution of plant development. We postulate that a mechanistic understanding of why such molecular alterations have a key role in development, morphology and evolution will have to rely on dynamic models of complex regulatory networks that consider the concerted action of genetic and nongenetic components, and that also incorporate the restrictions underlying the genotype to phenotype mapping process. Developmental Dynamics 244:1074-1095, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25733162 TI - Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. AB - This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade >= 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (>=10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15 plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887. PMID- 25733164 TI - Nutrient patterns and their relation to general and abdominal obesity in Iranian adults: findings from the SEPAHAN study. AB - BACKGROUND: Few studies have linked major dietary nutrient patterns to chronic diseases. Despite the growing evidence of associations between dietary patterns and obesity, we are aware of no study that examined the association between patterns of nutrient intake and obesity. OBJECTIVE: To identify major nutrient patterns in Iranian adults and investigate their association with general and abdominal obesity. METHODS: In this cross-sectional study that was conducted under the framework of the Study on the Epidemiology of Psychological Alimentary Health and Nutrition (SEPAHAN), dietary data were collected using a validated dish-based 106-item semi-quantitative food frequency questionnaire in 8691 subjects aged 18-55 years. Complete data of 6724 and 5203 adults were available for general and abdominal obesity, respectively. Data on anthropometric measures were collected through a self-administered questionnaire. General obesity was defined as body mass index >= 30 kg/m(2), and abdominal obesity as waist circumference > 102 cm for men and >88 cm for women. Daily intakes of 38 nutrients and bioactive compounds were calculated for each participant. Factor analysis, followed by a varimax rotation, was applied to derive major nutrient patterns. RESULTS: Three major nutrient patterns were identified: (1) The first pattern was high in fatty acids (including saturated, monounsaturated and polyunsaturated fatty acids), cholesterol, vitamin B12, vitamin E, zinc, choline, protein, pyridoxine, phosphorus and pantothenic acid; (2) the second pattern was high in thiamine, betaine, starch, folate, iron, selenium, niacin, calcium, and manganese; and (3) the third pattern was high in glucose, fructose, sucrose, vitamin C, potassium, total dietary fiber, copper and vitamin K. Men in the highest quintile of the second pattern were less likely to be generally obese in the fully adjusted model [odds ratio (OR) 0.39, 95 % confidence interval (CI) 0.20-0.76]. After adjustment for potential confounders, a significant positive association was observed between the third pattern and general obesity among men (OR 1.77, 95 % CI 1.04-3.04), but not women (OR 1.18, 95 % CI 0.74-1.88). No overall association was seen between patterns of nutrient intake and abdominal obesity in both genders. CONCLUSION: Major nutrient patterns were significantly associated with general, but not abdominal obesity among male participants of the SEPAHAN study. Further studies in other populations, along with future prospective studies, are required to confirm these findings. PMID- 25733166 TI - The value of Retrospective and Concurrent Think Aloud in formative usability testing of a physician data query tool. AB - OBJECTIVE: To compare the performance of the Concurrent (CTA) and Retrospective (RTA) Think Aloud method and to assess their value in a formative usability evaluation of an Intensive Care Registry-physician data query tool designed to support ICU quality improvement processes. METHODS: Sixteen representative intensive care physicians participated in the usability evaluation study. Subjects were allocated to either the CTA or RTA method by a matched randomized design. Each subject performed six usability-testing tasks of varying complexity in the query tool in a real-working context. Methods were compared with regard to number and type of problems detected. Verbal protocols of CTA and RTA were analyzed in depth to assess differences in verbal output. Standardized measures were applied to assess thoroughness in usability problem detection weighted per problem severity level and method overall effectiveness in detecting usability problems with regard to the time subjects spent per method. RESULTS: The usability evaluation of the data query tool revealed a total of 43 unique usability problems that the intensive care physicians encountered. CTA detected unique usability problems with regard to graphics/symbols, navigation issues, error messages, and the organization of information on the query tool's screens. RTA detected unique issues concerning system match with subjects' language and applied terminology. The in-depth verbal protocol analysis of CTA provided information on intensive care physicians' query design strategies. Overall, CTA performed significantly better than RTA in detecting usability problems. CTA usability problem detection effectiveness was 0.80 vs. 0.62 (p<0.05) respectively, with an average difference of 42% less time spent per subject compared to RTA. In addition, CTA was more thorough in detecting usability problems of a moderate (0.85 vs. 0.7) and severe nature (0.71 vs. 0.57). CONCLUSION: In this study, the CTA is more effective in usability-problem detection and provided clarification of intensive care physician query design strategies to inform redesign of the query tool. However, CTA does not outperform RTA. The RTA additionally elucidated unique usability problems and new user requirements. Based on the results of this study, we recommend the use of CTA in formative usability evaluation studies of health information technology. However, we recommend further research on the application of RTA in usability studies with regard to user expertise and experience when focusing on user profile customized (re)design. PMID- 25733165 TI - Virgin olive oil rich in phenolic compounds modulates the expression of atherosclerosis-related genes in vascular endothelium. AB - PURPOSE: Previous studies have shown the anti-inflammatory and antioxidant properties of phenolic compounds of virgin olive oil (VOO). However, the effect of bioavailable phenolic compounds on the vascular endothelium is unknown. We aimed to evaluate the effect of the consumption of virgin olive oil rich in phenolic compounds on the vascular endothelium. METHODS: We treated HUVEC with human serum obtained in fasting state and after the intake of a breakfast prepared with VOO with a high or low content of phenolic compounds. RESULTS: Treatment of HUVEC with serum obtained 2 h after the intake of the high-phenol VOO-based breakfast decreased p65 and MCP-1 gene expression (p < 0.001 and p = 0.002, respectively) and increased MT-CYB, SDHA and SOD1 gene expression (p = 0.004, p = 0.012 and p = 0.001, respectively), as compared with the treatment of HUVEC with the serum obtained 2 h after the intake of the low-phenol VOO-based breakfast. The treatment with serum obtained 4 h after the intake of the high phenol VOO-based breakfast decreased MCP-1 and CAT gene expression (p < 0.001 and p = 0.003, respectively) and increased MT-CYB gene expression (p < 0.001), as compared to the treatment with serum obtained 4 h after the intake of the low phenol VOO-based breakfast. CONCLUSION: Our results suggest that the consumption of virgin olive oil rich in phenolic compounds may reduce the risk of atherosclerosis development by decreasing inflammation and improving the antioxidant profile in the vascular endothelium. PMID- 25733168 TI - Optical coherence tomography: guided primary percutaneous coronary intervention in acute myocardial infarction. A bridge too far? PMID- 25733167 TI - IL10 receptor is a novel therapeutic target in DLBCLs. AB - Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs. PMID- 25733169 TI - The relationship between serum uric acid levels and angiographic severity of coronary heart disease. AB - BACKGROUND: Many studies have shown that the serum uric acid (SUA) level is associated with atherosclerosis. AIM: To determine the relationship between the SUA level and the presence and severity of coronary heart disease (CHD). METHODS: A total of 705 patients who underwent coronary angiography were included in this study. All patients were assessed for the presence of cardiovascular risk factors and ongoing medications. SUA levels were measured in all patients before the procedure after 12 h of fasting. The severity of CHD was assessed by the SYNTAX score. The independent association between the SUA and the severity of CHD was statistically evaluated using IBM SPSS Statistics 21 for Windows. RESULTS: The mean age of the study population was 60.2 +/- 11.0 years. 252 were female (35.7%) and 453 were male (64.3%). Of the patients, 59.0% had significant CHD, 34.6% had diabetes mellitus, 67.7% had hypertension, 55.3% had hyperlipidaemia, and 45.4% were current smokers. The mean SYNTAX score was 10.6 +/- 12.9. According to the SYNTAX score, 289 of the patients (41%) had normal coronary arteries and non significant CHD (controls, SYNTAX score: 0), 236 of the patients (33.5%) had mild CHD (SYNTAX score: 1-22), 97 (13.8%) had moderate CHD (SYNTAX score: 23-32), and 83 (11.8%) had severe CHD (SYNTAX score: >= 33). The mean SUA values were 5.3 +/- 1.5 mg/dL in the control group, 5.6 +/- 1.4 mg/dL in the mild CHD group, 6.2 +/- 1.6 mg/dL in the moderate CHD group, and 6.5 +/- 1.7 mg/dL in the severe CHD group. According to Spearman's rho analysis, a positive correlation between the SUA levels and the SYNTAX score was determined to be statistically significant (p < 0.001, r = 0.239; p = 0.002, r = 0.148 in men; p = 0.001, r = 0.204 in women). CONCLUSIONS: In this study, we found a positive correlation between the SUA level and the SYNTAX score. Therefore, this routine biochemical test can be used for the evaluation of the severity of CHD besides other risk factors in clinical practice. However, larger scale randomised studies are needed to show the effects of SUA on the severity of CHD. PMID- 25733170 TI - The relationship between epicardial fat tissue thickness and frequent ventricular premature beats. AB - BACKGROUND: Ventricular premature beats (VPBs) are one of the most common rhythm abnormalities. Structural heart diseases such as myocardial hypertrophy and left ventricular dysfunction are associated with VPBs. However, the exact mechanism of VPBs in patients without structural heart disease has not been revealed yet. Epicardial fat tissue (EFT) is a visceral fat around the heart. Increased EFT thickness is associated with myocardial structural and ultrastructural myocardial abnormalities, which may play a role in the development of VPBs. AIMS: To evaluate the possible relationship between EFT thickness and frequent VPBs. METHODS AND RESULTS: The study population consisted of 50 patients with VPBs and 50 control subjects. Frequent VPBs were defined as the presence of more than 10 beats per hour assessed by 24-h Holter electrocardiography monitoring. EFT thickness was measured by transthoracic echocardiography. Multivariable logistic regression analysis was used to assess factors related with frequent VPBs. Baseline demographic and biochemical features including age, gender, and rates of hypertension and diabetes mellitus were similar in both groups. EFT thickness was significantly higher in patients with frequent VPBs than in controls (3.3 +/- 1.3 mm vs. 2.2 +/- 0.8 mm, p < 0.001). In multivariable logistic regression analysis, EFT thickness was independently associated with VPB frequency (B = 1.030, OR = 2.802, p < 0.001). CONCLUSIONS: Patients with frequent VPBs had increased EFT thickness compared to control subjects. EFT thickness was independently associated with frequent VPBs. PMID- 25733171 TI - In-tunnel closure of patent foramen ovale with a FlatStent EFTM. AB - BACKGROUND: Devices for percutaneous closure of patent foramen ovale (PFO) are traditionally based on two opposing discs, leaving significant surface areas exposed in the left and right atrium. The FlatStent EFTM PFO Closure System (Coherex Inc., Salt Lake City, USA) represents a major departure from these devices because it is designed to focus primarily on the PFO tunnel, leaving minimal foreign material behind. AIM: To investigate the patient selection, effectiveness, and safety of in-tunnel closure with a FlatStent EFTM in patients with PFO of >= 4 mm tunnel length and < 12 mm diameter at preprocedural transoesophageal echocardiography (TEE). RESULTS: Among 46 consecutive patients undergoing PFO closure, a FlatStent EFTM could be implanted and resulted in initial successful closure (< 5 bubbles during Valsalva manoeuvre) in 21 (46%) patients. TEE at 162 +/- 40 and 317 +/- 162 days after implantation demonstrated functional closure in 90% and 95% of cases, respectively. No device or air embolisation, pericardial effusion, or thrombus formation was documented. Small in-tunnel peri-device colour Doppler left to right flow was documented in 10% and 2-6 mm protrusion of FlatStent EFTM along right atrial septum without any residual flow/bubble shunting in 14%. Patients with suboptimal closure (> 5 bubbles during Valsalva manoeuvre and/or in-tunnel colour flow) had shorter tunnel on preprocedural TEE (5.3 +/- 1.5 vs. 10.8 +/- 3.5 mm; p = 0.003). There was no difference in TEE diameter (1.8 +/- 0.5 vs. 2.0 +/- 0.5 mm; p = 0.38) and stretched diameter by sizing balloon (6.3 +/- 2.5 vs. 6.3 +/- 1.0 mm; p = 1.00). CONCLUSIONS: In-tunnel PFO closure with a FlatStent EFTM represents an effective and safe option only in carefully selected patients with long tunnel (> 4 mm) regardless of the diameter if it is < 12 mm. These criteria are fulfilled in < 50% of consecutive candidates for PFO closure. The new phenomenon of in-tunnel peri-device flow and FlatStent EFTM protrusion along the right atrial septum were documented during systematic TEE follow up. PMID- 25733172 TI - Atrial conduction abnormalities in patients with psoriasis vulgaris. AB - BACKGROUND: Psoriasis vulgaris is one of the most common chronic inflammatory skin disorders. Patients with psoriasis are at risk of developing atrial fibrillation (AF). The electromechanical delay (EMD) is the time interval from the onset of the P wave on surface electrocardiography (ECG) to the beginning of the A wave. Prolonged atrial EMD is an independent risk factor for the development of AF. AIM: This study investigated the intra- and interatrial EMD in patients with psoriasis. METHODS: This study included 85 adults with psoriasis vulgaris (Group 1) and 46 age- and sex-matched healthy individuals (Group 2). ECGs were obtained from all subjects, and atrial EMD variables were calculated. Results are reported as means +/- standard deviations and percentages. Continuous variables were analysed using Student's t-test. A p-value < 0.05 was considered statistically significant. RESULTS: Interatrial electromechanical delay (IA-EMD) and intra-left atrial electromechanical delay (ILA-EMD) were significantly longer in the psoriasis group compared with controls. A correlation analysis between psoriasis severity (PASI score) and the atrial conduction parameters revealed a significant positive correlation between PASI and IA-EMD (r = 0.261, p < 0.001). In addition, there was a positive correlation between high-sensitivity C-reactive protein (hsCRP) and IA-EMD (p = 0.022). CONCLUSIONS: The atrial conduction time was longer in patients with psoriasis vulgaris and it correlated with the severity of disease and hsCRP. Since the association between delayed conduction and AF is known, the measurement of intra-atrial conduction times could be a practical tool to estimate the AF risk in these patients. PMID- 25733173 TI - Ultrasound evaluation of forearm arteries in patients undergoing percutaneous coronary intervention via radial artery access: results of one-year follow-up. AB - BACKGROUND: A proven advantage of radial over femoral arterial access has led to an increase in the number of interventions performed via radial artery access in patients with acute coronary syndromes. Both assessment of the pulse volume and the Allen's test are subjective and subject to investigator bias. An ultrasound examination of the forearm arteries provides important information about the anatomy of the forearm vessels, and indirectly also about the efficiency of collateral blood supply to the hand. It also enables determination of the relevant vessel diameter before the planned intervention, and may be used to assess local complications. AIM: To assess the morphology of forearm blood vessels and measure the diameter of both radial and ulnar arteries at the cannulation site using ultrasound imaging. We also aimed to identify potential vascular anomalies and local complications associated with radial artery puncture. METHODS: The study included 109 patients with cardiologic indications for coronary angiography or coronary angioplasty. An ultrasound evaluation of forearm arteries was performed prior to the intervention, and the vascular anatomy was later verified by angiography during the procedure. Ultrasound measurements of the vessel diameter were also performed and local complications of the cannulation were assessed. Measurements were performed immediately after the procedure and at 30 days and 12 months. RESULTS: Fifty-nine right and 50 left forearm arteries were evaluated. Women were 29% of the study population. The mean patient age was 59.2 +/- 7.9 years. The mean diameter of the right radial artery was 2.17 +/- 0.54 mm, and the mean diameter of the left radial artery was 2.25 +/ 0.43 mm. The measurements revealed gender-related differences in forearm artery diameter (p = 0.003). Vascular anomalies of the radial artery were identified by ultrasound examination in 10% of subjects. A significant dilatation of the cannulated blood vessel was observed which lasted up to 12 months. An occlusion of the cannulated artery was demonstrated in 6.4% of patients. CONCLUSIONS: Ultrasound imaging is a reliable method to evaluate the diameter of forearm arteries and track their course in patients undergoing invasive cardiovascular procedures via radial artery access. The diameter of the radial artery by ultrasound evaluation is larger compared to that of the ulnar artery. The diameter of forearm arteries in women is smaller compared to men. A dilatation of the radial artery which may last up to 12 months develops following its percutaneous cannulation. Ultrasound imaging allows detection and monitoring of local complications such as radial artery occlusion. An unfavourable ratio of blood vessel diameter to the size of the used introducer sheath is a predictor of radial artery occlusion. Ultrasound imaging enables reliable evaluation of vascular anomalies involving the radial artery, especially within the distal forearm. PMID- 25733174 TI - The role of GRACE score in the prediction of high-risk coronary anatomy in patients with non-ST elevation acute coronary syndrome. AB - BACKGROUND: In patients with non-ST elevation acute coronary syndrome (NSTE-ACS), identification of the patients with high-risk coronary anatomy (HRCA) who are most likely to require coronary artery bypass grafting (CABG) is crucial. The SYNTAX score (SXscore) is an angiographic grading tool designed to determine the complexity of coronary artery disease. It appears that CABG offers significantly better outcomes in patients with SXscore >= 33, which shows severe HRCA. AIM: We sought to assess the accuracy of the GRACE score in predicting HRCA in terms of SXscore in patients with NSTE-ACS. METHODS: Patients admitted to our coronary unit with a diagnosis of NSTE-ACS and undergoing coronary angiography during hospitalisation were recruited to this study. Patients were categorised into two groups based on SXscore: HRCA (SXscore >= 33) and low-risk coronary anatomy (LRCA, SXscore < 33). The cut-off level of GRACE score for HRCA was established by receiver operator characteristic (ROC) analysis. RESULTS: We studied 207 consecutive patients (mean age: 59 +/- 11 years, 27.5% female). The GRACE score was 139 +/- 34 in the HRCA group and 114 +/- 33 in the LRCA group (p = 0.001). There was a significant positive correlation between SXscore and GRACE score (r = 0.338, p < 0.001). The area under ROC curve for GRACE score was 0.71 (95% CI 0.60 0.81, p = 0.001). A GRACE score of 123 was identified as the optimal cut-off to predict HRCA with a sensitivity of 71% and a specificity of 60%. In multivariate regression analysis, GRACE score >= 123 was the only variable that identified HRCA (OR 2.8, 95% CI 1.18-6.6, p = 0.019).Conclusions: Our study demonstrates that, in the setting of NSTE-ACS, patients with HRCA, who are most likely to require CABG, have higher GRACE scores at presentation. However, the ability of GRACE score to predict HRCA was modest. PMID- 25733175 TI - Stent length is a contributing factor of suboptimal stent expansion in drug eluting stents. AB - BACKGROUND: Failure to achieve optimal stent expansion poses a risk of treatment failure in percutaneous coronary intervention (PCI). Although intravascular ultrasound provides useful information for suboptimal stent expansion, a substantial portion of PCIs are currently being performed under angiographic guidance only. AIM: In order to evaluate the adequacy of stent expansion of four widely used drug-eluting stents in angiography-guided PCI, we performed a retrospective analysis of lesions undergoing PCI using quantitative coronary angiography. METHODS: A total of 112 de novo lesions were analysed. Minimal lumen diameter (MLD) was measured at peak pressure during stent deployment (MLD1), after stent deployment (MLD2), and after postdilatation (MLD3). Stent underexpansion, stent elastic recoil, and stent deficit were calculated. Optimal stent deployment was defined as final MLD >= 90% of predicted diameter. RESULTS: For deploying a stent balloon, higher than nominal pressure was used in 83% of cases (93/112). However, optimal deployment was observed in only 32% (36/112). Adjuvant post-dilatation was performed in 59% (45/76) of lesions with suboptimal expansion, which increased the optimal deployment rate by 60% (27/45). Final optimal stent deployment rate was achieved in 56% (63/112). We found that the MLD1 (p = 0.04), MLD3 (p = 0.02), final MLD (p = 0.04), and optimal stent deployment rate (p = 0.036) were significantly reduced in longer stent deployment lesions (>= 20 mm) compared to shorter lesions (< 20 mm). CONCLUSIONS: Stent length may be a contributing factor of suboptimal stent expansion in angiography guided PCI. PMID- 25733176 TI - Do left atrial strain and strain rate reflect intrinsic atrial function, or are they determined by left ventricular function? AB - BACKGROUND: Left atrial (LA) strain (S) and strain rate (SR) are reported as measures of intrinsic function. AIM: Since the LA and left ventricle (LV) are connected through the mitral annulus, we investigated: (1) if deformation indices in the LA are mostly predicted by deformation of the LV; (2) if timings of S and SR events are similar in both the LA and LV; and (3) if alteration of S and SR in patients with primarily LV dysfunction would be similar in the LA and LV. METHODS: We retrospectively assessed 50 asymptomatic women (Group 1) and 20 patients with recent (< 96 h) acute pulmonary oedema (10 women) (Group 2). Using speckle tracking, the amplitude and timings of S and SR were averaged from three apical views, for one cardiac cycle, starting from the P-wave. RESULTS: In Group 1, all deformation indices were higher in the LA compared with the LV (p < 0.001 for all). In Group 2, S and SR during LA contraction were higher in the LA vs. LV (p < 0.05 for both), but all other deformation indices were not different in the LA vs. LV. All timings of S and SR occurred simultaneously in LA and LV in both groups, except S during LA contraction in Group 1, which occurred slightly earlier in LA than in LV. By multiple regression analysis, the most important predictors of LA deformation indices were the corresponding LV deformation indices, especially in patients with LV dysfunction (Group 1: r = 0.35-0.52; Group 2: r = 0.76-0.85; p < 0.05 by Fisher r-to-z transform). CONCLUSIONS: LA deformation strongly reflects LV deformation both in asymptomatic subjects and in patients with LV dysfunction. With the possible exception of LA contraction in asymptomatic individuals, discriminating intrinsic LA function from LV influence is difficult using deformation analysis. PMID- 25733177 TI - Lower limb pneumatic compression during dobutamine stress echocardiography in patients with normal resting wall motion: will it increase diagnostic accuracy? AB - BACKGROUND: Pneumatic compression of the lower part of the body increases systemic vascular resistance and left ventricular afterload. AIM: We compared the diagnostic accuracy of dobutamine stress echocardiography (DSE) with pneumatic compression of the lower extremities, vs. standard DSE, for detection of angiographically significant coronary artery disease (CAD) in patients with normal baseline resting wall motion. METHODS: We enrolled 70 consecutive patients with no resting wall motion abnormalities (WMA), who underwent DSE. DSE was repeated with pneumatic compression of the lower extremities three days after the initial standard DSE. A positive test was defined as the induction of WMA in at least two contiguous non-overlap segments at any stage of dobutamine infusion. Significant coronary stenosis was defined as >= 50% obstruction of >= 1 sizable artery by coronary angiography. RESULTS: The mean age of the study cohort was 54.7 +/- 9.9 years; 55.7% were females. Thirty-eight (54.3%) patients had significant CAD. The mean test duration was 15.8 +/- 5.1 min for standard DSE and 11.7 +/- 4.1 min for DSE with pneumatic compression. Analysis of standard DSE revealed sensitivity, specificity, and positive and negative predictive values of 81.6%, 90.6%, 91.2%, and 80.6%, respectively; overall accuracy was 85.7%. Analysis of DSE with pneumatic compression revealed sensitivity, specificity, and positive and negative predictive values of 89.5%, 87.5%, 89.5%, and 87.5%, respectively; overall accuracy was 88.6%. CONCLUSIONS: In symptomatic patients with suspected CAD referred for evaluation by DSE, who have no resting wall motion abnormalities, pneumatic compression of the lower extremities during DSE improved the sensitivity but slightly reduced the specificity for detection of angiographically significant CAD, compared with standard DSE. Moreover, it reduced the test duration. PMID- 25733178 TI - Temporal trends and patterns in percutaneous treatment of coronary artery disease in Poland in the years 2005-2011. AB - BACKGROUND: According to a recent survey, Poland is one of the leaders of interventional cardiology in Europe in terms of the number of primary percutaneous coronary intervention (PCI) procedures per million inhabitants. AIM: To present temporal trends in epidemiology, demographics, treatment, and periprocedural outcome of patients referred for percutaneous coronary angiography and angioplasty in Poland in 2005-2011, based on the Polish National PCI Registry. METHODS: Patients who underwent percutaneous coronary angiography (ANGIO group) and/or angioplasty (PCI group) were included in the Polish National PCI Registry - a prospective observational registry study in Poland. RESULTS: There were 935,429 patients in the ANGIO group and 501,117 in the PCI group in Poland in 2005-2011. The number of catheterisation labs increased from 75 to 137, angiography procedures rose from 99,195 to 180,935, and PCIs from 50,297 to 99,614. The procedural mortality and stroke rates for the ANGIO group have remained stable whereas for the PCI group procedural mortality has increased over the years. The use of drug eluting stents (DESs) rose from 32.8% to 55.3% in stable angina and the use of a radial approach from 26.8% to 39.1%. CONCLUSIONS: Use of modern attributes of interventional cardiology like DES stents, radial approach, and treatment of higher risk patients has increased in Poland in 2005 2011. The adoption of the "Stent for Life" initiative has resulted in an increasing number of percutaneous coronary procedures over the years. PMID- 25733179 TI - Periprocedural checklist in the catheterisation laboratory is associated with decreased rate of treatment complications. AB - BACKGROUND: Interventional cardiology and electrophysiology are disciplines with a growing number of complex procedures, which are exposed to the occurrence of many complications. AIM: To assess efficacy and legitimacy of the periprocedural checklist in prevention of cardiovascular adverse events, in elective patients undergoing invasive diagnostic and treatment. METHODS: A total of 2064 patients directed to treatment in the catheterisation laboratory between May 2011 to August 2012 were analysed. Patients who were hospitalised without invasive diagnostics and treatment were not included in the study. Patients were divided into two groups: a control group - 1011 patients with invasive diagnostics and treatment before introduction of periprocedural checklist; and an intervention group - 1053 patients with invasive diagnostics and treatment after introduction of periprocedural checklist. We analysed the studied groups, assessing adverse events associated with hospitalisation and performed procedures. We also conducted subjective evaluation of checklists by medical staff on the basis of a questionnaire. RESULTS: Baseline characteristics between the studied groups were comparable except for a higher rate of stable coronary artery disease (50.7% vs. 39.6%, p L 0.001) and electrophysiology procedures in the control group. Implementation of a checklist was favourable in cases of decreased adverse events (6.8% vs. 3.9%, p = 0.004) especially bleedings (2.3% vs. 0.3%, p < 0.001). Multivariate analysis confirmed that lack of a periprocedural checklist during hospitalisation was an independent factor associated with a higher rate of adverse events (OR = 2.97, 95% CI 1.60-5.53, p = 0.001). Subjective evaluation of medical staff opinions showed that implementation of a checklist seems to be associated with improved communication skills, work organisation, prevention of the occurrence of medical errors, and reduced rate of complications associated with procedures. CONCLUSIONS: Introduction of a periprocedural checklist was associated with significant reduction of adverse events among patients undergoing invasive procedures. It also showed a positive influence on team communication, and organisation and quality of treatment, according to the opinions of medical staff. PMID- 25733180 TI - The evaluation of stress coping styles and type D personality in patients with coronary artery disease. AB - BACKGROUND: The relationship between depression and heart disease is very complex. In the group of patients with depression the coronary artery disease risk factors related to lifestyle (lack of physical activity, smoking, hypertension, and diabetes) are frequently observed. For many years, researchers have been interested in the relationship between personality and the tendency to collapse on somatic disorders. The result of this research was to create the concept of type D personality, which is formed by two dimensions: negative emotionality and social inhibition. These features have their reflection in many aspects of life, including in stressful situations. AIM: The prime goal of the study was to evaluate the prevalence of type D personality and dominant styles of coping with stress for patients with coronary artery disease. The study also tried to determine the correlation between the presence of type D personality and style of coping with stress in the examined group. METHODS: The studied group consistent of 100 patients (70 men and 30 women) with coronary heart disease. Patients were examined with the Type D Scale (DS14) and the Coping Inventory for Stressful Situations Questionnaire (CISS). RESULTS: Type D personality was found in 54% of cases for men and 47% for women. Distribution of type D personality did not differ for women and men. Analysis of the correlation between coping style in difficult situations and type D personality did not show that people with type D personality significantly more often chose a specific style of coping. CONCLUSIONS: Type D personality was found in 52% patients with stable coronary artery disease. Similar scores were observed for men and women. There was no evidence that patients with type D personality prefer a specific style of coping with stress. PMID- 25733181 TI - Branched dimerization of Tat peptide improves permeability to HeLa and hippocampal neuronal cells. AB - A dimeric branched peptide TATp-D designed as an analogue of the HIV-Tat protein transduction domain (TATp), a prototypical cell penetrating peptide (CPP), demonstrates significantly enhanced cell uptake at 0.25 to 2.5 MUM. Live cell confocal laser scanning microscopy revealed that multivalency dramatically improved the permeation potency of TATp-D to HeLa and primary hippocampal neuronal cells. The observed enhanced ability of TATp-D to translocate through the membrane is highlighted by a non-linear dependence on concentration, exhibiting the greatest uptake at sub-micromolar concentrations as compared to TATp. Multimerization via bis-Fmoc Lysine offered a synthetically straightforward method to investigate the effects of multivalent CPPs while offering orthogonal handles for cargo attachment, increasing the utility of CPPs at significantly lower concentrations. PMID- 25733182 TI - Urachal bladder in kidney transplanted patient with Prune Belly syndrome and patent urachus. PMID- 25733183 TI - Down-regulation of specific plastid ribosomal proteins suppresses thf1 leaf variegation, implying a role of THF1 in plastid gene expression. AB - Chloroplast development is regulated by many biological processes. However, these processes are not fully understood. Leaf variegation mutants have been used as powerful models to elucidate the genetic network of chloroplast development since the degree of leaf variegation is regulated by developmental and environmental cues. The thylakoid formation 1 (thf1) mutant is unique for its variegation in both leaves and cotyledons. Here, we reported a new suppressor gene of thf1 leaf variegation, designated sot8. Map-based cloning and DNA sequencing results showed that a single nucleotide mutation from G to A was detected in the second exon of the gene encoding the ribosomal protein small subunit 9 (PRPS9) in sot8-1, resulting in an amino acid change and a partial loss of PRPS9 function. However, sot8-1 was unable to rescue the thf1 phenotype in low photosystem II activity (Fv/Fm). In addition, we identified two T-DNA insertion mutants defective in plastid-specific ribosomal proteins (PSRPs), psrp2-1, and psrp5-1. Genetic analysis showed that knockdown of PSRP5 expression but not PSRP2 expression suppressed leaf variegation. Northern blotting results showed that precursors of plastid rRNAs over-accumulated in prps9-1 and psrp5-1, indicating that mutations in PRPS9 and PSRP5 cause a defect in rRNA processing. Consistently, inhibition of plastid protein synthesis by spectinomycin led to increased levels of plastid rRNA precursors in wild-type plants, suggesting that rRNA processing and plastid ribosomal assembly are coupled. Taken together, our data indicate that downregulating the expression of specific plastid ribosomal proteins suppresses thf1 leaf variegation, and provide new insights into a role of THF1 in plastid gene expression. PMID- 25733184 TI - The arc mutants of Arabidopsis with fewer large chloroplasts have a lower mesophyll conductance. AB - Photosynthetic cells of most land plant lineages have numerous small chloroplasts even though most algae, and even the early diverging land plant group the hornworts, tend to have one or a few large chloroplasts. One constraint that small chloroplasts could improve is the resistance to CO2 diffusion from the atmosphere to the chloroplast stroma. We examined the mesophyll conductance (inverse of the diffusion resistance) of mutant Arabidopsis thaliana plants with one or only a few large chloroplasts per cell. The accumulation and replication of chloroplasts (arc) mutants of A. thaliana were studied by model fitting to gas exchange data and (13)CO2 discrimination during carbon fixation. The two methods generally agreed, but the value of the CO2 compensation point of Rubisco (Gamma *) used in the model had a large impact on the estimated photosynthetic parameters, including mesophyll conductance. We found that having only a few large chloroplasts per cell resulted in a 25-50 % reduction in the mesophyll conductance at ambient CO2. PMID- 25733185 TI - Treatment of heart failure in real-world clinical practice: findings from the REFLECT-HF registry in patients with NYHA class II symptoms and a reduced ejection fraction. AB - BACKGROUND: Optimal medical therapy (OMT) for patients with chronic heart failure and a reduced ejection fraction (HF-REF) includes angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, plus a diuretic. HYPOTHESIS: We hypothesized that OMT is less often prescribed in HF-REF patients (<=35%) with New York Heart Association (NYHA) class II symptoms compared with those with NYHA class III/IV symptoms. METHODS: This was a cross-sectional, observational, multicenter survey of hospital-based cardiologists, office-based cardiologists, and general practitioners in Germany. RESULTS: Out of a total of 384 patients enrolled, 144 had REF <=35%. Patients with REF had NYHA class II symptoms in 39.6% (n = 57) and NYHA class III/IV symptoms in 60.4% (n = 87). The REF/NYHA class II group had a higher proportion of males than the REF/NYHA class III/IV group. For angiotensin converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers, prescription rates were high and comparable between groups. However, prescription rates for mineralocorticoid receptor antagonists were lower compared with other guideline-recommended treatments. Multivariate analyses indicated that OMT prescription was reduced for older patients and increased for patients cared for by an office-based cardiologist. CONCLUSIONS: Given the high proportion of patients with reduced left ventricular systolic function but only minor symptoms, HF-REF appears to be underdiagnosed, and a higher proportion of patients than are currently recognized could potentially be candidates for OMT. PMID- 25733186 TI - Expression of a novel epoxide hydrolase of Aspergillus usamii E001 in Escherichia coli and its performance in resolution of racemic styrene oxide. AB - The full-length cDNA sequence of Aueh2, a gene encoding an epoxide hydrolase of Aspergillus usamii E001 (abbreviated to AuEH2), was amplified from the total RNA. Synchronously, the complete DNA sequence containing 5', 3' flanking regions, eight exons and seven introns was cloned from the genomic DNA. In addition, a cDNA fragment of Aueh2 encoding a 395-aa AuEH2 was expressed in Escherichia coli. The catalytic activity of recombinant AuEH2 (re-AuEH2) was 1.44 U/ml using racemic styrene oxide (SO) as the substrate. The purified re-AuEH2 displayed the maximum activity at pH 7.0 and 35 degrees C. It was highly stable at a pH range of 5.0-7.5, and at 40 degrees C or below. Its activity was not obviously influenced by beta-mercaptoethanol, EDTA and most of metal ions tested, but was inhibited by Hg(2+), Sn(2+), Cu(2+), Fe(3+) and Zn(2+). The K m and V max of re AuEH2 were 5.90 mM and 20.1 U/mg towards (R)-SO, while 7.66 mM and 3.19 U/mg towards (S)-SO. Its enantiomeric ratio (E) for resolution of racemic SO was 24.2 at 10 degrees C. The experimental result of re-AuEH2 biasing towards (R)-SO was consistent with the analytical one by molecular docking (MD) simulation. PMID- 25733187 TI - Systemic mechanism of taste, flavour and palatability in brain. AB - Taste is considered as one of the five traditional senses and has the ability to detect the flavour of food and certain minerals. Information of taste is transferred to the cortical gustatory area for identification and discrimination of taste quality. Animals have memory recognition power to maintain the familiar foods which are already encountered. Animal shows neophobic response when it encounters novel taste and shows no hesitation when the food is known to be safe. Palatability is the hedonic reward provided by foods and fluids. Palatability is closely related to neurochemicals, and this chemical influences the consumption of food and fluid. Even though, the food is palatable that can become aversive and avoided as a consequence of postingestional unpleasant experience such as malaise. This review presents the overall view on brain mechanisms of taste, flavour and palatability. PMID- 25733188 TI - An old lady with Pediculosis pubis on the head hair. PMID- 25733189 TI - A pesticide monitoring survey in rivers and lakes of northern Greece and its human and ecotoxicological risk assessment. AB - A pesticide monitoring study covering the main rivers and lakes of Northern Greece (Macedonia, Thrace and Thessaly) was undertaken. A total of 416 samples were collected over a 1.5-year sampling period (September 1999- February 2001) from six rivers and ten lakes. The water samples were analyzed with an off-line solid phase extraction technique coupled with a gas chromatography ion trap mass spectrometer using an analytical method for 147 pesticides and their metabolites, including organochlorines, organophosphates, triazines, chloroacetanilides, pyrethroids, carbamates, phthalimides and other pesticides (herbicides, insecticides and fungicides). Based on the pesticide survey results, a human health carcinogenic and non-carcinogenic risk assessment was conducted for adults and children. Ecotoxicological risk assessment was also conducted using default endpoint values and the risk quotient method. Results showed that the herbicides metolachlor, prometryn, alachlor and molinate, were the most frequently detected pesticides (29%, 12.5%, 12.5% and 10%, respectively). They also exhibited the highest concentration values, often exceeding 1 MUg/L. Chlorpyrifos ethyl was the most frequently detected insecticide (7%). Seasonal variations in measured pesticide concentrations were observed in all rivers and lakes. The highest concentrations were recorded during May-June period, right after pesticide application. Concentrations of six pesticides were above the maximum allowable limit of 0.1 MUg/L set for drinking water. Alachlor, atrazine and a-HCH showed unacceptable carcinogenic risk estimates (4.5E-06, 4.6E-06 and 1.3E-04, respectively). Annual average concentrations of chlorpyriphos ethyl (0.031 MUg L), dicofol (0.01 MUg/L), dieldrin (0.02 MUg/L) and endosulfan a (0.065 MUg/L) exceeded the EU environmental quality standards. The risk quotient estimates for the insecticides chorpyrifos ethyl, diazinon and parathion methyl and herbicide prometryn were above acceptable risk values. The coupling of monitoring data to probabilistic human and ecotoxicological risk estimates could find use by Greek regulatory authorities, proposing effective pollution management schemes. PMID- 25733190 TI - Exposure of Daphnia magna to trichloroethylene (TCE) and vinyl chloride (VC): evaluation of gene transcription, cellular activity, and life-history parameters. AB - Trichloroethylene (TCE) is a ubiquitous contaminant classified as a human carcinogen. Vinyl chloride (VC) is primarily used to manufacture polyvinyl chloride and can also be a degradation product of TCE. Very few data exist on the toxicity of TCE and VC in aquatic organisms particularly at environmentally relevant concentrations. The aim of this study was to evaluate the sub-lethal effects (10 day exposure; 0.1; 1; 10 ug/L) of TCE and VC in Daphnia magna at the gene, cellular, and life-history levels. Results indicated impacts of VC on the regulation of genes related to glutathione-S-transferase (GST), juvenile hormone esterase (JHE), and the vitelline outer layer membrane protein (VMO1). On the cellular level, exposure to 0.1, 1, and 10 ug/L of VC significantly increased the activity of JHE in D. magna and TCE increased the activity of chitinase (at 1 and 10 ug/L). Results for life-history parameters indicated a possible tendency of TCE to affect the number of molts at the individual level in D. magna (p=0.051). Measurement of VG-like proteins using the alkali-labile phosphates (ALP) assay did not show differences between TCE treated organisms and controls. However, semi-quantitative measurement using gradient gel electrophoresis (213-218 kDa) indicated significant decrease in VG-like protein levels following exposure to TCE at all three concentrations. Overall, results indicate effects of TCE and VC on genes and proteins related to metabolism, reproduction, and growth in D. magna. PMID- 25733191 TI - A facile, solvent vapor-fumigation-induced, self-repair recrystallization of CH3NH3PbI3 films for high-performance perovskite solar cells. AB - A high-quality CH3NH3PbI3 film is crucial in the manufacture of a high performance perovskite solar cell. Here, a recrystallization process via facile fumigation with DMF vapor has been successfully introduced to self-repair of CH3NH3PbI3 films with poor coverage and low crystallinity prepared by the commonly used one-step spin-coating method. We found that the CH3NH3PbI3 films with dendritic structures can spontaneously transform to the uniform ones with full coverage and high crystallinity by adjusting the cycles of the recrystallization process. The mesostructured perovskite solar cells based on these repaired CH3NH3PbI3 films showed reproducible optimal power conversion efficiency (PCE) of 11.15% and average PCE of 10.25+/-0.90%, which are much better than that of devices based on the non-repaired CH3NH3PbI3 films. In addition, the hysteresis phenomenon in the current-voltage test can also be effectively alleviated due to the quality of the films being improved in the optimized devices. Our work proved that the fumigation of solvent vapor can modify metal organic perovskite films such as CH3NH3PbI3. It offers a novel and attractive way to fabricate high-performance perovskite solar cells. PMID- 25733192 TI - 5-Aminosalicylic acid, a specific drug for ulcerative colitis. AB - OBJECTIVE: The etiology of the inflammatory bowel diseases is unknown, although genetic factors play a role, and tobacco smoking has opposite effect on the two entities. Inflammation is central in the pathogenesis, and treatment is aiming to suppress it. The active part of salazopyrin, the oldest drug in use in the treatment of ulcerative colitis, is 5-aminosalicylic acid (5-ASA). In the present paper, we wanted to discuss the etiology and pathogenesis of ulcerative colitis in relation to the beneficial effects of 5-ASA and particularly whether this compound has a specific effect on ulcerative colitis. METHODS/RESULTS: 5-ASA seems to have a selective positive effect on ulcerative colitis in inducing remission, preventing relapse and possibly reducing the risk of cancer. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA does not have any known anti-inflammatory effect on other organs or other colonic inflammatory diseases like diverticulitis. Moreover, the effect on experimental colitis in rodents is not convincing. CONCLUSION: 5-ASA seems to have a specific effect on the inflammation in ulcerative colitis. Research on the mechanism of its action may give information on the etiology of ulcerative colitis. 5-ASA is a first-line treatment that should be given once daily in high doses and for long term to reduce the possibility of recurrence and risk of colonic cancer. Side effects with 5-ASA are rare, and every patient with ulcerative colitis who tolerate this drug, should be treated with 5-ASA. PMID- 25733193 TI - Borna disease virus possesses an NF-KB inhibitory sequence in the nucleoprotein gene. AB - Borna disease virus (BDV) has a non-segmented, negative-stranded RNA genome and causes persistent infection in many animal species. Previous study has shown that the activation of the IkappaB kinase (IKK)/NF-kappaB pathway is reduced by BDV infection even in cells expressing constitutively active mutant IKK. This result suggests that BDV directly interferes with the IKK/NF-kappaB pathway. To elucidate the mechanism for the inhibition of NF-kappaB activation by BDV infection, we evaluated the cross-talk between BDV infection and the NF-kappaB pathway. Using Multiple EM for Motif Elicitation analysis, we found that the nucleoproteins of BDV (BDV-N) and NF-kappaB1 share a common ankyrin-like motif. When THP1-CD14 cells were pre-treated with the identified peptide, NF-kappaB activation by Toll-like receptor ligands was suppressed. The 20S proteasome assay showed that BDV-N and BDV-N-derived peptide inhibited the processing of NF kappaB1 p105 into p50. Furthermore, immunoprecipitation assays showed that BDV-N interacted with NF-kappaB1 but not with NF-kappaB2, which shares no common motif with BDV-N. These results suggest BDV-N inhibits NF-kappaB1 processing by the 20S proteasome through its ankyrin-like peptide sequence, resulting in the suppression of IKK/NF-kappaB pathway activation. This inhibitory effect of BDV on the induction of the host innate immunity might provide benefits against persistent BDV infection. PMID- 25733194 TI - [Impact of maternal overnutrition on the periconceptional period]. AB - Overnutrition may lead to obesity. Maternal obesity may affect fertility not only via anovulation, but also through direct effects on oocytes and preimplantation embryos, indicating that the periconceptional period is sensitive to conditions of overnutrition. The periconceptional period includes from folliculogenesis to implantation. Animal model studies suggest that oocytes derived from obese females usually have a small size and mitochondrial abnormalities. These disruptions are probably induced by changes in the components of the ovarian follicular fluid. Experimental evidence also suggests that obesity may affect the microenvironment in oviducts and uterus, resulting in development of preimplantation embryos with reduced cell numbers and up-regulation of proinflammatory genes. However, further research is needed for in-depth characterization of the effects of maternal obesity during the periconceptional period. PMID- 25733195 TI - Ovary transcriptome profiling of Coilia nasus during spawning migration stages by Illumina sequencing. AB - Coilia nasus is an anadromous kind of small to moderate size fish species, and limited transcriptomics research has been performed. In the present study, we performed Illumina sequencing to produce a 22,996,612 clean reads representing with a total of 4,599,079,601 (4.5Gb) nucleotides comprehensive transcript dataset for ovary of C. nasus. Over 20 million total reads were assembled into 63,141 unigenes, and 27,027 annotated genes were predicted by Blastx and ESTScan, respectively. Applying Blast analysis and functional annotation (e.g., GO, COG, Swissprot and KEGG), we have sampled an extensive and diverse expressed gene catalog for C. nasus representing a large proportion of the genes expressed in the ovary development process. This approach will assist in the discovery and annotation of novel genes that play key roles in anadromous fish spawning migration process. PMID- 25733196 TI - Developing best-practice Bayesian Belief Networks in ecological risk assessments for freshwater and estuarine ecosystems: a quantitative review. AB - Bayesian Belief Networks (BBNs) are being increasingly used to develop a range of predictive models and risk assessments for ecological systems. Ecological BBNs can be applied to complex catchment and water quality issues, integrating multiple spatial and temporal variables within social, economic and environmental decision making processes. This paper reviews the essential components required for ecologists to design a best-practice predictive BBN in an ecological risk assessment (ERA) framework for aquatic ecosystems, outlining: (1) how to create a BBN for an aquatic ERA?; (2) what are the challenges for aquatic ecologists in adopting the best-practice applications of BBNs to ERAs?; and (3) how can BBNs in ERAs influence the science/management interface into the future? The aims of this paper are achieved using three approaches. The first is to demonstrate the best practice development of BBNs in aquatic sciences using a simple nutrient model. The second is to discuss the limitations and challenges aquatic ecologists encounter when applying BBNs to ERAs. The third is to provide a framework for integrating best-practice BBNs into ERAs and the management of aquatic ecosystems. A quantitative review of the application and development of BBNs in aquatic science from 2002 to 2014 was conducted to identify areas where continued best-practice development is required. We outline a best-practice framework for the integration of BBNs into ERAs and study of complex aquatic systems. PMID- 25733197 TI - Performance evaluation model of a pilot food waste collection system in Suzhou City, China. AB - This paper analyses the food waste collection and transportation (C&T) system in a pilot project in Suzhou by using a novel performance evaluation method. The method employed to conduct this analysis involves a unified performance evaluation index containing qualitative and quantitative indicators applied to data from Suzhou City. Two major inefficiencies were identified: a) low system efficiency due to insufficient processing capacity of commercial food waste facilities; and b) low waste resource utilization due to low efficiency of manual sorting. The performance evaluation indicated that the pilot project collection system's strong points included strong economics, low environmental impact and low social impact. This study also shows that Suzhou's integrated system has developed a comprehensive body of laws and clarified regulatory responsibilities for each of the various government departments to solve the problems of commercial food waste management. Based on Suzhou's experience, perspectives and lessons can be drawn for other cities and areas where food waste management systems are in the planning stage, or are encountering operational problems. PMID- 25733198 TI - SeriTM: A surgical scaffold for breast reconstruction or for bacterial growth? PMID- 25733199 TI - "NACsomes": A new classification system of the blood supply to the nipple areola complex (NAC) based on diagnostic breast MRI exams. AB - BACKGROUND: Breast MRIs have become increasingly common in breast cancer work-up. Previously obtained breast MRIs may facilitate oncoplastic surgery by delineating the blood supply to the nipple-areola complex (NAC). The aim of this study was to identify and classify the in vivo blood supply to the NAC using breast MRI exams. METHODS: Breast MRIs obtained over a one-year period were retrospectively reviewed. Patients with negative MRI findings (BI-RADS category 1) were included; patients with diagnoses of breast cancer or previous breast surgery were excluded. Twenty-six patients were evaluated. Dominant blood supply was determined by maximum filling at 70 s post-contrast. Blood supply to the NAC was classified into five anatomic zones: medial (type I), lateral (type II), central (type III), inferior (type IV) and superior (type V). RESULTS: Patient age ranged from 33 to 70 years. Fifty-two breasts were evaluated and 80 source vessels were identified (37 right, 43 left). Twenty-eight breasts had type I only blood supply, 22 breasts had multi-zone blood supply (type I + II, n = 20; type I + III n = 2), one breast had type II only blood supply, and a single breast had type III only blood supply. Anatomic symmetry was observed in 96% of patients. CONCLUSION: This study utilized MRI to evaluate in vivo vascular anatomy of the NAC, classify NAC perfusion ("NACsomes"), and assess vascular symmetry between breasts. Superomedial source vessels supplying the NAC were predominant. Preoperatively defining NAC blood supply may aid planning for oncoplastic procedures. PMID- 25733200 TI - "Going round the bend". A simple technical tip to aid dissection of the umbilicus during abdominoplasty. PMID- 25733202 TI - Vertebral, rib, and intraspinal anomalies in congenital scoliosis: a study on 202 Caucasians. AB - PURPOSE: To investigate vertebral, rib and intraspinal anomalies in patients with congenital scoliosis and their association with each other METHODS: Clinical data and preoperative imaging studies of 202 Caucasians with congenital scoliosis operated on at an educational hospital within 6 years were reviewed for vertebral, rib, and intraspinal anomalies. RESULTS: Rib and intraspinal anomalies were present in 57.4 and 21.8 % of patients, respectively. Most vertebral anomalies were located in the middle-lower thorax. Being the most common vertebral defect (53.5 %), failure of segmentation was significantly more common in males, whereas mixed defects were more frequent in females. Formation and mixed defects were associated with rib changes. Vertebral anomalies were more extensive in males than in females. The presence of multiple hemivertebrae was associated with rib deformity and intraspinal anomaly. Location of the vertebral anomalies varied with gender and rib involvement. Majority of rib changes were of simple type (70.7 %), significantly more common in males. Conversely, females had significantly more fused and bifid ribs. Two most common intraspinal anomalies were diastematomyelia (36.4 %) and syringomyelia (18.2 %). Intraspinal anomalies were located most frequently in the upper and lower thoracic regions. Syringomyelia and low conus were associated with female gender, and patients with rib changes suffered from intraspinal anomalies more frequently. No significant association was found between vertebral and intraspinal anomalies. CONCLUSIONS: The incidences of rib and intraspinal anomalies were 57.4 and 21.8 % in surgical Caucasians with congenital scoliosis, respectively. Unlike vertebral and intraspinal anomalies, rib and intraspinal anomalies were significantly associated. Male gender and intraspinal anomaly were associated with some previously suggested risk factors of curve progression. PMID- 25733201 TI - Effect of insulin sensitizer therapy on amino acids and their metabolites. AB - AIMS: Prior studies have reported that elevated concentrations of several plasma amino acids (AA), particularly branched chain (BCAA) and aromatic AA predict the onset of type 2 diabetes. We sought to test the hypothesis that circulating BCAA, aromatic AA and related AA metabolites decline in response to the use of insulin sensitizing agents in overweight/obese adults with impaired fasting glucose or untreated diabetes. METHODS: We performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI ~30kg/m(2)) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45mg per day) plus metformin (1000mg twice per day, N=12 participants) or placebo (N=13). We measured insulin sensitivity by the euglycemic-hyperinsulinemic clamp and fasting concentrations of AA and AA metabolites using ultra-pressure liquid chromatography tandem mass spectrometry before and after the three-month intervention. RESULTS: Insulin sensitizer therapy that significantly enhanced insulin sensitivity reduced 9 out of 33 AA and AA metabolites measured compared to placebo treatment. Moreover, insulin sensitizer therapy significantly reduced three functionally clustered AA and metabolite pairs: i) phenylalanine/tyrosine, ii) citrulline/arginine, and iii) lysine/alpha-aminoadipic acid. CONCLUSIONS: Reductions in plasma concentrations of several AA and AA metabolites in response to three months of insulin sensitizer therapy support the concept that reduced insulin sensitivity alters AA and AA metabolites. PMID- 25733203 TI - Diagnostic accuracy of multifidus muscle spontaneous activity by needle electromyography for the detection of lumbar foraminal and lateral exit-zone stenosis. AB - PURPOSE: The medial branch of the posterior ramus of the lumbar spinal nerve is well known to be innervated independently and to end in the multifidus muscle without anastomosis. This prospective cohort study aimed to determine the diagnostic specificity and sensitivity of multifidus muscle denervation (MMD) by needle electromyography (N-EMG) for lumbar foraminal and lateral exit-zone stenosis (LF/LEZS). METHODS: We enrolled 61 consecutive patients experiencing unilateral dysesthesia and/or leg pain in the L4 or L5 regions with suspicious LF/LEZS. The Japanese Orthopedic Association (JOA) score, Visual Analog Scale (VAS) for leg pain, and N-EMG were examined. In this study protocol, all patients received at least 3 months of conservative therapy. Surgery was performed on patients who experienced less than 50% VAS pain relief compared with their initial score after confirming the responsible level by lumbar nerve root block. The specificity of N-EMG was the proportion of patients who improved with conservative therapies (non-surgery) after 3 months. The sensitivity of N-EMG was the proportion of patients who improved with surgical therapies (surgery) after more than 12 months. RESULTS: Twenty-three patients underwent surgery. The initial lower JOA, positive Kemp test and motor weakness were significantly higher in the surgery group. The MMD by N-EMG indicated that 34 of 38 patients were negative in the non-surgery group. In the surgery group, 21 of 23 patients were positive. The diagnostic sensitivity and specificity were 91.3 and 92.1%, respectively. CONCLUSIONS: Needle electromyography is a simple and available additional method for the diagnosis of LF/LEZS. PMID- 25733206 TI - The decapod red pigment-concentrating hormone (Panbo-RPCH) is the first identified neuropeptide of the order Plecoptera and is interpreted as homoplastic character state. AB - This paper presents the first neuropeptide structure, identified by mass spectrometry, in two species of Plectoptera (stoneflies) and in one species of the coleopteran family Lycidae. In all three species, the octapeptide Panbo-RPCH (first identified in Pandalus borealis as a red pigment-concentrating hormone: pGlu-Leu-Asn-Phe-Ser-Pro-Gly-Trp amide) is present. A review of the literature available on invertebrate neuropeptides that are identified or predicted from expressed sequence tags, transcriptome shotgun assemblies, and from fully sequenced genomes, show that Panbo-RPCH is found in Malacostraca (Crustacea) and certain hemipteran Heteroptera (Insecta). To date, Panbo-RPCH has not been shown present in non-Malacostracan crustaceans, nor in basal taxa of the Insecta (Archaeognatha, Zygentoma, Ephemeroptera, Odonata). The present data adds to knowledge on the distribution of Panbo-RPCH, and when taking into account the most accepted, current phylogenetics of the Crustacea-Hexapoda relationship, this distribution of Panbo-RPCH in Malacostraca, Plecoptera, some hemipteran Heteroptera and in Coleoptera (Lycidae) can best be explained by homoplasy, implying parallel evolution. PMID- 25733204 TI - Perchlorate exposure does not modulate temporal variation of whole-body thyroid and androgen hormone content in threespine stickleback. AB - Previously we showed that exposure of threespine stickleback (Gasterosteus aculeatus) to the endocrine disruptor perchlorate results in pronounced structural changes in thyroid and gonad, while surprisingly, whole-body thyroid hormone concentrations remain unaffected. To test for hormone titer variations on a finer scale, we evaluated the interactive effects of time (diel and reproductive season) and perchlorate exposure on whole-body contents of triiodothyronine (T3), thyroxine (T4), and 11-ketotestosterone (11-KT) in captive stickleback. Adult stickleback were exposed to 100ppm perchlorate or control water and sampled at 4-h intervals across the 24-hday and at one time-point (1100h) weekly across the reproductive season (May-July). Neither whole-body T3 nor T4 concentration significantly differed across the day in control or perchlorate treated stickleback. Across the reproductive season, whole-body T3 concentration remained stable while T4 significantly increased. However, neither hormone concentration was significantly affected by perchlorate, verifying our previous studies. The concentration of whole-body 11-KT, a major fish androgen, displayed significant diel variation and also steadily declined across the reproductive season in untreated males; perchlorate exposure did not influence the concentration of 11-KT in either diel or reproductive season schedules. Diel and reproductive season variations in 11-KT content in male stickleback are likely related to reproductive physiology and behavior. The observed increase in T4 content across the reproductive season may be reflective of increased energy investment in reproduction near the end of the life cycle. PMID- 25733205 TI - Are endocrine and reproductive biomarkers altered in contaminant-exposed wild male Largemouth Bass (Micropterus salmoides) of Lake Mead, Nevada/Arizona, USA? AB - Male Largemouth Bass were sampled from two locations in Lake Mead (USA), a site influenced by treated municipal wastewater effluent and urban runoff (Las Vegas Bay), and a reference site (Overton Arm). Samples were collected in summer (July '07) and spring (March '08) to assess general health, endocrine and reproductive biomarkers, and compare contaminant body burdens by analyzing 252 organic chemicals. Sperm count and motility were measured in spring. Contaminants were detected at much higher frequencies and concentrations in fish from Las Vegas Bay than Overton Arm. Those with the highest concentrations included PCBs, DDTs, PBDEs, galaxolide, and methyl triclosan. Fish from Las Vegas Bay also had higher Fulton condition factor, hepatosomatic index, and hematocrit, and lower plasma 11 ketotestosterone concentration (KT). Gonadosomatic index (GSI) and sperm motility did not differ between sites, but sperm count was lower by nearly 50% in fish from Las Vegas Bay. A positive association between KT and GSI was identified, but this association was nonlinear. On average, maximal GSI was reached at sub maximal KT concentrations. In conclusion, the higher concentration of contaminant body burdens coupled with reduced levels of KT and sperm count in fish from Las Vegas Bay suggest that male reproductive condition was influenced by contaminant exposures. Also, the nonlinear KT-GSI association provided a framework to understand why GSI was similar between male bass from both sites despite their large difference in KT, and also suggested the existence of post-gonadal growth functions of KT at high concentrations. PMID- 25733207 TI - Unusual drainage pattern of a supracardiac total anomalous pulmonary venous connection. PMID- 25733208 TI - Detection of subtle left ventricular systolic dysfunction in patients with significant aortic regurgitation and preserved left ventricular ejection fraction: speckle tracking echocardiographic analysis. AB - AIMS: The aim of this study was to characterize left ventricular (LV) mechanics in symptomatic and asymptomatic patients with moderate-to-severe or severe aortic regurgitation (AR) and preserved ejection fraction (left ventricular ejection fraction) using two-dimensional speckle tracking echocardiography (2D-STE). The association between baseline LV strain and development of indications for surgery in asymptomatic patients was also evaluated. METHODS AND RESULTS: A total of 129 patients with moderate-to-severe or severe AR and LVEF >50% (age 55 +/- 17 years, 64% male, 53% asymptomatic at baseline) were included. Standard echocardiography and 2D-STE were performed at baseline. Compared with asymptomatic patients, symptomatic patients had significantly impaired LV longitudinal (-14.9 +/- 3.0 vs. -16.8 +/- 2.5%, P < 0.001), circumferential (-17.5 +/- 2.9 vs. -19.3 +/- 2.8%, P = 0.001), and radial (35.7 +/- 12.2 vs. 43.1 +/- 14.7%, P = 0.004) strains. Among 49 asymptomatic patients who were followed up, 26 developed indications for surgery (symptoms onset or LVEF <=50%). These patients had comparable LV volumes, LVEF, and colour Doppler assessments of AR jet at baseline, but more impaired LV longitudinal (P = 0.009) and circumferential (P = 0.017) strains compared with patients who remained asymptomatic. Impaired baseline LV longitudinal (per 1% decrease, HR = 1.21, P = 0.04) or circumferential (per 1% decrease, HR = 1.22, P = 0.04) strain was independently associated with the need for surgery. CONCLUSION: Multidirectional LV strain was more impaired in symptomatic than in asymptomatic patients with moderate-to severe or severe AR, despite preserved LVEF. In asymptomatic AR patients, longitudinal and circumferential strains identified patients who would require surgery during follow-up. PMID- 25733209 TI - Monocyte imaging after myocardial infarction with 19F MRI at 3 T: a pilot study in explanted porcine hearts. AB - AIM: Inflammation is a hallmark of cardiac healing after myocardial infarction and it determines subsequent cardiovascular morbidity and mortality. The aim of the present study was to explore whether inflammation imaging with two perfluorocarbon (PFC) nanoemulsions and fluorine magnetic resonance imaging ((19)F MRI) is feasible at 3.0 T with sufficient signal-to-noise ratio (SNR) using explanted hearts, an (19)F surface coil and dedicated MR sequences. METHODS AND RESULTS: Acute myocardial infarction (AMI) was induced by balloon angioplasty (50 min) of the distal left anterior descending artery in 12 pigs. One day thereafter, PFCs were injected intravenously to label circulating monocytes. Either emulsified perfluoro-15-crown-5 ether or already clinically applied perfluorooctyl bromide (PFOB) was applied. Four days after AMI and immediately after gadolinium administration, hearts were explanted and imaged with a 3.0 T Achieva MRI scanner. (19)F MRI could be acquired with an SNR of >15 using an in plane resolution of 2 * 2 mm(2) within <20 min for both agents. Combined late gadolinium enhancement (LGE) and (19)F MRI revealed that (19)F signal was inhomogenously distributed across LGE myocardium reflecting patchy macrophage infiltration as confirmed by histology. In whole hearts, we found an apico-basal (19)F gradient within LGE-positive myocardium. The (19)F-positive volume was always smaller than LGE volume. Ex vivo experiments on isolated monocytes revealed that pig and human cells phagocytize PFCs even more avidly than mouse monocytes. CONCLUSION: This pilot study demonstrates that (19)F MRI at 3.0 T with clinically applicable PFOB is feasible, thus highlighting the potential of (19)F MRI to monitor the inflammatory response after AMI. PMID- 25733210 TI - Ex vivo validation of 45 MHz intravascular ultrasound backscatter tissue characterization. AB - AIMS: The objectives of the present study are to describe the algorithm for VH((r)) IVUS using the 45-MHz rotational IVUS catheter and the associated ex vivo validation in comparison to the gold standard histology. METHODS AND RESULTS: The first phase of the present study was to construct the 45 MHz VH IVUS algorithm by using a total of 55 human coronary artery specimens [111 independent coronary lesions and 510 homogenous regions of interest (ROIs)], obtained at autopsy. Regions were selected from histology and matched with their corresponding IVUS data to build the plaque classification system using spectral analysis and statistical random forests. In the second phase, the ex vivo validation of the VH IVUS algorithm assessed a total of 1060 ROIs (120 lesions from 60 coronary arteries) in comparison with histology. In an independent manner, two interventional cardiologists also classified a randomly selected subset of the ROIs for assessment of inter- and intra-observer reproducibility of VH IVUS image interpretation.When including all ROIs, the predictive accuracies were 90.8% for fibrous tissue, 85.8% for fibro fatty tissue, 88.3% for necrotic core, and 88.0% for dense calcium. The exclusion of ROIs in the acoustically attenuated areas improved the predictive accuracies, ranging from 91.9 to 96.8%. The independent analysis of randomly selected 253 ROIs showed substantial agreement for inter observer (k = 0.66) and intra-observer (k = 0.88) reproducibility. CONCLUSION: Tissue classification by 45 MHz VH IVUS technology, when not influenced by calcium-induced acoustic attenuation, provided combined tissue accuracy >88% to identify tissue types compared with the gold standard histologic assessment, with high inter- and intra-observer reproducibility. PMID- 25733211 TI - Cellular imaging: a bright future for 19F-CMR. PMID- 25733212 TI - High shear stress-induced pulmonary hypertension alleviated by endothelial progenitor cells independent of autophagy. AB - BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by lung endothelial cell dysfunction and vascular remodeling. Endothelial progenitor cells (EPCs) have been proved to be a potential therapeutic strategy to treat PH. Autophagy has been found to be protective to hypoxia-induced PH. In this study, we applied high shear stress (HSS)-induced PH, and examined whether EPCs confer resistance against HSS-induced PH through autophagy. METHODS: Pulmonary microvascular endothelial cells (PMVECs) were cultured under HSS with pro inflammatory factors in an artificial capillary system to mimic the PH condition. Levels of p62, a selective autophagy substrate, were quantified by western blotting. Cell viability was determined by trypan blue exclusion test. RESULTS: The p62 level in PMVECs was increased at 4 hours after HSS, peaked at 12 hours and declined at 24 hours. The cell viability gradually decreased. Compared with PMVECs cultured by empty medium, in cells cultured by EPC-conditioned medium (EPC CM), the cell viability was significantly higher; however, p62 levels were also significantly higher, suggesting inhibition of autophagy by EPC-CM. Adding choloquine to suppress autophagy decreased the cell viability of PMVECs under PH. CONCLUSIONS: EPC-CM could suppress the autophagic activity of PMVECs in HSS induced PH. However, suppression of autophagy leads to cell death. EPCs could fight against PH through cellular or molecular pathways independent of autophagy. But it is not proved if induction of autophagy could be a potential strategy to treat HSS-induced PH as hypoxia-induced PH. PMID- 25733213 TI - Laparoscopic ureteroureterostomy with the intraoperative retrograde ureteroscopy assisted technique for inverted-Y ureteral duplication with a blind-ending branch. AB - Inverted-Y ureteral duplications are an extremely rare variant of congenital ureteral malformation with few cases reported in the literature. We describe here a case of inverted-Y ureteral duplication with a blind-ending branch, which was managed by laparoscopic ureteroureterostomy with the intraoperative retrograde ureteroscopy-assisted technique. This is the first report that reveals that inverted-Y ureteral duplication was managed by ureteroureterostomy in a laparoscopic approach. PMID- 25733214 TI - False Arterial Aneurysm due to Long Bone Exostosis: Presentation of Two Cases and Update on Proper Management. AB - Osteochondromas are the most common benign bone tumors. Vascular complications are unusual, with false arterial aneurysms being the majority among them. Although there are several reports of false aneurysms because of an exostosis in the femoro-popliteal region, cases presenting with a false aneurysm of the brachial artery are quite rare. Many suggestions have been made regarding prevention, diagnosis, and treatment of these false aneurysms, although there are no official guidelines. Therefore, this report aims to present 2 unusual cases of patients with a false aneurysm in the femoral and brachial artery, respectively, because of an exostosis. Literature data are discussed and useful conclusions regarding optimal management are made. PMID- 25733215 TI - Open Surgical Management of Hypogastric Artery during Aortic Surgery: Ligate or Not Ligate? AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is associated with 43% of cases with common iliac artery aneurysms and an extension of prosthetic replacement distal to the iliac bifurcation is needed. The decision about preserving the hypogastric artery (HA) is a source of discussion, in particular when only one HA is interested. The low risk of pelvic ischemia, even if existing, has to be compared with the greater technical difficulty of the vascular reconstruction. The aim of this study is to evaluate retrospectively the perioperative results in patients who underwent ligation or reconstruction of the HA during open surgical procedures for AAA. METHODS: Over a period of 11 years (January 2002 to December 2012), 1,487 patients were treated electively for AAA. In 235 cases (15.8%), the aneurysm involved the iliac bifurcation with need to extend distally the prosthetic reconstruction; among them, 63 patients were subjected to HA ligation (26.8%, group 1) and 172 to HA bypass (73.2%, group 2). Indication for ligation was the presence of extended HA aneurysm in 34 cases (54%) and heavy calcification of HA in 29 (46%). RESULTS: Perioperative mortality and morbidity rates were, respectively, 1.6% (1/63) and 7.9% (5/63) in group 1 and 1.2% (2/172) and 6.4% (11/172) in group 2 (P = 0.902 and 0.689). The incidence of buttock claudication was significantly higher in group 1 (6/63, 9.5% vs. 4/172, 2.3% P = 0.025), while there were no significant differences in other complications of pelvic ischemia. In group 2, higher intraoperative blood loss (754 +/- 721 vs. 996 +/- 608 mL, P = 0.011), longer operating time (283.2 +/- 104.7 vs. 302 +/- 109 min, P = 0.053), and longer postoperative length of stay (PLOS) (5.8 +/- 2.2 vs. 6.7 +/- 3.6 days, P = 0.049) occurred. CONCLUSIONS: HA bypass during open surgery for AAA is a safe procedure. If compared with ligation, it reduces the risk of buttock claudication without increasing perioperative morbidity and mortality. However, the increased complexity of the intervention involves an increase in blood loss, operating time, and PLOS. PMID- 25733216 TI - Emergent fully endovascular treatment of a free ruptured thoracoabdominal aneurysm. AB - To present a case of successful emergency complete endovascular repair of a ruptured type IV thoracoabdominal aortic aneurysms (TAAA) through chimney technique with off-the-shelf devices. A 64-year-old man with a free ruptured type IV TAAA. Open access was obtained at both common femoral arteries, both axillary arteries, and left common carotid artery. Covered stent grafts were located undeployed into the target arteries. An endoprosthesis was released in the suprarenal aorta, and soon after, covered stents were deployed in renal arteries and superior mesenteric artery. Type Ib and II endoleaks required an adjunctive endovascular treatment. Total endovascular repair with chimney technique may be the only life-saving option in patients unfit for open surgery and is effective in sealing the aneurysm and maintaining blood flow to the aortic branches. PMID- 25733217 TI - Complicated type B aortic dissection should not be treated with uncovered stents: a lesson not yet learned. AB - Whenever some basic rules for endovascular aortic repair of type B aortic dissection are not followed, iatrogenic complications may develop. A 64-year-old gentleman was referred to our institution for revision of previous treatment of complex type B aortic dissection with 2 bare stents. At 3 months, the most proximal aortic bare stent had entered, via the proximal tear, the false lumen. Aortic expansion and dynamic obstruction at the level of the renal arteries had also developed. In a first step, we removed the proximal aortic bare stent surgically. Few days later, 2 covered endografts were implanted into the true lumen of the thoracic aorta with clinical success. The rationale for using endovascular treatment in patients with complicated type B aortic dissection is coverage of the entry tear with covered nonoversized endografts. Negative results are achieved whenever these very simple rules are not strictly followed. PMID- 25733218 TI - Necrotizing soft tissue infection following a peripheral bypass. AB - BACKGROUND: Necrotizing soft tissue infection (NSTI), formerly referred to as necrotizing fasciitis, is a rare but serious postoperative complication. NSTI following arterial bypass is seen only once in the literature (for a coronary artery bypass) and is not mentioned following peripheral bypass. Although surgical site infections have been studied extensively, there are limited published data on postoperative NSTI and no data for NSTI following peripheral arterial bypass. CASE PRESENTATION: Here we present the first, to our knowledge, reported instance of an NSTI following a lower extremity peripheral bypass. Despite the continued function of the bypass, the patient became rapidly systemically ill with a focus at the surgical site. Because of prompt surgical debridement, the patient survived this severe infection, though did require an above the knee amputation to control the rapid spread of the disease. The patient, a native of American Samoa, was infected with organisms infrequently associated with NSTI, Morganella morganii and Aeromonas hydrophila. This article discusses the diagnosis and treatment of this rare postoperative complication, along with a brief review of the microbiology of the disease. CONCLUSIONS: NSTI is a rare but lethal postoperative complication. To our knowledge, this is the first reported case of an NSTI following an arterial peripheral bypass. This patient survived because of prompt and aggressive intervention. PMID- 25733219 TI - A novel suture technique for distal aorta-graft anastomosis in aortic aneurysm repair surgery: diagonal basting stitch. AB - We describe a novel suture technique of distal anastomosis between the graft and the aorta in ascending aortic aneurysm repair surgery. In this technique, the aortic graft is positioned inside the distal aortic lumen with an overlapping segment and circumferential or back wall part only diagonal basting stitches are performed without use of Teflon pledgets, strips, or bioadhesives. This new technique establishes a secure anastomosis line, shortens anastomosis time, and avoids the use of foreign materials. PMID- 25733220 TI - 24-Month Data from the BRAVISSIMO: A Large-Scale Prospective Registry on Iliac Stenting for TASC A & B and TASC C & D Lesions. AB - BACKGROUND: To evaluate the 24-month outcome of stenting in Trans-Atlantic Inter Society Consensus (TASC) A & B and TASC C & D iliac lesions in a controlled setting. METHODS: The BRAVISSIMO study is a prospective, nonrandomized, multicenter, multinational, monitored registry including 325 patients with aortoiliac lesions. The end point is the primary patency at 24 months, defined as a target lesion without a hemodynamically significant stenosis on duplex ultrasound (>50%, systolic velocity ratio >2.0). A separate analysis for TASC A & B versus TASC C & D population is performed. RESULTS: Between July 2009 and September 2010, 190 patients with TASC A or B and 135 patients with TASC C or D aortoiliac lesions were included. The demographic data were comparable for TASC A & B cohort and TASC C & D cohort. Technical success was 100%. Significantly more balloon-expandable stents were deployed in TASC A & B lesions, and considerably more self-expanding stents were placed in TASC C & D (P = 0.01). The 24-month primary patency rate after 24 months for the total population was 87.9% (88.0% for TASC A, 88.5% for TASC B, 91.9% for TASC C, and 84.8% for TASC D). No statistically significant difference was shown when comparing these groups. The 24-month primary patency rates were 92.1% for patients treated with the self expanding stent, 85.2% for patients treated with the balloon-expandable stent, and 75.3% for patients treated with a combination of both stents (P = 0.06). Univariate and multivariable regression analyses using Cox proportional hazards model identified only kissing stent configuration (P = 0.0012) and obesity (P = 0.0109) as independent predictors of restenosis (primary patency failure). Interestingly, as all TASC groups enjoyed high levels of patency, neither TASC category nor lesion length was predictive of restenosis. CONCLUSION: The 24-month data from this large, prospective, multicenter study confirm that endovascular therapy may be considered the preferred first-line treatment option of iliac lesions, irrespectively of TASC lesion category. PMID- 25733221 TI - Surgical Treatment of Isolated Interrupted Aortic Arch in a Young Female Diagnosed during Pregnancy. AB - Interrupted aortic arch (IAA) is a very rare pathology characterized by luminal discontinuity between ascending and descending aorta. IAA is commonly treated in pediatric ages, but the surgery is rarely used for adult patients. In this case report, we aimed to present a successful surgery in a young woman in whom IAA was diagnosed during pregnancy. PMID- 25733222 TI - Endovascular Treatment for Acute Type B Aortic Dissection Involving a Right-sided Aortic Arch and Kommerell's Diverticulum: A Case Report and Review of the Literature. AB - BACKGROUND: Aortic dissection involving a right-sided aortic arch (RAA) associated with Kommerell's diverticulum is extremely rare and remains a complicated entity for surgical therapy because of its anatomical characteristics. Fewer than 40 cases have been reported in the English language literature to date. METHODS: We reported a case of 69-year-old male patient who presented with acute type B aortic dissection involving an RAA associated with Kommerell's diverticulum, a stent-graft was accurately deployed and embolization of the left subclavian artery. In addition, a review of the literature was performed to examine its clinical presentation and the efficacy of management strategies. RESULTS: One year follow-up showed positive aortic remodeling with exclusion of Kommerell's diverticulum and thrombosis of the false lumen. CONCLUSIONS: An aortic dissection involving an RAA associated with Kommerell's diverticulum is an extremely rare condition. Endovascular therapy is technically feasible when the dissection involves this unusual vascular malformation. PMID- 25733223 TI - Successful emergent endovascular repair of a ruptured mycotic thoracic aortic aneurysm. AB - BACKGROUND: Mycotic thoracic aortic aneurysms are a life-threatening diagnosis and carry a high risk of morbidity and mortality in the perioperative setting. Traditional open repair consists of debridement, drainage, and either in situ or extra-anatomic bypass. Acute rupture portends a dismal prognosis; however, emergent endovascular repair of ruptured mycotic aneurysms has been described in the literature and we present a case of successful endovascular treatment of a ruptured mycotic descending thoracic aortic aneurysm. CASE REPORT: We report the case of a 42-year-old male with hypertension and active intravenous drug use who presented with 3 weeks of chest pain, dyspnea, and hemoptysis, and on computed tomography scan was found to have a contained 4.1-cm ruptured mycotic thoracic aortic aneurysm. Blood cultures were positive for methicillin-resistant Staphylococcus aureus. Emergent repair was recommended because of likelihood of further rupture and death. Thoracic endovascular aortic repair (TEVAR) was performed using a rifampin-soaked stent graft without complication. At 2-year follow-up, the patient was asymptomatic and imaging demonstrated the stent graft in excellent position, without endoleak, and complete resolution of the aneurysm sac. CONCLUSIONS: TEVAR can be safely employed to treat a ruptured mycotic thoracic aneurysm when open repair is not possible because of patient's comorbidity or complex rupture, as these patients face imminent death. Long-term follow-up is necessary for detection of endoleak, recurrence, or propagation of the aneurysm, and persistent bacterial infections. PMID- 25733224 TI - Incidence of Postoperative Deep Venous Thrombosis Is Higher among Cardiac and Vascular Surgery Patients as Compared with General Surgery Patients. AB - BACKGROUND: Unlike general surgery patients, most of vascular and cardiac surgery patients receive therapeutic anticoagulation during operations. The purpose of this study was to report the incidence of deep venous thrombosis (DVT) among cardiac and vascular surgery patients, compared with general surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent surgical procedures from 2005 to 2010. Patients who developed DVT within 30 days of an operation were identified. The incidence of DVT was compared among vascular, general, and cardiac surgery patients. Risk factors for developing postoperative DVT were identified and compared among these patients. RESULTS: Of total 2,669,772 patients underwent surgical operations in the period between 2005 and 2010. Of all the patients, 18,670 patients (0.69%) developed DVT. The incidence of DVT among different surgical specialties was cardiac surgery (2%), vascular surgery (0.99%), and general surgery (0.66%). The odds ratio for developing DVT was 1.5 for vascular surgery patients and 3 for cardiac surgery patients, when compared with general surgery patients (P < 0.001). The odds ratio for developing DVT after cardiac surgery was 2, when compared with vascular surgery (P < 0.001). CONCLUSIONS: The incidence of DVT is higher among vascular and cardiac surgery patients as compared with that of general surgery patients. Intraoperative anticoagulation does not prevent the occurrence of DVT in the postoperative period. These patients should receive DVT prophylaxis in the perioperative period, similar to other surgical patients according to evidence-based guidelines. PMID- 25733225 TI - Iliac artery stenosis complicating iliac vein stenting in a patient with a history of radiation and cancer: case report and literature review. AB - Radiation-associated venous stenosis is not as well described in the literature as radiation-induced arteritis and is mainly limited to case reports. Treatment of radiation-associated venous stenosis may be challenged by the patient's comorbidities, such as cancer, compressive tumor, or secondary thrombophilia. The endovascular treatment of venous occlusions is now widespread and is usually the preferred modality. This is especially true for lesions of the iliac venous system. However, the development of arterial stenosis after iliac vein stenting has not previously been reported in the literature as a complication. We present a case of left common iliac artery stenosis developing immediately after left iliac vein stenting for stenosis that developed secondary to extensive pelvic surgery and targeted radiotherapy. This case report illustrates the challenges in treating an iliac vein stenosis in a hostile pelvis, reports a previously unidentified complication of iliac vein stenting, documents the first reported cases of using kissing balloons in an artery and adjacent venous segment, and reviews the literature in regard to iliac vein and inferior vena cava stenting in patients with a history of neoplasm and radiation treatment. PMID- 25733226 TI - Anatomy and physiology of velopharyngeal closure and insufficiency. AB - The velopharynx is a complex structure that is responsible for separation of the oral and nasal cavities during speech production and swallowing. Incompetence of this mechanism can lead to hypernasality, with nasal air emission and incomprehensible speech, as well as nasopharyngeal regurgitation. There can be a significant social stigma associated with velopharyngeal dysfunction, and surgical treatment can be curative in many cases. Knowledge of the normal anatomy and physiology of the velopharyngeal complex is essential when planning for surgical repair. PMID- 25733227 TI - Nasometry, videofluoroscopy, and the speech pathologist's evaluation and treatment. AB - The speech-language pathologist (SLP) plays an important role in the assessment and management of children with velopharyngeal insufficiency (VPI). The SLP assesses speech sound production and oral nasal resonance and identifies the characteristics of nasal air emission to guide the clinical and surgical management of VPI. Clinical resonance evaluations typically include an oral motor exam, identification of nasal air emission, and analysis of the speech sound repertoire. Additional elements include perceptual assessment of intra-oral air pressure, the degree of hypernasality, and vocal loudness/quality. Clinical speech and resonance evaluations are typically the gold-standard evaluation method until a child reaches 3-4 years of age, when sufficient compliance levels and speech-language abilities allow for participation in instrumental testing. At that time, objective assessment measures are introduced, including nasometry, videofluoroscopy, and/or nasopharyngoscopy. Nasometry is a computer-based tool that quantifies nasal air escape and allows comparison of the score against normative data. Videofluoroscopy is a radiographic tool used to assess the shaping of the velum and closure of the velopharyngeal mechanism during speech production. Evaluation findings guide decision making regarding surgical candidacy and/or the therapeutic management of VPI. Surgery should always be pursued first when an anatomic deficit prevents velopharyngeal closure. Therapy should always be pursued in children who present with velopharyngeal mislearning and/or motor planning issues resulting in VPI. It is not uncommon for children to receive a combination of surgical intervention and speech resonance therapy during their VPI management course. Collaborative decision making between the otorhinolaryngologist and the SLP provides optimal patient care. PMID- 25733228 TI - Nasal endoscopy: new tools and technology for accurate assessment. AB - In this chapter the technique of nasal endoscopy is discussed. Standardized reporting of nasal endoscopy findings is essential in order to allow communication between different surgeons, speech therapists and endoscopists. Representative videos are provided for the normal examination, for coronal and sagittal velopharyngeal closure patterns, as well as for other anatomical variants of interest. Recommendations for tailoring surgical therapy based on the nasopharyngeal closure pattern are given, although the experience of the surgeon is an important factor for success of any surgical procedure for velopharyngeal insufficiency. Limitations and new frontiers of the technique of nasal endoscopy are also outlined. PMID- 25733229 TI - New technology: use of cine MRI for velopharyngeal insufficiency. AB - Cine magnetic resonance imaging (MRI) has been used since 1999 to evaluate velopharyngeal function. It allows the visualization of articulatory movement of the velopharyngeal port at rest and during speech. In addition, some studies have shown that it can be synched with audio and can define specific anatomic defects. Cine MRI also provides a non-invasive modality by which velopharyngeal closure can be evaluated. In this chapter, the utility and technique of cine MRI will be described. PMID- 25733230 TI - Validated patient-reported outcome instruments for velopharyngeal insufficiency. AB - Velopharyngeal insufficiency (VPI) affects speech, swallowing, and many psychosocial aspects of life in a way best measured by quality-of-life (QOL) instruments. QOL instruments are patient-reported outcome instruments that provide a method of measuring the value that patients place on their health related experiences. These instruments allow us to quantify patients' QOL during assessment as well as the clinical improvement that we seek with treatment. Two instruments have primarily been used in the VPI population: the Pediatric Voice Outcomes Survey (PVOS) and the VPI Effects on Life Outcomes (VELO) survey. Each has undergone a different level of assessment. The first step in using an instrument involves understanding how it functions. The PVOS was modified from an adult voice-specific functional status instrument. It was tested for reliability and validated against other patient-reported instruments and has been used to measure change in voice function with VPI surgery. The VELO was developed with comprehensive VPI-specific content and validated against several other measures important in VPI. It was found to be reliable and responsive to change in QOL. The VELO has several subscales (Speech Problems, Swallowing Problems, Situational Difficulty, Perception by Others, Emotional Impact, and Caregiver Impact) that can be used to understand the subtleties of QOL in patients with VPI. Comparison of the effect sizes shows that the VELO has a larger effect size (1.1) than the PVOS (0.6) and may be more capable of detecting change in QOL with treatment. These instruments can be useful for patient assessment, providing a framework for discussion and providing data for research. PMID- 25733231 TI - Prosthodontics rehabilitation in velopharyngeal insufficiency. AB - When surgical correction is less than successful or when children are poor candidates for surgery due to a large gap, a neuromuscular cause of velopharyngeal insufficiency (VPI), a strong gag reflex, or unfavorable anatomy, prosthetic intervention can result in the elimination of VPI. Surgery is ideal and best suited for long-term results; however, if needed, prosthetic correction can resolve VPI and is presented here. Indications for obturators, various designs, and clinical pearls when managing a child with an obturator are discussed. Correction of VPI must always be considered a multidisciplinary approach involving multiple modalities of treatment and specialties. PMID- 25733232 TI - Superiorly based pharyngeal flap. AB - First described in 1875 by Schoenborn as an inferiorly based flap, the pharyngeal flap is the most common surgical procedure performed for velopharyngeal insufficiency. Having undergone numerous modifications since its conception, the pharyngeal flap is now primarily designed as a superiorly based flap and is most effective for patients with good lateral wall motion but limited anterior posterior motion due to poor palatal excursion. The primary aims of this chapter are to provide the clinician with indications for when to consider utilizing the superiorly based pharyngeal flap and to give a stepwise description of how to perform the procedure. PMID- 25733233 TI - Sphincter pharyngoplasty. AB - First described in 1950 by Hynes for patients with velopharyngeal insufficiency following cleft palate repair, the sphincter pharyngoplasty is a frequently used procedure for treating velopharyngeal insufficiency that rivals the pharyngeal flap in some centers as the most frequently used procedure. This technique is most effective for patients with good anterior-posterior motion but limited lateral wall motion. The primary aims of this chapter are to provide the clinician with indications for when to consider utilizing the sphincter pharyngoplasty and to give a stepwise description of how to perform the procedure. PMID- 25733234 TI - Furlow double-opposing z-plasty. AB - First described in 1978 by Furlow for the repair of a cleft soft palate, the double-opposing z-plasty, also known as the Furlow palatoplasty, is an excellent procedure for repairing a submucous cleft. It is also useful in patients with touch closure who simply need lengthening of the soft palate and as an option for patients with anomalous carotid vasculature where pharyngeal flaps and sphincter pharyngoplasty are precarious. The primary aims of this chapter are to provide the clinician with indications for when to consider utilizing the Furlow palatoplasty and to give a stepwise description of how to perform the procedure. PMID- 25733235 TI - Posterior pharyngeal wall augmentation. AB - Posterior pharyngeal wall augmentation is a useful technique in selected patients with velopharyngeal insufficiency who have a small central velopharyngeal gap. Options for augmenting this region include using posterior pharyngeal wall flaps to create bulk and implanting various materials to fill in the central deficiency. Autologous and nonautologous implant materials are available and may be implanted through an incision or directly injected into the posterior pharyngeal wall. Previously described materials for implantation include cartilage, fat, fascia, silicone, acellular dermis, polytetrafluoroethylene, and calcium hydroxyapatite. Patient evaluation and surgical techniques for posterior pharyngeal wall augmentation are described. PMID- 25733236 TI - Persistent velopharyngeal insufficiency. AB - This chapter outlines the management of patients who have failed initial surgical correction of velopharyngeal insufficiency. Clinical judgment is required to determine the most appropriate revision option for each patient. PMID- 25733237 TI - Obstructive sleep apnea. AB - This chapter outlines the surgical management of children who experience symptoms of airway obstruction after undergoing pharyngeal flap surgery or sphincter pharyngoplasty for the correction of velopharyngeal insufficiency. It also describes the management of children with hyponasality following these corrective surgical interventions. PMID- 25733238 TI - Some but not All Tetrahymena Species Destroy Monolayer Cultures of Cells from a Wide Range of Tissues and Species. AB - The activities of Tetrahymena corlissi, Tetrahymena thermophila, and Tetrahymena canadensis were studied in coculture with cell lines of insects, fish, amphibians, and mammals. These ciliates remained viable regardless of the animal cell line partner. All three species could engulf animal cells in suspension. However, if the animal cells were monolayer cultures, the monolayers were obliterated by T. corlissi and T. thermophila. Both fibroblast and epithelial monolayers were destroyed but the destruction of human cell monolayers was done more effectively by T. thermophila. By contrast, T. canadensis was unable to destroy any monolayer. At 4 degrees C T. thermophila and T. corlissi did not carryout phagocytosis and did not destroy monolayers, whereas T. canadensis was able to carryout phagocytosis but still could not destroy monolayers. Therefore, monolayer destruction appeared to require phagocytosis, but by itself this was insufficient. In addition, the ciliates expressed a unique swimming behavior. Tetrahymena corlissi and T. thermophila swam vigorously and repeatedly into the monolayer, which seemed to loosen or dislodge cells, whereas T. canadensis swam above the monolayer. Therefore, differences in swimming behavior might explain why T. corlissi has been reported to be a pathogen but T. canadensis has not. PMID- 25733240 TI - Epidermal growth factor receptor is critical for angiotensin II-mediated hypertrophy in cerebral arterioles. AB - Angiotensin II (Ang II) is a major determinant of vascular remodeling in the cerebral circulation during chronic hypertension, which is an important risk factor for stroke. We examined the molecular mechanism of Ang II-mediated cerebrovascular remodeling that involves the epidermal growth factor receptor (EGFR) pathway. Mutant EGFR mice (waved-2), their heterozygous control (wild-type [WT]), and C57BL/6J mice were infused with Ang II (1000 ng kg(-1) min(-1)) or saline via osmotic minipumps for 28 days (n=8 per group). Eight of the Ang II infused C57BL/6J mice were cotreated with AG1478 (12 mg/kg per day, IP), a specific EGFR tyrosine kinase inhibitor. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined in pressurized fixed cerebral arterioles. Expression of phosphorylated EGFR (p-EGFR), caveolin-1 (Cav-1), and c-Src was determined by western blotting and immunohistochemistry. Mutation of EGFR or AG1478 treatment did not affect Ang II-induced hypertension. Ang II increased the expression of p EGFR in WT mice, confirming the activation of EGFR. Ang II induced hypertrophy and inward remodeling of cerebral arterioles in WT mice. Hypertrophy, but not remodeling, was prevented in waved-2 and AG1478-treated C57BL/6J mice. Ang II increased p-EGFR, Cav-1, and c-Src expression in WT but not in waved-2 or AG1478 treated C57BL/6J mice. These results suggest that Ang II-induced hypertrophy in cerebral arterioles involves EGFR-dependent signaling and may include Cav-1 and nonreceptor tyrosine kinase c-Src. This signaling pathway seems to be limited to Ang II-induced hypertrophy, but not inward remodeling, and is independent of blood pressure. PMID- 25733239 TI - Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease. AB - Cardiovascular disease is frequent in chronic kidney disease and has been related to angiotensin II, endothelin-1 (ET-1), thromboxane A2, and reactive oxygen species (ROS). Because activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS, which can generate ET-1, we tested the hypothesis that chronic kidney disease induces cyclooxygenase-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6 or TP-R+/+ and TP-R-/- mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin; increased plasma ET-1; and increased microvascular expression of p22(phox), cyclooxygenase-2, TP-Rs, preproendothelin and endothelin A receptors, and increased arteriolar remodeling. They had increased contractions to U-46,619 (118 +/- 3 versus 87 +/- 6, P<0.05) and ET-1 (108 +/- 5 versus 89 +/- 4, P<0.05), which were dependent on cellular and mitochondrial ROS, cyclooxygenase-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P<0.05). TP-R-/- mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by cyclooxygenase-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling, and contractility and may thereby coordinate vascular dysfunction in chronic kidney disease. PMID- 25733241 TI - Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. AB - Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had >=1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes (P<0.001). Corrected for differences in office blood pressure reductions among trials, TL diuretics resulted in a 12% additional risk reduction for cardiovascular events (P=0.049) and a 21% additional risk reduction for heart failure (P=0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension. PMID- 25733242 TI - Indapamide: is it the better diuretic for hypertension? PMID- 25733243 TI - Impaired neuronal nitric oxide synthase-mediated vasodilator responses to mental stress in essential hypertension. AB - Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42+/-14 years; blood pressure, 141+/-17/85+/-15 mm Hg; mean+/-SD) and 40 normotensive controls (38+/-14 years; 117+/-13/74+/-9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 MUmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the alpha-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37+/-7% versus 70+/-8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40+/-11% versus 3.0+/-14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89+/-14% to 43+/-14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39+/-8% to 67+/-13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events. PMID- 25733244 TI - Transcriptional regulation of renal dopamine D1 receptor function during oxidative stress. AB - There exists a strong link between oxidative stress, renal dopaminergic system, and hypertension. It is reported that reactive oxygen species attenuate renal proximal tubular dopamine receptor (D1R) function, which disrupts sodium regulation and leads to hypertension. However, the mechanisms for renal D1R dysfunction are not clear. We investigated the role of redox-sensitive transcription factors AP1 and SP3 in transcriptional suppression of D1R gene and subsequent D1R signaling. Human kidney proximal tubular cells were treated with a pro-oxidant l-buthionine sulfoximine (BSO) with and without an antioxidant tempol. In human kidney cells, BSO caused oxidative stress and reduced D1R mRNA and membrane receptor expression. Incubation of human kidney cells with SKF38393, a D1R agonist, caused a concentration-dependent inhibition of Na/K-ATPase. However, SKF38393 failed to inhibit Na/K-ATPase in BSO-treated cells. BSO increased AP1 and SP3 nuclear expression. Transfection with AP1- or SP3-specific siRNA abolished BSO-induced D1R downregulation. Treatment of rats with BSO for 4 weeks increased oxidative stress and SP3-AP1 expression and reduced D1R numbers in renal proximal tubules. These rats exhibited high blood pressure, and SKF38393 failed to inhibit proximal tubular Na/K-ATPase activity. Control rats were kept on tap water. Tempol per se had no effect on D1R expression or other signaling molecules but prevented BSO-induced oxidative stress, SP3-AP1 upregulation, and D1R dysfunction in both human kidney cells and rats. These data show that oxidative stress via AP1-SP3 activation suppresses D1R transcription and function. Tempol mitigates oxidative stress, blocks AP1-SP3 activation, and prevents D1R dysfunction and hypertension. PMID- 25733245 TI - Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. AB - Hydrochlorothiazide (HCTZ) has often been contrasted with chlorthalidone, but relatively little is known about HCTZ versus indapamide (INDAP). This systematic review retrieved 9765 publications, and from these, it identified 14 randomized trials with 883 patients comparing HCTZ with INDAP and chlorthalidone on antihypertensive potency or metabolic effects. To make fair comparisons, the dose of the diuretic in each arm was assigned 1 of 3 dose levels. In random effects meta-analysis, INDAP and chlorthalidone lowered systolic blood pressure more than HCTZ: -5.1 mm Hg (95% confidence interval, -8.7 to -1.6); P=0.004 and -3.6 mm Hg (95% confidence interval, -7.3 to 0.0); P=0.052, respectively. For both comparisons, there was minimal heterogeneity in effect across trials and no evidence for publication bias. The HCTZ-INDAP contrast was biased in favor of greater HCTZ potency because of a much greater contribution to the overall effect from trials in which the HCTZ arm had a higher dose level than the INDAP arm. For the HCTZ-INDAP comparison, no single trial was responsible for the overall result nor was it possible to detect significant modifications of this comparison by duration of follow-up, high- versus low-bias trials, or the presence or absence of background medications. There were no detectable differences between HCTZ and INDAP in metabolic adverse effects, including effects on serum potassium. In conclusion, these head-to-head comparisons demonstrate that, like chlorthalidone, INDAP is more potent than HCTZ at commonly prescribed doses without evidence for greater adverse metabolic effects. PMID- 25733246 TI - Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. AB - OBJECTIVE: To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). METHODS: Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52. RESULTS: Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 * 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 * 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts. CONCLUSION: In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade. PMID- 25733248 TI - Vibrational spectroscopic and molecular docking study of 4-Methylphenylquinoline 2-carboxylate. AB - FT-IR and FT-Raman spectra of 4-Methylphenylquinoline-2-carboxylate were recorded and analyzed. The structure of the molecule has been optimized and structural characteristics have been determined by density functional theory. The geometrical parameters (DFT) are in agreement with the XRD results. HOMO and LUMO and other chemical properties are reported. Nonlinear optical properties are also reported. A detailed molecular picture of the title compound and its interactions were obtained from NBO analysis. The negative (red and yellow) regions of the MEP are related to electrophilic reactivity and the positive (blue) regions to nucleophilic reactivity, as shown in the MEP plot and the carbonyl group and the phenyl rings are observed as electrophilic. PASS analysis predicts that the 4 Methylphenylquinoline-2-carboxylate might exhibit anti-diabetic activity. Molecular docking results suggest that the compound might exhibit inhibitory activity against GPb. PMID- 25733249 TI - Highly sensitive colorimetric determination of amoxicillin in pharmaceutical formulations based on induced aggregation of gold nanoparticles. AB - A novel, simple and highly sensitive colorimetric method is developed for determination of Amoxicillin (AMX). The system is based on aggregation of citrate capped gold nanoparticles (AuNP) in acetate buffer (pH=4.5) in the presence of the degradation product of Amoxicillin (DPAMX). It was found that the color of gold nanoparticles changed from red to purple and the intensity of surface plasmon resonance (SPR) peak of AuNPs decreased. A new absorption band was appeared in the wavelength range of 600-700nm upon addition of DPAMX. The absorbance ratio at the wavelength of 660 and 525nm (A660/A525) was chosen as the analytical signal indirectly related to AMX concentration. The linearity of the calibration graph was found over the concentration range of 0.3-4.5MUM AMX with a correlation coefficient of 0.9967. Under the optimum experimental conditions, the detection limit was found to be 0.15MUM. The applicability of the method was successfully demonstrated by analysis of AMX in pharmaceutical formulations including capsules and oral suspensions. PMID- 25733247 TI - Integration of metabolic activation with a predictive toxicogenomics signature to classify genotoxic versus nongenotoxic chemicals in human TK6 cells. AB - The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the molecular pathways involved in the response, is becoming more common. In a companion article, a genomic biomarker was developed in human TK6 cells to classify chemicals as genotoxic or nongenotoxic. Because TK6 cells are not metabolically competent, we set out to broaden the utility of the biomarker for use with chemicals requiring metabolic activation. Specifically, chemical exposures were conducted in the presence of rat liver S9. The ability of the biomarker to classify genotoxic (benzo[a]pyrene, BaP; aflatoxin B1, AFB1) and nongenotoxic (dexamethasone, DEX; phenobarbital, PB) agents correctly was evaluated. Cells were exposed to increasing chemical concentrations for 4 hr and collected 0 hr, 4 hr, and 20 hr postexposure. Relative survival, apoptosis, and micronucleus frequency were measured at 24 hr. Transcriptome profiles were measured with Agilent microarrays. Statistical modeling and bioinformatics tools were applied to classify each chemical using the genomic biomarker. BaP and AFB1 were correctly classified as genotoxic at the mid- and high concentrations at all three time points, whereas DEX was correctly classified as nongenotoxic at all concentrations and time points. The high concentration of PB was misclassified at 24 hr, suggesting that cytotoxicity at later time points may cause misclassification. The data suggest that the use of S9 does not impair the ability of the biomarker to classify genotoxicity in TK6 cells. Finally, we demonstrate that the biomarker is also able to accurately classify genotoxicity using a publicly available dataset derived from human HepaRG cells. PMID- 25733250 TI - Vibrational spectroscopy investigation and density functional theory calculations on (E)-N'-(4-methoxybenzylidene) benzohydrazide. AB - The FT-IR, FT-Raman and UV-Vis spectra of the Schiff base compound (E)-N'-(4 methoxybenzylidene) benzohydrazide (MBBH) have been recorded and analyzed. The optimized geometrical parameters were calculated. The complete vibrational assignments were performed on the basis of TED of the vibrational modes, calculated with the help of SQM method. NBO analysis has been carried out to explore the hyperconjugative interactions and their second order stabilization energy within the molecule. The molecular orbitals (MO's) and its energy gap were studied. The first order hyperpolarizability (beta0) and related properties (beta, alpha0, Deltaalpha) of MBBH are also calculated. All theoretical calculations were performed on the basis of B3LYP/6-311++G(d,p) level of theory. PMID- 25733251 TI - Synthesis and spectral characterization of silver embedded chitosan matrix nanocomposite for the selective colorimetric sensing of toxic mercury. AB - Polymer matrix type chitosan-silver nanocomposite containing different weight percentage of silver was synthesized by the chemical method. HRTEM images confirm the embedment of silver in the chitosan matrix. The binding of silver to the NH2 and OH groups of chitosan is evident from XPS and FTIR studies. An increase in the absorbance observed from UV-Vis analysis on raising the weight percentage of silver showed the increase in the amount of silver in the nanocomposite. The face centered cubic structure of silver and the semi-crystalline nature of chitosan are evident from the XRD studies. On interaction with mercury the UV-Vis spectra of the composite showed a decrease in intensity and a blue shift confirming the use of the composite as a colorimetric sensor for the detection of mercury. The limit of detection was found to be about 7.2*10(-8)M. High specificity and the sensitivity of the environmental friendly and non-toxic nanocomposite to detect very low concentrations of mercury make the system a perspective one. PMID- 25733252 TI - Application of the ratio difference spectrophotometry to the determination of ibuprofen and famotidine in their combined dosage form: comparison with previously published spectrophotometric methods. AB - Ratio difference spectrophotometric method was developed for the determination of ibuprofen and famotidine in their mixture form. Ibuprofen and famotidine were determined in the presence of each other by the ratio difference spectrophotometric (RD) method where linearity was obtained from 50 to 600MUg/mL and 2.5 to 25MUg/mL for ibuprofen and famotidine, respectively. The suggested method was validated according to ICH guidelines and successfully applied for the analysis of ibuprofen and famotidine in their pharmaceutical dosage forms without interference from any additives or excipients. PMID- 25733253 TI - Synthesis, X-ray, DFT and photophysical properties of some new ferrocenyl hydrazono thiazolidin-4-ones and their derivatives. AB - Cyclocondensation of thiosemicarbazone of 2-acetylferrocene with alpha-haloacids and alpha-haloketones afford new ferrocenyl hydrazono thiazolidin-4-ones and ferrocenyl hydrazono thiazoles respectively. Ferrocenyl hydrazono thiazolidin-4 one is easily converted into enamino ketone with N,N-dimethylformamide dimethyl acetal (DMF-DMA). The compounds were characterized by spectroscopic means and the structure of the new ferrocenyl hydrazono thiazolidin-4-one (3a) was determined by means of X-ray crystallography. The photophysical properties of these compounds were studied by means of UV/visible absorption spectroscopy and fluorescence spectroscopy. Density functional theory (DFT) calculations have been carried out with Gaussian 09W using B3LYP density functional method and 6-31G (d) basis set. (1)H and (13)C Nuclear Magnetic Resonance (NMR) have been calculated and correlated with experimental results. Antimicrobial activity studies of some new compounds have been reported. PMID- 25733254 TI - The spectroscopic and quantum chemical studies of 3,4-difluoroaniline. AB - Spectroscopic and structural investigations of 3,4-difluoroaniline molecule are presented by using experimental (FT-IR, FT-Raman, (1)H and (13)C NMR, and UV-Vis) techniques and theoretical (DFT approach) calculations. FT-IR and FT-Raman spectra of 3,4-difluoroaniline molecule are recorded in the region 4000-400cm(-1) and 3500-10cm(-1) in the liquid phase, respectively. The NMR chemical shifts ((1)H and (13)C) are recorded in chloroform-d solution. The UV absorption spectra of 3,4-difluoroaniline dissolved in ethanol and water are recorded in the range of 200-400nm. Experimental results are supported with the following theoretical calculations; the optimized geometry and vibrational (FT-IR and FT-Raman) spectra are carried out by DFT (B3LYP)/6-311++G(d,p) basis set calculations. The nuclear magnetic resonance spectra ((1)H and (13)C NMR) are obtained by using the gauge invariant atomic orbital method. Moreover, electronic characteristics, such as HOMO and LUMO energies, density of state diagrams, and molecular electrostatic potential surface are investigated. Nonlinear optical properties and thermodynamic features are also outlined theoretically. An excellent correlation of theoretical and experimental results provides a detailed description of the structural and physicochemical properties of the molecule. Thus, this work leads to a deep understanding of the characteristics of di-substituted aniline derivatives. PMID- 25733255 TI - Supramolecular protein assembly supports immobilization of a cytochrome P450 monooxygenase system as water-insoluble gel. AB - Diverse applications of the versatile bacterial cytochrome P450 enzymes (P450s) are hampered by their requirement for the auxiliary proteins, ferredoxin reductases and ferredoxins, that transfer electrons to P450s. Notably, this limits the use of P450s as immobilized enzymes for industrial purposes. Herein, we demonstrate the immobilization of a bacterial P450 and its redox protein partners by supramolecular complex formation using a self-assembled heterotrimeric protein. Employment of homodimeric phosphite dehydrogenase (PTDH) for cross-linking "proliferating cell nuclear antigen-utilized protein complex of P450 and its two electron transfer-related proteins" (PUPPET) yielded a gelling PUPPET-PTDH system capable of regenerating NADH for electron supply owing to its phosphite oxidation activity. The protein gel catalyzed monooxygenation in the presence of phosphite and NAD(+). The gel was completely water-insoluble and could be reused. This concept of oligomeric protein-insolubilized enzymes can be widely applied to various multienzymatic reactions such as cascade reactions and coupling reactions. PMID- 25733256 TI - Joseph J. Kaufman: renaissance man. PMID- 25733257 TI - Editorial comment. PMID- 25733258 TI - Four flawed arguments against prostate-specific antigen screening (and 1 good one). AB - Critics of prostate cancer screening have advanced several arguments as to why prostate-specific antigen (PSA) testing should be dramatically curtailed. In this personal reflection, I review 5 of these arguments, 4 of which are invalid. It is not true that the major randomized trial supporting prostate cancer screening, the European Randomized Study of Screening for Prostate Cancer, is flawed. Similarly, it is untrue that effects on prostate cancer mortality are only small, or that there are no effects at all on overall mortality. The fourth invalid argument is that PSA is a poor test and that it is impossible to tell whether screen-detected cancers are aggressive or indolent. But a fifth argument is indeed valid. PSA screening as it is currently practiced may not do more good than harm because of a high prevalence of screening of older men, gross overtreatment of low-risk disease, inadequate treatment of high-risk disease, and excessive rates of treatment at low-volume centers. The question for the urology community is whether it can be more restrictive about screening, biopsy, and treatment and more readily refer patients to higher volume institutions. Ultimately, the way to win the debate about PSA screening is not only to bring good data to bear but also to change practice so as to ensure that PSA screening does more good than harm. PMID- 25733259 TI - Analysis of commercial kidney stone probiotic supplements. AB - OBJECTIVE: To examine the levels of Oxalobacter formigenes in probiotic supplements marketed by PRO-LAB, Ltd, Toronto, Canada, and capsules of Oxalo purchased from Sanzyme Ltd, Hyderabad, India, and to measure the ability of these preparations to degrade oxalate in vitro. METHODS: Probiotic supplements and pure cultures of O. formigenes were cultured in a number of media containing oxalate. Optical density at 595 nm (OD595) was used to measure bacterial growth, and ion chromatography was used to measure loss of oxalate in culture media. O. formigenes-specific and degenerate Lactobacillus primers to the oxalate decarboxylase gene (oxc) were used in polymerase chain reaction (PCR). RESULTS: Incubating probiotic supplements in different media did not result in the growth of oxalate-degrading organisms. PCR indicated the absence of organisms harboring the oxc gene. Culture and 16S ribosomal ribonucleic acid gene sequencing indicated the PRO-LAB supplement contained viable Lactococcus lactis subsp. lactis (GenBank accession no. KJ095656.1), whereas Oxalo contained several Bacillus species and Lactobacillus plantarum. CONCLUSION: The probiotic supplement sold over the Internet by PRO-LAB Ltd and Sanzyme Ltd did not contain identifiable O. formigenes or viable oxalate-degrading organisms, and they are unlikely to be of benefit to calcium oxalate kidney stone patients. PMID- 25733260 TI - Surgical management of stone disease in patients with primary hyperoxaluria. AB - OBJECTIVE: To present our experience with surgical management of nephrolithiasis in patients with primary hyperoxaluria (PH). METHODS: A retrospective chart review from 1994 to 2012 was performed to identify patients with diagnosis of PH. RESULTS: A total of 14 patients with PH were identified with a median follow-up of 18.6 years (range, 0.9-51 years). Median ages at initial symptom and subsequent diagnosis were 6.7 years (range, 1.1-35.5 years) and 0.42 years (range, 0-33.25 years), respectively. Patients underwent a total of 54 procedures at our institution, including ureteroscopy (27 [50%]), percutaneous nephrolithotomy (15 [28%]), shock wave lithotripsy (8 [15%]), and combined procedures (4 [7%]). Overall nonintraparenchymal stone-free rate after the first, second, and third procedures were 59%, 76%, and 78%, respectively. On average, 1.6 procedures (range, 1-4) were required to rid patients of symptomatic stones, which subsequently afforded them a mean of 3.62 years (range, 0.25-21.5 years) without the need for additional intervention. There were 6 Clavien grade >=III complications in 4 patients, including immediate postoperative end-stage renal disease in 3 patients. CONCLUSION: Despite optimal medical and surgical management, patients experience recurrent acute stone events requiring multiple urologic interventions. Significant complications such as end-stage renal disease can occur secondary to surgical intervention. PMID- 25733261 TI - Contributing factors for fever after tubeless percutaneous nephrolithotomy. AB - OBJECTIVE: To evaluate the contributing factors for fever after tubeless percutaneous nephrolithotomy (PCNL). METHODS: Between May 2009 and December 2013, 395 tubeless PCNLs were performed at our hospital. After stone extraction, the bleeding points were cauterized for hemostasis to enable tubeless modification. In patients with troublesome bleeding after cauterization, oxidized regenerated cellulose (Surgicel) strips were used to tamponade the access tract to facilitate bleeding control. The contributory factors for fever were evaluated by a retrospective chart review. RESULTS: Forty-four patients (11.7%) developed fever after tubeless PCNL. There was no difference in gender, age, and body mass index in the development of fever. Episodes of febrile or septic urinary tract infection before PCNL were found to have occurred in 35 patients, but the incidence of postoperative fever was not significantly higher in these patients. There is no significant difference in the mean stone size in fever and nonfever patients. Complete staghorn stones were noted in 40 patients, and their fever rate was not significantly higher than patients with nonstaghorn stone. The operation time is not significantly higher in the group with urinary tract infection. Patients with postoperative fever had a high incidence of residual stones than the remaining patients (38.9% vs 20.4%). There was no significant difference in incidence of postoperative fever in patients with struvite stones than patients with nonstruvite stones. In patients who received Surgicel packing, the incidence of fever was not significantly higher. CONCLUSION: Incomplete stone extraction is a major contributing factor for the development of fever after tubeless PCNL. PMID- 25733262 TI - Usefulness of low-dose nonenhanced computed tomography with iterative reconstruction for evaluation of urolithiasis: diagnostic performance and agreement between the urologist and the radiologist. AB - OBJECTIVE: To evaluate the efficacy of low-dose nonenhanced computed tomography (LDCT) with iterative reconstruction (IR) technique for urologists to detect urolithiasis by comparing diagnostic performance and interobserver agreement between the urologist and the uroradiologist. PATIENTS AND METHODS: We evaluated the 116 patients with urinary stones (n = 197) using both conventional-dose nonenhanced computed tomography (CT) using filtered back projection (CDCT-FBP) and LDCT-IR. Scans were interpreted for stone characteristics, objective image noise, and subjective image assessment. Diagnostic performance and interobserver agreement of LDCT-IR were assessed between 1 urologist and 1 radiologist. RESULTS: There were no significant differences in all stones. The average effective dose (mSV) in the all size groups was 5.92 (CDCT-FBP) and 1.39 (LDCT IR), respectively (P <.001). The average effective dose reduction rate was 76.6%, allowing minimal additional radiation exposure from simultaneous CT. Objective image noise was higher in LDCT-IR (20.0-26.2; P <.01), but there was no significant difference in the Hounsfield unit between both CT protocols (52.3 and 56.7; P = .103). There were no cases of any unacceptable images in subjective image assessment. The sensitivity and specificity of LDCT-IR were 99.1%-100.0% with a diagnostic accuracy of 99.1%-100% for stones >=3 mm. Diagnostic performance was similar between the urologist and the radiologist. Interobserver agreement of LDCT-IR between the 2 reviewers was high with kappa values (0.901 1.000). CONCLUSION: LDCT-IR provided an excellent diagnostic performance and interobserver agreement between the urologist and the uroradiologist, reducing radiation exposure significantly; in real settings, the urologist should consider replacing LDCT-IR as the standard examination for detecting urolithiasis. PMID- 25733263 TI - Does hypertension impact 24-hour urine parameters in patients with nephrolithiasis? AB - OBJECTIVE: To examine the differences in 24-hour urine parameters and stone composition between patients with and without systemic hypertension (HTN) in a large cohort of stone formers. MATERIALS AND METHODS: We performed a retrospective review over a 10-year period of patients with stone, who had completed a 24-hour urinalysis (Litholink) and for whom demographic information was available, including the presence of HTN. Univariate and multivariate analyses were performed, comparing the 24-hour urinalysis profiles of patients with HTN with that of normotensive patients. RESULTS: Of the 1115 patients eligible for inclusion, 442 patients (40%) had HTN and 673 (60%) did not. Patients with HTN were significantly older, had a higher body mass index, and had a greater number of comorbid conditions than normotensive patients. Univariate analysis revealed significantly lower urine pH, calcium, supersaturation (SS) of calcium oxalate (CaOx) and SS calcium phosphate (all P <.05) in patients with HTN. Multivariate analysis showed significantly lower calcium, citrate, and SS CaOx in patients with HTN (all P <.05). CONCLUSION: Our results demonstrate lower levels of calcium and SS CaOx on univariate and multivariate analysis, as well as lower levels of citrate on multivariate analysis in patients with HTN. These results suggest that lower levels of citrate may contribute to stone formation to a greater degree in patients with HTN than abnormalities in calcium metabolism. PMID- 25733264 TI - Patient perceptions of physical and emotional discomfort related to urodynamic testing: a questionnaire-based study in men and women with and without neurologic conditions. AB - OBJECTIVE: To determine predictors of physical and emotional discomfort associated with urodynamic testing in men and women both with and without neurologic conditions. METHODS: An anonymous questionnaire-based study was completed by patients immediately after undergoing fluoroscopic urodynamic testing. Participants were asked questions pertaining to their perceptions of physical and emotional discomfort related to the study, their urologic and general health history, and demographics. Logistic regression was performed to determine predictors of physical and emotional discomfort. RESULTS: A total of 314 patients completed the questionnaire representing a response rate of 60%. Half of the respondents (50.7%) felt that the examination was neither physically nor emotionally uncomfortable, whereas 29.0% and 12.4% of respondents felt that the physical and emotional components of the examination were most uncomfortable, respectively. Placement of the urethral catheter was the most commonly reported component of physical discomfort (42.9%), whereas anxiety (27.7%) was the most commonly reported component of emotional discomfort. Presence of a neurologic problem (odds ratio, 0.273; 95% confidence interval, 0.121-0.617) and older age (odds ratio, 0.585; 95% confidence interval, 0.405-0.847) were factors associated with less physical discomfort. There were no significant predictors of emotional discomfort based on our model. CONCLUSION: Urodynamic studies were well tolerated regardless of gender. Presence of a neurologic condition and older age were predictors of less physical discomfort. These findings are useful in counseling patients regarding what to expect when having urodynamic procedures. PMID- 25733266 TI - Editorial comment. PMID- 25733265 TI - Morbidity of urologic surgical procedures: an analysis of rates, risk factors, and outcomes. AB - OBJECTIVE: To quantify national complication rates, perioperative outcomes, and predictors for a broad range of urologic procedures to demonstrate background rates and discuss benchmarking. METHODS: Urologic procedures from the National Surgical Quality Improvement Program (2006-2011) were analyzed to identify 30-day rates of 21 complications; outcomes (length of stay, reoperation, and death); and predictors including resident involvement for 18 specific procedures. Multivariate logistic regression models assessed predictors for any complication and for Clavien grade IV or V complication. RESULTS: A total of 39,700 procedures were included with abdominopelvic operations more morbid than endoscopic, scrotal, incontinence, or prolapse procedures. Cystectomy had the highest morbidity (10.8 days length of stay and 3.2% mortality), with 56% experiencing any complication followed by nephrectomy (21%), retroperitoneal lymph node dissection (20%), and radical retropubic prostatectomy (19%). Transurethral resection of bladder tumor (11%) and transurethral resection of the prostate (10%) had the highest rates for endoscopic procedures. Older age, American Society of Anesthesiologists class, dependent functional status, acute kidney injury (odds ratio [OR], 2.70 [1.89-3.87]), and >=5 units preoperative transfusion (OR, 4.44 [3.40-5.80]) were the strongest predictors of any complication. Higher ORs of similar predictors along with chronic obstructive pulmonary disorder (OR, 1.52 [1.21-1.92]) and steroid use (OR, 1.51 [1.07-2.14]) were associated with Clavien grade IV or V complication. Resident involvement increased odds of any complication (OR, 1.18 [1.09-1.29]), mostly for abdominopelvic and urogynecologic procedures, but not Clavien grade IV or V complication (P = .55). CONCLUSION: Complication rates of urologic procedures based on the retrospective experience of few surgeons do not allow for appropriate benchmarking. Baseline rates and benchmarks derived from the National Surgical Quality Improvement Program may help hospitals better track deficient areas and improvements in quality of care. Many predictors were similar across procedures, although magnitudes differed, and resident trainees did not impact rates of serious complications (Clavien-Dindo grade IV or V). PMID- 25733267 TI - Does socioeconomic status, age, or gender influence appointment attendance and completion of 24-hour urine collections? AB - OBJECTIVE: To examine the association of age, gender, and socioeconomic status with appointment attendance and completion of 24-hour urine collections to identify patient characteristics associated with barriers to treatment. METHODS: A retrospective review was performed under institutional review board approval for new patients scheduled at a single metabolic stone clinic over a 1.5-year period. Postal codes were used to identify poverty and education levels using US Census Bureau data. We evaluated 3 years of adherence based on "no shows," percentage of stone clinic appointments attended, and percentage of 24-hour urine collections completed. Quintile analyses were used to further explore nonlinear data. RESULTS: A total of 447 patients were included (246 men and 201 women). Mean age was 49 +/- 14.5 years. Younger age, areas of higher poverty, and areas of lower education were all weakly to moderately associated with increased "no show" rates and decreased clinic attendance. Men tended to not show for appointments more frequently than women (P = .043). When grouped by age groups, younger age was strongly correlated with decreased 24-hour urine collection completion (R = 0.75). When divided into age quintiles, relationships between "no shows" and clinic attendance were strengthened as they were when patients were divided into poverty quintiles. CONCLUSION: It is critical for providers to be aware of health disparities in medical stone management. Low education, high poverty, and younger age are associated with suboptimal evaluation follow-up. Of note, the lowest adherence was in younger patients, a population that requires the most urgent workup. PMID- 25733268 TI - The presence of Chlamydia is associated with increased leukocyte counts and pain severity in men with chronic pelvic pain syndrome. AB - OBJECTIVE: To examine the role of urinary chlamydial infection in patients with chronic prostatitis and/or chronic pelvic pain syndrome (CP-CPPS). METHODS: We recruited men aged 18-55 years over 4 years. We excluded patients with acute urethritis and any acute genitourinary infections. The participants evaluated their CP-CPPS-like symptoms with the Korean version National Institutes of Health Chronic Prostatitis Symptom Index questionnaires. We measured white blood cell (WBC) counts in expressed prostatic secretion (EPS). In-house nucleic acid amplification test for Chlamydia trachomatis and Neisseria gonorrhoeae detection and WBC counts were performed from the patient's first-voided urine. RESULTS: A total of 765 eligible men were classified into 3 groups: 196 in non-CP-CPPS, 410 in noninflammatory CP-CPPS, and 159 in inflammatory CP-CPPS groups. The chlamydia infected men showed higher pain, poor quality of life (QOL), and total scores in National Institutes of Health-Chronic Prostatitis Symptom Index questionnaires than the negative men (P = .041 for pain; P = .043 for QOL, and P = .027 for total). Multivariate analysis found that urinary chlamydial infection increased the risk of WBC count >=16 in EPS (adjusted odds ratio [OR], 2.189; 95% confidence interval [CI], 1.021-4.690; P = .044) and WBC count between 2 and 4 in urine (OR, 5.227; 95% CI, 2.503-10.918; P = .001). In addition, chlamydial infection also increased the risk of inflammatory CP-CPPS than the non-CP-CPPS group (OR, 2.448; 95% CI, 1.010-5.932; P = .044), whereas the patients with noninflammatory CP-CPPS were not affected (OR, 1.6557; 95% CI, 0.738-3.717; P = .221). CONCLUSION: Urinary chlamydial infection increased the pain scores and WBC counts in EPS and worsens the QOL in the patients with CP-CPPS. PMID- 25733269 TI - Differential proteomic profiling of spermatozoal proteins of infertile men with unilateral or bilateral varicocele. AB - OBJECTIVE: To compare the sperm protein profile between infertile men with unilateral varicocele and infertile men with bilateral varicocele. METHODS: This prospective study investigated 50 infertile patients with clinical varicocele (33 unilateral and 17 bilateral) seeking fertility workup between March 2012 and April 2014. Routine sperm parameters, reactive oxygen species, total antioxidant capacity, and sperm deoxyribonucleic acid fragmentation were assessed in their semen. Sperm protein profile was characterized only in pooled samples of 5 unilateral and 3 bilateral varicocele samples, respectively, using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and an Linear Trap Quadrupole-Orbitrap Elite hybrid mass spectrophotometer system. Differences in protein expression were analyzed using gel analysis software, followed by protein identification using mass spectroscopy analysis. Differentially expressed proteins and their abundance were quantified by comparing spectral counts, followed by bioinformatics analysis. RESULTS: Unique expression of 64 proteins in the bilateral group and 31 proteins in the unilateral group was obtained. Core functions of the top protein interaction networks were post-translational modification (~122 proteins associated with acetylation), protein folding, free radical scavenging, cell death, and survival. The top molecular and cellular functions were protein degradation, free radical scavenging, and post translational modifications, whereas the top pathways were protein ubiquitination and mitochondrial dysfunction. Major biological pathways for the 253 differentially expressed proteins were metabolism, apoptosis, and signal transduction. CONCLUSION: Functional proteomic profiling helps identify the differential processes or pathways that are affected based on the nature of varicocele (bilateral or unilateral) and provide insights into the mechanistic implications of varicocele-associated male infertility. PMID- 25733271 TI - Editorial comment. PMID- 25733270 TI - Margin, ischemia, and complications system to report perioperative outcomes of robotic partial nephrectomy: a European Multicenter Observational Study (EMOS project). AB - OBJECTIVE: To explore the margin, ischemia, and complications (MIC) system achievement rate within a population of patients who were treated with robotic partial nephrectomy (RAPN), at 3 different tertiary care centers, and to determine the factors predicting MIC achievement. METHODS: The study population consisted of 339 patients who underwent RAPN for cT1 renal tumors at 3 centers. Cancer control was defined as the absence of positive surgical margin. Ideal threshold of warm ischemia time (WIT) was considered <=20 minutes. Safety was defined as the absence of major complications. The achievement of MIC was considered as the fulfillment of all these 3 outcomes. The primary endpoint was to determine the MIC rate in our study population; the secondary endpoint was to detect factors affecting its achievement. RESULTS: The overall MIC rate was 67%. Median WIT was 17 minutes (range, 7-51 minutes). In 88 cases (26%), WIT was >20 minutes. Positive surgical margins were found in 22 patients (6.5%). Overall postoperative and major complication rates were 14.5% (n = 49) and 3.8% (n = 13). In multivariate logistic regression analysis, continuously coded and categorically coded preoperative aspects and dimensions used for an anatomical scores were an independent predictor of MIC achievement (odds ratio, 0.636; confidence interval, 0.436-0.928; P = .019 and odds ratio, 0.098; confidence interval, 0.030-0.326; P <.001). CONCLUSION: The MIC binary system may represent a useful tool to summarize the achievement of optimal perioperative outcomes of RAPN. In the current population, tumor complexity was significantly associated with MIC achievement. PMID- 25733272 TI - Reply: To PMID 25733270. PMID- 25733273 TI - Clinical outcomes of patients with nondiagnostic biopsy during cryoablation of small renal masses. AB - OBJECTIVE: To compare the outcomes of patients with biopsy-proven renal cell carcinoma (RCC), benign tumors (BTs), and nondiagnostic (ND) biopsies after renal cryoablation (RC). METHODS: We retrospectively reviewed medical records of 114 patients who underwent RC between 2003 and 2013. Patients were stratified according to biopsy histopathology results-RCC, BT, and ND biopsy. We recorded patient demographics and tumor features and examined oncologic outcomes among the 3 groups. RESULTS: RC was performed in 114 patients with 117 tumors. Seventy-two tumors (61.5%) were RCC, 18 (15.4%) were BTs (oncocytoma or angiomyolipoma), and 27 (23.1%) were ND. Patient characteristics and tumor features were similar among the 3 groups. The median follow-up was 26.5, 26.0, and 22.0 months in the RCC, BT, and ND biopsy groups, respectively (P = .18). Residual disease occurred in the RCC (1.4%) and ND biopsy (7.4%) groups, but not in the BT group (P = .19). All 9 patients (12.5%) who developed recurrent disease had biopsy-proven RCC. The 2- and 5-year recurrence-free survival rates (RFS) for patients with biopsy proven RCC were 90.2% and 81.2%, respectively. Because no patient in the BT and ND biopsy groups had a recurrence, their RFS was 100%. CONCLUSION: No patient with a BT or ND biopsy developed a local recurrence with short-term follow-up, whereas a recurrence developed in 12.5% of biopsy-proven RCC tumors. RFS for patients with biopsy-proven RCC was worse than the other 2 biopsy groups, although not statistically significant. Long-term follow-up in a larger cohort of patients is needed to further evaluate these preliminary findings. PMID- 25733274 TI - Effect of finasteride on serum androstenedione and risk of prostate cancer within the prostate cancer prevention trial: differential effect on high- and low-grade disease. AB - OBJECTIVE: To evaluate the effect of finasteride on serum androst-4-ene-3,17 dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial. METHODS: We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5alpha-reductase enzyme. RESULTS: We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease. CONCLUSION: The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5alpha-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression. PMID- 25733276 TI - Editorial comment. PMID- 25733275 TI - Complications after radical prostatectomy or radiotherapy for prostate cancer: results of a population-based, propensity score-matched analysis. AB - OBJECTIVE: To assess rates of treatment-related complications after radical prostatectomy or radiotherapy monotherapy, using propensity score matching to account for baseline differences between these patient populations. METHODS: On the basis of a population-based study of men undergoing surgery or radiotherapy for prostate cancer in Ontario between 2002 and 2009, we undertook a propensity score-matched analysis including age, comorbidity, and year of treatment to assess treatment-related complication end points. These included hospital admission; urologic, rectal, or anal procedures; open surgeries; and secondary malignancies. RESULTS: From the original cohort of 32,465 patients, 15,870 (48.9%) had surgery and 16,595 (51.1%) had radiation. Propensity score matching produced 8797 pairs (17,594 patients). Among these, when compared with patients treated with surgery, those treated with radiation experienced fewer admissions to hospital (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78-0.92) and urologic procedures (HR, 0.50; 95% CI, 0.46-0.53) at year 1 but higher rates at year 3 (HR, 5.65; 95% CI, 4.61-6.91 and HR, 1.86; 95% CI, 1.62-2.13, respectively) and year 5. Although there was no significant difference in open surgeries at year 1, patients undergoing radiotherapy were at higher risk by year 3 (HR, 2.06; 95% CI, 1.23-3.47) and this rose by year 5. Over the study period, patients undergoing radiotherapy experienced more rectal-anal procedures (HR, 2.64; 95% CI, 2.37-2.95) and were diagnosed with more secondary malignancies (HR, 2.44; 95% CI, 1.16-5.14). Direct matching produced similar results. CONCLUSION: From a propensity score-matched analysis, we found that patients undergoing radiation therapy for prostate cancer had higher rates of long-term complications in all 5 categories studied than patients undergoing surgery. PMID- 25733277 TI - Reply: To PMID 25733275. PMID- 25733278 TI - Muscular structure at the male bladder outlet examined with successive celloidin embedded slices. AB - OBJECTIVE: To re-examine the detailed anatomy of the muscular system at the bladder neck and proximal urethra in the male and to explore its function in urinary continence and micturition further. METHODS: The pelvic organs, including bladder, prostate, and rectum, were obtained from 20 formalin-fixed adult male cadavers and were removed from the pelvic cavity and embedded in celloidin in their entirety. The embedded block was cut into successive slices with an immersing-alcohol microtome. RESULTS: Circular muscle fibers of the detrusor at the bladder outlet consist of the anterior downward-projected circular muscle fibers of the bladder outlet (ADPC), the bilateral accumulated circular fibers, and the posterior circular fibers of the bladder outlet. Together, these fibers concentrically surround the internal urethral orifice and trigone muscle. The lower part of the ADPC surrounds the ventral surface of the proximal urethra. Longitudinal muscle fibers are radially inserted into the circular muscle around the internal urethral orifice. Numerous fibers from the ventral longitudinal muscle are inserted into the lower part of the ADPC. The upper part of the trigone muscle exists in bladder cavity; the lower part extends into the proximal urethra to surround the posterior and posterolateral surface of the urethra. CONCLUSION: The ADPC and the upward extension of the rhabdosphincter comprise the anterior fibromuscular stroma. The circular muscle of the bladder outlet may be responsible for closure; the longitudinal muscle of the bladder outlet may be responsible for opening of the internal urethral orifice and proximal urethra. PMID- 25733279 TI - Could nocturia be an indicator of an undiagnosed sleep disorder in male veterans? AB - OBJECTIVE: To determine if men presenting with nocturia and/or voiding complaints may have undiagnosed symptoms of sleep-disordered breathing (SDB). MATERIALS AND METHODS: We conducted a cross-sectional study with men presenting to the Veterans Administration Boston Healthcare System Urology clinic between August 2012 and January 2013. Patients were asked to complete the American Urological Association symptom score and the Berlin sleep questionnaire to evaluate their voiding complaints and sleep quality. We performed univariable and multivariable statistical analyses to identify correlations between a positive Berlin score and voiding symptoms, with an emphasis on nocturia. RESULTS: A total 618 completed questionnaires were included. More than 65% of patients reported nocturia. Of those reporting nocturia, 55% also had a positive Berlin score. The American Urological Association symptom score components of frequency and nocturia, as well as body mass index and hypertension, were shown to be significant independent predictors of a positive Berlin questionnaire, suggesting high likelihood of SDB. Conversely, a positive Berlin questionnaire was a significant independent predictor of nocturia, suggesting high degree of correlation between the 2 conditions. CONCLUSION: Nocturia and other voiding symptoms, such as frequency, predict a positive Berlin score, and vice versa. Patients with a positive Berlin score may have an undiagnosed sleep disorder, the sequelae of which can lead to significant health consequences. If present, treatment of SDB can ameliorate voiding symptoms. Urologists should consider administration of the Berlin score in their office, particularly in patients refractory to treatment for their voiding complaints, and if positive, consider referral to a sleep specialist. PMID- 25733280 TI - Editorial comment. PMID- 25733281 TI - Development of a noninvasive method to diagnose bladder outlet obstruction based on decorrelation of sequential ultrasound images. AB - OBJECTIVE: To develop an ultrasound (US)-based method for noninvasive diagnosing of bladder outlet obstruction, and the relationship between decorrelation of sequential US images and the degree of obstruction in a urethra model was studied. MATERIALS AND METHODS: A flexible model of a male urethra was constructed from 15% aqueous solution of polyvinyl alcohol cryogel. To create 4 different degrees of obstruction, polyvinyl alcohol rings representing the prostate were placed around the model. Each model was perfused at different flow rates (1-15 mL/s) with an aqueous solution containing scattering particles mimicking urine. At each flow rate, 10 sequential US images were acquired. The average correlation coefficients between the images were calculated and plotted as a function of the degree of obstruction and the flow rate. RESULTS: The average correlation decreased approximately linearly with an increase in the degree of obstruction. This decrease in correlation (decorrelation) might be due to turbulence caused by the obstruction. A higher degree of obstruction creates more turbulence and results in a higher decorrelation between sequential US images. CONCLUSION: Quantification of the decorrelation between sequential US images may provide us with a new approach to noninvasively diagnose bladder outlet obstruction. PMID- 25733282 TI - Is new visual prostate symptom score useful as International Prostate Symptom Score in the evaluation of men with lower urinary tract symptoms? A prospective comparison of 2 symptom scores in Turkish society. AB - OBJECTIVE: To evaluate the correlation between the visual prostate symptom score (VPSS) and the International Prostate Symptom Score (IPSS) and uroflowmetry parameters in Turkish men with lower urinary tract symptoms. MATERIAL: Between September 2013 and March 2014, a total of 191 patients who were admitted to the hospital with lower urinary tract symptoms were enrolled in the study. After the routine tests were performed, the patients were requested to fill the IPSS questionnaire consisting of 8 questions and the VPSS questionnaire consisting of 4 questions. Peak (Qmax) and average (Qave) urinary flow rates were measured. RESULTS: Mean age value was 62.8 years (range, 43-84 years). The education level was divided into 3 groups as follows: groups 1, 2, and 3 consisting of 98 patients (51.3%) with formal schooling (1-8 years education), 61 patients (31.9%) with 9-12 years education, and 32 patients (16.8%) with college or university education, respectively. There was a positive correlation between the total IPSS and the total VPSS (r = 0.72; P <.001). There was a negative correlation between the Qmax values and both the total IPSS (r = -0.53; P <.001) and the total VPSS (r = -0.3; P <.01), separately. The questionnaire was completed without any assistance by 25 (25.5%), 33 (54.1%), and 27 (84.4%) men for the IPSS and by 76 (77.6%), 54 (88.5%), and 31 (96.9%) men for the VPSS in groups 1, 2, and 3, respectively. CONCLUSION: The VPSS correlates significantly with the IPSS and can be reliably used in the elderly and low-educated patients for the assessment of symptom severity in men with lower urinary tract symptoms. PMID- 25733283 TI - Editorial comment. PMID- 25733284 TI - Reply: To PMID 25733282. PMID- 25733285 TI - Ureteral stent failure in pediatric patients under 10 years: occurrence and risk factors. AB - OBJECTIVE: To examine the occurrence of ureteral stent failure in pediatric patients aged <10 years and to determine risk factors for failure. METHODS: We performed a retrospective cohort analysis of 100 patients who underwent ureteral stent insertion between January 2006 and December 2013. All patients were aged <10 years and were followed up until ureteral stent removal. Information regarding patient demographics, reason for stent insertion, duration of stent maintenance, stent diameter and length, and postoperative results was collected. Risk factors for stent failure were analyzed. RESULTS: Ureteral stenting was performed in 114 ureter units. The median age at stenting was 34.1 months (interquartile range [IQR], 8.1-71.2 months), and the median duration of stent maintenance was 35.0 days (IQR, 21.0-44.3 days). A 3-Fr stent was used in 39.5% of patients. Stent failure was observed in 11 ureter units (9.6%) at a median of 11.5 days (IQR, 7.8-24.5 days) after insertion, and the stent was subsequently removed. Use of a 3-Fr ureteral stent was the only risk factor for the development of stent failure; the failure rate was 20.0% with this stent diameter. CONCLUSION: Ureteral stenting was a useful procedure with a high success rate, even in patients aged <10 years. A 3-Fr ureteral stent was the only risk factor for stent failure; its substantial failure rate should be considered when deciding whether to insert a stent. Also, short-term re-evaluation after ureteral stent insertion is mandatory, especially with 3-Fr ureteral stents. PMID- 25733286 TI - Urotherapy for tear production with painless urination. AB - We report a rare case of a 4-year-old girl with involuntary watering of eyes and facial redness during painless voiding since early infancy. Here, we describe her response to urotherapy with improvement of involuntary tearing during micturition, which although neither life threatening nor debilitating, may be quite bothersome for children and their parents, leading to anxiety, emotional burden, or embarrassment. We hypothesize that the lacrimal glands and the bladder and bowel have common central nervous system pathways and that bladder retraining and bowel management might be a potential treatment for this rare condition. PMID- 25733287 TI - Advanced childhood testicular yolk sac tumor with bone metastasis: a case report. AB - We report a case of advanced childhood testicular yolk sac tumor with bone metastasis, which was successfully treated by multimodal treatment. Optimal management of bone metastases from testicular yolk sac tumor in childhood is discussed. PMID- 25733288 TI - Use of appendix for renal transplant urinary diversion after complete transplant ureteral necrosis: a 12-year follow-up. AB - A 15-year-old African American male patient with a history of posterior urethral valves ablated as a newborn and who also had formation of an appendicopyelostomy at 3 years of age due to transplant ureteral necrosis subsequently underwent cadaveric renal transplant. At the time, this was a novel method for salvaging urinary diversion for the renal allograft previously reported in 2003. He most recently presented to Arkansas Children's Hospital for transplant rejection secondary to nonadherence with medications. We present an interval case report of a novel technique allowing a complicated cadaveric renal transplant to survive for 12 years. PMID- 25733289 TI - Primary renal mesenchymal chondrosarcoma: a case report. AB - A 16-year-old female patient presented to our emergency department with a left upper extremity radiculopathy prompting several imaging studies. Magnetic resonance imaging of the neck revealed multiple cervical vertebrae lesions and computed tomography imaging demonstrated a 15-cm calcified mass originating from the left kidney and extending into the surrounding structures. Pathologic assessment of the open left radical nephrectomy specimen revealed a primary renal mesenchymal chondrosarcoma, a tumor that has only been documented in 5 prior case reports in the literature. PMID- 25733290 TI - Pubic symphysis osteomyelitis in the prostate cancer survivor: clinical presentation, evaluation, and management. AB - OBJECTIVE: To describe pelvic bone osteomyelitis in the prostate cancer survivor, to report on clinical presentation and treatment, and to suggest an algorithmic approach to managing this syndrome complex. MATERIALS AND METHODS: A retrospective chart review from January 2011 to June 2014 was performed to identify prostate cancer patients with pubic symphysis osteomyelitis at a tertiary-care academic medical center with emphasis on genitourinary cancer survivorship. Data on clinical presentation and outcomes were reviewed. RESULTS: Ten patients were diagnosed with having osteomyelitis of the pubic symphysis with or without extension into the pubic rami. Three patients had associated rectal fistulas. Four patients had radical prostatectomy, 5 patients received radiotherapy, and 1 patient received high-intensity focused ultrasound as the primary treatment for prostate cancer. The most common presenting symptoms were pelvic and suprapubic pain, difficulty in walking, and recurrent urinary infections at a median of 7 years after prostate cancer treatment (range, 1.5-16 years). Eight of the 10 patients underwent pubic bone debridement with urinary and fecal diversion when needed. Two patients continue to be managed conservatively with suppressive antibiotics owing to low disease burden. Complete resolution of symptoms was noted in patients undergoing operative intervention, without any pelvic ring instability due to pubic bone resection. CONCLUSION: The combination of pelvic pain, difficulty with ambulation, and recurrent infections in a prostate cancer survivor should prompt investigation for pubic bone osteomyelitis-a poorly recognized syndrome complex that is best managed in a multidisciplinary setting. PMID- 25733291 TI - Androgen supplementation in rats increases the inflammatory response and prolongs urethral healing. AB - OBJECTIVE: To describe the effects of androgens on urethral wound healing, we compared the urethral healing process in castrated Sprague-Dawley rats with and without testosterone supplementation. METHODS: Of 30 castrated male Sprague Dawley rats, 15 received testosterone cypionate (3 mg/kg; T+ rats). All rats underwent an urethroplasty procedure and were sacrificed at postoperative days 5, 10, and 20. Neutrophils, macrophages, vessels, myofibroblasts, Ki67+ cells, collagen, and cytokines were quantified with immunofluorescence and real-time polymerase chain reaction. RESULTS: Penile length was significantly increased in T+ rats (21.8 vs 13.25 mm; P <.001) and operative time decreased (20.8 vs 23.3 minutes; P <.017). On day 5, T+ rats showed elevated neutrophil (727.4 vs 30.75 per high power field; P = .051) and macrophage counts (1295.8 vs 481.5 per high power field; P = .051) compared with those of T- rats. This elevation persisted throughout day 10 (291.7 vs 34; P = .002 and 1283.7 vs 110.2; P = .005) and day 20 (252.7 vs 12.2; P <.001 and 1672.7 vs 115.2; P <.001) reflecting increased and prolonged inflammation. Myofibroblasts were decreased in T+ rats on day 5 (215.7 vs 808.3; P <.001) and increased by day 10 (1490.1 vs 263.0; P = .001) and day 20 (1964.0 vs 210.0; P <.001) consistent with a delayed onset but with prolongation of the proliferative phase. Limitations include the use of castrated rats, which may have been exposed to androgens before castration. CONCLUSION: Testosterone supplementation leads to an increased inflammatory response and myofibroblast proliferation accompanied by prolonged inflammatory and proliferative phases. These novel findings suggest a delayed and possibly impaired urethral healing in the presence of excessive androgens. PMID- 25733292 TI - Management of concealed penis with modified penoplasty. AB - INTRODUCTION: To investigate the effect of penile degloving in combination with penoscrotal angle reconstruction for the correction of concealed penis. TECHNICAL CONSIDERATIONS: A foreskin circumcision incision was made along the coronal sulcus. After a sharp dissection under the superficial layer of tunica albuginea, the penile shaft was degloved to release the fibrous bands of the tunica dartos. Through a longitudinal incision or Z-plasty at the penoscrotal junction, securing of the tunica albuginea to the proximal tunica dartos was performed. The penoscrotal angle was reconstructed. This procedure effectively corrected the concealed penis, while correcting other problems such as phimosis. From August 2008 to August 2013, we performed 41 procedures for concealed penis. Correction was successful in all patients with an improved median length of 2.1 cm in the flaccid state. Follow-up ranged from 6 months to 2 years, and satisfactory cosmetic outcomes were obtained without scars or erectile discomfort. CONCLUSION: Our technique includes degloving and penoscrotal angle reconstruction, which provides proper visualization for fixation of the penile base. The longitudinal or Z-plasty incision also opened the degloving dead cavity, which was good for drainage. The procedure is straight forward with good functional and cosmetic outcomes and is thus ideal for correction of the concealed penis. PMID- 25733293 TI - Re: Woldu et al.: who really benefits from nephron-sparing surgery? (Urology 2014;84:860-868). PMID- 25733294 TI - Re: patient-reported sexual outcomes after holmium laser enucleation of the prostate: a 3-year follow-up study (Urology 2014;84:421-426). PMID- 25733295 TI - Reply by the authors. PMID- 25733296 TI - Re: Wolder et al.: who really benefits from nephron-sparing surgery? (Urology 2014;84:860-868). PMID- 25733297 TI - Re: Sener et al.: asymptomatic lower pole small renal stones: shock wave lithotripsy, flexible ureteroscopy, or observation? A prospective randomized trial (Urology 2015;85:33-37). PMID- 25733298 TI - Re: Tran et al.: anterior urethral valve associated with posterior urethral valves: report of 2 cases and review of the literature (Urology 2014;84:469-471). PMID- 25733299 TI - Reply by the authors. PMID- 25733300 TI - Reply by the authors. PMID- 25733302 TI - Lobe-specific expression of phosphodiesterase 5 in rat prostate. AB - OBJECTIVE: To investigate the level and location of phosphodiesterase 5 (PDE5) expression in rat prostate. METHODS: The ventral, dorsal, and lateral lobes of rat prostate were examined for PDE5 expression by Western blotting. Intact rat urogenital complex, including the urinary bladder and accessory reproductive glands, was examined for PDE5 expression by immunohistochemistry. Individual prostatic lobes were further examined by immunofluorescence for expression of PDE5, alpha-smooth muscle actin, and rat endothelial cell antigen. RESULTS: Western blot analysis showed that PDE5 was expressed at a significantly lower level in dorsal lobe (DL) than in ventral lobe (VL) or lateral lobe (LL). Immunohistochemistry and immunofluorescence analyses showed that PDE5 was expressed in both acinar epithelium and periacinar smooth muscle. However, although similar levels of smooth muscle PDE5 expression were observed in all 3 prostatic lobes, significantly lower level of epithelial PDE5 expression was found in DL compared with VL or LL. In prostatic blood vessels, PDE5 expression was clearly visible in the endothelium but not as easily detectable in the smooth muscle. CONCLUSION: PDE5 was expressed in the acinar epithelium and periacinar smooth muscle of rat prostate. However, the epithelial PDE5 expression was significantly less in DL than in VL or LL. Regardless, the acinar wall, not the blood vessel wall, is the predominant PDE5 expression site in rat prostate. PMID- 25733301 TI - Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. AB - OBJECTIVE: To evaluate programmed death ligand 1 (PD-L1) expression in urothelial carcinoma of the bladder in relationship with tumor-infiltrating CD8+ T cells. MATERIALS AND METHODS: Tissue microarrays were prepared from 56 cystectomy specimens performed at our hospital (1994-2002). PD-L1 immunoexpression was assessed using the murine antihuman PD-L1 monoclonal antibody 5H1. Extent of membranous PD-L1 expression was assigned in each spot. Spots showing >=5% expression were considered positive. Average PD-L1 expression per tumor was also calculated (5% positivity cutoff). "High CD8 density" was defined as the presence of >=60 CD8+ intraepithelial lymphocytes per high power field in a given spot. A tumor was considered high density if >=50% of its spots were of high density. RESULTS: PD-L1 expression was positive in approximately 20% of tumors. None of the benign urothelium spots expressed PD-L1. High CD8 density was observed in approximately 20% of cases. CD8 density did not correlate with PD-L1 expression. Overall survival (OS) and disease-specific survival (DSS) rates were 14% and 28%, respectively (median follow-up, 31.5 months). PD-L1 expression was associated with age at cystectomy (P = .01). Remaining clinicopathologic parameters were not associated with PD-L1 expression or CD8 density. High CD8 density was associated with favorable OS (P = .02) and DSS (P = .02). The same was true when CD8 density was adjusted for demographic and clinicopathologic parameters. There was no correlation between PD-L1 expression and outcome. CONCLUSION: High intratumoral CD8+ T cell density is associated with better OS and DSS in invasive urothelial carcinoma of the bladder. We found no correlation between PD-L1 expression and outcome. PMID- 25733303 TI - Nanowire analysis of cancer-testis antigens as biomarkers of aggressive prostate cancer. AB - OBJECTIVE: To demonstrate the ability of the nCounter Analysis System, a nanowire technology, to sensitively and accurately detect cancer-testis antigens (CTAs) in men with prostate cancer and correlate them with disease parameters. The clinical implementation of novel biomarkers is necessary to provide for individual disease treatment planning for men with prostate cancer. The CTAs, as cancer-associated biomarkers that may correlate with aggressive disease, have the potential to play an important role. METHODS: Formalin-fixed, paraffin embedded samples were used from men undergoing radical prostatectomy for prostate cancer. The expression of CTAs along with control genes was measured from formalin-fixed, paraffin-embedded prostate cancer tissues using real-time polymerase chain reaction and the nCounter assay. RESULTS: Using a nanowire-based assay, ribonucleic acid (RNA) expression levels of the CTAs CSAG2 and NOL4 were found to be significantly higher in men with Gleason score (GS) 8-10 disease than those with GS <=4+3 disease. On the contrary, the RNA expression level of PAGE4 was lower in men with GS 8-10 disease than those with GS <=6 group. This study demonstrates that CTAs can be detected with a nanostring assay that is translatable and that a set of CTAs correlates with the clinical characteristics of the disease. CONCLUSION: CTAs represent unique, cancer-associated biomarkers with potential utility in the clinic. The nCounter nanowire technology provides an opportunity to evaluate this panel of CTAs associated with aggressive prostate cancer in a multi-institutional fashion. PMID- 25733304 TI - Zinc induces a bell-shaped proliferative dose-response effect in cultured smooth muscle cells from benign prostatic hyperplasia. AB - OBJECTIVE: To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation. METHODS: The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-MUM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation. RESULTS: Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 MUM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner. CONCLUSION: The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH. PMID- 25733305 TI - Effects of the 5alpha-reductase inhibitor dutasteride on rat prostate alpha1A adrenergic receptor and its mediated contractility. AB - OBJECTIVE: To clarify the possible interference of the 5alpha-reductase inhibitor dutasteride with alpha-adrenergic blockers, whose action is mainly mediated by alpha1A-adrenergic receptor. METHODS: Male rats were divided into dutasteride and vehicle-treated groups. The drug treatment group was treated with oral dutasteride 0.5 mg/kg/d, and the control group received vehicle only for 2 months. After the 2-month treatment, the rats' ventral prostate weight changes and the testosterone and dihydrotestosterone levels in the serum were measured. In vitro organ-bath studies, real-time polymerase chain reaction, and tissue segment binding were performed to determine the expression of alpha1A-adrenergic receptors and its mediated contractility. RESULTS: Dutasteride treatment significantly decreased the rats' ventral prostate weight, increased their testosterone levels, and decreased the dihydrotestosterone levels in their serum. There were no marked changes in the alpha1A-adrenergic receptor messenger ribonucleic acid expression, relative phenylephrine-induced contractility, or nerve-mediated contractility between the groups. Dutasteride treatment caused no marked changes in the relative binding capacity of alpha1A-adrenergic receptor, whereas it greatly decreased the total protein expression of this subtype and its mediated maximal contraction in the whole ventral prostate. CONCLUSION: These results suggest that dutasteride does not interfere with alpha-adrenergic blockers but otherwise has beneficial effects on their actions. Therefore, the long-term administration of the combination of dutasteride with an alpha adrenergic blocker might be a better choice for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. PMID- 25733306 TI - Panoramic laparoscopic view of transverse testicular ectopia. AB - Transverse testicular ectopia (TTE) is a rare congenital anomaly in which both testes migrate toward the same hemiscrotum. We present a case of TTE in a 33-year old man. Laparoscopy showed the left spermatic vessels, accompanied by parietal peritoneum, which formed a septum that divided the pelvic space into two, were extending transversely from the left lateral side of the descending colon toward the right internal inguinal ring over the sigmoid colon. A panoramic laparoscopic view of the spermatic vessels in TTE can clearly demonstrate the descending pathway and partly contribute to our understanding of the etiologic mechanisms of TTE. PMID- 25733307 TI - Simultaneous urethrocutaneous and urethrocavernous fistula after proximal corporospongiosal shunt for priapism. AB - Proximal corporospongiosal shunts are used for the most refractory cases of priapism. Here, we present the case of a 58-year-old man whose priapism was only partially responsive to phenylephrine injections and distal shunting. Proximal shunting was required, and he subsequently developed fistulization of the proximal penile urethra into the skin and the corpora cavernosa. The formation of simultaneous urethrocutaneous and urethrocavernous fistulae is a rare complication of proximal corporospongiosal shunts that can be initially managed with urinary diversion with a suprapubic tube. PMID- 25733308 TI - Malignant epithelioid hemangioendothelioma of the adrenal gland treated by laparoscopic excision. AB - Epithelioid hemangioendothelioma is a rare vascular tumor mostly seen in liver, lung, and bone. Involvement of the adrenal gland has not been reported previously. Here, we report the first case of adrenal malignant epithelioid hemangioendothelioma in an 81-year-old man who was successfully treated by laparoscopic excision. PMID- 25733309 TI - Renal cell carcinoma and an incidental adrenal lesion: adrenal collision tumors. AB - Incidental adrenal lesions are common in patients with primary renal cell carcinoma (RCC). Modern cross-sectional imaging, especially phase-shift, magnetic resonance imaging, is an important adjunct in evaluating adrenal lesions. We present the case of an incidental left adrenal nodule consistent with an adenoma in a patient with a history of pT2 RCC status post right nephrectomy. He subsequently developed multiple renal lesions in the contralateral solitary kidney. Despite meeting radiographic criteria for an adenoma, surgical resection of the adrenal at the time of partial nephrectomy demonstrated RCC metastatic to the adrenal. PMID- 25733310 TI - [Continent urinary diversion following anterior exenteration]. AB - BACKGROUND: Quality of life after anterior or total exenteration is determined, among other factors, by the type of urinary diversion. There are two different types of urinary diversion: incontinent diversion (ureterocutaneostomy, ileal conduit, and colonic conduit) and continent diversions (continent cutaneous pouch, orthotopic neobladder, and rectal reservoir). RESULTS: Invasive bladder cancer and advanced or recurrent gynecological tumors are the main indications for continent urinary diversion in women. In patients with non-irradiated bladder cancer, an orthotopic neobladder (except those with tumor invasion of the bladder neck or urethra) or a rectal reservoir is an option. In patients who had received preoperative radiotherapy, non-irradiated bowel segments should be used for urinary diversion (e.g., the transverse colon). In patients with planned postoperative radiation, the urinary diversion should be outside the radiation field. CONCLUSION: Advantages and disadvantages of all types of urinary diversion should be objectively discussed with the patient. Especially exenteration for advanced or recurrent gynecological cancers should be performed in centers with a multidisciplinary team (gynecologist, urologist, radiotherapist, and in cases with complete exenteration the gastrointestinal surgeon). PMID- 25733312 TI - Foxc1 is required for early stage telencephalic vascular development. AB - BACKGROUND: The brain vascular system arises from the perineural vascular plexus (PNVP) which sprouts radially into the neuroepithelium and subsequently branches off laterally to form a secondary plexus in the subventricular zone (SVZ), the subventricular vascular plexus (SVP). The process of SVP formation remains to be fully elucidated. We investigated the role of Foxc1 in early stage vascular formation in the ventral telencephalon. RESULTS: The Foxc1 loss of function mutant mouse, Foxc1(ch/ch) , showed enlarged telencephalon and hemorrhaging in the ventral telencephalon by embryonic day 11.0. The mutant demonstrated blood vessel dilation and aggregation of endothelial cells in the SVZ after the invasion of endothelial cells through the radial path, which lead to failure of SVP formation. During this early stage of vascular development, Foxc1 was expressed in endothelial cells and pericytes, as well as in cranial mesenchyme surrounding the neural tube. Correspondingly, abnormal deposition pattern of basement membrane proteins around the vessels and increased strong Vegfr2 staining dots were found in the aggregation sites. CONCLUSIONS: These observations reveal an essential role for Foxc1 in the early stage of vascular formation in the telencephalon. PMID- 25733311 TI - Delivery of oligonucleotides with lipid nanoparticles. AB - Since their inception in the 1980s, oligonucleotide-based (ON-based) therapeutics have been recognized as powerful tools that can treat a broad spectrum of diseases. The discoveries of novel regulatory methods of gene expression with diverse mechanisms of action are still driving the development of novel ON-based therapeutics. Difficulties in the delivery of this class of therapeutics hinder their in vivo applications, which forces drug delivery systems to be a prerequisite for clinical translation. This review discusses the strategy of using lipid nanoparticles as carriers to deliver therapeutic ONs to target cells in vitro and in vivo. A discourse on how chemical and physical properties of the lipid materials could be utilized during formulation and the resulting effects on delivery efficiency constitutes the major part of this review. PMID- 25733314 TI - Optical diagnostics - spectropathology for the next generation. PMID- 25733313 TI - Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. AB - Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD, we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation, we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared with their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4(+) NPCs with a pharmacological inhibitor of glycogen synthase kinase 3, a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention. PMID- 25733315 TI - [Association of sleep-disordered breathing and malignant arrhythmias in patients with ischemic and dilated cardiomyopathy]. AB - Sleep-disordered breathing (SDB) has so far been a neglected comorbidity in patients with cardiac arrhythmias. Recently however, several studies have revealed a correlation between SDB and malignant ventricular arrhythmias. This review article is intended to provide the reader with an update on the pathophysiological association between SDB and ventricular arrhythmias, available clinical data, and therapeutic options. PMID- 25733316 TI - Revolving thrombus within the left atrium at atrial fibrillation ablation. AB - A 68-year-old man was referred for pulmonary vein (PV) isolation. Access to the left atrium was obtained via a single transseptal puncture. A heparin bolus was given immediately after puncture. Angiography of the left PV was performed. After the contrast wash-out, a contrasted longitudinal thrombus was shown revolving within the left atrium for several seconds before being expelled through the mitral and aortic valves. It is common practice in these procedures to administer an intravenous bolus of heparin immediately after the transseptal puncture. However, heparin has latency to become effective, and this can result in thromboembolic events. PMID- 25733317 TI - Effects of ivabradine therapy on heart failure biomarkers. AB - BACKGROUND: Heart rate (HR) reduction is associated with improved outcomes in patients with heart failure (HF) and biomarkers can be a valuable diagnostic tool in HF management. The primary aim of our study was to evaluate the short-term (6 months) effect of ivabradine on N-terminal pro B-type natriuretic peptide (NT proBNP), CA-125, and cystatin-C values in systolic HF outpatients, and secondary aim was to determine the relationship between baseline HR and the NT-proBNP, CA 125, cystatin-C, and clinical status variation with ivabradine therapy. METHODS: Ninety-eight patients (mean age: 65.81 +/- 10.20 years; 33 men), left ventricular ejection fraction < 35% with Simpson method, New York Heart Association (NYHA) class II-III, sinus rhythm and resting HR > 70/min, optimally treated before the study were included. Among them, two matched groups were formed: the ivabradine group and the control group. Patients received ivabradine with an average (range of 10-15) mg/day during 6 months of follow-up. Blood samples for NT-proBNP, CA 125, and cystatin-C were taken at baseline and at the end of a 6-month follow-up in both groups. RESULTS: There was a significant decrease in NYHA class in the ivabradine group (2.67 +/- +/- 0.47 vs. 1.85 +/- 0.61, p < 0.001). When ivabradine and control groups were compared, a significant difference was also found in NHYA class 6 months later (p = 0.013). A significant decrease was found in HR in the ivabradine and control groups (84.10 +/- 8.76 vs. 68.36 +/- +/- 8.32 bpm, p = 0.001; 84.51 +/- 10 vs. 80.40 +/- 8.3 bpm, p = 0.001). When both groups were compared, a significant difference was also found in HR after 6 months (p = 0.001). A significant decrease was found in cystatin-C (2.10 +/- 0.73 vs. 1.50 +/ 0.44 mg/L, p < 0.001), CA-125 (30.09 +/- 21.08 vs. 13.22 +/- 8.51 U/mL, p < 0.001), and NT-proBNP (1,353.02 +/- 1,453.77 vs. 717.81 +/- 834.76 pg/mL, p < 0.001) in the ivabradine group. When ivabradine and control groups were compared after 6 months, a significant decrease was found in all HF parameters (respectively; cystatin-C: p = 0.001, CA-125: p = 0.001, NT-proBNP: p = 0.001). Creatinine level was significantly decreased and glomerular filtration rate (GFR) was significantly increased in the ivabradine group (1.02 +/- 0.26 vs. 0.86 +/- 0.17, creatinine: p = 0.001; 79.26 +/- 18.58 vs. 92.48 +/- 19.88, GFR: p = 0.001). There was no significant correlation between NYHA classes (before and after ivabradine therapy) and biochemical markers, or HR. CONCLUSIONS: In the outpatients with systolic HF, persistent resting HF > 70/min with optimal medical therapy, the NT-proBNP, CA-125, and cystatin-C reductions were obtained with ivabradine treatment. Measurement of NT-proBNP, CA-125, and cystatin-C may prove to be useful in biomarker panels evaluating ivabradine therapy response in HF patients. PMID- 25733318 TI - Can thromboembolic risk be associated with erectile dysfunction in atrial fibrillation patients? AB - BACKGROUND: Erectile dysfunction (ED) is highly prevalent in patients with diseases of cardiovascular system, including patients with atrial fibrillation (AF). Reasons for this high co-prevalence include endothelial dysfunction, inflammation, oxidative and emotional stress associated with AF. Association of AF-induced prothrombotic state and possible microthrombi in penile arteries with ED remains unclear. The present study aims to assess if probability of AF associated risk of peripheral thromboembolism may be associated with ED in AF patients. METHODS: Probability of thromboembolic complications was assessed with two commonly used risk scores CHADS2 and CHA2DS2-VASc in a group of continuous AF patients. All patients were also asked to fill an IIEF-5 questionnaire designed for screening for ED. RESULTS: Mean CHADS2 score in the whole study group was 1.1 +/- 1.0 points and CHA2DS2- -VASc was 1.5 +/- 1.4 points. ED was present in 57.4% of the 129-person study population. In patients with ED, both CHADS2 (0.9 +/- 1.0 vs. 1.3 +/- 1.1; p = 0.03) and CHA2DS2-VASc (1.2 +/- 1.1 vs. 1.8 +/- 1.5; p = 0.03) scores were significantly higher than in the group without dysfunction. After dividing the patients according to age into groups younger than 65 years vs. >= 65 years, observed correlation was no longer significant in the younger group (p > 0.05). In patients >= 65 years, in whom the risk scores are routinely used, dysfunction both CHADS2 (1.1 +/- 0.9 vs. 2.0 +/- 0.9; p = 0.02) and CHA2DS2 VASc (2.3 +/- 1.1 vs. 3.4 +/- 1.3; p = 0.04) scores were higher in the group with ED. CONCLUSIONS: Erectile dysfunctions in AF patients are associated with elevated cardioembolic risk. We postulate that the diagnosis of ED should be considered an additional marker of prothrombotic state, and may be useful in clinical decision-making, especially in patients >= 65 years old. PMID- 25733319 TI - White blood cell count to mean platelet volume ratio as a novel non-invasive marker predicting long-term outcomes in patients with non-ST elevation acute coronary syndrome. AB - BACKGROUND: Total white blood cell (WBC) count and mean platelet volume have previously been shown to predict outcomes in acute coronary syndrome (ACS) patients. In this prospective study, we sought to determine the prognostic value of baseline WBC count to mean platelet volume ratio (WMR) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). METHODS: A total of 490 patients with NSTE-ACS were prospectively enrolled. The relationship between baseline WMR and major adverse cardiovascular events (MACE) incidence was assessed during a mean follow-up of 330.8 +/- 38 days. RESULTS: The patients' mean age was 60.4 +/- 12.9 year, 59% of them were male. The patients were categorized into two groups based on WMR values, high- and low-WMR groups (< 755 vs. >= 755). The incidence of MACE was significantly higher in high-WMR compared with that of low-WMR group (22.4% vs. 10.7%, p < 0.001). Total WBC counts (median 7.9 vs. 6.9 *103/MUL, p = 0.004), neutrophil count (median 4.6 vs. 4.2 *103/MUL, p = 0.021), and WMR (median 863.2 vs. 731.5, p = 0.001) were significantly higher in the MACE positive than MACE-negative group. The high-WMR was found to be significantly associated with the MACE-free survival rate (p < 0.001). In an adjusted cox regression model, the elevated WMR was independently predicted the incidence of MACE (hazard ratio 2.419, 95% CI 1.515-3.862, p < 0.001). CONCLUSIONS: The elevated baseline WMR independently predicted the MACE incidence in patients with NSTE-ACS during long-term follow-up. PMID- 25733320 TI - Influence of percutaneous pulmonary valve implantation on exercise capacity: Which group of patients benefits most from the intervention? AB - BACKGROUND: The aim of the study was to evaluate the role of cardiopulmonary exercise testing (CPET) parameters in assessing exercise capacity improvement after percutaneous pulmonary valve implantation (PPVI). Additionally, it aimed to determine if there are any baseline characteristics influencing that change. METHODS AND RESULTS: The study comprised 32 patients (mean age 26 +/- 9); 53% males; diagnosis: tetralogy of Fallot (n = 18), pulmonary atresia (n = 6), Ross procedure (n = 4), other (transposition of great arteries, pulmonary stenosis, double outlet right ventricle, common arterial trunk type II--n = 4) who underwent successful PPVI due to right ventricular out-flow tract dysfunction (predominant pulmonary regurgitation--n = 17, predominant pulmonary stenosis--n = 15). Treadmill CPET was performed before and a year after PPVI along with clinical evaluation, cardiac magnetic resonance and transthoracic echocardiography. Twelve months post successful PPVI (pulmonary valve competence restoration and pulmonary gradient reduction from 58.8 +/- 47.1 to 26.6 +/- 10.8 mm Hg) there was a significant decrease in the ventilatory equivalent for CO2 at peak exercise (EQCO2) (25.3 +/- 3.3 to 24.3 +/- 3.0, p = 0.04) and oxygen consumption at peak exercise (pVO2) (20.4 +/- 5.0 to 22.6 +/- 5.3 mL/kg/min, p = 0.04). Improved EQCO2 correlated with an increase in right and left ventricular ejection fraction (respectively R = -0.57, p = 0.002; R = -0.56, p = 0.002). In this study, no baseline factors that might affect improvement in exercise function were found. CONCLUSIONS: Successful PPVI leads to an improvement in exercise capacity and hemodynamic response to exercise. The correlation between the improvement in EQCO2 or peak VO2 and baseline characteristics was too weak to reliably identify the group of patients that will benefit from the procedure. PMID- 25733321 TI - Multidetector cardiac tomography: a useful tool before cardiac resynchronization therapy. AB - BACKGROUND: Left ventricular lead placement in a suitable coronary vein is a key determi-nant of responsiveness to cardiac resynchronization therapy (CRT). Multidetector cardiac tomography (MDCT) is a non-invasive alternative to depict cardiac venous anatomy although coronary sinus (CS) retrograde venography (RV) is the gold standard. The aim of this study was to evaluate the accuracy of MDCT to determine the presence of CS tributaries before CRT. METHODS: A retrospective analysis of 41 consecutive patients eligible to CRT was performed. MDCT was assessed in all patients before CRT and RV was achieved in 39 patients. Both methods evaluated the presence of the inferior interventricular vein (IIV), posterior vein (PV) and lateral main vein (LMV). CS ostium diameter and distance between the CS ostium and right atrium (RA) lateral wall were also measured. RESULTS: The IIV was identified in 100% of MDCT and in 43.6% of RV. In comparison to RV, the MDCT's sensitivity to identify PV and LMV was 100% for both, kappa coefficient of 0.792 (CI 95% 0.46-0.93) and 0.69 (CI 95% 0.46-0.91), respectively. There was no significant difference between ischemic and non ischemic patients regarding the presence of PV or LMV. Median CS antero-posterior diameter was 10.3 mm (IQR 7.5-13) and supero-inferior was 14.1 mm (IQR 11.5-17) (p < 0.01). A positive correlation (p < 0.001) between echocardiographic RA area and the distance from CS ostium to the RA lateral wall in the MDCT was observed. CONCLUSIONS: MDCT is as accurate as RV to depict CS and its tributaries (IIV, PV, LMV), and it could be useful as a non-invasive technique before CRT. PMID- 25733322 TI - Insulin resistance predicts the risk for recurrent coronary events in post infarction patients. AB - BACKGROUND: We investigated the risk for recurrent coronary events associated with insulin resistance in post-infarction patients from the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) study. METHODS: The association between insulin resistance expressed by Homeostatic Model As-sessment 2 for Insulin Resistance (HOMA2-IR) and the risk for recurrent coronary events was investigated in a cohort of 1,032 patients evaluated 2 months after myocardial infarction (MI) with a follow-up of 26 months. The endpoint for the study was recurrent coronary event defined as cardiac death, nonfatal MI, or unstable angina, whichever occurred first. We used time dependent survival analysis and Cox proportional hazards regression method to determine the association between HOMA2 categorized as high > 75th percentile and endpoints after adjustment for relevant clinical covariates and series of thrombogenic and dyslipogenic factors. RESULTS: High HOMA2-IR defined as in fourth quartile (>= 2.4) was associated with increased risk for recurrent coronary events (HR 1.44; CI 1.03-2.01; p = 0.03) after adjustment for the clinical covariates: age, gender, diabetes, prior MI, pulmonary congestion, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. The highest risk of cardiac events was observed in non-obese patients (body mass index [BMI] <= 30 kg/m2) with high HOMA2-IR (HR 1.5; CI 1.02-2.22; p = 0.038). The plasma level of plasminogen activa-tor inhibitor-1 was associated with higher risk for recurrent coronary events in patients with insulin resistance (HR 1.79; CI 1.05-3.03; p = 0.03, interaction p = 0.018). CONCLUSIONS: In conclusion, insulin resistance predicts recurrence of coronary events in post-infarction population. HOMA2-IR is better than BMI in stratifying risk of recurrent coronary events. PMID- 25733323 TI - Idiopathic acquired leukonychia totalis of the fingernails in a child treated successfully with zinc and amino acid supplementation. PMID- 25733324 TI - Predictors of Seclusion or Restraint Use Within Residential Treatment Centers for Children and Adolescents. AB - This study identified predictors of seclusion or restraint use among licensed and/or accredited residential treatment centers (RTCs) for children and youth in the United States responding to a federally-sponsored survey of mental health services. 693 licensed and/or accredited child and adolescent RTCs responded to questions about the demographic and admission status of clients served on an identified date, services offered, size, ownership, funding, and their use of seclusion or restraint practices within the preceding 12 months. Logistic regression was used to determine factors predicting facility use of seclusion or restraint. A large majority of licensed and/or accredited child and adolescent RTCs (82 %) reported using seclusion or restraint in the prior year. Contrary to prior research, individual patient characteristics (percent of males, minorities, and involuntary admissions) did not predict the use of coercive techniques. Instead facility and funding variables accounted for approximately 27 % of the variance in the use of seclusion or restraint. Larger, privately-owned RTC's funded primarily through public monies and which offered medication and programming for SED youth were more likely to endorse having used seclusion or restraint in the previous year. Despite visible policy and advocacy efforts to reduce seclusion and restraint use over the past decade, a majority of licensed and/or accredited RTCs for children and adolescents report using such practices. Findings emphasize the importance of examining facility-level variables in predicting their use, and highlight the disconnect between nationally espoused goals and current practices regarding coercive techniques in child and adolescent RTCs. PMID- 25733325 TI - Atrial Septostomy: A Contemporary Review. AB - Pulmonary arterial hypertension (PAH) is a rare disease, but it boasts significant morbidity and mortality. Although remarkable achievements have been made in the medical treatment of PAH, there is a role for invasive or surgical procedures in patients with progressive disease despite optimal medical therapy or with no access to such therapy. Atrial septostomy creates a right-to-left intracardiac shunt to decompress the overloaded right ventricle. Despite significant advances to validate and improve this palliative procedure, as well as recent reports of improved outcomes, it is only slowly being adopted. This article aims to detail the history, indications, contraindications, procedural techniques, and outcomes of atrial septostomy. We will also shed light on some of the newer interventions, inspired by the same physiological concept, that are being evaluated as potential palliative modalities in patients with PAH. PMID- 25733326 TI - Clinical and genetic analysis of a family diagnosed with familial hypobetalipoproteinemia in which the proband was diagnosed with diabetes mellitus. AB - OBJECTIVE: To perform clinical and genetic analysis of a family with familial hypobetalipoproteinemia in which the proband had been diagnosed with diabetes mellitus. METHODS: Direct sequencing was performed on candidate genes such as APOB, PCSK9, and ANGPTL3. The effect of the mutant gene on lipid profile was investigated using biochemical methods. RESULTS: A novel mutation Y344S in ANGPTL3 was identified but no variants were found in PCSK9 or APOB. Lipid profiles showed the levels of TG, TC, and LDL-C to be significantly lower in Y344S carriers than in non-carriers in this family. The levels of HDL-C and plasma concentrations of ANGPTL3 showed no significant differences. Western blot analysis revealed that the mutant ANGPTL3 proteins could not be secreted into the medium. CONCLUSION: A novel mutation Y344S was found in ANGPTL3 gene in two diabetic patients with familial hypobetalipoproteinemia. The family study and genetic analysis suggest that this set of gene mutation may be a genetic basis for the lipid phenotypes, and may become a vascular protective factor in the probands with high risk of atherosclerosis. PMID- 25733327 TI - Inhibition of soluble epoxide hydrolase in mice promotes reverse cholesterol transport and regression of atherosclerosis. AB - Adipose tissue is the body largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), which maintains plasma high-density lipoprotein (HDL) levels. HDLs have a protective role in atherosclerosis by mediating reverse cholesterol transport (RCT). Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has various beneficial effects on cardiovascular disease. The sEH is highly expressed in adipocytes, and it converts epoxyeicosatrienoic acids (EETs) into less bioactive dihydroxyeicosatrienoic acids. We previously showed that increasing EETs levels with a sEH inhibitor (sEHI) (t-AUCB) resulted in elevated ABCA1 expression and promoted ABCA1-mediated cholesterol efflux from 3T3-L1 adipocytes. The present study investigates the impacts of t-AUCB in mice deficient for the low density lipoprotein (LDL) receptor (Ldlr(-/-) mice) with established atherosclerotic plaques. The sEH inhibitor delivered in vivo for 4 weeks decreased the activity of sEH in adipose tissue, enhanced ABCA1 expression and cholesterol efflux from adipose depots, and consequently increased HDL levels. Furthermore, t-AUCB enhanced RCT to the plasma, liver, bile and feces. It also showed the reduction of plasma LDL-C levels. Consistently, t-AUCB-treated mice showed reductions in the size of atherosclerotic plaques. These studies establish that raising adipose ABCA1 expression, cholesterol efflux, and plasma HDL levels with t-AUCB treatment promotes RCT, decreasing LDL-C and atherosclerosis regression, suggesting that sEH inhibition may be a promising strategy to treat atherosclerotic vascular disease. PMID- 25733328 TI - Methyl protodioscin increases ABCA1 expression and cholesterol efflux while inhibiting gene expressions for synthesis of cholesterol and triglycerides by suppressing SREBP transcription and microRNA 33a/b levels. AB - Sterol regulatory element-binding proteins (SREBPs) regulate homeostasis of LDL, HDL and triglycerides. This study was aimed to determine if inhibition of SREBPs by methyl protodioscin (MPD) regulates downstream gene and protein expressions of lipid metabolisms. In THP-1 macrophages, MPD increases levels of ABCA1 mRNA and protein in dose- and time-dependent manners, and apoA-1-mediated cholesterol efflux. The underlying mechanisms for the effects is that MPD inhibits the transcription of SREBP1c and SREBP2, and decreases levels of microRNA 33a/b hosted in the introns of SREBPs, which leads to reciprocally increase ABCA1 levels. In HepG2 cells, MPD shows the same effects as these observed in THP-1 macrophages. MPD also decreases the gene expressions of HMGCR, FAS and ACC for cholesterol and fatty acid synthesis. MPD further promotes LDL receptor through reducing the PCSK9 level. Collectively, the study demonstrates that MPD potentially increase HDL cholesterol while reducing LDL cholesterol and triglycerides. PMID- 25733330 TI - The prognostic value of the serum eicosapentaenoic acid to arachidonic acid ratio in relation to clinical outcomes after endovascular therapy in patients with peripheral artery disease caused by femoropopliteal artery lesions. AB - BACKGROUND: The EPA/AA ratio has emerged as a predictor of mortality endpoints in cardiac disease; however, its prognostic value in peripheral artery disease (PAD) patients is unclear. We assessed the serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio in patients with PAD caused by femoropopliteal artery lesions, to determine whether it predicts clinical outcomes after endovascular therapy (EVT). METHODS AND RESULTS: We obtained serum EPA/AA ratios from 132 consecutive patients with PAD caused by femoropopliteal artery lesions before EVT. Patients were divided into two groups using the median value of serum EPA/AA ratios of the entire cohort; LOW group with the levels <=0.30 (n = 66) and HIGH group >0.30 (n = 66). The incidence of major adverse events (MAE), including major adverse limb events (MALE) and death from any cause, was determined. At a median follow-up interval of 24 months, MALE occurred in 40 patients (30.3%) and 11 patients (8.3%) died. Kaplan-Meier curve analysis demonstrated the survival probability from MAE was significantly worse in patients with EPA/AA ratio under the median (long-rank test chi(2) = 16.4; p < 0.001). Multivariate Cox regression analysis showed critical limb ischemia (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 1.84 to 6.46; p < 0.001) and the preprocedural serum EPA/AA ratios <=0.30 (HR: 2.74; 95% CI: 1.33 to 5.65; p = 0.006) independently predicted MAE after EVT. CONCLUSIONS: Lower serum EPA/AA ratios appear to be associated with a greater risk of MALE and death from any cause after EVT in patients with PAD caused by femoropopliteal artery lesions. PMID- 25733329 TI - Sedentary behaviour patterns and carotid intima-media thickness in Spanish healthy adult population. AB - OBJECTIVE: The aim of this study was to analyze the association between sedentary behaviour, as assessed by an accelerometer, and mean carotid intima-media thickness (IMT). METHODS: The study included 263 healthy subjects belonging to the EVIDENT study (59.3% women). Carotid IMT was measured by carotid ultrasonography. Sedentary behaviour was measured objectively over 7 days using ActiGraph accelerometers. Thresholds of 10 consecutive minutes were used to establish sedentary bouts, and assess the number (n/day), and length >=10 min (min/day). RESULTS: Total sedentary time and sedentary time in bouts >=10 min was higher in participants with a larger mean carotid IMT (>P75). Otherwise, this sedentary time in bouts >=10 min parameter was weakly associated with augmented carotid IMT injury in the logistic regression model. CONCLUSION: Total sedentary time and sedentary time in bouts >=10 min, as assessed by accelerometer, was positively but weakly associated with carotid IMT. Equally, this sedentary time in bouts >=10 min was associated with carotid injury, but disappears after adjusting for potential confounders. These findings support that reducing sedentary time and increasing breaks in bouts of sedentary time might represent a useful additional strategy in the cardiovascular disease prevention. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01083082. PMID- 25733331 TI - Perioperative Lung Protection Provided by High-Dose Ambroxol in Patients with Lung Cancer. AB - The purpose is to observe the clinical effect of large doses of ambroxol hydrochloride in lung protection during the perioperative period of lung cancer operation. Fifty-six lung cancer patients who have undergone open-thoracic pulmonary lobectomy were divided randomly into two groups, and were given normal and large doses of ambroxol hydrochloride, respectively, during their perioperative period. Statistics based on post-operation clinical observations were analyzed in terms of ease of expectoration and expectoration properties, duration of antibiotics dependence, occurrence of lung complications, and adverse reactions related to ambroxol hydrochloride. On the third and the seventh day, the experimental group showed signs of improvement in terms of ease of expectoration and expectoration properties, compared with the controlled group. In terms of occurrence of post-operation lung complications and duration of antibiotics dependence, the experimental group also performed better. Using large doses of ambroxol hydrochloride would result in better clinical effects than using normal doses in preventing post-operation complications, and its clinical value in lung protection during lung cancer perioperative period calls for further research and promotion. PMID- 25733332 TI - The Diagnosis Pattern of Mid-Trimester Fetal Chromosomal Aneuploidy in Xuzhou and the Clinical Applications. AB - The objective of this study is to explore the diagnosis pattern of mid-trimester fetal chromosomal aneuploidy and its clinical applications. A large group of pregnant women (18-34 years) received dual serological screening. The elderly pregnant women, who were at high and critical risk and refused amniocentesis, underwent non-invasive detection of fetal DNA upon recommendation. Then, the pregnant women with positive non-invasive detection results received amniocentesis, amniotic cell culture, and karyotype analysis for confirmation. In total, 24,520 women and 629 elderly women (>35 years) received amniocentesis, amniotic cell culture, and karyotype analysis, and 1512 women received non invasive detection of fetal DNA. A total of 275 women received invasive prenatal diagnosis. Seventeen cases of trisomy 21, 3 cases of trisomy 18, and 2 cases of sex chromosomal abnormality were diagnosed. The serological screening-gene detection-prenatal diagnosis for mid-trimester fetal chromosomal aneuploidy increased the detection rate, and decreased the frequency of invasive prenatal diagnosis. PMID- 25733333 TI - Interventional Catheterization Combined with Staphylococcin Aureus Injection in 112 Cases of Ischemic Necrosis of Femoral Heads. AB - The objective of this study was to investigate the effectiveness of interventional catheterization with staphylococcin aureus injection on ischemic necrosis of the femoral heads. By percutaneous catheterization of the femoral artery, papaverine, urokinase, compound Danshen, and anisodamine were injected intravenously into the arteries of the femoral head. Staphylococcin aureus injection was injected into the hit joint capsule on the side of the lesion to compare the conditions before and after surgery. The patients did the rehabilitation exercises of the hit joint 48 h after the surgery and had double crutches for 3-6 months. Of the 112 cases, 39 cases (34.8 %) were cured, 51 cases (45.6 %) were markedly effective, and 22 cases (19.6 %) were effective. Interventional catheterization combined with staphylococcin aureus injection given into the hit joint capsule is an effective way to treat ischemic necrosis of the femoral head by influencing the internal and external environments of the femoral head. PMID- 25733334 TI - Interlocking Intramedullary Nails in Fracture Treatment. AB - The aim of this study is to evaluate interlocking intramedullary nails in the treatment of fractures. We retrospectively reviewed 68 adult patients (for a total of 95 fractures) with isolated long-bone fractures who were treated with interlocking intramedullary nails between January 2010 and January 2012. The patients were followed for 18 months to observe the healing of the fracture, time, and the occurrence of complications in the shoulder, knee, and hip joint functions. After about a follow-up period of 26.2 months (range 18-39 months), all cases obtained bony union. The mean time to fracture union was 5.2 months. Cases of knees and hip joint functions of the femoral or tibial fracture and shoulder functions of the humeral fractures were observed. The interlocking intramedullary nails may be considered as an alternative method for isolated diaphyseal fractures of the extremities. The advantages of this method include small operative scars, reliable fixations, better fracture healings, and fewer complications. PMID- 25733335 TI - Treatment of Intestinal Paralysis Using Revised Major Purgative Decoction Combined with Nasointestinal Decompression: Experience with 31 Patients. AB - To investigate the feasibility of using a revised major purgative decoction in combination with nasointestinal decompression for the treatment of intestinal paralysis. 31 patients with intestinal paralysis underwent gastrointestinal decompression. A fluoroscopic guided tri-lumen nasointestinal decompression tube was placed, and the patients were randomly divided into two groups: patients in the study group (n = 16) received 100 ml of a revised major purgative decoction infused through the decompression tube, three times daily; and patients in the control group (n = 15) were given neostigmine 0.5 mg by muscle injection, twice daily. The clinical presentations and imaging findings both before and after the treatment were recorded and compared. A significant increase in decompression volumes and a rapid reduction in intra-abdominal pressure (IAP) were observed in all patients undergoing nasointestinal decompression (p < 0.05). Patients in the study group achieved significantly earlier restoration of intestinal function by presenting with earlier restoration of bowel sound, earlier passage of flatus and stools (p < 0.05). The deployment of gastrointestinal decompression using a long tri-lumen nasointestinal decompression tube is effective in reducing IAP and relieve abdominal distension, whereas revised major purgative decoction can enhance the recovery of intestinal function. The joint application of these two strategies is effective and safe in the management of intestinal paralysis and is worthy of adoption in clinical settings. PMID- 25733336 TI - First total synthesis of the marine natural products clavulolactones II and III. AB - The first total synthesis of the marine prostanoids clavulolactones II and III is presented from an easily accessible chiral, non-racemic cyclopentenone intermediate. Key steps involve selective TBDMS deprotection, selective reduction of the beta-side chain and aldol condensation. Clavulolactones II and III were successfully prepared from (S)-4-((tert-butyldimethylsilyl)oxy) cyclopent-2-en-1 one over nine steps, in overall yields of 21 and 7% respectively. PMID- 25733337 TI - Non-perturbative effects in spin glasses. AB - We present a numerical study of an Ising spin glass with hierarchical interactions--the hierarchical Edwards-Anderson model with an external magnetic field (HEA). We study the model with Monte Carlo (MC) simulations in the mean field (MF) and non-mean-field (NMF) regions corresponding to d >= 4 and d < 4 for the d-dimensional ferromagnetic Ising model respectively. We compare the MC results with those of a renormalization-group (RG) study where the critical fixed point is treated as a perturbation of the MF one, along the same lines as in the expansion for the Ising model. The MC and the RG method agree in the MF region, predicting the existence of a transition and compatible values of the critical exponents. Conversely, the two approaches markedly disagree in the NMF case, where the MC data indicates a transition, while the RG analysis predicts that no perturbative critical fixed point exists. Also, the MC estimate of the critical exponent nu in the NMF region is about twice as large as its classical value, even if the analog of the system dimension is within only ~2% from its upper critical-dimension value. Taken together, these results indicate that the transition in the NMF region is governed by strong non-perturbative effects. PMID- 25733338 TI - Neonatal Serum Phosphorus Levels and Enamel Defects in Very Low Birth Weight Infants. AB - BACKGROUND: Very low birth weight (VLBW) infants miss out on the period of greatest mineral accretion that occurs during the last trimester of pregnancy and are at higher risk of enamel defects. No studies have well described the relationship between neonatal nutrition and dental outcomes in preterm, VLBW infants. The objective of this study was to assess the differences in nutrition biomarkers, feeding intake, and comorbidities among VLBW infants with and without enamel defects. METHODS: A retrospective chart review of VLBW infants recruited for an ongoing longitudinal dental study between 2007 and 2010 was done. Participants were classified as cases and controls according to the presence/absence of developmental defects of enamel at 8 and/or 18-20 and/or 36 months. Demographics and medical and nutrition data were abstracted from 76 subjects' medical charts. RESULTS: Of the 76 VLBW subjects, 62% had enamel defects (hypoplasia and/or opacity). The only significant variable in the logistic regression analysis was that infants with a 1-mg/dL increase in serum phosphorus levels had a 68% reduction in the odds of having enamel hypoplasia (odds ratio, 0.322; P = .024). CONCLUSION: Neonatal lower serum phosphorus levels are significantly associated with enamel hypoplasia in VLBW infants younger than 3 years. PMID- 25733339 TI - Impact of Process Optimization and Quality Improvement Measures on Neonatal Feeding Outcomes at an All-Referral Neonatal Intensive Care Unit. AB - AIM: We hypothesized that the implementation of a feeding quality improvement (QI) program among premature neonates accelerates feeding milestones, safely lowering hospital length of stay (LOS) compared with the baseline period. METHODS: Baseline data were collected for 15 months (N = 92) prior to initiating the program, which involved development and implementation of a standardized feeding strategy in eligible premature neonates. Process optimization, implementation of feeding strategy, monitoring compliance, multidisciplinary feeding rounds, and continuous education strategies were employed. The main outcomes included the ability and duration to reach enteral feeds-120 (mL/kg/d), oral feeds-120 (mL/kg/d), and ad lib oral feeding. Balancing measures included growth velocities, comorbidities, and LOS. RESULTS: Comparing baseline versus feeding program (N = 92) groups, respectively, the feeding program improved the number of infants receiving trophic feeds (34% vs 80%, P < .002), trophic feeding duration (14.8 +/- 10.3 days vs 7.6 +/- 8.1 days, P < .0001), time to enteral feeds-120 (16.3 +/- 15.4 days vs 11.4 +/- 10.4 days, P < .04), time from oral feeding onset to oral feeds-120 (13.2 +/- 16.7 days vs 19.5 +/- 15.3 days, P < .0001), time from oral feeds-120 to ad lib feeds at discharge (22.4 +/- 27.2 days vs 18.6 +/- 21.3 days, P < .01), weight velocity (24 +/- 6 g/d vs 27 +/- 11 g/d, P < .03), and LOS (104.2 +/- 51.8 vs 89.3 +/- 46.0, P = .02). Mortality, readmissions within 30 days, and comorbidities were similar. CONCLUSIONS: Process optimization and the implementation of a standardized feeding strategy minimize practice variability, accelerating the attainment of enteral and oral feeding milestones and decreasing LOS without increasing adverse morbidities. PMID- 25733340 TI - Managing paediatric acute severe ulcerative colitis according to the 2011 ECCO ESPGHAN guidelines: Efficacy of infliximab as a rescue therapy. AB - BACKGROUND: The effectiveness of medical therapy in paediatric acute severe colitis is scarcely described. We aimed to assess the efficacy of infliximab in children prospectively enrolled at Sapienza University of Rome between May 2010 and 2012. METHODS: Clinical assessment and laboratory data were recorded at admission and at day 3 and 5. All patients received corticosteroids; infliximab was administered in refractory patients. Colectomy rate was assessed at 2-year follow-up. RESULTS: Thirty-one patients (mean age 10.6+/-4.9 years, 52% females) were included: 21 responded to corticosteroids (68%), 10 were refractory and received infliximab (32%). Among the latter, 2 required urgent colectomy (20%); 80% responded, however 50% of these required elective colectomy during follow-up. Patients refractory to corticosteroids showed a significantly shorter interval from ulcerative colitis diagnosis to acute severe colitis compared to responders (7.4+/-9.6 vs. 23.1+/-21.6 months, respectively; p=0.01), and a higher rate of colectomy at follow-up (50% vs. 14%, respectively; p=0.007). More than 2 courses of corticosteroids before acute severe colitis were predictive of surgical need (OR 4.4). CONCLUSION: Despite its short-term efficacy, infliximab did not modify the long-term surgical rate of paediatric acute severe colitis in our cohort. Children with an early severe colitis commonly need a second-line therapy, whilst frequent courses of corticosteroids are predictive of a poor outcome. PMID- 25733341 TI - Risk of microangiopathy in type 2 diabetes mellitus patients with or without chronic hepatitis C: Results of a retrospective long-term controlled cohort study. AB - BACKGROUND: Patients with chronic hepatitis C have an increased risk of diabetes mellitus but the type and risk of developing diabetes-related complications have not yet been evaluated. METHODS: In order to compare the incidence of diabetic microangiopathy in patients with new onset diabetes without microangiopathy we recruited 54 hepatitis C virus (HCV)-positive and 119 HCV-negative patients from January 2005 to December 2006. All patients were followed-up every 6 months for liver and diabetic complications and incidence of cardiovascular diseases up to December 2012 when data were retrospectively analyzed. RESULTS: The two cohorts were comparable at enrolment except for mean body mass index, obesity rate and family history of diabetes (p=0.007). After 7.2 years of follow-up, 13 HCV positive (24.1%) and 37 HCV-negative patients (31%) showed at least one microangiopathic complication (p=0.34); 5 HCV-positive (9.3%) and 13 HCV-negative patients (10.8%) reported cardiovascular diseases (p=0.2); 14 HCV-positive (24.5%) compared to 0 HCV-negative patients developed liver-related complications (p=0.0003). One HCV-positive patient died due to liver cancer, 1 HCV-negative patient died from myocardial infarction (p=0.3). Increasing age (HR=1.04, 95% CI: 1.00-1.07, p=0.04) and smoking (HR=2.94, 95% CI: 1.06-8.17, p=0.04) were positively associated to diabetic complications. CONCLUSIONS: Incidence of microangiopathy is not significantly different in diabetics with or without chronic hepatitis C. PMID- 25733342 TI - Behavioral and psychosocial correlates of adiposity and healthy lifestyle in Asian Indians. AB - AIMS: Adiposity is an important diabetes risk factor, and Asian Indians have elevated diabetes risk. This analysis assessed the relationship between behavioral and psychosocial factors and adiposity among Asian Indians to better understand factors driving elevated weight/waist circumference in this population. METHODS: This study used screening data (N=1285) from the D-CLIP study, a randomized controlled diabetes prevention trial in Chennai, India. Correlation tests and linear regression models were done to describe relationships among exposure variables (weight loss/exercise self-efficacy, fruit/vegetable intake, weekly exercise, past weight loss experience) and between these exposures and BMI or waist circumference. RESULTS: Exercise and weight loss self-efficacy were positively correlated with average minutes per week exercising (R=0.26, p<0.0001) and fruit (R=0.07, p<0.05) and vegetable intake (R=0.12, p<0.0001). Weekly fruit consumption, past weight loss experience, and weight loss self-efficacy, along with sex, age, and marital status, explained 13.6% and 25.9% in the variation in BMI and waist circumference, respectively. CONCLUSIONS: Low fruit consumption, unsuccessful past weight loss attempts, and low self-efficacy for weight loss are associated with higher BMI and waist circumference in this population. Understanding factors related to adiposity is important for preventing and treating weight gain. PMID- 25733343 TI - Translational research for Diabetes Self-Management in Sri Lanka: A randomized controlled trial. AB - AIMS: The study tested the hypothesis that a theory driven Diabetes Self Management (DSM) intervention delivered by trained nurses would result in a clinically significant improvement in glycaemic control. METHODS: Patients with an HbA1c >7.5% (58mmol/mol) and free of diabetes complications were enrolled into a randomized controlled trial (n=85). Intervention consisted of four sessions and monthly follow up for 6 months. Biochemical tests, and diet and physical activity assessments were done in both groups. Analysis of covariance was used to test the effectiveness of the intervention. RESULTS: At 6 months, there was a significant difference (P=0.001) in HbA1c between the groups controlling for baseline values and other variables. Based on the primary outcome, 28% in the intervention group achieved the target value of 6.5% HbA1c, compared to 8% in the "usual care" group (P<0.001; eta(2)=0.65). The reduction in total energy intake and increase in physical activity was significant in the intervention group between baseline and follow up. CONCLUSIONS: The DSM intervention has resulted in a clinically significant impact on glycaemia, change in diet and physical activity, and has demonstrated the feasibility of using it within existing care arrangements in a developing country setting. PMID- 25733344 TI - Reduced serum levels of adiponectin in tension-type headache. AB - BACKGROUND AND OBJECTIVES: Inflammatory mediators have been studied in tension type headache (TTH) pathophysiology; however, their role is not yet well established. The aim of the present study was to investigate adiponectin (ADP) and its association with clinical parameters and psychiatric comorbidities in TTH patients. METHODS: This was a cross sectional study including TTH patients and controls. Beck Depression (BDI) and Anxiety (BAI) Inventories, and Headache Impact Test (HIT-6) were recorded. Serum levels of ADP were measured by ELISA. RESULTS: Forty-eight TTH patients and forty-eight controls without headache were enrolled in the study. ADP levels were significantly lower among patients with TTH [31.1 (20.4-69.20) versus 37.8 (24.9-71.4) ng/mL (P=0.008)]. ADP levels were not influenced by BDI and BAI scores, body mass index (BMI), or HIT-6. CONCLUSION: ADP levels were reduced in TTH, independently of psychiatric comorbidities, BMI, and headache impact. PMID- 25733345 TI - Numerical analysis of multi-level versus short instrumentation for the treatment of thoracolumbar fractures. AB - PURPOSE: The research analyses the strength of metallic implants in posterior spinal instrumentation for the treatment of thoracolumbar fractures, considering extended and short fixation techniques on the immediate post-surgical load. Considering that short fixation may bring the advantage of a less invasive surgical procedure to the patient and may also result in lower costs, this evaluation becomes necessary. METHODS: Three-dimensional modelling of the thoracolumbar spine was initially performed. CT images were captured and converted for analysis with the ANSYS program. Both treatment techniques were analysed for stresses, and strains generated in the immediate postoperative period, when the fracture is still not healed. RESULTS: The maximum stress obtained for long fixation by the theory of Von Mises was 230 MPa, and it was located in the rod area next to the L2 vertebra. The maximum stress obtained for short fixation was 274.24 MPa, and it was located in the pedicle screw on the T12 vertebra. CONCLUSIONS: There were no significant differences between the two techniques, since the observed stresses are well below the flow stress of the material, ensuring good safety factor (ranging from 3.5 to 4.1). PMID- 25733346 TI - Two-level anterior cervical discectomy and fusion using self-locking stand-alone polyetheretherketone cages with two anchoring clips placed in the upper and lower vertebrae, respectively. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a widely accepted surgical procedure for the treatment of cervical degenerative disk diseases (CDDD). The purpose of our study was to investigate the reliability and efficacy of ACDF using self-locking stand-alone polyetheretherketone (PEEK) cages, with two anchoring clips placed in the upper and lower vertebrae, respectively. METHODS AND MATERIALS: Twenty-six patients who underwent ACDF using a stand-alone PEEK cage packed with local osteophytes and cancellous allograft bone from January 2010 to January 2012 were enrolled in this study. Clinical findings were assessed using a visual analog scale (VAS), Japanese Orthopaedic Association (JOA) score, neck disability index (NDI), and Odom criteria. Intervertebral height and cervical fusion status were assessed on X-ray. RESULTS: Twenty-six patients underwent ACDF using a stand-alone PEEK cervical cage. All patients had a minimum 2 years of follow-up. The operative levels were C3/4, C4/5 in seven patients, C4/5, C5/6 in 13 patients, and C4/5, C6/7 in six patients. At 3 days, 6 months, and 2 years of follow-ups, the JOA scores were 10.41 +/- 1.67, 13.78 +/- 1.91, 14.42 +/- 2.09, respectively, which was significantly higher (p < 0.01) than preoperative (7.34 +/- 1.71), whereas VAS overall pain score was 4.35 +/- 1.32, 1.73 +/- 0.44, 1.32 +/- 0.57, respectively, which was significantly lower (p < 0.01) than preoperative (8.01 +/- 1.16). The NDI preoperatively was 33.94 +/ 11.75, 23.53 +/- 10.92 at 3 days postoperatively, 12.64 +/- 8.36 at 6 months, and 10.74 +/- 7.92 at 2 years of follow-ups. Intervertebral height was 5.99 +/- 0.31 mm preoperatively, 8.70 +/- 0.23 mm at 3 days, 8.34 +/- 0.61 mm at 6 months, and 8.22 +/- 0.35 mm at 2 years of follow-ups. According to Odom criteria, 10 patients (38.4%) presented with an excellent clinical outcome, 15 good (57.6%), 1 fair (3.8%), and no patient presented a poor outcome. Solid fusion was achieved in all patients (100%) at a mean time of 4.5 months. CONCLUSION: ACDF using a self-locking stand-alone PEEK cage with two anchoring clips placed in the upper and lower vertebrae, respectively, could be considered a safe and effective substitute for fusion in patients with two-level CDDD; it can effectively restore the intervertebral height, facilitate radiologic follow-up, cause few complications, and lead to satisfactory outcomes. PMID- 25733347 TI - Toward beta cell replacement for diabetes. AB - The discovery of insulin more than 90 years ago introduced a life-saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell-derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes. PMID- 25733348 TI - Oxidative stress and mechanisms of ochronosis in alkaptonuria. AB - Alkaptonuria (AKU) is a rare metabolic disease due to a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD), involved in Phe and Tyr catabolism. Due to such a deficiency, AKU patients undergo accumulation of the metabolite homogentisic acid (HGA), which is prone to oxidation/polymerization reactions causing the production of a melanin-like pigment. Once the pigment is deposited onto connective tissues (mainly in joints, spine, and cardiac valves), a classical bluish-brown discoloration is imparted, leading to a phenomenon known as "ochronosis", the hallmark of AKU. A clarification of the molecular mechanisms for the production and deposition of the ochronotic pigment in AKU started only recently with a range of in vitro and ex vivo human models used for the study of HGA-induced effects. Thanks to redox-proteomic analyses, it was found that HGA could induce significant oxidation of a number of serum and chondrocyte proteins. Further investigations allowed highlighting how HGA-induced proteome alteration, lipid peroxidation, thiol depletion, and amyloid production could contribute to oxidative stress generation and protein oxidation in AKU. This review briefly summarizes the most recent findings on HGA-induced oxidative stress in AKU, helping in the clarification of the molecular mechanisms of ochronosis and potentially providing the basis for its pharmacological treatment. Future work should be undertaken in order to validate in vivo the results so far obtained in in vitro AKU models. PMID- 25733349 TI - A Systematic Review of the Impact of Physicians' Occupational Well-Being on the Quality of Patient Care. AB - BACKGROUND: It is widely held that the occupational well-being of physicians may affect the quality of their patient care. Yet, there is still no comprehensive synthesis of the evidence on this connection. PURPOSE: This systematic review studied the effect of physicians' occupational well-being on the quality of patient care. METHODS: We systematically searched PubMed, Embase, and PsychINFO from inception until August 2014. Two authors independently reviewed the studies. Empirical studies that explored the association between physicians' occupational well-being and patient care quality were considered eligible. Data were systematically extracted on study design, participants, measurements, and findings. The Medical Education Research Study Quality Instrument (MERSQI) was used to assess study quality. RESULTS: Ultimately, 18 studies were included. Most studies employed an observational design and were of average quality. Most studies reported positive associations of occupational well-being with patient satisfaction, patient adherence to treatment, and interpersonal aspects of patient care. Studies reported conflicting findings for occupational well-being in relation to technical aspects of patient care. One study found no association between occupational well-being and patient health outcomes. CONCLUSIONS: The association between physicians' occupational well-being and health care's ultimate goal-improved patient health-remains understudied. Nonetheless, research up till date indicated that physicians' occupational well-being can contribute to better patient satisfaction and interpersonal aspects of care. These insights may help in shaping the policies on physicians' well-being and quality of care. PMID- 25733351 TI - Concepts in solid tumor evolution. AB - Evolutionary mechanisms in cancer progression give tumors their individuality. Cancer evolution is different from organismal evolution, however, and we discuss where concepts from evolutionary genetics are useful or limited in facilitating an understanding of cancer. Based on these concepts we construct and apply the simplest plausible model of tumor growth and progression. Simulations using this simple model illustrate the importance of stochastic events early in tumorigenesis, highlight the dominance of exponential growth over linear growth and differentiation, and explain the clonal substructure of tumors. PMID- 25733352 TI - Statistical approaches for the determination of cut points in anti-drug antibody bioassays. AB - Cut points in immunogenicity assays are used to classify future specimens into anti-drug antibody (ADA) positive or negative. To determine a cut point during pre-study validation, drug-naive specimens are often analyzed on multiple microtiter plates taking sources of future variability into account, such as runs, days, analysts, gender, drug-spiked and the biological variability of un spiked specimens themselves. Five phenomena may complicate the statistical cut point estimation: i) drug-naive specimens may contain already ADA-positives or lead to signals that erroneously appear to be ADA-positive, ii) mean differences between plates may remain after normalization of observations by negative control means, iii) experimental designs may contain several factors in a crossed or hierarchical structure, iv) low sample sizes in such complex designs lead to low power for pre-tests on distribution, outliers and variance structure, and v) the choice between normal and log-normal distribution has a serious impact on the cut point. We discuss statistical approaches to account for these complex data: i) mixture models, which can be used to analyze sets of specimens containing an unknown, possibly larger proportion of ADA-positive specimens, ii) random effects models, followed by the estimation of prediction intervals, which provide cut points while accounting for several factors, and iii) diagnostic plots, which allow the post hoc assessment of model assumptions. All methods discussed are available in the corresponding R add-on package mixADA. PMID- 25733353 TI - Analysis of CCR7 mediated T cell transfectant migration using a microfluidic gradient generator. AB - T lymphocyte migration is crucial for adaptive immunity. Manipulation of signaling molecules controlling cell migration combined with in-vitro cell migration analysis provides a powerful research approach. Microfluidic devices, which can precisely configure chemoattractant gradients and allow quantitative single cell analysis, have been increasingly applied to cell migration and chemotaxis studies. However, there are a very limited number of published studies involving microfluidic migration analysis of genetically manipulated immune cells. In this study, we describe a simple microfluidic method for quantitative analysis of T cells expressing transfected chemokine receptors and other cell migration signaling probes. Using this method, we demonstrated chemotaxis of Jurkat transfectants expressing wild-type or C-terminus mutated CCR7 within a gradient of chemokine CCL19, and characterized the difference in transfectant migration mediated by wild-type and mutant CCR7. The EGFP-tagged CCR7 allows identification of CCR7-expressing transfectants in cell migration analysis and microscopy assessment of CCR7 dynamics. Collectively, our study demonstrated the effective use of the microfluidic method for studying CCR7 mediated T cell transfectant migration. We envision this developed method will provide a useful platform to functionally test various signaling mechanisms at the cell migration level. PMID- 25733354 TI - Functional assessment of mouse complement pathway activities and quantification of C3b/C3c/iC3b in an experimental model of mouse renal ischaemia/reperfusion injury. AB - The complement system is an essential component of our innate immunity, both for the protection against infections and for proper handling of dying cells. However, the complement system can also contribute to tissue injury and inflammatory responses. In view of novel therapeutic possibilities, there is an increasing interest in measurement of the complement system activation in the systemic compartment, both in the clinical setting as well as in experimental models. Here we describe in parallel a sensitive and specific sandwich ELISA detecting mouse C3 activation fragments C3b/C3c/iC3b, as well as functional complement ELISAs detecting specific activities of the three complement pathways at the level of C3 and at the level of C9 activation. In a murine model of renal ischaemia/reperfusion injury (IRI) we found transient complement activation as shown by generation of C3b/C3c/iC3b fragments at 24 h following reperfusion, which returned to base-line at 3 and 7 days post reperfusion. When the pathway specific complement activities were measured at the level of C3 activation, we found no significant reduction in any of the pathways. However, the functional complement activity of all three pathways was significantly reduced when measured at the level of C9, with the strongest reduction being observed in the alternative pathway. For all three pathways there was a strong correlation between the amount of C3 fragments and the reduction in functional complement activity. Moreover, at 24 h both C3 fragments and the functional complement activities showed a correlation with the rise in serum creatinine. Together our results show that determination of the systemic pathway specific complement activity is feasible in experimental mouse models and that they are useful in understanding complement activation and inhibition in vivo. PMID- 25733356 TI - Oxygen-assisted water partial dissociation on copper: a model study. AB - It is essential to understand and control the O-H bond cleavage on metal surfaces with pre-adsorbed oxygen atoms in heterogeneous catalytic processes. The adsorption and dissociation of water on clean and oxygen-pre-adsorbed copper surfaces, including Cu(111), Cu(110), Cu(100), Cu(210), Cu(211), Cu(310) and Cu(110)-(1 * 2), as well as Cu-ad-row and Cu-ad-atom, have been investigated by the density functional theory-generalized gradient approximation (DFT-GGA) method. The calculation results indicate that the presence of oxygen species significantly promotes the water dissociation. It is found that the promotion effect depends both on the adsorption energy of the pre-adsorbed oxygen and the distance between the pre-adsorbed oxygen and the stripped hydrogen in water: the more strongly the oxygen atom binds to the metal surface, the less the promotion effect it has on the water O-H bond cleavage; the shorter the distance between pre-adsorbed oxygen and hydrogen in water, the greater is the promotion effect. Based on electronic analysis, physical origin of the promotion effect can be attributed to the strong interaction of acid-base pair sites on oxygen-metal systems. PMID- 25733355 TI - Development of a toxicogenomics signature for genotoxicity using a dose optimization and informatics strategy in human cells. AB - The development of in vitro molecular biomarkers to accurately predict toxicological effects has become a priority to advance testing strategies for human health risk assessment. The application of in vitro transcriptomic biomarkers promises increased throughput as well as a reduction in animal use. However, the existing protocols for predictive transcriptional signatures do not establish appropriate guidelines for dose selection or account for the fact that toxic agents may have pleiotropic effects. Therefore, comparison of transcriptome profiles across agents and studies has been difficult. Here we present a dataset of transcriptional profiles for TK6 cells exposed to a battery of well characterized genotoxic and nongenotoxic chemicals. The experimental conditions applied a new dose optimization protocol that was based on evaluating expression changes in several well-characterized stress-response genes using quantitative real-time PCR in preliminary dose-finding studies. The subsequent microarray based transcriptomic analyses at the optimized dose revealed responses to the test chemicals that were typically complex, often exhibiting substantial overlap in the transcriptional responses between a variety of the agents making analysis challenging. Using the nearest shrunken centroids method we identified a panel of 65 genes that could accurately classify toxicants as genotoxic or nongenotoxic. To validate the 65-gene panel as a genomic biomarker of genotoxicity, the gene expression profiles of an additional three well-characterized model agents were analyzed and a case study demonstrating the practical application of this genomic biomarker-based approach in risk assessment was performed to demonstrate its utility in genotoxicity risk assessment. PMID- 25733357 TI - Editorial. PMID- 25733358 TI - Aging, cognitive load, dementia and hearing loss. AB - Sensorineural systems play a crucial role in the diagnosis, treatment and management of several neurological disorders. The function of the eye and ear represents a unique window for testing various conditions in cognitive decline or dementia. Touch and smell have also been found to be strongly involved in neurodegenerative conditions, and their decline has been significantly associated with the progression of the disease; hence, the idea that restoring sensory function in cognitively impaired adults might enable a significant improvement in their cognitive status, reducing the worldwide incidence and prevalence of dementia. Not all sensorineural 'windows' can benefit equally from the same procedures; however, hearing and vision can certainly gain the most from dependable therapeutic and other diagnostic options. The ear, including the vestibular system, deserves an honored place among the sensory organs in this context due mainly to the sophisticated electrical devices available that have amply demonstrated their effectiveness in treating hearing loss. Restoring an individual's hearing can reduce the cognitive 'load', i.e. the neural activity needed to understand/recognize the spoken word - an activity that becomes more demanding if the brain is obliged to recruit different neural populations to achieve the same performance, as happens in older adults with sensory impairments. The sensory interfaces may also facilitate the early diagnosis of conditions characterized by a lengthy preclinical phase, as well as enabling noninvasive, follow-up procedures to assess the outcome of rehabilitation measures and distinguish physiological brain aging from neurodegenerative disorders. The present study is a brief literature review on the issues and prospects relating to the unique relationship between hearing and cognitive decline, with a general introduction to the main topics before focusing on rehabilitation training with hearing aids and cochlear implants to combat cognitive decline. PMID- 25733359 TI - Hearing loss and dementia in the aging population. AB - For some years, policy makers and medical scientists have both begun to focus more on chronic noncommunicable diseases. It is well known that cardio cerebrovascular disease, tumors, diabetes, and chronic obstructive pulmonary disease (COPD), are considered areas of major interest in many scientific projects and health programs. The economic impact of cardio-cerebrovascular disease in EU alone is more than EUR 200 billion, while tumors have an impact of EUR 150 billion. The direct and indirect cost of brain disorders exceeds EUR 700 billion a year. Among the brain disorders, the devastating impact of dementia on affected individuals and the burden imposed on their families and society has made prevention and treatment of dementia a public health priority. Interventions that could merely delay the onset of dementia by 1 year would result in a more than 10% decrease in the global prevalence of dementia in 2050. Unfortunately, there are no known interventions that currently have such effectiveness. The manifestations of age-related hearing loss in many older adults are subtle and, thus, hearing loss is often perceived as an unfortunate but inconsequential part of aging. Researchers report that hearing loss seems to speed up age-related cognitive decline. Researchers suggest that treating hearing loss more aggressively could help delay cognitive decline and dementia. Furthermore, there is an increasing interest in better understanding the pathophysiologic correlations between hearing loss and dementia. Hearing loss in older adults, in fact, is associated independently with poorer cognitive functioning, incident dementia, and falls. Further research investigating the basis of this connection as well as the pathomechanism of the two diseases will further our ability to treat dementia. PMID- 25733360 TI - The prevalence of peripheral and central hearing impairment and its relation to cognition in older adults. AB - Age-related hearing loss (ARHL) and dementia are two highly prevalent conditions in the adult population. Recent studies have suggested that hearing loss is independently associated with poorer cognitive functioning. The aim of this study was to evaluate the prevalence of ARHL and cognitive impairment in a large sample of subjects older than 65 years and to correlate hearing function with cognitive function. A total of 488 subjects older than 65 years (mean age 72.8 years) participating in the Great Age Study underwent a complete audiological, neurological and neuropsychological evaluation as part of a multidisciplinary assessment. The prevalence of a hearing loss greater than 25 dB HL was 64.1%, of Central Auditory Processing Disorder (CAPD) was 14.3 and 25.3% of the subjects reported a hearing handicap as reported on the Hearing Handicap Inventory for the Elderly Screening Version questionnaire. Multiple logistic regression analysis corrected for gender, age and education duration showed that mild cognitive impairment (MCI) was significantly associated with hearing impairment (CAPD and hearing threshold; odds ratio 1.6, p = 0.05) and that Alzheimer's disease (AD) was significantly associated with CAPD (odds ratio 4.2, p = 0.05). Given that up to 80% of patients affected by MCI convert to AD, adding auditory tests to a screening cognitive battery might have value in the early diagnosis of cognitive decline. PMID- 25733361 TI - Predictive factors of cochlear implant outcomes in the elderly. AB - OBJECTIVE: To analyze predictive factors of cochlear implant outcomes and postoperative complications in the elderly. STUDY DESIGN: Prospective, longitudinal study performed in 10 tertiary referral centers. METHODS: Ninety four patients aged 65-85 years with a profound, postlingual hearing loss were evaluated before implantation, at time of activation, and 6 and 12 months after cochlear implantation. Speech perception and lipreading were measured using disyllabic word recognition in quiet and noise, and lipreading using disyllabic words and sentences. The influence of preoperative factors on speech perception in quiet and noise at 12 months was tested in a multivariate analysis. Complications, presence of tinnitus and of vestibular symptoms were collected at each evaluation. RESULTS: The effect of age was observed only in difficult noisy conditions at SNR 0 dB. Lipreading ability for words and sentences was negatively correlated with speech perception in quiet and noise. Better speech perception scores were observed in patients with shorter duration of hearing deprivation, persistence of residual hearing for the low frequencies, the use of a hearing aid before implantation, the absence of cardiovascular risk factors, and in those with implantation in the right ear. General and surgical complications were very rare, and the percentage of vestibular symptoms remained stable over time. CONCLUSION: This study demonstrates that cochlear implantation in the elderly is a well-tolerated procedure and an effective method to improve communication ability. Advanced age has a low effect on cochlear implant outcome. Analyses of predictive factors in this population provide a convincing argument to recommend treatment with cochlear implantation as early as possible in elderly patients with confirmed diagnosis of a severe-to-profound hearing loss and with only limited benefit from hearing aid use in one ear. PMID- 25733362 TI - Neural correlates of auditory-cognitive processing in older adult cochlear implant recipients. AB - With the growing number of older adults receiving cochlear implants (CI), there is general agreement that substantial benefits can be gained. Nonetheless, variability in speech perception performance is high, and the relative contribution and interactions among peripheral, central-auditory, and cognitive factors are not fully understood. The goal of the present study was to compare auditory-cognitive processing in older-adult CI recipients with that of older normal-hearing (NH) listeners by means of behavioral and electrophysiologic manifestations of a high-load cognitive task. Auditory event-related potentials (AERPs) were recorded from 9 older postlingually deafened adults with CI (age at CI >60) and 10 age-matched listeners with NH, while performing an auditory Stroop task. Participants were required to classify the speaker's gender (male/female) that produced the words 'mother' or 'father' while ignoring the irrelevant congruent or incongruent word meaning. Older CI and NH listeners exhibited comparable reaction time, performance accuracy, and initial sensory-perceptual processing (i.e. N1 potential). Nonetheless, older CI recipients showed substantially prolonged and less efficient perceptual processing (i.e. P3 potential). Congruency effects manifested in longer reaction time (i.e. Stroop effect), execution time, and P3 latency to incongruent versus congruent stimuli in both groups in a similar fashion; however, markedly prolonged P3 and shortened execution time were evident in older CI recipients. Collectively, older adults (CI and NH) employed a combined perceptual and postperceptual conflict processing strategy; nonetheless, the relative allotment of perceptual resources was substantially enhanced to maintain adequate performance in CI recipients. In sum, the recording of AERPs together with the simultaneously obtained behavioral measures during a Stroop task exposed a differential time course of auditory cognitive processing in older CI recipients that was not manifested in the behavioral end products of processing. These data may have implications regarding clinical evaluation and rehabilitation procedures that should be tailored specifically for this unique group of patients. PMID- 25733363 TI - Improvement of telephone communication in elderly cochlear implant patients. AB - INTRODUCTION: Elderly patients demonstrate more difficulty in telephone communication than in direct conversation. This deterioration in comprehension is due most likely to the narrowing of frequency range of transmission (300-3,400 Hz) and the lack of specific maps in the sound processor to accommodate the reduced information. AIMS: The goal of this study was to create a new 'telephone map' specific for phone use and to verify its effectiveness even in elderly patients. METHODS: Twenty cochlear implant (CI) adult patients divided into two age groups (under 60 and over 60 years) were included in the study. All patients were assessed with a word recognition test presented via recorded, conventional telephone-transmitted voice signal while using their everyday map (SB-map) and while using the experimental map (T-map). The latter was created by lowering the current level to the minimum value for electrodes representing frequencies outside the range of the telephone signal without changing the frequency bands assigned to them. RESULTS: In experimental listening conditions, the average recognition score using the SB-map was 65.5% in patients under 60 and 36.5% in patients over 60, while using the T-map it was 73.5 and 41.5%, respectively. This difference between the two maps was statistically significant in both groups (p ? 0.05) and was confirmed by subjective assessment. After 3 months of training provided to the over 60 CI group, subjects showed further improvement. DISCUSSION: The increase in comprehension skills by phone-transmitted speech with the T-map is objective and immediate in both groups of patients and proves to be improved further after training. The results demonstrate that it is possible to reduce the background noise and improve the ability to comprehend the phone message through changes to some map parameters. CONCLUSIONS: In light of the results obtained, we believe that our experimental map, applicable to all types of implants, currently represents a simple and effective solution to improve telephone communication in patients with CI. PMID- 25733364 TI - Cochlear implantation in the elderly. AB - Hearing disorders become an increasingly important issue that influences quality of life and many other economic factors. Due to the prolongation of human life and the more active lifestyles of people in retirement age, there is an increasing requirement for the available treatment options of hearing loss in the aging population. The aim of this study was to compare the hearing preservation outcomes of adult patients implanted with the CochlearTM Nucleus(r) CI422 when divided into two groups by age, younger and older than 65 years of age. The study cohort consisted of 62 patients implanted from January 2011 through December 2013 at our clinic. All patients were assessed and classified according to the hearing preservation classification. Comparing the results between subgroups, we observed that the degree of hearing preservation was greater in younger adults than in older adults. Results of this review may suggest that deeper insertion is to be recommended for an older population of cochlear implant recipients. PMID- 25733365 TI - Quality of life outcomes for cochlear implantation in the elderly. AB - OBJECTIVES: To determine whether individuals older than 60 years of age suffering from profound, bilateral, sensorineural hearing loss and unable to use hearing aids can benefit from a cochlear implant in order to improve hearing performance. Additionally, to evaluate how they manage the external components of their implanted system. MATERIALS AND METHODS: The records of 68 cochlear implant users over 60 years of age were reviewed. They had undergone tonal and speech audiometry evaluations of hearing before and after implantation. A subset of 27 elderly patients were asked to respond to a specially designed questionnaire regarding the use of the external components of the implanted system. RESULTS: Patients over 60 years of age benefit from cochlear implants. The earlier the implantation, the better the results tend to be. Certain limitations when using the external components of the implanted system were evident among the elderly. CONCLUSIONS: People >60 years of age suffering from profound, bilateral, sensorineural hearing loss show improved hearing performance following cochlear implantation. Using the implanted system includes some limitations that should be studied and overcome. PMID- 25733366 TI - Benefits of cochlear implantation in deafened adults. AB - AIM: The objective was to retrospectively analyze the benefits of cochlear implantation in deafened elderly (>65 years old). METHOD: Data from 30 elderly patients with a unilateral cochlear implant were included and analyzed. Audiometric threshold and speech data in aided and unaided conditions were examined at pre- and postimplant intervals at 3, 6, and 12 months after activation of the sound processor and compared. RESULTS: All patients demonstrated hearing benefits after implant and over time with results ranging from very good, good, to limited performance in a few cases. The mean postimplantation follow-up time was 2.74 years (minimum 1 year). Our study cohort demonstrates that cochlear implantation is a successful treatment method for improving speech perception in the auditory alone or auditory-visual mode for the majority of elderly patients. No correlations were observed between postimplant outcomes and age, or preimplant hearing thresholds and speech audiometry. CONCLUSION: Age is not a determining or limiting factor for post-CI outcome performance in deafened elderly patients. Counselling should consider the patient as a whole and include explanation of the risk for a minority of elderly patients who may demonstrate poor outcomes after implant, despite presenting as good candidates before implantation. PMID- 25733367 TI - Speech performance and training effects in the cochlear implant elderly. AB - OBJECTIVES: Cochlear implantation requires acclimatization to the electrical input. Usually, cochlear implant (CI) listeners undergo an auditory rehabilitation program that includes auditory training sessions. Recently, it was shown that a phoneme-based training may improve speech perception abilities even in experienced CI listeners. The current study focuses on whether the effect of an auditory training program depends on the age of CI listeners. DESIGN: Fifteen CI listeners took part in an auditory phoneme-based computer training program. Before and after training, speech recognition tests in moderate and difficult noise (+5 dB SNR and 0 dB SNR, respectively) were administered. Additionally, speech recognition was tested 6 months after the training (follow-up). A control group consisting of 12 subjects underwent audiometric testing without any auditory training. RESULTS: Speech perception in moderate noise improved significantly during the training as revealed by comparing pre- and posttraining scores evaluated in the moderate noise condition. No significant change was observed for the difficult noise situation at 0 dB SNR. The speech perception measures of the control group remained unchanged. No significant effect of age on the training effect was observed. CONCLUSION: Speech recognition can be improved even in experienced CI listeners. When motivated to participate, senior CI users with long-term CI experience may benefit in a similar way from an auditory, phoneme-based computer training program as younger CI users. PMID- 25733368 TI - Hemipelvectomy after severe pelvic injury in Factor VII deficiency toddler. AB - Traumatic hemipelvectomy is a lethal catastrophic injury. The reported average age of individuals surviving this trauma is 21 years old, suggesting the necessity of good physiological reserves to survive this type of injury. Dealing with this injury in children may call for special requirements throughout all the stages of diagnosis, treatment and rehabilitation. Experience in the resuscitation and subsequent treatment of individuals suffering from this traumatic condition in the paediatric population is even scarce. There are only several reported cases involving children and none of the paediatric cases suffered from comorbidities prior to their traumatic injury. The present report describes the successful management of a 16-month-old child with a medical history of a rare bleeding disorder a severe coagulation Factor VII deficiency who underwent right-sided traumatic hemipelvectomy. PMID- 25733369 TI - Utility of hepatitis C viral load monitoring on direct-acting antiviral therapy. AB - BACKGROUND: Hepatitis C virus (HCV) RNA loads serve as predictors of treatment response during interferon-based therapy. We evaluated the predictive ability of HCV RNA levels at end of treatment (EOT) for sustained virologic response (SVR12) during interferon-sparing direct-acting antiviral therapies. METHODS: HCV genotype 1-infected, treatment-naive patients were treated with sofosbuvir and ribavirin for 24 weeks (n = 55), sofosbuvir and ledipasvir for 12 weeks (n = 20), sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (n = 20), or sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (n = 19). Measurements of HCV RNA were performed using the Roche COBAS TaqMan HCV test and the Abbott RealTime HCV assay. Positive predictive value (PPV) and negative predictive value (NPV) of HCV RNA less than the lower limit of quantification (=LLOQ at EOT (range, 14-64 IU/mL) achieved SVR12 (NPV, 0%). Quantifiable HCV RNA (range, 15-57 IU/mL) was measured 2 weeks posttreatment in 4 individuals, and 4 weeks posttreatment in 1 patient (14 IU/mL). CONCLUSIONS: Contrary to past experience with interferon-containing treatments, low levels of quantifiable HCV RNA at EOT do not preclude treatment success. PMID- 25733370 TI - Influenza among afebrile and vaccinated healthcare workers. AB - BACKGROUND: To prevent transmission of influenza from healthcare workers (HCWs) to patients, many hospitals exclude febrile HCWs from working, but allow afebrile HCWs with respiratory symptoms to have contact with patients. During the 2013 2014 influenza season at our hospital, an influenza-positive HCW with respiratory symptoms but no fever was linked to a case of possible healthcare-associated influenza in a patient. Therefore, we implemented a temporary policy of mandatory influenza testing for HCWs with respiratory symptoms. METHODS: From 3 January through 28 February 2014, we tested HCWs with respiratory symptoms for influenza and other respiratory pathogens by polymerase chain reaction of flocked nasopharyngeal swabs. HCWs also reported symptoms and influenza vaccination status, and underwent temperature measurement. We calculated the proportion of influenza-positive HCWs with fever and prior influenza vaccination. RESULTS: Of 449 HCWs, 243 (54%) had a positive test for any respiratory pathogen; 34 (7.6%) HCWs tested positive for influenza. An additional 7 HCWs were diagnosed with influenza by outside physicians. Twenty-one (51.2%) employees with influenza had fever. Among influenza-infected HCWs, 20 had previously received influenza vaccination, 18 had declined the vaccine, and 3 had unknown vaccination status. There was no significant difference in febrile disease among influenza-infected employees who had received the influenza vaccine and those who had not received the vaccine (45% vs 61%; P = .32). CONCLUSIONS: Nearly half of HCWs with influenza were afebrile prior to their diagnosis. HCWs with respiratory symptoms but no fever may pose a risk of influenza transmission to patients and coworkers. PMID- 25733371 TI - Suppression of Peripheral Pain by Blockade of Voltage-Gated Calcium 2.2 Channels in Nociceptors Induces RANKL and Impairs Recovery From Inflammatory Arthritis in a Mouse Model. AB - OBJECTIVE: A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies inflammation and joint deformation. Patients with RA rate pain relief as the highest priority; however, few studies have addressed the efficacy and safety of therapies directed specifically toward pain pathways. The omega conotoxin MVIIA (ziconotide) is used in humans to alleviate persistent pain syndromes, because it specifically blocks the voltage-gated calcium 2.2 (CaV 2.2) channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The aims of this study were to investigate whether blockade of CaV 2.2 can suppress arthritis pain, and to examine the progression of induced arthritis during persistent CaV 2.2 blockade. METHODS: Transgenic mice expressing a membrane-tethered form of MVIIA under the control of a nociceptor-specific gene (MVIIA-transgenic mice) were used in the experiments. The mice were subjected to unilateral induction of joint inflammation using a combination of antigen and collagen. RESULTS: CaV 2.2 blockade mediated by tethered MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsided, MVIIA-transgenic mice showed continued inflammation, with up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. CONCLUSION: Taken together, our results indicate that alleviation of peripheral pain by blockade of CaV 2.2- mediated calcium influx and signaling in nociceptor sensory neurons impairs recovery from induced arthritis and point to the potentially devastating effects of using CaV 2.2 channel blockers as analgesics during inflammation. PMID- 25733372 TI - Dosimetric comparison of left-sided whole-breast irradiation with 3DCRT, forward planned IMRT, inverse-planned IMRT, helical tomotherapy, and volumetric arc therapy. AB - PURPOSE: This study evaluated the dose distribution and homogeneity of four different types of intensity-modulated radiotherapy (IMRT) in comparison with standard wedged tangential-beam three-dimensional conformal radiotherapy (3DCRT) of the left breast in patients who had undergone lumpectomy. MATERIALS AND METHODS: Five radiotherapy treatment plans, including 3DCRT, forward-planned IMRT (for-IMRT), inverse IMRT (inv-IMRT), helical tomotherapy (HT) and volumetric modulated arc therapy (VMAT), were created for 15 consecutive patients. RESULTS: All modalities presented similar target coverage. Target max doses were reduced with for-IMRT compared to 3DCRT, and these doses were further reduced with inv IMRT and HT. HT resulted in the lowest max doses delivered to the heart, left anterior descending artery (LAD), and ipsilateral lung, but had higher mean, max, and low doses delivered to contralateral breast. HT resulted in increased low doses to a large volume of healthy tissue. Compared to other techniques, all inverse-planned modalities significantly improved conformity number; however, VMAT had worse homogeneity. The for-IMRT plan significantly lowered monitor unit (MU) compared to the inverse-planned techniques. CONCLUSION: All modalities evaluated provide adequate coverage of the whole breast. For-IMRT improves target homogeneity compared with 3DCRT, but to a lesser degree than the inverse-planned inv-IMRT and HT. HT decreases the ipsilateral OAR volumes receiving higher and mean doses with an increase in the volumes receiving low doses, which is known to lead to an increased rate of radiation-induced secondary malignancies. PMID- 25733374 TI - Editorial: leukocyte-targeting toxins as therapeutics in allergic asthma. PMID- 25733375 TI - Editorial: ADAMs control inflammation from afar. PMID- 25733373 TI - Diagnostic and prognostic significances of MUC5B and TTF-1 expressions in resected non-small cell lung cancer. AB - To investigate the relationships between the expression of MUC5B and clinicopathological parameters, the expression of MUC5B was immunohistochemically studied. MUC5B expression was observed in 129 of 198 (65.2%) adenocarcinomas and in 4 of 49 (8.2%) squamous cell carcinomas (P < 0.00001). MUC5B expression was significantly associated with poorer differentiation (P = 0.0303), higher pathological TNM stage (p = 0.0153) and poorer prognosis of adenocarcinoma patients (P = 0.0017). Multivariable analysis with Cox proportional hazards models confirmed that MUC5B expression increased the hazard of death after adjusting for other clinicopathological factors (HR = 2.66; 95%CI, 1.26-5.61). We also immunohistochemically evaluated TTF-1 expression and found that the combination of MUC5B with TTF-1 is a useful marker for adenocarcinomas. The diagnostic accuracies of TTF-1 and MUC5B for adenocarcinoma were 83.8% and 70.4%, respectively. The accuracy increased to 94.3% when the two factors were combined. In survival analysis, the MUC5B(High)/TTF-1(-) group was significantly associated with a poorer outcome compared with the MUC5B(Low)/TTF-1(+) group (p < 0.0001). The present study suggested that the combination of MUC5B and TTF-1 expression is useful for discriminating adenocarcinomas from squamous cell carcinomas, yielding prognostic significance in patients with lung adenocarcinoma. PMID- 25733376 TI - Vascular mineralocorticoid receptor and blood pressure regulation. AB - The mineralocorticoid receptor (MR) is a major regulator of blood pressure by modulating sodium balance and blood volume in the distal nephron. The discovery of MR expression in both endothelial and vascular smooth muscle cells a decade ago raised questions about its role in the vascular wall and its involvement in blood pressure regulation. In vitro and in vivo pharmacological studies have shown that vascular MR is involved in several vascular properties such as extracellular matrix remodeling, inflammation and vascular reactivity. In this review, we focus on recent advances obtained using transgenic model with cell specific modulation of the expression MR in endothelium or smooth muscle and their impact on blood pressure. PMID- 25733377 TI - Urban farmers' markets: accessibility, offerings, and produce variety, quality, and price compared to nearby stores. AB - Most food-environment research has focused narrowly on select stores and restaurants. There has been comparatively less attention to non-storefront food sources like farmers' markets (FMs), particularly in urban communities. The objective of the present study was to assess FMs' potential contribution to an urban food environment in terms of specific foods offered, and compare FM accessibility as well as produce variety, quality, and price to that of nearby stores. Investigators conducted a detailed cross-sectional assessment of all FMs in Bronx County, NY, and of the nearest store(s) selling produce within a half mile walking distance (up to two stores per FM). The study included 26 FMs and 44 stores. Investigators assessed accessibility (locations of FMs and stores relative to each other, and hours of operation for each), variety (the number and type of all food items offered at FMs and all fresh produce items offered at stores), quality (where produce items were grown and if they were organic), and price (including any sales prices or promotional discounts). Analyses included frequencies, proportions, and variable distributions, as well as mixed-effect regressions, paired t-tests, and signed rank tests to compare FMs to stores. Geographic information systems (GIS) allowed for mapping of FM and store locations and determining street-network distances between them. The mean distance between FMs and the nearest store selling fresh produce was 0.15 miles (range 0.02-0.36 miles). FMs were open substantially fewer months, days, and hours than stores. FMs offered 26.4 fewer fresh produce items on average than stores (p values <0.02). FM produce items were more frequently local and organic, but often tended toward less-common/more-exotic and heirloom varieties. FMs were more expensive on average (p values <0.001 for pairwise comparisons to stores) - even for more-commonplace and "conventional" produce - especially when discounts or sales prices were considered. Fully, 32.8% of what FMs offered was not fresh produce at all but refined or processed products (e.g., jams, pies, cakes, cookies, donuts, juice drinks). FMs may offer many items not optimal for good nutrition and health, and carry less-varied, less-common fresh produce in neighborhoods that already have access to stores with cheaper prices and overwhelmingly more hours of operation. PMID- 25733378 TI - "The food represents": Barbadian foodways in the diaspora. AB - As migrants adjust to life in a new country, food practices often shift. The literature shows that many migrants alter their diets to more closely reflect those in the host nation, at least in public venues. Some adjust native dishes to accommodate available ingredients, but may view these changes as rendering foods less "traditional." However, Barbadian transnational migrants in Atlanta experience these alterations differently. They consciously perform Barbadianness by electing to serve "traditional" foods when eating with each other, or sharing with an American audience. Yet, while numerous changes are made to these "traditional" dishes, this does not make them less authentic. These shifts do not alter the legitimacy of a dish, but rather this interaction between the available ingredients and the attempt to create a traditional food is actually a practice of authenticity. The dynamic change that food undergoes in the migrant experience echoes the changing nature of Barbadian foodways throughout Caribbean history. PMID- 25733379 TI - Connectivity and functional profiling of abnormal brain structures in pedophilia. AB - Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. PMID- 25733380 TI - Pairing-up SOX to kick-start beta cell genesis. AB - The transcription factor SOX9 is regarded as a crucial player in pancreas development, both maintaining progenitors and later being required for beta cell differentiation. However, very little is known about the possible involvement of other SOX family members in such processes. In this issue, the work of Xu et al (DOI: 10.1007/s00125-015-3507-x ) shines a spotlight on SOX4, revealing this factor to be a major player in the beta cell program. Using conditional inactivation in mice, they show that SOX4 shares some functions in progenitors with SOX9, but also plays a distinct role at a later stage of development, during the maturation of endocrine cells. This information is timely as this final maturation process is currently the most challenging to reproduce in vitro when coaxing pluripotent stem cells to convert into beta cells. PMID- 25733381 TI - Erratum to: Proteomic analysis of protein extraction during hemofiltration with on-line endogenous reinfusion (HFR) using different polysulphone membranes. PMID- 25733382 TI - Semiconstrained total elbow arthroplasty for rheumatoid arthritis patients: clinical and radiological results of 1-8 years follow-up. AB - INTRODUCTION: We investigated whether the Discovery total elbow arthroplasty (TEA) system had good results and survival in rheumatoid arthritis (RA) patients. METHODS: In a prospective cohort study, one elbow surgeon performed TEA on 25 consecutive RA patients (31 elbows) between December 2004 and November 2012 using the Discovery system. We evaluated the preoperative elbow range of motion (ROM), functional outcome with QuickDash and quality of life with EQ-5D. An independent colleague evaluated the same parameters 1-8 years (mean 4.5) postoperatively. The medical records of the follow-up visits for the study period were available for review. RESULTS: A complete set of results was available for 19 patients (25 elbows). The mean ROM improved in flexion/extension from 88 degrees (SD 27) to 113 degrees (SD 19) and in pronation/supination from 55 degrees (SD 28) to 68 degrees (SD 22) (p < 0.05). The mean QuickDash also improved from 66.5 (SD 25.7) to 40.2 (SD 24) (p < 0.01). The mean EQ-5D improved from 0.68 (SD 0.2) to 0.75 (SD 0.13) but was not statistically significant (p = 0.09). Three patients were revised because of loosening, 2 more patients were re-operated. This resulted in a Kaplan-Meier survival of 90 % (CI 72-97) for the study period. CONCLUSION: The Discovery system has shown satisfactory results in RA patients even if the rate of complication remained relatively high. Further follow-up is required to investigate the radiological changes observed in some of our patients. PMID- 25733383 TI - Caging cancer. AB - This article summarizes the overall issues surrounding cancer for the general audience. Individual differences between patients include genetic and non-genetic differences manifested in various cellular pathways, tumor heterogeneity and variability, differing contribution of tumor microenvironment and potential toward metastasis. Successful treatment of individuals depends on correctly interpreting all these factors and appropriately addressing the actual features by using customized therapy strategies, simultaneously or sequentially. Currently used chemotherapy agents are cytotoxic and typically target one of the major pathways; therefore they have to be applied in combination regimes. Nanomedicines however, have the potential advantage that more than one feature can be built into a complex nanodevice. This yet untapped potential is illustrated on the example of a gadolinium fullerenol cage molecule. Gd@C82(OH)22 has low toxicity, influences several biologic features simultaneously, displays tumoristatic properties, and is effective against triple-negative breast cancer cells. A deeper understanding of the exact relations between the physicochemical characteristics of this system and the biologic events may lead to a new class of efficient anticancer pharmaceutics. FROM THE CLINICAL EDITOR: The search for the magic bullet in the treatment of cancer has long been the dream of clinicians and researchers worldwide. Inherent cellular characteristics of cancer cells have made this task extremely hard to reach. In this article, the author provided a concise summary on the understanding and challenges in the current battle and also illustrated the potential usefulness of the recently developed gadolinium fullerenol cage molecule by describing experimental data from various research groups. PMID- 25733384 TI - Five-year outcomes of percutaneous versus surgical coronary revascularization in patients with diabetes mellitus (from the CREDO-Kyoto PCI/CABG Registry Cohort 2). AB - We investigated the impact of diabetes mellitus on long-term outcomes of percutaneous coronary intervention (PCI) in the drug-eluting stent era versus coronary artery bypass grafting (CABG) in a real-world population with advanced coronary disease. We identified 3,982 patients with 3-vessel and/or left main disease of 15,939 patients with first coronary revascularization enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG Registry Cohort-2 (patients without diabetes: n = 1,984 [PCI: n = 1,123 and CABG: n = 861], and patients with diabetes: n = 1,998 [PCI: n = 1,065 and CABG: n = 933]). Cumulative 5-year incidence of all-cause death after PCI was significantly higher than after CABG both in patients without and with diabetes (19.8% vs 16.2%, p = 0.01, and 22.9% vs 19.0%, p = 0.046, respectively). After adjusting confounders, the excess mortality risk of PCI relative to CABG was no longer significant (hazard ratio [HR] 1.16; 95% confidence interval [CI] 0.88 to 1.54; p = 0.29) in patients without diabetes, whereas it remained significant (HR 1.31; 95% CI 1.01 to 1.70; p = 0.04) in patients with diabetes. The excess adjusted risks of PCI relative to CABG for cardiac death, myocardial infarction (MI), and any coronary revascularization were significant in both patients without (HR 1.59, 95% CI 1.01 to 2.51, p = 0.047; HR 2.16, 95% CI 1.20 to 3.87, p = 0.01; and HR 3.30, 95% CI 2.55 to 4.25, p <0.001, respectively) and with diabetes (HR 1.45, 95% CI 1.00 to 2.51, p = 0.047; HR 2.31, 95% CI 1.31 to 4.08, p = 0.004; and HR 3.70, 95% CI 2.91 to 4.69, p <0.001, respectively). There was no interaction between diabetic status and the effect of PCI relative to CABG for all-cause death, cardiac death, MI, and any revascularization. In conclusion, in both patients without and with diabetes with 3-vessel and/or left main disease, CABG compared with PCI was associated with better 5-year outcomes in terms of cardiac death, MI, and any coronary revascularization. There was no difference in the direction and magnitude of treatment effect of CABG relative to PCI regardless of diabetic status. PMID- 25733385 TI - Plasma levels of E-cadherin and MMP-13 in prostate cancer patients: correlation with PSA, testosterone and pathological parameters. AB - AIMS AND BACKGROUND: Prostate cancer is the most common malignant tumor in men. Serum prostate-specific antigen (PSA), Gleason score and clinical range at the time of diagnosis are important factors to predict prognosis and outcome after therapy but additional accurate and reliable biomarkers are still wanted. So far, few biomarkers of prostate cancer have been successfully implemented and are being used in clinical practice. However, modifications of E-cadherin and MMP-13 expression are likely to be involved in prostate cancer invasion and thus are potential biomarkers for prognosis. PATIENTS AND METHODS: We analyzed the concentrations of E-cadherin and MMP-13 in plasma of patients with prostate cancer at diagnosis and 3 and 6 months after the beginning of treatment and related these measures to free and total PSA and other clinical features. RESULTS: The concentration of E-cadherin was lower in patients with prostate cancer compared to the control group, but there was no difference in the concentration of MMP-13 between these two groups. During treatment, however, we found no significant differences between the concentrations of MMP-13 and E cadherin, but we observed a significant positive correlation between total PSA and E-cadherin plasma concentration at the third month of treatment and between total testosterone and MMP-13 plasma concentration before the start of treatment. CONCLUSIONS: The results suggest that these parameters could be used both in the diagnosis and prognosis of prostate cancer. PMID- 25733386 TI - [A curricular training of fourth year medical students in writing discharge summaries: the graduate view after two years]. AB - BACKGROUND: Preparing high quality discharge summaries is difficult for first year residents. For 5 years we have been training fourth year students how to write discharge summaries. Our goal is to facilitate the students' start into clinical work. Moreover, we intend to provide the students with a scheme to better memorize patients' histories. Two years after the tutorial the graduates were asked to evaluate the tutorial and to comment on its learning effects. METHODS: A total of 1228 fourth year students wrote a discharge summary on a patient in whose care the specific student was involved during his or her training in internal medicine. All summaries were read, commented on and graded by a consultant. Two years after the tutorial 310 graduates were invited to complete an online survey on this tutorial. RESULTS: 106 (34%) of all invited graduates completed the survey. The opinions on the tutorial greatly differed. In principal the students agreed that the tutorial was an important part of medical training and helped to better structure patients' medical data. The majority of the surveyed graduates, however, were not convinced of its practical usefulness for daily work. The students with the poorer grading found their grade less appropriate than the students with the better grading. CONCLUSIONS: Though our main goal could not be achieved in the view of the graduates, the overall opinion was rather positive. Problems with this kind of tutorial lay in the enormous effort of correction and in the discouraging effect of grading on the students with difficulties in the task. PMID- 25733388 TI - Identification of type I IFN in Chinese giant salamander (Andrias davidianus) and the response to an iridovirus infection. AB - The type I IFNs play a major role in the first line of defense against virus infections. In this study, the type I IFN gene designated gsIFN was identified and characterized in the Chinese giant salamander (Andrias davidianus). The genomic DNA of gsIFN contains 5 exons and 4 introns and has a total length of 5622 bp. The full-length cDNA sequence of gsIFN is 1113 bp and encodes a putative protein of 186 amino acids that has a 43% identity to type I IFN of Xenopus tropicalis. The deduced amino acid sequence has the C-terminal CAWE motif, that is mostly conserved in the higher vertebrate type I IFNs. Real-time fluorescence quantitative RT-PCR analysis revealed broad expression of gsIFN in vivo and the highest level expression in blood, kidney and spleen. Additionally, the expression of gsIFN at the mRNA level was significantly induced in peripheral blood leucocytes after stimulation with poly I:C and after infection with the Chinese giant salamander iridovirus (GSIV). A plasmid expressing gsIFN was constructed and transfected into the Chinese giant salamander muscle cell line. Expression of the IFN-inducible gene Mx was up-regulated in the gsIFN overexpressing cells after GSIV infection. The virus load and titer were significantly reduced compared with that in control cells. Additionally, a lower level of virus major capsid protein synthesis was confirmed by immunofluorescence assay compared to the control cells. These results suggest that the gsIFN gene plays an important role in the antiviral innate immune response. PMID- 25733389 TI - Haemophilus parasuis induces activation of NF-kappaB and MAP kinase signaling pathways mediated by toll-like receptors. AB - Glasser's disease in pigs caused by Haemophilus parasuis is characterized by a severe membrane inflammation. In our previous study, we have identified activation of the transcription factor NF-kappaB after H. parasuis infection of porcine epithelial cells. In this study, we found that H. parasuis infection also contributed to the activation of p38/JNK MAPK pathway predominantly linked to inflammation, but not the ERK MAPK pathway associated with growth, differentiation and development. Inhibition of NF-kappaB, p38 and JNK but not ERK activity significantly reduced IL-8 and CCL4 expression by H. parasuis. We also found TLR1, TLR2, TLR4 and TLR6 were required for NF-kappaB, p38 and JNK MAPK activation. Furthermore, MyD88 and TRIF signaling cascades were essential for H. parasuis-induced NF-kappaB activation. These results provided new insights into the molecular pathways underlying the inflammatory response induced by H. parasuis. PMID- 25733387 TI - IQGAP1: insights into the function of a molecular puppeteer. AB - The intracellular spatiotemporal organization of signaling events is critical for normal cellular function. In response to environmental stimuli, cells utilize highly organized signaling pathways that are subject to multiple layers of regulation. However, the molecular mechanisms that coordinate these complex processes remain an enigma. Scaffolding proteins (scaffolins) have emerged as critical regulators of signaling pathways, many of which have well-described functions in immune cells. IQGAP1, a highly conserved cytoplasmic scaffold protein, is able to curb, compartmentalize, and coordinate multiple signaling pathways in a variety of cell types. IQGAP1 plays a central role in cell-cell interaction, cell adherence, and movement via actin/tubulin-based cytoskeletal reorganization. Evidence also implicates IQGAP1 as an essential regulator of the MAPK and Wnt/beta-catenin signaling pathways. Here, we summarize the recent advances on the cellular and molecular biology of IQGAP1. We also describe how this pleiotropic scaffolin acts as a true molecular puppeteer, and highlight the significance of future research regarding the role of IQGAP1 in immune cells. PMID- 25733392 TI - In situ generation of hydroxyl radical by cobalt oxide supported porous carbon enhance removal of refractory organics in tannery dyeing wastewater. AB - In this study, cobalt oxide doped nanoporous activated carbon (Co-NPAC) was synthesized and used as a heterogeneous catalyst for the Fenton oxidation of organic dye chemicals used in tannery process. The nanoporous activated carbon (NPAC) was prepared from rice husk by precarbonization followed by chemical activation at elevated temperature (600 degrees C). The cobalt oxide was impregnated onto NPAC and characterized for UV-visible, Fluorescence spectroscopy, FT-IR, HR-TEM, XRD, BET surface area and XPS analyses. The hydroxyl radical generation potential of Co-NPAC from hydrogen peroxide decomposition was identified (lambda(exi), 320 nm; lambda(emi), 450 nm) by Excitation Emission Spectra (EES) analysis. The conditions for the degradation of tannery dyeing wastewater such as, Co-NPAC dose, concentration of H2O2, and temperature were optimized in heterogeneous Fenton oxidation process and the maximum percentage of COD removal was found to be 77%. The treatment of dyes in wastewater was confirmed through UV-Visible spectra, EES and FT-IR spectra analyses. PMID- 25733390 TI - Functional characterization of two novel non-synonymous alterations in CD46 and a Q950H change in factor H found in atypical hemolytic uremic syndrome patients. AB - Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation, characterized by hemolytic anemia, thrombocytopenia and acute renal failure. Mutations in complement inhibitors are major risk factors for development of aHUS. The three aHUS patients reported in this study had several previously identified alterations in complement inhibitors; e.g. risk haplotypes in CD46 and factor H but we also identified two novel heterozygous non-synonymous CD46 alterations (p.E142Q and p.G259V). Presence of G259V caused decreased expression of the recombinant mutant CD46 compared to wild type (WT). Western blot analysis showed that the majority of the expressed G259V protein was in the precursor form, suggesting that it is processed less efficiently than WT. Low CD46 expression on the surface of the patient's neutrophils confirmed the in vitro results. Further, G259V had a substantially impaired ability to act as a cofactor to factor I, in the degradation of both C3b and C4b. The E142Q mutant showed neither decreased expression nor impaired function. Two of the patients also had a heterozygous non-synonymous alteration in factor H (p.Q950H), reported previously in aHUS but not functionally tested. This variant showed moderately impaired function in hemolytic assays, both using patient sera and recombinant proteins. The recombinant Q950H also showed a somewhat decreased expression compared to WT but the complement inhibitory function in fluid phase was normal. Taken together, we report a novel CD46 alteration showing both a decreased protein expression and substantially impaired cofactor function (G259V) and another without an effect on expression or cofactor function (E142Q). Moreover, mild consequences of a previously reported aHUS associated rare variant in factor H (Q950H) was also revealed, underlining the clear need for functional characterization of each new aHUS associated mutation. PMID- 25733393 TI - Physical mechanisms of interaction of cold plasma with polymer surfaces. AB - Physical mechanisms of the interaction of cold plasmas with organic surfaces are discussed. Trapping of plasma ions by the CH2 groups of polymer surfaces resulting in their electrical charging is treated. Polyethylene surfaces were exposed to the cold radiofrequency air plasma for different intervals of time. The change in the wettability of these surfaces was registered. The experimentally established characteristic time scales of the interaction of cold plasma with polymer surfaces are inversely proportional to the concentration of ions. The phenomenological kinetic model of the electrical charging of polymer surfaces by plasmas is introduced and analyzed. PMID- 25733394 TI - Morphological transition of a conductive molecular organization with non-covalent from nanonetwork to nanofiber. AB - The formation of nanofiber morphology at a mesoscopic scale, and molecular level stacking of a tetrathiafulvalene (TTF) derivative with a chiral group were investigated by the one-dimensional growth method in interfacial molecular films. Monomolecular films of a TTF derivative with a chiral borneol group display a two dimensional phase transition at the air/water interface. At high surface pressures, nanonetwork domains are formed, where the TTF molecular planes are densely packed with an interlayer distance of 4.1 A. The formation of this network is attributed to the organized aggregation of the TTF derivatives, which is a result of strong intermolecular interactions. Subsequently, the growth of morphology is encouraged by the application of the one-dimensional growth method at low surface pressure conditions, varying compression speeds, and subphase temperatures. At low surface pressure and a subphase temperature of 15 degrees C, the TTF derivatives aggregated as nanofibers with close packing of molecules. Upon raising the subphase temperature, the thickness of the nanofibers was found to increase and hence, spontaneous morphogenesis at the air/water interface was achieved. PMID- 25733395 TI - Right ventricular segmentation in cardiac MRI with moving mesh correspondences. AB - This study investigates automatic propagation of the right ventricle (RV) endocardial and epicardial boundaries in 4D (3D+time) magnetic resonance imaging (MRI) sequences. Based on a moving mesh (or grid generation) framework, the proposed algorithm detects the endocardium and epicardium within each cardiac phase via point-to-point correspondences. The proposed method has the following advantages over prior RV segmentation works: (1) it removes the need for a time consuming, manually built training set; (2) it does not make prior assumptions as to the intensity distributions or shape; (3) it provides a sequence of corresponding points over time, a comprehensive input that can be very useful in cardiac applications other than segmentation, e.g., regional wall motion analysis; and (4) it is more flexible for congenital heart disease where the RV undergoes high variations in shape. Furthermore, the proposed method allows comprehensive RV volumetric analysis over the complete cardiac cycle as well as automatic detections of end-systolic and end-diastolic phases because it provides a segmentation for each time step. Evaluated quantitatively over the 48-subject data set of the MICCAI 2012 RV segmentation challenge, the proposed method yielded an average Dice score of 0.84+/-0.11 for the epicardium and 0.79+/-0.17 for the endocardium. Further, quantitative evaluations of the proposed approach in comparisons to manual contours over 23 infant hypoplastic left heart syndrome patients yielded a Dice score of 0.82+/-0.14, which demonstrates the robustness of the algorithm. PMID- 25733396 TI - [Infectious complications in autosomal dominant polycystic kidney disease]. AB - Despite advances in the management of autosomal dominant polycystic kidney disease over the past two decades, infection of liver and kidney cysts remains a serious and potentially threatening complication. Kidney cyst infection is the most frequent complication. It is differentiated from hemorrhage by the clinical presentation (mainly the severity and duration of fever), C-reactive protein (CRP) and white blood cells levels, and the density of the suspected cyst on computed tomography. Liver cyst infection occurs more frequently in patients with large cysts volumes. It can be life threatening and has a tendency to recur. In both infections, the best radiological imaging technique is positron emission tomography after intravenous injection of [18F]-fluorodeoxyglucose combined with computed tomography. Treatment with a fluoroquinolone should be continued for 6 weeks. Cyst aspiration is necessary only when cysts are very large and/or when infection is resistant to antibiotic treatment. In patients who are candidates to kidney transplantation, a history of recurrent kidney cyst infection justifies pre-transplant nephrectomy, while a past history of recurrent liver cyst infection or angiocholitis leads to consider liver transplantation. Among extrarenal and extrahepatic complications of polycystic disease, colic diverticulosis is reported to be associated with increased risk of infection in patients on hemodialysis and after kidney transplantation. However, this observation needs to be confirmed. PMID- 25733397 TI - Enhanced photocatalytic oxidation of gaseous elemental mercury by TiO2 in a high temperature environment. AB - The photo-oxidation of Hg(0) in a lab-scale reactor by titanium dioxide (TiO2) coated on the surface of glass beads was investigated at high temperatures. TiO2 was calcinated at four different temperatures of 300 degrees C, 400 degrees C, 500 degrees C and 600 degrees C (noted as Ti300, Ti400, Ti500 and Ti600) and characterized for its physicochemical properties. The calcinated TiO2 coating on the glass beads was then tested to compare the photo-oxidation efficiencies of Hg(0) with an incident light of 365 nm. The results showed that the oxidation efficiencies of Hg(0) for Ti400 and Ti500 were higher than those of Ti300 and Ti600. To enhance the photo-oxidation efficiency of Hg(0), Ti400 was selected to examine the wave lengths (lambda) of 254 nm, 365 nm and visible light with various influent Hg(0) concentrations. The effects of irradiation strength and the presence of oxygen on the photo-oxidation efficiency of Hg(0) were further investigated, respectively. This study revealed that the wave length (lambda) of 254 nm could promote the photo-oxidation efficiency of Hg(0) at 140 and 160 degrees C, while increasing the influent Hg(0) concentration and could enhance the photo-oxidation rate of Hg(0). However, the influence of 5% O2 present in the flue gas for the enhancement of Hg(0) oxidation was limited. Moreover, the intensity of the incident wave length of 365 nm and visible light were demonstrated to boost the photo-oxidation efficiency of Hg(0) effectively. PMID- 25733398 TI - Tungsten oxide--fly ash oxide composites in adsorption and photocatalysis. AB - A novel composite based on tungsten oxide and fly ash was hydrothermally synthetized to be used as substrate in the advanced treatment of wastewaters with complex load resulted from the textile industry. The proposed treatment consists of one single step process combining photocatalysis and adsorption. The composite's crystalline structure was investigated by X-ray diffraction and FTIR, while atomic force microscopy (AFM) and scanning electron microscopy (SEM) were used to analyze the morphology. The adsorption capacity and photocatalytic properties of the material were tested on mono- and multi-pollutants systems containing two dyes (Bemacid Blau - BB and Bemacid Rot - BR) and one heavy metal ion-Cu(2+), and the optimized process conditions were identified. The results indicate better removal efficiencies using the novel composite material in the combined adsorption and photocatalysis, as compared to the separated processes. Dyes removal was significantly enhanced in the photocatalytic process by adding hydrogen peroxide and the mechanism was presented and discussed. The pseudo second order kinetics model best fitted the experimental data, both in the adsorption and in the combined processes. The kinetic parameters were calculated and correlated with the properties of the composite substrate. PMID- 25733399 TI - Human induced pluripotent stem cells differentiate into insulin-producing cells able to engraft in vivo. AB - AIMS: New sources of insulin-secreting cells are strongly required for the cure of diabetes. Recent successes in differentiating embryonic stem cells, in combination with the discovery that it is possible to derive human induced pluripotent stem cells (iPSCs) from somatic cells, have raised the possibility that patient-specific beta cells might be derived from patients through cell reprogramming and differentiation. In this study, we aimed to obtain insulin producing cells from human iPSCs and test their ability to secrete insulin in vivo. METHODS: Human iPSCs, derived from both fetal and adult fibroblasts, were differentiated in vitro into pancreas-committed cells and then transplanted into immunodeficient mice at two different stages of differentiation (posterior foregut and endocrine cells). RESULTS: IPSCs were shown to differentiate in insulin-producing cells in vitro, following the stages of pancreatic organogenesis. At the end of the differentiation, the production of INSULIN mRNA was highly increased and 5 +/- 2.9 % of the cell population became insulin positive. Terminally differentiated cells also produced C-peptide in vitro in both basal and stimulated conditions. In vivo, mice transplanted with pancreatic cells secreted human C-peptide in response to glucose stimulus, but transplanted cells were observed to lose insulin secretion capacity during the time. At histological evaluation, the grafts resulted to be composed of a mixed population of cells containing mature pancreatic cells, but also pluripotent and some neuronal cells. CONCLUSION: These data overall suggest that human iPSCs have the potential to generate insulin-producing cells and that these differentiated cells can engraft and secrete insulin in vivo. PMID- 25733401 TI - Abamectin induces rapid and reversible hypoactivity within early zebrafish embryos. AB - During early zebrafish embryogenesis, spontaneous tail contractions represent the first sign of locomotion and result from innervation of primary motoneuron axons to target axial muscles. Based on a high-content screen, we previously demonstrated that exposure of zebrafish embryos to abamectin--an avermectin insecticide--from 5-25 hours post-fertilization (hpf) abolished spontaneous activity in the absence of effects on survival and gross morphology. Therefore, the objective of this study was to begin investigating the mechanism of abamectin induced hypoactivity in zebrafish. Similar to 384-well plates, static exposure of embryos to abamectin from 5-25 hpf in glass beakers resulted in elimination of activity at low micromolar concentrations. However, abamectin did not affect neurite outgrowth from spinal motoneurons and, compared with exposure from 5-25 hpf, embryos were equally susceptible to abamectin-induced hypoactivity when exposures were initiated at 10 and 23 hpf. Moreover, immersion of abamectin exposed embryos in clean water resulted in complete recovery of spontaneous activity relative to vehicle controls, suggesting that abamectin reversibly activated ligand-gated chloride channels and inhibited neurotransmission. To test this hypothesis, we pretreated embryos to vehicle or non-toxic concentrations of fipronil or endosulfan--two insecticides that antagonize the gamma-aminobutyric acid (GABA) receptor--from 5-23 hpf, and then exposed embryos to vehicle or abamectin from 23-25 hpf. Interestingly, activity levels within abamectin-exposed embryos pretreated with either antagonist were similar to embryos exposed to vehicle alone. Using quantitative PCR and phylogenetic analyses, we then confirmed the presence of GABA receptor alpha1 and beta2 subunits at 5, 10, and 23 hpf, and demonstrated that zebrafish GABA receptor subunits are homologous to mammalian GABA receptor subunits. Overall, our data collectively suggest that abamectin induces rapid and reversible hypoactivity within early zebrafish embryos, an effect that may be mediated through the GABA receptor. PMID- 25733400 TI - 1000 Norms Project: protocol of a cross-sectional study cataloging human variation. AB - BACKGROUND: Clinical decision-making regarding diagnosis and management largely depends on comparison with healthy or 'normal' values. Physiotherapists and researchers therefore need access to robust patient-centred outcome measures and appropriate reference values. However there is a lack of high-quality reference data for many clinical measures. The aim of the 1000 Norms Project is to generate a freely accessible database of musculoskeletal and neurological reference values representative of the healthy population across the lifespan. METHODS/DESIGN: In 2012 the 1000 Norms Project Consortium defined the concept of 'normal', established a sampling strategy and selected measures based on clinical significance, psychometric properties and the need for reference data. Musculoskeletal and neurological items tapping the constructs of dexterity, balance, ambulation, joint range of motion, strength and power, endurance and motor planning will be collected in this cross-sectional study. Standardised questionnaires will evaluate quality of life, physical activity, and musculoskeletal health. Saliva DNA will be analysed for the ACTN3 genotype ('gene for speed'). A volunteer cohort of 1000 participants aged 3 to 100 years will be recruited according to a set of self-reported health criteria. Descriptive statistics will be generated, creating tables of mean values and standard deviations stratified for age and gender. Quantile regression equations will be used to generate age charts and age-specific centile values. DISCUSSION: This project will be a powerful resource to assist physiotherapists and clinicians across all areas of healthcare to diagnose pathology, track disease progression and evaluate treatment response. This reference dataset will also contribute to the development of robust patient-centred clinical trial outcome measures. PMID- 25733402 TI - An explanation and invitation: making space for conversation in the digital world. PMID- 25733404 TI - Comparison of life history and genetic properties of cowpea bruchid strains and their response to hypoxia. AB - The cowpea bruchid (Callosobruchus maculatus) is the most important storage pest of grain legumes and comprises geographically distinct strains. Storage under a modified atmosphere with decreased O2 content represents an alternative to chemical fumigants for pest control of stored grains. In this study, we compared reproduction, development and survival, as well as genome size of bruchid strains from South India (SI), Burkina Faso (BF), Niger (CmNnC) and the United States (OH), reared on mung bean (Vigna radiata). Fecundity and egg-to-adult duration varied significantly among these strains. Notably, strain BF had the highest fecundity, and strain SI displayed the fastest development whereas strain OH was the slowest. Differences in adult lifespan among strains were only detected in unmated but not in the mated group. Genome size of SI females was significantly larger than that of OH females, and for all four strains, the female genomes were larger than those of their corresponding males. Furthermore, we studied effects of exposure to 1% O2+99% N2 on strains SI and BF. Mortality caused by hypoxia was influenced by not only developmental stage but also by insect strain. Eggs were most sensitive, particularly at the early stage, whereas the 3rd and 4th instar larvae were most tolerant and could survive up to 15 days of low O2. Strain SI was slightly more resistant than BF in egg and larval stages. Proteolytic activity prior to, during and after hypoxia treatment revealed remarkable metabolic plasticity of cowpea bruchids in response to modified atmosphere. PMID- 25733406 TI - Li(+) solvation in glyme-Li salt solvate ionic liquids. AB - Certain molten complexes of Li salts and solvents can be regarded as ionic liquids. In this study, the local structure of Li(+) ions in equimolar mixtures ([Li(glyme)]X) of glymes (G3: triglyme and G4: tetraglyme) and Li salts (LiX: lithium bis(trifluoromethanesulfonyl)amide (Li[TFSA]), lithium bis(pentafluoroethanesulfonyl)amide (Li[BETI]), lithium trifluoromethanesulfonate (Li[OTf]), LiBF4, LiClO4, LiNO3, and lithium trifluoroacetate (Li[TFA])) was investigated to discriminate between solvate ionic liquids and concentrated solutions. Raman spectra and ab initio molecular orbital calculations have shown that the glyme molecules adopt a crown-ether like conformation to form a monomeric [Li(glyme)](+) in the molten state. Further, Raman spectroscopic analysis allowed us to estimate the fraction of the free glyme in [Li(glyme)]X. The amount of free glyme was estimated to be a few percent in [Li(glyme)]X with perfluorosulfonylamide type anions, and thereby could be regarded as solvate ionic liquids. Other equimolar mixtures of [Li(glyme)]X were found to contain a considerable amount of free glyme, and they were categorized as traditional concentrated solutions. The activity of Li(+) in the glyme-Li salt mixtures was also evaluated by measuring the electrode potential of Li/Li(+) as a function of concentration, by using concentration cells against a reference electrode. At a higher concentration of Li salt, the amount of free glyme diminishes and affects the electrode reaction, leading to a drastic increase in the electrode potential. Unlike conventional electrolytes (dilute and concentrated solutions), the significantly high electrode potential found in the solvate ILs indicates that the solvation of Li(+) by the glyme forms stable and discrete solvate ions ([Li(glyme)](+)) in the molten state. This anomalous Li(+) solvation may have a great impact on the electrode reactions in Li batteries. PMID- 25733405 TI - Method for automatic adjustment of an insulin bolus calculator: in silico robustness evaluation under intra-day variability. AB - BACKGROUND AND OBJECTIVE: Insulin bolus calculators are simple decision support software tools incorporated in most commercially available insulin pumps and some capillary blood glucose meters. Although their clinical benefit has been demonstrated, their utilisation has not been widespread and their performance remains suboptimal, mainly because of their lack of flexibility and adaptability. One of the difficulties that people with diabetes, clinicians and carers face when using bolus calculators is having to set parameters and adjust them on a regular basis according to changes in insulin requirements. In this work, we propose a novel method that aims to automatically adjust the parameters of a bolus calculator. Periodic usage of a continuous glucose monitoring device is required for this purpose. METHODS: To test the proposed method, an in silico evaluation under real-life conditions was carried out using the FDA-accepted Type 1 diabetes mellitus (T1DM) UVa/Padova simulator. Since the T1DM simulator does not incorporate intra-subject variability and uncertainty, a set of modifications were introduced to emulate them. Ten adult and ten adolescent virtual subjects were assessed over a 3-month scenario with realistic meal variability. The glycaemic metrics: mean blood glucose; percentage time in target; percentage time in hypoglycaemia; risk index, low blood glucose index; and blood glucose standard deviation, were employed for evaluation purposes. A t-test statistical analysis was carried out to evaluate the benefit of the presented algorithm against a bolus calculator without automatic adjustment. RESULTS: The proposed method statistically improved (p<0.05) all glycemic metrics evaluating hypoglycaemia on both virtual cohorts: percentage time in hypoglycaemia (i.e. BG<70 mg/dl) (adults: 2.7+/-4.0 vs. 0.4+/-0.7, p=0.03; adolescents: 7.1+/-7.4 vs. 1.3+/-2.4, p=0.02) and low blood glucose index (LBGI) (adults: 1.1+/-1.3 vs. 0.3+/-0.2, p=0.002; adolescents: 2.0+/-2.19 vs. 0.7+/-1.4, p=0.05). A statistically significant improvement was also observed on the blood glucose standard deviation (BG SD mg/dL) (adults: 33.5+/-13.7 vs. 29.2+/-8.3, p=0.01; adolescents: 63.7+/ 22.7 vs. 44.9+/-23.9, p=0.01). Apart from a small increase in mean blood glucose on the adult cohort (129.9+/-11.9 vs. 133.9+/-11.6, p=0.03), the rest of the evaluated metrics, despite showing an improvement trend, did not experience a statistically significant change. CONCLUSIONS: A novel method for automatically adjusting the parameters of a bolus calculator has the potential to improve glycemic control in T1DM diabetes management. PMID- 25733407 TI - Assessing a low-cost accelerometer-based technique to estimate spatial gait parameters of lower-limb prosthesis users. AB - BACKGROUND AND AIM: Inexpensive methods for characterizing lower-limb prosthetic gait allow clinicians to monitor gait quality. This study assessed an established method for estimating step length using a low-cost accelerometer to estimate distance walked in lower-limb prosthesis users and explore the use of subject specific correction factors. TECHNIQUE: A three-axis accelerometer was attached to participants using straps. Validity and test-retest reliability of step length was assessed in able-bodied individuals using a motion capture system. Validity of distance walked was assessed with lower-limb prosthesis users. A regression equation was developed for prosthesis users to estimate a correction factor that minimized error. DISCUSSION: The system demonstrated excellent reliability and minimal mean error for both participant groups, but subject-specific correction factors did not provide substantial benefit. Estimate variability was high, suggesting the need for further refinement. Estimating distance walked and step length from low-cost accelerometers may be a valid, clinically accessible method for characterizing prosthetic gait. CLINICAL RELEVANCE: The use of a low-cost accelerometer may provide valid means for estimating step length and distance walked of lower-limb prosthesis users in a clinical environment for monitoring patient outcomes. PMID- 25733408 TI - Amputee socks: Sock thickness changes with normal use. AB - BACKGROUND: Prosthetic socks are expected to decrease in thickness and have reduced volume accommodation with normal use. It is unknown, however, to what degree they reduce in thickness over time. OBJECTIVE: The goal of this study was to determine a correlation between the age of a prosthetic sock (defined as the out-of-package time) and the resulting change in thickness under standardized weight-bearing and non-weight-bearing conditions. STUDY DESIGN: Experimental, mechanical assessment. METHODS: Used prosthetic socks were donated by donors with transtibial amputation. Sock thickness was measured on a custom instrument under conditions representative of normal use. Stress-thickness response was compared to that of equivalent new socks to quantify the effects of use on sock performance. RESULTS: Sock thickness changed non-linearly over time. On average, socks were 75% +/- 17% of their initial thickness after 1 month, while socks older than 1 month were 72% +/- 18% of their initial thickness. The elasticity of socks did not change with age. CONCLUSION: The volume accommodation provided by used socks cannot be reliably predicted by ply or age. Direct measurement of total sock thickness may provide meaningful insight to quantify prosthetic users' socket fit and guide volume accommodation recommendations. CLINICAL RELEVANCE: The mean difference in thickness between 3-ply and 5-ply used socks was equal to the standard deviation of each ply group (0.3mm). Therefore, it is possible that a 3-ply sock worn for as a little as 1 month could have a greater thickness than a 5-ply sock worn for a month. PMID- 25733409 TI - Editor's briefing. PMID- 25733410 TI - Really putting patients first: ensuring significant involvement for patients in healthcare decision making. PMID- 25733411 TI - Self-rated health in general practice: a plea for subjectivity. PMID- 25733412 TI - The CQC inspections: what they mean for general practice. PMID- 25733413 TI - Prescribing for patients with multimorbidity: aiming to tailor to patient-set goals. PMID- 25733415 TI - GP recruitment and retention. PMID- 25733416 TI - Patients could provide initial differential diagnoses. PMID- 25733417 TI - Optimising stroke prevention in patients with atrial fibrillation. PMID- 25733418 TI - The broken tannoy. PMID- 25733419 TI - Dostoyevsky in the consultation: the burden of freedom. PMID- 25733420 TI - Working with Polish migrants. PMID- 25733421 TI - Gravitating to sickness? A sociocultural hypothesis. PMID- 25733422 TI - Medically unexplained symptoms, dysmenorrhoea, mental health stigma, and YouTube. PMID- 25733423 TI - The humanities in medical education: lessons from the past. PMID- 25733424 TI - International primary care snapshots: New Zealand and Japan. PMID- 25733425 TI - The hidden hazards of spring: why pregnant women and the immunocompromised should avoid lambing. PMID- 25733426 TI - Opera: Rossini leads the way to Verdi. PMID- 25733430 TI - Jubilant? PMID- 25733431 TI - What should integrated care look like ... ? PMID- 25733432 TI - Electronic ambulance chasing: patient records, guidelines, and the law. PMID- 25733433 TI - Home-use faecal immunochemical testing: primary care diagnostic technology update. PMID- 25733434 TI - Patient perspectives on test result communication in primary care: a qualitative study. AB - BACKGROUND: Although the number of blood tests ordered in primary care continues to increase, efficient systems for the communication of blood test results to patients are lacking. This is a concern in terms of both patient safety and patient satisfaction. AIM: To gain an understanding of patient perspectives on organisational and technological aspects of current and prospective systems for communicating laboratory test results in primary care, and the influences that impact patients' preferred methods for receiving results. DESIGN AND SETTING: Qualitative study using patient focus groups in four primary care practices in Birmingham, UK. METHOD: The primary care practices were purposively selected to ensure they varied in size, socioeconomic environment, and the default pathways they used to communicate test results. A total of 26 patients from the four practices who had had a recent blood test were recruited. Over a 6 month period in 2011, six, 1-hour focus groups were conducted at the four practices involved in the study. RESULTS: Patients expressed a preference for receiving results from the ordering GP or a clinically qualified member of staff. Suggestions for refining current systems included improved access to phlebotomy appointments, better management of patient telephone calls, and a clear, accessible protocol for the communication of results. CONCLUSION: Despite the testing and result communication process being a core activity in primary care, it was found that practices could improve their service in a number of areas. Patients described frequent delays and inconsistency in both the level of information and the method of communication, as well as dissatisfaction with non-clinical staff relaying results. Patient preferences for result communication based on their experience of current systems have produced practical suggestions to improve processes. PMID- 25733435 TI - Patients' online access to their electronic health records and linked online services: a systematic review in primary care. AB - BACKGROUND: Online access to medical records by patients can potentially enhance provision of patient-centred care and improve satisfaction. However, online access and services may also prove to be an additional burden for the healthcare provider. AIM: To assess the impact of providing patients with access to their general practice electronic health records (EHR) and other EHR-linked online services on the provision, quality, and safety of health care. DESIGN AND SETTING: A systematic review was conducted that focused on all studies about online record access and transactional services in primary care. METHOD: Data sources included MEDLINE, Embase, CINAHL, Cochrane Library, EPOC, DARE, King's Fund, Nuffield Health, PsycINFO, OpenGrey (1999-2012). The literature was independently screened against detailed inclusion and exclusion criteria; independent dual data extraction was conducted, the risk of bias (RoB) assessed, and a narrative synthesis of the evidence conducted. RESULTS: A total of 176 studies were identified, 17 of which were randomised controlled trials, cohort, or cluster studies. Patients reported improved satisfaction with online access and services compared with standard provision, improved self-care, and better communication and engagement with clinicians. Safety improvements were patient led through identifying medication errors and facilitating more use of preventive services. Provision of online record access and services resulted in a moderate increase of e-mail, no change on telephone contact, but there were variable effects on face-to-face contact. However, other tasks were necessary to sustain these services, which impacted on clinician time. There were no reports of harm or breaches in privacy. CONCLUSION: While the RoB scores suggest many of the studies were of low quality, patients using online services reported increased convenience and satisfaction. These services positively impacted on patient safety, although there were variations of record access and use by specific ethnic and socioeconomic groups. Professional concerns about privacy were unrealised and those about workload were only partly so. PMID- 25733436 TI - Patient reactions to a web-based cardiovascular risk calculator in type 2 diabetes: a qualitative study in primary care. AB - BACKGROUND: Use of risk calculators for specific diseases is increasing, with an underlying assumption that they promote risk reduction as users become better informed and motivated to take preventive action. Empirical data to support this are, however, sparse and contradictory. AIM: To explore user reactions to a cardiovascular risk calculator for people with type 2 diabetes. Objectives were to identify cognitive and emotional reactions to the presentation of risk, with a view to understanding whether and how such a calculator could help motivate users to adopt healthier behaviours and/or improve adherence to medication. DESIGN AND SETTING: Qualitative study combining data from focus groups and individual user experience. Adults with type 2 diabetes were recruited through website advertisements and posters displayed at local GP practices and diabetes groups. METHOD: Participants used a risk calculator that provided individualised estimates of cardiovascular risk. Estimates were based on UK Prospective Diabetes Study (UKPDS) data, supplemented with data from trials and systematic reviews. Risk information was presented using natural frequencies, visual displays, and a range of formats. Data were recorded and transcribed, then analysed by a multidisciplinary group. RESULTS: Thirty-six participants contributed data. Users demonstrated a range of complex cognitive and emotional responses, which might explain the lack of change in health behaviours demonstrated in the literature. CONCLUSION: Cardiovascular risk calculators for people with diabetes may best be used in conjunction with health professionals who can guide the user through the calculator and help them use the resulting risk information as a source of motivation and encouragement. PMID- 25733437 TI - Ethnic differences in patients' preferences for prostate cancer investigation: a vignette-based survey in primary care. AB - BACKGROUND: Minority ethnic groups in the UK have worse outcomes for some cancer types compared with the white majority. Black males have worse staging at diagnosis of prostate cancer and often present as emergencies, suggesting possible delays in the diagnostic pathway. Delay may arise from lower awareness of cancer symptoms, reluctance to report symptoms, reduced desire for investigation, or a combination of these. Reduced desire for investigation was examined in this study AIM: To investigate whether black males in the UK would choose to be tested for prostate cancer compared with the white majority. DESIGN AND SETTING: A vignette (hypothetical scenario)-based, electronic survey of male patients aged >=40 years from four general practices in Bristol, UK. METHOD: The vignettes described possible prostate cancer symptoms (equating to risk levels of 2%, 5%, and 10%), investigative procedures, and possible outcomes. Participants indicated whether they would choose investigation in these scenarios. Analysis used logistic regression, with preference for investigation as the outcome variable and ethnicity as the main explanatory variable. RESULTS: In total, 449 (81%) of 555 participants opted for investigation, regardless of risk levels; of these, the acceptance rate was 94% (251 out of 267) among white males and 70% (198 out of 285) among black males. In multivariable analyses, preference for investigation was lower in black males, even after controlling for relevant confounding factors including specific risk level (odds ratio 0.13; 95% confidence interval = 0.07 to 0.25; P<0.001). CONCLUSION: Black males are less likely to opt for investigation at any risk level of prostate cancer compared with white males. This may explain some of their late-stage presentation at diagnosis and subsequent poorer outcomes. PMID- 25733438 TI - Refugee experiences of general practice in countries of resettlement: a literature review. AB - BACKGROUND: Refugees and asylum seekers often struggle to use general practice services in resettlement countries. AIM: To describe and analyse the literature on the experiences of refugees and asylum seekers using general practice services in countries of resettlement. DESIGN AND SETTING: Literature review using systematic search and narrative data extraction and synthesis methodologies. International, peer-reviewed literature published in English language between 1990 and 2013. METHOD: Embase, Ovid MEDLINE, PsycINFO, CSA Sociological Abstracts, and CINAHL databases were searched using the terms: refugee, asylum seeker, experience, perception, doctor, physician, and general practitioner. Titles, abstracts and full texts were reviewed and were critically appraised. Narrative themes describing the refugee or asylum seeker's personal experiences of general practice services were identified, coded, and analysed. RESULTS: From 8722 papers, 85 were fully reviewed and 23 included. These represented the experiences of approximately 864 individuals using general practice services across 11 countries. Common narrative themes that emerged were: difficulties accessing general practice services, language barriers, poor doctor-patient relationships, and problems with the cultural acceptability of medical care. CONCLUSION: The difficulties refugees and asylum seekers experience accessing and using general practice services could be addressed by providing practical support for patients to register, make appointments, and attend services, and through using interpreters. Clinicians should look beyond refugee stereotypes to focus on the needs and expectations of the individual. They should provide clear explanations about unfamiliar clinical processes and treatments while offering timely management. PMID- 25733439 TI - Developing patient reference groups within general practice: a mixed-methods study. AB - BACKGROUND: Clinical commissioning groups (CCGs) are required to demonstrate meaningful patient and public engagement and involvement (PPEI). Recent health service reforms have included financial incentives for general practices to develop patient reference groups (PRGs). AIM: To explore the impact of the patient participation direct enhanced service (DES) on development of PRGs, the influence of PRGs on decision making within general practice, and their interface with CCGs. DESIGN AND SETTING: A mixed-methods approach within three case study sites in England. METHOD: Three case study sites were tracked for 18 months as part of an evaluation of PPEI in commissioning. A sub-study focused on PRGs utilising documentary and web-based analysis; results were mapped against findings of the main study. RESULTS: Evidence highlighted variations in the establishment of PRGs, with the number of active PRGs via practice websites ranging from 27% to 93%. Such groups were given a number of descriptions such as patient reference groups, patient participation groups, and patient forums. Data analysis highlighted that the mode of operation varied between virtual and tangible groups and whether they were GP- or patient-led, such analysis enabled the construction of a typology of PRGs. Evidence reviewed suggested that groups functioned within parameters of the DES with activities limited to practice level. Data analysis highlighted a lack of strategic vision in relation to such groups, particularly their role within an overall patient and PPEI framework). CONCLUSION: Findings identified diversity in the operationalisation of PRGs. Their development does not appear linked to a strategic vision or overall PPEI framework. Although local pragmatic issues are important to patients, GPs must ensure that PRGs develop strategic direction if health reforms are to be addressed. PMID- 25733440 TI - What to give the patient who has everything? A qualitative study of prescribing for multimorbidity in primary care. AB - BACKGROUND: Using clinical guidelines in the management of patients with multimorbidity can lead to the prescription of multiple and sometimes conflicting medications. AIM: To explore how GPs make decisions when prescribing for multimorbid patients, with a view to informing intervention design. DESIGN AND SETTING: In-depth qualitative interviews incorporating chart-stimulated recall with purposively sampled GPs in the Republic of Ireland. METHOD: Grounded theory analysis with iterative theory development. RESULTS: Twenty GPs were interviewed about 51 multimorbid cases. In these cases, GPs integrated information from multiple sources including the patient, specialists, and evidence-based medicine. Difficulties arose when recommendations or preferences conflicted, to which GPs responded by 'satisficing': accepting care that they deemed satisfactory and sufficient for a particular patient. Satisficing was manifest as relaxing targets for disease control, negotiating compromise with the patient, or making 'best guesses' about the most appropriate course of action to take. In multimorbid patients perceived as stable, GPs preferred to 'maintain the status quo' rather than rationalise medications, even in cases with significant polypharmacy. Proactive changes in medications were facilitated by continuity of care, sufficient consultation time, and open lines of communication with the patient, other healthcare professionals, and other GPs. CONCLUSION: GPs respond to conflicts in the management of multimorbid patients by making compromises between patient-centred and evidence-based care. These findings will be used to inform interventions that aim to care in multimorbidity. PMID- 25733441 TI - Patient information materials in general practices and promotion of health literacy: an observational study of their effectiveness. AB - BACKGROUND: Government policy in the UK emphasises providing patients with good health information to encourage participation in their health care. Patient information leaflets (PILs) form part of this policy and have been shown to affect patient health outcomes; however, many are poorly written. AIM: To describe the PILs in general practice surgeries in Stoke-on-Trent in terms of readability and variety of content. DESIGN AND SETTING: An observational study of randomly selected GP practices (n = 17) across Stoke-on-Trent. METHOD: PILs were assessed for readability (Flesch Reading Ease and Flesch-Kincaid Grade Level) and compared with national skills level data and with the recommended level for medical information. The PILs were also categorised for content using the Rudd (2007) health material classification framework. RESULTS: A total of 345 PILs were collected and assessed. Only 24.3% meet recommended reading-level criteria. Compared with national skills levels, over 75% of the PILs collected were too complex for at least 15% of the English population. Of the PILs, 47.8% were classified as 'systems navigation' (information regarding services); 22.9% were disease prevention (screening and immunisations); 14.2% personal and public safety; and less than 10% were for managing illness or health promotion. CONCLUSION: Current PILs in general practices do not all promote health literacy. Information only accessible to a proportion of higher skilled patients may increase inequalities in health. Less than 10% of PILs promote managing illness or healthy lifestyles. Processes must be put in place to improve the readability and variety of content of PILs in GP practices. PMID- 25733442 TI - Effects of the economic crisis and social support on health-related quality of life: first wave of a longitudinal study in Spain. AB - BACKGROUND: Economic recession affects quality of life by increasing rates of mental disorders in particular. Social support can be an important protective factor. AIM: To estimate the impact of being personally affected by an economic crisis on health-related quality of life (HRQoL), taking into account the possible buffering effect of perceived social support. DESIGN AND SETTING: Data from the first wave (March 2012 to November 2012) of the 'Social Support and Quality of Life Study', a longitudinal study carried out in a primary health care centre in a deprived neighbourhood of Barcelona, Spain. METHOD: A total of 143 participants were assessed using the 12-item Short-Form Health Survey, the List of Threatening Experiences and the Duke Social Support scales. The effect of economic crisis on mental and physical HRQoL was assessed using ordinary least squares regression models to test the interaction between social support and having experienced an economic crisis. RESULTS: There was no statistical association between having suffered an economic crisis and physical HRQoL. The interaction between social support and economic crisis was also tested without finding any statistical association. An interaction was detected between social support and economic crisis in relation to mental HRQoL; those who had low levels of social support and had also experienced an economic crisis had the lowest levels of mental HRQoL. CONCLUSION: Social support constitutes a safety net that offers protection against the adverse effect of economic recessions on mental health. Primary care professionals are in a key position to promote social activities and to strengthen social networks in the community. PMID- 25733443 TI - Heart valve disease in general practice: a clinical overview. PMID- 25733444 TI - Prevalence of helminth infestation during pregnancy and its association with maternal anemia and low birth weight. AB - OBJECTIVE: To determine the prevalence of helminth infestation during pregnancy and the associated risks of adverse maternal and infant outcomes. METHODS: A cross-sectional study of women with a singleton pregnancy of at least 34 weeks was conducted at a teaching hospital in Benin City, Nigeria, between April 1 and September 30, 2010. Socioeconomic and clinical data were obtained. Stool samples were used to determine helminth infection. Birth weight was recorded at delivery. Multivariable analysis was used to assess the link between helminth infestation and maternal and perinatal outcomes. RESULTS: Among 178 women, 31 (17.4%) had a helminth infestation (15 [8.4%] had ascariasis, 8 [4.5%] trichuriasis, and 25 [14.0%] hookworm infestation). Multivariate analysis found that helminth infestations was associated with maternal anemia (adjusted odds ratio 12.4; 95% confidence interval 4.2-36.3) and low birth weight (adjusted odds ratio 6.8; 95% confidence interval 2.1-21.9). CONCLUSION: Approximately one in five women had a helminth infestation in the third trimester of pregnancy. Maternal helminth infestation significantly increased the risks of maternal anemia and low birth weight, indicating that routine administration of anthelminthic drugs during early pregnancy might improve perinatal outcomes. PMID- 25733445 TI - Genome level analysis of bacteriocins of lactic acid bacteria. AB - Bacteriocins are antimicrobial peptides which are ribosomally synthesized by mainly all bacterial species. LABs (lactic acid bacteria) are a diverse group of bacteria that include around 20 genera of various species. Though LABs have a tremendous potential for production of anti-microbial peptides, this group of bacteria is still underexplored for bacteriocins. To study the diversity among bacteriocin encoding clusters and the putative bacteriocin precursors, genome mining was performed on 20 different species of LAB not reported to be bacteriocin producers. The phylogenetic tree of gyrB, rpoB, and 16S rRNA were constructed using MEGA6 software to analyze the diversity among strains. Putative bacteriocins operons identified were found to be diverse and were further characterized on the basis of physiochemical properties and the secondary structure. The presence of at least two cysteine residues in most of the observed putative bacteriocins leads to disulphide bond formation and provide stability. Our data suggests that LABs are prolific source of low molecular weight non modified peptides. PMID- 25733446 TI - Effects of crude oil and dispersed crude oil on the critical swimming speed of puffer fish, Takifugu rubripes. AB - In order to examine the effects of crude oil and dispersed crude oil (DCO) on the swimming ability of puffer fish, Takifugu rubripes, the critical swimming speeds (U crit) of fish exposed to different concentrations of water-soluble fraction (WSF) of crude oil and DCO solution were determined in a swimming flume. WSF and DCO significantly affected the U crit of puffer fish (p < 0.05). The U crit of puffer fish exposed to 136 mg L(-1) WSF and 56.4 mg L(-1) DCO decreased 48.7 % and 43.4 %, respectively. DCO was more toxic to puffer fish than WSF. These results suggested that crude oil and chemically dispersed oil could weaken the swimming ability of puffer fish. PMID- 25733447 TI - Comparison of accumulation of four metalloids in Allium sativum. AB - In this study, we evaluated the accumulation and metabolism of four metalloids: arsenic (As), selenium (Se), antimony (Sb), and tellurium (Te) in garlic to determine whether garlic can be used for the phytoremediation of those metalloids. Garlic was able to efficiently accumulate As and Se, the two-fourth period metalloids. However, it was not able to accumulate Sb and Te, the two fifth-period metalloids, because their bioaccumulation factors were below one. Speciation analyses revealed that four metalloids could be metabolized in garlic, although their metabolites could not be identified yet. Results also suggested that garlic was able to distinguish the metalloids in groups 15 and 16 and the fourth and fifth periods, i.e., As, Se, Sb, and Te. Therefore, garlic is one of the potential plants for the phytoremediation of the fourth-period metalloids. PMID- 25733448 TI - mecA Gene Dissemination Among Staphylococcal and Non-staphylococcal Isolates Shed in Surface Waters. AB - Aquatic ecosystems represent important vehicles for the dissemination of antibiotic resistant bacteria and antibiotic resistance genes. Of particular interest are methicillin-resistant staphylococci (MRS) harboring mecA gene that confers their resistance to beta-lactams. Therefore, in this study, water samples collected from different locations of a river impacted by surrounding facilities and domestic effluents were analyzed to learn more about the occurrence of MRS and mecA gene. Out of 290, 12 surface water isolates displayed resistance to both cefoxitin and oxacillin antibiotics. Resistant staphylococcal and non staphylococcal isolates, identified by 16S rRNA sequencing, were found to harbor mecA gene. The phylogenetic tree of partial mecA sequences obtained from staphylococcal and non-staphylococcal isolates showed sequence similarity values of 8 %-100 %. Surface water bodies receive contaminated waters via runoff, effluents from industrial, agricultural, and municipal discharges. Therefore, surface waters are not only hot spots for mecA harboring staphylococcal isolates but also non-staphylococcal isolates and require special scientific consideration. PMID- 25733449 TI - Molecular mechanisms of congenital hyperinsulinism. AB - Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic beta-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI. PMID- 25733450 TI - Willard J Visek, MD, PhD (1922-2014). PMID- 25733451 TI - Health effects of sugars: in search of novel, unsuspected pathogenic pathways. PMID- 25733452 TI - Serum unmetabolized folic acid: the straw that broke dihydrofolate reductase's back? PMID- 25733453 TI - Food insecurity and poor sleep: another consequence of food insecurity in the United States. PMID- 25733454 TI - The Dietary Patterns Methods Project: synthesis of findings across cohorts and relevance to dietary guidance. AB - The Dietary Patterns Methods Project (DPMP) was initiated in 2012 to strengthen research evidence on dietary indices, dietary patterns, and health for upcoming revisions of the Dietary Guidelines for Americans, given that the lack of consistent methodology has impeded development of consistent and reliable conclusions. DPMP investigators developed research questions and a standardized approach to index-based dietary analysis. This article presents a synthesis of findings across the cohorts. Standardized analyses were conducted in the NIH-AARP Diet and Health Study, the Multiethnic Cohort, and the Women's Health Initiative Observational Study (WHI-OS). Healthy Eating Index 2010, Alternative Healthy Eating Index 2010 (AHEI-2010), alternate Mediterranean Diet, and Dietary Approaches to Stop Hypertension (DASH) scores were examined across cohorts for correlations between pairs of indices; concordant classifications into index score quintiles; associations with all-cause, cardiovascular disease (CVD), and cancer mortality with the use of Cox proportional hazards models; and dietary intake of foods and nutrients corresponding to index quintiles. Across all cohorts in women and men, there was a high degree of correlation and consistent classifications between index pairs. Higher diet quality (top quintile) was significantly and consistently associated with an 11-28% reduced risk of death due to all causes, CVD, and cancer compared with the lowest quintile, independent of known confounders. This was true for all diet index-mortality associations, with the exception of AHEI-2010 and cancer mortality in WHI-OS women. In all cohorts, survival benefit was greater with a higher-quality diet, and relatively small intake differences distinguished the index quintiles. The reductions in mortality risk started at relatively lower levels of diet quality. Higher scores on each of the indices, signifying higher diet quality, were associated with marked reductions in mortality. Thus, the DPMP findings suggest that all 4 indices capture the essential components of a healthy diet. PMID- 25733455 TI - Eicosapentaenoic acid reduces adipocyte hypertrophy and inflammation in diet induced obese mice in an adiposity-independent manner. AB - BACKGROUND: Obesity is associated with an overexpansion of adipose tissue, along with increases in blood pressure, glycemia, inflammation, and thrombosis. Research to develop nutritional interventions to prevent or treat obesity and its associated diseases is greatly needed. Previously, we demonstrated the ability of eicosapentaenoic acid (EPA) to prevent high-fat (HF) diet-induced obesity, insulin resistance, and inflammation in mice. OBJECTIVE: The objective of the current study was to determine the mechanisms mediating the anti-inflammatory and antilipogenic actions of EPA. METHODS: In a previous study, male C57BL/6J mice were fed a low-fat diet (10% of energy from fat), an HF diet (45% of energy from fat), or an HF diet supplemented with EPA (45% of energy from fat; 36 g/kg EPA; HF+EPA) for 11 wk or an HF diet for 6 wk and then switched to the HF+EPA diet for 5 wk. In this study, we used histology/immunohistochemistry, gene expression, and metabolomic analyses of white adipose tissue from these mice. In addition, cultured mouse 3T3-L1 adipocytes were treated with 100 MUM EPA for 48 h and then used for extracellular flux assays with untreated 3T3-L1 adipocytes used as a control. RESULTS: Compared with the HF diet, the HF+EPA diet significantly reduced body weight, adiposity, adipocyte size, and macrophage infiltration into adipose tissue. No significant differences in overall body weight or fat pad weights were observed between HF-fed mice vs. those fed the HF+EPA diet for a short time after first inducing obesity with the HF diet. Interestingly, both histology and immunohistochemistry results showed a significantly lower mean adipocyte size and macrophage infiltration in mice fed the HF diet and then switched to the HF+EPA diet vs. those fed HF diets only. This indicated that EPA was able to prevent as well as reverse HF-diet-induced adipocyte inflammation and hypertrophy and that some of the metabolic effects of EPA were independent of body weight or adiposity. In addition, adipose tissue metabolomic data and cultured adipocyte extracellular flux bioenergetic assays indicated that EPA also regulated mitochondrial function by increasing fatty acid oxidation and oxygen consumption, respectively. CONCLUSION: With the use of mice and cultured adipocytes, we showed that EPA ameliorates HF-diet effects at least in part by increasing oxygen consumption and fatty acid oxidation and reducing adipocyte size, adipogenesis, and adipose tissue inflammation, independent of obesity. PMID- 25733456 TI - Genetic variations in magnesium-related ion channels may affect diabetes risk among African American and Hispanic American women. AB - BACKGROUND: Prospective studies consistently link low magnesium intake to higher type 2 diabetes (T2D) risk. OBJECTIVE: We examined the association of common genetic variants [single nucleotide polymorphisms (SNPs)] in genes related to magnesium homeostasis with T2D risk and potential interactions with magnesium intake. METHODS: Using the Women's Health Initiative-SNP Health Association Resource (WHI-SHARe) study, we identified 17 magnesium-related ion channel genes (583 SNPs) and examined their associations with T2D risk in 7287 African-American (AA; n = 1949 T2D cases) and 3285 Hispanic-American (HA; n = 611 T2D cases) postmenopausal women. We performed both single- and multiple-locus haplotype analyses. RESULTS: Among AA women, carriers of each additional copy of SNP rs6584273 in cyclin mediator 1 (CNNM1) had 16% lower T2D risk [OR: 0.84; false discovery rate (FDR)-adjusted P = 0.02]. Among HA women, several variants were significantly associated with T2D risk, including rs10861279 in solute carrier family 41 (anion exchanger), member 2 (SLC41A2) (OR: 0.54; FDR-adjusted P = 0.04), rs7174119 in nonimprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) (OR: 1.27; FDR-adjusted P = 0.04), and 2 SNPs in mitochondrial RNA splicing 2 (MRS2) (rs7738943: OR = 1.55, FDR-adjusted P = 0.01; rs1056285: OR = 1.48, FDR-adjusted P = 0.02). Even with the most conservative Bonferroni adjustment, two 2-SNP haplotypes in SLC41A2 and MRS2 region were significantly associated with T2D risk (rs12582312-rs10861279: P = 0.0006; rs1056285-rs7738943: P = 0.002). Among women with magnesium intake in the lowest 30% (AA: <=0.164 g/d; HA: <=0.185 g/d), 4 SNP signals were strengthened [rs11590362 in claudin 19 (CLDN19), rs823154 in SLC41A1, rs5929706 and rs5930817 in membra; HA: >=0.313 g/d), rs6584273 in CNNM1 (OR: 0.71; FDR-adjusted P = 0.04) and rs1800467 in potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) (OR: 2.50; FDR-adjusted P = 0.01) were significantly associated with T2D risk. CONCLUSIONS: Our findings suggest important associations between genetic variations in magnesium-related ion channel genes and T2D risk in AA and HA women that vary by amount of magnesium intake. PMID- 25733457 TI - Compared to sucrose, previous consumption of fructose and glucose monosaccharides reduces survival and fitness of female mice. AB - BACKGROUND: Intake of added sugar has been shown to correlate with many human metabolic diseases, and rodent models have characterized numerous aspects of the resulting disease phenotypes. However, there is a controversy about whether differential health effects occur because of the consumption of either of the two common types of added sugar-high-fructose corn syrup (fructose and glucose monosaccharides; F/G) or table sugar (sucrose, a fructose and glucose disaccharide). OBJECTIVES: We tested the equivalence of sucrose- vs. F/G containing diets on mouse (Mus musculus) longevity, reproductive success, and social dominance. METHODS: We fed wild-derived mice, outbred mice descended from wild-caught ancestors, a diet in which 25% of the calories came from either an equal ratio of F/G or an isocaloric amount of sucrose (both diets had 63% of total calories as carbohydrates). Exposure lasted 40 wk, starting at weaning (21 d of age), and then mice (104 females and 56 males) were released into organismal performances assays-seminatural enclosures where mice competed for territories, resources, and mates for 32 wk. Within enclosures all mice consumed the F/G diet. RESULTS: Females initially fed the F/G diet experienced a mortality rate 1.9 times the rate (P = 0.012) and produced 26.4% fewer offspring than females initially fed sucrose (P = 0.001). This reproductive deficiency was present before mortality differences, suggesting the F/G diet was causing physiologic performance deficits prior to mortality. No differential patterns in survival, reproduction, or social dominance were observed in males, indicating a sex specific outcome of exposure. CONCLUSION: This study provides experimental evidence that the consumption of human-relevant levels of F/G is more deleterious than an isocaloric amount of sucrose for key organism-level health measures in female mice. PMID- 25733458 TI - Apiaceous vegetable consumption decreases PhIP-induced DNA adducts and increases methylated PhIP metabolites in the urine metabolome in rats. AB - BACKGROUND: Heterocyclic aromatic amines, such as 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP), are carcinogenic compounds produced during heating of protein-containing foods. Apiaceous vegetables inhibit PhIP-activating enzymes, whereas cruciferous vegetables induce both PhIP-activating and detoxifying enzymes. OBJECTIVE: We investigated the effects of these vegetables, either alone or combined, on PhIP metabolism and colonic DNA adduct formation in rats. METHODS: Male Wistar rats were fed cruciferous vegetables (21%, wt:wt), apiaceous vegetables (21%, wt:wt), or a combination of both vegetables (10.5% wt:wt of each). Negative and positive control groups were fed an AIN-93G diet. After 6 d, all groups received an intraperitoneal injection of PhIP (10 mg . kg body weight(-1)) except for the negative control group, which received only vehicle. Urine was collected for 24 h after the injection for LC-tandem mass spectrometry metabolomic analyses. On day 7, rats were killed and tissues processed. RESULTS: Compared with the positive control, cruciferous vegetables increased the activity of hepatic PhIP-activating enzymes [39.5% and 45.1% for cytochrome P450 (CYP) 1A1 (P = 0.0006) and CYP1A2 (P < 0.0001), respectively] and of uridine 5'-diphospho-glucuronosyltransferase 1A (PhIP-detoxifying) by 24.5% (P = 0.0267). Apiaceous vegetables did not inhibit PhIP-activating enzymes, yet reduced colonic PhIP-DNA adducts by 20.4% (P = 0.0496). Metabolomic analyses indicated that apiaceous vegetables increased the relative abundance of urinary methylated PhIP metabolites. The sum of these methylated metabolites inversely correlated with colonic PhIP-DNA adducts (r = -0.43, P = 0.01). We detected a novel methylated urinary PhIP metabolite and demonstrated that methylated metabolites are produced in the human liver S9 fraction. CONCLUSIONS: Apiaceous vegetables did not inhibit the activity of PhIP-activating enzymes in rats, suggesting that the reduction in PhIP-DNA adducts may involve other pathways. Further investigation of the importance of PhIP methylation in carcinogen metabolism is warranted, given the inverse correlation of methylated PhIP metabolites with a biomarker of carcinogenesis and the detection of a novel methylated PhIP metabolite. PMID- 25733459 TI - A high-protein breakfast induces greater insulin and glucose-dependent insulinotropic peptide responses to a subsequent lunch meal in individuals with type 2 diabetes. AB - BACKGROUND: The previous meal modulates the postprandial glycemic responses to a subsequent meal; this is termed the second-meal phenomenon. OBJECTIVE: This study examined the effects of high-protein vs. high-carbohydrate breakfast meals on the metabolic and incretin responses after the breakfast and lunch meals. METHODS: Twelve type 2 diabetic men and women [age: 21-55 y; body mass index (BMI): 30-40 kg/m(2)] completed two 7-d breakfast conditions consisting of 500-kcal breakfast meals as protein (35% protein/45% carbohydrate) or carbohydrate (15% protein/65% carbohydrate). On day 7, subjects completed an 8-h testing day. After an overnight fast, the subjects consumed their respective breakfast followed by a standard 500-kcal high-carbohydrate lunch meal 4 h later. Blood samples were taken throughout the day for assessment of 4-h postbreakfast and 4-h postlunch total area under the curve (AUC) for glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP 1). RESULTS: Postbreakfast glucose and GIP AUCs were lower after the protein (17%) vs. after the carbohydrate (23%) condition (P < 0.05), whereas postbreakfast insulin, C-peptide, glucagon, and GLP-1 AUCs were not different between conditions. A protein-rich breakfast may reduce the consequences of hyperglycemia in this population. Postlunch insulin, C-peptide, and GIP AUCs were greater after the protein condition vs. after the carbohydrate condition (second meal phenomenon; all, P < 0.05), but postlunch AUCs were not different between conditions. The overall glucose, glucagon, and GLP-1 responses (e.g., 8 h) were greater after the protein condition vs. after the carbohydrate condition (all, P < 0.05). CONCLUSIONS: In type 2 diabetic individuals, compared with a high carbohydrate breakfast, the consumption of a high-protein breakfast meal attenuates the postprandial glucose response and does not magnify the response to the second meal. Insulin, C-peptide, and GIP concentrations demonstrate the second-meal phenomenon and most likely aid in keeping the glucose concentrations controlled in response to the subsequent meal. The trial was registered at www.clinicaltrials.gov/ct2/show/NCT02180646 as NCT02180646. PMID- 25733460 TI - Sugar-sweetened product consumption alters glucose homeostasis compared with dairy product consumption in men and women at risk of type 2 diabetes mellitus. AB - BACKGROUND: Dietary patterns characterized by high intakes of fruits and vegetables, whole grains, low-fat dairy products, and low glycemic load have been associated with lower type 2 diabetes mellitus (T2DM) risk. In contrast, dietary patterns that include high intakes of refined grains, processed meats, and high amounts of added sugars have been associated with increased T2DM risk. OBJECTIVE: This randomized, 2-period crossover trial compared the effects of dairy and sugar sweetened product (SSP) consumption on insulin sensitivity and pancreatic beta cell function in men and women at risk of the development of T2DM who habitually consume sugar-sweetened beverages. METHODS: In a randomized, controlled crossover trial, participants consumed dairy products (474 mL/d 2% milk and 170 g/d low-fat yogurt) and SSPs (710 mL/d nondiet soda and 108 g/d nondairy pudding), each for 6 wk, with a 2-wk washout between treatments. A liquid meal tolerance test (LMTT) was administered at baseline and the end of each period. RESULTS: Participants were 50% female with a mean age and body mass index of 53.8 y and 32.2 kg/m(2), respectively. Changes from baseline were significantly different between dairy product and SSP conditions for median homeostasis model assessment 2-insulin sensitivity (HOMA2-%S) (1.3 vs. -21.3%, respectively, P = 0.009; baseline = 118%), mean LMTT disposition index (-0.03 vs. -0.36, respectively, P = 0.011; baseline = 2.59), mean HDL cholesterol (0.8 vs. -4.2%, respectively, P = 0.015; baseline = 44.3 mg/dL), and mean serum 25-hydroxyvitamin D [25(OH)D] (11.7 vs. 3.3, respectively, P = 0.022; baseline = 24.5 MUg/L). Changes from baseline in LMTT Matsuda insulin sensitivity index (-0.10 vs. -0.49, respectively; baseline = 4.16) and mean HOMA2-beta-cell function (-2.0 vs. 5.3%, respectively; baseline = 72.6%) did not differ significantly between treatments. CONCLUSION: These results suggest that SSP consumption is associated with less favorable values for HOMA2 %S, LMTT disposition index, HDL cholesterol, and serum 25(OH)D in men and women at risk of T2DM vs. baseline values and values during dairy product consumption. This trial was registered at clinicaltrials.gov as NCT01936935. PMID- 25733461 TI - Metabolic responses of healthy or prediabetic adults to bovine whey protein and sodium caseinate do not differ. AB - BACKGROUND: Casein is considered a slowly digestible protein compared with whey protein, and this may cause differences in hormone responses and the kinetics of delivering amino acids into the circulation. OBJECTIVE: We investigated whether postprandial plasma hormone and metabolite responses were different when bovine casein or whey protein was co-administered with carbohydrates in healthy and prediabetic adults. METHODS: White healthy male adults (n = 15) and white, well defined male and female prediabetic adults (n = 15) received test drinks randomly on 3 different occasions at least 2 d apart which contained 50 g of maltodextrin19 (MD19) alone or in combination with 50 g of whey protein isolate (WPI) or 50 g of sodium caseinate (SC). Blood samples were collected over a 240 min time period and were analyzed for hormone profiles and defined metabolites. RESULTS: No evidence was found that gastric emptying was different between the 2 protein drinks. Both proteins increased peak plasma insulin concentrations in prediabetic persons by 96% compared with MD19 (each, P < 0.05), which was accompanied by a reduction of peak venous blood glucose by 21% (each, P < 0.0001) without a difference between the 2 proteins. Peak plasma glucagon concentrations increased by 101% in both groups after the protein drinks (P < 0.05). The WPI drink also increased peak plasma glucose-dependent insulinotropic polypeptide concentrations in healthy volunteers by 56% (P < 0.01). Differences in plasma metabolite concentrations in volunteers could be attributed exclusively to the differences in the amino acid composition of the 2 proteins ingested. CONCLUSION: The WPI and the SC drinks similarly reduced postprandial glucose excursions when ingested with carbohydrates in healthy and prediabetic volunteers. Under our experimental conditions, however, no evidence was found that gastrointestinal processing of the 2 protein varieties differed substantially. This trial was registered at clinicaltrials.gov as DRKS00005682. PMID- 25733462 TI - Calcium ingestion suppresses appetite and produces acute overcompensation of energy intake independent of protein in healthy adults. AB - BACKGROUND: Prior evidence suggests that high-calcium intake influences postprandial appetite and insulinemia, possibly due to elevated incretins. In vitro and ex vivo models demonstrate that extracellular calcium and protein synergistically enhance secretion of incretins. This is yet to be shown in humans. OBJECTIVE: This study was designed to assess energy intake compensation in response to protein and calcium ingestion. METHODS: Twenty healthy adults (13 men; 7 women) completed 4 trials in a randomized, double-blind crossover design separated by >=48 h. During the trials, each participant consumed a low-calcium and low-protein control preload [(CON); 4 g and 104 mg, respectively], a high protein preload (PRO; 29 g), a high-calcium preload (CAL; 1170 mg), or a high protein and high-calcium preload (PROCAL). Blood samples were collected at baseline and 15, 30, 45, and 60 min after preload ingestion to determine insulin and incretin hormone concentrations. Energy intake was assessed by a homogenous test meal 60 min after the preload. Visual analog scales were completed immediately before blood sampling to assess subjective appetite sensations. RESULTS: Relative to the CON, the PRO produced 100% (95% CI: 85%, 115%) energy compensation, whereas the CAL produced significant overcompensation [118% (95% CI: 104%, 133%)], which was significantly more positive than with the PRO (P < 0.05). The PROCAL resulted in energy compensation of 109% (95% CI: 95%, 123%), which tended to be greater than with the PRO (P = 0.06). The mean difference in appetite sensations relative to the CON was not significantly different between the PRO (-3 mm; 95% CI: -8, 3 mm), CAL (-5 mm; 95% CI: -9, 0 mm), and PROCAL (-5 mm; 95% CI: -10, -1 mm) (P > 0.05). CONCLUSIONS: The addition of protein to a preload results in almost perfect energy compensation, whereas the addition of calcium, with or without protein, suppresses appetite and produces overcompensation of subsequent energy intake. The role of circulating insulin and incretin concentrations in these responses, however, remains unclear. This trial was registered at clinicaltrials.gov as NCT01986036. PMID- 25733463 TI - Quantitative feed restriction rather than caloric restriction modulates the immune response of growing rabbits. AB - BACKGROUND: Short-term feed restriction strategies are used in rabbits to reduce postweaning digestive disorders, but little is known about the involvement of the immune system in these beneficial effects. OBJECTIVE: In the present study, the consequences of feed and energy restriction on immune response were investigated. METHODS: At weaning, 320 male and female rabbits were assigned to 4 groups differing in dietary digestible energy (DE) concentrations and intake levels: a low-energy ad libitum-feed (LE100) group, a low-energy restricted-feed (LE75) group, a high-energy ad libitum-feed (HE100) group, and a high-energy restricted feed (HE75) group. The high-energy groups consumed 10.13 MJ DE/kg of feed, whereas the low-energy groups consumed 9.08 MJ DE/kg (formulated values). Intake amounts for the restricted groups were 75% those of the ad libitum groups. Rabbits consumed these diets until age 63 d, after which they consumed feed ad libitum for 9 d. Ten rabbits per group and per age were killed at ages 42, 50, 63, and 72 d. Spleens and appendixes were weighed; Peyer's patch surface area was determined by image analysis; plasma total immunoglobulin (Ig) G and anti ovalbumin IgG; and fecal and plasma IgA concentrations were determined by ELISA; and ileal expressions of cytokines were measured by quantitative reverse transcriptase-polymerase chain reaction at ages 50 and 63 d. RESULTS: The relative weight and size of the lymphoid organs were not affected by treatments. Concentrations of plasma total IgA (-41% at 63 d and -29% at 72 d), IgG (-22% at 72 d), and anti-ovalbumin IgG (-41% at 63 d) were lower with feed restriction. Fecal IgA concentrations were lower with quantitative restriction (-40%, -52%, and -65% at age 42, 50, and 63 d, respectively) and energy restriction (-56%, 46%, and -73% at ages 50, 63, and 72 d, respectively). Feed-restricted rabbits tended to have greater expressions of interleukin (IL) 1beta and IL-2 and lower expressions of tumor necrosis factor alpha (P < 0.1). CONCLUSION: These results demonstrated that, in rabbits, restriction and, to a lesser extent, dietary energy concentration modulate gut immunity. PMID- 25733464 TI - The green algal carotenoid siphonaxanthin inhibits adipogenesis in 3T3-L1 preadipocytes and the accumulation of lipids in white adipose tissue of KK-Ay mice. AB - BACKGROUND: Siphonaxanthin, a xanthophyll present in green algae, has been shown to possess antiangiogenic and apoptosis-inducing activities. OBJECTIVE: We evaluated the antiobesity effects of siphonaxanthin by using a 3T3-L1 cell culture system and in diabetic KK-Ay mice. METHODS: 3T3-L1 cells were differentiated with or without 5 MUmol/L siphonaxanthin, and lipid accumulation and critical gene expressions for adipogenesis were examined. In vivo, 4-wk-old male KK-Ay mice were administered daily oral treatment of 1.3 mg siphonaxanthin for 6 wk and body weight, visceral fat weight, serum variables, and gene expressions involved in lipid metabolism were evaluated. RESULTS: Compared with the other carotenoids evaluated, siphonaxanthin potently inhibited adipocyte differentiation. Siphonaxanthin significantly suppressed lipid accumulation at noncytotoxic concentrations of 2.5 and 5 MUmol/L by 29% and 43%, respectively. The effects of siphonaxanthin were largely limited to the early stages of adipogenesis. Siphonaxanthin significantly inhibited protein kinase B phosphorylation by 48% and 72% at 90 and 120 min, respectively. The expressions of key adipogenesis genes, including CCAAT/enhancer binding protein alpha (Cebpa), peroxisome proliferator activated receptor gamma (Pparg), fatty acid binding protein 4 (Fabp4), and stearoyl coenzyme A desaturase 1 (Scd1), were elevated by 1.6- to 166-fold during adipogenesis. After 8 d of adipocyte differentiation, siphonaxanthin significantly lowered gene expression of Cebpa, Pparg, Fabp4, and Scd1 by 94%, 83%, 95%, and 90%, respectively. Moreover, oral administration of siphonaxanthin to KK-Ay mice significantly reduced the total weight of white adipose tissue (WAT) by 13%, especially the mesenteric WAT by 28%. Furthermore, siphonaxanthin administration reduced lipogenesis and enhanced fatty acid oxidation in adipose tissue. Siphonaxanthin was observed to highly accumulate in mesenteric WAT, and the accumulation in the mesenteric WAT was almost 2- and 3-fold that in epididymal (P = 0.14) and perirenal (P < 0.05) WAT, respectively. CONCLUSION: These results provide evidence that siphonaxanthin may effectively regulate adipogenesis in 3T3-L1 cells and diabetic KK-Ay mice. PMID- 25733465 TI - Child experience of food insecurity is associated with child diet and physical activity. AB - BACKGROUND: Food insecurity is associated with deficits in child development and health, but little is known about how children's specific food-insecurity experiences play out through nutritional and non-nutritional pathways that may compromise well-being. OBJECTIVE: This study used child self-reports of food insecurity to examine the types of food-insecurity experiences that were most prevalent and the relations between child food insecurity (CFI), child diet, and child physical activity (PA). METHODS: A total of 3605 fourth- and fifth-grade children whose schools participated in the Network for a Healthy California Children's PowerPlay! campaign completed 24-h diary-assisted recalls and surveys including items from the Child Food Security Assessment and questions about PA. Data were analyzed by using regression and logistic regression models. RESULTS: CFI was present in 60% of the children and included experiences of cognitive, emotional, and physical awareness of food insecurity. Greater levels of CFI were associated with higher consumption of energy, fat, sugar, and fiber and a diet lower in vegetables. For instance, a child at the highest level of CFI, on average, consumed ~494 kJ/d (118 kcal), 8 g/d of sugar, and 4 g/d of fat more than a food-secure child. Higher CFI was associated with a marginally significant difference (P = 0.06) in minutes of PA (17 min/d less for children at the highest level of CFI vs. those who were food secure) and with significantly greater perceived barriers to PA. CONCLUSIONS: CFI is a troublingly frequent, multidomain experience that influences children's well-being through both nutritional (dietary) and non-nutritional (e.g., PA) pathways. CFI may lead to poor-quality diet and less PA and their developmental consequences. Practitioners should consider CFI when assessing child health and well-being and can do so by asking children directly about their CFI experiences. PMID- 25733466 TI - Dietary sodium reduction does not affect circulating glucose concentrations in fasting children or adults: findings from a systematic review and meta-analysis. AB - BACKGROUND: Although evidence shows that reduced sodium intake lowers blood pressure, some studies suggest that sodium reduction may adversely affect insulin resistance and glucose tolerance. OBJECTIVES: The objectives were to assess the effects of sodium reduction on glucose tolerance, evaluate strengths and weaknesses of the relevant scientific literature, and provide direction for future research. METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, and Web of Science through August 2014. Both randomized and nonrandomized intervention trials were included in our meta-analyses. The effects of sodium reduction on glucose tolerance were evaluated in 37 articles, but because of a lack of comparable data, 8 trials were excluded from the meta-analyses. RESULTS: Participants were 10-79 y old, either primarily healthy or with hypertension. In meta-analyses of 20 randomized, crossover trials (n = 504 participants) and 9 nonrandomized crossover trials (n = 337), circulating glucose concentrations of fasting participants were not affected by reduction in sodium intake. In contrast, in meta-analyses of 19 of the 20 randomized, crossover trials (n = 494), fasting insulin concentrations were 9.53 pmol/L higher (95% CI: 5.04, 14.02 pmol/L higher) with sodium reduction. In 9 nonrandomized trials (n = 337), fasting insulin did not differ with reduced sodium intake. Results differed little when the analyses were restricted to studies with a low risk of bias and duration of >=7 d. CONCLUSIONS: This meta-analysis revealed no evidence that, in trials with a short intervention and large reductions in sodium, circulating glucose concentrations differed between groups. Recommendations for future studies include extending intervention durations, ensuring comparability of groups at baseline through randomization, and assessing sodium intakes relevant to population sodium reduction. In addition, analyses on other metabolic variables were limited because of the number of trials reporting these outcomes and lack of consistency across measures, suggesting a need for comparable measures of glucose tolerance across studies. PMID- 25733467 TI - Zinc absorption from biofortified maize meets the requirements of young rural Zambian children. AB - BACKGROUND: The zinc content of maize, a major global food staple, is generally insufficient alone to meet the requirements of young children. OBJECTIVES: The primary objective of this study was to determine whether substitution of biofortified maize (34 MUg zinc/g grain) for control maize (21 MUg zinc/g) was adequate to meet zinc physiologic requirements in young children for whom maize was the major food staple. A secondary objective was to compare total daily zinc absorption when maize flour was fortified with zinc oxide to a total concentration of 60 MUg zinc/g. METHODS: Participants included 60 rural Zambian children with a mean age of 29 mo who were randomly assigned to receive 1 of 3 maize types (control, biofortified, or fortified) all of which were readily consumed (>100 g on 1 d). Total daily zinc intake (from maize and low-zinc relish) was determined from duplicate diet collections. Multiplication by fractional absorption of zinc, measured by a dual isotope ratio technique, determined the total daily zinc absorption on the day the test meals were given. RESULTS: The mean +/- SD total daily zinc intake (milligrams per day) from the biofortified maize (5.0 +/- 2.2) was higher (P < 0.0001) than for the control maize (2.3 +/- 0.9). Intake of zinc from the fortified maize (6.3 +/- 2.6) did not differ from the biofortified maize. Fractional absorption of zinc from control maize (0.28 +/- 0.10) did not differ from the biofortified maize (0.22 +/ 0.06). Total daily absorption of zinc (milligrams per day) from the biofortified maize (1.1 +/- 0.5) was higher (P = 0.0001) than for the control maize (0.6 +/- 0.2), but did not differ from the fortified maize (1.2 +/- 0.4). CONCLUSIONS: These results indicate that feeding biofortified maize can meet zinc requirements and provide an effective dietary alternative to regular maize for this vulnerable population. This trial was registered at clinicaltrials.gov as NCT02208635. PMID- 25733468 TI - Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. AB - BACKGROUND: Serum total folate consists mainly of 5-methyltetrahydrofolate (5 methylTHF). Unmetabolized folic acid (UMFA) may occur in persons consuming folic acid-fortified foods or supplements. OBJECTIVES: We describe serum 5-methylTHF and UMFA concentrations in the US population >=1 y of age by demographic variables and fasting time, stratified by folic acid-containing dietary supplement use. We also evaluate factors associated with UMFA concentrations >1 nmol/L. METHODS: Serum samples from the cross-sectional NHANES 2007-2008 were measured for 5-methylTHF (n = 2734) and UMFA (n = 2707) by HPLC-tandem mass spectrometry. RESULTS: In supplement users compared with nonusers, we found significantly higher geometric mean concentrations of 5-methylTHF (48.4 and 30.7 nmol/L, respectively) and UMFA (1.54 and 0.794 nmol/L, respectively). UMFA concentrations were detectable (>0.3 nmol/L) in >95% of supplement users and nonusers, regardless of demographic or fasting characteristics; concentrations differed significantly by age and fasting time, but not by sex and race ethnicity, both in supplement users and nonusers. The prevalence of UMFA concentrations >1 nmol/L was 33.2% overall and 21.0% in fasting (>=8 h) adults (>=20 y of age). Using multiple logistic regression analysis, UMFA concentrations >1 nmol/L were associated with being older, non-Hispanic black, nonfasting (<8 h), having smaller body surface area, higher total folic acid intake (diet and supplements), and higher red blood cell folate concentrations. In fasting adults, a decrease in the mean daily alcohol consumption was also associated with increased odds of UMFA concentrations >1 nmol/L. CONCLUSIONS: UMFA detection was nearly ubiquitous, and concentrations >1 nmol/L were largely but not entirely explained by fasting status and by total folic acid intake from diet and supplements. These new UMFA data in US persons >=1 y of age provide much-needed information on this vitamer in a fortified population with relatively high use of dietary supplements. PMID- 25733469 TI - A healthy diet is associated with less endothelial dysfunction and less low-grade inflammation over a 7-year period in adults at risk of cardiovascular disease. AB - BACKGROUND: A healthy diet rich in fish, fruit, and vegetables, but moderate in alcohol and low in dairy products and meat, has been associated with a lower rate of incident cardiovascular disease (CVD). The underlying mechanisms, however, remain unclear. Endothelial dysfunction and low-grade inflammation play important roles in CVD. A healthy diet might modify these phenomena. OBJECTIVE: We investigated the associations between the above food groups and overall biomarker scores of endothelial dysfunction and low-grade inflammation in a 7-y longitudinal study. METHODS: Using longitudinal data from 557 participants at increased CVD risk from the CODAM (Cohort on Diabetes and Atherosclerosis Maastricht) Study, we assessed diet intake by food-frequency questionnaire and measured plasma biomarkers of endothelial dysfunction [von Willebrand factor, soluble vascular cell adhesion molecule 1, soluble endothelial selectin, soluble thrombomodulin, soluble intercellular adhesion molecule 1 (sICAM-1)] and low grade inflammation [C-reactive protein, serum amyloid A, interleukin (IL)-6, IL 8, tumor necrosis factor alpha, and sICAM-1]. At baseline, participants were aged 59.6 +/- 6.9 y. Measurements were performed then and after 7 y. Biomarkers were combined into overall scores (sum of z scores; higher scores indicating worse function). Longitudinal data were analyzed with generalized estimating equations and adjusted for sex, age, glucose metabolism, energy intake, body mass index, physical activity, alcohol consumption, and smoking. RESULTS: Higher consumption of fish (per 100 g/wk), but not total consumption of vegetables, fruit, alcohol containing beverages, dairy products, or meat, was associated with a lower overall endothelial dysfunction score over 7 y (beta: -0.027; 95% CI: -0.051, 0.004). No associations were observed with the overall low-grade inflammation score. Further food component analyses indicated that consumption of more lean fish (per 100 g/wk) and raw vegetables (per 100 g/d), and fewer high-fat dairy products (per 100 g/d) was associated with less endothelial dysfunction [(beta: 0.038; 95% CI: -0.072, -0.005), (beta: -0.095; 95% CI: -0.191, 0.000), and (beta: -0.070; 95% CI: -0.131, -0.009), respectively]. Consumption of more fresh fruit (per 100 g/d), wine (per 100 mL/wk), and poultry (per 100 g/d), and fewer high fat dairy products (per 100 g/d) was associated with less low-grade inflammation [(beta: -0.074; 95% CI: -0.133, -0.015), (beta:-0.006; 95% CI: -0.013, 0.001), (beta:-0.247; 95% CI: -0.479, -0.014), and (beta:-0.100; 95% CI: -0.182, -0.019), respectively]. CONCLUSION: These data suggest that the dietary modification of endothelial dysfunction and low-grade inflammation, processes that are important in atherothrombosis, is possible. PMID- 25733470 TI - Low serum 25-hydroxyvitamin D concentrations are associated with increased likelihood of having depressive symptoms among Japanese workers. AB - BACKGROUND: Accumulating evidence suggests a protective role of vitamin D against mood disorders; however, epidemiologic studies are scarce in working populations. OBJECTIVE: We investigated cross-sectionally the association of serum vitamin D status and depressive symptoms among Japanese workers. METHODS: Participants were 1786 employees (9% women), aged 19-69 y, who received health check-ups and participated in a nutrition and health survey. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured with the use of a competitive protein binding assay. Depressive symptoms were assessed by using the Center for Epidemiologic Studies Depression (CES-D) scale. Logistic regression was used to estimate ORs with adjustment for potential confounding variables including dietary factors. RESULTS: Overall, 92% of study participants had suboptimal vitamin D status [25(OH)D <30 MUg/L]. Depressive symptoms were inversely associated with 25(OH)D. Compared with those with a 25(OH)D concentration of <20 MUg/L, multivariable-adjusted ORs (95% CIs) for depressive symptoms (CES-D scale score >=16) were 0.75 (0.59, 0.95) and 0.66 (0.41, 1.06) for those with a 25(OH)D concentration of 20-29 MUg/L and >=30 MUg/L, respectively (P-trend = 0.01). After further adjustment for leisure-time physical activity and shift work (factors closely related to photo-initiated vitamin D production), the OR (95% CI) for the highest category of 25(OH)D was 0.70 (0.43, 1.14). The association between 25(OH)D and depressive symptoms appears to be linear, according to restricted cubic spline regression. CONCLUSION: Results suggest that lower concentrations of circulating vitamin D are associated with increased likelihood of having depressive symptoms among apparently healthy workers. PMID- 25733471 TI - Higher diet quality is inversely associated with mortality in African-American women. AB - BACKGROUND: Diet quality has been inversely associated with overall mortality in white populations, but the evidence in African-American populations is limited. OBJECTIVE: The goal of the present study was to assess diet quality in relation to all-cause mortality in the Black Women's Health Study, a follow-up study of African-American women begun in 1995. METHODS: Data used in this study were obtained via biennial questionnaires from 1995 to 2011. Based on food-frequency questionnaire data collected in 1995 and 2001, we calculated an index-based diet quality score [Dietary Approaches to Stop Hypertension (DASH)] and derived dietary patterns (prudent and Western) with the use of factor analysis. We followed 37,001 women who were aged 30-69 y and free of cancer, cardiovascular disease, and diabetes at baseline for mortality through 2011. Multivariable Cox regression was used to estimate HRs and 95% CIs. Analyses were conducted in 2014. RESULTS: Based on a total of 1678 deaths during 16 y of follow-up, higher DASH scores were associated with reduced all-cause mortality (HR: 0.75; 95% CI: 0.63, 0.89 for highest vs. lowest quintiles). The DASH components most strongly associated with lower mortality were high intake of whole grains and low intake of red and processed meat. A Western dietary pattern, characterized by high intake of red and processed meat, was associated with increased all-cause mortality rates (HR: 1.37; 95% CI: 1.17, 1.60 for highest vs. lowest quintiles of score); a prudent dietary pattern was not associated with risk. CONCLUSION: A DASH-style diet high in intake of whole grains and low in consumption of red meat is associated with reduced mortality rates in healthy African-American women. PMID- 25733472 TI - Dietary variety is inversely associated with body adiposity among US adults using a novel food diversity index. AB - BACKGROUND: Consuming a variety (vs. monotony) of energy-poor, nutrient-dense foods may help individuals adhere to dietary patterns favorably associated with weight control. OBJECTIVE: The objective of this study was to examine whether greater healthful food variety quantified using the US Healthy Food Diversity (HFD) index favorably influenced body adiposity. METHODS: Men and nonpregnant, nonlactating women aged >=20 y with two 24-h recalls from the cross-sectional NHANES 2003-2006 (n = 7470) were included in this study. Dietary recalls were merged with the MyPyramid Equivalent database to generate the US HFD index, which ranges from 0 to ~1, with higher scores indicative of diets with a higher number and proportion of healthful foods. Multiple indicators of adiposity including BMI, waist-to-height ratio, android-to-gynoid fat ratio, fat mass index (FMI), and percentage body fat were assessed across US HFD index quintiles. ORs and 95% CIs were computed with use of multivariable logistic regression (SAS v. 9.3). RESULTS: The US HFD index was inversely associated with most adiposity indicators in both sexes. After multivariable adjustment, the odds of obesity, android-to gynoid ratio >1, and high FMI were 31-55% lower (P-trend < 0.01) among women in quintile 5 vs. quintile 1 of the US HFD index. Among men, the odds of obesity, waist-to-height ratio >=0.5, and android-to-gynoid ratio >1 were 40-48% lower (P trend <= 0.01) in quintile 5 vs. quintile 1 of the US HFD index. CONCLUSIONS: Higher US HFD index values were inversely associated with indicators of body adiposity in both sexes, indicating that greater healthful food variety may protect against excess adiposity. This study explicitly recognizes the potential benefits of dietary variety in obesity management and provides the foundation to support its ongoing evaluation. PMID- 25733473 TI - Greater healthful food variety as measured by the US Healthy Food Diversity index is associated with lower odds of metabolic syndrome and its components in US adults. AB - BACKGROUND: Consuming a wider variety of nutrient-dense foods may promote adherence to healthful dietary patterns, leading to improved dietary quality and enhanced metabolic health. OBJECTIVE: We used the US Healthy Food Diversity (HFD) index to simultaneously measure dietary variety, quality, and proportionality, hypothesizing a priori that race/ethnicity may moderate associations between diet and health. METHODS: A representative sample of adults (n = 7470) aged 20+ y with two 24-h recalls and complete outcome data from the cross-sectional NHANES 2003 2006 were selected. US HFD values were generated using a previously validated equation with a theoretical range from 0 to nearly 1, with higher scores indicative of more varied diets with a higher proportion of healthful food groups. Metabolic syndrome (MetS) was defined using the most recent harmonized definition. Survey-weighted multivariable linear and logistic regression, adjusted for demographic factors, smoking, energy, screen time, and leisure activity, were used to compute means and ORs (95% CIs). RESULTS: Adults in the third vs. first US HFD tertile had 21% lower odds of MetS [OR (95% CI): 0.79 (0.64, 0.98)] as well as lower odds of hypertension [0.83 (0.70, 0.995] and elevated waist circumference [0.75 (0.66, 0.86] after multivariable adjustment (P trend < 0.05). The age- and sex-adjusted odds of low serum HDL cholesterol and impaired fasting plasma glucose (P-trend < 0.05) were lower in the highest vs. lowest US HFD tertile but attenuated with multivariable adjustment (P = 0.06 and 0.22, respectively). Notably, the US HFD index was only protective against adiposity among non-Hispanic white (NHW) and non-Hispanic black (NHB) adults, and MetS associations were driven by NHW adults. No associations were observed among Hispanic adults for any MetS components. CONCLUSIONS: Greater healthful food variety was associated with lower odds of MetS and some MetS components in the total population, NHW adults, and NHB adults. This study provides preliminary evidence that healthful food diversity may protect against MetS and highlights the need for longitudinal and experimental research. PMID- 25733474 TI - Multivitamin-mineral use is associated with reduced risk of cardiovascular disease mortality among women in the United States. AB - BACKGROUND: Multivitamin-mineral (MVM) products are the most commonly used supplements in the United States, followed by multivitamin (MV) products. Two randomized clinical trials (RCTs) did not show an effect of MVMs or MVs on cardiovascular disease (CVD) mortality; however, no clinical trial data are available for women with MVM supplement use and CVD mortality. OBJECTIVE: The objective of this research was to examine the association between MVM and MV use and CVD-specific mortality among US adults without CVD. METHODS: A nationally representative sample of adults from the restricted data NHANES III (1988-1994; n = 8678; age >=40 y) were matched with mortality data reported by the National Death Index through 2011 to examine associations between MVM and MV use and CVD mortality by using Cox proportional hazards models, adjusting for multiple potential confounders. RESULTS: We observed no significant association between CVD mortality and users of MVMs or MVs compared with nonusers; however, when users were classified by the reported length of time products were used, a significant association was found with MVM use of >3 y compared with nonusers (HR: 0.65; 95% CI: 0.49, 0.85). This finding was largely driven by the significant association among women (HR: 0.56; 95% CI: 0.37, 0.85) but not men (HR: 0.79; 95% CI: 0.44, 1.42). No significant association was observed for MV products and CVD mortality in fully adjusted models. CONCLUSIONS: In this nationally representative data set with detailed information on supplement use and CVD mortality data ~20 y later, we found an association between MVM use of >3 y and reduced CVD mortality risk for women when models controlled for age, race, education, body mass index, alcohol, aspirin use, serum lipids, blood pressure, and blood glucose/glycated hemoglobin. Our results are consistent with the 1 available RCT in men, indicating no relation with MVM use and CVD mortality. PMID- 25733475 TI - Plasma nutrient biomarkers are associated with waist-to-height ratio in youth with type 1 diabetes. AB - BACKGROUND: Plasma fatty acids (FAs) and micronutrients have been associated with central obesity in adults; however, previous studies of these associations in adults have yielded mixed results. In addition, no comparable research has been conducted among youth with type 1 diabetes (T1D). OBJECTIVE: We investigated the cross-sectional and longitudinal associations between plasma nutrient biomarkers and waist-to-height ratio (WHtR) in youth with T1D. METHODS: These analyses included 1324 youth aged 3-20 y at T1D diagnosis with a baseline visit in the SEARCH (Search for Diabetes in Youth) Study and a subset of 1178 of these youth with a follow-up visit an average of 23 mo (range: 16-40 mo) after their baseline visit. Plasma phospholipid FAs and vitamins were measured, and estimated desaturase activities were calculated at baseline. Anthropometric measurements and diabetes-related assessments were collected at each visit. Multiple linear regression was used to examine the association between plasma nutrient biomarkers and WHtR. RESULTS: In cross-sectional analysis, plasma palmitic acid (P = 0.004), dihomo-gamma-linolenic acid (DGLA; P = 0.017) and Delta6 desaturase (D6D; P = 0.006) were positively correlated with WHtR after adjustment of confounders. Oleic acid (OA; P = 0.002), linoleic acid (LA; P = 0.015), Delta9 desaturase 18 (D9D-18; P = 0.027), and vitamin D (P < 0.0001) were negatively correlated with WHtR after adjustment. Weight status was an effect modifier (P < 0.05). In normal weight youth, vitamin D (P = 0.003) was negatively associated with WHtR. In obese youth, stearic acid (P = 0.037), DGLA (P < 0.0001), and D6D (P < 0.0001) were positively associated and OA (P = 0.0008), D9D-18 (P = 0.0006), and vitamin D (P < 0.0001) were negatively associated with WHtR. In longitudinal analysis, baseline linoleic acid (P = 0.018), n-6:n-3 (omega-3:omega-6) FA ratio (P = 0.029), vitamin D (P = 0.003), and vitamin E (P < 0.0001) were negatively correlated with WHtR at follow-up only in obese participants. CONCLUSIONS: In T1D youth, plasma FAs and vitamins are associated with WHtR and are modified by weight status. These associations are particularly marked in obese youth. PMID- 25733476 TI - Sociodemographic, psychological, and lifestyle characteristics are associated with a liking for salty and sweet tastes in French adults. AB - BACKGROUND: Various studies have shown that sensory liking influences dietary behavior and that individual characteristics are related to food intake and weight status, but little is known about individual profiles associated with salt and sweet liking. OBJECTIVE: The aim of the present study was to investigate the association between a liking for salty and sweet tastes (i.e., a liking for foods rich in salt or sugar and preferred amounts of salt or sugar seasoning in foods) and sociodemographic, psychological, and lifestyle characteristics in a large sample. METHODS: Individual factors and liking scores were collected by validated questionnaires from 37,181 French adults participating in the NutriNet-Sante study, a large web-based observational cohort launched in 2009 that studies relations between nutrition and health. The associations were assessed by multivariable multinomial logistic regression models adjusted for socioeconomic, anthropometric, and health variables. RESULTS: In both genders, with increasing age, individuals were more likely to have a high salt liking (men, OR: 1.24; 95% CI: 1.18, 1.30; women, OR: 1.14, 95% CI: 1.09, 1.19), whereas they were less likely to have a strong sweet liking (men, OR: 0.87; 95% CI: 0.83, 0.91; women, OR: 0.66; 95% CI: 0.64, 0.68). Current smokers (men, OR: 2.30; 95% CI: 1.90, 2.78; women, OR: 1.50; 95% CI: 1.36, 1.66) and heavy drinkers (men, OR: 2.92; 95% CI: 2.37, 3.58; women, OR: 2.57, 95% CI: 2.22, 2.98) were more likely to like salt than nonsmokers and alcohol abstainers. Regarding the sweet taste, women smokers were less likely to like sweets (OR: 0.80; 95% CI: 0.72, 0.89). Highly uncontrolled eaters [men, OR: 2.39; 95% CI: 2.04, 2.80; women, OR: 2.22; 95% CI: 1.99, 2.47) and highly emotional women (OR: 1.35; 95% CI: 1.18, 1.55) were more likely to have a high liking for sweets than slightly uncontrolled eaters and nonemotional eaters, whereas those with high cognitive restraint (men, OR: 0.39; 95% CI: 0.33, 0.46; women, OR: 0.55; 95% CI: 0.50, 0.60) and former weight-loss dieters (men, OR: 0.60; 95% CI: 0.52, 0.70; women, OR: 0.68; 95% CI: 0.62, 0.73) were less likely to have a strong sweet liking compared with those with low cognitive restraint and never-dieters. CONCLUSION: An unhealthy lifestyle that includes smoking and alcohol consumption may influence salt liking, and eating behavior may have an impact on sweet liking. Further research is needed to study the influence of individual factors and sensory liking on dietary intake and weight status. This study was registered at the European Clinical Trials Database as 2013-000929-31. PMID- 25733477 TI - Beverage habits and mortality in Chinese adults. AB - BACKGROUND: There is limited research examining beverage habits, one of the most habitual dietary behaviors, with mortality risk. OBJECTIVE: This study examined the association between coffee, black and green tea, sugar-sweetened beverages (soft drinks and juice), and alcohol and all-cause and cause-specific mortality. METHODS: A prospective data analysis was conducted with the use of the Singapore Chinese Health Study, including 52,584 Chinese men and women (aged 45-74 y) free of diabetes, cardiovascular disease (CVD), and cancer at baseline (1993-1998) and followed through 2011 with 10,029 deaths. Beverages were examined with all-cause and cause-specific (cancer, CVD, and respiratory disease) mortality risk with the use of Cox proportional hazards regression. RESULTS: The associations between coffee, black tea, and alcohol intake and all-cause mortality were modified by smoking status. Among never-smokers there was an inverse dose-response association between higher amounts of coffee and black tea intake and all-cause, respiratory-related, and CVD mortality (black tea only). The fully adjusted HRs for all-cause mortality for coffee for <1/d, 1/d, and >=2/d relative to no coffee intake were 0.89, 0.86, and 0.83, respectively (P-trend = 0.0003). For the same black tea categories the HRs were 0.95, 0.90, and 0.72, respectively (P-trend = 0.0005). Among ever-smokers there was no association between coffee or black tea and the outcomes. Relative to no alcohol, light to moderate intake was inversely associated with all-cause mortality (HR: 0.87; 95% CI: 0.79, 0.96) in never smokers with a similar magnitude of association in ever-smokers. There was no association between heavy alcohol intake and all-cause mortality in never-smokers and a strong positive association in ever-smokers (HR: 1.56; 95% CI: 1.40, 1.74). Green tea and sugar-sweetened beverages were not associated with all-cause or cause-specific mortality. CONCLUSIONS: Higher coffee and black tea intake was inversely associated with mortality in never-smokers, light to moderate alcohol intake was inversely associated with mortality regardless of smoking status, heavy alcohol intake was positively associated with mortality in ever-smokers, and there was no association between sugar-sweetened beverages and green tea and mortality. PMID- 25733478 TI - Higher-protein diets are associated with higher HDL cholesterol and lower BMI and waist circumference in US adults. AB - BACKGROUND: Protein intake above the RDA attenuates cardiometabolic risk in overweight and obese adults during weight loss. However, the cardiometabolic consequences of consuming higher-protein diets in free-living adults have not been determined. OBJECTIVE: This study examined usual protein intake [g/kg body weight (BW)] patterns stratified by weight status and their associations with cardiometabolic risk using data from the NHANES, 2001-2010 (n = 23,876 adults >=19 y of age). METHODS: Linear and decile trends for association of usual protein intake with cardiometabolic risk factors including blood pressure, glucose, insulin, cholesterol, and triglycerides were determined with use of models that controlled for age, sex, ethnicity, physical activity, poverty-income ratio, energy intake (kcal/d), carbohydrate (g/kg BW) and total fat (g/kg BW) intake, body mass index (BMI), and waist circumference. RESULTS: Usual protein intake varied across deciles from 0.69 +/- 0.004 to 1.51 +/- 0.009 g/kg BW (means +/- SEs). Usual protein intake was inversely associated with BMI (-0.47 kg/m(2) per decile and -4.54 kg/m(2) per g/kg BW) and waist circumference (-0.53 cm per decile and -2.45 cm per g/kg BW), whereas a positive association was observed between protein intake and HDL cholesterol (0.01 mmol/L per decile and 0.14 mmol/L per g/kg BW, P < 0.00125). CONCLUSIONS: Americans of all body weights typically consume protein in excess of the RDA. Higher-protein diets are associated with lower BMI and waist circumference and higher HDL cholesterol compared to protein intakes at RDA levels. Our data suggest that Americans who consume dietary protein between 1.0 and 1.5 g/kg BW potentially have a lower risk of developing cardiometabolic disease. PMID- 25733479 TI - Food insecurity is associated with poor sleep outcomes among US adults. AB - BACKGROUND: Although food insecure (FI) adults are at risk of chronic conditions, little research attention is given to their health behaviors, such as sleep. OBJECTIVE: We examined the associations between adult food security status and sleep duration, sleep latency, and sleep complaints reported to a health care professional. METHODS: Our population-based sample included 5637 men and 5264 women (>=22 y) who participated in the NHANES 2005-2010. Food security status was assessed with USDA's 10-item adult Food Security Survey Module. Self-reported information about sleep duration, sleep latency, and sleep complaints to a health care professional were used as sleep outcomes. Multiple linear, stratified by sex, and logistic regression models were used to estimate the association between food security status and the 3 sleep outcomes. RESULTS: Very low food secure (FS) women reported significantly shorter sleep duration than fully FS women (difference: -30 +/- 5.2 min; P < 0.01); however, no relation to sleep duration was observed among men. Among men, participants who were marginally FS (4 +/- 1.1 min), low FS (4 +/- 1.7 min), and very low FS (5 +/- 1.8 min) reported significantly longer sleep latency than fully FS men (P < 0.05), but no association with sleep latency was observed among women. The divergent patterns in sleep duration and latency were likely because of our reference groups reporting undesirable sleep outcomes; fully FS men reported inadequate sleep and fully FS women reported long sleep latency. Among both men and women, marginally FS (OR: 1.64; 95% CI: 1.24, 2.16), low FS (OR: 1.63; 95% CI: 1.16, 2.30), and very low FS (OR: 1.99; 95% CI: 1.36, 2.92) participants were more likely to report sleep complaints than their fully FS counterparts (P < 0.05). CONCLUSIONS: Poor sleep quantity and quality may predispose FI adults to adverse health outcomes. PMID- 25733480 TI - Household food insecurity is positively associated with depression among low income supplemental nutrition assistance program participants and income-eligible nonparticipants. AB - BACKGROUND: Food insecurity is associated with adverse mental health outcomes. Given that federal food assistance programs, such as the Supplemental Nutrition Assistance Program (SNAP), aim to alleviate food insecurity, there may be heterogeneity in the association between food insecurity and depression by SNAP participation status. OBJECTIVE: With the use of data from the 2005-2010 NHANES, we examined the associations between household food security and depression and whether these differed by SNAP participation. METHODS: The study population was restricted to 3518 adults with household incomes <=130% of the federal poverty level. Food insecurity was assessed with the 18-item US Household Food Security Survey Module; a score of >=3 was considered food insecure. Depression was assessed with the 9-item Patient Health Questionnaire and was defined as a score of >=10. Multivariate logistic regression models examined the associations between food insecurity and depression, adjusting for sociodemographic and health characteristics. RESULTS: The overall prevalence of depression was 9.3%, ranging from 6.7% among SNAP nonparticipants to 12.8% among SNAP participants. For every depressive symptom, there was a dose-response relation, such that a higher prevalence was observed with worsening food insecurity. After multivariate adjustment, food insecurity was positively associated with depression (P-trend < 0.0001), but SNAP participation modified this relation (P-interaction = 0.03). Among low-income, eligible nonparticipants, very low food security was significantly associated with higher odds of depression (OR: 5.10; 95% CI: 3.09, 8.41). Among SNAP participants, very low food security was also associated with higher odds of depression but at a lower magnitude (OR: 2.21; 95% CI: 1.54, 3.17). CONCLUSION: The complex relation between food insecurity and mental health may vary on the basis of SNAP participation status. Programmatic efforts to address the risk of depression among their beneficiaries may positively affect the mental health of low-income adults. PMID- 25733481 TI - Poor thiamin and riboflavin status is common among women of childbearing age in rural and urban Cambodia. AB - BACKGROUND: Thiamin deficiency in infancy is the underlying cause of beriberi, which can be fatal without rapid treatment. Reports of thiamin deficiency are common in Cambodia; however, population representative data are unavailable. Because B-complex vitamin deficiencies commonly occur in combination, riboflavin was also investigated. OBJECTIVE: We determined the biomarker status of thiamin and riboflavin in women of childbearing age in rural and urban Cambodia. METHODS: We measured thiamin (erythrocyte thiamin diphosphate; TDP) and riboflavin (erythrocyte glutathione reductase activity coefficient; EGRac) status in a representative sample of Cambodian women (aged 20-45 y) in urban Phnom Penh (n = 146) and rural Prey Veng (n = 156), Cambodia, and, for comparison purposes, in a convenience sample of women in urban Vancouver, British Columbia, Canada (n = 49). RESULTS: Thiamin insufficiency (TDP <= 90 nmol/L) was common among both urban (39%) and rural (59%) Cambodian women (P < 0.001), whereas <20% of Vancouver women were thiamin insufficient (P < 0.001). The prevalence of suboptimal and deficient riboflavin status (EGRac >= 1.3) was 89%, 92%, and 70% among women in Phnom Penh, Prey Veng, and Vancouver, respectively (P < 0.001). CONCLUSIONS: Suboptimal status of both thiamin and riboflavin were common in Cambodian women, with substantially higher rates among women living in rural Prey Veng than in urban Phnom Penh. Strategies may be needed to improve the thiamin and riboflavin status of women in Cambodia. The unexpected finding of high riboflavin inadequacy status in Vancouver women warrants further investigation. PMID- 25733482 TI - Seasonality modifies the effect of a lipid-based nutrient supplement for pregnant rural women on birth length. AB - BACKGROUND: Maternal nutritional status is a major determinant of low birth weight and fluctuates across seasons. Seasonality may influence the outcome of prenatal nutrition interventions that aim to enhance fetal growth. OBJECTIVE: This study investigated seasonal modifications of the efficacy of a randomized controlled prenatal nutrition intervention trial in pregnant women to improve fetal growth in rural Burkina Faso. METHODS: The second Micronutriments et Sante de la Mere et de l'Enfant study compared a lipid-based nutrient supplement (LNS) fortified with multiple micronutrients (MMNs) to an MMN supplement. Truncated Fourier series were used to characterize seasonality in birth outcomes. Models that included the Fourier series and newborn and maternal characteristics were used to assess seasonal effect modifications of prenatal supplementation on birth outcomes. RESULTS: Birth weight, birth length, small for gestational age as a proxy for intrauterine growth retardation, and preterm birth were significantly related to date of birth and showed important seasonal variations. LNSs, which supply energy in addition to MMNs, resulted in a significant increase in birth length (+13.5 mm, 95% CI: 6.5, 20.5 mm) at the transition from rain to dry season (September to November) compared to MMNs alone. CONCLUSIONS: The climatologic and agricultural seasonal patterns in Burkina Faso affect the efficacy of prenatal LNSs on birth length. In this context, prenatal MMN supplementation programs should be complemented by energy supplementation during the annual rain season to promote fetal growth. This trial was registered at clinicaltrials.gov as NCT00909974. PMID- 25733483 TI - Supplementing pregnant mice with a specific mixture of nondigestible oligosaccharides reduces symptoms of allergic asthma in male offspring. AB - BACKGROUND: Previously, maternal supplementation with short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS; ratio 9:1) was shown to affect maternal and fetal immune status in mice. OBJECTIVE: This study was designed to test the long-term effects of supplementation of mice with scGOS/lcFOS before and during pregnancy on the immune response in the offspring, using an ovalbumin (OVA)-induced model for experimental allergic asthma. METHODS: Female Balb/c mice were fed a control diet or a diet supplemented with 3% scGOS/lcFOS and mated to C57BL/6 males. All dams were fed the control diet after delivery. At 6 wk, male offspring received an intraperitoneal injection of aluminum hydroxide and OVA (control and scGOS/lcFOS group) or saline (sham group). The acute allergic skin response (ASR) after intradermal challenge with OVA or saline was measured at 8 wk. After 3 airway challenges with nebulized OVA or saline, lung function was measured. RESULTS: The scGOS/lcFOS group had a significantly lower acute ASR (85 +/- 9 MUm) than the control group (124 +/- 9 MUm; P = 0.01). Lower lung resistance from a response to methacholine challenge was seen in the scGOS/lcFOS group. OVA-specific immunoglobulin (Ig)E concentrations in the control group [93 +/- 45 arbitrary unit (AU)] and the scGOS/lcFOS group (67 +/- 45 AU) were higher than in the sham group (11 +/- 2 AU). OVA specific IgG2a concentrations in the scGOS/lcFOS (146 +/- 24 AU) were higher than in the sham group (2 +/- 0.3 AU) and control group (18 +/- 3.5 AU; P < 0.05). Finally, the scGOS/lcFOS group had a higher percentage of regulatory T cells (1.11% +/- 0.07%) than the sham group (0.14% +/- 0.03%) and the control group (0.11% +/- 0.02%; P < 0.05). CONCLUSION: Maternal supplementation of mice with scGOS/lcFOS during pregnancy leads to a significant decrease in allergic symptoms in the offspring. PMID- 25733485 TI - Cryopreservation prevents iron-initiated highly unsaturated fatty acid loss during storage of human blood on chromatography paper at -20 degrees C. AB - BACKGROUND: Fingertip prick whole blood collection on chromatography paper is amenable to high-throughput fatty acid (FA) profiling for large clinical and field studies. However, sample storage is problematic because highly unsaturated FAs (HUFAs) in erythrocytes rapidly degrade in samples stored at -20 degrees C. OBJECTIVE: The aim of the current study was to determine the mechanism of HUFA degradation and to develop prevention protocols. METHODS: Free fatty acid (FFA) standards and whole blood reference material from a single participant were used to examine sample storage at -20 degrees C for up to 90 d in triplicate. Iron chelation with deferoxamine (0-5000 MUg), antioxidant protection with butylated hydroxytoluene (50 MUg), cryopreservation with glycerol, and blood drying were examined using whole blood on chromatography strips. Biological replicate blood samples from additional participants (n = 6) with a range of omega-3 (n-3) HUFA concentrations were similarly assessed. RESULTS: FFAs were relatively stable when stored on chromatography strips at -20 degrees C. Glycerol treatment prevented HUFA degradation in whole blood reference material for 30 d (45 +/- 0.4 to 46.8 +/- 0.1, means +/- SDs) compared to untreated saline controls (45.9 +/- 1.0 to 6.8 +/- 0.2). Pretreatment of paper for blood spots with deferoxamine and drying blood before storage slowed, but not entirely prevented, HUFA degradation over 30 d to 22% and 19% below baseline, respectively, compared to 86-92% in the controls. Protection against HUFA degradation with blood drying and glycerol treatment was confirmed in the biological replicate study and confirmed by prevention of cell lysis. CONCLUSIONS: HUFA degradation during storage at -20 degrees C appears to be due to hemolysis and subsequent iron-initiated peroxidation. This degradation may be prevented by glycerol, iron chelation, and/or dried blood spotting. A more thorough understanding of methods to prevent degradation during storage is critical with increasing use of FA profiling in large clinical studies. PMID- 25733484 TI - Fetal iron deficiency and genotype influence emotionality in infant rhesus monkeys. AB - BACKGROUND: Anemia during the third trimester of fetal development affects one third of the pregnancies in the United States and has been associated with postnatal behavioral outcomes. This study examines how fetal iron deficiency (ID) interacts with the fetal monoamine oxidase A (MAOA) genotype. MAOA metabolizes monoamine neurotransmitters. MAOA polymorphisms in humans affect temperament and modify the influence of early adverse environments on later behavior. OBJECTIVE: The aim of the study was to advance translation of developmental ID research in animal models by taking into account genetic factors that influence outcomes in human populations. METHODS: Male infant rhesus monkeys 3-4 mo old born to mothers fed an ID (10 ppm iron) diet were compared with controls (100 ppm iron). Infant monkeys with high- or low-transcription rate MAOA polymorphisms were equally distributed between diet groups. Behavioral responses to a series of structured experiences were recorded during a 25-h separation of the infants from their mothers. RESULTS: Infant monkeys with low-transcription MAOA polymorphisms more clearly demonstrated the following ID effects suggested in earlier studies: a 4% smaller head circumference, a 39% lower cortisol response to social separation, a 129% longer engagement with novel visual stimuli, and 33% lesser withdrawal in response to a human intruder. The high MAOA genotype ID monkeys demonstrated other ID effects: less withdrawal and emotionality after social separation and lower "fearful" ratings. CONCLUSION: MAOA * ID interactions support the role of monoamine neurotransmitters in prenatal ID effects in rhesus monkeys and the potential involvement of common human polymorphisms in determining the pattern of neurobehavioral effects produced by inadequate prenatal nutrition. PMID- 25733487 TI - An homolog of the Frz Phosphoenolpyruvate:carbohydrate phosphoTransferase System of extraintestinal pathogenic Escherichia coli is encoded on a genomic island in specific lineages of Streptococcus agalactiae. AB - We identified a Streptococcus agalactiae metabolic region (fru2) coding for a Phosphoenolpyruvate:carbohydrate phosphoTransferase System (PTS) homologous to the Frz system of extraintestinal pathogenic Escherichia coli strains. The Frz system is involved in environmental sensing and regulation of the expression of adaptation and virulence genes in E. coli. The S. agalactiae fru2 region codes three subunits of a PTS transporter of the fructose-mannitol family, a transcriptional activator of PTSs of the MtlR family, an allulose-6 phosphate-3 epimerase, a transaldolase and a transketolase. We demonstrated that all these genes form an operon. The fru2 operon is present in a 17494-bp genomic island. We analyzed by multilocus sequence typing a population of 492 strains representative of the S. agalactiae population and we showed that the presence of the fru2 operon is linked to the phylogeny of S. agalactiae. The fru2 operon is always present within strains of clonal complexes CC 1, CC 7, CC 10, CC 283 and singletons ST 130 and ST 288, but never found in other CCs and STs. Our results indicate that the fru2 operon was acquired during the evolution of the S. agalactiae species from a common ancestor before the divergence of CC 1, CC 7, CC 10, CC 283, ST 130 and ST 288. As S. agalactiae strains of CC 1 and CC 10 are frequently isolated from adults with invasive disease, we hypothesize that the S. agalactiae Fru2 system senses the environment to allow the bacterium to adapt to new conditions encountered during the infection of adults. PMID- 25733488 TI - Single TCR-Vbeta2 evaluation discloses the circulating T cell clone in Sezary syndrome: one family fits all! AB - Sezary Syndrome (SS/L-CTCL) is a rare but aggressive variant of cutaneous T cell lymphoma (CTCL), characterized by erythroderma, lymphadenopathy, and the presence of a circulating memory CD4(+) T cell malignant clone with a skin homing behavior, lacking CD26 and CD49d and over-expressing CD60. The availability of a panel of monoclonal antibodies recognizing distinct TCR-Vbeta families, allows to typify the clone by flow cytometry in about 70 % of cases. The TCR-Vbeta repertoire of 533 individuals, comprising 308 patients affected by CTCL, 50 healthy donors, and subjects affected by various non-neoplastic dermatological affections was evaluated by flow cytometry. Statistical analyses were performed using the SPSS statistical software package for Microsoft Windows (SPSS, version 21, Chicago, IL). TCR-Vbeta2 levels below 5.4 % or above 39.5 %, within total CD4(+) T cells, showed the best balance between sensitivity (98.1 %) and specificity (96 %) to identify the presence of a clone in the peripheral blood of patients affected by SS. Based on this observation, a "two-step" procedure in the detection of the malignant T cell clone in CTCLs is herein suggested. TCR-Vbeta2 assessment in all cases (first step). In the case of TCR-Vbeta2 levels above 39.5 %, the presence of a clonal expansion of this family is suggested, deserving further confirmation by means of T cell gene rearrangement evaluation. In patients having a TCR-Vbeta2 reactivity below 5.4 % (second step), the entire TCR Vbeta repertoire should be evaluated to typify the expanded clone. In conclusion, the single TCR-Vbeta2 expression check, instead of the entire repertoire assessment, represents an easy and cost-effective method for the recognition of CTCL aggressive leukemic variant. PMID- 25733490 TI - Occurrence and prevalence of fish-borne Anisakis larvae in the spotted mackerel Scomber australasicus from Taiwanese waters. AB - Anisakid nematodes have been found in a variety of marine fishes throughout the world and they are known to cause anisakiasis in human hosts. The present study investigated the prevalence of potentially zoonotic anisakid larvae in spotted mackerel caught from Taiwanese waters where fish represents an important food sources. Anisakis third-stage larvae (L3, n=502) were isolated from 250 spotted mackerel Scomber australasicus. Anisakis L3 larvae were divided morphologically into two types, Anisakis type I larvae had a longer ventriculus and mucron while type II larvae had a shorter ventriculus and no mucron. Anisakis species were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of the internal transcribed spacer (ITS) regions of ribosomal DNA and direct sequencing. A simple molecular taxonomic key, utilizing RFLP by two restriction enzymes HinfI and HhaI, enabled the differentiation of the genus Anisakis. The prevalence, mean intensity and mean abundance of Anisakis nematodes recorded for the total specimens were 72.8%, 2.8 (1-15) and 2.0 (0-15), respectively. Anisakis pegreffii was determined to be the dominant species (prevalence=57.2%) and important agent of human anisakiasis. A recombinant genotype (Anisakis simplex sensu stricto * A. pegreffii) was identified as the subdominant species (25.3%) followed by Anisakis typica (10%), Anisakis physeteris (4.0%), Anisakis paggiae (3.0%) and Anisakis brevispiculata (0.5%). The topology of the maximum likelihood and neighbor-joining trees show two well supported clades: one includes the species of A. pegreffii and the other includes A. paggiae, A. physeteris and A. brevispiculata, while A. typica has basal position to all other Anisakis spp. analyzed. This study advances our knowledge of the prevalence of different Anisakis spp. in the spotted mackerel from Taiwanese waters, which is helpful for monitoring the fish populations throughout a diverse array of aquatic ecosystems. More importantly, we provide the concise characterization of multiple Anisakis spp. by PCR-RFLP, which could also be applicable for the rapid diagnosis of human anisakiasis. PMID- 25733489 TI - The epidemiology of observed temperament: Factor structure and demographic group differences. AB - This study investigated the factor structure of observational indicators of children's temperament that were collected across the first three years of life in the Family Life Project (N=1205) sample. A four-factor model (activity level, fear, anger, regulation), which corresponded broadly to Rothbart's distinction between reactivity and regulation, provided an acceptable fit the observed data. Tests of measurement invariance demonstrated that a majority of the observational indicators exhibited comparable measurement properties for male vs. female, black vs. white, and poor vs. not-poor children, which improved the generalizability of these results. Unadjusted demographic group comparisons revealed small to moderate sized differences (Cohen ds=|.23-.42|) in temperamental reactivity and moderate to large sized differences (Cohen ds=-.64--.97) in regulation. Collectively, demographic variables explained more of the variation in regulation (R(2)=.25) than in reactivity (R(2)=.02-.06). Follow-up analyses demonstrated that race differences were substantially diminished in magnitude and better accounted for by poverty. These results help to validate the distinction between temperamental reactivity and regulation using observational indicators. PMID- 25733491 TI - Effect of temperature on life history traits during immature development of Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae) from Cordoba city, Argentina. AB - We investigated how ambient temperature under fluctuating conditions affects the larval-pupal immature traits of Aedes aegypti and Culex quinquefasciatus mosquitoes from Cordoba city, Argentina, and established each species development threshold and physiological time. Based on life tables, three cohorts of each mosquito species were reared in the laboratory under small fluctuating temperatures conditions of 15.2+/-1.7 degrees C, 17.9+/-1.6 degrees C, 21.6+/-0.7 degrees C and 25.3+/-0.4 degrees C for Ae. aegypti, and 16.6+/-1.7 degrees C, 18.7+/-1.7 degrees C and 25.2+/-0.3 degrees C for Cx. quinquefasciatus. Immature development time and survival values, and also thermal development threshold and physiological time were estimated. Development times of all larval and pupal stages of Ae. aegypti and Cx. quinquefasciatus were significantly affected by the rearing temperatures, decreasing when temperature increased. Mean Ae. aegypti total (larva+pupa) development time ranged from 21.9 to 8.6 days, at 15.2 and 25.3 degrees C, whereas, for Cx. quinquefasciatus varied between 23.5 to 9.2 days at 16.6 and 25.2 degrees C, respectively. Larval and pupal survival of both species was affected by different rearing temperatures, increasing in general as temperature increased. For Ae. aegypti the total immature survival ranged from 26% at 15.2 degrees C to 92% at 21.6 degrees C; however, temperature did not have significant effect on this variable. The total immature survival of Cx. quinquefasciatus was significantly and positively affected by temperatures, ranging from 32 to 88%, at 16.6 and 25.2 degrees C. The temperature development threshold and the physiological time estimated for Ae. aegypti and Cx. quinquefasciatus were 11.11 degrees C and 93.74 degree-days, and 10.96 degrees C and 136.87 degree-days, respectively. The results of the present study showed that temperature significantly affects the larval-pupal immature traits of these mosquito species of sanitary importance, from the central region of Argentina. All the parameters recorded are useful for the development of mosquito management models. PMID- 25733492 TI - Trypanothione reductase inhibitors: Overview of the action of thioridazine in different stages of Chagas disease. AB - Thioridazine (TDZ) is a phenothiazine that has been shown to be one of the most potent phenothiazines to inhibit trypanothione reductase irreversibly. Trypanothione reductase is an essential enzyme for the survival of Trypanosoma cruzi in the host. Here, we reviewed the use of this drug for the treatment of T. cruzi experimental infection. In our laboratory, we have studied the effect of TDZ for the treatment of mice infected with different strains of T. cruzi and treated in the acute or in the chronic phases of the experimental infection, using two different schedules: TDZ at a dose of 80 mg/kg/day, for 3 days starting 1h after infection (acute phase), or TDZ 80 mg/kg/day for 12 days starting 180 days post infection (d.p.i.) (chronic phase). In our experience, the treatment of infected mice, in the acute or in the chronic phases of the infection, with TDZ led to a large reduction in the mortality rates and in the cardiac histological and electrocardiographical abnormalities, and modified the natural evolution of the experimental infection. These analyses reinforce the importance of treatment in the chronic phase to decrease, retard or stop the evolution to chagasic myocardiopathy. Other evidence leading to the use of this drug as a potential chemotherapeutic agent for Chagas disease treatment is also revised. PMID- 25733493 TI - Long-term outcome of intravitreal pegaptanib sodium as maintenance therapy in Japanese patients with neovascular age-related macular degeneration. AB - PURPOSE: To evaluate the results of a 3-year follow-up of intravitreal pegaptanib sodium injection as maintenance therapy for the treatment of neovascular age related macular degeneration (AMD) in Japanese patients. METHODS: In this prospective, uncontrolled interventional study, 20 eyes of 19 patients with treatment-naive AMD who had received 3 consecutive monthly injections of 0.5 mg/0.05 mL ranibizumab as the induction treatment and had shown clinical/anatomical improvement were enrolled. An intravitreal injection of 0.3 mg/0.09 mL pegaptanib sodium was administered as the maintenance therapy every 6 weeks. Booster treatments using ranibizumab were allowed if clinical deterioration was judged to be present. The primary outcome measures were the best-corrected visual acuity (BCVA) and the central foveal thickness (CFT) as evaluated using spectral-domain optical coherence tomography. RESULTS: Sixteen of the 20 eyes (80 %) were assessed at the 3-year follow-up. The mean logMAR BCVA improved significantly from 0.56 +/- 0.31 before the induction treatment to 0.24 +/- 0.25 at baseline (P < 0.001) and was well maintained at 156 weeks (0.25 +/- 0.28, P = 0.938). Moreover, the mean CFT also decreased significantly from 346 +/ 111 MUm before the induction treatment to 232 +/- 54 MUm at baseline (P < 0.001) and was well preserved at 156 weeks (210 +/- 59 MUm, P = 0.278). Thirteen eyes (81.3 %) received an unscheduled booster treatment, and no severe systemic or ocular side effects occurred during follow-up. CONCLUSION: Intravitreal pegaptanib sodium injection as the maintenance therapy was effective in stabilizing the vision of patients with AMD in whom induction treatment led to improved BCVA, as evaluated at the 3-year follow-up. PMID- 25733494 TI - A Bayesian Vector Multidimensional Scaling Procedure Incorporating Dimension Reparameterization with Variable Selection. AB - We propose a two-way Bayesian vector spatial procedure incorporating dimension reparameterization with a variable selection option to determine the dimensionality and simultaneously identify the significant covariates that help interpret the derived dimensions in the joint space map. We discuss how we solve identifiability problems in a Bayesian context that are associated with the two way vector spatial model, and demonstrate through a simulation study how our proposed model outperforms a popular benchmark model. In addition, an empirical application dealing with consumers' ratings of large sport utility vehicles is presented to illustrate the proposed methodology. We are able to obtain interpretable and managerially insightful results from our proposed model with variable selection in comparison with the benchmark model. PMID- 25733495 TI - Personalised care planning for adults with chronic or long-term health conditions. AB - BACKGROUND: Personalised care planning is a collaborative process used in chronic condition management in which patients and clinicians identify and discuss problems caused by or related to the patient's condition, and develop a plan for tackling these. In essence it is a conversation, or series of conversations, in which they jointly agree goals and actions for managing the patient's condition. OBJECTIVES: To assess the effects of personalised care planning for adults with long-term health conditions compared to usual care (i.e. forms of care in which active involvement of patients in treatment and management decisions is not explicitly attempted or achieved). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, ProQuest, clinicaltrials.gov and WHO International Clinical Trials Registry Platform to July 2013. SELECTION CRITERIA: We included randomised controlled trials and cluster-randomised trials involving adults with long-term conditions where the intervention included collaborative (between individual patients and clinicians) goal setting and action planning. We excluded studies where there was little or no opportunity for the patient to have meaningful influence on goal selection, choice of treatment or support package, or both. DATA COLLECTION AND ANALYSIS: Two of three review authors independently screened citations for inclusion, extracted data, and assessed risk of bias. The primary outcomes were effects on physical health, psychological health, subjective health status, and capabilities for self management. Secondary outcomes included effects on health related behaviours, resource use and costs, and type of intervention. A patient advisory group of people with experience of living with long-term conditions advised on various aspects of the review, including the protocol, selection of outcome measures and emerging findings. MAIN RESULTS: We included 19 studies involving a total of 10,856 participants. Twelve of these studies focused on diabetes, three on mental health, one on heart failure, one on end-stage renal disease, one on asthma, and one on various chronic conditions. All 19 studies included components that were intended to support behaviour change among patients, involving either face-to-face or telephone support. All but three of the personalised care planning interventions took place in primary care or community settings; the remaining three were located in hospital clinics. There was some concern about risk of bias for each of the included studies in respect of one or more criteria, usually due to inadequate or unclear descriptions of research methods. Physical healthNine studies measured glycated haemoglobin (HbA1c), giving a combined mean difference (MD) between intervention and control of -0.24% (95% confidence interval (CI) -0.35 to -0.14), a small positive effect in favour of personalised care planning compared to usual care (moderate quality evidence).Six studies measured systolic blood pressure, a combined mean difference of -2.64 mm/Hg (95% CI -4.47 to -0.82) favouring personalised care (moderate quality evidence). The pooled results from four studies showed no significant effect on diastolic blood pressure, MD -0.71 mm/Hg (95% CI -2.26 to 0.84).We found no evidence of an effect on cholesterol (LDL-C), standardised mean difference (SMD) 0.01 (95% CI -0.09 to 0.11) (five studies) or body mass index, MD -0.11 (95% CI -0.35 to 0.13) (four studies).A single study of people with asthma reported that personalised care planning led to improvements in lung function and asthma control. Psychological healthSix studies measured depression. We were able to pool results from five of these, giving an SMD of -0.36 (95% CI 0.52 to -0.20), a small effect in favour of personalised care (moderate quality evidence). The remaining study found greater improvement in the control group than the intervention group.Four other studies used a variety of psychological measures that were conceptually different so could not be pooled. Of these, three found greater improvement for the personalised care group than the usual care group and one was too small to detect differences in outcomes. Subjective health statusTen studies used various patient-reported measures of health status (or health-related quality of life), including both generic health status measures and condition-specific ones. We were able to pool data from three studies that used the SF-36 or SF-12, but found no effect on the physical component summary score SMD 0.16 (95% CI -0.05 to 0.38) or the mental component summary score SMD 0.07 (95% CI -0.15 to 0.28) (moderate quality evidence). Of the three other studies that measured generic health status, two found improvements related to personalised care and one did not.Four studies measured condition-specific health status. The combined results showed no difference between the intervention and control groups, SMD -0.01 (95% CI -0.11 to 0.10) (moderate quality evidence). Self-management capabilitiesNine studies looked at the effect of personalised care on self-management capabilities using a variety of outcome measures, but they focused primarily on self efficacy. We were able to pool results from five studies that measured self efficacy, giving a small positive result in favour of personalised care planning: SMD 0.25 (95% CI 0.07 to 0.43) (moderate quality evidence).A further five studies measured other attributes that contribute to self-management capabilities. The results from these were mixed: two studies found evidence of an effect on patient activation, one found an effect on empowerment, and one found improvements in perceived interpersonal support. Other outcomesPooled data from five studies on exercise levels showed no effect due to personalised care planning, but there was a positive effect on people's self reported ability to carry out self-care activities: SMD 0.35 (95% CI 0.17 to 0.52).We found no evidence of adverse effects due to personalised care planning.The effects of personalised care planning were greater when more stages of the care planning cycle were completed, when contacts between patients and health professionals were more frequent, and when the patient's usual clinician was involved in the process. AUTHORS' CONCLUSIONS: Personalised care planning leads to improvements in certain indicators of physical and psychological health status, and people's capability to self-manage their condition when compared to usual care. The effects are not large, but they appear greater when the intervention is more comprehensive, more intensive, and better integrated into routine care. PMID- 25733496 TI - Influence of the body mass index on the occurrence of falls in patients with type 2 diabetes mellitus. AB - To assess the influence of the body mass index (BMI) on the occurrence of falls in adults with type 2 diabetes mellitus, receiving primary health care. We collected data from 134 patients (56.7+/-9.4 y.o.), none of them were seeking medical care due to sensory or balance decline. During the first evaluation, they reported falls, replied to a questionnaire of symptoms related to balance and had a sensory evaluation. After a 6 months follow-up, they reported falls again and, according to the occurrence of falls during the preceding year, patients were classified in 2 groups: no falls (N=92) and falls (N=42). The occurrence of falls was related to BMI, gender and age. Compared to patients with no falls, patients with falls had a greater BMI and comprised a higher proportion of patients with a BMI >=35; patients with a BMI >=35 were younger than patients with a BMI <35. A total symptom score >=4 allowed the classification of 77.7% of the patients with falls and 59.5% with no falls. In adults with type 2 diabetes mellitus, a BMI >=35 may have an influence on balance and the occurrence of falls, which might be independent from aging. Patients should be aware of this risk and receive counsel on modifiable risk factors. PMID- 25733497 TI - Lack of association between leptin G-2548A polymorphisms and obesity risk: Evidence based on a meta-analysis. AB - BACKGROUND: The prevalence of obesity is increasing in most industrialized and developing countries. We aimed to investigate the association between leptin (LEP) G-2548A polymorphisms and the risk of obesity. METHODS: We searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases for studies that evaluated the association between LEP G-2548A polymorphisms and obesity risk prior to March 2014. The odds ratio (OR) and its 95% confidence interval (95% CI) were calculated to estimate the risk of obesity. Meta-analysis of subgroup populations and different control sources was conducted using homozygote (AA vs. GG), allelic (A vs. G), dominant (AA+GA vs. GG), recessive (AA vs. GG+GA), and heterozygote (AG vs. GG) models. The heterogeneity of the studies was assessed using chi(2)-tests based on Q-statistics. The pooled ORs were calculated using a random-effects model if there was no heterogeneity; otherwise, a random-effects model was used. Two authors extracted the data independently. The funnel plots, Begg's and Egger's test were used to assess publication bias. All statistical analyses were performed using STATA 12.0 software. RESULTS: Nine case-controlled publications that evaluated the association between LEP G-2548A polymorphisms and obesity risk, which included 2594 subjects (1235 obesity cases and 1359 controls), were included in our meta-analysis. No significant association between this polymorphism and obesity risk was observed (P>0.05). Significant heterogeneity was detected among the studies. The results of subgroup analysis according to ethnicity and different control groups suggested that LEP G 2548A polymorphisms might increase the obesity risk in African populations in the homozygote (AA vs. GG: OR=2.38, 95% CI=1.15-4.93, P=0.020) and recessive (AA vs. GG+GA: OR=2.03, 95% CI=1.34-3.06, P=0.001) models. CONCLUSIONS: Overall, this meta-analysis indicated that LEP G-2548A polymorphisms are not associated with obesity risk, although significant associations were observed in the homozygote model (AA vs. GG) and the recessive model (AA vs. GG+GA) in Africa populations. Further studies are still needed to validate and confirm this association. PMID- 25733498 TI - Structural insight of DNA topoisomerases I from camptothecin-producing plants revealed by molecular dynamics simulations. AB - DNA topoisomerase I (Top1) catalyzes changes in DNA topology by cleaving and rejoining one strand of the double stranded (ds)DNA. Eukaryotic Top1s are the cellular target of the plant-derived anticancer indole alkaloid camptothecin (CPT), which reversibly stabilizes the Top1-dsDNA complex. However, CPT-producing plants, including Camptotheca acuminata, Ophiorrhiza pumila and Ophiorrhiza liukiuensis, are highly resistant to CPT because they possess point-mutated Top1. Here, the adaptive convergent evolution is reported between CPT production ability and mutations in their Top1, as a universal resistance mechanism found in all tested CPT-producing plants. This includes Nothapodytes nimmoniana, one of the major sources of CPT. To obtain a structural insight of the resistance mechanism, molecular dynamics simulations of CPT- resistant and -sensitive plant Top1s complexed with dsDNA and topotecan (a CPT derivative) were performed, these being compared to that for the CPT-sensitive human Top1. As a result, two mutations, Val617Gly and Asp710Gly, were identified in O. pumila Top1 and C. acuminata Top1, respectively. The substitutions at these two positions, surprisingly, are the same as those found in a CPT derivative-resistant human colon adenocarcinoma cell line. The results also demonstrated an increased linker flexibility of the CPT-resistant Top1, providing an additional explanation for the resistance mechanism found in CPT-producing plants. These mutations could reflect the long evolutionary adaptation of CPT-producing plant Top1s to confer a higher degree of resistance. PMID- 25733499 TI - Alcohol dose dumping: The influence of ethanol on hot-melt extruded pellets comprising solid lipids. AB - The objective of the present study was to investigate interactions between alcohol and hot-melt extruded pellets and the resulting drug release behavior. The pellets were composed of vegetable calcium stearate as matrix carrier and paracetamol or codeine phosphate as model drugs. Two solid lipids (Compritol(r) and Precirol(r)) were incorporated into the matrix to form robust/compact pellets. The drug release characteristics were a strong function of the API solubility, the addition of solid lipids, the dissolution media composition (i.e., alcohol concentration) and correspondingly, the pellet wettability. Pellets comprising paracetamol, which is highly soluble in ethanol, showed alcohol dose dumping regardless of the matrix composition. The wettability increased with increasing ethanol concentrations due to higher paracetamol solubilities yielding increased dissolution rates. For pellets containing codeine phosphate, which has a lower solubility in ethanol than in acidic media, the wettability was a function of the matrix composition. Dose dumping occurred for formulations comprising solid lipids as they showed increased wettabilities with increasing ethanol concentrations. In contrast, pellets comprising calcium stearate as single matrix component showed robustness in alcoholic media due to wettabilities that were not affected by the addition of ethanol. The results clearly indicate that the physico-chemical properties of the drug and the matrix systems are crucial for the design of ethanol-resistant dosage forms. Moreover, hydrophobic calcium stearate can be considered a suitable matrix system that minimizes the risk of ethanol-induced dose dumping for certain API's. PMID- 25733501 TI - Identification and characterization of multidrug-resistant Salmonella enterica serotype Albert isolates in the United States. AB - Salmonella enterica is one of the most common causes of bacterial foodborne illness in the United States. Although most Salmonella infections are self limiting, antimicrobial treatment of invasive salmonellosis is critical. The primary antimicrobial treatment options include fluoroquinolones or extended spectrum cephalosporins, and resistance to these antimicrobial drugs may complicate treatment. At present, S. enterica is composed of more than 2,600 unique serotypes, which vary greatly in geographic prevalence, ecological niche, and the ability to cause human disease, and it is important to understand and mitigate the source of human infection, particularly when antimicrobial resistance is found. In this study, we identified and characterized 19 S. enterica serotype Albert isolates collected from food animals, retail meat, and humans in the United States during 2005 to 2013. All five isolates from nonhuman sources were obtained from turkeys or ground turkey, and epidemiologic data suggest poultry consumption or live-poultry exposure as the probable source of infection. S. enterica serotype Albert also appears to be geographically localized to the midwestern United States. All 19 isolates displayed multidrug resistance, including decreased susceptibility to fluoroquinolones and resistance to extended-spectrum cephalosporins. Turkeys are a likely source of multidrug resistant S. enterica serotype Albert, and circulation of resistance plasmids, as opposed to the expansion of a single resistant strain, is playing a role. More work is needed to understand why these resistance plasmids spread and how their presence and the serotype they reside in contribute to human disease. PMID- 25733500 TI - Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A. AB - Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 MUg/ml. The proportion of Asian enteric fever isolates with an MIC of <= 16 MUg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of >= 13 mm to a 5-MUg azithromycin disk identified S. Typhi isolates with an MIC of <= 16 MUg/ml with a sensitivity of 99.7%. An azithromycin MIC of <= 16 MUg/ml or disk inhibition zone size of >= 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 MUg/ml and to determine MIC and disk breakpoints for S. Paratyphi A. PMID- 25733502 TI - Mass spectrometry imaging reveals heterogeneous efavirenz distribution within putative HIV reservoirs. AB - Persistent HIV replication within active viral reservoirs may be caused by inadequate antiretroviral penetration. Here, we used mass spectrometry imaging with infrared matrix-assisted laser desorption-electrospray ionization to quantify the distribution of efavirenz within tissues from a macaque dosed orally to a steady state. Intratissue efavirenz distribution was heterogeneous, with the drug concentrating in the lamina propria of the colon, the primary follicles of lymph nodes, and the brain gray matter. These are the first imaging data of an antiretroviral drug in active viral reservoirs. PMID- 25733503 TI - Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system. AB - A multidrug-resistant Klebsiella pneumoniae isolate exhibiting heteroresistance to colistin was investigated. The colistin-resistant subpopulation harbored a single amino acid change (Asp191Tyr) in protein PhoP, which is part of the PhoPQ two-component system that activates pmrHFIJKLM expression responsible for l aminoarabinose synthesis and polymyxin resistance. Complementation assays with a wild-type phoP gene restored full susceptibility to colistin. Then, analysis of the colistin-susceptible subpopulation showed a partial deletion (25 bp) in the phoP gene compared to that in the colistin-resistant subpopulation. That deletion disrupted the reading frame of phoP, leading to a longer and inactive protein (255 versus 223 amino acids long). This is the first report showing the involvement of mutation(s) in PhoP in colistin resistance. Furthermore, this is the first study to decipher the mechanisms leading to colistin heteroresistance in K. pneumoniae. PMID- 25733504 TI - Efficacy of skin and nasal povidone-iodine preparation against mupirocin resistant methicillin-resistant Staphylococcus aureus and S. aureus within the anterior nares. AB - Mupirocin decolonization of nasal Staphylococcus aureus prior to surgery decreases surgical-site infections; however, treatment requires 5 days, compliance is low, and resistance occurs. In 2010, 3M Company introduced povidone iodine (PVP-I)-based skin and nasal antiseptic (Skin and Nasal Prep [SNP]). SNP has rapid, broad-spectrum antimicrobial activity. We tested SNP's efficacy using full-thickness tissue (porcine mucosal [PM] and human skin) explant models and human subjects. Prior to or following infection with methicillin-resistant Staphylococcus aureus (MRSA) (mupirocin sensitive and resistant), explants were treated with Betadine ophthalmic preparation (Bet), SNP, or mupirocin (Bactroban nasal ointment [BN]) or left untreated. One hour posttreatment, explants were washed with phosphate-buffered saline (PBS) plus 2% mucin. One, 6, or 12 h later, bacteria were recovered and enumerated. Alternatively, following baseline sampling, human subjects applied two consecutive applications of SNP or saline to their anterior nares. One, 6, and 12 h after application of the preparation (postprep), nasal swabs were obtained, and S. aureus was enumerated. We observed that treatment of infected PM or human skin explants with SNP resulted in >2.0 log10 CFU reduction in MRSA, regardless of mupirocin sensitivity, which was significantly different from the values for BN- and Bet-treated explants and untreated controls 1 h, 6 h, and 12 h after being washed with PBS plus mucin. Swabbing the anterior nares of human subjects with SNP significantly reduced resident S. aureus compared to saline 1, 6, and 12 h postprep. Finally, pretreatment of PM explants with SNP, followed by a mucin rinse prior to infection, completely prevented MRSA infection. We conclude that SNP may be an attractive alternative for reducing the bioburden of anterior nares prior to surgery. PMID- 25733505 TI - Third-generation-cephalosporin-resistant Klebsiella pneumoniae isolates from humans and companion animals in Switzerland: spread of a DHA-producing sequence type 11 clone in a veterinary setting. AB - Characterization of third-generation-cephalosporin-resistant Klebsiella pneumoniae isolates originating mainly from one human hospital (n = 22) and one companion animal hospital (n = 25) in Bern (Switzerland) revealed the absence of epidemiological links between human and animal isolates. Human infections were not associated with the spread of any specific clone, while the majority of animal infections were due to K. pneumoniae sequence type 11 isolates producing plasmidic DHA AmpC. This clonal dissemination within the veterinary hospital emphasizes the need for effective infection control practices. PMID- 25733506 TI - Profiling of beta-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2. AB - Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with beta-lactam containing chemical probes. Compounds that target a single PBP could provide important information about the specific role(s) of each enzyme, making identification of such molecules important. We evaluated 22 commercially available beta-lactams for inhibition of the PBPs in live Escherichia coli strain DC2. Whole cells were titrated with beta-lactam antibiotics and subsequently incubated with a fluorescent penicillin derivative, Bocillin-FL (Boc-FL), to label uninhibited PBPs. Protein visualization was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation and fluorescent scanning. The examined beta-lactams exhibited diverse PBP selectivities, with amdinocillin (mecillinam) showing selectivity for PBP2, aztreonam, piperacillin, cefuroxime, cefotaxime, and ceftriaxone for PBP3, and amoxicillin and cephalexin for PBP4. The remaining beta-lactams did not block any PBPs in the DC2 strain of E. coli or inhibited more than one PBP at all examined concentrations in this Gram-negative organism. PMID- 25733507 TI - Influence of inflammation on voriconazole metabolism. AB - Voriconazole pharmacokinetics shows a large inter- and intrapatient variability. Inflammation is associated with changes in the expression of CYP isoenzymes. Here, we evaluated the influence of inflammation, marked by C-reactive protein (CRP) levels in blood, on the metabolism of voriconazole. Observational data showed an association between CRP level and the ratio of voriconazole N-oxide to voriconazole. PMID- 25733508 TI - Heterogeneity of genetic pathways toward daptomycin nonsusceptibility in Staphylococcus aureus determined by adjunctive antibiotics. AB - Daptomycin is increasingly used in combination with other antibiotics to enhance antimicrobial efficacy and/or to mitigate the emergence of daptomycin nonsusceptibility (DNS). This study used a clinical methicillin-resistant Staphylococcus aureus (MRSA) strain in which DNS emerged upon therapy to examine the influence of antibiotic combinations on the development of mutations in specific genes (mprF, rpoBC, dltA, cls2, and yycFG) previously associated with DNS. Whole genomes of bacteria obtained following 28 days of in vitro exposure to daptomycin with or without adjunctive clarithromycin, linezolid, oxacillin, or trimethoprim-sulfamethoxazole were sequenced, and the sequences were compared to that of the progenitor isolate. The addition of oxacillin to medium containing daptomycin prevented the emergence of mprF mutation but did not prevent rpoBC mutation (P < 0.01). These isolates maintained susceptibility to daptomycin during the combined exposure (median MIC, 1 mg/liter). Daptomycin plus clarithromycin or linezolid resulted in low-level (1.5 to 8 mg/liter) and high level (12 to 96 mg/liter) DNS, respectively, and did not prevent mprF mutation. However, these same combinations prevented rpoBC mutation. Daptomycin alone or combined with linezolid or trimethoprim-sulfamethoxazole resulted in high-level DNS and mutations in mprF plus rpoBC, cls2, and yycFG. Combining daptomycin with different antimicrobials alters the mutational space available for DNS development, thereby favoring the development of predictable collateral susceptibilities. PMID- 25733509 TI - Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients. AB - Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved. PMID- 25733510 TI - Effects of azithromycin, metronidazole, amoxicillin, and metronidazole plus amoxicillin on an in vitro polymicrobial subgingival biofilm model. AB - Chronic periodontitis is one of the most prevalent human diseases and is caused by dysbiosis of the subgingival microbiota. Treatment involves primarily mechanical disruption of subgingival biofilms and, in certain cases, adjunctive use of systemic antibiotic therapy. In vitro biofilm models have been developed to study antimicrobial agents targeting subgingival species. However, these models accommodate a limited number of taxa, lack reproducibility, and have low throughput. We aimed to develop an in vitro multispecies biofilm model that mimics subgingival plaque, to test antimicrobial agents. Biofilms were cultivated using the Calgary Biofilm Device and were exposed to amoxicillin (AMX), metronidazole (MTZ), azithromycin (AZM), and AMX-MTZ at four different concentrations for 12, 24, or 36 h. Chlorhexidine (CHX) (0.12%) was used as the positive control. The compositions of the biofilms were analyzed by checkerboard DNA-DNA hybridization, and the percent reduction in biofilm metabolic activity was determined using 2,3,5-triphenyltetrazolium chloride and spectrophotometry. Thirty-five of the 40 species used in the inoculum were consistently recovered from the resulting in vitro biofilms. After 36 h of exposure at the 1:27 dilution, AMX-MTZ reduced metabolic activity 11% less than CHX (q = 0.0207) but 54% more than AMX (q = 0.0031), 72% more than MTZ (q = 0.0031), and 67% more than AZM (q = 0.0008). Preliminary evidence of a synergistic interaction between AMX and MTZ was also observed. In summary, we developed reproducible biofilms with 35 subgingival bacterial species, and our results suggested that the combination of AMX and MTZ had greater antimicrobial effects on these in vitro multispecies biofilms than expected on the basis of the independent effects of the drugs. PMID- 25733511 TI - 30S Subunit-dependent activation of the Sorangium cellulosum So ce56 aminoglycoside resistance-conferring 16S rRNA methyltransferase Kmr. AB - Methylation of bacterial 16S rRNA within the ribosomal decoding center confers exceptionally high resistance to aminoglycoside antibiotics. This resistance mechanism is exploited by aminoglycoside producers for self-protection while functionally equivalent methyltransferases have been acquired by human and animal pathogenic bacteria. Here, we report structural and functional analyses of the Sorangium cellulosum So ce56 aminoglycoside resistance-conferring methyltransferase Kmr. Our results demonstrate that Kmr is a 16S rRNA methyltransferase acting at residue A1408 to confer a canonical aminoglycoside resistance spectrum in Escherichia coli. Kmr possesses a class I methyltransferase core fold but with dramatic differences in the regions which augment this structure to confer substrate specificity in functionally related enzymes. Most strikingly, the region linking core beta-strands 6 and 7, which forms part of the S-adenosyl-l-methionine (SAM) binding pocket and contributes to base flipping by the m(1)A1408 methyltransferase NpmA, is disordered in Kmr, correlating with an exceptionally weak affinity for SAM. Kmr is unexpectedly insensitive to substitutions of residues critical for activity of other 16S rRNA (A1408) methyltransferases and also to the effects of by-product inhibition by S adenosylhomocysteine (SAH). Collectively, our results indicate that adoption of a catalytically competent Kmr conformation and binding of the obligatory cosubstrate SAM must be induced by interaction with the 30S subunit substrate. PMID- 25733512 TI - Impact of beta-lactamase inhibition on the activity of ceftaroline against Mycobacterium tuberculosis and Mycobacterium abscessus. AB - The production of beta-lactamases Bla(Mab) and BlaC contributes to beta-lactam resistance in Mycobacterium abscessus and Mycobacterium tuberculosis, respectively. Ceftaroline was efficiently hydrolyzed by these enzymes. Inhibition of M. tuberculosis BlaC by clavulanate decreased the ceftaroline MIC from >= 256 to 16 to 64 MUg/ml, but these values are clinically irrelevant. In contrast, the ceftaroline-avibactam combination should be evaluated against M. abscessus since it inhibited growth at lower and potentially achievable drug concentrations. PMID- 25733515 TI - A group's physical attractiveness is greater than the average attractiveness of its members: the group attractiveness effect. AB - We tested whether the perceived physical attractiveness of a group is greater than the average attractiveness of its members. In nine studies, we find evidence for the so-called group attractiveness effect (GA-effect), using female, male, and mixed-gender groups, indicating that group impressions of physical attractiveness are more positive than the average ratings of the group members. A meta-analysis on 33 comparisons reveals that the effect is medium to large (Cohen's d = 0.60) and moderated by group size. We explored two explanations for the GA-effect: (a) selective attention to attractive group members, and (b) the Gestalt principle of similarity. The results of our studies are in favor of the selective attention account: People selectively attend to the most attractive members of a group and their attractiveness has a greater influence on the evaluation of the group. PMID- 25733514 TI - Development of a microarray-based tool to characterize vaginal bacterial fluctuations and application to a novel antibiotic treatment for bacterial vaginosis. AB - The healthy vaginal microbiota is generally dominated by lactobacilli that confer antimicrobial protection and play a crucial role in health. Bacterial vaginosis (BV) is the most prevalent lower genital tract infection in women in reproductive age and is characterized by a shift in the relative abundances of Lactobacillus spp. to a greater abundance of strictly anaerobic bacteria. In this study, we designed a new phylogenetic microarray-based tool (VaginArray) that includes 17 probe sets specific for the most representative bacterial groups of the human vaginal ecosystem. This tool was implemented using the ligase detection reaction universal array (LDR-UA) approach. The entire probe set properly recognized the specific targets and showed an overall sensitivity of 6 to 12 ng per probe. The VaginArray was applied to assess the efficacy of rifaximin vaginal tablets for the treatment of BV, analyzing the vaginal bacterial communities of 22 BV affected women treated with rifaximin vaginal tablets at a dosage of 25 mg/day for 5 days. Our results showed the ability of rifaximin to reduce the growth of various BV-related bacteria (Atopobium vaginae, Prevotella, Megasphaera, Mobiluncus, and Sneathia spp.), with the highest antibiotic susceptibility for A. vaginae and Sneathia spp. Moreover, we observed an increase of Lactobacillus crispatus levels in the subset of women who maintained remission after 1 month of therapy, opening new perspectives for the treatment of BV. PMID- 25733513 TI - Statins and voriconazole induce programmed cell death in Acanthamoeba castellanii. AB - Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a life-threatening encephalitis. In order to treat those infections properly, it is necessary to target the treatment not only to the trophozoite but also to the cyst. Furthermore, it may be advantageous to avoid parasite killing by necrosis, which may induce local inflammation. We must also avoid toxicity of host tissue. Many drugs which target eukaryotes are known to induce programmed cell death (PCD), but this process is poorly characterized in Acanthamoeba. Here, we study the processes of programmed cell death in Acanthamoeba, induced by several drugs, such as statins and voriconazole. We tested atorvastatin, fluvastatin, simvastatin, and voriconazole at the 50% inhibitory concentrations (IC50s) and IC90s that we have previously established. In order to evaluate this phenomenon, we investigated the DNA fragmentation, one of the main characteristics of PCD, with quantitative and qualitative techniques. Also, the changes related to phosphatidylserine exposure on the external cell membrane and cell permeability were studied. Finally, because caspases are key to PCD pathways, caspase activity was evaluated in Acanthamoeba. All the drugs assayed in this study induced PCD in Acanthamoeba. To the best of our knowledge, this is the first study where PCD induced by drugs is described quantitatively and qualitatively in Acanthamoeba. PMID- 25733516 TI - Vaccination of cattle with the N terminus of LppQ of Mycoplasma mycoides subsp. mycoides results in type III immune complex disease upon experimental infection. AB - Contagious bovine pleuropneumonia (CBPP) is a serious respiratory disease of cattle caused by Mycoplasma mycoides subsp. mycoides. Current vaccines against CBPP induce short-lived immunity and can cause severe postvaccine reactions. Previous studies have identified the N terminus of the transmembrane lipoprotein Q (LppQ-N') of M. mycoides subsp. mycoides as the major antigen and a possible virulence factor. We therefore immunized cattle with purified recombinant LppQ-N' formulated in Freund's adjuvant and challenged them with M. mycoides subsp. mycoides. Vaccinated animals showed a strong seroconversion to LppQ, but they exhibited significantly enhanced postchallenge glomerulonephritis compared to the placebo group (P = 0.021). Glomerulonephritis was characterized by features that suggested the development of antigen-antibody immune complexes. Clinical signs and gross pathological scores did not significantly differ between vaccinated and placebo groups. These findings reveal for the first time the pathogenesis of enhanced disease as a result of antibodies against LppQ during challenge and also argue against inclusion of LppQ-N' in a future subunit vaccine for CBPP. PMID- 25733517 TI - Sequence elements upstream of the core promoter are necessary for full transcription of the capsule gene operon in Streptococcus pneumoniae strain D39. AB - Streptococcus pneumoniae is a major bacterial pathogen in humans. Its polysaccharide capsule is a key virulence factor that promotes bacterial evasion of human phagocytic killing. While S. pneumoniae produces at least 94 antigenically different types of capsule, the genes for biosynthesis of almost all capsular types are arranged in the same locus. The transcription of the capsular polysaccharide (cps) locus is not well understood. This study determined the transcriptional features of the cps locus in the type 2 virulent strain D39. The initial analysis revealed that the cps genes are cotranscribed from a major transcription start site at the -25 nucleotide (G) upstream of cps2A, the first gene in the locus. Using unmarked chromosomal truncations and a luciferase-based transcriptional reporter, we showed that the full transcription of the cps genes not only depends on the core promoter immediately upstream of cps2A, but also requires additional elements upstream of the core promoter, particularly a 59-bp sequence immediately upstream of the core promoter. Unmarked deletions of these promoter elements in the D39 genome also led to significant reduction in CPS production and virulence in mice. Lastly, common cps gene (cps2ABCD) mutants did not show significant abnormality in cps transcription, although they produced significantly less CPS, indicating that the CpsABCD proteins are involved in the encapsulation of S. pneumoniae in a posttranscriptional manner. This study has yielded important information on the transcriptional characteristics of the cps locus in S. pneumoniae. PMID- 25733518 TI - Anti-CD20 antibody therapy and susceptibility to Pneumocystis pneumonia. AB - Anti-CD20 antibody therapy has been a useful medication for managing non Hodgkin's lymphoma as well as autoimmune diseases characterized by autoantibody generation. CD20 is expressed during most developmental stages of B lymphocytes; thus, CD20 depletion leads to B-lymphocyte deficiency. As the drug has become more widely used, there has been an increase in the number of case reports of patients developing Pneumocystis pneumonia. The role of anti-CD20 in Pneumocystis jirovecii infection is under debate due to the fact that most patients receiving it are on a regimen of multiple immunosuppressive medications. To address the specific role of CD20 depletion in host immunity against Pneumocystis, we examined a murine anti-CD20 depleting antibody. We demonstrated that anti-CD20 alone is permissive for Pneumocystis infection and that anti-CD20 impairs components of type II immunity, such as production of interleukin-4 (IL-4), IL-5, and IL-13 by whole-lung cells, in response to Pneumocystis murina. We also demonstrated that CD4(+) T cells from mice treated with anti-CD20 during Pneumocystis infection are incapable of mounting a protective immune response when transferred into Rag1(-/-) mice. Thus, CD20(+) cells are critical for generating protective CD4(+) T-cell immune responses against this organism. PMID- 25733519 TI - Adrenal steroids modulate the immune response during Brucella abortus infection by a mechanism that depends on the regulation of cytokine production. AB - Human brucellosis is a protean disease with a diversity of clinical signs and symptoms resulting from infection with Brucella species. Recent reports suggest a cross-regulation between adrenal steroids (cortisol and dehydroepiandrosterone [DHEA]) and the immune system. Monocytes and macrophages are the main replication niche for Brucella. Therefore, we investigated the role of adrenal hormones on the modulation of the immune response mediated by macrophages in B. abortus infection. Cortisol treatment during B. abortus infection significantly inhibits cytokine, chemokine, and MMP-9 secretion. In contrast, DHEA treatment had no effect. However, DHEA treatment increases the expression of costimulatory molecules (CD40, CD86), the adhesion molecule CD54, and major histocompatibility complex class I (MHC-I) and MHC-II expression on the surface of B. abortus infected monocytes. It is known that B. abortus infection inhibits MHC-I and MHC II expression induced by gamma interferon (IFN-gamma) treatment. DHEA reverses B. abortus downmodulation of the MHC-I and -II expression induced by IFN-gamma. Taken together, our data indicate that DHEA immune intervention may positively affect monocyte activity during B. abortus infection. PMID- 25733520 TI - PD-1 deficiency enhances humoral immunity of malaria infection treatment vaccine. AB - Malaria infection treatment vaccine (ITV) is a promising strategy to induce homologous and heterologous protective immunity against the blood stage of the parasite. However, the underlying mechanism of protection remains largely unknown. Here, we found that a malaria-specific antibody (Ab) could mediate the protective immunity of ITV-immunized mice. Interestingly, PD-1 deficiency greatly elevated the levels of both malaria-specific total IgG and subclass IgG2a and enhanced the protective efficacy of ITV-immunized mice against the blood-stage challenge. A serum adoptive-transfer assay demonstrated that the increased Ab level contributed to the enhanced protective efficacy of the immunized PD-1 deficient mice. Further study showed that PD-1 deficiency could also promote the expansion of germinal center (GC) B cells and malaria parasite-specific TFH cells in the spleens of ITV-immunized mice. These results suggest that PD-1 deficiency improves the protective efficacy of ITV-immunized mice by promoting the generation of malaria parasite-specific Ab and the expansion of GC B cells. The results of this study provide new evidence to support the negative function of PD 1 on humoral immunity and will guide the design of a more effective malaria vaccine. PMID- 25733521 TI - The assembly of GM1 glycolipid- and cholesterol-enriched raft-like membrane microdomains is important for giardial encystation. AB - Although encystation (or cyst formation) is an important step of the life cycle of Giardia, the cellular events that trigger encystation are poorly understood. Because membrane microdomains are involved in inducing growth and differentiation in many eukaryotes, we wondered if these raft-like domains are assembled by this parasite and participate in the encystation process. Since the GM1 ganglioside is a major constituent of mammalian lipid rafts (LRs) and known to react with cholera toxin B (CTXB), we used Alexa Fluor-conjugated CTXB and GM1 antibodies to detect giardial LRs. Raft-like structures in trophozoites are located in the plasma membranes and on the periphery of ventral discs. In cysts, however, they are localized in the membranes beneath the cyst wall. Nystatin and filipin III, two cholesterol-binding agents, and oseltamivir (Tamiflu), a viral neuraminidase inhibitor, disassembled the microdomains, as evidenced by reduced staining of trophozoites with CTXB and GM1 antibodies. GM1- and cholesterol-enriched LRs were isolated from Giardia by density gradient centrifugation and found to be sensitive to nystatin and oseltamivir. The involvement of LRs in encystation could be supported by the observation that raft inhibitors interrupted the biogenesis of encystation-specific vesicles and cyst production. Furthermore, culturing of trophozoites in dialyzed medium containing fetal bovine serum (which is low in cholesterol) reduced raft assembly and encystation, which could be rescued by adding cholesterol from the outside. Our results suggest that Giardia is able to form GM1- and cholesterol-enriched lipid rafts and these raft domains are important for encystation. PMID- 25733522 TI - CD4+ T cell response correlates with naturally acquired antibodies against Plasmodium vivax tryptophan-rich antigens. AB - Tryptophan-rich proteins play important biological functions for the Plasmodium parasite. Plasmodium vivax contains remarkably large numbers of such proteins belonging to the "Pv-fam-a" family that need to be characterized. Earlier, we reported the presence of memory T cells and naturally acquired antibodies against 15 of these proteins in P. vivax malaria-exposed individuals (M. Zeeshan, H. Bora, and Y. D. Sharma, J Infect Dis 207:175-185, 2013, http://dx.doi.org/10.1093/infdis/jis650). Here, we sought to characterize and ascertain the cross talk between effector responses of T and B cells in malarial patients against all Pv-fam-a family proteins. Therefore, we expressed the remaining 21 of these proteins in Escherichia coli and studied the humoral and cellular immune responses based on the same parameters used in our previous study. Naturally acquired IgG antibodies were detected against all 21 antigens in P. vivax patient sera (37.7 to 94.4% seropositivity). These antigens were able to activate the lymphocytes of P. vivax-exposed individuals, and the activated CD4(+) T lymphocytes produced higher levels of Th1 (interleukin-2 [IL-2] and gamma interferon [IFN-gamma]) and Th2 (IL-4 and IL-10) cytokines than the healthy controls, but the response was Th2 biased. The combined results of present and previous studies seem to suggest a striking link between induction of the CD4(+) T cell response and naturally acquired antibodies against all 36 proteins of the Pv-fam-a family, the majority of them having conserved sequences in the parasite population. Further work is required to utilize this information to develop immunotherapeutic treatments for this disease. PMID- 25733523 TI - The collagen binding protein Cnm contributes to oral colonization and cariogenicity of Streptococcus mutans OMZ175. AB - Streptococcus mutans is the etiological agent of dental caries and one of the many bacterial species implicated in infective endocarditis. The expression of the collagen-binding protein Cnm by S. mutans has been associated with extraoral infections, but its relevance for dental caries has only been theorized to date. Due to the collagenous composition of dentinal and root tissues, we hypothesized that Cnm may facilitate the colonization of these surfaces, thereby enhancing the pathogenic potential of S. mutans in advancing carious lesions. As shown for extraoral endothelial cell lines, Cnm mediates the invasion of oral keratinocytes and fibroblasts by S. mutans. In this study, we show that in the Cnm(+) native strain, OMZ175, Cnm mediates stringent adhesion to dentinal and root tissues as well as collagen-coated surfaces and promotes both cariogenicity and carriage in vivo. In vitro, ex vivo, and in vivo experiments revealed that while Cnm is not universally required for S. mutans cariogenicity, it contributes to (i) the invasion of the oral epithelium, (ii) enhanced binding on collagenous surfaces, (iii) implantation of oral biofilms, and (IV) the severity of caries due to a native Cnm(+) isolate. Taken together, our findings reveal that Cnm is a colonization factor that contributes to the pathogenicity of certain S. mutans strains in their native habitat, the oral cavity. PMID- 25733524 TI - Escherichia coli EDL933 requires gluconeogenic nutrients to successfully colonize the intestines of streptomycin-treated mice precolonized with E. coli Nissle 1917. AB - Escherichia coli MG1655, a K-12 strain, uses glycolytic nutrients exclusively to colonize the intestines of streptomycin-treated mice when it is the only E. coli strain present or when it is confronted with E. coli EDL933, an O157:H7 strain. In contrast, E. coli EDL933 uses glycolytic nutrients exclusively when it is the only E. coli strain in the intestine but switches in part to gluconeogenic nutrients when it colonizes mice precolonized with E. coli MG1655 (R. L. Miranda et al., Infect Immun 72:1666-1676, 2004, http://dx.doi.org/10.1128/IAI.72.3.1666 1676.2004). Recently, J. W. Njoroge et al. (mBio 3:e00280-12, 2012, http://dx.doi.org/10.1128/mBio.00280-12) reported that E. coli 86-24, an O157:H7 strain, activates the expression of virulence genes under gluconeogenic conditions, suggesting that colonization of the intestine with a probiotic E. coli strain that outcompetes O157:H7 strains for gluconeogenic nutrients could render them nonpathogenic. Here we report that E. coli Nissle 1917, a probiotic strain, uses both glycolytic and gluconeogenic nutrients to colonize the mouse intestine between 1 and 5 days postfeeding, appears to stop using gluconeogenic nutrients thereafter in a large, long-term colonization niche, but continues to use them in a smaller niche to compete with invading E. coli EDL933. Evidence is also presented suggesting that invading E. coli EDL933 uses both glycolytic and gluconeogenic nutrients and needs the ability to perform gluconeogenesis in order to colonize mice precolonized with E. coli Nissle 1917. The data presented here therefore rule out the possibility that E. coli Nissle 1917 can starve the O157:H7 E. coli strain EDL933 of gluconeogenic nutrients, even though E. coli Nissle 1917 uses such nutrients to compete with E. coli EDL933 in the mouse intestine. PMID- 25733525 TI - Cause of Death in Patients with Reduced Kidney Function. AB - Information on common causes of death in people with CKD is limited. We hypothesized that, as eGFR declines, cardiovascular mortality and mortality from infection account for increasing proportions of deaths. We calculated eGFR using the CKD Epidemiology Collaboration equation for residents of Alberta, Canada who died between 2002 and 2009. We used multinomial logistic regression to estimate unadjusted and age- and sex-adjusted differences in the proportions of deaths from each cause according to the severity of CKD. Cause of death was classified as cardiovascular, infection, cancer, other, or not reported using International Classification of Diseases codes. Among 81,064 deaths, the most common cause was cancer (31.9%) followed by cardiovascular disease (30.2%). The most common cause of death for those with eGFR>=60 ml/min per 1.73 m(2) and no proteinuria was cancer (38.1%); the most common cause of death for those with eGFR<60 ml/min per 1.73 m(2) was cardiovascular disease. The unadjusted proportion of patients who died from cardiovascular disease increased as eGFR decreased (20.7%, 36.8%, 41.2%, and 43.7% of patients with eGFR>=60 [with proteinuria], 45-59.9, 30-44.9, and 15-29.9 ml/min per 1.73 m(2), respectively). The proportions of deaths from heart failure and valvular disease specifically increased with declining eGFR along with the proportions of deaths from infectious and other causes, whereas the proportion of deaths from cancer decreased. In conclusion, we found an inverse association between eGFR and specific causes of death, including specific types of cardiovascular disease, infection, and other causes, in this cohort. PMID- 25733526 TI - Influence of visual acuity on suicidal ideation, suicide attempts and depression in South Korea. AB - BACKGROUND: To assess the influence of visual acuity (VA) on suicidal ideation, suicide attempts and depression. METHODS: From 2008 to 2012, a total of 28 919 nationally representative participants aged 19 years or older in the Korea National Health and Nutrition Examination Survey underwent additional ophthalmological examinations by the Korean Ophthalmologic Society. Associations between best corrected VA in the better-seeing eye based on decimal fraction and mental health were identified using multivariable logistic regression analysis after adjusting for possible biopsychosocial confounders. Self-reported mental health (suicidal ideation, suicide attempt and depression), Euro Quality of Life Visual Analog Scale and counselling experience were evaluated by direct interviews. A nomogram for risk of suicidal ideation was generated. RESULTS: By multivariable logistic regression analysis, low VA was significantly associated with suicidal ideation and suicide attempt but not depression. Participants with a VA of no light perception to 0.2 had a nearly twofold and threefold increased risk of suicidal ideation (adjusted OR, 1.85; 95% CI 1.04 to 3.27) and suicidal attempt (adjusted OR, 3.44; 95% CI 0.92 to 12.79), compared with participants with a VA of 1.0. Sociodemographic disparities, including age and socioeconomic status, existed for suicidal ideation, suicidal attempt and depression. Euro Quality of Life-Visual Analog Scale significantly decreased as VA decreased and was lower in participants who attempted suicide. CONCLUSIONS: Low VA was associated with the occurrence of suicidal ideation or a suicide attempt. Ophthalmologists should embrace their responsibility to help reduce suicidality and prevent suicides in patients with low VA by encouraging them to seek psychiatric care. PMID- 25733527 TI - Retinal angiography with real-time speckle variance optical coherence tomography. AB - This report describes a novel, non-invasive and label-free optical imaging technique, speckle variance optical coherence tomography (svOCT), for visualising blood flow within human retinal capillary networks. This imaging system uses a custom-built swept source OCT system operating at a line rate of 100 kHz. Real time processing and visualisation is implemented on a consumer grade graphics processing unit. To investigate the quality of microvascular detail acquired with this device we compared images of human capillary networks acquired with svOCT and fluorescein angiography. We found that the density of capillary microvasculature acquired with this svOCT device was visibly greater than fluorescein angiography. We also found that this svOCT device had the capacity to generate en face images of distinct capillary networks that are morphologically comparable with previously published histological studies. Finally, we found that this svOCT device has the ability to non-invasively illustrate the common manifestations of diabetic retinopathy and retinal vascular occlusion. The results of this study suggest that graphics processing unit accelerated svOCT has the potential to non-invasively provide useful quantitative information about human retinal capillary networks. Therefore svOCT may have clinical and research applications for the management of retinal microvascular diseases, which are a major cause of visual morbidity worldwide. PMID- 25733528 TI - Protocol-driven adjustment of ocular hypotensive medication in patients at low risk of conversion to glaucoma. AB - AIM: To investigate the safety and potential savings of decreasing medication use in low-risk patients with ocular hypertension (OH). METHODS: Patients with OH receiving pressure-lowering medication identified by medical record review at a university hospital underwent examination by a glaucoma specialist with assessment of visual field (VF), vertical cup-to-disc ratio (vCDR), central corneal thickness and intraocular pressure (IOP). Subjects with estimated 5-year risk of glaucoma conversion <15% were asked to discontinue >=1 medication, IOP was remeasured 1 month later and risk was re-evaluated at 1 year. RESULTS: Among 212 eyes of 126 patients, 44 (20.8%) had 5-year risk >15% and 14 (6.6%) had unreliable baseline VF. At 1 month, 15 patients (29 eyes, 13.7%) defaulted follow up or refused to discontinue medication and 11 eyes (5.2%) had risk >15%. The remaining 69 patients (107 eyes, 50.7%) successfully discontinued 141 medications and completed 1-year follow-up. Mean IOP (20.5+/-2.65 mm Hg vs 20.3+/-3.40, p=0.397) did not change, though mean VF pattern SD (1.58+/-0.41 dB vs 1.75+/-0.56 dB, p=0.001) and glaucoma conversion risk (7.31+/-3.74% vs 8.76+/-6.28%, p=0.001) increased at 1 year. Mean defect decreased (-1.42+/-1.60 vs -1.07+/-1.52, p=0.022). One eye (0.47%) developed a repeatable VF defect and 13 eyes (6.1%) had 5-year risk >15% at 1 year. The total 1-year cost of medications saved was US$4596. CONCLUSIONS: Nearly half (43.9%) of low-risk OH eyes in this setting could safely reduce medications over 1 year, realising substantial savings. PMID- 25733529 TI - Upper extremity deep vein thrombosis in a TV cameraman. AB - We report the case of a 40-year-old right-handed man who developed a right subclavian vein thrombosis due to work as a TV cameraman. He presented with a sudden onset of marked swelling and blue discolouration of his right arm 3 weeks after the most strenuous and prolonged episode of TV camera work that he had ever undertaken. This involved carrying a 9kg camera on his shoulder, with his right arm flexed and abducted, for a 60min period with provocation of severe pain and marked discomfort persisting during the subsequent 3 weeks before presentation. A clinical diagnosis of upper extremity deep vein thrombosis (UEDVT) was made, with the diagnosis confirmed by ultrasound. He was treated with catheter-induced thrombolysis and a 3 month course of anticoagulation. He was advised that his UEDVT was caused by his occupation and that he should no longer work as a cameraman. This case shows the importance of identifying any occupational cause of UEDVT. PMID- 25733530 TI - Psychosocial work environment and leisure-time physical activity: the Stormont study. AB - BACKGROUND: Research findings on the relationship between the psychosocial work environment and leisure-time physical activity (LTPA) are equivocal. This might partly be due to studies having focused on a restricted set of psychosocial dimensions, thereby failing to capture all relevant domains. AIMS: To examine cross-sectional associations between seven psychosocial work environment domains and LTPA in a large sample of UK civil servants and to profile LTPA and consider this in relation to UK government recommendations on physical activity. METHODS: In 2012 Northern Ireland Civil Service employees completed a questionnaire including measures of psychosocial working conditions (Management Standards Indicator Tool) and LTPA. We applied bivariate correlations and linear regression analyses to examine relations between psychosocial working conditions and LTPA. RESULTS: Of 26000 civil servants contacted, 5235 (20%) completed the questionnaire. 24% of men and 17% of women reported having undertaken 30min or more of physical activity on five or more days in the past week. In men, job control (-0.08) and peer support (-0.05) were weakly but significantly negatively correlated with LTPA, indicating that higher levels of exposure to these psychosocial hazards was associated with lower levels of LTPA. Job role (-0.05) was weakly but significantly negatively correlated with LTPA in women. These psychosocial work characteristics accounted for 1% or less of the variance in LTPA. CONCLUSIONS: Longitudinal research to examine cause-effect relations between psychosocial work characteristics and LTPA might identify opportunities for psychosocial job redesign to increase employees' physical activity during leisure time. PMID- 25733531 TI - Death and work: recognition of occupational association and coroner's investigation. AB - BACKGROUND: The degree of recognition of occupation as a contributory factor at the time of death certification is not known and there are few data describing the frequency with which a link to work is confirmed by the coroner. The medical examiner (ME) in England and Wales has a remit to scrutinize the circumstances of death and ensure accurate certificate completion with a requirement to pay specific attention to occupational factors. AIMS: To examine work assessment in the death certification process. METHODS: Deaths between March 2011 and December 2012 scrutinized by the Sheffield ME were assessed to identify the number of cases in which occupation was recorded and considered, the proportion of deaths referred to the coroner on the grounds of occupational history and the subsequent action taken by the coroner. RESULTS: A total of 5018 deaths were included in the study. Occupation was recorded in medical documentation used to complete the medical certificate of cause of death (MCCD) in 32% (1581) of cases. Of 1775 cases referred to the coroner by the ME, 8% (142) were on the grounds of occupation with 102 of these requiring autopsy, inquest or both. A total of 50 deaths were confirmed by the coroner as due to industrial disease. CONCLUSIONS: Our study describes an important step towards improving the validity of data on occupational mortality, using trained independent review prior to medical certification. Wider implementation of the ME scheme can improve the accuracy of MCCD completion and improve judgement of the contribution of occupation to an individual's death. PMID- 25733533 TI - DDR2 inhibition reduces migration and invasion of murine metastatic melanoma cells by suppressing MMP2/9 expression through ERK/NF-kappaB pathway. AB - Metastatic melanoma is one of the most deadly and evasive cancers. Collagen I in the extracellular matrix promotes the migration and invasion of tumor cells through the production of matrix metalloproteinase (MMP) 2 and 9. Discoidin domain receptor (DDR) 2 is a collagen receptor that is implicated in several cancer types including breast and prostate cancers. However, the role of DDR2 in the migration and invasion of murine melanoma cells is less studied. In the present study, we investigated the effects and underlying mechanisms of DDR2 in migration and invasion of B16BL6 melanoma cells in response to collagen I. Results demonstrated that DDR2 is expressed and is phosphorylated by collagen I in the cells. Upon down-regulation of DDR2 using small-interfering RNA (siRNA) approach, both of the cell migratory and invasive phenotypes were significantly attenuated when compared with the control cells. This effect was mediated via suppression of MMP2/9 upon DDR2 inhibition. Furthermore, inhibition of DDR2 by specific siRNA markedly reduced the activation of extracellular regulated kinase (ERK) 1 and 2 and nuclear factor of kappa B (NF-kappaB) in the cells when compared with the control cells. Overall, these data demonstrated that DDR2 siRNA mediated suppression of ERK1/2 and NF-kappaB could down-regulate the expressions of MMP2/9 in response to collagen I to reduce the migratory and invasive phenotypes of the cells. PMID- 25733532 TI - The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials. AB - OBJECTIVE: With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids. METHODS: Through the NorthStar Network, standardised clinical data including the NorthStar Ambulatory Assessment score (NSAA) on 513 ambulant UK boys with DMD were analysed from 2004 to 2012. For the analysis of the genetic subpopulation, we also included data from 172 Italian boys with DMD. NSAA raw scores were converted into linear scores. RESULTS: On the linearised NSAA, we observed an average decline of 8 units/year (4 units on raw NSAA analysis) after age 7. The median age at loss of ambulation (LOA) was 13 years (95% CI 12.1 to 13.5); 2 years prior to LOA, the estimated mean linearised NSAA score was 42/100 (13/34 raw scale). Starting glucocorticoids between 3 and 5 years conferred an additional gain in motor function of 3 units/year (1.3 raw units) up to age 7. When analysing the effect of genotype in the UK and Italian cumulative cohorts, individuals with deletions amenable to exons 44 and 46 skipping declined at a slower rate over 2 years (9 units (4 raw units), p<0.001), while 53 and 51 skippable deletions showed a faster decline of 14 (4.5; p<0.001) and 5 linearised units (2.4 NSAA units; p=0.02), respectively. CONCLUSIONS: Our study provides a novel insight on the current natural history of DMD, which will be instrumental for the design of future clinical trials. PMID- 25733534 TI - Over-expression of miR-125a-5p inhibits proliferation in C2C12 myoblasts by targeting E2F3. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs of 20-25 nucleotides in length. It has been shown that miRNAs play important roles in the proliferation of many types of cells, including myoblasts. In this study, we used real-time quantitative polymerase chain reaction, western blotting, EdU, flow cytometry, and CCK-8 assay to explore the role of miR-125a-5p during the proliferation of C2C12 myoblasts. It was found that the expression of miR-125a-5p was decreased during C2C12 myoblast proliferation. Over-expression of miR-125a-5p inhibited C2C12 myoblast proliferation as indicated by EdU staining, flow cytometry, and CCK8 assay. It was also found that miR-125a-5p could negatively regulate E2F3 expression at posttranscriptional level, via a specific target site in the 3' untranslated region. Knockdown of E2F3 showed a similar inhibitory effect on C2C12 myoblast proliferation. Thus, our findings suggest that miR-125a-5p may act as a negative regulator of C2C12 myoblast proliferation by targeting E2F3. PMID- 25733535 TI - In defense of position uncertainty: a reply to Dunabeitia, Orihuela, and Carreiras (2014). PMID- 25733536 TI - The impact of literacy on position uncertainty. PMID- 25733537 TI - The Effects of Tryptophan on Everyday Interpersonal Encounters and Social Cognitions in Individuals with a Family History of Depression. AB - BACKGROUND: Individuals with a family history of depression show subtle abnormalities in the processing of social stimuli. This could negatively affect their interpersonal functioning and contribute to their depression risk. Repeated administration of the serotonin precursor tryptophan has previously been shown to increase agreeable behavior and reduce quarrelsome behavior in irritable people, who are also considered at risk for depression. METHODS: To examine the effects of tryptophan on social functioning in individuals with a family history of depression, 40 men and women with at least one first-degree relative with depression received tryptophan (1g three times a day) and placebo for 14 days each in a double-blind crossover design and recorded their social behavior and mood during everyday interpersonal encounters. Participants also provided daily ratings of their positive and negative cognitions concerning their social functioning. RESULTS: Tryptophan improved mood. Unexpectedly, tryptophan increased quarrelsome behavior and reduced agreeable behavior, specifically during interactions at home. The behavioral effects of tryptophan were not moderated by mood or by the interaction partner. Negative social cognitions were lower when tryptophan was given second and lower during placebo when placebo was given second. CONCLUSION: Overall, tryptophan may not alter social behavior in individuals with a family history of depression as it does in irritable people. However, the behavioral effects of tryptophan at home might be seen as a way for individuals with a family history of depression to achieve more control. Over time, this may positively influence the way they feel and think about themselves in a social context. PMID- 25733539 TI - Acupuncture for joint symptoms related to aromatase inhibitor therapy in postmenopausal women with early-stage breast cancer: a narrative review. AB - BACKGROUND: Aromatase inhibitor-induced musculoskeletal syndrome (AIMSS) leads to discontinuation of aromatase inhibitor therapy in a significant proportion of patients with breast cancer. Acupuncture is popular among cancer patients and has previously been shown to improve symptoms in a range of musculoskeletal complaints. AIM: To determine the effectiveness and safety of acupuncture for the management of AIMSS in postmenopausal women with early-stage breast cancer. METHODS: A literature search was carried out for randomised controlled trials (RCTs) on acupuncture for AIMSS in postmenopausal women with early-stage breast cancer. Characteristics of trials and outcomes were extracted from the retrieved articles, which were also assessed for risk of bias and quality of reporting. RESULTS: Four RCTs were retrieved of sample size 32-67 (totalling 190 participants). Compliance with treatment was high and rates of adverse events were low. Of the three two-arm RCTs, two found no difference between acupuncture and sham acupuncture and one found that acupuncture was statistically superior to sham acupuncture. The fourth RCT, which incorporated three arms, found acupuncture and sham acupuncture to be statistically superior to usual care but there was no difference between true and sham acupuncture. Three trials that used non-penetrating sham as the control found no effect of acupuncture over sham, but the one trial that used superficial needle insertion found acupuncture to be superior. CONCLUSIONS: Acupuncture is safe and results in improvement in AIMSS symptoms, but similar benefits are also elicited by non-penetrating sham acupuncture. Future research should seek to establish the durability of improvements. PMID- 25733538 TI - Enhanced Cocaine-Associated Contextual Learning in Female H/Rouen Mice Selectively Bred for Depressive-Like Behaviors: Molecular and Neuronal Correlates. AB - BACKGROUND: Major depression has multiple comorbidities, in particular drug use disorders, which often lead to more severe and difficult-to-treat illnesses. However, the mechanisms linking these comorbidities remain largely unknown. METHODS: We investigated how a depressive-like phenotype modulates cocaine related behaviors using a genetic model of depression: the Helpless H/Rouen (H) mouse. We selected the H mouse line for its long immobility duration in the tail suspension test when compared to non-helpless (NH) and intermediate (I) mice. Since numerous studies revealed important sex differences in drug addiction and depression, we conducted behavioral experiments in both sexes. RESULTS: All mice, regardless of phenotype or sex, developed a similar behavioral sensitization after 5 daily cocaine injections (10 mg/kg). Male H and NH mice exhibited similar cocaine-induced conditioned place preference scores that were only slightly higher than in I mice, whereas female H mice strikingly accrued much higher preferences for the cocaine-associated context than those of I and NH mice. Moreover, female H mice acquired cocaine-associated context learning much faster than I and NH mice, a facilitating effect that was associated to a rapid increase in striatal and accumbal brain-derived neurotrophic factor levels (BDNF; up to 35% 24 h after cocaine conditioning). Finally, when re-exposed to the previously cocaine-associated context, female H mice displayed greater Fos activation in the cingulate cortex, nucleus accumbens, and basolateral amygdala. CONCLUSIONS: Our data indicate that neurobiological mechanisms such as alterations in associative learning, striato-accumbal BDNF expression, and limbic-cortico-striatal circuit reactivity could mediate enhanced cocaine vulnerability in female depressive-like mice. PMID- 25733540 TI - Results from a survey of national immunization programmes on home-based vaccination record practices in 2013. AB - BACKGROUND: Data on home-based records (HBRs) practices within national immunization programmes are non-existent, making it difficult to determine whether current efforts of immunization programmes related to basic recording of immunization services are appropriately focused. METHODS: During January 2014, WHO and the United Nations Children's Fund sent a one-page questionnaire to 195 countries to obtain information on HBRs including type of record used, number of records printed, whether records were provided free-of-charge or required by schools, whether there was a stock-out and the duration of any stock-outs that occurred, as well as the total expenditure for printing HBRs during 2013. RESULTS: A total of 140 countries returned a completed HBR questionnaire. Two countries were excluded from analysis because they did not use a HBR during 2013. HBR types varied across countries (vaccination only cards, 32/138 [23.1%]; vaccination plus growth monitoring records, 31/138 [22.4%]; child health books, 48/138 [34.7%]; combination of these, 27/138 [19.5%] countries). HBRs were provided free-of-charge in 124/138 (89.8%) respondent countries. HBRs were required for school entry in 62/138 (44.9%) countries. Nearly a quarter of countries reported HBR stock-outs during 2013. Computed printing cost per record was =5 min. Overall, 1105 participants from 11 trials were included; of them, 552 received statin therapy preoperatively. Postoperative AF occurred in 19% of these participants when compared with 36% of those not treated with statins (odds ratio 0.41, 95% confidence interval 0.31-0.54, P < 0.00001, using a random-effects model). Atrial fibrillation prevention by statin pretreatment was consistent across different subgroups. CONCLUSION: Short-term statin pretreatment may reduce the risk of postoperative AF among patients undergoing cardiac surgery. PMID- 25733552 TI - Beat-to-beat T-wave amplitude variability in the risk stratification of right ventricular outflow tract-premature ventricular complex patients. AB - AIMS: Premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT) may occasionally trigger monomorphic ventricular tachycardia (MVT), polymorphic ventricular tachycardia (PVT), or ventricular fibrillation (VF). We examined whether an analysis of the ventricular repolarization instability could differentiate PVT/VF triggered by RVOT-PVCs from benign RVOT-PVCs or MVT. METHODS: We evaluated the ventricular repolarization instability as assessed by the beat-to-beat T-wave amplitude variability (TAV) using Holter recordings in patients with RVOT-PVCs but with no structural heart disease. We determined the prematurity index, defined as the ratio of the coupling interval of the first ventricular tachycardia (VT) beat or isolated PVC to the preceding R-R interval just before the VT or isolated PVC in the Holter recordings. The study patients were classified into RVOT-PVCs/MVT (n = 33) and PVT/VF (n = 10). RESULTS: The two groups did not differ with respect to the age, sex, and left ventricular ejection fraction. There was no significant difference in the prematurity index between the two groups (RVOT-PVCs/MVT 0.66 +/- 0.16 vs. PVT/VF 0.61 +/- 0.13, P = 0.60). The patients with PVT/VF had a significantly larger maximum TAV than those with RVOT-PVCs/MVT (31 +/- 13 vs. 68 +/- 40 uV, P < 0.001). Patients with a higher than median value of the TAV (33 uV) were at increased risk of PVT/VF vs. those with a lower than median value, after adjusting for the age and sex [9.25 (95% confidence interval: 1.27-19.2); P = 0.03]. CONCLUSIONS: The TAV analysis is a useful measure to identify the subset of usually benign RVOT-PVC/MVT patients prone to PVT/VF. PMID- 25733553 TI - Health literacy and informed decision making regarding colorectal cancer screening: a systematic review. AB - Making an informed decision about participation in colorectal cancer (CRC) screening may be challenging for invitees with lower health literacy skills. The aim of this systematic review is to explore to what extent the level of a person's health literacy is related to their informed decision making concerning CRC screening. We searched for peer-reviewed studies published between 1950 and May 2013 in MEDLINE, EMBASE, SciSearch and PsycINFO. Studies were included when health literacy was studied in relation to concepts underpinning informed decision making (awareness, risk perception, perceived barriers and benefits, knowledge, attitude, deliberation). The quality of the studies was determined and related to the study results. The search returned 2254 papers. Eight studies in total were included, among which seven focused on knowledge, four focused on attitudes or beliefs concerning CRC screening, and one focused on risk perception. The studies found either no association or a positive association between health literacy and concepts underpinning informed decision making. Some studies showed that higher health literacy was associated with more CRC screening knowledge and a more positive attitude toward CRC screening. The results of studies that obtained a lower quality score were no different than studies that obtained a higher quality score. In order to obtain more insight into the association between health literacy and informed decision making in CRC cancer screening, future research should study the multiple aspects of informed decision making in conjunction instead of single aspects. PMID- 25733554 TI - Digital methods in epidemiology can transform disease control. PMID- 25733555 TI - Advancing digital methods in the fight against communicable diseases. AB - Important advances are being made in the fight against communicable diseases by using new digital tools. While they can be a challenge to deploy at-scale, GPS enabled smartphones, electronic dashboards and computer models have multiple benefits. They can facilitate program operations, lead to new insights about the disease transmission and support strategic planning. Today, tools such as these are used to vaccinate more children against polio in Nigeria, reduce the malaria burden in Zambia and help predict the spread of the Ebola epidemic in West Africa. PMID- 25733556 TI - Malaria genomics: tracking a diverse and evolving parasite population. AB - Malaria parasites are continually evolving to evade the immune system and human attempts to control the disease. To eliminate malaria from regions where it is deeply entrenched we need ways of monitoring what is going on in the parasite population, detecting problematic changes as soon as they arise, and executing a prompt and effective response based on a deep understanding of this natural evolutionary process. Powerful new tools to address this problem are emerging from the fast-growing field of genomic epidemiology, driven by new sequencing technologies and computational methods that allow parasite genome variation to be studied in much greater detail and in many more samples than was previously considered possible. These new tools will provide a deep understanding of what is going on in the parasite population, generating actionable knowledge for strategic planning of control interventions, for monitoring their effects and steering them for greatest impact, and for raising the alert if things start to go wrong. PMID- 25733557 TI - The promise of reverse vaccinology. AB - Reverse vaccinology (RV) is a computational approach that aims to identify putative vaccine candidates in the protein coding genome (proteome) of pathogens. RV has primarily been applied to bacterial pathogens to identify proteins that can be formulated into subunit vaccines, which consist of one or more protein antigens. An RV approach based on a filtering method has already been used to construct a subunit vaccine against Neisseria meningitidis serogroup B that is now registered in several countries (Bexsero). Recently, machine learning methods have been used to improve the ability of RV approaches to identify vaccine candidates. Further improvements related to the incorporation of epitope-binding annotation and gene expression data are discussed. In the future, it is envisaged that RV approaches will facilitate rapid vaccine design with less reliance on conventional animal testing and clinical trials in order to curb the threat of antibiotic resistance or newly emerged outbreaks of bacterial origin. PMID- 25733558 TI - Remotely measuring populations during a crisis by overlaying two data sources. AB - BACKGROUND: Societal instability and crises can cause rapid, large-scale movements. These movements are poorly understood and difficult to measure but strongly impact health. Data on these movements are important for planning response efforts. We retrospectively analyzed movement patterns surrounding a 2010 humanitarian crisis caused by internal political conflict in Cote d'Ivoire using two different methods. METHODS: We used two remote measures, nighttime lights satellite imagery and anonymized mobile phone call detail records, to assess average population sizes as well as dynamic population changes. These data sources detect movements across different spatial and temporal scales. RESULTS: The two data sources showed strong agreement in average measures of population sizes. Because the spatiotemporal resolution of the data sources differed, we were able to obtain measurements on long- and short-term dynamic elements of populations at different points throughout the crisis. CONCLUSIONS: Using complementary, remote data sources to measure movement shows promise for future use in humanitarian crises. We conclude with challenges of remotely measuring movement and provide suggestions for future research and methodological developments. PMID- 25733559 TI - Poverty, health and satellite-derived vegetation indices: their inter-spatial relationship in West Africa. AB - BACKGROUND: Previous analyses have shown the individual correlations between poverty, health and satellite-derived vegetation indices such as the normalized difference vegetation index (NDVI). However, generally these analyses did not explore the statistical interconnections between poverty, health outcomes and NDVI. METHODS: In this research aspatial methods (principal component analysis) and spatial models (variography, factorial kriging and cokriging) were applied to investigate the correlations and spatial relationships between intensity of poverty, health (expressed as child mortality and undernutrition), and NDVI for a large area of West Africa. RESULTS: This research showed that the intensity of poverty (and hence child mortality and nutrition) varies inversely with NDVI. From the spatial point-of-view, similarities in the spatial variation of intensity of poverty and NDVI were found. CONCLUSIONS: These results highlight the utility of satellite-based metrics for poverty models including health and ecological components and, in general for large scale analysis, estimation and optimisation of multidimensional poverty metrics. However, it also stresses the need for further studies on the causes of the association between NDVI, health and poverty. Once these relationships are confirmed and better understood, the presence of this ecological component in poverty metrics has the potential to facilitate the analysis of the impacts of climate change on the rural populations afflicted by poverty and child mortality. PMID- 25733560 TI - Targeting HIV services to male migrant workers in southern Africa would not reverse generalized HIV epidemics in their home communities: a mathematical modeling analysis. AB - BACKGROUND: Migrant populations such as mine workers contributed to the spread of HIV in sub-Saharan Africa. We used a mathematical model to estimate the community wide impact of targeting treatment and prevention to male migrants. METHODS: We augmented an individual-based network model, EMOD-HIV v0.8, to include an age dependent propensity for males to migrate. Migrants were exposed to HIV outside their home community, but continued to participate in HIV transmission in the community during periodic visits. RESULTS: Migrant-targeted interventions would have been transformative in the 1980s to 1990s, but post-2015 impacts were more modest. When targetable migrants comprised 2% of adult males, workplace HIV prevention averted 3.5% of community-wide infections over 20 years. Targeted treatment averted 8.5% of all-cause deaths among migrants. When migrants comprised 10% of males, workplace prevention averted 16.2% of infections in the community, one-quarter of which were among migrants. Workplace prevention and treatment acted synergistically, averting 17.1% of community infections and 11.6% of deaths among migrants. These estimates do not include prevention of secondary spread of HIV or tuberculosis at the workplace. CONCLUSIONS: Though cost effective, targeting migrants cannot collapse generalized epidemics in their home communities. Such a strategy would only have been possible prior to the early 1990s. However, migrant-targeted interventions synergize with general-population expansion of HIV services. PMID- 25733561 TI - Transmission modeling and health systems: the case of TB in India. AB - BACKGROUND: TB in India presents the challenges of a complex disease in a complex healthcare system. Mathematical models, offering a framework for capturing such complexities, have proven useful in exploring strategies for the control of TB. As the use of such techniques develops in future, it is important to understand what aspects of the healthcare system are most critical for models to faithfully capture. METHODS: We ask what type of intervention should be prioritized for the control of TB, amongst: improved diagnosis of TB per visit to a healthcare provider; improved treatment success; and increased identification of TB cases in the community? Using simple mathematical models, calibrated to the national TB epidemic in India, we explore how the relative importance of each of these interventions is affected by different assumptions for the patient pathway in careseeking, thus outlining aspects of the healthcare system that may matter most for the transmission dynamics of TB. RESULTS: We illustrate that, under a range of plausible parameter assumptions, it is possible to generate conditions under which a case-finding intervention would be prioritized over improvement of diagnosis and treatment, and vice versa. Key data needs include: the proportion of patients not contacting the healthcare system, and the mean patient delay before first seeking care. CONCLUSIONS: For mathematical models addressing strategic priorities for TB control, it is important to adequately quantify the dynamics of careseeking. We outline ways in which these data gaps may be addressed, and questions for future work. PMID- 25733562 TI - Adult vector control, mosquito ecology and malaria transmission. AB - BACKGROUND: Standard advice regarding vector control is to prefer interventions that reduce the lifespan of adult mosquitoes. The basis for this advice is a decades-old sensitivity analysis of 'vectorial capacity', a concept relevant for most malaria transmission models and based solely on adult mosquito population dynamics. Recent advances in micro-simulation models offer an opportunity to expand the theory of vectorial capacity to include both adult and juvenile mosquito stages in the model. METHODS: In this study we revisit arguments about transmission and its sensitivity to mosquito bionomic parameters using an elasticity analysis of developed formulations of vectorial capacity. RESULTS: We show that reducing adult survival has effects on both adult and juvenile population size, which are significant for transmission and not accounted for in traditional formulations of vectorial capacity. The elasticity of these effects is dependent on various mosquito population parameters, which we explore. Overall, control is most sensitive to methods that affect adult mosquito mortality rates, followed by blood feeding frequency, human blood feeding habit, and lastly, to adult mosquito population density. CONCLUSIONS: These results emphasise more strongly than ever the sensitivity of transmission to adult mosquito mortality, but also suggest the high potential of combinations of interventions including larval source management. This must be done with caution, however, as policy requires a more careful consideration of costs, operational difficulties and policy goals in relation to baseline transmission. PMID- 25733563 TI - Extracting transmission networks from phylogeographic data for epidemic and endemic diseases: Ebola virus in Sierra Leone, 2009 H1N1 pandemic influenza and polio in Nigeria. AB - BACKGROUND: Phylogeography improves our understanding of spatial epidemiology. However, application to practical problems requires choices among computational tools to balance statistical rigor, computational complexity, sensitivity to sampling strategy and interpretability. METHODS: We introduce a fast, heuristic algorithm to reconstruct partially-observed transmission networks (POTN) that combines features of phylogenetic and transmission tree approaches. We compare the transmission network generated by POTN with existing algorithms (BEAST and SeqTrack), and discuss the benefits and challenges of phylogeographic analysis on examples of epidemic and endemic diseases: Ebola virus, H1N1 pandemic influenza and polio. RESULTS: For the 2014 Sierra Leone Ebola virus outbreak and the 2009 H1N1 outbreak, all three methods provide similarly plausible transmission histories but differ in detail. For polio in northern Nigeria, we discuss performance trade-offs between the POTN and discrete phylogeography in BEAST and conclude that spatial history reconstruction is limited by under-sampling. CONCLUSIONS: POTN is complementary to available tools on densely-sampled data, fails gracefully on under-sampled data and is scalable to accommodate larger datasets. We provide further evidence for the utility of phylogeography for understanding transmission networks of rapidly evolving epidemics. We propose simple heuristic criteria to identify how sampling rates and disease dynamics interact to determine fundamental limitations of phylogeographic inference. PMID- 25733564 TI - Discovering dynamic patterns from infectious disease data using dynamic mode decomposition. AB - BACKGROUND: The development and application of quantitative methods to understand disease dynamics and plan interventions is becoming increasingly important in the push toward eradication of human infectious diseases, exemplified by the ongoing effort to stop the spread of poliomyelitis. METHODS: Dynamic mode decomposition (DMD) is a recently developed method focused on discovering coherent spatial temporal modes in high-dimensional data collected from complex systems with time dynamics. The algorithm has a number of advantages including a rigorous connection to the analysis of nonlinear systems, an equation-free architecture, and the ability to efficiently handle high-dimensional data. RESULTS: We demonstrate the method on three different infectious disease sets including Google Flu Trends data, pre-vaccination measles in the UK, and paralytic poliomyelitis wild type-1 cases in Nigeria. For each case, we describe the utility of the method for surveillance and resource allocation. CONCLUSIONS: We demonstrate how DMD can aid in the analysis of spatial-temporal disease data. DMD is poised to be an effective and efficient computational analysis tool for the study of infectious disease. PMID- 25733565 TI - Maternal alcohol intake around the time of conception causes glucose intolerance and insulin insensitivity in rat offspring, which is exacerbated by a postnatal high-fat diet. AB - Alcohol consumption throughout pregnancy can cause metabolic dysregulation, including glucose intolerance in progeny. This study determined if periconceptional (PC) alcohol (12% v/v in a liquid diet) (PC:EtOH) consumed exclusively around conception results in similar outcomes in Sprague-Dawley rats. Control (C) rats were given a liquid diet containing no alcohol but matched to ensure equal caloric intake. PC maternal alcohol intake (from 4 days before conception until day 4 of gestation), resulted in offspring with elevated fasting plasma glucose (~10-25%, P < 0.05), impaired glucose tolerance (P < 0.05), and decreased insulin sensitivity (P < 0.01) at 6 months of age. This was associated with increased hepatic gluconeogenesis and sex-specific alterations in peripheral protein kinase B (AKT) signaling. These changes were accompanied by increased mRNA expression of DNA methyltransferases (DNMTs) 1, 3a, and 3b (1.5- to 1.9 fold, P < 0.05) in fetal liver in late gestation, suggesting PC:EtOH may cause epigenetic changes that predispose offspring to metabolic dysfunction. Exposure to a postnatal (PN) high-fat and cholesterol diet (HFD) from 3 months of age caused hyperinsulinemia (~2-fold increase, P < 0.001) and exacerbated the metabolic dysfunction in male offspring exposed to PC:EtOH but had no additive effects in females. Given many women may drink alcohol while planning a pregnancy, it is crucial to increase public awareness regarding the effects of alcohol consumption around conception on offspring health. PMID- 25733566 TI - Regulation of homologous recombinational repair by lamin B1 in radiation-induced DNA damage. AB - DNA double-strand breaks (DSBs) are the major lethal lesion induced by ionizing radiation (IR). RAD51-dependent homologous recombination (HR) is one of the most important pathways in DSB repair and genome integrity maintenance. However, the mechanism of HR regulation by RAD51 remains unclear. To understand the mechanism of RAD51-dependent HR, we searched for interacting partners of RAD51 by a proteomics analysis and identified lamin B1 in human cells. Lamins are nuclear lamina proteins that play important roles in the structural organization of the nucleus and the regulation of chromosome functions. Immunoblotting analyses revealed that siRNA-mediated lamin B1 depletion repressed the DNA damage dependent increase of RAD51 after IR. The repression was abolished by the proteasome inhibitor MG132, suggesting that lamin B1 stabilizes RAD51 by preventing proteasome-mediated degradation in cells with IR-induced DNA damage. We also showed that lamin B1 depletion repressed RAD51 focus formation and decreased the survival rates after IR. On the basis of these results, we propose that lamin B1 promotes DSB repair and cell survival by maintaining the RAD51 protein levels for HR upon DSB induction after IR. PMID- 25733567 TI - ACTH controls thymocyte homeostasis independent of glucocorticoids. AB - It has been known for decades that lowering the circulating glucocorticoid (GC) concentration as in Addison's disease or after removing the adrenals results in thymus enlargement, largely due to thymocyte expansion. This has been attributed to the loss of the proapoptotic effects on thymocytes by adrenal GCs. Here, we test this concept and report that ACTH directly controls thymic growth post adrenalectomy (ADX) independent of the proapoptotic effect of GCs. This was supported by the finding that ADX caused thymus enlargement and a 1.7-fold (P < 0.001) increase in thymocyte number in GR(LckCre) mice resistant to GC-induced thymocyte apoptosis, similar to the increase seen in wild-type mice (2.2-fold; P < 0.01). We show by immunostaining that melanocortin receptor subtype 2, which selectively binds ACTH, is partly expressed on the thymic epithelium. Furthermore, ACTH in comparison to vehicle induced a 2.0-fold (P < 0.01) increase in fetal thymic organ culture thymocyte numbers in vitro and enhanced 2.2-fold (P < 0.05) the expression of delta-like ligand 4, a factor that supports T-cell development. Additionally, adrenalectomized GR(LckCre) mice treated with ACTH under conditions that repressed endogenous ACTH secretion showed increased thymocyte cellularity (1.9-fold; P < 0.01) and splenic naive T-cell numbers (2.5 fold; P < 0.001) compared to when treated with PBS. Altogether, our results show that ACTH directly controls thymocyte homeostasis independent of GCs. These results revise the old paradigm behind compensatory thymus growth following ADX, now demonstrating that ACTH has a central role in regulating thymocyte expansion when systemic GC concentration is low. PMID- 25733568 TI - An integrated biopsychosocial model of childhood maltreatment and psychosis. AB - There is now a well-established link between childhood maltreatment and psychosis. It is, however, unclear what the mechanisms are by which this occurs. Here, we propose a pathway linking the experience of childhood maltreatment with biological changes in the brain and suggest a psychological intervention to ameliorate its effects. PMID- 25733569 TI - Assessing early-onset hallucinations in the touch-screen generation. AB - The increasing development of apps for digital devices provides an opportunity for new instruments to assess hallucinations in young individuals. Here we present the Multisensory HAllucinations Scale for Children (MHASC), dedicated to assessing complex early-onset hallucinations. The MHASC will soon be translated into multilanguage versions with the support of the International Consortium of Hallucination Research. PMID- 25733570 TI - Letters, green cards, telephone calls and postcards: systematic and meta-analytic review of brief contact interventions for reducing self-harm, suicide attempts and suicide. AB - BACKGROUND: There is growing interest in brief contact interventions for self harm and suicide attempt. AIMS: To synthesise the evidence regarding the effectiveness of brief contact interventions for reducing self-harm, suicide attempt and suicide. METHOD: A systematic review and random-effects meta-analyses were conducted of randomised controlled trials using brief contact interventions (telephone contacts; emergency or crisis cards; and postcard or letter contacts). Several sensitivity analyses were conducted to examine study quality and subgroup effects. RESULTS: We found 14 eligible studies overall, of which 12 were amenable to meta-analyses. For any subsequent episode of self-harm or suicide attempt, there was a non-significant reduction in the overall pooled odds ratio (OR) of 0.87 (95% CI 0.74-1.04, P = 0119) for intervention compared with control. The number of repetitions per person was significantly reduced in intervention v. control (incidence rate ratio IRR = 066, 95% CI 0.54-0.80, P<0001). There was no significant reduction in the odds of suicide in intervention compared with control (OR = 0.58, 95% CI 0.24-1.38). CONCLUSIONS: A non-significant positive effect on repeated self-harm, suicide attempt and suicide and a significant effect on the number of episodes of repeated self-harm or suicide attempts per person (based on only three studies) means that brief contact interventions cannot yet be recommended for widespread clinical implementation. We recommend further assessment of possible benefits in well-designed trials in clinical populations. PMID- 25733571 TI - The psychiatric ward as a therapeutic space. PMID- 25733572 TI - The psychiatric ward as a therapeutic space. PMID- 25733573 TI - Author's reply. The psychiatric ward as a therapeutic space. PMID- 25733574 TI - Discharges to prison from medium secure psychiatric units. PMID- 25733575 TI - Authors' reply. Discharges to prison from medium secure psychiatric units. PMID- 25733577 TI - Cohort Profile Update: The 1982 Pelotas (Brazil) Birth Cohort Study. AB - In this manuscript, we update the profile of the 1982 Pelotas Birth Cohort Study.In 1982, 5914 live births whose families lived in the urban are of Pelotas were enrolled in the cohort. In 2012-13, we tried to locate the whole original cohort; 3701 participants were interviewed who, added to the 325 known deaths, represented a follow-up rate of 68.1%. In contrast to the previous home interviews, in this wave all participants were invited to visit the research clinic to be interviewed and examined. The visit was carried out at a mean age of 30.2 years and mainly focused on four categories of outcomes: (i) mental health; (ii) body composition; (iii) precursors of complex chronic diseases; and (iv) human capital. Requests for collaboration by outside researchers are welcome. PMID- 25733578 TI - Cohort Profile: The Shanghai Men's Health Study. AB - The Shanghai Men's Health Study (SMHS) is a population-based cohort study of 61,480 men aged 40-74 years, launched in 2002 in urban Shanghai to investigate the contribution of lifestyle/environmental factors and genetic susceptibility to cancer and other non-communicable diseases (NCDs). At baseline, trained interviewers collected detailed information on personal and dietary habits, occupational/medical history and physical activity, and took anthropometric measurements (response rate: 74%). Blood, urine and DNA were collected from 75%, 89% and 89% of participants, respectively. The cohort has been followed up through a combination of in-person surveys every 3-4 years and annual record linkage with cancer and vital statistics registries. Response rates for in-person follow-up surveys were over 91% and coverage for mortality nearly 100%. SMHS participants have a high smoking rate (58.6%) and moderate alcohol-drinking rate (29.3%), but low obesity rate (2.6%). They have a low calorie intake from fat (16.2% of total calorie intake) and protein (16.4%), high calorie intake from carbohydrates (67.4%), and high intake of soy food, cruciferous vegetables and fish (156.5, 110.6 and 51.7 g/day, respectively). With its unique exposure pattern and wealth of data and biological samples, the SMHS is well positioned for long-term research into NCD aetiology and prognosis. Information about accessing the SMHS resources can be found at: http://www.mc.vanderbilt.edu/swhs smhs/. PMID- 25733580 TI - Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. AB - Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the beta-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the beta-globin locus with minimal off-target modification. By co-delivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34(+) hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rgamma(null) mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34(+) cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers. PMID- 25733581 TI - CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells. AB - In follicular lymphoma (FL), follicular helper T cells (TFH) have been depicted as one of the main components of the malignant B-cell niche and a promising therapeutic target. Although defined by their capacity to sustain FL B-cell growth together with specific gene expression and cytokine secretion profiles, FL TFH constitute a heterogeneous cell population. However, specific markers reflecting such functional heterogeneity are still lacking. In this study, we demonstrate that CD10 identifies a subset of fully functional germinal center TFH in normal secondary lymphoid organs. Importantly, this subset is amplified in the FL context, unlike in other B-cell lymphomas with a follicular growth pattern. Furthermore, whereas FL-TFH produce high levels of interleukin (IL)-21 and low levels of IL-17 irrespectively of their CD10 expression, CD10(pos) FL-TFH specifically exhibit an IL-4(hi)IFN-gamma(lo)TNF-alpha(hi) cytokine profile associated with a high capacity to sustain directly and indirectly malignant B cell survival. Altogether, our results highlight the important role of this novel functional subset in the FL cell niche. PMID- 25733579 TI - beta2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. beta2-glycoprotein I (beta2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact beta2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize beta2GPI/HLA class II complexes in the absence of phospholipids. In situ association between beta2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against beta2GPI/HLA class II complexes mediated complement dependent cytotoxicity against cells expressing the complexes. These data suggest that beta2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis. PMID- 25733582 TI - EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. AB - Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow-derived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon regulated host responses. PMID- 25733583 TI - DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia. AB - Idiopathic CD4 lymphopenia (ICL) is a rare heterogeneous immunological syndrome of unclear etiology. ICL predisposes patients to severe opportunistic infections and frequently leads to poor vaccination effectiveness. Chronic immune activation, expansion of memory T cells, and impaired T-cell receptor (TCR) signaling have been reported in ICL, but the mechanistic and causative links remain unclear. We show that late-differentiated T cells in 20 patients with ICL displayed defective TCR responses and aging markers similar to those found in T cells from elderly subjects. Intrinsic T-cell defects were caused by increased expression of dual-specific phosphatase 4 (DUSP4). Normalization of DUSP4 expression using a specific siRNA improved CD4(+) T-cell activity in ICL, as this restored TCR-induced extracellular signal-regulated kinase activation and increased the expression of the costimulatory molecules CD27 and CD40L. Conversely, repeated TCR stimulation led to defective signaling and DUSP4 overexpression in control CD4(+) T cells. This was associated with gradual acquisition of a memory phenotype and was curtailed by DUSP4 silencing. These findings identify a premature T-cell senescence in ICL that might be caused by chronic T-cell activation and a consequential DUSP4-dependent dampening of TCR signaling. PMID- 25733584 TI - Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. AB - Treatment of vaso-occlusive crises (VOC) or events in sickle cell disease (SCD) remains limited to symptom relief with opioids. Animal models support the effectiveness of the pan-selectin inhibitor GMI-1070 in reducing selectin mediated cell adhesion and abrogating VOC. We studied GMI-1070 in a prospective multicenter, randomized, placebo-controlled, double-blind, phase 2 study of 76 SCD patients with VOC. Study drug (GMI-1070 or placebo) was given every 12 hours for up to 15 doses. Other treatment was per institutional standard of care. All subjects reached the composite primary end point of resolution of VOC. Although time to reach the composite primary end point was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P = .19 for both) were observed in the active treatment group vs the placebo group. As a secondary end point, GMI 1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P = .010). These results support a phase 3 study of GMI-1070 (now rivipansel) for SCD VOC. This trial was registered at www.clinicaltrials.gov as #NCT01119833. PMID- 25733585 TI - A novel chimeric phage lysin with high in vitro and in vivo bactericidal activity against Streptococcus pneumoniae. AB - OBJECTIVES: Streptococcus pneumoniae is becoming increasingly antibiotic resistant worldwide and new antimicrobials are urgently needed. Our aim was new chimeric phage endolysins, or lysins, with improved bactericidal activity by swapping the structural components of two pneumococcal phage lysozymes: Cpl-1 (the best lysin tested to date) and Cpl-7S. METHODS: The bactericidal effects of four new chimeric lysins were checked against several bacteria. The purified enzymes were added at different concentrations to resuspended bacteria and viable cells were measured after 1 h. Killing capacity of the most active lysin, Cpl 711, was tested in a mouse bacteraemia model, following mouse survival after injecting different amounts (25-500 MUg) of enzyme. The capacity of Cpl-711 to reduce pneumococcal biofilm formation was also studied. RESULTS: The chimera Cpl 711 substantially improved the killing activity of the parental phage lysozymes, Cpl-1 and Cpl-7S, against pneumococcal bacteria, including multiresistant strains. Specifically, 5 MUg/mL Cpl-711 killed >=7.5 log of pneumococcal R6 strain. Cpl-711 also reduced pneumococcal biofilm formation and killed 4 log of the bacterial population at 1 MUg/mL. Mice challenged intraperitoneally with D39_IU pneumococcal strain were protected by treatment with a single intraperitoneal injection of Cpl-711 1 h later, resulting in about 50% greater protection than with Cpl-1. CONCLUSIONS: Domain swapping among phage lysins allows the construction of new chimeric enzymes with high bactericidal activity and a different substrate range. Cpl-711, the most powerful endolysin against pneumococci, offers a promising therapeutic perspective for the treatment of multiresistant pneumococcal infections. PMID- 25733586 TI - Surveillance of antibiotic susceptibility of urinary tract pathogens for a population of 5.6 million over 4 years. AB - OBJECTIVES: To retrospectively analyse routine susceptibility testing data to describe antimicrobial non-susceptibility trends in isolates of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa from urine samples in a population of 5.6 million people over a 4 year period. METHODS: De-duplicated laboratory data submitted to the AmSurv surveillance system from the West Midlands region of England and results of submissions to the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit were extracted for the period 2010-13. Descriptive analysis of the non-susceptibility of selected Gram-negative organisms to key antibiotics, as recommended for monitoring in the UK Five Year Antimicrobial Resistance Strategy, was undertaken. RESULTS: During the study period, there were 431 461 reports for E. coli, 23 786 for K. pneumoniae and 6985 for P. aeruginosa from urine specimens. These represented 61%, 3% and 1%, respectively, of all organisms isolated from urine specimens. There was a linear increase in non-susceptibility to third-generation cephalosporins for E. coli and K. pneumoniae, and to ciprofloxacin for E. coli, in specimens from both hospital and community settings (P < 0.001). The proportions of E. coli and K. pneumoniae reported non-susceptible to meropenem and/or imipenem remained low during the study period, with no evidence of linear trend (P >= 0.05). CONCLUSIONS: Automated antimicrobial resistance surveillance enabled, for the first time in England, the systematic monitoring of resistance in bacteria responsible for urinary tract infections in a defined population, and thereby provided a representative indication of the burden of resistance in Gram negative bacteria in hospital and community settings. PMID- 25733588 TI - Surgeon who carried out home circumcisions is struck off UK register after "blatant disregard" for patient safety. PMID- 25733589 TI - Animals, Pictures, and Skeletons: Andreas Vesalius's Reinvention of the Public Anatomy Lesson. AB - In this paper, I examine the procedures used by Andreas Vesalius for conducting public dissections in the early sixteenth century. I point out that in order to overcome the limitations of public anatomical demonstration noted by his predecessors, Vesalius employed several innovative strategies, including the use of animals as dissection subjects, the preparation and display of articulated skeletons, and the use of printed and hand-drawn illustrations. I suggest that the examination of these three strategies for resolving the challenges of public anatomical demonstration helps us to reinterpret Vesalius's contributions to sixteenth-century anatomy. PMID- 25733587 TI - Increased systemic immune activation and inflammatory profile of long-term HIV infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity. AB - OBJECTIVES: The objective of this study was to analyse the respective roles of personal factors and HIV infection markers on the systemic immune activation/inflammatory profile of long-term antiretroviral treatment-controlled patients. PATIENTS AND METHODS: A panel of soluble immune activation/inflammatory biomarkers was measured in 352 HIV-infected treatment-controlled patients from the APROCO-COPILOTE cohort, all of whom were started on a PI in 1997-99 and had a final evaluation 11 years later, and in 59 healthy controls. RESULTS: A total of 81.5% of the patients were male, with the following characteristics: median age 49 years; 620 CD4 cells/mm(3); 756 CD8 cells/mm(3); CD4/CD8 ratio 0.81; BMI 23.0 kg/m(2); waist-to-hip ratio 0.95. Markers of inflammation-high-sensitivity (hs) IL-6 (median and IQR) (1.3 pg/L, 0.7-2.6), hs C-reactive protein (CRP) (2.1 mg/L, 0.9-4.5) and D-dimer (252 ng/mL, 177-374)-were elevated compared with healthy controls (P < 0.001) and strongly related to each other, as were markers of immune activation [soluble (s) CD14 (1356 ng/mL, 1027-1818), beta2-microglobulin (2.4 mg/L, 2.0-3.1) and cystatin-C (0.93 mg/L, 0.82-1.1)]. Inflammatory and immune activation markers were also associated with each other. In HIV-infected patients: age was related to D-dimer, beta2-microglobulin and cystatin-C levels; being a smoker was related to increased IL-6 and cystatin-C; and BMI and waist-to hip ratio were related to CRP. Conversely, markers of HIV infection, current CD4 or CD8 values, CD4 nadir, CD4/CD8 ratio, AIDS stage at initiation of PIs, current viral load and duration of ART were not associated with immune activation/inflammation markers. CONCLUSIONS: In these long-term treatment controlled HIV-infected patients, all systemic markers of inflammation and immune activation were increased compared with healthy controls. This was related to demographic and behavioural factors, but not to markers of severity of the HIV infection. Intervention to decrease low-grade inflammation must thus prioritize modifiable personal factors. PMID- 25733590 TI - Photo quiz. A painful and disfiguring lesion on the face. PMID- 25733593 TI - Supreme Court case could upend Affordable Care Act. PMID- 25733592 TI - Investigating the relationship between quality of primary care and premature mortality in England: a spatial whole-population study. AB - OBJECTIVES: To quantify the relationship between a national primary care pay-for performance programme, the UK's Quality and Outcomes Framework (QOF), and all cause and cause-specific premature mortality linked closely with conditions included in the framework. DESIGN: Longitudinal spatial study, at the level of the "lower layer super output area" (LSOA). SETTING: 32482 LSOAs (neighbourhoods of 1500 people on average), covering the whole population of England (approximately 53.5 million), from 2007 to 2012. PARTICIPANTS: 8647 English general practices participating in the QOF for at least one year of the study period, including over 99% of patients registered with primary care. INTERVENTION: National pay-for-performance programme incentivising performance on over 100 quality-of-care indicators. MAIN OUTCOME MEASURES: All-cause and cause specific mortality rates for six chronic conditions: diabetes, heart failure, hypertension, ischaemic heart disease, stroke, and chronic kidney disease. We used multiple linear regressions to investigate the relationship between spatially estimated recorded quality of care and mortality. RESULTS: All-cause and cause-specific mortality rates declined over the study period. Higher mortality was associated with greater area deprivation, urban location, and higher proportion of a non-white population. In general, there was no significant relationship between practice performance on quality indicators included in the QOF and all-cause or cause-specific mortality rates in the practice locality. CONCLUSIONS: Higher reported achievement of activities incentivised under a major, nationwide pay-for-performance programme did not seem to result in reduced incidence of premature death in the population. PMID- 25733595 TI - Black men less willing than white men to be investigated for prostate cancer. PMID- 25733594 TI - Cardiac resynchronization therapy restores sympathovagal balance in the failing heart by differential remodeling of cholinergic signaling. AB - RATIONALE: Cardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular function and reduce mortality. The underlying mechanisms are incompletely understood. Although beta-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored. OBJECTIVE: We hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and beta-adrenergic responsiveness in dyssynchronous HF that are restored by CRT. METHODS AND RESULTS: Canine tachypaced dyssynchronous HF and CRT models were generated to interrogate responses specific to dyssynchronous versus resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic, and invasive hemodynamic data were collected from normal controls, dyssynchronous HF and CRT models. Left ventricular tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (n=42-104 myocytes per model; 6-9 hearts per model). Human left ventricular myocardium was obtained for biochemical analyses from explanted failing (n=18) and nonfailing (n=7) hearts. The M2 subtype of muscarinic acetylcholine receptors was upregulated in human and canine HF compared with nonfailing controls. CRT attenuated the increased M2 subtype of muscarinic acetylcholine receptor expression and Galphai coupling and enhanced M3 subtype of muscarinic acetylcholine receptor expression in association with enhanced calcium cycling, sarcomere shortening, and beta-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both dyssynchronous HF and CRT myocytes. CONCLUSIONS: Remodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF. PMID- 25733596 TI - Umbilical clamping should be deferred to protect blood flow to newborns, recommends expert review. PMID- 25733597 TI - Doctors in India plan to launch network against corruption and unethical practices. PMID- 25733598 TI - Evaluation of Diffusion-Weighted Magnetic Resonance Imaging for Follow-up and Treatment Response Assessment of Lymphoma: Results of an 18F-FDG-PET/CT Controlled Prospective Study in 64 Patients. AB - PURPOSE: To determine the value of diffusion-weighted MRI (DWI-MRI) for treatment response assessment in 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-avid lymphoma. EXPERIMENTAL DESIGN: Patients with FDG-avid Hodgkin (HL) or non-Hodgkin lymphoma (NHL) at pretherapeutic 18F-FDG-PET/CT, who had also undergone pretherapeutic whole-body DWI-MRI, were included in this prospective study. Depending on the histologic lymphoma subtype, patients received different systemic treatment regimens, and follow-up DWI-MRI and 18F-FDG-PET/CT were performed at one or more time points, depending on the clinical course. For each follow-up DWI-MRI, region based rates of agreement, and rates of agreement in terms of treatment response (complete remission, partial remission, stable disease, or progressive disease), relative to the corresponding 18F-FDG-PET/CT, were calculated. RESULTS: Sixty four patients were included: 10 with HL, 22 with aggressive NHL, and 32 with indolent NHL. The overall region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.4%. For the 51 interim examinations (performed after 1-3 therapy cycles), region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.2%, and for the 48 end-of-treatment examinations, agreement was 99.8%. No significant differences, in terms of region-based agreement between DWI-MRI and 18F-FDG-PET/CT, were observed between the three lymphoma groups (HL, aggressive NHL, indolent NHL; P = 0.25), or between interim and end-of-treatment examinations (P = 0.21). With regard to treatment response assessment, DWI-MRI agreed with 18F-FDG-PET/CT in 99 of 102 follow-up examinations (97.1%), with a kappa value of 0.94 (P < 0.0001). CONCLUSIONS: In patients with FDG-avid lymphoma, DWI-MRI may be a feasible alternative to 18F-FDG-PET/CT for follow-up and treatment response assessment. PMID- 25733600 TI - Erratum. PMID- 25733599 TI - Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. AB - PURPOSE: Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment and also missed opportunities for curative therapy. EXPERIMENTAL DESIGN: An 8 biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish "favorable" versus "nonfavorable" pathology independently and relative to current risk classification systems National Comprehensive Cancer Network (NCCN and D'Amico). RESULTS: A favorable biomarker risk score of <=0.33, and a nonfavorable risk score of >0.80 (possible range between 0 and 1) were defined on "false-negative" and "false-positive" rates of 10% and 5%, respectively. At a risk score <=0.33, predictive values for favorable pathology in very low-risk and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for nonfavorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two coprimary endpoints, separating favorable from nonfavorable pathology (AUC, 0.68; P < 0.0001; OR, 20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65; P < 0.0001; OR, 12.95). CONCLUSIONS: The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision making following prostate biopsy. PMID- 25733601 TI - SNMMI industry forum created to work together on areas of promise. PMID- 25733602 TI - HHS announces new quality goals and strategies. PMID- 25733603 TI - Enrollment trends in technologist training. PMID- 25733604 TI - SNMMI leadership update: reaching out to develop a unified voice. PMID- 25733607 TI - JNM update for 2014. PMID- 25733608 TI - Does attention speed up processing? Decreases and increases of processing rates in visual prior entry. AB - Selective visual attention improves performance in many tasks. Among others, it leads to "prior entry"--earlier perception of an attended compared to an unattended stimulus. Whether this phenomenon is purely based on an increase of the processing rate of the attended stimulus or if a decrease in the processing rate of the unattended stimulus also contributes to the effect is, up to now, unanswered. Here we describe a novel approach to this question based on Bundesen's Theory of Visual Attention, which we use to overcome the limitations of earlier prior-entry assessment with temporal order judgments (TOJs) that only allow relative statements regarding the processing speed of attended and unattended stimuli. Prevalent models of prior entry in TOJs either indirectly predict a pure acceleration or cannot model the difference between acceleration and deceleration. In a paradigm that combines a letter-identification task with TOJs, we show that indeed acceleration of the attended and deceleration of the unattended stimuli conjointly cause prior entry. PMID- 25733609 TI - The fsr Quorum-Sensing System and Cognate Gelatinase Orchestrate the Expression and Processing of Proprotein EF_1097 into the Mature Antimicrobial Peptide Enterocin O16. AB - A novel antimicrobial peptide designated enterocin O16 was purified from Enterococcus faecalis. Mass spectrometry showed a monoisotopic mass of 7,231 Da, and N-terminal Edman degradation identified a 29-amino-acid sequence corresponding to residues 90 to 119 of the EF_1097 protein. Bioinformatic analysis showed that enterocin O16 is composed of the 68 most C-terminal residues of the EF_1097 protein. Introduction of an in-frame isogenic deletion in the ef1097 gene abolished the production of enterocin O16. Enterocin O16 has a narrow inhibitory spectrum, as it inhibits mostly lactobacilli. Apparently, E. faecalis is intrinsically resistant to the antimicrobial peptide, as no immunity connected to the production of enterocin O16 could be identified. ef1097 has previously been identified as one of three loci regulated by the fsr quorum-sensing system. The introduction of a nonsense mutation into fsrB consistently impaired enterocin O16 production, but externally added gelatinase biosynthesis-activating pheromone restored the antimicrobial activity. Functional genetic analysis showed that the EF_1097 proprotein is processed extracellularly into enterocin O16 by the metalloprotease GelE. Thus, it is evident that the fsr quorum-sensing system constitutes the regulatory unit that controls the expression of the EF_1097 precursor protein and the protease GelE and that the latter is required for the formation of enterocin O16. On the basis of these results, this study identified antibacterial antagonism as a novel aspect related to the function of fsr and provides a rationale for why ef1097 is part of the fsr regulon. IMPORTANCE: The fsr quorum-sensing system modulates important physiological functions in E. faecalis via the activity of GelE. The present study presents a new facet of fsr signaling. The system controls the expression of three primary target operons (fsrABCD, gelE-sprE, and ef1097-ef1097b). We demonstrate that the concerted expression of these operons constitutes the elements necessary for the production of a bacteriocin-type peptide and that antimicrobial antagonism is an intrinsic function of fsr. The bacteriocin enterocin O16 consists of the 68 most C-terminal residues of the EF_1097 secreted proprotein. The GelE protease processes the EF_1097 proprotein into enterocin O16. In this manner, fsr signaling enables E. faecalis populations to express antimicrobial activity in a cell density dependent manner. PMID- 25733610 TI - The Bacillus subtilis tyrZ gene encodes a highly selective tyrosyl-tRNA synthetase and is regulated by a MarR regulator and T box riboswitch. AB - Misincorporation of D-tyrosine (D-Tyr) into cellular proteins due to mischarging of tRNA(Tyr) with D-Tyr by tyrosyl-tRNA synthetase inhibits growth and biofilm formation of Bacillus subtilis. Furthermore, many B. subtilis strains lack a functional gene encoding D-aminoacyl-tRNA deacylase, which prevents misincorporation of D-Tyr in most organisms. B. subtilis has two genes that encode tyrosyl-tRNA synthetase: tyrS is expressed under normal growth conditions, and tyrZ is known to be expressed only when tyrS is inactivated by mutation. We hypothesized that tyrZ encodes an alternate tyrosyl-tRNA synthetase, expression of which allows the cell to grow when D-Tyr is present. We show that TyrZ is more selective for L-Tyr over D-Tyr than is TyrS; however, TyrZ is less efficient overall. We also show that expression of tyrZ is required for growth and biofilm formation in the presence of D-Tyr. Both tyrS and tyrZ are preceded by a T box riboswitch, but tyrZ is found in an operon with ywaE, which is predicted to encode a MarR family transcriptional regulator. Expression of tyrZ is repressed by YwaE and also is regulated at the level of transcription attenuation by the T box riboswitch. We conclude that expression of tyrZ may allow growth when excess D-Tyr is present. IMPORTANCE: Accurate protein synthesis requires correct aminoacylation of each tRNA with the cognate amino acid and discrimination against related compounds. Bacillus subtilis produces D-Tyr, an analog of L-Tyr that is toxic when incorporated into protein, during stationary phase. Most organisms utilize a D-aminoacyl-tRNA deacylase to prevent misincorporation of D Tyr. This work demonstrates that the increased selectivity of the TyrZ form of tyrosyl-tRNA synthetase may provide a mechanism by which B. subtilis prevents misincorporation of D-Tyr in the absence of a functional D-aminoacyl-tRNA deacylase gene. PMID- 25733611 TI - Identification and characterization of mutations conferring resistance to D-amino acids in Bacillus subtilis. AB - Bacteria produce d-amino acids for incorporation into the peptidoglycan and certain nonribosomally produced peptides. However, D-amino acids are toxic if mischarged on tRNAs or misincorporated into protein. Common strains of the Gram positive bacterium Bacillus subtilis are particularly sensitive to the growth inhibitory effects of D-tyrosine due to the absence of D-aminoacyl-tRNA deacylase, an enzyme that prevents misincorporation of D-tyrosine and other D amino acids into nascent proteins. We isolated spontaneous mutants of B. subtilis that survive in the presence of a mixture of D-leucine, D-methionine, D tryptophan, and D-tyrosine. Whole-genome sequencing revealed that these strains harbored mutations affecting tRNA(Tyr) charging. Three of the most potent mutations enhanced the expression of the gene (tyrS) for tyrosyl-tRNA synthetase. In particular, resistance was conferred by mutations that destabilized the terminator hairpin of the tyrS riboswitch, as well as by a mutation that transformed a tRNA(Phe) into a tyrS riboswitch ligand. The most potent mutation, a substitution near the tyrosine recognition site of tyrosyl-tRNA synthetase, improved enzyme stereoselectivity. We conclude that these mutations promote the proper charging of tRNA(Tyr), thus facilitating the exclusion of D-tyrosine from protein biosynthesis in cells that lack D-aminoacyl-tRNA deacylase. IMPORTANCE: Proteins are composed of L-amino acids. Mischarging of tRNAs with D-amino acids or the misincorporation of D-amino acids into proteins causes toxicity. This work reports on mutations that confer resistance to D-amino acids and their mechanisms of action. PMID- 25733612 TI - Positive autoregulation of mrkHI by the cyclic di-GMP-dependent MrkH protein in the biofilm regulatory circuit of Klebsiella pneumoniae. AB - Klebsiella pneumoniae is an important cause of nosocomial infections, primarily through the formation of surface-associated biofilms to promote microbial colonization on host tissues. Expression of type 3 fimbriae by K. pneumoniae facilitates surface adherence, a process strongly activated by the cyclic di-GMP (c-di-GMP)-dependent transcriptional activator MrkH. In this study, we demonstrated the critical importance of MrkH in facilitating K. pneumoniae attachment on a variety of medically relevant materials and demonstrated the mechanism by which bacteria activate expression of type 3 fimbriae to colonize these materials. Sequence analysis revealed a putative MrkH recognition DNA sequence ("MrkH box"; TATCAA) located in the regulatory region of the mrkHI operon. Mutational analysis, electrophoretic mobility shift assay, and quantitative PCR experiments demonstrated that MrkH binds to the cognate DNA sequence to autoregulate mrkHI expression in a c-di-GMP-dependent manner. A half turn deletion, but not a full-turn deletion, between the MrkH box and the -35 promoter element rendered MrkH ineffective in activating mrkHI expression, implying that a direct interaction between MrkH and RNA polymerase exists. In vivo analyses showed that residues L260, R265, N268, C269, E273, and I275 in the C-terminal domain of the RNA polymerase alpha subunit are involved in the positive control of mrkHI expression by MrkH and revealed the regions of MrkH required for DNA binding and transcriptional activation. Taken together, the data suggest a model whereby c-di-GMP-dependent MrkH recruits RNA polymerase to the mrkHI promoter to autoactivate mrkH expression. Increased MrkH production subsequently drives mrkABCDF expression when activated by c-di-GMP, leading to biosynthesis of type 3 fimbriae and biofilm formation. IMPORTANCE: Bacterial biofilms can cause persistent infections that are refractory to antimicrobial treatments. This study investigated how a commonly encountered hospital-acquired pathogen, Klebsiella pneumoniae, controls the expression of MrkH, the principal regulator of type 3 fimbriae and biofilm formation. We discovered a regulatory circuit whereby MrkH acts as a c-di-GMP-dependent transcriptional activator of both the gene cluster of type 3 fimbriae and the mrkHI operon. In this positive feedback loop, whereby MrkH activates its own production, K. pneumoniae has evolved a mechanism to ensure rapid MrkH production, expression of type 3 fimbriae, and subsequent biofilm formation under favorable conditions. Deciphering the molecular mechanisms of biofilm formation by bacterial pathogens is important for the development of innovative treatment strategies for biofilm infections. PMID- 25733613 TI - Interaction network and localization of Brucella abortus membrane proteins involved in the synthesis, transport, and succinylation of cyclic beta-1,2 glucans. AB - Cyclic beta-1,2-glucans (CbetaG) are periplasmic homopolysaccharides that play an important role in the virulence and interaction of Brucella with the host. Once synthesized in the cytoplasm by the CbetaG synthase (Cgs), CbetaG are transported to the periplasm by the CbetaG transporter (Cgt) and succinylated by the CbetaG modifier enzyme (Cgm). Here, we used a bacterial two-hybrid system and coimmunoprecipitation techniques to study the interaction network between these three integral inner membrane proteins. Our results indicate that Cgs, Cgt, and Cgm can form both homotypic and heterotypic interactions. Analyses carried out with Cgs mutants revealed that the N-terminal region of the protein (Cgs region 1 to 418) is required to sustain the interactions with Cgt and Cgm as well as with itself. We demonstrated by single-cell fluorescence analysis that in Brucella, Cgs and Cgt are focally distributed in the membrane, particularly at the cell poles, whereas Cgm is mostly distributed throughout the membrane with a slight accumulation at the poles colocalizing with the other partners. In summary, our results demonstrate that Cgs, Cgt, and Cgm form a membrane-associated biosynthetic complex. We propose that the formation of a membrane complex could serve as a mechanism to ensure the fidelity of CbetaG biosynthesis by coordinating their synthesis with the transport and modification. IMPORTANCE: In this study, we analyzed the interaction and localization of the proteins involved in the synthesis, transport, and modification of Brucella abortus cyclic beta-1,2 glucans (CbetaG), which play an important role in the virulence and interaction of Brucella with the host. We demonstrate that these proteins interact, forming a complex located mainly at the cell poles; this is the first experimental evidence of the existence of a multienzymatic complex involved in the metabolism of osmoregulated periplasmic glucans in bacteria and argues for another example of pole differentiation in Brucella. We propose that the formation of this membrane complex could serve as a mechanism to ensure the fidelity of CbetaG biosynthesis by coordinating synthesis with the transport and modification. PMID- 25733614 TI - Heterotrimeric NADH-oxidizing methylenetetrahydrofolate reductase from the acetogenic bacterium Acetobacterium woodii. AB - The methylenetetrahydrofolate reductase (MTHFR) of acetogenic bacteria catalyzes the reduction of methylene-THF, which is highly exergonic with NADH as the reductant. Therefore, the enzyme was suggested to be involved in energy conservation by reducing ferredoxin via electron bifurcation, followed by Na(+) translocation by the Rnf complex. The enzyme was purified from Acetobacterium woodii and shown to have an unprecedented subunit composition containing the three subunits RnfC2, MetF, and MetV. The stable complex contained 2 flavin mononucleotides (FMN), 23.5 +/- 1.2 Fe and 24.5 +/- 1.5 S, which fits well to the predicted six [4Fe4S] clusters in MetV and RnfC2. The enzyme catalyzed NADH:methylviologen and NADH:ferricyanide oxidoreductase activity but also methylene-tetrahydrofolate (THF) reduction with NADH as the reductant. The NADH:methylene-THF reductase activity was high (248 U/mg) and not stimulated by ferredoxin. Furthermore, reduction of ferredoxin, alone or in the presence of methylene-THF and NADH, was never observed. MetF or MetVF was not able to catalyze the methylene-THF-dependent oxidation of NADH, but MetVF could reduce methylene-THF using methyl viologen as the electron donor. The purified MTHFR complex did not catalyze the reverse reaction, the endergonic oxidation of methyl THF with NAD(+) as the acceptor, and this reaction could not be driven by reduced ferredoxin. However, addition of protein fractions made the oxidation of methyl THF to methylene-THF coupled to NAD(+) reduction possible. Our data demonstrate that the MTHFR of A. woodii catalyzes methylene-THF reduction according to the following reaction: NADH + methylene-THF -> methyl-THF + NAD(+). The differences in the subunit compositions of MTHFRs of bacteria are discussed in the light of their different functions. IMPORTANCE: Energy conservation in the acetogenic bacterium Acetobacterium woodii involves ferredoxin reduction followed by a chemiosmotic mechanism involving Na(+)-translocating ferredoxin oxidation and a Na(+)-dependent F1Fo ATP synthase. All redox enzymes of the pathway have been characterized except the methylenetetrahydrofolate reductase (MTHFR). Here we report the purification of the MTHFR of A. woodii, which has an unprecedented heterotrimeric structure. The enzyme reduces methylene-THF with NADH. Ferredoxin did not stimulate the reaction; neither was it oxidized or reduced with NADH. Since the last enzyme with a potential role in energy metabolism of A. woodii has now been characterized, we can propose a quantitative bioenergetic scheme for acetogenesis from H2 plus CO2 in the model acetogen A. woodii. PMID- 25733615 TI - Oxygen-dependent regulation of bacterial lipid production. AB - Understanding the mechanisms of lipid accumulation in microorganisms is important for several reasons. In addition to providing insight into assembly of biological membranes, lipid accumulation has important applications in the production of renewable fuels and chemicals. The photosynthetic bacterium Rhodobacter sphaeroides is an attractive organism to study lipid accumulation, as it has the ability to increase membrane production at low O2 tensions. Under these conditions, R. sphaeroides develops invaginations of the cytoplasmic membrane to increase its membrane surface area for housing of the membrane-bound components of its photosynthetic apparatus. Here we use fatty acid levels as a reporter of membrane lipid content. We show that, under low-O2 and anaerobic conditions, the total fatty acid content per cell increases 3-fold. We also find that the increases in the amount of fatty acid and photosynthetic pigment per cell are correlated as O2 tensions or light intensity are changed. To ask if lipid and pigment accumulation were genetically separable, we analyzed strains with mutations in known photosynthetic regulatory pathways. While a strain lacking AppA failed to induce photosynthetic pigment-protein complex accumulation, it increased fatty acid content under low-O2 conditions. We also found that an intact PrrBA pathway is required for low-O2-induced fatty acid accumulation. Our findings suggest a previously unknown role of R. sphaeroides transcriptional regulators in increasing fatty acid and phospholipid accumulation in response to decreased O2 tension. IMPORTANCE: Lipids serve important functions in living systems, either as structural components of membranes or as a form of carbon storage. Understanding the mechanisms of lipid accumulation in microorganisms is important for providing insight into the assembly of biological membranes and additionally has important applications in the production of renewable fuels and chemicals. In this study, we investigate the ability of Rhodobacter sphaeroides to increase membrane production at low O2 tensions in order to house its photosynthetic apparatus. We demonstrate that this bacterium has a mechanism to increase lipid content in response to decreased O2 tension and identify a transcription factor necessary for this response. This is significant because it identifies a transcriptional regulatory pathway that can increase microbial lipid content. PMID- 25733616 TI - Evidence that biosynthesis of the second and third sugars of the archaellin Tetrasaccharide in the archaeon Methanococcus maripaludis occurs by the same pathway used by Pseudomonas aeruginosa to make a di-N-acetylated sugar. AB - Methanococcus maripaludis has two surface appendages, archaella and type IV pili, which are composed of glycoprotein subunits. Archaellins are modified with an N linked tetrasaccharide with the structure Sug-1,4-beta-ManNAc3NAmA6Thr-1,4-beta GlcNAc3NAcA-1,3-beta-GalNAc, where Sug is (5S)-2-acetamido-2,4-dideoxy-5-O-methyl alpha-L-erythro-hexos-5-ulo-1,5-pyranose. The pilin glycan has an additional hexose attached to GalNAc. In this study, genes located in two adjacent, divergently transcribed operons (mmp0350-mmp0354 and mmp0359-mmp0355) were targeted for study based on annotations suggesting their involvement in biosynthesis of N-glycan sugars. Mutants carrying deletions in mmp0350, mmp0351, mmp0352, or mmp0353 were nonarchaellated and synthesized archaellins modified with a 1-sugar glycan, as estimated from Western blots. Mass spectroscopy analysis of pili purified from the Deltammp0352 strain confirmed a glycan with only GalNAc, suggesting mmp0350 to mmp0353 were all involved in biosynthesis of the second sugar (GlcNAc3NAcA). The Deltammp0357 mutant was archaellated and had archaellins with a 2-sugar glycan, as confirmed by mass spectroscopy of purified archaella, indicating a role for MMP0357 in biosynthesis of the third sugar (ManNAc3NAmA6Thr). M. maripaludis mmp0350, mmp0351, mmp0352, mmp0353, and mmp0357 are proposed to be functionally equivalent to Pseudomonas aeruginosa wbpABEDI, involved in converting UDP-N-acetylglucosamine to UDP-2,3-diacetamido-2,3-dideoxy d-mannuronic acid, an O5-specific antigen sugar. Cross-domain complementation of the final step of the P. aeruginosa pathway with mmp0357 supports this hypothesis. IMPORTANCE: This work identifies a series of genes in adjacent operons that are shown to encode the enzymes that complete the entire pathway for generation of the second and third sugars of the N-linked tetrasaccharide that modifies archaellins of Methanococcus maripaludis. This posttranslational modification of archaellins is important, as it is necessary for archaellum assembly. Pilins are modified with a different N-glycan consisting of the archaellin tetrasaccharide but with an additional hexose attached to the linking sugar. Mass spectrometry analysis of the pili of one mutant strain provided insight into how this different glycan might ultimately be assembled. This study includes a rare example of an archaeal gene functionally replacing a bacterial gene in a complex sugar biosynthesis pathway. PMID- 25733617 TI - Evolution of molybdenum nitrogenase during the transition from anaerobic to aerobic metabolism. AB - Molybdenum nitrogenase (Nif), which catalyzes the reduction of dinitrogen to ammonium, has modulated the availability of fixed nitrogen in the biosphere since early in Earth's history. Phylogenetic evidence indicates that oxygen (O2) sensitive Nif emerged in an anaerobic archaeon and later diversified into an aerobic bacterium. Aerobic bacteria that fix N2 have adapted a number of strategies to protect Nif from inactivation by O2, including spatial and temporal segregation of Nif from O2 and respiratory consumption of O2. Here we report the complement of Nif-encoding genes in 189 diazotrophic genomes. We show that the evolution of Nif during the transition from anaerobic to aerobic metabolism was accompanied by both gene recruitment and loss, resulting in a substantial increase in the number of nif genes. While the observed increase in the number of nif genes and their phylogenetic distribution are strongly correlated with adaptation to utilize O2 in metabolism, the increase is not correlated with any of the known O2 protection mechanisms. Rather, gene recruitment appears to have been in response to selective pressure to optimize Nif synthesis to meet fixed N demands associated with aerobic productivity and to more efficiently regulate Nif under oxic conditions that favor protein turnover. Consistent with this hypothesis, the transition of Nif from anoxic to oxic environments is associated with a shift from posttranslational regulation in anaerobes to transcriptional regulation in obligate aerobes and facultative anaerobes. Given that fixed nitrogen typically limits ecosystem productivity, our observations further underscore the dynamic interplay between the evolution of Earth's oxygen, nitrogen, and carbon biogeochemical cycles. IMPORTANCE: Molybdenum nitrogenase (Nif), which catalyzes the reduction of dinitrogen to ammonium, has modulated the availability of fixed nitrogen in the biosphere since early in Earth's history. Nif emerged in an anaerobe and later diversified into aerobes. Here we show that the transition of Nif from anaerobic to aerobic metabolism was accompanied by both gene recruitment and gene loss, resulting in a substantial increase in the number of nif genes. While the observed increase in the number of nif genes is strongly correlated with adaptation to utilize O2 in metabolism, the increase is not correlated with any of the known O2 protective mechanisms. Rather, gene recruitment was likely a response to more efficiently regulate Nif under oxic conditions that favor protein turnover. PMID- 25733618 TI - Mechanism for inhibition of Vibrio cholerae ToxT activity by the unsaturated fatty acid components of bile. AB - The Gram-negative curved bacillus Vibrio cholerae causes the severe diarrheal illness cholera. During host infection, a complex regulatory cascade results in production of ToxT, a DNA-binding protein that activates the transcription of major virulence genes that encode cholera toxin (CT) and toxin-coregulated pilus (TCP). Previous studies have shown that bile and its unsaturated fatty acid (UFA) components reduce virulence gene expression and therefore are likely important signals upon entering the host. However, the mechanism for the bile-mediated reduction of TCP and CT expression has not been clearly defined. There are two likely hypotheses to explain this reduction: (i) UFAs decrease DNA binding by ToxT, or (ii) UFAs decrease dimerization of ToxT. The work presented here elucidates that bile or UFAs directly affect DNA binding by ToxT. UFAs, specifically linoleic acid, can enter V. cholerae when added exogenously and are present in the cytoplasm, where they can then interact with ToxT. Electrophoretic mobility shift assays (EMSAs) with ToxT and various virulence promoters in the presence or absence of UFAs showed a direct reduction in ToxT binding to DNA, even in promoters with only one ToxT binding site. Virstatin, a synthetic ToxT inhibitor, was previously shown to reduce ToxT dimerization. Here we show that virstatin affects DNA binding only at ToxT promoters with two binding sites, unlike linoleic acid, which affects ToxT binding promoters having either one or two ToxT binding sites. This suggests a mechanism in which UFAs, unlike virstatin, do not affect dimerization but affect monomeric ToxT binding to DNA. IMPORTANCE: Vibrio cholerae must produce the major virulence factors cholera toxin (CT) and toxin-coregulated pilus (TCP) to cause cholera. CT and TCP production depends on ToxT, the major virulence transcription activator. ToxT activity is negatively regulated by unsaturated fatty acids (UFAs) present in the lumen of the upper small intestine. This study investigated the mechanism for inhibition of ToxT activity by UFAs and found that UFAs directly reduce specific ToxT binding to DNA at virulence promoters and subsequently reduce virulence gene expression. UFAs inhibit ToxT monomers from binding DNA. This differs from the inhibitory mechanism of a synthetic ToxT inhibitor, virstatin, which inhibits ToxT dimerization. Understanding the mechanisms for inhibition of virulence could lead to better cholera therapeutics. PMID- 25733619 TI - Identification of the linkage between A-polysaccharide and the core in the A lipopolysaccharide of Porphyromonas gingivalis W50. AB - Porphyromonas gingivalis synthesizes two lipopolysaccharides (LPSs), O-LPS and A LPS. The structure of the core oligosaccharide (OS) of O-LPS and the attachment site of the O-polysaccharide (O-PS) repeating unit [ -> 3)-alpha-D-Galp-(1 -> 6) alpha-D-Glcp-(1 -> 4)-alpha-L-Rhap-(1 -> 3)-beta-D-GalNAcp-(1 -> ] to the core have been elucidated using the DeltaPG1051 (WaaL, O-antigen ligase) and DeltaPG1142 (Wzy, O-antigen polymerase) mutant strains, respectively. The core OS occurs as an "uncapped" glycoform devoid of O-PS and a "capped" glycoform that contains the attachment site of O-PS via beta-d-GalNAc at position O-3 of the terminal alpha-(1 -> 3)-linked mannose (Man) residue. In this study, the attachment site of A-PS to the core OS was determined based on structural analysis of SR-type LPS (O-LPS and A-LPS) isolated from a P. gingivalis DeltaPG1142 mutant strain by extraction with aqueous hot phenol to minimize the destruction of A-LPS. Application of one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy in combination with methylation analysis showed that the A-PS repeating unit is linked to a nonterminal alpha-(1 -> 3)-linked Man of the "capped core" glycoform of outer core OS at position O-4 via a -> 6)-[alpha-D Man-alpha-(1 -> 2)-alpha-D-Man-1-phosphate -> 2]-alpha-D-Man-(1 -> motif. In order to verify that O-PS and A-PS are attached to almost identical core glycoforms, we identified a putative alpha-mannosyltransferase (PG0129) in P. gingivalis W50 that may be involved in the formation of core OS. Inactivation of PG0129 led to the synthesis of deep-R-type LPS with a truncated core that lacks alpha-(1 -> 3)-linked mannoses and is devoid of either O-PS or A-PS. This indicated that PG0129 is an alpha-1,3-mannosyltransferase required for synthesis of the outer core regions of both O-LPS and A-LPS in P. gingivalis. IMPORTANCE: Porphyromonas gingivalis, a Gram-negative anaerobe, is considered to be an important etiologic agent in periodontal disease, and among the virulence factors produced by the organism are two lipopolysaccharides (LPSs), O-LPS and A-LPS. The structures of the O-PS and A-PS repeating units, the core oligosaccharide (OS), and the linkage of the O-PS repeating unit to the core OS in O-LPS have been elucidated by our group. It is important to establish whether the attachment site of the A-PS repeating unit to the core OS in A-LPS is similar to or differs from that of the O-PS repeating unit in O-LPS. As part of understanding the biosynthetic pathway of the two LPSs in P. gingivalis, PG0129 was identified as an alpha-mannosyltransferase that is involved in the synthesis of the outer core regions of both O-LPS and A-LPS. PMID- 25733620 TI - Sociality in Escherichia coli: Enterochelin Is a Private Good at Low Cell Density and Can Be Shared at High Cell Density. AB - Many bacteria produce secreted iron chelators called siderophores, which can be shared among cells with specific siderophore uptake systems regardless of whether the cell produces siderophores. Sharing secreted products allows freeloading, where individuals use resources without bearing the cost of production. Here we show that the Escherichia coli siderophore enterochelin is not evenly shared between producers and nonproducers. Wild-type Escherichia coli grows well in low iron minimal medium, and an isogenic enterochelin synthesis mutant (DeltaentF) grows very poorly. The enterochelin mutant grows well in low-iron medium supplemented with enterochelin. At high cell densities the DeltaentF mutant can compete equally with the wild type in low-iron medium. At low cell densities the DeltaentF mutant cannot compete. Furthermore, the growth rate of the wild type is unaffected by cell density. The wild type grows well in low-iron medium even at very low starting densities. Our experiments support a model where at least some enterochelin remains associated with the cells that produce it, and the cell associated enterochelin enables iron acquisition even at very low cell density. Enterochelin that is not retained by producing cells at low density is lost to dilution. At high cell densities, cell-free enterochelin can accumulate and be shared by all cells in the group. Partial privatization is a solution to the problem of iron acquisition in low-iron, low-cell-density habitats. Cell-free enterochelin allows for iron scavenging at a distance at higher population densities. Our findings shed light on the conditions under which freeloaders might benefit from enterochelin uptake systems. IMPORTANCE: Sociality in microbes has become a topic of great interest. One facet of sociality is the sharing of secreted products, such as the iron-scavenging siderophores. We present evidence that the Escherichia coli siderophore enterochelin is relatively inexpensive to produce and is partially privatized such that it can be efficiently shared only at high producer cell densities. At low cell densities, cell-free enterochelin is scarce and only enterochelin producers are able to grow in low-iron medium. Because freely shared products can be exploited by freeloaders, this partial privatization may help explain how enterochelin production is stabilized in E. coli and may provide insight into when enterochelin is available for freeloaders. PMID- 25733622 TI - Predicting therapeutic weight loss. PMID- 25733621 TI - Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay. AB - A high-throughput phenotypic screen based on a Citrobacter freundii AmpC reporter expressed in Escherichia coli was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization of sulfonyl piperazine and pyrazole compounds, each with novel mechanisms of action. E. coli mutants resistant to these compounds display no cross-resistance to antibiotics of other classes. Resistance to the sulfonyl piperazine maps to LpxH, which catalyzes the fourth step in the synthesis of lipid A, the outer membrane anchor of lipopolysaccharide (LPS). To our knowledge, this compound is the first reported inhibitor of LpxH. Resistance to the pyrazole compound mapped to mutations in either LolC or LolE, components of the essential LolCDE transporter complex, which is required for trafficking of lipoproteins to the outer membrane. Biochemical experiments with E. coli spheroplasts showed that the pyrazole compound is capable of inhibiting the release of lipoproteins from the inner membrane. Both of these compounds have significant promise as chemical probes to further interrogate the potential of these novel cell wall components for antimicrobial therapy. IMPORTANCE: The prevalence of antibacterial resistance, particularly among Gram-negative organisms, signals a need for novel antibacterial agents. A phenotypic screen using AmpC as a sensor for compounds that inhibit processes involved in Gram-negative envelope biogenesis led to the identification of two novel inhibitors with unique mechanisms of action targeting Escherichia coli outer membrane biogenesis. One compound inhibits the transport system for lipoprotein transport to the outer membrane, while the other compound inhibits synthesis of lipopolysaccharide. These results indicate that it is still possible to uncover new compounds with intrinsic antibacterial activity that inhibit novel targets related to the cell envelope, suggesting that the Gram negative cell envelope still has untapped potential for therapeutic intervention. PMID- 25733623 TI - Babies with big appetites: do genes influence infant food reward? PMID- 25733624 TI - Cocoa flavanols and cognition: regaining chocolate in old age? PMID- 25733625 TI - Are the recent secular increases in the waist circumference of adults independent of changes in BMI? AB - BACKGROUND: Several studies showed that the waist circumference of US adults has increased over the past 25 y. However, because of the high correlation between waist circumference and body mass index (BMI; in kg/m2) (r ~ 0.9), it is uncertain if these trends in waist circumference exceed those expected on the basis of BMI changes over this time period. OBJECTIVE: We assessed whether the recent trend in waist circumference was independent of changes in BMI, age, and race-ethnicity. DESIGN: We analyzed data from the 1999-2000 through 2011-2012 cycles of the NHANES. RESULTS: The mean waist circumference increased by ~2 cm (in men) and ~4 cm (in women) in adults in the United States over this 12-y period. In men, this increase was very close to what would be expected because of the 0.7 increase in mean BMI over this period. However, in women, most of the secular increase in waist circumference appeared to be independent of changes in BMI (mean: 0.6), age, and race-ethnicity over the 12-y period. We estimated that, independent of changes in these covariates, the mean waist circumference increased by 0.2 cm in men and 2.4 cm in women from 1999-2000 through 2011-2012; only the latter estimate was statistically significant. CONCLUSIONS: Our results indicate that, in women but not men, the recent secular trend in waist circumference is greater than what would be expected on the basis of changes in BMI. Possible reasons for this secular increase, along with sex differences, are uncertain. PMID- 25733626 TI - Lathosterol-to-cholesterol ratio in serum predicts cholesterol-lowering response to plant sterol consumption in a dual-center, randomized, single-blind placebo controlled trial. AB - BACKGROUND: Benefits of plant sterols (PS) for cholesterol lowering are compromised by large variability in efficacy across individuals. High fractional cholesterol synthesis measured by deuterium incorporation has been associated with nonresponse to PS consumption; however, prospective studies that show this association have yet to be conducted. OBJECTIVE: The goal was to test whether the lathosterol-to-cholesterol ratio (L:C ratio), a surrogate marker of endogenous cholesterol synthesis, serves as an a priori predictor of cholesterol lowering in response to PS consumption. DESIGN: Sixty-three mildly hypercholesterolemic adults who were preselected as possessing either high endogenous cholesterol synthesis [HS; n = 24; L:C = 2.03 +/- 0.39 MUmol/mmol (mean +/- SD)] or low endogenous cholesterol synthesis (LS; n = 39; L:C = 0.99 +/- 0.28 MUmol/mmol) on the basis of baseline L:C consumed 2 g PS/d or a placebo for 28 d with the use of a dual-center, single-blind, randomized crossover design. Plasma lipid and noncholesterol sterol concentrations were measured at the end of each phase. RESULTS: PS consumption lowered total cholesterol (TC; -0.25 +/- 0.05 mmol/L; P < 0.0001) and LDL cholesterol (-0.17 +/- 0.04 mmol/L; P < 0.0001) overall. Specifically, LS individuals responded to PS treatment with a reduction in TC ( 0.40 +/- 0.07 mmol/L; P < 0.0001) and LDL cholesterol (-0.29 +/- 0.05 mmol/L; P = 0.0002), whereas HS individuals failed to show cholesterol lowering (TC: -0.09 +/ 0.09 mmol/L; P = 0.2843; LDL cholesterol: -0.05 +/- 0.07 mmol/L; P = 0.4917). The odds of LS participants responding to PS consumption with cholesterol lowering better than the mean cholesterol lowering in all participants were 4.25 (95% CI: 1.242, 14.556; P = 0.0211) for TC and 3.36 (95% CI: 1.112, 10.161; P = 0.0317) for LDL cholesterol, which was higher than for HS participants. CONCLUSIONS: The L:C ratio predicts the extent of reduction in circulating TC and LDL cholesterol in response to PS consumption. Cholesterol synthesis assessment may thus have a use in identifying responders and nonresponders to PS therapy. PMID- 25733627 TI - Is complying with the recommendations of sodium intake beneficial for health in individuals at high cardiovascular risk? Findings from the PREDIMED study. AB - BACKGROUND: Excess sodium intake is associated with high blood pressure, a major risk factor for cardiovascular disease (CVD). It is unknown whether decreasing sodium intake to <2300 mg/d has an effect on CVD or all-cause mortality. OBJECTIVE: The objective was to assess whether reductions in sodium intake to <2300 mg/d were associated with either an increased or a decreased risk of fatal and nonfatal CVD and all-cause mortality. DESIGN: This observational prospective study of the PREvencion con DIeta MEDiterranea (PREDIMED) trial included 3982 participants at high CVD risk. Sodium intake was evaluated with a validated food frequency questionnaire and categorized as low (<1500 mg/d), intermediate (>=1500 to <=2300 mg/d), high (>2300 to <=3400 mg/d), or very high (>3400 mg/d). Subsequently, 1-y and 3-y changes in sodium intake were calculated. Multivariate relative risks were assessed by using Cox proportional hazards ratios. Marginal structural models with inverse probability weighting were used to test the effect of changes in sodium intake and the Mediterranean diet (MedDiet). RESULTS: We documented 125 CVD events and 131 deaths after a 4.8-y median follow-up. Sodium intake <2300 mg/d was associated with a lower risk of all-cause mortality: 48% (HR: 0.52; 95% CI: 0.30, 0.91; P = 0.02) and 49% (HR: 0.51; 95% CI: 0.26, 0.98; P = 0.04) after 1 and 3 y, respectively. Increasing sodium intake after 1 y was associated with a 72% (HR: 1.72; 95% CI: 1.01, 2.91; P = 0.04) higher risk of CVD events. The incidence rate of CVD was reduced for those who reduced their sodium intake and were randomly assigned to MedDiet interventions [4.1/10,000 (95% CI: 3.1, 8.0) compared with 4.4/10,000 (95% CI: 2.7, 12.4) person-years; P = 0.002]. CONCLUSIONS: Decreasing sodium intake to <2300 mg/d was associated with a reduced risk of all-cause mortality, whereas increasing the intake to >2300 mg/d was associated with a higher risk of CVD. Our observational data suggest that sodium intake <2300 mg/d was associated with an enhanced beneficial effect of the MedDiet on CVD. These results should be interpreted with caution, and other confirmatory studies are necessary. PMID- 25733628 TI - Predicting successful long-term weight loss from short-term weight-loss outcomes: new insights from a dynamic energy balance model (the POUNDS Lost study). AB - BACKGROUND: Currently, early weight-loss predictions of long-term weight-loss success rely on fixed percent-weight-loss thresholds. OBJECTIVE: The objective was to develop thresholds during the first 3 mo of intervention that include the influence of age, sex, baseline weight, percent weight loss, and deviations from expected weight to predict whether a participant is likely to lose 5% or more body weight by year 1. DESIGN: Data consisting of month 1, 2, 3, and 12 treatment weights were obtained from the 2-y Preventing Obesity Using Novel Dietary Strategies (POUNDS Lost) intervention. Logistic regression models that included covariates of age, height, sex, baseline weight, target energy intake, percent weight loss, and deviation of actual weight from expected were developed for months 1, 2, and 3 that predicted the probability of losing <5% of body weight in 1 y. Receiver operating characteristic (ROC) curves, area under the curve (AUC), and thresholds were calculated for each model. The AUC statistic quantified the ROC curve's capacity to classify participants likely to lose <5% of their body weight at the end of 1 y. The models yielding the highest AUC were retained as optimal. For comparison with current practice, ROC curves relying solely on percent weight loss were also calculated. RESULTS: Optimal models for months 1, 2, and 3 yielded ROC curves with AUCs of 0.68 (95% CI: 0.63, 0.74), 0.75 (95% CI: 0.71, 0.81), and 0.79 (95% CI: 0.74, 0.84), respectively. Percent weight loss alone was not better at identifying true positives than random chance (AUC <=0.50). CONCLUSIONS: The newly derived models provide a personalized prediction of long-term success from early weight-loss variables. The predictions improve on existing fixed percent-weight-loss thresholds. Future research is needed to explore model application for informing treatment approaches during early intervention. PMID- 25733629 TI - Effectiveness in improving knowledge, practices, and intakes of "key problem nutrients" of a complementary feeding intervention developed by using linear programming: experience in Lombok, Indonesia. AB - BACKGROUND: Complementary feeding recommendations (CFRs) with the use of locally available foods can be developed by using linear programming (LP). Although its potential has been shown for planning phases of food-based interventions, the effectiveness in the community setting has not been tested to our knowledge. OBJECTIVE: We aimed to assess effectiveness of promoting optimized CFRs for improving maternal knowledge, feeding practices, and child intakes of key problem nutrients (calcium, iron, niacin, and zinc). DESIGN: A community-intervention trial with a quasi-experimental design was conducted in East Lombok, West Nusa Tenggara Province, Indonesia, on children aged 9-16 mo at baseline. A CFR group (n = 240) was compared with a non-CFR group (n = 215). The CFRs, which were developed using LP, were promoted in an intervention that included monthly cooking sessions and weekly home visits. The mother's nutrition knowledge and her child's feeding practices and the child's nutrient intakes were measured before and after the 6-mo intervention by using a structured interview, 24-h recall, and 1-wk food-frequency questionnaire. RESULTS: The CFR intervention improved mothers' knowledge and children's feeding practices and improved children's intakes of calcium, iron, and zinc. At the end line, median (IQR) nutrient densities were significantly higher in the CFR group than in the non-CFR group for iron [i.e., 0.6 mg/100 kcal (0.4-0.8 mg/100 kcal) compared with 0.5 mg/100 kcal (0.4-0.7 mg/100 kcal)] and niacin [i.e., 0.8 mg/100 kcal (0.5-1.0 mg/100 kcal) compared with 0.6 mg/100 kcal (0.4-0.8 mg/100 kcal)]. However, median nutrient densities for calcium, iron, niacin, and zinc in the CFR group (23, 0.6, 0.7, and 0.5 mg/100 kcal, respectively) were still below desired densities (63, 1.0, 0.9, and 0.6 mg/100 kcal, respectively). CONCLUSIONS: The CFRs significantly increased intakes of calcium, iron, niacin, and zinc, but nutrient densities were still below desired nutrient densities. When the adoption of optimized CFRs is constrained by economic access for or acceptability of nutrient-dense foods, other strategies need to be incorporated into interventions to ensure adequate intakes of these nutrients. PMID- 25733630 TI - In Ivorian school-age children, infection with hookworm does not reduce dietary iron absorption or systemic iron utilization, whereas afebrile Plasmodium falciparum infection reduces iron absorption by half. AB - BACKGROUND: In sub-Saharan Africa, parasitic diseases and low bioavailable iron intake are major causes of anemia. Anemia results from inflammation, preventing iron recycling and decreasing dietary iron absorption. Hookworm, Plasmodium, and Schistosoma infections contribute to anemia, but their influence on dietary iron absorption and recycling is unknown. OBJECTIVE: The objective was to measure inflammation biomarkers, hepcidin, iron absorption, and utilization pre- and posttreatment in children with afebrile malaria, hookworm, and Schistosoma haematobium infection. DESIGN: Ivorian children aged 11-17 y with afebrile Plasmodium falciparum (n = 17), hookworm (n = 16), or S. haematobium infection (n = 8) consumed a syrup containing 3 mg 57Fe as ferrous sulfate and received an intravenous infusion of 50 MUg 58Fe as ferrous citrate. Children were treated for their respective infection, and the iron studies were repeated 4 wk later. Iron and inflammation biomarkers and hepcidin were measured. RESULTS: Geometric mean iron absorptions in the afebrile malaria and hookworm groups were 12.9% and 32.2% (P < 0.001) before treatment and 23.6% and 30.0% (P = 0.113) after treatment, respectively. Treatment of afebrile malaria reduced inflammation (P < 0.001) and serum hepcidin (P = 0.004) and improved iron absorption (P = 0.003). Treatment of hookworm infection neither affected inflammation biomarkers nor altered iron absorption. Similarly, there was a lack of treatment effects in the S. haematobium-infected group; however, the small sample size limits conclusions. Geometric mean iron utilization ranged between 79.1% and 88.0% in the afebrile malaria and hookworm groups with no significant differences pre- and posttreatment. CONCLUSIONS: In school-age children, hookworm infection does not produce inflammation or increase serum hepcidin, and it does not influence iron absorption or utilization. In contrast, afebrile malaria causes inflammation, increases hepcidin, and reduces iron absorption but not utilization. These findings provide insights into the iron metabolism and the etiology of anemia in parasitic infections. PMID- 25733631 TI - A metabolomics approach to the identification of biomarkers of sugar-sweetened beverage intake. AB - BACKGROUND: The association between sugar-sweetened beverages (SSBs) and health risks remains controversial. To clarify proposed links, reliable and accurate dietary assessment methods of food intakes are essential. OBJECTIVE: The aim of this present work was to use a metabolomics approach to identify a panel of urinary biomarkers indicative of SSB consumption from a national food consumption survey and subsequently validate this panel in an acute intervention study. DESIGN: Heat map analysis was performed to identify correlations between 1H nuclear magnetic resonance (NMR) spectral regions and SSB intakes in participants of the National Adult Nutrition Survey (n = 565). Metabolites were identified and receiver operating characteristic (ROC) analysis was performed to assess sensitivity and specificity of biomarkers. The panel of biomarkers was validated in an acute study (n = 10). A fasting first-void urine sample and postprandial samples (2, 4, 6 h) were collected after SSB consumption. After NMR spectroscopic profiling of the urine samples, multivariate data analysis was applied. RESULTS: A panel of 4 biomarkers-formate, citrulline, taurine, and isocitrate-were identified as markers of SSB intake. This panel of biomarkers had an area under the curve of 0.8 for ROC analysis and a sensitivity and specificity of 0.7 and 0.8, respectively. All 4 biomarkers were identified in the SSB sample. After acute consumption of an SSB drink, all 4 metabolites increased in the urine. CONCLUSIONS: The present metabolomics-based strategy proved to be successful in the identification of SSB biomarkers. Future work will ascertain how to translate this panel of markers for use in nutrition epidemiology. PMID- 25733632 TI - Comparison of appetite responses to high- and low-glycemic index postexercise meals under matched insulinemia and fiber in type 1 diabetes. AB - BACKGROUND: Patients with type 1 diabetes face heightened risk of hypoglycemia after exercise. Subsequent overfeeding, as a preventative measure against hypoglycemia, negates the energy deficit after exercise. Patients are also required to reduce the insulin dose administered with postexercise foods to further combat hypoglycemia. However, the insulin dose is dictated solely by the carbohydrate content, even though postprandial glycemia is vastly influenced by glycemic index (GI). With a need to control the postexercise energy balance, appetite responses after meals differing in GI are of particular interest. OBJECTIVES: We assessed the appetite response to low-glycemic index (LGI) and high-glycemic index (HGI) postexercise meals in type 1 diabetes patients. This assessment also offered us the opportunity to evaluate the influence of GI on appetite responses independently of insulinemia, which confounds findings in individuals without diabetes. DESIGN: Ten physically active men with type 1 diabetes completed 2 trials in a randomized crossover design. After 45 min of treadmill exercise at 70% of the peak oxygen uptake, participants consumed an LGI (GI ~37) or HGI (GI ~92) meal with a matched macronutrient composition, negligible fiber content, and standardized insulin-dose administration. The postprandial appetite response was determined for 180 min postmeal. During this time, circulating glucose, insulin, glucagon, and glucagon-like peptide-1 (GLP-1) concentrations and subjective appetite ratings were determined. RESULTS: The HGI meal produced an ~60% greater postprandial glucose area under the curve (AUC) than did the LGI meal (P = 0.008). Insulin, glucagon, and GLP-1 did not significantly differ between trials (P > 0.05). The fullness AUC was ~25% greater after the HGI meal than after the LGI meal (P < 0.001), whereas hunger sensations were ~9% lower after the HGI meal than after the LGI meal (P = 0.001). CONCLUSION: Under conditions of matched insulinemia and fiber, an HGI postexercise meal suppresses feelings of hunger and augments postprandial fullness sensations more so than an otherwise equivalent LGI meal in type 1 diabetes patients. PMID- 25733633 TI - Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial. AB - BACKGROUND: Muscle weakness and fatigue are common symptoms in multiple sclerosis (MS). Green tea catechins such as (-)epigallocatechin-3-gallate (EGCG) are known to improve energy metabolism at rest and during exercise. OBJECTIVE: We tested the hypothesis that EGCG improves energy metabolism and substrate utilization in patients with MS. DESIGN: Eighteen patients (8 men) with relapsing-remitting MS (expanded disability status scale score <4.5, all receiving glatiramer acetate) participated in this randomized, double-blind, placebo-controlled, crossover trial at a clinical research center. All patients received EGCG (600 mg/d) and placebo over 12 wk (4-wk washout in between). After each intervention, fasting and postprandial energy expenditure (EE), as well as fat oxidation (FAOx) and carbohydrate oxidation (CHOx) rates, were measured either at rest or during 40 min of exercise (0.5 W/kg). At rest, blood samples and microdialysates from adipose tissue and skeletal muscle were also taken. RESULTS: At rest, postprandial EE and CHOx, as well as adipose tissue perfusion and glucose supply, were significantly lower in men but higher in women receiving EGCG compared with placebo. During exercise, postprandial EE was lower after EGCG than after placebo, indicating an increased working efficiency (men > women). After placebo, exercise EE was mainly fueled by FAOx in both men and women. After EGCG, there was a shift to a higher and more stable CHOx during exercise in men but not in women. CONCLUSIONS: Our data indicate that EGCG given to patients with MS over 12 wk improves muscle metabolism during moderate exercise to a greater extent in men than in women, possibly because of sex-specific effects on autonomic and endocrine control. PMID- 25733634 TI - Effect of protein overfeeding on energy expenditure measured in a metabolic chamber. AB - BACKGROUND: Energy expenditure (EE) increases with overfeeding, but it is unclear how rapidly this is related to changes in body composition, increased body weight, or diet. OBJECTIVE: The objective was to quantify the effects of excess energy from fat or protein on energy expenditure of men and women living in a metabolic chamber. DESIGN: We conducted a randomized controlled trial in 25 participants who ate ~40% excess energy for 56 d from 5%, 15%, or 25% protein diets. Twenty-four-hour EE (24EE) and sleeping EE (SleepEE) were measured on days 1, 14, and 56 of overfeeding and on day 57 while consuming the baseline diet (usually day 57). Metabolic and molecular markers of muscle metabolism were measured in skeletal muscle biopsy specimens. RESULTS: In the low-protein diet group whose excess energy was fat, the 24EE and SleepEE did not increase during the first day of overfeeding. When extra energy contained protein, both 24EE and SleepEE increased in relation to protein intake (r = 0.50, P = 0.02). The 24EE over 8 wk in all 3 groups was correlated with protein intake (r = 0.60, P = 0.004) but not energy intake (r = 0.16; P = 0.70). SleepEE was unchanged by overfeeding in the low-protein diet group, and baseline surface area predicted increased 24EE in this group. Protein and fat oxidation were reciprocally related during overfeeding. Observed 24EE was higher than predicted on days 1 (P <= 0.05), 14 (P = 0.0001), and 56 (P = 0.0007). There was no relation between change in fat mass and change in EE. CONCLUSIONS: Excess energy, as fat, does not acutely increase 24EE, which rises slowly as body weight increases. Excess energy as protein acutely stimulates 24EE and SleepEE. The strongest relation with change in 24EE was the change in energy expenditure in tissue other than muscle or fat-free mass. PMID- 25733635 TI - Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults. AB - BACKGROUND: Research indicates that the chronic consumption of flavonoids is associated with cognitive benefits in adults with mild cognitive impairment and neurodegenerative disease, although to our knowledge, there have been no such studies in healthy older adults. Furthermore, the effects of commonly consumed orange juice flavanones on cognitive function remain unexplored. OBJECTIVE: We investigated whether 8 wk of daily flavanone-rich orange juice consumption was beneficial for cognitive function in healthy older adults. DESIGN: High-flavanone (305 mg) 100% orange juice and an equicaloric low-flavanone (37 mg) orange flavored cordial (500 mL) were consumed daily for 8 wk by 37 healthy older adults (mean age: 67 y) according to a crossover, double-blind, randomized design separated by a 4-wk washout. Cognitive function, mood, and blood pressure were assessed at baseline and follow-up by using standardized validated tests. RESULTS: Global cognitive function was significantly better after 8-wk consumption of flavanone-rich juice than after 8-wk consumption of the low flavanone control. No significant effects on mood or blood pressure were observed. CONCLUSIONS: Chronic daily consumption of flavanone-rich 100% orange juice over 8 wk is beneficial for cognitive function in healthy older adults. The potential for flavanone-rich foods and drinks to attenuate cognitive decline in aging and the mechanisms that underlie these effects should be investigated. PMID- 25733636 TI - Origins of food reinforcement in infants. AB - BACKGROUND: Rapid weight gain in infancy is associated with a higher risk of obesity in children and adults. A high relative reinforcing value of food is cross-sectionally related to obesity; lean children find nonfood alternatives more reinforcing than do overweight/obese children. However, to our knowledge, there is no research on how and when food reinforcement develops. OBJECTIVE: This study was designed to assess whether the reinforcing value of food and nonfood alternatives could be tested in 9- to 18-mo-old infants and whether the reinforcing value of food and nonfood alternatives is differentially related to infant weight status. DESIGN: Reinforcing values were assessed by using absolute progressive ratio schedules of reinforcement, with presentation of food and nonfood alternatives counterbalanced in 2 separate studies. Two nonfood reinforcers [Baby Einstein-Baby MacDonald shows (study 1, n = 27) or bubbles (study 2, n = 30)] were tested against the baby's favorite food. Food reinforcing ratio (FRR) was quantified by measuring the reinforcing value of food (Food Pmax) in proportion to the total reinforcing value of food and a nonfood alternative (DVD Pmax or BUB Pmax). RESULTS: Greater weight-for-length z score was associated with a greater FRR of a favorite food in study 1 (FRR-DVD) (r = 0.60, P < 0.001) and FRR of a favorite food in study 2 (FRR-BUB) (r = 0.49, P = 0.006), primarily because of the strong association between greater weight-for-length z score and lower DVD Pmax (r = -0.71, P < 0.0001) and BUB Pmax (r = -0.53, P = 0.003). Infant monthly weight gain was positively associated with FRR-DVD (r = 0.57, P = 0.009) and FRR-BUB (r = 0.37, P = 0.047). CONCLUSIONS: Our newly developed paradigm, which tested 2 different nonfood alternatives, demonstrated that lean infants find nonfood alternatives more reinforcing than do overweight/obese infants. This observation suggests that strengthening the alternative reinforcers may have a protective effect against childhood obesity. PMID- 25733637 TI - Association of cesarean delivery with anemia in infants and children in 2 large longitudinal Chinese birth cohorts. AB - BACKGROUND: Cesarean delivery may reduce placental-fetal transfusion and thus increase the risk of early childhood anemia compared with vaginal delivery, but this notion has not been carefully studied in longitudinal cohorts. OBJECTIVE: The aim was to assess the association of cesarean delivery with anemia in infants and children in 2 longitudinal Chinese birth cohorts from different socioeconomic settings. DESIGN: Cohort 1 was recruited from 5 counties in northeastern China and cohort 2 from 21 counties or cities in southeastern China. Cohort 1 involved 17,423 infants born during 2006-2009 to mothers with early pregnancy baseline hemoglobin concentrations ranging from 100 to 177 g/L, whereas cohort 2 involved 122,777 children born during 1993-1996 to mothers with baseline hemoglobin concentrations ranging from 60 to 190 g/L. The main outcomes were anemia at 6 and 12 mo in cohort 1 and at 58 mo in cohort 2. Multiple logistic regressions were used to estimate adjusted ORs of anemia for cesarean compared with vaginal delivery. Stratified analyses were performed by pre- and postlabor cesarean delivery and according to maternal baseline hemoglobin concentration (<=109, 110 119, 120-129, and >=130 g/L). RESULTS: Cesarean delivery was not associated with anemia at 6 mo in cohort 1 (adjusted OR: 1.05; 95% CI: 0.93, 1.19); however, cesarean delivery was associated with increased anemia at 12 mo in cohort 1 (adjusted OR: 1.19; 95% CI: 1.04, 1.37) and at 58 mo in cohort 2 (adjusted OR: 1.11; 95% CI: 1.08, 1.15). The positive associations for anemia at 12 and 58 mo were consistent across maternal hemoglobin subgroups and persisted for cesarean delivery subtypes. CONCLUSION: Cesarean delivery is likely associated with anemia in children, which suggests a possible need for exploring changes in obstetric care that might prevent anemia in cesarean-delivered children. PMID- 25733638 TI - Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles. AB - BACKGROUND: Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs) but also contains the neurotoxicant methyl mercury (MeHg). PUFAs may modify the relation between prenatal MeHg exposure and child development either directly by enhancing neurodevelopment or indirectly through the inflammatory milieu. OBJECTIVE: The objective was to investigate the associations of prenatal MeHg exposure and maternal PUFA status with child development at 20 mo of age. DESIGN: The Seychelles Child Development Study Nutrition Cohort 2 is an observational study in the Republic of Seychelles, a high-fish-eating population. Mothers were enrolled during pregnancy and their children evaluated at 20 mo of age by using the Bayley Scales of Infant Development II (BSID-II), the MacArthur Bates Communicative Development Inventories (CDI), and the Infant Behavior Questionnaire-Revised. There were 1265 mother-child pairs with complete data. RESULTS: Prenatal MeHg exposure had no direct associations with neurodevelopmental outcomes. Significant interactions were found between MeHg and PUFAs on the Psychomotor Developmental Index (PDI) of the BSID-II. Increasing MeHg was associated with lower PDI but only in children of mothers with higher n 6/n-3. Among mothers with higher n-3 PUFAs, increasing MeHg was associated with improved PDI. Higher maternal docosahexaenoic acid (DHA) was associated with improved CDI total gestures (language development) but was significantly adversely associated with the Mental Development Index (MDI), both with and without MeHg adjustment. Higher n-6:n-3 ratios were associated with poorer scores on all 3 CDI outcomes. CONCLUSIONS: We found no overall adverse association between prenatal MeHg exposure and neurodevelopmental outcomes. However, maternal PUFA status as a putative marker of the inflammatory milieu appeared to modify the associations of prenatal MeHg exposure with the PDI. Increasing DHA status was positively associated with language development yet negatively associated with the MDI. These findings may indicate the existence of an optimal DHA balance with respect to arachidonic acid for different aspects of neurodevelopment. PMID- 25733640 TI - Effect of initiating enteral protein feeding on whole-body protein turnover in critically ill patients. AB - BACKGROUND: Critically ill patients are susceptible to protein catabolism. Enteral feeding may ameliorate protein loss, but its effect is not well characterized in terms of protein kinetics. OBJECTIVE: We established a method of quantifying the effect of enteral protein feeding on whole-body protein turnover and studied critically ill patients receiving early enteral nutrition. DESIGN: In a proof-of-concept study, we established, in healthy subjects (n = 6), a method of measuring the effect of continuous enteral protein feeding on whole-body protein turnover by using 13C-phenylalanine (13C-Phe) intrinsically labeled casein by a nasogastric feeding tube and an intravenous 2H5-Phe tracer. The protocol was applied to study critically ill patients (n = 10) during the initial hypocaloric-hyponitrogenous dose of enteral nutrition. RESULTS: Patients were catabolic with a negative protein balance. The median splanchnic extraction fraction of hourly dietary Phe intake was 92% (range: 86-99%); that is, the availability of dietary Phe in arterial plasma was low. In patients with a stable parenteral amino acid supply (n = 7), the median net protein balance improved during enteral feeding from -8.6 to -5.8 MUmol . kg body weight-1 . h-1 (P = 0.018). CONCLUSIONS: Whole-body protein turnover and the contribution of dietary protein can be quantified in critically ill patients by using intravenous and enteral stable-isotope Phe tracers. The whole-body protein balance improved during early hypocaloric-hyponitrogenous enteral protein feeding in these patients. PMID- 25733639 TI - Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial. AB - BACKGROUND: Recent evidence has indicated that flavanol consumption may have many health benefits in humans, including improved cognitive activities. OBJECTIVE: The aim was to evaluate the effect of flavanol consumption on cognitive performance in cognitively intact elderly subjects. DESIGN: This was a double blind, controlled, parallel-arm study conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 wk a drink containing 993 mg [high flavanol (HF)], 520 mg [intermediate flavanol (IF)], or 48 mg [low flavanol (LF)] cocoa flavanols (CFs). Cognitive function was assessed at baseline and after 8 wk by using the Mini Mental State Examination (MMSE), the Trail Making Test (TMT) A and B, and the Verbal Fluency Test (VFT). RESULTS: The changes in MMSE score in response to the 3 different treatments were not different. In contrast, there was a positive impact of the intervention on specific aspects of cognitive function. Mean changes (+/-SEs) in the time required to complete the TMT A and B after consumption of the HF (-8.6 +/- 0.4 and -16.5 +/- 0.8 s, respectively) and IF ( 6.7 +/- 0.5 and -14.2 +/- 0.5 s, respectively) drinks significantly (P < 0.0001) differed from that after consumption of the LF drinks (-0.8 +/- 1.6 and -1.1 +/- 0.7 s, respectively). Similarly, VFT scores significantly improved among all treatment groups, but the magnitude of improvement in the VFT score was significantly (P < 0.0001) greater in the HF group (7.7 +/- 1.1 words/60 s) than in the IF (3.6 +/- 1.2 words/60 s) and LF (1.3 +/- 0.5 words/60 s) groups. Significantly different improvements in insulin resistance (P < 0.0001), blood pressure (P < 0.0001), and lipid peroxidation (P = 0.001) were also observed for the HF and IF groups in comparison with the LF group. Changes in insulin resistance explained ~17% of changes in composite z score (partial r2 = 0.1703, P < 0.0001). CONCLUSIONS: This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age. PMID- 25733641 TI - Adherence to cancer prevention guidelines and cancer incidence, cancer mortality, and total mortality: a prospective cohort study. AB - BACKGROUND: Several health agencies have issued guidelines promoting behaviors to reduce chronic disease risk; however, little is known about the impact of such guidelines, particularly on cancer incidence. OBJECTIVE: The objective was to determine whether greater adherence to the American Cancer Society (ACS) cancer prevention guidelines is associated with a reduction in cancer incidence, cancer mortality, and total mortality. DESIGN: The NIH-AARP Diet and Health Study, a prospective cohort study of 566,401 adults aged 50-71 y at recruitment in 1995 1996, was followed for a median of 10.5 y for cancer incidence, 12.6 y for cancer mortality, and 13.6 y for total mortality. Participants who reported a history of cancer or who had missing data were excluded, yielding 476,396 subjects for analysis. We constructed a 5-level score measuring adherence to ACS guidelines, which included baseline body mass index, physical activity, alcohol intake, and several aspects of diet. Cox proportional hazards models were used to compute HRs and 95% CIs for the association of the adherence score with cancer incidence, cancer mortality, and total mortality. All analyses included fine adjustment for cigarette smoking. RESULTS: Among 476,396 participants, 73,784 incident first cancers, 16,193 cancer deaths, and 81,433 deaths from all causes were identified in the cohort. Adherence to ACS guidelines was associated with reduced risk of all cancers combined: HRs (95% CIs) for the highest compared with the lowest level of adherence were 0.90 (0.87, 0.93) in men and 0.81 (0.77, 0.84) in women. Fourteen of 25 specific cancer sites showed a reduction in risk associated with increased adherence. Adherence was also associated with reduced cancer mortality [HRs (95% CIs) were 0.75 (0.70, 0.80) in men and 0.76 (0.70, 0.83) in women] and reduced all-cause mortality [HRs (95% CIs) were 0.74 (0.72, 0.76) in men and 0.67 (0.65, 0.70) in women]. CONCLUSIONS: In both men and women, adherence to the ACS guidelines was associated with reductions in all-cancer incidence and the incidence of cancer at specific sites, as well as with reductions in cancer mortality and total mortality. These data suggest that, after accounting for cigarette smoking, adherence to a set of healthy behaviors may have considerable health benefits. PMID- 25733642 TI - Tea and coffee and risk of endometrial cancer: cohort study and meta-analysis. AB - BACKGROUND: Previous reports, mostly from retrospective studies, suggested possible protective effects of both tea and coffee against endometrial cancer, but recent reports from prospective studies generally showed weaker or null associations. OBJECTIVES: We investigated endometrial cancer risk in relation to tea and coffee consumption in a large prospective study and did a meta-analysis of published results. DESIGN: Daily consumption of tea and coffee was recorded in 560,356 participants (without a hysterectomy) in the UK Million Women Study of whom 4067 women developed endometrial cancer during 5.2 million person-years of follow up (average: 9.3 y per woman). RESULTS: With the use of Cox proportional hazards regression, we showed no significant association between endometrial cancer risk and consumption of either tea (multivariate adjusted RR per cup daily: 1.00; 95% CI: 0.98, 1.02) or coffee (RR per cup daily: 0.98; 95% CI: 0.96, 1.01). Our meta-analyses showed no significant association between endometrial cancer risk and tea consumption and a weak association for coffee consumption in prospective studies, but there may have been selective publication of only part of the evidence. CONCLUSIONS: There is little or no association between tea consumption and endometrial cancer risk. If there is any association with coffee consumption, it appears to be weak. PMID- 25733643 TI - The costs of inadequate breastfeeding of infants in Mexico. AB - BACKGROUND: Breastfeeding is vital for child survival, health, and development. Mexico has very low rates of breastfeeding and experienced a severe decrease in the prevalence of exclusive breastfeeding from 21% in 2006 to 14% in 2012. OBJECTIVE: The objective of the article was to estimate the pediatric costs of inadequate breastfeeding in Mexico associated with the following acute health conditions: respiratory infections, otitis media, gastroenteritis, necrotizing enterocolitis (NEC), and sudden infant death syndrome (SIDS). DESIGN: The authors estimated the economic costs of inadequate breastfeeding as follows: the sum of direct health care costs for diseases whose risk increases when infants are non exclusively breastfed <6 mo or are not breastfed from ages 6 to <11 mo, lost future earnings due to premature infant death, and the costs of purchasing infant formula. Incidence cases were retrieved from national surveillance systems, except for NEC and SIDS, which were estimated from the literature. A sensitivity analysis was carried out to provide a range of costs based on different assumptions of the number of incident cases of all infant health outcomes examined. The model applied to the cohort of 1-y-old children born in 2012. RESULTS: The total annual costs of inadequate breastfeeding in Mexico for the studied cohort ranged from $745.6 million to $2416.5 million, where the costs of infant formula accounted for 11-38% of total costs. A range of 1.1-3.8 million reported cases of disease and from 933 to 5796 infant deaths per year for the diseases under study are attributed to inadequate infant breastfeeding practices; altogether these represent nearly 27% of the absolute number of episodes of such diseases. CONCLUSIONS: This study provides costs of inadequate breastfeeding that had not been quantified in Mexico. The costs presented in this article provide the minimum amount that the country should invest to achieve better breastfeeding practices. PMID- 25733645 TI - Trends in group inequalities and interindividual inequalities in BMI in the United States, 1993-2012. AB - BACKGROUND: Marked increases in mean body mass index (BMI) and prevalence of obesity and overweight in the United States are well known. However, whether these average increases were accompanied by changing dispersion (or SD) remains understudied. OBJECTIVE: We investigated population-level changes in the BMI distribution over time to understand how changes in dispersion reflect between group compared with within-group inequalities in weight gain in the United States. DESIGN: Using data from the Behavioral Risk Factor Surveillance System survey (1993-2012), we analyzed associations between mean, SD, and median BMI and BMI at the 5th and 95th percentiles for 3,050,992 non-Hispanic white, non Hispanic black, and Hispanic men and women aged 25-64 y. RESULTS: Overall, an increase of 1.0 in mean BMI (in kg/m2) was associated with an increase of 0.70 (95% CI: 0.67, 0.73) in the SD of BMI. A change of 1.0 in median BMI was associated with a change of 0.18 (95% CI: 0.14, 0.21) in the BMI value at the 5th percentile compared with a change of 2.94 (95% CI: 2.81, 3.07) at the 95th percentile. Quantile-quantile plots showed unequal changes in the BMI distribution, with pronounced changes at higher percentiles. Similar patterns were observed in subgroups stratified by sex, race-ethnicity, and education with non-Hispanic black women and women with less than a high school education having highest mean BMI, SD of BMI, and BMI values at the 5th and 95th percentiles. CONCLUSIONS: Mean BMI and the percentage of overweight and obese individuals do not fully describe population changes in BMI. Increases in within-group inequality in BMI represent an underrecognized characteristic of population-level weight gain. Crucially, similar increases in dispersion within groups suggest that growing inequalities in BMI at the population level are not driven by these socioeconomic and demographic factors. Future research should focus on understanding factors driving inequalities in weight gain between individuals. PMID- 25733644 TI - Associations of key diet-quality indexes with mortality in the Multiethnic Cohort: the Dietary Patterns Methods Project. AB - BACKGROUND: Healthy dietary patterns have been linked positively with health and longevity. However, prospective studies in diverse populations in the United States addressing dietary patterns and mortality are limited. OBJECTIVE: We assessed the ability of the following 4 diet-quality indexes [the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH)] to predict the reduction in risk of mortality from all causes, cardiovascular disease (CVD), and cancer. DESIGN: White, African American, Native Hawaiian, Japanese American, and Latino adults (n = 215,782) from the Multiethnic Cohort completed a quantitative food-frequency questionnaire. Scores for each dietary index were computed and divided into quintiles for men and women. Mortality was documented over 13-18 y of follow-up. HRs and 95% CIs were computed by using adjusted Cox models. RESULTS: High HEI-2010, AHEI-2010, aMED, and DASH scores were all inversely associated with risk of mortality from all causes, CVD, and cancer in both men and women (P-trend < 0.0001 for all models). For men, the HEI-2010 was consistently associated with a reduction in risk of mortality for all causes (HR: 0.75; 95% CI: 0.71, 0.79), CVD (HR: 0.74; 95% CI: 0.69, 0.81), and cancer (HR: 0.76; 95% CI: 0.70, 0.83) when lowest and highest quintiles were compared. In women, the AHEI and aMED showed large reductions for all-cause mortality (HR: 0.78; 95% CI: 0.74, 0.82), the AHEI showed large reductions for CVD (HR: 0.76; 95% CI: 0.69, 0.83), and the aMED showed large reductions for cancer (HR: 0.84; 95% CI: 0.76, 0. 92). CONCLUSION: These results, in a US multiethnic population, suggest that consuming a dietary pattern that achieves a high diet-quality index score is associated with lower risk of mortality from all causes, CVD, and cancer in adult men and women. PMID- 25733646 TI - Vitamin supplementation on the risk of venous thrombosis: results from the MEGA case-control study. AB - BACKGROUND: Whether vitamin supplements decrease venous thrombosis risk is controversial. Previous reports did not all take confounding fully into account, either by randomization or by extensive adjustment. OBJECTIVE: The aim of our study was to determine whether vitamin supplementation decreases the risk of venous thrombosis. DESIGN: A large case-control study included 2506 patients with venous thrombosis, 2506 partner controls, and 2684 random-digit dialing (RDD) controls. When patients were compared with RDD controls, unconditional logistic regression was used to calculate ORs with 95% CIs. When patients were compared with partner controls, conditional logistic regression was used, providing further adjustment for unmeasured confounding. RESULTS: Vitamin use yielded a 37% lower risk of venous thrombosis than no vitamin use (OR: 0.63; 95% CI: 0.57, 0.70) when comparing patients with RDD controls. Adjustment for several putative confounders did not change the estimate (OR: 0.68; 95% CI: 0.61, 0.77). The fully adjusted ORs for vitamin A, vitamin B-6, vitamin B-12, folic acid, vitamin C, vitamin D, vitamin E, and multivitamin use were in the same range. However, when patients were compared with partner controls, ORs attenuated to unity. Results were similar for provoked and unprovoked events, as well as for deep vein thrombosis and pulmonary embolism. CONCLUSIONS: After extensive adjustments, vitamin supplementation was no longer associated with a decreased risk of venous thrombosis in this study. Previous positive results may have been spurious as a result of uncontrolled confounding. PMID- 25733648 TI - Sodium monitoring in commercially processed and restaurant foods. AB - BACKGROUND: Most sodium in the US diet comes from commercially processed and restaurant foods. Sodium reduction in these foods is key to several recent public health efforts. OBJECTIVE: The objective was to provide an overview of a program led by the USDA, in partnership with other government agencies, to monitor sodium contents in commercially processed and restaurant foods in the United States. We also present comparisons of nutrients generated under the program to older data. DESIGN: We track ~125 commercially processed and restaurant food items ("sentinel foods") annually using information from food manufacturers and periodically by nationwide sampling and laboratory analyses. In addition, we monitor >1100 other commercially processed and restaurant food items, termed "priority-2 foods" (P2Fs) biennially by using information from food manufacturers. These foods serve as indicators for assessing changes in the sodium content of commercially processed and restaurant foods in the United States. We sampled all sentinel foods nationwide and reviewed all P2Fs in 2010-2013 to determine baseline sodium concentrations. RESULTS: We updated sodium values for 73 sentinel foods and 551 P2Fs in the USDA's National Nutrient Database for Standard Reference (releases 23 26). Sodium values changed by at least 10% for 43 of the sentinel foods, which, for 31 foods, including commonly consumed foods such as bread, tomato catsup, and potato chips, the newer sodium values were lower. Changes in the concentrations of related nutrients (total and saturated fat, total sugar, potassium, or dietary fiber) that were recommended by the 2010 Dietary Guidelines for Americans for reduced or increased consumption accompanied sodium reduction. The results of sodium reduction efforts, based on resampling of the sentinel foods or re-review of P2Fs, will become available beginning in 2015. CONCLUSION: This monitoring program tracks sodium reduction efforts, improves food composition databases, and strengthens national nutrition monitoring. PMID- 25733647 TI - Physical activity and all-cause mortality across levels of overall and abdominal adiposity in European men and women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC). AB - BACKGROUND: The higher risk of death resulting from excess adiposity may be attenuated by physical activity (PA). However, the theoretical number of deaths reduced by eliminating physical inactivity compared with overall and abdominal obesity remains unclear. OBJECTIVE: We examined whether overall and abdominal adiposity modified the association between PA and all-cause mortality and estimated the population attributable fraction (PAF) and the years of life gained for these exposures. DESIGN: This was a cohort study in 334,161 European men and women. The mean follow-up time was 12.4 y, corresponding to 4,154,915 person years. Height, weight, and waist circumference (WC) were measured in the clinic. PA was assessed with a validated self-report instrument. The combined associations between PA, BMI, and WC with mortality were examined with Cox proportional hazards models, stratified by center and age group, and adjusted for sex, education, smoking, and alcohol intake. Center-specific PAF associated with inactivity, body mass index (BMI; in kg/m2) (>30), and WC (>=102 cm for men, >=88 cm for women) were calculated and combined in random-effects meta-analysis. Life tables analyses were used to estimate gains in life expectancy for the exposures. RESULTS: Significant interactions (PA * BMI and PA * WC) were observed, so HRs were estimated within BMI and WC strata. The hazards of all-cause mortality were reduced by 16-30% in moderately inactive individuals compared with those categorized as inactive in different strata of BMI and WC. Avoiding all inactivity would theoretically reduce all-cause mortality by 7.35% (95% CI: 5.88%, 8.83%). Corresponding estimates for avoiding obesity (BMI >30) were 3.66% (95% CI: 2.30%, 5.01%). The estimates for avoiding high WC were similar to those for physical inactivity. CONCLUSION: The greatest reductions in mortality risk were observed between the 2 lowest activity groups across levels of general and abdominal adiposity, which suggests that efforts to encourage even small increases in activity in inactive individuals may be beneficial to public health. PMID- 25733649 TI - Malian children with moderate acute malnutrition who are treated with lipid-based dietary supplements have greater weight gains and recovery rates than those treated with locally produced cereal-legume products: a community-based, cluster randomized trial. AB - BACKGROUND: Moderate acute malnutrition (MAM), defined as weight-for-length z score between -3 and -2 or midupper arm circumference between 11.5 and 12.5 cm, affects ~33 million children aged <5 y worldwide. OBJECTIVE: The objective was to compare the effects of 4 dietary supplements for the treatment of MAM. DESIGN: Twelve community health centers in rural Mali were randomly assigned to provide to 1264 MAM children aged 6-35 mo one of 4 dietary supplements containing ~500 kcal/d for 12 wk: 1) ready-to-use, lipid-based supplementary food (RUSF); 2) special corn-soy blend (CSB++); 3) locally processed, fortified flour (Misola); or 4) locally milled flours plus oil, sugar, and micronutrient powder (LMF). RESULTS: In total, 1178 children (93.2%) completed the study. The adjusted mean (95% CI) change in weight (kg) from baseline was greater with RUSF than with the locally processed blends and was intermediate with CSB++ [1.16 (1.08, 1.24) for RUSF, 1.04 (0.96, 1.13) for CSB++, 0.91 (0.82, 0.99) for Misola, and 0.83 (0.74, 0.92) for LMF; P < 0.001]. For length change, RUSF and CSB++ differed significantly from LMF. Sustained recovery rates were higher with RUSF (73%) than with Misola (61%) and LMF (58%), P < 0.0001; CSB++ recovery rates (68%) did not differ from any of the other groups. CONCLUSIONS: RUSF was more effective, but more costly, than other dietary supplements for the treatment of MAM; CSB++ yielded intermediate results. The benefits of treatment should be considered in relation to product costs and availability. PMID- 25733650 TI - High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. AB - BACKGROUND: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. OBJECTIVE: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. DESIGN: Folic acid supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. RESULTS: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5 Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. CONCLUSIONS: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient. PMID- 25733651 TI - Moderate weight loss in obese and overweight men preserves bone quality. AB - BACKGROUND: Weight loss (WL) negatively affects bone mineral density (BMD) in older populations and has specifically been shown in women. OBJECTIVE: In this prospective controlled trial, we examined variables of bone quality and endocrine changes after intentional WL in men. DESIGN: Thirty-eight overweight and obese [mean +/- SD body mass index (in kg/m2): 31.9 +/- 4.4; age: 58 +/- 6 y] men were recruited to either WL through caloric restriction or weight maintenance (WM) for 6 mo. RESULTS: There was a -7.9 +/- 4.4% and +0.2 +/- 1.6% change in body weight in the WL and WM groups, respectively. There was a greater increase in femoral neck and total body BMD and bone mineral content (BMC) in the WM group than in the WL group (P-interaction effect < 0.05). In contrast, there was a trend for the tibia cortical thickness and area to decrease more in the WM group than in the WL group (P <= 0.08). There was a decrease in the periosteal circumference in both groups over time (P < 0.01) and no statistically significant changes in trabecular bone. Circulating total, free, and bioavailable estradiol decreased in the WL group compared with the WM group, and changes were different between groups (P < 0.05). Serum total and bioavailable testosterone increased in both groups (P < 0.01). Serum 25-hydroxyvitamin D increased to a similar extent in both groups (P < 0.05). CONCLUSIONS: Moderate WL in overweight and obese men did not decrease BMD at any anatomical site or alter cortical and trabecular bone and geometry. Also, despite increased BMD at some sites when maintaining excess body weight, cortical bone showed a trend in the opposite direction. PMID- 25733652 TI - n-3 Long-chain PUFAs reduce respiratory morbidity caused by iron supplementation in iron-deficient South African schoolchildren: a randomized, double-blind, placebo-controlled intervention. AB - BACKGROUND: Although iron supplementation in malaria-free areas mostly reduces infectious morbidity, it can sometimes increase morbidity from infections as a result of the dependence of pathogenic microorganisms on iron. Supplementation with n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) improved morbidity in several human studies. However, information on the combined effect of iron and n-3 LCPUFA supplementation on infectious morbidity is limited. OBJECTIVE: We determined whether n-3 LCPUFAs and iron supplementation, alone or in combination, affected absenteeism and illness in iron-deficient schoolchildren with low fish intake. DESIGN: A total of 321 South African children (aged 6-11 y) with iron deficiency (ID) were randomly divided into 4 groups to receive 1) iron plus placebo, 2) a mixture of docosahexaenoic acid and eicosapentaenoic acid (DHA/EPA) plus placebo, 3) iron plus DHA/EPA, or 4) placebo plus placebo as oral supplements 4 times/wk for 8.5 mo. Morbidity was recorded, and iron-status indexes were measured. The total phospholipid fatty acid composition of peripheral blood mononuclear cell membranes was analyzed in a subsample (n = 130). RESULTS: Iron supplementation increased the number of days with illness when all symptoms were considered (B: 0.87; 95% CI: 0.71, 1.03) as well as illness that was specifically caused by respiratory symptoms (B: 1.45; 95% CI: 1.21, 1.70), whereas DHA/EPA reduced the number of days with illness at school (B: -0.96; 95% CI: -1.33, -0.59). The increases caused by iron were reduced to the levels seen in the placebo plus placebo group when iron was provided in combination with DHA/EPA as indicated by significant iron * DHA/EPA interactions (both P < 0.001). CONCLUSION: Iron supplementation increased morbidity (mostly respiratory) in iron-deficient South African schoolchildren with low DHA/EPA intake, but when iron was given in combination with DHA/EPA, this effect was prevented. PMID- 25733653 TI - Bifidobacterium animalis subsp. lactis fails to prevent common infections in hospitalized children: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The incidence of nosocomial infections in children in developed countries is still high, ranging from 8% to 30%, and standard preventive measures, such as increased hygiene, are not sufficiently efficacious. One of the potential strategies for their prevention is the use of probiotics. OBJECTIVE: The aim of the study was to investigate the role of Bifidobacterium animalis subsp. lactis in preventing nosocomial infections in the acute hospital setting. DESIGN: We conducted a randomized, double-blind, placebo-controlled trial in 727 hospitalized children (aged 1-18 y). The children were randomly allocated to receive placebo (placebo group, n = 365) or B. animalis subsp. lactis at a dose of 10(9) colony-forming units/d (intervention group, n = 362) once daily for the entire duration of the hospital stay. Nosocomial infections were defined as infections that occurred >48 h after hospital admission and that were not present or incubating at the time of admission. RESULTS: Analysis was performed on an intention-to-treat basis. There was no difference in the study primary outcome or incidence of common nosocomial gastrointestinal and respiratory tract infections between groups (22 vs. 29 infections, respectively; incidence rate ratio = 0.76; 95% CI: 0.41, 1.36; P = 0.32). No difference was found for the duration of common nosocomial infections [mean (range): 3.58 (1-7) vs. 3.79 (1-8) d, in placebo vs. intervention group; P = 0.74]. There was also no difference between the intervention and placebo groups for any of the other secondary outcomes (incidence of gastrointestinal and respiratory tract infections separately, duration of gastrointestinal and respiratory infections, and duration of hospitalization) and exploratory outcomes (gastrointestinal and respiratory symptoms, severity of gastrointestinal and respiratory tract infections, and the use of antibiotics). CONCLUSIONS: The results of this study show that the use of B. animalis subsp. lactis failed to prevent nosocomial infections in an acute setting pediatric hospital in children who were >1 y of age. However, it should be taken into account that the overall incidence of nosocomial infections was lower than expected. This trial was registered at clinicaltrials.gov as NCT01702766. PMID- 25733654 TI - Relations between body mass, height, fat mass, and waist circumference in American and Korean men and women. PMID- 25733655 TI - A meta-analysis is suited to nullify the effects of n-3 PUFAs on cognitive function. PMID- 25733656 TI - Reply to RA Murphy and R Winwood. PMID- 25733657 TI - Stable isotopes, diet, and diabetes incidence. PMID- 25733658 TI - Reply to KJ Petzke. PMID- 25733660 TI - An analysis of folic acid supplementation in women presenting for antenatal care. AB - BACKGROUND: Neural tube defects (NTDs) are major congenital malformations that are potentially preventable if the woman takes periconceptional folic acid (FA) supplements. A recent report found that NTD incidence had increased in Ireland. This study examined the usage of FA supplementation in women presenting for antenatal care in a maternity hospital. METHODS: Women were recruited at their convenience in the first trimester. Their clinical and sociodemographic details were computerized. Maternal weight and height were measured before calculating body mass index. Detailed FA questionnaires were completed under supervision of a trained researcher. RESULTS: While 96.1% (n = 564) out of 587 reported that they took FA after they became pregnant, only 24.7% (n = 145) took it for >12 weeks preconceptionally as recommended. Only 5.7% (n = 6) of obese women took high-dose FA as recommended. On univariate analysis, the strongest predictors of preconceptional FA usage were higher maternal age, higher education and income, being married, being nulliparous, not smoking, infertility treatment and planned pregnancy. On multivariate analysis, both planned pregnancy and nulliparity were the most important predictors of preconceptional FA use. CONCLUSIONS: Our study shows that current recommendations to prevent NTDs by FA supplementation pre pregnancy are not being fully implemented in Ireland. We recommend a review of current public health policies on FA supplementation. PMID- 25733661 TI - The acquisition of problem behavior in individuals with developmental disabilities as a behavioral cusp. AB - A behavioral cusp has been defined as a behavior change that produces contact with new contingencies with important and far-reaching consequences. The concept of behavioral cusps has most frequently been used to select target skills taught to learners and to evaluate the importance of those skills; however, the concept is equally applicable to behavior changes that bring about important and far reaching negative consequences. Although it has been acknowledged that socially undesirable behavior change can also qualify as a behavioral cusp, this area of the cusp concept has been under-examined. In this article, an undesirable behavior change, the acquisition of problem behavior in individuals with developmental disabilities, is compared with criteria for behavioral cusps previously identified in the literature. The advantages of viewing problem behavior as a behavioral cusp are outlined, and implications for practice and research from a behavioral cusp approach to problem behavior are provided. PMID- 25733662 TI - Persons with multiple disabilities engage in stimulus choice and postural control with the support of a technology-aided program. AB - Technology-aided programs have been reported to help persons with disabilities develop adaptive responding and control problem behavior/posture. This study assessed one such program in which choice of stimulus events was used as adaptive responding for three adults with multiple disabilities. A computer system presented the participants stimulus samples. For each sample, they could perform a choice response (gaining access to the related stimulus whose length they could extend) or abstain from responding (making the system proceed to the next sample). Once choice responding had strengthened, the program also targeted the participants' problem posture (i.e., head and trunk forward bending). The stimulus exposure gained with a choice response was interrupted if the problem posture occurred. All three participants successfully (a) managed choice responses and access to preferred stimuli and (b) gained postural control (i.e., reducing the problem posture to very low levels). The practical implications of those results are discussed. PMID- 25733663 TI - Evaluation of interventions to reduce multiply controlled vocal stereotypy. AB - This study examined four interventions targeted at decreasing multiply controlled vocal stereotypy for a 12-year-old boy diagnosed with autism spectrum disorder and a severe intellectual disability. These interventions included Noncontingent Music, Differential Reinforcement of Other Behaviors, Self-Recording, and Functional Communication Training (FCT). In addition to measuring vocal stereotypy during each condition, task engagement and challenging behavior were also monitored. Across conditions, vocal stereotypy did not vary significantly from baseline except in FCT, when it decreased significantly. Task engagement was higher in this condition as well. It is hypothesized that FCT provided an enriched environment by increasing social interaction and access to desired items as well as removal of less preferred activities. For these reasons, there was a decrease in the need for the participant to engage in vocal stereotypy and challenging behavior and increase in his ability to engage in a task. PMID- 25733664 TI - Role of Conserved Proline Residues in Human Apolipoprotein A-IV Structure and Function. AB - Apolipoprotein (apo)A-IV is a lipid emulsifying protein linked to a range of protective roles in obesity, diabetes, and cardiovascular disease. It exists in several states in plasma including lipid-bound in HDL and chylomicrons and as monomeric and dimeric lipid-free/poor forms. Our recent x-ray crystal structure of the central domain of apoA-IV shows that it adopts an elongated helical structure that dimerizes via two long reciprocating helices. A striking feature is the alignment of conserved proline residues across the dimer interface. We speculated that this plays important roles in the structure of the lipid-free protein and its ability to bind lipid. Here we show that the systematic conversion of these prolines to alanine increased the thermodynamic stability of apoA-IV and its propensity to oligomerize. Despite the structural stabilization, we noted an increase in the ability to bind and reorganize lipids and to promote cholesterol efflux from cells. The novel properties of these mutants allowed us to isolate the first trimeric form of an exchangeable apolipoprotein and characterize it by small-angle x-ray scattering and chemical cross-linking. The results suggest that the reciprocating helix interaction is a common feature of all apoA-IV oligomers. We propose a model of how self-association of apoA-IV can result in spherical lipoprotein particles, a model that may have broader applications to other exchangeable apolipoprotein family members. PMID- 25733665 TI - Extracellular processing of the cartilage proteoglycan aggregate and its effect on CD44-mediated internalization of hyaluronan. AB - In many cells hyaluronan receptor CD44 mediates the endocytosis of hyaluronan and its delivery to endosomes/lysosomes. The regulation of this process remains largely unknown. In most extracellular matrices hyaluronan is not present as a free polysaccharide but often is found in complex with other small proteins and macromolecules such as proteoglycans. This is especially true in cartilage, where hyaluronan assembles into an aggregate structure with the large proteoglycan termed aggrecan. In this study when purified aggrecan was added to FITC conjugated hyaluronan, no internalization of hyaluronan was detected. This suggested that the overall size of the aggregate prevented hyaluronan endocytosis and furthermore that proteolysis of the aggrecan was a required prerequisite for local, cell-based turnover of hyaluronan. To test this hypothesis, limited C terminal digestion of aggrecan was performed to determine whether a size range of aggrecan exists that permits hyaluronan endocytosis. Our data demonstrate that only limited degradation of the aggrecan monomer was required to allow for hyaluronan internalization. When hyaluronan was combined with partially degraded, dansyl chloride-labeled aggrecan, blue fluorescent aggrecan was also visualized within intracellular vesicles. It was also determined that sonicated hyaluronan of smaller molecular size was internalized more readily than high molecular mass hyaluronan. However, the addition of intact aggrecan to hyaluronan chains sonicated for 5 and 10 s reblocked their endocytosis, whereas aggregates containing 15-s sonicated hyaluronan were internalized. These data suggest that hyaluronan endocytosis is regulated in large part by the extracellular proteolytic processing of hyaluronan-bound proteoglycan. PMID- 25733666 TI - Signaling pathways that control rho kinase activity maintain the embryonic epicardial progenitor state. AB - This study identifies signaling pathways that play key roles in the formation and maintenance of epicardial cells, a source of progenitors for coronary smooth muscle cells (SMCs). After epithelial to mesenchymal transition (EMT), mesenchymal cells invade the myocardium to form coronary SMCs. RhoA/Rho kinase activity is required for EMT and for differentiation into coronary SMCs, whereas cAMP activity is known to inhibit EMT in epithelial cells by an unknown mechanism. We use outgrowth of epicardial cells from E9.5 isolated mouse proepicardium (PE) explants, wild type and Epac1 null E12.5 mouse heart explants, adult rat epicardial cells, and immortalized mouse embryonic epicardial cells as model systems to identify signaling pathways that regulate RhoA activity to maintain the epicardial progenitor state. We demonstrate that RhoA activity is suppressed in the epicardial progenitor state, that the cAMP-dependent Rap1 GTP exchange factor (GEF), Epac, known to down-regulate RhoA activity through activation of Rap1 GTPase activity increased, that Rap1 activity increased, and that expression of the RhoA antagonistic Rnd proteins known to activate p190RhoGAP increased and associated with p190RhoGAP. Finally, EMT is associated with increased p63RhoGEF and RhoGEF-H1 protein expression, increased GEF-H1 activity, with a trend in increased p63RhoGEF activity. EMT is suppressed by partial silencing of p63RhoGEF and GEF-H1. In conclusion, we have identified new signaling molecules that act together to control RhoA activity and play critical roles in the maintenance of coronary smooth muscle progenitor cells in the embryonic epicardium. We suggest that their eventual manipulation could promote revascularization after myocardial injury. PMID- 25733667 TI - Constitutive phosphorylation of cardiac myosin regulatory light chain in vivo. AB - In beating hearts, phosphorylation of myosin regulatory light chain (RLC) at a single site to 0.45 mol of phosphate/mol by cardiac myosin light chain kinase (cMLCK) increases Ca(2+) sensitivity of myofilament contraction necessary for normal cardiac performance. Reduction of RLC phosphorylation in conditional cMLCK knock-out mice caused cardiac dilation and loss of cardiac performance by 1 week, as shown by increased left ventricular internal diameter at end-diastole and decreased fractional shortening. Decreased RLC phosphorylation by conventional or conditional cMLCK gene ablation did not affect troponin-I or myosin-binding protein-C phosphorylation in vivo. The extent of RLC phosphorylation was not changed by prolonged infusion of dobutamine or treatment with a beta-adrenergic antagonist, suggesting that RLC is constitutively phosphorylated to maintain cardiac performance. Biochemical studies with myofilaments showed that RLC phosphorylation up to 90% was a random process. RLC is slowly dephosphorylated in both noncontracting hearts and isolated cardiac myocytes from adult mice. Electrically paced ventricular trabeculae restored RLC phosphorylation, which was increased to 0.91 mol of phosphate/mol of RLC with inhibition of myosin light chain phosphatase (MLCP). The two RLCs in each myosin appear to be readily available for phosphorylation by a soluble cMLCK, but MLCP activity limits the amount of constitutive RLC phosphorylation. MLCP with its regulatory subunit MYPT2 bound tightly to myofilaments was constitutively phosphorylated in beating hearts at a site that inhibits MLCP activity. Thus, the constitutive RLC phosphorylation is limited physiologically by low cMLCK activity in balance with low MLCP activity. PMID- 25733669 TI - Meckel's diverticulum complicated by axial torsion and gangrene. AB - Meckel's diverticulum is a remnant of the omphalomesenteric duct and is the most common congenital anomalies of the gastrointestinal tract. It has been known to mimic different disease states making its diagnosis difficult. Common complications consist of bleeding, intestinal obstruction and inflammation. The patient discussed in this case study was a 29-year-old Hispanic female who presented with right lower quadrant abdominal pain. A CT scan showed a normal appendix, thickened terminal ileum and a high-grade distal small bowel obstruction with a possible closed-loop obstruction. Laparoscopy revealed Meckel's diverticulum with the rare complication of torsion. The mechanism of torsion has been postulated but with little evidence. The purpose of this case report is to discuss the apparent mechanism of axial torsion secondary to the presence of a mesodiverticular band, provide visual evidence at surgery and recommend all Meckel's diverticulum associated with a mesodiverticular band be resected to prevent further complications. PMID- 25733668 TI - Shu1 is a cell-surface protein involved in iron acquisition from heme in Schizosaccharomyces pombe. AB - Iron is an essential metal cofactor that is required for many biological processes. Eukaryotic cells have consequently developed different strategies for its acquisition. Until now, Schizosaccharomyces pombe was known to use reductive iron uptake and siderophore-bound iron transport to scavenge iron from the environment. Here, we report the identification of a gene designated shu1(+) that encodes a protein that enables S. pombe to take up extracellular heme for cell growth. When iron levels are low, the transcription of shu1(+) is induced, although its expression is repressed when iron levels rise. The iron-dependent down-regulation of shu1(+) requires the GATA-type transcriptional repressor Fep1, which strongly associates with a proximal promoter region of shu1(+) in vivo in response to iron repletion. HA4-tagged Shu1 localizes to the plasma membrane in cells expressing a functional shu1(+)-HA4 allele. When heme biosynthesis is selectively blocked in mutated S. pombe cells, their ability to acquire exogenous hemin or the fluorescent heme analog zinc mesoporphyrin IX is dependent on the expression of Shu1. Further analysis by absorbance spectroscopy and hemin-agarose pulldown assays showed that Shu1 interacts with hemin, with a KD of ~2.2 MUm. Taken together, results reported here revealed that S. pombe possesses an unexpected pathway for heme assimilation, which may also serve as a source of iron for cell growth. PMID- 25733670 TI - Missing pancreatic isthmus during pancreaticoduodenectomy. AB - Pancreatic malformations usually represent a surgical challenge, however, depending on the anatomical location even complex procedures such as pancreatic head resection may be facilitated. In a 78-year-old-woman the unique observation of a missing pancreatic isthmus was made during pylorus-preserving pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. Resection of the pancreatic head could be performed without the usual cross-section at the isthmus, the pancreatic remnant was drained by pancreaticogastrostomy. Complete agenesis of the dorsal pancreas with missing neck, body and tail of the pancreas has been shown to be associated with malignant pancreatic tumors, as demonstrated in this case of partial agenesis (missing isthmus) of the dorsal pancreas. The missing pancreatic isthmus is a unique, not yet described finding during pancreatic exploration for tumor resection. In the absence of previous abdominal trauma, a partial agenesis of the dorsal pancreas could explain this malformation. PMID- 25733671 TI - External iliac artery occlusion in a paediatric patient following handlebar trauma. AB - Arterial occlusion following blunt trauma is an uncommon occurrence. We report an unusual case of delayed external iliac artery occlusion in a young male following blunt abdominal injury. He was successfully treated with thromboendarterectomy and saphenous vein patch repair. There have only been a handful of documented cases occurring in the paediatric population. All patients presenting with groin injury from this mechanism should be carefully investigated and monitored for risk of vascular injury. PMID- 25733672 TI - Infant colic--a baby's migraine? PMID- 25733673 TI - Severe Musculoskeletal Pain in a Patient With Systemic Lupus Erythematosus. PMID- 25733674 TI - Adolescent With Lymphadenopathy in the Absence of Systemic Symptoms. PMID- 25733675 TI - Causal inference methods to assess safety upper bounds in randomized trials with noncompliance. AB - BACKGROUND: Premature discontinuation and other forms of noncompliance with treatment assignment can complicate causal inference of treatment effects in randomized trials. The intent-to-treat analysis gives unbiased estimates for causal effects of treatment assignment on outcome, but may understate potential benefit or harm of actual treatment. The corresponding upper confidence limit can also be underestimated. PURPOSE: To compare estimates of the hazard ratio and upper bound of the two-sided 95% confidence interval from causal inference methods that account for noncompliance with those from the intent-to-treat analysis. METHODS: We used simulations with parameters chosen to reflect cardiovascular safety trials of diabetes drugs, with a focus on upper bound estimates relative to 1.3, based on regulatory guidelines. A total of 1000 simulations were run under each parameter combination for a hypothetical trial of 10,000 total subjects randomly assigned to active treatment or control at 1:1 ratio. Noncompliance was considered in the form of treatment discontinuation and cross-over at specified proportions, with an assumed true hazard ratio of 0.9, 1, and 1.3, respectively. Various levels of risk associated with being a non complier (independent of treatment status) were evaluated. Hazard ratio and upper bound estimates from causal survival analysis and intent-to-treat were obtained from each simulation and summarized under each parameter setting. RESULTS: Causal analysis estimated the true hazard ratio with little bias in almost all settings examined. Intent-to-treat was unbiased only when the true hazard ratio = 1; otherwise it underestimated both benefit and harm. When upper bound estimates from intent-to-treat were >=1.3, corresponding estimates from causal analysis were also >=1.3 in almost 100% of the simulations, regardless of the true hazard ratio. When upper bound estimates from intent-to-treat were <1.3 and the true hazard ratio = 1, corresponding upper bound estimates from causal analysis were >=1.3 in up to 66% of the simulations under some settings. LIMITATIONS: Simulations cannot cover all scenarios for noncompliance in real randomized trials. CONCLUSION: Causal survival analysis was superior to intent-to-treat in estimating the true hazard ratio with respect to bias in the presence of noncompliance. However, its large variance should be considered for safety upper bound exclusion especially when the true hazard ratio = 1. Our simulations provided a broad reference for practical considerations of bias-variance trade off in dealing with noncompliance in cardiovascular safety trials of diabetes drugs. Further research is warranted for the development and application of causal inference methods in the evaluation of safety upper bounds. PMID- 25733676 TI - A multi-site randomized clinical trial to reduce suicidal ideation in suicidal adult outpatients with Major Depressive Disorder: Development of a methodology to enhance safety. AB - BACKGROUND/AIMS: Suicide is a major public health concern, yet there are very few randomized clinical trials that have been conducted to reduce suicidal ideation in patients at risk of suicide. We describe the rationale and refinements of such a trial that is designed to assess the effect of a hypnotic medication on suicidal ideation in adult outpatients currently experiencing suicidal ideation. METHODS: "Reducing Suicidal Ideation Through Insomnia Treatment" is a multi-site randomized clinical trial that includes three recruiting sites and one data management site. This 4-year study is in its second year of recruitment. The purpose of the study is to compare hypnotic medication versus placebo as an add on treatment to a selective serotonin reuptake inhibitor as a means of reducing suicidal ideation in depressed adult outpatients with insomnia and suicidal ideation. The safety features of the study follow the 2001 National Institutes of Health guidelines for studies that include patients at risk of suicide. RESULTS: In total, 584 potential participants have undergone telephone screening; 67% of these failed the phone screen, most often due to an absence of expressed suicidal ideation (26% of the telephone screen fails). A total of 115 people appeared for a face-to-face baseline assessment, and 40 of these had completed a taper off of their ineffective psychotropic medications before the baseline assessments. In all, 64% of those who completed baseline assessments failed to proceed to randomization, most commonly because of no clinically significant suicidal ideation (51% of those excluded at baseline). One participant was offered and accepted voluntary psychiatric hospitalization in lieu of study participation. Thus far, 40 participants have been randomized into the study and 88.7% of scheduled visits have been attended, with 93.8% adherence to the selective serotonin reuptake inhibitor and 91.6% adherence to the randomized hypnotic versus placebo. None of the randomized participants have required hospitalization or had a suicide attempt. CONCLUSION: By carefully considering the inclusion and exclusion criteria and other safety features, the safe conduct of randomized clinical trials in suicidal adult patients is possible, including the inclusion of participants who have undergone a prescribed tapering off of psychotropic medications prior to baseline assessment. PMID- 25733678 TI - Behavioral and Movement Disorders due to Long-Lasting Myoclonic Status Epilepticus Misdiagnosed as ADHD in a Patient With Juvenile Myoclonic Epilepsy: Electroclinical Findings and Related Hemodynamic Changes. AB - Epilepsy and attention-deficit/hyperactivity disorder (ADHD) likely share common underlying neural mechanisms, as often suggested by both the evidence of electroencephalography (EEG) abnormalities in ADHD patients without epilepsy and the coexistence of these 2 conditions. The differential diagnosis between epilepsy and ADHD may consequently be challenging. In this report, we describe a patient presenting with a clinical association of "tics" and behavioral disorders that appeared 6 months before our first observation and had previously been interpreted as ADHD. A video-EEG evaluation documented an electroclinical pattern of myoclonic status epilepticus. On the basis of the revised clinical data, the EEG findings, the good response to valproate, the long-lasting myoclonic status epilepticus, and the enduring epileptic abnormalities likely causing behavioral disturbances, the patient's symptoms were interpreted as being the expression of untreated juvenile myoclonic epilepsy. The EEG-functional magnetic resonance imaging study revealed, during clinical generalized spike-and-wave and polyspike and-wave discharges, positive blood oxygen level-dependent (BOLD) signal changes bilaterally in the thalamus, the prefrontal cortex (Brodmann area 6, supplementary motor area) and the cerebellum, and negative BOLD signal changes in the regions of the default mode network. Such findings, which are typical of BOLD changes observed in idiopathic generalized epilepsy, may also shed light on the anatomofunctional network underlying ADHD. PMID- 25733677 TI - Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems. AB - Cluster randomized trials randomly assign groups of individuals to examine research questions or test interventions and measure their effects on individuals. Recent emphasis on quality improvement, comparative effectiveness, and learning health systems has prompted expanded use of pragmatic cluster randomized trials in routine health-care settings, which in turn poses practical and ethical challenges that current oversight frameworks may not adequately address. The 2012 Ottawa Statement provides a basis for considering many issues related to pragmatic cluster randomized trials but challenges remain, including some arising from the current US research and health-care regulations. In order to examine the ethical, regulatory, and practical questions facing pragmatic cluster randomized trials in health-care settings, the National Institutes of Health Health Care Systems Research Collaboratory convened a workshop in Bethesda, Maryland, in July 2013. Attendees included experts in clinical trials, patient advocacy, research ethics, and research regulations from academia, industry, the National Institutes of Health Collaboratory, and other federal agencies. Workshop participants identified substantial barriers to implementing these types of cluster randomized trials, including issues related to research design, gatekeepers and governance in health systems, consent, institutional review boards, data monitoring, privacy, and special populations. We describe these barriers and suggest means for understanding and overcoming them to facilitate pragmatic cluster randomized trials in health-care settings. PMID- 25733679 TI - Individualized care plans. PMID- 25733680 TI - Outcomes of a Stepcut Lengthening Calcaneal Osteotomy for Adult-Acquired Flatfoot Deformity. AB - BACKGROUND: Lateral column lengthening is used to correct abduction deformity at the midfoot and improve talar head coverage in patients with flatfoot deformity. It was our hypothesis that following a stepcut lengthening calcaneal osteotomy (SLCO), patients would have adequate correction of the deformity, a high union rate of the osteotomy, and improvement in clinical outcome scores. METHODS: We retrospectively reviewed 37 consecutive patients who underwent SLCO for the treatment of stage IIB flatfoot deformity with a minimum 2-year follow-up. Deformity correction was assessed using preoperative and postoperative weight bearing radiographs. Healing of the osteotomy was assessed by computed tomography. Clinical outcomes included the FAOS and SF-36 questionnaires. The Wilcoxon signed-rank test was used to compare clinical outcome scores. An alpha level of .05 was deemed statistically significant. RESULTS: Healing of the osteotomy occurred at a mean of 7.7 weeks postoperatively. The talonavicular (TN) coverage angle improved from 34.0 to 8.8 (P < .001), the percentage of TN uncoverage improved from 40.9% to 17.7% (P < .001), and the TN incongruency angle improved from 68.1 to 8.7 (P < .001). In addition, there was an improvement in FAOS pain (P < .001), daily activities (P < .001), sport activities (P = .006), and quality of life scores (P < .001). Overall SF-36 scores also showed improvement postoperatively (P < .001). There was no incidence of delayed union, nonunion, or graft collapse. CONCLUSION: Following SLCO, patients demonstrated excellent healing, good correction of the deformity, and improvement in clinical outcomes scores. The SLCO is an alternative to the Evans osteotomy for lateral column lengthening. LEVEL OF EVIDENCE: Level IV, retrospective case review. PMID- 25733681 TI - RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology. AB - Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) make profound contributions to both physiology and pathology. While it is widely believed that direct (PDGF-mediated) activation is the primary mode of activating PDGFRs, the discovery that they can also be activated indirectly begs the question of the relevance of the indirect mode of activating PDGFRs. In the context of a blinding eye disease, indirect activation of PDGFRalpha results in persistent signaling, which suppresses the level of p53 and thereby promotes viability of cells that drive pathogenesis. Under the same conditions, PDGFRbeta fails to undergo indirect activation. In this paper, we report that RasGAP (GTPase-activating protein of Ras) prevented indirect activation of PDGFRbeta. RasGAP, which associates with PDGFRbeta but not PDGFRalpha, reduced the level of mitochondrion-derived reactive oxygen species, which are required for enduring activation of PDGFRs. Furthermore, preventing PDGFRbeta from associating with RasGAP allowed it to signal enduringly and drive pathogenesis of a blinding eye disease. These results indicate a previously unappreciated role of RasGAP in antagonizing indirect activation of PDGFRbeta, define the underlying mechanism, and raise the possibility that PDGFRbeta-mediated diseases involve indirect activation of PDGFRbeta. PMID- 25733682 TI - The control operated by the cell cycle machinery on MEF2 stability contributes to the downregulation of CDKN1A and entry into S phase. AB - MEF2s are pleiotropic transcription factors (TFs) which supervise multiple cellular activities. During the cell cycle, MEF2s are activated at the G0/G1 transition to orchestrate the expression of the immediate early genes in response to growth factor stimulation. Here we show that, in human and murine fibroblasts, MEF2 activities are downregulated during late G1. MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. Unscheduled MEF2 transcription during the cell cycle reduces cell proliferation, whereas its containment sustains DNA replication. The CDK inhibitor p21/CDKN1A gene is a MEF2 target gene required to exert this antiproliferative influence. MEF2C and MEF2D bind a region within the first intron of CDKN1A, presenting epigenetic markers of open chromatin. Importantly, H3K27 acetylation within this regulative region depends on the presence of MEF2D. We propose that following the initial engagement in the G0/G1 transition, MEF2C and MEF2D must be polyubiquitylated and degraded during G1 progression to diminish the transcription of the CDKN1A gene, thus favoring entry into S phase. PMID- 25733683 TI - Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4. AB - Cyclin D and cyclin-dependent kinase 4 (cdk4) are overexpressed in a variety of tumors, but their levels are not accurate indicators of oncogenic activity because an accessory factor such as p27(Kip1) is required to assemble this unstable dimer. Additionally, tyrosine (Y) phosphorylation of p27 (pY88) is required to activate cdk4, acting as an "on/off switch." We identified two SH3 recruitment domains within p27 that modulate pY88, thereby modulating cdk4 activity. Via an SH3-PXXP interaction screen, we identified Brk (breast tumor related kinase) as a high-affinity p27 kinase. Modulation of Brk in breast cancer cells modulates pY88 and increases resistance to the cdk4 inhibitor PD 0332991. An alternatively spliced form of Brk (Alt Brk) which contains its SH3 domain blocks pY88 and acts as an endogenous cdk4 inhibitor, identifying a potentially targetable regulatory region within p27. Brk is overexpressed in 60% of breast carcinomas, suggesting that this facilitates cell cycle progression by modulating cdk4 through p27 Y phosphorylation. p27 has been considered a tumor suppressor, but our data strengthen the idea that it should also be considered an oncoprotein, responsible for cyclin D-cdk4 activity. PMID- 25733684 TI - Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation. AB - In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity. PMID- 25733685 TI - Nfkb1 activation by the E26 transformation-specific transcription factors PU.1 and Spi-B promotes Toll-like receptor-mediated splenic B cell proliferation. AB - Generation of antibodies against T-independent and T-dependent antigens requires Toll-like receptor (TLR) engagement on B cells for efficient responses. However, the regulation of TLR expression and responses in B cells is not well understood. PU.1 and Spi-B (encoded by Sfpi1 and Spib, respectively) are transcription factors of the E26 transformation-specific (ETS) family and are important for B cell development and function. It was found that B cells from mice knocked out for Spi-B and heterozygous for PU.1 (Sfpi1(+/-) Spib(-/-) [PUB] mice) proliferated poorly in response to TLR ligands compared to wild-type (WT) B cells. The NF-kappaB family member p50 (encoded by Nfkb1) is required for lipopolysaccharide (LPS) responsiveness in mice. PUB B cells expressed reduced Nfkb1 mRNA transcripts and p50 protein. The Nfkb1 promoter was regulated directly by PU.1 and Spi-B, as shown by reporter assays and chromatin immunoprecipitation analysis. Occupancy of the Nfkb1 promoter by PU.1 was reduced in PUB B cells compared to that in WT B cells. Finally, infection of PUB B cells with a retroviral vector encoding p50 substantially restored proliferation in response to LPS. We conclude that Nfkb1 transcriptional activation by PU.1 and Spi-B promotes TLR-mediated B cell proliferation. PMID- 25733686 TI - Hog1 targets Whi5 and Msa1 transcription factors to downregulate cyclin expression upon stress. AB - Yeast cells have developed complex mechanisms to cope with extracellular insults. An increase in external osmolarity leads to activation of the stress-activated protein kinase Hog1, which is the main regulator of adaptive responses, such as gene expression and cell cycle progression, that are essential for cellular survival. Upon osmostress, the G1-to-S transition is regulated by Hog1 through stabilization of the cyclin-dependent kinase inhibitor Sic1 and the downregulation of G1 cyclin expression by an unclear mechanism. Here, we show that Hog1 interacts with and phosphorylates components of the core cell cycle transcriptional machinery such as Whi5 and the coregulator Msa1. Phosphorylation of these two transcriptional regulators by Hog1 is essential for inhibition of G1 cyclin expression, for control of cell morphogenesis, and for maximal cell survival upon stress. The control of both Whi5 and Msa1 by Hog1 also revealed the necessity for proper coordination of budding and DNA replication. Thus, Hog1 regulates G1 cyclin transcription upon osmostress to ensure coherent passage through Start. PMID- 25733687 TI - Nucleosome spacing generated by ISWI and CHD1 remodelers is constant regardless of nucleosome density. AB - Arrays of regularly spaced nucleosomes are a hallmark of chromatin, but it remains unclear how they are generated. Recent genome-wide studies, in vitro and in vivo, showed constant nucleosome spacing even if the histone concentration was experimentally reduced. This counters the long-held assumption that nucleosome density determines spacing and calls for factors keeping spacing constant regardless of nucleosome density. We call this a clamping activity. Here, we show in a purified system that ISWI- and CHD1-type nucleosome remodelers have a clamping activity such that they not only generate regularly spaced nucleosome arrays but also generate constant spacing regardless of nucleosome density. This points to a functionally attractive nucleosome interaction that could be mediated either directly by nucleosome-nucleosome contacts or indirectly through the remodelers. Mutant Drosophila melanogaster ISWI without the Hand-Sant-Slide (HSS) domain had no detectable spacing activity even though it is known to remodel and slide nucleosomes. This suggests that the role of ISWI remodelers in generating constant spacing is not just to mediate nucleosome sliding; they actively contribute to the attractive interaction. Additional factors are necessary to set physiological spacing in absolute terms. PMID- 25733688 TI - Interaction with OGG1 is required for efficient recruitment of XRCC1 to base excision repair and maintenance of genetic stability after exposure to oxidative stress. AB - XRCC1 is an essential protein required for the maintenance of genomic stability through its implication in DNA repair. The main function of XRCC1 is associated with its role in the single-strand break (SSB) and base excision repair (BER) pathways that share several enzymatic steps. We show here that the polymorphic XRCC1 variant R194W presents a defect in its interaction with the DNA glycosylase OGG1 after oxidative stress. While proficient for single-strand break repair (SSBR), this variant does not colocalize with OGG1, reflecting a defect in its involvement in BER. Consistent with a role of XRCC1 in the coordination of the BER pathway, induction of oxidative base damage in XRCC1-deficient cells complemented with the R194W variant results in increased genetic instability as revealed by the accumulation of micronuclei. These data identify a specific molecular role for the XRCC1-OGG1 interaction in BER and provide a model for the effects of the R194W variant identified in molecular cancer epidemiology studies. PMID- 25733691 TI - The long road to renown: the 2015 Vilcek Foundation Prizes. PMID- 25733689 TI - Promyelocytic Leukemia Protein Isoform II Promotes Transcription Factor Recruitment To Activate Interferon Beta and Interferon-Responsive Gene Expression. AB - To trigger type I interferon (IFN) responses, pattern recognition receptors activate signaling cascades that lead to transcription of IFN and IFN-stimulated genes (ISGs). The promyelocytic leukemia (PML) protein has been implicated in these responses, although its role has not been defined. Here, we show that PML isoform II (PML-II) is specifically required for efficient induction of IFN-beta transcription and of numerous ISGs, acting at the point of transcriptional complex assembly on target gene promoters. PML-II associated with specific transcription factors NF-kappaB and STAT1, as well as the coactivator CREB binding protein (CBP), to facilitate transcriptional complex formation. The absence of PML-II substantially reduced binding of these factors and IFN regulatory factor 3 (IRF3) to IFN-beta or ISGs promoters and sharply reduced gene activation. The unique C-terminal domain of PML-II was essential for its activity, while the N-terminal RBCC motif common to all PML isoforms was dispensable. We propose a model in which PML-II contributes to the transcription of multiple genes via the association of its C-terminal domain with relevant transcription complexes, which promotes the stable assembly of these complexes at promoters/enhancers of target genes, and that in this way PML-II plays a significant role in the development of type I IFN responses. PMID- 25733690 TI - Glycan motif profiling reveals plasma sialyl-lewis x elevations in pancreatic cancers that are negative for sialyl-lewis A. AB - The sialyl-Lewis A (sLeA) glycan forms the basis of the CA19-9 assay and is the current best biomarker for pancreatic cancer, but because it is not elevated in ~25% of pancreatic cancers, it is not useful for early diagnosis. We hypothesized that sLeA-low tumors secrete glycans that are related to sLeA but not detectable by CA19-9 antibodies. We used a method called motif profiling to predict that a structural isomer of sLeA called sialyl-Lewis X (sLeX) is elevated in the plasma of some sLeA-low cancers. We corroborated this prediction in a set of 48 plasma samples and in a blinded set of 200 samples. An antibody sandwich assay formed by the capture and detection of sLeX was elevated in 13 of 69 cancers that were not elevated in sLeA, and a novel hybrid assay of sLeA capture and sLeX detected 24 of 69 sLeA-low cancers. A two-marker panel based on combined sLeA and sLeX detection differentiated 109 pancreatic cancers from 91 benign pancreatic diseases with 79% accuracy (74% sensitivity and 78% specificity), significantly better than sLeA alone, which yielded 68% accuracy (65% sensitivity and 71% specificity). Furthermore, sLeX staining was evident in tumors that do not elevate plasma sLeA, including those with poorly differentiated ductal adenocarcinoma. Thus, glycan-based biomarkers could characterize distinct subgroups of patients. In addition, the combined use of sLeA and sLeX, or related glycans, could lead to a biomarker panel that is useful in the clinical diagnosis of pancreatic cancer. Precis: This paper shows that a structural isomer of the current best biomarker for pancreatic cancer, CA19-9, is elevated in the plasma of patients who are low in CA19-9, potentially enabling more comprehensive detection and classification of pancreatic cancers. PMID- 25733692 TI - Meeting report on immunoreceptors 2014. PMID- 25733693 TI - Erratum. PMID- 25733694 TI - Erratum. PMID- 25733695 TI - Retraction. PMID- 25733696 TI - Predicting morbidity and mortality in acute pancreatitis in an Indian population: a comparative study of the BISAP score, Ranson's score and CT severity index. AB - OBJECTIVE: Our aim was to prospectively evaluate the accuracy of the bedside index for severity in acute pancreatitis (BISAP) score in predicting mortality, as well as intermediate markers of severity, in a tertiary care centre in east central India, which caters mostly for an economically underprivileged population. METHODS: A total of 119 consecutive cases with acute pancreatitis were admitted to our institution between November 2012 and October 2014. BISAP scores were calculated for all cases, within 24 hours of presentation. Ranson's score and computed tomography severity index (CTSI) were also established. The respective abilities of the three scoring systems to predict mortality was evaluated using trend and discrimination analysis. The optimal cut-off score for mortality from the receiver operating characteristics (ROC) curve was used to evaluate the development of persistent organ failure and pancreatic necrosis (PNec). RESULTS: Of the 119 cases, 42 (35.2%) developed organ failure and were classified as severe acute pancreatitis (SAP), 47 (39.5%) developed PNec, and 12 (10.1%) died. The area under the curve (AUC) results for BISAP score in predicting SAP, PNec, and mortality were 0.962, 0.934 and 0.846, respectively. Ranson's score showed a slightly lower accuracy for predicting SAP (AUC 0.956) and mortality (AUC 0.841). CTSI was the most accurate in predicting PNec, with an AUC of 0.958. The sensitivity and specificity of BISAP score, with a cut-off of >=3 in predicting mortality, were 100% and 69.2%, respectively. CONCLUSIONS: The BISAP score represents a simple way of identifying, within 24 hours of presentation, patients at greater risk of dying and the development of intermediate markers of severity. This risk stratification method can be utilized to improve clinical care and facilitate enrolment in clinical trials. PMID- 25733697 TI - Aberrant LPL Expression, Driven by STAT3, Mediates Free Fatty Acid Metabolism in CLL Cells. AB - While reviewing chronic lymphocytic leukemia (CLL) bone marrow slides, we identified cytoplasmic lipid vacuoles in CLL cells but not in normal B cells. Because lipoprotein lipase (LPL), which catalyzes hydrolysis of triglycerides into free fatty acids (FFA), is aberrantly expressed in CLL, we investigated whether LPL regulates the oxidative metabolic capacity of CLL cells. We found that unlike normal B cells, CLL cells metabolize FFAs. Because STAT3 is constitutively activated in CLL cells and because we identified putative STAT3 binding sites in the LPL promoter, we sought to determine whether STAT3 drives the aberrant expression of LPL. Transfection of luciferase reporter gene constructs driven by LPL promoter fragments into MM1 cells revealed that STAT3 activates the LPL promoter. In addition, chromatin immunoprecipitation confirmed that STAT3 binds to the LPL promoter. Furthermore, transfection of CLL cells with STAT3-shRNA downregulated LPL transcripts and protein levels, confirming that STAT3 activates the LPL gene. Finally, transfection of CLL cells with LPL-siRNAs decreased the capacity of CLL cells to oxidize FFAs and reduced cell viability. IMPLICATIONS: Our study suggests that CLL cells adopt their metabolism to oxidize FFA. Activated STAT3 induces LPL, which catalyzes the hydrolysis of triglycerides into FFA. Therefore, inhibition of STAT3 is likely to prevent the capacity of CLL cells to utilize FFA. PMID- 25733700 TI - For optimal outcomes, children belong in homes. PMID- 25733698 TI - COX-2 Elevates Oncogenic miR-526b in Breast Cancer by EP4 Activation. AB - MicroRNAs (miRs) are small regulatory molecules emerging as potential biomarkers in cancer. Previously, it was shown that COX-2 expression promotes breast cancer progression via multiple mechanisms, including induction of stem-like cells (SLC), owing to activation of the prostaglandin E2 receptor EP4 (PTGER4). COX-2 overexpression also upregulated microRNA-526b (miR-526b), in association with aggressive phenotype. Here, the functional roles of miR-526b in breast cancer and the mechanistic role of EP4 signaling in miR-526b upregulation were examined. A positive correlation was noted between miR-526b and COX-2 mRNA expression in COX 2 disparate breast cancer cell lines. Stable overexpression of miR-526b in poorly metastatic MCF7 and SKBR3 cell lines resulted in increased cellular migration, invasion, EMT phenotype and enhanced tumorsphere formation in vitro, and lung colony formation in vivo in immunodeficient mice. Conversely, knockdown of miR 526b in aggressive MCF7-COX-2 and SKBR3-COX-2 cells reduced oncogenic functions and reversed the EMT phenotype, in vitro. Furthermore, it was determined that miR 526b expression is dependent on EP4 receptor activity and downstream PI3K-AKT and cyclic AMP (cAMP) signaling pathways. PI3K-AKT inhibitors blocked EP4 agonist mediated miR-526b upregulation and tumorsphere formation in MCF7 and SKBR3 cells. NF-kappaB inhibitor abrogates EP agonist-stimulated miRNA expression in MCF7 and T47D cells, indicating that the NF-kappaB pathway is also involved in miR-526b regulation. In addition, inhibition of COX-2, EP4, PI3K, and PKA in COX-2 overexpressing cells downregulated miR-526b and its functions in vitro. Finally, miR-526b expression was significantly higher in cancerous than in noncancerous breast tissues and associated with reduced patient survival. In conclusion, miR 526b promotes breast cancer progression, SLC-phenotype through EP4-mediated signaling, and correlates with breast cancer patient survival. IMPLICATIONS: This study presents novel findings that miRNA 526b is a COX-2 upregulated, oncogenic miRNA promoting SLCs, the expression of which follows EP4 receptor-mediated signaling, and is a promising biomarker for monitoring and personalizing breast cancer therapy. PMID- 25733701 TI - Response to out-of-home placement clinical report. PMID- 25733702 TI - Author's response. PMID- 25733705 TI - CCR 20th anniversary commentary: In the beginning, there was PS-341. AB - Proteasome inhibitors have a 20-year history in cancer therapy. The first proteasome inhibitor, bortezomib, a breakthrough treatment for multiple myeloma, moved rapidly through development from the bench in 1994 to first FDA approval in 2003. Clinical Cancer Research has chronicled the development of proteasome inhibitors with publication of reports on bortezomib, carfilzomib, and the oral proteasome inhibitor ixazomib (MLN9708). PMID- 25733706 TI - CCR 20th anniversary commentary: Preclinical study of proteasome inhibitor bortezomib in head and neck cancer. AB - In a study published in the May 1, 2001, issue of Clinical Cancer Research, Sunwoo and colleagues provided evidence for proteasome inhibition of NF-kappaB and tumorigenesis, supporting early-phase clinical trials in solid malignancies of the upper aerodigestive tract. Subsequent clinical studies uncovered a dichotomy of responses in patients with hematopoietic and solid malignancies, and the mechanisms of resistance. PMID- 25733707 TI - Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. AB - Emerging evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy even for tumors that were historically considered as nonimmunogenic. Immunotherapy is emerging as a major modality in non-small cell lung cancer (NSCLC) treatment focusing on vaccine approaches to elicit specific immune responses and development of inhibitors of the molecular mediators of cancer-induced immunosuppression (immune checkpoints) to boost antitumor immune responses. Amplification of the host response against evolving tumors through vaccination is being investigated in ongoing clinical trials with tumor cell vaccines; however, the clinical efficacy of these agents has been limited. Blocking inhibitory pathways such as the CTL antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) checkpoint pathways with mAbs has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand 1 (PD-L1) antibodies have shown durable responses in NSCLC, with a favorable safety profile and manageable side effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naive patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. PMID- 25733709 TI - Rick Horwitz: words do not suffice. PMID- 25733708 TI - Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression. AB - PURPOSE: To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI). EXPERIMENTAL DESIGN: Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting. RESULTS: Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines. CONCLUSIONS: In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal IRI clinical activity are warranted. PMID- 25733710 TI - Assessing actin's growth rate. PMID- 25733712 TI - Stemness factor Sall4 is required for DNA damage response in embryonic stem cells. AB - Mouse embryonic stem cells (ESCs) are genetically more stable than somatic cells, thereby preventing the passage of genomic abnormalities to their derivatives including germ cells. The underlying mechanisms, however, remain largely unclear. In this paper, we show that the stemness factor Sall4 is required for activating the critical Ataxia Telangiectasia Mutated (ATM)-dependent cellular responses to DNA double-stranded breaks (DSBs) in mouse ESCs and confer their resistance to DSB-induced cytotoxicity. Sall4 is rapidly mobilized to the sites of DSBs after DNA damage. Furthermore, Sall4 interacts with Rad50 and stabilizes the Mre11 Rad50-Nbs1 complex for the efficient recruitment and activation of ATM. Sall4 also interacts with Baf60a, a member of the SWI/SNF (switch/sucrose nonfermentable) ATP-dependent chromatin-remodeling complex, which is responsible for recruiting Sall4 to the site of DNA DSB damage. Our findings provide novel mechanisms to coordinate stemness of ESCs with DNA damage response, ensuring genomic stability during the expansion of ESCs. PMID- 25733711 TI - The cell biology of fat expansion. AB - Adipose tissue is a complex, multicellular organ that profoundly influences the function of nearly all other organ systems through its diverse metabolite and adipokine secretome. Adipocytes are the primary cell type of adipose tissue and play a key role in maintaining energy homeostasis. The efficiency with which adipose tissue responds to whole-body energetic demands reflects the ability of adipocytes to adapt to an altered nutrient environment, and has profound systemic implications. Deciphering adipocyte cell biology is an important component of understanding how the aberrant physiology of expanding adipose tissue contributes to the metabolic dysregulation associated with obesity. PMID- 25733713 TI - DNA2 drives processing and restart of reversed replication forks in human cells. AB - Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5'-to-3' polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors. PMID- 25733714 TI - Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. AB - Replication fork reversal protects forks from breakage after poisoning of Topoisomerase 1. We here investigated fork progression and chromosomal breakage in human cells in response to a panel of sublethal genotoxic treatments, using other topoisomerase poisons, DNA synthesis inhibitors, interstrand cross-linking inducers, and base-damaging agents. We used electron microscopy to visualize fork architecture under these conditions and analyzed the association of specific molecular features with checkpoint activation. Our data identify replication fork uncoupling and reversal as global responses to genotoxic treatments. Both events are frequent even after mild treatments that do not affect fork integrity, nor activate checkpoints. Fork reversal was found to be dependent on the central homologous recombination factor RAD51, which is consistently present at replication forks independently of their breakage, and to be antagonized by poly (ADP-ribose) polymerase/RECQ1-regulated restart. Our work establishes remodeling of uncoupled forks as a pivotal RAD51-regulated response to genotoxic stress in human cells and as a promising target to potentiate cancer chemotherapy. PMID- 25733716 TI - Xenografts as models of clonal selection and acquired resistance to therapy. PMID- 25733715 TI - GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin cytoskeleton dynamics. AB - Intermediate filament (IF) attachment to intercellular junctions is required for skin and heart integrity, but how the strength and dynamics of this attachment are modulated during normal and pathological remodeling is poorly understood. We show that glycogen synthase kinase 3 (GSK3) and protein arginine methyltransferase 1 (PRMT-1) cooperate to orchestrate a series of posttranslational modifications on the IF-anchoring protein desmoplakin (DP) that play an essential role in coordinating cytoskeletal dynamics and cellular adhesion. Front-end electron transfer dissociation mass spectrometry analyses of DP revealed six novel serine phosphorylation sites dependent on GSK3 signaling and four novel arginine methylation sites including R2834, the mutation of which has been associated with arrhythmogenic cardiomyopathy (AC). Inhibition of GSK3 or PRMT-1 or overexpression of the AC-associated mutant R2834H enhanced DP-IF associations and delayed junction assembly. R2834H blocked the GSK3 phosphorylation cascade and reduced DP-GSK3 interactions in cultured keratinocytes and in the hearts of transgenic R2834H DP mice. Interference with this regulatory machinery may contribute to skin and heart diseases. PMID- 25733718 TI - Polypharmacy Among Adults Aged 65 Years and Older in the United States: 1988 2010. AB - BACKGROUND: Older adults frequently have several chronic health conditions which require multiple medications. We illustrated trends in prescription medication use over 20 years in the United States, and described characteristics of older adults using multiple medications in 2009-2010. METHODS: Participants included 13,869 adults aged 65 years and older in the National Health & Nutrition Examination Survey (1988-2010). Prescription medication use was verified by medication containers. Potentially inappropriate medications were defined by the 2003 Beers Criteria. RESULTS: Between 1988 and 2010 the median number of prescription medications used among adults aged 65 and older doubled from 2 to 4, and the proportion taking >=5 medications tripled from 12.8% (95% confidence interval: 11.1, 14.8) to 39.0% (35.8, 42.3).These increases were driven, in part, by rising use of cardioprotective and antidepressant medications. Use of potentially inappropriate medications decreased from 28.2% (25.5, 31.0) to 15.1% (13.2, 17.3) between 1988 and 2010. Higher medication use was associated with higher prevalence of functional limitation, activities of daily living limitation, and confusion/memory problems in 2009-2010, although these associations did not remain after adjustment for covariates. In multivariable models, older age, number of chronic conditions, and annual health care visits were associated with increased odds of using both 1-4 and >=5 medications. Additionally, body mass index, higher income-poverty ratio, former smoking, and non-black non-white race were associated with use of >=5 medications. CONCLUSIONS: Prescription medication use increased dramatically among older adults between 1988 and 2010. Contemporary older adults on multiple medications have worse health status compared with those on less medications, and appear to be a vulnerable population. PMID- 25733719 TI - Plantarflexor Muscle-Tendon Properties are Associated With Mobility in Healthy Older Adults. AB - BACKGROUND: Muscle mass, strength, and power are known determinants of mobility in older adults but there is limited knowledge on the influence of muscle architecture or tendon properties on mobility. The purpose of this study was to examine the relationship between mobility and plantarflexor muscle-tendon properties in healthy older adults. METHODS: A total of 52 subjects (age 70-81 years) were measured for 6-minute walk test (6MWT), timed "up and go"-test (TUG), isometric plantarflexion strength, Achilles tendon stiffness, triceps surae muscle architecture, lower extremity lean mass, isometric leg extension strength, and leg extension power. Partial correlations and multivariate regression models adjusted for sex, age, body mass, and height were used to examine the relationship between mobility (6MWT and TUG) and lower limb muscle-tendon properties. RESULTS: Multivariate regression models revealed that Achilles tendon stiffness (p = .020), plantarflexion strength (p = .022), and medial gastrocnemius fascicle length (p = .046) were independently associated with 6MWT. Plantarflexion strength (p = .037) and soleus fascicle length (p = .031) were independently associated with TUG. CONCLUSIONS: Plantarflexor muscle-tendon properties were associated with mobility in older adults independent of lower extremity lean mass, leg extension strength, or power. Plantarflexion strength was a stronger predictor of mobility than leg extension strength or power. The novel finding of this study was that muscle architecture and tendon properties explained interindividual differences in mobility. This study highlights the importance of the plantarflexors for mobility in older adults and provides understanding of possible mechanisms of age-related decline in mobility. PMID- 25733721 TI - Bullying, social hierarchies, poverty, and health outcomes. PMID- 25733723 TI - Social dominance in childhood and its evolutionary underpinnings: why it matters and what we can do. PMID- 25733722 TI - Social dominance, school bullying, and child health: what are our ethical obligations to the very young? AB - BACKGROUND: Recent research shows that by age 5, children form rigid social hierarchies, with some children consistently subordinated, and then later, bullied. Further, several studies suggest that enduring mental and physical harm follow. It is time to analyze the health burdens posed by early social dominance and to consider the ethical implications of ongoing socially caused harms. METHODS: First, we reviewed research demonstrating the health impact of early childhood subordination. Second, we used philosophical conceptions of children's rights and social justice to consider whether children have a right to protection and who has an obligation to protect them from social harms. RESULTS: Collectively, recent studies show that early subordination is instantiated biologically, increasing lifetime physical and mental health problems. The pervasive, and enduring nature of these harms leads us to argue that children have a right to be protected. Further, society has a role responsibility to protect children because society conscripts children into schools. Society's promise to parents that schools will be fiduciaries entails an obligation to safeguard each child's right to a reasonably open future. Importantly, this role responsibility holds independently of bearing any causal responsibility for the harm. This new argument based on protecting from harm is much stronger than previous equality of opportunity arguments, and applies broadly to other social determinants of health. CONCLUSIONS: Social institutions have a role responsibility to protect children that is not dependent on playing a causal role in the harm. Children's rights to protection from social harms can be as strong as their rights to protection from direct bodily harms. PMID- 25733724 TI - The ethical and policy implications of research on income inequality and child well-being. AB - BACKGROUND AND OBJECTIVES: Child well-being is important for lifelong health and well-being. Although there is a robust evidence base linking social determinants of health (eg, relative poverty and income inequality) to child well-being, social and public health policy tends to focus on interventions to mitigate their effects, rather than remove the root causes. The goal of this study was to examine associations between child well-being and income inequality. METHODS: We compared reported rates of childhood well-being in the 2007 and 2013 UNICEF reports on child well-being in wealthy countries. Twenty indicators of child well being (excluding child poverty) were defined consistently in both the 2007 and 2013 reports. These variables were used to create an indicator of change in child well-being over the approximate decade 2000 to 2010. For our analyses of income inequality, we used the Organization for Economic Cooperation and Development Gini coefficient of income inequality for 2009 and change between 2000 and 2009, respectively. RESULTS: The overall index of child well-being in 2013 was closely and negatively correlated with income inequality (r = -0.60, P = .004) but not with average income (r = -0.3460, P = .12). Adjustment for income inequality, children in relative poverty, and the child poverty gap did not change the lack of association between average income and child well-being in 2013 in wealthy countries. Between 2000 and 2010, child well-being scores improved most in Italy, Norway, Portugal, the United Kingdom, and Germany. The biggest declines were seen in Sweden, Canada, Japan, Switzerland, and France. Countries that experienced the largest increases in income inequality had significantly greater declines in child well-being (r = -0.51, P = .02). CONCLUSIONS: Children born into socioeconomically disadvantaged families suffer worse child well-being and its lifelong implications, in all societies, worldwide. Our analyses show, however, that some wealthy societies are able to mitigate these inequalities; these societies have better child well-being, on average. This outcome has less to do with specific welfare policies or targeted interventions for poor children than to a societal commitment to greater equality. PMID- 25733725 TI - Neighborhood adversity, child health, and the role for community development. AB - Despite medical advances, childhood health and well-being have not been broadly achieved due to rising chronic diseases and conditions related to child poverty. Family and neighborhood living conditions can have lasting consequences for health, with community adversity affecting health outcomes in significant part through stress response and increased allostatic load. Exposure to this "toxic stress" influences gene expression and brain development with direct and indirect negative consequences for health. Ensuring healthy child development requires improving conditions in distressed, high-poverty neighborhoods by reducing children's exposure to neighborhood stressors and supporting good family and caregiver functioning. The community development industry invests more than $200 billion annually in low-income neighborhoods, with the goal of improving living conditions for residents. The most impactful investments have transformed neighborhoods by integrating across sectors to address both the built environment and the social and service environment. By addressing many facets of the social determinants of health at once, these efforts suggest substantial results for children, but health outcomes generally have not been considered or evaluated. Increased partnership between the health sector and community development can bring health outcomes explicitly into focus for community development investments, help optimize intervention strategies for health, and provide natural experiments to build the evidence base for holistic interventions for disadvantaged children. The problems and potential solutions are beyond the scope of practicing pediatricians, but the community development sector stands ready to engage in shared efforts to improve the health and development of our most at risk children. PMID- 25733726 TI - Bone morphogenetic protein 7 attenuates epithelial-mesenchymal transition induced by silica. AB - The epithelial-mesenchymal transition (EMT) is a critical process in the pulmonary fibrosis. It has been reported that bone morphogenetic protein 7 (BMP 7) was able to reverse EMT in proximal tubular cells. Therefore, we test the hypothesis that EMT contributes to silica-induced pulmonary fibrosis and BMP-7 inhibits EMT in silica-induced pulmonary fibrosis. Progressive silica-induced pulmonary fibrosis in the rat was used as a model of silicosis. Epithelial and mesenchymal markers were measured from rat fibrotic lungs. Then the effects of BMP-7 on the EMT were further confirmed in A549 cells. There are increases of vimentin as a mesenchymal marker and decreases of E-cadherin as an epithelial marker in the silica-exposed rat lungs, which is in agreement with the A549 cells data. However, BMP-7 treatment significantly reduced expression of vimentin in the rat pulmonary fibrosis model and in A549 cells. In conclusion, EMT contributes to silica-induced pulmonary fibrosis. Meanwhile, the treatment of BMP 7 can inhibit silica-induced EMT in vitro and in vivo. PMID- 25733727 TI - Inconsistency between manganese superoxide dismutase expression and its activity involved in the degeneration of recognition function induced by chronic aluminum overloading in mice. AB - Manganese (Mn) superoxide dismutase (SOD) is mainly located in mitochondrial matrix and is responsible for scavenging about 80% free radicals from oxidative and phospharylative process in mitochondria. It was reported that the insufficiency of Mn SOD expression or activity was connected to the development of neurodegenerative diseases. In this article, we investigated the time course related to the changes of Mn SOD expression and its activity from mouse brain as well as the recognition dysfunction in chronic aluminum (Al) overloading mice. Aluminum gluconate solution (equal to Al 400 mg/kg) was given to mice once a day, 6 days per week for 12 weeks via intragastric gavage. The learning and memory function, malondialdehyde (MDA) level as well as expression and activity of Mn SOD in cortex were determined. It was found that function of passive learning and memory and spatial recognition decreased, MDA level and Mn SOD expression increased during the period of chronic Al loading, but the Mn SOD activity rose from the 4th week and then decreased from the 8th week in cortex in Al overloading mice compared with the control. The results indicated that the inconsistency between Mn SOD expression and its activity might contribute to the development of recognition dysfunction induced by chronic Al overload. PMID- 25733728 TI - Effect of recombinant human erythropoietin on mitomycin C-induced oxidative stress and genotoxicity in rat kidney and heart tissues. AB - Mitomycin C (MMC) is an antineoplastic agent used for the treatment of several human malignancies. Nevertheless, the prolonged use of the drug may result in a serious heart and kidney injuries. Recombinant human erythropoietin (rhEPO) has recently been shown to exert an important cytoprotective effect in experimental brain injury and ischemic acute renal failure. The aim of the present work is to investigate the cardioprotective and renoprotective effects of rhEPO against MMC induced oxidative damage and genotoxicity. Our results showed that MMC induced oxidative stress and DNA damage. rhEPO administration in any treatment conditions decreased oxidative damage induced by MMC. It reduced malondialdehyde and protein carbonyl levels. rhEPO ameliorated reduced glutathione plus oxidized glutathione modulation and the increased catalase activity after MMC treatment. Furthermore, rhEPO restored DNA damage caused by MMC. We concluded that rhEPO administration especially in pretreatment condition protected rats against MMC-induced heart and renal oxidative stress and genotoxicity. PMID- 25733729 TI - Thrombolytic therapy in a patient with inferolateral myocardial infarction after carbon monoxide poisoning. AB - INTRODUCTION: ST segment elevation myocardial infarction (STEMI) due to coronary artery occlusion caused by intracoronary thrombosis in the setting of acute carbon monoxide (CO) poisoning is a very rare presentation. We present a case of intracoronary large and mobile thrombus formation after CO poisoning. CASE PRESENTATION: A previously healthy 50-year-old woman was referred for CO poisoning. She had chest pain after exposure to CO. Her initial mental status was preoccupied with chest pain. Her initial CO fraction was 28.1%, and initial laboratory data showed creatine kinase-myocardial isoenzyme of 134 U/L (upper limit 25 U/L) and troponin I of >50 ng/mL (upper limit 0.06 ng/mL). Electrocardiography was carried out on admission, revealing an ST segment elevation in the inferolateral leads. After initial evaluation, coronary angiography was performed and an intracoronary large mobile thrombus was seen in the proximal left anterior descending (LAD) artery with no significant stenosis. We administered tenecteplase with heparin. After the thrombolytic therapy, ST elevation in the inferolateral leads resolved. Repeat angiography was performed after 24 h; the thrombus in LAD had resolved. The patient was discharged after 5 days, with persistent Q wave in the inferior leads and mild hypokinesia of the inferoposterior wall suggesting myocardial injury. CONCLUSION: We describe intracoronary thrombus formation induced by CO poisoning. Because intracoronary thrombus can result in myocardial infarction, its consideration following CO poisoning is important. Patients with CO poisoning who have symptoms of STEMI should be carefully evaluated with serial electrocardiograms, cardiac biomarkers, and an echocardiogram. When there is evidence of acute myocardial injury, a primer in coronary angiography can determine which patients could benefit from intervention. PMID- 25733730 TI - The Michigan Healthy School Action Tools process generates improvements in school nutrition policies and practices, and student dietary intake. AB - The Michigan Healthy School Action Tools (HSAT) is an online self-assessment and action planning process for schools seeking to improve their health policies and practices. The School Nutrition Advances Kids study, a 2-year quasi-experimental intervention with low-income middle schools, evaluated whether completing the HSAT with a facilitator assistance and small grant funding resulted in (1) improvements in school nutrition practices and policies and (2) improvements in student dietary intake. A total of 65 low-income Michigan middle schools participated in the study. The Block Youth Food Frequency Questionnaire was completed by 1,176 seventh-grade students at baseline and in eighth grade (during intervention). Schools reported nutrition-related policies and practices/education using the School Environment and Policy Survey. Schools completing the HSAT were compared to schools that did not complete the HSAT with regard to number of policy and practice changes and student dietary intake. Schools that completed the HSAT made significantly more nutrition practice/education changes than schools that did not complete the HSAT, and students in those schools made dietary improvements in fruit, fiber, and cholesterol intake. The Michigan HSAT process is an effective strategy to initiate improvements in nutrition policies and practices within schools, and to improve student dietary intake. PMID- 25733731 TI - Medical pot users sue for right to grow. PMID- 25733732 TI - A 66-year-old woman with spontaneous rib fracture. PMID- 25733734 TI - Radiation-dose knowledge needs improving. PMID- 25733735 TI - Brief interventions for alcohol misuse. PMID- 25733736 TI - Nipple discharge. PMID- 25733737 TI - No more "internes": CAIR rebrands. PMID- 25733738 TI - Repeated flu shots may blunt effectiveness. PMID- 25733739 TI - A systemic failure to address at-risk drinking and alcohol use disorders: the Canadian story. PMID- 25733740 TI - Healing words. PMID- 25733741 TI - Effectiveness of interventions designed to reduce the use of imaging for low-back pain: a systematic review. AB - BACKGROUND: Rates of imaging for low-back pain are high and are associated with increased health care costs and radiation exposure as well as potentially poorer patient outcomes. We conducted a systematic review to investigate the effectiveness of interventions aimed at reducing the use of imaging for low-back pain. METHODS: We searched MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials from the earliest records to June 23, 2014. We included randomized controlled trials, controlled clinical trials and interrupted time series studies that assessed interventions designed to reduce the use of imaging in any clinical setting, including primary, emergency and specialist care. Two independent reviewers extracted data and assessed risk of bias. We used raw data on imaging rates to calculate summary statistics. Study heterogeneity prevented meta-analysis. RESULTS: A total of 8500 records were identified through the literature search. Of the 54 potentially eligible studies reviewed in full, 7 were included in our review. Clinical decision support involving a modified referral form in a hospital setting reduced imaging by 36.8% (95% confidence interval [CI] 33.2% to 40.5%). Targeted reminders to primary care physicians of appropriate indications for imaging reduced referrals for imaging by 22.5% (95% CI 8.4% to 36.8%). Interventions that used practitioner audits and feedback, practitioner education or guideline dissemination did not significantly reduce imaging rates. Lack of power within some of the included studies resulted in lack of statistical significance despite potentially clinically important effects. INTERPRETATION: Clinical decision support in a hospital setting and targeted reminders to primary care doctors were effective interventions in reducing the use of imaging for low-back pain. These are potentially low-cost interventions that would substantially decrease medical expenditures associated with the management of low-back pain. PMID- 25733742 TI - On the Association Between Repeat Bully Victimizations and Carrying a Firearm: Evidence in a National Sample. AB - Bullying is a significant public concern. The purpose of the present study is to investigate whether being repeatedly victimized by a bully during childhood and adolescence is associated with gun carrying in adolescence and adulthood. Using data from the National Longitudinal Survey of Youth 1997, we found that just over one fourth of the respondents reported carrying a gun at some point in their lifetime. Respondents experiencing repeat bully victimizations reported higher rates of gun carrying during the last 12 months and the last 30 days. No support was found for the association of repeat bully victimizations and carrying a gun to school. Individuals victimized during childhood (before the age of 12) and during adolescence were found to be at risk of carrying a gun later in the life course. Repeat bully victimizations should be considered a marker for gun carrying behaviors in adolescence and adulthood. PMID- 25733743 TI - Randomized Trial of Group Music Therapy With Chinese Prisoners: Impact on Anxiety, Depression, and Self-Esteem. AB - This study investigated the effects of group music therapy on improving anxiety, depression, and self-esteem in Chinese prisoners. Two-hundred male prisoners were randomly assigned to music therapy (n = 100) or standard care (n = 100). The music therapy had 20 sessions of group therapy compared with standard care. Anxiety (State and Trait Anxiety Inventory [STAI]), depression (Beck Depression Inventory [BDI]), and self-esteem (Texas Social Behavior Inventory [TSBI], Rosenberg Self-Esteem Inventory [RSI]) were measured by standardized scales at baseline, mid-program, and post-program. Data were analyzed based on the intention to treat principle. Compared with standard care, anxiety and depression in the music therapy condition decreased significantly at mid-test and post-test; self-esteem improved significantly at mid-test (TSBI) and at post-test (TSBI, RSI). Improvements were greater in younger participants (STAI-Trait, RSI) and/or in those with a lower level of education (STAI-State, STAI-Trait). Group music therapy seems to be effective in improving anxiety, depression, and self-esteem and was shown to be most beneficial for prisoners of younger age or with lower education level. PMID- 25733744 TI - University Students' Views on Political Influences and the Status of Law in Post Reform China: A Moderation and Mediation Analysis. AB - Scholars categorize societies into "rule of man" societies, "rule by law" societies, and "rule of law" societies on the basis of a status of law. After 1978, China's leaders invoked law as an alternative to the arbitrariness of the Cultural Revolution. In this study, we used quantitative methods to explore university students' views on the status of law in post-reform China. Surveys were conducted in three national universities located in different regions of China. Responses from university students show that their perceptions of well developed legislation and perceptions of the publicity of law are associated with their perceptions of equality before the law, which could be the consequence of a "rule of law" system. However, the study found that university students are of the view that the political nature of legislation and interference in law enforcement moderate the relationship between legislation and equality before the law. The political nature of legislation also moderates the mediation effect of interference in law enforcement between law publicity and equality before the law. As such, the article concludes that although university students are no longer primary movers in China's social and political development after the Tiananmen incident, they are still knowledgeable if not critical about the status of law and its political implications. PMID- 25733745 TI - The Thief With a Thousand Faces and the Victim With None: Identifying Determinants for Online Identity Theft Victimization With Routine Activity Theory. AB - Available evidence suggests that identity theft is a growing problem that has significant consequences for victims, not the least of which is billions of dollars in financial losses. However, very little is known about the correlates or causes of identity theft victimization. Utilizing a nationally representative sample of individuals from the Canadian General Social Survey, the current study attempts to address this deficiency by examining the link between victims' online routine activities and their online identity theft victimization. It was found that certain routine activities directly influence the likelihood of experiencing identity theft. Potential research and policy implications also are discussed. PMID- 25733746 TI - Late preterm birth and neurocognitive performance in late adulthood: a birth cohort study. AB - OBJECTIVES: We studied if late preterm birth (34 weeks 0 days-36 weeks 6 days of gestation) is associated with performance on the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) in late adulthood and if maximum attained lifetime education moderated these associations. METHODS: Participants were 919 Finnish men and women born between 1934 and 1944, who participated in the Helsinki Birth Cohort Study. They underwent the CERAD-NB at a mean age of 68.1 years. Data regarding gestational age (late preterm versus term) were extracted from hospital birth records, and educational attainment data were gathered from Statistics Finland. RESULTS: After adjustment for major confounders, those born late preterm scored lower on word list recognition (mean difference: -0.33 SD; P = .03) than those born at term. Among those who had attained a basic or upper secondary education, late preterm birth was associated with lower scores on word list recognition, constructional praxis, constructional praxis recall, clock drawing, Mini-Mental State Examination, and memory total and CERAD total 2 compound scores (mean differences: >0.40 SD; P values <.05), and had a 2.70 times higher risk of mild cognitive impairment (Mini-Mental State Examination score: <26 points) (P = .02). Among those with tertiary levels of education, late preterm birth was not associated with CERAD-NB scores. CONCLUSIONS: Our findings offer new insight into the lifelong consequences of late preterm birth, and they add late preterm birth as a novel risk factor to the list of neurocognitive impairment in late adulthood. Our findings also suggest that attained lifetime education may mitigate aging-related neurocognitive impairment, especially among those born late preterm. PMID- 25733747 TI - Antipsychotic medication prescribing in children enrolled in Medicaid. AB - BACKGROUND: Although the increase in treatment of children and adolescents with antipsychotic medications has been well documented, much less is known about the factors related to the use of these agents and how closely the treatment follows best practice recommendations. METHODS: Prescribers of each antipsychotic medication prescription issued for a Medicaid-insured child in Vermont aged <18 years were sent a prior authorization survey that assessed several domains including the clinical indication, other treatments, metabolic monitoring, prescriber specialty, and prescription origin. These variables were combined to categorize prescriptions as following indications approved by the US Food and Drug Administration (FDA) and best practice guidelines. RESULTS: The response rate of the survey was 80%, with 677 surveys from 147 prescribers available for analysis; more than one-half of the respondents were primary care clinicians. Overall, the clinical indication for an antipsychotic prescription followed best practice guidelines 91.7% of the time, with overall best practice guidelines followed at a rate of 50.1%. An FDA indication was followed in 27.2% of cases. Psychiatrists were significantly more likely to follow best practice guidelines than nonpsychiatrists. Antipsychotic medications were typically used only after other pharmacologic and nonpharmacologic treatments were ineffective, although previous treatment with cognitive-behavioral therapy was uncommon (15.5%). Metabolic monitoring that included serial laboratory tests was reported in 57.2% of cases. CONCLUSIONS: Current prescribing patterns of antipsychotic medications for children and adolescents follow best practice guidelines approximately one half of the time, with nonadherence often related to lack of metabolic monitoring. PMID- 25733748 TI - Another step towards celiac screening. PMID- 25733749 TI - Early intervention for toddlers with language delays: a randomized controlled trial. AB - OBJECTIVE: Early interventions for toddlers with expressive and receptive language delays have not resulted in positive expressive language outcomes. This randomized controlled trial tested the effects on language outcomes of a caregiver-implemented communication intervention targeting toddlers at risk for persistent language delays. METHODS: Participants included 97 toddlers, who were between 24 and 42 months with language scores at least 1.33 SDs below the normative mean and no other developmental delays, and their caregivers. Toddlers were randomly assigned to the caregiver-implemented intervention or a usual-care control group. Caregivers and children participated in 28 sessions in which caregivers were taught to implement the intervention. The primary outcome was the Preschool Language Scale, Fourth Edition, a broad-based measure of language. Outcome measurement was not blinded. RESULTS: Caregivers in the intervention improved their use of all language facilitation strategies, such as matched turns (adjusted mean difference, intervention-control, 40; 95% confidence interval 34 to 46; P < .01). Children in the intervention group had significantly better receptive language skills (5.3; 95% confidence interval 0.15 to 10.4), but not broad-based expressive language skills (0.37, 95% confidence interval -4.5 to 5.3; P = .88). CONCLUSIONS: This trial provides preliminary evidence of the short term effects of systematic caregiver instruction on caregiver use of language facilitation strategies and subsequent changes in children's language skills. Future research should investigate the ideal dosage levels for optimizing child outcomes and determine which language facilitation strategies are associated with specific child outcomes. Research on adaptations for families from culturally and linguistically diverse backgrounds is needed. PMID- 25733750 TI - A slice of peace. PMID- 25733752 TI - Gestational age and developmental risk in moderately and late preterm and early term infants. AB - OBJECTIVES: The objective of this study was to evaluate the association between gestational age (GA) at birth and risk of developmental delay at 8 and 18 months of corrected postnatal age. METHODS: During 2008 to 2011, infants at a corrected postnatal age of 8 or 18 months attending health centers in Santiago, Chile, were recruited. Participants completed a form on biographical and demographic characteristics and the Chilean validated version of the Ages and Stages Questionnaires, Third Edition (ASQ). Logistic regression was used to detect the capacity of GA to predict scores < -2 SDs on the basis of the Chilean ASQ reference group, in at least 1 ASQ domain, adjusted by different control variables. RESULTS: A total of 1667 infants were included in the analysis. An inverse "dose response" relationship between developmental delay risk and GA at birth was found, both in the crude and adjusted models. Compared with those born full term, the odds ratio for developmental delay risk was 1.56 for those born early term (95% confidence interval [CI]: 1.19-2.06), 2.58 for infants born late preterm (95%CI: 1.66-4.01), and 3.01 for those born moderately preterm (95%CI: 1.59-5.71). CONCLUSIONS: An inverse dose-response relationship between GA and risk of developmental delay was found in the tested population. Future prospective studies and predictive models are needed to understand whether this higher developmental risk in moderately and late preterm infants is transient and modifiable or persists throughout life, allowing for better targeting of early intervention strategies. PMID- 25733754 TI - Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Overdiagnosis and underdiagnosis of attention deficit/hyperactivity disorder (ADHD) are widely debated, fueled by variations in prevalence estimates across countries, time, and broadening diagnostic criteria. We conducted a meta-analysis to: establish a benchmark pooled prevalence for ADHD; examine whether estimates have increased with publication of different editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM); and explore the effect of study features on prevalence. METHODS: Medline, PsycINFO, CINAHL, Embase, and Web of Science were searched for studies with point prevalence estimates of ADHD. We included studies of children that used the diagnostic criteria from DSM-III, DSM-III-R and DSM-IV in any language. Data were extracted on sampling procedure, sample characteristics, assessors, measures, and whether full or partial criteria were met. RESULTS: The 175 eligible studies included 179 ADHD prevalence estimates with an overall pooled estimate of 7.2% (95% confidence interval: 6.7 to 7.8), and no statistically significant difference between DSM editions. In multivariable analyses, prevalence estimates for ADHD were lower when using the revised third edition of the DSM compared with the fourth edition (P = .03) and when studies were conducted in Europe compared with North America (P = .04). Few studies used population sampling with random selection. Most were from single towns or regions, thus limiting generalizability. CONCLUSIONS: Our review provides a benchmark prevalence estimate for ADHD. If population estimates of ADHD diagnoses exceed our estimate, then overdiagnosis may have occurred for some children. If fewer, then underdiagnosis may have occurred. PMID- 25733753 TI - Physician response to parental requests to spread out the recommended vaccine schedule. AB - OBJECTIVES: To assess among US physicians (1) frequency of requests to spread out recommended vaccination schedule for children <2 years, (2) attitudes regarding such requests, and (3) strategies used and perceived effectiveness in response to such requests. METHODS: An e-mail and mail survey of a nationally representative sample of pediatricians and family physicians from June 2012 through October 2012. RESULTS: The response rate was 66% (534 of 815). In a typical month, 93% reported some parents of children <2 years requested to spread out vaccines; 21% reported >= 10% of parents made this request. Most respondents thought these parents were putting their children at risk for disease (87%) and that it was more painful for children (84%), but if they agreed to requests, it would build trust with families (82%); further, they believed that if they did not agree, families might leave their practice (80%). Forty percent reported this issue had decreased their job satisfaction. Most agreed to spread out vaccines when requested, either often/always (37%) or sometimes (37%); 2% would often/always, 4% would sometimes, and 12% would rarely dismiss families from their practice if they wanted to spread out the primary series. Physicians reported using a variety of strategies in response to requests but did not think they were effective. CONCLUSIONS: Virtually all providers encounter requests to spread out vaccines in a typical month and, despite concerns, most are agreeing to do so. Providers are using many strategies in response but think few are effective. Evidence-based interventions to increase timely immunization are needed to guide primary care and public health practice. PMID- 25733755 TI - Government health care spending and child mortality. AB - BACKGROUND: Government health care spending (GHS) is of increasing importance to child health. Our study determined the relationship between reductions in GHS and child mortality rates in high- and low-income countries. METHODS: The authors used comparative country-level data for 176 countries covering the years 1981 to 2010, obtained from the World Bank and the Institute for Health Metrics and Evaluation. Multivariate regression analysis was used to determine the association between changes in GHS and child mortality, controlling for differences in infrastructure and demographics. RESULTS: Data were available for 176 countries, equating to a population of ~ 5.8 billion as of 2010. A 1% decrease in GHS was associated with a significant increase in 4 child mortality measures: neonatal (regression coefficient [R] 0.0899, P = .0001, 95% confidence interval [CI] 0.0440-0.1358), postneonatal (R = 0.1354, P = .0001, 95% CI 0.0678 0.2030), 1- to 5-year (R = 0.3501, P < .0001, 95% CI 0.2318-0.4685), and under 5 year (R = 0.5207, P < .0001, 95% CI 0.3168-0.7247) mortality rates. The effect was evident up to 5 years after the reduction in GHS (P < .0001). Compared with high-income countries, low-income countries experienced greater deteriorations of ~ 1.31 times neonatal mortality, 2.81 times postneonatal mortality, 8.08 times 1- to 5-year child mortality, and 2.85 times under 5-year mortality. CONCLUSIONS: Reductions in GHS are associated with significant increases in child mortality, with the largest increases occurring in low-income countries. PMID- 25733756 TI - Expanding the definition of long-term follow-up to late adulthood. PMID- 25733751 TI - Clinical features of celiac disease: a prospective birth cohort. AB - OBJECTIVES: To investigate clinical features of celiac disease (CD) and their association with risk factors for CD in a genetic risk birth cohort. METHODS: Children from 6 clinical centers in 4 countries positive for HLA-DR3-DQ2 or DR4 DQ8 were annually screened for tissue transglutaminase antibodies (tTGA) and assessed for symptoms by questionnaires. Associations of symptoms with anthropometrics, known risk factors for CD, tTGA levels, and mucosal lesions in those biopsied were examined. RESULTS: Of 6706 screened children, 914 developed persistent positive tTGA, 406 underwent biopsies, and 340 had CD. Compared with age-matched tTGA-negative children, those with persistent tTGA were more likely to have symptoms at 2 (34% vs 19%, P < .001) and 3 years of age (28% vs 19%, P = .009) but not at 4 years (27% vs 21%, NS). Z-scores for height, weight, and BMI did not differ between groups. In children with persistent tTGA, having >= 1 symptom was associated with family history of CD (odds ratio = 2.59, 95% confidence interval, 1.21-5.57) but not with age, gender, or HLA-DR3-DQ2 homozygosity. At seroconversion, tTGA levels were higher in symptomatic than asymptomatic children (P < .001), in those from CD families (P < .001), and in US participants (P < .001) but not associated with age, gender, or HLA genotype. tTGA levels correlated with severity of mucosal lesions both in symptomatic (r = 0.53, P < .001) and asymptomatic children (r = 0.22, P = .01). CONCLUSIONS: A majority of children detected with persistent tTGA in screenings are asymptomatic and have normal growth by age 4 years. tTGA levels correlate more strongly with severity of mucosal lesions in symptomatic as compared with asymptomatic children. PMID- 25733757 TI - Pneumonia in childhood and impaired lung function in adults: a longitudinal study. AB - BACKGROUND: Diminished lung function and increased prevalence of asthma have been reported in children with a history of early lower respiratory illnesses (LRIs), including pneumonia. Whether these associations persist up to adulthood has not been established. METHODS: As part of the prospective Tucson Children's Respiratory Study, LRIs during the first 3 years of life were ascertained by pediatricians. Spirometry was performed at ages 11, 16, 22, and 26 years. The occurrence of asthma/wheeze during the previous year was ascertained at ages 11, 13, 16, 18, 22, 24, 26, and 29 years. Longitudinal random effects models and generalized estimating equations were used to assess the relation of LRIs to lung function and asthma. RESULTS: Compared with participants without early-life LRIs, those with pneumonia had the most severe subsequent lung function impairment, with mean +/- SE deficits of -3.9% +/- 0.9% (P < .001) and -2.5% +/- 0.8% (P = .001) for pre- and post-bronchodilator FEV1:FVC ratio from age 11 to 26 years, respectively. Pneumonia was associated with increased risk for asthma (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.11-3.44) and wheeze (OR: 1.94; 95% CI: 1.28-2.95) over the same age range. Early non-pneumonia LRIs were associated with mildly impaired pre-bronchodilator FEV1 (-62.8 +/- 27.9 mL, P = .024) and FEV1:FVC ratio (-1.1 +/- 0.5%, P = .018), and wheeze (OR: 1.37; 95% CI: 1.09 1.72). CONCLUSIONS: Early pneumonia is associated with asthma and impaired airway function, which is partially reversible with bronchodilators and persists into adulthood. Early pneumonia may be a major risk factor for adult chronic obstructive pulmonary disease. PMID- 25733758 TI - Measles imported to the United States by children adopted from China. AB - In July 2013, the National Immunization Program of China was notified by the US Centers for Disease Control and Prevention that measles was detected in 3 newly adopted, special needs children with cerebral palsy (CP) from China. We report an investigation of measles transmission in China that led to infection of these children. Interviews were conducted with welfare institute staff and panel physicians; health records of the potentially exposed population were reviewed; and immunization coverage was assessed among institute residents. Five residents with CP, all unvaccinated against measles, among who were the 3 adoptees, were linked epidemiologically into 3 generations of measles transmission antecedent to the US outbreak. In a random sample of residents, first dose of measles containing vaccine (MCV1) and MCV2 coverage was 16 of 17 (94%) and 7 of 11 (64%) among children with CP, and 100% (32 of 32) and 96% (21 of 22) among children without CP. Vaccinators reported reluctance to vaccinate children with CP because the China pharmacopeia lists encephalopathy as a contraindication to vaccination. Panel physicians reported to investigators no necessity of vaccination for adoptees to the United States if US parents sign an affidavit exempting the child from vaccination. We recommend that the China pharmacopeia vaccine contraindications be reviewed and updated, the United States should reconsider allowing vaccination exemptions for internationally adopted children unless there are true medical contraindications to vaccination, and US pediatricians should counsel adopting parents to ensure that their child is up-to-date on recommended vaccinations before coming to the United States. PMID- 25733759 TI - 13-year-old girl with recurrent, episodic, persistent vomiting: out of the pot and into the fire. AB - Cyclic vomiting syndrome (CVS) is a well-established cause of recurrent vomiting in the pediatric population. Severe vomiting with chronic cannabis use, known as cannabinoid hyperemesis syndrome, has recently been more widely recognized as an etiology of persistent episodic vomiting. In turn, patients presenting with frequent episodes of CVS are now increasingly being screened for cannabinoid use. Because patients with persistent vomiting are also frequently prescribed a proton pump inhibitor (PPI) for their gastrointestinal symptoms, it is important to be aware of the potential for a PPI to cause an interaction that can lead to false positive urine cannabinoid screening. We describe a case of a false-positive urine cannabinoid screen in a patient with CVS who received a dose of intravenous pantoprazole. The primary reference regarding drug screen interference from PPIs can be found in the pantoprazole package insert that refers to pre-Food and Drug Administration approval data. Although multiple sources on the Internet report the possibility of positive cannabinoid screens from pantoprazole, there are no known published reports of the phenomenon in the medical literature. PMID- 25733760 TI - Influenza: deja vu all over again. PMID- 25733761 TI - Adrenal insufficiency. AB - Adrenal insufficiency is a life-threatening condition that occurs secondary to impaired secretion of adrenal glucocorticoid and mineralocorticoid hormones. This condition can be caused by primary destruction or dysfunction of the adrenal glands or impairment of the hypothalamic-pituitary-adrenal axis. In children, the most common causes of primary adrenal insufficiency are impaired adrenal steroidogenesis (congenital adrenal hyperplasia) and adrenal destruction or dysfunction (autoimmune polyendocrine syndrome and adrenoleukodystrophy), whereas exogenous corticosteroid therapy withdrawal or poor adherence to scheduled corticosteroid dosing with long-standing treatment constitute the most common cause of acquired adrenal insufficiency. Although there are classic clinical signs (eg, fatigue, orthostatic hypotension, hyperpigmentation, hyponatremia, hyperkalemia, and hypoglycemia) of adrenal insufficiency, its early clinical presentation is most commonly vague and undefined, requiring a high index of suspicion. The relevance of early identification of adrenal insufficiency is to avoid the potential lethal outcome secondary to severe cardiovascular and hemodynamic insufficiency. The clinician must be aware of the need for increased corticosteroid dose supplementation during stress periods. PMID- 25733762 TI - Pediatric movement disorders. AB - On the basis of some research evidence and consensus, identification of acute opsoclonus, ataxia, or myoclonus should prompt consideration of an underlying neuroblastoma. On the basis of some research evidence and consensus, surgical treatment options should be considered for children with dystonia, including secondary dystonias, such as those related to cerebral palsy, and include intrathecal baclofen pumps and deep brain stimulation. On the basis of some research evidence and clinical experience, tetrabenazine may be effective in treating chorea. On the basis of strong research evidence, although seldom inherently dangerous, tics may be uncomfortable for affected children and interfere with academic achievement and social development. On the basis of some research evidence and clinical experience, topiramate may be an effective treatment for tic disorders. PMID- 25733763 TI - Nephrotic syndrome. AB - On the basis of observational studies, the most common cause of nephrotic syndrome in school-aged children is minimal change disease. On the basis of research evidence and consensus, corticosteroids are considered first-line therapy for treatment of nephrotic syndrome. On the basis of consensus, prednisone therapy should be initiated at doses of 60 mg/m2 per day (2 mg/kg per day) administered for 4 to 6 weeks, followed by 40 mg/m2 per dose (1.5 mg/kg) every other day for at least 6 to 8 weeks. On the basis of consensus and expert opinion, it is important to recognize and manage the complications that can arise in patients with nephrotic syndrome, such as dyslipidemia, infection, and thrombosis. On the basis of research evidence, consensus, and expert opinion, several alternative therapies have been observed to have variable efficacy in children with both corticosteroid-dependent and corticosteroid-resistant nephrotic syndrome, although caution must be exercised in the administration of these corticosteroid-sparing medications secondary to toxic adverse effects. On the basis of observational studies, the course of nephrotic syndrome in most patients is that of relapse and remission. PMID- 25733764 TI - Case 1: Persistent fevers and abdominal pain in a 13-year-old neutropenic patient. PMID- 25733765 TI - Case 2: Recurrent fever and thrombocytopenia in a 4-year-old girl. PMID- 25733766 TI - Case 3: Abdominal pain and vomiting in a 4-year-old boy. PMID- 25733767 TI - Stridor. PMID- 25733768 TI - Bicycle safety. PMID- 25733769 TI - 14-year-old boy with painful nail changes. AB - Doxycycline is a classically implicated cause of phototoxic reactions. Photo onycholysis is a rare manifestation of phototoxicity. Nail changes may typically include nail pain, subungual hemorrhages, or distal onycholysis. Self-resolution can be expected in 3 to 6 months. Patients prescribed doxycycline should be counseled about the potential for phototoxicity and the need for appropriate sun protection while taking the medication. PMID- 25733770 TI - Stem cell-derived nodal-like cardiomyocytes as a novel pharmacologic tool: insights from sinoatrial node development and function. AB - Since the first reports on the isolation and differentiation of stem cells, and in particular since the early success in driving these cells down a cardiac lineage, there has been interest in the potential of such preparations in cardiac regenerative therapy. Much of the focus of such research has been on improving mechanical function after myocardial infarction; however, electrophysiologic studies of these preparations have revealed a heterogeneous mix of action potential characteristics, including some described as "pacemaker" or "nodal like," which in turn led to interest in the therapeutic potential of these preparations in the treatment of rhythm disorders; several proof-of-concept studies have used these cells to create a biologic alternative to electronic pacemakers. Further, there are additional potential applications of a preparation of pacemaker cells derived from stem cells, for example, in high-throughput screens of new chronotropic agents. All such applications require reasonably efficient methods for selecting or enriching the "nodal-like" cells, however, which in turn depends on first defining what constitutes a nodal-like cell since not all pacemaking cells are necessarily of nodal lineage. This review discusses the current state of the field in terms of characterizing sinoatrial-like cardiomyocytes derived from embryonic and induced pluripotent stem cells, markers that might be appropriate based on the current knowledge of the gene program leading to sinoatrial node development, what functional characteristics might be expected and desired based on studies of the sinoatrial node, and recent efforts at enrichment and selection of nodal-like cells. PMID- 25733773 TI - Transparency of care. PMID- 25733771 TI - WRKY42 modulates phosphate homeostasis through regulating phosphate translocation and acquisition in Arabidopsis. AB - The Arabidopsis (Arabidopsis thaliana) WRKY transcription factor family has more than 70 members, and some of them have been reported to play important roles in plant response to biotic and abiotic stresses. This study shows that WRKY42 regulated phosphate homeostasis in Arabidopsis. The WRKY42-overexpressing lines, similar to the phosphate1 (pho1) mutant, were more sensitive to low-inorganic phosphate (Pi) stress and had lower shoot Pi content compared with wild-type plants. The PHO1 expression was repressed in WRKY42-overexpressing lines and enhanced in the wrky42 wrky6 double mutant. The WRKY42 protein bound to the PHO1 promoter under Pi-sufficient condition, and this binding was abrogated during Pi starvation. These data indicate that WRKY42 modulated Pi translocation by regulating PHO1 expression. Furthermore, overexpression of WRKY42 increased root Pi content and Pi uptake, whereas the wrky42 mutant had lower root Pi content and Pi uptake rate compared with wild-type plants. Under Pi-sufficient condition, WRKY42 positively regulated PHOSPHATE TRANSPORTER1;1 (PHT1;1) expression by binding to the PHT1;1 promoter, and this binding was abolished by low-Pi stress. During Pi starvation, the WRKY42 protein was degraded through the 26S proteasome pathway. Our results showed that AtWRKY42 modulated Pi homeostasis by regulating the expression of PHO1 and PHT1;1 to adapt to environmental changes in Pi availability. PMID- 25733774 TI - Management of resistant hypertension. PMID- 25733775 TI - Directed Evolution: Past, Present and Future. AB - Directed evolution, the laboratory process by which biological entities with desired traits are created through iterative rounds of genetic diversification and library screening or selection, has become one of the most useful and widespread tools in basic and applied biology. From its roots in classical strain engineering and adaptive evolution, modern directed evolution came of age twenty years ago with the demonstration of repeated rounds of PCR-driven random mutagenesis and activity screening to improve protein properties. Since then, numerous techniques have been developed that have enabled the evolution of virtually any protein, pathway, network or entire organism of interest. Here we recount some of the major milestones in the history of directed evolution, highlight the most promising recent developments in the field, and discuss the future challenges and opportunities that lie ahead. PMID- 25733776 TI - Modeling spatial segregation and travel cost influences on utilitarian walking: Towards policy intervention. AB - We develop an agent-based model of utilitarian walking and use the model to explore spatial and socioeconomic factors affecting adult utilitarian walking and how travel costs as well as various educational interventions aimed at changing attitudes can alter the prevalence of walking and income differentials in walking. The model is validated against US national data. We contrast realistic and extreme parameter values in our model and test effects of changing these parameters across various segregation and pricing scenarios while allowing for interactions between travel choice and place and for behavioral feedbacks. Results suggest that in addition to income differences in the perceived cost of time, the concentration of mixed land use (differential density of residences and businesses) are important determinants of income differences in walking (high income walk less), whereas safety from crime and income segregation on their own do not have large influences on income differences in walking. We also show the difficulty in altering walking behaviors for higher income groups who are insensitive to price and how adding to the cost of driving could increase the income differential in walking particularly in the context of segregation by income and land use. We show that strategies to decrease positive attitudes towards driving can interact synergistically with shifting cost structures to favor walking in increasing the percent of walking trips. Agent-based models, with their ability to capture dynamic processes and incorporate empirical data, are powerful tools to explore the influence on health behavior from multiple factors and test policy interventions. PMID- 25733778 TI - Are we ready for the rising silent epidemic of metabolic syndrome and chronic non communicable disease in Ethiopia? PMID- 25733777 TI - Effects on serum fractalkine by diet and omega-3 fatty acid intervention: relation to clinical outcome. AB - Introduction. Fractalkine is a chemokine associated with atherosclerosis. Increased serum levels have been reported in unstable coronary artery disease (CAD) and to predict mortality in heart failure. Mediterranean-like diet and omega-3 fatty acids (n3-PUFA) have documented cardioprotective and anti inflammatory effects. We have investigated the effect of Mediterranean-like dietary counseling and n-3 PUFA on serum fractalkine in an elderly population and its ability to predict cardiovascular disease (CVD). Materials and Methods. 563 men (age 64-75 yrs) at high risk of CAD were randomized into a 2 * 2 factorial designed trial for 3-year dietary counseling and/or n-3 PUFA supplementation (2.4 g/d). Circulating levels of fractalkine were measured at baseline and at end of study. Clinical events were recorded after 3 years. Results. Fractalkine levels were significantly reduced in all groups from baseline to 3 years (P < 0.001, all), but without between-group differences in changes. Fractalkine levels at baseline were not predictive for CVD events (n = 68) or total mortality. Lower fractalkine levels were observed in smokers (P = 0.019). Conclusions. Reduced levels of fractalkine from baseline to 3 years were observed, however, without any influence of Mediterranean-like diet or n-3 PUFA supplementation. Fractalkine levels at baseline were not predictive for later CVD events. PMID- 25733779 TI - Asymptomatic urinary tract infection among pregnant women receiving ante-natal care in a traditional birth home in Benin City, Nigeria. AB - BACKGROUND: A good proportion of pregnant women patronize traditional birth homes in Nigeria for ante-natal care. This study aimed at determining the prevalence, risk factors, and susceptibility profile of etiologic agents of urinary tract infection among ante-natal attendees in a traditional birth home in Benin City, Nigeria. METHODS: Clean-catch urine was collected from 220 pregnant women attending a traditional birth home in Benin City, Nigeria. Urine samples were processed, and microbial isolates identified using standard bacteriological procedures. A cross-sectional study design was used. RESULTS: The prevalence of urinary tract infection among pregnant women was 55.0%, significantly affected by parity and gestational age (P<0.05). Mixed infection was recorded among 13(10.7%) pregnant women, and was unaffected by maternal age, parity, gravidity, gestational age, and educational status. Irrespective of trimester Escherichia coli was the most prevalent etiologic agent of urinary tract infection, followed by Staphylococcus aureus. The flouroquinolones were the most effective antibacterial agents, while Sulphamethoxazole-trimetoprim, Amoxicillin, Nalidixic acid, and Nitrofurantoin had poor activity against uropathogens isolated. CONCLUSIONS: The prevalence of urinary tract infection among pregnant women was 55.0% and significantly affected by gestational age and parity. The most prevalent etiologic agent observed was Escherichia coli. With the exception of the flouroquinolones, aminoglycoside, and Amoxicillin-cluvanate, the activity of other antibiotics used on uropathogens were poor. Health education of the traditional birth attendant and her clients by relevant intervention agencies is strongly advocated. PMID- 25733780 TI - The effects of a dentifrice containing propolis on Mutans Streptococci: a clinico microbiological study. AB - BACKGROUND: Propolis is a natural resinous mixture produced by honeybees, which exhibits anti-microbial, anti-inflammatory, cytostatic and cariostatic properties. The aim of the study was to evaluate the anti-bacterial efficacy of a propolis based dentifrice on Mutans Streptococci colonizing the oral cavity of young patients using Dentocult(r) SM strip mutans test. METHODS: Screening of 367 male subjects within the age group of 7-12 years was carried out. A total of 30 children were included in the study. They were instructed to use a Propolis dentifrice (Probee,TM Quasi-Medical Products, Seoul Propolis) daily for three minutes over a period of four weeks. Plaque and salivary samples were collected at baseline, 1(st) week, 3(rd) week and 4(th) week and were analyzed for Mutans Streptococci count using Dentocult(r) SM strip Mutans kit (Orion Diagnostica Oy, Finland). Student paired t-test and Friedman test were used for statistical analysis. RESULTS: It was unveiled that mean Mutans streptococci count at 1(st) week and 4(th) week, showed significant reduction (p<=0.0001), compared to baseline scores. Using Friedman's test, statistically significant difference was found between baseline and 1(st) week, 3(rd) week and 4(th) week follow up (P < 0.001). CONCLUSION: Propolis dentifrice reduces in-vivo microbial load in microenvironments especially against Mutans streptococci in the oral cavity of young patients. Thus, it's potential to be inculcated and used as an alternative measure to prevent dental caries can be considered and further investigation involving greater number of participants is recommended. PMID- 25733781 TI - Health service utilization and reported satisfaction among adolescents in Dejen District, Ethiopia: a cross-sectional study. AB - BACKGROUND: There is no adequate health service or counseling specifically suitable for adolescents in Ethiopia. Adolescents' satisfaction on the health service provided is important to increase utilization and quality of care. The objective of this study was to assess health service utilization, reported satisfaction and predictors of satisfaction among adolescents of 15-19 years in Dejen District. METHODS: A community based cross-sectional study was done from February 05 to 17, 2012. Interview method was used to collect data from 690 adolescents. Following stratification into urban and rural, six kebeles were selected by lottery method. Study participants allocated proportionally to households' size of kebele. Households were selected randomly, and one from each household was used. Descriptive measures and binary logistic regression were used to identify independent predictors for health service satisfaction. RESULT: Among 690 adolescents, 313(45%) used health service. Of these, 190 (60.7%) were satisfied. Physical proximity (AOR=3.6, 95% CI: 1.8, 7.3), drug availability (AOR=2.7, 95% CI: 1.3, 5.8), health services availability (AOR=2.5, 95% CI: 1.1, 6.0), treatment in separate room (AOR=2.9, 95% CI: 1.4, 5.6), checked all adolescents problem (AOR=4.0, 95% CI: 2.0, 8.5), treated with respect (AOR=3.0, 95% CI: 1.4, 5.7) and opportunity to explain feeling (AOR=3.3, 95% CI: 1.7, 6.6) were predictors of satisfaction. CONCLUSION: Adolescents' health service utilization and satisfaction were low. Adolescents' perception of accessibility, acceptability and interaction with health workers' had significant influence on health services satisfaction. Therefore, health professionals and administrators should work on availing services with close proximity and acceptable behavior in order to increase adolescents' satisfaction. PMID- 25733782 TI - Prevalence of physical, verbal and nonverbal sexual harassments and their association with psychological distress among Jimma University female students: a cross-sectional study. AB - BACKGROUND: A number of studies conducted on sexual harassment focused on general magnitude rather than specific details of the various forms of sexual harassment and their effect on psychological health. Thus, the objective of this study was to assess the prevalence rates of the various forms of sexual harassments and their associations with psychological distress among Jimma University female students. METHODS: Three hundred and eighty five (385) female participants were selected from all colleges using stratified and systematic sampling techniques. A structured questionnaire consisting of items on the various forms of sexual harassment and psychological distress was administered. RESULT: The prevalence rates of physical, verbal and nonverbal sexual harassments were 78.2%, 90.4% and 80.0%, respectively, while the prevalence rate of psychological distress among students who had experienced sexual harassment was 63.0%. The multivariable logistic regression analyses indicated that students who were physically [adjusted OR = 3.950, 95% CI = (1.979, 7.884)] and nonverbally [(adjusted OR = 12.099, 95% CI= (5.190, 28.205] harassed were 4 and 12 times more likely to experience psychological distress, respectively, adjusted for all other variables. CONCLUSION: The prevalence of various forms of sexual harassment were higher and strongly associated with psychological distress. Important implications for University officials and policy makers including creating harassment free University have been drawn. Otherwise, female students tend to dropout and their academic achievements suffer a lot as a result of psychological distress; and the government's effort for realizing the gender parity in education would be compromised. PMID- 25733783 TI - Human rotavirus group a serotypes causing gastroenteritis in children less than 5 years and HIV-infected adults in Viwandani slum, Nairobi. AB - BACKGROUND: Rotavirus remains a leading cause of acute gastroenteritis in children worldwide with an estimated 2000 deaths each day in developing countries. Due to HIV/AIDS scourge in Kenya, it is possible that rotavirus related gastroenteritis has been aggravated in adults. The Global Alliance for Immunizations has ranked rotavirus infection a priority for vaccine, and, to ensure its success, there is a need to document the local strain(s) circulating in different regions. METHODS: A cross-sectional study was conducted to document human rotavirus group A serotypes in children below 5 years and HIV-infected adults in Viwandani slum in Nairobi, Kenya. A total of 260 (128 from children and 132 from HIV infected adults) fecal specimen samples were analyzed from August 2012 to July 2013. Screening for rotavirus was done by antigen based enzyme immune-sorbent assay (ELISA), Polyacrylamide gel electrophoresis (PAGE) was used to detect rotavirus electropherotypes and finally genotyping was done by RT-PCR using genotype-specific primer sets targeting VP4 and VP7 genes. RESULTS: Rotavirus was detected in 23% and 8% of children and adult, respectively. Prevalence was high in children of < 2 years and adults of > 48 years. Long electropherotypes accounted for 80% and 60% while short electropherotypes accounted for 20% and 40% in children and adult, respectively. The common globally distributed strains, G1 and G3, accounted for 60% detections while the unusual G9 strain accounted for 80% infection in adults. G1P[8] was the common genotypic combination in children, accounting for 40% infection, whereas G9 [P8] accounted for 60% of the infections in adults. CONCLUSION: This study shows the existence of strain diversity between rotavirus circulating in children and adults within this study group. It further shows that as currently constituted, the 2 vaccines recommended for rotavirus would cover the circulating strain in Viwandani slum. Finally, there is a need for continuous rotavirus strain surveillance in children and a further focus on HIV infected adults. PMID- 25733784 TI - Cardiovascular response to acute cold stress in non-obese and obese healthy adults. AB - BACKGROUND: Obesity is a global epidemic with important health care and financial implications. The cold pressor test (CPT) which is considered to be a sympathy excitatory manoeuvre is a simple, noninvasive and validated test. The objective of this study was to assess and compare the cardiovascular response to cold pressor test in non-obese and obese healthy adults. METHODS: The study included 400 subjects, of which the study group included 200 adults who had body mass index (BMI) of more than 30 Kg/m,(2) and 200 non-obese adults were enrolled as controls with BMI less than 25 kg/m(2). The study was conducted for a period of two months. CPT was used to assess cardiac response to acute cold exposure in the present study. Baseline systolic and diastolic blood pressure recording was done using mercury sphygmomanometer during resting condition and following cold pressor test. The results were expressed as mean, standard deviation, and data were analyzed using ANOVA test. P < 0.05 was considered statistically significant. RESULTS: The mean change in systolic blood pressure before and after cold pressor test (CPT) was less in obese (7.12 +/- 5.28) as compared to non obese subjects (10.38 +/-6.35). This was statistically significant which indicates impaired sympathetic function in otherwise healthy obese. CONCLUSION: The study concluded that blood pressure response to cold pressor test was reduced in obese compared to non-obese subjects indicating reduced sympathetic activity in healthy obese adults. PMID- 25733785 TI - Evaluation of quality of life of adult cancer patients attending Tikur Anbessa specialized referral hospital, Addis Ababa Ethiopia. AB - BACKGROUND: Little is known about the quality of life of cancer patients in the Ethiopian context. This study evaluated quality of life of cancer patients in Ethiopia. METHODS: A cross-sectional study was conducted in Addis Ababa University Tikur Anbessa Specialized Referral Hospital Addis Ababa, Ethiopia (TASRH) from March to May 2013. A total of 388 cancer patients were included. Translated in to Amharic, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QOL C-30) was used to measure Quality of life (QoL). The data was analyzed with SPSS Version 17.0. RESULTS: Among the participants, 251(64.7%) were men and 138(35.6%) were below the age of 40 years. Large proportion of patients were diagnosed with breast cancer, 114(29.4%), and cervical cancer, 102(26.3%), and the clinical stages during the beginning of therapy were at stage II a 133(34.3%). The mean of global health status/QoL was 57.28 (SD= 25.28). Quality of life was found to be associated with some functional scales as role functioning, P<=0.001, social function, P=0.00, and symptom scales as pain, P=0.00, loss of appetite, P=0.004, and financial impact, P=0.02, but no associations were noted in relation to socio demographic characteristics. CONCLUSIONS: Quality of life assessments should be included in patient treatment protocols to improve their quality of life since being a cancer patient may be associated with a high level of impairment in different aspects of life. PMID- 25733786 TI - Association of some socio-economic and socio-demographic variables with wasting among pre-school children of North Bengal, India. AB - BACKGROUND: Undernutrition is a global public health problem that causes premature morbidity and ill-health conditions and has long-lasting physiological effects in children. The present study assesses the prevalence of wasting [low mid-upper arm circumference (MUAC)-for-age] among children and to determine the association of wasting with different socio-economic and socio-demographic variables. METHODS: The present cross-sectional study was conducted among 1222 pre-school children (boys: 589; girls: 633), aged 1-5 years, in Darjeeling district, North Bengal, India, using multistage stratified random sampling method. The MUAC was measured using the standard anthropometric procedure. Low MUAC-for-age was assessed by comparing with a standard age-sex-specific reference population (WHO, 1995). Children with MUAC value were found to be the z-scores < 3SD, and <-2 SD were considered to be severely and moderately wasted, respectively. The socio-economic and socio-demographic variables were recorded using structured schedule methods. The data were statistically analyzed based on descriptive statistics, chi-square analysis and logistic regression using SPSS (version, 17.0). RESULTS: The age-specific mean MUAC ranged from 126.1-142.5 mm (boys) and 126.9-136.4 mm (girls). The prevalence of wasting was very high (boys: 62.3%; girls: 63.3%) (p>0.05). The logistic regression analysis observed that age, gender, birth order, area (rural), maternal education, household income and mothers' age were significantly associated with the prevalence of wasting (p<0.05). CONCLUSION: Using MUAC-for-age, a high prevalence of wasting was observed among the children. Birth order, maternal education and maternal occupation were important determinants of wasting. There is an urgent requirement of nutritional intervention programmes to ameliorate the nutritional status of the children. PMID- 25733787 TI - Drug prescribing pattern for under-fives in a paediatric clinic in South-Western Nigeria. AB - BACKGROUND: The audit of drug prescribing pattern in under-five children is essential in identifying the various types of non-rational prescribing such as polypharmacy and irrational use of antimicrobials. The primary objective of this study was to determine the drug prescribing pattern for children aged below five years attending the paediatric outpatient clinic of a tertiary hospital in Ado Ekiti, South-West Nigeria. METHODS: A cross-sectional study was carried out using the medical records of patients who attended the paediatric clinic of the hospital between April 1 and October 30, 2013. The medical records of patients aged below five years were selected monthly for the period of the study using a regular interval ratio. Drug use indicators were assessed using the WHO guidelines on investigation of drug use in health care facilities. RESULTS: There were 293(55.7%) prescriptions collected from male patients and 233(44.3% from female patients with a total of 1369 prescribed drugs (2.6 +/- 1.1 drugs per prescription). A total of three hundred and seventy-four (71.1%) patients had at least one antibiotic prescribed with antibiotics accounting for 28.2% of all drugs prescribed, while 13.5% of all encounters had an injection prescribed. Prescribing by generic name was done in 68.9 +/- 26.5% of all prescribed medications, and 60.4% of all prescribed medications were from the latest version of the Nigerian Essential Drug List. Three hundred and twelve children (59.3%) had at least one anti-malarial drug prescribed while analgesics drugs accounted for 6.1% of all prescriptions. CONCLUSION: This study showed that over prescription of antibiotics, significant use of injections and prescribing by generic name are real issues among Nigerian paediatric prescribers. PMID- 25733788 TI - Relationship between emotional intelligence and organizational citizenship behavior in critical and emergency nurses in south east of Iran. AB - BACKGROUND: Several factors including emotional intelligence affect the efficiency of people. It seems that organizational behavior of each person is strongly influenced by emotional intelligence. Therefore, the present study is aimed to examine the relationship between emotional intelligence and organizational citizenship behavior in critical and emergency nurses in teaching hospitals supervised by Kerman Medical University in Southeast of Iran. METHODS: This study employed a descriptive cross sectional design. A census sample consisted of 150 critical and emergency nurses working in teaching hospitals supervised by Kerman Medical University participated in this study. Emotional intelligence and organizational citizenship behavior questionnaire was used to assess nurses' emotional intelligence and organizational citizenship behavior by available sampling method. RESULTS: The results showed that the mean age of the participants was 35 years. Most participants (94%) were females and belonged to the age group of 26-30 years. Overall mean score of organizational citizenship behavior scale was 88.21 (+/-10.4). In the organizational citizenship behavior categories, altruism mean score was higher than the other mean scores. Overall mean score of emotional intelligence was (121.08 +/- 17.56). In the subgroups of emotional intelligence, mean score of the relationship management, was higher than the average of other factors. Pearson's correlation coefficient showed no significant relationship between emotional intelligence and organizational citizenship behavior (p >= 0.05). CONCLUSIONS: The study suggests that health care managers should organize systematic and dynamic policies and procedures in dealing with emotional intelligence and organizational citizenship behavior to assist critical and emergency nurses. PMID- 25733789 TI - Maternal mortality predictors in women with hypertensive disorders of pregnancy: a retrospective cohort study. AB - BACKGROUND: Hypertensive disorders of pregnancy (HDP) are multisystem disorders unique to human pregnancy. They are becoming the leading causes of maternal mortality worldwide, with the majority of deaths occurring in low income countries. However, little is known about the predictors of maternal mortality in women with HDP. METHODS: A retrospective cohort study was conducted between 2008 and 2013 in three university teaching hospitals among 1015 women admitted with a diagnosis of HDP. Statistically significant associations were assessed by the hazard ratio (HR) with 95% confidence using the Cox proportional hazards model and by the Log Rank test using the Kaplan-Meier survival analyses. RESULTS: There were 51(5%) maternal deaths and the majority died after they developed eclampsia. The median delay in arrival among the deaths was longer than the survivors. The multivariate survival analyses showed an increased risk of maternal mortality among women with eclampsia (HR=8.4), no antenatal care (HR=2.3), being grand multiparous (HR=2.8), having low diastolic blood pressure (HR=4.5), high creatinine level (HR=9.9), use of diazepam as anticonvulsant (HR=2.7) and untreated with antihypertensive drug (HR=4.2). CONCLUSIONS: The case fatality rate of HDP was among the highest in the world and a delay in initiation of treatment because of delay in health care-seeking contributed to the majority of maternal deaths. PMID- 25733790 TI - Acute loss of vision in a young woman: a case report on psychogenic blindness. AB - BACKGROUND: Acute loss of vision needs urgent attention and treatment. We report on a young Ethiopian woman who experienced acute bilateral blindness. In the presence of normal ophthalmological findings psychogenic blindness has to be considered. CASE DETAILS: A 21 years old woman was admitted to the psychiatry clinic at Jimma University specialized Hospital, Jimma, South West Ethiopia. She had not been able to see for a few days. Ophthalmological and neurological examinations showed normal findings. No severe psychopathology was found. Stressful life events had preceded the appearance of the symptoms. An attitude of accepting the perspective of the patient of a seemingly organic disease is a precondition for a successful intervention. Treatment aimed at a gradual return to normal functioning. The patient regained her sight and fully recovered. The final psychiatric diagnosis was psychogenic blindness. CONCLUSION: The psychosocial intervention was successful and encouraging for the patient and clinicians. PMID- 25733791 TI - Life-threatening angiomyxoma of the larynx. AB - BACKGROUND: Angiomyxoma is a benign proliferative mesenchymal tumor and a very rare mass in the larynx. There is not enough information about the etiology, clinical finding, treatment and prognosis of laryngeal angiomyxoma. CASE DETAILS: A 52 years old man presented with respiratory distress. Also, he had suffered from dysphagia, dysphonia, cough, and obstructive sleep apnea in the supine position for 6 months. He was operated on via transoral approach under general anesthesia with orotracheal intubation. The mass was encapsulated and completely removed. The histopathologic diagnosis was reported as angiomyxoma. CONCLUSION: Angiomyxoma should be considered in the differential diagnosis of the larynx masses. The treatment of angiomyxomas of the larynx is surgical. The mass can be usually excised intraorally or endoscopically. PMID- 25733792 TI - Are the undergradute medical students well-informed of organ transplantation? PMID- 25733793 TI - windex: Analyzing Convergent Evolution Using the Wheatsheaf Index in R. AB - SUMMARY: windex is a package developed for the R statistical environment to provide novel tools for the analysis of convergent evolution. The recently described Wheatsheaf index provides quantitative measures of the strength of convergence and opens up new possibilities for exploring this evolutionary phenomenon. The windex package allows implementation of this method with additional functions that can be used to create plots and perform statistical tests. R provides compatibility with other packages, and the R environment is familiar to many researchers. AVAILABILITY: The windex package is freely available from CRAN: http://cran.r-project.org/web/packages/windex/. Consequently, windex can be installed directly from R and is distributed under the GNU General Public License 2.0. PMID- 25733794 TI - Array platform modeling and analysis (a). PMID- 25733795 TI - Extending information retrieval methods to personalized genomic-based studies of disease. AB - Genomic-based studies of disease now involve diverse types of data collected on large groups of patients. A major challenge facing statistical scientists is how best to combine the data, extract important features, and comprehensively characterize the ways in which they affect an individual's disease course and likelihood of response to treatment. We have developed a survival-supervised latent Dirichlet allocation (survLDA) modeling framework to address these challenges. Latent Dirichlet allocation (LDA) models have proven extremely effective at identifying themes common across large collections of text, but applications to genomics have been limited. Our framework extends LDA to the genome by considering each patient as a "document" with "text" detailing his/her clinical events and genomic state. We then further extend the framework to allow for supervision by a time-to-event response. The model enables the efficient identification of collections of clinical and genomic features that co-occur within patient subgroups, and then characterizes each patient by those features. An application of survLDA to The Cancer Genome Atlas ovarian project identifies informative patient subgroups showing differential response to treatment, and validation in an independent cohort demonstrates the potential for patient specific inference. PMID- 25733796 TI - Mapping Splicing Quantitative Trait Loci in RNA-Seq. AB - BACKGROUND: One of the major mechanisms of generating mRNA diversity is alternative splicing, a regulated process that allows for the flexibility of producing functionally different proteins from the same genomic sequences. This process is often altered in cancer cells to produce aberrant proteins that drive the progression of cancer. A better understanding of the misregulation of alternative splicing will shed light on the development of novel targets for pharmacological interventions of cancer. METHODS: In this study, we evaluated three statistical methods, random effects meta-regression, beta regression, and generalized linear mixed effects model, for the analysis of splicing quantitative trait loci (sQTL) using RNA-Seq data. All the three methods use exon-inclusion levels estimated by the PennSeq algorithm, a statistical method that utilizes paired-end reads and accounts for non-uniform sequencing coverage. RESULTS: Using both simulated and real RNA-Seq datasets, we compared these three methods with GLiMMPS, a recently developed method for sQTL analysis. Our results indicate that the most reliable and powerful method was the random effects meta-regression approach, which identified sQTLs at low false discovery rates but higher power when compared to GLiMMPS. CONCLUSIONS: We have evaluated three statistical methods for the analysis of sQTLs in RNA-Seq. Results from our study will be instructive for researchers in selecting the appropriate statistical methods for sQTL analysis. PMID- 25733797 TI - An Improved Version of Logistic Bayesian LASSO for Detecting Rare Haplotype Environment Interactions with Application to Lung Cancer. AB - The importance of haplotype association and gene-environment interactions (GxE) in the context of rare variants has been underlined in voluminous literature. Recently, a software based on logistic Bayesian LASSO (LBL) was proposed for detecting GxE, where G is a rare (or common) haplotype variant (rHTV)-it is called LBL-GxE. However, it required relatively long computation time and could handle only one environmental covariate with two levels. Here we propose an improved version of LBL-GxE, which is not only computationally faster but can also handle multiple covariates, each with multiple levels. We also discuss details of the software, including input, output, and some options. We apply LBL GxE to a lung cancer dataset and find a rare haplotype with protective effect for current smokers. Our results indicate that LBL-GxE, especially with the improvements proposed here, is a useful and computationally viable tool for investigating rare haplotype interactions. PMID- 25733798 TI - Evaluating methods for modeling epistasis networks with application to head and neck cancer. AB - Epistasis helps to explain how multiple single-nucleotide polymorphisms (SNPs) interact to cause disease. A variety of tools have been developed to detect epistasis. In this article, we explore the strengths and weaknesses of an information theory approach for detecting epistasis and compare it to the logistic regression approach through simulations. We consider several scenarios to simulate the involvement of SNPs in an epistasis network with respect to linkage disequilibrium patterns among them and the presence or absence of main and interaction effects. We conclude that the information theory approach more efficiently detects interaction effects when main effects are absent, whereas, in general, the logistic regression approach is appropriate in all scenarios but results in higher false positives. We compute epistasis networks for SNPs in the FSD1L gene using a two-phase head and neck cancer genome-wide association study involving 2,185 cases and 4,507 controls to demonstrate the practical application of the methods. PMID- 25733799 TI - New approaches to treating Alzheimer's disease. AB - To date, no truly efficacious drugs for Alzheimer's disease (AD) have been developed; moreover, all new anti-AD drugs developed since 2003 have failed. To succeed where previous ones have failed in drug development, new approaches for AD therapy are needed. Here we discuss the potential application of network medicine as a new approach to AD treatment. Unlike traditional approaches focused on a single target/pathway, network medicine targets and restores disease disrupted networks through simultaneous modulation of numerous proteins (targets)/pathways involved in AD pathogenesis. We consider several drug candidates under development for AD therapy, including Keap1-Nrf2 regulators, endogenous neurogenic agents, and hypoxia-inducible factor 1 (HIF-1) activators. These drug candidates are multi-target ligands with the potential to further develop as network medicines, since they act as master regulators to initiate a broad range of cellular defense mechanisms/cytoprotective genes that exert their efficacy in a holistic way. We also explore their diverse mechanisms of action and potential disease-modifying effects, which may have profound implications for drug discovery. PMID- 25733800 TI - Population pharmacokinetics of pegaptanib sodium (Macugen((r))) in patients with diabetic macular edema. AB - OBJECTIVE: Population pharmacokinetic modeling of pegaptanib was undertaken to determine influence of renal function on apparent clearance. METHODS: In a randomized, double-masked multicenter trial, intravitreal pegaptanib (0.3, 1.0, or 3.0 mg/eye) was administered in patients with diabetic macular edema every 6 weeks for 12-30 weeks. A one-compartment model with first-order absorption, distribution volume, and clearance was used to characterize the pegaptanib plasma concentration-time profile. RESULTS: In 58 patients, increases in area under the concentration-time curve (AUC) to end of the dosing interval (AUC0-tau) and maximum concentration with repeat doses were <6%, indicating minimal plasma accumulation. Sex and race did not have clinically significant effects on pegaptanib exposure. In the final model, the AUC extrapolated to infinite time and maximum concentration increased by >=50% in older patients (aged >68 years) relative to younger patients due to decreases in creatinine clearance (CRCL), a significant predictor of clearance. Pegaptanib clearance was reduced by 29% when CRCL decreased by 50%. The change in exposure with CRCL (range, 0-190 mL/minute) was < 10-fold with 0.3-3.0 mg doses. CONCLUSION: While pegaptanib clearance and AUC were significantly influenced by CRCL, the predicted exposure in patients with renal insufficiency or renal failure shows no evidence that a dose adjustment is warranted, given the tenfold margin of safety observed over the dose range of 0.3-3.0 mg. PMID- 25733801 TI - Social deprivation as a risk factor for late presentation of proliferative diabetic retinopathy. AB - PURPOSE: The aim of this study was to determine whether social deprivation is a risk factor for late presentation of patients with proliferative diabetic retinopathy and whether it affects their access to urgent laser treatment. METHODS: Using a 2:1 case: control design, 102 patients referred to a UK teaching hospital as part of the UK Diabetic Retinopathy National Screening Programme were identified for the period between 1 June 2010 to 1 June 2013. Social deprivation was scored using the Index of Multiple Deprivation 2010. Additional variables considered included age, duration of disease, ethnicity, and HbA1c at time of referral. RESULTS: The cases comprised 34 patients referred with proliferative (grade R3) retinopathy with a control group of 68 patients with lower retinopathy grades; two control patients were excluded due to incomplete data. On univariate analysis, R3 retinopathy was associated with higher social deprivation (P<0.001, Mann-Whitney U-test), and with higher HbA1c (11.5% vs 8.4%; P<0.001, Mann-Whitney U-test). Forward stepwise multivariable analysis showed that the association of R3 retinopathy with deprivation was significant even after adjusting for HbA1c (P=0.016). On univariate analysis South Asian ethnicity was also identified as being a risk factor for presentation with R3 retinopathy, but this was no longer significant when HbA1c was adjusted for in a forward stepwise logistic regression analysis. CONCLUSION: In our cohort social deprivation appears to be associated with late presentation of proliferative diabetic retinopathy. Our study supports the need to target these groups to reduce preventable blindness and to identify strategies which overcome barriers to care. PMID- 25733802 TI - Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration. AB - Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and "real-world" outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography. PMID- 25733803 TI - Antidrug antibodies against TNF-blocking agents: correlations between disease activity, hypersensitivity reactions, and different classes of immunoglobulins. AB - Although anti-TNF drugs have changed the clinical course of rheumatoid arthritis (RA), survival rates and resistance-to-therapy data confirm that about 30% of RA patients fail to respond. The aim of this study was to evaluate the correlations between the development of antidrug antibodies, specific IgG4 antibodies against TNF inhibitors, and resistance to therapy in RA patients. This retrospective study involved 129 patients with established RA naive to biological agents (98 females and 32 males, mean age 56.7+/-12.3 years, disease duration 6.3+/-1.2 years, baseline Disease Activity Score [DAS]-28 3.2-5.6) who received treatment with anti-TNF agents after the failure of conventional disease-modifying antirheumatic drugs (32 received infliximab [IFX], 58 etanercept [ETN], and 39 adalimumab [ADA]). After 6 months of treatment, the patients were classified as being in remission (DAS28 <2.6), having low disease activity (LDA; DAS28 2.6 3.2), or not responding (NR: DAS28 >3.2). The patients were also tested for serum antidrug antibodies and IgG4 antibodies against TNF inhibitors. After 24 weeks of treatment, 38% of the ETN-treated patients and 28% of those treated with ADA had injection-site reactions; the rate of systemic reactions in the IFX group was 25%. The differences among the three groups were not statistically significant (P=0.382; ETN versus ADA P=0.319). The percentages of patients with adverse events stratified by drug response were: LDA 8% and NR 18% in the ADA group; in remission 3%, LDA 22%, and NR 10% in the ETN group; and LDA 6% and NR 16% in the IFX group (P=0.051). The percentages of patients with antidrug antibodies were: ADA 33.3%, ETN 11.5%, and IFX 10.3% (P=0.025; ADA versus ETN P=0.015). The percentages of patients with IgG4 antibodies were: ADA 6%, ETN 13%, and IFX 26% (P=0.017; ADA versus ETN P=0.437). Associations between antidrug antibodies, specific IgG4 antibodies, and adverse reactions were not significant for any of the three drugs. IgG4 levels were higher in the ADA group than in the other two groups, and higher in the patients with worse DAS28 (NR) and in those experiencing adverse events. These data suggest a possible association between IgG4 levels and worse DAS28 (r (2)=5.8%, P=0.011). The presence of specific IgG4 antibodies against TNF blockers in patients with RA might affect the drugs' activity. Patients with injection-site reactions and IgG4 against ETN may show a decreased response. PMID- 25733804 TI - Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia. AB - The introduction of targeted therapy against CD20(+) with the monoclonal antibody rituximab has dramatically improved the survival of B-cell non-Hodgkin lymphoma including chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Unfortunately, CLL remains incurable with chemoimmunotherapy, with many patients having refractory or relapsing disease after rituximab-containing therapy. Obinutuzumab (GA101) is a novel humanized Type II anti-CD20 monoclonal antibody that has been investigated and compared to rituximab. Here, we provide an overview of obinutuzumab, including its mechanisms of action, preclinical data, and Phase I to III clinical studies. Preclinical data illustrate obinutuzumab's higher potency compared to rituximab through antibody-dependent cellular cytotoxicity and direct cell death. Recently, the CLL11 study presented a significant benefit from obinutuzumab chemoimmunotherapy and supports its use for treatment-naive unfit CLL patients. Herein, we review that obinutuzumab is both a safe and effective alternative to rituximab. PMID- 25733805 TI - Response to Miller et al: resistant mutations in CML and Ph(+) ALL - role of ponatinib. PMID- 25733806 TI - Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies. AB - Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10 shogaol, ar-curcumene, beta-bisabolene, beta-sesquiphelandrene, 6-gingerdione, ( )-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via pi-pi stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger-drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger-drug interactions. PMID- 25733807 TI - Anesthetic drug midazolam inhibits cardiac human ether-a-go-go-related gene channels: mode of action. AB - Midazolam is a short-acting benzodiazepine that is in wide clinical use as an anxiolytic, sedative, hypnotic, and anticonvulsant. Midazolam has been shown to inhibit ion channels, including calcium and potassium channels. So far, the effects of midazolam on cardiac human ether-a-go-go-related gene (hERG) channels have not been analyzed. The inhibitory effects of midazolam on heterologously expressed hERG channels were analyzed in Xenopus oocytes using the double electrode voltage clamp technique. We found that midazolam inhibits hERG channels in a concentration-dependent manner, yielding an IC50 of 170 MUM in Xenopus oocytes. When analyzed in a HEK 293 cell line using the patch-clamp technique, the IC50 was 13.6 MUM. Midazolam resulted in a small negative shift of the activation curve of hERG channels. However, steady-state inactivation was not significantly affected. We further show that inhibition is state-dependent, occurring within the open and inactivated but not in the closed state. There was no frequency dependence of block. Using the hERG pore mutants F656A and Y652A we provide evidence that midazolam uses a classical binding site within the channel pore. Analyzing the subacute effects of midazolam on hERG channel trafficking, we further found that midazolam does not affect channel surface expression. Taken together, we show that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression. These data add to the current understanding of the pharmacological profile of the anesthetic midazolam. PMID- 25733808 TI - Tazarotene as alternative topical treatment for onychomycosis. AB - BACKGROUND: Distal and lateral onychomycoses are the most frequent forms of onychomycosis, causing subungual hyperkeratosis that usually limits local penetration of antimycotic drugs. Tazarotene exerts anti-inflammatory and immune modulating activities toward both infective agents and damaged keratinocytes. Given the well-documented efficacy of tazarotene on hyperkeratotic nail psoriasis, we investigated its therapeutic use in onychomycosis. PATIENTS AND METHODS: We designed a preliminary open clinical trial in patients affected by distal and lateral subungual onychomycosis of the toenails and verified the fungistatic activity of tazarotene in vitro. Fifteen patients were treated with topical tazarotene 0.1% gel once per day for 12 weeks. Mycological cultures and potassium hydroxide stains of nail samples were performed at the beginning and at the end of the study. Treatment was considered effective when clinical healing and negative mycological culture were obtained. Onycholysis, nail bed discoloration, and subungual hyperkeratosis were measured using standardized methodologies and analyzed by means of Mann-Whitney test and analysis of variance. Fungistatic activity of tazarotene was evaluated by disk diffusion assay. RESULTS: Six patients (40%) reached a mycological cure on target nail samples already after 4 weeks of treatment. Complete clinical healing and negative cultures were reached in all patients at week 12, with a significant improvement of all clinical parameters of the infected nails. Disk diffusion assay after 48 hours of incubation with tazarotene solution showed a central area of inhibition in all examined fungal cultures. CONCLUSION: Our results documented a good clinical outcome using topical tazarotene 0.1% gel in distal and lateral subungual onychomycosis and its fungistatic activity of tazarotene in vitro. The majority of patients appeared cured at a 6-month follow-up. The efficacy and safety of tazarotene must be confirmed on a larger number of patients, although already documented in nail psoriasis patients often affected by onychomycosis. PMID- 25733809 TI - Treatment with a herbal formula B401 enhances neuroprotection and angiogenesis in the R6/2 mouse model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disease characterized by motor dysfunction and early death. Despite years of research, the mechanisms responsible for chronic neurodegeneration of HD remain elusive. Chinese traditional medicines might provide new insights or new therapy for HD. The Chinese herbal formula B401 is a well-known Taiwan-US patent formula and a health supplement for promoting blood circulation and enhancing brain function. This study aimed to elucidate the neuroprotective effects of the Chinese herbal formula B401 on the syndrome of HD. Then, we compared the life span and body weight of R6/2 HD mice with and without oral B401 treatment. The ameliorative effects of B401 on the symptom of HD mice were investigated through behavior tests. Expressions of proteins for neuroprotection, angiogenesis, and inflammation in the brain tissue of R6/2 HD mice were compared by using immunostaining and Western blotting techniques. Our study in vitro showed that viabilities of glutamate-treated SH-SY5Y cells were significantly increased under B401 treatment. Our results in vivo showed that duration of survival was increased, body weight loss was reduced, and motor ability was improved in R6/2 HD mice under oral B401 treatment. Subcutaneous microcirculation was enhanced in 3-month R6/2 HD mice under intraperitoneal B401 injections as observed by using moorFLPI laser Doppler imager. Atrophy of cerebrum, midbrain, and cerebellum in 3 month R6/2 HD mice under oral B401 treatment was alleviated as observed by utilizing magnetic resonance imaging. Evidence from immunostaining and Western blotting analysis showed that expressions of mutant huntingtin and tumor necrosis factor-alpha were reduced, while expressions of brain-derived neurotrophic factor and vascular endothelial growth factor were enhanced in the brain tissue of 2 month R6/2 HD mice under oral B401 treatment. We suggest that the herbal formula B401 can be developed as a medical supplement for ameliorating neurodegenerative diseases of HD via reducing mutant huntingtin aggregation and excitotoxicity, enhancing neuroprotection and angiogenesis, and alleviating inflammation in the brain. PMID- 25733810 TI - Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. AB - INTRODUCTION: Gastric cancer is a fatal malignancy with a rising incidence rate. Effective methods for early diagnosis, monitoring metastasis, and prognosis are currently unavailable for gastric cancer. In this study, we examined the association of programmed death ligand-1 (PD-L1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with the prognosis of gastric cancer. METHODS: The expressions of PD-L1 and APE1 were detected by immunohistochemistry in 107 cases of human gastric carcinoma. The correlation of PD-L1 and APE1 expression with the clinicopathologic features of gastric carcinoma was analyzed by SPSS version 19.0. RESULTS: The positive expression rates of PD-L1 and APE1 in gastric cancer tissues were 50.5% (54/107) and 86.9% (93/107), respectively. PD-L1 and APE1 positive expressions were significantly associated with depth of invasion, lymph node metastasis, pathological type, overall survival, and higher T stage. Furthermore, the expression of PD-L1 in highly differentiated gastric cancers was higher than that in poorly differentiated cancers (P=0.008). Moreover, the expression of APE1 and PD-L1 in gastric cancers was positively correlated (r=0.336, P<0.01). Multivariate analysis showed that the depth of invasion was a significant prognostic factor (risk ratio 19.91; P=0.000), but there was no significant relationship with PD-L1, APE1, prognosis, and other characteristics. CONCLUSION: The deregulation of PD-L1 and APE1 might contribute to the development and the poor prognosis of gastric cancer. Our findings suggest that high expression of PD-L1 and APE1 is a risk factor of gastric cancer and a new biomarker to predict the prognosis of gastric cancer. Furthermore, our findings suggest that targeting the PD-L1 and APE1 signaling pathways may be a new strategy for cancer immune therapy and targeted therapy for gastric cancer, especially in patients with deep invasion and lymph node metastasis. PMID- 25733811 TI - Design, synthesis, and computational studies on dihydropyrimidine scaffolds as potential lipoxygenase inhibitors and cancer chemopreventive agents. AB - Dihydropyrimidine scaffold has a wide range of potential pharmacological activities such as antiviral, antitubercular, antimalarial, anti-inflammatory, and anticancer properties. 5-Lipoxygenase enzyme is an enzyme responsible for the metabolism of arachidonic acid to leukotrienes. The elevated levels of this enzyme and its metabolites in cancer cells have a direct relation on the development of cancer when compared to normal cells. The development of novel lipoxygenase inhibitors can have a major role in cancer therapy. A series of substituted 1,4-dihydropyrimidine analogues were synthesized and characterized by (1)H-NMR, (13)C-NMR, and HRMS. Molecular docking against lipoxygenase enzyme (protein data bank code =3V99) was done using Molecular Operating Environment 2013.08 and Leadit 2.1.2 softwares and showed high affinities. The synthesized compounds were tested for their lipoxygenase inhibitory activity and showed inhibition ranging from 59.37%+/-0.66% to 81.19%+/-0.94%. The activity was explained by a molecular docking study. The title compounds were also tested for cytotoxic activity against two human cancer cell lines Michigan Cancer Foundation 7 and human melanoma cells and a normal peripheral blood mononuclear cell line. PMID- 25733812 TI - Effects of combined dietary supplementation with fenofibrate and Schisandrae Fructus pulp on lipid and glucose levels and liver function in normal and hypercholesterolemic mice. AB - BACKGROUND: Currently, combined therapy using herbs and synthetic drugs has become a feasible therapeutic intervention against some diseases. The purpose of this study was to assess the effects of supplementation with fenofibrate (FF), a chemical drug used for the treatment of hyperlipidemia, and the aqueous extract of Schisandrae Fructus (SF, a Chinese herb) pulp (AqSF-P) or an SF-related synthetic analog, bicyclol (BY), on serum/hepatic lipid levels and liver status in normal and hypercholesterolemic (HCL) mice. METHODS: Male mice obtained from the Institute of Cancer Research (ICR) were fed on a normal diet (ND) or high cholesterol/bile salt (0.5%/0.15%, w/w) diet (HCBD) containing FF (0.03% or 0.1%, w/w) with or without AqSF-P (0.3%-9.0%, based on crude herbal material, w/w) or BY (0.025%, w/w) for 10 days. Then serum lipid levels and alanine aminotransferase (ALT) activity, as well as hepatic triglyceride (TG), total cholesterol (TC), and glucose levels, were measured. RESULTS: Oral supplementation with FF significantly reduced serum and hepatic TG, TC, and hepatic glucose levels (approximately 79%) in mice fed with ND or HCBD. FF supplementation combined with AqSF-P or BY increased FF-induced reduction in hepatic TC and TG contents in ND-fed mice (up to 67%) and in HCBD-fed mice (up to 54%), when compared with FF supplementation alone. Hepatic glucose-lowering effect of FF was enhanced (up to 19%) by AqSF-P cosupplementation in both normal and HCL mice. FF supplementation enhanced the excretion of fecal TC (by 75%) in mice fed with HCBD. Fecal TC contents were increased by 14%/9% in the combination therapy with FF and AqSF-P in ND-/HCBD-fed mice. Serum ALT activity was elevated by 45% in HCBD-fed mice. FF caused a significant increase in ALT activity by 198% and 120% in normal and HCL mice, respectively. BY markedly attenuated the ALT activity by 54% in mice fed with ND supplemented with 0.1% FF and by 42% in mice fed with HCBD supplemented with 0.03% FF. CONCLUSION: AqSF-P cosupplementation augmented the hepatic lipid-/glucose-lowering effects of FF. BY ameliorated FF induced liver injury in normal and HCL mice. PMID- 25733813 TI - Proteomic response to 5,6-dimethylxanthenone 4-acetic acid (DMXAA, vadimezan) in human non-small cell lung cancer A549 cells determined by the stable-isotope labeling by amino acids in cell culture (SILAC) approach. AB - 5,6-Dimethylxanthenone 4-acetic acid (DMXAA), also known as ASA404 and vadimezan, is a potent tumor blood vessel-disrupting agent and cytokine inducer used alone or in combination with other cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC) and other cancers. However, the latest Phase III clinical trial has shown frustrating outcomes in the treatment of NSCLC, since the therapeutic targets and underlying mechanism for the anticancer effect of DMXAA are not yet fully understood. This study aimed to examine the proteomic response to DMXAA and unveil the global molecular targets and possible mechanisms for the anticancer effect of DMXAA in NSCLC A549 cells using a stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data showed that treatment with DMXAA modulated the expression of 588 protein molecules in A549 cells, with 281 protein molecules being up regulated and 306 protein molecules being downregulated. Ingenuity pathway analysis (IPA) identified 256 signaling pathways and 184 cellular functional proteins that were regulated by DMXAA in A549 cells. These targeted molecules and signaling pathways were mostly involved in cell proliferation and survival, redox homeostasis, sugar, amino acid and nucleic acid metabolism, cell migration, and invasion and programed cell death. Subsequently, the effects of DMXAA on cell cycle distribution, apoptosis, autophagy, and reactive oxygen species (ROS) generation were experimentally verified. Flow cytometric analysis showed that DMXAA significantly induced G1 phase arrest in A549 cells. Western blotting assays demonstrated that DMXAA induced apoptosis via a mitochondria-dependent pathway and promoted autophagy, as indicated by the increased level of cytosolic cytochrome c, activation of caspase 3, and enhanced expression of beclin 1 and microtubule-associated protein 1A/1B light chain 3 (LC3-II) in A549 cells. Moreover, DMXAA significantly promoted intracellular ROS generation in A549 cells. Collectively, this SILAC study quantitatively evaluates the proteomic response to treatment with DMXAA that helps to globally identify the potential molecular targets and elucidate the underlying mechanism of DMXAA in the treatment of NSCLC. PMID- 25733814 TI - Human mesenchymal stem cells as delivery of osteoprotegerin gene: homing and therapeutic effect for osteosarcoma. AB - Biological treatments have been studied extensively and previous studies have proved that osteoprotegerin (OPG) can inhibit the development and progress of human osteosarcoma. However, the utility of biologic agents for cancer therapy has a short half-life, which can hardly deliver to and function in tumor sites efficiently. Mesenchymal stem cells (MSCs) have the potential to migrate to tumor sites. In this study, MSCs transfected with adenoviruses carrying the OPG gene (MSCs-OPG) were used via the tail vein to treat athymic nude mice (nu/nu) bearing osteosarcoma. In vivo and ex vivo images were used to validate the MSCs homing to tumors. The therapeutic effect for osteosarcoma was evaluated by observations on growth of tumors and bone destruction. The results showed that infected MSCs-OPG labeled with red fluorescent protein (RFP) can migrate to tumor sites and express OPG protein. The treatment by MSCs-OPG reduced the tumor growth and inhibited bone destruction in vivo. All these indicated that MSCs can deliver OPG to tumor sites, which could be a new direction of biological treatment for human osteosarcoma. PMID- 25733815 TI - 1-1-12 one-step wash-in scheme for desflurane low flow anesthesia: performance without nitrous oxide. AB - BACKGROUND: We reported a 1-1-12 wash-in scheme for desflurane-nitrous oxide (N2O) low flow anesthesia that is simple, rapid, and predictable. There remain some situations where N2O should be avoided, which limits the generalizability of this wash-in scheme. The objective of our study was to determine the performance of this scheme in contexts where N2O is not used. METHODS: We recruited 106 patients scheduled for elective surgery under general anesthesia. After induction and intubation, wash-in was started with a fresh gas flow of air:O2 1:1 L/min and a vaporizer concentration of desflurane of 12%. Controlled ventilation was then adjusted to maintain PACO2 at 30-35 mmHg. RESULTS: The alveolar concentration of desflurane (FAD) rose rapidly from 0% to 6% in 4 minutes in the same pattern as observed in our previous study in which N2O was used. An FAD of 7% was achieved in 6 minutes. An FAD of 1% to 7% occurred at 0.6, 1, 1.5, 2, 3, 4, and 6 minutes. The rise in heart rate during wash-in was statistically significant, although not clinically so. There was a slight but statistically significant decrease in blood pressure, but this had no clinical significance. CONCLUSION: Performance of the 1 1-12 wash-in scheme is independent of the use of N2O. Respective FADs of 1%, 2%, 3%, 4%, 5%, 6%, and 7% can be expected at 0.6, 1, 1.5, 2, 3, 4, and 6 minutes. PMID- 25733816 TI - Synthesis of an anthraquinone derivative (DHAQC) and its effect on induction of G2/M arrest and apoptosis in breast cancer MCF-7 cell line. AB - Anthraquinones are an important class of naturally occurring biologically active compounds. In this study, anthraquinone derivative 1,3-dihydroxy-9,10 anthraquinone-2- carboxylic acid (DHAQC) (2) was synthesized with 32% yield through the Friedel-Crafts condensation reaction. The mechanisms of cytotoxicity of DHAQC (2) in human breast cancer MCF-7 cells were further investigated. Results from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that DHAQC (2) exhibited potential cytotoxicity and selectivity in the MCF-7 cell line, comparable with the naturally occurring anthraquinone damnacanthal. DHAQC (2) showed a slightly higher IC50 (inhibitory concentration with 50% cell viability) value in the MCF-7 cell line compared to damnacanthal, but it is more selective in terms of the ratio of IC50 on MCF-7 cells and normal MCF-10A cells. (selective index for DHAQC (2) was 2.3 and 1.7 for damnacanthal). The flow cytometry cell cycle analysis on the MCF-7 cell line treated with the IC50 dose of DHAQC (2) for 48 hours showed that DHAQC (2) arrested MCF-7 cell line at the G2/M phase in association with an inhibited expression of PLK1 genes. Western blot analysis also indicated that the DHAQC (2) increased BAX, p53, and cytochrome c levels in MCF-7 cells, which subsequently activated apoptosis as observed in annexin V/propidium iodide and cell cycle analyses. These results indicate that DHAQC (2) is a synthetic, cytotoxic, and selective anthraquinone, which is less toxic than the natural product damnacanthal, and which demonstrates potential in the induction of apoptosis in the breast cancer MCF-7 cell line. PMID- 25733817 TI - Bardoxolone methyl induces apoptosis and autophagy and inhibits epithelial-to mesenchymal transition and stemness in esophageal squamous cancer cells. AB - Natural and synthetic triterpenoids have been shown to kill cancer cells via multiple mechanisms. The therapeutic effect and underlying mechanism of the synthetic triterpenoid bardoxolone methyl (C-28 methyl ester of 2-cyano-3,12 dioxoolean-1,9-dien-28-oic acid; CDDO-Me) on esophageal cancer are unclear. Herein, we aimed to investigate the anticancer effects and underlying mechanisms of CDDO-Me in human esophageal squamous cell carcinoma (ESCC) cells. Our study showed that CDDO-Me suppressed the proliferation and arrested cells in G2/M phase, and induced apoptosis in human ESCC Ec109 and KYSE70 cells. The G2/M arrest was accompanied with upregulated p21Waf1/Cip1 and p53 expression. CDDO-Me significantly decreased B-cell lymphoma-extra large (Bcl-xl), B-cell lymphoma 2 (Bcl-2), cleaved caspase-9, and cleaved poly ADP ribose polymerase (PARP) levels but increased the expression level of Bcl-2-associated X (Bax). Furthermore, CDDO Me induced autophagy in both Ec109 and KYSE70 cells via suppression of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. There were interactions between the autophagic and apoptotic pathways in Ec109 and KYSE70 cells subject to CDDO-Me treatment. CDDO-Me also scavenged reactive oxygen species through activation of the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) pathway in Ec109 and KYSE70 cells. CDDO-Me inhibited cell invasion, epithelial-mesenchymal transition, and stemness in Ec109 and KYSE70 cells. CDDO-Me significantly downregulated E cadherin but upregulated Snail, Slug, and zinc finger E-box-binding homeobox 1 (TCF-8/ZEB1) in Ec109 and KYSE70 cells. CDDO-Me significantly decreased the expression of octamer-4, sex determining region Y-box 2 (Sox-2), Nanog, and B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), all markers of cancer cell stemness, in Ec109 and KYSE70 cells. Taken together, these results indicate that CDDO-Me is a promising anticancer agent against ESCC. Further studies are warranted to explore the molecular targets, efficacy and safety of CDDO-Me in the treatment of ESCC. PMID- 25733818 TI - The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells. AB - Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB 231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3 II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and beta catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy. PMID- 25733819 TI - A computational and functional study elicits the ameliorating effect of the Chinese herbal formula Huo Luo Xiao Ling Dan on experimental ischemia-induced myocardial injury in rats via inhibition of apoptosis. AB - Ischemic heart disease (IHD) is the leading cause of death worldwide and remains a major life-threatening factor in humans. Apoptosis has been implicated in the pathogenesis of IHD. The Chinese herbal formula Huo Luo Xiao Ling Dan (HLXLD), one of the commonly used Chinese herbal formulas, consists of Salviae miltiorrhizae, Angelica sinensis, Gummi olibanum, and Commiphora myrrha, with a wide spectrum of pharmacological activity. However, the mechanism of action and molecular targets of HLXLD in the treatment of IHD are unclear. This study aimed to computationally predict the molecular interactions between the major active components of HLXLD and key regulators of apoptosis and then examine the effect of HLXLD on coronary artery ligation-induced acute myocardial ischemia in rats. The molecular interactions between the major active components of HLXLD, including ferulic acid, ligustilide, succinic acid, vanillic acid, tanshinone IIA, tanshinone IIB, danshensu, salvianolic acid A, salvianolic acid C, protocatechuic aldehyde, and beta-boswellic acid and human protein molecules including B cell lymphoma-extra large (Bcl-xl), B cell lymphoma 2 antagonist/killer 1 (Bak1), B cell lymphoma 2 (Bcl-2), procaspase 3, and caspase 9 with regard to hydrogen bond formation, charge interaction, and pi-pi stacking using Discovery Studio((r)) program 3.1. The 12 HLXLD components were predicted by ADMET (absorption, distribution, metabolism, excretion and toxicity) Predictor to have favorable pharmacokinetic and low hepatotoxicity profiles. The acute myocardial ischemia was established by surgical ligation of the left anterior descending coronary artery. The rats were divided into a sham operative group, a model group, a positive control group treated with 0.2 mg/kg isosorbide mononitrate, and groups treated with 2.7, 5.4, or 10.8 g/kg HLXLD. The results showed that administration of HLXLD increased mean arterial pressure, left ventricular systolic pressure, heart rate, and maximal rate of rise/descent of left ventricular pressure levels. Administration of HLXLD significantly ameliorated coronary artery ligation-induced tissue damage in the left ventricle, with restored arrangement of myocardial fibers and recovered myoplasm in rats. Furthermore, HLXLD markedly increased the expression level of Bcl-2 but decreased the level of cleaved caspase 3. Taken together, administration of HLXLD attenuated acute myocardial ischemia-induced damage in cardiomyocytes and inhibited apoptotic death of cardiomyocytes, thereby exerting a cardioprotective effect in rats with IHD. These findings suggest that HLXLD may represent a promising herbal formula for the treatment of cardiovascular disease by counteracting apoptotic cell death via multiple active compounds. More studies are warranted to fully elucidate the mechanisms of action, identify the therapeutic targets, and validate the efficacy and safety of HLXLD in the treatment of IHD. PMID- 25733820 TI - Hsa-microRNA-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: a bioinformatic and clinical study and the therapeutic implication. AB - The aberrant expression of human microRNA-181a-1 (hsa-miR-181a) has been implicated in the pathogenesis of various cancers, serving as an oncogene or a tumor suppressor. However, the role of hsa-miR-181a in the pathogenesis of endometrial carcinoma (EC) and its clinical significance are unclear. This study aimed to search for the molecular targets of hsa-miR-181a using bioinformatic tools and then determine the expression levels of hsa-miR-181a in normal, hyperplasia, and EC samples from humans. To predict the targets of hsa-miR-181a, ten different algorithms were used, including miRanda-mirSVR, DIANA microT v5.0, miRDB, RNA22 v2, TargetMiner, TargetScan 6.2, PicTar, MicroCosm Targets v5, and miRWALK. Two algorithms, TarBase 6.0 and miRTarBase, were used to identify the validated targets of hsa-miR-181a-5p (a mature product of hsa-miR-181a), and the web-based Database for Annotation, Visualization and Integrated Discovery (DAVID) 6.7 was used to provide biological functional interpretation of the validated targets of hsa-miR-181a-5p. A total of 78 formalin-fixed, paraffin-embedded tissue specimens from 65 patients and 13 healthy subjects were collected and examined, including normal endometrium (n=13), endometrial hyperplasia (n=18), and EC (37 type I and 10 type II EC cases). Our bioinformatic studies have showed that hsa-miR-181a might regulate a large number of target genes that are important in the regulation of critical cell processes, such as cell fate, cell survival, metabolism, and cell death. To date, 313 targets of hsa-miR-181a have been validated, and 22 of these targets are cancer genes. The precision of predictions by all the algorithms for hsa-miR-181a-1's targets was low. Many of these genes are involved in tumorigenesis of various cancers, including EC, based on the DAVID and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In comparison with normal endometrial tissue, the expression level of hsa-miR 181a was significantly increased in type I and type II EC (P<0.05), and type II EC exhibited a significant higher expression level of hsa-miR-181a than that in type I EC (P<0.05). In addition, there was a significant increase in the expression level of hsa-miR-181a in type II EC compared with endometrial hyperplasia (P<0.05). Taken together, these results suggest that hsa-miR-181a may serve as an oncogene in endometrial tumorigenesis and that hsa-miR-181a might be used as a new biomarker in the prediction of prognosis of EC in clinical practice. More functional and mechanistic studies are needed to validate the role of hsa-miR-181a in the development, progression, and metastasis of EC. PMID- 25733822 TI - Electrochemotherapy in combination with chemoradiotherapy in the treatment of oral carcinomas in advanced stages of disease: efficacy, safety, and clinical outcomes in a small number of selected cases. AB - INTRODUCTION: Electrochemotherapy (ECT) is a new therapeutic method that is used in oncology as palliative treatment in patients with recurrent head and neck tumors and who are not candidates for standard therapeutic options. The aim of our study was to evaluate the cytoreductive effect of ECT in patients subjected to chemoradiotherapy for squamous cell carcinoma of the oral cavity. The primary endpoint of the study was to verify tumor debulking after ECT treatment as neoadjuvant, before conventional chemoradiotherapy. The secondary endpoint was to assess the safety and tolerability of ECT treatment. MATERIALS AND METHODS: This experimental study was conducted at the Division of Otolaryngology, University of Catanzaro, Italy. From February 2013 to February 2014, four patients were enrolled, two males and two females, with a mean age of 56 years (range: 47-65 years), and with squamous cell carcinoma of the oral cavity in advanced stages of disease (T3-T4). All patients, with their informed consent, received ECT treatment in accordance with the Standard Operating Procedures defined in the European Standard Operating Procedures on Electrochemotherapy (ESOPE) study, followed by conventional chemoradiotherapy. Their response to ECT treatment was assessed after 30 days. For each patient, the following parameters were evaluated with the appropriate forms: local tumor control, control of pain (analgesia postsurgery scale [APS]), and quality of life (Short Form [36] Health Survey [SF 36]; v1). RESULTS: Three of four patients (75%) showed a partial response, whereas in one patient (25%), the disease remained stable. The treatment was well tolerated by all patients, according to the APS and SF-36 results. CONCLUSION: Although the study was conducted on a small number of cases, data from this study show that ECT represents a safe and effective treatment in terms of tumor cytoreduction and locoregional control of the disease. It also allows good control of postoperative pain and short hospitalization. PMID- 25733821 TI - Liraglutide reduces lipogenetic signals in visceral adipose of db/db mice with AMPK activation and Akt suppression. AB - Liraglutide, a glucagon-like peptide-1 analog, has been proved to reduce body weight and visceral adipose tissue (VAT) in human studies. In this study, we aimed at examining lipogenetic signal changes in VAT after weight-loss with liraglutide in db/db mice. The mice were divided into two groups: liraglutide treated group (n=14, 8-week-old, fasting glucose. >10 mmol/L, liraglutide 300 MUg/kg twice a day for 4 weeks) and control group (n=14, saline). We found body weight gain and food intake were reduced after liraglutide treatment (P<0.05). Compared to the control group, the VAT weights were significantly lower in the treated group (2.32+/-0.37 g versus 3.20+/-0.30 g, P<0.01) than that in control group. In VAT, compared with control group, the lipogenetic transcription factors PPARgamma and C/EBPalpha expressions were both reduced with pAMPK and pACC increased 3.5-fold and 2.31-fold respectively, while pAkt and pP38MAPK were reduced 0.38-fold and 0.62-fold respectively (P<0.01). In conclusion, VAT was reduced after weight loss with AMPK activation and Akt suppression with liraglutide treatment, which was associated with reduction of lipogenetic process in VAT. PMID- 25733823 TI - Combination dolutegravir-abacavir-lamivudine in the management of HIV/AIDS: clinical utility and patient considerations. AB - The current standard of care for human immunodeficiency virus (HIV) treatment is a three-drug regimen containing a nonnucleoside reverse transcriptase inhibitor, a protease inhibitor, or an integrase strand transfer inhibitor (INSTI) plus two nucleoside/tide reverse transcriptase inhibitors. Given their potency, safety, and distinctive mechanism of action, INSTIs represent an important advance in HIV type 1 (HIV-1) therapy. Dolutegravir (DTG) is a new-generation INSTI recently approved for the treatment of HIV-1-infected adult patients, with distinct advantages compared with other available antiretroviral agents. In well-designed, large clinical trials, DTG-containing regimens have demonstrated either noninferiority or superiority to current first-line agents such as raltegravir-, darunavir/ritonavir-, and efavirenz-containing regimens. The favorable safety profile, low potential for drug interactions, minimal impact on lipids, good tolerability, and high resistance barrier of DTG makes this compound one of the preferred choices for HIV therapy in multiple clinical scenarios, including treatment-naive and treatment-experienced patients. DTG is the only antiretroviral drug not yet associated with de novo emergence of resistance mutations in treatment-naive individuals. However, data from in vitro studies and clinical trial suggest the possibility of cross-resistance between first- and second-generation INSTIs. Even though these profiles are infrequent at the moment, they need to be monitored in all current patients treated with INSTIs. With its potent activity, good tolerability, simplicity of dosing, and minimal drug interaction profile, DTG will likely play a major role in the management of patients with HIV-1 infection. On the basis of clinical trial data, current guidelines endorse DTG in combination with nucleoside/tide reverse transcriptase inhibitors as one of the recommended regimens in antiretroviral therapy-naive patients. Most of the favorable clinical experiences from clinical trials are based on the combination of DTG with abacavir/lamivudine, and DTG is planned to be coformulated with abacavir/lamivudine. This will provide a further advantage, given that single tablet regimens are associated with higher adherence rates as well as improvement in quality of life and enhanced patient preference. PMID- 25733824 TI - The prevalence and consequences of malnutrition risk in elderly Albanian intensive care unit patients. AB - PURPOSE: Many investigators have reported rising numbers of elderly patients admitted to the intensive care units (ICUs). The aim of the study was to estimate the prevalence of malnutrition risk in the ICU by comparing the prevalence of malnutrition between older adults (aged 65 years and above) and adults (aged 18 64 years), and to examine the negative consequences associated with risk of malnutrition in older adults. MATERIALS AND METHODS: A prospective cohort study in the ICU of the University Hospital Center of Tirana, Albania, was conducted. Logistic regression analysis was used to analyze the effect of malnutrition risk on the length of ICU stay, the duration of being on the ventilator, the total complications, the infectious complications, and the mortality. RESULTS: In this study, 963 patients participated, of whom 459 patients (47.7%) were aged >=65 years. The prevalence of malnutrition risk at the time of ICU admission of the patients aged >=65 years old was 71.24%. Logistic regression adjusted for confounders showed that malnutrition risk was an independent risk factor of poor clinical outcome for elderly ICU patients, for 1) infections (odds ratio [OR] =4.37; 95% confidence interval [CI]: 2.61-7.31); 2) complications (OR =6.73; 95% CI: 4.26-10.62); 3) mortality (OR =2.68; 95% CI: 1.72-4.18); and 4) ICU length of stay >14 days (OR =5.18, 95% CI: 2.43-11.06). CONCLUSION: Malnutrition risk is highly prevalent among elderly ICU patients, especially among severely ill patients with malignancy admitted to the emergency ward. ICU elderly patients at malnutrition risk will have higher complication and infection rates, longer duration of ICU stay, and increased mortality. Efforts should be made to implement a variety of nutritional care strategies, to change the nutritional practices not only at ward level, but nationally, according to the best clinical practice and recent guidelines. PMID- 25733825 TI - The therapeutic effects of bone marrow mesenchymal stem cells after optic nerve damage in the adult rat. AB - Optic nerve trauma is a common occurrence that results in irreversible blindness. Currently, no effective strategies are known to prevent optic nerve degeneration. We assessed the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) after optic nerve crush in the adult rat. Our results showed that BMSCs significantly promoted the regeneration of injured axons compared with phosphate buffered saline alone. Therefore, BMSC transplantation may be effective for the treatment of central nervous system disorders. PMID- 25733826 TI - Clinical variables impacting on the estimation of utilities in chronic obstructive pulmonary disease. AB - PURPOSE: Health utilities are widely used in health economics as a measurement of an individual's preference and show the value placed on different health states over a specific period. Thus, health utilities are used as a measure of the benefits of health interventions in terms of quality-adjusted life years. This study aimed to determine the demographic and clinical variables significantly associated with health utilities for chronic obstructive pulmonary disease (COPD) patients. PATIENTS AND METHODS: This was a multicenter, observational, cross sectional study conducted between October 2012 and April 2013. Patients were aged >=40 years, with spirometrically confirmed COPD. Utility values were derived from the preference-based generic questionnaire EQ-5D-3L applying weighted Spanish societal preferences. Demographic and clinical variables associated with utilities were assessed by univariate and multivariate linear regression models. RESULTS: Three hundred and forty-six patients were included, of whom 85.5% were male. The mean age was 67.9 (standard deviation [SD] =9.7) years and the mean forced expiratory volume in 1 second (%) was 46.2% (SD =15.5%); 80.3% were former smokers, and the mean smoking history was 54.2 (SD =33.2) pack-years. Median utilities (interquartile range) were 0.81 (0.26) with a mean value of 0.73 (SD =0.29); 22% of patients had a utility value of 1 (ceiling effect) and 3.2% had a utility value lower than 0. The factors associated with utilities in the multivariate analysis were sex (beta =-0.084, 95% confidence interval [CI]: 0.154; -0.013 for females), number of exacerbations the previous year (-0.027, 95% CI: -0.044; -0.010), and modified Medical Research Council Dyspnea Scale (mMRC) score (-0.123 [95% CI: -0.185; -0.061], -0.231 [95% CI: -0.301; -0.161], and -0.559 [95% CI: -0.660; -0.458] for mMRC scores 2, 3, and 4 versus 1), all P<0.05. CONCLUSION: Multivariate analysis showed that female sex, frequent exacerbations, and an increased level of dyspnea were the main factors associated with reduced utility values in patients with COPD. PMID- 25733827 TI - Antibiotics against Pseudomonas aeruginosa for COPD exacerbation in ICU: a 10 year retrospective study. AB - SUMMARY: Chronic obstructive pulmonary disease (COPD) is a frequent source of hospitalization. Antibiotics are largely prescribed during COPD exacerbation. Our hypothesis is that large broad-spectrum antibiotics are more and more frequently prescribed. Our results confirm this trend and highlight that the increase in large broad-spectrum use in COPD exacerbation is largely unexplained. BACKGROUND: Acute COPD exacerbation (AECOPD) is frequently due to respiratory tract infection, and the benefit of antipseudomonal antibiotics (APA) is still debated. Health care-associated pneumonia (HCAP) was defined in 2005 and requires broad spectrum antibiotherapy. The main objectives are to describe the antibiotic use for AECOPD in intensive care unit and to identify factors associated with APA use and AECOPD prognosis. METHODS: We conducted a monocentric, retrospective study on all AECOPDs in the intensive care unit treated by antibiotics for respiratory tract infection. Treatment failure (TF) was defined by death, secondary need for mechanical ventilation, or secondary systemic steroid treatment. A multivariate analysis was used to assess factors associated with APA prescription and TF. RESULTS: From January 2000 to December 2011, 111 patients were included. Mean age was 69 years (+/-12), mean forced expiratory volume 38% of theoretic value (+/ 13). Thirty-five (31%) patients were intubated, and 52 (47%) were treated with noninvasive ventilation. From 107 patients, 8 (7%) cases of Pseudomonas aeruginosa were documented. APAs were prescribed in 21% of patients before 2006 versus 57% after (P=0.001). TF prevalence was 31%. Risk factors for P. aeruginosa in COPD and HCAP diagnosis did not influence APA, whereas the post-2006 period was independently associated with APA prescription (odds ratio 6.2; 95% confidence interval 1.9-20.3; P=0.0013). APA did not improve TF (odds ratio 1.09; 95% confidence interval 0.37-3.2). CONCLUSION: HCAP guidelines were followed by an increase in APA use in AECOPD, without an improvement in prognosis. HCAP prevalence cannot account for the increasing APA trend. Time effect reveals a drift in practices. The microbiological effect of such a drift must be evaluated. PMID- 25733828 TI - Differential nanoreprotoxicity of silver nanoparticles in male somatic cells and spermatogonial stem cells. AB - BACKGROUND: Silver nanoparticles (AgNPs) possess unique physical, chemical, and biological properties. AgNPs have been increasingly used as anticancer, antiangiogenic, and antibacterial agents for the treatment of bacterial infections in open wounds as well as in ointments, bandages, and wound dressings. The present study aimed to investigate the effects of two different sizes of AgNPs (10 nm and 20 nm) in male somatic Leydig (TM3) and Sertoli (TM4) cells and spermatogonial stem cells (SSCs). METHODS: Here, we demonstrate a green and simple method for the synthesis of AgNPs using Bacillus cereus culture supernatants. The synthesized AgNPs were characterized using ultraviolet and visible absorption spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy (TEM). The toxicity of the synthesized AgNPs was evaluated by the effects on cell viability, metabolic activity, oxidative stress, apoptosis, and expression of genes encoding steroidogenic and tight junction proteins. RESULTS: AgNPs inhibited the viability and proliferation of TM3 and TM4 cells in a dose- and size-dependent manner by damaging cell membranes and inducing the generation of reactive oxygen species, which in turn affected SSC growth on TM3 and TM4 as feeder cells. Small AgNPs (10 nm) were more cytotoxic than medium-sized nanoparticles (20 nm). TEM revealed the presence of AgNPs in the cell cytoplasm and nucleus, and detected mitochondrial damage and enhanced formation of autosomes and autolysosomes in the AgNP-treated cells. Flow cytometry analysis using Annexin V/propidium iodide staining showed massive cell death by apoptosis or necrosis. Real-time polymerase chain reaction and western blot analyses indicated that in TM3 and TM4 cells, AgNPs activated the p53, p38, and pErk1/2 signaling pathways and significantly downregulated the expression of genes related to testosterone synthesis (TM3) and tight junctions (TM4). Furthermore, the exposure of TM3 and TM4 cells to AgNPs inhibited proliferation and self-renewal of SSCs. CONCLUSION: Our results suggest that AgNPs exhibit size-dependent nanoreprotoxicity in male somatic cells and SSCs, strongly suggesting that applications of AgNPs in commercial products must be carefully evaluated. Further studies of AgNPs-induced nanoreprotoxicity in animal models are required. PMID- 25733829 TI - Binding of plasma proteins to titanium dioxide nanotubes with different diameters. AB - Titanium and titanium alloys are considered to be one of the most applicable materials in medical devices because of their suitable properties, most importantly high corrosion resistance and the specific combination of strength with biocompatibility. In order to improve the biocompatibility of titanium surfaces, the current report initially focuses on specifying the topography of titanium dioxide (TiO2) nanotubes (NTs) by electrochemical anodization. The zeta potential (zeta-potential) of NTs showed a negative value and confirmed the agreement between the measured and theoretically predicted dependence of zeta potential on salt concentration, whereby the absolute value of zeta-potential diminished with increasing salt concentrations. We investigated binding of various plasma proteins with different sizes and charges using the bicinchoninic acid assay and immunofluorescence microscopy. Results showed effective and comparatively higher protein binding to NTs with 100 nm diameters (compared to 50 or 15 nm). We also showed a dose-dependent effect of serum amyloid A protein binding to NTs. These results and theoretical calculations of total available surface area for binding of proteins indicate that the largest surface area (also considering the NT lengths) is available for 100 nm NTs, with decreasing surface area for 50 and 15 nm NTs. These current investigations will have an impact on increasing the binding ability of biomedical devices in the body leading to increased durability of biomedical devices. PMID- 25733830 TI - Nanoformulation of D-alpha-tocopheryl polyethylene glycol 1000 succinate-b poly(epsilon-caprolactone-ran-glycolide) diblock copolymer for siRNA targeting HIF-1alpha for nasopharyngeal carcinoma therapy. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a crucial transcription factor that plays an important role in the carcinogenesis and development of nasopharyngeal carcinoma. In this research, a novel biodegradable D-alpha tocopheryl polyethylene glycol 1000 succinate-b-poly(epsilon-caprolactone-ran glycolide) (TPGS-b-(PCL-ran-PGA)) nanoparticle (NP) was prepared as a delivery system for small interfering ribonucleic acid (siRNA) molecules targeting HIF 1alpha in nasopharyngeal carcinoma gene therapy. The results showed that the NPs could efficiently deliver siRNA into CNE-2 cells. CNE-2 cells treated with the HIF-1alpha siRNA-loaded TPGS-b-(PCL-ran-PGA) NPs showed reduction of HIF-1alpha expression after 48 hours of incubation via real-time reverse transcriptase polymerase chain reaction and Western blot analysis. The cytotoxic effect on CNE 2 cells was significantly increased by HIF-1alpha siRNA-loaded NPs when compared with control groups. In a mouse tumor xenograft model, the HIF-1alpha siRNA loaded NPs efficiently suppressed tumor growth, and the levels of HIF-1alpha mRNA and protein were significantly decreased. These results suggest that TPGS-b-(PCL ran-PGA) NPs could function as a promising genetic material carrier in antitumor therapy, including therapy for nasopharyngeal carcinoma. PMID- 25733831 TI - Preparation and in vitro antitumor effects of cytosine arabinoside-loaded genipin poly-l-glutamic acid-modified bacterial magnetosomes. AB - To solve the problem of synthesized magnetic nanoparticles in cancer therapy, a new drug delivery system synthesized from bacteria was used to load cytosine arabinoside (Ara-C). Genipin (GP) and poly-l-glutamic acid (PLGA) were selected as dual cross-linkers. The preparation and characterization of Ara-C-loaded GP PLGA-modified bacterial magnetosomes (BMs) (ABMs-P), as well as their in vitro antitumor effects, were all investigated. Transmission electron micrographs (TEM) and Fourier transform infrared (FTIR) spectroscopy suggested that Ara-C could be bound to the membrane of BMs modified by GP-PLGA. The diameters of the BMs and ABMs-P were 42.0+/-8.6 nm and 74.9+/-8.2 nm, respectively. The zeta potential revealed that the nanoparticles were stable. Moreover, this system exhibited optimal drug-loading properties and long-term release behavior. The optimal encapsulation efficiency and drug-loading were 64.1%+/-6.6% and 38.9%+/-2.4%, respectively, and ABMs-P could effectively release 90% Ara-C within 40 days, without the release of an initial burst. In addition, in vitro antitumor experiments elucidated that ABMs-P is cytotoxic to HL-60 cell lines, with an inhibition rate of 95%. The method of coupling drugs on BMs using dual cross linkers is effective, and our results reveal that this new system has potential applications for drug delivery in the future. PMID- 25733832 TI - Toward a magic or imaginary bullet? Ligands for drug targeting to cancer cells: principles, hopes, and challenges. AB - There are many problems directly correlated with the systemic administration of drugs and how they reach their target site. Targeting promises to be a hopeful strategy as an improved means of drug delivery, with reduced toxicity and minimal adverse side effects. Targeting exploits the high affinity of cell-surface targeted ligands, either directly or as carriers for a drug, for specific retention and uptake by the targeted diseased cells. One of the most important parameters which should be taken into consideration in the selection of an appropriate ligand for targeting is the binding affinity (K D). In this review we focus on the importance of binding affinities of monoclonal antibodies, antibody derivatives, peptides, aptamers, DARPins, and small targeting molecules in the process of selection of the most suitable ligand for targeting of nanoparticles. In order to provide a critical comparison between these various options, we have also assessed each technology format across a range of parameters such as molecular size, immunogenicity, costs of production, clinical profiles, and examples of the level of selectivity and toxicity of each. Wherever possible, we have also assessed how incorporating such a targeted approach compares with, or is superior to, original treatments. PMID- 25733833 TI - Antifungal efficacy of itraconazole-loaded TPGS-b-(PCL-ran-PGA) nanoparticles. AB - This research was conducted to formulate biodegradable itraconazole (ITZ)-loaded d-a-tocopheryl polyethylene glycol 1000 succinate-b-poly(e-caprolactone-ran glycolide) (TPGS-b-(PCL-ran-PGA); TPP) nanoparticles (NPs) (designed as ITZ loaded TPP NPs) to improve antifungal efficacy. ITZ-loaded TPP NPs were prepared by a modified double-emulsion method, and their size distribution, morphology, zeta potential, drug encapsulation efficiency, drug-release profile, and antifungal effects were characterized. The cytotoxicity of ITZ-loaded-TPP NPs on HeLa cells and fibroblasts was measured using the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) method. The in vivo antifungal activity of ITZ-loaded-TPP NPs was examined in mice by administrating 5*10(5) colony forming units of Candida albicans through the tail vein. The survival rate and survival time of the mice was observed. The fungal count and pathology of lung tissue was analyzed. The data showed that ITZ-loaded-TPP NPs have size of 265+/-5.8 nm, zeta potential of -31+/-0.5 mV, high encapsulation efficiency (95%), and extended drug release profile. ITZ-loaded-TPP NPs at a high concentration of 25 mg/mL had no cytotoxicity on HeLa cells and fibroblasts. Furthermore, ITZ-loaded-TPP NPs achieved a higher level of antifungal activity both in vitro and in vivo. The survival rate and duration was higher in mice treated by ITZ-loaded-TPP NPs than in the other groups (P<0.05). In conclusion, ITZ-loaded-TPP NPs significantly improved ITZ bioavailability by increasing its aqueous dispersibility and extending the duration of drug release, thereby improving the antifungal efficacy of the ITZ agent. PMID- 25733834 TI - Effect of surface roughness on osteogenesis in vitro and osseointegration in vivo of carbon fiber-reinforced polyetheretherketone-nanohydroxyapatite composite. AB - As United States Food and Drug Administration-approved implantable material, carbon fiber-reinforced polyetheretherketone (CFRPEEK) possesses an adjustable elastic modulus similar to cortical bone and is a prime candidate to replace surgical metallic implants. The bioinertness and inferior osteogenic properties of CFRPEEK, however, limit its clinical application as orthopedic/dental implants. In this study, CFRPEEK-nanohydroxyapatite ternary composites (PEEK/n HA/CF) with variable surface roughness have been successfully fabricated. The effect of surface roughness on their in vitro cellular responses of osteoblast like MG-63 cells (attachment, proliferation, apoptosis, and differentiation) and in vivo osseointegration is evaluated. The results show that the hydrophilicity and the amount of Ca ions on the surface are significantly improved as the surface roughness of composite increases. In cell culture tests, the results reveal that the cell proliferation rate and the extent of osteogenic differentiation of cells are a function of the size of surface roughness. The composite with moderate surface roughness significantly increases cell attachment/proliferation and promotes the production of alkaline phosphatase (ALP) activity and calcium nodule formation compared with the other groups. More importantly, the PEEK/n-HA/CF implant with appropriate surface roughness exhibits remarkably enhanced bioactivity and osseointegration in vivo in the animal experiment. These findings will provide critical guidance for the design of CFRPEEK-based implants with optimal roughness to regulate cellular behaviors, and to enhance biocompability and osseointegration. Meanwhile, the PEEK/n-HA/CF ternary composite with optimal surface roughness might hold great potential as bioactive biomaterial for bone grafting and tissue engineering applications. PMID- 25733835 TI - Cell type-specific response to high intracellular loading of polyacrylic acid coated magnetic nanoparticles. AB - Magnetic nanoparticles (NPs) are a special type of NP with a ferromagnetic, electron-dense core that enables several applications such as cell tracking, hyperthermia, and magnetic separation, as well as multimodality. So far, superparamagnetic iron oxide NPs (SPIONs) are the only clinically approved type of metal oxide NPs, but cobalt ferrite NPs have properties suitable for biomedical applications as well. In this study, we analyzed the cellular responses to magnetic cobalt ferrite NPs coated with polyacrylic acid (PAA) in three cell types: Chinese Hamster Ovary (CHO), mouse melanoma (B16) cell line, and primary human myoblasts (MYO). We compared the internalization pathway, intracellular trafficking, and intracellular fate of our NPs using fluorescence and transmission electron microscopy (TEM) as well as quantified NP uptake and analyzed uptake dynamics. We determined cell viability after 24 or 96 hours' exposure to increasing concentrations of NPs, and quantified the generation of reactive oxygen species (ROS) upon 24 and 48 hours' exposure. Our NPs have been shown to readily enter and accumulate in cells in high quantities using the same two endocytic pathways; mostly by macropinocytosis and partially by clathrin mediated endocytosis. The cell types differed in their uptake rate, the dynamics of intracellular trafficking, and the uptake capacity, as well as in their response to higher concentrations of internalized NPs. The observed differences in cell responses stress the importance of evaluation of NP-cell interactions on several different cell types for better prediction of possible toxic effects on different cell and tissue types in vivo. PMID- 25733837 TI - Neurosyphilis with psychotic symptoms and Parkinsonism in a young girl. AB - A 15-year-old girl with neurosyphilis was misdiagnosed as having viral encephalitis with psychotic symptoms and Parkinsonism. We found that she was experiencing visual hallucinations, persecutory delusions, flattening of affect, poorness of thought, tremors, four-limb rigidity, and restlessness, and she was unable to communicate with others. The Venereal Disease Research Laboratory serum test and further lumbar puncture enabled us to diagnose her with neurosyphilis. After antibiotic treatment, her psychotic symptoms and Parkinsonism were relieved. From this case, we believe that it is important to keep organic psychosis in mind during the diagnostic workup, and we argue that routine syphilis screening is necessary in psychiatry clinical practice. PMID- 25733836 TI - Internalization and fate of silica nanoparticles in C2C12 skeletal muscle cells: evidence of a beneficial effect on myoblast fusion. AB - The use of silica nanoparticles for their cellular uptake capability opens up new fields in biomedical research. Among the toxicological effects associated with their internalization, silica nanoparticles induce apoptosis that has been recently reported as a biochemical cue required for muscle regeneration. To assess whether silica nanoparticles could affect muscle regeneration, we used the C2C12 muscle cell line to study the uptake of fluorescently labeled NPs and their cellular trafficking over a long period. Using inhibitors of endocytosis, we determined that the NP uptake was an energy-dependent process mainly involving macropinocytosis and clathrin-mediated pathway. NPs were eventually clustered in lysosomal structures. Myoblasts containing NPs were capable of differentiation into myotubes, and after 7 days, electron microscopy revealed that the NPs remained primarily within lysosomes. The presence of NPs stimulated the formation of myotubes in a dose-dependent manner. NP internalization induced an increase of apoptotic myoblasts required for myoblast fusion. At noncytotoxic doses, the NP uptake by skeletal muscle cells did not prevent their differentiation into myotubes but, instead, enhanced the cell fusion. PMID- 25733838 TI - One-year follow-up in patients with brainstem infarction due to large-artery atherothrombosis. AB - BACKGROUND: Posterior circulation infarction accounts for approximately 25% of the ischemic strokes. A number of different conditions may be associated with the development of brainstem infarction. Prognosis and recurrence rate of brainstem infarction due to large-artery atherothrombosis is still controversial. METHODS: A total of 826 patients with ischemic stroke were admitted to our clinic during a 15-month period. Patients with clinical and radiological evidence of brainstem infarction were comprehensively assessed with appropriate vascular imaging modalities and for cardiological causes. Subjects with an established diagnosis of large-artery atherothrombosis were followed up for 1 year in terms of prognosis and recurrence rates. RESULTS: Of the 101 patients with an established brainstem infarction, the diagnostic work-up indicated the presence of large artery atherothrombosis as the causative factor in 53. A recurrent stroke was detected in the posterior circulation within the first 3 months in 5.8% and within 1 year in 9.8% of these individuals. The 1-year mortality rate was 11.7%. All patients with recurrent stroke had intracranial vascular narrowing at baseline. CONCLUSION: Our findings demonstrate a particularly high rate of recurrence and mortality at 1 year among patients who have a brainstem infarction due to intracranial arterial stenosis. PMID- 25733839 TI - The clinical basis of orthorexia nervosa: emerging perspectives. AB - Orthorexia nervosa describes a pathological obsession with proper nutrition that is characterized by a restrictive diet, ritualized patterns of eating, and rigid avoidance of foods believed to be unhealthy or impure. Although prompted by a desire to achieve optimum health, orthorexia may lead to nutritional deficiencies, medical complications, and poor quality of life. Despite its being a distinct behavioral pattern that is frequently observed by clinicians, orthorexia has received very little empirical attention and is not yet formally recognized as a psychiatric disorder. In this review, we synthesize existing research to identify what is known about the symptoms, prevalence, neuropsychological profile, and treatment of orthorexia. An examination of diagnostic boundaries reveals important points of symptom overlap between orthorexia and anorexia nervosa, obsessive-compulsive disorder (OCD), obsessive compulsive personality disorder (OCPD), somatic symptom disorder, illness anxiety disorder, and psychotic spectrum disorders. Neuropsychological data suggest that orthorexic symptoms are independently associated with key facets of executive dysfunction for which some of these conditions already overlap. Discussion of cognitive weaknesses in set-shifting, external attention, and working memory highlights the value of continued research to identify intermediate, transdiagnostic endophenotypes for insight into the neuropathogenesis of orthorexia. An evaluation of current orthorexia measures indicates a need for further psychometric development to ensure that subsequent research has access to reliable and valid assessment tools. Optimized assessment will not only permit a clearer understanding of prevalence rates, psychosocial risk factors, and comorbid psychopathology but will also be needed to index intervention effectiveness. Though the field lacks data on therapeutic outcomes, current best practices suggest that orthorexia can successfully be treated with a combination of cognitive-behavioral therapy, psychoeducation, and medication. PMID- 25733840 TI - Reducing drug-herb interaction risk with a computerized reminder system. AB - BACKGROUND: Traditional Chinese medicine (TCM) and Western medicine are both popular in Taiwan. Approximately 14.1% of Taiwanese residents use Western drugs and Chinese herbs concurrently; therefore, drug-herb interaction is critical to patient safety. This paper presents a new procedure for reducing the risk of drug interactions. METHODS: Hospital computer systems are modified to ensure that drug herb interactions are automatically detected when a TCM practitioner is writing a prescription. A pop-up reminder appears, warning of interactions, and the practitioner may adjust doses, delete herbs, or leave the prescription unchanged. A pharmacist will receive interaction information through the system and provide health education to the patient. RESULTS: During the 2011-2013 study period, 256 patients received 891 herbal prescriptions with potential drug-herb interactions. Three of the 50 patients who concurrently used ginseng and antidiabetic drugs manifested hypoglycemia (fasting blood sugar level <=70 mg/dL). CONCLUSION: Drug herb interactions can cause adverse reactions. A computerized reminder system can enable TCM practitioners to reduce the risk of drug-herb interactions. In addition, health education for patients is crucial in avoiding adverse reaction by the interactions. PMID- 25733841 TI - Factors that increase external pressure to the fibular head region, but not medial region, during use of a knee-crutch/leg-holder system in the lithotomy position. AB - BACKGROUND: Paralysis of the common peroneal nerve is one of the relatively common nerve injuries related to the lithotomy position with the use of a knee crutch/leg-holder system. Several risk factors have been implicated in lithotomy position-related common peroneal nerve paralysis during operation. MATERIALS AND METHODS: In the present study, 21 young healthy volunteers participated in the investigation of the causes of the paralysis of the common peroneal nerve in the lithotomy position using a knee-crutch/leg-holder; Knee Crutch. We assessed the external pressure applied to the fibular head and medial regions using the Big Mat pressure-distribution measurement system. Relationships between the peak contact pressure and physical characteristics, such as sex, height, weight, body mass index (BMI), and fibular head circumference, were analyzed. RESULTS: The peak contact pressure to the fibular head region was greater for males than for females. For all subjects, significant positive correlations were observed between the peak contact pressure to the fibular head region and weight, BMI, or fibular head circumference. However, there was no significant difference between the peak contact pressure to the fibular head region and height for any subjects. Moreover, there was no sex-related difference in the peak contact pressure to the fibular medial region, and no significant differences between the peak contact pressure to the fibular medial region and height, weight, BMI, or fibular head circumference. CONCLUSION: External pressure to the fibular head region is greater for males than for females using a knee-crutch/leg-holder system in the lithotomy position. In addition, the external pressure to the fibular head region, but not the fibular medial region, increases with increasing weight, BMI, and fibular head circumference. Therefore, these patient-related characteristics may contribute to the risk of developing lower-extremity neuropathy, leading to injury or ischemia of the common peroneal nerve. PMID- 25733842 TI - Antithrombotic therapy for long-term secondary prevention of acute coronary syndrome in high-risk patients. AB - Patients with acute coronary syndrome (ACS) represent a major clinical burden, because they tend to experience recurrent ischemic events. Acute management of patients with ACS includes combination antithrombotic therapy composed of a parenteral anticoagulant and dual-antiplatelet therapy. Dual-antiplatelet therapy is also recommended for long-term secondary prevention of ACS. Despite advances in the antithrombotic therapies available, clinical trials suggest that patients with ACS still facea10% risk of another event within 12-15 months of the index event. Certain patient populations, such as elderly patients and those with renal impairment or heart failure, are at higher risk of recurrent ACS events, because these patients have more vascular ischemic and bleeding risk factors than most other patients. Evidence from the GRACE and CRUSADE registries suggests underuse of the guideline-recommended evidence-based therapies for the management of ACS in such patients. This review summarizes the current standard of care for patients with ACS, focusing on long-term secondary antithrombotic strategies. Registry data are used to identify high-risk patient populations; the recent antiplatelet and anticoagulant Phase III trial data are summarized to highlight any patient populations who receive greater or lesser benefit from specific long term antithrombotic strategies. Guideline recommendations are discussed and suggestions are provided to help improve implementation of long-term secondary prevention strategies and patient prognosis after an ACS event. PMID- 25733844 TI - Gasoline abuse in a 10-year-old child with mental retardation: a case report. AB - Inahalant abuse is of increasing interest in India. The age of onset is typically during adolescence. Gasoline inhalant use is rarely reported in adolescents with intellectual deficit. We report a case of petrol dependence in a 10-year-old child with mental retardation. Possible effect of petrol huffing on behavior and cognition is discussed. PMID- 25733843 TI - Platelet function tests: a comparative review. AB - In physiological hemostasis a prompt recruitment of platelets on the vessel damage prevents the bleeding by the rapid formation of a platelet plug. Qualitative and/or quantitative platelet defects promote bleeding, whereas the high residual reactivity of platelets in patients on antiplatelet therapies moves forward thromboembolic complications. The biochemical mechanisms of the different phases of platelet activation - adhesion, shape change, release reaction, and aggregation - have been well delineated, whereas their complete translation into laboratory assays has not been so fulfilled. Laboratory tests of platelet function, such as bleeding time, light transmission platelet aggregation, lumiaggregometry, impedance aggregometry on whole blood, and platelet activation investigated by flow cytometry, are traditionally utilized for diagnosing hemostatic disorders and managing patients with platelet and hemostatic defects, but their use is still limited to specialized laboratories. To date, a point-of care testing (POCT) dedicated to platelet function, using pertinent devices much simpler to use, has now become available (ie, PFA-100, VerifyNow System, Multiplate Electrode Aggregometry [MEA]). POCT includes new methodologies which may be used in critical clinical settings and also in general laboratories because they are rapid and easy to use, employing whole blood without the necessity of sample processing. Actually, these different platelet methodologies for the evaluation of inherited and acquired bleeding disorders and/or for monitoring antiplatelet therapies are spreading and the study of platelet function is strengthening. In this review, well-tried and innovative platelet function tests and their methodological features and clinical applications are considered. PMID- 25733845 TI - n-type thermoelectric material Mg2Sn0.75Ge0.25 for high power generation. AB - Thermoelectric power generation is one of the most promising techniques to use the huge amount of waste heat and solar energy. Traditionally, high thermoelectric figure-of-merit, ZT, has been the only parameter pursued for high conversion efficiency. Here, we emphasize that a high power factor (PF) is equivalently important for high power generation, in addition to high efficiency. A new n-type Mg2Sn-based material, Mg2Sn0.75Ge0.25, is a good example to meet the dual requirements in efficiency and output power. It was found that Mg2Sn0.75Ge0.25 has an average ZT of 0.9 and PF of 52 MUW?cm(-1)?K(-2) over the temperature range of 25-450 degrees C, a peak ZT of 1.4 at 450 degrees C, and peak PF of 55 MUW?cm(-1)?K(-2) at 350 degrees C. By using the energy balance of one-dimensional heat flow equation, leg efficiency and output power were calculated with Th = 400 degrees C and Tc = 50 degrees C to be of 10.5% and 6.6 W?cm(-2) under a temperature gradient of 150 degrees C?mm(-1), respectively. PMID- 25733846 TI - TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis. AB - Transcription activator-like effector nuclease (TALEN)-mediated genome modification has been applied successfully to create transgenic animals in various species, such as mouse, pig, and even monkey. However, transgenic cattle with gene knockin have yet to be created using TALENs. Here, we report site specific knockin of the transcription activator-like effector (TALE) nickase mediated SP110 nuclear body protein gene (SP110) via homologous recombination to produce tuberculosis-resistant cattle. In vitro and in vivo challenge and transmission experiments proved that the transgenic cattle are able to control the growth and multiplication of Mycobacterium bovis, turn on the apoptotic pathway of cell death instead of necrosis after infection, and efficiently resist the low dose of M. bovis transmitted from tuberculous cattle in nature. In this study, we developed TALE nickases to modify the genome of Holstein-Friesian cattle, thereby engineering a heritable genome modification that facilitates resistance to tuberculosis. PMID- 25733847 TI - Rationally designed fluorogenic protease reporter visualizes spatiotemporal dynamics of apoptosis in vivo. AB - Fluorescence resonance energy transfer-based reporters have been widely used in imaging cell signaling; however, their in vivo application has been handicapped because of poor signal. Although fluorogenic reporters overcome this problem, no such reporter of proteases has been demonstrated for in vivo imaging. Now we have redesigned an infrared fluorescent protein so that its chromophore incorporation is regulated by protease activity. Upon protease activation, the infrared fluorogenic protease reporter becomes fluorescent with no requirement of exogenous cofactor. To demonstrate biological applications, we have designed an infrared fluorogenic executioner-caspase reporter, which reveals spatiotemporal coordination between cell apoptosis and embryonic morphogenesis, as well as dynamics of apoptosis during tumorigenesis in Drosophila. The designed scaffold may be used to engineer reporters of other proteases with specific cleavage sequence. PMID- 25733848 TI - Spray-combustion synthesis: efficient solution route to high-performance oxide transistors. AB - Metal-oxide (MO) semiconductors have emerged as enabling materials for next generation thin-film electronics owing to their high carrier mobilities, even in the amorphous state, large-area uniformity, low cost, and optical transparency, which are applicable to flat-panel displays, flexible circuitry, and photovoltaic cells. Impressive progress in solution-processed MO electronics has been achieved using methodologies such as sol gel, deep-UV irradiation, preformed nanostructures, and combustion synthesis. Nevertheless, because of incomplete lattice condensation and film densification, high-quality solution-processed MO films having technologically relevant thicknesses achievable in a single step have yet to be shown. Here, we report a low-temperature, thickness-controlled coating process to create high-performance, solution-processed MO electronics: spray-combustion synthesis (SCS). We also report for the first time, to our knowledge, indium-gallium-zinc-oxide (IGZO) transistors having densification, nanoporosity, electron mobility, trap densities, bias stability, and film transport approaching those of sputtered films and compatible with conventional fabrication (FAB) operations. PMID- 25733849 TI - Boosting CRISPR/Cas9 multiplex editing capability with the endogenous tRNA processing system. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9) system is being harnessed as a powerful tool for genome engineering in basic research, molecular therapy, and crop improvement. This system uses a small guide RNA (gRNA) to direct Cas9 endonuclease to a specific DNA site; thus, its targeting capability is largely constrained by the gRNA-expressing device. In this study, we developed a general strategy to produce numerous gRNAs from a single polycistronic gene. The endogenous tRNA-processing system, which precisely cleaves both ends of the tRNA precursor, was engineered as a simple and robust platform to boost the targeting and multiplex editing capability of the CRISPR/Cas9 system. We demonstrated that synthetic genes with tandemly arrayed tRNA-gRNA architecture were efficiently and precisely processed into gRNAs with desired 5' targeting sequences in vivo, which directed Cas9 to edit multiple chromosomal targets. Using this strategy, multiplex genome editing and chromosomal-fragment deletion were readily achieved in stable transgenic rice plants with a high efficiency (up to 100%). Because tRNA and its processing system are virtually conserved in all living organisms, this method could be broadly used to boost the targeting capability and editing efficiency of CRISPR/Cas9 toolkits. PMID- 25733850 TI - Perceived intent motivates people to magnify observed harms. AB - Existing moral psychology research commonly explains certain phenomena in terms of a motivation to blame. However, this motivation is not measured directly, but rather is inferred from other measures, such as participants' judgments of an agent's blameworthiness. The present paper introduces new methods for assessing this theoretically important motivation, using tools drawn from animal-model research. We test these methods in the context of recent "harm-magnification" research, which shows that people often overestimate the damage caused by intentional (versus unintentional) harms. A preliminary experiment exemplifies this work and also rules out an alternative explanation for earlier harm magnification results. Exp. 1 asks whether intended harm motivates blame or merely demonstrates the actor's intrinsic blameworthiness. Consistent with a motivational interpretation, participants freely chose blaming, condemning, and punishing over other appealing tasks in an intentional-harm condition, compared with an unintentional-harm condition. Exp. 2 also measures motivation but with converging indicators of persistence (effort, rate, and duration) in blaming. In addition to their methodological contribution, these studies also illuminate people's motivational responses to intentional harms. Perceived intent emerges as catalyzing a motivated social cognitive process related to social prediction and control. PMID- 25733851 TI - Implantable hydrogel embedded dark-gold nanoswitch as a theranostic probe to sense and overcome cancer multidrug resistance. AB - Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. Here, we describe facile means to overcome resistance by silencing the multidrug resistance protein 1 (MRP1), before chemotherapeutic drug delivery in vivo with a single local application. Our platform contains hydrogel embedded with dark-gold nanoparticles modified with 5-fluorouracil (5-FU) intercalated nanobeacons that serve as an ON/OFF molecular nanoswitch triggered by the increased MRP1 expression within the tumor tissue microenvironment. This nanoswitch can sense and overcome MDR prior to local drug release. The nanobeacons comprise a 5-FU intercalated DNA hairpin, which is labeled with a near-infrared (NIR) dye and a dark-quencher. The nanobeacons are designed to open and release the intercalated drug only upon hybridization of the DNA hairpin to a complementary target, an event that restores fluorescence emission due to nanobeacons conformational reorganization. Despite the cross-resistance to 5-FU, more than 90% tumor reduction is achieved in vivo in a triple-negative breast cancer model following 80% MRP1 silencing compared with the continuous tumor growth following only drug or nanobeacon administration. Our approach can be applied to reverse cross-resistance to other chemotherapeutic drugs and restore treatment efficacy. As a universal nanotheranostic probe, this platform can pave the way to early cancer detection and treatment. PMID- 25733852 TI - The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers. AB - Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies. PMID- 25733853 TI - Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. AB - Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca(2+) channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca(2+) imaging and whole-lysosome patch clamping, lysosomal Ca(2+) release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na(+) selective currents were not up-regulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca(2+) signaling. PMID- 25733854 TI - Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution. AB - Cytokine therapy can activate potent, sustained antitumor responses, but collateral toxicity often limits dosages. Although antibody-cytokine fusions (immunocytokines) have been designed with the intent to localize cytokine activity, systemic dose-limiting side effects are not fully ameliorated by attempted tumor targeting. Using the s.c. B16F10 melanoma model, we found that a nontoxic dose of IL-2 immunocytokine synergized with tumor-specific antibody to significantly enhance therapeutic outcomes compared with immunocytokine monotherapy, concomitant with increased tumor saturation and intratumoral cytokine responses. Examination of cell subset biodistribution showed that the immunocytokine associated mainly with IL-2R-expressing innate immune cells, with more bound immunocytokine present in systemic organs than the tumor microenvironment. More surprisingly, immunocytokine antigen specificity and Fcgamma receptor interactions did not seem necessary for therapeutic efficacy or biodistribution patterns because immunocytokines with irrelevant specificity and/or inactive mutant Fc domains behaved similarly to tumor-specific immunocytokine. IL-2-IL-2R interactions, rather than antibody-antigen targeting, dictated immunocytokine localization; however, the lack of tumor targeting did not preclude successful antibody combination therapy. Mathematical modeling revealed immunocytokine size as another driver of antigen targeting efficiency. This work presents a safe, straightforward strategy for augmenting immunocytokine efficacy by supplementary antibody dosing and explores underappreciated factors that can subvert efforts to purposefully alter cytokine biodistribution. PMID- 25733855 TI - Evidence for recent, population-specific evolution of the human mutation rate. AB - As humans dispersed out of Africa they adapted to new environmental challenges, including changes in exposure to mutagenic solar radiation. Humans in temperate latitudes have acquired light skin that is relatively transparent to UV light, and some evidence suggests that their DNA damage response pathways have also experienced local adaptation. This raises the possibility that different populations have experienced different selective pressures affecting genome integrity. Here, I present evidence that the rate of a particular mutation type has recently increased in the European population, rising in frequency by 50% during the 40,000-80,000 y since Europeans began diverging from Asians. A comparison of SNPs private to Africa, Asia, and Europe in the 1000 Genomes data reveals that private European variation is enriched for the transition 5'-TCC-3' > 5'-TTC-3'. Although it is not clear whether UV played a causal role in changing the European mutational spectrum, 5'-TCC-3' -> 5'-TTC-3' is known to be the most common somatic mutation present in melanoma skin cancers, as well as the mutation most frequently induced in vitro by UV. Regardless of its causality, this change indicates that DNA replication fidelity has not remained stable even since the origin of modern humans and might have changed numerous times during our recent evolutionary history. PMID- 25733856 TI - Ocean-driven thinning enhances iceberg calving and retreat of Antarctic ice shelves. AB - Iceberg calving from all Antarctic ice shelves has never been directly measured, despite playing a crucial role in ice sheet mass balance. Rapid changes to iceberg calving naturally arise from the sporadic detachment of large tabular bergs but can also be triggered by climate forcing. Here we provide a direct empirical estimate of mass loss due to iceberg calving and melting from Antarctic ice shelves. We find that between 2005 and 2011, the total mass loss due to iceberg calving of 755 +/- 24 gigatonnes per year (Gt/y) is only half the total loss due to basal melt of 1516 +/- 106 Gt/y. However, we observe widespread retreat of ice shelves that are currently thinning. Net mass loss due to iceberg calving for these ice shelves (302 +/- 27 Gt/y) is comparable in magnitude to net mass loss due to basal melt (312 +/- 14 Gt/y). Moreover, we find that iceberg calving from these decaying ice shelves is dominated by frequent calving events, which are distinct from the less frequent detachment of isolated tabular icebergs associated with ice shelves in neutral or positive mass balance regimes. Our results suggest that thinning associated with ocean-driven increased basal melt can trigger increased iceberg calving, implying that iceberg calving may play an overlooked role in the demise of shrinking ice shelves, and is more sensitive to ocean forcing than expected from steady state calving estimates. PMID- 25733857 TI - Improving recombinant Rubisco biogenesis, plant photosynthesis and growth by coexpressing its ancillary RAF1 chaperone. AB - Enabling improvements to crop yield and resource use by enhancing the catalysis of the photosynthetic CO2-fixing enzyme Rubisco has been a longstanding challenge. Efforts toward realization of this goal have been greatly assisted by advances in understanding the complexities of Rubisco's biogenesis in plastids and the development of tailored chloroplast transformation tools. Here we generate transplastomic tobacco genotypes expressing Arabidopsis Rubisco large subunits (AtL), both on their own (producing tob(AtL) plants) and with a cognate Rubisco accumulation factor 1 (AtRAF1) chaperone (producing tob(AtL-R1) plants) that has undergone parallel functional coevolution with AtL. We show AtRAF1 assembles as a dimer and is produced in tob(AtL-R1) and Arabidopsis leaves at 10 15 nmol AtRAF1 monomers per square meter. Consistent with a postchaperonin large (L)-subunit assembly role, the AtRAF1 facilitated two to threefold improvements in the amount and biogenesis rate of hybrid L8(A)S8(t) Rubisco [comprising AtL and tobacco small (S) subunits] in tob(AtL-R1) leaves compared with tob(AtL), despite >threefold lower steady-state Rubisco mRNA levels in tob(AtL-R1). Accompanying twofold increases in photosynthetic CO2-assimilation rate and plant growth were measured for tob(AtL-R1) lines. These findings highlight the importance of ancillary protein complementarity during Rubisco biogenesis in plastids, the possible constraints this has imposed on Rubisco adaptive evolution, and the likely need for such interaction specificity to be considered when optimizing recombinant Rubisco bioengineering in plants. PMID- 25733858 TI - Plasmodium falciparum chloroquine resistance transporter is a H+-coupled polyspecific nutrient and drug exporter. AB - Extrusion of chloroquine (CQ) from digestive vacuoles through the Plasmodium falciparum CQ resistance transporter (PfCRT) is essential to establish CQ resistance of the malaria parasite. However, the physiological relevance of PfCRT and how CQ-resistant PfCRT gains the ability to transport CQ remain unknown. We prepared proteoliposomes containing purified CQ-sensitive and CQ-resistant PfCRTs and measured their transport activities. All PfCRTs tested actively took up tetraethylammonium, verapamil, CQ, basic amino acids, polypeptides, and polyamines at the expense of an electrochemical proton gradient. CQ-resistant PfCRT exhibited decreased affinity for CQ, resulting in increased CQ uptake. Furthermore, CQ competitively inhibited amino acid transport. Thus, PfCRT is a H(+)-coupled polyspecific nutrient and drug exporter. PMID- 25733859 TI - Prepregnancy body mass and weight gain during pregnancy in India and sub-Saharan Africa. AB - Despite being wealthier, Indian children are significantly shorter and smaller than African children. These differences begin very early in life, suggesting that they may in part reflect differences in maternal health. By applying reweighting estimation strategies to the Demographic and Health Surveys, this paper reports, to my knowledge, the first representative estimates of prepregnancy body mass index and weight gain during pregnancy for India and sub Saharan Africa. I find that 42.2% of prepregnant women in India are underweight compared with 16.5% of prepregnant women in sub-Saharan Africa. Levels of prepregnancy underweight for India are almost seven percentage points higher than the average fraction underweight among women 15-49 y old. This difference in part reflects a previously unquantified relationship among age, fertility, and underweight; childbearing is concentrated in the narrow age range in which Indian women are most likely to be underweight. Further, because weight gain during pregnancy is low, averaging about 7 kg for a full-term pregnancy in both regions, the average woman in India ends pregnancy weighing less than the average woman in sub-Saharan Africa begins pregnancy. Poor maternal health among Indian women is of global significance because India is home to one fifth of the world's births. PMID- 25733860 TI - Activation of protein synthesis in mouse uterine epithelial cells by estradiol 17beta is mediated by a PKC-ERK1/2-mTOR signaling pathway. AB - The uterine epithelium of mice and humans undergoes cyclical waves of cell proliferation and differentiation under the regulation of estradiol-17beta (E2) and progesterone (P4). These epithelial cells respond to E2 with increased protein and DNA synthesis, whereas P4 inhibits only the E2-induced DNA synthetic response. Here we show that E2 regulates protein synthesis in these epithelial cells through activating PKC that in turn stimulates ERK1/2 to phosphorylate and thereby activate the central regulator of protein synthesis mechanistic target of rapamycin (mTOR). This mTOR pathway is not inhibited by P4. Inhibitor studies with an estrogen receptor (ESR1) antagonist showed the dependence of this mTOR pathway on ESR1 but that once activated, a phosphorylation cascade independent of ESR1 propagates the pathway. E2 also stimulates an IGF1 receptor (IGF1R) to PI3 kinase to AKT to GSK-3beta pathway required for activation of the canonical cell cycle machinery that is inhibited by P4. PKC activation did not stimulate this pathway nor does inhibition of PKC or ERK1/2 affect it. These studies therefore indicate a mechanism whereby DNA and protein synthesis are regulated by two ESR1 activated pathways that run in parallel with only the one responsible for the initiation of DNA synthesis blocked by P4. Inhibition of mTOR by rapamycin in vivo resulted in inhibition of E2-induced protein and DNA synthesis. Proliferative diseases of the endometrium such as endometriosis and cancer are common and E2 dependent. Thus, defining this mTOR pathway suggests that local (intrauterine or peritoneal) rapamycin administration might be a therapeutic option for these diseases. PMID- 25733861 TI - MinD-like ATPase FlhG effects location and number of bacterial flagella during C ring assembly. AB - The number and location of flagella, bacterial organelles of locomotion, are species specific and appear in regular patterns that represent one of the earliest taxonomic criteria in microbiology. However, the mechanisms that reproducibly establish these patterns during each round of cell division are poorly understood. FlhG (previously YlxH) is a major determinant for a variety of flagellation patterns. Here, we show that FlhG is a structural homolog of the ATPase MinD, which serves in cell-division site determination. Like MinD, FlhG forms homodimers that are dependent on ATP and lipids. It interacts with a complex of the flagellar C-ring proteins FliM and FliY (also FliN) in the Gram positive, peritrichous-flagellated Bacillus subtilis and the Gram-negative, polar flagellated Shewanella putrefaciens. FlhG interacts with FliM/FliY in a nucleotide-independent manner and activates FliM/FliY to assemble with the C-ring protein FliG in vitro. FlhG-driven assembly of the FliM/FliY/FliG complex is strongly enhanced by ATP and lipids. The protein shows a highly dynamic subcellular distribution between cytoplasm and flagellar basal bodies, suggesting that FlhG effects flagellar location and number during assembly of the C-ring. We describe the molecular evolution of a MinD-like ATPase into a flagellation pattern effector and suggest that the underappreciated structural diversity of the C-ring proteins might contribute to the formation of different flagellation patterns. PMID- 25733862 TI - Macronutrient balance, reproductive function, and lifespan in aging mice. AB - In invertebrates, reproductive output and lifespan are profoundly impacted by dietary macronutrient balance, with these traits achieving their maxima on different diet compositions, giving the appearance of a resource-based tradeoff between reproduction and longevity. For the first time in a mammal, to our knowledge, we evaluate the effects of dietary protein (P), carbohydrate (C), fat (F), and energy (E) on lifespan and reproductive function in aging male and female mice. We show that, as in invertebrates, the balance of macronutrients has marked and largely opposing effects on reproductive and longevity outcomes. Mice were provided ad libitum access to one of 25 diets differing in P, C, F, and E content, with reproductive outcomes assessed at 15 months. An optimal balance of macronutrients exists for reproductive function, which, for most measures, differs from the diets that optimize lifespan, and this response differs with sex. Maximal longevity was achieved on diets containing a P:C ratio of 1:13 in males and 1:11 for females. Diets that optimized testes mass and epididymal sperm counts (indicators of gamete production) contained a higher P:C ratio (1:1) than those that maximized lifespan. In females, uterine mass (an indicator of estrogenic activity) was also greatest on high P:C diets (1:1) whereas ovarian follicle number was greatest on P:C 3:1 associated with high-F intakes. By contrast, estrous cycling was more likely in mice on lower P:C (1:8), and the number of corpora lutea, indicative of recent ovulations, was greatest on P:C similar to those supporting greatest longevity (1:11). PMID- 25733863 TI - Pigeons trade efficiency for stability in response to level of challenge during confined flight. AB - Individuals traversing challenging obstacles are faced with a decision: they can adopt traversal strategies that minimally disrupt their normal locomotion patterns or they can adopt strategies that substantially alter their gait, conferring new advantages and disadvantages. We flew pigeons (Columba livia) through an array of vertical obstacles in a flight arena, presenting them with this choice. The pigeons selected either a strategy involving only a slight pause in the normal wing beat cycle, or a wings-folded posture granting reduced efficiency but greater stability should a misjudgment lead to collision. The more stable but less efficient flight strategy was not used to traverse easy obstacles with wide gaps for passage but came to dominate the postures used as obstacle challenge increased with narrower gaps and there was a greater chance of a collision. These results indicate that birds weigh potential obstacle negotiation strategies and estimate task difficulty during locomotor pattern selection. PMID- 25733864 TI - Steric clashes with bound OMP peptides activate the DegS stress-response protease. AB - Escherichia coli senses envelope stress using a signaling cascade initiated when DegS cleaves a transmembrane inhibitor of a transcriptional activator for response genes. Each subunit of the DegS trimer contains a protease domain and a PDZ domain. During stress, unassembled outer-membrane proteins (OMPs) accumulate in the periplasm and their C-terminal peptides activate DegS by binding to its PDZ domains. In the absence of stress, autoinhibitory interactions, mediated by the L3 loop, stabilize inactive DegS, but it is not known how this autoinhibition is reversed during activation. Here, we show that OMP peptides initiate a steric clash between the PDZ domain and the L3 loop that results in a structural rearrangement of the loop and breaking of autoinhibitory interactions. Many different L3-loop sequences are compatible with activation but those that relieve the steric clash reduce OMP activation dramatically. Our results provide a compelling molecular mechanism for allosteric activation of DegS by OMP-peptide binding. PMID- 25733865 TI - KCC2 activity is critical in limiting the onset and severity of status epilepticus. AB - The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of gamma-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl(-) extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE. PMID- 25733866 TI - Proteome-wide analysis of mutant p53 targets in breast cancer identifies new levels of gain-of-function that influence PARP, PCNA, and MCM4. AB - The gain-of-function mutant p53 (mtp53) transcriptome has been studied, but, to date, no detailed analysis of the mtp53-associated proteome has been described. We coupled cell fractionation with stable isotope labeling with amino acids in cell culture (SILAC) and inducible knockdown of endogenous mtp53 to determine the mtp53-driven proteome. Our fractionation data highlight the underappreciated biology that missense mtp53 proteins R273H, R280K, and L194F are tightly associated with chromatin. Using SILAC coupled to tandem MS, we identified that R273H mtp53 expression in MDA-MB-468 breast cancer cells up- and down-regulated multiple proteins and metabolic pathways. Here we provide the data set obtained from sequencing 73,154 peptide pairs that then corresponded to 3,010 proteins detected under reciprocal labeling conditions. Importantly, the high impact regulated targets included the previously identified transcriptionally regulated mevalonate pathway proteins but also identified two new levels of mtp53 protein regulation for nontranscriptional targets. Interestingly, mtp53 depletion profoundly influenced poly(ADP ribose) polymerase 1 (PARP1) localization, with increased cytoplasmic and decreased chromatin-associated protein. An enzymatic PARP shift occurred with high mtp53 expression, resulting in increased poly-ADP ribosylated proteins in the nucleus. Mtp53 increased the level of proliferating cell nuclear antigen (PCNA) and minichromosome maintenance 4 (MCM4) proteins without changing the amount of pcna and mcm4 transcripts. Pathway enrichment analysis ranked the DNA replication pathway above the cholesterol biosynthesis pathway as a R273H mtp53 activated proteomic target. Knowledge of the proteome diversity driven by mtp53 suggests that DNA replication and repair pathways are major targets of mtp53 and highlights consideration of combination chemotherapeutic strategies targeting cholesterol biosynthesis and PARP inhibition. PMID- 25733867 TI - Two-dimensional IR spectroscopy of the anti-HIV agent KP1212 reveals protonated and neutral tautomers that influence pH-dependent mutagenicity. AB - Antiviral drugs designed to accelerate viral mutation rates can drive a viral population to extinction in a process called lethal mutagenesis. One such molecule is 5,6-dihydro-5-aza-2'-deoxycytidine (KP1212), a selective mutagen that induces A-to-G and G-to-A mutations in the genome of replicating HIV. The mutagenic property of KP1212 was hypothesized to originate from its amino-imino tautomerism, which would explain its ability to base pair with either G or A. To test the multiple tautomer hypothesis, we used 2D IR spectroscopy, which offers subpicosecond time resolution and structural sensitivity to distinguish among rapidly interconverting tautomers. We identified several KP1212 tautomers and found that >60% of neutral KP1212 is present in the enol-imino form. The abundant proportion of this traditionally rare tautomer offers a compelling structure based mechanism for pairing with adenine. Additionally, the pKa of KP1212 was measured to be 7.0, meaning a substantial population of KP1212 is protonated at physiological pH. Furthermore, the mutagenicity of KP1212 was found to increase dramatically at pH <7, suggesting a significant biological role for the protonated KP1212 molecules. Overall, our data reveal that the bimodal mutagenic properties of KP1212 result from its unique shape shifting ability that utilizes both tautomerization and protonation. PMID- 25733868 TI - Comprehensive analysis of heterotrimeric G-protein complex diversity and their interactions with GPCRs in solution. AB - Agonist binding to G-protein-coupled receptors (GPCRs) triggers signal transduction cascades involving heterotrimeric G proteins as key players. A major obstacle for drug design is the limited knowledge of conformational changes upon agonist binding, the details of interaction with the different G proteins, and the transmission to movements within the G protein. Although a variety of different GPCR/G protein complex structures would be needed, the transient nature of this complex and the intrinsic instability against dissociation make this endeavor very challenging. We have previously evolved GPCR mutants that display higher stability and retain their interaction with G proteins. We aimed at finding all G-protein combinations that preferentially interact with neurotensin receptor 1 (NTR1) and our stabilized mutants. We first systematically analyzed by coimmunoprecipitation the capability of 120 different G-protein combinations consisting of alphai1 or alphasL and all possible betagamma-dimers to form a heterotrimeric complex. This analysis revealed a surprisingly unrestricted ability of the G-protein subunits to form heterotrimeric complexes, including betagamma-dimers previously thought to be nonexistent, except for combinations containing beta5. A second screen on coupling preference of all G-protein heterotrimers to NTR1 wild type and a stabilized mutant indicated a preference for those Galphai1betagamma combinations containing gamma1 and gamma11. Heterotrimeric G proteins, including combinations believed to be nonexistent, were purified, and complexes with the GPCR were prepared. Our results shed new light on the combinatorial diversity of G proteins and their coupling to GPCRs and open new approaches to improve the stability of GPCR/G-protein complexes. PMID- 25733870 TI - Structure of superhard tungsten tetraboride: a missing link between MB2 and MB12 higher borides. AB - Superhard metals are of interest as possible replacements with enhanced properties over the metal carbides commonly used in cutting, drilling, and wear resistant tooling. Of the superhard metals, the highest boride of tungsten--often referred to as WB4 and sometimes as W(1-x)B3--is one of the most promising candidates. The structure of this boride, however, has never been fully resolved, despite the fact that it was discovered in 1961--a fact that severely limits our understanding of its structure-property relationships and has generated increasing controversy in the literature. Here, we present a new crystallographic model of this compound based on refinement against time-of-flight neutron diffraction data. Contrary to previous X-ray-only structural refinements, there is strong evidence for the presence of interstitial arrangements of boron atoms and polyhedral bonding. The formation of these polyhedral--slightly distorted boron cuboctahedra--appears to be dependent upon the defective nature of the tungsten-deficient metal sublattice. This previously unidentified structure type has an intermediary relationship between MB2 and MB12 type boride polymorphs. Manipulation of the fractionally occupied metal and boron sites may provide insight for the rational design of new superhard metals. PMID- 25733869 TI - Whole-genome sequence of the Tibetan frog Nanorana parkeri and the comparative evolution of tetrapod genomes. AB - The development of efficient sequencing techniques has resulted in large numbers of genomes being available for evolutionary studies. However, only one genome is available for all amphibians, that of Xenopus tropicalis, which is distantly related from the majority of frogs. More than 96% of frogs belong to the Neobatrachia, and no genome exists for this group. This dearth of amphibian genomes greatly restricts genomic studies of amphibians and, more generally, our understanding of tetrapod genome evolution. To fill this gap, we provide the de novo genome of a Tibetan Plateau frog, Nanorana parkeri, and compare it to that of X. tropicalis and other vertebrates. This genome encodes more than 20,000 protein-coding genes, a number similar to that of Xenopus. Although the genome size of Nanorana is considerably larger than that of Xenopus (2.3 vs. 1.5 Gb), most of the difference is due to the respective number of transposable elements in the two genomes. The two frogs exhibit considerable conserved whole-genome synteny despite having diverged approximately 266 Ma, indicating a slow rate of DNA structural evolution in anurans. Multigenome synteny blocks further show that amphibians have fewer interchromosomal rearrangements than mammals but have a comparable rate of intrachromosomal rearrangements. Our analysis also identifies 11 Mb of anuran-specific highly conserved elements that will be useful for comparative genomic analyses of frogs. The Nanorana genome offers an improved understanding of evolution of tetrapod genomes and also provides a genomic reference for other evolutionary studies. PMID- 25733871 TI - BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1. AB - The DNA damage response (DDR) is crucial for genomic integrity. BRIT1 (breast cancer susceptibility gene C terminus-repeat inhibitor of human telomerase repeat transcriptase expression), a tumor suppressor and early DDR factor, is recruited to DNA double-strand breaks (DSBs) by phosphorylated H2A histone family, member X (gamma-H2AX), where it promotes chromatin relaxation by recruiting the switch/sucrose nonfermentable (SWI-SNF) chromatin remodeler to facilitate DDR. However, regulation of BRIT1 recruitment is not fully understood. The baculovirus IAP repeat (BIR)-containing ubiquitin-conjugating enzyme (BRUCE) is an inhibitor of apoptosis protein (IAP). Here, we report a non-IAP function of BRUCE in the regulation of the BRIT1-SWI-SNF DSB-response pathway and genomic stability. We demonstrate that BRIT1 is K63 ubiquitinated in unstimulated cells and that deubiquitination of BRIT1 is a prerequisite for its recruitment to DSB sites by gamma-H2AX. We show mechanistically that BRUCE acts as a scaffold, bridging the ubiquitin-specific peptidase 8 (USP8) and BRIT1 in a complex to coordinate USP8 catalyzed deubiquitination of BRIT1. Loss of BRUCE or USP8 impairs BRIT1 deubiquitination, BRIT1 binding with gamma-H2AX, the formation of BRIT1 DNA damage foci, and chromatin relaxation. Moreover, BRUCE-depleted cells display reduced homologous recombination repair, and BRUCE-mutant mice exhibit repair defects and genomic instability. These findings identify BRUCE and USP8 as two hitherto uncharacterized critical DDR regulators and uncover a deubiquitination regulation of BRIT1 assembly at damaged chromatin for efficient DDR and genomic stability. PMID- 25733872 TI - Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2. AB - Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1(fl/fl) mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre(ERT);Hes1(fl/fl) mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2delta (CaMK2delta) as a cofactor of Hes1; CaMK2delta was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2delta to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders. PMID- 25733873 TI - Endosymbiotic gene transfer from prokaryotic pangenomes: Inherited chimerism in eukaryotes. AB - Endosymbiotic theory in eukaryotic-cell evolution rests upon a foundation of three cornerstone partners--the plastid (a cyanobacterium), the mitochondrion (a proteobacterium), and its host (an archaeon)--and carries a corollary that, over time, the majority of genes once present in the organelle genomes were relinquished to the chromosomes of the host (endosymbiotic gene transfer). However, notwithstanding eukaryote-specific gene inventions, single-gene phylogenies have never traced eukaryotic genes to three single prokaryotic sources, an issue that hinges crucially upon factors influencing phylogenetic inference. In the age of genomes, single-gene trees, once used to test the predictions of endosymbiotic theory, now spawn new theories that stand to eventually replace endosymbiotic theory with descriptive, gene tree-based variants featuring supernumerary symbionts: prokaryotic partners distinct from the cornerstone trio and whose existence is inferred solely from single-gene trees. We reason that the endosymbiotic ancestors of mitochondria and chloroplasts brought into the eukaryotic--and plant and algal--lineage a genome sized sample of genes from the proteobacterial and cyanobacterial pangenomes of their respective day and that, even if molecular phylogeny were artifact-free, sampling prokaryotic pangenomes through endosymbiotic gene transfer would lead to inherited chimerism. Recombination in prokaryotes (transduction, conjugation, transformation) differs from recombination in eukaryotes (sex). Prokaryotic recombination leads to pangenomes, and eukaryotic recombination leads to vertical inheritance. Viewed from the perspective of endosymbiotic theory, the critical transition at the eukaryote origin that allowed escape from Muller's ratchet--the origin of eukaryotic recombination, or sex--might have required surprisingly little evolutionary innovation. PMID- 25733874 TI - Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling. AB - It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon (Oncorhynchus nerka) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner-recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts. PMID- 25733875 TI - Anthropogenic warming has increased drought risk in California. AB - California is currently in the midst of a record-setting drought. The drought began in 2012 and now includes the lowest calendar-year and 12-mo precipitation, the highest annual temperature, and the most extreme drought indicators on record. The extremely warm and dry conditions have led to acute water shortages, groundwater overdraft, critically low streamflow, and enhanced wildfire risk. Analyzing historical climate observations from California, we find that precipitation deficits in California were more than twice as likely to yield drought years if they occurred when conditions were warm. We find that although there has not been a substantial change in the probability of either negative or moderately negative precipitation anomalies in recent decades, the occurrence of drought years has been greater in the past two decades than in the preceding century. In addition, the probability that precipitation deficits co-occur with warm conditions and the probability that precipitation deficits produce drought have both increased. Climate model experiments with and without anthropogenic forcings reveal that human activities have increased the probability that dry precipitation years are also warm. Further, a large ensemble of climate model realizations reveals that additional global warming over the next few decades is very likely to create ~ 100% probability that any annual-scale dry period is also extremely warm. We therefore conclude that anthropogenic warming is increasing the probability of co-occurring warm-dry conditions like those that have created the acute human and ecosystem impacts associated with the "exceptional" 2012-2014 drought in California. PMID- 25733876 TI - Climate change and pollution speed declines in zebrafish populations. AB - Endocrine disrupting chemicals (EDCs) are potent environmental contaminants, and their effects on wildlife populations could be exacerbated by climate change, especially in species with environmental sex determination. Endangered species may be particularly at risk because inbreeding depression and stochastic fluctuations in male and female numbers are often observed in the small populations that typify these taxa. Here, we assessed the interactive effects of water temperature and EDC exposure on sexual development and population viability of inbred and outbred zebrafish (Danio rerio). Water temperatures adopted were 28 degrees C (current ambient mean spawning temperature) and 33 degrees C (projected for the year 2100). The EDC selected was clotrimazole (at 2 MUg/L and 10 MUg/L), a widely used antifungal chemical that inhibits a key steroidogenic enzyme [cytochrome P450(CYP19) aromatase] required for estrogen synthesis in vertebrates. Elevated water temperature and clotrimazole exposure independently induced male-skewed sex ratios, and the effects of clotrimazole were greater at the higher temperature. Male sex ratio skews also occurred for the lower clotrimazole exposure concentration at the higher water temperature in inbred fish but not in outbred fish. Population viability analysis showed that population growth rates declined sharply in response to male skews and declines for inbred populations occurred at lower male skews than for outbred populations. These results indicate that elevated temperature associated with climate change can amplify the effects of EDCs and these effects are likely to be most acute in small, inbred populations exhibiting environmental sex determination and/or differentiation. PMID- 25733877 TI - Dynamical evidence for causality between galactic cosmic rays and interannual variation in global temperature. AB - As early as 1959, it was hypothesized that an indirect link between solar activity and climate could be mediated by mechanisms controlling the flux of galactic cosmic rays (CR) [Ney ER (1959) Nature 183:451-452]. Although the connection between CR and climate remains controversial, a significant body of laboratory evidence has emerged at the European Organization for Nuclear Research [Duplissy J, et al. (2010) Atmos Chem Phys 10:1635-1647; Kirkby J, et al. (2011) Nature 476(7361):429-433] and elsewhere [Svensmark H, Pedersen JOP, Marsh ND, Enghoff MB, Uggerhoj UI (2007) Proc R Soc A 463:385-396; Enghoff MB, Pedersen JOP, Uggerhoj UI, Paling SM, Svensmark H (2011) Geophys Res Lett 38:L09805], demonstrating the theoretical mechanism of this link. In this article, we present an analysis based on convergent cross mapping, which uses observational time series data to directly examine the causal link between CR and year-to-year changes in global temperature. Despite a gross correlation, we find no measurable evidence of a causal effect linking CR to the overall 20th-century warming trend. However, on short interannual timescales, we find a significant, although modest, causal effect between CR and short-term, year-to-year variability in global temperature that is consistent with the presence of nonlinearities internal to the system. Thus, although CR do not contribute measurably to the 20th-century global warming trend, they do appear as a nontraditional forcing in the climate system on short interannual timescales. PMID- 25733878 TI - Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. AB - Cortical gamma band oscillations (GBO, 30-80 Hz, typically ~40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ~40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia. PMID- 25733879 TI - How to divide and conquer the world, one step at a time. PMID- 25733880 TI - Dramatically reduced spliceosome in Cyanidioschyzon merolae. AB - The human spliceosome is a large ribonucleoprotein complex that catalyzes pre mRNA splicing. It consists of five snRNAs and more than 200 proteins. Because of this complexity, much work has focused on the Saccharomyces cerevisiae spliceosome, viewed as a highly simplified system with fewer than half as many splicing factors as humans. Nevertheless, it has been difficult to ascribe a mechanistic function to individual splicing factors or even to discern which are critical for catalyzing the splicing reaction. We have identified and characterized the splicing machinery from the red alga Cyanidioschyzon merolae, which has been reported to harbor only 26 intron-containing genes. The U2, U4, U5, and U6 snRNAs contain expected conserved sequences and have the ability to adopt secondary structures and form intermolecular base-pairing interactions, as in other organisms. C. merolae has a highly reduced set of 43 identifiable core splicing proteins, compared with ~90 in budding yeast and ~140 in humans. Strikingly, we have been unable to find a U1 snRNA candidate or any predicted U1 associated proteins, suggesting that splicing in C. merolae may occur without the U1 small nuclear ribonucleoprotein particle. In addition, based on mapping the identified proteins onto the known splicing cycle, we propose that there is far less compositional variability during splicing in C. merolae than in other organisms. The observed reduction in splicing factors is consistent with the elimination of spliceosomal components that play a peripheral or modulatory role in splicing, presumably retaining those with a more central role in organization and catalysis. PMID- 25733881 TI - Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. AB - Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity. PMID- 25733883 TI - Functional analysis of (4S)-limonene synthase mutants reveals determinants of catalytic outcome in a model monoterpene synthase. AB - Crystal structural data for (4S)-limonene synthase [(4S)-LS] of spearmint (Mentha spicata L.) were used to infer which amino acid residues are in close proximity to the substrate and carbocation intermediates of the enzymatic reaction. Alanine scanning mutagenesis of 48 amino acids combined with enzyme fidelity analysis [percentage of (-)-limonene produced] indicated which residues are most likely to constitute the active site. Mutation of residues W324 and H579 caused a significant drop in enzyme activity and formation of products (myrcene, linalool, and terpineol) characteristic of a premature termination of the reaction. A double mutant (W324A/H579A) had no detectable enzyme activity, indicating that either substrate binding or the terminating reaction was impaired. Exchanges to other aromatic residues (W324H, W324F, W324Y, H579F, H579Y, and H579W) resulted in enzyme catalysts with significantly reduced activity. Sequence comparisons across the angiosperm lineage provided evidence that W324 is a conserved residue, whereas the position equivalent to H579 is occupied by aromatic residues (H, F, or Y). These results are consistent with a critical role of W324 and H579 in the stabilization of carbocation intermediates. The potential of these residues to serve as the catalytic base facilitating the terminal deprotonation reaction is discussed. PMID- 25733882 TI - PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. AB - Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a variety of human cancers and are attractive targets for cancer therapy. The MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF-02341066) has demonstrated promising clinical activity in ROS1 fusion-positive non-small cell lung cancer. However, emerging clinical evidence has shown that patients can develop resistance by acquiring secondary point mutations in ROS1 kinase. In this study we characterized the ROS1 activity of PF-06463922, a novel, orally available, CNS-penetrant, ATP competitive small-molecule inhibitor of ALK/ROS1. In vitro, PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1 fusions and inhibited the crizotinib-refractory ROS1(G2032R) mutation and the ROS1(G2026M) gatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase. A crystal structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions contributing to the high-affinity binding. In vivo, PF-06463922 showed marked antitumor activity in tumor models expressing FIG-ROS1, CD74-ROS1, and the CD74-ROS1(G2032R) mutation. Furthermore, PF-06463922 demonstrated antitumor activity in a genetically engineered mouse model of FIG-ROS1 glioblastoma. Taken together, our results indicate that PF 06463922 has potential for treating ROS1 fusion-positive cancers, including those requiring agents with CNS-penetrating properties, as well as for overcoming crizotinib resistance driven by ROS1 mutation. PMID- 25733884 TI - Place field expansion after focal MEC inactivations is consistent with loss of Fourier components and path integrator gain reduction. AB - Both hippocampal place fields and medial entorhinal cortex (MEC) grid fields increase in scale along the dorsoventral axis. Because the connections from MEC to hippocampus are topographically organized and divergent, it has been hypothesized that place fields are generated by a Fourier-like summation of inputs over a range of spatial scales. This hypothesis predicts that inactivation of dorsal MEC should cause place field expansion, whereas inactivation of ventral MEC should cause field contraction. Inactivation of dorsal MEC caused substantial expansion of place fields; however, as inactivations were made more ventrally, the effect diminished but never switched to contraction. Expansion was accompanied by proportional decreases in theta power, intrinsic oscillation frequencies, phase precession slopes, and firing rates. Our results are most consistent with the predicted loss of specific Fourier components coupled with a path integration gain reduction, which raises the overall place field scale and masks the contraction expected from ventral inactivations. PMID- 25733885 TI - Disentangling mechanisms that mediate the balance between stochastic and deterministic processes in microbial succession. AB - Ecological succession and the balance between stochastic and deterministic processes are two major themes within microbial ecology, but these conceptual domains have mostly developed independent of each other. Here we provide a framework that integrates shifts in community assembly processes with microbial primary succession to better understand mechanisms governing the stochastic/deterministic balance. Synthesizing previous work, we devised a conceptual model that links ecosystem development to alternative hypotheses related to shifts in ecological assembly processes. Conceptual model hypotheses were tested by coupling spatiotemporal data on soil bacterial communities with environmental conditions in a salt marsh chronosequence spanning 105 years of succession. Analyses within successional stages showed community composition to be initially governed by stochasticity, but as succession proceeded, there was a progressive increase in deterministic selection correlated with increasing sodium concentration. Analyses of community turnover among successional stages--which provide a larger spatiotemporal scale relative to within stage analyses--revealed that changes in the concentration of soil organic matter were the main predictor of the type and relative influence of determinism. Taken together, these results suggest scale-dependency in the mechanisms underlying selection. To better understand mechanisms governing these patterns, we developed an ecological simulation model that revealed how changes in selective environments cause shifts in the stochastic/deterministic balance. Finally, we propose an extended--and experimentally testable--conceptual model integrating ecological assembly processes with primary and secondary succession. This framework provides a priori hypotheses for future experiments, thereby facilitating a systematic approach to understand assembly and succession in microbial communities across ecosystems. PMID- 25733886 TI - Mutation of a single residue in the ba3 oxidase specifically impairs protonation of the pump site. AB - The ba3-type cytochrome c oxidase from Thermus thermophilus is a membrane-bound protein complex that couples electron transfer to O2 to proton translocation across the membrane. To elucidate the mechanism of the redox-driven proton pumping, we investigated the kinetics of electron and proton transfer in a structural variant of the ba3 oxidase where a putative "pump site" was modified by replacement of Asp372 by Ile. In this structural variant, proton pumping was uncoupled from internal electron transfer and O2 reduction. The results from our studies show that proton uptake to the pump site (time constant ~65 MUs in the wild-type cytochrome c oxidase) was impaired in the Asp372Ile variant. Furthermore, a reaction step that in the wild-type cytochrome c oxidase is linked to simultaneous proton uptake and release with a time constant of ~1.2 ms was slowed to ~8.4 ms, and in Asp372Ile was only associated with proton uptake to the catalytic site. These data identify reaction steps that are associated with protonation and deprotonation of the pump site, and point to the area around Asp372 as the location of this site in the ba3 cytochrome c oxidase. PMID- 25733887 TI - Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release. AB - Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation. PMID- 25733888 TI - Nanomechanics and intermolecular forces of amyloid revealed by four-dimensional electron microscopy. AB - The amyloid state of polypeptides is a stable, highly organized structural form consisting of laterally associated beta-sheet protofilaments that may be adopted as an alternative to the functional, native state. Identifying the balance of forces stabilizing amyloid is fundamental to understanding the wide accessibility of this state to peptides and proteins with unrelated primary sequences, various chain lengths, and widely differing native structures. Here, we use four dimensional electron microscopy to demonstrate that the forces acting to stabilize amyloid at the atomic level are highly anisotropic, that an optimized interbackbone hydrogen-bonding network within beta-sheets confers 20 times more rigidity on the structure than sequence-specific sidechain interactions between sheets, and that electrostatic attraction of protofilaments is only slightly stronger than these weak amphiphilic interactions. The potential biological relevance of the deposition of such a highly anisotropic biomaterial in vivo is discussed. PMID- 25733889 TI - Effects of large-scale deforestation on precipitation in the monsoon regions: remote versus local effects. AB - In this paper, using idealized climate model simulations, we investigate the biogeophysical effects of large-scale deforestation on monsoon regions. We find that the remote forcing from large-scale deforestation in the northern middle and high latitudes shifts the Intertropical Convergence Zone southward. This results in a significant decrease in precipitation in the Northern Hemisphere monsoon regions (East Asia, North America, North Africa, and South Asia) and moderate precipitation increases in the Southern Hemisphere monsoon regions (South Africa, South America, and Australia). The magnitude of the monsoonal precipitation changes depends on the location of deforestation, with remote effects showing a larger influence than local effects. The South Asian Monsoon region is affected the most, with 18% decline in precipitation over India. Our results indicate that any comprehensive assessment of afforestation/reforestation as climate change mitigation strategies should carefully evaluate the remote effects on monsoonal precipitation alongside the large local impacts on temperatures. PMID- 25733890 TI - Origin of the HIV-1 group O epidemic in western lowland gorillas. AB - HIV-1, the cause of AIDS, is composed of four phylogenetic lineages, groups M, N, O, and P, each of which resulted from an independent cross-species transmission event of simian immunodeficiency viruses (SIVs) infecting African apes. Although groups M and N have been traced to geographically distinct chimpanzee communities in southern Cameroon, the reservoirs of groups O and P remain unknown. Here, we screened fecal samples from western lowland (n = 2,611), eastern lowland (n = 103), and mountain (n = 218) gorillas for gorilla SIV (SIVgor) antibodies and nucleic acids. Despite testing wild troops throughout southern Cameroon (n = 14), northern Gabon (n = 16), the Democratic Republic of Congo (n = 2), and Uganda (n = 1), SIVgor was identified at only four sites in southern Cameroon, with prevalences ranging from 0.8-22%. Amplification of partial and full-length SIVgor sequences revealed extensive genetic diversity, but all SIVgor strains were derived from a single lineage within the chimpanzee SIV (SIVcpz) radiation. Two fully sequenced gorilla viruses from southwestern Cameroon were very closely related to, and likely represent the source population of, HIV-1 group P. Most of the genome of a third SIVgor strain, from central Cameroon, was very closely related to HIV-1 group O, again pointing to gorillas as the immediate source. Functional analyses identified the cytidine deaminase APOBEC3G as a barrier for chimpanzee-to-gorilla, but not gorilla-to-human, virus transmission. These data indicate that HIV-1 group O, which spreads epidemically in west central Africa and is estimated to have infected around 100,000 people, originated by cross species transmission from western lowland gorillas. PMID- 25733892 TI - Dynamical phase transition in the open Dicke model. AB - The Dicke model with a weak dissipation channel is realized by coupling a Bose Einstein condensate to an optical cavity with ultranarrow bandwidth. We explore the dynamical critical properties of the Hepp-Lieb-Dicke phase transition by performing quenches across the phase boundary. We observe hysteresis in the transition between a homogeneous phase and a self-organized collective phase with an enclosed loop area showing power-law scaling with respect to the quench time, which suggests an interpretation within a general framework introduced by Kibble and Zurek. The observed hysteretic dynamics is well reproduced by numerically solving the mean-field equation derived from a generalized Dicke Hamiltonian. Our work promotes the understanding of nonequilibrium physics in open many-body systems with infinite range interactions. PMID- 25733891 TI - Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics. AB - Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg(2+) cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, alpha-carboxy nucleoside phosphonate (alpha-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that alpha-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the alpha-CNP acts as the potential equivalent of the alpha-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the alpha-CNP chelate Mg(2+), mimicking the chelation by the beta- and gamma-phosphate oxygens of dNTPs. alpha-CNPs (i) do not require metabolic activation (phosphorylation), (ii) bind directly to the substrate binding site, (iii) chelate one of the two active site Mg(2+) ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, alpha-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg(2+)-dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. alpha CNPs represent an entirely novel and broad technological platform for the development of specific substrate active- or regulatory-site inhibitors with therapeutic potential. PMID- 25733893 TI - Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH. AB - Aberrant cleavage of amyloid precursor protein (APP) by gamma-secretase contributes to the development of Alzheimer's disease. More than 200 disease derived mutations have been identified in presenilin (the catalytic subunit of gamma-secretase), making modulation of gamma-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact gamma-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to gamma secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Abeta42, Abeta40, and Abeta38. The molar ratio of the cleavage products Abeta42 over Abeta40 by PSH is nearly identical to that by gamma secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of gamma-secretase also modulate PSH similarly in terms of the Abeta42/Abeta40 ratio. Structural analysis reveals association of a known gamma-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of gamma-secretase. PMID- 25733894 TI - Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. AB - Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/beta catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/beta-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis. PMID- 25733895 TI - Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma. AB - High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC. PMID- 25733896 TI - Nonsense suppression by near-cognate tRNAs employs alternative base pairing at codon positions 1 and 3. AB - Premature termination codons (PTCs) in an mRNA ORF inactivate gene function by causing production of a truncated protein and destabilization of the mRNA. Readthrough of a PTC allows ribosomal A-site insertion of a near-cognate tRNA, leading to synthesis of a full-length protein from otherwise defective mRNA. To understand the mechanism of such nonsense suppression, we developed a yeast system that allows purification and sequence analysis of full-length readthrough products arising as a consequence of endogenous readthrough or the compromised termination fidelity attributable to the loss of Upf (up-frameshift) factors, defective release factors, or the presence of the aminoglycoside gentamicin. Unlike classical "wobble" models, our analyses showed that three of four possible near-cognate tRNAs could mispair at position 1 or 3 of nonsense codons and that, irrespective of whether readthrough is endogenous or induced, the same sets of amino acids are inserted. We identified the insertion of Gln, Tyr, and Lys at UAA and UAG, whereas Trp, Arg, and Cys were inserted at UGA, and the frequency of insertion of individual amino acids was distinct for specific nonsense codons and readthrough-inducing agents. Our analysis suggests that the use of genetic or chemical means to increase readthrough does not promote novel or alternative mispairing events; rather, readthrough effectors cause quantitative enhancement of endogenous mistranslation events. Knowledge of the amino acids incorporated during readthrough not only elucidates the decoding process but also may allow predictions of the functionality of readthrough protein products. PMID- 25733898 TI - Climate change in the Fertile Crescent and implications of the recent Syrian drought. AB - Before the Syrian uprising that began in 2011, the greater Fertile Crescent experienced the most severe drought in the instrumental record. For Syria, a country marked by poor governance and unsustainable agricultural and environmental policies, the drought had a catalytic effect, contributing to political unrest. We show that the recent decrease in Syrian precipitation is a combination of natural variability and a long-term drying trend, and the unusual severity of the observed drought is here shown to be highly unlikely without this trend. Precipitation changes in Syria are linked to rising mean sea-level pressure in the Eastern Mediterranean, which also shows a long-term trend. There has been also a long-term warming trend in the Eastern Mediterranean, adding to the drawdown of soil moisture. No natural cause is apparent for these trends, whereas the observed drying and warming are consistent with model studies of the response to increases in greenhouse gases. Furthermore, model studies show an increasingly drier and hotter future mean climate for the Eastern Mediterranean. Analyses of observations and model simulations indicate that a drought of the severity and duration of the recent Syrian drought, which is implicated in the current conflict, has become more than twice as likely as a consequence of human interference in the climate system. PMID- 25733897 TI - Four basic residues critical for the ion selectivity and pore blocker sensitivity of TMEM16A calcium-activated chloride channels. AB - TMEM16A (transmembrane protein 16) (Anoctamin-1) forms a calcium-activated chloride channel (CaCC) that regulates a broad array of physiological properties in response to changes in intracellular calcium concentration. Although known to conduct anions according to the Eisenman type I selectivity sequence, the structural determinants of TMEM16A anion selectivity are not well-understood. Reasoning that the positive charges on basic residues are likely contributors to anion selectivity, we performed whole-cell recordings of mutants with alanine substitution for basic residues within the putative pore region and identified four residues on four different putative transmembrane segments that significantly increased the permeability of the larger halides and thiocyanate relative to that of chloride. Because TMEM16A permeation properties are known to shift with changes in intracellular calcium concentration, we further examined the calcium dependence of anion selectivity. We found that WT TMEM16A but not mutants with alanine substitution at those four basic residues exhibited a clear decline in the preference for larger anions as intracellular calcium was increased. Having implicated these residues as contributing to the TMEM16A pore, we scrutinized candidate small molecules from a high-throughput CaCC inhibitor screen to identify two compounds that act as pore blockers. Mutations of those four putative pore-lining basic residues significantly altered the IC50 of these compounds at positive voltages. These findings contribute to our understanding regarding anion permeation of TMEM16A CaCC and provide valuable pharmacological tools to probe the channel pore. PMID- 25733899 TI - Impacts of biological globalization in the Mediterranean: unveiling the deep history of human-mediated gamebird dispersal. AB - Humans have a long history of moving wildlife that over time has resulted in unprecedented biotic homogenization. It is, as a result, often unclear whether certain taxa are native to a region or naturalized, and how the history of human involvement in species dispersal has shaped present-day biodiversity. Although currently an eastern Palaearctic galliform, the black francolin (Francolinus francolinus) was known to occur in the western Mediterranean from at least the time of Pliny the Elder, if not earlier. During Medieval times and the Renaissance, the black francolin was a courtly gamebird prized not only for its flavor, but also its curative, and even aphrodisiac qualities. There is uncertainty, however, whether this important gamebird was native or introduced to the region and, if the latter, what the source of introduction into the western Mediterranean was. Here we combine historical documentation with a DNA investigation of modern birds and archival (13th-20th century) specimens from across the species' current and historically documented range. Our study proves the black francolin was nonnative to the western Mediterranean, and we document its introduction from the east via several trade routes, some reaching as far as South Asia. This finding provides insight into the reach and scope of long distance trade routes that serviced the demand of European aristocracy for exotic species as symbols of wealth and prestige, and helps to demonstrate the lasting impact of human-mediated long-distance species dispersal on current day biodiversity. PMID- 25733900 TI - Different personal propensities among scientists relate to deeper vs. broader knowledge contributions. AB - Scientific journal publications, and their contributions to knowledge, can be described by their depth (specialized, domain-specific knowledge extensions) and breadth (topical scope, including spanning multiple knowledge domains). Toward generating hypotheses about how scientists' personal dispositions would uniquely predict deeper vs. broader contributions to the literature, we assumed that conducting broader studies is generally viewed as less attractive (e.g., riskier) than conducting deeper studies. Study 1 then supported our assumptions: the scientists surveyed considered a hypothetical broader study, compared with an otherwise-comparable deeper study, to be riskier, a less-significant opportunity, and of lower potential importance; they further reported being less likely to pursue it and, in a forced choice, most chose to work on the deeper study. In Study 2, questionnaire measures of medical researchers' personal dispositions and 10 y of PubMed data indicating their publications' topical coverage revealed how dispositions differentially predict depth vs. breadth. Competitiveness predicted depth positively, whereas conscientiousness predicted breadth negatively. Performance goal orientation predicted depth but not breadth, and learning goal orientation contrastingly predicted breadth but not depth. Openness to experience positively predicted both depth and breadth. Exploratory work behavior (the converse of applying and exploiting one's current knowledge) predicted breadth positively and depth negatively. Thus, this research distinguishes depth and breadth of published knowledge contributions, and provides new insights into how scientists' personal dispositions influence research processes and products. PMID- 25733902 TI - Pollinator recognition by a keystone tropical plant. AB - Understanding the mechanisms enabling coevolution in complex mutualistic networks remains a central challenge in evolutionary biology. We show for the first time, to our knowledge, that a tropical plant species has the capacity to discriminate among floral visitors, investing in reproduction differentially across the pollinator community. After we standardized pollen quality in 223 aviary experiments, successful pollination of Heliconia tortuosa (measured as pollen tube abundance) occurred frequently when plants were visited by long-distance traplining hummingbird species with specialized bills (mean pollen tubes = 1.21 +/- 0.12 SE) but was reduced 5.7 times when visited by straight-billed territorial birds (mean pollen tubes = 0.20 +/- 0.074 SE) or insects. Our subsequent experiments revealed that plants use the nectar extraction capacity of tropical hummingbirds, a positive function of bill length, as a cue to turn on reproductively. Furthermore, we show that hummingbirds with long bills and high nectar extraction efficiency engaged in daily movements at broad spatial scales (~1 km), but that territorial species moved only short distances (<100 m). Such pollinator recognition may therefore affect mate selection and maximize receipt of high-quality pollen from multiple parents. Although a diffuse pollinator network is implied, because all six species of hummingbirds carry pollen of H. tortuosa, only two species with specialized bills contribute meaningfully to its reproduction. We hypothesize that this pollinator filtering behavior constitutes a crucial mechanism facilitating coevolution in multispecies plant-pollinator networks. However, pollinator recognition also greatly reduces the number of realized pollinators, thereby rendering mutualistic networks more vulnerable to environmental change. PMID- 25733901 TI - Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. AB - Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders. PMID- 25733903 TI - Regulatory link between DNA methylation and active demethylation in Arabidopsis. AB - De novo DNA methylation through the RNA-directed DNA methylation (RdDM) pathway and active DNA demethylation play important roles in controlling genome-wide DNA methylation patterns in plants. Little is known about how cells manage the balance between DNA methylation and active demethylation activities. Here, we report the identification of a unique RdDM target sequence, where DNA methylation is required for maintaining proper active DNA demethylation of the Arabidopsis genome. In a genetic screen for cellular antisilencing factors, we isolated several REPRESSOR OF SILENCING 1 (ros1) mutant alleles, as well as many RdDM mutants, which showed drastically reduced ROS1 gene expression and, consequently, transcriptional silencing of two reporter genes. A helitron transposon element (TE) in the ROS1 gene promoter negatively controls ROS1 expression, whereas DNA methylation of an RdDM target sequence between ROS1 5' UTR and the promoter TE region antagonizes this helitron TE in regulating ROS1 expression. This RdDM target sequence is also targeted by ROS1, and defective DNA demethylation in loss of-function ros1 mutant alleles causes DNA hypermethylation of this sequence and concomitantly causes increased ROS1 expression. Our results suggest that this sequence in the ROS1 promoter region serves as a DNA methylation monitoring sequence (MEMS) that senses DNA methylation and active DNA demethylation activities. Therefore, the ROS1 promoter functions like a thermostat (i.e., methylstat) to sense DNA methylation levels and regulates DNA methylation by controlling ROS1 expression. PMID- 25733904 TI - In-use product stocks link manufactured capital to natural capital. AB - In-use stock of a product is the amount of the product in active use. In-use product stocks provide various functions or services on which we rely in our daily work and lives, and the concept of in-use product stock for industrial ecologists is similar to the concept of net manufactured capital stock for economists. This study estimates historical physical in-use stocks of 91 products and 9 product groups and uses monetary data on net capital stocks of 56 products to either approximate or compare with in-use stocks of the corresponding products in the United States. Findings include the following: (i) The development of new products and the buildup of their in-use stocks result in the increase in variety of in-use product stocks and of manufactured capital; (ii) substitution among products providing similar or identical functions reflects the improvement in quality of in-use product stocks and of manufactured capital; and (iii) the historical evolution of stocks of the 156 products or product groups in absolute, per capita, or per-household terms shows that stocks of most products have reached or are approaching an upper limit. Because the buildup, renewal, renovation, maintenance, and operation of in-use product stocks drive the anthropogenic cycles of materials that are used to produce products and that originate from natural capital, the determination of in-use product stocks together with modeling of anthropogenic material cycles provides an analytic perspective on the material linkage between manufactured capital and natural capital. PMID- 25733905 TI - Endocannabinoids are conserved inhibitors of the Hedgehog pathway. AB - Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids. PMID- 25733906 TI - Vapor hydrogen and oxygen isotopes reflect water of combustion in the urban atmosphere. AB - Anthropogenic modification of the water cycle involves a diversity of processes, many of which have been studied intensively using models and observations. Effective tools for measuring the contribution and fate of combustion-derived water vapor in the atmosphere are lacking, however, and this flux has received relatively little attention. We provide theoretical estimates and a first set of measurements demonstrating that water of combustion is characterized by a distinctive combination of H and O isotope ratios. We show that during periods of relatively low humidity and/or atmospheric stagnation, this isotopic signature can be used to quantify the concentration of water of combustion in the atmospheric boundary layer over Salt Lake City. Combustion-derived vapor concentrations vary between periods of atmospheric stratification and mixing, both on multiday and diurnal timescales, and respond over periods of hours to variations in surface emissions. Our estimates suggest that up to 13% of the boundary layer vapor during the period of study was derived from combustion sources, and both the temporal pattern and magnitude of this contribution were closely reproduced by an independent atmospheric model forced with a fossil fuel emissions data product. Our findings suggest potential for water vapor isotope ratio measurements to be used in conjunction with other tracers to refine the apportionment of urban emissions, and imply that water vapor emissions associated with combustion may be a significant component of the water budget of the urban boundary layer, with potential implications for urban climate, ecohydrology, and photochemistry. PMID- 25733907 TI - Sequential de novo centromere formation and inactivation on a chromosomal fragment in maize. AB - The ability of centromeres to alternate between active and inactive states indicates significant epigenetic aspects controlling centromere assembly and function. In maize (Zea mays), misdivision of the B chromosome centromere on a translocation with the short arm of chromosome 9 (TB-9Sb) can produce many variants with varying centromere sizes and centromeric DNA sequences. In such derivatives of TB-9Sb, we found a de novo centromere on chromosome derivative 3 3, which has no canonical centromeric repeat sequences. This centromere is derived from a 288-kb region on the short arm of chromosome 9, and is 19 megabases (Mb) removed from the translocation breakpoint of chromosome 9 in TB 9Sb. The functional B centromere in progenitor telo2-2 is deleted from derivative 3-3, but some B-repeat sequences remain. The de novo centromere of derivative 3-3 becomes inactive in three further derivatives with new centromeres being formed elsewhere on each chromosome. Our results suggest that de novo centromere initiation is quite common and can persist on chromosomal fragments without a canonical centromere. However, we hypothesize that when de novo centromeres are initiated in opposition to a larger normal centromere, they are cleared from the chromosome by inactivation, thus maintaining karyotype integrity. PMID- 25733909 TI - Reply to Cao and Zhang: Tightening nonfossil emissions alone is inefficient for PM2.5 mitigation in China. PMID- 25733908 TI - Horizontal gene transfer and gene dosage drives adaptation to wood colonization in a tree pathogen. AB - Some of the most damaging tree pathogens can attack woody stems, causing lesions (cankers) that may be lethal. To identify the genomic determinants of wood colonization leading to canker formation, we sequenced the genomes of the poplar canker pathogen, Mycosphaerella populorum, and the closely related poplar leaf pathogen, M. populicola. A secondary metabolite cluster unique to M. populorum is fully activated following induction by poplar wood and leaves. In addition, genes encoding hemicellulose-degrading enzymes, peptidases, and metabolite transporters were more abundant and were up-regulated in M. populorum growing on poplar wood chip medium compared with M. populicola. The secondary gene cluster and several of the carbohydrate degradation genes have the signature of horizontal transfer from ascomycete fungi associated with wood decay and from prokaryotes. Acquisition and maintenance of the gene battery necessary for growth in woody tissues and gene dosage resulting in gene expression reconfiguration appear to be responsible for the adaptation of M. populorum to infect, colonize, and cause mortality on poplar woody stems. PMID- 25733910 TI - Tightening nonfossil emissions control: A potential opportunity for PM2.5 mitigation in China. PMID- 25733911 TI - Circulating tumor-derived DNA is shorter than somatic DNA in plasma. PMID- 25733912 TI - Breaking down silos: engaging students to help fix the US health care system. AB - PROBLEM: The field of health care is becoming a team effort as patient care becomes increasingly complex and multifaceted. Despite the need for multidisciplinary education, there persists a lack of student engagement and collaboration among health care disciplines, which presents a growing concern as students join the workforce. APPROACH: In October 2013, the Emory-Georgia Tech Healthcare Innovation Program organized a student driven symposium entitled "US Healthcare: What's Broken and How to Fix It: The Student Perspective". The symposium engaged students from multiple disciplines to work together in addressing problems associated with US health care delivery. The symposium was organized and carried out by a diverse group of student leaders from local institutions who adopted a multidisciplinary approach throughout the planning process. OUTCOMES: The innovative planning process leading up to the symposium revealed that many of the student-discipline groups lacked an understanding of one another's role in health care, and that students were interested in learning how to work together to leverage each other's profession. The symposium was widely attended and positively received by students and faculty from the Atlanta metropolitan area, and has since helped to promote interdepartmental collaboration and multidisciplinary education across institutions. NEXT STEPS: The student symposium will become an annual event and incorporate broader discipline representation, as well as a patient perspective. Proposals for additional institution-wide, multidisciplinary educational offerings are being addressed with the help of faculty and health care providers across the network. Accordingly, the implementation of student-driven symposia to engage students and stimulate institution-wide changes may be a beneficial and cost-effective means for academic health centers looking to facilitate multidisciplinary health care education. PMID- 25733913 TI - The multidisciplinary management of bone and soft tissue sarcoma: an essential organizational framework. AB - The rarity of bone and soft tissue sarcoma, the difficulty in interpretation of imaging and histology, the plethora of treatment modalities, and the complexity and intensity of the treatment contribute to the need for systematic multidisciplinary team management of patients with these diseases. An integrated multidisciplinary clinic and team with a structured sarcoma tumor board facilitate team coordination and communication. This paper reviews the rationale for multidisciplinary management of sarcoma and details the operational structure of the Multidisciplinary Sarcoma Clinic and Sarcoma Tumor Board. The structured Multidisciplinary Sarcoma Tumor Board provides opportunity for improvement in logistics, teaching, quality, and enrollment in clinical trials. PMID- 25733914 TI - Production, Purification, and Identification of Cholest-4-en-3-one Produced by Cholesterol Oxidase from Rhodococcus sp. in Aqueous/Organic Biphasic System. AB - Cholest-4-en-3-one has positive uses against obesity, liver disease, and keratinization. It can be applied in the synthesis of steroid drugs as well. Most related studies are focused on preparation of cholest-4-en-3-one by using whole cells as catalysts, but production of high-quality cholest-4-en-3-one directly from cholesterol oxidase (COD) using an aqueous/organic two-phase system has been rarely explored. This study set up an enzymatic reaction system to produce cholest-4-en-3-one. We developed and optimized the enzymatic reaction system using COD from COX5-6 (a strain of Rhodococcus) instead of whole-cell biocatalyst. This not only simplifies and accelerates the production but also benefits the subsequent separation and purification process. Through extraction, washing, evaporation, column chromatography, and recrystallization, we got cholest-4-en-3-one with purity of 99.78%, which was identified by nuclear magnetic resonance, mass spectroscopy, and infrared spectroscopy. In addition, this optimized process of cholest-4-en-3-one production and purification can be easily scaled up for industrial production, which can largely decrease the cost and guarantee the purity of the product. PMID- 25733915 TI - The aryl hydrocarbon receptor: a review of its role in the physiology and pathology of the integument and its relationship to the tryptophan metabolism. AB - The aryl hydrocarbon receptor (AHR) is a cytosolic receptor for low molecular weight molecules, of which the most widely recognized ligand is 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), and the most widely recognized effect, chloracne. Adverse effects of manipulation were most recently and graphically demonstrated by the poisoning of Viktor Yushchenko during the Ukrainian presidential elections of 2004. However, recent research has revealed a receptor with wide-ranging, and at times, paradoxical actions. It was arguably among the first biological receptors to be utilized by dermatologists, dating from the time of topical tar preparations as a therapeutic agent. I provide a review outlining the role AHR plays in the development, cellular oxidation/antioxidation, responses to ultraviolet light, melanogenesis, epidermal barrier function, and immune regulation and its relationship to tryptophan metabolism. Finally, I will review the role of AHR in diseases of the integument. PMID- 25733917 TI - The role of dolutegravir in the management of HIV infection. AB - Dolutegravir is the most recent integrase strand transfer inhibitor approved for HIV-1 infection in both treatment-naive and experienced patients. As a tricyclic carbamoyl pyridone analog, dolutegravir is rapidly absorbed and distributes through the cerebrospinal fluid. It is hepatically metabolized by uridine diphosphate glucuronosyl transferase 1A1; no inhibition or induction of cytochrome P450 enzymes is noted. As a substrate of CYP 3A4, dolutegravir is affected by rifampin, efavirenz, tipranavir/ritonavir, fosamprenavir/ritonavir, and dose increase is required. Dolutegravir inhibits the organic cation transporter 2, resulting in decreased creatinine clearance with no apparent decrease in renal function. Other adverse effects are minimal but include diarrhea, headache, and nausea. Clinical trials in treatment-naive and experienced patients are ongoing and will be presented in this text. PMID- 25733916 TI - Ragweed-induced allergic rhinoconjunctivitis: current and emerging treatment options. AB - Ragweed (Ambrosia spp.) is an annually flowering plant whose pollen bears high allergenic potential. Ragweed-induced allergic rhinoconjunctivitis has long been seen as a major immunologic condition in Northern America with high exposure and sensitization rates in the general population. The invasive occurrence of ragweed (A. artemisiifolia) poses an increasing challenge to public health in Europe and Asia as well. Possible explanations for its worldwide spread are climate change and urbanization, as well as pollen transport over long distances by globalized traffic and winds. Due to the increasing disease burden worldwide, and to the lack of a current and comprehensive overview, this study aims to review the current and emerging treatment options for ragweed-induced rhinoconjunctivitis. Sound clinical evidence is present for the symptomatic treatment of ragweed induced allergic rhinoconjunctivitis with oral third-generation H1-antihistamines and leukotriene antagonists. The topical application of glucocorticoids has also been efficient in randomized controlled clinical trials. Combined approaches employing multiple agents are common. The mainstay of causal treatment to date, especially in Northern America, is subcutaneous immunotherapy with the focus on the major allergen, Amb a 1. Beyond this, growing evidence from several geographical regions documents the benefit of sublingual immunotherapy. Future treatment options promise more specific symptomatic treatment and fewer side effects during causal therapy. Novel antihistamines for symptomatic treatment are aimed at the histamine H3-receptor. New adjuvants with toll-like receptor 4 activity or the application of the monoclonal anti-immunoglobulin E antibody, omalizumab, are supposed to enhance conventional immunotherapy. An approach targeting toll-like receptor 9 by synthetic cytosine phosphate-guanosine oligodeoxynucleotides promises a new treatment paradigm that aims to modulate the immune response, but it has yet to be proven in clinical trials. PMID- 25733918 TI - Facial skin pores: a multiethnic study. AB - Skin pores (SP), as they are called by laymen, are common and benign features mostly located on the face (nose, cheeks, etc) that generate many aesthetic concerns or complaints. Despite the prevalence of skin pores, related literature is scarce. With the aim of describing the prevalence of skin pores and anatomic features among ethnic groups, a dermatoscopic instrument, using polarized lighting, coupled to a digital camera recorded the major features of skin pores (size, density, coverage) on the cheeks of 2,585 women in different countries and continents. A detection threshold of 250 MUm, correlated to clinical scorings by experts, was input into a specific software to further allow for automatic counting of the SP density (N/cm(2)) and determination of their respective sizes in mm(2). Integrating both criteria also led to establishing the relative part of the skin surface (as a percentage) that is actually covered by SP on cheeks. The results showed that the values of respective sizes, densities, and skin coverage: 1) were recorded in all studied subjects; 2) varied greatly with ethnicity; 3) plateaued with age in most cases; and 4) globally refected self-assessment by subjects, in particular those who self-declare having "enlarged pores" like Brazilian women. Inversely, Chinese women were clearly distinct from other ethnicities in having very low density and sizes. Analyzing the present results suggests that facial skin pore's morphology as perceived by human eye less result from functional criteria of associated appendages such as sebaceous glands. To what extent skin pores may be viewed as additional criteria of a photo-altered skin is an issue to be further addressed. PMID- 25733919 TI - Plain tobacco packaging in Australia: 26 months on. PMID- 25733920 TI - A pilot trial on subjects with lactose and/or oligosaccharides intolerance treated with a fixed mixture of pure and enteric-coated alpha- and beta galactosidase. AB - AIM: Lactose and complex carbohydrates maldigestion, common food intolerances due to low gut content of alpha- and beta-galactosidase, lead to abdominal symptoms including pain, diarrhea, bloating, flatulence, and cramping. Commonly, intolerant patients are advised by physicians to avoid the offending foods (dairy foods, cereals, beans, etc). This food-limiting option, however, has possible nutritional risks. We have therefore evaluated the impact of using pure, enteric coated alpha- plus beta-galactosidase on gut symptoms in intolerant subjects instead of avoidance of the offending foods. METHODS: Sixteen subjects intolerant to lactose and/or complex carbohydrates were enrolled and evaluated in terms of gut symptoms with 1) uncontrolled diet, 2) diet devoid of offending foods, and 3) uncontrolled diet along with pure, enteric-coated alpha- and beta-galactosidase (DDM Galactosidase((r))). RESULTS: Even with the uncontrolled diet, intolerant subjects treated with DDM Galactosidase((r)) exhibited reduced gut symptoms (bloating, flatulence, diarrhea, and constipation) significantly better than the control treatment as well as having a diet devoid of offending foods. CONCLUSION: DDM Galactosidase((r)) is a valid and safe optional treatment to counteract lactose and complex carbohydrate intolerance in subjects who prefer not to avoid, at least partially, offending foods. PMID- 25733921 TI - IBS-like symptoms in patients with ulcerative colitis. AB - Ulcerative colitis (UC) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders that, until recently, have been considered dichotomous conditions falling on either side of a functional-organic divide. However, persistent gastrointestinal symptoms, akin to those of IBS, are observed in up to one in three patients with quiescent UC. Whether these lower gastrointestinal symptoms are secondary to coexistent IBS or occult UC disease activity is uncertain, but when objective evidence of disease activity is lacking, escalation of conventional pharmacotherapy in such patients is often ineffective. The etiologies of both UC and IBS remain unclear, but dysregulation of the enteric nervous system, an altered microbiome, low-grade mucosal inflammation, and activation of the brain-gut axis is common to both; this suggests that some overlap between the two conditions is plausible. How best to investigate and manage IBS-type symptoms in UC patients remains unclear. Studies that have assessed patients with UC who meet criteria for IBS for subclinical inflammation have been conflicting in their results. Although evidence-based treatments for IBS exist, their efficacy in UC patients reporting these types of symptoms remains unclear. Given the disturbances in gut microbiota in UC, and the possible role of the brain-gut axis in the generation of such symptoms, treatments such as probiotics, fecal transfer, antidepressants, or psychological therapies would seem logical approaches to use in this group of patients. However, there are only limited data for all of these therapies; this suggests that randomized controlled trials to investigate their efficacy in this setting may be warranted. PMID- 25733923 TI - Bilateral granulosa cell tumors: a novel malignant manifestation of multiple endocrine neoplasia 1 syndrome found in a patient with a rare menin in-frame deletion. AB - INTRODUCTION: Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene. CASE REPORT: A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo-oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A). DISCUSSION: Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity. CONCLUSION: To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described. PMID- 25733922 TI - Moyamoya disease and syndromes: from genetics to clinical management. AB - Moyamoya angiopathy is characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of a network of abnormal collateral vessels. This chronic cerebral angiopathy is observed in children and adults. It mainly leads to brain ischemic events in children, and to ischemic and hemorrhagic events in adults. This is a rare condition, with a marked prevalence gradient between Asian countries and Western countries. Two main nosological entities are identified. On the one hand, moyamoya disease corresponds to isolated moyamoya angiopathy, defined as being "idiopathic" according to the Guidelines of the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. This entity is probably multifactorial and polygenic in most patients. On the other hand, moyamoya syndrome is a moyamoya angiopathy associated with an underlying condition and forms a very heterogeneous group with various clinical presentations, various modes of inheritance, and a variable penetrance of the cerebrovascular phenotype. Diagnostic and evaluation techniques rely on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) conventional angiography, and cerebral hemodynamics measurements. Revascularization surgery can be indicated, with several techniques. Characteristics of genetic moyamoya syndromes are presented, with a focus on recently reported mutations in BRCC3/MTCP1 and GUCY1A3 genes. Identification of the genes involved in moyamoya disease and several monogenic moyamoya syndromes unraveled different pathways involved in the development of this angiopathy. Studying genes and pathways involved in monogenic moyamoya syndromes may help to give insights into pathophysiological models and discover potential candidates for medical treatment strategies. PMID- 25733924 TI - Prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depression: An open-label, multicenter, pilot study of efficacy, safety and effect on headache-related disability, depression, and anxiety. AB - BACKGROUND: Chronic migraine is associated with significant headache-related disability and psychiatric comorbidity. OnabotulinumtoxinA (BOTOX((r))) is effective and well tolerated in the prophylactic treatment of chronic migraine. This study aimed to provide preliminary data on the efficacy and safety of prophylactic onabotulinumtoxinA in patients with chronic migraine and comorbid depressive symptoms. METHODS: This was a prospective, open-label, multicenter pilot study. Eligible patients met International Classification of Headache Disorders 2nd edition Revision criteria for chronic migraine and had associated depressive symptoms, including Patient Health Questionnaire depression module scores of 5-19. Eligible participants received 155 units of onabotulinumtoxinA, according to the PREEMPT protocol, at baseline and week 12. Assessments included headache frequency, the Headache Impact TestTM, the Migraine Disability Assessment, the Beck Depression Inventory((r))-II, the nine-item Patient Health Questionnaire depression module, and the seven-item Generalized Anxiety Disorder questionnaire. Adverse events were also monitored. RESULTS: Overall, 32 participants received treatment. At week 24, there were statistically significant mean (standard deviation [SD]) improvements relative to baseline in the number of headache/migraine-free days (+8.2 [5.8]) (P<0.0001) and in the number of headache/migraine days (-8.2 [5.8]) (P<0.0001) per 30-day period. In addition, there were significant improvements in Headache Impact Test scores (-6.3 [6.9]) (P=0.0001) and Migraine Disability Assessment scores (-44.2 [67.5]) (P=0.0058). From baseline to week 24, statistically significant improvements were also seen in Beck Depression Inventory-II (-7.9 [6.0]) (P<0.0001), Patient Health Questionnaire depression module (-4.3 [4.7]) (P<0.0001), and Generalized Anxiety Disorder questionnaire (-3.5 [5.0]) (P=0.0002) scores. No serious adverse events were reported. Adverse events considered related to treatment occurred in 30% of patients and were mild or moderate. CONCLUSION: Prophylactic onabotulinumtoxinA was well tolerated in patients with chronic migraine and comorbid depression, and was effective in reducing headache frequency, impact, and related disability, which led to statistically significant improvements in depression and anxiety symptoms. PMID- 25733925 TI - Nitric oxide dysregulation in the pathogenesis of preeclampsia among Ghanaian women. AB - BACKGROUND: Preeclampsia (PE) is still a disease of theories as the exact cause remains uncertain. Widespread vascular endothelial cell dysfunction is thought to mediate the generalized vasospasm and hypertension characteristic of PE. Altered nitric oxide (NO) production has been associated with the endothelial dysfunction in the pathogenesis of PE but conflicting results have emerged from previous studies. OBJECTIVES: To determine maternal serum levels of NO, a biomarker of endothelial function, in nonpregnant, normal pregnant, and preeclamptic women. MATERIALS AND METHODS: This was a cross-sectional case-control study of 277 women comprising 75 nonpregnant, 102 normal pregnant, and 100 preeclamptic women conducted at the Korle Bu Teaching Hospital between April and June 2011. About 5 mL of venous blood was obtained from the participants for the various investigations after meeting the inclusion criteria and signing to a written consent. Serum levels of NO were determined by Griess reaction. The data obtained were analyzed with SPSS version 20. RESULTS: The study showed significantly elevated serum levels of NO in preeclamptic women (82.45+/-50.31 MUM) compared with normal pregnant (33.12+/-17.81 MUM) and nonpregnant (16.92+/-11.41 MUM) women with P<0.001. The alteration in maternal serum NO levels was significantly more profound in early-onset (severe) PE (119.63+/-45.860 MUM) compared to that of late-onset (mild) disease (62.44+/-40.44 MUM) with P<0.001, indicating a more severe vascular endothelial cell dysfunction in the early-onset disease. CONCLUSION: This study has determined a profound NO upregulation in PE evidenced by significant elevation of NO metabolite levels compared to normal pregnancy. This might be due to deranged endothelial function with dysregulated production of NO to restore the persistent hypertension characteristic of PE. PMID- 25733926 TI - Afatinib for the treatment of metastatic non-small cell lung cancer. AB - Targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harboring sensitizing mutations in the tyrosine kinase (TKI) domain has led to a significant change in the management of this disease. The classic or sensitizing mutations are G719X mutation in exon 18, in-frame deletions or insertion of exon 19, L858R or L861Q mutation in exon 21. Approximately 90% of these mutations are exon 19 deletion or exon 21 L858R point mutation. Gefitinib and erlotinib are reversible first-generation inhibitors of mutant EGFR, and treatment with these agents in the first-line setting has demonstrated a progression-free survival of 9.5-13.7 months. However, the majority of these patients ultimately develop resistance to these drugs. Afatinib is an irreversible pan-ErbB inhibitor that was developed to circumvent the problem of resistance to first-generation TKIs. The LUX-Lung studies have evaluated the efficacy and toxicities of afatinib in treatment-naive and refractory NSCLC patients. The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib causes toxicities similar to those of the first-generation EGFR TKIs, such as diarrhea, rash, acne, and stomatitis, and overall is well tolerated. This article focuses on the clinical studies of afatinib in patients with NSCLC. PMID- 25733927 TI - L-carnitine supplementation in patients with HIV/AIDS and fatigue: a double blind, placebo-controlled pilot study. AB - BACKGROUND: The purpose of this study was to determine the effect of L-carnitine supplementation on fatigue in patients with terminal human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, patients who had end-stage HIV/AIDS with carnitine deficiency and fatigue received 3 g of oral L-carnitine or placebo for 2 weeks, followed by a 2-week, open-label phase with the same amount of L-carnitine for all patients. The primary outcome was the degree of fatigue according to the Brief Fatigue Inventory. Secondary outcomes included serum carnitine and lactate levels, physical, emotional, social, and functional well-being, performance status, mood, and CD4 count. RESULTS: Eighteen patients in the treatment arm and 17 in the placebo arm completed the trial. At the end of the double-blind phase, total and free carnitine levels in the treatment arm rose from 28+/-9 to 48+/-17 nM/L (P<0.001) and from 24+/-8 to 40+/ 13 nM/L (P<0.001) respectively, with no changes in the placebo arm. The primary outcome, ie, fatigue measured at the end of the blinded phase, did not improve. Secondary outcomes of function, quality of life, and mood did not show improvement either. The secondary outcome of serum lactate decreased from baseline in the treatment group (1.45+/-0.76 to 1.28+/-0.52 mmol/L) and increased in the placebo group (1.38+/-0.62 to 1.84+/-0.74 mmol/L; P<0.005). CONCLUSION: Our study suggests that 3 g of oral L-carnitine supplementation for 2 weeks in terminally ill HIV/AIDS patients does not improve fatigue. This study might help to determine the dose and duration of treatment used in future clinical trials, as higher doses and/or longer periods of supplementation might be needed in order to detect an improvement. The reduction in serum lactate levels suggests a potential role for L-carnitine supplementation in patients undergoing certain types of antiretroviral therapy. This study contributes evidence-based data to the field of alternative and complementary medicine, a multibillion dollar industry in which controlled studies are not the norm. PMID- 25733928 TI - Transvaginal retropubic sling systems: efficacy and patient acceptability. AB - Stress urinary incontinence is a common, disabling, and costly medical problem that affects approximately 50% of women with urinary incontinence. Suburethral retropubic slings have been developed as a minimally invasive and effective surgical option, and they have been used as a first-line treatment for stress urinary incontinence since 1995. However, complications including vaginal extrusion, erosion, pain, bleeding, infections, lower urinary tract symptoms, urinary retention, and incontinence have been reported with use of the slings. Several companies manufacture sling kits, and the sling kits vary with regard to the composition of the mesh and introducer needle. The aim of this review was to determine which sling kit was most effective for patients, had minimal reported side effects, and was best accepted by patients and surgeons. In a review of the literature, it was found that a total of 38 studies were published between 1995 and 2014 that reported on eight tension-free retropubic sling kits: SPARC, RetroArc, Align, Advantage, Lynx, Desara, Supris, and Gynecare TVT. The Gynecare TVT was the most cited sling kit; the second most cited was the SPARC. This review provides a summary of the studies that have examined positive and negative outcomes of the retropubic tension-free suburethral sling procedure using various sling kits. Overall, the results of the literature review indicated that data from comparisons of the available sling kits are insufficient to make an evidenced-based recommendation. Therefore, the decision regarding which sling kit is appropriate to use in surgery is determined by the medical provider's preference, training, and past experience, and not by the patient. PMID- 25733929 TI - Health education during antenatal care: the need for more. AB - The aim of health education during antenatal is to provide advice, education, reassurance and support, to address and treat the minor problems of pregnancy, and to provide effective screening during the pregnancy. Exploring current practices in this regard revealed the need for more organized educational activities to ensure high quality and clients satisfaction. PMID- 25733930 TI - Vaginal Lactobacillus: biofilm formation in vivo - clinical implications. AB - Vaginal lactobacilli provide protection against intrusive pathogenic bacteria. Some Lactobacillus spp. produce in vitro a thick, protective biofilm. We report in vivo formation of biofilm by vaginal Lactobacillus jensenii. The biofilm formation was captured in fresh wet-mount microscopic samples from asymptomatic patients after treatment for recurrent bacterial vaginitis. In vivo documentation of biofilm formation is in our opinion noteworthy, and has significant clinical implications, among which are the possibility to isolate, grow, and therapeutically utilize lactobacilli to prevent recurrent vaginal infections and preterm labor associated with vaginal microbial pathogens. PMID- 25733931 TI - What health service support do families need for optimal breastfeeding? An in depth exploration of young infant feeding practices in Cambodia. AB - BACKGROUND: Appropriate and timely breastfeeding practices markedly improve lifelong health outcomes for newborns, children, and mothers. Exclusive breastfeeding is reported to be widely practiced in Cambodia, and important progress has been made toward achieving improved child health outcomes, but newborn mortality has been slow to reduce and breastfeeding practices remain suboptimal. METHODS: Formative research was conducted in Takeo province, Cambodia to describe the practical, cultural, and social factors underlying current breastfeeding behaviors to inform the design of a newborn survival intervention that may improve breastfeeding. In-depth interviews, observations, a collection of visual media, and focus groups were employed to gather qualitative data. RESULTS: The results revealed knowledge and practice gaps in behavior that likely contribute to breastfeeding barriers, particularly in the areas of infant latch, milk production, feeding frequency, and the use of breast milk substitutes. The predominant theme identified in the research was a dearth of detailed information, advice, and counseling for mothers beyond the message to exclusively breastfeed for 6 months. CONCLUSION: Future newborn survival interventions and postnatal care counseling in this area must go beyond the exclusive breastfeeding message. To achieve further impact, it will be necessary to disseminate comprehensive and locally appropriate information on breastfeeding and to improve counseling in order to support successful breastfeeding and to contribute to population-level health gains. PMID- 25733932 TI - Look-alike, sound-alike medication errors: a novel case concerning a Slow-Na, Slow-K prescribing error. AB - A 59-year-old man was mistakenly prescribed Slow-Na instead of Slow-K due to incorrect selection from a drop-down list in the prescribing software. This error was identified by a pharmacist during a home medicine review (HMR) before the patient began taking the supplement. The reported error emphasizes the need for vigilance due to the emergence of novel look-alike, sound-alike (LASA) drug pairings. This case highlights the important role of pharmacists in medication safety. PMID- 25733933 TI - Superior mesenteric artery syndrome: a unique complication following carboplatin based chemotherapy. AB - Superior mesenteric artery syndrome (SMAS) is an uncommon condition, attributable to vascular compression of the third part of the duodenum between the superior mesenteric artery and the abdominal aorta. It can present in patients due to mechanical compression or severe weight loss. We present a unique case of SMAS in a patient undergoing carboplatin-based chemotherapy for mesothelioma. An 81-year old male with mesothelioma was treated with carboplatin-based chemotherapy. He subsequently suffered a progressive, unintentional 18 kg weight loss and presented acutely with intense epigastric pain, severe nausea, and vomiting. Diagnosis was confirmed by abdominal computed tomography and esophagogram with upper gastrointestinal series, which revealed gastric and duodenal distention and a narrow angle between the superior mesenteric artery and aorta, causing compression of the duodenum. Prompt recognition of this syndrome allowed us to treat our patient successfully and avoid the risks of operative interventions. To our knowledge, this is the first reported case of SMAS in patients receiving carboplatin. Furthermore, this case of SMAS was unique in that it was due to weight loss as compared with mechanical obstruction. Our experience illustrates the importance of considering SMAS in chemotherapy patients, especially those with substantial weight loss. A high index of suspicion for this potential complication coupled with appropriate radiographic studies are necessary for early diagnosis and can prevent severe consequences. PMID- 25733934 TI - Severe iatrogenic bradycardia related to the combined use of beta-blocking agents and sodium channel blockers. AB - PURPOSE: Drug-induced bradycardia is common during antiarrhythmic therapy; the major culprits are beta-blockers. However, whether other antiarrhythmic drugs are also a significant cause of this, alone or in combination with beta-blockers, is not well known. METHODS: We retrospectively investigated the records of all patients hospitalized at our institution for drug-related bradycardia from the years 2004 to 2012. Patients with cardiac disease and electrolytic or hormonal abnormalities that could cause bradyarrhythmias were excluded. RESULTS: Eight patients were identified (mean age, 79+/-5 years; range, 71-85 years; 6 women). Three patients were taking only beta-blockers (hereafter referred to as the BB group), while five patients were on both beta-blockers and Na channel blockers (hereafter referred to as the BB + Na group). Heart rates ranged from 20~49 beats/minute on arrival. The initial electrocardiogram showed sinus bradycardia (n=6) or sinus arrest with escape beats (n=2). QRS duration was 80-100 ms. The clinical presentation of the BB + Na group was considerably worse than that of the BB group, and included cardiogenic shock and heart failure. Four of the BB + Na patients had been on their medications for over 300 days. The BB group recovered solely with drug discontinuation, while 4 of the 5 patients in the BB + Na group needed additional treatments, such as intravenous administration of atropine or adrenergic agonist and temporary pacing. Bradycardia did not recur during follow-up (median, 687 days). CONCLUSION: Although wide QRS ventricular tachyarrhythmia is a better known proarrhythmic effect of Na channel blockers, life-threatening bradycardia may also occur in combination with beta-blockers in the elderly, even months after the start of medication, and at plasma concentrations that do not prolong QRS width. PMID- 25733935 TI - Localization for robotic capsule looped by axially magnetized permanent-magnet ring based on hybrid strategy. AB - To actively maneuver a robotic capsule for interactive diagnosis in the gastrointestinal tract, visualizing accurate position and orientation of the capsule when it moves in the gastrointestinal tract is essential. A possible method that encloses the circuits, batteries, imaging device, etc into the capsule looped by an axially magnetized permanent-magnet ring is proposed. Based on expression of the axially magnetized permanent-magnet ring's magnetic fields, a localization and orientation model was established. An improved hybrid strategy that combines the advantages of particle-swarm optimization, clone algorithm, and the Levenberg-Marquardt algorithm was found to solve the model. Experiments showed that the hybrid strategy has good accuracy, convergence, and real time performance. PMID- 25733936 TI - Bone bruises in anterior cruciate ligament injured knee and long-term outcomes. A review of the evidence. AB - BACKGROUND: Bone bruises are frequently associated with anterior cruciate ligament (ACL) tears as a result of trauma or direct shear stress of the bone. PURPOSE: To review the evidence regarding the characteristics of the bone bruise associated with ACL tears, its relevance on clinical outcomes, and its progression over time. In particular, the long-term effects of the bone bruise on the knee osteochondral architecture and joint function were evaluated. STUDY DESIGN: Review; level of evidence: 4. METHODS: An electronic search was performed on PubMed. Combinations of keywords included: "bone bruise AND knee"; "bone bruise AND anterior cruciate ligament"; "bone bruise AND osteo-chondral defects". Any level of evidence studies concerning bone bruises in patients with partial or complete ACL tears were retrieved. RESULTS: A total of 25 studies were included; three of them investigated biomechanical parameters, seven were concerned with clinical outcomes, and 15 were radiological studies. Evaluation of the bone bruise is best performed using a fat-saturated T2-weighted fast spin echo exam or a short tau inversion recovery sequence where fat saturation is challenging. The location of the injury has been demonstrated to be more frequent in the lateral compartment of the joint (lateral femoral condyle and lateral tibial plateau). It is associated with ACL tears in approximately 70% of cases, often with collateral ligament or meniscal tears. Mid- and long-term outcomes demonstrated a complete healing of the marrow lesions at magnetic resonance imaging, but chondral defects detected with T1rho sequences are still present 1 year after the ACL injury. Functional examination of the knee, through clinical International Knee Documentation Committee scores, did not show any correlation with the bone bruise. CONCLUSION: Although bone bruise presence yields to higher pain levels, no correlation with functional outcomes was reported. Most studies have a short term follow-up (<2 years) compared to the length of time it takes to develop post traumatic osteoarthritis, so it still remains unclear whether the initial joint injury and bone bruise have a direct relationship to long-term function. PMID- 25733937 TI - The evolution of cognitive-behavioral therapy for psychosis. AB - Cognitive therapy for psychosis has developed over the past 30 years from initial case studies, treatment manuals, pilot randomized controlled studies to fully powered and methodologically rigorous efficacy and, subsequently, effectiveness trials. Reviews and meta-analyses have confirmed the benefits of the interventions. Considered appraisal by government and professional organizations has now led to its inclusion in international treatment guidelines for schizophrenia. Patients consistently ask for access to psychotherapeutic interventions, and it is slowly becoming available in many European countries and other parts of the world, eg, US and the People's Republic of China. However, it remains unacceptably difficult to access for the vast majority of people with psychosis who could benefit from it. Psychosis affects people in the prime of their lives and leads to major effects on their levels of distress, well-being, and functioning, and also results in major costs to society. Providing effective interventions at an early stage has the potential to reduce the high relapse rates that occur after recovery from first episode and the ensuing morbidity and premature mortality associated with psychosis. PMID- 25733938 TI - Necrotizing fasciitis: risk factors of mortality. AB - BACKGROUND: Necrotizing fasciitis (NF) is a serious infection of skin and soft tissues that rapidly progresses along the deep fascia. It becomes a fatal soft tissue infection with high mortality rate if treatment is delayed. Early diagnosis for emergency surgical debridement and broad-spectrum antibiotic therapy were the optimal treatments to reduce the mortality rate of NF. OBJECTIVE: The aim of this study was to identify risk factors that increased the mortality rate in patients with NF under routine clinical practices. METHODS: A retrospective cohort study was performed at three general hospitals located in northern Thailand. All medical records of patients with surgically confirmed NF treated between January 2009 and December 2012 were reviewed. Clinical predictors for mortality were analyzed using multivariable risk regression analysis. RESULTS: Of a total of 1,504 patients with a diagnosis of NF, 19.3% (n=290) died in hospital and 80.7% (n=1,214) survived. From multivariable analysis, being female (risk ratio [RR] =1.37, 95% confidence interval [CI] =1.01-1.84); age >60 (RR=1.39, 95% CI =1.25-1.53); having chronic heart disease (RR=1.64, 95% CI=1.18 2.28), cirrhosis (RR =2.36, 95% CI=1.70-3.27), skin necrosis (RR =1.22, 95% CI=1.15-1.28), pulse rate >130/min (RR =2.26, 95% CI=1.79-2.85), systolic BP <90 mmHg (RR =2.05, 95% CI =1.44-2.91), and serum creatinine >=1.6 mg/dL (RR=3.06, 95% CI=2.08-4.50) were risk factors for mortality. CONCLUSION: Prognostic factors for mortality in NF patients included being female; age >60; or having chronic heart disease, cirrhosis, skin necrosis, pulse rate >130/min, systolic BP <90 mmHg, and serum creatinine >=1.6 mg/dL. Thus, disease progression to mortality may occur in such patients presenting one of these risk factors. Further examination or close monitoring for systemic involvement may be advantageous to reduce morbidity and mortality. PMID- 25733939 TI - The Human Genome Project, and recent advances in personalized genomics. AB - The language of "personalized medicine" and "personal genomics" has now entered the common lexicon. The idea of personalized medicine is the integration of genomic risk assessment alongside other clinical investigations. Consistent with this approach, testing is delivered by health care professionals who are not medical geneticists, and where results represent risks, as opposed to clinical diagnosis of disease, to be interpreted alongside the entirety of a patient's health and medical data. In this review we consider the evidence concerning the application of such personalized genomics within the context of population screening, and potential implications that arise from this. We highlight two general approaches which illustrate potential uses of genomic information in screening. The first is a narrowly targeted approach in which genetic profiling is linked with standard population-based screening for diseases; the second is a broader targeting of variants associated with multiple single gene disorders, performed opportunistically on patients being investigated for unrelated conditions. In doing so we consider the organization and evaluation of tests and services, the challenge of interpretation with less targeted testing, professional confidence, barriers in practice, and education needs. We conclude by discussing several issues pertinent to health policy, namely: avoiding the conflation of genetics with biological determinism, resisting the "technological imperative", due consideration of the organization of screening services, the need for professional education, as well as informed decision making and public understanding. PMID- 25733940 TI - How do disease perception, treatment features, and dermatologist-patient relationship impact on patients assuming topical treatment? An Italian survey. AB - BACKGROUND: Psoriasis largely affects daily activities and social interactions and has a strong impact on patients' quality of life. Psoriatic patients have different attitudes toward their condition. Topical medications are essential for the treatment of psoriasis, but the majority of patients do not adhere to these therapies. OBJECTIVE: The history of treatment success or failure seems to influence patient attitude toward topical therapy. Therefore, it is important to understand the psychological, experiential, and motivational aspects that could be critical for treatment adherence, and to describe the different attitudes toward topical treatment. Furthermore, the physician-patient relationship and the willingness to trust the dermatologist may have a substantial role in encouraging or discouraging patients' attitudes toward topical therapy. METHODS: A survey was designed to collect aspects that could be relevant to understanding different patient attitudes toward psoriasis and its treatments. A total of 495 self administered questionnaires compiled by psoriatic patients were analyzed from 20 Italian specialized hospital centers in order to provide a nationwide picture. RESULTS: Psoriatic patients have different perceptions and experiences in relation to their condition: half of them consider psoriasis as a disease, while the other half consider psoriasis as a disorder or a nuisance. Topical therapy is the most widely used treatment, even though it is not considered the most effective one and often perceived to be cosmetic. The main findings are: 1) inadequate patient education about this disease, 2) lack of information about topical treatment, and 3) lack of results within the expected time frame. Furthermore, physicians need to build a good relationship with psoriatic patients in order to motivate them, to trust in their care, and to adhere to treatment. CONCLUSION: This survey adds new and important details about daily life and well being and the needs of psoriatic patients, providing suggestions for dermatologists to improve patients management. PMID- 25733941 TI - Quality of life in adolescent and young adult cancer patients: a systematic review of the literature. AB - INTRODUCTION: Adolescent and young adult (AYA) cancer survivors experience many unique challenges and quality of life (QoL) effects that persist beyond cancer diagnosis and treatment. Due to continuous improvements in technology and cancer treatments resulting in improved survival rates, the identification of late effects, survivorship issues, and QoL is moving to the forefront of cancer research. The goal of this systematic review was to identify key psychosocial factors impacting QoL in AYA oncology populations. METHODS: A systematic review of the literature was conducted using combinations of these phrases or keywords: "adolescent and young adult or AYA" AND "health outcomes OR quality of life OR psychology" AND "neoplasm OR cancer OR oncology". A total of 35 articles were included in this review. Studies were classified into two categories: AYA perceptions and stakeholder perceptions. RESULTS: AYA cancer survivors were more likely to have "worse" or impaired QoL compared with the general population, regardless of other demographic factors. AYAs described both positive and negatives experiences with their medical care, the educational information received, and the supportive care services. Although health care professionals were likely to underestimate or misjudge the health preferences and support needs of AYAs, these perceptions varied across disciplines and levels of experience. CONCLUSION: The literature is lacking in sufficient evidence-based interventions to improve QoL in AYA cancer populations. Further, the tools to adequately measure QoL in this population are also unsatisfactory. The literature, however, consistently shows agreement regarding the unique needs of this population, indicating a trend toward health care standardization within age ranges or life stages. We suggest the need for AYA-specific programs in health care institutions that comprise a multidisciplinary team that addresses all the unique medical and QoL needs of AYAs. PMID- 25733942 TI - Cost-effectiveness analysis of antiretroviral therapy in a cohort of HIV-infected patients starting first-line highly active antiretroviral therapy during 6 years of observation. AB - OBJECTIVES: Costs may play a role in deciding how and when to start highly active antiretroviral therapy (HAART) in a naive patient. The aim of the present study was to assess the cost- effectiveness of treatment with HAART in a large clinical cohort of naive adults to determine the potential role of single-tablet regimens in the management of patients with human immunodeficiency virus (HIV). An incremental cost-effectiveness ratio analysis was performed, including a quality adjusted life year approach. RESULTS: In total, 741 patients (females comprising 25.5%) were retrospectively included. The mean age was 39 years, the mean CD4 cell count was 266 cells/MUL, and the mean viral load was 192,821 copies/mL. The most commonly used backbone was tenofovir + emtricitabine (77.6%); zidovudine + lamivudine was used in 10%, lamivudine + abacavir in 3%, and other nucleoside reverse transcriptase inhibitor (NRTI) or NRTI-free regimens in 9.4% of patients. NNRTIs were used in 52.8% of cases, boosted protease inhibitors in 44.1%, and unboosted protease inhibitors and integrase inhibitors in 0.7% and 2.4%, respectively. Starting therapy at CD4 >500 cells/MUL and CD4 351-500 cells/MUL rather than at <201 cells/MUL was the more cost-effective approach. The same consideration was not true comparing current indications with the possibility to start HAART at any CD4 value (eg, >500 cells per MUL); in this case, the incremental cost-effectiveness ratio value was ?199,130 per quality-adjusted life year gained, a higher value than the one suggested in guidelines. The single tablet regimen (STR) invariably dominated any other therapeutic approach. Sensitivity analysis was performed, and starting right away with an STR was cost effective even when compared with therapeutic strategies contemplating STR as simplification. CONCLUSION: By integrating clinical data with economic variables, our study offers an estimate of the cost-effectiveness of the various first-line treatment strategies for patients infected with HIV and provides significant evidence to be used in future prospective pharmacoeconomic evaluations. PMID- 25733944 TI - Young women selling sex online - narratives on regulating feelings. AB - The current study concerns young women's life stories of their experiences selling sex online before the age of 18. The aim was to gain an understanding of young women's perceptions of the reasons they started, continued, and stopped selling sex. The study included interviews with 15 young women between the ages of 15 and 25 (M=18.9). Thematic analysis was used to identify similarities and differences in the narratives. Three themes and eight sub-themes were identified in relation to different stages in their lives in the sex trade. The themes were organized into three parts, each with its own storyline: "Entering - adverse life experiences"; traumatic events: feeling different and being excluded. "Immersion using the body as a tool for regulating feelings"; being seen: being touched: being in control: affect regulation and self-harming. "Exiting - change or die"; living close to death: the process of quitting. The informants all had stable social lives in the sense that they had roofs over their heads, food to eat, and no substance-abuse issues. None had a third party who arranged the sexual contacts and none were currently trafficked. They described how their experiences of traumatic events and of feeling different and excluded had led them into the sex trade. Selling sex functioned as a way to be seen, to handle traumatic events, and to regulate feelings. Professionals working with young people who sell sex online need to understand the complex web of mixed feelings and emotional needs that can play a role in selling sex. Young people selling sex might need guidance in relationship building as well as help processing traumatic experiences and ending self-harming behavior. Further studies are needed on the functions of online sex selling and on the exit process for young people, in order to prevent entrance and facilitate exiting. PMID- 25733943 TI - Hematopoietic stem and progenitor cell harvesting: technical advances and clinical utility. AB - Hematopoietic stem and progenitor cell (HSPC) transplantations require prior harvesting of allogeneic or autologous HSPCs. HSPCs are usually present in bone marrow (BM) during the entire life, in cord blood (CB) at birth, or in peripheral blood (PB) under particular circumstances. HSPCs were first harvested in BM and later in CB and PB, as studies showed interesting features of such grafts. All harvesting methods were in use throughout the years, except BM harvesting for HSPC autologous transplantation, which was replaced by PB harvesting. BM, CB, and PB harvesting methods have been developed, and materials and devices technically improved to increase the number of HSPCs harvested. In parallel, knowing the features of the donors or patients associated with successful numbers of HSPCs allows the adaptation of appropriate harvesting methods. Moreover, it is important to ensure the safety of donors or patients while harvesting. This review describes the methods used for harvesting based on recent studies or developments around these methods, and more particularly, the means developed to increase the numbers of HSPCs harvested in each method. It also explains briefly the influence of technical improvements in HSPC harvesting on potential changes in HSPC graft composition. PMID- 25733945 TI - Biliary stent migration to hepatic duct-case report of a late complication. AB - Endoscopic retrieval of proximally migrated biliary plastic stents may be technically challenging and sometimes unsuccessful. Here we report the case of a 59-year-old woman with a migrated biliary stent in the right hepatic duct, which was diagnosed after the patient presented with cholangitis. The patient presented with constant abdominal pain in the right upper quadrant lasting for two days, along with nausea and bilious vomiting. The stent was retrieved by a polypectomy snare after failure of biliary basket and forceps. We performed a novel procedure for extraction of a migrated plastic stent, by using a polypectomy snare. PMID- 25733946 TI - Selective Neck Dissection (IIa, III): A Rational Replacement for Extended Supraomohyoid Neck Dissection in Patients with N0 Supraglottic and Glottic Squamous Cell Carcinoma. AB - OBJECTIVES: To evaluate the effectiveness of selective neck dissection of sublevel IIa and level III in cases of glottis and supraglottic laryngeal carcinoma in the absence of lymph node metastasis and to show if there is value in dissecting the sublevel IIb or level IV in these cases. PATIENTS AND METHODS: Twenty-five patients with N0 glottic or supraglottic cancer were subjected to unilateral or bilateral selective neck dissection according to the site and the extent of the tumor, and the specimens were histopathologically examined for metastasis. RESULTS: Twenty-five patients (23 males and 2 females) with mean age of 55.72 years were included in the study. Lymph node metastasis to sublevel IIa and level III was found in 6/25 (24%) cases with glottic or supraglottic carcinoma, while to sublevel IIb and level IV was found in 1/25 (4%) with P-value of 0.05, which is statistically significant. CONCLUSION: Selective neck dissection of level IIb is not required in cases of the supraglottic laryngeal cancer. Dissection of sublevel IIa and level III takes less time and is effective. Dissection of level IV is not needed in the case of supraglottic cancer. PMID- 25733947 TI - Unhealthy weight control practices: culprits and clinical recommendations. AB - Preoccupation with weight status and a desire to lose weight appears common. Many individuals seek "magic bullet" approaches to weight loss and waive the risks of using these products. In this paper, we review the challenges of weight maintenance, highlight some unhealthy weight control practices, and discuss the futility and potential danger of unregulated weight control agents. Novel clinical strategies are discussed that health care providers may use to triage patients with obesity in an attempt to make ethical and personalized treatment decisions. PMID- 25733948 TI - Summative assessment in a doctor of pharmacy program: a critical insight. AB - BACKGROUND: The Canadian-accredited post-baccalaureate Doctor of Pharmacy program at Qatar University trains pharmacists to deliver advanced patient care. Emphasis on acquisition and development of the necessary knowledge, skills, and attitudes lies in the curriculum's extensive experiential component. A campus-based oral comprehensive examination (OCE) was devised to emulate a clinical viva voce and complement the extensive formative assessments conducted at experiential practice sites throughout the curriculum. We describe an evaluation of the final exit summative assessment for this graduate program. METHODS: OCE results since the inception of the graduate program (3 years ago) were retrieved and recorded into a blinded database. Examination scores among each paired faculty examiner team were analyzed for inter-rater reliability and linearity of agreement using intraclass correlation and Spearman's correlation coefficient measurements, respectively. Graduate student ranking from individual examiner OCE scores was compared with that of other relative ranked student performance. RESULTS: Sixty one OCEs were administered to 30 graduate students over 3 years by a composite of eleven different pairs of faculty examiners. Intraclass correlation measures demonstrated that examiner team reliability was low and linearity of agreements was inconsistent. Only one examiner team in each respective academic year was found to have statistically significant inter-rater reliability, and linearity of agreements was inconsistent in all years. No association was found between examination performance rankings and other academic parameters. CONCLUSION: Critical review of our final summative assessment implies it is lacking robustness and defensibility. Measures are in place to continue the quality improvement process and develop and implement an alternative means of evaluation within a more authentic context. PMID- 25733949 TI - Nutrition guidelines for undergraduate medical curricula: a six-country comparison. AB - AIM: To assess nutrition curriculum guidelines for undergraduate medical education in the United States, Canada, the United Kingdom, Republic of Ireland, Australia, and New Zealand to highlight potential opportunities for shared learning on the advancement of nutrition in medical education. METHODS: A comprehensive list of professional bodies, councils, organizations, and other groups relevant to education or nutrition was compiled for each country after a review of relevant white and gray literature. All documents that were published from 2000 onwards, and that provided guidance on nutrition education within undergraduate medical education for one of the identified countries were included in the review. Each curriculum guideline was evaluated for 1) the organization's or group's role in undergraduate medical education; 2) the extent of nutrition related recommendations; and 3) mandatory implementation. RESULTS: In the countries reviewed, a total of six nutrition-related curriculum guidelines were identified. All countries, aside from the Republic of Ireland, currently have externally visible curriculum guidelines to inform medical schools in undergraduate nutrition education, yet there is little evidence of mandatory enforcement. Curriculum guidelines predominantly focus on basic nutrition principles, nutrition assessment, the role of nutrition in health, interdisciplinary teamwork, and the provision of nutrition counseling. Notable differences exist regarding the scope and detail of curriculum guidelines for the reviewed countries. CONCLUSION: There are promising developments in nutrition curriculum guidelines for medical schools within the reviewed countries. Differences in the scope and detail of nutrition curriculum guidelines may influence the nutrition education provided to medical students, and the subsequent nutrition care provided by doctors in these countries. Consideration is required as to how to monitor and evaluate the nutrition competence of doctors in relation to routine health care practices, as well as the impact of their competency levels on patients' nutrition behavior and health outcomes. PMID- 25733950 TI - Pursuit of the "truth" about mental illness: the significance of findings in neuropsychiatric research, and lessons from the past. AB - Technology in genetics and brain imaging has advanced so rapidly that it is difficult to be knowledgeable about all the new tools being used in the pursuit of progress toward understanding and treating mental illness. While findings from new studies remain promising, caution is needed with regard to their current applicability to clinical use, both to predict who is likely to become ill and who is likely to respond to medication. A perspective on the past, using schizophrenia as an example, illustrates important findings that were published, had much visibility, and caused a flurry of new related studies, but then slowly disappeared, either to be abandoned as an artifact of the assay or study design, an epiphenomenon, or as simply nonreplicated findings not leading to further progress. Remembering that good science is "the pursuit of the truth" and not joining the latest "bandwagon fad" of "believers" is an important principle to adhere to when participating in the politics of science. PMID- 25733951 TI - Prediction of treatment outcomes in psychiatry--where do we stand ? AB - Psychiatric treatment relies on a solid armamentarium of pharmacologic and nonpharmacologic treatment modalities that perform reasonably well for many patients but leave others in a state of chronic disability or troubled by problematic side effects. Treatment planning in psychiatry remains an art that depends on considerable trial and error. Thus, there is an urgent need for better tools that will provide a means for matching individual patients with the most effective treatments while minimizing the risk of adverse events. This review will consider the current state of the science in predicting treatment outcomes in psychiatry. Genetic and other biomarkers will be considered alongside clinical diagnostic, and family history data. Problems inherent in prediction medicine will also be discussed, along with recent developments that support the hope that psychiatry can do a better job in quickly identifying the best treatments for each patient. PMID- 25733952 TI - Computational modeling of drug response with applications to neuroscience. AB - The development of novel high-throughput technologies has opened up the opportunity to deeply characterize patient tissues at various molecular levels and has given rise to a paradigm shift in medicine towards personalized therapies. Computational analysis plays a pivotal role in integrating the various genome data and understanding the cellular response to a drug. Based on that data, molecular models can be constructed that incorporate the known downstream effects of drug-targeted receptor molecules and that predict optimal therapy decisions. In this article, we describe the different steps in the conceptual framework of computational modeling. We review resources that hold information on molecular pathways that build the basis for constructing the model interaction maps, highlight network analysis concepts that have been helpful in identifying predictive disease patterns, and introduce the basic concepts of kinetic modeling. Finally, we illustrate this framework with selected studies related to the modeling of important target pathways affected by drugs. PMID- 25733953 TI - Neuroimaging-based biomarkers for treatment selection in major depressive disorder. AB - The use of neuroimaging approaches to identify likely treatment outcomes in patients with major depressive disorder is developing rapidly. Emerging work suggests that resting state pretreatment metabolic activity in the fronto-insular cortex may distinguish between patients likely to respond to psychotherapy or medication and may function as a treatment-selection biomarker. In contrast, high metabolic activity in the subgenual anterior cingulate cortex may be predictive of poor outcomes to both medication and psychotherapy, suggesting that nonstandard treatments may be pursued earlier in the treatment course. Although these findings will require replication before clinical adoption, they provide preliminary support for the concept that brain states can be measured and applied to the selection of a specific treatment most likely to be beneficial for an individual patient. PMID- 25733954 TI - Neuroimaging biomarkers to predict treatment response in schizophrenia: the end of 30 years of solitude? AB - Studies that have used structural magnetic resonance imaging (MRI) suggest that individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, and in the white matter tracts that connect them. Furthermore, these studies suggest that brain alterations may be particularly prominent, already at illness onset, in those individuals more likely to have poorer outcomes (eg, higher number of hospital admissions, and poorer symptom remission, level of functioning, and response to the first treatment with antipsychotic drugs). The fact that, even when present, these brain alterations are subtle and distributed in nature, has limited, until now, the utility of MRI in the clinical management of these disorders. More recently, MRI approaches, such as machine learning, have suggested that these neuroanatomical biomarkers can be used for direct clinical benefits. For example, using support vector machine, MRI data obtained at illness onset have been used to predict, with significant accuracy, whether a specific individual is likely to experience a remission of symptoms later on in the course of the illness. Taken together, this evidence suggests that validated, strong neuroanatomical markers could be used not only to inform tailored intervention strategies in a single individual, but also to allow patient stratification in clinical trials for new treatments. PMID- 25733957 TI - Using biomarkers to predict treatment response in major depressive disorder: evidence from past and present studies. AB - Major depressive disorder (MDD) is a heterogeneous condition with a variable response to a wide range of treatments. Despite intensive efforts, no biomarker has been identified to date that can reliably predict response or non-response to any form of treatment, nor has one been identified that can be used to identify those at high risk of developing treatment-resistant depression (ie, non-response to a sequence of treatments delivered for adequate duration and intensity). This manuscript reviews some past areas of research that have proved informative, such as studies using indexes of hypercortisolism or sleep disturbance, and more recent research findings using measures of inflammation and different indicators of regional cortical activation to predict treatment response. It is concluded that, although no method has yet been demonstrated to be sufficiently accurate to be applied in clinical practice, progress has been made. It thus seems likely that--at some point in the not-too-distant future--it will be possible to prospectively identify, at least for some MDD patients, the likelihood of response or non-response to cognitive therapy or various antidepressant medications. PMID- 25733955 TI - Clinical predictors of therapeutic response to antipsychotics in schizophrenia. AB - The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available. PMID- 25733956 TI - Intermediate phenotypes and biomarkers of treatment outcome in major depressive disorder. AB - Major depressive disorder (MDD) is a pleomorphic illness originating from gene x environment interactions. Patients with differing symptom phenotypes receive the same diagnosis and similar treatment recommendations without regard to genomics, brain structure or function, or other physiologic or psychosocial factors. Using this present approach, only one third of patients enter remission with the first medication prescribed, and patients may take longer than 1 year to enter remission with repeated trials. Research to improve treatment effectiveness recently has focused on identification of intermediate phenotypes (IPs) that could parse the heterogeneous population of patients with MDD into subgroups with more homogeneous responses to treatment. Such IPs could be used to develop biomarkers that could be applied clinically to match patients with the treatment that would be most likely to lead to remission. Putative biomarkers include genetic polymorphisms, RNA and protein expression (transcriptome and proteome), neurotransmitter levels (metabolome), additional measures of signaling cascades, oscillatory synchrony, neuronal circuits and neural pathways (connectome), along with other possible physiologic measures. All of these measures represent components of a continuum that extends from proximity to the genome to proximity to the clinical phenotype of depression, and there are many levels along this continuum at which useful IPs may be defined. Because of the highly integrative nature of brain systems and the complex neurobiology of depression, the most useful biomarkers are likely to be those with intermediate proximity both to the genome and the clinical phenotype of MDD. Translation of findings across the spectrum from genotype to phenotype promises to better characterize the complex disruptions in signaling and neuroplasticity that accompany MDD, and ultimately to lead to greater understanding of the causes of depressive illness. PMID- 25733958 TI - Prediction of individual response to antidepressants and antipsychotics: an integrated concept. AB - In both clinical trials and daily practice, there can be substantial inter- and even intraindividual variability in response--whether beneficial or adverse--to antidepressants and antipsychotic medications. So far, no tools have become available to predict the outcome of these treatments in specific patients. This is because the causes of such variability are often not known, and when they are, there is no way of predicting the effects of their various potential combinations in an individual. Given this background, this paper presents a conceptual framework for understanding known factors and their combinations so that eventually clinicians can better predict what medication(s) to select and at what dose they can optimize the outcome for a given individual. This framework is flexible enough to be readily adaptable as new information becomes available. The causes of variation in patient response are grouped into four categories: (i) genetics; (ii) age; (iii) disease; and (iv) environment (internal). Four cases of increasing complexity are used to illustrate the applicability of this framework in a clinically relevant way In addition, this paper reviews tools that the clinician can use to assess for and quantify such inter- and intraindividual variability. With the information gained, treatment can be adjusted to compensate for such variability, in order to optimize outcome. Finally, the limitations of existing antidepressant and antipsychotic therapy and the way they reduce current ability to predict response is discussed. PMID- 25733961 TI - The collection of the Herpetological Museum of the University of Antioquia (northwestern Colombia). AB - Northwestern South America harbors one of the richest herpetofauna in the world. The connection among several biogeographic provinces along with climatic and orographic complexity makes this region an important contributor to the Neotropical biodiversity. Despite of this importance, the amphibian and reptile fauna in this area remains largely unknown as few herpetological collections has been made in recent decades. Motivated by this, the Herpetological Museum at the Universidad de Antioquia (Medellin, Colombia) has been increasing the collection in the last 16 years to better understand the herpetofaunal diversity and thus contribute to ecological, systematic, biogeographic and conservation research in the Neotropics. Here, we present the results of this effort and highlight how future collection will impact our understanding of the Neotropical herpetofauna. PMID- 25733960 TI - Ethical and public policy challenges for pharmacogenomics. AB - It is timely to consider the ethical and social questions raised by progress in pharmacogenomics, based on the current importance of pharmacogenomics for avoidance of predictable side effects of drugs, and for correct choice of medications in certain cancers. It has been proposed that the entire population be genotyped for drug-metabolizing enzyme polymorphisms, as a measure that would prevent many untoward and dangerous drug reactions. Pharmacologic treatment targeting based on genomics of disease can be expected to increase greatly in the coming years. Policy and ethical issues exist on consent for large-scale genomic pharmacogenomic data collection, public vs corporate ownership of genomic research results, testing efficacy and safety of drugs used for rare genomic indications, and accessibility of treatments based on costly research that is applicable to relatively few patients. In major psychiatric disorders and intellectual deficiency, rare and de novo deletion or duplication of chromosomal segments (copy number variation), in the aggregate, are common causes of increased risk. This implies that the policy problems of pharmacogenomics will be particularly important for the psychiatric disorders. PMID- 25733959 TI - Pharmacogenetics and outcome with antipsychotic drugs. AB - Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future. PMID- 25733962 TI - Fauna europaea: Diptera - brachycera. AB - Fauna Europaea provides a public web-service with an index of scientific names (including important synonyms) of all extant multicellular European terrestrial and freshwater animals and their geographical distribution at the level of countries and major islands (east of the Urals and excluding the Caucasus region). The Fauna Europaea project comprises about 230,000 taxonomic names, including 130,000 accepted species and 14,000 accepted subspecies, which is much more than the originally projected number of 100,000 species. Fauna Europaea represents a huge effort by more than 400 contributing taxonomic specialists throughout Europe and is a unique (standard) reference suitable for many user communities in science, government, industry, nature conservation and education. The Diptera-Brachycera is one of the 58 Fauna Europaea major taxonomic groups, and data have been compiled by a network of 55 specialists. Within the two-winged insects (Diptera), the Brachycera constitute a monophyletic group, which is generally given rank of suborder. The Brachycera may be classified into the probably paraphyletic 'lower brachyceran grade' and the monophyletic Eremoneura. The latter contains the Empidoidea, the Apystomyioidea with a single Nearctic species, and the Cyclorrhapha, which in turn is divided into the paraphyletic 'aschizan grade' and the monophyletic Schizophora. The latter is traditionally divided into the paraphyletic 'acalyptrate grade' and the monophyletic Calyptratae. Our knowledge of the European fauna of Diptera-Brachycera varies tremendously among families, from the reasonably well known hoverflies (Syrphidae) to the extremely poorly known scuttle flies (Phoridae). There has been a steady growth in our knowledge of European Diptera for the last two centuries, with no apparent slow down, but there is a shift towards a larger fraction of the new species being found among the families of the nematoceran grade (lower Diptera), which due to a larger number of small-sized species may be considered as taxonomically more challenging. Most of Europe is highly industrialised and has a high human population density, and the more fertile habitats are extensively cultivated. This has undoubtedly increased the extinction risk for numerous species of brachyceran flies, yet with the recent re discovery of Thyreophoracynophila (Panzer), there are no known cases of extinction at a European level. However, few national Red Lists have extensive information on Diptera. For the Diptera-Brachycera, data from 96 families containing 11,751 species are included in this paper. PMID- 25733963 TI - Description of male Tyloridasataraensis Kulkarni, 2014 (Araneae, Tetragnathidae) with notes on habits and conservation status. AB - The male sex of Tyloridasataraensis Kulkarni, 2014 is described based on specimens from the type locality. The distinguishing characters from its closest species Tyloridaventralis (Thorell, 1877) are detailed. An interesting behaviour of going underwater by T.sataraensis, on disturbance is recorded and tested for significance. The surveys have shown sighting of this species only to the perennial streams of the rocky outcrops in Satara region. The potential threats to this species and the possible conservation status based on known distribution are discussed. PMID- 25733964 TI - An exhaustive inventory of coniferous trees in an agricultural landscape. AB - BACKGROUND: Various species of forest trees are commonly used for ornamental purposes and are therefore frequently found in non-forest ecosystems. These trees constitute a significant component of the trees outside forests (TOF). Although increasingly recognized as prominent feature of agricultural lands and built-up areas, not much is known, however, about TOF since they are generally absent from forest inventories. NEW INFORMATION: In the present study, we focus on the coniferous tree species that constitute potential hosts for a forest defoliator, the pine processionary moth Thaumetopoeapityocampa Den. & Schiff. (Lepidoptera, Notodontidae). We carried out an exhaustive inventory of all pines (Pinus spp.), cedars (Cedrus spp.) and Douglas-fir (Pseudotsugamenziesii) in a 22 * 22 km study window located in the open-field region of Beauce in the centre of France. We recorded a total of 3834 individuals or small groups host trees corresponding a density of 7.9 occurrences per 100 ha. We provide the spatial coordinates of the points without differentiation between tree species. PMID- 25733966 TI - Dr. James w. Fleshman and dr. Warren e. Lichliter. PMID- 25733967 TI - Rectal cancer. PMID- 25733965 TI - Single-cell transcriptogenomics reveals transcriptional exclusion of ENU-mutated alleles. AB - Recently, great progress has been made in single cell genomics and transcriptomics. Here, we present an integrative method, termed single-cell transcriptogenomics (SCTG), in which whole exome sequencing and RNA-seq is performed concurrently on single cells. This methodology enables one to track germline and somatic variants directly from the genome to the transcriptome in individual cells. Mouse embryonic fibroblasts were treated with the powerful mutagen ethylnitrosourea (ENU) and subjected to SCTG. Interestingly, while germline variants were found to be transcribed in an allelically balanced fashion, a significantly different pattern of allelic exclusion was observed for ENU-mutant variants. These results suggest that the adverse effects of induced mutations, in contrast to germline variants, may be mitigated by allelically biased transcription. They also illustrate how SCTG can be instrumental in the direct assessment of phenotypic consequences of genomic variants. PMID- 25733968 TI - Current concepts in rectal cancer. AB - The history of rectal cancer management informs current therapy and points us in the direction of future improvements. Multidisciplinary team management of rectal cancer will move us to personalized treatment for individuals with rectal cancer in all stages. PMID- 25733969 TI - Utilizing the multidisciplinary team for planning and monitoring care and quality improvement. AB - Multidisciplinary team management of patients with rectal cancer requires a dedicated group of surgeons, medical and radiation oncologists, pathologists, radiologists, and mid-level providers who meet to discuss every patient with rectal cancer. The data from that meeting is collected prospectively, recommendations made for case, follow-up obtained, and quality issues monitored. Improved case is the result. PMID- 25733970 TI - Techniques in total mesorectal excision surgery. AB - Advances in the surgical management of rectal cancer have placed the quality of total mesorectal excision (TME) as the major predictor in overall survival. A standardized TME technique along with quality increases the percentage of patients undergoing a complete TME. Quality measurements of TME will place increasing demands on surgeons maintaining competence with present and future techniques. These efforts will improve the outcome of the rectal cancer patients. PMID- 25733971 TI - Changing the Way We Manage Rectal Cancer-Standardizing TME from Open to Robotic (Including Laparoscopic). AB - Standardizing total mesorectal excision (TME) has been a topic of interest since 1979 when Professor Richard J. Heald first described TME and a new approach to rectal cancer. The procedure is optimized only if every one of the relevant factors is tackled with precise attention to detail, so that the preoperative, operative, and postoperative practice is standardized completely. The same concept of TME standardization applies today regardless of technique chosen, that is, open laparoscopic, single-incision laparoscopic surgery, or robotic. This article reviews the relevant operative factors in performing a quality TME, looking at both the oncologic and nononcologic advantages and disadvantages. It supports TME as the standard of care in obtaining a negative circumferential margin for mid and lower-third rectal cancers, and discusses the role of tumor specific mesorectal excision for upper-third rectal cancers. It discusses the new options and challenges each operative technique holds, and identifies the same standardized principles each must obey to provide the highest quality of oncologic resection. The operative documentation of these critical features from diagnostic workup to pathological reporting is also emphasized. PMID- 25733972 TI - Replacing Transanal Excision with Transanal Endoscopic Microsurgery and/or Transanal Minimally Invasive Surgery for Early Rectal Cancer. AB - The use of local resection of rectal polyps and early rectal cancer has progressed to become the standard of care in most institutions with a colorectal surgery specialist. The use of transanal excision (TAE) with anorectal retractors and standard instrumentation has been supplanted by the application of endoscopic techniques which allow direct video augmented visualization. The transanal endoscopic microsurgery method provides a 3D view and works under a constant flow of air to keep the rectal vault open. Instruments capable of accomplishing a surgical excision and suture closure work through a long 4 cm tube set at the anal canal. The newest version of TAE is transanal minimally invasive surgery which is similar to a single-site laparoscopic technique using a hand access port at the anal canal to maintain a seal for insufflation of the rectum, regular 2D video camera for visualization, and laparoscopic instrumentation through the port in the anus. Each of these techniques is described in detail and the outcomes compared, which show the progress being made in this area of colorectal surgery. PMID- 25733973 TI - Pathologic processing of the total mesorectal excision. AB - Total mesorectal excision (TME) is the current optimal surgical treatment for patients with rectal carcinoma. A complete TME is related to lower local recurrence rates and increased patient survival. Many confounding factors in the patient's anatomy and prior therapy can make it difficult to obtain a perfect plane, and thus a complete TME. The resection specimen can be thoroughly evaluated, grossly and microscopically, to identify substandard surgical outcomes and increased risk of local recurrence. Complete and accurate data reporting is critical for patient care and helps surgeons improve their technique. PMID- 25733974 TI - The molecular basis of rectal cancer. AB - The majority of rectal carcinomas are sporadic in nature, and relevant testing for driver mutations to guide therapy is important. A thorough family history is necessary and helpful in elucidating a potential hereditary predilection for a patient's carcinoma. The adequate diagnosis of a heritable tendency toward colorectal carcinoma alters the management of a patient disease and permits the implementation of various surveillance algorithms as preventive measures. PMID- 25733975 TI - SALMO and S3M: A Saliva Model and a Single Saliva Salt Model for Equilibrium Studies. AB - A model of synthetic saliva (SALMO, SALiva MOdel) is proposed for its use as standard medium in in vitro equilibrium and speciation studies of real saliva. The concentrations come out from the literature analysis of the composition of both real saliva and synthetic saliva. The chief interactions of main inorganic components of saliva, as well as urea and amino acids, are taken into account on the basis of a complex formation model, which also considers the dependence of the stability constants of these species on ionic strength and temperature. These last features allow the modelling of the speciation of saliva in different physiological conditions deriving from processes like dilution, pH, and temperature changes. To simplify equilibrium calculations, a plain approach is also proposed, in order to take into account all the interactions among the major components of saliva, by considering the inorganic components of saliva as a single 1 : 1 salt (MX), whose concentration is c MX = (1/2)?c i (c i = analytical concentration of all the ions) and z ion charge calculated as z=+/-(I/c MX)(1/2) = +/-1.163. The use of the Single Saliva Salt Model (S3M) considerably reduces the complexity of the systems to be investigated. In fact, only four species deriving from internal ionic medium interactions must be considered. PMID- 25733976 TI - Brand name and generic proton pump inhibitor prescriptions in the United States: insights from the national ambulatory medical care survey (2006-2010). AB - Introduction. Proton pump inhibitors (PPI) are one of the most commonly prescribed medication classes with similar efficacy between brand name and generic PPI formulations. Aims. We determined demographic, clinical, and practice characteristics associated with brand name PPI prescriptions at ambulatory care visits in the United States. Methods. Observational cross sectional analysis using the National Ambulatory Medical Care Survey (NAMCS) of all adult (>=18 yrs of age) ambulatory care visits from 2006 to 2010. PPI prescriptions were identified by using the drug entry code as brand name only or generic available formulations. Descriptive statistics were reported in terms of unweighted patient visits and proportions of encounters with brand name PPI prescriptions. Global chi-square tests were used to compare visits with brand name PPI prescriptions versus generic PPI prescriptions for each measure. Poisson regression was used to determine the incidence rate ratio (IRR) for generic versus brand PPI prescribing. Results. A PPI was prescribed at 269.7 million adult ambulatory visits, based on 9,677 unweighted visits, of which 53% were brand name only prescriptions. In 2006, 76.0% of all PPI prescriptions had a brand name only formulation compared to 31.6% of PPI prescriptions in 2010. Visits by patients aged 25-44 years had the greatest proportion of brand name PPI formulations (57.9%). Academic medical centers and physician-owned practices had the greatest proportion of visits with brand name PPI prescriptions (58.9% and 55.6% of visits with a PPI prescription, resp.). There were no significant differences in terms of median income, patient insurance type, or metropolitan status when comparing the proportion of visits with brand name versus generic PPI prescriptions. Poisson regression results showed that practice ownership type was most strongly associated with the likelihood of receiving a brand name PPI over the entire study period. Compared to HMO visits, patient visits at academic medical centers (IRR 4.2, 95% CI 2.2-8.0), physician-owned practices (IRR 3.9, 95% CI 2.1-7.1), and community health centers (IRR 3.6, 95% CI 1.9-6.6) were all more likely to have brand name PPIs. Conclusion. PPI prescriptions with brand name only formulations are most strongly associated with physician practice type. PMID- 25733977 TI - Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma. AB - Objective. The aim of this study was to investigate the prognostic value of MicroRNA-210 (miR-210) expression in patients with non-small-cell lung cancer (NSCLC). Methods. We examined the miR-210 expression of samples of 80 patients, who underwent surgical resection at Fukushima Medical University from 2004 to 2007, by using quantitative RT-PCR. The relationship between miR-210 expression and clinicopathological factors as well as histological subtype was statistically analyzed. Results. miR-210 expression showed an inverse correlation with disease free and overall survival in patients with NSCLC. Significant correlations were found between miR-210 expression and lymph node metastasis, late disease stages, and poor prognosis in patients with adenocarcinoma. Multivariate Cox analysis indicated that miR-210 expression was an independent prognostic factor for disease-free survival in patients with adenocarcinoma. Conclusions. We showed that miR-210 may be a prognostic biomarker for patients with NSCLC, especially for those with lung adenocarcinoma. PMID- 25733978 TI - Development and Validation of GC-ECD Method for the Determination of Metamitron in Soil. AB - This paper aims at developing and validating a convenient, rapid, and sensitive method for estimation of metamitron from soil samples.Determination andquantification was carried out by Gas Chromatography on microcapillary column with an Electron Capture Detector source. The compound was extracted from soil using methanol and cleanup by C-18 SPE. After optimization, the method was validated by evaluating the analytical curves, linearity, limits of detection, and quantification, precision (repeatability and intermediate precision), and accuracy (recovery). Recovery values ranged from 89 to 93.5% within 0.05- 2.0 ug L(-1) with average RSD 1.80%. The precision (repeatability) ranged from 1.7034 to 1.9144% and intermediate precision from 1.5685 to 2.1323%. Retention time was 6.3 minutes, and minimum detectable and quantifiable limits were 0.02 ng mL(-1) and 0.05 ng g(-1), respectively. Good linearity (R (2) = 0.998) of the calibration curves was obtained over the range from 0.05 to 2.0 ug L(-1). Results indicated that the developed method is rapid and easy to perform, making it applicable for analysis in large pesticide monitoring programmes. PMID- 25733979 TI - Characterization of human knee and chin adipose-derived stromal cells. AB - Animal study findings have revealed that individual fat depots are not functionally equivalent and have different embryonic origins depending on the anatomic location. Mouse bone regeneration studies have also shown that it is essential to match the Hox code of transplanted cells and host tissues to achieve correct repair. However, subcutaneous fat depots from any donor site are often used in autologous fat grafting. Our study was thus carried out to determine the embryonic origins of human facial (chin) and limb (knee) fat depots and whether they had similar features and molecular matching patterns. Paired chin and knee fat depots were harvested from 11 subjects and gene expression profiles were determined by DNA microarray analyses. Adipose-derived stromal cells (ASCs) from both sites were isolated and analyzed for their capacity to proliferate, form clones, and differentiate. Chin and knee fat depots expressed a different HOX code and could have different embryonic origins. ASCs displayed a different phenotype, with chin-ASCs having the potential to differentiate into brown-like adipocytes, whereas knee-ASCs differentiated into white adipocytes. These results highlighted different features for these two fat sites and indicated that donor site selection might be an important factor to be considered when applying adipose tissue in cell-based therapies. PMID- 25733980 TI - Hospital physicians' work stressors in different medical specialities: a statistical group comparison. AB - BACKGROUND: Some studies on the occupational health of hospital physicians have found that working conditions have different effects on physician's well-being and health in different medical specialities. There has been no comparative study of the effects of various work stressors in different specialities. This study aims to close this gap. METHODS: German hospital physicians were asked about their working conditions and aspects of health. The short version of the Instrument for Stress-Related Job Analysis for Hospital Physicians was used to measure working conditions. Irritation and emotional exhaustion were used to assess health. Physicians were also asked for socio-demographic aspects, including their medical speciality. RESULTS: Data from 763 hospital physicians were included in the analyses. Significant differences between medical specialities were demonstrated for time pressure, uncertainty, frustration about how work needs to be done and social stressors with patients. Physicians in internal medicine showed consistently high levels of stressors. Time pressure, frustration about how work needs to be done, and emotional dissonance were found to be significantly related to both aspects of health. CONCLUSIONS: The results showed that some medical specialities are more affected by specific stressors. It is therefore discussed how improvements can be implemented. Furthermore, it is illustrated which stressors are especially relevant for health. These relationships to health should be investigated in further research and in longitudinal designs to allow hints of causal relationships. PMID- 25733981 TI - Tissue is an issue in the search for biomarkers in idiopathic pulmonary fibrosis. AB - Biological markers, i.e., biomarkers, in lung tissue may make it possible to connect cell biological phenomena to the pathogenetic mechanisms in idiopathic pulmonary fibrosis (IPF). This review focuses on the lung tissue biomarkers, which have been compared with relevant clinical endpoints or with the most common differential diagnostic lung diseases. In addition, studies conducted on lung tissue samples and investigated by transcriptomic or proteomic methodologies have been included. Several studies have observed changes in alveolar epithelium and extracellular matrix supporting the current hypotheses of the pathogenesis of IPF. In many studies, however, alterations in inflammatory cells have been revealed, a phenomenon not currently incorporated into pathogenetic theories. Combining lung tissue material with other non-solid organs with clinically meaningful endpoints may prove to be the most beneficial approach in the search for non-invasive biomarkers. PMID- 25733982 TI - How can we best respect patient autonomy in breast cancer treatment decisions? AB - Helping patients to maximize their autonomy in breast cancer decision-making is an important aspect of patient-centered care. Shared decision-making is a strategy that aims to maximize patient autonomy by integrating the values and preferences of the patient with the biomedical expertise of the physician. Application of this approach in breast cancer decision-making has not been uniform across cancer-specific interventions (e.g., surgery, chemotherapy), and in some circumstances may present challenges to evidence-based care delivery. Increasingly precise estimates of individual patients' risk of recurrence and commensurate predicted benefit from certain therapies hold significant promise in helping patients exercise autonomous decision-making for their breast cancer care, yet will also likely complicate decision-making for certain subgroups of patients. PMID- 25733983 TI - Evaluation of low-dose aspirin for primary prevention of ischemic stroke among patients with diabetes: a retrospective cohort study. AB - BACKGROUND: Low-dose aspirin is recommended to reduce the risk of cardiovascular disease. However, the questions with regard to primary prevention have been raised among patients with diabetes. We evaluated low-dose aspirin use for preventing ischemic stroke in patients with diabetes using a national health insurance database. METHODS: Using data from the Korean Health Insurance Review and Assessment Service database from January 1, 2005, through December 31, 2009, a population-based retrospective cohort study was conducted with incident patients with diabetes aged 40 to 99 years old with the initial use of low-dose aspirin during the index period from January 1, 2006 to December 31, 2007. We matched each low-dose aspirin user to one non-user using a propensity score. The Cox proportional hazards model was used to compare the risk of hospitalization for ischemic stroke in users and nonusers of low-dose aspirin until December 31, 2009. RESULTS: Out of 261,065 incident patients with diabetes, 15,849 (6.2%) were low-dose aspirin users. Compared to non-users, the adjusted hazard ratio (95% confidence interval) of low-dose aspirin users for hospitalization due to ischemic stroke was 1.73 (95% CI; 1.41-2.12). In a sensitivity analysis of study subjects with more than 1 year follow-up periods, slightly higher adjusted hazard ratio (1.97, 95% CI; 1.51-2.62) was observed. In the subgroup analyses, there were no significant changes in the risk of hospitalization for ischemic stroke irrespective of gender, age, or comorbidity. CONCLUSIONS: In this study of patients with diabetes, the use of low-dose aspirin showed an increased risk of hospitalization for ischemic stroke. These results suggest that low-dose aspirin use for the primary prevention of ischemic stroke should be reconsidered in patients with diabetes. PMID- 25733984 TI - Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. AB - INTRODUCTION: Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer's disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer's disease neuropathology) in patients presenting with CBS. METHODS: In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal). RESULTS: A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen's kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD). CONCLUSIONS: Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD. PMID- 25733985 TI - Effects of tumor necrosis factor alpha blocker adalimumab in experimental spinal cord injury. AB - OBJECTIVE: Tumor necrosis factor alpha (TNF-alpha) have proven effects in pathogenesis of neuroinflammation after spinal cord injury (SCI). Current study is designed to evaluate the effects of an anti-TNF-alpha agent, adalimumab, on spinal cord clip compression injury in rats. METHODS: Thirty two male adult Wistar rats were divided into four groups (sham, trauma, infliximab, and adalimumab groups) and SCI was introduced using an aneurysm clip. Animals in treatment groups received 5 mg/kg subcutaneous adalimumab and infliximab right after the trauma. Malondialdehyde (MDA) levels were studied in traumatized spinal cord tissues 72 hours after the injury as a marker of lipid peroxidation. RESULTS: Animals that received anti-TNF-alpha agents are found to have significantly decreased MDA levels. MDA levels were significantly different between the trauma and infliximab groups (p<0.01) and trauma and adalimumab groups (p=0.022). There was no significant difference in neurological evaluation of the rats using Tarlov scale. CONCLUSION: These results suggest that, like infliximab, adalimumab has favorable effects on lipid peroxidation induced by spinal cord trauma in rats. PMID- 25733986 TI - Change in plasma vascular endothelial growth factor after gamma knife radiosurgery for meningioma: a preliminary study. AB - OBJECTIVE: The purpose of this study was to investigate changes in the plasma level of vascular endothelial growth factor (VEGF) after Gamma Knife radiosurgery (GKRS) for the treatment of meningioma. METHODS: Fourteen patients with meningiomas had peripheral venous blood collected at the time of GKRS and at 1 week, 1 month, 3 month and 6 month visits. Plasma VEGF levels were measured using commercially available enzyme-linked immunosorbent assay. For controls, peripheral blood samples were obtained from 20 healthy volunteers. RESULTS: The mean plasma VEGF level (29.6 pg/mL) in patients with meningiomas before GKRS was significantly lower than that of the control group (62.4 pg/mL, p=0.019). At 1 week after GKRS, the mean plasma VEGF levels decreased to 23.4 pg/mL, and dropped to 13.9 pg/mL at 1 month, 14.8 pg/mL at 3 months, then increased to 27.7 pg/mL at 6 months. Two patients (14.3%) with peritumoral edema (PTE) showed a level of VEGF 6 months after GKRS higher than their preradiosurgical level. There was no significant association found in an analysis of correlation between PTE and tumor size, marginal dose, age, and sex. CONCLUSION: Our study is first in demonstrating changes of plasma VEGF after stereotactic radiosurgery (SRS) for meningioma. This study may provide a stimulus for more work related to whether measurement of plasma level has a correlation with tumor response after SRS for meningioma. PMID- 25733987 TI - Impaired voluntary wheel running behavior in the unilateral 6-hydroxydopamine rat model of Parkinson's disease. AB - OBJECTIVE: The aim of this study was to investigate voluntary wheel running behavior in the unilateral 6-hydroxydopamine (6-OHDA) rat model. METHODS: Male Sprague-Dawley rats were assigned to 2 groups : 6-OHDA group (n=17) and control group (n=8). The unilateral 6-OHDA rat model was induced by injection of 6-OHDA into unilateral medial forebrain bundle using a stereotaxic instrument. Voluntary wheel running activity was assessed per day in successfully lesioned rats (n=10) and control rats. Each behavioral test lasted an hour. The following parameters were investigated during behavioral tests : the number of running bouts, the distance moved in the wheel, average peak speed in running bouts and average duration from the running start to the peak speed. RESULTS: The number of running bouts and the distance moved in the wheel were significantly decreased in successfully lesioned rats compared with control rats. In addition, average peak speed in running bouts was decreased, and average duration from the running start to the peak speed was increased in lesioned animals, which might indicate motor deficits in these rats. These behavioral changes were still observed 42 days after lesion. CONCLUSION: Voluntary wheel running behavior is impaired in the unilateral 6-OHDA rat model and may represent a useful tool to quantify motor deficits in this model. PMID- 25733988 TI - Elevated cellular retinoic Acid binding protein-I in cerebrospinal fluid of patients with hemorrhagic cerebrovascular diseases : preliminary study. AB - OBJECTIVE: Elevated cellular retinoic acid binding protein-I (CRABP-I) is thought to be related to the abnormal proliferation and migration of smooth muscle cells (SMCs). Accordingly, a higher CRABP-I level could cause disorganized vessel walls by causing immature SMC phenotypes and altering extracellular matrix proteins which could result in vulnerable arterial walls with inadequate responses to hemodynamic stress. We hypothesized that elevated CRABP-I level in the cerebrospinal fluid (CSF) could be related to subarachnoid hemorrhage (SAH). Moreover, we also extended this hypothesis in patients with vascular malformation according to the presence of hemorrhage. METHODS: We investigated the CSF of 26 patients : SAH, n=7; unruptured intracranial aneurysm (UIA), n=7; arteriovenous malformation (AVM), n=4; cavernous malformation (CM), n=3; control group, n=5. The optical density of CRABP-I was confirmed by Western blotting and presented as mean+/-standard error of the measurement. RESULTS: CRABP-I in SAH (0.33+/-0.09) was significantly higher than that in the UIA (0.12+/-0.01, p=0.033) or control group (0.10+/-0.01, p=0.012). Hemorrhage presenting AVM (mean 0.45, ranged 0.30 0.59) had a higher CRABP-I level than that in AVM without hemorrhage presentation (mean 0.16, ranged 0.14-0.17). The CRABP-I intensity in CM with hemorrhage was 0.21 and 0.31, and for CM without hemorrhage 0.14. Overall, the hemorrhage presenting group (n=11, 0.34+/-0.06) showed a significantly higher CRABP-I intensity than that of the non-hemorrhage presenting group (n=10, 0.13+/-0.01, p=0.001). CONCLUSION: The results suggest that elevated CRABP-I in the CSF could be related with aneurysm rupture. Additionally, a higher CRABP-I level seems to be associated with hemorrhage development in vascular malformation. PMID- 25733989 TI - Association of carotid intraplaque hemorrhage and territorial acute infarction in patients with acute neurological symptoms using carotid magnetization-prepared rapid acquisition with gradient-echo. AB - OBJECTIVE: The purpose of our study was to assess prevalence of carotid intraplaque hemorrhage (IPH) and associations between territorial acute infarction and IPH on magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) in patients with acute neurologic symptoms. METHODS: 83 patients with suspected acute neurologic symptoms were evaluated with both brain diffusion weighted imaging (DWI) and carotid MPRAGE sequences. Carotid plaque with high signal intensity on MPRAGE of >200% that of adjacent muscle was categorized as IPH. We analyzed the prevalence of IPH and its correlation with territorial acute infarction. RESULTS: Of 166 arteries, 39 had a carotid artery plaque. Of these arteries, 26 had carotid artery stenosis less than 50%. In all carotid arteries, MR-depicted IPH was found in 7.2% (12/166). High-signal intensity on DWI was found in 17.5% (29/166). Combined lesion with ipsilateral high-signal intensity on DWI and IPH on carotid MPRAGE sequence was found in 6 lesions (6/166, 3.6%). Of patients with carotid artery plaque, MR-predicted IPH was found in 30.8% (12/39) and match lesions with high-signal intensity on DWI and MPRAGE was found in 15.4% (6/39). MR-predicted IPH was significantly higher prevalence in high grade stenosis group (p=0.010). Relative risk between carotid MPRAGE-positive signal and ipsilateral high-signal intensity on DWI in arteries with carotid artery plaques was 6.8 (p=0.010). CONCLUSION: Carotid MPRAGE-positive signal in patients was associated with an increased risk of territorial acute infarction as detected objectively by brain DWI. The relative risk of stroke was increased in high-grade stenosis categories. PMID- 25733990 TI - Minimally invasive option using percutaneous pedicle screw for instability of metastasis involving thoracolumbar and lumbar spine : a case series in a single center. AB - OBJECTIVE: To report a minimally invasive treatment option using percutaneous pedicle screw fixation with adjuvant treatment for metastatic thoraco-lumbar and lumbar spinal tumors. METHODS: This is a retrospective study of charts of patients with spinal metastases. All were older than 18 years of age and were considered to have more than 3 months of life expectancy. The patients had single or two level lesions, and compression fracture or impending fracture. Exclusion criterion was metastasis showing severe epidural compression with definite neurological symptoms. Usually spinal segments from one level above to below pathology were stabilized. Visual analog scale (VAS) score for pain assessment and Frankel scale for neurological deficit were used, while pre- and post operative performance status was evaluated using the Eastern Cooperative Oncology Group (ECOG). RESULTS: Twelve patients (nine men, three women; median age 54.29 years) underwent surgery. All patients presented with back pain with/without radicular pain. There were no early complications and perioperative mortalities. Following surgery, a significant difference between average pre- and post operative VAS scores was found (p=0.003). Overall, 91.8% of patients (11/12) experienced improvement in their ECOG score post-operatively. The mean ambulation time was 196.9 days [95% confidence interval (CI), 86.2-307.6 days; median, 97 days]. During follow-up, nine patients died and the mean overall survival time in enrolled twelve patients was 249.9 days (95% CI, 145.3-354.4 days; median, 176 days). CONCLUSION: Minimally invasive treatment using percutaneous pedicle screw fixation with adjuvant treatment is a good alternative treatment option for potential instability of the thoraco-lumbar and lumbar spinal metastasis. PMID- 25733991 TI - Survival rates and risk factors for cephalad and L5-s1 adjacent segment degeneration after L5 floating lumbar fusion : a minimum 2-year follow-up. AB - OBJECTIVE: Although the L5-S1 has distinct structural features in comparison with other lumbar spine segments, not much is known about adjacent segment degeneration (ASD) at the L5-S1 segment. The aim of study was to compare the incidence and character of ASD of the cephalad and L5-S1 segments after L5 floating lumbar fusion. METHODS: From 2005 to 2010, 115 patients who underwent L5 floating lumber fusion were investigated. The mean follow-up period was 46.1 months. The incidence of radiological and clinical ASD of the cephalad and the L5 S1 segments was compared using survival analysis. Risk factors affecting ASD were analyzed using a log rank test and the Cox proportional hazard model. RESULTS: Radiological ASD of the L5-S1 segment had a statistically significant higher survival rate than that of the cephalad segment (p=0.001). However, clinical ASD of the L5-S1 segment was significantly lower survival rates than that of the cephalad segment (p=0.038). Risk factor analysis showed that disc degeneration of the cephalad segment and preoperative spinal stenosis of the L5-S1 segment were risk factors. CONCLUSION: In L5 floating fusion, radiological ASD was more common in the cephalad segment and clinical ASD was more common in the L5-S1 segment. At the L5-S1 segment, the degree of spinal stenosis appears to be the most influential risk factor in ASD incidences, unlike the cephalad segment. PMID- 25733992 TI - Incidence of venous thromboembolic complications in instrumental spinal surgeries with preoperative chemoprophylaxis. AB - OBJECTIVE: Venous thromboembolism (VTE) after spinal surgery affects a patients' postoperative recovery and also carries a mortality risk. Some studies recommended chemical prophylaxis for high-risk patients and for those after complex spinal surgeries. However, chemoprophylaxis for VTE in spinal surgery is underemployed and there is no agreement on the use of VTE prophylaxis in spinal surgery. The aim of this study was to document the incidence of VTE after an elective instrumental spinal surgery, among those receiving preoperative chemoprophylaxis as compared with patients who did not receive it. METHODS: This study was carried out on eighty-nine patients allocated randomly to receive either low molecular weight heparin (LMWH) or no prophylaxis before elective instrumental spinal surgery. All patients received postoperative compression stockings. A compression Doppler ultrasonography was performed for all patients to detect postoperative deep vein thrombosis. In addition, further imaging studies were performed for patients suspected of VTE. RESULTS: Three (3.3%) patients were diagnosed with VTE. One of them had received preoperative chemoprophylaxis. There were no significant difference in incidence of VTE between the two groups (p>0.95; 95% confidence interval, 0.06-8.7). Laterality of gender and postsurgical recumbence duration were all independent predictors of VTE (p=0.01 and p<0.001, respectively). CONCLUSION: The difference in the incidence of thromboembolic complications between the two groups was not significant. Moreover, we found that preoperative prophylactic LMWH injection has no major bleeding complications altering postoperative course; still, the issue concerning the initiation time of chemoprophylaxis in spinal surgery remains unclear. PMID- 25733993 TI - The efficacy analysis of endoscopic third ventriculostomy in infantile hydrocephalus. AB - OBJECTIVE: To investigate the efficacy of endoscopic third ventriculostomy (ETV) for infantile hydrocephalus. METHODS: Retrospectively reviewed the 17 infantile hydrocephalus cases who were treated with ETV between July 2009 and June 2013. The study includes 17 patients (4 Han and 13 Hui) between the ages of 51 and 337 days. Five cases with encephalitis history and 2 cases with cerebral hemorrhage, with the remaining 10 cases congenital hydrocephalus. ETVs were performed for all patients with 1 case failing because the severe ventricle inflammatory adhesion, excessive exudation, and vague basilar artery. RESULTS: Among the 16 successful cases 7 cases improved remarkably : heads and ventricles reduced and cerebral cortexes thickening morphologically. The ventricles of the remaining cases were unchanged. CONCLUSION: The ethnic minority account for the majority of the patients in this study. ETV is effective for infantile obstructive hydrocephalus. PMID- 25733994 TI - Decompression of the sciatic nerve entrapment caused by post-inflammatory scarring. AB - A rare case of chronic pain of entrapment neuropathy of the sciatic nerve successfully relieved by surgical decompression is presented. A 71-year-old male suffered a chronic right buttock pain of duration of 7 years which radiating to the right distal leg and foot. His pain developed gradually over one year after underwenting drainage for the gluteal abscess seven years ago. A cramping buttock and intermittently radiating pain to his right foot on sitting, walking, and voiding did not respond to conventional treatment. An MRI suggested a post inflammatory adhesion encroaching the proximal course of the sciatic nerve beneath the piriformis as it emerges from the sciatic notch. Upon exploration of the sciatic nerve, a fibrotic tendinous scar beneath the piriformis was found and released proximally to the sciatic notch. His chronic intractable pain was completely relieved within days after the decompression. However, thigh weakness and hypesthesia of the foot did not improve. This case suggest a need for of more prompt investigation and decompression of the chronic sciatic entrapment neuropathy which does not improve clinically or electrically over several months. PMID- 25733995 TI - Paradoxical exacerbation of symptoms with obstruction of the venous outflow after gamma knife radiosurgery for treatment of a dural arteriovenous fistula of the cavernous sinus. AB - A 59-year-old female presented with progressive right proptosis, chemosis and ocular pain. An imaging work-up including conventional catheter angiography showed a right-sided dural arteriovenous fistula of the cavernous sinus, which drained into the right superior petrosal sinus, right superior ophthalmic vein, and right inferior ophthalmic vein, and cortical venous reflux was seen via the right petrosal vein in the right posterior fossa. After failure of transvenous embolization, the patient underwent Gamma Knife radiosurgery (GKRS). At one month after GKRS, she developed increasing ocular pain and occipital headache. Repeat angiography showed partial obliteration of the fistula and loss of drainage via the superior and inferior ophthalmic veins with severe congestion, resulting in slow flow around the right cerebellar hemisphere. Prompt transarterial embolization relieved the patient's ocular symptoms and headache. We report on a case of paradoxical exacerbation of symptoms resulting from obstruction of the venous outflow after GKRS for treatment of a dural arteriovenous fistula of the cavernous sinus. PMID- 25733996 TI - Delayed traumatic diaphragm hernia after thoracolumbar fracture in a patient with ankylosing spondylitis. AB - Traumatic diaphragm hernia can occur in rare cases and generally accompanies thoracic or abdominal injuries. When suffering from ankylosing spondylitis, a small force can develop into vertebral fracture and an adjacent structural injury, and lead to diaphragm hernia without accompanying concomitant thoracoabdominal injury. A high level of suspicion may be a most reliable diagnostic tool in the detection of a diaphragm injury, and we need to keep in mind a possibility in a patient with ankylosing spondylitis and a thoracolumbar fracture, even in the case of minor trauma. PMID- 25733997 TI - Solitary cervical neurenteric cyst in an adolescent patient. AB - Spinal neurenteric cysts are uncommon congenital lesions, furthermore solitary neurenteric cysts of the upper cervical spine are very rare. A 15-year-old boy having an intraspinal neurenteric cyst located at cervical spine presented with symptoms of neck pain and both shoulders pain for 2 months. Cervical spine magnetic resonance (MR) imaging demonstrated an intradural extramedullary cystic mass at the C1-3 level without enhancement after gadolinium injection. There was no associated malformation on the MR imaging, computed tomography, and radiography. Hemilaminectomy at the C1-3 levels was performed and the lesion was completely removed through a posterior approach. Histological examination showed the cystic wall lined with ciliated pseudostratified columnar epithelium containing mucinous contents. Neurenteric cyst should be considered in the diagnosis of spinal solitary cystic mass. PMID- 25733998 TI - Undetected metallic chopstick stabbed on neck resulting tinnitus and foreign body sensation. AB - Penetrating neck injuries constitute 5-10% of all trauma cases. These injuries may cause life-threatening suppurative or vascular complications, but the severity and extent of damage depends upon the inflicting object and the involved structures. If significant complications are not expected, then it is best to leave the foreign body embedded and avoid surgical risks. We present a rare case of a foreign body embedded in the neck causing tinnitus and foreign body sensation. PMID- 25733999 TI - Globus pallidus interna deep brain stimulation for chorea-acanthocytosis. AB - Chorea-acanthocytosis (ChAc) is a rare hereditary disorder characterized by involuntary choreiform movements and erythrocytic acanthocytosis. Pharmacotherapy for control of involuntary movements has generally been of limited benefit. Deep brain stimulation (DBS) has recently been used for treatment of some refractory cases of ChAc. We report here on the effect of bilateral high-frequency DBS of globus pallidus interna in a patient with ChAc. PMID- 25734000 TI - Exploring the construct validity of the Patient Perception Measure - Osteopathy (PPM-O) using classical test theory and Rasch analysis. AB - BACKGROUND: Evaluation of patients' experience of their osteopathic treatment has recently been investigated leading to the development of the Patient Perception Measure - Osteopathy (PPM-O). The aim of the study was to investigate the construct validity of the PPM-O. METHODS: Patients presenting to osteopathy student-led teaching clinics at two Australian universities were asked to complete two questionnaires after their treatment: a demographic questionnaire and the PPM-O. Confirmatory factor analysis (CFA) and Rasch analysis were used to investigate the construct validity of the PPM-O. RESULTS: Data from the present study did not fit the a-priori 6-domain structure in the CFA. Modifications to the 6-domain model were then made based on the CFA results, and this analysis identified two factors: 1) Education & Information (9 items); and 2) Cognition & Fatigue (6 items). These two factors were Rasch analysed individually. Two items were removed from the Cognition & Fatigue factor during the analysis. The two factors independently were unidimensional. CONCLUSIONS: The study produced a 2 factor, 13-item questionnaire that assesses the patients' perception of their osteopathic treatment using the items from a previous questionnaire. The results of the current study provide evidence for the construct validity of the PPM-O and the small number of items makes it feasible to implement into both clinical and research settings. Further research is now required to establish the measures' validity in a variety of patient populations. PMID- 25734001 TI - Is the right to health compatible with sustainability? PMID- 25734002 TI - Career opportunities in global health: A snapshot of the current employment landscape. PMID- 25734003 TI - Ebola and the need for restructuring pharmaceutical incentives. PMID- 25734004 TI - Comparing verbal autopsy cause of death findings as determined by physician coding and probabilistic modelling: a public health analysis of 54 000 deaths in Africa and Asia. AB - BACKGROUND: Coverage of civil registration and vital statistics varies globally, with most deaths in Africa and Asia remaining either unregistered or registered without cause of death. One important constraint has been a lack of fit-for purpose tools for registering deaths and assigning causes in situations where no doctor is involved. Verbal autopsy (interviewing care-givers and witnesses to deaths and interpreting their information into causes of death) is the only available solution. Automated interpretation of verbal autopsy data into cause of death information is essential for rapid, consistent and affordable processing. METHODS: Verbal autopsy archives covering 54 182 deaths from five African and Asian countries were sourced on the basis of their geographical, epidemiological and methodological diversity, with existing physician-coded causes of death attributed. These data were unified into the WHO 2012 verbal autopsy standard format, and processed using the InterVA-4 model. Cause-specific mortality fractions from InterVA-4 and physician codes were calculated for each of 60 WHO 2012 cause categories, by age group, sex and source. Results from the two approaches were assessed for concordance and ratios of fractions by cause category. As an alternative metric, the Wilcoxon matched-pairs signed ranks test with two one-sided tests for stochastic equivalence was used. FINDINGS: The overall concordance correlation coefficient between InterVA-4 and physician codes was 0.83 (95% CI 0.75 to 0.91) and this increased to 0.97 (95% CI 0.96 to 0.99) when HIV/AIDS and pulmonary TB deaths were combined into a single category. Over half (53%) of the cause category ratios between InterVA-4 and physician codes by source were not significantly different from unity at the 99% level, increasing to 62% by age group. Wilcoxon tests for stochastic equivalence also demonstrated equivalence. CONCLUSIONS: These findings show strong concordance between InterVA 4 and physician-coded findings over this large and diverse data set. Although these analyses cannot prove that either approach constitutes absolute truth, there was high public health equivalence between the findings. Given the urgent need for adequate cause of death data from settings where deaths currently pass unregistered, and since the WHO 2012 verbal autopsy standard and InterVA-4 tools represent relatively simple, cheap and available methods for determining cause of death on a large scale, they should be used as current tools of choice to fill gaps in cause of death data. PMID- 25734005 TI - Unemployment, public-sector health care expenditure and HIV mortality: An analysis of 74 countries, 1981-2009. AB - BACKGROUND: The global economic downturn has been associated with increased unemployment and reduced public-sector expenditure on health care (PSEH). We determined the association between unemployment, PSEH and HIV mortality. METHODS: Data were obtained from the World Bank and the World Health Organisation (1981 2009). Multivariate regression analysis was implemented, controlling for country specific demographics and infrastructure. Time-lag analyses and robustness-checks were performed. FINDINGS: Data were available for 74 countries (unemployment analysis) and 75 countries (PSEH analysis), equating to 2.19 billion and 2.22 billion people, respectively, as of 2009. A 1% increase in unemployment was associated with a significant increase in HIV mortality (men: 0.1861, 95% CI: 0.0977 to 0.2744, P = 0.0000, women: 0.0383, 95% CI: 0.0108 to 0.0657, P = 0.0064). A 1% increase in PSEH was associated with a significant decrease in HIV mortality (men: -0.5015, 95% CI: -0.7432 to -0.2598, P = 0.0001; women: -0.1562, 95% CI: -0.2404 to -0.0720, P = 0.0003). Time-lag analysis showed that significant changes in HIV mortality continued for up to 5 years following variations in both unemployment and PSEH. INTERPRETATION: Unemployment increases were associated with significant HIV mortality increases. PSEH increases were associated with reduced HIV mortality. The facilitation of access-to-care for the unemployed and policy interventions which aim to protect PSEH could contribute to improved HIV outcomes. PMID- 25734006 TI - Dual secured nano-melittin for the safe and effective eradication of cancer cells. AB - The clinical application of natural and synthetic amphipathic peptides (e.g., melittin) for cancer therapy is hindered by their notorious side effect, lysing red blood cells. To safely deliver a therapeutic peptide to the tumor tissue and kill cancer cells, we developed an environment-sensitive peptide delivery system, dual secured nano-sting (DSNS), through the combination of a zwitterionic glycol chitosan and disulfide bonds. Melittin loaded DSNS could kill almost 100% of MCF 7, HCT-116, SKOV-3, and NCI/ADR-RES (multidrug resistant) cancer cells at the concentration of 5 MUM, while not showing any hemolytic effect. PMID- 25734007 TI - Update on the treatment of metastatic clear cell and non-clear cell renal cell carcinoma. AB - The advent of new knowledge surrounding the molecular pathology of renal-cell carcinoma (RCC) has culminated in a number of emerging targeted therapies. In just the last year, several new studies have been able to translate our understanding of tumor biology into significantly improved outcomes in patients with advanced RCC. The objective of this review is to describe new developments in targeted treatments and immunotherapies for patients with both clear-cell and non-clear cell metastatic RCC following the 2014 American Society of Clinical Oncology (ASCO) annual conference. We will discuss new applications of anti-VGF agents and PD-1 inhibitors in order to shed light on emerging avenues of RCC treatment that show considerable promise. PMID- 25734009 TI - Full-thickness retinochoroidal incision in the management of central retinal vein occlusion. AB - Purpose. To evaluate the clinical outcomes in patients with central retinal vein occlusion (CRVO) treated with full-thickness retinochoroidal incisions and to compare whether there is difference in treatment response in ischemic and nonischemic CRVO. Methods. Retrospective study of patients of CRVO receiving full thickness retinochoroidal incisions in Changhua Christian Hospital. Fluorescein angiography (FA), slit-lamp biomicroscopy, indirect funduscopy, best corrected visual acuity, and central macular thickness (CMT) measured by optical coherence tomography were performed pre- and postoperatively. Patients were divided into an ischemic and nonischemic group according to the findings of FA. Patients were followed up for at least 1 year. Results. Twenty-eight eyes (14 ischemic and 14 nonischemic CRVO) were included. Functional retinochoroidal venous anastomosis (RCVA) was achieved in 48 of the 65 retinochoroidal incisions (73.8%). Central macular thickness (CMT) and retinal hemorrhage decreased significantly after the surgery. Significant visual gain was observed postoperatively in the nonischemic group, but not in the ischemic group. Postoperative complications included vitreous hemorrhage (17.8%), neovascular glaucoma (7.1%), and preretinal fibrovasular membrane (10.7%), all of which were in the ischemic group. Conclusions. RCVA formation induced by retinochoroidal incisions could improve venous flow, and decrease CMT and retinal hemorrhage. However, only eyes with nonischemic CRVO showed visual improvement. PMID- 25734008 TI - Early transduction produces highly functional chimeric antigen receptor-modified virus-specific T-cells with central memory markers: a Production Assistant for Cell Therapy (PACT) translational application. AB - BACKGROUND: Virus-specific T-cells (VSTs) proliferate exponentially after adoptive transfer into hematopoietic stem cell transplant (HSCT) recipients, eliminate virus infections, then persist and provide long-term protection from viral disease. If VSTs behaved similarly when modified with tumor-specific chimeric antigen receptors (CARs), they should have potent anti-tumor activity. This theory was evaluated by Cruz et al. in a previous clinical trial with CD19.CAR-modified VSTs, but there was little apparent expansion of these cells in patients. In that study, VSTs were gene-modified on day 19 of culture and we hypothesized that by this time, sufficient T-cell differentiation may have occurred to limit the subsequent proliferative capacity of the transduced T cells. To facilitate the clinical testing of this hypothesis in a project supported by the NHLBI-PACT mechanism, we developed and optimized a good manufacturing practices (GMP) compliant method for the early transduction of VSTs directed to Epstein-Barr virus (EBV), Adenovirus (AdV) and cytomegalovirus (CMV) using a CAR directed to the tumor-associated antigen disialoganglioside (GD2). RESULTS: Ad-CMVpp65-transduced EBV-LCLs effectively stimulated VSTs directed to all three viruses (triVSTs). Transduction efficiency on day three was increased in the presence of cytokines and high-speed centrifugation of retroviral supernatant onto retronectin-coated plates, so that under optimal conditions up to 88% of tetramer-positive VSTs expressed the GD2.CAR. The average transduction efficiency of early-and late transduced VSTs was 55 +/- 4% and 22 +/- 5% respectively, and early-transduced VSTs maintained higher frequencies of T cells with central memory or intermediate memory phenotypes. Early-transduced VSTs also had higher proliferative capacity and produced higher levels of TH1 cytokines IL 2, TNF-alpha, IFN-gamma, MIP-1alpha, MIP-1beta and other cytokines in vitro. CONCLUSIONS: We developed a rapid and GMP compliant method for the early transduction of multivirus-specific T-cells that allowed stable expression of high levels of a tumor directed CAR. Since a proportion of early-transduced CAR VSTs had a central memory phenotype, they should expand and persist in vivo, simultaneously protecting against infection and targeting residual malignancy. This manufacturing strategy is currently under clinical investigation in patients receiving allogeneic HSCT for relapsed neuroblastoma and B-cell malignancies (NCT01460901 using a GD2.CAR and NCT00840853 using a CD19.CAR). PMID- 25734010 TI - In Vitro Selection of a Single-Stranded DNA Molecular Recognition Element against Clostridium difficile Toxin B and Sensitive Detection in Human Fecal Matter. AB - Toxin B is one of the major virulence factors of Clostridium difficile, a bacterium that is responsible for a significant number of diarrhea cases in acute care settings. Due to the prevalence of C. difficile induced diarrhea, rapid and correct diagnosis is crucial in the disease management. In this study, we have employed a stringent in vitro selection method to identify single-stranded DNA molecular recognition elements (MRE) specific for toxin B. At the end of the 12 round selection, one MRE with high affinity (K d = 47.3 nM) for toxin B was identified. The selected MRE demonstrated low cross binding activities on negative targets: bovine serum albumin, Staphylococcus aureus alpha toxin, Pseudomonas aeruginosa exotoxin A, and cholera toxin of Vibrio cholera. A modified sandwich ELISA assay was developed utilizing the selected ssDNA MRE as the antigen capturing element and achieved a sensitive detection of 50 nM of toxin B in human fecal preparations. PMID- 25734011 TI - Effect of Diffusion on Discoloration of Congo Red by Alginate Entrapped Turnip (Brassica rapa) Peroxidase. AB - Enzymatic discoloration of the diazo dye, Congo red (CR), by immobilized plant peroxidase from turnip "Brassica rapa" is investigated. Partially purified turnip peroxidase (TP) was immobilized by entrapment in spherical particles of calcium alginate and was assayed for the discoloration of aqueous CR solution. Experimental data revealed that pH, reaction time, temperature, colorant, and H2O2 concentration play a significant role in dye degradation. Maximum CR removal was found at pH 2.0, constant temperature of 40 degrees C in the presence of 10 mM H2O2, and 180 mg/L of CR. More than 94% of CR was removed by alginate immobilized TP after 1 h of incubation in a batch process under optimal conditions. About 74% removal efficiency was retained after four recycles. Diffusional limitations in alginate beads such as effectiveness factor eta, Thiele modulus Phi, and effective diffusion coefficients (D e ) of Congo red were predicted assuming a first-order biodegradation kinetic. Results showed that intraparticle diffusion resistance has a significant effect on the CR biodegradation rate. PMID- 25734012 TI - Effect of maternal iron deficiency anemia on the iron store of newborns in ethiopia. AB - Iron deficiency anemia among pregnant women is a widespread problem in developing countries including Ethiopia, though its influence on neonatal iron status was inconsistently reported in literature. This cross-sectional study was conducted to compare hematologic profiles and iron status of newborns from mothers with different anemia status and determine correlation between maternal and neonatal hematologic profiles and iron status in Ethiopian context. We included 89 mothers and their respective newborns and performed complete blood count and assessed serum ferritin and C-reactive protein levels from blood samples collected from study participants. Maternal median hemoglobin and serum ferritin levels were 12.2 g/dL and 47.0 ng/mL, respectively. The median hemoglobin and serum ferritin levels for the newborns were 16.2 g/dL and 187.6 ng/mL, respectively. The mothers were classified into two groups based on hemoglobin and serum ferritin levels as iron deficient anemic (IDA) and nonanemic (NA) and newborns of IDA mothers had significantly lower levels of serum ferritin (P = 0.017) and hemoglobin concentration (P = 0.024). Besides, newborns' ferritin and hemoglobin levels showed significant correlation with maternal hemoglobin (P = 0.018; P = 0.039) and ferritin (P = 0.000; P = 0.008) levels. We concluded that maternal IDA may have an effect on the iron stores of newborns. PMID- 25734013 TI - Arginine adjunctive therapy in active tuberculosis. AB - Background. Dietary supplementation has been used as a mechanism to augment the immune system. Adjunctive therapy with L-arginine has the potential to improve outcomes in active tuberculosis. Methods. In a randomized clinical trial 63 participants with smear-positive pulmonary tuberculosis in Markazi Province of Iran were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. The final treatment success, sputum conversion, weight gain, and clinical symptoms after one and two months were considered as primary outcomes and secondary outcomes were ESR, CRP, and Hg. Data were collected and analyzed with SPSS software (ver. 18). Results. Arginine supplementation reduced constitutional symptoms (P = 0.032) in patients with smear-positive TB at the end of the first month of treatment. Arginine treated patients had significantly increased BMI at the end of the first and second months of treatment (P = 0.032 and P = 0.04) and a reduced CRP at the end of the first month of treatment (P = 0.03) versus placebo group. Conclusion. Arginine is useful as an adjunctive therapy in patients with active tuberculosis, in which the effects are more likely mediated by the increased production of nitric oxide and improved constitutional symptoms and weight gain. This trial is registered with Clinical Trials Registry of Iran: IRCT201211179855N2. PMID- 25734014 TI - Design and Synthesis of Novel Hybrid Molecules against Malaria. AB - The effective treatment of malaria can be very complex: Plasmodium parasites develop in multiple stages within a complex life cycle between mosquitoes as vectors and vertebrates as hosts. For the full and effective elimination of parasites, an effective drug should be active against the earliest stages of the Plasmodium infection: liver stages (reduce the progress of the infection), blood stages (cure the clinical symptoms), and gametocytes (inhibit the transmission cycle). Towards this goal, here we report the design, the synthetic methodology, and the characterization of novel hybrid agents with combined activity against Plasmodium liver stages and blood stages and gametocytes. The divergent synthetic approach allows the access to differently linked primaquine-chloroquine hybrid templates in up to eight steps. PMID- 25734015 TI - Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents. AB - Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series. PMID- 25734016 TI - Posttraumatic stress and posttraumatic stress disorder after termination of pregnancy and reproductive loss: a systematic review. AB - OBJECTIVE: The aims of this systematic review were to integrate the research on posttraumatic stress (PTS) and posttraumatic stress disorder (PTSD) after termination of pregnancy (TOP), miscarriage, perinatal death, stillbirth, neonatal death, and failed in vitro fertilisation (IVF). METHODS: Electronic databases (AMED, British Nursing Index, CINAHL, MEDLINE, SPORTDiscus, PsycINFO, PubMEd, ScienceDirect) were searched for articles using PRISMA guidelines. RESULTS: Data from 48 studies were included. Quality of the research was generally good. PTS/PTSD has been investigated in TOP and miscarriage more than perinatal loss, stillbirth, and neonatal death. In all reproductive losses and TOPs, the prevalence of PTS was greater than PTSD, both decreased over time, and longer gestational age is associated with higher levels of PTS/PTSD. Women have generally reported more PTS or PTSD than men. Sociodemographic characteristics (e.g., younger age, lower education, and history of previous traumas or mental health problems) and psychsocial factors influence PTS and PTSD after TOP and reproductive loss. CONCLUSIONS: This systematic review is the first to investigate PTS/PTSD after reproductive loss. Patients with advanced pregnancies, a history of previous traumas, mental health problems, and adverse psychosocial profiles should be considered as high risk for developing PTS or PTSD following reproductive loss. PMID- 25734017 TI - Assessment of the exercise intensity of short stick exercises in elderly individuals. AB - The present study was to obtain basic data for applying the short stick exercises to frail elderly individuals. A total of 20 individuals aged >=60 years (10 men, and 10 women) with independence in activities of daily living participated in a short stick exercise program. During the exercise program, the time required and the number of times the short stick was dropped were investigated. The exercise intensity was also evaluated based on expired gas and heart rate measurements. The mean exercise intensity of the short stick exercises was 1.9 +/- 0.3 metabolic equivalents (METs), equivalent to talking while standing or walking indoors. Compared to the early elderly (those aged 60 to 74 years), the late elderly (those aged >=75 years) had a significantly higher number of stick drops and significantly lower increase in heart rate from resting to the warming-up exercise. The short stick exercises had a low exercise intensity and can be applicable to exercise interventions of the frail elderly individuals. However, in the case of the late elderly, the high frequency of short stick drops and the change in heart rate during warming up must be considered. PMID- 25734019 TI - Desmoid Tumor of the Popliteal Fossa during Pregnancy. AB - Desmoid tumors are fibroblastic neoplasms that have an intermediate behavior with a highly aggressive infiltrative growth arising from deep muscle or aponeurosis. We present the case of a 34-year-old woman that developed a painless mass in the right popliteal fossa during pregnancy after intracytoplasmic sperm injection and hormonal therapy. The MRI scan showed a hyperintense mass of 6,7 cm * 4,7 cm * 3,8 cm surrounding the lateral head of the gastrocnemius muscle. The open biopsy was done one week after delivery, and the histology showed a desmoid tumor. We performed the resection one week later and found the common peroneal nerve completely surrounded by the tumor. The close resection due to the neurolysis was the reason why an adjuvant radiation with 56 Gy was done. The last clinical examination, 18 month later, did not show any signs of recurrence and an excellent functional outcome. This case demonstrates the possible influences of pregnancy and hormonal therapy on the evolution of desmoid tumors. PMID- 25734018 TI - Altered intra- and interregional synchronization in resting-state cerebral networks associated with chronic tinnitus. AB - OBJECTIVE: Subjective tinnitus is hypothesized to arise from aberrant neural activity; however, its neural bases are poorly understood. To identify aberrant neural networks involved in chronic tinnitus, we compared the resting-state functional magnetic resonance imaging (fMRI) patterns of tinnitus patients and healthy controls. MATERIALS AND METHODS: Resting-state fMRI measurements were obtained from a group of chronic tinnitus patients (n = 29) with normal hearing and well-matched healthy controls (n = 30). Regional homogeneity (ReHo) analysis and functional connectivity analysis were used to identify abnormal brain activity; these abnormalities were compared to tinnitus distress. RESULTS: Relative to healthy controls, tinnitus patients had significant greater ReHo values in several brain regions including the bilateral anterior insula (AI), left inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the left AI showed enhanced functional connectivity with the left middle frontal gyrus (MFG), while the right AI had enhanced functional connectivity with the right MFG; these measures were positively correlated with Tinnitus Handicap Questionnaires (r = 0.459, P = 0.012 and r = 0.479, P = 0.009, resp.). CONCLUSIONS: Chronic tinnitus patients showed abnormal intra- and interregional synchronization in several resting-state cerebral networks; these abnormalities were correlated with clinical tinnitus distress. These results suggest that tinnitus distress is exacerbated by attention networks that focus on internally generated phantom sounds. PMID- 25734020 TI - Remarkably Few Sputum Cultures from People with Parkinson's Disease during Hospital In-Patient Admission. AB - Although respiratory tract infections can be a common complication in people with Parkinson's disease (PD), there is little published data on the nature of such infections in this patient group. We wished to investigate whether sputum samples were being taken from PD patients in order to establish whether an infection was present and if so which bacteria were responsible for the infection. We recorded the number of positive sputum samples taken from admission to North Tyneside General Hospital in North-East England across a ten-year period from June 2001 to June 2011. Of 643 in-patient episodes involving people with PD, positive sputum samples were recorded for only 12 episodes (1.9%) in eight patients. All patients were in early stage disease. In all admissions to the NHS Trust running the hospital, there were 23,069 sputum cultures from 1,056,693 in-patient episodes (2.2%). Our findings may reflect the difficultly of expectorating in many people with PD, particularly in late-stage disease. Since people with PD are especially vulnerable to respiratory tract infections, clinicians need to ensure that, where possible, a sputum sample is obtained from people with PD when clinically indicated. PMID- 25734021 TI - Study of Grape Polyphenols by Liquid Chromatography-High-Resolution Mass Spectrometry (UHPLC/QTOF) and Suspect Screening Analysis. AB - Suspect screening analysis is a targeted metabolomics method in which the identification of compounds relies on specific available information, such as their molecular formula and isotopic pattern. This method, coupled to liquid chromatography-high-resolution mass spectrometry, is effective in the study of grape metabolomics, in particular for characterization of flavonols, stilbene derivatives, and anthocyanins. For identification of compounds expected in the samples, a new database of putative compounds was expressly constructed by using the molecular information on potential metabolites of grape and wine from the literature and other electronic databases. Currently, this database contains around 1,100 compounds. The method allows identification of several hundred grape metabolites with two analyses (positive and negative ionization modes), and performing of data reprocessing using "untargeted" algorithms also provided the identification of some flavonols and resveratrol trimers and tetramers in grape for the first time. This approach can be potentially used in the study of metabolomics of varieties of other plant species. PMID- 25734022 TI - Quantification of Sunscreen Benzophenone-4 in Hair Shampoos by Hydrophilic Interactions Thin-Layer Chromatography/Densitometry or Derivative UV Spectrophotometry. AB - Benzophenone-4 (BZ4) was separated from surfactants, dyes, preservatives, and other components of hair shampoos by thin-layer chromatography on silica gel 60 stationary phase, with ethyl acetate-ethanol-water-pH 6 phosphate buffer (15 : 7 : 5 : 1 v/v/v/v) as mobile phase. Densitometry scanning of chromatograms was performed at 285 nm. The densitometric calibration curve for BZ4 was nonlinear (second-degree polynomial), with R > 0.999. The limits of detection and quantification were ca. 0.03 and ca. 0.1 MUg spot(-1), respectively. The results obtained by HPTLC-densitometry were compared to those obtained by zero and 2nd derivative UV spectrophotometry. In the case of spectrophotometric methods, calibration curves were linear with R > 0.9998. The chromatographic method was fully validated. PMID- 25734023 TI - A Structural Study of Escherichia coli Cells Using an In Situ Liquid Chamber TEM Technology. AB - Studying cell microstructures and their behaviors under living conditions has been a challenging subject in microbiology. In this work, in situ liquid chamber TEM was used to study structures of Escherichia coli cells in aqueous solutions at a nanometer-scale resolution. Most of the cells remained intact under electron beam irradiation, and nanoscale structures were observed during the TEM imaging. The analysis revealed structures of pili surrounding the E. coli cells; the movements of the pili in the liquid were also observed during the in situ tests. This technology also allowed the observation of features of the nucleoid in the E. coli cells. Overall, in situ TEM can be applied as a valuable tool to study real-time microscopic structures and processes in microbial cells residing in native aqueous solutions. PMID- 25734024 TI - Determination of sinomenine in cubosome nanoparticles by HPLC technique. AB - We applied HPLC technique to quantitatively analyze sinomenine in cubosome nanoparticles. The chromatographic method was performed by using an isocratic system. The mobile phase was composed of methanol-PBS(pH6.8)-triethylamine (50 : 50 : 0.1%) with a flow rate of 1 mL/min; the detection wavelength was at 265 nm. Sinomenine can be successfully separated with good linearity (the regression equation is A = 10835C + 1058; R (2) = 1.0) and perfect recovery (102.2%). The chromatograph technique was proper for quality control of sinomenine in cubosome nanoparticles. PMID- 25734025 TI - Pathogenesis, Epidemiology, Diagnosis and Clinical Aspects of Smith-Lemli-Opitz Syndrome. AB - INTRODUCTION: Smith-Lemli-Opitz Syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability. AREAS COVERED: In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients. We then explore the underlying biochemical defect and pathophysiological alterations that may contribute to the many disease manifestations. Subsequently we explore the epidemiology and succinctly discuss population genetics as they relate to SLOS. The next section presents the diagnostic possibilities. Thereafter, the treatment and management as is standard of care are presented. EXPERT OPINION: Even though the knowledge of the underlying molecular mutations and the biochemical alterations is being rapidly accumulated, there is currently no efficacious therapy addressing neurological dysfunction. We discuss the difficulty of treating this disorder, which manifests as a combination of a malformation syndrome and an inborn error of metabolism. A very important factor in developing new therapies is the need to rigorously establish efficacy in controlled trials. PMID- 25734026 TI - Phialosimplex salinarum, a new species of Eurotiomycetes from a hypersaline habitat. AB - Salt mines represent an extreme environment with hypersaline conditions, complete darkness, and low nutrient availability. The diversity of filamentous fungi in such habitats is largely unknown. Eight strains of an unknown fungus were isolated from water samples of the salt mine in Berchtesgaden (Bavaria, Germany). They could be assigned to the ascomycete genus Phialosimplex, based on their common characteristics of producing conidia in chains or in heads on single phialides. Species of this genus are hitherto known to cause mycoses in dogs and have been found in mummies. Using molecular and morphological methods, the isolates are established as a new species, Phialosimplex salinarum sp. nov. Basipetospora halophila is also transferred to Phialosimplex as P. halophila comb. nov. PMID- 25734027 TI - Phacidium and Ceuthospora (Phacidiaceae) are congeneric: taxonomic and nomenclatural implications. AB - The morphologically diverse genus Ceuthospora has traditionally been linked to Phacidium sexual morphs via association, though molecular or cultural data to confirm this relationship have been lacking. The aim of this study was thus to resolve the relationship of these two genera by generating nucleotide sequence data for three loci, ITS, LSU and RPB2. Based on these results, Ceuthospora is reduced to synonymy under the older generic name Phacidium. Phacidiaceae (currently Helotiales) is suggested to constitute a separate order, Phacidiales (Leotiomycetes), as sister to Helotiales, which is clearly paraphyletic. Phacidiaceae includes Bulgaria, and consequently the family Bulgariaceae becomes a synonym of Phacidiaceae. Several new combinations are introduced in Phacidium, along with two new species, P. pseudophacidioides, which occurs on Ilex and Chamaespartium in Europe, and Phacidium trichophori, which occurs on Trichophorum cespitosum subsp. germanicum in The Netherlands. The generic name Allantophomopsiella is introduced to accommodate A. pseudotsugae, a pathogen of conifers, while Gremmenia is resurrected to accommodate the snow-blight pathogens of conifers, G. abietis, G. infestans, and G. pini-cembrae. PMID- 25734028 TI - Online identification guides for Australian smut fungi (Ustilaginomycotina) and rust fungi (Pucciniales). AB - Interactive identification keys for Australian smut fungi (Ustilaginomycotina and Pucciniomycotina, Microbotryales) and rust fungi (Pucciniomycotina, Pucciniales) are available online at http://collections.daff.qld.gov.au. The keys were built using Lucid software, and facilitate the identification of all known Australian smut fungi (317 species in 37 genera) and 100 rust fungi (from approximately 360 species in 37 genera). The smut and rust keys are illustrated with over 1,600 and 570 images respectively. The keys are designed to assist a wide range of end users including mycologists, plant health diagnosticians, biosecurity scientists, plant pathologists, and university students. The keys are dynamic and will be regularly updated to include taxonomic changes and incorporate new detections, taxa, distributions and images. Researchers working with Australian smut and rust fungi are encouraged to participate in the on-going development and improvement of these keys. PMID- 25734029 TI - Cercosporoid fungi (Mycosphaerellaceae) 2. Species on monocots (Acoraceae to Xyridaceae, excluding Poaceae). AB - Cercosporoid fungi (formerly Cercospora s. lat.) represent one of the largest groups of hyphomycetes belonging to the Mycosphaerellaceae (Ascomycota). They include asexual morphs, asexual holomorphs, or species with mycosphaerella-like sexual morphs. Most of them are leaf-spotting plant pathogens with special phytopathological relevance. In the first part of a new monographic work, cercosporoid hyphomycetes occurring on other fungi (fungicolous species), on ferns (pteridophytes) and gymnosperms were treated. This second part deals with cercosporoid fungi on monocots (Liliopsida; Equisetopsida, Magnoliidae, Lilianae), which covers species occurring on host plants belonging to families arranged in alphabetical order from Acoraceae to Xyridaceae, excluding Poaceae (cereals and grasses) which requires a separate treatment. The species are described and illustrated in alphabetical order under the particular cercosporoid genera, supplemented by keys to the species concerned. A detailed introduction, a survey of currently recognised cercosporoid genera, a key to the genera concerned, and a discussion of taxonomically relevant characters were published in the first part of this series. Neopseudocercospora, an additional recently introduced cercosporoid genus, is briefly discussed. The following taxonomic novelties are introduced: Cercospora alpiniigena sp. nov., C. neomaricae sp. nov., Corynespora palmicola comb. nov., Exosporium miyakei comb. nov., E. petersii comb. nov., Neopseudocercospora zambiensis comb. nov., Passalora caladiicola comb. nov., P. streptopi comb. nov., P. togashiana comb. nov., P. tranzschelii var. chinensis var. nov., Pseudocercospora beaucarneae comb. nov., P. constrictoflexuosa comb. et stat. nov., P. curcumicola sp. nov., P. dispori comb. nov., P. smilacicola sp. nov., P. urariigena nom. nov., Zasmidium agavicola comb. nov., Z. cercestidis-afzelii comb. nov., Z. citri-griseum comb. nov., Z. cyrtopodii comb. nov., Z. gahnae comb. nov., Z. indicum comb. nov., Z. liriopes comb. nov., Z. mycovellosielloides sp. nov., Z. scleriae comb. nov., Z. smilacicola comb. nov., and Z. thaliae comb. nov. PMID- 25734030 TI - Mycoparasitic species of Sphaerellopsis, and allied lichenicolous and other genera. AB - Species of Sphaerellopsis (sexual morph Eudarluca) are well-known cosmopolitan mycoparasites occurring on a wide range of rusts. Although their potential role as biocontrol agents has received some attention, the molecular phylogeny of the genus has never been resolved. Based on morphology and DNA sequence data of the large subunit nuclear ribosomal RNA gene (LSU, 28S) and the internal transcribed spacers (ITS) and 5.8S rRNA gene of the nrDNA operon, the genus Sphaerellopsis is shown to belong to Leptosphaeriaceae in Dothideomycetes. Sphaerellopsis is circumscribed, and the sexually typified generic name Eudarluca treated as a synonym on the basis that Sphaerellopsis is more commonly used in literature, is the older generic name, and is the morph commonly encountered by plant pathologists in the field. A neotype is designated for Sphaerellopsis filum, and two new species are introduced, S. macroconidialis and S. paraphysata spp. nov. Species previously incorrectly placed in Sphaerellopsis are allocated to Neosphaerellopsis gen. nov. as N. thailandica, and to the genus Acrocalymma, as A. fici. The genus Rhizopycnis is nestled among species of Acrocalymma, and reduced to synonymy based on its morphology and DNA phylogeny, while Acrocalymmaceae is introduced as novel family to accommodate members of this genus in the Dothideomycetes. Furthermore, Sphaerellopsis proved to be phylogenetically closely allied to a lichenicolous complex of phoma-like taxa, for which the new genera Diederichomyces and Xenophoma are established. Several new combinations are introduced, namely D. xanthomendozae, D. ficuzzae, D. caloplacae, D. cladoniicola, D. foliaceiphila, and X. puncteliae combs. nov, while Paraphaeosphaeria parmeliae sp. nov. is newly described. PMID- 25734031 TI - Phylogenetic and morphological comparison of Pluteus variabilicolor and P. castri (Basidiomycota, Agaricales). AB - Based on several collections from Italy, a detailed description (including also macrophotographs, microphotographs, and drawings) of the morphological characters of the poorly known Pluteus variabilicolor, originally described from Hungary, is provided. The analysis of the ITS sequences placed this species within the P. leoninus clade of sect. Hispidoderma, in spite of the presence of clavate elements in the pileipellis. According to the molecular comparison of the type collections, Pluteus castri, a species recently described on the basis of material collected in Japan and Central Russia, is reduced to a synonym of P. variabilicolor. PMID- 25734032 TI - Phylogeny and morphology of dematiaceous freshwater microfungi from Peru. AB - A survey of freshwater ascomycetes conducted along an elevational gradient in Peru in the Districts of Cusco, Junin, and Madre de Dios yielded specimens of Cancellidium applanatum, Cordana abramovii, Sporoschisma juvenile, S. uniseptatum, and S. saccardoi. With the exception of S. saccardoi, these are new records for Peru. Molecular data was generated for three previously unsequenced species: Cancellidium applanatum, Cordana abramovii and Sporoschisma saccardoi. These taxa are reported herein from the neotropics with an accompanying phylogeny based on partial 28S nuclear ribosomal large-subunit sequence data. The sexual morph of S. saccardoi has previously been linked to Melanochaeta hemipsila through cultural studies. Molecular data from ascospores and conidia of M. hemipsila and S. saccardoi, respectively, were used to demonstrate a genetic connection of the sexual and asexual morphs of these fungi for the first time, resulting in the new combination Sporoschisma hemipsila being made. PMID- 25734033 TI - Multiple barcode assessment within the Saprolegnia-Achlya clade (Saprolegniales, Oomycota, Straminipila) brings order in a neglected group of pathogens. AB - The Saprolegnia-Achlya clade comprises species of major environmental and economic importance due to their negative impact on aquaculture and aquatic ecosystems by threatening fishes, amphibians, and crustaceans. However, their taxonomy and phylogenetic relationships remain unresolved and suffer from many inconsistencies, which is a major obstacle to the widespread application of molecular barcoding to identify pathogenic strains with quarantine implications. We assessed phylogenetic relationships of major genera using three commonly used markers (ITS, SSU rRNA, and LSU rRNA). A consensus tree of the three genes provided support for nine clades encompassing eleven documented genera and a new clade (SAP1) that has not been described morphologically. In the course of this study, we isolated a new species, Newbya dichotoma sp. nov., which provided the only culture available for this genus. In parallel, we attempted to summarize the evolution of traits in the different genera, but their successive reversals rendered the inference of ancestral states impossible. This highlights even more the importance of a bar-coding strategy for saprolegniacean parasite detection and monitoring. PMID- 25734034 TI - Fungal Nomenclature at IMC10: Report of the Nomenclature Sessions. AB - Three Nomenclature Sessions were convened during the 10(th) International Mycological Congress (IMC10) in Bangkok on 3-8 August 2014. In addition a Questionnaire was given to all delegates. This Report reviews and summarizes the views expressed in the Sessions and in the responses to the Questionnaire. The issues covered related to aspects of: registration, protected names, forgotten names, pleomorphic fungi, lichenized fungi, typification, diagnoses, and governance. In addition, reports were received from working groups preparing lists of names to be proposed for protection, and controversial cases of competing names were discussed. The Congress was mandated to ratify decisions of the Nomenclature Committee for Fungi (NCF) on the appointment of repositories for the registration of new fungal names. After discussion in the Sessions on the decision of the NCF to appoint three such bodies, a Resolution to that effect was approved by the Congress. The Congress also adopted a Resolution asking that the opinions of mycologists on future directions for the nomenclature of fungi be taken into account in formulating changes in the rules for consideration at the International Botanical Congress in 2017. PMID- 25734035 TI - The importance of fungi and mycology for addressing major global challenges*. AB - In the new bioeconomy, fungi play a very important role in addressing major global challenges, being instrumental for improved resource efficiency, making renewable substitutes for products from fossil resources, upgrading waste streams to valuable food and feed ingredients, counteracting life-style diseases and antibiotic resistance through strengthening the gut biota, making crop plants more robust to survive climate change conditions, and functioning as host organisms for production of new biological drugs. This range of new uses of fungi all stand on the shoulders of the efforts of mycologists over generations: the scientific discipline mycology has built comprehensive understanding within fungal biodiversity, classification, evolution, genetics, physiology, ecology, pathogenesis, and nutrition. Applied mycology could not make progress without this platform. To unfold the full potentials of what fungi can do for both environment and man we need to strengthen the field of mycology on a global scale. The current mission statement gives an overview of where we are, what needs to be done, what obstacles to overcome, and which potentials are within reach. It further provides a vision for how mycology can be strengthened: The time is right to make the world aware of the immense importance of fungi and mycology for sustainable global development, where land, water and biological materials are used in a more efficient and more sustainable manner. This is an opportunity for profiling mycology by narrating the role played by fungi in the bioeconomy. Greater awareness and appreciation of the role of fungi can be used to build support for mycology around the world. Support will attract more talent to our field of study, empower mycologists around the world to generate more funds for necessary basic research, and strengthen the global mycology network. The use of fungi for unlocking the full potentials of the bioeconomy relies on such progress. The fungal kingdom can be an inspiration for even more. PMID- 25734037 TI - Repair of Large Lip Vermilion defects with Mutual Cross Lip Musculomucosal Flaps. AB - BACKGROUND: Vermilion irregularities are common secondary deformities after cleft lip repair, regressed or resected hemangiomas, trauma and tumor surgeries. Vermilion deficiency attracts considerable attention and detracts from an otherwise excellent lip repair. Minor and moderate vermilion defects can be corrected with upper lip advancement, rotation flaps, tongue flaps or grafts. Major defects defy correction with local flaps. A technique is described for correction of large absolute tissue defects of the vermilion using Mutual Cross Lip Musculomucosal Flaps (MCLMF) Or Ahmad-Ali's flaps. METHODS: This technique was applied in eight patients with major vermilion defects secondary to hemangioma regression, neoplasia, and trauma. Reconstruction with MCLMF led to create a balanced donor and recipient lips appearance and function. RESULTS: There were no postoperative complications. Surgical results were satisfactory in all patients, and sufficient lip mobility with adequate bulk was maintained. One patient demonstrated minimal transient lip tightening. CONCLUSION: Use of Ahmad Ali's flaps in selected patients resulted in successful reconstruction of severe vermilion defects. PMID- 25734036 TI - IMA Genome-F 3: Draft genomes of Amanita jacksonii, Ceratocystis albifundus, Fusarium circinatum, Huntiella omanensis, Leptographium procerum, Rutstroemia sydowiana, and Sclerotinia echinophila. AB - The genomes of fungi provide an important resource to resolve issues pertaining to their taxonomy, biology, and evolution. The genomes of Amanita jacksonii, Ceratocystis albifundus, a Fusarium circinatum variant, Huntiella omanensis, Leptographium procerum, Sclerotinia echinophila, and Rutstroemia sydowiana are presented in this genome announcement. These seven genomes are from a number of fungal pathogens and economically important species. The genome sizes range from 27 Mb in the case of Ceratocystis albifundus to 51.9 Mb for Rutstroemia sydowiana. The latter also encodes for a predicted 17 350 genes, more than double that of Ceratocystis albifundus. These genomes will add to the growing body of knowledge of these fungi and provide a value resource to researchers studying these fungi. PMID- 25734038 TI - Modified simple decompression of ulnar nerve in treatment of cubital tunnel syndrome. AB - BACKGROUND: There are two main surgical approaches, simple ulnar nerve decompression at the elbow, and anterior transposition of the nerve in treatment of cubital tunnel syndrome. Both techniques were reported in literature in details with similar reported success rates. Here, we present a modified simple decompression surgical technique in treatment of cubital tunnel syndrome. METHODS: Fifty eight patients diagnosed with cubital tunnel syndrome undergoing the presented technique were enrolled. This procedure consisted of ulnar nerve decompression at the elbow and a supplementary procedure of inter-muscular septum transverse cut between triceps and brachialis muscle above the elbow. RESULTS: Complete sensory recovery was observed in 35 (60.3%) patients, however, mild and occasional sensory symptoms remained in 15 (25.9%), and moderate symptoms persisted in 6 (10.3%) patients. In two patients (3.4%), no sensory improvement was recorded. Post-operatively, muscular hypotrophy improved completely in 5 out of 12 patients (41.7%). However, in the remaining 7 patients (58.3%) with muscular atrophy, motor recovery never took place. CONCLUSION: The presented modified simple decompression technique was shown to be an effective and safe procedure for the treatment of cubital tunnel syndrome without any complications. PMID- 25734039 TI - Incidence of breast cancer in fars province, southern iran: a hospital-based study. AB - BACKGROUND: Breast cancer is still considered as one of the most common female cancers worldwide regardless of the countries' level of development. This study determines the incidence of breast cancer in Fars Province, Southern Iran. METHODS: This study used patients' records from Shiraz University of Medical Sciences Cancer Registry Centre, which is a Hospital-Based Registry of Nemazee Hospital. Data were recorded based on International Classification of Diseases for Oncology (ICD-O) and compromised all invasive cancers in ICD-10 categories of C-00 to C-80. The findings were shown as the number of cases by site (ICD-10) and gender, with crude incidence (CRs), age-specific incidence and age-standardized incidence rates (ASRs) per 100,000 persons per year, performed by direct method using the world standard population. RESULTS: The age group of 40-49 years had the highest rate of breast cancer and naturally most cases were post-menopause ones. Most cases were diagnosed in moderate differentiated state with an increasing trend. Early diagnosis of in situ neoplasms has not increased over time in comprised with malignant cases. The number of diagnosed cases has sharply increased after year 2004 especially during post-menopause period. CONCLUSION: As the number of diagnosed cases has increased during post-menopausal period, screening and health programs seem necessary for menopause women. PMID- 25734040 TI - Use of local perforator flaps for post burn reconstruction. AB - BACKGROUND: Mainstay of post-burn reconstruction is release and split skin grafting. Pedicle flaps are cumbersome to the patient, require multiple procedures and hospitalization. Free flaps are technically demanding and facilities are not universally available. Here we evaluated the local perforator flaps for post-burn reconstruction. METHODS: We have used sixteen perforator propellar flaps for post-burn reconstruction for various areas of body. RESULTS: All flaps did well without any recontracture and need of splintage. CONCLUSION: Local perforator flaps should be considered as one of the primary treatment options for post burn reconstruction. PMID- 25734041 TI - Anaplastic large cell lymphoma associated with breast implants. AB - A forty two years old woman with a history of bilateral breast augmentation for cosmetic reasons was presented for poor healing of the surgical site. Tissue and periprosthetic fluid were removed from the wound site revealing an atypical lymphoid infiltrate. Subsequently the patient developed axillary lymph adenopathy. Excisional biopsy was performed. Flow cytometry was non-diagnostic. She continued to heal poorly and eventually had removal of implant during a simple mastectomy. A nodular area in the breast specimen showed ALK negative anaplastic large cell lymphoma (ALCL). The patient was treated in the private section, with only a pathology consultation being done at our institution (Figures 1-3). PMID- 25734042 TI - Combination surgical excision and fractional carbon dioxide laser for treatment of rhinophyma. AB - Rhinophyma is a severe late complication of rosacea, which is characterized by progressive hyperplasia of sebaceous glands and connective tissue involving the lower two-thirds of the nose. It can be an emotionally devastating disorder, and serve as a medium for occult cancers and other health problems. Many surgical treatments have been advocated, as well as dermabrasion and laser therapy. In light of the problems faced with these individual therapy modalities, we advocate a combination therapy of surgical debulking and fractionated Carbon dioxide laser therapy. By excising the tissue first, we not only decreased the amount of time needed for the procedure, we were also able to preserve a histopathologic specimen that can be examined for occult cancers. After debulking, the fractionated carbon dioxide laser is then used to blend. By using fractionated carbon dioxide, we avoided the complications associated with non-fractionated carbon dioxide lasers, such as delayed healing times, hypopigmentation, hyperpigmentation, scarring, and persistent redness. We report our experience in two patients with rhinophyma who underwent a combination of surgical excision and fractional Co2 laser therapy for treatment. Pre- and postoperative protocols and treatment parameters are discussed. Both patients had excellent cosmetic and functional results and were followed for at least one year. PMID- 25734043 TI - Fibrinolysinoma after direct injection of fibrinolysin for treatment of nasal tip swelling: a case report. AB - Rhinoplasty is one of the most common aesthetic procedures in the world. It is the most common aesthetic surgery procedure in Iran. Achieving complete patient satisfaction is almost impossible but improving the aesthetics and function of the nose is the aim of surgery. This report describes a 34 years old woman with a large bump in the tip of the nose after three times cosmetic rhinoplasties. The first time was done 4 years before referral to our center as a reduction rhinoplasty operation. The next two subsequent surgeries were performed for revision and correcting the dorsal irregularities and supra tip bulge. Unfortunately the supratip bulge persisted and subsequent subcutaneous injections of corticosteroids and fibrinolysin were carried out. She developed a bulbous tip nose deformity. Therefore, after a few months; she was referred to our center. Surgical exploration showed a lesion in the supratip region and histopathologic examination showed a foreign body reaction and granuloma formation. PMID- 25734044 TI - Anaplastic large cell lymphoma associated with breast implant: a case report. AB - Primary breast lymphoma represents less than 1% of all primary breast malignancies and most primary breast lymphomas are of B-Cell origin. The association of anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma (ALCL), a very rare form of primary breast lymphoma, with silicone filled breast implants has been suggested and several case reports supported this proposal, especially in Western countries. Here we describe one of the first cases of primary breast ALK-negative ALCL in association with saline-filled silicone breast implants evaluated in Iran, where the rising number of breast reconstructive and aesthetic surgeries would commit both surgical pathologists and plastic surgeons to be familiar with this entity. PMID- 25734045 TI - Breast implants and breast cancer. PMID- 25734046 TI - The effect of enoxaparin and clopidogrel on survival of random skin flap in rat animal model. AB - BACKGROUND: Necrosis of skin flaps is considered as an important complication in reconstructive surgery. We conducted an experimental study to investigate the efficacy of low-molecular weight heparin, clopidogrel and their combination to improve the flap survival. METHODS: Forty male, adult Sprague-Dawlay rats were divided randomly into 4 groups. Standard rectangular, distally based dorsal random pattern skin flap was elevated. To prevent the graft effect, a sterile sheet was put under the flap. No pharmacological agent was administered for the control group. In group 2, single subcutaneous dose of enoxaparin (3.2 mg/kg) was immediately administrated after surgery. In group 3, clopidogrel (25 mg/kg) was given orally for 7 days. In group 4, both enoxaparin and clopidogrel were administrated. The rats were evaluated on post-operative day 7 for viable and necrotic portions of flaps. RESULTS: The mean and SD of necrosis was 17.79+2.5 cm in the control group, 16.20+/-3.1 cm in low-molecular weight heparin, 15.25+3.8 cm in combined therapy group and 13.69+2.7 cm in clopidogrel group. Clopidogrel was the only pharmaceutical agent that produced a significant increase in the flap survival area. CONCLUSION: Clopidogrel may be an effective pharmaceutical agent that significantly increases viability of random skin flaps in rats, but low-molecular weight heparin and their combination did not have any significant beneficial effects. PMID- 25734047 TI - Histopathological evaluation of reduction mammaplasty specimens to detect occult breast cancer: a report from southern iran. AB - BACKGROUND: Reduction mammaplasty (RM) is among the commonly performed procedures by plastic surgeons. Occult breast cancers are rarely detected in these specimens. The purpose of the study was to describe histopathological evaluation of reduction mammaplasty specimens to detect occult breast cancer in Southern Iran. METHODS: The histological diagnosis of 350 RM specimens from 175 patients to detect occult breast cancer was evaluated retrospectively. This study determines the incidence of breast cancer too. RESULTS: Microscopic examination revealed that 233 specimens had no pathological changes, 106 showed evidences of fibrocystic disease, 2 were diagnosed as fibroadenoma, 4 were diagnosed as adenosis and one was diagnosed as a phylloides tumor. Furthermore, 4 specimens were diagnosed as carcinomas; 2 as medullary carcinoma and 2 as intraductal carcinoma. Four occult carcinomas were detected in young, unmarried women. CONCLUSION: Thorough gross and microscopic examination helped to detect these occult carcinomas and also helped in planning futuretreatments. We consider a thorough gross examination and sampling of mammaplasty specimens to be mandatory. PMID- 25734048 TI - Evaluation of female patients motivating factors for aesthetic surgery. AB - BACKGROUND: Nowadays, plastic surgeries are among the most popular types of surgeries around the world and Iran has one of the highest rankings in this respect regarding its population size. Based on these facts, the present study was conducted in order to evaluate the volunteers' motivations attitudes and informational sources in Tehran, Iran. METHODS: The study was conducted on a cross-sectional basis. All patients who underwent plastic surgeries during years 2005 and 2006 were evaluated and all the required information was recorded and statistically analyzed. RESULTS: Seventy five patients were enrolled. Their average age was 33+/-13 years (minimum of 17 and maximum of 63 years old). Rhinoplasty (52%) and abdominoplasty (8%) were the most and least common performed surgeries, respectively. The major important motivators were family, friends, classmates, and colleagues (40%) and the least were magazines and journals (4%).10.7% oftheparticipants described theposture and function of the target organs as perfect, but they planned to improve its aesthetic or functional aspects by surgery. CONCLUSION: Those who achieve their information of aesthetic surgery from mass media have a better understanding of this field. Also, the motivational stimuli for performing aesthetic surgeries have shown to be different from what were previously deemed. PMID- 25734049 TI - The synergistic effect of bleomycin, triamcinolone and epinephrine in treatment of hemangioma and arteriovenous malformations. AB - BACKGROUND: Hemangioma is the most common tumor of neonatal period and it is almost always appeared by the end of the first week of life and can be found mostly in head and neck area. This study evaluated the synergistic effect of bleomycin, triamcinolone and epinephrine in treatment of hemangioma and arteriovenous malformations. METHODS: In this multicenter study, a combination of bleomycin, triamcinolone and epinephrine was injected intralesionaly for treatment of hemangiomas and arteriovenous malformations and their synergistic effect was evaluated in 32 patients. RESULTS: Hemangiomas and low-flow arteriovenous malformations were treated well with their combination while port wine spots and high-flow lesions response were relatively poor. CONCLUSION: It seems that the combination of bleomycin, triamcinolone and epinephrine may be a good choice in treatment of hemangioma and arteriovenous malformations. PMID- 25734050 TI - Effects of platelet-rich plasma on cartilage grafts in rabbits as an animal model. AB - BACKGROUND: Cartilage tissue has limited regenerative capacity and the management of cartilage defects has always been a challenging issue. Platelet-rich plasma (PRP) has been recently been used to improve healing of cartilage defects. In the present experiment, we aimed to investigate the effects of PRP on regeneration capacity as well as survival of the cartilage grafts in a rabbit model. METHODS: In 15 white New Zealand rabbits, auricular cartilage was used to produce 4 pieces of cartilage (each about 2*2 cm). Two samples were diced to small pieces and 2 samples left intact. PRP was prepared using 5 ml of auricular blood. After measuring of the weight and volume of cartilages, they mixed with either normal saline or PRP and then implanted on the back of the rabbit. After 12 weeks, the implants were removed and the weight and volume were measured and the numbers of nucleated lacunae were counted on H & E staining. RESULTS: Histological findings showed that in both the intact and diced cartilages, adding PRP resulted in increasing regeneration of chondrocytes. Moreover, adding PRP to intact cartilages had a significant effect in maintaining the grafts 'weight and volume (p<0.05) but in diced cartilages, this effect was not significant. CONCLUSION: Our findings yielded valuable information on the effect of PRP on survival and regeneration of autologous cartilage grafts as the extent of angiogenesis and the diameters of vessels were more pronounced in the side using PRP and markedly lesser reduction of weight and volume were visible in this group. PRP was effective in increasing survival and regeneration capacity of cartilage grafts in rabbit model. PMID- 25734051 TI - Factors affecting patients undergoing cosmetic surgery in bushehr, southern iran. AB - BACKGROUND: Although, there have been extensive research on the motivations driving patient to undergo cosmetic procedures, there is still a big question mark on the persuasive factors which may lead individuals to undergo cosmetic surgery. The present study evaluated various factors affecting patients undergoing cosmetic surgery in Bushehr, Southern Iran. METHODS: From 24th March 2011 to 24th March 2012, eighty-one women and 20 men who wished to be operated in Fatemeh Zahra Hospital in Bushehr, Southern Iran and Pars Clinic, Iran were enrolled by a simple random sampling method. They all completed a questionnaire to consider reasons for cosmetic procedures. The collected data were statistically analyzed. RESULTS: Demographical, sociological and psychological factors such as age, gender, educational level, marital status, media, perceived risks, output quality, depression and self-improvement were determined as factors affecting tendency of individuals to undergo cosmetic surgery in this region. Trend to undergo cosmetic surgery was more prevalent in educational below bachelor degree, married subjects, women population of 30-45 years age group. Education level, age, marital status and gender were respectively the influential factors in deciding to undergo cosmetic surgery. Among the socio-psychological factors, self-improvement, finding a better job opportunity, rivalry, media, health status as well as depression were the most persuasive factors to encourage people to undergo cosmetic surgery too. Cost risk was not important for our samples in decision making to undergo cosmetic surgery. CONCLUSION: We need to fully understand the way in which the combination of demographic, social and psychological factors influence decision-making to undergo cosmetic surgery. PMID- 25734052 TI - Cavernous sinus and generalized venous thrombosis following rhinoplasty in a young patient. AB - Venous thromboembolism at lower age groups and in the absence of other known risk factors should raise doubt of underlying genetic disorders and thombophilia. It is discovered unexpectedly in various medical procedures and may cause severe complications and life threatening problems. In the current study, potentially life threatening complications of a genetic disorder in a previously healthy case is discussed. The important point in this case was delay onset of complication and its severity when was unexpectedly discovered. This situation may happen in almost every cosmetic operation and when the surgeon is not well prepared for managing this medical condition that it may lead to a dramatically poor prognosis for the patient. PMID- 25734053 TI - Management of the lateral walls in crooked nose. AB - In crooked noses, the lateral walls are different in shape and symmetry. Although the septum is very important to obtain a straight nose, identical and symmetrical lateral walls are needed for a straight looking nasal dorsum. As well as the septum, lateral walls also contribute in nasal skeletal support and stability. Thus, obtaining identical and symmetrical lateral walls is important. In order to obtain symmetrical and stable lateral walls, the requirements are to equalize the height, to set in a symmetric location and finally to stabilize the symmetry. These requirements must be taken into consideration while performing the steps of rhinoplasty, namely, hump resection, osteotomies and stabilization by spreader grafts or flaps. Here, we describe the management of the lateral walls in crooked nose in 7 cases. PMID- 25734054 TI - Complex nasal and periorbital reconstruction using locoregional flaps: a case report. AB - Facial reconstruction is one of the most challenging problems faced by a reconstructive surgeon. We present a case of complex facial reconstruction with a composite trauma to the nose resulting in near total loss of skin and lining along with complete loss of left eyebrow with exposed frontal bone and partial loss of the left eyelid. We combined a temporoparietal fascial flap for reconstruction of the eyebrows and covering the exposed frontal bone and prefabricated forehead flap with skin graft for nasal reconstruction. Proper planning and staging of the surgical procedures and use of local flaps gave us good aesthetic and functional outcome with a satisfied patient. PMID- 25734055 TI - Genetic variability of Candida albicans Sap8 propeptide in isolates from different types of infection. AB - The secreted aspartic proteases (Saps) are among the most studied virulence determinants in Candida albicans. These proteins are translated as pre-pro enzymes consisting of a signal sequence followed by a propeptide and the mature enzyme. The propeptides of secreted proteinases are important for the correct processing, folding/secretion of the mature enzyme. In this study, the DNA sequences of C. albicans Saps were screened and a microsatellite was identified in SAP8 propeptide region. The genetic variability of the repetitive region of Sap8 propeptide was determined in 108 C. albicans independent strains isolated from different types of infection: oral infection (OI), oral commensal (OC), vulvovaginal candidiasis (VVC), and bloodstream infections (BSI). Nine different propeptides for Sap8 processing were identified whose frequencies varied with the type of infection. OC strains presented the highest gene diversity while OI isolated the lowest. The contribution of the Saps to mucosal and systemic infections has been demonstrated and recently Sap8 has been implicated in the cleavage of a signalling glycoprotein that leads to Cek1-MAPK pathway activation. This work is the first to identify a variable microsatellite in the propeptide of a secreted aspartic protease and brings new insights into the variability of Sap8. PMID- 25734056 TI - Transcriptional activity of human endogenous retroviruses in human peripheral blood mononuclear cells. AB - Human endogenous retroviruses (HERVs) have been implicated in human physiology and in human pathology. A better knowledge of the retroviral transcriptional activity in the general population and during the life span would greatly help the debate on its pathologic potential. The transcriptional activity of four HERV families (H, K, W, and E) was assessed, by qualitative and quantitative PCR, in PBMCs from 261 individuals aged from 1 to 80 years. Our results show that HERV-H, HERV-K, and HERV-W, but not HERV-E, are transcriptionally active in the test population already in the early childhood. In addition, the transcriptional levels of HERV-H, HERV-K, and HERV-W change significantly during the life span, albeit with distinct patterns. Our results, reinforce the hypothesis of a physiological correlation between HERVs activity and the different stages of life in humans. Studies aiming at identifying the factors, which are responsible for these changes during the individual's life, are still needed. Although the observed phenomena are presumably subjected to great variability, the basal transcriptional activity of each individual, also depending on the different ages of life, must be carefully considered in all the studies involving HERVs as causative agents of disease. PMID- 25734057 TI - Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder. AB - Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders. PMID- 25734058 TI - Cinnabar induces renal inflammation and fibrogenesis in rats. AB - The purpose of this study was to investigate whether cinnabar causes renal inflammation and fibrosis in rats. Rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks. The control rats were treated with solvent (5% carboxymethylcellulose solution) over the same time periods, respectively. Renal mercury (RHg), urinary mercury (UHg), serum creatinine (SCr), urine kidney injury molecule 1 (KIM-1), renal pathology, and renal mediators were examined. At both 8 weeks and 12 weeks, RHg, UHg, and urine KIM-1 were significantly higher in the cinnabar group than in the control group, although SCr was unchanged. Kidney lesions in the cinnabar-treated rats occurred mainly in the tubules and interstitium, including vacuolization, protein casts, infiltration of inflammatory cells, and slight increase in interstitial collagen. In addition, mild mesangial proliferation was observed in glomeruli. Moreover, the expression of inflammatory and fibrogenic mediators was upregulated in the cinnabar group. In conclusion, cinnabar may cause kidney damage due to the accumulation of mercury, and renal inflammation and slight fibrogenesis may occur in rats. In the clinic, the potential risk of renal injury due to the prolonged consumption of cinnabar should be considered even though the agent is relatively nontoxic. PMID- 25734060 TI - Electroporation loading of membrane-impermeable molecules to investigate intra- and intercellular Ca2+ signaling. AB - Electroporation is a technique that temporarily induces pores in the plasma membranes of cells, thereby allowing plasma membrane-impermeable substances to enter the cells. This loading method requires an electrical drive circuit providing an electroporation signal, an electrode to apply the signal to a localized zone in a cell monolayer, and a special solution that has a low electrical conductivity. To avoid impairment of cell function and cell death from the electroporation procedure itself, the applied electrical signal should ideally be a high-frequency oscillating signal (50 kHz) without any direct current (DC) component. Here, we describe the detailed procedure of electroporation loading. PMID- 25734059 TI - Time for a break: admissions to an urban emergency department after working out- a retrospective study from Switzerland. AB - BACKGROUND: The present retrospective study was intended to investigate whether working out and other low-speed sports can provoke cardiovascular, neurological, or traumatic damage. MATERIAL AND METHODS: Patient data from 2007 to 2013 was collected and saved at the university department of emergency medicine in an electronic patient record database. RESULTS: Of the 138 patients included in this study, 83.3% (n = 115) were male and 16.7% female (n = 23). Most admissions were due to musculoskeletal accidents (n = 77; 55.8%), followed by neurological incidents (n = 23; 16.7%), cardiovascular incidents (n = 19; 13.8%), soft tissue injuries (n = 3; 2.2%), and others (n = 16; 11.6%). The mean age of the allover injured people was 36.7 years. The majority of the patients (n = 113; 81.9%) were treated as outpatients; 24 (17.4%) were inpatients. Discussion. In Switzerland, this is the first study that describes emergency department admissions after workout and examines trauma and neurological and cardiovascular incidents. As specific injuries, such as brain haemorrhages, STEMIs, and epileptic seizures, were relatively frequent, it was hypothesised that workout with its physiological changes may be an actual trigger for these injuries, at least for a specific population. CONCLUSION: Strenuous physical activity may trigger the risk of cardiovascular, neurological, or trauma events. PMID- 25734061 TI - Flash photolysis of caged IP3 to trigger intercellular Ca2+ waves. AB - Caged IP3 is an inactive form of the second messenger IP3, consisting of the biologically active molecule linked to a cage group through a photolabile bond. This bond is cleaved by exposure to brief "flashes" of ultraviolet (UV) light, thereby releasing the active IP3 molecule. The protection of caged IP3 against metabolic transformation in combination with a defined time point of fast photoliberation of IP3 provides an efficient way to temporally and spatially control the cytosolic release of IP3 and subsequent increase of cytoplasmic Ca(2+). These properties make it an ideal method for kinetic studies and also a well-suited procedure to initiate intercellular Ca(2+) waves from a point source of IP3. This protocol describes cell loading with membrane impermeable caged IP3 and the UV flash illumination procedure. PMID- 25734062 TI - Tamoxifen administration to mice. AB - The strategy of fusing a protein of interest to a hormone-binding domain (HBD) of a steroid hormone receptor allows fine control of the activity of the fused protein. Such fusion proteins are inactive in the absence of ligand, because they are complexed with a variety of intracellular polypeptides. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. In the murine estrogen receptor (ER) fusion system, proteins are fused to the HBD of the ER. The system relies on the use of a mutant ER known as ER(TAM). Compared to the wild-type HBD, ER(TAM) has 1000-fold lower affinity for estrogen, yet remains responsive to activation by the synthetic steroid 4 hydroxytamoxifen (4-OHT). Because 4-OHT is expensive, animals can be treated with the cheaper precursor tamoxifen, which is converted into 4-OHT by a liver enzyme. Here we present an overview of the methods used to deliver tamoxifen to mice. The most used method is intraperitoneal injection, because the amount of administered compound can be better controlled, but delivery by oral gavage is also possible. For short-term and immediate-effect studies or when conversion of tamoxifen by the liver is to be avoided, 4-OHT can be used directly. PMID- 25734063 TI - Northern blots: capillary transfer of RNA from agarose gels and filter hybridization using standard stringency conditions. AB - In this protocol, an RNA sample, fractionated by gel electrophoresis, is transferred from the gel onto a membrane by capillary transfer. Short-wave UV light is used to fix the transferred RNA to the membrane. The membrane is then pretreated to block nonspecific probe-binding sites, and hybridization of the immobilized RNA to a (32)P-labeled DNA or RNA probe specific for the mRNA of interest is performed. Finally, the membrane is washed and subjected to autoradiography or phosphorimaging. Because exposure to UV cross-links the RNA to the membrane, the membrane can be stripped and hybridized with other probes. The procedure is suitable for detecting poly(A)(+)-selected mRNA or mRNA in total cellular RNA if the target transcript is relatively abundant. Using DNA or RNA probes labeled to 1 * 10(8)-10 * 10(8) cpm/ug, it should be possible to detect ~5 pg of a specific RNA. PMID- 25734064 TI - An alternative method for processing northern blots after capillary transfer. AB - Different laboratories use different methods for the prehybridization, hybridization, and washing steps of the northern blotting procedure. In this protocol, a northern blot is pretreated with Church and Gilbert hybridization buffer to block nonspecific probe-binding sites. The immobilized RNA is then hybridized to a DNA probe specific for the RNA of interest. Finally, the membrane is washed and subjected to autoradiography or phosphorimaging. The solutions and conditions described here may be ideal for those who prefer to use fewer ingredients in their solutions. This protocol is designed to achieve the same goals as other northern blotting approaches. It minimizes background (nonspecific adherence of probe to membrane and nonspecific hybridization) and maximizes specific hybridization to RNAs immobilized on a membrane. PMID- 25734065 TI - Isolation of ribosomes and polysomes. AB - Here we describe a preparative differential centrifugation protocol for the isolation of ribosomes from a crude cell homogenate. The subcellular fraction obtained is enriched in ribosome monomers and polysomes. The protocol has been optimized for the homogenization and collection of the ribosomal fraction from prokaryotic cells, mammalian and plant tissues, reticulocytes, and chloroplasts. The quality of the ribosomal preparation is enhanced by the removal of the remaining cellular components and adsorbed proteins by pelleting through a sucrose cushion with a high concentration of monovalent salts, NH4Cl or KCl. The different components of the ribosomal fraction isolated using this protocol can be further purified by sucrose gradient centrifugation. PMID- 25734066 TI - Purification of 70S ribosomes. AB - Here we describe the further purification of prokaryotic ribosomal particles obtained after the centrifugation of a crude cell lysate through a sucrose cushion. In this final purification step, a fraction containing ribosomes, ribosomal subunits, and polysomes is centrifuged through a 7%-30% (w/w) linear sucrose gradient to isolate tight couple 70S ribosomes, as well as dissociated 30S and 50S subunits. The tight couples fraction, or translationally active ribosome fraction, is composed of intact vacant ribosomes that can be used in cell-free translation systems. PMID- 25734067 TI - Purification of polysomes. AB - Isolated polysomes (also known as translating ribosomes or polyribosomes) are mRNA-ribosome complexes that are frequently used for the in vitro study of the regulation of protein synthesis. Here we describe a protocol for the isolation of prokaryotic and plant polysomes by sucrose gradient sedimentation. The protocol allows for the separation of multiple ribosomes attached to mRNA from run-off ribosome monomers. In addition to collecting the polysome pellet, if the sucrose gradients used in this protocol are fractionated, it is possible to isolate and quantify the polysomes, the ribosome monomers, and the ribosomal subunits. PMID- 25734068 TI - Combinatorial analysis of mRNA expression patterns in mouse embryos using hybridization chain reaction. AB - Multiplexed fluorescent hybridization chain reaction (HCR) and advanced imaging techniques can be used to evaluate combinatorial gene expression patterns in whole mouse embryos with unprecedented spatial resolution. Using HCR, DNA probes complementary to mRNA targets trigger chain reactions in which metastable fluorophore-labeled DNA HCR hairpins self-assemble into tethered fluorescent amplification polymers. Each target mRNA is detected by a probe set containing one or more DNA probes, with each probe carrying two HCR initiators. For multiplexed experiments, probe sets for different target mRNAs carry orthogonal initiators that trigger orthogonal DNA HCR amplification cascades labeled by spectrally distinct fluorophores. As a result, in situ amplification is performed for all targets simultaneously, and the duration of the experiment is independent of the number of target mRNAs. We have used multiplexed fluorescent in situ HCR and advanced imaging technologies to address questions of cell heterogeneity and tissue complexity in craniofacial patterning and anterior neural development. In the sample protocol presented here, we detect three different mRNA targets: Tg(egfp), encoding the enhanced green fluorescent protein (GFP) transgene (typically used as a control); Twist1, encoding a transcription factor involved in cell lineage determination and differentiation; and Pax2, encoding a transcription factor expressed in the mid-hindbrain region of the mouse embryo. PMID- 25734069 TI - Evaluating yeast filamentous growth at the single-cell level. AB - Budding yeast can undergo filamentous growth in response to nutrient limitation. Filament formation can be examined under glucose-limiting conditions by the single-cell invasive growth assay, or under nitrogen-limiting conditions with the pseudohyphal growth assay, both described here. The single-cell assay allows robust quantitation of changes in budding pattern and cell length, and most cells in the population show the response. The pseudohyphal growth assay reveals filamentous patterns in larger microcolonies and adjoining subpopulations of cells. Historically, the single-cell assay has been used to study filamentous growth in haploid cells and the pseudohyphal growth assay in diploid cells. However, both assays can be used in either cell type. PMID- 25734070 TI - Evaluating the activity of the filamentous growth mitogen-activated protein kinase pathway in yeast. AB - Mitogen-activated protein kinase (MAPK) pathways are evolutionarily conserved signaling pathways that regulate diverse processes in eukaryotes. One such pathway regulates filamentous growth, a nutrient limitation response in budding yeast and other fungal species. This protocol describes three assays used to measure the activity of the filamentous growth pathway. First, western blotting for phosphorylated (activated) MAPKs (P~MAPKs; Slt2p, Kss1p, Fus3p, and Hog1p) provides a measure of MAPK activity in yeast and other fungal species. Second, the PGU1 gene is a transcriptional target of the filamentous growth pathway. Cells that undergo filamentous growth secrete Pgu1p, an endopolygalacturonase that degrades the plant-specific polysaccharide pectin. We describe an assay that measures secreted pectinase activity, which reflects an active filamentous growth pathway. Finally, in yeast, two mucin-like glycoproteins, Msb2 and Flo11, regulate filamentous growth. Secretion of the processed and shed glycodomain of Msb2 is an indicator of MAPK activity. Flo11, the major adhesion molecule that controls filamentous growth and biofilm/mat formation, is also shed from cells. Detecting shed mucins with epitope-tagged versions of the proteins (secretion profiling) provides information about the regulation of filamentous growth across fungal species. PMID- 25734071 TI - Electroporation loading and flash photolysis to investigate intra- and intercellular Ca2+ signaling. AB - Many cellular functions are driven by variations in the intracellular Ca(2+) concentration ([Ca(2+)]i), which may appear as a single-event transient [Ca(2+)]i elevation, repetitive [Ca(2+)]i increases known as Ca(2+) oscillations, or [Ca(2+)]i increases propagating in the cytoplasm as Ca(2+) waves. Additionally, [Ca(2+)]i changes can be communicated between cells as intercellular Ca(2+) waves (ICWs). ICWs are mediated by two possible mechanisms acting in parallel: one involving gap junctions that form channels directly linking the cytoplasm of adjacent cells and one involving a paracrine messenger, in most cases ATP, that is released into the extracellular space, leading to [Ca(2+)]i changes in neighboring cells. The intracellular messenger inositol 1,4,5-trisphosphate (IP3) that triggers Ca(2+) release from Ca(2+) stores is crucial in these two ICW propagation scenarios, and is also a potent trigger to initiate ICWs. Loading inactive, "caged" IP3 into cells followed by photolytic "uncaging" with UV light, thereby liberating IP3, is a well-established method to trigger [Ca(2+)]i changes in single cells that is also effective in initiating ICWs. We here describe a method to load cells with caged IP3 by local electroporation of monolayer cell cultures and to apply flash photolysis to increase intracellular IP3 and induce [Ca(2+)]i changes, or initiate ICWs. Moreover, the electroporation method allows loading of membrane-impermeable agents that interfere with IP3 and Ca(2+) signaling. PMID- 25734072 TI - The estrogen receptor fusion system in mouse models: a reversible switch. AB - Reversible regulatory mouse models have significantly contributed to our understanding of normal tissue and cancer biology, providing the opportunity to temporally control initiation, progression, and evolution of physiological and pathological events. The tamoxifen inducible system, one of the best characterized "reversible switch" models, has a number of beneficial features. In this system, the hormone-binding domain of the mammalian estrogen receptor is used as a heterologous regulatory domain. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. We summarize the advantages and drawbacks of the system, describe several mouse models that rely on it, and discuss potential improvements that could render it even more useful and versatile. PMID- 25734073 TI - Investigating filamentous growth and biofilm/mat formation in budding yeast. AB - In response to nutrient limitation, budding yeast can undergo filamentous growth by differentiating into elongated chains of interconnected cells. Filamentous growth is regulated by signal transduction pathways that oversee the reorganization of cell polarity, changes to the cell cycle, and an increase in cell adhesion that occur in response to nutrient limitation. Each of these changes can be easily measured. Yeast can also grow colonially atop surfaces in a biofilm or mat of connected cells. Filamentous growth and biofilm/mat formation require cooperation among individuals; therefore, studying these responses can shed light on the origin and genetic basis of multicellular behaviors. The assays introduced here can be used to study analogous behaviors in other fungal species, including pathogens, which require filamentous growth and biofilm/mat formation for virulence. PMID- 25734074 TI - Multiphoton excitation of fluorescent probes. AB - This introduction reviews the multiphoton excitation cross sections of extrinsic and intrinsic fluorophores, genetically engineered probes, and nanoparticles. We will review the known two-photon excitation cross sections of biological indicators and will discuss several related issues such as how to theoretically estimate and experimentally gauge the two-photon cross section of an indicator. We provide practical guides for experimentally estimating the excitation cross section. PMID- 25734075 TI - A Welcome to Open Forum Infectious Diseases (OFID). PMID- 25734076 TI - Quotidian changes of genital tract cytokines in human immunodeficiency virus-1 infected women during the menstrual cycle. AB - The role of hormonal changes throughout the menstrual cycle on genital tract inflammation during chronic human immunodeficiency virus (HIV) infection is not well defined, but it has implications for HIV prevention. We assessed daily levels of 26 vaginal cytokines and chemokines from 15 women infected with HIV-1. Taking into account coexisting sexually transmitted infections, behavioral factors, and menstruation, this study illustrates cyclic patterns of granulocyte macrophage colony-stimulating factor, interferon-alpha2, interleukin (IL)-6, IL 10, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and tumor necrosis factor (TNF)-alpha. Progesterone was associated with levels of granulocyte colony stimulating factor, IL-1alpha, and monocyte chemoattractant protein-1. Interferon alpha2, IL-6, MIP-1alpha, MIP-1beta, and TNF-alpha levels predicted HIV shedding, but these associations were heavily influenced by the menstrual cycle. PMID- 25734078 TI - Heparin-binding protein: a diagnostic biomarker of urinary tract infection in adults. AB - BACKGROUND: Urinary tract infections (UTIs) are associated with significant morbidity and high frequency of antibiotic prescription. Diagnosing UTI is often difficult, particularly in the critically ill patient and in patients with unspecific and mild symptoms. The standard rapid tests have limited value, and there is a need for more reliable diagnostic tools. Heparin-binding protein (HBP) is released from neutrophils and has previously been studied as a diagnostic and predictive biomarker in different bacterial infections. METHODS: This prospective survey enrolled adult patients at 2 primary care units and 2 hospital emergency departments, to investigate in urine HBP as a biomarker of UTI. In addition, urine levels of interleukin-6, white blood cells, and nitrite were analyzed and compared with HBP. Based on symptoms of UTI and microbiological findings, patients were classified into different groups, UTI (cystitis and pyelonephritis) and no UTI. RESULTS: Three hundred ninety patients were evaluated. The prevalence of UTI in the study group was 45.4%. The sensitivity and specificity for HBP in urine as a marker for UTI were 89.2% and 89.8%, respectively. The positive and negative predictive values were 90.2% and 88.8%, respectively. Heparin-binding protein was the best diagnostic marker for UTI, with an area-under-curve value of 0.94 (95% confidence interval, 0.93-0.96). Heparin-binding protein was significantly better in distinguishing cystitis from pyelonephritis, compared with the other markers. CONCLUSIONS: An elevated level of HBP in the urine is associated with UTI and may be a useful diagnostic marker in adult patients with a suspected UTI. PMID- 25734077 TI - Cystatin C-based renal function changes after antiretroviral initiation: a substudy of a randomized trial. AB - BACKGROUND: The effects of antiretrovirals on cystatin C-based renal function estimates are unknown. METHODS: We analyzed changes in renal function using creatinine and cystatin C-based estimating equations in 269 patients in A5224s, a substudy of study A5202, in which treatment-naive patients were randomized to abacavir/lamivudine or tenofovir/emtricitabine with open-label atazanavir/ritonavir or efavirenz. RESULTS: Changes in renal function significantly improved (or declined less) with abacavir/lamivudine treatment compared with tenofovir/emtricitabine using the Cockcroft-Gault formula (P = .016) and 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; P = .030) and 2012 CKD-EPI cystatin C-creatinine (P = .025). Renal function changes significantly improved (or declined less) with efavirenz compared with atazanavir/ritonavir (P < .001 for all equations). Mean (95% confidence interval) renal function changes specifically for tenofovir/emtricitabine combined with atazanavir/ritonavir were -8.3 (-14.0, -2.6) mL/min with Cockcroft-Gault; -14.9 ( 19.7, -10.1) mL/min per 1.73(2) with Modification of Diet in Renal Disease; -12.8 (-16.5, -9.0) mL/min per 1.73(2) with 2009 CKD-EPI; +8.9 (4.2, 13.7) mL/min per 1.73(2) with 2012 CKD-EPI cystatin C; and -1.2 (-5.1, 2.6) mL/min per 1.73(2) with 2012 CKD-EPI cystatin C-creatinine. Renal function changes for the other treatment arms were more favorable but similarly varied by estimating equation. CONCLUSIONS: Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used. PMID- 25734079 TI - New onset of kaposi sarcoma in a human immunodeficiency virus-1-infected homosexual man, despite early antiretroviral treatment, sustained viral suppression, and immune restoration. AB - This is a rare case of new onset Kaposi sarcoma in a man infected with human immunodeficiency virus (HIV) and receiving antiretroviral treatment since primary HIV infection, with normal CD4(+) cell count and suppressed viral load. The presentation questions the general understanding of Kaposi sarcoma as an acquired immune deficiency syndrome-defining disease occurring predominantly in severely immunocompromised patients infected with HIV. PMID- 25734080 TI - Empiric vancomycin use in febrile neutropenic oncology patients. AB - Vancomycin is commonly added as empiric therapy for febrile neutropenia. A retrospective chart review was conducted at a large community teaching institution to evaluate vancomycin use in oncology patients. The results revealed that a majority of empiric vancomycin therapy was inappropriate, raising concern for antibiotic resistance and prompting opportunities for improvement. PMID- 25734081 TI - ID Learning Unit: Understanding and Interpreting Testing for Clostridium difficile. AB - Understanding and interpreting the molecular tests for Clostridium difficile is challenging because there are several different types of assays and most laboratories combine multiple tests in order to assess for presence of disease. This learning unit demonstrates the basic principles of each test along with its strengths and weaknesses, and illustrates how the tests are used in clinical practice. PMID- 25734082 TI - An enabling act. AB - Infection with human T-lymphotropic virus type 1 (HTLV-1) can be associated with hematologic malignancy, inflammatory syndromes, or infectious complications. Herein, we bring attention to HTLV-1 infection complications as we discuss a case of disseminated cryptococcosis in a patient with HTLV-1-associated T cell lymphoma. PMID- 25734083 TI - Relationship between hepatitis C clinical testing site and linkage to care. AB - BACKGROUND: The Centers for Disease Control and Prevention recommends one-time hepatitis C virus (HCV) testing of the population born between 1945 and 1965 with follow-up RNA testing for those with reactive serology. To increase the rate of diagnosis, testing may be considered in settings other than outpatient clinics (OC), such as inpatient wards (IP) or emergency department (ED). METHODS: We used electronic medical records to create a retrospective cohort with reactive HCV serology between 2005 and 2010 at an urban safety net hospital. We determined factors associated with linkage to HCV care as measured by HCV RNA testing, and we evaluated the rate of linkage to care according to diagnosis location (OC, IP, or ED). RESULTS: Individuals, 37 828, were tested and 5885 (16%) were reactive. Seropositivity was similar across all sites. Of the 4466 patients who met inclusion criteria, 3400 (76%) were diagnosed in the OC, whereas 967 (22%) and 99 (2%) were tested in the IP and the ED, respectively. A total of 2135 (48%) underwent HCV RNA testing. Using multivariable regression modeling, the following factors were independently associated with HCV RNA testing: diagnosis in the OC (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.42-1.90); age at diagnosis in decades (OR, 0.98; 95% CI, 0.98-0.99); private insurance (OR, 1.17; 95% CI, 1.01-1.34); and >=10 visits after diagnosis (OR, 2.15; 95% CI, 1.89 2.44). CONCLUSION: There is an opportunity to increase HCV diagnosis by testing in sites other than the OC, but this opportunity needs to be coupled with robust initiatives to improve linkage to care. PMID- 25734084 TI - Antiretroviral Therapy (ART) Use, Human Immunodeficiency Virus (HIV)-1 RNA Suppression, and Medical Causes of Hospitalization Among HIV-Infected Intravenous Drug Users in the Late ART Era. AB - BACKGROUND: Antiretroviral therapy (ART) has reduced the rates and changed the causes of hospital admission. However, human immunodeficiency virus-positive intravenous drug users (HIV-IDU) continue to have increased hospitalizations and discharge diagnosis are less defined in the late ART era. Our aim was to examine ART use, HIV-1 RNA suppression, and hospital discharge diagnoses among HIV-IDU admitted to an urban hospital. METHODS: A retrospective analysis was made of HIV IDU admitted for medical causes for the first time (2006-2010). Surgical, obstetric, or mental (except HIV-associated neurocognitive disorder) diagnoses were excluded. Clinical characteristics, number of admissions, and primary discharge diagnoses were determined for each patient. RESULTS: Three hundred and seventy-five admissions were recorded among 197 hospitalized HIV-IDU. Lifetime prevalence of ART use was 83.2% (164 of 197) and the rate of HIV-1 RNA <50 copies/mL was 38.1% (75 of 197). Primary discharge diagnosis groups were as follows: bacterial infections (59.2%), chronic end-organ damage (16.8%), complications derived from injected drug use (16.8%), malignancies (9.1%), and opportunistic infections (6.6%). Chronic end-organ damage was diagnosed more frequently in patients with HIV-1 RNA <50 copies/mL (36% vs 4.9%; P < .000), and complications derived from injected drug use (23.8% vs 5.3%; P < .0008) and acquired immune deficiency syndrome (AIDS) opportunistic infections (19.8% vs 1.3% P < .019) were usually diagnosed in patients with HIV-1 RNA detectable viral load. CONCLUSIONS: Human immunodeficiency virus-positive intravenous drug users are admitted to hospitals mainly for non-AIDS-related illnesses; however, sustained HIV-1 RNA viral load suppression is poor and determines hospital discharge diagnoses. Providers need to be aware of the management of HIV-related comorbidities and reinforce strategies to improve ART retention in this population. PMID- 25734085 TI - High Mortality Among Human Immunodeficiency Virus (HIV)-Infected Individuals Before Accessing or Linking to HIV Care: A Missing Outcome in the Cascade of Care? AB - BACKGROUND: The "cascade of care" displays the proportion of individuals who are infected with human immunodeficiency virus (HIV), diagnosed, linked, retained, on antiretroviral treatment, and HIV suppressed. We examined the implications of including death in the use of this cascade for program and public health performance metrics. METHODS: Individuals newly diagnosed with HIV and living in Calgary between 2006 and 2013 were included. Through linkage with Public Health and death registries, the deaths (ie, all-cause mortality) and their distribution within the cascade were determined. Mortality rates are reported per 100 person years. RESULTS: Estimated new HIV infections were 680 (543 confirmed and 137 unknown cases). Forty-three individuals, after diagnosis, were never referred for HIV care. Despite referral(s), 88 individuals (18%) never attended the clinic for HIV care. Of individuals retained in care, 87% received antiretroviral therapy and 76% achieved viral suppression. Thirty-six deaths were reported (mortality rate, 1.50/100 person-years). One diagnosis was made posthumously. Deaths (20 of 35; 57%) occurred for individuals linked but not retained in care (6.93/100 person-years), and 70% were HIV-related. Mortality rate for patients in care was 0.79/100 person-years. Retained patients with detectable viremia had a death rate of 2.49/100, which contrasted with 0.28/100 person-years in those with suppressed viremia. Eight of these 15 deaths (53%) were HIV-related. CONCLUSIONS: Over half of deaths occurred in those referred but not effectively linked or retained in HIV care, and these cases may be easily overlooked in standard HIV mortality studies. Inclusion of deaths into the cascade may further enhance its value as a public health metric. PMID- 25734086 TI - Factors associated with cancer incidence and with all-cause mortality after cancer diagnosis among human immunodeficiency virus-infected persons during the combination antiretroviral therapy era. AB - BACKGROUND: Little is known about survival and factors associated with mortality after cancer diagnosis among persons infected with human immunodeficiency virus (HIV). METHODS: Using Poisson regression, we analyzed incidence rates of acquired immune deficiency syndrome (AIDS)-defining cancers (ADC), non-AIDS-defining infection-related cancers (NADCI), and non-AIDS-defining noninfection-related cancers (NADCNI) among HIV Outpatient Study participants seen at least twice from 1996-2010. All-cause mortality within each cancer category and by calendar period (1996-2000, 2001-2005, 2006-2010) were examined using Kaplan-Meier survival methods and log-rank tests. We identified risk factors for all-cause mortality using multivariable Cox proportional hazard models. RESULTS: Among 8350 patients, 627 were diagnosed with 664 cancers. Over the 3 time periods, the age- and sex adjusted incidence rates for ADC and NADCNI declined (both P < .001) and for NADCI did not change (P = .13). Five-year survival differed by cancer category (ADC, 54.5%; NADCI, 65.8%; NADCNI, 65.9%; P = .018), as did median CD4 cell count (107, 241, and 420 cells/mm(3); P < .001) and median log10 viral load (4.1, 2.3, and 2.0 copies/mL; P < .001) at cancer diagnosis, respectively. Factors independently associated with increased mortality for ADC were lower nadir CD4 cell count (hazard ratio [HR] = 3.02; 95% confidence interval [CI], 1.39-6.59) and detectable viral load (>=400 copies/mL; HR = 1.72 [95% CI, 1.01-2.94]) and for NADCNI, age (HR = 1.50 [95% CI, 1.16-1.94]), non-Hispanic black race (HR = 1.92 [95% CI, 1.15-3.24]), lower nadir CD4 cell count (HR = 1.77 [95% CI, 1.07 2.94]), detectable viral load (HR = 1.96 [95% CI, 1.18-3.24]), and current or prior tobacco use (HR = 3.18 [95% CI, 1.77-5.74]). CONCLUSIONS: Since 1996, ADC and NADCNI incidence rates have declined. Survival after cancer diagnosis has increased with concomitant increases in CD4 cell count in recent years. Advances in HIV therapy, including early initiation of combination antiretroviral therapy, may help reduce mortality risk among HIV-infected persons with cancer. PMID- 25734087 TI - Green herring syndrome: bacterial infection in patients with mucormycosis cavitary lung disease. AB - Mucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease. PMID- 25734088 TI - Multisite Laboratory Evaluation of a Dual Human Immunodeficiency Virus (HIV)/Syphilis Point-of-Care Rapid Test for Simultaneous Detection of HIV and Syphilis Infection. AB - BACKGROUND: Recently, test developers have created rapid point-of-care tests that can simultaneously detect multiple infections within the same specimen using a single device. The SD BIOLINE Duo HIV/Syphilis rapid point-of-care test uses a solid-phase immunochromatographic assay to detect immunoglobulin (Ig)G, IgM, and IgA antibodies to human immunodeficiency virus (HIV)-specific antigens (HIV-1 gp41, sub O, HIV-2 gp36) and recombinant Treponema pallidum antigen (17 kDa) in human serum. This study was a multisite laboratory-based evaluation of the performance of SD BIOLINE HIV/Syphilis Duo test using previously characterized sera in 6 countries. METHODS: Laboratories in Ghana, Mexico, Laos, Togo, Kenya, and Myanmar participated in the evaluation during 2012-2013. Each site characterized sera using T pallidum particle agglutination assay or T pallidum hemagglutination assay and HIV enzyme immunoassay, Western blot, and/or HIV antibody rapid tests. Those gold standard test results were compared with SD BIOLINE Duo test results. We calculated the sensitivity and specificity of test performance and used the exact binomial method to calculate 95% confidence intervals (CIs). RESULTS: The sensitivity and specificity for the HIV antibody test component (n = 2336) were estimated at 99.91% (95% CI, 99.51% and 100%) and 99.67% (95% CI, 99.16% and 99.91%), respectively. For the T pallidum test component (n = 2059), the sensitivity and specificity were estimated at 99.67% (95% CI, 98.82% and 99.96%) and 99.72% (95% CI, 99.29% and 99.92%), respectively. CONCLUSIONS: The sensitivity and specificity of the SD BIOLINE HIV/Syphilis Duo test were consistently high across sera specimens from 6 countries around the world. Dual rapid tests should be considered for improved HIV and syphilis screening coverage. PMID- 25734089 TI - Safety Profile of the Merck Human Immunodeficiency Virus-1 Clade B gag DNA Plasmid Vaccine With and Without Adjuvants. AB - The immunogenicity results from 3 phase I trials of the Merck DNA human immunodeficiency virus (HIV) vaccine have previously been reported. Because preventive DNA vaccine strategies continue to be leveraged for diverse infections, the safety and tolerability results from these studies can inform the field moving forward, particularly regarding adverse reactions and adjuvants. No serious vaccine-related adverse events were reported during the 3-dose priming phase. Pain at the injection site was more common with adjuvanted formulations than with the phosphate-buffered saline diluent alone. Febrile reactions were usually low grade. Although the AlPO4 or CRL1005 adjuvants used in these studies did not significantly enhance the immunogenicity of the DNA vaccine, adverse events were numerically more common with adjuvanted formulations than without adjuvants. PMID- 25734090 TI - Do clinical trials fit in a private medical practice? PMID- 25734091 TI - Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study. AB - OBJECTIVES: We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry. METHODS: Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-nucleotide polymorphisms (SNPs), CCR5 Delta32 genotype, and human leukocyte antigen (HLA) class I alleles and viral coreceptor usage were explored. RESULTS: Viral phenotypes were obtained from 593 patients with available genome-wide SNP data. Forty-four percent of subjects had virus capable of using CXCR4 for entry as determined by phenotyping. Overall, no associations, including those between polymorphisms in genes encoding viral coreceptors and their promoter regions or in HLA genes previously associated with HIV-1 disease progression, passed the statistical threshold for genome-wide significance (P < 5.0 * 10(-8)) in any comparison. However, the presence of viruses able to use CXCR4 for entry was marginally associated with the CCR5 Delta32 genotype in the nongenome-wide analysis. CONCLUSIONS: No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome wide level. Although the sample size had limited power to definitively exclude genetic associations, these results suggest that host genetic factors, including those that influence coreceptor expression or the immune pressures leading to viral envelope diversity, are either rare or have only modest effects in determining HIV-1 coreceptor usage. PMID- 25734092 TI - Urinalysis in acute care of adults: pitfalls in testing and interpreting results. AB - BACKGROUND: Rapid urine tests for infection (urinalysis, dipstick) have low up front costs. However, many false positives occur, with important downstream consequences, including unnecessary antibiotics. We studied indications, collection technique, and results of urinalyses in acute care. METHODS: This research was a prospective observational study of a convenience sample of emergency department (ED) patients who had urinalysis performed between June 1, 2012 and February 15, 2013 at an urban teaching hospital. Analyses were conducted via t tests, chi(2) tests, and multivariable logistic regression. RESULTS: Of 195 cases included in the study, the median age was 56 and 70% of participants were female. There were specific symptoms or signs of urinary tract infection (UTI) in 74 cases (38%; 95% confidence interval [CI], 31%-45%), nonspecific symptoms or signs in 83 cases (43%; 95% CI, 36%-50%), and no symptoms or signs of UTI in 38 cases (19%; 95% CI, 14%-25%). The median age was 51 (specific symptoms), 58 (nonspecific symptoms), and 61 (no symptoms), respectively (P = .005). Of 137 patients who produced the specimen without assistance, 78 (57%; 95% CI, 48%-65%) received no instructions on urine collection. Correct midstream clean-catch technique was used in 8 of 137 cases (6%). Presence of symptoms or signs was not associated with a new antibiotic prescription, but positive urinalysis (OR, 4.9; 95% CI, 1.7-14) and positive urine culture (OR, 3.6; 95% CI, 1.1-12) were. Of 36 patients receiving antibiotics, 10 (28%; 95% CI, 13%-43%) had no symptoms or nonspecific symptoms. CONCLUSION: In this sample at an urban teaching hospital ED, urine testing was not driven by symptoms. Improving practice may lower costs, improve efficiency of care, decrease unnecessary data that can distract providers and impair patient safety, decrease misdiagnosis, and decrease unnecessary antibiotics. PMID- 25734093 TI - Corticosteroid effects on sputum culture in pulmonary tuberculosis: a meta regression analysis. AB - OBJECTIVES: There is increasing interest in the potential role of adjunctive anti inflammatory therapy to accelerate tuberculosis (TB) treatment. Sputum culture conversion is an important biomarker predictor of durable TB cure. METHODS: This study used meta-regression analysis to examine the relationship between corticosteroid dose and sputum culture conversion, using published data from controlled clinical trials including 1806 corticosteroid-treated TB patients. RESULTS: Linear models with 2 or 3 variables, including corticosteroid dose and the proportion of culture positive control subjects, predicted therapeutic benefit of corticosteroids at 1 and 2 months. The 3-variable model predicted that 134 mg of prednisolone per day, given together with standard 4-drug TB chemotherapy, would reduce the proportion of positive culture at 2 months from 15% to 2%. The estimate accounts for a 50% reduction in steroid exposure due to rifampin. A proportion of 2% of subjects with positive cultures at 2 months has been proposed as a target for new 4-month TB regimens. CONCLUSIONS: These positive findings must be tempered by recognition that the metabolic and cardiovascular risks of corticosteroids administered at this dose for this duration are unlikely to be acceptable when examined from a patient-level benefit risk perspective. In future research studies to shorten TB treatment, biologic anti-inflammatory therapies with similar therapeutic effects but superior safety profiles should be considered. PMID- 25734094 TI - Impact of human immunodeficiency virus on the severity of buruli ulcer disease: results of a retrospective study in cameroon. AB - BACKGROUND: Buruli ulcer is the third most common mycobacterial disease after tuberculosis and leprosy and is particularly frequent in rural West and Central Africa. However, the impact of HIV infection on BU severity and prevalence remains unclear. METHODS: This was a retrospective study of data collected at the Akonolinga District Hospital, Cameroon, from January 1, 2002 to March 27, 2013. Human immunodeficiency virus prevalence among BU patients was compared with regional HIV prevalence. Baseline characteristics of BU patients were compared between HIV-negative and HIV-positive patients and according to CD4 cell count strata in the latter group. Buruli ulcer time-to-healing was assessed in different CD4 count strata, and factors associated with BU main lesion size at baseline were identified. RESULTS: Human immunodeficiency virus prevalence among BU patients was significantly higher than the regional estimated prevalence in each group (children, 4.00% vs 0.68% [P < .001]; men, 17.0% vs 4.7% [P < .001]; women, 36.0% vs 8.0% [P < .001]). Individuals who were HIV positive had a more severe form of BU, with an increased severity in those with a higher level of immunosuppression. Low CD4 cell count was significantly associated with a larger main lesion size (beta-coefficient, -0.50; P = .015; 95% confidence interval [CI], -0.91-0.10). Buruli ulcer time-to-healing was more than double in patients with a CD4 cell count below 500 cell/mm(3) (hazard ratio, 2.39; P = .001; 95% CI, 1.44-3.98). CONCLUSION: Patients who are HIV positive are at higher risk for BU. Human immunodeficiency virus-induced immunosuppression seems to have an impact on BU clinical presentation and disease evolution. PMID- 25734095 TI - Spinal and paraspinal fungal infections associated with contaminated methylprednisolone injections. AB - BACKGROUND: A nationwide outbreak of fungal infections was traced to injection of Exserohilum-contaminated methylprednisolone. We describe our experience with patients who developed spinal or paraspinal infection after injection of contaminated methylprednisolone. METHODS: Data were assembled from the Michigan Department of Community Health, electronic medical records, and magnetic resonance imaging (MRI) reports. RESULTS: Of 544 patients who received an epidural injection from a contaminated lot of methylprednisolone at a pain clinic in southeastern Michigan, 153 (28%) were diagnosed at our institution with probable or confirmed spinal or paraspinal fungal infection at the injection site. Forty-one patients had both meningitis and spinal or paraspinal infection, and 112 had only spinal or paraspinal infection. Magnetic resonance imaging abnormalities included abscess, phlegmon, arachnoiditis, and osteomyelitis. Surgical debridement in 116 patients revealed epidural phlegmon and epidural abscess most often. Among 26 patients with an abnormal MRI but with no increase or change in chronic pain, 19 (73%) had infection identified at surgery. Fungal infection was confirmed in 78 patients (51%) by finding hyphae in tissues, positive polymerase chain reaction, or culture. Initial therapy was voriconazole plus liposomal amphotericin B in 115 patients (75%) and voriconazole alone in 38 patients (25%). As of January 31, 2014, 20 patients remained on an azole agent. Five patients died of infection. CONCLUSIONS: We report on 153 patients who had spinal or paraspinal fungal infection at the site of epidural injection of contaminated methylprednisolone. One hundred sixteen (76%) underwent operative debridement in addition to treatment with antifungal agents. PMID- 25734096 TI - Higher human T-lymphotropic virus type 1 subtype C proviral loads are associated with bronchiectasis in indigenous australians: results of a case-control study. AB - BACKGROUND: We previously suggested that infection with the human T-lymphotropic virus type 1 (HTLV-1) subtype C is associated with bronchiectasis among Indigenous Australians. Bronchiectasis might therefore result from an HTLV-1 mediated inflammatory process that is typically associated with a high HTLV-1 proviral load (PVL). Human T-lymphotropic virus type 1 PVL have not been reported for Indigenous Australians. METHODS: Thirty-six Indigenous adults admitted with bronchiectasis from June 1, 2008, to December 31, 2009 were prospectively recruited and matched by age, sex, and ethno-geographic origin to 36 controls. Case notes and chest high-resolution computed tomographs were reviewed, and pulmonary injury scores were calculated. A PVL assay for the HTLV-1c subtype that infects Indigenous Australians was developed and applied to this study. Clinical, radiological, and virological parameters were compared between groups and according to HTLV-1 serostatus. RESULTS: Human T-lymphotropic virus type 1 infection was the main predictor of bronchiectasis in a multivariable model (adjusted risk ratio [aRR], 1.84; 95% confidence interval [CI], 1.19-2.84; P = .006). Moreover, the median HTLV-1c PVL (interquartile range) for cases was >100 fold that of controls (cases, 0.319 [0.007, 0.749]; controls, 0.003 [0.000, 0.051] per 100 peripheral blood lymphocytes; P = .007), and HTLV-1c PVL were closely correlated with radiologically determined pulmonary injury scores (Spearman's rho = 0.7457; P = .0000). Other predictors of bronchiectasis were positive Strongyloides serology (aRR, 1.69; 95% CI, 1.13-2.53) and childhood skin infections (aRR, 1.62; 95% CI, 1.07-2.44). Bronchiectasis was the major predictor of death (aRR, 2.71; 95% CI, 1.36-5.39; P = .004). CONCLUSIONS: These data strongly support an etiological association between HTLV-1 infection and bronchiectasis in a socially disadvantaged population at risk of recurrent lower respiratory tract infections. PMID- 25734097 TI - Rates of pneumococcal disease in adults with chronic medical conditions. AB - BACKGROUND: Although it is widely accepted that adults with immunocompromising conditions are at greatly increased risk of pneumococcal infection, the extent of risk among immunocompetent adults with chronic medical conditions is less certain, particularly in the current era of universal vaccination of children with pneumococcal conjugate vaccines. METHODS: We conducted a retrospective cohort study using data from 3 healthcare claims repositories (2006-2010) to compare rates of pneumococcal disease in immunocompetent adults with chronic medical conditions ("at-risk") and immunocompromised adults ("high-risk"), with rates in adults without these conditions ("healthy"). Risk profiles and episodes of pneumococcal disease-all-cause pneumonia, pneumococcal pneumonia, and invasive pneumococcal disease (IPD)-were ascertained from diagnosis, procedure, and drug codes. RESULTS: Rates of all-cause pneumonia among at-risk persons aged 18-49 years, 50-64 years, and >=65 years were 3.2 (95% confidence interval [CI], 3.1 3.2), 3.1 (95% CI, 3.1-3.1), and 3.0 (95% CI, 3.0-3.0) times the rates in age matched healthy counterparts, respectively. We identified rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and neuromuscular or seizure disorders as additional at-risk conditions for pneumococcal disease. Among persons with at-risk conditions, the rate of all-cause pneumonia substantially increased with the accumulation of concurrent at-risk conditions (risk stacking): among persons 18-49 years, rate ratios increased from 2.5 (95% CI, 2.5-2.5) in those with 1 at-risk condition to 6.2 (95% CI, 6.1-6.3) in those with 2 conditions, and to 15.6 (95% CI, 15.3-16.0) in those with >=3 conditions. Findings for pneumococcal pneumonia and IPD were similar. CONCLUSIONS: Despite widespread use of pneumococcal conjugate vaccines, rates of pneumonia and IPD remain disproportionately high in adults with at-risk conditions, including those with conditions not currently included in the Advisory Committee on Immunization Practices' guidelines for prevention and those with multiple at-risk conditions. PMID- 25734098 TI - Bacteremia with Aerococcus sanguinicola: Case Series with Characterization of Virulence Properties. AB - BACKGROUND: Since Aerococcus sanguinicola was designated as a species in 2001, only a few cases of bacteremia have been reported. The aim with this study was to describe the clinical presentation of A sanguinicola bacteremia and to determine the antibiotic susceptibility and the capacity of the bacteria to form biofilm and to induce platelet aggregation. METHODS: Isolates of A sanguinicola from blood cultures were retrospectively identified from 2 clinical microbiology laboratories for 2006 to 2012. Species identity was confirmed through sequencing of the 16S rRNA gene. The medical charts of patients were reviewed. The minimum inhibitory concentration (MIC) for relevant antibiotics was determined. Biofilm formation was measured as the amount of crystal violet absorbed. Platelet aggregation was determined by aggregometry. RESULTS: Eleven cases of A sanguinicola bacteremia were identified. All patients were male and the median age was 82 years (range 67-93). Nine patients fulfilled criteria for severe sepsis, and 2 patients died at hospital. Two patients were diagnosed with infective endocarditis. Most patients had underlying urinary tract diseases or an indwelling urinary tract catheter. Five patients suffered from dementia. None of the patients was treated with immunosuppressive medications. The MIC values of the isolates were in line with previous reports, with low MICs for penicillin, cefotaxime, and vancomycin. All 11 isolates produced biofilms but not all could induce platelet aggregation. CONCLUSIONS: A sanguinicola can cause severe infections in elderly men with urinary tract abnormalities and the bacteria possess potential virulence mechanisms. PMID- 25734099 TI - Candida pneumonia in intensive care unit? AB - It has been questioned if Candida pneumonia exists as a clinical entity. Only histopathology can establish the definite diagnosis. Less invasive diagnostic strategies lack specificity and have been insufficiently validated. Scarcity of this pathomechanism and nonspecific clinical presentation make validation and the development of a clinical algorithm difficult. In the present study, we analyze whether Candida pneumonia exists in our critical care population. We used a bronchoalveolar lavage (BAL) specimen database that we have built in a structural diagnostic approach to ventilator-associated pneumonia for more than a decade consisting of 832 samples. Microbiological data were linked to clinical information and available autopsy data. We searched for critically ill patients with respiratory failure with no other microbiological or clinical explanation than exclusive presence of Candida species in BAL fluid. Five cases could be identified with Candida as the likely cause of pneumonia. PMID- 25734100 TI - Endothelial activation and repair during hantavirus infection: association with disease outcome. AB - BACKGROUND: Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated. METHODS: The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1). RESULTS: Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity. CONCLUSIONS: Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions. PMID- 25734101 TI - Hypervirulent Klebsiella pneumoniae. AB - Hypervirulent strains of Klebsiella pneumoniae are associated with abscess formation, commonly hepatic, and metastatic spread, even in healthy patients. We describe a case of this clinical syndrome, genotypic and phenotypic features of the isolate, and briefly review epidemiology, clinical manifestations, and pathogenesis of this underappreciated syndrome. PMID- 25734102 TI - Influenza hospitalizations among american indian/alaska native people and in the United States general population. AB - BACKGROUND: Historically, American Indian/Alaska Native (AI/AN) people have experienced a disproportionate burden of infectious disease morbidity compared with the general US population. We evaluated whether a disparity in influenza hospitalizations exists between AI/AN people and the general US population. METHODS: We used Indian Health Service hospital discharge data (2001-2011) for AI/AN people and 13 State Inpatient Databases (2001-2008) to provide a comparison to the US population. Hospitalization rates were calculated by respiratory year (July-June). Influenza-specific hospitalizations were defined as discharges with any influenza diagnoses. Influenza-associated hospitalizations were calculated using negative binomial regression models that incorporated hospitalization and influenza laboratory surveillance data. RESULTS: The mean influenza-specific hospitalization rate/100 000 persons/year during the 2001-2002 to 2007-2008 respiratory years was 18.6 for AI/AN people and 15.6 for the comparison US population. The age-adjusted influenza-associated hospitalization rate for AI/AN people (98.2; 95% confidence interval [CI], 51.6-317.8) was similar to the comparison US population (58.2; CI, 34.7-172.2). By age, influenza-associated hospitalization rates were significantly higher among AI/AN infants (<1 year) (1070.7; CI, 640.7-2969.5) than the comparison US infant population (210.2; CI, 153.5-478.5). CONCLUSIONS: American Indian/Alaska Native people had higher influenza-specific hospitalization rates than the comparison US population; a significant influenza-associated hospitalization rate disparity was detected only among AI/AN infants because of the wide CIs inherent to the model. Taken together, the influenza-specific and influenza-associated hospitalization rates suggest that AI/AN people might suffer disproportionately from influenza illness compared with the general US population. PMID- 25734103 TI - Fatal chagas disease among solid-organ transplant recipients in Colombia. AB - Chagas disease continues to cause substantial morbidity and mortality in endemic areas in Latin America. Although there have been some well documented successes in halting the transmission of Chagas disease through preventive interventions to decrease vector-borne and blood-transfusion cases, this parasitic infection continues to be transmitted through these routes in some areas as well through perinatal and foodborne routes. In addition, transmission through solid-organ transplantation has been described in nonendemic settings due to the increasing globalization of Chagas disease to the United States of America, Europe, and other areas. Because there has been a concomitant increase in the number of solid organ transplantations performed in Latin American settings endemic for American trypanosomiasis, there is increasing concern for the potential reactivation of Trypanosoma cruzi in a previously infected recipient and as a result of aggressive immunosuppression; or via transmission from organs donated by a latently infection donor transplanted onto an uninfected recipient. In this study, we report 2 cases of Chagas disease reactivation in 2 solid-organ transplant recipients in Northeastern Colombia, and we discuss the implications for screening as a crucial strategy for preventing transmission in endemic settings. PMID- 25734104 TI - Severe morbidity and mortality risk from malaria in the United States, 1985-2011. AB - BACKGROUND: Recent reports of Plasmodium vivax associated with severe syndromes and mortality from malaria endemic areas questions the "benign" course of non falciparum malarias. METHODS: We retrospectively analyzed data from patients reported to the US Centers for Disease Control and Prevention with a diagnosis of malaria parasite single-species infection between 1985 and 2011. Patients classified as having severe illness were further classified according to outcome (survival versus death) and clinical syndrome. RESULTS: Among all cases, .9% of Plasmodium falciparum cases resulted in death and 9.3% were classified as severe, whereas .09% of P. vivax cases resulted in death and 1.3% were classified as severe. The odds ratios for severe illness among 15 272 diagnoses of P. falciparum relative to patients diagnosed with P. vivax (n = 12 152), Plasmodium malariae (n = 1254), or Plasmodium ovale (n = 903) was 7.5, 5.7, and 5.0, respectively (P < .0001 for all); in contrast, the corresponding odds ratios for death among those severely ill was 1.6, 1.1, and .8 (P > .1 for all), respectively. Compared with P. vivax (n = 163), the odds of P. falciparum cases classified as severely ill (n = 1416) were 1.9 (P = .0006), .5 (P = .001), and 1.3 times (P = .1) as likely to present as cerebral, acute respiratory distress, and renal syndromes, respectively. CONCLUSIONS: Although less common, patients presenting with non-falciparum even in the United States can develop severe illness, and severe illness in patients having malaria of any species threatens life. PMID- 25734105 TI - A study of viral hepatitis e infection in a tertiary care hospital in mysore, South India. AB - BACKGROUND: In this study, we aimed to explore the clinical and epidemiological profile of all patients with hepatitis E virus (HEV) who were admitted to a tertiary care hospital in Mysore, India and to further assess various factors that influence the prognosis of these patients. METHODS: Two hundred ninety patients with HEV infection were included in the study and interviewed. They were subjected to clinical examination and laboratory investigations, including complete hemogram, renal, and liver function tests. Viral markers for HBV, HAV, HCV, and HEV by hepatitis B surface antigen, anti-HAV, anti-HCV, and anti-HEV antibodies, respectively, were done using the enzyme-linked immunosorbent assay method. Final outcome was recorded in the form of discharge or death. RESULTS: Males had higher (82.8%) incidence of HEV infection. Yellowish discoloration of urine was the most common symptom, and icterus was the most common sign at presentation. Hepatomegaly was most common finding on abdominal examination. Mean duration of hospital stay was higher among diabetics (10 days vs 7.11 +/- 3.52 days). Overall, mortality observed was 3.45%. A higher mean age (P = .000) and duration of hospital stay (P = .000) were associated with higher mortality. Mortality was significantly higher among patients with alcohol abuse (25% vs 0%) (P = .004). Higher mean prothrombin time-international normalised ratio (PT-INR) (1.6 +/- 0.13 vs 1.21 +/- 0.32), total bilirubin (20.3 +/- 5.08 vs 11.33 +/- 7.26 mg/dL), and direct bilirubin (15.05 +/- 3.64 vs 6.35 +/- 3.71 mg/dL) were associated with higher mortality, whereas lower mean serum albumin (2.6 +/- 0.11 vs 3.41 +/- 0.40 gm/dL) was associated with higher mortality. Increase in renal parameters (ie, urea [97 +/- 33.48 vs 32.43 +/- 18.41 mg/dL] and creatinine [2.9 +/- 1.38 vs 1.12 +/- 0.64 mg/dL]) and electrolyte imbalances (ie, hyperkalemia [5.95 +/- 1.21 vs 4.29 +/- 0.51 mmol/L] and hyponatremia [123 +/- 3.56 vs 136.04 +/- 2.97 mmol/L]) were associated with higher mortality. There were 20-fold increases in mean serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) values (SGPT: SGOT = 1.148) and a 1-fold increase in mean alkaline phosphatase. CONCLUSIONS: Higher mean age, duration of hospital stay, PT-INR, total bilirubin, direct bilirubin, blood urea, serum creatinine, potassium values, alcohol abuse, presence of ascites, and fulminant hepatitis were associated with higher mortality, whereas lower mean serum albumin and sodium values were associated with higher mortality. Diabetics had a higher mean duration of hospital stay. PMID- 25734106 TI - Impact of Xpert MTB/RIF on Antiretroviral Therapy-Associated Tuberculosis and Mortality: A Pragmatic Randomized Controlled Trial. AB - INTRODUCTION: GeneXpert(r) MTB/RIF (Xpert) is now widely distributed in high human immunodeficiency virus (HIV)/tuberculosis (TB)-burden countries. Yet, whether the test improves patient-important outcomes within HIV treatment programs in limited resource settings is unknown. METHODS: To investigate whether use of Xpert for TB screening prior to initiation of antiretroviral treatment (ART) improves patient-important outcomes, in a pragmatic randomized controlled trial we assigned 424 patients to Xpert or fluorescence sputum smear microscopy (FM) at ART initiation. The primary endpoint was a composite of 3-month mortality and ART-associated TB. RESULTS: There was no difference in overall TB diagnosis at ART initiation (20% [n = 43] Xpert vs 21% [n = 45] FM; P = .80), with most patients in both groups treated empirically. There was no difference in time to TB treatment initiation {5 days (interquartile range [IQR], 3-13) vs 8 days [IQR, 3-23; P = .26]} or loss to follow-up (32 [15%] vs 38 [18%]; P = 0.38). Although a nonsignificant reduction in mortality occurred in the Xpert group (11 [6%] vs 17 [10%]; 95% CI, -9% to 2%; P = .19), there was no difference in the composite outcome (9% [n = 17] Xpert vs 12% [n = 21] FM; difference -3%; 95% CI, -9% to 4%). CONCLUSIONS: Among HIV-infected initiating ART, centralized TB screening with Xpert did not reduce the rate of ART-associated TB and mortality, compared with fluorescence microscopy. PMID- 25734107 TI - High rates of virological suppression in a cohort of human immunodeficiency virus positive adults receiving antiretroviral therapy in ethiopian health centers irrespective of concomitant tuberculosis. AB - BACKGROUND: Antiretroviral therapy (ART) initiation during treatment for tuberculosis (TB) improves survival in human immunodeficiency virus (HIV)/TB coinfected patients. We compared virological suppression (VS) rates, mortality, and retention in care in HIV-positive adults receiving care in 5 Ethiopian health centers with regard to TB coinfection. METHODS: Human immunodeficiency virus positive ART-naive adults eligible for ART initiation were prospectively recruited. At inclusion, all patients underwent microbiological investigations for TB (sputum smear, liquid culture, and polymerase chain reaction). Virological suppression rates after 6 months of ART (VS; viral load <40 and <400 copies/mL) with regard to TB status was the primary outcome. The impact of HIV/TB coinfection on VS rates was determined by multivariate regression analysis. Mortality and retention in care were analyzed by proportional hazard models. RESULTS: Among 812 participants (TB, 158; non-TB, 654), 678 started ART during the follow-up period (TB, 135; non-TB, 543). No difference in retention in care between TB and non-TB patients was observed during follow-up; 25 (3.7%) patients died, and 17 (2.5%) were lost to follow-up (P = .30 and P = .83, respectively). Overall rates of VS at 6 months were 72.1% (<40 copies/mL) and 88.7% (<400 copies/mL), with similar results for subjects with and without TB coinfection (<40 copies/mL: 65 of 92 [70.7%] vs 304 of 420 [72.4%], P = .74; <400 copies/mL: 77 of 92 [83.7%] vs 377 of 420 [89.8%], P = .10, respectively). CONCLUSIONS: High rates of VS can be achieved in adults receiving ART at health centers, with no significant difference with regard to TB coinfection. These findings demonstrate the feasibility of combined ART and anti-TB treatment in primary healthcare in low-income countries. CLINICAL TRIALS REGISTRATION: NCT01433796. PMID- 25734108 TI - Substantial overlap between incarceration and tuberculosis in atlanta, georgia, 2011. AB - Standard tuberculosis case reporting captures incarceration at diagnosis only. This retrospective analysis of 106 US-born adults with prevalent tuberculosis in 2011 found that 46.2% had documented histories of being in jail or prison, including 16.0% during the year before diagnosis. PMID- 25734109 TI - Voriconazole-Resistant Penicillium oxalicum: An Emerging Pathogen in Immunocompromised Hosts. AB - Penicillium species are rarely reported agents of infections in immunocompromised patients. We report 3 cases of invasive mycosis caused by voriconazole-resistant Penicillium oxalicum in patients with acute myeloid leukemia, diabetes mellitus, and chronic obstructive pulmonary disease, while on voriconazole therapy. Penicillium oxalicum has not been previously recognized as a cause of invasive mycoses. PMID- 25734111 TI - Good-bye Agar-Agar: What's Coming for Infectious Disease (ID) Diagnostic Tests (Acute and Convalescent ID Doctors). PMID- 25734110 TI - The spread and control of norovirus outbreaks among hospitals in a region: a simulation model. AB - BACKGROUND: Because hospitals in a region are connected via patient sharing, a norovirus outbreak in one hospital may spread to others. METHODS: We utilized our Regional Healthcare Ecosystem Analyst software to generate an agent-based model of all the acute care facilities in Orange County (OC), California and simulated various norovirus outbreaks in different locations, both with and without contact precautions. RESULTS: At the lower end of norovirus reproductive rate (R0) estimates (1.64), an outbreak tended to remain confined to the originating hospital (<=6.1% probability of spread). However, at the higher end of R0 (3.74), an outbreak spread 4.1%-17.5% of the time to almost all other OC hospitals within 30 days, regardless of the originating hospital. Implementing contact precautions for all symptomatic cases reduced the probability of spread to other hospitals within 30 days and the total number of cases countywide, but not the number of other hospitals seeing norovirus cases. CONCLUSIONS: A single norovirus outbreak can continue to percolate throughout a system of different hospitals for several months and appear as a series of unrelated outbreaks, highlighting the need for hospitals within a region to more aggressively and cooperatively track and control an initial outbreak. PMID- 25734112 TI - A Glimpse of the Early Years of the Human Immunodeficiency Virus Epidemic: A Fellow's Experience in 2014. AB - Human immunodeficiency virus (HIV) is a manageable chronic disease in the United States, yet the first author's experience on a general infectious diseases (ID) consult service illustrates that certain areas of the United States still experience high rates of acquired immune deficiency syndrome-related complications. PMID- 25734113 TI - Nonencapsulated Streptococcus pneumoniae Cause Acute Otitis Media in the Chinchilla That Is Enhanced by Pneumococcal Surface Protein K. AB - BACKGROUND: Use of the pneumococcal conjugate vaccine has led to serotype replacement of carriage and acute otitis media (AOM) pneumococcal isolates. Increases in nonencapsulated Streptococcus pneumoniae (NESp) isolates have also occurred, and there are increasing reports of NESp-associated disease. Disease prevalence and virulence factors of NESp isolates have not been studied. METHODS: A chinchilla model of pneumococcal AOM was utilized, and disease was assessed through bacterial enumeration along with scoring visible signs of pathology. An adhesion-invasion assay using a human epithelial cell line was performed. RESULTS: Nonencapsulated Streptococcus pneumoniae strains containing pneumococcal surface protein K (PspK) were more likely to cause AOM and pathology upon infection. Deletion of PspK from an isolate significantly reduced bacterial loads. Increased epithelial cell adhesion correlated with increased virulence of NESp isolates naturally lacking PspK. Furthermore, expression of PspK by an avirulent NESp resulted in virulence. CONCLUSIONS: The presence of PspK increased the disease potential of NESp. Pneumococcal surface protein K is not the only virulence factor of NESp in AOM. Expression of PspK in an avirulent NESp mediated the progression to pneumococcal disease. Genetic exchange between pneumococci may allow dissemination of PspK, increasing the potential of NESp disease. The current study is the first report of a NESp-specific virulence factor. PMID- 25734114 TI - Obesity Trends and Body Mass Index Changes After Starting Antiretroviral Treatment: The Swiss HIV Cohort Study. AB - BACKGROUND: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized. METHODS: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART. RESULTS: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06 0.24] kg/m(2)) and CD4 nadir <199 cells/uL compared to nadir >350 (P < .001). Annualized BMI change during years 1-4 was associated with CD4 nadir <100 cells/uL compared to nadir >350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change. CONCLUSIONS: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0 1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited. PMID- 25734115 TI - Incidence of herpes simplex virus type 2 infections in Africa: a systematic review. AB - The burden of HSV type 2 varies substantially by region, with the highest incidence and prevalence in sub-Saharan Africa. We undertook a systematic review to identify studies reporting prospective data on incidence rates in men and women in Africa. Of 18 eligible studies, 7 were conducted in high-risk populations. Among women, incidence rates appeared to be higher in those with high-risk sexual behavior, with rates ranging from 3 to 23 per 100 person-years. In contrast, incidence rates in men appeared to be lower, ranging from 1 to 12 per 100 person-years. Risk factors for HSV-2 in women included prevalent human immunodeficiency virus (HIV) infection, younger age at sexual initiation, and sexual activity. Among men, condom use and circumcision had a protective effect, whereas prevalent HIV increased the risk of HSV-2 acquisition. This review draws attention to the high HSV-2 acquisition rates reported in Africa, thereby identifying an efficient setting for preventative HSV-2 vaccine trials. PMID- 25734116 TI - Invasive Haemophilus influenzae Disease in Adults >=65 Years, United States, 2011. AB - BACKGROUND: Since the introduction of the Haemophilus influenzae serotype b vaccine, H influenzae epidemiology has shifted. In the United States, the largest burden of disease is now in adults aged >=65 years. However, few data exist on risk factors for disease severity and outcome in this age group. METHODS: A retrospective case-series review of invasive H influenzae infections in patients aged >=65 years was conducted for hospitalized cases reported to Active Bacterial Core surveillance in 2011. RESULTS: There were 299 hospitalized cases included in the analysis. The majority of cases were caused by nontypeable H influenzae, and the overall case fatality ratio (CFR) was 19.5%. Three or more underlying conditions were present in 63% of cases; 94% of cases had at least 1. Patients with chronic heart conditions (congestive heart failure, coronary artery disease, and/or atrial fibrillation) (odds ratio [OR], 3.27; 95% confidence interval [CI], 1.65-6.46), patients from private residences (OR, 8.75; 95% CI, 2.13-35.95), and patients who were not resuscitate status (OR, 2.72; 95% CI, 1.31-5.66) were more likely to be admitted to the intensive care unit (ICU). Intensive care unit admission (OR, 3.75; 95% CI, 1.71-8.22) and do not resuscitate status (OR, 12.94; 95% CI, 4.84-34.55) were significantly associated with death. CONCLUSIONS: Within this age group, burden of disease and CFR both increased significantly as age increased. Using ICU admission as a proxy for disease severity, our findings suggest several conditions increased risk of disease severity and patients with severe disease were more likely to die. Further research is needed to determine the most effective approach to prevent H influenzae disease and mortality in older adults. PMID- 25734117 TI - Learning Data-Driven Patient Risk Stratification Models for Clostridium difficile. AB - BACKGROUND: Although many risk factors are well known, Clostridium difficile infection (CDI) continues to be a significant problem throughout the world. The purpose of this study was to develop and validate a data-driven, hospital specific risk stratification procedure for estimating the probability that an inpatient will test positive for C difficile. METHODS: We consider electronic medical record (EMR) data from patients admitted for >=24 hours to a large urban hospital in the U.S. between April 2011 and April 2013. Predictive models were constructed using L2-regularized logistic regression and data from the first year. The number of observational variables considered varied from a small set of well known risk factors readily available to a physician to over 10 000 variables automatically extracted from the EMR. Each model was evaluated on holdout admission data from the following year. A total of 34 846 admissions with 372 cases of CDI was used to train the model. RESULTS: Applied to the separate validation set of 34 722 admissions with 355 cases of CDI, the model that made use of the additional EMR data yielded an area under the receiver operating characteristic curve (AUROC) of 0.81 (95% confidence interval [CI], .79-.83), and it significantly outperformed the model that considered only the small set of known clinical risk factors, AUROC of 0.71 (95% CI, .69-.75). CONCLUSIONS: Automated risk stratification of patients based on the contents of their EMRs can be used to accurately identify a high-risk population of patients. The proposed method holds promise for enabling the selective allocation of interventions aimed at reducing the rate of CDI. PMID- 25734118 TI - Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis. AB - No clinical trials have investigated the use of ceftaroline fosamil for salvage therapy of methicillin-resistant Staphylococcus aureus bacteremia and endocarditis. We report data on 29 patients who received ceftaroline +/- another antimicrobial for this indication. Ninety percent of patients had microbiologic cure and 31% had treatment success with a median follow-up of 6 months. PMID- 25734119 TI - Estimated Prevalence of Tuberculosis Infection Among a New York City Clinic Population Using Interferon-gamma Release Assays. AB - BACKGROUND: Elimination of tuberculosis (TB) in the United States requires treating not only persons with active disease but also those infected with TB. Achieving this goal requires understanding local TB infection prevalence and identifying subgroups at increased risk for infection and disease. METHODS: The study population included all patients tested with an interferon-gamma release assay (IGRA) test at New York City (NYC) public TB clinics from October 1, 2006 to December 31, 2011. Patients who were not a case or contact at testing (general clinic patients) and who had a positive QuantiFERON-Gold In-Tube (QFT-GIT) test result were compared with those with indeterminate or negative results to identify characteristics associated with positive results. New York City TB surveillance data were used to identify clinic patients later diagnosed with active TB disease. RESULTS: A total of 69 273 IGRA tests were conducted. Among 20 066 patients tested with QFT-GIT, 16% tested positive, 83% tested negative, and <1% were indeterminate. Of 18 481 general clinic patients, 14% had a positive QFT GIT result. Nine percent of United States-born patients compared with 19% of foreign-born patients had a positive result. Increasing age and birth in a high incidence country were associated with a higher likelihood of having a positive result. One patient with a negative QFT-GIT result was identified as a TB case 2 years later. CONCLUSIONS: Using QFT-GIT data, the background prevalence of TB infection in NYC was estimated. Patient characteristics associated with a positive QFT-GIT result were consistent with known TB risk factors. Results suggest that IGRAs are reliable tests for TB infection. PMID- 25734120 TI - Determinants of Clostridium difficile Infection Incidence Across Diverse United States Geographic Locations. AB - BACKGROUND: Clostridium difficile infection (CDI) is no longer restricted to hospital settings, and population-based incidence measures are needed. Understanding the determinants of CDI incidence will allow for more meaningful comparisons of rates and accurate national estimates. METHODS: Data from active population- and laboratory-based CDI surveillance in 7 US states were used to identify CDI cases (ie, residents with positive C difficile stool specimen without a positive test in the prior 8 weeks). Cases were classified as community associated (CA) if stool was collected as outpatients or <=3 days of admission and no overnight healthcare facility stay in the past 12 weeks; otherwise, cases were classified as healthcare-associated (HA). Two regression models, one for CA CDI and another for HA-CDI, were built to evaluate predictors of high CDI incidence. Site-specific incidence was adjusted based on the regression models. RESULTS: Of 10 062 cases identified, 32% were CA. Crude incidence varied by geographic area; CA-CDI ranged from 28.2 to 79.1/100 000 and HA-CDI ranged from 45.7 to 155.9/100 000. Independent predictors of higher CA-CDI incidence were older age, white race, female gender, and nucleic acid amplification test (NAAT) use. For HA-CDI, older age and a greater number of inpatient-days were predictors. After adjusting for relevant predictors, the range of incidence narrowed greatly; CA-CDI rates ranged from 30.7 to 41.3/100 000 and HA-CDI rates ranged from 58.5 to 94.8/100 000. CONCLUSIONS: Differences in CDI incidence across geographic areas can be partially explained by differences in NAAT use, age, race, sex, and inpatient-days. Variation in antimicrobial use may contribute to the remaining differences in incidence. PMID- 25734121 TI - Incidence of herpes zoster and persistent post-zoster pain in adults with or without diabetes in the United States. AB - BACKGROUND: This study was designed to assess the association between diabetes and herpes zoster (HZ) and persistent post-zoster pain (PPZP). METHODS: We used a United States-based, 2005-2009 retrospective observational study of medical and pharmacy claims from adults in 3 large national databases. Incidence rate ratios were used to compare HZ incidence by diabetes status. Multivariate regressions assessed the age and sex-adjusted risk of diabetes on HZ and PPZP as a function of immune competence. National projections of HZ and PPZP cases were obtained. RESULTS: Among 51 million enrollees (~88 million person-years [PYs] at risk), we identified 420 515 HZ cases. Patients with diabetes represented 8.7% of the PYs analyzed but accounted for 14.5% of the HZ cases and 20.3% of the PPZP cases. The crude incidence of HZ was 78% higher (7.96 vs 4.48 cases/1000 PY; P < .01) and the rate of PPZP was 50% higher (5.97% vs 3.93%; P < .01) in individuals with diabetes than without. Individuals with diabetes had 45% higher adjusted risk of HZ (hazard ratio [HR] = 1.45; 95% confidence intervals [CIs], 1.43-1.46) and 18% higher adjusted odds of PPZP (odds ratio = 1.18; 95% CI, 1.13-1.24). The risk of HZ associated with diabetes among immune-compromised individuals was weaker (HR = 1.10; 95% CI, 1.07-1.14) and the risk of PPZP was no longer significant. Every year, approximately 1.2 million HZ cases occur in US adults, 13% of these occur in individuals with diabetes. CONCLUSIONS: Diabetes is a risk factor for HZ and PPZP in the US adult population. This association is stronger in immune-competent individuals. PMID- 25734122 TI - Influenza a outbreak in an ambulatory stem cell transplant center. AB - BACKGROUND: In the era of cost-consciousness regarding healthcare , provision of medical services in an outpatient setting has become increasingly attractive. We report an influenza outbreak in an ambulatory stem cell transplant center in 2013 that highlights unique identification and infection control challenges in this setting. METHODS: Nasopharyngeal swabs were performed on patients with suspected influenza-like illnesses (ILI), defined by subjective fever or measured temperature of >=37.7 degrees C (>=100 degrees F) with cough or sore throat during July 25, 2013 through August 7, 2013. In addition, testing was triggered by an elevated C-reactive protein (CRP). Specimens were analyzed by using eSensor Respiratory Viral Panel. Clinical and epidemiologic information was collected in real time, and frequencies were calculated on demographics, baseline clinical parameters, treatment methods, comorbidities, and symptoms of affected persons. RESULTS: Thirty-one patients had influenza A (H3N2) infection during July 25, 2013 through August 7, 2013. Only 7 patients (23%) met the Centers for Disease Control and Prevention and Council of State and Territorial Epidemiologists ILI case definition. Twenty-five patients (81%) had received >=1 transplant, with 13 (42%) having occurred within 1 year before the outbreak. Twenty-five patients (81%) had received B-cell active chemotherapy <60 days before influenza diagnosis, 6 (19%) were neutropenic, and 25 (81%) lymphopenic. Among clinical and laboratory markers analyzed, abnormal CRP was the most sensitive screening tool for influenza. Twelve (39%) patients were hospitalized (median stay, 10 days; range, 2-20). No deaths occurred. CONCLUSIONS: Immunocompromised hosts with influenza have atypical presentations. Existing surveillance case definitions might be insufficient to reliably identify influenza outbreaks in such patients. PMID- 25734123 TI - Isolated facial vein thrombophlebitis: a variant of lemierre syndrome. AB - Lemierre syndrome is a rare complication of acute tonsillitis. It is caused by the anaerobic bacterium Fusobacterium necrophorum and is characterized by bacteremia and septic thrombosis of the internal jugular vein. Dissemination of septic emboli may occur. The diagnosis can be difficult since different organs can be involved. We discuss a case of Lemierre syndrome in a 35-year-old woman with isolated thrombophlebitis of the facial vein and fusobacteria growth in blood culture. This case emphasizes the need for awareness of the condition. PMID- 25734124 TI - A Case of Septic Arthritis of the Shoulder Due to Yersinia enterocolitica with Review of the Literature. AB - Yersinia enterocolitica infection rarely can cause extra-intestinal infections. We present a case of septic arthritis of the shoulder due to this organism in an elderly man with liver and cardiac disease. We review previously published cases of Y. enterocolitica septic arthritis, and discuss risk factors and management. PMID- 25734125 TI - Time-Dependent Predictors of Loss to Follow-Up in a Large HIV Treatment Cohort in Nigeria. AB - BACKGROUND: Most evaluations of loss to follow-up (LTFU) in human immunodeficiency virus (HIV) treatment programs focus on baseline predictors, prior to antiretroviral therapy (ART) initiation. As risk of LTFU is a continuous issue, the aim of this evaluation was to augment existing information with further examination of time-dependent predictors of loss. METHODS: This was a retrospective evaluation of data collected between 2004 and 2012 by the Harvard School of Public Health and the AIDS Prevention Initiative in Nigeria as part of PEPFAR-funded program in Nigeria. We used multivariate modeling methods to examine associations between CD4(+) cell counts, viral load, and early adherence patterns with LTFU, defined as no refills collected for at least 2 months since the last scheduled appointment. RESULTS: Of 51 953 patients initiated on ART between 2004 and 2011, 14 626 (28%) were LTFU by 2012. Factors associated with increased risk for LTFU were young age, having nonincome-generating occupations or no education, being unmarried, World Health Organization (WHO) stage, having a detectable viral load, and lower CD4(+) cell counts. In a subset analysis, adherence patterns during the first 3 months of ART were associated with risk of LTFU by month 12. CONCLUSIONS: In settings with limited resources, early adherence patterns, as well as CD4(+) cell counts and unsuppressed viral load, at any time point in treatment are predictive of loss and serve as effective markers for developing targeted interventions to reduce rates of attrition. PMID- 25734126 TI - Low Multiplicity of HIV-1 Infection and No Vaccine Enhancement in VAX003 Injection Drug Users. AB - BACKGROUND: We performed human immunodeficiency virus type 1 (HIV-1) transmitted/founder (T/F) virus analysis of the VAX003 vaccine efficacy trial participants to characterize the transmission bottleneck and test for vaccine associated reduction or enhancement of infection in this injection drug user (IDU) cohort. METHODS: We performed single genome sequencing of plasma vRNA from 50 subjects sampled in early HIV infection. Sequences were analyzed phylogenetically, T/F viruses enumerated, and a sieve analysis performed. RESULTS: Eight of 19 (42%) placebo recipients were productively infected by more than 1 virus (range 1-5, median 1, mean 1.7). This frequency of multiple virus transmission was greater than reported for heterosexual cohorts (19%, P = .03) but not statistically different from vaccine recipients (22.6%, P > .05), where the range was 1-3, median 1, and mean 1.3 (P > .05 for all comparisons). An atypical sieve effect was detected in Env V2 but was not associated with reduction or enhancement of virus acquisition. CONCLUSIONS: The number of T/F viruses in IDUs was surprising low, with 95% of individuals infected by only 1-3 viruses. This finding suggests that a successful vaccine or other prevention modality generally needs to protect against only one or a few viruses regardless of risk behavior. T/F analysis identified an atypical genetic sieve in the V2 region of Envelope and found no evidence for vaccine-mediated enhancement in VAX003. PMID- 25734127 TI - Fatal acanthamoeba encephalitis in a patient with a total artificial heart (syncardia) device. AB - Acanthamoeba encephalitis is an uncommon but often fatal infection complication. Here we report the first case of Acanthamoeba encephalitis in a patient with a Total Artificial Heart device. PMID- 25734128 TI - The Linkage Outcomes of a Large-scale, Rapid Transfer of HIV-infected Patients From Hospital-based to Community-based Clinics in South Africa. AB - BACKGROUND: President's Emergency Plan for AIDS Relief (PEPFAR) funding changes have resulted in human immunodeficiency virus (HIV) clinic closures. We evaluated linkage to care following a large-scale patient transfer from a PEPFAR-funded, hospital-based HIV clinic to government-funded, community-based clinics in Durban. METHODS: All adults were transferred between March and June 2012. Subjects were surveyed 5-10 months post-transfer to assess self-reported linkage to the target clinic. We validated self-reports by auditing records at 8 clinics. Overall success of transfer was estimated using linkage to care data for both reached and unreached subjects, adjusted for validation results. RESULTS: Of the 3913 transferred patients, 756 (19%) were assigned to validation clinics; 659 (87%) of those patients were reached. Among those reached, 468 (71%) had a validated clinic record visit. Of the 46 who self-reported attending a different validation clinic than originally assigned, 39 (85%) had a validated visit. Of the 97 patients not reached, 59 (61%) had a validated visit at their assigned clinic. Based on the validation rates for reached and unreached patients, the estimated success of transfer for the cohort overall was 82%. CONCLUSIONS: Most patients reported successful transfer to a community-based clinic, though a quarter attended a different clinic than assigned. Validation of attendance highlights that nearly 20% of patients may not have linked to care and may have experienced a treatment interruption. Optimizing transfers of HIV care to community sites requires collaboration with receiving clinics to ensure successful linkage to care. PMID- 25734129 TI - Novel Mutation in Cytochrome B of Plasmodium falciparum in One of Two Atovaquone Proguanil Treatment Failures in Travelers Returning From Same Site in Nigeria. AB - BACKGROUND: Atovaquone-proguanil (AP) is the most commonly used treatment for uncomplicated Plasmodium falciparum malaria in the United States. Apparent AP treatment failures were reported 7 months apart in 2 American travelers who stayed in the same compound for foreign workers in Rivers State, Nigeria. METHODS: We analyzed pretreatment (day 0) and day of failure samples from both travelers for mutations in the P falciparum cytochrome B (pfcytb) and dihydrofolate reductase (pfdhfr) genes associated with resistance to atovaquone and cycloguanil, the active metabolite of proguanil, respectively. We genotyped the parasites and sequenced their mitochondrial genomes. RESULTS: On day 0, both travelers had proguanil-resistant genotypes but atovaquone-sensitive cytb sequences. Day of failure samples exhibited mutations in cytb for both travelers. One traveler had the common Y268S mutation, whereas the other traveler had a previously unreported mutation, I258M. The travelers had unrelated parasite genotypes and different mitochondrial genomes. CONCLUSIONS: Despite the infections likely having been contracted in the same site, there is no evidence that the cases were related. The mutations likely arose independently during the acute infection or treatment. Our results highlight the importance of genotyping parasites and sequencing the full cytb and dhfr genes in AP failures to rule out transmission of AP-resistant strains and identify novel mechanisms of AP resistance. PMID- 25734130 TI - Diagnosing diabetic foot osteomyelitis: narrative review and a suggested 2-step score-based diagnostic pathway for clinicians. AB - The diabetic foot infection remains a major cause of morbidity and mortality in many patients and remains a challenging diagnosis for most clinicians. Diagnosis is largely based on clinical signs supplemented by various imaging tests. Magnetic resonance imaging (MRI) is not readily available to many clinicians, and bone biopsy, which is the accepted criterion standard for diagnosis, is rarely performed routinely. This evidence-based review and the proposed diagnostic scoring pathway substratifies the current International Working Group on the Diabetes Foot guidelines for diagnosing diabetic foot osteomyelitis into a convenient 2-step diagnostic pathway for clinicians. This proposed diagnostic approach will need further validation prospectively, but it can serve as a useful diagnostic tool during the initial assessment and management of diabetic foot infections. A MEDLINE search of English-language articles on diabetic foot osteomyelitis published between 1986 and March 2014 was conducted. Additional articles were also identified through a search of references from the retrieved articles, published guidelines, systematic reviews, and meta-analyses. PMID- 25734132 TI - Fatal Granulomatous Amebic Encephalitis Due to Balamuthia mandrillaris in New Mexico: A Case Report. AB - Balamuthia mandrillaris is a free-living amoeba that can cause granulomatous amebic encephalitis (GAE). We report a case in an individual with a history of alcohol abuse, cocaine use, and ditch water exposure. This is the first reported case of GAE due to B mandrillaris in New Mexico. PMID- 25734133 TI - Toxocariasis after slug ingestion characterized by severe neurologic, ocular, and pulmonary involvement. AB - Human toxocariasis is generally a benign, self-curing disease, and neurologic involvement is quite exceptional. In this study, we report a case of toxocariasis caused by ingestion of an unusual transport host, namely live slugs. The clinical picture comprised eosinophilic lung involvement with severe neurologic disorders in relation to vasculitis as well as retinal detachment. PMID- 25734131 TI - Phylogenetic Clades 6 and 8 of Enterohemorrhagic Escherichia coli O157:H7 With Particular stx Subtypes are More Frequently Found in Isolates From Hemolytic Uremic Syndrome Patients Than From Asymptomatic Carriers. AB - BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection causes severe diseases such as bloody diarrhea and hemolytic uremic syndrome (HUS). Although EHEC O157:H7 strains have exhibited high genetic variability, their abilities to cause human diseases have not been fully examined. METHODS: Clade typing and stx subtyping of EHEC O157:H7 strains, which were isolated in Japan during 1999-2011 from 269 HUS patients and 387 asymptomatic carriers (ACs) and showed distinct pulsed-field gel electrophoresis patterns, were performed to determine relationships between specific lineages and clinical presentation. RESULTS: Clades 6 and 8 strains were more frequently found among the isolates from HUS cases than those from ACs (P = .00062 for clade 6, P < .0001 for clade 8). All clade 6 strains isolated from HUS patients harbored stx2a and/or stx2c, whereas all clade 8 strains harbored either stx2a or stx2a/stx2c. However, clade 7 strains were predominantly found among the AC isolates but less frequently found among the HUS isolates, suggesting a significant association between clade 7 and AC (P < .0001). Logistic regression analysis revealed that 0-9 year old age is a significant predictor of the association between clade 8 and HUS. We also found an intact norV gene, which encodes for a nitric oxide reductase that inhibits Shiga toxin activity under anaerobic condition, in all clades 1-3 isolates but not in clades 4-8 isolates. CONCLUSIONS: Early detection of EHEC O157:H7 strains that belonged to clades 6/8 and harbored specific stx subtypes may be important for defining the risk of disease progression in EHEC-infected 0- to 9-year-old children. PMID- 25734134 TI - Varicella zoster virus pneumonitis and brainstem encephalitis without skin rash in an immunocompetent adult. AB - Varicella zoster virus (VZV) pneumonitis and brainstem encephalitis developed in an immunocompetent adult without rash. Chest computed tomography exhibited nodularity; lung biopsy revealed multinucleated giant cells, Cowdry A inclusions, VZV antigen, and DNA. Varicella zoster virus central nervous system disease was verified by cerebrospinal fluid (CSF) anti-VZV IgG antibody with reduced serum/CSF ratios. PMID- 25734135 TI - Hepatitis C in sub-saharan Africa: urgent need for attention. AB - The hepatitis C virus (HCV), which was not recognized as an infectious agent until the 1980s, is responsible for a worldwide epidemic. The World Health Organization estimates global prevalence at 2.8%, with 185 million persons infected. In contrast to hepatitis B, where successful vaccine campaigns have reduced the disease burden, much less progress has been made toward the control of HCV. Phylogenetic studies suggest that HCV originated in Africa and has been endemic in some regions for at least 500-600 years. However, little is known about the epidemiology, transmission, and clinical course of HCV in Africa. With the advent of highly effective anti-HCV agents, there exists great potential to at least curb the global epidemic. For regions such as sub-Saharan Africa, however, this will require a thorough understanding of the regional population level epidemiology, risk factors, and transmission mechanisms. Only then can effective treatment and prevention strategies be introduced. PMID- 25734136 TI - Plasmodium falciparum Infection Does Not Affect Human Immunodeficiency Virus Viral Load in Coinfected Rwandan Adults. AB - BACKGROUND: Plasmodium falciparum infection has been reported to increase human immunodeficiency virus (HIV) viral load (VL), which can facilitate HIV transmission. We prospectively studied the impact of mild P falciparum coinfection on HIV VL in Rwanda. METHODS: We measured plasma HIV VL at presentation with malaria infection and weekly for 4 weeks after artemether lumefantrine treatment in Rwandan adults infected with HIV with P falciparum malaria. Regression analyses were used to examine associations between malaria infection and HIV VL changes. Samples with detectable virus underwent genotypic drug-resistance testing. RESULTS: We enrolled 28 HIV-malaria coinfected patients and observed 27 of them for 5 weeks. Three patients (11%) were newly diagnosed with HIV. Acute P falciparum infection had no significant effect on HIV VL slope over 28 days of follow-up. Ten patients with VL <40 copies/mL at enrollment maintained viral suppression throughout. Seventeen patients had a detectable VL at enrollment including 9 (53%) who reported 100% adherence to ARVs; 3 of these had detectable genotypic drug resistance. CONCLUSIONS: Unlike studies from highly malaria-endemic areas, we did not identify an effect of P falciparum infection on HIV VL; therefore, malaria is not likely to increase HIV-transmission risk in our setting. However, routine HIV testing should be offered to adults presenting with acute malaria in Rwanda. Most importantly, we identified a large percentage of patients with detectable HIV VL despite antiretroviral (ARV) therapy. Some of these patients had HIV genotypic drug resistance. Larger studies are needed to define the prevalence and factors associated with detectable HIV VL in patients prescribed ARVs in Rwanda. PMID- 25734137 TI - Active Surveillance and Decolonization Without Isolation Is Effective in Preventing Methicillin-Resistant Staphylococcus aureus Transmission in the Psychiatry Units. AB - BACKGROUND: Control of methicillin-resistant Staphylococcus aureus (MRSA) is difficult in select populations. We used molecular typing to study the effect of universal surveillance and decolonization of carriers, without isolation, on MRSA transmission in a specialized unit. METHODS: Patients admitted to the unit were screened for nasal MRSA at admission and discharge. Those who acquired MRSA during their stay were identified and linked to carriers with shared time in unit. Molecular typing of isolates was performed to identify transmission. RESULTS: Of 3285 admissions, 82% were tested for MRSA nasal carriage; the discharge screening compliance was 64.7%. Admission prevalence was 2.3% among patients screened, and 7 (0.42%) acquired nasal MRSA during their stay. All patients who acquired MRSA shared time in the unit with a colonized patient. There were 3.9 MRSA acquisitions per 1000 at-risk days. Isolates from 5 patients that acquired MRSA during their stay as well as their potential donors (11 donor: recipient patient pairs) were available for typing. Pulsed-field gel electrophoresis matched 1 acquisition isolate to a colonized patient isolate. There were no MRSA infections during the study period. CONCLUSIONS: Despite less than perfect nasal screening compliance and exemption from traditional isolation precautions, acquisition of MRSA was 0.42% in this patient population over a course of 4.75 years, including a single case of acquisition, genetically similar to a known potential donor source. Screening for MRSA colonization and decolonizing of carriers was sufficient in reducing transmission in this vulnerable population. PMID- 25734138 TI - Sensitivity and specificity of procalcitonin in predicting bacterial infections in patients with renal impairment. AB - BACKGROUND: It is unclear whether procalcitonin is an accurate predictor of bacterial infections in patients with renal impairment, although it is used as a biomarker for early diagnosis of sepsis. We determined the sensitivity, specificity, positive and negative predictive values, accuracy and best predictive value of procalcitonin for predicting bacterial infection in adult patients with severe renal impairment. METHODS: Retrospective study at a single center community teaching hospital involving 473 patients, ages 18-65, with Modification of Diet in Renal Disease eGFR <=30 ml/min per 1.73 m(2), admitted between January 2009 and June 2012, with 660 independent hospital visits. A positive or negative culture (blood or identifiable focus of infection) was paired to the highest procalcitonin result performed 48 hours before or after collecting the culture. RESULTS: The sensitivity and specificity to predict bacterial infection, using a procalcitonin level threshold of 0.5 ng/mL, was 0.80 and 0.35 respectively. When isolating for presence of bacteremia, the sensitivity and specificity were 0.89 and 0.35 respectively. An equation adjusting for optimum thresholds of procalcitonin levels for predicting bacterial infection at different levels of eGFR had a sensitivity and specificity of 0.55 and 0.80 respectively. CONCLUSIONS: Procalcitonin is not a reliably sensitive or specific predictor of bacterial infection in patients with renal impairment when using a single threshold. Perhaps two thresholds should be employed, where below the lower threshold (i.e. 0.5 ng/mL) bacterial infection is unlikely with a sensitivity of 0.80, and above the higher threshold (i.e. 3.2 ng/mL) bacterial infection is very likely with a specificity of 0.75. PMID- 25734139 TI - Novel Fidaxomicin Treatment Regimens for Patients With Multiple Clostridium difficile Infection Recurrences That Are Refractory to Standard Therapies. AB - Reports of fidaxomicin treatment for patients with multiple recurrent Clostridium difficile infections ([mrCDI] ie, more than 2 CDI episodes) indicate symptomatic response to this agent, but 50% have subsequent mrCDI episodes. In an effort to improve outcomes in patients with mrCDI we used novel regimens of fidaxomicin based on strategies used with vancomycin. Of 8 patients who received a 10-day chaser of fidaxomicin given twice daily after a course of vancomycin, 3 (38%) experienced a subsequent recurrence. Two (18%) of 11 patients who completed a 14- to 33-day course of fidaxomicin in a tapering dose experienced a recurrence, both of whom received additional antibiotics before that recurrence. The median symptom-free interval (SFI) after fidaxomicin taper was greater than the median SFI after the most effective prior regimen for those patients (257 days [interquartile range, 280] vs 25 days [interquartile range, 30], respectively; P = .003). A fidaxomicin chaser or taper regimen may be effective in patients with mrCDI, but the number of patients treated is small, and randomized comparative data are not available. PMID- 25734140 TI - Standardized electrolyte supplementation and fluid management improves survival during amphotericin therapy for cryptococcal meningitis in resource-limited settings. AB - BACKGROUND: Amphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa. METHODS: Human immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001 2002, and universal in 2006-2012. In 2001-2009, serum potassium (K(+)) was monitored on days 1, 7, and 14 of treatment with replacement (K(+), Mg(2+)) per clinician discretion. In 2011-2012, K(+) was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K(+), Mg(2+)) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies. RESULTS: With limited intravenous fluids, the 14-day survival was 49% in 2001 2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006-2010 (P = .003). In 2011-2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006-2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011-2012 with universal supplementation (P < .001). CONCLUSIONS: Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K(+), Mg(2+)), as part of comprehensive amphotericin-based cryptococcal therapy. PMID- 25734141 TI - Staphylococcus aureus Infections After Elective Cardiothoracic Surgery: Observations From an International Randomized Placebo-Controlled Trial of an Investigational S aureus Vaccine. AB - BACKGROUND: An unmet need to prevent Staphylococcus aureus (SA) infections after cardiothoracic surgery persists despite current practices. Cost-effective implementation of preventive strategies requires contemporary knowledge about modifiable risk factors. METHODS: From 2007 to 2011, an international, double blind, randomized placebo-controlled trial of a novel SA vaccine (V710) was conducted in 7664 adults scheduled for median sternotomy at 164 sites. We analyzed SA infections developing up to 360 days postoperatively in 3832 placebo recipients. RESULTS: Coronary artery bypass grafting was performed in 80.8% (3096 of 3832) of placebo recipients. The overall incidence of any postoperative SA infection was 3.1% (120 of 3832). Invasive SA infections (including bacteremia and deep sternal-wound infections) developed in 1.0%. Methicillin-resistant SA (MRSA) accounted for 19% (23 of 120) of SA infections, with 57% (13 of 23) of the MRSA infections occurring in diabetic patients. All-cause mortality was 4.1% (153 of 3712) in patients without SA infection, 7.2% (7 of 97) in methicillin susceptible SA (MSSA) infections, and 17.3% (4 of 23) in MRSA infections (P < .01). Staphylococcus aureus nasal carriage was detected preoperatively in 18.3% (701 of 3096) patients, including 1.6% colonized with MRSA. Postoperative SA infections occurred in 7.0% (49 of 701) of colonized patients versus 2.3% (71 of 3131) of patients without colonization (relative risk = 3.1 [95% confidence interval, 2.2-4.4]). CONCLUSIONS: In this large international cohort of patients undergoing cardiac surgery and observed prospectively, invasive postoperative SA infections occurred in 1% of adult patients despite modern perioperative management. The attributable mortality rates were 3% for MSSA and 13% for MRSA infections. Preoperative nasal colonization with SA increased the risk of postoperative infection threefold. The utility of strategies to reduce this incidence warrants continued investigation. PMID- 25734142 TI - Neuraminidase-Inhibiting Antibody Response to H5N1 Virus Vaccination in Chronically Ill and Immunocompromised Patients. AB - Neuraminidase-inhibiting (NAi) antibodies have been reported to be an independent correlate of protection from influenza disease, but the NAi antibody response to influenza vaccination has never been assessed in chronically ill or immunocompromised participants. Using an enzyme-linked lectin assay, we demonstrated that 2 immunizations with a Vero cell culture-derived, whole-virus H5N1 A/Vietnam vaccine induces NAi antibodies in 94.3% of chronically ill and 83.8% of immunocompromised participants. A booster with a heterologous A/Indonesia H5N1 vaccine induced comparable NAi antibody titers in both groups and resulted in 100% seropositivity. These data support prepandemic H5N1 vaccination strategies for these highly vulnerable risk groups. PMID- 25734143 TI - Drivers and trajectories of resistance to new first-line drug regimens for tuberculosis. AB - BACKGROUND: New first-line drug regimens for treatment of tuberculosis (TB) are in clinical trials: emergence of resistance is a key concern. Because population level data on resistance cannot be collected in advance, epidemiological models are important tools for understanding the drivers and dynamics of resistance before novel drug regimens are launched. METHODS: We developed a transmission model of TB after launch of a new drug regimen, defining drug-resistant TB (DR TB) as resistance to the new regimen. The model is characterized by (1) the probability of acquiring resistance during treatment, (2) the transmission fitness of DR-TB relative to drug-susceptible TB (DS-TB), and (3) the probability of treatment success for DR-TB versus DS-TB. We evaluate the effect of each factor on future DR-TB prevalence, defined as the proportion of incident TB that is drug-resistant. RESULTS: Probability of acquired resistance was the strongest predictor of the DR-TB proportion in the first 5 years after the launch of a new drug regimen. Over a longer term, however, the DR-TB proportion was driven by the resistant population's transmission fitness and treatment success rates. Regardless of uncertainty in acquisition probability and transmission fitness, high levels (>10%) of drug resistance were unlikely to emerge within 50 years if, among all cases of TB that were detected, 85% of those with DR-TB could be appropriately diagnosed as such and then successfully treated. CONCLUSIONS: Short term surveillance cannot predict long-term drug resistance trends after launch of novel first-line TB regimens. Ensuring high treatment success of drug-resistant TB through early diagnosis and appropriate second-line therapy can mitigate many epidemiological uncertainties and may substantially slow the emergence of drug resistant TB. PMID- 25734144 TI - Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia related progressive multifocal leukoencephalopathy. AB - In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement. PMID- 25734145 TI - A leukocyte score to improve clinical outcome predictions in bacteremic pneumococcal pneumonia in adults. AB - BACKGROUND: Bacteremic pneumococcal pneumonia (BPP) is associated with high and early mortality. A simple procedure to predict mortality is crucial. METHODS: All adult patients with BPP admitted from 2005 through 2013 to the University Hospital of Dijon, France, were enrolled to study 30-day mortality and associated factors, particularly leukocyte counts. A simple leukocyte score was created by adding 1 point each for neutropenia (<1500 cells/mm(3)), lymphopenia (<400), and monocytopenia (<200). RESULTS: One hundred and ninety-two adult patients (mean age, 69 years; standard deviation [SD], 19 years) who had developed and were hospitalized for BPP (58% community-acquired) were included. The 30-day crude mortality rate was 21%. The mean Pneumonia Severity Index score was high at 127.3 (SD = 41.3). Among the 182 patients who had a white blood cell count, 34 (19%) had a high leukocyte score (>=2). Multivariate analysis revealed that mortality was significantly associated with a high leukocyte score (odds ratio, 6.28; 95% confidence interval, 2.35-16.78), a high respiratory rate, a low serum bicarbonate level, and an altered mental status (all P < .05). The leukocyte score was not significantly dependent on the previous state of immunosuppression, alcoholism, or viral coinfection, but it did correlate with an acute respiratory distress syndrome and a low serum bicarbonate level. CONCLUSIONS: This new leukocyte score, in combination with the well known predictive factors, seems of interest in predicting the risk of death in BPP. A high score correlated with organ dysfunction and probably reflects the level of immunoparalysis. Its predictive value has to be confirmed in other cohorts. PMID- 25734146 TI - Clinical Implications of Detectable Baseline Hepatitis C Virus-Genotype 1 NS3/4A Protease Variants on the Efficacy of Boceprevir Combined With Peginterferon/Ribavirin. AB - BACKGROUND: We analyzed the impact of pretreatment variants conferring boceprevir resistance on sustained virologic response (SVR) rates achieved with boceprevir plus peginterferon-alpha/ribavirin (P/R) for hepatitis C virus (HCV)-genotype-1 infection. METHODS: NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs). Baseline samples pooled from 6 phase II or phase III clinical trials were analyzed for RAVs by population sequencing. Interferon (IFN) responsiveness was predefined as >1 log reduction in HCV-RNA level during the initial 4-week lead-in treatment with P/R before boceprevir was added. The effective boceprevir-concentration inhibiting RAV growth by 50% (EC50) was determined using a replicon assay relative to the wild-type referent. RESULTS: Sequencing was performed in 2241 of 2353 patients (95.2%) treated with boceprevir. At baseline, RAVs were detected in 178 patients (7.9%), including 153 of 1498 genotype-1a infections (10.2%) and 25 of 742 genotype-1b infections (3.4%) (relative risk, 3.03; 95% confidence interval [CI], [2.01, 4.58]). For IFN responders, SVR24 (SVR assessed 24 weeks after discontinuation of all study medications) rates were 78% and 76% with or without RAVs detected at baseline, respectively. For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]). Sustained virologic response was achieved in 7 of 8 (87.5%) IFN-nonresponders with baseline variants exhibiting <=2-fold increased EC50 for boceprevir in a replicon assay, whereas only 1 of 15 (7%) IFN nonresponders with baseline RAVs associated with >=3-fold increased EC50 achieved SVR. CONCLUSIONS: Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period. PMID- 25734148 TI - Hypermucoviscous Klebsiella syndrome without liver abscess in a patient with immunoglobulin g2 immune deficiency. AB - BACKGROUND: Hypermucoviscous Klebsiella pneumoniae (HMVKP) emerged as a cause of invasive infections in South-East (SE) Asia. It has become the most common cause of liver abscess in that region, and it is a significant causative organism in endogenous endophthalmitis and meningitis. During the past decade, cases of this uniquely virulent organism have been reported outside of SE Asia, with a propensity to affect individuals of SE Asian descent. Cases have been reported from North America including Canada. METHODS: We report a case of a patient of Filipino descent living in Canada who presented with recurrent HMVKP bacteremia in the absence of pyogenic liver abscess or other localized metastatic Klebsiella infection. RESULTS: Investigations identified an immunoglobulin (Ig)G2 deficiency and low IgM indicating potential common variable immunodeficiency, and administration of intravenous immunoglobulins was associated with prevention of further recurrences. CONCLUSIONS: To our knowledge, this is the first report of HMVKP associated with predisposing antibody deficiency. PMID- 25734147 TI - Association of first-line and second-line antiretroviral therapy adherence. AB - BACKGROUND: Adherence to first-line antiretroviral therapy (ART) may be an important indicator of adherence to second-line ART. Evaluating this relationship may be critical to identify patients at high risk for second-line failure, thereby exhausting their treatment options, and to intervene and improve patient outcomes. METHODS: Adolescents and adults (n = 436) receiving second-line ART were administered standardized questionnaires that captured demographic characteristics and assessed adherence. Optimal and suboptimal cumulative adherence were defined as percentage adherence of >=90% and <90%, respectively. Bivariable and multivariable binomial regression models were used to assess the prevalence of suboptimal adherence percentage by preswitch adherence status. RESULTS: A total of 134 of 436 (30.7%) participants reported suboptimal adherence to second-line ART. Among 322 participants who had suboptimal adherence to first line ART, 117 (36.3%) had suboptimal adherence to second-line ART compared with 17 of 114 (14.9%) who had optimal adherence to first-line ART. Participants who had suboptimal adherence to first-line ART were more likely to have suboptimal adherence to second-line ART (adjusted prevalence ratio, 2.4; 95% confidence interval, 1.5-3.9). CONCLUSIONS: Adherence to first-line ART is an important predictor of adherence to second-line ART. Targeted interventions should be evaluated in patients with suboptimal adherence before switching into second-line therapy to improve their outcomes. PMID- 25734149 TI - The successful application of a national peer advisory committee for physicians who provide salvage regimens to heavily antiretroviral-experienced patients in mexican human immunodeficiency virus clinics. AB - BACKGROUND: Designing optimal antiretroviral (ARV) salvage regimens for multiclass drug-resistant, human immunodeficiency virus (HIV)-infected patients demands specific clinical skills. Our aim was to assess the virologic and immunologic effects of the treatment recommendations drafted by a peer advisory board to physicians caring for heavily ARV-experienced patients. METHODS: We conducted a nationwide, HIV clinic-based, cohort study in Mexico. Adults infected with HIV were assessed for a median of 33 months (interquartile range [IQR] = 22 43 months). These patients had experienced the virologic failure of at least 2 prior ARV regimens and had detectable viremia while currently being treated; their physicians had received therapeutic advice, by a panel of experts, regarding the ARV salvage regimen. The primary endpoint was the incidence of loss of virologic response (plasma HIV-RNA levels of <200 copies per mL, followed by levels above this threshold) during the follow-up assessment using an observed failure competing risks regression analysis. RESULTS: A total of 611 patients were observed (median ARV therapy exposure = 10.5 years; median prior regimens = 4). The probabilities of virologic failure were 11.9%, 14.4%, 16.9%, and 19.4% at the 12-, 24-, 36-, and 48-month follow-up assessments, respectively. Of the 531 patients who achieved a confirmed plasma HIV-RNA level below 200 copies per mL, the median increase in blood CD4(+) T-cell count was 162 cells per mL (IQR = 45 304 cells per mL). CONCLUSIONS: In routine practice, a high rate of patients with extensive ARV experience, who received an optimized salvage regimen recommended by a peer advisory committee, achieved a long-term sustained virologic response and immune reconstitution. PMID- 25734150 TI - Lack of Awareness of Human Immunodeficiency Virus (HIV) Infection: Problems and Solutions With Self-reported HIV Serostatus of Men Who Have Sex With Men. AB - BACKGROUND: Lack of human immunodeficiency virus (HIV) infection awareness may be a driver of racial disparities in HIV infection among men who have sex with men (MSM). Lack of awareness is typically measured by comparing HIV test result to self-reported HIV status. This measure may be subject to reporting bias and alternatives are needed. METHODS: The InvolveMENt study examined HIV disparities between black and white MSM from Atlanta. Among HIV-positive participants who did not report knowing they were positive, we examined other measures of awareness: HIV viral load (VL) <1000 copies/mL (low VL), antiretroviral (ARV) drugs in blood, and previous HIV case surveillance report. RESULTS: Using self-report only, 32% (62 of 192) of black and 16% (7 of 45) of white MSM were not aware of their HIV infection (P = .03). Using self-report and low VL, 25% (48 of 192) black and 16% (7 of 45) white MSM lacked awareness (P = .18). Using self-report and ARVs, 26% (50 of 192) black and 16% (7 of 45) white MSM lacked awareness (P = .14). Using self-report and surveillance report, 15% (28 of 192) black and 13% (6 of 45) white MSM lacked awareness (P = .83). CONCLUSIONS: Self-report only may overestimate true lack of awareness of HIV status for black MSM. If, as our data suggest, black MSM are not less likely to be aware of their HIV infection than are white MSM, then this factor is not a substantial driver of HIV disparity. Future HIV research that depends on accurate measurement of HIV status awareness should consider including additional laboratory and case surveillance data. PMID- 25734151 TI - Elevated carbon monoxide to carbon dioxide ratio in the exhaled breath of mice treated with a single dose of lipopolysaccharide. AB - BACKGROUND: Analysis of volatile organic chemicals in breath holds promise for noninvasive diagnosis and monitoring of patients, but investigation of this in experimental mouse models has been limited. Of particular interest is endogenous production of carbon monoxide as a biomarker of inflammation and, more particularly, during sepsis. METHODS: Using a nose-only collection procedure for unanesthetized individual adult mice and sensitive gas chromatography of carbon monoxide (CO) and carbon dioxide (CO2) of sampled breath, we investigated the responses of mice to one-time injections with different doses of purified Escherichia coli lipopolysaccharide. Two strains of mice were examined: BALB/c and C3H, including an endotoxin-resistant mutant (HeJ) as well as the wild type (HOuJ). RESULTS: The CO to CO2 ratio increased in a dose-responsive manner within hours in treated BALC/c mice but not control mice. The CO/CO2 values declined to the range of control mice within 48-72 h after the injection of lipopolysaccharide. Breath CO/CO2 values correlated with systemic inflammation biomarkers in serum and heme oxygenase-1 gene expression in blood. C3H/HOuJ mice, but not the HeJ mice, had similar increases of the CO/CO2 ratio in response to the endotoxin. CONCLUSIONS: Carbon monoxide concentrations in exhaled breath of at least 2 strains of mice increase in response to single injections of endotoxin. The magnitude of increase was similar to what was observed with a bacteremia model. These findings with an experimental model provide a rationale for further studies of normalized CO concentrations in human breath as an informative biomarker for staging and monitoring of sepsis. PMID- 25734152 TI - Other respiratory viruses are important contributors to adult respiratory hospitalizations and mortality even during peak weeks of the influenza season. AB - BACKGROUND: During peak weeks of seasonal influenza epidemics, severe respiratory infections without laboratory confirmation are typically attributed to influenza. METHODS: In this prospective study, specimens and demographic and clinical data were collected from adults admitted with respiratory symptoms to 4 hospitals during the 8-10 peak weeks of 2 influenza seasons. Specimens were systematically tested for influenza and 13 other respiratory viruses (ORVs) by using the Luminex RVP FAST assay. RESULTS: At least 1 respiratory virus was identified in 46% (21% influenza, 25% noninfluenza; 2% coinfection) of the 286 enrolled patients in 2011 2012 and in 62% (46% influenza, 16% noninfluenza; 3% coinfection) of the 396 enrolled patients in 2012-2013. Among patients aged >=75 years, twice as many ORVs (32%) as influenza viruses (14%) were detected in 2011-2012. During both seasons, the most frequently detected ORVs were enteroviruses/rhinoviruses (7%), respiratory syncytial virus (6%), human metapneumovirus (5%), coronaviruses (4%), and parainfluenza viruses (2%). Disease severity was similar for influenza and ORVs during both seasons. CONCLUSIONS: Although ORV contribution relative to influenza varies by age and season, during the peak weeks of certain influenza seasons, ORVs may be a more frequent cause of elderly hospitalization than influenza. PMID- 25734153 TI - Acute Small-Bowel Obstruction From Intestinal Anisakiasis After the Ingestion of Raw Clams; Documenting a New Method of Marine-to-Human Parasitic Transmission. AB - Enteric anisakiasis is a known parasitic infection. To date, human infection has been reported as resulting from the inadvertent ingestion of the anisakis larvae when eating raw/undercooked fish, squid, or eel. We present a first reported case of intestinal obstruction caused by anisakiasis, after the ingestion of raw clams. PMID- 25734154 TI - High Proportion of Indeterminate QuantiFERON-TB Gold In-Tube Results in an Inpatient Population Is Related to Host Factors and Preanalytical Steps. AB - BACKGROUND: QuantiFERON-TB Gold In-Tube test (QFT-GIT) can be used as an alternative to tuberculin skin testing (TST) for the targeted testing of latent tuberculosis. Due to many shortcomings with TST, QFT-GIT usage is increasing. QFT GIT implementation in the inpatient setting remains unclear. METHODS: We retrospectively identified patients admitted to a tertiary care academic center who received either a TST or a QFT-GIT in the 18 months prior to and after QFT GIT implementation in March 2012. Risk factors associated with indeterminate results were evaluated. RESULTS: The proportion of inpatients receiving a test for tuberculosis infection doubled following QFT-GIT implementation (1.4% vs 2.9%). After QFT-GIT became available, 75% of tested people received a QFT-GIT and 25% received a TST. We found indeterminate test results in 19.8%. Independent predictors of indeterminate results were female sex (adjusted odds ratio [AOR], 1.64), lymphopenia (AOR, 2.21), hypoalbuminemia (AOR, 6.81) and sample collection by nonphlebotomists (AOR, 3.0, vs phlebotomists). Of patients who had indeterminate results, 42% had a subsequent indeterminate result on repeat testing. All indeterminate results were due to a low mitogen response. CONCLUSIONS: QFT-GIT testing in the inpatient setting is associated with a high proportion of indeterminate results that is associated with host factors and preanalytical errors. Careful selection of patients to be tested and training on sample processing for QFT-GIT testing should be considered to decrease indeterminate results. PMID- 25734155 TI - Clinical utility of indium 111-labeled white blood cell scintigraphy for evaluation of suspected infection. AB - BACKGROUND: We sought to characterize the clinical utility of indium 111 ((111)In)-labeled white blood cell (WBC) scans by indication, to identify patient populations who might benefit most from this imaging modality. METHODS: Medical records for all patients who underwent (111)In-labeled WBC scans at our tertiary referral center from 2005 to 2011 were reviewed. Scan indication, results, and final diagnosis were assessed independently by 2 infectious disease physicians. Reviewers also categorized the clinical utility of each scan as helpful vs not helpful with diagnosis and/or management according to prespecified criteria. Cases for which clinical utility could not be determined were excluded from the utility assessment. RESULTS: One hundred thirty-seven scans were included in this analysis; clinical utility could be determined in 132 (96%) cases. The annual number of scans decreased throughout the study period, from 26 in 2005 to 13 in 2011. Forty-one (30%) scans were positive, and 85 (62%) patients were ultimately determined to have an infection. Of the evaluable scans, 63 (48%) scans were deemed clinically useful. Clinical utility varied by scan indication: (111)In labeled WBC scans were more helpful for indications of osteomyelitis (35/50, 70% useful) or vascular access infection (10/15, 67% useful), and less helpful for evaluation of fever of unknown origin (12/35, 34% useful). CONCLUSIONS: (111)In labeled WBC scans were useful for patient care less than half of the time at our center. Targeted ordering of these scans for indications in which they have greater utility, such as suspected osteomyelitis and vascular access infections, may optimize test utilization. PMID- 25734156 TI - Aspirin Use for Primary and Secondary Prevention in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Patients. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with increased risk of myocardial infarction (MI). The use of aspirin for primary and secondary MI prevention in HIV infection has not been extensively studied. METHODS: We performed a cross-sectional study of 4037 patients infected with HIV and 36 338 demographics-matched control patients in the Partners HealthCare System HIV cohort. We developed an algorithm to ascertain rates of nonepisodic acetylsalicylic acid (ASA) use using medication and electronic health record free text data. We assessed rates of ASA use among HIV-infected and HIV-uninfected (negative) patients with and without coronary heart disease (CHD). RESULTS: Rates of ASA use were lower among HIV-infected compared with HIV-uninfected patients (12.4% vs 15.3%, P < .001), with a relatively greater difference among patients with >=2 CHD risk factors (22.1% vs 42.4%, P < .001). This finding was present among men and among patients in the 30-39 and 40-49 age groups. Among patients with prevalent CHD using ASA for secondary prevention, rates of ASA use were also lower among HIV-infected patients compared with HIV-uninfected patients (51.6% vs 65.4%, P < .001). CONCLUSIONS: Rates of ASA use were lower among HIV-infected patients compared with controls, with a greater relative difference among those with elevated CHD risk and those with known CHD. Further studies are needed to investigate the optimal strategies for ASA use among patients infected with HIV. PMID- 25734157 TI - Seroincidence of Influenza Among HIV-infected and HIV-uninfected Men During the 2009 H1N1 Influenza Pandemic, Bangkok, Thailand. AB - Among 368 Thai men who have sex with men with paired serum samples collected before and during the 2009 H1N1 influenza pandemic, we determined influenza A (H1N1)pdm09 seroconversion rates (>=4-fold rise in antibody titers by hemagglutination inhibition or microneutralization assays). Overall, 66 of 232 (28%) participants seroconverted after the first year of A(H1N1)pdm09 activity, and 83 of 234 (35%) participants seroconverted after the second year. Influenza A(H1N1)pdm09 seroconversion did not differ between human immunodeficiency virus (HIV)-infected (55 of 2157 [35%]) and HIV-uninfected (71 of 2211 [34%]) participants (P = .78). Influenza A(H1N1)pdm09 seroconversion occurred in approximately one third of our Thai study population and was similar among HIV infected and HIV-uninfected participants. PMID- 25734158 TI - Death with tuberculosis in california, 1994-2008. AB - BACKGROUND: Identifying factors associated with tuberculosis (TB) deaths will inform efforts to prevent deaths. METHODS: We examined deaths among patients with culture-confirmed TB reported to the California TB Registry during 1994-2008. We calculated the age-adjusted percentage of deaths before and during TB treatment and estimated trends. We constructed multivariable logistic regression models to identify factors associated with death during treatment. RESULTS: Of 40 125 patients with culture-confirmed TB, 4565 (11%) died: 1146 (25%) died before treatment started, and 3419 (75%) died during treatment. The age-adjusted percentage of patients who died before and during treatment declined from 1994 to 2008 (3.5% to 2%, and 10.4% to 7.2%, respectively, both P < .0001). We identified several risk factors for death that may be addressed with public health efforts: acquired multidrug resistance (adjusted odds ratio [aOR] = 4.67; 95% confidence interval [CI], 2.09-10.45); care in the private sector (aOR = 3.08; 95% CI, 2.75 3.44); and an initial treatment regimen of <3 drugs (aOR = 2.07; 95% CI, 1.63 2.64). We identified other risk factors for death that could be used as markers for intensified diagnostic and treatment processes in hospital: human immunodeficiency virus coinfection; meningeal, peritoneal, and disseminated TB; substance use; and abnormal chest radiograph without cavities. CONCLUSIONS: In California, 1 in 9 TB patients died with a potentially curable disease. Public health departments might prevent deaths in patients with TB by strengthening partnerships with private providers, intensifying diagnostic and treatment processes for patients at risk of death in hospital, optimizing treatment regimens for patients with comorbidities, and preventing the acquisition of drug resistance. PMID- 25734159 TI - Safety, Reactogenicity, and Immunogenicity of Inactivated Monovalent Influenza A(H5N1) Virus Vaccine Administered With or Without AS03 Adjuvant. AB - BACKGROUND: The national stockpile for influenza pandemic preparedness includes vaccines against an array of strains and adjuvants that could be utilized to induce immunologic priming as a pandemic wave emerges. We assessed the feasibility of a strategy that allows the flexibility of postmanufacture mixture of vaccine and adjuvant at the point of care. METHODS: We conducted a randomized, double-blind, multicenter trial among healthy adults aged 18-49 years who received 2 doses of inactivated influenza A/Indonesia/05/2005 (H5N1 clade 2.2.3) virus vaccine containing either 3.75, 7.5, or 15 ug of hemagglutinin (HA) with or without AS03 adjuvant, administered 21 days apart. Subjects were observed for local (injection site) and systemic reactogenicity and adverse events. Sera were tested for hemagglutination inhibition (HAI) and microneutralization (MN) antibody levels against the homologous strain and 4 heterologous avian strains. RESULTS: Vaccine containing ASO3 adjuvant was associated with significantly more local reactions compared with nonadjuvanted vaccine, but these were short-lived and resolved spontaneously. Although the immune response to nonadjuvanted vaccine was poor, 2 doses of AS03-adjuvanted vaccine containing as little as 3.75 ug of HA elicited robust immune responses resulting in seroprotective titers (>=1:40) to the homologous strain in >=86% of subjects by HAI and in 95% of subjects by MN. Cross-clade antibody responses were also observed with AS03-adjuvanted vaccine, but not nonadjuvanted vaccine. CONCLUSIONS: AS03 adjuvant formulated with inactivated vaccine at the administration site significantly enhanced the immune responses to H5N1 vaccine and has the potential to markedly improve vaccine responses and accelerate delivery during an influenza pandemic. CLINICAL TRIALS REGISTRATION: NCT01317758. PMID- 25734160 TI - IDSA Ebola Summary-August 2014. PMID- 25734161 TI - Accuracy of noninvasive intraocular pressure or optic nerve sheath diameter measurements for predicting elevated intracranial pressure in cryptococcal meningitis. AB - BACKGROUND: Cryptococcal meningitis is associated with increased intracranial pressure (ICP). Therapeutic lumbar puncture (LP) is recommended when the initial ICP is >250 mm H2O, yet the availability of manometers in Africa is limited and not always used where available. We assessed whether intraocular pressure could be a noninvasive surrogate predictor to determine when additional therapeutic LPs are necessary. METHODS: Ninety-eight human immunodeficiency virus-infected Ugandans with suspected meningitis (81% Cryptococcus) had intraocular pressure measured using a handheld tonometer (n = 78) or optic nerve sheath diameter (ONSD) measured by ultrasound (n = 81). We determined the diagnostic performance of these methods for predicting ICP vs a standard manometer. RESULTS: The median ICP was 225 mm H2O (interquartile range [IQR], 135-405 mm H2O). The median intraocular pressure was 28 mm Hg (IQR, 22-37 mm Hg), and median ultrasound ONSD was 5.4 mm (IQR, 4.95-6.1 mm). ICP moderately correlated with intraocular pressure (rho = 0.45, P < .001) and with ultrasound ONSD (rho = 0.44, P < .001). There were not discrete threshold cutoff values for either tonometry or ultrasound ONSD that provided a suitable cutoff diagnostic value to predict elevated ICP (>200 mm H2O). However, risk of elevated ICP >200 mm H2O was increased with an average intraocular pressure >28 mm Hg (relative risk [RR] = 3.03; 95% confidence interval [CI], 1.55-5.92; P < .001) or an average of ONSD >5 mm (RR = 2.39; 95% CI, 1.42-4.03; P = .003). As either intraocular pressure or ONSD increased, probability of elevated ICP increased (ie, positive predictive value increased). CONCLUSIONS: Noninvasive intraocular pressure measurements by tonometry or ultrasound correlate with cerebrospinal fluid opening pressure, but both are a suboptimal replacement for actual ICP measurement with a manometer. PMID- 25734162 TI - Mumps antibody response in young adults after a third dose of measles-mumps rubella vaccine. AB - BACKGROUND: Mumps outbreaks in populations with high 2-dose measles-mumps-rubella (MMR) vaccine coverage raise the question whether a third dose of MMR vaccine (MMR3) is needed. However, data on the immunogenicity of MMR3 are limited. We assessed mumps virus neutralizing antibody levels pre- and post-MMR3 in a nonoutbreak setting. METHODS: Mumps antibody titers were assessed at baseline, 1 month, and 1 year after MMR3 in subjects aged 18-28 years. RESULTS: At baseline, 5 of 656 (0.8%) subjects had seronegative mumps neutralizing antibody titers and 38 (5.8%) had low titers. One year post-MMR3, these numbers declined to 3 (0.5%) and 16 (2.4%), respectively. Subjects with low baseline titers were more likely to have low 1-month and 1-year titers (R (2) = 0.81-0.87, P < .0001). Compared to baseline, geometric mean titers were significantly higher at 1 month (P < .0001) and 1 year (P < .01) post-MMR3; however, reverse cumulative distribution curves showed only minimal shifts in mumps titers from baseline to 1 month and 1 year. CONCLUSIONS: Very few subjects had negative or low baseline mumps titers. Nonetheless, mumps titers had modest but significant increases when measured 1 month and 1 year post-MMR3. This temporary increase in titers could decrease susceptibility to disease during outbreaks, but may have limited value for routine use in vaccinated populations. PMID- 25734163 TI - A Clinical Scoring Algorithm for Determination of the Risk of Tuberculosis in HIV Infected Adults: A Cohort Study Performed at Ethiopian Health Centers. AB - BACKGROUND: The World Health Organization (WHO) tuberculosis (TB) symptom screening instrument (WHO-TB) can identify human immunodeficiency virus (HIV) infected individuals at low risk of tuberculosis (TB); however, many patients report WHO-TB symptoms and require further TB investigations. We hypothesized that further clinical scoring could classify subjects with a positive WHO-TB screening result (WHO-TB(+)) for the likelihood of TB. METHODS: HIV-infected adults eligible to initiate antiretroviral therapy (ART) were recruited and prospectively followed at 5 Ethiopian health centers. Irrespective of symptoms, all participants underwent sputum bacteriological testing for TB. Symptoms, physical findings, hemoglobin, and CD4 cell count results were compared between subjects with and those without bacteriologically confirmed TB. Variables associated with TB in WHO-TB(+) individuals were used to construct a scoring algorithm with multiple logistic regression analysis. RESULTS: Among 812 participants, 137 (16.9%) had TB. One hundred fifty-nine persons (20%) had a negative WHO-TB screen, 10 of whom had TB (negative predictive value [NPV], 94% [95% confidence interval {CI}, 90%-97.5%]). For WHO-TB(+) subjects, the following variables were independently associated with TB, and were assigned 1 point each in the clinical scoring algorithm: cough, Karnofsky score <=80, mid-upper arm circumference <20 cm, lymphadenopathy, and hemoglobin <10 g/dL. Among subjects with 0-1 points, 20 of 255 had TB (NPV, 92% [95% CI, 89%-95%]), vs 19 of 34 participants with >=4 points (positive predictive value, 56% [95% CI, 39%-73%]). The use of WHO-TB alone identified 159 of 784 (20%) with a low risk of TB, vs 414 of 784 (53%) using WHO-TB followed by clinical scoring (P< .001). The difference in proportions of confirmed TB in these subsets was nonsignificant (6.3% vs 7.2%; P= .69). CONCLUSIONS: Clinical scoring can further classify HIV-infected adults with positive WHO-TB screen to assess the risk of TB, and would reduce the number of patients in need of further TB investigations before starting ART. CLINICAL TRIALS REGISTRATION: NCT01433796. PMID- 25734164 TI - Whole Genome Sequencing of a Methicillin-Resistant Staphylococcus aureus Pseudo Outbreak in a Professional Football Team. AB - Two American football players on the same team were diagnosed with methicillin resistant Staphylococcus aureus (MRSA) skin and soft tissue infections on the same day. Our investigation, including whole genome sequencing, confirmed that players did not transmit MRSA to one another nor did they acquire the MRSA from a single source within the training facility. PMID- 25734165 TI - Unusual presentation of chikungunya virus infection with concomintant erysipelas in a returning traveler from the Caribbean: a case report. AB - Chikungunya fever is a mosquito-borne febrile illness caused by Chikungunya virus (CHIKV), an alphavirus from the Togaviridae family. It is transmitted by primarily Aedes aegytpi and Aedes albopictus mosquitos [1]. Once of little importance in the Americas, local transmission was identified in the Caribbean in late 2013. More than 1000 travelers returning to the continental United States have been diagnosed with CHIKV. More importantly, there have been 9 documented cases of autochthonous disease in Florida as of September 16, 2014 [2]. PMID- 25734166 TI - Hepatitis e vaccine to prevent morbidity and mortality during epidemics. AB - Recurrent, large, waterborne epidemics of hepatitis E virus (HEV) occur regularly after monsoon rains contaminate water supplies in Asia or during humanitarian crises in Africa. These epidemics commonly affect thousands of persons, and it has a high mortality in pregnant women who become infected. Although a subunit HEV vaccine has been developed by Chinese investigators and was found to be highly effective and safe in a large clinical trial, this vaccine is only available in China. Until it is prequalified by the World Health Organization, the vaccine may not be available for use outside of China in low-income countries that lack national vaccine regulatory agencies. In this manuscript, we explore possible strategies for providing access to this potentially important vaccine for international use in responding to epidemics of HEV in low-resource countries. PMID- 25734167 TI - World health organization approaches to evaluating the potential use and quality of hepatitis e vaccine. PMID- 25734168 TI - Urinary tract infections in male veterans with human immunodeficiency virus. AB - Treatment duration for men with urinary tract infection (UTI) and human immunodeficiency virus (HIV) infection is unknown. Fiscal year 2009 Veterans Affairs administrative data were used to compare men with HIV and UTI with non HIV men with UTI. Antimicrobial selection and duration were similar. Shorter treatment (<=7 days) did not affect recurrence, suggesting that treatment beyond 7 days may be unnecessary. PMID- 25734169 TI - Mumps serum antibody levels before and after an outbreak to assess infection and immunity in vaccinated students. AB - BACKGROUND: Since 2009, various mumps outbreaks have occurred in the Netherlands, affecting mostly young adults vaccinated against mumps. In this retrospective study, we estimated attack rates for symptomatic and asymptomatic mumps virus infection based on mumps-specific immunoglobulin (Ig)G concentrations in paired blood samples obtained before and after the mumps outbreaks, collected in 2 university cities. We aimed to identify a serological correlate of immune protection and risk factors for mumps virus infection. METHODS: Mumps-specific IgG levels were measured by Luminex technology in paired pre- and post-outbreak samples from students from Leiden (n = 135) and Utrecht (n = 619). Persons with a 4-fold increase in mumps IgG concentrations or mumps IgG concentrations >1500 RU/mL were assumed to have had a mumps virus infection. RESULTS: Attack rates for symptomatic and asymptomatic mumps virus infection were 2.0% and 3.8%, respectively. Pre-outbreak mumps-specific IgG concentrations were lower among cases than among noncases (P = .005) despite vaccination history, but no serological cutoff for immune protection could be established. Mumps among housemates was significantly associated with serological evidence for mumps virus infection (odds ratio, 7.25 [95% confidence interval, 3.20-16.40]; P < .001). CONCLUSIONS: Symptomatic and asymptomatic mumps virus infections in vaccinated persons can be identified by retrospective assessment of mumps-specific IgG antibodies in blood samples. PMID- 25734171 TI - Disseminated Cutaneous Mycobacterium chelonae Infection in a Patient With Acute Myeloid Leukemia. AB - We report a case of disseminated cutaneous Mycobacterium chelonae infection in a patient who was treated with chemotherapy for acute myeloid leukemia. We discuss the clinical manifestations, diagnosis, and treatment of this unusual infection in neutropenic patients. PMID- 25734170 TI - Point-of-Use Mixing of Influenza H5N1 Vaccine and MF59 Adjuvant for Pandemic Vaccination Preparedness: Antibody Responses and Safety. A Phase 1 Clinical Trial. AB - BACKGROUND: Avian influenza A/H5N1 has threatened human health for nearly 2 decades. Avian influenza A vaccine without adjuvant is poorly immunogenic. A flexible rapid tactic for mass vaccination will be needed if a pandemic occurs. METHODS: A multicenter, randomized, blinded phase 1 clinical trial evaluated safety and antibody responses after point-of-use mixing of influenza A/Indonesia/05/2005 (H5N1) vaccine with MF59 adjuvant. Field-site pharmacies mixed 3.75, 7.5, or 15 mcg of antigen with or without MF59 adjuvant just prior to intramuscular administration on days 0 and 21 of healthy adults aged 18-49 years. RESULTS: Two hundred and seventy subjects were enrolled. After vaccination, titers of hemagglutination inhibition antibody >=1:40 were achieved in 80% of subjects receiving 3.75 mcg + MF59 vs only 14% receiving 15 mcg without adjuvant (P < .0001). Peak hemagglutination inhibition antibody geometric mean titers for vaccine + MF59 were ~65 regardless of antigen dose, and neutralizing titers were 2- to 3-fold higher. Vaccine + MF59 produced cross-reactive antibody responses against 4 heterologous H5N1 viruses. Excellent safety and tolerability were demonstrated. CONCLUSIONS: Point-of-use mixing of H5N1 antigen and MF59 adjuvant achieved target antibody titers in a high percentage of subjects and was safe. The feasibility of the point-of-use mixing should be studied further. PMID- 25734172 TI - The effect of hepatitis C virologic clearance on cardiovascular disease biomarkers in human immunodeficiency virus/hepatitis C virus coinfection. AB - BACKGROUND: Successful hepatitis C virus (HCV) treatment may reduce cardiovascular disease (CVD) risk and improve levels of CVD biomarkers produced outside the liver (nonhepatic biomarkers). METHODS: Stored serum or plasma from before and 24 weeks after end of HCV treatment (EOT) from human immunodeficiency virus (HIV)/HCV-coinfected subjects who received up to 72 weeks of peginterferon/ribavirin, 27 with and 27 without sustained virologic response (SVR) matched by race, ethnicity and sex, were tested for nonhepatic (soluble intercellular adhesion molecule-1 [sICAM-1], soluble P-selectin [sP-selectin], interleukin [IL]-6, d-dimer, and lipoprotein-associated phospholipase A2 [Lp PLA2]) and hepatic (cholesterol and high-sensitivity C-reactive protein) CVD and macrophage activation markers (soluble CD163 [sCD163] and soluble CD14). Changes in biomarkers and their association with SVR were examined by t tests or Wilcoxon tests and regression models. RESULTS: Of the 54 subjects, 30 were white, 24 were black, and 44 were male. Pretreatment levels of nonhepatic biomarkers were high: sICAM-1 overall median, 439.2 ng/mL (interquartile range [IQR], 365.6-592.8]; sP selectin, 146.7 ng/mL (IQR, 94.1-209.9), and IL-6, 2.32 pg/mL (IQR, 1.61-3.49). Thirty-seven of 52 (71%) subjects had Lp-PLA2 >235 ng/mL. Sustained virologic response was associated with decrease in sICAM-1 (P = .033) and sCD163 (P = .042); this result was attenuated after controlling for changes in the alanine aminotransferase level. At 24 weeks after EOT, 17 (63%) SVRs had Lp-PLA2 >235 ng/mL vs 25 (93%) non-SVRs (P = .021). CONCLUSIONS: Hepatitis C virus clearance may reduce hepatic and, subsequently, systemic inflammation and CVD risk in HIV/HCV coinfection. PMID- 25734173 TI - Detection of High Cerebrospinal Fluid Levels of (1->3)-beta-d-Glucan in Cryptococcal Meningitis. AB - BACKGROUND: (1->3)-beta-d-Glucan (BDG) is a helpful diagnostic marker for many invasive fungal infections. However, BDG is not thought to be useful in diagnosing cryptococcosis. We evaluated the utility of BDG as an adjunct diagnostic tool for patients infected with human immunodeficiency virus (HIV) and presenting with suspected cryptococcal meningitis. METHODS: The Fungitell assay was used to measure BDG concentrations in cerebrospinal fluid (CSF) (n = 177) and serum (n = 109) of HIV-infected Ugandans and South Africans with suspected meningitis. Correlations between BDG concentrations and quantitative CSF cryptococcal cultures, CSF cryptococcal antigen (CRAG) titers, and 18 different CSF cytokine concentrations were assessed using non-parametric tests. Mixed models evaluated longitudinal changes in CSF BDG concentrations. Survival analyses were used to evaluate BDG's relationship with mortality. RESULTS: The Fungitell BDG assay provided 89% sensitivity and 85% specificity in CSF for cryptococcal meningitis. Serum sensitivity was suboptimal (79%). Cerebrospinal fluid BDG concentrations at diagnosis were median (interquartile range) 343 (200 597) pg/mL in cryptococcal patients and 37 (23-46) pg/mL in patients without cryptococcosis. Sensitivity in CSF improved to 98% (53 of 54) when initial fungal burdens were >=10 000 colony-forming units/mL. (1->3)-beta-d-Glucan normalized rapidly after initiating antifungal therapy. Baseline BDG concentrations correlated with CSF fungal burden (rho = 0.820; P < .001), CSF CRAG lateral flow assay titers (rho = 0.780, P < .001), and monocyte chemotactic protein-1 levels in CSF (P = .047). In patients with cryptococcal meningitis, BDG >=500 pg/mL at diagnosis was associated with increased 10-week mortality. CONCLUSIONS: (1->3) beta-d-Glucan is detectable in the CSF of HIV-infected patients with Cryptococcus, and it may provide useful prognostic information. Sensitivity is less than CRAG; however, BDG normalizes rapidly, unlike CRAG, making BDG potentially useful in diagnosing recurrent episodes. PMID- 25734174 TI - Improving public reporting and data validation for complex surgical site infections after coronary artery bypass graft surgery and hip arthroplasty. AB - BACKGROUND: Deep and organ/space surgical site infections (D/OS SSI) cause significant morbidity, mortality, and costs. Rates are publicly reported and increasingly used as quality metrics affecting hospital payment. Lack of standardized surveillance methods threaten the accuracy of reported data and decrease confidence in comparisons based upon these data. METHODS: We analyzed data from national validation studies that used Medicare claims to trigger chart review for SSI confirmation after coronary artery bypass graft surgery (CABG) and hip arthroplasty. We evaluated code performance (sensitivity and positive predictive value) to select diagnosis codes that best identified D/OS SSI. Codes were analyzed individually and in combination. RESULTS: Analysis included 143 patients with D/OS SSI after CABG and 175 patients with D/OS SSI after hip arthroplasty. For CABG, 9 International Classification of Diseases, 9th Revision (ICD-9) diagnosis codes identified 92% of D/OS SSI, with 1 D/OS SSI identified for every 4 cases with a diagnosis code. For hip arthroplasty, 6 ICD-9 diagnosis codes identified 99% of D/OS SSI, with 1 D/OS SSI identified for every 2 cases with a diagnosis code. CONCLUSIONS: This standardized and efficient approach for identifying D/OS SSI can be used by hospitals to improve case detection and public reporting. This method can also be used to identify potential D/OS SSI cases for review during hospital audits for data validation. PMID- 25734175 TI - Long-term outcome of pyogenic vertebral osteomyelitis: a cohort study of 260 patients. AB - BACKGROUND: The long-term outcome of patients with pyogenic vertebral osteomyelitis (PVO) has not been fully assessed. METHODS: We conducted a retrospective cohort study to describe the long-term outcome of PVO and to assess risk factors for treatment failure in patients evaluated at our institution between 1994 and 2002. Patients were observed until July 1, 2013. RESULTS: Two hundred sixty patients with PVO were included in this study. Twenty-seven percent (70) of patients developed their infection after an invasive spinal procedure. Staphylococcus aureus accounted for 40% (103) of infections. Forty-nine percent (128) of patients underwent spinal surgery as part of their initial therapy. The median duration of parenteral antimicrobial therapy was 42 days (interquartile range, 38-53). The estimated 2-, 5-, and 10-year cumulative probability of treatment failure-free survival was 72%, 69%, and 69%, respectively. Seventy-five percent of patients who developed treatment failure did so within 4.7 months of diagnosis. Residual neurological defects and persistent back pain were seen in 16% and 32% of patients, respectively. In a multivariate analysis, longer duration of symptoms before diagnosis and having an infection with S. aureus were associated with increased risk of treatment failure. CONCLUSIONS: Increasing duration of symptoms and infection with S. aureus were associated with treatment failure in patients with PVO. Most treatment failures occurred early after initiation of treatment. Pyogenic vertebral osteomyelitis is associated with a high 2-year failure rate. Persistent neurological deficits and back pain are common after therapy. PMID- 25734176 TI - High-density lipoprotein-mediated cholesterol efflux capacity is improved by treatment with antiretroviral therapy in acute human immunodeficiency virus infection. AB - BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) have decreased high-density lipoprotein (HDL)-cholesterol and increased cardiovascular disease (CVD). Reverse cholesterol transport from macrophages may be inhibited by HIV and contribute to increased CVD. Human studies have not investigated longitudinal effects of HIV and antiretroviral therapy (ART) on cholesterol efflux. METHODS: Subjects with acute HIV infection were randomized to ART or not. Cholesterol efflux capacity was determined ex vivo after exposure of murine macrophages to apolipoprotein B-depleted patient sera obtained at baseline and after 12 weeks. RESULTS: After 12 weeks, HIV RNA decreased most in subjects randomized to ART. Available data on cholesterol demonstrated that efflux capacity from Abca1(+/+) macrophages was increased most by sera obtained from ART treated subjects (20.5% +/- 5.0% to 24.3 % +/- 6.9%, baseline to 12 weeks, P = .007; ART group [n = 6] vs 18.0 % +/- 3.9% to 19.1 % +/- 2.9%, baseline to 12 weeks, P = .30; untreated group [n = 6] [P = .04 ART vs untreated group]). Change in HIV RNA was negatively associated with change in Abca1(+/+) macrophage cholesterol efflux (r = - 0.62, P = .03), and this finding remained significant (P = .03) after controlling for changes in HDL-cholesterol, CD4(+) cells, and markers of monocyte or macrophage activation. CONCLUSIONS: In subjects acutely infected with HIV, ATP-binding cassette transporter A1-mediated cholesterol efflux was stimulated to a greater degree over time by apolipoprotein B-depleted serum from subjects randomized to ART. The improvement in cholesterol efflux capacity is independently related to reduction in viral load. PMID- 25734177 TI - Resistance patterns and clinical significance of Candida colonization and infection in combat-related injured patients from iraq and afghanistan. AB - BACKGROUND: Penetrating wounds with environmental contamination are associated with a range of infectious complications, including fungus. This is the first study to examine the epidemiology, resistance patterns, and outcomes of Candida infections and colonization in United States military patients injured in Iraq and Afghanistan. METHODS: Clinical information associated with initial unique and serial Candida isolates collected from patients (June 2009-October 2013) through the Trauma Infectious Disease Outcomes Study (TIDOS) was evaluated. Susceptibilities were performed using Sensititre YeastOne (YO-9) plates and interpreted by Clinical Laboratory and Standards Institute (CLSI) and adjusted European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. RESULTS: The analysis included 127 patients with 131 unique Candida isolates, of which 102 were Candida albicans and 29 non-albicans Candida spp. Overall, 99% of patients were male with a median age of 23 and an injury severity score of 22. Injuries were primarily due to blasts (77%) and sustained among personnel serving in Afghanistan (89%). There was a median of 7 days from injury to Candida isolation, and 74 isolates were associated with infection. In the multivariate analysis, non-albicans Candida spp were associated with prior antifungal exposure, blood isolates, and wound isolates (P < .01). Nonsusceptibility by CLSI and EUCAST criteria was associated with non-albicans Candida spp (P < .05). Patients with Candida isolation had a 7.1% mortality rate, compared with 1.4% from the overall TIDOS population. CONCLUSIONS: Candida isolation from patients with penetrating war injuries may identify a population at higher risk for death. Prospective studies are needed to determine whether targeted antifungals and surgical management will affect this mortality rate. PMID- 25734178 TI - Subgroup differences in response to 8 weeks of ledipasvir/sofosbuvir for chronic hepatitis C. AB - Treatment of hepatitis C virus (HCV) infection with ledipasvir/sofosbuvir promises tremendous benefits, but high cost may impede implementation of this regimen. Subgroups with excellent response to 8 weeks of treatment might respond to a shorter course. In ION-3, 423 previously untreated HCV genotype 1-infected patients without cirrhosis had outcome data after receiving ledipasvir/sofosbuvir for 8 weeks. After reanalyzing published ION-3 data, we found that sustained virologic response (SVR) rates varied significantly by gender (P = .002) and rs12979860 genotype (P trend = .03), exceeding 98% in women and rs12979860-CC individuals. The very high SVR rates in these subgroups suggest that these factors might be considered in selecting patients to receive 8 weeks of ledipasvir/sofosbuvir and support shorter trials of this regimen in selected patients. PMID- 25734179 TI - Candida esophagitis in a human immunodeficiency virus-1-positive elite controller with hepatitis C virus cirrhosis. AB - We describe a case of Candida esophagitis in a human immunodeficiency virus elite controller with a preserved CD4 count, a population in which opportunistic infections are almost never seen. The patient has hepatitis C virus coinfection and compensated cirrhosis, suggesting a possible multifactorial etiology of immune dysregulation. PMID- 25734180 TI - Acute Human Immunodeficiency Virus (HIV) Syndrome After Nonadherence to Antiretroviral Therapy in a Patient With Chronic HIV Infection: A Case Report. AB - We report a rare case of acute human immunodeficiency virus (HIV) syndrome in a patient with chronic HIV infection with acute illness indistinguishable from acute retroviral syndrome. The patient presented with an acute febrile mononucleosis-like illness after increasing nonadherence to antiretroviral therapy. A marked increase in HIV RNA level of 1 220 000 copies/mL from less than 20 copies/mL occurred within 3 weeks. The diagnosis of acute HIV syndrome was made after alternative causes of illness were ruled out. PMID- 25734182 TI - Hybrid swarm intelligence optimization approach for optimal data storage position identification in wireless sensor networks. AB - The current high profile debate with regard to data storage and its growth have become strategic task in the world of networking. It mainly depends on the sensor nodes called producers, base stations, and also the consumers (users and sensor nodes) to retrieve and use the data. The main concern dealt here is to find an optimal data storage position in wireless sensor networks. The works that have been carried out earlier did not utilize swarm intelligence based optimization approaches to find the optimal data storage positions. To achieve this goal, an efficient swam intelligence approach is used to choose suitable positions for a storage node. Thus, hybrid particle swarm optimization algorithm has been used to find the suitable positions for storage nodes while the total energy cost of data transmission is minimized. Clustering-based distributed data storage is utilized to solve clustering problem using fuzzy-C-means algorithm. This research work also considers the data rates and locations of multiple producers and consumers to find optimal data storage positions. The algorithm is implemented in a network simulator and the experimental results show that the proposed clustering and swarm intelligence based ODS strategy is more effective than the earlier approaches. PMID- 25734183 TI - Hanle detection for optical clocks. AB - Considering the strong inhomogeneous spatial polarization and intensity distribution of spontaneous decay fluorescence due to the Hanle effect, we propose and demonstrate a universe Hanle detection configuration of electron shelving method for optical clocks. Experimental results from Ca atomic beam optical frequency standard with electron-shelving method show that a designed Hanle detection geometry with optimized magnetic field direction, detection laser beam propagation and polarization direction, and detector position can improve the fluorescence collection rate by more than one order of magnitude comparing with that of inefficient geometry. With the fixed 423 nm fluorescence, the improved 657 nm optical frequency standard signal intensity is presented. The potential application of the Hanle detection geometry designed for facilitating the fluorescence collection for optical lattice clock with a limited solid angle of the fluorescence collection has been discussed. The Hanle detection geometry is also effective for ion detection in ion optical clock and quantum information experiments. Besides, a cylinder fluorescence collection structure is designed to increase the solid angle of the fluorescence collection in Ca atomic beam optical frequency standard. PMID- 25734181 TI - Drug repositioning for gynecologic tumors: a new therapeutic strategy for cancer. AB - The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery. PMID- 25734184 TI - Numerical study of plasmonic efficiency of gold nanostripes for molecule detection. AB - In plasmonics, the accurate computation of the electromagnetic field enhancement is necessary in determining the amplitude and the spatial extension of the field around nanostructures. Here, the problem of the interaction between an electromagnetic excitation and gold nanostripes is solved. An optimization scheme, including an adaptive remeshing process with error estimator, is used to solve the problem through a finite element method. The variations of the electromagnetic field amplitude and the plasmonic active zones around nanostructures for molecule detection are studied in this paper taking into account the physical and geometrical parameters of the nanostripes. The evolution between the sizes and number of nanostripes is shown. PMID- 25734185 TI - Information technology in critical care: review of monitoring and data acquisition systems for patient care and research. AB - There is a broad consensus that 21st century health care will require intensive use of information technology to acquire and analyze data and then manage and disseminate information extracted from the data. No area is more data intensive than the intensive care unit. While there have been major improvements in intensive care monitoring, the medical industry, for the most part, has not incorporated many of the advances in computer science, biomedical engineering, signal processing, and mathematics that many other industries have embraced. Acquiring, synchronizing, integrating, and analyzing patient data remain frustratingly difficult because of incompatibilities among monitoring equipment, proprietary limitations from industry, and the absence of standard data formatting. In this paper, we will review the history of computers in the intensive care unit along with commonly used monitoring and data acquisition systems, both those commercially available and those being developed for research purposes. PMID- 25734187 TI - Design and implementation of streaming media server cluster based on FFMpeg. AB - Poor performance and network congestion are commonly observed in the streaming media single server system. This paper proposes a scheme to construct a streaming media server cluster system based on FFMpeg. In this scheme, different users are distributed to different servers according to their locations and the balance among servers is maintained by the dynamic load-balancing algorithm based on active feedback. Furthermore, a service redirection algorithm is proposed to improve the transmission efficiency of streaming media data. The experiment results show that the server cluster system has significantly alleviated the network congestion and improved the performance in comparison with the single server system. PMID- 25734186 TI - Physiochemical studies of sodium chloride on mungbean (Vigna radiata L. Wilczek) and its possible recovery with spermine and gibberellic acid. AB - The physiological and biochemical responses to increasing NaCl concentrations, along with low concentrations of gibberellic acid or spermine, either alone or in their combination, were studied in mungbean seedlings. In the test seedlings, the root-shoot elongation, biomass production, and the chlorophyll content were significantly decreased with increasing NaCl concentrations. Salt toxicity severely affected activities of different antioxidant enzymes and oxidative stress markers. Activities of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT) increased significantly over water control. Similarly, oxidative stress markers such as proline, malondialdehyde (MDA), and hydrogen peroxide (H2O2) contents also increased as a result of progressive increase in salt stress. Combined application of NaCl along with low concentrations of either gibberellic acid (5 uM) or spermine (50 uM) in the test seedlings showed significant alterations, that is, drastic increase in seedling elongation, increased biomass production, increased chlorophyll content, and significant lowering in all the antioxidant enzyme activities as well as oxidative stress marker contents in comparison to salt treated test seedlings, leading to better growth and metabolism. Our study shows that low concentrations of either gibberellic acid or spermine will be able to overcome the toxic effects of NaCl stress in mungbean seedlings. PMID- 25734188 TI - The use of ion mobility mass spectrometry to assist protein design: a case study on zinc finger fold versus coiled coil interactions. AB - The dramatic conformational change in zinc fingers on binding metal ions for DNA recognition makes their structure-function behaviour an attractive target to mimic in de novo designed peptides. Mass spectrometry, with its high throughput and low sample consumption provides insight into how primary amino acid sequence can encode stable tertiary fold. We present here the use of ion mobility mass spectrometry (IM-MS) coupled with molecular dynamics (MD) simulations as a rapid analytical platform to inform de novo design efforts for peptide-metal and peptide-peptide interactions. A dual peptide-based synthetic system, ZiCop based on a zinc finger peptide motif, and a coiled coil partner peptide Pp, have been investigated. Titration mass spectrometry determines the relative binding affinities of different divalent metal ions as Zn(2+) > Co(2+) ? Ca(2+). With collision induced dissociation (CID), we probe complex stability, and establish that peptide-metal interactions are stronger and more 'specific' than those of peptide-peptide complexes, and the anticipated hetero-dimeric complex is more stable than the two homo-dimers. Collision cross-sections (CCS) measurements by IM-MS reveal increased stability with respect to unfolding of the metal-bound peptide over its apo-form, and further, larger collision cross sections for the hetero-dimeric forms suggest that dimeric species formed in the absence of metal are coiled coil like. MD supports these structural assignments, backed up by data from visible light absorbance measurements. PMID- 25734189 TI - Label-free free-solution nanoaperture optical tweezers for single molecule protein studies. AB - Nanoaperture optical tweezers are emerging as useful label-free, free-solution tools for the detection and identification of biological molecules and their interactions at the single molecule level. Nanoaperture optical tweezers provide a low-cost, scalable, straight-forward, high-speed and highly sensitive (SNR ~ 33) platform to observe real-time dynamics and to quantify binding kinetics of protein-small molecule interactions without the need to use tethers or labeling. Such nanoaperture-based optical tweezers, which are 1000 times more efficient than conventional optical tweezers, have been used to trap and isolate single DNA molecules and to study proteins like p53, which has been claimed to be in mutant form for 75% of human cancers. More recently, nanoaperture optical tweezers have been used to probe the low-frequency (in the single digit wavenumber range) Raman active modes of single nanoparticles and proteins. Here we review recent developments in the field of nanoaperture optical tweezers and how they have been applied to protein-antibody interactions, protein-small molecule interactions including single molecule binding kinetics, and protein-DNA interactions. In addition, recent works on the integration of nanoaperture optical tweezers at the tip of optical fiber and in microfluidic environments are presented. PMID- 25734190 TI - Copper-catalyzed aerobic carboxygenation and N-arylation of [1,2,3]triazolo[1,5 a]pyridines towards pyridinium triazolinone ylides. AB - Copper-catalyzed aerobic oxyarylation of [1,2,3]triazolo[1,5-a]pyridines is developed. Notably molecular oxygen was utilized as one of the reagents and the transformation resulted in the formation of novel pyridinium triazolinone ylides. A basic mechanism for the one-pot process is proposed and further functionalization of the ylidic products were also presented. PMID- 25734191 TI - Innovative technologies for rehabilitation and health promotion: what is the evidence? PMID- 25734193 TI - Alarm system management: evidence-based guidance encouraging direct measurement of informativeness to improve alarm response. AB - Although there are powerful incentives for creating alarm management programmes to reduce 'alarm fatigue', they do not provide guidance on how to reduce the likelihood that clinicians will disregard critical alarms. The literature cites numerous phenomena that contribute to alarm fatigue, although many of these, including total rate of alarms, are not supported in the literature as factors that directly impact alarm response. The contributor that is most frequently associated with alarm response is informativeness, which is defined as the proportion of total alarms that successfully conveys a specific event, and the extent to which it is a hazard. Informativeness is low across all healthcare applications, consistently ranging from 1% to 20%. Because of its likelihood and strong evidential support, informativeness should be evaluated before other contributors are considered. Methods for measuring informativeness and alarm response are discussed. Design directions for potential interventions, as well as design alternatives to traditional alarms, are also discussed. With the increased attention and investment in alarm system management that alarm interventions are currently receiving, initiatives that focus on informativeness and the other evidence-based measures identified will allow us to more effectively, efficiently and reliably redirect clinician attention, ultimately improving alarm response. PMID- 25734194 TI - Sofosbuvir (Sovaldi degrees ). Active against hepatitis C virus, but evaluation is incomplete . AB - About 50% of patients with chronic hepatitis C virus (HCV) genotype 1 infection have a sustained virological response to a 48-week course of the peginterferon alfa + ribavirin combination. Adding a viral protease inhibitor to this combination for 12 to 32 weeks enhances antiviral effects but increases the risk of serious adverse effects. Between 70% and 80% of patients with HCV genotype 2 or 3 infection have a sustained virological response to a 24-week course of the peginterferon alfa + ribavirin combination. Sofosbuvir, a nucleotide inhibitor of viral (or HCV) NS5B RNA polymerase,has been authorised in the European Union for the treatment of chronic hepatitis C, in combination with other drugs. Despite the inclusion of several clinical trials, initial evaluation of sofosbuvir provides only a minimal picture of the harm-benefit balance. Sofosbuvir has not been compared directly with viral protease inhibitors in randomised clinical trials. In a trial involving 121 patients with HCV genotype 1 infection, the sustained viral response rate was 90% when sofosbuvir was added to the peginterferon alfa + ribavirin combination for 12 weeks, versus about 60% with peginterferon alfa + ribavirin alone. In a randomised, unblinded, noninferiority trial in 527 previously untreated patients with HCV genotype 2 or 3 infection, sofosbuvir + ribavirin combination therapy given for 12 weeks had virological efficacy similar to peginterferon alfa-2a + ribavirin combination therapy given for 24 weeks. However, there were signs that sofosbuvir might be less effective against HCV genotype 3. In an uncontrolled study of 114 patients with HCV genotype 1 infection who could not receive peginterferon alfa, the sofosbuvir + ribavirin combination yielded sustained virological responses in about 75% of cases. Similar results were obtained in a double-blind, placebo-controlled trial in 280 patients with HCV genotype 2 or 3 infection. Too few cases of HCV genotype 4, 5 or 6 infection were included in clinical trials to determine the value of sofosbuvir in these patients. The adverse effects of sofosbuvir are poorly documented, mainly because of the limited number of patients in clinical trials and the lack of blinding in several trials. In particular, more data are needed on possible effects on the heart, blood cells and muscle. Renal failure can lead to sofosbuvir overdose, while co-administration of P-glycoprotein inhibitors can lead to sofosbuvir under dosing. There are no data available on the use of sofosbuvir in pregnant women. Contraception is necessary when sofosbuvir is used in combination with ribavirin because the latter drug is teratogenic, potentially for several months after treatment discontinuation. When HCV liver disease warrants medical treatment, sofosbuvir seems to be at least as effective as viral protease inhibitors such as boceprevir, and also less toxic. Its use can shorten treatment duration by several months. There are many uncertainties, however, about its adverse effects and drug interactions. Adding sofosbuvir to the peginterferon a/fa + ribavirin combination is an option for patients with genotype 1 infection,while sofosbuvir is an alternative to peginterferon a/fa for patients with genotype 2 or 3 infection. Waiting for more thorough evaluation is another reasonable option, depending on clinical status, given the slow progression of hepatitis C and the many outstanding questions concerning sofosbuvir. PMID- 25734195 TI - Chemotherapy for anaplastic thyroid cancer using docetaxel and cisplatin: report of eight cases. AB - Anaplastic thyroid carcinoma has a dismal prognosis and lacks an established therapeutic strategy. We have recently conducted chemotherapy with docetaxel and cisplatin as part of multimodal treatment for eight patients with anaplastic thyroid carcinoma. Docetaxel (75 mg/m2) and cisplatin (75 mg/m2) were administered on day 1 every 4 weeks for six courses. This chemotherapy was used as induction therapy in one patient, as therapy for distant metastases in five patients and as postoperative adjuvant therapy in two patients. Three patients showed partial responses and three patients showed stable disease. After excluding the two patients receiving the treatment as adjuvant therapy the response rate was 50 %. Grade 3 or 4 leukocytopenia occurred in seven patients (88 %), but these adverse events were tolerable. Chemotherapy with docetaxel and cisplatin may thus be feasible for anaplastic thyroid carcinoma. PMID- 25734196 TI - Each patient is a priority. PMID- 25734197 TI - [One year of home treatment in Donauworth]. PMID- 25734198 TI - [Emotions steer thinking....]. PMID- 25734199 TI - Clinical evaluation of medical devices: light at the end of the tunnel? PMID- 25734200 TI - European Heart Journal in Japan: 62nd Annual Meeting of the Japanese College of Cardiology. PMID- 25734201 TI - The evolution of lead extraction. PMID- 25734202 TI - Transvenous lead extraction clinically successful in 98% of patients. PMID- 25734203 TI - What the adult electrophysiologist needs to know about paediatric catheter ablation. PMID- 25734204 TI - New ablation catheter receives CE mark of approval. PMID- 25734205 TI - Women more likely to develop anxiety and depression after myocardial infarction than men. PMID- 25734206 TI - Offie Soldin, PhD, MBA. PMID- 25734207 TI - Ebola in women--what the Ob-Gyns should know. PMID- 25734208 TI - Postmenopausal hormone therapy and blood pressure revisited. PMID- 25734209 TI - Calcium-collagen chelate supplementation reduces bone loss in osteopenic postmenopausal women. PMID- 25734211 TI - Author's reply: To PMID 25131779. PMID- 25734210 TI - Content and implementation of clinical decisions in the routine care of people with severe mental illness. AB - BACKGROUND: Clinical decision making (CDM) in the treatment of people with severe mental illness relates to a wide range of life domains. AIMS: To examine content of CDM in mental health care from the perspectives of service users and staff and to investigate variation in implementation of decisions for differing content. METHOD: As part of the European multicenter study clinical decision making and outcome in routine care for people with severe mental illness (ISRCTN75841675), 588 service users and their clinicians were asked to identify the decisions made during their last meeting. Decisions were then coded into content categories. Two months later, both parties reported if these decisions had been implemented. RESULTS: Agreement between patients and staff regarding decision making was moderate (k = 0.21-0.49; p < 0.001). Decisions relating to medication and social issues were most frequently identified. Overall reported level of implementation was 73.5% for patients and 74.7% for staff, and implementation varied by decision content. CONCLUSIONS: A variety of relevant decision topics were shown for mental health care.Implementation rates varied in relation to topic and may need different consideration within the therapeutic dyad. PMID- 25734212 TI - John Fitzpatrick: an appreciation. PMID- 25734213 TI - DL-3-n-butylphthalide inhibits platelet activation via inhibition of cPLA2 mediated TXA2 synthesis and phosphodiesterase. AB - Aberrant platelet activation plays a critical role in the pathogenesis of heart attack and stroke. DL-3-n-butylphthalide (NBP) has been approved in China to treat stroke with multiple mechanisms. The anti-stroke effects of NBP may be related to its antiplatelet effects reported in rats in addition to its antioxidative, antiapoptotic, and angiogenic effects. However, the effects and the underlying mechanisms of NBP on human platelets are not yet clear. In this study, we found that NBP concentration-dependently inhibited human platelet aggregation and ATP release induced by ADP, thrombin, U46619, arachidonic acid, or collagen. NBP also inhibited PAC-1 binding induced by ADP or thrombin and platelet spreading on immobilized fibrinogen. NBP reduced TXA2 synthesis induced by thrombin or collagen via inhibiting cPLA2 phosphorylation, concomitantly with a marked decrease in intracellular calcium mobilization. Moreover, NBP also inhibited human platelet phosphodiesterase (PDE) and elevated 3,5-cyclic adenosine monophosphate level in platelets. In conclusion, NBP significantly inhibits human platelet activation via inhibition of cPLA2-mediated TXA2 synthesis and PDE, and may be effective as an antiplatelet drug to treat other arterial thrombotic diseases. PMID- 25734214 TI - The expanding field of platelet-bacterial interconnections. AB - Given their small size, platelets are emerging as being one of the most important entities in the bloodstream. Not only do they play a key role in maintaining thrombosis and haemostasis, platelets also play a critical role in orchestrating the immune response. Being the first cell at the site of injury, they are perfectly placed to assess the extent of the damage and recruit immune cells as is necessary. As a first line of defence, platelets can act as primitive immune cells themselves by interacting with invading pathogens. A number of platelet receptors have been shown to interact with bacteria either directly or indirectly, involving a plasma protein bridge. This review will discuss the molecular mechanisms that exist between platelets and bacteria and the functional response to the interaction. We will also discuss the importance of considering animal models of disease and the use of physiological shear when studying platelet-bacterial interactions. PMID- 25734215 TI - Characterization of UBO-QIC as a Galphaq inhibitor in platelets. AB - Galphaq plays an important role in platelet activation by agonists such as thrombin, adenosine diphosphate (ADP) and thromboxane. The significance of Galphaq signaling in platelets was established using YM254890, a Galphaq/11 specific inhibitor and Galphaq knockout murine platelets. However, YM-254890 is no longer available for investigators and there is a need to characterize other Galphaq inhibitors. The aim of this study is to characterize the specificity of a compound, {L-threonine,(3R)-N-acetyl-3-hydroxy-L-leucyl-(aR)-a hydroxybenzenepropanoyl-2,3-idehydro-N-methylalanyl-L-alanyl-N-methyl-L-alanyl (3R)-3-[[(2S,3R)-3-hydroxy-4-methyl-1-oxo-2-[(1-oxopropyl)amino]pentyl]oxy]-L leucyl-N,O-dimethyl-,(7 -> 1)-lactone (9CI)} (UBO-QIC), as a Galphaq inhibitor in platelets. Human platelets treated with UBO-QIC showed a concentration-dependent inhibition of platelet aggregation and secretion by protease-activated receptors (PAR) agonists, U46619 and ADP. UBO-QIC also abolished Galphaq pathway signaling events such as calcium mobilization and pleckstrin phosphorylation. UBO-QIC had no nonspecific effects on the Galpha12/13 pathway since platelet shape change was intact in Galphaq knockout murine platelets stimulated with PAR agonists in the presence of the inhibitor. In addition, UBO-QIC-treated platelets did not affect collagen-related peptide-induced platelet activation suggesting that this inhibitor had no non-specific effects on the GPVI pathway. Furthermore, Akt phosphorylation downstream of the Galphai and Galphaz pathways, and vasodilator stimulated phosphoprotein phosphorylation downstream of the Galphas pathway were not inhibited in UBO-QIC-treated platelets. UBO-QIC is a specific inhibitor for Galphaq, which can be a useful tool for investigating Galphaq-coupled receptor signaling pathways in platelets. PMID- 25734216 TI - Novel mutations of integrin alphaIIb and beta3 genes in Turkish children with Glanzmann's thrombasthenia. AB - Glanzmann's thrombasthenia (GT) is an inherited disorder of platelet aggregation, characterized by qualitative and quantitative defect on platelet alphaIIbbeta3 integrin (GpIIb/IIIa), resulting in lifelong bleeding tendency due to defective platelet plug formation. The alphaIIb gene (ITGA2B) and beta3 gene (ITGB3) are closely located at chromosome 17q21.31-32. ITGA2B consist of 30 exons and encoding alpha chain, whereas ITGB3 has 15 exons and encoding beta chain. Until now, according to the Human Gene Mutation Database (HGMD), 138 mutations at ITGA2B gene and 101 mutations at ITGB3 gene have been identified. We aimed to determine whether there was any mutation in the ITGA2B and ITGB3 genes, and a correlation between clinical phenotype and genotype in Turkish GT patients. We examined 20 patients with GT followed at the Department of Pediatric Hematology, Meram Faculty of Medicine, for Clinical and Laboratory Findings and Molecular Genetic Analysis. Peripheral blood was collected from patients, and a written informed consent for genetic analysis was obtained from parents. DNA was isolated from by proteinase K and phenol/chloroform extraction. ITGA2B and ITGB3 genes were screened by polymerase chain reaction. There were 12 females and 8 males with a median age of 15.25 years. Major clinical presentations of these patients were mucocutaneous bleedings. The most common bleeding type was epistaxis (85%). Life-threatening bleedings were seen in five patients. Seven (35%) patients showed various mutations in the ITGA2B or ITGB3 genes. We detected four novel mutations in three different regions and two mutations defined previously within the ITGA2B gene. These changes are at exon 4; c.570 T > G alteration, at exon 13 c.1277 T > A, c.1291 T > G alterations, at exon 19 c.1921A > G alterations. And from the start point of exon 14, behind 107 bases, we detected a heterozygous alteration at Thymine to Guanine. According to PolyPhen Database Program and NCBI Multiple Alignment Tool Database, four transitions are conserved at evolutionary process, so we can say that these transitions are novel mutations. c. 468T > G alteration at exon 4 and c. 1378 T > A alteration at exon 13 were reported to HGMD previously. Screening the exons of the ITGB3 gene from the same patient groups, we reported a novel missense mutation at exon 5, at nucleotide 680. No correlation was found between clinical phenotype and genotype. These mutations were described for the first time in Turkish population, and all novel mutations are not defined previously. Furthermore, collaborative studies are needed for the population point of view. PMID- 25734217 TI - Colistin-related thrombocytopenia. PMID- 25734218 TI - Diabetes-related quality measure attainment: canagliflozin versus sitagliptin based on a pooled analysis of 2 clinical trials. AB - OBJECTIVE: To evaluate attainment of diabetes-related quality measures with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus. STUDY DESIGN: This post hoc analysis used pooled data from two 52-week, randomized, double-blind, phase 3 clinical trials that evaluated the comparative efficacy of canagliflozin and sitagliptin. One trial evaluated patients on metformin at baseline with add-on canagliflozin 100 mg, canagliflozin 300 mg, or sitagliptin 100 mg; the other trial evaluated patients on metformin and a sulfonylurea at baseline with add-on canagliflozin 300 mg or sitagliptin 100 mg. METHODS: Individual diabetes-related quality measures, including glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), and change in body weight, were assessed. RESULTS: At baseline, the proportions of patients meeting criteria for all quality measures were similar between groups. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 100 mg demonstrated either comparable or superior glycemic control. Additionally, canagliflozin 100 mg versus sitagliptin 100 mg demonstrated superior attainment of BP, BMI, and weight related quality measures; no difference was seen with respect to LDL-C. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 300 mg demonstrated superior glycemic control at all thresholds of A1C, and superior BP, BMI, and weight-related quality measures; there was no difference in LDL-C quality measure attainment. CONCLUSION: We evaluated the comparative efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg on quality measure attainment after 52 weeks of treatment. Compared with sitagliptin 100 mg, canagliflozin 100 mg demonstrated comparable or superior attainment of diabetes related quality measures. Compared with sitagliptin 100 mg, canagliflozin 300 mg demonstrated superior diabetes-related quality measure attainment, including glycemic, BP, and weight-related quality measures; there was no difference in LDL C quality measure attainment between either dosage of canagliflozin and the 100 mg dosage of sitagliptin. PMID- 25734219 TI - Psychological and psychotherapeutic approaches for people with motor neuron disease: A qualitative study. AB - The aim of the study was to review current psychological and psychotherapeutic approaches for people with MND used by therapists in Ireland and to gain an insight into approaches used elsewhere. We used a qualitative study collecting data from eight therapists in Ireland and two therapists in the UK and Italy using semi-structured interviews and analysed the results using principles of grounded theory. Therapists' approaches included supporting the person in the 'here and now' by providing a 'fine focus' on what they can still do, re affirming the person in their ability to have an active role in their life and supporting the person in exploring their emotions. The desired outcome was to provide the person with space to talk, express feelings and be able to self direct. In conclusion, there is no consensus about a specific approach, due to the complexity of the disease and the variety of presentations. Different approaches may be required during disease progression. The findings indicate that therapists would benefit from having experience of MND, the limitations in mobility, communication and cognitive processing. PMID- 25734220 TI - Enantioselective ruthenium-catalyzed carbonyl allylation via alkyne-alcohol C-C bond-forming transfer hydrogenation: allene hydrometalation vs oxidative coupling. AB - Chiral ruthenium(II) complexes modified by Josiphos ligands catalyze the reaction of alkynes with primary alcohols to form homoallylic alcohols with excellent control of regio-, diastereo-, and enantioselectivity. These processes represent the first examples of enantioselective carbonyl allylation using alkynes as allylmetal equivalents. PMID- 25734221 TI - One-pot synthesis of C18-functionalized core-shell magnetic mesoporous silica composite as efficient sorbent for organic dye. AB - In this work, a facile one-pot strategy was proposed for the synthesis of C18 functionalized core-shell magnetic mesoporous silica composite (Fe3O4/mSiO2-C18). The Fe3O4/mSiO2-C18 composite, with an average size of 80 nm and a functionalized mesoporous silica shell of about 30 nm in thickness, has excellent adsorption ability toward methylene blue dye (MB) due to the large surface area (303 m(2) g( 1)) and the abundant hydrophobic C18 groups. The adsorption equilibrium was achieved within 20 min and the adsorption behavior of MB on Fe3O4/mSiO2-C18 composite fitted the pseudo-second-order kinetic model well (k2=1.29*10(-2) g mg( 1) min(-1), q(e)=144.72 mg g(-1), h(o)=270.27 mg g(-1) min(-1) under 25 degrees C and an initial MB concentration of 10 mg L(-1)). Langmuir and Freundlich isothermal adsorption models can both be used to describe the adsorption process and the maximum Langmuir adsorption capacity of MB on Fe3O4/mSiO2-C18 at 25 degrees C and pH 7.5 is 363.64 mg g(-1). Thermodynamic parameters show that the adsorption reaction is exothermic and spontaneous (DeltaH(0)=-63.49 kJ mol(-1), DeltaG(0)=-7.80 kJ mol(-1)). Ionic strength and pH affected the adsorption slightly. In addition, the MB adsorbed sorbent can be readily separated from water solution by an external magnet because of the high magnetic saturation value (22.62 emu g(-1)). After being regenerated by treatment with acidic methanol, the sorbent could be reused for at least 5 cycles with a little decrease in adsorption capacity. PMID- 25734222 TI - Adsorption of hyaluronic acid on solid supports: role of pH and surface chemistry in thin film self-assembly. AB - Owing to its biocompatibility, resistance to biofouling, and desirable physicochemical and biological properties, hyaluronic acid (HA) has been widely used to modify the surface of various materials. The role of various physicochemical factors in HA adsorption remains, however, to be clarified. Herein, we employed quartz crystal microbalance with dissipation (QCM-D) in order to investigate HA adsorption at different pH conditions onto three substrates silicon oxide, amine-terminated self-assembled monolayer (SAM) on gold, and carboxylic acid-terminated SAM on gold. The QCM-D experiments indicated specific pH conditions where either strong or weak HA adsorption occurs. The morphology of the adsorbed HA layers was investigated by atomic force microscopy (AFM), and we identified that strong HA adsorption produced a complete, homogenous and smooth HA layer, while weak HA adsorption resulted in rough and inhomogeneous HA layers. The observed specifics of the kinetics of HA adsorption, including a short initial linear phase and subsequent long non-linear phase, were described by using a mean-field kinetic model taking HA diffusion limitations and reconfiguration in the adsorbed state into account. The findings extend the physicochemical background of design strategies for improving the use of passive HA adsorption for surface modification applications. PMID- 25734223 TI - Template synthesis of hollow silver hexapods using hexapod-shaped silver oxide mesoparticles. AB - One powerful method to make nanoparticles is template-based approach. Because such templates confine the size and shape of nanoparticles, diverse nanoparticles can be prepared through such method. For example, hollow gold (Au) nanoparticles are easily fabricated using silver (Ag) nanoparticles as templates. Ag nanoparticles in a solution containing Au(3+) are readily oxidized to Ag(+) and dissolved into the solution, while Au(3+) are reduced and deposited near Ag nanoparticles. Because the reactivity of Au(3+) is lower than that of Ag(+), this exchange reaction readily occurs, resulting in hollow Au nanoparticles. In this paper, we use morphology-controlled silver oxide (Ag2O) mesoparticles as a sacrificial template to make well-defined Ag mesoparticles. The hexapod-shaped Ag2O mesoparticles are synthesized by retarding its reaction rate using bis (p sulfonatophenyl) phenylphosphine dehydrate dipotassium as a ligand, and reduced into Ag hexapods by sodium borohydride. Complete conversion of Ag2O into Ag is confirmed by a series of characterization procedure, and the shape and size of Ag2O hexapods are retained during the reduction process. Reduced Ag hexapods have hollow inner structure, and interestingly show single crystalline phase, which is contrary to the previous report. A new mechanism is introduced to explain formation of hollow structure and its single crystalline phase. PMID- 25734224 TI - A new plasmonic device made of gold nanoparticles and temperature responsive polymer brush on a silicon substrate. AB - This paper reports a general stepwise route assembling interface-mediated RAFT polymerization of 2-methoxyethoxy ethyl methacrylate and conversion of dodecyl trithiocarbonate end groups to thiol groups for gold nanoparticle assemblies. We intended by this way a new plasmonic device made of gold nanoparticles (Au NPs) and temperature responsive [poly((2-methoxyethoxy)ethyl) methacrylate] [poly(MEO2 MA)] brush on a silicon substrate. This polymeric layer replies to temperature changing by conformational variation and is therefore able to change the distance between the Au NPs on the brush layer with 5,5-dithiobis(2-dinitrobenzoic acid) (DTNB). We show that an increment of the external temperature reversibly stimulates a significant increase of the DTNB SERS signal. PMID- 25734225 TI - In silico identification of PAP-1 binding sites in the Kv1.2 potassium channel. AB - Voltage-gated potassium channels of the Kv1 family play a crucial role in the generation and transmission of electrical signals in excitable cells affecting neuronal and cardiac activities. Small-molecule blockage of these channels has been proposed to occur via a cooperative mechanism involving two main blocking sites: the inner-pore site located below the selectivity filter, and a side pocket cavity located between the pore and the voltage sensor. Using 0.5 MUs molecular dynamics simulation trajectories complemented by docking calculations, the potential binding sites of the PAP-1 (5-(4-phenoxybutoxy)psoralen) blocker to the crystal structure of Kv1.2 channel have been studied. The presence of both mentioned blocking sites at Kv1.2 is confirmed, adding evidence in favor of a cooperative channel blockage mechanism. These observations provide insight into drug modulation that will guide further developments of Kv inhibitors. PMID- 25734226 TI - Three-dimensionally interconnected TaS3 nanowire network as anode for high performance flexible Li-ion battery. AB - Here we demonstrated tantalum trisulfide (TaS3) nanowires as a new self-supported and flexible anode material for Li-ion batteries with high specific capacity and excellent electrochemical cycling. The TaS3 nanofibers were fabricated by a solid state reaction process, delivering a good reversible capacity of ~400 mAhg(-1) after 100 cycles at 0.1C with only 0.1% decay per cycle compared with the initial charge capacity. Cycled at 10C, it displays a capacity as high as 60 mAh g(-1). The continuous and interconnected TaS3 nanowires not only enable fast access of electrons and ions but also grant the electrode with high mechanical flexibility. PMID- 25734227 TI - Importance of long-time simulations for rare event sampling in zinc finger proteins. AB - Molecular dynamics (MD) simulation methods have seen significant improvement since their inception in the late 1950s. Constraints of simulation size and duration that once impeded the field have lessened with the advent of better algorithms, faster processors, and parallel computing. With newer techniques and hardware available, MD simulations of more biologically relevant timescales can now sample a broader range of conformational and dynamical changes including rare events. One concern in the literature has been under which circumstances it is sufficient to perform many shorter timescale simulations and under which circumstances fewer longer simulations are necessary. Herein, our simulations of the zinc finger NEMO (2JVX) using multiple simulations of length 15, 30, 1000, and 3000 ns are analyzed to provide clarity on this point. PMID- 25734228 TI - Live predators, robots, and computer-animated images elicit differential avoidance responses in zebrafish. AB - Emotional disturbances constitute a major health issue affecting a considerable portion of the population in western countries. In this context, animal models offer a relevant tool to address the underlying biological determinants and to screen novel therapeutic strategies. While rodents have traditionally constituted the species of choice, zebrafish are now becoming a viable alternative. As zebrafish gain momentum in biomedical sciences, considerable efforts are being devoted to developing high-throughput behavioral tests. Here, we present a comparative study of zebrafish behavioral response to fear-evoking stimuli offered via three alternative methodologies. Specifically, in a binary-choice test, we exposed zebrafish to an allopatric predator Astronotus ocellatus, presented in the form of a live subject, a robotic replica, and a computer animated image. The robot's design and operation were inspired by the morphology and tail-beat motion of its live counterpart, thereby offering a consistent three dimensional stimulus to focal fish. The computer-animated image was also designed after the live subject to replicate its appearance. We observed that differently from computer-animated images, both the live predator and its robotic replica elicited robust avoidance response in zebrafish. In addition, in response to the robot, zebrafish exhibited increased thrashing behavior, which is considered a valid indicator of fear. Finally, inter-individual response to a robotic stimulus is more consistent than that shown in response to live stimuli and animated images, thereby increasing experimental statistical power. Our study supports the view that robotic stimuli can constitute a promising experimental tool to elicit targeted behavioral responses in zebrafish. PMID- 25734229 TI - Stereotactic body radiotherapy: A survey of contemporary practice in six selected European countries. PMID- 25734230 TI - Synthesis, physical properties, and light-emitting diode performance of phenazine based derivatives with three, five, and nine fused six-membered rings. AB - Realizing the control of emission colors of single molecules is very important in the development of full-color emitting materials. Herein, three novel phenazine derivatives (2,3,7,8-tetrakis(decyloxy)phenazine (2a), 2,3-didecyloxy-5,14-diaza 7,12-dioxo-9,10- dicyanopentacene (2b), and 2,3,13,14-tetradecyloxy-5,11,16,22 tetraaza-7,9,18,20-tetraoxo-8,19-dicyanoenneacene (2c)) have been successfully synthesized and fully characterized. Compound 2c can emit blue light in toluene solution (450 nm), green light in the powder/film state (502/562 nm), and red light in the 2c/TFA state (610 nm). The OLED with 2c emits a strong green light at a peak of 536 nm with a maximum luminance of the OLED of about 8600 cd m(-2), which indicates that 2c could be a promising fluorescent dye for OLED applications. PMID- 25734231 TI - Light-controlled morphologies of self-assembled triarylamine-fullerene conjugates. AB - A family of triarylamine-fullerene conjugates has been synthesized and shown to self-assemble upon light stimulation in chlorinated solvents. This light-induced process primarily involves excitation of triarylamine derivatives, which then oxidize and stack with their neutral counterparts to form charge transfer complexes in the form of p-conducting channels, while fullerenes are consequently enforced in coaxial n-conducting columnar arrangements. These supramolecular heterojunctions can be organized over very long distances in micrometric fibers when a controlled amount of photons is provided from a white light source to initiate the process. Surprisingly, when sunlight or UV light is used instead, the nanostructuration leads to monodisperse spherical objects due to the nature of the nucleation-growth process involved in the stacks formation. This control over the supramolecular morphology of organic self-assemblies using the nature of light is of general interest for the design of functional responsive materials. PMID- 25734232 TI - Effect of hydrophilic silica nanoparticles on the magnetorheological properties of ferrofluids: a study using opto-magnetorheometer. AB - For many technological applications of ferrofluids, the magnetorheological properties require being precisely controlled. We study the effect of hydrophilic silica on the magnetorheology of an oil-based ferrofluid containing Fe3O4 nanoparticles of size ~10 nm. We observe that the presence of silica nanoparticles lowers the yield stresses, viscoelastic moduli, and shear thinning behavior of the ferrofluid because of the weakening of dipolar interactions, which was evident from the observed lower yield stresses exponent (<2). The ferrofluid containing silica exhibits a dominant elastic behavior, a reduced hysteresis during the forward and reverse magnetic field sweeps, and a longer linear viscoelastic regime under nonlinear deformation. The Mason number plots at low shear rates and magnetic fields show deviations from the master curve in the presence of silica. The magnetic field induced microstructures, visualized using opto-magnetorheometer, showed columnar aggregate structures along the field directions, which are reoriented along the shear flow direction at high shear rates. The image analysis shows that the average thickness of the columnar aggregates in pure ferrofluid is much larger than that of the mixed system, which suggests that the intervening silica matrix hampers the zippering transition of columns at higher magnetic field and shear rates. Our results suggest that optimization of rheological properties of ferrofluids is possible by carefully adding suitable silica nanoparticles, which may find practical applications such as dynamic seals, heat transfer, sensors, and opto-fluidic devices, etc. PMID- 25734233 TI - Stable ferroelectric liquid crystals derived from salicylaldimine-core. AB - Five pairs of enantiomers derived from salicylaldimine-core have been prepared by condensing (R)- or (S)-4-(octan-2-yloxy)anilines with 4-formyl-3-hydroxyphenyl 4 (n-alkoxy)benzoates. They have been designed to probe the correlation between molecular structure and mesomorphism, and especially to provide stable mesogens having potential for applications in ferroelectric liquid crystal devices. Thus, they have been substituted with a chiral tail at one end and by n-alkoxy chains of varying length at the other terminal. A detailed study confirms an indistinguishable behavior of all ten mesogens exhibiting an enantiotropic chiral smectic C (SmC*) phase besides blue phase (BP) and chiral nematic (N*) phase. The SmC* phase occurring over a 50-70 degrees C thermal width shows ferroelectric switching with spontaneous polarization (Ps) value crossing over 100 nC/cm(2). Circular dichroism spectroscopic study of the mesophases confirms the chromophores of the molecules being in the macroscopic chiral (helical) environment. PMID- 25734235 TI - Adsorption of nucleic Acid bases, ribose, and phosphate by some clay minerals. AB - Besides having a large capacity for taking up organic molecules, clay minerals can catalyze a variety of organic reactions. Derived from rock weathering, clay minerals would have been abundant in the early Earth. As such, they might be expected to play a role in chemical evolution. The interactions of clay minerals with biopolymers, including RNA, have been the subject of many investigations. The behavior of RNA components at clay mineral surfaces needs to be assessed if we are to appreciate how clays might catalyze the formation of nucleosides, nucleotides and polynucleotides in the "RNA world". The adsorption of purines, pyrimidines and nucleosides from aqueous solution to clay minerals is affected by suspension pH. With montmorillonite, adsorption is also influenced by the nature of the exchangeable cations. Here, we review the interactions of some clay minerals with RNA components. PMID- 25734234 TI - The origin and evolution of ribonucleotide reduction. AB - Ribonucleotide reduction is the only pathway for de novo synthesis of deoxyribonucleotides in extant organisms. This chemically demanding reaction, which proceeds via a carbon-centered free radical, is catalyzed by ribonucleotide reductase (RNR). The mechanism has been deemed unlikely to be catalyzed by a ribozyme, creating an enigma regarding how the building blocks for DNA were synthesized at the transition from RNA- to DNA-encoded genomes. While it is entirely possible that a different pathway was later replaced with the modern mechanism, here we explore the evolutionary and biochemical limits for an origin of the mechanism in the RNA + protein world and suggest a model for a prototypical ribonucleotide reductase (protoRNR). From the protoRNR evolved the ancestor to modern RNRs, the urRNR, which diversified into the modern three classes. Since the initial radical generation differs between the three modern classes, it is difficult to establish how it was generated in the urRNR. Here we suggest a model that is similar to the B12-dependent mechanism in modern class II RNRs. PMID- 25734236 TI - Molecular determinants of biased agonism at the dopamine D2 receptor. AB - The development of biased (functionally selective) ligands provides a formidable challenge in medicinal chemistry. In an effort to learn to design functionally selective molecular tools for the highly therapeutically relevant dopamine D2 receptor, we synthesized a collection of agonists based on structurally distinct head groups derived from canonical or atypical dopaminergic pharmacophores. The test compounds feature a long lipophilic appendage that was shown to mediate biased signaling. By employing functional assays and molecular dynamics simulations, we could show that atypical dopamine surrogates of type 1 and 2 promote biased signaling, while ligands built from classical dopaminergic head groups (type 3 and 4) typically elicit more balanced signaling profiles. Besides this, we found a strong influence of the stereochemistry of type 4 aminotetraline derived agonists on functional selectivity at D2 receptors. Whereas the (S) enantiomer behaved as a full agonist, the biased ligand (R)-4 induced poor G protein coupling but substantial beta-arrestin recruitment. PMID- 25734237 TI - Auto Therapy: Using Automobiles as Vehicles for Reminiscence With Older Adults. AB - Reminiscence can be beneficial for older adults and contribute to well-being and ego integrity. In this exploratory pilot study, researchers assessed the feasibility and tolerability of a novel reminiscence intervention using automobiles as the focal point. Nineteen older adults (N = 19) were asked to reminisce using photographs of automobiles from across their lifespan. The RE-AIM framework was used to assess the intervention in terms of reach, effectiveness, adoption, implementation, and maintenance. The intervention was well-received, quickly established rapport, and effectively fostered reminiscence. Social workers may find this intervention useful in helping older adults to explore their lives. PMID- 25734238 TI - Socioeconomic inequalities in attitudes towards cancer: an international cancer benchmarking partnership study. AB - Socioeconomic status (SES) differences in attitudes towards cancer have been implicated in the differential screening uptake and the timeliness of symptomatic presentation. However, the predominant emphasis of this work has been on cancer fatalism, and many studies focus on specific community subgroups. This study aimed to assess SES differences in positive and negative attitudes towards cancer in UK adults. A population-based sample of UK adults (n=6965, age>=50 years) completed the Awareness and Beliefs about Cancer scale, including six belief items: three positively framed (e.g. 'Cancer can often be cured') and three negatively framed (e.g. 'A cancer diagnosis is a death sentence'). SES was indexed by education. Analyses controlled for sex, ethnicity, marital status, age, self-rated health, and cancer experience. There were few education-level differences for the positive statements, and overall agreement was high (all>90%). In contrast, there were strong differences for negative statements (all Ps<0.001). Among respondents with lower education levels, 57% agreed that 'treatment is worse than cancer', 27% that cancer is 'a death sentence' and 16% 'would not want to know if I have cancer'. Among those with university education, the respective proportions were 34, 17 and 6%. Differences were not explained by cancer experience or health status. In conclusion, positive statements about cancer outcomes attract near-universal agreement. However, this optimistic perspective coexists alongside widespread fears about survival and treatment, especially among less-educated groups. Health education campaigns targeting socioeconomically disadvantaged groups might benefit from a focus on reducing negative attitudes, which is not necessarily achieved by promoting positive attitudes. PMID- 25734239 TI - Most participate in faecal immunochemical test-based colorectal cancer screening out of curiosity about their chances of developing cancer. AB - Several clinical trials have shown that colorectal cancer (CRC) screening can reduce cancer deaths. Its effectiveness is affected by the participation level. To develop targeted invitations, we need to understand why individual persons decide to participate. To evaluate reasons for participation among persons invited for faecal immunochemical test-based CRC screening, a total of 10,265 asymptomatic persons aged 50-75 years were invited to a Dutch CRC screening pilot (2008-2009). Reasons for participation were elicited by a questionnaire. A total of 3554 (66%) participants returned the questionnaire. Obtaining more certainty about the chances of developing cancer (ticked by 88%) and the occurrence of cancer in the family or the circle of acquaintances (18%) were the most frequently selected reasons for participation. We also explored reasons for nonparticipation among nonparticipants. In this subgroup, comorbidity and the absence of symptoms were the most frequently reported reasons for declining to participate, but the response rate was low. The vast majority of the participants decided to take up the screening because they wanted to know more about their chances of developing cancer. PMID- 25734240 TI - Compressive stress induces dephosphorylation of the myosin regulatory light chain via RhoA phosphorylation by the adenylyl cyclase/protein kinase A signaling pathway. AB - Mechanical stress that arises due to deformation of the extracellular matrix (ECM) either stretches or compresses cells. The cellular response to stretching has been actively studied. For example, stretching induces phosphorylation of the myosin regulatory light chain (MRLC) via the RhoA/RhoA-associated protein kinase (ROCK) pathway, resulting in increased cellular tension. In contrast, the effects of compressive stress on cellular functions are not fully resolved. The mechanisms for sensing and differentially responding to stretching and compressive stress are not known. To address these questions, we investigated whether phosphorylation levels of MRLC were affected by compressive stress. Contrary to the response in stretching cells, MRLC was dephosphorylated 5 min after cells were subjected to compressive stress. Compressive loading induced activation of myosin phosphatase mediated via the dephosphorylation of myosin phosphatase targeting subunit 1 (Thr853). Because myosin phosphatase targeting subunit 1 (Thr853) is phosphorylated only by ROCK, compressive loading may have induced inactivation of ROCK. However, GTP-bound RhoA (active form) increased in response to compressive stress. The compression-induced activation of RhoA and inactivation of its effector ROCK are contradictory. This inconsistency was due to phosphorylation of RhoA (Ser188) that reduced affinity of RhoA to ROCK. Treatment with the inhibitor of protein kinase A that phosphorylates RhoA (Ser188) induced suppression of compression-stimulated MRLC dephosphorylation. Incidentally, stretching induced phosphorylation of MRLC, but did not affect phosphorylation levels of RhoA (Ser188). Together, our results suggest that RhoA phosphorylation is an important process for MRLC dephosphorylation by compressive loading, and for distinguishing between stretching and compressing cells. PMID- 25734241 TI - Assessing the reliability of MRI-CBCT image registration to visualize temporomandibular joints. AB - OBJECTIVES: To evaluate image quality of two methods of registering MRI and CBCT images of the temporomandibular joint (TMJ), particularly regarding TMJ articular disc-condyle relationship and osseous abnormality. METHODS: MR and CBCT images for 10 patients (20 TMJs) were obtained and co-registered using two methods (non guided and marker guided) using Mirada XD software (Mirada Medical Ltd, Oxford, UK). Three radiologists independently and blindly evaluated three types of images (MRI, CBCT and registered MRI-CBCT) at two times (T1 and T2) on two criteria: (1) quality of MRI-CBCT registrations (excellent, fair or poor) and (2) TMJ disc condylar position and articular osseous abnormalities (osteophytes, erosions and subcortical cyst, surface flattening, sclerosis). RESULTS: 75% of the non-guided registered images showed excellent quality, and 95% of the marker-guided registered images showed poor quality. Significant difference was found between the non-guided and marker-guided registration (chi(2) = 108.5; p < 0.01). The interexaminer variability of the disc position in MRI [intraclass correlation coefficient (ICC) = 0.50 at T1, 0.56 at T2] was lower than that in MRI-CBCT registered images [ICC = 0.80 (0.52-0.92) at T1, 0.84 (0.62-0.93) at T2]. Erosions and subcortical cysts were noticed less frequently in the MRI-CBCT images than in CBCT images. CONCLUSIONS: Non-guided registration proved superior to marker-guided registration. Although MRI-CBCT fused images were slightly more limited than CBCT alone to detect osseous abnormalities, use of the fused images improved the consistency among examiners in detecting disc position in relation to the condyle. PMID- 25734242 TI - Cysticercosis of the masseter: MRI and sonographic correlation. AB - Cysticercal involvement of the masseter is an uncommon manifestation of a relatively common parasitic infestation. Sonographic evaluation of many isolated cases of cysticercosis has been extensively described. However, there are scanty reports on MRI appearance of cysticercal involvement of the masseter. This report presents classical imaging appearance of cysticercal involvement of the masseter on sonography and MRI. The pattern of the disease and MRI appearance of lesions in the masseter, highlighting the role of diffusion-weighted images, are described. PMID- 25734243 TI - MRI with intraoral orthodontic appliance-a comparative in vitro and in vivo study of image artefacts at 1.5 T. AB - OBJECTIVES: We investigated artefacts caused from orthodontic appliances at 1.5-T MRI of the head and neck region and whether the image quality can be improved utilizing the artefact-minimizing sequence WARP. METHODS: In vitro tests were performed by phantom measurements of different orthodontic devices applying different types of MR sequences [echoplanar imaging (EPI), turbo spin echo (TSE) and TSE-WARP, gradient echo (GRE)]. Two independent readers determined after calibration the level of artefacts. Subsequently, the interobserver agreement was calculated. The measurement of artefacts was based on the American Society for Testing Materials Standard F 2119-07. For in vivo imaging, one test person was scanned with an inserted multibracket appliance. The level of artefacts for 27 target regions was evaluated. RESULTS: In vitro: ceramic brackets and ferromagnetic steel brackets produced artefact radii up to 1.12 and 7.40 cm, respectively. WARP reduced these artefacts by an average of 32.7%. The Bland Altman-Plot indicated that maximum measurement differences of 3 mm have to be expected with two calibrated observers. In vivo: the EPI sequence for brain imaging was not analysable. The TSE sequence of the brain did not demonstrate artefacts except for the nasal cavity. Conversely, the TSE sequence of the cervical spine revealed severe artefacts in the midface region. The GRE sequence appeared to be more susceptible to artefacts than did the TSE sequence. CONCLUSIONS: In vitro measurements allow an estimation of the in vivo artefact size. Orthodontic appliances may often remain intraorally when performing MRI. WARP showed a more significant effect in vitro than in vivo. PMID- 25734244 TI - Transcriptomic analysis of human placenta in intrauterine growth restriction. AB - BACKGROUND: Intrauterine growth restriction (IUGR) is a frequent complication of pregnancy defined as a restriction of fetal growth. The objective of this work was to improve the knowledge on the pathophysiology of IUGR using a genome-wide method of expression analysis. METHODS: We analyzed differentially expressed genes in pooled placental tissues from vascular IUGR (four pools of three placentas) and normal pregnancies (four pools of three placentas) using a long nucleotide microarray platform (Nimblegen). We first did a global bioinformatics analysis based only on P value without any a priori. We secondly focused on "target" genes among the most modified ones. Finally, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed on an extended panel of tissue samples (n = 62) on selected "target". RESULTS: We identified 636 modified genes among which 206 were upregulated (1.5 and higher; P < 0.05). Groups of patients were classified unambiguously. Genes involved in mitochondrial function and oxidative phosphorylation were decreased affecting three out of five complexes of the respiratory chain of the mitochondria, and thus energy production and metabolism. Among the most induced genes, we identified LEP, IGFBP1, and RBP4. CONCLUSION: Complementary studies on the role and function of LEP, IGFBP1, and RBP4 in IUGR pathophysiology and also in fetal programming remain necessary. PMID- 25734245 TI - Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice. AB - BACKGROUND: Phlebotomy-induced anemia (PIA) is common in preterm infants. The hippocampus undergoes rapid differentiation during late fetal/early neonatal life and relies on adequate oxygen and iron to support oxidative metabolism necessary for development. Anemia shortchanges these two critical substrates, potentially altering hippocampal development and function. METHODS: PIA (hematocrit <25%) was induced in neonatal mice pups from postnatal day (P)3 to P14. Neurochemical concentrations in the hippocampus were determined using in vivo (1)H NMR spectroscopy at 9.4T and compared with control animals at P14. Gene expression was assessed using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: PIA decreased brain iron concentration, increased hippocampal lactate and creatine concentrations, and decreased phosphoethanolamine (PE) concentration and the phosphocreatine/creatine ratio. Hippocampal transferrin receptor (Tfrc) gene expression was increased, while the expression of calcium/calmodulin dependent protein kinase type IIalpha (CamKIIalpha) was decreased in PIA mice. CONCLUSION: This clinically relevant model of neonatal anemia alters hippocampal energy and phospholipid metabolism and gene expression during a critical developmental period. Low target hematocrits for preterm neonates in the neonatal intensive care unit (NICU) may have potential adverse neural implications. PMID- 25734246 TI - Integration of gene expression and DNA-methylation profiles improves molecular subtype classification in acute myeloid leukemia. AB - BACKGROUND: Acute Myeloid Leukemia (AML) is characterized by various cytogenetic and molecular abnormalities. Detection of these abnormalities is important in the risk-classification of patients but requires laborious experimentation. Various studies showed that gene expression profiles (GEP), and the gene signatures derived from GEP, can be used for the prediction of subtypes in AML. Similarly, successful prediction was also achieved by exploiting DNA-methylation profiles (DMP). There are, however, no studies that compared classification accuracy and performance between GEP and DMP, neither are there studies that integrated both types of data to determine whether predictive power can be improved. APPROACH: Here, we used 344 well-characterized AML samples for which both gene expression and DNA-methylation profiles are available. We created three different classification strategies including early, late and no integration of these datasets and used them to predict AML subtypes using a logistic regression model with Lasso regularization. RESULTS: We illustrate that both gene expression and DNA-methylation profiles contain distinct patterns that contribute to discriminating AML subtypes and that an integration strategy can exploit these patterns to achieve synergy between both data types. We show that concatenation of features from both data sets, i.e. early integration, improves the predictive power compared to classifiers trained on GEP or DMP alone. A more sophisticated strategy, i.e. the late integration strategy, employs a two-layer classifier which outperforms the early integration strategy. CONCLUSION: We demonstrate that prediction of known cytogenetic and molecular abnormalities in AML can be further improved by integrating GEP and DMP profiles. PMID- 25734247 TI - Biomarkers in substance use disorders. AB - The prevention and treatment of substance use disorders (SUDs), including addiction, would benefit from having better biomarkers for the classification of patients into categories that are reproducible and have predictive validity. Direct measurement of drugs or their metabolites in various body fluids constitutes a clinically valuable biomarker but one that can only be used to corroborate acute or relatively recent drug use. Thus, there is an urgent need for biomarkers that reflect chronic drug exposure as well as biomarkers that predict or correlate with disease trajectories and treatment responses. Advances in tools and technologies to investigate genetics, epigenetics and epitranscriptomics, and human brain function and neurochemistry (brain imaging tools including EEG) offer unprecedented opportunities for the development of such biomarkers. Progress in this area will not only enhance our ability to screen and treat patients with SUDs but also accelerate research on the neurobiological processes that underlie SUDs. PMID- 25734248 TI - siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA. AB - There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs. PMID- 25734249 TI - Autoantibody response against NALP5/MATER in primary ovarian insufficiency and in autoimmune Addison's disease. AB - CONTEXT: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. OBJECTIVES: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. METHODS: Autoantibodies against NALP5/MATER and inhibin chains-alpha and -betaA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. RESULTS: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-alpha/betaA autoantibodies. CONCLUSIONS: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI. PMID- 25734250 TI - Organ specificity in autoimmune diseases: thyroid and islet autoimmunity in alopecia areata. AB - CONTEXT: Multiple autoimmune diseases, such as autoimmunity against the thyroid gland and pancreatic islets, are often observed in a single patient. Although alopecia areata (AA) is one of the most frequent organ-specific autoimmune diseases, the association of AA with other autoimmune diseases and the genetic basis of the association remain to be analyzed. OBJECTIVE: The aim of this study was to clarify the similarities and differences in HLA and clinical characteristics of thyroid and islet autoimmunity in patients with AA. PARTICIPANTS: A total of 126 patients with AA were newly recruited. Anti-islet and antithyroid autoantibodies were tested, and genotypes of HLA genes were determined. RESULTS: Among the autoimmune diseases associated with AA, autoimmune thyroid disease was most frequent (10.0%), followed by vitiligo (2.7%) and rheumatoid arthritis (0.9%) but not type 1 diabetes (0.0%). The prevalence of thyroid-related autoantibodies in patients with AA was significantly higher than that in controls (TSH receptor antibody [TRAb]: 42.7% vs 1.2%, P = 1.6 * 10(-46); thyroid peroxidase antibody: 29.1% vs 11.6%; P = 1.7 * 10(-6)), whereas the prevalence of islet-related autoantibodies was comparable between patients with AA and control subjects. The frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, was significantly higher in TRAb-positive (12.8%, P = .0028, corrected P value [Pc] = .02) but not TRAb-negative (7.1%, not significant) patients with AA than in control subjects (4.5%). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc < .0003 and Pc < .0008, respectively). CONCLUSION: AA was associated with thyroid autoimmunity but not islet autoimmunity, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease. PMID- 25734251 TI - Preablation 131-I scans with SPECT/CT contribute to thyroid cancer risk stratification and 131-I therapy planning. AB - CONTEXT: The use of preablation diagnostic radioiodine scans for risk stratification and radioiodine therapy planning for differentiated thyroid cancer (DTC) remains controversial. OBJECTIVE: The objective was to assess the contribution of preablation diagnostic 131-I scans with SPECT/CT (Dx 131-I scan) to (1) the risk stratification and (2) the postoperative management of DTC. DESIGN: The study was designed as a prospective sequential patient series. SETTING: The study was conducted at a University hospital. PATIENTS: Three hundred twenty patients (pts) with DTC (219F; 101M, mean age 47.3 +/- 16.4 y, range 10-90) were studied. INTERVENTION: Using clinical and histopathology information an endocrinologist performed risk stratification and determined postoperative management with respect to radioiodine therapy (RAI) planning. The decision to withhold or to administer RAI, and the recommended low, medium or high therapeutic 131-I activity were recorded. Dx 131-I scans were performed and interpreted by two nuclear medicine physicians as showing thyroid remnant, cervical nodal, or distant metastases. The endocrinologist then reperformed risk stratification and reformulated management after consideration of Dx 131-I scans and stimulated thyroglobulin (Tg) information. MAIN OUTCOME MEASURE: Main outcome measures were changes in risk stratification and management after Dx 131-I scans. RESULTS: Detection of unsuspected nodal and distant metastases and elevated stimulated Tg levels resulted in a change in the estimated risk of recurrence in 15% of patients, and management in 31% of patients, as compared to initial risk stratification and management based on histopathology alone. CONCLUSIONS: Both imaging data and stimulated thyroglobulin levels acquired at the time of Dx 131-I scans are consequential for 131-I therapy planning, providing information that changes risk stratification in 15% of patients as compared to recurrence risk estimation based on histopathology alone. Dx 131-I scans contribute to risk stratification by defining residual nodal and distant metastatic disease, changing clinical management in 29.4% of patients. PMID- 25734252 TI - Glycated hemoglobin levels are mostly dependent on nonglycemic parameters in 9398 Finnish men without diabetes. AB - CONTEXT: Determinants of the variance in glycated hemoglobin (HbA1c) among individuals without type 2 diabetes remain largely unknown. OBJECTIVE: We investigated the determinants of HbA1c, fasting plasma glucose, and 2-hour glucose in an oral glucose tolerance test and the associations of these glycemic markers with insulin sensitivity and insulin secretion in Finnish men without type 2 diabetes. DESIGN AND SETTING: The design and setting were the cross sectional population-based Metabolic Syndrome in Men study including 10 197 Finnish men, aged 45-70 years, and randomly selected from the population register of Kuopio, Eastern Finland. PARTICIPANTS: Participants were a total of 9398 men without type 2 diabetes or with newly diagnosed type 2 diabetes at baseline (mean age 57 +/- 7 y; body mass index 27.0 +/- 4.0 kg/m(2), mean +/- SD) in the Metabolic Syndrome in Men study cohort. INTERVENTIONS: The intervention included an oral glucose tolerance test. MAIN OUTCOME MEASURES: Glycemic and nonglycemic determinants of the variance in HbA1c among participants without type 2 diabetes and the association of HbA1c with insulin secretion and insulin sensitivity were measured. RESULTS: Age, fasting plasma glucose, and high-sensitivity C-reactive protein were the strongest determinants of HbA1c, explaining 12% of the variance in HbA1c levels in participants without type 2 diabetes. Disposition index (insulin secretion) and the Matsuda insulin sensitivity index (insulin sensitivity) explained only less than 2% of the variance in HbA1c in the participants without type 2 diabetes. CONCLUSIONS: The variance in HbA1c among men without type 2 diabetes was largely determined by nonglycemic factors and only weakly by impaired insulin sensitivity and insulin secretion. PMID- 25734253 TI - The effects of bariatric surgery on pancreatic lipid metabolism and blood flow. AB - CONTEXT: Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE: The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN: This was a longitudinal study. SETTING: The study was conducted in a clinical research center. PARTICIPANTS: This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS: Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES: Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of beta-cell function, glucose tolerance, and insulin sensitivity. RESULTS: Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and beta-cell function. CONCLUSIONS: Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes. PMID- 25734255 TI - Correction: The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PMID- 25734254 TI - Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. AB - CONTEXT: Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD). OBJECTIVE: The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response. DESIGN: This was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014. SETTING: The study was conducted at the National Institutes of Health (Bethesda, Maryland). PARTICIPANTS: Patients clinically diagnosed with lipodystrophy, leptin less than 8 ng/mL (males) or less than 12 (females), age older than 6 months, and one or more metabolic abnormalities (diabetes, insulin resistance, or hypertriglyceridemia) participated in the study. INTERVENTION: The interventions included sc metreleptin injections (0.06-0.24 mg/kg . d). MAIN OUTCOMES AND MEASURES: Changes in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured. RESULTS: Baseline metabolic parameters were similar in 55 GLD [HbA1c 8.4% +/- 2.3%; triglycerides, geometric mean (25th, 75th percentile), 467 mg/dL (200, 847)] and 31 PLD patients [HbA1c 8.1% +/- 2.2%, triglycerides 483 mg/dL (232, 856)] despite different body fat and endogenous leptin. At 12 months, metreleptin decreased HbA1c (to 6.4% +/- 1.5%, GLD, P < .001; 7.3% +/- 1.6%, PLD, P = .004) and triglycerides [to 180 mg/dL (106, 312), GLD, P < .001; 326 mg/dL (175, 478), PLD, P = .02]. HbA1c and triglyceride changes over time significantly differed between GLD and PLD. In subgroup analyses, metreleptin improved HbA1c and triglycerides in all GLD subgroups except those with baseline triglycerides less than 300 mg/dL and all PLD subgroups except baseline triglycerides less than 500 mg/dL, HbA1c less than 8%, or endogenous leptin greater than 4 ng/mL. CONCLUSIONS: In addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin. PMID- 25734256 TI - Combinatorial Activity of Flavonoids with Antibiotics Against Drug-Resistant Staphylococcus aureus. AB - The use of resistance-modifying agents is a potential strategy that is used to prolong the effective life of antibiotics in the face of increasing antibiotic resistance. Since certain flavonoids are potent bacterial efflux pump inhibitors, we assessed morin, rutin, quercetin, hesperidin, and (+)-catechin for their combined activity with the antibiotics ciprofloxacin, tetracycline, erythromycin, oxacillin, and ampicillin against drug-resistant strains of Staphylococcus aureus, including methicillin-resistant S. aureus. Four established methods were used to determine the combined efficacy of each combination: microdilution checkerboard assays, time-kill determinations, the Etest, and dual disc-diffusion methods. The cytotoxicity of the flavonoids was additionally evaluated in a mouse fibroblast cell line. Quercetin and its isomer morin decreased by 3- to 16-fold the minimal inhibitory concentration of ciprofloxacin, tetracycline, and erythromycin against some S. aureus strains. Rutin, hesperidin, and (+)-catechin did not promote any potentiation of antibiotics. Despite the potential cytotoxicity of these phytochemicals at a high concentration (fibroblast IC50 of 41.8 and 67.5 mg/L, respectively), quercetin is commonly used as a supplement for several therapeutic purposes. All the methods, with exception of the time-kill assay, presented a high degree of congruence without any apparent strain specificity. PMID- 25734257 TI - Validating a standardised test battery for synesthesia: Does the Synesthesia Battery reliably detect synesthesia? AB - Synesthesia is a neurological condition that gives rise to unusual secondary sensations (e.g., reading letters might trigger the experience of colour). Testing the consistency of these sensations over long time intervals is the behavioural gold standard assessment for detecting synesthesia (e.g., Simner, Mulvenna et al., 2006). In 2007 however, Eagleman and colleagues presented an online 'Synesthesia Battery' of tests aimed at identifying synesthesia by assessing consistency but within a single test session. This battery has been widely used but has never been previously validated against conventional long term retesting, and with a randomly recruited sample from the general population. We recruited 2847 participants to complete The Synesthesia Battery and found the prevalence of grapheme-colour synesthesia in the general population to be 1.2%. This prevalence was in line with previous conventional prevalence estimates based on conventional long-term testing (e.g., Simner, Mulvenna et al., 2006). This reproduction of similar prevalence rates suggests that the Synesthesia Battery is indeed a valid methodology for assessing synesthesia. PMID- 25734258 TI - Dextrin-based nanomagnetogel: in vivo biodistribution and stability. AB - The biodistribution profile of a new dextrin nanomagnetogel, which consists of gamma-Fe2O3 superparamagnetic nanoparticles loaded within a polymeric matrix of modified dextrin, was studied in mice. The nanomagnetogel bear a monomodal size distribution profile (average diameter 110 nm) close to neutral surface charge and higher relaxivity (r2 = 215-248 mM(-1) s(-1) and r2/r1 = 13-11) than those of commercial formulations (r2 = 160-177 mM(-1) s(-1) and r2/r1 = 4-7). Also, the observed blood half-life-approximately 4 h-is superior to that of similar commercially available formulations, which remain for a few minutes in circulation. PEGylation resulted in 1.7- and 1.2-fold lower accumulation in the liver and spleen, respectively, within the first 24 h. Noteworthy, a good correlation was obtained between the amount of polymer (quantified by scintigraphy) in the spleen, 48 h after administration, and the amount of iron physically loaded through hydrophobic interactions (quantified by ICP) indicating the absence of iron leakage from the polymeric matrix. This study provides evidence of the in vivo stability of a self-assembled nanomagnetogel, a relevant feature which is seldom reported in the literature. PMID- 25734260 TI - Systematics of molecular self-assembled networks at topological insulators surfaces. AB - The success of topological insulators (TI) in creating devices with unique functionalities is directly connected to the ability of coupling their helical spin states to well-defined perturbations. However, up to now, TI-based heterostructures always resulted in very disordered interfaces, characterized by strong mesoscopic fluctuations of the chemical potential that make the spin momentum locking ill-defined over length scales of few nanometers or even completely destroy topological states. These limitations call for the ability to control topological interfaces with atomic precision. Here, we demonstrate that molecular self-assembly processes driven by inherent interactions among the constituents offer the opportunity to create well-defined networks at TIs surfaces. Even more remarkably, we show that the symmetry of the overlayer can be finely controlled by appropriate chemical modifications. By analyzing the influence of the molecules on the TI electronic properties, we rationalize our results in terms of the charge redistribution taking place at the interface. Overall, our approach offers a precise and fast way to produce tailor-made nanoscale surface landscapes. In particular, our findings make organic materials ideal TIs counterparts, because they offer the possibility to chemically tune both electronic and magnetic properties within the same family of molecules, thereby bringing us a significant step closer toward an application of this fascinating class of materials. PMID- 25734259 TI - Ultra-sensitive detection of Plasmodium falciparum by amplification of multi-copy subtelomeric targets. AB - BACKGROUND: Planning and evaluating malaria control strategies relies on accurate definition of parasite prevalence in the population. A large proportion of asymptomatic parasite infections can only be identified by surveillance with molecular methods, yet these infections also contribute to onward transmission to mosquitoes. The sensitivity of molecular detection by PCR is limited by the abundance of the target sequence in a DNA sample; thus, detection becomes imperfect at low densities. We aimed to increase PCR diagnostic sensitivity by targeting multi-copy genomic sequences for reliable detection of low-density infections, and investigated the impact of these PCR assays on community prevalence data. METHODS AND FINDINGS: Two quantitative PCR (qPCR) assays were developed for ultra-sensitive detection of Plasmodium falciparum, targeting the high-copy telomere-associated repetitive element 2 (TARE-2, ~250 copies/genome) and the var gene acidic terminal sequence (varATS, 59 copies/genome). Our assays reached a limit of detection of 0.03 to 0.15 parasites/MUl blood and were 10* more sensitive than standard 18S rRNA qPCR. In a population cross-sectional study in Tanzania, 295/498 samples tested positive using ultra-sensitive assays. Light microscopy missed 169 infections (57%). 18S rRNA qPCR failed to identify 48 infections (16%), of which 40% carried gametocytes detected by pfs25 quantitative reverse-transcription PCR. To judge the suitability of the TARE-2 and varATS assays for high-throughput screens, their performance was tested on sample pools. Both ultra-sensitive assays correctly detected all pools containing one low density P. falciparum-positive sample, which went undetected by 18S rRNA qPCR, among nine negatives. TARE-2 and varATS qPCRs improve estimates of prevalence rates, yet other infections might still remain undetected when absent in the limited blood volume sampled. CONCLUSIONS: Measured malaria prevalence in communities is largely determined by the sensitivity of the diagnostic tool used. Even when applying standard molecular diagnostics, prevalence in our study population was underestimated by 8% compared to the new assays. Our findings highlight the need for highly sensitive tools such as TARE-2 and varATS qPCR in community surveillance and for monitoring interventions to better describe malaria epidemiology and inform malaria elimination efforts. PMID- 25734261 TI - Species, extinct before we know them? AB - Species are going extinct rapidly, while taxonomic catalogues are still incomplete for even the best-known taxa. Intensive fieldwork is finding species so rare and threatened that some become extinct within years of discovery. Recent bird extinctions in Brazil's coastal forests suggest that some species may have gone extinct before we knew of their existence. PMID- 25734262 TI - Spliceosomes. PMID- 25734263 TI - Plant grafting. AB - Since ancient times, people have cut and joined together plants of different varieties or species so they would grow as a single plant - a process known as grafting (Figures 1 and 2). References to grafting appear in the Bible, ancient Greek and ancient Chinese texts, indicating that grafting was practised in Europe, the Middle East and Asia by at least the 5(th) century BCE. It is unknown where or how grafting was first discovered, but it is likely that natural grafting, the process by which two plants touch and fuse limbs or roots in the absence of human interference (Figure 3), influenced people's thinking. Such natural grafts are generally uncommon, but are seen in certain species, including English ivy. Parasitic plants, such as mistletoe, that grow and feed on often unrelated species may have also contributed to the development of grafting as a technique, as people would have observed mistletoe growing on trees such as apples or poplars. PMID- 25734264 TI - A cyclopean neural mechanism compensating for optical differences between the eyes. AB - The two eyes of an individual routinely differ in their optical and neural properties, yet percepts through either eye remain more similar than predicted by these differences. Little is known as to how the brain resolves this conflicting information. Differences in visual inputs from the two eyes have been studied extensively in the context of binocular vision and rivalry [1], but it remains unknown how the visual system calibrates and corrects for normal variability in image quality between the eyes, and whether this correction is applied to each eye separately or after their signals have converged. To test this, we used adaptive optics to control and manipulate the blur projected on each retina, and then compared judgments of image focus through either eye and how these judgments were biased by adapting to different levels of blur. Despite significant interocular differences in the magnitude of optical blur, the blur level that appeared best focused was the same through both eyes, and corresponded to the ocular blur of the less aberrated eye. Moreover, for both eyes, blur aftereffects depended on whether the adapting blur was stronger or weaker than the native blur of the better eye, with no aftereffect when the blur equaled the aberrations of the better eye. Our results indicate that the neural calibration for the perception of image focus reflects a single 'cyclopean' site that is set monocularly by the eye with better optical quality. Consequently, what people regard as 'best-focused' matches the blur encountered through the eye with better optics, even when judging the world through the eye with poorer optics. PMID- 25734265 TI - Neuronal wiring: linking dendrite placement to synapse formation. AB - Understanding the processes that drive the formation of synapses between specific neurons within a circuit is critical to understanding how neural networks develop. A new study of synapse formation between motor neurons and pre-synaptic partners highlights the importance of dendrite placement. PMID- 25734266 TI - Cyanobacterial evolution: fresh insight into ancient questions. AB - The invention of oxygenic photosynthesis by cyanobacteria 2.4 billion years ago forever transformed Earth. This biogeochemical shift set into motion the evolution of subsequent microbial metabolisms and lifestyles. A new study provides a novel approach in piecing together evidence for how this evolutionary transition may have occurred. PMID- 25734267 TI - Genome evolution: groping in the soil interstices. AB - Centipedes are a very old lineage of terrestrial animals. The first completely sequenced myriapod genome reveals that the blind centipede Strigamia maritima has no gene for light-sensory proteins, lacks the canonical circadian clock and possesses unusual features related to chemosensory perception. PMID- 25734268 TI - Multisensory perception: pinpointing visual enhancement by appropriate odors. AB - Multisensory contributions to perception are well studied, but their underlying brain mechanisms are poorly understood. A new study has exploited advances in fly optogenetics to pinpoint mechanisms that enhance responses to visual motion in the presence of ecologically relevant odors. PMID- 25734269 TI - Tumor biology: with a little help from my dying friends. AB - Apoptosis is an essential form of cell death underlying daily tissue regeneration. In tumor biology, apoptosis resistance is a well-established hallmark of cancer that is targeted by therapeutic approaches. A new study assigns a hitherto-underestimated function to this 'deadly friend': apoptotic cells promote tumor growth, accumulation of tumor-associated macrophages, and angiogenesis. PMID- 25734270 TI - Circadian biology: rhythms leave their imprint. AB - A recent study has revealed that loss of neuronal expression of the paternally imprinted gene Ube3a in Angelman syndrome results in selective neuronal loss of robust circadian oscillations, with a resulting behavioural phenotype, and adipose tissue accumulation. PMID- 25734271 TI - Cortical control: learning from the lamprey. AB - The function of the motor cortex has been a persistent mystery. A recent study has found striking correspondence between the descending projections of lamprey pallium and mammalian motor cortex, encouraging comparative studies of the origin (and role) of forebrain motor control. PMID- 25734272 TI - Left-right asymmetry: cilia and calcium revisited. AB - Leftward flow generated by motile cilia is known to underlie left-right asymmetry in vertebrate embryos. A new study now links intraciliary calcium oscillations to cilia motility and the downstream nodal signaling cascade that drives left-sided development. PMID- 25734274 TI - [Prosthetic rehabilitation of partially edentulous patients: fixed - removable - combined? Metal - ceramics - all - ceramics? Implants? Anything goes! Part 2: two case studies represent the fixed, respectively the combined fixed-removable prosthetic restoration by utilization of implants]. AB - The prosthetic rehabilitation of two partially edentulous patients is presented: one Patient was restored by permanent crowns and bridges attached to natural teeth and to implants, the second was treated by crowns attached to natural teeth and removable implant- supported prostheses. Depending on esthetic requirements and the localization of preparation margins all- or metal-ceramics were used for single crowns, metal-ceramics was used for bridges. In general, a well coordinated cooperation of dentist, surgeon and dental technician in treatment planning and realization is required for a successful prosthetic rehabilitation. PMID- 25734273 TI - Functional analysis of GmCPDs and investigation of their roles in flowering. AB - The onset of floral development is a pivotal switch in the life of soybean. Brassinosteroids (BRs), a group of steroidal phytohormones with essential roles in plant growth and development, are associated with flowering induction. Genes involved in BR biosynthesis have been studied to a great extent in Arabidopsis, but the study of these genes has been limited in soybean. In this study, four CPD homologs (GmCPDs) catalyzing BR synthesis were isolated from soybean. Transcripts were mainly confined to cotyledons and leaves and were down-regulated in response to exogenous BR. Bioinformatic analysis showed strong sequence and structure similarity between GmCPDs and AtCPD as well as CPDs of other species. Overexpression of GmCPDs in an Arabidopsis BR-deficient mutant rescued the phenotype by restoring the biosynthesis pathway, revealing the functional roles of each GmCPDs in. Except for the rescue of root development, leaf expansion and plant type architecture, GmCPDs in expression also complemented the late flowering phenotype of Arabidopsis mutants deficient in CPD. Further evidence in soybean plants is that the expression levels of GmCPDs in are under photoperiod control in Zigongdongdou, a photoperiod-sensitive variety, and show a sudden peak upon floral meristem initiation. Together with increased GmCPDs in expression in the leaves and cotyledons of photoperiod-insensitive early-maturity soybean, it is clear that GmCPDs in contribute to flowering development and are essential in the early stages of flowering regulation. PMID- 25734275 TI - Comparative phylogeography highlights the double-edged sword of climate change faced by arctic- and alpine-adapted mammals. AB - Recent studies suggest that alpine and arctic organisms may have distinctly different phylogeographic histories from temperate or tropical taxa, with recent range contraction into interglacial refugia as opposed to post-glacial expansion out of refugia. We use a combination of phylogeographic inference, demographic reconstructions, and hierarchical Approximate Bayesian Computation to test for phylodemographic concordance among five species of alpine-adapted small mammals in eastern Beringia. These species (Collared Pikas, Hoary Marmots, Brown Lemmings, Arctic Ground Squirrels, and Singing Voles) vary in specificity to alpine and boreal-tundra habitat but share commonalities (e.g., cold tolerance and nunatak survival) that might result in concordant responses to Pleistocene glaciations. All five species contain a similar phylogeographic disjunction separating eastern and Beringian lineages, which we show to be the result of simultaneous divergence. Genetic diversity is similar within each haplogroup for each species, and there is no support for a post-Pleistocene population expansion in eastern lineages relative to those from Beringia. Bayesian skyline plots for four of the five species do not support Pleistocene population contraction. Brown Lemmings show evidence of late Quaternary demographic expansion without subsequent population decline. The Wrangell-St. Elias region of eastern Alaska appears to be an important zone of recent secondary contact for nearctic alpine mammals. Despite differences in natural history and ecology, similar phylogeographic histories are supported for all species, suggesting that these, and likely other, alpine- and arctic-adapted taxa are already experiencing population and/or range declines that are likely to synergistically accelerate in the face of rapid climate change. Climate change may therefore be acting as a double-edged sword that erodes genetic diversity within populations but promotes divergence and the generation of biodiversity. PMID- 25734276 TI - How to be the best dentist. PMID- 25734277 TI - Matrixing for MID success. AB - The proper use of matrices can lead to successful, stable dental restorations. Their importance is further advanced in MID restorations. The 3 Cs of contour, contact, and control properly exercised with correct placement of matrices can enhance the long-term success of any restoration. Matrices create healthy gingival contours, mimic natural tooth contours, and also create good healthy contacts. All of these benefits can be achieved while controlling the flow of bonding products from the gums and keeping sulcular fluids from contaminating the bonding surfaces. PMID- 25734278 TI - 3D printing, polymethyl methacrylate acrylic, and fully milled zirconia for anterior implant restorations: the brave new world of prosthetic dentistry. PMID- 25734279 TI - Case no. 11: dear John. PMID- 25734280 TI - Aging, communication, and oral health. PMID- 25734281 TI - Creating predictable posterior composite resin. PMID- 25734282 TI - Implant-assisted removable partial dentures as an alternative treatment for partial edentulism: a review of the literature. AB - This study reviewed the current literature concerning implant-assisted removable partial dentures (RPDs) in order to present the existing knowledge about performance issues. An electronic search was conducted on the PubMed database for published English-language articles that contained information about implant assisted RPDs. A review of these articles indicated that the combination of dental implants with RPDs constitutes a cost-efficient prosthetic protocol that can offer solutions to problematic aspects of treatment with removable partial dentures. Well-designed studies are still needed to provide robust evidence on critical issues, such as design guidelines, long-term survival of implants associated with RPDs, and their effect on patients' quality of life. PMID- 25734283 TI - Surface characteristics of resin composite materials after finishing and polishing. AB - This in vitro study determined the surface roughness (Ra) and absolute gloss (AG) values for 2 resin composites: a microhybrid and a microfill. Eight groups (n = 4) of each resin composite were prepared, along with 4 controls (Mylar strip) for the 2 resin composites. After finishing with a medium polishing disc, the specimens from each resin composite material were subjected to 7 polishing procedures, and Ra measurements and AG values were determined. Two-way ANOVA and Fisher's LSD multiple comparisons revealed significant differences (P <= 0.05). For both materials, the control group produced the lowest Ra values and highest AG values, and the medium polishing disc produced the highest Ra values and lowest AG values. Of the 2 resin composites, the microhybrid had lower mean Ra and higher mean AG than the microfill for the majority of the polishing procedures. Pearson's r correlation coefficient (P <= 0.001) indicated an inverse linear relationship between Ra and AG. PMID- 25734284 TI - Nitric oxide and inflammatory periodontal disease. AB - Free radicals are species capable of independent existence that contain 1 or more unpaired electrons. These species are beneficial to the host if secreted in appropriate amounts, and may act as powerful antibacterial agents or help in the regulation of vascular tone in the endothelium. In healthy individuals, there is an appropriate balance between free radicals and their scavengers. This balance can be shifted to an unhealthy pro-oxidant state when the production of free radicals is increased, resulting in serious cell damage leading to progressive inflammatory diseases of the periodontium and periapical tissues, and/or precancerous and cancerous lesions of the oral cavity. Free radicals can be important biomarkers for these diseases when clinical symptoms are not present. Nitric oxide (NO) is a free radical gas and an inflammatory biomarker. The aim of this paper is to present the role of NO in periodontal health and inflammation. PMID- 25734285 TI - Comparative analysis of polymerization shrinkage of different resin composites. AB - This study sought to compare the shrinkage of 3 resin composites after polymerization, using different curing modes and 2 methods of analysis, with 45 samples in each group. To evaluate free linear shrinkage, specimens were prepared in Teflon molds (8 mm diameter x 2 mm thick) with 1 of 2 methacrylate-based resins or a silorane-based resin. To evaluate wall-to-wall shrinkage, cavities (1.5 mm thick x 3 mm diameter) were prepared in 45 healthy bovine incisors and then restored. In both tests, the same curing lights were used: conventional quartz-tungsten-halogen, a conventional light-emitting diode (LED), and an exponential LED. Gaps were measured microscopically, and the gap percentage was calculated. The results were analyzed by 2-way ANOVA and Tukey's test (alpha = 0.05). Curing modes differed significantly in the free linear shrinkage test group, while resin composites did not. In the wall-to-wall shrinkage group, there were significant differences between the resin composites. PMID- 25734286 TI - The effect of specially designed and managed occlusal devices on patient symptoms and pain: a cohort study. AB - There is limited data regarding the benefit of using an occlusal device to help patients resolve a variety of symptoms involving temporomandibular disorder, as well as head, neck, and shoulder pain. The purpose of this study was to evaluate the effect of a carefully adjusted occlusal device on 12 symptoms to determine if there was enough evidence to justify a randomized control trial of this methodology. Splints were designed to ensure a stable, reproducible, mandibular position in a cohort of 157 dental patients with mixed histories of the following 12 symptoms: temporomandibular joint "pop," "click," and lock; jaw, neck, shoulder, and mouth-opening pain; headache; earache; tinnitus; and clenching and grinding of teeth. The results showed significant improvement (P < 0.001) in 11 of the 12 symptoms. PMID- 25734287 TI - Hepatic abscess linked to oral actinomycetes: a case report. AB - Organ abscesses are rare, life-threatening complications that can be caused by bacteremia from oral infections. Metastatic infection is a well-established concept. Dental and periapical infections can cause infections in distant organs and tissues. The frequency of these systemic infections and systemic diseases is open to debate, as some patients are more susceptible to infections than others. This article presents the case report of a 52-year-old woman who was hospitalized with a hepatic abscess after a routine periodontal maintenance procedure. The patient had poor oral health, involving several nonrestorable teeth, multiple failed endodontic treatments, and asymptomatic chronic periapical pathologies. Her dental history included previous diagnoses of moderate generalized chronic periodontitis and advanced localized periodontitis. It was possible that bacteremia developed during her most recent dental treatment, leading to the hepatic abscess. Systemic antibiotic therapy, drainage of the hepatic abscess, and oral rehabilitation resulted in complete recovery. PMID- 25734288 TI - Talon cusp variations: 2 case reports. AB - Talon cusps in anterior teeth are relatively rare developmental anomalies. They are characterized by the presence of an accessory cusp-like structure projecting from the cingulum area or cementoenamel junction. Facial talons occur very rarely; <10 cases have been described in the literature. This article attempts to describe the variants of this anomaly with 2 case reports involving facial and bilateral palatal manifestation. PMID- 25734289 TI - How concerns for bisphosphonate-induced osteonecrosis of the jaw affect clinical practice among dentists: a study from the South Texas Oral Health Network. AB - Bisphosphonate-induced osteonecrosis of the jaw (BONJ) represents a growing concern for dentists and patients in that it may alter clinical care. This study assessed the knowledge and perceptions of practicing dentists in relation to the risk of BONJ and how their knowledge and perceptions influence their decisions when developing treatment plans. For this study, a sample of dentists (n = 93) in South Texas completed a 38-item survey about BONJ knowledge and perception and their current clinical practices for patients undergoing bisphosphonate therapy. Knowledge score groupings reflected differences between low knowledge and high knowledge dentists in terms of their behavior concerning medical history, alternative treatments offered, and routine blood testing for patients on bisphosphonate therapy. PMID- 25734290 TI - Maxillary first molar with 8 root canals detected by CBCT scanning: a case report. AB - Maxillary molars are prone to exhibit some of the most complex root canal configurations in endodontics. These complexities can result in diagnostic dilemmas, as well as management challenges. This case report illustrates how a cone beam computed tomography (CBCT) scan confirmed an unusual maxillary first molar with 3 root canals each in the mesiobuccal and distobuccal roots and 2 canals in the palatal root. This article illustrates how CBCT scanning and a dental operating microscope can facilitate a better understanding of complex root canal anatomies, ultimately allowing the dentist to clean, shape, and obturate root canal systems more efficiently. PMID- 25734291 TI - Comparison of the effectiveness of 3 irrigation devices for the cleaning of root canal walls instrumented with oscillatory and rotary techniques. AB - In this study, scanning electron microscopy (SEM) was used to evaluate the smear layer removal of 3 irrigation devices. The study hypothesis was that more contemporary side-vented needles and brush-covered needles are more efficient for smear layer removal of root canals than traditional needles. The aim of this study was to compare the effectiveness of these irrigation devices in the cleansing of root canals instrumented with oscillatory and rotary systems. Sixty single-rooted teeth were divided according to instrumentation and irrigation techniques into 6 groups. The teeth were prepared for SEM analysis to evaluate the cleansing of cervical, middle, and apical thirds. For all groups, the cleansing of the cervical and middle thirds was better than that of the apical third (P < 0.05). Regardless of the instrumentation technique, no statistically significant differences were found between the groups regarding the cleansing of root canal walls (P > 0.05). PMID- 25734292 TI - Effects of cyclic loading and toothbrush abrasion on cervical lesion formation. AB - This study sought to determine the effect of cyclic loading and toothbrush abrasion (with and without abrasive slurries) on cervical lesion formation. The roots of extracted human third molars were embedded in acrylic resin, leaving 2 mm of root structure and crowns exposed. Teeth were divided into 6 groups (n = 10) with the following treatments: no treatment (control), cyclic load in distilled water, brushing with distilled water, cyclic load followed by brushing with distilled water, brushing with toothpaste slurry, and cyclic load followed by brushing with toothpaste slurry. Cyclic loading and toothbrushing machines subjected the teeth to 1.6 million cyclic loads and 30,000 brushing strokes, the equivalent of 4 years of function and brushing for an average patient. The teeth were scanned with a 3-dimensional optical profilometer to determine the volumetric loss of tooth structure. Load cycling had no significant effect on cervical tooth loss. Brushing with toothpaste resulted in significantly greater cervical tooth loss than brushing with water, which in turn was significantly greater than no treatment at all. PMID- 25734293 TI - Re-treating a maxillary second molar with 6 root canals assisted by cone beam computed tomography. AB - It is important to sterilize and obturate the entire expanse of the root canal system effectively to prevent endodontic failure. This article presents a case involving endodontic re-treatment of a maxillary second molar with an unusual morphology consisting of 6 root canals. Five were identified during clinical exploration, and the sixth was identified using cone beam computed tomography. PMID- 25734294 TI - A pediatric viewpoint on peripheral ossifying fibroma: a case report. AB - A peripheral ossifying fibroma (POF) is a type of reactive hyperplasia that is found exclusively on the gingiva. It is identified through histologic evidence of calcifications and ossifications that are seen in the context of a hypercellular fibroblastic stroma. This article presents the case of a POF in a 7-year-old girl, and examines the pediatric considerations for diagnosing and managing this lesion. PMID- 25734295 TI - An oral clinical approach to Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome is a rare hereditary disease that can have negative effects on one's quality of life. The main clinical features are multiple nevoid basal cell carcinomas, odontogenic keratocysts, congenital skeletal abnormalities, calcification of the falx cerebri, facial dysmorphism, and skin depressions (pits) on the palms and soles. Diagnosis is based on major and minor clinical and radiological criteria and can be confirmed by DNA analysis. This article describes the case of a child with Gorlin-Goltz syndrome and outlines the clinical manifestations of the disease. PMID- 25734296 TI - [The modern approaches to the treatment of chronic suppurative otitis with cholesteatoma]. AB - The objective of the present study was to evaluate the long-term outcomes of the surgical treatment of chronic suppurative otitis with cholesteatoma in terms of prevention of a residual disease and its relapses. The results of the postoperative observation of 149 patients during the period from 2009 till 2013 are presented. All the patients underwent sanation surgery with the obliteration of paratympanic spaces followed by the restoration of the posterior wall of the external auditory meatus and simultaneous tympanoplasty (closed-type surgery). The patients were examined one year after the treatment with the use of the MRI technology in the non-EPI DWI regime for the purpose of monitoring the residual disorders and relapses of cholesteatoma. The follow-up observation revealed 9 cases of residual cholesteatoma, no relapse of chronic suppurative otitis was documented. PMID- 25734297 TI - [Analysis of the effectiveness of tympanoplasty in the patients presenting with chronic otitis media complicated by perforation]. AB - AIM: The objective of the present study was to analyse the causes behind reperforation of the tympanic membrane in the patients presenting with chronic otitis media (mesotympanitis) after type I--III intrameatal tympanoplasty. Characteristic of the patients and methods of investigation. Intrameatal type I- III tympanoplasty with the use of autotransplants was performed in 652 patients presenting with chronic otitis media complicated by perforation of the tympanic membrane (CPOM). Fifty (7.6%) of these patients suffered recurrent perforation within one year after the primary treatment. The analysis of the medical histories, the character of secondary perforations, and intraoperative findings in 50 patients provided the data for the elucidation of the causes of poor anatomical and morphological outcomes of the surgical treatment. RESULTS: It was shown that the anatomical and morphological effectiveness of type I--III intrameatal tympanoplasty in the patients with CPOM amounted to 92.4%. The main causes of reperforation are an extensive defect of the tympanic membrane, tympanic cavity mucositis associated with the compromised function of the Eustachian tube, in-growth of epidermis into the structures of the tympanic membrane, and the combination of these conditions as well as technical difficulties inherent in the surgical intervention. PMID- 25734298 TI - [Clinical and roentgenological diagnostics of the severity of mucositis in the patients presenting with chronic suppurative otitis media]. AB - The objective of the present study was to determine the prevalence of mucositis and its roentgenological manifestations in the patients presenting with chronic suppurative otitis media (CSOM). A total of 390 patients with CSOM (mesotympanitis) and 85 ones suffering CSOM with concomitant mucositis were available for the observation. The signs of mucositis were evaluated based on the patients' complaints, results of otomicroscopy, and computed tomography (CT) of the temporal bones. This randomized clinical study involving 390 patients presenting with CSOM revealed the signs of mucositis in 44.6% of the cases. Analysis of the results of temporal bone CT performed in 85 patients with CSOM and mucositis in the absence exacerbation has demonstrated the possibility of detecting mucositis and evaluating its severity from the changes in the airness of the tympanic cavity, attics, and antrum due to the presence of the pathological substrate in these regions. PMID- 25734299 TI - [Certain peculiarities of the clinical picture of mastoiditis in the children]. AB - The objective of the present study was to analyse the cases of acute otitis media complicated by mastoiditis in the children given the surgical treatment during the period from 2009 till 2012. A total of 46 patients underwent antromastoidotomy. The main clinical variants of the disease, their incidence, the age composition of the affected children, and the principal etiological factors were determined. PMID- 25734300 TI - [Cochleovestibular disorders in the patients suffering from migraine of the basilar type]. AB - The objective of the present study was to improve diagnostics of basilar type migraine (BTM) based on the results of neurological, vestibulometric, and audiological studies of 11 patients. Peculiarities of the clinical picture of this disease and the medical histories of these patients are described. The pathogenetic role of labyrinthine hydrops and the difficulties encountered in diagnostics of Meniere's disease are discussed. PMID- 25734301 TI - [The hearing function in the patients presenting with the intralabyrinthine distribution of giant cholesteatoma]. AB - The objective of the present study was to evaluate the state of the hearing function in the patients presenting with the intralabyrinthine distribution of giant cholesteatoma before and after the surgical treatment based on the results of examination by the subjective and objective methods. The possibility of preservation of the hearing function after the surgical intervention has been demonstrated. PMID- 25734302 TI - [The problems of hearing impairment in the flying staff of commercial aviation in Russia]. AB - The authors discuss the problems pertaining to the growing incidence of hearing impairment in the members of the flying staff employed in commercial aviation of Russia and the main criteria used to elucidate the causes behind occupational diseases of the organs of hearing. Special attention is given to the principal normative documents regulating the methodological basis on which the acoustic factor in the aircraft cockpit is evaluated, peculiarities of occupational sensorineural hearing impairment and the methods for its detection. The main errors in the determination of the relationship between the working conditions and the diseases of the organs of hearing are discussed. PMID- 25734303 TI - [The intraoperative monitoring of the gas pressure in the middle ear]. AB - The objective of the present work was to elucidate the patterns and mechanisms underlying the changes of gas pressure in the middle ear during the operation of stapedoplasty with a view to the application of the data obtained for objective recording of the stapedial reflex at the time of surgical intervention. Ten subjects with the unaffected hearing function were recruited for the study. Tympanometry was carried out at one-minute intervals starting from the onset of feeding nitrogen monooxide till the completion of septoplasty. It was shown that the surgical intervention under inhalation anesthesia is associated with periodic rises and drops in the gas pressure in the middle ear within a range from 500 dPA to 88 dPA with a period from 5.7 to 22 minutes. It is argued that these changes can be attributed to the periodic opening of the Eustachian tube when the gas pressure reaches a certain level due to continuous diffusion of nitrogen monooxide into the middle ear (the "preventive" release of pressure) followed by the passive closure of the auditory tube. The authors propose based on the results of the study recommendations on the performance of stapedial reflexometry during the surgical intervention with the use of impedancometry. PMID- 25734304 TI - [The potential of tone audiometry for the determination of the sound-absorbing properties of various materials]. AB - The objective of the present work was to experimentally estimate the potential of the tone audiometry technique for the determination of the sound-absorbing properties of various material. The study included 15 subjects at the age from 19 to 32 years. Their audiological examination was followed by the placement of the 5*7 cm spacer plate from the study material beneath the bone vibrator telephone to determine the bone sound-conduction threshold; no air-marking was undertaken. The sound absorption by the study materials of interest was determined in each octave-band from 250 to 8000 Hz from the difference between the starting audiogram and the audiogram of the material of interest. The study was carried out in three stages: (1) evaluation of sound absorption of each of the five materials, (2) measurement of the same parameter in the combinations of 2--4 layers for increasing sound absorption, and (3) fixation of the bone conduction telephone by the operator's hand (the head-mounted harness was used for the same purpose at stages 1 and 2). The experiments demonstrated that the study of bone sound conduction by means of tone audiometry allows to estimate the sound absorption of various materials. This technique may be applied for the development of a subjective method for the measurement of sound absorption in order to evaluate the acoustic effectiveness of materials that can be used to construct individual protective anti-noise devices. PMID- 25734305 TI - [The role of respiratory viruses in etiology of rhinosinisitis in the children]. AB - The objective of the present study was to elucidate the role of respiratory viruses in etiology of acute rhinosinusitis (ARS) in the children and adolescents. We analysed the results of a microbiologial study of 50 aspirates from the paranasl sinuses. It was shown that acute rhinosinusitis had bacterial and viral-bacterial etiology in 8% and 24% of the cases respectively. In 42% of the cases the pathogen could not be identified by any of the methods used in the study. PMID- 25734306 TI - [The clinical and oncological aspects of the treatment of laryngeal and laryngopharyngeal cancer]. AB - The objective of the present study was to estimate the justification of extended cervical lymphodissections and to evaluate the influence of adjuvant medicamental therapy in combination with the targeted treatment on the results of the management of oncological conditions. The 81 patients included in the study were allocated to the three groups. Group 1 was comprised of the patients (n=28) given neoadjuvant therapy and surgical treatment. Group 2 included the patients (n=27) undergoing the surgical treatment followed by remote gamma-therapy during the postoperative period. Group 3 consisted of the patients (n=26) receiving both the surgical treatment and targeted adjuvant medicamental therapy. The study has demonstrated that percent of wound complications after 2--3 courses of polychemotherapy in the patients of group 1 was higher by a factor of 5 in comparison with the patients of the two other groups. Wound healing by second intention was documented in 59% of the patients in group 1 and 10% of those in both groups 2 and 3. The five-year survival rate in the patients of group 3 was estimated at 38.5% (6.4 and 8.9% higher than in groups 1 and 2 respectively). PMID- 25734307 TI - [The clinical and epidemiological characteristics of exudative otitis media in the child population of the city of Almaty]. AB - The objective of the present study was to evaluate specific features of the prevalence of exudative otitis media (EOM) among the children residing in the city of Almaty based on the analysis of applications of such patients for medical assiatance to the Department of Otorhinolaryngology of the "Atlant-Med"" Clinic during the period from 2010 till 2012. Diagnosis of exudative otitis media was confirmed by routine examination of ENT organs supplemented by otoendoscopy, tympanometry, and registration of delayed evoked otoacoustic emission. The relative frequency of inflammatory diseases of the middle ear in the structure of overall ENT morbidity in the child population of Almaty was estimated at 18.4+/ 0.4%. Half of the patients (1116 or 49.8+/-1.1%) with middle ear pathology applied to the Clinic for the treatment of exudative otitis media. The frequency of applications for medical assistance in connection with the inflammatory diseases of the middle ear (especially acute otitis media) increased during the autumn months, i.e. in the periods characterized by repeated sharp changes in the air temperature. The same trend was documented with respect to EOM; the frequency of application for medical aid among the patients with this pathology increased during winter, spring, and autumn periods and fell down to a minimum in the summer. PMID- 25734308 TI - [The use of the lactate-fortified milk whey for the prolongation of the functional life of the voice prostheses]. AB - The objective of the present study was to develop the method for the prolongation of the functional life of the voice prostheses in the patients who underwent laryngectomy with special reference to the decrease of the risk of mycotic infection in the laryngo-oesophageal region. The original method is proposed with the application of the lactate-fortified milk whey that makes it possible to maintain the high concentration of living lactic acid bacteria in the laryngo oesophageal segment where the voice prosthesis is located. The method was tested on 73 patients. It permitted to significantly prolong the functional life of the voice prostheses (from 12 to 20 months) and prevent mycotic infection. It is concluded that the proposed method promotes the improvement of the patients' quality of life following laryngectomy for the treatment of cancer. PMID- 25734309 TI - [The influence of gel-like recombinant interferon alpha-2b on the clinical course of acute respiratory infection and the state of mucosal immunity in the pregnant women]. AB - The objective of the present study was to evaluate the state of local immunity of the mucous membrane in the nose of the pregnant women presenting with acute respiratory infection (ARI). A total of 55 women with this condition were examined at the outpatient basis starting from week 14 of the gestation period. Viferon gel was administered intranasally to 34 such patients. The clinical and immunological effectiveness of the application of the topical form of this recombinant interferon alpha-2b preparation in these patients was evaluated. It is concluded that the inclusion of Viferon in the combined treatment of ARI in the pregnant women significantly decreases the frequency of bacterial complications. Simultaneously, this preparation reduces the IL-8 level in the nasal secretion in comparison with its initial value. PMID- 25734310 TI - [The experimental substantiation of the application of bone cement for the reconstruction of postoperative defects in the walls of paranasal sinuses]. AB - The objective of the present study was to evaluate the biocompatibility of bone cement used in plastic surgery of the anterior wall of the paranasal sinusis. This material was used to shape a fragment corresponding to the bone defect to be placed subperiosteally. This experimental study has demonstrated that the anterior wall of the paranasal sinusis can be reconstructed within 1.5--3 months after surgery owing to the formation of a granulation tissue replaced in the course of time by the connective tissue, coarse-fibred tissue and, locally, bone plate tissue (in that order). PMID- 25734312 TI - [Mucolytic therapy of sinusitis]. AB - The authors overview the articles concerning the treatment of sinusitis with the use of mucolytic preparations published in the Russian-speaking and foreign literature during the period from 1987 to 2013. Special attention is given to GeloMyrtol and GeloMyrtol forte therapy. The analysis of the papers of interest has demonstrated that the herbal medicinal products based on standardized myrtol have a number of advantages over other preparations of the same type. It is concluded, taking into consideration the evidence-based effectiveness of GeloMyrtol and simplicity of its application, that this remedy can be prescribed to the patients suffering from sinusitis. PMID- 25734311 TI - [The possibilities for the treatment of exudative otitis media in the children presenting with chronic adenoiditis]. AB - The objective of the present study was to improve the effectiveness of medicamental therapy of exudative otitis media in the children with recurrent and chronic adenoiditis. It was shown that the use of fluifort (carbocysteine lysine salt) for the treatment of exudative otitis media in the children presenting with chronic adenoiditis is a more effective approach in comparison with the expectant management. It is concluded that the application of carbocysteine lysine salt in combination with the mometasone furoate nasal spray ensures the rapid elimination of the symptoms of adenoiditis and significantly accelerates the resolution of exudative otitis media compared with the monotherapeutic treatment. PMID- 25734313 TI - [Foreign bodies (disk batteries) in the nose]. AB - This paper reports the results of analysis of the treatment of 8 children after the removal a disk battery from the nasal cavity. It was shown that the restoration of all the structures of the nasal cavity is possible if the foreign body remains in it during a short (up to 5 hours) time. The longer presence of such a body in the nasal cavity gives rise to post-traumatic defects, in the first place septal perforations and injuries to the inferior turbinated bone. In such cases, the foreign body must be immediately removed from the nasal cavity, and the child should be placed under thorough medical observation taking into consideration the long process of rejection of necrotic tissues and healing of the resulting defects. PMID- 25734314 TI - [Bilateral traumatic transverse fracture of the temporal bones with the injury to the cochlear-vestibular analyzer]. PMID- 25734315 TI - [Destructive mastoiditis with thrombosis of the sigmoid sinus in a 8 year-old child presenting with concomitant chicken pox]. AB - The specific clinical feature of mastoidities that developed in a patient presenting with chicken pox was the rapid progress in temporal bone destruction with partial thrombosis of the sigmoid sinusis in the absence of typical manifestations of mastoiditis. The pronounced destructive changes found in a series of CT images were regarded as the indications for urgent antromastoidotomy with the puncture of the sigmoid sinusis. PMID- 25734316 TI - [The importance of test control for the post-graduate education in clinical rhinology]. AB - This publication deals with the problems pertaining to the improvement of the system of the post-graduate education in otorhinolaryngology with special reference to one of its topical fields, clinical rhinology. The authors emphasize the importance of one of the principal components of the post-graduate education under the present-day conditions, namely organization of control and self-control of learning the new material, self-monitoring and individual correction of the level of knowledge. Special attention is given to the training tests that can be used to adequately simulate the decision-making process with respect to a concrete clinical situation. It is concluded that the systematic application of test control is one of the most important prerequisites for the enhancement of the effectiveness of the post-graduate education in clinical otorhinolaryngology. PMID- 25734317 TI - Azide and trans-cyclooctene dUTPs: incorporation into DNA probes and fluorescent click-labelling. AB - 5-Azidomethyl dUTP and two 5-trans-cyclooctene dUTPs with different linkers between the TCO and the uracil base have been incorporated into DNA by primer extension, reverse-transcription and PCR amplification. For azidomethyl dUTP the PCR reaction was successful even when the modified dUTP was not supplemented with dTTP. In one case 335 azidomethyl dU residues were incorporated into the 523 base pair amplicon using this methodology. 5-Azidomethyl dUTP was found to be a better substrate for DNA polymerases than the trans-cyclooctene dUTPs. However, the inverse electron demand Diels-Alder reaction between cyclooctene DNA and a tetrazine Cy3-dye was more efficient than the strain-promoted reaction between azide DNA and a bicyclo [6.1.0] non-4-yne Cy3 dye. PMID- 25734318 TI - Malignant phyllodes tumour presenting as a massive fungating breast mass and silent thrombo-embolism. AB - INTRODUCTION: We report an unusual case of a massive malignant phyllodes tumour that had almost replaced the entire breast presenting with severe chronic blood loss, extensive deep venous thrombosis (DVT) and a silent pulmonary embolus. PRESENTATION: Long-standing neglected massive fungating ulcerative mass larger than the left haemothorax. DISCUSSION: Phyllodes tumours are rare fibro epithelial breast lesions that have the propensity to grow rapidly to a large size if neglected. Larger tumours are more likely to be malignant with an overall metastatic rate around 10%. An incidental pulmonary embolus arising from extensive silent lower limb deep vein thrombosis requiring an IVC filter complicated the surgical management. CONCLUSION: Phyllodes tumours are rare and account for approximately 0.3-0.5% of all breast tumours [1]. They have the propensity to be fast growing. However, tumours reaching a massive size (>10cm) are rare with few reports in the literature. PMID- 25734319 TI - Isolated renal pelvis rupture secondary to blunt trauma: Case report. AB - INTRODUCTION: Isolated rupture of the renal pelvis is a very rare condition and thus causes delays in the diagnosis of the rupture. It is most commonly seen in the setting of obstructive ureteric calculus. Other rare causes include neoplasms, trauma, and iatrogenic procedures. Diagnosis is usually established on computed tomography (CT) which demonstrates the extravasation of the contrast in the peripelvic, perinephric, or retroperitoneal collections. PRESENTATION OF CASE: A 27-year-old male patient was admitted to our hospital due to multiple traumas associated with motor vehicle accidents. The patient had clear urine output. A large pelvic rupture was detected by abdominal contrast-enhanced CT and after consulting with other departments, emergency repair of the renal pelvis was performed and a ureteral stent was implanted. DISCUSSION: Only a few isolated cases of pelvis rupture with resultant extravasation have been reported in the literature. The treatment of pelvic rupture should be preceded by the removal of underlying causes, followed by conservative management. However, surgical intervention should be warranted in the emergency cases presenting with the symptoms that may impede the decision-making process and in the cases whose diagnosis cannot be clarified by radiological techniques. CONCLUSION: Renal pelvic injury must be considered in the differential diagnosis of blunt trauma. Surgical intervention may be necessary in some cases. We present a case who underwent surgery due to isolated renal pelvis rupture caused by blunt abdominal trauma. PMID- 25734320 TI - From less to maximally invasiveness in cervical spine surgery: A "nightmare" case who deserve consideration. AB - INTRODUCTION: Multilevel cervical myelopathy without surgical treatment is generally poor in the neurological deficit without surgical decompression. The two main surgical strategies used for the treatment of multilevel cervical myelopathy are anterior decompression via anterior corpectomy or posterior decompression via laminctomy/laminoplasty. PRESENTATION OF CASE: We present the case of a 62 year-old lady, harboring rheumatoid artritis (RA) with gait disturbances, pain, and weakness in both arms. A C5 and C6 somatectomy, C4-C7 discectomy and, instrumentation and fusion with telescopic distractor "piston like", anterior plate and expandable screws were performed. Two days later the patient complained dysfagia, and a cervical X-ray showed hardware dislocation. So a C4 somatectomy, telescopic extension of the construct up to C3 with expandible screws was performed. After one week the patient complained again soft dysfagia. New cervical X-ray showed the pull out of the cranial screws (C3). So the third surgery "one stage combined" an anterior decompression with fusion along with posterior instrumentation, and fusion was performed. DISCUSSION: There is a considerable controversy over which surgical approach will receive the best clinical outcome for the minimum cost in the compressive cervical myelopathy. However, the most important factors in patient selection for a particular procedure are the clinical symptoms and the radiographic alignment of the spine. the goals of surgery for cervical multilevel stenosis include the restoration of height, alignment, and stability. CONCLUSION: We stress the importance of a careful patients selection, and invocated still the importance for 360 degrees cervical fixation. PMID- 25734321 TI - Estimating the additive benefit of surgical excision to stereotactic radiosurgery in the management of metastatic brain disease. AB - BACKGROUND: There are limited data on the benefits of surgical tumor resection plus stereotactic radiosurgery (SRS) in comparison with SRS alone for patients with oligometastatic brain disease. OBJECTIVE: To determine the benefit of adding resection to SRS. METHODS: We reviewed 162 consecutive patients with oligometastatic brain disease, who underwent surgical tumor resection and SRS boost (n = 49) or SRS alone (n = 113). Patients receiving prior whole brain radiation therapy were excluded. Factors related to patient survival and time-to local recurrence (TTLR) were determined by Cox regression. The effect of complete resection + SRS boost on survival was further explored by propensity score matching. RESULTS: The average age of the cohort was 65.3 years, it was 49.4% female, and included 260 brain tumors, of which 119 tumors were single. Seventy three brain tumors recurred (28%). TTLR was related to radiation-sensitive pathology (hazards ratio [HR] = 0.34, P = .001), treatment volume (HR = 1.078/mL, P = .002), and complete tumor resection (HR = 0.37, P = .015). Factors related to survival were age (HR = 1.21/decade, P = .037), Eastern Cooperative Oncology Group performance score (HR = 1.9, P = .001), and complete surgical resection (HR = 0.55, P = .01). Propensity score matched analysis of complete surgical resection + SRS boost (n = 40) vs SRS alone (n = 80) yielded nearly identical survival results (HR = 0.52, P = .030) compared with the initial unmatched sample. Incomplete tumor resection had both median survival and TTLR equivalent to SRS alone. CONCLUSION: Complete surgical resection + SRS boost is associated with improved survival and reduced likelihood of local tumor recurrence in comparison with SRS alone. Incomplete resection did not improve survival or TTLR compared with SRS alone. PMID- 25734322 TI - Topographical risk factor analysis of new neurological deficits following precentral gyrus resection. AB - BACKGROUND: Precentral gyrus resections (PGRs) have been regarded as excessively hazardous interventions because of the risk of postoperative major neurological complications. OBJECTIVE: To evaluate the neurological deterioration that follows PGRs and to assess the topographical risk factors associated with these morbidities. METHODS: We reviewed 33 consecutive patients who experienced pharmacologically intractable epilepsy and underwent PGR with intraoperative cortical stimulation and mapping while under awake anesthesia. The etiological diagnoses were brain neoplasm in 26 patients (78.8%), cortical lesion in 4 (12.1%), and no lesion in 3 (9.1%). The mean follow-up period was 62.6 months (range, 12-146 months). All topographical analyses of the resected quadrant area were performed based on postoperative magnetic resonance images. RESULTS: After PGR, 22 patients (66.7%) experienced neurological worsening, including 5 permanent deficits (15.2%) and 17 transient deficits (51.5%). Permanent deficits included 2 instances of weakness, 1 dysarthria, 1 dysesthesia, and 1 fine movement disturbance of the hand. While the neurological risk for anterior lower quadrant PGR was 20.0% (1/5), the risk for posterior upper quadrant PGR was 100.0% (10/10). The anterior upper and posterior lower quadrant PGR caused neurological deteriorations in 60.0% (6/10) and 62.5% (5/8) of the patients, respectively. In a multivariate analysis, PGR of the posterior and upper quadrant sections were significant risk factors for post-PGR neurological deteriorations (P = .022 and 0.030, respectively). CONCLUSION: The posterior upper quadrant of the precentral gyrus was vulnerable to post-resective neurological impairment. PMID- 25734323 TI - Morphological parameters associated with middle cerebral artery aneurysms. AB - BACKGROUND: Morphological factors contribute to the hemodynamics of the middle cerebral artery (MCA). OBJECTIVE: To identify image-based morphological parameters that correlated with the presence of MCA aneurysms. METHODS: Image based anatomic parameters obtained from 110 patients with and without MCA bifurcation aneurysms were evaluated with Slicer, an open-source image analysis software, to generate 3-dimensional models of the aneurysms and surrounding vascular architecture. We examined segment lengths, diameters, and vessel-to vessel angles of the parent and daughter vessels at the MCA bifurcation. In order to reduce confounding by genetic and clinical risk factors, 2 control groups were selected: group A (the unaffected contralateral side of patients with unilateral MCA bifurcation aneurysms) and group B (patients without intracranial aneurysms or other vascular malformations). Univariate and multivariate analyses were performed to determine statistical significance. RESULTS: One hundred ten patients who were evaluated from 2007 to 2014 were analyzed (73 patients with MCA aneurysms and 37 control patients). Multivariate analysis revealed that a smaller parent artery diameter (group A: odds ratio [OR] 0.20, P < .01, group B: OR 0.23, P < .01) and a larger daughter-to-daughter branch angle (group A: OR 1.01, P = .04, group B: OR 1.02, P = .04) were most strongly associated with MCA aneurysm presence after adjusting for other morphological factors. CONCLUSION: Smaller parent artery diameter and larger daughter-to-daughter branch angles are associated with the presence of MCA bifurcation aneurysms. These easily measurable parameters may provide objective metrics to assess aneurysm formation and growth risk stratification in high-risk patients. PMID- 25734324 TI - Altered ulnar nerve kinematic behavior in a cadaver model of entrapment. AB - BACKGROUND: Ulnar nerve entrapment at the elbow is more than a compressive lesion of the nerve. The tensile biomechanical consequences of entrapment are currently marginally understood. OBJECTIVE: To evaluate the effects of tethering on the kinematics of the ulnar nerve as a model of entrapment neuropathy. METHODS: The ulnar nerve was exposed in 7 fresh cadaver arms, and markers were placed at 1-cm increments along the nerve, centered on the retrocondylar region. Baseline translation (pure sliding) and strain (stretch) were measured in response to progressively increasing tension produced by varying configurations of elbow flexion and wrist extension. Then the nerves were tethered by suturing to the cubital tunnel retinaculum and again exposed to progressively increasing tension from joint positioning. RESULTS: In the native condition, for all joint configurations, the articular segment of the ulnar nerve exhibited greater strain than segments proximal and distal to the elbow, with a maximum strain of 28 +/- 1% and translation of 11.6 +/- 1.8 mm distally. Tethering the ulnar nerve suppressed translation, and the distal segment experienced strains that were more than 50% greater than its maximum strain in an untethered state. CONCLUSION: This work provides a framework for evaluating regional nerve kinematics. Suppressed translation due to tethering shifted the location of high strain from articular to more distal regions of the ulnar nerve. The authors hypothesize that deformation is thus shifted to a region of the nerve less accustomed to high strains, thereby contributing to the development of ulnar neuropathy. PMID- 25734325 TI - In reply: anatomical variations of the presigmoid suprabulbar infralabyrinthine approach. PMID- 25734327 TI - Self-organization of plant vascular systems: claims and counter-claims about the flux-based auxin transport model. AB - The plant hormone auxin plays a central role in growth and morphogenesis. In shoot apical meristems, auxin flux is polarized through its interplay with PIN proteins. Concentration-based mathematical models of the flux can explain some aspects of phyllotaxis for the L1 surface layer, where auxin accumulation points act as sinks and develop into primordia. The picture differs in the interior of the meristem, where the primordia act as auxin sources, leading to the initiation of the vascular system. Self-organization of the auxin flux involves large numbers of molecules and is difficult to treat by intuitive reasoning alone; mathematical models are therefore vital to understand these phenomena. We consider a leading computational model based on the so-called flux hypothesis. This model has been criticized and extended in various ways. One of the basic counter-arguments is that simulations yield auxin concentrations inside canals that are lower than those seen experimentally. Contrary to what is claimed in the literature, we show that the model can lead to higher concentrations within canals for significant parameter regimes. We then study the model in the usual case where the response function Phi defining the model is quadratic and unbounded, and show that the steady state vascular patterns are formed of loopless directed trees. Moreover, we show that PIN concentrations can diverge in finite time, thus explaining why previous simulation studies introduced cut-offs which force the system to have bounded PIN concentrations. Hence, contrary to previous claims, extreme PIN concentrations are not due to numerical problems but are intrinsic to the model. On the other hand, we show that PIN concentrations remain bounded for bounded Phi, and simulations show that in this case, loops can emerge at steady state. PMID- 25734326 TI - Plasma concentrations of BDNF and IGF-1 in abstinent cocaine users with high prevalence of substance use disorders: relationship to psychiatric comorbidity. AB - Recent studies have identified biomarkers related to the severity and pathogenesis of cocaine addiction and common comorbid psychiatric disorders. Monitoring these plasma mediators may improve the stratification of cocaine users seeking treatment. Because the neurotrophic factors are involved in neural plasticity, neurogenesis and neuronal survival, we have determined plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 3 (IGFBP-3) in a cross-sectional study with abstinent cocaine users who sought outpatient treatment for cocaine (n = 100) and age/body mass matched controls (n = 85). Participants were assessed with the diagnostic interview 'Psychiatric Research Interview for Substance and Mental Disorders'. Plasma concentrations of these peptides were not different in cocaine users and controls. They were not associated with length of abstinence, duration of cocaine use or cocaine symptom severity. The pathological use of cocaine did not influence the association of IGF-1 with age observed in healthy subjects, but the correlation between IGF-1 and IGFBP-3 was not significantly detected. Correlation analyses were performed between these peptides and other molecules sensitive to addiction: BDNF concentrations were not associated with inflammatory mediators, lipid derivatives or IGF-1 in cocaine users, but correlated with chemokines (fractalkine/CX3CL1 and SDF-1/CXCL12) and N-acyl-ethanolamines (N palmitoyl-, N-oleoyl-, N-arachidonoyl-, N-linoleoyl- and N-dihomo-gamma linolenoyl-ethanolamine) in controls; IGF-1 concentrations only showed association with IGFBP-3 concentrations in controls; and IGFBP-3 was only correlated with N-stearoyl-ethanolamine concentrations in cocaine users. Multiple substance use disorders and life-time comorbid psychopathologies were common in abstinent cocaine users. Interestingly, plasma BDNF concentrations were exclusively found to be decreased in users diagnosed with both primary and cocaine-induced disorders for mood and anxiety disorders. In summary, BDNF, IGF-1 and IGFBP-3 were not affected by a history of pathological use of cocaine supported by the absence of associations with other molecules sensitive to cocaine addiction. However, BDNF was affected by comorbid mood disorders. Further research is necessary to elucidate the role of BDNF and IGF-1 in the transition to cocaine addiction and associated psychiatric comorbidity. PMID- 25734328 TI - Enhanced production of steviol glycosides in mycorrhizal plants: a concerted effect of arbuscular mycorrhizal symbiosis on transcription of biosynthetic genes. AB - Stevia rebaudiana (Bertoni) produces steviol glycosides (SGs)--stevioside (stev) and rebaudioside-A (reb-A) that are valued as low calorie sweeteners. Inoculation with arbuscular mycorrhizal fungi (AMF) augments SGs production, though the effect of this interaction on SGs biosynthesis has not been studied at molecular level. In this study transcription profiles of eleven key genes grouped under three stages of the SGs biosynthesis pathway were compared. The transcript analysis showed upregulation of genes encoding 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway enzymes viz.,1-deoxy-D-xylulose 5-phospate synthase (DXS), 1-deoxy-D-xylulose 5-phospate reductoisomerase (DXR) and 2-C-methyl-D erytrithol 2,4-cyclodiphosphate synthase (MDS) in mycorrhizal (M) plants. Zn and Mn are imperative for the expression of MDS and their enhanced uptake in M plants could be responsible for the increased transcription of MDS. Furthermore, in the second stage of SGs biosynthesis pathway, mycorrhization enhanced the transcription of copalyl diphosphate synthase (CPPS) and kaurenoic acid hydroxylase (KAH). Their expression is decisive for SGs biosynthesis as CPPS regulates flow of metabolites towards synthesis of kaurenoid precursors and KAH directs these towards steviol synthesis instead of gibberellins. In the third stage glucosylation of steviol to reb-A by four specific uridine diphosphate (UDP)-dependent glycosyltransferases (UGTs) occurs. While higher transcription of all the three characterized UGTs in M plants explains augmented production of SGs; higher transcript levels of UGT76G1, specifically improved reb-A to stev ratio implying increased sweetness. The work signifies that AM symbiosis upregulates the transcription of all eleven SGs biosynthesis genes as a result of improved nutrition and enhanced sugar concentration due to increased photosynthesis in M plants. PMID- 25734329 TI - Changes in cell size and number and in rhizodermal development contribute to root tip swelling of Hyoscyamus albus roots subjected to iron deficiency. AB - Root tip swelling is a common phenomenon observed when plant roots are subjected to Fe deficiency. We analysed whether an increase in cell number or an enlargement of cell width was involved in this phenomenon. Root tips of Hyoscyamus albus cultured with or without Fe were stained with fluorescent SYTO14 and analysed by confocal laser-scanning microscopy. Time-course and position based examination revealed that the inhibition of longitudinal cell elongation and acceleration of transverse cell enlargement under Fe deficiency started from the tips and then extended towards the base during the time-course period. An increase in cell number also occurred behind the tips. In addition, the development of rhizodermal protrusions was observed on the surface of roots subjected to Fe deficiency. These results indicated that changes in cell size and number and in root hair development were all involved in root tip swelling. PMID- 25734331 TI - The accuracy of target delineation in laryngeal and hypopharyngeal cancer. AB - BACKGROUND AND PURPOSE: To determine the spatial correspondence between the gross tumor volume (GTV) delineated on computer tomography (CT) and the actual tumor on histopathology. MATERIAL AND METHODS: Sixteen patients with T3 or T4 laryngeal or hypopharyngeal cancer underwent a CT scan before total laryngectomy. The GTV was delineated on CT by three independent observers and by consensus between the three observers. After surgery, whole-mount hematoxylin-eosin stained (H&E) sections were obtained. One pathologist delineated the tumor in the H&E sections (tumorH&E). The reconstructed specimen was registered to the CT scan in order to compare the GTV to the tumorH&E in three dimensions. The overlap between the GTV and the tumorH&E was calculated and the distance between the volumes was determined. RESULTS: Tumor tissue was delineated in 203 of 516 H&E sections. For 14 patients a detailed analysis could be performed. The GTV volume was on average 1.7 times larger than the volume of the tumorH&E. The mean coverage of the tumorH&E by the consensus GTV was 88%. tumorH&E tissue was found at 1.6 mm to 12.9 mm distance outside the GTV depending on observer and patient. CONCLUSIONS: GTVs delineated on CT for laryngeal and hypopharyngeal cancer were 1.7 times larger than the tumor. Complete coverage of the tumor by the GTV was, however, not obtained. PMID- 25734332 TI - Comparison between loureirin A and cochinchinenin C on the interaction with human serum albumin. AB - The interactions of loureirin A (LA) and cochinchinenin C (CC) with human serum albumin (HSA) under simulated physiological conditions (pH = 7.4) have been studied with fluorescence, UV-vis absorption spectroscopic method and molecular docking technique. The results indicated that there was a synergistic interaction between LA and CC, and the fluorescence quenching of HSA by LA (or CC) was a combined quenching procedure (dynamic and static quenching). At low compound concentrations, the quenching constants KSV of CC was larger than that of LA, which meant the CC efficacy may be better than that of LA. The negative ?H and ?S values suggested hydrogen bonds and van der Waals forces played the major role in the binding of LA (or CC) to HSA. The efficiency of energy transfer and distance between the compounds and HSA was calculated. Moreover, the results of synchronous and three-dimensional fluorescence demonstrated that the HSA microenvironment was changed in the presence of LA (or CC). Finally, the binding of LA (or CC) to HSA was modeled by molecular docking, which is in good accordance with the experimental studies. PMID- 25734333 TI - Do biological and bedsite characteristics influence survival of neonatal white tailed deer? AB - Coyotes recently expanded into the eastern U.S. and potentially have caused localized white-tailed deer population declines. Research has focused on quantifying coyote predation on neonates, but little research has addressed the potential influence of bedsite characteristics on survival. In 2011 and 2012, we radiocollared 65 neonates, monitored them intensively for 16 weeks, and assigned mortality causes. We used Program MARK to estimate survival to 16 weeks and included biological covariates (i.e., sex, sibling status [whether or not it had a sibling], birth weight, and Julian date of birth). Survival to 16 weeks was 0.141 (95% CI = 0.075-0.249) and the top model included only sibling status, which indicated survival was lower for neonates that had a sibling. Predation was the leading cause of mortality (35 of 55; 64%) and coyotes were responsible for the majority of depredations (30 of 35; 86%). Additionally, we relocated neonates for the first 10 days of life and measured distance to firebreak, visual obstruction, and plant diversity at bedsites. Survival of predation to 10 days (0.726; 95% CI = 0.586-0.833) was weakly associated with plant diversity at bedsites but not related to visual obstruction. Our results indicate that neonate survival was low and coyote predation was an important source of mortality, which corroborates several recent studies from the region. Additionally, we detected only weak support for bedsite cover as a covariate to neonate survival, which indicates that mitigating effects of coyote predation on neonates may be more complicated than simply managing for increased hiding cover. PMID- 25734334 TI - Spontaneous portohepatic venous shunt: ultrasonographic aspect. AB - We aimed to describe the imaging findings of a spontaneous portohepatic venous shunt. This is a rare entity, especially when it is not associated with risk factors such as portal hypertension or liver trauma. We report the case of a 67 year-old woman admitted to our clinic for progressive asthenia, loss of appetite, and progressive upper abdominal pain. We performed several blood tests, abdominal ultrasonography, contrast-enhanced abdominal ultrasonography, and abdominal computed tomographic scan to establish and confirm the diagnosis. Findings of ultrasound revealed a cystic mass in the right liver lobe. Liver enzymes were normal, and viral hepatitis markers as well as serology for Echinococcus granulosus were negative. There were no signs of liver cirrhosis or portal hypertension. Abdominal ultrasound and contrast-enhanced ultrasound established the diagnosis of portohepatic venous shunt; this was also confirmed by abdominal computed tomographic scan. Because the patient did not present any risk factors, the diagnosis was of spontaneous portohepatic venous shunt. PMID- 25734335 TI - Implementation of a wireless sensor network for heart rate monitoring in a senior center. AB - OBJECTIVE: Wearable sensor systems are widely used to monitor vital sign in hospitals and in recent years have also been used at home. In this article we present a system that includes a ring probe, sensor, radio, and receiver, designed for use as a long-term heart rate monitoring system in a senior center. The primary contribution of this article is successfully implementing a cheap, large-scale wireless heart rate monitoring system that is stable and comfortable to use 24 h a day. MATERIALS AND METHODS: We developed new finger ring sensors for comfortable continuous wearing experience and used dynamic power adjustment on the ring so the sensor can detect pulses at different strength levels. RESULTS: Our system has been deployed in a senior center since May 2012, and 63 seniors have used this system in this period. During the 54-h system observation period, 10 alarms were set off. Eight of them were due to abnormal heart rate, and two of them were due to loose probes. The monitoring system runs stably with the senior center's existing WiFi network, and achieves 99.48% system availability. The managers and caregivers use our system as a reliable warning system for clinical deterioration. CONCLUSIONS: The results of the year-long deployment show that the wireless group heart rate monitoring system developed in this work is viable for use within a designated area. PMID- 25734336 TI - Heterogeneity of Leishmania donovani parasites complicates diagnosis of visceral leishmaniasis: comparison of different serological tests in three endemic regions. AB - Diagnostic tests for visceral leishmaniasis that are based on antigens of a single Leishmania strain can have low diagnostic performance in regions where heterologous parasites predominate. The aim of this study was to investigate and compare the performance of five serological tests, based on different Leishmania antigens, in three endemic countries for visceral leishmaniasis. A total number of 231 sera of symptomatic and asymptomatic cases and controls from three endemic regions of visceral leishmaniasis in East Sudan, North India and South France were evaluated by following serological tests: rKLO8- and rK39 ELISA, DAT (ITMA DAT) and two rapid tests of rK39 (IT LEISH) and rKE16 (Signal-KA). Overall, rKLO8 and rK39 ELISA were most sensitive in immunocompetent patients from all endemic regions (96-100%) and the sensitivity was reduced to 81.8% in HIV co-infected patients from France. Sera of patients from India demonstrated significantly higher antibody responses to rKLO8 and rK39 compared with sera from Sudan (p<0.0001) and France (p<0.0037). Further, some Indian and Sudanese patients reacted better with rKLO8 than rK39. Sensitivity of DAT (ITMA-DAT) was high in Sudan (94%) and India (92.3%) but low in France being 88.5% and 54.5% for VL and VL/HIV patients, respectively. In contrast, rapid tests displayed high sensitivity only in patients from India (96.2%) but not Sudan (64-88%) and France (73.1-88.5% and 63.6-81.8% in VL and VL/HIV patients, respectively). While the sensitivity varied, all tests showed high specificity in Sudan (96.7-100%) and India (96.6%).Heterogeneity of Leishmania parasites which is common in many endemic regions complicates the diagnosis of visceral leishmaniasis. Therefore, tests based on homologous Leishmania antigens are required for particular endemic regions to detect cases which are difficult to be diagnosed with currently available tests. PMID- 25734338 TI - Attenuation of tick-borne encephalitis virus using large-scale random codon re encoding. AB - Large-scale codon re-encoding (i.e. introduction of a large number of synonymous mutations) is a novel method of generating attenuated viruses. Here, it was applied to the pathogenic flavivirus, tick-borne encephalitis virus (TBEV) which causes febrile illness and encephalitis in humans in forested regions of Europe and Asia. Using an infectious clone of the Oshima 5-10 strain ("wild-type virus"), a cassette of 1.4kb located in the NS5 coding region, was modified by randomly introducing 273 synonymous mutations ("re-encoded virus"). Whilst the in cellulo replicative fitness of the re-encoded virus was only slightly reduced, the re-encoded virus displayed an attenuated phenotype in a laboratory mouse model of non-lethal encephalitis. Following intra-peritoneal inoculation of either 2.105 or 2.106 TCID50 of virus, the frequency of viraemia, neurovirulence (measured using weight loss and appearance of symptoms) and neuroinvasiveness (detection of virus in the brain) were significantly decreased when compared with the wild-type virus. Mice infected by wild-type or re-encoded viruses produced comparable amounts of neutralising antibodies and results of challenge experiments demonstrated that mice previously infected with the re-encoded virus were protected against subsequent infection by the wild-type virus. This constitutes evidence that a mammalian species can be protected against infection by a virulent wild-type positive-stranded RNA virus following immunisation with a derived randomly re-encoded strain. Our results demonstrate that random codon re encoding is potentially a simple and effective method of generating live attenuated vaccine candidates against pathogenic flaviviruses. PMID- 25734337 TI - Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. AB - STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue specific inactivation of Stat3 in mice results in increased Kras(G12D)-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-kappaB-induced IL 8 expression by sequestering NF-kappaB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3-NF-kappaB-IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance. PMID- 25734340 TI - Research to real-world application: experts weigh in on the underuse of anticoagulants. AB - Although numerous studies have shown that anticoagulants can reduce the risk of stroke and thromboembolic events in patients with nonvalvular atrial fibrillation, they are underprescribed in the clinical setting. While standardized risk scoring assessments are recommended in treatment guidelines to determine when anticoagulant use may be appropriate, they are not widely used in the real-world clinical setting. Many factors contribute to anticoagulant underuse, including patient characteristics and comorbidities. Reluctance to prescribe an anticoagulant may also stem from concerns about bleeding or other perceived risks. In addition, physicians may be discouraged from prescribing anticoagulant therapy, particularly warfarin, if follow-up care and monitoring is potentially unfeasible. Patient fears of treatment and lack of access to the healthcare system also contribute to underuse. Increased awareness and education, medical therapy management programs, better care coordination, and improvements in monitoring and follow-up programs may help to increase the use of anticoagulant therapies in appropriate patients. PMID- 25734339 TI - Association between IL-6-174G/C polymorphism and the risk of sepsis and mortality: a systematic review and meta-analysis. AB - BACKGROUND: Recent studies have reported the association between IL-6-174G/C polymorphism and sepsis. However, the results are inconclusive and conflicting. To better understand the role of IL-6-174G/C polymorphism in sepsis, we conducted a comprehensive meta-analysis. METHODOLOGY: Literature search was conducted through PubMed, Embase, Web of Knowledge databases until July 29, 2013. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effect model based on heterogeneity test in total and subgroup analyses. RESULTS: Twenty studies on the risk of sepsis and seven studies on sepsis mortality were included. None of the results showed evidence of a significant association between IL-6-174G/C polymorphism and sepsis risk in overall analysis or subgroup analyses based on sepsis type, ethnicity, source of control and age under any genetic model (the allele comparison, the codominant, the recessive or the dominant model). Although there was a statistically significant association between IL-6-174 G/C polymorphism and sepsis-related mortality under the recessive model, the significance did not exist after Bonferroni's correction. CONCLUSIONS: Current evidence does not support a direct effect of IL-6-174 G/C polymorphism on the risk of sepsis. In addition, there was no association between IL-6-174 G/C polymorphism and sepsis mortality after Bonferroni's correction. Further analyses of gene-environment interactions and more studies based on larger sample size and homogeneous sepsis patients are required. PMID- 25734342 TI - Practices in in vitro fertilization. PMID- 25734341 TI - A study of the effects of exercise on the urinary metabolome using normalisation to individual metabolic output. AB - Aerobic exercise, in spite of its multi-organ benefit and potent effect on the metabolome, has yet to be investigated comprehensively via an untargeted metabolomics technology. We conducted an exploratory untargeted liquid chromatography mass spectrometry study to investigate the effects of a one-h aerobic exercise session in the urine of three physically active males. Individual urine samples were collected over a 37-h protocol (two pre-exercise and eight post-exercise). Raw data were subjected to a variety of normalization techniques, with the most effective measure dividing each metabolite by the sum response of that metabolite for each individual across the 37-h protocol expressed as a percentage. This allowed the metabolite responses to be plotted on a normalised scale. Our results highlight significant metabolites located in the following systems: purine pathway, tryptophan metabolism, carnitine metabolism, cortisol metabolism, androgen metabolism, amino acid oxidation, as well as metabolites from the gastrointestinal microbiome. Many of the significant changes observed in our pilot investigation mirror previous research studies, of various methodological designs, published within the last 15 years, although they have never been reported at the same time in a single study. PMID- 25734343 TI - Best practices in in vitro fertilization. PMID- 25734344 TI - Prognostic factors for IVF success: diagnostic testing and evidence-based interventions. AB - Numerous tests and interventions have been proposed for optimizing performance in preparation for in vitro fertilization (IVF) treatment. We critically appraised the available evidence underpinning some of the popular investigations and treatments, including the role of hysteroscopy, laparoscopy, ovarian reserve tests, sperm function tests, as well as the role of lifestyle modifications or surgery for endometriosis, fibroids, and endometrial polyps. We also reviewed the evidence behind novel techniques, such as the use of endometrial injury before IVF. Only a few of the aforementioned modalities are justified based on the available research evidence. Other factors may affect the uptake of a test or intervention before IVF, namely the complexity of the proposed modality, its potential for harm, and its cost-effectiveness. PMID- 25734346 TI - Optimal oocyte retrieval and embryo transfer techniques: where we are and how we got here. AB - Oocyte retrieval is most safely accomplished with conscious sedation via a transvaginal approach under ultrasound guidance with low-pressure aspiration. Follicle flushing has not been shown to improve outcomes. The type of vaginal surgical preparation and the use of antibiotics have not been demonstrated to affect outcomes. As the final step in a rigorous assisted reproductive technology (ART) cycle, precise technique in embryo transfer is essential. Based on current findings, the recommended embryo transfer technique includes the use of an ultrasound-guided transcervical approach with a full bladder using a soft catheter. The transfer depth of the embryo should be in the mid-portion of the uterus with a quick steady insertion followed by pressure on the syringe during withdrawal of the catheter. It is acceptable to encourage immediate ambulation after embryo transfer. PMID- 25734345 TI - Best practices for controlled ovarian stimulation in in vitro fertilization. AB - As applications for IVF have expanded over the years, so too have approaches to controlled ovarian stimulation (COS) for IVF. With this expansion and improved knowledge of basic reproductive biology, there is increasing interest in how COS practice influences IVF outcomes, and whether or not specific treatment scenarios call for personalized approaches to COS. For the majority of women undergoing COS and their treating physicians, the goal is to achieve a healthy live birth through IVF in a fresh cycle. Opinions on how COS strategy best leads to this common goal varies among centers as many clinicians base COS strategy not on evidence obtained through prospective randomized trials, but rather through observational studies and experience. Overall, when it comes to COS most clinicians recognize the approach should not be "one size fits all," but rather a patient-centered approach that takes the existing evidence into consideration. We outline the existing evidence for best practices in COS for IVF, highlighting how these practices may be incorporated into a patient-centered approach. PMID- 25734347 TI - To ICSI or Not to ICSI. AB - Intracytoplasmic sperm injection (ICSI) is the most effective assisted reproductive procedure enabling fertilization in severe forms of male factor indications and male gamete dysfunction. Reliability of ICSI has allowed the expansion of its application to other forms of infertility rendering it the most popular assisted reproduction technology (ART) insemination method worldwide. The concern related to the invasiveness of ICSI together with the arbitrary selection of the inseminating spermatozoon has induced the execution of studies to compare the performance of ICSI in non-male factor infertility with standard in vitro insemination approach. Not surprisingly, the outcome has evidenced that ICSI does not yield higher pregnancy rates than in vitro fertilization but functions invariably as a normalizer of fertilization mollifying the absent or low fertilization. The follow-up studies on ICSI children have evidenced that the procedure is safe and the slightly higher incidences of neonatal malformations or de novo gonosomal abnormalities are related to the genetics of the infertile couples. Furthermore, ICSI is accepted for some specific indications such as low number and poor morphology oocytes, thicker zona, excess polyspermia, PGD/PGS/PGT (preimplantation genetic diagnosis/preimplantation genetic screening/preimplantation genetic testing), discordant HCV/HIV (hepatitis C virus/human immunodeficiency virus) couples, in vitro maturation (IVM), and oocyte cryopreservation. Only the advent of new biomarkers in combination with routine semen analysis capable of identifying the fertilization competence of the spermatozoon can guide the reproductive physician toward the proper insemination method. PMID- 25734348 TI - Optimal human embryo culture. AB - A large contributor to success during in vitro fertilization (IVF) lies in the processes occurring within the IVF laboratory. These processes make up the "culture system." This system entails numerous procedures and technical steps that must be optimized to produce a competent embryo. Notably, variations exist between programs that include differences in patient population, clinical stimulation, and other factors. Thus, a single "optimal" culture system to be utilized between all laboratories is likely not feasible. Rather, laboratory procedures should be optimized based on an individual laboratory's performance. That being said, within the scientific literature, there are key components, approaches, and techniques within the culture system that have been shown to be superior to alternatives. These key components important in improving embryo culture are discussed. PMID- 25734349 TI - Luteal phase support in in vitro fertilization. AB - It has been well demonstrated that luteal phase physiology is disrupted in in vitro fertilization (IVF) cycles conducted with either gonadotropin-releasing hormone (GnRH) agonists or antagonists, and that supplementation of the luteal phase with either exogenous progesterone or human chorionic gonadotropin (hCG) is necessary to optimize IVF cycle outcomes. Though both progesterone and hCG supplementation resulted in comparable pregnancy rates, hCG supplementation was associated with increased risk for ovarian hyperstimulation syndrome (OHSS). For that reason progesterone has been used for luteal support by most IVF programs around the world. Vaginal progesterone preparations have been shown definitively to be equally efficacious and better tolerated by patients than intramuscular progesterone injections, but new data on the subcutaneous and oral progesterone are also emerging. New evidence has been accumulating on the benefits of low-dose luteal hCG supplementation in GnRH-antagonist cycles where GnRH agonists are used for the final maturation trigger. New approaches to luteal phase support as well as new formulations of progesterone have been developed since the last comprehensive review was published in 2011. In this article, we examine current evidence for efficacy, dosing, and timing of progesterone preparations as well as the role of hCG for luteal support in IVF cycles triggered with GnRH agonists. We also discuss the data on the role of estrogen supplementation in the luteal phase, optimal duration of progesterone support in early pregnancy, and progesterone replacement in frozen embryo transfer cycles and donor egg recipient cycles. PMID- 25734350 TI - Human embryo cryopreservation-methods, timing, and other considerations for optimizing an embryo cryopreservation program. AB - The contribution of embryo cryopreservation to the birth rate per in vitro fertilization cycle has escalated from a rare subsidy to a vital tool that is called upon to augment the cycle outcome. Embryology laboratories must identify the embryo stage, quality criteria and methodology that will optimize their ability to preserve each embryo's reproductive potential. This chapter reviews the principles of cryopreservation, outcomes based on embryo stage and cryopreservation method and benchmarks that may be employed by the laboratory to measure the performance of their embryo cryopreservation program. PMID- 25734351 TI - Cryopreserved embryo transfer: endometrial preparation and timing. AB - The objective of this article was to review and synthesize information from the scientific literature pertaining to the preparation of endometrium for cryopreserved embryo transfer. This article is a critical review of selected scientific literature, synthesis, and formulation of opinion. Estrogen and progesterone are necessary and sufficient to induce endometrial receptivity in cryopreserved embryo transfer cycles. A variety of regimens have been described including natural cycles using endogenous ovarian hormones and artificial or programmed cycles with exogenously administered steroid hormones. To achieve optimal synchrony between embryo and endometrium, the timing of progesterone administration needs to be adjusted to the developmental stage of the thawed embryos. There is currently no evidence that any single regimen or adjuvant substance results in superior outcomes in cryopreserved embryo transfer cycles, although timing of progesterone administration does matter. Although no single regimen of endometrial preparation for cryopreserved embryo transfer has been proven superior to the others, the relative convenience and ease of use do vary, depending on the route of administration chosen and any adjuvant added to the cycle. PMID- 25734352 TI - The difficult in vitro fertilization patient: an individualized approach. AB - In general, standardized in vitro fertilization (IVF) protocols and practice regimens can be applied with success for most patients. Such approaches, however, may not be effective for some women who do not "fit the mold" and for whom highly individualized treatments are more suitable. In this article, we outline our personal experience and treatment approaches for these challenging patients. PMID- 25734353 TI - Diagnostic Precursors to Bipolar Disorder in Offspring of Parents With Bipolar Disorder: A Longitudinal Study. AB - OBJECTIVE: The authors sought to identify diagnostic risk factors of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder ("high-risk offspring"). METHOD: High-risk offspring 6-18 years old (N=391) and demographically matched offspring (N=248) of community parents without bipolar disorder were assessed longitudinally with standardized diagnostic instruments by staff blind to parental diagnoses. Follow-up assessments were completed in 91% of the offspring (mean follow-up interval, 2.5 years; mean follow-up duration, 6.8 years). RESULTS: Compared with community offspring, high-risk offspring had significantly higher rates of subthreshold mania or hypomania (13.3% compared with 1.2%), manic, mixed, or hypomanic episodes (9.2% compared with 0.8%), and major depressive episodes (32.0% compared with 14.9%). They also had higher rates of attention deficit hyperactivity disorder (30.7% compared with 18.1%), disruptive behavior disorders (27.4% compared with 15.3%), anxiety disorders (39.9% compared with 21.8%), and substance use disorders (19.9% compared with 10.1%), but not unipolar major depressive disorder (major depression with no bipolarity; 18.9% compared with 13.7%). Multivariate Cox regressions showed that in the high-risk offspring, subthreshold manic or hypomanic episodes (hazard ratio=2.29), major depressive episodes (hazard ratio=1.99), and disruptive behavior disorders (hazard ratio=2.12) were associated with subsequent manic, mixed, or hypomanic episodes. Only subthreshold manic or hypomanic episodes (hazard ratio=7.57) were associated when analyses were restricted to prospective data. CONCLUSIONS: Subthreshold manic or hypomanic episodes were a diagnostic risk factor for the development of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder and should be a target for clinical assessment and treatment research. Major depressive episodes and disruptive behavior disorders are also indications for close clinical monitoring of emergent bipolarity in high-risk offspring. PMID- 25734355 TI - Arachidonic acid-stimulated platelet tests: Identification of patients less sensitive to aspirin treatment. AB - Serum thromboxane-B2 (TxB2), together with arachidonic acid (AA)-induced platelet aggregation, are, at the moment, the most used tests to identify patients displaying high on-aspirin treatment platelet reactivity (HAPR). Both tests are specific for aspirin action on cyclooxygenase-1. While the correlation between serum TxB2 assay and clinical outcome is established, data are conflicting with regard to aspirin treatment and a possible association with AA-stimulated platelet markers and clinical outcome. To understand such discrepancy, we performed a retrospective study to compare both assays. We collected data from 132 patients receiving a daily dose of aspirin (100 mg/day) and data from 48 patients receiving aspirin on alternate days. All Patients who received a daily dose of aspirin were studied for AA-induced platelet aggregation together with serum TxB2 levels and AA-induced TxB2 formation was also studied in 71 patients out of entire population. Consistent with recommendations in the literature, we defined HAPR by setting a cut-off point at 3.1 ng/ml for serum levels of thromboxane B2 and 20% for AA-induced platelet aggregation. According to this cut off point, we divided our overall population into two groups: (1) TxB2 < 3.1 ng/ml and (2) TxB2 > 3.1 ng/ml. We found low agreement between such tests to identify patients displaying HAPR. Our results show that AA-induced platelet aggregation >20% identify a smaller number of HAPR patients in comparison with TxB2. A good correlation between serum TxB2 and arachidonic acid-induced TxB2 production was found (r = 0.76619). PMID- 25734354 TI - Cerebral Small Vessel Disease and Association With Higher Incidence of Depressive Symptoms in a General Elderly Population: The AGES-Reykjavik Study. AB - OBJECTIVE: The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) leads to depressive symptoms by disruption of brain structures involved in mood regulation. However, longitudinal data on the association between CSVD and depressive symptoms are scarce. The authors investigated the association between CSVD and incident depressive symptoms. METHOD: Longitudinal data were taken from the Age, Gene/Environment Susceptibility-Reykjavik Study of 1,949 participants free of dementia and without baseline depressive symptoms (mean age: 74.6 years [SD=4.6]; women, 56.6%). MRI markers of CSVD, detected at baseline (2002-2006) and follow-up (2007-2011), included white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces, and total brain parenchyma volume. Incident depressive symptoms were defined by a score >=6 on the 15-item Geriatric Depression Scale and/or use of antidepressant medication. RESULTS: Depressive symptoms occurred in 10.1% of the participants. The association for a greater onset of depressive symptoms was significant for participants with 1 standard deviation increase in white matter hyperintensity volume over time, new subcortical infarcts, new Virchow-Robin spaces, 1 standard deviation lower total brain volume at baseline, and 1 standard deviation decreased total brain volume over time, after adjustments for cognitive function and sociodemographic and cardiovascular factors. Results were qualitatively similar when change in the Geriatric Depression Scale score over time was used as the outcome instead of incident depressive symptoms. CONCLUSIONS: Most markers of progression of CSVD over time and some markers of baseline CSVD are associated with concurrently developing new depressive symptoms. These findings support the vascular depression hypothesis. PMID- 25734356 TI - Effect of nontronite smectite clay on the chemical evolution of several organic molecules under simulated martian surface ultraviolet radiation conditions. AB - Most of the phyllosilicates detected at the surface of Mars today are probably remnants of ancient environments that sustained long-term bodies of liquid water at the surface or subsurface and were possibly favorable for the emergence of life. Consequently, phyllosilicates have become the main mineral target in the search for organics on Mars. But are phyllosilicates efficient at preserving organic molecules under current environmental conditions at the surface of Mars? We monitored the qualitative and quantitative evolutions of glycine, urea, and adenine in interaction with the Fe(3+)-smectite clay nontronite, one of the most abundant phyllosilicates present at the surface of Mars, under simulated martian surface ultraviolet light (190-400 nm), mean temperature (218 +/- 2 K), and pressure (6 +/- 1 mbar) in a laboratory simulation setup. We tested organic-rich samples that were representative of the evaporation of a small, warm pond of liquid water containing a high concentration of organics. For each molecule, we observed how the nontronite influences its quantum efficiency of photodecomposition and the nature of its solid evolution products. The results reveal a pronounced photoprotective effect of nontronite on the evolution of glycine and adenine; their efficiencies of photodecomposition were reduced by a factor of 5 when mixed at a concentration of 2.6 * 10(-2) mol of molecules per gram of nontronite. Moreover, when the amount of nontronite in the sample of glycine was increased by a factor of 2, the gain of photoprotection was multiplied by a factor of 5. This indicates that the photoprotection provided by the nontronite is not a purely mechanical shielding effect but is also due to stabilizing interactions. No new evolution product was firmly identified, but the results obtained with urea suggest a particular reactivity in the presence of nontronite, leading to an increase of its dissociation rate. PMID- 25734357 TI - Allosterically controlled threading of polymers through macrocyclic dimers. AB - As part of an ongoing study to construct a molecular Turing machine in which a polymer chain is encoded via allosteric information transfer between macrocyclic complexes, we describe the thermodynamic and kinetic characterization of a multicomponent self-assembled system based on a zinc porphyrin macrocyclic compound, a bidentate ligand (1,4-diazabicyclo[2.2.2]octane, DABCO), and a viologen-substituted polymer guest. Initial addition of DABCO to the porphyrin macrocycle in chloroform solution leads to the formation of a stable 2:1 (porphyrin:DABCO) dimeric complex, even under dilute conditions, by means of strong cooperative interactions involving hydrogen and metal-ligand bonds. Further titration of the porphyrin-DABCO mixtures with the polymer gives rise to a complex array of species in the solution. The system is analyzed in detail by a combination of spectroscopic measurements and computational modeling. Each association constant in the binding scheme and the fraction of each individual complex that is formed in solution are determined precisely using a mass-balance model. Kinetic studies revealed that the rates of the polymer threading and dethreading in and out of the dimeric system are remarkably slow, indicating that the polymer is locked inside the cavity of the stable 2:1 dimeric complex as a result of strong allosteric interactions. PMID- 25734358 TI - Role of the Na(+)/K(+)-ATPase beta-subunit in peptide-mediated transdermal drug delivery. AB - In this work, we discovered that the Na(+)/K(+)-ATPase beta-subunit (ATP1B1) on epidermal cells plays a key role in the peptide-mediated transdermal delivery of macromolecular drugs. First, using a yeast two-hybrid assay, we screened candidate proteins that have specific affinity for the short peptide TD1 (ACSSSPSKHCG) identified in our previous work. Then, we verified the specific binding of TD1 to ATP1B1 in yeast and mammalian cells by a pull-down ELISA and an immunoprecipitation assay. Finally, we confirmed that TD1 mainly interacted with the C-terminus of ATP1B1. Our results showed that the interaction between TD1 and ATP1B1 affected not only the expression and localization of ATP1B1, but also the epidermal structure. In addition, this interaction could be antagonized by the exogenous competitor ATP1B1 or be inhibited by ouabain, which results in the decreased delivery of macromolecular drugs across the skin. The discovery of a critical role of ATP1B1 in the peptide-mediated transdermal drug delivery is of great significance for the future development of new transdermal peptide enhancers. PMID- 25734359 TI - Substrate hydrophobicity and cell composition influence the extent of rate limitation and masking of isotope fractionation during microbial reductive dehalogenation of chlorinated ethenes. AB - This study investigated the effect of intracellular microscale mass transfer on microbial carbon isotope fractionation of tetrachloroethene (PCE) and trichloroethene (TCE). Significantly stronger isotope fractionation was observed for crude extracts vs intact cells of Sulfurospirillum multivorans, Geobacter lovleyi, Desulfuromonas michiganensis, Desulfitobacterium hafniense strain PCE-S, and Dehalobacter restrictus. Furthermore, carbon stable isotope fractionation was stronger for microorganisms with a Gram-positive cell envelope compared to those with a Gram-negative cell envelope. Significant differences were observed between model organisms in cellular sorption capacity for PCE (S. multivorans-K(d-PCE) = 0.42-0.51 L g(-1); D. hafniense-K(d-PCE) = 0.13 L g(-1)), as well as in envelope hydrophobicity (S. multivorans 33.0 degrees to 72.2 degrees ; D. hafniense 59.1 degrees to 60.8 degrees ) when previously cultivated with fumarate or PCE as electron acceptor, but not for TCE. Cell envelope properties and the tetrachloroethene reductive dehalogenase (PceA-RDase) localization did not result in significant effects on observed isotope fractionation of TCE. For PCE, however, systematic masking of isotope effects as a result of microscale mass transfer limitation at microbial membranes was observed, with carbon isotope enrichment factors of -2.20/00, -1.5 to -1.60/00, and -1.00/00 (CI95% < +/- 0.20/00) for no membrane, hydrophilic outer membrane, and outer + cytoplasmic membrane, respectively. Conclusively, rate-limiting mass transfer barriers were (a) the outer membrane or cell wall and (b) the cytoplasmic membrane in case of a cytoplasmic location of the RDase enzyme. Overall, our results indicate that masking of isotope fractionation is determined by (1) hydrophobicity of the degraded compound, (2) properties of the cell envelope, and (3) the localization of the reacting enzyme. PMID- 25734360 TI - Coplanar induction enabled by asymmetric permittivity of dielectric materials for mechanical energy conversion. AB - Triboelectric nanogenerator (TENG) is a newly emerged technology for harvesting mechanical energy, which has the promise for various practical applications. Here, we introduce a new principle of TENG in which induced current is generated between two coplanar electrodes because of different dielectric fillers of distinct permittivities. The manipulation of permittivity of dielectric materials for TENG is first reported, demonstrating a novel route in designing high performance TENGs. When repeatedly contacting with an object, a TENG having lateral dimensions of 21 mm * 10 mm can produce an open-circuit voltage of 58.5 V and a short-circuit current of 44.7 MUA. The instantaneous output power density can reach up to 708 MUW. Besides, the new design incorporates all electrodes into a single plane, greatly simplifying the structure, promoting robustness, and providing a viable solution for device miniaturization. PMID- 25734361 TI - Interdomain interface-mediated target recognition by the Scribble PDZ34 supramodule. AB - Tandem-arranged PDZ [PSD-95 (postsynaptic density-95), Dlg (discs large homologue) and ZO-1 (zonula occludens-1)] domains often form structural and functional supramodules with distinct target-binding properties. In the present study, we found that the two PDZ domains within the PDZ34 tandem of Scribble, a cell polarity regulator, tightly pack in a 'front-to-back' mode to form a compact supramodule. Although PDZ4 contains a distorted alphaB/betaB pocket, the attachment of PDZ4 to PDZ3 generates an unexpected interdomain pocket that is adjacent to and integrates with the canonical alphaB/betaB pocket of PDZ3 to form an expanded target-binding groove. The structure of the PDZ34-target peptide complex further demonstrated that the peptide binds to this expanded target binding groove with its upstream residues anchoring into the interdomain pocket directly. Mutations of the interdomain pocket and disruptions of the PDZ34 supramodule both interfere with its target-binding capacity. Therefore, the interdomain interface between the PDZ34 supramodule is intrinsically required for its target recognition and determines its target-binding specificity. This interdomain interface-mediated specific recognition may represent a novel mode of target recognition and would broaden the target-binding versatility for PDZ supramodules. The supramodular nature and target recognition mode of the PDZ34 tandem found in the present study would also help to identify the new binding partners of Scribble and thus may direct further research on the PDZ domain mediated assembly of Scribble polarity complexes. PMID- 25734362 TI - Prolonged infusion of estradiol benzoate into the stalk median eminence stimulates release of GnRH and kisspeptin in ovariectomized female rhesus macaques. AB - Our recent study indicates that a brief infusion (20 min) of estradiol (E2) benzoate (EB) into the stalk-median eminence (S-ME) stimulates GnRH release with a latency of approximately 10 minutes. In contrast to the effect induced by a brief infusion of EB, it has previously been shown that systemic EB administration suppresses release of GnRH, kisspeptin, and LH with a latency of several hours, which is known as the negative feedback action of E2. We speculated that the differential results by these 2 modes of EB administration are due to the length of E2 exposure. Therefore, in the present study, the effects of EB infusion for periods of 20 minutes, 4 hours, or 7 hours into the S ME of ovariectomized female monkeys on the release of GnRH and kisspeptin were examined using a microdialysis method. To assess the effects of the EB infusion on LH release, serum samples were also collected. The results show that similar to the results with 20-minute infusion, both 4- and 7-hour infusions of EB consistently stimulated release of GnRH and kisspeptin from the S-ME accompanied by LH release in the general circulation. In contrast, sc injection of EB suppressed all 3 hormones (GnRH, kisspeptin, and LH) measured. It is concluded that regardless of the exposure period, direct E2 action on GnRH and kisspeptin neurons in the S-ME, where their neuroterminals are present, is stimulatory, and the E2-negative feedback effects do not occur at the S-ME level. PMID- 25734363 TI - Ventral tegmental area neurotensin signaling links the lateral hypothalamus to locomotor activity and striatal dopamine efflux in male mice. AB - Projections from the lateral hypothalamic area (LHA) innervate components of the mesolimbic dopamine (MLDA) system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), to modulate motivation appropriately for physiologic state. Neurotensin (NT)-containing LHA neurons respond to multiple homeostatic challenges and project to the VTA, suggesting that these neurons could link such signals to MLDA function. Indeed, we found that pharmacogenetic activation of LHA NT neurons promoted prolonged DA-dependent locomotor activity and NAc DA efflux, suggesting the importance of VTA neurotransmitter release by LHA NT neurons for the control of MLDA function. Using a microdialysis-mass spectrometry technique that we developed to detect endogenous NT in extracellular fluid in the mouse brain, we found that activation of LHA NT cells acutely increased the extracellular concentration of NT (a known activator of VTA DA cells) in the VTA. In contrast to the prolonged elevation of extracellular NAc DA, however, VTA NT concentrations rapidly returned to baseline. Intra-VTA infusion of NT receptor antagonist abrogated the ability of LHA NT cells to increase extracellular DA in the NAc, demonstrating that VTA NT promotes NAc DA release. Thus, transient LHA derived NT release in the VTA couples LHA signaling to prolonged changes in DA efflux and MLDA function. PMID- 25734364 TI - Rich spectroscopic and molecular dynamic studies on the interaction of cytotoxic Pt(II) and Pd(II) complexes of glycine derivatives with calf thymus DNA. AB - Some amino acid derivatives, such as R-glycine, have been synthesized together with their full spectroscopic characterization. The sodium salts of these bidentate amino acid ligands have been interacted with [M(bpy)(H2O)2](NO3)2 giving the corresponding some new complexes with formula [M(bpy)(R-gly)]NO3 (where M is Pt(II) or Pd(II), bpy is 2,2'-bipyridine and R-gly is butyl-, hexyl- and octyl-glycine). Due to less solubility of octyl derivatives, the biological activities of butyl and hexyl derivatives have been tested against chronic myelogenous leukemia cell line, K562. The interaction of these complexes with highly polymerized calf thymus DNA has been extensively studied by means of electronic absorption, fluorescence and other measurements. The experimental results suggest that these complexes positive cooperatively bind to DNA presumably via groove binding. Molecular dynamic results show that the DNA structure is largely maintained its native structure in hexylglycine derivative water mixtures and at lower temperatures. The simulation data indicates that the more destabilizing effect of butylglycine is induced by preferential accumulation of these molecules around the DNA and due to their more negative free energy of binding via groove binding. PMID- 25734365 TI - Trauma, attentional biases, and revictimization among young adults. AB - Individuals with previous histories of trauma are at increased risk for subsequent victimization and the development of posttraumatic stress disorder, depression, and anxiety disorders. Attentional biases to threat-related stimuli are thought to impact one's ability to recognize future risk in his or her environment and may explain high rates of revictimization. Although the literature has identified three possible types of attentional biases among victims of trauma (i.e., interference, facilitation, and avoidance), findings are mixed. The current study examined attentional biases to threats among a sample of men and women with no, some, and multiple incident interpersonal and non interpersonal trauma histories. It was hypothesized that those with multiple incident interpersonal trauma histories would demonstrate an interference effect (i.e., slower response times to threat-related words). Participants (N = 309) were 18- to 29-year-old college students. Self-report measures assessed trauma history, posttraumatic stress, and other psychological sequelae. Attentional biases were assessed using a dot probe computer task. Contrary to hypotheses, no significant differences in response times in the presence of threat-related words or neutral words were found among groups. Results suggest that multiple traumatized individuals do not exhibit attentional bias to threats compared to individuals with some or no trauma. PMID- 25734367 TI - Using a sequence of estrogen response elements as a DNA aptamer for estrogen receptors in vitro. AB - Estrogen receptors (ERs) are overexpressed in approximately 70% of breast cancer cases, and they play an important role in tumorigenesis. ERs are strong predictive factors for measuring responses to hormonal therapies. Aptamers are short and single stranded oligonucleotides that are able to recognize target molecules with high affinity. In the present study, we selected and synthesized an oligonucleotide, which has a similar sequence to estrogen response element in the Xenopus Vitellogenin A2 gene. The synthesized oligonucleotide was evaluated by using immunostaining of paraffin-embedded breast cancer tissues and treating MCF-7 human mammary carcinoma cell line in vitro. We found that the synthesized oligonucleotide had a high binding affinity to ER similar to estradiol. Using a specific anti-ER antibody as a standard control, we showed that the synthesized oligonucleotide specifically recognized and immunostained tumor cells of breast cancer without cross-reaction with normal tissues. The overall agreement of ER detection between the anti-ER antibody and the ER aptamer was 97.1% (kappa value=0.943; 95% CI=0.879-1.006; p<0.002). Similar to tamoxifen or fulvestrant, the oligonucleotide also had an inhibitory effect on cell proliferation of MCF-7 cell line in a dose- and time-dependent fashion but had no cytotoxic effect on human normal mammary epithelial cells. Therefore, the synthesized oligonucleotide may be used as an aptamer for immunostaining of paraffin-embedded tissue sections for breast cancer diagnosis, as well as a potential ER antagonist in the treatment of breast cancer. PMID- 25734366 TI - Ionizing Radiation Stimulates Expression of Pro-Osteoclastogenic Genes in Marrow and Skeletal Tissue. AB - Exposure to ionizing radiation can cause rapid mineral loss and increase bone resorbing osteoclasts within metabolically active, cancellous bone tissue leading to structural deficits. To better understand mechanisms involved in rapid, radiation-induced bone loss, we determined the influence of total body irradiation on expression of select cytokines known both to stimulate osteoclastogenesis and contribute to inflammatory bone disease. Adult (16 week), male C57BL/6J mice were exposed to either 2 Gy gamma rays ((137)Cs, 0.8 Gy/min) or heavy ions ((56)Fe, 600MeV, 0.50-1.1 Gy/min); this dose corresponds to either a single fraction of radiotherapy (typical total dose is >=10 Gy) or accumulates over long-duration interplanetary missions. Serum, marrow, and mineralized tissue were harvested 4 h-7 days later. Gamma irradiation caused a prompt (2.6-fold within 4 h) and persistent (peaking at 4.1-fold within 1 day) rise in the expression of the obligate osteoclastogenic cytokine, receptor activator of nuclear factor kappa-B ligand (Rankl), within marrow cells over controls. Similarly, Rankl expression peaked in marrow cells within 3 days of iron exposure (9.2-fold). Changes in Rankl expression induced by gamma irradiation preceded and overlapped with a rise in expression of other pro-osteoclastic cytokines in marrow (eg, monocyte chemotactic protein-1 increased by 11.9-fold, and tumor necrosis factor-alpha increased by 1.7-fold over controls). The ratio, Rankl/Opg, in marrow increased by 1.8-fold, a net pro-resorption balance. In the marrow, expression of the antioxidant transcription factor, Nfe2l2, strongly correlated with expression levels of Nfatc1, Csf1, Tnf, and Rankl. Radiation exposure increased a serum marker of bone resorption (tartrate-resistant acid phosphatase) and led to cancellous bone loss (16% decrement after 1 week). We conclude that total body irradiation (gamma or heavy-ion) caused temporal elevations in the concentrations of specific genes expressed within marrow and mineralized tissue related to bone resorption, including select cytokines that lead to osteoclastogenesis and elevated resorption; this is likely to account for rapid and progressive deterioration of cancellous microarchitecture following exposure to ionizing radiation. PMID- 25734368 TI - Decreased Susceptibility to Macrolide-Lincosamide in Mycoplasma synoviae Is Associated with Mutations in 23S Ribosomal RNA. AB - The mechanism responsible for acquired decreased susceptibility to macrolides (14 membered erythromycin [Ery], 16-membered tylosin [Ty] and tilmicosin [Tm]) and to lincosamides (lincomycin [Ln]) was investigated in Mycoplasma synoviae, a pathogen that causes respiratory infections and synovitis in chicken and turkey. Sequence analysis of domains II and V of the two 23S rRNA alleles and ribosomal proteins L4 and L22 was performed on 49 M. synoviae isolates, M. synoviae type strain WVU1853, and reference strain FMT showing minimal inhibitory concentrations (MICs) to Ty (<= 0.015 to 2 MUg/ml), Tm (0.03 to >= 8 MUg/ml), and Ln (0.125 to 8 MUg/ml); MICs to Ery ranged from 32 to >= 128 MUg/ml. Our results showed that the nucleotide substitution G748A (Escherichia coli numbering) in domain II of one or both 23S rRNA alleles may account for a slight increase in MICs to Ty and Tm (up to 0.5 and 2 MUg/ml, respectively). No correlation between the presence of G748A and decreased susceptibility to Ln was found. However, the presence of the point mutations A2058G or A2059G in domain V of one or both alleles of the 23S rRNAs was correlated with a more significant decrease in susceptibility to Ty (1-2 MUg/ml), Tm (>= 8 MUg/ml), and Ln (>= 8 MUg/ml). All M. synoviae isolates tested had a G2057A transition in the 23S rRNAs consistent with previously described intrinsic resistance to Ery. Mutations G64E (one isolate) and Q90K/H (two isolates) were identified in the L4 and L22 proteins, respectively, but their impact on decreased susceptibility to macrolides and lincomycin was not clear. PMID- 25734369 TI - Phase behavior of binary mixture systems of saturated-unsaturated mixed-acid triacylglycerols: effects of glycerol structures and chain-chain interactions. AB - We systematically examined the phase behavior of binary mixtures of mixed-acid triacylglycerols (TAGs) containing palmitic and oleic acid moieties 1,3-dioleoyl 2-palmitoyl-glycerol (OPO), 1,2-dipalmitoyl-3-oleoyl-rac-glycerol (PPO), and 1,2 dioleoyl-3-palmitoyl-rac-glycerol (OOP), which are widely present in natural fats and are employed in the food, pharmaceutical, and cosmetic industries. Differential scanning calorimetry and X-ray diffraction methods were applied to observe the mixing behavior of PPO/OPO, OOP/OPO, and PPO/OOP under metastable and stable conditions. The results led to three conclusions: (1) Eutectic behavior was observed in PPO/OPO. (2) Molecular compound (MC) crystals were formed in the mixtures of OOP/OPO and PPO/OOP. (3) However, the MC crystals occurred only under metastable conditions and tended to separate into component TAGs to form eutectic mixture systems after 17 months of incubation. These results were contrary to those of previous studies on 1,3-dipalmitoyl-2-oleoyl glycerol (POP)/OPO and POP/PPO in which the MC crystals were thermodynamically stable. We determined that specific molecular interactions may cause this different phase behavior (stability of POP/OPO and POP/PPO MC crystals and metastability of OOP/OPO and PPO/OOP MC crystals). All results confirm the significant effects of molecular structures of glycerol groups, interactions of fatty acid chains, and polymorphism of the component TAGs on the mixing behavior of mixed-acid TAGs. PMID- 25734370 TI - A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. AB - Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying sigma* orbitals of the C S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, pi-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur sigma* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C-S sigma* orbitals and proteins are illustrated. PMID- 25734371 TI - Florid cutaneous manifestations with acanthosis nigricans in a lung cancer patient. PMID- 25734372 TI - New school meal regulations increase fruit consumption and do not increase total plate waste. AB - BACKGROUND: The 2010 Healthy, Hunger-Free Kids Act required the USDA to update the nutrition standards of the National School Lunch Program. New policies were implemented in the 2012-2013 school year. These changes were followed by anecdotal reports of increased food waste. Empirical research is needed to reliably measure student intake and plate waste before and after this policy change. METHODS: Food consumption and waste was collected annually from a cohort of middle school students in 12 schools in an urban, low-income school district before (spring 2012) and after (spring 2013 and 2014) policy changes. Generalized linear regression was used to compare pre- versus postpolicy selection and consumption of entrees, fruits, vegetables, and milk. RESULTS: Comparing 2012 to 2014, the percentage of students choosing fruit significantly increased from 54% to 66% and fruit consumption remained high at 74%. Student selection of fruit increased by 9% for each additional type of fruit offered with the meal. The proportion of students who chose a vegetable dropped from 68% to 52%, but students selecting vegetables ate nearly 20% more of them, effectively lowering vegetable waste. Entree consumption increased significantly from 71% to 84%, thereby also decreasing waste. CONCLUSIONS: Students responded positively to the new lunches. They consumed more fruit, threw away less of the entrees and vegetables, and consumed the same amount of milk. Overall, the revised meal standards and policies appear to have significantly lowered plate waste in school cafeterias. PMID- 25734373 TI - Surface confined retro Diels-Alder reaction driven by the swelling of weak polyelectrolytes. AB - Recently, the type of reactions driven by mechanical force has increased significantly; however, the number of methods for activating those mechanochemical reactions stays relatively limited. Furthermore, in situ characterization of a reaction is usually hampered by the inherent properties of conventional methods. In this study, we report a new platform that utilizes mechanical force generated by the swelling of surface tethered weak polyelectrolytes. An initiator with Diels-Alder (DA) adduct structure was applied to prepare the polyelectrolyte-carboxylated poly(OEGMA-r-HEMA), so that the force could trigger the retro DA reaction. The reaction was monitored in real time by quartz crystal microbalance and confirmed with atomic force microscopy and X-ray photoelectron spectroscopy. Compared with the conventional heating method, the swelling-induced retro DA reaction proceeded rapidly with high conversion ratio and selectivity. A 23.61 kcal/mol theoretical energy barrier supported the practicability of this retro DA reaction being triggered mechanically at ambient temperature. During swelling, the tensile force was controllable and persistent. This unique feature imparts this mechanochemical platform the potential to "freeze" an intermediate state of a reaction for in situ spectroscopic observations, such as surface-enhanced Raman spectroscopy and frequency generation spectroscopy. PMID- 25734374 TI - Proteinlike copolymers as encapsulating agents for small-molecule solutes. AB - We describe the utilization of proteinlike copolymers (PLCs) as encapsulating agents for small-molecule solutes. We perform Monte Carlo simulations on systems containing PLCs and model solute molecules in order to understand how PLCs assemble in solution and what system conditions promote solute encapsulation. Specifically, we explore how the chemical composition of the PLCs and the range and strength of molecular interactions between hydrophobic segments on the PLC and solute molecules affect the solute encapsulation efficiency. The composition profiles of the hydrophobic and hydrophilic segments, the solute, and implicit solvent (or voids) within the PLC globule are evaluated to gain a complete understanding of the behavior in the PLC/solute system. We find that a single chain PLC encapsulates solute successfully by collapsing the macromolecule to a well-defined globular conformation when the hydrophobic/solute interaction is at least as strong as the interaction strength among hydrophobic segments and the interaction among solute molecules is at most as strong as the hydrophobic/solute interaction strength. Our results can be used by experimentalists as a framework for optimizing unimolecular PLC solute encapsulation and can be extended potentially to applications such as "drug" delivery via PLCs. PMID- 25734375 TI - Autophagy researchers. PMID- 25734376 TI - Ozonolysis reactions of monoterpenes: a variational transition state investigation. AB - The O3-initiated oxidation reactions of alpha-pinene ([1S,5S]-2,6,6 trimethylbicyclo[3.1.1]hept-2-ene), beta-pinene ([1R,5R]-6,6-dimethyl-2 methylenebicyclo[3.1.1]heptane), camphene ([1R,4S]-2,2-dimethyl-3 methylenebicyclo[2.2.1]heptane) and sabinene ([1R,5R]-4-methylene-1-(1 methylethyl)bicycle[3.1.0]hexane), four monoterpenes typically emitted into the atmosphere, were studied at the B3LYP/6-31+G(2d,2p) level of theory. The rate coefficients were calculated on the basis of the variational transition state theory for two kinetic models, in order to investigate the reaction mechanism: first assuming a direct bimolecular reaction and the second, assuming the formation of a prebarrier-complex, which further reacts forming the corresponding molozonide. The barrier heights leading to the formation of exo-conformers of the molozonides of alpha-pinene and camphene are lower than the barrier heights for the formation of the endo-conformers of these molozonides, whereas the inverse trend is observed for beta-pinene and sabinene. The canonical variational rate coefficients are found in reasonable agreement with the experimental data, especially when the prebarrier complexes are considered. Microcanonical variational rate coefficients are also calculated, as a final validation test, being found in an expected agreement with the canonical rate coefficients. The best predictions for the rate coefficients at 298 K, based on the microcanonical variational method, for alpha-pinene, beta-pinene, camphene, and sabine are (in units cm(3) molecule(-1) s(-1)): 6.92 * 10(-17), 1.06 * 10(-17), 4.61 * 10(-19), and 4.81 * 10(-17), respectively. Our results suggest that the prebarrier complex is an important specie in the ozone addition mechanism and should be taken into account for the proper description of the overall kinetics. PMID- 25734377 TI - Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) and Ligand Choreography: Newcomers Take the Stage. AB - Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor gamma (PPARgamma) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARgamma agonists, consisting of PPARgamma Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARgamma ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARgamma ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARgamma-mediated antidiabetic drugs. PMID- 25734379 TI - Unveiling surface redox charge storage of interacting two-dimensional heteronanosheets in hierarchical architectures. AB - Two-dimensional (2D) heteronanosheets are currently the focus of intense study due to the unique properties that emerge from the interplay between two low dimensional nanomaterials with different properties. However, the properties and new phenomena based on the two 2D heteronanosheets interacting in a 3D hierarchical architecture have yet to be explored. Here, we unveil the surface redox charge storage mechanism of surface-exposed WS2 nanosheets assembled in a 3D hierarchical heterostructure using in situ synchrotron X-ray absorption and Raman spectroscopic methods. The surface dominating redox charge storage of WS2 is manifested in a highly reversible and ultrafast capacitive fashion due to the interaction of heteronanosheets and the 3D connectivity of the hierarchical structure. In contrast, compositionally identical 2D WS2 structures fail to provide a fast and high capacitance with different modes of lattice vibration. The distinctive surface capacitive behavior of 3D hierarchically structured heteronanosheets is associated with rapid proton accommodation into the in-plane W-S lattice (with the softening of the E2g bands), the reversible redox transition of the surface-exposed intralayers residing in the electrochemically active 1T phase of WS2 (with the reversible change in the interatomic distance and peak intensity of W-W bonds), and the change in the oxidation state during the proton insertion/deinsertion process. This proposed mechanism agrees with the dramatic improvement in the capacitive performance of the two heteronanosheets coupled in the hierarchical structure. PMID- 25734378 TI - Epigenetic Mechanisms of Serotonin Signaling. AB - Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression. PMID- 25734380 TI - The relative length of the patient and the primary care interval in patients with 28 common and rarer cancers. AB - BACKGROUND: Appreciating variation in the length of pre- or post-presentation diagnostic intervals can help prioritise early diagnosis interventions with either a community or a primary care focus. METHODS: We analysed data from the first English National Audit of Cancer Diagnosis in Primary Care on 10 953 patients with any of 28 cancers. We calculated summary statistics for the length of the patient and the primary care interval and their ratio, by cancer site. RESULTS: Interval lengths varied greatly by cancer. Laryngeal and oropharyngeal cancers had the longest median patient intervals, whereas renal and bladder cancer had the shortest (34.5 and 30 compared with 3 and 2 days, respectively). Multiple myeloma and gallbladder cancer had the longest median primary care intervals, and melanoma and breast cancer had the shortest (20.5 and 20 compared with 0 and 0 days, respectively). Mean patient intervals were longer than primary care intervals for most (18 of 28) cancers, and notably so (two- to five-fold greater) for 10 cancers (breast, melanoma, testicular, vulval, cervical, endometrial, oropharyngeal, laryngeal, ovarian and thyroid). CONCLUSIONS: The findings support the continuing development and evaluation of public health interventions aimed at shortening patient intervals, particularly for cancers with long patient interval and/or high patient interval over primary care interval ratio. PMID- 25734381 TI - Assessing the impact of an English national initiative for early cancer diagnosis in primary care. AB - BACKGROUND: The Cancer Networks Supporting Primary Care programme was a National Health Service (NHS) initiative in England between 2011 and 2013 that aimed to better understand and improve referral practices for suspected cancer. METHODS: A mixed methods evaluation using semi-structured interviews with purposefully sampled key stakeholders and an analysis of Cancer Waiting Times and Hospital Episode Statistics data for all 8179 practices in England were undertaken. We compared periods before (2009/10) and at the end (2012/13) of the initiative for practices taking up any one of four specified quality improvement initiatives expected to change referral practice in the short to medium term and those that did not. RESULTS: Overall, 38% of general practices were involved in at least one of four quality improvement activities (clinical audit, significant event analysis, use of risk assessment tools and development of practice plans). Against an overall 29% increase in urgent cancer referrals between 2009/10 and 2012/13, these practices had a significantly higher increase in referral rate, with reduced between-practice variation. There were no significant differences between the two groups in conversion, detection or emergency presentation rates. Key features of successful implementation at practice and network level reported by participants included leadership, organisational culture and physician involvement. Concurrent health service reforms created organisational uncertainty and limited the programme's effectiveness. CONCLUSIONS: Specific primary care initiatives promoted by cancer networks had an additional and positive impact on urgent referrals for suspected cancer. Successful engagement with the programmes depended on effective and well-supported leadership by cancer networks and their general practitioner (GP) leads. PMID- 25734383 TI - The impact of national cancer awareness campaigns for bowel and lung cancer symptoms on sociodemographic inequalities in immediate key symptom awareness and GP attendances. AB - BACKGROUND: National campaigns focusing on key symptoms of bowel and lung cancer ran in England in 2012, targeting men and women over the age of 50 years, from lower socioeconomic groups. METHODS: Data from awareness surveys undertaken with samples of the target audience (n=1245/1140 pre-/post-bowel campaign and n=1412/1246 pre-/post-lung campaign) and Read-code data extracted from a selection general practitioner (GP) practices (n=355 for bowel and n=486 for lung) were analysed by population subgroups. RESULTS: Unprompted symptom awareness: There were no significant differences in the magnitude of shift in ABC1 vs C2DE groups for either campaign. For the bowel campaign, there was a significantly greater increase in awareness of blood in stools in the age group 75+ years compared with the 55-74 age group, and of looser stools in men compared with women. Prompted symptom awareness: Endorsement of 'blood in poo' remained stable, overall and across different population subgroups. Men showed a significantly greater increase in endorsement of 'looser poo' as a definite warning sign of bowel cancer than women. There were no significant differences across subgroups in endorsement of a 3-week cough as a definite warning sign of lung cancer. GP attendances: Overall, there were significant increases in attendances for symptoms directly linked to the campaigns, with the largest percentage increase seen in the 50-59 age group. For the bowel campaign, the increase was significantly greater for men and for practices in the most-deprived quintile, whereas for lung the increase was significantly greater for practices in the least-deprived quintile. CONCLUSIONS: The national bowel and lung campaigns reached their target audience and have also influenced younger and more affluent groups. Differences in impact within the target audience were also seen. There would seem to be no unduly concerning widening in inequalities, but further analyses of the equality of impact across population subgroups is warranted. PMID- 25734384 TI - Preliminary results of a feasibility study of the use of information technology for identification of suspected colorectal cancer in primary care: the CREDIBLE study. AB - BACKGROUND: We report the findings of a feasibility study using information technology to search electronic primary care records and to identify patients with possible colorectal cancer. METHODS: An algorithm to flag up patients meeting National Institute for Health and Care Excellence (NICE) urgent referral criteria for suspected colorectal cancer was developed and incorporated into clinical audit software. This periodically flagged up such patients aged 60 to 79 years. General practitioners (GPs) reviewed flagged-up patients and decided on further clinical management. We report the numbers of patients identified and the numbers that GPs judged to need further review, investigations or referral to secondary care and the final diagnoses. RESULTS: Between January 2012 and March 2014, 19,580 records of patients aged 60 to 79 years were searched in 20 UK general practices, flagging up 809 patients who met urgent referral criteria. The majority of the patients had microcytic anaemia (236 (29%)) or rectal bleeding (205 (25%)). A total of 274 (34%) patients needed further clinical review of their records; 199 (73%) of these were invited for GP consultation, and 116 attended, of whom 42 were referred to secondary care. Colon cancer was diagnosed in 10 out of 809 (1.2%) flagged-up patients and polyps in a further 28 out of 809 (3.5%). CONCLUSIONS: It is technically possible to identify patients with colorectal cancer by searching electronic patient records. PMID- 25734382 TI - Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review. AB - BACKGROUND: It is unclear whether more timely cancer diagnosis brings favourable outcomes, with much of the previous evidence, in some cancers, being equivocal. We set out to determine whether there is an association between time to diagnosis, treatment and clinical outcomes, across all cancers for symptomatic presentations. METHODS: Systematic review of the literature and narrative synthesis. RESULTS: We included 177 articles reporting 209 studies. These studies varied in study design, the time intervals assessed and the outcomes reported. Study quality was variable, with a small number of higher-quality studies. Heterogeneity precluded definitive findings. The cancers with more reports of an association between shorter times to diagnosis and more favourable outcomes were breast, colorectal, head and neck, testicular and melanoma. CONCLUSIONS: This is the first review encompassing many cancer types, and we have demonstrated those cancers in which more evidence of an association between shorter times to diagnosis and more favourable outcomes exists, and where it is lacking. We believe that it is reasonable to assume that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers. PMID- 25734385 TI - Applying symptom appraisal models to understand sociodemographic differences in responses to possible cancer symptoms: a research agenda. AB - BACKGROUND: Sociodemographic inequalities in the stage of diagnosis and cancer survival may be partly due to differences in the appraisal interval (time from noticing a bodily change to perceiving a reason to discuss symptoms with a health care professional). A number of symptom appraisal models have been developed describing the psychological factors that underlie how people make sense of symptoms, although none explicitly focus on sociodemographic characteristics. METHODS: We therefore conducted a conceptual review synthesising all symptom appraisal models, and focus on potential links with sociodemographics that could be the focus of future research. RESULTS: Common psychological elements across nine symptom appraisal models included knowledge, attention, expectation and identity, all of which could be sensitive to sociodemographic factors. For example, lower socioeconomic status (SES), male sex and older age are associated with lower health literacy generally and lower cancer symptom knowledge. Limited attentional resources, lower expectations about health and lack of social support also hamper symptom interpretation, and would be likely to be more prevalent in those from lower SES backgrounds. Symptom heuristics ('rules of thumb') may lead to symptoms being normalised because they are common within the social network, potentially disadvantaging older populations. CONCLUSIONS: A better understanding of the processes through which people interpret their symptoms, and the way these processes differ by sociodemographic factors, could help guide the development of interventions with the aim of reducing inequalities in cancer outcomes. PMID- 25734386 TI - Change in public awareness of symptoms and perceived barriers to seeing a doctor following Be Clear on Cancer campaigns in England. AB - BACKGROUND: English Be Clear on Cancer (BCOC) campaigns aim to promote early presentation of potential cancer symptoms by (i) giving information on symptoms to look out for, and (ii) emphasising the approachability of the general practitioner (GP). This study examined public awareness of the targeted symptoms and perceived approachability of the GP before and after the national bowel and lung campaigns. METHODS: The Cancer Research UK Cancer Awareness Measure (CAM) was included in the Opinions and Lifestyle survey (known then as the 'Opinions Survey') run by the Office for National Statistics in October and November 2010 and 2012. Change in awareness of symptoms and barriers to help-seeking related to those targeted in the campaigns between the 2010 and 2012 surveys, was compared with change in awareness of symptoms and barriers not targeted by the campaigns. RESULTS: Recall of 'persistent cough' or 'hoarseness' as a sign of cancer increased from 18% in 2010 to 26% in 2012 (P<0.001), and 'change in bowel/bladder habits' increased from 21% to 43% (P<0.01). Recognition of these symptoms (from a list of symptoms) also increased significantly (both P-values <0.01). Awareness of non-targeted symptoms did not increase (all P-values >0.02). Barriers to visiting the GP targeted in the campaign (the doctor would be difficult to talk to and being worried about wasting the doctor's time) did not change, although several non-targeted barriers reduced. CONCLUSIONS: BCOC campaigns run in England in 2012 were associated with increased public awareness of some key symptoms of lung and bowel cancer. Barriers to visiting the GP that were targeted in the campaign were not reduced, indicating that a different approach may be needed to shift public attitudes towards GPs. PMID- 25734387 TI - A differentiated approach to referrals from general practice to support early cancer diagnosis - the Danish three-legged strategy. AB - When aiming to provide more expedited cancer diagnosis and treatment of cancer at an earlier stage, it is important to take into account the symptom epidemiology throughout the pathway, from first bodily sensation until the start of cancer treatment. This has implications for how primary-care providers interpret the presentation and decisions around patient management and investigation. Symptom epidemiology has consequences for how the health-care system might best be organised. This paper argues for and describes the organisation of the Danish three-legged strategy in diagnosing cancer, which includes urgent referral pathways for symptoms suspicious of a specific cancer, urgent referral to diagnostic centres when we need quick and profound evaluation of patients with nonspecific, serious symptoms and finally easy and fast access to 'No-Yes Clinics' for cancer investigations for those patients with common symptoms in whom the diagnosis of cancer should not be missed. The organisation of the health care system must reflect the reality of symptoms presented in primary care. The organisational change is evaluated and monitored with a comprehensive research agenda, data infrastructure and education. PMID- 25734388 TI - Cancer detection in primary care: insights from general practitioners. AB - BACKGROUND: General practitioners (GPs) have a key role in cancer detection as the usual first point of contact for patients with potential cancer symptoms. Nevertheless, there is limited work that investigates their perceptions of their role in the early detection of cancer. To address this gap, we aimed to gain an in-depth understanding of cancer diagnosis from the perspective of GPs. METHODS: Individual face-to-face semi-structured interviews were conducted with 55 GPs from the North and North East of England and Greater London. All interviews were recorded and professionally transcribed verbatim. Repeated reading and co-coding engendered systematic thematic analysis across the interview material. RESULTS: Three main themes emerged from the analysis of our data. First, we identified the burden of early cancer detection in general practice, both related to the anxiety and symptoms patients bring to GPs and the need for GPs to recognise patterns of cancer symptoms and refer appropriately; second, this burden is intensified by a perceived fragmentation of services within the National Health Service (NHS); and third, it is made more complex by the interface between general practice and public health. CONCLUSIONS: GPs occupy a challenging but pivotal role in cancer detection. It is crucial that this role be supported by policy and research. PMID- 25734389 TI - Stage at diagnosis and early mortality from cancer in England. AB - BACKGROUND: Stage at diagnosis is a key predictor of overall cancer outcome. For the first time, stage completeness is high enough for robust analysis for the whole of England. METHODS: We analysed data from the National Cancer Registration Service's (NCRS) Cancer Analysis System on persons diagnosed with breast, colorectal, lung, prostate or ovarian cancers in England in 2012. One-year relative survival (followed-up to the end of 2013) was calculated along with adjusted excess rate ratios, for mortality within 1 year. RESULTS: One-year relative survival decreased with increasing stage at diagnosis. For breast, prostate and colorectal cancers survival showed a major reduction for stage 4 cancers, whereas for lung and ovarian cancers there were substantial decreases in relative survival for each level of increase in stage. Excess rate ratios for mortality within 1 year of diagnosis showed that stage and age were the most important cofactors, but they also identified the statistically significant effects of sex, income deprivation and geographic area of residence. CONCLUSIONS: Further reductions in mortality may be most effectively achieved by diagnosing all cancers before they progress to stage 4, but for lung and ovarian cancers there is also a need for a stage shift to earlier stages together with efforts to improve stage-specific survival at all stages. PMID- 25734390 TI - Estimating the potential survival gains by eliminating socioeconomic and sex inequalities in stage at diagnosis of melanoma. AB - BACKGROUND: Although inequalities in cancer survival are thought to reflect inequalities in stage at diagnosis, little evidence exists about the size of potential survival gains from eliminating inequalities in stage at diagnosis. METHODS: We used data on patients diagnosed with malignant melanoma in the East of England (2006-2010) to estimate the number of deaths that could be postponed by completely eliminating socioeconomic and sex differences in stage at diagnosis after fitting a flexible parametric excess mortality model. RESULTS: Stage was a strong predictor of survival. There were pronounced socioeconomic and sex inequalities in the proportion of patients diagnosed at stages III-IV (12 and 8% for least deprived men and women and 25 and 18% for most deprived men and women, respectively). For an annual cohort of 1025 incident cases in the East of England, eliminating sex and deprivation differences in stage at diagnosis would postpone approximately 24 deaths to beyond 5 years from diagnosis. Using appropriate weighting, the equivalent estimate for England would be around 215 deaths, representing 11% of all deaths observed within 5 years from diagnosis in this population. CONCLUSIONS: Reducing socioeconomic and sex inequalities in stage at diagnosis would result in substantial reductions in deaths within 5 years of a melanoma diagnosis. PMID- 25734391 TI - Diagnosing cancer earlier: reviewing the evidence for improving cancer survival. PMID- 25734392 TI - Implementing a QCancer risk tool into general practice consultations: an exploratory study using simulated consultations with Australian general practitioners. AB - BACKGROUND: Reducing diagnostic delays in primary care by improving the assessment of symptoms associated with cancer could have significant impacts on cancer outcomes. Symptom risk assessment tools could improve the diagnostic assessment of patients with symptoms suggestive of cancer in primary care. We aimed to explore the use of a cancer risk tool, which implements the QCancer model, in consultations and its potential impact on clinical decision making. METHODS: We implemented an exploratory 'action design' method with 15 general practitioners (GPs) from Victoria, Australia. General practitioners applied the risk tool in simulated consultations, conducted semi-structured interviews based on the normalisation process theory and explored issues relating to implementation of the tool. RESULTS: The risk tool was perceived as being potentially useful for patients with complex histories. More experienced GPs were distrustful of the risk output, especially when it conflicted with their clinical judgement. Variable interpretation of symptoms meant that there was significant variation in risk assessment. When a risk output was high, GPs were confronted with numerical risk outputs creating challenges in consultation. CONCLUSIONS: Significant barriers to implementing electronic cancer risk assessment tools in consultation could limit their uptake. These relate not only to the design and integration of the tool but also to variation in interpretation of clinical histories, and therefore variable risk outputs and strong beliefs in personal clinical intuition. PMID- 25734393 TI - Understanding missed opportunities for more timely diagnosis of cancer in symptomatic patients after presentation. AB - The diagnosis of cancer is a complex, multi-step process. In this paper, we highlight factors involved in missed opportunities to diagnose cancer more promptly in symptomatic patients and discuss responsible mechanisms and potential strategies to shorten intervals from presentation to diagnosis. Missed opportunities are instances in which post-hoc judgement indicates that alternative decisions or actions could have led to more timely diagnosis. They can occur in any of the three phases of the diagnostic process (initial diagnostic assessment; diagnostic test performance and interpretation; and diagnostic follow-up and coordination) and can involve patient, doctor/care team, and health-care system factors, often in combination. In this perspective article, we consider epidemiological 'signals' suggestive of missed opportunities and draw on evidence from retrospective case reviews of cancer patient cohorts to summarise factors that contribute to missed opportunities. Multi-disciplinary research targeting such factors is important to shorten diagnostic intervals post presentation. Insights from the fields of organisational and cognitive psychology, human factors science and informatics can be extremely valuable in this emerging research agenda. We provide a conceptual foundation for the development of future interventions to minimise the occurrence of missed opportunities in cancer diagnosis, enriching current approaches that chiefly focus on clinical decision support or on widening access to investigations. PMID- 25734394 TI - The impact of eliminating age inequalities in stage at diagnosis on breast cancer survival for older women. AB - BACKGROUND: Older women with breast cancer have poorer relative survival outcomes, but whether achieving earlier stage at diagnosis would translate to substantial reductions in mortality is uncertain. METHODS: We analysed data on East of England women with breast cancer (2006-2010) aged 70+ years. We estimated survival for different stage-deprivation-age group strata using both the observed and a hypothetical stage distribution (assuming that all women aged 75+ years acquired the stage distribution of those aged 70-74 years). We subsequently estimated deaths that could be postponed beyond 5 years from diagnosis if women aged 75+ years had the hypothetical stage distribution. We projected findings to the English population using appropriate age and socioeconomic group weights. RESULTS: For a typically sized annual cohort in the East of England, 27 deaths in women with breast cancer aged 75+ years can be postponed within 5 years from diagnosis if their stage distribution matched that of the women aged 70-74 years (4.8% of all 566 deaths within 5 years post diagnosis in this population). Under assumptions, we estimate that the respective number for England would be 280 deaths (5.0% of all deaths within 5 years post diagnosis in this population). CONCLUSIONS: The findings support ongoing development of targeted campaigns aimed at encouraging prompt presentation in older women. PMID- 25734395 TI - The role of primary care in cancer diagnosis via emergency presentation: qualitative synthesis of significant event reports. AB - BACKGROUND: Patients diagnosed with cancer in the context of an emergency presentation (EP) have poorer outcomes. It is often assumed that such patients present to the emergency department without consulting their general practitioner (GP). Little work has been done to identify primary care involvement before hospital attendance. METHODS: Participating primary care practices completed a significant event audit (SEA) report for the last patient diagnosed with cancer as a result of an EP. Accounts were synthesised and a qualitative approach to analysis undertaken. RESULTS: SEAs for 222 patients were analysed. A range of cancers were included, the most common being lung (32.4%) and upper gastrointestinal (19.8%). In most cases, patients had contact with their practice before diagnosis, primarily in the period immediately before admission. In only eight cases had there been no input from primary care. Accounts of protracted primary care contact generally demonstrated complexity, often related to comorbidity, patient-mediated factors or reassurance provided by negative investigations. Learning points identified by practices centred on the themes of presentation and diagnosis, consultation and safety-netting, communication and system issues, patient factors and referral guidelines. CONCLUSIONS: There is extensive primary care input into patients whose diagnosis results from EP, and for the most part potential 'delay' in referral can be reasonably explained by the complexity of the presentation or by coexisting patient factors. PMID- 25734396 TI - Cancer-specific variation in emergency presentation by sex, age and deprivation across 27 common and rarer cancers. AB - BACKGROUND: Although overall sociodemographic and cancer site variation in the risk of cancer diagnosis through emergency presentation has been previously described, relatively little is known about how this risk may vary differentially by sex, age and deprivation group between patients with a given cancer. METHODS: Data from the Routes to Diagnosis project on 749,645 patients (2006-2010) with any of 27 cancers that can occur in either sex were analysed. Crude proportions and crude and adjusted odds ratios were calculated for emergency presentation, and interactions between sex, age and deprivation with cancer were examined. RESULTS: The overall proportion of patients diagnosed through emergency presentation varied greatly by cancer. Compared with men, women were at greater risk for emergency presentation for bladder, brain, rectal, liver, stomach, colon and lung cancer (e.g., bladder cancer-specific odds ratio for women vs men, 1.50; 95% CI 1.39-1.60), whereas the opposite was true for oral/oropharyngeal cancer, lymphomas and melanoma (e.g., oropharyngeal cancer-specific odds ratio for women vs men, 0.49; 95% CI 0.32-0.73). Similarly, younger patients were at higher risk for emergency presentation for acute leukaemia, colon, stomach and oesophageal cancer (e.g., colon cancer-specific odds ratio in 35-44- vs 65-74-year-olds, 2.01; 95% CI 1.76-2.30) and older patients for laryngeal, melanoma, thyroid, oral and Hodgkin's lymphoma (e.g., melanoma specific odds ratio in 35-44- vs 65-74 year-olds, 0.20; 95% CI 0.12-0.33). Inequalities in the risk of emergency presentation by deprivation group were greatest for oral/oropharyngeal, anal, laryngeal and small intestine cancers. CONCLUSIONS: Among patients with the same cancer, the risk for emergency presentation varies notably by sex, age and deprivation group. The findings suggest that, beyond tumour biology, diagnosis through an emergency route may be associated both with psychosocial processes, which can delay seeking of medical help, and with difficulties in suspecting the diagnosis of cancer after presentation. PMID- 25734397 TI - Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a prospective cohort study. AB - BACKGROUND: This prospective cohort study aimed to identify symptom and patient factors that influence time to lung cancer diagnosis and stage at diagnosis. METHODS: Data relating to symptoms were collected from patients upon referral with symptoms suspicious of lung cancer in two English regions; we also examined primary care and hospital records for diagnostic routes and diagnoses. Descriptive and regression analyses were used to investigate associations between symptoms and patient factors with diagnostic intervals and stage. RESULTS: Among 963 participants, 15.9% were diagnosed with primary lung cancer, 5.9% with other thoracic malignancies and 78.2% with non-malignant conditions. Only half the cohort had an isolated first symptom (475, 49.3%); synchronous first symptoms were common. Haemoptysis, reported by 21.6% of cases, was the only initial symptom associated with cancer. Diagnostic intervals were shorter for cancer than non-cancer diagnoses (91 vs 124 days, P=0.037) and for late-stage than early stage cancer (106 vs 168 days, P=0.02). Chest/shoulder pain was the only first symptom with a shorter diagnostic interval for cancer compared with non-cancer diagnoses (P=0.003). CONCLUSIONS: Haemoptysis is the strongest symptom predictor of lung cancer but occurs in only a fifth of patients. Programmes for expediting earlier diagnosis need to focus on multiple symptoms and their evolution. PMID- 25734398 TI - Reliability and validity of instrumented soccer equipment. AB - Ankle ligament sprains are the most common injury in soccer. The high rate of these injuries demonstrates a need for novel data collection methodologies. Therefore, soccer shoes and shin guards were instrumented with inertial sensors to measure ankle joint kinematics in the field. The purpose of this study was to assess test-retest reliability and concurrent criterion validity of a kinematic assessment using the instrumented soccer equipment. Twelve soccer athletes performed athletic maneuvers in the laboratory and field during 2 sessions. In the laboratory, ankle joint kinematics were simultaneously measured with the instrumented equipment and a conventional motion analysis system. Reliability was assessed using ICC and validity was assessed using correlation coefficients and RMSE. While our design criteria of good test-retest reliability was not supported (ICC > .80), sagittal plane ICCs were mostly fair to good and similar to motion analysis results; and sagittal plane data were valid (r = .90-98; RMSE < 5 degrees ). Frontal and transverse plane data were not valid (r < .562; RMSE > 3 degrees ). Our results indicate that the instrumented soccer equipment can be used to measure sagittal plane ankle joint kinematics. Biomechanical studies support the utility of sagittal plane measures for lower extremity injury prevention. PMID- 25734399 TI - [Preventive vaccinations in dentistry]. AB - The purpose of this current paper is to give a simple update and overview about vaccinations for dental health care workers considering the new guidelines published in February 2014 by the Swiss Federal Office of Public Health. It is recommended to have at least a valid protection against hepatitis B, measles, mumps, rubella, influenza, varicella, diphtheria, tetanus, poliomyelitis and pertussis. Dental health care workers are highly exposed and high risk carriers for inoculable diseases, therefore regular refreshment of vaccinations is necessary for public health and their own health. PMID- 25734400 TI - Photophysical properties and synthesis of new dye-cyclooctyne conjugates for multicolor and advanced microscopy. AB - Cyclooctyne conjugates with fluorophores are often used for bioorthogonal labeling in cells and tissues. However, no comprehensive library of one cyclooctyne core structure with different fluorescent dyes spanning the whole visible spectrum up to the NIR had been described so far. Hence, we synthesized and evaluated one cyclooctyne core structure which is easily accessible for the attachment of different dyes for multicolor imaging, FRET analysis, and study of metabolism in vivo. For these reasons we developed an easy one step synthesis starting from a known cyclooctyne. In combination with NHS-activated dyes, the cyclooctyne reacted to the dye DAB-MFCO conjugates within only 1-2 h at room temperature with high yields. We created conjugates with dyes that have high brightness and are bleaching stable with wavelengths from green to NIR. The ability to label glycans on cell surfaces was tested. All dye DAB-MFCO conjugates undergo click reactions on azide functionalized glycan structures with satisfactory photophysical properties. In total, seven different dye DAB-MFCO conjugates were synthesized; their photophysical properties and suitability for click labeling in biological applications were evaluated, making them suitable for single molecule and high resolution measurements. PMID- 25734401 TI - Pudendal nerve injury in men with fecal incontinence after radiotherapy for prostate cancer. AB - BACKGROUND: The precise etiology of fecal incontinence (FI), which occurs frequently following external beam radiotherapy (EBRT) for prostate carcinoma is unknown. It is possibly related to pelvic nerve injury. The aim of this study was to assess the incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared to men with FI but no history of EBRT. MATERIAL AND METHODS: Data were evaluated from 74 men with intact anal sphincters on endo-anal ultrasound (17 post-EBRT) who had been investigated for FI at a tertiary center. Wexner incontinence scores, pudendal nerve function, anorectal manometry, and rectal sensitivity were compared between the two patient groups. RESULTS: Post radiotherapy patients were older (77+/-6 vs. 62+/-17 years, p<0.005) and had worse incontinence than those with no history of radiotherapy (Wexner score; 13+/ 3 vs. 8+/-4; p<0.005). Bilateral pudendal nerve terminal motor latency (PNTML) was abnormal in 87% of radiotherapy versus 22% of non-radiotherapy patients (p<0.001) and the significant difference persisted even after correction for age differences. Anal sphincter pressures and rectal sensitivity for both groups were similar. CONCLUSION: There is a markedly higher incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared with men with FI from other etiologies. The increased severity of incontinence in radiotherapy patients is not matched by alterations in either anal sphincter pressures or rectal sensitivity compared to FI in non-ERBT patients. PMID- 25734402 TI - State medical licensure for telemedicine and teleradiology. AB - Physician medical licensure is state based for historical and constitutional reasons. It may also provide the best method for guaranteeing patient protection from unqualified, incompetent, impaired, or unprofessional practitioners of medicine. However, a significant cost for physicians practicing telemedicine is having to obtain multiple state medical licenses. There is reasonable likelihood that model legislation for the practice of telemedicine across state boundaries will be passed in the next few years, providing physicians with a simpler process for license reciprocity in multiple states via interstate licensing compacts. Physicians would have to be licensed in the state in which the patient resides. Patient complaints would still be adjudicated by the medical licensing board in the state where the patient resides according applicable state legislation. PMID- 25734403 TI - Synthesis and characterization of [Fe(BPMEN)ACC]SbF6: a structural and functional mimic of ACC-oxidase. AB - A mononuclear Fe(II) complex bearing 1-aminocyclopropane-1-carboxylic acid (ACCH) was synthesized and characterized. X-ray crystallography demonstrated that ACC binds to the Fe(II) ion in a bidentate mode constituting the first structural mimic of the expected binding of ACC to the Fe(II) center of the ethylene forming enzyme ACC-oxidase (ACCO). [Fe(BPMEN)ACC]SbF6 also constitutes a functional biomimetic complex of ACCO, as it reacts with hydrogen peroxide producing ethylene. PMID- 25734404 TI - CO2 separation, capture and reuse: a web themed issue. PMID- 25734405 TI - Second derivative multispectral algorithm for quantitative assessment of cutaneous tissue oxygenation. AB - We report a second derivative multispectral algorithm for quantitative assessment of cutaneous tissue oxygen saturation (StO2). The algorithm is based on a forward model of light transport in multilayered skin tissue and an inverse algorithm for StO2 reconstruction. Based on the forward simulation results, a parameter of a second derivative ratio (SDR) is derived as a function of cutaneous tissue StO2. The SDR function is optimized at a wavelength set of 544, 552, 568, 576, 592, and 600 nm so that cutaneous tissue StO2 can be derived with minimal artifacts by blood concentration, tissue scattering, and melanin concentration. The proposed multispectral StO2 imaging algorithm is verified in both benchtop and in vivo experiments. The experimental results show that the proposed multispectral imaging algorithm is able to map cutaneous tissue StO2 in high temporal resolution with reduced measurement artifacts induced by different skin conditions in comparison with other three commercial tissue oxygen measurement systems. These results indicate that the multispectral StO2 imaging technique has the potential for noninvasive and quantitative assessment of skin tissue oxygenation with a high temporal resolution. PMID- 25734406 TI - Transurethral light delivery for prostate photoacoustic imaging. AB - Photoacoustic imaging has broad clinical potential to enhance prostate cancer detection and treatment, yet it is challenged by the lack of minimally invasive, deeply penetrating light delivery methods that provide sufficient visualization of targets (e.g., tumors, contrast agents, brachytherapy seeds). We constructed a side-firing fiber prototype for transurethral photoacoustic imaging of prostates with a dual-array (linear and curvilinear) transrectal ultrasound probe. A method to calculate the surface area and, thereby, estimate the laser fluence at this fiber tip was derived, validated, applied to various design parameters, and used as an input to three-dimensional Monte Carlo simulations. Brachytherapy seeds implanted in phantom, ex vivo, and in vivo canine prostates at radial distances of 5 to 30 mm from the urethra were imaged with the fiber prototype transmitting 1064 nm wavelength light with 2 to 8 mJ pulse energy. Prebeamformed images were displayed in real time at a rate of 3 to 5 frames per second to guide fiber placement and beamformed offline. A conventional delay-and-sum beamformer provided decreasing seed contrast (23 to 9 dB) with increasing urethra-to-target distance, while the short-lag spatial coherence beamformer provided improved and relatively constant seed contrast (28 to 32 dB) regardless of distance, thus improving multitarget visualization in single and combined curvilinear images acquired with the fiber rotating and the probe fixed. The proposed light delivery and beamforming methods promise to improve key prostate cancer detection and treatment strategies. PMID- 25734407 TI - Evaluation of Clinical and Pathologic Risk Factors May Reduce the Rate of Multimodality Treatment of Early Cervical Cancer. AB - OBJECTIVE: To assess the rate of postoperative adjuvant treatment in patients who underwent radical hysterectomy for early cervical cancer and to suggest criteria for the triage of patients who have a high probability of multimodality treatment. METHODS: This was a multicenter retrospective study of 514 patients with FIGO stages IA2-IIA cervical cancer who underwent radical hysterectomy between 1999 and 2010. The patients were divided into 2 groups according to whether or not postoperative radiation was administered. The 2 groups were compared with regard to clinical and histopathologic variables divided into major and minor criteria (intermediate risk factors) based on lymph nodes status, parametrial involvement, tumor size, deep stromal invasion, and lymph-vascular space invasion. RESULTS: We identified 294 (57.2%) patients who received adjuvant postoperative radiotherapy (RT) or chemoradiation. Fifty-three percent of these patients who were treated by adjuvant radiation had only intermediate risk factors. Combining the various combinations of 2 out of 3 of the following criteria, we found that 89% of patients with tumors >=2 cm and lymph-vascular space invasion received RT, 76% of patients with tumors >=2 cm and depth of invasion >10 mm received RT, and 87% of patients with tumors depth of invasion >10 mm and lymph-vascular space invasion received RT. CONCLUSIONS: This study suggests that in patients with early cervical cancer, clinicopathologic evaluation of tumor size and lymph-vascular space invasion should be undertaken before performing radical hysterectomy. This approach can serve to tailor treatment, reducing the rate of employing both radical hysterectomy and chemoradiation. PMID- 25734409 TI - Can Ultrasound Performed in Prolonged Second Stage of Labor Predict the Difficulty and Success Rates of Operative Vaginal Delivery? AB - OBJECTIVE: To evaluate different sonographic methods for the prediction of the difficulty and the success of operative vaginal delivery (OPD). MATERIALS AND METHODS: A prospective study was performed on 45 term singleton uncomplicated pregnancies with prolonged 2nd stage of delivery with cephalic presentation. Measurements of the fetal head, relations between the fetal head and maternal pelvic parameters during rest and during maternal pushing were taken using translabial ultrasound. RESULTS: 29 cases of OPD were successful and 4 cases failed ending in cesarean section. The passage of the biparietal diameter (BPD) of the infrapubic line (IPL) was statistically correlated with the success of OPD. Head station, passage of the BPD of the IPL, percentage of head after the IPL, circumference of head after IPL were all correlated with the difficulty of OPD. When the distance between the widest diameter of the head and the IPL is < 1.2 cm, there is a 90 % probability of success of OPD. When that distance is > 3.3 cm, there is 90 % probability of cesarean section. When the percentage of head beyond the IPL was > 54 %, there was 90 % probability of successful OPD. DISCUSSION: Translabial ultrasound is useful in the prediction of the difficulty and the success of OPD. The higher the extent of head that passed the IPL, the less difficult the OPD and the greater the success rate of the OPD. PMID- 25734410 TI - Sonoelastographic Findings of Carpal Tunnel Injection. AB - PURPOSE: The objectives of this study were to compare sonoelastographic color findings of the perineural area between carpal tunnel syndrome patients and healthy volunteers, and to analyze elastographic findings in that area before and immediately after intracarpal tunnel injection in carpal tunnel syndrome patients. MATERIALS AND METHODS: We studied both hands of 15 healthy volunteers (7 men, 8 women; mean age: 60.1 years, range: 41 - 88 years) and 72 hands from 70 patients with symptomatic carpal tunnel syndrome (24 men, 46 women; mean age: 54.2 years, range: 24 - 83 years). Sonoelastographic color distribution was assessed in the perineural area between the median nerve and adjacent flexor tendons. The color elastograms were graded using the following system: Grade 1 as red (softest), grade 2 as yellow (soft), grade 3 as green (hard), grade 4 as blue (hardest). The patients were treated with corticosteroid injection and were reassessed with sonoelastography immediately after the injection. RESULTS: The median color grading in the perineural area of carpal tunnel syndrome patients was grade 3 (3.1 +/- 0.3, mean +/- 95 % Cl), which was stiffer than that of healthy volunteers (grade 1, 1.9 +/- 0.4) (p < 0.0001). Immediately after injection, the diffusion of the injected fluid was observed as having a softer appearance (grade 1, 1.4 +/- 0.2) (p < 0.0001). CONCLUSION: The perineural area surrounding the median nerve in carpal tunnel syndrome patients was stiffer than that in healthy volunteers. Diffusion of the injected fluid in the carpal tunnel was seen as a softer finding after injection in real time using sonoelastography. PMID- 25734412 TI - Four Steps in Diagnosing Complete Agenesis of the Corpus Callosum in Prenatal Life. AB - PURPOSE: Among congenital brain anomalies, complete agenesis of the corpus callosum (cACC) including cases of callosal hypoplasia has a prevalence of 1.8 per 10 000 in the general population. It is also one of the most challenging brain anomalies to detect during the mid-trimester ultrasound scan. Standard axial planes do not provide enough information to make the definitive diagnosis of cACC. MATERIALS AND METHODS: From our library of images and ultrasound reports, we reviewed our most recent cases of complete agenesis of the corpus callosum in the fetus at the mid-trimester scan. In our analysis we included only cases that were confirmed postnatally or by autopsy. Exams were performed between January 2010 and June 2012. All of the patients were scanned transabdominally by means of 2 D and static 3 D. From the 2 D and 3 D images we identified 4 anatomical views that consistently gave us enough information to identify cACC: axial biparietal transthalamic view (AX1); axial biparietal falx view (AX2); coronal transthalamic view (COR); mid-sagittal view (SAG). RESULTS: From our library 30 cases were selected with confirmed cACC postnatally or in autopsy findings. The mean gestational age at the time of referral to our center was 20.7 weeks (range 19 - 23 weeks). In all analyzed cases sufficient 2 D images were found and in 93.3 % of them informative 3 D volumes were also available for off line review. We identified the following patterns of cACC at the mid-trimester scan: A- normal size of 3 rd ventricle + normal size of the lateral ventricles or mild ventriculomegaly; B1- dilated 3 rd ventricle + normal size of the lateral ventricles; B2- dilated 3 rd ventricle + mild or moderate ventriculomegaly; C- dilated 3 rd ventricle + severe ventriculomegaly; D- gross dilatation of 3 rd ventricle with the appearance of interhemispheric cyst. The AX1 view revealed: absence of the cavum septum pellucidi in all cases; dilatation of the third ventricle in 86.6 % of cases; separation of frontal horns in 83.3 % of cases; ventriculomegaly in 73.3 % of cases, including 13.6 % with severe forms. The AX2 view showed separation of the interhemispheric fissure (IHF) in 90 % of cases and upward displacement of the 3 rd ventricle in 80 % of cases. The COR view confirmed separation of the interhemispheric fissure in 90 % of cases including gross separation in 7.4 % of cases; absence of CC fibers at this level and descent of the falx towards the roof of the 3 rd ventricle in all cases, and upward displacement of the 3 rd ventricle in 80 % of cases. The SAG view revealed the absence of the CSP-CC complex in all cases and dilatation of the 3 rd ventricle in 86.6 % of cases. CONCLUSION: 1. We suggest a stepwise ultrasound diagnostic approach for cACC and variations of this condition. 2. We suggest a classification of characteristic patterns found in fetuses with proven cACC based on findings presented in axial views. PMID- 25734411 TI - Cervical Strain Elastography in Pregnancy and Association with Maternal Factors. AB - Purpose To assess cervical elasticity in different regions by sonoelastography, to compare the results to the Bishop score, cervical length, week of pregnancy and other maternal factors (age, weight, parity) and to evaluate the reproducibility of the method. Materials and Methods 131 patients between 17 - 41 gestational weeks were examined by transvaginal cervical strain elastography. In the sagittal view strain values were calculated in 7 regions of interest (ROI; external and internal os anterior/posterior, middle part anterior/posterior, cervical canal). In the cross sectional views strain values in 3 ROIs were evaluated at the level of the internal and external cervical os (anterior/posterior, cervical canal). The intra- and interobserver variance was tested. Results Strain values differed highly significantly in different parts of the cervix (p < 0.001). The anterior parts and the cervical canal were significantly softer with increasing gestational age and Bishop score, and the posterior parts were significantly harder with increasing maternal age, weight, parity. Cervical length showed an inverse relationship to cervical softness. The intra- and interobserver variance was low. Conclusion Elastography is a reproducible method for the evaluation of cervical elasticity in pregnancy. It showed a significant association with the Bishop score and other maternal factors and could provide additional information about changes in cervical stiffness in pregnancy. PMID- 25734413 TI - Elastography Improves the Accuracy of Ultrasound in the Preoperative Assessment of abdominal wall endometriosis. AB - PURPOSE: To assess the role of elastography in preoperative ultrasound assessment of abdominal wall endometriosis (AWE) location. MATERIALS AND METHODS: 33 patients qualified for surgical excision of AWE were included in the study. Preoperative assessment of AWE was performed transabdominally on a Samsung Medison V20 Prestige with a transvaginal probe and Elastoscan(r) option. The following B-mode settings were used: focus set to the lower end of the lesion, gain adjusted to obtain best image quality, tissue harmonic imaging activated. For elastographic examinations the color map from red (soft) to purple (hard) and the alpha blend option (a blend of B-mode and elastographic image) were used. AWE location was first assessed by B-mode ultrasound as: superficial (located in SCT only; SCT visible between the fascia and the lesion; intact fascia), intermediate (located in SCT or in RAM; no subcutaneous or muscle tissue between the lesion and the fascia; fascia infiltrated); or deep (located in RAM; muscle tissue visible between the lesion and the fascia; fascia intact). Then the AWE location was assessed by alphablend elastography as: superficial (hard lesion in soft SCT; soft SCT between the fascia and the lesion; no hard areas on the fascia); intermediate (hard lesion in soft SCT or soft RAM; no soft subcutaneous or muscle tissue between the lesion and the fascia; hard areas on the fascia); or deep (hard lesion located in RAM; soft muscle tissue between the fascia and the lesion; no hard areas on the fascia). These findings were verified during surgery. The surgeons were blinded to the results of elastography. The influence of obesity on the accuracy of ultrasound and elastography in assessing the location of AWE was evaluated. RESULTS: During surgery superficial AWE was found in 6, intermediate in 19 and deep in 8 patients. Preoperative ultrasound assessment was correct in 33.3 % of cases, while adding the elastography option improved the accuracy of AWE location assessment to 87.9 % (p < 0.05). The diagnostic accuracy of ultrasound alone, but not with the elastography option, was significantly decreased in the preoperative assessment of AWE location in overweight and obese patients. 4 patients required implantation of a mesh. In all cases the pathological examination confirmed the diagnosis of AWE. CONCLUSION: Elastography significantly improved the accuracy of ultrasound in evaluating the depth of infiltration of AWE, is not affected by increased BMI, and should be considered in patients qualified for surgical treatment of AWE. PMID- 25734414 TI - Palladium-catalyzed aerobic oxidative dehydrogenation of cyclohexenes to substituted arene derivatives. AB - A palladium(II) catalyst system has been identified for aerobic dehydrogenation of substituted cyclohexenes to the corresponding arene derivatives. Use of sodium anthraquinone-2-sulfonate (AMS) as a cocatalyst enhances the product yields. A wide range of functional groups are tolerated in the reactions, and the scope and limitations of the method are described. The catalytic dehydrogenation of cyclohexenes is showcased in an efficient route to a phthalimide-based TRPA1 activity modulator. PMID- 25734415 TI - Lipid and Metabolite Deregulation in the Breast Tissue of Women Carrying BRCA1 and BRCA2 Genetic Mutations. AB - PURPOSE: To use localized correlated spectroscopy (COSY) to assess for an altered biochemical state or states in breast tissue of women with BRCA gene mutations that potentially constitute preinvasive conditions. MATERIALS AND METHODS: Institutional review board approval was obtained. Participants provided written informed consent. In vivo localized COSY images were recorded at 3 T in the breast tissue of women carrying BRCA1 (n = 9) or BRCA2 (n = 14) gene mutations and were compared with images in healthy control subjects with no family history of breast cancer (n = 10). All participants underwent contrast material-enhanced MR imaging and ultrasonography (US). Statistical significance was calculated with the Mann-Whitney two-sided nonparametric test. RESULTS: No abnormality was recorded with MR imaging or US. Metabolite levels in the BRCA1 cohort were reduced by 79% (P = .014) when compared with triglycerides level, and there was a 19% increase in lipid unsaturation and triglyceride levels (P = .027 and P = .086, respectively) when compared with cellular cholesterol level. Cholesterol level was reduced by 47% (P = .027) when compared with diallylic lipid level. Metabolite levels in the BRCA2 cohort showed increased unsaturation of 21% (P = .030) relative to triglycerides level. Comparison of the BRCA1 and BRCA2 cohorts showed a 47% (P = .002) increase in cholesterol level in the BRCA2 cohort when compared with diallylic lipid level and a 52% (P = .003) increase when compared with triglycerides level. Levels of diallylic lipid, unsaturated lipid, triglycerides, and terminal methyl on the acyl chain are reduced by 46% (P = .002), 57% (P = .003), 66% (P = .003), and 29% (P = .010), respectively, when compared with cholesterol level. CONCLUSION: Localized COSY recorded significant changes in women with BRCA1 and BRCA2 gene mutations when compared with control subjects. If these changes are ultimately proven to be a premalignant stage, this method may prove useful in screening. PMID- 25734416 TI - An overview of immunosuppression in solid organ transplantation. AB - Significant advancements in solid organ transplantation immunosuppressive medications and regimens have resulted in improved outcomes over the years. A multidrug approach involving medications with different mechanisms of action is commonly used. Induction therapy can involve the use of antibody agents or higher doses of medications used for maintenance therapy. A calcineurin inhibitor, an antiproliferative agent, and a corticosteroid commonly serve as the initial triple medication regimen. Due to the potential for nephrotoxicity with the use of calcineurin inhibitors and chronic conditions with the prolonged use of corticosteroids, various withdrawal strategies are used in practice. Antimicrobial agents are prescribed to provide prophylaxis against certain viral, fungal, and bacterial infections. Other concomitant medications in the regimens for patients who have undergone transplantation vary depending on patient specific factors and conditions. PMID- 25734408 TI - Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. AB - RATIONALE: Limited data exist about the international burden of severe sepsis in critically ill children. OBJECTIVES: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. METHODS: A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. MEASUREMENTS AND MAIN RESULTS: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. CONCLUSIONS: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted. PMID- 25734417 TI - Managed care implications of improving long-term outcomes in organ transplantation. AB - Refinements in solid organ transplantation techniques have resulted in improvements in patient and graft survival, and transplants are a cost-effective option for appropriate patients. Lack of improvement in graft survival, despite a reduction in acute rejection episodes, has sparked interest in both newer medications/treatment regimens and strategies to improve outcomes. Even as transplant professionals seek to optimize the therapeutic regimen for each patient, there are steps that managed care can take to further reduce costs and improve patient and graft survival. This review addresses factors that impact graft survival and focuses on the role of managed care clinicians in adherence assessment and improvement as a means to enhance patient and graft outcomes. Improvements in graft and patient survival are expected to preserve and maximize the usefulness of the limited supply of organ and financial-related resources in the United States. PMID- 25734418 TI - Solid organ transplantation overview and delection criteria. AB - The field of solid organ transplantation has seen significant advances in surgical techniques, medical diagnosis, selection process, and pharmacotherapy over the past 6 decades. Despite these advances, however, there remains a significant imbalance between the supply of organs available for transplant and the number of patients registered on transplant waiting lists. Notably, the past decade has shown gradual increases in the number of candidates waiting for a kidney, while the number of transplants performed in the United States has declined every year for the past 3 years. The waiting list for heart transplants has been the most rapidly growing list. Fortunately, policies designed to improve procurement, screening, and distribution are helping to make transplantation more efficient and organs more accessible, allowing sicker patients to undergo transplants more quickly. This article presents an overview of the most common solid organ transplantations performed (kidney, liver, heart, and lung), along with the requirements, risks, and complications associated with them. PMID- 25734419 TI - Anti-tumor activity of a polysaccharide from blueberry. AB - Blueberries (Vaccinium spp.) are rich in bioactive compounds. However, the biological activity of polysaccharides from blueberry has not been reported so far. This study evaluated the anti-tumor and immunological activities of a polysaccharide (BBP3-1) from blueberry in S180-bearing mice. The experimental results indicated that BBP3-1 (100 mg.kg-1.d-1) inhibited the tumor growth rate by 73.4%. Moreover, this group, compared with the model control, had shown an effect of increasing both the spleen and thymus indices (p < 0.05), increasing phagocytosis by macrophages (p < 0.05), boosting the proliferation and transformation of lymphocytes (p < 0.01), promoting the secretion of TNF-alpha, IFN-gamma, and IL-2 (p < 0.05) and improving NK cell activity (p < 0.01). From this study, we could easily conclude that BBP3-1 has the ability to inhibit tumor progression and could act as a good immunomodulator. PMID- 25734420 TI - Impact of dissolved organic matter on bacterial tactic motility, attachment, and transport. AB - Bacterial dispersal is a key driver of the ecology of microbial contaminant degradation in soils. This work investigated the role of dissolved organic matter (DOM) in the motility, attachment, and transport of the soil bacterium Pseudomonas putida G7 in saturated porous media. The study is based on the hypothesis that DOM quality is critical to triggering tactic motility and, consequently, affects bacterial transport and dispersal. Sunflower root exudates, humic acids (HA), and the synthetic oleophilic fertilizer S-200 were used as representatives of fresh, weathered, and artificially processed DOM with high nitrogen and phosphorus contents, respectively. We studied DOM levels of 16-130 mg L(-1), which are representative of DOM concentrations typically found in agricultural soil pore water. In contrast to its responses to HA and S-200, strain G7 exhibited a tactic behavior toward root exudates, as quantified by chemotaxis assays and single-cell motility observations. All DOM types promoted bacterial transport through sand at high concentrations (~ 130 mg L(-1)). At low DOM concentrations (~ 16 mg L(-1)), the enhancement occurred only in the presence of sunflower root exudates, and this enhancement did not occur with G7 bacteria devoid of flagella. Our results suggest that tactic DOM effectors strongly influence bacterial transport and the interception probability of motile bacteria by collector surfaces. PMID- 25734421 TI - Bioinspired porous octacalcium phosphate/silk fibroin composite coating materials prepared by electrochemical deposition. AB - The biomimetic structure and composition of biomaterials are recognized as critical factors that determine their biological performance. A bioinspired nano micro structured octacalcium phosphate (OCP)/silk fibroin (SF) composite coating on titanium was achieved through a mild electrochemically induced deposition method. Findings indicate that SF plays a critical role in constructing the unique biomimetic hierarchical structure of OCP/SF composite coating layers. In vitro cell culture tests demonstrate that the presence of OCP/SF composite coatings, with highly ordered and hierarchically porous structure, greatly enhance cellular responses. The coatings developed in this study have considerable potential for various hard tissue engineering and applications. PMID- 25734422 TI - Role and structural characterization of plant aldehyde dehydrogenases from family 2 and family 7. AB - Aldehyde dehydrogenases (ALDHs) are responsible for oxidation of biogenic aldehyde intermediates as well as for cell detoxification of aldehydes generated during lipid peroxidation. So far, 13 ALDH families have been described in plants. In the present study, we provide a detailed biochemical characterization of plant ALDH2 and ALDH7 families by analysing maize and pea ALDH7 (ZmALDH7 and PsALDH7) and four maize cytosolic ALDH(cALDH)2 isoforms RF2C, RF2D, RF2E and RF2F [the first maize ALDH2 was discovered as a fertility restorer (RF2A)]. We report the crystal structures of ZmALDH7, RF2C and RF2F at high resolution. The ZmALDH7 structure shows that the three conserved residues Glu(120), Arg(300) and Thr(302) in the ALDH7 family are located in the substrate-binding site and are specific to this family. Our kinetic analysis demonstrates that alpha-aminoadipic semialdehyde, a lysine catabolism intermediate, is the preferred substrate for plant ALDH7. In contrast, aromatic aldehydes including benzaldehyde, anisaldehyde, cinnamaldehyde, coniferaldehyde and sinapaldehyde are the best substrates for cALDH2. In line with these results, the crystal structures of RF2C and RF2F reveal that their substrate-binding sites are similar and are formed by an aromatic cluster mainly composed of phenylalanine residues and several nonpolar residues. Gene expression studies indicate that the RF2C gene, which is strongly expressed in all organs, appears essential, suggesting that the crucial role of the enzyme would certainly be linked to the cell wall formation using aldehydes from phenylpropanoid pathway as substrates. Finally, plant ALDH7 may significantly contribute to osmoprotection because it oxidizes several aminoaldehydes leading to products known as osmolytes. PMID- 25734424 TI - Correction: Hepatitis B and Delta virus are prevalent but often subclinical co infections among HIV infected patients in Guinea-Bissau, West Africa: a cross sectional study. PMID- 25734423 TI - Proteomic analysis of mitochondrial-associated ER membranes (MAM) during RNA virus infection reveals dynamic changes in protein and organelle trafficking. AB - RIG-I pathway signaling of innate immunity against RNA virus infection is organized between the ER and mitochondria on a subdomain of the ER called the mitochondrial-associated ER membrane (MAM). The RIG-I adaptor protein MAVS transmits downstream signaling of antiviral immunity, with signaling complexes assembling on the MAM in association with mitochondria and peroxisomes. To identify components that regulate MAVS signalosome assembly on the MAM, we characterized the proteome of MAM, ER, and cytosol from cells infected with either chronic (hepatitis C) or acute (Sendai) RNA virus infections, as well as mock-infected cells. Comparative analysis of protein trafficking dynamics during both chronic and acute viral infection reveals differential protein profiles in the MAM during RIG-I pathway activation. We identified proteins and biochemical pathways recruited into and out of the MAM in both chronic and acute RNA viral infections, representing proteins that drive immunity and/or regulate viral replication. In addition, by using this comparative proteomics approach, we identified 3 new MAVS-interacting proteins, RAB1B, VTN, and LONP1, and defined LONP1 as a positive regulator of the RIG-I pathway. Our proteomic analysis also reveals a dynamic cross-talk between subcellular compartments during both acute and chronic RNA virus infection, and demonstrates the importance of the MAM as a central platform that coordinates innate immune signaling to initiate immunity against RNA virus infection. PMID- 25734425 TI - Association between traffic-related air pollution in schools and cognitive development in primary school children: a prospective cohort study. AB - BACKGROUND: Air pollution is a suspected developmental neurotoxicant. Many schools are located in close proximity to busy roads, and traffic air pollution peaks when children are at school. We aimed to assess whether exposure of children in primary school to traffic-related air pollutants is associated with impaired cognitive development. METHODS AND FINDINGS: We conducted a prospective study of children (n = 2,715, aged 7 to 10 y) from 39 schools in Barcelona (Catalonia, Spain) exposed to high and low traffic-related air pollution, paired by school socioeconomic index; children were tested four times (i.e., to assess the 12-mo developmental trajectories) via computerized tests (n = 10,112). Chronic traffic air pollution (elemental carbon [EC], nitrogen dioxide [NO2], and ultrafine particle number [UFP; 10-700 nm]) was measured twice during 1-wk campaigns both in the courtyard (outdoor) and inside the classroom (indoor) simultaneously in each school pair. Cognitive development was assessed with the n back and the attentional network tests, in particular, working memory (two-back detectability), superior working memory (three-back detectability), and inattentiveness (hit reaction time standard error). Linear mixed effects models were adjusted for age, sex, maternal education, socioeconomic status, and air pollution exposure at home. Children from highly polluted schools had a smaller growth in cognitive development than children from the paired lowly polluted schools, both in crude and adjusted models (e.g., 7.4% [95% CI 5.6%-8.8%] versus 11.5% [95% CI 8.9%-12.5%] improvement in working memory, p = 0.0024). Cogently, children attending schools with higher levels of EC, NO2, and UFP both indoors and outdoors experienced substantially smaller growth in all the cognitive measurements; for example, a change from the first to the fourth quartile in indoor EC reduced the gain in working memory by 13.0% (95% CI 4.2%-23.1%). Residual confounding for social class could not be discarded completely; however, the associations remained in stratified analyses (e.g., for type of school or high-/low-polluted area) and after additional adjustments (e.g., for commuting, educational quality, or smoking at home), contradicting a potential residual confounding explanation. CONCLUSIONS: Children attending schools with higher traffic-related air pollution had a smaller improvement in cognitive development. PMID- 25734428 TI - [Physical activity on prescription undeservedly on the "unnecessary list"--what happens now?]. PMID- 25734427 TI - [Sickle cell anemia causes varied symptoms and high morbidity. Serious prognosis in the most common genetic disease in the world]. AB - Sickle cell anemia is a life-threatening disease, and the most common genetic disease in the world. The prevalence of sickle cell anemia in Sweden is unknown. Sickle cell anemia is an important disease, because of its variable complications, in many medical and surgical specialties. The overview highlights common medical problems encountered in sickle cell anemia presented through a case report of a pregnant woman. PMID- 25734426 TI - Genetic characteristics of mitochondrial DNA was associated with colorectal carcinogenesis and its prognosis. AB - Clinical value of mitochondrial DNA has been described in colorectal cancer (CRC). To clarify its role in colorectal carcinogenesis, mitochondrial microsatellite instability (mtMSI) and other markers were investigated in CRCs and their precancerous lesions, as a multitier genetic study. DNA was isolated from paired normal and tumoral tissues in 78 tubular adenomas (TAs), 34 serrated polyps (SPs), and 100 CRCs. mtMSI, nucleus microsatellite instability (nMSI), KRAS mutation, and BRAF mutation were investigated in these tumors and their statistical analysis was performed. mtMSI was found in 30% of CRCs and 21.4% of precancerous lesions. Mitochondrial copy number was higher in SPs than TAs and it was associated with mtMSI in low grade TAs. KRAS and BRAF mutations were mutually exclusive in TAs and SPs. CRCs with mtMSI showed shorter overall survival times than the patients without mtMSI. In CRCs without nMSI or BRAF mutation, mtMSI was a more accurate marker for predicting prognosis. The genetic change of mitochondrial DNA is an early and independent event in colorectal precancerous lesions and mtMSI and mitochondrial contents are associated with the tubular adenoma-carcinoma sequence, resulting in poor prognosis. This result suggested that the genetic change in mitochondrial DNA appears to be a possible prognosis marker in CRC. PMID- 25734429 TI - [Threatened treatment of bacterial sexually transmitted infections. The Medical Products Agency and the Public Health Agency issues new recommendation]. PMID- 25734430 TI - [The medic creating partnerships for global health]. PMID- 25734431 TI - [Reply, the Swedish Medical Association on healthcare IT-systems: Integrity is an important issue for the Medical Association]. PMID- 25734432 TI - [Ending reply from Jonas Lindeberg: Incorrect diagnosis code--a pitfall in the medical record]. PMID- 25734433 TI - [Reply from the "Unnecessary group": Physical activity on prescription locks the discussion]. PMID- 25734434 TI - [New role for executive officers in internship education. A piece of cake or heavy responsibility?]. PMID- 25734436 TI - [An atheist facing death]. PMID- 25734435 TI - [Speaking! Diagnosis in the emergency room--How does the Swedish National Board of Health and Welfare benefit from "working diagnoses"?]. PMID- 25734438 TI - [Quality control of internship education--eagerly awaited regulation]. PMID- 25734437 TI - [Ligament injuries and forearm fractures--the relationship is still missed]. PMID- 25734439 TI - [Large volumes are necessary for high-quality care]. PMID- 25734440 TI - [Our responsibility to reflect on the madness]. PMID- 25734441 TI - [Everyday primary health care in the Amazon]. PMID- 25734442 TI - [Legal ethics and psychiatry's most challenging questions]. PMID- 25734443 TI - [The physician's private moral limitations]. PMID- 25734444 TI - Comparing the factors correlated with tuberculosis-specific and non-tuberculosis specific deaths in different age groups among tuberculosis-related deaths in Taiwan. AB - BACKGROUND: Nearly 20% of tuberculosis (TB) patients die within one year, and TB related mortality rates remain high in Taiwan. The study aimed to identify factors correlated with TB-specific deaths versus non-TB-specific deaths in different age groups among TB-related mortalities. METHODS: A retrospective cohort study was conducted from 2006-2008 with newly registered TB patients receiving follow-up for 1 year. The national TB database from the Taiwan-CDC was linked with the National Vital Registry System and the National Health Insurance database. A chi-squared test and logistic regression were used to analyse the correlated factors related to TB-specific and non-TB-specific deaths in different age groups. RESULTS: Elderly age (odds ratio [OR] 2.68-8.09), Eastern residence (OR 2.01), positive sputum bacteriology (OR 2.54), abnormal chest X-ray (OR 2.28), and comorbidity with chronic kidney disease (OR 2.35), stroke (OR 1.74) or chronic liver disease (OR 1.29) were most likely to be the cause of TB-specific deaths, whereas cancer (OR 0.79) was less likely to be implicated. For non-TB specific deaths in patients younger than 65 years of age, male sex (OR 2.04) and comorbidity with HIV (OR 5.92), chronic kidney disease (OR 8.02), stroke (OR 3.75), cancer (OR 9.79), chronic liver disease (OR 2.71) or diabetes mellitus (OR 1.38) were risk factors. CONCLUSIONS: Different factors correlated with TB specific deaths compared with non-TB-specific deaths, and the impact of comorbidities gradually decreased as age increased. To reduce TB-specific mortality, special consideration for TB patients with old age, Eastern residence, positive sputum bacteriology and comorbidity with chronic kidney disease or stroke is crucial. In particular, Eastern residence increased the risk of TB specific death in all age groups. In terms of TB deaths among patients younger than 65 years of age, patients with HIV, chronic kidney disease or cancer had a 6 10 times increased risk of non-TB-specific deaths. PMID- 25734447 TI - Correction: When whole-genome alignments just won't work: kSNP v2 software for alignment-free SNP discovery and phylogenetics of hundreds of microbial genomes. PMID- 25734445 TI - Later cART initiation in migrant men from sub-Saharan Africa without advanced HIV disease in France. AB - OBJECTIVE: To compare the time from entry into care for HIV infection until combination antiretroviral therapy (cART) initiation between migrants and non migrants in France, excluding late access to care. METHODS: Antiretroviral-naive HIV-1-infected individuals newly enrolled in the FHDH cohort between 2002-2010, with CD4 cell counts >200/MUL and no previous or current AIDS events were included. In three baseline CD4 cell count strata (200-349, 350-499, >= 500/MUL), we examined the crude time until cART initiation within three years after enrollment according to geographic origin, and multivariable hazard ratios according to geographic origin, gender and HIV-transmission group, with adjustment for baseline age, enrollment period, region of care, plasma viral load, and HBV/HBC coinfection. RESULTS: Among 13338 individuals, 9605 (72.1%) were French natives (FRA), 2873 (21.4%) were migrants from sub-Saharan Africa/non French West Indies (SSA/NFW), and 860 (6.5%) were migrants from other countries. Kaplan-Meier probabilities of cART initiation were significantly lower in SSA/NFW than in FRA individuals throughout the study period, regardless of the baseline CD4 stratum. After adjustment, the likelihood of cART initiation was respectively 15% (95%CI, 1-28) and 20% (95%CI, 2-38) lower in SSA/NFW men than in FRA men who had sex with men (MSM) in the 350-499 and >= 500 CD4 strata, while no difference was observed between other migrant groups and FRA MSM. CONCLUSION: SSA/NFW migrant men living in France with CD4 >350/MUL at entry into care are more likely to begin cART later than FRA MSM, despite free access to treatment. Administrative delays in obtaining healthcare coverage do not appear to be responsible. PMID- 25734446 TI - Predicting cognitive function from clinical measures of physical function and health status in older adults. AB - INTRODUCTION: Current research suggests that the neuropathology of dementia including brain changes leading to memory impairment and cognitive decline-is evident years before the onset of this disease. Older adults with cognitive decline have reduced functional independence and quality of life, and are at greater risk for developing dementia. Therefore, identifying biomarkers that can be easily assessed within the clinical setting and predict cognitive decline is important. Early recognition of cognitive decline could promote timely implementation of preventive strategies. METHODS: We included 89 community dwelling adults aged 70 years and older in our study, and collected 32 measures of physical function, health status and cognitive function at baseline. We utilized an L1-L2 regularized regression model (elastic net) to identify which of the 32 baseline measures were strongly predictive of cognitive function after one year. We built three linear regression models: 1) based on baseline cognitive function, 2) based on variables consistently selected in every cross-validation loop, and 3) a full model based on all the 32 variables. Each of these models was carefully tested with nested cross-validation. RESULTS: Our model with the six variables consistently selected in every cross-validation loop had a mean squared prediction error of 7.47. This number was smaller than that of the full model (115.33) and the model with baseline cognitive function (7.98). Our model explained 47% of the variance in cognitive function after one year. DISCUSSION: We built a parsimonious model based on a selected set of six physical function and health status measures strongly predictive of cognitive function after one year. In addition to reducing the complexity of the model without changing the model significantly, our model with the top variables improved the mean prediction error and R-squared. These six physical function and health status measures can be easily implemented in a clinical setting. PMID- 25734448 TI - Differences in field effectiveness and adoption between a novel automated chlorination system and household manual chlorination of drinking water in Dhaka, Bangladesh: a randomized controlled trial. AB - The number of people served by networked systems that supply intermittent and contaminated drinking water is increasing. In these settings, centralized water treatment is ineffective, while household-level water treatment technologies have not been brought to scale. This study compares a novel low-cost technology designed to passively (automatically) dispense chlorine at shared handpumps with a household-level intervention providing water disinfection tablets (Aquatab), safe water storage containers, and behavior promotion. Twenty compounds were enrolled in Dhaka, Bangladesh, and randomly assigned to one of three groups: passive chlorinator, Aquatabs, or control. Over a 10-month intervention period, the mean percentage of households whose stored drinking water had detectable total chlorine was 75% in compounds with access to the passive chlorinator, 72% in compounds receiving Aquatabs, and 6% in control compounds. Both interventions also significantly improved microbial water quality. Aquatabs usage fell by 50% after behavioral promotion visits concluded, suggesting intensive promotion is necessary for sustained uptake. The study findings suggest high potential for an automated decentralized water treatment system to increase consistent access to clean water in low-income urban communities. PMID- 25734449 TI - Development of the Internet-Enabled System for Exercise Telerehabilitation and Cardiovascular Training. AB - OBJECTIVE: Sustained exercise training could significantly improve patient rehabilitation and management of noncommunicable diseases in the community. This study aimed to develop a universal telecare system for delivery of exercise rehabilitation and cardiovascular training services at home. MATERIALS AND METHODS: An innovative bilateral leg training device was equipped with an electronic system for the ongoing measurement of training activities with the device. A single-item parameter reflecting the intensity of training was monitored using several modern telecommunication technologies. According to the application protocol, eight volunteers first tried the device for 30-60 min to determine their personal training capacity. Then, they were provided with equipment to use at home for 4 weeks. Adherence to daily training was assessed by the number of training days per week, training intensity, and duration of training sessions. RESULTS: The system provided reliable recording of training activities with the device using (1) long-term data logging without an ongoing connection to the computer, (2) wireless monitoring and recording of training activities on a stand-alone computer, and (3) a secure cloud-based monitoring over the Internet connection using electronic devices, including smartphones. Overall analysis of recordings and phone feedbacks to participants took only approximately 5 h for the duration of study. CONCLUSIONS: This study, although of a pilot nature, described the comprehensive exercise telerehabilitation system integrating mobile training equipment with personalized training protocols and remote monitoring. A single-item electronic parameter of the system usage facilitated time-effective data management. Wireless connection allowed various locations of device application and several monitoring arrangements ranging from real-time monitoring to long-term recording of exercise activities. A cloud-based software platform enabled management of multiple users at distance. Implementation of this model may facilitate both accessibility and availability of personalized exercise telerehabilitation services. Further studies would validate it in the clinical and healthcare environment. PMID- 25734451 TI - Strong piezoelectricity in (1 - x)(K0.4Na0.6)(Nb0.96Sb0.04)O3-xBi0.5K0.5Zr1 ySnyO3 lead-free binary system: identification and role of multiphase coexistence. AB - Here we report a strong piezoelectric activity in (1 - x)(K0.4Na0.6)(Nb0.96Sb0.04)O3-xBi0.5K0.5Zr1-ySnyO3 lead-free ceramics by designing different phase boundaries. The phase boundaries concerning rhombohedral-orthorhombic-tetragonal (R-O-T) and rhombohedral-tetragonal (R-T) multiphase coexistence were attained by changing BKZS and Sn contents and then were identified by the X-ray diffraction patterns as well as temperature dependent permittivity and nu1 Raman modes associated with BO6 perovskite octahedron. A high strain (strain = 0.21-0.28% and d33* = 707-880 pm/V) and a strong piezoelectric coefficient (d33 = 415-460 pC/N) were shown in the ceramics located at the multiphase coexistence region. The reported results of this work are superior to that (d33* ~ 570 pm/V and d33 ~ 416 pC/N) of the textured (K,Na,Li)(Nb,Ta,Sb)O3 ceramics [Nature 2004, 432, 84]. We believe that the material system of this work will become one of the most promising candidates for piezoelectric actuators. PMID- 25734450 TI - Surgical complications of primary rhegmatogenous retinal detachment: a meta analysis. AB - BACKGROUND: To investigate the surgical complications of scleral buckling (SB) and pars plana vitrectomy (PPV) performed on primary rhegmatogenous retinal detachment (RRD) and to discover which surgical procedures bring fewer complications. METHODS: An electronic literature search using the PubMed database, ISI Web of Knowledge and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials and observational studies comparing SB with PPV on primary RRD. Outcome measures included intra-operative complications and early and late post-operative complications. RESULTS: During the operation, significantly less subretinal hemorrhage occurred in the PPV group than in the SB group (OR = 4.71; 95%CI, 1.33-16.64; p = 0.02) and the hypotony incidence was significantly higher in the SB group (OR = 18.24; 95%CI, 2.37 140.44; p = 0.005); however, the occurrence of iatrogenic breaks was significantly lower in the SB group (OR = 0.05; 95%CI, 0.01-0.21; p<0.0001). In the early stage of post-operation, significantly higher incidence of choroidal detachment was identified in the SB group than in the PPV group (OR = 10.19; 95%CI, 2.36-44.09; p = 0.002); patients undergoing SB had significantly higher odds of residual subretinal fluid (OR = 14.71; 95%CI, 1.84-117.32; p = 0.01); the occurrence of high intraocular pressure was significantly lower in the SB group (OR = 0.46; 95%CI, 0.23-0.89; p = 0.02); and no significant difference was shown in the incidence of epithelia defect (p = 0.37) between the two groups. In the late stage of post-operation, the incidence of diplopia/extraocular muscle dysfunction was significantly higher in the SB group (OR = 4.04; 95%CI, 1.30 12.52; p = 0.02); and significantly less cataract was observed in the SB group (OR = 0.20; 95%CI, 0.14-0.30; p<0.00001); no significant difference was found in the incidences of cystoid macular edema (p = 0.65), macular pucker (p = 0.52), post-operative proliferative vitreoretinopathy (p = 0.73) and epiretinal membrane (p = 0.47) in other late post-operative complications. CONCLUSIONS: This meta analysis suggests that PPV could be considered as potential surgical management on primary RRD. PMID- 25734452 TI - Beef quality parameters estimation using ultrasound and color images. AB - BACKGROUND: Beef quality measurement is a complex task with high economic impact. There is high interest in obtaining an automatic quality parameters estimation in live cattle or post mortem. In this paper we set out to obtain beef quality estimates from the analysis of ultrasound (in vivo) and color images (post mortem), with the measurement of various parameters related to tenderness and amount of meat: rib eye area, percentage of intramuscular fat and backfat thickness or subcutaneous fat. PROPOSAL: An algorithm based on curve evolution is implemented to calculate the rib eye area. The backfat thickness is estimated from the profile of distances between two curves that limit the steak and the rib eye, previously detected. A model base in Support Vector Regression (SVR) is trained to estimate the intramuscular fat percentage. A series of features extracted on a region of interest, previously detected in both ultrasound and color images, were proposed. In all cases, a complete evaluation was performed with different databases including: color and ultrasound images acquired by a beef industry expert, intramuscular fat estimation obtained by an expert using a commercial software, and chemical analysis. CONCLUSIONS: The proposed algorithms show good results to calculate the rib eye area and the backfat thickness measure and profile. They are also promising in predicting the percentage of intramuscular fat. PMID- 25734453 TI - Context for practice: surgical-acquired pressure ulcers, colostomy irrigation, and urethral versus suprapubic indwelling urinary catheters. PMID- 25734454 TI - Moisturizing capabilities of 4 topical skin creams. PMID- 25734455 TI - Moisturizing capabilities of four topical skin creams: reply. PMID- 25734456 TI - The effect of 2 adhesive products on skin integrity used for fixation of hip and knee surgical dressings: a randomized controlled trial. AB - PURPOSE: The aim of this study was to compare effects of 2 adhesive products, a nonwoven porous adhesive bandage (NPAB) and transparent film adhesive bandage (TFAB), on skin integrity for fixation of hip and knee surgical dressings. MATERIALS AND METHODS: A prospective, randomized study was conducted on 300 patients who underwent hip and knee surgery (arthroplasty, fixation of fractures, tumor operations, etc). Participants were randomized into 2 equal groups according to the applied surgical dressing fixation product (NPAB or TFAB). Skin changes (edema, erythema, blister, peeling of blister, mechanical peeling, and maceration), drying of incision, serous discharge, and early infection symptoms were evaluated. RESULTS: The skin integrity was found to be impaired in 4.0% (n = 6) of the 150 NPAB patients and in 10.7% (n = 16) of the 150 TFAB patients (P = .02). Logistic regression analysis showed that the risk of impaired skin integrity increased 2.5-fold when TFAB was applied (P = .03). CONCLUSION: The NPAB was associated with a reduced likelihood of impaired skin integrity following hip and knee surgery. PMID- 25734457 TI - Medical device-related hospital-acquired pressure ulcers: development of an evidence-based position statement. AB - Hospital-acquired pressure ulcers (HAPUs) are a problem in the acute care setting causing pain, loss of function, infection, extended hospital stay, and increased costs. In spite of best practice strategies, occurrences of pressure ulcers continue. Many of these HAPUs are related to a medical device. Correct assessment and reporting of device-related HAPUs were identified as an important issue in our organization. Following the Iowa Model for Evidence-Based Practice to Promote Quality Care, a task force was created, a thorough review of current evidence and clinical practice recommendations was performed, and a definition for medical device-related HAPU and an evidence-based position statement were developed. Content of the statement was reviewed by experts and appropriate revisions were made. This position statement provides guidance and structure to accurately identify and report device-related HAPU across our 18 healthcare facilities. Through the intentional focus on pressure ulcer prevention and evidence-based practice in our organization and the use of this position statement, identification and reporting of device-related HAPUs have improved with a decrease in overall HAPU rates of 33% from 2011 and 2012. This article describes the development and implementation of this device-related HAPU position statement within our organization. PMID- 25734458 TI - Does colostomy irrigation affect functional outcomes and quality of life in persons with a colostomy? AB - BACKGROUND: Colostomy irrigation may be used by patients with colostomies to regulate bowel evacuations by stimulating emptying of the colon at regularly scheduled times. OBJECTIVE: This Evidence-Based Report Card reviews the effect of colostomy irrigation on frequency of bowel evacuation, flatus production, odor, and health-related quality of life. SEARCH STRATEGY: We systematically reviewed the literature for studies that evaluated health-related quality of life in persons aged 18 years or older with colostomies of the sigmoid or descending left colon. A professional librarian performed the literature search, which yielded 499 articles using the search terms "colostomy," "colostomies," "therapeutic irrigation," "irrigation," and "irrigator." Following title and abstract reviews, we identified and retrieved 4 studies that met inclusion criteria. FINDINGS: Colostomy irrigation reduces the frequency of bowel evacuations when compared to spontaneous evacuation and containment using a pouching system. Regular irrigation is associated with reductions in pouch usage. This change in bowel evacuation function frequently results in absence of bowel evacuations for 24 hours or longer, enabling some to discontinue ongoing use of a pouching system. Subjects using CI report reductions in flatus and odors associated with presence of a colostomy. One study was identified that found persons using CI reported higher health-related quality of life than did those who managed their colostomies with spontaneous evacuation using the Digestive Disease Quality of Life-15, but no differences were found when health-related quality of life was measured using the more generic instrument, the Medical Outcomes Study: Short Form-36. CONCLUSION: Instruction on principles and techniques of colostomy irrigation should be considered when managing patients with a permanent, left sided colostomy. PMID- 25734459 TI - Revisiting colostomy irrigation: a viable option for persons with permanent descending and sigmoid colostomies. AB - Colostomy irrigation (CI) is the regular irrigation of the bowel for persons with a permanent colostomy of the descending or sigmoid colon. Although this technique was first described in the 1920s, a recent study of 985 WOC nurses found that almost half (47%) do not routinely teach CI to persons with colostomies. In a systematic review (Evidence-Based Report Card) published in this issue of the Journal, we summarized current best evidence concerning the effect of CI on bowel function and found that irrigation reduces the frequency of bowel elimination episodes and allows some patients to reduce or eliminate ongoing use of a pouching system. This article describes techniques for teaching CI and discussed additional findings associated with CI. PMID- 25734460 TI - Preoperative teaching and stoma marking in an inpatient population: a quality improvement process using a FOCUS-Plan-Do-Check-Act model. AB - Preoperative teaching and stoma marking are supported by research and included in clinical practice guidelines from the WOCN Society and others. Using a FOCUS-Plan Do-Check-Act model of Total Quality Management, a multidisciplinary team was formed that developed a flow chart outlining the process of care for patients undergoing planned ostomy surgery that included an educational intervention that enabled staff nurses to perform preoperative stoma site marking and education. After 3 months, we found a statistically significant increase in the number of surgical patients who received these evidence-based interventions (14% vs 64%; chi = 9.32; P = .002). PMID- 25734461 TI - Comparing transurethral and suprapubic catheterization for long-term bladder drainage: a qualitative study of the patients' perspective. AB - PURPOSE: To explore why men and women decide to have a suprapubic catheter, how the decision is made, and to compare people's experiences of suprapubic and transurethral catheterization for long-term bladder drainage. DESIGN: Narrative interviews followed by thematic analysis. SUBJECTS AND SETTING: Thirty-six long term catheter users living in England, Wales, or Scotland were interviewed. The sample included men and women from various socioeconomic backgrounds, with a wide range of conditions. They were aged 22 to 96 years (M = 57 years). METHODS: Interviews lasted between 1 and 3 hours; they were audiotaped and fully transcribed for analysis. A qualitative interpretive approach was taken, combining thematic analysis with constant comparison. RESULTS: Some respondents were satisfied with or preferred a urethral catheter; others preferred a suprapubic catheter because they perceived that suprapubic catheters led to fewer infections, were more hygienic, more comfortable, improved self-image, allowed a sense of control, and were better suited for sexual relations. Participants also mentioned the decision-making process, including how the decision was made to have a suprapubic catheter and where to insert the catheter at a particular point in the abdomen. Even with a suprapubic catheter, some worried about sex or were put off sexual intimacy because of the catheter. CONCLUSION: Our findings suggest that patients should be better informed before a suprapubic catheter is inserted and that issues such as sex should be raised in consultations when appropriate. PMID- 25734462 TI - Experiences of leg bag users and emerging design priorities. AB - PURPOSE: The purpose of the study was to explore participants' experiences of urinary incontinence and leg bag use in order to identify priorities for product redesign. SUBJECTS AND SETTING: Twenty-nine leg bag users and 5 carers and healthcare professionals participated in the study. They were recruited through a UK hospital Trust and a UK-wide charity for people with bladder and bowel control problems. DESIGN: The study employed a descriptive design with qualitative and quantitative elements to determine current experiences with urinary drainage leg bags and identify potential ways to improve their design. METHODS: Data collection occurred during semistructured face-to-face and telephone semistructured interviews. RESULTS: Thematic analysis revealed that leg bag design and performance influenced users' relationships, confidence, and ability to socialize. The most significant issues related to leg bag use were reliable functioning without leakage, secure positioning, and discretion when worn under clothing. All participants reported having experienced significant urine leakage due to usability issues with the leg bags. CONCLUSIONS: Respondents identified a number of design issues with current leg bags that need to be addressed to improve the ease of use and overall experience when using leg bags for containing urinary output. The findings have been used to define design requirements for further development of leg bags and their component parts. PMID- 25734463 TI - Knowledge, attitudes, beliefs, and practices in registered nurses and care aids about urinary incontinence in Korean nursing homes: a cross-sectional survey. AB - PURPOSE: The purpose of this study was to describe knowledge, attitudes, beliefs, and practices about urinary incontinence among Korean RNs and care aids and to identify correlates of continence care practices. METHOD: A cross-sectional survey was used to gather self-reported data from 338 nursing staff, including 135 RNs and 203 care aids, from 61 nursing homes in Korea by using an existing instrument adapted for Korean nursing staff. The instrument consists of 18 items designed to measure knowledge about urinary incontinence, 18 items querying attitudes toward continence care, 17 items focusing on beliefs about undesirable consequences to older adults with urinary incontinence, and 28 items querying on continence care practice. RESULTS: Registered nurses had higher knowledge about urinary incontinence and they had more positive attitudes toward continence care practice than care aids. Attitudes, facility bed capacity, and continuing education on urinary incontinence were significantly related (P < .05) to RNs' continence care practice scores (R = 0.285; P < .001), while care aids' practice scores were associated with knowledge and attitudes (R = 0.163; P < .001). CONCLUSIONS: Attitude plays an important role in continence care practice for both RNs and care aids in Korean nursing homes. In addition, continence care practice of RNs may be influenced by updating clinical competencies. For care aids, continence care practice can be influenced by improving basic knowledge of urinary incontinence. PMID- 25734464 TI - Palliative management of malodorous squamous cell carcinoma of the oral cavity with Manuka honey. AB - BACKGROUND: The management of malignant malodorous wounds within the oral cavity can be challenging due to limited availability of dressings that are safe, efficacious, and ingestible. CASE DESCRIPTION: An 80-year-old woman with squamous cell carcinoma of the oral cavity was admitted to home care with complaints and distress related to extreme malodor. CONCLUSION: Manuka honey proved a safe, effective, palliative treatment to reduce odor and inflammation in wounds secondary to squamous cell carcinoma of the oral cavity in this patient. PMID- 25734465 TI - Bilateral gluteal ischemic necrosis mistaken for stage IV pressure wound: case report and discussion. AB - BACKGROUND: Sacral and gluteal pressure wounds are a common problem in elderly and critically ill patients. Prompt and accurate diagnosis is important to determine the best plan of treatment. CASE: A 48-year-old female was hospitalized with severe trunk pain and bilateral necrotic gluteal wounds present for more than 1 year initially diagnosed as stage IV pressure ulcers; she reported pain radiating to her lower extremities. She had multiple comorbid conditions, including peripheral vascular disease, smoking, and hypertension. CONCLUSION: Wound care providers should be aware of this differential diagnosis especially in patients with history of vascular disease. PMID- 25734468 TI - Assessment of Filtered Back Projection, Adaptive Statistical, and Model-Based Iterative Reconstruction for Reduced Dose Abdominal Computed Tomography. AB - PURPOSE: To compare standard of care and reduced dose (RD) abdominal computed tomography (CT) images reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), model-based iterative reconstruction (MBIR) techniques. MATERIALS AND METHODS: In an Institutional Review Board-approved, prospective clinical study, 28 patients (mean age 59 +/- 13 years ), undergoing clinically indicated routine abdominal CT on a 64-channel multi-detector CT scanner, gave written informed consent for acquisition of an additional RD (<1 milli-Sievert) abdomen CT series. Sinogram data of RD series were reconstructed with FBP, ASIR, and MBIR and compared with FBP images of standard dose abdomen CT. Two radiologists performed randomized, independent, and blinded comparison for lesion detection, lesion margin, visibility of normal structures, and diagnostic confidence. RESULTS: Mean CT dose index volume was 10 +/- 3.4 mGy and 1.3 +/- 0.3 mGy for standard and RD CT, respectively. There were 73 "true positive" lesions detected on standard of care CT. Nine lesions (<8 mm in size) were missed on RD abdominal CT images which included liver lesions, liver cysts, kidney cysts, and paracolonic abscess. These lesions were missed regardless of patient size and types of iterative reconstruction techniques used for reconstruction of RD data sets. The visibility of lesion margin was suboptimal in (23/28) patients with RD FBP, (15/28) patients with RD ASIR, and (14/28) patients with RD MBIR compared to standard of care FBP images (P < 0.001). Diagnostic confidence for the assessment of lesions on RD images was suboptimal in most patients regardless of iterative reconstruction techniques. CONCLUSIONS: Clinically significant lesions (< 8 mm) can be missed on abdominal CT examinations acquired at a CT dose index volume of 1.3 mGy regardless of patients' size and reconstruction techniques (FBP, ASIR, and MBIR). PMID- 25734469 TI - Demonstrating photoluminescence from Au is electronic inelastic light scattering of a plasmonic metal: the origin of SERS backgrounds. AB - Temperature-dependent surface-enhanced Raman scattering (SERS) is used to investigate the photoluminescence and background continuum always present in SERS but whose origin remains controversial. Both the Stokes and anti-Stokes background is found to be dominated by inelastic light scattering (ILS) from the electrons in the noble metal nanostructures supporting the plasmon modes. The anti-Stokes background is highly temperature dependent and is shown to be related to the thermal occupation of electronic states within the metal via a simple model. This suggests new routes to enhance SERS sensitivities, as well as providing ubiquitous and calibrated real-time temperature measurements of nanostructures. PMID- 25734470 TI - Antibody-ligand interactions for hydrophobic charge-induction chromatography: a surface plasmon resonance study. AB - This article describes the use of surface plasmon resonance (SPR) spectroscopy to study antibody-ligand interactions for hydrophobic charge-induction chromatography (HCIC) and its versatility in investigating the surface and solution factors affecting the interactions. Two density model surfaces presenting the HCIC ligand (mercapto-ethyl-pyridine, MEP) were prepared on Au using a self-assembly technique. The surface chemistry and structure, ionization, and protein binding of such model surfaces were characterized by X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS), contact-angle titration, and SPR, respectively. The influences of the surface and solution factors, e.g., ligand density, salt concentration, and solution pH, on protein adsorption were determined by SPR. Our results showed that ligand density affects both equilibrium and dynamic aspects of the interactions. Specifically, a dense ligand leads to an increase in binding strength, rapid adsorption, slow desorption, and low specificity. In addition, both hydrophobic interactions and hydrogen bonding contribute significantly to the protein adsorption at neutral pH, while the electrostatic repulsion is overwhelmed under acidic conditions. The hydrophobic interaction at a high concentration of lyotropic salt would cause drastic conformational changes in the adsorbed protein. Combined with the self-assembly technique, SPR proves to be a powerful tool for studying the interactions between an antibody and a chromatographic ligand. PMID- 25734471 TI - [Editorial]. PMID- 25734472 TI - [Preterm infants at the limit of viability. Joint recommendation of the German Society of Obstetrics and Gynecology, the German Society for Pediatric and Adolescent Medicine, German Society of Perinatal Medicine, Academy for Ethics in Medicine, Society of Neonatology and Pediatric Intensive Medicine, composed of German Midwives Association and the Federation "The premature child" ,]. PMID- 25734473 TI - [Preterm infants at the limit of viability. Make the best possible decision]. PMID- 25734474 TI - Management of complicated monochorionic twin pregnancies. AB - Multiple gestation is associated with an increased risk for adverse pregnancy outcome. Monochorionic twins are at risk for complications specific to these pregnancies, such as twin-twin transfusion syndrome (TTTS) or twin reverse arterial perfusion (TRAP) sequence. In this article we give an overview on prenatal diagnosis, treatment and outcome of twin pregnancies complicated by TTTS and TRAP sequence. PMID- 25734475 TI - [Prognostic factors of perinatal short-term outcome in severe placental insufficiency using Doppler sonography to assess end-diastolic absent and reverse blood flow in umbilical arteries]. AB - Significant placental insufficiency, indicated by Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV), is associated with increased morbidity and mortality. Analysis of blood flow in the ductus venosus should assist in early intrauterine recognition of threatened foetuses. 58 high risk pregnancies with umbilical AREDV were repeatedly examined (n=364). Doppler findings were correlated with neonatal signs of deterioration (ratio of normoblasts to leukocytes, pH, base excess, Apgar score), as well as short-term morbidity [need for intubation, duration of assisted respiration, evidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH grade III+IV)] against the analysis of the blood flow findings (normal or increased pulsitility, absence or reverse end-diastolic flow) in the umbilical arteries (AU), the middle cerebral arteries (ACM) and ductus venosus (DV) relating these to birth weight and the duration of the pregnancy. The median period of observation was 12.8 days, 48% of the foetuses showed an abnormal ductus venosus flow and 26% an absent venous or reverse end-diastolic flow. The median date of delivery was 30 weeks, with a mean birth weight of 816 g. 93% were live births with 12% dying postnatally. Although the criteria for postnatal morbidity (BPD, NEC, IVH III+IV) and mortality did not correlate with changes in arterial and venous Doppler parameters in our group, there was a significant relationship between the normoblast count, known to be a marker of chronic hypoxia. The Apgar 10 minte score, umbilical arterial pH and base excess were correlated with changes in the DV flow curves. Healthy survival started, irrespective of arterial or venous blood flow criteria, from 27+0 weeks of pregnancy. If born between 27.0 and 30+6 weeks, the infants were more likely to be healthy the less the blood flow had been compromised. A birth weight of 590 g (sensitivity 62.5%; specificity 93.5%) and gestational age of 28+5 weeks (sensitivity 87.5%; specificity 90.3%) were shown to be cut-off points between healthy survival and survival with serious neonatal complications. PMID- 25734476 TI - A population based evaluation of the mode of delivery in association with infertility treatment from 1990-2012. AB - BACKGROUND: This study refers to population based data and investigates the development of the mode of delivery associated with infertility treatment over the last 23 years. METHODS: All 1 202,557 deliveries in Hesse, Germany, between 1990 and 2012 were assessed. 2.2% of the study population, 26,761, had a delivery subsequent to infertility treatment based on the Hessian Perinatal Registry (HEPE). An evaluation in this subgroup was performed investigating the associations between the mode of delivery and the gestational week and the mother's age. RESULTS: A continuous and significant (p<0.01) increase of cesarean section (CS) rates subsequent to infertility treatment (1990: 41,3%; 2012: 55,9%) as well as a conversely also significant (p<0.01) reduction of vaginal operative and spontaneous deliveries associated with infertility treatment between 1990 and 2012 was found. Furthermore, the preterm delivery rate and the proportion of deliveries of parturients older than 35 years of age in association with infertility treatment raised over the last years. Rates of full-term deliveries and deliveries of women younger than 35 years remained stable during the observation period. DISCUSSION: The rate of cesarean section is continuously rising over the last 23 years with regard to parturients subsequent to infertility treatment. The CS rate is significantly higher compared to women with a spontaneous pregnancy and in comparison to the data from 20 years ago. Most recently, the number of CS (51,2%) exceeded the number of vaginal deliveries (48,8%) in Hesse subsequent to infertility treatment for the first time. PMID- 25734477 TI - [Thrombophilia and HELLP syndrome in pregnancy - case report and overview of the literature]. AB - Thrombophilia is a prothrombotic state that can be caused by genetic disorders, such as the factor-V-Leiden or prothrombin mutation, as well as by acquired changes like oestrogen-induced APC resistance and the antiphospholipid syndrome. Pregnancy induces multiple procoagulant changes in the haemostatic system, increasing the risk of venous thromboembolism in women with a thrombophilia even further. Additionally, thrombophilias are suggested to be associated with a number of pregnancy complications such as recurrent miscarriage, stillbirth, preeclampsia and HELLP syndrome. Increased local activation of coagulation may directly influence trophoblast expansion and invasion, causing thereby an impaired trophoblast development and insufficient widening of spiral arteries in the first trimenon, which results in placenta-mediated pregnancy complications like preeclampsia or HELLP syndrome. Besides, macro- and microthrombosis in the vessels of placental stemm villi and spiral arteries may lead to multiple infarctions with release of necrotic trophoblast fragments and inflammatory cytokines playing an important role in the pathogenesis of recurrent pregnancy loss and stillbirth. For women with a known thrombophilia it is recommended to carry out either only postpartal or combined ante- and postpartal thrombosis prophylaxis with low-molecular weight heparins (LMWH) depending on the individual risk stratification. The effectiveness of the LMWH administration for prevention of thrombophilia-induced pregnancy complications and improvement of the pregnancy outcome is currently a matter of debate. Furthermore, an additional application of acetyIsalicylic acid (ASA) should be considered in the management of women with the antiphospholipid antibody syndrome. In the current article we present the case of a 28-year-old woman with the heterozygous prothrombin mutation, HELLP syndrome, a late miscarriage and a stillbirth in the anamnesis, who delivered 3 healthy babies under antenatal LMWH prophylaxis combined with intensive interdisciplinary prenatal care. PMID- 25734478 TI - Enhanced retention of encapsulated ions in cross-linked polymersomes. AB - Polymer vesicles (polymersomes) composed of poly(butadiene-b-poly(ethylene oxide)) (PB-b-PEO) are known for their stability and limited permeability. However, when these vesicles are diluted, substances, such as ions, encapsulated in the aqueous cavity can be released due to vesicle disruption. In previous studies, we have shown that these vesicles can be loaded efficiently with sufficient quantities of radionuclides to allow application in radionuclide therapy and pharmacokinetics evaluation, provided that there is no loss of the encapsulated radionuclides when diluted in the bloodstream. In this paper, in order to stabilize the carriers, we propose to cross-link the hydrophobic part of the polymersome membrane and to investigate whether such cross-linking induced by gamma radiation can enhance the retention of ions (radionuclides). Retention of ions encapsulated in the lumen in such cross-linked carriers has not been previously quantitatively evaluated, although it is of ultimate importance in any medical application. Here, we also investigate how cross-linking affects the transport of radionuclides (loading) through the membrane of the vesicles. The integrity of the vesicles as a function of the radiation dose is also investigated, including morphological changes. The results show that cross linking hinders the transport of ions through the membrane, which also leads to higher retention of ions encapsulated prior to cross-linking in the vesicles. Electron micrographs show that the shape of the polymersomes is not greatly affected by gamma radiation when left in the original solvent (phosphate buffered saline (PBS) or Milli-Q water), but when diluted in a good solvent for both blocks, i.e., tetrahydrofuran (THF), disintegration of the vesicles and the appearance of droplet-like structures is observed, which had not been reported previously. The results of the present study help to formulate polymersomes as carriers for radionuclide therapy, demonstrating a way to prevent in vivo release of radionuclides, caused by dilution-induced destabilization of the nanocarriers. PMID- 25734479 TI - Ultrasonographic comparison of two landmarks for the internal jugular vein: high versus conventional approach. AB - OBJECTIVE: We assessed and compared two landmarks (conventional vs. high approach) used in internal jugular vein (IJV) cannulation with respect to the degree of overlap with the carotid artery (CA) and the cross-sectional area (CSA) of the IJV using ultrasonography. PATIENTS AND METHODS: Forty-eight adult patients were included. Using ultrasonography, the percentage overlaps with the CA and the CSA of both IJVs were measured in the supine and Trendelenburg positions using conventional and high approaches. With the conventional approach, the IJV is penetrated at the apex of Sedillot's triangle, formed by the clavicle and the sternal and clavicular heads of the sternocleidomastoid muscle. The high approach involves the midpoint between the sternal notch and the mastoid process. RESULTS: The degree of overlap with the CA was 30.5 (7.5-69.4)% [median (interquartile range)] and 0.0 (0.0-25.4)% with the conventional and high approaches, respectively, for the right IJV (P<0.001) in the Trendelenburg position with 30 degrees head rotation. The CSA of the right IJV was 1.22 (0.92 2.01) and 0.98 (0.79-1.72) cm with the conventional and high approaches, respectively (P<0.001), in the Trendelenburg position with 30 degrees head rotation. IJV was more deeply positioned using the high approach than the conventional approach (P<0.001). CONCLUSION: The high approach for IJV cannulation decreased both the degree of overlap with the CA and CSA of the IJV and increased the depth of the IJV from the skin compared with the conventional approach. PMID- 25734480 TI - Cryoprecipitate administration after trauma. AB - OBJECTIVES: Haemorrhage remains among the most preventable causes of trauma death. Massive transfusion protocols, as part of 'haemostatic resuscitation', have been implemented in most trauma centres. Relative to the attention to the ideal ratio of red blood cells to fresh frozen plasma and platelets, cryoprecipitate treatment has been infrequently discussed. We aimed to outline the use of cryoprecipitate during trauma resuscitation and analyse outcomes in patients who received cryoprecipitate after hypofibrinogenaemia detection. METHODS: A retrospective review of registry data on all major trauma patients (Injury Severity Score>15) presenting to a level I trauma centre over a 4-year period (2008-2011) was conducted. We selected all patients who had received cryoprecipitate and then analysed patients who had received cryoprecipitate following the detection of hypofibrinogenaemia (<1.0 g/l). Mortality at hospital discharge among hypofibrinogenaemic patients who had received cryoprecipitate was compared with that among patients who had not received cryoprecipitate. RESULTS: Of 3996 trauma patients, 3571 had fibrinogen levels recorded. Most patients (n=3517, 98.5%) had initial fibrinogen counts of 1.0 g/l or higher, and cryoprecipitate was administered to a small proportion of these patients (n=126, 3.6%). Of the 54 patients with hypofibrinogenaemia on arrival, one patient died immediately and was excluded from further analysis. Of the 53 patients, 30 received cryoprecipitate and 28/53 died (53%). There was no difference in mortality between those who had received and those who had not received cryoprecipitate (14/30 vs. 14/23, P=0.31). CONCLUSION: Administration of cryoprecipitate was uncommon during trauma resuscitation, even among patients with hypofibrinogenaemia on presentation. This study provides no evidence towards improved outcomes from administration of cryoprecipitate. PMID- 25734482 TI - Independent action between DvSnf7 RNA and Cry3Bb1 protein in southern corn rootworm, Diabrotica undecimpunctata howardi and Colorado potato beetle, Leptinotarsa decemlineata. AB - In recent years, corn rootworm (CRW)-resistant maize events producing two or more CRW-active Bt proteins have been commercialized to enhance efficacy against the target pest(s) by providing multiple modes of action (MoA). The maize hybrid MON 87411 has been developed that produces the CRW-active Cry3Bb1 Bt protein (hereafter Cry3Bb1) and expresses a RNAi-mediated MoA that also targets CRW. As part of an environmental risk assessment for MON 87411, the potential for an interaction between the CRW-active DvSnf7 RNA (hereafter DvSnf7) and Cry3Bb1 was assessed in 12-day diet incorporation bioassays with the southern corn rootworm (SCR, Diabrotica undecimpunctata howardi). The potential for an interaction between DvSnf7 and Cry3Bb1 was evaluated with two established experimental approaches. The first approach evaluated each substance alone and in combination over three different response levels. For all three response levels, observed responses were shown to be additive and not significantly different from predicted responses under the assumption of independent action. The second approach evaluated the potential for a fixed sub-lethal concentration of Cry3Bb1 to decrease the median lethal concentration (LC50) of DvSnf7 and vice-versa. With this approach, the LC50 value of DvSnf7 was not altered by a sub-lethal concentration of Cry3Bb1 and vice-versa. In addition, the potential for an interaction between the Cry3Bb1 and DvSnf7 was tested with Colorado potato beetle (CPB, Leptinotarsa decemlineata), which is sensitive to Cry3Bb1 but not DvSnf7. CPB assays also demonstrated that DvSnf7 does not alter the activity of Cry3Bb1. The results from this study provide multiple lines of evidence that DvSnf7 and Cry3Bb1 produced in MON 87411 have independent action. PMID- 25734484 TI - Stress heterogeneities in sheared type-I collagen networks revealed by Boundary Stress Microscopy. AB - Disordered fiber networks provide structural support to a wide range of important materials, and the combination of spatial and dynamic complexity may produce large inhomogeneities in mechanical properties, an effect that is largely unexplored experimentally. In this work, we introduce Boundary Stress Microscopy to quantify the non-uniform surface stresses in sheared collagen gels. We find local stresses exceeding average stresses by an order of magnitude, with variations over length scales much larger than the network mesh size. The strain stiffening behavior observed over a wide range of network mesh sizes can be parameterized by a single characteristic strain and associated stress, which describes both the strain stiffening regime and network yielding. The characteristic stress is approximately proportional to network density, but the peak boundary stress at both the characteristic strain and at yielding are remarkably insensitive to concentration. PMID- 25734483 TI - CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCgamma1 activation: evidence from mice and humans. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides. METHODS AND FINDINGS: In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCgamma1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCgamma1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCgamma1 or pharmacological inhibition of PLCgamma1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease. CONCLUSIONS: Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCgamma1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL. PMID- 25734485 TI - Invitation cards during pregnancy enhance male partner involvement in prevention of mother to child transmission (PMTCT) of human immunodeficiency virus (HIV) in Blantyre, Malawi: a randomized controlled open label trial. AB - INTRODUCTION: Male involvement (MI) is vital for the uptake of Prevention of Mother to Child Transmission (PMTCT) of Human Immunodeficiency Virus (HIV) interventions. Partner notification (PN) is among the strategies identified for MI in PMTCT services. The purpose of this randomized controlled trial was to evaluate the efficacy of an invitation card to the male partners as a strategy for MI in PMTCT services by comparing the proportion of pregnant women that were accompanied by their partners between the intervention and the non-intervention study groups. METHODS: Pregnant women attending antenatal care without a male partner at South Lunzu and Mpemba health centres in Blantyre, Malawi, were enrolled in the study from June to December 2013. In an intention-to-treat analysis, we compared all participants that were randomized in the invitation card group with the standard of care (SoC) group. Risk ratios (RR) with 95% confidence intervals (CI) were computed to assess the efficacy of the invitation card. RESULTS: Of the 462 randomized women, 65/230 (28.26%) of the women in the invitation card group reported to the antenatal care clinic with their partners compared to 44/232 (18.97%) women in the SoC group. In an unadjusted intention-to treat analysis women in the invitation card group were 50% more likely to be accompanied by their male partners than those in the SoC group RR: 1.49 (95% CI: 1.06-2.09); p = 0.02. Our random effects analysis showed that there was no clustering by site of recruitment with an inter cluster correlation coefficient (ICC) of 1.98 x 10(-3), (95% CI: 1.78 x10(-7) - 0.96 x 10(-1)); p =0.403. CONCLUSION: An invitation card significantly increased the proportion of women who were accompanied by their male partners for the PMTCT services. An invitation card is a feasible strategy for MI in PMTCT. PMID- 25734487 TI - The Mechanism of Interferon Refractoriness During Hepatitis C Virus Infection and Its Reversal with a Peroxisome Proliferator-Activated Receptor alpha Agonist. AB - Patients who respond poorly to therapies for hepatitis C virus (HCV) infection display a characteristic phenotype with high basal hepatic interferon-stimulated gene (ISG) expression, but limited induction following interferon (IFN) treatment. The molecular pathways that mediate this refractory state are not known. We examined whether the AMPK activator metformin, the PPARgamma agonist pioglitazone, or the PPARalpha agonist WY-14643 could potentiate IFN responses, reverse IFN refractoriness, and enhance viral eradication in hepatocytes. WY 14643 demonstrated the strongest antiviral synergy with IFN-alpha and so was tested in the context of chronic IFN activation. Cells rendered refractory to IFN by IFN-alpha pretreatment were resensitized by WY-14643, as demonstrated by improved STAT1 phosphorylation, promoter activation, and ISG expression. WY-14643 treatment reduced the expression of key negative regulators of IFN signaling: the AXL receptor tyrosine kinase, suppressor of cytokine signaling (SOCS) 1 and 3, which are upregulated in the IFN-refractory state. AXL is a novel regulator of IFN-alpha signaling that is induced by HCV infection in vitro and which may drive SOCS3 expression. Our data suggests that PPARalpha agonists could be a useful adjunct treatment for chronic HCV infection by reducing the expression of AXL/SOCS and increasing the sensitivity to IFN. PMID- 25734488 TI - Ruthenium catalysts bearing a benzimidazolylidene ligand for the metathetical ring-closure of tetrasubstituted cycloolefins. AB - Deprotonation of 1,3-di(2-tolyl)benzimidazolium tetrafluoroborate with a strong base afforded 1,3-di(2-tolyl)benzimidazol-2-ylidene (BTol), which dimerized progressively into the corresponding dibenzotetraazafulvalene. The complexes [RhCl(COD)(BTol)] (COD is 1,5-cyclooctadiene) and cis-[RhCl(CO)2(BTol)] were synthesized to probe the steric and electronic parameters of BTol. Comparison of the percentage of buried volume (%VBur) and of the Tolman electronic parameter (TEP) of BTol with those determined previously for 1,3-dimesitylbenzimidazol-2 ylidene (BMes) revealed that the two N-heterocyclic carbenes displayed similar electron donicities, yet the 2-tolyl substituents took a slightly greater share of the rhodium coordination sphere than the mesityl groups, due to a more pronounced tilt. The anti,anti conformation adopted by BTol in the molecular structure of [RhCl(COD)(BTol)] ensured nonetheless a remarkably unhindered access to the metal center, as evidenced by steric maps. Second-generation ruthenium benzylidene and isopropoxybenzylidene complexes featuring the BTol ligand were obtained via phosphine exchange from the first generation Grubbs and Hoveyda Grubbs catalysts, respectively. The atropisomerism of the 2-tolyl substituents within [RuCl2(=CHPh)(PCy3)(BTol)] was investigated by using variable temperature NMR spectroscopy, and the molecular structures of all four possible rotamers of [RuCl2(=CH-o-O(i)PrC6H4)(BTol)] were determined by X-ray crystallography. Both complexes were highly active at promoting the ring-closing metathesis (RCM) of model alpha,omega-dienes. The replacement of BMes with BTol was particularly beneficial to achieve the ring-closure of tetrasubstituted cycloalkenes. More specifically, the stable isopropoxybenzylidene chelate enabled an almost quantitative RCM of two challenging substrates, viz., diethyl 2,2-bis(2 methylallyl)malonate and N,N-bis(2-methylallyl)tosylamide, within a few hours at 60 degrees C. PMID- 25734486 TI - Collagen matrix as a tool in studying fibroblastic cell behavior. AB - Type I collagen is a fibrillar protein, a member of a large family of collagen proteins. It is present in most body tissues, usually in combination with other collagens and other components of extracellular matrix. Its synthesis is increased in various pathological situations, in healing wounds, in fibrotic tissues and in many tumors. After extraction from collagen-rich tissues it is widely used in studies of cell behavior, especially those of fibroblasts and myofibroblasts. Cells cultured in a classical way, on planar plastic dishes, lack the third dimension that is characteristic of body tissues. Collagen I forms gel at neutral pH and may become a basis of a 3D matrix that better mimics conditions in tissue than plastic dishes. PMID- 25734490 TI - The effect of MLC speed and acceleration on the plan delivery accuracy of VMAT. AB - OBJECTIVE: To determine a new metric utilizing multileaf collimator (MLC) speeds and accelerations to predict plan delivery accuracy of volumetric modulated arc therapy (VMAT). METHODS: To verify VMAT delivery accuracy, gamma evaluations, analysis of mechanical parameter difference between plans and log files, and analysis of changes in dose-volumetric parameters between plans and plans reconstructed with log files were performed with 40 VMAT plans. The average proportion of leaf speeds ranging from l to h cm s(-1) (Sl-h and l-h = 0-0.4, 0.4 0.8, 0.8-1.2, 1.2-1.6 and 1.6-2.0), mean and standard deviation of MLC speeds were calculated for each VMAT plan. The same was carried out for accelerations in centimetre per second squared (Al-h and l-h = 0-4, 4-8, 8-12, 12-16 and 16-20). The correlations of those indicators to plan delivery accuracy were analysed with Spearman's correlation coefficient (rs). RESULTS: The S1.2-1.6 and mean acceleration of MLCs showed generally higher correlations to plan delivery accuracy than did others. The highest rs values were observed between S1.2-1.6 and global 1%/2 mm (rs = -0.698 with p < 0.001) as well as mean acceleration and global 1%/2 mm (rs = -0.650 with p < 0.001). As the proportion of MLC speeds and accelerations >0.4 and 4 cm s(-2) increased, the plan delivery accuracy of VMAT decreased. CONCLUSION: The variations in MLC speeds and accelerations showed considerable correlations to VMAT delivery accuracy. ADVANCES IN KNOWLEDGE: As the MLC speeds and accelerations increased, VMAT delivery accuracy reduced. PMID- 25734489 TI - Intraoperative radiotherapy in early stage breast cancer: potential indications and evidence to date. AB - Following early results of recent studies of intraoperative radiotherapy (IORT) in the adjuvant treatment of patients with early breast cancer, the clinical utility of IORT is a subject of much recent debate within the breast oncology community. This review describes the intraoperative techniques available, the potential indications and the evidence to date pertaining to local control and toxicity. We also discuss any implications for current practice and future research. PMID- 25734492 TI - Ankle Dorsiflexion Displacement During Landing is Associated With Initial Contact Kinematics but not Joint Displacement. AB - The ankle, knee, and hip joints work together in the sagittal plane to absorb landing forces. Reduced sagittal plane motion at the ankle may alter landing strategies at the knee and hip, potentially increasing injury risk; however, no studies have examined the kinematic relationships between the joints during jump landings. Healthy adults (N = 30; 15 male, 15 female) performed jump landings onto a force plate while three-dimensional kinematic data were collected. Joint displacement values were calculated during the loading phase as the difference between peak and initial contact angles. No relationship existed between ankle dorsiflexion displacement during landing and three-dimensional knee and hip displacements. However, less ankle dorsiflexion displacement was associated with landing at initial ground contact with larger hip flexion, hip internal rotation, knee flexion, knee varus, and smaller plantar flexion angles. Findings of the current study suggest that restrictions in ankle motion during landing may contribute to contacting the ground in a more flexed position but continuing through little additional motion to absorb the landing. Transverse plane hip and frontal plane knee positioning may also occur, which are known to increase the risk of lower extremity injury. PMID- 25734491 TI - Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. AB - The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans but virtually absent in rodents, called outer radial glia (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined progenitor subtype-specific sorting with transcriptome-wide RNA sequencing to identify genes enriched in human ORG, which included targets of the transcription factor neurogenin and previously uncharacterized, evolutionarily dynamic long noncoding RNAs. Activating the neurogenin pathway in ferret progenitors promoted delamination and outward migration. Finally, single-cell transcriptional profiling in human, ferret and mouse revealed more cells coexpressing proneural neurogenin targets in human than in other species, suggesting greater neuronal lineage commitment and differentiation of self-renewing progenitors. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors. PMID- 25734494 TI - Hardware-amenable structural learning for spike-based pattern classification using a simple model of active dendrites. AB - This letter presents a spike-based model that employs neurons with functionally distinct dendritic compartments for classifying high-dimensional binary patterns. The synaptic inputs arriving on each dendritic subunit are nonlinearly processed before being linearly integrated at the soma, giving the neuron the capacity to perform a large number of input-output mappings. The model uses sparse synaptic connectivity, where each synapse takes a binary value. The optimal connection pattern of a neuron is learned by using a simple hardware-friendly, margin enhancing learning algorithm inspired by the mechanism of structural plasticity in biological neurons. The learning algorithm groups correlated synaptic inputs on the same dendritic branch. Since the learning results in modified connection patterns, it can be incorporated into current event-based neuromorphic systems with little overhead. This work also presents a branch-specific spike-based version of this structural plasticity rule. The proposed model is evaluated on benchmark binary classification problems, and its performance is compared against that achieved using support vector machine and extreme learning machine techniques. Our proposed method attains comparable performance while using 10% to 50% less in computational resource than the other reported techniques. PMID- 25734493 TI - Neuronal calcium wave propagation varies with changes in endoplasmic reticulum parameters: a computer model. AB - Calcium (Ca2+) waves provide a complement to neuronal electrical signaling, forming a key part of a neuron's second messenger system. We developed a reaction diffusion model of an apical dendrite with diffusible inositol triphosphate (IP3), diffusible Ca2+, IP3 receptors (IP3Rs), endoplasmic reticulum (ER) Ca2+ leak, and ER pump (SERCA) on ER. Ca2+ is released from ER stores via IP3Rs upon binding of IP3 and Ca2+. This results in Ca2+-induced-Ca2+-release (CICR) and increases Ca2+ spread. At least two modes of Ca2+ wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell and a pseudo-saltatory model where Ca2+ regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized IP3R distribution: (1) continuous homogeneous ER, (2) hotspots with increased IP3R density (IP3R hotspots), and (3) areas of increased ER density (ER stacks). All three modes produced Ca2+ waves with velocities similar to those measured in vitro (approximately 50-90 MUm /sec). Continuous ER showed high sensitivity to IP3R density increases, with time to onset reduced and speed increased. Increases in SERCA density resulted in opposite effects. The measures were sensitive to changes in density and spacing of IP3R hotspots and stacks. Increasing the apparent diffusion coefficient of Ca2+ substantially increased wave speed. An extended electrochemical model, including voltage-gated calcium channels and AMPA synapses, demonstrated that membrane priming via AMPA stimulation enhances subsequent Ca2+ wave amplitude and duration. Our modeling suggests that pharmacological targeting of IP3Rs and SERCA could allow modulation of Ca2+ wave propagation in diseases where Ca2+ dysregulation has been implicated. PMID- 25734495 TI - The benefits of modeling slack variables in SVMs. AB - In this letter, we explore the idea of modeling slack variables in support vector machine (SVM) approaches. The study is motivated by SVM+, which models the slacks through a smooth correcting function that is determined by additional (privileged) information about the training examples not available in the test phase. We take a closer look at the meaning and consequences of smooth modeling of slacks, as opposed to determining them in an unconstrained manner through the SVM optimization program. To better understand this difference we only allow the determination and modeling of slack values on the same information--that is, using the same training input in the original input space. We also explore whether it is possible to improve classification performance by combining (in a convex combination) the original SVM slacks with the modeled ones. We show experimentally that this approach not only leads to improved generalization performance but also yields more compact, lower-complexity models. Finally, we extend this idea to the context of ordinal regression, where a natural order among the classes exists. The experimental results confirm principal findings from the binary case. PMID- 25734496 TI - Simultaneous multichannel signal transfers via chaos in a recurrent neural network. AB - We propose neural network model that demonstrates the phenomenon of signal transfer between separated neuron groups via other chaotic neurons that show no apparent correlations with the input signal. The model is a recurrent neural network in which it is supposed that synchronous behavior between small groups of input and output neurons has been learned as fragments of high-dimensional memory patterns, and depletion of neural connections results in chaotic wandering dynamics. Computer experiments show that when a strong oscillatory signal is applied to an input group in the chaotic regime, the signal is successfully transferred to the corresponding output group, although no correlation is observed between the input signal and the intermediary neurons. Signal transfer is also observed when multiple signals are applied simultaneously to separate input groups belonging to different memory attractors. In this sense simultaneous multichannel communications are realized, and the chaotic neural dynamics acts as a signal transfer medium in which the signal appears to be hidden. PMID- 25734497 TI - Positive effects of bFGF modified rat amniotic epithelial cells transplantation on transected rat optic nerve. AB - PURPOSE: Effective therapy for visual loss caused by optic nerve injury or diseases has not been achieved even though the optic nerve has the regeneration potential after injury. This study was designed to modify amniotic epithelial cells (AECs) with basic fibroblast growth factor (bFGF) gene, preliminarily investigating its effect on transected optic nerve. METHODS: A human bFGF gene segment was delivered into rat AECs (AECs/hbFGF) by lentiviral vector, and the gene expression was examined by RT-PCR and ELISA. The AECs/hbFGF and untransfected rat AECs were transplanted into the transected site of the rat optic nerve. At 28 days post transplantation, the survival and migration of the transplanted cells was observed by tracking labeled cells; meanwhile retinal ganglion cells (RGCs) were observed and counted by employing biotin dextran amine (BDA) and Nissl staining. Furthermore, the expression of growth associated protein 43 (GAP-43) within the injury site was examined with immunohistochemical staining. RESULTS: The AECs/hbFGF was proven to express bFGF gene and secrete bFGF peptide. Both AECs/hbFGF and AECs could survive and migrate after transplantation. RGCs counting implicated that RGCs numbers of the cell transplantation groups were significantly higher than that of the control group, and the AECs/hbFGF group was significantly higher than that of the AECs group. Moreover GAP-43 integral optical density value in the control group was significantly lower than that of the cell transplantation groups, and the value in the AECs/hbFGF group was significantly higher than that of the AECs group. CONCLUSIONS: AECs modified with bFGF could reduce RGCs loss and promote expression of GAP-43 in the rat optic nerve transected model, facilitating the process of neural restoration following injury. PMID- 25734499 TI - Morpholino-functionalized nanochannel array for label-free single nucleotide polymorphisms detection. AB - The sensitive identification of single nucleotide polymorphisms becomes increasingly important for disease diagnosis, prevention, and practical applicability of pharmacogenomics. Herein, we propose a simple, highly selective, label-free single nucleotide polymorphisms (SNPs) sensing device by electrochemically monitoring the diffusion flux of ferricyanide probe across probe DNA/morpholino duplex functionalized nanochannels of porous anodic alumina. When perfectly matched or mismatched target DNA flows through the nanochannels modified with probe DNA/morpholino duplex, it competes for the probe DNA from morpholino, resulting in a change of the surface charges. Thus, the diffusion flux of negatively charged electroactive probe ferricyanide is modulated since it is sensitive to the surface charge due to the electrostatic interactions in electric double layer-merged nanochannels. Monitoring of the change in diffusion flux of probe enables us to detect not only a single base or two base mismatched sequence but also the specific location of the mismatched base. As is demonstrated, SNPs in the PML/RARalpha fusion gene, known as a biomarker of acute promyelocytic leukemia (APL), have been successfully detected. PMID- 25734498 TI - Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1 cytosolic free calcium pathway. AB - Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase 8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain. PMID- 25734500 TI - Effect of water vapor on Pd-loaded SnO2 nanoparticles gas sensor. AB - The effect of water vapor on Pd-loaded SnO2 sensor was investigated through the oxygen adsorption behavior and sensing properties toward hydrogen and CO under different humidity conditions. On the basis of the theoretical model reported previously, it was found that the mainly adsorbed oxygen species on the SnO2 surface in humid atmosphere was changed by loading Pd, more specifically, for neat SnO2 was O(-), while for 0.7% Pd-SnO2 was O(2-). The water vapor poisoning effect on electric resistance and sensor response was reduced by loading Pd. Moreover the sensor response in wet atmosphere was greatly enhanced by loading Pd. It seems that the electron depletion layer by p-n junction of PdO-SnO2 may impede OH(-) adsorption. PMID- 25734501 TI - Molecular identification and functional characterization of the fatty acid- and retinoid-binding protein gene Rs-far-1 in the burrowing nematode Radopholus similis (Tylenchida: Pratylenchidae). AB - Fatty acid- and retinoid-binding protein (FAR) is a nematode-specific protein expressed in the nematode hypodermis. It is involved in nematode development, reproduction, and infection and can disrupt the plant defense reaction. In this study, we obtained the full-length sequence of the far gene from Radopholus similis (Rs-far-1), which is 828 bp long and includes a 558 bp ORF encoding 186 amino acids. A protein homology analysis revealed that Rs-FAR-1 is 75% similar to Mj-FAR-1 from Meloidogyne javanica. A neighbor-joining phylogenetic tree was inferred and showed that Rs-FAR-1 is most similar to Pv-FAR-1 from Pratylenchus vulnus. A fluorescence-based ligand-binding analysis confirmed that Rs-FAR-1 can combine with fatty acids and retinol. qPCR was used to assess Rs-far-1 expression levels at different developmental stages in different R. similis populations, and its expression was 2.5 times greater in the highly pathogenic Rs-C population than in the less pathogenic Rs-P population. The highest expression was found in females, followed by eggs, juveniles and males. When R. similis was treated with Rs-far-1 dsRNA for 36 h, the reproduction and pathogenicity decreased significantly. In situ hybridization revealed Rs-far-1 transcripts in the R. similis hypodermis. Additionally, R. similis treated with Rs-far-1 dsRNA or water were inoculated into Arabidopsis thaliana. Allene oxide synthase (AOS) expression in A. thaliana was upregulated during early infection in both treatments and then returned to the expression levels of the control plant. Compared with the control plant, AOS expression significantly decreased in A. thaliana inoculated with water-treated R. similis but significantly increased in A. thaliana inoculated with Rs-far-1 dsRNA-treated R. similis. This finding indicates that Rs-far-1 regulates AOS expression in A. thaliana. Rs-FAR-1 plays a critical role in R. similis development, reproduction, and infection and can disturb the plant defense reaction. Therefore, Rs-far-1 is an important target gene to control R. similis. PMID- 25734502 TI - Factors associated with parent concern for child weight and parenting behaviors. AB - BACKGROUND: A parent's perception about their child's overweight status is an important precursor or determinant of preventative actions. Acknowledgment of, and concern for, overweight may be moderated by the parent's own weight status whereas engaging in healthy behaviors at home may promote healthy weight status. It is hypothesized that normal weight parents are more likely to engage in healthy behaviors and acknowledge overweight in their own children whereas heavier parents may report more concern about child weight. METHODS: A total of 1745 parents of first- through fifth-grade students completed a questionnaire assessing reactions to a school BMI report and perceptions about BMI issues. Specific items included perceptions of child's weight status, concern for child weight status, and preventive practices. Parents also provided information about their own weight status. Relationships between measured child weight, perceived child weight, parent weight, parent concern, and healthy behaviors were examined. RESULTS: Overweight parents were more likely to identify overweight in their child and report concern about their child's weight. Concern was higher for parents of overweight children than of normal weight children. Normal weight parents and parents of normal weight children reported more healthy behaviors. CONCLUSIONS: Results support the hypothesis that normal weight parents are more likely to engage in healthy behaviors and that overweight parents are more likely to report concern about child weight. However, overweight parents are also more likely to acknowledge overweight status in their own child. Future research should examine links between parent concern and actual pursuit of weight management assistance. PMID- 25734503 TI - Socioeconomic position and stage at diagnosis of head and neck cancer - a nationwide study from DAHANCA. AB - BACKGROUND: Socioeconomic differences in survival after head and neck squamous cell carcinoma (HNSCC) are among the greatest for any malignancy. To improve our understanding of the mechanisms by which socioeconomic position influences HNSCC survival, we investigated the association between socioeconomic position and advanced stage HNSCC at diagnosis. MATERIAL AND METHODS: Men and women with HNSCC diagnosed between 1992 and 2008 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database, which contains detailed information on all cases of HNSCC treated in Denmark. Individual information on the following four socioeconomic indicators: highest attained educational level, cohabitation status, disposable income and degree of urbanisation were obtained from Statistics Denmark. For the 9683 cases on which there was full information, we estimated odds ratios (ORs) for a diagnosis of advanced stage (TNM III-IV) HNSCC in multivariate logistic regression models by site (glottic, non-glottic larynx, oropharynx, hypopharynx and oral cancer), with adjustment for age, gender, period of diagnosis, education, income, cohabitation status, degree of urbanisation and comorbidity in accordance with a causal diagram. RESULTS: For all HNSCC sites, the ORs for advanced stage at diagnosis were increased for patients with low income and for men living alone. For glottic and oral cancers, the ORs for advanced stage HNSCC increased systematically by decreasing length of education. Increased ORs were found for hypopharynx cancer patients living in rural areas or provincial cities. Having one or more comorbid conditions was associated with an increased OR for advanced stage oral cancer but with a decreased OR for oropharynx cancer. CONCLUSION: In this nationwide population-based study, socioeconomic differences in stage at diagnosis were found for all HNSCC subsites. Focus on the high risk for advanced stage HNSCC among vulnerable patients may be beneficial during referral and diagnosis in order to improve HNSCC outcomes. PMID- 25734504 TI - The discharge of certain amounts of industrial microplastic from a production plant into the River Danube is permitted by the Austrian legislation. AB - Numerous studies have quantified the amount of plastic litter in aquatic ecosystems and tried to assess its impacts and threats. This reflects a rising awareness of plastic as an environmental problem. As a next logical step, identifying and regulating the sources must be in the focus of scientific efforts. We report on a spillage of industrial microplastic (IMP) from a production plant situated at an Austrian Danube tributary. This is the first identified point source of IMP litter in freshwater systems. However, due to generous thresholds established by the Austrian government substantial amounts of IMP are legally introduced into running waters. PMID- 25734505 TI - Advanced oxidation (H2O2 and/or UV) of functionalized carbon nanotubes (CNT-OH and CNT-COOH) and its influence on the stabilization of CNTs in water and tannic acid solution. AB - The properties of carbon nanotubes (CNTs) functionalized with -OH and -COOH groups during simulated water treatment with H2O2 and/or UV were tested. There following properties of CNTs were investigated: specific surface area, elemental composition (CHN), dynamic light scattering, Raman spectroscopy, X-ray photoelectron spectroscopy and changes in the CNTs structure were observed using transmission electron microscopy. Treatment of CNTs with H2O2 and/or UV affected their properties. This effect, however, was different depending on the functionalization of CNTs and also on the factor used (UV and/or H2O2). H2O2 plays a key role as a factor modifying the surface of CNT-OHs, whereas the properties of CNT-COOHs were most affected by UV rays. A shortening of the nanotubes, exfoliation, the opening of their ends, and changes in the surface charge were observed as a result of the action of UV and/or H2O2. The changes in observed parameters may influence the stability of the aqueous suspensions of CNTs. PMID- 25734506 TI - Synthesis and enzymatic studies of bisubstrate analogues for farnesyl diphosphate synthase. AB - Farnesyl diphosphate synthase catalyzes the sequential chain elongation reactions between isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) to form geranyl diphosphate (GPP) and between IPP and GPP to give farnesyl diphosphate (FPP). Bisubstrate analogues containing the allylic and homoallylic substrates were synthesized by joining fragments for IPP and the allylic diphosphates with a C-C bond between the methyl group at C3 in IPP and the Z methyl group at C3 in DMAPP (3-OPP) and GPP (4-OPP), respectively. These constructs placed substantial limits on the conformational space available to the analogues relative to the two substrates. The key features of the synthesis of bisubstrate analogues 3-OPP and 4-OPP are a regioselective C-alkylation of the dianion of 3-methyl-3-buten-1-ol (5), a Z-selective cuprate addition of alkyl groups to an alpha,beta-alkynyl ester intermediate, and differential activation of allylic and homoallylic alcohols in the analogues, followed by a simultaneous displacement of the leaving groups with tris(tetra-n-butylammonium) hydrogen diphosphate to give the corresponding bisdiphosphate analogues. The bisubstrate analogues were substrates for FPP synthase, giving novel seven-membered ring analogues of GPP and FPP. The catalytic efficiencies for cyclization of 3-OPP and 4-OPP were similar to those for chain elongation with IPP and DMAPP. PMID- 25734507 TI - Negatively charged glyconanoparticles modulate and stabilize the secondary structures of a gp120 V3 loop peptide: toward fully synthetic HIV vaccine candidates. AB - The third variable region (V3 peptide) of the HIV-1 gp120 is a major immunogenic domain of HIV-1. Controlling the formation of the immunologically active conformation is a crucial step to the rational design of fully synthetic candidate vaccines. Herein, we present the modulation and stabilization of either the alpha-helix or beta-strand conformation of the V3 peptide by conjugation to negatively charged gold glyconanoparticles (GNPs). The formation of the secondary structure can be triggered by the variation of the buffer concentration and/or pH as indicated by circular dichoism. The peptide on the GNPs shows increased stability toward peptidase degradation as compared to the free peptide. Moreover, only the V3beta-GNPs bind to the anti-V3 human broadly neutralizing mAb 447-52D as demonstrated by surface plasmon resonance (SPR). The strong binding of V3beta GNPs to the 447-52D mAb was the starting point to address its study as immunogen. V3beta-GNPs elicit antibodies in rabbits that recognize a recombinant gp120 and the serum displayed low but consistent neutralizing activity. These results open up the way for the design of new fully synthetic HIV vaccine candidates. PMID- 25734508 TI - Carboxylic acid catalyzed hydration of acetaldehyde. AB - Electronic structure calculations of the pertinent stationary points on the potential energy surface show that carboxylic acids can act effectively as catalysts in the hydration of acetaldehyde. Barriers to this catalyzed process correlate strongly with the pKa of the acid, providing the potential to provide the predictive capacity of the effectiveness of carboxylic acid catalysts. Transition states for the acid-catalyzed systems take the form of pseudo-six membered rings through the linear nature of their hydrogen bonds, which accounts for their relative stability compared to the more strained direct and water catalyzed systems. When considered as a stepwise reaction of a dimerization followed by reaction/complexation, it is likely that collisional stabilization of the prereactive complex is more likely than reaction in the free gas phase, although the catalyzed hydration does retain the potential to proceed on water surfaces or in droplets. Lastly, it is observed that postreactive diol-acid complexes are significantly stable (~12-17 kcal/mol) relative to isolated products, suggesting the possibility of long-lived hygroscopic species that could act as a seed molecule for condensation of secondary organic aerosols. PMID- 25734509 TI - Educational attainment influences levels of homozygosity through migration and assortative mating. AB - Individuals with a higher education are more likely to migrate, increasing the chance of meeting a spouse with a different ancestral background. In this context, the presence of strong educational assortment can result in greater ancestry differences within more educated spouse pairs, while less educated individuals are more likely to mate with someone with whom they share more ancestry. We examined the association between educational attainment and F roh (= the proportion of the genome consisting of runs of homozygosity [ROHs]) in ~2,000 subjects of Dutch ancestry. The subjects' own educational attainment showed a nominally significant negative association with F roh (p = .045), while the contribution of parental education to offspring F roh was highly significant (father: p < 10(-5); mother: p = 9 * 10(-5)), with more educated parents having offspring with fewer ROHs. This association was significantly and fully mediated by the physical distance between parental birthplaces (paternal education: pmediation = 2.4 * 10(-4); maternal education: pmediation = 2.3 * 10(-4)), which itself was also significantly associated with F roh (p = 9 * 10(-5)). Ancestry informative principal components from the offspring showed a significantly decreasing association with geography as parental education increased, consistent with the significantly higher migration rates among more educated parents. Parental education also showed a high spouse correlation (Spearman's rho = .66, p = 3 * 10(-262)). We show that less educated parents are less likely to mate with the more mobile parents with a higher education, creating systematic differences in homozygosity due to ancestry differences not directly captured by ancestry informative principal components (PCs). Understanding how behaviors influence the genomic structure of a population is highly valuable for studies on the genetic etiology of behavioral, cognitive, and social traits. PMID- 25734510 TI - Knockdown of corticotropin-releasing factor in the central amygdala reverses persistent viscerosomatic hyperalgesia. AB - Gastrointestinal nociception is exacerbated by chronic stress through an unknown mechanism. The amygdala is a key nucleus involved in the autonomic and neuroendocrine responses to stress. The goal of this study was to test the hypothesis that prolonged exposure of the central amygdala (CeA) to stress or the stress hormone cortisol (or corticosterone in rats) induces nociceptive behaviors mediated by corticotropin-releasing factor (CRF) within the CeA. We selectively knocked down CRF in the CeA via antisense oligodeoxynucleotides (ASO) in animals with targeted, stereotaxically placed corticosterone (CORT) micropellets or following repeated water avoidance stress (WAS). CRF expression in the CeA was analyzed concurrently with the assessment of visceral hypersensitivity to colonic distension and mechanical somatic withdrawal threshold. The responses were characterized at 7 or 28 days post implantation of the CORT micropellet or following 7 days of WAS. Exposure of the CeA to elevated CORT or WAS increased CRF expression and heightened visceral and somatic sensitivity. Infusion of CRF ASO into the CeA decreased CRF expression and attenuated visceral and somatic hypersensitivity in both models. Our study provides important evidence for a CRF mediated mechanism specifically within the CeA that regulates stress-induced visceral and somatic nociception. PMID- 25734511 TI - Total serum cholesterol, atherogenic indices and their longitudinal association with depressive symptoms among US adults. AB - Serum cholesterol, both total and lipoprotein fractions, has been associated with mid- and late-life depression. Using longitudinal data on a large and ethnically diverse sample of urban adults, the associations of serum lipid profile measured by high or low total cholesterol (TC; >200 mg dl(-1); <160 mg dl(-1)) and by atherogenic indices, namely high total cholesterol and low-density lipoprotein cholesterol relative to high-density lipoprotein cholesterol, with change in total and domain-specific depressive symptoms over time were examined. Findings were compared by sex. (Hypothesis 1) In addition, baseline depressive symptoms as predictors for longitudinal change in lipid profile trajectory were tested. (Hypothesis 2) Mixed-effects regression analyses stratified by sex was used. Sample sizes of participants (n) and repeated observations (n') were: Hypothesis 1 (Men: n=826 ; n'=1319; Women: n=1099 ; n'=1817); Hypothesis 2 (Men: n=738; n'=1230; Women: n=964; n'=1678). As hypothesized, a higher level of atherogenic indices was linked to faster increase in depressive symptom scores, particularly depressed affect and interpersonal problems, though this relationship was found only among women. Among men a U-shaped relationship between baseline TC and longitudinal increase in somatic complaints and a direct link between low TC and longitudinal putative improvement in positive affect was found. On excluding statin users among women, low TC was associated with slower increase in depressed affect over time, whereas high TC was associated with faster increase in interpersonal problems. In summary, atherogenic indices were directly linked to faster increase in depressive symptoms among women only. More studies are needed to explain these sex-specific associations. PMID- 25734512 TI - Identification of genes and gene pathways associated with major depressive disorder by integrative brain analysis of rat and human prefrontal cortex transcriptomes. AB - Despite moderate heritability estimates, progress in uncovering the molecular substrate underpinning major depressive disorder (MDD) has been slow. In this study, we used prefrontal cortex (PFC) gene expression from a genetic rat model of MDD to inform probe set prioritization in PFC in a human post-mortem study to uncover genes and gene pathways associated with MDD. Gene expression differences between Flinders sensitive (FSL) and Flinders resistant (FRL) rat lines were statistically evaluated using the RankProd, non-parametric algorithm. Top ranking probe sets in the rat study were subsequently used to prioritize orthologous selection in a human PFC in a case-control post-mortem study on MDD from the Stanley Brain Consortium. Candidate genes in the human post-mortem study were then tested against a matched control sample using the RankProd method. A total of 1767 probe sets were differentially expressed in the PFC between FSL and FRL rat lines at (q?0.001). A total of 898 orthologous probe sets was found on Affymetrix's HG-U95A chip used in the human study. Correcting for the number of multiple, non-independent tests, 20 probe sets were found to be significantly dysregulated between human cases and controls at q?0.05. These probe sets tagged the expression profile of 18 human genes (11 upregulated and seven downregulated). Using an integrative rat-human study, a number of convergent genes that may have a role in pathogenesis of MDD were uncovered. Eighty percent of these genes were functionally associated with a key stress response signalling cascade, involving NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells), AP-1 (activator protein 1) and ERK/MAPK, which has been systematically associated with MDD, neuroplasticity and neurogenesis. PMID- 25734513 TI - Dopaminergic function and intertemporal choice. PMID- 25734514 TI - Altered hippocampal-dependent memory and motor function in neuropilin 2-deficient mice. AB - Semaphorins have an important role in synapse refinement in the mammalian nervous system. The class 3 semaphorin-3F (Sema3F) acting through neuropilin 2/plexin-A3 (Nrp2/PlexA3) holoreceptor complex signals in vivo to restrain apical dendritic spine morphogenesis of cortical pyramidal neurons and hippocampal neurons during postnatal development and mediates excitatory synaptic transmission. Semaphorin signaling has been implicated in the etiology of a number of neurodevelopmental disorders; however, the effects on behavior and mental function of dysregulated Sema3F-Nrp2 signaling have not been fully addressed. The present study is the first behavioral investigation of mice harboring a mutation of the nrp2 gene. Given that loss of Nrp2 signaling alters cortical and hippocampal synaptic organization, we investigated performance of nrp2-deficient mice on learning and sensorimotor function that are known to depend on cortical and hippocampal circuitry. When compared with age-matched controls, nrp2 null mice showed striking impairments in object recognition memory and preference for social novelty. In addition, nrp2(-/-) mice displayed impaired motor function in the rotarod test and in observations of grooming behavior. Exploration of novel olfactory sensory stimuli and nociception were unaffected by the loss of Nrp2. Overall, loss of Nrp2 may induce aberrant processing within hippocampal and corticostriatal networks that may contribute to neurodevelopmental disease mechanisms. PMID- 25734515 TI - 11beta-HSD1 modulates LPS-induced innate immune responses in adipocytes by altering expression of PTEN. AB - Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) represents a therapeutic target for treating hyperglycemia in type 2 diabetes. Here, we investigate the effects of 11beta-HSD1 on the innate immune response of adipocytes to produce proinflammatory cytokines. The 11beta-HSD1 inhibitor emodin, or 11beta-HSD1-targeted small interfering RNA, dose dependently suppressed IL-6, IL-1beta, and TNF-alpha expression in lipopolysaccharide-treated 3T3-L1 adipocytes. Inhibiting 11beta-HSD1 also reduced phosphatase and tensin homologue (PTEN) expression, a negative regulator of phosphatidylinositol 3 kinase effects, whereas 1pM cortisone or dexamethasone induced IL-6 and PTEN levels. PTEN-targeted small interfering RNA decreased IL-6, IL-1beta, and TNF alpha without affecting 11beta-HSD1 levels. Correspondingly, emodin increased phosphorylated protein kinase B (p-PKB) (Ser473) to PKB ratio but not p-PKB (Thr308) to PKB ratio. Emodin did not increase the p-PKB (Ser473) to PKB ratio when the rapamycin-insensitive companion of mTOR was depleted, further supporting the involvement of mammalian target of rapamycin complex 2 in PKB phosphorylation. Moreover, emodin suppressed phosphorylated inhibitor of kappaB alpha (p-IkappaBalpha) to IkappaBalpha ratio and reduced nuclear factor kappa B subunit p50 in the nuclear fraction. In contrast, 1pM cortisone or dexamethasone decreased p-PKB (Ser473) to PKB ratio, increased p-IkappaBalpha to IkappaBalpha ratio, and increased nuclear NF-kappaB subunit p50. Additionally, wortmannin had similar effects on IL-6, p-PKB (Ser473) to PKB ratio, and p-IkappaBalpha to IkappaBalpha ratio as 1pM cortisone or dexamethasone. Finally, emodin treatment of streptozotocin diabetic rats on a high-fat diet reduced levels of IL-6, PTEN, Cluster of Differentiation 68, and the ratio of p-IkappaBalpha to IkappaBalpha in visceral fat, indicating that our findings in vitro may also apply to visceral fat in vivo. Together, these results suggest that inhibiting 11beta-HSD1 reduces lipopolysaccharide-induced proinflammatory innate immune responses in adipocytes by down-regulating PTEN expression, leading to activation of the PI3K/PKB pathway. PMID- 25734516 TI - 17beta-Estradiol increases persistent Na(+) current and excitability of AVPV/PeN Kiss1 neurons in female mice. AB - In vitro slice studies have revealed that there are significant differences in the spontaneous firing activity between anteroventral periventricular/periventricular preoptic nucleus (AVPV/PeN) and arcuate nucleus (ARC) kisspeptin (Kiss1) neurons in females. Although both populations express similar endogenous conductances, we have discovered that AVPV/PeN Kiss1 neurons express a subthreshold, persistent sodium current (INaP) that dramatically alters their firing activity. Based on whole-cell recording of Kiss1-Cre-green fluorescent protein (GFP) neurons, INaP was 4-fold greater in AVPV/PeN vs ARC Kiss1 neurons. An LH surge-producing dose of 17beta-estradiol (E2) that increased Kiss1 mRNA expression in the AVPV/PeN, also augmented INaP in AVPV/PeN neurons by 2-fold. Because the activation threshold for INaP was close to the resting membrane potential (RMP) of AVPV/PeN Kiss1 neurons (-54 mV), it rendered them much more excitable and spontaneously active vs ARC Kiss1 neurons (RMP = -66 mV). Single-cell RT-PCR revealed that AVPV/PeN Kiss1 neurons expressed the requisite sodium channel alpha-subunit transcripts, NaV1.1, NaV1.2, and NaV1.6 and beta subunits, beta2 and beta4. Importantly, NaV1.1alpha and -beta2 transcripts in AVPV/PeN, but not ARC, were up-regulated 2- to 3-fold by a surge-producing dose of E2, similar to the transient calcium current channel subunit Cav3.1. The transient calcium current collaborates with INaP to generate burst firing, and selective blockade of INaP by riluzole significantly attenuated rebound burst firing and spontaneous activity. Therefore, INaP appears to play a prominent role in AVPV/PeN Kiss1 neurons to generate spontaneous, repetitive burst firing, which is required for the high-frequency-stimulated release of kisspeptin for exciting GnRH neurons and potentially generating the GnRH surge. PMID- 25734517 TI - Maternal Blood Manganese and Early Neurodevelopment: The Mothers and Children's Environmental Health (MOCEH) Study. AB - BACKGROUND: Manganese is an essential trace element and common component of water, soil, and air. Prenatal manganese exposure may affect fetal and infantile neurodevelopment, but reports on in utero manganese exposure and infant neurodevelopment are rare. OBJECTIVE: This study was conducted to investigate a relationship between maternal blood manganese level and neurodevelopment of infants at 6 months of age. METHODS: Data were obtained from the Mothers and Children's Environmental Health (MOCEH) birth cohort study. The study population included 232 pairs of pregnant women and their infants at 6 months of age. Maternal blood manganese was measured at term, just before delivery. Mental and psychomotor development in infancy was assessed at 6 months of age using the Bayley Scales of Infant Development. The relationship between maternal blood manganese level and the mental and psychomotor development indexes (MDI and PDI) was estimated for manganese modeled as a linear and as a categorical variable and using penalized splines for nonlinear modeling. RESULTS: Mean +/- SD maternal blood manganese concentration was 22.5 +/- 6.5 MUg/L. After adjustment for potential confounders, blood manganese was used as a continuous variable in a linear and nonlinear model. Associations between maternal blood manganese and MDI and PDI scores followed an inverted U-shape dose-response curve after adjustment for potential confounders, with lower scores associated with both low and high blood concentrations [MDI: likelihood-ratio test (LRT) p = 0.075, PDI: LRT p = 0.038]. Associations of both outcomes with increasing blood manganese shifted from positive to negative at concentrations of 24-28 MUg/L in this cohort of term, normal birth weight children. CONCLUSION: Although no cut-off point has been established to define manganese toxicity, both high and low blood manganese levels may be associated with neurobehavioral function in infants. PMID- 25734518 TI - Clonality and micro-diversity of a nationwide spreading genotype of Mycobacterium tuberculosis in Japan. AB - Mycobacterium tuberculosis transmission routes can be estimated from genotypic analysis of clinical isolates from patients. In Japan, still a middle-incidence country of TB, a unique genotype strain designated as 'M-strain' has been isolated nationwide recently. To ascertain the history of the wide spread of the strain, 10 clinical isolates from different areas were subjected to genome-wide analysis based on deep sequencers. Results show that all isolates possessed common mutations to those of referential strains. The greatest number of accumulated single nucleotide variants (SNVs) from the oldest coalescence was 13 nucleotides, indicating high clonality of these isolates. When an SNV common to the isolates was used as a surrogate marker of the clone, authentic clonal isolates with variation in a reliable subset of variable number of tandem repeat (VNTR) genotyping method can be selected successfully from clinical isolates populations of M. tuberculosis. When the authentic clones can also be assigned to sub-clonal groups by SNVs derived from the genomic comparison, they are classifiable into three sub-clonal groups with a bias of geographical origins. Feedback from genomic analysis of clinical isolates of M. tuberculosis to genotypic markers will be an efficient strategy for the big data in various settings for public health actions against TB. PMID- 25734520 TI - Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors. AB - Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6 selective inhibitors as chemical biology tools and ultimately as new therapeutic agents. Herein we report the design, synthesis, and phenotypic screening of a novel class of 3-aminopyrrolidinone-based hydroxamic acids as HDAC6 inhibitors. In particular, the alpha-methyl-substituted enantiomer 33 (3-S) showed significant in-cell tubulin acetylation (Tub-Ac) with an EC50 of 0.30 MUM but limited impact on p21 levels at various concentrations. In enzyme inhibition assays, 33 demonstrated high selectivity for HDAC6 with an IC50 of 0.017 MUM and selectivity indexes of 10 against HDAC8 and over 4000 against HDAC1-3 isoforms. Moreover, 33 has suitable drug metabolism and pharmacokinetics properties compared with other hydroxamic acid-based HDAC inhibitors, warranting further biological studies and development as a selective HDAC6 inhibitor. PMID- 25734521 TI - Indications and appropriateness of inferior vena cava filter placement. AB - BACKGROUND: Several professional societies have published guidelines for the placement of inferior vena cava (IVC) filters. The authors wanted to determine how frequently patients in their hospital had IVC filters placed based on current indications and to compare guidelines published by the American College of Chest Physicians (ACCP) and the Society of Interventional Radiologists (SIR). METHODS: The authors performed a structured review of the medical records of 180 patients identified by International Classification of Diseases, Ninth Revision, codes who had IVC filter placement at their hospital between July 1, 2007, and June 30, 2012. Indications for placement were based on current recommendations from the ACCP and SIR. RESULTS: These patients had a mean age of 62.4 +/- 15.7 years and included 96 men and 84 women. One hundred forty patients had a history of deep venous thrombosis, pulmonary emboli or both. One hundred seven patients had permanent filters inserted, 34 had retrievable filters inserted and 39 had an unknown type of filter inserted. Forty-one patients (22.7%) had no definite indication for IVC filter insertion based on SIR guidelines, and 72 (40%) had no definite indication based on ACCP guidelines. There was a good agreement between the ACCP guidelines and the SIR guidelines when indications were categorized. Only one retrievable filter was removed. CONCLUSIONS: Twenty to forty percent of the patients with IVC filter insertions in their hospital had no definite indication documented in the medical record. A performance improvement activity to evaluate the use of IVC filters, such as a dedicated clinic, may be useful. PMID- 25734519 TI - Functional changes in the human auditory cortex in ageing. AB - Hearing loss, presbycusis, is one of the most common sensory declines in the ageing population. Presbycusis is characterised by a deterioration in the processing of temporal sound features as well as a decline in speech perception, thus indicating a possible central component. With the aim to explore the central component of presbycusis, we studied the function of the auditory cortex by functional MRI in two groups of elderly subjects (>65 years) and compared the results with young subjects (45 years old), members of a larger family, people of low income or low education, and those who perceived themselves to be obese valued front-of-pack nutritional labeling. WTP estimates across all countries provided an average accepted added price of $4.32 to the overall yearly food expenditure (95% confidence interval, 3.33-3.68). CONCLUSIONS: Overall, perceived value of labeling is low. However, factors affecting the value for consumer of nutritional labeling appear to be strictly linked to the socioeconomic and health status of the respondents. PMID- 25734530 TI - Correction: association between cutaneous nevi and breast cancer in the nurses' health study: a prospective cohort study. AB - [This corrects the article DOI: 10.1371/journal.pmed.1001659.]. PMID- 25734531 TI - Efficient removal of uranium from aqueous solution by zero-valent iron nanoparticle and its graphene composite. AB - Zero-valent iron nanoparticle (ZVI-np) and its graphene composites were prepared and applied in the removal of uranium under anoxic conditions. It was found that solutions containing 24 ppm U(VI) could be completely cleaned up by ZVI-nps, regardless of the presence of NaHCO3, humic acid, mimic groundwater constituents or the change of solution pH from 5 to 9, manifesting the promising potential of this reactive material in permeable reactive barrier (PRB) to remediate uranium contaminated groundwater. In the measurement of maximum sorption capacity, removal efficiency of uranium kept at 100% until C0(U) = 643 ppm, and the saturation sorption of 8173 mg U/g ZVI-nps was achieved at C0(U) = 714 ppm. In addition, reaction mechanisms were clarified based on the results of SEM, XRD, XANES, and chemical leaching in (NH4)2CO3 solution. Partially reductive precipitation of U(VI) as U3O7 was prevalent when sufficient iron was available; nevertheless, hydrolysis precipitation of U(VI) on surface would be predominant as iron got insufficient, characterized by releases of Fe(2+) ions. The dissolution of Fe(0) cores was assigned to be the driving force of continuous formation of U(VI) (hydr)oxide. The incorporation of graphene supporting matrix was found to facilitate faster removal rate and higher U(VI) reduction ratio, thus benefitting the long-term immobilization of uranium in geochemical environment. PMID- 25734532 TI - Decolorization and mineralization of Allura Red AC aqueous solutions by electrochemical advanced oxidation processes. AB - The decolorization and mineralization of solutions containing 230 mg L(-1) of the food azo dye Allura Red AC at pH 3.0 have been studied upon treatment by electrochemical oxidation with electrogenerated H2O2 (EO-H2O2), electro-Fenton (EF) and photoelectro-Fenton (PEF). Experiments were performed with a stirred tank reactor containing a boron-doped diamond (BDD) or Pt anode and an air diffusion cathode to generate H2O2. The main oxidants were hydroxyl radicals formed at the anode surface from water oxidation and in the bulk from Fenton's reaction between H2O2 and added Fe(2+). The oxidation ability increased in the sequence EO-H2O2 < EF < PEF and faster degradation was always obtained using BDD. PEF process with BDD yielded almost total mineralization following similar trends in SO4(2-), ClO4(-) and NO3(-) media, whereas in Cl(-) medium, mineralization was inhibited by the formation of recalcitrant chloroderivatives. GC-MS analysis confirmed the cleavage of the -N=N- bond with formation of two main aromatics in SO4(2-) medium and three chloroaromatics in Cl(-) solutions. The effective oxidation of final oxalic and oxamic acids by BDD along with the photolysis of Fe(III)-oxalate species by UVA light accounted for the superiority of PEF with BDD. NH4(+), NO3(-) and SO4(2-) ions were released during the mineralization. PMID- 25734533 TI - Enhanced sulfamethazine removal by steam-activated invasive plant-derived biochar. AB - Recent investigations have shown frequent detection of pharmaceuticals in soils and waters posing potential risks to human and ecological health. Here, we report the enhanced removal of sulfamethazine (SMT) from water by physically activated biochar. Specifically, we investigated the effects of steam-activated biochars synthesized from an invasive plant (Sicyos angulatus L.) on the sorption of SMT in water. The properties and sorption capacities of steam-activated biochars were compared with those of conventional non-activated slow pyrolyzed biochars. Sorption exhibited pronounced pH dependence, which was consistent with SMT speciation and biochar charge properties. A linear relationship was observed between sorption parameters and biochar properties such as molar elemental ratios, surface area, and pore volumes. The isotherms data were well described by the Freundlich and Temkin models suggesting favorable chemisorption processes and electrostatic interactions between SMT and biochar. The steam-activated biochar produced at 700 degrees C showed the highest sorption capacity (37.7 mg g(-1)) at pH 3, with a 55% increase in sorption capacity compared to that of non activated biochar produced at the same temperature. Therefore, steam activation could potentially enhance the sorption capacities of biochars compared to conventional pyrolysis. PMID- 25734534 TI - Immobilization of selenite via two parallel pathways during in situ bioremediation. AB - It is widely understood that selenite can be biologically reduced to elemental selenium. Limited studies have shown that selenite can also be immobilized through abiotic precipitation with sulfide, a product of biological sulfate reduction. We demonstrate that both pathways significantly contribute to selenite immobilization in a microfluidic flow cell having a transverse mixing zone between propionate and selenite that mimics the reaction zone along the margins of a selenite plume undergoing bioremediation in the presence of background sulfate. The experiment showed that red particles of amorphous elemental selenium precipitate on the selenite-rich side of the mixing zone, while long crystals of selenium sulfides precipitate on the propionate-rich side of the mixing zone. We developed a continuum-scale reactive transport model that includes both pathways. The simulated results are consistent with the experimental results, and indicate that spatial segregation of the two selenium precipitates is due to the segregation of the more thermodynamic favorable selenite reduction and the less thermodynamically favorable sulfate reduction. The improved understanding of selenite immobilization and the improved model can help to better design in situ bioremediation processes for groundwater contaminated by selenite or other contaminants (e.g., uranium(IV)) that can be immobilized via similar pathways. PMID- 25734535 TI - Nasoalveolar molding in cleft care--experience in 40 patients from a single centre in Germany. AB - Nasoalveolar molding (NAM) has gained wide acceptance and evidence in cleft therapy. However, standardized treatment protocols and experiences recorded from European centres are lacking. The results of 40 infants with cleft lip and palate treated with presurgical NAM according to the Grayson technique were analyzed. Standardized parameters of cleft width and nasal symmetry were measured in pre- and posttreatment plaster casts and in digitalized 3-dimensional STL models. Statistical analyses were performed by using Student's t-test in a per-protocol manner. 27 out of 40 infants completed NAM and were analyzed. In 13 patients NAM was either temporarily interrupted or terminated prematurely due to skin irritations or lack of parental support. These cases were excluded from statistical analysis, resulting in a drop-out rate of 32.5%. Intersegmental alveolar distance (ISAD), intersegmental lip distance (ISLD), nostril height (NH), nostril width (NW) and columella deviation angle (CDA) were significantly changed in unilateral cleft lip and palate (UCLP) (n = 8). In unilateral cleft lip (UCL) (n = 9), only ISLD, NH and CDA were significantly changed. ISAD of the right and left side, ISLD of the right and left side, premaxilla deviation angle, nostril height and columella length were changed significantly in bilateral cleft lip and palate (BCLP) cases (n = 10). NAM is a suitable presurgical treatment modality. A positive effect has been seen in UCLP and BCLP infants, as compared with their birth status. PMID- 25734536 TI - Posttraumatic stress in survivors 1 month to 19 years after an airliner emergency landing. AB - Posttraumatic stress (PTS) is common in survivors from life-threatening events. Little is known, however, about the course of PTS after life threat in the absence of collateral stressors (e.g., bereavement, social stigma, property loss) and there is a scarcity of studies about PTS in the long term. This study assessed the short- and long-term course of PTS, and the influence of gender, education and age on the level and course of PTS, in survivors from a non-fatal airliner emergency landing caused by engine failure at an altitude of 1 km. There were 129 persons on board. A survey including the Impact of Event Scale was distributed to 106 subjects after 1 month, 4 months, 14 months, and 25 months, and to 95 subjects after 19 years (response rates 64-83%). There were initially high levels of PTS. The majority of changes in PTS occurred from 1 to 4 months after the event. There were small changes from 4 to 25 months but further decrease in PTS thereafter. Female gender was associated with higher levels of PTS whereas gender was unrelated to the slope of the short- and long-term trajectories. Higher education was related to a quicker recovery although not to initial or long-term PTS. Age was not associated with PTS. The present findings suggest that a life-threatening experience without collateral stressors may produce high levels of acute posttraumatic stress, yet with a benign prognosis. The findings further implicate that gender is unrelated to trajectories of recovery in the context of highly similar exposure and few collateral stressors. PMID- 25734537 TI - Content of methylated inositols in familiar edible plants. AB - Familiar plants contain large amounts of inositols; soybean, white clover, red clover, bush clover, locust tree, wisteria, and kudzu of the legume family contain pinitol (3-O-methyl-chiro-inositol) at approximately 200-600 mg/100 g fresh weight (FW). The contents of pinitol in other plants were 260 mg/100 g FW for sticky mouse-ear, 275 mg/100 g FW for chickweed, and 332 mg/100 g FW for ginkgo. chiro-Inositol of 191 and 156 mg/100 g FW was also found in dandelion and Japanese mallotus, respectively. Ononitol (4-O-methyl-myo-inositol) of 166 mg/100 g FW was found in sticky mouse-ear. Furthermore, young leaves of ginkgo contained sequoyitol (5-O-methyl-myo-inositol) of 287 mg/100 g FW. Hydroxyl radical scavenging activities of the methylated inositols were higher than those of the original inositols. Effective uses of these familiar edible plants are expected to promote good health. PMID- 25734538 TI - The potential protective role of the combination of IL-22 and TNF-alpha against genital tract Chlamydia trachomatis infection. AB - Th22 cells are a novel class of lymphocytes characterized by the secretion of both IL-22 and TNF-alpha. In summary, Th22 cells have little or no direct impact on other immune cells, but exert selective effects on epithelia. It is not known, however, whether Th22 cells play a role in genital mucosal immunity. Here, we demonstrate that IL-22 and TNF-alpha synergistically induce several immunomodulatory molecules, such as the antimicrobial peptide mBD-2 (murine beta defensin 2) and the antimicrobial chemokines CXCL-9, -10, and -11 in primary murine oviduct epithelial cells (MOECs). The induction of innate immunity is relevant in an in vitro infection model, in which MOECs stimulated with Th22 cell supernatants or recombinant IL-22 and TNF-alpha effectively inhibit the growth of Chlamydia trachomatis and maintain the survival of the epithelia compared with IL 22 or TNF-alpha alone. In summary, we demonstrate that the Th22 cell cytokines IL 22 and TNF-alpha play important roles in genital tract infection. The potential for Th22 cell cytokines to modulate innate immune mediators may lead to the development of new topical agents to treat and/or prevent immune-mediated sexually transmitted diseases (STDs). In summary, we demonstrate that IL-22 and TNF-alpha represent a potent, synergistic cytokine combination for inducing genital mucosal immunity. PMID- 25734539 TI - Thermoset-cross-linked lignocellulose: a moldable plant biomass. AB - The present work demonstrates a high biomass content (i.e., up to 90% by weight) and moldable material by controlled covalent cross-linking of lignocellulosic particles by a thermoset through epoxide-hydroxyl reactions. As an example for lignocellulosic biomass, Eastern redcedar was employed. Using scanning fluorescence microscopy and vibrational spectroscopy, macroscopic to molecular scale interactions of the thermoset with the lignocellulose have been revealed. Impregnation of the polymer resin into the biomass cellular network by capillary action as well as applied pressure results in a self-organizing structure in the form of thermoset microrods in a matrix of lignocellulose. We also infer permeation of the thermoset into the cell walls from the reaction of epoxides with the hydroxyls of the lignin. Compression tests reveal, at 30% thermoset content, thermoset-cross-linked lignocellulose has superior mechanical properties over a commercial wood plastic composite while comparable stiffness and strength to bulk epoxy and wood, respectively. The failure mechanism is understood to be crack propagation along the particle-thermoset interface and/or interparticle thermoset network. PMID- 25734540 TI - Function and evolutionary origin of unicellular camera-type eye structure. AB - The ocelloid is an extraordinary eyespot organelle found only in the dinoflagellate family Warnowiaceae. It contains retina- and lens-like structures called the retinal body and the hyalosome. The ocelloid has been an evolutionary enigma because of its remarkable resemblance to the multicellular camera-type eye. To determine if the ocelloid is functionally photoreceptive, we investigated the warnowiid dinoflagellate Erythropsidinium. Here, we show that the morphology of the retinal body changed depending on different illumination conditions and the hyalosome manifests the refractile nature. Identifying a rhodopsin gene fragment in Erythropsidinium ESTs that is expressed in the retinal body by in situ hybridization, we also show that ocelloids are actually light sensitive photoreceptors. The rhodopsin gene identified is most closely related to bacterial rhodopsins. Taken together, we suggest that the ocelloid is an intracellular camera-type eye, which might be originated from endosymbiotic origin. PMID- 25734541 TI - Characteristics of anginal patients with high resting myocardial blood flow measured with N-13 ammonia PET/CT. AB - OBJECTIVES: We hypothesized that anginal patients with low coronary flow reserve (CFR) could have variable clinical features according to resting myocardial blood flow (MBF). Therefore, we analyzed the clinical and imaging characteristics according to resting MBF in anginal patients. METHODS: We enrolled 70 patients who underwent N-13 ammonia PET-computed tomography (CT) for evaluation of angina. Resting and stress MBF values were obtained and resting MBF was corrected with rate-pressure product to exclude the effect of heart rate and blood pressure on resting MBF. Clinical and imaging characteristics were compared on the basis of MBF and CFR. RESULTS: Among patients with CFR less than 2.0, those with high resting MBF (>=1.0 ml/min/g) had significantly fewer number of smokers, were younger, had lower Agatston calcium scores, and had less coronary stenosis compared with those with low resting MBF (<1.0 ml/min/g). In contrast, there was no significant difference in clinical or imaging findings according to resting MBF when compared among all patients or within those with CFR greater than or equal to 2.0. The subgroup analysis of patients with CFR less than 2.0 revealed lower Agatston calcium score and less coronary stenosis in patients with high resting MBF regardless of stress MBF. CONCLUSION: High resting MBF is associated with a lower rate of smoking, younger age, less coronary calcium burden, and less coronary stenosis compared with low resting MBF in anginal patients with low CFR. Moreover, in these patients, favorable angiographic features were mainly associated with high resting MBF, irrespective of stress MBF. Therefore, resting MBF should be reviewed to validate the clinical significance of low CFR measured by N-13 ammonia PET/CT especially in anginal patients showing low CFR. PMID- 25734542 TI - Succinate dehydrogenase mutation-related paragangliomas: conventional versus PET/CT diagnostic work-up. PMID- 25734543 TI - Is there still a French eating model? A taxonomy of eating behaviors in adults living in the Paris metropolitan area in 2010. AB - BACKGROUND: Meal times in France still represent an important moment in everyday life. The model of three rigorously synchronized meals is still followed by a majority of people, while meal frequencies have flattened in other European or North-American countries. We aimed to examine the "French model" of eating behavior by identifying and characterizing distinct meal patterns. METHODS: Analyses were based on data from the SIRS cohort, a representative survey of the adult population in the Paris area. A clustering algorithm was applied to meal variables (number, time, location, with whom the meal is usually shared and activities associated with meals). Regression models were used to investigate associations between patterns and socio-demographic, social environment and perceived food quality variables. RESULTS: Five different patterns were identified among 2994 participants. The first three types (prevalence 33%, 17% and 24%) followed a three-meal pattern, with differences in locations and social interactions mainly related to time constraints and age. More marked differences were observed in the remaining two types. In the fourth type (prevalence 13%), individuals ate one or two meals per day, often with an irregular schedule, at home and in front of the television. They frequently were unemployed and had lower income. Breakfast skipping, increased snacking and a low adherence to dietary guidelines suggested that this behavior might have health consequences. In the fifth type (12%), people also ate two meals or less per day, possibly with the same consequences on food quality. However, meals were often taken outside the home, in social settings, and individuals following this pattern were typically active, integrated, young people, suggesting that this pattern might be an adaptation to a modern urban lifestyle. CONCLUSIONS: While a majority of the population still follows the three-meal pattern, our analysis distinguished two other eating patterns associated with specific sociological profiles. PMID- 25734545 TI - Correction: Escherichia coli STb enterotoxin dislodges claudin-1 from epithelial tight junctions. PMID- 25734544 TI - Risk factors for men's lifetime perpetration of physical violence against intimate partners: results from the international men and gender equality survey (IMAGES) in eight countries. AB - This paper examines men's lifetime physical intimate partner violence (IPV) perpetration across eight low- and middle-income countries to better understand key risk factors that interventions can target in order to promote gender equality and reduce IPV. We use data from men (n = 7806) that were collected as part of the International Men and Gender Equality Survey (IMAGES) in Bosnia and Herzegovina, Brazil, Chile, Croatia, Democratic Republic of Congo (DRC), India, Mexico, and Rwanda. Results show that there is wide variation across countries for lifetime self-reported physical violence perpetration (range: 17% in Mexico to 45% in DRC), men's support for equal roles for men and women, and acceptability of violence against women. Across the sample, 31% of men report having perpetrated physical violence against a partner in their lifetime. In multivariate analyses examining risk factors for men ever perpetrating physical violence against a partner, witnessing parental violence was the strongest risk factor, reinforcing previous research suggesting the inter-generational transmission of violence. Additionally, having been involved in fights not specifically with an intimate partner, permissive attitudes towards violence against women, having inequitable gender attitudes, and older age were associated with a higher likelihood of ever perpetrating physical IPV. In separate analyses for each country, we found different patterns of risk factors in countries with high perpetration compared to countries with low perpetration. Findings are interpreted to identify key knowledge gaps and directions for future research, public policies, evaluation, and programming. PMID- 25734546 TI - Gram-positive and Gram-negative subcellular localization using rotation forest and physicochemical-based features. AB - BACKGROUND: The functioning of a protein relies on its location in the cell. Therefore, predicting protein subcellular localization is an important step towards protein function prediction. Recent studies have shown that relying on Gene Ontology (GO) for feature extraction can improve the prediction performance. However, for newly sequenced proteins, the GO is not available. Therefore, for these cases, the prediction performance of GO based methods degrade significantly. RESULTS: In this study, we develop a method to effectively employ physicochemical and evolutionary-based information in the protein sequence. To do this, we propose segmentation based feature extraction method to explore potential discriminatory information based on physicochemical properties of the amino acids to tackle Gram-positive and Gram-negative subcellular localization. We explore our proposed feature extraction techniques using 10 attributes that have been experimentally selected among a wide range of physicochemical attributes. Finally by applying the Rotation Forest classification technique to our extracted features, we enhance Gram-positive and Gram-negative subcellular localization accuracies up to 3.4% better than previous studies which used GO for feature extraction. CONCLUSION: By proposing segmentation based feature extraction method to explore potential discriminatory information based on physicochemical properties of the amino acids as well as using Rotation Forest classification technique, we are able to enhance the Gram-positive and Gram negative subcellular localization prediction accuracies, significantly. PMID- 25734547 TI - Monocyte-derived dendritic cells from cirrhotic patients retain similar capacity for maturation/activation and antigen presentation as those from healthy subjects. AB - Few studies have investigated the impact of liver cirrhosis on dendritic cell function. The purpose of this study was to compare the activation and antigen presentation capacity of monocyte-derived dendritic cells (MoDC) from cirrhotic patients (CIR) relative to healthy donors (HD). MoDC from CIR and HD were matured, phenotyped, irradiated and pulsed with 15mer peptides for two hepatocellular carcinoma-related antigens, alphafetoprotein and glypican-3, then co-cultured with autologous T-cells. Expanded T-cells were evaluated by interferon-gamma ELISPOT and intracellular staining. 15 CIR and 7 HD were studied. While CD14+ monocytes from CIR displayed enhanced M2 polarization, under MoDC-polarizing conditions, we identified no significant difference between HD and CIR in maturation-induced upregulation of co-stimulation markers. Furthermore, no significant differences were observed between CIR and HD in subsequent expansion of tumor antigen-specific IFNgamma+ T-cells. CONCLUSION: MoDCs isolated from cirrhotic individuals retain similar capacity for in vitro activation, maturation and antigen-presentation as those from healthy donors. PMID- 25734548 TI - Development and Validation of an Immuno-PET Tracer as a Companion Diagnostic Agent for Antibody-Drug Conjugate Therapy to Target the CA6 Epitope. AB - PURPOSE: To develop and compare three copper 64 ((64)Cu)-labeled antibody fragments derived from a CA6-targeting antibody (huDS6) as immuno-positron emission tomography (immuno-PET)-based companion diagnostic agents for an antibody-drug conjugate by using huDS6. MATERIALS AND METHODS: Three antibody fragments derived from huDS6 were produced, purified, conjugated to 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and evaluated in the following ways: (a) the affinity of the fragments and the DOTA conjugates was measured via flow cytometry, (b) the stability of the labeled fragments was determined ex vivo in human serum over 24 hours, and (c) comparison of the in vivo imaging potential of the fragments was evaluated in mice bearing subcutaneous CA6-positive and CA6-negative xenografts by using serial PET imaging and biodistribution. Isotype controls with antilysozyme and anti-DM4 B-Fabs and blocking experiments with an excess of either B-Fab or huDS6 were used to determine the extent of the antibody fragment (64)Cu-DOTA-B-Fab binding specificity. Immunoreactivity and tracer kinetics were evaluated by using cellular uptake and 48-hour imaging experiments, respectively. Statistical analyses were performed by using t tests, one-way analysis of variance, and Wilcoxon and Mann-Whitney tests. RESULTS: The antibody fragment (64)Cu-DOTA-B-Fab was more than 95% stable after 24 hours in human serum, had an immunoreactivity of more than 70%, and allowed differentiation between CA6-positive and CA6 negative tumors in vivo as early as 6 hours after injection, with a 1.7-fold uptake ratio between tumors. Isotype and blocking studies experiments showed tracer-specific uptake in antigen-positive tumors, despite some nonspecific uptake in both tumor models. CONCLUSION: Three antibody fragments were produced and examined as potential companion diagnostic agents. (64)Cu-DOTA-B-Fab is a stable and effective immuno-PET tracer for CA6 imaging in vivo. PMID- 25734549 TI - Combined Assessment of High-Sensitivity Troponin T and Noninvasive Coronary Plaque Composition for the Prediction of Cardiac Outcomes. AB - PURPOSE: To determine the risk-stratification ability of plaque volume and composition assessment with cardiac computed tomographic (CT) angiography and high-sensitivity troponin T (hsTnT) in patients at intermediate risk for coronary artery disease (CAD). MATERIALS AND METHODS: The study complied with the Declaration of Helsinki and was approved by the local ethics committee. All patients gave written informed consent. Five hundred twenty-one consecutive patients (mean age +/- standard deviation, 62 years +/- 10; 256 men and 265 women) were included in this prospective, observational, longitudinal, single center study. Quantitative cardiac CT angiography analysis was performed in all patients (for 7690 coronary segments), whereas biomarkers (hsTnT and high sensitivity C-reactive protein) were available in 408 patients (78%). To evaluate the incremental value of cardiac CT angiography and hsTnT for the prediction of cardiovascular events, multivariate Cox regression and integrated discrimination improvement analysis were applied. RESULTS: In 521 patients, 13 hard cardiac events occurred during a mean follow-up period of 2.3 years +/- 1.1 (median, 2.4 years; range, 0.5-4.5 years), while 23 patients underwent late coronary revascularization. The Duke clinical score was 51% +/- 30, indicating intermediate risk. The presence of no plaques or purely calcified versus noncalcified plaques, plaque volume according to tertiles, and increased hsTnT (>=14 pg/mL) was independently associated with hard cardiac events (hazard ratio [HR] = 26.08, 95% confidence interval [CI]: 2.78, 244.99; HR = 12.14, 95% CI: 1.87, 78.74; and HR = 10.31, 95% CI: 2.72, 39.0, respectively; P < .01 for all). Patients with increased hsTnT and plaque burden (n = 53) showed the highest incidence for hard cardiac events (annual rate, 12.7%), followed by those with either increased hsTnT or plaque burden (n = 145; annual rate = 0.44%, P < .03), while those with lower hsTnT and plaque burden exhibited excellent outcomes and no hard event during the follow-up duration (n = 210; annual rate = 0%, P < .001). CONCLUSION: Use of hsTnT as a marker of myocardial microinjury and cardiac CT angiography as a marker of the total atherosclerotic burden improves the prediction of cardiac outcome in patients with presumably stable CAD and may aid in personalized risk stratification in patients at intermediate risk. PMID- 25734550 TI - Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation: Risk Factors and Clinical Significance. AB - PURPOSE: To evaluate the frequency, risk factors, and clinical significance of aggressive intrasegmental recurrence (AIR) found after radiofrequency (RF) ablation for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. Between March 2005 and December 2010, 539 patients (414 men, 125 women; mean age, 57.91 years; age range, 30-82 years) underwent ultrasonography-guided percutaneous RF ablation as a first-line treatment for a single HCC classified as Barcelona Clinic Liver Cancer (BCLC) stage 0 or A. AIR of HCC was defined as (a) initial tumor recurrence with disease-free status at least 6 months after initial RF ablation and (b) the simultaneous development of multiple nodular (at least three) or infiltrative tumor recurrence in the treated segment. Patients were stratified into two groups: those with AIR (n = 20) and those without AIR (n = 519) during follow-up. Risk factors for AIR were assessed with logistic regression analysis, and risk factors for long-term overall survival were assessed with time-dependent Cox proportional hazard models. RESULTS: In a median follow-up period of 49 months (range, 6-95 months), AIR was observed in 3.7% of the patients (20 of 539 patients), with the frequency increasing to 15% in the subgroup with periportal HCC (11 of 72 patients). AIRs manifested as either multiple nodular type (n = 14, BCLC stage A or B) or diffusely infiltrative type with tumor thrombus formation (n = 6, BCLC stage C). At multivariate analysis, periportal tumor location and younger patient age were significant risk factors for AIR. The presence of AIR during the follow-up period has a significant effect on the overall survival rate (hazard ratio = 5.72, P = .002). CONCLUSION: The overall frequency of AIR after RF ablation for HCC was low, with periportal location and patient age showing a significant relationship to the development of AIR. The occurrence of AIR had an adverse effect on overall survival rate. PMID- 25734551 TI - Nonhypervascular Hypointense Nodules at Gadoxetic Acid-enhanced MR Imaging in Chronic Liver Disease: Diffusion-weighted Imaging for Characterization. AB - PURPOSE: To compare the diagnostic performance of magnetic resonance (MR) imaging features, including those on diffusion-weighted (DW) and T2-weighted images, in differentiating between hypovascular hepatocellular carcinoma (HCC) and dysplastic nodules seen as hypointense nodules at hepatobiliary phase gadoxetic acid-enhanced MR imaging. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need to obtain informed patient consent. There were 53 patients (39 men and 14 women; age range, 32-75 years) with histologically proven hypovascular HCCs (n = 25) and/or dysplastic nodules (n = 31) who underwent gadoxetic acid-enhanced MR imaging at 3.0-T between March 2011 and January 2014. Images of 25 HCCs and 31 dysplastic nodules were analyzed for nodule size; signal intensity on T1- and T2-weighted, portal venous phase, and DW (b value = 800 sec/mm(2)) images; and intralesional fat. Correlations between the hyperintensity grade of lesions and the liver-to-lesion signal intensity ratio at T2-weighted and DW imaging were determined by means of analysis with generalized estimating equations. RESULTS: Hyperintensity at T2 weighted and DW imaging and hypointensity in the portal venous phase were significant features for differentiating hypovascular HCCs from dysplastic nodules (P < .05). The sensitivity of DW imaging tended to be higher than that of T2-weighted imaging (72.0% [18 of 25] vs 40.0% [10 of 25]; P = .008 for grade 2 and 3 hyperintensity). Use of the parameter of hyperintensity similar to or slightly lower than the signal intensity of the spleen on DW images (b value = 800 sec/mm(2)) yielded a specificity of 100% (31 of 31) for the diagnosis of hypovascular HCC by differentiating it from a dysplastic nodule. CONCLUSION: Hyperintensity at DW imaging could be a useful MR imaging feature for differentiating hypovascular HCCs from dysplastic nodules seen as hypointense nodules at gadoxetic acid-enhanced MR imaging. PMID- 25734552 TI - Minimizing Systemic Leakage of Cisplatin during Percutaneous Isolated Pancreas Perfusion Chemotherapy: A Pilot Study. AB - PURPOSE: To evaluate the feasibility of percutaneous isolated pancreas perfusion (PIPP) by using a pig model. MATERIALS AND METHODS: All experiments were approved by the institutional Animal Experiment Ethics Committee. Fifteen pigs were assigned to five groups, and PIPP was performed. Angiographic and dye injection studies were performed to confirm the patency of the PIPP system (group 1). Blood that contained cisplatin (1.5 mg per kilogram of body weight) in an extracorporeal circuit was circulated through the pancreas at three infusion rates (40, 60, and 80 mL/min) to determine the optimal infusion rate in terms of safety and pharmacologic effectiveness (groups 2, 3, and 4, respectively). Chronological laboratory data and histologic findings were assessed in group 5, which received the optimal infusion rate. Maximum platinum concentration (Cmax) and area under the platinum concentration-time curve were compared by using the Kruskal-Wallis and Mann-Whitney U tests. RESULTS: Angiography and dye injection confirmed the patency of the PIPP system. Histopathologic examinations showed no abnormalities in the pancreas or other organs at a 40 mL/min infusion rate of cisplatin. However, edematous changes in the pancreas were observed at higher infusion rates. The pharmacologic effectiveness did not differ significantly among groups; therefore, the optimal infusion rate of 40 mL/min was selected. The median pancreatic-to-systemic exposure ratios were 71.8 for Cmax and 54.8 for the area under the curve. All laboratory data remained normal or returned to pretreatment levels within 1 week. CONCLUSION: PIPP at a 40 mL/min infusion rate appears to be safe and feasible for perfusion of the pancreas. PMID- 25734553 TI - Reliability of automated breast density measurements. AB - PURPOSE: To estimate the reliability of a reference standard two-dimensional area based method and three automated volumetric breast density measurements by using repeated measures. MATERIALS AND METHODS: Thirty women undergoing screening mammography consented to undergo a repeated left craniocaudal examination performed by a second technologist in this prospective institutional review board approved HIPAA-compliant study. Breast density was measured by using an area based method (Cumulus ABD) and three automated volumetric methods (CumulusV [University of Toronto], Volpara [version 1.4.5; Volpara Solutions, Wellington, New Zealand), and Quantra [version 2.0; Hologic, Danbury, Conn]). Discrepancy between the first and second breast density measurements (Delta1-2) was obtained for each algorithm by subtracting the second measurement from the first. The Delta1-2 values of each algorithm were then analyzed with a random-effects model to derive Bland-Altman-type limits of measurement agreement. RESULTS: Variability was higher for Cumulus ABD and CumulusV than for Volpara or Quantra. The within breast density measurement standard deviations were 3.32% (95% confidence interval [CI]: 2.65, 4.44), 3.59% (95% CI: 2.86, 4.48), 0.99% (95% CI: 0.79, 1.33), and 1.64% (95% CI: 1.31, 1.39) for Cumulus ABD, CumulusV, Volpara, and Quantra, respectively. Although the mean discrepancy between repeat breast density measurements was not significantly different from zero for any of the algorithms, larger absolute breast density discrepancy (Delta1-2) values were associated with larger breast density values for Cumulus ABD and CumulusV but not for Volpara and Quantra. CONCLUSION: Variability in a repeated measurement of breast density is lowest for Volpara and Quantra; these algorithms may be more suited to incorporation into a risk model. PMID- 25734554 TI - Differentiation between Subtypes of Primary Progressive Aphasia by Using Cortical Thickness and Diffusion-Tensor MR Imaging Measures. AB - PURPOSE: To test a multimodal magnetic resonance (MR) imaging-based approach composed of cortical thickness and white matter (WM) damage metrics to discriminate between variants of primary progressive aphasia (PPA) that are nonfluent and/or agrammatic (NFVPPA) and semantic (SVPPA). MATERIALS AND METHODS: This study was approved by the local ethics committees on human studies, and written informed consent from all patients was obtained before their enrollment. T1-weighted and diffusion-tensor (DT) MR images were obtained from 13 NFVPPA patients, 13 SVPPA patients, and 23 healthy control participants. Cortical thickness and DT MR imaging indices from the long-associative and interhemispheric WM tracts were obtained. A random forest (RF) analysis was used to identify the image features associated with each clinical syndrome. Individual patient classification was performed by using receiver operator characteristic curve analysis with cortical thickness, DT MR imaging, and a combination of the two modalities. RESULTS RF analysis showed that the best markers to differentiate the two PPA variants at an individual patient level among cortical thickness and DT MR imaging metrics were diffusivity abnormalities of the left inferior longitudinal and uncinate fasciculi and cortical thickness measures of the left temporal pole and inferior frontal gyrus. A combination of cortical thickness and DT MR imaging measures (the so-called gray-matter-and-WM model) was able to distinguish patients with NFVPPA and SVPPA with the following classification pattern: area under the curve, 0.91; accuracy, 0.89; sensitivity, 0.92; specificity, 0.85. Leave-one-out analysis demonstrated that the gray matter and WM model is more robust than the single MR modality models to distinguish PPA variants (accuracy was 0.86, 0.73, and 0.68 for the gray matter and WM model, the gray matter-only model, and the WM-only model, respectively). CONCLUSION: A combination of structural and DT MR imaging metrics may provide a quantitative procedure to distinguish NFVPPA and SVPPA patients at an individual patient level. The discrimination accuracies obtained suggest that the gray matter and WM model is potentially relevant for the differential diagnosis of the PPA variants in clinical practice. PMID- 25734555 TI - Reading the Writing in Radiology: 1923-2013. AB - The style and tone of the writing in Radiology has changed over the years since its first publication in 1923. Many of the tonal changes have occurred transiently and likely in relation to political and professional issues in play at a particular time. Others represent more consistent trends in the evolution of the professional writing style. In this report, we analyze the tone of the editorial content from 1923 to 2013 in a historical context as well as progressive changes in readability parameters involving both editorial and technical content. PMID- 25734556 TI - Size-specific Dose Estimates for Chest, Abdominal, and Pelvic CT: Effect of Intrapatient Variability in Water-equivalent Diameter. AB - PURPOSE: To develop software to automatically calculate size-specific dose estimates (SSDEs) and to assess the effect of variations in water-equivalent diameter (Dw) along the z-axis on SSDE for computed tomographic (CT) examinations of the torso. MATERIALS AND METHODS: In this institutional review board-approved, HIPAA-compliant, retrospective study, a software program was used to calculate Dw at each image position in 102 consecutive CT examinations of the combined chest, abdomen, and pelvis. SSDE was calculated by multiplying the size-dependent conversion factor and volume CT dose index (CTDIvol) at each image position. The variations in Dw along the z-axis were determined for six hypothetical scanning ranges: chest alone; abdomen alone; pelvis alone; chest and abdomen; abdomen and pelvis; and chest, abdomen, and pelvis. Mean SSDE was calculated in two ways: (a) from the SSDE at each position and (b) from the mean CTDIvol over each scan range and the conversion factor corresponding to Dw at the middle of the scan range. Linear regression analysis was performed to determine the correlation between SSDE values calculated in these two ways. RESULTS: Across patients, for scan ranges 1-6, the mean of the difference between maximal and minimal Dw within a given patient was 5.2, 4.9, 2.5, 6.0, 5.6, and 6.5 cm, respectively. The mean SSDE values calculated by using the two methods were in close agreement, with root mean square differences of 0.9, 0.5, 0.5, 1.4, 1.0, and 1.1 mGy or 6%, 3%, 2%, 9%, 4%, and 6%, for the scan ranges of chest; abdomen; pelvis; chest and abdomen; abdomen and pelvis; and chest, abdomen, and pelvis, respectively. CONCLUSION: Using the mean CTDIvol from the whole scan range and Dw from the image at the center of the scan range provided an easily obtained estimate of SSDE for the whole scan range that agreed well with values from an image-by-image approach, with a root mean square difference less than 1.4 mGy (9%). PMID- 25734557 TI - Breast Cancer: Radiogenomic Biomarker Reveals Associations among Dynamic Contrast enhanced MR Imaging, Long Noncoding RNA, and Metastasis. AB - PURPOSE: To perform a radiogenomic analysis of women with breast cancer to study the multiscale relationships among quantitative computer vision-extracted dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging phenotypes, early metastasis, and long noncoding RNA (lncRNA) expression determined by means of high-resolution next-generation RNA sequencing. MATERIALS AND METHODS: In this institutional review board-approved study, an automated image analysis platform extracted 47 computational quantitative features from DCE MR imaging data in a training set (n = 19) to screen for MR imaging biomarkers indicative of poor metastasis-free survival (MFS). The lncRNA molecular landscape of the candidate feature was defined by using an RNA sequencing-specific negative binomial distribution differential expression analysis. Then, this radiogenomic biomarker was applied prospectively to a validation set (n = 42) to allow prediction of MFS and lncRNA expression by using quantitative polymerase chain reaction analysis. RESULTS: The quantitative MR imaging feature, enhancing rim fraction score, was predictive of MFS in the training set (P = .007). RNA sequencing analysis yielded an average of 55.7 * 10(6) reads per sample and identified 14 880 lncRNAs from a background of 189 883 transcripts per sample. Radiogenomic analysis allowed identification of three previously uncharacterized and five named lncRNAs significantly associated with high enhancing rim fraction, including Homeobox transcript antisense intergenic RNA (HOTAIR) (P < .05), a known predictor of poor MFS in patients with breast cancer. Independent validation confirmed the association of the enhancing rim fraction phenotype with both MFS (P = .002) and expression of four of the top five differentially expressed lncRNAs (P < .05), including HOTAIR. CONCLUSION: The enhancing rim fraction score, a quantitative DCE MR imaging lncRNA radiogenomic biomarker, is associated with early metastasis and expression of the known predictor of metastatic progression, HOTAIR. PMID- 25734558 TI - Discovery of novel new Delhi metallo-beta-lactamases-1 inhibitors by multistep virtual screening. AB - The emergence of NDM-1 containing multi-antibiotic resistant "Superbugs" necessitates the needs of developing of novel NDM-1inhibitors. In this study, we report the discovery of novel NDM-1 inhibitors by multi-step virtual screening. From a 2,800,000 virtual drug-like compound library selected from the ZINC database, we generated a focused NDM-1 inhibitor library containing 298 compounds of which 44 chemical compounds were purchased and evaluated experimentally for their ability to inhibit NDM-1 in vitro. Three novel NDM-1 inhibitors with micromolar IC50 values were validated. The most potent inhibitor, VNI-41, inhibited NDM-1 with an IC50 of 29.6 +/- 1.3 MUM. Molecular dynamic simulation revealed that VNI-41 interacted extensively with the active site. In particular, the sulfonamide group of VNI-41 interacts directly with the metal ion Zn1 that is critical for the catalysis. These results demonstrate the feasibility of applying virtual screening methodologies in identifying novel inhibitors for NDM-1, a metallo-beta-lactamase with a malleable active site and provide a mechanism base for rational design of NDM-1 inhibitors using sulfonamide as a functional scaffold. PMID- 25734563 TI - Salacinol and related analogs: new leads for type 2 diabetes therapeutic candidates from the Thai traditional natural medicine Salacia chinensis. AB - The antidiabetic effect of a hot water extract of stems of Salacia chinensis (SCE) was evaluated in vivo in KK-Ay mice, a typical type 2 diabetes mellitus mice model. Administration of CE-2 dietary feed containing 0.25 and/or 0.50% of SCE for three weeks to KK-Ay mice significantly suppressed the elevation of both blood glucose and HbA1c levels without significant changes in body weight or food intake. Glucose tolerance was improved by administration to KK-Ay mice for 27 days of AIN93M purified dietary feed containing 0.12% of SCE. No suppressive effect with respect to HbA1c level was observed when AIN93M/Glc dietary feed in which all digestible glucides were replaced with glucose was administered with SCE. Thus, alpha-glucosidase inhibitory activity approved as the mechanism of action of the antidiabetic effect of SCE by in vitro investigation was reconfirmed also in in vivo studies. Evaluation of the alpha-glucosidase inhibitory activity of the active constituents, salacinol (1), kotalanol (3), and neokotalanol (4), by employing human alpha-glucosidases revealed that these compounds inhibited them as potently (IC50 = 3.9-4.9 MUM for maltase) as they inhibited rat small intestinal alpha-glucosidase. The principal sulfonium constituents (1-4) were highly stable in an artificial gastric juice. In addition, 1-4 were hardly absorbed from the intestine in an experiment using the in situ rat ligated intestinal loop model. The results indicate that these sulfoniums are promising leads for a new type of anti-diabetic agents. PMID- 25734564 TI - A review of dietary selenium intake and selenium status in Europe and the Middle East. AB - This is a systematic review of existing data on dietary selenium (Se) intake and status for various population groups in Europe (including the United Kingdom (UK)) and the Middle East. It includes English language systematic reviews, meta analyses, randomised controlled trials, cohort studies, cross-sectional and case control studies obtained through PUBMED searches from January, 2002, to November, 2014, for European data and from 1990 to November 2014, for Middle Eastern data. Reports were selected if they included data on Se intake and status. The search identified 19 European/UK studies and 15 investigations in the Middle East that reported Se intake and Se concentration in water and/or food and 48 European/UK studies and 44 investigations in the Middle East reporting Se status. Suboptimal Se status was reported to be widespread throughout Europe, the UK and the Middle East, and these results agreed with previous reports highlighting the problem. Eastern European countries had lower Se intake than Western European countries. Middle Eastern studies provided varying results, possibly due to varying food habits and imports in different regions and within differing socioeconomic groups. In conclusion, Se intake and status is suboptimal in European and Middle Eastern countries, with less consistency in the Middle East. PMID- 25734566 TI - Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. AB - BACKGROUND: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). METHODS: Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. RESULTS: Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. CONCLUSIONS: Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity. PMID- 25734565 TI - Emphasizing the health benefits of vitamin D for those with neurodevelopmental disorders and intellectual disabilities. AB - People with neurodevelopmental disorders and intellectual disabilities have much greater health care needs. Mainly staying indoors, such people generally have low 25-hydroxyvitamin D (25(OH)D) concentrations. The Vitamin D Task Force of the American Academy of Developmental Medicine and Dentistry (AADMD) reviewed the evidence of 25(OH)D concentrations that benefit the health of persons with developmental disabilities. Maintaining recommended optimal serum 25(OH)D concentrations year long will benefit skeletal development in infants, children, and adolescents, and benefit musculoskeletal health and neuromuscular coordination in adult patients, and decrease risk of falls. Maintaining optimal concentrations decreases risks and severities of autoimmune diseases, cardiovascular disease, many types of cancer, dementia, types 1 and 2 diabetes mellitus, and respiratory tract infections. Other benefits include improved dental and oral health and improved physical performance. The Task Force recommends that 25(OH)D concentrations for optimal health to be in the range of 75 to 125 nmol/L, which can be achieved using between 800 and 4000 IU/day vitamin D3 and sensible exposure to solar UVB radiation. The paper also discusses the potential risks of higher 25(OH)D concentrations, the evidence from and limitations of randomized controlled trials, and the recommendations by various groups and agencies. PMID- 25734568 TI - Derotational osteotomies utilizing a trochanteric-start intramedullary nail. PMID- 25734567 TI - Recording large extracellular spikes in microchannels along many axonal sites from individual neurons. AB - The numerous connections between neuronal cell bodies, made by their dendrites and axons, are vital for information processing in the brain. While dendrites and synapses have been extensively studied, axons have remained elusive to a large extent. We present a novel platform to study axonal physiology and information processing based on combining an 11,011-electrode high-density complementary metal-oxide semiconductor microelectrode array with a poly(dimethylsiloxane) channel device, which isolates axons from somas and, importantly, significantly amplifies recorded axonal signals. The combination of the microelectrode array with recording and stimulation capability with the microfluidic isolation channels permitted us to study axonal signal behavior at great detail. The device, featuring two culture chambers with over 30 channels spanning in between, enabled long-term recording of single spikes from isolated axons with signal amplitudes of 100 MUV up to 2 mV. Propagating signals along axons could be recorded with 10 to 50 electrodes per channel. We (i) describe the performance and capabilities of our device for axonal electrophysiology, and (ii) present novel data on axonal signals facilitated by the device. Spontaneous action potentials with characteristic shapes propagated from somas along axons between the two compartments, and these unique shapes could be used to identify individual axons within channels that contained many axonal branches. Stimulation through the electrode array facilitated the identification of somas and their respective axons, enabling interfacing with different compartments of a single cell. Complex spike shapes observed in channels were traced back to single cells, and we show that more complicated spike shapes originate from a linear superposition of multiple axonal signals rather than signal distortion by the channels. PMID- 25734569 TI - Unusual entrapment of deep peroneal nerve after femoral distal extension osteotomy. AB - The lateral exposure of the supracondylar femur includes the risk of damaging the neurovascular structures or tightening of the neurological structures within the popliteal fossa may occur as a complication of the osteotomy. Although different pathways of common peroneal nerve (CPN) have been reported throughout the literature, division of deep and superficial branches above the supracondylar femur level has not been reported. A 15-year-old boy with bilateral knee flexion contracture and spastic diplegic cerebral palsy underwent bilateral femoral distal extension osteotomy. The authors found an unusual higher division of CPN above the supracondylar femur level. This report is aimed at warning surgeons about the division of the CPN at a higher level and highlighting a need for a high-powered cadaveric research. PMID- 25734571 TI - Attention and response control in ADHD. Evaluation through integrated visual and auditory continuous performance test. AB - This study assesses attention and response control through visual and auditory stimuli in a primary care pediatric sample. The sample consisted of 191 participants aged between 7 and 13 years old. It was divided into 2 groups: (a) 90 children with ADHD, according to diagnostic (DSM-IV-TR) (APA, 2002) and clinical (ADHD Rating Scale-IV) (DuPaul, Power, Anastopoulos, & Reid, 1998) criteria, and (b) 101 children without a history of ADHD. The aims were: (a) to determine and compare the performance of both groups in attention and response control, (b) to identify attention and response control deficits in the ADHD group. Assessments were carried out using the Integrated Visual and Auditory Continuous Performance Test (IVA/CPT, Sandford & Turner, 2002). Results showed that the ADHD group had visual and auditory attention deficits, F(3, 170) = 14.38; p < .01, deficits in fine motor regulation (Welch's t-test = 44.768; p < .001) and sensory/motor activity (Welch'st-test = 95.683, p < .001; Welch's t test = 79.537, p < .001). Both groups exhibited a similar performance in response control, F(3, 170) = .93, p = .43.Children with ADHD showed inattention, mental processing speed deficits, and loss of concentration with visual stimuli. Both groups yielded a better performance in attention with auditory stimuli. PMID- 25734570 TI - Personal networks and mortality risk in older adults: a twenty-year longitudinal study. AB - BACKGROUND: Research on aging has consistently demonstrated an increased chance of survival for older adults who are integrated into rich networks of social relationships. Theoretical explanations state that personal networks offer indirect psychosocial and direct physiological pathways. We investigate whether effects on and pathways to mortality risk differ between functional and structural characteristics of the personal network. The objective is to inquire which personal network characteristics are the best predictors of mortality risk after adjustment for mental, cognitive and physical health. METHODS AND FINDINGS: Empirical tests were carried out by combining official register information on mortality with data from the Longitudinal Aging Study Amsterdam (LASA). The sample included 2,911 Dutch respondents aged 54 to 85 at baseline in 1992 and six follow-ups covering a time span of twenty years. Four functional characteristics (emotional and social loneliness, emotional and instrumental support) and four structural characteristics (living arrangement, contact frequency, number of contacts, number of social roles) of the personal network as well as mental, cognitive and physical health were assessed at all LASA follow-ups. Statistical analyses comprised of Cox proportional hazard regression models. Findings suggest differential effects of personal network characteristics on survival, with only small gender differences. Mortality risk was initially reduced by functional characteristics, but disappeared after full adjustment for the various health variables. Mortality risk was lowest for older adults embedded in large (HR = 0.986, 95% CI 0.979-0.994) and diverse networks (HR = 0.948, 95% CI 0.917-0.981), and this effect continued to show in the fully adjusted models. CONCLUSIONS: Functional characteristics (i.e. emotional and social loneliness) are indirectly associated with a reduction in mortality risk, while structural characteristics (i.e. number of contacts and number of social roles) have direct protective effects. More research is needed to understand the causal mechanisms underlying these relations. PMID- 25734572 TI - The thermochemistry of cubane 50 years after its synthesis: a high-level theoretical study of cubane and its derivatives. AB - The gas-phase enthalpy of formation of cubane (603.4 +/- 4 kJ mol(-1)) was calculated using an explicitly correlated composite method (W1-F12). The result obtained for cubane, together with the experimental value for the enthalpy of sublimation, 54.8 +/- 2.0 kJ mol(-1), led to 548.6 +/- 4.5 kJ mol(-1) for the solid-phase enthalpy of formation. This value is only 6.8 kJ mol(-1) higher than the 50-year-old original calorimetric result. The carbon-hydrogen bond dissociation enthalpy (C-H BDE) of cubane (438.4 +/- 4 kJ mol(-1)), together with properties relevant for its experimental determination using gas-phase ion thermochemistry, namely the cubane gas-phase acidity (1704.6 +/- 4 kJ mol(-1)), cubyl radical electron affinity (45.8 +/- 4 kJ mol(-1)), cubane ionization energy (1435.1 +/- 4 kJ mol(-1)), cubyl radical cation proton affinity (918.8 +/- 4 kJ mol(-1)), cubane cation appearance energy (1099.6 +/- 4 kJ mol(-1)), and cubyl ionization energy (661.2 +/- 4 kJ mol(-1)), were also determined. These values were compared with those calculated for unstrained hydrocarbons (viz., methane, ethane, and isobutane). The strain energy of cubane (667.2 kJ mol(-1)) and cubyl radical (689.4 kJ mol(-1)) were independently estimated via quasihomodesmotic reactions. These values were related via a simple model to the C-H BDE in cubane. Taking into account the accuracy of the computational method, the comparison with high-precision experimental results, and the data consistency afforded by the relevant thermodynamic cycles, we claim an uncertainty better than +/-4 kJ mol( 1) for the new enthalpy of formation values presented. PMID- 25734573 TI - Characterizing pulmonary hypertension-related hospitalization costs among Medicare Advantage or commercially insured patients with pulmonary arterial hypertension: a retrospective database study. AB - OBJECTIVES: This study assessed pulmonary hypertension (PH)-related hospitalizations, including readmissions, among US patients with pulmonary arterial hypertension (PAH), a rare disease characterized by high morbidity and premature mortality. STUDY DESIGN: Analysis of claims data (January 1, 2007-April 30, 2011) from adult enrollees with commercial or Medicare Advantage with Part D coverage from a large US health plan. METHODS: Patients with PAH were identified based on >= 1 medical claim with a PH-related diagnostic code (International Classification of Diseases, Ninth Edition, Clinical Modification code 416.0 for primary pulmonary hypertension or 416.8 for other chronic pulmonary heart disease) and >= 1 pharmacy claim for a medication indicated for PAH or frequently used in PAH. Data were analyzed for patients with >= 1 hospitalization with a primary or secondary diagnostic code of PH. PH-related hospitalizations were defined as those with >= 1 PH-related diagnostic code. The principal diagnosis was defined as the diagnosis most frequently in the first-listed position on a hospitalization's facility claims. Total hospitalization costs (inflated to 2011 US$) and length of stay (LOS) were analyzed. A subgroup analysis evaluated readmissions. RESULTS: Of 4009 enrollees meeting inclusion criteria, 2275 had >= 1 PH-related hospitalization during follow-up: 56.9% were female, 59.4% were < 65 years old, and 67.8% had commercial insurance. Mean (SD) costs across all hospitalizations were $46,118 ($135,137) for commercially insured and $16,319 ($30,046) for Medicare Advantage enrollees; LOS was 10.9 (20.4) and 12.8 (21.2) days, respectively. Costs and LOS were higher for admissions with a principal diagnosis of PH compared with other principal diagnoses: $61,922 ($213,596) versus $42,455 ($108,925) and 14.2 (32.3) versus 10.2 (16.4) days, respectively, for the commercially insured, and $19,584 ($29,501) versus $15,904 ($30,097) and 16.7 (25.7) versus 12.3 (20.5) days, respectively, for Medicare Advantage enrollees. Of the 954 patients who experienced >= 1 PH-related readmission within the first year after discharge from the initial hospitalization, 483 (50.6%), 246 (25.8%), and 225 (23.6%) patients had 1, 2, and >= 3 readmissions, respectively. CONCLUSIONS: PH-related hospitalizations incur substantial healthcare costs and require long hospital stays for patients with PAH; many are readmitted within 1 year. Improved treatment approaches are needed to reduce PAH disease progression leading to costly and burdensome inpatient stays. PMID- 25734574 TI - Origin of chemoselectivity in N-heterocyclic carbene catalyzed cross-benzoin reactions: DFT and experimental insights. AB - An exploration into the origin of chemoselectivity in the NHC-catalyzed cross benzoin reaction reveals several key factors governing the preferred pathway. In the first computational study to explore the cross-benzoin reaction, a piperidinone-derived triazolium catalyst produces kinetically controlled chemoselectivity. This is supported by (1)H NMR studies as well as a series of crossover experiments. Major contributors include the rapid and preferential formation of an NHC adduct with alkyl aldehydes, a rate-limiting carbon-carbon bond formation step benefiting from a stabilizing pi-stacking/pi-cation interaction, and steric penalties paid by competing pathways. The energy profile for the analogous pyrrolidinone-derived catalyst was found to be remarkably similar, despite experimental data showing that it is less chemoselective. The chemoselectivity could not be improved through kinetic control; however, equilibrating conditions show substantial preference for the same cross-benzoin product kinetically favored by the piperidinone-derived catalyst. PMID- 25734575 TI - [Science provides the knowledge?]. PMID- 25734577 TI - Molecular Dynamics Simulation of Water between Metal Walls under an Electric Field: Dielectric Response and Dynamics after Field Reversal. AB - We study water between parallel metal walls under an applied electric field accounting for the image effect at T = 298 K. The electric field due to the surface charges serves to attract and orient nearby water molecules, whereas it tends to a constant determined by the mean surface charge density away from the walls. We find Stern boundary layers with thicknesses of about 5 A and a homogeneously polarized bulk region. The molecules in the layers respond more sensitively to the applied field than the molecules in the bulk. As a result, the potential drop in the layers is larger than that in the bulk unless the cell length exceeds 10 nm. We also examine the hydrogen bonds, which tend to make small angles with respect to the walls in the layers even without an applied field. The average local field considerably deviates from the classical Lorentz field and the local field fluctuations are very large in the bulk. If we suppose a nanometer-sized sphere around each molecule, the local field contribution from its exterior is nearly equal to that from the continuum electrostatics and that from its interior yields the deviation from the classical Lorentz field. As a nonequilibrium problem, we investigate the dynamics after a reversal of applied field, where the relaxation is mostly caused by large-angle rotational jumps after 1 ps due to the presence of the hydrogen bond network. The molecules undergoing these jumps themselves form hydrogen-bonded clusters heterogeneously distributed in space. PMID- 25734576 TI - Analysis of miRNA expression profiles in breast cancer using biclustering. AB - BACKGROUND: MicroRNAs (miRNAs) are important key regulators in multiple cellular functions, due to their a crucial role in different physiological processes. MiRNAs are differentially expressed in specific tissues, during specific cell status, or in different diseases as tumours. RNA sequencing (RNA-seq) is a Next Generation Sequencing (NGS) method for the analysis of differential gene expression. Using machine learning algorithms, it is possible to improve the functional significance interpretation of miRNA in the analysis and interpretation of data from RNA-seq. Furthermore, we tried to identify some patterns of deregulated miRNA in human breast cancer (BC), in order to give a contribution in the understanding of this type of cancer at the molecular level. RESULTS: We adopted a biclustering approach, using the Iterative Signature Algorithm (ISA) algorithm, in order to evaluate miRNA deregulation in the context of miRNA abundance and tissue heterogeneity. These are important elements to identify miRNAs that would be useful as prognostic and diagnostic markers. Considering a real word breast cancer dataset, the evaluation of miRNA differential expressions in tumours versus healthy tissues evidenced 12 different miRNA clusters, associated to specific groups of patients. The identified miRNAs were deregulated in breast tumours compared to healthy controls. Our approach has shown the association between specific sub-class of tumour samples having the same immuno-histo-chemical and/or histological features. Biclusters have been validated by means of two online repositories, MetaMirClust database and UCSC Genome Browser, and using another biclustering algorithm. CONCLUSIONS: The obtained results with biclustering algorithm aimed first of all to give a contribute in the differential expression analysis in a cohort of BC patients and secondly to support the potential role that these non-coding RNA molecules could play in the clinical practice, in terms of prognosis, evolution of tumour and treatment response. PMID- 25734578 TI - The differences in ultrasound and clinicopathological features between basal-like and normal-like subtypes of triple negative breast cancer. AB - PURPOSE: The aim of this study was to identify the ultrasound features and clinicopathological characteristics of basal-like subtype of triple negative breast cancers (TNBCs). MATERIALS AND METHODS: This study was approved by the ethical board of the Second Affiliated Hospital of Harbin Medical University. The patients' clinicopathological information was available. The ultrasound features of 62 tumors from 62 TNBC patients were interpreted. The immunohistochemical results of cytokertain5/6 (CK5/6) and Epidermal Growth Factor Receptor (EGFR) were used to classify the tumor into basal-like and normal-like groups. The association of the ultrasound features interpreted by experienced ultrasound doctors with the immunohistochemical classification was studied. RESULTS: Of the 62 TNBC cases, 42 (67.7%) exhibited the basal-like phenotype and 20 (32.3%) exhibited the normal-like phenotype based on the immunohistochemical CK5/6 and EGFR markers. Of all the tumors, 90.3% were invasive carcinomas. The basal-like tumors were significantly associated with a maximum diameter on ultrasound of more than 20 mm (36, 85.7%) (P = 0.0014). The normal-like tumors usually exhibited lateral shadows (15, 75%) (P = 0.0115) as well as microlobulated margins (12, 60%) (P = 0.0204) compared to the basal-like subtype. Other ultrasound features showed no significant differences between the two groups. CONCLUSIONS: Although ultrasound cannot yet be used to differentiate between the basal-like subtype and normal-like subtype of TNBC, ultrasound can be used to provide some useful information to the clinicians. PMID- 25734579 TI - Lower body predictors of glenohumeral compressive force in high school baseball pitchers. AB - The purpose of this study was to better understand how lower body kinematics relate to peak glenohumeral compressive force and develop a regression model accounting for variability in peak glenohumeral compressive force. Data were collected for 34 pitchers. Average peak glenohumeral compressive force was 1.72% +/- 33% body weight (1334.9 N +/- 257.5). Correlation coefficients revealed 5 kinematic variables correlated to peak glenohumeral compressive force (P < .01, alpha = .025). Regression models indicated 78.5% of the variance in peak glenohumeral compressive force (R2 = .785, P < .01) was explained by stride length, lateral pelvis flexion at maximum external rotation, and axial pelvis rotation velocity at release. These results indicate peak glenohumeral compressive force increases with a combination of decreased stride length, increased pelvic tilt at maximum external rotation toward the throwing arm side, and increased pelvis axial rotation velocity at release. Thus, it may be possible to decrease peak glenohumeral compressive force by optimizing the movements of the lower body while pitching. Focus should be on both training and conditioning the lower extremity in an effort to increase stride length, increase pelvis tilt toward the glove hand side at maximum external rotation, and decrease pelvis axial rotation at release. PMID- 25734580 TI - Political attitudes develop independently of personality traits. AB - The primary assumption within the recent personality and political orientations literature is that personality traits cause people to develop political attitudes. In contrast, research relying on traditional psychological and developmental theories suggests the relationship between most personality dimensions and political orientations are either not significant or weak. Research from behavioral genetics suggests the covariance between personality and political preferences is not causal, but due to a common, latent genetic factor that mutually influences both. The contradictory assumptions and findings from these research streams have yet to be resolved. This is in part due to the reliance on cross-sectional data and the lack of longitudinal genetically informative data. Here, using two independent longitudinal genetically informative samples, we examine the joint development of personality traits and attitude dimensions to explore the underlying causal mechanisms that drive the relationship between these features and provide a first step in resolving the causal question. We find change in personality over a ten-year period does not predict change in political attitudes, which does not support a causal relationship between personality traits and political attitudes as is frequently assumed. Rather, political attitudes are often more stable than the key personality traits assumed to be predicting them. Finally, the results from our genetic models find that no additional variance is accounted for by the causal pathway from personality traits to political attitudes. Our findings remain consistent with the original construction of the five-factor model of personality and developmental theories on attitude formation, but challenge recent work in this area. PMID- 25734581 TI - Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma. AB - PURPOSE: Limited data are available to guide neoadjuvant treatment of borderline resectable (BRPC) and locally advanced (LAPC) pancreatic cancer. MATERIAL AND METHODS: We updated our institutional outcomes with a neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) approach. An IRB-approved analysis was performed of all BRPC and LAPC patients treated with our departmental treatment protocol. After staging, medically fit patients underwent chemotherapy for 2-3 months, with regimen at the discretion of the treating medical oncologist. Patients then received SBRT delivered in five consecutive daily fractions with median total radiation doses of 30 Gy to tumor and 40 Gy dose painted to tumor vessel interfaces. This was followed by restaging imaging for possible resection. Overall survival (OS), event free survival (EFS), and locoregional control (LRC) rates were estimated and compared by Kaplan-Meier and log-rank methods. RESULTS: We identified 159 patients, 110 BRPC and 49 LAPC, with 14.0 months median overall follow-up. The resection and margin negative (R0) rate for BRPC patients who completed neoadjuvant therapy was 51% and 96%, respectively. Estimated median OS was 19.2 months for BRPC patients and 15.0 months for LAPC patients (p = 0.402). Median OS was 34.2 months for surgically resected patients versus 14.0 months for unresected patients (p < 0.001). Five of 21 (24%) LAPC patients receiving FOLFIRINOX chemotherapy underwent R0 resection. In LAPC, FOLFIRINOX recipients underwent R0 resection more often than other chemotherapy recipients (5 of 21 vs. 0 of 28, p = 0.011). There was a trend for improved survival in those resected LAPC patients (p = 0.09). For those not undergoing resection, one year LRC was 78%. Any grade >= 3 potentially radiation-related toxicity rate was 7%. CONCLUSIONS: These data underscore the feasibility, safety, and effectiveness of neoadjuvant SBRT and chemotherapy for BRPC and LAPC. PMID- 25734585 TI - FIP-WGO joint session: coping with common gastrointestinal symptoms in the community, World Digestive Health Day and Gastro 2015! PMID- 25734582 TI - Prevalence of vitamin D deficiency in sickle cell disease: a systematic review. AB - Vitamin D deficiency has emerged as a public health focus in recent years and patients with sickle cell disease (SCD) reportedly have a high prevalence of the condition. Our objectives were to summarize definitions of vitamin D deficiency and insufficiency used in the literature, and to determine the prevalence and magnitude of each in patients with SCD through a systematic review conducted according to PRISMA guidelines. From a PubMed search, 34 potential articles were identified and 15 met eligibility criteria for inclusion. Definitions of deficiency and insufficiency varied greatly across studies making direct comparisons difficult. This review provides evidence to suggest that suboptimal vitamin D levels are highly prevalent among those with SCD, far more so than in comparable non-SCD patients or matched control populations. Defining deficiency as vitamin D < 20 ng/mL, prevalence estimates in SCD populations range from 56.4% to 96.4%. When compared with results from the population-based National Health and Nutrition Examination Survey, however, the general African American population appeared to have a similarly high prevalence of vitamin D deficiency. African American patients with and without SCD were both substantially higher than that of Caucasians. What remains to be determined is whether there are adverse health effects for patients with SCD because of concurrent vitamin D deficiency. PMID- 25734583 TI - Immunoglobulin isotypes in Atlantic salmon, Salmo salar. AB - There are three major immunoglobulin (Ig) isotypes in salmonid fish: IgM, IgD and IgT, defined by the heavy chains MU, delta and tau, respectively. As a result of whole genome duplication in the ancestor of the salmonid fish family, Atlantic salmon (Salmo salar) possess two highly similar Ig heavy chain gene complexes (A and B), comprising two MU genes, two delta genes, three intact tau genes and five tau pseudogenes. The MUA and MUB genes correspond to two distinct sub-populations of serum IgM. The IgM-B sub-variant has a characteristic extra cysteine near the C-terminal part of the heavy chain and exhibits a higher degree of polymer disulfide cross-linking compared to IgM-A. The IgM-B:IgM-A ratio in serum is typically 60:40, but skewed ratios are also observed. The IgT isotype appears to be specialized to mucosal immune responses in salmonid fish. The concentration of IgT in serum is 100 to 1000 times lower than IgM. Secreted forms of IgD have been detected in rainbow trout, but not yet in Atlantic salmon. PMID- 25734586 TI - Species-specific photorespiratory rate, drought tolerance and isoprene emission rate in plants. AB - The effect of drought on plant isoprene emission varies tremendously across species and environments. It was recently shown that an increased ratio of photosynthetic electron transport rate (ETR) to net carbon assimilation rate (NAR) consistently supported increased emission under drought. In this commentary, we highlight some of the physiological aspects of drought tolerance that are central to the observed variability. We briefly discuss some of the issues that must be addressed in order to refine our understanding of plant isoprene emission response to drought and increasing global temperature. PMID- 25734588 TI - Using Audience Response Systems to Enhance Chronic, Noncancer Pain Knowledge Acquisition Among Veterans. AB - BACKGROUND: Educating patients on factual information related to chronic pain and self-management improves knowledge, pain outcomes, and compliance. The current study assesses changes in pain knowledge among veterans who attended a 12-week "Pain Education School" and examines whether or not the addition of an active learning component (i.e., use of an audience response system [ARS]) leads to greater increases in pain knowledge. MATERIALS AND METHODS: A sample of 102 veterans 24-84 years of age who elected to participate in the 12-week pain education program was evaluated. Only a subgroup of veterans (n=69) had access to the ARS. RESULTS: A 2*2 repeated-measures multivariate analyses of variance was conducted to examine changes in pain knowledge, pain beliefs, stage of readiness to adopt a self-management approach, and depressive symptoms over time and to explore the impact of ARS use on pain knowledge acquisition. Participants reported a statistically significant difference between their pre- and posttest measures of pain beliefs (p=0.04), stage of readiness to adopt a self-management approach (p=0.00), and depressive symptoms (p=0.00). Veterans who used the ARS demonstrated significantly greater increases in pain knowledge acquisition after completing the pain education program than those who did not (p=0.03). CONCLUSIONS: Findings provide support for the incorporation of ARS in pain education programming to facilitate active learning and to increase knowledge acquisition. Findings also provide evidence for the effectiveness of pain education programs in improving veterans' attitudes about their pain, increasing readiness to engage in self-management, and decreasing depressive symptoms. PMID- 25734589 TI - Computerization in medicine. PMID- 25734590 TI - Cholinesterase inhibitors for rarer dementias associated with neurological conditions. AB - BACKGROUND: Rarer dementias include Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), frontotemporal dementia (FTD), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP). Cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, are considered to be the first-line medicines for Alzheimer's disease and some other dementias, such as dementia in Parkinson's disease. Cholinesterase inhibitors are hypothesised to work by inhibiting the enzyme acetylcholinesterase (AChE) which breaks down the neurotransmitter acetylcholine. Cholinesterase inhibitors may also lead to clinical improvement for rarer dementias associated with neurological conditions. OBJECTIVES: To assess the efficacy and safety of cholinesterase inhibitors for cognitive impairment or dementia associated with neurological conditions. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, several trial registries and grey literature sources in August 2013. SELECTION CRITERIA: We included randomised, double-blind, controlled trials assessing the efficacy of treatment of rarer dementias associated with neurological conditions with currently marketed cholinesterase inhibitors. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials, and extracted data. We used the standard methodological procedures of the Cochrane Collaboration. MAIN RESULTS: We included eight RCTs involving 567 participants. Six studies used a simple parallel-group design; the other two consisted of an open-label treatment period followed by a randomised phase. All trials were well concealed for allocation and double-blind, however the sample sizes of most trials were small. All trials used placebo as control. We performed meta-analyses for some outcomes in patients with MS. For all other conditions, results are presented narratively.Two trials included patients with HD; one found that cholinesterase inhibitor use in the short-term had no statistically significant impact on the cognitive portion of the Alzheimer Disease Assessment Scale (ADAS Cog; 1 study, WMD 1.00, 95% CI -1.66 to 3.66, P = 0.46; low quality evidence), Unified Huntington's Disease Rating Scale (UHDRS) Verbal Fluency Test (1 study, WMD -1.20, 95% CI -7.97 to 5.57, P = 0.73; low quality evidence), UHDRS Symbol Digit Modalities Test (SDMT; 1 study, WMD 2.70, 95% CI -0.95 to 6.35, P = 0.15; low quality evidence) and other psychometric tests. The other study found that cholinesterase inhibitor use in the medium-term improved the results of the verbal fluency test (1 study, WMD 6.43, 95% CI 0.66 to 12.20, P = 0.03; moderate quality evidence) and California Verbal Learning Test - Second Edition (CVLT-II) Recognition Task (1 study, WMD 2.42, 95% CI 0.17 to 4.67, P = 0.04; moderate quality evidence). There was no statistically significant difference between groups on the SDMT (1 study, WMD -0.31, 95% CI -7.77 to 7.15, P = 0.94; moderate quality evidence), CVLT-II trials 1-5 (1 study, WMD -2.09, 95% CI -11.65 to 7.47, P = 0.67; moderate quality evidence), short-delay recall (1 study, WMD 0.35, 95% CI -2.87 to 3.57, P = 0.83; moderate quality evidence), or long-delay recall (1 study, WMD -0.14, 95% CI -3.08 to 2.80, P = 0.93; moderate quality evidence), and other psychometric tests.Four trials included patients with MS; one found no differences between the cholinesterase inhibitors (short-term) and placebo groups on the Wechsler Memory Scales general memory score (1 study, WMD 0.90, 95% CI 0.52 to 2.32, P = 0.22; low quality evidence). The three other trials found that, in the medium-term - cholinesterase inhibitors improved the clinician's impression of cognitive change (2 studies, OR 1.96, 95% CI 1.06 to 3.62, P = 0.03; high quality evidence). However, the treatment effect on other aspects of cognitive change were unclear, measured by the Selective Reminding Test (3 studies, WMD 1.47, 95% CI -0.39 to 3.32, P = 0.12; high quality evidence), patient's self-reported impression of memory change (2 studies, OR 1.67, 95% CI 0.93 to 3.00, P = 0.08; high quality evidence) and cognitive change (1 study, OR 0.95, 95% CI 0.45 to 1.98, P = 0.89; high quality evidence), clinician's impression of memory change (1 study, OR 1.50, 95% CI 0.59 to 3.84, P = 0.39; moderate quality evidence), other psychometric tests, and activities of daily living - patient reported impact of multiple sclerosis activities (1 study, WMD 1.18, 95% CI -3.02 to 0.66, P = 0.21; low quality evidence).One study on patients with CADASIL found a beneficial effect of cholinesterase inhibitors on the Executive interview, and Trail Making Test parts A and B. The impact of cholinesterase inhibitors on the Vascular ADAS-Cog score (1 study, WMD 0.04, 95% CI -1.57 to 1.65, P = 0.96; high quality evidence), the Clinical Dementia Rating Scale Sum of Boxes (1 study, WMD -0.09, 95% CI -0.48 to 0.03, P = 0.65; high quality evidence) Disability Assessment for Dementia scale (1 study, WMD 0.58, 95% CI -2.72 to 3.88, P = 0.73; moderate quality evidence), and other measures was unclearOne study included patients with FTD. This trial consisted of an open label treatment period followed by a randomised, double-blind, placebo-controlled phase. No data of primary outcomes were reported in this study.In the included studies, the most common side effect was gastrointestinal symptoms. For all conditions, compared to the treatment group, the placebo group experienced significantly less nausea (6 studies, 44/257 vs. 22/246, OR 2.10, 95% CI 1.22 to 3.62, P = 0.007; high quality evidence), diarrhoea (6 studies, 40/257 vs. 13/246, OR 3.26, 95% CI 1.72 to 6.19, P = 0.0003; moderate quality evidence) and vomiting (3 studies, 17/192 vs. 3/182, OR 5.76, 95% CI 1.67 to 19.87, P = 0.006; moderate quality evidence). AUTHORS' CONCLUSIONS: The sample sizes of most included trials were small, and some of the results were extracted from only one study. There were no poolable data for HD, CADASIL and FTD patients and there were no results for patients with PSP. Current evidence shows that the efficacy on cognitive function and activities of daily living of cholinesterase inhibitors in people with HD, CADASIL, MS, PSP or FTD is unclear, although cholinesterase inhibitors are associated with more gastrointestinal side effects compared with placebo. PMID- 25734591 TI - Problems with the nested granularity of feature domains in bioinformatics: the eXtasy case. AB - BACKGROUND: Data from biomedical domains often have an inherit hierarchical structure. As this structure is usually implicit, its existence can be overlooked by practitioners interested in constructing and evaluating predictive models from such data. Ignoring these constructs leads to potentially problematic and the routinely unrecognized bias in the models and results. In this work, we discuss this bias in detail and propose a simple, sampling-based solution for it. Next, we explore its sources and extent on synthetic data. Finally, we demonstrate how the state-of-the-art variant prioritization framework, eXtasy, benefits from using the described approach in its Random forest-based core classification model. RESULTS AND CONCLUSIONS: The conducted simulations clearly indicate that the heterogeneous granularity of feature domains poses significant problems for both the standard Random forest classifier and a modification that relies on stratified bootstrapping. Conversely, using the proposed sampling scheme when training the classifier mitigates the described bias. Furthermore, when applied to the eXtasy data under a realistic class distribution scenario, a Random forest learned using the proposed sampling scheme displays much better precision that its standard version, without degrading recall. Moreover, the largest performance gains are achieved in the most important part of the operating range: the top of prioritized gene list. PMID- 25734593 TI - [From contents to competency. Educational strategies for the physicians of the 3rd millennium]. AB - Italy, as well as many other countries, is facing the problem to adapt medical education to the challenges of a rapidly changing, globalised world. One main concern is the mismatch of competencies to patient and population needs, which calls for an orientation to a competency-based medical education. Competency is defined as the ability to use knowledge, skills and attitudes in a professional context. Addressing to competency the educational design implies to overcome the boundaries of disciplines to consider mainly the final outcome. A number of international initiatives have defined systems of competency, such as TUNING Medicine or CanMeds, which can form a sound base for the development of a national system. An overall picture of professional competencies allows also to design a continuum between pre- and post-graduate training, up to the continuous professional development. A second essential issue is the adoption of the point of view of complexity in considering the educational system, as well as to focus on reflective thinking as a meta-competency. The National Conference of the Directors of Medical Curricula is running a set of initiatives to support this process of change. PMID- 25734594 TI - [Students of today, physicians of tomorrow. Educational priorities for innovative teaching methods in medicine]. AB - In the past three years there has been increasing debate regarding the educational system of physicians in Italy, mainly due to the implementation of radical changes in the selection and admission criteria to medical courses. From the students' point of view, it is possible to identify different educational challenges to be faced in order to develop a more adequate learning system.First of all, it is necessary to elaborate an accurate planning of the physicians based on the needs of the Italian Healthcare System with a proportionate regulation of access to medical and specialty courses. Secondly, there is the strong need to update the traditional curricula based on a biological reductionist perspective with innovative and integrated courses that could teach new essential topics in a radically changed and globalized world, such as global health or medical ethics. Thirdly, it is crucial to introduce innovative teaching methods that could help students improve and evaluate their practical skills and participate actively in their own education, developing the attitudes and competences needed in their future profession. PMID- 25734595 TI - [Does nutrition matter? Why nutritional care is neglected in Italian hospitals?]. AB - It is surprising how little attention nutrition has received from healthcare providers, in particular in the hospital environment. The discipline of nutrition is also no longer included in regular graduate courses in medicine. The underlying causes of this phenomenon are hard to determine, but they are part of the current paradigmatic shift underway in medicine. Nutrition is a complex and challenging science for most care givers, as it also pertains to their behaviours that should be consistent with health and nutrition messages they deliver to patients. The clinical and economic impact is of great relevance, raising serious ethical issues if not adequately addressed. It is time to re-establish at least a basic level of appropriate nutrition prescription beyond general counseling, with the aim to restore the integrity of the doctor-patient relationship. PMID- 25734596 TI - [How much nutrition matters for children]. AB - Overweight/obesity is a growing epidemic in the Western world and a leading cause of morbidity and mortality, mainly from cardiovascular disease. Doctors are going to play a major role as they are being called on to adapt their practices to confront it. In particular, nutrition seems to be at the core of obesity in children. The ascending trend of this phenomenon in pediatric age, with inherent healthcare implications, was already reported in epidemiological studies of the mid '90s. Public health programs of primary prevention should be stimulated and recommended, with the aim of promoting diet and lifestyle changes in the general population. In addition, accurate anthropometric measurements should be performed for use by pediatricians, who should focus efforts on preventing obesity during infancy and childhood. Nutrition plays such a pivotal role that it may be considered a valuable treatment strategy for multiple pediatric conditions, including celiac disease, Crohn's disease, short bowel syndrome, galactosemia, congenital deficiency of urea cycle enzymes. In view of all this, it would be advisable that food science be given higher relevance in medical education. PMID- 25734597 TI - [Artificial nutrition: technical, scientific and ethical considerations]. AB - Artificial nutrition (AN) is a relatively new medical treatment which started in the 1960 with parenteral nutrition (PN) and over the last 20 years has come to include enteral nutrition (EN) in hospitals and homes. Enormous clinical progress and continual evolution in techniques aimed at rendering organ funtion substitution more complete and efficient have come to the point where AN can only be suitably performed (indications for therapy, treatment regimen and monitoring) in specialized institutions. However, there has been much discussion about whether artificial nutrition should be considered a medical intervention or an essential intervention of care: in 2004 the Terri Schiavo case became worldwide news and the suspension of AN was decided by the law courts. In Italy, on 5 September 2014, the Council of State gave its opinion on case of Eluana Englaro. In 2007 the Italian Association for Dietetics and Clinical Nutrition (ADI) and the Professional Board of Physicians of the Province of Terni, have shared a paper that takes into account the scientific, technical and ethical considerations of AN in the light of the relative codes. The intent of this position paper was to supply a framework of clinical practices, ethical principles, and professional guidelines that will impart information and can assist decision making regarding AN and hydration. The document is still relevant today. PMID- 25734598 TI - [Italy's Slow Medicine: a new paradigm in medicine]. AB - Italy's Slow Medicine was founded in 2011 as a movement aimed to promote processes of care based on appropriateness, but within a relation of listening, dialogue and decision sharing with the patient. The mission of Slow Medicine is synthetized by three key words: measured, because it acts with moderation, gradually and without waste; respectful, because it is careful in preserving the dignity and values of each person; and equitable, because it is committed to ensuring access to appropriate care for all. In a short time, the association spreads at national and international level, gathering the needs of change of a growing number of health professionals, patients and citizens, committed to manage health problems with a new cultural and methodological paradigm. Medicine is soaked with inappropriateness, wastes, conflicts of interest, and many cliches induce professionals and patients to consume more and more healthcare services in the illusion that it is always better doing more for improving health. Moreover, the dominant reductionist cultural model, on which the concept of health and disease is based today, considers man as a machine, investigated by a growing number of specialists, particularly interested in the pathophysiological mechanisms of diseases. The interest is mainly focused on technologies, while the person along with the relations with his/her family and the social environment are completely neglected. The systemic approach adopted by Slow Medicine, on the contrary, teaches us that health and disease are complex phenomena and the life of a person is more than the sum of the chemical reactions that occur in its cells. At different levels of complexity, in fact, new and unexpected properties appear, such as thinking, emotions, pleasure, health. These properties are not detectable in the individual elements and can only be studied using methods of analysis and knowledge belonging to other domains of knowledge, such as humanity sciences: philosophy, anthropology, psychology, ethics, art, etc. Operationally, Slow Medicine has launched the "Doing more does not mean doing better" campaign similar to "Choosing Wisely" in the United States, which aims to improve clinical appropriateness through the reduction of unnecessary tests and treatments: as first step, the specialty societies involved (30 by now) should indicate five tests or treatments commonly used in Italy's clinical practice that do not provide any benefit to most patients but may cause harm. PMID- 25734599 TI - [Disentangling the differential contribution of hypertension and aging on dementia risk]. AB - Dementia is among the most frequent causes of disability in the elderly. Up today, there are no effective therapies that allow to modify the disease course. Great efforts have been made in studying biological correlates of dementia. A growing body of evidence is reporting that classical cardiovascular risk factors are potent predictors of several forms of dementia. Although hypertension has been the most studied in relation to cognitive function, it is yet difficult to pool results and draw strong inferences, due to relevant methodological differences across studies. The association between blood pressure and dementia seems to be complex and far from being unidirectional. Both high and low blood pressure levels have been reported to be associated with impairment in cognitive function in older subjects. Age-related changes in both blood pressure levels and cognitive function, as well as vascular brain damage and systemic arterial aging, may exert a confounding role. Future longitudinal studies are deemed necessary in order to obtain consistent results. In general, the hypothesis of dementia prevention by risk factor control at a population level needs to be established. PMID- 25734600 TI - [Estimate of the prevalence of Parkinson's disease by using electronic health archives]. AB - OBJECTIVE: To estimate the prevalence of Parkinson's disease using electronic health archives and to obtain a knowledge base for its governance. MATERIALS: Drug prescriptions, tax-exemptions and hospital discharge records relating to assisted of Health Services Agency "Triestina" in the year 2011. RESULTS: We identified 909 cases (crude prevalence rate: 380/100.000). The percentage contribution of drug prescriptions, tax-exemptions and hospital discharge records is: 81.5%, 36.1% and 35.2%. CONCLUSIONS: The use of drug prescriptions to detect patients with Parkinson's disease can be effectively supplemented by data of hospital discharges and tax-exemptions, but they still show an underestimation of 17%. PMID- 25734601 TI - [Motion pictures and medicine]. PMID- 25734602 TI - dipSPAdes: Assembler for Highly Polymorphic Diploid Genomes. AB - While the number of sequenced diploid genomes have been steadily increasing in the last few years, assembly of highly polymorphic (HP) diploid genomes remains challenging. As a result, there is a shortage of tools for assembling HP genomes from the next generation sequencing (NGS) data. The initial approaches to assembling HP genomes were proposed in the pre-NGS era and are not well suited for NGS projects. To address this limitation, we developed the first de Bruijn graph assembler, dipSPAdes, for HP genomes that significantly improves on the state-of-the-art assemblers for HP diploid genomes. PMID- 25734603 TI - The role of medical group practice administrators in the adoption and implementation of Medicare's physician quality reporting system. AB - BACKGROUND: Although there are numerous studies of the factors influencing the adoption of quality assurance (QA) programs by medical group practices, few have focused on the role of group practice administrators. PURPOSE: To gain insights into the role these administrators play in QA programs, we analyzed how medical practices adopted and implemented the Medicare Physician Quality Reporting System (PQRS), the largest physician quality reporting system in the United States. METHODOLOGY: We conducted focus group interviews in 2011 with a national convenience sample of 76 medical group practice administrators. Responses were organized and analyzed using the innovation decision framework of Van de Ven and colleagues. FINDINGS: Administrators conducted due diligence on PQRS, influenced how the issue was presented to physicians for adoption, and managed implementation thereafter. Administrators' recommendations were heavily influenced by practice characteristics, financial incentives, and practice commitments to early adoption of quality improvement innovations. Virtually, all who attempted it agreed that PQRS was straightforward to implement. However, the complexities of Medicare's PQRS reports impeded use of the data by administrators to support quality management. DISCUSSION: Group practice administrators are playing a prominent role in activities related to the quality of patient care- they are not limited to the business side of the practice. Especially, as PQRS becomes more nearly universal after 2014, Medicare should take account of the role that administrators play, by more actively engaging administrators in shaping these programs and making it easier for administrators to use the results. PRACTICE IMPLICATIONS: More research is needed on the rapidly evolving role of nonphysician administration in medical group practices. Practice administrators have a larger role than commonly understood in how quality reporting initiatives are adopted and used and are in an exceptional position to influence the more appropriate use of these resources if supported by more useful forms of quality reporting. PMID- 25734604 TI - An empirically based model for knowledge management in health care organizations. AB - BACKGROUND: Knowledge management (KM) encompasses strategies, processes, and practices that allow an organization to capture, share, store, access, and use knowledge. Ideal KM combines different sources of knowledge to support innovation and improve performance. PURPOSES: Despite the importance of KM in health care organizations (HCOs), there has been very little empirical research to describe KM in this context. This study explores KM in HCOs, focusing on the status of current intraorganizational KM. The intention is to provide insight for future studies and model development for effective KM implementation in HCOs. METHODOLOGY/APPROACH: A qualitative methods approach was used to create an empirically based model of KM in HCOs. Methods included (a) qualitative interviews (n = 24) with senior leadership to identify types of knowledge important in these roles plus current information-seeking behaviors/needs and (b) in-depth case study with leaders in new executive positions (n = 2). The data were collected from 10 HCOs. Our empirically based model for KM was assessed for face and content validity. FINDINGS: The findings highlight the paucity of formal KM in our sample HCOs. Organizational culture, leadership, and resources are instrumental in supporting KM processes. An executive's knowledge needs are extensive, but knowledge assets are often limited or difficult to acquire as much of the available information is not in a usable format. We propose an empirically based model for KM to highlight the importance of context (internal and external), and knowledge seeking, synthesis, sharing, and organization. Participants who reviewed the model supported its basic components and processes, and potential for incorporating KM into organizational processes. DISCUSSION: Our results articulate ways to improve KM, increase organizational learning, and support evidence-informed decision-making. PRACTICE IMPLICATIONS: This research has implications for how to better integrate evidence and knowledge into organizations while considering context and the role of organizational processes. PMID- 25734605 TI - Prediagnostic Serum Organochlorine Concentrations and Metastatic Prostate Cancer: A Nested Case-Control Study in the Norwegian Janus Serum Bank Cohort. AB - BACKGROUND: Organochlorine (OC) insecticides and polychlorinated biphenyls (PCBs) have been shown to have estrogenic, antiestrogenic, or antiandrogenic properties; as a result, the impact of exposure to these compounds and risk of hormonal cancers, such as prostate cancer, is a concern. OBJECTIVES: We conducted a nested case-control study, using prospectively collected serum, to estimate associations between OC exposures and metastatic prostate cancer in a population-based cohort from Norway. METHODS: Sera from 150 cases and 314 controls matched on date of blood draw, age at blood draw, and region was used to determine concentrations of 11 OC pesticide metabolites and 34 PCB congeners. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for quartiles of lipid-corrected metabolite levels were calculated using conditional logistic regression. RESULTS: Metastatic prostate cancer was two times as likely among men with serum concentrations of oxychlordane in the highest quartile compared with those in the lowest quartile (OR = 2.03; 95% CI: 1.03, 4.03; p-trend 0.05). Elevated but nonsignificant ORs were estimated for the highest versus lowest quartile of heptachlor epoxide, HCB, and mirex, although these exposures were correlated with oxychlordane. Findings for specific PCB congeners showed a significant inverse association between natural log-transformed lipid-adjusted PCB 44 and metastatic prostate cancer (OR = 0.74; 95% CI: 0.56, 0.97; p-trend = 0.02). CONCLUSIONS: Our study highlights the importance of estimating associations with specific OC chemicals and suggests a possible role of OC insecticides and PCBs in the etiology of metastatic prostate cancer. CITATION: Koutros S, Langseth H, Grimsrud TK, Barr DB, Vermeulen R, Portengen L, Wacholder S, Beane Freeman LE, Blair A, Hayes RB, Rothman N, Engel LS. 2015. Prediagnostic serum organochlorine concentrations and metastatic prostate cancer: a nested case-control study in the Norwegian Janus Serum Bank cohort. Environ Health Perspect 123:867-872; http://dx.doi.org/10.1289/ehp.1408245. PMID- 25734607 TI - Racial differences in the neutrophil-to-lymphocyte ratio in patients with non-ST segment elevation myocardial infarction. AB - OBJECTIVES: The neutrophil-to-lymphocyte ratio (NLR) predicts short-term and long term mortalities in patients with stable and unstable coronary artery disease. However, it has been reported that white blood cell and neutrophil counts vary considerably among different races. We aimed to assess the impact of racial difference on NLR in our diverse population with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS: We carried out a retrospective analysis of 456 consecutive NSTEMI patients who had undergone coronary angiography. The patients were divided into four groups on the basis of self-reported race: White, Hispanic, African-American, and Asian. NLR was compared among the four groups. Univariate and multivariate linear regression analyses were carried out between NLR and baseline clinical characteristics and angiographic findings. The primary outcome was inhospital mortality. RESULTS: The median NLR in the entire study population was 3.47 (interquartile range, 2.16-5.57). NLR differed significantly among the four groups according to the Kruskal-Wallis test (P=0.03). NLR was significantly lower in the African-American group compared with the White group according to the Steel-Dwass test (P=0.03). Multivariate analysis revealed that African-American ethnicity was negatively associated with NLR (P=0.04). The second multivariate analysis using the White group as a reference also revealed that African-American ethnicity was negatively associated with NLR (P=0.04). There was no significant difference in inhospital mortality among the four groups. CONCLUSION: The present study demonstrated an independent association between race and NLR in patients with NSTEMI, suggesting that a tailored cutoff value according to race would provide more precise prognostic information. PMID- 25734606 TI - Extracorporeal shockwave myocardial therapy is efficacious in improving symptoms in patients with refractory angina pectoris--a multicenter study. AB - OBJECTIVE: Medically refractory angina remains a significant health concern despite major advances in revascularization techniques and emerging medical therapies. We aimed to determine the safety and efficacy of extracorporeal shockwave myocardial therapy (ESMT) in managing angina pectoris. METHODS: A single-arm multicenter prospective study was designed aiming to determine the safety and efficacy of ESMT. Patients of functional Canadian Cardiovascular Society class II-IV, despite stable and optimal medical management, with documented myocardial segments with reversible ischemia and/or hibernation on the basis of echocardiography/single-photon emission computerized tomography (SPECT) were enrolled from 2010 to 2012. A total of 111 patients were enrolled, 33 from Indonesia, 21 from Malaysia, and 57 from Philippines. Patients underwent nine cycles of ESMT over 9 weeks. Patients were followed up for 3-6 months after ESMT treatment. During follow-up, patients were subjected to clinical evaluation, the Seattle Angina Questionnaire, assessment of nitrate intake, the 6-min walk test, echocardiography, and SPECT. RESULTS: The mean age of the population was 62.9+/ 10.9 years. The summed difference score on pharmacologically induced stress SPECT improved from 9.53+/-17.87 at baseline to 7.77+/-11.83 at follow-up (P=0.0086). Improvement in the total Seattle Angina Questionnaire score was seen in 83% of patients (P<0.0001). Sublingual nitroglycerin use significantly decreased (1.14+/ 1.01 tablets per week at baseline to 0.52+/-0.68 tablets per week at follow-up; P=0.0215). There were no changes in left ventricular function on echocardiography (0.33+/-9.97, P=0.93). The Canadian Cardiovascular Society score improved in 74.1% of patients. CONCLUSION: This multicenter prospective trial demonstrated that ESMT is both a safe and an efficacious means of managing medically refractory angina. PMID- 25734608 TI - Congenital renal tumor: metanephric adenoma, nephrogenic rest, or malignancy? AB - We report a renal tumor detected by prenatal ultrasound and resected at 2 months of age. This 9-cm, solid mass was composed of tubular and papillary structures lined by small, uniform epithelial cells. There was local invasion into renal parenchyma and a tumor deposit in a hilar lymph node. The tumor was immunopositive for WT1, pankeratin, and CD10; focally positive for CK7; and negative for EMA and TFE3. Based on morphology and immunophenotype, the favored diagnosis was metanephric adenoma over Wilms tumor, renal cell carcinoma, and nephrogenic rest. However, metanephric adenoma only occasionally occurs in children and has never been reported prenatally. Alternatively, this tumor might be a congenital Wilms tumor that differentiated completely. Although the nature of the tumor remains unconfirmed, resection appears to have been curative; the patient remains disease-free 18 months following surgery alone. PMID- 25734609 TI - Parallel feedback loops control the basal activity of the HOG MAPK signaling cascade. AB - Tight regulation of the MAP kinase Hog1 is crucial for survival under changing osmotic conditions. Interestingly, we found that Hog1 phosphorylates multiple upstream components, implying feedback regulation within the signaling cascade. Taking advantage of an unexpected link between glucose availability and Hog1 activity, we used quantitative single cell measurements and computational modeling to unravel feedback regulation operating in addition to the well-known adaptation feedback triggered by glycerol accumulation. Indeed, we found that Hog1 phosphorylates its activating kinase Ssk2 on several sites, and cells expressing a non-phosphorylatable Ssk2 mutant are partially defective for feedback regulation and proper control of basal Hog1 activity. Together, our data suggest that Hog1 activity is controlled by intertwined regulatory mechanisms operating with varying kinetics, which together tune the Hog1 response to balance basal Hog1 activity and its steady-state level after adaptation to high osmolarity. PMID- 25734610 TI - Changes in access to structural social capital and its influence on self-rated health over time for middle-aged men and women: a longitudinal study from northern Sweden. AB - Until recently, most studies on social capital and health have been cross sectional making it difficult to draw causal conclusions. This longitudinal study used data from 33,621 individuals (15,822 men and 17,799 women) from the Vasterbotten Intervention Program, to analyse how changes in access to individual social capital influence self-rated health (SRH) over time. Two forms of structural social capital, i.e. informal socializing and social participation, were measured. Age, sex, education, marital status, smoking, snuff, physical activity, alcohol consumption, high blood pressure, and body mass index were analysed as potential confounders. The association between changes in access to structural social capital and SRH in the follow-up was adjusted for SRH at baseline, as well as for changes in the socio-demographic and health-risk variables over time. The results support that changes in access to structural social capital over time impact on SRH. Remaining with no/low level of informal socializing over time increased the odds ratio for poor SRH for both men and women (OR of 1.45; 95%CI = 1.22-1.73 among men and OR of 1.56; 95%CI = 1.33-1.84 among women). Remaining with no/low levels of social participation was also detrimental to SRH in men and women (OR 1.14; 95%CI = 1.03-1.26 among men and OR 1.18; 95%CI = 1.08-1.29 among women). A decrease in informal socializing over time was associated with poor SRH for women and men (OR of 1.35; 95%CI = 1.16 1.58 among men and OR of 1.57; 95%CI = 1.36-1.82 among women). A loss of social participation had a negative effect on SRH among men and women (OR of 1.16; 95%CI = 1.03-1.30 among men and OR of 1.15; 95%CI = 1.04-1.27 among women). Gaining access to social participation was harmful for SRH for women (OR 1.17; 95%CI = 1.05-1.31). Structural social capital has complex and gendered effects on SRH and interventions aiming to use social capital for health promotion purposes require an awareness of its gendered nature. PMID- 25734611 TI - Pain and self-assessed health: does the association vary by age? AB - The association between pain and self-assessed health among adults age 20 and older is examined with data from the 2003-2004 National Health and Nutrition Examination Survey, a cross-sectional nationally representative survey of the civilian, non-institutionalized US population. Models emphasize whether and how the association differs across age cohorts. 5032 respondents age 20 and older were asked about their experience with pain. Responses are used to create two different pain measures: general and site-specific. Self-assessed health is categorized into groups that are ordered from fair/poor to excellent. Bivariate analyses and ordered logistic regressions reveal pain, measured both ways, have robust inverse associations with self-assessed health. Associations remain robust after adjusting for a series of health conditions and indicators plus demographic, socioeconomic and social support characteristics. Models test the effect of age by pain interactions on self-assessed health and confirm substantial variation across cohorts. Those of middle-age, 40-59, display the strongest association while self-assessed health is virtually unassociated among older-old, those 80 and older. Findings suggest that the way pain impacts self assessed health varies by age cohort. Conclusions discuss the importance of considering pain as a health condition and the implications of the findings for well-being across age cohorts. PMID- 25734612 TI - Mobility and health sector development in China and India. AB - China and India are both attempting to create comprehensive healthcare systems in the context of rapid but uneven economic growth and rapidly changing burdens of disease. While in each country the referencing of international policies and work experience abroad have been part of this process, research has yet to examine the kind of knowledge that is exchanged or the various actors involved in knowledge circulation. Based on a study of two sub-national contexts, this article focuses on the role Chinese and Indian health professionals who have studied and worked overseas play in introducing ideas and practices about healthcare provision and health education. We found that experience abroad influenced individuals, institutions, and each society differently and with some contradictory effects. International experience clearly contributed to personal growth and led individuals to support the adoption of new institutional practices, such as more egalitarian relations between doctors and patients and between students and teachers. However, the content of what individuals learned overseas and the mechanisms through which this knowledge was introduced back into homeland settings often reinforced rather than ameliorated institutional hierarchies and social inequalities. While the scope of this research was limited, we suggest that more explicit analysis of the role professional migrants play in transferring ideas and practices within the health sector would be valuable for policymakers and funders seeking to support a more productive interaction between local and global knowledge. PMID- 25734613 TI - Gaps in capacity for respiratory care in developing countries. Nigeria as a case study. AB - There are unmet needs for respiratory medical care in developing countries. We sought to evaluate the quality and capacity for respiratory care in low- and lower-middle-income countries, using Nigeria as a case study. We obtained details of the respiratory practice of consultants and senior residents (fellows) in respiratory medicine in Nigeria via a semistructured questionnaire administered to physician attendees at the 2013 National Congress of the Nigerian Thoracic Society. Out of 76 society-registered members, 48 attended the congress, 40 completed the questionnaire, and 35 provided complete data (73% adjusted response rate). Respondents provided information on the process and costs of respiratory medicine training and facility, equipment, and supply capacities at the institutions they represented. Approximately 83% reported working at a tertiary level (teaching) hospital; 91% reported capacity for sputum smear analysis for acid alcohol-fast bacilli, 37% for GeneXpert test cartridges, and 20% for BACTEC liquid sputum culture. Only 34% of respondents could perform full spirometry on patients, and none had the capacity for performing a methacholine challenge test or for measuring the diffusion capacity for carbon monoxide. We estimated the proportion of registered respiratory physicians to the national population at 1 per 2.3 million individuals. Thirteen states with an estimated combined population of 57.7 million offer no specialist respiratory services. Barriers to development of this capacity include the high cost of training. We conclude that substantial gaps exist in the capacity and quality of respiratory care in Nigeria, a pattern that probably mirrors most of sub-Saharan Africa and other countries of similar economic status. Health policy makers should address these gaps systematically. PMID- 25734614 TI - Polymer sol-gel composite inverse opal structures. AB - We report on the formation of composite inverse opal structures where the matrix used to form the inverse opal contains both silica, formed using sol-gel chemistry, and poly(ethylene glycol), PEG. We find that the morphology of the inverse opal structure depends on both the amount of PEG incorporated into the matrix and its molecular weight. The extent of organization in the inverse opal structure, which is characterized by scanning electron microscopy and optical reflectance data, is mediated by the chemical bonding interactions between the silica and PEG constituents in the hybrid matrix. Both polymer chain terminus Si O-C bonding and hydrogen bonding between the polymer backbone oxygens and silanol functionalities can contribute, with the polymer mediating the extent to which Si O-Si bonds can form within the silica regions of the matrix due to hydrogen bonding interactions. PMID- 25734615 TI - Structural investigation of the A-site vacancy in scheelites and the luminescence behavior of two continuous solid solutions A(1-1.5x)Eu(x)?(0.5x)WO4 and A(0.64 0.5y)Eu(0.24)Li(y)?(0.12-0.5y)WO4 (A = Ca, Sr; ? = vacancy). AB - Scheelite compounds with Eu(3+) substitution are well-known red-phosphors. We prepared and performed a detailed structural characterization of A(1 1.5x)Eu(x)?(0.5x)WO4 and A(0.64-0.5y)Eu(0.24)Li(y)?(0.12-0.5y)WO4 (A = Ca, Sr; ? = vacancy) to confirm the A-site vacancy mechanism for charge balance when bivalent A cations were substituted by Eu(3+). All compounds crystallize in I41/a with a disordered arrangement of A(2+), Eu(3+), ? at the A-site. The title compounds are all good red phosphors with a high R/O ratio (~10), indicating that Eu(3+) is located at a significantly distorted cavity. A(1-1.5x)Eu(x)?(0.5x)WO4 shows a saturation phenomenon at a high doping level, x = 0.20. With the incorporation of Li(+), the emission intensity was generally enhanced compared to the Li(+)-free samples, moreover, an increase of the Li(+) content reduces the content of vacancies, resulting in further increase of the luminescence intensity. PMID- 25734616 TI - Identification of individual biofilm-forming bacterial cells using Raman tweezers. AB - A method for in vitro identification of individual bacterial cells is presented. The method is based on a combination of optical tweezers for spatial trapping of individual bacterial cells and Raman microspectroscopy for acquisition of spectral "Raman fingerprints" obtained from the trapped cell. Here, Raman spectra were taken from the biofilm-forming cells without the influence of an extracellular matrix and were compared with biofilm-negative cells. Results of principal component analyses of Raman spectra enabled us to distinguish between the two strains of Staphylococcus epidermidis. Thus, we propose that Raman tweezers can become the technique of choice for a clearer understanding of the processes involved in bacterial biofilms which constitute a highly privileged way of life for bacteria, protected from the external environment. PMID- 25734617 TI - Isolation of an arsenate-respiring bacterium from a redox front in an arsenic polluted aquifer in West Bengal, Bengal Basin. AB - Natural pollution of groundwater by arsenic adversely affects the health of tens of millions of people worldwide, with the deltaic aquifers of SE Asia being particularly polluted. The pollution is caused primarily by, or as a side reaction of, the microbial reduction of sedimentary Fe(III)-oxyhydroxides, but the organism(s) responsible for As release have not been isolated. Here we report the first isolation of a dissimilatory arsenate reducer from sediments of the Bengal Basin in West Bengal. The bacterium, here designated WB3, respires soluble arsenate and couples its reduction to the oxidation of acetate; WB3 is therefore implicated in the process of arsenic pollution of groundwater, which is largely by arsenite. The bacterium WB3 is also capable of reducing dissolved Fe(III) citrate, solid Fe(III)-oxyhydroxide, and elemental sulfur, using acetate as the electron donor. It is a member of the Desulfuromonas genus and possesses a dissimilatory arsenate reductase that was identified using degenerate polymerase chain reaction primers. The sediment from which WB3 was isolated was brown, Pleistocene sand at a depth of 35.2 m below ground level (mbgl). This level was some 3 cm below the boundary between the brown sands and overlying reduced, gray, Holocene aquifer sands. The color boundary is interpreted to be a reduction front that releases As for resorption downflow, yielding a high load of labile As sorbed to the sediment at a depth of 35.8 mbgl and concentrations of As in groundwater that reach >1000 MUg/L. PMID- 25734618 TI - Whither the "signature wounds of the war" after the war: estimates of incidence rates and proportions of TBI and PTSD diagnoses attributable to background risk, enhanced ascertainment, and active war zone service, active component, U.S. Armed Forces, 2003-2014. AB - Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are "signature wounds" of the Afghanistan/Iraq wars; however, many TBI/PTSD cases are not war related. During the wars, diagnoses of TBI/PTSD among military members increased because risks of TBI/PTSD, and capabilities to detect cases, increased. This report summarizes TBI/PTSD diagnosis experiences of three cohorts of overseas deployers in relation to the natures of their exposures to active war service and enhanced case ascertainment efforts. The findings suggest that, during the war, the proportions of PTSD diagnoses attributable to war zone service decreased from approximately 80% to less than 50%, while the proportions attributable to enhanced case ascertainment increased from less than 10% to nearly 50%. The proportions of TBI diagnoses attributable to war zone service more than tripled from 2003-2005 (13.1%) through 2007-2009 (44.8%); the proportions attributable to enhanced ascertainment also markedly increased, but not until after 2007. By the end of the war, war zone service and enhanced ascertainment accounted for similar proportions of all PTSD and TBI diagnoses. If programs and resources currently focused on TBI and PTSD continue, rates of diagnoses post-war will greatly exceed those pre-war. PMID- 25734619 TI - Surveillance snaphshot: Responses to the traumatic brain injury (TBI) screening questions on the 2012 version of the post-deployment health assessement (DD Form 2796). PMID- 25734620 TI - Measles and mumps among service members and other beneficiaries of the U.S. Military Health System, January 2007-December 2014. AB - Measles and mumps are highly communicable infectious diseases whose causative viruses are spread through airborne droplets and infected surfaces. Individuals at highest risk are infants and unvaccinated individuals. Despite effective vaccines, there have been recent increases in incidence in the U.S. of both infections. During the surveillance period, there were 14 confirmed measles cases and 99 confirmed mumps cases among U.S. military members and other beneficiaries of the U.S. Military Health System. Only one of the confirmed cases of measles was in a service member. Children aged 5 years and younger accounted for the greatest proportion of confirmed measles cases (50.0%); the greatest proportions of confirmed mumps cases were for children aged 1-5 years and adults aged 26-30 years (22.2% and 17.2%, respectively). California had more cases of both measles and mumps than any other state. Recent trends in measles and mumps in civilian populations in the U.S. highlight the importance of primary and booster vaccinations. PMID- 25734621 TI - Charge separation between polar {111} surfaces of CoO octahedrons and their enhanced visible-light photocatalytic activity. AB - Crystal facet engineering of semiconductors has been proven to be an effective strategy to increase photocatalytic performances. However, the mechanism involved in the photocatalysis is not yet known. Herein, we report our success in that photocatalytic performances of the Cl(-) ion capped CoO octahedrons with exposed {111} facets were activated by a treatment using AgNO3 and NH3.H2O solutions. The clean CoO {111} facets were found to be highly reactivity faces. On the basis of the polar structure of the exposed {111} surfaces, a charge separation model between polar {111} surfaces is proposed. There is an internal electric field between polar {111} surfaces due to the spontaneous polarization. The internal electric field provides a driving force for charge separation. The reduction and oxidation reactions selectively take place on the positive and negative polar {111} surfaces. The charge separation model provides a clear insight into charge transfer in the semiconductor nanocrystals with high photocatalytic activities and offer guidance to design more effective photocatalysts, solar cells, photoelectrodes, and other photoelectronic devices. PMID- 25734622 TI - Synergistic interactions among metabolic syndrome components and homeostasis model assessment of insulin resistance in a middle-aged general population over time. AB - BACKGROUND: Insulin resistance is considered a hallmark feature of the metabolic syndrome, but how metabolic syndrome components and insulin resistance measures interact over time is unclear. The homeostasis model assessment of insulin resistance (HOMA-IR) is a static index of insulin resistance typically used in epidemiological studies. We explored how HOMA-IR is affected by clustering metabolic syndrome components over time in a population of middle-aged, healthy subjects. METHODS: A total of 1757 subjects aged 41.3+/-7.5 years (39% males) free from diabetes at baseline were followed-up for a median of 5.7 years. At baseline and at the end of observation, we determined metabolic syndrome components and HOMA-IR. RESULTS: Cross-sectionally, HOMA-IR was synergistically increased by clustering of at least two to three metabolic syndrome components as determined at baseline and at study end by departure from additivity. Some combinations of metabolic syndrome components were associated with a significant synergic increase in HOMA-IR, and some combinations of two components entailed a synergistic risk of developing metabolic syndrome. Over time, the average change in HOMA-IR was more than additively affected by change in the number of metabolic syndrome components. Baseline HOMA-IR values were predictive of incident metabolic syndrome independent from age, sex, and each metabolic syndrome component. CONCLUSIONS: We show synergistic interaction between clustering metabolic syndrome components and insulin resistance, estimated by HOMA-IR, cross sectionally and over time. This more than additive effect explains the incremental value of HOMA-IR in predicting metabolic risk. PMID- 25734623 TI - Eremophilane Sesquiterpenes and Diphenyl Thioethers from the Soil Fungus Penicillium copticola PSU-RSPG138. AB - Four new compounds including two eremophilane sesquiterpenes, penicilleremophilanes A (1) and B (2), as well as two sulfur-containing biphenols, penicillithiophenols A (3) and B (4), were isolated from the soil fungus Penicillium copticola PSU-RSPG138 together with 16 known compounds. Their structures were elucidated by spectroscopic methods. Known sporogen AO-1 exhibited significant antimalarial activity against Plasmodium falciparum with an IC50 value of 1.53 MUM and cytotoxic activity to noncancerous (Vero) cell lines with an IC50 value of 4.23 MUM. Although compound 1 was approximately half as active against P. falciparum with the IC50 value of 3.45 MUM, it showed much weaker cytotoxic activity. PMID- 25734624 TI - Reversible chemochromic MoO3 nanoribbons through zerovalent metal intercalation. AB - Molybdenum trioxide (alpha-MoO3) is a 2D layered oxide with use in electrochromic and photochromic devices owing to its ability to reversibly change color between transparent and light blue with electrochemical or hydrogen intercalation. Despite its significant application potential, MoO3 performance is largely limited by the destructiveness of these intercalation techniques, insignificant coloration, and slow color response. We demonstrate a reversible chemochromic method, using intercalation of zerovalent metals into alpha-MoO3 nanoribbons (Sn, ~2 at. %; Co, ~4 at. %), to chemically alter MoO3 from transparent white to a deep blue indigo, resulting in enhanced coloration and chemically tunable optical properties. We present two strategies to reversibly tune the color response of MoO3 nanoribbons. Chromism can be reversed (i) by complete oxidative deintercalation with hydrogen peroxide or iodine or (ii) through a temperature driven disorder-order phase transition of the intercalated zerovalent metal. PMID- 25734625 TI - Eco- and genotoxicological assessments of two reactive textile dyes. AB - Contamination of natural waters has been one of the major problems of modern society and the textile industry is rated as an important polluting source, due to the generation of large amounts of wastewaters. The aim of this study was to assess textile dyes Reactive Blue 19 (RB19, anthraquinone dye) and Reactive Red 120 (RR120, azo dye) in terms of the potential to induce adverse effects on aquatic organisms and humans. Thus, these dyes were tested using the following assays: Microtox assay (Vibrio fischeri); brine shrimp (Artemia salina); Daphnia similis; and Comet with normal human dermal fibroblasts as well as Ames test (TA98, TA100, YG1041, YG1042--with and without S9). RB19 was relatively nontoxic to all aquatic bioindicators analyzed with an EC50 of more than 100 mg/L, whereas RR120 was only moderately toxic to A. salina with a EC50-48h of 81.89 mg/L. Mutagenicity through base pair substitution was observed with RB19 in the presence of S9 (Ames-positive). The comet assay did not demonstrate any apparent genotoxic effects for any tested dye. Although mutagenicity was detected with RB19, the mutagenic effect observed may be considered weak compared to the ability to induce DNA damage by other classes of dyes such as disperse dyes. Therefore, these dyes may be classified as nonmutagens (RR120) or weak mutagens (RB19) and relatively nontoxic for aquatic organisms. However, it is noteworthy that the weak acute toxicity to A. salina induced by RR120 is sufficient to suggest potential damage to the aquatic ecosystem and emphasizes the need for biomonitoring dye levels in wastewater systems. PMID- 25734626 TI - Gill histopathologies following exposure to nanosilver or silver nitrate. AB - Fish gill is the site for many crucial physiological functions. It is among the first sites of xenobiotic exposure, and gill histopathological alterations may be detected soon after toxicant exposure. Silver (Ag) is one of the most toxic metals to aquatic organisms mainly due to its ability to disrupt ionic regulation. The goal of this study was to determine the effect of ionic and nanoscale Ag on fathead minnow gills by examining gill histology and Na(+)/K(+) ATPase immunoreactivity. Fathead minnows were exposed to two measured concentrations of silver nitrate (AgNO3: 1.3 or 3.7 MUg/L as Ag(+)), citrate silver nanoparticles (citrate-AgNP: 15 or 39 MUg/L), and polyvinylpyrrolidone AgNP (PVP-AgNP) (AgNP: 11 or 50 MUg/L). Circulatory disturbances were the most prevalent gill alterations detected and were significantly increased in all Ag treatment groups compared to control. AgNO3 (1.3 MUg/L) was the only treatment that significantly elevated the number of total mucous goblet cells present. In all other Ag treatments, the percent of degenerated goblet cells was significantly increased compared to control. When the sum of all histopathological abnormalities (weighted index) was calculated, all Ag groups displayed a significantly higher index, with citrate-AgNP having the highest toxicity (index of 10 +/- 0.32 versus 2.4 +/- 0.6 in controls). Gill Na(+)/K(+) ATPase immunoreactivity was decreased by Ag. These results indicated that both AgNO3 and AgNP created similar disruptions in gill structure and ionic regulation, possibly due to the ionic Ag portion of each treatment. PMID- 25734627 TI - Essential and toxic elements in clays for pharmaceutical and cosmetic use. AB - Essential and toxic elements (Al, Si, P, S, K, Ca, Ti, Mn, Fe, Ni, Cu, Zn, As, Br, Rb, Sr, Ba, Cd, Ce, Nd, Pb, U, Th, and La) were determined by energy dispersive polarized x-ray fluorescence spectrometry (EDPXRF) in 15 samples of clay materials for pharmaceutical and cosmetic use. The investigated samples were grouped according to their mineralogical composition determined by x-ray powder diffraction (XRPD). Samples consisting of smectites showed the lowest content of K, Zn, La, Ce, Nd, Pb, Ti, and Th and highest quantity of Sr, Br, and U. The sample containing smectite and kaolinite displayed the lowest content of Ca, Fe, Mn, Cu, Ni, and Sr and highest amount of Al, Si, Ba, Zn, As, La, Ce, Pb, and Th. Samples composed of illite demonstrated minimal amounts of Br and maximal content of K, Rb, Ti, and Fe. In all samples analyzed, Cd and Hg levels were below 2 mg/kg. PMID- 25734628 TI - Phthalate concentrations in personal care products and the cumulative exposure to female adults and infants in Shanghai. AB - Phthalate esters (PE) are synthetic chemicals widely used in industry, and have been detected in personal care products (PCP). Recent findings of human reports demonstrated endocrine-disrupting action associated with phthalate exposures. The aims of this study were to (1) measure levels of 11 PE in 198 PCP collected from retail markets in Shanghai and (2) assess daily dermal exposure in adult females and infants. The health risk of cumulative exposure to eight PE on reproductive system function derived from dermal PCP use was further assessed by utilizing the hazard index (HI) approach. Diethyl phthalate (DEP) was the most frequently detected compound (29.8%), followed by diisobutyl phthalate (DiBP) (6.6%). The geometric mean (GM) concentrations of daily exposure to DEP, bis(2-methoxyethyl) phthalate (DMEP), DiBP, dibutyl phthalate (DBP), diphenyl phthalate (DPP), and bis(2-ethylhexyl) phthalate (DEHP) in female adults were 0.018, 0.012, 0.002, 0.001, 0.003, and 0.002 MUg/kg body weight (bw)/d, respectively. The GM daily exposure levels to PE in infants and adult females were similar except for DEHP, which was higher in infants. DEP exposure was highest in both subpopulations at either GM or maximal level. All HI of 8 PE were far less than 1, ranging from 0.0002 to 0.005, indicating no cumulative reproductive risks to these populations. DBP, DMEP, and DEHP were three major contributors to the cumulative HI. In summary, the level of phthalate in PCP from Shanghai retail markets posed no apparent cumulative risk to adult females and infants in China. PMID- 25734629 TI - Application of brown bear (Ursus arctos) records for retrospective assessment of mercury. AB - Because mercury (Hg) is released into the atmosphere, wildlife living in habitats located far from point sources of metal may still be at risk. Mercury accumulation, previously considered a risk for aquatic ecosystems, is also found in many wildlife terrestrial species. The aim of the present study was to examine total Hg concentrations in the brown bear (Ursus arctos) by measurement of metal in hair from museum collections in Iran. Another objective of this investigation was to characterize the risk of Hg exposure in bears in several parts of Iran. Brown bear (Ursus arctos) hair samples (n = 35) were collected from 14 provinces in Iran for analysis of Hg contamination, performed using an advanced mercury analyzer (model Leco 254 AMA, USA) according to ASTM standard D-6722. Total Hg levels in Iranian bears from all areas ranged from 115.81 to 505.82 MUg/kg, with a mean of 193.39 ng/g. Mercury concentrations in brown bear hair from different provinces in Iran were as follows in descending order: Khorasan Razavi > Esfahan > Khozestan > Yazd > Lorestan > Charmahalva Bakhtiari > Bushehr > Mazandaran > Markazi > Tehran > Ardebil > Gilan > East Azerbaijan. The highest content of Hg was found in the south (206.62 +/- 31.95 ng/g), whereas the lowest levels were detected in the west (167.71 +/- 32.97 ng/g). Overall total Hg content in bear hair was below harmful levels for this species. A decreasing trend was noted in the period 1986-2006, which may be mainly due to reduction of global Hg emissions. Data suggest that food habits and habitat are two important factors that influence Hg accumulation in bears. PMID- 25734630 TI - Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough? AB - BACKGROUND: Pseudomonas aeruginosa (Pa) infection is an important contributor to the progression of cystic fibrosis (CF) lung disease. The cornerstone treatment for Pa infection is the use of inhaled antibiotics. However, there is substantial lung disease heterogeneity within and between patients that likely impacts deposition patterns of inhaled antibiotics. Therefore, this may result in airways below the minimal inhibitory concentration of the inhaled agent. Very little is known about antibiotic concentrations in small airways, in particular the effect of structural lung abnormalities. We therefore aimed to develop a patient specific airway model to predict concentrations of inhaled antibiotics and to study the impact of structural lung changes and breathing profile on local concentrations in airways of patients with CF. METHODS: In- and expiratory CT scans of children with CF (5-17 years) were scored (CF-CT score), segmented and reconstructed into 3D airway models. Computational fluid dynamic (CFD) simulations were performed on 40 airway models to predict local Aztreonam lysine for inhalation (AZLI) concentrations. Patient-specific lobar flow distribution and nebulization of 75 mg AZLI through a digital Pari eFlow model with mass median aerodynamic diameter range were used at the inlet of the airway model. AZLI concentrations for central and small airways were computed for different breathing patterns and airway surface liquid thicknesses. RESULTS: In most simulated conditions, concentrations in both central and small airways were well above the minimal inhibitory concentration. However, small airways in more diseased lobes were likely to receive suboptimal AZLI. Structural lung disease and increased tidal volumes, respiratory rates and larger particle sizes greatly reduced small airway concentrations. CONCLUSIONS: CFD modeling showed that concentrations of inhaled antibiotic delivered to the small airways are highly patient specific and vary throughout the bronchial tree. These results suggest that anti-Pa treatment of especially the small airways can be improved. PMID- 25734631 TI - Special Issue on "Analytical Methods for Oxidized Biomolecules and Antioxidants" The use of isoprostanoids as biomarkers of oxidative damage, and their role in human dietary intervention studies. AB - Isoprostanoids are a group of non-enzymatic oxidized lipids from polyunsaturated fatty acids. They are commonly used as biomarkers for oxidative damage, to assess in vivo lipid peroxidation in diseases related to the vascular system and neurodegeneration. Currently, there is a mismatch with the outcome in the use of these biomarkers in intervention studies, particularly when testing the effect of antioxidants such as vitamins C and E, or zinc, or a cocktail of these, with other food components. Much of this is because the biomarkers, the method of measurement, and the duration of supplementation are unsuitable. In this review, we will highlight the formation of isoprostanoids from their respective fatty acids, and their application as biomarkers for oxidative damage in vivo, considering human dietary intervention studies evaluating plasma and urine, using mass spectrometry techniques. PMID- 25734632 TI - Genetics: Myeloproliferative neoplasms-order of mutations counts! PMID- 25734633 TI - Risk factors: HRT increases risk of ovarian cancer. PMID- 25734634 TI - Epidemiology: Cancer survival: global variation and long-term trends. PMID- 25734635 TI - Breast cancer: CLEOPATRA sheds light on how to tackle metastatic disease. PMID- 25734636 TI - CD30-targeting immunoconjugates and bystander effects. PMID- 25734637 TI - After counterfeit Avastin(r)--what have we learned and what can be done? AB - Three years have passed since the FDA announced that it had detected counterfeit versions of the injectable anticancer drug bevacizumab (Avastin((r)), Genentech, USA) in the US drug-supply chain. Following this discovery, almost 1,000 FDA warning letters were sent to physicians and medical practices in 48 different states and two US territories, as more batches of counterfeit Avastin were uncovered. In response, criminal prosecutions have been pursued against certain distributors and clinicians, and other individuals who trafficked, sold, purchased, and/or administered an unsafe and ineffective treatment while also defrauding the government. Although limited and targeted legal action has been taken, patients potentially affected by this seminal patient safety event have not been appropriately identified. Hence, despite the clear and documented patient-safety and public-health risks posed by the transnational criminal trade in counterfeit medicines, the case study of counterfeit bevacizumab detection in the USA demonstrates the continued lack of information, knowledge, and solutions that would be necessary to protect those who are most affected--the patients. In response, we call for greater investment in multisector, multistakeholder strategies to enhance surveillance for counterfeit medicines and enable improvements in communication of risk information, to better protect patients with cancer. PMID- 25734638 TI - Making surgical missions a joint operation: NGO experiences of visiting surgical teams and the formal health care system in Guatemala. AB - Each year, thousands of Guatemalans receive non-emergent surgical care from short term medical missions (STMMs) hosted by local non-governmental organizations (NGOs) and staffed by foreign visiting medical teams (VMTs). The purpose of this study was to explore the perspectives of individuals based in NGOs involved in the coordination of surgical missions to better understand how these missions articulate with the larger Guatemalan health care system. During the summers of 2011 and 2013, in-depth interviews were conducted with 25 representatives from 11 different Guatemalan NGOs with experience with surgical missions. Transcripts were analysed for major themes using an inductive qualitative data analysis process. NGOs made use of the formal health care system but were limited by several factors, including cost, issues of trust and current ministry of health policy. Participants viewed the government health care system as a potential resource and expressed a desire for more collaboration. The current practices of STMMs are not conducive to health system strengthening. The role of STMMs must be defined and widely understood by all stakeholders in order to improve patient safety and effectively utilise health resources. Priority should be placed on aligning the work of VMTs with that of the larger health care system. PMID- 25734640 TI - Turnover of grassland roots in mountain ecosystems revealed by their radiocarbon signature: role of temperature and management. AB - Root turnover is an important carbon flux component in grassland ecosystems because it replenishes substantial parts of carbon lost from soil via heterotrophic respiration and leaching. Among the various methods to estimate root turnover, the root's radiocarbon signature has rarely been applied to grassland soils previously, although the value of this approach is known from studies in forest soils. In this paper, we utilize the root's radiocarbon signatures, at 25 plots, in mountain grasslands of the montane to alpine zone of Europe. We place the results in context of a global data base on root turnover and discuss driving factors. Root turnover rates were similar to those of a subsample of the global data, comprising a similar temperature range, but measured with different approaches, indicating that the radiocarbon method gives reliable, plausible and comparable results. Root turnover rates (0.06-1.0 y(-1)) scaled significantly and exponentially with mean annual temperatures. Root turnover rates indicated no trend with soil depth. The temperature sensitivity was significantly higher in mountain grassland, compared to the global data set, suggesting additional factors influencing root turnover. Information on management intensity from the 25 plots reveals that root turnover may be accelerated under intensive and moderate management compared to low intensity or semi-natural conditions. Because management intensity, in the studied ecosystems, co-varied with temperature, estimates on root turnover, based on mean annual temperature alone, may be biased. A greater recognition of management as a driver for root dynamics is warranted when effects of climatic change on belowground carbon dynamics are studied in mountain grasslands. PMID- 25734639 TI - Is metabolic syndrome predictive of prevalence, extent, and risk of coronary artery disease beyond its components? Results from the multinational coronary CT angiography evaluation for clinical outcome: an international multicenter registry (CONFIRM). AB - Although metabolic syndrome is associated with increased risk of cardiovascular disease and events, its added prognostic value beyond its components remains unknown. This study compared the prevalence, severity of coronary artery disease (CAD), and prognosis of patients with metabolic syndrome to those with individual metabolic syndrome components. The study cohort consisted of 27125 consecutive individuals who underwent >= 64-detector row coronary CT angiography (CCTA) at 12 centers from 2003 to 2009. Metabolic syndrome was defined as per NCEP/ATP III criteria. Metabolic syndrome patients (n = 690) were matched 1:1:1 to those with 1 component (n = 690) and 2 components (n = 690) of metabolic syndrome for age, sex, smoking status, and family history of premature CAD using propensity scoring. Major adverse cardiac events (MACE) were defined by a composite of myocardial infarction (MI), acute coronary syndrome, mortality and late target vessel revascularization. Patients with 1 component of metabolic syndrome manifested lower rates of obstructive 1-, 2-, and 3-vessel/left main disease compared to metabolic syndrome patients (9.4% vs 13.8%, 2.6% vs 4.5%, and 1.0% vs 2.3%, respectively; p < 0.05), while those with 2 components did not (10.5% vs 13.8%, 2.8% vs 4.5% and 1.3% vs 2.3%, respectively; p > 0.05). At 2.5 years, metabolic syndrome patients experienced a higher rate of MACE compared to patients with 1 component (4.4% vs 1.6%; p = 0.002), while no difference observed compared to individuals with 2 components (4.4% vs 3.2% p = 0.25) of metabolic syndrome. In conclusion, Metabolic syndrome patients have significantly greater prevalence, severity, and prognosis of CAD compared to patients with 1 but not 2 components of metabolic syndrome. PMID- 25734641 TI - Recognizing complex upper extremity activities using body worn sensors. AB - To evaluate arm-hand therapies for neurological patients it is important to be able to assess actual arm-hand performance objectively. Because instruments that measure the actual quality and quantity of specific activities in daily life are lacking, a new measure needs to be developed. The aims of this study are to a) elucidate the techniques used to identify upper extremity activities, b) provide a proof-of-principle of this method using a set of activities tested in a healthy adult and in a stroke patient, and c) provide an example of the method's applicability in daily life based on readings taken from a healthy adult. Multiple devices, each of which contains a tri-axial accelerometer, a tri-axial gyroscope and a tri-axial magnetometer were attached to the dominant hand, wrist, upper arm and chest of 30 healthy participants and one stroke patient, who all performed the tasks 'drinking', 'eating' and 'brushing hair' in a standardized environment. To establish proof-of-principle, a prolonged daily life recording of 1 participant was used to identify the task 'drinking'. The activities were identified using multi-array signal feature extraction and pattern recognition algorithms and 2D-convolution. The activities 'drinking', 'eating' and 'brushing hair' were unambiguously recognized in a sequence of recordings of multiple standardized daily activities in a healthy participant and in a stroke patient. It was also possible to identify a specific activity in a daily life recording. The long term aim is to use this method to a) identify arm-hand activities that someone performs during daily life, b) determine the quantity of activity execution, i.e. amount of use, and c) determine the quality of arm-hand skill performance. PMID- 25734642 TI - A new open-loop fiber optic gyro error compensation method based on angular velocity error modeling. AB - With the open-loop fiber optic gyro (OFOG) model, output voltage and angular velocity can effectively compensate OFOG errors. However, the model cannot reflect the characteristics of OFOG errors well when it comes to pretty large dynamic angular velocities. This paper puts forward a modeling scheme with OFOG output voltage u and temperature T as the input variables and angular velocity error Deltaomega as the output variable. Firstly, the angular velocity error Deltaomega is extracted from OFOG output signals, and then the output voltage u, temperature T and angular velocity error Deltaomega are used as the learning samples to train a Radial-Basis-Function (RBF) neural network model. Then the nonlinear mapping model over T, u and Deltaomega is established and thus Deltaomega can be calculated automatically to compensate OFOG errors according to T and u. The results of the experiments show that the established model can be used to compensate the nonlinear OFOG errors. The maximum, the minimum and the mean square error of OFOG angular velocity are decreased by 97.0%, 97.1% and 96.5% relative to their initial values, respectively. Compared with the direct modeling of gyro angular velocity, which we researched before, the experimental results of the compensating method proposed in this paper are further reduced by 1.6%, 1.4% and 1.42%, respectively, so the performance of this method is better than that of the direct modeling for gyro angular velocity. PMID- 25734643 TI - Engineering a Ca+++-sensitive (bio)sensor from the pore-module of a potassium channel. AB - Signals recorded at the cell membrane are meaningful indicators of the physiological vs. pathological state of a cell and will become useful diagnostic elements in nanomedicine. In this project we present a coherent strategy for the design and fabrication of a bio-nano-sensor that monitors changes in intracellular cell calcium concentration and allows an easy read out by converting the calcium signal into an electrical current in the range of microampere that can be easily measured by conventional cell electrophysiology apparatus. PMID- 25734644 TI - Sensor data fusion for body state estimation in a bipedal robot and its feedback control application for stable walking. AB - We report on a sensor data fusion algorithm via an extended Kalman filter for estimating the spatial motion of a bipedal robot. Through fusing the sensory information from joint encoders, a 6-axis inertial measurement unit and a 2-axis inclinometer, the robot's body state at a specific fixed position can be yielded. This position is also equal to the CoM when the robot is in the standing posture suggested by the detailed CAD model of the robot. In addition, this body state is further utilized to provide sensory information for feedback control on a bipedal robot with walking gait. The overall control strategy includes the proposed body state estimator as well as the damping controller, which regulates the body position state of the robot in real-time based on instant and historical position tracking errors. Moreover, a posture corrector for reducing unwanted torque during motion is addressed. The body state estimator and the feedback control structure are implemented in a child-size bipedal robot and the performance is experimentally evaluated. PMID- 25734646 TI - Feasibility of multiple micro-particle trapping--a simulation study. AB - Both optical tweezers and acoustic tweezers have been demonstrated for trapping small particles in diverse biomedical applications. Compared to the optical tweezers, acoustic tweezers have deeper penetration, lower intensity, and are more useful in light opaque media. These advantages enable the potential utility of acoustic tweezers in biological science. Since the first demonstration of acoustic tweezers, various applications have required the trapping of not only one, but more particles simultaneously in both the axial and lateral direction. In this research, a method is proposed to create multiple trapping patterns, to prove the feasibility of trapping micro-particles. It has potential ability to electronically control the location and movement of the particles in real-time. A multiple-focus acoustic field can be generated by controlling the excitation of the transducer elements. The pressure and intensity of the field are obtained by modeling phased array transducer. Moreover, scattering force and gradient force at various positions are also evaluated to analyze their relative components to the effect of the acoustic tweezers. Besides, the axial and lateral radiation force and the trapping trajectory are computed based on ray acoustic approach. The results obtained demonstrate that the acoustic tweezers are capable of multiple trapping in both the axial and lateral directions. PMID- 25734645 TI - The utility and limitations of contrast-enhanced ultrasound for the diagnosis and treatment of prostate cancer. AB - In association with the widespread use of prostate specific antigen (PSA) screening, the numbers of men identified with early-stage prostate cancer (PCa) are increasing in the developed countries, including Japan. However, the accurate localization of PCa lesions in diagnostic imaging is still difficult because PCa has a tendency to be multifocal in the prostate gland. Contrast-enhanced ultrasound (CEUS) improves the detection of PCa by visualizing cancerous lesions in order to target a needle biopsy. CEUS has the potential to enable not only accurate diagnoses but also novel treatments such as focal therapy. The combination of CEUS and other modalities is expected to improve the diagnosis of PCa and its treatment. PMID- 25734647 TI - A robust Kalman framework with resampling and optimal smoothing. AB - The Kalman filter (KF) is an extremely powerful and versatile tool for signal processing that has been applied extensively in various fields. We introduce a novel Kalman-based analysis procedure that encompasses robustness towards outliers, Kalman smoothing and real-time conversion from non-uniformly sampled inputs to a constant output rate. These features have been mostly treated independently, so that not all of their benefits could be exploited at the same time. Here, we present a coherent analysis procedure that combines the aforementioned features and their benefits. To facilitate utilization of the proposed methodology and to ensure optimal performance, we also introduce a procedure to calculate all necessary parameters. Thereby, we substantially expand the versatility of one of the most widely-used filtering approaches, taking full advantage of its most prevalent extensions. The applicability and superior performance of the proposed methods are demonstrated using simulated and real data. The possible areas of applications for the presented analysis procedure range from movement analysis over medical imaging, brain-computer interfaces to robot navigation or meteorological studies. PMID- 25734648 TI - Sensor4PRI: a sensor platform for the protection of railway infrastructures. AB - Wireless Sensor Networks constitute pervasive and distributed computing systems and are potentially one of the most important technologies of this century. They have been specifically identified as a good candidate to become an integral part of the protection of critical infrastructures. In this paper we focus on railway infrastructure protection and we present the details of a sensor platform designed to be integrated into a slab track system in order to carry out both installation and maintenance monitoring activities. In the installation phase, the platform helps operators to install the slab tracks in the right position. In the maintenance phase, the platform collects information about the structural health and behavior of the infrastructure when a train travels along it and relays the readings to a base station. The base station uses trains as data mules to upload the information to the internet. The use of a train as a data mule is especially suitable for collecting information from remote or inaccessible places which do not have a direct connection to the internet and require less network infrastructure. The overall aim of the system is to deploy a permanent economically viable monitoring system to improve the safety of railway infrastructures. PMID- 25734649 TI - A wind energy powered wireless temperature sensor node. AB - A wireless temperature sensor node composed of a piezoelectric wind energy harvester, a temperature sensor, a microcontroller, a power management circuit and a wireless transmitting module was developed. The wind-induced vibration energy harvester with a cuboid chamber of 62 mm * 19.6 mm * 10 mm converts ambient wind energy into electrical energy to power the sensor node. A TMP102 temperature sensor and the MSP430 microcontroller are used to measure the temperature. The power management module consists of LTC3588-1 and LT3009 units. The measured temperature is transmitted by the nRF24l01 transceiver. Experimental results show that the critical wind speed of the harvester was about 5.4 m/s and the output power of the harvester was about 1.59 mW for the electrical load of 20 kOmega at wind speed of 11.2 m/s, which was sufficient to power the wireless sensor node to measure and transmit the temperature every 13 s. When the wind speed increased from 6 m/s to 11.5 m/s, the self-powered wireless sensor node worked normally. PMID- 25734650 TI - Experiential thinking in creationism--a textual analysis. AB - Creationism is a religiously motivated worldview in denial of biological evolution that has been very resistant to change. We performed a textual analysis by examining creationist and pro-evolutionary texts for aspects of "experiential thinking", a cognitive process different from scientific thought. We observed characteristics of experiential thinking as follows: testimonials (present in 100% of sampled creationist texts), such as quotations, were a major form of proof. Confirmation bias (100% of sampled texts) was represented by ignoring or dismissing information that would contradict the creationist hypothesis. Scientifically irrelevant or flawed information was re-interpreted as relevant for the falsification of evolution (75-90% of sampled texts). Evolutionary theory was associated to moral issues by demonizing scientists and linking evolutionary theory to atrocities (63-93% of sampled texts). Pro-evolutionary rebuttals of creationist claims also contained testimonials (93% of sampled texts) and referred to moral implications (80% of sampled texts) but displayed lower prevalences of stereotypical thinking (47% of sampled texts), confirmation bias (27% of sampled texts) and pseudodiagnostics (7% of sampled texts). The aspects of experiential thinking could also be interpreted as argumentative fallacies. Testimonials lead, for instance, to ad hominem and appeals to authorities. Confirmation bias and simplification of data give rise to hasty generalizations and false dilemmas. Moral issues lead to guilt by association and appeals to consequences. Experiential thinking and fallacies can contribute to false beliefs and the persistence of the claims. We propose that science educators would benefit from the systematic analysis of experiential thinking patterns and fallacies in creationist texts and pro-evolutionary rebuttals in order to concentrate on scientific misconceptions instead of the scientifically irrelevant aspects of the creationist-evolutionist debate. PMID- 25734651 TI - Recognizing subtle signs and symptoms of pediatric cancer. PMID- 25734652 TI - Use of Mini-Grant to Disseminate Evidence-Based Interventions for Cancer Prevention and Control. AB - Mini-grants are an increasingly common tool for engaging communities in evidence based interventions for promoting public health. This article describes efforts by 4 Centers for Disease Control and Prevention/National Cancer Institute-funded Cancer Prevention and Control Research Network centers to design and implement mini-grant programs to disseminate evidence-based interventions for cancer prevention and control. This article also describes source of evidence-based interventions, funding levels, selection criteria, time frame, number and size of grants, types of organizations funded, selected accomplishments, training and technical assistance, and evaluation topics/methods. Grant size ranged from $1000 to $10 000 (median = $6250). This mini-grant opportunity was characterized by its emphasis on training and technical assistance for evidence-based programming and dissemination of interventions from National Cancer Institute's Research-Tested Intervention Programs and Centers for Disease Control and Prevention's Guide to Community Preventive Services. All projects had an evaluation component, although they varied in scope. Mini-grant processes described can serve as a model for organizations such as state health departments working to bridge the gap between research and practice. PMID- 25734653 TI - Preparing Master of Public Health Graduates to Work in Local Health Departments. AB - OBJECTIVE: To identify key competencies and skills that all master of public health (MPH) graduates should have to be prepared to work in a local health department. METHODS: In 2011-2012, the New York City Department of Health and Mental Hygiene administered electronic surveys to 2 categories of staff: current staff with an MPH as their highest degree, and current hiring managers. RESULTS: In all, 312 (77%) staff members with an MPH as their highest degree and 170 (57%) hiring managers responded to the survey. Of the respondents with an MPH as their highest degree, 85% stated that their MPH program prepared them for work at the New York City Health Department. Skills for which MPH graduates most often stated they were underprepared included facility in using SAS(r) statistical software, quantitative data analysis/statistics, personnel management/leadership, and data collection/database management/data cleaning. Among the skills hiring managers identified as required of MPH graduates, the following were most often cited as those for which newly hired MPH graduates were inadequately prepared: quantitative data analysis, researching/conducting literature reviews, scientific writing and publication, management skills, and working with contracts/requests for proposals. CONCLUSION: These findings suggest that MPH graduates could be better prepared to work in a local health department upon graduation. To be successful, new MPH graduate hires should possess fundamental skills and knowledge related to analysis, communication, management, and leadership. Local health departments and schools of public health must each contribute to the development of the current and future public health workforce through both formal learning opportunities and supplementary employment-based training to reinforce prior coursework and facilitate practical skill development. PMID- 25734654 TI - Serum-free and xenobiotic-free preservation of cultured human limbal epithelial cells. AB - AIM/PURPOSE OF THE STUDY: To develop a one-week storage method, without serum and xenobiotics, that would maintain cell viability, morphology, and phenotype of cultured human limbal epithelial sheets. MATERIALS AND METHODS: Human limbal explants were cultured on intact human amniotic membranes for two weeks. The sheets were stored in a hermetically sealed container at 23 degrees C in either a serum-free medium with selected animal serum-derived compounds (Quantum 286) or a xenobiotic-free medium (Minimal Essential Medium) for 4 and 7 days. Stored and non-stored cultures were analyzed for cell viability, amniotic membrane and epithelial sheet thickness, and a panel of immunohistochemical markers for immature cells (DeltaNp63alpha, p63, Bmi-1, C/EBP?, ABCG2 and K19), differentiated cells (K3 and Cx43), proliferation (PCNA), and apoptosis (Caspase 3). RESULTS: The cell viability of the cultures was 98 +/- 1% and remained high after storage. Mean central thickness of non-stored limbal epithelial sheets was 23 +/- 3 MUm, and no substantial loss of cells was observed after storage. The non-stored epithelial sheets expressed a predominantly immature phenotype with DeltaNp63alpha positivity of more than 3% in 9 of 13 cultures. After storage, the expression of ABCG2 and C/EBP? was reduced for the 7 day Quantum 286-storage group; (P = 0.04), and Bmi-1 was reduced after 4 day Quantum 286-storage; (P = 0.02). No other markers varied significantly. The expression of differentiation markers was unrelated to the thickness of the epithelia and amniotic membrane, apart from ABCG2, which correlated negatively with thickness of limbal epithelia (R = -0.69, P = 0.01) and DeltaNp63alpha, which correlated negatively with amniotic membrane thickness (R = -0.59, P = 0.03). CONCLUSION: Limbal epithelial cells cultured from explants on amniotic membrane can be stored at 23 degrees C in both serum-free and xenobiotic-free media, with sustained cell viability, ultrastructure, and DeltaNp63alpha-positivity after both 4 and 7 days. PMID- 25734655 TI - Theoretical investigation on excited-state cyclization reactions of platinum sensitized dithienylethene complexes. AB - The ring-closing reaction commonly occurs at the lowest singlet excited state when the open-form dithienylethene is irradiated at about 300 nm. A lower-energy light, at 425 nm, can also elicit this ring-closing reaction when there is a connection between the dithienylethene and platinum-terpyridyl segment to form a complex through an ethynyl linker or an ethynyl-ether linker. Through the calculation of the energy levels, we propose the ring-closing process as follows. The light absorbed by the platinum-terpyridyl unit excites the molecule to a singlet excited state. Meanwhile, this electronic state of the molecule transfers to the lowest triplet excited state through intersystem crossing and internal conversion. When energy is asborbed from the environment, this state goes up to a higher triplet state around the dithienylethene part, where the ring-closing reaction takes place. Moreover, different patterns of linkers bring about different efficiency of the reaction, and a direct shared linker may facilitate the ring-closing process. In addition, the conjugated linker also causes the maximum wavelength of the complex to red shift because the energy gap between the involved frontier molecular orbitals becomes lower. PMID- 25734656 TI - Microstructural inhomogeneity of electrical conductivity in subcutaneous fat tissue. AB - Microscopic peculiarities stemming from a temperature increase in subcutaneous adipose tissue (sWAT) after applying a radio-frequency (RF) current, must be strongly dependent on the type of sWAT. This effect is connected with different electrical conductivities of pathways inside (triglycerides in adipocytes) and outside (extra-cellular matrix) the cells and to the different weighting of these pathways in hypertrophic and hyperplastic types of sWAT. The application of the RF current to hypertrophic sWAT, which normally has a strongly developed extracellular matrix with high concentrations of hyaluronan and collagen in a peri-cellular space of adipocytes, can produce, micro-structurally, a highly inhomogeneous temperature distribution, characterized by strong temperature gradients between the peri-cellular sheath of the extra-cellular matrix around the hypertrophic adipocytes and their volumes. In addition to normal temperature effects, which are generally considered in body contouring, these temperature gradients can produce thermo-mechanical stresses on the cells' surfaces. Whereas these stresses are relatively small under normal conditions and cannot cause any direct fracturing or damage of the cell structure, these stresses can, under some supportive conditions, be theoretically increased by several orders of magnitude, causing the thermo-mechanical cell damage. This effect cannot be realized in sWAT of normal or hyperplastic types where the peri-cellular structures are under developed. It is concluded that the results of RF application in body contouring procedures must be strongly dependent on the morphological structure of sWAT. PMID- 25734657 TI - Observation of single-spin Dirac fermions at the graphene/ferromagnet interface. AB - With the discovery and first characterization of graphene, its potential for spintronic applications was recognized immediately. Since then, an active field of research has developed trying to overcome the practical hurdles. One of the most severe challenges is to find appropriate interfaces between graphene and ferromagnetic layers, which are granting efficient injection of spin-polarized electrons. Here, we show that graphene grown under appropriate conditions on Co(0001) demonstrates perfect structural properties and simultaneously exhibits highly spin-polarized charge carriers. The latter was conclusively proven by observation of a single-spin Dirac cone near the Fermi level. This was accomplished experimentally using spin- and angle-resolved photoelectron spectroscopy, and theoretically with density functional calculations. Our results demonstrate that the graphene/Co(0001) system represents an interesting candidate for applications in devices using the spin degree of freedom. PMID- 25734658 TI - Formation of ether-functionalized ionic-liquid-based aqueous two-phase systems and their application in separation of protein and saccharides. AB - Ionic-liquid (IL)-based aqueous two-phase systems (ATPSs) have attracted much attention in the separation technology. In this work, we synthesized five novel ether-functionalized ILs and studied their applications in ATPS formation. The phase diagrams for several systems were determined at 298.15 K. An as-prepared IL (1-(2-butoxy-ethyl)-3-methylimidazolium chloride) was chosen as a representative to construct ATPSs for separation of bovine serum albumin (BSA) from aqueous saccharide solutions. Results showed that 76.1-94.3% of BSA was enriched into the IL-rich top phase and almost all the saccharides were extracted into the salt rich bottom phase in a one-step separation process. The main factors affecting the separation process, such as kinds of saccharides and the amount of inorganic salts, were discussed. Furthermore, the size distributions of aggregates in the IL-rich top phase were determined by dynamic light scattering (DLS), and accordingly the possible mechanism for the separation was investigated. PMID- 25734660 TI - Promising management of pazopanib-induced liver toxicity. PMID- 25734659 TI - Tumor and stromal-based contributions to head and neck squamous cell carcinoma invasion. AB - Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic disease requires changes not only in the carcinoma cells, but also in the surrounding stromal cells and tumor microenvironment. Within the microenvironment, acellular contributions from the surrounding extracellular matrix, along with contributions from various infiltrating immune cells, tumor associated fibroblasts, and endothelial cells facilitate the spread of tumor cells from the primary site to the rest of the body. Thus far, most attempts to limit metastatic spread through therapeutic intervention have failed to show patient benefit in clinic trails. The goal of this review is highlight the complexity of invasion-promoting interactions in the HNSCC tumor microenvironment, focusing on contributions from tumor and stromal cells in order to assist future therapeutic development and patient treatment. PMID- 25734661 TI - A few bad apples: a model of disease influenced agent behaviour in a heterogeneous contact environment. AB - For diseases that infect humans or livestock, transmission dynamics are at least partially dependent on human activity and therefore human behaviour. However, the impact of human behaviour on disease transmission is relatively understudied, especially in the context of heterogeneous contact structures such as described by a social network. Here, we use a strategic game, coupled with a simple disease model, to investigate how strategic agent choices impact the spread of disease over a contact network. Using beliefs that are based on disease status and that build up over time, agents choose actions that stochastically determine disease spread on the network. An agent's disease status is therefore a function of both his own and his neighbours actions. The effect of disease on agents is modelled by a heterogeneous payoff structure. We find that the combination of network shape and distribution of payoffs has a non-trivial impact on disease prevalence, even if the mean payoff remains the same. An important scenario occurs when a small percentage (called noncooperators) have little incentive to avoid disease. For diseases that are easily acquired when taking a risk, then even when good behavior can lead to disease eradication, a small increase in the percentage of noncooperators (less than 5%) can yield a large (up to 25%) increase in prevalence. PMID- 25734662 TI - A spiking neural network model of model-free reinforcement learning with high dimensional sensory input and perceptual ambiguity. AB - A theoretical framework of reinforcement learning plays an important role in understanding action selection in animals. Spiking neural networks provide a theoretically grounded means to test computational hypotheses on neurally plausible algorithms of reinforcement learning through numerical simulation. However, most of these models cannot handle observations which are noisy, or occurred in the past, even though these are inevitable and constraining features of learning in real environments. This class of problem is formally known as partially observable reinforcement learning (PORL) problems. It provides a generalization of reinforcement learning to partially observable domains. In addition, observations in the real world tend to be rich and high-dimensional. In this work, we use a spiking neural network model to approximate the free energy of a restricted Boltzmann machine and apply it to the solution of PORL problems with high-dimensional observations. Our spiking network model solves maze tasks with perceptually ambiguous high-dimensional observations without knowledge of the true environment. An extended model with working memory also solves history dependent tasks. The way spiking neural networks handle PORL problems may provide a glimpse into the underlying laws of neural information processing which can only be discovered through such a top-down approach. PMID- 25734663 TI - Economic evaluation of a fluocinolone acetonide intravitreal implant for patients with DME based on the FAME study. AB - INTRODUCTION: Diabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes. DME is a complex disease characterized by the deposition of fluid and proteins within the intraretinal layers, and the disease is recognized as being mediated by multiple cytokines, requiring a multifactorial therapeutic approach. Iluvien (fluocinolone acetonide intravitreal implant) 0.19 mg contains a corticosteroid, fluocinolone acetonide [FAc], and is indicated for the treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. METHODS: A Markov model was constructed in Microsoft Excel with a 15-year time horizon comparing the healthcare and productivity costs with health outcomes from treatment. The model was structured around 13 best corrected visual acuity states using Early Treatment Diabetic Retinopathy Study scores. Observations and extrapolations from the Fluocinolone Acetonide for Diabetic Macular Edema study were applied to determine observed and ongoing treatment effects. RESULTS: The expected incremental cost-effectiveness ratio for treatment with an FAc implant is $38,763, assuming 40% of patients are treated unilaterally; when 100% of patients receive unilateral treatment with an FAc implant, it is cost-saving. CONCLUSION: Administering an FAc implant to patients with DME previously treated with a corticosteroid is a cost-effective treatment option for ophthalmologists. PMID- 25734664 TI - Homology and evolution of the chaetae in Echiura (Annelida). AB - Echiura is traditionally regarded as a small phylum of unsegmented spiralian worms. Molecular analyses, however, provide unquestionable evidence that Echiura are derived annelids that lost segmentation. Like annelids, echiurans possess chaetae, a single ventral pair in all species and one or two additional caudal hemi-circles of chaetae in two subgroups, but their evolutionary origin and affiliation to annelid chaetae are unresolved. Since annelids possess segmental pairs of dorsal (notopodial) and ventral (neuropodial) chaetae that are arranged in a row, the ventral chaetae in Echiura either represent a single or a paired neuropodial group of chaetae, while the caudal circle may represent fused rows of chaetae. In annelids, chaetogenesis is generally restricted to the ventral part of the notopodial chaetal sac and to the dorsal part of the neuropodial chaetal sac. We used the exact position of the chaetal formation site in the echiuran species, Thalassema thalassemum (Pallas, 1766) and Echiurus echiurus (Pallas, 1767), to test different hypotheses of the evolution of echiurid chaetae. As in annelids, a single chaetoblast is responsible for chaetogenesis in both species. Each chaeta of the ventral pair arises from its own chaetal sac and possesses a lateral formation site, evidencing that the pair of ventral chaetae in Echiura is homologous to a pair of neuropodia that fused on the ventral side, while the notopodia were reduced. Both caudal hemi-circles of chaetae in Echiurus echiurus are composed of several individual chaetal sacs, each with its own formative site. This finding argues against a homology of these hemi-circles of chaetae and annelids' rows of chaetae and leads to the hypothesis that the caudal chaetal rings evolved once within the Echiura by multiplication of ventral chaetae. PMID- 25734665 TI - Ultrafast time resolved spectroscopic studies on the generation of the ketyl sugar biradical by intramolecular hydrogen abstraction among ketoprofen and purine nucleoside dyads. AB - Intramolecular hydrogen abstraction reactions among ketoprofen (KP) and purine nucleoside dyads have been proposed to form ketyl-sugar biradical intermediates in acetonitrile. Femtosecond transient absorption studies on KP and purine nucleoside dyads reveal that the triplet state of the KP moiety of the dyads with cisoid structure decay faster (due to an intramolecular hydrogen abstraction reaction to produce a ketyl-sugar biradical intermediate) than the triplet state of the KP moiety of the dyads with transoid structure detected in acetonitrile solvent. For the cisoid 5-KP-dG dyad, the triplet state of the KP moiety decays too fast to be observed by ns-TR(3); only the ketyl-sugar biradical intermediates are detected by ns-TR(3) in acetonitrile. For the cisoid 5-KP-dA dyad, the triplet states of the KP moiety could be observed at early nanosecond delay times, and then it quickly undergoes intramolecular hydrogen abstraction to produce a ketyl-sugar biradical intermediate. For the cisoid 5-KPGly-dA and transoid 3-KP-dA dyads, the triplet state of the KP moiety had a longer lifetime due to the long distance chain between the KP moiety and the purine nucleoside (5 KPGly-dA) and the transoid structure (3-KP-dA). The experimental and computational results suggest that the ketyl-sugar biradical intermediate is generated with a higher efficiency for the cisoid dyad. However, the transoid dyad exhibits similar photochemistry behavior as the KP molecule, and no ketyl sugar biradical intermediate was observed in the ns-TR(3) experiments for the transoid 3-KP-dA dyad. PMID- 25734666 TI - [Living donor donation: donors are at risk during pregnancy]. PMID- 25734667 TI - [Atherosclerosis: cholesterol efflux capacity: a new independent risk factor]. PMID- 25734668 TI - [Risk factors: after myocardial infarct men and women have a different risk]. PMID- 25734669 TI - [Lipid lowering by rosuvastatin: how do statins differ?]. PMID- 25734670 TI - [67-year-old man with ripping thoracic pain]. PMID- 25734671 TI - [Lung cancer therapy in transition: targeted therapies are coming]. PMID- 25734672 TI - [Lung cancer screening and management of small pulmonary nodules]. AB - Worldwide lung cancer is the leading cause of death from cancer. Most lung cancers are diagnosed at an advanced stage, so survival after lung cancer is generally poor. Diagnosis of lung cancer at earlier stages may be associated with an increased survival rate. This indicates that the implementation of lung cancer screening programs at the population level by means of low dose computed tomography might helpful to improve the outcome and mortality of lung cancer patients. By means of rapid advances in imaging technologies over the last decades it became possible to detect small lung nodules as small as a couple of millimeters. This recent developments require management algorithms to guide the clinical management of suspicious and indeterminate lung nodules found in computer tomography during lung cancer screening or by incidental finding.This review will focus on both, the recent advances in lung cancer screening and the guidelines for the management of small pulmonary nodules. PMID- 25734673 TI - [Treatment of advanced non-small-cell lung cancer with driver mutations]. AB - Advanced non-small-cell lung cancer is no longer one disease but the collective name for different diseases defined by clinical, histological, immunohistochemical and, to an increasing extent, molecular biomarkers. This article deals with the treatment options we gained by identifying so called driver mutations in a growing subset of these cancers. For patients whose tumors are characterized by a targetable molecular alteration such as an activating EGFR Mutation, an ALK-translocation or a ROS1-rearrangement, we see prolonged survival and oral treatments with tyrosine kinase inhibitors demonstrate superiority to chemotherapy in terms of response (remission rate), progression free survival and quality of life. We provide a review of the literature and discuss the status quo of the diagnostic need and the therapeutic options in Germany and Europe. PMID- 25734674 TI - [Non-small cell lung cancer: news from immunotherapy]. AB - Immune evasion is recognized as a key strategy for survival and progression of several cancer entities including non-small cell lung cancer. Hence, various approaches to restore anti-tumor immune responses are currently investigated. In particular, agents targeting immune checkpoint receptors, such as the cytotoxic T lymphocyte antigen-4 receptor and programmed death-1 receptor have shown promise in early clinical trials. With multiple studies under way, there are high expectations that treatment outcomes in patients with lung cancer who are ineligible for complete surgical resection may be improved with the incorporation of immunotherapies in the various treatment cascades. PMID- 25734675 TI - [German prevention act is coming]. PMID- 25734676 TI - [How to do - the chest tube drainage]. AB - A chest tube is used to drain the contents of the pleural space to reconstitute the physiologic pressures within the pleural space and to allow the lungs to fully expand. Indications for chest tube placement include pneumothorax, hemothorax, pleural effusion, pleural empyema, and major thoracic surgery. The most appropriate site for chest tube placement is the 4th or 5th intercostal space in the mid- or anterior- axillary line. Attention to technique in placing the chest tube is vital to avoid complications from the procedure. Applying the step-by-step technique presented, placement of a chest tube is a quick and safe procedure. Complications - frequently occurring when the tube is inserted with a steel trocar - include hemothorax, dislocation, lung lacerations, and injury to organs in the thoracic or abdominal cavity." PMID- 25734677 TI - [Syndrome of inadequate ADH secretion: pitfalls in diagnosis and therapy]. AB - Euvolemic hyponatremia is most frequently caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Causes of SIADH-induced hyponatremia are myriad and include tumors, pulmonary diseases or central nervous system disorders. SIADH can also be induced by a broad spectrum of drugs such as antidepressants and antiepileptics. The unfavorable prognostic relevance of hyponatremia is often underestimated. SIADH therapy focuses on the treatment of the underlying disease. Thus, a thorough differential diagnostic assessment of the genesis of SIADH is crucial. Therapy options for euvolemic hyponatremia include fluid restriction, administration of hyperosmolar saline solution in case of severe symptoms, or therapy with tolvaptan. Tolvaptan is a selective, oral vasopressin-V2-receptor-antagonist that inhibits ADH-induced retention of electrolyte-free water in the connecting duct of the kidney. This inhibition results in an increased serum sodium level. Close monitoring of serum sodium levels and volume status is imperative, especially during the initial phase of therapy. Fluid restriction is unnecessary during tolvaptan therapy; a previously prescribed fluid re-striction should be stopped when therapy begins. Treatment with tolvaptan can often result in a rapid and controlled improvement of the symptoms. Different cases presented in this article illustrate the diversity of SIADH in clinical practice relating to its diagnosis and its therapy as well as difficulties in identifying the underlying cause in clinical practice. PMID- 25734678 TI - [Calciphylaxis]. AB - Calciphylaxis (calcific uremic arteriolopathy, CUA) is a rare disease at the interface of nephrology, dermatology and cardiovascular medicine. CUA typically occurs in chronic dialysis patients. However, anecdotal reports also exist about cases in patients without relevant kidney disease. Clinically CUA is characterized by the stepwise development of superficial painful sensations and cutaneous lesions similar to livedo reticularis. Skin necrosis and ulceration represent the full-blown, "late" clinical picture. Panniculitis and circumferential calcification of cutaneous arterioles dominate the histological picture together with endothelial detachment. The prognosis of CUA is poor due to high morbidity and mortality largely resulting from underlying cardiovascular disease or septicemia. The aetiology of CUA is incompletely understood. Previous oral anticoagulation with vitamin K antagonists is considered as a risk factor. Unfortunately, evidence-based therapeutic options are absent, since controlled treatment trials have not been conducted yet. Long-term pain and wound management are mandatory. In the absence of controlled prospective trials registry studies such as the German CUA registry (www.calciphylaxis.net) support data collecting and analysis upon good clinical practice and may stimulate exchange of expertise and networking. PMID- 25734679 TI - [Aortic Valve Endocarditis: diagnosis and therapy]. PMID- 25734680 TI - [Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology]. AB - Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN 3 trial did meet its primary safety endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation. PMID- 25734681 TI - [Is scientific misconduct preventable? stem cell scandal 2014: study was faked]. PMID- 25734682 TI - [Survey on information needs of cancer patients and their relatives in Germany]. AB - INTRODUCTION: Cancer patients generally have a great need for disease-related information. They prefer to be informed personally by the attending doctor. Yet, they also use other sources, mostly from medical laypersons or public media. The goal of our survey was to obtain insight into information patients get and their requirements regarding information. METHODS AND PARTICIPANTS: Using a standardized questionnaire, we conducted a survey on 226 patients and 32 relatives, who attended meetings providing information for cancer patients. RESULTS: Patients were generally content or highly content with the information they got. The direct consultation with the doctor is the most important source of information especially for older patients. Information by other patients and self help groups rank second, followed by internet and online chats, which both are of minor importance for patients older than 60 years. From the patients' point of view, sources of information should be individualized and comprehensive, provided by experts and allowing for questions. Patients prefer one constant person for communication. Remarkably, empathic communication was not rated as important. Age and gender are not associated with these preferences for these characteristics of sources of information. DISCUSSION: Patients' and relatives' desire for an individualized, comprehensive counseling with high expertise provided by one person points to the limits of resources of the health system. The importance of additional information material will rise accordingly. This material should be tailored to the needs of diverse patient groups. PMID- 25734683 TI - [Is heart rate adequately controlled in chronic systolic heart failure patients in Germany? results from a nationwide survey (INDICATE)]. AB - BACKGROUND: Elevated resting heart rate is associated with increased morbidity and mortality in patients with chronic systolic heart failure (CHF). Lowering of heart rate improves cardiovascular outcome in these patients. Therefore, heart rate reduction is an important element of therapeutic management and consistently reflected in current European guidelines for heart failure. Methods: The INDICATE study was initiated as a multicenter nationwide cross-sectional survey aiming to analyze the current quality of care in outpatients with CHF (documented left ventricular systolic dysfunction) in Germany. 20 consecutive patients were to be included in the survey from February until June 2012 by 793 cardiologic private practices. Detailed documentation of each patient was performed using a standardized questionnaire. RESULTS: CHF was known for more than 6 months in 88 % of the 15 148 included patients. Mean heart rate in the study population was 73 +/- 13 min-1. In 42 % of patients the heart rate was >= 75 min-1. 86 % were treated with betablockers. However, higher doses of betablockers were not associated with lower resting heart rate. 27 % of patients remained on heart rates >= 75 min-1 although receiving at least 50 % of betablocker target dose. CONCLUSION: INDICATE reveals a considerable proportion of outpatients with CHF showing an elevated heart rate despite beta blockade - irrespective of applied dose. These results emphasize the importance of optimizing the pharmacological management of resting heart rate according to guidelines in these patients. PMID- 25734685 TI - BgN-Score and BsN-Score: bagging and boosting based ensemble neural networks scoring functions for accurate binding affinity prediction of protein-ligand complexes. AB - BACKGROUND: Accurately predicting the binding affinities of large sets of protein ligand complexes is a key challenge in computational biomolecular science, with applications in drug discovery, chemical biology, and structural biology. Since a scoring function (SF) is used to score, rank, and identify drug leads, the fidelity with which it predicts the affinity of a ligand candidate for a protein's binding site has a significant bearing on the accuracy of virtual screening. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited predictive power has been a major roadblock toward cost-effective drug discovery. Therefore, in this work, we present novel SFs employing a large ensemble of neural networks (NN) in conjunction with a diverse set of physicochemical and geometrical features characterizing protein-ligand complexes to predict binding affinity. RESULTS: We assess the scoring accuracies of two new ensemble NN SFs based on bagging (BgN-Score) and boosting (BsN-Score), as well as those of conventional SFs in the context of the 2007 PDBbind benchmark that encompasses a diverse set of high-quality protein families. We find that BgN-Score and BsN-Score have more than 25% better Pearson's correlation coefficient (0.804 and 0.816 vs. 0.644) between predicted and measured binding affinities compared to that achieved by a state-of-the-art conventional SF. In addition, these ensemble NN SFs are also at least 19% more accurate (0.804 and 0.816 vs. 0.675) than SFs based on a single neural network that has been traditionally used in drug discovery applications. We further find that ensemble models based on NNs surpass SFs based on the decision-tree ensemble technique Random Forests. CONCLUSIONS: Ensemble neural networks SFs, BgN-Score and BsN-Score, are the most accurate in predicting binding affinity of protein-ligand complexes among the considered SFs. Moreover, their accuracies are even higher when they are used to predict binding affinities of protein-ligand complexes that are related to their training sets. PMID- 25734686 TI - Provision of Speech-Language Pathology Telepractice Services Using Apple iPads. AB - This exploratory study evaluated the effectiveness of Apple (Cupertino, CA) iPad((r)) (second generation) to deliver telepractice speech and/or language services. Five children and their parents/guardians, as well as four adult participants, received services for communication disorders in a university clinic setting over two academic semesters. The children met some of their speech goals and all of their language goals. All adult clients met some of their communication goals. Personal opinions about telepractice did not change statistically before and after therapy. The major problem identified during the study was skipping and/or freezing of images on the iPads during interactions with FaceTime((r)) (Apple). Further studies are needed to investigate the feasibility of using Apple iPads in telepractice. PMID- 25734684 TI - Comparative analysis of metagenomes from three methanogenic hydrocarbon-degrading enrichment cultures with 41 environmental samples. AB - Methanogenic hydrocarbon metabolism is a key process in subsurface oil reservoirs and hydrocarbon-contaminated environments and thus warrants greater understanding to improve current technologies for fossil fuel extraction and bioremediation. In this study, three hydrocarbon-degrading methanogenic cultures established from two geographically distinct environments and incubated with different hydrocarbon substrates (added as single hydrocarbons or as mixtures) were subjected to metagenomic and 16S rRNA gene pyrosequencing to test whether these differences affect the genetic potential and composition of the communities. Enrichment of different putative hydrocarbon-degrading bacteria in each culture appeared to be substrate dependent, though all cultures contained both acetate- and H2-utilizing methanogens. Despite differing hydrocarbon substrates and inoculum sources, all three cultures harbored genes for hydrocarbon activation by fumarate addition (bssA, assA, nmsA) and carboxylation (abcA, ancA), along with those for associated downstream pathways (bbs, bcr, bam), though the cultures incubated with hydrocarbon mixtures contained a broader diversity of fumarate addition genes. A comparative metagenomic analysis of the three cultures showed that they were functionally redundant despite their enrichment backgrounds, sharing multiple features associated with syntrophic hydrocarbon conversion to methane. In addition, a comparative analysis of the culture metagenomes with those of 41 environmental samples (containing varying proportions of methanogens) showed that the three cultures were functionally most similar to each other but distinct from other environments, including hydrocarbon-impacted environments (for example, oil sands tailings ponds and oil-affected marine sediments). This study provides a basis for understanding key functions and environmental selection in methanogenic hydrocarbon-associated communities. PMID- 25734687 TI - Acute effects of black currant consumption on salivary flow rate and secretion rate of salivary immunoglobulin a in healthy smokers. AB - The role of saliva in maintaining oral health and homeostasis is based on its physicochemical properties and biological activities of its components, including salivary immunoglobulin A (IgA). Both salivary rates and immunological status of saliva are found to be compromised in smokers. The aim of this study was to investigate the acute time-dependent effect of smoking and black currant consumption on the salivary flow rate (SFR) and salivary IgA secretion rate (sIgA SR) in healthy smokers. SFR, sIgA levels in saliva, and sIgA SRs were determined in healthy smokers (n=8) at eight times of assessment within three consecutive interventions: at the baseline; 5, 30, and 60 min after smoking; 5, 30, and 60 min after black currant consumption (100 g), followed by smoking; and 5 min after black currant consumption. Smoking induced a significant delayed effect on SFR measured 60 min after smoking (P=.03), while black currant consumption preceding smoking prevented that effect. Salivary IgA concentrations and sIgA flow rates were not acutely influenced by smoking. Black currant consumption preceding smoking induced a significant decrease in sIgA concentrations 5 min after the intervention compared with the baseline (P=.046), with a further increasing trend, statistically significant, 60 min after the intervention (P=.025). Although smoking cessation is the most important strategy in the prevention of chronic diseases, the obtained results suggest that the influence of black currant consumption on negative effects of tobacco smoke on salivary flow and immunological status of saliva could partly reduce the smoking-associated risk on oral health. PMID- 25734688 TI - Potential electron mediators to extract electron energies of RBC glycolysis for prolonged in vivo functional lifetime of hemoglobin vesicles. AB - Developing a functional blood substitute as an alternative to donated blood for clinical use is believed to relieve present and future blood shortages, and to reduce the risks of infection and blood type mismatching. Hemoglobin vesicle (HbV) encapsulates a purified and concentrated human-derived Hb solution in a phospholipid vesicle (liposome). The in vivo safety and efficacy of HbV as a transfusion alternative have been clarified. Auto-oxidation of ferrous Hb in HbV gradually increases the level of ferric methemoglobin (metHb) and impairs the oxygen transport capabilities. The extension of the functional half-life of HbV has recently been proposed using an electron mediator, methylene blue (MB), which acts as a shuttle between red blood cells (RBC) and HbV. MB transfers electron energies of NAD(P)H, produced by RBC glycolysis, to metHb in HbV. Work presented here focuses on screening of 15 potential electron mediators, with appropriate redox potential and water solubility, for electron transfer from RBC to HbV. The results are assessed with regard to the chemical properties of the candidates. The compounds examined in this study were dimethyl methylene blue (DMB), methylene green, azure A, azure B, azure C, toluidine blue (TDB), thionin acetate, phenazine methosulfate, brilliant cresyl blue, cresyl violet, gallocyanine, toluylene blue, indigo carmine, indigotetrasulfonate, and MB. Six candidates were found to be unsuitable because of their insufficient diffusion across membranes, or overly high or nonexistent reactivity with relevant biomolecules. However, 9 displayed favorable metHb reduction. Among the suitable candidates, phenothiazines DMB and TDB exhibited effectiveness like MB did. In comparison to MB, they showed faster reduction by electron-donating NAD(P)H, coupled with showing a lower rate of reoxidation in the presence of molecular oxygen. Ascertaining the best electron mediator can provide a pathway for extending the lifetime and efficiency of potential blood substitutes. PMID- 25734689 TI - Redox potential tuning through differential quinone binding in the photosynthetic reaction center of Rhodobacter sphaeroides. AB - Ubiquinone forms an integral part of the electron transport chain in cellular respiration and photosynthesis across a vast number of organisms. Prior experimental results have shown that the photosynthetic reaction center (RC) from Rhodobacter sphaeroides is only fully functional with a limited set of methoxy bearing quinones, suggesting that specific interactions with this substituent are required to drive electron transport and the formation of quinol. The nature of these interactions has yet to be determined. Through parameterization of a CHARMM compatible quinone force field and subsequent molecular dynamics simulations of the quinone-bound RC, we have investigated and characterized the interactions of the protein with the quinones in the Q(A) and Q(B) sites using both equilibrium simulation and thermodynamic integration. In particular, we identify a specific interaction between the 2-methoxy group of ubiquinone in the Q(B) site and the amide nitrogen of GlyL225 that we implicate in locking the orientation of the 2 methoxy group, thereby tuning the redox potential difference between the quinones occupying the Q(A) and Q(B) sites. Disruption of this interaction leads to weaker binding in a ubiquinone analogue that lacks a 2-methoxy group, a finding supported by reverse electron transfer electron paramagnetic resonance experiments of the Q(A)-Q(B)- biradical and competitive binding assays. PMID- 25734690 TI - Foodborne mycotoxicoses, risk assessment and underestimated hazard of masked mycotoxins and joint mycotoxin effects or interaction. AB - The existing hazard of joint mycotoxin exposure of animals/humans and the significance of masked mycotoxins in foods or feeds and their respective contributions to the development of some food born mycotoxicoses is briefly reviewed. The importance of joint mycotoxin interaction in the complex etiology of some foodborn mycotoxicoses is covered in depth. The toxicity of low contamination levels of some combinations of mycotoxins ingested often by farm animals was carefully studied. The appropriate hygiene control and the necessary risk assessment in regard to mycotoxin contamination of foods and feeds are briefly analyzed and some useful prophylactic measures and management of the risk of mycotoxin contamination, in addition to tolerable daily intakes are also described. A reference is also made to the most suitable methods of veterinary hygiene control in some practical situations in order to prevent mycotoxins contaminating commercial food commodities and endangering public health. PMID- 25734691 TI - The relative vertex clustering value--a new criterion for the fast discovery of functional modules in protein interaction networks. AB - BACKGROUND: Cellular processes are known to be modular and are realized by groups of proteins implicated in common biological functions. Such groups of proteins are called functional modules, and many community detection methods have been devised for their discovery from protein interaction networks (PINs) data. In current agglomerative clustering approaches, vertices with just a very few neighbors are often classified as separate clusters, which does not make sense biologically. Also, a major limitation of agglomerative techniques is that their computational efficiency do not scale well to large PINs. Finally, PIN data obtained from large scale experiments generally contain many false positives, and this makes it hard for agglomerative clustering methods to find the correct clusters, since they are known to be sensitive to noisy data. RESULTS: We propose a local similarity premetric, the relative vertex clustering value, as a new criterion allowing to decide when a node can be added to a given node's cluster and which addresses the above three issues. Based on this criterion, we introduce a novel and very fast agglomerative clustering technique, FAC-PIN, for discovering functional modules and protein complexes from a PIN data. CONCLUSIONS: Our proposed FAC-PIN algorithm is applied to nine PIN data from eight different species including the yeast PIN, and the identified functional modules are validated using Gene Ontology (GO) annotations from DAVID Bioinformatics Resources. Identified protein complexes are also validated using experimentally verified complexes. Computational results show that FAC-PIN can discover functional modules or protein complexes from PINs more accurately and more efficiently than HC-PIN and CNM, the current state-of-the-art approaches for clustering PINs in an agglomerative manner. PMID- 25734692 TI - Intended use for a neoadjuvant chemoradiation response prediction test for locally advanced esophageal adenocarcinoma: a survey analysis of thoracic surgeons in the US. AB - OBJECTIVE: A multi-analyte immunohistochemistry (IHC) based test (DecisionDx-EC * *DecisionDx-EC, Castle Biosciences, Incorporated, Friendswood, TX. Hereafter referred to as the "IHC-based test". ) was developed and proved able to accurately predict response to neoadjuvant chemoradiotherapy (neoCTRT) in esophageal adenocarcinoma (EC) patients with locoregional disease. A survey was conducted with surgeons attending the 2013 Society of Thoracic Surgeons Annual Conference to assess their intention to change standard of care patient treatment based on predictive results obtained from this test. RESEARCH DESIGN AND METHODS: Fifty-seven thoracic surgeons were provided a questionnaire regarding the current clinical management of locoregional EC patients, and their intention to change management strategy if a patient is predicted by the multi-analyte IHC-based test to experience pathological complete response (pathCR) or extremely resistant to neoCTRT (exCTRT). RESULTS: Forty-four out of 46 enrolled respondents indicated that they administer neoCTRT followed by surgery to treat locally advanced EC. Fifteen (32%) respondents presently prescribing neoCTRT to EC patients acknowledged that a pathCR prediction provided by the multi-analyte IHC-based test would change their current regimens. Conversely, 28 surgeons (61%) would be willing to adjust their current strategy for patients predicted to be resistant to neoCTRT, significantly more than the case where patients are predicted to be pathCR (p = 0.01). Twenty-five percent (25%) of surgeons willing to adjust treatment in response to a patient being a potential exCTRT chose to remove CTRT from the strategy, and instead would choose surgery alone for these patients. CONCLUSIONS: Results from the current survey show that patients' response to neoCTRT predicted by the multi-analyte IHC-based test has a significant influence on the decision-making process in the clinic. Nearly twice as many surgeons stated an intention to change strategy with the knowledge that the patient is likely to have extreme resistance to planned treatments than when one is a potential responder. The current survey study is limited by its 'intended use' nature, therefore does not reflect physicians' real action in the clinic upon implementation of this test. However, survey results strongly suggest that use of the IHC-based predictive test is of great interest to physicians, and would likely contribute to more individualized treatment for patients with distinct sensitivity to neoCTRT. PMID- 25734693 TI - The utility of chloroquine in cancer therapy. AB - BACKGROUND: The anti-malarial drug chloroquine has recently been discovered as a novel anti-tumor agent. This article is to review the recent development of chloroquine being used in cancer therapy. METHODS: PubMed, ScienceDirect and ClinicalKey served as the major databases. Key words included 'chloroquine', 'cancer', and 'autophagy'. The publication date was up to June 2015. RESULTS: Chloroquine mainly executes its anti-tumor function through inhibition of autophagy. It can accumulate inside the lysosome resulting in lysosomal membrane permeabilization (LMP) which will eventually lead to apoptosis. Chloroquine has been shown to stabilize p53 and induce p53-dependent apoptosis or cell cycle arrest. It can also inhibit ABC (ATP-binding cassette) family protein. The anti cancer effect of chloroquine has been observed both in vitro and in vivo. However, it is considered more as a potential chemotherapy and radiotherapy sensitizer rather than an antineoplastic. CONCLUSION: Although the utility of chloroquine is promising in cancer therapy, some safety issues have been brought to attention, and further studies on safety profile and the signs of clinical activity of chloroquine including its derivatives should be conducted. PMID- 25734694 TI - Determinants of intestinal permeability in healthy first-degree relatives of individuals with Crohn's disease. AB - BACKGROUND: The Genetics, Environmental, Microbial Project is a multicenter study assessing etiological factors in Crohn's disease by studying healthy first-degree relatives (FDRs) of individuals affected by Crohn's disease. We aimed to evaluate the contribution of genetic, microbial, and environmental factors to the determination of intestinal permeability in healthy FDRs. METHODS: IP was assessed using the lactulose-mannitol ratio (LacMan ratio). FDRs were genotyped for 167 inflammatory bowel disease-associated single nucleotide polymorphisms. Taxonomic profile of the fecal microbiota was determined by Illumina MiSeq pyrosequencing of 16S ribosomal RNA. The associations of LacMan ratio with demographic factors, inflammatory bowel disease-associated single nucleotide polymorphisms and the fecal microbiota were assessed. RESULTS: One thousand, one hundred ninety-six white FDRs were included [corrected]. Eleven percent of FDRs had an elevated LacMan ratio (>=0.03). A multivariate analysis demonstrated that younger subjects and nonsmokers had higher LacMan ratios, P = 3.62 * 10-4 and P = 0.03, respectively. The LacMan ratio was not significantly heritable, H2r, 0.13, P = 0.13. There was no association between any of the 167 inflammatory bowel disease-associated risk variants and LacMan ratio nor was there a correlation between fecal microbial composition and the LacMan ratio. CONCLUSIONS: We did not find LacMan ratio to be significantly heritable suggesting that the contribution of genetic factors to the determination of intestinal permeability in healthy FDRs is modest. Environmental factors, such as smoking, are likely more important determinants. The effect of age on intestinal barrier function has been underappreciated. PMID- 25734696 TI - Pediatric pathology fellowship graduates of ACGME-accredited programs: survey findings. PMID- 25734695 TI - Effects of Adipocyte Aryl Hydrocarbon Receptor Deficiency on PCB-Induced Disruption of Glucose Homeostasis in Lean and Obese Mice. AB - BACKGROUND: Coplanar polychlorinated biphenyls (PCBs) promote adipocyte inflammation and impair glucose homeostasis in lean mice. The diabetes-promoting effects of lipophilic PCBs have been observed only during weight loss in obese mice. The molecular mechanisms linking PCB exposures to impaired glucose metabolism are unclear. OBJECTIVES: In this study we tested the hypothesis that coplanar PCBs act at adipocyte aryl hydrocarbon receptors (AhRs) to promote adipose inflammation and impair glucose homeostasis in lean mice and in obese mice during weight loss. METHODS AND RESULTS: PCB-77 administration impaired glucose and insulin tolerance in LF (low fat diet)-fed control (AhR(fl/fl)) mice but not in adipocyte AhR-deficient mice (AhR(AdQ)). Unexpectedly, AhR(AdQ) mice exhibited increased fat mass when fed a standard LF or high fat (HF) diet. In mice fed a HF diet, both genotypes became obese, but AhR(AdQ) mice administered vehicle (VEH) exhibited increased body weight, adipose mass, adipose inflammation, and impaired glucose tolerance compared with AhR(fl/fl) controls. Impairment of glucose homeostasis in response to PCB-77 was not observed in obese mice of either genotype. However, upon weight loss, AhR(fl/fl) mice administered PCB-77 exhibited increased abundance of adipose tumor necrosis factor-alpha (TNF alpha) mRNA and impaired glucose homeostasis compared with those administered VEH. In contrast, PCB-77 had no effect on TNF-alpha or glucose homeostasis in AhR(AdQ) mice exhibiting weight loss. CONCLUSIONS: Our results demonstrate that adipocyte AhR mediates PCB-induced adipose inflammation and impairment of glucose homeostasis in mice. Moreover, deficiency of AhR in adipocytes augmented the development of obesity, indicating that endogenous ligand(s) for AhR regulate adipose homeostasis. PMID- 25734697 TI - Using a call center to encourage linkage to care following mobile HIV counseling and testing. AB - Engaging newly diagnosed HIV+ individuals in treatment is a significant global challenge. As South Africa expands HIV counseling and testing (HCT) services, the growing numbers of people diagnosed with HIV will need innovative links to care approaches in order for treatment to be most effective. While definitions vary, we have defined "linkage to care" as connecting an HIV+ individual to medical care, so that CD4 cell test results are obtained and antiretroviral therapy (ART) eligibility assessed. The study is of HIV+ participants (n = 1096), from either Limpopo or Gauteng provinces from a "Links to Care" program. A two-pronged expanded HCT service was used, which included a community outreach approach to address HIV testing and a call center to encourage and track each patient's linkage to care post-HIV diagnosis. The majority of individuals (51%) were linked to care with a mean time to linkage of 31 days (with most individuals linked in less than 14 days). More females (54%) were linked to care than males (47%) and had higher CD4 cell counts than males; females had a mean CD4 cell count of 440, while males took longer to link to care and had a lower mean CD4 cell count of 331. Females of 23 years or younger had the lowest linkage rate of all females. Findings suggest that expanding HCT services to include innovative links to care approaches can improve linkage to care and subsequently impact HIV prevention. PMID- 25734698 TI - Predicting selective liver X receptor beta agonists using multiple machine learning methods. AB - Liver X receptor (LXR) alpha and beta are cholesterol sensors; they respond to excess cholesterol and stimulate reverse cholesterol transport. Activating LXRs represents a promising therapeutic option for dyslipidemia. However, activating LXRalpha may cause unwanted lipogenicity. A better anti-dyslipidemia strategy would be to develop selective LXRbeta agonists that do not activate LXRalpha. In this paper, a data set of 234 selective and non-selective LXRbeta agonists was collected from the literature. For the first time, we derived the classification models from the data set to predict selective LXRbeta agonists using multiple machine learning methods (naive Bayesian (NB), Recursive Partitioning (RP), Support Vector Machine (SVM), and k-Nearest Neighbors (kNN) methods) with optimized property descriptors and structural fingerprints. The models were optimized from 324 multiple machine learning models, and most of the models showed high predictive abilities (overall predictive accuracies of >80%) for both training and test sets. The top 15 models were evaluated using an external test set of 76 compounds (all containing new scaffolds), and 10 of them displayed overall predictive accuracies exceeding 90%. The top models can be used for the virtual screening of selective LXRbeta agonists. The NB models can identify privileged and unprivileged fragments for selective LXRbeta agonists, and the fragments can be used to guide the design of new selective LXRbeta agonists. PMID- 25734699 TI - Communication skills training curriculum for pulmonary and critical care fellows. AB - RATIONALE: The Accreditation Council for Graduate Medical Education requires physicians training in pulmonary and critical care medicine to demonstrate competency in interpersonal communication. Studies have shown that residency training is often insufficient to prepare physicians to provide end-of-life care and facilitate patient and family decision-making. Poor communication in the intensive care unit (ICU) can adversely affect outcomes for critically ill patients and their family members. Despite this, communication training curricula in pulmonary and critical care medicine are largely absent in the published literature. OBJECTIVES: We evaluated the effectiveness of a communication skills curriculum during the first year of a pulmonary and critical care medicine fellowship using a family meeting checklist to provide formative feedback to fellows during ICU rotations. We hypothesized that fellows would demonstrate increased competence and confidence in the behavioral skills necessary for facilitating family meetings. METHODS: We evaluated a 12-month communication skills curriculum using a pre-post, quasiexperimental design. Subjects for this study included 11 first-year fellows who participated in the new curriculum (intervention group) and a historical control group of five fellows who had completed no formal communication curriculum. Performance of communication skills and self-confidence in family meetings were assessed for the intervention group before and after the curriculum. The control group was assessed once at the beginning of their second year of fellowship. RESULTS: Fellows in the intervention group demonstrated significantly improved communication skills as evaluated by two psychologists using the Family Meeting Behavioral Skills Checklist, with an increase in total observed skills from 51 to 65% (P <= 0.01; Cohen's D effect size [es], 1.13). Their performance was also rated significantly higher when compared with the historical control group, who demonstrated only 49% of observed skills (P <= 0.01; es, 1.55). Fellows in the intervention group also showed significantly improved self-confidence scores upon completion of the curriculum, with an increase from 77 to 89% (P <= 0.01; es, 0.87) upon completion of the curriculum CONCLUSIONS: A structured curriculum that includes abundant opportunities for fellows to practice and receive feedback using a behavioral checklist during their ICU rotations helps to develop physicians with advanced communication skills. PMID- 25734700 TI - Chiral sensing by nonchiral tetrapyrroles. AB - Enantiomeric excess (ee) is a measure of the purity of an enantiomer of a chiral compound with respect to the presence of the complementary enantiomer. It is an important aspect of chemistry, especially in the fields of pharmaceuticals and asymmetric catalysis. Existing methods for determination of enantiomeric excesses using nuclear magnetic resonance (NMR) spectroscopy mostly rely on special chiral reagents (auxiliaries) that form two or more diastereomeric complexes with a chiral compound. As a result of this, the NMR spectrum of each enantiomer is different, allowing the determination of enantiomeric excess. In this Account, we describe a molecular design process that has allowed us to prepare prochiral solvating agents for NMR determination of ee of a wide variety of analyte types. At the outset of this work, we initially encountered the phenomenon of NMR peak splitting in the oxoporphyrinogen (OxP) host component of a supramolecular host guest complex, where the extent of the splitting is apparently proportional to the guests' ee. Upon closer examination of the mechanism of action, it was found that several complicating factors, including prototropic tautomerism, macrocyclic inversion (ring-flipping), and 1:2 host-guest stoichiometry, obstruct potential applications of OxP as a chiral solvating agent. By considering the molecular conformation of the OxP host, a saddle-shaped calix[4]pyrrole, we moved to study the tetraphenylporphyrin (TPP) dication since it has a similar form, and it was found that it could also be used to probe ee. However, although TPP does not suffer from disadvantageous tautomeric processes, it is still subject to macrocyclic inversion and has the additional serious disadvantage of operating for ee sensing only at depressed temperatures. The intrinsic disadvantages of the OxP and TPP systems were finally overcome by covalently modifying the OxP chromophore by regioselective N-alkylation at one face of the molecule. This procedure yields a host Bz2OxP that undergoes 1:1 host-guest interactions, cannot be protonated (and so does not suffer drawbacks due to tautomeric processes), and can interact solely through hydrogen bonding with a much wider range of analyte types, including acids, esters, amines (including amino acid derivatives), and ketones, for the determination of their ee at room temperature. Chiral sensing, in this case, can be understood by considering the breakdown of the host's symmetry when it interacts with a chiral guest under fast exchange. Furthermore, chirality discrimination (i.e., which is the major enantiomer in a sample) can be performed by addition of a small amount of one of the known enantiomers. Adaptation of a symmetrical molecule for ee sensing presents certain intrinsic advantages, including identical binding constants of each enantiomer. Our results indicate that other symmetrical molecules might also be useful as NMR probes of enantiopurity. These systems could provide insights into important chirality principles such as majority rule, intermolecular chirality transfer, and asymmetric reactions. The Bz2OxP system is also of note from the point of view that it does not rely on the formation of diastereomers. PMID- 25734702 TI - Early bone formation adjacent to oxidized and machined implant surfaces: a histologic study. AB - Various designs of dental implants representing different geometries and surface technologies are commercially available for patient treatment. However, data with regard to the biologic events that occur immediately after implant placement, regardless of the surface characteristic, are scarce. It has become a common procedure to perform immediate/early prosthetic loading rather than delayed loading. The goal of this study was to observe the early biologic events of peri implant healing to understand the role of surface modifications in relation to the early phases of bone integration. The secondary goal was to observe the possible differences in the healing pattern at two oral implant surfaces differing in morphology and roughness (Ra, with Ra values ranging from 0.5 MUm (machined surface; MS) to 1.5 MUm (oxidized surface; OS). A total of 36 implants were placed in six foxhound dogs, equally divided between machined and oxidized surfaces. Three implants were positioned per hemimandible following a randomization scheme. Each animal was euthanized at a specific time point for histologic observation and histomorphometry: immediately after implant insertion and after 24 hours, 7 days, 15 days, 30 days, and 90 days. The study demonstrated an extremely low bone-implant contact (BIC) for both OS and MS implant surfaces during the first 15 days after implant placement (ranging from 12.9% to 26.9% independent of the implant surface). Increased BIC values were observed only in the 30- and 90-day specimens. The presence and the degradation of residual bone particles acted as centers for new bone formation, with osteoblasts lining osteoid tissue and subsequently woven bone independent of the implant surface characteristics. The bone-forming activity appeared strongly reduced after 30 days of healing and seemed to be complete only in the 90-day specimens, where abundant lamellar bone was evident. There is a continuing effort to develop improved titanium surfaces to achieve more rapid osseointegration and improve BIC, with the ultimate goal of applying occlusal load as early as possible. Since immediate or early implant loading is applied during and not after the first 15 days, the findings in the present study of an extremely low BIC and limited mineralized bone formation for both implant surfaces during the first 15 days after implant placement suggest that the surface roughness may not be a key factor for successful osseointegration of immediately or early loaded implants. Within the limits of this study, it can be stated that osseointegration follows a similar healing pattern with machined and oxidized implant surfaces. PMID- 25734701 TI - Estimating the life course of influenza A(H3N2) antibody responses from cross sectional data. AB - The immunity of a host population against specific influenza A strains can influence a number of important biological processes, from the emergence of new virus strains to the effectiveness of vaccination programmes. However, the development of an individual's long-lived antibody response to influenza A over the course of a lifetime remains poorly understood. Accurately describing this immunological process requires a fundamental understanding of how the mechanisms of boosting and cross-reactivity respond to repeated infections. Establishing the contribution of such mechanisms to antibody titres remains challenging because the aggregate effect of immune responses over a lifetime are rarely observed directly. To uncover the aggregate effect of multiple influenza infections, we developed a mechanistic model capturing both past infections and subsequent antibody responses. We estimated parameters of the model using cross-sectional antibody titres to nine different strains spanning 40 years of circulation of influenza A(H3N2) in southern China. We found that "antigenic seniority" and quickly decaying cross-reactivity were important components of the immune response, suggesting that the order in which individuals were infected with influenza strains shaped observed neutralisation titres to a particular virus. We also obtained estimates of the frequency and age distribution of influenza infection, which indicate that although infections became less frequent as individuals progressed through childhood and young adulthood, they occurred at similar rates for individuals above age 30 y. By establishing what are likely to be important mechanisms driving epochal trends in population immunity, we also identified key directions for future studies. In particular, our results highlight the need for longitudinal samples that are tested against multiple historical strains. This could lead to a better understanding of how, over the course of a lifetime, fast, transient antibody dynamics combine with the longer term immune responses considered here. PMID- 25734703 TI - A mixed-model study assessing orthodontic tooth extrusion for the reestablishment of biologic width. A systematic review and exploratory randomized trial. AB - This study assessed the use of orthodontic extrusion (OE) for biologic width reestablishment (BWR) and compared two protocols for BWR: periodontal flap surgery (FS) performed either before (FS + OE) or after (OE + FS) extrusion. Databases were screened up to March 2013 for studies on OE, and outcomes from 13 patients treated by OE + FS or FS + OE were assessed. The results of the literature showed that OE + fiberotomy led to a greater amount of root extrusion than OE alone. The clinical/radiographic assessment demonstrated no significant differences between groups (P > .05). Within groups, there was an improvement in the keratinized tissue (P = .034) and in probing depth (P = .025) for OE + FS. PMID- 25734704 TI - Osseointegrated implants in vertical ridge augmentation with a nonresorbable membrane: a retrospective study of 75 implants with 1 to 6 years of follow-up. AB - The aim of this study was to retrospectively evaluate 75 implants inserted in vertically augmented bone at the time of or prior to implant placement after 1 to 6 years of prosthetic loading. The study included 21 patients (29 surgical sites). The vertical procedure was performed combining a titanium-reinforced expanded polytetrafluoroethylene membrane with autograft (7 sites), allograft (5 sites), or auto-xenograft (17 sites). Healing was uneventful in 24 surgical sites. Three sites showed premature exposure, and two sites presented an abscess. Two implants were lost, for a cumulative survival rate of 93.6%. Mean bone remodeling at 1, 2, 3, 4, 5, and 6 years was 0.34, 0.72, 1.04, 0.84, 0.56, and 0.61 mm, respectively. The implant success rate was higher with a simultaneous approach (82.5%) compared with a staged approach (66.8%). Implants surrounded by keratinized mucosa revealed a higher success rate (82.1%) than those without it (58.4%). PMID- 25734705 TI - Evaluating residual dentin thickness following various mandibular anterior tooth preparations for zirconia full-coverage single crowns: an in vitro analysis. AB - The objective of this study was to evaluate the residual dentin thickness (RDT) after different tooth preparations. Ninety mandibular anterior teeth were divided into three groups: central incisors, lateral incisors, and canines. Specimens were prepared for single-crown coverage with shoulder, slight chamfer, and knife edge finish lines. Specimens were sectioned and divided into four subgroups according to measurement areas: (1) buccal, (2) distal, (3) lingual, and (4) mesial. The RDT was analyzed statistically by means of one-way analysis of variance and Tukey post hoc test (P = .05). Significant differences were found for shoulder but not for slight chamfer and knife-edge finish lines. The interproximal areas wound up being critical due to thin RDT, potentially interfering with the structural and biologic integrity of teeth. PMID- 25734706 TI - A 10-year retrospective radiographic study of implantium dental implants. AB - A retrospective radiographic study was conducted from five private dental offices on patients requesting dental implant therapy to replace their missing teeth. All implants were placed and restored by early 2000, and patients were encouraged to continue their dental care at the same office. The records were reviewed and analyzed by the clinicians, who had more than 15 years of dental experience at the time of the initial patient treatment. A total of 74 patients with 242 implants were recalled up to 10 years (mean follow-up: 9.21 +/- 1.7 years) after loading. There were five implant failures from this radiographic observation period, resulting in a 97.9% dental implant survival rate. The mean crestal bone level change on the mesial aspect was -0.36 +/- 1.05 mm, while the mean crestal bone level change on the distal aspect was -0.18 +/- 0.96 mm. Thus, the overall mean bone loss was -0.28 +/- 0.05 mm. The dental implants, which had a sandblasted, large-grit, acid-etched surface, appeared to achieve successful osseointegration in this long-term observation period, and the implant system's unique design and surface features resulted in a stable osseous crest without bone loss to the first thread. PMID- 25734707 TI - Fence technique for localized three-dimensional bone augmentation: a technical description and case reports. AB - This study presents a novel bone reconstructive technique based on guided bone regeneration for localized three-dimensional hard tissue augmentation. This two stage technique utilized a titanium osteosynthesis plate and a collagen membrane to form a physical barrier resembling a fence that contains bone graft biomaterial composed of a combination of deproteinized bovine bone matrix and autologous bone grafted from intraoral sites. Six patients were treated. At 6 months postsurgery, an increase in bone volume of 953 mm3 was shown. Mean maximum linear augmentation in the vertical direction was 6.75 mm. Histologic analysis of the regenerated area revealed the presence of compact newly formed bone with no sign of inflammation. A total of 13 implants were placed. Peri-implant marginal bone level was 0.94 mm at implant placement and 1.30 mm after 6 months. The patients were satisfied with the procedure and no complications were observed. PMID- 25734708 TI - Innovative regeneration technology to solve peri-implantitis by Er:YAG laser based on the microbiologic diagnosis: a case series. AB - Peri-implantitis is an emerging problem, and corrective therapy requires a method for decontaminating the complex surface structure of the implant body and sterilizing the surrounding tissue. The erbium:yttrium-aluminum-garnet (Er:YAG) laser has proven to effectively allow tissue to regenerate when used for peri implantitis. The power of the Er:YAG laser is absorbed by a water molecule; therefore, its target neither rises in temperature nor carbonizes. An antibacterial remedy based on the bacteriologic diagnosis, followed by debridement and sterilization of the implant surface and peri-implant tissues by Er:YAG laser is efficacious for peri-implantitis treatment. The aim of this report was to present the effectiveness of the Er:YAG laser for peri-implant bone regeneration. This case series of two patients showed that antibiotic therapy reduced the bacterial amount from the peri-implantitis sites significantly and that Er:YAG laser therapy, along with the bone augmentation, enhanced bone regeneration in the peri-implant bony defects. PMID- 25734709 TI - Lateral alveolar ridge augmentation using tenting screws, acellular dermal matrix, and freeze-dried bone allograft alone or with particulate autogenous bone. AB - This randomized prospective study evaluated the clinical benefits of using a corticocancellous mixture of freeze-dried bone allograft alone or in combination (1:1) with particulated autogenous bone for horizontal ridge augmentation and subsequent implant placement. Twenty-four patients with atrophic ridges received lateral ridge augmentations with particulate grafts placed around tenting screws and covered with a fixed acellular dermal matrix membrane. Thirty-three standard diameter implants were successfully placed in 21 patients after a 24-week graft healing period. Three patients experienced early postoperative infections following the grafting procedure (12.5% of sites). At reentry, the allograft alone group showed similar average horizontal ridge width gains (3.33 +/- 0.83 mm) to the combination group (3.09 +/- 0.63 mm; P = .44). The mean graft resorption between baseline and reentry averaged 13.89%. PMID- 25734710 TI - Clinical and histologic comparative study of subepithelial connective tissue graft and extracellular matrix membrane. A preliminary split-mouth study in humans. AB - The purpose of this randomized, controlled, split-mouth study was to compare the behavior of the extracellular matrix membrane (EMM) with autogenous subepithelial connective tissue graft (SCTG) when used as a biologic barrier in the covering of immediate implant placement after modified edentulous ridge expansion. A total of five patients between 40 and 59 years of age (three men, two women) were selected for this study and randomly assigned to one of two groups: EMM (test) or SCTG (control). Treatments were randomly assigned at the same surgical appointment. A total of 29 screw-shaped titanium implants were inserted. Clinical examinations and prophylaxis were performed in recall sessions at 2, 4, and 16 weeks postsurgery. A soft tissue biopsy was performed at both sides 4 months postsurgery. This study indicates that both procedures were effective and predictable in barrier membrane coverage after bone expansion and immediate implant placement. The use of EMM may be a valid alternative to SCTG as a biologic barrier in bone expansion procedures. The use of EMM eliminates the need for the palatal donor site and, as such, provides a less invasive solution. PMID- 25734711 TI - Computer-guided implant placement for rehabilitation of the edentulous maxilla with two impacted canines: an approach without extraction of the impacted teeth. AB - The aim of this report was to suggest an alternative approach to avoid impacted canine extraction by utilizing computer-guided implant placement for providing an implant adjacent to the impacted canine without contact to the impacted tooth. In cases when the adjacent area is available for implant placement, a computerized three-dimensional (3D) planning system can be used to place implants in a way that avoids the impacted canine. Tilted implants could be used to achieve the proper support for implant-supported fixed dentures without damaging the impacted teeth. Following careful 3D planning, a computer-derived surgical stent is used to guide the surgical placement of the implants in the proper place. Since the position of the implants is known prior to the surgical procedure, a prefabricated provisional restoration is delivered immediately at the end of the surgery. Following a waiting period of 6 months, the implant-supported definitive restoration is fabricated using the same technique and delivered to the patient, making sure that proper maintenance and oral home care hygiene are feasible. This suggested treatment modality, when suitable, could provide a relatively short treatment time, a less invasive procedure, and fewer potential complications compared to the extraction of an impacted canine, massive bone grafting, and implant placement. Also, it might be assumed that the use of the native bone, as suggested here, rather than an augmented bone could lead to better long-term results. PMID- 25734712 TI - Evaluation of a porcine collagen matrix used to augment keratinized tissue and increase soft tissue thickness around existing dental implants. AB - Implant-supported prostheses often present with mucogingival deficiencies that may cause esthetic or hygienic issues. These issues may present as limited or no keratinized tissue, irregular soft tissue contour or concavity, and gray "showthrough" of the implant abutment and root forms. An interpositional soft tissue graft substitute that generates keratinized tissue and increases soft tissue thickness would be beneficial, as it would reduce donor site morbidity and be available in unlimited, off-the-shelf supply. Thirty patients were assessed as part of a multicenter, practice-based evaluation of the material. A xenogeneic collagen matrix was placed as an interpositional graft on the buccal aspect of implant sites; sites were reassessed at 6 months posttreatment. Results indicated that the collagen matrix increased tissue thickness and keratinized tissue around existing dental implants. PMID- 25734713 TI - Clinical evaluation of autologous platelet-rich fibrin in the treatment of multiple adjacent gingival recession defects: a 12-month study. AB - Leukocyte- and platelet-rich fibrin (L-PRF) belongs to a new generation of platelet concentrates. There are limited numbers of studies focused on the use of L-PRF in gingival recession defects. This study evaluated the safety and effectiveness of using L-PRF membranes as a substitute for free connective tissue grafts (CTGs) as a treatment method for gingival recession defects. A total of 44 Miller Class I/II gingival recessions that were bilateral, adjacent, and greater than 3 mm in size were selected. Each recession site was randomly assigned to the test group (L-PRF) or the control group (CTG). After 12 months, root coverage was 76.63% and 77.36% in the L-PRF and CTG groups, respectively. It is suggested that L-PRF membrane may be an alternative graft material for treating multiple adjacent recessions greater than 3 mm in size without a requirement for additional surgery. PMID- 25734714 TI - Accuracy of optical dental digitizers: an in vitro study. AB - The aim of this study was to evaluate the accuracy, in terms of trueness and precision, of optical dental scanners. An experimental acrylic resin cast was created and digitized using a microcomputed tomography (microCT) scanner, which served as the reference model. Five polyether impressions were made of the acrylic resin cast to create five stone casts. Each dental digitizer (Imetric, Lava ST, Smart Optics, KaVo Everest) made five scans of the acrylic resin cast and one scan of every stone cast. The scans were superimposed and compared using metrology software. Deviations were calculated between the datasets obtained from the dental digitizers and the microCT scanner (= trueness) and between datasets from the same dental digitizer (= precision). With exception of the Smart Optics scanner, there were no significant differences in trueness for the acrylic resin cast. For the stone casts, however, the Lava ST performed better than Imetric, which did better than the KaVo scanner. The Smart Optics scanner demonstrated the highest deviation. All digitizers demonstrated a significantly higher trueness for the acrylic resin cast compared to the plaster cast, except the Lava ST. The Lava ST was significantly more precise compared to the other scanners. Imetric and Smart Optics also demonstrated a higher level of precision compared to the KaVo scanner. All digitizers demonstrated some degree of error. Stone cast copies are less accurate because of difficulties with scanning the rougher surface or dimensional deformations caused during the production process. For complex, large span reconstructions, a highly accurate scanner should be selected. PMID- 25734715 TI - Block versus particulate/titanium mesh for ridge augmentation for mandibular lateral incisor defects: clinical and histologic analysis. AB - The purpose of this study was to clinically, histologically, and immunohistochemically evaluate the quantity and quality of newly regenerated bone by means of direct clinical measuring and biopsy specimens of alveolar ridges augmented by autogenous cortical bone or titanium micromesh-both filled with autogenous particulate bone graft in the anterior jaws. For the preliminary study, 10 alveolar bone defects in five partially edentulous patients (two men and three women), between 19 and 35 years old (mean: 25.4, SD: 5.94) were selected. Bone defects were randomly (coin toss) divided into two groups: A (micromesh) and B (bone block). The donor site was the mandibular symphysis in all cases. On the return appointment, operative grafts appeared well incorporated into the native bone, which suggests that good contact and fit between the graft and the recipient site had been obtained during the first surgery. Histologic investigations confirmed excellent integration and revascularization of the graft in both study groups, with formation of new bone tissue without any relevant inflammation. PMID- 25734716 TI - Efficacy of the lateral advanced flap in root-coverage procedures for mandibular central incisors: a 5-year clinical study. AB - The aim of this study was to determine the efficacy of the lateral advanced flap in root-coverage procedures for mandibular incisors and to evaluate pain after treatment. A total of 15 patients who required treatment for gingival recessions were selected from the University of Genoa Laser and Restorative Dentistry Department. The inclusion criteria were the presence of at least one 3-mm gingival recession defect of a mandibular incisor and 3 mm or more of keratinized tissue width on the immediately adjacent tooth. One calibrated masked examiner performed the clinical measurements, including recession depth and width, probing depth, clinical attachment level, and keratinized tissue width. Patients were checked 7, 14, and 30 days after surgery and were included in supportive periodontal maintenance every 4 months. Further follow-ups were done at the first, third, and fifth year postsurgery when the same baseline assessment parameters were recorded according to the root-coverage esthetic score (RES). Numeric score recorded pain evaluations showed a mean of 3 at the day of the surgery, 2 in the first day after the surgery, and no significant scores were referred in the following days. Mean recession depth was 3.2 +/- 1.3 mm at baseline; at 5 years, RES showed a positive increase of all scores. The laterally coronally advanced surgical technique was very effective in treating isolated gingival recessions. It combined the esthetic and root-coverage advantages of the coronally advanced flap with the increased gingival thickness and keratinized tissue associated with the lateral gingival flap. PMID- 25734720 TI - The sea at Le Havre: Claude Monet. PMID- 25734721 TI - Clinical trial data: share and share alike? PMID- 25734722 TI - Leading by example--health systems improving the care of employees. PMID- 25734729 TI - A piece of my mind. In the hands of another. PMID- 25734730 TI - Housing as a remedy for chronic homelessness. PMID- 25734731 TI - Improving the long-term management of benign thyroid nodules. PMID- 25734732 TI - Effect of scattered-site housing using rent supplements and intensive case management on housing stability among homeless adults with mental illness: a randomized trial. AB - IMPORTANCE: Scattered-site housing with Intensive Case Management (ICM) may be an appropriate and less-costly option for homeless adults with mental illness who do not require the treatment intensity of Assertive Community Treatment. OBJECTIVE: To examine the effect of scattered-site housing with ICM services on housing stability and generic quality of life among homeless adults with mental illness and moderate support needs for mental health services. DESIGN, SETTING, AND PARTICIPANTS: The At Home/Chez Soi project was an unblinded, randomized trial. From October 2009 to July 2011, participants (N = 1198) were recruited in 4 Canadian cities (Vancouver, Winnipeg, Toronto, and Montreal), randomized to the intervention group (n = 689) or usual care group (n = 509), and followed up for 24 months. INTERVENTIONS: The intervention consisted of scattered-site housing (using rent supplements) and off-site ICM services. The usual care group had access to existing housing and support services in their communities. MAIN OUTCOMES AND MEASURES: The primary outcome was the percentage of days stably housed during the 24-month period following randomization. The secondary outcome was generic quality of life, assessed by a EuroQoL 5 Dimensions (EQ-5D) health questionnaire. RESULTS: During the 24 months after randomization, the adjusted percentage of days stably housed was higher among the intervention group than the usual care group, although adjusted mean differences varied across sites. [table: see text] The mean change in EQ-5D score from baseline to 24 months among the intervention group was not statistically different from the usual care group (60.5 [95%CI, 58.6 to 62.5] at baseline and 67.2 [95%CI, 65.2 to 69.1] at 24 months for the intervention group vs 62.1 [95% CI, 59.9 to 64.4] at baseline and 68.6 [95%CI, 66.3 to 71.0] at 24 months for the usual care group, difference in mean changes, 0.10 [95%CI, -2.92 to 3.13], P=.95). CONCLUSIONS AND RELEVANCE: Among homeless adults with mental illness in 4 Canadian cities, scattered site housing with ICM services compared with usual access to existing housing and community services resulted in increased housing stability over 24 months, but did not improve generic quality of life. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN42520374. PMID- 25734734 TI - The natural history of benign thyroid nodules. AB - IMPORTANCE: Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed. OBJECTIVE: To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed. MAIN OUTCOMES AND MEASURES: Baseline nodule growth (primary end point) was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up. RESULTS: Nodule growth occurred in 153 patients (15.4% [95% CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1% [95% CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9 mm (95% CI, 4.2-5.5 mm), from 13.2 mm (95% CI, 12.1-14.2 mm) to 18.1 mm (95% CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95% CI 1.4-3.4] for 2 nodules; OR, 3.2 [95% CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95% CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2 mL (OR, 2.9 [95% CI, 1.7-4.9] for volumes >0.2 to <1 mL and OR, 3.0 [95% CI, 1.8-5.1] for volumes >=1 mL), and male sex (OR, 1.7 [95% CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95% CI 0.3-0.9]). In 184 individuals (18.5% [95% CI, 16.4% 20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3% [95% CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3% [95% CI, 7.5%-11.1%]), with detection of one cancer. CONCLUSIONS AND RELEVANCE: Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow up of asymptomatic thyroid nodules. PMID- 25734733 TI - Effect of sedative premedication on patient experience after general anesthesia: a randomized clinical trial. AB - IMPORTANCE: Sedative premedication is widely administered before surgery, but little clinical evidence supports its use. OBJECTIVE: To assess the efficacy of sedative premedication on perioperative patient experience. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial, the PremedX study, enrolled 1062 adult patients who were younger than 70 years and had been scheduled for various elective surgeries under general anesthesia at 5 French teaching hospitals (in Marseille, Montpellier, Nimes, and Nice) between January 2013 and June 2014. Neurosurgery, obstetrical, cardiac, and outpatient surgery were excluded. INTERVENTIONS: Patients were randomized to 3 groups of 354 participants each to receive 2.5 mg of lorazepam, no premedication, or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was perioperative patient experience assessed 24 hours after surgery with a validated questionnaire (Evaluation du Vecu de l'Anesthesie Generale; EVAN-G) describing 6 domains of satisfaction and a global index (score range, 0-100; high scores represent high satisfaction); secondary outcomes included time to extubation and early cognitive recovery. A subgroup analysis was planned a priori in patients with a high level of preoperative anxiety. RESULTS: Premedication with lorazepam did not improve the EVAN-G mean global index for overall level of patient satisfaction (72 [95% CI, 70-73]; n = 330) compared with no premedication (73 [95% CI, 71-74]; n = 319) or placebo (71 [95% CI, 70-73]; n = 322) (P = .38). Among patients with heightened preoperative anxiety, there were no significant differences found in the EVAN-G mean global index between the lorazepam group (68 [95% CI, 65-72]; n = 87) and the no premedication group (73 [95% CI, 69-77]; n = 57) or the placebo group (70 [95% CI, 67-72]; n = 87) (P = .18). Time to extubation was 17 minutes (95% CI, 14-20 minutes) in the lorazepam group, 12 minutes (95% CI, 11-13 minutes) for the no premedication group, and 13 minutes (95% CI, 12-14 minutes) for the placebo group (P < .001) and the rate of early cognitive recovery was 51% (95% CI, 45%-56%), 71% (95% CI, 66%-76%), and 64% (95% CI, 59%-69%), respectively (P < .001). CONCLUSIONS AND RELEVANCE: Among patients undergoing elective surgery under general anesthesia, sedative premedication with lorazepam compared with placebo or no premedication did not improve the self-reported patient experience the day after surgery, but was associated with modestly prolonged time to extubation and a lower rate of early cognitive recovery. The findings suggest a lack of benefit with routine use of lorazepam as sedative premedication in patients undergoing general anesthesia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01901003. PMID- 25734735 TI - Single- vs double-lung transplantation in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis since the implementation of lung allocation based on medical need. AB - IMPORTANCE: Outcomes of single- and double-lung transplantation have not been rigorously assessed since the allocation of donor lungs according to medical need as quantified by the Lung Allocation Score, which began in 2005. OBJECTIVE: To compare outcomes in single- and double-lung transplant recipients since the Lung Allocation Score was implemented. DESIGN, SETTING, AND PARTICIPANTS: In this exploratory analysis, adults with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) who underwent lung transplantation in the United States between May 4, 2005, and December 31, 2012, were identified in the United Network for Organ Sharing thoracic registry, with follow-up to December 31, 2012. Posttransplantation graft survival was assessed with Kaplan-Meier analysis. Propensity scores were used to control for treatment selection bias. A multivariable flexible parametric prognostic model was used to characterize the time-varying hazard associated with single- vs double-lung transplantation. EXPOSURE: Single- or double-lung transplantation. MAIN OUTCOMES AND MEASURES: Composite of posttransplant death and graft failure (retransplantation). RESULTS: Patients with IPF (n = 4134, of whom 2010 underwent single-lung and 2124 underwent double-lung transplantation) or COPD (n = 3174, of whom 1299 underwent single-lung and 1875 underwent double-lung transplantation) were identified as having undergone lung transplantation since May 2005. Median follow-up was 23.5 months. Of the patients with IPF, 1380 (33.4%) died and 115 (2.8%) underwent retransplantation; of the patients with COPD, 1138 (34.0%) died and 59 (1.9%) underwent retransplantation. After confounders were controlled for with propensity score analysis, double-lung transplants were associated with better graft survival in patients with IPF (adjusted median survival, 65.2 months [interquartile range {IQR}, 21.4-91.3 months] vs 50.4 months [IQR, 17.0-87.5 months]; P < .001) but not in patients with COPD (adjusted median survival, 67.7 months [IQR, 25.2-89.6 months] vs 64.0 months [IQR, 25.2-88.7 months]; P = .23). The interaction between diagnosis type (COPD or IPF) and graft failure was significant (P = .049). Double-lung transplants had a time-varying association with graft survival; a decreased instantaneous late hazard for death or graft failure among patients with IPF was noted at 1 year and persisted at 5 years postoperatively (instantaneous hazard at 5 years, hazard ratio, 0.67 [95% CI, 0.52-0.84] in patients with IPF and 0.89 [95% CI, 0.71-1.13] in patients with COPD). CONCLUSIONS AND RELEVANCE: In an exploratory analysis of registry data since implementation of a medical need-based lung allocation system, double-lung transplantation was associated with better graft survival than single-lung transplantation in patients with IPF. In patients with COPD, there was no survival difference between single- and double-lung transplant recipients at 5 years. PMID- 25734736 TI - Irritable bowel syndrome: a clinical review. AB - IMPORTANCE: Irritable bowel syndrome (IBS) affects 7% to 21% of the general population. It is a chronic condition that can substantially reduce quality of life and work productivity. OBJECTIVES: To summarize the existing evidence on epidemiology, pathophysiology, and diagnosis of IBS and to provide practical treatment recommendations for generalists and specialists according to the best available evidence. EVIDENCE REVIEW: A search of Ovid (MEDLINE) and Cochrane Database of Systematic Reviews was performed for literature from 2000 to December 2014 for the terms pathophysiology, etiology, pathogenesis, diagnosis, irritable bowel syndrome, and IBS. The range was expanded from 1946 to December 2014 for IBS, irritable bowel syndrome, diet, treatment, and therapy. FINDINGS: The database search yielded 1303 articles, of which 139 were selected for inclusion. IBS is not a single disease but rather a symptom cluster resulting from diverse pathologies. Factors important to the development of IBS include alterations in the gut microbiome, intestinal permeability, gut immune function, motility, visceral sensation, brain-gut interactions, and psychosocial status. The diagnosis of IBS relies on symptom-based criteria, exclusion of concerning features (symptom onset after age 50 years, unexplained weight loss, family history of selected organic gastrointestinal diseases, evidence of gastrointestinal blood loss, and unexplained iron-deficiency anemia), and the performance of selected tests (complete blood cell count, C-reactive protein or fecal calprotectin, serologic testing for celiac disease, and age-appropriate colorectal cancer screening) to exclude organic diseases that can mimic IBS. Determining the predominant symptom (IBS with diarrhea, IBS with constipation, or mixed IBS) plays an important role in selection of diagnostic tests and treatments. Various dietary, lifestyle, medical, and behavioral interventions have proven effective in randomized clinical trials. CONCLUSIONS AND RELEVANCE: The diagnosis of IBS relies on the identification of characteristic symptoms and the exclusion of other organic diseases. Management of patients with IBS is optimized by an individualized, holistic approach that embraces dietary, lifestyle, medical, and behavioral interventions. PMID- 25734737 TI - The link between dietary sugar intake and cardiovascular disease mortality: an unresolved question. PMID- 25734738 TI - Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. AB - CLINICAL QUESTION: Are pharmacological interventions associated with better quality sleep and alertness in shift workers? BOTTOM LINE: Low-quality evidence shows that melatonin is associated with 24 minutes longer daytime sleep after the shift but not with faster falling asleep compared with placebo. There is no association between hypnotics, such as zopiclone, and sleep outcomes, alertness, or harms. The alertness-promoting medications armodafinil and modafinil are associated with improved alertness during shift work but are also associated with headache and nausea. PMID- 25734739 TI - A 55-year-old man with severe papilledema. PMID- 25734740 TI - Medicaid prior authorization policies for pediatric use of antipsychotic medications. PMID- 25734741 TI - Treatment of late-stage syphilis. PMID- 25734742 TI - Treatment of late-stage syphilis. PMID- 25734743 TI - Treatment of late-stage syphilis--reply. PMID- 25734744 TI - Fenoldopam and acute kidney injury. PMID- 25734745 TI - Multifactorial risk assessment for atherosclerotic cardiovascular disease. PMID- 25734746 TI - Fenoldopam and acute kidney injury--reply. PMID- 25734748 TI - Multifactorial risk assessment for atherosclerotic cardiovascular disease--reply. PMID- 25734750 TI - "Jumping Frenchmen of Maine". PMID- 25734751 TI - JAMA patient page. Irritable bowel syndrome. PMID- 25734752 TI - Impact of wood combustion for secondary heating and recreational purposes on particulate air pollution in a suburb in Finland. AB - Little information is available on the concentrations of ambient fine particles (PM2.5) in residential areas where wood combustion is common for recreational purposes and secondary heating. Further, the validity of central site measurements of PM2.5 as a measure of exposure is unclear. Therefore, outdoor PM2.5 samples were repeatedly collected at a central site and home outdoor locations from a panel of 29 residents in a suburb in Kuopio, Finland. Source apportionment results from the central site were used to estimate the contributions from local sources, including wood combustion, to PM2.5 and absorption coefficient (ABS) at home outdoor locations. Correlations between the central and home outdoor concentrations of PM2.5, ABS, and their local components were analyzed for each home. At the central site, the average PM2.5 was 6.0 MUg m(-)(3) during the heating season, and the contribution from wood combustion (16%) was higher than the contribution from exhaust emissions (12%). Central site measurements predicted poorly daily variation in PM2.5 from local sources. In conclusion, wood combustion significantly affects air quality also in areas where it is not the primary heating source. In epidemiological panel studies, central site measurements may not sufficiently capture daily variation in exposure to PM2.5 from local wood combustion. PMID- 25734753 TI - Epidemiologic features of metabolic syndrome in a general Mongolian population. AB - BACKGROUND: Although cardiovascular health is a crucial problem for Mongolian people, little information about metabolic syndrome, which is well known to be associated with the development of cardiovascular disease, is available in Mongolia. The aim of this study was to observe the epidemiological features of metabolic syndrome in a general Mongolian population. METHODS: This cross sectional study was performed in 1911 general Mongolian subjects (717 men, 1194 women), who were >=40 years old and free of ischemic heart disease, by using a dataset from a nationwide population-based cohort study in Mongolia. The prevalence of metabolic syndrome, as defined by International Diabetes Federation criteria, was determined. Alcohol consumption, smoking habits, and physical activity were evaluated. Education, marital status, income, and occupation were also examined as factors of socioeconomic status (SES). Their association with metabolic syndrome was determined by logistic regression models. RESULTS: The prevalence of metabolic syndrome was significantly higher in women (n=488, 40.6%) than in men (n=138, 19.4%). The prevalence of metabolic syndrome was high, especially in the Khangai region, in women. Moderate-to-high alcohol consumption was a significantly positively associated factor of metabolic syndrome in men [odds ratio (OR)=2.01; 95% confidence interval (CI) 1.15-3.51; adjusted odds ratio (AOR)=2.41; 95% CI 1.31-4.44] and widowed status was a significantly positively associated factor of metabolic syndrome in women (OR=1.61, 95% CI 1.18 2.18; AOR=1.49, 95% CI 1.07-2.08). CONCLUSIONS: Metabolic syndrome was prevalent in women compared with men among Mongolian adults. Preventive strategies aimed at men with a higher alcohol consumption and women with widowed status may help reduce metabolic syndrome, thereby improving cardiovascular health conditions in Mongolia. PMID- 25734754 TI - Stress increases cue-triggered "wanting" for sweet reward in humans. AB - Stress can increase reward pursuits: This has traditionally been seen as an attempt to relieve negative affect through the hedonic properties of a reward. However, reward pursuit is not always proportional to the pleasure experienced, because reward processing involves distinct components, including the motivation to obtain a reward (i.e., wanting) and the hedonic pleasure during the reward consumption (i.e., liking). Research conducted on rodents demonstrates that stress might directly amplify the cue-triggered wanting, suggesting that under stress wanting can be independent from liking. Here, we aimed to test whether a similar mechanism exists in humans. We used analog of a Pavlovian-Instrumental Transfer test (PIT) with an olfactory reward to measure the cue triggered wanting for a reward but also the sensory hedonic liking felt during the consumption of the same reward. The analog of a PIT procedure, in which participants learned to associate a neutral image and an instrumental action with a chocolate odor, was combined with either a stress-inducing or stress-free behavioral procedure. Results showed that compared with participants in the stress-free condition, those in the stress condition mobilized more effort in instrumental action when the reward-associated cue was displayed, even though they did not report the reward as being more pleasurable. These findings suggest that, in humans, stress selectively increases cue-triggered wanting, independently of the hedonic properties of the reward. Such a mechanism supports the novel explanation proposed by animal research as to why stress often produces cue-triggered bursts of binge eating, relapses in drug addiction, or gambling. PMID- 25734755 TI - Occasion setting during a spatial-search task with pigeons. AB - A spatial task was used to investigate if a stimulus could set the occasion for responding to a landmark. Pigeons were trained with a positive occasion setter (OS; a colored background display) signaling the contingency between a landmark (LM; visual patterned stimulus) and the location of a rewarded response. The two most common tests of an OS (transfer tests and post-training extinction of the OS) were then conducted. In Experiment 1, two occasion setting pairs were trained (+<-XA/YB->+/A-/B-) with unique spatial relationships to a reinforced goal location. Transfer tests (XB- and YA-) revealed more responding to a landmark when paired with the same OS from training (e.g., XA) than on transfer tests, which was greater still than landmark-only trials (A-). Three pigeons demonstrated good spatial control of responding by the LM on transfer tests. In Experiment 2, the contingency and spatial relationship (e.g., left or right) between LM A and the goal were signaled by the OS (+<-XA/YA->+/+<-ZB/C->+/A-/B-). LM C was trained without an OS to assess the role of training history during transfer. Transfer tests again indicated an OS could facilitate responding and the LM controlled the location of responding. Training history affected spatial control, but not facilitation, by LM C. Lastly, post-training extinction of X had no effect on facilitation or spatial control during subsequent XA trials. These experiments are the first to evaluate conditional control of spatial information by landmarks using both of the standard tests for occasion setting. PMID- 25734756 TI - Pavlovian conditioning and cumulative reinforcement rate. AB - In 5 experiments using delay conditioning of magazine approach with rats, reinforcement rate was varied either by manipulating the mean interval between onset of the conditioned stimulus (CS) and unconditioned stimulus (US) or by manipulating the proportion of CS presentations that ended with the US (trial based reinforcement rate). Both manipulations influenced the acquisition of responding. In each experiment, a specific comparison was made between 2 CSs that differed in their mean CS-US interval and in their trial-based reinforcement rate, such that the cumulative reinforcement rate-the cumulative duration of the CS between reinforcements-was the same for the 2 CSs. For example, a CS reinforced on 100% of trials with a mean CS-US interval of 60 s was compared with a CS reinforced on 33% of trials and a mean duration of 20 s. Across the 5 experiments, conditioning was virtually identical for the 2 CSs with matched cumulative reinforcement rate. This was true as long as the timing of the US was unpredictable and, thus, response rates were uniform across the length of the CS. We conclude that the effects of CS-US interval and of trial-based reinforcement rate are reducible entirely to their common effect on cumulative reinforcement rate. We discuss the implications of this for rate-based, trial-based, and real time associative models of conditioning. PMID- 25734757 TI - Memory systems interaction in the pigeon: working and reference memory. AB - Pigeons' performance on a working memory task, symbolic delayed matching-to sample, was used to examine the interaction between working memory and reference memory. Reference memory was established by training pigeons to discriminate between the comparison cues used in delayed matching as S+ and S- stimuli. Delayed matching retention tests then measured accuracy when working and reference memory were congruent and incongruent. In 4 experiments, it was shown that the interaction between working and reference memory is reciprocal: Strengthening either type of memory leads to a decrease in the influence of the other type of memory. A process dissociation procedure analysis of the data from Experiment 4 showed independence of working and reference memory, and a model of working memory and reference memory interaction was shown to predict the findings reported in the 4 experiments. (PsycINFO Database Record PMID- 25734758 TI - Antibacterial coatings on titanium surfaces: a comparison study between in vitro single-species and multispecies biofilm. AB - Dental plaque is a biofilm that causes dental caries, gingivitis, and periodontitis. Most of the studies in antibacterial coatings have been conducted by in vitro single-species biofilm formation, but oral biofilm involves more than 700 different bacterial species that are able to interact. Therefore, new studies are focused on in vitro multispecies biofilm models that mimic in vivo biofilms. The aim of the present work was to study different antibacterial coatings onto titanium surfaces and evaluate the in vitro antimicrobial properties of the surfaces on two different bacterial species and an oral biofilm. The lactate dehydrogenase assay determined that treated samples did not affect fibroblast viability. In addition, the viability of microorganisms on modified samples was evaluated by a LIVE/DEAD BacLight bacterial viability kit. Although a decrease in viable bacteria onto treated samples was obtained, the results showed differences in effectiveness when single-biofilm and oral plaque were tested. It confirms, as we expected, the distinct sensitivities that bacterial strains have. Thus, this multispecies biofilms model holds a great potential to assess antibacterial properties onto samples for dental purposes. PMID- 25734759 TI - Validation of the Cyberchondria Severity Scale (CSS): replication and extension with bifactor modeling. AB - Internet help seeking behaviors are increasingly common. Despite the positives associated with technology, cyberchondria, or the process of increased anxiety in response to internet medical information seeking, is on the rise. The Cyberchondria Severity Scale (CSS) was recently developed to provide a valid measure of cyberchondria across multiple dimensions. The current study sought to extend previous work on the CSS factor structure by examining a bifactor model. Participants (N=526) from a community sample completed the CSS via online crowd sourcing. Results revealed that the bifactor model of the CSS provided superior fit to the data, suggesting that it is useful to conceptualize the CSS as containing a General Cyberchondria factor that is orthogonal to its subfactors. Similar to previous work, the CSS Mistrust factor does not appear to be necessary to this construct. Finally, results revealed unique relations between General and Specific Cyberchondria factors with lower-order health anxiety dimensions. PMID- 25734760 TI - Air- and water-resistant noble metal coated ferromagnetic cobalt nanorods. AB - Cobalt nanorods possess ideal magnetic properties for applications requiring magnetically hard nanoparticles. However, their exploitation is undermined by their sensitivity toward oxygen and water, which deteriorates their magnetic properties. The development of a continuous metal shell inert to oxidation could render them stable, opening perspectives not only for already identified applications but also for uses in which contact with air and/or aqueous media is inevitable. However, the direct growth of a conformal noble metal shell on magnetic metals is a challenge. Here, we show that prior treatment of Co nanorods with a tin coordination compound is the crucial step that enables the subsequent growth of a continuous noble metal shell on their surface, rendering them air- and water-resistant, while conserving the monocrystallity, metallicity and the magnetic properties of the Co core. Thus, the as-synthesized core-shell ferromagnetic nanorods combine high magnetization and strong uniaxial magnetic anisotropy, even after exposure to air and water, and hold promise for successful implementation in in vitro biodiagnostics requiring probes of high magnetization and anisotropic shape. PMID- 25734761 TI - Praeruptorin A inhibits in vitro migration of preosteoclasts and in vivo bone erosion, possibly due to its potential to target calmodulin. AB - Excessive activity and/or increased number of osteoclasts lead to bone resorption related disorders. Here, we investigated the potential of praeruptorin A to inhibit migration/fusion of preosteoclasts in vitro and bone erosion in vivo. Praeruptorin A inhibited the RANKL-induced migration/fusion of preosteoclasts accompanied by the nuclear translocation of NFATc1, a master regulator of osteoclast differentiation. Antimigration/fusion activity of praeruptorin A was also confirmed by evaluating the mRNA expression of fusion-mediating molecules. In silico binding studies and several biochemical assays further revealed the potential of praeruptorin A to bind with Ca(2+)/calmodulin and inhibit its downstream signaling pathways, including the Ca(2+)/calmodulin-CaMKIV-CREB and Ca(2+)/calmodulin-calcineurin signaling axis responsible for controlling NFATc1. In vivo application of praeruptorin A significantly reduced lipopolysaccharide induced bone erosion, indicating its possible use to treat bone resorption related disorders. In conclusion, praeruptorin A has the potential to inhibit migration/fusion of preosteoclasts in vitro and bone erosion in vivo by targeting calmodulin and inhibiting the Ca(2+)/calmodulin-CaMKIV-CREB-NFATc1 and/or Ca(2+)/calmodulin-calcineurin-NFATc1 signaling axis. PMID- 25734762 TI - Structural and ultrastructural study of rat liver influenced by electromagnetic radiation. AB - Mobile communication systems are undoubtedly an environmental source of electromagnetic radiation (EMR). There is an increasing concern regarding the interactions of EMR with the humans. The aim of this study was to examine the effects of EMR on Wistar rat liver. Mature rats were exposed to electromagnetic field of frequency 2.45 GHz and mean power density of 2.8 mW/cm2 for 3 h/d for 3 wk. Samples of the liver were obtained 3 h after the last irradiation and processed histologically for light and transmission electron microscopy. Data demonstrated the presence of moderate hyperemia, dilatation of liver sinusoids, and small inflammatory foci in the center of liver lobules. Structure of hepatocytes was not altered and all described changes were classified as moderate. Electron microscopy of hepatocytes revealed vesicles of different sizes and shapes, lipid droplets, and proliferation of smooth endoplasmic reticulum. Occasionally necrotizing hepatocytes were observed. Our observations demonstrate that EMR exposure produced adverse effects on rat liver. PMID- 25734763 TI - Determination of the genotype and phenotype of serum paraoxonase 1 (PON1) status in a group of agricultural and nonagricultural workers in the Coquimbo Region, Chile. AB - Paraoxonase 1 (PON1) is a glycosylated enzyme that is found associated with high density lipoproteins in blood. In addition to its endogenous antioxidant role, this enzyme is also involved in hydrolysis of organophosphate (OP) pesticides in plasma. PON1 activity shows great variability in the population as a result of a polymorphism in the coding sequence that is expressed as a Glu(Q)/Arg(R) substitution at position 192 of the amino acid sequence. The aim of this study was to determine the activity levels (phenotype) and genotype of PON1 in a group of 85 agricultural workers occupationally exposed to OP pesticides and compared to 97 control subjects without occupational exposure. Allelic and genotypic frequencies of PON1Q192R polymorphism, as well as their catalytic activities, were established for the first time in a group of agricultural Chilean workers. The Q allele was more frequently represented in our studied population (approximately 60%). The Q allele is less efficient than the R allele at metabolizing chlorpyrifos (CPF), the most widely used OP pesticide in the geographical areas where samples were obtained. Further, a large interindividual variability in PON1 activity was observed, suggesting wide variation of individual susceptibility to CPF, an issue that needs to be considered in human monitoring studies. PMID- 25734764 TI - Mixture genotoxicity of 2,4-dichlorophenoxyacetic acid, acrylamide, and maleic hydrazide on human Caco-2 cells assessed with comet assay. AB - Assessment of genotoxic properties of chemicals is mainly conducted only for single chemicals, without taking mixture genotoxic effects into consideration. The current study assessed mixture effects of the three known genotoxic chemicals, 2,4-dichlorophenoxyacetic acid (2,4-D), acrylamide (AA), and maleic hydrazide (MH), in an experiment with a fixed ratio design setup. The genotoxic effects were assessed with the single-cell gel electrophoresis assay (comet assay) for both single chemicals and the ternary mixture. The concentration ranges used were 0-1.4, 0-20, and 0-37.7 mM for 2,4-D, AA, and MH, respectively. Mixture toxicity was tested with a fixed ratio design at a 10:23:77% ratio for 2.4-D:AA:MH. Results indicated that the three chemicals yielded a synergistic mixture effect. It is not clear which mechanisms are responsible for this interaction. A few possible interactions are discussed, but further investigations including in vivo studies are needed to clarify how important these more-than-additive effects are for risk assessment. PMID- 25734765 TI - Microbial pathogens in wastewater treatment plants (WWTP) in Hamburg. AB - Microbial pathogens are among the major health problems associated with water and wastewater. Classical indicators of fecal contamination include total coliforms, Escherichia coli, and Clostridium perfringens. These fecal indicators were monitored in order to obtain information regarding their evolution during wastewater treatment processes. Helminth eggs survive for a long duration in the environment and have a high potential for waterborne transmission, making them reliable contaminant indicators. A large quantity of helminth eggs was detected in the wastewater samples using the Bailanger method. Eggs were found in the influent and effluent with average concentration ranging from 11 to 50 eggs/L. Both E. coli and total coliforms concentrations were significantly 1- to 3-fold higher in influent than in effluent. The average concentrations of E. coli ranged from 2.5*10(3) to 4.4*10(5) colony-forming units (CFU)/100 ml. Concentrations of total coliforms ranged from 3.6*10(3) to 7.9*10(5) CFU/100 ml. Clostridium perfringens was also detected in influent and effluent of wastewater treatment plants (WWTP) at average concentrations ranging from 5.4*10(2) to 9.1*10(2) most probable number (MPN)/100 ml. Significant Spearman rank correlations were found between helminth eggs and microbial indicators (total coliform, E. coli, and C. perfringens) in the WWTP. There is therefore need for additional microbial pathogen monitoring in the WWTP to minimize public health risk. PMID- 25734766 TI - Scales of freshwater fish Labeo rohita as bioindicators of water pollution in Tung Dhab Drain, Amritsar, Punjab, India. AB - This study examined the impact of municipal wastewater on scale morphology of freshwater fish Labeo rohita. Fish were exposed to sublethal concentrations (17.7, 26.6, or 35.4%) of municipal wastewater for durations of 15, 30, and 60 d. Recovery experiments were also performed for a duration of 60 d. Scales were extracted after respective exposure periods, cleaned, and processed for scanning electron microscopy. Results showed concentration- and exposure duration dependent alterations in the morphology of scales. Severe damage was observed at the anterior and posterior portions of scales in the form of lepidontal breakage and uprooting, destructions at the base of circuli and radii along with complete structural loss in the focal region and adjacent circuli and radii, and alterations in structure of tubercles. Data indicate that scales of fish L. rohita may be employed as bioindicators of water pollution and could be incorporated into water monitoring surveillance. PMID- 25734767 TI - Ozone exposure initiates a sequential signaling cascade in airways involving interleukin-1beta release, nerve growth factor secretion, and substance P upregulation. AB - Previous studies demonstrated that interleukin-1beta (IL-1beta) and nerve growth factor (NGF) increase synthesis of substance P (SP) in airway neurons both after ozone (O3) exposure and by direct application. It was postulated that NGF mediates O3-induced IL-1beta effects on SP. The current study specifically focused on the influence of O3 on IL-1beta, NGF, and SP levels in mice bronchoalveolar lavage fluid (BALF) and whether these mediators may be linked in an inflammatory-neuronal cascade in vivo. The findings showed that in vivo O3 exposure induced an increase of all three proteins in mouse BALF and that O3 induced elevations in both NGF and SP are mediated by the inflammatory cytokine IL-1beta. Further, inhibition of NGF reduced O3 induced increases of SP in both the lung BALF and lung tissue, demonstrating NGF serves as a mediator of IL-1beta effects on SP. These data indicate that IL-1beta is an early mediator of O3 induced rise in NGF and subsequent SP release in mice in vivo. PMID- 25734769 TI - Epidemiology: Spotlight on CKD deaths-increasing mortality worldwide. PMID- 25734768 TI - Renal effects of targeted anticancer therapies. AB - The use of novel targeted anticancer agents has led to overall improvement in the prognosis of many patients affected by various malignancies, but has also been associated with an increased risk of poorly characterized toxic effects to different organs, including the kidneys. The high prevalence of kidney impairment in the general population complicates the issue further. Nephrologists most frequently work with patients with cancer when they are asked to investigate kidney function to assess the need for dose adjustments in anticancer therapy. A thorough knowledge of the renal safety profile of novel life-prolonging anticancer therapies, specific features of their metabolism, and pharmacokinetic and pharmacodynamic properties (under normal circumstances as well as in the setting of renal replacement therapy) is, therefore, necessary to preserve kidney function as far as possible and to ensure optimum treatment. In this Review we summarize the present knowledge of renal toxic effects from novel targeted anticancer agents and discuss whether the management of patients' treatment needs to be modified. We also advocate the development of a new onconephrology subspeciality. PMID- 25734770 TI - Cytochrome 4A11 Genetic Polymorphisms Increase Susceptibility to Ischemic Stroke and Associate with Atherothrombotic Events After Stroke in Chinese. AB - To evaluate the associations between four single-nucleotide polymorphisms (SNPs) in CYP4A11 and CYP4F2 and ischemic stroke (IS), and between these variants and atherothrombotic events after stroke. IS patients (n=396) and controls (n=378) were genotyped for two CYP4A11 SNPs (rs2269231 and rs9333025) and two CYP4F2 SNPs (rs2108622 and rs3093135). Patients were followed up for 12 months after the stroke for the atherothrombotic events. The frequency of the rs9333025 GG genotype was significantly higher in IS patients than in controls. Logistic regression analysis showed that the presence of rs9333025 GG in patients was associated with significantly higher risk of IS. Cox regression analysis revealed that the rs9333025 GG genotype was an independent risk factor for atherothrombotic events after stroke. The rs9333025 GG genotype increases patients' susceptibility to IS and is associated with high frequencies of atherothrombotic events in stroke patients. PMID- 25734771 TI - Women's responses to intimate partner violence in Rwanda: Rethinking agency in constrained social contexts. AB - This paper explores instances of agency in women's responses to intimate partner violence (IPV) in Rwanda. The literature on women's responses to IPV conceptualises agency primarily as an individual's capacity to take action by reporting violence or leaving a relationship, obscuring other ways women may respond to violence in contexts where reporting or leaving are unlikely. We aim to replace this narrow conceptualisation of agency with a social constructivist focus on the meanings women attribute to possible IPV responses. We draw on data from a study of IPV in Rwanda, which includes semi-structured interviews with women experiencing violence and four focus group discussions with women community members (n = 39). Our findings highlight sociocultural, economic, political-legal and historical constraints that shape women's actions in this context. In relation to these constraints, women describe four possible responses to IPV: reporting the violence; seeking emotional support; 'fighting back' against violence; or remaining silent. While reporting and leaving violent relationships are identified, women also discuss the social constraints that make these actions extremely difficult. In designing effective strategies, we conclude that public health strategies need to consider women's understandings of their own actions, particularly in social contexts where certain actions may be constrained. PMID- 25734773 TI - Dispersion behavior and aqueous foams in mixtures of a vesicle-forming surfactant and edible nanoparticles. AB - In an attempt to prepare ultrastable aqueous foams composed entirely of food grade ingredients, we describe the foamability and foam stability of aqueous phases containing either calcium carbonate particles (CaCO3), sodium stearoyl lactylate surfactant (SSL), or their mixtures. Techniques including zeta potential measurements, adsorption isotherm determination, contact angles and optical and cryo-scanning electron microscopy are used to probe the interaction between particles and surfactant molecules. Aqueous dispersions of inherently hydrophilic cationic CaCO3 nanoparticles do not foam to any great extent. By contrast, aqueous dispersions of anionic SSL, which forms a lamellar phase/vesicles, foam progressively on increasing the concentration. Despite their foamability being low compared to that of micelle-forming surfactant sodium dodecyl sulfate, they are much more stable to collapse with half-lives (of up to 40 days) of around 2 orders of magnitude higher above the respective aggregation concentrations. We believe that, in addition to surfactant lamellae around bubbles, the bilayers within vesicles contain surfactant chains in a solidlike state yielding indestructible aggregates that jam the aqueous films between bubbles, reducing the drainage rate and both bubble coalescence and gas-transfer between bubbles. In mixtures of particles and surfactant, the adsorption of SSL monomers occurs on particle surfaces, leading to an increase in their hydrophobicity, promoting particle adsorption to bubble surfaces. Ultrastable foams result with half-lives of around an order of magnitude higher again at low concentrations and foams which lose only around 30% of their volume within a year at high concentrations. In the latter case, we evidence a high surface density of discrete surfactant-coated particles at bubble surfaces, rendering them stable to coalescence and disproportionation. PMID- 25734772 TI - A household-based study of contact networks relevant for the spread of infectious diseases in the highlands of Peru. AB - BACKGROUND: Few studies have quantified social mixing in remote rural areas of developing countries, where the burden of infectious diseases is usually the highest. Understanding social mixing patterns in those settings is crucial to inform the implementation of strategies for disease prevention and control. We characterized contact and social mixing patterns in rural communities of the Peruvian highlands. METHODS AND FINDINGS: This cross-sectional study was nested in a large prospective household-based study of respiratory infections conducted in the province of San Marcos, Cajamarca-Peru. Members of study households were interviewed using a structured questionnaire of social contacts (conversation or physical interaction) experienced during the last 24 hours. We identified 9015 reported contacts from 588 study household members. The median age of respondents was 17 years (interquartile range [IQR] 4-34 years). The median number of reported contacts was 12 (IQR 8-20) whereas the median number of physical (i.e. skin-to-skin) contacts was 8.5 (IQR 5-14). Study participants had contacts mostly with people of similar age, and with their offspring or parents. The number of reported contacts was mainly determined by the participants' age, household size and occupation. School-aged children had more contacts than other age groups. Within-household reciprocity of contacts reporting declined with household size (range 70%-100%). Ninety percent of household contact networks were complete, and furthermore, household members' contacts with non-household members showed significant overlap (range 33%-86%), indicating a high degree of contact clustering. A two-level mixing epidemic model was simulated to compare within household mixing based on observed contact networks and within-household random mixing. No differences in the size or duration of the simulated epidemics were revealed. CONCLUSION: This study of rural low-density communities in the highlands of Peru suggests contact patterns are highly assortative. Study findings support the use of within-household homogenous mixing assumptions for epidemic modeling in this setting. PMID- 25734774 TI - Smooth muscle-like tissue constructs with circumferentially oriented cells formed by the cell fiber technology. AB - The proper functioning of many organs and tissues containing smooth muscles greatly depends on the intricate organization of the smooth muscle cells oriented in appropriate directions. Consequently controlling the cellular orientation in three-dimensional (3D) cellular constructs is an important issue in engineering tissues of smooth muscles. However, the ability to precisely control the cellular orientation at the microscale cannot be achieved by various commonly used 3D tissue engineering building blocks such as spheroids. This paper presents the formation of coiled spring-shaped 3D cellular constructs containing circumferentially oriented smooth muscle-like cells differentiated from dedifferentiated fat (DFAT) cells. By using the cell fiber technology, DFAT cells suspended in a mixture of extracellular proteins possessing an optimized stiffness were encapsulated in the core region of alginate shell microfibers and uniformly aligned to the longitudinal direction. Upon differentiation induction to the smooth muscle lineage, DFAT cell fibers self-assembled to coiled spring structures where the cells became circumferentially oriented. By changing the initial core-shell microfiber diameter, we demonstrated that the spring pitch and diameter could be controlled. 21 days after differentiation induction, the cell fibers contained high percentages of ASMA-positive and calponin-positive cells. Our technology to create these smooth muscle-like spring constructs enabled precise control of cellular alignment and orientation in 3D. These constructs can further serve as tissue engineering building blocks for larger organs and cellular implants used in clinical treatments. PMID- 25734775 TI - Role of Bmi-1 in regulation of ionizing irradiation-induced epithelial mesenchymal transition and migration of breast cancer cells. AB - Radiotherapy is a widely used treatment for cancer. However, recent studies suggest that ionizing radiation (IR) can promote tumor invasion and metastasis. Bmi-1, a member of the polycomb group protein family, has been observed as a regulator of oxidative stress and promotes metastasis in some tumors. But, its potential role in the metastasis induced by IR of breast cancer has not been explored. In our study, we found that increased levels of Bmi-1 were correlated to EMT of breast cancer cells. Through analyzing the EMT state and metastasis of breast cancer induced by IR, we found the metastatic potential of breast cancer cells can either be inhibited or accelerated by IR following a time-dependent pattern. Silencing Bmi-1 completely abolished the ability of the IR to alter, reduce or increase, the migration of breast cancer cells. Also, when Bmi-1 was knocked down, the effect of inhibition of PI3K/AKT signaling on EMT affected by IR was blocked. These results suggest that Bmi-1 is a key gene in regulation of EMT and migration of breast cancer cells induced by IR through activation of PI3K/AKT signaling; therefore, Bmi-1 could be a new target for inhibiting metastasis caused by IR. PMID- 25734777 TI - Clinical Relevance of Foam Rolling on Hip Extension Angle in a Functional Lunge Position. AB - The objective of this study was to examine the duration of effectiveness of foam rolling on hip extension angles in a dynamic lunge position. Thirty-one subjects were assigned to control (n = 15) or intervention (n = 16) group. All the subjects followed the same testing timeline; 3 testing sessions, with 2 lunges in each session. The intervention group performed foam rolling between each lunge in sessions 1 and 2, and 5 times in 7 days between sessions 1 and 2. They did not foam roll during the week between sessions 2 and 3 or in session 3. The control group did not foam roll at all. Hip extension angles were recorded using Dartfish software and subjects filled out a global perceived effect scale rating the feeling of the second lunge and the intervention for each session. A 6 * 2 mixed effects analysis of variance was run with post hoc t-tests revealing significant gains in hip extension within session 2 for the intervention group (p <= 0.05). Hip extension angles returned to baseline values after subject's ceased foam rolling for 1 week. Global perceived effect scores were higher for the intervention group and 29 of 32 words of descriptive feedback included positive words regarding foam rolling. We concluded that consistent foam rolling produced increases in hip extension during a dynamic lunge, but these effects are not seen within the first exposure. Foam rolling received positive reception and perceived improvements in hip extension. The findings indicate that repeated foam rolling is beneficial, both objectively and subjectively, for increasing range of motion immediately preceding a dynamic activity. PMID- 25734776 TI - Ectopic expression of vaccinia virus E3 and K3 cannot rescue ectromelia virus replication in rabbit RK13 cells. AB - As a group, poxviruses have been shown to infect a wide variety of animal species. However, there is individual variability in the range of species able to be productively infected. In this study, we observed that ectromelia virus (ECTV) does not replicate efficiently in cultured rabbit RK13 cells. Conversely, vaccinia virus (VACV) replicates well in these cells. Upon infection of RK13 cells, the replication cycle of ECTV is abortive in nature, resulting in a greatly reduced ability to spread among cells in culture. We observed ample levels of early gene expression but reduced detection of virus factories and severely blunted production of enveloped virus at the cell surface. This work focused on two important host range genes, named E3L and K3L, in VACV. Both VACV and ECTV express a functional protein product from the E3L gene, but only VACV contains an intact K3L gene. To better understand the discrepancy in replication capacity of these viruses, we examined the ability of ECTV to replicate in wild type RK13 cells compared to cells that constitutively express E3 and K3 from VACV. The role these proteins play in the ability of VACV to replicate in RK13 cells was also analyzed to determine their individual contribution to viral replication and PKR activation. Since E3L and K3L are two relevant host range genes, we hypothesized that expression of one or both of them may have a positive impact on the ability of ECTV to replicate in RK13 cells. Using various methods to assess virus growth, we did not detect any significant differences with respect to the replication of ECTV between wild-type RK13 compared to versions of this cell line that stably expressed VACV E3 alone or in combination with K3. Therefore, there remain unanswered questions related to the factors that limit the host range of ECTV. PMID- 25734778 TI - Mouth Rinsing With Carbohydrate Solutions at the Postprandial State Fail to Improve Performance During Simulated Cycling Time Trials. AB - Mouth rinsing with carbohydrate (CHO) solutions during cycling time trials results in performance enhancements; however, most studies have used approximately 6% CHO solutions. Therefore, the purpose of this study was to compare the effectiveness of mouth rinsing with 4, 6, and 8% CHO solutions on 1 hour simulated cycling time trial performance. On 4 occasions, 7 trained male cyclists completed at the postprandial period, a set amount of work as fast as possible in a randomized counterbalanced order. The subjects rinsed their mouth for 5 seconds, on completion of each 12.5% of the trial, with 25 ml of a non-CHO placebo and 4, 6, and 8% CHO solutions. No additional fluids were consumed during the time trial. Heart rate (HR), ratings of perceived exertion (RPE), thirst (TH), and subjective feelings (SF) were recorded after each rinse. Furthermore, blood samples were drawn every 25% of the trial to measure blood glucose and blood lactate concentrations, whereas whole-body CHO oxidation was monitored continuously. Time to completion was not significant between conditions with the placebo, 4, 6, and 8% conditions completing the trials in 62.0 +/- 3.0, 62.8 +/- 4.0, 63.4 +/- 3.4, and 63 +/- 4.0 minutes, respectively. There were no significant differences between conditions in any of the variables mentioned above; however, significant time effects were observed for HR, RPE, TH, and SF. Post hoc analysis showed that TH and SF of subjects in the CHO conditions but not in the placebo were significantly increased by completion of the time trial. In conclusion, mouth rinsing with CHO solutions did not impact 1-hour cycling performance in the postprandial period and in the absence of fluid intake. Our findings suggest that there is scope for further research to explore the activation regions of the brain and whether they are receptive to CHO dose, before specific recommendations for athletic populations are established. Consequently, mouth rinsing as a practical strategy for coaches and athletes is questionable under specific conditions and should be carefully considered before its inclusion. Emphasis should be focused on appropriate dietary and fluid strategies during training and competition. PMID- 25734779 TI - Mechanical Determinants of Faster Change of Direction and Agility Performance in Female Basketball Athletes. AB - Change of direction (COD) and agility require the integration of multiple components to produce a faster performance. However, the mechanisms contributing to a faster performance without the confounding factor of athlete expertise or gender is currently unknown. Therefore, the purpose of this study was to assess body composition, strength, and kinetic profile required for a faster COD and agility performance across multiple directional changes. Six faster and 6 slower (n = 12) elite female basketball athletes completed a maximal dynamic back squat; eccentric and concentric only back squat; isometric midthigh pull; whole-body scan to determine lean, fat, and total mass; 505 COD test; T-test; and a multidirectional agility test over in-ground force plates to obtain relevant kinetic measures. Group (faster and slower) by test (2 * 3) multivariate analyses of variance with follow-up analyses of variance were conducted to examine differences between faster and slower groups and each COD and agility test (p <= 0.05). Faster athletes during the 505 COD test produced significantly greater vertical force (p = 0.002) and eccentric and isometric strength capacity (p = 0.001). Faster agility and T-test athletes demonstrated significantly shorter contact times (p = 0.001), greater propulsive impulse (p = 0.02), isometric strength, and relative lean mass compared with slower athletes. Differences between faster athletes across each test seem to be attributed to the mechanical demands of the directional change, increasing force and impulse application as the degree of directional change increased. These findings indicate that different mechanical properties are required to produce a faster COD and agility performances, and the importance of a greater strength capacity to enable greater mechanical adjustment through force production and body control, during different directional changes. PMID- 25734780 TI - Anthropometric and Somatotype Characteristics of Young Soccer Players: Differences Among Categories, Subcategories, and Playing Position. AB - Considering that anthropometric parameters are important factors in the performance of the soccer players, the aim of this study was to explore the differences in anthropometric and somatotype characteristics of Italian young soccer players. Weight, height, body mass index, and somatotype of 112 young soccer players, grouped in Giovanissimi "A" (14 years), "B" (13 years), and "C" (12 years) as well as Allievi "B" (15 years) and "A" (16 years) and "Juniores" (older than 17 years), were evaluated. Statistical analysis tests were computed at p <= 0.05, and an analysis of variance for each somatotype was calculated to analyze the main effects and interactions of the factors: categories, subcategories, and playing position. Bonferroni's post hoc analysis was used to identify differences among mean values. Considering all subjects, we have found significant differences in categories, subcategories, and playing position between anthropometric values and a somatotype value of 2.8-3.8-2.9. Significant differences have found among goalkeepers and the others playing position in endomorphy (p <= 0.001) and with defenders and midfielders in ectomorphy (p < 0.01) components, whereas no differences in mesomorphy. Analyzing the interaction between subcategories and playing position factors, a significant effect was found only in the endomorphy component (p = 0.05). The analysis of anthropometric characteristic of Italian young soccer players indicates that players have high muscularity value and low adiposity. This study showed the presence of somatotype differences for playing position within categories also in the youngest categories and subcategories, in particular, in the endomorphy component. Young soccer players should be trained with more appropriate and specific training load to avoid the increased injury risk during adolescence. PMID- 25734781 TI - Does Testosterone Modulate Mood States and Physical Performance in Young Basketball Players? AB - This study aimed to examine and compare mood states profile and physical performance during different training phases between 2 groups of adolescent basketball players that were differentiated according to baseline testosterone concentration (T). The basketball players were submitted to an intensified training period (OVL) followed by a tapering period (TP). Twenty-three young male basketball players initiated the study. Experimental criteria data were used to stratify 16 players into high-testosterone (HTC) or low-testosterone (LTC) concentration groups. All the 16 athletes undertook 5 weeks of OVL followed by a 3-week TP. Saliva sampling, Yo-Yo intermittent recovery level 1 (Yo-Yo IRL1) test and the T-test were conducted at the beginning (T1), after OVL (T2), and after TP (T3). A similar increase in internal training load was observed during OVL when compared with TP in both groups (p < 0.05). No difference in mood states was observed between groups (p > 0.05); however, LTC displayed a higher score for fatigue (p < 0.05) and a lower score for energy index (p < 0.05) in OVL, compared with TP. A significant improvement in the Yo-Yo IRL1 test and the T-test was observed (T1 to T3) (p < 0.05), with no difference between groups (p > 0.05). In conclusion, these results suggest that LTC athletes may be more susceptible to changes in mood states during intensified training periods. In addition, data indicate that a periodized training program successfully improved the physical performance (endurance and agility) of young basketball players; however, this improvement was not affected by testosterone level. PMID- 25734782 TI - Relationship Between ACTN3 R577X Polymorphism and Physical Abilities in Polish Athletes. AB - The purpose of this study was to examine the association between alpha-actinin 3 (ACTN3) R577X polymorphism and physical abilities of male athletes performing various sports (volleyball, ice hockey, canoeing, swimming). One hundred eighty five subjects were recruited for the study. The following measurements were taken: height of jump and power output in countermovement jump and spike jump (SPJ) and muscle strength of 10 muscle groups. The R577X polymorphism of ACTN3 was typed using polymerase chain reaction restriction fragment length polymorphism. The results showed that RR genotype carriers develop greater power output in SPJ than RX and XX individuals (44.6 +/- 11.1, 42.6 +/- 11.0, and 38.4 +/- 7.9 W.kg(-1) for RR, RX, and XX genotypes, respectively) and height of jump in SPJ (0.537 +/- 0.075, 0.523 +/- 0.072, and 0.498 +/- 0.053 m for RR, RX, and XX genotypes, respectively). Muscle strength did not differ between genotype groups. This suggests that the ACTN3 gene has a greater impact on determining dynamic movements than influencing static muscle strength. PMID- 25734783 TI - Acute Myosin Heavy Chain Isoform mRNA Expression in Response to Two Resistance Exercise Intensities With Equal Volume Load in Resistance-Trained Men. AB - The purpose of this study was to determine if resistance exercise intensity, in the context of equal volume load, differentially affected myosin heavy chain (MHC) isoform messenger RNA (mRNA) expression in resistance-trained men. In a crossover, uniform-balanced design, 10 male participants (23.7 +/- 2.8 years, 178.8 +/- 5.9 cm, 85.9 +/- 9.2 kg) completed 2 lower-body resistance exercise sessions of different intensities with equal volume load. For the higher intensity exercise session, participants performed 5 sets of 6 repetitions at 80% of 1 repetition maximum (1RM). For the lower-intensity exercise session, participants performed 3 sets of 16 repetitions at 50% of 1RM. Muscle samples from the vastus lateralis were acquired before exercise (PRE), 45 minutes postexercise (45MINPE), 3 hours postexercise (3HRPE), 24 hours postexercise (24HRPE), and 48 hours postexercise (48HRPE). Statistical analyses of mRNA expression were performed using separate 2 * 5 two-way repeated-measures analyses of variance for each criterion variable (p <= 0.05). There were no statistically significant interactions between intensity and time. Likewise, there were no significant differences between exercise intensity in MHC expression. Expression of mRNA for all MHC isoforms decreased at all postexercise time points, except 3HRPE (p = 0.051), compared with PRE following both exercise bouts (p <= 0.05). The results of this study found no difference in mRNA expression of MHC isoforms as a function of resistance exercise intensity. In addition, in contrast to results found in previous studies of untrained men, MHC mRNA expression seems to decrease in response to acute resistance exercise in previously resistance trained men. PMID- 25734784 TI - Pre- and Post-Activity Stretching Practices of Collegiate Athletic Trainers in the United States. AB - Popp, JK, Bellar, DM, Hoover, DL, Craig, BW, Leitzelar, BN, Wanless, EA, and Judge, LW. Pre- and post-activity stretching practices of collegiate athletic trainers in the United States. J Strength Cond Res 31(9): 2347-2354, 2017-The aim of the study was to investigate the knowledge and practices of collegiate certified athletic trainers (ATs) in the United States. Participants (n = 521) were provided an overview of the study and a hyperlink to a web-based survey. The "pre- and post-activity practices in athletic training questionnaire" consisted of demographic items and elements to measure knowledge and practices related to pre- and post-activity stretching routines. In previous studies, the survey demonstrated construct validity, alpha = 0.722. Pearson chi-square test was used to evaluate goodness of fit, and kappa was calculated to measure agreement between items. Only 32.2% of ATs recommended dynamic stretching (DS) to be performed pre-activity, whereas a larger percentage (42.2%) recommended a combination of static stretching (SS) and DS. Athletic trainers reported that only 28.0% of athletes are performing DS before activity. Conversely, 60.6% of collegiate ATs recommended SS postexercise, and 61.0% of athletes agree and perform after workout SS (kappa = 0.761, p < 0.001). Collegiate ATs seem to underuse the current research evidence, which indicates that DS is more beneficial than SS when used pre-activity, and ATs continue to regularly incorporate SS in their pre-activity routines. However, there is evidence that collegiate ATs in the United States emphasize SS postactivity in a manner consistent with current research. PMID- 25734785 TI - An optical method for serum calcium and phosphorus level assessment during hemodialysis. AB - Survival among hemodialysis patients is disturbingly low, partly because vascular calcification (VC) and cardiovascular disease are highly prevalent. Elevated serum phosphorus (P) and calcium (Ca) levels play an essential role in the formation of VC events. The purpose of the current study was to reveal optical monitoring possibilities of serum P and Ca values during dialysis. Twenty-eight patients from Tallinn (Estonia) and Linkoping (Sweden) were included in the study. The serum levels of Ca and P on the basis of optical information, i.e., absorbance and fluorescence of the spent dialysate (optical method) were assessed. Obtained levels were compared in means and SD. The mean serum level of Ca was 2.54 +/- 0.21 and 2.53 +/- 0.19 mmol/L; P levels varied between 1.08 +/- 0.51 and 1.08 +/- 0.48 mmol/L, measured in the laboratory and estimated by the optical method respectively. The levels achieved were not significantly different (p = 0.5). The Bland-Altman 95% limits of agreement between the two methods varied from -0.19 to 0.19 for Ca and from -0.37 to 0.37 in the case of P. In conclusion, optical monitoring of the spent dialysate for assessing the serum levels of Ca and P during dialysis seems to be feasible and could offer valuable and continuous information to medical staff. PMID- 25734786 TI - A survey demonstrating lack of consensus on the sequence of medications for treatment of hyperkalemia among pediatric critical care providers. AB - OBJECTIVE: Hyperkalemia is one of the reversible causes of cardiac arrest in children. The Advanced Cardiovascular Life Support guidelines have specific recommendations on the choice and sequence of medications for treatment of life threatening hyperkalemia. However, the Pediatric Advanced Life Support guidelines have no specific treatment recommendations. The objective of this study was to measure the extent to which opinions diverge among pediatricians on the choice and sequence of medication administration in the management of hyperkalemia during cardiac arrest. DESIGN: Scenario-based survey. SETTING: A hypothetical hospital area covered by the pediatric rapid response team. PATIENTS: A hypothetical scenario of a 7-year old child receiving a blood transfusion who is suddenly unresponsive and found to be in pulseless ventricular tachycardia with stat labs revealing a potassium level of 8.3. INTERVENTIONS: A scenario-based survey of PICU fellows and attendings at a PICU Fellows Boot Camp. MEASUREMENT AND MAIN RESULTS: Eighty-four fellows and 24 attendings responded to the survey. The response rate was 89%. Calcium was chosen most frequently as the first drug to be administered (calcium chloride, 40/115 [34.8%]; calcium gluconate, 62/115 [53.9%]) while 38 of 115 respondents (33%) chose a drug other than calcium. Only 17 of 115 respondents (15%) would use calcium, sodium bicarbonate, insulin, and dextrose in the advanced cardiovascular life support-recommended sequence. PICU attendings were significantly more likely to administer the advanced cardiovascular life support-recommended sequence than fellows (attendings, 8/24 [33%] vs fellows, 9/84 [11%]; p = 0.007). CONCLUSION: This survey revealed notable variability in the choice and sequence of medications for treatment of life-threatening hyperkalemia with surprisingly few participants in compliance with the advanced cardiovascular life support hyperkalemia guidelines. A standardized approach for pediatric life-threatening hyperkalemia is recommended to improve resuscitation quality. PMID- 25734787 TI - Lanthanum-mediated C-H bond activation of propyne and identification of La(C3H2) isomers. AB - eta(2)-Propadienylidenelanthanum [La(eta(2)-CCCH2)] and deprotiolanthanacyclobutadiene [La(HCCCH)] of La(C3H2) are identified from the reaction mixture of neutral La atom activation of propyne in the gas phase. The two isomers are characterized with mass-analyzed threshold ionization spectroscopy combined with electronic structure calculations and spectral simulations. La(eta(2)-CCCH2) and La(HCCCH) are formed by concerted 1,3- and 3,3 dehydrogenation, respectively. Both isomers prefer a doublet ground state with a La 6s-based unpaired electron, and La(eta(2)-CCCH2) is slightly more stable than La(HCCCH). Ionization of the neutral doublet state of either isomer produces a singlet ion state by removing the La-based electron. The geometry change upon ionization results in the excitation of a symmetric metal-hydrocarbon stretching mode in the ionic state, whereas thermal excitation leads to the observation of the same stretching mode in the neutral state. Although the La atom is in a formal oxidation state of +2, the ionization energies of these metal-hydrocarbon radicals are lower than that of the neutral La atom. Deuteration has a very small effect on the ionization energies of the two isomers and the metal-hydrocarbon stretching mode of La(eta(2)-CCCH2), but it reduces considerably the metal-ligand stretching frequencies of La(HCCCH). PMID- 25734788 TI - TNFalpha transport induced by dynamic loading alters biomechanics of intact intervertebral discs. AB - OBJECTIVE: Intervertebral disc (IVD) degeneration is an important contributor to the development of back pain, and a key factor relating pain and degeneration are the presence of pro-inflammatory cytokines and IVD motion. There is surprisingly limited understanding of how mechanics and inflammation interact in the IVD. This study investigated interactions between mechanical loading and pro-inflammatory cytokines in a large animal organ culture model to address fundamental questions regarding (i.) how inflammatory mediators arise within the IVD, (ii.) how long inflammatory mediators persist, and (iii.) how inflammatory mediators influence IVD biomechanics. METHODS: Bovine caudal IVDs were cultured for 6 or 20-days under static & dynamic loading with or without exogenous TNFalpha in the culture medium, simulating a consequence of inflammation of the surrounding spinal tissues. TNFalpha transport within the IVD was assessed via immunohistochemistry. Changes in IVD structural integrity (dimensions, histology & aggrecan degradation), biomechanical behavior (Creep, Recovery & Dynamic stiffness) and pro-inflammatory cytokines in the culture medium (ELISA) were assessed. RESULTS: TNFalpha was able to penetrate intact IVDs when subjected to dynamic loading but not static loading. Once transported within the IVD, pro-inflammatory mediators persisted for 4-8 days after TNFalpha removal. TNFalpha exposure induced changes in IVD biomechanics (reduced diurnal displacements & increased dynamic stiffness). DISCUSSION: This study demonstrated that exposure to TNFalpha, as might occur from injured surrounding tissues, can penetrate healthy intact IVDs, induce expression of additional pro-inflammatory cytokines and alter IVD mechanical behavior. We conclude that exposure to pro-inflammatory cytokine may be an initiating event in the progression of IVD degeneration in addition to being a consequence of disease. PMID- 25734789 TI - The Gold Standard Program for smoking cessation is effective for participants over 60 years of age. AB - BACKGROUND: Tobacco smoking is more prevalent among the elderly than among the young, and the elderly also have the most frequent contact with the health care system. The aim of this study was to evaluate the effectiveness of the Gold Standard Program, which is an intensive six-week smoking cessation program, on continuous self-reported abstinence rates after six months, on participants over the age of 60 years in a real life setting. METHODS: This was a retrospective cohort study from the national Danish smoking cessation database. RESULTS: The database registered 7369 participants over the age of 60 years (range 60-82) and 24,294 below 60 years (range 15-59). Continuous abstinence rate after six months was 37% for the elderly compared to 35% for the younger (p<0.05). The significant variables for continuous abstinence were: living with another adult (OR 1.10), prior professional recommendation for smoking cessation (OR 1.12), being compliant with program (OR 1.35) and being abstinent at end of course (OR 13.3). CONCLUSIONS: Participants over the age of 60 years had significantly higher continuous abstinence rates after six months than the participants less than 60 years. It is never too late for health professionals to recommend and educate patients about smoking cessation programs even if they are over 60 years of age. PMID- 25734790 TI - Pit latrine emptying behavior and demand for sanitation services in Dar Es Salaam, Tanzania. AB - Pit latrines are the main form of sanitation in unplanned areas in many rapidly growing developing cities. Understanding demand for pit latrine fecal sludge management (FSM) services in these communities is important for designing demand responsive sanitation services and policies to improve public health. We examine latrine emptying knowledge, attitudes, behavior, trends and rates of safe/unsafe emptying, and measure demand for a new hygienic latrine emptying service in unplanned communities in Dar Es Salaam (Dar), Tanzania, using data from a cross sectional survey at 662 residential properties in 35 unplanned sub-wards across Dar, where 97% had pit latrines. A picture emerges of expensive and poor FSM service options for latrine owners, resulting in widespread fecal sludge exposure that is likely to increase unless addressed. Households delay emptying as long as possible, use full pits beyond what is safe, face high costs even for unhygienic emptying, and resort to unsafe practices like 'flooding out'. We measured strong interest in and willingness to pay (WTP) for the new pit emptying service at 96% of residences; 57% were WTP>=U.S. $17 to remove >=200 L of sludge. Emerging policy recommendations for safe FSM in unplanned urban communities in Dar and elsewhere are discussed. PMID- 25734791 TI - Rationally modified estrogen receptor protein as a bio-recognition element for the detection of EDC pollutants: strategies and opportunities. AB - The estrogen receptor protein (ER) can bind a vast number of organic pollutants widely spread in the environment and collectively known as Endocrine Disrupting Chemicals, EDCs. Its broad selectivity makes it an ideal bio-recognition element for the detection of EDCs. Here we describe the strategy and rationale for the design of ER based biosensors and assays that generate a signal in the presence of EDCs. The opportunity to use either natural or rationally modified ER molecules is discussed. The latter approach was successfully applied in the EU FP7 project RADAR, with the aim to develop a novel biosensor for the detection of organic pollutants both in the environment and in commercial water products. PMID- 25734792 TI - Effects of weather and heliophysical conditions on emergency ambulance calls for elevated arterial blood pressure. AB - We hypothesized that weather and space weather conditions were associated with the exacerbation of essential hypertension. The study was conducted during 2009 2010 in the city of Kaunas, Lithuania. We analyzed 13,475 cards from emergency ambulance calls (EACs), in which the conditions for the emergency calls were made coded I.10-I.15. The Kaunas Weather Station provided daily records of air temperature (T), wind speed (WS), relative humidity, and barometric pressure (BP). We evaluated the associations between daily weather variables and daily number of EACs by applying a multivariate Poisson regression. Unfavorable heliophysical conditions (two days after the active-stormy geomagnetic field or the days with solar WS>600 km/s) increased the daily number of elevated arterial blood pressure (EABP) by 12% (RR=1.12; 95% confidence interval (CI) 1.04-1.21); and WS>=3.5 knots during days of T<1.5 degrees C and T>=12.5 degrees C by 8% (RR=1.08; CI 1.04-1.12). An increase of T by 10 degrees C and an elevation of BP two days after by 10 hPa were associated with a decrease in RR by 3%. An additional effect of T was detected during days of T>=17.5 degrees C only in females. Women and patients with grade III arterial hypertension at the time of the ambulance call were more sensitive to weather conditions. These results may help in the understanding of the population's sensitivity to different weather conditions. PMID- 25734793 TI - Impact of a small cell on the RF-EMF exposure in a train. AB - The deployment of a miniature mobile-phone base station or small cell in a train car significantly improves the coverage and the capacity of a mobile network service on the train. However, the impact of the small cell on the passengers' exposure to radio-frequency electromagnetic fields (RF-EMF) is unknown. In this study, we assessed experimentally the RF-EMF exposure of a mobile-phone user who is either connected to the outdoor macrocell network or to an in-train small cell, while traveling on the train, by means of the absorbed-dose concept, which combines the base station downlink exposure with the mobile-phone uplink exposure. For Global System for Mobile Communications (GSM) technology at 1800 MHz, we found that by connecting to a small cell, the brain exposure of the user could realistically be reduced by a factor 35 and the whole-body exposure by a factor 11. PMID- 25734794 TI - Can integrated watershed management contribute to improvement of public health? A cross-sectional study from hilly tribal villages in India. AB - Tribal people living in hilly areas suffer from water scarcity in many parts of the world, including India. Water scarcity adversely impacts all aspects of life, including public health. Implementation of an Integrated Watershed Management Programme (IWMP) can help solve the problems arising out of water scarcity in such areas. However, the knowledge about and views of the water scarcity sufferers on the public health implications of IWMP have not been well documented. This cross-sectional study was performed in six purposively selected tribal villages located in Maharashtra, India. In three of the villages IWMP had been implemented (IWMV), but not in the other three (NWMV). The head of each household in all villages was interviewed using a questionnaire covering various public health aspects relevant to the villages. A total of 286/313 (92%) households participated in the study. Compared to NWMV, respondents in IWMV experienced significantly lesser prolonged water scarcity (OR=0.39), had greater number of toilets (OR=6.95), cultivated more variety of crops (OR=2.61), had lower migration (OR=0.59), higher number of girls continuing education (OR=3.04) and better utilized modern healthcare facilities in the antenatal, natal and postnatal period (OR=3.75, 2.57, 4.88 respectively). Thus, tribal people in IWMP implemented villages reported advantages in many aspects of public health. PMID- 25734795 TI - Comment on "Methane emissions from process equipment at natural gas production sites in the United States: pneumatic controllers". PMID- 25734796 TI - Pencil-beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity-modulated radiotherapy. AB - BACKGROUND: Concurrent chemoradiotherapy cures most patients with anal squamous cell carcinoma at the cost of significant treatment-related toxicities. Intensity modulated radiotherapy (IMRT) reduces side effects compared to older techniques, but whether proton beam therapy (PBT) offers additional advantages is unclear. MATERIAL AND METHODS: Eight patients treated with PBT for anal cancer were chosen for this study. We conducted detailed plan comparisons between pencil-beam scanning PBT via two posterior oblique fields and seven-field IMRT. Cumulative dose-volume histograms were analyzed by Wilcoxon signed-rank test, and plan delivery robustness was assessed via verification computed tomography (CT) scans obtained during treatment. RESULTS: Compared to IMRT, PBT reduced low dose radiation (<= 30 Gy) to the small bowel, total pelvic bone marrow, external genitalia, femoral heads, and bladder (all p < 0.05) without compromising target coverage. For PBT versus IMRT, mean small bowel volume receiving >= 15 Gy (V15) was 81 versus 151 cm(3), mean external genitalia V20 was 14 versus 40%, and mean total pelvic bone marrow V15 was 66 versus 83% (all p = 0.008). The lumbosacral bone marrow dose was higher with PBT due to beam geometry. PBT was delivered with <= 1.3% interfraction deviation in the dose received by 98% of the clinical target volumes. CONCLUSION: Pencil-beam scanning PBT is clinically feasible and can be robustly delivered for anal cancer patients. Compared with IMRT, PBT reduces low dose radiation to important organs at risk in this population. While the clinical benefit of these differences remains to be shown, existing data suggest that limiting low dose to the small bowel and pelvic bone marrow may reduce treatment toxicity. PMID- 25734797 TI - Voltage-controlled ferroelastic switching in Pb(Zr0.2Ti0.8)O3 thin films. AB - We report a voltage controlled reversible creation and annihilation of a-axis oriented ~10 nm wide ferroelastic nanodomains without a concurrent ferroelectric 180 degrees switching of the surrounding c-domain matrix in archetypal ferroelectric Pb(Zr0.2Ti0.8)O3 thin films by using the piezo-response force microscopy technique. In previous studies, the coupled nature of ferroelectric switching and ferroelastic rotation has made it difficult to differentiate the underlying physics of ferroelastic domain wall movement. Our observation of distinct thresholds for ferroelectric and ferroelastic switching allows us investigate the ferroelastic switching cleanly and demonstrate a new degree of nanoscale control over the ferroelastic domains. PMID- 25734798 TI - Structural and functional investigation of flavin binding center of the NqrC subunit of sodium-translocating NADH:quinone oxidoreductase from Vibrio harveyi. AB - Na+-translocating NADH:quinone oxidoreductase (NQR) is a redox-driven sodium pump operating in the respiratory chain of various bacteria, including pathogenic species. The enzyme has a unique set of redox active prosthetic groups, which includes two covalently bound flavin mononucleotide (FMN) residues attached to threonine residues in subunits NqrB and NqrC. The reason of FMN covalent bonding in the subunits has not been established yet. In the current work, binding of free FMN to the apo-form of NqrC from Vibrio harveyi was studied showing very low affinity of NqrC to FMN in the absence of its covalent bonding. To study structural aspects of flavin binding in NqrC, its holo-form was crystallized and its 3D structure was solved at 1.56 A resolution. It was found that the isoalloxazine moiety of the FMN residue is buried in a hydrophobic cavity and that its pyrimidine ring is squeezed between hydrophobic amino acid residues while its benzene ring is extended from the protein surroundings. This structure of the flavin-binding pocket appears to provide flexibility of the benzene ring, which can help the FMN residue to take the bended conformation and thus to stabilize the one-electron reduced form of the prosthetic group. These properties may also lead to relatively weak noncovalent binding of the flavin. This fact along with periplasmic location of the FMN-binding domains in the vast majority of NqrC-like proteins may explain the necessity of the covalent bonding of this prosthetic group to prevent its loss to the external medium. PMID- 25734799 TI - Proteomic detection of immunoglobulin light chain variable region peptides from amyloidosis patient biopsies. AB - Immunoglobulin light chain (LC) amyloidosis (AL) is caused by deposition of clonal LCs produced by an underlying plasma cell neoplasm. The clonotypic LC sequences are unique to each patient, and they cannot be reliably detected by either immunoassays or standard proteomic workflows that target the constant regions of LCs. We addressed this issue by developing a novel sequence template based workflow to detect LC variable (LCV) region peptides directly from AL amyloid deposits. The workflow was implemented in a CAP/CLIA compliant clinical laboratory dedicated to proteomic subtyping of amyloid deposits extracted from either formalin-fixed paraffin-embedded tissues or subcutaneous fat aspirates. We evaluated the performance of the workflow on a validation cohort of 30 AL patients, whose amyloidogenic clone was identified using a novel proteogenomics method, and 30 controls. The recall and negative predictive values of the workflow, when identifying the gene family of the AL clone, were 93 and 98%, respectively. Application of the workflow on a clinical cohort of 500 AL amyloidosis samples highlighted a bias in the LCV gene families used by the AL clones. We also detected similarity between AL clones deposited in multiple organs of systemic AL patients. In summary, AL proteomic data sets are rich in LCV region peptides of potential clinical significance that are recoverable with advanced bioinformatics. PMID- 25734800 TI - Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. AB - OBJECTIVE: Determine whether MS-specific DNA methylation profiles can be identified in whole blood or purified immune cells from untreated MS patients. METHODS: Whole blood, CD4+ and CD8+ T cell DNA from 16 female, treatment naive MS patients and 14 matched controls was profiled using the HumanMethylation450K BeadChip. Genotype data were used to assess genetic homogeneity of our sample and to exclude potential SNP-induced DNA methylation measurement errors. RESULTS: As expected, significant differences between CD4+ T cells, CD8+ T cells and whole blood DNA methylation profiles were observed, regardless of disease status. Strong evidence for hypermethylation of CD8+ T cell, but not CD4+ T cell or whole blood DNA in MS patients compared to controls was observed. Genome-wide significant individual CpG-site DNA methylation differences were not identified. Furthermore, significant differences in gene DNA methylation of 148 established MS-associated risk genes were not observed. CONCLUSION: While genome-wide significant DNA methylation differences were not detected for individual CpG sites, strong evidence for DNA hypermethylation of CD8+ T cells for MS patients was observed, indicating a role for DNA methylation in MS. Further, our results suggest that large DNA methylation differences for CpG-sites tested here do not contribute to MS susceptibility. In particular, large DNA methylation differences for CpG-sites within 148 established MS candidate genes tested in our study cannot explain missing heritability. Larger studies of homogenous MS patients and matched controls are warranted to further elucidate the impact of CD8+ T cell and more subtle DNA methylation changes in MS development and pathogenesis. PMID- 25734801 TI - Pattern of increasing HbA1c levels in patients with diabetes mellitus before clinical detection of pancreatic cancer - a population-based nationwide case control study. AB - BACKGROUND: Diabetes mellitus is a risk factor for pancreatic cancer. Impaired insulin resistance might precede the clinical detection of this cancer by several years. METHODS: This was a nested case-control population-based study assessing the pattern of glycated hemoglobin (HbA1c) change before clinical detection of pancreatic cancer in a population of individuals with diabetes mellitus. All patients registered in the Swedish National Diabetes Register with a prescription of an anti-diabetic drug between 2005 and 2011 were identified. For each case of pancreatic cancer, 10 controls were randomly selected, matched for age, sex, and factors related to diabetes mellitus. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between HbA1c and pancreatic cancer. RESULTS: In total, 391 cases and 3910 matched controls were identified. The risk of pancreatic cancer was increased more than two-fold in individuals with the highest HbA1c quartile compared with the lowest (OR 1.96, 95% CI 1.40-2.75). The risk of pancreatic cancer remained elevated when comparing the highest HbA1c quartile measured within five years from the clinical detection of pancreatic cancer to the lowest HbA1c quartile (p-value for trend < 0.05). No association was found between HbA1c and pancreatic cancer if HbA1c was measured > 5 years before the clinical detection of pancreatic cancer. CONCLUSIONS: The pattern of increasing HbA1c in patients with diabetes mellitus preceded the clinical detection of pancreatic cancer by up to five years. These findings indicate that there is a lead time of several years during which the development of pancreatic cancer might be detectable through screening in patients with diabetes mellitus. PMID- 25734802 TI - Evidence of nanotubular self-organization in solution and solid states of heterochiral cyclo 1:1 [alpha/alpha-N(alpha)-Bn-hydrazino]mers series. AB - The cyclization of heterochiral 1:1 [alpha/alpha-N(alpha)-Bn-hydrazino]mers leads to the corresponding cyclotetramer and cyclohexamer 3 and 4. X-ray crystallographic analysis of 3 unveils its ability to self-assemble into nanotubular structures. Further experiments conducted in the solid state through SEM analyses demonstrate the capability of 3 and 4 to form aerogels consisting of a network of nontwisted fibers, thus confirming the presence of self-organization within this series of mixed-hydrazinopeptides. Subsequent FTIR and NMR studies demonstrate the presence of an equilibrium between monomeric (intramolecular H bonds) and nanotubular (intermolecular H-bonds) forms in solution. This equilibrium can be modified by varying the solvent. PMID- 25734803 TI - Epidermoid metaplasia of the esophagus with an unusual appearance on magnification. PMID- 25734804 TI - Recurrent bladder cancer presenting as rectal linitis plastica. PMID- 25734805 TI - Transgastric endoscopic ultrasound with fine-needle aspiration and ERCP using percutaneous-assisted transprosthetic endoscopic therapy in a gastric bypass patient. PMID- 25734806 TI - Delayed removal of a deeply migrated pigtail pancreatic stent in a normal pancreatic duct. PMID- 25734807 TI - Successful endoscopic ultrasound-guided fine-needle aspiration through a gastroduodenal stent for the diagnosis of recurrent gallbladder carcinoma. PMID- 25734808 TI - Successful endoscopic dilation of severe bilioenteric strictures with a wire guided diathermic dilator and short-type single-balloon enteroscope. PMID- 25734809 TI - Immunoglobulin G4-related disease (IgG4-RD) affecting the esophagus, stomach, and liver. PMID- 25734810 TI - Use of a scissors forceps for the endoscopic removal of a distally migrated self expandable metallic stent adhering to the duodenal mucosa. PMID- 25734811 TI - Conditional Deletion of Kit in Melanocytes: White Spotting Phenotype Is Cell Autonomous. AB - It is well established that cell-intrinsic signaling through the receptor tyrosine kinase KIT is critical for the development of neural crest-derived melanocytes. Nevertheless, it is not entirely clear whether Kit acts exclusively in a melanocyte-autonomous manner or in addition indirectly through other cell types. To address this question in vivo, we generated a targeted allele of Kit that allowed for CRE recombinase-mediated deletion of the transmembrane domain of KIT. Mice carrying one copy of the targeted allele and expressing CRE under the melanoblast/melanocyte-specific tyrosinase promoter exhibited a white spotting phenotype that was even more extensive compared with that found in mice heterozygous for a Kit-null allele. This phenotype is unlikely the result of sequestration of KIT ligand by neighboring cells or by potentially secreted forms of KIT because the spotting phenotype could not be rescued by overexpression of KITL. Likewise, overexpression of endothelin-3 or hepatocyte growth factor was unable to rescue melanocytes in these mice. Although the severity of the observed phenotype remains to be explained, the findings indicate that melanocyte selective impairment of Kit is sufficient to interfere with normal melanocyte development. PMID- 25734812 TI - Loss-of-Function Mutations in the Gene Encoding Filaggrin Are Not Strongly Associated with Chronic Actinic Dermatitis. PMID- 25734813 TI - SIRT1 Activation Ameliorates Aldara-Induced Psoriasiform Phenotype and Histology in Mice. PMID- 25734816 TI - Abstracts from the 2014 Addiction Health Services Research (AHSR) Conference, October 15-17, 2014, Boston, MA. PMID- 25734815 TI - Analysis of CARD14 Polymorphisms in Pityriasis Rubra Pilaris: Activation of NF kappaB. PMID- 25734814 TI - The Characterization of Varicella Zoster Virus-Specific T Cells in Skin and Blood during Aging. AB - Reactivation of the varicella zoster virus (VZV) increases during aging. Although the effects of VZV reactivation are observed in the skin (shingles), the number and functional capacity of cutaneous VZV-specific T cells have not been investigated. The numbers of circulating IFN-gamma-secreting VZV-specific CD4(+) T cells are significantly decreased in old subjects. However, other measures of VZV-specific CD4(+) T cells, including proliferative capacity to VZV antigen stimulation and identification of VZV-specific CD4(+) T cells with an major histocompatibility complex class II tetramer (epitope of IE-63 protein), were similar in both age groups. The majority of T cells in the skin of both age groups expressed CD69, a characteristic of skin-resident T cells. VZV-specific CD4(+) T cells were significantly increased in the skin compared with the blood in young and old subjects, and their function was similar in both age groups. In contrast, the number of Foxp3(+) regulatory T cells and expression of the inhibitory receptor programmed cell death -1 PD-1 on CD4(+) T cells were significantly increased in the skin of older humans. Therefore, VZV-specific CD4(+) T cells in the skin of older individuals are functionally competent. However, their activity may be restricted by multiple inhibitory influences in situ. PMID- 25734819 TI - Foreword. The exponential increase in the development of natural gas. PMID- 25734818 TI - Correlating coating characteristics with the performance of drug-coated balloons- a comparative in vitro investigation of own established hydrogel- and ionic liquid-based coating matrices. AB - Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies. In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty. PMID- 25734817 TI - A combined gene signature of hypoxia and notch pathway in human glioblastoma and its prognostic relevance. AB - Hypoxia is a hallmark of solid tumors including glioblastoma (GBM). Its synergism with Notch signaling promotes progression in different cancers. However, Notch signaling exhibits pleiotropic roles and the existing literature lacks a comprehensive understanding of its perturbations under hypoxia in GBM with respect to all components of the pathway. We identified the key molecular cluster(s) characteristic of the Notch pathway response in hypoxic GBM tumors and gliomaspheres. Expression of Notch and hypoxia genes was evaluated in primary human GBM tissues by q-PCR. Clustering and statistical analyses were applied to identify the combination of hypoxia markers correlated with upregulated Notch pathway components. We found well-segregated tumor-clusters representing high and low HIF-1alpha/PGK1-expressors which accounted for differential expression of Notch signaling genes. In combination, a five-hypoxia marker set (HIF 1alpha/PGK1/VEGF/CA9/OPN) was determined as the best predictor for induction of Notch1/Dll1/Hes1/Hes6/Hey1/Hey2. Similar Notch-axis genes were activated in gliomaspheres, but not monolayer cultures, under moderate/severe hypoxia (2%/0.2% O2). Preliminary evidence suggested inverse correlation between patient survival and increased expression of constituents of the hypoxia-Notch gene signature. Together, our findings delineated the Notch-axis maximally associated with hypoxia in resected GBM, which might be prognostically relevant. Its upregulation in hypoxia-exposed gliomaspheres signify them as a better in-vitro model for studying hypoxia-Notch interactions than monolayer cultures. PMID- 25734820 TI - Current perspectives on unconventional shale gas extraction in the Appalachian Basin. AB - The Appalachian Basin is home to three major shales, the Upper Devonian, Marcellus, and Utica. Together, they contain significant quantities of tight oil, gas, and mixed hydrocarbons. The Marcellus alone is estimated to contain upwards of 500 trillion cubic feet of natural gas. The extraction of these deposits is facilitated by a combination of horizontal drilling and slick water stimulation (e.g., hydraulic fracturing) or "fracking." The process of fracking requires large volumes of water, proppant, and chemicals as well as a large well pad (3-7 acres) and an extensive network of gathering and transmission pipelines. Drilling can generate about 1,000 tons of drill cuttings depending on the depth of the formation and the length of the horizontal bore. The flowback and produced waters that return to the surface during production are high in total dissolved solids (TDS, 60,000-350,000 mg L(-1)) and contain halides (e.g., chloride, bromide, fluoride), strontium, barium, and often naturally occurring radioactive materials (NORMs) as well as organics. The condensate tanks used to store these fluids can off gas a plethora of volatile organic compounds. The waste water, with its high TDS may be recycled, treated, or disposed of through deep well injection. Where allowed, open impoundments used for recycling are a source of air borne contamination as they are often aerated. The gas may be "dry" (mostly methane) or "wet," the latter containing a mixture of light hydrocarbons and liquids that need to be separated from the methane. Although the wells can produce significant quantities of natural gas, from 2-7 bcf, their initial decline rates are significant (50-75%) and may cease to be economic within a few years. This review presents an overview of unconventional gas extraction highlighting the environmental impacts and challenges. PMID- 25734821 TI - Long-term impacts of unconventional drilling operations on human and animal health. AB - Public health concerns related to the expansion of unconventional oil and gas drilling have sparked intense debate. In 2012, we published case reports of animals and humans affected by nearby drilling operations. Because of the potential for long-term effects of even low doses of environmental toxicants and the cumulative impact of exposures of multiple chemicals by multiple routes of exposure, a longitudinal study of these cases is necessary. Twenty-one cases from five states were followed longitudinally; the follow-up period averaged 25 months. In addition to humans, cases involved food animals, companion animals and wildlife. More than half of all exposures were related to drilling and hydraulic fracturing operations; these decreased slightly over time. More than a third of all exposures were associated with wastewater, processing and production operations; these exposures increased slightly over time. Health impacts decreased for families and animals moving from intensively drilled areas or remaining in areas where drilling activity decreased. In cases of families remaining in the same area and for which drilling activity either remained the same or increased, no change in health impacts was observed. Over the course of the study, the distribution of symptoms was unchanged for humans and companion animals, but in food animals, reproductive problems decreased and both respiratory and growth problems increased. This longitudinal case study illustrates the importance of obtaining detailed epidemiological data on the long term health effects of multiple chemical exposures and multiple routes of exposure that are characteristic of the environmental impacts of unconventional drilling operations. PMID- 25734822 TI - Human exposure to unconventional natural gas development: A public health demonstration of periodic high exposure to chemical mixtures in ambient air. AB - Directional drilling and hydraulic fracturing of shale gas and oil bring industrial activity into close proximity to residences, schools, daycare centers and places where people spend their time. Multiple gas production sources can be sited near residences. Health care providers evaluating patient health need to know the chemicals present, the emissions from different sites and the intensity and frequency of the exposures. This research describes a hypothetical case study designed to provide a basic model that demonstrates the direct effect of weather on exposure patterns of particulate matter smaller than 2.5 microns (PM2.5) and volatile organic chemicals (VOCs). Because emissions from unconventional natural gas development (UNGD) sites are variable, a short term exposure profile is proposed that determines 6-hour assessments of emissions estimates, a time scale needed to assist physicians in the evaluation of individual exposures. The hypothetical case is based on observed conditions in shale gas development in Washington County, Pennsylvania, and on estimated emissions from facilities during gas development and production. An air exposure screening model was applied to determine the ambient concentration of VOCs and PM2.5 at different 6 hour periods of the day and night. Hourly wind speed, wind direction and cloud cover data from Pittsburgh International Airport were used to calculate the expected exposures. Fourteen months of daily observations were modeled. Higher than yearly average source terms were used to predict health impacts at periods when emissions are high. The frequency and intensity of exposures to PM2.5 and VOCs at a residence surrounded by three UNGD facilities was determined. The findings show that peak PM2.5 and VOC exposures occurred 83 times over the course of 14 months of well development. Among the stages of well development, the drilling, flaring and finishing, and gas production stages produced higher intensity exposures than the hydraulic fracturing stage. Over one year, compressor station emissions created 118 peak exposure levels and a gas processing plant produced 99 peak exposures over one year. The screening model identified the periods during the day and the specific weather conditions when the highest potential exposures would occur. The periodicity of occurrence of extreme exposures is similar to the episodic nature of the health complaints reported in Washington County and in the literature. This study demonstrates the need to determine the aggregate quantitative impact on health when multiple facilities are placed near residences, schools, daycare centers and other locations where people are present. It shows that understanding the influence of air stability and wind direction is essential to exposure assessment at the residential level. The model can be applied to other emissions and similar sites. Profiles such as this will assist health providers in understanding the frequency and intensity of the human exposures when diagnosing and treating patients living near unconventional natural gas development. PMID- 25734823 TI - Reported health conditions in animals residing near natural gas wells in southwestern Pennsylvania. AB - Natural gas extraction activities, including the use of horizontal drilling and hydraulic fracturing, may pose potential health risks to both human and animal populations in close proximity to sites of extraction activity. Because animals may have increased exposure to contaminated water and air as well as increased susceptibility to contaminant exposures compared to nearby humans, animal disease events in communities living near natural gas extraction may provide "sentinel" information useful for human health risk assessment. Community health evaluations as well as health impact assessments (HIAs) of natural gas exploration should therefore consider the inclusion of animal health metrics in their assessment process. We report on a community environmental health survey conducted in an area of active natural gas drilling, which included the collection of health data on 2452 companion and backyard animals residing in 157 randomly-selected households of Washington County, Pennsylvania (USA). There were a total of 127 reported health conditions, most commonly among dogs. When reports from all animals were considered, there were no significant associations between reported health condition and household proximity to natural gas wells. When dogs were analyzed separately, we found an elevated risk of 'any' reported health condition in households less than 1km from the nearest gas well (OR = 3.2, 95% CI 1.07 9.7), with dermal conditions being the most common of canine disorders. While these results should be considered hypothesis generating and preliminary, they suggest value in ongoing assessments of pet dogs as well as other animals to better elucidate the health impacts of natural gas extraction on nearby communities. PMID- 25734824 TI - Marcellus and mercury: Assessing potential impacts of unconventional natural gas extraction on aquatic ecosystems in northwestern Pennsylvania. AB - Mercury (Hg) is a persistent element in the environment that has the ability to bioaccumulate and biomagnify up the food chain with potentially harmful effects on ecosystems and human health. Twenty-four streams remotely located in forested watersheds in northwestern PA containing naturally reproducing Salvelinus fontinalis (brook trout), were targeted to gain a better understanding of how Marcellus shale natural gas exploration may be impacting water quality, aquatic biodiversity, and Hg bioaccumulation in aquatic ecosystems. During the summer of 2012, stream water, stream bed sediments, aquatic mosses, macroinvertebrates, crayfish, brook trout, and microbial samples were collected. All streams either had experienced hydraulic fracturing (fracked, n = 14) or not yet experienced hydraulic fracturing (non-fracked, n = 10) within their watersheds at the time of sampling. Analysis of watershed characteristics (GIS) for fracked vs non-fracked sites showed no significant differences (P > 0.05), justifying comparisons between groups. Results showed significantly higher dissolved total mercury (FTHg) in stream water (P = 0.007), lower pH (P = 0.033), and higher dissolved organic matter (P = 0.001) at fracked sites. Total mercury (THg) concentrations in crayfish (P = 0.01), macroinvertebrates (P = 0.089), and predatory macroinvertebrates (P = 0.039) were observed to be higher for fracked sites. A number of positive correlations between amount of well pads within a watershed and THg in crayfish (r = 0.76, P < 0.001), THg in predatory macroinvertebrates (r = 0.71, P < 0.001), and THg in brook trout (r = 0.52, P < 0.01) were observed. Stream-water microbial communities within the Deltaproteobacteria also shared a positive correlation with FTHg and to the number of well pads, while stream pH (r = -0.71, P < 0.001), fish biodiversity (r = -0.60, P = 0.02), and macroinvertebrate taxa richness (r = -0.60, P = 0.01) were negatively correlated with the number of well pads within a watershed. Further investigation is needed to better elucidate relationships and pathways of observed differences in stream water chemistry, biodiversity, and Hg bioaccumulation, however, initial findings suggest Marcellus shale natural gas exploration is having an effect on aquatic ecosystems. PMID- 25734825 TI - Data inconsistencies from states with unconventional oil and gas activity. AB - The quality and availability of unconventional oil and gas (O&G) data in the United States have never been compared methodically state-to-state. By conducting such an assessment, this study seeks to better understand private and publicly sourced data variability and to identify data availability gaps. We developed an exploratory data-grading tool - Data Accessibility and Usability Index (DAUI) - to guide the review of O&G data quality. Between July and October 2013, we requested, collected, and assessed 5 categories of unconventional O&G data (wells drilled, violations, production, waste, and Class II disposal wells) from 10 states with active drilling activity. We based our assessment on eight data quality parameters (accessibility, usability, point location, completeness, metadata, agency responsiveness, accuracy, and cost). Using the DAUI, two authors graded the 10 states and then averaged their scores. The average score received across all states, data categories, and parameters was 67.1 out of 100, largely insufficient for proper data transparency. By state, Pennsylvania received the highest average ( = 93.5) and ranked first in all but one data category. The lowest scoring state was Texas ( = 44) largely due to its policy of charging for certain data. This article discusses the various reasons for scores received, as well as methodological limitations of the assessment metrics. We argue that the significant variability of unconventional O&G data-and its availability to the public-is a barrier to regulatory and industry transparency. The lack of transparency also impacts public education and broader participation in industry governance. This study supports the need to develop a set of data best management practices (BMPs) for state regulatory agencies and the O&G industry, and suggests potential BMPs for this purpose. PMID- 25734826 TI - Scintillation gamma spectrometer for analysis of hydraulic fracturing waste products. AB - Flowback and produced wastewaters from unconventional hydraulic fracturing during oil and gas explorations typically brings to the surface Naturally Occurring Radioactive Materials (NORM), predominantly radioisotopes from the U238 and Th232 decay chains. Traditionally, radiological sampling are performed by sending collected small samples for laboratory tests either by radiochemical analysis or measurements by a high-resolution High-Purity Germanium (HPGe) gamma spectrometer. One of the main isotopes of concern is Ra226 which requires an extended 21-days quantification period to allow for full secular equilibrium to be established for the alpha counting of its progeny daughter Rn222. Field trials of a sodium iodide (NaI) scintillation detector offers a more economic solution for rapid screenings of radiological samples. To achieve the quantification accuracy, this gamma spectrometer must be efficiency calibrated with known standard sources prior to field deployments to analyze the radioactivity concentrations in hydraulic fracturing waste products. PMID- 25734827 TI - Well water contamination in a rural community in southwestern Pennsylvania near unconventional shale gas extraction. AB - Reports of ground water contamination in a southwestern Pennsylvania community coincided with unconventional shale gas extraction activities that started late 2009. Residents participated in a survey and well water samples were collected and analyzed. Available pre-drill and post-drill water test results and legacy operations (e.g., gas and oil wells, coal mining) were reviewed. Fifty-six of the 143 respondents indicated changes in water quality or quantity while 63 respondents reported no issues. Color change (brown, black, or orange) was the most common (27 households). Well type, when known, was rotary or cable tool, and depths ranged from 19 to 274 m. Chloride, sulfate, nitrate, sodium, calcium, magnesium, iron, manganese and strontium were commonly found, with 25 households exceeding the secondary maximum contaminate level (SMCL) for manganese. Methane was detected in 14 of the 18 houses tested. The 26 wells tested for total coliforms (2 positives) and E. coli (1 positive) indicated that septic contamination was not a factor. Repeated sampling of two wells in close proximity (204 m) but drawing from different depths (32 m and 54 m), revealed temporal variability. Since 2009, 65 horizontal wells were drilled within a 4 km (2.5 mile) radius of the community, each well was stimulated on average with 3.5 million gal of fluids and 3.2 million lbs of proppant. PA DEP cited violations included an improperly plugged well and at least one failed well casing. This study underscores the need for thorough analyses of data, documentation of legacy activity, pre-drill testing, and long term monitoring. PMID- 25734828 TI - Age-related variation in health status after age 60. AB - BACKGROUND: Disability, functionality, and morbidity are often used to describe the health of the elderly. Although particularly important when planning health and social services, knowledge about their distribution and aggregation at different ages is limited. We aim to characterize the variation of health status in a 60+ old population using five indicators of health separately and in combination. METHODS: 3080 adults 60+ living in Sweden between 2001 and 2004 and participating at the SNAC-K population-based cohort study. Health indicators: number of chronic diseases, gait speed, Mini Mental State Examination (MMSE), disability in instrumental-activities of daily living (I-ADL), and in personal ADL (P-ADL). RESULTS: Probability of multimorbidity and probability of slow gait speed were already above 60% and 20% among sexagenarians. Median MMSE and median I-ADL showed good performance range until age 84; median P-ADL was close to zero up to age 90. Thirty% of sexagenarians and 11% of septuagenarians had no morbidity and no impairment, 92% and 80% of them had no disability. Twenty-eight% of octogenarians had multimorbidity but only 27% had some I-ADL disability. Among nonagenarians, 13% had severe disability and impaired functioning while 12% had multimorbidity and slow gait speed. CONCLUSIONS: Age 80-85 is a transitional period when major health changes take place. Until age 80, most people do not have functional impairment or disability, despite the presence of chronic disorders. Disability becomes common only after age 90. This implies an increasing need of medical care after age 70, whereas social care, including institutionalization, becomes a necessity only in nonagenarians. PMID- 25734829 TI - A Mobile Health Application to Predict Postpartum Depression Based on Machine Learning. AB - BACKGROUND: Postpartum depression (PPD) is a disorder that often goes undiagnosed. The development of a screening program requires considerable and careful effort, where evidence-based decisions have to be taken in order to obtain an effective test with a high level of sensitivity and an acceptable specificity that is quick to perform, easy to interpret, culturally sensitive, and cost-effective. The purpose of this article is twofold: first, to develop classification models for detecting the risk of PPD during the first week after childbirth, thus enabling early intervention; and second, to develop a mobile health (m-health) application (app) for the Android((r)) (Google, Mountain View, CA) platform based on the model with best performance for both mothers who have just given birth and clinicians who want to monitor their patient's test. MATERIALS AND METHODS: A set of predictive models for estimating the risk of PPD was trained using machine learning techniques and data about postpartum women collected from seven Spanish hospitals. An internal evaluation was carried out using a hold-out strategy. An easy flowchart and architecture for designing the graphical user interface of the m-health app was followed. RESULTS: Naive Bayes showed the best balance between sensitivity and specificity as a predictive model for PPD during the first week after delivery. It was integrated into the clinical decision support system for Android mobile apps. CONCLUSIONS: This approach can enable the early prediction and detection of PPD because it fulfills the conditions of an effective screening test with a high level of sensitivity and specificity that is quick to perform, easy to interpret, culturally sensitive, and cost-effective. PMID- 25734830 TI - Doxorubicin induces apoptosis in Jurkat cells by mitochondria-dependent and mitochondria-independent mechanisms under normoxic and hypoxic conditions. AB - In this study, we investigated the molecular mechanism of doxorubicin (dxr) induced cytotoxicity on Jurkat cells - a model cell of human acute lymphoblastic leukemia - under normoxic (20% O2) and hypoxic (5% O2) conditions. Using in-cell western analysis, immunofluorescence, flow cytometry analysis, and biochemical inhibitors, we evaluated several oxidative stress (OS) and cell death markers. It was found that dxr (5-100 MUmol/l) induced apoptosis by OS mechanisms involving DNA fragmentation (8-48%), loss of mitochondrial membrane potential (DeltaPsim, 33-92%), and H2O2 production (15-42%) under normoxia. In addition, dxr (10 MUmol/l) induced activation and/or nuclei translocation of NF-kappaB (6.6, 1.6 fold increase), p53 (4.3, 3.1 f), c-Jun (9.5, 5.0 f), apoptosis-inducing factor (AIF) (1.9, 3.9 f), caspase-3 (3.7, 1.9 f), overexpression of Parkin (2.1, 1.2 f)/PINK-1 (2.1 f) proteins, and reduced DJ-1 levels by half compared with untreated cells under normoxia, according to immunofluorescence and in-cell western analysis, respectively. In contrast, dxr (10 MUmol/l) could not induce apoptosis in Jurkat cells under hypoxia. Effectively, dxr significantly reduced DNA fragmentation (6%), expression levels of cell death (e.g. p53, c-Jun, caspase 3, AIF), and OS (e.g. Parkin) markers, whereas it increased DeltaPsim, hypoxia inducible factor 1-alpha (HIF-1alpha, 3.1, 2.3 f), NF-kappaB (6.8, 2.0 f), and DJ 1 (1.3, 1.0 f) levels. This investigation suggests that dxr might efficiently eliminate acute lymphoblastic leukemia cells by OS-induced apoptosis under normoxic conditions through a minimal completeness of cell death signaling (i.e. mitochondria-caspase-3/AIF-dependent pathways) and through a direct DNA damage process. However, hypoxic conditions may reduce the effectiveness of dxr toxicity. PMID- 25734831 TI - Isoflavone lupiwighteone induces cytotoxic, apoptotic, and antiangiogenic activities in DU-145 prostate cancer cells. AB - Isoflavones constitute a large series of compounds found in many plants. They make up an important part of the diet and have a broad spectrum of biological activities such as cytotoxic and antitumor effects. Lupiwighteone (Lup) is an isoflavone-type compound. It is distributed widely in wild-growing plants such as Glycyrrhiza glabra, Lupinus, and Lotus pedunculatus. On the basis of existing research, Lup shows antioxidant and antimicrobial effects, but its antitumor activity has not been reported as yet. This study aimed to examine the antitumor activity of Lup, explore its antitumor mechanism in a human prostate carcinoma cell line (DU-145), and evaluate its antiangiogenetic activity in the human umbilical vein endothelial cell line (HUVEC). The results showed that Lup could inhibit the growth of DU-145 and HUVEC cells in a concentration-dependent and time-dependent manner by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Flow cytometry analysis indicated that Lup could induce cell cycle arrest, cells apoptosis, mitochondrial membrane potential loss, and an increase in intracellular reactive oxygen species of DU-145 cells. Upregulation of Bax, cytochrome c, caspase-3, and PARP-1 protein expressions and downregulation of Bcl 2, procaspase-9, and p-Akt protein expressions were observed by western blot after the treatment of Lup. Furthermore, the effects of Lup on the cellular behavior of HUVECs were also investigated. Altogether, our data proved the anticancer and antiangiogenesis potential of Lup. PMID- 25734832 TI - Optimized combinations of bortezomib, camptothecin, and doxorubicin show increased efficacy and reduced toxicity in treating oral cancer. AB - Oral cancer continues to be a major cause of morbidity and mortality worldwide. Treatment of oral cancer with combinatorial drugs is increasingly being performed as drugs with different molecular targets often exert synergistic effects, thereby enhancing treatment efficacy. Current combinatorial drug regimens often combine the tolerable dosages of individual drugs. However, the optimized ratio of a drug combination and sequence of drug administration could contribute toward the synergy, leading to increased efficacy and reduced dosages. This report aims to study the possible synergistic effects of three anticancer drugs, a proteasome inhibitor, bortezomib, a topoisomerase I inhibitor, Camptothecin, and a DNA intercalation drug, Doxorubicin, when used in combination for treating oral cancer. To rapidly optimize the three-drug regimen with minimal experimental efforts, a Feedback System Control optimization technique, a recent platform technique developed particularly for drug combination screening, was applied. The optimized regimen showed a therapeutic window (death rate difference between cancer cells and normal cells) close to 100%. This is the first report on the use of a combination of bortezomib, Camptothecin, and Doxorubicin in the treatment of oral cancer. Our results indicate that to have the most synergistic anticancer effect, the drugs in the optimized regimen should be dosage specific and ratio specific. Furthermore, the sequence of drug administration plays a vital role in ensuring that the combination is effective. The optimized regimen reported here has the potential to considerably increase the cure rate of oral cancer and reduce the toxicity of chemotherapy. PMID- 25734833 TI - Increased expression of endoplasmic reticulum protein 29 in lung adenocarcinoma is associated with chemosensitivity to gemcitabine. AB - Lung adenocarcinoma is the leading cause of cancer-related death worldwide. The aim of the present study was to investigate the potential function of endoplasmic reticulum protein 29 (ERp29) in lung adenocarcinoma. We examined the expression of ERp29 in 75 patients with lung adenocarcinoma by immunohistochemical analysis, as well as its association with clinicopathological features. We further tested the effects of inhibiting ERp29 on cell proliferation, migration ability, and chemosensitivity to gemcitabine in human lung adenocarcinoma cell lines. ERp29 was significantly overexpressed in lung adenocarcinoma when compared with matched nontumor tissues. However, we did not observe significant associations of ERp29 with any of the clinicopathologic characteristics, including sex, age, differentiation, tumor, node, and metastasis stage, T stage, and lymph node metastasis. Downregulation of ERp29 by small interfering RNA did not affect cell growth, but impaired cell migration of lung adenocarcinoma cells. Inhibition of ERp29 significantly enhanced the chemosensitivity of lung adenocarcinoma cells to gemcitabine. These results support a probable treatment combination of gemcitabine and inhibition of ERp29 overexpression for lung adenocarcinoma to promote the clinical curative effects. PMID- 25734834 TI - Monitoring the multitask mechanism of DNase I activity using graphene nanoassemblies. AB - Here we have demonstrated that graphene serves as a remarkable platform for monitoring the multitask activity of an enzyme with fluorescence spectroscopy. Our studies showed that four different simultaneous enzymatic tasks of DNase I can be observed and measured in a high throughput fashion using graphene oxide and oligonucleotide nanoassemblies. We have used phosphorothioate modified oligonucleotides to pinpoint the individual and highly specific functions of DNase I with single stranded DNA, RNA, and DNA/DNA and DNA/RNA duplexes. DNase I resulted in fluorescence recovery in the nanoassemblies and enhanced the intensity tremendously in the presence of sequence specific DNA or RNA molecules with different degrees of amplification. Our study enabled us to discover the sources of this remarkable signal enhancement, which has been used for biomedical applications of graphene for sensitive detection of specific oncogenes. The significant difference in the signal amplification observed for the detection of DNA and RNA molecules is a result of the positive and/or reductive signal generating events with the enzyme. In the presence of DNA there are four possible ways that the fluorescence reading is influenced, with two of them resulting in a gain in signal while the other two result in a loss. Since the observed signal is a summation of all the events together, the absence of the two fluorescence reduction events with RNA gives a greater degree of fluorescence signal enhancement when compared to target DNA molecules. Overall, our study demonstrates that graphene has powerful features for determining the enzymatic functions of a protein and reveals some of the unknowns observed in the graphene and oligonucleotide assemblies with DNase I. PMID- 25734835 TI - Development of Pseudorotaxanes and Rotaxanes: From Synthesis to Stimuli Responsive Motions to Applications. PMID- 25734837 TI - Traumatic brain injury and juvenile offending: complex causal links offer multiple targets to reduce crime. PMID- 25734836 TI - Conditional control of alternative splicing through light-triggered splice switching oligonucleotides. AB - The spliceosome machinery is composed of several proteins and multiple small RNA molecules that are involved in gene regulation through the removal of introns from pre-mRNAs in order to assemble exon-based mRNA containing protein-coding sequences. Splice-switching oligonucleotides (SSOs) are genetic control elements that can be used to specifically control the expression of genes through correction of aberrant splicing pathways. A current limitation with SSO methodologies is the inability to achieve conditional control of their function paired with high spatial and temporal resolution. We addressed this limitation through site-specific installation of light-removable nucleobase-caging groups as well as photocleavable backbone linkers into synthetic SSOs. This enables optochemical OFF -> ON and ON -> OFF switching of their activity and thus precise control of alternative splicing. The use of light as a regulatory element allows for tight spatial and temporal control of splice switching in mammalian cells and animals. PMID- 25734838 TI - Prevalence and predictors of externalizing behavior in young adult survivors of pediatric traumatic brain injury. AB - OBJECTIVES: To investigate rates of clinically significant externalizing behavior (EB) in young adult survivors of pediatric traumatic brain injury (TBI) and evaluate the contribution of pre- and postinjury risk and resilience factors to EB outcomes 16 years after injury. SETTING: Melbourne, Australia. PARTICIPANTS: Fifty-five young adults (mean age = 23.85 years; injury age: 1.0-12 years) admitted to an emergency department following TBI between 1993 and 1997. DESIGN: Longitudinal prospective study with data collected at the acute, 10-year, and 16 year postinjury time points. MAIN MEASURES: Severity of TBI, adaptive functioning, family functioning, full-scale IQ, executive functioning, social communication, and symptoms of EB. RESULTS: One of every 4 young people with a history of pediatric TBI demonstrated clinical or subthreshold levels of EB in young adulthood. More frequent EB was associated with poorer preinjury adaptive functioning, lower full-scale IQ, and more frequent pragmatic communication difficulty. CONCLUSION: Pediatric TBI is associated with an elevated risk for externalizing disorders in the transition to adulthood. Results underscore the need for screening and assessment of TBI among young offenders and suggest that early and long-term targeted interventions may be required to address risk factors for EB in children and young people with TBI. PMID- 25734839 TI - Language impairments in youths with traumatic brain injury: implications for participation in criminal proceedings. AB - As many as 30% of incarcerated juveniles have a history of traumatic brain injury (TBI). Moderate or severe TBI is associated with a high risk of impairment in language comprehension and expression, which may have profound effects on juveniles' ability to understand and express themselves in criminal proceedings. In this article, we review common language impairments in youths with TBI and discuss potential effects of these impairments on 3 stages of US criminal proceedings: (1) initial encounter with law enforcement; (2) interrogation and Miranda rights; and (3) competence to undergo trial proceedings. We then describe language assessment tools and procedures that may be helpful in legal contexts. Our aim was to inform clinicians and legal staff working with juvenile defendants with TBI, with the long-term goal of developing empirically based guidelines to ensure that juvenile defendants with TBI can fully and effectively participate in criminal proceedings. PMID- 25734840 TI - The prevalence of traumatic brain injury among young offenders in custody: a systematic review. AB - OBJECTIVES: To examine the prevalence of traumatic brain injury (TBI) among young people in custody and to compare this with estimates within the general youth population. DESIGN: Systematic review of research from various national contexts. Included studies were assessed for the relevance of the definition of TBI and the research population, and the quality of the study design. RESULTS: Ten studies were identified for inclusion in the review. Four of these studies included control groups. No studies examining comorbidity of TBI and other neurodevelopmental disorders among incarcerated young people were identified. CONCLUSION: Reported prevalence rates of brain injury among incarcerated youth range from 16.5% to 72.1%, with a rate of 100% reported among a sample of young people sentenced to death. This suggests considerable levels of need among incarcerated young people. Where control groups or directly comparable studies within the general population exist, there is strong and consistent evidence of a prevalence of TBI among incarcerated youth that is substantially greater than that in the general population. This disparity is seemingly more pronounced as the severity of the injury increases. PMID- 25734841 TI - Traumatic brain injury in juvenile offenders: findings from the comprehensive health assessment tool study and the development of a specialist linkworker service. AB - BACKGROUND: Young people in contact with the youth juvenile justice system have well-documented vulnerabilities including high rates of mental health and neurodevelopmental disorders. Studies have suggested that they may also be at increased risk of traumatic brain injury (TBI). OBJECTIVE: (1) To describe the profile of a cohort of juvenile offenders with TBI and associated comorbidity with other neurodevelopmental disorders, mental health needs, and offending behavior. (2) To describe the development of a specialist brain injury service for juvenile offenders with TBI within custody. METHODS: Ninety-three male participants aged 15 to 18 years were consecutively admitted to a custodial secure facility. They were evaluated using a range of different neurocognitive and mental health measures including the Rivermead Post-Concussion Symptoms Questionnaire and the Comprehensive Health Assessment Tool. RESULTS: Eight-two percent of those interviewed reported experiencing at least 1 TBI, and 44% reported ongoing neuropsychological symptoms. Eighteen percent of those sustaining a TBI reported moderate-severe postconcussion symptoms. CONCLUSIONS: There is a high prevalence of TBI in juvenile offenders in custody, with many experiencing multiple episodes. This study highlights the need for further research in this area. An example of a specialist brain injury linkworker service is described as one example of a model of service delivery for this group. PMID- 25734842 TI - A brief overview of the Coma Recovery Scale-revised: updates from the COMBI. PMID- 25734843 TI - Caesium bis(5-bromosalicylaldehyde thiosemicarbazonato-kappa3O,N,S)ferrate(III): supramolecular arrangement of low-spin FeIII complex anions mediated by Cs+ cations. AB - The synthesis and crystal structure determination (at 293 K) of the title complex, Cs[Fe(C(8)H(6)BrN(3)OS)(2)], are reported. The compound is composed of two dianionic O,N,S-tridentate 5-bromosalicylaldehyde thiosemicarbazonate(2-) ligands coordinated to an Fe(III) cation, displaying a distorted octahedral geometry. The ligands are orientated in two perpendicular planes, with the O- and S-donor atoms in cis positions and the N-donor atoms in trans positions. The complex displays intermolecular N-H...O and N-H...Br hydrogen bonds, creating R4(4)(18) rings, which link the Fe(III) units in the a and b directions. The Fe(III) cation is in the low-spin state at 293 K. PMID- 25734844 TI - Exo conformers of N-(pyridin-2-yl)- and N-(pyridin-3-yl)norbornene-5,6 dicarboximide crystals. AB - Two isomeric pyridine-substituted norbornenedicarboximide derivatives, namely N (pyridin-2-yl)-exo-norbornene-5,6-dicarboximide, (I), and N-(pyridin-3-yl)-exo norbornene-5,6-dicarboximide, (II), both C(14)H(12)N(2)O(4), have been crystallized and their structures unequivocally determined by single-crystal X ray diffraction. The molecules consist of norbornene moieties fused to a dicarboximide ring substituted at the N atom by either pyridin-2-yl or pyridin-3 yl in an anti configuration with respect to the double bond, thus affording exo isomers. In both compounds, the asymmetric unit consists of two independent molecules (Z' = 2). In compound (I), the pyridine rings of the two independent molecules adopt different conformations, i.e. syn and anti, with respect to the methylene bridge. The intermolecular contacts of (I) are dominated by C-H...O interactions. In contrast, in compound (II), the pyridine rings of both molecules have an anti conformation and the two independent molecules are linked by carbonyl-carbonyl interactions, as well as by C-H...O and C-H...N contacts. PMID- 25734845 TI - Synthesis and crystal structure of a novel prochiral ketoimine: (E)-acetophenone O-diphenylphosphoryl oxime. AB - A novel activated prochiral ketoimine, (E)-acetophenone O-diphenylphosphoryl oxime, C(20)H(18)NO(2)P, with an electron-withdrawing substituent on the imine N atom similar to other prochiral ketoimines, has been synthesized and the X-ray crystal stucture determined. The molecules pack together in the solid state via weak intermolecular C-H...O interactions and both face-to-face and edge-to-face pi-stacking interactions. PMID- 25734846 TI - [Mn12O12(O2CMe)12(NO3)4(H2O)4]: facile synthesis of a new type of Mn12 complex. AB - The title dodecanuclear Mn complex, namely dodeca-MU(2)-acetato-kappa(24)O:O' tetraaquatetra-MU(2)-nitrato-kappa(8)O:O'-tetra-MU(4)-oxido-octa-MU(3)-oxido tetramanganese(IV)octamanganese(III) nitromethane tetrasolvate, [Mn(12)(CH(3)COO)(12)(NO(3))(4)O(12)(H(2)O)(4)].4CH(3)NO(2), was synthesized by the reaction of Mn(2+) and Ce(4+) sources in nitromethane with an excess of acetic acid. This compound is distinct from the previously known single-molecule magnet [Mn(12)O(12)(O(2)CMe)(16)(H(2)O)(4)], synthesized by Lis [Acta Cryst. (1980), B36, 2042-2044]. It is the first Mn(12)-type molecule containing nitrate ligands to be directly synthesized without the use of a preformed cluster. Additionally, this molecule is distinct from all other known Mn(12) complexes due to intermolecular hydrogen bonds between the nitrate and water ligands, which give rise to a three-dimensional network. The complex is compared to other known Mn(12) molecules in terms of its structural parameters and symmetry. PMID- 25734847 TI - Tris(tri-o-tolyl phosphite-kappaP)nickel: a coordinatively unsaturated nickel(0) complex. AB - A previously reported complex, [Ni(C(21)H(21)O(3)P)(3)] or Ni[P(O-o-tolyl(3))(3)] [Gosser & Tolman (1970). Inorg. Chem. 9, 2350-2353], crystallized in the monoclinic space group C2/c, and its solid-state structure was determined. The Ni(0) atom adopts an essentially trigonal-planar geometry as a consequence of the steric congestion of the ligands. Three of the phenoxy rings on two phosphite ligands were modelled as being disordered over two sets of sites, and the occupancy factors were set at 0.5 after trial refinement and intramolecular contact considerations. The exact ligand cone angle has been calculated to be 163.6 degrees . PMID- 25734848 TI - Towards validating new enzymatic routes for synthetic conversion: 7,10-bis-O (2,2,2-trichloroethoxycarbonyl)-10-deacetyl baccatin III-ethyl acetate-water (1/1/1). AB - The title compound, C(34)H(38)C(l6)O(14).C(4)H(8)O(2).H(2)O, prepared by the reaction of 10-deacetyl baccatin III with 2,2,2-trichloroethyl chloroformate in pyridine, crystallizes via strong intermolecular hydrogen bonds and noncovalent interactions between 7,10-bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetyl baccatin III (7,10-di-Troc-DAB), water and ethyl acetate. A detailed comparison of the molecular conformation with those of related structures is presented. PMID- 25734849 TI - Incorporating two different chromophores onto a silicon atom: the crystal structure and photophysical properties of 9-{4-[(9,9-dimethyl-9H-fluoren-2 yl)dimethylsilyl]phenyl}-9H-carbazole. AB - The crystal structure of the title bifunctional silicon-bridged compound, C(35)H(31)NSi, (I), has been determined. The compound crystallizes in the centrosymmetric space group P2(1)/c. In the crystal structure, the pairs of aryl rings in the two different chromophores, i.e. 9-phenyl-9H-carbazole and 9,9 dimethyl-9H-fluorene, are positioned orthogonally. In the crystal packing, no classical hydrogen bonding is observed. UV-Vis absorption and fluorescence emission spectra show that the central Si atom successfully breaks the electronic conjugation between the two different chromophores, and this was further analysed by density functional theory (DFT) calculations. PMID- 25734850 TI - Captopril and its dimer captopril disulfide: comparative structural and conformational studies. AB - The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3 sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C(9)H(15)NO(3)S, (1), and its dimer disulfide metabolite, 1,1'-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1 diyl]}bis-L-proline, C(18)H(28)N(2)O(6)S(2), (2), were determined by single crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P2(1)2(1)2(1), while compound (2) crystallizes in the monoclinic space group P2(1), both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O-H...O and relatively weak C-H...O interactions seem to be effective in both structures and, together with S-H...O and C-H...S contacts, they create three-dimensional networks. PMID- 25734851 TI - Two polymorphs of 5-cyclohexyl-5-ethylbarbituric acid and their packing relationships with other barbiturates. AB - Polymorph (Ia) (m.p. 474 K) of the title compound, C(12)H(18)N(2)O(3), displays an N-H...O=C hydrogen-bonded layer structure which contains R(6)(6)(28) rings connecting six molecules, as well as R2(2)(8) rings linking two molecules. The 3 connected hydrogen-bonded net resulting from these interactions has the hcb topology. Form (Ib) (m.p. 471 K) displays N-H...O=C hydrogen-bonded looped chains in which neighbouring molecules are linked to one another by two different R(2)(2)(8) rings. Polymorph (Ia) is isostructural with the previously reported form II of 5-(2-bromoallyl)-5-isopropylbarbituric acid (noctal) and polymorph (Ib) is isostructural with the known crystal structures of four other barbiturates. PMID- 25734852 TI - The peptide NCbz-Val-Tyr-OMe and aromatic pi-pi interactions. AB - The peptide N-benzyloxycarbonyl-L-valyl-L-tyrosine methyl ester or NCbz-Val-Tyr OMe (where NCbz is N-benzyloxycarbonyl and OMe indicates the methyl ester), C(23)H(28)N(2)O(6), has an extended backbone conformation. The aromatic rings of the Tyr residue and the NCbz group are involved in various attractive intra- and intermolecular aromatic pi-pi interactions which stabilize the conformation and packing in the crystal structure, in addition to N-H...O and O-H...O hydrogen bonds. The aromatic pi-pi interactions include parallel-displaced, perpendicular T-shaped, perpendicular L-shaped and inclined orientations. PMID- 25734853 TI - A list of organometallic kryptoracemates. AB - The vast majority of racemic solutions of chiral compounds apparently crystallize at room temperature in non-Sohncke space groups as racemic crystals. However, kryptoracemic crystals composed of nearly enantiomeric pairs occasionally crystallize at room temperature, or appear as low-temperature phases, in Sohncke space groups. As a complement to the previously published catalog of organic kryptoracemates [Fabian & Brock (2010). Acta Cryst. B66, 94-103], 1412 chiral organometallic crystal structures have now been extracted from the Cambridge Structural Database and analyzed. 26 are listed herein as credible kryptoracemates. The possible influence of temperature is discussed, together with some problems in characterizing and classifying these structures. PMID- 25734854 TI - Syntheses and crystal structures of two magnesium-tetrazole compounds in salt and polymeric forms. AB - Two alkaline earth-tetrazole compounds, namely catena poly[[[triaquamagnesium(II)]-MU-5,5'-(azanediyl)ditetrazolato kappa(3)N(1),N(1'):N(5)] hemi{bis[MU-5,5'-(azanediyl)ditetrazolato kappa(3)N(1),N(1'):N(2)]bis[triaquamagnesium(II)]} monohydrate], {[Mg(C(2)HN(9))(H(2)O)(3)][Mg(2)(C(2)HN(9))(2)(H(2)O)(6)]0.5.H(2)O}n, (I), and bis[5-(pyrazin-2-yl)tetrazolate] hexaaquamagnesium(II), (C(5)H(3)N(6))[Mg(H(2)O)(6)], (II), have been prepared under hydrothermal conditions. Compound (I) is a mixed dimer-polymer based on magnesium ion centres and can be regarded as the first example of a magnesium-tetrazolate polymer in the crystalline form. The structure shows a complex three-dimensional hydrogen bonded network that involves magnesium-tetrazolate dimers, solvent water molecules and one-dimensional magnesium-tetrazolate polymeric chains. The intrinsic cohesion in the polymer chains is ensured by N-H...N hydrogen bonds, which form R(2)(2)(7) rings, thus reinforcing the propagation of the polymer chain along the a axis. The crystal structure of magnesium tetrazole salt (II) reveals a mixed ribbon of hydrogen-bonded rings, of types R(2)(2)(7), R(2)(2)(9) and R(2)(4)(10), running along the c axis, which are linked by R(2)(4)(16) rings, generating a 4,8-c flu net. PMID- 25734855 TI - Cocrystals of 6-methyl-2-thiouracil: presence of the acceptor-donor acceptor/donor-acceptor-donor synthon. AB - The results of seven cocrystallization experiments of the antithyroid drug 6 methyl-2-thiouracil (MTU), C(5)H(6)N(2)OS, with 2,4-diaminopyrimidine, 2,4,6 triaminopyrimidine and 6-amino-3H-isocytosine (viz. 2,6-diamino-3H-pyrimidin-4 one) are reported. MTU features an ADA (A = acceptor and D = donor) hydrogen bonding site, while the three coformers show complementary DAD hydrogen-bonding sites and therefore should be capable of forming an ADA/DAD N-H...O/N-H...N/N H...S synthon with MTU. The experiments yielded one cocrystal and six cocrystal solvates, namely 6-methyl-2-thiouracil-2,4-diaminopyrimidine-1-methylpyrrolidin-2 one (1/1/2), C(5)H(6)N(2)OS.C(4)H(6)N(4).2C(5)H(9)NO, (I), 6-methyl-2-thiouracil 2,4-diaminopyrimidine (1/1), C(5)H(6)N(2)OS.C(4)H(6)N(4), (II), 6-methyl-2 thiouracil-2,4-diaminopyrimidine-N,N-dimethylacetamide (2/1/2), 2C(5)H(6)N(2)OS.C(4)H(6)N(4).2C(4)H(9)NO, (III), 6-methyl-2-thiouracil-2,4 diaminopyrimidine-N,N-dimethylformamide (2/1/2), C(5)H(6)N(2)OS.0.5C(4)H(6)N(4).C(3)H(7)NO, (IV), 2,4,6-triaminopyrimidinium 6 methyl-2-thiouracilate-6-methyl-2-thiouracil-N,N-dimethylformamide (1/1/2), C(4)H(8)N(5)(+).C(5)H(5)N(2)OS(-).C(5)H(6)N(2)OS.2C(3)H(7)NO, (V), 6-methyl-2 thiouracil-6-amino-3H-isocytosine-N,N-dimethylformamide (1/1/1), C(5)H(6)N(2)OS.C(4)H(6)N(4)O.C(3)H(7)NO, (VI), and 6-methyl-2-thiouracil-6-amino 3H-isocytosine-dimethyl sulfoxide (1/1/1), C(5)H(6)N(2)OS.C(4)H(6)N(4)O.C(2)H(6)OS, (VII). Whereas in cocrystal (I) an R(2)(2)(8) interaction similar to the Watson-Crick adenine/uracil base pair is formed and a two-dimensional hydrogen-bonding network is observed, the cocrystals (II)-(VII) contain the triply hydrogen-bonded ADA/DAD N-H...O/N-H...N/N-H...S synthon and show a one-dimensional hydrogen-bonding network. Although 2,4 diaminopyrimidine possesses only one DAD hydrogen-bonding site, it is, due to orientational disorder, triply connected to two MTU molecules in (III) and (IV). PMID- 25734856 TI - Structure determination and modeling of monoclinic trioctylphosphine oxide. AB - Trioctylphosphine oxide (TOPO), C(24)H(51)OP, was recrystallized from ambient evaporation in acetone. TOPO single crystals form with a monoclinic P2(1)/c structure. Fourier transform IR (FT-IR) spectroscopy captures the characteristic stretching modes from the seven methylene groups, the phosphoryl P=O bond, and the phosphoryl-carbon bond. PMID- 25734857 TI - An integrated approach of gene expression and DNA-methylation profiles of WNT signaling genes uncovers novel prognostic markers in acute myeloid leukemia. AB - BACKGROUND: The wingless-Int (WNT) pathway has an essential role in cell regulation of hematopoietic stem cells (HSC). For Acute Myeloid Leukemia (AML), the malignant counterpart of HSC, currently only a selective number of genes of the WNT pathway are analyzed by using either gene expression or DNA-methylation profiles for the identification of prognostic markers and potential candidate targets for drug therapy. It is known that mRNA expression is controlled by DNA methylation and that specific patterns can infer the ability to differentiate biological differences, thus a combined analysis using all WNT annotated genes could provide more insight in the WNT signaling. APPROACH: We created a computational approach that integrates gene expression and DNA promoter methylation profiles. The approach represents the continuous gene expression and promoter methylation profiles with nine discrete mutually exclusive scenarios. The scenario representation allows for a refinement of patient groups by a more powerful statistical analysis, and the construction of a co-expression network. We focused on 268 WNT annotated signaling genes that are derived from the molecular signature database. RESULTS: Using the scenarios we identified seven prognostic markers for overall survival and event-free survival. Three genes are novel prognostic markers; two with favorable outcome (PSMD2, PPARD) and one with unfavorable outcome (XPNPEP). The remaining four genes (LEF1, SFRP2, RUNX1, and AXIN2) were previously identified but we could refine the patient groups. Three AML risk groups were further analyzed and the co-expression network showed that only the good risk group harbors frequent promoter hypermethylation and significantly correlated interactions with proteasome family members. CONCLUSION: Our results provide novel insights in WNT signaling in AML, we discovered new and previously identified prognostic markers and a refinement of the patient groups. PMID- 25734858 TI - Disordered eating and alcohol use among college women: associations with race and big five traits. AB - Excessive alcohol use and disordered eating are considerable health-related problems among college women. The purpose of the present study was to examine how specific patterns of disordered eating (i.e., anorexia, bulimia, binge eating) are related to alcohol use and related problems and the influence of racial group membership and Big Five personality traits on the co-occurrence of these behaviors. Participants were 153 undergraduate women. Results indicated that White women reported more binge drinking, alcohol-related problems, disordered eating, anorexia nervosa symptoms, and bulimia nervosa symptoms than non-White women. Women with higher levels of openness and who engage in extreme exercise, dieting, fasting, or purging were more at risk for heavy and problematic alcohol use. Implications for the treatment of co-occurring disorders among college students and further research are discussed. PMID- 25734859 TI - Effects of charge and surface ligand properties of nanoparticles on oxidative stress and gene expression within the gut of Daphnia magna. AB - Concern has been raised regarding the current and future release of engineered nanomaterials into aquatic environments from industry and other sources. However, not all nanomaterials may cause an environmental impact and identifying which nanomaterials may be of greatest concern has been difficult. It is thought that the surface groups of a functionalized nanoparticles (NPs) may play a significant role in determining their interactions with aquatic organisms, but the way in which surface properties of NPs impact their toxicity in whole organisms has been minimally explored. A major point of interaction of NPs with aquatic organisms is in the gastrointestinal tract as they ingest particulates from the water column or from the sediment. The main goal of this study was to use model gold NP (AuNPs) to evaluate the potential effects of the different surfaces groups on NPs on the gut of an aquatic model organism, Daphnia magna. In this study, we exposed daphnids to a range of AuNPs concentrations and assessed the impact of AuNP exposure in the daphnid gut by measuring reactive oxygen species (ROS) production and expression of genes associated with oxidative stress and general cellular stress: glutathione S-transferase (gst), catalase (cat), heat shock protein 70 (hsp70), and metallothionein1 (mt1). We found ROS formation and gene expression were impacted by both charge and the specific surface ligand used. We detected some degree of ROS production in all NP exposures, but positively charged AuNPs induced a greater ROS response. Similarly, we observed that, compared to controls, both positively charged AuNPs and only one negatively AuNP impacted expression of genes associated with cellular stress. Finally, ligand-AuNP exposures showed a different toxicity and gene expression profile than the ligand alone, indicating a NP specific effect. PMID- 25734861 TI - Effect of audience response system technology on learning outcomes in health students and professionals: an updated systematic review. AB - AIM: : Audience response system (ARS) technology is a recent innovation that is increasingly being used by health educators to improve learning outcomes. Equivocal results from previous systematic review research provide weak support for the use of ARS for improving learning outcomes at both short and long terms. This review sought to update and critically review the body of controlled experimental evidence on the use of ARS technology on learning outcomes in health students and professionals. METHODS: This review searched using all identified keywords both electronic databases (CINAHL, Embase, ERIC, Medline, Science Direct, Scopus, and Web of Science) and reference lists of retrieved articles to find relevant published studies for review, from 2010 to April 2014. A descriptive synthesis of important study characteristics and effect estimates for learning outcomes was done. RESULTS: Three controlled trials in 321 participants from the United States were included for review. ARS knowledge retention scores were lower than the control group in one study, higher than control group provided that immediate feedback was given about each question in one study, and equivalent between intervention and control groups in another study. CONCLUSION: There is an absence of good quality evidence on effectiveness of ARS technologies for improving learning outcomes in health students and professionals. PMID- 25734860 TI - Glycemic Variability Is Associated with Frequency of Blood Glucose Testing and Bolus: Post Hoc Analysis Results from the ProAct Study. AB - INTRODUCTION: The ProAct study has shown that a pump switch to the Accu-Chek((r)) Combo system (Roche Diagnostics Deutschland GmbH, Mannheim, Germany) in type 1 diabetes patients results in stable glycemic control with significant improvements in glycated hemoglobin (HbA1c) in patients with unsatisfactory baseline HbA1c and shorter pump usage time. PATIENTS AND METHODS: In this post hoc analysis of the ProAct database, we investigated the glycemic control and glycemic variability at baseline by determination of several established parameters and scores (HbA1c, hypoglycemia frequency, J-score, Hypoglycemia and Hyperglycemia Indexes, and Index of Glycemic Control) in participants with different daily bolus and blood glucose measurement frequencies (less than four day, four or five per day, and more than five per day, in both cases). The data were derived from up to 299 patients (172 females, 127 males; age [mean+/-SD], 39.4+/-15.2 years; pump treatment duration, 7.0+/-5.2 years). RESULTS: Participants with frequent glucose readings had better glycemic control than those with few readings (more than five readings per day vs. less than four readings per day: HbA1c, 7.2+/-1.1% vs. 8.0+/-0.9%; mean daily blood glucose, 151+/-22 mg/dL vs. 176+/-30 mg/dL; percentage of readings per month >300 mg/dL, 10+/-4% vs. 14+/-5%; percentage of readings in target range [80-180 mg/dL], 59% vs. 48% [P<0.05 in all cases]) and had a lower glycemic variability (J-score, 49+/-13 vs. 71+/-25 [P<0.05]; Hyperglycemia Index, 0.9+/-0.5 vs. 1.9+/-1.2 [P<0.05]; Index of Glycemic Control, 1.9+/-0.8 vs. 3.1+/-1.6 [P<0.05]; Hypoglycemia Index, 0.9+/-0.8 vs. 1.2+/-1.3 [not significant]). Frequent self monitoring of blood glucose was associated with a higher number of bolus applications (6.1+/-2.2 boluses/day vs. 4.5+/-2.0 boluses/day [P<0.05]). Therefore, a similar but less pronounced effect on glycemic variability in favor of more daily bolus applications was observed (more than five vs. less than four bolues per day: J-score, 57+/-17 vs. 63+/-25 [not significant]; Hypoglycemia Index, 1.0+/-1.0 vs. 1.5+/-1.4 [P<0.05]; Hyperglycemia Index, 1.3+/-0.6 vs. 1.6+/ 1.1 [not significant]; Index of Glycemic Control, 2.3+/-1.1 vs. 3.1+/-1.7 [P<0.05]). CONCLUSIONS: Pump users who perform frequent daily glucose readings have a better glycemic control with lower glycemic variability. PMID- 25734862 TI - A comparison of univariate and bivariate models in meta-analysis of diagnostic accuracy studies. AB - AIM: : An implicit diagnostic threshold has been thought to be the cause of between-study variation in meta-analyses of diagnostic accuracy studies. Bivariate models have been used to account for implicit diagnostic thresholds. However, little difference in estimates of test performance has been reported between univariate and bivariate models. This study aims to undertake another comparison of these two models in order to determine if spectrum effects could better explain the variation across studies. METHODS: Studies were selected from those provided in Ohle et al.'s meta-analysis and quality scored using QUADAS 2. Univariate analyses of sensitivity and specificity were computed using two models: one bias-adjusted and the other not. The univariate sensitivity and specificity results were compared with the bivariate logit-normal summary ROC method. RESULTS: Similar results were obtained when using summary ROC and univariate pooling methods for sensitivity and specificity. Differences in study characteristics were found for outlier studies in univariate analyses, suggesting spectrum effects. CONCLUSION: Univariate pooling methods provide an estimate of test performance for an average disease spectrum which is possibly why results concur with the bivariate models. A better appreciation of such spectrum effects can be demonstrated through univariate analyses, especially when the forest plots are examined in either bias-adjusted or non-bias-adjusted univariate models. PMID- 25734863 TI - Should the drinks industry have a role in establishing public health policy to reduce alcohol-related harm? PMID- 25734864 TI - Validation of a new tool for the assessment of study quality and reporting in exercise training studies: TESTEX. AB - INTRODUCTION: Several established tools are available to assess study quality and reporting of randomized controlled trials; however, these tools were designed with clinical intervention trials in mind. In exercise training intervention trials some of the traditional study quality criteria, such as participant or researcher blinding, are extremely difficult to implement. METHODS: We developed the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX) - a study quality and reporting assessment tool, designed specifically for use in exercise training studies. Our tool is a 15-point scale (5 points for study quality and 10 points for reporting) and addresses previously unmentioned quality assessment criteria specific to exercise training studies. RESULTS: There were no systematic differences between the summated TESTEX scores of each observer [H(2)=0.392, P=0.822]. There was a significant association between the summated TESTEX scores of the three observers, with almost perfect agreement between observers 1 and 2 [intra-class correlation coefficient (ICC)=0.93, 95% confidence interval (CI) 0.82-0.97, P<0.001], observers 1 and 3 (ICC= 0.96, 95% CI 0.89 0.98, P<0.001) and observers 2 and 3 (ICC=0.91, 95% CI 0.75-0.96, P<0.001). CONCLUSIONS: The TESTEX scale is a new, reliable tool, specific to exercise scientists, that facilitates a comprehensive review of exercise training trials. PMID- 25734865 TI - Health care worker hand hygiene in the pediatric special care unit at Mulago National Referral Hospital in Uganda: a best practice implementation project. AB - INTRODUCTION: The hands of a health care worker are a common vehicle of pathogen transmission in hospital settings. Health care worker hand hygiene is therefore critical for patients' well being. Whilst failure of health care workers to comply with the best hand hygiene practice is a problem in all health care settings, issues of lack of access to adequate cleaning equipment and in some cases even running water make practicing good hand hygiene particularly difficult in low-resource developing country settings. This study reports an audit and feedback project that focused on the hand hygiene of the health care worker in the pediatric special care unit of the Mulago National Referral Hospital, which is a low-resource setting in Uganda. OBJECTIVE: To improve hand hygiene among health care workers in the pediatric special care unit and thereby contribute to reducing transmission of health care worker-associated pathogens. METHODS: The Joanna Briggs Institute three-phase Practical Application of Clinical Evidence System audit and feedback tool for promoting evidence utilization and change in health care was used. In phase one of the project, stakeholders were engaged and seven evidence-based audit criteria were developed. A baseline audit was then conducted. In phase two, barriers underpinning areas of noncompliance found in the baseline audit were identified and three strategies - education, reminders and provision of hand cleaning equipment - were implemented to overcome them. In phase three, a follow-up audit was conducted. RESULTS: Compliance with best practice hygiene was found to be poor in the baseline audit for all but one of the audit criteria. Following the implementation of the strategies, hand hygiene improved. The compliance rate increased substantially across all criteria. Staff education achieved 100%, whilst criterion 4 increased to 70%. However, use of alcohol-based hand-rub for hand hygiene only improved to 66%, and for six of the seven audit criteria, compliance remained below 74%. CONCLUSION: The project provides another example of how audit can be used as a tool to improve health practice, even in a low-resource setting. At the same time, it showed how difficult it is to achieve compliance with best hand hygiene practice in a low resource hospital. The project highlights the importance of continued education/awareness raising on the importance of good hand hygiene practice as well as investment in infrastructure and cleaning supplies for achieving and sustaining good hand hygiene among workers in a low-resource hospital setting. A key contribution of the project was the legacy it left in the form of knowledge about how to use audit and feedback as a tool to promote the best practice. A similar project has been implemented in the maternity ward at the hospital and further audits are planned. PMID- 25734866 TI - Infraclavicular brachial plexus block for regional anaesthesia of the lower arm. PMID- 25734867 TI - Psychosocial interventions for patients with head and neck cancer. PMID- 25734868 TI - Antibiotics for sore throat. PMID- 25734869 TI - Perioperatively acquired disorders of coagulation. AB - PURPOSE OF REVIEW: To provide an overview of acquired coagulopathies that can occur in various perioperative clinical settings. Also described are coagulation disturbances linked to antithrombotic medications and currently available strategies to reverse their antithrombotic effects in situations of severe hemorrhage. RECENT FINDINGS: Recent studies highlight the link between low fibrinogen and decreased fibrin polymerization in the development of acquired coagulopathy. Particularly, fibrin(ogen) deficits are observable after cardiopulmonary bypass in cardiac surgery, on arrival at the emergency room in trauma patients, and with ongoing bleeding after child birth. Regarding antithrombotic therapy, although new oral anticoagulants offer the possibility of efficacy and relative safety compared with vitamin K antagonists, reversal of their anticoagulant effect with nonspecific agents, including prothrombin complex concentrate, has provided conflicting results. Specific antidotes, currently being developed, are not yet licensed for clinical use, but initial results are promising. SUMMARY: Targeted hemostatic therapy aims to correct coagulopathies in specific clinical settings, and reduce the need for allogeneic transfusions, thus preventing massive transfusion and its deleterious outcomes. Although there are specific guidelines for reversing anticoagulation in patients treated with antiplatelet agents or warfarin, there is currently little evidence to advocate comprehensive recommendations to treat drug-induced coagulopathy associated with new oral anticoagulants. PMID- 25734870 TI - Improving parental stress levels among mothers living with HIV: a randomized control group intervention study. AB - Limited knowledge exists regarding parenting efficacy interventions for mothers living with HIV (MLH). This study evaluated the impact of a supportive group intervention on lowering parenting stress among MLH. Eighty MLH were randomized to a parenting (N=34) or health focused (control) (N=46) group intervention. Pre- and post-intervention stress levels were assessed using the Parental Stress Index Short Form (PSI/SF). Differences in PSI/SF scores were examined using ANOVA, and predictors of PSI/SF scores were evaluated using multivariable linear regression. Findings indicate that both groups experienced significant decreases in parenting stress from baseline to post-intervention (p=0.0001), with no significant differences between interventions. At baseline, 41% of participants were identified as highly stressed and 30% as clinically stressed, with PSI/SF scores above the 85(th) and 90(th) percentile, respectively. Amongst the highly stressed subpopulation, significant improvements in PSI/SF scores for Parental Distress PSI/SF (p=0.039), Difficult Child PSI/SF (p=0.048), and total PSI/SF (p=0.036) were seen, with greater improvements in the parenting intervention. Among the clinically stressed subpopulation, significant improvements in total post intervention PSI/SF scores were seen (p=0.049), with greater improvements in the parenting intervention. Results indicate that screening for high levels of stress should be considered in clinical practice to effectively implement stress reducing interventions among MLH. PMID- 25734871 TI - Pathological changes in the immune organs of broiler chickens fed on corn naturally contaminated with aflatoxins B1 and B2. AB - The purpose of this study was to evaluate the underlying basis for aflatoxin induced immunosuppression in the broiler chicken by detecting pathological lesions and apoptosis in thymus, bursa of Fabricius (BF) and spleen. COBB500TM male broiler chicks were randomly allocated to two groups. The control group was fed on a basal corn-based diet while the other group (the AFB group) was fed on a similar diet but the corn was naturally contaminated with aflatoxins B1 and B2. Histopathological examination revealed that in the AFB group there was more nuclear debris in the three immune organs and obvious congestion of red pulp in the spleen, when compared with the control group. Ultrastructural examination showed lesions in the lymphocytes and reticulocytes of the three immune organs, the mucosal epithelium of the BF and the plasmocytes of the spleen. Increased apoptotic cells and an impaired membrane system (including nuclear membrane, mitochondria and endoplasmic reticulum [ER]) could be observed in the three immune organs in birds of the AFB group. In the plasmocytes, dilated rough endoplasmic reticulum contained electron-dense matrix. By flow cytometry, the percentages of apoptosis were significantly higher (P < 0.01) in the three organs of the AFB group than those of the control group. These observations suggested that the lesions of the immune organs were related to the immunosuppression, and that the apoptosis might be initiated by the mitochondrial pathway and ER chaperone pathway. PMID- 25734872 TI - Masochism and pathological gambling. AB - That all pathological gamblers have an "unconscious wish to lose," an idea first expressed by Freud and Bergler, is neither true nor useful; wrong as well, however, are the reasons for neglecting masochism in relation to gambling. There is a small but clinically significant subgroup of pathological gamblers who are masochistic. I present clinical vignettes and a more extended treatment account to illustrate its importance. Masochism has been a confusing concept. As used here it refers to the deliberate seeking of pain, loss, suffering, or humiliation. There may be pleasure in pain, or an obligatory combining of pleasure and pain. A sense of power and control may be achieved through suffering. The case material illustrates clinically useful types (sexual masochism, masochistic personality disorder, moral masochism, relational masochism) as well as some common masochistic dynamics encountered in the treatment of pathological gamblers. These masochistic patterns are often identifiable during the initial evaluation. Distinguishing features may include a reversal of normal attitudes about winning and losing, the absence of an early winning phase, sometimes a memorable early loss. Gamblers may sabotage opportunities for success or create unnecessary obstacles for themselves. Losing may be more comfortable than winning or may be overtly sexualized. PMID- 25734873 TI - Discussion of masochism and pathological gambling: a review of masochism. PMID- 25734874 TI - Motivation, masochism, and slot machine gambling. AB - In the interaction between the rapidly proliferating slot gambling machines and Americans' minds and brains, there are subtle lures that keep people playing, and that even the game devisers do not fully understand. As they project onto the random machines, people enter a zone that resembles a meditative trance I have called praying to the god of chance. Masochism as it applies to gambling is a dynamic concept that requires the suffering to be viewed by imagined and projected parental imagos, who reward the gambler with love if not gambling success. Other motivations are evident in slot machine players, such as grief gambling and a fantasy of controlling losses. While gambling is as universal as religious instincts, state sponsorship of machine gambling is a conflict of interest for government, which is established to promote the general welfare, not addict the citizenry to raise revenues. PMID- 25734875 TI - Homicide-suicide and duty to warn. AB - This retrospective study of medical examiner records from three counties reported on 252 persons who killed 302 victims before killing themselves and reviews the Tarasoff ruling that set the standard for duty to warn and/or protect third parties whose lives are threatened by a patient. The three sites varied significantly for the perpetrator in terms of race, employment, cause of death, and motive. Female offenders killed more children under the age of 10 and adolescents than did male offenders. Evidence of premeditation included suicide notes and weapon brought to the crime scene, while strangulation indicated a spontaneous domestic homicide. Implications for practice are discussed including the importance of evaluating violent thoughts, fantasies, and behaviors in acute emergency settings and recommendations include second opinion consultation for Tarasoff-type cases and psychological autopsy review for completed homicide suicide cases. PMID- 25734876 TI - Psychodynamic systems of residential treatment: another view from Riggs. AB - Many patients lack the capacity to manage intense affects between therapy sessions, and as a result are caught in impasses as treatment becomes organized around fending off the next crisis or recovering from the last. Risk of suicide is often part of this presentation. Among the range of interventions that may help such patients emerge from impasse and treatment resistance is residential treatment, particularly psychodynamic residential treatment. We describe the role of residential treatment for such patients and offer an illustrative case example. PMID- 25734878 TI - Words apart: the challenge of using interpreters in psychodynamic psychotherapy. PMID- 25734877 TI - Psychodynamic considerations in psychotherapy using interpreters: perspectives from psychiatry residents. PMID- 25734879 TI - Visions: Umbria. PMID- 25734881 TI - Erratum. PMID- 25734883 TI - Atmospheric evolution of sulfur emissions from Kilauea: real-time measurements of oxidation, dilution, and neutralization within a volcanic plume. AB - The high atmospheric concentrations of toxic gases, particulate matter, and acids in the areas immediately surrounding volcanoes can have negative impacts on human and ecological health. To better understand the atmospheric fate of volcanogenic emissions in the near field (in the first few hours after emission), we have carried out real-time measurements of key chemical components of the volcanic plume from Kilauea on the Island of Hawai'i. Measurements were made at two locations, one ~ 3 km north-northeast of the vent and the other 31 km to the southwest, with sampling at each site spanning a range of meteorological conditions and volcanic influence. Instrumentation included a sulfur dioxide monitor and an Aerosol Chemical Speciation Monitor, allowing for a measurement of the partitioning between the two major sulfur species (gas-phase SO2 and particulate sulfate) every 5 min. During trade wind conditions, which sent the plume toward the southwest site, sulfur partitioning exhibited a clear diurnal pattern, indicating photochemical oxidation of SO2 to sulfate; this enabled the quantitative determination of plume age (5 h) and instantaneous SO2 oxidation rate (2.4 * 10(-6) s(-1) at solar noon). Under stagnant conditions near the crater, the extent of SO2 oxidation was substantially higher, suggesting faster oxidation. The particles within the plume were extremely acidic, with pH values (controlled largely by ambient relative humidity) as low as -0.8 and strong acidity (controlled largely by absolute sulfate levels) up to 2200 nmol/m(3). The high variability of sulfur partitioning and particle composition underscores the chemically dynamic nature of volcanic plumes, which may have important implications for human and ecological health. PMID- 25734884 TI - Comparison of fasting plasma glucose and glycated hemoglobin for diagnosing diabetes in a Taiwanese population. AB - BACKGROUND: The purposes of this study were to examine the impact of using glycated hemoglobin (HbA1c) as a diagnostic criterion for (pre)diabetes and to determine the appropriate HbA1c cutoff value in a Taiwanese population. METHODS: We used a dataset from the Clinical Informatics Research & Development Center of Taichung Veteran General Hospital. Fasting plasma glucose (FPG) and HbA1c test results were obtained from outpatient laboratory reports produced from January 1, 2011, to April 30, 2012. A total of 4920 blood tests were analyzed. For each potential HbA1c cutoff value, the sensitivity, specificity, positive and negative predictive values, and area under the receiver operator characteristic curve (AUC) were calculated at FPG levels of 100 and 126 mg/dL. Two-sample t- and chi sqaured tests were used to compare differences in characteristics between individuals matching the definitions of diabetes set by the American Diabetes Association (ADA) in 2009 and 2010. RESULTS: Among the 4920 study subjects, 580 people had an FPG value < 126 mg/dL and an HbA1c >= 6.5%. After the diagnostic criterion of HbA1c percentage was applied, the numbers of patients with normoglycemia and prediabetes decreased, whereas the number of diabetic patients increased. For FPG levels of 100 and 126 mg/dL, the HbA1c cutoff points were 5.95% and 6.35%, respectively. CONCLUSIONS: More patients were diagnosed with diabetes when HbA1c was added as a diagnostic criterion. HbA1c thresholds of 5.95% and 6.35% were highly specific for prediabetes and diabetes, respectively, in Taiwanese adults. PMID- 25734886 TI - High performance of low band gap polymer-based ambipolar transistor using single layer graphene electrodes. AB - Bottom-contact bottom-gate organic field-effect transistors (OFETs) are fabricated using a low band gap pDTTDPP-DT polymer as a channel material and single-layer graphene (SLG) or Au source/drain electrodes. The SLG-based ambipolar OFETs significantly outperform the Au-based ambipolar OFETs, and thermal annealing effectively improves the carrier mobilities of the pDTTDPP-DT films. The difference is attributed to the following facts: (i) the thermally annealed pDTTDPP-DT chains on the SLG assume more crystalline features with an edge-on orientation as compared to the polymer chains on the Au, (ii) the morphological features of the thermally annealed pDTTDPP-DT films on the SLG electrodes are closer to the features of those on the gate dielectric layer, and (iii) the SLG electrode provides a flatter, more hydrophobic surface that is favorable for the polymer crystallization than the Au. In addition, the preferred carrier transport in each electrode-based OFET is associated with the HOMO/LUMO alignment relative to the Fermi level of the employed electrode. All of these experimental results consistently explain why the carrier mobilities of the SLG based OFET are more than 10 times higher than those of the Au-based OTFT. This work demonstrates the strong dependence of ambipolar carrier transport on the source/drain electrode and annealing temperature. PMID- 25734887 TI - Implications for multiple sclerosis in the era of the Affordable Care Act: a clinical overview. AB - Multiple sclerosis (MS) is a chronic, often debilitating disease of the central nervous system (CNS) that affects between 400,000 and 570,000 persons in the United States, with an incidence among females 2 to 3 times that of males. The cause of MS is currently unknown, but immediate family history, low blood levels of vitamin D, and cigarette smoking, among other factors, appear to increase the risk of developing MS. MS is considered an immune-mediated disease, whereby immune cells target and attack the CNS, predominantly the axonal membrane known as the myelin sheath. Depending on which areas of the brain or spinal cord are affected, this can result in a variety of waxing and waning neurologic symptoms. Most patients will eventually suffer from progressive disability that can greatly impact their quality of life. Symptoms such as fatigue, difficulty with ambulation, and depression are common among patients with MS and can affect their ability to work and care for themselves. Costs due to treatment and lost productivity place a significant economic burden on patients, caregivers, families, and society. Current and future treatments may help limit the personal and societal costs of MS by delaying disability and disease progression. PMID- 25734885 TI - A novel bipartite centrosome coordinates the apicomplexan cell cycle. AB - Apicomplexan parasites can change fundamental features of cell division during their life cycles, suspending cytokinesis when needed and changing proliferative scale in different hosts and tissues. The structural and molecular basis for this remarkable cell cycle flexibility is not fully understood, although the centrosome serves a key role in determining when and how much replication will occur. Here we describe the discovery of multiple replicating core complexes with distinct protein composition and function in the centrosome of Toxoplasma gondii. An outer core complex distal from the nucleus contains the TgCentrin1/TgSfi1 protein pair, along with the cartwheel protein TgSas-6 and a novel Aurora-related kinase, while an inner core closely aligned with the unique spindle pole (centrocone) holds distant orthologs of the CEP250/C-Nap protein family. This outer/inner spatial relationship of centrosome cores is maintained throughout the cell cycle. When in metaphase, the duplicated cores align to opposite sides of the kinetochores in a linear array. As parasites transition into S phase, the cores sequentially duplicate, outer core first and inner core second, ensuring that each daughter parasite inherits one copy of each type of centrosome core. A key serine/threonine kinase distantly related to the MAPK family is localized to the centrosome, where it restricts core duplication to once per cycle and ensures the proper formation of new daughter parasites. Genetic analysis of the outer core in a temperature-sensitive mutant demonstrated this core functions primarily in cytokinesis. An inhibition of ts-TgSfi1 function at high temperature caused the loss of outer cores and a severe block to budding, while at the same time the inner core amplified along with the unique spindle pole, indicating the inner core and spindle pole are independent and co-regulated. The discovery of a novel bipartite organization in the parasite centrosome that segregates the functions of karyokinesis and cytokinesis provides an explanation for how cell cycle flexibility is achieved in apicomplexan life cycles. PMID- 25734888 TI - Implications for multiple sclerosis in the era of the Affordable Care Act: an evolving treatment paradigm. AB - The treatment paradigm for multiple sclerosis (MS) continues to evolve as additional pharmacotherapeutic options become available. Furthermore, treatment individualization has become more feasible as new medications with distinct mechanisms of action and improved adverse event profiles have reached the market. As such, clinicians should familiarize themselves with the available treatment options, paying particular attention to their various advantages and disadvantages. In order to offer patients optimal MS therapy, it is crucial for clinicians to stay current with the changing landscape of multiple sclerosis. This article provides a review of the available pharmacotherapeutic options for treating MS, discusses the impact of adherence to therapy, and describes the importance of managing comorbidities often experienced by patients with MS. PMID- 25734889 TI - Implications for multiple sclerosis in the era of the Affordable Care Act: the shifting managed care landscape. AB - Multiple sclerosis (MS) is a disorder of the central nervous system that is associated with disability, reduced quality of life, extensive medical and nonmedical costs, and lost productivity. Specialty medications that are crucial to effective disease management, helping to prevent debilitating episodes of relapse, account for a substantial portion of the medical expenditures associated with MS. Although these therapies are not considered cost-effective by conventional definitions, they are comparable to one another in cost effectiveness estimates, leaving the complex task of designing cost-efficient formulary management strategies to managed care professionals. Current epidemiologic data suggest that most patients with MS are covered by some form of healthcare insurance, but plan designs and formulary restrictions may still create access barriers for some patients. The Affordable Care Act (ACA) is recent federal legislation that seeks to provide new consumer protections, improve healthcare quality and accessibility while mitigating expenditures, and increase accountability of healthcare insurance companies. The impact of the ACA on specialty pharmaceuticals is unclear at this time, but it does appear to have already begun improving healthcare coverage across the population. Managed care professionals must work within the confines of the ACA to provide better and more affordable care that targets overall cost reductions rather than just pharmacy expenses. PMID- 25734890 TI - Local Rademacher Complexity: sharper risk bounds with and without unlabeled samples. AB - We derive in this paper a new Local Rademacher Complexity risk bound on the generalization ability of a model, which is able to take advantage of the availability of unlabeled samples. Moreover, this new bound improves state-of-the art results even when no unlabeled samples are available. PMID- 25734891 TI - Metsulfuron-methyl-based herbicidal ionic liquids. AB - Ten sulfonylurea-based herbicidal ionic liquids (HILs) were prepared by combining the metsulfuron-methyl anion with various cation types including quaternary ammonium ([bis(2-hydroxyethyl)methyloleylammonium](+), [2 hydroxyethyltrimethylammonium](+)), pyridinium ([1-dodecylpyridinium](+)), piperidinium ([1-methyl-1-propylpiperidinium](+)), imidazolium ([1-allyl-3 methylimidazolium](+), [1-butyl-3-methylimidazolium](+)), pyrrolidinium ([1-butyl 1-methylpyrrolidinium](+)), morpholinium ([4-decyl-4-methylmorpholinium](+)), and phosphonium ([trihexyltetradecylphosphonium](+) and [tetrabutylphosphonium](+)). Their herbicidal efficacy was studied in both greenhouse tests and field trials. Preliminary results for the greenhouse tests showed at least twice the activity for all HILs when compared to the activity of commercial Galmet 20 SG, with HILs with phosphonium cations being the most effective. The results of two-year field studies showed significantly less enhancement of activity than observed in the greenhouse; nonetheless, it was found that the herbicidal efficacy was higher than that of the commercial analog, and efficacy varied depending on the plant species. PMID- 25734892 TI - Skeletal octahedral nanoframe with Cartesian coordinates via geometrically precise nanoscale phase segregation in a Pt@Ni core-shell nanocrystal. AB - Catalytic properties of nanoparticles can be significantly enhanced by controlling nanoscale alloying and its structure. In this work, by using a facet controlled Pt@Ni core-shell octahedron nanoparticle, we show that the nanoscale phase segregation can have directionality and be geometrically controlled to produce a Ni octahedron that is penetrated by Pt atoms along three orthogonal Cartesian axes and is coated by Pt atoms along its edges. This peculiar anisotropic diffusion of Pt core atoms along the ?100? vertex, and then toward the ?110? edges, is explained via the minimum strain energy for Ni-Ni pair interactions. The selective removal of the Ni-rich phase by etching then results in structurally fortified Pt-rich skeletal PtNi alloy framework nanostructures. Electrochemical evaluation of this hollow nanoframe suggests that the oxygen reduction reaction (ORR) activity is greatly improved compared to conventional Pt catalysts. PMID- 25734893 TI - Multiple sclerosis: Biomarkers predict conversion from clinically isolated syndrome to multiple sclerosis. PMID- 25734894 TI - Beyond Negative Affectivity: A Hierarchical Model of Global and Transdiagnostic Vulnerabilities for Emotional Disorders. AB - BACKGROUND: Negative affectivity (NA) has been linked to anxiety and depression (DEP). Identifying the common factors between anxiety and DEP is important when explaining their overlap and comorbidity. However, general factors such as NA tend to have differential relationships with different disorders, suggesting the need to identify mediators in order to explicate these relationships. METHODS: The current study tests a theoretically and empirically derived hierarchical model of emotional disorders including both a general factor (NA) and transdiagnostic risk factors [anxiety sensitivity (AS) and intolerance of uncertainty (IoU)] using structural equation modeling. AS was tested as a mid level factor between NA and panic disorder/agoraphobia, while IoU was tested as a mid-level factor between NA and social phobia, generalized anxiety disorder, obsessive-compulsive disorder, and DEP. Data from 642 clinical outpatients with a heterogeneous presentation of emotional disorders were available for analysis. RESULTS: The hierarchical model fits the data adequately. Moreover, while a simplified model removing AS and IoU fits the data well, it resulted in a significant loss of information for all latent disorder constructs. LIMITATIONS: Data were unavailable to estimate post-traumatic stress disorder or specific phobias. Future work will need to extend to other emotional disorders. CONCLUSIONS: This study demonstrates the importance of both general factors that link disorders together and semi-specific transdiagnostic factors partially explaining their heterogeneity. Including these mid-level factors in hierarchical models of psychopathology can help account for additional variance and help to clarify the relationship between disorder constructs and NA. PMID- 25734895 TI - Growth hormone and early treatment. AB - Growth hormone (GH) treatment is approved by the US Food and Drug Administration (FDA) not only for GH deficiency (GHD) but also for other childhood growth disorders with growth failure and/or short stature. GHD is the most frequent endocrine disorder presenting with short stature in childhood. During neonatal period, metabolic effects due to congenital GHD require a prompt replacement therapy to avoid possible life-threatening complications. In childhood and adolescence, growth impairment is the most evident effect of GHD and early treatment has the aim of restore normal growth and to reach normal adult height. We reassume in this review the conditions causing GHD and the diagnostic challenge to reach an early diagnosis, and an early treatment, necessary to obtain the best results. Finally, we summarize results obtained in clinical studies about pediatric patients with GHD treated at an early age, in which a marked early catch-up growth and a normalization of adult height were obtained. PMID- 25734896 TI - Pedometer- and accelerometer-based exercise in subjects with diabetes mellitus. AB - AIM: Pedometers and accelerometers have recently become applicable for not only monitoring but increasing level of physical activity (PA). We summarize the effects of pedometer- and accelerometer-based exercise interventions on glucose metabolism in subjects with diabetes mellitus (DM). METHODS: We searched intervention studies that investigated the effects of step-defined exercise interventions using pedometers and accelerometers on the levels of glucose metabolism markers, such as plasma glucose and hemoglobin A1c (HbA1c), in adult subjects with type 2 DM. The study characteristics and findings of glucose metabolism markers were reviewed. RESULTS: Of 16 eligible studies reviewed, significant improvements in glucose metabolism markers were found in the intervention group compared to that observed in the control group in six studies: the HbA1c level in four studies, both the HbA1c and plasma glucose levels in one study and continuous glucose monitoring in one study. Four of these six studies emphasized a significance of PA intensity in addition to PA amount. Five studies found a significant increase in the number of steps, but only one of these studies showed significant reductions in glucose metabolism markers. No studies demonstrated a dose-response relationship between changes in the number of steps and glucose metabolism markers. CONCLUSION: Limited studies showed significant improvements in glucose metabolism markers and steps among subjects with type 2 DM. Future studies are needed regarding how to use pedometers and accelerometers to achieve improvements in glucose metabolism with increases in PA in such subjects, especially more focus on PA intensity. PMID- 25734897 TI - Domain-independent neural underpinning of task-switching: an fMRI investigation. AB - The ability to shift between different tasks according to internal or external demands, which is at the core of our behavioral flexibility, has been generally linked to the functionality of left fronto-parietal regions. Traditionally, the left and right hemispheres have also been associated with verbal and spatial processing, respectively. We therefore investigated with functional MRI whether the processes engaged during task-switching interact in the brain with the domain of the tasks to be switched, that is, verbal or spatial. Importantly, physical stimuli were exactly the same and participants' performance was matched between the two domains. The fMRI results showed a clearly left-lateralized involvement of fronto-parietal regions when contrasting task-switching versus single task blocks in the context of verbal rules. A more bilateral pattern, especially in the prefrontal cortex, was instead observed for switching between spatial tasks. Moreover, while a conjunction analysis showed that the core regions involved in task-switching, independently of the switching context, were localized both in left inferior prefrontal and parietal cortices and in bilateral supplementary motor area, a direct analysis of functional lateralization revealed that hemispheric asymmetries in the frontal lobes were more biased toward the left side for the verbal domain than for the spatial one and vice versa. Overall, these findings highlight the role of left fronto-parietal regions in task switching, above and beyond the specific task requirements, but also show that hemispheric asymmetries may be modulated by the more specific nature of the tasks to be performed during task-switching. PMID- 25734898 TI - Molecular modeling as a predictive tool for the development of solid dispersions. AB - In this study molecular modeling is introduced as a novel approach for the development of pharmaceutical solid dispersions. A computational model based on quantum mechanical (QM) calculations was used to predict the miscibility of various drugs in various polymers by predicting the binding strength between the drug and dimeric form of the polymer. The drug/polymer miscibility was also estimated by using traditional approaches such as Van Krevelen/Hoftyzer and Bagley solubility parameters or Flory-Huggins interaction parameter in comparison to the molecular modeling approach. The molecular modeling studies predicted successfully the drug-polymer binding energies and the preferable site of interaction between the functional groups. The drug-polymer miscibility and the physical state of bulk materials, physical mixtures, and solid dispersions were determined by thermal analysis (DSC/MTDSC) and X-ray diffraction. The produced solid dispersions were analyzed by X-ray photoelectron spectroscopy (XPS), which confirmed not only the exact type of the intermolecular interactions between the drug-polymer functional groups but also the binding strength by estimating the N coefficient values. The findings demonstrate that QM-based molecular modeling is a powerful tool to predict the strength and type of intermolecular interactions in a range of drug/polymeric systems for the development of solid dispersions. PMID- 25734899 TI - Density functional theory based analysis of photoinduced electron transfer in a triazacryptand based K+ sensor. AB - The electronic structure and photoinduced electron transfer processes in a K(+) fluorescent sensor that comprises a 4-amino-naphthalimide derived fluorophore with a triazacryptand ligand is investigated using density functional theory (DFT) and time-dependent density functional theory (TDDFT) in order to rationalize the function of the sensor. The absorption and emission energies of the intense electronic excitation localized on the fluorophore are accurately described using a DeltaSCF Kohn-Sham DFT approach, which gives excitation energies closer to experiment than TDDFT. Analysis of the molecular orbital diagram arising from DFT calculations for the isolated molecule or with implicit solvent cannot account for the function of the sensor, and it is necessary to consider the relative energies of the electronic states formed from the local excitation on the fluorophore and the lowest fluorophore -> chelator charge transfer state. The inclusion of solvent in these calculations is critical since the strong interaction of the charge transfer state with the solvent lowers its energy below the local fluorophore excited state making a reductive photoinduced electron transfer possible in the absence of K(+), while no such process is possible when the sensor is bound to K(+). The rate of electron transfer is quantified using Marcus theory, which gives a rate of electron transfer of k(ET) = 5.98 * 10(6) s(-1). PMID- 25734900 TI - Sphingosine-1-phosphate mediates ICAM-1-dependent monocyte adhesion through p38 MAPK and p42/p44 MAPK-dependent Akt activation. AB - Up-regulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation. Sphingosine-1-phosphate (S1P) has been shown to play a key role in inflammation via adhesion molecules induction, and then causes lung injury. However, the mechanisms underlying S1P-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. The effect of S1P on ICAM-1 expression was determined by Western blot and real-time PCR. The involvement of signaling pathways in these responses was investigated by using the selective pharmacological inhibitors and transfection with siRNAs. S1P markedly induced ICAM-1 expression and monocyte adhesion which were attenuated by pretreatment with the inhibitor of S1PR1 (W123), S1PR3 (CAY10444), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), PI3K (LY294002), or AP-1 (Tanshinone IIA) and transfection with siRNA of S1PR1, S1PR3, c-Src, EGFR, PDGFR, p38, p42, JNK1, c-Jun, or c-Fos. We observed that S1P-stimulated p42/p44 MAPK and p38 MAPK activation was mediated via a c Src/EGFR and PDGFR-dependent pathway. S1P caused the c-Src/EGFR/PDGFR complex formation. On the other hand, we demonstrated that S1P induced p42/p44 MAPK and p38 MAPK-dependent Akt activation. In addition, S1P-stimulated JNK1/2 phosphorylation was attenuated by SP600125 or PP1. Finally, S1P enhanced c-Fos mRNA levels and c-Jun phosphorylation. S1P-induced c-Jun activation was reduced by PP1, AG1478, AG1296, U0126, SP600125, SB202190, or LY294002. These results demonstrated that S1P-induced ICAM-1 expression and monocyte adhesion were mediated through S1PR1/3/c-Src/EGFR, PDGFR/p38 MAPK, p42/p44 MAPK/Akt-dependent AP-1 activation. PMID- 25734902 TI - Response to comment on "Methane emissions from process equipment at natural gas production sites in the United States: pneumatic controllers". PMID- 25734901 TI - Membrane environment modulates the pKa values of transmembrane helices. AB - In this work, we apply the recently developed constant pH molecular dynamics technique to study protonation equilibria of titratable side chains in the context of simple transmembrane (TM) helices and explore the effect of pH on their configurations in membrane bilayers. We observe that, despite a significant shift toward neutral states, considerable population of different side chains stay in the charged state that give rise to pKa values around 9.6 for Asp and Glu and 4.5 to 6 for His and Lys side chains, respectively. These charged states are highly stabilized by favorable interactions between head groups, water molecules, and the charged side chains that are facilitated by substantial changes in the configuration of the peptides. The pH dependent configurations and the measured pKa values are in good agreement with relatively recent solid state NMR measurements. Our results presented here demonstrate that all-atom constant pH molecular dynamics can be applied to membrane proteins and peptides to obtain reliable pKa values and pH dependent behavior for these systems. PMID- 25734903 TI - Tigecycline susceptibility and the role of efflux pumps in tigecycline resistance in KPC-producing Klebsiella pneumoniae. AB - KPC-producing Klebsiella pneumoniae isolates have emerged as important pathogens of nosocomial infections, and tigecycline is one of the antibiotics recommended for severe infections caused by KPC-producing K. pneumoniae. To identify the susceptibility profile of KPC-producing K. pneumoniae to tigecycline and investigate the role of efflux pumps in tigecycline resistance, a total of 215 KPC-producing K. pneumoniae isolates were collected. The minimum inhibitory concentration (MIC) of tigecycline was determined by standard broth microdilution tests. Isolates showing resistance to tigecycline underwent susceptibility test with efflux pump inhibitors. Expression levels of efflux pump genes (acrB and oqxB) and their regulators (ramA, marA, soxS and rarA) were examined by real-time PCR, and the correlation between tigecycline MICs and gene expression levels were analysed. Our results show that the tigecycline resistance rate in these isolates was 11.2%. Exposure of the tigecycline-resistant isolates to the efflux pump inhibitor NMP resulted in an obvious decrease in MICs and restored susceptibility to tigecycline in 91.7% of the isolates. A statistically significant association between acrB expression and tigecycline MICs was observed, and overexpression of ramA was found in three tigecycline-resistant isolates, further analysis confirmed ramR mutations existed in these isolates. Transformation of one mutant with wild-type ramR restored susceptibility to tigecycline and repressed overexpression of ramA and acrB. These data indicate that efflux pump AcrAB, which can be up-regulated by ramR mutations and subsequent ramA activation, contributed to tigecycline resistance in K. pneumoniae clinical isolates. PMID- 25734904 TI - Impact of TP53 codon 72 and MDM2 SNP 309 polymorphisms in pancreatic ductal adenocarcinoma. AB - Single-nucleotide polymorphisms (SNPs) of TP53 (codon 72, rs1042522) and MDM2 promoter (SNP 309, rs2279744) have been associated with risk for various human cancers. However, studies analyzing these polymorphisms in pancreatic ductal adenocarcinoma (PDAC) are lacking. We investigated TP53 codon 72 and MDM2 SNP 309 polymorphisms in 32 patients with PDAC, 16 patients with chronic pancreatitis (CP), and 32 normal controls, using formalin-fixed paraffin-embedded tissue. We also examined TP53 and MDM2 protein immunohistochemistry (IHC) to assess the involvement of these differences in malignant transformation and disease progression. TP53 Pro/Pro genotype was significantly more frequent in PDAC patients than in controls (65.6 vs. 15.6%, p < 0.001) and no significant difference was found between CP patients (37.5%) and controls. In MDM2 SNP 309, there were no significant differences among the three groups. Based on the Kaplan Meier analysis, overall survival was significantly shorter in MDM2 G/G genotypes compared with other genotypes (G/T and T/T) (359 vs. 911 days, p = 0.016) whereas no significant differences in TP53 genotypes were observed (638 vs. 752 days, p = 0.471). Although TP53 IHC was frequent in PDAC patients (53.1%), TP53 and MDM2 protein expression was not correlated with polymorphisms. Our study demonstrated TP53 codon 72 polymorphism is potentially a genetic predisposing factor while MDM2 SNP 309 polymorphism might be useful in predicting survival outcome. PMID- 25734906 TI - Fear of progression in patients with gastrointestinal stromal tumors (GIST): Is extended lifetime related to the Sword of Damocles? AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare and before 2000, patients had a dismal prognosis with a median survival of less than a year after tumor metastasis. However, the median overall survival has increased to more than five years following the introduction of imatinib and other tyrosine kinase inhibitors (TKI). Little is known about the psychosocial consequences of treatment of GIST, but this is important because patients now are treated and live for longer. This cross-sectional study assessed quality of life, distress, and fear of cancer recurrence or progression in patients with GIST. MATERIAL AND METHODS: Eighty-six patients with localized or metastatic GIST were asked to participate. Patients completed self-report questionnaires including the EORTC Quality of Life Questionnaire, Hospital Anxiety and Depression Scale, Impact of Event Scale, Cancer Worry Scale, and Fear of Cancer Recurrence Inventory. RESULTS: Fifty-four patients (median age 63.3 years) completed the questionnaires, 33 (61%) of whom were receiving TKI treatment at the time of the study. Overall, the GIST patients had a good global quality of life, but 28 patients had high levels of fear of cancer recurrence/progression. This high level of fear was not related to patient- or treatment-related variables. These patients experienced significantly higher levels of psychological distress, functional impairments, and difficulty making plans for the future than did patients with lower levels of fear. CONCLUSIONS: More attention should be paid to specific cancer-related problems, such as fear of cancer recurrence/progression, in addition to general quality of life issues in patients with GIST. PMID- 25734905 TI - Molecular epidemiology of imported cases of leishmaniasis in Australia from 2008 to 2014. AB - Leishmaniasis is a vector borne disease caused by protozoa of the genus Leishmania. Human leishmaniasis is not endemic in Australia though imported cases are regularly encountered. This study aimed to provide an update on the molecular epidemiology of imported leishmaniasis in Australia. Of a total of 206 biopsies and bone marrow specimens submitted to St Vincent's Hospital Sydney for leishmaniasis diagnosis by PCR, 55 were found to be positive for Leishmania DNA. All PCR products were subjected to restriction fragment length polymorphism analysis for identification of the causative species. Five Leishmania species/species complexes were identified with Leishmania tropica being the most common (30/55). Travel or prior residence in a Leishmania endemic region was the most common route of acquisition with ~47% of patients having lived in or travelled to Afghanistan. Cutaneous leishmaniasis was the most common manifestation (94%) with only 3 cases of visceral leishmaniasis and no cases of mucocutaneous leishmaniasis encountered. This report indicates that imported leishmaniasis is becoming increasingly common in Australia due to an increase in global travel and immigration. As such, Australian clinicians must be made aware of this trend and consider leishmaniasis in patients with suspicious symptoms and a history of travel in endemic areas. This study also discusses the recent identification of a unique Leishmania species found in native kangaroos and a potential vector host which could create the opportunity for the establishment of a local transmission cycle within humans. PMID- 25734907 TI - Real-time visualization of nanoparticles interacting with glioblastoma stem cells. AB - Nanoparticle-based therapy represents a novel and promising approach to treat glioblastoma, the most common and lethal malignant brain cancer. Although similar therapies have achieved significant cytotoxicity in cultured glioblastoma or glioblastoma stem cells (GSCs), the lack of an appropriate approach to monitor interactions between cells and nanoparticle-based therapies impedes their further clinical application in human patients. To address this critical issue, we first obtained NOTCH1 positive GSCs from patient-derived primary cultures. We then developed a new imaging approach to directly observe the dynamic nature of nanoparticles at the molecular level using in situ transmission electron microscopy (TEM). Utilizing these tools we were able to visualize real-time movements of nanoparticles interacting with GSCs for the first time. Overall, we show strong proof-of-concept results that real-time visualization of nanoparticles in single cells can be achieved at the nanoscale using TEM, thereby providing a powerful platform for the development of nanotherapeutics. PMID- 25734909 TI - The 6-min Walk Test Reflects Functional Capacity in Primary Care and Obese Patients. AB - The main purpose of this study was to determine the association between the 6-min walk test distance (6MWTD) and physical functional capacity (PF) in primary care patients, as well as in obese individuals. We studied 351 subjects (age=56.8+/ 14.6 years; BMI=29.4+/-5.7 kg/m(2); 68% women), including 141 obese subjects (BMI>=30 kg/m(2)), recruited in 10 different family practices. Physical (PCS) and mental component summary of the health-related quality of life (HRQOL) and the 8 sub-scores were measured using the Short Form-36 Health Survey. Anthropometry, vital signs and physical testing were measured according to standardized protocols. Recreational physical activity (LPA) and sedentary levels were determined using the Canadian Community Health Survey. In a stepwise multivariate analysis, 65% of the 6MWTD variance was explained by PF of the HRQOL, age, quadriceps strength, number of chronic diseases, LPA categories, BMI, resting heart rate, PCS, height and TV-viewing categories in primary care subjects. In the obese individuals, PF, age, quadriceps strength and BMI explained 57% of the 6MWTD variance. In these 2 groups, 44% of the 6MWTD variance is explained by PF only. To conclude, the 6MWTD is strongly associated with PF of the HRQOL. Thus, it adequately reflects physical limitations in daily life activities of primary care patients, including obese individuals. PMID- 25734908 TI - Occurrence of a multimeric high-molecular-weight glyceraldehyde-3-phosphate dehydrogenase in human serum. AB - Cellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a phylogenetically conserved, ubiquitous enzyme that plays an indispensable role in energy metabolism. Although a wealth of information is available on cellular GAPDH, there is a clear paucity of data on its extracellular counterpart (i.e., the secreted or extracellular GAPDH). Here, we show that the extracellular GAPDH in human serum is a multimeric, high-molecular-weight, yet glycolytically active enzyme. The high-molecular-weight multimers of serum GAPDH were identified by immunodetection on one- and two-dimensional gel electrophoresis using multiple antibodies specific for various epitopes of GAPDH. Partial purification of serum GAPDH by DEAE Affigel affinity/ion exchange chromatography further established the multimeric composition of serum GAPDH. In vitro data demonstrated that human cell lines secrete a multimeric, high-molecular-weight enzyme similar to that of serum GAPDH. Furthermore, LC-MS/MS analysis of extracellular GAPDH from human cell lines confirmed the presence of unique peptides of GAPDH in the high molecular-weight subunits. Furthermore, data from pulse-chase experiments established the presence of high-molecular-weight subunits in the secreted, extracellular GAPDH. Taken together, our findings demonstrate the presence of a high-molecular-weight, enzymatically active secretory GAPDH in human serum that may have a hitherto unknown function in humans. PMID- 25734910 TI - Tibiofemoral contact biomechanics following meniscocapsular separation and repair. AB - Meniscocapsular separations are often seen in knees with other intra-articular pathology. The consequences of these tears with regard to knee contact mechanics are currently unknown, and the biomechanical advantages of repair have not been measured. We hypothesize that tears to the meniscocapsular junction will cause an increase in tibiofemoral contact pressure and a decrease in contact area, with a return to more normal conditions after repair. 10 fresh-frozen cadaver knees each underwent 10 cycles of axial compressive loading in full extension under three different testing conditions: intact, meniscocapsular separation, and repair. A pressure sensor matrix was inserted into the medial joint space and used to measure magnitude and location of contact pressure and area. Mean contact pressure increased from 0.80+/-0.17 MPa in the intact knee to 0.88+/-0.19 MPa with separation, with a decrease to 0.78+/-0.14 MPa following repair. Peak pressures followed a similar trend with 2.59+/-0.41, 3.03+/-0.48, and 2.84+/-0.40 MPa for the same three groups, respectively. While none of the changes seen was statistically significant, even these small changes would potentially create degenerative changes at the articular surface over prolonged (i. e., months or years) standing, walking, and activity in the unrepaired state. PMID- 25734911 TI - Repeated cessation and resumption of resistance training attenuates increases in arterial stiffness. AB - Although high-intensity resistance training (RT) increases arterial stiffness, removing weightlifting stimuli returns arterial stiffness to baseline levels within relatively short periods during 4-8 weeks. This study investigates the effects of repeated RT cessation and resumption on arterial stiffness. Eighteen young healthy subjects were randomly assigned to a group that performed continuous RT (CRT, n=9) and a group that performed periodic RT (PRT, n=9). Both groups performed RT at 75% of one repetition maximum for 3 days per week. The CRT group continuously trained for 16 weeks, whereas the PRT group performed 3 cycles of 4 weeks training, with 2 weeks detraining intervals between cycles. The carotid-femoral pulse wave velocity in the CRT group significantly increased (P<0.05) at 4, 6, 10, 12, 16 and 20 weeks from baseline, whereas in the PRT group it significantly increased (P<0.05) after 4, 10 and 16 weeks from baseline, and was significantly lower (P<0.05) than that of the CRT group after 6, 10, 12, 16 and 20 weeks. Muscle mass and strength in the both groups significantly increased after 16 weeks from baseline and persisted for 20 weeks (P<0.05). These results suggest that PRT, including short-term repeated cessation and resumption, attenuates increases in arterial stiffness. PMID- 25734912 TI - Activity Profiles of Successful and Less-successful Semi-elite Rugby League Teams. AB - This study investigated whether match intensities during predefined periods differed among successful and less-successful rugby league teams. 4 semi-elite rugby league teams were split into 'high-success' and 'low-success' groups based on their success rates. Movement was recorded using a global positioning system (10 Hz) during 20 rugby league matches. Following the peak ball-in-play time period, the high-success group was able to maintain ball-in-play time that was: (1) 22% greater than the low-success group (P=0.01) and (2) greater than their mean period of match-play (P=0.01). In the peak and mean periods of match play, hit-up forwards from the high-success group covered less total distance (P=0.02; P=0.01), less high-intensity running distance (P=0.01; P=0.01) and were involved in a greater number of collisions (P=0.03; P=0.01) than hit-up forwards from the low-success group. These results demonstrate that greater amounts of high intensity running and total distance are not related to competitive success in semi-elite rugby league. Rather, competitive success is associated with involvement of hit-up forwards in a greater number of collisions and the ability of high-success teams to maintain a higher ball-in-play time following the peak period. Strength and conditioning programs that: (1) emphasize high-intensity running and neglect to combine these running demands with collisions, and (2) do not offer exposure to match specific ball-in-play time demands, may not provide sufficient physiological preparation for teams to be successful in rugby league. PMID- 25734913 TI - Effects of repeated concentric and eccentric contractions on tendon blood circulation. AB - Previous studies demonstrated that treatment involving eccentric training was effective in the conservative management of chronic tendinosis. However, the mechanisms for these phenomena are unknown. The purpose of this study was to compare changes in blood circulation of the tendons after the repeated concentric and eccentric contractions. 11 healthy males volunteered for this study. Subjects performed the repeated concentric (CON) and eccentric (ECC) contractions (5 sets of 10 maximal voluntary contractions) of the plantar flexors. During and after repeated contractions, oxyhemoglobin (Oxy), deoxyhemoglobin (Deoxy), total hemoglobin (THb), and oxygen saturation (StO2) of the Achilles tendons were measured using red laser lights. Oxy and THb increased during and after ECC, but not CON. Deoxy decreased during both CON and ECC. Increase in StO2 during and after ECC was greater than that during and after CON. These results suggested that changes in blood circulation of the Achilles tendon during and after repeated eccentric contractions were more remarkable than those during and after repeated concentric contractions. PMID- 25734914 TI - The Effect of Stress and Recovery on Field-test Performance in Floorball. AB - Physical and psychosocial stress and recovery are important performance determinants. A holistic approach that monitors these performance determinants over a longer period of time is lacking. Therefore this study aims to investigate the effect of a player's physical and psychosocial stress and recovery on field test performance. In a prospective non-experimental cohort design 10 female Dutch floorball players were monitored over 6 months. To monitor physical and psychosocial stress and recovery, daily training-logs and 3-weekly the Recovery Stress Questionnaire for Athletes (RESTQ-Sport) were filled out respectively. To determine field-test performance 6 Heart rate Interval Monitoring System (HIMS) and 4 Repeated Modified Agility T-test (RMAT) measurements were performed. Multilevel prediction models were applied to account for within-players and between-players field-test performance changes. The results show that more psychosocial stress and less psychosocial recovery over 3-6 weeks before testing decrease HIMS performance (p<=0.05). More physical stress over 6 weeks before testing improves RMAT performance (p<=0.05). In conclusion, physical and psychosocial stress and recovery affect submaximal interval-based running performance and agility up to 6 weeks before testing. Therefore both physical and psychosocial stress and recovery should be monitored in daily routines to optimize performance. PMID- 25734915 TI - A phase II study to evaluate lenalidomide in combination with metronomic-dose cyclophosphamide in patients with heavily pretreated classical Hodgkin lymphoma. AB - BACKGROUND: Relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT) remains a challenge. For these patients treatments with different mechanisms of action rather than classical chemotherapy are needed. PATIENTS AND METHODS: Patients with R/R cHL after ASCT were recruited in a phase II trial (EUDRA CT: 2009-016588-12). Lenalidomide was administered at 20 mg/day for 21 days and cyclophosphamide at 50 mg/day for 28 days (cycles every 28 days). Dose escalation for lenalidomide was permitted. In 2009 we considered that this treatment would be promising if response rate were over 60% and a Simon two-stage binomial design was used to calculate the sample size. A total of 46 patients were planned but the trial would be stopped if less than seven responses after four cycles were obtained in the first 16 patients. RESULTS: The trial was closed early because only five responses were observed after four cycles in the first 16 patients included. Median age was 34 years (18 77). The median number of previous lines was five (2-6). At inclusion, 10 patients were primary refractory and 11 refractory to the last therapy. A total of 110 cycles were administered, with grade>=3 toxicity in 43 cycles (39%). One non-neutropenic patient developed septic shock resulting in death. An ORR of 38% (1 CR and 5 PR) was observed and a total of 10 patients (62%) achieved clinical benefit. Median progression free survival and overall survival were seven and 19 months, respectively. With a median follow-up of 19 months (3-38+), three-year progression-free and overall survival were 6% and 31%, respectively. CONCLUSION: The optimistic assumptions of this trial led to an early closure. However, the promising clinical benefit observed with the oral combination of lenalidomide and metronomic cyclophosphamide may justify its use for outpatient palliative treatment. PMID- 25734916 TI - Chiroptical studies on brevianamide B: vibrational and electronic circular dichroism confronted. AB - Chiroptical spectroscopies, such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD), are highly sensitive techniques to probe molecular conformation, configuration, solvation, and aggregation. Here we report the application of these techniques to study the fungal metabolite brevianamide B. Comparison of the experimental ECD and VCD spectra with the density functional theory simulated counterparts establishes that VCD is the more reliable technique to assign absolute configuration due to the larger functional and dispersion dependence of computed ECD spectra. Despite a low amount of available material and a relatively unusual example of using VCD carbonyl multiplets, the absolute configuration could be reliably predicted, strengthening the case for application of VCD in the study of complex natural products. Spectral and crystallographic evidence for or against the formation of a dimeric aggregate is discussed; in solution, the VCD spectra strongly suggest only monomeric species are present. PMID- 25734917 TI - FASTAptamer: A Bioinformatic Toolkit for High-throughput Sequence Analysis of Combinatorial Selections. AB - High-throughput sequence (HTS) analysis of combinatorial selection populations accelerates lead discovery and optimization and offers dynamic insight into selection processes. An underlying principle is that selection enriches high fitness sequences as a fraction of the population, whereas low-fitness sequences are depleted. HTS analysis readily provides the requisite numerical information by tracking the evolutionary trajectory of individual sequences in response to selection pressures. Unlike genomic data, for which a number of software solutions exist, user-friendly tools are not readily available for the combinatorial selections field, leading many users to create custom software. FASTAptamer was designed to address the sequence-level analysis needs of the field. The open source FASTAptamer toolkit counts, normalizes and ranks read counts in a FASTQ file, compares populations for sequence distribution, generates clusters of sequence families, calculates fold-enrichment of sequences throughout the course of a selection and searches for degenerate sequence motifs. While originally designed for aptamer selections, FASTAptamer can be applied to any selection strategy that can utilize next-generation DNA sequencing, such as ribozyme or deoxyribozyme selections, in vivo mutagenesis and various surface display technologies (peptide, antibody fragment, mRNA, etc.). FASTAptamer software, sample data and a user's guide are available for download at http://burkelab.missouri.edu/fastaptamer.html. PMID- 25734918 TI - Correction: atorvastatin improves survival in septic rats: effect on tissue inflammatory pathway and on insulin signaling. PMID- 25734919 TI - Aberrant methylation inactivates somatostatin and somatostatin receptor type 1 in head and neck squamous cell carcinoma. AB - PURPOSE: The aim of this study was to define somatostatin (SST) and somatostatin receptor type 1 (SSTR1) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker. METHODS: Gene expression was measured by quantitative RT-PCR. Promoter methylation status was determined by quantitative methylation-specific PCR (Q-MSP) in HNSCC. RESULTS: Methylation was associated with transcription inhibition. SST methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040). SSTR1 hypermethylation in 64% of cases was correlated with tumor size (P = 0.037), stage (P = 0.037), SST methylation (P < 0.001), and expression of galanin (P = 0.03), GALR2 (P = 0.014), TAC1 (P = 0.023), and tachykinin receptor type 1 (TACR1) (P = 0.003). SST and SSTR1 promoter hypermethylation showed highly discriminating receiver operator characteristic curve profiles, which clearly distinguished HNSCC from adjacent normal mucosal tissues. Concurrent hypermethylation of galanin and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.0001). Among patients with oral cavity and oropharynx cancer, methylation of both SST and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.028). In multivariate logistic-regression analysis, concomitant methylation of galanin and SSTR1 was associated with an odds ratio for recurrence of 12.53 (95% CI, 2.62 to 59.8; P = 0.002). CONCLUSIONS: CpG hypermethylation is a likely mechanism of SST and SSTR1 gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker. PMID- 25734920 TI - High Prevalence of Escherichia coli-Producing CTX-M-15 Extended-Spectrum Beta Lactamases in Poultry and Human Clinical Isolates in Romania. AB - Use of antibiotics in food animals may contribute to development and spread of resistant organisms, particularly so in some countries. The aim of this study was two-fold; first, to establish the prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in chicken production in a region within Romania. Second, to study the relatedness of ESBL-producing E. coli isolates recovered from broilers, abattoir workers where the chickens were slaughtered and from the human clinical specimens from two regional hospitals. The results indicated a very high (69%) rate of carriage of ESBL and AmpC-producing E. coli in chickens with 36% CTX-M producers. Sequencing showed that chickens in Romania have the highest worldwide prevalence (53%) of blaCTX-M-15 reported in poultry E. coli isolates. The majority (53%) of the extended-spectrum cephalosporin resistant E. coli carried plasmid-mediated blaampC genes, mostly blaCMY-2 type, one of the highest prevalences reported in Europe. The predominant CTX-M type found in the human clinical E. coli isolates was blaCTX-M-15 and most isolates coharbored blaOXA-1, blaTEM, and aac(6')-ib-cr. The majority (60%) of the human clinical isolates belonged to the pandemic virulent clone B2-ST131. The clonal relationship between broiler and the human CTX-M-producing E. coli isolates was assessed by macrorestriction pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), which indicated strain diversity with no common STs found between human and poultry isolates. Moreover, IncI1 was the most prevalent replicon found in broiler ESBL-producing E. coli isolates and also in transconjugants, indicating that plasmids and not clonal spread may play a role in the transfer of blaCTX-M genes. This study identifies a high prevalence of ESBL-producing E. coli from broiler chickens in Romania with a high occurrence incidence of blaCTX-M-15, which reflects the main ESBL type found in human E. coli infections in this country. PMID- 25734921 TI - Spirituality as a scientific construct: testing its universality across cultures and languages. AB - Using data obtained from 4004 participants across eight countries (Canada, India, Japan, Korea, Poland, Slovakia, Uganda, and the U.S.), the factorial reliability, validity and structural/measurement invariance of a 30-item version of Expressions of Spirituality Inventory (ESI-R) was evaluated. The ESI-R measures a five factor model of spirituality developed through the conjoint factor analysis of several extant measures of spiritual constructs. Exploratory factor analyses of pooled data provided evidence that the five ESI-R factors are reliable. Confirmatory analyses comparing four and five factor models revealed that the five dimensional model demonstrates superior goodness-of-fit with all cultural samples and suggest that the ESI-R may be viewed as structurally invariant. Measurement invariance, however, was not supported as manifested in significant differences in item and dimension scores and in significantly poorer fit when factor loadings were constrained to equality across all samples. Exploratory analyses with a second adjective measure of spirituality using American, Indian, and Ugandan samples identified three replicable factors which correlated with ESI R dimensions in a manner supportive of convergent validity. The paper concludes with a discussion of the meaning of the findings and directions needed for future research. PMID- 25734922 TI - Factors Affecting Staff Perceptions of Tele-ICU Service in Rural Hospitals. AB - INTRODUCTION: Telemedicine is designed to increase access to specialist care, especially in settings distant from tertiary-care centers. One of the more established telemedicine applications in hospitals is the tele-intensive care unit (tele-ICU). Perceptions of tele-ICU users are not well studied. Thus, we undertook a study focused on assessing staff acceptance at multiple hospitals that had implemented a tele-ICU system. MATERIALS AND METHODS: We designed a survey instrument that gathered perceptions on multiple facets of tele-ICU use and administered it to clinical and administrative staff at 28 hospitals that had implemented a tele-ICU system. We also conducted interviews at half of these hospitals to gain a deeper understanding of factors affecting staff perceptions of tele-ICU services. RESULTS: The 145 survey respondents were generally positive about all facets of the service. Analyses found no significant differences in comparisons between critical access and larger hospitals or between clinical and administrative/managerial respondents, although a few differences between providers and nurses emerged. Respondents at hospitals averaging more tele-ICU use and that had implemented it longer were significantly (p<0.05) more positive in their responses on multiple survey items than other respondents. Interviews corroborated and provided insight into survey responses. CONCLUSIONS: Tele-ICU was particularly valued when critical access hospitals retained critical care patients during special circumstances and when the tele-ICU hub could monitor patients to provide relief for local providers and nurses. Tele-ICU can aid rural hospitals, but multiple delivery models are warranted to meet disparate needs. PMID- 25734923 TI - Corneal abrasion in hysterectomy and prostatectomy: role of laparoscopic and robotic assistance. AB - BACKGROUND: Radical prostatectomy (RP) is most commonly performed laparoscopically with a robot (robotic-assisted laparoscopic radical prostatectomy, R/PROST). Hysterectomy, which may be open hysterectomy (O/HYST) or laparoscopic hysterectomy (L/HYST), has been increasingly frequently done via robot (R/HYST). Small case series suggest increased corneal abrasions (CAs) with less invasive techniques. METHODS: The authors identified RP (166,942), O/HYST (583,298), or L/HYST (216,890) discharges with CA in the Nationwide Inpatient Sample (2000-2011). For 2009-2011, they determined odds ratios (ORs) and 95% confidence intervals (CIs) for CA, in R/PROST, non-R/PROST, L/HYST, O/HYST, and R/HYST. Uni- and multivariate models studied CA risk depending on surgical procedure, age, race, year, chronic illness, and malignancy. RESULTS: In 2000 2011, 0.18% RP, 0.13% L/HYST, and 0.03% O/HYST sustained CA. Compared with 17,554 non-R/PROSTs (34 abrasions, 0.19%) in 2009-2011, OR was not significantly higher in 28,521 R/PROSTs (99, 0.35%; OR 1.508; CI 0.987 to 2.302; P < 0.057). CA significantly increased in L/HYST (70/51,323; 0.136%) versus O/HYST (70/191,199; 0.037%; OR 3.821; CI 2.594 to 5.630; P < 0.0001), further increasing in R/HYST (63/21, 213; 0.297%; OR 6.505; CI 4.323 to 9.788; P < 0.0001). For hysterectomy, risk of CA increased with age (OR 1.020; CI 1.007 to 1.034; P < 0.003) and number of chronic conditions (OR 1.139; CI 1.065 to 1.219; P < 0.0001). CA risk was likewise elevated in R/HYST with number of chronic conditions. Being African American significantly decreased CA risk in R/PROST and in R/HYST or L/HYST. CONCLUSIONS: L/HYST increased CA nearly four-fold, and R/HYST approximately 6.5 fold versus O/HYST. Identifiable preoperative factors are associated with either increased risk (age, chronic conditions) or decreased risk (race). PMID- 25734924 TI - Genotyping and characterization of CTX-M-15 -producing Klebsiella pneumoniae isolated from an Iranian hospital. AB - The aims were to describe the genetic characterization of blaCTX-M-1 group gene in Klebsiella pneumoniae and to investigate the relationship between isolates by MLVA and PFGE. We analyzed 36 CTX-M group 1-ESBL producing K. pneumoniae. rmpA and wcaG virulence genes were identified by PCR. The genetic environment of blaCTX-M-1 was analyzed by PCR and sequencing. Plasmid replicons were determined using PCR-based replicon typing. The isolates were typed by MLVA and PFGE. All blaCTX-M-1 were blaCTX-M-15. The wcaG and rmpA were detected in 1 and 2 isolates, respectively. IncF were the most frequently detected replicons (63.88%). In all isolates, ISEcp1 was found upstream and orf477 downstream of blaCTX-M-15, IS26 was found in two isolates. MLVA identified 20 MLVA types, whereas PFGE identified 25 different profiles. The dissemination of CTX-M-15 in our isolates was due to the clonal spread of isolates and to the genetic transfer of mobile elements among unrelated strains. PMID- 25734925 TI - Comparison of patient outcomes in Magnet(r) and non-magnet hospitals. PMID- 25734926 TI - Author response. PMID- 25734927 TI - Group think, organizational strategy, and change. AB - This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author discusses group think and the effect on organizational strategy and sustainable change. PMID- 25734928 TI - Exemplary professional practice: the core of a magnet(r) organization. AB - This month, the director of the Magnet Recognition Program(r) provides an in depth look at the Magnet(r) Model component exemplary professional practice, what it takes to establish such a practice, and how it can help organizations achieve extraordinary results. PMID- 25734929 TI - Complexity and change in nurse workflows. AB - As systems evolve over time, their natural tendency is to become increasingly more complex. Studies in the field of complex systems have generated new perspectives on management in social organizations such as hospitals. Much of this research appears as a natural extension of the cross-disciplinary field of systems theory. This is the 20th in a series of articles applying complex systems science to the traditional management concepts of planning, organizing, directing, coordinating, and controlling. In this article, the authors discuss how nurse workflow is characteristic of complex adaptive systems and the need for caution when selecting a performance improvement method. PMID- 25734930 TI - Nurses' perceptions of patient rounding. AB - OBJECTIVE: This descriptive pilot study explored hospital staff nurses' perceptions toward the practice of patient rounding. BACKGROUND: Rounding has re emerged as a standard practice initiative among nurses in hospitals and has been associated with a decrease in call lights and falls, increased patient satisfaction and safety, and quieter nursing units. Regardless of these outcomes, controversy exists among nurses regarding rounding. METHODS: The Nurses' Perception of Patient Rounding Scale (K. Neville, unpublished manuscript, 2010) was developed to gain an understanding of nurses' perceptions of rounding. RESULTS: Nurses identified rounding as valuable and perceived hourly rounding to be beneficial to patients and families but significantly less beneficial to their own professional practice. Challenges to rounding as a practice include issues of documentation, patient ratios, and skill mix. CONCLUSION: Findings support the need for further research to address the challenges of patient rounding for nursing. PMID- 25734931 TI - Objective measurement of critical-thinking ability in registered nurse applicants. AB - This first part of a 2-phase study examined the relationship between general pediatric nursing knowledge, critical thinking (CT) ability of newly hired nurse, as determined by a custom Health Education System Inc exam and the length of orientation necessary to meet the required clinical competencies. A descriptive correlational study design was used to administer the customized computer-based examination to 98 nurses at the beginning of employment at a large pediatric healthcare organization. The examination results were statistically significant in the determination of CT ability and a correlation to the ability to provide clinically competent patient care. The custom examination provided an objective measurement of CT ability in the nurse's specific domain of knowledge. PMID- 25734932 TI - Application of simulation technology to enhance the role of the professional nurse. AB - With the expected nursing shortfall, uncertain economy, and projected increase in volume of persons requiring healthcare, the current models of care delivery cannot be sustained. New delivery models are necessary to maximize nurses' knowledge, expertise, and time. The authors describe the use of computer simulation using principles of Lean to help design a care delivery model with an enhanced role for the professional nurse. PMID- 25734933 TI - Energy capacity model for nurses: the impact of relaxation and restoration. AB - OBJECTIVE: This study assessed the effect of stress management techniques and a restoration room on energy renewal of nurses. BACKGROUND: Nursing stress is linked to increased turnover, decreased well-being, and decreased decision-making capabilities. Energy renewal may be an effective method of addressing stress induced exhaustion and its negative effects. METHODS: Stress reduction techniques and a restoration room were provided on a pilot unit. Results were measured with the Nursing Stress Scale (NSS), payroll data, and room usage diaries. RESULTS: There was an overall reduction in NSS scores. The room was used less often than anticipated. The sample size was inadequate to measure reduction in unplanned time off. Anecdotally, nurses felt positive about the room and continue to use it. Results were limited by sample size and a positive baseline work environment but promising enough to explore further. CONCLUSIONS: Results suggest that further study is warranted with a larger sample in Magnet(r) and non-Magnet settings. PMID- 25734934 TI - Implementation of 2 nurse practitioner inpatient models. AB - Opportunities for nurse practitioners in acute care settings are expanding owing to the restricted hours for medical residents. This is coupled with national initiatives to improve the quality of care driven by patients, insurers, and national healthcare organizations that wish to enhance access to healthcare for all Americans. The authors discuss 2 care delivery models that were designed and implemented at Massachusetts General Hospital with nurses acting as full partners in the redesign. PMID- 25734935 TI - Promoting a culture of international professional practice for nursing through a twinning relationship. AB - This article illustrates the impact of a twinning relationship between the nursing services of Huashan Hospital, Fudan University (HH), in Shanghai, China, and of Massachusetts General Hospital (MGH) in Boston, Massachusetts. Through twinning, the healthcare leaders and nursing staff at HH learned key concepts, skills, and methods from their MGH colleagues, enhancing the role, presence, and overall impact of nursing in their organization. Strategies to advance a nursing leadership development agenda included establishing twinning relationships and immersing nurse leaders into each other's practice arena via nurse visitation exchanges. This collaborative effort, although only 3 years old, begins the process of modeling twinning for replication among nurses and across organizations internationally. Improvements in nursing care delivery and patient care at both organizations are attributed to this project. PMID- 25734937 TI - Electrical Myostimulation (EMS) Improves Glucose Metabolism and Oxygen Uptake in Type 2 Diabetes Mellitus Patients--Results from the EMS Study. AB - AIMS: In patients with type 2 diabetes mellitus (T2DM) exercise training is recommended to improve glycemic control. Electrical myostimulation (EMS) of skeletal muscles is a new method to increase exercise capacity in patients with chronic heart failure. The aim of this study was to investigate the effects of EMS in T2DM on glucose metabolism, body composition, and exercise performance using a newly designed stimulation suit that involves trunk, leg, and arm muscles. SUBJECTS AND METHODS: Fifteen individuals (nine males; 61.7+/-14.8 years old) were trained for 10 weeks twice weekly for 20 min with EMS. Effects on glucose, glycosylated hemoglobin (HbA(1c)), oxygen consumption, and body composition were evaluated. RESULTS: There was a significant increase of oxygen uptake at the aerobic threshold from 12.3+/-0.8 to 13.3+/-0.7 mL/kg/min (P=0.003) and of maximal work capacity from 96.9+/-6.4 to 101.4+/-7.9 W (P=0.046), with a concomitant trend for improved maximal oxygen uptake (from 14.5+/-0.9 to 14.7+/ 0.9 mL/kg/min [P=0.059]). Fasting blood glucose level decreased from 164.0+/-12.5 to 133.4+/-9.9 mg/dL (P=0.001), and HbA(1c) level decreased from 7.7+/-0.3% to 7.2+/-0.3% (P=0.041), whereas mean total weight (from 101.5+/-4.0 to 103.1+/-4.3 kg) and proportion of body fat (from 38.8+/-3.2% to 40.3+/-3.4%) remained statistically unchanged. CONCLUSIONS: EMS can improve glucose metabolism and functional performance in T2DM patients. These data suggest that EMS might emerge as a novel additional therapeutic mode of exercise training and might help patients to overcome their sedentary lifestyle. PMID- 25734936 TI - Perturbation of the c-Myc-Max protein-protein interaction via synthetic alpha helix mimetics. AB - The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic alpha-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer's binding to its canonical E-box DNA sequence without causing protein protein dissociation, heralding a new mechanistic class of "direct" c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc-Max heterodimers over Max-Max homodimers with IC50 values as low as 5.6 MUM. Finally, these compounds inhibited the proliferation of c-Myc expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc-Max heterodimers remained intact. PMID- 25734938 TI - Pharmacokinetic studies of ginkgolide K in rat plasma and tissues after intravenous administration using ultra-high performance liquid chromatography tandem mass spectrometry. AB - Ginkgolide K (GK), a derivative compound of ginkgolide B, has been recently isolated from the leaves of Ginkgo biloba. It is a powerful natural platelet activate factor (PAF) antagonist, and also has obvious protect effects for cerebral ischemia. However, no reports have been described for the pharmacokinetic study of GK. In this study, a simple, sensitive and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method has been developed for the determination of GK in rat plasma and tissues. Biological samples were pretreated by an efficient liquid-liquid extraction with ethyl acetate. The chromatographic separation was achieved on an Agilent ZORBAX SB-Aq column (4.6 mm * 50 mm, 1.8 MUm) with a mobile phase of 0.5% aqueous formic acid (A)-menthol (B). Quantitation was carried out on a triple quadruple mass spectrometry using positive electrospray ionization in multiple reaction monitoring mode. Diazepam was used as internal standard (IS). The ion transitions monitored were set at m/z 407.10 -> 389.20 and m/z 285.08 -> 193.10 for GK and IS, respectively. The developed method was fully validated and successfully applied to the pharmacokinetics and tissue distribution study of GK after intravenous administration. The current results have indicated that pharmacokinetic parameters of GK vary in a dose-dependent manner with rapid elimination in 4h. The major distribution tissues of GK in rats were liver and kidney. This study would provide critical information to promote the future study of GK. PMID- 25734939 TI - Development of a solvent-free analytical method for paracetamol quantitative determination in Blood Brain Barrier in vitro model. AB - A Reversed Phase-High Performance Liquid Chromatography/Diode Array Detection method was developed and validated for paracetamol quantification in cell culture fluid from an in vitro Blood Brain Barrier model. The chromatographic method and sample preparation were developed using only aqueous solvents. The column was a XTerra RP18 150 * 4.6mm, 3.5 MUm with a guard column XTerra RP18 20 * 4.6 mm, 3.5 MUm at 35 degrees C and the mobile phase was composed by 100% formate buffer 20 mM at pH 4 and flow rate was set at 1 mL/min. The detection was at 242 nm. The sample was injected at 10 MUL. Validation was performed using the accuracy profile approach. The analytical procedure was validated with the acceptance limits at +/- 10% over a range of concentration from 1 to 58 mg L(-1). The procedure was then used in routine to determine paracetamol concentration in a brain blood barrier in vitro model. Application of the Unither paracetamol formulation in Blood Brain Barrier model allowed the determination and comparison of the transcellular passage of paracetamol at 37 degrees C and 4 degrees C, that excludes paracellular or non specific leakage. PMID- 25734940 TI - Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion. AB - In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan. PMID- 25734941 TI - Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score. AB - BACKGROUND: Limited data exists regarding biomarker use to predict left ventricular (LV) reverse remodeling (R2). Our aim was to examine the value of soluble ST2 (ST2), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT), and galectin-3 relative to LV-R2 in systolic heart failure (HF), and to develop a clinical score for LV-R2 prediction. METHODS: R2 was defined as a) LV ejection fraction (LVEF) increase >=15%, or b) LVEF increase >=10% plus reduction of LV end-systolic diameter index >=20% or LV end-systolic volume >=40%, for 12 months. RESULTS: We studied 304 patients (79.6% men, mean age 66.1 +/- 12.3 years) with baseline LVEF <40%. R2 was observed in 104 patients (34.2%). In univariable logistic regression, factors associated with R2 were age (p=0.02), non-ischemic etiology of HF (p<0.001), NYHA functional class (p=0.02), baseline LVEF (p=0.005), absence of left bundle branch block (LBBB; p=0.002), ST2 (p=0.004), NT-proBNP (p=0.005), and hs-cTnT (p<0.001); HF duration achieved borderline significance (p=0.08). In multivariable analysis, ST2 remained the only biomarker associated with LV-R2. We developed the ST2-R2 score for use in clinical practice for predicting R2; variables included were ST2 <48 ng/mL, non-ischemic etiology, absence of LBBB, HF duration <12 months, baseline LVEF <24%, and beta-blocker treatment. The score had an area under the curve of 0.79 in the derivation cohort and 0.73 in a separate validation cohort. CONCLUSIONS: The ST2-R2 score, which includes the novel biomarker ST2 and five clinical variables, reasonably predicts LV-R2 in systolic HF patients. ST2 was the only studied biomarker that was independently associated with R2. PMID- 25734942 TI - Effects of a hydroxyapatite-coated nanotube surface of titanium on MC3T3-E1 cells: an in vitro study. AB - PURPOSE: To compare the biological behavior of mouse osteoblast-like cells (MC3T3 E1) on hydroxyapatite (HA)-coated nanotube surface of titanium and plasma-sprayed HA (HA-PS)-coated titanium surface. MATERIALS AND METHODS: The HA-coated nanotube surface of titanium were fabricated by anodization coupled with alternative immersion method (AIM). MC3T3-E1 osteoblast cells cultured in vitro were seeded onto these different surfaces; their growth states were examined by a confocal laser scanning microscope; the proliferation behavior, alkaline phosphatase (ALP) activity, osteocalcin (OCN) secretion, and analysis of osteoblastic gene expressions were also compared in detail. RESULTS: Significant increases in ALP activity and OCN production on days 7 and 14 (P < 0.05) were observed for AIM coated HA (HA-AIM) surfaces. However, cells cultured on HA-AIM-coated surfaces showed a delayed growth pattern. Real-time polymerase chain reaction analyses showed significantly higher relative mRNA expression levels of osteoblastic genes (runt-related protein 2, osterix, osteopontin, OCN) in cells cultured on the HA AIM-coated nanotube surfaces as compared with cells cultured on the HA-PS and baer Ti surfaces. CONCLUSION: The current research showed that the HA-AIM-coated nanotubular Ti surfaces enhance osteoblast differentiation, which had the potential to further improve osseointegration. PMID- 25734943 TI - Decontamination methods using a dental water jet and dental floss for microthreaded implant fixtures in regenerative periimplantitis treatment. AB - OBJECTIVE: This study evaluated decontamination methods using a dental water jet and dental floss on microthreaded implants for regenerative periimplantitis therapy. MATERIALS AND METHODS: In 6 beagle dogs, experimental periimplantitis was induced, and decontamination procedures, including manual saline irrigation (control group), saline irrigation using a dental water jet (group 1) and saline irrigation using a dental water jet with dental flossing (group 2), were performed. After in situ decontamination procedures, some of the implant fixtures (n = 4 per group) were retrieved for analysis by SEM, whereas other fixtures (n = 4 per group) underwent regenerative therapy. After 3 months of healing, the animals were killed. RESULTS: The SEM examination indicated that decontamination of the implant surfaces was the most effective in group 2, with no changes in implant surface morphology. The histological examination also revealed that group 2 achieved significantly greater amounts of newly formed bone (6.75 +/- 2.19 mm; P = 0.018), reosseointegration (1.88 +/- 1.79 mm; P = 0.038), and vertical bone fill (26.69 +/- 18.42%; P = 0.039). CONCLUSION: Decontamination using a dental water jet and dental floss on microthreaded implants showed positive mechanical debridement effects and positive bone regeneration effects. PMID- 25734944 TI - Bone regeneration with a collagen model polypeptides/alpha-tricalcium phosphate sponge in a canine tibia defect model. AB - INTRODUCTION: We evaluated the effects of synthesized collagen model polypeptides consisting of a proline-hydroxyproline-glycine (poly(PHG)) sequence combined with porous alpha-tricalcium phosphate (alpha-TCP) particles on bone formation in a canine tibia defect model. MATERIALS AND METHODS: The porous alpha-TCP particles were mixed with a poly(PHG) solution, and the obtained sponge was then cross linked and characterized by x-ray diffraction and scanning electron microscopy. Tibia defects were analyzed in 12 healthy beagles using microcomputed tomography and histological evaluation. RESULTS: At 2 and 4 weeks, the volume density of new bone was higher in the poly(PHG)/alpha-TCP group than in poly(PHG) alone group (P < 0.05); however, there was no difference at 8 weeks (P > 0.05). Histological evaluation at 4 weeks after implantation revealed that the poly(PHG) had degraded, and newly formed bone was present on the surface of the alpha-TCP particles. At 8 weeks, continuous cortical bone formation with a Haversian structure covered the top of the bone defects in both groups. CONCLUSION: This study demonstrates that the composite created using porous alpha-TCP particles and poly(PHG) is sufficiently adaptable for treating bone defects. PMID- 25734945 TI - Biomechanical evaluation of resistance to insertion torque of different implant systems and insertion driver types. AB - PURPOSE: The aim of this study was to quantify the resistance to torque of different implant systems and their connection devices using in vitro torsion tests. MATERIALS AND METHODS: Three internal connection systems, 1 conventional system with internal torque and 1 conventional system with a mounting device used as a control group were tested on 5 groups. RESULTS: Rupture torque (in newton meter): Biomet 3i Certain group 4 showed a statistically significant higher average (2.65 N.m), followed in order by Biomet 3i Osseotite group 5 (2.18 N.m), Bonelike group 2 (1.80 N.m). Angle deformation/rupture: all groups obtained similar values, without significant differences. Elastic limit (in newton meter): Bonelike group 2 (1.06 N.m) showed similar behavior to group 1 (1.39 N.m) (Nobel Biocare), without significant differences, whereas Bonelike group 3 showed a significantly lower value (0.93 N.m). Maximum torque (in newton meter): Biomet 3i Certain group 4 showed significantly higher values in relation to other groups (2.80 N.m). CONCLUSIONS: The greater contact area the system is built on, the greater resistance against insertion torque, as internal hexagon implants with a greater contact area and external hexagon implants using a mounting device showed higher resistance to insertion torque. PMID- 25734946 TI - Bone regenerative potential of modified biphasic graft materials. AB - PURPOSE: To investigate the bone regenerative effect of polymer and collagen incorporation to synthetic bone graft materials. MATERIALS AND METHODS: The bone ingrowth of biphasic graft materials was tested in a rabbit calvaria defect model after chemical characterization: HA/TCP (25%/75%) with collagen, HA/TCP (25%/75%) without collagen, (HA/TCP)/PLGA (85%/15%) with collagen, (HA/TCP)/PLGA (65%/35%) with collagen and a commercially available (HA/TCP)/PLGA (50%/50%) (ReOssTM, Intra-Lock International, Boca Raton, FL) was used as control. After 4 and 8 weeks, the retrieved samples were subjected to histomorphometrical analysis. RESULTS: Histomorphometry presented no significant differences concerning the bone formation between the different groups at both 4 and 8 weeks. Evidently, the (HA/TCP)/PLGA (65%/35%) with collagen presented the least amount of soft tissue incorporation within the defect. The same group possessed higher amounts of bone graft material within the defect throughout the 8-week observation period, whereas the other groups seemed to decrease in volume from 4 to 8 weeks. CONCLUSION: Changing the PLGA percentage to 35% within the biphasic graft material seemed to maintain its volume and prevented soft tissue migration, which could be clinically beneficial. PMID- 25734947 TI - Retrospective long-term evaluation of dental implants in totally and partially edentulous patients: part II: periimplant disease. AB - PURPOSE: This retrospective longitudinal study aims to assess long-term outcomes of osseointegrated dental implants placed in partially and totally edentulous patients. MATERIAL AND METHODS: Patients who were willing to sign the informed consent and attend a check-up were included. The prevalence of periimplant disease was calculated. Cases were further divided into mucositis or periimplantitis. Uni- and multi-variate statistical analyses were conducted to determine the influence of various factors. RESULTS: A total of 105 patients who had received 342 implants were included. Mean follow-up was 13.19 +/- 3.70 years. The prevalence of periimplant disease was 14.2% of the analyzed implants and 21% of patients. An additional 4.8% of patients reported a previous presence of periimplant disease without current disease. The prevalence of mucositis and periimplantitis was 11.2% and 1.7%, respectively, of analyzed implants. Factors with possible influence on the presence of periimplant disease were gender, alcohol consumption, chemotherapy and/or head and neck radiotherapy, history of periodontal disease, and years of function. CONCLUSION: In our sample, periimplant disease was not infrequent, being present in 1 of 5 patients at the final check-up. PMID- 25734948 TI - Medication-related osteonecrosis of the jaws from once per year intravenous zoledronic acid (Reclast): report of 4 cases. AB - Osteonecrosis of the jaws is a commonly reported side effect with patients prescribed oral antiresorptive medications to treat osteoporosis and osteopenia. Oral antiresorptive agents are considered as the standard of care for the prevention and treatment of women with postmenopausal osteoporosis. Because of patient's noncompliance of the antiresorptive medications, which may require once weekly or once-monthly oral ingestion, a new once a year intravenous (IV) infusion of zoledronic acid was recently introduced in the management of osteoporosis. Reports of medication-related osteonecrosis of the jaw (MRONJ) have been reported in patients with cancer treated with multiple doses of IV zoledronic acid. However, there is a paucity of reports occurring with the once yearly infusion of zoledronic acid (Reclast) for the management of osteoporosis. In this article, we report 4 cases of patients who had a history of long-term oral antiresorptive therapy and now were taking the once-yearly IV zoledronic acid (Reclast) and soon developed MRONJ after completing surgery of the maxilla and mandible. PMID- 25734949 TI - Teriparatide therapy for bisphosphonate-related osteonecrosis of the jaw associated with dental implants. AB - This report describes a case of teriparatide (TPTD) therapy for bisphosphonate (BP)-related osteonecrosis of the jaw induced after implant placement. A 75-year old woman taking oral BP was referred with uncontrolled osteonecrosis of the mandible related to the implant placement. With conservative treatment, BP was suspended and daily subcutaneous injections of 20 MUm/d TPTD were started. After 4 months of the therapy, fixture removal and sequestrectomy were performed. Histological analysis revealed necrotic lamellar bone and empty osteocytic lacunae. In contrast, multiple irregular reversal lines of the lamellar bone and active osteoblasts were noted adjacent to the lesion. There was a significant increase in serum C-terminal telopeptide cross-link of type 1 collagen and serum osteocalcin after commencement of the therapy. After 7 months off therapy, the serum levels of the 2 markers remained at a high level compared with the baseline. PMID- 25734950 TI - A comparison study on ribonuclease A modifications induced by substituted p benzoquinones. AB - In this paper, we present our investigation on ribonuclease A (RNase) modifications induced by 1,4-benzoquinone (PBQ), 2-methyl-1,4-benzoquinone (MBQ), and 2-chloro-1,4-benzoquinone (CBQ). The goal of the study was to evaluate quinone-induced protein modifications as well as substituent effects, utilizing several techniques such as SDS-PAGE, fluorescence spectroscopy, microscopy, and LC-ESI(+)-QTOF-MS. SDS-PAGE experiments revealed that all quinones modify RNase through oligomerization as well as polymeric aggregation; with CBQ functioning as the most efficient quinone while MBQ was least efficient. The fluorescence emission was found to be less intense and the anisotropy values were found to be slightly higher for the modified RNase compared to the unmodified RNase. UV-Vis spectroscopy indicated that all three quinones formed adducts in which they were covalently linked to RNase. Confocal imaging analysis showed that the presence of CBQ resulted in massive RNase aggregation, while PBQ-treated RNase formed much smaller aggregates. MBQ-treated RNase exhibited micrographic features that closely resembled those of the unmodified RNase. LC-ESI(+)-QTOF-MS studies indicated the nature of PBQ- and CBQ-induced RNase modifications are complex mainly due to simultaneously occurrence of both adduct formation and oligomerization. Kinetic studies on quinone reactivity toward lysine revealed the rank order of CBQ>PBQ?MBQ, based on the second-order rate constants. We also utilized scanning electron microscopy in order to investigate the effect of modified RNase on the biomineralization of salts. PMID- 25734951 TI - Ratiometric iridium(III) complex-based phosphorescent chemodosimeter for Hg(2+) applicable in time-resolved luminescence assay and live cell imaging. AB - A novel iridium(III) complex-based probe Ir4-1 has been designed and synthesized conveniently by incorporating the chemodosimeter into phosphorescent luminophor, which displayed ratiometric luminescence change from yellowish-green to reddish yellow only toward Hg(2+) ions in aqueous media via desulfurization and intramolecular cyclization with a broad pH range of 5-10. The phosphorescent chemodosimeter could eliminate effectively the signal interference from the short lived fluorescent background, and the signal-to-noise ratio of the detection was improved distinctly by using time-resolved photoluminescence technique. Furthermore, the mechanism of phosphoresce change of the chemodosimeter was analyzed in detail by time-dependent density functional theory (TD-DFT) calculations, and the probe with long-wavelength emission could be applied to label cells and monitor intracellular Hg(2+) effectively by luminescence ratio imaging. PMID- 25734952 TI - The utility of rodent models of autism spectrum disorders. AB - PURPOSE OF REVIEW: This review discusses the ways that rodent models of autism spectrum disorders (ASDs) have been used to gain critical information about convergent molecular pathways, the mechanisms underlying altered microcircuit structure and function, and as a screen for potential cutting edge-treatments for ASDs. RECENT FINDINGS: There is convergent evidence that impaired developmental pruning of connections may be a common finding among several mouse models of ASDs. Recent studies have uncovered impaired autophagy by pathological mTOR activation as a potential contributor to microcircuit dysfunction and behavior. ASD-related disinhibition and exaggerated synaptic plasticity in multiple distinct circuits in cortex and reward circuits in striatum also contribute to social dysfunction and repetitive behaviors. New exciting molecular therapeutic techniques have reversed cognitive deficits in models of ASD, indicating that mouse models could be used for preclinical translational studies of new treatments. SUMMARY: Rodent models of ASDs coupled to new emerging technologies for genome editing, cell-specific functional and structural imaging, and neuronal activity manipulation will yield critical insights into ASD pathogenesis and fuel the emergence of new treatments. PMID- 25734953 TI - Redefining epilepsy. AB - PURPOSE OF REVIEW: In 2014, the definition of epilepsy was revised by the International League Against Epilepsy (ILAE). RECENT FINDINGS: A conceptual definition of epilepsy was proposed by the ILAE in 2005, as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by its psychosocial consequences. Practical application of the epilepsy definition usually is taken to mean at least two unprovoked seizures more than 24 h apart, but a 2014 practical definition refines the description. With this definition, epilepsy is a disease of the brain with either: (1) at least two unprovoked (or reflex) seizures occurring more than 24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals past the applicable age of an age dependent epilepsy syndrome or those who have remained seizure-free for the past 10 years, with no seizure medicines for the past 5 years. SUMMARY: A consensus process has refined the definition of epilepsy. PMID- 25734954 TI - Resting-state functional connectivity in epilepsy: growing relevance for clinical decision making. AB - PURPOSE OF REVIEW: Seizures produce dysfunctional, maladaptive networks, making functional connectivity an ideal technique for identifying complex brain effects of epilepsy. We review the current status of resting-state functional connectivity (rsFC) research, highlighting its potential added value to epilepsy surgery programs. RECENT FINDINGS: RsFC research has demonstrated that the brain impact of seizures goes beyond the epileptogenic zone, changing connectivity patterns in widespread cortical regions. There is evidence for abnormal connectivity, but the degree to which these represent adaptive or maladaptive plasticity responses is unclear. Empirical associations with cognitive performance and psychiatric symptoms have helped understand deleterious impacts of seizures outside the epileptogenic zone. Studies in the prediction of outcome suggest that there are identifiable presurgical patterns of functional connectivity associated with a greater likelihood of positive cognitive or seizure outcomes. SUMMARY: The role of rsFC remains limited in most clinical settings, but shows great promise for identifying epileptic circuits and foci, predicting outcomes following surgery, and explaining cognitive deficits and psychiatric symptoms of epilepsy. RsFC has demonstrated that even focal epilepsies constitute a network and brain systems disorder. By providing a tool to both identify and characterize the brain network impact of epileptiform activity, rsFC can make a strong contribution to presurgical algorithms in epilepsy. PMID- 25734956 TI - Fusion of raft-like lipid bilayers operated by a membranotropic domain of the HSV type I glycoprotein gH occurs through a cholesterol-dependent mechanism. AB - A wealth of evidence indicates that lipid rafts are involved in the fusion of the viral lipid envelope with the target cell membrane. However, the interplay between these sterol- and sphingolipid-enriched ordered domains and viral fusion glycoproteins has not yet been clarified. In this work we investigate the molecular mechanism by which a membranotropic fragment of the glycoprotein gH of the Herpes Simplex Virus (HSV) type I (gH625) drives fusion of lipid bilayers formed by palmitoyl oleoyl phosphatidylcholine (POPC)-sphingomyelin (SM) cholesterol (CHOL) (1 : 1 : 1 wt/wt/wt), focusing on the role played by each component. The comparative analysis of the liposome fusion assays, Dynamic Light Scattering (DLS), spectrofluorimetry, Neutron Reflectivity (NR) and Electron Spin Resonance (ESR) experiments, and Molecular Dynamics (MD) simulations shows that CHOL is fundamental for liposome fusion to occur. In detail, CHOL stabilizes the gH625-bilayer association by specific interactions with the peptide Trp residue. The interaction with gH625 causes an increased order of the lipid acyl chains, whose local rotational motion is significantly hampered. SM plays only a minor role in the process, favoring the propagation of lipid perturbation to the bilayer inner core. The stiffening of the peptide-interacting bilayer leaflet results in an asymmetric perturbation of the membrane, which is locally destabilized thus favoring fusion events. Our results show that viral fusion glycoproteins are optimally suited to exert a high fusogenic activity on lipid rafts and support the relevance of cholesterol as a key player of membrane related processes. PMID- 25734955 TI - Mechanisms of sudden unexplained death in epilepsy. AB - PURPOSE OF REVIEW: Human and experimental research has identified cardioautonomic and respiratory dysfunction as a frequent accompaniment in human and animal model events of sudden unexpected death in epilepsy (SUDEP). This review aims to provide an overview of the scientific evidence behind the currently accepted risk factors and working hypotheses regarding SUDEP pathophysiology. RECENT FINDINGS: Epidemiological analysis of public health burden of SUDEP has shown that it rates second only to stroke in the years of potential life lost. Clinical and experimental studies uncovered the dynamic cardiorespiratory dysfunction interictally and imminently to SUDEP, and model systems have facilitated discoveries in SUDEP mechanistic understanding and application of pilot therapeutic interventions. Pilot molecular profiling of human SUDEP has uncovered complex genomic structure in the candidate gene network. SUMMARY: Extensive clinical and experimental work has established a rationale for the conceptual thinking about SUDEP mechanisms. The application of the global molecular profiling will be invaluable in unraveling the individually unique genomic complexities and interactions that underlie the physiological signature of each patient. At the same time, sophisticated model systems will be critical in the iterative translation of human genetics, physiology, pharmacological interventions, and in testing preventive interventions. PMID- 25734957 TI - Prostaglandin E1 potentiates the effects of P2Y12 blockade on ADP-mediated platelet aggregation in vitro: Insights using short thromboelastography. AB - In addition to adenosine diphosphate (ADP), a number of platelet function tests including the VerifyNow P2Y12 assay (VN-P2Y12) employ prostaglandin E1 (PGE1) to improve specificity for P2Y12 blockade by mitigating the contribution of the P2Y1 pathway on ADP-mediated platelet aggregation. Using short thromboelastography (s TEG), we have previously shown that VN-P2Y12 overestimates the functional effect of clopidogrel in some individuals. We investigated whether PGE1 systematically increases the inhibitory effects of P2Y12 blockade on ADP-mediated platelet aggregation in an in vitro model. Using s-TEG, we measured ADP-induced platelet aggregation either in the presence or absence of PGE1 (11 or 22 nM) in blood samples taken from healthy volunteers pre-incubated with prasugrel active metabolite (PAM; 0, 1, 3 or 10 uM). Individually, both PGE1 (p < 0.02) and PAM (p < 0.0001) inhibited ADP-mediated platelet aggregation in a dose-dependent manner, as expected. Furthermore, inclusion of PGE1 augmented inhibition of ADP-mediated platelet aggregation in response to PAM (p < 0.02) in a dose-dependent manner such that a 10-fold higher dose of PAM was required to attain equivalent inhibition of ADP-mediated platelet aggregation to that achieved by 1 uM PAM in the presence of 11 nM PGE1. In conclusion, PGE1 potentiates the anti-aggregatory effects of P2Y12 blockade on ADP-mediated platelet aggregation. Assays that employ PGE1 with ADP may therefore overestimate therapeutic response to prasugrel in a proportion of individuals, potentially making them unsuitable candidates for guiding delivery of personalized antiplatelet therapy. PMID- 25734958 TI - Evaluation of an adsorption system to concentrate VOC in air streams prior to catalytic incineration. AB - Catalytic combustion is a well-developed process for the removal of volatile organic compounds (VOCs). In order to reduce both the amount of catalyst needed for incineration and the surface area of recuperative heat exchangers, an evaluation of the use of thermal swing adsorption as a previous step for VOC concentration is made. An air stream containing ethyl acetate and ethanol (employed as solvents in printing processes) has been taken as a case study. Based on the characteristics of the adsorption/desorption system and the properties of the stream to be treated, a monolithic rotor concentrator with activated carbon as adsorbent material is adopted. Once the temperature of the inlet desorption stream TD is chosen, the minimum possible desorption flow rate, WD,min, and the amount of adsorbent material can be properly defined according to the extent of the Mass Transfer Zone (MTZ) at the end of the adsorption stage. An approximate procedure to speed up the calculations needed for sizing the bed and predicting the operating variables is also presented. In the case studied here, the concentration of the VOC stream can reach 6 times that of the primary effluent when TD = 200 degrees C is chosen. PMID- 25734960 TI - The effects of matrix-metallo- proteinases and chlorhexidine on the adhesive bond. AB - The bond stability between dentin and filling material is the major challenge in modern adhesive techniques. A resin-dentin bond created by the etch-and-rinse technique considerably loses strength within 0.5 to 5 years. This may lead to secondary caries, hypersensitivity and finally loss of restorations. The decrease in bond strength is mainly due to two factors which are related to the collagen network of dentin and its constituent matrix-metalloproteinases (MMPs). Firstly, the collagen fibres exposed by the etching process using 37% phosphoric acid may not be completely infiltrated by subsequently applied adhesive bonding agents. In consequence, a thin layer of exposed, but non-infiltrated collagen remains at the bottom of the hybrid layer, resulting in nanoleakage. Secondly, this non infiltrated collagen contains active MMPs that may degrade collagen by hydrolysis. Within dentin, these enzymes physiologically are inactive, but they become activated by phosphoric acid and acidic components of bonding agents. As a result, the hybrid layer disintegrates and the bond strength gradually diminishes. However, when chlorhexidine is used as a therapeutic primer following the etching process using 37% phosphoric acid, MMPs are inhibited in a non specific manner, such that both the hybrid layer and the dentin bond strength are supposed to be preserved for a lon- ger time period. Based on the studies included in this literature review, the use of a pure aqueous solution of 0.2% chlorhexidine as an additional therapeutic primer can be recommended for etch-and rinse systems. PMID- 25734961 TI - PCSK9 inhibitors: the next frontier in low-density lipoprotein lowering. AB - The discovery and elucidation of the role of the low-density lipoprotein receptor (LDL-R) in familial hypercholesterolemia (FH) ushered in the statin group of drugs. These drugs, in addition to lowering low-density lipoprotein cholesterol (LDL-C), result in a significant reduction in cardiovascular events (CVE) and mortality. Recently, a gain-of-function mutation in another protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), was reported to result in a FH phenotype by promoting degradation of the LDL-R. More importantly, loss-of function mutations in the same gene resulted in low LDL-C and a reduction in CVE, making this an enticing target for drug development. Numerous strategies have been developed to target PCSK9, the most successful being monoclonal antibodies (mAbs) that bind PCSK9. These mAbs have been shown to reduce LDL-C around 50% as either monotherapy with diet or in combination with statin therapy. In this short perspective, we discuss the biochemistry and biology of PCSK9 in relation to lipid metabolism and the promising studies in humans demonstrating a substantial reduction in LDL-C with relative good short-term safety of PCSK9 mAbs. PMID- 25734962 TI - Biomimetic magnetic silk scaffolds. AB - Magnetic silk fibroin protein (SFP) scaffolds integrating magnetic materials and featuring magnetic gradients were prepared for potential utility in magnetic field assisted tissue engineering. Magnetic nanoparticles (MNPs) were introduced into SFP scaffolds via dip-coating methods, resulting in magnetic SFP scaffolds with different strengths of magnetization. Magnetic SFP scaffolds showed excellent hyperthermia properties achieving temperature increases up to 8 degrees C in about 100 s. The scaffolds were not toxic to osteogenic cells and improved cell adhesion and proliferation. These findings suggest that tailored magnetized silk-based biomaterials can be engineered with interesting features for biomaterials and tissue-engineering applications. PMID- 25734963 TI - Management of biochemically recurrent prostate cancer following local therapy. AB - Localized therapy for prostate cancer is often curative; however, 20% to 30% of patients experience a recurrence. Men with biochemical recurrence (BCR) are typically identified following routine monitoring of prostatespecific antigen after treatment for localized disease. These patients exhibit no signs of prostate cancer. Initial evaluation attempts to determine whether the BCR is due to local recurrence or systemic disease. Depending on the type of initial local therapy, treatment options for local recurrence include salvage radiation therapy or salvage prostatectomy. If systemic recurrence is suspected, other options must balance the onset of metastatic disease with avoidance of overtreatment. The most common treatment is androgen deprivation therapy (ADT) via gonadotropinreleasing hormone agonists or antagonists. Because there are challenges associated with standard ADT, other treatment options are being investigated, including a number of natural products. PMID- 25734964 TI - Managing advanced prostate cancer: the rapidly changing treatment landscape. AB - The FDA approval of 5 new therapeutic agents within a 4-year time frame, all of which potentially improve survival for patients with metastatic castration resistant prostate cancer, is unprecedented in oncology. The diversity of the mechanisms of action of these agents is compelling, including the first and only therapeutic cancer vaccine, the first approved use of an alpha emitter, 2 novel next generation hormonal therapy agents, and a second-generation taxane. However, with this therapeutic bounty comes new challenges in the optimal use of these new and expensive agents in a disease well known for its heterogeneity. PMID- 25734965 TI - Management of early-stage prostate cancer. AB - Prostate cancer is the second most common cancer diagnosed in men, with a median age of diagnosis of 66 years. Early disease is often asymptomatic, and diagnosis is based on abnormal prostate specific antigen (PSA) levels followed by a transrectal ultrasound-guided biopsy, digital rectal exam, or both. Disease staging after diagnosis is used to evaluate prognosis and determine the treatment approach. Biomarkers are useful for prostate cancer screening and as prognostic factors. The most important biomarker is PSA; however, newer prognostic factors may be more specific for prostate cancer. The goal of treatment is to identify patients who are most likely to benefit from therapy while minimizing treatment related complications. Treatment options include watchful waiting/ active surveillance, radical prostatectomy, external beam radiation therapy, brachytherapy, cryotherapy, androgen deprivation therapy, and combination therapy. Additional studies to evaluate comparative effectiveness and cost effectiveness of therapies would be beneficial, as availability of these data are limited. PMID- 25734966 TI - Formulation and optimization by experimental design of eco-friendly emulsions based on d-limonene. AB - d-Limonene is a natural occurring solvent that can replace more pollutant chemicals in agrochemical formulations. In the present work, a comprehensive study of the influence of dispersed phase mass fraction, phi, and of the surfactant/oil ratio, R, on the emulsion stability and droplet size distribution of d-limonene-in-water emulsions stabilized by a non-ionic triblock copolymer surfactant has been carried out. An experimental full factorial design 3(2) was conducted in order to optimize the emulsion formulation. The independent variables, phi and R were studied in the range 10-50 wt% and 0.02-0.1, respectively. The emulsions studied were mainly destabilized by both creaming and Ostwald ripening. Therefore, initial droplet size and an overall destabilization parameter, the so-called turbiscan stability index, were used as dependent variables. The optimal formulation, comprising minimum droplet size and maximum stability was achieved at phi=50 wt%; R=0.062. Furthermore, the surface response methodology allowed us to obtain the formulation yielding sub-micron emulsions by using a single step rotor/stator homogenizer process instead of most commonly used two-step emulsification methods. In addition, the optimal formulation was further improved against Ostwald ripening by adding silicone oil to the dispersed phase. The combination of these experimental findings allowed us to gain a deeper insight into the stability of these emulsions, which can be applied to the rational development of new formulations with potential application in agrochemical formulations. PMID- 25734968 TI - Development of melamine-formaldehyde resin microcapsules with low formaldehyde emission suited for seed treatment. AB - To reduce the application frequency and improve the efficacy of insecticides, melamine-formaldehyde (MF) resin microcapsules suited for seed treatment containing a mixture of fipronil and chlorpyrifos were prepared by in situ polymerization. A formaldehyde/melamine molar ratio of 4:1 yielded microcapsules with the smallest size and the most narrow size distribution. The level of unreacted formaldehyde in the microcapsule suspension increased proportionally with the F/M molar ratio. When the MF resin microcapsule suspension was used as a seed treatment to coat peanut seeds, the unreacted formaldehyde did not significantly inhibit the seedling emergence, but the ongoing release of formaldehyde generated from the degradation of MF resins played an important role in inhibiting emergence. Melamine was shown to be an effective formaldehyde scavenger that mitigated this inhibition when it was incorporated within the microcapsule wall. Field experiments showed that MF-resin-encapsulated mixtures of fipronil and chlorpyrifos have much greater efficacies against white grubs than the conventional formulation. PMID- 25734967 TI - S-layer fusion protein as a tool functionalizing emulsomes and CurcuEmulsomes for antibody binding and targeting. AB - Selective targeting of tumor cells by nanoparticle-based drug delivery systems is highly desirable because it maximizes the drug concentration at the desired target while simultaneously protecting the surrounding healthy tissues. Here, we show a design for smart nanocarriers based on a biomimetic approach that utilizes the building principle of virus envelope structures. Emulsomes and CurcuEmulsomes comprising a tripalmitin solid core surrounded by phospholipid layers are modified by S-layer proteins that self-assemble into a two-dimensional array to form a surface layer. One significant advantage of this nanoformulation is that it increases the solubility of the lipophilic anti-cancer agent curcumin in the CurcuEmulsomes by a factor of 2700. In order to make the emulsomes specific for IgG, the S-layer protein is fused with two protein G domains. This S-layer fusion protein preserves its recrystallization characteristics, forming an ordered surface layer (square lattice with 13 nm unit-by-unit distance). The GG domains are presented in a predicted orientation and exhibit a selective binding affinity for IgG. PMID- 25734969 TI - Characterizing Older Adults' Involvement in Naturally Occurring Retirement Community (NORC) Supportive Service Programs. AB - Naturally Occurring Retirement Community (NORC) Supportive Service Programs constitute one of the longest-standing models for age-friendly community initiatives. As a support-focused model, NORC programs typically offer a range of benefits--including direct services, group activities, and broader community development activities--that are intended to engage older adults with diverse needs, preferences, and interests. Moreover, NORC programs are designed to be used according to the needs of the particular participant engaging with them at a particular point in time. This range and flexibility of benefits indicate the importance of more systematically characterizing the ways in which older adults are involved with NORC programs. For this purpose, we used data from in-depth interviews with 35 residents across 6 NORC programs in New York City. Qualitative analysis revealed 6 ordered categories of involvement: (a) consciously no involvement; (b) involved, but not consciously; (c) relationship with staff only; (d) selectively involved with a strong sense of security; (e) NORC program leaders; and (f) dependence on the NORC program. Overall, results indicate how older adults' involvement in NORC programs can be characterized beyond their utilization of specific types of services and by their relationship with the program as a whole. Findings suggest the importance for outcomes research on NORC programs and related models to consider subgroup differences by involvement. Results also provide directions for theory development on engagement in voluntary programs, as well as for practice to enhance older adults' involvement in supportive service programs. PMID- 25734970 TI - Molecular Dynamics Simulations of Ternary Complexes: Comparisons of LEAFY Protein Binding to Different DNA Motifs. AB - LEAFY (LFY) is a plant-specific transcription factor, with a variety of roles in different species. LFY contains a conserved DNA-binding domain (DBD) that determines its DNA-binding specificity. Recently, the structures of the dimeric LFY-DBD bound to different DNA motifs were successively solved by X-ray crystallography. In this article, molecular dynamics (MD) simulations are employed to study two crystal structures of DNA-bound LFY protein from angiosperms and the moss Physcomitrella patens, respectively. The comparison of stabilities of the two systems is consistent with the experimental data of binding affinities. The calculation of hydrogen bonds showed that position 312 in LFY determines the difference of DNA-binding specificity. By using principal component analysis (PCA) and free energy landscape (FEL) methods, the open-close conformational change of the dimerization interface was found to be important for the system stability. At the dimerization interface, the protein-protein interaction has multiple influences on the cooperative DNA binding of LFY. The following analysis of DNA structural parameters further revealed that the protein protein interaction contributes varying roles according to the specific DNA binding efficiency. We propose that the protein-protein interaction serves a dual function as a connector between LFY monomers and a regulator of DNA-binding specificity. It will improve the robustness and adaptivity of the LFY-DNA ternary structure. This study provides some new insights into the understanding of the dynamics and interaction mechanism of dimeric LFY-DBD bound to DNA at the atomic level. PMID- 25734972 TI - Connective tissue diseases. Can SLE be treated by altering T-cell metabolism? PMID- 25734971 TI - Trojan horses and guided missiles: targeted therapies in the war on arthritis. AB - Despite major advances in the treatment of rheumatoid arthritis (RA) led by the success of biologic therapies, the lack of response to therapy in a proportion of patients, as well as therapy discontinuation owing to systemic toxicity, are still unsolved issues. Unchecked RA might develop into progressive structural joint damage, loss of function and long-term disability, disorders which are associated with a considerable health-economic burden. Therefore, new strategies are required to actively target and deliver therapeutic agents to disease sites in order to promote in situ activity and decrease systemic toxicity. Polymer-drug conjugates can improve the pharmacokinetics of therapeutic agents, conferring desirable properties such as increased solubility and tissue penetration at sites of active disease. Additionally, nanotechnology is an exciting modality in which drugs are encapsulated to protect them from degradation or early activation in the circulation, as well as to reduce systemic toxicity. Together with the targeting capacity of antibodies and site-specific peptides, these approaches will facilitate selective accumulation of therapeutic agents in the inflamed synovium, potentially improving drug efficacy at disease sites without affecting healthy tissues. This Review aims to summarize key developments in the past 5 years in polymer conjugation, nanoparticulate drug delivery and antibody or peptide-based targeting--strategies that might constitute the platform for the next generation of RA therapeutics. PMID- 25734973 TI - Musculoskeletal biology and bioengineering. A new in vivo stem cell model for regenerative rheumatology. AB - With advances in stem cell techniques for the bioengineering and regeneration of musculoskeletal tissues comes added complexity in our understanding of stem cell biology. How will the recent discovery of a novel stem cell subset, termed osteochondroreticular stem cells, contribute to progression in the field? PMID- 25734974 TI - Musculoskeletal biology and bioengineering. Growth plate or articular: whatever your cartilage type, thyroid hormones are in control! PMID- 25734976 TI - Inflammation. Potent small molecule extinguishes the NLRP3 inflammasome. PMID- 25734975 TI - Tendon injury: from biology to tendon repair. AB - Tendon is a crucial component of the musculoskeletal system. Tendons connect muscle to bone and transmit forces to produce motion. Chronic and acute tendon injuries are very common and result in considerable pain and disability. The management of tendon injuries remains a challenge for clinicians. Effective treatments for tendon injuries are lacking because the understanding of tendon biology lags behind that of the other components of the musculoskeletal system. Animal and cellular models have been developed to study tendon-cell differentiation and tendon repair following injury. These studies have highlighted specific growth factors and transcription factors involved in tenogenesis during developmental and repair processes. Mechanical factors also seem to be essential for tendon development, homeostasis and repair. Mechanical signals are transduced via molecular signalling pathways that trigger adaptive responses in the tendon. Understanding the links between the mechanical and biological parameters involved in tendon development, homeostasis and repair is prerequisite for the identification of effective treatments for chronic and acute tendon injuries. PMID- 25734977 TI - Membrane-assisted growth of DNA origami nanostructure arrays. AB - Biological membranes fulfill many important tasks within living organisms. In addition to separating cellular volumes, membranes confine the space available to membrane-associated proteins to two dimensions (2D), which greatly increases their probability to interact with each other and assemble into multiprotein complexes. We here employed two DNA origami structures functionalized with cholesterol moieties as membrane anchors--a three-layered rectangular block and a Y-shaped DNA structure--to mimic membrane-assisted assembly into hierarchical superstructures on supported lipid bilayers and small unilamellar vesicles. As designed, the DNA constructs adhered to the lipid bilayers mediated by the cholesterol anchors and diffused freely in 2D with diffusion coefficients depending on their size and number of cholesterol modifications. Different sets of multimerization oligonucleotides added to bilayer-bound origami block structures induced the growth of either linear polymers or two-dimensional lattices on the membrane. Y-shaped DNA origami structures associated into triskelion homotrimers and further assembled into weakly ordered arrays of hexagons and pentagons, which resembled the geometry of clathrin-coated pits. Our results demonstrate the potential to realize artificial self-assembling systems that mimic the hierarchical formation of polyhedral lattices on cytoplasmic membranes. PMID- 25734978 TI - Highly loaded behavior of kinesins increases the robustness of transport under high resisting loads. AB - Kinesins are nano-sized biological motors which walk by repeating a mechanochemical cycle. A single kinesin molecule is able to transport its cargo about 1 MUm in the absence of external loads. However, kinesins perform much longer range transport in cells by working collectively. This long range of transport by a team of kinesins is surprising because the motion of the cargo in cells can be hindered by other particles. To reveal how the kinesins are able to accomplish their tasks of transport in harsh intracellular circumstances, stochastic studies on the kinesin motion are performed by considering the binding and unbinding of kinesins to microtubules and their dependence on the force acting on kinesin molecules. The unbinding probabilities corresponding to each mechanochemical state of kinesin are modeled. The statistical characterization of the instants and locations of binding are captured by computing the probability of unbound kinesin being at given locations. It is predicted that a group of kinesins has a more efficient transport than a single kinesin from the perspective of velocity and run length. Particularly, when large loads are applied, the leading kinesin remains bound to the microtubule for long time which increases the chances of the other kinesins to bind to the microtubule. To predict effects of this behavior of the leading kinesin under large loads on the collective transport, the motion of the cargo is studied when the cargo confronts obstacles. The result suggests that the behavior of kinesins under large loads prevents the early termination of the transport which can be caused by the interference with the static or moving obstacles. PMID- 25734980 TI - Treatment of pain at sexual activity (dyspareunia) with intravaginal dehydroepiandrosterone (prasterone). AB - OBJECTIVE: This study aims to confirm the local effects of intravaginal prasterone on moderate to severe dyspareunia, a symptom of vulvovaginal atrophy (VVA) associated with menopause. METHODS: In a prospective, randomized, double blind, placebo-controlled phase III clinical trial, we examined the effects of daily intravaginal prasterone (6.5 mg) on four co-primary objectives, namely, percentage of vaginal parabasal cells, percentage of vaginal superficial cells, vaginal pH, and moderate to severe dyspareunia identified by women as the most bothersome VVA symptom. RESULTS: After daily intravaginal prasterone administration for 12 weeks, the percentage of parabasal cells decreased by 45.8% compared with placebo (P < 0.0001), the percentage of superficial cells increased by 4.7% over placebo (P < 0.0001), and vaginal pH decreased by 0.83 pH units compared with placebo (P < 0.0001). The severity of most bothersome dyspareunia decreased by 46% over placebo (P = 0.013) at 12 weeks, whereas moderate to severe vaginal dryness decreased by 0.43 severity score units (or 42%) compared with placebo (P = 0.013). On gynecologic evaluation, a 14.4% to 21.1% improvement in vaginal secretions, epithelial integrity, epithelial surface thickness, and color over placebo (P = 0.0002 to P < 0.0001) was observed. Serum steroids, in agreement with the physiology of intracrinology and menopause, remained well within reference postmenopausal concentrations. All endometrial biopsies at 12 weeks have shown atrophy. CONCLUSIONS: Daily intravaginal prasterone (0.50%; 6.5 mg) treatment has clinically and statistically significant beneficial effects on the four co-primary objectives of VVA, according to US Food and Drug Administration guidelines. No significant drug-related adverse effect in line with the strictly local action of treatment has been reported, thus providing a high benefit-to-risk ratio for intravaginal prasterone. PMID- 25734979 TI - Development of a 12 month screener based on items from the Bayley II Scales of Infant Development for use in Low Middle Income countries. AB - OBJECTIVES: The purpose of the current study was to adapt the Bayley Scales of Infant Development II for use as a screening measure that could be used by health care professionals in Low Middle Income (LMI) countries with 12 month old infants to determine if they needed further assessment and early intervention. METHODS: The adaptations were made as part of a larger study of children participating in a home-based early intervention program in India, Pakistan, and Zambia. Using Item Response Theory, a brief 12 month screener, with excellent sensitivity and specificity was identified. RESULTS: The proposed 12 month screener contains 7 mental/cognitive items and 5 motor items. Children who cannot perform more than 3 items on the mental scale (sensitivity 79%, specificity 85%) and/or 3 items on the motor scale (sensitivity 96%, specificity 95%) should be referred for further assessment. CONCLUSION: This screener can reliably be used to determine if a child needs further developmental assessment. PMID- 25734981 TI - Association of serum eicosapentaenoic acid to arachidonic acid ratio with microalbuminuria in a population of community-dwelling Japanese. AB - BACKGROUND: Epidemiological evidence suggests that the increased intake of omega 3 polyunsaturated fatty acids can prevent atherosclerosis-related cardiovascular diseases. Recently, serum eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio has been reported to be a predictive marker of cardiovascular events. Accordingly, we examined the relationship between serum EPA/AA ratio and microalbuminuria. METHODS: We enrolled 444 residents (174 males and 270 females, mean age 66.6 +/- 9.3 years) who underwent a physical examination in Uku town (fishing area) in Japan. They received blood tests including serum levels of EPA and AA, and urine test to examine microalbuminuria. Eating and drinking patterns were evaluated by a brief self-administered diet history questionnaire. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (UACR) >=30 mg/g Cr. RESULTS: The mean EPA/AA ratio was 0.66 +/- 0.3 in males and 0.51 +/- 0.2 in females. Multiple stepwise regression analyses revealed that systolic blood pressure (p < 0.0001), high sensitive C-reactive protein (p < 0.01), serum EPA/AA ratio (p < 0.01, inversely), and hemoglobin A1c (p < 0.05) were significantly associated with microalbuminuria. In the group with low serum EPA/AA ratio, the prevalence of microalbuminuria was significantly higher than the other, after the adjustments for confounding factors (odds ratio, 3.45; 95% confidence interval, 1.47-8.13; p < 0.01). CONCLUSION: The present study demonstrated that serum EPA/AA ratio was strongly associated with microalbuminuria. PMID- 25734982 TI - A novel compound 4010B-30 upregulates apolipoprotein A-I gene expression through activation of PPARgamma in HepG2 cells. AB - OBJECTIVE: Apolipoprotein (Apo) A-I is the major lipoprotein content of HDL and upregulating endogenous ApoA-I expression has been proposed as a desirable approach to raise the functional HDL. In this study we investigated the effect of a novel small molecule 4010B-30 on transcriptional regulation of ApoA-I gene in HepG2 cells, and the influence on the level of ApoA-I expression and function. Then the mechanisms by which 4010B-30 regulated ApoA-I expression was further explored. METHODS AND RESULTS: In human hepatic HepG2 cells, 4010B-30 increased the mRNA level and the protein production of ApoA-I both in cell lysates and media. The 4010B-30-induced ApoA-I containing particles increased cholesterol efflux from RAW264.7 macrophages. 4010B-30 also upregulated ABCA1 expression confirmed by transcriptional activity assay and Western blot analysis in both HepG2 and RAW264.7 cells. Promoter luciferase assay was used to identify the 4010B-30-responsive region which is mapped to the proximal -277bp region of the ApoA-I promoter. Further study indicated that the regulation of 4010B-30 on ApoA I transcription or protein expression in HepG2 cells was abrogated with the suppression of PPARgamma by its small interfering RNA or a specific inhibitor, GW9662. CONCLUSIONS: These findings suggest that the novel small molecular upregulator 4010B-30 increases ApoA-I gene expression, thereby enhances its function of promoting cholesterol efflux, as well as ABCA1 expression in vitro, and activation of PPARgamma is required for 4010B-30 to induce hepatic ApoA-I production. PMID- 25734983 TI - Upper versus lower limb exercise training in patients with intermittent claudication: a systematic review. AB - Lower extremity (LE) exercise training has been shown to contribute to improvements in Maximum Walking Distance (MWD), Claudication Distance (CD), peak oxygen uptake (VO2peak) and Quality of Life (QoL) in patients with intermittent claudication (IC). However, little is known regarding the efficacy of upper extremity (UE) exercise training in comparison to the widely used LE training. The objective of this systematic literature review is to identify and synthesize the available literature on the effects of UE versus LE exercises using the International Classification of Functioning (ICF) conceptual framework. A total of 6 randomized controlled trials comparing UE to LE exercises were included in this study. Two of the articles were considered to be of high quality using the PEDro grading list. Both UE and LE training groups demonstrated significant improvements in MWD, CD, VO2peak and QoL in comparison to the control group but LE was not better than UE training. This supports the use of UE training as an alternative to LE, which could provide symptomatic relief to patients with IC without the discomfort caused during the LE training. PMID- 25734985 TI - Roles of ubiquitination and SUMOylation on prostate cancer: mechanisms and clinical implications. AB - The initiation and progression of human prostate cancer are highly associated with aberrant dysregulations of tumor suppressors and proto-oncogenes. Despite that deletions and mutations of tumor suppressors and aberrant elevations of oncogenes at the genetic level are reported to cause cancers, emerging evidence has revealed that cancer progression is largely regulated by posttranslational modifications (PTMs) and epigenetic alterations. PTMs play critical roles in gene regulation, cellular functions, tissue development, diseases, malignant progression and drug resistance. Recent discoveries demonstrate that ubiquitination and SUMOylation are complicated but highly-regulated PTMs, and make essential contributions to diseases and cancers by regulation of key factors and signaling pathways. Ubiquitination and SUMOylation pathways can be differentially modulated under various stimuli or stresses in order to produce the sustained oncogenic potentials. In this review, we discuss some new insights about molecular mechanisms on ubiquitination and SUMOylation, their associations with diseases, oncogenic impact on prostate cancer (PCa) and clinical implications for PCa treatment. PMID- 25734984 TI - tRNA biology in mitochondria. AB - Mitochondria are the powerhouses of eukaryotic cells. They are considered as semi autonomous because they have retained genomes inherited from their prokaryotic ancestor and host fully functional gene expression machineries. These organelles have attracted considerable attention because they combine bacterial-like traits with novel features that evolved in the host cell. Among them, mitochondria use many specific pathways to obtain complete and functional sets of tRNAs as required for translation. In some instances, tRNA genes have been partially or entirely transferred to the nucleus and mitochondria require precise import systems to attain their pool of tRNAs. Still, tRNA genes have also often been maintained in mitochondria. Their genetic arrangement is more diverse than previously envisaged. The expression and maturation of mitochondrial tRNAs often use specific enzymes that evolved during eukaryote history. For instance many mitochondria use a eukaryote-specific RNase P enzyme devoid of RNA. The structure itself of mitochondrial encoded tRNAs is also very diverse, as e.g., in Metazoan, where tRNAs often show non canonical or truncated structures. As a result, the translational machinery in mitochondria evolved adapted strategies to accommodate the peculiarities of these tRNAs, in particular simplified identity rules for their aminoacylation. Here, we review the specific features of tRNA biology in mitochondria from model species representing the major eukaryotic groups, with an emphasis on recent research on tRNA import, maturation and aminoacylation. PMID- 25734987 TI - Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2+ breast cancer. AB - Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2 breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained. PMID- 25734986 TI - Recent advances in proteomic studies of adipose tissues and adipocytes. AB - Obesity is a chronic disease that is associated with significantly increased levels of risk of a number of metabolic disorders. Despite these enhanced health risks, the worldwide prevalence of obesity has increased dramatically over the past few decades. Obesity is caused by the accumulation of an abnormal amount of body fat in adipose tissue, which is composed mostly of adipocytes. Thus, a deeper understanding of the regulation mechanism of adipose tissue and/or adipocytes can provide a clue for overcoming obesity-related metabolic diseases. In this review, we describe recent advances in the study of adipose tissue and/or adipocytes, focusing on proteomic approaches. In addition, we suggest future research directions for proteomic studies which may lead to novel treatments of obesity and obesity-related diseases. PMID- 25734988 TI - In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model. AB - N-methyl-D-aspartate receptor (NMDAR) antagonists have been shown to reduce mechanical hypersensitivity in animal models of inflammatory pain. However, their clinical use is associated with significant dose-limiting side effects. Small conductance Ca-activated K channels (SK) have been shown to modulate NMDAR activity in the brain. We demonstrate that in vivo activation of SK channels in the spinal cord can alleviate mechanical hypersensitivity in a rat model of inflammatory pain. Intrathecal (i.t.) administration of the SK channel activator, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309), attenuates complete Freund adjuvant (CFA)-induced mechanical hypersensitivity in a dose-dependent manner. Postsynaptic expression of the SK channel subunit, SK3, and apamin-sensitive SK channel-mediated currents recorded from superficial laminae are significantly reduced in the dorsal horn (DH) after CFA. Complete Freund adjuvant-induced decrease in SK-mediated currents can be reversed in vitro by bath application of NS309. In addition, immunostaining for the SK3 subunit indicates that SK3 containing channels within DH neurons can have both somatic and dendritic localization. Double immunostaining shows coexpression of SK3 and NMDAR subunit, NR1, compatible with functional interaction. Moreover, we demonstrate that i.t. coadministration of NS309 with an NMDAR antagonist reduces the dose of NMDAR antagonist, DL-2-amino-5-phosphonopentanoic acid (DL-AP5), required to produce antinociceptive effects in the CFA model. This reduction could attenuate the unwanted side effects associated with NMDAR antagonists, giving this combination potential clinical implications. PMID- 25734989 TI - Modality-specific mechanisms of protein kinase C-induced hypersensitivity of TRPV1: S800 is a polymodal sensitization site. AB - TRPV1 is a nociceptive ion channel activated by polymodal stimuli such as capsaicin, proton, and noxious heat. Multiple inflammatory mediators activate protein kinases, especially protein kinase C (PKC), which phosphorylates TRPV1. Emerging evidence suggests that phosphorylation of TRPV1 constitutes specific signals underpinning pathological nociception. Although the mechanisms of hypersensitivity of TRPV1 to capsaicin are well studied, the phosphorylation residues that contribute to hypersensitivity to heat or acid have not been identified. In this study, we investigated modality-specific mechanisms of PKC induced hypersensitivity using mutagenic ablation of PKC-associated phosphorylation sites in TRPV1. In heterologous systems, TRPV1 S502 and S800, but not T704, are known to be involved in hypersensitivity to capsaicin after the application of phorbol myristate acetate (PMA), a PKC agonist. Unlike capsaicin, PMA-induced hypersensitivity to heat was attenuated in TRPV1 mutants T704A and S800A, but not in S502A. In contrast, PMA-induced hypersensitivity to acid was attenuated only in S800A. To examine the roles of these phosphorylation sites in more physiologically relevant conditions, TRPV1 and mutants were tested in sensory neurons from TRPV1-null mice. In sensory neurons expressing mutated TRPV1, we found that alanine mutation of S800 commonly attenuates PMA-induced hypersensitivity to capsaicin, heat, and acid. Moreover, bradykinin-induced hypersensitivity to capsaicin was largely attenuated by the S800A mutation. These results suggest that mechanisms of PKC-induced hypersensitivity of TRPV1 are modality specific and that S800 is a polymodal sensitization site integrating multiple inflammatory signals in nociceptors. Our data provide a rationale for a novel approach targeting TRPV1 S800 for antihyperalgesia. PMID- 25734990 TI - Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye. AB - Chronic dry eye disease (DE) is associated with an unstable tear film and symptoms of ocular discomfort. The characteristics of symptoms suggest a key role for central neural processing; however, little is known about central neuroplasticity and DE. We used a model for tear deficient DE and assessed effects on eye blink behavior, orbicularis oculi muscle activity (OOemg), and trigeminal brainstem neural activity in male rats. Ocular-responsive neurons were recorded at the interpolaris/caudalis transition (Vi/Vc) and Vc/upper cervical cord (Vc/C1) regions under isoflurane, whereas OOemg activity was recorded under urethane. Spontaneous tear volume was reduced by ~50% at 14 days after exorbital gland removal. Hypertonic saline-evoked eye blink behavior in awake rats was enhanced throughout the 14 days after surgery. Saline-evoked neural activity at the Vi/Vc transition and in superficial and deep laminae at the Vc/C1 region was greatly enhanced in DE rats. Neurons from DE rats classified as wide dynamic range displayed enlarged convergent periorbital receptive fields consistent with central sensitization. Saline-evoked OOemg activity was markedly enhanced in DE rats compared with controls. Synaptic blockade at the Vi/Vc transition or the Vc/C1 region greatly reduced hypertonic saline-evoked OOemg activity in DE and sham rats. These results indicated that persistent tear deficiency caused sensitization of ocular-responsive neurons at multiple regions of the caudal trigeminal brainstem and enhanced OOemg activity. Central sensitization of ocular related brainstem circuits is a significant factor in DE and likely contributes to the apparent weak correlation between peripheral signs of tear dysfunction and symptoms of irritation. PMID- 25734991 TI - Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration. AB - Small-fiber neuropathy (SFN) is hallmarked by degeneration of small unmyelinated peripheral nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal nerve fibers, a pathological biomarker of skin nerve degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin nerve degeneration. PMID- 25734992 TI - Health care expenditures associated with pediatric pain-related conditions in the United States. AB - The primary objective of this study was to assess the impact of pediatric pain related conditions on health care expenditures. We analyzed data from a nationally representative sample of 6- to 17-year-old children captured in the 2007 National Health Interview Survey and 2008 Medical Expenditure Panel Survey. Health care expenditures of children with pain-related conditions were compared with those of children without pain-related conditions. Pain-related conditions were associated with incremental health care expenditures of $1339 (95% confidence interval [CI], $248-$2447) per capita. Extrapolated to the nation, pediatric pain-related conditions were associated with $11.8 billion (95% CI, $2.18-$21.5 billion) in total incremental health care expenditures. The incremental health care expenditures associated with pediatric pain-related conditions were similar to those of attention deficit and hyperactivity disorder ($9.23 billion; 95% CI, $1.89-$18.1 billion), but more than those associated with asthma ($5.35 billion; 95% CI, $0-$12.3 billion) and obesity ($0.73 billion; 95% CI, $6.28-$8.81 billion). Health care expenditures for pediatric pain-related conditions exert a considerable economic burden on society. Efforts to prevent and treat pediatric pain-related conditions are urgently needed. PMID- 25734993 TI - Reactive oxygen species mediate visceral pain-related amygdala plasticity and behaviors. AB - Accumulating evidence suggests an important contribution of reactive oxygen species (ROS) to pain and neuropsychiatric disorders, but their role in pain related plasticity in the brain is largely unknown. Neuroplasticity in the central nucleus of the amygdala (CeA) correlates positively with pain behaviors in different models. Little is known, however, about mechanisms of visceral pain related amygdala changes. The electrophysiological and behavioral studies reported here addressed the role of ROS in the CeA in a visceral pain model induced by intracolonic zymosan. Vocalizations to colorectal distension and anxiety-like behavior increased after intracolonic zymosan and were inhibited by intra-CeA application of a ROS scavenger (tempol, a superoxide dismutase mimetic). Tempol also induced a place preference in zymosan-treated rats but not in controls. Single-unit recordings of CeA neurons in anesthetized rats showed increases of background activity and responses to visceral stimuli after intracolonic zymosan. Intra-CeA application of tempol inhibited the increased activity but had no effect under normal conditions. Whole-cell patch-clamp recordings of CeA neurons in brain slices from zymosan-treated rats showed that tempol decreased neuronal excitability and excitatory synaptic transmission of presumed nociceptive inputs from the brainstem (parabrachial area) through a combination of presynaptic and postsynaptic actions. Tempol had no effect in brain slices from sham controls. The results suggest that ROS contribute to visceral pain-related hyperactivity of amygdala neurons and amygdala-dependent behaviors through a mechanism that involves increased excitatory transmission and excitability of CeA neurons. PMID- 25734994 TI - Race effects on temporal summation to heat pain in youth. AB - Racial differences in pain responsiveness have been demonstrated in adults. However, it is unclear whether racial differences are also present in youth and whether they extend to experimental pain indices assessing temporal summation of second pain (TSSP). Temporal summation of second pain provides an index of pain sensitivity and may be especially relevant in determining risk for chronic pain. This study assessed pain tolerance and TSSP to evoked thermal pain in 78 healthy youth (age range, 10-17), 51% of whom were African American and 49% were non Hispanic white. Multilevel models revealed within-individual increases in pain ratings during the temporal summation task in non-Hispanic white youth that were consistent with TSSP. Pain ratings did not change significantly during the temporal summation task in African-American youth. Baseline evoked pain ratings were significantly higher in African-American compared with non-Hispanic white youth. These findings suggest that enhanced responsiveness to evoked thermal pain in African Americans is present in adolescence but is unlikely to be related to elevated TSSP. These results may have implications for understanding racial differences in chronic pain experience in adulthood. PMID- 25734995 TI - TMPRSS2, a novel membrane-anchored mediator in cancer pain. AB - More than half of all cancer patients have significant pain during the course of their disease. The strategic localization of TMPRSS2, a membrane-bound serine protease, on the cancer cell surface may allow it to mediate signal transduction between the cancer cell and its extracellular environment. We show that TMPRSS2 expression is not only dramatically increased in the primary cancers of patients but TMPRSS2 immunopositivity is also directly correlated with cancer pain severity in these patients. TMPRSS2 induced proteolytic activity, activated trigeminal neurons, and produced marked mechanical hyperalgesia when administered into the hind paw of wild-type mice but not PAR2-deficient mice. Coculture of human cancer cells with murine trigeminal neurons demonstrated colocalization of TMPRSS2 with PAR2. These results point to a novel role for a cell membrane anchored mediator in cancer pain, as well as pain in general. PMID- 25734996 TI - Parents--to help or hinder pain memories in children. PMID- 25734997 TI - Automated Internet-based pain coping skills training to manage osteoarthritis pain: a randomized controlled trial. AB - Osteoarthritis (OA) places a significant burden on worldwide public health because of the large and growing number of people affected by OA and its associated pain and disability. Pain coping skills training (PCST) is an evidence based intervention targeting OA pain and disability. To reduce barriers that currently limit access to PCST, we developed an 8-week, automated, Internet-based PCST program called PainCOACH and evaluated its potential efficacy and acceptability in a small-scale, 2-arm randomized controlled feasibility trial. Participants were 113 men and women with clinically confirmed hip or knee OA and associated pain. They were randomized to a group completing PainCOACH or an assessment-only control group. Osteoarthritis pain, pain-related interference with functioning, pain-related anxiety, self-efficacy for pain management, and positive and negative affect were measured before intervention, midway through the intervention, and after intervention. Findings indicated high acceptability and adherence: 91% of participants randomized to complete PainCOACH finished all 8 modules over 8 to 10 weeks. Linear mixed models showed that, after treatment, women who received the PainCOACH intervention reported significantly lower pain than that in women in the control group (Cohen d = 0.33). Intervention effects could not be tested in men because of their low pain and small sample size. Additionally, both men and women demonstrated increases in self-efficacy from baseline to after intervention compared with the control group (d = 0.43). Smaller effects were observed for pain-related anxiety (d = 0.20), pain-related interference with functioning (d = 0.13), negative affect (d = 0.10), and positive affect (d = 0.24). Findings underscore the value of continuing to develop an automated Internet-based approach to disseminate this empirically supported intervention. PMID- 25734999 TI - The effects of emotion regulation strategies on the pain experience: a structured laboratory investigation. AB - Although emotion regulation modulates the pain experience, inconsistencies have been identified regarding the impact of specific regulation strategies on pain. Our goal was to examine the effects of emotion suppression and cognitive reappraisal on automatic (ie, nonverbal) and cognitively mediated (ie, verbal) pain expressions. Nonclinical participants were randomized into either a suppression (n = 58), reappraisal (n = 51), or monitoring control (n = 42) condition. Upon arrival to the laboratory, participants completed the Emotion Regulation Questionnaire, to quantify self-reported suppression and reappraisal tendencies. Subsequently, they completed a thermal pain threshold and tolerance task. They were then provided with instructions to use, depending on their experimental condition, suppression, reappraisal, or monitoring strategies. Afterward, they were exposed to experimentally induced pain. Self-report measures of pain, anxiety, and tension were administered, and facial expressions, heart rate, and galvanic skin response were recorded. The Facial Action Coding System was used to quantify general and pain-related facial activity (ie, we defined facial actions that occurred during at least 5% of pain stimulation periods as "pain-related actions"). Reappraisal and suppression induction led to reductions in nonverbal and verbal indices of pain. Moreover, self-reported tendencies to use suppression and reappraisal (as measured by the Emotion Regulation Questionnaire) did not interact with experimental condition in the determination of participants' responses. Results suggest that consciously applying emotion regulation strategies during a painful task can moderate both cognitively mediated (e.g., verbal) and automatic (e.g., facial activity) expressions of pain. PMID- 25734998 TI - Protease-activated receptor 2 activation is sufficient to induce the transition to a chronic pain state. AB - Protease-activated receptor type 2 (PAR2) is known to play an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout (PAR2(-/-)) mice. We have tested the hypothesis that specific activation of PAR2 is sufficient to induce a chronic pain state through extracellular signal regulated kinase (ERK) signaling to protein synthesis machinery. We have further tested whether the maintenance of this chronic pain state involves a brain derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (trkB)/atypical protein kinase C (aPKC) signaling axis. We observed that intraplantar injection of the novel highly specific PAR2 agonist, 2-aminothiazol-4-yl-LIGRL-NH2 (2-at), evokes a long-lasting acute mechanical hypersensitivity (median effective dose ~12 pmoles), facial grimacing, and causes robust hyperalgesic priming as revealed by a subsequent mechanical hypersensitivity and facial grimacing to prostaglandin E2 (PGE2) injection. The promechanical hypersensitivity effect of 2-at is completely absent in PAR2(-/-) mice as is hyperalgesic priming. Intraplantar injection of the upstream ERK inhibitor, U0126, and the eukaryotic initiation factor (eIF) 4F complex inhibitor, 4EGI-1, prevented the development of acute mechanical hypersensitivity and hyperalgesic priming after 2-at injection. Systemic injection of the trkB antagonist ANA-12 similarly inhibited PAR2 mediated mechanical hypersensitivity, grimacing, and hyperalgesic priming. Inhibition of aPKC (intrathecal delivery of ZIP) or trkB (systemic administration of ANA-12) after the resolution of 2-at-induced mechanical hypersensitivity reversed the maintenance of hyperalgesic priming. Hence, PAR2 activation is sufficient to induce neuronal plasticity leading to a chronic pain state, the maintenance of which is dependent on a BDNF/trkB/aPKC signaling axis. PMID- 25735000 TI - OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. AB - OnabotulinumtoxinA (onabotA) has shown efficacy in chronic migraine (CM). Its mechanism of action, however, remains obscure. We have analysed whether treatment with onabotA is able to induce changes in interictal plasma calcitonin gene related peptide (CGRP) concentrations, which have been shown to be increased in patients with CM. Calcitonin gene-related peptide levels were determined in samples obtained from the right antecubital vein using ELISA, outside a migraine attack and having taken no symptomatic medication in the previous 24 hours, in 83 patients with CM (average age 44 years; 94% females) before and 1 month after treatment with 155 to 195 U of onabotA. CGRP levels after onabotA treatment (median, 51.89 pg/mL; range, 199.4-10.2) were significantly lower as compared with CGRP levels obtained before onabotA treatment (median, 74.09 pg/mL; range, 241.0-11.4; P = 0.001). Pretreatment CGRP levels in responders (76.85 pg/mL) were significantly higher than those seen in nonresponders (50.45 pg/mL; P = 0.001). One month after treatment, the CGRP levels did not change in nonresponders (51.89 pg/mL; P not significant), but significantly decreased in responders (52.48 pg/mL; P = 0.003). A number of demographic factors, clinical features, and comorbidities were not different in responders as compared with those of nonresponders. These results confirm that interictal CGRP levels can be of help in predicting the response to onabotA and suggest that the mechanism of action of onabotA in CM is the reversal of sensitization as a result of the inhibition of CGRP release. PMID- 25735001 TI - Disease-related differences in resting-state networks: a comparison between localized provoked vulvodynia, irritable bowel syndrome, and healthy control subjects. AB - Localized provoked vulvodynia (LPVD) affects approximately 16% of the female population, but biological mechanisms underlying symptoms remain unknown. Like in other often comorbid chronic pain disorders, altered sensory processing and modulation of pain, including central sensitization, dysregulation of endogenous pain modulatory systems, and attentional enhancement of pain perception, have been implicated. The aim of this study was to test whether regions of interest showing differences in LPVD compared to healthy control subjects (HCs) in structural and evoked-pain neuroimaging studies, also show alterations during rest when compared with HCs and a chronic pain control group (irritable bowel syndrome [IBS]). Functional magnetic resonance imaging was performed during resting state in 87 age-matched premenopausal females (29 LPVD, 29 HCs, and 29 IBS). Group-independent component analysis and general linear models were applied to investigate group differences in the intrinsic connectivity of regions comprising sensorimotor, salience, and default mode resting-state networks. Subjects with LPVD showed substantial alterations in the intrinsic connectivity of these networks compared with HCs and IBS. The intrinsic connectivity of many of the regions showing group differences during rest were moderately associated with clinical symptom reports in LPVD. Findings were robust to controlling for affect and medication usage. The current findings indicate that subjects with LPVD have alterations in the intrinsic connectivity of regions comprising the sensorimotor, salience, and default mode networks. Although shared brain mechanisms between different chronic pain disorders have been postulated, the current findings suggest that some alterations in functional connectivity may show disease specificity. PMID- 25735003 TI - DNA transfer by examination tools--a risk for forensic casework? AB - The introduction of profiling systems with increased sensitivity has led to a concurrent increase in the risk of detecting contaminating DNA in forensic casework. To evaluate the contamination risk of tools used during exhibit examination we have assessed the occurrence and level of DNA transferred between mock casework exhibits, comprised of cotton or glass substrates, and high-risk vectors (scissors, forceps, and gloves). The subsequent impact of such transfer in the profiling of a target sample was also investigated. Dried blood or touch DNA, deposited on the primary substrate, was transferred via the vector to the secondary substrate, which was either DNA-free or contained a target sample (dried blood or touch DNA). Pairwise combinations of both heavy and light contact were applied by each vector in order to simulate various levels of contamination. The transfer of dried blood to DNA-free cotton was observed for all vectors and transfer scenarios, with transfer substantially lower when glass was the substrate. Overall touch DNA transferred less efficiently, with significantly lower transfer rates than blood when transferred to DNA-free cotton; the greatest transfer of touch DNA occurred between cotton and glass substrates. In the presence of a target sample, the detectability of transferred DNA decreased due to the presence of background DNA. Transfer had no impact on the detectability of the target profile, however, in casework scenarios where the suspect profiles are not known, profile interpretation becomes complicated by the addition of contaminating alleles and the probative value of the evidence may be affected. The results of this study reiterate the need for examiners to adhere to stringent laboratory cleaning protocols, particularly in the interest of contamination minimisation, and to reduce the handling of items to prevent intra-item transfer. PMID- 25735002 TI - Activation of peripheral KCNQ channels relieves gout pain. AB - Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK). Benzbromarone consistently attenuates BK-, formalin-, or monosodium urate induced inflammatory pain in rat and mouse models. Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout. PMID- 25735004 TI - [Prosthetic rehabilitation of partially edentulous patients: fixed - removable - combined? Metal - ceramics - all - ceramics? Implants? Anything goes! Part 1: two example cases of a combined fixed-removable restoration]. AB - After a careful diagnosis, treatment planning and pretreatment, two partially edentulous patients were restored partly by onlays, crowns and bridges, partly by removable prostheses. According to esthetic and functional demands all- and/or metal-ceramic restorations were used as well as cast frame prostheses with clasps or extracoronal attachments. PMID- 25735005 TI - PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population. AB - Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost. PMID- 25735007 TI - Enhanced nitrogen and phosphorus removal by an advanced simultaneous sludge reduction, inorganic solids separation, phosphorus recovery, and enhanced nutrient removal wastewater treatment process. AB - An advanced wastewater treatment process (SIPER) was developed to simultaneously decrease sludge production, prevent the accumulation of inorganic solids, recover phosphorus, and enhance nutrient removal. The feasibility of simultaneous enhanced nutrient removal along with sludge reduction as well as the potential for enhanced nutrient removal via this process were further evaluated. The results showed that the denitrification potential of the supernatant of alkaline treated sludge was higher than that of the influent. The system COD and VFA were increased by 23.0% and 68.2%, respectively, after the return of alkaline-treated sludge as an internal C-source, and the internal C-source contributed 24.1% of the total C-source. A total of 74.5% of phosphorus from wastewater was recovered as a usable chemical crystalline product. The nitrogen and phosphorus removal were improved by 19.6% and 23.6%, respectively, after incorporation of the side stream system. Sludge minimization and excellent nutrient removal were successfully coupled in the SIPER process. PMID- 25735008 TI - The comparison of lightweight mesh and standard mesh in incisional hernia repair with the open sublay technique: the results of a meta-analysis. AB - PURPOSE: Incisional hernia repair with prosthetic mesh is necessary to reduce the high recurrence rate. Standard meshes have been suggested to be overengineered, and there is conflicting results about the application of lightweight and standard mesh in incisional hernia repair. The aim of this study was to compare the clinical outcomes following the use of lightweight mesh and standard mesh in open incisional hernia repair. METHODS: A systematic literature review was undertaken to identify studies comparing the outcomes of lightweight mesh and standard mesh in incisional hernia repair with the open sublay technique. RESULTS: The present meta-analysis pooled the effects of outcomes of total 1002 patients enrolled into 5 comparative trials. The use of lightweight mesh in incisional hernia repair was associated with a reduction of chronic pain (OR=0.24; 95% CI, 0.10, 0.57). Statistically, there was no difference in the postoperative recurrence between the 2 groups (RD=0.00; 95% CI, -0.03, 0.03), no difference in the incidence of hematoma (OR=1.0; 95% CI, 0.54, 1.85), seroma (OR=0.83; 95% CI, 0. 52, 1.31), wound infection (OR=0.96; 95% CI, 0. 60, 1.54), stiff abdomen, and foreign body sensation (OR=0.33; 95% CI, 0. 02, 4.31). Furthermore, quality of life and health status between the 2 kinds of mesh groups were also similar. CONCLUSIONS: In the procedure of open incisional hernia repair, the use of lightweight mesh seems to be associated with less chronic pain, and without the increase of recurrence and other postoperative complications. However, based on the short-term follow-up of the included studies, long-term well-designed RCTs are needed to evaluate the real outcomes. PMID- 25735009 TI - Synergism between cryoablation and GM-CSF: enhanced immune function of splenic dendritic cells in mice with glioma. AB - Glioma is the most common malignant primary brain tumor, and it has a poor prognosis. Studies have shown that cryoablation can activate antitumor immunoeffects by promoting the augmentation of dendritic cells (DCs). Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to be useful for immunotherapy against glioma because it can stimulate DCs to present tumor antigen. Previous studies have shown that cryoablation and GM-CSF can exert antitumor effects. To test the hypothesis that combined therapy with cryoablation and GM-CSF for glioma could synergistically improve specific antiglioma immunity in mice, we tested the validity of this assumption in a murine subcutaneous GL261 glioma model. C57BL/6 mice with subcutaneous GL261 glioma were created and divided into four groups: no treatment, GM-CSF injection, cryoablation treatment, and GM-CSF and cryoablation combined treatment (n=20 in each group). Serial immune indicators were detected at sequential time points during treatment. Compared with the other groups, in the combined treatment group, DCs were more activated and their numbers were markedly upregulated, the secretion of interferon-gamma from Th1 cells of mice spleen was increased, and the cytolytic activity of CD8 CTLs exerted a more significant cytotoxic effect on GL261 glioma cells (P<0.05 for all). Furthermore, these changes peaked on the 7th day after treatment, and then gradually reduced, until the 21st day; these changes were higher than those at pretreatment (P<0.05). It is concluded that combined therapy with argon-helium cryoablation and GM-CSF could synergistically enhance the activation of DCs and induce a robust tumor-specific immunologic response in glioma-bearing mice. PMID- 25735010 TI - Transposition surgery for inferior rectus fibrosis. AB - Congenital fibrosis of the extraocular muscles is a rare hereditary strabismus disorder. A case of congenital fibrosis of the inferior rectus muscles with severe chin-up posture and bilateral limitation of up gaze is reported. Bilateral large recessions of the tight inferior rectus muscles provided only partial improvement. Residual head posture and hypotropia were successfully corrected with bilateral horizontal rectus muscle transpositions toward the superior rectus muscles, despite persistently tight inferior rectus muscles at the time of surgery. PMID- 25735011 TI - Swept-source optical coherence tomography of retinal cavernous hemangioma: a new imaging modality. AB - The authors report a new, non-invasive diagnostic method in the diagnosis of retinal cavernous hemangioma (RCH). A 6-year-old girl was referred for a non clearing retinal hemorrhage of 6 months' duration. Fourier-domain optical coherence tomography (FD-OCT) showed an intraretinal lesion with cystic-like internal appearance. Optical shadowing was present, preventing establishment of any subretinal component to the lesion. Swept-source OCT (SS-OCT) showed an intraretinal lesion consisting of a group of clearly defined grape-like caverns with overlying preretinal tissue. Wide-field fundus fluorescein angiography (WF FFA) confirmed the diagnosis of RCH. SS-OCT was superior to FD-OCT in showing the internal anatomy of the RCH and allowing for the measurement of its structures, confirming the intraretinal location of the lesion and the presence of an associated preretinal tissue. SS-OCT may assist in cases in which hemorrhage prevents an accurate diagnosis by ophthalmoscopy or angiography, thus becoming an alternative imaging method to confirm the diagnosis of RCH while avoiding the risks of fluorescein angiography in children. PMID- 25735012 TI - Substance use disorders in the U.S. Armed forces. PMID- 25735013 TI - Total force fitness: the military family fitness model. AB - The military lifestyle can create formidable challenges for military families. This article describes the Military Family Fitness Model (MFFM), a comprehensive model aimed at enhancing family fitness and resilience across the life span. This model is intended for use by Service members, their families, leaders, and health care providers but also has broader applications for all families. The MFFM has three core components: (1) family demands, (2) resources (including individual resources, family resources, and external resources), and (3) family outcomes (including related metrics). The MFFM proposes that resources from the individual, family, and external areas promote fitness, bolster resilience, and foster well-being for the family. The MFFM highlights each resource level for the purpose of improving family fitness and resilience over time. The MFFM both builds on existing family strengths and encourages the development of new family strengths through resource-acquiring behaviors. The purpose of this article is to (1) expand the military's Total Force Fitness (TFF) intent as it relates to families and (2) offer a family fitness model. This article will summarize relevant evidence, provide supportive theory, describe the model, and proffer metrics that support the dimensions of this model. PMID- 25735014 TI - The strategic genius of Jonathan Letterman: the relevancy of the American Civil War to current health care policy makers. AB - With expanding health insurance coverage, innovative technologies, improved diagnostic acumen, and pharmaceutical additions combining to increase life expectancy, quality of life, and concomitant costs, the American health care system is under significant stress. However, it pales in comparison to the challenges faced by health care leaders during the American Civil War. As we approach the 150th anniversary of the conclusion of that war, it is appropriate to review key strategic health care decisions faced by military leaders during the Civil War and how their resultant outcomes may provide an appropriate perspective for today's leaders. PMID- 25735015 TI - Development and evaluation of a behavioral pain management treatment program in a Veterans Affairs Medical Center. AB - Chronic pain complaints are highly prevalent among Veterans seeking Veterans Affairs health care, and the implementation of effective behavioral health interventions is vital to meet patient needs. Research supports the use of cognitive behavioral therapy for the treatment of chronic pain; however, varying guidelines regarding length of treatment and modality (i.e., group vs. individual) complicate clinical planning and program development. This study aimed to evaluate treatment outcomes and equivalence of 3 variations (12, 10, and 6 weeks of group treatment) of cognitive behavioral therapy for chronic pain using clinical program data collected from Veterans enrolled in Veterans Affairs health services in a large tertiary care setting. Across groups, Veterans showed improvements in negative pain-related thinking and decreases in pain-related disability and distress. In general, patient outcomes regarding pain-related distress and disability for the 6-week group were equivalent or better than the 12- and 10-week groups. Preliminary results support the effectiveness of brief behavioral interventions for chronic pain. The findings have important practical implications, as briefer treatments may offer comparable therapeutic impact as longer, more time-intensive treatment protocols. This study offers a unique examination of treatment development and evaluation processes informed by real world clinical needs and patient feedback. PMID- 25735016 TI - Description of musculoskeletal injuries occurring in female soldiers deployed to Afghanistan. AB - Each year musculoskeletal injuries (MSIs) result in thousands of lost duty days and medical discharges. Women represent 15% of the Army and have higher incidence of injury than male soldiers; studies that have investigated MSIs in deployed women are lacking. Therefore, the purpose of this prospective cohort study was to investigate MSIs in women during a 9-month deployment to Afghanistan. Participants were recruited from three Brigade Combat Teams. Participants completed a demographic survey before deployment and a second survey on occupational demands and MSIs after deployment. Of the 160 women, 57 (36%) suffered 78 MSIs resulting in 1,642 days of limited duty, a median of 7 days per MSI, losing 10% of the available duty time to MSIs. Most injuries affected the knee (24%) or low back (18%). Soldiers attributed the majority of injuries (27%) to physical training and trips/falls (17%). Of the MSIs, 93% caused limitations to physical training and 76% resulted in large limitations to occupational tasks. Most MSIs (41%) resolved within 3 weeks and most (37%) occurred before the fourth month of deployment. Prevention measures should target knee and low back injuries. Physical training should be further investigated to discover modifications capable of reducing injuries. PMID- 25735017 TI - Tuberculosis as a force health protection threat to the United States military. AB - Tuberculosis (TB) is a communicable disease that poses a threat to force health protection to the U.S. military. The rate of TB disease in the military is low; however, there are unique challenges for its control in this setting. As a low risk population, TB testing in the U.S. military can be scaled back from the universal testing approach used previously. Reactivation of latent TB infection (LTBI) present at accession into service is the most important factor leading to TB disease; therefore, its diagnosis and treatment among recruits should be given a high priority. Deployment and overseas military service is an uncommon but important source of TB infection, and rigorous surveillance should be ensured. Case management of TB disease and LTBI can be improved by the use of cohort reviews at the service and installation levels and case finding and delays in the diagnosis of TB disease can be improved by education of providers, as well as increased use of molecular diagnostic tests. Program outcomes can be improved by making LTBI treatment compulsory, offering shorter treatment regimens, and increasing accountability through oversight and evaluation. The diagnosis of LTBI can be improved by implementing targeted testing in all settings and reducing confirmatory interferon-gamma release assay testing. PMID- 25735019 TI - A pilot study examining the impact of care provider support program on resiliency, coping, and compassion fatigue in military health care providers. AB - OBJECTIVES: The Care Provider Support Program (CPSP) was created as a way to improve the resiliency of military health care providers. The purpose of this pilot study was to update what is currently known about the resiliency, coping, and compassion fatigue of military and civilian registered nurses, licensed practical nurses (LPNs), and medics who treat wounded Soldiers and whether these factors can be improved over a sustained period of time. METHODS: A prospective cohort pilot study was implemented to investigate the long-term effects of CPSP training on military and civilian nurses, LPNs, and medics (n = 93) at an Army Medical Center utilizing the Connor-Davidson Resilience Scale, the Ways of Coping Questionnaire, and Professional Quality of Life Questionnaire. Twenty-eight participants returned follow-up questionnaires. RESULTS: CPSP was significant in reducing burnout as measured by the Professional Quality of Life questionnaire, leading to decreased compassion fatigue. CPSP training did not affect resiliency scores on the Connor-Davidson resilience scale or coping scores as measured by the Ways of Coping Questionnaire. CONCLUSIONS: on the basis of the results of this study, CPSP training was effective in reducing burnout, which often leads to decreased compassion fatigue in a group of military and civilian registered nurses, LPNs, and medics. PMID- 25735018 TI - Combat exposure, PTSD symptoms, and cognition following blast-related traumatic brain injury in OEF/OIF/OND service members and Veterans. AB - Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are frequently documented among the Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans. This study will investigate both combat exposure and PTSD as factors that may influence objective cognitive outcomes following blast-related mild TBI (mTBI). Participants included 54 OEF/OIF/OND veterans who had been exposed to blast and reported symptoms consistent with mTBI and 43 combat-deployed control participants who had no history of blast exposure or TBI. Raw scores from the Controlled Oral Word Association Test, Trail Making Test, Color-Word Interference Test, and Verbal Selective Reminding Test were used to measure cognitive functioning. All participants demonstrated adequate effort on the Word Memory Test. Demographics, injury characteristics, overall intellectual functioning, and total scores from the PTSD Checklist-Civilian Version (PCL-C) and Combat Exposure Scale (CES) were used as the predictors for each cognitive measure. History of mTBI was significantly associated with higher PCL-C and CES scores. Multivariable linear regression, however, showed no significant differences in cognitive performance between groups. The absence of effect of mTBI, PTSD, and combat exposure on cognitive functioning noted in this study may be partially explained by the inclusion of only those participants who passed performance validity testing. PMID- 25735020 TI - Differential impact of combat on postdeployment symptoms in female and male veterans of iraq and afghanistan. AB - OBJECTIVES: We aimed to describe differences in combat experience for male and female veterans and characterize differential effects on postdeployment physical and mental health symptoms, including aggression. METHODS: Retrospective cross sectional health screening data from 554 Operation Enduring Freedom and Operation Iraqi Freedom veterans who enrolled for Veterans Affairs health care in San Diego were examined including measures of combat experience, pain intensity, traumatic brain injury symptoms, military sexual trauma, post-traumatic stress disorder, depression, alcohol use, and aggression. RESULTS: Although male veterans (n = 458) experienced significantly higher rates of combat than female veterans (n = 96), both experienced similar levels of postdeployment post-traumatic stress disorder and depression symptoms as well self-reported aggressive behavior compared to male veterans. Female veterans had higher rates of military sexual trauma and lower alcohol consumption than male veterans. CONCLUSIONS: All Operation Enduring Freedom and Operation Iraqi Freedom veterans returning from deployment may benefit from broad-based screening of physical and mental health symptoms, beyond those currently mandated by Veterans Affairs, including anger and aggression. PMID- 25735021 TI - Prehospital pain medication use by U.S. Forces in Afghanistan. AB - We report the results of a process improvement initiative to examine the current use and safety of prehospital pain medications by U.S. Forces in Afghanistan. Prehospital pain medication data were prospectively collected on 309 casualties evacuated from point of injury (POI) to surgical hospitals from October 2012 to March 2013. Vital signs obtained from POI and flight medics and on arrival to surgical hospitals were compared using one-way analysis of variance test. 119 casualties (39%) received pain medication during POI care and 283 (92%) received pain medication during tactical evacuation (TACEVAC). Morphine and oral transmucosal fentanyl citrate were the most commonly used pain medications during POI care, whereas ketamine and fentanyl predominated during TACEVAC. Ketamine was associated with increase in systolic blood pressure compared to morphine (+7 +/- 17 versus -3 +/- 14 mm Hg, p = 0.04). There was no difference in vital signs on arrival to the hospital between casualties who received no pain medication, morphine, fentanyl, or ketamine during TACEVAC. In this convenience sample, fentanyl and ketamine were as safe as morphine for prehospital use within the dose ranges administered. Future efforts to improve battlefield pain control should focus on improved delivery of pain control at POI and the role of combination therapies. PMID- 25735022 TI - Cross-sectional analysis of Dutch repatriated service members from southern Afghanistan (2003-2014). AB - BACKGROUND: A systematic analysis of the complete medical support organization of the Dutch Armed Forces regarding repatriated service members from Afghanistan has not been performed so far. METHODS: All information were collated in a specifically designed electronic database and gathered from the archive of the Central Military Hospital for all Dutch service members receiving treatment for wounds or diseases sustained in the Afghan theater from July 2003 till January 2014. RESULTS: Traumatic injuries were the main cause (63%, 141/223) of repatriation, and improvised explosive devices the major (67%, 60/89) mechanism of injury in the battle casualty group. The mean time between injury and medical evacuation from Afghanistan was 8 days, and this was reduced to 3.6 days in case of polytrauma casualties (ISS > 15). CONCLUSIONS: Sixty percent of all Dutch medical evacuations from Afghanistan were not directly related to combat operations. A standard medical examination/endurance test in the predeployment phase could be useful as screening tool in reduction of the disease nonbattle injury casualty rate. Shorter transport intervals might improve morbidity and mortality of casualties, a timeframe of 48 to 72 hours for receiving definitive treatment seems feasible. Further research is necessary to identify delay factors and possible improvements in the medical support organization. PMID- 25735024 TI - Physical training in boots and running shoes: a historical comparison of injury incidence in basic combat training. AB - For many years, U.S. Army soldiers performed physical training (PT) in a modified duty uniform and combat boots. The belief that PT in combat boots was associated with injuries lead to the introduction of running shoes for PT in 1982. A historical comparison was conducted examining injuries before and after the change to running shoes in Basic Combat Training (BCT). Searches in literature databases and other sources identified 16 studies with quantitative data on injury incidence during 8-week BCT cycles. Employing studies with similar injury definitions (n = 12), injury incidence was compared in the boot and running shoe periods using meta-analyses, chi(2) statistics, and risk ratios (RRs) with 95% confidence intervals (95% CIs). The boot and shoe periods demonstrated little difference in overall injury incidence (men: RR[boot/shoes] = 1.04, 95% CI = 0.91 1.18, p = 0.50; women: RR = 0.94, 95% CI = 0.85-1.05, p = 0.27) or in lower extremity injury incidence (men: RR[boot/shoes] = 0.91, 95% CI = 0.64-1.30, p = 0.66; women: RR = 1.06, 95% CI = 0.89-1.27, p = 0.51). These analyses provided little support for a reduction in injury risk after the switch from boots to running shoes for PT in BCT. A large randomized, prospective cohort study should be conducted to determine if injury rates are different when PT is conducted in running shoes versus boots. PMID- 25735025 TI - Adapted marching distances and physical training decrease recruits' injuries and attrition. AB - There is evidence that progressive loading of physical demands at the beginning of basic military service and specific physical training can reduce injury incidences. Therefore, aim of this study was to measure the effects of a progressive increase in marching distances and an adapted physical training program on injury incidence and attrition rate in a Swiss Army infantry training school. One company reduced the distances covered on foot during the first 4 weeks of basic military training. A second company performed an adapted physical training program for 10 weeks. A third company participated in both interventions combined, and a fourth company served as a control group without any intervention. The injury incidences and attrition rates of 651 male recruits were registered during 21 weeks of military service. Several predictor variables for injury and attrition, such as physical fitness, previous injuries, level of previous physical activity, smoking, motivation, and socioeconomic factors, were assessed as well. The data were analyzed using binary logistic backward regressions. Each intervention separately had a favorable effect on injury prevention. However, combining the 2 interventions resulted in the greatest reduction in injury incidence rate (-33%). Furthermore, the adapted physical training successfully reduced the military service attrition rates (-53%). PMID- 25735023 TI - Characteristics of maxillofacial injuries and safety of in-theater facial fracture repair in severe combat trauma. AB - The study objectives were to characterize maxillofacial injuries and assess the safety of in-theater facial fracture repair in U.S. military personnel with severe combat trauma from Iraq and Afghanistan. We performed a retrospective chart review of the Expeditionary Medical Encounter Database from 2004 to 2010. 1,345 military personnel with combat-related maxillofacial injuries were identified. Injury severity was quantified with the Abbreviated Injury Scale and Injury Severity Score. Service members with maxillofacial injury and severe combat trauma (Injury Severity Score >= 16) were included. The distribution of facial fractures, types, and outcomes of surgical repairs, incidence of traumatic brain injury, concomitant head and neck injuries, burn rate/severity, and rates of Acinetobacter baumannii colonization and surgical site infection were analyzed. The prevalence of maxillofacial injury in the Expeditionary Medical Encounter Database was 22.7%. The most common mechanism of injury was improvised explosive device (65.7%). Midface trauma and facial burns were common. Approximately 64% of the study sample sustained traumatic brain injury. Overall, 45.6% (109/239) had at least one facial bone fracture. Of those with facial fractures, 64.2% (n = 70) underwent surgical repair. None of the service members who underwent in-theater facial fracture repair developed A. baumannii facial wound infection or implant extrusion. PMID- 25735026 TI - Body mass index trends of military dependents: a cross-sectional study. AB - BACKGROUND: Obesity is an epidemic affecting many people in the United States, to include military beneficiaries, with immediate and long-term implications on health care utilization and costs. We compared the body mass index (BMI) of officer vs. enlisted military-dependent spouses. METHODS: Retrospective chart review of 7,226 random dependent spouses cared for at Madigan Army Medical Center. Statistical analysis of BMI was performed comparing the spouses of commissioned officers and enlisted soldiers. RESULTS: There are a higher percentage of overweight and obese enlisted spouses when compared to officer spouses. In all age groups, BMI was 2.6 to 4.8 points higher in enlisted spouses, in both all-inclusive and female-specific analyses (p < 0.001). Male spouse BMI was not statistically different. BMI generally increased with age, with a statistically significant difference in BMI between age groups (p < 0.001). CONCLUSIONS: Our study shows that the average BMI of enlisted soldier's female spouses is significantly higher than officer spouses of similar age groups. A much larger proportion of enlisted spouses are obese. This analysis provides public health information for military primary care doctors and identifies at risk individuals for targeted education and interventions. PMID- 25735027 TI - Smoking cessation and improvement in physical performance among young men. AB - Tobacco use among young adults is a major public health challenge. Near-term benefits of cessation may motivate active young people to quit or avoid smoking. Military basic training includes mandatory tobacco cessation, as well as uniform physical conditioning regimes, creating an opportunity to evaluate changes in physical performance metrics in direct relation to smoking cessation. These analyses included data from all men who completed Marine Corps recruit training in San Diego, California, between 2002 and 2006. Recruits reported tobacco use and other health metrics on a pretraining survey. Initial and final aerobic run times were recorded over the 3-month training period. Multivariable linear regression analyses assessed changes in run-speed relative to pre-enlistment smoking history. Among 52,419 young men included in analyses, 13,248 (25.3%) reported smoking before enlistment. Average run-speeds improved among all groups of recruits; however, improvement was greater among prior smokers compared to recruits with no history of smoking (average increase of 0.31 vs. 0.21 miles per hour) and statistically significant in multivariate analyses. Smoking cessation in this cohort of young men resulted in improved physical aerobic performance, independent of other behavioral health characteristics. These data may be useful in promoting and motivating smoking cessation among young, active adults. PMID- 25735028 TI - Complementary and Alternative Medicine practices in military personnel and families presenting to a military emergency department. AB - OBJECTIVES: Limited published literature is available on Complementary and Alternative Medicine (CAM) use and attitudes toward CAM in the military community. We sought to evaluate past experiences with CAM, common conditions for which CAM is used, and willingness to use acupuncture for acute conditions in an Emergency Department (ED) setting by patients and family members presenting to a tertiary military treatment facility (MTF). METHODS: After institutional review board approval, an 18-item questionnaire was distributed to a convenience sample of ED patients presenting to a Navy MTF. RESULTS: A response was obtained from 1,005 respondents with 45% describing previous or current CAM use. Massage, chiropractic, herbal, and acupuncture were most frequently employed. The most common reasons for use of CAM therapies are described. The majority (88%) of surveyed participants reported that CAM therapies should be offered by the MTF and 80% reported a willingness to use acupuncture in the ED setting. CONCLUSION: CAM therapies are used by the military community for a wide variety of conditions. The use of acupuncture in the ED for treatment of presenting complaints was met with interest by respondents. Further studies are necessary to determine indications, efficacy, and patient satisfaction with such therapy in an emergent setting. PMID- 25735029 TI - Effects of alpha-blocker therapy on active duty military and military retirees for benign prostatic hypertrophy on diabetic complications. AB - OBJECTIVES: Determine if men with type 2 diabetes who take alpha-blockers (ABs) for benign prostatic hypertrophy gain additional benefit with reduced diabetic complications. METHODS: Chart review of 1,100 men with type 2 diabetes and benign prostatic hypertrophy taking either an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. RESULTS: Of the 1,100 men, 330 took ABs and 770 did not take ABs. Despite no difference in blood pressure between men taking or not taking ABs, those taking them had more evidence of renal and cardiovascular disease. The prevalence of complications varied among the AB types with tamsulosin users having more coronary artery disease diagnoses and doxazosin users having more renal disease diagnoses. CONCLUSIONS: ABs when prescribed for benign prostatic hypertrophy not only failed to give additional protection against developing diabetic complications but were associated with more cardiovascular and renal disease diagnoses. Prospective randomized controlled trials are necessary to determine if there is a causal relationship between ABs and adverse outcomes in patients with type 2 diabetes and benign prostatic hypertrophy already on an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. PMID- 25735030 TI - The material culture of military medicine. PMID- 25735031 TI - Laparoscopic staging of ovarian immature teratomas: a report on three cases. AB - BACKGROUND: Ovarian malignant germ cell tumors (MGCT) tend to occur in younger women and are amenable to fertility sparing surgery. Traditionally, most ovarian cancers are staged via laparotomy; however, laparoscopy is a potential alternative to laparotomy for surgical staging in malignant germ cell tumors. CASE: Three patients with immature teratoma were surgically staged with laparoscopy over a 1-year period at our institution. All patients underwent an initial surgery, unilateral salpingo-oophorectomy, for a complex adnexal mass that demonstrated immature teratoma on final pathology. Laparoscopic surgical staging was performed for all patients, with peritoneal and omental biopsies and pelvic and para-aortic lymph node dissection. Two patients with Stage IA disease secondary to negative biopsies and lymph nodes were observed. One patient was found to have omental disease; she underwent chemotherapy and remains in remission. As of last follow-up, no recurrences have been documented. CONCLUSION: Laparoscopic surgical staging of immature teratomas discovered occult disease in one case allowing for appropriate treatment decisions based on minimally invasive surgical findings. Laparoscopy represents a viable, and potentially preferable, option for surgical staging in patients with immature teratoma not initially diagnosed on frozen section. Determination of adequacy of laparoscopic staging needs long-term surveillance and outcome results. PMID- 25735032 TI - Spontaneous intracranial hypotension: trendelenberg just may be the answer. AB - Spontaneous intracranial hypotension may share some characteristics with the more common causes of headaches such as migraines or tension headaches, but its diagnosis and treatment is much more laborious and invasive. Here, the case of a 31-year-old man with multiple weeks of positional headaches is described. This symptom persisted following multiple blood patches, and progressed to worsening mental status, encephalopathy, and eventually obtundation with Glascow Coma Score less than 8. Surgery was required; however, small improvement was seen on imaging or in the patient's status. When the patient's position was changed to 20 degrees of Trendelenberg, immediate improvement was seen, leading to a full recovery. Although epidural blood patch is considered the treatment mainstay for spontaneous intracranial hypotension, this case shows another factor to consider in the treatment of this difficult condition. PMID- 25735033 TI - Exercise-induced cardiac arrest in a sickle cell trait-positive Air Force recruit: a case report. AB - In October 2011, a sickle cell trait (SCT)-positive Air Force recruit collapsed and died immediately following his physical fitness test. The cause of death was reported to be a cardiac dysrhythmia secondary to an acute sickling crisis. Although it is well known that SCT-positive individuals have a significant risk of exercise-related death (ERD), this case is notable in that none of the commonly cited risk factors were present, including exertional heat injury, dehydration, training at altitude, and rhabdomyolysis. Our findings challenge the commonly held assertion exertional heat illness is the fundamental underlying etiology in these cases, and that the current Department of Defense's policy on SCT screening is ineffective at mitigating the risk of ERD in SCT-positive recruits. Furthermore, we argue that without a clearer understanding of the precise risk factors for ERD in this population, screening programs may actually shift excessive health risks onto those without SCT. PMID- 25735034 TI - Percutaneous CT-guided drainage of a postoperative intra-abdominal abscess in a combat environment. AB - Combat medical care results in limited resource availability, which can prompt creativity in treatment of otherwise common conditions. A postoperative intra abdominal abscess is not an uncommon occurrence following traumatic hollow viscous injury in the deployed environment, but treatment is often limited to surgical drainage only. Herein, we describe a novel use of a dual-lumen central venous catheter to obtain percutaneous drainage of a postoperative intra abdominal abscess. PMID- 25735035 TI - Permanent retinal injury from recreational laser pointer. AB - This case report was performed to display the visually significant damage to the retina that can occur with brief exposure to a handheld laser pointer. Laser use in the military is ever increasing in form of target designators, rangefinders, or radar warning systems with powers far greater than used in this case. There is great potential for future cases of retinal damage among active duty members, and the importance of prevention through laser safety programs and recognition through trained medical personnel is paramount. PMID- 25735036 TI - Case report: waardenburg syndrome. AB - PURPOSE: A case of Waardenburg syndrome type 1 is described and relevant literature is reviewed to raise awareness about this rare syndrome, including the classification of each subtype and the differentiating clinical manifestations. CASE REPORT: A 44-year-old African-American female presented for a routine evaluation with hearing loss, dystopia canthorum (W index = 2.74), and almost complete gray hair. In addition, she presented with heterochromia irides, different fundus pigmentation between eyes. The patient did not have any upper limbs defect, cranial skeletal abnormalities, or intestinal disorders. CONCLUSION: Facial abnormalities and a white forelock are prominent features difficult to overlook during a routine ophthalmological examination. A careful medical history in patients with suspected Waardenburg syndrome is important to accurately classify this rare condition and to identify potential systemic implications associated to each subtype. The associated systemic complications can be addressed and managed through referral to the appropriate subspecialties. PMID- 25735037 TI - Gut bacteria are rarely shared by co-hospitalized premature infants, regardless of necrotizing enterocolitis development. AB - Premature infants are highly vulnerable to aberrant gastrointestinal tract colonization, a process that may lead to diseases like necrotizing enterocolitis. Thus, spread of potential pathogens among hospitalized infants is of great concern. Here, we reconstructed hundreds of high-quality genomes of microorganisms that colonized co-hospitalized premature infants, assessed their metabolic potential, and tracked them over time to evaluate bacterial strain dispersal among infants. We compared microbial communities in infants who did and did not develop necrotizing enterocolitis. Surprisingly, while potentially pathogenic bacteria of the same species colonized many infants, our genome resolved analysis revealed that strains colonizing each baby were typically distinct. In particular, no strain was common to all infants who developed necrotizing enterocolitis. The paucity of shared gut colonizers suggests the existence of significant barriers to the spread of bacteria among infants. Importantly, we demonstrate that strain-resolved comprehensive community analysis can be accomplished on potentially medically relevant time scales. PMID- 25735039 TI - Prostaglandin release during femtosecond laser-assisted cataract surgery: main inducer. AB - PURPOSE: To investigate a possible correlation between intraocular prostaglandin concentrations and partial steps of laser-assisted cataract surgery. METHODS: Aqueous humor was collected from 67 patients after laser-assisted cataract surgery pretreatment (only capsulotomy, only fragmentation, or both) and at the beginning of routine cataract surgery. Total prostaglandin levels were measured in all four groups using an enzyme-linked immunoassay. RESULTS: Significantly higher levels of aqueous humor prostaglandins were detected right after the full treatment (capsulotomy and fragmentation [330.6 +/- 110.6 pg/mL; P = .01] or only laser capsulotomy [362.4 +/- 117.5 pg/mL; P = .01]), whereas the control group showed lower values (52.5 +/- 8.1 pg/mL). By itself, laser-assisted cataract surgery fragmentation did not lead to a prostaglandin increase (186.8 +/- 114.0 pg/mL; P = .14). CONCLUSIONS: This study identified the anterior capsulotomy as the main trigger for an increase of prostaglandins in the aqueous humor immediately after laser-assisted cataract surgery. Optimized energy settings in combination with nonsteroidal anti-inflammatory drugs might help reduce the phenomenon of laser-induced miosis. PMID- 25735038 TI - Impaired fast-spiking interneuron function in a genetic mouse model of depression. AB - Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans. PMID- 25735040 TI - Influence of ocular features and incision width on surgically induced astigmatism after cataract surgery. AB - PURPOSE: To identify factors associated with surgically induced astigmatism (SIA) following phacoemulsification. METHODS: Six hundred five eyes underwent phacoemulsification with a 2.2-mm (the 2.2-mm group, n = 248) or 2.75-mm (the 2.75-mm group, n = 357) superior limbal incision. Preoperative axial length, anterior chamber depth, corneal curvature, and intra-ocular pressure were measured. Corneal curvature and intraocular pressure were measured at 1 day, 1 week, and 1, 2, and 3 months postoperatively. SIA, corneal flattening, and torque were calculated using the Alpins method. The effect of preoperative corneal astigmatism meridian on SIA was also examined. Differences in SIA between the 2.2 and 2.75-mm groups were explored, and correlations between SIA and preoperative corneal astigmatism, anterior chamber depth, axial length, age, and intraocular pressure were analyzed. RESULTS: SIA, corneal flattening, and torque were smaller in the 2.2-mm group than in the 2.75-mm group at 1 week (P = .003, .006, and .014, respectively), but not statistically different thereafter. Higher preoperative corneal astigmatism, older age, and shallower anterior chamber depth were associated with greater SIA in both groups. The effect of astigmatism meridian on SIA was more noticeable in the 2.75-mm group. Shorter axial length and lower intraocular pressures were associated with greater SIA in the 2.75-mm group but not in the 2.2-mm group. CONCLUSIONS: Reducing limbal incision width and considering patient age, the meridian and magnitude of corneal astigmatism, anterior chamber depth, axial length, and intraocular pressure, and adjusting the flattening component of SIA input for toric intraocular lens power calculation could potentially improve the astigmatism control in refractive lens surgery. PMID- 25735041 TI - Evaluation of rotation and visual outcomes after implantation of monofocal and multifocal toric intraocular lenses. AB - PURPOSE: To evaluate rotational stability and its influence on postoperative visual acuity of different monofocal and multifocal toric intraocular lenses (IOLs). METHODS: A prospective interventional study was designed. Ninety-one patients with a mean age of 71.65 +/- 11.82 years were implanted with toric IOLs after phacoemulsification. Three monofocal toric IOLs (the Lentis LT [Oculentis, Berlin, Germany], enVista [Bausch & Lomb, Rochester, NY], and AcrySof IQ [Alcon Laboratories, Inc., Fort Worth, TX]) and one multifocal toric IOL (AcrySof IQ ReSTOR; Alcon Laboratories, Inc.) were implanted. Preoperative and postoperative images were taken to calculate the misalignment due to the marking method. To evaluate rotation in the different follow-up visits, another photograph was taken 1 hour and 1, 7 and 30 days postoperatively. Refraction, uncorrected distance visual acuity (UDVA), and corrected distance visual acuity were measured 30 days postoperatively. RESULTS: Postoperative UDVA was 0.1 logMAR or better in 64.6% of eyes implanted with monofocal IOLs and 46.4% of eyes implanted with multifocal IOLs. The enVista toric IOL showed the best UDVA compared to the other monofocal IOLs, with 81% of eyes with 0.1 logMAR or better. The mean misalignment in the total group studied was 0.07 degrees +/- 0.60 degrees ; 69.6% of monofocal IOLs and 67.9% of multifocal IOLs showed less than 5 degrees of rotation. A correlation was found between postoperative UDVA and rotation in the monofocal and multifocal IOLs implanted (r = 0.439 [P < .011] and = 0.787 [P = .001], respectively). CONCLUSIONS: At 1 month postoperatively, UDVA was slightly more affected by IOL rotation in multifocal than monofocal toric IOLs. The marking method was also effective. PMID- 25735042 TI - Adjustment of anterior corneal astigmatism values to incorporate the likely effect of posterior corneal curvature for toric intraocular lens calculation. AB - PURPOSE: To establish if average refractive overcorrection or undercorrection of corneal astigmatism based on the "rule" of the astigmatism occurs if toric intraocular lenses (IOLs) are calculated on the basis of anterior corneal measurements, and to calculate an adjustment for individual eyes to avoid this systematic error. METHODS: One hundred forty-three consecutive eyes of 115 patients underwent phacoemulsification with IOL powers calculated using anterior corneal curvature data alone. Eyes were grouped as either "with-the-rule" or "against-the-rule" on the basis of the steep anterior corneal meridian. Targeted versus achieved astigmatic outcomes were compared. Main outcome measure was residual refractive astigmatism following the insertion of a toric IOL due to the likely effect of posterior corneal astigmatism. RESULTS: Significant prediction errors in astigmatic outcome occurred only with IOL cylinders of 2 diopters or less. Overcorrection occurred by a factor of 1.38 in with-the-rule eyes and undercorrection occurred by a factor of 0.65 in against-the-rule eyes. CONCLUSIONS: A coefficient of adjustment of 0.75 for with-the-rule eyes and 1.41 for against-the-rule eyes can be applied to the corneal astigmatism power value to calculate a more appropriate IOL cylinder power than that calculated by using unadjusted anterior corneal curvature measurements. These adjustment coefficients apply only to those eyes that would have received IOLs with 2 diopters of cylinder or less and calculated with such unadjusted measurements. Greater IOL cylinder powers are sufficiently accurately calculated using unadjusted values. PMID- 25735043 TI - Quantitative analysis of Microdistortions in Bowman's Layer using optical coherence tomography after SMILE among different myopic corrections. AB - PURPOSE: To quantitatively analyze the characteristics of Bowman's layer microdistortions after femtosecond laser small incision lenticule extraction (SMILE) among different myopic corrections, and their correlations with stromal lenticule thickness. METHODS: In this nonrandomized, prospective, controlled study, 63 eyes of 32 consecutive patients undergoing SMILE were divided into three groups according to the preoperative spherical equivalent (SE): greater than -6.00 D (20 eyes), -3.00 to -6.00 D (26 eyes), and -3.00 D or less (17 eyes). Measurement by slit-lamp microscope, uncorrected distance visual acuity (UDVA), manifest refraction, and Fourier-domain optical coherence tomography (FD OCT) were conducted preoperatively and 1 day and 1 month postoperatively. Index M was calculated according to the OCT images to indicate the quantity of microdistortions in Bowman's layer. RESULTS: Microdistortions in Bowman's layer were observed in 65.0% (13 of 20 eyes) and 30.8% (8 of 26 eyes) in the greater than -6.00 D and -3.00 to -6.00 D groups, respectively, 1 day postoperatively, and in 60% (12 of 20 eyes) and 23.1% (6 of 26 eyes) 1 month later. No Bowman's layer microdistortion was detected in the -3.00 D or less group postoperatively. The quantitative index M of microdistortions was higher in the greater than -6.00 D group than in the -3.00 to -6.00 D group at 1 day and 1 month (P < .05). There was no statistically significant difference between the indexes M on 1 day compared to 1 month. Index M was correlated with the preoperative SE and lenticule thickness (P < .05). CONCLUSION: The incidence and range of microdistortions in Bowman's layer detected after SMILE are positively correlated with the myopic correction. High myopia tends to develop more microdistortions in Bowman's layer after SMILE. PMID- 25735044 TI - Matched comparison study of total and partial epithelium removal in corneal cross linking. AB - PURPOSE: To compare the 1-year results of total versus partial epithelium removal in corneal cross-linking in the treatment of progressive keratoconus. METHODS: This retrospective study compared the results of total (the total group) versus partial (the partial group) approaches of epithelium removal in corneal cross linking. Eighty eyes of 65 patients (40 eyes in each group) were enrolled. The mean age of the participants was 25.48 +/- 4.80 years and 62.5% were male. One year changes in vision parameters, refraction, and Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany) indices were compared between the two groups using repeated measures analysis of variance. RESULTS: One year after corneal cross linking, uncorrected distance visual acuity in the total and partial group improved by 0.13 +/- 0.42 and 0.12 +/- 0.36 logMAR (P = .447), respectively, and corrected distance visual acuity improved by 0.00 +/- 0.19 and 0.13 +/- 0.20 logMAR (P = .001), respectively. Spherical equivalent decreased by 0.44 +/- 1.25 diopters (D) in the total group and 0.56 +/- 1.47 D in the partial group (P = .710). The decrease in maximum keratometry was 0.39 +/- 0.93 and 0.01 +/- 0.95 D in the total and partial group, respectively (P = .037), and the decrease in mean keratometry was 0.42 +/- 0.93 and 0.00 +/- 0.65 D (P = .015), respectively. Central corneal thickness decreased by 18.39 +/- 20.66 MUm in the total group and 0.11 +/- 13.29 MUm in the partial group (P < .001). CONCLUSIONS: One year after corneal cross-linking, both approaches showed similar results in terms of uncorrected distance visual acuity. With the partial approach, there was slightly better corrected distance visual acuity improvement and central corneal thickness maintenance, but slightly better corneal flattening was achieved with the total removal. Long-term studies are needed to compare these two approaches in terms of stability of results and stopping the progression of keratoconus. PMID- 25735045 TI - Corneal asymmetry analysis by pentacam scheimpflug tomography for keratoconus diagnosis. AB - PURPOSE: To evaluate intereye corneal asymmetry in Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany) indices as a diagnostic method between normal patients and patients with keratoconus. METHODS: A retrospective, observational case series of 177 healthy, 44 indeterminate, and 121 patients with keratoconus classified by Pentacam ectasia detection indices, randomized to analysis and validation datasets. Intereye asymmetry in 20 Scheimpflug tomography corneal descriptors was calculated and compared to develop diagnostic models. RESULTS: Intereye asymmetry was not correlated with anisometropia in healthy controls but was correlated with the ectasia grade of the worse eye in patients with keratoconus. Patients with keratoconus had significantly greater intereye asymmetry in all descriptors except for relational thickness indices. Intereye asymmetry in front elevation at the thinnest corneal location afforded the single highest diagnostic performance (71% sensitivity and 85% specificity), whereas the best multivariate model combining intereye asymmetry in anterior and posterior keratometry, corneal thickness, and front and back elevation at the thinnest point provided 65% sensitivity and 97% specificity. Multivariate models upheld their performance in the validation dataset. Most (more than 90%) indeterminate patients, according to conventional Pentacam analysis, showed within-normal-range corneal asymmetry. CONCLUSIONS: Healthy corneas are markedly symmetric irrespective of anisometropia, but corneal asymmetry analysis does not provide sufficient sensitivity to be used alone for detecting keratoconus. However, its remarkable specificity suggests that it could be used combined with conventional single cornea Pentacam analysis to reduce the false-positive rate or in dubious cases. PMID- 25735046 TI - Study of the force dynamics at the capsular interface related to ciliary body stimulation in a primate model. AB - PURPOSE: To study the mechanical dynamics between the zonuli-capsular complex and an accommodating intraocular lens mechanics simulator using pharmacological stimulation of the ciliary body in a primate eye. METHODS: Following phacoemulsification removal of the lens, force/movement gauges simulating the accommodating intraocular lens mechanics were implanted in 8 primate eyes (4 positioned in-the-bag and 4 on-the-bag). The gauge readings were taken under full effect of pilocarpine 4% or atropine 1% starting 6 weeks after surgery and following 3-month intervals for 30 months. RESULTS: An average movement of 390 um for on-the-bag gauges and 145 um for in-the-bag gauges was documented at 3 months postoperatively. The mechanical compliance of in-the-bag gauges rapidly deteriorated with capsular fibrosis developing inside the gauge and the capsular bag shrinking around it. On-the-bag gauges remained functional but the initial compliance was compromised over time by the pressure build up caused by the fibrotic capsular bag. CONCLUSIONS: Following phacoemulsification, capsular fibrosis causes disappearance of the mechanical forces detected by an in-the-bag gauge. An on-the-bag gauge detects active forces at the sulcus lasting at least 5 years, although the contracting capsule pressure compromises its compliance. These findings have important implications for future accommodating intraocular lens designs. PMID- 25735048 TI - Comparison of higher-order aberration induction between manual microkeratome and femtosecond laser flap creation. AB - PURPOSE: To compare the mean change in aberrations produced by a mechanical microkeratome and femtosecond laser. METHODS: This was a retrospective study of 62 consecutive near emmetropic eyes that underwent LASIK and satisfied the following criteria: negligible laser ablation (for spherical equivalent of 0.00 to +0.50 diopters and maximum meridian of +0.50 diopters), and preoperative and at least 3 months postoperative Placido-based corneal aberrometry (ATLAS; Carl Zeiss Meditec, Jena, Germany). Eyes were divided into two groups according to the method used for flap creation: mechanical microkeratome (Hansatome zero compression microkeratome; Bausch & Lomb, Rochester, NY [mechanical microkeratome group]) or femtosecond laser (VisuMax; Carl Zeiss Meditec, Jena, Germany [femtosecond laser group]). The root mean square total and individual higher order aberrations were compared between the two groups. RESULTS: Corneas with mechanical flaps, on average, possessed statistically significantly higher trefoil and horizontal coma (P < .001). There was no change in higher-order aberrations, except for spherical aberration in the femtosecond laser group. Average change in coma did not correlate with hinge position. Both groups showed statistically significant changes in spherical aberration (P < .001), although this was most likely due to the small hyperopic ablation performed. CONCLUSIONS: There was greater induction of specific aberrations with the microkeratome than the femtosecond laser. Hinge position did not appear to influence the induction of coma directly, contrary to previously published reports. The difference in aberrations induction between the two groups might be due to the differences in flap thickness profiles. PMID- 25735049 TI - Error in the estimation of ablation centration using pachymetric difference maps. PMID- 25735050 TI - Flap thickness in femtosecond laser. PMID- 25735051 TI - Medicare program; contract year 2016 policy and technical changes to the Medicare Advantage and the Medicare Prescription Drug Benefit programs. Final rule. AB - This final rule amends the Medicare Advantage (MA) program (Part C) regulations and Medicare Prescription Drug Benefit Program (Part D) regulations to implement statutory requirements; improve program efficiencies; strengthen beneficiary protections; clarify program requirements; improve payment accuracy; and make various technical changes. Additionally, this rule finalizes two technical changes that reinstate previously approved but erroneously removed regulation text sections. PMID- 25735052 TI - Announcement of ruling: implementing United States v.Windsor for purposes of entitlement and enrollment in Medicare hospital insurance and supplementary medical insurance. Notice of CMS ruling. AB - This document announces a CMS Ruling that states the CMS policies for implementing United States v. Windsor ("Windsor''), in which the Supreme Court held that section 3 of the Defense of Marriage Act (DOMA), enacted in 1996, is unconstitutional. Section 3 of DOMA defined ''marriage'' and "spouse'' as excluding same-sex marriages and same-sex spouses, and effectively precluded the Federal government from recognizing same-sex marriages and spouses. PMID- 25735053 TI - Medical devices; physical medicine devices; classification of the powered exoskeleton. Final order. AB - : The Food and Drug Administration (FDA) is classifying the powered exoskeleton into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the powered exoskeleton's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 25735054 TI - In memoriam: John C. Norman (1930-2014). PMID- 25735055 TI - Editorial commentary. PMID- 25735056 TI - Basic Health Program; federal funding methodology for program year 2016. Final methodology. AB - This document provides the methodology and data sources necessary to determine federal payment amounts made in program year 2016 to states that elect to establish a Basic Health Program under the Affordable Care Act to offer health benefits coverage to low-income individuals otherwise eligible to purchase coverage through Affordable Insurance Exchanges. PMID- 25735057 TI - Patient Protection and Affordable Care Act; establishment of the Multi-State Plan Program for the Affordable Insurance Exchanges. Final rule. AB - The U.S. Office of Personnel Management (OPM) is issuing a final rule implementing modifications to the Multi-State Plan (MSP) Program based on the experience of the Program to date. OPM established the MSP Program pursuant to the Affordable Care Act. This rule clarifies the approach used to enforce the applicable standards of the Affordable Care Act with respect to health insurance issuers that contract with OPM to offer MSP options; amends MSP standards related to coverage area, benefits, and certain contracting provisions under section 1334 of the Affordable Care Act; and makes non-substantive technical changes. PMID- 25735058 TI - Reply: To PMID 25120407. PMID- 25735059 TI - [Solidagoren(r) Liquid in uncomplicated urinary tract infections]. PMID- 25735060 TI - Caring for caregivers: facing up to tough challenges. AB - This paper, the first in a series of three, sets the stage for two accompanying papers detailing a pair of groundbreaking initiatives to support "at risk" caregivers of high-needs older persons and children in Toronto. Although caregiver burden and stress are often conceptualized primarily as a function of the needs of cared-for persons and the capacity of caregivers, fragmented formal care systems also play a key role. Solutions must take individual-level and system-level factors into account; clarify expectations about what we expect unpaid caregivers to do; redefine the unit of care to include caregivers; and think beyond short-term fixes to mechanisms, such as interdisciplinary teams and integrated care plans, that promote forward planning, accountability, best practices and crisis avoidance. PMID- 25735061 TI - Thermographic study on the preservability of heat effects of footbath with salt. AB - Infrared thermography provides a non-invasive and dynamic measure of heat. The thermal preservability effects of a salt footbath were evaluated by the infrared thermography technique. The subjects were 23 healthy college students. Feet were soaked for 10 min in a 40-42 degrees C normal footbath. Room temperature was set at 26.5-28 degrees C. At the same time on another day within 3 days of the normal footbath experiment, the same feet were soaked for 10 min in a 40-42 degrees C salt footbath. We measured blood pressure, heart rate and temperatures of the feet, second toes, hands and middle fingers, just before and after immersion and at 10-min intervals thereafter. Mean blood pressure changes showed no difference between the normal and the salt footbath. Mean heart rate changes were higher during the normal footbath than at 0, 15 and 20 min during the salt footbath, respectively (p < 0.05). Mean thermal preservability of the feet tended to be lower after the normal footbath than at 20 and 30 min, respectively, after the salt footbath, but these differences did not reach a statistical significance. Mean thermal preservability of the hands and middle fingers was significantly lower after the normal footbath than at 20 and 30 min, respectively, after the salt footbath (p < 0.05). The results suggest that stimulation by a salt footbath affects surface skin temperature, and that stimulation aimed at increasing skin thermal preservability shows a significant difference between normal and salt footbaths. PMID- 25735062 TI - An appropriate compression pace is important for securing the quality of hands only CPR--a manikin study. AB - It is important to implement good quality chest compressions for cardiopulmonary resuscitation (CPR). This manikin study examined the effects of different compression rates on chest compression depth variables using a metronome sound guide. Fifty sixth-year dentistry students participated in the study. Each participant performed CPR at 3 different compression rates, 110, 100, and 90 compressions per min (pace-110-g, pace-100-g, and pace-90-g) for 2 consecutive one-minute sets with a ten-second break between the sets. The percentage of compressions deeper than 5 cm at pace-110-g decreased significantly from 22.1 +/- 4.7% in the first set to 16.7 +/- 4.4%* in the second set (*p < 0.05 vs. the first set). However, no significant differences were observed between the first and second sets at pace-100-g and pace-90-g. The results obtained for pace-110-g were compared in detail by gender. In the male group, the percentage of compressions deeper than 5 cm was 43.5 +/- 7.5% in the first set, and this decreased significantly to 34.6 +/- 7.6%* in the second set (*p < 0.001 vs. the first set). However, the percentage of compressions deeper than 5 cm in the female group was 2.3 +/- 1.6%* in the first set and 0.2 +/- 0.2%* in the second set (*p < 0.05 vs. male). Our study demonstrated that the compression pace of 110 compressions per min was inadequate to provide chest compressions of an appropriate depth, which decreased rapidly. Therefore, limiting the rate of compressions to within a certain number per min may contribute to minimizing deteriorations in compression depth in hands-only CPR. PMID- 25735063 TI - Cost-effectiveness of the introduction of low-dose CT screening in Japanese smokers aged 55 to 74 years old. AB - The validity of low-dose CT screening for lung cancer in heavy smokers was supported by the results of National Lung Screening Trials (NLST) conducted in the U.S.A. The present study investigated the appropriateness of the introduction of low-dose CT screening for lung cancer in Japanese smokers aged between 55 and 74 years old, in terms of cost-effectiveness and age. To examine changes in the shift from conventional chest radiography (CR) to low-dose CT (LDCT) screening for lung cancer, we estimated the incremental cost-effectiveness ratio (ICER) using Iinuma's mathematical model, and also conducted sensitivity analysis to determine the requirements for the introduction of a population-based screening. As the result, the incremental cost for one life-year saved was one million yen or lower when the costs of the screening were 8,000 and 6,000 yen and the recall rate was 10% for male and female smokers aged 55 to 59 years old, respectively. The recall rate was smaller when the interval between cancer screenings was two years, and the subjects were males. The higher the age of the subject, the smaller the incremental cost. In conclusion, at present, the mean cost of the LDCT test is approximately 10,000 yen in Japan. With a reduction in this cost by a few thousand yen, all Japanese smokers aged 55 to 74 years will be able to undergo LDCT screening for lung cancer annually. PMID- 25735064 TI - A case of gastric cancer following living donor liver transplantation. AB - Only a few cases of de novo malignancy, especially gastric cancer after living donor liver transplantation (LDLT), have been reported. We report a case of gastric cancer following LDLT, after which immunosuppressants were minimized in accordance with the results of the mixed lymphocyte reaction (MLR) assay. A 65 year-old woman had previously undergone LDLT for hepatocellular carcinoma associated with hepatitis B virus infection. The liver graft had been donated by her son. During the course of postoperative surveillance with the MLR assay in order to minimize immunosuppressants, she was incidentally found to have gastric cancer during an endoscopic examination, 8 years after the liver transplantation. She underwent total gastrectomy with lymph node dissection. In this case, gastric cancer was detected 8 years after LDLT, which is longer than previously reported intervals between LDLT and malignancy detection. The number of patients undergoing LDLT is increasing, and the prognosis after liver transplantation has improved. Therefore, endoscopic surveillance programs are important for detecting malignancies in the early stages in liver transplant recipients. PMID- 25735065 TI - [Role of acute alcohol poisoning and craniocerebral trauma in the mechanism of death caused by subarachnoid hemorrhage]. AB - OBJECTIVE: To investigate the relation between the expression of tPA, MMP-2, MMP 9 and AEG-1 in the human brain tissue and the ethanol concentration under the acute alcohol poison, and to analyze the role of alcohol and trauma in the mechanism of death of subarachnoid hemorrhage. METHODS: Fifteen real cases were collected in this study. The brain tissues were researched by histological examination and the concentration of ethanol in heart blood were detected. The tPA, MMP-2, MMP-9 and AEG-1 in brainstem, brain and cerebellum were observed respectively by immunohistochemistry. RESULTS: In alcohol poisoning groups with or without trauma, the acute alcohol toxicity resulted in the swelling of brain tissues. The tPA, MMP-2, MMP-9 and AEG-1 of brainstem, brain and cerebellum showed high expression in alcohol victims, and the tPA in cerebellum showed no difference. The expression of the MMP-2, MMP-9 and AEG-1 showed good relation with the ethanol concentration in blood (P < 0.05, r > 0.6). CONCLUSION: The expressions of tPA, MMP-2, MMP-9 and AEG-1 are significant higher in alcohol victims, and expressions of MMP-2 and MMP-9 and AEG-1 have positive correlation with the alcohol concentration. The alcohol has acute toxicity to brain cells. PMID- 25735066 TI - [1H-MRS study on the metabolites of first dorsal interossei]. AB - OBJECTIVE: To estimate the application of prognosis evaluation of ulnar nerve injury by 1H-magnetic resonance spectroscopy (1H-MRS). METHODS: The metabolites of first dorsal interossei (FDI) of two hands from 12 healthy volunteers and 1 volunteer with complete ulnar nerve injury were detected by 1H-MRS and the data were statistically analyzed. RESULTS: For the FDI of healthy adults, the female peaks area of extra-myocellular lipids (EMCL) was higher than the male (P < 0.05); There was no significant difference in Cho, Cr and intra-myocellular lipids (IMCL) between male and female (P > 0.05); There was no significant difference in all the peaks area between the left and right hand (P > 0.05). The EMCL peak of the injury side was higher than that of the healthy side, and the area of FDI was reduced in the volunteer with ulnar nerve injury. CONCLUSION: Noninvasive and quantitative detection of 1H-MRS may be valuable for prognosis evaluation of peripheral nerve injury. PMID- 25735067 TI - [Establishment of miniSTR fluorescent detection system and its forensic application]. AB - OBJECTIVE: To establish miniSTR fluorescent detection system with all detected fragments below 150 bp and to enhance the efficiency of detecting the degraded DNA samples. METHODS: All candidate primers were designed by Primer Premier 5 and screened by FastPCR 6.0. The miniSTR multiplex system was established by these selected loci labeling by four fluorescent dye. The parameters of PCR and primer concentrations were subsequently optimized. The electrophoresis was fulfilled under POP4 on 3100-Avant and the typing data was validated by standard DNA 9947A and 007. Fresh blood samples and difficult degraded DNA samples were tested to evaluate the usefulness of the system. RESULTS: All amplicons in the established miniSTR fluorescent detection system (D12ATA63, D2S1776, D1GATA113, D4S2408, D17S974, D20S482, D3S3053, Amelogenin, D6S474, D9S1122) were less than 150bp. The profile showed a balanced peak height without extra stutter by optimal protocol. Allele frequencies showed no deviations from Hardy-Weinberg equilibrium. The system showed accumulated probability of discrimination 0.999 999 983 and accumulated triplet excluding probability of paternity 0.996 8. It could detect corrupt muscle tissue, low copy number DNA samples and human tissues fixed by 40% formaldehyde solution for 12 days. CONCLUSION: The miniSTR fluorescent detection system could be solely used for personal identification of degraded DNA samples or complementally used for paternity tests. And the system could enhance the ability of detecting the trace and degraded DNA. PMID- 25735068 TI - [Forensic application of 30 InDel loci in Han and She nationalities of Eastern China]. AB - OBJECTIVE: To evaluate the forensic application value of 30 insertion/deletion (InDel) loci included in Investigator DIPplex Kit in Han and She nationalities of Eastern China. METHODS: A total of 565 unrelated individuals in Han nationality and 119 ones in She nationality of Eastern China were investigated using Investigator DIPplex Kit. Allele frequencies, population genetics parameters of the 30 InDel loci were statistically calculated. RESULTS: In Han nationality, the mean Ho was 0.413 3, the mean DP was 0.551 1, the mean PIC was 0.320 0. And in She nationality, the mean Ho was 0.389 6, the mean DP was 0.543 3, the mean PIC was 0.310 0. No deviation from Hardy-Weinberg equilibrium was observed in Han and She nationalities (P > 0.05). CONCLUSION: The 30 loci in Investigator DIPplex Kit show good genetic diversity in Han and She nationalities, and could be used as a supplemental tool for some special paternity cases. PMID- 25735069 TI - [Species identification and absolute quantification of biological samples by droplet digital PCR]. AB - OBJECTIVE: To test droplet digital PCR for species identification and absolute quantification of biological sample. METHODS: Specific primers and probes for human mtDNA encoding gene ND4 and 16S rRNA were designed, and the species specificity was assessed on DNA samples derived from human and common animals. To determine the sensitivity and stability of droplet digital PCR for species identification and absolute quantification, gradient dilution series of recombinant plasmid and 16 human DNA samples were analyzed. RESULTS: Human recombinant plasmid FAM (ND4) could be used in detecting the samples of human. And the results of detecting were consistent with all levels of diluted concentrations. Droplet digital PCR was able to detect low and single copy of target DNA. CONCLUSION: Droplet digital PCR, with high sensitivity and specificity, is fully amenable for species identification and absolute quantification of biological samples, also it can be applied on routine forensic examination. PMID- 25735070 TI - [DNA aptamer selection in vitro for determining ketamine by FluMag-SELEX]. AB - OBJECTIVE: To select specific DNA aptamer for determining ketamine by FluMag SELEX. METHODS: Based on magnetic beads with tosyl surface modification as solid carrier and ketamine as target, a random ssDNA library with total length of 78 bp in vitro was compounded. After 13 rounds screening, DNA cloning and sequencing were done. Primary and secondary, structures were analyzed. The affinity, specificity and Kd values of selected aptamer were measured by monitoring the fluorescence intensity. RESULTS: Two ssDNA aptamers (Apt#4 and Apt#8) were successfully selected with high and specific abilities to bind ketamine as target with Kd value of 0.59 and 0.66 MUmol/L. The prediction of secondary structure was main stem-loop and G-tetramer. The stem was the basis of stability of aptamer's structure. And loop and G-tetramer was the key of specific binding of ketamine. CONCLUSION: FluMag-SELEX can greatly improve the selection efficiency of the aptamer, obtain the ketamine-binding DNA aptamer, and develop a new method for rapid detection of ketamine. PMID- 25735071 TI - [Impact injuries of pedestrians: 90 cases study]. AB - OBJECTIVE: To explore the relationship between pedestrian traffic accidents and the type of vehicles and summarize the characteristics. METHODS: Ninety cases of pedestrian traffic accidents were reviewed, and the relationship between the types of vehicles and the injuries (site, feature and severity) were analyzed. RESULTS: Different impact injuries were caused by different types of vehicles. The primary sites of the impact injuries depended on the body posture and the height of protruding parts of the front when the accident happened. The injury characteristics were related to the size, direction of acting force and contact surface. CONCLUSION: The analysis of position, feature, and severity of pedestrian injury can determine the type of injury vehicle. PMID- 25735072 TI - [Poisoning by exhaust gas of the imperfect combustion of natural gas: 22 cases study]. AB - OBJECTIVE: To analyze the case characteristics of poisoning by exhaust gas of the imperfect combustion of natural gas and provide references for forensic identification and prevention of such accidents. METHODS: Twenty-two cases of poisoning by exhaust gas of the imperfect combustion of natural gas in Minhang District during 2004 to 2013 were collected. Some aspects such as general conditions of deaths, incidence time, weather, field investigation, and autopsy were retrospectively analyzed. RESULTS: In the 22 cases, there were 15 males and 16 females. The age range was between 2 and 82 years old. The major occurring time was in January or February (8 cases in each) and the cases almost occurred in small area room (21 cases). There was wide crack next to the exhaust port when the gas water heater was been used in all cases. CONCLUSION: There are more prone to occurrence of exhaust gas poisoning of imperfect combustion of natural gas in small area room with a ventilation window near the exhaust port of gas water heated. It shows that the scene of combustion exhaust gas poisoning should be more concerned in the cold season. PMID- 25735073 TI - Medical legal dispute in hospitals of different grades: a retrospective study on 206 cases.. AB - OBJECTIVE: To analyze the characteristics of medical malpractice from different grades of hospitals and to explore forensic investigation strategies in assessing medical dispute. METHODS: A total of 206 cases of medical dispute from 2009 to 2010 investigated by the Department of Forensic Medicine in Nanjing Medical University were selected and analyzed according to fault incidence, fault-prone part, and degree of causality in the treatment. RESULTS: Among the 206 cases analyzed, tertiary hospitals, secondary hospitals and primary hospitals showed medium, high and low error rate, respectively. A majority of medical malpractice cases were distributed in the departments of surgery, medicine and gynecology. CONCLUSION: The frequency and severity of medical malpractice in primary hospitals were high, which were gradually reduced in tertiary and secondary hospitals. PMID- 25735074 TI - [Analysis of 130 forensic expertise cases of simple orbital fracture]. AB - OBJECTIVE: To analyze the features of orbital fracture and to discuss its forensic expertise points. METHODS: One hundred and thirty cases of simple orbital fracture from 2010 to 2012 collected from one public security bureau were retrospectively analyzed such as age, gender, tools, position and morphology of the fracture, periorbital and orbital compound injury and the follow-up results after 6 months. RESULTS: In the 130 cases, the wounded were mainly young men and hit by fist. The fracture of simple medial orbital wall accounted for up to 81.5% in all cases. In the periorbital and orbital compound injury, laceration and contusion of eyelid and ethmoidal cellules and maxillary sinus always occurred. After 6 months follow-up, there were 30 cases of comminuted fracture remained enophthalmos compared with the uninjured side. CONCLUSION: It is inappropriate to judge the fracture of simple medial orbital wall as minor injury. We should judge the degree of simple orbital fracture after the injury is stable. Detailed ophthalmology inspection is necessary for forensic expertise of simple orbital fracture. PMID- 25735075 TI - [Research development and application of virtopsy]. AB - Autopsy represents traditional and classical examination in forensic medicine. It was suggested that conventional autopsy, nowadays sometimes rejected or not tolerated by people for its damage to corpse. Virtopsy offers a non-invasive investigation approach and can also reflect fracture, soft-tissue injury, wound track, organ trauma objectively and accurately. Thus, virtopsy can provide visual and powerful evidence for forensic pathological practice. This article mainly synthesizes the latest literature at home and abroad and reviews application of virtopsy in forensic trauma identification, mechanical asphyxia, drowning, hypothermia and hyperpothermia, disease diagnosis and research of finite element method applicated in trauma investigation to illustrate this new direction of forensic research. PMID- 25735076 TI - [Screening and identification of forensic molecular markers of injury using MALDI TOF-MS imaging mass spectrometry]. AB - There are many deficiencies in forensic traumatic molecular markers detected by the techniques of traditional immunohistology and molecular biology, because these markers are isolated and obscure of the mechanism of interaction. The imaging mass spectrometry (IMS) is more suitable for the forensic molecular markers using function of screening, analysis and graphical representation. In this paper, the techniques and the latest research in screening and identification of typical molecular markers by IMS based on matrix-assisted laser adsorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) are reviewed. And its application values in forensic injury are discussed. PMID- 25735077 TI - [Research progress on the phenotype informative SNP in forensic science]. AB - Single nucleotide polymorphism (SNP) refers to the single base sequence variation in specific location of the human genome. Phenotype informative SNP has gradually become one of the research hot spots in forensic science. In this paper, the forensic research situation and application prospect of phenotype informative SNP in the characteristics of hair, eye and skin color, height, and facial feature are reviewed. PMID- 25735080 TI - [JSN and MHLW Clinical Practice Guidelines for IgA nephropathy 2014]. PMID- 25735079 TI - [In memory of Dr. Shozo Koshikawa]. PMID- 25735078 TI - Sudden death due to brainstem leukemic hemorrhage: a case report. PMID- 25735081 TI - [JSN and MHLW Clinical Practice Guidelines for RPGN 2014]. PMID- 25735082 TI - [Advances in kidney development and application for regenerative medicine]. PMID- 25735083 TI - [Evolution of epigenetics in kidney diseases]. PMID- 25735084 TI - [Kidney and hypertension]. PMID- 25735085 TI - [New strategy for the treatment of autosomal dominant polycystic kidney disease]. PMID- 25735086 TI - [Study on blood pressure standard in children using the automatic sphygmomanometer]. AB - In Japan, two treatment guidelines exist for pediatric patients with hypertension. The Guidelines for Drug Therapy in Pediatric Patients with Cardiovascular Diseases (JCS2012), by the Japanese Circulation Society, cite the stethoscopy-based American guidelines. The Guidelines for the Management of Hypertension (JSH2009), by the Japanese Society of Hypertension, focus on Japanese data obtained from automated sphygmomanometry. The frequent use of automated sphygmomanometers in clinical practice implies that the JSH2009 guidelines might be better; however with strict low reference values for the diastolic phase, overtreatment may result. Only the Japanese Circulation Society's guidelines include a therapeutic strategy, and the Chronic Kidney Disease (CKD) Guide, CKD Guidelines, and school urinary screening tests all cite these guidelines on stethoscopy-based blood pressure determination. Stethoscopy should be conducted during a medical examination; however, due to limited time in clinical practice, most physicians use automated sphygmomanometers while nevertheless relying on the Japanese Circulation Society reference values--which are stethoscopy-based. To find a compromise, we compared reference values in Japan with those from South Korea (automated sphygmomanometer-based) and those from the United States (stethoscopy-based). Moreover, we examined the results of recent accuracy tests for automated sphygmomanometers. Although the JSH2009 reference values for the systolic phase were consistent with those in the United States (stethoscopy-based), the reference values for the diastolic phase were lower. We observed the same tendency when comparing JSH2009 reference values with those in South Korea (automated sphygmomanometer-based). Conversely, there were only small differences between automated sphygmomanometry and mercury measurement, and we found it was possible to substitute the values from automated sphygmomanometry for stethoscopy. A large-scale study that takes into account patient height, measurement method, and treatment criteria is required to establish appropriate reference values. Even if automated sphygmomanometry is used until appropriate values are established, we consider the criteria provided in the American guidelines as appropriate. PMID- 25735088 TI - [Surgical treatment to the attic in the middle ear cholesteatoma]. PMID- 25735087 TI - [Case of a 14-year-old boy with chronic tubulointerstitial nephritis first diagnosed as acute focal bacterial nephritis]. AB - A 14-year-old boy was admitted to a general hospital because of prolonged fever of unknown origin. After Enterococcus feacalis was detected from his urine and abdominal contrast enhanced computed tomography and 99m-Tc dimercaptosuccinic acid scintigram showed multiple focal defects, he was diagnosed as acute focal bacterial nephritis (AFBN). His condition recovered as a result of Ampicillin (ABPC)and Cefotaxime infusion. There was no specific finding in voiding cystography. Six months later, his fever recurred and he was diagnosed as refractory AFBN because Enterococcus feacalis was detected in his urine again. He was treated with ABPC and Meropenem (MEPM) infusion, but the fever persisted and his renal function deteriorated. He was transferred to our hospital for intensive treatment. On admission, blood examination showed findings of inflammation (WBC 14,400/MUL, CRP 3.7 mg/dL, erythrocyte sedimentation rate : 69 mm/h, IgG : 2,107 mg/dL) and renal impairment (Cr : 1.8 mg/dL, cystatin C : 2.0 mg/L). Although neither pyuria nor pathogenic bacteria were detected in his urine, Enterococcusfeacalis was detected at the hospital where he had been treated previously, hence we started treatment for AFBN with ABPC, MEPM, Levofloxacin, then Linezolid. However, the fever persisted and his renal function deteriorated (Cr 2.0 mg/dL). Kidney-specific accumulation was found in Ga scintigraphy, which suggested chronic inflammation. Clinical course and laboratory findings showed no symptoms of bacterial, viral, fungal, or tuberculous infections nor collagen disease. Although renal biopsy revealed no glomerular abnormality, tubulointerstitial edema, fibrosis and tubulitis were observed. Rupture of the tubular basal membrane and non-caseating granulomas also existed. Pathological findings did not match those of renal sarcoidosis. Ophthalmological screening negated the existence of tubulointerstitial nephritis with uveitis syndrome. After methylprednisolone pulse therapy, the fever recovered immediately and his renal impairment imroved gradually (Cr 1.49 mg/dL). He continues to undergo treatment as an outpatient. Although tubulointerstitial nephritis is rare in children, some patients have a poor renal prognosis. It is important to determine the existence of tubulointerstitial nephritis on treating a patient with renal impairment. PMID- 25735089 TI - [Investigation of self-renewal mechanism about CD133+ cancer stem cells in human laryngeal carcinoma Hep-2 cell line]. AB - OBJECTIVE: To investigate the self-renewal mechanism of CD133+ cancer stem cells from Hep-2 cell line. METHOD: The CD133+ cells were sorted by flow cytometry from Hep-2 cell line. Then the sorted CD133+ cells were cultured in RPMI1640. The ability of self-renewal of CD133+ cells were tested by MTT assay. mRNA and protein expression of self-renewal related genes were detected by western blot and RT- PCR. RESULT: (3.10 +/- 0.21)% of Hep-2 cells expressed the membrane antigen CD133. CD133+ fraction was raised to (90.20 +/- 5.51)% by flow cytometry. In vitro culture and growth curve showed CD133+ cells had more active proliferation ability than CD133- cells, which showed statistically significant difference between these two group (P < 0.01). RT- PCR and western blot results showed upregulated mRNA and protein expression of Fas, c-myc, survivin in CD133+ group (P < 0.01). In the same time, the ratio of Bcl-2/Bax gene expression was obviously increased in CD133+ group. Self-renewal related gene such as beta catenin, SHH, SMOH and Bmi-1,Gli-1 were all up-regulated in CD133+ group both in mRNA and protein. On the contrary, PTCH gene was down-regulated. CONCLUSION: CD133 positive cells are a small proportion of a Hep-2 cell line. The results of this experiment verified that CD133 positive cells owned the properties of cancer stem cells. Upregulated anti-apoptotic gene is the foundatiom of self-renewal mechanism of CD133+ cells. Cancer stem cells related signal pathways such as Hedgehog, Wnt and Bmi-1 pathway are in state of activation. The identification of self-renewal mechanism about cancer stem cell provides a powerful tool to investigate the tumorigenic process in the larynx and to develop therapies targeting to these signal pathways. PMID- 25735090 TI - [Expression and significance of DNA-dependent protein kinase in human laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To study the expression of DNA-dependent protein kinase (DNA-PK) in human laryngeal squamous cell carcinoma (LSCC) and normal laryngeal mucosa (NLM), and to analysize the relationship between the expression and the clinicopathologic parameters of LSCC. METHOD: Immunohistochemical technique (Envision) was used to detect the expression of DNA-PK in 64 cases of LSCC and 15 cases of NLM. To investigate an investigation was conducted on the relationship between the expression and clinico-pathological features of LSCC. RESULT: DNA-PK was lowly expressed in NLM and highly expressed in LSCC,the positive rate of DNA PK expression was 26.67% (4/15), 78.13% (50/64), respectively, and there was significant different difference between the two groups (P < 0.05). Its expression was correlated with the level of histodifferentiation (P < 0.05), but not with TNM stages and neck lymph node metastasis (P > 0.05). CONCLUSION: DNA-PK may be involved in disease development of LSCC. PMID- 25735091 TI - [Factors and prevention measures of postoperative infection in laryngeal cancer patients]. AB - OBJECTIVE: To investigate the factors of postoperative infection in patients with laryngeal cancer,and propose preventive measures,to provide a theoretical basis for the control of hospital infection. METHOD: Here we conducted an epidemiological study of 259 patients undergoing surgery in our hospital laryngeal surgery, and analyzed the influencing factors of postoperative infection. RESULT: Among 259 patients, 18 cases (6.95%) patients had postoperative infection; multifactor by Logistic regression analysis showed that there was a correlation about patients postoperative infection was associated with age (OR = 20.694, P < 0.05), preoperative radiotherapy (OR = 19.719, P < 0.05), hospitalization (OR = 10.679, P < 0.05 ), operative time (OR = 14.387, P < 0.05), type of surgery (OR = 4.771, P < 0.05), tracheostomy (OR = 55.795, P < 0.05), antibiotic use (OR = 12. 486, P < 0.05) and postoperative nutritional support (OR = 7.928, P < 0.05). CONCLUSION: Strict implementation of the treatment of laryngeal surgery aseptic,shorter hospital stay and operative time, strengthen the operating room disinfection, perioperative, and postoperative care of patients with nutrition, rational use of antibiotics,planned radiotherapy for advanced tumor, are the key measure to reduce postoperative infection rate of laryngeal. PMID- 25735092 TI - [Assessment of quality of life for laryngeal cancer patients after laryngectomy]. AB - OBJECTIVE: This study was designed to develop a rating scale of quality of life (QOL) which fits laryngeal cancer patients after laryngectomy. METHOD: The item pool was developed on the definition of QOL from WHO and the principles and procedures of ddveloping a rating scale. Five methods had been used in the item selection including, such as subjective evaluation methods, discrete tendency, correlation coefficient method, stepwise regression analysis, and factor analysis. The survey was conducted in 126 laryngeal cancer patients after laryngectomy in order to assess the reliability and validity of the rating scale. RESULT: (1) A rating scale of QOL which fits laryngeal cancer patients after laryngectomy including six domains and 27 items is was developed. (2) The split half reliability coefficient of the scale is 0.802, and the Cronbach' alpha coefficient is 0.794. (3) It is inferred from the correlation analysis that there are strong correlation between items and their own domains; conversely there are weak correlation between items and other domains. Correlation coefficient is 0.731 between total score and self-rating score. CONCLUSION: The reliability and validity of the rating scale is proved to work well. PMID- 25735093 TI - [The clinical value of sentinel lymph node detection in laryngeal and hypopharyngeal carcinoma patients with clinically negative neck by methylene blue method and radiolabeled tracer method]. AB - OBJECTIVE: To investigate the clinical value of sentinel lymph node (SLN) detection in laryngeal and hypopharyngeal carcinoma patients with clinically negative neck (cN0) by methylene blue method, radiolabeled tracer method and combination of these two methods. METHOD: Thirty-three patients with cN0 laryngeal carcinoma and six patients with cN0 hypopharyngeal carcinoma underwent SLN detection using both of methylene blue and radiolabeled tracer method. All these patients were accepted received the injection of radioactive isotope 99 Tc(m)-sulfur colloid (SC) and methylene blue into the carcinoma before surgery, then all these patients underwent intraopertive lymphatic mapping with a handheld gamma-detecting probe and blue-dyed SLN. After the mapping of SLN, selected neck dissections and tumor resections were peformed. The results of SLN detection by radiolabeled tracer, dye and combination of both methods were compared. RESULT: The detection rate of SLN by radiolabeled tracer, methylene blue and combined method were 89.7%, 79.5%, 92.3% respectively. The number of detected SLN was significantly different between radiolabeled tracer method and combined method, and also between methylene blue method and combined method. The detection rate of methylene blue and radiolabeled tracer method were significantly different from combined method (P < 0.05). Nine patients were found to have lymph node metastasis by final pathological examination. The accuracy and negative rate of SLN detection of the combined method were 97.2% and 11.1%. CONCLUSION: The combined method using radiolabeled tracer and methylene blue can improve the detection rate and accuracy of sentinel lymph node detection. Furthermore, sentinel lymph node detection can accurately represent the cervical lymph node status in cN0 laryngeal and hypopharyngeal carcinoma. PMID- 25735094 TI - [Haplotype analysis of XRCC3 gene and laryngeal]. AB - OBJECTIVE: To explore the association of XRCC3 gene polymorphisms and haplotypes with laryngeal. METHOD: We selected 4 tag SNPs (rs12432907, rs861536, rs861537, rs861531, rs861531) for the present study. 310 laryngeal patients and 310 healthy control subject were genotyping. The distribution of genotypes and haplotypes in these two group was compared. RESULT: The distributions of rs12432907 was significantly different between these two groups. The CCAG haplotype frequency was higher in laryngeal group than that in control group. But TCAG and TTAG haplotype frequency was were lower in the laryngeal patient than that those in the control subject. CONCLUSION: XRCC3 gene polymorphism was associated with the risk of laryngeal patients. PMID- 25735095 TI - [Evaluation of the diagnostic accuracy of modified Berlin questionnaire on predicting obstructive sleep apnea-hypopnea syndrome in adults]. AB - OBJECTIVE: To evaluate the diagnostic value of modified Berlin questionnaire on predicting obstructive sleep apnea-hypopnea syndrome (OSAHS)in Chinese adults. METHOD: Differ from the original version, BMI cut-off point was adjusted to 25.0 in modified Berlin questionnaire according to the Asia -Pacific obesity definition. A total number of 244 samples who experienced polysomnography (PSG) were included. After well informed, each patient finished questionnaire by an interview. The results of the original and modified questionnaires and polysomnography reports were compared with polysomnography reports to evaluate the diagnostic accuracy of the modified Berlin questionnaire. RESULT: In male population, the sensitivity and specificity of original Berlin questionnaire were 74.03% and 65.71%, respectively. The percentage of diagnostic consistency was 72.49%, and Kappa coefficient was 0.304 (P < 0.01). In aspect of modified version, the sensitivity and specificity were 92.21% and 48.57%. The percentage of diagnostic consistency was 84.13%, and Kappa coefficient was 0.437 (P < 0.01). In female population, the sensitivity and specificity of original version were 50.00% and 61.90%, respectively. The percentage of diagnostic consistency was 54.55%, and Kappa coefficient was 0.110 (P > 0.01). When comes to the modified Berlin questionnaire, the sensitivity and specificity were 76.47% and 47.62% in female subjects, and the percentage of consistency agreement was 65.45%, with a Kappa coefficient 0.248 (P > 0.01). CONCLUSION: Compared to the original version, the modified Berlin questionnaire has a better diagnostic consistency with a considerable sensitivity and specificity in male population. However, in female subjects group, the consistency of the modified Berlin questionnaire was still not significant remains unsatisfactory, although P value has been improved. Modified Berlin questionnaire could be. used as a primary screening tool for male OSAHS patients. However, but the screening questionnaire for female should still be need to be further explored. PMID- 25735096 TI - [Analysis the relationship of mean platelet volume and nasal obstructive disease]. AB - OBJECTIVE: High mean platelet volume (MPV) values are a risk factor for cardiovascular diseases. Our aim was to investigate the association between nasal obstructive disease and MPV value. METHOD: This study included 40 patients with nasal obstructive disease and 30 age-and sex-matched healthy subjects as controls. The levels of the number of platelets, MPV, platelet distribution width (PDW) were evaluated and compared in the two groups. Then the MPV was compared in the patients before and after operation in the study group. RESULT: Platelet count is significantly lower in the study group than the control group [(215.0 +/ 47.5) x 10(9)/L versus (237.8 +/- 46.2) x 10(9)/L]; MPV and PDW is significantly higher in the study group [(10.7 +/- 0.7) fL versus (10.3 +/- 0.8) fL]; [(12.9 +/ 2.0) % versus (12.0 +/- 1.3) %]. Comparing to preoperation, MPV values of the study group is significantly decreased after nasal obstructive operations [(10.7 +/- 0.7) fL versus (10.4 +/- 0.6) fL]. CONCLUSION: MPV levels are elevated in patients with nasal obstructive disease, and can be decreased by nasal obstructive operation. PMID- 25735097 TI - [Serum S100 protein and NSE levels and significance of changes after treatment in patients with severe OSAHS]. AB - OBJECTIVE: Understand the changes before and after treatment in patients with severe OSAHS serum S100beta protein, NSE levels and cognitive function. To investigate the molecular mechanisms of cognitive dysfunction in patients with severe OSAHS. Serum S100beta protein, NSE levels and cognitive function were examined before and after the therapy. METHOD: Select one hundred patients diagnosed as severe OSAHS were included, by polysomnography (PSG) diagnosis of severe OSAHS patients. Determination of serum S100beta protein, and NSE levels and theat the same time be MoCA score were checked at after the day after admission, CPAP treatment for the 7th days after CPAP treatment and the 90th day after, comprehensive treatment in these patients for 3 months. Assessment of severe OSAHS patients with serum S100beta protein, NSE basic level and MoCA score situation. Comparison of three groups serum S100beta protein, NSE levels and MoCA score changes. Serum S100beta protein, NSE detection assay (ELISA) method using enzyme-linked immunosorbent. RESULT: (1) Severe OSAHS patients with serum S100beta protein, and NSE levels in severe OSAHS patients were positively correlated with AHI, but negatively correlated with lowest oxygen saturation (LSaO2); (2) MoCA score in patients with severe OSAHS was significantly negatively correlated with AHI, but positively correlated with LSaO2; (3) S100beta protein, NSE levels were negatively correlated with MoCA score; (4) Compared with admission, serum S100beta protein, and NSE levels in these patients have declined after 7 days CPAP therapy, compared with admission the difference was statistically significant (P < 0.05). After 3 months of comprehensive treatment, patients' serum S100beta protein and, NSE levels were significantly decreased, compared with the admission and the 7th days after CPAP treatment. The difference was statistically significant (P < 0.05). (5) After CPAP treatment for 7 days, the MoCA scores were slightly higher, but have there was no statistically significant difference compared with the admission (P > 0.05). After 3 months of comprehensive treatment, MoCA score improved significantly, compared with the admission and 7 days after CPAP treatment the difference was statistically significant (P < 0.05). CONCLUSION: Comprehensive treatment can reduce serum S100beta protein, and NSE levels, and improve MoCA score. Disease severity in patients with OSAHS have a correlation some relative.with the serum S100beta protein, NSE levels and MoCA score. Long-term hypoxemia and the structure of sleep disorders may be the cause of elevated serum S100beta protein, NSE levels elevated and causes of cognitive dysfunction. Comprehensive treatment can improve patient hypoxemia, correct disorders of sleep structure ,and can improve cognitive function and to improve the quality of life of patients. PMID- 25735098 TI - [Velopharyngoplasty combined with hard palete shorting soft palete forward to the treatment of type II moderately severe obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To explore the curative effect of velopharyngoplasty (VPP) combined with hard palate shorting and soft palate forward in the treatment of type II moderately severe obstructive sleep apnea hypopnea syndrome (OSAHS). METHOD: Thirty-two patients with OSAHS with and the obstructed surface located in soft palate were subjected to VPP combined with hard palate shorting and soft palate forward. The ESS scores, result of PSG included AHI and the lowest oxyhemoglobin saturation before and after operation were compared. RESULT: The effective rate of VPP was 78.12% this group. The grade of ESS, PSG and the lowest oxyhemoglobin saturation was statistically significant before and after the operation (P < 0.05). In the other 7 cases whose AHI decrease less than 50%, the grade of ESS, AHI and the lowest oxyhemoglobin saturation was also statistically significant. CONCLUSION: VPP combined with hard palate shorting and soft palate forward can improve the surgical effective rate obviously for OSAHS patients. PMID- 25735099 TI - [Endoscope-assisted superficial parotidectomy via retroauricular hairline approach: anatomical study]. AB - OBJECTIVE: To provide anantomical basis for the endoscope-assisted partial superficial parotidectomy via retroauricular hairline approach (EASPRHA) and assess its feasibility and safety. METHOD: The surgical anatomy of retroauricular hairline region and parotid gland region were observed in 15 fresh human cadavers (30 halves). The EASPRHA was performed on 5 human cadavers (10 halves). After the procedure, the related vascular and neural structures were evaluated. RESULT: The retroauricular hairline region extends between superficial musculoaponeurotic system and superficial cervical fascia. On the superficial surface of the upper sternocleidomastoid lie the lesser occipital nerve, the great auricular nerve and the external jugular vein. The bifurcation of great auricular nerve is(22.85 +/- 2.01) mm from the bottom of earlobe. The parotid gland region extends between parotidomassteric fascia and parotid gland parenchyma. The facial nerve emerging from the stylomastoid foramen runs across the superficial surface of base of styloid process, passes through the interspace between cartilage of external acoustic meatus and posterior belly of digastric muscle, and enters the parotid gland. The bifurcation of facial nerve trunk is (19.10 +/- 3.10)mm from the mastoidale and (39.49 +/- 5.78) mm from the mandibular angle. Above the posterior belly of digastric muscle, the posterior auricular artery arises from the posterior wall of the external carotid artery with its main stem running over the superficial surface of facial nerve trunk. In all endoscope-assisted operations, the partial superficial parotidectomy was successful without the need for an additional incision. No major neurovascular damage wasobserved. CONCLUSION: A thorough knowledge of the surgical anatomy of retroauricular hairline region and parotid gland region is an essential requirement in performing the safe and feasible EASPRHA. PMID- 25735100 TI - [The expression and significance of miRNA-324-3p and WNT2B in nasopharyngeal carcinoma]. AB - OBJECTIVE: To investigate the expression and significance of miRNA-324-3p and its target gene WNT2B in tissue specimens of nasopharyngeal carcinoma (NPC) specimens. METHOD: qRT-PCR was used to detect the expression of miRNA-324-3p and WNT2B mRNA, and Western blot was applied to assay the expression of WNT2B protein in 39 cases of NPC specimens and 21 cases of non-carcinoma epithelium. The relationship between their expression levels and clinicopathological characteristics and their correlation with clinical pathological parameters was analyzed. RESULT: The expression of miRNA-324-3p was significantly down-regulated decreased but WNT2B mRNA/protein increased obviously in NPC specimens (P < 0.01). A negative correlation between miRNA-324-3p and WNT2B was spotted (P < 0.05). The expression levels of these markers were closely correlated with T stage, clinic stage and cervical lymph node metastasis (P < 0.05). CONCLUSION: The loss of miRNA-324-3p and ectopic WNT2B might co-induce the initiation and progression of NPC. PMID- 25735101 TI - [Meta-analysis of association between MMP-1-1607 polymorphism and head and neck cancer risk in asia population]. AB - OBJECTIVE: To analyze and explore the association between the 1607(1G/2G) single nucleotide polymorphism (SNP) in promoter of matrix metalloproteinase-1 (MMP-1) gene and susceptibility of head and neck cancer (HNC) by Meta-analysis. METHOD: By the end of January 2014, the published literatures were collected for the case control studies evaluating the relationship between HNC and -1607 SNP of MMP-1 gene from English and Chinese literature databases according to the inclusion and exclusion criteria. Then the meta-analysis, the heterogeneity, bias and sensitivity of the results of the eligible literatures were conducted by Stata 10. 0. RESULT: A total of 9 studies including 2049 patients with HNC and 2158 controls were extracted for systematic review on the association of MMP-1 (-1607) 1G/2G SNP with the risk of HNC. Meta-analysis which based on random effects model showed that MMP-1 (-1607) 1G/2G SNP can significantly increase the risk of HNC[1G2G + 2G2G vs. 1G1G: OR = 1.45, 95% CI 1.25-1.68, P < 0.01; 2G2G vs. 1G1G + 1G2G:OR = 1.77, 95% CI 1.37-2.30, P < 0.01; 2G vs. 1G: OR = 1.52, 95% CI 1.26 1.85, P < 0.01; 2G2G vs. 1G1G: OR = 2.06, 95% CI 1.41-3.01, P < 0.01). CONCLUSION: MMP-1 (-1607) 1G/2G SNP has close relationship with HNC susceptibility, people who with 2G2G genotype carriers are susceptible to HNC. PMID- 25735102 TI - [Clinical analysis of microsurgical anterolateral thigh free flap for head and neck region reconstruction]. AB - OBJECTIVE: To summarize the experience of improving survival rate of microsurgical free flap transfers for head and neck reconstruction. METHOD: One hundred and seventy-nine consecutive microsurgical free flap transfers performed in patients with head and neck region defects after surgical procedure due to carcinoma were reviewed. The microsurgical free flap survival rate and postoperative complication were evaluated. RESULT: The overall success rate of flap was 98.9%. The overall complication rate was 7.8%. The flap crisis rate was postoperative flap crisis incidence rate was 4.4%. The success rate of immediate surgical exploration within 6 hours successfully rescued the flap in were 6 six cases, and the other else two cases cut died flap and repaired the region defect in the head and neck with pectoralis major myocutaneous flap. CONCLUSION: Key factors in improving the succeess rate are to guarantee vascular anastomosis patency, to achieve a good haemostasis, and to promptly closely observe discover blood vessel flap crisis after operation in the first 6 hours and immediate surgical exploration. PMID- 25735103 TI - [Function of three-dimensional reconstruction of CT scan to the operation of eagle syndrome]. AB - OBJECTIVE: To investigate the guiding function of three-dimensional CT scan in the operation of eagle syndrome. METHOD: There were 48 cases of eagle syndrome hospitalized during July 2006 to June 2010 who underwent both three-dimensional reconstruction of CT scan and adem position and lateral X ray film. The images were measured by specialist of radiology department. RESULT: The detail of styloid process is showed more precisely by three-dimensional CT scan, which is able to determine the existence of interrupt, decline, ossification in styloid process. There was significant difference in the measured value (20.83%) between X ray and CT scan (4.16 +/- 1.27)cm vs (3.11 +/- 0.62)cm, P < 0.05, in 10 cases. We could not touch styloid process in oral approach in 6 cases (12. 5%), which also had diagnostic confliction between X ray and three-dimensional CT scan. Five patients whose styloid process could not be touched during surgery had longer operation time than the other 41 patients. CONCLUSION: Three-dimensional CT has good repeatability, high detailed distinguishability, which is an important basis to diagnose eagle syndrome. When X ray shows prolonged styloid process which can not be palpable in oral, we suggest further three-dimensional CT to avoid unnecessary surgery. PMID- 25735104 TI - [AG200 and polysomnography in patients with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To study the clinical value of polysomnography (PSG) and ApneaGraph (AG200) in the diagnosis evaluation of obstructive sleep apnea hypopnea syndrome (OSAHS). METHOD: From January to December in 2012, 67 OSAHS patients diagnosed by PSG were examined by AG200. The apnea hypopnea index (AHI), hypopnea index (HI), apnea index (AI), the lowest oxygen saturation (LSaO2) was were detected and the results were analyzed statistically. RESULT: Significant differences were observed in AI, AHI, LSaO2 between AG200 and PSG (P < 0.05, respectively). No statistically significant difference was found in HI. The differences in HI between AG200 and PSG were not significant (P > 0.05). AHI, HI and LSaO2 was were significantly correlated between AG200 and PSG (r = 0.870, 0.743, 0.374, 0.716, P < 0.01). CONCLUSION: AG200 could not replace PSG but could identify the level of upper airway obstruction. PMID- 25735105 TI - [Relationship between the major histocompatibility complex class I chain-related gene A expression and clinicopathologic features in laryngeal squamous carcinoma]. AB - OBJECTIVE: To investigate the expression of major histocompatibility complex class I chain-related gene A (MICA) in laryngeal squamous cell carcinoma(LSCC), and its clinical significance. METHOD: Immunohistochemistry and RT-PCR were used to detect the expression of the MICA in LSCC and normal tissue samples. The relationship between the expression of MICA and the clinicopathologic features features were was analyzed. RESULT: Compared to the expression of MICA in normal tissues samples, the expression of MICA in LSCC tissue was significantly increased (P < 0.01). MICA expression level in carcinoma tissue was closely related to the tumor-differentiation degree and TNM staging. CONCLUSION: Our study suggests that MICA may play an important role in the invasion and metastasis of LSCC, and could be a potential tumor maker for LSCC. PMID- 25735106 TI - [Inhibitive effect of matrine modification X on the growth of human nasopharyngeal carcinoma CNE2 cell xenografts in nude mice]. AB - OBJECTIVE: To evaluate the inhibitive effect of matrine modification X on the growth of human nasopharyngeal carcinoma CNE2 cell xenografts in nude mice. METHOD: Tumor model was established by subcutaneous inoculation of nasopharyngeal carcinoma cell CNE2 into nude mice, which was used to evaluate the antitumor effect of matrine modification X in vivo. The expression levels of Bax, Bcl-2, Caspase3 were detected by real-time PCR and western blot. RESULT: The growth of xenografts in nude mice was significantly suppressed after application of matrine modification X in a dose-dependent manner. The inhibition rates were 32.55% and 44.89% when treated at medium and high dose respectively. Real-time fluorescence quantitative-PCR and Western Blot results showed that the expression of Bax and Caspase3 increased, while the expression of Bcl-2 decreased in a dose-dependent manner. The change of high dose group was obvious, and the difference was statistically significant (P < 0.05). CONCLUSION: Matrine modification X could significantly inhibit the growth of human nasopharyngeal carcinoma CNE2 cell xenografts in nude mice, probably by inducing the apoptosis of nasopharyngeal carcinoma cells, and the possible mechanism is related to regulating the expression level of Bax/Bcl-2 and Casepase3. PMID- 25735107 TI - [Cause and treatment analysis of arytenoid dislocation caused by endotracheal intubation after general anesthesia of children]. PMID- 25735108 TI - [Diagnosis and treatment of 10 cases of parathyroid adenoma]. PMID- 25735109 TI - [The contrast application research of ultrasound knife in parotid gland surgery]. PMID- 25735110 TI - [Clinical observation of concurrent chemotherapy combined with microwave hyperthermia in treatment of nasopharyngeal carcinoma with cervical lymph node metastasis]. PMID- 25735111 TI - [Practical nasal foreign body extracter]. PMID- 25735112 TI - [Malignant peripheral nerve sheath tumor in the maxillary sinus: a case report]. AB - We report a case of 46-year-old xanthoderm woman who was diagnosed as malignant peripheral nerve sheath tumors of right maxillary sinus, and have a literature review. Histology confirmed a diagnosis of malignant peripheral nerve sheath tumor. The woman had the right total maxillectomy and postoperative adjuvant radiotherapy. There is no local recurrence or metastasis of one year following up. Literature review revealed MPNST in the nasal cavity and para-nasal sinuses were not common with poor prognosis. The main cause of death is local recurrence and metastasis. Surgical resection showed more advantage than adjuvant radiotherapy and chemotherapy. PMID- 25735113 TI - [Endoscopic pleomorphic adenoma of nasal septum resection assisted by low temperature plasm radiofrequency: a case report]. AB - We present an extremely rare case of pleomorphic adenoma of the nasal septum in a 24-year old woman who went to consultation because of right nasal neoplasm. The radiologic discoveries by computerized tomography showed a tumor in the right nasal septum. Incisional biopsy was done, with a histopathological report of pleomorphic adenoma. Later, nasal endoscopy was used to remove the neoplasm and histology revealed pleomorphic adenoma of the nasal septum. PMID- 25735114 TI - [Large mixed tumors of salivary: two cases reports]. AB - It is rare that large mixed tumors of salivary gland located in the nose and uvula. The patient who had mixed tumors of salivary gland at nose found exophytic growth tumor for half a year. The other patient who had mixed tumors of salivary gland at uvula felt swallowing foreign body sensation for one year, and dysphagia for one month. After surgical resection, the symptoms disappear. PMID- 25735115 TI - [Tears ago fossae endoscopic approach wing palatine fossa cyst excision]. AB - In this paper, patients with the left ear hearing loss, aural fullness. CT: the left wing palatine nest sites. MRI: on the left wing palatine timid benign lesions; Electric listening: conductive deafness. Acoustic immittance: B type curve. Clinical diagnosis: the left wing palatine fossa cyst, left ear secretory otitis media. PMID- 25735116 TI - [On the right side of the amygdala salivary glands ectopic case report]. AB - The patient complained of recurrent sore throat for 2 years, who was diagnosed parapharyngeal abscess or tonsillitis for four times during June 16, 2012 to April 16, 2013. Special physical examination: left or right lateral pharyngeal wall is slightly elevated. Routine blood test showed increasing white blood cells and neutrophils. Oropharyngeal CT showed right lateral pharyngeal wall swelling and abscess formation? Repeated puncture showed no obvious purulent secretions. Symptoms were improved after anti-inflammatory treatment, but it recurrently happened later. Bilateral tonsillectomy was performed under general anesthesia on April 29, 2013. Pathological report (May 6, 2013) showed: (left) chronic tonsillitis with lymphoid hyperplasia; chronic inflammation in (right) tonsil tissue, and salivary gland tissue is also observed, considering as the hyperplasia of ectopic salivary gland tissue and interstitial lymphocytic oinfiltration. PMID- 25735117 TI - [Branchial cleft cyst carcinoma: a case report and literature review]. AB - The patient complained of a 20 days history of isolated mass in the right cervical region. The lesion was successfully eradicated by surgical removal. Histopathology established branchial cleft cyst carcinoma (BCCC) as the diagnosis. More attentions should be paid to the diagnosis of BCCC. Primary leisions were essential for the suspected cases. Importantly, only after excluding the metastatic squamous carcinoma in lymph nodes and other primary diseases, the diagnosis of BCCC would be established. Therapeutic strategies include complete local excision, radical neck dissection, and post-operative radiotherapy. PMID- 25735118 TI - [MicroRNA expression profiles in enhancement of radiotherapy and the mechanisms]. AB - MicroRNAs are a class of small (-22nt) non-coding RNAs that bind to the 3' untranslated regions (3'-UTRs) of their target mRNAs in a complementary or partially complementary manner via the seed sequence in their 5'-region to regulate biological effect. MicroRNAs also expressin malignant tumors and have close relations with occurrence, development and other biological characteristics of tumor. The effect of radiotherapy and the prognosis of cancer patients are limited and influenced by radioresistant all the time. In recent years, the application of microRNAs to improve the radiation sensitivity of tumor cells is a new field in tumor biotherapy. This paper mainly reviews the identification of related microRNAs participating in and regulating the formation of radiosensitivity/radioresistent, and the research progress of their possible mechanisms. PMID- 25735119 TI - Diagnosis of acute severe colitis. AB - It is important to assess the severity of ulcerative colitis (UC) in order to decide the intensity of treatment and predict outcome. The criteria instituted by Truelove and Witts almost 60 years back are still being used. However, they lack a scoring system and offer no clear definition for the moderate group. The criteria with scoring system and endoscopic criteria (Mayo Score) seems to be more useful clinically. Endoscopic assessment is very important and a cautious attempt should always be made even if it enables a limited colonoscopic examination. Proctosigmoidoscopy is advocated at initial stages and after 5 to 7 days. The criteria for severity in general are same for pan-colitis and limited disease. PMID- 25735120 TI - Natural history of first episode of acute severe colitis. AB - The first attack of ulcerative colitis can be acute and severe in 2-50% of patients. Acute severe colitis needs to be distinguished from various other conditions including severe infective colitis and ischaemic colitis. In those treated traditionally with intravenous corticosteroids, 30-40% require colectomy within a period of 6 months. The use of rescue therapies has modified this paradigm. Cyclosporine use averts early colectomy but most of these patients eventually require colectomy. The use of infliximab also averts early colectomy, but its long-term efficacy remains uncertain. Data suggests that the colectomy rate has reduced in recent years. Whether this is due to the increasing use of early aggressive therapy or whether or is part of the natural evolution of the disease, remains to be determined. PMID- 25735121 TI - Factors precipitating acute ulcerative colitis. AB - Ulcerative colitis is characterized by mucosal inflammation of a variable length of the colon starting from the rectum. The precise etiopathogenesis is unknown but it occurs in genetically susceptible individuals who manifest an abnormal immunological response against gut commensal bacteria. The disease course is characterized by multiple spontaneous relapses and remissions. Two pathogens namely CMV and C. difficile have been associated with disease exacerbation in specific clinical situations. Whereas C. difficile may produce worsening of the disease in those exposed to broad spectrum antibiotics, CMV reactivation is seen only in patients with moderate to severe steroid refractory disease. The importance of these two super-infections can be gauged by the fact that both the ACG and the ECCO recommend testing for these two pathogens in appropriate clinical situations. The applicability of these guidelines in the Indian scenario has yet to be determined in view of the bacterial and parasitic infections endemic in tropical countries. The guidelines for diagnosis and management of these two super-infections in the presence of ulcerative colitis are discussed in this review. PMID- 25735122 TI - Intensive intravenous regime for acute severe colitis. AB - Acute severe exacerbation of ulcerative colitis is a potentially life threatening medical emergency. The management of acute severe ulcerative colitis depends on early recognition and prompt initiation of intensive intravenous treatment along with continuous objective monitoring for possible medical failure. The intensive regime is the accepted standard of care. This includes primarily a) intravenous corticosteroids, b) intravenous supportive management, and d) intravenous antibiotics in instances. This review discusses the timing, duration and dosage of the intensive intravenous treatment including the evidence based protocol for effective monitoring to enable timely escalation to second line therapy & colectomy. PMID- 25735123 TI - Cyclosporine in steroid refractory acute severe colitis. AB - Approximately 15-20% patients with ulcerative colitis (UC) suffer from a severe flare during their lifetime which required hospitalization. Intravenous corticosteroids are the first line of therapy for acute severe UC. While almost 70-80% of patients respond to corticosteroids 20% do not. Although colectomy for UC is curative, it has its problems such as increased frequency of stool and pouchitis, which led to search for colon rescue therapy. Cyclosporine and anti tumor necrosis factor-alpha (anti-TNF a) have emerged as effective colon rescue therapy. While the short-term efficacy of cyclosporine in preventing colectomy is 64-86%, the long-term efficacy is not as good and almost 70% eventually require colectomy over 1-7 years. The efficacy of cyclosporine is equivalent both at a high and low doses and cyclosporine is now used most often as a low dose regime in patients with steroid refractory acute severe UC. Furthermore, recent data suggest that the both cyclosporine and infliximab are equally effective in steroid refractory acute severe UC. Monitoring patients for adverse events and serum cyclosporine levels is mandatory. The response to both cyclosporine and infliximab is rapid and usually occurs within 4-5 days. Despite mounting evidence of its efficacy, cyclosporine remains largely underused because it requires intense monitoring for toxicity especially at higher dosage. Gastroenterologists need to be more familiar with cyclosporine for the management of steroid refractory acute severe UC. PMID- 25735124 TI - Biological therapy in acute severe ulcerative colitis: Indian experience. AB - Biologicals have a well established role as rescue therapy in management of steroid refractory cases of Ulcerative colitis and Crohn's disease. However, high cost and potential risk of infections like tuberculosis limits their use in developing countries. As there is paucity of data on the use of various biological agents from developing countries like India, we are reporting the limited Indian experience with the available agents. Infliximab has been used as a rescue therapy for severe refractory Ulcerative colitis while other agents have been used as a part of multicentre clinical trials. PMID- 25735125 TI - Surgical management of acute ulcerative colitis. PMID- 25735126 TI - Algorithm for managing severe ulcerative colitis. AB - Acute severe ulcerative colitis as defined by Truelove Witt's criteria is a medical emergency which requires hospitalization. Patient requires close clinical monitoring with assessment of daily vital parameters, stool frequency, serum electrolytes and daily abdominal examination Intravenous corticosteroids are the mainstay of therapy. Approximately two thirds of patients will respond to steroids. Response to steroids should be assessed at day 3 of admission and partial/non-responders should be considered for alternative medical therapy/surgery. Medical rescue therapies include intravenous cyclosporin and infliximab. This article provides an time bound step up algorithm for management of acute severe ulcerative colitis. PMID- 25735127 TI - [A clinical study on 106 infant cases who received detailed hearing tests after newborn hearing screening]. AB - Newborn hearing screening (NHS) has been conducted widely in Japan in the last decade, however, there seems to be some confusion regarding the significance of NHS or management of the results obtained from NHS among clinics and practitioners. The system of NHS in Japan should be improved and refined through continuous evaluation of NHS, in terms of cost effectiveness in particular, so that NHS can be conducted more efficiently and effectively. To achieve this goal, the authors thought it important to clarify the current status and roles of our department as a facility for infants with congenital hearing impairment. In the present study, we studied 106 infant cases who were referred to the Department of Otolaryngology in Kyoto University Hospital after NHS before the age of twelve months in a period of seven years from 2006 to 2012 via retrospective chart reviewing. 79.2% of 96 infants who were qualified as referred either unilaterally or bilaterally following NHS were diagnosed as having hearing impairment in any form, either unilateral or bilateral, or conductive and/or sensorineural. The positive agreement rate was 88.7% in 53 cases who were qualified as referred bilaterally in NHS, demonstrating a high reliability of the NHS system. Twenty four cases were diagnosed as having the need for hearing aids and were assigned to treatment and education. All the infants who underwent cochlear implantation in our department had severe bilateral hearing impairment of more than 105 dBnHL in both ears at the first examination. Moreover, a number of infants who were qualified as having passed in both ears in NHS or who had failed to receive NHS at birth were revealed as having hearing impairment and needed treatment later in the first year of their life, suggesting that NHS should be conducted in combination with periodical health checkups by family practitioners in order to identify infants with hearing impairment earlier in their life with higher efficacy. PMID- 25735128 TI - [A case of hypopharyngeal ulceration due to cytomegarovirus infection]. AB - Cytomegalovirus (CMV) is a common opportunistic infection in immunosuppressive patients. One of the organs often involved is the gastrointestinal tract, but the pharynx, especially hypopharyngeal involvement, is rare. In this report, we present a case of a 61-year-old male compromised host, admitted to the hospital for the treatment of dermatomyositis, who presented with hypopharyngeal ulceration due to cytomegalovirus infection. Multiple deep ulcerative lesions with thick belaque, or with a protruding bony edge were observed in the adjacent areas in/around the hypopharynx, which repeatedly demonstrated exacerbation and remission in a relatively short period. The lesions developed acute bleeding and required emergency operative hemostasis. The ulcerations completely disappeared after the treatment with gancyclovir. We reviewed our case as well as other cases reported so far, and extracted the points we should be aware of when we encounter a case of hypopharyngeal ulceration based on cytomegalovirus infection; 1. acute bleeding, 2. paralysis of the vocal cords and subsequent breathing difficulty, 3. pharyngeal perforation. PMID- 25735129 TI - [Operative field limited by in the case of a tonsillectomy due to temporomandibular arthrosis--a case report]. AB - We report herein on a patient with unexpected trismus after the induction of general anesthesia due to temporomandibular arthrosis. A 30 year old man visited our hospital complaining of hematuria, and he was scheduled for bil tonsillectomy under general anesthesia. Preoperative examination revealed no evidence of difficult airway and no sign of trismus. Despite the administration of muscle relaxants, it was impossible to expand the operative field due to by trismus after the introduction of general anesthesia. Malignant hyperthermia was excluded, and the trismus was judged to be due to temporomandibular arthrosis. Manual repositioning was performed, trismus was improved and expansion of the surgical field became possible. During any head and neck surgical procedure, if an otolaryngologist should encounter trismus after the induction of general anesthesia, temporomandibular arthrosis should be borne in mind if temporomandibular arthrosis is diagnosed as the cause, manual repositioning should be employed as soon as possible. PMID- 25735130 TI - [A case of hereditary angioedema defined by gene analysis]. AB - Hereditary angioedema (HAE) is a disease that is characterized by localized edema that can occur anywhere in the body, and is caused by a mutation of the C1 inhibitor gene. In the oto-rhino-laryngological region, it occurs in the mouth, pharynx, larynx, and on the face. Occasionally, laryngopharyngeal edema can in particular sometimes be fatal. We report herein on a case of a 59-year-old female who was admitted to our hospital for further evaluation and treatment of laryngopharyngeal edema. She had a history of subcutaneous edema during pregnancy and ascites of unknown origin without a definitive diagnosis. On admission, there were low C1 inhibitor and complement C4 levels, and normal C1q levels. As the patient had no family history of HAE, we performed gene analysis, which revealed mutation of the C 1-inhibitor gene in Exon7. In cases of HAE without family history, gene analysis is required for accurate diagnosis. PMID- 25735131 TI - [New evidence of an old problem: the coupling of genome replication to cell growth in bacteria]. AB - The problem of coordinating genome replication with cell growth in bacteria was posed over four decades ago. Unlike for eukaryotes, this problem has not been completely solved even for Escherichia coli, which has been comprehensively studied by molecular biologists, to say nothing of other bacteria. Current models of the bacterial life cycle solve the coupling problem by introducing a phenomenological hypothesis that considers the dynamic coordination of growth and replication but does not unveil the underlying molecular mechanisms. Here we review the mechanisms regulating genome replication initiation with regards to their coupling to growth processes in the three best investigated bacterial species: E. coli, Bacillus subtilis, and Caulobacter crescentus. A putative correlation between the type of cell growth laws and the actual mechanisms regulating the replication of DNA formed during the process of evolution in various classes of bacteria, is discussed, including those intracellular parasites in which degenerative evolution his discarded most of their genomes. We contemplate the concept of a universal growth law for bacterial cells and some features in the formation of a primitive negative replication regulating mechanism in the context of the coupling problem. PMID- 25735132 TI - [Comparative chromosomal analysis of populations of phytophilous chironomidae Glyptotendipes glaucus (Mg.) from Chernobyl-affected territory]. AB - The karyopools of the phytophilous chiromomid species of Glyptotendipes glaucus (Mg.) were studied. Chironomids originated from a number of reservoirs located in the Novozybkovsky rayon of the Bryansk region, which was affected by the Chernobyl radioactive release, and two reservoirs located in the Saratov region. Differences in the inversion spectrum and frequencies, both among Bryansk and between Bryansk and Saratov populations, were found. There were no new inversions in the Novozybkovsky populations; however, structurally small rearrangements in long chromosomes were noted. Typical abnormalities included mosaicism of the chromosome morphotypes in cells of the same saline gland, which was especially distinctive in the larvae from the forbidden zone; decondensation of the telomere regions of chromosomes; and mosaic asynapsis of the chromosome IV homologs (up to complete disjunction). Also, several larvae were polyploids. Other species of Glyptotendipes inhabiting the Novozybkovsky reservoirs were represented by the single species of G. paripes (near the Korchy settlement). The karyotypes of its several larvae were represented by an unorganized chromosomal substance. The other Glyptotendipes species seem to have lower adaptive abilities under the conditions in question and were eliminated from precatastrophe biotopes, while G. glaucus succeeded in adaptating to the new environment. PMID- 25735133 TI - [Antirestriction activity of the mercury resistance nonconjugative transposon Tn5053 is controlled by the protease ClpXP]. AB - When transformed into Escherichia coli K12 strains, the mercury resistance transposon Tn5053@ exhibits high antirestriction activity against the EcoKI type I restriction and modification system. The products of the genes merR and ardD contribute to the antirestriction activity of Tn5053. The merR gene encodes the MerR protein, the transcription regulator of the mer operon genes. The ardD gene is responsible for ArdD protein synthesis and is located within the tni operon. In the following study, it was demonstrated that the antirestriction activity of the transposon Tn5053 is absent in E. coli K12 strains with the mutant genes clpX, clpP, and recA. The antirestriction effect of Tn5053 is not enhanced by 2 aminopurine. The Tn5053 antirestriction activity is not altered in E. coli K12 with the mutant dam gene; however, it is decreased in the E. coli K12 mutD. It is assumed that the activities of the MerR and ArdD proteins lead to the formation of a significant amount of unmodified DNA in the bacterial cell, causing the SOS dependent reduction of the EcoKI (R2M2S) enzyme activity associated with ClpXP induced proteolysis of the R-subuinit. PMID- 25735134 TI - [Molecular genetic diversity of the pea (Pisum sativum L.) from the collection of N.I. Vavilov Research Institute of Plant Industry as detected by AFLP analysis]. AB - In this work, a pea selection obtained from the Vavilov Research Institute collection comprising 83 P. sativum samples, including representatives of three subspecies, was studied using the ?FL? labeling method. Local cultivars for different uses with maximum ecological and geographical diversity (including those from the centers of origin of the species) were predominantly chosen for the study; a number of their morphological and biological characteristics were evaluated. We obtained 382 polymorphic AFLP fragments; each sample was characterized by a unique set of these fragments. The genetic diversity of the studied material was evaluated, and a wide range of genetic differences in the investigated samples (0.07-0.27) was demonstrated. The affiliation of the samples to the certain subspecies was not confirmed by the obtained data; the ecogeographical differentiation of the samples was not reflected by the data. Factor analysis allowed us to identify the sample groups of European and Asian origin and the intermediate nature of most of the samples from the studied selection. PMID- 25735135 TI - [Genetic and phenotypic differentiation of Calluna vulgaris (L.) Hull in Pritobolie and Europe]. AB - Geographic variation and differentiation of the chloroplast DNA haplotypes and morpho-anatomical leaf parameters were assessed in a number of eastern European groups of Calluna vulgaris (L.)Hull populations and in the Pritobolien group of populations of this species in Western Siberia, which have long been isolated from the European populations. Sharply pronounced genetic and phenotypic distances and their gradients between the Pritobolien and European population groups were revealed. These distances were many times higher than those between the relatively homogeneous eastern European groups. The data obtained generally supported the hypothesis on the phenogenetic divergence of the Pritobolien marginal populations of C. vulgaris from the European, probably at the subspecies level. PMID- 25735136 TI - [Analysis of genetic structure and differentiation of the bog and dry land populations of Pinus sibirica du tour based on nuclear microsatellite loci]. AB - We evaluated the population structure of the bog and dry land populations of the Siberian pine Pinus sibirica (P. sibrica) in Western Siberia using nuclear genome markers. Six pairs of nuclear microsatellite loci were used for this analysis. We detected 30 allelic variants in 120 individuals of four populations of P. Sibirica. We established that the studied populations differ by genetic structure. The most essential differences were identified between the Siberian pine population from oligotrophic bog and the group of populations from dry land within eutrophic bogs and near settlements P. sibirica forest (F(ST) = 0.019; D(N) = 0.053). We estimated that diversification of the West Siberian populations of P. sibirica exceeded 2.4% (F(ST) = 0.024), based on an analysis of SSR markers. PMID- 25735137 TI - [Genetic diversity of populations of a rare species of Dictamnus gymnostylis Stev. in Bashkir Cis-Urals]. AB - We examined genetic diversity in populations of Dictamnus gymnostylis Stev., a rare species growing in the Bashkir Cis-Urals, based on the analysis of 8 gene enzyme systems and detected a fairly high level of intraspecific genetic diversity and population differentiation. We determined the average number of alleles per locus. (A) as 1.57; the portion of polymorphic loci (P95) as 0.508; the observed heterozygosity (H(o)) as 0.139; and the expected heterozygosity (H(e)) as 0.169. Of the total genetic diversity, 88.3% stems from variability within populations, and 11:7% is due to variation among populations. The average value for the Nei's genetic distance (D) constituted 0.028. PMID- 25735138 TI - [Variability and relationships of the Far Eastern species of sculpins Myoxocephalus and Megalocottus (Cottidae) based on mtDNA markers and karyological data]. AB - The phylogenetic relationships among five species of sculpins, including Myoxocephalus stelleri, M. brantii, M. jaok, M. ochotensis, and Megalocottus platycephalus, were estimated from the sequence variability of the mtDNA cytochrome b (cytb) and cytochrome oxidase 1 (CO1) genes. Analysis of the topologies of combined phylogenetic trees showed that all of the morphologically described species from different genera represented monophyletic groups with high support of branch robustness. Haplotypes with different karyotypes from different geographical localities with an intragroup nucleotide diversity of 43% were combined into the M. stelleri clade. All of the species (except for M. stelleri from the Sea of Japan and the Okhotsk Sea coast of the Hokkaido Island) were characterized by relatively low values of the intragroup variation, along with high values of interspecific variation of mtDNA-encoded markers. Studies of the M. stelleri karyotypes using Ag-banding showed that karyotypes of the individuals from the Sea of Japan and Okhotsk differed not only in the number of chromosomes (2n) but also in the number of active nucleolus organizers (NO) and stained NO blocks, calling into question whether they belong to a single species. The observed discrepancy between the phylogenetic topologies and karyological data is discussed in relation to the informative capacity of mtDNA fragments and the phenomenon of intraspecific chromosomal polymorphism. PMID- 25735139 TI - A note on the presence of B chromosome in the small Japanese field mouse, Apodemus argenteus, in Central Honshu, Japan. AB - Previously, many studies have revealed the presence of B chromosomes in wild mouse taxa of the genus Apodemus (Rodentia, Muridae). In one of the Apodemus species, A. argenteus, which is endemic to Japan, it is known that B chromosomes were confirmed only in individuals (2n = 46 + B chromosome) from Hokkaido, Japan. There is no report of the presence of B chromosomes from other localities in the Japanese Islands. In this study, we analyzed the chromosomal constitutions of 43 individuals of A. argenteus from three localities in Honshu, Japan. A total of three individuals from central Honshu showed 2n = 47, and each individual carrieda dot-like B chromosome. In addition, these B chromosome features were analyzed by differential staining methods, and the C- and QM-banding patterns of the B chromosomes were identical to those of the X chromosomal heterochromatic region showing the delayed-fluorescent response. Thus, it is considered that these B chromosomes would be derived from the heterochromatin of the X chromosomes, as reported in previously published papers. PMID- 25735140 TI - [Polymorphism of the myogens locus in some representatives of sturgeons (Acipenseridae)]. AB - This study investigates muscle proteins in Russian (Acipenser gueldensiaedtii Brandt), Siberian (Acipenser baerii Brandt), and Amur (Acipenser shrencki Brandt) sturgeons using the method of polyacrylamide gel electrophoresis. A group of fractions, which is presumably the product of a polyallelic duplicated MY-1* locus, is recorded among the general pool of proteins. Data from densitometric analysis makes it possible to put forward a hypothesis about an eight-gene determination of this system of proteins. The highest heterogeneity and polymorphism was revealed in the Russian sturgeon. Analysis of the genotype distribution in samples of the studied species allowed us to make an assumption that the genetic structure of spawning sturgeon stocks is significantlymetamorphosed under the influence of anthropogenic and natural factors. PMID- 25735141 TI - [Polymorphism of 5-HTTLPR and Stin2 loci of the serotonin transporter gene in males of African ethnic populations Hadza and Datoga]. AB - A molecular-genetic study of 5-HTTLPR and the Stin2 loci of the serotonin transporter gene (5-HTTL) in males of the African ethnic populations Hadza and Datoga, which differ in the level of culturally acceptable aggression, was carried out. The distribution of allele and genotype frequencies of these two loci was established. It was shown that the frequency distribution of genotypes and alleles among Hadza and Datoga in the examined samples is practically identical by the VNTR-polymorphism of both loci. However, the Hadza populations, as compared to Datoga, showed a significant (p = 0.006) increase in the frequency of the transcriptionally less active allele L(G) of the 5-HTTLPR locus. For the first time, the structure of the allelic variant of locus Stin2 with eight repetitions (Stin2.8) is described and established for African populations. The test for independence of the frequency distribution of the alleles of the studied loci showed highly significant linkage disequilibrium among Hadza (p << 0.001) and Datoga (p = 0.021). In analysis of the genotype combinations of two loci, it was revealed that thestudied populations differed significantly by the L(A)L(G) 10/12 genotype (p << 0.001). When combining the genotypes, no significant differences between the populations based on their expression activity were identified. We assume that the identified combined genotypes reflect the effects of similar behavioral traits for both populations. PMID- 25735142 TI - [Features of the Udmurt mitochondrial gene pool in relation to tribal structure]. AB - We present novel data on mitochondrial DNA polymorphism in the Udmurt population, which represents a Finno-Ugric ethnos residing in the Volga-Ural region. Our analysis of the Udmurt mtDNA polymorphisms have shown that neighboring ethnoses had almost no effecton formation of the Udmurtian intraethnic diversity. These results strongly indicate that genetic differences in the Udmurtian population are determined by their tribal structure rather than their geographic location. PMID- 25735143 TI - [Combinations of cytokine gene network polymorphic markers as potential predictors of myocardial infarction]. AB - With the intent to identify informative predictors of myocardial infarction (MI) development in an ethnically homogenous group of Russian men after MI (255 subjects) and in a corresponding control group (257 subjects), an analysis of genotype frequency distribution for polymorphic DNA markers (SNP) rs16944 ( 511C>T, IL1B gene), rs1800796 (-572G>C, IL6 gene), rs1800872 (-592C>A, IL10 gene), rs3212227 (1159AA, TNF), rs909253 (252A>C, LTA), rs767455 (36A>G, TNFRSF1A) was conducted. Using the Monte Carlo method and a Markov chain (APSampler), allele combinations associated both with decreased and increased MI risk were revealed. The most significant results were obtained for IL6*C/C (P = 3 x 10(-4), OR = 6.3 CI 2.37-16.75 10(-4)), LTA*A+IL6*G/G (FDR = 2.3, OR = 0.25 CI 0.14-0.46), LTA*G/G + IL12B*A/A (FDR = 0.0053, OR = 4.92 CI 1.8-13.33), TNF*G + LTA*G/G + TNFRSF1A*A (FDR = 0.013, OR = 4.38, CI 1.6-12.01), TNFRSF1A*G + IL10*A/A + IL12B*C (FDR = 0.016, OR = 8.79, CI 2.17-35.63), TNF*G + LTA*G?G + IL10*C (FDR = 0.0105, OR = 3.54 CI 1.55-8.09). PMID- 25735144 TI - [Characteristics of migration in the population of Yevpatoria (Crimea)]. AB - Indicators characterizing population migration were calculated according to the marriage records of Yevpatoria (Crimea) of 1960/1961, 1985, and 1994/1995. The marital migration coefficient m in those years was 0.80, 0.75, and 0.66, the endogamy index was 0.04, 0.08, and 0.15, and the rate of marriage contingency by birthplace was 0.15, 0.16, and 0.19, respectively. The highest values of the positive mating assortative index were recorded for people from the Caucasus, Central, Central Black Earth Oblast, and Northwest regions of Russia in 1960/1961 and for migrants from Moldavia, the republics of Central Asia and Caucasus, Western Siberia, and Ukraine in 1985. In 1994/1995, natives of Yevpatoria were also included in this group. The average distance of migration by year was 909, 1280, and 1314 km, and the marital distance was 960, 1397, and 1171 km. The "radius" of the Yevpatoria population, in accordance with the Maleco model in the years under study, was 98, 134, and 137 km. The distance isolation indicator b was decreasing and amounted to 0.00049, 0.00043, and 0.00038. Inthe migration flow in all of the periods, the majority of immigrants came from different regions of Ukraine outside Crimea (27-31%), followed by natives of various places in Crimea (21-24%.), Central (3.6-8.5%), and Central Black Earth (1.8-6.1%) regions of Russia, and the South Caucasus (4.0-5.7%). The proportion of Russians and Jews decreased in the migration flow, while the proportion of Ukrainians and representatives of non-Slavic nationalities increased. PMID- 25735145 TI - [Expression of acylamidase gene in Rhodococcus erythropolis strains]. AB - The expression of a new acylamidase gene from R. erythropolis 37 was studied in Rhodococcus erythropolis strains. This acylamidase, as a result of its unique substrate specificity, can hydrolyse N-substituted amides (4'-nitroacetanilide, N isopropylacrylamide, N'N-dimethylaminopropylacrylamide). A new expression system based on the use of the promoter region of nitrilhydratase genes from R. rhodochrous M8 was created to achieve constitutive synthesis of acylamidase in R. erythropolis cells. A fourfold improvement in the acylamidase activity of recombinant R. erythropolis cells as compared with the parent wild-type strain was obtained through the use of the new expression system. PMID- 25735146 TI - [The role of genetic control and self-assembly in gametophyte sporoderm ontogeny: hypotheses and experiment]. AB - A review of our own and literature data on mechanisms of sporoderm development (of the wall of pollen grains and spores) is represented here in the light of colloidal relationships-so-called micellar hypothesis (Gabarayeva and Hemsley, 2006; Hemsley and Gabarayeva, 2007) which suggests the participation of self assembly in development. The development of the exines (ofsporopollenin containing part of the sporo- derm) in 5 species from remote taxa has been traced in detail and interpreted as a micellar sequence. The experimental modelling of exine-like structures, carried out in vitro where physico-chemical regularities of colloidal systems (hydrophobic relationships) were the driving motive, is a strong evidence of the relevance of the micellar hypothesis and emphasizes a promising character of these studies. The correlation between ge- nomic control and self-assembly in arrangement of complex biological walls is discussed. PMID- 25735147 TI - [Neurulation continues: the parade commander is...apical constriction]. AB - Neurulation is traditionally defined as the process of closure of the neural tube. New data have shown that the major driving forces ofneurulation continue to operate with the closure of the neural tube, at least until the central canal of the neural tube has formed. Owing to this, the paper proposes to distinguish two periods of neurulation. According to these notions, early neurulation corresponds to the period of closure of the neural tube, and late neurulation corresponds to the period of formation of the central canal. Examples of neural tube defects that affect late neurulation are discussed. PMID- 25735148 TI - [Sponge cell reaggregation: mechanisms and dynamics of the process]. AB - Sponges (Porifera) are lower metazoans whose organization is characterized by a high plasticity of anatomical and cellular structures. One of the manifestations of this plasticity is the ability of sponge cells to reaggregate after dissociation of tissues. This review brings together the available data on the reaggregation of sponge cells that have been obtained to date since the beginning of the 20th century. It considers the behavior of dissociated cells in suspension, the mechanisms and factors involved in reaggregation, and the rate and stages of this process in different representatives of this phylum. In addition, this review provides information about the histological structure of multicellular aggregates formed during reaggregation of cells and the regenerative morphogenetic processes leading to the formation of normal sponges from these multicellular aggregates. PMID- 25735149 TI - [Low expression of activin A in mouse and human embryonic teratocarcinoma cells]. AB - TGFP3 family factors play an important role in regulating the balance of self renewal and differentiation of mouse and human pluripotent stem and embryonic teratocarcinoma cells. The expression patterns of TGFbeta family signaling ligands and functional roles of these signaling pathways differ significantly in mouse and human embryonic stem cells, but the activity and functional role of these factors in mouse and human embryonic teratocarcinoma cells were not sufficiently investigated. Comparative quantitative real-time PCR analysis of the expression of TGF@[beta] family factors in mouse embryonic stem, embryonic germ, and embryonic teratocarcinoma cells showed that embryonic teratocarcinoma cells express lower ActivinA than pluripotent stem cells but similar levels of factors Nodal, Lefty 1, TGFbeta1, BMP4, and GDF3. In human nullipotent embryonic teratocarcinoma PA-1 cells, most factors of the TGFbeta family (ACTIVINA, NODAL, LEFTY 1, BMP4, and GDF3) are expressed at lower levels than in human embryonic stem cells: Thus, in mouse and human nullipotent teratocarcinoma cells, theexpression of ActivinA is significantly reduced com- pared ivith embryonic stem cells. Presumably, these differences may be associated with changes in the functional activity of the respective signaling pathways and deregulation of proliferative and antiproliferative mechanisms in embryonic teratocarcinoma cells. PMID- 25735150 TI - [Ontogenetic diversity of colonies and intercellular cytoplasmic bridges in the algae of the genuis Volvox]. AB - In all representatives of the genus Volvox, cells of cleaving embryos are connected by cytoplasmic bridges, which play an important role in the process of young colony inversion. However, during subsequent development, the intercellular bridges are retained not in all species of Volvox; the occurrence of the bridges in an adult colony correlates withthe small size of mature gonidia (asexual reproductive cells) and with the presence of cell growth in the intervals between divisions. This complex of ontogenetic features is derived and arises independently in three evolutionary lineages of colonial volvocine algae. A putative role of the syncytial state of adult colonies for the evolution of developmental cycles in Volvox is discussed. PMID- 25735151 TI - [Diversity of the mitochondrial DNA cytochrome B gene of the field mouse Apodemus Agrarius Pallas, 1771 in the south of the Russian far east]. AB - We studied the variability of a fragment of the cytochrome b gene and the corresponding amino acid sequence of the field mouse Apodemus agrarius (Pallas, 1771) in the South of Primorskii krai (Far East of Russia). A significant polymorphism of these traits was detected. High indices of molecular diversity were obtained. The topology of the phylogenetic tree and the median networks suggest that the population of field mice in the south of Primorskii krai originated from three maternal lines. It was noted that clustering of haplotypes on a territorial basis is absent, and the field mouse population in southern Primorskii krai can be considered as one of the key points in maintaining a high genetic diversity of the species. PMID- 25735152 TI - [Phenotypic and phytochemical differences between Mentha arvensis L. and Mentha canadiensis L]. AB - A taxonomic study of anatomical, morphological, and phytochemical characteristics of Mentha arvensis L. and Mentha canadiensis L. using hierarchical cluster analysis has been conducted and the differences between the species studied have been revealed. The ratio between the lengths of the calyx tube and the calyx lobes, the number of secretory glands on the upper and lower surfaces of the leaf, and the composition of the essen- tial oil were shown to be the most appropriate parameters for classification. PMID- 25735153 TI - [Characteristics of extracellular invertase of Saccharomyces cerevisiae in Heterologous expression of the suc2 gene in Solarium Tuberosum plants]. AB - Some properties and activity of extracellular invertase in the Saccharomyces cerevisiae yeasts encoded by the suc2 gene in heterologous expression were described. It was shown that the target suc2 gene is actively expressed in the genome of the transformed potato plants and S. cerevisiae invertase synthesized by this gene is transported into the apoplast due to the signal peptide of the proteinase II inhibitor. This enzyme is present in the apoplast in a soluble form and absorbed into the cell wall. PMID- 25735154 TI - [New data on the phylogeography and genetic diversity of the brown bear Ursus arctos Linnaeus, 1758 of northeastern Eurasia (mtDNA control region polymorphism analysis)]. AB - An analysis of polymorphism of the fragment of the control region of mitochondrial DNA of 53 tissue samples of the brown bear Ursus arctos from several regions of the eastern part of Russia was carried out. It was found that most of the described haplotypes belong to cluster 3a, the most common in Eurasia, and do not form regionally specific haplogroups. However, among the bears from Western and Eastern Siberia, as well as the island of Kunashir, three haplotypes were identified, which are close to the haplogroup typical of Eastern Hokkaido bears. The assumption was made of the existence in Siberia and the Far East of one or more Pleistocene refugia. PMID- 25735155 TI - [Size structure of the sable in the Lake Baikal Region: a decadal analysis over the last sixty years]. AB - The skull sizes of eight Lake Baikal sable populations (n = 1859) were studied. It was noted that six of them constitute a homogeneous group of the small forms of the species. The decadal dynamics of 17 craniometric characters was analyzed. An increase in the skull size in the second half of the 20th century, common for both males and females, was revealed. The average growth trend over a decade was determined for the condylobasal skull length;-it amounted to 0.15 mm in males and 0.11 mm in females. It was established that decadal deviations in sizes are, in most cases, not significant statistically; they are of an oppositely directed nature and do not disturb the species stability. PMID- 25735156 TI - [Intracellular transmission of the cholinergic signal in the chick amnion]. AB - The role of the system of deposited calcium in the mediation of contractile reactions to carbachol in an isolated amnion of 11-13 day old chicken embryo was studied. It was found that thapsigargin (2 microM, 20 min), an inhibitor of the endoplasmic reticulum Ca2+ -ATPases, decreases the tonic reaction to carbachol by 40 +/- 2%. In the presence of U73122 (5-10 microM, 10 min), a phosphoinositide specific phospholipase C inhibitor, the rhythmic contractile reaction of the amnion to carbachol is blocked, whereas the tonic reactiondecreases to 47 +/- 9% of the initial one. Ryanodine (10 rM, 5 min) inhibits the spontaneous contractile activity of the amnion and decreases the tonic reaction to carbachol to 36 +/- 3% relative to control. In the presense of ryano- dine, nifedipine (0.05 microM) completely blocks the tonic reaction to carbachol. Thus, calcium mobilized from intracellular stores via inositol trisphosphate and ryanodine receptors is involved in realization of contractile reactions, mediated by M3 receptors, in the chick amnion. PMID- 25735157 TI - [Ecology of nutrition and differentiation of the trophic niches of bats (Chiroptera: Vespertilionidae) in floodplain ecosystems of the Samara Bend]. AB - A complex analysis of the food range of 15 bat species inhabiting floodplain ecosystems of the Samara Bend has been performed. It is shown that, in bats, an important component of the structuring of their communities is the division of food resources. The guild structure and position of species in the trophic space are described. Seven food guilds consisting of nonspecialized and specialized species are distinguished. It is noted that most species are characterized by a wide overlapping of their trophic niches, which may be a consequence of their weak competition in an environment that is rich in food resources. PMID- 25735158 TI - [Energy and mass transfer and the productivity of the main ecosystems of Siberia (according to the results of measurements by the method of turbulent pulsations). 2. Carbon exchange and productivity]. AB - Using direct measurements of CO2 fluxes by the method of turbulent pulsations, it was shown that the studied middle-taiga pine forest, raised bog, true steppe, and southern tundra along the Yenisei meridian (approximately 90 degrees E) are stocks of carbon of different capacity in the annual output. The tundra starts to function as a stock of carbon from June; the forest and bog, from May; and the steppe, from the end of April. In the transitional seasons and winter, the ecosystems are a weak source of carbon: the tundra already in September; the forest and bog, from October; and the steppe, from November. The photosynthetic productivity of the forest and steppe ecosys- tems (480-530 g C/(m x year) exceeds 2-2.5 times the productivity ofbogs and tundras (200-220 g C/(m x year). The relationships between the thermal balance structure and CO2 exchange are shown. Possible feedbacks between the carbon exchange between the ecosystems and the atmosphere as a result of climate warming in the region are assessed. PMID- 25735159 TI - [The intensity of phytodetrite decomposition in Larch Forest of the permafrost zone in central Siberia]. AB - Based on the results of long-term investigations, quantitative assessment ofphytodetrite mineralization rates is provided. Their role in the biological cycle of larch stands growing in the permafrost zone of Central Evenkia is discussed. It is demonstrated that their destruction in the subshrub-sphagnum and cowberry-green moss larch stands is extremely slow, the plant litter contains the most cecalcitrant organic matter demonstrating the lowest decomposition coefficient of 0.03-0.04 year(-1), whereas fresh components of the plant litter have 3- to 4-fold higher values. An insignificant input of N and C from the analyzed mortmass to the soil has been registered. It has been revealed that the changes in N and C in the decomposition components are closely related to the quantitative dynamics (biomass) of microorganisms, such as hydrolytics and, especially, micromicetes. PMID- 25735160 TI - [Body mass and excretion of phosphorus in aqueous invertebrates]. AB - Empirical materials on the dependence of the intensity of mineral phosphorus excretion (Ex) on the body mass (W) in invertebrates are summarized. The parameters of the average dependence of Ex on Win animals at 20 degrees C are determined. The main factors that influence the parameters ofthis dependence are discussed. It is shown that the decrease of Ex with an increase of Win animals is, as a rule, more significant compared with the decrease in the intensity of metabolism. PMID- 25735161 TI - [Morphobiochemical adaptations of Mediterranean Littorina punctata (Gmelin, 1790) (Mollusca, Gastropoda) to survival under supralittoral conditions]. AB - Behavioral and morphobiochemical adaptations of Littorina punctata to dwelling under supralittoral condi- tions are analyzed. A quantitative estimation of the hemoglobin content in the radular tissues of the mollusk is given. PMID- 25735162 TI - [Intracellular localization of transcription factor PROX1 in the human retina in ontogeny]. AB - The spatiotemporal intracellular localization of the transcription factor PROX1 in the human retina during prenatal development (fetal weeks 9.5 to 31) and in the adult human retina was studied for the first time. The PROX1 protein was identified in the cell nuclei of the neuroblast retinal layers at the stage of active cell proliferation (fetal week 9.5) as well as in the nuclei of differentiating neurons of the inner nuclear retinal layer (horizontal, amacrine, and bipolar cells) from weeks 13 to 31 of prenatal development. The PROX1 protein localization in the adult retina was the same as at the late stage of prenatal development. Our results indicate the involvement of the transcription factor PROX1 in the regulation of proliferation of progenitor cells and differentiation of the inner nuclear layer cells of the human retina. These results confirm the conservative functions of Prox1/PROX1 in the vertebrate retina. PMID- 25735163 TI - [Comparative cytogenetic study of the tetraploid Matricaria chamomilla L. and Matricaria inodora L]. AB - A comparative cytogenetic study of the autotetraploid breed of Matricaria chamomilla L. (M. recutita L.) and Matricaria inodora L. was carried out by DAPI banding, fluorescent hybridization in situ (FISH) with 26S and 5S rDNA probes, and analysis of meiosis. All chromosomes were identified in both karyotypeson the basis of DAPI-banding images and 26S and 5S rDNA distribution, and species specific idiograms were composed for both M. chamomilla and M. indora taking into account the polymorphous variants of DAPI-banding images, showing the location of the 26S and 5S rDNA sites. PMID- 25735164 TI - [Protective action of glutamate antibodies on increased expression of genes of programmed death of rat brain cells induced by injection of a beta-amyloid fragment (25-35)]. AB - Glutamate antibodies intranasally administered to Wistar rats at a dose of 300 MUg/kg reduced the elevated levels of expression of Aifml, Casp3, and Parp 1 genes in the prefrontal cortex and Aifml and Casp3 genes in the hippocampus on the third day after administration of the beta-amyloid fragment Abeta25-35 into the Meynert nuclei of the brain. Changes in Aifm1, Bax, Casp3, and Parp 1 gene expression were not found in the hypothalamus, and changes in Bax gene expression were not found in the brain structures studied. The discovered features of gene expression in the prefrontal cortex and hippocampus are considered in terms of development of various cell-death programs, which are modulated by glutamate antibodies. PMID- 25735165 TI - [Morphophysiological and biochemical characteristics of potato plants with various expression rates of the Delta12 acyl-lipid desaturase gene]. AB - This paper reports on morphophysiological and biochemical characteristics of control and potato plants (Solarium tuberosum L., Skoroplodnyi cultivar) transformed with the Delta12 acyl-lipid desaturase gene (desA) grown long-term in vitro. The transformed plants showed faster growth and faster ontogenesis as compared to controls, which was accompanied with changes in the accumulation of photosynthetic pigments (chlorophylls a and b, carotenoids) and phenolic compounds, including flavonoids in the leaves. These characteristics were pronounced to a high degree in Line II plants with high expression rates of the desA gene, whereas Line I plants (moderate expression rate) were similar to control plants in many parameters. PMID- 25735166 TI - [A novel, unusual (at least for beetles) mode of Kenyon cell production in the diving beetle Cybister laterlimarginalis Deg. (Coleoptera: Dytiscidae)]. AB - Kenyon cell production in the mushroom bodies of Cybister lateralimarginalis is a peculiar process. It has been found that each proliferative center contains one giant neuroblast, which divides unequally, and its smaller daughter cell becomes the 2nd order neuroblast dividing unequally as well. The smaller daughter cell of this neuroblast becomes a ganglion mother cell. The latter, as usual, divides equally producing two Kenyon cells. PMID- 25735167 TI - [Specific manifestations of polyvariant life cycles in ground beetles (Coleoptera, Carabidae) along latitudinal gradient]. AB - The life cycles of Carabidae are highly diverse, and 25 variants of these cycles are realized In the European part of Russia, from semideserts to continental tundras. The diversity of the life cycle spectrum sharply decreases (by more than half) upon transition from nemoral to boreal forest communities, and its phenological unification takes place at high latitudes. The greatest proportion of species with polyvariant development (25%) is characteristic of temporal latitudes, which may be explained by relatively long growing season and considerable cenotic diversity. In both southern (semidesert and steppe) and northern regions (middle and northern boreal forests), this proportion does not exceed 5%. At low latitudes, the polyvariant pattern of development is often manifested in the form of facultative bivoltine life cycles or as facultative biennial life cycles in species with the initial "spring" breeding type. PMID- 25735168 TI - [The effects of geomagnetic storms on proteinase and glycosidase activities in fish intestinal mucosa]. AB - It has been demonstrated that the glycosidase activity of cyprinoid fishes (carp and crucian carp) exposed to a geomagnetic storm for up to 20 h considerably decreases; however, the proteinase activity is weakly altered (a statistically significant decrease in the enzyme activity has been observed only in fasting fish). An in vitro study of the effects of individual half hour intervals of the geomagnetic storm that correspond to the main and recovery phases on the same enzyme activities demonstrates the opposite trend. Independently of the experimental conditions, geomagnetic storms have been shown to influence the enzyme system of fasting fish negatively. PMID- 25735169 TI - [Effect of space flight factors simulated in ground-based experiments on the behavior, discriminant learning, and exchange of monoamines in different brain structures of rats]. AB - Experimental treatment (long-term fractionated gamma-irradiation, antiorthostatic hypodynamia, and the combination of these factors) simulating the effect of space flight in ground-based experiments rapidly restored the motor and orienting investigative activity of animals (rats) in "open-field" tests. The study of the dynamics of discriminant learning of rats of experimental groups did not show significant differences from the control animals. It was found that the minor effect of these factors on the cognitive performance of animals correlated with slight changes in the concentration ofmonoamines in the brain structures responsible for the cognitive, emotional, and motivational functions. PMID- 25735170 TI - [Decline of Gammarus lacustris Sars (Crustacea: Amphipoda) population in the delta of the Selenga River]. AB - We determined the amphipod population characteristics from the water bodies of the delta of the Selenga River, where Gammarus lacustris Sars, 1863 was industrially harvested until the 1990s. In 2011, the population density of G. lacustris varied from 80 to 10 200 in Lapkhai Lake and from 80 to 2320 ind./m2 in Krivaya Channel. The low population density (< 40 ind./m2) in Gryaznoe Lake, together with the absence of the species in the waters of the former Zhilishchenskoe Lake, confirms the indications of population density decline in the associated waters of the delta. Population growth of G. lacustris was limited primarily by changes in the hydromorphology of the lakes and waterways due to floods of the early 1990s and the subsequent period of extremely low flow of the Selenga River. PMID- 25735171 TI - [Temperature conditions of the formation of frost damages in conifer trees in the high latitudes of Western Siberia]. AB - Frost damage to the bottom of the stem at a height of 0.2 m and at the height of the position of the thermometer in the weather station (2 m) and higher in the Siberian spruce (Picea obovata Ledeb.) and Siberian larch (Larix sibirica Ledeb.) growing at the northern limits of their natural habitat were studied in order to reveal the upper threshold temperature conditions of their formation. Possible causes of differences in the distribution of frost damage in the stem of the spruce and larch are discussed. PMID- 25735172 TI - [Evaluation of seasonal dynamics of crop yield in agrocenoses on the basis of satellite data and mathematical model]. AB - An integrated approach based on satellite remote sensing data and the results of mathematical model analysis was tested for applicability in evaluating the crop yield and total of phytomass of agrocenosis and identifying its type. The dynamics of the normalized difference vegetation index (NDVI) and the total aboveground phytomass of agrocenosis proved to be qualitatively similar. An analysis performed using the mathematical model and taking into account air temperature showed the possibility of making and refining prognosis of crop yield. In this course, the vegetative and generative parts of the agrocenosis were distinguished, and it was found that the model data matched the ground survey data under optimal environmental conditions. PMID- 25735173 TI - [Study of mycobiota in the reclaimed Nazarovo coal mine (Krasnoyarsk Krai)]. AB - This paper presents the results of study of species diversity and certain aspects of macromycete ecology in reclaimed areas of Nazarovo coal mine. A relatively low number of species and ecological groups of fungi on the reclaimed areas were revealed. PMID- 25735174 TI - [FGF2 signaling pathway components in tissues of the posterior eye sector in the adult newt Pleurodeles waltl]. AB - The FGF2 signaling pathway components in tissues of the posterior wall in the normal and regenerating eye of the adult Pleurodeles waltl newt were detected for the first time. The fgf2 gene expression was found in the retina, retinal pigment epithelium, and choroid using polymerase chain reaction (PCR). A high homology of the mRNA nucleotide sequence of the most conservative fgf2 gene region in the P. waltl with the fgf2 orthologs in other vertebrates was proved. The Fgf2 protein aminoacid sequence of the P. waltl newt demonstrates even more homology with this growth factor in other vertebrates. The Fgf2 protein with a molecular weight 35 kDa was found in the studied eye tissues using Western blot hybridization. Localization of the Fgf2 protein and its Fgfr receptors was immunohistochemically studied in the pigment epithelium, choroid, central and growth retina regions of the newt native eye, and in the connective cilium of photoreceptors. Using real time PCR and immunohistochemistry methods, it was found that the fgf2 gene down regulation and a decrease in the intensity of the immunochemical reaction of its protein product (Fgf2) occur in the early period after the retina removal (in 4-8 days) (as compared with those in the same department of the unoperated eye). PMID- 25735175 TI - [Genetic structure of the Siberian Sucker (Catostomus catostomus rostratus) according to data on sequence variation of the mtDNA cytochrome B gene]. AB - Data regarding the structure and variation of the nucleotide sequence of the cytochrome b gene of mitochondrial DNA of the Siberian Sucker from the Kolyma River were obtained. Analysis of the median network revealed that evolutionary lines diverged from a common ancestor. Penetration of the sucker into Asia from Northern America took place between the Early and Middle Pleistocene. Prolonged reproductive isolation of the Siberian and Northern American suckers led to interspecies divergence with the appearance of amino acid substitutions, which, apparently, fixed due to positive selection. The Siberian Sucker appeared to have three modifications of the Cytb protein. PMID- 25735176 TI - [Effects of amyloid-beta peptide Abeta(25-35) on glycolytic and antioxidant enzymes of different ages]. AB - Amyloid-beta peptide Abeta(25-35) was shown to cause lysis of rat erythrocytes of different ages. The toxicity of Abeta(25-35) positively correlated with both the erythrocyte age andthe peptide concentration. The activity of glycolytic, antioxidant, and Na+/K(+)-ATPase enzymes decreased with erythrocyte aging in vivo. In vitro Abeta(25-35) reduced the activity of hexokinase, phosphofructokinase, pyruvate kinase, glutathione peroxidase, and glutathione transferase and increased Na+/K(+)-ATPase activity in aged erythrocytes to a greater degree than in young cells. PMID- 25735177 TI - [Diagnostics of thyroid cancer: limitations of the existing methods and perspectives for future developments]. AB - A novel approach to the development of a precise method of intraoperative diagnostics of thyroid cancer has been proposed on the basis of fundamental study of proteasomes in malignant tumors of mammals and human. The method is based on estimation of proteasome activity in small fragments of the tumor and adjacent tissues. PMID- 25735178 TI - [Activity and growth efficiency of heterotrophic bacteria in Rybinsk Reservoir]. AB - The active fraction, production, and respiration of heterotrophic bacteria are determined to assess their growth efficiency and their role in the carbon cycle in the pelagic zone of Rybinsk Reservoir in summer. The greater part of organic substances assimilated by bacteria is mineralized to CO2. It has been established that the essential part of the constructive and energy metabolism of bacteria is supported by the input of allochthonous substances. Bacterioplankton, producing the biomass at their expense, performs functions similar to the functions of phytoplankton, and substantially supports the structural and functional organization of the planktonic food web in the reservoir. PMID- 25735179 TI - [Parental behavior of the beluga whale (Delphinapterus leucas) in natural environment]. AB - The parental behavior of beluga whales observed in a summer reproductive gathering (near Solovetsky Island, Onega Bay, White Sea) is described, including the parturition process. A tight association between the female and its newborn infant has been traced by the case study of a stillborn calf. Individual behavioral patterns of a mother and calves observable only in natural habitats are detailed. PMID- 25735180 TI - [The structure of the epithelial surface of the gastrointestinal tract of pikas (Ochotona pallasi and O. dauurica, Lagomorpha, Ochotonidae): functional and species specificity]. AB - The macro- and microrelief of the surface of the digestive tract mucosa of two pika species--Pallas's (Ochotona pallasi) and Daurian (O. dauurica)--were studied in detail using whole-mount preparations and scanning electron microscopy. The structural features of the intestinal mucosal surface specific of mammals, such as the formation of projections on the crest of the cecal spiral fold and microcells in the colonic ampulla, were studied. It was found that the colonic mucosa forms sparse large conical villi in pocket cavities and on the surface of muscle bands. Significant differences in the cecal mucosal relief were found between the species studied. The possible functional significance of the identified morphological features is discussed. PMID- 25735181 TI - [Social play in the development of sibling relations in Eurasian lynx (Lynx lynx)]. AB - Social play fulfills an important function in creating and maintaining relations between siblings. However, its relationship with the intralitter social processes is poorly understood. It was noticed that, in Eurasian lynx (Lynx lynx) litters, sex differences in social play are absent in the first 2-3 months of life. Itwas found that the most intense periods of play behavior (at an age of 9 and 1-2 weeks) coincide with periods of aggression. Gradual change in play interactions, which require close physical contact by play elements with increased motor activity, are described. This reflects the changes in the relevance of certain skills of lynx cubs as they grow older. PMID- 25735182 TI - [Effects of neonatal fluvoxamine administration to white rats and their correction by semax treatment]. AB - The aim of this work was to study the delayed effects of chronic neonatal administration of the selective serotonin reuptake inhibitor fluvoxamine (FA) to white rat pups and to estimate the possibility to correct these effects by treatment with semax. Fluvoxamine was injected intraperitoneally at a dose of 10 mg/kg from postnatal days 1 to 14, and semax was injected intranasally at a dose of 0.05 mg/kg from postnatal days 15 to 28. It was shown that neonatal FA administration produced a significant delay in animal somatic growth. A loss in body weight was detected both during FA administration and 4-6 weeks after the last injection. Furthermore, FA administration increased the anxiety level and disturbed the learning ability of animals. The negative consequences of neonatal FA administration were largely compensated by Semax. PMID- 25735183 TI - [Interannual fluctuations of zooplankton in the Kola Section (Barents Sea) in relation to environmental factors]. AB - An analysis of interannual variations of zooplankton composition and biomass in the Kola Section (Barents Sea) in summer was conducted based on the data of 2003 2010. Maximum values of the mean water temperature and temperature anomaly were found in 2006 and in 2007. Variations in the zooplankton composition and relative biomass of common species were studied in relation to climatic factors. It is discussed which parameters may be used as indicators of climatic changes in the southern Barents Sea. PMID- 25735184 TI - [The role of birds in the maintenance of tick-borne infections in the Tomsk anthropurgic foci]. AB - The role of birds in the focus of tick-borne infections was studied from 2006 to 2011. The frequency index of ticks carried by ground dwelling birds is about 49.7%. The index of their abundance is 3.8. The larvae of ticks have been found on birds in 43.8% of cases. Nymphs and adult ticks have been found in 39.9 and 16.3%, respectively. It was revealed that Ixodex pavlovskyi was transferred and dominated in the urban microfoci because of its ornithophily. The markers of infectious agents have been recorded in 42 of 60 bird species under study. PMID- 25735185 TI - [Dynamics of nitrogen, phosphorus, and potassium content in shoots of plants in urban plantations]. AB - The characteristics of dynamics of total nitrogen, potassium, and phosphorus content in the shoots of plants growing in plantations of different environmental categories in a large industrial center were studied. In the urban environment, an increased nitrogen content in plant shoots, the disturbance of the balance of the basic mineral elements and change in their distribution pattern in structural parts of plant shoots, and the disturbance of autumnal physiological efflux of elements from leaves to dormant shoots were detected. PMID- 25735186 TI - [Lead uptake by plants inoculated with plant growth-promoting rhizobacteria in heavy metal-contaminated soil]. AB - The effects of plant growth-promoting rhizobacteria of the genus Pseudomonas on the growth and elemental composition of barley plants were examined in pot experiments under artificial contamination of soil with water-soluble Pb compounds. Bacterial inoculation reduced Pb uptake by plants at the beginning and in the first half of the growing season due to the binding of the heavy metal in organic compounds and stable complexes in the rhizosphere soil without changes in the soil medium reaction. The bacterium P. fluorescens 21 had a maximum capacity for Pb immobilization and contributed to the minimum metal uptake into plants. Application of bacterium P. fluorescens 21 eliminated Pb toxicity and increased the plant weight to the level characteristic of the uncontaminated soil. PMID- 25735187 TI - Association of vitamin C with the risk of age-related cataract: a meta-analysis. AB - PURPOSE: Whether vitamin C is a protective factor for age-related cataract remains unclear. Thus, we conducted a meta-analysis to summarize the evidence from epidemiological studies of vitamin C and the risk of age-related cataract. METHODS: Pertinent studies were identified by searching in PubMed and in Webscience. The random effect model was used to combine the results. Meta regression and subgroups analyses were used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Finally, 15 articles with 20 studies for vitamin C intake and eight articles with 10 studies for serum ascorbate were included in this meta-analysis. The relative risk (RR) and 95% confidence interval of cataract for the highest versus the lowest category of vitamin C intake was 0.814 (0.707-0.938), and the associations were significant in America and Asia. Significant association of cataract risk with highest versus the lowest category of serum ascorbate was found in general [0.704 (0.564-0.879)]. Inverse associations were also found between serum ascorbate and nuclear cataract and posterior subcapsular cataract. CONCLUSIONS: Higher vitamin C intake and serum ascorbate might be inversely associated with risk of cataract. Vitamin C intake should be advocated for the primary prevention of cataract. PMID- 25735188 TI - Polaron pair mediated triplet generation in polymer/fullerene blends. AB - Electron spin is a key consideration for the function of organic semiconductors in light-emitting diodes and solar cells, as well as spintronic applications relying on organic magnetoresistance. A mechanism for triplet excited state generation in such systems is by recombination of electron-hole pairs. However, the exact charge recombination mechanism, whether geminate or nongeminate and whether it involves spin-state mixing is not well understood. In this work, the dynamics of free charge separation competing with recombination to polymer triplet states is studied in two closely related polymer-fullerene blends with differing polymer fluorination and photovoltaic performance. Using time-resolved laser spectroscopic techniques and quantum chemical calculations, we show that lower charge separation in the fluorinated system is associated with the formation of bound electron-hole pairs, which undergo spin-state mixing on the nanosecond timescale and subsequent geminate recombination to triplet excitons. We find that these bound electron-hole pairs can be dissociated by electric fields. PMID- 25735189 TI - Reply: To PMID 25287943. PMID- 25735190 TI - Hematopoietic stem cell transplantation-associated thrombotic microangiopathy accompanied by renal arteriolar C4d deposition. AB - HSCT-associated thrombotic microangiopathy (TA-TMA) is a severe complication with a poor prognosis. Recently, it has been reported that complement system dysregulation, such as CFH autoantibodies and deletions CFH-related genes 3 and 1, induced TA-TMA. In addition, C4d-positive renal arterioles are both a good marker of complement system activation and a useful diagnostic tool for TA-TMA. Because dysregulation of the complement system is associated with TA-TMA, the complement system might be a therapeutic target, such as eculizumab, a terminal complement inhibitor. Herein, we describe an eight-yr-old boy who developed TA TMA accompanied by severe renal dysfunction. His renal specimen showed diffuse C4d deposition in the renal arterioles, which is consistent with TA-TMA. Although the patient gradually improved without eculizumab, renal arteriolar C4d staining in sample with TA-TMA shows the complement system activation and may guide the target therapy using the eculizumab. PMID- 25735191 TI - Glucose- and pH-responsive nanogated ensemble based on polymeric network capped mesoporous silica. AB - In this paper, a glucose and pH-responsive release system based on polymeric network capped mesoporous silica nanoparticles (MSN) has been presented. The poly(acrylic acid) (PAA) brush on MSN was obtained through the surface-initiated atom transfer radical polymerization (SI-ATRP) of t-butyl acrylate and the subsequent hydrolysis of the ester bond. Then the PAA was glycosylated with glucosamine to obtain P(AA-AGA). To block the pore of silica, the P(AA-AGA) chains were cross-linked through the formation of boronate esters between 4,4 (ethylenedicarbamoyl)phenylboronic acid (EPBA) and the hydroxyl groups of P(AA AGA). The boronate esters disassociated in the presence of glucose or in acidic conditions, which lead to opening of the mesoporous channels and the release of loaded guest molecules. The rate of release could be tuned by varying the pH or the concentration of glucose in the environment. The combination of two stimuli exhibited an obvious enhanced release capacity in mild acidic conditions (pH 6.0). PMID- 25735192 TI - Test validity and intra-rater reliability in the measurement of scapular position sense in asymptomatic young adults. AB - It is suggested that scapular joint position sense (JPS) contributes to scapular stability. However, there is a lack of studies describing the measurement method for three-dimensional (3D) scapular JPS. The purposes of this study were to investigate the measurement repeatability and validity of the scapular JPS, and examine the effect of arm dominance on the scapular JPS in asymptomatic young adults. Ten subjects participated in this study. The scapular JPS was measured as scapular reposition errors during scapular elevation, depression, protraction, and retraction. Both the 3D scapular kinematics and clinical scale rule measurement were recorded during the test. The results showed that the measurement of scapular reposition errors resulted in moderate to excellent within-day intra-rater reliability with intraclass correlation coefficient ICC(3,2) between 0.60 and 0.99 for 3D scapular rotations, between 0.56 and 0.96 for 3D scapular displacement, and between 0.73 and 0.98 for the clinical scale ruler measurement. Scapular reposition errors measured using a 3D electromagnetic tracking device and using a scale ruler had a significant relationship (r=0.74 0.98). There was no significant difference in scapular reposition errors between the dominant and non-dominant shoulders. Our findings indicated that both the 3D tracking device and scale ruler resulted in a reliable measurement of scapular JPS and the clinical measurement method could be used to provide valid data for scapular JPS evaluation. In addition, arm dominance did not influence the scapular JPS in asymptomatic young adults. PMID- 25735193 TI - Increased libido associated with donepezil treatment: a case report. AB - Inappropriate verbal and physical sexual behaviour is not common among individuals with dementia, but when it does occur, it can have profound consequences. We report a case of 79-year-old woman with dementia of the Alzheimer's type who complained of increased libido after an increased dose of donepezil, which was being used along with tianeptine. Donepezil withdrawal led to the resolution of increased libido, but when it was reintroduced, increased libido reappeared once again (Naranjo score: 7). Increased libido was not reported by the patient during the 6-year follow-up period after donepezil withdrawal. A potential mechanism of acetylcholinesterase inhibitor-induced increased libido and the current literature on hypersexuality as a side-effect of donepezil treatment are discussed. PMID- 25735194 TI - Micro-trichome as a class I homeodomain-leucine zipper gene regulates multicellular trichome development in Cucumis sativus. AB - Plant trichomes serve as a highly suitable model for investigating cell differentiation at the single-cell level. The regulatory genes involved in unicellular trichome development in Arabidopsis thaliana have been intensively studied, but genes regulating multicellular trichome development in plants remain unclear. Here, we characterized Cucumis sativus (cucumber) trichomes as representative multicellular and unbranched structures, and identified Micro trichome (Mict), using map-based cloning in an F2 segregating population of 7,936 individuals generated from a spontaneous mict mutant. In mict plants, trichomes in both leaves and fruits, are small, poorly developed, and denser than in the wild type. Sequence analysis revealed that a 2,649-bp genomic deletion, spanning the first and second exons, occurred in a plant-specific class I homeodomain leucine zipper gene. Tissue-specific expression analysis indicated that Mict is strongly expressed in the trichome cells. Transcriptome profiling identified potential targets of Mict including putative homologs of genes known in other systems to regulate trichome development, meristem determinacy, and hormone responsiveness. Phylogenic analysis charted the relationships among putative homologs in angiosperms. Our paper represents initial steps toward understanding the development of multicellular trichomes. PMID- 25735196 TI - Selecting category specific visual information: Top-down and bottom-up control of object based attention. AB - The ability to select, within the complexity of sensory input, the information most relevant for our purposes is influenced by both internal settings (i.e., top down control) and salient features of external stimuli (i.e., bottom-up control). We here investigated using fMRI the neural underpinning of the interaction of top down and bottom-up processes, as well as their effects on extrastriate areas processing visual stimuli in a category-selective fashion. We presented photos of bodies or buildings embedded into frequency-matched visual noise to the subjects. Stimulus saliency changed gradually due to an altered degree to which photos stood-out in relation to the surrounding noise (hence generating stronger bottom up control signals). Top-down settings were manipulated via instruction: participants were asked to attend one stimulus category (i.e., "is there a body?" or "is there a building?"). Highly salient stimuli that were inconsistent with participants' attentional top-down template activated the inferior frontal junction and dorsal parietal regions bilaterally. Stimuli consistent with participants' current attentional set additionally activated insular cortex and the parietal operculum. Furthermore, the extrastriate body area (EBA) exhibited increased neural activity when attention was directed to bodies. However, the latter effect was found only when stimuli were presented at intermediate saliency levels, thus suggesting a top-down modulation of this region only in the presence of weak bottom-up signals. Taken together, our results highlight the role of the inferior frontal junction and posterior parietal regions in integrating bottom-up and top-down attentional control signals. PMID- 25735195 TI - A systematic review and meta-analysis of premature mortality in bipolar affective disorder. AB - OBJECTIVE: To review and complete meta-analysis of studies estimating standardised mortality ratios (SMRs) in bipolar affective disorder (BPAD) for all cause and cause-specific mortalities. METHOD: Cause-specific mortality was grouped into natural and unnatural causes. These subgroups were further divided into circulatory, respiratory, neoplastic and infectious causes, and suicide and other violent deaths. Summary SMRs were calculated using random-effects meta analysis. Heterogeneity was examined via subgroup analysis and meta-regression. RESULTS: Systematic searching found 31 studies meeting inclusion criteria. Summary SMR for all-cause mortality = 2.05 (95% CI 1.89-2.23), but heterogeneity was high (I(2) = 96.2%). This heterogeneity could not be accounted for by date of publication, cohort size, mid-decade of data collection, population type or geographical region. Unnatural death summary SMR = 7.42 (95% CI 6.43-8.55) and natural death = 1.64 (95% CI 1.47-1.83). Specifically, suicide SMR = 14.44 (95% CI 12.43-16.78), other violent death SMR = 3.68 (95% CI 2.77-4.90), deaths from circulatory disease = 1.73 (95% CI 1.54-1.94), respiratory disease = 2.92 (95% CI 2.00-4.23), infection = 2.25 (95% CI 1.70-3.00) and neoplasm = 1.14 (95% CI 1.10 1.21). CONCLUSION: Despite considerable heterogeneity, all summary SMR estimates and a large majority of individual studies showed elevated mortality in BPAD compared to the general population. This was true for all causes of mortality studied. PMID- 25735197 TI - Development of Predictive Value of Urinary Cytokine Profile Induced During Intravesical Bacillus Calmette-Guerin Instillations for Bladder Cancer. AB - BACKGROUND: We sought to demonstrate a correlation between the response to treatment and the profile of urinary cytokine production during bacillus Calmette Guerin (BCG) therapy. MATERIAL AND METHODS: From December 2008 to February 2011, 23 patients were included in a prospective study. All patients received 6 instillations of BCG weekly. The mean follow-up period of the population was 16.9 +/- 8.4 months. Refractory disease or recurrence was observed in 5 patients. Urine samples were collected and stored at -80 degrees C, before and 4 hours after the first, third, and sixth BCG instillations. The cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17, interferon-gamma [IFNgamma] and tumor necrosis factor-alpha) were quantified within the collected urine samples using cytometric bead array analysis. The quantitative variables were analyzed using Student's t test, and regression statistical analysis was performed. RESULTS: Urinary cytokine production had increased strongly 4 hours after the sixth instillation but only mildly to moderately after the first and third instillations. IL-2 and IL-6 showed the most dramatic changes after the BCG instillations. Different urinary cytokine production profiles were demonstrated. A trend was observed for the BCG-refractory/recurrence group, with high baseline IL-6 levels, followed by low IL-6 levels before the instillations; low baseline IL-2 levels with only minor changes during treatment; the absence of IFNgamma and IL-17 production; and a low peak of cytokine production at the end of treatment. CONCLUSION: Analysis of the urinary cytokine production levels during BCG therapy reflect a specific immune response induced in each patient. Their assessment could allow a more reliable selection of patients eligible for this type of treatment and could help justify the use of maintenance BCG therapy. PMID- 25735198 TI - Pooled Analysis of C-Reactive Protein Levels and Mortality in Prostate Cancer Patients. AB - INTRODUCTION: Previous studies have reported that higher C-reactive protein (CRP) levels are significantly associated with worse outcome in prostate cancer patients. The size of each individual study was not large enough to allow sufficient statistical power to draw conclusions. We conducted a pooled analysis of individual data of published studies to evaluate the association between increased CRP level and risk of death in prostate cancer, and to find the best CRP cutoff that could predict mortality. MATERIALS AND METHODS: Original research studies on prostate cancer survival and CRP levels were identified (n = 6). Corresponding authors were contacted and invited to share individual data. Two data sets were received (235 patients). The combined hazard ratio (HR) was calculated and adjusted for age, prostate-specific antigen, hemoglobin, and alkaline phosphatase. The best cutoff of CRP was explored using X-title software version 3.6.1. RESULTS: High CRP level was statistically significantly associated with mortality (meta-HR, 1.83 [95% confidence interval (CI), 1.51-2.21]), without evidence of heterogeneity among studies. At pooled analysis, adjusted pooled HR for CRP < 5 versus >= 5 mg/L was 1.44 (95% CI, 1.02-20.4). The best CRP cutoff was 12 mg/L: the adjusted HRpooled for CRP < 12 versus >= 12 mg/L was 1.53 (95% CI, 1.01-2.32). CONCLUSION: Increased CRP levels are associated with overall survival in prostate cancer patients. Because CRP is an affordable and readily available assay, it might hold promise in improving prognostication and potentially to predict the activity of specific therapeutic agents. PMID- 25735199 TI - Complete Biochemical Response (Prostate Specific Antigen) to Sipuleucel-T in Metastatic Castrate-Resistant Prostate Cancer: A Case Report With Docetaxel Chemotherapy Administered Just Before Sipuleucel-T. PMID- 25735200 TI - Pathways to change: Use trajectories following trauma-informed treatment of women with co-occurring post-traumatic stress disorder and substance use disorders. AB - INTRODUCTION AND AIMS: Despite advances towards integration of care for women with co-occurring substance use disorder (SUD) and post-traumatic stress disorder (PTSD), low abstinence rates following SUD/PTSD treatment remain the norm. The utility of investigating distinct substance use trajectories is a critical innovation in the detection and refining of effective interventions for this clinical population. DESIGN AND METHODS: The present study reanalysed data from the largest randomised clinical trial to date for co-occurring SUD and PTSD in women (National Drug Abuse Treatment Clinical Trials Network; Women and Trauma Study). Randomised participants (n = 353) received one of two interventions in addition to treatment as usual for SUD: (i) trauma-informed integrative treatment for PTSD/SUD; or (ii) an active control psychoeducation course on women's health. The present study utilised latent growth mixture models (LGMM) with multiple groups to estimate women's substance use patterns during the 12-month follow-up period. RESULTS: Findings provided support for three different trajectories of substance use in the post-treatment year: (i) consistently low likelihood and use frequency; (ii) consistently high likelihood and use frequency; and (iii) high likelihood and moderate use frequency. Covariate analyses revealed improvement in PTSD severity was associated with membership in a specific substance use trajectory, although receiving trauma-informed treatment was not. Additionally, SUD severity, age and after-care efforts were shown to be related to trajectory membership. DISCUSSION AND CONCLUSIONS: Findings highlight the necessity of accounting for heterogeneity in post-treatment substance use, relevance of trauma informed care in SUD recovery and benefits of incorporating methodologies like LGMM when evaluating SUD treatment outcomes. PMID- 25735201 TI - Comparison of diabetes-associated secondary healthcare utilization between alternative oral antihyperglycaemic dual therapy combinations with metformin in patients with type 2 diabetes: an observational cohort study. AB - AIMS: To compare diabetes-associated secondary healthcare utilization in patients with type 2 diabetes (T2DM) prescribed sulphonylureas (SUs) versus other oral antihyperglycaemic agents (OHAs) as an add-on to metformin monotherapy (metformin + SU vs metformin + OHA). METHODS: This retrospective cohort study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Adults with T2DM initiated on metformin + SU or metformin + OHA from April 2003 to March 2012 were identified. Patients were matched using propensity scores. Diabetes-associated secondary healthcare visits were counted from >6 months post initiation of dual therapy until treatment change or end of follow-up. Outcomes were calculated as rate ratios, adjusted for over-dispersion using negative binomial regression and propensity score for covariates. RESULTS: After propensity score matching, 1704 patients were included in each cohort. For the primary objective (diabetes-associated inpatient and outpatient visits combined), the metformin + SU cohort had a directionally higher rate of diabetes-associated secondary healthcare utilization than the metformin + OHA cohort [adjusted rate ratio 1.12, 95% confidence interval (CI) 0.97-1.29]. For the secondary outcomes, the adjusted rate ratio was 1.38 (95% CI 0.95-2.00) for inpatient admissions and 1.10 (95% CI 0.95-1.28) for outpatient visits. Macrovascular complications, accounting for 77.2% of inpatient admissions, occurred at a statistically significantly higher rate in the metformin + SU cohort than in the metformin + OHA cohort (adjusted rate ratio 1.77, 95% CI 1.15-2.71). CONCLUSIONS: This study found a statistically significant higher rate of inpatient admissions for macrovascular complications and cardiology outpatient visits and, overall, a directionally higher rate of secondary healthcare utilization for patients prescribed metformin + SU than for those prescribed metformin + OHA. This adds to the evidence that long-term and health economic outcomes should be considered in treatment decisions for patients with type 2 diabetes. PMID- 25735202 TI - Cross-cultural adaptation of an Arabic version of the 10-item hearing handicap inventory. AB - OBJECTIVE: The purpose of this study was to translate and culturally adapt an Arabic version of the hearing handicap inventory for the elderly - screening (HHIE-S). DESIGN: The HHIE-S was translated following cross-cultural adaptation guidelines, and pretested in 20 elderly patients with hearing impairment. Next, the adapted Arabic HHIE-S underwent psychometric evaluation. The results were confirmed by pure-tone audiometer (PTA) examination. The patients completed the HHIE-S again after one hour. The validation of the questionnaire using Cronbach's alpha (internal consistency), (construct validity), and intraclass correlation coefficients (repeatability) was performed. STUDY SAMPLE: Twenty elderly subjects with hearing impairment were recruited for the pretesting stage, and 100 elderly subjects were recruited for the psychometric evaluation stage. Patients with acute illness, functional dependency, cognitive impairment, and previous users of hearing aids were excluded. RESULTS: The adapted Arabic HHIE-S showed good internal consistency (alpha = 0.902). Construct validity was good, as high correlations were found between the scale and the PTA outcome (r = 0.688, p = 0.000). Repeatability was high (ICC = 0.986). CONCLUSIONS: This study showed that the adapted Arabic HHIE-S is a valid and reliable questionnaire for the assessment of handicapping hearing impairment in Egyptian elderly patients. PMID- 25735203 TI - The medial olivocochlear reflex in children during active listening. AB - OBJECTIVE: To determine if active listening modulates the strength of the medial olivocochlear (MOC) reflex in children. DESIGN: Click-evoked otoacoustic emissions (CEOAEs) were recorded from the right ear in quiet and in four test conditions: one with contralateral broadband noise (BBN) only, and three with active listening tasks wherein attention was directed to speech embedded in contralateral BBN. STUDY SAMPLE: Fifteen typically-developing children (ranging in age from 8 to14 years) with normal hearing. RESULTS: CEOAE levels were reduced in every condition with contralateral acoustic stimulus (CAS) when compared to preceding quiet conditions. There was an additional systematic decrease in CEOAE level with increased listening task difficulty, although this effect was very small. These CEOAE level differences were most apparent in the 8-18 ms region after click onset. CONCLUSIONS: Active listening may change the strength of the MOC reflex in children, although the effects reported here are very subtle. Further studies are needed to verify that task difficulty modulates the activity of the MOC reflex in children. PMID- 25735204 TI - Retrospective audiological analysis of bone conduction versus round window vibratory stimulation in patients with mixed hearing loss. AB - OBJECTIVE: To compare audiological outcomes in mild-to-moderate mixed hearing loss patients treated with a bone-anchored hearing aid or an active middle-ear implant. Analysis aimed to refine criteria used in preoperative selection of implant type. DESIGN: Retrospective comparative analysis of audiological data. Follow-up time ranged between 0.55 and 8.8 years. STUDY SAMPLE: For detailed comparative analysis, 12 patients (six in each group) with comparable bone conduction thresholds and similar clinical characteristics were selected. A larger cohort of 48 patient files were used to evaluate overall audiological indication criteria (24 per group). RESULTS: In free-field tone audiometry, Baha patients showed mean aided thresholds between 40-48 dB, whereas hearing thresholds for VSB patients were 25-43 dB. Baha and VSB users had mean WRS of 56% and 82%, respectively, at 65 dB. Better speech understanding in noise was seen with the VSB. CONCLUSION: Analysis of the main cohort (n = 48) showed that treatment with round window vibroplasty leads to better hearing performance than treatment with a bone-anchored hearing device, if the bone conduction pure-tone average (0.5 to 4 kHz) is poorer than 35 dB HL. Audiological analysis in the smaller comparative analysis showed similar findings. PMID- 25735205 TI - Will diminishing cochlear delay affect speech perception in noise? AB - OBJECTIVE: Normal auditory systems appear well habituated to time/phase delays inherent to sound encoding along the hearing organ, sending frequency information non-simultaneously to the central auditory system. Eliminating, or simply perturbing, the cochlear delay might be expected to decrease speech recognition ability, especially under demanding listening conditions. Resources of a larger scale investigation permitted a preliminary examination of this issue, particularly on a relevant timescale of empirically demonstrated cochlear delays. DESIGN: In a randomized controlled trial study, word recognition was tested for mono-syllabic tokens treated digitally to exacerbate, if not diminish/nullify, such delays. Speech-weighted noise was used to interfere with listening to time frequency reversed (nominally no delay) versus non-reversed (natural timing) transforms under three treatments of speech tokens: (1) original-digitally recorded; digitally processed to emphasize (2) transient versus (3) quasi-steady state components. STUDY SAMPLE: Ten normal-hearing young-adult females. RESULTS: The findings failed to demonstrate statistically significant differences between delay conditions for any of the three speech-token treatments. CONCLUSIONS: An algorithm putatively diminishing frequency-dependent cochlear delays failed to systematically deteriorate performance in all subjects for the fixed time frequency transform, stimulus parameters, and test materials employed. Yet, trends were evident such that some effect of perturbing cochlear delays could not be ruled out completely. PMID- 25735206 TI - "The beginning of wisdom is the definition of terms" - Socrates. PMID- 25735207 TI - From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD. AB - Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology. PMID- 25735208 TI - Stereoselective synthesis, biological evaluation, and modeling of novel bile acid derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists. AB - GP-BAR1 (also known as TGR5), a novel G-protein coupled receptor regulating various non-genomic functions via bile acid signaling, has emerged as a promising target for metabolic disorders, including obesity and type II diabetes. However, given that many bile acids (BAs) are poorly tolerated for systemic therapeutic use, there is significant need to develop GP-BAR1 agonists with improved potency and specificity and there also is significant impetus to develop a stereoselective synthetic methodology for GP-BAR1 agonists. Here, we report the development of highly stereo-controlled strategies to investigate a series of naturally occurring bile acid derivatives with markedly enhanced GP-BAR1 activity. These novel GP-BAR1 agonists are evaluated in vitro using luciferase based reporter and cAMP assays to elucidate their biological properties. In vivo studies revealed that the GP-BAR1 agonist 23(S)-m-LCA increased intestinal GLP-1 transcripts by 26-fold. Additionally, computational modeling studies of selected ligands that exhibit enhanced potency and specificity for GP-BAR1 provide information on potential binding sites for these ligands in GP-BAR1. PMID- 25735209 TI - Reconstructing long-term human impacts on plant communities: an ecological approach based on lake sediment DNA. AB - Paleoenvironmental studies are essential to understand biodiversity changes over long timescales and to assess the relative importance of anthropogenic and environmental factors. Sedimentary ancient DNA (sedaDNA) is an emerging tool in the field of paleoecology and has proven to be a complementary approach to the use of pollen and macroremains for investigating past community changes. SedaDNA based reconstructions of ancient environments often rely on indicator taxa or expert knowledge, but quantitative ecological analyses might provide more objective information. Here, we analysed sedaDNA to investigate plant community trajectories in the catchment of a high-elevation lake in the Alps over the last 6400 years. We combined data on past and present plant species assemblages along with sedimentological and geochemical records to assess the relative impact of human activities through pastoralism, and abiotic factors (temperature and soil evolution). Over the last 6400 years, we identified significant variation in plant communities, mostly related to soil evolution and pastoral activities. An abrupt vegetational change corresponding to the establishment of an agropastoral landscape was detected during the Late Holocene, approximately 4500 years ago, with the replacement of mountain forests and tall-herb communities by heathlands and grazed lands. Our results highlight the importance of anthropogenic activities in mountain areas for the long-term evolution of local plant assemblages. SedaDNA data, associated with other paleoenvironmental proxies and present plant assemblages, appear to be a relevant tool for reconstruction of plant cover history. Their integration, in conjunction with classical tools, offers interesting perspectives for a better understanding of long-term ecosystem dynamics under the influence of human-induced and environmental drivers. PMID- 25735210 TI - Inclusion of sorghum, millet and cottonseed meal in broiler diets: a meta analysis of effects on performance. AB - A meta-analysis was conducted (i) to evaluate broiler response to partial or total substitution of corn by sorghum and millet and (ii) to determine the effect of soybean meal replacement by cottonseed meal in broiler diet. The database included 190 treatments from 29 experiments published from 1990 to 2013. Bird responses to an experimental diet were calculated relative to the control (Experimental-Control), and were submitted to mixed-effect models. Results showed that diets containing millet led to similar performance as the corn-based ones for all parameters, whereas sorghum-based diets decreased growth performance. No major effect of the level of substitution was observed with millet or cottonseed meal. No effect of the level of substitution of sorghum on feed intake was found; however, growth performance decreased when the level of substitution of corn by sorghum increased. Cottonseed meal was substituted to soybean meal up to 40% and found to increase feed intake while reducing growth performance. Young birds were not more sensitive to these ingredients than older birds since there was no negative effect of these ingredients on performance in the starter phase. Results obtained for sorghum pointed out the necessity to find technological improvements that will increase the utilization of these feedstuffs in broiler diet. An additional work is scheduled to validate these statistical results in vivo and to evaluate the interactions induced with the simultaneous inclusions of sorghum, millet and cottonseed meal in broiler feeding. PMID- 25735211 TI - Thioredoxin 1 and glutaredoxin 2 contribute to maintain the phenotype and integrity of neurons following perinatal asphyxia. AB - BACKGROUND: Thioredoxin (Trx) family proteins are crucial mediators of cell functions via regulation of the thiol redox state of various key proteins and the levels of the intracellular second messenger hydrogen peroxide. Their expression, localization and functions are altered in various pathologies. Here, we have analyzed the impact of Trx family proteins in neuronal development and recovery, following hypoxia/ischemia and reperfusion. METHODS: We have analyzed the regulation and potential functions of Trx family proteins during hypoxia/ischemia and reoxygenation of the developing brain in both an animal and a cellular model of perinatal asphyxia. We have analyzed the distribution of 14 Trx family and related proteins in the cerebellum, striatum, and hippocampus, three areas of the rat brain that are especially susceptible to hypoxia. Using SH-SY5Y cells subjected to hypoxia and reoxygenation, we have analyzed the functions of some redoxins suggested by the animal experiment. RESULTS AND CONCLUSIONS: We have described/discovered a complex, cell-type and tissue-specific expression pattern following the hypoxia/ischemia and reoxygenation. Particularly, Grx2 and Trx1 showed distinct changes during tissue recovery following hypoxia/ischemia and reoxygenation. Silencing of these proteins in SH-SY5Y cells subjected to hypoxia reoxygenation confirmed that these proteins are required to maintain the normal neuronal phenotype. GENERAL SIGNIFICANCE: These findings demonstrate the significance of redox signaling in cellular pathways. Grx2 and Trx1 contribute significantly to neuronal integrity and could be clinically relevant in neuronal damage following perinatal asphyxia and other neuronal disorders. PMID- 25735212 TI - Biomodulation of Inflammatory Cytokines Related to Oral Mucositis by Low-Level Laser Therapy. AB - This study evaluated the effects of LLLT on the expression of inflammatory cytokines related to the development of oral mucositis by gingival fibroblasts. Primary gingival fibroblasts were seeded on 24-well plates (10(5) cells/well) for 24 h. Fresh serum-free culture medium (DMEM) was then added, and cells were placed in contact with LPS (Escherichia coli, 1 MUg mL(-1)), followed by LLLT irradiation (LaserTABLE-InGaAsP diode prototype-780 nm, 25 mW) delivering 0, 0.5, 1.5 or 3 J cm(-2)2. Cells without contact with LPS were also irradiated with the same energy densities. Gene expression of TNF-alpha, IL-1beta, IL-6 and IL-8 was evaluated by Real-Time PCR, and protein synthesis of these cytokines was determined by enzyme-linked immunosorbent (ELISA) assay. Data were statistically analyzed by the Kruskal-Wallis test, complemented by the Mann-Whitney test (P < 0.05). LPS treatment increased the gene expression and protein synthesis of TNF alpha, IL-6 and IL-8, while the expression of IL-1beta was not affected. For LPS treated groups, LLLT promoted significant decreases in the expression of TNF alpha, IL-6, and IL-8 at 1.5 J cm(-2) and 3 J cm(-2). These results demonstrate that LLLT promoted a beneficial biomodulatory effect on the expression of inflammatory cytokines related to oral mucositis by human gingival fibroblasts. PMID- 25735213 TI - Protected DNA strand displacement for enhanced single nucleotide discrimination in double-stranded DNA. AB - Single nucleotide polymorphisms (SNPs) are a prime source of genetic diversity. Discriminating between different SNPs provides an enormous leap towards the better understanding of the uniqueness of biological systems. Here we report on a new approach for SNP discrimination using toehold-mediated DNA strand displacement. The distinctiveness of the approach is based on the combination of both 3- and 4-way branch migration mechanisms, which allows for reliable discrimination of SNPs within double-stranded DNA generated from real-life human mitochondrial DNA samples. Aside from the potential diagnostic value, the current study represents an additional way to control the strand displacement reaction rate without altering other reaction parameters and provides new insights into the influence of single nucleotide substitutions on 3- and 4-way branch migration efficiency and kinetics. PMID- 25735214 TI - The efficacy of ELISA commercial kits for the screening of equine infectious anemia virus infection. AB - The most used and reliable indicator of Equine infectious anemia virus (EIAV) infection is the detection of its specific antibodies in horse serum. In the present study, the performance of two commercial ELISA tests for the detection of EIAV antibodies as well as the potential advantages of their use as an EIAV infection screening tool were evaluated in 302 horse serum samples. Both ELISA assays showed 100% diagnostic sensitivity, and 92.3-94.3% diagnostic specificity. Discordant results were analyzed by immunoblot. The results showed that both ELISA tests are very efficient at detecting EIAV infected animals, allowing to identify a higher number of positive horse cases. Thus, ELISA assays can be useful tools in EIA control and eradication. PMID- 25735215 TI - AA479 antiserum: new reagent for the serotype characterization of atypical variants of Shigella flexneri. AB - Shigella flexneri is divided into 13 serotypes based on the combination of antigenic determinants present in the O-antigen. A new O-antigen modification with phosphoethanolamine has been identified. The presence of this antigenic determinant (called E1037) is recognized by monoclonal antibody MASF IV-1. Given the increasing incidence of these new variants and the difficulty in supplying the monoclonal antibody to our country, we produced a polyclonal antiserum (AA479) through immunization with a S. flexneri Xv strain. The antiserum specificity was assessed by slide agglutination against isolates from clinical cases and a culture collection representing all Shigella serotypes. The results obtained demonstrated a 100% correlation between AA479 absorbed antiserum and monoclonal antibody MASF IV-1. The availability of AA479 antiserum in every public hospital in Argentina will allow us to identify atypical S. flexneri isolates in order to strengthen Shigella surveillance in our country and to compare with global epidemiological data. PMID- 25735216 TI - [Respiratory viral diagnosis by using an automated system of multiplex PCR (FilmArray) compared to conventional methods]. AB - Acute respiratory infections, which are commonly caused by viruses, are an important cause of morbidity and mortality in children. In Argentina, national surveillance programs for the detection of respiratory viruses are usually performed by using immunofluorescence (IF) assays, although it is well known that molecular methods are more sensitive. An automated multiplex PCR device, the FilmArray-Respiratory Panel (FilmArray-RP), can detect 17 viral and 3 bacterial pathogens in a closed system that requires only 5 min of hands-on time and 1h of instrumentation time. A total of 315 respiratory samples from children under 6 years of age suffering from acute respiratory infections, were studied by IF for 8 respiratory viruses and by RT-PCR for rhinoviruses. Later, these samples were tested by the FilmArray-RP. The positivity frequency obtained for the 9 viruses tested was 75% by IF/RT-PCR and 92% by the FilmArray-RP. The positive and negative percent agreement between both methods was 70.5% whereas the negative percent agreement was 99.6% (95% confidence interval:65.5-75.1 and 99.2-99.8 respectively). The FilmArray-RP allowed a higher positive diagnosis (97%) and detected other viruses such as coronavirus NL63, 229E, OC43, HKU1 (10%) and bocavirus (18%). In addition, this method identified multiple coinfections (39%) with 2, 3, 4 and up to 5 different viruses. At present, IF is still the most frequently used method in most Latin American countries for respiratory viruses diagnosis due to its low cost, its capability to process a high number of samples simultaneously and the fast determination of results for the most frequent viruses, which are available within 5h. However, the coming incorporation of molecular methods in routine procedures will significantly increase the diagnostic yield of these infections. PMID- 25735217 TI - Current concepts in minimally invasive surgery of the thorax. AB - Thoracoscopy is a technique that has been shown to decrease patient morbidity and is rapidly becoming more diversely applied for diagnostic and therapeutic interventions in veterinary medicine. This article describes the basic equipment and application of thoracoscopy in small animal surgery. The diagnostic and therapeutic applications are introduced and briefly described. PMID- 25735218 TI - Age-related changes in large-conductance calcium-activated potassium channels in mammalian circadian clock neurons. AB - Aging impairs the function of the suprachiasmatic nucleus (SCN, the central mammalian clock), leading to a decline in the circadian rhythm of many physiological processes, including sleep-wake rhythms. Recent studies have found evidence of age-related changes in the circadian regulation of potassium currents; these changes presumably lead to a decrease in the SCN's electrical rhythm amplitude. Current through large-conductance Ca(2+)-activated K(+) (BK) channels promote rhythmicity in both SCN neuronal activity and behavior. In many neuron types, changes in BK activity are correlated with changes in intracellular Ca(2+) concentration ([Ca(2+)]i). We performed patch-clamp recordings of SCN neurons in aged mice and observed that the circadian modulation of BK channel activity was lost because of a reduction in BK currents during the night. This reduced current diminished the afterhyperpolarization, depolarized the resting membrane potential, widened the action potential, and increased [Ca(2+)]i. These data suggest that reduced BK current increases [Ca(2+)]i by altering the action potential waveform, possibly contributing to the observed age-related phenotype. PMID- 25735219 TI - On-demand d-modafinil may be an effective treatment option for lifelong premature ejaculation: a case report. AB - Premature ejaculation (PE) is considered to be the most common form of male sexual dysfunction. Given that acute oral administration of d-isomer of modafinil (d-modafinil) can extend the latency to ejaculation in rats without suppressing sexual behaviour, the effects of on-demand d-modafinil treatment were examined on a 30-year-old male patient with lifelong PE. The patient was instructed to take d modafinil 100 mg 3 h prior to the sexual relation for four times and was invited for a control visit. The patient was re-evaluated 2 weeks later. He reported that his IELT increased to 15 min. He reported heartburn and insomnia when he used d modafinil for the first time; however, these symptoms were transient and did not recur after the initial dose. Overall, he reported considerable improvement and noted that he feels much better with the treatment. Based on this limited data, on-demand d-modafinil seems to be an effective treatment for men with lifelong PE. The side effects were transient and mild in the reported case. Further randomised clinical trials are necessary to elucidate the therapeutic concept of this drug in patients with lifelong PE. PMID- 25735220 TI - Population-based method for investigating adherence to international recommendations for pathology reporting of primary cutaneous melanoma: Results of a EUROCARE-5 high resolution study. AB - AIM: Our study aim was to investigate the degree of adherence to international recommendations for cutaneous melanoma pathology reports at the population level by a EUROCARE high resolution study. METHODS: The availability of nine characteristics - predominant cell type, tumour-infiltrating lymphocytes, mitotic index, histological subtype, growth phase, Clark level, Breslow thickness, ulceration, and sentinel-node biopsy - was examined on pathology reports of a random sample of 636 cases diagnosed in 2003-2005 in seven Italian cancer registries: Biella, Ferrara, Firenze, Latina, Ragusa, Reggio Emilia, Romagna. The odds of having (versus not having) information for all four core characteristics (last four listed above) were estimated. RESULTS: Sentinel node biopsy was available most often, followed by Clark level, Breslow thickness, histological subtype and ulceration. Information on all nine characteristics was more often available in Biella and Ferrara (northern Italy) than elsewhere. Information on all four core items was available for 78% of cases. Odds of four-core-item availability were higher (than mean) in Biella and lower in Latina (centre) and Ragusa (south). CONCLUSIONS: The availability of information important for staging and management was good overall on pathology reports, but varied with geography. It is likely to be improved by wider dissemination of reporting guidelines and adoption of a standardised synoptic reporting system. PMID- 25735221 TI - Development of radioiodinated lipophilic cationic compounds for myocardial imaging. AB - INTRODUCTION: Tc-99m compounds are mainly used in myocardial blood flow studies. These compounds, however, are produced by a generator and alternate single photon emission computed tomography (SPECT) radiopharmaceuticals are therefore required to avoid the risks posed by generator failure. Three radiolabeled compounds, including [(125)I]p-iodobenzyl triphenylphosphonium ([(125)I]ITPP), [(125)I]p Iodobenzyl dipropylphenylphosphonium ([(125)I]IDPP) and [(125)I]p-iodobenzyl methyldiphenylphosphonium ([(125)I]IMPP), have been synthesized in the current study. All three of these compounds contain a lipophilic cation, which enhances their cell permeability properties and allows them to accumulate in the myocardium as SPECT probes. METHODS: 4-(2-Tributylstannyl) benzyl alcohol was mixed with [(125)I]NaI in the presence of aqueous hydrogen peroxide and hydrochloric acid to allow for the synthesis of 4-[(125)I]iodobenzyl alcohol. Bromination of the alcohol under standard conditions gave 4-[(125)I]iodo benzyl bromide, which was treated with triphenylphosphine, dipropylphenylphosphine or methyldiphenylphosphine to give [(125)I]ITPP, [(125)I]IDPP and [(125)I]IMPP, respectively. These compounds were evaluated in biodistribution and SPECT studies in normal ddY mice. RESULTS: All three of the radiolabeled compounds were synthesized in approximately 60% yield with radiochemical purities greater than 99%. The specific activity of each compound was 74 GBq/MUmol. The results of the biodistribution and SPECT studies showed that all compounds accumulated preferentially in the heart in vivo, especially [(125)I]IDPP. CONCLUSION: [(123)I] IDPP could be used in clinical practice as a novel myocardial imaging agent. PMID- 25735222 TI - In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study. AB - INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16beta-[(18)F]fluoro 5alpha-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain. METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study. PMID- 25735223 TI - Monitoring therapeutic response of human ovarian cancer to trastuzumab by SPECT imaging with (99m)Tc-peptide-Z(HER2:342). AB - INTRODUCTION: Patients with human epidermal growth factor receptor 2 (HER2) positive cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. How to systemically assess tumor HER2 expression and identifying appropriate use of anti-HER2 therapies by noninvasive imaging in vivo is an urgent issue. The purpose of this study was to evaluate SPECT imaging of (99m)Tc Gly-(D)Ala-Gly-Gly-Z(HER2:342) ((99m)Tc-peptide-Z(HER2:342)) for monitoring therapeutic response to trastuzumab in nude mice bearing HER2-positive SKOV-3 xenografts. METHODS: Nude mice bearing HER2-positive SKOV-3 xenografts were treated with trastuzumab (treatment group) or saline (control) with ten mice in each group. Mice in trastuzumab-treated group were given trastuzumab intraperiotoneally 4 mg/kg on day 1 and 2 mg/kg on day 8; Mice in control group were given physiological saline on day 1 and 8. Mice body weights and tumour volume were monitored every three days during treatment. In vivo SPECT imaging was performed in mice of the two groups using (99m)Tc-peptide-Z(HER2:342) before treatment, on day 8 and 15 after treatment. Radiolabeled probe uptake in tumours was measured as the ratio of radioactive counts in the tumour to that in the contralateral equivalent region (T/NT). After SPECT imaging on day 15, all the mice were euthanized, biodistribution studies of the SKOV-3 xenografts were carried out to validate the imaging results and HER2 expression of the transplanted tumours was analyzed by immunohistochemistry (IHC). Correlation analysis was performed between T/NT ratios acquired by in vivo SPECT imaging on day 15 and the HER2 level of tumours. In vitro cell binding capacity of (99m)Tc Z(HER2:342) with SKOV-3 cells in the absence and presence of varying amount of trastuzumab were also conducted in the study. RESULTS: Twenty mice body weight in the two groups gradually increased during treatment, but there was no statistical difference (p > 0.05). Though volumes of SKOV-3 xenografts gradually increased in each group during the treatment, the transplanted tumours in trastuzumab-treated group had a slower growth than those in control group (p < 0.05). Compared with the baseline, the results of in vivo imaging showed that radionuclide accumulation in transplanted tumours reduced significantly in trastuzumab-treated group after treatment (p < 0.05), whereas the tumour accumulation in control group increased after treatment. Biodistribution studies demonstrated that the results corresponded well with in vivo imaging data. Immunohistochemical staining confirmed the significant reduction in tumor HER2 level upon trastuzumab treatment, and there was an obviously positive correlation between T/NT ratios and HER2 level of tumours with correlation coefficient rs = 0.919, p < 0.05. There was no significant significance in cell binding ratios between varying amount of trastuzumab and the absence of trastuzumab (p > 0.05). CONCLUSIONS: The early response to trastuzumab in mice bearing SKOV-3 xenografts was successfully monitored by SPECT imaging using (99m)Tc-peptide-Z(HER2:342). This approach may be valuable in monitoring the therapeutic response in HER 2-positive tumours under HER2-targeted therapy. PMID- 25735224 TI - Overexpression of a Novel Tumor Metastasis Suppressor Gene TMSG1/LASS2 Induces Apoptosis via a Caspase-dependent Mitochondrial Pathway. AB - The tumor metastasis suppressor gene 1 (TMSG1), also designated homo sapiens longevity assurance homologue 2 of yeast LAG1 (LASS2), is a novel tumor metastatic suppressor gene. Although its effects on metastasis have been reported, its biological functions remain unclear. The purpose of this study was to investigate the effects of TMSG1/LASS2 protein on apoptosis and proliferation in human embryonic kidney cell lines HEK293 and 293 T and explore the potential mechanisms. Cell growth, morphology, expressions of apoptotic-related proteins and cell cycle distribution were evaluated in HEK293 and 293 T cells transfected with TMSG1/LASS2 expression plasmids or vector controls. MTT assays showed that overexpression of TMSG1/LASS2 inhibited cell proliferation; and morphological observations and flow cytometric assays with Annexin V/propidium iodide showed TMSG1/LASS2 overexpression increased apoptosis in these cells. Western blot analysis demonstrated that overexpression of TMSG1/LASS2 resulted in the downregulation of Bcl-2, release of cytochrome c from mitochondria, activation of procaspase-9 and procaspase-3, and the cleavage of PARP. Subsequent cell cycle analysis showed that TMSG1/LASS2 overexpression inhibited cell proliferation by mediating the induction of G0/G1 cell cycle arrest. Together, these results confirmed that TMSG1/LASS2 is a potential metastasis suppressor gene, and suggested that the mechanism involved the induction of apoptosis and inhibition of cell proliferation via a caspase-dependent mitochondrial pathway. PMID- 25735225 TI - [Clinical and radiological findings in a case of pseudohypoparathyroidism type 1a. Albright hereditary osteodystrophy]. PMID- 25735227 TI - Cardiorespiratory of land and water walking on a non motorized treadmill. AB - AIM: This study was designed to assess submaximal cardiac and pulmonary demand imposed by walking on a non motorized treadmill in land and in water condition. METHODS: Eight healthy young subjects (mean age, body mass and height: 26.5 +/- 2.8 years; 66.7 +/- 9.60 kg; 172 +/- 8.07 cm) performed one maximal treadmill running test on land and a submaximal incremental test (treadmill speed 2, 3, 4 km.h-1; 5 minutes step duration; 15 minutes total duration) in land (L) at 2, 3, 4 km.h-1 (L2, L3, L4) and in water (W) at 2, 3, 4 km.h-1 (W2, W3, W4). Individual stride frequency at any given submaximal walking speed on land was used to perform comparable water tests. Heart rate (HR) and oxygen consumption (VO2) were continuously measured during the tests. RESULTS: Rest heart rate (%max) decreased immediately after water immersion [land HR(%max) 42 b.min-1+/-3; water HR(%max) 36 b.min-1 +/- 5, P<0.05] while the other physiological parameters were comparable between land and water condition [land VO2(%max) 9.44 mL.Kg.min-1 +/- 1.54; water VO2(%max) 7.75 ml.Kg.min-1 +/- 2.4, p>0.05; land ventilation [VE(%max)] 8.71 L.min-1 +/- 2.37; water VE(%max) 7.67 L.min-1 +/- 2.79, p>0.05; land respiratory exchange ratio (RER) 0.77 +/- 0.5 water RER 0.75 +/- 0.07, P>0.05]. During exercise at 2, 3 and 4 Km.h-1, reserve heart rate [HRR (%max)] was higher during water walking (W2 35 +/- 10; W3 54 +/- 11; W4 76 +/- 9 b.min-1) than during land walking (L2 23 +/- 5; L3 39 +/- 7; L4 58 +/- 8 b.min-1, P<0.05). VO2and VE were not different. CONCLUSION: The findings suggest that water walking on a non motorized treadmill elicits similar VO2but higher HR than land walking; this factor should be considered when prescribing exercise intensity in water using heart rate. PMID- 25735226 TI - Analysis of accumulation patterns and preliminary study on the condensation mechanism of proanthocyanidins in the tea plant [Camellia sinensis]. AB - In the present study, proanthocyanidins were qualitatively and quantitatively identified using hydrolysis and thiolysis assays, NP-HPLC, HPLC-ESI-MS, MALDI-TOF MS, (1)H-NMR, and (13)C-NMR techniques in different organs of tea plants. The results showed that in leaves, the tri-hydroxyl, cis- and galloylated flavan-3 ols were the main monomeric catechins units, and (epi)catechin was found to be the major unit of polymeric flavan-3-ols when the degree of polymerization was greater than five. In roots, the PAs were found to be abundant, and epicatechin formed the predominant extension unit of oligomeric and polymeric PAs. In order to understand the mechanism of proanthocyanidins polymerization, auto condensation of the flavan-3-ols was investigated. The results showed that the same trimers (m/z 865) were detected in the extracts of tea plants and in the non enzymatic in vitro assay, in weak acid as well as weak alkaline solutions at room temperature, when the substrates used were either procyanidin B2 and monomeric flavan-3-ols (epicatechin or catechin), or only procyanidin B2. This suggested that procyanidin B2 not only released carbocation as electrophilic upper units, but also could be used as nucleophilic lower units directly itself, to form the procyanidin trimer in vitro or in vivo. PMID- 25735228 TI - Review of clinical approaches and diagnostic quantities used in pedobarographic measurements. AB - The non-invasive nature of pedobarographic measurements is particularly attractive to researchers for analyzing and characterizing the impact of specific pathological foot conditions. However, adequate clinical use of pedobarographic technology requires a profound technical and methodological knowledge. Several papers summarized the technical capacities of pedobarographic technology. Moreover, methodological expertise has grown considerably during the last two decades. Therefore, two crucial decisions have to be made before pathomechanical modelling or functional interpretation of foot and lower limb disorders can be pursued. The first is the selection of the specific method to analyse the dynamic plantar footprint, and the second is the choice of parameters to quantify the results. In the first part of this paper, we review the different methods used to analyse the dynamic plantar footprint and discuss their conceptual backgrounds. We also aim to illustrate the clinical relevance of each method and elaborate on the future perspectives. In the second part, we review quantification methods of pedobarographic measurements. The latter is of primary relevance to clinicians and investigators with a special interest in foot and lower limb biomechanics. PMID- 25735229 TI - Physical activity among other health-related behaviors in treatment of alcoholism. AB - AIM: Objective of the paper was to verify an association between the locus of control (LOC) and the level of physical activity (PA) in the group of alcohol addicts. METHODS: The study included 136 individuals (Females=53; Males=83; mean age 39.02+/-9.01 years) with established alcohol dependence, and an age- and education-matched control group (N.=289; Females=170; Females=119). Both groups were examined using Health Behavior Inventory by Juczynski, Rotter's Internal External Locus of Control Scale, and an inventory of physical activity objectives (IPAO) by Lipowski and Zaleski. RESULTS: The alcoholics and the controls were characterized by similar average number of hours spent weekly for PA, but the former group declared slightly higher variability in its forms. Compared to males, female alcoholics spent significantly more time exercising. The alcoholics with various educational levels differed in terms of the PA form number: better educated males preferred greater variability in this matter (F=4.70; P=0.011). An opposite phenomenon was documented in the case of the locus of control (LOC): the level of LOC turned out to be lower among worse educated men (F=4.70; P=0.011). In contrast, female alcoholics with various educational levels did not differ significantly in terms of PA, health-seeking behavior, or LOC levels. Analysis of the control group revealed that educational level exerted significant effect on the number of hours spent on PA; the latter parameter was the highest among better educated respondents (F=6.50; P=0.002). CONCLUSION: Increased level of internal control can regulate health-related behaviors of alcoholics. The association between LOC and the role of PA is modulated by such sociodemographic factors as the level of education and gender. PMID- 25735230 TI - Acute exercise leads to increased HbA1c and fructosamine levels in athletes with type 1 diabetes. PMID- 25735231 TI - 3D-printed biosensor with poly(dimethylsiloxane) reservoir for magnetic separation and quantum dots-based immunolabeling of metallothionein. AB - Currently, metallothioneins (MTs) are extensively investigated as the molecular biomarkers and the significant positive association of the MT amount was observed in tumorous versus healthy tissue of various types of malignant tumors, including head and neck cancer. Thus, we proposed a biosensor with fluorescence detection, comprising paramagnetic nanoparticles (nanomaghemite core with gold nanoparticles containing shell) for the magnetic separation of MT, based on affinity of its sulfhydryl groups toward gold. Biosensor was crafted from PDMS combined with technology of 3D printing and contained reservoir with volume of 50 MUL linked to input (sample/detection components and washing/immunobuffer) and output (waste). For the immunolabeling of immobilized MT anti-MT antibodies conjugated to CdTe quantum dots through synthetic heptapeptide were employed. After optimization of fundamental conditions of the immunolabeling (120 min, 20 degrees C, and 1250 rpm) we performed it on a surface of paramagnetic nanoparticles in the biosensor reservoir, with evaluation of fluorescence of quantum dots (lambdaexc 400 nm, and lambdaem 555 nm). The developed biosensor was applied for quantification of MT in cell lines derived from spinocellular carcinoma (cell line 122P-N) and fibroblasts (122P-F) and levels of the biomarker were found to be about 90 nM in tumor cells and 37 nM in fibroblasts. The proposed system is able to work with low volumes (< 100 MUL), with low acquisition costs and high portability. PMID- 25735232 TI - Shrinkage estimation of the genomic relationship matrix can improve genomic estimated breeding values in the training set. AB - KEY MESSAGE: We evaluated several methods for computing shrinkage estimates of the genomic relationship matrix and demonstrated their potential to enhance the reliability of genomic estimated breeding values of training set individuals. In genomic prediction in plant breeding, the training set constitutes a large fraction of the total number of genotypes assayed and is itself subject to selection. The objective of our study was to investigate whether genomic estimated breeding values (GEBVs) of individuals in the training set can be enhanced by shrinkage estimation of the genomic relationship matrix. We simulated two different population types: a diversity panel of unrelated individuals and a biparental family of doubled haploid lines. For different training set sizes (50, 100, 200), number of markers (50, 100, 200, 500, 2,500) and heritabilities (0.25, 0.5, 0.75), shrinkage coefficients were computed by four different methods. Two of these methods are novel and based on measures of LD, the other two were previously described in the literature, one of which was extended by us. Our results showed that shrinkage estimation of the genomic relationship matrix can significantly improve the reliability of the GEBVs of training set individuals, especially for a low number of markers. We demonstrate that the number of markers is the primary determinant of the optimum shrinkage coefficient maximizing the reliability and we recommend methods eligible for routine usage in practical applications. PMID- 25735233 TI - Recent advances in the fabrication and structure-specific applications of graphene-based inorganic hybrid membranes. AB - The preparation and applications of graphene (G)-based materials are attracting increasing interests due to their unique electronic, optical, magnetic, thermal, and mechanical properties. Compared to G-based hybrid and composite materials, G based inorganic hybrid membrane (GIHM) offers enormous advantages ascribed to their facile synthesis, planar two-dimensional multilayer structure, high specific surface area, and mechanical stability, as well as their unique optical and mechanical properties. In this review, we report the recent advances in the technical fabrication and structure-specific applications of GIHMs with desirable thickness and compositions. In addition, the advantages and disadvantages of the methods utilized for creating GIHMs are discussed in detail. Finally, the potential applications and key challenges of GIHMs for future technical applications are mentioned. PMID- 25735234 TI - A new synthetic route to substituted tetracenes and pentacenes via stereoselective [4+2] cycloadditions of 1,4-dihydro-1,4-epoxynaphthalene and isobenzofuran. AB - Stereoselective [4+2] cycloadditions of 1,4-dihydro-1,4-epoxynaphthalene and isobenzofuran were described. Among several possibilities, syn-exo and/or anti endo isomers were selectively produced depending on the substitution pattern of the reactants. Importantly, the syn-exo isomer underwent acid promoted aromatization, affording the corresponding tetracene. These findings enabled us to prepare a substituted pentacene with electron withdrawing groups. PMID- 25735235 TI - Distinct segment-specific functions of calyculin A-sensitive protein phosphatases in the regulation of cAMP-triggered events in ejaculated bull spermatozoa. AB - Livestock spermatozoa possess more tenacious suppressors of cAMP-triggered events including capacitation-associated changes-than laboratory animal spermatozoa, leading to flagellar hyperactivation. In order to identify the suppressors, we examined effects of an inhibitor of serine/threonine protein phosphatases (calyculin A) on cAMP-triggered changes in the protein phosphorylation state, and subsequent occurrence of hyperactivation and acrosome reaction in ejaculated bull spermatozoa. Ejaculated spermatozoa were incubated in cAMP-supplemented medium, then assessed for motility, acrosome morphology, and phosphorylated protein localization. The addition of calyculin A greatly enhanced cAMP-triggered protein phosphorylation at serine/threonine and tyrosine residues in the connecting piece and induction of flagellar hyperactivation. Most hyperactivated spermatozoa exhibited extremely asymmetrical bends at the middle piece, which produced intensive twisting or figure-eight movements. In the sperm head, however, cAMP triggered dephosphorylation of serine/threonine-phosphorylated proteins and subsequent acrosome reaction were abolished by the addition of calyculin A. Based on these results, we suggest that calyculin A-sensitive protein phosphatases in the connecting piece are suppressors of cAMP-triggered events leading to hyperactivation. By contrast, similar protein phosphatases in the sperm head accelerate cAMP-triggered events leading to the acrosome reaction. These findings are consistent with the indication that calyculin A-sensitive protein phosphatases have distinct functions in the regulation of cAMP-triggered events in different regions of ejaculated bull spermatozoa. PMID- 25735237 TI - X-ray phase contrast tomography by tracking near field speckle. AB - X-ray imaging techniques that capture variations in the x-ray phase can yield higher contrast images with lower x-ray dose than is possible with conventional absorption radiography. However, the extraction of phase information is often more difficult than the extraction of absorption information and requires a more sophisticated experimental arrangement. We here report a method for three dimensional (3D) X-ray phase contrast computed tomography (CT) which gives quantitative volumetric information on the real part of the refractive index. The method is based on the recently developed X-ray speckle tracking technique in which the displacement of near field speckle is tracked using a digital image correlation algorithm. In addition to differential phase contrast projection images, the method allows the dark-field images to be simultaneously extracted. After reconstruction, compared to conventional absorption CT images, the 3D phase CT images show greatly enhanced contrast. This new imaging method has advantages compared to other X-ray imaging methods in simplicity of experimental arrangement, speed of measurement and relative insensitivity to beam movements. These features make the technique an attractive candidate for material imaging such as in-vivo imaging of biological systems containing soft tissue. PMID- 25735236 TI - Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women. AB - The rate of muscle loss with aging is higher in men than women. However, women have smaller muscles throughout the adult life. Protein content is a major determinant of skeletal muscle size. This study was designed to determine if age and sex differentially impact basal muscle protein synthesis and mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling. We performed a secondary data analysis on a cohort of 215 healthy, non-obese (BMI<30kg.m(-2)) young (18-40y; 74 men, 52 women) and older (60-87y; 57 men, 32 women) adults. The database contained information on physical characteristics, basal muscle protein fractional synthetic rate (FSR; n=215; stable isotope methodology) and mTORC1 signaling (n=125, Western blotting). FSR and mTORC1 signaling were measured at rest and after an overnight fast. mTORC1 and S6K1 phosphorylation were higher (p<0.05) in older subjects with no sex differences. However, there were no age or sex differences or interaction for muscle FSR (p>0.05). Body mass index, fat free mass, or body fat was not a significant covariate and did not influence the results. We conclude that age and sex do not influence basal muscle protein synthesis. However, basal mTORC1 hyperphosphorylation in the elderly may contribute to insulin resistance and the age-related anabolic resistance of skeletal muscle protein metabolism to nutrition and exercise. PMID- 25735238 TI - In vitro reconstitution of a PKS pathway for the biosynthesis of galbonolides in Streptomyces sp. LZ35. AB - The galbonolides are 14-membered macrolide antibiotics with a macrocyclic backbone similar to that of erythromycins. Galbonolides exhibit broad-spectrum antifungal activities. Retro-biosynthetic analysis suggests that the backbone of galbonolides is assembled by a type I modular polyketide synthase (PKS). Unexpectedly, the galbonolide biosynthetic gene cluster, gbn, in Streptomyces sp. LZ35 encodes a hybrid fatty acid synthase (FAS)-PKS pathway. In vitro reconstitution revealed the functions of GbnA (an AT-ACP didomain protein), GbnC (a FabH-like enzyme), and GbnB (a novel multidomain PKS module without AT and ACP domains) responsible for assembling the backbone of galbonolides, respectively. To our knowledge, this study is the first biochemical characterization of a hybrid FAS-PKS pathway for the biosynthesis of 14-membered macrolides. The identification of this pathway provides insights into the evolution of PKSs and could facilitate the design of modular pools for synthetic biology. PMID- 25735239 TI - Tuning electronic and magnetic properties of GaN nanosheets by surface modifications and nanosheet thickness. AB - Density-functional theory calculations are performed to investigate the effects of surface modifications and nanosheet thickness on the electronic and magnetic properties of gallium nitride (GaN) nanosheets (NSs). Unlike the bare GaN NSs terminating with polar surfaces, the systems with hydrogenated Ga (H-GaN), fluorinated Ga (F-GaN), and chlorinated Ga (Cl-GaN) preserve their initial wurtzite structures and exhibit ferromagnetic states. The abovementioned three different decorations on Ga atoms are energetically more favorable for thicker GaN NSs. Moreover, as the thickness increases, H-GaN and F-GaN NSs undergo semiconductor to metal and half-metal to metal transition, respectively, while Cl GaN NSs remain completely metallic. The predicted diverse and tunable electronic and magnetic properties highlight the potential of GaN NSs for novel electronic and spintronic nanodevices. PMID- 25735240 TI - Effects of extradural cortical stimulation on motor recovery in a rat model of subacute stroke. AB - PURPOSE: Previous studies demonstrated that administering extradural cortical stimulation (ECS) to rats during the acute phase of a photothrombotic infarct enhances motor recovery. However, the effect of ECS during the subacute phase was unknown. We aimed to evaluate the effects of ECS on motor recovery in a rat model of subacute photothrombotic stroke. METHODS: Photothrombotic ischemic injury to the left sensorimotor cortex (SMC) was induced in 41 male Sprague-Dawley rats using Rose-bengal dye (20 mg/kg) and cold light. The rats were randomly divided into two groups: ECS on infarcted SMC (ECS group) and no ECS on infarcted SMC (non-stimulated group). The ECS group received continuous ECS for 14 days starting from day 5 after the stroke onset. Behavioral training with the single pellet reaching task (SPRT) was performed daily for all of the rats from the fifth day after stroke onset. After 19 days, brain sections were immunostained to allow the quantification of infarct volumes and the evaluation of the neuronal markers. RESULTS: The SPRT scores showed significantly faster and greater improvement in the ECS group than in the non-stimulated group. There were no significant differences in infarct size. However, in the ECS group, significantly more doublecortin-labeled cells were identified close to the penumbra region of the cerebral cortex. CONCLUSIONS: ECS in the subacute phase improved the behavior motor function in the stroke rat model, and induced a significant axonal sprouting in the peri-infarct area. PMID- 25735241 TI - Theta burst stimulation to characterize changes in brain plasticity following mild traumatic brain injury: A proof-of-principle study. AB - PURPOSE: Recent studies investigating the effects of mild traumatic brain injury (mTBI) suggest the presence of unbalanced excitatory and inhibitory mechanisms within primary motor cortex (M1). Whether these abnormalities are associated with impaired synaptic plasticity remains unknown. METHODS: The effects of continuous theta burst stimulation (cTBS) on transcranial magnetic stimulation-induced motor evoked potentials (MEPs) were assessed on average two weeks and six weeks following mTBI in five individuals. RESULTS: The procedure was well-tolerated by all participants. Continuous TBS failed to induce a significant reduction of MEP amplitudes two weeks after the injury, but response to cTBS normalized six weeks following injury, as a majority of patients became asymptomatic. CONCLUSIONS: These preliminary results suggest that cTBS can be used to assess M1 synaptic plasticity in subacute phase following mTBI and may provide insights into neurobiological substrates of symptoms and consequences of mTBI. PMID- 25735242 TI - RNAi KNOCKDOWN OF BmRab3 LED TO LARVA AND PUPA LETHALITY IN SILKWORM Bombyx mori L. AB - Rab3 GTPases are known to play key a role in vesicular trafficking, and express highest in brain and endocrine tissues. In mammals, Rab3 GTPases are paralogs unlike in insect. In this study, we cloned Rab3 from the silk gland tissue of silkworm Bombyx mori, and identified it as BmRab3. Our in silico analysis indicated that BmRab3 is an isoform with a theoretical isoelectric point and molecular weight of 5.52 and 24.3 kDa, respectively. Further, BmRab3 showed the C terminal hypervariability for GGT2 site but having two other putative guanine nucleotide exchange factor/GDP dissociation inhibitor interaction sites. Multiple alignment sequence indicated high similarities of BmRab3 with Rab3 isoforms of other species. The phylogeny tree showed BmRab3 clustered between the species of Tribolium castaneum and Aedes aegypti. Meanwhile, the expression analysis of BmRab3 showed the highest expression in middle silk glands (MSGs) than all other tissues in the third day of fifth-instar larva. Simultaneously, we showed the differential expression of BmRab3 in the early instar larva development, followed by higher expression in male than female pupae. In vivo dsRNA interference of BmRab3 reduced the expression of BmRab3 by 75% compared to the control in the MSGs in the first day. But as the worm grew to the third day, the difference of BmRab3 between knockdown and control was only about 10%. The knockdown later witnessed underdevelopment of the larvae and pharate pupae lethality in the overall development of silkworm B. mori L. PMID- 25735243 TI - Willingness to Take PrEP and Potential for Risk Compensation Among Highly Sexually Active Gay and Bisexual Men. AB - Once-daily Truvada (Emtricitabine/Tenofovir) as a method of pre-exposure prophylaxis (PrEP) is one of the most promising biomedical interventions to eliminate new HIV infections; however, uptake among gay, bisexual, and other men who have sex with men has been slow amidst growing concern in popular/social media that PrEP use will result in reduced condom use (i.e., risk compensation). We investigated demographic, behavioral, and psychosocial differences in willingness to use PrEP as well as the perceived impact of PrEP on participants' condom use in a sample of 206 highly sexually active HIV-negative gay and bisexual men. Nearly half (46.1 %) said they would be willing to take PrEP if it were provided at no cost. Although men willing to take PrEP (vs. others) reported similar numbers of recent casual male partners (<6 weeks), they had higher odds of recent receptive condomless anal sex (CAS)-i.e., those already at high risk of contracting HIV were more willing to take PrEP. Neither age, race/ethnicity, nor income were associated with willingness to take PrEP, suggesting equal acceptability among subpopulations that are experiencing disparities in HIV incidence. There was limited evidence to suggest men would risk compensate. Only 10 % of men who had not engaged in recent CAS felt that PrEP would result in them starting to have CAS. Men who had not tested for HIV recently were also significantly more likely than others to indicate willingness to take PrEP. Offering PrEP to men who test infrequently may serve to engage them more in routine HIV/STI testing and create a continued dialogue around sexual health between patient and provider in order to prevent HIV infection. PMID- 25735244 TI - Introduction of human pharmaceuticals from wastewater treatment plants into the aquatic environment: a rural perspective. AB - Incomplete removal of pharmaceuticals during wastewater treatment can result in their discharge into the aquatic environment. The discharge of pharmaceuticals in wastewater treatment plant (WWTP) effluents into rivers, lakes and the oceans has led to detectable concentrations of pharmaceuticals in the aquatic environment in many countries. However, to date studies of WWTP discharges into the aquatic environment have largely been confined to areas of relatively high population density, industrial activity or systems impacted on by such areas. In this work, two sites in the far north of Scotland were used to assess whether, and which, pharmaceuticals were being introduced into natural waters in a rural environment with low population density. Samples from two WWTPs (with differing modes of operation), and one receiving water, the River Thurso, were analysed for the presence of 12 pharmaceuticals (diclofenac, clofibric acid, erythromycin, ibuprofen, mefenamic acid, paracetamol, propranolol, sulfamethoxazole, tamoxifen, trimethoprim and dextropropoxyphene). Ten of the 12 pharmaceuticals investigated were detected in at least one of the 40 WWTP effluent samples. Maximum concentrations ranged from 7 ng L(-1) (sulfamethoxazole) to 22.8 MUg L(-1) (paracetamol) with diclofenac and mefenamic acid being present in all of samples analysed at concentrations between 24.2 and 927 ng L(-1) and 11.5 and 22.8 MUg L( 1), respectively. Additionally, the presence of four pharmaceuticals at ng L(-1) levels in the River Thurso, into which one of the WWTPs discharges, shows that such discharges result in measurable levels of pharmaceuticals in the environment. This provides direct evidence that, even in rural areas with low population densities, effluents from WWTPs can produce quantifiable levels of human pharmaceutical in the natural aquatic environment. These observations indicate that human pharmaceuticals may be considered as contaminants, with potential to influence water quality, management and conservation not only in urban and industrial regions but also those more rural in nature. PMID- 25735245 TI - Physiological and biochemical response of soil-grown barley (Hordeum vulgare L.) to cerium oxide nanoparticles. AB - A soil microcosm study was performed to examine the impacts of cerium oxide nanoparticles (nCeO2) on the physiology, productivity, and macromolecular composition of barley (Hordeum vulgare L.). The plants were cultivated in soil treated with nCeO2 at 0, 125, 250, and 500 mg kg(-1) (control, nCeO2-L, nCeO2-M, and nCeO2-H, respectively). Accumulation of Ce in leaves/grains and its effects on plant stress and nutrient loading were analyzed. The data revealed that nCeO2 H promoted plant development resulting in 331 % increase in shoot biomass compared with the control. nCeO2 treatment modified the stress levels in leaves without apparent signs of toxicity. However, plants exposed to nCeO2-H treatment did not form grains. Compared with control, nCeO2-M enhanced grain Ce accumulation by as much as 294 % which was accompanied by remarkable increases in P, K, Ca, Mg, S, Fe, Zn, Cu, and Al. Likewise, nCeO2-M enhanced the methionine, aspartic acid, threonine, tyrosine, arginine, and linolenic acid contents in the grains by up to 617, 31, 58, 141, 378, and 2.47 % respectively, compared with the rest of the treatments. The findings illustrate the beneficial and harmful effects of nanoceria in barley. PMID- 25735246 TI - Effects of low-dose cadmium exposure during gestation and lactation on development and reproduction in rats. AB - Cadmium (Cd) is an important toxic chemical due to its increasing levels in the environment and its resulting accumulation in humans and animals. The present study was performed to evaluate the long-term effects of low doses of Cd administered in offspring by oral route to rats during pregnancy and lactation. There were no adverse effects on the physical and sexual development in the pups, except to delay the development of offspring. The relative weights of livers and kidneys in the adult female offspring were significantly decreased after exposure to 10 ppm Cd. These results indicated that there were adverse effects on growth and development from exposure to 5 or 10 ppm Cd in utero and during lactation. The results also showed differential gender sensitivity effects on the organ weights. PMID- 25735247 TI - Harvesting all electrogenerated excitons through metal assisted delayed fluorescent materials. AB - Highly efficient and stable palladium complexes that exhibit both phosphorescence and delayed fluorescence are developed. It is demonstrated that the emission from the two processes can be separately tuned through rational ligand modification. External quantum efficiencies over 20% are achieved and stable devices demonstrate an operational lifetime to 90% initial luminance estimated at over 20 000 h at 100 cd m(-2) . PMID- 25735248 TI - Genetic Contribution of Polymorphisms in Glutathione S-Transferases to Brain Tumor Risk. AB - Existing data have shown a major effect of glutathione S-transferase (GST) single nucleotide polymorphisms on activities of detoxification-related enzymes, and it is the functional importance that leads to extensive research on the association of GST polymorphisms with the risk of developing brain tumor. Previously reported associations, nevertheless, remain inconsistent. This study aimed to reevaluate the association with new information from recent research articles. We weekly searched multiple databases, aiming to cover all studies looking at the associations being examined in this work. Eligibility of studies was evaluated based on predesigned inclusion criteria. To assess the association of GST polymorphisms with brain tumor risk, we calculated genotypic ORs by comparing the number of genotypes between cases and controls. We also detected interstudy heterogeneity, publication bias, and single studies' influence. A total of 13 research articles were identified through databases and hand search. We found significantly elevated risk of brain tumor associated with GSTT1 null status in individuals of European ethnicity (OR 1.46, 95% CI 1.12-1.92). In the analysis of GSTP1 I105V, we observed that Val/Val genotype compared to the Ile/Ile genotype was more prone to a reduced brain tumor risk (OR 0.77, 95% CI 0.64-0.93). Such major effects were similarly seen for GSTP1 A114V (OR 1.14, 95% CI 1.01-1.29 for Val/Val + Ala/Val vs. Ala/Ala). When data were limited to glioma, we found a significant elevation associated with the combination of Val/Val and Ala/Val genotypes (OR 1.18, 95% CI 1.01-1.37). However, no clear association was detected between other polymorphisms investigated and glioma. These statistical data suggest that some of the polymorphisms at GST loci are possibly associated with the genetic risk of brain tumor. PMID- 25735252 TI - Activated STAT3 correlates with prognosis of non-small cell lung cancer and indicates new anticancer strategies. AB - PURPOSE: Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) occurs in many human tumors. Many studies have provided compelling evidence for the critical role of aberrant STAT3 activity in malignant transformation and tumor progression. But few of them provided data on whether activated STAT3 overexpression correlated with patients' prognosis. Here, we define the relationship between phosphorylated STAT3 (pSTAT3) function and prognosis of non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical analyses were carried out on 82 surgically resected NSCLC tissues to evaluate the expression level of pSTAT3. The Kaplan-Meier method was used to calculate the survival rate, and the log-rank test was performed to compare the survival difference. Cox regression analysis was performed to identify prognostic risk factors. All statistic analyses were performed with SPSS11.5 statistical software. Differences were considered significant when the P value was <0.05. RESULTS: In this study, we identified nuclear pSTAT3 expression in 59.76 % of tumors. pSTAT3 expression was correlated with differentiation degree of tumors (P < 0.05), lymph node metastasis status (P < 0.01), clinical stage of tumors (P < 0.01) and the prognosis of NSCLC patients after surgical resection (P < 0.05). CONCLUSIONS: pSTAT3 overexpression is an important factor related to prognosis of NSCLC patients and indicates new anticancer strategies. PMID- 25735253 TI - Effects of anaerobic training on paraoxonase-1 enzyme (PON1) activities of high density lipoprotein subgroups and its relationship with PON1-Q192R phenotype. AB - AIM: Paraoxonase-1 (PON1) is an antiatherosclerotic enzyme located on high density lipoprotein (HDL). The effects of anaerobic exercise on PON1 activity are unknown. Here we investigated the effects of anaerobic judo training on three different activities of same PON1 enzyme (TDPON1), including basal PON1, salt stimulated PON1 (SPON1), and arylesterase (AE) activities, of serum, HDL, and HDL subgroups (HDLs; HDL and its subgroups) and its relationship with PON1-Q192R phenotype (PON1P). METHODS: Our study included 18 Turkish national female judoists (mean age: 17.9 +/- 0.8 years). Before and after 5 months of anaerobic training, critical speed (CS), TDPON1 activities, cholesterol levels in the serum and supernatants of HDLs obtained by polyethylene glycol, and other major blood lipids and lipoproteins (BLLPs) including triglycerides were determined using blood samples taken after overnight fasting. PON1P groups (PGs) were categorized as QQ (QG; persons with low activity) and R carriers (QR + RR) (RG; persons with high activity) according to SPON1/AE activity ratios. The results were considered statistically significant at P <= 0.05. RESULTS: Anaerobic training resulted in significantly increased the cholesterol levels of HDLs (except HDL2-C) in all subjects, but not HDLs-C in PGs. Anaerobic training resulted in significant increases in most TDPON1 activities of serum and HDLs in all subjects and (except AE) in PGs, whereas SPON1 and HDL2 AE activities increased only in the RG, which was related to PON1P. However, PON1P was not related to other measured markers, including basal BLLP profiles. CONCLUSIONS: Anaerobic training improved most TDPON1 activities of serum and HDLs and HDLs -C levels (except HDL2-C) in all subjects, but not HDLs-C in PGs. The beneficial effects of anaerobic training on SPON1 and HDL2 AE activities were depend on PON1P. The lack of response of HDL2-C to anaerobic exercise will require further research. PMID- 25735254 TI - Selective cardiac surveillance in patients with gynecologic cancer undergoing treatment with pegylated liposomal doxorubicin (PLD). AB - OBJECTIVE: The study objective was to examine the safety and cost savings of selective cardiac surveillance (CS) during treatment with pegylated liposomal doxorubicin (PLD). METHODS: A retrospective, dual institution study of women receiving PLD for the treatment of a gynecologic malignancy was performed. The study period was 2002-2014. At both institutions, a selective strategy for CS was implemented in which only high-risk women with a cardiac history or with symptoms suggestive of cardiac toxicity during PLD treatment underwent a cardiac evaluation. Patient demographics, clinical and treatment history were evaluated. Cost analyses were performed utilizing professional/technical fee rates for echocardiogram and multi-gated acquisition scan for each state. RESULTS: PLD was administered in 184 women. The mean patient age was 62.7years, and 79% were treated for recurrent ovarian or peritoneal carcinoma. The median cumulative administered dose of PLD was 300mg/m(2); 24 received >550mg/m(2). The median follow-up time was 20months. Of the 184 patients, the majority (n=157, 85.3%) did not undergo either an initial cardiac evaluation or surveillance during or post PLD treatment. Fifty-three patients considered high risk for anthracycline induced cardiotoxicity underwent CS. Only three patients (1.6%) in the entire cohort developed CHF that was possibly related to PLD treatment; all had significant pre-existing cardiac risk factors. Selective instead of routine use of CS in the study population resulted in a cost savings of $182,552.28. CONCLUSION: Utilizing cardiac surveillance in select women undergoing PLD treatment for gynecologic malignancies resulted in significant health care cost savings without adversely impacting clinical outcomes. PMID- 25735255 TI - PRSS3 expression is associated with tumor progression and poor prognosis in epithelial ovarian cancer. AB - OBJECTIVE: PRSS3 is an atypical isoform of trypsin that has been associated with breast, lung, and pancreatic cancers. This study aimed to elucidate the role of PRSS3 in tumor tissues of patients with epithelial ovarian cancer (EOC) and to investigate the prognostic value of this marker. METHODS: PRSS3 expression was evaluated by immunohistochemistry and real-time PCR (RT-PCR) in ovarian cancers, benign ovarian tumors and the ovaries of age-matched normal patients. Correlations between clinicopathologic variables and PRSS3 expression in EOC tissues and the prognostic value of PRSS3 for progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: PRSS3 expression was significantly elevated in EOC tissues compared to benign ovarian tumors and normal ovarian controls at both the mRNA and protein levels. There was a good correlation between the PRSS3 expression levels measured by the two different techniques. High PRSS3 expression in EOC tissues was significantly associated with advanced FIGO stage and lymph node metastasis. In a univariate survival analysis of the ovarian carcinoma cohort, positive expression of PRSS3 was significantly associated with shortened patient survival. Importantly, PRSS3 expression was a significant independent prognostic parameter in the multivariate analysis. CONCLUSIONS: These findings indicate that PRSS3 overexpression can be used as a predictor of clinical outcome in patients with ovarian cancer and may therefore represent a new prognostic marker. PMID- 25735256 TI - Improving quality and decreasing cost in gynecologic oncology care. Society of gynecologic oncology recommendations for clinical practice. AB - OBJECTIVE: To identify potential cost savings in gynecologic oncology care without sacrificing quality. METHODS: Members of the Clinical Practice Committee of the Society of Gynecologic Oncology were asked to review current practice patterns in gynecologic oncology and assess the potential for cost savings founded on evidence-based medicine and current guidelines. RESULTS: Five clinical practices were identified including the following: vaginal cytology for endometrial cancer survivors; colposcopy for low grade cytologic abnormalities for cervical cancer survivors; routine imaging studies for gynecologic cancer survivors; screening for ovarian cancer with serum biomarkers and ultrasound; and improving palliative care for gynecologic cancer patients. Review of the published literature and guidelines were performed to make evidence-based recommendations for cost effective quality gynecologic oncology care. RECOMMENDATIONS: * Do not perform Pap tests of the vaginal cuff in patients with a history of endometrial cancer. * Do not perform colposcopy for low grade Pap tests in women with a history of cervical cancer. * Avoid routine imaging for cancer surveillance in asymptomatic women with gynecologic cancer, specifically ovarian, endometrial, cervical, vulvar and vaginal cancer. * Do not screen women at low risk for ovarian cancer with ultrasound or CA-125 or other biomarkers. * Do not delay basic level palliative care for women with advanced or relapsed gynecologic cancer, do refer to a palliative care specialist when needed, and avoid unnecessary treatments at life's end. PMID- 25735257 TI - The anatomical record and whales: we're peas in the same pod. PMID- 25735258 TI - Formation of a fluorous/organic biphasic supramolecular octopus assembly for enhanced porphyrin phosphorescence in air. AB - The trinuclear triangle-shaped system [tris{3,5-bis(heptafluoropropyl)-1,2,4 triazolatosilver(I)}] (1) and the multi-armed square-shaped metalloporphyrin PtOEP or the free porphyrin base H2OEP serve as excellent octopus hosts (OEP=2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphine). Coupling of the fluorous/organic molecular octopi 1 and H2OEP or PtOEP by strong quadrupole quadrupole and metal-pi interactions affords the supramolecular assemblies [1?PtOEP] or [1?H2OEP] (2 a), which feature nanoscopic cavities surrounding the upper triangular and lower square cores. The fluorous/organic biphasic configuration of [1?PtOEP] leads to an increase in the phosphorescence of PtOEP under ambient conditions. Guest molecules can be included in the biphasic double octopus assembly in three different site-selective modes. PMID- 25735259 TI - Women's attitudes towards a pre-conception healthy lifestyle programme. AB - Nearly half of US women begin pregnancy overweight or obese and more than half of overweight or obese pregnant women experience excessive gestational weight gain. Recent lifestyle intervention programmes have helped women avoid excessive weight gain during pregnancy, but helping women lose weight before pregnancy may be a more effective way to improve pregnancy outcomes. This study assessed women's attitudes towards pre-conception diet and weight management interventions. An anonymous survey was conducted in patients waiting in a health maintenance organization's obstetrics and primary care waiting rooms. It focused on attitudes towards participating in a pre-conception, lifestyle change programme. Eighty percent of the 126 women surveyed were pregnant or considering pregnancy within 5 years. Of the 126 respondents, 60 (48%) were overweight or obese. Of these, 96% rated healthy diet and healthy weight before pregnancy as very important or important and 77% favoured a healthy lifestyle programme (diet, weight management and physical activity) before becoming pregnant. Likewise, overweight or obese women reported being likely or highly likely to participate in specific intervention programme aspects such as keeping phone appointments (77%), using a programme website (70%) and keeping food and exercise records (63%). Survey results show that women in this population believe that adopting a healthy lifestyle and losing weight are important before pregnancy and that they are enthusiastic about programmes that will help them achieve those goals in preparation for pregnancy. PMID- 25735261 TI - Novel de novo mutations in EFTUD2 detected by exome sequencing in mandibulofacial dysostosis with Microcephaly syndrome. PMID- 25735260 TI - Outcome-based anatomic criteria for defining the hostile aortic neck. AB - OBJECTIVE: There is abundant evidence linking hostile proximal aortic neck anatomy to poor outcome after endovascular aortic aneurysm repair (EVAR), yet the definition of hostile anatomy varies from study to study. This current analysis was undertaken to identify anatomic criteria that are most predictive of success or failure at the aortic neck after EVAR. METHODS: The study group comprised 221 patients in the Aneurysm Treatment using the Heli-FX Aortic Securement System Global Registry (ANCHOR) clinical trial, a population enriched with patients with challenging aortic neck anatomy and failure of sealing. Imaging protocols were not protocol specified but were performed according to the institution's standard of care. Core laboratory analysis assessed the three-dimensional centerline reformatted computed tomography scans. Failure at the aortic neck was defined by type Ia endoleak occurring at the time of the initial endograft implantation or during follow-up. Receiver operating characteristic curve analysis was used to assess the value of each anatomic measure in the classification of aortic neck success and failure and to identify optimal thresholds of discrimination. Binary logistic regression was performed after excluding highly intercorrelated variables, creating a final model with significant predictors of outcome after EVAR. RESULTS: Among the 221 patients, 121 (54.8%) remained free of type Ia endoleak and 100 (45.2%) did not. Type Ia endoleaks presented immediately after endograft deployment in 58 (58.0%) or during follow-up in 42 (42.0%). Receiver operating characteristic curve analysis identified 12 variables where the classification of patients with type Ia endoleak was significantly more accurate than chance alone. Increased aortic neck diameter at the lowest renal artery (P = .013) and at 5 mm (P = .008), 10 mm (P = .008), and 15 mm (P = .010) distally; aneurysm sac diameter (P = .001), common iliac artery diameters (right, P = .012; left, P = .032), and a conical (P = .049) neck configuration were predictive of endoleak. By contrast, increased aortic neck length (P = .050), a funnel-shaped aortic neck (P = .036), and neck mural thrombus content, as measured by average thickness (P = .044) or degrees of circumferential coverage (P = .029), were protective against endoleak. Binary logistic regression identified three variables independently predictive of type Ia endoleak. Neck diameter at the lowest renal artery (P = .002, cutpoint 26 mm) and neck length (P = .017, cutpoint 17 mm) were associated with endoleak, whereas some mural neck thrombus content was protective (P = .001, cutpoint 11 degrees of circumferential coverage). CONCLUSIONS: A limited number of independent anatomic variables are predictive of type Ia endoleak after EVAR, including aortic neck diameter and aortic neck length, whereas mural thrombus in the neck is protective. This study suggests that anatomic measures with identifiable threshold cutpoints should be considered when defining the hostile aortic neck and assessing the risk of complications after EVAR. PMID- 25735262 TI - Cognitive predictors of understanding treatment decisions in patients with newly diagnosed brain metastasis. AB - BACKGROUND: Medical decision-making capacity is a higher-order functional skill that refers to a patient's ability to make informed, sound decisions related to care and treatment. In a medical context, understanding is the most cognitively demanding consent standard and refers to a patient's ability to comprehend information to the extent that informed decisions can be made. METHODS: The association between reasoning and cognition was examined using data from 41 patients with diagnosed brain metastasis. All diagnoses were made by a board certified radiation oncologist and were verified histologically. In total, 41 demographically matched, cognitively healthy controls were also included to aid in classifying patients with brain metastasis according to reasoning status (ie, intact or impaired). RESULTS: Results indicate that measures of simple attention, verbal fluency, verbal memory, processing speed, and executive functioning were all associated with understanding, and that verbal memory and phonemic fluency were the primary cognitive predictors. Using these two primary predictors, equations can be constructed to predict the ability to understand treatment decisions in patients with brain metastasis. CONCLUSIONS: Although preliminary, these data demonstrate how cognitive measures can estimate understanding as it relates to medical decision-making capacities in these patients. Clinically, these findings suggest that poor verbal memory and expressive language function could serve as "red flags" for reduced consent capacity in this patient population, thus signaling that a more comprehensive medical decision-making capacity evaluation is warranted. PMID- 25735263 TI - Monitoring minute ventilation versus respiratory rate to measure the adequacy of ventilation in patients undergoing upper endoscopic procedures. AB - Endoscopic procedures performed under conscious sedation require careful monitoring of respiratory status to prevent adverse outcomes. This study utilizes a non-invasive respiratory volume monitor (RVM) that provides continuous real time measurements of minute ventilation (MV), tidal volume and respiratory rate (RR) to assess the adequacy of ventilation during endoscopy. Digital respiratory traces were collected from 51 patients undergoing upper endoscopy with propofol sedation using an impedance-based RVM. Baseline MV for each patient was derived from a 30 s period of quiet breathing prior to sedation (MVBASELINE). Capnography data were also collected. Because RR from capnography was frequently unavailable, the RVM RR's were used for analysis. RR rate values were compared the MV measurements and sensitivity and specificity of RR to predict inadequate ventilation (MV <40 % MVBASELINE) were calculated. Initial analysis revealed that there is a weak correlation between an MV measurement and its corresponding RR measurement (r = 0.05). If MV is an actual indictor of respiratory performance, using RR as a proxy is grossly inadequate. Simulating a variety of RR alarm conditions [4-8 breaths/min (bpm)] showed that a substantial fraction of low MV measurements (MV <40 % MVBASELINE) went undetected (at 8 bpm, >70 % low MV measurements were missed; at 6 bpm, >82 % were missed; and at 4 bpm, >90 % were missed). A cut-off of 6 bpm had a sensitivity of only 18.2 %; while <40 % of all RR alarms would have coincided with a low MV (39.4 % PPV). Low RR measurements alone do not reflect episodes of low MV and are not sufficient for accurate assessment of respiratory status. RVM provides a new way to collect MV measurements which provide more comprehensive data than RR alone. Further work is ongoing to evaluate the use of MV data during procedural sedation. PMID- 25735264 TI - Journal of clinical monitoring and computing 2014 end of year summary: respiration. PMID- 25735265 TI - Intrayear household income dynamics and adolescent school behavior. AB - Economic life for most American households is quite dynamic. Such income instability is an understudied aspect of households' economic contexts that may have distinct consequences for children. We examine the empirical relationship between household income instability, as measured by intrayear income change, and adolescent school behavior outcomes using a nationally representative sample of households with adolescents from the Survey of Income and Program Participation 2004 panel. We find an unfavorable relationship between income instability and adolescent school behaviors after controlling for income level and a large set of child and family characteristics. Income instability is associated with a lower likelihood of adolescents being highly engaged in school across the income spectrum and predicts adolescent expulsions and suspensions, particularly among low-income, older, and racial minority adolescents. PMID- 25735266 TI - Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part II: Importance of physicochemical properties and dose in animal and in vitro studies as a basis for risk assessment. AB - The objective of the Part II analysis was to evaluate animal and in vitro toxicology studies of CoCr particles with respect to their physicochemistry and dose relevance to metal-on-metal (MoM) implant patients as derived from Part I. In the various toxicology studies, physicochemical characteristics were infrequently considered and administered doses were orders of magnitude higher than what occurs in patients. Co was consistently shown to rapidly release from CoCr particles for distribution and elimination from the body. CoCr micron sized particles appear more biopersistent in vivo resulting in inflammatory responses that are not seen with similar mass concentrations of nanoparticles. We conclude, that in an attempt to obtain data for a complete risk assessment, future studies need to focus on physicochemical characteristics of nano and micron sized particles and on doses and dose metrics relevant to those generated in patients or in properly conducted hip simulator studies. PMID- 25735267 TI - Guanidine-based polymer brushes grafted onto silica nanoparticles as efficient artificial phosphodiesterases. AB - Polymer brushes grafted to the surface of silica nanoparticles were fabricated by atom-transfer radical polymerization (ATRP) and investigated as catalysts in the cleavage of phosphodiesters. The surfaces of silica nanoparticles were functionalized with an ATRP initiator. Surface-initiated ATRP reactions, in varying proportions, of a methacrylate moiety functionalized with a phenylguanidine moiety and an inert hydrophilic methacrylate species afforded hybrid nanoparticles that were characterized with potentiometric titrations, thermogravimetric analysis, and SEM. The activity of the hybrid nanoparticles was tested in the transesterification of the RNA model compound 2-hydroxypropyl para nitrophenylphosphate (HPNP) and diribonucleoside monophosphates. A high catalytic efficiency and a remarkable effective molarity, thus overcoming the effective molarities previously observed for comparable systems, indicate the existence of an effective cooperation of the guanidine/guanidinium units and a high level of preorganization in the nanostructure. The investigated system also exhibits a marked and unprecedented selectivity for the diribonucleoside sequence CpA. The results presented open up the way for a novel and straightforward strategy for the preparation of supramolecular catalysts. PMID- 25735268 TI - Reply. PMID- 25735269 TI - Point/counterpoint. Radiotherapy is an appropriate treatment to consider for patients infected with the Ebola virus. PMID- 25735270 TI - Multiattribute probabilistic prostate elastic registration (MAPPER): application to fusion of ultrasound and magnetic resonance imaging. AB - PURPOSE: Transrectal ultrasound (TRUS)-guided needle biopsy is the current gold standard for prostate cancer diagnosis. However, up to 40% of prostate cancer lesions appears isoechoic on TRUS. Hence, TRUS-guided biopsy has a high false negative rate for prostate cancer diagnosis. Magnetic resonance imaging (MRI) is better able to distinguish prostate cancer from benign tissue. However, MRI guided biopsy requires special equipment and training and a longer procedure time. MRI-TRUS fusion, where MRI is acquired preoperatively and then aligned to TRUS, allows for advantages of both modalities to be leveraged during biopsy. MRI TRUS-guided biopsy increases the yield of cancer positive biopsies. In this work, the authors present multiattribute probabilistic postate elastic registration (MAPPER) to align prostate MRI and TRUS imagery. METHODS: MAPPER involves (1) segmenting the prostate on MRI, (2) calculating a multiattribute probabilistic map of prostate location on TRUS, and (3) maximizing overlap between the prostate segmentation on MRI and the multiattribute probabilistic map on TRUS, thereby driving registration of MRI onto TRUS. MAPPER represents a significant advancement over the current state-of-the-art as it requires no user interaction during the biopsy procedure by leveraging texture and spatial information to determine the prostate location on TRUS. Although MAPPER requires manual interaction to segment the prostate on MRI, this step is performed prior to biopsy and will not substantially increase biopsy procedure time. RESULTS: MAPPER was evaluated on 13 patient studies from two independent datasets-Dataset 1 has 6 studies acquired with a side-firing TRUS probe and a 1.5 T pelvic phased-array coil MRI; Dataset 2 has 7 studies acquired with a volumetric end-firing TRUS probe and a 3.0 T endorectal coil MRI. MAPPER has a root-mean-square error (RMSE) for expert selected fiducials of 3.36 +/- 1.10 mm for Dataset 1 and 3.14 +/- 0.75 mm for Dataset 2. State-of-the-art MRI-TRUS fusion methods report RMSE of 3.06 2.07 mm. CONCLUSIONS: MAPPER aligns MRI and TRUS imagery without manual intervention ensuring efficient, reproducible registration. MAPPER has a similar RMSE to state-of-the-art methods that require manual intervention. PMID- 25735271 TI - Objective function to obtain multiple representative waveforms for a novel helical CT scan protocol. AB - PURPOSE: To develop objective functions for selecting multiple representative respiratory waveforms. A specific application considered is to reduce the number of swiping scans in a novel helical CT scan protocol to harvest efficiency and dose reduction benefit. METHODS: The authors consider a general class of potential objective functions consisting of weighted norms on pointwise profile differentials. The authors utilize the Lagrangian approach and derive proper conditions on the formulation based on first and second order optimality conditions. The derived objective functions are applied to clinically acquired respiratory trajectories for swipe subset selection to verify the validity and generality of the proposed rationale. An end-to-end 4DCT reconstruction comparison is performed using a swipe subset of data corresponding to 3 out of the full 25 waveforms to assess the consequence in image quality and dose. RESULTS: Their results show that maximizing the proposed objective function with the suggested parameters yields maximal spread of trajectories among the selected subset. 4DCT Reconstruction using the chosen subset of data indicates the potential for further dose reduction by about 5 to 10 folds without significant sacrifice in image quality. Experimental results also support further generalization to include slice prioritization. CONCLUSIONS: The authors have derived a formulation that is both simple and general as a metric to quantify the spread of a set of respiratory trajectories, which can be used for subset selection with potential computation and dose reduction benefit when applied to a newly developed helical 4DCT scan protocol. PMID- 25735272 TI - Clinical evaluation of the iterative metal artifact reduction algorithm for CT simulation in radiotherapy. AB - PURPOSE: To clinically evaluate an iterative metal artifact reduction (IMAR) algorithm prototype in the radiation oncology clinic setting by testing for accuracy in CT number retrieval, relative dosimetric changes in regions affected by artifacts, and improvements in anatomical and shape conspicuity of corrected images. METHODS: A phantom with known material inserts was scanned in the presence/absence of metal with different configurations of placement and sizes. The relative change in CT numbers from the reference data (CT with no metal) was analyzed. The CT studies were also used for dosimetric tests where dose distributions from both photon and proton beams were calculated. Dose differences and gamma analysis were calculated to quantify the relative changes between doses calculated on the different CT studies. Data from eight patients (all different treatment sites) were also used to quantify the differences between dose distributions before and after correction with IMAR, with no reference standard. A ranking experiment was also conducted to analyze the relative confidence of physicians delineating anatomy in the near vicinity of the metal implants. RESULTS: IMAR corrected images proved to accurately retrieve CT numbers in the phantom study, independent of metal insert configuration, size of the metal, and acquisition energy. For plastic water, the mean difference between corrected images and reference images was -1.3 HU across all scenarios (N = 37) with a 90% confidence interval of [-2.4, -0.2] HU. While deviations were relatively higher in images with more metal content, IMAR was able to effectively correct the CT numbers independent of the quantity of metal. Residual errors in the CT numbers as well as some induced by the correction algorithm were found in the IMAR corrected images. However, the dose distributions calculated on IMAR corrected images were closer to the reference data in phantom studies. Relative spatial difference in the dose distributions in the regions affected by the metal artifacts was also observed in patient data. However, in absence of a reference ground truth (CT set without metal inserts), these differences should not be interpreted as improvement/deterioration of the accuracy of calculated dose. With limited data presented, it was observed that proton dosimetry was affected more than photons as expected. Physicians were significantly more confident contouring anatomy in the regions affected by artifacts. While site specific preferences were detected, all indicated that they would consistently use IMAR corrected images. CONCLUSIONS: IMAR correction algorithm could be readily implemented in an existing clinical workflow upon commercial release. While residual errors still exist in IMAR corrected images, these images present with better overall conspicuity of the patient/phantom geometry and offer more accurate CT numbers for improved local dosimetry. The variety of different scenarios included herein attest to the utility of the evaluated IMAR for a wide range of radiotherapy clinical scenarios. PMID- 25735273 TI - Measurements of isocenter path characteristics of the gantry rotation axis with a smartphone application. AB - PURPOSE: For stereotactic radiosurgery, the AAPM Report No. 54 [AAPM Task Group 42 (AAPM, 1995)] requires the overall stability of the isocenter (couch, gantry, and collimator) to be within a 1 mm radius. In reality, a rotating system has no rigid axis and thus no isocenter point which is fixed in space. As a consequence, the isocenter concept is reviewed here. It is the aim to develop a measurement method following the revised definitions. METHODS: The mechanical isocenter is defined here by the point which rotates on the shortest path in the room coordinate system. The path is labeled as "isocenter path." Its center of gravity is assumed to be the mechanical isocenter. Following this definition, an image based and radiation-free measurement method was developed. Multiple marker pairs in a plane perpendicular to the assumed gantry rotation axis of a linear accelerator are imaged with a smartphone application from several rotation angles. Each marker pair represents an independent measuring system. The room coordinates of the isocenter path and the mechanical isocenter are calculated based on the marker coordinates. The presented measurement method is by this means strictly focused on the mechanical isocenter. RESULTS: The measurement result is available virtually immediately following completion of measurement. When 12 independent measurement systems are evaluated, the standard deviations of the isocenter path points and mechanical isocenter coordinates are 0.02 and 0.002 mm, respectively. CONCLUSIONS: The measurement is highly accurate, time efficient, and simple to adapt. It is therefore suitable for regular checks of the mechanical isocenter characteristics of the gantry and collimator rotation axis. When the isocenter path is reproducible and its extent is in the range of the needed geometrical accuracy, it should be taken into account in the planning process. This is especially true for stereotactic treatments and radiosurgery. PMID- 25735274 TI - Verification and compensation of respiratory motion using an ultrasound imaging system. AB - PURPOSE: The purpose of this study was to determine if it is feasible to use ultrasound imaging as an aid for moving the treatment couch during diagnosis and treatment procedures associated with radiation therapy, in order to offset organ displacement caused by respiratory motion. A noninvasive ultrasound system was used to replace the C-arm device during diagnosis and treatment with the aims of reducing the x-ray radiation dose on the human body while simultaneously being able to monitor organ displacements. METHODS: This study used a proposed respiratory compensating system combined with an ultrasound imaging system to monitor the compensation effect of respiratory motion. The accuracy of the compensation effect was verified by fluoroscopy, which means that fluoroscopy could be replaced so as to reduce unnecessary radiation dose on patients. A respiratory simulation system was used to simulate the respiratory motion of the human abdomen and a strain gauge (respiratory signal acquisition device) was used to capture the simulated respiratory signals. The target displacements could be detected by an ultrasound probe and used as a reference for adjusting the gain value of the respiratory signal used by the respiratory compensating system. This ensured that the amplitude of the respiratory compensation signal was a faithful representation of the target displacement. RESULTS: The results show that performing respiratory compensation with the assistance of the ultrasound images reduced the compensation error of the respiratory compensating system to 0.81 2.92 mm, both for sine-wave input signals with amplitudes of 5, 10, and 15 mm, and human respiratory signals; this represented compensation of the respiratory motion by up to 92.48%. In addition, the respiratory signals of 10 patients were captured in clinical trials, while their diaphragm displacements were observed simultaneously using ultrasound. Using the respiratory compensating system to offset, the diaphragm displacement resulted in compensation rates of 60%-84.4%. CONCLUSIONS: This study has shown that a respiratory compensating system combined with noninvasive ultrasound can provide real-time compensation of the respiratory motion of patients. PMID- 25735275 TI - Image quality dependency on system configuration and tube voltage in chest tomosynthesis-a visual grading study using an anthropomorphic chest phantom. AB - PURPOSE: To investigate the potential benefit of increasing the dose per projection image in chest tomosynthesis, performed at the current standard dose level, by reducing the angular range covered or the projection image density and to evaluate the influence of the tube voltage on the image quality. METHODS: An anthropomorphic chest phantom was imaged using nine different projection image configurations and ten different tube voltages with the GE VolumeRAD tomosynthesis system. The resulting image sets were representative of being acquired at the same total effective dose. This was achieved partly by applying a simulated dose reduction to the projection images due to restrictions concerning the tube load settings on the VolumeRAD system. Four observers were included in a visual grading study where the reconstructed tomosynthesis section images were rated according to a set of image quality criteria. Image quality was evaluated relative to the default configuration and default tube voltage on the VolumeRAD system. RESULTS: Overall, the image quality decreased with decreasing projection image density. Regarding angular range covered by the projection images, the image quality increased with decreasing angular range for two of the criteria, whereas for a criterion related to the depth resolution in the section images the reduced angular ranges resulted in inferior image quality as compared to the default configuration. The image quality showed little dependence on the tube voltage. CONCLUSIONS: At the standard dose level of the VolumeRAD system, the potential benefits from increasing the dose per projection do not fully compensate for the negative effects resulting from a reduction in the number of projection images. Consequently, the default configuration consisting of 60 projection images acquired over 30 degrees is a good alternative. The tube voltage used in tomosynthesis does not have a large impact on the image quality. PMID- 25735276 TI - Computer aided detection of surgical retained foreign object for prevention. AB - PURPOSE: Surgical retained foreign objects (RFOs) have significant morbidity and mortality. They are associated with approximately $1.5 * 10(9) annually in preventable medical costs. The detection accuracy of radiographs for RFOs is a mediocre 59%. The authors address the RFO problem with two complementary technologies: a three-dimensional (3D) gossypiboma micro tag, the MUTag that improves the visibility of RFOs on radiographs, and a computer aided detection (CAD) system that detects the MUTag. It is desirable for the CAD system to operate in a high specificity mode in the operating room (OR) and function as a first reader for the surgeon. This allows for fast point of care results and seamless workflow integration. The CAD system can also operate in a high sensitivity mode as a second reader for the radiologist to ensure the highest possible detection accuracy. METHODS: The 3D geometry of the MUTag produces a similar two dimensional (2D) depiction on radiographs regardless of its orientation in the human body and ensures accurate detection by a radiologist and the CAD. The authors created a data set of 1800 cadaver images with the 3D MUTag and other common man-made surgical objects positioned randomly. A total of 1061 cadaver images contained a single MUTag and the remaining 739 were without MUTag. A radiologist marked the location of the MUTag using an in-house developed graphical user interface. The data set was partitioned into three independent subsets: a training set, a validation set, and a test set, consisting of 540, 560, and 700 images, respectively. A CAD system with modules that included preprocessing MUTag enhancement, labeling, segmentation, feature analysis, classification, and detection was developed. The CAD system was developed using the training and the validation sets. RESULTS: On the training set, the CAD achieved 81.5% sensitivity with 0.014 false positives (FPs) per image in a high specificity mode for the surgeons in the OR and 96.1% sensitivity with 0.81 FPs per image in a high sensitivity mode for the radiologists. On the independent test set, the CAD achieved 79.5% sensitivity with 0.003 FPs per image in a high specificity mode for the surgeons and 90.2% sensitivity with 0.23 FPs per image in a high sensitivity mode for the radiologists. CONCLUSIONS: To the best of the authors' knowledge, this is the first time a 3D MUTag is used to produce a recognizable, substantially similar 2D projection on radiographs regardless of orientation in space. It is the first time a CAD system is used to search for man made objects over anatomic background. The CAD system for the MUTags achieved reasonable performance in both the high specificity and the high sensitivity modes. PMID- 25735277 TI - Development of solid-state avalanche amorphous selenium for medical imaging. AB - PURPOSE: Active matrix flat panel imagers (AMFPI) have limited performance in low dose applications due to the electronic noise of the thin film transistor (TFT) array. A uniform layer of avalanche amorphous selenium (a-Se) called high gain avalanche rushing photoconductor (HARP) allows for signal amplification prior to readout from the TFT array, largely eliminating the effects of the electronic noise. The authors report preliminary avalanche gain measurements from the first HARP structure developed for direct deposition onto a TFT array. METHODS: The HARP structure is fabricated on a glass substrate in the form of p-i-n, i.e., the electron blocking layer (p) followed by an intrinsic (i) a-Se layer and finally the hole blocking layer (n). All deposition procedures are scalable to large area detectors. Integrated charge is measured from pulsed optical excitation incident on the top electrode (as would in an indirect AMFPI) under continuous high voltage bias. Avalanche gain measurements were obtained from samples fabricated simultaneously at different locations in the evaporator to evaluate performance uniformity across large area. RESULTS: An avalanche gain of up to 80 was obtained, which showed field dependence consistent with previous measurements from n-i-p HARP structures established for vacuum tubes. Measurements from multiple samples demonstrate the spatial uniformity of performance using large area deposition methods. Finally, the results were highly reproducible during the time course of the entire study. CONCLUSIONS: We present promising avalanche gain measurement results from a novel HARP structure that can be deposited onto a TFT array. This is a crucial step toward the practical feasibility of AMFPI with avalanche gain, enabling quantum noise limited performance down to a single x-ray photon per pixel. PMID- 25735278 TI - Fast, automatic, and accurate catheter reconstruction in HDR brachytherapy using an electromagnetic 3D tracking system. AB - PURPOSE: In high dose rate brachytherapy (HDR-B), current catheter reconstruction protocols are relatively slow and error prone. The purpose of this technical note is to evaluate the accuracy and the robustness of an electromagnetic (EM) tracking system for automated and real-time catheter reconstruction. METHODS: For this preclinical study, a total of ten catheters were inserted in gelatin phantoms with different trajectories. Catheters were reconstructed using a 18G biopsy needle, used as an EM stylet and equipped with a miniaturized sensor, and the second generation Aurora((r)) Planar Field Generator from Northern Digital Inc. The Aurora EM system provides position and orientation value with precisions of 0.7 mm and 0.2 degrees , respectively. Phantoms were also scanned using a MUCT (GE Healthcare) and Philips Big Bore clinical computed tomography (CT) system with a spatial resolution of 89 MUm and 2 mm, respectively. Reconstructions using the EM stylet were compared to MUCT and CT. To assess the robustness of the EM reconstruction, five catheters were reconstructed twice and compared. RESULTS: Reconstruction time for one catheter was 10 s, leading to a total reconstruction time inferior to 3 min for a typical 17-catheter implant. When compared to the MUCT, the mean EM tip identification error was 0.69 +/- 0.29 mm while the CT error was 1.08 +/- 0.67 mm. The mean 3D distance error was found to be 0.66 +/- 0.33 mm and 1.08 +/- 0.72 mm for the EM and CT, respectively. EM 3D catheter trajectories were found to be more accurate. A maximum difference of less than 0.6 mm was found between successive EM reconstructions. CONCLUSIONS: The EM reconstruction was found to be more accurate and precise than the conventional methods used for catheter reconstruction in HDR-B. This approach can be applied to any type of catheters and applicators. PMID- 25735279 TI - Patient position alters attenuation effects in multipinhole cardiac SPECT. AB - PURPOSE: Dedicated cardiac cameras offer improved sensitivity over conventional SPECT cameras. Sensitivity gains are obtained by large numbers of detectors and novel collimator arrangements such as an array of multiple pinholes that focus on the heart. Pinholes lead to variable amounts of attenuation as a source is moved within the camera field of view. This study evaluated the effects of this variable attenuation on myocardial SPECT images. METHODS: Computer simulations were performed for a set of nine point sources distributed in the left ventricular wall (LV). Sources were placed at the location of the heart in both an anthropomorphic and a water-cylinder computer phantom. Sources were translated in x, y, and z by up to 5 cm from the center. Projections were simulated with and without attenuation and the changes in attenuation were compared. A LV with an inferior wall defect was also simulated in both phantoms over the same range of positions. Real camera data were acquired on a Discovery NM530c camera (GE Healthcare, Haifa, Israel) for five min in list-mode using an anthropomorphic phantom (DataSpectrum, Durham, NC) with 100 MBq of Tc-99m in the LV. Images were taken over the same range of positions as the simulations and were compared based on the summed perfusion score (SPS), defect width, and apparent defect uptake for each position. RESULTS: Point sources in the water phantom showed absolute changes in attenuation of <=8% over the range of positions and relative changes of <=5% compared to the apex. In the anthropomorphic computer simulations, absolute change increased to 20%. The changes in relative attenuation caused a change in SPS of <1.5 for the water phantom but up to 4.2 in the anthropomorphic phantom. Changes were larger for axial than for transverse translations. These results were supported by SPS changes of up to six seen in the physical anthropomorphic phantom for axial translations. Defect width was also seen to significantly increase. The position-dependent changes were removed with attenuation correction. CONCLUSIONS: Translation of a source relative to a multipinhole camera caused only small changes in homogeneous phantoms with SPS changing <1.5. Inhomogeneous attenuating media cause much larger changes to occur when the source is translated. Changes in SPS of up to six were seen in an anthropomorphic phantom for axial translations. Attenuation correction removes the position-dependent changes in attenuation. PMID- 25735280 TI - Pulmonary nodule detection in CT images based on shape constraint CV model. AB - PURPOSE: Accurate detection of pulmonary nodules remains a technical challenge in computer-aided diagnosis systems because some nodules may adhere to the blood vessels or the lung wall, which have low contrast compared to the surrounding tissues. In this paper, the analysis of typical shape features of candidate nodules based on a shape constraint Chan-Vese (CV) model combined with calculation of the number of blood branches adhered to nodule candidates is proposed to reduce false positive (FP) nodules from candidate nodules. METHODS: The proposed scheme consists of three major stages: (1) Segmentation of lung parenchyma from computed tomography images. (2) Extraction of candidate nodules. (3) Reduction of FP nodules. A gray level enhancement combined with a spherical shape enhancement filter is introduced to extract the candidate nodules and their sphere-like contour regions. FPs are removed by analysis of the typical shape features of nodule candidates based on the CV model using spherical constraint and by investigating the number of blood branches adhered to the candidate nodules. The constrained shapes of CV model are automatically achieved from the extracted candidate nodules. RESULTS: The detection performance was evaluated on 127 nodules of 103 cases including three types of challenging nodules, which are juxta-pleural nodules, juxta-vascular nodules, and ground glass opacity nodules. The free-receiver operating characteristic (FROC) curve shows that the proposed method is able to detect 88% of all the nodules in the data set with 4 FPs per case. CONCLUSIONS: Evaluation shows that the authors' method is feasible and effective for detection of three types of nodules in this study. PMID- 25735281 TI - Measuring interfraction and intrafraction lung function changes during radiation therapy using four-dimensional cone beam CT ventilation imaging. AB - PURPOSE: Adaptive ventilation guided radiation therapy could minimize the irradiation of healthy lung based on repeat lung ventilation imaging (VI) during treatment. However the efficacy of adaptive ventilation guidance requires that interfraction (e.g., week-to-week), ventilation changes are not washed out by intrafraction (e.g., pre- and postfraction) changes, for example, due to patient breathing variability. The authors hypothesize that patients undergoing lung cancer radiation therapy exhibit larger interfraction ventilation changes compared to intrafraction function changes. To test this, the authors perform the first comparison of interfraction and intrafraction lung VI pairs using four dimensional cone beam CT ventilation imaging (4D-CBCT VI), a novel technique for functional lung imaging. METHODS: The authors analyzed a total of 215 4D-CBCT scans acquired for 19 locally advanced non-small cell lung cancer (LA-NSCLC) patients over 4-6 weeks of radiation therapy. This set of 215 scans was sorted into 56 interfraction pairs (including first day scans and each of treatment weeks 2, 4, and 6) and 78 intrafraction pairs (including pre/postfraction scans on the same-day), with some scans appearing in both sets. VIs were obtained from the Jacobian determinant of the transform between the 4D-CBCT end-exhale and end inhale images after deformable image registration. All VIs were deformably registered to their corresponding planning CT and normalized to account for differences in breathing effort, thus facilitating image comparison in terms of (i) voxelwise Spearman correlations, (ii) mean image differences, and (iii) gamma pass rates for all interfraction and intrafraction VI pairs. For the side of the lung ipsilateral to the tumor, we applied two-sided t-tests to determine whether interfraction VI pairs were more different than intrafraction VI pairs. RESULTS: The (mean +/- standard deviation) Spearman correlation for interfraction VI pairs was r(Inter)=0.52+/-0.25, which was significantly lower than for intrafraction pairs (r(Intra)=0.67+/-0.20, p = 0.0002). Conversely, mean absolute ventilation differences were larger for interfraction pairs than for intrafraction pairs, with |DeltaV(Inter)|=0.42+/-0.65 and |DeltaV(Intra)|=0.32+/-0.53, respectively (p < 10(-15)). Applying a gamma analysis with ventilation/distance tolerance of 25%/10 mm, we observed mean pass rate of (69% +/- 20%) for interfraction VIs, which was significantly lower compared to intrafraction pairs (80% +/- 15%, with p ~ 0.0003). Compared to the first day scans, all patients experienced at least one subsequent change in median ipsilateral ventilation >=10%. Patients experienced both positive and negative ventilation changes throughout treatment, with the maximum change occurring at different weeks for different patients. CONCLUSIONS: The authors' data support the hypothesis that interfraction ventilation changes are larger than intrafraction ventilation changes for LA NSCLC patients over a course of conventional lung cancer radiation therapy. Longitudinal ventilation changes are observed to be highly patient-dependent, supporting a possible role for adaptive ventilation guidance based on repeat 4D CBCT VIs. We anticipate that future improvement of 4D-CBCT image reconstruction algorithms will improve the capability of 4D-CBCT VI to resolve interfraction ventilation changes. PMID- 25735282 TI - Characterizing energy dependence and count rate performance of a dual scintillator fiber-optic detector for computed tomography. AB - PURPOSE: Kilovoltage (kV) x-rays pose a significant challenge for radiation dosimetry. In the kV energy range, even small differences in material composition can result in significant variations in the absorbed energy between soft tissue and the detector. In addition, the use of electronic systems in light detection has demonstrated measurement losses at high photon fluence rates incident to the detector. This study investigated the feasibility of using a novel dual scintillator detector and whether its response to changes in beam energy from scatter and hardening is readily quantified. The detector incorporates a tissue equivalent plastic scintillator and a gadolinium oxysulfide scintillator, which has a higher sensitivity to scatter x-rays. METHODS: The detector was constructed by coupling two scintillators: (1) small cylindrical plastic scintillator, 500 MUm in diameter and 2 mm in length, and (2) 100 micron sheet of gadolinium oxysulfide 500 MUm in diameter, each to a 2 m long optical fiber, which acts as a light guide to transmit scintillation photons from the sensitive element to a photomultiplier tube. Count rate linearity data were obtained from a wide range of exposure rates delivered from a radiological x-ray tube by adjusting the tube current. The data were fitted to a nonparalyzable dead time model to characterize the time response. The true counting rate was related to the reference free air dose air rate measured with a 0.6 cm(3) Radcal((r)) thimble chamber as described in AAPM Report No. 111. Secondary electron and photon spectra were evaluated using Monte Carlo techniques to analyze ionization quenching and photon energy absorption characteristics from free-in-air and in phantom measurements. The depth/energy dependence of the detector was characterized using a computed tomography dose index QA phantom consisting of nested adult head and body segments. The phantom provided up to 32 cm of acrylic with a compatible 0.6 cm(3) calibrated ionization chamber to measure the reference air kerma. RESULTS: Each detector exhibited counting losses of 5% when irradiated at a dose rate of 26.3 mGy/s (Gadolinium) and 324.3 mGy/s (plastic). The dead time of the gadolinium oxysulfide detector was determined to be 48 ns, while the dead time of the plastic scintillating detector was unable to accurately be calculated due to poor counting statistics from low detected count rates. Noticeable depth/energy dependence was observed for the plastic scintillator for depths greater than 16 cm of acrylic that was not present for measurements using the gadolinium oxysulfide scintillator, leading us to believe that quenching may play a larger role in the depth dependence of the plastic scintillator than the incident x-ray energy spectrum. When properly corrected for dead time effects, the energy response of the gadolinium oxysulfide scintillator is consistent with the plastic scintillator. Using the integrated dual detector method was superior to each detector individually as the depth-dependent measure of dose was correctable to less than 8% between 100 and 135 kV. CONCLUSIONS: The dual scintillator fiber optic detector accommodates a methodology for energy dependent corrections of the plastic scintillator, improving the overall accuracy of the dosimeter across the range of diagnostic energies. PMID- 25735283 TI - Comparison between target margins derived from 4DCT scans and real-time tumor motion tracking: insights from lung tumor patients treated with robotic radiosurgery. AB - PURPOSE: A unique capability of the CyberKnife system is dynamic target tracking. However, not all patients are eligible for this approach. Rather, their tumors are tracked statically using the vertebral column for alignment. When using static tracking, the internal target volume (ITV) is delineated on the four dimensional (4D) CT scan and an additional margin is added to account for setup uncertainty [planning target volume (PTV)]. Treatment margins are difficult to estimate due to unpredictable variations in tumor motion and respiratory pattern during the course of treatment. The inability to track the target and detect changes in respiratory characteristics might result in geographic misses and local tumor recurrences. The purpose of this study is to develop a method to evaluate the adequacy of ITV-to-PTV margins for patients treated in this manner. METHODS: Data from 24 patients with lesions in the upper lobe (n = 12), middle lobe (n = 3), and lower lobe (n = 9) were included in this study. Each patient was treated with dynamic tracking and underwent 4DCT scanning at the time of simulation. Data including the 3D coordinates of the target over the course of treatment were extracted from the treatment log files and used to determine actual target motion in the superior-inferior (S-I), anterior-posterior (A-P), and left-right (L-R) directions. Different approaches were used to calculate anisotropic and isotropic margins, assuming that the tumor moves as a rigid body. Anisotropic margins were calculated by separating target motion in the three anatomical directions, and a uniform margin was calculated by shifting the gross tumor volume contours in the 3D space and by computing the percentage of overlap with the PTV. The analysis was validated by means of a theoretical formulation. RESULTS: The three methods provided consistent results. A uniform margin of 4.5 mm around the ITV was necessary to assure 95% target coverage for 95% of the fractions included in the analysis. In the case of anisotropic margins, the expansion required in the S-I direction was larger (8.1 mm) than those in the L-R (4.9 mm) and A-P (4.5 mm) directions. This margin accounts for variations of target position within the same treatment fraction. CONCLUSIONS: The use of bony alignment for CyberKnife lung stereotactic body radiation therapy requires careful considerations, in terms of the potential for increased toxicity or local miss. Our method could be used by other centers to determine the adequacy of ITV to-PTV margins for their patients. PMID- 25735284 TI - Model-based versus specific dosimetry in diagnostic context: comparison of three dosimetric approaches. AB - PURPOSE: The dosimetric assessment of novel radiotracers represents a legal requirement in most countries. While the techniques for the computation of internal absorbed dose in a therapeutic context have made huge progresses in recent years, in a diagnostic scenario the absorbed dose is usually extracted from model-based lookup tables, most often derived from International Commission on Radiological Protection (ICRP) or Medical Internal Radiation Dose (MIRD) Committee models. The level of approximation introduced by these models may impact the resulting dosimetry. The aim of this work is to establish whether a more refined approach to dosimetry can be implemented in nuclear medicine diagnostics, by analyzing a specific case. METHODS: The authors calculated absorbed doses to various organs in six healthy volunteers administered with flutemetamol ((18)F) injection. Each patient underwent from 8 to 10 whole body 3D PET/CT scans. This dataset was analyzed using a Monte Carlo (MC) application developed in-house using the toolkit gate that is capable to take into account patient-specific anatomy and radiotracer distribution at the voxel level. They compared the absorbed doses obtained with GATE to those calculated with two commercially available software: OLINDA/EXM and STRATOS implementing a dose voxel kernel convolution approach. RESULTS: Absorbed doses calculated with gate were higher than those calculated with OLINDA. The average ratio between gate absorbed doses and OLINDA's was 1.38 +/- 0.34 sigma (from 0.93 to 2.23). The discrepancy was particularly high for the thyroid, with an average GATE/OLINDA ratio of 1.97 +/- 0.83 sigma for the six patients. Differences between STRATOS and GATE were found to be higher. The average ratio between GATE and STRATOS absorbed doses was 2.51 +/- 1.21 sigma (from 1.09 to 6.06). CONCLUSIONS: This study demonstrates how the choice of the absorbed dose calculation algorithm may introduce a bias when gamma radiations are of importance, as is the case in nuclear medicine diagnostics. PMID- 25735285 TI - Monitoring tumor state from thermal images in animal and human models. AB - PURPOSE: Thermography is a potentially useful method for tumor progress monitoring since it is noninvasive, nonradiative, low-cost, and rapid. Perfusion and metabolism are dominant factors for determining tumor temperature difference and are also correlated to the tumor's growth rate. Therefore, estimating them from the tumor thermal image can be a very useful tumor monitoring method, since thermal changes occur before physical changes. The goal of this work was to study the effect of tumor state on the thermal image in different tumor types, using simulations and measurements. METHODS: Simulated tumor models, representing flat and extruding tumors, typical to transplantable and natural tumors, respectively, were simulated and the effects of tumor metabolism and perfusion on the temperature difference were analyzed. Data regarding tumor size and measured temperature differences were obtained from the literature, discussing five types of transplantable tumors in mice and rats. The growth rates of all tumors were calculated by fitting tumor size measurements to a tumor growth model and were used as an indicator to tumor aggressiveness. Tumor temperature difference was calculated by taking the effect of its extruding shape into account, according to a previously published method. Tumor state was estimated from the normalized temperature differences using simulations and compared to the calculated aggressiveness rates. Computational models of human breast cancers, both in round and flat breast models, were recreated using a finite-element-method heat transfer simulation. Tumor size and state were simulated according to the results obtained from the animal tumor analysis, representing two different tumor aggressiveness levels. The calculated temperature difference as a function of tumor size was calculated for each test case. RESULTS: Perfusion was shown to be highly dominant in determining the tumor's temperature difference. Since both metabolism and perfusion were shown to have a linear effect on the temperature difference, a conversion value was defined between them. The analysis of the animal experimental results showed correlations between tumor aggressiveness and the following factors: the normalized temperature difference, the estimated tumor state, and the temperature difference change rate. The simulated human breast cancer models analysis showed highly varying temperature differences between the simulated models. Although for each model there is a clear difference between the temperature differences of the test cases simulated, the large differences between the results might make tumor state estimation difficult. However, reviewing the gradient of the tumor temperature change as a function of tumor size showed that the ratio between the gradients of both test cases was similar for all models. Therefore, the effect of model errors and differences in the simulated tissue structure and properties and the environmental conditions between the different models, can be mitigated. This pattern may be used to estimate tumor state in in vivo experiments. CONCLUSIONS: Continuous monitoring of tumor temperature difference produces valuable information on tumor state and aggressiveness that can be used both in the clinic and in the laboratory. Monitoring can be either performed on a single image, or continuous on multiple images, revealing changes in tumor state. PMID- 25735286 TI - Sinogram restoration in computed tomography with an edge-preserving penalty. AB - PURPOSE: With the goal of producing a less computationally intensive alternative to fully iterative penalized-likelihood image reconstruction, our group has explored the use of penalized-likelihood sinogram restoration for transmission tomography. Previously, we have exclusively used a quadratic penalty in our restoration objective function. However, a quadratic penalty does not excel at preserving edges while reducing noise. Here, we derive a restoration update equation for nonquadratic penalties. Additionally, we perform a feasibility study to extend our sinogram restoration method to a helical cone-beam geometry and clinical data. METHODS: A restoration update equation for nonquadratic penalties is derived using separable parabolic surrogates (SPS). A method for calculating sinogram degradation coefficients for a helical cone-beam geometry is proposed. Using simulated data, sinogram restorations are performed using both a quadratic penalty and the edge-preserving Huber penalty. After sinogram restoration, Fourier-based analytical methods are used to obtain reconstructions, and resolution-noise trade-offs are investigated. For the fan-beam geometry, a comparison is made to image-domain SPS reconstruction using the Huber penalty. The effects of varying object size and contrast are also investigated. For the helical cone-beam geometry, we investigate the effect of helical pitch (axial movement/rotation). Huber-penalty sinogram restoration is performed on 3D clinical data, and the reconstructed images are compared to those generated with no restoration. RESULTS: We find that by applying the edge-preserving Huber penalty to our sinogram restoration methods, the reconstructed image has a better resolution-noise relationship than an image produced using a quadratic penalty in the sinogram restoration. However, we find that this relatively straightforward approach to edge preservation in the sinogram domain is affected by the physical size of imaged objects in addition to the contrast across the edge. This presents some disadvantages of this method relative to image-domain edge-preserving methods, although the computational burden of the sinogram-domain approach is much lower. For a helical cone-beam geometry, we found applying sinogram restoration in 3D was reasonable and that pitch did not make a significant difference in the general effect of sinogram restoration. The application of Huber-penalty sinogram restoration to clinical data resulted in a reconstruction with less noise while retaining resolution. CONCLUSIONS: Sinogram restoration with the Huber penalty is able to provide better resolution-noise performance than restoration with a quadratic penalty. Additionally, sinogram restoration with the Huber penalty is feasible for helical cone-beam CT and can be applied to clinical data. PMID- 25735287 TI - A method for modeling laterally asymmetric proton beamlets resulting from collimation. AB - PURPOSE: To introduce a method to model the 3D dose distribution of laterally asymmetric proton beamlets resulting from collimation. The model enables rapid beamlet calculation for spot scanning (SS) delivery using a novel penumbra reducing dynamic collimation system (DCS) with two pairs of trimmers oriented perpendicular to each other. METHODS: Trimmed beamlet dose distributions in water were simulated with MCNPX and the collimating effects noted in the simulations were validated by experimental measurement. The simulated beamlets were modeled analytically using integral depth dose curves along with an asymmetric Gaussian function to represent fluence in the beam's eye view (BEV). The BEV parameters consisted of Gaussian standard deviations (sigmas) along each primary axis (sigma(x1),sigma(x2),sigma(y1),sigma(y2)) together with the spatial location of the maximum dose (MU(x),MU(y)). Percent depth dose variation with trimmer position was accounted for with a depth-dependent correction function. Beamlet growth with depth was accounted for by combining the in-air divergence with Hong's fit of the Highland approximation along each axis in the BEV. RESULTS: The beamlet model showed excellent agreement with the Monte Carlo simulation data used as a benchmark. The overall passing rate for a 3D gamma test with 3%/3 mm passing criteria was 96.1% between the analytical model and Monte Carlo data in an example treatment plan. CONCLUSIONS: The analytical model is capable of accurately representing individual asymmetric beamlets resulting from use of the DCS. This method enables integration of the DCS into a treatment planning system to perform dose computation in patient datasets. The method could be generalized for use with any SS collimation system in which blades, leaves, or trimmers are used to laterally sharpen beamlets. PMID- 25735288 TI - Impact of range shifter material on proton pencil beam spot characteristics. AB - PURPOSE: To quantitatively investigate the effect of range shifter materials on single-spot characteristics of a proton pencil beam. METHODS: An analytic approximation for multiple Coulomb scattering ("differential Moliere" formula) was adopted to calculate spot sizes of proton spot scanning beams impinging on a range shifter. The calculations cover a range of delivery parameters: six range shifter materials (acrylonitrile butadiene styrene, Lexan, Lucite, polyethylene, polystyrene, and wax) and water as reference material, proton beam energies ranging from 75 to 200 MeV, range shifter thicknesses of 4.5 and 7.0 g/cm(2), and range shifter positions from 5 to 50 cm. The analytic method was validated by comparing calculation results with the measurements reported in the literature. RESULTS: Relative to a water-equivalent reference, the spot size distal to a wax or polyethylene range shifter is 15% smaller, while the spot size distal to a range shifter made of Lexan or Lucite is about 6% smaller. The relative spot size variations are nearly independent of beam energy and range shifter thickness and decrease with smaller air gaps. CONCLUSIONS: Among the six material investigated, wax and polyethylene are desirable range shifter materials when the spot size is kept small. Lexan and Lucite are the desirable range shifter materials when the scattering power is kept similar to water. PMID- 25735289 TI - IBEX: an open infrastructure software platform to facilitate collaborative work in radiomics. AB - PURPOSE: Radiomics, which is the high-throughput extraction and analysis of quantitative image features, has been shown to have considerable potential to quantify the tumor phenotype. However, at present, a lack of software infrastructure has impeded the development of radiomics and its applications. Therefore, the authors developed the imaging biomarker explorer (IBEX), an open infrastructure software platform that flexibly supports common radiomics workflow tasks such as multimodality image data import and review, development of feature extraction algorithms, model validation, and consistent data sharing among multiple institutions. METHODS: The IBEX software package was developed using the MATLAB and c/c++ programming languages. The software architecture deploys the modern model-view-controller, unit testing, and function handle programming concepts to isolate each quantitative imaging analysis task, to validate if their relevant data and algorithms are fit for use, and to plug in new modules. On one hand, IBEX is self-contained and ready to use: it has implemented common data importers, common image filters, and common feature extraction algorithms. On the other hand, IBEX provides an integrated development environment on top of MATLAB and c/c++, so users are not limited to its built-in functions. In the IBEX developer studio, users can plug in, debug, and test new algorithms, extending IBEX's functionality. IBEX also supports quality assurance for data and feature algorithms: image data, regions of interest, and feature algorithm-related data can be reviewed, validated, and/or modified. More importantly, two key elements in collaborative workflows, the consistency of data sharing and the reproducibility of calculation result, are embedded in the IBEX workflow: image data, feature algorithms, and model validation including newly developed ones from different users can be easily and consistently shared so that results can be more easily reproduced between institutions. RESULTS: Researchers with a variety of technical skill levels, including radiation oncologists, physicists, and computer scientists, have found the IBEX software to be intuitive, powerful, and easy to use. IBEX can be run at any computer with the windows operating system and 1GB RAM. The authors fully validated the implementation of all importers, preprocessing algorithms, and feature extraction algorithms. Windows version 1.0 beta of stand-alone IBEX and IBEX's source code can be downloaded. CONCLUSIONS: The authors successfully implemented IBEX, an open infrastructure software platform that streamlines common radiomics workflow tasks. Its transparency, flexibility, and portability can greatly accelerate the pace of radiomics research and pave the way toward successful clinical translation. PMID- 25735290 TI - Investigating CT to CBCT image registration for head and neck proton therapy as a tool for daily dose recalculation. AB - PURPOSE: Intensity modulated proton therapy (IMPT) of head and neck (H&N) cancer patients may be improved by plan adaptation. The decision to adapt the treatment plan based on a dose recalculation on the current anatomy requires a diagnostic quality computed tomography (CT) scan of the patient. As gantry-mounted cone beam CT (CBCT) scanners are currently being offered by vendors, they may offer daily or weekly updates of patient anatomy. CBCT image quality may not be sufficient for accurate proton dose calculation and it is likely necessary to perform CBCT CT number correction. In this work, the authors investigated deformable image registration (DIR) of the planning CT (pCT) to the CBCT to generate a virtual CT (vCT) to be used for proton dose recalculation. METHODS: Datasets of six H&N cancer patients undergoing photon intensity modulated radiation therapy were used in this study to validate the vCT approach. Each dataset contained a CBCT acquired within 3 days of a replanning CT (rpCT), in addition to a pCT. The pCT and rpCT were delineated by a physician. A Morphons algorithm was employed in this work to perform DIR of the pCT to CBCT following a rigid registration of the two images. The contours from the pCT were deformed using the vector field resulting from DIR to yield a contoured vCT. The DIR accuracy was evaluated with a scale invariant feature transform (SIFT) algorithm comparing automatically identified matching features between vCT and CBCT. The rpCT was used as reference for evaluation of the vCT. The vCT and rpCT CT numbers were converted to stopping power ratio and the water equivalent thickness (WET) was calculated. IMPT dose distributions from treatment plans optimized on the pCT were recalculated with a Monte Carlo algorithm on the rpCT and vCT for comparison in terms of gamma index, dose volume histogram (DVH) statistics as well as proton range. The DIR generated contours on the vCT were compared to physician-drawn contours on the rpCT. RESULTS: The DIR accuracy was better than 1.4 mm according to the SIFT evaluation. The mean WET differences between vCT (pCT) and rpCT were below 1 mm (2.6 mm). The amount of voxels passing 3%/3 mm gamma criteria were above 95% for the vCT vs rpCT. When using the rpCT contour set to derive DVH statistics from dose distributions calculated on the rpCT and vCT the differences, expressed in terms of 30 fractions of 2 Gy, were within [-4, 2 Gy] for parotid glands (D(mean)), spinal cord (D(2%)), brainstem (D(2%)), and CTV (D(95%)). When using DIR generated contours for the vCT, those differences ranged within [-8, 11 Gy]. CONCLUSIONS: In this work, the authors generated CBCT based stopping power distributions using DIR of the pCT to a CBCT scan. DIR accuracy was below 1.4 mm as evaluated by the SIFT algorithm. Dose distributions calculated on the vCT agreed well to those calculated on the rpCT when using gamma index evaluation as well as DVH statistics based on the same contours. The use of DIR generated contours introduced variability in DVH statistics. PMID- 25735292 TI - Initial implementation of the conversion from the energy-subtracted CT number to electron density in tissue inhomogeneity corrections: an anthropomorphic phantom study of radiotherapy treatment planning. AB - PURPOSE: To achieve accurate tissue inhomogeneity corrections in radiotherapy treatment planning, the authors had previously proposed a novel conversion of the energy-subtracted computed tomography (CT) number to an electron density (DeltaHU rho(e) conversion), which provides a single linear relationship between DeltaHU and rho(e) over a wide range of rho(e). The purpose of this study is to present an initial implementation of the DeltaHU-rho(e) conversion method for a treatment planning system (TPS). In this paper, two example radiotherapy plans are used to evaluate the reliability of dose calculations in the DeltaHU-rho(e) conversion method. METHODS: CT images were acquired using a clinical dual-source CT (DSCT) scanner operated in the dual-energy mode with two tube potential pairs and an additional tin (Sn) filter for the high-kV tube (80-140 kV/Sn and 100-140 kV/Sn). Single-energy CT using the same DSCT scanner was also performed at 120 kV to compare the DeltaHU-rho(e) conversion method with a conventional conversion from a CT number to rho(e) (Hounsfield units, HU-rho(e) conversion). Lookup tables for rho(e) calibration were obtained from the CT image acquisitions for tissue substitutes in an electron density phantom (EDP). To investigate the beam hardening effect on dosimetric uncertainties, two EDPs with different sizes (a body EDP and a head EDP) were used for the rho(e) calibration. Each acquired lookup table was applied to two radiotherapy plans designed using the XiO TPS with the superposition algorithm for an anthropomorphic phantom. The first radiotherapy plan was for an oral cavity tumor and the second was for a lung tumor. RESULTS: In both treatment plans, the performance of the DeltaHU-rho(e) conversion was superior to that of the conventional HU-rho(e) conversion in terms of the reliability of dose calculations. Especially, for the oral tumor plan, which dealt with dentition and bony structures, treatment planning with the HU rho(e) conversion exhibited apparent discrepancies between the dose distributions and dose-volume histograms (DVHs) of the body-EDP and head-EDP calibrations. In contrast, the dose distributions and DVHs of the body-EDP and head-EDP calibrations coincided with each other almost perfectly in the DeltaHU-rho(e) conversion for 100-140 kV/Sn. The difference between the V100's (the mean planning target volume receiving 100% of the prescribed dose; a DVH parameter) of the body-EDP and head-EDP calibrations could be reduced to less than 1% using the DeltaHU-rho(e) conversion, but exceeded 11% for the HU-rho(e) conversion. CONCLUSIONS: The DeltaHU-rho(e) conversion can be implemented for currently available TPS's without any modifications or extensions. The DeltaHU-rho(e) conversion appears to be a promising method for providing an accurate and reliable inhomogeneity correction in treatment planning for any ill-conditioned scans that include (i) the use of a calibration EDP that is nonequivalent to the patient's body tissues, (ii) a mismatch between the size of the patient and the calibration EDP, or (iii) a large quantity of high-density and high-atomic-number tissue structures. PMID- 25735291 TI - Optimization approaches to volumetric modulated arc therapy planning. AB - Volumetric modulated arc therapy (VMAT) has found widespread clinical application in recent years. A large number of treatment planning studies have evaluated the potential for VMAT for different disease sites based on the currently available commercial implementations of VMAT planning. In contrast, literature on the underlying mathematical optimization methods used in treatment planning is scarce. VMAT planning represents a challenging large scale optimization problem. In contrast to fluence map optimization in intensity-modulated radiotherapy planning for static beams, VMAT planning represents a nonconvex optimization problem. In this paper, the authors review the state-of-the-art in VMAT planning from an algorithmic perspective. Different approaches to VMAT optimization, including arc sequencing methods, extensions of direct aperture optimization, and direct optimization of leaf trajectories are reviewed. Their advantages and limitations are outlined and recommendations for improvements are discussed. PMID- 25735293 TI - Optothermal profile of an ablation catheter with integrated microcoil for MR thermometry during Nd:YAG laser interstitial thermal therapies of the liver-an in vitro experimental and theoretical study. AB - PURPOSE: Flexible microcoils integrated with ablation catheters can improve the temperature accuracy during local MR-thermometry in Nd:YAG laser interstitial thermal therapies. Here, the authors are concerned with obtaining a preliminary confirmation of the clinical utility of the modified catheter. They investigate whether the thin-film substrate and copper tracks of the printed coil inductor affect the symmetry of the thermal profile, and hence of the lesion produced. METHODS: Transmission spectroscopy in the near infrared was performed to test for the attenuation at 1064 nm through the 25 MUm thick Kapton substrate of the microcoil. The radial transmission profile of an infrared high-power, light emitting diode with >80% normalized power at 1064 nm was measured through a cross section of the modified applicator to assess the impact of the copper inductor on the optical profile. The measurements were performed in air, as well as with the applicator surrounded by two types of scattering media; crystals of NaCl and a layer of liver-mimicking gel phantom. A numerical model based on Huygens-Fresnel principle and finite element simulations, using a commercially available package (COMSOL Multiphysics), were employed to compare with the optical measurements. The impact of the modified optical profile on the thermal symmetry was assessed by examining the high resolution microcoil derived thermal maps from a Nd:YAG laser ablation performed on a liver-mimicking gel phantom. RESULTS: Less than 30% attenuation through the Kapton film was verified. Shadowing behind the copper tracks was observed in air and the measured radial irradiation correlated well with the diffraction pattern calculated numerically using the Huygens-Fresnel principle. Both optical experiments and simulations, demonstrate that shadowing is mitigated by the scattering properties of a turbid medium. The microcoil derived thermal maps at the end of a Nd:YAG laser ablation performed on a gel phantom in a 3 T scanner confirm that the modified irradiation pattern does not disrupt the thermal symmetry, even though, unlike tissue, the gel is minimally scattering. CONCLUSIONS: The results from this initial assessment indicate that microcoils can be safely integrated with ablation catheters and ensure that the complete necrosis of the liver tumor can still be achieved. PMID- 25735294 TI - Recovery and normalization of triple coincidences in PET. AB - PURPOSE: Triple coincidences in positron emission tomography (PET) are events in which three gamma-rays are detected simultaneously. These events, though potentially useful for enhancing the sensitivity of PET scanners, are discarded or processed without special consideration in current systems, because there is not a clear criterion for assigning them to a unique line-of-response (LOR). Methods proposed for recovering such events usually rely on the use of highly specialized detection systems, hampering general adoption, and/or are based on Compton-scatter kinematics and, consequently, are limited in accuracy by the energy resolution of standard PET detectors. In this work, the authors propose a simple and general solution for recovering triple coincidences, which does not require specialized detectors or additional energy resolution requirements. METHODS: To recover triple coincidences, the authors' method distributes such events among their possible LORs using the relative proportions of double coincidences in these LORs. The authors show analytically that this assignment scheme represents the maximum-likelihood solution for the triple-coincidence distribution problem. The PET component of a preclinical PET/CT scanner was adapted to enable the acquisition and processing of triple coincidences. Since the efficiencies for detecting double and triple events were found to be different throughout the scanner field-of-view, a normalization procedure specific for triple coincidences was also developed. The effect of including triple coincidences using their method was compared against the cases of equally weighting the triples among their possible LORs and discarding all the triple events. The authors used as figures of merit for this comparison sensitivity, noise-equivalent count (NEC) rates and image quality calculated as described in the NEMA NU-4 protocol for the assessment of preclinical PET scanners. RESULTS: The addition of triple-coincidence events with the authors' method increased peak NEC rates of the scanner by 26.6% and 32% for mouse- and rat-sized objects, respectively. This increase in NEC-rate performance was also reflected in the image-quality metrics. Images reconstructed using double and triple coincidences recovered using their method had better signal-to-noise ratio than those obtained using only double coincidences, while preserving spatial resolution and contrast. Distribution of triple coincidences using an equal-weighting scheme increased apparent system sensitivity but degraded image quality. The performance boost provided by the inclusion of triple coincidences using their method allowed to reduce the acquisition time of standard imaging procedures by up to ~25%. CONCLUSIONS: Recovering triple coincidences with the proposed method can effectively increase the sensitivity of current clinical and preclinical PET systems without compromising other parameters like spatial resolution or contrast. PMID- 25735295 TI - Monitoring local heating around an interventional MRI antenna with RF radiometry. AB - PURPOSE: Radiofrequency (RF) radiometry uses thermal noise detected by an antenna to measure the temperature of objects independent of medical imaging technologies such as magnetic resonance imaging (MRI). Here, an active interventional MRI antenna can be deployed as a RF radiometer to measure local heating, as a possible new method of monitoring device safety and thermal therapy. METHODS: A 128 MHz radiometer receiver was fabricated to measure the RF noise voltage from an interventional 3 T MRI loopless antenna and calibrated for temperature in a uniformly heated bioanalogous gel phantom. Local heating (DeltaT) was induced using the antenna for RF transmission and measured by RF radiometry, fiber-optic thermal sensors, and MRI thermometry. The spatial thermal sensitivity of the antenna radiometer was numerically computed using a method-of-moment electric field analyses. The gel's thermal conductivity was measured by MRI thermometry, and the localized time-dependent DeltaT distribution computed from the bioheat transfer equation and compared with radiometry measurements. A "H-factor" relating the 1 g-averaged DeltaT to the radiometric temperature was introduced to estimate peak temperature rise in the antenna's sensitive region. RESULTS: The loopless antenna radiometer linearly tracked temperature inside a thermally equilibrated phantom up to 73 degrees C to within +/-0.3 degrees C at a 2 Hz sample rate. Computed and MRI thermometric measures of peak DeltaT agreed within 13%. The peak 1 g-average temperature was H = 1.36 +/- 0.02 times higher than the radiometric temperature for any media with a thermal conductivity of 0.15-0.50 (W/m)/K, indicating that the radiometer can measure peak 1 g-averaged DeltaT in physiologically relevant tissue within +/-0.4 degrees C. CONCLUSIONS: Active internal MRI detectors can serve as RF radiometers at the MRI frequency to provide accurate independent measures of local and peak temperature without the artifacts that can accompany MRI thermometry or the extra space needed to accommodate alternative thermal transducers. A RF radiometer could be integrated in a MRI scanner to permit "self-monitoring" for assuring device safety and/or monitoring delivery of thermal therapy. PMID- 25735296 TI - Segmentation of myocardium from cardiac MR images using a novel dynamic programming based segmentation method. AB - PURPOSE: Myocardium segmentation in cardiac magnetic resonance (MR) images plays a vital role in clinical diagnosis of the cardiovascular diseases. Because of the low contrast and large variation in intensity and shapes, myocardium segmentation has been a challenging task. A dynamic programming (DP) based segmentation method, incorporating the likelihood and shape information of the myocardium, is developed for segmenting myocardium in cardiac MR images. METHODS: The endocardium, i.e., the left ventricle blood cavity, is segmented for initialization, and then the optimal epicardium contour is determined using the polar-transformed image and DP scheme. In the DP segmentation scheme, three techniques are proposed to improve the segmentation performance: (1) the likelihood image of the myocardium is constructed to define the external cost in the DP, thus the cost function incorporates prior probability estimation; (2) the adaptive search range is introduced to determine the polar-transformed image, thereby excluding irrelevant tissues; (3) the connectivity constrained DP algorithm is developed to obtain an optimal closed contour. Four metrics, including the Dice metric (Dice), root mean squared error (RMSE), reliability, and correlation coefficient, are used to assess the segmentation accuracy. The authors evaluated the performance of the proposed method on a private dataset and the MICCAI 2009 challenge dataset. The authors also explored the effects of the three new techniques of the DP scheme in the proposed method. RESULTS: For the qualitative evaluation, the segmentation results of the proposed method were clinically acceptable. For the quantitative evaluation, the mean (Dice) for the endocardium and epicardium was 0.892 and 0.927, respectively; the mean RMSE was 2.30 mm for the endocardium and 2.39 mm for the epicardium. In addition, the three new techniques in the proposed DP scheme, i.e., the likelihood image of the myocardium, the adaptive search range, and the connectivity constrained DP algorithm, improved the segmentation performance for the epicardium with 0.029, 0.047, and 0.007 in terms of the Dice and 0.98, 1.31, and 0.21 mm in terms of the RMSE, respectively. CONCLUSIONS: The three techniques (the likelihood image of the myocardium, the adaptive search range, and the connectivity constrained DP algorithm) can improve the segmentation ability of the DP method, and the proposed method with these techniques has the ability to achieve the acceptable segmentation result of the myocardium in cardiac MR images. Therefore, the proposed method would be useful in clinical diagnosis of the cardiovascular diseases. PMID- 25735297 TI - Detection of microcalcifications by characteristic magnetic susceptibility effects using MR phase image cross-correlation analysis. AB - PURPOSE: To develop and evaluate a new method for detecting calcium deposits using their characteristic magnetic susceptibility effects on magnetic resonance (MR) images at high fields and demonstrate its potential in practice for detecting breast microcalcifications. METHODS: Characteristic dipole signatures of calcium deposits were detected in magnetic resonance phase images by computing the cross-correlation between the acquired data and a library of templates containing simulated phase patterns of spherical deposits. The influence of signal-to-noise ratio and various other MR parameters on the results were assessed using simulations and validated experimentally. The method was tested experimentally for detection of calcium fragments within gel phantoms and calcium like inhomogeneities within chicken tissue at 7 T with optimized MR acquisition parameters. The method was also evaluated for detection of simulated microcalcifications, modeled from biopsy samples of malignant breast cancer, inserted in silico into breast magnetic resonance imaging (MRIs) of healthy subjects at 7 T. For both assessments of calcium fragments in phantoms and biopsy based simulated microcalcifications in breast MRIs, receiver operator characteristic curve analyses were performed to determine the cross-correlation index cutoff, for achieving optimal sensitivity and specificity, and the area under the curve (AUC), for measuring the method's performance. RESULTS: The method detected calcium fragments with sizes of 0.14-0.79 mm, 1 mm calcium-like deposits, and simulated microcalcifications with sizes of 0.4-1.0 mm in images with voxel sizes between (0.2 mm)(3) and (0.6 mm)(3). In images acquired at 7 T with voxel sizes of (0.2 mm)(3)-(0.4 mm)(3), calcium fragments (size 0.3-0.4 mm) were detected with a sensitivity, specificity, and AUC of 78%-90%, 51%-68%, and 0.77%-0.88%, respectively. In images acquired with a human 7 T scanner, acquisition times below 12 min, and voxel sizes of (0.4 mm)(3)-(0.6 mm)(3), simulated microcalcifications with sizes of 0.6-1.0 mm were detected with a sensitivity, specificity, and AUC of 75%-87%, 54%-87%, and 0.76%-0.90%, respectively. However, different microcalcification shapes were indistinguishable. CONCLUSIONS: The new method is promising for detecting relatively large microcalcifications (i.e., 0.6-0.9 mm) within the breast at 7 T in reasonable times. Detection of smaller deposits at high field may be possible with higher spatial resolution, but such images require relatively long scan times. Although mammography can detect and distinguish the shape of smaller microcalcifications with superior sensitivity and specificity, this alternative method does not expose tissue to ionizing radiation, is not affected by breast density, and can be combined with other MRI methods (e.g., dynamic contrast enhanced MRI and diffusion weighted MRI), to potentially improve diagnostic performance. PMID- 25735298 TI - Bowtie filters for dedicated breast CT: theory and computational implementation. AB - PURPOSE: To design bowtie filters with improved properties for dedicated breast CT to improve image quality and reduce dose to the patient. METHODS: The authors present three different bowtie filters designed for a cylindrical 14-cm diameter phantom with a uniform composition of 40/60 breast tissue, which vary in their design objectives and performance improvements. Bowtie design #1 is based on single material spectral matching and produces nearly uniform spectral shape for radiation incident upon the detector. Bowtie design #2 uses the idea of basis material decomposition to produce the same spectral shape and intensity at the detector, using two different materials. Bowtie design #3 eliminates the beam hardening effect in the reconstructed image by adjusting the bowtie filter thickness so that the effective attenuation coefficient for every ray is the same. All three designs are obtained using analytical computational methods and linear attenuation coefficients. Thus, the designs do not take into account the effects of scatter. The authors considered this to be a reasonable approach to the filter design problem since the use of Monte Carlo methods would have been computationally intensive. The filter profiles for a cone-angle of 0 degrees were used for the entire length of each filter because the differences between those profiles and the correct cone-beam profiles for the cone angles in our system are very small, and the constant profiles allowed construction of the filters with the facilities available to us. For evaluation of the filters, we used Monte Carlo simulation techniques and the full cone-beam geometry. Images were generated with and without each bowtie filter to analyze the effect on dose distribution, noise uniformity, and contrast-to-noise ratio (CNR) homogeneity. Line profiles through the reconstructed images generated from the simulated projection images were also used as validation for the filter designs. RESULTS: Examples of the three designs are presented. Initial verification of performance of the designs was done using analytical computations of HVL, intensity, and effective attenuation coefficient behind the phantom as a function of fan-angle with a cone-angle of 0 degrees . The performance of the designs depends only weakly on incident spectrum and tissue composition. For all designs, the dynamic range requirement on the detector was reduced compared to the no-bowtie-filter case. Further verification of the filter designs was achieved through analysis of reconstructed images from simulations. Simulation data also showed that the use of our bowtie filters can reduce peripheral dose to the breast by 61% and provide uniform noise and CNR distributions. The bowtie filter design concepts validated in this work were then used to create a computational realization of a 3D anthropomorphic bowtie filter capable of achieving a constant effective attenuation coefficient behind the entire field-of-view of an anthropomorphic breast phantom. CONCLUSIONS: Three different bowtie filter designs that vary in performance improvements were described and evaluated using computational and simulation techniques. Results indicate that the designs are robust against variations in breast diameter, breast composition, and tube voltage, and that the use of these filters can reduce patient dose and improve image quality compared to the no-bowtie-filter case. PMID- 25735299 TI - 3D high spectral and spatial resolution imaging of ex vivo mouse brain. AB - PURPOSE: Widely used MRI methods show brain morphology both in vivo and ex vivo at very high resolution. Many of these methods (e.g., T2*-weighted imaging, phase sensitive imaging, or susceptibility-weighted imaging) are sensitive to local magnetic susceptibility gradients produced by subtle variations in tissue composition. However, the spectral resolution of commonly used methods is limited to maintain reasonable run-time combined with very high spatial resolution. Here, the authors report on data acquisition at increased spectral resolution, with 3 dimensional high spectral and spatial resolution MRI, in order to analyze subtle variations in water proton resonance frequency and lineshape that reflect local anatomy. The resulting information compliments previous studies based on T2* and resonance frequency. METHODS: The proton free induction decay was sampled at high resolution and Fourier transformed to produce a high-resolution water spectrum for each image voxel in a 3D volume. Data were acquired using a multigradient echo pulse sequence (i.e., echo-planar spectroscopic imaging) with a spatial resolution of 50 * 50 * 70 MUm(3) and spectral resolution of 3.5 Hz. Data were analyzed in the spectral domain, and images were produced from the various Fourier components of the water resonance. This allowed precise measurement of local variations in water resonance frequency and lineshape, at the expense of significantly increased run time (16-24 h). RESULTS: High contrast T2*-weighted images were produced from the peak of the water resonance (peak height image), revealing a high degree of anatomical detail, specifically in the hippocampus and cerebellum. In images produced from Fourier components of the water resonance at 7.0 Hz from the peak, the contrast between deep white matter tracts and the surrounding tissue is the reverse of the contrast in water peak height images. This indicates the presence of a shoulder in the water resonance that is not present at +7.0 Hz and may be specific to white matter anatomy. Moreover, a frequency shift of 6.76 +/- 0.55 Hz was measured between the molecular and granular layers of the cerebellum. This shift is demonstrated in corresponding spectra; water peaks from voxels in the molecular and granular layers are consistently 2 bins apart (7.0 Hz, as dictated by the spectral resolution) from one another. CONCLUSIONS: High spectral and spatial resolution MR imaging has the potential to accurately measure the changes in the water resonance in small voxels. This information can guide optimization and interpretation of more commonly used, more rapid imaging methods that depend on image contrast produced by local susceptibility gradients. In addition, with improved sampling methods, high spectral and spatial resolution data could be acquired in reasonable run times, and used for in vivo scans to increase sensitivity to variations in local susceptibility. PMID- 25735300 TI - Effectiveness, safety and feasibility of an evidence-based insulin infusion protocol targeting moderate glycaemic control in intensive cardiac care units. AB - OBJECTIVES: To assess the effectiveness, safety and feasibility of the revised, simplified nurse-managed version of our insulin infusion protocol, adapted to the new recommended glycaemic target of 140 to 180 mg/dL (Desio Diabetes Diagram i.v. 140-180). METHODS: All clinical responses to the Desio Diabetes Diagram i.v. 140 180 in use for 3 years were recorded in patients with diabetes or hyperglycaemia admitted to our intensive cardiac care unit. To assess the feasibility, we asked nurses to complete an ad hoc questionnaire anonymously when the new insulin infusion protocol had been in use for 2 years. RESULTS: From December 2010 to December 2013, 276 patients (173 men, median age 75 years) were treated according to the Desio Diabetes Diagram i.v. 140-180. The median time to reach glycaemic target was 4 h (Q1-Q3 2-8) in 128 patients with blood glucose >180 mg/dL and 2 h (Q1-Q3 1-4) in 82 patients with blood glucose <140 mg/dL. Once the target had been reached, insulin infusion was maintained for a median of 38 h (Q1-Q3 24-48) with blood glucose between 140 and 180 mg/dL for 58.3% of the infusion time. Over a total of 11,863 h of infusion, seven blood glucose <70 mg/dL occurred. The Desio Diabetes Diagram i.v. 140-180 protocol was considered easy to use by 93% of nurses. CONCLUSIONS: The Desio Diabetes Diagram i.v. 140-180 protocol, fully managed by nurses, with insulin and glucose intravenous infusion proved effective, safe and feasible in maintaining blood glucose between 140 and 180 mg/dL in patients with diabetes or hyperglycaemia admitted to the intensive cardiac care unit for acute cardiac events. PMID- 25735301 TI - A cross-sectional assessment of the prevalence of multiple chronic conditions and medication use in a sample of community-dwelling adults with fibromyalgia in Olmsted County, Minnesota. AB - OBJECTIVES: The objective of this study was to evaluate the problem of multiple chronic conditions and polypharmacy in patients with fibromyalgia. DESIGN: Retrospective medical record review. SETTING: Olmsted County, Minnesota. PARTICIPANTS: 1111 adults with fibromyalgia. PRIMARY AND SECONDARY OUTCOME MEASURES: Number and type of chronic medical and psychiatric conditions, medication use. RESULTS: Medical record review demonstrated that greater than 50% of the sample had seven or more chronic conditions. Chronic joint pain/degenerative arthritis was the most frequent comorbidity (88.7%), followed by depression (75.1%), migraines/chronic headaches (62.4%) and anxiety (56.5%). Approximately, 40% of patients were taking three or more medications for symptoms of fibromyalgia. Sleep aids were the most commonly prescribed medications in our sample (33.3%) followed by selective serotonin reuptake inhibitors (28.7%), opioids (22.4%) and serotonin norepinephrine reuptake inhibitors (21.0%). CONCLUSIONS: The results of our study highlight the problem of multiple chronic conditions and high prevalence of polypharmacy in fibromyalgia. Clinicians who care for patients with fibromyalgia should take into consideration the presence of multiple chronic conditions when recommending medications. PMID- 25735302 TI - Gene-expression novelty in allopolyploid cotton: a proteomic perspective. AB - Allopolyploidization is accompanied by changes in gene expression that are thought to contribute to phenotypic diversification. Here we describe global changes in the single-celled cotton fiber proteome of two natural allopolyploid species (Gossypium hirsutum and G. barbadense) and living models of their diploid parents using two different proteomic approaches. In total, 1323 two-dimensional gel electrophoresis spots and 1652 identified proteins by isobaric tags for relative and absolute quantitation were quantitatively profiled during fiber elongation. Between allopolyploids and their diploid A- and D-genome progenitors, amounts of differential expression ranged from 4.4 to 12.8%. Over 80% of the allopolyploid proteome was additively expressed with respect to progenitor diploids. Interestingly, the fiber proteome of G. hirsutum resembles the parental A-genome more closely, where long, spinable fiber first evolved, than does the fiber proteome of G. barbadense. More protein expression patterns were A-dominant than D-dominant in G. hirsutum, but in G. barbadense, the direction of expression level dominance switched from the D-genome to the A-genome during fiber development. Comparison of developmental changes between the two allopolyploid species revealed a high level of proteomic differentiation despite their shared ancestry, relatively recent evolutionary divergence, and similar gross morphology. These results suggest that the two allopolyploid species have achieved superficially similar modern fiber phenotypes through different evolutionary routes at the proteome level. We also detected homeolog-specific expression for 1001 proteins and present a novel approach to infer the relationship between homeolog-specific and duplicate expression patterns. Our study provides a proteomic perspective on understanding evolutionary consequences of allopolyploidization, showing how protein expression has been altered by polyploidization and subsequently has diversified among species. PMID- 25735307 TI - The reverse glove technique to remove strangulated fingers. PMID- 25735305 TI - Genetic analysis of members of the species Oropouche virus and identification of a novel M segment sequence. AB - Oropouche virus (OROV) is a public health threat in South America, and in particular in northern Brazil, causing frequent outbreaks of febrile illness. Using a combination of deep sequencing and Sanger sequencing approaches, we determined the complete genome sequences of eight clinical isolates that were obtained from patient sera during an Oropouche fever outbreak in Amapa state, northern Brazil, in 2009. We also report the complete genome sequences of two OROV reassortants isolatd from two marmosets in Minas Gerais state, south-east Brazil, in 2012 that contained a novel M genome segment. Interestingly, all 10 isolates possessed a 947 nt S segment that lacked 11 residues in the S-segment 3' UTR compared with the recently redetermined Brazilian prototype OROV strain BeAn19991. OROV maybe circulating more widely in Brazil and in the non-human primate population than previously appreciated, and the identification of yet another reassortant highlights the importance of bunyavirus surveillance in South America. PMID- 25735308 TI - Pyrocarbon proximal interphalangeal joint arthroplasty: a medium to long term follow-up of a single surgeon series. AB - We retrospectively reviewed a consecutive single surgeon series of 57 Ascension pyrocarbon proximal interphalangeal joint arthroplasties, with a mean follow-up of 7.1 years (range 2 years to 11 years 6 months). We assessed the ranges of motion, deformity, stability and pain of the operated joints, grip strength of the hand and patient satisfaction. Of the cases, 44 were for osteoarthritis, five for rheumatoid arthritis and eight for post-traumatic arthritis. The median post operative active arc of motion was from 0 degrees to 60 degrees . The median post-operative visual analogue pain score was 0.3 out of ten. Thirty six of the joints had no complications; 14 had minor complications (squeak, slight swan neck); three required early reoperation (joint release, flexor tenodesis); and five required implant removal. A total of 69% of our patients would have the same operation if they had to make the decision again. The Kaplan-Meier survival method estimates the mean implant survival to be 10.7 years (95% confidence intervals 9.96-11.37 years). All five failures occurred during the first 2 years.Level of evidence 4 (Case-series). PMID- 25735309 TI - Methodology of development of a Delirium clinical application and initial feasibility results. AB - BACKGROUND: Delirium is a highly prevalent condition in the hospital settings, with prevalence rates ranging from 6% to 56%, based on previous studies. A recent review provides evidence for the need of practice tools at the point of care to increase impact and to improve patient outcomes related to delirium care. The major challenge is to help maintain the skill-sets required by clinicians and allied healthcare workers over time. There have been massive advancements in smartphone technologies, as well as several papers being published recently about how clinicians could be application developers. OBJECTIVE: The following study will serve to illustrate how the authors made use of the latest advances in application creation technologies in designing a Delirium education application, containing protocols that are appropriate to their healthcare setting. The study in itself will serve as a pilot project aimed at implementing smartphone technologies in delirium education, to determine its feasibility as well as user's perspectives towards such an implementation. METHODOLOGY: The Delirium UHN Application was developed between the months of February 2013 to September 2014. Making use of the methodologies shared by Zhang MWB et al., the authors embarked on the development of the web-based and the native application. The web-based application was developed using HTML5 programming language and with the aid of an online application builder. Psychiatry residents and allied health professionals, at the University of Toronto were recruited to help evaluate the pilot web-based version of the application. RESULTS: Since the introduction of the web-based application during the delirium awareness week, there has been a total of 1165 unique access to the online web-based application. Of significance, there is a shift in the confidence levels of the participants with regards to the management of delirium after using the application. The majority of the participants (44.0%) reported being moderately comfortable with managing delirium prior to the usage of the application, but this changed after the implementation of the application, with 39.0% reporting being very confident and 44.0% being extremely confident about managing delirium after using the application. 69.0% of the participants also perceived the smartphone application to be of use to their clinical care for delirious patients. CONCLUSIONS: This study is one of the first to demonstrate the potential usage of smartphone innovations in delirium education. The current study demonstrated the added feasibility of smartphone applications, and demonstrated that users perceived that they are more abled with managing delirium after the usage of the smartphone application. PMID- 25735310 TI - Immediate effects of ankle balance taping with kinesiology tape on the dynamic balance of young players with functional ankle instability. AB - BACKGROUND: Soccer, one of the most popular and well-known sports worldwide, involves complex motions such as running, quick changes in direction, jumping, and landing, all of which have a high risk of injury. Among them, ankle injuries are the most frequent. OBJECTIVE: This study investigated the immediate effects of ankle balance taping (ABT) with kinesiology tape on the dynamic balance of young male soccer players with functional ankle instability (FAI). METHODS: Nine young male soccer players with FAI in their dominant ankle were randomly subjected to no-, placebo-, and real-ABT conditions. After the appropriate treatment was administered, the dynamic balance was measured using the Star Excursion Balance Test (SEBT). RESULTS: In terms of the anterior and posterolateral reach distances on the SEBT, the real-ABT condition showed statistically significant increases compared to the no- and placebo-ABT conditions (p < 0.05), while in the case of posteromedial reach distances, the real-ABT condition showed a statistically significant increase (p < 0.05) compared to the no-ABT condition. CONCLUSION: ABT using kinesiology tape can be expected to improve the dynamic balance of young male soccer players with FAI. PMID- 25735311 TI - Biomechanical evaluation of a new technique for external fixation of unstable supracondylar humerus fractures in children. AB - BACKGROUND: Closed reduction and percutaneous pinning is regarded as the treatment of choice for unstable supracondylar humerus fractures, but there are cases in which the use of external fixation is preferable. OBJECTIVE: The aim of this study was to investigate whether the method of external fixation could be considered as a stable alternative to percutaneous pinning and whether there was a difference in stability between two different external fixator constructs. METHODS: Eighteen synthetic humeri were allocated to three groups of six bones each. The specimens of group 1 were fixed by crossed pinning, those of group 2 by a new variation of an external fixator and the specimens of group 3 by an established variation of it. Osteotomy displacement was measured under static loading in internal and external rotation, as well as in extension and flexion. RESULTS: The external fixators proved to be significantly more stable than crossed pinning in sagittal loading. In internal rotation loading the new variation of the external fixator showed the best results. CONCLUSIONS: In case of fractures that can't be replaced by closed reduction the new variation of external fixator should be preferred to the established variation or open reduction and crossed pinning. PMID- 25735312 TI - Harmonic to noise ratio improvement in oesophageal speech. AB - BACKGROUND: This manuscript presents oesophageal speech enhancement. Patients who have undergone a laryngectomy as a result of larynx cancer, that is, laryngectomees, have communication problems. Due to removal of the larynx, oesophageal speech has extremely low intelligibility. OBJECTIVE: Thus, it is necessary to process acoustical parameters, such as Harmonic to Noise Ratio (HNR) in order to increase intelligibility. METHODS: The research focused on oesophageal Spanish /a/ phoneme improvement. In order to enhance oesophageal speech two techniques were applied: Kalman filtering and an algorithm which stabilizes the vocal tract poles. Speech enhancement was measured using the MDVP tool. The oesophageal voice database was compiled with the help of the local association of laryngectomees. RESULTS: The results show an average improvement of 4.2 dB in the HNR. Statistically, differences on average between the original and processed voices, (p < 0.001) for HNR parameter were proven to be significant and we therefore conclude that voice quality was improved due to evidence of a higher HNR on average. CONCLUSIONS: As a conclusion, the study confirms oesophageal voice enhancement since speech parameters are closer to the normal average range. Subjectively, the oesophageal breathing noise is reduced substantially, as is reflected in the MOS test. PMID- 25735313 TI - Treadmill training with tilt sensor functional electrical stimulation for improving balance, gait, and muscle architecture of tibialis anterior of survivors with chronic stroke: A randomized controlled trial. AB - BACKGROUND: Gait training is important for stroke rehabilitation, such as using the treadmill training with functional electrical stimulation (FES). OBJECTIVE: This study was to investigate the effects of the treadmill training with tilt sensor FES on the balance, gait, and muscle architecture of the tibialis anterior in stroke survivors. METHODS: The study was a randomized controlled trial. Thirty four stroke survivors were recruited and screened eligibility criteria. Thirty two participants were randomly allocated to two groups using random allocation software: Treadmill training with Tilt Sensor FES (TTSF) group (n= 16) and Treadmill training with Placebo Tilt Sensor FES (TPTSF) group (n= 16). TTSF group performed gait training on treadmill with tilt sensor FES, and TPTSF group performed gait training on treadmill with placebo tilt sensor FES. Two participants were dropped during this study, and 30 participants were included at post-test. Balance and gait were measured using the timed up and go (TUG) test, berg balance scale (BBS), and 10 m walk test (10 mWT). Ultrasound imaging was used to measure the muscle architecture of the tibialis anterior. RESULTS: After intervention, there were significant improvements in the TUG, BBS, and 10 mWT compared to baseline in both groups (p< 0.05). At follow-up, the TUG, BBS, 10 mWT, and muscle architecture of tibialis anterior on the paretic side showed significant improvements in the TTSF group compared to TPTSF group (p< 0.05). CONCLUSIONS: The findings of this study suggest that TTSF can be an effective intervention for improving balance, gait ability, and muscle architecture of tibialis anterior of stroke survivors. PMID- 25735314 TI - Life expectancy of colon, breast, and testicular cancer patients: an analysis of US-SEER population-based data. AB - BACKGROUND: Cancer survivorship is an increasingly important issue in cancer control. Life expectancy of patients diagnosed with breast, colon, and testicular cancers, stratified by age at diagnosis and time since diagnosis, is provided as an indicator to evaluate future mortality risks and health care needs of cancer survivors. PATIENTS AND METHODS: The standard period life table methodology was applied to estimate excess mortality risk for cancer patients diagnosed in 1985 2011 from SEER registries and mortality data of the general US population. The sensitivity of life expectancy estimates on different assumptions was evaluated. RESULTS: Younger patients with colon cancer showed wider differences in life expectancy compared with that of the general population (11.2 years in women and 10.7 in men at age 45-49 years) than older patients (6.3 and 5.8 at age 60-64 years, respectively). Life expectancy progressively increases in patients surviving the first years, up to 4 years from diagnosis, and then starts to decrease again, approaching that of the general population. For breast cancer, the initial drop in life expectancy is less marked, and again with wider differences in younger patients, varying from 8.7 at age 40-44 years to 2.4 at ages 70-74 years. After diagnosis, life expectancy still decreases with time, but less than that in the general population, slowly approaching that of cancer-free women. Life expectancy of men diagnosed with testicular cancer at age 30 years is estimated as 45.2 years, 2 years less than cancer-free men of the same age. The difference becomes 1.3 years for patients surviving the first year, and then slowly approaches zero with increasing survival time. CONCLUSIONS: Life expectancy provides meaningful information on cancer patients, and can help in assessing when a cancer survivor can be considered as cured. PMID- 25735315 TI - Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN). AB - A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, radiopharmaceuticals and radiation therapy, and bone targeted therapies. Many of these agents can be nephrotoxic, including targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here, we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to vascular endothelial growth factor or VEGF receptor(s) (VEGF/VEGFR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor2 (HER2), BRAF, anaplastic lymphoma kinase (ALK), programmed cell death protein-1 or its ligand (PD-1/PDL-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and mammalian target of rapamycin (mTOR). The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers. PMID- 25735316 TI - Integrative molecular profiling of routine clinical prostate cancer specimens. AB - BACKGROUND: Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. PATIENTS AND METHODS: We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. RESULTS: We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. CONCLUSIONS: Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications. PMID- 25735318 TI - Atrial Septal Aneurysms and Supraventricular Arrhythmias: The Role of Atrial Electromechanical Delay. AB - BACKGROUND: Paroxysmal supraventricular arrhythmias (SVAs) frequently occur in patients with atrial septal aneurysm (ASA). The aim of the current study was to evaluate the electrocardiographic (P-wave duration and dispersion) and echocardiographic (atrial electromechanical delay, AEMD) noninvasive indicators of atrial conduction heterogeneity in healthy ASA subjects without interatrial shunt and to assess the AEMD role in predicting the SVAs onset in this population. MATERIALS AND METHODS: One hundered ASA patients (41 males, mean age of 32.5 +/- 8 years) and 100 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of SVAs during a 4-year follow-up, through 30-day external loop recorder (ELR) monitoring performed every 3 months. ASAs were diagnosed by transthoracic echocardiography based on the criteria of a minimal aneurismal base of >=15 mm and an excursion of >=10 mm. Intra-AEMD and inter-AEMD of both atria were measured through tissue Doppler echocardiography. P wave dispersion (PD) was carefully measured using 12-lead electrocardiogram (ECG). RESULTS: Compared to the healthy control group, the ASA group showed a statistically significant increase in inter-AEMD, intra-left AEMD, maximum P-wave duration, and PD. Dividing the ASA group into 2 subgroups (patients with or without SVAs), the inter-AEMD, intra-left AEMD, P max, and PD were significantly higher in the subgroup with SVAs compared to the subgroup without SVAs. There were significant good correlations of intra-left AEMD and inter-AEMD with PD. A cutoff value of 40.1 msec for intra-left AEMD had a sensitivity of 82% and a specificity of 83% in identifying ASA patients at risk for SVA. CONCLUSION: Our results showed that the echocardiographic AEMD indices (intra-left and inter AEMD) and the PD were significantly increased in healthy ASA subjects without interatrial shunt. PD and AEMD represent noninvasive, inexpensive, useful, and simple parameters to assess the SVAs' risk in ASA patients. PMID- 25735317 TI - Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. AB - BACKGROUND: We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT). PATIENTS AND METHODS: mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups. RESULTS: Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2-10.3] and 8.4 (95% CI 7.2-9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70-1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. CONCLUSIONS: The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population. CLINICAL TRIAL NUMBER: NCT01878422. PMID- 25735319 TI - Comparing the driving behaviours of individuals with frontotemporal lobar degeneration and those with Alzheimer's disease. AB - BACKGROUND: Assessing driving aptitude in dementia patients is critically important for both patient and public safety. However, there have been only a few reports on the driving behaviours and accident risk of patients with dementia, especially frontotemporal lobar degeneration (FTLD). Therefore, we compared the characteristics of driving behaviours in patients with FTLD and those with Alzheimer's disease (AD). METHODS: The subjects were 28 FTLD and 67 AD patients who visited the Department of Psychiatry, Kochi Medical School Hospital. We conducted semi-structured interviews with their families and caregivers about traffic accident history and changes in patient driving behaviours after dementia onset and then compared the findings between the two groups. RESULTS: Overall changes in driving behaviours were reported in 89% (25/28) and 76% (51/67) of the FTLD and AD patients, respectively (P = 0.17). In the FTLD group, difficulty in judging inter-vehicle distances, ignoring road signs and traffic signals, and distraction were reported in 50% (14/28), 61% (17/28), and 50% (14/28) of patients, respectively, and 75% (21/28) patients had caused a traffic accident after dementia onset. The risk of causing an accident was higher in the FTLD group than in the AD group (odds ratio = 10.4, 95% confidence interval = 3.7 29.1). In addition, the mean duration between dementia onset and a traffic accident was 1.35 years in the FTLD group compared with 3.0 years in the AD group (P < 0.01). CONCLUSIONS: Patients with FTLD were more likely to show dangerous driving behaviours than those with AD, and the risk of causing a traffic accident may be higher in patients with FTLD from an early disease stage. PMID- 25735320 TI - Verification of the correlation between progression-free survival and overall survival considering magnitudes of survival post- progression in the treatment of four types of cancer. AB - BACKGROUND: With development and application of new and effective anti-cancer drugs, the median survival post-progression (SPP) is often prolonged, and the role of the median SPP on surrogacy performance should be considered. To evaluate the impact of the median SPP on the correlation between progression-free survival (PFS) and overall survival (OS), we performed simulations for treatment of four types of cancer, advanced gastric cancer (AGC), metastatic colorectal cancer (MCC), glioblastoma (GBM), and advanced non-small-cell lung cancer (ANSCLC). MATERIALS AND METHODS: The effects of the median SPP on the statistical properties of OS and the correlation between PFS and OS were assessed. Further, comparisons were made between the surrogacy performance based on real data from meta-analyses and simulation results with similar scenarios. RESULTS: The probability of a significant gain in OS and HR for OS was decreased by an increase of the SPP/ OS ratio or by a decrease of observed treatment benefit for PFS. Similarly, for each of the four types of cancer, the correlation between PFS and OS was reduced as the median SPP increased from 2 to 12 months. Except for ANSCLC, for which the median SPP was equal to the true value, the simulated correlation between PFS and OS was consistent with the values derived from meta analyses for the other three kinds of cancer. Further, for these three types of cancer, when the median SPP was controlled at a designated level (i.e., < 4 months for AGC, < 12 months for MCC, and <6 months for GBM), the correlation between PFS and OS was strong; and the power of OS reached 34.9% at the minimum. CONCLUSIONS: PFS is an acceptable surrogate endpoint for OS under the condition of controlling SPPs for AGC, MCC, and GBM at their limit levels; a similar conclusion cannot be made for ANSCLC. PMID- 25735321 TI - Impact of bilateral breast cancer on prognosis: synchronous versus metachronous tumors. AB - BACKGROUND: The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. MATERIALS AND METHODS: Between 2005 and 2009 we identified 110 cases of bilateral breast cancer (BBC) ; 49 patients had synchronous (duration between the occurrence of carcinoma in both breasts was less than 12 months) and 61 had metachronous (duration was more than one year with no ipsilateral local recurrence). We compared the patient characteristics including age, menopausal status, clinical stage, tumor size, histological classification, lymph node status, and hormone receptor and Her-2 status. We also compared the treatment given and overall and disease free survival (DFS) of both groups. RESULTS: Synchronous cases tend to present more aggressively than metachronous cases and age at first presentation adversely affects survival. The 5 year overall survival was 78.7% for metachronous and 60% for synchronous. Patients with positive hormonal status had better five year disease free survival in metachronous compared to synchronous cases, at 76% and 63%, respectively. Age at first presentation >45years had better DFS (65%) compared to those with age <=45 years (52%) at 5 years follow up. CONCLUSIONS: Patients with synchronous breast cancer may have worse prognosis. Young age and hormone receptor negative were risk factors in our study. Close follow up and early detection of contralateral breast cancer is mandatory. PMID- 25735322 TI - Plasma phosphoproteome and differential plasma phosphoproteins with opisthorchis viverrini-related cholangiocarcinoma. AB - This study was conducted to investigate the plasma phosphoproteome and differential plasma phosphoproteins in cases of of Opisthorchis viverrini (OV) related cholangiocarcinoma (CCA). Plasma phosphoproteomes from CCA patients (10) and non-CCA subjects (5 each for healthy subjects and OV infection) were investigated using gel-based and solution-based LC-MS/MS. Phosphoproteins in plasma samples were enriched and analyzed by LC-MS/MS. STRAP, PANTHER, iPath, and MeV programs were applied for the identification of their functions, signaling and metabolic pathways; and for the discrimination of potential biomarkers in CCA patients and non-CCA subjects, respectively. A total of 90 and 60 plasma phosphoproteins were identified by gel-based and solution-based LC-MS/MS, respectively. Most of the phosphoproteins were cytosol proteins which play roles in several cellular processes, signaling pathways, and metabolic pathways (STRAP, PANTHER, and iPath analysis). The absence of serine/arginine repetitive matrix protein 3 (A6NNA2), tubulin tyrosine ligase-like family, member 6, and biorientation of chromosomes in cell division protein 1-like (Q8NFC6) in plasma phosphoprotein were identified as potential biomarkers for the differentiation of healthy subjects from patients with CCA and OV infection. To differentiate CCA from OV infection, the absence of both serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform and coiled-coil domain-containing protein 126 precursor (Q96EE4) were then applied. A combination of 5 phosphoproteins may new alternative choices for CCA diagnosis. PMID- 25735323 TI - Impact of age, tumor size, lymph node metastasis, stage, receptor status and menopausal status on overall survival of breast cancer patients in Pakistan. AB - BACKGROUND: Survival of breast cancer patients depends on a number of factors which are not only prognostic but are also predictive. A number of studies have been carried out worldwide to find out prognostic and predictive significance of different clinicopathological and molecular variables in breast cancer. This study was carried out at Nuclear Medicine, Oncology and Radiotherapy Institute (NORI), Islamabad, to find out the impact of different factors on overall survival of breast cancer patients coming from Northern Pakistan. MATERIALS AND METHODS: This observational retrospective study was carried out in the Oncology Department of NORI Hospital. A total of 2,666 patients were included. Data were entered into SPSS 20. Multinomial logistic regression analysis was performed to determine associations of different variables with overall survival. P values <0.05 were considered significant. RESULTS: The mean age of the patients was 47.6 years, 49.5% being postmenopausal. Some 1,708 were ER positive and 1,615 were PR positive, while Her 2 neu oncogene positivity was found in 683. A total of 1,237 presented with skin involvement and 426 had chest wall involvement. Some 1,663 had > 5cm tumors. Lymph node involvement was detected in 2,131. Overall survival was less than 5 years in 669 patients, only 324 surviving for more than 10 years, and in the remainder overall survival was in the range of 5-10 years. CONCLUSIONS: Tumor size, lymph node metastases, receptor status, her 2 neu positivity, skin involvement, and chest wall involvement have significant effects whereas age and menopausal status have no significant effect on overall survival of breast cancer patients in Pakistan. PMID- 25735324 TI - Short low concentration cisplatin treatment leads to an epithelial mesenchymal transition-like response in DU145 prostate cancer cells. AB - BACKGROUND: Prostate cancer is one of the main causes of cancer death, and drug resistance is the leading reason for therapy failure. However, how this occurs is largely unknown. We therrfore aimed to study the response of DU145 cells to cisplatin. MATERIALS AND METHODS: Du145 prostate cancer cells were treated with a low dose of cisplatin for 24 h and cell viability and number were determined by MTT assay and trypan blue exclusion assay, respectively. The real time polymerase chain reaction (PCR) was used to assess responses to cisplatin treatment. RESULTS: After 24h 2 MUg/ml treatment did not result in significant reduction in cell viability or number. However, it led to enhanced cancer cell invasiveness. E cadherin mRNA was reduced, and vimentin, Snail, Slug, metalloproteinase 9 (MMP9) mRNA expression increased significantly, a feature of epithelial-mesenchymal transition (EMT). CONCLUSIONS: Short time low concentration cisplatin treatment leads to elevated invasiveness of DU145 cancer cells and this is possibly due to EMT. PMID- 25735325 TI - Expression of glypican-3 is highly associated with pediatric hepatoblastoma: a systemic analysis. AB - OBJECTIVE: Glypican-3 (GPC3) is reported to be an oncofetal protein that is a useful diagnostic immunomarker for hepatoblastoma. However, the results are not inclusive. This study systemically investigated the association between expression of GPC3 and pediatric hepatoblastoma. METHODS: Clinical studies evaluating the association were identified using a predefined search strategy. GPC3 immunohistochemistry was applied in the pathological diagnosis of hepatoblastoma using the monoclonal antibodies with formalin-fixed and paraffin embedded specimens. Positive predictive rates for the association between expression of GPC3 and pediatric hepatoblastoma were calculated. RESULTS: Specimens from four clinical studies which including 134 patients with pediatric hepatoblastoma tested by GPC3 immunohistochemistry were considered eligible for inclusion. Systemic analysis showed that, in all patients, pooled positive predictive rate of the association between expression of GPC3 and pediatric hepatoblastoma was 95.5% (128/134). CONCLUSION: This systemic analysis suggests that the expression of glypican-3 is highly associated with the diagnosis of pediatric hepatoblastoma. PMID- 25735326 TI - SRD5A2 gene polymorphisms and the risk of benign prostatic hyperplasia but not prostate cancer. AB - BACKGROUND: Testosterone, a primary androgen in males, is converted into its most active form, dihydrotestosterone (DHT), by 5alpha-reductase type 2 (encoded by the SRD5A2 gene) in the prostate. DHT is necessary for prostatic growth and has five times higher binding affinity than testosterone for androgen receptors. We hypothesized that polymorphic variations in the SRD5A2 gene may affect the risk of benign prostatic hyperplasia and prostate cancer. MATERIALS AND METHODS: We analyzed SRD5A2 gene polymorphisms in 217 BPH patients, 192 PCa cases, and 171 controls. Genotyping was undertaken using direct DNA sequencing. Genotype data were compared between cases and controls using a Chi square statistical tool. RESULTS: We found that the A49T locus was monomorphic with 'AA' genotype in all subjects. At V89L locus, the presence of 'VV' showed a marginally significant correlation with increased BPH risk (p=0.047). At the (TA)n locus, longer TA repeats were found to be protective against BPH (p=0.003). However, neither of these polymoprhisms correlated with the risk of PCa. CONCLUSIONS: We conclude that A49T is monomorphic in the study population, VV marginally correlates with BPH risk, and longer (TA)n repeats are protective against BPH. None of these polymorphisms affect the risk of PCa. PMID- 25735327 TI - Genotypes of hepatitis C virus in relapsed and non-respondent patients and their response to anti-viral therapy in district Mardan, Khyber Pakhtunkhawa, Pakistan. AB - Hepatitis C is a blood-borne infectious disease of liver, caused by a small enveloped, positive-single stranded RNA virus, called the hepatitis C virus (HCV). HCV belongs to the Flaviviridae family and has 6 genotypes and more than 100 subtypes. It is estimated that 185 million people are infected with HCV worldwide and 5% of these are in Pakistan. The study was designed to evaluate different genotypes of HCV circulating in District Mardan and to know about the behavior of these genotypes to different anti-viral regimes. In this study 3,800 patients were exposed to interferon alfa-2a plus Ribavirin treatment for 6-months and subjected to real-time PCR to check the viral response. Among these 3,677 (97%) patients showed no detectable HCV RNA while 123 (3%) patients (non responders) remained positive for HCV RNA. Genotypes of their analyzed showed that most of them belonged to the 3a genotype. Non-responders (123) and relapsed (5) patients were subjected to PEG-interferon and Ribavirin therapy for next 6 months, which resulted into elimination of HCV RNA from 110 patients. The genotypes of the persisting resistant samples to anti-viral treatment were 3b, 2a, 1a and 1b. Furthermore, viral RNA from 6 patients remained un-typed while 4 patients showed mixed infections. HCV was found more resistant to antiviral therapy in females as compared to mals. The age group 36-45 in both females and males was found most affected by infection. In general 3a is the most prevalent genotype circulating in district Mardan and the best anti-viral therapy is PEG interferon plus Ribavirin but it is common practice that due to the high cost patients receive interferon alfa-2a plus Ribavirin with consequent resistance in 3% patients given this treatment regime. PMID- 25735328 TI - Expression of Cox-2 and Bcl-2 in Paget's disease of the breast. AB - BACKGROUND: Paget's disease (PD) is a rare form of intraepithelial adenocarcinoma that involves breast and extramammarian tissues. It is often associated with ductal carcinoma in situ and/or invasive ductal cancer. Molecular pathways that play a role in development of Paget's disease are stil unclear. Expression patterns of Cox-2 and bcl-2 were therefore assessed. MATERIALS AND METHODS: Patients with a histopathological diagnosis of Paget's disease were included in this study. Patient files were analysed retrospectively. RESULTS: Invasive cancer was diagnosed in 35 (76.1%) of the patients, 7 (15.2%) had ductal carcinoma in situ and 4 (8.7%) patients had no associated neoplasm. Twenty four (52.2%) patients showed COX-2 expression in Paget cells whereas no expression was seen in 22 (47.8%) patients. No relation was found between COX-2 expression and the lesion underlying Paget's disease (p=0.518). Bcl-2 expression in Paget cells was found positive in 12 (26.1%) and negative in 27 (58,7%) cases. There was no relation between Bcl-2 expression and the lesion accompanying Paget's disease (p=0.412). No relation was observed between COX-2 expression and Bcl-2 expression (p=0.389). CONCLUSIONS: In breast cancer, COX-2 expression is associated with poor prognostic factors. As COX-2 expression increases the tendency to metastasize also increases. In our study we found a significantly high COX-2 expression in Paget's disease of the breast. We suggest that COX-2 expression and inflammatory processes may play a role in pathogenesis of the Paget's disease of the breast. PMID- 25735329 TI - Pathological investigation of vertebral tumor metastasis from unknown primaries- a systematic analysis. AB - BACKGROUND: This systematic analysis was conducted to investigate pathological diagnosis of vertebral tumor metastasis with unknown primaries. METHODS: Clinical studies conducted to pathologically investigate vertebral tumor metastasis were identified using a predefined search strategy. Pooled diagnosis (PD) of each pathological confirmation was calculated. RESULTS: For vertebral tumor metastasis, 5 clinical studies which included 762 patients were considered eligible for inclusion. Systematic analysis suggested that, for all patients with vertebral tumor metastasis, dominant PD was pathologically confirmed with lung cancer in 21.7% (165/762), with breast cancer in 26.6% (203/762) and with prostate cancer in 19.2% (146/762) . Other diagnosis that could be confirmed included lymphoma, multiple myeloma, renal cancer, for example, in this cohort of patients. CONCLUSIONS: This systemic analysis suggested that breast, lung and prostate lesions could be the most common pathological types of cancer for vertebral tumor metastasis formunknown primaries, and other common diagnoses could include lymphoma, multiple myeloma, renal cancer. PMID- 25735330 TI - Polymorphisms in genes of the de novo lipogenesis pathway and overall survival of hepatocellular carcinoma patients undergoing transarterial chemoembolization. AB - Aberrant expression of genes in de novo lipogenesis (DNL) pathway were associated with various cancers, including hepatocellular carcinoma (HCC). Single nucleotide polymorphisms (SNPs) of DNL genes have been reported to be associated with prognosis of some malignancies. However, the effects of SNPs in DNL genes on overall survival of HCC patients receiving transarterial chemoembolization (TACE) treatment are still unknown. In present study, nine SNPs in three genes (ACLY, ACACA and FASN) in DNL pathway were genotyped using the Sequenom iPLEX genotyping system in a hospital-based cohort with 419 HCC patients treated with TACE, and their associations with HCC overall survival were evaluated by Cox proportional hazard regression analysis under three genetic models (additive, dominant and recessive). Although we did not find any significant results in total analysis (all p>0.05), our stratified data showed that SNP rs9912300 in ACLY gene was significantly associated with overall survival of HCC patients with lower AFP level and SNP rs11871275 in ACACA gene was significantly associated with overall survival of HCC patients with higher AFP level. We further identified the significant interactions between AFP level and SNP rs9912300 or rs11871275 in the joint analysis. Conclusively, our data suggest that genetic variations in genes of DNL pathway may be a potential biomarker for predicting clinical outcome of HCC patients treated with TACE. PMID- 25735331 TI - Systematic review of available guidelines on fertility preservation of young patients with breast cancer. AB - BACKGROUND: Since the survival rate of breast cancer patients has improved, harmful effects of new treatment modalities on fertility of the young breast cancer patients has become a focus of attention. This study aimed to systematically review and critically appraise all available guidelines for fertility preservation in young breast cancer patients. MATERIALS AND METHODS: Major citation databases were searched for treatment guidelines. Experts from relevant disciplines appraised the available guidelines. The AGREE II Instrument that includes 23 criteria in seven domains (scope and purpose of the guidelines, stakeholder involvement, rigor of development, clarity, applicability, editorial independence, and overall quality) was used to apprise and score the guidelines. RESULTS: The search strategy retrieved 2,606 citations; 72 were considered for full-text screening and seven guidelines were included in the study. There was variability in the scores assigned to different domains among the guidelines. ASCO (2013), with an overall score of 68.0%, had the highest score, and St Gallen, with an overall score of 24.7%, had the lowest scores among the guidelines. CONCLUSIONS: With the promising survival rate among breast cancer patients, more attention should be given to include specific fertility preservation recommendations for young breast cancer patients. PMID- 25735332 TI - Cognitive behavioral therapy in breast cancer patients--a feasibility study of an 8 week intervention for tumor associated fatigue treatment. AB - BACKGROUND: Tumor associated fatigue (TAF) or cancer related fatigue (CRF) is not a new concept. Nonetheless, no real headway has been made in the quantitative analysis of its successful treatment via cognitive behavioral therapy. Since 20 to 30% of all breast cancer patients suffer from anxiety and/or depression within the first year of their diagnosis, this issue needs to be addressed and a standard treatment protocol has to be developed. This study focused on developing a simple, reproducible and short (8 weeks) protocol for the cognitive behavioral therapy support of tumor associated fatigue patients. MATERIALS AND METHODS: Between the year 2011 and 2012, 23 breast cancer patients fulfilled the diagnosis TAF requirements and were introduced into this study. Our method focused on a psycho-oncological support group using a predetermined, highly structured and reproducible, cognitive behavioral therapy treatment manual. Eight weekly, 90 minute sessions were conducted and patients were evaluated before and after this eight session block. Tumor fatigue specific questionnaires such as the multidimensional fatigue inventory (MFI) as well as the hospital anxiety and depression scale (HADS) were used in order to quantitatively evaluate patient TAF. RESULTS: Of the 23 patients enrolled in the study, only 7 patients fulfilled the TAF diagnostic criteria after the psycho-oncological group treatment. This represents a 70% reduction in diagnosable tumor associated fatigue. The HADS analysis showed a 33% reduction in patient anxiety as well as a 57% reduction in patient depression levels. The MFI scores showed a significant reduction in 4 of the 5 evaluate categories. With the exception of the "mental fatigue" MFI category all results were statistically significant. CONCLUSIONS: This study showed that a highly structured, cognitive behavioral therapy group intervention will produce significant improvements in breast cancer patient tumor associated fatigue levels after only 8 weeks. PMID- 25735333 TI - Mortality determinants in colorectal cancer patients at different grades: a prospective, cohort study in Iran. AB - BACKGROUND: Colorectal cancer (CRC) is an important cause of mortality and morbidity in many communities worldwide. This population based study was conducted to assess determinants of colorectal mortality in Iranian patients. MATERIALS AND METHODS: A cohort of 1,127 cases of confirmed colorectal cancer registered in a population based registry covering 10 referral hospital in Tehran, Iran, were followed for five years. Information about tumor characteristics, smoking status and family history were collected at base line and survival status were followed every six months by contacting patient or next of kin (if patients died during the follow-up). The cause of death for each case was validated by verbal autopsy and referring to patient medical records at the time of death. The data were analyzed by Stata software using univariate and multivariate analysis (Cox regression). In building the model a p value of less than 5% was considered as significant. RESULTS: The age at diagnosis was 53.5+/ 14 years. Sixty one percent were male. Colorectal mortality among the patients was 96.9 person-years among men and 83 person-years among women. Seventy five percent of patients lived for 2.72 years, 50% for 5.83, and 25% for 13 years after the diagnosis of colorectal cancer. The age at diagnosis was significantly different between men and women (p<0.03). Higher tumor grade predicted higher death rate; the adjusted hazard ratios were 1.79 (95%CI, 0.88-3.61), 2.16 (95%CI, 1.07-4.37), and 3.1 (95%CI, 1.51-6.34) for grades II, III, and IV respectively when they were compared with grade I as reference. Ethnicity, marital status, family history of cancer, and smoking were related to survival with different degrees of magnitude. CONCLUSIONS: Among many factors related to survival among the colorectal patients, tumor grade and smoking showed the highest magnitudes of association. PMID- 25735334 TI - Effect of CXCR4 and CD133 co-expression on the prognosis of patients with stage II~III colon cancer. AB - BACKGROUND: To explore the relationship between CXCR4, CD133 co-expression and clinicopathological features as well as prognosis of patients with phase II~III colon cancer. MATERIALS AND METHODS: Forty-nine paraffin-embedded samples of tumor tissue and epithelial tissue adjacent to cancer were collected from patients with colon cancer undergoing radical surgery in Baotou Cancer Hospital from January, 2010 to June, 2011. CXCR4 and CD133 expression was detected using immunohistochemistry and its relationship with clinicopathological features and the 3-year survival rate was analyzed. RESULTS: In the tumor tissue and colonic epithelial tissue adjacent to cancer, the positive expression rates of CXCR4 were respectively 61.2% (30/49) and 8.16% (4/49), while those of CD133 being 36.7% (18/49) and 6.12% (3/49). CXCR4 and CD133 expression in tumor tissue was not related to patient age, gender, primary focal sites, tumor size, TNM staging, histological type, tumor infiltration depth and presence or absence of lymphatic metastasis, but CXCR4 and CD133 co-expression was associated with TNM staging and lymphatic metastasis. The 3-year survival rate of patients with CXCR4 and CD133 co-expression was 27.3% (3/11), and that of the remainderwas 76.3% (29/38), the difference being significant (chi2=7.0206, p=0.0081). CONCLUSIONS: CXCR4 and CD133 co-expression may be a risk factor for poor prognosis of patients with stage II~III colon cancer. PMID- 25735335 TI - RASAL1 attenuates gastric carcinogenesis in nude mice by blocking RAS/ERK signaling. AB - Recent studies have suggested that the RAS protein activator like-1 (RASAL1) functions as a tumor suppressor in vitro and may play an important role in the development of gastric cancer. However, whether or not RASAL1 suppresses tumor growth in vivo remains to be determined. In the present study, we investigated the role of RASAL1 in gastric carcinogenesis using an in vivo xenograft model. A lentiviral RASAL1 expression vector was constructed and utilized to transfect the human poorly differentiated gastric adenocarcinoma cell line, BGC-823. RASAL1 expression levels were verified by quantitative real-time RT-PCR and Western blotting analysis. Then, we established the nude mice xenograft model using BGC 823 cells either over-expressing RASAL1 or normal. After three weeks, the results showed that the over-expression of RASAL1 led to a significant reduction in both tumor volume and weight compared with the other two control groups. Furthermore, in xenograft tissues the increased expression of RASAL1 in BGC-823 cells caused decreased expression of p-ERK1/2, a downstream moleculein the RAS/RAF/MEK/ERK signal pathway. These findings demonstrated that the over-expression of RASAL1 could inhibit the growth of gastric cancer by inactivation of the RAS/RAF/MEK/ERK pathway in vivo. This study indicates that RASAL1 may attenuate gastric carcinogenesis. PMID- 25735337 TI - Knowledge regarding early detection of cancer among romanian women having relatives with cancer. AB - Cancers can be detected in early stages through awareness of suspicious symptoms or by specific actions undertaken by individuals or participation in medical checks or screening programmes. The present research had three objectives: to assess the knowledge of Romanian women who have relatives with cancer with regard to cancer symptoms and detection methods; to identify socio-demographics factors influencing their level of knowledge; provide information regarding the attitudes of women from the study regarding medical help-seeking in case of any symptom which might be associated with cancer. This cross-sectional study was performed in an oncological hospital from Cluj-Napoca, Romania. It involved 160 women aged 18-70 years, who had relatives with cancer. An anonymous questionnaire was filled in by the participants. The results showed that around 10% of the study sample recognized all the 8 listed symptoms associated with cancer and all the 7 listed methods for cancer detection. The results of the linear regression analyses show that the level of knowledge regarding both symptoms and methods for detection was higher among younger women (B=-0.390, p<0.01, respectively B=-0.260; p<0.01), among those living in urban areas (B=0.872, p<0.01, respectively B=0.676; p<0.01) and those having higher educational level (B=0.883, p<0.001, respectively B=0.536; p<0.001). The majority of the participants agreed with the importance of looking for medical help within weeks up to one month in case that a symptom which might be associated with cancer was observed. The study underlines the necessity that much more information should be given to women who have relatives with cancer about what they can do to detect cancer in an early stage. This is especially needed for older women, women living in rural areas and women having a lower educational level. PMID- 25735336 TI - Compliance with smoke-free policies in korean bars and restaurants in california: a descriptive analysis. AB - BACKGROUND: Compliance with California's smoke-free restaurant and bar policies may be more a function of social contingencies and less a function of legal contingencies. The aims of this study were: 1) to report indications of compliance with smoke-free legislation in Korean bars and restaurants in California; 2) to examine the demographic, smoking status, and acculturation factors of who smoked indoors; and 3) to report social cues in opposition to smoking among a sample of Koreans in California. MATERIALS AND METHODS: Data were collected by telephone surveys administered by bilingual interviewers between 2007-2009, and included California adults of Korean descent who visited a Korean bar or restaurant in a typical month (N=2,173, 55% female). RESULTS: 1% of restaurant-going participants smoked inside while 7% observed someone else smoke inside a Korean restaurant. Some 23% of bar-going participants smoked inside and 65% observed someone else smoke inside a Korean bar. Presence of ashtrays was related to indoor smoking in bars and restaurants. Among participants who observed smoking, a higher percentage observed someone ask a smoker to stop (17.6%) or gesture to a smoker (27.0%) inside Korean restaurants (N=169) than inside Korean bars (n=141, 17.0% observed verbal cue and 22.7% observed gesture). Participants who smoked inside were significantly younger and more acculturated than participants who did not. Less acculturated participants were significantly more to likely to be told to stop smoking. CONCLUSIONS: Ten years after implementation of ordinances, smoking appears to be common in Korean bars in California. PMID- 25735338 TI - Knowledge and beliefs of Malaysian adolescents regarding cancer. AB - BACKGROUND: Few studies have explored the knowledge and attitudes of adolescents toward cancer prevention and treatment. This lack of research and its potential utility in the development of new educational initiatives and screening methods, or the reconstruction of existing ones, provided the impetus for this study. The primary research aim was to assess secondary school student knowledge of cancer and determine whether or not they possessed basic knowledge of cancer symptoms, risk factors, and treatments and to determine the relationship between cancer knowledge and key demographic factors. MATERIALS AND METHODS: The Management and Science University conducted a cross-sectional study analyzing responses through cross-tabulation with the socio-demographic data collected. RESULTS: The findings of our quantitative analysis suggest that Malaysian youth generally possess a moderate knowledge about cancer. Quantitative analyses found that socioeconomic inequalities and bias in education present as important factors contributing to cancer awareness, prevention, and treatment among Malaysian adolescents. CONCLUSIONS: The findings indicate that Malaysian youth generally possess a moderate knowledge about cancer but the current deficiencies in initiatives directed to cancer awareness continue to hinder the improvement in prevention of cancer among Malaysian adolescents. PMID- 25735339 TI - Ginsenoside Rh2 differentially mediates microRNA expression to prevent chemoresistance of breast cancer. AB - Chemoresistance is the most common cause of chemotherapy failure during breast cancer (BCA) treatment. It is generally known that the mechanisms of chemoresistance in tumors involve multiple genes and multiple signaling pathways,; if appropriate drugs are used to regulate the mechanisms at the gene level, it should be possible to effectively reverse chemoresistance in BCA cells. It has been confirmed that chemoresistance in BCA cells could be reversed by ginsenoside Rh2 (G-Rh2). Preliminary studies of our group identified some drug- resistance specific miRNA. Accordingly, we proposed that G-Rh2 could mediate drug resistance specific miRNA and corresponding target genes through the gene regulatory network; this could cut off the drug-resistance process in tumors and enhance treatment effects. G-Rh2 and breast cancer cells were used in our study. Through pharmaceutical interventions, we could explore how G-Rh2 could inhibit chemotherapy resistance in BCA, and analyze its impact on related miRNA and target genes. Finally, we will reveal the anti-resistance molecular mechanisms of G-Rh2 from a different angle in miRNA-mediated chemoresistance signals among cells. PMID- 25735340 TI - Pathologic response during chemo-radiotherapy and variation of serum VEGF levels could predict effects of chemo-radiotherapy in patients with esophageal cancer. AB - BACKGROUND: To investigate the relationship between pathologic tumor response to concurrent chemo- radiotherapy and variation of serum VEGF in patients with esophageal cancer. MATERIALS AND METHODS: Forty six patients with esophageal cancer who were treated with concurrent chemo-radiotherapy were enrolled. Endoscopic and pathologic examination was conducted before and four weeks afterwards. Serum level of VEGF was documented before, four weeks later and after chemo-radiotherapy. The relationship between pathologic response and the variation of serum level of VEGF and its influence on the prognosis were investigated. RESULTS: Serum level of VEGF decreased remarkably during and after chemo-radiotherapy in patients whose pathologic response was severe (F=5.393, 4.587, P(0.05). There were no statistical differences of serum VEGF level before, during and after chemo-radiotherapy for patients whose pathologic response was moderate or mild. There were 18 (85.7%), 7 (53.8%) and 6 patients (50.0%) whose serum VEGF level dropped in the severe, moderate and mild group, respectively, with significant differences among these groups (p=0.046). Two year survival rates of patients with severe, moderate and mild pathologic response were 61.9%, 53.8% and 33.3% respectively, and no statistically difference between severe and mild group regarding OS (p=0.245) was tested. CONCLUSIONS: Tumor pathologic response during chemo-radiotherapy and the changes of serum VEGF lever could predict curative effects of chemo-radiotherapy in patients with esophageal cancer. PMID- 25735341 TI - Incidence of cisplatin-induced nephrotoxicity and associated factors among cancer patients in Indonesia. AB - BACKGROUND: Cisplatin is still used as a first-line medication for solid tumors. Nephrotoxicity is a serious side effect that can decrease renal function and restrict applicable doses. This research aimed to obtain the profile of cisplatin induced nephrotoxicity and its associated factors in adult cancer patients at Dharmais National Cancer Hospital (DNCH). MATERIALS AND METHODS: The design was cross-sectional with data obtained from patient medical records. We retrospectively reviewed adult cancer patients treated with cisplatin >=60mg/m2 for at least four consecutive chemotherapy cycles from August 2011 to November 2013. The nephrotoxicity criterion was renal function decline characterized by creatinine clearance <60 ml/min using the Cockroft-Gault (CG) equation. RESULTS: Eighty-eight subjects received at least four chemotherapy cycles of cisplatin. The prevalence of cisplatin nephrotoxicity was 34.1%. Symptoms could be observed after the first cycle of chemotherapy, and the degree of renal impairment was higher with increased numbers of cycles (r=-0.946, r2=89.5%). Factors that affected the decline of renal function were patient age (p=0.008, OR=3.433, 95%CI= 1.363-8.645) and hypertension (p=0.026, OR=2.931, 95%CI=1.120-7.670). CONCLUSIONS: Cisplatin nephrotoxicity occurred in more than one-third of patients after the fourth cycle of chemotherapy and worsened after each cycle despite preventive strategies such as hydration. The decline of renal function induced by cisplatin >=60 mg/m2 was affected by age and hypertension. PMID- 25735342 TI - Lack of influence of the ACE1 gene I/D polymorphism on the formation and growth of benign uterine leiomyoma in Turkish patients. AB - Uterine leiomyomas (ULM), are benign tumors of the smooth muscle cells of the myometrium. They represent a common health problem and are estimated to be present in 30-70% of clinically reproductive women. Abnormal angiogenesis and vascular-related growth factors have been suggested to be associated with ULM growth. The angiotensin-I converting enzyme (ACE) is related with several tumors. The aim of this study was to identify possible correlation between ULM and the ACE I/D polymorphism, to evaluate whether the ACE I/D polymorphism could be a marker for early diagnosis and prognosis. ACE I/D was amplified with specific primer sets recognizing genomic DNA from ULM (n=72) and control (n=83) volunteers and amplicons were separated on agarose gels. The observed genotype frequencies were in agreement with Hardy-Weinberg equilibrium (chi2=2.162, p=0.339). There was no association between allele frequencies and study groups (chi2=0.623; p=0.430 for ACE I allele, chi2=0.995; p=0.339 for ACE D allele). In addition, there were no significant differences between ACE I/D polymorphism genotype frequencies and ULM range in size and number (chi2=1.760; p=0.415 for fibroid size, chi2=0.342; p=0.843 for fibroid number). We conclude that the ACE gene I/D polymorphism is not related with the size or number of ULM fibroids in Turkish women. Thus it cannot be regarded as an early diagnostic parameter nor as a risk estimate for ULM predisposition. PMID- 25735343 TI - High quality tissue miniarray technique using a conventional TV/radio telescopic antenna. AB - BACKGROUND: The tissue microarray (TMA) is widely accepted as a fast and cost effective research tool for in situ tissue analysis in modern pathology. However, the current automated and manual TMA techniques have some drawbacks restricting their productivity. Our study aimed to introduce an improved manual tissue miniarray (TmA) technique that is simple and readily applicable to a broad range of tissue samples. MATERIALS AND METHODS: In this study, a conventional TV/radio telescopic antenna was used to punch tissue cores manually from donor paraffin embedded tissue blocks which were pre-incubated at 40oC. The cores were manually transferred, organized and attached to a standard block mould, and filled with liquid paraffin to construct TmA blocks without any use of recipient paraffin blocks. RESULTS: By using a conventional TV/radio antenna, it was possible to construct TmA paraffin blocks with variable formats of array size and number (2 mm x 42, 2.5-mm x 30, 3-mm x 24, 4-mm x 20 and 5-mm x 12 cores). Up to 2-mm x 84 cores could be mounted and stained on a standard microscopic slide by cutting two sections from two different blocks and mounting them beside each other. The technique was simple and caused minimal damage to the donor blocks. H and E and immunostained slides showed well-defined tissue morphology and array configuration. CONCLUSIONS: This technique is easy to reproduce, quick, inexpensive and creates uniform blocks with abundant tissues without specialized equipment. It was found to improve the stability of the cores within the paraffin block and facilitated no losses during cutting and immunostaining. PMID- 25735344 TI - Primary thyroid lymphoma: multi-slice computed tomography findings. AB - BACKGROUND: The objective of this study was to investigate the MSCT characteristics of PTL in order to enhance the awareness of this uncommon entity among both clinicians and radiologists. MATERIALS AND METHODS: The clinicopathological data and MSCT images of 27 patients with PTL were retrospectively reviewed. The MSCT appearances were classified into three types: type 1, solitary nodule surrounded by normal thyroid tissue; type 2, multiple nodules in the thyroid, and type 3, enlarged thyroid glands with a reduced attenuation with or without peripheral thin hyperattenuating thyroid tissue. RESULTS: The patients were enrolled in the study with a mean age of 68 years (range, 51-86years) and compression symptoms or enlarged cervical lymph nodes at diagnosis. Hashimoto's thyroiditis was in 20 patients. All patients had non Hodgkin lymphoma of B-cell in origin, including 22 cases of diffuse large B-cell lymphoma (DLBCL) and 5 of low-grade B-cell lymphoma of mucosa- associated lymphoid tissue (MALT). For MSCT appearance, type 1 pattern was observed in 2 patients, type 2 in 8, and seventeen type 3 in 17. The lesions occurred in more than one lobe with a mean maximal transverse diameter of 6.9 cm and an ill defined margin. Most tumors showed a homogeneous attenuation equal to that of surrounding muscles before contrast and obvious enhancement after contrast. Cervical lymph node involvement and invasion of the trahea and (or) esophagus were mainly observed in patients with DLBCL. CONCLUSIONS: PTL should be clinically considered in elder patients presenting with a history of Hashimoto's thyroiditis and cervical lymphadenopathy. The MSCT characteristics of PTL includes a mass diffusely affecting more than one thyroid lobe, isointense to muscle and obvious enhancement before and after contrast. DLBCL, the most common histological subtype of PTL, is associated with a higher invasive tendency. PMID- 25735345 TI - Quantitative assessment of the diagnostic role of CDH13 promoter methylation in lung cancer. AB - In order to explore the association between cadherin 13 (CDH13) gene promoter methylation and lung carcinoma (LC) risk, we carried out a meta-analysis with searching of PubMed, Web of Science. Ultimately, 17 articles were identified and analysised by STATA 12.0 software. Overall, we found a significant relationship between CDH13 promoter methylation and LC risk (odds ratio=6.98, 95% confidence interval: 4.21-11.56, p<0.001). Subgroup analyses further revealed that LC risk was increased for individuals carrying the methylated CDH13 compared with those with unmethylated CDH13. Hence, our study identified a strong association between CDH13 gene promoter methylation and LC and highlighted a promising potential for CDH13 methylation in LC risk prediction. PMID- 25735346 TI - Genetic susceptibility to oral cancer due to combined effects of GSTT1, GSTM1 and CYP1A1 gene variants in tobacco addicted patients of Pashtun ethnicity of Khyber Pakhtunkhwa province of Pakistan. AB - Associations of GSTT1, GSTM1 and CYP1A1 gene variants with risk of developing oral cancer were evaluated in this study. A case-control study was conducted in Pashtun population of Khyber Pakhtunkhwa province of Pakistan in which 200 hospital based oral cancer cases and 151 population based healthy controls exposed to similar environmental conditions were included. Sociodemographic data were obtained and blood samples were collected with informed consent for analysis. GSTM1 and GSTT1 were analysed through conventional PCR method while specific RT-PCR method was used to detect CYP1A1 polymorphisms. Results were analyzed for conditional logistic regression model by SPSS version 20. The study shows that patients with either GSTM1 or GSTT1 null genotypes have significantly higher risk of oral cancer (adjusted odds (OR): (3.019 (1.861-4.898) and 3.011(1.865-4.862), respectively), which further increased when either one or both null genes were present in combination (adjusted odds (OR): (3.627 (1.981 6.642 and 9.261 (4.495-19.079), respectively). CYP1A1 rs4646903 gene variants individually showed weak association OR: 1.121 (0.717-1.752); however, in the presence of GSTM1 and/or GSTT1 null genotypes further increasing the association (adjusted odds (ORs): 4.576 (2.038-10.273), 5.593 (2.530-12.362) and 16.10 (3.854 67.260 for GSTM/GSTT null and CYP1A1 wild type, GSTM/GSTT either null and CYP1A1 variant alleles, and all 3 gene polymorphisms combinations, respectively). Our findings suggest that presence of GSTM1 and/or GSTT1 null genotypes along with variant alleles of CYP1A1 may be the risk alleles for oral cancer susceptibility in Pashtun population. PMID- 25735347 TI - Mutation detection of E6 and LCR genes from HPV 16 associated with carcinogenesis. AB - Human papillomavirus (HPV) is responsible for one of the most frequent sexually transmitted infections. The first phylogenetic analysis was based on a LCR region fragment. Nowadays, 4 variants are known: African (Af-1, Af-2), Asian-American (AA) and European (E). However the existence of sub-lineages of the European variant havs been proposed, specific mutations in the E6 and LCR sequences being possibly related to persistent viral infections. The aim of this study was a phylogenetic study of HPV16 sequences of endocervical samples from Cordoba, in order to detect the circulating lineages and analyze the presence of mutations that could be correlated with malignant disease. The phylogenetic analysis determined that 86% of the samples belonged to the E variant, 7% to AF-1 and the remaining 7% to AF-2. The most frequent mutation in LCR sequences was G7521A, in 80% of the analyzed samples; it affects the binding site of a transcription factor that could contribute to carcinogenesis. In the E6 sequences, the most common mutation was T350G (L83V), detected in 67% of the samples, associated with increased risk of persistent infection. The high detection rate of the European lineage correlated with patterns of human migration. This study emphasizes the importance of recognizing circulating lineages, as well as the detection of mutations associated with high-grade neoplastic lesions that could be correlated to the development of carcinogenic lesions. PMID- 25735348 TI - Common misconceptions and future intention to smoke among secondary school students in Malaysia. AB - BACKGROUND: The prevalence of smoking among secondary school children continues to remain unchanged over the last 3 decades even though awareness regarding the health effects of smoking is increasing. Common misconceptions about smoking and parental influence could be factors influencing future intentions to smoke among these students. Hence, we looked at the common misconceptions as well as student perceptions about their future intention to smoke among Form 4 students in Shah Alam, Malaysia. MATERIALS AND METHODS: This study was conducted by distribution of a questionnaire developed as part of the Global Youth Tobacco Survey to Form 4 student in 3 schools at Shah Alam. RESULTS: Prevalence of smoking (current smokers) was 7.5%. Almost half of the children came from families where one or both parents smoked and a third of the parents had no discussion regarding consequences of smoking with them. A large number of students were classified as "triers" as they had tried smoking and were unsure of whether they would not be smoking in the future. Contrary to our expectations, students generally felt smoking did make one feel more uncomfortable and helped one to reduce body weight. Most students seemed to be aware of the ill-effects of smoking on health. They felt they had received adequate information from school regarding the effects on smoking on health. CONCLUSIONS: Our study showed that even though Form 4 students in Shah Alam were knowledgeable about ill-effects of smoking and were taught so as part of their school curriculum, the prevalence of smoking was still high. Students in the "trier group" represent a potential group of future smokers and strategies targeting tobacco control may be aimed at tackling these vulnerable individuals. Efforts are also needed to help educate secondary school children about common misconceptions and dispel myths associated with cigarette smoking. PMID- 25735349 TI - Malignant transformation rate and p53, and p16 expression in teratomatous skin of ovarian mature cystic teratoma. AB - OBJECTIVE: To investigate the incidence of malignant transformation and P53 and P16 expression in teratomatous skin of ovarian mature cystic teratoma. MATERIALS AND METHODS: Data on ovarian teratoma specimens in nearly 10 years were reviewed. P53 and P16 expression were detected by immunohistochemistry in 25 cases of teratomatous skin of ovarian mature cystic teratoma, 20 cases of squamous cell carcinoma and 2 cases of squamous cell carcinoma originated from teratomatous skin. RESULTS: Of 1913 cases of ovarian mature cystic teratoma in nearly 10 years, only two cases of squamous cell carcinoma were found in teratomatous skin, with malignant transformation rate of 0.1045%. P53 expression was detected in 2 cases squamous cell carcinoma originated from teratomatous skin and P16 overexpression in one. There were no expressions of P53 and P16 in 25 cases of teratomatous skin of ovarian mature cystic teratoma. Of 20 cases of squamous cell carcinoma P53 overexpression (positive rate of 55%) was detected in 11 cases, P16 overexpression (positive rate of 35%) in 7 cases. The positive rates of P53 and P16 expression in squamous cell carcinomas were significantly higher than that in the teratomatous skins (p< 0.001, p= 0.002). CONCLUSIONS: There was low risk of malignant transformation in teratomatous skin of ovarian mature cystic teratoma which can be explained by lower P53 and P16 expressionin teratomas than that in squamous cell carcinoma. PMID- 25735350 TI - Steroidal saponins from Paris polyphylla induce apoptotic cell death and autophagy in A549 human lung cancer cells. AB - BACKGROUND: Paris polyphylla (Chinese name: Chonglou) had been traditionally used for a long time and shown anti-cancer action. Based on the previous study that paris polyphylla steroidal saponins (PPSS) induced cytotoxic effect in human lung cancer A549 cells, this study was designed to further illustrate the mechanisms underlying. MATERIALS AND METHODS: The mechanisms involved in PPSS-induced A549 cell death were investigated by phase contrast microscopy and fluorescence microscopy, flow cytometry and western blot analysis, respectively. RESULTS: PPSS decreased the proportion of viable A549 cells, and exposure of A549 cells to PPSS led to both apoptosis and autophagy. Apoptosis was due to activations of caspase 8, caspase-3, as well as cleavage of PARP, and autophagy was confirmed by up regulation of Beclin 1 and the conversion from LC3 I to LC3 II. CONCLUSIONS: PPSS was able to induce lung cancer A549 cell apoptosis and autophagy in vitro, the results underlining the possibility that PPSS would be a potential candidate for intervention against lung cancer. PMID- 25735351 TI - Matrix metalloproteinase-9 -1562T allele and its combination with MMP-2 -735 C allele are risk factors for breast cancer. AB - BACKGROUND: Expression of matrix metalloproteinases (MMPs) is up-regulated in human cancers. The aim of present study was to investigate the role of MMP-9 C 1562T polymorphism and its interaction with MMP- 2 C-735T polymorphism in susceptibility to breast cancer in a population from Western Iran with Kurdish ethnic background. MATERIALS AND METHODS: The study sample of 205 individuals consisted of 101 breast cancer patients and 104 healthy subjects. MMP-9 C-1562T and MMP-2 C-735T variants were identified using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Among 67.4% of studied patients the breast cancer developed in the third and forth decades of the life. The frequency of MMP-9 T allele was 17.3% in patients and 10.1% in controls. The presence of T allele significantly increased the risk of breast cancer by 1.87-fold [OR=1.87 (95% CI 1.05-3.33, p=0.035)]. The frequency of MMP-9 CT+TT genotype tended to be higher in those patients with a family history of cancer in first degree-relatives (36.8%) than those without a family history (28.3%, p=0.37). We observed an interaction between the MMP-9 -1562 T allele with MMP-2 -735 C allele that significantly increased the risk of breast cancer [OR=1.42 (95% CI 1.02- 1.98, p=0.036)]. CONCLUSIONS: The present study demonstrated that MMP-9 C-1562T polymorphism alone and in combination with MMP-2 C-735T polymorphism increased the risk of breast cancer that might be a useful biomarker in identifying women at risk of developing breast cancer. Also, this study revealed that in most women from Western Iran breast cancer presents in third and fourth decades of life. PMID- 25735352 TI - BreastLight apparatus performance in detection of breast masses depends on mass size. AB - BACKGROUND: Accurate measurement of breast mass size is fundamental for treatment planning. We evaluated performance of BreastLight apparatus in detection breast of masses with this in mind. MATERIALS AND METHODS: From July 2011 to September 2013, a total of 500 women referred to mammography unit in Yazd, Iran for screening were recruited to this study. Performance of BreastLight in detection breast masses regard their sizeing, measured with clinical breast examination (CBE), mammography and sonography, was assessed. Sonographic and mammography examinations were performed according to breast density among women in two groups of women younger (n=105) and older (n=395) than 30 years. Size correlations were performed using Spearman rho analysis. Differences between mass size as assessed with the different methods (mammography, sonography, and clinical examination) and the BreastLight detection were analyzed using chi2-trend test. RESULTS: Performance of the BreastLight in detection of lesions smaller than or equal to 1 cm assessed by CBE, mammography and sonography was 4.4%,7.7% and 12.5% and for masses larger than 4 cm was 65%, 100% and 57.1%, respectively. The performance of BreastLight in detection was significantly increased with larger masses (p<0.001). CONCLUSIONS: We conclude that clinical measurement of breast cancer size is as accurate as that from mammography or ultrasound. Accuracy can be improved by the use of a simple formula of both clinical and mammographic measurements. PMID- 25735353 TI - Which one is more effective, filgrastim or lenograstim, during febrile neutropenia attack in hospitalized patients with solid tumors? AB - BACKGROUND: Chemotherapy-induced febrile neutropenia (FN) with solid tumors causes mortality and morbidity at a significant rate. The purpose of this study was to compare the effects of filgastrim and lenograstim started with the first dose of antibiotics in hospitalized patients diagnosed with FN. MATERIALS AND METHODS: Between February 2009 and May 2012, 151 patients diagnosed with FN were evaluated, retrospectively. In those considered appropriate for hospitalization, convenient antibiotic therapy with granulocyte colony stimulating factors was started within first 30 minutes by completing necessary examinations in accordance with FEN guide recommendations. RESULTS: In this study, 175 febrile neutropenia attacks in 151 patients were examined. Seventy three of the patients were male and 78 were female. The average age was 53.6 and 53.6, respectively. The most common solid tumor was breast carcinoma in 38 (25%) . One hundred and five FN patients (58%) were those who received granulocyte colony stimulating factors as primary prophylaxis. CONCLUSIONS: While studies comparing both drugs generally involve treatments started for prophylaxis, this study compared the treatment given during the febrile neutropenia attack. Compared to lenograstim, filgastrim shortens the duration of hospitalization during febrile neutropenia attack by facilitating faster recovery with solid tumors. PMID- 25735354 TI - Expression of epidermal growth factor-like domain 7 is increased by transcatheter arterial embolization of liver tumors. AB - BACKGROUND: Epidermal growth factor-like domain multiple 7 (EGFL7), recently identified as a secreted protein regulated by oxygen exposure, plays a critical role in promoting metastasis of hepatocellular carcinoma (HCC). Transcatheter arterial embolization (TAE) is widely used for treatment of HCC, resulting in hypoxia in tumors and surrounding liver tissues. Accordingly, we proposed the hypothesis that there could be a relationship between expression of EGFL7 and response to TAE. MATERIALS AND METHODS: We established a rabbit VX2 liver tumor model using percutaneous puncture technique guided by computed tomography. TAE and sham embolization were performed and the results were confirmed by MRI 3 weeks after inoculation. We investigated the EGFL7 expression of the two groups at 6h and 3 days after intervention by means of immunohistochemistry and Western blotting. RESULTS: Immunohistochemical staining demonstrated that the levels of EGFL7 protein significantly increased in the TAE-treated tumors compared with the control group at 6 hours (P=0.031) and 3 days (P=0.020) after intervention. Meanwhile, the relative EGFL7 protein detected in TAE group also up-regulated compared with the control group at 6 hours (P=0.020) and 3 days (P=0.024) after intervention. CONCLUSIONS: This study reveals an increase of EGFL7 expression in rabbit VX2 liver tumors after TAE. The role of EGFL7 in HCC, especially its biological behavior after TAE, needs further investigation. PMID- 25735355 TI - Hypermethylation of TET1 promoter is a new diagnosic marker for breast cancer metastasis. AB - Breast cancer metastasis is a major cause of cancer-related death in women. However, markers for diagnosis of breast cancer metastasis are rare. Here, we reported that TET1, a tumor suppressor gene, was downregulated and hypermethylated in highly metastatic breast cancer cell lines. Moreover, silencing of TET1 in breast cancer cells increased the migration and spreading of breast cancer cells. In breast cancer clinical samples, TET1 expression was reduced in LN metastases compared with primary tissues. Besides, the methylation level of the TET1 promoter was increased significantly in LN metastases. Taken together, these findings indicate that promoter hypermethylation may contribute to the downregulation of TET1 and could be used as a promising marker for diagnosis in patients with breast cancer metastasis. PMID- 25735356 TI - Tobacco chewing and adult mortality: a case-control analysis of 22,000 cases and 429,000 controls, never smoking tobacco and never drinking alcohol, in South India. AB - BACKGROUND: Tobacco is consumed in both smoking and smokeless forms in India. About 35-40% of tobacco consumption in India is in the latter. The study objective was to describe the association between chewing tobacco and adult mortality. MATERIALS AND METHODS: A case-control study was conducted in urban (Chennai city) and rural (Villupuram district) areas in Tamil Nadu state in South India. Interviewed in 1998-2000 about 80,000 families (48,000 urban and 32,000 rural) with members who had died during 1995-1998. These were the cases and their probable underlying cause of death was arrived at by verbal autopsy. Controls were 600,000 (500,000 urban, 100,000 rural) individuals from a survey conducted during 1998-2001 in the same two study areas from where cases were included. RESULTS: Mortality analyses were restricted to non-smoking non-drinkers aged 35 69. The age, sex, education and study area adjusted mortality odds ratio was 30% higher (RR:1.3, 95%CI:1.2-1.4) in ever tobacco chewers compared to never chewers and was significant for deaths from respiratory diseases combined (RR:1.5, 95%CI:1.4-1.7), respiratory tuberculosis (RR:1.7, 95%CI:1.5-1.9), cancers all sites combined (RR:1.5, 95%CI:1.4-1.7) and stroke (RR:1.4, 95%CI:1.2-1.6). Of the cancers, the adjusted mortality odds ratio was significant for upper aero digestive, stomach and cervical cancers. Chewing tobacco caused 7.1% of deaths from all medical causes. CONCLUSIONS: The present study is the first large study in India analysing non-smoking non-drinkers. Statistically significant excess risks were found among ever tobacco chewers for respiratory diseases combined, respiratory tuberculosis, stroke and cancer (all sites combined) compared to never tobacco chewers. PMID- 25735357 TI - Contralateral breast cancer: a clinico-pathological study of second primaries in opposite breasts after treatment of breast malignancy. AB - BACKGROUND: Breast cancer is by far the most frequent cancer of women (23 % of all cancers), ranking second overall when both sexes are considered together. Contralateral breast cancer (CBC) is becoming an important public health issue because of the increased incidence of primary breast cancer and improved survival. The present communication concerns a study to evaluate the role of various clinico-pathological factors on the occurrence of contralateral breast cancer. MATERIALS AND METHODS: A detailed analysis was carried out with respect to age, menopausal status, family history, disease stage, surgery performed, histopathology, hormone receptor status, and use of chemotherapy or hormonal therapy. The diagnosis of CBC was confirmed on histopathology report. Relative risk with 95%CI was calculated for different risk factors of contralateral breast cancer development. RESULTS: CBC was found in 24 (4.5%) out of 532 patients. Mean age of presentation was 43.2 years. Family history of breast cancer was found in 37.5% of the patients. There was statistically significant higher rate (83.3%) of CBC in patients in age group of 20-40 years with RR=11.3 (95% CI: 1.4, 89.4, p=0.006) seen in 20-30 years and RR=10.8 (95% CI:1.5-79.6, p=0.002) in 30-40 years as compared to older age of 60-70 years. Risk of development was higher in premenopausal women (RR=8.6, 95% CI: 3.5-21.3, p<=0.001). Women with family history of breast cancer had highest rate (20.9%) of CBC (RR=5.4, 95% CI: 2.5 11.6, p<=0.001). Use of hormonal therapy in hormone receptor positive patients was protective factor in occurrence of CBC but not significant (RR=0.7, 95% CI: 0.3-1.5, p=0.333). CONCLUSIONS: Younger age, premenopausal status, and presence of family history were found to be significant risk factors for the development of CBC. Use of hormonal therapy in hormone receptor positive patients might be protective against occurrence of CBC but did not reach significance. PMID- 25735358 TI - Survival effect of supportive care services for Turkish patients with metastatic gastric cancer. AB - BACKGROUND: Gastric cancer is the second most common cause of cancer- related deaths worldwide and ranks 11th or 14th among all deaths. Patients with advanced disease require supportive care along with the medical and/ or surgical treatment. AIM: To assess the need for palliative care for patients with advanced tumours along with standard clinical therapy. MATERIALS AND METHODS: Eighty-four patients with metastatic (stage 4) gastric cancer, including both patients who had received surgical treatment or not , were followed up in Bagcilar Training and Research Hospital, Division of Medical Oncology between 2011 and 2014. They were categorised as supportive care (-) (Group 1, n=37) and (+) groups (Group 2, n=47) and evaluated retrospectively. RESULTS: Demographic characteristics of the patients were as follows: mean age, Group 1, 65.2+/-10.5 years, Group 2,63.7+/ 11.3 years; male/female ratio, Group 1, 21/16, Group 2, 28/19; distribution of Eastern Cooperative Oncology Group (ECOG) performance scores of 0 and 1, Group 1, ECOG 0 (n=9) and 1 (n=14), Group 2, ECOG 0 (34) and 1 (n=13) (p<0.0001); patients receiving second-line, Group 1 (n=7) and Group 2 (n=22) (p<0.008) or third - line chemotherapy,Group 2 (n=6) (p<0.02); mortality rates, Group 1, (n=28; 75.6%) and Group 2 (n=30; 63.8%); progression-free survival (PFS) rates, Group 1, 17.4+/-6 weeks, Group 2, 28.3+/-16.2 weeks; statistically significant overall survival rates, Group 1, 20.8+/-8.2 weeks and Group 2, 28.3 +/- 162 weeks (p<0.01). CONCLUSIONS: The supportive care team (medical oncologist, general surgeon, internal medicine specialist, algologist, psychiatrist and radiologist) can play a role in the treatment of metastatic gastric tumours, with improvements shown in terms of the performance status of cases, eligibility of patients to be on chemotherapy programmes for longer duration and overall survival rates in Turkey. PMID- 25735359 TI - BRCA1 and BRCA2 common mutations in iranian breast cancer patients: a meta analysis. AB - BACKGROUND: To date several common mutations in BRCA1 and BRCA2 associated with breast cancer have been reported in different populations. However, the common BRCA1 and BRCA2 mutations among breast cancer patients in Iran have not been described in detail. MATERIALS AND METHODS: To comprehensively assess the frequency and distribution of the most common BRCA1 and BRCA2 mutations in Iranian breast cancer patients, we conducted this meta-analysis on 13 relevant published studies indentified in a literature search on PubMed and SID. RESULTS: A total of 11 BRCA1 and BRCA2 distinct common mutations were identified, reported twice or more in the articles, of which 10 (c.2311T>C, c.3113A>G, c.4308T>C, c.4837A>G, c.2612C>T, c.3119G>A, c.3548A>G, c.5213G>A c.IVS16-92A/G, and c.IVS16 68A/G) mutations were in BRCA1, and 1 (c.4770A>G) was in BRCA2. The mutations were in exon 11, exon 13, intron 16, and exon 20 of BRCA1 and exon 11 of BRCA2. All have been previously reported in different populations. CONCLUSIONS: These meta analysis results should be helpful in understanding the possibility of any first true founder mutation of BRCA1/BRCA2 in the Iranian population. In addition, they will be of significance for diagnostic testing, genetic counseling and for epidemiological studies. PMID- 25735360 TI - Psychosocial reaction patterns to alopecia in female patients with gynecological cancer undergoing chemotherapy. AB - This study aims to clarify the psychosocial reactions of female patients with gynecological cancer undergoing chemotherapy and in the process of suffering from alopecia and to examine their nursing support. The target group comprised female patients who had received two or more cycles of chemotherapy, were suffering from alopecia, and were aged 30-65. Data were collected from semi-structured interviews, conducted from the time the patients were informed by their doctors that they might experience alopecia due to chemotherapy to the time they actually experienced alopecia and until they were able to accept the change. Inductive qualitative analysis was employed to close in on the subjective experiences of the cancer patients. The results showed the existence of six phases in the psychosocial reactions in the process of alopecia: phase one was the reaction after the doctor's explanation; phase two was the reaction when the hair starts to fall out; phase three was the reaction when the hair starts to intensely fall out; phase four was the reaction when the hair has completely fallen out; phase five was the reaction to behavior for coping with alopecia; and phase six was the reaction to change in interpersonal human relationships. The results also made it clear that there are five types of reaction patterns as follows: 1) treatment priority interpersonal relationship maintenance type; 2) alopecia agitated interpersonal relationship maintenance type; 3) alopecia agitated interpersonal relationship reduction type; 4) alopecia denial interpersonal relationship reduction type; and 5) alopecia denial treatment interruption type. It is important to find out which of the five types the patients belong to early during treatment and provide support so that nursing intervention that suits each individual can be practiced. The purpose of this study is to make clear the process in which patients receiving chemotherapy come to accept alopecia and to examine evidence-based nursing care on patients with strong mental distress from alopecia. PMID- 25735361 TI - Analysis of FHIT gene methylation in egyptian breast cancer women: association with clinicopathological features. AB - BACKGROUND: Fragile histidine triad (FHIT) gene is a tumor suppressor gene which involved in breast cancer pathogenesis. Epigenetics alterations in FHIT contributes to tumorigenesis of breast cancer. OBJECTIVE: Our objective was to study FHIT promoter region hypermethylation in Egyptian breast cancer patients and its association with clinicopathological features. MATERIALS AND METHODS: Methylation-specific polymerase chain reaction was performed to study the hypermethylation of FHIT promoter region in 20 benign breast tissues and 30 breast cancer tissues. RESULTS: The frequency of hypermethylation of FHIT promoter region was significantly increased in breast cancer patients compared to bengin breast disease patients. The Odd ?s ratio (95%CI) of development of breast cancer in individuals with FHIT promoter hypermethylation (MM) was 11.0 (1.22 250.8). There were also significant associations between FHIT promoter hypermethylation and estrogen, progesterone receptors negativity, tumor stage and nodal involvment in breast cancer pateints. CONCLUSIONS: Our results support an association between FHIT promotor hypermethylation and development of breast cancer in Egyptian breast cancer patients. FHIT promoter hypermethylation is associated with some poor prognostic features of breast cancer. PMID- 25735362 TI - Treatment of human thyroid carcinoma cells with the g47delta oncolytic herpes simplex virus. AB - BACKGROUND: Thyroid carcinoma is the most common malignancy of the endocrine organs. Although the majority of thyroid cancer patients experience positive outcomes, anaplastic thyroid carcinoma is considered one of the most aggressive malignancies. Current therapeutic regimens do not confer a significant survival benefit, and new therapies are urgently needed. Oncolytic herpes simplex virus (oHSV) may represent a promising therapy for cancer. In the present study, we investigated the therapeutic effects of a third-generation HSV vector, G47Delta, on various human thyroid carcinoma cell lines in vitro. Two subcutaneous (s.c.) models of anaplastic thyroid carcinoma were also established to evaluate the in vivo anti-tumor efficacy of G47Delta. MATERIALS AND METHODS: The human thyroid carcinoma cell line ARO, FRO, WRO, and KAT-5, were infected with G47Deltaat different multiplicities of infection (MOIs) in vitro. The survival rates of infected cells were calculated each day. Two s.c. tumor models were established using ARO and FRO cells in Balb/c nude mice, which were intratumorally (i.t.) treated with either G47Deltaor mock. Tumor volumes and mouse survival times were documented. RESULTS: G47Delta was highly cytotoxic to different types of thyroid carcinomas. For ARO, FRO, and KAT-5, greater than 30% and 80% of cells were killed at MOI=0.01 and MOI=0.1, respectively on day 5. WRO cells displayed modest sensitivity to G47Delta, with only 21% and 38% of cells killed. In the s.c. tumor model, both of the anaplastic thyroid carcinoma cell lines (ARO and FRO) were highly sensitive to G47Delta G47Delta significantly inhibited tumor growth and prolonged the survival of mice bearing s.c. ARO and FRO tumors. CONCLUSIONS: The oHSV G47Delta can effectively kill different types of human thyroid carcinomas in vitro. G47Delta significantly inhibited growth of anaplastic thyroid carcinoma in vivo and prolonged animal survival. Therefore, G47Delta may hold great promise for thyroid cancer patients. PMID- 25735363 TI - Novel mutations in IL-10 promoter region -377 (C>T), -150 (C>A) and their association with psoriasis in the saudi population. AB - BACKGROUND: Psoriasis, a common cutaneous disorder characterized by inflammation and abnormal epidermal proliferation with a prevalence of 2-3% in the general population, may be linked to certain types of cancer. Several studies have reported an association between interleukin 10 (IL-10) variant polymorphisms and inflammatory diseases such as psoriasis vulgaris although the results vary according to the population studied. No studies have been performed in the Saudi population. The present study concerned novel variants and other genetic polymorphisms of the promoter and exonic regions of the IL10 gene in patients with moderate to severe psoriasis and potential differences in genotype compared to a group of healthy volunteers. MATERIALS AND METHODS: Patients with moderate to severe psoriasis and healthy controls with no personal or family history of psoriasis were selected from the central region of Saudi Arabia. Polymorphisms of the IL 10 gene of both groups were genotyped. RESULTS: We observed two novel variants in 5'UTR region of the promoter precursor with higher prevalence of the genotype with both wild-type alleles in patients compared to the healthy control group. The differences at positions -377 and -150 were significantly associated with disease, both the variants conferred strong protection against psoriasis in Saudi patients. CONCLUSIONS: This observation provides further support for the importance of the part that IL10 plays in the pathophysiology of this disease. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of IL-10 in psoriasis. PMID- 25735364 TI - Prevalence of anxiety may not be elevated in thai ovarian cancer patients following treatment. AB - BACKGROUND: To compare prevalence of anxiety in ovarian cancer patients following primary treatment to that of normal women and to examine predicting factor. MATERIALS AND METHODS: In this cross-sectional study, 56 ovarian cancer patients who had primary surgical treatment within the past five years (cancer group) and 56 age-matched women who attended an outpatient clinic for check-ups (non-cancer group) were recruited from June 2013 to January 2014. The hospital anxiety and depression scale (HADS), was used to determine anxiety level of the participants with the score of >=11 suggestive of anxiety. The prevalence of anxiety symptoms and mean HADS scores for anxiety were compared between the study groups. For those with ovarian cancer, associations of demographic and clinical factors with anxiety was examined. A p-value of <0.05 was considered significant. RESULTS: Participants in the non-cancer group had higher rate of medical comorbidity, higher salary, and more frequent university education. The prevalence of anxiety was not different between the groups, at 7.1% each. The mean HADS scores for anxiety subscale were not significantly different between the groups, 5.0 in the cancer group vs 6.1 in the non-cancer group (p=0.09). On multivariable analysis, no demographic or clinical factors significantly associated with anxiety were identified. For the cancer group, no association between any particular factors and anxiety was demonstrated. CONCLUSIONS: The prevalence of anxiety in women with ovarian cancer following primary treatment was comparable to that of normal women seeking routine check-up. PMID- 25735365 TI - End stage palliative care of head and neck cancer: a case study. AB - BACKGROUND: Locally advanced head and neck cancer is generally incurable and has a short survival rate. This study aimed to evaluate symptom relief, disease response, and acute toxicity after palliative hypo-fractionated radiotherapy and long-term survival in affected patients. MATERIALS AND METHODS: Between January 2011 to December 2011, 80 patients who were histopathologically diagnosed as having stage III or stage IV head and neck squamous cell carcinoma based on Eastern Cooperative Oncology Group (ECOG) performance status 1-3, were offered palliative radiotherapy (20 Gy/5Fr/5 Days). Later these patients were evaluated on 30th day after completion of treatment for disease response based on World Health Organisation (WHO) criteria and palliation of symptoms using symptomatic response grading and acute toxicities by the Radiation Therapy Oncology Group (RTOG). Many patients were given post radiation therapy (RT) palliative chemotherapy for appropriate palliative care and a few patients were selected for further curative RT. The overall survival was also evaluated among this group of patients with last follow up date of 1st May, 2014. RESULTS: The most common presenting complaint was pain followed by dysphagia. Most patients (60-70%) had appreciable relief in their presenting symptoms. A good response was observed in the majority following palliative RT; a few patients had progressive disease and some had stable and regressed disease. None of the patients experienced radiation toxicity that required hospital admission. Almost all showed grade one and two acute skin and mucosal toxicity one month after completion of treatment. The mean survival days for patients given only hypofractionated palliative RT was 307 days, those with post palliative RT and palliative chemotherapy was 390 days and patients who went on to receive further palliative RT and curative RT dose had significantly overall survival of 582 days. CONCLUSIONS: Advanced head and neck cancer should be identified for suitable palliative hypofractionated radiotherapy to achieve acceptable symptom relief in a great proportion of patients and should be followed by palliative chemotherapy or curative RT in suitable cases for long term symptom-free survival. PMID- 25735366 TI - Geographic disparities in prostate cancer outcomes--review of international patterns. AB - BACKGROUND: This study reviewed the published evidence as to how prostate cancer outcomes vary across geographical remoteness and area level disadvantage. MATERIALS AND METHODS: A review of the literature published from January 1998 to January 2014 was undertaken: Medline and CINAHL databases were searched in February to May 2014. The search terms included terms of 'Prostate cancer' and 'prostatic neoplasms' coupled with 'rural health', 'urban health', 'geographic inequalities', 'spatial', 'socioeconomic', 'disadvantage', 'health literacy' or 'health service accessibility'. Outcome specific terms were 'incidence', 'mortality', 'prevalence', 'survival', 'disease progression', 'PSA testing' or 'PSA screening', 'treatment', 'treatment complications' and 'recurrence'. A further search through internet search engines was conducted to identify any additional relevant published reports. RESULTS: 91 papers were included in the review. While patterns were sometimes contrasting, the predominate patterns were for PSA testing to be more common in urban (5 studies out of 6) and affluent areas (2 of 2), higher prostate cancer incidence in urban (12 of 22) and affluent (18 of 20), greater risk of advanced stage prostate cancer in rural (7 of 11) and disadvantaged (8 of 9), higher survival in urban (8 of 13) and affluent (16 of 18), greater access or use of definitive treatment services in urban (6 of 9) and affluent (7 of 7), and higher prostate mortality in rural (10 of 20) and disadvantaged (8 of 16) areas. CONCLUSIONS: Future studies may need to utilise a mixed methods approach, in which the quantifiable attributes of the individuals living within areas are measured along with the characteristics of the areas themselves, but importantly include a qualitative examination of the lived experience of people within those areas. These studies should be conducted across a range of international countries using consistent measures and incorporate dialogue between clinicians, epidemiologists, policy advocates and disease control specialists. PMID- 25735367 TI - Inflammatory breast cancer in Tunisia from 2005 to 2010: epidemiologic and anatomoclinical transitions from published data. AB - AIM: To report epidemiologic and anatomoclinical transitions of inflammatory breast cancer (IBC) in Tunisia. MATERIALS AND METHODS: Data including clinico pathological data for208 cases of T4d or PEV 3 non-metastatic breast cancer diagnosed between 2005 and 2010 were collected from patient records. Chi2 and Z tests were used to compare variables with two Tunisian historical series and a series about Arab-American patients. RESULTS: Thirty three percent of our patients had their first child before 23 years of age and 56% had their menarche before 12 years, 75% never receiving oral contraception. Obesity was observed in 42% of women and IBC occurred during pregnancy in 13% of cases. Tumor grade was II-III in 90% of cases, HR was negative in 52%, HER2 was over expressed in 31% and invasion of more than 3 axillary nodes occurred in 18% of patients. We observed a pCR rate of 19% after neoadjuvant treatment (anthracyline-taxane used in 79%, trastuzumab in 27% ). Compared to historical Tunisian series (since 1996), IBC epidemiology remained stable in terms of median age, menopausal status and obesity. However we observed a significant decrease in median clinical tumor size and number of positive axillary lymph nodes. Comparison to IBC in Arab Americans showed a significant difference in terms of median age, menopausal status, positivity of hormonal receptors and educational level. CONCLUSIONS: Our assessment of epidemiologic transition showed a reduction of clinco-pathological stage of IBC, keeping the same characteristics as compared to Tunisian historical series over a period of 14 years. Features seem to be different in Arab-American patients, probably related to migration, "occidentalization" of life style and improvement in socio-economic level. PMID- 25735368 TI - Serum biomarkers for early detection of hepatocellular carcinoma associated with HCV infection in egyptian patients. AB - BACKGROUND: Early detection of hepatocellular carcinoma using serological markers with better sensitivity and specificity than alpha fetoprotein (AFP) is needed. AIMS: The aim of this study was to evaluate the diagnostic value of serum sICAM 1, beta-catenin, IL-8, proteasome and sTNFR-II in early detection of HCC. MATERIALS AND METHODS: Serum levels of IL-8, sICAM-1, sTNFR-II, proteasome and beta-catenin were measured by ELISA assay in 479 serum samples from 192 patients with HCC, 96 patients with liver cirrhosis (LC), 96 patients with chronic hepatitis C (CHC) and 95 healthy controls. RESULTS: Serum levels of proteasome, sICAM-1, beta-catenin and alphaFP were significantly elevated in HCC group compared to other groups (P-value<0.001), where serum level of IL-8 was significantly elevated in the LC and HCC groups compared to CHC and control groups (P-value <0.001), while no significant difference was noticed in patients with HCC and LC (P-value=0.09). Serum level of sTNFR- II was significantly elevated in patients with LC compared to HCC, CHC and control groups (P-value <0.001); also it was significantly higher in HCC compared to CHC and control groups (P-value <0.001). ROC curve analysis of the studied markers between HCC and other groups revealed that the serum level of proteasome had sensitivity of 75.9% and specificity of 73.4% at a cut-off value of 0.32 MUg/ml with AUC 0.803 sICAM-1 at cut off value of 778ng/ml, the sensitivity was 75.8% and the specificity was 71.8% with AUC 0.776. beta-catenin had sensitivity and specificity of 70% and 68.6% respectively at a cut off value of 8.75ng/ml with an AUC of 0.729. sTNFR-II showed sensitivity of 86.3% and specificity of 51.8% at a cut off value of 6239.5pg/ml with an AUC of 0.722. IL-8 had sensitivity of 70.4% and specificity of 52.3% at a cut off value of 51.5pg/ml with AUC 0.631. CONCLUSIONS: Our data supported the role of proteasome, sICAM-1, sTNFR-II and beta-catenin in early detection of HCC. Also, using this panel of serological markers in combination with alphaFP may offer improved diagnostic performance over alphaFP alone in the early detection of HCC. PMID- 25735369 TI - Anal papanicolaou smear in women with abnormal cytology: a thai hospital experience. AB - BACKGROUND: Anal intraepithelial lesions (AIL) are likely to represent a precursor for anal cancer. Women infected with human immunodeficiency virus (HIV) may be at higher risk of anal cancer but a screening program for AIL still is not routinely recommended. We here studied the relationship of dysplastic cells from cervical and anal cytology in HIV-infected women. MATERIALS AND METHODS: This prospective study was conducted in Prapokklao Hospital, Thailand during 2013 2014. Five hundred and ninety nine HIV-infected women were recruited. Participants who had cytological reports of equally or over "abnormal squamous/glandular cells of undetermined significance" (ASC-US) were classified as abnormal cervical or anal cytology. Descriptive statistics and logistic regression analysis were used to evaluate correlations between groups. RESULTS: HIV-infected women with abnormal cervical cytology had 3.8 times more risk (adjusted odd ratio 3.846, 95% confidence interval 1.247-11.862, p-value. 019) for abnormal anal cytology. The major problem of the anal Pap test in this study was the inadequacy of the collected specimens for evaluation (34.4%, 206/599). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of cervical and anal Pap tests were 93.9/12.0, 87.3/96.9, 39.7/21.4, 99.4/94.1 and 88.1/91.4 percent, respectively. CONCLUSIONS: Abnormal cervical cytology in HIV-infected women indicates elevated risk for abnormal anal cytology. The sensitivity of the anal Pap test for detection of AIL 2/3 in HIV infected women was quite low while specificity was excellent. Inadequacy of specimen collection for evaluation was a major limitation. Improvement of sample collection is recommended for future investigations. PMID- 25735370 TI - The economic burden of cancer in Korea in 2009. AB - BACKGROUND: Cancer imposes a significant economic burden on individuals, families and society. The purpose of this study was to estimate the economic burden of cancer using the healthcare claims and cancer registry data in Korea in 2009. MATERIALS AND METHODS: The economic burden of cancer was estimated using the prevalence data where patients were identified in the Korean Central Cancer Registry. We estimated the medical, non-medical, morbidity and mortality cost due to lost productivity. Medical costs were calculated using the healthcare claims data obtained from the Korean National Health Insurance (KNHI) Corporation. Non medical costs included the cost of transportation to visit health providers, costs associated with caregiving for cancer patients, and costs for complementary and alternative medicine (CAM). Data acquired from the Korean National Statistics Office and Ministry of Labor were used to calculate the life expectancy at the time of death, age- and gender-specific wages on average, adjusted for unemployment and labor force participation rate. Sensitivity analysis was performed to derive the current value of foregone future earnings due to premature death, discounted at 3% and 5%. RESULTS: In 2009, estimated total economic cost of cancer amounted to $17.3 billion at a 3% discount rate. Medical care accounted for 28.3% of total costs, followed by non-medical (17.2%), morbidity (24.2%) and mortality (30.3%) costs. CONCLUSIONS: Given that the direct medical cost sharply increased over the last decade, we must strive to construct a sustainable health care system that provides better care while lowering the cost. In addition, a comprehensive cancer survivorship policy aimed at lower caregiving cost and higher rate of return to work has become more important than previously considered. PMID- 25735371 TI - Importance of meta-analysis and practical obstacles in oncological and epidemiological studies: statistics very close but also far! AB - Studies of epidemiological and prognostic factors are very important for oncology practice. There is a rapidly increasing amount of research and resultant knowledge in the scientific literature. This means that health professionals have major challenges in accessing relevant information and they increasingly require best available evidence to make their clinical decisions. Meta-analyses of prognostic and other epidemiological factors are very practical statistical approaches to define clinically important parameters. However, they also feature many obstacles in terms of data collection, standardization of results from multiple centers, bias, and commentary for intepretation. In this paper, the obstacles of meta-analysis are briefly reviewed, and potential problems with this statistical method are discussed. PMID- 25735372 TI - Clinicopathological factors and gastric cancer prognosis in the iranian population: a meta-analysis. AB - BACKGROUND: Gastric cancer is the most common cancer in the Iranian population. The aim of this study was to determine the effect of clinicopathological factors on prognosis by meta-analysis. MATERIALS AND METHODS: A literature search was conducted using MEDLINE, EMBASE and Cochrane library and extensive literature search using the Persian databases until February 2011. Prospective follow up studies with multivariate analysis of overall survival of the patients with gastric cancer were included in this review. The data were analyzed by CMA.2. Publication bias are checked by funnel plot and data are shown as Forest plots. RESULTS: From a total of 63 articles, 14 retrospective studies which examined 5 prognostic factors and involving 10,500 patients were included. Tumor size (>35mm) was the main significant factor predicting an unfavorable prognosis for the patients with gastric cancer (RR=1.829 , p<0.001) followed by presence of distant metastases (RR=1.607 , p<0.001), poor differentiation (RR=1.408 , p<0.001) and male sex (RR=1.194, p<0.001). Lymph node metastases (RR=1.058, p=0.698) and moderate differentiation (RR=0.836, p=0.043) were not statistically significant as prognostic factors. CONCLUSIONS: This meta-analysis suggests that tumor size>35mm, poor differentiation, presence of distant metastasis and male gender are strongly associated with a poor prognosis in Iranian patients with gastric cancer. PMID- 25735373 TI - Single life time cytological screening in high risk women as an economical and feasible approach to control cervical cancer in developing countries like India. AB - In view of funding crunches and inadequate manpower in cytology in developing countries like India, single lifetime screening for cervical cancer has been suggested. In this study, an attempt was made to identify high risk groups of women for this screening to make it more effective for early detection. Cytological data were derived from the ongoing routine cervical cytology screening program for women attending Gynaecology Out Patient Department of Queen Mary's Hospital of K.G.Medical University, Lucknow, India during a span of 35 years (April 1971 - December 2005). Cervical smears in a total of 38,256 women were cytologically evaluated. The frequencies of squamous intraepithelial lesions of cervix (SIL) and carcinoma cervix were found to be 7.0% and 0.6%, respectively, in the series. Predisposing factors related to cervical carcinogenesis were analyzed in detail to establish the most vulnerable groups of women for single life time screening. The incidence of SIL and carcinoma cervix was found to be maximal in women above the age of 40 years irrespective of parity and in multiparous women (with three or more children) irrespective of age. The incidence of cervical cytopathologies was significantly higher in symptomatic women, the frequency of SIL being alarmingly higher in women complaining of contact bleeding and that of carcinoma cervix in older women with postmenopausal bleeding. It is consequently felt that single life time screening must include the three groups of women delineated above. Such selective screening appears to be the most economical, cost effective and feasible approach to affordably control the menace of cervical cancer in developing countries like India. PMID- 25735374 TI - Anti-cancer properties of a sesquiterpene lactone-bearing fraction from Artemisia khorassanica. AB - BACKGROUND: Artemisia species are important medicinal plants throughout the world. The present in vitro study, using a sesquiterpene lactone-bearing fraction prepared from Artemisia khorassanica (SLAK), sought to investigate anti-cancer properties of this plant and elucidate potential underlying mechanisms for the effects. MATERIALS AND METHODS: Anti-cancer potential was evaluated by toxicity against human melanoma and fibroblast cell lines. To explore the involved pathways, pattern of any cell death was determined using annexin-V/PI staining and also the expression of Bax and cytochrome c was investigated by Western blotting. RESULTS: The results showed that SLAK selectively caused a concentration-related inhibition of proliferation of melanoma cells that was associated with remarkable increase in early events and over-expression of both Bax and cytochrome c. CONCLUSIONS: The current experiment indicates that Artemisia may have anti-cancer activity. We anticipate that the ingredients may be employed as therapeutic candidates for melanoma. PMID- 25735375 TI - Microvessel density as a prognostic factor in ovarian cancer: a systematic review and meta-analysis. AB - BACKGROUND: The prognostic value of microvessel density (MVD), reflecting angiogenesis, detected in ovarian cancer is currently controversial. Here we performed a meta-analysis of all relevant eligible studies. MATERIALS AND METHODS: A comprehensive search of online PubMed, Medline, EMBASE and Sciencedirect was performed to identify all related articles. The search strategy was designed as 'microvessel density', 'ovarian cancer', 'ovarian neoplasm', 'CD34' and 'angiogenesis'. RESULTS: The studies were categorized by author/year, number of patients, FIGO stage, histology, cutoff value for microvessel density, types of survival analysis, methods of hazard rations (HR) estimation, HR and its 95% confidence interval (CI). Combined hazard ratios suggested that high MVD was associated with poor overall survival (OS) and progression-free survival (PFS), with HR and 95% CIs of 1.84 (1.33-2.35) and 1.36 (1.06-1.66), respectively. Subgroup analysis showed that high MVD detected by CD34 was relevant for OS [HR=1.67 (1.36-2.35)], but not MVD detected with other antibodies [HR=2.11 (0.90 3.31)]. Another subgroup analysis indicated that high MVD in patients without pre chemotherapy, but not with pre- chemotherapy, was associated with OS [HR=1.88(1.59-2.18 and HR=1.70 (-0.18-3.59)]. CONCLUSIONS: The OS and PFS with high MVD were significant poorer than with low MVD in ovarian cancer patients. However, high MVD detected by CD34 seems to be more associated with survival for patients without pre-chemotherapy. PMID- 25735376 TI - Knockdown of Med19 suppresses proliferation and enhances chemo-sensitivity to cisplatin in non-small cell lung cancer cells. AB - Mediator 19 (Med19) is a component of the mediator complex which is a coactivator for DNA-binding factors that activate transcription via RNA polymerase II. Accumulating evidence has shown that Med19 plays important roles in cancer cell proliferation and tumorigenesis. The involvement of Med19 in sensitivity to the chemotherapeutic agent cisplatin was here investigated. We employed RNA interference to reduce Med19 expression in human non-small cell lung cancer (NSCLC) cell lines and analyzed their phenotypic changes. The results showed that after Med19 siRNA transfection, expression of Med19 mRNA and protein was dramatically reduced (p<0.05). Meanwhile, impaired growth potential, arrested cell cycle at G0/G1 phase and enhanced sensitivity to cisplatin were exhibited. Apoptosis and caspase-3 activity were increased when cells were exposed to Med19 siRNA and/or cisplatin. The present findings suggest that Med19 facilitates tumorigenic properties of NSCLC cells and knockdown of Med19 may be a rational therapeutic tool for lung cancer cisplatin sensitization. PMID- 25735377 TI - Prognostic factors, treatment and outcome in a Turkish population with endometrial stromal sarcoma. AB - PURPOSE: To analyze treatment modalities and prognostic factors in patients with Stage I-II endometrial stromal sarcoma (ESS). MATERIALS AND METHODS: Twenty four patients (nineteen with low-grade ESS [LGESS] and five with high-grade ESS [HGESS]) were assessed retrospectively in terms of general characteristics, prognostic factors, treatment methods and survival. RESULTS: Twenty patients were at Stage I and three were at Stage II. The stage of one patient could not be determined. With respect to age and comorbidity, no statistically significant difference was found among disease-free survival (DFS) (p=0.990; p=0.995). However, DFS was significantly shorter in Stage II than Stage I patients (p=0.002). It was also significantly shorter in HGESS patients than in LGESS patients (p=0.000). There was no statistically significant differences among the overall survival (OVS) times of patients with respect to age at diagnosis and comorbid disease (p=0.905; p=0.979) but OVS was significantly shorter in patients with HGESS (p=0.00) and Stage II disease (p=0.001). No statistically significant difference was found with respect to OVS between patients who received radiotherapy (RT) and those who did not receive RT (p=0.055). It was not statistically possible to include other treatment modalities in the analysis because of the small sample size. CONCLUSIONS: Grade and stage of a tumour were found to be the most important prognostic factors. It was not possible to determine the optimal surgical method and the effect of adjuvant treatment since the number of cases was insufficient. PMID- 25735378 TI - Matrix metalloproteinase-2 -1306 C>T gene polymorphism is associated with reduced risk of cancer: a meta-analysis. AB - Matrix metalloproteinase-2 (MMP2) is an endopeptidase, mainly responsible for degradation of extracellular matrix components, which plays an important role in cancer disease. A single nucleotide polymorphism (SNP) at -1306 disrupts a Sp1 type promoter site. The results from the published studies on the association between MMP2 -1306 C>T polymorphism and cancer risk are contradictory and inconclusive. In the present study, a meta-analysis was therefore performed to evaluate the strength of any association between the MMP2 -1306 C>T polymorphism and risk of cancer. We searched all eligible studies published on association between MMP2 -1306 C>T polymorphism and cancer risk in PubMed (Medline), EMBASE and Google Scholar online web databases until December 2013. Genotype distribution data were collected to calculate the pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) to examine the strength of the association. A total of 8,590 cancer cases and 9,601 controls were included from twenty nine eligible case control studies. Overall pooled analysis suggested significantly reduced risk associated with heterozygous genotype (CT vs CC: OR=0.758, 95%CI=0.637 to 0.902, p=0.002) and dominant model (TT+CT vs CC: OR=0.816, 95%CI=0.678 to 0.982, p=0.032) genetic models. However, allelic (T vs C: OR=0.882, 95%CI=0.738 to 1.055, p=0.169), homozygous (TT vs CC: OR=1.185, 95%CI=0.825 to 1.700, p=0.358) and recessive (TT vs CC+CT: OR=1.268, 95%CI=0.897 to 1.793, p=0.179) models did not show any risk. No evidence of publication bias was detected during the analysis. The results of present meta-analysis suggest that the MMP2 -1306 C>T polymorphism is significantly associated with reduced risk of cancer. However, further studies with consideration of different populations will be required to evaluate this relationship in more detail. PMID- 25735379 TI - Association of the PTEN IVS4 (rs3830675) gene polymorphism with reduced risk of cancer: evidence from a meta-analysis. AB - PTEN (phosphatase and tensin homologue), as a tumor suppressor gene, plays a significant role in regulating cell growth, proliferation, and apoptosis. Results from published studies for association between the PTEN IVS4 I/D (rs3830675) polymorphism and cancer risk are inconsistent and inconclusive. We therefore conducted a meta-analysis to evaluate the potential association between PTEN IVS4 I/D polymorphism and risk of cancer in detail. We searched PubMed (Medline) and EMBASE web databases to cover all relevant studies published until December 2013. The meta-analysis was carried out and pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were used to appraise the strength of association. A total of 1,993 confirmed cancer cases and 3,200 controls were included from six eligible case-control studies. Results from overall pooled analysis suggested a significant effect of the PTEN IVS4 I/D polymorphism and cancer risk in all genetic models, i.e., allele (I vs D: OR=0.743, 95%CI=0.648 to 0.852, p=0.001), homozygous (II vs DD: OR=0.673, 95%CI=0.555 to 0.816, p=0.001), heterozygous (ID vs DD: OR=0.641, 95%CI=0.489 to 0.840, p=0.001), dominant (II+ID vs DD: OR=0.626, 95%CI=0.489 to 0.802, p=0.001) and recessive (II vs DD+ID: OR=0.749, 95%CI=0.631 to 0.889, p=0.001). Significant publication bias was detected during the analysis. The present meta-analysis suggests that the PTEN IVS4 I/D polymorphism is significantly associated with reduced risk of cancer. However, future larger studies with other groups of populations are warranted to clarify this association. PMID- 25735380 TI - Effect of hormone therapy on long-term outcomes of patients with human epidermal growth factor receptor 2- and hormone receptor-positive metastatic breast cancer: real world experience in China. AB - BACKGROUND: Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer, more than half are also hormone receptor (HR)-positive. Although HR is a predictive factor for the efficacy of hormone therapy, there are still some uncertainties in regard to the effects on patients with HR-positive and HER2 positive metastatic breast cancers due to the potential resistance to hormone therapy caused by co-expression of HR and HER2. There are no clinical trials directly comparing the efficacy of hormonal therapy with chemotherapy. MATERIALS AND METHODS: To examine the real-world effect of hormone therapy on patients with HR-positive and HER2-positive metastatic breast cancers, a cross-sectional study of a representative sample of the Chinese population was conducted. The study included 113 patients who received first-line and second-line palliative treatment between 2005 and 2010 in the Cancer Institute and Hospital, Chinese Academy of Medical Science. The effect of hormone therapy on overall survival (OS) was studied. RESULTS: The patients who received hormone therapy (n=51) had better overall survival in contrast to those who received chemotherapy with anti HER2 therapy (n=62) in first- or second-line treatment. The difference was of borderline statistical significance (51.8m vs 31.9m, p=0.065). In addition, the effect of hormone therapy did not differ significantly with other prognostic factors, including age (<=50 years or >50 years), disease free survival (>=2 years or < 2 years) and site of metastasis (visceral or bone/soft tissue). On multivariate analysis, administration of hormone therapy was associated with a trend toward a favorable prognosis (p=0.148, HR=0.693, 95%CI 0.422-1.139). Age more than 50 years was the sole independent harmful prognostic factor (p<0.001, HR=2.797, 95%CI 1.676-4.668). CONCLUSIONS: Our data suggest that hormonel therapy may improve outcomes of the patients with ER-positive and HER2-positive metastatic breast cancer. PMID- 25735381 TI - Vitamin B2 intake and the risk of colorectal cancer: a meta-analysis of observational studies. AB - BACKGROUND: A systematic review and meta-analysis of observational studies evaluated the association of intake of vitamin B2 with the incidence of colorectal cancer. MATERIALS AND METHODS: Relevant studies were identified in MEDLINE via PubMed (published up to April 2014). We extracted data from articles on vitamin B2 and used multivariable-adjusted odds ratio (OR) and a random effects model for analysis. RESULTS: We found 8 articles meeting the inclusion criteria (4 of cohort studies and 4 of case-control studies) and a total of 7,750 colorectal cancer cases were included in this meta-analysis. The multivariable adjusted OR for pooled studies for the association of the highest versus lowest vitamin B2 intake and the risk of colorectal cancer was 0.83 (95% confidence interval [95%CI]:0.75,0.91). We performed a sensitivity analysis for vitamin B2. If we omitted the study by Vecchia et al., the pooled OR was 0.86 (95%CI, 0.77,0.96). CONCLUSIONS: This is the first meta-analysis to study links between vitamin B2 and colorectal cancer. We found vitamin B2 intake was inversely associated with risk of colorectal cancer. However, further research and large sample studies need to be conducted to better validate the result. PMID- 25735382 TI - Evaluation of antitumor and antioxidant activity of Sargassum tenerrimum against Ehrlich ascites carcinoma in mice. AB - CONTEXT: In the last half century, discovering, developing and introducing of clinical agents from marine sources have seen great successes, with examples including the anti-cancer compound trabectedin. However, with increasing need for new anticancer drugs, further exploration for novel compounds from marine organism sources is strongly justified. OBJECTIVE: The major aim of this study was to evaluate the antitumor and antioxidant potential of Sargassum tenerrimum J.Agardh (Sargassaceae) on Ehrlich ascites carcinoma (EAC) in Swiss albino mice. MATERIALS AND METHODS: An ethanol extract of S. tenerrimum (EEST) from whole algae was used to evaluate cytotoxicity followed by in vivo assessment of toxicity, using biochemical parameters including hepatic and non-hepatic enzymes. Antioxidant properties were examined in animals bearing EAC treated with daily oral administration of 100-300 mg/kg extract suspension. RESULTS: Antitumor effects of EEST in EAC bearing mice was observed with LD50 1815 mg/kg. Parameters like body weight, tumor volume, packed cell volume, tumor cell count, mean survival time and increase in life span in animals in the EAC bearing animals treated with EEST 300 mg/kg was comparable with control group. Significant differences were also seen with changes in total protein content, hepatic enzymes contents, MDA level, and free radical scavenging enzymes in untreated vs. EEST treated group animals. CONCLUSIONS: Evaluation of antioxidant enzymes and hepatic enzymes in the EAC animal model treated with EEST exhibited similar effects as the positive control drug 5-flurouracil. S. tenerrimum extracts contain effective antioxidants with significant antitumor activity. PMID- 25735383 TI - Could the platelet-to-lymphocyte ratio be a novel marker for predicting invasiveness of cervical pathologies? AB - PURPOSE: To determine whether the preoperative platelet to lymphocyte ratio (PLR) could predict invasiveness of cervical pathologies. MATERIALS AND METHODS: Patients with preinvasive and invasive diseases were reviewed retrospectively, over a nine-year period, 2005-2014. The pathological records and completed blood counts of the patients were collected and recorded in the SPSS program. Patients were divided in two groups, preinvasive and invasive. RESULTS: The median PLR was significantly higher in the invasive group than in the preinvasive group (p=0.03). There was a correlation between invasion of cervical cancer and white blood cell count, red cell distributing width (RDW), neutrophil-lymphocyte ratio (NLR), and PLR. CONCLUSIONS: This study showed that patients with uterine cervical cancer may present with leukocytosis, increased RDW, NLR and PLR. These cheap and easily available parameters, especially PLR, may provide useful information about the invasiveness of cervical lesions. PMID- 25735384 TI - Level of awareness of cervical and breast cancer risk factors and safe practices among college teachers of different states in india: do awareness programmes have an impact on adoption of safe practices? AB - BACKGROUND: Breast and cervical cancers are the most common causes of cancer mortality among women in India, but actually they are largely preventable diseases. Although early detection is the only way to reduce morbidity and mortality, there are limited data on breast and cervical cancer knowledge, safe practices and attitudes of teachers in India. The purpose of this study is to assess the level of awareness and impact of awareness programs in adoption of safe practices in prevention and early detection. MATERIALS AND METHODS: This assessment was part of a pink chain campaign on cancer awareness. During cancer awareness events in 2011 at various women colleges in different parts in India, a pre-test related to cervical cancer and breast cancer was followed by an awareness program. Post-tests using the same questionnaire were conducted at the end of the interactive session, at 6 months and 1 year. RESULTS: A total of 156 out of 182 teachers participated in the study (overall response rate was 85.7 %). Mean age of the study population was 42.4 years (range- 28-59 yrs). There was a significant increase in level of knowledge regarding cervical and breast cancer at 6 months and this was sustained at 1 year. Adoption of breast self examination (BSE) was significantly more frequent in comparison to CBE, mammography and the Pap test. Magazines and newspapers were sources for knowledge regarding screening tests for breast cancer in more than 60% of teachers where as more than 75% were educated by doctors regarding the Pap test. Post awareness at 6 months and 1 year, there was a significant change in alcohol and smoking habits. Major reasons for not doing screening test were found to be ignorance (50%), lethargic attitude (44.8%) and lack of time (34.6%). CONCLUSIONS: Level of knowledge of breast cancer risk factors, symptoms and screening methods was high as compared to cervical cancer. There was a significant increase in level of knowledge regarding cervical and breast cancer at 6 months and this was sustained at 1 year. Adoption of BSE was significantly greater in comparison to CBE, mammography and the Pap test. To inculcate safe practices in lifestyle of people, awareness programmes such as pink chain campaign should be conducted more widely and frequently. PMID- 25735385 TI - Prognostic significance of preoperative anemia, leukocytosis and thrombocytosis in chinese women with epithelial ovarian cancer. AB - Malignant tumors are often accompanied by increased risk of hematological abnormalities. However, few studies have reported any prognostic impact of preoperative thrombocytosis, leukocytosis and anemia in epithelia ovarian cancer (EOC). This study aimed to investigate preoperative hematological parameters for anemia, leukocytosis and thombocytosis in relation to established prognostic factors and survival in EOC cases. A total of 816 Chinese women treated for EOC were retrospectively included in the study focusing on the relationship between preoperative hemoglobin, leukocyte and platelet counts, and a panel of clinicopathologic characteristics and outcome. Preoperative anemia was present in 13.4%, leukocytosis in 16.7% and thrombocytosis in 22.8% . Additionally, EOC patients with low differentiation grade, advanced stage, lymph node (LN) metastasis, residual disease >= 1cm, ascites volume >1,000ml, serum cancer antigen 125 (CA125) >675U/ml, and disease recurrence had the higher prevalence of preoperative anemia, leukocytosis and thrombocytosis (all p<0.05). Moreover, EOC patients with older age or postmenopausal EOC patients had the higher prevalence of thrombocytosis (28.7% vs 17.3% or 26.0% vs 17.7%). Furthermore, in a Cox proportional hazard model, thrombocytosis was an independent factor for progression-free survival (PFS) and overall survival (OS) (p<0.001). Conclusively, preoperative anemia, leukocytosis or thrombocytosis in EOC patients is closely associated with more malignant disease phenotype and poorer prognosis. Significantly, thrombocytosis may independently predict the disease- specific survival for EOC patients. PMID- 25735386 TI - Semaphoring mAb: a new guide in RIT in inhibiting the proliferation of human skin carcinoma. AB - Semaphoring is a transmembrane receptor which participates in many cytokine mediated signal pathways that are closely related to the angiogenesis, occurrence and development of carcinoma. The present study was designed to access the effect of mono-antibody (mAb) guided radioimmunotherapy (RIT) on skin carcinoma and investigate the potential mechanisms. Semaphoring mAb was acquired from mice (Balb/c), purified with rProtein A column; purity, concentration and activity were tested with SDS-PAGE and indirect ELISA; specificity and expression on the cutanuem carcinoma line and tissue were tested by Western blotting; morphology change was assessed by microscopy. MTT assay and colony inhibition tests were carried out to test the influence on the proliferation of tumor cells; Western blotting was also carried out for expression of apoptosis-associated (caspase-3, Bax, Bcl-2) and proliferation-related (PI3K, p-Akt, Akt, p-ERK1/2, ERK1/2) proteins and analyse the change in signal pathways (PI3K/Akt and MEK/ERK). The purity of purified semaphorin mAb was 96.5% and the titer is about 1?106. Western blotting showed semaphoring mAb to have specifically binding stripes with semaphoring b1b2 protein, B16F10, and A431 cells at 39KDa, 100KDa and 130KDa, respectively. Positive expression was detected both in cutanuem carcinoma line and tissue and it mostly located in cell membranes. MMT assay revealed dose relate and time-relate inhibitory effect of semaphorin mAb on A431 and B16F10. Colony inhibition tests also showed dose-relate inhibitory effects. Western blotting demonstrated the expression of apoptosis and proliferation-related protein and changes in signal pathway. In conclusion, we demonstrated that semaphorin is highly expressed on the tumor cell-surfaces and RIT with semaphorin mAb has effect in inhibiting proliferation and accelerating apoptosis of tumor cells. PMID- 25735387 TI - Oral concentrated grape juice suppresses expression of NF-kappa B, TNF-alpha and iNOS in experimentally induced colorectal carcinogenesis in Wistar rats. AB - The aim of this study was to evaluate the effects of grape juice on colon carcinogenesis induced by azoxymethane (AOM) and expression of NF-kB, iNOS and TNF- alpha. METHODS: Forty male Wistar rats were divided into 7 groups: G1, control; G2, 15 mg/kg AOM; G3, 1% grape juice 2 weeks before AOM; G4, 2% grape juice 2 weeks before AOM; G5, 1% grape juice 4 weeks after AOM; G6, 2% grape juice 4 weeks after AOM; G7, 2% grape juice without AOM. Histological changes and aberrant crypt foci (ACF) were studied, while RNA expression of NF- kB, TNF- and iNOS was evaluated by qPCR. RESULTS: The number of ACF was higher in G2, and G4 presented a smaller number of crypts per focus than G5 (p=0.009) and G6. Small ACF (1-3) were more frequent in G4 compared to G2, G5 and G6 (p=0.009, p=0.009 and p=0.041, respectively). RNA expression of NF-kB was lower in G3 and G4 compared to G2 (p=0.004 and p=0.002, respectively). A positive correlation was observed between TNF- alpha and NF-kB gene expression (p=0.002). In conclusion, the administration of 2% grape juice before AOM reduced the crypt multiplicity, attenuating carcinogenesis. Lower expression of NF-kB was observed in animals exposed to grape juice for a longer period of time, regardless of concentration. PMID- 25735388 TI - KRT13, FAIM2 and CYP2W1 mRNA expression in oral squamous cell carcinoma patients with risk habits. AB - BACKGROUND: Expression of KRT13, FAIM2 and CYP2W1 appears to be influenced by risk habits, thus exploring the associations of these genes in oral squamous cell cancer (OSCC) with risk habits, clinico-pathological parameters and patient survival may be beneficial in identifying relevant biomarkers with different oncogenic pathways. MATERIALS AND METHODS: cDNAs from 41 OSCC samples with and without risk habits were included in this study. Quantitative real-time PCR was used to analyze KRT13, FAIM2 and CYP2W1 in OSCC. The housekeeping gene (GAPDH) was used as an endogenous control. RESULTS: Of the 41 OSCC samples, KRT13 was down-regulated in 40 samples (97.6%), while FAIM2 and CYP2W1 were down-regulated in 61.0% and 48.8%, respectively. Overall, there were no associations between KRT13, FAIM2 and CYP2W1 expression with risk habits, selected socio-demographic and clinico-pathological parameters and patient survival. CONCLUSIONS: Although this study was unable to show significance, there were some tendencies in the associations of KRT13, FAIM2 and CYP2W1 expression in OSCC with selected clinic pathological parameters and survival. PMID- 25735389 TI - Estimation of leucine aminopeptidase and 5-nucleotidase increases alpha fetoprotein sensitivity in human hepatocellular carcinoma cases. AB - PURPOSE: To find parameters that can increase alpha-fetoprotein (AFP) sensitivity and so help in accurate diagnosis and rapid management of hepatocullular carcinoma (HCC), as AFP has limited utility of distinguishing HCC from benign hepatic disorders for its high false-positive and false negative rates. MATERIALS AND METHODS: Serum levels of AFP, 5'-nucleotidase enzyme activity (5-NU) and leucine aminopeptidase enzyme (LAP) activity were measured in 40 individuals. RESULTS: LAP and 5'NU were elevated in HCC at p<0.001. Pearson correlation coefficients showed that changes in AFP exhibited positive correlation with both 5'-NU and LAP at (p<0.001). The complementary use of LAP only with AFP resulted in an increase in sensitivity of AFP from 75% to 90% in detecting HCC. The complementary use of both LAP and 5-NU with AFP resulted in an increased sensitivity of AFP in detecting HCC from 75% to 95%. CONCLUSIONS: LAP and 5-FU can be determined in HCC patients in combination with AFP to improve its sensitivity and decrease false negative results. PMID- 25735390 TI - Mechanistic studies of cyclin-dependent kinase inhibitor 3 (CDKN3) in colorectal cancer. AB - Colorectal cancer is one of the most severe subtypes of cancer, and has the highest propensity to manifest as metastatic disease. Because of the lack of knowledge of events that correlate with tumor cell migration and invasion, few therapeutic options are available. The current study aimed to explore the mechanism of colorectal cancer in hope of identifying the ideal target for future treatment. We first discovered the pro-tumor effect of a controversial cell cycle regulator, cylin-dependent kinase inhibitor 3 (CDKN3), which is highly expressed in colorectal cancer, and the possible related signaling pathways, by bioinformatics tools. We found that CDKN3 had remarkable effects in suppressing colorectal cancer cell proliferation and migration, inducing cell cycle arrest and apoptosis in a colorectal cancer cell line, SW480 cells. Our study, for the first time, provided consistent evidence showing overexpression of cell cycle regulator CDKN3, in colorectal cancer. The in vitro studies in SW480 cells revealed a unique role of CDKN3 in regulating cellular behavior of colorectal cancer cells, and implied the possibility of targeting CDKN3 as a novel treatment for colorectal cancer. PMID- 25735391 TI - Prognostic factors influencing clinical outcomes of malignant glioblastoma multiforme: clinical, immunophenotypic, and fluorescence in situ hybridization findings for 1p19q in 816 chinese cases. AB - Malignant glioblastoma multiforme (GBM) is the most malignant brain tumor and despite recent advances in diagnostics and treatment prognosis remains poor. In this retrospective study, we assessed the clinical and radiological parameters, as well as fluorescence in situ hybridization (FISH) of 1p19q deletion, in a series of cases. A total of 816 patients with GBM who received surgery and radiation between January 2010 and May 2014 were included in this study. Kaplan Meier survival analysis and Cox regression analysis were used to find the factors independently influencing patient progression free survival (PFS) and overall survival (OS). Age at diagnosis, preoperative Karnofsky Performance Scale (KPS) score, KPS score change at 2 weeks after operation, neurological deficit symptoms, tumor resection extent, maximal tumor diameter, involvement of eloquent cortex or deep structure, involvement of brain lobe, Ki-67 and MMP9 expression level and adjuvant chemotherapy were statistically significant factors (p<0.05) for both PFS and OS in the univariate analysis. Cox proportional hazards modeling revealed that age <=50 years, preoperative KPS score >=80, KPS score change after operation >=0, involvement of single frontal lobe, deep structure involvement, low Ki-67 and MMP9 expression and adjuvant chemotherapy were independent favorable factors (p<0.05) for patient clinical outcomes. PMID- 25735392 TI - Knowledge and awareness about breast cancer and its early symptoms among medical and non-medical students of Southern Punjab, Pakistan. AB - Breast cancer is the leading cause of morbidity and mortality globally but has an even more significant impact in developing countries. Pakistan has the highest prevalence among Asian countries. A general lack of public awareness regarding the disease often results in late diagnosis and poor treatment outcomes. The literacy rate of the Southern Punjab (Pakistan) is low compared to its Northern part. It is therefore vital that university students and especially medical students develop a sound knowledge about the disease so that they can spread awareness to others who may be less educated. This study therefore considers current knowledge and understanding about the early signs of breast cancer amongst a study group of medical and non-medical university students of the Southern Punjab, Pakistan. A cross-sectional descriptive analysis of the university students was carried out using a self-administered questionnaire to assess their awareness of breast cancer from March to May 2014. A total of 566 students participated in this study, out of which 326 were non-medical and 240 were from a medical discipline. Statistical analysis was carried out using Graph Pad Prism Version 5 with a significance level set at p<0.05. The mean age of the non medical and medical participants was 23 (SD 2.1) and 22 (SD 1.3) years, respectively. Less than 35% students were aware of the early warning signs of the breast cancer development. Knowledge of medical students about risk factors was significantly better than the non medical ones, but on the whole was insufficient. Our study indicated that knowledge regarding breast cancer was generally insufficient amongst the majority of the university students (75% non medical and 55% medical) of Southern Punjab, Pakistan. This study highlights the need to formulate an awareness campaign and to organize conferences to promote breast cancer awareness among students in this region. PMID- 25735393 TI - Efficacy and tolerability of weekly docetaxel, cisplatin, and 5-fluorouracil for locally advanced or metastatic gastric cancer patients with ECOG performance scores of 1 and 2. AB - BACKGROUND: Docetaxel, cisplatin, 5-fluorouracil (DCF) given every three weeks is an effective, but palliative regimen and significantly toxic especially in patients who have a low performance score. Here, we aimed to evaluate the efficacy and tolerability of a weekly formulation of DCF in locally advanced and metastatic gastric cancer patients. MATERIALS AND METHODS: 64 gastric cancer patients (13 locally advanced and 51 metastatic) whose ECOG (Eastern Cooperative Oncology Group) performance status (PS) was 1-2 and who were treated with at least two cycles of weekly DCF protocol as first-line treatment were included retrospectively. The weekly DCF protocol included 25mg/m2 docetaxel, 25mg/m2 cisplatin, and 24 hours infusion of 750mg/m2 5-fluorouracil, repeated every week. Disease and patient characteristics, prognostic factors, treatment response, grade 3-4 toxicity related to treatment, progression free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Of the patients, 41 were male and 23 were female; the median age was 63 (29-82) years. Forty-one patients were ECOG 1 and 23 were ECOG-2. Of the total, 81.2% received at least three cycles of chemotherapy. Partial response was observed in 28.1% and stabilization in 29.7%. Overall, the disease was controlled in 57.8% whereas progression was noted in 42.2%. The median time to progression was 4 months (95%CI, 2.8-5.2 months) and median overall survival was 12 months (95%CI, 9.2-14.8 months). The evaluation of patients for grade 3-4 toxicity revealed that 10.9% had anemia, 7.8% had thrombocytopenia and 10.9% had neutropenia. Non-hematologic toxicity included renal toxicity (7.8%) and thrombosis (1.6%). CONCLUSIONS: In patients with locally advanced or metastatic gastric cancer who were not candidates for DCF administered every-3-weeks, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients. PMID- 25735394 TI - Side population cell level in human breast cancer and factors related to disease free survival. AB - Side population (SP) cells have stem cell-like properties with a capacity for self-renewal and are resistant to chemotherapy and radiotherapy. Therefore the presence of SP cells in human breast cancer probably has prognostic value. OBJECTIVE: To investigate the characteristics of SP cells and identify the relationship between the SP cells levels and clinico-pathological parameters of the breast tumor and disease-free survival (DFS) in breast cancer patients. MATERIALS AND METHODS: A total of 122 eligible breast cancer patients were consecutively recruited from January 1, 2006 to December 31, 2007 at Yunnan Tumor Hospital. All eligible subjects received conventional treatment and were followed up for seven years. Predictors of recurrence and/or metastasis and DFS were analyzed using Cox regression analysis. Human breast cancer cells were also obtained from fresh human breast cancer tissue and cultured by the nucleic acid dye Hoechst33342 with Verapami. Flow cytometry (FCM) was employed to isolate the cells of SP and non-SP types. RESULTS: In this study, SP cells were identified using flow cytometric analysis with Hoechst 33342 dye efflux. Adjusted for age, tumor size, lymph nodal status, histological grade, the Cox model showed a higher risk of recurrence and/or metastasis positively associated with the SP cell level (1.75, 1.02-2.98), as well as with axillary lymph node metastasis (2.99, 1.76 5.09), pathology invasiveness type (1.7, 1.14-2.55), and tumor volume doubling time (TVDT) (1.54, 1.01-2.36). CONCLUSIONS: The SP cell level is independently associated with tumor progression and clinical outcome after controlling for other pathological factors. The axillary lymph node status, TVDT and the status of non-invasive or invasive tumor independently predict the prognosis of breast cancer. PMID- 25735395 TI - Expression of PGDH correlates with cell growth in both esophageal squamous cell carcinoma and adenocarcinoma. AB - Esophageal cancer represents the fourth most common gastrointestinal cancer and generally confers a poor prognosis. Prostaglandin-producing cyclo-oxygenase has been implicated in the pathogenesis of esophageal cancer growth. Here we report that prostaglandin dehydrogenase, the major enzyme responsible for prostaglandin degradation, is significantly reduced in expression in esophageal cancer in comparison to normal esophageal tissue. Reconstitution of PGDH expression in esophageal cancer cells suppresses cancer cell growth, at least in part through preventing cell proliferation and promoting cell apoptosis. The tumor suppressive role of PGDH applies equally to both squamous cell carcinoma and adenocarcinoma, which enriches our understanding of the pathogenesis of esophageal cancer and may provide an important therapeutic target. PMID- 25735396 TI - The role of intervening illnesses and injuries in prolonging the disabling process. AB - OBJECTIVES: To evaluate the relationship between intervening illnesses and injuries leading to hospitalization and restricted activity, respectively, and prolongation of disability in four essential activities of daily living in newly disabled older persons. DESIGN: Prospective cohort study. SETTING: Greater New Haven, Connecticut. PARTICIPANTS: Community-living persons aged 70 and older who had at least one episode of disability from March 1998 to June 2013 (N=632). MEASUREMENTS: Disability and exposure to intervening illesses and injuries leading to hospitalization and restricted activity, respectively, were assessed every month. Prolongation of disability was operationalized in two complementary ways: as a dichotomous outcome, based on the persistence of any disability, and as a count of the number of disabled activities. RESULTS: During a median follow up of 114 months, the 632 participants experienced 2,764 disability episodes. The mean exposure rates for hospitalization and restricted activity were 80.7 (95% confidence interval (CI)=73.7-88.4) and 173.6 (95% CI=162.5-185.5), respectively, per 1,000 person-months. After adjustment for multiple disability risk factors, the likelihood of disability prolongation was 2.5 times as great (odds ratio (OR) 2.54, 95% CI=2.05-3.15) for hospitalization and 1.2 times as great (1.21, 95% CI=1.06-1.40) for restricted activity as for no hospitalization or restricted activity, and the mean number of disabilities was 35% (risk ratio (RR)=1.35, 95% CI=1.30-1.39) greater in the setting of hospitalization and 7% (1.07, 95% CI=1.05 1.09) greater in the setting of restricted activity. CONCLUSION: Intervening illnesses and injuries leading to hospitalization and restricted activity, respectively, are strongly associated with prolongation of disability in newly disabled older adults. Efforts to prevent and more-aggressively manage these intervening events have the potential to break the cycle of disability in older persons. PMID- 25735397 TI - Fluvastatin Upregulates the Expression of Tissue Factor Pathway Inhibitor in Human Umbilical Vein Endothelial Cells. AB - AIM: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are cholesterol-lowering drugs with a variety of pleiotropic effects including antithrombotic properties. Tissue factor pathway inhibitor (TFPI), which is produced predominantly in endothelial cells and platelets, inhibits the initiating phase of clot formation. We investigated the effect of fluvastatin on TFPI expression in cultured endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with fluvastatin (0-10MUM). The expression of TFPI mRNA and antigen were detected by RT-PCR and western blotting, respectively. The effects of mevalonate intermediates, small GTP-binding inhibitors, and signal transduction inhibitors were also evaluated to identify which pathway was involved. A luciferase reporter assay was performed to evaluate the effect of fluvastatin on TFPI transcription. The stability of TFPI mRNA was estimated by quantitating its levels after actinomycin D treatment. RESULTS: Fluvastatin increased TFPI mRNA expression and antigen in HUVECs. Fluvastatin induced TFPI expression was reversed by co-treatment with mevalonate or geranylgeranylpyrophosphate (GGPP). NSC23766 and Y-27632 had no effect on TFPI expression. SB203580, GF109203, and LY294002 reduced fluvastatin-induced TFPI upregulation. Moreover, fluvastatin did not significantly affect TFPI promoter activity. TFPI mRNA degradation in the presence of actinomycin D was delayed by fluvastatin treatment. CONCLUSIONS: Fluvastatin increases endothelial TFPI expression through inhibition of mevalonate-, GGPP-, and Cdc42-dependent signaling pathways, and activation of the p38 MAPK, PI3K, and PKC pathways. This study revealed unknown mechanisms of the anticoagulant effect of statins and gave a new insight to its therapeutic potential for the prevention of thrombotic diseases. PMID- 25735398 TI - Highly stretchable and wearable graphene strain sensors with controllable sensitivity for human motion monitoring. AB - Because of their outstanding electrical and mechanical properties, graphene strain sensors have attracted extensive attention for electronic applications in virtual reality, robotics, medical diagnostics, and healthcare. Although several strain sensors based on graphene have been reported, the stretchability and sensitivity of these sensors remain limited, and also there is a pressing need to develop a practical fabrication process. This paper reports the fabrication and characterization of new types of graphene strain sensors based on stretchable yarns. Highly stretchable, sensitive, and wearable sensors are realized by a layer-by-layer assembly method that is simple, low-cost, scalable, and solution processable. Because of the yarn structures, these sensors exhibit high stretchability (up to 150%) and versatility, and can detect both large- and small scale human motions. For this study, wearable electronics are fabricated with implanted sensors that can monitor diverse human motions, including joint movement, phonation, swallowing, and breathing. PMID- 25735399 TI - C-Geranylated Flavanones from Paulownia tomentosa Fruits as Potential Anti inflammatory Compounds Acting via Inhibition of TNF-alpha Production. AB - Eleven new C-geranylated flavonoids, tomentodiplacones L, M, and N (1, 2, 10), tomentodiplacol B (3), 3',4'-O-dimethyl-5'-hydroxydiplacone (4), mimulones F, G, and H (5, 6, 7), paulowniones A (8) and B (9), tomentone (11), and 3',4',5' trimethoxyflavanone (12), together with 11 known flavonoids (13-23), were isolated from fruits of Paulownia tomentosa. The structures of the compounds isolated were determined by spectroscopic data interpretation. The ability of compounds 1-23, together with the nonprenylated flavanones eriodictyol (24) and naringenin (25), to reduce the production of the pro-inflammatory cytokine TNF alpha in THP-1 cells after bacterial lipopolysaccharide stimulation was evaluated using an in vitro screening test. The preliminary structure-activity relationships of these derivatives were also studied, and the correlation of their TNF-alpha inhibitory activity with their lipophilicity was investigated. The mechanism of action of compounds with significant antiphlogistic potential (4, 7, 10, 14, 22) was investigated. These compounds reduced both the secretion of TNF-alpha and the level of its corresponding mRNA. Compounds 4, 7, 10, 14, and 22 inhibited the nuclear translocation of NF-kappaB, which controls the expression of TNF-alpha, by blocking the degradation of IkappaB. PMID- 25735400 TI - Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4 year data. AB - AIMS: To assess the long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. METHODS: The present study was an extension of an earlier randomized, double-blind, phase III study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatment-group comparisons were calculated. RESULTS: At 208 weeks, dapagliflozin compared with glipizide produced sustained reductions in glycated haemoglogin (HbA1c): -0.30% [95% confidence interval (CI), -0.51 to 0.09], in total body weight: -4.38 kg (95% CI -5.31 to -3.46) and in systolic blood pressure (SBP): -3.67 mmHg (95% CI -5.92 to -1.41). The HbA1c coefficient of failure was significantly lower for dapagliflozin than for glipizide: 0.19 (95% CI 0.12-0.25) versus 0.61 (95% CI 0.49-0.72, difference -0.42; p = 0.0001). Dapagliflozin was not associated with glomerular function deterioration, while this occurred more frequently in patients in the glipizide group. Fewer patients reported hypoglycaemia in the dapagliflozin compared with the glipizide group (5.4 vs 51.5%). Genital and urinary tract infections were more common with dapagliflozin than with glipizide, but their incidence decreased with time and all events responded well to antimicrobial treatment. CONCLUSIONS: In patients completing 4 years of treatment, dapagliflozin was well tolerated and associated with sustained glycaemic efficacy and greater reductions in body weight and SBP versus glipizide. PMID- 25735401 TI - Enhancement motives moderate the relationship between high-arousal positive moods and drinking quantity: Evidence from a 22-day experience sampling study. AB - INTRODUCTION AND AIMS: Individuals who consume alcohol may be distinguished by their drinking motives. Enhancement motives involve drinking to enhance positive moods. Research on the moderating effect of enhancement motives on the within person relation between daily positive mood and drinking has not differentiated between high- (e.g. hyper) and low-arousal (e.g. cheerful) positive moods. The present study addressed this limitation. We hypothesised that enhancement motives would positively moderate the relationship between mid-afternoon high-arousal positive mood and evening drinking. DESIGN AND METHODS: Using a palm pilot-based experience sampling design, 143 undergraduate drinkers answered daily surveys assessing positive mood (mid-afternoon) and drinks (evening) for 22 consecutive days. RESULTS: As hypothesised, enhancement motives strengthened the relation between high-arousal positive moods and drinking. Upon closer examination, the mood-drinking slope for those high in enhancement motives was unexpectedly flat, whereas the mood-drinking slope for those low in enhancement motives was negative. DISCUSSION AND CONCLUSIONS: We demonstrated that high enhancement motivated drinkers exhibit a high, stable drinking level, regardless of the intensity of their high-arousal positive mood. In contrast, low enhancement motivated drinkers decrease their drinking when in a high-arousal positive mood state. Clinicians may be able to help reduce heavy alcohol consumption in enhancement-motivated drinkers by teaching them to reduce their drinking when in a high-arousal positive mood state. PMID- 25735402 TI - Population genomic analysis uncovers African and European admixture in Drosophila melanogaster populations from the south-eastern United States and Caribbean Islands. AB - Drosophila melanogaster is postulated to have colonized North America in the past several 100 years in two waves. Flies from Europe colonized the east coast United States while flies from Africa inhabited the Caribbean, which if true, make the south-east US and Caribbean Islands a secondary contact zone for African and European D. melanogaster. This scenario has been proposed based on phenotypes and limited genetic data. In our study, we have sequenced individual whole genomes of flies from populations in the south-east US and Caribbean Islands and examined these populations in conjunction with population sequences from the west coast US, Africa, and Europe. We find that west coast US populations are closely related to the European population, likely reflecting a rapid westward expansion upon first settlements into North America. We also find genomic evidence of African and European admixture in south-east US and Caribbean populations, with a clinal pattern of decreasing proportions of African ancestry with higher latitude. Our genomic analysis of D. melanogaster populations from the south-east US and Caribbean Islands provides more evidence for the Caribbean Islands as the source of previously reported novel African alleles found in other east coast US populations. We also find the border between the south-east US and the Caribbean island to be the admixture hot zone where distinctly African-like Caribbean flies become genomically more similar to European-like south-east US flies. Our findings have important implications for previous studies examining the generation of east coast US clines via selection. PMID- 25735403 TI - Ectopic lignification in primary cellulose-deficient cell walls of maize cell suspension cultures. AB - Maize (Zea mays L.) suspension-cultured cells with up to 70% less cellulose were obtained by stepwise habituation to dichlobenil (DCB), a cellulose biosynthesis inhibitor. Cellulose deficiency was accompanied by marked changes in cell wall matrix polysaccharides and phenolics as revealed by Fourier transform infrared (FTIR) spectroscopy. Cell wall compositional analysis indicated that the cellulose-deficient cell walls showed an enhancement of highly branched and cross linked arabinoxylans, as well as an increased content in ferulic acid, diferulates and p-coumaric acid, and the presence of a polymer that stained positive for phloroglucinol. In accordance with this, cellulose-deficient cell walls showed a fivefold increase in Klason-type lignin. Thioacidolysis/GC-MS analysis of cellulose-deficient cell walls indicated the presence of a lignin like polymer with a Syringyl/Guaiacyl ratio of 1.45, which differed from the sensu stricto stress-related lignin that arose in response to short-term DCB treatments. Gene expression analysis of these cells indicated an overexpression of genes specific for the biosynthesis of monolignol units of lignin. A study of stress signaling pathways revealed an overexpression of some of the jasmonate signaling pathway genes, which might trigger ectopic lignification in response to cell wall integrity disruptions. In summary, the structural plasticity of primary cell walls is proven, since a lignification process is possible in response to cellulose impoverishment. PMID- 25735404 TI - Similar cerebral protective effectiveness of antegrade and retrograde cerebral perfusion during deep hypothermic circulatory arrest in aortic surgery: a meta analysis of 7023 patients. AB - In aortic arch surgery, deep hypothermic circulatory arrest (DHCA) combined with cerebral perfusion is employed worldwide as a routine practice. Even though antegrade cerebral perfusion (ACP) is more widely used than retrograde cerebral perfusion (RCP), the difference in benefit and risk between ACP and RCP during DHCA is uncertain. The purpose of this meta-analysis is to compare neurologic outcomes and early mortality between ACP and RCP in patients who underwent aortic surgery during DHCA. PubMed, EMBASE, and the Cochrane Library were searched using the key words "antegrade," "retrograde," "cerebral perfusion," "cardiopulmonary bypass," "extracorporeal circulation," and "cardiac surgery" for studies reporting on clinical endpoints including early mortality, stroke, temporary neurologic dysfunction (TND), and permanent neurologic dysfunction (PND) in aortic surgery requiring DHCA with ACP or RCP. Heterogeneity was analyzed with the Cochrane Q statistic and I(2) statistic. Publication bias was tested with Begg's funnel plot and Egger's test. Thirty-four studies were included in this meta-analysis, with 4262 patients undergoing DHCA + ACP and 2761 undergoing DHCA + RCP. The overall pooled relative risk for TND was 0.722 (95% CI = [0.579, 0.900]), and the z-score for overall effect was 2.9 (P = 0.004). There was low heterogeneity (I(2) = 18.7%). The analysis showed that patients undergoing DHCA + ACP had better outcomes than those undergoing DHCA + RCP in terms of TND, while there were no significant differences between groups in terms of PND, stroke, and early mortality. This meta-analysis indicates that DHCA + ACP has an advantage over DHCA + RCP in terms of TND, while the two methods show similar results in terms of PND, early mortality, and stroke. PMID- 25735405 TI - The contribution of NF-kappaB signalling to immune regulation and tolerance. AB - BACKGROUND: Immune regulation is necessary to control inflammatory responses and to prevent autoimmune diseases. Therefore, mechanisms of central and peripheral tolerance have evolved to ensure that T cells recognize antigens as self- or non self-antigens. The thymus is crucially important for central tolerance induction to self-antigens via negative selection of T cells. However, if T cells escape negative selection in the thymus and enter the periphery, peripheral mechanisms are active to warrant immune tolerance. Secondary lymphoid organs, as well as tolerogenic dendritic cells and regulatory T cells, play an important role in peripheral tolerance. In chronic inflammatory diseases, tertiary lymphoid organs are sometimes formed that may also be involved in the induction of peripheral tolerance. This review discusses the main processes that are involved in immune regulation and tolerance, and focuses on the contribution of NF-kappaB signalling to these processes. MATERIAL AND METHODS: This narrative review is based on peer reviewed publications listed on PubMed up to December 2014. The focus of our literature search was on studies investigating the role of (non)canonical NF kappaB signalling in central and peripheral mechanisms of tolerance. Only studies published in English language were considered. RESULTS: This review discusses the immune phenotype of mutant mice with defective (non)canonical NF-kappaB signalling, corroborated with human data, and emphasizes the contribution of the noncanonical NF-kappaB pathway to immune regulation and tolerance induction. CONCLUSIONS: Noncanonical NF-kappaB signalling has an important immunoregulatory role in the immune system and contributes to both central and peripheral mechanisms of tolerance. PMID- 25735406 TI - Effect of egg yolk plasma on dog sperm cryopreservation. AB - This study evaluated the quality of frozen-thawed dog spermatozoon after the inclusion of egg yolk plasma (EYP) instead of whole egg yolk (EY) in the cryopreservation extender and after distinct periods of exposure to EYP. Seven mongrel dogs were used as sperm donors, and EYP was obtained by centrifugation. In Experiment 1, post-thawing sperm motility (MOT) and integrity of membrane (INT) and acrosome (ACR) were superior for spermatozoon extended with 20% EYP T2 than with 20% EY (P < 0.05), although normal sperm morphology (MOR) did not differ (P > 0.05). In Experiment 2, after ejaculates extended with 20% EYP were cooled at 5 degrees C for 2, 6 and 10 h before freezing, MOT, INT and ACR were similar among periods (P > 0.05). Thus, dog spermatozoon extended with 20% EYP can be kept cooled for up to 10 h prior to freezing, achieving post-thawing quality greater than that obtained with the inclusion of EY in freezing extenders. PMID- 25735407 TI - Dynamic formation of single-atom catalytic active sites on ceria-supported gold nanoparticles. AB - Catalysis by gold supported on reducible oxides has been extensively studied, yet issues such as the nature of the catalytic site and the role of the reducible support remain fiercely debated topics. Here we present ab initio molecular dynamics simulations of an unprecedented dynamic single-atom catalytic mechanism for the oxidation of carbon monoxide by ceria-supported gold clusters. The reported dynamic single-atom catalytic mechanism results from the ability of the gold cation to strongly couple with the redox properties of the ceria in a synergistic manner, thereby lowering the energy of redox reactions. The gold cation can break away from the gold nanoparticle to catalyse carbon monoxide oxidation, adjacent to the metal/oxide interface and subsequently reintegrate back into the nanoparticle after the reaction is completed. Our study highlights the importance of the dynamic creation of active sites under reaction conditions and their essential role in catalysis. PMID- 25735408 TI - The significant work of parenting. PMID- 25735409 TI - Work transition narratives. PMID- 25735410 TI - Usability-for-one. AB - This paper proposes usability-for-one as a new conceptual framework for understanding usability as it relates to Rehabilitation and Assistive Technology (R&AT). It argues that just as ergonomics for individual R&AT users is practiced as ergonomics-for-one, usability as it relates to individual R&AT users can be conceptualised as usability-for-one. The implications for R&AT service delivery and research are discussed. PMID- 25735411 TI - Work performance evaluation and QoL of adults with High Functioning Autism Spectrum Disorders (HFASD). AB - BACKGROUND: Studies suggest that adults with High Functioning Autism Spectrum Disorders (HFASD) are reliant on others for support in functioning in everyday life and employment. OBJECTIVES: This study followed a work placement program for people with HFASD over a nine months period. It aimed to measure the trajectory of their work performance and Quality of life on jobs in the open market. METHODS: Twenty-six participants with HFASD ages 18-40 underwent extensive evaluation and based on it were placed in various jobs on the open market. Participants were followed for nine months at their work place at four different time points. QoL was self-assessed in addition to work performance (WPE) which was assessed both by first-hand and team member's accounts. Team members are health professional who accompany and support the participants in the transition to their jobs. RESULTS: All 26 participants were able to maintain their jobs during the nine months of follow-up. WPE was perceived as high to start with, and its scores slightly improved by both people with HFASD and team members. Self report suggests a significant change in the quality of life of the participants, specifically in their evaluations of self-competency. CONCLUSIONS: This study enhances the importance of providing people with HFASD with work placing programs and following up during actual work performance. PMID- 25735412 TI - Latent Growth Mixture Models to estimate PTSD trajectories. PMID- 25735413 TI - Latent trajectory studies: the basics, how to interpret the results, and what to report. AB - BACKGROUND: In statistics, tools have been developed to estimate individual change over time. Also, the existence of latent trajectories, where individuals are captured by trajectories that are unobserved (latent), can be evaluated (Muthen & Muthen, 2000). The method used to evaluate such trajectories is called Latent Growth Mixture Modeling (LGMM) or Latent Class Growth Modeling (LCGA). The difference between the two models is whether variance within latent classes is allowed for (Jung & Wickrama, 2008). The default approach most often used when estimating such models begins with estimating a single cluster model, where only a single underlying group is presumed. Next, several additional models are estimated with an increasing number of clusters (latent groups or classes). For each of these models, the software is allowed to estimate all parameters without any restrictions. A final model is chosen based on model comparison tools, for example, using the BIC, the bootstrapped chi-square test, or the Lo-Mendell-Rubin test. METHOD: To ease the use of LGMM/LCGA step by step in this symposium (Van de Schoot, 2015) guidelines are presented which can be used for researchers applying the methods to longitudinal data, for example, the development of posttraumatic stress disorder (PTSD) after trauma (Depaoli, van de Schoot, van Loey, & Sijbrandij, 2015; Galatzer-Levy, 2015). The guidelines include how to use the software Mplus (Muthen & Muthen, 1998-2012) to run the set of models needed to answer the research question: how many latent classes exist in the data? The next step described in the guidelines is how to add covariates/predictors to predict class membership using the three-step approach (Vermunt, 2010). Lastly, it described what essentials to report in the paper. CONCLUSIONS: When applying LGMM/LCGA models for the first time, the guidelines presented can be used to guide what models to run and what to report. PMID- 25735414 TI - Applications of Latent Growth Mixture Modeling and allied methods to posttraumatic stress response data. AB - BACKGROUND: Scientific research into mental health outcomes following trauma is undergoing a revolution as scientists refocus their efforts to identify underlying dimensions of health and psychopathology. This effort is in stark contrast to the previous focus which was to characterize individuals based on Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic status (Insel et al., 2010). A significant unresolved issue underlying this shift is how to characterize clinically relevant populations without reliance on the categorical definitions provided by the DSM. Classifying individuals based on their pattern of stress adaptation over time holds significant promise for capturing inherent inter-individual heterogeneity as responses including chronicity, recovery, delayed onset, and resilience can only be determined longitudinally (Galatzer-Levy & Bryant, 2013) and then characterizing these patterns for future research (Depaoli, Van de Schoot, Van Loey, & Sijbrandij, 2015). Such an approach allows for the identification of phenominologically similar patterns of response to diverse extreme environmental stressors (Bonanno, Kennedy, Galatzer-Levy, Lude, & Elfstom, 2012; Galatzer-Levy & Bonanno, 2012; Galatzer-Levy, Brown, et al., 2013; Galatzer-Levy, Burton, & Bonanno, 2012) including translational animal models of stress adaptation (Galatzer-Levy, Bonanno, Bush, & LeDoux, 2013; Galatzer-Levy, Moscarello, et al., 2014). The empirical identification of heterogeneous stress response patterns can increase the identification of mechanisms (Galatzer-Levy, Steenkamp, et al., 2014), consequences (Galatzer-Levy & Bonanno, 2014), treatment effects (Galatzer-Levy, Ankri, et al., 2013), and prediction (Galatzer-Levy, Karstoft, Statnikov, & Shalev, 2014) of individual differences in response to trauma. METHOD: METHODological and theoretical considerations for the application of Latent Growth Mixture Modeling (LGMM) and allied methods such as Latent Class Growth Analysis (LCGA) for the identification of heterogeneous populations defined by their pattern of change over time will be presented (Van De Schoot, 2015). Common pitfalls including non-identification, over identification, and issues related to model specification will be discussed as well as the benefits of applying such methods along with the theoretical grounding of such approaches. CONCLUSIONS: LGMM and allied methods have significant potential for improving the science of stress pathology as well as our understanding of healthy adaptation (resilience). PMID- 25735415 TI - Using Bayesian statistics for modeling PTSD through Latent Growth Mixture Modeling: implementation and discussion. AB - BACKGROUND: After traumatic events, such as disaster, war trauma, and injuries including burns (which is the focus here), the risk to develop posttraumatic stress disorder (PTSD) is approximately 10% (Breslau & Davis, 1992). Latent Growth Mixture Modeling can be used to classify individuals into distinct groups exhibiting different patterns of PTSD (Galatzer-Levy, 2015). Currently, empirical evidence points to four distinct trajectories of PTSD patterns in those who have experienced burn trauma. These trajectories are labeled as: resilient, recovery, chronic, and delayed onset trajectories (e.g., Bonanno, 2004; Bonanno, Brewin, Kaniasty, & Greca, 2010; Maercker, Gabler, O'Neil, Schutzwohl, & Muller, 2013; Pietrzak et al., 2013). The delayed onset trajectory affects only a small group of individuals, that is, about 4-5% (O'Donnell, Elliott, Lau, & Creamer, 2007). In addition to its low frequency, the later onset of this trajectory may contribute to the fact that these individuals can be easily overlooked by professionals. In this special symposium on Estimating PTSD trajectories (Van de Schoot, 2015a), we illustrate how to properly identify this small group of individuals through the Bayesian estimation framework using previous knowledge through priors (see, e.g., Depaoli & Boyajian, 2014; Van de Schoot, Broere, Perryck, Zondervan-Zwijnenburg, & Van Loey, 2015). METHOD: We used latent growth mixture modeling (LGMM) (Van de Schoot, 2015b) to estimate PTSD trajectories across 4 years that followed a traumatic burn. We demonstrate and compare results from traditional (maximum likelihood) and Bayesian estimation using priors (see, Depaoli, 2012, 2013). Further, we discuss where priors come from and how to define them in the estimation process. RESULTS: We demonstrate that only the Bayesian approach results in the desired theory-driven solution of PTSD trajectories. Since the priors are chosen subjectively, we also present a sensitivity analysis of the Bayesian results to illustrate how to check the impact of the prior knowledge integrated into the model. CONCLUSIONS: We conclude with recommendations and guidelines for researchers looking to implement theory driven LGMM, and we tailor this discussion to the context of PTSD research. PMID- 25735416 TI - Well-constructed single-layer molybdenum disulfide nanorose cross-linked by three dimensional-reduced graphene oxide network for superior water splitting and lithium storage property. AB - A facile one-step solution reaction route for growth of novel MoS2 nanorose cross linked by 3D rGO network, in which the MoS2 nanorose is constructed by single layered or few-layered MoS2 nanosheets, is presented. Due to the 3D assembled hierarchical architecture of the ultrathin MoS2 nanosheets and the interconnection of 3D rGO network, as well as the synergetic effects of MoS2 and rGO, the as-prepared MoS2-NR/rGO nanohybrids delivered high specific capacity, excellent cycling and good rate performance when evaluated as an anode material for lithium-ion batteries. Moreover, the nanohybrids also show excellent hydrogen evolution catalytic activity and durability in an acidic medium, which is superior to MoS2 nanorose and their nanoparticles counterparts. PMID- 25735417 TI - ERRATUM: Long-range magnetic interaction and frustration in double perovskites Sr2NiIrO6 and Sr2ZnIrO6. PMID- 25735420 TI - Leadership in transformation: a longitudinal study in a nursing organization. AB - PURPOSE: Not only does leadership produce changes, but those changes produce leadership in organisations. The purpose of this paper is to present a theoretical and empirical analysis of the transformation of leadership at two different historical points in a health care organisation. It leans on the perspective of social constructionism, drawing especially from the ideas of Berger and Luckmann (1966). The paper seeks to improve understanding of how leaders themselves construct leadership in relation to organisational change. DESIGN/METHODOLOGY/APPROACH: The empirical material was gathered in a longitudinal case study in a nursing organisation in two different historical and situational points. It consists of written narratives produced by nurse leaders that are analysed by applying discourse analysis. FINDINGS: The empirical study revealed that the constructions of leadership were dramatically different at the two different historical and situational points. Leadership showed up as a complex, fragile and changing phenomenon, which fluctuates along with the other organisational changes. The results signal the importance of agency in leadership and the central role of "significant others". ORIGINALITY/VALUE: The paper questions the traditional categorisation and labelling of leadership as well as the cross-sectional studies in understanding leadership transformation. Its originality relates to the longitudinal perspective on transformation of leadership in the context of a health care organisation. PMID- 25735419 TI - Powerless positions, silenced voices? - critical views on health and social care management. AB - PURPOSE: The purpose of this paper is to provide background to this special issue and consider how critically oriented research can be applied to health and social care management. DESIGN/METHODOLOGY/APPROACH: Basic principles of critical management studies are introduced briefly to frame subsequent papers in this issue. FINDINGS: In order to identify the wicked problems and darker sides of the care field, there is a need to study things in alternative ways through critical lenses. Giving a voice to those in less powerful positions may result in redefinition and redesign of conventional roles and agency of patients, volunteers and professionals and call into question the taken-for-granted understanding of health and social care management. ORIGINALITY/VALUE: The special issue as a whole was designed to enhance critical approaches to the discussion in the field of health and social care. This editorial hopefully raises awareness of CMS and serves as an opening for further discussion on critical views in the research on management and organization in this field. PMID- 25735418 TI - Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. AB - Focused ultrasound (FUS) has recently been investigated as a new mode of non invasive brain stimulation, which offers exquisite spatial resolution and depth control. We report on the elicitation of explicit somatosensory sensations as well as accompanying evoked electroencephalographic (EEG) potentials induced by FUS stimulation of the human somatosensory cortex. As guided by individual specific neuroimage data, FUS was transcranially delivered to the hand somatosensory cortex among healthy volunteers. The sonication elicited transient tactile sensations on the hand area contralateral to the sonicated hemisphere, with anatomical specificity of up to a finger, while EEG recordings revealed the elicitation of sonication-specific evoked potentials. Retrospective numerical simulation of the acoustic propagation through the skull showed that a threshold of acoustic intensity may exist for successful cortical stimulation. The neurological and neuroradiological assessment before and after the sonication, along with strict safety considerations through the individual-specific estimation of effective acoustic intensity in situ and thermal effects, showed promising initial safety profile; however, equal/more rigorous precautionary procedures are advised for future studies. The transient and localized stimulation of the brain using image-guided transcranial FUS may serve as a novel tool for the non-invasive assessment and modification of region-specific brain function. PMID- 25735421 TI - Constructing accountability in inter-organisational collaboration: the implications of a narrow performance-based focus. AB - PURPOSE: The purpose of this paper is to analyse how accounts of collaboration practice were made and used to construct accountability in the empirical context of coordination associations, a Swedish form of collaboration between four authorities in health and social care. They feature pooled budgets, joint leadership and joint reporting systems, intended to facilitate both collaboration and (shared) accountability. DESIGN/METHODOLOGY/APPROACH: Empirical data were collected in field observations in local, regional and national settings. In addition, the study is based on analysis of local association documents such as evaluations and annual reports, and analysis of national agency reports. FINDINGS: Accountability is constructed hierarchically with a narrow focus on performance, and horizontal (shared) accountability as well as outcomes are de emphasised. Through this narrow construction of accountability the coordination associations are re-created as hierarchical and accountability is delegated rather than shared. RESEARCH LIMITATIONS/IMPLICATIONS: Features such as pooled budgets, joint leadership and joint reporting systems can support collaboration but do not necessarily translate into shared accountability if accountability is interpreted and constructed hierarchically. PRACTICAL IMPLICATIONS: When practice conforms to what is counted and accounted for, using the hierarchical and narrow construction of accountability, the result may be that the associations become an additional authority. That would increase rather than decrease fragmentation in the field. ORIGINALITY/VALUE: This research derives from first-hand observations of actor-to-actor episodes complemented with the analysis of documents and reports. It provides critical analysis of the construction and evaluation of accounts and accountability related to practice and performance in collaboration. The main contribution is the finding that despite the conditions intended to facilitate inter-organisational collaboration and horizontal accountability, the hierarchical accountability persisted. PMID- 25735422 TI - Professional autonomy under pressure: towards a dialectical approach. AB - PURPOSE: The purpose of this paper is to explore the process of evolution of medical autonomy as an analytic and historical aspect of the medical work organization in a public bureaucracy. DESIGN/METHODOLOGY/APPROACH: The authors draw on the analytic concept of organizational contradictions (Heydebrand, 1977) to inform a dialectical approach in organizational analysis. Semi-structured interviews with 20 doctors of a Greek general public hospital were conducted and archival data were collected. FINDINGS: The findings suggest that the historical development of two contradictions characterize the process of medical autonomy evolution. The first contradiction tends to develop between medical autonomy, as a self-control relation, and the established division of labour through which bureaucratic control is exercised over the allocation of resources and over the distribution of healthcare service. The second contradiction tends to develop between those reified aspects of the medical work organization and the ongoing organizing activity, i.e. activity towards extending, intensifying and centralizing organizational control over labour, resources and the distribution of healthcare services. These contradictions indicate a pressure towards constraining health professionals' power to self-define their relationship with patients and towards curtailing their discretionary domain over the use of resources. ORIGINALITY/VALUE: This paper offers an empirical approach to materialist dialectics for organizational analysis towards conceptualizing change as a historical process. PMID- 25735423 TI - Economic and demographic challenges for social care. AB - PURPOSE: The purpose of this paper is to analyse the impact of reforms designed to address economic and demographic challenges in England with reference to the authors' own empirical work providing a critique of their impact and suggesting a way to improve the quality of social care for older people. DESIGN/METHODOLOGY/APPROACH: The research was a qualitative study conducted in a participatory manner in which older people were positioned as co-creators of the research study. This involved setting the scope of the study and identifying and refining the themes used in the analysis of an inquiry board and interviews. FINDINGS: The research findings highlight the threat of recent moves that emphasise "independence" and "self-management" particularly as they risk marginalising some groups of older people and reducing the quality of care. An alternative approach drawn from the ethics of care is suggested. RESEARCH LIMITATIONS/IMPLICATIONS: The research study focused on a narrow selection of older people and future work will wish to explore concepts of "care" and "independence" in additional contexts and of reforms in other geographies. PRACTICAL IMPLICATIONS: The researchers argue that the current reform agenda threatens the quality of care services and suggest improvements to the way in which services might be organised and presented. SOCIAL IMPLICATIONS: It is intended that the research will contribute to social policy debates and particularly those that focus on social care. The study also looks to contribute to current work in the fields of critical gerontology, feminist ethics and the management of public services more generally. ORIGINALITY/VALUE: The paper presents a novel and critical viewpoint of current social care policy in England and will therefore be of interest to policy-makers and to professionals. PMID- 25735424 TI - Volunteers in a hospital - opportunity or threat? Exploratory study from Finland. AB - PURPOSE: Finland represents one of the Nordic welfare states where the role of the public sector as the organiser and provider of health and social care is strong. However, the amount of voluntary work in social and health care services is surprisingly big. The strongest advocates for keeping the volunteers outside are hospitals and health centres while at the same time they are suffering from shortages of staff and staff is reporting lack of time to provide needed care for their patients. The purpose of this paper is to report the results of a study of the attitudes of professionals towards voluntary work in hospitals. DESIGN/METHODOLOGY/APPROACH: The paper is based on an exploratory study done in three hospitals, two from an urban area and one in a rural area. The interviewees represent nursing and care staff (n=21). The main questions were how staff members see options, constraints and drawbacks of volunteering regarding professional roles, work division, coordination and management. FINDINGS: Attitudes of staff varied from positive to conditional. The approaches towards voluntary work varied from holistic to task-centred or patient-centred and were linked with organisational approach, professional approach or considerations of patients' well-being. Critical views were expressed related to managerial issues, patients' safety and quality of care. Increasing the amount of voluntary work done in hospitals would require a considered strategy and a specifically designed process for coordination, management and rules on the division of labour. RESEARCH LIMITATIONS/IMPLICATIONS: The research raised themes for further quantitative studies to elaborate the findings on the similarities and differences of the opinions of different staff categories and to be able to develop further the heuristic model of volunteer management triangle suggested in the paper. SOCIAL IMPLICATIONS: The study raises questions of the need and promotion of volunteers in general and especially in health care services. It also raises critical views related to voluntary work in hospitals. ORIGINALITY/VALUE: The study is a new initiative to discuss voluntary work and how to manage volunteers in hospitals. It provides valuable knowledge for practitioners in health care involved in volunteer management and coordination. PMID- 25735425 TI - People with multimorbidity: forgotten outsiders or dynamic self-managers? AB - PURPOSE: The purpose of this paper is to draw attention to the discursive construction of multimorbidity. The study illustrates how the social reality of multimorbidity and the agency of patients are discursively constructed in scientific articles addressing care for people with multiple chronic conditions. DESIGN/METHODOLOGY/APPROACH: The study is based on the postmodern assumptions about the power of talk and language in the construction of reality. Totally 20, scientific articles were analysed by critically oriented discourse analysis. The interpretations of the findings draw on the agency theories and principals of critical management studies. FINDINGS: Four discourses were identified: medical, technical, collaborative and individual. The individual discourse challenges patients to become self-managers of their health. It may, however, go too far in the pursuit of patients' active agency. The potential restrictions and consequences of a "business-like" orientation must be paid careful attention when dealing with patients with multimorbidity. RESEARCH LIMITATIONS/IMPLICATIONS: The data consisted solely of scientific texts and findings therefore serve as limited illustrations of the discursive construction of multimorbidity. In future, research focusing for example on political documents and practice talk of professionals and patients is needed. Social implications - The findings highlight the power of talk and importance of ethical considerations in the development of care for challenging patient groups. ORIGINALITY/VALUE: By identifying the prevailing discourses the study attempts to cast doubt on the taken-for-granted understandings about the agency of patients with multimorbidity. PMID- 25735426 TI - Corrigendum. The influence of body mass index on the accumulation of advanced glycation end products in hemodialysis patients. AB - Correction to: European Journal of Clinical Nutrition (2015) 69, 309-313; doi: 10.1038/ejcn.2014.261; published online 14 January 2015 Since the publication of this article, the authors have noticed that several of the author names were published incorrectly. The correct author names are listed above. The .html and online PDF versions have also been amended. The authors apologise for any inconvenience caused. PMID- 25735427 TI - Impact of Severe Tricuspid Regurgitation on Accuracy of Echocardiographic Pulmonary Artery Systolic Pressure Estimation. AB - INTRODUCTION: Transthoracic Doppler echocardiography (DE) is recommended for screening and monitorization of pulmonary arterial hypertension (PAH). However, some recent studies have suggested that Doppler echocardiographic pulmonary artery systolic pressure (PASP) estimates may frequently be inaccurate. Some hemodynamic and echocardiographic factors are known to contribute to discordant results. The aim of this study was to determine whether severe tricuspid regurgitation (TR) has any impact on true estimation of PASP by DE. MATERIALS AND METHODS: We retrospectively identified all PAH patients who underwent right heart catheterization (RHC) and had an echocardiogram within the same hospitalization period. Patients were divided into two groups according to the presence of severe TR: Group 1 consisted of 36 patients with mild-moderate TR and group 2 of 36 patients with severe TR. For these two groups, the agreement between echocardiographic and catheterization PASP measurements was evaluated by Bland Altman analysis, separately. RESULTS: In group 1, the bias for the echocardiographic estimates of the PASP was 2.5 mmHg and 62.5% of the echocardiographic estimates were accurate (<=10 mmHg difference with RHC measurement). In group 2, the bias was 16.25 mmHg and echocardiography was accurate in 37.5% of the patients. To clarify the association between PASP overestimation on DE and the presence of severe TR, regression analysis was performed. Severe TR was found as the only independent predictor of PASP overestimation on echocardiography after multivariate analysis. CONCLUSION: The results of the study show that in patients with PAH, the presence of severe TR is associated with an overestimated PASP measurement on echocardiography. PMID- 25735428 TI - Stereotactic body radiotherapy with helical TomoTherapy for medically inoperable early stage primary and second-primary non-small-cell lung neoplasm: 1-year outcome and toxicity analysis. AB - OBJECTIVE: This study investigated the effectiveness of stereotactic body radiotherapy with helical TomoTherapy (T-SBRT) for treating medically inoperable primary and second-primary early stage non-small-cell lung neoplasm (SPLN) and evaluated whether the movement of organizing pneumonia (OP) within the irradiation field (IF) can be detected via analysis of radiological changes. METHODS: Patients (n = 16) treated for 1 year (2011-12) at our hospital by T-SBRT at a total dose of 60 Gy in five fractions were examined retrospectively. Outcome and toxicity were recorded and were separately described for SPLN. CT scans were reviewed by a single radiologist. RESULTS: Of the 16 patients, 5 (31.3%) had primary lung malignancies, 10 (62.5%) had SPLN, and 1 case (6.3%) had isolated mediastinal metastasis of lung neoplasm. Pathological evidence was obtained for 72.2% of all lesions. The median radiological follow-up was 11 months (10.5 months for SPLN). For all cases, the 6- and 12-month survival rates were 100% and 77.7% (100% and 71.4%, respectively, for SPLN), and the 6- and 12-month locoregional control rates were 100% in all cases. 2 (12.5%) of 16 patients developed grade 3 late transient radiation pneumonitis following steroid therapy and 1 (6.3%) presented asymptomatic infiltrates comparable to OP opacities. CONCLUSION: T-SBRT seems to be safe and effective. ADVANCES IN KNOWLEDGE: Mild OP is likely associated with radiation-induced anomalies in the IF, identification of migrating opacities can help discern relapse of radiation-induced opacities. PMID- 25735429 TI - Dramatic emotional therapy for dementia patients. PMID- 25735430 TI - Diabetes-Specific Quality of Life of Korean Children and Adolescents With Type 1 Diabetes. AB - PURPOSE: The purpose of this study was to explore the quality of life of children in Korea with type 1 diabetes and related factors. METHODS: Children were recruited from a diabetes camp. Data were collected using four instruments: the PedsQLTM 3.2 Diabetes Module, Self-Efficacy for Diabetes Self-Management, the Center for Epidemiological Studies Depression Scale for Children, and the Diabetes Management Behavior Scale. RESULTS: Children who were older (t = 2.197, p = .041), male (t = -3.579, p = .002), and less depressed (t = -2.859, p = .010) were more likely to have better quality of life. CONCLUSION: Further research is needed in children with type 1 diabetes in countries where this disease is rare, and governmental support and public awareness are limited. PMID- 25735431 TI - High Mobility Group Box 1 Promotes Angiogenesis from Bone Marrow-derived Endothelial Progenitor Cells after Myocardial Infarction. AB - AIMS: High mobility group box 1 (HMGB1) is a DNA-binding protein secreted into the extracellular space from necrotic cells that acts as a cytokine. We examined the role of HMGB1 in angiogenesis from bone marrow-derived cells in the heart using transgenic mice exhibiting the cardiac-specific overexpression of HMGB1 (HMGB1-TG). METHODS: HMGB1-TG mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow cells from green fluorescent protein mice through the tail vein. After bone marrow transplantation, the left anterior descending artery was ligated to induce myocardial infarction (MI). RESULTS: Flow cytometry revealed that the levels of circulating endothelial progenitor cells (EPCs) mobilized from the bone marrow increased after MI in the HMGB-TG mice versus the WT mice. In addition, the size of MI was smaller in the HMGB1-TG mice than in the WT mice, and immunofluorescence staining demonstrated that the number of engrafted vascular endothelial cells derived from bone marrow in the border zones of the MI areas was increased in the HMGB1-TG mice compared to that observed in the WT mice. Moreover, the levels of cardiac vascular endothelial growth factor after MI were higher in the HMGB1-TG mice than in the WT mice. CONCLUSIONS: The present study demonstrated that HMGB1 promotes angiogenesis and reduces the MI size by enhancing the mobilization and differentiation of bone marrow cells to EPCs as well as their migration to the border zones of the MI areas and engraftment as vascular endothelial cells in new capillaries or arterioles in the infarcted heart. PMID- 25735433 TI - Risk of major morbidity and death in older adults with suicidal intent: a cross sectional analysis from the National Poison Data System, 2000-2009. AB - OBJECTIVES: To describe suicide-related exposures in older persons according to sex, age, and substance category reported to U.S. poison control centers (PCCs) and report the crude relative risk (RR) of major effects and death from pharmaceuticals and nonpharmaceutical substances after single- and multiple substance exposures. DESIGN: Cross-sectional analysis of American Association of Poison Control Centers National Poison Data System (NPDS) data. SETTING: Calls to U.S. PCCs. PARTICIPANTS: NPDS cases involving individuals aged 60 and older with an exposure to a pharmaceutical or nonpharmaceutical substance and suicide as the reason (n=46,494). MEASUREMENTS: Major effect and death probabilities for single- and multiple-substance exposures to pharmaceuticals and nonpharmaceuticals were determined. In the NPDS, a major effect is defined as symptoms or signs that are life-threatening or resulted in significant residual disability or disfigurement. Crude RRs of major effects or death were estimated for single and multiple pharmaceutical substances in comparison with nonpharmaceutical substances. RESULTS: Single-substance exposures occurred in 53.3% of cases. Overall, 92.3% involved pharmaceuticals and 64.4% involved women. In the total sample, 12.7% (5,895/46,494) of exposures resulted in major effect, and 1.9% (884/46,494) resulted in death. The crude RR of major effects in single-substance pharmaceutical exposures was significantly lower than with nonpharmaceutical exposures (RR=0.54, 95% confidence interval (CI)=0.49-0.59), as was death (RR=0.25, 95% CI=0.20-0.30). For multiple-substance exposures, the crude RR of major effects from pharmaceuticals was similar to that for nonpharmaceuticals (RR=0.92, 95% CI=0.80-1.06), whereas the crude RR of death from pharmaceuticals was significantly lower (RR=0.55, 95% CI=0.40-0.77). CONCLUSION: These findings can inform suicide prevention strategies that focus on decreasing at-risk older adults' access to dangerous medications and chemicals in the home. PMID- 25735432 TI - A thymine-adenine dinucleotide repeat polymorphism near IL28B is associated with spontaneous clearance of hepatitis C virus. AB - BACKGROUND: Genome-wide association studies have revealed several single nucleotide polymorphisms around interleukin 28B (IL28B) that are strongly associated with hepatitis C virus (HCV) clearance. However, their predictive value is not perfect, which suggests that other genetic factors may also be involved in HCV clearance. We previously reported a wide variation in the length of a thymine-adenine (TA) dinucleotide repeat in the promoter region of IL28B and that the transcriptional activity of the promoter increased gradually in a TA repeat length-dependent manner. METHODS: We determined the length of the TA repeats of 1,060 Japanese and 201 African-American samples to investigate the relation to spontaneous HCV clearance. RESULTS: The distribution of the TA repeats greatly differed between the two ethnicities. The variation ranged from 10 to 18 repeats, and the most frequent allele, 12, accounted for over 80% for Japanese. The African-American data showed a gently sloping distribution, and the allele with six repeats was detected only in the African-American sample. The TA repeats 11 or greater were correlated with spontaneous clearance. Multiple logistic regression analysis extracted the genotype of the TA repeats as an independent factor in both the Japanese [p = 0.0004, odds ratio (OR) = 13.02 95% confidence interval (CI) = 2.59-237.0] and African-American (p = 0.027, OR = 3.70 95% CI = 1.16-11.8) populations. CONCLUSIONS: A long TA repeat in the promoter region of IL28B was associated with spontaneous HCV clearance. Although its efficacy may be limited in Japanese population because of its allele distribution, this novel genetic factor will be useful for predicting HCV clearance especially for the African Americans. PMID- 25735434 TI - Tamlana nanhaiensis sp. nov., isolated from surface seawater collected from the South China Sea. AB - A polyphasic taxonomic study was performed on a strain, designated FHC16(T), which was isolated from surface seawater collected from the South China Sea. Cells of strain FHC16(T) are Gram stain-negative, oxidase- and catalase-positive and non-motile rods. Growth was observed at 15-37 degrees C (optimum, 25-30 degrees C), at pH 6.0-9.0 (optimum, pH 7.0) and in the presence of 0-5 % (w/v) NaCl (optimum, 3%). 16S rRNA gene sequence analysis showed that strain FHC16(T) is most closely related to Tamlana sedimentorum JCM 19808(T) (98.2% sequence similarity). The ANI value between strain FHC16(T) and T. sedimentorum JCM 19808(T) was found to be 81.82-81.81%. The DNA-DNA hybridization estimated value between strain FHC16(T) and T. sedimentorum JCM 19808(T) was determined to be 25.8 +/- 2.41%. The principal fatty acids (>5% of the total) were found to be iso C(15:0), iso G-C(15:1), iso-C(17:0) 3-OH, iso-C(15:0) 3-OH and summed feature 3 (comprising C(16:1)omega7c/C(16:1)omega6c). The strain was found to have MK-6 as the major respiratory menaquinone, which is consistent with the other three recognized Tamlana species, T. sedimentorum, Tamlana crocina and Tamlana agarivorans. The polar lipids were found to comprise phosphatidylethanolamine, one unidentified aminophospholipid, two unidentified aminolipids and seven unidentified lipids. The G+C content of the chromosomal DNA was determined to be 34.2 mol%. On the basis of phenotypic, chemotaxonomic and molecular data, strain FHC16(T) is considered to represent a novel species of the genus Tamlana, for which the name Tamlana nanhaiensis sp. nov. is proposed. The type strain is FHC16(T) (.LMG 27420(T) = CGMCC 1.12469(T) = MCCC 1A06648(T)). PMID- 25735435 TI - Heterologous expression of galbonolide biosynthetic genes in Streptomyces coelicolor. AB - The galbonolide antibiotics are non-glycosylated heptaketide 14-membered macrolides. These antibiotics exhibit broad-spectrum fungicidal activities, including against the human pathogen Cryptococcus neoformans. Previously, galbonolides B and E were isolated from the marine actinomycete Streptomyces sp. LZ35. By bioinformatics analysis, the putative galbonolide biosynthetic gene cluster, gbn, was identified in the genome of strain LZ35. In order to verify that the core genes (gbnA-E) are sufficient for synthesizing the basic structure of galbonolide as previously proposed, we performed the heterologous expression of gbnA-E in a "clean background" host Streptomyces coelicolor ZM12, in which all the native polyketide synthase genes have been deleted. As expected, the production of galbonolide B (1) was detected in the transformant. To the best of our knowledge, this is the first report that demonstrates the essential role of gbnA-E in the biosynthesis of galbonolides by heterologous expression. This heterologous expression system would be helpful to generate novel galbonolide derivatives by co-overexpression of unusual biosynthesis extender units. PMID- 25735436 TI - A new low-noise signal acquisition protocol and electrode placement for electrocochleography (ECOG) recordings. AB - Electrocochleography (ECOG) is a low-amplitude electrophysiological measurement technique primarily used as an assistive tool for the diagnosis of Meniere's disease. Of the two types of ECOG, transtympanic (TT) and extratympanic (ET), ET ECOG has gained popularity due to its noninvasive nature; however, it suffers from increased susceptibility to various types of noise, due to the low-signal amplitude (~1 uV scale) associated with the method. Therefore, reliably obtaining ECOG recordings involves an environment that minimally interferes with the recording, a low-noise signal recorder, and a carefully executed recording protocol. We propose a new method that involves a modified ear electrode and electrode placement protocol that offers a solution to reducing noise in ET-ECOG. Noise suppression is achieved by minimizing background biological noise, and thermal noise from electrode impedances, which were identified to be the main contributors to signal degradation in ET-ECOG. Results show that the proposed method yields a >2.6 dB improvement in SNR in comparison with the conventional method (p < 0.05); thus, a SNR obtained with ~880 repetitions using conventional method can be achieved with ~360 repetitions. Improved SNR demonstrate that the proposed method is capable of achieving faster recordings, while maintaining similar or better SNR compared to conventional methods. PMID- 25735438 TI - Glycogen Storage Disease Type I Presenting with Hypertension During Infancy. PMID- 25735437 TI - A mechanical chest compressor closed-loop controller with an effective trade-off between blood flow improvement and ribs fracture reduction. AB - Chest compression (CC) is a significant emergency medical procedure for maintaining circulation during cardiac arrest. Although CC produces the necessary blood flow for patients with heart arrest, improperly deep CC will contribute significantly to the risk of chest injury. In this paper, an optimal CC closed loop controller for a mechanical chest compressor (OCC-MCC) was developed to provide an effective trade-off between the benefit of improved blood perfusion and the risk of ribs fracture. The trade-off performance of the OCC-MCC during real automatic mechanical CCs was evaluated by comparing the OCC-MCC and the traditional mechanical CC method (TMCM) with a human circulation hardware model based on hardware simulations. A benefit factor (BF), risk factor (RF) and benefit versus risk index (BRI) were introduced in this paper for the comprehensive evaluation of risk and benefit. The OCC-MCC was developed using the LabVIEW control platform and the mechanical chest compressor (MCC) controller. PID control is also employed by MCC for effective compression depth regulation. In addition, the physiological parameters model for MCC was built based on a digital signal processor for hardware simulations. A comparison between the OCC MCC and TMCM was then performed based on the simulation test platform which is composed of the MCC, LabVIEW control platform, physiological parameters model for MCC and the manikin. Compared with the TMCM, the OCC-MCC obtained a better trade off and a higher BRI in seven out of a total of nine cases. With a higher mean value of cardiac output (1.35 L/min) and partial pressure of end-tidal CO2 (15.7 mmHg), the OCC-MCC obtained a larger blood flow and higher BF than TMCM (5.19 vs. 3.41) in six out of a total of nine cases. Although it is relatively difficult to maintain a stable CC depth when the chest is stiff, the OCC-MCC is still superior to the TMCM for performing safe and effective CC during CPR. The OCC-MCC is superior to the TMCM in performing safe and effective CC during CPR and can be incorporated into the current version of mechanical CC devices for high quality CPR, in both in-hospital and out-of-hospital CPR settings. PMID- 25735439 TI - A review of the use of tanning beds as a dermatological treatment. AB - INTRODUCTION: In-office phototherapy is an effective treatment for many dermatologic conditions, however, many patients are unable to adhere to the rigorous travel and time commitments sometimes needed. Tanning bed facilities are nearly ubiquitous in modern society and could represent a more convenient means to obtain ultraviolet (UV) exposure when office phototherapy is not feasible. The purpose of this study was to review available evidence on the use of tanning facilities as a treatment for dermatologic conditions. METHODS: PubMed was searched on February 2015 for "tanning beds" and "phototherapy", and with some dermatologic conditions sensitive to UV light, including "psoriasis", "mycosis fungoides", "acne", "atopic dermatitis" and "eczema". From there, further articles were found using the reference sections of the initial papers. A similar methodology was used with the Google Scholar search engine. Only articles in English and prospective studies were included in this review. RESULTS: We found studies validating the use of tanning facilities for psoriasis treatment. Use as a treatment option for atopic dermatitis, mycosis fungoides, acne, scleroderma, vitiligo, and pruritus, as well as other UV sensitive dermatoses, may also be beneficial. This study is limited by the lack of double-blind, placebo-controlled trials, long-term follow-up studies, and meta-analyses for tanning facility use in dermatologic phototherapy, and by the lack of standardization of both tanning facilities and exposure dosing. CONCLUSION: Unsupervised sun exposure is a standard recommendation for some patients to obtain phototherapy. Selected use of commercial tanning beds in the treatment of dermatologic conditions may be another useful and effective treatment for those patients with an inability to access office-based or home-based phototherapy. PMID- 25735440 TI - Connecting deterministic and stochastic metapopulation models. AB - In this paper, we study the relationship between certain stochastic and deterministic versions of Hanski's incidence function model and the spatially realistic Levins model. We show that the stochastic version can be well approximated in a certain sense by the deterministic version when the number of habitat patches is large, provided that the presence or absence of individuals in a given patch is influenced by a large number of other patches. Explicit bounds on the deviation between the stochastic and deterministic models are given. PMID- 25735441 TI - Facilitators and Challenges in Psychosocial Adaptation to Being at Increased Familial Risk of Breast Cancer. AB - Little is known about the process of psychosocial adaptation to familial risk in tested and untested individuals at increased familial risk of cancer. This paper presents findings from a qualitative study of 36 women participating in the Kathleen Cuningham Consortium for Research into Familial Breast cancer (kConFab) Psychosocial study. Facilitators and challenges in psychosocial adaptation were identified through semi-structured interviews. The women, who were either tested (carriers or non-carriers of breast cancer susceptibility mutations) or untested (ineligible for testing or eligible but delayed or declined testing), described personal, support network and healthcare characteristics that impacted on the adaptation process. Challenges in one domain could be overcome by facilitators in other domains and key differences relating to whether women had undergone testing, or not, were identified. Tested and untested women with an increased familial risk of breast cancer may benefit from support tailored to their mutation testing status in order to enhance adaptation. PMID- 25735442 TI - Using ApoE Genotyping to Promote Healthy Lifestyles in Finland - Psychological Impacts: Randomized Controlled Trial. AB - Common health recommendations often incite very little public response, as people instead require individualized information. The purpose of this study was to assess the psychological effects of personal genetic information, provided by different apoE genotypes, as a tool to promote lifestyle changes. This study was a one-year intervention study using healthy adults, aged 20-67 years (n = 107). Their experiences of state anxiety, threat and stage of change were measured three times over a 12 months period. These psychological experiences were assessed, during the genetic information gathering, for three groups: a high-risk group (E4+, n = 16); a low-risk group (E4-, n = 35); and a control group (n = 56). The psychological effects of personal genetic risk information were shown to be short-term, although the levels of state anxiety and threat experiences in the high-risk group both remained at a slightly higher level than in the baseline. Threat experiences differed almost significantly (alpha = 0.017) between the E4+ and E4- groups (p = 0.034). Information on the apoE genotype impacted the experience of cardiovascular threat; this effect was most intense immediately after genetic feedback was received. However, fears of threat and anxiety may not be an obstacle for using gene information to motivate healthy, stable adults towards making lifestyle changes. Further studies should thus focus on how to utilize genetic screening in prevention of lifestyle-related diseases. PMID- 25735443 TI - Direct growth of large-area graphene and boron nitride heterostructures by a co segregation method. AB - Graphene/hexagonal boron nitride (h-BN) vertical heterostructures have recently revealed unusual physical properties and new phenomena, such as commensurate incommensurate transition and fractional quantum hall states featured with Hofstadter's butterfly. Graphene-based devices on h-BN substrate also exhibit high performance owing to the atomically flat surface of h-BN and its lack of charged impurities. To have a clean interface between the graphene and h-BN for better device performance, direct growth of large-area graphene/h-BN heterostructures is of great importance. Here we report the direct growth of large-area graphene/h-BN vertical heterostructures by a co-segregation method. By one-step annealing sandwiched growth substrates (Ni(C)/(B, N)-source/Ni) in vacuum, wafer-scale graphene/h-BN films can be directly formed on the metal surface. The as-grown vertically stacked graphene/h-BN structures are demonstrated by various morphology and spectroscopic characterizations. This co segregation approach opens up a new pathway for large-batch production of graphene/h-BN heterostructures and would also be extended to the synthesis of other van der Waals heterostructures. PMID- 25735444 TI - Rectal cancer threatening or affecting the prostatic plane: is partial prostatectomy oncologically adequate? Results of a multicentre retrospective study. AB - AIM: The management of rectal cancer threatening or affecting the prostatic plane is still under debate. The role of preoperative chemo radiotherapy and the extent of prostatectomy seem to be key points in the treatment of these tumours. The aim of the present study was to evaluate the pathological circumferential margin status and the local recurrence rate following different therapeutic options. METHOD: A multicentre, retrospective study was conducted of patients with rectal cancer threatening or affecting the prostatic plane, but not the bladder, judged by magnetic resonance imaging (MRI). The use of preoperative chemoradiotherapy and the type of urologic resection were correlated with the status of the pathological circumferential resection margin (CRM) and local recurrence. RESULTS: A consecutive series of 126 men with rectal cancer threatening (44) or affecting (82) the prostatic plane on preoperative staging and operated with local curative intent between 1998 and 2010 was analysed. In patients who did not have chemoradiotherapy but had a preoperative threatened anterior margin the CRM positive rate was 25.0%. In patients who did not have preoperative chemoradiotherapy but did have an affected margin, the CRM-positive rate was 41.7%. When preoperative radiotherapy was given, the respective CRM infiltration rates were 7.1 and 20.7%. In patients having preoperative chemoradiotherapy followed by prostatic resection the rate of CRM positivity was 2.4%. Partial prostatectomy after preoperative chemoradiotherapy resulted in a free anterior CRM in all cases, but intra-operative urethral damage occurred in 36.4% of patients who underwent partial prostatectomy, resulting in a postoperative urinary fistula in 18.2% of patients. CONCLUSION: Preoperative chemoradiation is mandatory in male patients with a threatened or affected anterior circumferential margin on preoperative MRI. In patients with preoperative prostatic infiltration, prostatic resection is necessary. In this group of patients partial prostatectomy seems to be oncologically safe. PMID- 25735445 TI - Sperm concentration is poorly associated with hypoandrogenism in infertile men. AB - OBJECTIVE: To evaluate the utility of routine hormone evaluation in all men presenting for infertility by understanding the relationship between sperm concentration and hypoandrogenism. METHODS: We performed a retrospective cross sectional study between September 2013 and May 2014 at a tertiary referral center in Utah. Ninety-four men presenting for infertility consecutively between the ages of 18 and 55 years were identified. Our primary outcome was rate of hypoandrogenism among infertile men defined as the baseline total serum testosterone levels <300 ng/dL or bioavailable testosterone (BAT) levels <155 ng/dL. Secondary outcomes included association of normospermia, oligozoospermia, or azoospermia with biochemical or clinical hypoandrogenism. RESULTS: Thirty-nine men (41%) had a total serum testosterone level of <300 ng/dL, and 41 men (43%) had a BAT level <155 ng/dL. Biochemical and symptomatic hypoandrogenism was common; 17 men (18%) had a total testosterone level <300 ng/dL and >= 3 positive Androgen Deficiency in Aging Male (ADAM) responses, and 18 men (19%) had a BAT level of <155 ng/dL and >= 3 positive ADAM responses. Sperm concentration (normospermia, oligozoospermia, and azoospermia) was not associated with biochemical hypoandrogenism (total testosterone level <300 ng/dL or BAT level <155 ng/dL), symptomatic hypoandrogenism (>= 3 positive ADAM responses), or sexual dysfunction (Sexual Health Inventory for Men score <21). CONCLUSION: Hypoandrogenism is common among infertile men, and routine hormonal evaluation may identify hypoandrogenism in many infertile men with otherwise normal semen analysis. Sperm concentration (normospermia, oligozoospermia, and azoospermia) is not well associated with hypoandrogenism in infertile men. PMID- 25735446 TI - Health expenditure on alcohol and other drug treatment in Australia (2012/2013). AB - INTRODUCTION AND AIMS: Analysis of the health expenditure on alcohol and other drug (AOD) treatment provides important information regarding the funding sources and distribution of AOD treatment funds. This study aimed to provide an estimate of annual health expenditure on AOD treatment in Australia and document a methodology for future estimates. DESIGN AND METHODS: The study followed international standards for health accounts and calculated health expenditure for the federal government, state/territory governments and private expenditure for the year 2012/2013. Multiple data sources were used to generate the estimates. RESULTS: The total expenditure was estimated at AUD$1.2 billion in 2012/2013. The states/territories account for 51% of this total, the Commonwealth 31% and private sources 18%. In 2012/2013, AOD treatment represented 0.8% of total health care spending. DISCUSSION AND CONCLUSIONS: The higher proportion of expenditure in AOD treatment programs outside hospitals is consistent with the community focused models of care for AOD treatment. The Commonwealth's investment in AOD treatment funding resides predominantly in its dedicated AOD treatment grant programs. The analysis of health expenditure does not tell us whether the investment mix is effective in reducing AOD-related harm and producing positive health outcomes, but it provides the basis for analysis of the distributions of expenditure between funding sources and assessment of AOD treatment spending relative to all health areas, and creates a base for tracking trends over time. PMID- 25735447 TI - Evolution and selection of Rhg1, a copy-number variant nematode-resistance locus. AB - The soybean cyst nematode (SCN) resistance locus Rhg1 is a tandem repeat of a 31.2 kb unit of the soybean genome. Each 31.2-kb unit contains four genes. One allele of Rhg1, Rhg1-b, is responsible for protecting most US soybean production from SCN. Whole-genome sequencing was performed, and PCR assays were developed to investigate allelic variation in sequence and copy number of the Rhg1 locus across a population of soybean germplasm accessions. Four distinct sequences of the 31.2-kb repeat unit were identified, and some Rhg1 alleles carry up to three different types of repeat unit. The total number of copies of the repeat varies from 1 to 10 per haploid genome. Both copy number and sequence of the repeat correlate with the resistance phenotype, and the Rhg1 locus shows strong signatures of selection. Significant linkage disequilibrium in the genome outside the boundaries of the repeat allowed the Rhg1 genotype to be inferred using high density single nucleotide polymorphism genotyping of 15 996 accessions. Over 860 germplasm accessions were found likely to possess Rhg1 alleles. The regions surrounding the repeat show indications of non-neutral evolution and high genetic variability in populations from different geographic locations, but without evidence of fixation of the resistant genotype. A compelling explanation of these results is that balancing selection is in operation at Rhg1. PMID- 25735448 TI - Prostate magnetic resonance spectroscopic imaging at 1.5tesla with endorectal coil versus 3.0tesla without endorectal coil: comparison of spectral quality. AB - OBJECTIVES: To compare the spectral quality of prostate magnetic resonance spectroscopic imaging (MRSI) at 1.5Tesla with endorectal coil (ER-1.5T) to MRSI at 3.0Tesla without coil (3.0T). METHODS: In 30 patients, the spectral quality of 6107 voxels at ER-1.5T and that of 5667 at 3.0T were visually evaluated by three radiologists. RESULTS: There were 57.6% good quality voxels at ER-1.5T versus 64.3% at 3.0T (P=.121). The posterior two rows showed better quality at ER-1.5T (P=.047). CONCLUSION: There is no significant difference in overall spectral quality between ER-1.5T and 3.0T, although ER-1.5T shows better quality close to the endorectal coil. PMID- 25735449 TI - Metachronous colonic metastasis from pancreatic cancer presenting as mechanical obstruction: a case report. AB - Colonic metastasis from pancreatic cancer is extremely rare. We present the case of a 64-year-old man who developed colonic metastasis of pancreatic cancer 2 years after distal pancreatectomy. The level of carbohydrate antigen 19-9 (CA19 9) was elevated to 5133.0 U/ml. Pathologic diagnosis was a metastasis from the primary pancreatic cancer. Based on the present case, colonic metastasis should be included in the differential diagnosis of colonic mass with elevated CA 19-9 and history of curative resection of primary pancreatic cancer. PMID- 25735450 TI - Simplified protocol of cardiac 18F-fluorodeoxyglucose positron emission tomography viability study in normoglycemic patients with known coronary artery disease. AB - PURPOSE: The purpose was to evaluate quality of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) myocardial scans and its correlation with background glucose (BG) after simplified 5% intravenous glucose load protocol. METHODS: An intravenous glucose load protocol was applied in 69 normoglycemic patients with confirmed coronary artery disease. The blood glucose level was measured every 15 min. RESULTS: Eighty-four percent of images were optimal, 8.7% suboptimal, and 7.3% uninterpretable. The quality of 18F-FDG-PET was BG independent and body mass index dependent (P=.0007). CONCLUSIONS: Simplified glucose load protocol is a safe and efficient method of preparation for FDG cardiac viability study in patients with normoglycemia. PMID- 25735451 TI - Isolation and characterization of Chinese standard fulvic acid sub-fractions separated from forest soil by stepwise elution with pyrophosphate buffer. AB - XAD-8 adsorption technique coupled with stepwise elution using pyrophosphate buffers with initial pH values of 3, 5, 7, 9, and 13 was developed to isolate Chinese standard fulvic acid (FA) and then separated the FA into five sub fractions: FApH3, FApH5, FApH7, FApH9 and FApH13, respectively. Mass percentages of FApH3-FApH13 decreased from 42% to 2.5%, and the recovery ratios ranged from 99.0% to 99.5%. Earlier eluting sub-fractions contained greater proportions of carboxylic groups with greater polarity and molecular mass, and later eluting sub fractions had greater phenolic and aliphatic content. Protein-like components, as well as amorphous and crystalline poly(methylene)-containing components were enriched using neutral and basic buffers. Three main mechanisms likely affect stepwise elution of humic components from XAD-8 resin with pyrophosphate buffers including: 1) the carboxylic-rich sub-fractions are deprotonated at lower pH values and eluted earlier, while phenolic-rich sub-fractions are deprotonated at greater pH values and eluted later. 2) protein or protein-like components can be desorbed and eluted by use of stepwise elution as progressively greater pH values exceed their isoelectric points. 3) size exclusion affects elution of FA sub fractions. Successful isolation of FA sub-fractions will benefit exploration of the origin, structure, evolution and the investigation of interactions with environmental contaminants. PMID- 25735453 TI - Overexpression of potato miR482e enhanced plant sensitivity to Verticillium dahliae infection. AB - Verticillium wilt of potato is caused by the fungus pathogen Verticillium dahliae. Present sRNA sequencing data revealed that miR482 was in response to V. dahliae infection, but the function in potato is elusive. Here, we characterized potato miR482 family and its putative role resistance to Verticillium wilt. Members of the potato miR482 superfamily are variable in sequence, but all variants target a class of disease-resistance proteins with nucleotide binding site (NBS) and leucine-rich repeat (LRR) motifs. When potato plantlets were infected with V. dahliae, the expression level of miR482e was downregulated, and that of several NBS-LRR targets of miR482e were upregulated. Transgenic potato plantlets overexpressing miR482e showed hypersensitivity to V. dahliae infection. Using sRNA and degradome datasets, we validated that miR482e targets mRNAs of NBS LRR disease-resistance proteins and triggers the production of trans-acting (ta) siRNAs, most of which target mRNAs of defense-related proteins. Thus, the hypersensitivity of transgenic potato could be explained by enhanced miR482e and miR482e-derived ta-siRNA-mediated silencing on NBS-LRR-disease-resistance proteins. It is speculated that a miR482-mediated silencing cascade mechanism is involved in regulating potato resistance against V. dahliae infection and could be a counter defense action of plant in response to pathogen infection. PMID- 25735452 TI - N-butylidenephthalide attenuates Alzheimer's disease-like cytopathy in Down syndrome induced pluripotent stem cell-derived neurons. AB - Down syndrome (DS) patients with early-onset dementia share similar neurodegenerative features with Alzheimer's disease (AD). To recapitulate the AD cell model, DS induced pluripotent stem cells (DS-iPSCs), reprogrammed from mesenchymal stem cells in amniotic fluid, were directed toward a neuronal lineage. Neuroepithelial precursor cells with high purity and forebrain characteristics were robustly generated on day 10 (D10) of differentiation. Accumulated amyloid deposits, Tau protein hyperphosphorylation and Tau intracellular redistribution emerged rapidly in DS neurons within 45 days but not in normal embryonic stem cell-derived neurons. N-butylidenephthalide (Bdph), a major phthalide ingredient of Angelica sinensis, was emulsified by pluronic F127 to reduce its cellular toxicity and promote canonical Wnt signaling. Interestingly, we found that F127-Bdph showed significant therapeutic effects in reducing secreted Abeta40 deposits, the total Tau level and the hyperphosphorylated status of Tau in DS neurons. Taken together, DS-iPSC derived neural cells can serve as an ideal cellular model of DS and AD and have potential for high-throughput screening of candidate drugs. We also suggest that Bdph may benefit DS or AD treatment by scavenging Abeta aggregates and neurofibrillary tangles. PMID- 25735454 TI - Minimally invasive ventricular assist device surgery. AB - The use of mechanical circulatory support to treat patients with congestive heart failure has grown enormously, recently surpassing the number of annual heart transplants worldwide. The current generation of left ventricular assist devices (LVADs), as compared with older devices, is characterized by improved technologies and reduced size. The result is that minimally invasive surgery is now possible for the implantation, explantation, and exchange of LVADs. Minimally invasive procedures improve surgical outcome; for example, they lower the rates of operative complications (such as bleeding or wound infection). The miniaturization of LVADs will continue, so that minimally invasive techniques will be used for most implantations in the future. In this article, we summarize and describe minimally invasive state-of-the-art implantation techniques, with a focus on the most common LVAD systems in adults. PMID- 25735455 TI - Corrigendum: Polluted dust promotes new particle formation and growth. PMID- 25735457 TI - Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. AB - The Cystic Fibrosis p.Ile1234Val missense mutation actually creates a new dual splicing site possibly used either as a new acceptor or donor. Here, we aimed to test the accuracy of in silico predictions by comparing them with in vitro and ex vivo functional analyses of this mutation for an accurate CF diagnosis/prognosis. To this end, we applied a new in vitro strategy using a CFTR mini-gene which includes the complete CFTR coding sequence plus intron 22 (short version) which allows the assessment of alternatively spliced mRNA levels as well as the properties of the resulting abnormal CFTR protein regarding processing, intracellular localization and function. Our data demonstrate that p.Ile1234Val leads to usage of the alternative splicing donor (but not acceptor) resulting in alternative CFTR transcripts lacking 18 nts of exon 22 which produce a truncated CFTR protein with residual Cl- channel function. These results recapitulate data from native tissues of a CF patient. In conclusion, the existing in silico prediction models have limited application and ex vivo functional assessment of mutation effects should be made. Alternatively the in vitro strategy adopted here can be applied to assess the disease liability of mutations for an accurate CF diagnosis/prognosis. PMID- 25735458 TI - Reduced risk of nontuberculous mycobacteria in cystic fibrosis adults receiving long-term azithromycin. AB - BACKGROUND: Azithromycin reduces exacerbations in cystic fibrosis (CF) patients. Our aim was to investigate its association with nontuberculous mycobacteria isolation and macrolide susceptibility. METHODS: From 2006 to 2010, all adult CF subjects at Cochin Hospital (Paris, France) harboring at least one positive NTM isolate were identified (Cases). In a nested case-control study, each Case was individually matched for age and gender with up to 4 CF adults with no NTM isolate (Controls). Clinical data at the time of first NTM isolate (index date) in Cases were compared with those of Controls using multivariate conditional regression analysis. RESULTS: CF subjects with positive NTM isolates (Cases, n=41) were matched to 155 Controls. Among Cases, 48.7% had isolates from Mycobacterium avium complex and 58.5% from Mycobacterium abscessus complex, and 31 Cases fulfilled the 2007 American Thoracic Society criteria for NTM infection (ATS+ Cases). Cases and ATS+ Cases were more likely to have low body mass index and colonization with Aspergillus fumigatus. Azithromycin was associated with a two-fold reduction in NTM isolates. Only one M. avium complex isolate had acquired macrolide resistance. CONCLUSION: These data suggest that azithromycin is a primary prophylaxis for NTM infection in CF adults. PMID- 25735459 TI - Secondhand effects of alcohol use among students in Vietnam. AB - BACKGROUND: In many countries worldwide, heavy drinking can cause harm not only to drinkers but also to those around them. OBJECTIVE: To examine the prevalence and predictors of secondhand effects of alcohol use among students in Vietnam. DESIGN: In this cross-sectional study, a multistage sampling strategy was used to select 6,011 students (from the first to final study year) of 12 universities/faculties in four provinces in Vietnam. During class, students filled in a questionnaire asking for demographic information, and about alcohol related problems and details of secondhand effects of alcohol during the past year. Exploratory factor analysis of the secondhand effects indicated two factors: non-bodily harm and bodily harm. A logistic regression model was used to explore the association between predictors and non-bodily harm and bodily harm. RESULTS: The prevalence of secondhand effects of alcohol is high among students in Vietnam: 77.5% had non-bodily effects and 34.2% had bodily effects. More than 37% of the population reported three to four non-bodily effects and more than 12% reported two to three bodily harms due to the drinking of others. However, most respondents who reported secondhand effects experienced these less than once per month. Factors most strongly associated with the yearly non-bodily harm were the weekly drinking habits of the people the respondents live with, and living in a smaller city; the factor most strongly associated with the yearly bodily harm was the respondent's own alcohol-related problems. Moreover, weekly drinking habits of the people the respondents live with, and respondent's own alcohol-related problems are strongly associated with the frequent experience of non-bodily and bodily effects of alcohol. CONCLUSIONS: In addition to dealing with alcohol related harm of drinkers themselves, preventing secondhand effects should also be a major focus of prevention policy. PMID- 25735460 TI - Plasticity Region Genes jhp0940, jhp0945, jhp0947, and jhp0949 of Helicobacter pylori in Isolates from Mexican Children. AB - BACKGROUND: The genes jhp0940, jhp0945, jhp0947, and jhp0949 belong to the plasticity region of the Helicobacter pylori genome. Due to their prevalence in isolates from patients with gastritis, duodenal ulcer, and gastric cancer, they have been proposed as markers of gastroduodenal diseases. These genes are associated with pro-inflammatory cytokine induction through the NF-kappaB activation pathway. Nevertheless, the status of these genes is unknown in H. pylori isolates from children. The aim of the present work was to determine the frequency of the jhp0940-jhp0945-jhp0947-jhp0949 genes in H. pylori isolates from children. MATERIALS AND METHODS: We identified the jhp0940, jhp0945, jhp0947, and jhp0949 genes and the relationship of each with the virulence factors cagA, cagPAI, and dupA by PCR in 49 isolates of H. pylori from children. The results were corroborated using dot blots. In addition, we compared the prevalence of these genes with the prevalence in adults. RESULTS: The prevalence of jhp0940 (53.1%), jhp0945 (44.9%), jhp0947 (77.6%), and jhp0949 (83.7%) was determined in the isolates from children, as was the prevalence of the virulence genes cagA (63.3%), cagPAI (71.4%), and dupA (37.5%). No association was found between the four genes of the plasticity region and the virulence genes. The presence of the intact locus integrated by jhp0940-jhp0945-jhp0947-jhp0949 was very common among the isolates from children. CONCLUSION: The genes jhp0940, jhp0947, and jhp0949 were present in more than 50% of the H. pylori isolates, and the joint presence of jhp0940-jhp0945-jhp0947-jhp0949 was very frequent. The frequency of these genes in isolates from children could contribute to the virulence of H. pylori and the evolution of the infection. PMID- 25735461 TI - Secondary spectral components of substrate-borne vibrational signals affect male preference. AB - Animal sexual signals contain information about both compatibility and quality of the signaller, but combined with influence of the signalling medium, the complexity of mate selection makes it difficult to separate different components of this process. We approached the problem of teasing apart different functions of sexual signals by using the planthopper Hyalesthes obsoletus, which uses unimodal vibrational communication, as a model. Vibrational signals are known to encode information about identity in their temporal pattern, while a useful cue for quality may reside in their spectral properties. In this study, we demonstrate a connection between spectral properties and attractiveness of female signals based on male behavioural response to signal playback. Artificially increasing the amplitude of high-frequency components increases signal attractiveness and vice versa, which indicates that spectral properties could function as an index of quality. Presence of high-frequency spectral components might indicate a larger or healthier individual, but direct connection with female fitness is not yet clear. In addition, we found that H. obsoletus males are able to exploit female pulses as directional cues and can discriminate between female signals of different attractiveness coming from spatially separated sources. PMID- 25735462 TI - Influences on the use of observational methods by practitioners when identifying risk factors in physical work. AB - Most observational methods for musculoskeletal disorder risk assessment have been developed by researchers to be applied in specific situations, and practitioners could find difficulties in their use in real-work conditions. The main objective of this study was to identify the factors which have an influence on how useful the observational techniques are perceived to be by practitioners and to what extent these factors influence their perception. A survey was conducted on practitioners regarding the problems normally encountered when implementing these methods, as well as the perceived overall utility of these techniques. The results show that practitioners place particular importance on the support the methods provide in making decisions regarding changes in work systems and how applicable they are to different types of jobs. The results of this study can serve as guide to researchers for the development of new assessment techniques that are more useful and applicable in real-work situations. PMID- 25735463 TI - Dog and cat exposure and respective pet allergy in early childhood. AB - BACKGROUND: The association of dog and cat exposure in early childhood with the incidence of respective allergies has remained controversial. The aim of the study was to obtain population-based evidence on the association of early exposure to dog or cat, or both, with dog and cat allergies. METHODS: The study population was identified from the nationwide population register comprising all children aged 1-4 yr (N = 4779) born between 2001 and 2005 and living in the province of South Karelia, Finland. Cross-sectional questionnaire data on pet exposure in infancy and physician-diagnosed pet allergies were obtained from 3024 participants and merged with longitudinally accumulated data on sIgE and skin prick tests indicating allergic sensitization abstracted from all patient records in the area. RESULTS: The adjusted relative incidence of positive test results (with 95% confidence intervals) was 2.69 (1.45-5.02) for dog and 5.03 (2.47-10.2) for cat allergens among children exposed to a respective pet alone compared with children without such exposure. The corresponding adjusted prevalence odds ratios for diagnosed dog and cat allergies were 1.75 (0.77-3.79) and 5.13 (2.30-11.4), respectively. The association between pet exposure and the incidence of positive test results was independent of parents' allergies. CONCLUSIONS: Early exposure to dog and cat at home is associated with a higher incidence of respective pet allergy during the first four years of life. Further evidence from population based studies with longer follow-up is required to justify any recommendation concerning early pet contacts with a view to preventing pet allergies later in life. PMID- 25735464 TI - Expression profile of bio-defense genes in Penaeus monodon gills in response to formalin inactivated white spot syndrome virus vaccine. AB - White spot syndrome virus (WSSV) is the most devastating pathogen of penaeid shrimp. While developing technology to vaccinate shrimp against WSSV, it is imperative to look into the immune response of the animal at molecular level. However, very little information has been generated in this direction. The present study is an attempt to understand the expression of bio-defense genes in gill tissues of Penaeus monodon in response to formalin inactivated WSSV. A WSSV vaccine with a viral titer of 1*10(9) DNA copies was prepared and orally administered to P. monodon at a rate of 1.75*10(6) DNA copies of inactivated virus preparation (IVP) day(-1) for 7days. The animals were challenged with WSSV on 1st and 5th day post vaccination, and temporal expression of bio-defense genes in gill tissues was studied. Survival of 100% and 50% were observed respectively on 1st and 5th day post vaccination challenge. The humoral immune genes prophenoloxidase (proPO), alpha 2-macroglobulin (alpha2M), crustin and PmRACK, and the cell mediated immune genes caspase and Rab7 were up regulated in gill tissue upon vaccination and challenge. The expression of humoral gene crustin and cellular gene Rab7 was related to survival in IVP administered shrimp. Results of the study suggest that these genes have roles in protecting shrimp from WSSV on vaccination. PMID- 25735465 TI - Medication assisted treatment discontinuation in pregnant and postpartum women with opioid use disorder. AB - BACKGROUND: Increasing use of opioids has led to an increase in the number of pregnant and postpartum women in medication assisted treatment (MAT) for opioid use disorder. METHODS: We (1) conducted a systematic review of published literature on MAT discontinuation (methadone and buprenorphine) in pregnant and postpartum women and (2) determined methadone discontinuation rates in a retrospective cohort (2006-2013) of pregnant and postpartum women in a university affiliated methadone clinic. RESULTS: We found limited generalizable literature reports of discontinuation rates, with a range of prenatal discontinuation rates from 0 to 33% and rates which spanned various prenatal and postnatal periods from 26 to 64%. In our cohort of 229 women, 251 pregnancies were reported, with a prenatal methadone discontinuation rate of 11.0%. Based on a Cox proportional hazards model controlling for age, pregnancy outcome, and duration of treatment prior to delivery, the probability of methadone discontinuation at or before 6 months postpartum was 56.0%. Duration of methadone treatment prior to delivery was inversely associated with risk for postpartum discontinuation of treatment (HR = 0.98, 95% CI (0.96, 0.99)). CONCLUSIONS: We conclude that the postpartum period is a time of increased risk for discontinuation of MAT. More accurate assessment of rates of pre- and postpartum MAT discontinuation, as well as further investigation of factors affecting these rates, is warranted. Development and testing of interventions to encourage early prenatal enrollment in MAT and improve postnatal retention in MAT would benefit pregnant women and new mothers with opioid use disorder. PMID- 25735466 TI - Longitudinal analysis of pain and illicit drug use behaviors in outpatients on methadone maintenance. AB - BACKGROUND: Little is known about the experience of chronic pain and the occurrence of illicit drug use behaviors in the population enrolled in methadone maintenance treatment (MMT) programs. METHODS: This is a secondary analysis of longitudinal data from two MMT samples enrolled in a randomized controlled trial of hepatitis care coordination. Patients completed pain, illicit drug use, and other questionnaires at baseline and 3, 9, and 12 months later. Associations were sought over time between the presence or absence of clinically significant pain (average daily pain >= 4 or mean pain interference >= 4 during the past week) and current illicit drug use (i.e., non-therapeutic opioid, cocaine or amphetamine use identified from self-report or urine drug screening). RESULTS: Of 404 patients providing complete data, within-patient variability in pain and illicit drug use was high across the four assessment periods. While 263 denied pain at baseline, 118 (44.9%) later experienced clinically significant pain during >= 1 follow-up assessments. Of 180 patients (44.6%) without evidence of illicit drug use at baseline, only 109 (27.0%) had similar negative drug use at all follow-up assessments. Across four assessment periods, there was no significant association between pain group status and current illicit drug use. CONCLUSIONS: This one year longitudinal analysis did not identify a significant association between pain and illicit drug use in MMT populations. This finding conflicts with some earlier investigations and underscores the need for additional studies to clarify the complex association between pain and substance use disorders in patients in MMT program settings. PMID- 25735467 TI - Perceived risk of regular cannabis use in the United States from 2002 to 2012: differences by sex, age, and race/ethnicity. AB - INTRODUCTION: Cannabis is one of the most widely used psychoactive substances in the United States (U.S.). Perceived risk of use is associated with substance use; the recent debate surrounding medicalization and legalization of cannabis in the U.S. has the potential to impact perceived risk of use. Recent estimates are needed to assess temporal changes in, and identify correlates of, perceived risk of cannabis use. METHODS: Utilizing data from the 2002-2012 survey years of the National Survey on Drug Use and Health, chi-squared statistics and logistic regression were used to describe temporal changes in perceived risk of regular cannabis use (i.e., once or twice a week), to explore correlates of perceived risk, and to report frequency of cannabis use. RESULTS: Between 2002 and 2012, perceived great risk of regular cannabis use varied significantly overall (p < 0.001). The prevalence of past year non-daily (p < 0.001) and daily use varied significantly during this time (p < 0.001). Controlling for survey year and other confounders, characteristics associated with increased odds of perceived great risk of regular cannabis use included: female sex; Non-White race/ethnicity; age 50+; and family income of $20,000-49,999. Characteristics associated with decreased odds of perceived great risk included: ages 12-17 and 18-25; high school education or greater; total family income of $75,000+; past year non-daily and daily cannabis use; and survey years 2008-2012. CONCLUSIONS: Findings characterize trends of perceived risk of regular cannabis use, and past year non daily and daily cannabis use. Longitudinal studies of the influence of legal status of cannabis at the state-level are needed. PMID- 25735469 TI - Tracking AJA progress. PMID- 25735468 TI - Factors associated with being asked to initiate someone into injection drug use. AB - AIMS: Injection drug use initiation typically involves an established person who injects drugs (PWID) helping the injection-naive person to inject. Prior to initiation, PWID may be involved in behaviors that elevate injection initiation risk for non-injectors such as describing how to inject and injecting in front of injection-naive people. In this analysis, we examine whether PWID who engage in either of these behaviors are more likely to be asked to initiate someone into drug injection. METHODS: Interviews with PWID (N = 602) were conducted in California between 2011 and 2013. Multivariate analysis was conducted to determine factors associated with being asked to initiate someone. RESULTS: The sample was diverse in terms of age, race/ethnicity, and drug use patterns. Seventy-one percent of the sample had ever been asked to initiate someone. Being asked to initiate someone was associated with having injected in front of non injectors (Adjusted Odds Ratio [AOR] = 1.80, 95% Confidence Interval [CI] = 1.12, 2.91), having described injection to non-injectors (AOR = 3.63; 95% CI = 2.07, 6.36), and doing both (AOR = 9.56; 95% CI = 4.43, 20.65) as compared to doing neither behavior (referent). Being female (AOR = 1.73; 95% CI = 1.10, 2.73) and non-injection prescription drug misuse in the last 30 days (AOR = 1.69; 95% CI = 1.12, 2.53) were also associated with having been asked to initiate someone. CONCLUSION: Reducing initiation into injection drug use is an important public health goal. Intervention development to prevent injection initiation should include established PWID and focus on reducing behaviors associated with requests to initiate injection and reinforcing refusal skills and intentions among established PWID. PMID- 25735470 TI - Active ageing: realising its potential. PMID- 25735471 TI - Research in hospital discharge procedures addresses gaps in care continuity in the community, but leaves gaping holes for people with dementia: a review of the literature. AB - AIM: To examine the literature on the impact of the discharge experience of patients with dementia and their continuity of care. METHODS: Peer-reviewed and grey literature published in the English language between 1995 and 2014 were systematically searched using Medline, CINAHL, PubMed, PsycINFO and Cochrane library databases, using a combination of the search terms Dementia, Caregivers, Integrated Health Care Systems, Managed Care, Patient Discharge. Also reviewed were Department of Health and Ageing and Alzheimer's Australia research reports between 2000 and 2014. RESULTS: The review found a wide range of studies that raise concerns in relation to the quality of care provided to people with dementia during hospital discharge and in transitional care. CONCLUSION: Discharge planning and transitional care for patients with dementia are not adequate and are likely to lead to readmission and other poor health outcomes. PMID- 25735472 TI - Australian and New Zealand Society for Geriatric Medicine: position statement - frailty in older people. PMID- 25735474 TI - [Bilateral hidronephrosis caused by giant rectosigmoid fecaloma in a young adult]. PMID- 25735473 TI - Vascular function, insulin action, and exercise: an intricate interplay. AB - Insulin enhances the compliance of conduit arteries, relaxes resistance arterioles to increase tissue blood flow, and dilates precapillary arterioles to expand muscle microvascular blood volume. These actions are impaired in the insulin resistant states. Exercise ameliorates endothelial dysfunction and improves insulin responses in insulin resistant patients, but the precise underlying mechanisms remain unclear. The microvasculature critically regulates insulin action in muscle by modulating insulin delivery to the capillaries nurturing the myocytes and trans-endothelial insulin transport. Recent data suggest that exercise may exert its insulin-sensitizing effect via recruiting muscle microvasculature to increase insulin delivery to and action in muscle. The current review focuses on how the interplay among exercise, insulin action, and the vasculature contributes to exercise-mediated insulin sensitization in muscle. PMID- 25735475 TI - Improving person-centered mobility care in nursing homes: a feasibility study. AB - Person-centered care is often equated with quality nursing home care. At the same time, quality mobility care contributes to residents' independence and quality of life. Realist evaluation and mixed methods were employed to evaluate the feasibility of a multi-faceted training intervention focused on person-centered mobility care. Staff and ambulatory residents of a ninety bed Australian nursing home with 3 units--one dementia-specific--participated. The intervention consisted of training sessions, weekly mobility care huddles and reflective practice sessions with individual staff. This study demonstrated the feasibility of an intervention aiming to improve person-centered mobility care in nursing homes; it was practical and well accepted. Study methods and outcome measures were suitable. Outcome measures demonstrated capacity to determine the effectiveness of the intervention in a larger randomized controlled trial. Focus groups provided insights regarding the context and mechanisms of change. Future research is recommended to evaluate intervention effectiveness and sustainability. PMID- 25735476 TI - Altered axonal excitability properties and nerve edema in POEMS syndrome. AB - OBJECTIVE: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating neuropathy with upregulation of vascular endothelial growth factor (VEGF). This study aimed to elucidate axonal excitability properties and their relation to VEGF levels and nerve edema in POEMS neuropathy. METHODS: Axonal excitability measurement and nerve ultrasound were performed in the median nerve of 33 patients with POEMS syndrome. Serum VEGF levels were measured by ELISA. RESULTS: Compared with normal subjects (n=87), POEMS patients showed longer strength-duration time constant, fanning-out of threshold electrotonus curves, and greater threshold changes in a hyperpolarizing current-threshold relationship. Nerve ultrasound showed significant enlargement in POEMS patients. Serum VEGF levels and the extent of nerve edema partly correlated with nerve conduction slowing, as well as persistent sodium currents and inward rectification. CONCLUSIONS: In POEMS syndrome, patterns of changes in excitability properties could suggest increased persistent sodium currents, and impaired potassium and inward rectifying channels. The findings were not consistent with depolarization due to nerve edema and compression ischemia. SIGNIFICANCE: In addition to demyelination, nerve edema induced by upregulated VEGF, and upregulated inflammatory cytokines could modulate profiles of POEMS neuropathy. PMID- 25735477 TI - Effective connectivity in long-term EEG monitoring in preterm infants. AB - OBJECTIVE: Electroencephalogram (EEG) is commonly used to monitor brain activity in preterm neonates. Long-term EEG is used to predict outcomes by total band power. This study reports effective connectivity analyses in the fronto-parietal network in preterm infants. METHOD: Directed transfer functions (DTFs) were used in fully automated calculations of effective connectivity. Continuous eight channel EEG recordings were performed for three full days starting at a median of 5.3h (2.5-11.2h) after birth. Analyses were performed using the channels Fp1, Fp2, P3 and P4. DTF were calculated every second in every connection and channel for all frequencies from 1 Hz to 30 Hz. The median connectivity was used in the connectivity assessment. RESULTS: Parieto-frontal connectivity was significantly higher (0.22) than fronto-parietal connectivity (0.05). There was a significant decrease in parieto-frontal connectivity between day one (0.18) and three. Conversely, there was a significant increase in fronto-parietal connectivity from day one to day three (0.07). CONCLUSION: Significant changes are seen in connectivity from day one to three, but there were no certain connectivity differences between gestational ages. SIGNIFICANCE: A rapid change in fronto parietal connectivity was seen from day one to three which may indicate fast postpartum maturation. PMID- 25735478 TI - CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. AB - CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks. PMID- 25735479 TI - Stakeholders' perspectives on biobank-based genomic research: systematic review of the literature. AB - The success of biobank-based genomic research is widely dependent on people's willingness to donate their tissue. Thus, stakeholders' opinions should be considered in the development of best practice guidelines for research and recruiting participants. We systematically analyzed the empirical literature describing different stakeholders' views towards ethical questions with regard to type of consent, data sharing and return of incidental findings. Patients are more open to one-time general consent than the public. Only a small proportion desires recontact if the research aim changed. A broad consent model would prevent only a small proportion of patients from participating in research. Although professionals are concerned about a risk of reidentification, patients and the public support data sharing and find that the benefit of research outweighs the potential risk of reidentification. However, they desire detailed information about the privacy protection measures. Regarding the return of incidental findings, the public and professionals focus on clinically actionable results, whereas patients are interested in receiving as much information as possible. For professionals, concrete guidelines that help managing the return of incidental findings should be warranted. For this it would be helpful addressing the different categories - actionable, untreatable and inheritable diseases - upfront with patients and public. PMID- 25735481 TI - Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent. AB - Corneal ectasias, among which keratoconus (KC) is the single most common entity, are one of the most frequent reasons for corneal grafting in developed countries and a threatening complication of laser in situ keratomileusis. Genome-wide association studies have previously found lysyl oxidase (LOX) and hepatocyte growth factor (HGF) associated with susceptibility to KC development. The aim of our study was to validate the effects of seven single-nucleotide polymorphisms (SNPs) within LOX and HGF over KC. Unrelated Czech cases with KC of European descent (108 males and 57 females, 165 cases in total) and 193 population and gender-matched controls were genotyped using Kompetitive Allele Specific PCR assays. Fisher's exact tests were used to assess the strength of associations. Evidence for association was found for both of the tested loci. It was strongest for rs3735520:G>A near HGF (allelic test odds ratio (OR)=1.45; 95% confidence interval (CI), 1.06-1.98; P=0.018) with A allele being a risk factor and rs2956540:G>C (OR=0.69; 95% CI, 0.50-0.96; P=0.024) within LOX with C allele having a protective effect. This first independent association validation of rs2956540:G>C and rs3735520:G>A suggests that these SNPs may serve as genetic risk markers for KC in individuals of European descent. PMID- 25735482 TI - Kullback-Leibler divergence for detection of rare haplotype common disease association. AB - Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haplotypes may shed light on the underlying disease causal mechanism, a feat unmatched by SNV-based collapsing methods. In recent years, data mining approaches have been adapted to detect rare haplotype association. However, as they rely on an assumed underlying disease model and require the specification of a null haplotype, results can be erroneous if such assumptions are violated. In this paper, we present a haplotype association method based on Kullback-Leibler divergence (hapKL) for case-control samples. The idea is to compare haplotype frequencies for the cases versus the controls by computing symmetrical divergence measures. An important property of such measures is that both the frequencies and logarithms of the frequencies contribute in parallel, thus balancing the contributions from rare and common, and accommodating both deleterious and protective, haplotypes. A simulation study under various scenarios shows that hapKL has well-controlled type I error rates and good power compared with existing data mining methods. Application of hapKL to age-related macular degeneration (AMD) shows a strong association of the complement factor H (CFH) gene with AMD, identifying several individual rare haplotypes with strong signals. PMID- 25735480 TI - Performance of the 12-item WHODAS 2.0 in prodromal Huntington disease. AB - The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM 5), recommends the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 for routine clinical use. We tested the utility of the 12-item WHODAS 2.0 in prodromal Huntington disease. Using data from 726 participants and 630 companions over a 3-year follow-up, linear mixed models were fitted to test (1) baseline and longitudinal differences by progression group; (2) participant and companion differences within each group; and (3) sensitivity of the 12-item WHODAS in comparison to the 36-item WHODAS and the Total Functional Capacity (TFC) score from the Unified Huntington's Disease Rating Scale. Participants showed baseline group differences whereas companions showed baseline and longitudinal group differences. Companions reported worse functional decline over time than participants as the disease progresses. The 12-item WHODAS detected longitudinal change better than the 36-item WHODAS and the TFC in the medium progression group. Results suggest the 12-item WHODAS 2.0 can detect baseline and longitudinal differences in prodromal HD and may be useful in HD clinical trials. PMID- 25735483 TI - Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis. AB - Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis. PMID- 25735485 TI - A rationally designed amino-borane complex in a metal organic framework: a novel reusable hydrogen storage and size-selective reduction material. AB - A novel amino-borane complex inside a stable metal organic framework was synthesized for the first time. It releases hydrogen at a temperature of 78 degrees C with no volatile contaminants and can be well reused. Its application as a size-selective reduction material in organic synthesis was also demonstrated. PMID- 25735484 TI - Syndromic X-linked intellectual disability segregating with a missense variant in RLIM. AB - We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A>G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID. PMID- 25735486 TI - Isolated Left Ventricular Diastolic Collapse Due to Extra-Thoracic Compression. AB - Isolated collapse of the left ventricle (LV) in diastole is not a very common finding on two-dimensional echocardiography. Reported cases in the literature were due to either loculated postoperative pericardial effusion/hematoma or left pleural effusion. To our knowledge, this is the first case report of LV diastolic collapse secondary to extra-thoracic compression. PMID- 25735487 TI - Magnetotransport across the metal-graphene hybrid interface and its modulation by gate voltage. AB - The graphene-metal contact is very important for optimizing the performance of graphene based electronic devices. However, it is difficult to probe the properties of the graphene/metal interface directly via transport measurements in traditional graphene lateral devices, because the dominated transport channel is graphene, not the interface. Here, we employ the Au/graphene/Au vertical and lateral hybrid structure to unveil the metal-graphene interface properties, where the transport is dominated by the charge carriers across the interface. The magnetoresistance (MR) of Au/monolayer graphene/Au and Au/stacked two-layered graphene/Au devices is measured and modulated by gate voltage, demonstrating that the interface is a device. The gate-tunable MR is identified from the graphene lying on the SiO2 substrate and underneath the top metal electrode. Our unique structures couple the in-plane and out-of-plane transport and display linear MR with small amplitude oscillations at low temperatures. Under a magnetic field, the electronic coupling between the graphene edge states and the electrode leads to the appearance of quantum oscillations. Our results not only provide a new pathway to explore the intrinsic transport mechanism at the graphene/metal interface but also open up new vistas of magnetoelectronics. PMID- 25735488 TI - Electrochemical in situ investigations of SEI and dendrite formation on the lithium metal anode. AB - This comparative work studies the self-enforcing heterogeneity of lithium deposition and dissolution as the cause for dendrite formation on the lithium metal anode in various liquid organic solvent based electrolytes. In addition, the ongoing lithium corrosion, its rate and thus the passivating quality of the SEI are investigated in self-discharge measurements. The behavior of the lithium anode is characterized in two carbonate-based standard electrolytes, 1 M LiPF6 in EC/DEC (3 : 7) and 1 M LiPF6 in EC/DMC (1 : 1), and in two alternative electrolytes 1 M LiPF6 in TEGDME and 1 M LiTFSI in DMSO, which have been proposed in the literature as promising electrolytes for lithium metal batteries, more specifically for lithium/air batteries. As a result, electrolyte decomposition, SEI and dendrite formation at the lithium electrode as well as their mutual influences are understood in the development of overpotentials, surface resistances and lithium electrode surface morphologies in subsequent lithium deposition and dissolution processes. A general model of different stages of these processes could be elaborated. PMID- 25735490 TI - Anti-inflammatory, antioxidant, and antiparkinsonian effects of adenosine A2A receptor antagonists. AB - The purpose of the study was to examine derivatives of annelated xanthines (imidazo-, pyrimido-, and diazepino-purinediones) for potential anti-inflammatory effects in carrageenan-induced paw edema in mice. Additionally, their antioxidant activity using the FRAP (ferric-reducing ability of plasma) assay and lipid peroxidation in rat brain homogenate were analyzed. All the studied derivatives showed affinity for adenosine A2A receptor. The preliminary assays found that five (KD-114, KD-57, KD-129, KD-50, and KD-358) pyrimidopurinedione derivatives, administered intraperitoneally (i.p.) at a dose of 100mg/kg, had stronger anti inflammatory effects. At a concentration of 10-5M, three of the derivatives KD 57, KD-114, and KD-129 most influenced the total antioxidant ability. The most efficient anti-inflammatory compound, KD-114, also showed the strongest binding to A2A receptors and when administered at a dose of 5mg/kg (i.p.), effectively reversed haloperidol-induced catalepsy and significantly increased the striatal extracellular dopamine level in the rat striatum. This effect was weaker than the one produced by CSC (1mg/kg i.p.), and only slightly weaker than that produced by ZM 241385 (3mg/kg i.p.) used as reference drugs. From the results of the present studies, it may be concluded that anti-inflammatory and antiparkinsonian effects of the examined compounds correlate with their influence on adenosine A2A receptors, the most probable antagonism to these subtype receptors. PMID- 25735489 TI - Rationale and design of a patient-centered medical home intervention for patients with end-stage renal disease on hemodialysis. AB - In the U.S., more than 400,000 individuals with end-stage renal disease (ESRD) require hemodialysis (HD) for renal replacement therapy. ESRD patients experience a high burden of morbidity, mortality, resource utilization, and poor quality of life (QOL). Under current care models, ESRD patients receive fragmented care from multiple providers at multiple locations. The Patient-Centered Medical Home (PCMH) is a team approach, providing coordinated care across the healthcare continuum. While this model has shown some early benefits for complex chronic diseases such as diabetes, it has not been applied to HD patients. This study is a non-randomized quasi-experimental intervention trial implementing a Patient Centered Medical Home for Kidney Disease (PCMH-KD). The PCMH-KD extends the existing dialysis care team (comprised of a nephrologist, dialysis nurse, dialysis technician, social worker, and dietitian) by adding a general internist, pharmacist, nurse coordinator, and a community health worker, all of whom will see the patients together, and separately, as needed. The primary goal is to implement a comprehensive, multidisciplinary care team to improve care coordination, quality of life, and healthcare use for HD patients. Approximately 240 patients will be recruited from two sites; a non-profit university-affiliated dialysis center and an independent for-profit dialysis center. Outcomes include (i) patient-reported outcomes, including QOL and satisfaction; (ii) clinical outcomes, including blood pressure and diet; (iii) healthcare use, including emergency room visits and hospitalizations; and (iv) staff perceptions. Given the significant burden that patients with ESRD on HD experience, enhanced care coordination provides an opportunity to reduce this burden and improve QOL. PMID- 25735491 TI - Functional interaction between the orexin-1 and CB1 receptors within the nucleus accumbens in the conditioned place preference induced by the lateral hypothalamus stimulation. AB - Several studies have shown that chemical stimulation of the lateral hypothalamus (LH) by carbachol induces the conditioned place preference (CPP) in rats. LH is the main source of the orexinergic neurons and sends projections to some areas of the brain such as the nucleus accumbens (NAc). We tried to determine the role of intra-accumbal orexin-1 (OX1) receptors in development (acquisition) and expression of reward-related behaviors induced by LH stimulation and involvement of CB1 cannabinoid receptors in this area. Adult male Wistar rats were unilaterally implanted by two separate cannulae into the LH and NAc. The CPP paradigm was done; conditioning scores and locomotor activities were recorded. The results showed that intra-accumbal administration of SB334867 as a selective OX1 receptor antagonist (1, 3, 10 and 30nM/0.5MUl DMSO) 5min before intra-LH carbachol (250nM/0.5MUl saline) during 3-day conditioning phase, could dose dependently inhibit the development of LH-induced CPP. In expression experiments, intra-NAc administration of SB334867 on the test day could decrease the expression of LH stimulation-induced CPP. Furthermore, concurrent intra-accumbal administration of effective/ineffective doses of SB334867 and AM251 (45 and 15MUM) as a CB1 receptor antagonist, before carbachol during the conditioning phase, could attenuate the development of LH stimulation-induced CPP. It seems that the orexinergic projection from the LH to the NAc is involved in the LH stimulation-induced CPP and OX1 receptor in the NAc has a substantial role in this phenomenon. Our findings also suggest the existence a functional interaction between OX1 and CB1 receptors within the NAc in place preference. PMID- 25735492 TI - Sex differences in conditioned nicotine reward are age-specific. AB - Women constitute half of all smokers and many studies suggest that adult males and females differ in factors that maintain tobacco smoking, yet there is limited information about sex differences in nicotine reward during adolescence. Limited studies suggest that adolescent male rats self-administer more nicotine than adults, suggesting that drug administration during adolescence leads to different behavioral effects than during adulthood. In the present study, male rats developed a significant conditioned place preference (CPP) to lower doses of nicotine than females, regardless of age. In addition, adolescents were more sensitive than adults. In female rats, adolescents exhibited a CPP of greater magnitude than adult females. In males, the magnitude of the CPP did not differ as a function of age, but adolescents exhibited CPP to lower doses than adults. There also were differences in nicotinic acetylcholinergic receptor binding in nucleus accumbens and caudate putamen in response to nicotine across age and sex. These findings suggest that it is necessary to consider sex- and age-specific effects of drugs such as nicotine when developing strategies for improving smoking cessation treatments. PMID- 25735494 TI - Orthostatic hypotension at different times after standing erect in elderly adults. PMID- 25735493 TI - The mixed-action delta/mu opioid agonist MMP-2200 does not produce conditioned place preference but does maintain drug self-administration in rats, and induces in vitro markers of tolerance and dependence. AB - Previous work in our laboratories provides preclinical evidence that mixed-action delta/mu receptor glycopeptides have equivalent efficacy for treating pain with reduced side effect profiles compared to widely used mu agonist analgesics such as morphine. This study evaluated the rewarding and reinforcing effects of a lead candidate, mixed-action delta/mu agonist MMP-2200, using a conditioned place preference assay as well as a drug self-administration procedure in rats. In place conditioning studies, rats underwent a 2-week conditioning protocol and were then tested for chamber preference. Rats receiving MMP-2200, at previously determined analgesic doses, could not distinguish between the drug and saline paired chamber, whereas rats receiving the opioid agonist morphine showed a strong preference for the morphine-paired chamber. In self-administration studies, rats were trained to respond for the high efficacy mu opioid receptor agonist fentanyl on an FR5 schedule of reinforcement. Following complete dose response determinations for fentanyl, a range of doses of MMP-2200 as well as morphine were tested. Relative to the mu agonist morphine, MMP-2200 maintained a significantly lower number of drug infusions. To begin investigating potential molecular mechanisms for the reduced side effect profile of MMP-2200, we also examined betaarrestin2 (betaarr2) recruitment and chronic MMP-2200 induced cAMP tolerance and super-activation at the human delta and mu receptors in vitro. MMP 2200 efficaciously recruited betaarr2 to both receptors, and induced cAMP tolerance and super-activation equivalent to or greater than morphine at both receptors. The in vivo findings suggest that MMP-2200 may be less reinforcing than morphine but may have some abuse potential. The reduced side effect profile cannot be explained by reduced betaarr2 recruitment or reduced cAMP tolerance and superactivation at the monomeric receptors in vitro. PMID- 25735495 TI - Description of Advanced Practice Nurses Interventions Through the Nursing Interventions Classification in Different Care Settings for Older People: A Qualitative Study. AB - PURPOSE: To identify the interventions provided by advanced practice nurses to older people in different contexts with standardized nursing language. DATA SOURCE: This is a qualitative study. Content analysis was applied to the texts of experimental research papers about advanced practice nursing for older people. Deductive coding through the Nursing Intervention Classification was carried out. DATA SYNTHESIS: Seventy-three interventions codified with the Nursing Intervention Classification were extracted, mainly related to the behavioral and healthcare system domains, which could be explained due to the need for improving the psychosocial functioning and self-care of these patients to preserve their quality of life. CONCLUSION AND IMPLICATION FOR NURSING PRACTICE: Advanced practice nurses interventions can be better described, reported, and analyzed along different contexts with standardized languages. PMID- 25735496 TI - A structural model of age, grey matter volumes, education, and personality traits. AB - BACKGROUND: When the relationship between ageing and changes in personality traits is considered, it is important to know how they are influenced by biological and environmental factors. The present study examined the relationships between various factors associated with the effect of ageing on personality traits, including structural changes of the brain and environmental factors such as education. METHODS: We recruited 41 healthy subjects. We administered the NEO Five-Factor Inventory to assess personality factors. Magnetic resonance imaging was performed, and regional grey matter (GM) volumes were obtained. We identified associations in the correlation analysis of age, cerebral GM volume, years of education, and the personality trait of openness. Path analysis was used to estimate the relationships among these factors. RESULTS: The path analysis model of age, GM volume, years of education, and the personality trait of openness revealed that age has an indirect negative association with openness through GM volume and years of education. Ageing was related to a decrease in GM volume, which was in turn related to a decrease in the openness score. Older subjects generally had fewer years of education, which was related to a lower openness score. CONCLUSIONS: Maintaining openness against the effects of ageing is desirable, and our results imply that interventions against age-related cerebral atrophy and the promotion of opportunities for higher education may contribute to the development and stability of a healthy personality during the adult life course. PMID- 25735498 TI - Pecs block for anesthesia in breast surgery of the elderly. PMID- 25735497 TI - Efficacy of palonosetron and ramosetron on postoperative nausea and vomiting related to intravenous patient-controlled analgesia with opioids after gynecological laparoscopic surgery (double-blinded prospective randomized controlled trial). AB - PURPOSE: The study was designed to assess the efficacy of palonosetron and ramosetron in preventing postoperative nausea and vomiting (PONV) related to intravenous (IV) patient-controlled analgesia (PCA) with opioids after gynecological laparoscopic surgery. METHODS: Patients were randomly allocated to 4 groups-C, P, R0.3 and RPCA. At the end of surgery, group C received an infusion of 50 ml normal saline, group P received palonosetron 75 MUg mixed in 50 ml normal saline, and groups R0.3 and RPCA received ramosetron 0.3 mg mixed in 50 ml normal saline. A PCA pump containing fentanyl was connected for all groups; however, ramosetron 0.6 mg was mixed with the PCA regimen for the RPCA group. PONV and postoperative pain were assessed. RESULTS: PONV incidence and scale, and Rhodes index in RPCA group between 24 and 72 h after discharge from the post anesthetic care unit (PACU) showed significantly lower values, compared with the other groups. PONV incidence and scale, and Rhodes index in P group and R0.3 group were lower than the corresponding values in C group at all times, without statistical significance. CONCLUSION: A single dose of palonosetron 75 MUg or ramosetron 0.3 mg was unable to prevent PONV related to IV PCA with opioids in patients undergoing gynecological laparoscopic surgery. The combination of a single dose of ramosetron 0.3 mg, followed by ramosetron 0.6 mg mixed with PCA, significantly decreased PONV compared with a single dose of palonosetron 75 MUg or ramosetron 0.3 mg. PMID- 25735499 TI - Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy. AB - Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy. PMID- 25735500 TI - Detection of KIT and PDGFRA mutations in the plasma of patients with gastrointestinal stromal tumor. AB - In subsets of gastrointestinal stromal tumors (GISTs), mutations of the KIT and PDGFRA receptor tyrosine kinases correlate with tumor prognosis and response to tyrosine kinase inhibitors (TKIs). Determining genotypes in TKI-resistant GISTs is challenging due to the potential risks and limitations of repeated biopsies during the course of treatment. We prospectively collected plasma samples from three GIST patients harboring KIT mutations that were detected in tissue DNA. The plasma samples were then analyzed for mutations in KIT, PDGFRA, and BRAF via next generation sequencing. We were able to identify primary KIT mutations in all plasma samples. Additional mutations, including KIT exon 17 S821F and PDGFRA exon 18 D842V, were detected in the patient-matched plasma samples during follow-up and appeared to result in decreased sensitivity to TKIs. Our results demonstrate an approach by which primary and secondary mutations are readily detected in blood-derived circulating tumor DNA from patients with GIST. These mutations can be used as biomarkers for prediction of treatment response. The identification of a resistance mutation in plasma DNA will allow early change to alternative TKIs or dose escalation of imatinib for optimal patient management. PMID- 25735501 TI - Comparison of Periarticular Multimodal Drug Injection and Femoral Nerve Block for Postoperative Pain Management in Total Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - The analgesic efficacy and safety of periarticular multimodal drug injection (PMDI) compared with femoral nerve block (FNB) for postoperative pain management in total knee arthroplasty (TKA) still remains controversial. We therefore conducted a meta-analysis to quantitatively compare PMDI to FNB in TKA. 10 randomized controlled trials (RCTs) with 744 TKAs in 728 patients were included in this study. The meta-analysis showed that single shot FNB may have better pain relief in the early postoperative period compared with single shot PMDI, and continuous PMDI provided postoperative analgesia comparable to that of continuous FNB. No significant difference was seen in regard to the complications between the two groups. However, due to the variation of the included studies, no firm conclusions can be drawn. PMID- 25735502 TI - The successful binomium of multivariate strategies and electrophoresis for the Quality by Design separation of a class of drugs: the case of triptans. AB - Quality by Design (QbD) approach was followed having as analytical target profile the determination of different antimigraine drugs (seven triptans, TRP) available on the market. Multivariate strategies were used for defining the design space and solvent-modified MEKC was the selected analytical method. The versatility of electrophoretic technique, allowing a fine modulation of experimental parameters, made it possible to define the design space (DS). The DS limited a suitable range of experimental parameters in which all possible combinations of variables led to an electrokinetic method able to determine all the considered analytes with a predefined quality. Design of experiments and risk analysis fully assisted the method development from the initial investigation of MEKC knowledge space to the DS definition and finally to the control strategy. Applying the working operative conditions, the baseline separation of TRP was obtained in less than 9 min. The method was finally used for the quantification of three TRP in different pharmaceutical products. PMID- 25735503 TI - Erratum to: Differences in Psychopathology Between Immigrant and Native Adolescents Admitted to a Psychiatric Inpatient Unit. PMID- 25735504 TI - Is there any change in pelvic floor electromyography during the first 6 months after radical retropubic prostatectomy? AB - The aim of this study is to determine electromyographic pelvic floor muscles activity during the first 6 months post RRP and its relationship to urinary continence. Thirty-eight men (mean age of 63.1 +/- 5.7 year) with prostate cancer scheduled for open radical retropubic prostatectomy were evaluated. EXCLUSION CRITERIA: pelvic radiotherapy, systemic or neurologic diseases, pre-operative International Prostate Symptoms Score (IPSS) >7 and OABq >=8. Surface electromyography (sEMG) evaluation, IPSS, Urinary Distress Inventory, Incontinence Impact Questionnaire, and Overactive Bladder Questionnaire-short form were applied before and at 1, 3, and 6 months after RRP. Six months after surgery, 18 men (47.4 %) presented urinary leakage. The sEMG evaluations within the first 6 months presented changes in fast contraction amplitude (p = 0.006), rest amplitude after fast contraction (p = 0.04), 10 s sustained contraction mean amplitude (p = 0.024) and final rest amplitude (p = 0.011). We observed that continent and incontinent patients as a group presented electromyographic changes during the first 6 months after radical prostatectomy that could be justified by the denervation/reinnervation of the external urethral sphincter. This finding is consistent with the adaptation of the pelvic floor musculature to the new urethral sphincter condition following surgery. PMID- 25735505 TI - Scintigraphic assessment of renal function in steel plant workers occupationally exposed to lead. AB - OBJECTIVES: Occupational exposure to lead may produce kidney damage, but existing data on the dose range associated with nephrotoxicity are inconclusive. We here assessed renal function under conditions of low to moderate lead exposure using renal scintigraphy. METHODS: Fifty-three male foundrymen (exposed group) and fourty male office workers (control group) from a steel plant were included in the study. Glomerular and tubular renal function were assessed by means of (99m)Tc-DTPA and (99m)Tc-EC clearance, respectively. Urinary markers of glomerular dysfunction (albumin) and tubular damage (alpha1-microglobulin (alpha1M), beta2-microglobulin (beta2M), retinol-binding protein (RBP), N-acetyl beta-glucosaminidase (NAG) activity) were determined using latex beads tests or colorimetry. The lead concentration in blood was measured with atomic absorption spectrometry. RESULTS: The blood lead concentrations were 145.8 (121.3-175.3) and 39.3 (35.1-44.1) ug/l (geometric mean, 95(th) CI, p<0.001) in the exposed and control groups, respectively. Subjects exposed to lead presented with increased (99m)Tc-DTPA clearance (158.3 (148.4-168.8) vs. 135.9 (127.9-144.4) ml/min; p<0.01) and urinary albumin excretion (7.61 (6.28-9.22) vs. 4.78 (4.05-5.65) mg/g creatinine; p<0.001). (99m)Tc-EC clearance and excretion of alpha1M, beta2M, RBP and NAG were not significantly different between the groups. Significant correlations between (99m)Tc-DTPA clearance and blood lead concentrations (r=0.45; p<0.01) and between urinary albumin excretion and blood lead concentrations (r=0.71; p<0.001) were noted. CONCLUSIONS: Use of renal scintigraphy in present study revealed measurable alterations of renal function under the conditions of low-level lead exposure and suggest that increased glomerular filtration may be an early indicator of kidney damage in subjects occupationally exposed to lead. PMID- 25735506 TI - Tissue distribution of indium after repeated intratracheal instillations of indium-tin oxide into the lungs of hamsters. AB - OBJECTIVES: The aim of this study was to analyze the tissue distribution of indium after intratracheally instilling indium-tin oxide (ITO) into the lungs of hamsters. METHODS: Male Syrian hamsters received an intratracheal dose of 3 mg/kg or 6 mg/kg of ITO particles containing 2.2 mg/kg or 4.5 mg/kg of indium, twice weekly for 8 weeks. In parallel, control hamsters received only an intratracheal dose of distilled water. A subset of hamsters was euthanized periodically throughout the study from 8 up to 78 weeks after the final instillation. The distribution of indium in the lungs, liver, kidneys and spleen, as well as pathological changes in the liver, kidneys, and spleen, was determined. RESULTS: The contents of indium in the lungs in the two ITO groups gradually decreased over the 78-week observation period, with elimination half-lives of approximately 142 weeks for the 3 mg/kg ITO group and 124 weeks for the 6 mg/kg ITO. The indium concentrations in the liver, kidneys, and spleen gradually increased throughout the observation period. Although foci of the lesions were observed histopathologically in the extrapulmonary organs among the two ITO groups, the control group showed similar lesions. CONCLUSIONS: The results clearly demonstrate that the clearance of indium from the body is extremely slow after intratracheal instillation in hamsters. PMID- 25735507 TI - Ascorbic acid attenuates acute pulmonary oxidative stress and inflammation caused by zinc oxide nanoparticles. AB - OBJECTIVES: It is known that inhalation of zinc oxide nanoparticles (ZnO NPs) induces acute pulmonary dysfunction, including oxidative stress, inflammation, and injury, but there are no reports on how to prevent these adverse effects. We have previously reported that the pulmonary symptoms caused by ZnO NPs were associated with oxidative stress; in the present study, we therefore investigated the use of ascorbic acid (AA), which is known as vitamin C, to prevent these toxic effects. METHODS: A ZnO NP dispersion was introduced into rat lungs by intratracheal injection, and thereafter a 1% aqueous AA solution was given as drinking water. Bronchoalveolar lavage fluid was collected at 1 day and 1 week after injection, and lactate dehydrogenase (LDH) activity, heme oxygenase-1 (HO 1), and interleukin-6 (IL-6) levels were measured. In addition, expression of the chemokine cytokine-induced neutrophil chemoattractants (CINCs), HO-1, and metallothionein-1 (MT-1) genes in the lungs were determined. RESULTS: Acute oxidative stress induced by ZnO NPs was suppressed by supplying AA. Increases in LDH activity and IL-6 concentration were also suppressed by AA, as was the expression of the CINC-1, CINC-3, and HO-1 genes. CONCLUSIONS: Oral intake of AA prevents acute pulmonary oxidative stress and inflammation caused by ZnO NPs. Intake of AA after unanticipated exposure to ZnO NPs is possibly the first effective treatment for the acute pulmonary dysfunction they cause. PMID- 25735508 TI - Surveys on the competencies of specialist occupational physicians and effective methods for acquisition of competencies in Japan. AB - OBJECTIVES: The aim of this study was to study the necessary competencies for specialist occupational physicians in Japan and the effective training methods for acquiring them. METHODS: A competency list (61 items) was developed for the questionnaires in the study by making use of existing competency lists from the Japan Society for Occupational Health (JSOH) as well as lists from the US and Europe. Certified senior occupational physicians (CSOPs) in the certification program of the JSOH completed a questionnaire on the necessary competencies. Examiners of the examination for certified occupational physicians (COPs) completed another questionnaire on effective training methods. RESULTS: All 61 competencies in the questionnaires were evaluated as "necessary". Some of the competencies in the list from the JSOH were evaluated lower than the items added from the American and European lists. When the respondents were categorized into a "practical group", the members of which mainly provided occupational health services, an "academic group", the members of which belonged to research or education institutes such as medical schools, and all others, the practical group evaluated some competencies significantly higher than the academic group, particularly those related to work accommodation. Among three options for training methods, the most effective methods were lectures and textbooks for 5 competency items, on-the-job training (OJT) for 30 items, and case-based learning (CBL) for 29 items. CONCLUSIONS: Some competencies should be added to the JSOH list. CBL should be introduced in training programs for specialist occupational physicians. PMID- 25735509 TI - Effect of workstation height and distance on upper extremity muscle activity during repetitive below-the-knee assembly work. AB - OBJECTIVES: To determine the activity of the upper trapezius, serratus anterior, anterior deltoid, biceps brachii. and lower trapezius muscles in healthy adults during below-the-knee assembly work. METHODS: Fifteen right-handed male subjects participated in this study. The electrical activities, measured by EMG, of the right upper trapezius, serratus anterior, anterior deltoid, biceps brachii. and lower trapezius were measured during below-the-knee assembly work at four workstations of varying height and distance from the participant (workstation 1, below-the-knee assembly work with a height of 15 cm above the floor and a reach distance of 30 cm; workstation 2, height of 15 cm and distance of 45 cm; workstation 3, height of 30 cm and distance of 30 cm; workstation 4, height of 30 cm and distance of 45 cm). Muscle activity at the four workstations was represented as a percentage of the reference voluntary isometric contraction (RVIC). RESULTS: Height: Upper and lower trapezius activity increased significantly during below the knee assembly work as height above the floor increased. The activities of the serratus anterior and biceps brachii muscles increased significantly during low-height below-the-knee assembly work. Distance: The activities of the upper trapezius, serratus anterior, anterior deltoid and biceps brachii increased significantly during below-the-knee assembly work at a far distance (45 cm). The lower trapezius muscle activity increased significantly during below-the-knee assembly work at a close distance (30 cm). CONCLUSIONS: Below-knee workers should engage in work close to themselves, since distance appears to be a stronger risk factor for injury than height above the floor. PMID- 25735510 TI - Consumption patterns and levels among households with HIV positive members and economic impoverishment due to medical spending in Pune city, India. AB - HIV infection poses a serious threat to the economy of a household. Out of pocket (OOP) health spending can be prohibitive and can drag households below poverty level. Based on the data collected from a cross-sectional survey of 401 households with HIV+ members in Pune city, India, this paper examines the consumption levels and patterns among households, and comments on the economic impoverishment resulting from OOP medical spending. Analysis reveals that households with HIV members spend a major portion of their monthly consumption expenditure on food items. Medical expenditure constitutes a large portion of their total consumption spending. Expenditure on children's education constitutes a minor proportion of total monthly spending. A high proportion of medical expenditure has a bearing on the economic condition of households with HIV members. Poverty increases by 20% among the studied HIV households when OOP health spending is adjusted. It increases 18% among male-headed households and 26% among female-headed households. The results reiterate the need of greater support from the government in terms of accessibility and affordability of health care to save households with HIV members from economic catastrophe. PMID- 25735511 TI - Investigation of Paclitaxel Resistant R306C Mutation in beta-Tubulin-A Computational Approach. AB - Paclitaxel is the most effective chemotherapeutic agent used for the treatment of a broad spectrum of solid tumors. However, observed paclitaxel resistance in clinical trials presents one of the major obstacles for cancer chemotherapy. Most importantly, resistance due to beta-tubulin mutations (R306C) has been intensely debated in recent years. Despite all efforts, mechanism of resistance is still not well understood. In this study, computational techniques were employed to uncover the effect of R306C mutation in the beta-tubulin structure and its function. The tools such as I-Mutant, CUPSAT and Fold-X were employed to address the consequence of R306C mutation in the structural stability of beta-tubulin. Further, molecular docking and molecular dynamics study was employed to understand the functional impact of beta-tubulin mutation. Our results suggest that the R306C mutation causes a significant reduction in the binding affinity between beta-tubulin and paclitaxel. Further, docked complex analysis indicates that destruction of conservative hydrogen bond maintained by the residues Arg282 and Gly360 should be responsible for the large conformation changes of the binding pocket in R306C mutant. Finally, molecular dynamics simulations study confirms the stable binding of paclitaxel with native type beta-tubulin structure rather than mutant (R306C) type. We certainly believe that this study will provide useful guidance for the development of novel inhibitors that are less susceptible to drug resistance. PMID- 25735512 TI - Very low mammographic breast density predicts poorer outcome in patients with invasive breast cancer. AB - OBJECTIVES: To examine the prognostic value of mammographic breast density (MBD) and mammographic features and their relationship with established prognostic factors in patients with invasive breast cancer. METHODS: Mammographic characteristics of 270 patients were analyzed. MBD was classified according to percentile density (<5%, 5-10%, 10-25%, 25-50%, 50-75%, >75%) and further categorized into very low density (VLD; <10%), low density (LOD; <25%) and mixed density (MID; >25%). Mammographic features were compared with established prognostic factors and patient outcomes while correcting for possible confounders. RESULTS: MBD was inversely associated with tumour grade (p = 0.019). Patients with LOD breasts had worse prognoses compared to those with MID breasts (disease-free survival 74.7% vs. 84.8%, p = 0.048; overall survival 75.3% vs. 90.2%, p = 0.003). Patients with VLD breasts showed the strongest significance compared to the remaining patients, even after adjusting for age, body mass index, and menopausal status. No other mammographic feature was prognostically significant. In Cox regression analysis, VLD proved to be an independent, poor prognostic feature (hazard ratio = 3.275; p < 0.001). CONCLUSION: In patients with newly diagnosed breast cancer, very low MBD proved to be an independent prognostic feature, associated with higher tumour grade and predicted worse survival even after correcting for possible confounders. KEY POINTS: * Percentile mammographic breast density was associated with patient prognosis. * Very low density proved to be an independent poor prognostic factor. * Only patients with densities <10% displayed this difference in survival. * Mammographic breast density was inversely associated with histological tumour grade. PMID- 25735513 TI - CT-guided Interstitial Brachytherapy of Hepatocellular Carcinoma before Liver Transplantation: an Equivalent Alternative to Transarterial Chemoembolization? AB - OBJECTIVES: Transarterial chemoembolization (TACE) is established as bridging therapy of HCC listed for transplantation (LT). CT-guided brachytherapy (CTB) has not been evaluated as a bridging concept. We compared CTB and TACE for bridging before LT in HCC patients. METHODS: Twelve patients with HCC received LT after CTB (minimal tumour dose, 15-20 Gy). Patients were matched (CTB:TACE, 1:2) by sex, age, number and size of lesions, and underlying liver disease with patients who received TACE before transplantation. Study endpoints were extent of necrosis at histopathology and recurrence rate after OLT. RESULTS: There were no significant differences between the CTB and TACE groups regarding Child-Pugh category (p = 0.732), AFP (0.765), time on waiting list (p = 0.659), number (p = 0.698) and size (p = 0.853) of HCC lesions, fulfilment of Milan-criteria (p = 0.638), or previous liver-specific treatments. CTB achieved higher tumour necrosis rates than TACE (p = 0.018). The 1- and 3-year recurrence rate in the CTB group was 10 and 10 % vs. TACE, 14 and 30 % (p = 0.292). CONCLUSIONS: Our data show comparable or even better response and post-LT recurrence rates of CTB compared to TACE for treating HCC in patients prior to LT. CTB should be further evaluated as an alternative bridging modality, especially for patients not suited for TACE. KEY POINTS: * CT-guided interstitial brachytherapy (CTB) is a promising alternative to transarterial chemoembolization (TACE). * CTB instead of TACE is possible for bridging to liver transplantation in HCC patients. * HCC recurrence was not associated with CTB despite potential tumour seeding. PMID- 25735514 TI - Prevalence and configuration of pulmonary nodules on multi-row CT in children without malignant diseases. AB - OBJECTIVES: To assess the prevalence and morphologic characterization of pulmonary nodules in children on a chest computed tomography (CT). METHODS: Two hundred and fifty-nine trauma chest CTs in children aged 0-18 years were retrospectively reviewed by two radiologists, each with more than 10 years of experience. Images were acquired on a 64-row CT. Pulmonary lobes with trauma affections such as contusion or haemorrhage were excluded. All pulmonary nodules were evaluated for distance from the pleural surface, location, calcification and size on axial slices. RESULTS: A total of 1,190/1,295 (92%) pulmonary lobes without traumatic injury were included in this study. In 86 of 259 (33%) patients, 131 pulmonary nodules were detected. Number of nodules per patient ranged from 1 to 4. Calcifications were seen in 19% (25) of all nodules. Diameters ranged from 1 to 5 mm. 59% (77) were located in the lower lobes, 9% (12) in the middle lobe and 32% (42) in the upper lobes. 84% of the non-calcified nodules >2 mm showed a slightly angular or triangular (mostly pleural nodes) shape. CONCLUSIONS: Pulmonary nodules smaller than 5 mm can be detected frequently in children without malignant disease and are predominantly located in the lower lobes. KEY POINTS: * Pulmonary nodules in children with trauma CTs were retrospectively analysed * Pulmonary nodules seen on CT are frequent in children without malignant disease * Nodules in this group are more frequent in the lower lobes * No age dependency for the number of pulmonary nodules in children was observed. PMID- 25735515 TI - Subcentimeter hypervascular nodule with typical imaging findings of hepatocellular carcinoma in patients with history of hepatocellular carcinoma: natural course on serial gadoxetic acid-enhanced MRI and diffusion-weighted imaging. AB - OBJECTIVES: To evaluate the natural course of subcentimeter hypervascular nodules at high risk for developing into hepatocellular carcinomas (SHNHR) using serial magnetic resonance imaging (MRI) in patients with a history of hepatocellular carcinoma (HCC). METHODS: An SHNHR was defined as a subcentimeter hypervascular nodule having typical imaging findings of HCC on gadoxetic acid-enhanced MRI and diffusion-weighted imaging. We included 39 patients with 46 SHNHRs (mean size +/- standard deviation, 6.1 +/- 1.6 mm; range, 3.2 - 9.0 mm). Overt HCC was defined as pathology proven HCC or a nodule larger than 1 cm with typical imaging findings of HCC. The cumulative rate and the independent predictive factors for progression to overt HCC were evaluated. RESULTS: The median follow-up period was 139 days (range, 64 - 392 days). The cumulative progression rate to overt HCC at 3, 6, 9, and 12 months was 13.9%, 61.7%, 83.2%, and 89.9%. The initial size of SHNHR was a significant predictor of progression to overt HCC, with an optimal cut-off value of 5.5 mm. CONCLUSION: The progression rate of SHNHR to overt HCC within 12 months was high (89.9%) in patients with history of HCC. The initial size of SHNHR was an important predictor for progression to overt HCC. KEY POINTS: * Most SHNHRs (89.9%) progressed to overt HCCs within 12 months. * Initial size was an important predictor for progression to overt HCCs. * The optimal cut-off value for initial nodule size was 5.5 mm. PMID- 25735516 TI - Ocean currents generate large footprints in marine palaeoclimate proxies. AB - Fossils of marine microorganisms such as planktic foraminifera are among the cornerstones of palaeoclimatological studies. It is often assumed that the proxies derived from their shells represent ocean conditions above the location where they were deposited. Planktic foraminifera, however, are carried by ocean currents and, depending on the life traits of the species, potentially incorporate distant ocean conditions. Here we use high-resolution ocean models to assess the footprint of planktic foraminifera and validate our method with proxy analyses from two locations. Results show that foraminifera, and thus recorded palaeoclimatic conditions, may originate from areas up to several thousands of kilometres away, reflecting an ocean state significantly different from the core site. In the eastern equatorial regions and the western boundary current extensions, the offset may reach 1.5 degrees C for species living for a month and 3.0 degrees C for longer-living species. Oceanic transport hence appears to be a crucial aspect in the interpretation of proxy signals. PMID- 25735518 TI - Five-year survival after cryoablation of stage I non-small cell lung cancer in medically inoperable patients. AB - PURPOSE: To evaluate retrospectively the long-term survival of patients with early-stage non-small cell lung cancer (NSCLC) treated with cryoablation. MATERIALS AND METHODS: Cryoablation was performed on 47 T1N0M0 NSCLCs in 45 consecutive patients between 2006 and January 2011. All ablative procedures were performed with 16-gauge or 13-gauge cryoprobes. The number of probes used was determined by the size and geometry of the tumor. Local and regional recurrence rates were monitored. Complications were assessed by the Society of Interventional Radiology (SIR) classification system. RESULTS: The 5-year survival rate was 67.8% +/- 15.3, the cancer-specific survival rate at 5 years was 56.6% +/- 16.5, and the 5-year progression-free survival rate was 87.9% +/- 9. The probe per unit tumor diameter was 1.4 probes/cm. In eight patients, 16 gauge cryoprobes were used. Two cases were performed with a single needle. The remaining cases were performed with 13-gauge cryoprobes except for one case in which both probe sizes were used. The combined local and regional recurrence rate was 36.2%. Major complications occurred in 6.4% of patients, including two cases of hemoptysis and a prolonged placement of a chest tube requiring mechanical sclerosis in one patient. There were no deaths in the first 30 days after treatment. CONCLUSIONS: Cryoablation is associated with a good overall long-term survival with minimally significant complications. Cryoablation is a potentially curative, viable therapeutic option for patients with stage I NSCLC who are deemed medically inoperable. PMID- 25735517 TI - Customising informed consent procedures for people with schizophrenia in India. AB - BACKGROUND: There is little information on how the ethical and procedural challenges involved in the informed participation of people with schizophrenia in clinical trials are addressed in low- and middle-income countries (LMICs). The informed consent procedure used in the collaborative community care for people with schizophrenia in India (COPSI) RCT was developed keeping these challenges in mind. We describe the feasibility of conducting the procedure from the trial, researcher and participants perspectives and describe the reasons for people consenting to participate in the trial or refusing to do so. METHODS: Three sources of information were used to describe the feasibility of the COPSI consent procedure: key process indicators for the trial perspective, data from a specially designed post-interview form for participant's observations and focus group discussion (FGD) with the research interviewers. Categorical data were analysed by calculating frequencies and proportions, while the qualitative data from the FGD, and the reasons for participation or refusal were analysed using a thematic content analysis approach. FINDINGS: 434 people with schizophrenia and their primary caregiver(s) were approached for participation in the trial. Consent interviews were conducted with 332, of whom 303 (91%) agreed to participate in the trial. Expectation of improvement was the most common reason for agreeing to participate in the trial, while concerns related to the potential disclosure of the illness, especially for women, were an important reason for refusing consent. CONCLUSIONS: The COPSI consent procedure demonstrates preliminary, observational information about the feasibility of customising informed consent procedures for people with schizophrenia LMIC contexts. This and other similar innovations need to be refined and rigorously tested to develop evidence-based guidelines for informed consent procedures in such settings. PMID- 25735519 TI - Scrubbing with Charles Dotter on an angioplasty. PMID- 25735521 TI - Should transjugular intrahepatic portosystemic shunt stent grafts be underdilated? AB - Although underdilation of transjugular intrahepatic portosystemic shunt (TIPS) stent grafts is commonly performed to limit complications arising from excessive portosystemic shunting, it is uncertain whether underdilated stents retain their smaller diameter indefinitely or eventually expand to nominal caliber. In this investigation, postprocedure computed tomography (CT) was used to compare diameters of underdilated TIPSs and TIPSs expanded to a nominal diameter of 10 mm in 61 cases. The groups had comparable shunt diameters on post-TIPS imaging (9.8 mm vs 9.9 mm; P = .079), with similar incidences of hepatic encephalopathy (34% vs 20%; P = .372), indicating stent self-expansion over time, and bringing into question the advantages of underdilation for customization of shunt caliber. PMID- 25735522 TI - Transjugular intrahepatic portosystemic shunt endografts: a decade in and due for revision? PMID- 25735523 TI - Automatic three-dimensional detection of prostatic arteries using cone-beam CT during prostatic arterial embolization. AB - The purpose of this study was to evaluate the automatic three-dimensional detection of prostatic arteries (PAs) with the use of dual-phase cone-beam computed tomography (CT) imaging and vessel-tracking software during prostatic artery (PA) embolization (PAE). In six patients, six right PAs and five left PAs were detected by using the software (sensitivity, 92%). The false-positive arteries (right side, 14%; left side, 25%) were deleted after cone-beam CT review. Automatic software detection of PAs from cone-beam CT may permit identification of the PA during PAE. PMID- 25735524 TI - Occlusion of small arteries in the neuroendovascular and head and neck territory initial experiences with a microvascular plug. AB - The microvascular plug (MVP, UNO; Reverse Medical Corp, Irvine, California) is designed for occlusion of small vessels that are accessible only by microcatheters. This report describes eight neuroendovascular cases, including aneurysms and acute or imminent hemorrhage, treated with 10 microvascular plug devices. Instantaneous flow arrest was observed in all but two cases, in which the device was undersized, requiring supplementary coiling or microvascular plug replacement, respectively. Persistent occlusion was confirmed on follow-up examinations. There was one adverse event, which involved inadvertent device detachment after repeated resheathing. The microvascular plug appears to be suitable for the designated purpose. Further studies need to evaluate safety and confirm long-term durability of the results. PMID- 25735525 TI - Early introduction of IR to premedical and medical students: initiatives at a single U.S. Institution. PMID- 25735526 TI - Pancreatic arteriovenous malformation embolization with onyx. PMID- 25735527 TI - Ultrasound-guided angio-seal deployment. PMID- 25735528 TI - Contrast-induced thrombosis: are we aware? PMID- 25735529 TI - Proximal ureteric obstruction caused by glue migration following selective renal artery embolization. PMID- 25735530 TI - Acute renal failure after renal denervation. PMID- 25735531 TI - Stent-assisted coil embolization for a traumatic pseudoaneurysm of the visceral aortic segment. PMID- 25735532 TI - Aspiration thrombectomy using the penumbra catheter. PMID- 25735533 TI - Treatment of cystic lymphangioma by transcatheter lymphatic sclerotherapy and embolization. PMID- 25735534 TI - Frey syndrome: factors influencing the time to event. AB - Frey syndrome is a common complication after parotidectomy. The time from surgery to disease onset may be quite long; therefore, a time-to-event analysis was performed for the occurrence of this syndrome post-parotidectomy. Three hundred and thirty-four patients who underwent a parotidectomy between January 2002 and November 2012 were identified (retrospective study). Of these patients, 102 developed Frey syndrome post-surgery and 232 did not. The time-to-onset analysis enabled us to estimate the risk ratio associated with different types of parotid gland tumours, various parotidectomy procedures, and repeat parotidectomy, which is useful for predicting preoperative and surgical risk. The risk of developing Frey syndrome was lower in patients with malignant tumours than in those with benign tumours (risk ratio 0.351, 95% confidence interval (CI) 0.155-0.594). Risk ratios for lumpectomy PA (pre-auricular area), superficial parotidectomy, and total parotidectomy with respect to lumpectomy T (tail) were 4.378 (95% CI 1.168 16.410), 8.040 (95% CI 3.286-19.670), and 8.174 (95% CI 3.076-21.723), respectively. Repeat parotidectomy also increased the risk of developing Frey syndrome (risk ratio 3.214, 95% CI 1.547-6.678). No effect of the use of a superficial muscular aponeurotic system (SMAS) flap on the risk of developing Frey syndrome was detected (P=0.888). PMID- 25735535 TI - Chemical and structural analyses of titanium plates retrieved from patients. AB - The aim of this study was to evaluate the microscopic structure and chemical composition of titanium bone plates and screws retrieved from patients with a clinical indication and to relate the results to the clinical conditions associated with the removal of these devices. Osteosynthesis plates and screws retrieved from 30 patients between January 2010 and September 2013 were studied by metallographic, gas, and energy dispersive X-ray (EDX) analyses and the medical records of these patients were reviewed. Forty-eight plates and 238 screws were retrieved. The time elapsed between plate and screw insertion and removal ranged between 11 days and 10 years. Metallographic analysis revealed that all the plates were manufactured from commercially pure titanium (CP-Ti). The screw samples analyzed consisted of Ti-6Al-4V alloy, except four samples, which consisted of CP-Ti. Titanium plates studied by EDX analysis presented greater than 99.7% titanium by mass. On gas analysis of Ti-6Al-4V screws, three samples were outside the standard values. One CP-Ti screw sample and one plate sample also presented an oxygen analysis value above the standard. The results indicated that the physical properties and chemical compositions of the plates and screws did not correspond with the need to remove these devices or the time of retention. PMID- 25735536 TI - Piezoelectric surgery--primary bone grafting in craniofacial trauma revisited. AB - Reconstruction of the frontal bar following complex craniofacial fractures involving the frontal sinus is a central strategic element, and inaccurate reduction can result in contour defects and non-union. Such defects can be reconstructed using autogenous bone from the inner table of a calvarial graft. Traditionally this is done with rotary instruments and osteotomes. In this article, we describe the use of piezoelectric surgery to harvest the graft. This technique allows for more precise and less destructive harvesting of autogenous bone with the additional benefit of reducing the risk of injury to the surgeon. PMID- 25735537 TI - Regulation of the alkaloid biosynthesis by miRNA in opium poppy. AB - Opium poppy (Papaver somniferum) is an important medicinal plant producing benzylisoquinoline alkaloids (BIA). MicroRNAs (miRNAs) are endogenous small RNAs (sRNAs) of approximately 21 nucleotides. They are noncoding, but regulate gene expression in eukaryotes. Although many studies have been conducted on the identification and functions of plant miRNA, scarce researches on miRNA regulation of alkaloid biosynthesis have been reported. In this study, a total of 316 conserved and 11 novel miRNAs were identified in opium poppy using second generation sequencing and direct cloning. Tissue-specific regulation of miRNA expression was comparatively analysed by miRNA microarray assays. A total of 232 miRNAs were found to be differentially expressed among four tissues. Likewise, 1469 target transcripts were detected using in silico and experimental approaches. The Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that miRNA putatively regulates carbohydrate metabolism and genetic information processing. Additionally, miRNA target transcripts were mostly involved in response to stress against various factors and secondary-metabolite biosynthesis processes. Target transcript identification analyses revealed that some of the miRNAs might be involved in BIA biosynthesis, such as pso-miR13, pso miR2161 and pso-miR408. Additionally, three putatively mature miRNA sequences were predicted to be targeting BIA-biosynthesis genes. PMID- 25735538 TI - Resolving relaxometry and diffusion properties within the same voxel in the presence of crossing fibres by combining inversion recovery and diffusion weighted acquisitions. AB - PURPOSE: A comprehensive image-based characterization of white matter should include the ability to quantify myelin and axonal attributes irrespective of the complexity of fibre organization within the voxel. While progress has been made with diffusion MRI-based approaches to measure axonal morphology, to date available myelin metrics simply assign a single scalar value to the voxel, reflecting some form of average of its constituent fibres. Here, a new experimental framework that combines diffusion MRI and relaxometry is introduced. It provides, for the first time, the ability to assign to each unique fibre system within a voxel, a unique value of the longitudinal relaxation time, T1, which is largely influenced by the myelin content. METHODS: We demonstrate the method through simulations, in a crossing fibres phantom, in fixed brains and in vivo. RESULTS: The method is capable of recovering unique values of T1 for each fibre population. CONCLUSION: The ability to extract fibre-specific relaxometry properties will provide enhanced specificity and, therefore, sensitivity to differences in white matter architecture, which will be invaluable in many neuroimaging studies. Further the enhanced specificity should ultimately lead to earlier diagnosis and access to treatment in a range of white matter diseases where axons are affected. PMID- 25735539 TI - Differentially expressed genes match bill morphology and plumage despite largely undifferentiated genomes in a Holarctic songbird. AB - Understanding the patterns and processes that contribute to phenotypic diversity and speciation is a central goal of evolutionary biology. Recently, high throughput sequencing has provided unprecedented phylogenetic resolution in many lineages that have experienced rapid diversification. The Holarctic redpoll finches (Genus: Acanthis) provide an intriguing example of a recent, phenotypically diverse lineage; traditional sequencing and genotyping methods have failed to detect any genetic differences between currently recognized species, despite marked variation in plumage and morphology within the genus. We examined variation among 20 712 anonymous single nucleotide polymorphisms (SNPs) distributed throughout the redpoll genome in combination with 215 825 SNPs within the redpoll transcriptome, gene expression data and ecological niche modelling to evaluate genetic and ecological differentiation among currently recognized species. Expanding upon previous findings, we present evidence of (i) largely undifferentiated genomes among currently recognized species; (ii) substantial niche overlap across the North American Acanthis range; and (iii) a strong relationship between polygenic patterns of gene expression and continuous phenotypic variation within a sample of redpolls from North America. The patterns we report may be caused by high levels of ongoing gene flow between polymorphic populations, incomplete lineage sorting accompanying very recent or ongoing divergence, variation in cis-regulatory elements, or phenotypic plasticity, but do not support a scenario of prolonged isolation and subsequent secondary contact. Together, these findings highlight ongoing theoretical and computational challenges presented by recent, rapid bouts of phenotypic diversification and provide new insight into the evolutionary dynamics of an intriguing, understudied non-model system. PMID- 25735540 TI - Long-tip high-speed atomic force microscopy for nanometer-scale imaging in live cells. AB - Visualization of morphological dynamics of live cells with nanometer resolution under physiological conditions is highly desired, but challenging. It has been demonstrated that high-speed atomic force microscopy is a powerful technique for visualizing dynamics of biomolecules under physiological conditions. However, application of high-speed atomic force microscopy for imaging larger objects such as live mammalian cells has been complicated because of the collision between the cantilever and samples. Here, we demonstrate that attaching an extremely long (~3 MUm) and thin (~5 nm) tip by amorphous carbon to the cantilever allows us to image the surface structure of live cells with the spatiotemporal resolution of nanometers and seconds. We demonstrate that long-tip high-speed atomic force microscopy is capable of imaging morphogenesis of filopodia, membrane ruffles, pit formation, and endocytosis in COS-7, HeLa cells and hippocampal neurons. PMID- 25735541 TI - Germ-cell hub position in a heteropteran testis correlates with the sequence and location of spermatogenesis and production of elaborate sperm bundles. AB - In insects, spermatogonial cells undergo several mitotic divisions with incomplete cytokinesis, and then proceed through meiosis and spermatogenesis in synchrony. The cells derived from a single spermatogonial cell are referred to as a cyst. In the water strider Aquarius remigis, spermiogenesis occurs within two bi-lobed testes. In contrast to most insects, in which the germ-cell hub is located apically and sequential stages of spermatogenesis can be seen moving toward the base of the testis, each lobe of the water strider testis contains a single germ-cell hub located medially opposite to the efferent duct of the lobe; the developing cysts are displaced toward the distal ends of the lobe as spermiogenesis proceeds. Water strider sperm have both a long flagellum and an unusually long acrosome. The water strider spermatids elongate most of the flagellum prior to morphogenesis of the acrosome, and exhibit several stages of nuclear remodeling before the final, mature sperm nucleus is formed. The maturing sperm are aligned in register in the cyst, and the flagella fold into a coiled bundle while their acrosomes form a rigid helical process that extends from the cyst toward the efferent duct. PMID- 25735542 TI - Is the charge transport in dye-sensitized solar cells really understood? AB - Electrical transients following laser excitation of dye-sensitized solar cells, thus far described by a complex model in the literature, are not consistent with this model. In particular, there are always delays of the electrical signal after the laser pulse. Although the correct theory has not yet been found, the present article is a step toward an improved understanding. PMID- 25735543 TI - Oxidative C-H bond functionalization and ring expansion with TMSCHN2 : a copper(I)-catalyzed approach to dibenzoxepines and dibenzoazepines. AB - Tricyclic dibenzoxepines and dibenzazepines are important therapeutic agents for the pharmaceutical industry and academic research. However, their syntheses are generally rather tedious, requiring several steps that involve a Wagner-Meerwein type rearrangement under harsh conditions. Herein, we present the first copper(I) catalyzed oxidative C?H bond functionalization and ring expansion with TMSCHN2 to yield these important derivatives in a facile and straightforward way. PMID- 25735544 TI - Gender differences in access to methadone maintenance therapy in a Canadian setting. AB - INTRODUCTION AND AIMS: Methadone maintenance therapy (MMT) is an evidence-based treatment for opioid addiction. While gender differences in MMT pharmacokinetics, drug use patterns and clinical profiles have been previously described, few studies have compared rates of MMT use among community-recruited samples of persons who inject drugs (PWID). DESIGN AND METHODS: The present study used prospective cohorts of PWID followed between May 1996 and May 2013 in Vancouver, British Columbia, Canada. We investigated potential factors associated with time to methadone initiation using Cox proportional hazards modelling. Stratified analyses were used to examine for gender differences in rates of MMT enrolment. RESULTS: Overall, 1848 baseline methadone-naive PWID were included in the study, among whom 595 (32%) were female. In an adjusted model, male gender was independently associated with increased time to MMT initiation and an overall lower rate of enrolment [adjusted relative hazard = 0.74 (95% confidence interval: 0.65-0.85)]. Among both female and male PWID, Caucasian ethnicity and daily injection heroin use were associated with decreased time to methadone initiation, while in females, pregnancy was also associated with more rapid initiation. DISCUSSION AND CONCLUSIONS: These data highlight gender differences in methadone use among a population of community-recruited PWID. While factors associated with methadone use were similar between genders, rates of use were lower among male PWID, highlighting the need to consider gender when designing strategies to improve recruitment into MMT. [Bach P, Milloy M-J, Nguyen P, Koehn J, Guillemi S, Kerr T, Wood E. Gender differences in access to methadone maintenance therapy in a Canadian setting. Drug Alcohol Rev 2015;34:503-7]. PMID- 25735545 TI - Diffusion length and Langevin recombination of singlet and triplet excitons in organic heterojunction solar cells. AB - We derived new expressions for the diffusion length of singlet and triplet excitons by using the Foster and Dexter transfer mechanisms, respectively, and have found that the diffusion lengths of singlet and triplet excitons are comparable. By using the Langevin recombination theory, we derived the rate of recombination of dissociated free charges into their excitonic states. We found that in some organic polymers the probabilities of recombination of free charge carriers back into the singlet and triplet states are approximately 65.6 and 34.4 %, respectively, indicating that Langevin-type recombination into triplet excitons in organic semiconductors is less likely. This implies that the creation of triplet excitons may be advantageous in organic solar cells, because this may lead to dissociated free charge carriers that can be collected at their respective electrodes, which should result in better conversion efficiency. PMID- 25735546 TI - Current progress of targetron technology: development, improvement and application in metabolic engineering. AB - Targetrons are mobile group II introns that can recognize their DNA target sites by base-pairing RNA-DNA interactions with the aid of site-specific binding reverse transcriptases. Targetron technology stands out from recently developed gene targeting methods because of the flexibility, feasibility, and efficiency, and is particularly suitable for the genetic engineering of difficult microorganisms, including cellulolytic bacteria that are considered promising candidates for biomass conversion via consolidated bioprocessing. Along with the development of the thermotargetron method for thermophiles, targetron technology becomes increasingly important for the metabolic engineering of industrial microorganisms aiming at biofuel/chemical production. To summarize the current progress of targetron technology and provide new insights on the use of the technology, this paper reviews the retrohoming mechanisms of both mesophilic and thermophilic targetron methods based on various group II introns, investigates the improvement of targetron tools for high target efficiency and specificity, and discusses the current applications in the metabolic engineering for bacterial producers. Although there are still intellectual property and technical restrictions in targetron applications, we propose that targetron technology will contribute to both biochemistry research and the metabolic engineering for industrial productions. PMID- 25735547 TI - A de novo proximal 3q29 chromosome microduplication in a patient with oculo auriculo vertebral spectrum. AB - Oculo auriculo vertebral spectrum (OAVS; OMIM 164210) is a clinically and genetically heterogeneous disorder originating from an abnormal development of the first and second branchial arches. Main clinical characteristics include defects of the aural, oral, mandibular, and vertebral development. Anomalies of the cardiac, pulmonary, renal, skeletal, and central nervous systems have also been described. We report on a 25-year-old male showing a spectrum of clinical manifestations fitting the OAVS diagnosis: hemifacial microsomia, asymmetric mandibular hypoplasia, preauricular pits and tags, unilateral absence of the auditory meatus, dysgenesis of the inner ear and unilateral microphthalmia. A SNP array analysis identified a de novo previously unreported microduplication spanning 723 Kb on chromosome 3q29. This rearrangement was proximal to the 3q29 microdeletion/microduplication syndrome region, and encompassed nine genes including ATP13A3 and XXYLT1, which are involved in the organogenesis and regulation of the Notch pathway, respectively. The present observation further expands the spectrum of genomic rearrangements associated to OAVS, underlying the value of array-based studies in patients manifesting OAVS features. PMID- 25735549 TI - New roles and challenges within the healthcare workforce: a Heideggerian perspective. AB - PURPOSE: The purpose of this paper is to explore insights based on the phenomenology of Martin Heidegger, on the dynamic relationships between human experience and work roles. DESIGN/METHODOLOGY/APPROACH: Drawing on the findings of a hermeneutic phenomenological study of nurse mentors, the topics of new roles and role challenges are explored, along with a consideration of their relevance to wider issues of workforce redesign. Heidegger's philosophy of Dasein, in particular his concepts of inauthentic and authentic self, provided an interpretational lens. This paper applies these philosophical concepts to challenges associated with a changing workforce. FINDINGS: Concepts elaborating human existence as proposed by Heidegger may offer analytic structures for understanding shifts in the lived experience of a changing workplace. In particular, the concepts could help managers to explore the implications of introducing novel work roles or extending roles. The understanding gained can also extend to situations where work practices may need to be challenged. ORIGINALITY/VALUE: As work roles and skill mix undergo rapid shifts, this paper offers an original way of understanding the experience of work roles. PMID- 25735550 TI - Doing transformational change in the English NHS in the context of "big bang" redisorganisation. AB - PURPOSE: The purpose of this paper is to examine a bold and ambitious scheme known as the North East transformation system (NETS). The principal aim of the NETS is the achievement of a step-change in the quality of health services delivered to people living in the North East region of England. The paper charts the origins of the NETS and its early journey before describing what happened to it when the UK coalition government published its proposals for unexpected major structural change in the NHS. This had a profound impact on the leadership and direction of the NETS and resulted in it taking a different direction from that intended. DESIGN/METHODOLOGY/APPROACH: The research design took the form of a mixed methods, longitudinal 3.5-year study aimed at exploring transformational change in terms of content, context, process and outcomes. The sample of study sites comprised 14 NHS trusts in the North East region chosen to provide geographical coverage of the area and to reflect the scale, scope and variety of the bodies that formed part of the NETS programme. The qualitative component of the research, which the paper draws upon, included 68 semi-structured interviews, observational studies and focus groups. Data analysis made use of both deductive and inductive frameworks. The deductive framework adopted was Pettigrew et al.'s "receptive contexts for change" and four of the eight factors stood out as especially important and form the basis of the paper. FINDINGS: The fate of the NETS was shaped and influenced by the eight factors comprising the Pettigrew et al. receptive contexts for change framework but four factors in particular stood out as being especially significant: environmental pressure, quality and coherence of policy, key people leading change, supportive organisational culture. Perhaps the most significant lesson from the NETS is that achieving whole systems change is particularly vulnerable to the vicissitudes of politics especially where that system, like the UK NHS, is itself subject to those very same pressures. Yet, despite having an enormous influence on health policy, the political context is frequently avoided in research or not regarded as instrumental in determining the outcomes in respect of transformational change. RESEARCH LIMITATIONS/IMPLICATIONS: The chief limitation is the credibility and authenticity of the interviews captured at particular points in time. These formed the datebase for subsequent analysis. The authors sought to guard against possible bias by supplementing interviews with observational studies and focus groups as well as running two dissemination events at which emerging findings from the study were subjected to independent external scrutiny and comment. These events provided a form of validation for the key study findings. PRACTICAL IMPLICATIONS: The research findings demonstrate the importance of context for the likely outcome and success of complex transformational change initiatives. These require time to become embedded and demonstrate results especially when focused on changing culture and behaviour. But, in practice, allowing sufficient time during which the organisation may remain sufficiently stable to allow the change intervention to run its course and become embedded and sustainable is highly problematic. The consequence is that bold and ambitious efforts like the NETS are not given the space and stability to prove themselves. Too often, politics and external environmental pressures intrude in ways that may prove dysfunctional and negative. SOCIAL IMPLICATIONS: Unless a different approach to transformational change and its leadership and management is adopted, then changing the NHS to enable it to appear more responsive to changing health care needs and expectations will remain a cause for concern. Ultimately the public will be the losers if the NHS remains insensitive to changing needs and expectations. The patient experience was at the centre of the NETS programme. ORIGINALITY/VALUE: The study is original insofar as no other has sought to evaluate the NETS independently and over a reasonable time period. The research design, based on a mixed-methods approach, is unusual in evaluations of this nature. The study's conclusions are not so original but their value lies in largely confirming and reinforcing the findings from other studies. It perhaps goes further in stressing the impact of politics on health policy and the negative consequences of constant organisational change on attempts to achieve deep change in the way the NHS is organised and led. PMID- 25735551 TI - Promoting competition in Swedish primary care. AB - PURPOSE: The purpose of this paper is to examine the role of accreditation documents (ADs) in the competition based on provider quality in a quasi-market for primary healthcare. DESIGN/METHODOLOGY/APPROACH: The paper uses a mixed method research methodology to analyse two primary healthcare ADs in two Swedish regions. In total, 19 interviews were conducted with actors involved in the creation and use of such documents. FINDINGS: This paper points to the crucial role of ADs in the identification of quality differences that influence the competition in primary healthcare. This finding contrasts with the commonly held laissez-faire idea that competition causes providers to develop their own service concepts and where the invisible hand creates quality differences. The paper adds to the discussion with its detailed description of how ADs create competition among primary healthcare providers through selection processes, quality differentiation, and ranking. RESEARCH LIMITATIONS/IMPLICATIONS: The paper does not explore quality differences in the medical treatment of patients in primary healthcare centres. PRACTICAL IMPLICATIONS: The paper provides insights for politicians on how to use ADs to control competition and regulate choice. ORIGINALITY/VALUE: The paper takes an innovative approach to the examination of how ADs increase the competition in primary healthcare choice. PMID- 25735552 TI - The impact of an integrated medical leadership programme. AB - PURPOSE: The purpose of this paper is to determine the impact of an integrated Medical Leadership Programme (MLP) on a cohort of participating specialty doctors and the NHS services with which they were engaged. DESIGN/METHODOLOGY/APPROACH: This was a qualitative study designed to obtain rich textual data on a novel training intervention. Semi-structured interviews were conducted with participating MLP trainees at fixed points throughout the programme in order to capture their experiences. Resulting data were triangulated with data from extant documentation, including trainees' progress reports and summaries of achievements. Recurring discourses and themes were identified using a framework thematic analysis. FINDINGS: Evidence of the positive impact upon trainees and NHS services was identified, along with challenges. Evidence of impact across all the domains within the national Medical Leadership Competency Framework was also identified, including demonstrating personal qualities, working with others, managing services, improving services and setting direction. RESEARCH LIMITATIONS/IMPLICATIONS: Data were drawn from interviews with a small population of trainees undertaking a pilot MLP in a single deanery, so there are inevitable limitations for generalisability in the quantitative sense. Whilst the pilot trainees were a self-selected group, it was a group of mixed origin and ability. PRACTICAL IMPLICATIONS: The study has provided valuable lessons for the design of future leadership programmes aimed at doctors in training. ORIGINALITY/VALUE: Identifying the effectiveness of an innovative model of delivery with regard to the Medical Leadership Curriculum may assist with medical staff engagement and support health service improvements to benefit patient care. PMID- 25735553 TI - Nurse managers' role in older nurses' intention to stay. AB - PURPOSE: The purpose of this paper is to propose and test a model of the underlying mechanisms linking perceived availability of human resource (HR) practices relevant to older nurses and older nurses' intentions to stay with their hospitals. DESIGN/METHODOLOGY/APPROACH: Quantitative data were collected from randomly selected older registered nurses (N=660) engaged in direct patient care in hospitals in Canada. Structural equation modelling was used to test the hypothesized model. FINDINGS: The relationship between perceptions of HR practices (performance evaluation, recognition/respect) and intentions to stay was mediated by the perceived fairness with which nurse managers managed these HR practices and nurse manager satisfaction. When nurse managers were perceived to administer the HR practices fairly (high perceived procedural justice), older nurses were more satisfied with their nurse manager and, in turn, more likely to intend to stay. RESEARCH LIMITATIONS/IMPLICATIONS: The cross-sectional research design does not allow determination of causality. PRACTICAL IMPLICATIONS: It is important that nurse managers receive training to increase their awareness of the needs of older nurses and that nurse managers be educated on how to manage HR practices relevant to older nurses in a fair manner. Equally important is that hospital administrators and HR managers recognize the importance of providing such HR practices and supporting nurse managers in managing these practices. ORIGINALITY/VALUE: The findings increase the understanding of how HR practices tailored to older nurses are related to the intentions of these nurses to remain with their hospital, and especially the crucial role that first-line nurse managers play in this process. PMID- 25735554 TI - Leadership for health commissioning in the new NHS. AB - PURPOSE: The purpose of this paper is to explore the early experiences of those involved with the development of Clinical Commissioning Groups (CCGs), examining how the aspiration towards a "clinically-led" system is being realised. The authors investigate emerging leadership approaches within CCGs in light of the criterion for authorisation that calls for "great leaders". DESIGN/METHODOLOGY/APPROACH: Qualitative research was carried out in eight case studies (CCGs) across England over a nine-month period (September 2011 to May 2012) when CCGs were in their early development. The authors conducted a mix of interviews (with GPs and managers), observations (at CCG meetings) and examined associated documentation. Data were thematically analysed. FINDINGS: The authors found evidence of two identified approaches to leadership - positive deviancy and responsible guardianship - being undertaken by GPs and managers in the developing CCGs. Historical experiences and past ways of working appeared to be influencing current developments and a commonly emerging theme was a desire for the CCG to "do things differently" to the previous commissioning bodies. The authors discuss how the current reorganisation threatens the guardianship approach to leadership and question if the new systems being implemented to monitor CCGs' performance may make it difficult for CCGs to retain creativity and innovation, and thus the ability to foster the positive deviant approach to leadership. ORIGINALITY/VALUE: This is a large scale piece of qualitative research carried out as CCGs were beginning to develop. It provides insight into how leadership is developing in CCGs highlighting the complexity involved in these roles. PMID- 25735555 TI - Reforming primary healthcare: from public policy to organizational change. AB - PURPOSE: Governments everywhere are implementing reform to improve primary care. However, the existence of a high degree of professional autonomy makes large scale change difficult to achieve. The purpose of this paper is to elucidate the change dynamics and the involvement of professionals in a primary healthcare reform initiative carried out in the Canadian province of Quebec. DESIGN/METHODOLOGY/APPROACH: An empirical approach was used to investigate change processes from the inception of a public policy to the execution of changes in professional practices. The data were analysed from a multi-level, combined contextualist-processual perspective. Results are based on a longitudinal multiple-case study of five family medicine groups, which was informed by over 100 interviews, questionnaires, and documentary analysis. FINDINGS: The results illustrate the multiple processes observed with the introduction of planned large scale change in primary care services. The analysis of change content revealed that similar post-change states concealed variations between groups in the scale of their respective changes. The analysis also demonstrated more precisely how change evolved through the introduction of "intermediate change" and how cycles of prescribed and emergent mechanisms distinctively drove change process and change content, from the emergence of the public policy to the change in primary care service delivery. RESEARCH LIMITATIONS/IMPLICATIONS: This research was conducted among a limited number of early policy adopters. However, given the international interest in turning to the medical profession to improve primary care, the results offer avenues for both policy development and implementation. PRACTICAL IMPLICATIONS: The findings offer practical insights for those studying and managing large-scale transformations. They provide a better understanding of how deliberate reforms coexist with professional autonomy through an intertwining of change content and processes. ORIGINALITY/VALUE: This research is one of few studies to examine a primary care reform from emergence to implementation using a longitudinal multi-level design. PMID- 25735556 TI - Does CEO compensation impact patient satisfaction? AB - PURPOSE: This study examines the relationship between CEO compensation and patient satisfaction in Ontario, Canada. The purpose of this paper is to determine what impact hospital CEO compensation has on hospital patient satisfaction. DESIGN/METHODOLOGY/APPROACH: The analyses in this study were based on data of 261 CEO-hospital-year observations in a sample of 103 nonprofit hospitals. A number of linear regressions were conducted, with patient satisfaction as the dependent variable and CEO compensation as the independent variable of interest. Controlling variables included hospital size, type of hospital, and frequency of adverse clinical outcomes. FINDINGS: CEO compensation does not significantly influence hospital patient satisfaction. Both patient satisfaction and CEO compensation appear to be driven primarily by hospital size. Patient satisfaction decreases, while CEO compensation increases, with the number of acute care beds in a hospital. In addition, CEO compensation does not even appear to moderate the influence of hospital size on patient satisfaction. RESEARCH LIMITATIONS/IMPLICATIONS: There are several limitations to this study. First, observations of CEO-hospital-years in which annual nominal CEO compensation was below $100,000 were excluded, as they were not publicly available. Second, this research was limited to a three-year range. Third, this study related the compensation of individual CEOs to a measure of performance based on a multitude of patient satisfaction surveys. Finally, this research is restricted to not-for-profit hospitals in Ontario, Canada. PRACTICAL IMPLICATIONS: The findings seem to suggest that hospital directors seeking to improve patient satisfaction may find their efforts frustrated if they focus exclusively on the hospital CEO. The findings highlight the need for further research on how CEOs may, through leading and supporting those hospital clinicians and staff that interact more closely with patients, indirectly enhance patient satisfaction. ORIGINALITY/VALUE: To the best of the authors' knowledge, no research has examined the relationship between hospital CEO compensation and patient satisfaction. This research fills the gap and provides a basis for future research. PMID- 25735557 TI - Organizing integrated care for older persons: strategies in Sweden during the past decade. AB - PURPOSE: The purpose of this paper is to describe and analyse ways of organizing integrated care for older persons in Sweden during the past decade. DESIGN/METHODOLOGY/APPROACH: The data consist of 62 cases of development work, described in official reports. A meta-analysis of cases was performed, including content analysis of each case. A theoretical framework comprising different forms of integration (co-ordination, contracting, co-operation and collaboration) was applied. FINDINGS: Co-operation was common and collaboration, including multiprofessional teamwork, was rare in the cases. Contracting can be questioned as being a form of integration, and the introduction of consumer choice models appeared problematic in inter-organization integration. Goals stated in the cases concerned steering and designing care, rather than outcome specifications for older persons. Explicit goals to improve integration in itself could imply that the organizations adapt to strong normative expectations in society. Trends over the decade comprised development of local health care systems, introduction of consumer choice models and contracting out. RESEARCH LIMITATIONS/IMPLICATIONS: Most cases were projects, but others comprised evaluations of regular organization of integrated care. These evaluations were often written normatively, but constituted the conditions for practice and were important study contributions. PRACTICAL IMPLICATIONS: Guiding clinical practice to be aware of importance of setting follow-up goals. SOCIAL IMPLICATIONS: Awareness of the risk that special funds may impede sustainable strategies development. ORIGINALITY/VALUE: A theoretical framework of forms of integration was applied to several different strategies, which had been carried out mostly in practice. The study contributes to understanding of how different strategies have been developed and applied to organize integrated care, and highlights some relationships between integration theory and practice. PMID- 25735558 TI - Spinal mediation of motor learning and memory in the rat fetus. AB - Fetal rats can alter patterns of interlimb coordination after experience with a yoke that links two legs together. Yoke training results in a pronounced increase in conjugate limb movements (CLM). To determine whether yoke motor learning is mediated by spinal cord circuitry, fetal subjects at embryonic Day 20 (E20) received yoke training after mid-thoracic spinal cord transection or sham surgery. Both spinal and sham-treated fetuses exhibited an increase in CLM during training. In a second experiment, fetuses received initial yoke training, then were transected or sham treated before a 2nd training. Spinal and sham fetuses that were yoked during both training sessions exhibited a more rapid rise in CLM than those yoked only in the later session. These findings indicate that motor learning in fetal rats can be supported by spinal cord circuitry alone, and that savings implies a form of motor memory localized in the spinal cord. PMID- 25735559 TI - An iGlu receptor antagonist and its simultaneous use with an anticancer drug for cancer therapy. AB - Glutamate receptor antagonists have been known to play a crucial role in the treatment of many neuronal diseases. Recently, these antagonists have also shown therapeutic effects in the treatment of cancer. In this study, an ionotropic glutamate (iGlu) receptor antagonist, 4-hydroxyphenylacetyl spermine (L1), was used concurrently with a common anticancer drug, doxorubicin (Dox), for simultaneous cancer therapy. Mesoporous silica nanoparticles (MSNPs) were employed as the delivery vehicle for both L1 and Dox by conjugating the iGlu receptor antagonist on the surface and encapsulating Dox within the mesopores. Dox was then trapped within the mesopores by functionalizing a redox-cleavable capping group on the MSNP surface, and it could be released upon exposure to the reductive glutathione. In vitro studies on B16F10 and NIH3T3 cell lines revealed that the iGlu receptor antagonist L1 exhibited therapeutic as well as targeting effects. In addition, the simultaneous use of therapeutic L1 and Dox proved to be synergistic in the treatment of cancer. The present work demonstrated the feasibility of employing a delivery system to deliver both neuroprotective drug and anticancer drug for efficient anticancer treatment. PMID- 25735560 TI - Ex vivo heat retention of different eyelid warming masks. AB - PURPOSE: Meibomian gland dysfunction (MGD) appears to be the most common cause of evaporative dry eye, in which the meibum has an altered chemical structure that increases its melting point. Eyelid warming masks slowly transfer heat, preferably between 40 and 45 degrees C to the inner meibomian glands, in an attempt to melt or soften the stagnant meibum. This ex vivo study evaluates the heat retention properties of commercially available masks over a 12-min interval. METHODS: Five eyelid-warming masks (MGDRx EyeBag(r), EyeDoctor(r), Bruder(r), TranquileyesTM, Thera degrees Pearl((r)) were heated following manufacturer's instructions and heat retention was assessed at 1-min interval for 12 min on a non-conductive surface. A facecloth warmed with hot tap water was used as comparison. RESULTS: All masks reached above 40 degrees C within the first 2 min after heating and remained so for 5 min, with the exception of the facecloth, which lasted only 3 min and quickly degraded to 30 degrees C within 10 min. The Bruder(r) and TranquileyesTM reached >50 degrees C, after heating and the Bruder(r) maintained >50 degrees C for nearly 6 min. The MGDRx EyeBag(r), and Thera degrees Pearl(r) had the most stable heat retention between 2 and 9 min, remaining between the targeted temperature. CONCLUSIONS: Heat retention profiles are different for commercially available eyelid warming masks. This ex vivo study highlights that despite the popularity of the time-honored facecloth, it is poor at retaining the desired heat over a 5-10 min interval. Clinical studies need to corroborate these results, remembering that ocular tissue parameters may be factors to consider. PMID- 25735561 TI - Disorganised stroma determined on pre-treatment breast cancer biopsies is associated with poor response to neoadjuvant chemotherapy: Results from the NEOZOTAC trial. AB - INTRODUCTION: The tumor-associated stroma is of importance for tumor progression and is generally accepted to have a significant influence on patient prognosis. However, little is known regarding specific features of tumor-associated stromal tissues and response to (neoadjuvant) chemotherapy. This study investigated the predictive value of extracellular matrix organization on response to chemotherapy in patients treated in the NEOZOTAC trial. METHODS: Stromal organisation was analyzed via a simple method using image analysis software on hematoxylin and eosin (H&E)-stained slides from primary tumor biopsies collected as part of the NEOZOTAC trial. Heidenhain's AZAN trichrome-stained slides were also analyzed for comparison of collagen evaluation. Sections were stained for phospho-Smad2 (pS2) in order to determine the relationship of TGF-beta signaling with stromal organization. RESULTS: A statistically significant relationship was observed between stroma consisting of organised collagen and pathological response to neoadjuvant chemotherapy (Odds Ratio 0.276, 95%CI 0.124-0.614, P = 0.002). This parameter was also related to ER-status (P = 0.003), clinical tumor -status (P = 0.041), nodal status (P = 0.029) and pS2 status (P = 0.025). Correlation between stromal organisation determined on H&E-stained and AZAN-stained tissue sections was high (Pearson's correlation coefficient = 0.806). CONCLUSION: Intratumoral stromal organisation determined using pre-treatment breast cancer biopsies was related to pathological response to chemotherapy. This parameter might play a role in the management of breast cancer for identifying those patients that are likely to benefit from neoadjuvant chemotherapy. PMID- 25735562 TI - NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer. AB - NFAT transcription factors are key regulators of gene expression in immune cells. In addition, NFAT1-induced genes play diverse roles in mediating the progression of various solid tumors. Here we show that NFAT1 induces the expression of the IL8 gene by binding to its promoter and leading to IL8 secretion. Thapsigargin stimulation of breast cancer cells induces IL8 expression in an NFAT-dependent manner. Moreover, we show that NFAT1-mediated IL8 production promotes the migration of primary human neutrophils in vitro and also promotes neutrophil infiltration in tumor xenografts. Furthermore, expression of active NFAT1 effectively suppresses the growth of nascent and established tumors by a non cell autonomous mechanism. Evaluation of breast tumor tissue reveals that while the levels of NFAT1 are similar in tumor cells and normal breast epithelium, cells in the tumor stroma express higher levels of NFAT1 compared to normal stroma. Elevated levels of NFAT1 also correlate with increased neutrophil infiltrate in breast tumors. These data point to a mechanism by which NFAT1 orchestrates the communication between breast cancer cells and host neutrophils during breast cancer progression. PMID- 25735563 TI - Microscale magnetic field modulation for enhanced capture and distribution of rare circulating tumor cells. AB - Immunomagnetic assay combines the powers of the magnetic separation and biomarker recognition and has been an effective tool to perform rare Circulating Tumor Cells detection. Key factors associated with immunomagnetic assay include the capture rate, which indicates the sensitivity of the system, and distributions of target cells after capture, which impact the cell integrity and other biological properties that are critical to downstream analyses. Here we present a theoretical framework and technical approach to implement a microscale magnetic immunoassay through modulating local magnetic field towards enhanced capture and distribution of rare cancer cells. Through the design of a two-dimensional micromagnet array, we characterize the magnetic field generation and quantify the impact of the micromagnets on rare cell separation. Good agreement is achieved between the theory and experiments using a human colon cancer cell line (COLO205) as the capture targets. PMID- 25735564 TI - Prevention and intervention research with Latino families: a translational approach. AB - The present paper takes a translational approach in applying the themes of the current special section to prevention and intervention science in Latino families. The paper reviews the current literature on cultural processes in prevention and intervention research with Latino families. Overall, many prevention and intervention programs have either been developed specifically for Latino families or have been modified for Latino families with great attention paid to the socio-cultural needs of these families. Nevertheless, few studies have tested the role of cultural values or acculturation processes on outcomes. We make recommendations based on findings within basic science and in particular this special section on the incorporation of these values and processes into prevention and intervention science with Latino families. PMID- 25735565 TI - 2-Dimensional changes of the soft tissue profile of augmented and non-augmented human extraction sockets: a randomized pilot study. AB - AIM: This study identified the soft tissue changes of the alveolar ridge at different time points within 12 weeks after tooth extraction with and without socket augmentation. MATERIALS AND METHODS: In 38 patients with single tooth extractions, 40 sockets were augmented and 39 extraction sockets were not augmented. At 2, 4, 6, 8 and 12 weeks impressions were taken and casts digitized with a laser scanner. The horizontal and vertical changes were compared between augmented and non-augmented sites. A p-value <0.05 was considered statistically significant. RESULTS: The mean changes of augmented sockets were between 0.4 mm (2 weeks) and 0.8 mm (12 weeks). In non-augmented sockets changes of 0.7 mm (2 weeks) and of 1.0 mm (12 weeks) were demonstrated. The mean values differed significantly between the buccal and oral region (p < 0.01). Overall, there were significant differences of the mean dimensional changes regarding time (p < 0.01) and augmentation (p < 0.01). CONCLUSIONS: Augmented sockets showed less resorption within 4 weeks after extraction compared to non-augmented sockets. Non augmented sockets showed a continuous dimensional loss with a great variation over 12 weeks whereas augmented sockets had the highest degree of resorption between 4 and 6 weeks. At 12 weeks a comparable resorption in augmented and non augmented sockets was observed. PMID- 25735566 TI - Systemic or Endoventricular Thrombolysis to Treat HeartWare Left Ventricle Assist Device Thrombosis: A Clinical Dilemma. AB - Endoventricular thrombolytic procedure (ETP) has been used to treat continuous flow left ventricle assist device (CF-LVAD) thrombosis. The study aims to investigate the occurrence of complications after ETP. Data were retrospectively reviewed and analyzed in a series of patients who underwent CF-LVAD followed by ETP. Since November 2010, 20 patients underwent HeartWare CF-LVAD implantation at our institute. Four patients (20%) developed pump thrombosis and underwent a total of nine ETPs with tissue plasminogen activator infused into the left ventricle. The mean age was 60.2 +/- 9 years. ETP was performed via either the femoral (n = 6) or radial artery (n = 3). Five ETPs (55.5%) were complicated by left and right radial artery occlusion, two by groin hematomas, and one by femoral artery false aneurysm. ETP carries a strong risk of vascular access complications that, in CF-LVAD patients, may add to the already complex clinical profile and economic burden; thus, a less invasive treatment is advisable whenever required. PMID- 25735567 TI - Quantitative evaluation of duodenal eosinophils and mast cells in adult patients with functional dyspepsia. AB - The role of duodenal eosinophils and mast cells (MCs) in the pathogenesis of functional dyspepsia (FD) remains poorly understood. This study aimed to examine the counts and degranulation of duodenal eosinophils and MCs in FD patients to explore the association between FD and both cell types. We recruited 141 FD patients and 39 healthy controls for this study. Biopsy specimens were collected from the duodenal bulb (D1) and the descending part (D2) of the duodenum of all participants. Eosinophil counts and degranulation, and MC counts and degranulation at both sites were quantitatively evaluated by hematoxylin and eosin staining, major basic protein immunostaining, and toluidine blue staining, respectively. Receiver operating characteristic analysis was applied to evaluate the diagnostic accuracy of these parameters in identifying FD cases. We found that the eosinophil counts at D2 were considerably increased in FD patients compared with healthy controls, and that the proportion of cases with eosinophil degranulation at D2 was significantly higher in the FD group. In addition, FD patients showed significantly increased MC counts and degranulation both at D1 and D2, and receiver operating characteristic analysis further demonstrated that these parameters, in particular the degranulation of MCs, appear to be highly sensitive and specific for the identification of FD patients. Our findings suggest that the increased eosinophil counts and degranulation at D2, and the increased MC counts and degranulation at D1 and D2 may be the histologic markers of FD. MC degranulation at D1 and D2 appears to be highly sensitive and specific for FD identification. PMID- 25735568 TI - [A degreasing worker with pneumatosis cystoides intestinalis caused by trichloroethylene exposure]. PMID- 25735569 TI - The dynamics of the RNA world: insights and challenges. AB - The RNA world hypothesis of the origin of life, in which RNA emerged as both enzyme and information carrier, is receiving solid experimental support. The prebiotic synthesis of biomolecules, the catalytic aid offered by mineral surfaces, and the vast enzymatic repertoire of ribozymes are only pieces of the origin of life puzzle; the full picture can only emerge if the pieces fit together by either following from one another or coexisting with each other. Here, we review the theory of the origin, maintenance, and enhancement of the RNA world as an evolving population of dynamical systems. The dynamical view of the origin of life allows us to pinpoint the missing and the not fitting pieces: (1) How can the first self-replicating ribozyme emerge in the absence of template directed information replication? (2) How can nucleotide replicators avoid competitive exclusion despite utilizing the very same resources (nucleobases)? (3) How can the information catastrophe be avoided? (4) How can enough genes integrate into a cohesive system in order to transition to a cellular stage? (5) How can the way information is stored and metabolic complexity coevolve to pave to road leading out of the RNA world to the present protein-DNA world? PMID- 25735570 TI - Cloning and expression of hepatic synaptotagmin 1 in mouse. AB - Mouse hepatic synaptotagmin 1 (SYT1) cDNA was cloned, characterized and compared to the brain one. The hepatic transcript was 1807 bp in length, smaller than the brain, and only encoded by 9 of 11 gene exons. In this regard, 5'-and 3' untranslated regions were 66 and 476 bp, respectively; the open reading frame of 1266 bp codified for a protein of 421 amino acids, identical to the brain, with a predicted molecular mass of 47.4 kDa and highly conserved across different species. Immunoblotting of protein showed two isoforms of higher molecular masses than the theoretical prediction based on amino acid sequence suggesting posttranslational modifications. Subcellular distribution of protein isoforms corresponded to plasma membrane, lysosomes and microsomes and was identical between the brain and liver. Nonetheless, the highest molecular weight isoform was smaller in the liver, irrespective of subcellular location. Quantitative mRNA tissue distribution showed that it was widely expressed and that the highest values corresponded to the brain, followed by the liver, spleen, abdominal fat, intestine and skeletal muscle. These findings indicate tissue-specific splicing of the gene and posttranslational modification and the variation in expression in the different tissues might suggest a different requirement of SYT1 for the specific function in each organ. PMID- 25735571 TI - Amniocytes from aneuploidy embryos have enhanced random aneuploidy and signs of senescence - can these findings be related to medical problems? AB - OBJECTIVES: Genomic aneuploidy is a common cause of human genetic disorders. Individuals with aneuploidy tend to develop malignancies. Recent studies correlated aneuploidy with early aging, senescence and organ dysfunction. This study investigated potential explanations for these increased risks by evaluating random aneuploidy and senescence rates in amniocytes from fetuses with aneuploidy. METHODS: The rates of random aneuploidy in amniocytes from normal pregnancies were evaluated and compared to amniocytes from fetuses with trisomies 21, 18 and 47,XXY using a FISH technique with X+Y, 9 and 18 probes. Senescence was evaluated by calculating the percentage of amniocytes with fragmented nuclei: senescence associated heterochromatin foci (SAHF), using DAPI staining. RESULTS: Significantly increased rates of cells with aneuploidy were observed in trisomies 18 and 21, and 47,XXY (p<0.001) compared to the control group for the somatic and sex chromosomes. Increased rates of amniocytes with SAHFs were observed among the trisomy samples compared to the control group. CONCLUSIONS: Higher incidence of random aneuploidy and senescence were observed in amniocytes from fetuses with trisomy. These findings might explain the greater lifetime tendency to develop malignancies and diseases related to early aging in these individuals. PMID- 25735572 TI - Regulatory function of beta1,4-galactosyltransferase I expression on Lewis-Y glycan and embryo implantation. AB - beta1,4-Galactosyltransferase I (beta1,4-GalT-I), a key enzyme in glycobiology, mediates several biological mechanisms. However, the correlation between beta-1,4 GalT-I expression in the uterine endometrium and embryo implantation remains unclear. This study aims to elucidate the relationship between beta1,4-GalT-I and Lewis(Y) (Le(Y)) glycan during embryo implantation. So far, using green fluorescent protein as an indicator, beta1,4-GalT-I interference plasmid (pcDNA3.0-siGalT I), overexpression plasmid (pcDNA3.0-HA-GalT I), interference control plasmid (control pcDNA3.0-siGalT I), and empty vector (pcDNA3.0) were transfected into human uterine epithelial RL95-2 cells that imitate the receptive endometrium. Invasive embryos at pre-implantation and treated RL95-2 cells were co-cultured to determine embryo attachment in each of the transfection groups. The results showed that plasmid transfection was successful in all the groups. beta1,4-GalT-I and Fucosyltransferase 1 (FUT1) gene expression declined in the interference group, and the synthesis of Le(Y) decreased accordingly, but the expression of this antigen increased in the overexpression group. After co culturing of the embryos and 36h transfection of RL95-2, the results of these in vitro implantation models showed that the attachment rate was lower in the interference group (30.0 +/- 0.2%) than in the untreated group (50.0 +/- 0.6%), empty vector group (50.0 +/- 0.2%), and interference control group (46.7 +/- 0.6%), however, it was highest in the overexpression group (70.0 +/- 0.2%). These results indicated that beta1,4-galactosyltransferase I possibly regulate mutual uterus-embryo adhesion and embryo implantation by regulating cell surface Le(Y) glycan expression. PMID- 25735573 TI - High-level primary clarithromycin resistance of Helicobacter pylori in Morocco: a prospective multicenter molecular study. PMID- 25735575 TI - Specialist multidisciplinary hypertrophic cardiomyopathy clinics: should they be the standard of care? PMID- 25735576 TI - Prospects for improving outcomes in systemic sclerosis-related pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Approximately one in 10 will develop PAH during their lifetime. These patients have a worse prognosis than those with PAH due to other causes. The most common clinical feature of SSc-PAH in the early stages is non-specific exercise intolerance that can be erroneously attributed to other manifestations of SSc. Screening provides an opportunity for early identification of SSc-PAH and prompt initiation of therapies with the potential to improve quality of life and survival. International guidelines recommend annual transthoracic Doppler echocardiography (TTE), but TTE has limitations. The tricuspid regurgitant jet required for estimating the systolic pulmonary artery pressure is absent in up to 39% of patients, including a proportion with PAH. This has prompted a move to new screening algorithms that are less dependent on TTE. Not all pulmonary hypertension (PH) in patients with SSc is PAH. Other causes include PH secondary to left heart disease, interstitial lung disease-related PH, chronic thromboembolic PH and pulmonary veno-occlusive disease. With the advent of evidence-based therapies, including newer agents such as macitentan, riociguat and selexipag, the establishment of centres with expertise in PAH and the focus on early detection, there has been considerable improvement in survival. The role of anti-coagulation for SSc-PAH has been the subject of a recent meta-analysis of nine observational studies that suggests it may confer a survival benefit, but to date, there have been no randomised controlled trials to confirm this. PMID- 25735577 TI - Treatment of patients with multiple myeloma who are not eligible for stem cell transplantation: position statement of the myeloma foundation of Australia Medical and Scientific Advisory Group. AB - Options for treatment of elderly patients with multiple myeloma have expanded substantially following the development of immunomodulatory drugs (IMiD), proteasome inhibitors and with enhancement in safety of high-dose therapy and autologous stem cell transplant (HDT + ASCT). The recognition of biological heterogeneity among elderly patients has made delivery of therapy more challenging. An individualised approach to treatment selection is recommended in an era in which highly efficacious treatment options are available for transplant ineligible patients. Here, we summarise recommendations for patients who are considered unsuitable for HDT + ASCT, including pretreatment considerations, and induction, maintenance and supportive care therapies. PMID- 25735578 TI - Incidence of pulmonary embolism: a comparison of two Australian hospitals. AB - In this retrospective observational study, we noted that there were significantly more admissions at the public than the private hospital due to both a principal (1.87 vs 0.83 per 1000, P < 0.001) and secondary diagnosis of pulmonary embolism (PE) (3.10 vs 2.01 per 1000, P = 0.002), with no difference in mortality. There was a highly significant increase in secondary PE diagnoses at the private hospital (R(2) = 0.68, beta = 0.14, P = 0.003) over the study period. Despite disparate rates of PE between the two hospitals, there was no difference in mortality, suggesting there may be an element of overdiagnosis. PMID- 25735579 TI - Does the BRAF(V600E) mutation herald a new treatment era for Erdheim-Chester disease? A case-based review of a rare and difficult to diagnose disorder. AB - Erdheim-Chester disease is a multi-system histiocyte disorder characterised by histological xanthogranulomatous inflammation. We report a 67-year-old man who had fatal multi-systemic Erdheim-Chester disease involvement, including retroperitoneal fibrosis, dilated cardiomyopathy and bone pain that was diagnosed late in its course and was refractory to interferon-alfa. A pathogenic BRAF(V600E) mutation, identified after death in this patient, provides insights into pathogenesis and opens potential lines of treatment. PMID- 25735580 TI - Physicians need to take the lead in deprescribing. AB - Inappropriate polypharmacy and its associated harm pose a significant threat to older patients. The prescribing decisions of physicians greatly influence what other practitioners prescribe. Minimising medication-related harm requires physicians to adopt a systematic approach to the deliberate and judicious deprescribing of potentially inappropriate medicines in at-risk individuals. PMID- 25735581 TI - ANCA-negative crescentic glomerulonephritis closely following two episodes of sepsis. PMID- 25735582 TI - Successful maintenance of molecular remission in chronic myelogenous leukaemia during pregnancy with transition from imatinib to pegylated interferon. PMID- 25735583 TI - Recurrent phaeochromocytoma along the laparoscopic portal sites. PMID- 25735584 TI - Improving the system for managing cancer pain. PMID- 25735585 TI - Familial pulmonary arterial hypertension at a tertiary referral unit: patterns in presentation and prognosis. PMID- 25735586 TI - Ahead of consensus: a paediatric antifungal prophylaxis census. PMID- 25735587 TI - Regional differences in ventilation-perfusion ratio may help explain the differential diagnosis in interstitial lung disease. PMID- 25735588 TI - Arise the systems physician: a comment. PMID- 25735589 TI - [Consensus on the detection and management of prediabetes. Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society]. AB - In Spain, according to the Di@bet.es study, 13.8% of the adult population suffers from diabetes and 14.8% from some form of prediabetes (impaired glucose tolerance, impaired fasting glucose or both). Since early detection of prediabetes can facilitate the implementation of therapeutic measures to prevent its progression to diabetes, we believe that preventive strategies in primary care and specialized clinical settings should be agreed. Screening for diabetes and prediabetes using a specific questionnaire (FINDRISC) and/or the measurement of fasting plasma glucose in high risk patients leads to detecting patients at risk of developing diabetes and it is necessary to consider how they should be managed. The intervention in lifestyle can reduce the progression to diabetes and reverse a prediabetic state to normal and is a cost-effective intervention. Some drugs, such as metformin, have also been shown effective in reducing the progression to diabetes but are not superior to non-pharmacological interventions. Finally, an improvement in some cardiovascular risk factors has been observed although there is no strong evidence supporting the effectiveness of screening in terms of morbility and mortality. The Consensus and Clinical Guidelines Working Group of the Spanish Diabetes Society has issued some recommendations that have been agreed by the Sociedad Espanola de Endocrinologia y Nutricion, Sociedad Espanola de Endocrinologia Pediatrica, Sociedad Espanola de Farmacia Comunitaria, Sociedad Espanola de Medicina Familiar y Comunitaria, Sociedad Espanola de Medicos Generales, Sociedad Espanola de Medicos de Atencion Primaria, Sociedad Espanola de Medicina Interna, Asociacion de Enfermeria Comunitaria and Red de Grupos de Estudio de la Diabetes en Atencion Primaria. PMID- 25735590 TI - Neurotoxicity and synaptic plasticity impairment of N-acetylglucosamine polymers: implications for Alzheimer's disease. AB - We assessed whether polymers of N-acetylglucosamine (GlcNAc) have any pathogenetic role in Alzheimer's disease (AD). First, by using specific dyes, we found deposits of polymers of GlcNAc in sporadic but not in familial AD. We found that neurons and microglia exposed to GlcNAc and uridine diphosphate (UDP)-GlcNAc are able to form GlcNAc polymers, which display a significant neurotoxicity in vitro. Moreover, the exposure of organotypic hippocampal cultures to the same compounds led to synaptic impairment with decreased levels of syntaxin and synaptophysin. In addition, acute hippocampal slices treated with GlcNAc/UDP GlcNAc showed a clear reduction of long-term potentiation of excitatory synapses. Finally, we demonstrated that microglial cells are able to phagocytose chitin particles and, when exposed to GlcNAc/UDP-GlcNAc, show cellular activation and intracellular deposition of GlcNAc polymers that are eventually released in the extracellular space. Taken together, our results indicate that both microglia and neurons produce GlcNAc polymers, which trigger neurotoxicity both directly and through microglia activation. GlcNAc polymer-driven neurotoxicity offers novel pathogenic insights in sporadic AD and new therapeutic options. PMID- 25735591 TI - Vessel network formation in response to intermittent hypoxia is frequency dependent. AB - A combined experimental and mathematical model of intermittent hypoxia (IH) conditioned engineered tissue was used to characterize the effects of IH on the formation of in vitro vascular networks. Results showed that the frequency of hypoxic oscillations has pronounced influence on the vascular response of endothelial cells and fibroblasts. PMID- 25735592 TI - Bioprocess of Kosa bioaerosols: effect of ultraviolet radiation on airborne bacteria within Kosa (Asian dust). AB - Kosa (Asian dust) is a well-known weather phenomenon in which aerosols are carried by the westerly winds from inland China to East Asia. Recently, the frequency of this phenomenon and the extent of damage caused have been increasing. The airborne bacteria within Kosa are called Kosa bioaerosols. Kosa bioaerosols have affected ecosystems, human health and agricultural productivity in downwind areas. In order to develop a new and useful bacterial source and to identify the source region of Kosa bioaerosols, sampling, isolation, identification, measurement of ultraviolet (UV) radiation tolerance and experimental simulation of UV radiation conditions were performed during Kosa bioaerosol transportation. We sampled these bioaerosols using a Cessna 404 airplane and a bioaerosol sampler at an altitude of approximately 2900 m over the Noto Peninsula on March 27, 2010. The bioaerosol particles were isolated and identified as Bacillus sp. BASZHR 1001. The results of the UV irradiation experiment showed that the UV radiation tolerance of Kosa bioaerosol bacteria was very high compared with that of a soil bacterium. Moreover, the UV radiation tolerance of Kosa bioaerosol spores was higher than that of soil bacterial spores. This suggested that Kosa bioaerosols are transported across the atmosphere as living spores. Similarly, by the experimental simulation of UV radiation conditions, the limited source region of this Kosa bioaerosol was found to be southern Russia and there was a possibility of transport from the Kosa source area. PMID- 25735593 TI - The use of validated outcome measures in the chiropractic care of pregnant patients: A systematic review of the literature. AB - BACKGROUND: Healthcare systems recognize the need to incorporate patient-reported outcomes as part of their clinical and research measures. We performed this review on the use of validated outcome measures in the chiropractic care of pregnant patients. METHODS: Pubmed, CINAHL, Medline, Index to Chiropractic Literature and MANTIS were searched for (1) primary investigation reports (i.e., case reports, case series, case control, randomized controlled trials and survey or surveillance studies) published in English; (2) involving the care of pregnant patient(s) and (3) utilizing a valid outcome measure. RESULTS: Our review found 8 articles using the Patient's Global Impression of Change, the NRS, the Oswestry, Bournemouth, Fear Avoidance Belief and Quebec Disability questionnaires, PROMIS 29 and the Measure Yourself Medical Outcome Profile. CONCLUSION: Despite their heterogeneity and inconsistency of use in the studies reviewed, our findings demonstrate some measure of effectiveness in the chiropractic care of pregnant patients. PMID- 25735595 TI - Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction. AB - Age is a risk factor for cardiovascular disease, suggesting a causal relationship between age-related changes and vascular damage. Endothelial dysfunction is an early pathophysiological hallmark in the development of cardiovascular disease. Senescence, the cellular equivalent of aging, was proposed to be involved in endothelial dysfunction, but functional data showing a causal relationship are missing.Endothelium-dependent vasodilation was measured in aortic rings ex vivo. We investigated aortas from aged C57Bl/6 mice (24-28 months), in which p16 (INK4a) and p19 (ARF) expression, markers of stress-induced senescence, were significantly induced compared to young controls (4-6 months). To reflect telomere shortening in human aging, we investigated aortas from telomerase deficient (Terc(-/-)) mice of generation 3 (G3). Endothelium-dependent vasodilation in aged wildtype and in Terc(-/-) G3 mice was impaired. A combination of the superoxide dismutase mimetic 1-Oxyl-2,2,6, 6-tetramethyl-4 hydroxypiperidine (TEMPOL) and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin significantly improved endothelium-dependent vasodilation in aged wildtype and Terc(-/-) G3 mice compared to untreated controls. We show that both, aging and senescence induced by telomere shortening, cause endothelial dysfunction that can be restored by antioxidants, indicating a role for oxidative stress. The observation that cellular senescence is a direct signalling event leading to endothelial dysfunction holds the potential to develop new targets for the prevention of cardiovascular disease. PMID- 25735594 TI - The environmental genomics of metazoan thermal adaptation. AB - Continued and accelerating change in the thermal environment places an ever greater priority on understanding how organisms are going to respond. The paradigm of 'move, adapt or die', regarding ways in which organisms can respond to environmental stressors, stimulates intense efforts to predict the future of biodiversity. Assuming that extinction is an unpalatable outcome, researchers have focussed attention on how organisms can shift in their distribution to stay in the same thermal conditions or can stay in the same place by adapting to a changing thermal environment. How likely these respective outcomes might be depends on the answer to a fundamental evolutionary question, namely what genetic changes underpin adaptation to the thermal environment. The increasing access to and decreasing costs of next-generation sequencing (NGS) technologies, which can be applied to both model and non-model systems, provide a much-needed tool for understanding thermal adaptation. Here we consider broadly what is already known from non-NGS studies about thermal adaptation, then discuss the benefits and challenges of different NGS methodologies to add to this knowledge base. We then review published NGS genomics and transcriptomics studies of thermal adaptation to heat stress in metazoans and compare these results with previous non-NGS patterns. We conclude by summarising emerging patterns of genetic response and discussing future directions using these increasingly common techniques. PMID- 25735596 TI - Morpho-syntactic reading comprehension in children with early and late cochlear implants. AB - This study explores morpho-syntactic reading comprehension in 19 Spanish children who received a cochlear implant (CI) before 24 months of age (early CI [e-CI]) and 19 Spanish children who received a CI after 24 months (late CI [l-CI]). They all were in primary school and were compared to a hearing control (HC) group of 19 children. Tests of perceptual reasoning, working memory, receptive vocabulary, and morpho-syntactic comprehension were used in the assessment. It was observed that while children with l-CI showed a delay, those with e-CI reached a level close to that which was obtained by their control peers in morpho-syntactic comprehension. Thus, results confirm a positive effect of early implantation on morpho-syntactic reading comprehension. Inflectional morphology and simple sentence comprehension were noted to be better in the e-CI group than in the l-CI group. The most important factor in distinguishing between the HC and l-CI groups or the e-CI and l-CI groups was verbal inflectional morphology. PMID- 25735598 TI - Metallophthalocyanin-ocenes: scandium phthalocyanines with an eta(5)-bound Cp ring. AB - A series of new scandium complexes supported by the phthalocyanine (Pc) ligand have been prepared and structurally characterized. Reaction of ScCl3 with phthalonitrile affords a mixture of PcScCl (1) and unreacted ScCl3, which upon addition of LiCH(SiMe3)2 yields THF-soluble PcSc(MU-Cl2)Li(THF)2 (2). Metathesis with NaCp or LiCp* generates PcSc(eta(5)-C5H5) and PcSc(eta(5)-C5Me5), respectively, which represent the first examples of eta(5)-Cp metal phthalocyanines where the Cp fragment sandwiches the metal centre. PMID- 25735599 TI - The structure and properties of graphene on gold nanoparticles. AB - Graphene covered metal nanoparticles constitute a novel type of hybrid material, which provides a unique platform to study plasmonic effects, surface-enhanced Raman scattering (SERS), and metal-graphene interactions at the nanoscale. Such a hybrid material is fabricated by transferring graphene grown by chemical vapor deposition onto closely spaced gold nanoparticles produced on a silica wafer. The morphology and physical properties of nanoparticle-supported graphene are investigated by atomic force microscopy, optical reflectance spectroscopy, scanning tunneling microscopy and spectroscopy (STM/STS), and confocal Raman spectroscopy. This study shows that the graphene Raman peaks are enhanced by a factor which depends on the excitation wavelength, in accordance with the surface plasmon resonance of the gold nanoparticles, and also on the graphene nanoparticle distance which is tuned by annealing at moderate temperatures. The observed SERS activity is correlated with the nanoscale corrugation of graphene. STM and STS measurements show that the local density of electronic states in graphene is modulated by the underlying gold nanoparticles. PMID- 25735600 TI - Nonbacterial thrombotic endocarditis. PMID- 25735597 TI - Ribosomal proteins: functions beyond the ribosome. AB - Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation, their ribosome-independent functions have also been greatly appreciated. Over the past decade, more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress. In addition, these ribosomal proteins are involved in various physiological and pathological processes. This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins, as well as the ribosome independent functions of ribosomal proteins in tumorigenesis, immune signaling, and development. We also propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics. PMID- 25735601 TI - Peptides containing blocks of different charge densities facilitate cell uptake of oligonucleotides. AB - Polyelectrolyte complexes (PECs) are of great importance in drug delivery and gene therapy. The density and the distribution of the charges are key parameters of a polyelectrolyte, determining the structure of the complex and the kinetics of the complexation. Using peptides of precisely-controlled charge density as model molecules, we showed that the presence of weakly-charged peptides, (KGGG)5 or (KGKG)5, did not affect the complexation of highly-charged peptides (KKKK)5 with 21 bp oligonucleotides. However, peptide containing blocks of different charge densities, such as (KKKK)5-b-(KGGG)5 or (KKKK)5-b-(KGKG)5, exhibited superior performance during complexation. With a relatively uniform small size, the complex was also stable in serum. More importantly, the cellular uptake of the complex was greatly enhanced by a ratio of 40-60%, compared to that of the complex formed by uniformly-charged peptides. We attributed the improvement to the structure of the complex, in which the highly-charged blocks form the core with the oligonucleotide whilst the weakly-charged blocks dangle outside, preventing the complexes from further aggregation. PMID- 25735602 TI - Obturator Neuralgia: A Rare Complication of Tension-free Vaginal Tape Sling Complete Resolution After Laparoscopic Tension-free Vaginal Tape Removal. AB - STUDY OBJECTIVE: To show a technique of retropubic tension-free vaginal tape (TVT) removal using both a transvaginal and laparoscopic approach in the treatment of a rare condition, obturator neuralgia. DESIGN: A step-by-step explanation of the patient's condition, diagnosis, surgical technique, and postoperative results using video, pictures, and medical illustrations (education video). SETTING: TVT retropubic slings have become the gold standard for the treatment of stress urine incontinence over the last decade. Despite high cure rates, the TVT is not without potential complications. Typical complications include urine retention, incomplete bladder emptying, frequency, urgency, urethral erosion, vaginal extrusion, vaginal pain, and dyspareunia. The most common complication for sling removal/revision is chronic pain. The TVT obturator neuralgia is a rare and specific type of chronic pain that is normally associated with transobturator tape slings. The purpose of this video is to present an extremely rare complication of TVT retropubic slings, present symptoms and signs of obturator nerve compression, show the normal and the actual position of this patient's TVT sling, describe the laparoscopic removal of the TVT sling, and present the postoperative course and resolution of the patient's pain. The patient signed a release for her video to be used for educational and teaching purposes. INTERVENTION: A combined transvaginal and laparoscopic approach in a patient with lower abdominal, levator, and obturator-type pain after a TVT retropubic procedure. CONCLUSION: In patients suffering from obturator neuralgia after a retropubic sling, surgeons should include the sling as a potential causative factor in the differential diagnosis. Surgeons should consider removing the sling based on the patient's symptoms. If the patient suffers from only vaginal pain and dyspareunia, then the surgeon should consider only the removal of the vaginal portion of the sling. In patients with obturator neuralgia, retropubic, and/or lower abdominal pain, one should consider a combined transvaginal and laparoscopic approach in an attempt to remove the majority of the sling and release tension between 2 points of fixation. PMID- 25735603 TI - Safety in numbers: does perceived safety mediate associations between the neighborhood social environment and physical activity among women living in disadvantaged neighborhoods? AB - OBJECTIVE: The aim of this study is to examine associations between the neighborhood social environment and leisure-time physical activity (LTPA)(1) and walking among women, and whether these associations are mediated by perceived personal safety. METHODS: Women (n = 3784) living in disadvantaged urban and rural neighborhoods within Victoria, Australia completed a self-administered survey on five social environment variables (neighborhood crime, neighborhood violence, seeing others walking and exercising in the neighborhood, social trust/cohesion), perceived personal safety, and their physical activity in 2007/8. Linear regression analyses examined associations between social environment variables and LTPA and walking. Potential mediating pathways were assessed using the product-of-coefficients test. Moderated mediation by urban/rural residence was examined. RESULTS: Each social environment variable was positively associated with engaging in at least 150 min/week of LTPA (OR = 1.16 to 1.56). Only two social environment variables, seeing others walking (OR = 1.45) and exercising (OR = 1.31), were associated with >= 150 min/week of walking. Perceived personal safety mediated all associations. Stronger mediation was found in urban areas for crime, violence and social trust/cohesion. CONCLUSION: The neighborhood social environment is an important influence on physical activity among women living in disadvantaged areas. Feelings of personal safety should not be included in composite or aggregate scores relating to the social environment. PMID- 25735604 TI - Patterns and predictors of state adult obesity prevention legislation enactment in US states: 2010-2013. AB - OBJECTIVE: This study examined bill- and state-level factors associated with enactment of adult obesity prevention legislation in US states. METHODS: A review of bills in the Rudd Center for Food Policy and Obesity's legislative database identified 487 adult obesity prevention bills, or proposed legislation, introduced between 2010 and 2013. Multilevel models were constructed to examine bill- and state-level characteristics associated with enactment. RESULTS: From 2010 to 2013, 81 (17%) of obesity prevention bills introduced were enacted across 35 states and the District of Columbia. Bills introduced in 2010 were more likely to be enacted than in 2013 (OR=9.49; 95% CI: 2.61-34.5). Bills focused on access to healthy food, physical activity, general and educational programs, as well as modifying rules and procedures (e.g., preemption) had greater odds of enactment relative to food and beverage taxes (OR=8.18; 95% CI: 2.85-23.4 healthy food; OR=17.3; 95% CI: 4.55-65.7 physical activity; OR=15.2; 95% CI: 4.80-47.9 general; OR=13.7; 95% CI: 3.07-61.5 rules). CONCLUSION: The year of bill introduction and overall bill enactment rate were related to adult obesity prevention legislation enactment in states. This study highlights the importance of a bill's topic area for enactment and provides insights for advocates and policymakers trying to address enactment barriers. PMID- 25735605 TI - Great Taste, Less Waste: a cluster-randomized trial using a communications campaign to improve the quality of foods brought from home to school by elementary school children. AB - OBJECTIVE: Great Taste, Less Waste (GTLW), a communications campaign, capitalized on the synergy between healthy eating and eco-friendly behaviors to motivate children to bring more fruits and vegetables and fewer sugar-sweetened beverages (SSBs) to school. METHODS: A cluster-randomized trial in Eastern Massachusetts elementary schools in 2011-2012 tested the hypothesis that GTLW would improve the quality of foods from home more than a nutrition-only campaign--Foods 2 Choose (F2C)--or control. Lunch and snack items from home were measured at baseline and 7 months later using digital photography. Mixed linear models compared change in mean servings of fruits, vegetables, and SSBs among groups, and change in mean prevalence of packaging type. Change in prevalence of food items of interest was compared among groups using generalized linear models. RESULTS: Five hundred and eighty-two third and fourth graders from 82 classrooms in 12 schools participated. At follow-up, no significant differences were observed between groups in change in mean servings or change in prevalence of items of interest. No packaging differences were observed. CONCLUSION: GTLW was well received, but no significant changes were observed in the quality of food brought to school. Whether classrooms are an effective environment for change remains to be explored. ClinicalTrials.gov identifier: NCT0157384. PMID- 25735606 TI - Reducing the volume, exposure and negative impacts of advertising for foods high in fat, sugar and salt to children: A systematic review of the evidence from statutory and self-regulatory actions and educational measures. AB - PURPOSE: To identify and review evidence on 1) the effectiveness of statutory and self-regulatory actions to reduce the volume, exposure or wider impact of advertising for foods high in fat, sugar and salt (HFSS) to children, and 2) the role of educational measures. DESIGN/METHODOLOGY/APPROACH: A systematic review of three databases (Medline, CINAHL and PsycINFO) and grey literature was carried out. Relevant evidence included studies evaluating advertising bans and restrictions, advertising literacy programmes and parental communication styles. Relevant media included TV, internet, radio, magazines and newspaper advertising. No studies were excluded based on language or publication date. FINDINGS: Forty seven publications were included: 19 provided evidence for the results of statutory regulation, 25 for self-regulation, and six for educational approaches. Outcome measures varied in approach, quality and results. Findings suggested statutory regulation could reduce the volume of and children's exposure to advertising for foods HFSS, and had potential to impact more widely. Self regulatory approaches showed varied results in reducing children's exposure. There was some limited support for educational measures. DISCUSSION: Consistency in measures from evaluations over time would assist the development and interpretation of the evidence base on successful actions and measures to reduce the volume, exposure and impact of advertising for foods HFSS to children. PMID- 25735607 TI - Symptoms and characteristics of individuals with profound hyponatremia: a prospective multicenter observational study. AB - OBJECTIVES: To assess symptoms and characteristics of hyponatremia, the most common electrolyte disturbance in hospitalized individuals and a condition that is associated with substantial morbidity and mortality. DESIGN: Prospective observational multicenter study. SETTING: Two Swiss academic centers. PARTICIPANTS: Individuals with profound hypoosmolar hyponatremia (sodium<125 mmol/L) (N=298). MEASUREMENTS: All symptoms and complete medical history including current medications, therapy management, and in-hospital outcomes were recorded. RESULTS: The median age of all participants was 71 (interquartile range (IQR) 60-80), 195 (65%) were female, and mean serum sodium value on admission was 120 mmol/L (IQR 116-123 mmol/L). Frequent clinical symptoms were nausea (n=130, 44%), acute vomiting (n=91, 30%), generalized weakness (n=205, 69%), fatigue (n=175, 59%), gait disturbance (n=92, 31%), recurrent falls (n=47, 16%), and acute falls (n=60, 20%). Fractures were reported in 11 participants (4%). More severe symptoms such as acute epileptic seizures and focal neurological deficits were identified in 16 (5%) and 17 (5%) participants, respectively. The most common comorbidities were hypertension (n=199, 67%), congestive heart failure (n=44, 15%), chronic renal failure (n=64, 21%), pulmonary disease (82, 28%), and central nervous system disease (n=114, 38%). During hospitalization, 12 (4%) participants died, and 103 (35%) needed treatment in the intensive care unit. CONCLUSION: A wide spectrum of symptoms accompanies profound hyponatremia. Most participants had moderate symptoms mirroring chronic hyponatremia with brain cell adaptation. Participants with profound hyponatremia had several comorbidities. PMID- 25735608 TI - Late-life homicide-suicide: a national case series in New Zealand. AB - Homicide-suicide is a rare event, but it has a significant impact on the family and community of the perpetrator and victim(s). The phenomenon of late-life homicide-suicide has not been previously studied in New Zealand, and there is only limited data in the international literature. The aim of this study is to systematically review coroners' records of late-life homicide-suicides in New Zealand. After ethics approval was granted, the Coronial Services of New Zealand was approached to provide records of all closed cases with a suicide verdict (age 65+) over a five-year period (July 2007-December 2012). Of the 225 suicides, 4 cases of homicide-suicide were identified (an estimated incidence of 0.12 per 100,000 per persons year). All four perpetrators were men; three had been farmers. Their ages ranged from 65 to 82. One case occurred in the context of an underlying psychiatric illness (psychotic depression in bipolar disorder). Firearms were used in three cases. Two cases were categorized as spousal/consortial subtype, one case as filicide-suicide, and one case as siblicide-suicide. The prospect of major social upheaval in the form of losing their homes was present in all four cases. The findings of this case series were consistent with the limited existing literature on homicide-suicide. Age-related biopsychosocial issues were highlighted in this case series of late-life homicide suicide. Additionally, evaluating firearm licences in high-risk groups may represent a prevention strategy. PMID- 25735609 TI - Angiopoietin-like protein 2 promotes inflammatory conditions in the ligamentum flavum in the pathogenesis of lumbar spinal canal stenosis by activating interleukin-6 expression. AB - PURPOSE: Chronic inflammation is thought to cause ligamentum flavum (LF) degeneration and hypertrophy in lumbar spinal canal stenosis (LSCS). Angiopoietin like protein 2 (Angptl2) is highly expressed in hypertrophied LF. Because Angptl2 regulates interleukin-6 (IL-6) expression in various tissues, we investigated whether IL-6 is expressed in hypertrophied LF and, if so, does Angptl2 induce IL 6 expression in LF fibroblasts. METHODS: LF tissue was obtained from LSCS patients and non-LSCS patients. Polymerase chain reaction (PCR) for Angptl2 and IL-6 genes and immunohistochemistry for IL-6 protein were performed in LF tissue. Fibroblasts from LF tissue were used for in vitro experiments. Expression of integrin alpha5beta1 (an Angptl2 receptor) and Angptl2 binding to receptors on LF fibroblasts were examined by fluorescence-activated cell sorter analysis and cell adhesion assays. After Angptl2 recombinant protein treatment, NF-kappaB activation and IL-6 expression in LF fibroblasts were investigated by immunocytochemistry, PCR, and enzyme-linked immunosorbent assay. RESULTS: IL-6 mRNA expression was increased in hypertrophied LF tissue from LSCS patients and positively correlated with LF thickness and Angptl2 mRNA expression. IL-6 protein was highly expressed in LF fibroblasts in hypertrophied LF tissue. In vitro experiments demonstrated integrin alpha5beta1 expression on LF fibroblasts and Angptl2 binding to cells via receptors. Angptl2 stimulation promoted NF-kappaB nuclear translocation and induced IL-6 expression and secretion in LF fibroblasts. CONCLUSIONS: Angptl2 promotes inflammation in LF tissue by activating IL-6 expression, leading to LF degeneration and hypertrophy. PMID- 25735610 TI - Incidental durotomy in spine surgery: first aid in ten steps. AB - INTRODUCTION: Incidental durotomy (ID) is the most common complication of spine surgery. Revision procedures, ossification of the yellow ligament, or synovial cysts are well-known risk factors. The size, shape, and severity of ID are unpredictable, ranging from a pinpoint hole to a several centimeters large dural laceration with transected fibers following the slippage of a cutting burr. Furthermore, the occurrence of ID is always unexpected. Intra-operative management is often based on a steep learning curve rather than a structured scheme. PURPOSE: To provide an intra-operative ten-step closure technique (10ST) for IDs of varying severity. METHODS: A database of 4020 consecutive surgeries for lumbar degenerative disease over the past 4 years was searched for ID. The records of 176 patients were analyzed. Two dural repair techniques were compared: the "individual" technique (InT) and the 10ST. RESULTS: The overall prevalence of ID was 4.4%. The prevalence was lowest in virgin micro-discectomies (1.7%) and ranged from 3.6% in decompression for spinal canal stenosis up to 14.5% in revision procedures. All surgeries were performed with the aid of a microscope. Among 107 primary surgeries, the InT achieved a single-stage closure of the ID in 96 procedures (89.7%). Among 20 virgin surgeries, the 10ST was successful in all cases (P = 0.21). Among 42 re-do procedures following failed attempts to stop cerebrospinal fluid (CSF) leakage, the InT achieved single-stage closure in 36 procedures (85.7%). The 10ST was successful in all 26 cases (P = 0.03). The follow-up was 1 year. CONCLUSIONS: The 10ST should be considered for successful single-stage closure in primary repair of ID. PMID- 25735611 TI - Bulimia nervosa: online interventions. AB - INTRODUCTION: Up to 1% of people in the community may have bulimia nervosa, characterised by an intense preoccupation with body weight, binge-eating episodes, and use of extreme measures to counteract the feared effects of overeating. People with bulimia nervosa are of normal weight or are overweight, making the condition distinct from anorexia nervosa. After 10 years, about half of people with bulimia nervosa will have recovered fully, one third will have made a partial recovery, and 10% to 20% will still have symptoms. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of online interventions for people with bulimia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found eight studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: applications (apps) or online programmes used as an adjunct to face-to-face therapy, delivery of self-help online, and delivery of therapy online. PMID- 25735612 TI - Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy. AB - The superfamily of organic anion-transporting polypeptides (OATPs, gene symbol SLCO) includes important transporters handling a variety of endogenous and xenobiotic substrates. Currently, 11 human OATPs are known and their substrates include endogenous hormones and their conjugates, anticancer drugs, and imaging agents. The contribution of OATPs to the in vivo disposition of these substrates has been extensively investigated. An accumulating body of evidence also indicates that the expression of some OATPs may be up- or downregulated in several types of cancers, suggesting potential pathogenic roles during the development and progression of cancer. Given that the role of OATPs in handling cancer therapeutics has been already covered by several excellent reviews, this review will focus on the recent progresses on the topic, in particular the role of OATPs in the disposition of anticancer drugs, the impact of OATP genetic variations on the function of OATPs, and the OATPs differentially expressed in cancer and their potential roles in cancer development, progression, and treatment. PMID- 25735614 TI - Accuracy of Vigileo/Flotrac monitoring system in morbidly obese patients. AB - PURPOSE: Our goal was to assess the accuracy of measuring cardiac output (CO) by the FloTrac/Vigileo (CO(V)) device in comparison with thermodilution technique through pulmonary artery catheterization (PAC(TD)) in morbidly obese patients. MATERIAL AND METHODS: Cardiac output in 8 morbidly obese patients was assessed twice at upright and lying position breathing ambient air. At least 4 consecutive CO measurements with 10 mL of ice-cold saline injections were performed each time. Simultaneous CO measurements were recorded with both single-bolus thermodilution and CO(V). RESULTS: One hundred thirty-two CO data pairs were collected. The overall mean single-bolus thermodilution 6.2 +/- 1.1 L/min was lower than the overall mean CO(V) 7.8 +/- 1.6 L/min (P < .001). Lin concordance coefficient indicated that overall agreement between PAC(TD) and CO(V) was poor, 0.29. Lin concordance coefficient in sitting position was 0.29, 95% confidence interval (0.17-0.40) and in lying position was 0.30, 95% confidence interval (0.15-0.44). The Bland-Altman plot analysis showed systematically higher values from CO(V) in comparison with PAC(TD). These differences increased in presence of high CO measurements. In 3 of 8 patients, the percentage error was lower than 20%, whereas in the other 5, it was higher than 20%. Of these 5, in 2 cases, the percentage error was greater than 50%. CONCLUSION: Data obtained using CO(V) vs PAC(TD) measurements showed poor correlation. The results were not interchangeable. PMID- 25735613 TI - Virtual anthropology: useful radiological tools for age assessment in clinical forensic medicine and thanatology. AB - Virtual anthropology consists of the introduction of modern slice imaging to biological and forensic anthropology. Thanks to this non-invasive scientific revolution, some classifications and staging systems, first based on dry bone analysis, can be applied to cadavers with no need for specific preparation, as well as to living persons. Estimation of bone and dental age is one of the possibilities offered by radiology. Biological age can be estimated in clinical forensic medicine as well as in living persons. Virtual anthropology may also help the forensic pathologist to estimate a deceased person's age at death, which together with sex, geographical origin and stature, is one of the important features determining a biological profile used in reconstructive identification. For this forensic purpose, the radiological tools used are multislice computed tomography and, more recently, X-ray free imaging techniques such as magnetic resonance imaging and ultrasound investigations. We present and discuss the value of these investigations for age estimation in anthropology. PMID- 25735615 TI - Differential microfluidic sensor on printed circuit board for biological cells analysis. AB - Coulter principal based resistive pulse sensor has been demonstrated as an important platform in biological cell detection and enumeration since several decades ago. Recently, the miniaturized micro-Coulter counter has attracted much attention due to its advantages in point of care diagnostics for on chip detection and enumeration of rare cells, such as circulating tumor cells. In this paper, we present a microfluidic cytometer with differential amplifier based on Coulter principle on a SU-8 coated printed circuit board substrate. The electrical current changes induced by the blockage of the microparticles in the sensing aperture are calibrated by polystyrene particles of standard size. Finally, HeLa cells are used to evaluate the performance of the proposed device for enumeration of biological samples. The proposed cytometer is built upon the cheap and widely available printed circuit board substrate and shows its great potential as personalized healthcare monitor. PMID- 25735616 TI - A Nonlinear Size-Dependent Equivalent Circuit Model for Single-Cell Electroporation on Microfluidic Chips. AB - Electroporation (EP) is a process of applying a pulsed intense electric field on the cell membrane to temporarily induce nanoscale electropores on the plasma membrane of biological cells. A nonlinear size-dependent equivalent circuit model of a single-cell electroporation system is proposed to investigate dynamic electromechanical behavior of cells on microfluidic chips during EP. This model consists of size-dependent electromechanical components of a cell, electrical components of poration media, and a microfluidic chip. A single-cell microfluidic EP chip with 3D microelectrode arrays along a microchannel is designed and fabricated to experimentally analyze the permeabilization of a cell. Predicted electrical current responses of the model are in good agreement (average error of 6%) with that of single-cell EP. The proposed model can successfully predict the time responses of transmembrane voltage, pore diameter, and pore density at four different stages of permeabilization. These stages are categorized based on electromechanical changes of the lipid membrane. The current-voltage characteristic curve of the cell membrane during EP is also investigated at different EP stages in detail. The model can precisely predict the electric breakdown of different cell lines at a specific critical cell membrane voltage of the target cell lines. PMID- 25735617 TI - Clinicians' Perception of Patient Readiness for Treatment: An Emerging Theme in Implementation Science? AB - Despite a training program to help veterans administration (VA) clinicians implement evidence-based psychotherapies (EBPs) for posttraumatic stress disorder (PTSD), uptake has been limited. To understand clinicians' implementation challenges, we performed thematic analysis of semi-structured telephone interviews guided by the Promoting Action on Research Implementation in Health Services framework. Our sample included 22 psychotherapists in VA PTSD clinics in one region. We identified a theme not captured by our implementation framework: clinicians' perceptions about their patients' readiness for treatment. Clinician perception of patient readiness may be important to the uptake of EBPs and should be considered in mental health implementation work. PMID- 25735618 TI - Characteristics of Successful and Unsuccessful Mental Health Referrals of Refugees. AB - In this community based participatory research study, we explored key characteristics of mental health referrals of refugees using stories of providers collected through an on-line survey. Ten coders sorted 60 stories of successful referrals and 34 stories of unsuccessful referrals into domains using the critical incident technique. Principal components analysis yielded categories of successful referrals that included: active care coordination, establishing trust, proactive resolution of barriers, and culturally responsive care. Unsuccessful referrals were characterized by cultural barriers, lack of care coordination, refusal to see refugees, and system and language barriers. Recommendations for training and policy are discussed. PMID- 25735620 TI - Visualizing Risk: Images, Risk and Fear in a Health Campaign. AB - This essay considers the structure of risk in health campaign formation and design by examining an early 20th century federal campaign to reduce infant mortality. Health campaigns navigate the gap between study and practice, translating quantitative findings into prescriptive responses for individual consumers of the text. By focusing specifically on the visual rhetoric of risk, this campaign serves as a case study to examine how the public was taught to see and understand risk and preventive health at a critical point in the development of public health in the United States. PMID- 25735619 TI - Implementing a Measurement Feedback System in Community Mental Health Clinics: A Case Study of Multilevel Barriers and Facilitators. AB - Measurement feedback systems (MFSs) have been proposed as a means of improving practice. The present study examined the implementation of a MFS, the Contextualized Feedback System (CFS), in two community-based clinic sites. Significant implementation differences across sites provided a basis for examining factors that influenced clinician uptake of CFS. Following the theoretical implementation framework of Aarons et al. (Adm Policy Mental Health Mental Health Serv Res 38(1):4-23, 2011), we coded qualitative data collected from eighteen clinicians (13 from Clinic U and 5 from Clinic R) who participated in semi-structured interviews about their experience with CFS implementation. Results suggest that clinicians at both clinics perceived more barriers than facilitators to CFS implementation. Interestingly, clinicians at the higher implementing clinic reported a higher proportion of barriers to facilitators (3:1 vs. 2:1); however, these clinicians also reported a significantly higher level of organizational and leadership supports for CFS implementation. Implications of these findings are discussed. PMID- 25735621 TI - Multi-detector CT and MRI of microembolized myocardial infarct: monitoring of left ventricular function, perfusion, and myocardial viability in a swine model. AB - BACKGROUND: Patients with acute myocardial infarct (MI) show additional damage after coronary interventions. PURPOSE: To longitudinally quantify structural and functional changes in the left ventricle (LV) subjected to microembolized MI using multidisciplinary computed tomography (MDCT) and independent reference methods. MATERIAL AND METHODS: Swine (n = 20) served as controls (group I) or were subjected to a combination of coronary occlusion, microembolization, and reperfusion and imaged at 3 days (group II) or 3 days and 5 weeks (group III). LV volumes, perfusion, and MI mass were quantified on cine, perfusion, and delayed contrast enhancement (DE) MDCT. MRI, cardiac injury biomarkers, histochemical and histopathologic stains were used as independent references. RESULTS: MDCT showed a reduction in ejection fraction and increased end systolic volume (31 +/- 2% and 82 +/- 3 mL, respectively) of group III compared with I (48 +/- 2% and 57 +/- 1 mL, respectively). It also demonstrated perfusion deficits in microembolized MI and peri-infarcts. DE-MDCT delineated microvascular obstruction (MVO) zones embedded in acute microembolized MI and microinfarct specks resulting from persistent MVO by deposited microemboli in microvessels of peri-infarct zone. Bland-Altman test showed close agreements between the extents of microembolized MI measured on DE-MDCT, DE-MRI, and histochemical TTC staining, but not between these modalities and microscopy. MI resorption was evident between 3 days and 5 weeks (13.4 +/- 0.5 g and 9.8 +/- 0.5 g, P < 0.017) and histologic examination revealed incomplete healing. Injury biomarkers were increased after intervention. CONCLUSION: MDCT can longitudinally quantify regional perfusion deficits, LV dysfunction, and resorption of microembolized MI. MDCT or MRI can be used alternatively after coronary interventions in cases of contraindications for one modality or the other. PMID- 25735622 TI - Topographic distribution and characteristics of normal gastric regional lymph nodes on diffusion-weighted magnetic resonance imaging. AB - BACKGROUND: Current lack of recognition of normal gastric regional lymph nodes (GRLNs) and inherent defect of morphological imaging limit the accuracy of preoperative nodal (N) staging of gastric cancer. PURPOSE: To map the distribution of normal GRLNs and evaluating the characteristics of GRLNs with diffusion-weighted imaging (DWI) in healthy population. MATERIAL AND METHODS: Forty-nine enrolled healthy volunteers were divided into two age groups and underwent conventional magnetic resonance imaging (MRI) and DWI examinations. The characteristics of GRLNs in 14 regional stations, including short axis diameter (SD), short-to-long axis diameter ratio (SLR), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and apparent diffusion coefficient (ADC), were recorded and compared between age groups and among different stations. RESULTS: The normal GRLNs were mainly distributed in station 7 in both age groups, followed by stations 3, 8, and 9. The SLR was lower in the young group than in the old group (P = 0.034) while SD, SNR, CNR, and ADC were significantly higher in the young group compared to the old group, P = 0.045, 0.041, 0.037, and 0.042, respectively. SD was different among stations in both age groups (P = 0.002, 0.001), especially bigger in station 8, and the SNRs and CNRs of stations 8 and 9 were relatively high in the old group (P = 0.031, 0.035), while there was no difference in ADC value. CONCLUSION: Better understanding of the appearances of normal GRLNs on conventional MRI and DWI may help to build more appropriate imaging criteria for GRLN assessment in gastric cancer. PMID- 25735623 TI - Association of goal orientation with work engagement and burnout in emergency nurses. AB - OBJECTIVES: Goal orientation is a mindset towards the achievement of work-related goals, and it has been found to be related to occupational well-being. This study explored to what extent the 4-dimensional model of goal orientation adds additional variance to the explanation of burnout and work engagement in emergency nurses, after controlling for demographics, job characteristics and organizational variables. METHODS: Self-report questionnaires including the Leiden Quality of Work Questionnaire for Nurses, Goal Orientation Questionnaire, Maslach Burnout Inventory and Utrecht Work Engagement Scale were completed by 170 out of 274 emergency nurses from 13 secondary Belgian hospitals (response rate 62%). Hierarchical multiple regression analyses were conducted. RESULTS: Goal orientation explained 14 and 13% of the variance in burnout and work engagement respectively. Job control was predictive of both outcomes. Job demands was a predictor of burnout, and social support predicted work engagement. Reward was related to work engagement. The mastery-approach goal orientation was strongly related to an increase in work engagement and to a decrease in burnout. The performance-avoidance goal orientation was strongly related to a decrease in work engagement and to an increase in burnout. The performance-approach and mastery avoidance goal orientations were not predictive for the two outcome variables. CONCLUSIONS: Goal orientation explains additional variance in burnout and work engagement over and above work characteristics and organizational variables. A mastery-approach goal orientation appears to be beneficial while a performance avoidance goal orientation is not. Hospital management should therefore invest in personal involvement and growth of ER-nurses and in a rewarding organizational culture. PMID- 25735624 TI - Possible production of arsenic hemoglobin adducts via exposure to arsine. AB - OBJECTIVES: Arsine is an arsenic compound generated as a by-product in metal refineries. Accidental poisoning occurs sporadically; however, the administrative level for workers has not been established. Thus, it is essential to identify a highly specific biomarker for risk management in the workplace. The aim of this study was to identify an arsenic adduct, a potential biomarker, in the plasma. METHODS: Preserved mouse blood was exposed to arsine in vitro, and the plasma was separated. The residual clot of the control sample was hemolyzed using ultrapure water, and the supernatant was collected. Plasma from mice exposed to arsine in vivo was also separated from blood. Immunoprecipitation assays were conducted using all samples after ultrafiltration, and three fractions were collected. The total arsenic concentration in each fraction was quantified using inductively coupled plasma mass spectrometry (ICP-MS). The three in vitro samples and the eluate fraction from immunoprecipitation were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: In the exposed samples, the arsenic concentration in the fraction containing immunocomplexes was higher when immunoprecipitation was conducted with an anti globin antibody. Three peaks were specifically observed in arsine-exposed samples after MALDI-TOF-MS analysis. Two of them were around m/z 15,000, and the other was m/z 15,700. The latter peak was confirmed even after immunoprecipitation. CONCLUSIONS: Globin forms an adduct with arsenic after both in vitro and in vivo exposure to arsine. This adduct together with hemoglobinuria could be a candidate biomarker of acute arsine poisoning in plasma. PMID- 25735625 TI - Organizational justice and insomnia: Relationships between justice components and insomnia symptoms among private company workers in Japan. AB - OBJECTIVES: Organizational justice (OJ) is an important psychosocial factor and it consists of several components. Previous studies have shown that low perceived OJ is associated with various health problems. However, the relationships between each justice component and health outcomes have not been fully examined. The purpose of this study was to clarify the relationships between OJ and insomnia, including OJ components and insomnia symptoms. METHODS: Cross-sectional self reported questionnaire data from 1,893 employees (92.2% of subjects) were collected. OJ was measured using the Japanese version of the OJ questionnaire, which has four components (distributive, procedural, interpersonal and informational). Insomnia was assessed with the Athens Insomnia Scale. Logistic regression analysis, with insomnia as a dependent variable and OJ as an independent variable, was conducted. RESULTS: Subjects with low overall OJ had a higher risk of insomnia (adjusted odds ratio (AOR), 2.37; 95% confidence interval (CI), 1.59 to 3.53) and two insomnia symptoms (AOR of 2.47 and 95% CI of 1.68 to 3.65 for sleep induction problem; AOR of 1.73 and 95% CI of 1.21 to 2.48 for sleep maintenance problem). The four justice components were all associated with insomnia and sleep induction problems. Sleep maintenance problems were associated with only the distributive justice component. CONCLUSIONS: All four justice components were associated with both insomnia and sleep induction problems. Sleep maintenance problems, however, showed different features. Specifically, the distributive justice component seemed to be a key factor in the relationship between OJ and insomnia. These findings might provide useful information for preventing the adverse effects of insomnia. PMID- 25735626 TI - Promising biological monitoring for occupational 1,2-Dichloropropane exposure by urinalysis for unmetabolized solvent. AB - OBJECTIVES: The aim of this study was to examine the applicability of urinalysis for unmetabolized solvent to biomonitor 1,2-dichloropropane (1,2-DCP) exposure. METHODS: Thirty three male printers exposed to 1,2-DCP and 5 nonexposed male controls participated in the study. The 8-hr average levels of exposure to 1,2 DCP in air and 1,2-DCP in the end-of-shift urine samples were measured with capillary FID-GC. RESULTS: The geometric mean (the maximum) concentrations was 7.1 ppm (23.1 ppm) for 1,2-DCP in air, and the level in urine (without correction for urine density) was 77 ug/l (247 ug/l). A regression analysis showed a correlation coefficient of 0.909 (p<0.01). No 1,2-DCP was detected in the urine samples from nonexposed subjects. CONCLUSIONS: The high correlation and low background (essentially zero) showed that urinalysis for unmetabolized 1,2-DCP is a promising tool for biomonitoring of occupational exposure to this carcinogenic solvent at lower levels (e.g. <1 ppm). PMID- 25735627 TI - Properties of ammonium ion-water clusters: analyses of structure evolution, noncovalent interactions, and temperature and humidity effects. AB - Although ammonium ion-water clusters are abundant in the biosphere, some information regarding these clusters, such as their growth route, the influence of temperature and humidity, and the concentrations of various hydrated clusters, is lacking. In this study, theoretical calculations are performed on ammonium ion water clusters. These theoretical calculations are focused on determining the following characteristics: (1) the pattern of cluster growth; (2) the percentages of clusters of the same size at different temperatures and humidities; (3) the distributions of different isomers for the same size clusters at different temperatures; (4) the relative strengths of the noncovalent interactions for clusters of different sizes. The results suggest that the dipole moment may be very significant for the ammonium ion-water system, and some new stable isomers were found. The nucleation of ammonium ions and water molecules is favorable at low temperatures; thus, the clusters observed at high altitudes might not be present at low altitudes. High humidity can contribute to the formation of large ammonium ion-water clusters, whereas the formation of small clusters may be favorable under low-humidity conditions. The potential energy surfaces (PES) of these different sized clusters are complicated and differ according to the distribution of isomers at different temperatures. Some similar structures are observed between NH4(+)(H2O)n and M(H2O)n (where M represents an alkali metal ion or water molecule); when n = 8, the clusters begin to form the closed-cage geometry. As the cluster size increases, these interactions become progressively weaker. The successive binding energy at the DF-MP2-F12/VDZ-F12 level is better than that at the PW91PW91/6-311++G(3df, 3pd) level and is consistent with the experimentally determined values. PMID- 25735628 TI - Characterization of two pigeon paramyxovirus type 1 isolates in China. AB - For over three decades, there has been a continuing panzootic caused by a virulent variant avian paramyxovirus type 1 strain, the so-called pigeon paramyxovirus type 1. It is found primarily in racing pigeons, but it has also spread to wild birds and poultry. In this study, two pigeon paramyxovirus type 1 strains, SD12 and BJ13, obtained from diseased pigeons in China, were characterized. Phylogenetic analysis based on complete sequences allowed characterization of both strains as genotype VI, class II. Further phylogenetic analysis of a 374-nucleotide section of the fusion gene showed that SD12 fell into lineage VIbii-d and BJ13 into VIbii-f. The deduced amino acid sequence of the cleavage site of the fusion protein confirmed that both isolates contained the virulent motif (112)K/RRQKR?F(117) at the cleavage site. Nevertheless, the values of intracerebral pathogenicity indices showed the SD12 isolate to be a velogenic strain and BJ13 isolate to be a mesogenic strain. The SD12 isolate was further investigated via clinical observation, RNA detection, histopathology and viral serology in experimentally infected 3-week-old chickens. It showed a mild pathological phenotype in chickens, with viral replication restricted to a few tissues. The molecular mechanism for the SD12 isolate to have a virulent motif but low levels of virulence for chickens requires further study. PMID- 25735629 TI - Oncostatin M Promotes Osteoblastic Differentiation of Human Vascular Smooth Muscle Cells Through JAK3-STAT3 Pathway. AB - Vascular calcification is a clinically significant component of atherosclerosis and arises from chronic vascular inflammation. Oncostatin M (OSM) derived from plaque macrophages may contribute to the development of atherosclerotic calcification. Here, we investigated the stimulatory effects of OSM on osteoblastic differentiation of human vascular smooth muscle cells (HVSMC) derived from various arteries including umbilical artery, aorta, and coronary artery and its signaling pathway. Osteoblastic differentiation was induced by exposure of HVSMC to osteogenic differentiation medium (ODM) (10% fetal bovine serum, 0.1 MUM dexamethasone, 10 mM beta-glycerophosphate and 50 MUg/ml ascorbic acid 2-phosphate in Dulbecco's modified Eagle's medium [DMEM]). OSM significantly increased alkaline phosphate (ALP) activity and matrix mineralization in HVSMC from all sources. Osteoblast marker genes such as ALP and Runx2 were also up regulated by OSM in these cells. OSM treatment induced activation of STAT3 in HVSMC from umbilical artery as evidenced by immunoblot. Moreover, not only a JAK3 inhibitor, WHI-P154, but also knockdown of JAK3 by siRNA prevented the OSM induced ALP activity and matrix mineralization in umbilical artery HVSMC. On the other hand, silencing of STAT3 almost completely suppressed OSM-induced ALP expression and matrix mineralization in HVSMC from all sources. These data suggest that OSM promotes osteoblastic differentiation of vascular smooth muscle cells through JAK3/STAT3 pathway and may contribute to the development of atherosclerotic calcification. PMID- 25735630 TI - [Eye muscle surgery]. AB - Eye muscle surgery is as a rule surgery on healthy eyes. It therefore requires particularly high standards in terms of a lack of complications and predictability of surgical results. Misalignment of the eyes, binocular diplopia and ocular torticollis are all indications for eye muscle surgery as are enlargement of the binocular visual field, asthenopic complaints in heterophoria or the stabilization of binocular functions. Eye muscle surgery is binocular surgery and differs from monocular surgery. It has its own complications and requires specific skills. PMID- 25735631 TI - [Pseudodominant inheritance of pseudoxanthoma elasticum]. AB - Pseudoxanthoma elasticum (PXE) is a system disease due to mutations in the ABCC6 gene with characteristic alterations in the eyes, the skin and the cardiovascular system. Herein, we report on two families with PXE in two subsequent generations due to genetically confirmed pseudodominance. A literature review revealed that PXE due to mutations in ABCC6 follows an autosomal recessive inheritance and that disease manifestation in two subsequent generations is due to pseudodominance. PMID- 25735632 TI - [Bilateral retinal artery occlusion]. PMID- 25735633 TI - Corrigendum: Force-dependent conformational switch of alpha-catenin controls vinculin binding. PMID- 25735635 TI - Response to: "Prediction of Voriconazole Non-Linear Pharmacokinetics Using a Paediatric Physiologically Based Pharmacokinetic Modelling Approach". PMID- 25735636 TI - Seminal fluid promotes in vitro sperm-oviduct binding in the domestic cat (Felis catus). AB - From many endangered or threatened species which are expected to profit from assisted reproduction techniques, mainly epididymal sperm of dead or freshly castrated males are available. These sperm had contact to epididymal secretion products but not to seminal fluid components. Notably, products of accessory sex glands have been shown in domestic animals to condition sperm for fertilization, in particular by mediating sperm-oviduct interaction. We report for the first time that motile epididymal sperm from domestic cats are able to bind to fresh oviduct epithelial cell explants from preovulatory females (median [min, max] of 10 [8, 16] and 10 [8, 17] sperm per 0.01 mm(2) explant surface from both isthmic and ampullar regions, respectively). More sperm attach to the explants when epididymal sperm were preincubated for 30 minutes with seminal fluid separated from electroejaculates of mature tomcats (median [min, max] of 17 [13, 25] and 16 [12, 21] sperm per 0.01 mm(2) explant surface from isthmus and ampulla, respectively). The proportion of bound sperm increased from a median of 54% to 62% by seminal fluid treatment. Sperm-oviduct binding could be facilitated by the decelerated sperm motion which was observed in seminal fluid-treated samples or supported by seminal fluid proteins newly attached to the sperm surface. Seminal fluid had no effect on the proportion of sperm with active mitochondria. Extent and pattern of sperm interaction in vitro were independent of explant origin from isthmus or ampulla. Sperm were attached to both cilia and microvilli of the main epithelial cell types present in all explants. In contrast to published sperm binding studies with porcine and bovine oviduct explants where predominantly the anterior head region of sperm was attached to ciliated cells, the tails of some cat sperm were firmly stuck to the oviduct cell surfaces, whereas the heads were wobbling. Whether this response is a preliminary step toward phagocytosis or a precondition to capacitation and fertilization remains to be determined. In conclusion, treatment of epididymal sperm with seminal fluid or particular protein components should be considered in future investigations for its potential to improve the outcome of artificial insemination in felids. PMID- 25735634 TI - Clinical pharmacokinetics of inhaled antimicrobials. AB - Administration of inhaled antimicrobials affords the ability to achieve targeted drug delivery into the respiratory tract, rapid entry into the systemic circulation, high bioavailability and minimal metabolism. These unique pharmacokinetic characteristics make inhaled antimicrobial delivery attractive for the treatment of many pulmonary diseases. This review examines recent pharmacokinetic trials with inhaled antibacterials, antivirals and antifungals, with an emphasis on the clinical implications of these studies. The majority of these studies revealed evidence of high antimicrobial concentrations in the airway with limited systemic exposure, thereby reducing the risk of toxicity. Sputum pharmacokinetics varied widely, which makes it challenging to interpret the result of sputum pharmacokinetic studies. Many no vel inhaled antimicrobial therapies are currently under investigation that will require detailed pharmacokinetic studies, including combination inhaled antimicrobial therapies, inhaled nanoparticle formulations of several antibacterials, inhaled non antimicrobial adjuvants, inhaled antiviral recombinant protein therapies and semi synthetic inhaled antifungal agents. Additionally, the development of new inhaled delivery devices, particularly for mechanically ventilated patients, will result in a pressing need for additional pharmacokinetic studies to identify optimal dosing regimens. PMID- 25735637 TI - Sex and laterality differences in parkinsonian impairment and transcranial ultrasound in never-treated schizophrenics and their first degree relatives in an Andean population. AB - We tested the hypothesis that loss of substantia nigra neurons in subjects at risk of schizophrenia (1), as reflected by midbrain hyperechogenicity (2) and parkinsonian motor impairment (3), is asymmetric and influenced by sex. We evaluated 62 subjects with never-treated chronic schizophrenia, 80 of their adult, unaffected first degree relatives and 62 healthy controls (matched by sex and age to the cases), part of an Andean population of Northern Argentina. Parkinsonism was scored blindly using UPDRS-3 (Unified Parkinson's Disease Rating Scale) on videotaped exams by 2 independent raters. Transcranial ultrasound was performed by an expert sonographist blind to subject condition with a 2.5 MHz transducer through a temporal bone window. Quantification of echogenic area was carried out on saved images by a different evaluator. We found a significant difference in parkinsonian motor impairment between patients, their relatives as well as controls. All three groups showed worse parkinsonism on the left side than the right, corresponding with increased echogenicity on the right substantia nigra compared with the left. Females had significantly more right echogenicity than males, and patients and unaffected relatives were significantly more echogenic than controls on that side. On the left, only female patients had significant echogenicity. Our data supports the notion that unaffected relatives of schizophrenic subjects have increased parkinsonism and concomitant brainstem abnormalities which may represent a vulnerability to the disease. Both motor and brainstem abnormalities are asymmetric and influenced by sex. PMID- 25735638 TI - Host-induced gene silencing of an essential chitin synthase gene confers durable resistance to Fusarium head blight and seedling blight in wheat. AB - Fusarium head blight (FHB) and Fusarium seedling blight (FSB) of wheat, caused by Fusarium pathogens, are devastating diseases worldwide. We report the expression of RNA interference (RNAi) sequences derived from an essential Fusarium graminearum (Fg) virulence gene, chitin synthase (Chs) 3b, as a method to enhance resistance of wheat plants to fungal pathogens. Deletion of Chs3b was lethal to Fg; disruption of the other Chs gene family members generated knockout mutants with diverse impacts on Fg. Comparative expression analyses revealed that among the Chs gene family members, Chs3b had the highest expression levels during Fg colonization of wheat. Three hairpin RNAi constructs corresponding to the different regions of Chs3b were found to silence Chs3b in transgenic Fg strains. Co-expression of these three RNAi constructs in two independent elite wheat cultivar transgenic lines conferred high levels of stable, consistent resistance (combined type I and II resistance) to both FHB and FSB throughout the T3 to T5 generations. Confocal microscopy revealed profoundly restricted mycelia in Fg infected transgenic wheat plants. Presence of the three specific short interfering RNAs in transgenic wheat plants was confirmed by Northern blotting, and these RNAs efficiently down-regulated Chs3b in the colonizing Fusarium pathogens on wheat seedlings and spikes. Our results demonstrate that host induced gene silencing of an essential fungal chitin synthase gene is an effective strategy for enhancing resistance in crop plants under field test conditions. PMID- 25735639 TI - Impacts of early viability selection on management of inbreeding and genetic diversity in conservation. AB - Maintaining genetic diversity is a crucial goal of intensive management of threatened species, particularly for those populations that act as sources for translocation or re-introduction programmes. Most captive genetic management is based on pedigrees and a neutral theory of inheritance, an assumption that may be violated by selective forces operating in captivity. Here, we explore the conservation consequences of early viability selection: differential offspring survival that occurs prior to management or research observations, such as embryo deaths in utero. If early viability selection produces genotypic deviations from Mendelian predictions, it may undermine management strategies intended to minimize inbreeding and maintain genetic diversity. We use empirical examples to demonstrate that straightforward approaches, such as comparing litter sizes of inbred vs. noninbred breeding pairs, can be used to test whether early viability selection likely impacts estimates of inbreeding depression. We also show that comparing multilocus genotype data to pedigree predictions can reveal whether early viability selection drives systematic biases in genetic diversity, patterns that would not be detected using pedigree-based statistics alone. More sophisticated analysis combining genomewide molecular data with pedigree information will enable conservation scientists to test whether early viability selection drives deviations from neutrality across wide stretches of the genome, revealing whether this form of selection biases the pedigree-based statistics and inference upon which intensive management is based. PMID- 25735640 TI - Quantitative detection of nitric oxide in exhaled human breath by extractive electrospray ionization mass spectrometry. AB - Exhaled nitric oxide (eNO) is a useful biomarker of various physiological conditions, including asthma and other pulmonary diseases. Herein a fast and sensitive analytical method has been developed for the quantitative detection of eNO based on extractive electrospray ionization mass spectrometry (EESI-MS). Exhaled NO molecules selectively reacted with 2-phenyl-4, 4, 5, 5 tetramethylimidazoline-1-oxyl-3-oxide (PTIO) reagent, and eNO concentration was derived based on the EESI-MS response of 1-oxyl-2-phenyl-4, 4, 5, 5 tetramethylimidazoline (PTI) product. The method allowed quantification of eNO below ppb level (~0.02 ppbv) with a relative standard deviation (RSD) of 11.6%. In addition, eNO levels of 20 volunteers were monitored by EESI-MS over the time period of 10 hrs. Long-term eNO response to smoking a cigarette was recorded, and the observed time-dependent profile was discussed. This work extends the application of EESI-MS to small molecules (<30 Da) with low proton affinity and collision-induced dissociation efficiency, which are usually poorly visible by conventional ion trap mass spectrometers. Long-term quantitative profiling of eNO by EESI-MS opens new possibilities for the research of human metabolism and clinical diagnosis. PMID- 25735641 TI - Dendritic cell-based autologous tumor vaccines for head and neck squamous cell carcinoma. AB - BACKGROUND: An autologous vaccine of apoptotic tumor cells (ATCs) and dendritic cells (DCs) was administered to patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) to study safety and feasibility. METHODS: Autologous DCs were generated from monocytes, loaded with ATCs, and delivered intranodally. Delayed-type hypersensitivity (DTH) and immunological endpoints were measured prevaccination and postvaccination. Clinical follow-up was required. RESULTS: Tumors obtained from 30 patients yielded 2 * 10(6) to 2 * 10(8) tumor cells. Only 19 of 30 (63%) were sterile. Ten of 30 patients (33%) had >=1 * 10(7) sterile tumor cells required for vaccine production. Eight of 10 patients had positive recall DTH. Five of 10 patients were leukapheresed to generate DCs. Four of 5 patients were vaccinated. ATC-reactive T cells were detected in 3 of 4 patients. All 4 patients survived >5 years. The trial failed to enroll the projected 12 patients and was terminated. CONCLUSION: This vaccine was safe and immunogenic but feasible only in patients with HNSCC with positive prevaccine DTH and >=1 * 10(7) sterile tumor cells. All vaccinated patients were long-term disease-free survivors. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E494-E501, 2016. PMID- 25735642 TI - The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjogren's syndrome. AB - OBJECTIVE: To determine whether the Sjogren's syndrome B (SSB)-positive/Sjogren's syndrome A (SSA)-negative antibody profile is associated with key phenotypic features of SS. METHODS: Among registrants in the Sjogren's International Collaborative Clinical Alliance (SICCA) with possible or established SS, we compared anti-SSA/anti-SSB reactivity profiles against concurrent phenotypic features. We fitted logistic regression models to explore the association between anti-SSA/anti-SSB reactivity profile and each key SS phenotypic feature, controlling for potential confounders. RESULTS: Among 3297 participants, 2061 (63%) had negative anti-SSA/anti-SSB, 1162 (35%) had anti-SSA with or without anti-SSB, and 74 (2%) anti-SSB alone. Key SS phenotypic features were more prevalent and had measures indicative of greater disease activity in those participants with anti-SSA, either alone or with anti-SSB, than in those with anti-SSB alone or negative SSA/SSB serology. These between-group differences were highly significant and not explained by confounding by age, race/ethnicity or gender. Participants with anti-SSB alone were comparable to those with negative SSA/SSB serology in their association with these key phenotypic features. Among SICCA participants classified with SS on the basis of the American-European Consensus Group or American College of Rheumatology criteria, only 2% required the anti-SSB-alone test result to meet these criteria. CONCLUSIONS: The presence of anti-SSB, without anti-SSA antibodies, had no significant association with SS phenotypic features, relative to seronegative participants. The solitary presence of anti-SSB antibodies does not provide any more support than negative serology for the diagnosis of SS. This serological profile should thus be interpreted cautiously in clinical practice and potentially eliminated from future classification criteria. PMID- 25735643 TI - EULAR recommendations for patient education for people with inflammatory arthritis. AB - OBJECTIVES: The task force aimed to: (1) develop evidence-based recommendations for patient education (PE) for people with inflammatory arthritis, (2) identify the need for further research on PE and (3) determine health professionals' educational needs in order to provide evidence-based PE. METHODS: A multidisciplinary task force, representing 10 European countries, formulated a definition for PE and 10 research questions that guided a systematic literature review (SLR). The results from the SLR were discussed and used as a basis for developing the recommendations, a research agenda and an educational agenda. The recommendations were categorised according to level and strength of evidence graded from A (highest) to D (lowest). Task force members rated their agreement with each recommendation from 0 (total disagreement) to 10 (total agreement). RESULTS: Based on the SLR and expert opinions, eight recommendations were developed, four with strength A evidence. The recommendations addressed when and by whom PE should be offered, modes and methods of delivery, theoretical framework, outcomes and evaluation. A high level of agreement was achieved for all recommendations (mean range 9.4-9.8). The task force proposed a research agenda and an educational agenda. CONCLUSIONS: The eight evidence-based and expert opinion-based recommendations for PE for people with inflammatory arthritis are intended to provide a core framework for the delivery of PE and training for health professionals in delivering PE across Europe. PMID- 25735644 TI - High-performance all-polymer solar cells via side-chain engineering of the polymer acceptor: the importance of the polymer packing structure and the nanoscale blend morphology. AB - The effectiveness of side-chain engineering is demonstrated to produce highly efficient all-polymer solar cells (efficiency of 5.96%) using a series of naphthalene diimide-based polymer acceptors with controlled side chains. The dramatic changes in the polymer packing, blend morphology, and electron mobility of all-polymer solar cells elucidate clear trends in the photovoltaic performances. PMID- 25735645 TI - Direct catalytic enantio- and diastereoselective ketone aldol reactions of isocyanoacetates. AB - A catalytic asymmetric aldol addition/cyclization reaction of unactivated ketones with isocyanoacetate pronucleophiles has been developed. A quinine-derived aminophosphine precatalyst and silver oxide were found to be an effective binary catalyst system and promoted the reaction to afford chiral oxazolines possessing a fully substituted stereocenter with good diastereoselectivities and excellent enantioselectivities. PMID- 25735646 TI - Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn's disease. AB - Certolizumab pegol (CZP), an anti-tumor necrosis factor alpha agent, is an effective therapy for Crohn's disease (CD). A population pharmacokinetic (PK) analysis of subcutaneously administered CZP was performed using data from 2157 CD patients from 9 separate studies. The aim was to determine which covariates influence the disposition of CZP. The final CZP population PK model consisted of a baseline, first-order absorption, and 1-compartment disposition. CZP antibodies were treated as a structural model covariate and caused apparent clearance (CL/F) to increase from 0.685 to 2.74 L/day. Body surface area (BSA) influenced both CL/F and apparent volume of distribution (V/F) in a linear fashion; both parameters increased by more than 53% and 49%, respectively, across the range of BSA measurements in the data. Albumin influenced CZP CL/F in a nonlinear fashion; CL/F decreased from 1.05 to 0.613 L/day with increasing albumin concentrations in antibody-negative patients. C-reactive protein (CRP) had a borderline influence and CL/F increased by more than 20% across the range of CRP measurements in the data set. Race had a minor influence on V/F. The determined covariates' impact on CZP disposition may be of clinical utility in CZP therapy of CD patients when the PK/pharmacodynamic relationship becomes available. PMID- 25735648 TI - Scaffold identification of a new class of potent and selective BCRP inhibitors. AB - We recently reported the synthesis and quantitative structure-activity relationships of a new breast cancer resistance protein (BCRP) inhibitor class. In the study presented herein, we investigated the possibility to better define the scaffold of this compound class by removing or modifying the aromatic ring A with various substituents selected on the basis of their electronic and lipophilic properties. The results show that this aromatic ring is important, but not essential, for activity. Many of the selected substituents led to compounds with low activity, but in some cases activity was retained. Among these, a phenolic hydroxy group proved to impart as much potency to the molecule as a hydroxyethyl side chain, initially considered necessary for activity. This derivative is one of the most active compounds in this class, maintaining an inhibitory activity similar to that of the reference compound; it is also selective for BCRP. PMID- 25735649 TI - Six additional cases of SEDC due to the same and recurrent R989C mutation in the COL2A1 gene--the clinical and radiological follow-up. PMID- 25735651 TI - Challenges in economic modeling of anticancer therapies: an example of modeling the survival benefit of olaparib maintenance therapy for patients with BRCA mutated platinum-sensitive relapsed ovarian cancer. AB - OBJECTIVE: The aim of this paper is to describe a four health-state, semi-Markov model structure with health states defined by initiation of subsequent treatment, designed to make best possible use of the data available from a phase 2 clinical trial. METHOD: The approach is illustrated using data from a sub-group of patients enrolled in a phase 2 clinical trial of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (NCT00753545). A semi-Markov model was developed with four health states: progression-free survival (PFS), first subsequent treatment (FST), second subsequent treatment (SST), and death. Transition probabilities were estimated by fitting survival curves to trial data for time from randomization to FST, time from FST to SST, and time from SST to death. RESULTS: Survival projections generated by the model are broadly consistent with the outcomes observed in the clinical trial. However, limitations of the trial data (small sample size, immaturity of the PFS and overall survival [OS] end-points, and treatment switching) create uncertainty in estimates of survival. CONCLUSION: The model framework offers a promising approach to evaluating cost-effectiveness of a maintenance therapy for patients with cancer, which may be generalizable to other chronic diseases. PMID- 25735650 TI - Improving the implementation of responsible alcohol management practices by community sporting clubs: A randomised controlled trial. AB - INTRODUCTION AND AIMS: Despite an increased prevalence of risky alcohol consumption and alcohol-related harm among members of sporting groups and at sporting venues, sporting clubs frequently fail to implement alcohol management practices consistent with liquor legislation and best practice guidelines. The aim of this study was to assess the impact of a multi-strategy intervention in improving the implementation of responsible alcohol management practices by sports clubs. DESIGN AND METHODS: A randomised controlled trial was conducted with 87 football clubs, with half randomised to receive a multi-strategy intervention to support clubs to implement responsible alcohol management practices. The 2-year intervention, which was based on implementation and capacity building theory and frameworks, included project officer support, funding, accreditation rewards, printed resources, observational audit feedback, newsletters, training and support from state sporting organisations. Interviews were undertaken with club presidents at baseline and post-intervention to assess alcohol management practice implementation. RESULTS: Post-intervention, 88% of intervention clubs reported implementing '13 or more' of 16 responsible alcohol management practices, which was significantly greater than the proportion of control groups reporting this level of implementation (65%) [odds ratio: 3.7 (95% confidence interval: 1.1-13.2); P = 0.04]. All intervention components were considered highly useful and three-quarters or more of clubs rated the amount of implementation support to be sufficient. DISCUSSION AND CONCLUSIONS: The multi strategy intervention was successful in improving alcohol management practices in community sports clubs. Further research is required to better understand implementation barriers and to assess the long-term sustainability of the change in club alcohol management practices. PMID- 25735652 TI - Utilities for asthma and COPD according to category of severity: a comprehensive literature review. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are incurable diseases that impact quality-of-life. OBJECTIVE: To summarize original research articles that measured or utilized preference-based utilities or disutilities according to disease severity. METHODS: Medline and Embase were searched from inception until the end of November 2014. Two reviewers independently searched the literature with differences settled through discussion. Data extracted included utility scores as determined in original research categorized according to disease severity as well as disutilities associated with exacerbations or comorbidities. Data were tabulated and analyzed descriptively. RESULTS: In total, 862 articles were identified, 790 were rejected, and 69 analyzed. There were 44 dealing with COPD and 25 with asthma. Average utilities determined by research were 0.828 +/- 0.062, 0.765 +/- 0.090, 0.711 +/- 0.120, and 0.607 +/- 0.120 for mild, moderate, severe, and very severe COPD, respectively. Utilities used in economic analyses were 0.866 +/- 0.038, 0.770 +/- 0.024, 0.739 +/- 0.045, and 0.596 +/- 0.075, respectively. Disutilities (annual) ranged from 0.002-0.378; major and minor exacerbations had respective disutilities of 0.287 and 0.108. For asthma patients, utilities were for 0.86 +/- 0.32, 0.83 +/- 0.065, and 0.74 +/- 0.029, for mild, moderate, and severe disease, respectively. CONCLUSIONS: Utilities have been summarized according to severity category of asthma and COPD. These values should be useful for researchers undertaking economic analyses of these diseases. PMID- 25735653 TI - Lysosomal proteins in cell death and autophagy. AB - Nearly 60 years ago, lysosomes were first described in the laboratory of Christian de Duve, a discovery that significantly contributed to him being awarded a share of the 1974 Nobel Prize in Physiology or Medicine for elucidating 'the structural and functional organization of the cell'. Initially thought of as a simple waste degradation facility of the cell, these organelles recently emerged as signalling centres with connections to major cellular processes. This review provides an overview of the many roles of lysosomal proteins in two of these processes: cell death and autophagy. We discuss both resident lysosomal proteins as well those that temporarily associate with lysosomes to influence autophagy and cell death pathways. Particular focus is given to studies in mammalian cells and in vivo systems. PMID- 25735655 TI - 18FDG SUV in the primary tumor and lymph node metastases is not predictive for development of distant metastases in high risk head and neck cancer patients. AB - BACKGROUND: Pretreatment screening on distant metastases is particularly useful in head and neck squamous cell carcinoma (HNSCC) patients with high risk factors. METHODS: In a retrospective study of 88 patients with previously identified clinical high risk factors the predictive value of standardized uptake value (SUV) of 18F-fluorodeoxyglucose (FDG) in the primary tumor and in the lymph node metastases for the development of distant metastases was examined. Different SUVs corrected for plasma glucose levels and body mass index were calculated and analysed in different patient groups: all patients (n=88), patients with a follow up >6months (n=73), not previously treated patients (n=51) and not previously treated patients with a follow up >6months (n=40). RESULTS: Twenty-four of the 88 (27%) high risk HNSCC patients were diagnosed with distant metastases during screening and follow up. No correlation was found between different SUVs of the primary tumor and lymph nodes metastases and the development of distant metastases. CONCLUSION: SUVs of primary tumor and lymph node on FDG-PET are not predictive for distant metastases in a (selected) group of patients with already high risk factors for distant metastases. PMID- 25735654 TI - Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma. AB - OBJECTIVE: Patients with head and neck squamous cell carcinoma (HNSCC) containing TP53 mutation and 3p deletion ("double-hit") have poorer prognosis compared to patients with either event alone ("single-hit"). The etiology for worse clinical outcomes in patients with "double-hit" cancers is unclear. We compared radiosensitivity of cell lines containing both TP53 mutations and deletion of Fragile Histidine Triad (FHIT, the gene most commonly associated with 3p deletion) to "single-hit" lines with only TP53 mutation. We compared radiosensitivity in a "single-hit" cell line with TP53 mutation converted to "double-hit" using RNA interference targeting FHIT. Finally, we compared matrixmetalloproteinase-2/9 (MMP-2/9) activity, a previously-established biomarker for tumor aggressiveness, in xenograft tumors derived from these cell lines. MATERIALS/METHODS: TP53 mutation and FHIT deletion profiles of HNSCC lines were established using Cancer Cell Line Encyclopedia (CCLE). We used RNA interference to convert a "single-hit" cell line (SCC4) to "double-hit". Cultured cells were examined for radiosensitivity and cisplatin sensitivity. MMP-2/9 activity was evaluated in "double-hit" versus "single-hit" tumors using ratiometric activatable cell-penetrating peptide (RACPP) in tongue (n=17) and flank xenografts (n=4). RESULTS: Radiotherapy caused greater double-stranded DNA breaks in "single-hit" vs naturally occurring and engineered "double-hit" cells. In-vivo, "double-hit" xenografts demonstrated higher MMP-2/9 activity compared to "single-hit" xenografts (p<0.01). There was no difference in cisplatin sensitivity between the cell lines. CONCLUSIONS: TP53 mutation combined with FHIT deletion correlates with decreased radiosensitivity in HNC cell lines. Xenograft from "double-hit" cells exhibit increased MMP-2/9 activity. These findings may in part account for the worse clinical outcome seen in patients with HNSCC "double hit" tumors. PMID- 25735656 TI - Enhanced Electrochemiluminescence from a Stoichiometric Ruthenium(II) Iridium(III) Complex Soft Salt. AB - Electrochemiluminescence (ECL) and electrochemistry are reported for a heterometallic soft salt, [Ru(dtbubpy)3 ][Ir(ppy)2 (CN)2 ]2 ([Ir][Ru][Ir]), consisting of a 2:1 ratio of complementary charged Ru and Ir complexes possessing two different emission colors. The [Ru](2+) and [Ir](-) moieties in the [Ir][Ru][Ir] greatly reduce the energy required to produce ECL. Though ECL intensity in the annihilation path was enhanced 18* relative to that of [Ru(bpy)3 ](2+) , ECL in the co-reactant path with tri-n-propylamine was enhanced a further 4*. Spooling spectroscopy gives insight into ECL mechanisms: the unique light emission at 634 nm is due to the [Ru](2+) * excited state and no [Ir](-) * was generated in either route. Overall, the soft salt system is anticipated to be attractive and suitable for the development of efficient and low-energy-cost ECL detection systems. PMID- 25735657 TI - Processing of Spontaneous Emotional Responses in Adolescents and Adults with Autism Spectrum Disorders: Effect of Stimulus Type. AB - Recent research has shown that adults with autism spectrum disorders (ASD) have difficulty interpreting others' emotional responses, in order to work out what actually happened to them. It is unclear what underlies this difficulty; important cues may be missed from fast paced dynamic stimuli, or spontaneous emotional responses may be too complex for those with ASD to successfully recognise. To explore these possibilities, 17 adolescents and adults with ASD and 17 neurotypical controls viewed 21 videos and pictures of peoples' emotional responses to gifts (chocolate, a handmade novelty or Monopoly money), then inferred what gift the person received and the emotion expressed by the person while eye movements were measured. Participants with ASD were significantly more accurate at distinguishing who received a chocolate or homemade gift from static (compared to dynamic) stimuli, but significantly less accurate when inferring who received Monopoly money from static (compared to dynamic) stimuli. Both groups made similar emotion attributions to each gift in both conditions (positive for chocolate, feigned positive for homemade and confused for Monopoly money). Participants with ASD only made marginally significantly fewer fixations to the eyes of the face, and face of the person than typical controls in both conditions. Results suggest adolescents and adults with ASD can distinguish subtle emotion cues for certain emotions (genuine from feigned positive) when given sufficient processing time, however, dynamic cues are informative for recognising emotion blends (e.g., smiling in confusion). This indicates difficulties processing complex emotion responses in ASD. PMID- 25735658 TI - Latent instabilities in metallic LaNiO3 films by strain control of Fermi-surface topology. AB - Strain control is one of the most promising avenues to search for new emergent phenomena in transition-metal-oxide films. Here, we investigate the strain induced changes of electronic structures in strongly correlated LaNiO3 (LNO) films, using angle-resolved photoemission spectroscopy and the dynamical mean field theory. The strongly renormalized eg-orbital bands are systematically rearranged by misfit strain to change its fermiology. As tensile strain increases, the hole pocket centered at the A point elongates along the kz-axis and seems to become open, thus changing Fermi-surface (FS) topology from three- to quasi-two-dimensional. Concomitantly, the FS shape becomes flattened to enhance FS nesting. A FS superstructure with Q1 = (1/2,1/2,1/2) appears in all LNO films, while a tensile-strained LNO film has an additional Q2 = (1/4,1/4,1/4) modulation, indicating that some instabilities are present in metallic LNO films. Charge disproportionation and spin-density-wave fluctuations observed in other nickelates might be their most probable origins. PMID- 25735659 TI - Medical device market in China. AB - With China's growing old-age population and economic presence on the international stage, it has become important to evaluate its domestic and foreign market contribution to medical devices. Medical devices are instruments or apparatuses used in the prevention, rehabilitation, treatment, or knowledge generation with respect to disease or other abnormal conditions. This article provides information drawn from recent publications to describe the current state of the Chinese domestic market for medical devices and to define opportunities for foreign investment potential therein. Recent healthcare reforms implemented to meet rising demand due to an aging and migrating population are having a positive effect on market growth-a global market with a projected growth of 15% per year over the next decade. PMID- 25735660 TI - Performance evaluation of contrast-detail in full field digital mammography systems using ideal (Hotelling) observer vs. conventional automated analysis of CDMAM images for quality control of contrast-detail characteristics. AB - PURPOSE: The purpose of this work was to evaluate the contrast-detail performance of full field digital mammography (FFDM) systems using ideal (Hotelling) observer Signal-to-Noise Ratio (SNR) methodology and ascertain whether it can be considered an alternative to the conventional, automated analysis of CDMAM phantom images. METHODS: Five FFDM units currently used in the national breast screening programme were evaluated, which differed with respect to age, detector, Automatic Exposure Control (AEC) and target/filter combination. Contrast-detail performance was analysed using CDMAM and ideal observer SNR methodology. The ideal observer SNR was calculated for input signal originating from gold discs of varying thicknesses and diameters, and then used to estimate the threshold gold thickness for each diameter as per CDMAM analysis. The variability of both methods and the dependence of CDMAM analysis on phantom manufacturing discrepancies also investigated. RESULTS: Results from both CDMAM and ideal observer methodologies were informative differentiators of FFDM systems' contrast detail performance, displaying comparable patterns with respect to the FFDM systems' type and age. CDMAM results suggested higher threshold gold thickness values compared with the ideal observer methodology, especially for small diameter details, which can be attributed to the behaviour of the CDMAM phantom used in this study. In addition, ideal observer methodology results showed lower variability than CDMAM results. CONCLUSION: The Ideal observer SNR methodology can provide a useful metric of the FFDM systems' contrast detail characteristics and could be considered a surrogate for conventional, automated analysis of CDMAM images. PMID- 25735661 TI - Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice. AB - Neurogenesis occurs in the adult hippocampus and is enhanced by dietary restriction (DR), and neurogenesis enhancement is paralleled by circulating ghrelin level enhancement. We have previously reported that ghrelin modulates adult neurogenesis in the hippocampus. In order to investigate the possible role of ghrelin in DR-induced hippocampal neurogenesis in adult mice, ghrelin knockout (GKO) mice and wild-type (WT) mice were maintained for 3 months on DR or ad libitum (AL) diets. Protein levels of ghrelin in the stomach and the hippocampus were increased by DR in WT mice. One day after BrdU administration, the number of BrdU-labeled cells in the hippocampal dentate gyrus was decreased in GKO mice maintained on the AL diet. DR failed to alter the proliferation of progenitor cells in both WT and GKO mice. Four weeks after BrdU injection, the number of surviving cells in the dentate gyrus was decreased in AL-fed GKO mice. DR increased survival of newborn cells in WT mice, but not in GKO mice. Levels of brain-derived neurotrophic factor protein in the hippocampus were similar between WT and GKO mice, and were increased by DR both in WT and GKO mice. These results suggest that elevated levels of ghrelin during DR may have an important role in the enhancement of neurogenesis induced by DR. PMID- 25735662 TI - Vestibular stimulation by magnetic fields. AB - Individuals working next to strong static magnetic fields occasionally report disorientation and vertigo. With the increasing strength of magnetic fields used for magnetic resonance imaging studies, these reports have become more common. It was recently learned that humans, mice, and zebrafish all demonstrate behaviors consistent with constant peripheral vestibular stimulation while inside a strong, static magnetic field. The proposed mechanism for this effect involves a Lorentz force resulting from the interaction of a strong static magnetic field with naturally occurring ionic currents flowing through the inner ear endolymph into vestibular hair cells. The resulting force within the endolymph is strong enough to displace the lateral semicircular canal cupula, inducing vertigo and the horizontal nystagmus seen in normal mice and in humans. This review explores the evidence for interactions of magnetic fields with the vestibular system. PMID- 25735663 TI - Helicobacter pylori Might Induce TGF-beta1-Mediated EMT by Means of cagE. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT), in which polarized epithelial cells have mesenchymal cell phenotypes, is thought to be a key process of invasion and metastasis of cancer. Transforming growth factor beta-1 (TGF beta1) is known to be carcinogenic and Helicobacter pylori is a predominant carcinogen of gastric cancer. Our study aimed to determine whether TGF-beta1 or H. pylori infection enhances EMT process and cytotoxin-associated gene E (CagE) is associated with EMT. MATERIALS AND METHODS: Human gastric cancer cell AGS and MKN45 were treated with recombinant TGF-beta1 or H. pylori including cagE negative (DeltacagE) mutant. Besides the assessment of EMT-related markers expression levels by means of RT-qPCR, Western blot, and immunofluorescence assay, the induction of in vitro EMT on gastric cancer cells (AGS and MKN cell lines) was confirmed by wound-healing assay and invasion assay. RESULTS: When gastric cancer cells were treated with TGF-beta1 or various strains of cagE positive H. pylori, EMT-related marker altered significantly. However, the DeltacagE mutant did not. Wound-healing assay and invasion assay showed enhanced migration ability of the cells treated with cagE-positive H. pylori but not in DeltacagE mutant. CONCLUSIONS: EMT induction in gastric cancer cells by TGF-beta1 was confirmed. Only infection with cagE-positive H. pylori upregulated the TGF beta1-mediated EMT pathway and consequently promotes EMT. Therefore, H. pylori might induce TGF-beta1-mediated EMT associated with the cagE. PMID- 25735664 TI - Carbosilane dendrimers inhibit alpha-synuclein fibrillation and prevent cells from rotenone-induced damage. AB - This study investigates the role of carbosilane dendrimers in fibrillation of alpha-synuclein and prevention of the mouse hippocampal cell (mHippoE-18) from rotenone-induced damage. Examining the interaction between carbosilane dendrimers and alpha-synuclein, we found that the dendrimers inhibit fibril formation. We also investigated cell viability, the production of reactive oxygen species (ROS), and mitochondrial membrane potential. mHippoE-18 cells were preincubated with carbosilane dendrimers before rotenone was added. All the dendrimers possess potential protection activity. Preincubation with dendrimers contributed to: increased viability, higher mitochondrial membrane potential, and reduced ROS level in cells. The probable mechanism of cell protection lies in the ability of dendrimers to capture rotenone by encapsulating or binding to its surface groups. The fact that dendrimers have prevention potential is important in the search for new pharmacological strategies against neurodegenerative disorders. PMID- 25735665 TI - The effect of shear and extensional viscosities on atomization of Newtonian and non-Newtonian fluids in ultrasonic inhaler. AB - The paper contains results of the experimental study on atomization process of aqueous solutions of glycerol and aqueous solutions of glycerol-polyacrylamide (Rokrysol WF1) in an ultrasonic inhaler. In experiments the different concentration aqueous solutions of glycerol and glycerol-polyacrylamide have been tested. The results have been obtained by the use of laser diffraction technique. The differences between characteristics of ultrasonic atomization for test liquids have been observed. The analysis of drop size histograms shows that the different sizes of drops have been formed during atomization process. The present study confirmed the previous reports which suggested that the drops size changes with the increase in viscosity of solution changes in spray characteristics were also observed. It has been shown that the shear and extensional viscosities affect the process of atomization. PMID- 25735666 TI - Can preschool-aged children swallow several minitablets at a time? Results from a clinical pilot study. AB - Minitablets are a novel, multi-compartment solid drug formulation, particularly intended for children between 1 and 6 years of age. Available literature shows that even infants are capable of swallowing a single minitablet. In this study, we have explored the level of acceptance of minitablets administered in units of 5 or 10. A group of thirty two 2-year-old children (2-years) and twenty eight 3 year-old children (3-years) have been enrolled in the study. Each child was asked to swallow placebo minitablets (2mm or 3mm) suspended in a fruity jelly on a spoon. The swallowing of minitablets (with or without chewing) was registered for 75% of 2-year-olds and for 93% of 3-year-olds. Moreover, most of the children (57% of all participants) were fully capable of swallowing all units without chewing (2-years: 50%; 3-years: 64%). However, no statistically significant differences in the swallowing ability were observed in gender and age groups. None of the children choked. Neither the number, nor the diameter of the administered minitablets have significantly influenced the ability to swallow units. The results show that minitablets administered in several units mixed with jelly food are safe and could be accepted by a pediatric population. PMID- 25735667 TI - Graphene-oxide stabilization in electrolyte solutions using hydroxyethyl cellulose for drug delivery application. AB - Stabilization of graphene oxide (GO) in physiological solution is performed using hydroxyethyl cellulose (HEC) to make the resultant nanohybrid suitable for targeted drug delivery purposes. Short and long term stability of GO suspensions with different ionic strengths were assessed using ultraviolet-visible spectroscopy (UV-vis), atomic force microscopy (AFM) and zeta potential measurements. Results depicted that HEC effectively stabilized GO in electrolyte solutions and the mechanism of stabilization appeares to be depended on HEC content. Drug loading and release behavior of folic acid (FA) as a model drug, from GO-HEC nanohybrid were studied to assess its application in drug delivery systems. Results showed the nanohybrid could be highly loaded by folic acid. Moreover, HEC content in the nanohybrid played an important role in final application to make it applicable either as a carrier for controllable drug release or as a folate-targeted drug carrier. In addition, according to cytotoxicity results, the nanohybrid showed good biocompatibility which indeed confirms its potential application as a drug carrier. PMID- 25735668 TI - Development, optimization and evaluation of long chain nanolipid carrier for hepatic delivery of silymarin through lymphatic transport pathway. AB - In the present study, nanostructured lipid carriers (NLCs) with three different lipid combinations (solid lipid:liquid lipid) were prepared through emulsification and ultrasonication using a Box-Behnken design. From the design, the best lipid combination was glyceryl monostearate and oleic acid, which gives particle of smaller size (223.73 +/- 43.39nm) with high drug entrapment efficiency (78.65 +/- 2.2%). In vitro release studies show that 84.60 +/- 5.66% of drug was released in 24h. In vivo studies revealed that drug absorption occurs through lymphatic pathway as only 5.008 +/- 0.011MUg/ml of peak plasma concentration was achieved in blood plasma in presence of chylomicron inhibitor. The peak plasma concentration (Cmax) for silymarin loaded NLC was found to be 25.565 +/- 0.969MUg/ml as compared to silymarin suspension whose Cmax was found to be 14.050 +/- 0.552 MUg/ml, this confirms 2-fold increase in relative bioavailability. In vivo studies revealed that 19.268 +/- 1.29MUg of drug reaches to liver in 2h whereas negligible drug concentration reported in other organs. It was concluded that drug loaded NLCs was beneficial for targeting liver or other lymphatic disorders through lymphatic transport pathway. Finally, the main purpose of modifying lymphatic transport system was successfully achieved through NLCs. PMID- 25735669 TI - Development of a modified - solid dispersion in an uncommon approach of melting method facilitating properties of a swellable polymer to enhance drug dissolution. AB - The study aimed to develop a modified-solid dispersion method using a swellable hydrophilic polymers accompanied by a conventional carrier to enhance the dissolution of a drug that possesses poor water solubility. Two swellable polymers (hydroxypropyl methylcellulose and polyethylene oxide) were swelled in melted polyethylene glycol 6000 (PEG 6000) in different ratios and under different conditions. The type, amount, and, especially, incorporation method of the swellable polymers were crucial factors affecting the dissolution rate, crystallinity, and molecular interaction of the drug. Interestingly, the method in which the swellable polymer was thoroughly mixed with the melted PEG 6000 as the first step was more effective in increasing drug dissolution than the method in which the drug was introduced to the melted PEG 6000 followed by the addition of the swellable polymer. This system has potential for controlling drug release due to high swelling capabilities of these polymers. Therefore, the current study can be considered to be a promising model for formulations of controlled release systems containing solid dispersions. PMID- 25735670 TI - [Religion, tradition and fashion - hard masters[editorial]]. PMID- 25735671 TI - [The chicken and the egg? Gastroesophageal reflux and respiratory disorders [editorial]]. PMID- 25735672 TI - [Respiratory and gastrointestinal symptoms in 7-10 year old children in Reykjavik, Iceland]. AB - INTRODUCTION: Asthma and rhinitis are common diseases in children often but not always caused by allergy. Gastroesophageal reflux is also prevalent in children and relationship with respiratory symptoms has been suggested. The aim of this study was to investigate this relationship in schoolchildren. MATERIAL AND METHODS: As a part of multi-centre cross-sectional food allergy study (Europrevall), a short questionnaire was sent out to 2895 schoolchildren in Reykjavik 7-10 year old. Of the 2346 (81%) children we received answers from we selected those that answered positively to questions regarding common foods and a random sample of those who denied any symptoms related to food. The selected children were invited to further study where they answered an extensive questionnaire that included questions regarding respiratory and gastrointestinal symptoms. RESULTS: A significant correlation was found between a history of wheezing over the previous year and vomiting, (p<0.001) and feeling nauseous (p<0.001) in the past 6 months. There was also a correlation between asthma in the previous year and feeling nauseous (p<0.05), having a a burning or painful feeling in the middle of the chest (p<0.001) as well as nasal symptoms and vomiting (p<0.01), feeling nauseous (p<0.01), having a burning or painful feeling in the middle of the chest (p<0.01) and having a sour taste, like a taste of vomit in the mouth (p<0.001). CONCLUSION: This study shows a significant correlation between symptoms of gastroesophageal reflux and respiratory and nasal symptoms. Clinicians should be aware of this association though the nature and direction of this association is still unclear. PMID- 25735673 TI - [Results of pre-hospital cardiac resuscitation in the Reykjavik area 2004-2007]. AB - INTRODUCTION: In the Reykjavik area, a physician staffed ambulance -responded to cardiac arrests from 1982-2007. The aim of this study was to assess the outcome of attempted pre-hospital cardiac resuscitations in the period from 2004-2007 and compare to previous studies. MATERIAL AND METHODS: All cases of attempted prehospital resuscitations in cardiac arrests of presumed cardiac etiology. Data was gathered according to the Utstein template. RESULTS: Of a total of 289 cases in cardiac arrest, resuscitation was attempted in 279 and 200 of those were presumed to have a cardiac etiology. Men were 76% of the patients and the average age was 67.7 years. Average response time was 6.3 min. One hundred and seven (54%) survived to hospital admission and 50 (25%) survived to discharge compared to 16-19% in previous studies (p=0.16). The presenting rhythm was ventricular fibrillation/ventricular tachycardia (VF/VT) in 50% of the cases, 30% was in asystole and 20% in pulseless electrical activity (PEA). Of those admitted to intensive care unit/ department and had ventricular fibrillation on the first rhythm strip 70% were discharged during 2004-2007 compared to 49% during 1999 2002 (p=0.01). Bystander CPR was provided in 62% of witnessed cases compared to 54% in a previous study (p=0.26). One hundred and twenty (60%) were witnessed cases of which 37 (31%) survived to hospital discharge compared to 5 (8%)of non witnessed cases (p<0.01). CONCLUSION: One in every four cardiac arrest patients in the Reykjavik area survives to discharge. This is similar to previous studies in the area (16-19%) and high compared to international studies 3-16%. Survival of those admitted to intensive care unit/ department and had ventricular fibrillation on the first rhythm strip was significantly higher compared to previous studies. Survival was found to be significantly higher if the cardiac arrest was witnessed. PMID- 25735674 TI - [Prevalence and diversity of emotional abuse and neglect in childhood in Iceland]. AB - INTRODUCTION: Parenting styles that include abuse can harm the development of the child's brain with a long or short-term impact on his/her health and behaviour. The scope and diversity of abuse are important determinants, and neglect is one of its most serious manifestations. The aim of the study is to examine the prevalence and diversity of emotional abuse and neglect reported by adult Icelanders in their childhood, and how such experience had influenced their evaluation of their upbringing. MATERIALS AND METHODS: Icelanders 18 years and older were randomly selected from the national population register. They were invited to express their perception of their upbringing, and answer questions regarding their experience of 8 specific forms of emotional abuse in childhood, and neglect. RESULTS: Of 966 interviewees, 663 (69%) had experienced one or more of the 8 forms of emotional abuse. Those younger than 30 years were 2.9 times more likely to have such an experience compared to those who were older (95% CI 1.9 to 4.3). The perception of upbringing as bad or acceptable compared to good was significantly related to the number of forms of emotional abuse applied (p<0.0001) and the scope of its application (p<0.0001). In total 105 (11%) considered that they had experienced neglect in childhood. Significantly more men than women had experienced emotional abuse (p= 0.0020), whereas women reported neglect (p=0.0440). CONCLUSION: More than 2/3 of adult Icelanders report experience of one or more out of 8 different forms of emotional abuse and 1/10 report neglect. Parenting styles can be changed, e.g. with education, social support, and legislation. PMID- 25735675 TI - Ex-PRESS glaucoma filter: an MRI compatible metallic orbital foreign body imaged at 1.5 and 3T. AB - AIM: To report on the MRI compatibility of the Ex-PRESS glaucoma filtration device, a tiny metallic implant placed into the anterior chamber of the eye that is much smaller than traditional glaucoma shunts, and to educate the radiology community regarding its appearance. MATERIALS AND METHODS: Seven patients with Ex PRESS glaucoma filtration devices were identified that had undergone MRI at San Francisco General Hospital/University of California San Francisco Medical Center by searching and cross-referencing the radiology reporting system and the electronic medical record. MRI images were reviewed for artefact interfering with interpretation. Ophthalmology examinations were reviewed for evidence of complications. RESULTS: Eighteen individual MRI examinations were performed during 12 unique MRI events on these 7 patients. 13/18 individual MRI examinations and 7/12 MRI events were performed at 3 T with the others performed at 1.5 T. Mean time from Ex-PRESS implantation to MRI was 17.5 months. Mean time from MRI to first ophthalmology examination was 1.1 months and from MRI to latest ophthalmology examination was 6.6 months. Susceptibility artefact did not interfere with image interpretation and no complications related to MRI were encountered. CONCLUSION: The Ex-PRESS glaucoma filtration device appears to be safe for MRI at 1.5 and 3 T and does not produce significant susceptibility artefact to affect diagnostic interpretation adversely. PMID- 25735676 TI - Re: Validating a threshold of ocular gaze deviation for the prediction of acute ischaemic stroke. PMID- 25735677 TI - Further development of laryngoscopes for anaesthesia-the Macintosh blade. PMID- 25735678 TI - Anaesthesia and intensive care in 2015: maintaining our mission. PMID- 25735679 TI - Dexamethasone-an effective antiemetic, but is it safe? PMID- 25735680 TI - Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. AB - Defects in the genes coding for the skeletal muscle ryanodine receptor (RYR1) and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) have been identified as causative for malignant hyperthermia (MH). Sixty-two MH susceptible individuals presenting to the same diagnostic centre had copy deoxyribonucleic acid, derived from muscle ribonucleic acid, sequenced to identify variants with the potential to be responsible for the MH phenotype in both RYR1 and CACNA1S. These genetic findings were combined with clinical episode details and in vitro contracture test results to improve our understanding of the Australian MH cohort. Twelve novel variants were identified in RYR1 and six in CACNA1S. Known RYR1 causative mutations were identified in six persons and novel variants in RYR1 and CACNA1S in a further 17 persons. Trends indicated higher mutation identification in those with more definitive clinical episodes and stronger in vitro contracture test responses. PMID- 25735681 TI - A survey of antiemetic dexamethasone administration-frequency of use and perceptions of benefits and risks. AB - Postoperative nausea and vomiting (PONV) is a significant concern for anaesthetists. There are many agents from different classes that are effective in both preventing and treating PONV. Dexamethasone is a very effective antiemetic, but there are concerns regarding its safety. We performed an anonymous survey of a random selection of the fellows of the Australian and New Zealand College of Anaesthetists to ascertain patterns of practice in relation to PONV prophylaxis and treatment and also to determine awareness of the risks and benefits of perioperative dexamethasone administration. The response rate was 33%. From the responses, 71.2% of all patients undergoing general anaesthesia in the respondents' institutions receive PONV prophylaxis in total and 46.6% receive dexamethasone. No respondent gives more than a single dose of dexamethasone and there was an almost equal split between those who administer 4 and 8 mg, with a smaller number dosing on a weight basis. 5HT-3 receptor antagonists and dexamethasone are the preferred first-line PONV prophylactic agents and 5HT-3 receptor antagonists and droperidol are the preferred first-line PONV therapeutic agents. Concerns relating to the safety of dexamethasone were expressed by 80% of respondents. From this survey, we concluded that the PONV practice of the respondents is largely compliant with recent consensus guidelines, although PONV prophylaxis appears to be given more routinely. It also appears that more education is required on issues regarding dexamethasone safety. PMID- 25735682 TI - Efficacy of the APACHE II score at ICU discharge in predicting post-ICU mortality and ICU readmission in critically ill surgical patients. AB - In this study, we evaluated the efficacy of the discharge Acute Physiology and Chronic Health Evaluation (APACHE) II score in predicting post-intensive care unit (ICU) mortality and ICU readmission during the same hospitalisation in a surgical ICU. Of 1190 patients who were admitted to the ICU and stayed >48 hours between October 2007 and March 2010, 23 (1.9%) died and 86 (7.2%) were readmitted after initial ICU discharge, with 26 (3.0%) admitted within 48 hours. The area under the receiver operating characteristics curve of the discharge and admission APACHE II scores in predicting in-hospital mortality was 0.631 (95% confidence interval [CI] 0.603 to 0.658) and 0.669 (95% CI 0.642 to 0.696), respectively (P=0.510). The area under the receiver operating characteristics curve of discharge and admission APACHE II scores for predicting all forms of readmission was 0.606 (95% CI 0.578 to 0.634) and 0.574 (95% CI 0.545 to 0.602), respectively (P=0.316). The area under the receiver operating characteristics curve of discharge APACHE II score in predicting early ICU readmissions was, however, higher than that of admission APACHE II score (0.688 [95% CI 0.660 to 0.714] versus 0.505 [95% CI 0.476 to 0.534], P=0.001). The discharge APACHE II score (odds ratio [OR] 1.1, 95% CI 1.01 to 1.22, P=0.024), unplanned ICU readmission (OR 20.0, 95% CI 7.6 to 53.1, P=0.001), eosinopenia at ICU discharge (OR 6.0, 95% CI 1.34 to 26.9, P=0.019), and hospital length-of-stay before ICU admission (OR 1.02, 95% CI 1.01 to 1.03, P=0.021) were significant independent factors in predicting post-ICU mortality. This study suggests that the discharge APACHE II score may be useful in predicting post-ICU mortality and is superior to the admission APACHE II score in predicting early ICU readmission in surgical ICU patients. PMID- 25735683 TI - The effects of haemodilution with albumin on coagulation in vitro as assessed by rotational thromboelastometry. AB - We investigated the in vitro viscoelastic changes of progressive haemodilution with 4% albumin compared with normal saline (NS) using rotational thromboelastometry (ROTEM((r)), Pentapharm Co., Munich, Germany). Whole blood samples obtained from 20 healthy volunteers were diluted in vitro with 4% albumin or NS by 10%, 20% and 40%. Fibrinogen concentration and ROTEM((r)) (EXTEM [screening test for the extrinsic haemostasis system], FIBTEM [EXTEM-based assay for the fibrin part of the clot]) variables including coagulation time, clot formation time (CFT), alpha-angle, maximum clot firmness and lysis index were measured in the undiluted sample and at each degree of haemodilution. There was no significant difference in fibrinogen concentration at equivalent haemodilutions with normal saline and 4% albumin solutions. Forty percent haemodilution with albumin significantly prolonged coagulation time (EXTEM P=0.007, FIBTEM P=0.0001) and significantly decreased lysis index (FIBTEM P=0.009) compared with NS. A significant decrease in maximum clot firmness from undiluted measurements (P=0.05) was observed at lower haemodilutions with albumin (20% with EXTEM, 10% with FIBTEM) compared with NS (40% with EXTEM and FIBTEM). The adverse effects of large degrees of haemodilution with 4% albumin solution are in excess of what can be explained by haemodilution alone. This study suggests that large degrees of haemodilution with albumin impair fibrinogen activity to a greater extent than equivalent degrees of haemodilution with NS. PMID- 25735684 TI - The epidemiology of sepsis during rapid response team reviews in a teaching hospital. AB - In a three-month retrospective study, we assessed the proportion of rapid response team (RRT) calls associated with systemic inflammatory response syndrome (SIRS) and sepsis. We also documented the site of infection (whether it was community- or hospital-acquired), antibiotic modifications after the call and in hospital outcomes. Amongst 358 RRT calls, two or more SIRS criteria were present in 277 (77.4%). Amongst the 277 RRT calls with SIRS criteria, 159 (57.4%) fulfilled sepsis criteria in the 24 hours before and 12 hours after the call. There were 118 of 277 (42.6%) calls with SIRS criteria but no evidence of sepsis and 62 of 277 (22.3%) calls associated with both criteria for sepsis as well as an alternative cause for SIRS. Hence, 159 (44.4%) of all 358 RRT calls over the three-month study period fulfilled criteria for sepsis and in 97 (159-62) (27.1%) of the 358 calls, there were criteria for sepsis without other causes for SIRS criteria. The most common sites of infection were respiratory tract (86), abdominal cavity (38), urinary tract (26) and bloodstream (26). Infection was hospital-acquired in 91 (57.2%) and community-acquired in 67 (42.1%) cases, respectively. Patients were on antibiotics in 127 of 159 (79.9%) cases before the RRT call and antibiotics were added or modified in 76 of 159 (47.8%) cases after RRT review. The hospital length-of-stay of patients who received an RRT call associated with sepsis was longer than those who did not (16.0 [8.0 to 28.5] versus 10 days [6.0 to 18.0]; P=0.002). PMID- 25735685 TI - Measuring the clinical learning environment in anaesthesia. AB - The learning environment describes the way that trainees perceive the culture of their workplace. We audited the learning environment for trainees throughout Australia and New Zealand in the early stages of curriculum reform. A questionnaire was developed and sent electronically to a large random sample of Australian and New Zealand College of Anaesthetists trainees, with a 26% final response rate. This new instrument demonstrated good psychometric properties, with Cronbach's alpha ranging from 0.81 to 0.91 for each domain. The median score was equivalent to 78%, with the majority of trainees giving scores in the medium range. Introductory respondents scored their learning environment more highly than all other levels of respondents (P=0.001 for almost all comparisons). We present a simple questionnaire instrument that can be used to determine characteristics of the anaesthesia learning environment. The instrument can be used to help assess curricular change over time, alignment of the formal and informal curricula and strengths and weaknesses of individual departments. PMID- 25735686 TI - Hypertonic saline in paediatric traumatic brain injury: a review of nine years' experience with 23.4% hypertonic saline as standard hyperosmolar therapy. AB - We describe the protocolised use of 23.4% hypertonic saline solution (HTS) for intracranial hypertension in the context of traumatic brain injury in the paediatric population. This study represents the largest published data on the use of 23.4% HTS in the paediatric population. In this retrospective cohort, we focus on the efficacy, biochemical and metabolic consequences of 23.4% HTS administration in a Level 1 paediatric trauma centre. Mortality in the first seven days was 6% (2/32) with a mean intensive care unit length-of-stay of ten days (range 2 to 25, standard deviation [SD] 6). All-cause hospital mortality was 6%, with no deaths after the seven-day study period. Mean intracranial pressure (ICP) response to HTS was 10 mmHg (range 1 to 30, SD 8). For biochemistry data, the mean highest daily serum sodium was 148 mmol/l (139 to 161, SD 6), mean highest serum chloride was 115 mmol/l (range 101 to 132, SD 8) with matched mean serum base excess of -1.5 mmol/l (range 2 to -8, SD 3) and mean peak serum creatinine was 73 mmol/l (range 32 to 104, SD 32). Glasgow outcome scores of >3 (independent function) were achieved in 74% of patients. We describe the use of 23.4% HTS, demonstrating it to be a practical and efficacious method of delivering osmoles and may be advantageous in minimising total fluid volume. Thus, the bolus versus infusion debate may best be served via combining both approaches. PMID- 25735687 TI - Intensive care unit admission in patients following rapid response team activation: call factors, patient characteristics and hospital outcomes. AB - Rapid Response Systems (RRSs) have been widely introduced throughout hospital health systems, yet there is limited research on the characteristics and outcomes of patients admitted to an intensive care unit (ICU) following RRS activation. Using database extraction, this study examined the factors associated with ICU admission and patient outcome in patients receiving RRS activation in a tertiary level hospital between 2009 and 2013. Of 3004 RRS activations, 392 resulted in ICU admissions. Call factors associated with ICU admission and increased hospital mortality included tachypnoea (P <0.001 and P <0.001, respectively), hypoxia (P <0.001 and P <0.001, respectively) and having multiple Medical Emergency Team call triggers breached simultaneously (P <0.001 and P <0.001, respectively). Patients with seizures (P <0.001) and tachycardia (P=0.004) were more likely to survive to hospital discharge. Patient factors associated with ICU admission included young age (P <0.001) and having severe liver disease (P <0.001). Factors associated with increased hospital mortality included delayed RRS activation (P <0.001), increased age (P <0.001) and comorbidities including ischaemic heart disease (P=0.006), congestive heart failure (P <0.001), chronic kidney disease (P <0.001) and severe liver disease (P <0.001). Multiple factors relating to both the nature of the RRS activation call and patient characteristics are associated with ICU admission and hospital mortality post RRS activation. This information may be useful for risk stratification of deteriorating patients and determination of appropriate escalation. PMID- 25735688 TI - Characteristics and outcomes of critically ill Aboriginal and/or Torres Strait Islander patients in North Queensland. AB - A retrospective cohort analysis of an admission database for the intensive care unit at The Townsville Hospital was undertaken to describe the characteristics and short-term outcomes of critically ill Aboriginal and Torres Strait Islander patients. The Townsville Hospital is the tertiary referral centre for Northern Queensland and services a region in which Aboriginal and Torres Strait Islander people constitute 9.6% of the population. Aboriginal and Torres Strait Islander patients were significantly younger and had higher rates of invasive mechanical ventilation, emergency admissions and transfers from another hospital. Despite these factors, intensive care mortality did not differ between groups (9.4% versus 7.7%, P=0.1). Higher Acute Physiology and Chronic Health Evaluation III-j scores were noted in the Aboriginal and Torres Strait Islander population requiring emergency admission (65 versus 60, P=0.022) but were lower for elective admission (38 versus 42, P <0.001). Despite higher predicted hospital mortality for Aboriginal and Torres Strait Islander patients requiring emergency admission, no significant difference was observed (20.1% versus 19.1%, P=0.656). In a severity adjusted model, Aboriginal and/or Torres Strait Islander status did not statistically significantly alter the risk of death (odds ratio 0.88, 95% confidence interval 0.65, 1.2, P=0.398). Though Aboriginal and Torres Strait Islander patients requiring intensive care differed in admission characteristics, mortality was comparable to other critically ill patients. PMID- 25735689 TI - The impact of a cadaver-based airway lab on critical care fellows' direct laryngoscopy skills. AB - This study sought to determine the impact of a cadaver-based airway lab on critical care medicine fellows' direct laryngoscopy skills and hypothesised that fellows can improve their self-reported percentage of glottic opening (POGO) scores in cadaver models to achieve POGO scores similar to that of expert faculty. Nineteen fellows attended an airway management skills laboratory utilising five modified cadavers. Initial fellow POGO (POGOi) visualised was recorded at the onset with direct laryngoscopy. Maximum fellow POGO score with optimised direct laryngoscopy was recorded after two additional hours of teaching and also during a testing phase several days later. Data was assessed for significant differences between trainee POGO scores at each time interval and between trainee POGO scores and expert scores. A departmental procedural database was utilised to examine success rates of intubation as a clinical correlation. Fellows' mean POGOi scores, averaged across all five specimens, were significantly lower than both their maximum POGO scores and their testing phase POGO scores. Mean POGOi scores for fellows, averaged over all five cadavers, were lower than the instructors' POGOi scores. There was no difference between fellows' and instructors' mean maximum POGO or mean testing phase POGO scores. Clinical success rates of intubation were over 98%. A short training session using modified cadavers can be utilised to teach new critical care medicine fellows additional techniques for airway management and assist them in obtaining higher POGO scores, similar to those of expert instructors. Success rates of clinical intubations were favourable in the wake of this training. PMID- 25735690 TI - A comparison of outcomes among hospital survivors with and without severe comorbidity admitted to the intensive care unit. AB - Little is known about the experiences of patients with severe comorbidity discharged from Intensive Care Units (ICUs). This project aimed to determine the effects of an ICU stay for patients with severe comorbidity by comparing 1) quality of life (QOL), 2) the symptom profile of hospital survivors and 3) health service use after hospital discharge for patients admitted to ICU with and without severe comorbidity. A case-control study was used. Patients with severe comorbidity were matched to a contemporaneous cohort of ICU patients by age and severity of illness. Assessment tools were the Medical Outcome Study 36-item short-form and European Organisation for Research and Treatment of Cancer QLQ-C15 PAL questionnaires for QOL and the Symptom Assessment Scale for symptom distress. A proportional odds assumption was performed using an ordinal regression model. The difference in QOL outcome was the dependent variable for each pair. Health service use after discharge from ICU was monitored with patient diaries. Patients aged 18+ years admitted to an ICU in a metropolitan teaching hospital between 2011 and 2012 were included. We recruited 30 cases and 30 controls. QOL improved over the six months after hospital discharge for patients with and without severe comorbidity (P <0.01) within the groups but there was no difference found between the groups (P >0.3). There was no difference in symptoms or health service use between patients with and without severe comorbidity. ICU admission for people with severe comorbidity can be appropriate to stabilise the patient's condition and is likely to be followed by some overall improvement over the six months after hospital discharge. PMID- 25735691 TI - Review of critical incidents in a university department of anaesthesia. AB - In 2011, our hospital started a new system of 100% procedural audit of anaesthesia work, in which we incorporated the reporting of critical incidents. This monitoring of critical incidents has enabled identification of the spectrum of incidents and risk factors and helped in the education of trainees and specialists. In this review, we analyse 379 incidents that had been reported among 44,915 anaesthetics administered in a two-year period. The risk of incidents was higher in patients of lower American Society of Anesthesiologists physical status, anaesthesia of long duration and anaesthesia carried out after hours. The most common incidents were airway problems and drug administration problems. Fifty-nine percent of incidents were evaluated to be preventable and adverse outcomes occurred in 48% of cases. Human factors were the major contributors to incidents. We suggest that incorporating critical incident reporting as part of a 100% procedural audit facilitated, rather than discouraged, the reporting of critical incidents, even though reporting was not anonymous. The rate of incident reporting increased from 0.37% to 0.84%. PMID- 25735692 TI - Gastric rupture following nasopharyngeal catheter oxygen delivery-a report of two cases. AB - Iatrogenic gastric distension and subsequent rupture following nasal or nasopharyngeal catheter oxygen delivery is a rare but life-threatening condition that requires urgent laparotomy. We report two cases recently encountered at our institution. Both patients exhibited symptoms of abdominal pain and distension following oxygen delivery involving a nasopharyngeal catheter during procedural sedation. Oxygen flow rates were 4 l/minute in both cases. The diagnosis was made by urgent imaging. Both patients survived following laparotomy and repair of gastric rupture. Seventeen cases have been reported previously in the literature. We recommend avoidance of nasal or nasopharyngeal catheters and the use of alternative oxygen delivery methods such as nasal prongs and face masks. PMID- 25735693 TI - Maternal pulmonary oedema during foetoscopic surgery. AB - We report a case of maternal pulmonary oedema necessitating intubation and ventilation with associated hyperchloraemic metabolic acidosis during foetoscopic laser surgery for twin-twin transfusion syndrome (TTTS), believed to be secondary to absorption of normal saline irrigation fluid. TTTS complicates 10% to 20% of monochorionic twin pregnancies and develops due to imbalanced vascular anastomoses and consequent unidirectional transfusion between the twins. The recipient is at risk of cardiac failure due to circulatory overload and the donor twin becomes hypoperfused. The recipient is polyhydramniotic and the donor is oligohydramniotic. Untreated severe TTTS has a mortality rate of up to 90%. Treatment options include delivery if viable, serial amnioreduction or foetoscopic laser ablation of the communicating vessels. Since the Eurofoetus study, laser ablation has been the mainstay of treatment for pre-viable TTTS, involving insertion of endoscopes transabdominally into the polyhydramniotic sac to allow visualisation and ablation of the anastosmotic vessels. Amnioreduction does not correct the underlying pathology and offers very little in advanced disease. Foetoscopic laser ablation leads to an improved survival past 28 days and a lower incidence of neurological complications compared to serial amnioreduction. PMID- 25735694 TI - D-blade C-MAC videolaryngoscopyTM with the frova intubating introducerTM. PMID- 25735695 TI - Hyperthermia in brain dead patients. PMID- 25735696 TI - Neuromuscular blocking agents: high-alert medications with ongoing risks of error. PMID- 25735697 TI - A quicker and more reliable method of excluding inadvertent arterial puncture during central venous line insertion. PMID- 25735698 TI - Unexplained hypercarbia may indicate subcutaneous emphysema during laparoscopy. PMID- 25735699 TI - Limitations of ultrasound-guided central venous cannulation. PMID- 25735700 TI - Postpartum buttock numbness: a series of 95 cases. PMID- 25735701 TI - Error proofing to reduce the incidence of retained guide-wires after central venous catheterisation-a call to anaesthetists and manufacturers for collaborative action. PMID- 25735702 TI - Preliminary report of a novel model using human umbilical vein endothelium in whole umbilical cord preparations to examine the in vitro effects of lipopolysaccharide and hypertonic saline on the gene expression of inflammatory mediators. PMID- 25735703 TI - Package inserts: to believe or not to believe. PMID- 25735704 TI - Epidural catheter knot immediately after catheter insertion. PMID- 25735705 TI - Perforation of a Meckel's diverticulum by a mussel shell fragment. PMID- 25735706 TI - Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. AB - BACKGROUND: Lung cancer is one of the leading causes of cancer-related death. At the time of diagnosis, more than half of the patients will have disseminated disease and, yet, diagnosing can be challenging. New methods are desired to improve the diagnostic work-up. Exosomes are cell-derived vesicles displaying various proteins on their membrane surfaces. In addition, they are readily available in blood samples where they constitute potential biomarkers of human diseases, such as cancer. Here, we examine the potential of distinguishing non small cell lung carcinoma (NSCLC) patients from control subjects based on the differential display of exosomal protein markers. METHODS: Plasma was isolated from 109 NSCLC patients with advanced stage (IIIa-IV) disease and 110 matched control subjects initially suspected of having cancer, but diagnosed to be cancer free. The Extracellular Vesicle Array (EV Array) was used to phenotype exosomes directly from the plasma samples. The array contained 37 antibodies targeting lung cancer-related proteins and was used to capture exosomes, which were visualised with a cocktail of biotin-conjugated CD9, CD63 and CD81 antibodies. RESULTS: The EV Array analysis was capable of detecting and phenotyping exosomes in all samples from only 10 uL of unpurified plasma. Multivariate analysis using the Random Forests method produced a combined 30-marker model separating the two patient groups with an area under the curve of 0.83, CI: 0.77-0.90. The 30-marker model has a sensitivity of 0.75 and a specificity of 0.76, and it classifies patients with 75.3% accuracy. CONCLUSION: The EV Array technique is a simple, minimal-invasive tool with potential to identify lung cancer patients. PMID- 25735707 TI - Non-invasive repeated therapeutic stimulation for aphasia recovery: a multilingual, multicenter aphasia trial. AB - Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30 days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45 minutes speech and language therapy session for 10 days. Efficacy is evaluated at 1 and 30 days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add an effective new strategy for early stage poststroke aphasia rehabilitation. PMID- 25735708 TI - Cost burden of stroke mimics and transient ischemic attack after intravenous tissue plasminogen activator treatment. AB - BACKGROUND: Treatment decisions for patients with acute stroke symptoms are based on pertinent history, neurologic examination, laboratory studies, and head computed tomography. In this setting, patients with stroke mimic (SM) may mistakenly receive intravenous tissue plasminogen activator (IV-rtPA). The goal of this study was to investigate the excess direct/indirect hospital costs among patients who received IV-rtPA when final diagnosis was not ischemic stroke. METHODS: We reviewed the records of 535 IV-rtPA-treated patients who presented to our primary stroke centers. The diagnosis of SM or transient ischemic attack (TIA) was based on patient presentation, hospital course, electroencephalography, and negative neuroimaging studies. The excess cost analysis compared actual direct and indirect hospital costs of a patient to what their direct and indirect hospital costs would have been had they primarily been diagnosed with mimic or TIA. RESULTS: Seventy-four patients post-IV-rtPA treatment had final diagnosis of SM; 21 had TIAs. The excess direct and indirect hospital costs for mimics were $257,975 and $152,813, respectively. The median excess cost was $5401 per admission. The excess total cost for TIAs was $85,026 with a median of $3407 per admission. CONCLUSIONS: Administration of IV-rtPA to patients with SMs remains prevalent and costly. Certain clinical or radiographic characteristics can help diagnose mimics; however, more studies need to be done to determine the feasibility and effectiveness of further clinical investigations among suspected SM patients who are within the thrombolysis treatment window. PMID- 25735709 TI - Comparison of cardiac output measured by oesophageal Doppler ultrasonography or pulse pressure contour wave analysis. AB - BACKGROUND: Maintaining adequate organ perfusion during high-risk surgery requires continuous monitoring of cardiac output to optimise haemodynamics. Oesophageal Doppler Cardiac Output monitoring (DCO) is commonly used in this context, but has some limitations. Recently, the cardiac output estimated by pulse pressure analysis- (PPCO) was developed. This study evaluated the agreement of cardiac output variations estimated with 9 non-commercial algorithms of PPCO compared with those obtained with DCO. METHODS: High-risk patients undergoing neurosurgery were monitored with invasive blood pressure and DCO. For each patient, 9 PPCO algorithms and DCO were recorded before and at the peak effect for every haemodynamic challenge. RESULTS: Sixty-two subjects were enrolled; 284 events were recorded, including 134 volume expansions and 150 vasopressor boluses. Among the 9 algorithms tested, the Liljestrand-Zander model led to the smallest bias (0.03 litre min(-1) [-1.31, +1.38] (0.21 litre min(-1) [-1.13; 1.54] after volume expansion and -0.13 litre min(-1) [-1.41, 1.15] after vasopressor use). The corresponding percentage of the concordance was 91% (86% after volume expansion and 94% after vasopressor use). The other algorithms, especially those using the Winkessel concept and the area under the pressure wave, were profoundly affected by the vasopressor. CONCLUSIONS: Among the 9 PPCO algorithms examined, the Liljestrand-Zander model demonstrated the least bias and best limits of agreement, especially after vasopressor use. Using this particular algorithm in association with DCO calibration could represent a valuable option for continuous cardiac output monitoring of high risk patients. CLINICAL TRIAL REGISTRATION: Comite d'ethique de la Societe de Reanimation de Langue Francaise No. 11-356. PMID- 25735710 TI - Intraoperative awareness: controversies and non-controversies. AB - Intraoperative awareness, with or without recall, continues to be a topic of clinical significance and neurobiological interest. In this article, we review evidence pertaining to the incidence, sequelae, and prevention of intraoperative awareness. We also assess which aspects of the complication are well understood (i.e. non-controversial) and which require further research for clarification (i.e. controversial). PMID- 25735712 TI - Fibrinogen concentrates for post-partum haemorrhage? Do not miss the most relevant population! PMID- 25735711 TI - Memory formation during anaesthesia: plausibility of a neurophysiological basis. AB - As opposed to conscious, personally relevant (explicit) memories that we can recall at will, implicit (unconscious) memories are prototypical of 'hidden' memory; memories that exist, but that we do not know we possess. Nevertheless, our behaviour can be affected by these memories; in fact, these memories allow us to function in an ever-changing world. It is still unclear from behavioural studies whether similar memories can be formed during anaesthesia. Thus, a relevant question is whether implicit memory formation is a realistic possibility during anaesthesia, considering the underlying neurophysiology. A different conceptualization of memory taxonomy is presented, the serial parallel independent model of Tulving, which focuses on dynamic information processing with interactions among different memory systems rather than static classification of different types of memories. The neurophysiological basis for subliminal information processing is considered in the context of brain function as embodied in network interactions. Function of sensory cortices and thalamic activity during anaesthesia are reviewed. The role of sensory and perisensory cortices, in particular the auditory cortex, in support of memory function is discussed. Although improbable, with the current knowledge of neurophysiology one cannot rule out the possibility of memory formation during anaesthesia. PMID- 25735713 TI - Multifaceted bench comparative evaluation of latest intensive care unit ventilators. AB - BACKGROUND: Independent bench studies using specific ventilation scenarios allow testing of the performance of ventilators in conditions similar to clinical settings. The aims of this study were to determine the accuracy of the latest generation ventilators to deliver chosen parameters in various typical conditions and to provide clinicians with a comprehensive report on their performance. METHODS: Thirteen modern intensive care unit ventilators were evaluated on the ASL5000 test lung with and without leakage for: (i) accuracy to deliver exact tidal volume (VT) and PEEP in assist-control ventilation (ACV); (ii) performance of trigger and pressurization in pressure support ventilation (PSV); and (iii) quality of non-invasive ventilation algorithms. RESULTS: In ACV, only six ventilators delivered an accurate VT and nine an accurate PEEP. Eleven devices failed to compensate VT and four the PEEP in leakage conditions. Inspiratory delays differed significantly among ventilators in invasive PSV (range 75-149 ms, P=0.03) and non-invasive PSV (range 78-165 ms, P<0.001). The percentage of the ideal curve (concomitantly evaluating the pressurization speed and the levels of pressure reached) also differed significantly (range 57-86% for invasive PSV, P=0.04; and 60-90% for non-invasive PSV, P<0.001). Non-invasive ventilation algorithms efficiently prevented the decrease in pressurization capacities and PEEP levels induced by leaks in, respectively, 10 and 12 out of the 13 ventilators. CONCLUSIONS: We observed real heterogeneity of performance amongst the latest generation of intensive care unit ventilators. Although non-invasive ventilation algorithms appear to maintain adequate pressurization efficiently in the case of leakage, basic functions, such as delivered VT in ACV and pressurization in PSV, are often less reliable than the values displayed by the device suggest. PMID- 25735714 TI - First Enterovirus D68 (EV-D68) cases detected in hospitalised patients in a tertiary care university hospital in Spain, October 2014. AB - Several outbreaks of Enterovirus 68 (EV-D68) have recently been reported in the USA and Canada, causing substantial hospitalisation of children with severe respiratory disease. The acute flaccid paralysis detected in the USA and Canada among children with EV-D68 infection has raised concerns about the aetiological role of this EV serotype in severe neurological disease. The circulation of EV D68 in the general European population seems to be low, but European Centre for Disease Prevention and Control (ECDC) recommends being vigilant to new cases, particularly in severely ill hospitalised patients. In October 2014, enteroviruses were detected in respiratory samples collected from five hospitalised patients, children and adults. Phylogenetic analysis of partial VP1 sequences confirmed that the detected enteroviruses belonged to the D68 serotype, which were also similar to strains reported in USA (2014). However, all five patients developed respiratory symptoms, but only one required ICU admission. None of the patients described had symptoms of neurological disease. Other considerations related to the detection methods used for the diagnosis of respiratory enteroviruses are also discussed. In conclusion, additional evidence has been provided that supports the role of EV-D68 in respiratory infections in hospitalised patients. PMID- 25735716 TI - Switching from tenofovir containing regimens to boosted protease inhibitor monotherapy: Impact on renal function. AB - OBJECTIVE: To evaluate the effect on creatinine clearance (CG-CrCl, Cockcroft Gault equation) of switching to boosted protease inhibitor (PI) monotherapy in patients receiving a triple drug antiretroviral regimen containing TDF. METHODS: All patients who had received a TDF-containing regimen for at least one year and had been switched to PI monotherapy were included. A rapid decrease in CG-CrCl during exposure to TDF was defined as a decrease in CG-CrCl at least five times higher than the expected due to age (0.4ml/min/year by the years of exposure to TDF). In this subgroup of patients, we considered improvement if the last value of CG-CrCl on PI monotherapy was 10% higher than the last value of CG-CrCl before switching to PI monotherapy. A multivariate logistic regression was constructed to identify factors associated to renal improvement after switching to bPI monotherapy. RESULTS: 64 patients included. The median (IQR) annual change in CG CrCl during PI monotherapy was significantly lower than the median (IQR) annual change while exposed to TDF [-0.9 (-4.7 to +2.8) ml/min vs. -4 (-8 to -1) ml/min, p=0.001]. 44 patients experienced a rapid decline during TDF exposition. After switch to PI monotherapy, 15/44 (34%, 95% CI: 21-50%) had an improved CG-CrCl and 16/44 (36%, CI 23-52%) experienced a further decline in CG-CrCl. The only variable associated to CG-CrCl improvement was a more rapid CG-CrCl decline in the last year of exposure to TDF. CONCLUSION: Switching to PI monotherapy partially reversed CG-CrCl decrease associated to TDF use, especially in patients with a more rapid decline while receiving TDF. PMID- 25735715 TI - [Acellular vaccines (DTPa/dTpa) against whooping cough, protection duration]. AB - INTRODUCTION: An increase in whooping cough in most of the developed countries has been detected in the last decade. OBJECTIVE: To determine whether the administration of dTpa vaccine instead of DTPa fifth dose is contributing to the appearance of these cases. METHODS: A descriptive study based on cases of whooping cough reported during an epidemic period in the city of Alicante in the first 5 months of 2014. Only pertussis cases confirmed by PCR were included in the study, and only those vaccinated with 5 doses were included in the analysis of the period of protection. RESULTS: A total of 104 cases of pertussis confirmed by PCR were reported, with 85 cases (82%) having had 5 doses of vaccine. The mean time and standard deviation (SD) of protection was 2.1+/-1.1 years with dTpa, and 5.1+/-1.5 years with DTPa (p<.001). In the protection, adjusted for age, it was observed that, after 3 years, only 47.6% of people vaccinated with dTpa were still protected, while people vaccinated with DTPa were 100% protected (P<.001). CONCLUSIONS: This study found that people who were properly vaccinated against pertussis and received their last re-vaccination dose with dTpa had a shorter period of protection than those who were vaccinated with DTPa. PMID- 25735717 TI - Antimicrobial susceptibility and typing of Neisseria gonorrhoeae strains from Southern Spain, 2012-2014. AB - BACKGROUND: Gonorrhoea remains an important health problem worldwide. The latest European guidelines have recommended the introduction of dual antimicrobial therapy due to the increase in its resistance to antimicrobial agents. METHODS: In the present study, the susceptibility to some antibiotics was evaluated, and the typing of Neisseria gonorrhoeae strains was also performed. All Neisseria gonorrhoeae (NG) strains isolated from January 2012 to October 2014 were included in this work. Gonococcal isolates were tested for susceptibility according to the recommendations of both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). A total of 65 isolates were typed by the NG multi-antigen sequence types (NG-MAST) technique. RESULTS: The most frequent types found were ST 1407, ST 5405, ST 2992, and ST 5120. If CLSI and EUCAST criteria were applied, an ST 9807 type was found non-susceptible to ceftriaxone and cefixime (MIC 0.5MUg/mL). When only EUCAST breakpoints were taken into account, three strains were also resistant to cefixime (MIC 0.25MUg/mL) and two isolates were resistant to ceftriaxone (MIC 0.19 and 0.25MUg/mL, respectively). The majority of strains were resistant to ciprofloxacin, and all Neisseria gonorrhoeae strains were susceptible to spectinomycin; twenty-five percent of isolates were resistant to azithromycin. CONCLUSIONS: The implementation of antimicrobial surveillance programs at regional level should be part of an overall gonococcal infection control strategy. Efforts should be made to perform antimicrobial susceptibility, a "cured test" in all gonorrhoea cases, and identify treatment failures to verify emerging resistance. Some types have been associated with decreased susceptibility to cephalosporins, making molecular typing a useful tool to predict antimicrobial resistance. PMID- 25735718 TI - Novel chemistry for undruggable targets. PMID- 25735719 TI - Should Cerebral Near-infrared Spectroscopy be Standard of Care in Adult Cardiac Surgery? AB - Near-infrared spectroscopy (NIRS) is non-invasive, easy to use, and offers real time monitoring of the oxygen content of cerebral tissue. An effective and user friendly method of cerebral monitoring stands to offer a significant advance in patient care during adult cardiac surgery, particularly for surgery in which the continuity of cerebral vessels may be compromised. While the current evidence does not definitively show improvement in neurological outcomes, it can be argued that the overall risk to benefit ratio falls on the side of NIRS. NIRS also gives information about the oxygenation of systemic tissues. It may be that in surgery that does not involve the aortic arch, the value of NIRS will be in increased individualisation of patient management and improved systemic perfusion, impacting general outcomes as much as neurological outcomes. This review will summarise the need for neuromonitoring and the principles of NIRS. It will examine the thresholds used to define desaturation, the evidence for clinical benefit from NIRS, and the criticisms and limitations of NIRS. It will also discuss the uses of NIRS beyond improving neurological outcomes alone. PMID- 25735720 TI - Radial artery spasm and perforation: simple solutions for challenging cases. AB - Transradial access for percutaneous coronary intervention and diagnostic coronary angiography has been increasingly utilised in the routine practice in most catheterisation laboratories as it reduces the incidence of major access site complications such as bleeding and haematoma. Radial artery spasm with or without perforation is one of the more frequent reasons for converting from radial to femoral access. In this article, the balloon-assisted technique and Sheathless EauCath (Asahi Intecc, Aichi, Japan) are demonstrated to overcome radial artery spasm with associated significant perforation in two cases. PMID- 25735721 TI - Cultured chondrocyte and porcine cartilage-derived substance (PCS) construct as a possible dorsal augmentation material in rhinoplasty: A preliminary animal study. AB - As there is no single ideal material for dorsal augmentation in rhinoplasty, there has been a continuing need for the development of improved materials. Therefore, we aimed to evaluate the outcome of using a novel tissue-engineered construct composed of autologous chondrocytes cultured with a porcine cartilage derived substance (PCS) scaffold as an augmentation material in rhinoplasty. A scaffold derived from decellularized and powdered porcine articular cartilage was prepared. The rabbit articular cartilage was used as the source of homologous chondrocytes, which were expanded and cultured with the PCS scaffold for 7 weeks. The chondrocyte-PCS constructs were then surgically implanted on the nasal dorsum of six rabbits. Four and eight weeks after implantation, the gross morphology, radiologic images, and histologic features of the site of implant were analyzed. The rabbits showed no signs of postoperative inflammation and infection. The degree of dorsal augmentation was maintained during the 8-week postoperative observation period. Postoperative histologic examinations showed chondrocyte proliferation without an inflammatory response. However, neo-cartilage formation from the constructs was not confirmed. The biocompatibility and structural features of tissue-engineered chondrocyte-PCS constructs indicate their potential as candidate dorsal augmentation material for use in rhinoplasty. PMID- 25735722 TI - On-top plasty as a treatment for floating finger. PMID- 25735724 TI - DNAzyme tunable lead(II) gating based on ion-track etched conical nanochannels. AB - A simple biomimetic ionic gate has been developed by modifying lead(II) ion responsive DNAzymes onto the inner surface of ion-etched polymer nanochannels. PMID- 25735723 TI - MiR-21 controls in situ expansion of CCR6+ regulatory T cells through PTEN/AKT pathway in breast cancer. AB - Our recent evidence showed that prior expansion of CCR6(+) Foxp3(+) regulatory T cells (Tregs) was important for their dominant enrichment in tumor tissue, which was closely related to poor prognosis of breast cancer patients. However, the underlying regulation mechanism of expansion of CCR6(+) Tregs in situ remains largely unknown. In this study, we reported that miR-21 was highly expressed in CCR6(+) Tregs in tumor tissues from a murine breast cancer model. And silencing of miR-21 could significantly reduce the proliferation of CCR6(+) Tregs in vitro. Adoptive cell-transfer assay further showed that silencing of miR-21 could alter the enrichment of CCR6(+) Tregs in the tumor mass and endow effectively antitumor effect of CD8(+) T cells using a murine breast cancer model. Mechanistic evidence showed that silencing of miR-21 enhanced the expression of its target phosphatase and tensin homolog deleted on chromosome ten (PTEN) and subsequently altered the activation of Akt pathway, which was ultimately responsible for reduced proliferation activity of CCR6(+) Tregs. Finally, we further revealed that miR-21 was also highly expressed on CCR6(+) Tregs in clinical breast cancer patients. Therefore, miR-21 can act as a fine tuner in the regulation of PTEN/Akt pathway transduction in the expansion of CCR6(+) Tregs in tumor sites and provided a novel insight into the development of therapeutic strategies for promoting T-cell immunity by regulating distinct subset of Tregs through targeting specific miRNAs. PMID- 25735725 TI - Four-Dimensional Speckle Tracking Echocardiography in Patients with Hypertrophic Cardiomyopathy. AB - OBJECTIVE: Abnormal left ventricular (LV) deformational mechanics have been demonstrated in patients with hypertrophic cardiomyopathy (HCM) using two dimensional (2D) speckle tracking echocardiography, but there is not enough information about the four-dimensional speckle tracking echocardiography (4DSTE) in these patients. The objective of the study was to identify and quantify the left ventricular contractility in patients with HCM using 4DSTE. METHODS: Thirty patients [age, 54.6 +/- 12.1 years; 12 (40%) women] with diagnosis of nonobstructive HCM and 20 healthy controls [age, 47.42 +/- 11.43 years; 8 (40%) women] underwent 4DSTE measurement of longitudinal, radial, circumferential, and area strains. RESULTS: Patients with HCM showed lower longitudinal (-13.5% vs. 20.3%, P < 0.001) and radial (33.4% vs. 43.6%, P < 0.001) strain, but higher circumferential (-22.7% vs. -15.9%, P < 0.001) and area (-30.7% vs. -22.1%, P < 0.001) strain than control subjects. Peak LV twist showed significantly higher values in patients with HCM (13.7 +/- 5.3 vs. 11.3 +/- 4.8, P < 0.005). CONCLUSIONS: Patients with HCM have reduced longitudinal and radial strain but increased circumferential and area strain on 4DSTE. These results are found appropriate with previous 2DSTE studies. Thus, 4DSTE is useful to determine LV deformational mechanics. PMID- 25735726 TI - Cucurbit[n]uril-capped upconversion nanoparticles as highly emissive scaffolds for energy acceptors. AB - Spontaneous adsorption of cucurbit[n]uril CB[n] (n=6, 7, and 8) on the surface of naked upconversion nanoparticles (UCNPs), in particular, NaYF4:Er3+(2%),Yb3+(18%) gave rise to UCNP@CB[n] exclusion complexes. These complexes proved to be highly stable as well as highly emissive under near-infrared excitation. By using two tricyclic basic dyes (specifically, methylene blue and pyronin Y) as a proof of concept, we demonstrate that the UCNP@CB[n] (n=6, 7) nanohybrids can form exclusion complexes with this type of dyes via the CB carbonyl free portal, i.e., UCNP@CB@dye hybrids, thus making it possible to locate a high concentration of the dyes close to the UCNP and, consequently, leading to efficient energy transfer from the UCNP to the dye. PMID- 25735727 TI - Gold-palladium core@shell nanoalloys: experiments and simulations. AB - In this work, we report a facile synthesis route, structural characterization, and full atomistic simulations of gold-palladium nanoalloys. Through aberration corrected-STEM, UV-vis spectroscopy and EDS chemical analysis, we were able to determine that Au(core)-Pd(shell) bimetallic nanoparticles were formed. Using different computational approaches, we were capable of establishing how the size of the core and the thickness of the shell will affect the thermodynamic stability of several core-shell nanoalloys. Finally, grand canonical simulations using different sampling procedures were used to study the growth mechanism of Pd atoms on Au seeds of different shapes. PMID- 25735728 TI - Effect of chitosan on spoilage bacteria, Escherichia coli and Listeria monocytogenes in cured chicken meat. AB - The effects of essential oil (EO) of oregano and chitosan on the microbial quality and growth inhibition of Listeria monocytogenes and Escherichia coli O157:H7 in the Iranian traditional ready-to-barbecue chicken was evaluated. Thus, three groups of samples were prepared. One of them was considered to evaluate for aerobic plate count (APC), lactic acid bacteria (LAB), psychrophilic and enterobacteriacae counts and the other two groups were inoculated with E. coli O157:H7 and L. monocytogenes 4b to investigate the effect of oregano EO and chitosan on pathogenic bacteria. All groups were stored at 3, 8 and 20 degrees C. Oregano showed antibacterial effects against APC, LAB, psychrophilics, enterobacteriacae and E. coli O157:H7, whereas, such an effect was not observed against L. monocytogenes. Chitosan individually did not show an inhibitory effect on the spoilage-inducing bacteria and E. coli, but was effective against L. monocytogenes. Using chitosan and oregano EO in combination can reduce the number of spoilage and safety indicators and also the two food-borne pathogens in ready to-barbecue chicken meat. PMID- 25735729 TI - Similarity of currently circulating H1N1 virus with the 2009 pandemic clone: viability of an imminent pandemic. AB - The first influenza pandemic in the 21st century commenced in March, 2009 causing nearly 300,000 deaths globally within the first year of the pandemic. In late 2013 and in early 2014, there was gradual increase in the reported case of H1N1 infection and according to World Health Organization (WHO) report, influenza activity increased in several areas of the Southern Hemisphere and was dominated by the H1N1 pandemic strain of 2009. In the present study, a comprehensive comparison of the global amino acid composition and the structural features of all HA gene sequences of H1N1, available in the Flu Database (NCBI), from 1918 to December, 2014 has been performed to trace out the possibility of a further H1N1 pandemic in near future. The results suggest that the increased potential to enhance pathogenicity for the H1N1 samples of 2013 (latter part) and 2014 could lead to a more severe outbreak in the near future. PMID- 25735730 TI - Use of multiplexed tandem PCR to estimate the prevalence and intensity of Theileria orientalis infections in cattle. AB - This study employed a semi-quantitative, multiplexed tandem PCR (MT-PCR) to assess the prevalence and infection intensity of four genotypes (buffeli, chitose, ikeda and type 5) of Theileria orientalis in cattle in Australia. Genomic DNA samples from blood samples (n=448) collected from 27 to 32 dairy cows from each of 15 dairy herds with a history of recent theileriosis outbreaks (Group 1), and from blood samples available from 24 cows with or without oriental theileriosis (Group 2) were tested using MT-PCR. Results revealed that all four genotypes were present in Group 1 cattle; genotype buffeli had the highest prevalence (80.5%), followed by genotypes ikeda (71.4%), chitose (38.6%) and type 5 (20.3%). Genotype ikeda had the highest average infection intensity in the cattle (relating to 55,277 DNA copies), followed by buffeli, chitose and type 5 (6354-51,648 copies). For Group 2, results indicated that genotype ikeda had a significantly higher average intensity of infection than buffeli in symptomatic cattle (P<0.001), and symptomatic cattle had a higher intensity of ikeda than asymptomatic cattle (P=0.004). Future studies should assess the utility of the present MT-PCR assay as a diagnostic and epidemiological tool in other parts of Australasia and the world. PMID- 25735731 TI - Comparison of the identification and ease of use of two alarm sound sets by critical and acute care nurses with little or no music training: a laboratory study. AB - The melodic alarm sound set for medical electrical equipment that was recommended in the International Electrotechnical Commission's IEC 60601-1-8 standard has proven difficult for clinicians to learn and remember, especially clinicians with little prior formal music training. An alarm sound set proposed by Patterson and Edworthy in 1986 might improve performance for such participants. In this study, 31 critical and acute care nurses with less than one year of formal music training identified alarm sounds while they calculated drug dosages. Sixteen nurses used the IEC and 15 used the Patterson-Edworthy alarm sound set. The mean (SD) percentage of alarms correctly identified by nurses was 51.3 (25.6)% for the IEC alarm set and 72.1 (18.8)% for the Patterson-Edworthy alarms (p = 0.016). Nurses using the Patterson-Edworthy alarm sound set reported that it was easier to distinguish between alarm sounds than did nurses using the IEC alarm sound set (p = 0.015). Principles used to construct the Patterson-Edworthy alarm sounds should be adopted for future alarm sound sets. PMID- 25735732 TI - GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R. AB - Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of Talphabeta and Tgammadelta IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r(-/-) mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R-dependent mechanism of action. Furthermore, Glp1r(-/-) mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r(-/-) recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity. PMID- 25735733 TI - Comparison of 3D C-arm fluoroscopy and 3D image-guided navigation for minimally invasive pelvic surgery. AB - PURPOSE: This study aims to compare the efficacy and accuracy of percutaneous screw fixation using three-dimensional [Formula: see text] navigation and conventional C-arm fluoroscopy in pelvic fracture surgery. METHODS: This was a retrospective study of 81 patients with pelvic fractures treated using percutaneous screw fixation between June 2005 and January 2011. All pelvic fractures were treated with closed reduction, small open reduction, or medium open reduction. Intraoperative radiation exposure, fixation, surgical outcome, and functional recovery were compared based on the fluoroscopy navigation method used during screw fixation. Radiographic follow-up was assessed at 1, 3, 6, and 9 months postoperatively, and a CT scan was completed at 9 months postoperatively. RESULTS: A total of 130 cannulated screws were placed. Average screw fixation time and fluoroscopy exposure time in [Formula: see text] group were lower than the C-arm fluoroscopy group ([Formula: see text] vs [Formula: see text]) [Formula: see text]. Seventy-four of the 81 patients made a full recovery. Successful outcome was confirmed with radiological imaging and postoperative follow-up at 6-24 months. No delayed union or nonunion was detected. No significant difference in functional recovery at 6 months postoperative was found due to the fluoroscopy imaging technique. CONCLUSIONS: Percutaneous screw fixation using the [Formula: see text] navigational system minimizes the fluoroscope exposure and screw insertion time, while improving screw insertion accuracy. Moreover, the [Formula: see text] navigational system provided a reliable method for fluoroscopy imaging in pelvic fractures. PMID- 25735734 TI - Work domain constraints for modelling surgical performance. AB - PURPOSE: Three main approaches can be identified for modelling surgical performance: a competency-based approach, a task-based approach, both largely explored in the literature, and a less known work domain-based approach. The work domain-based approach first describes the work domain properties that constrain the agent's actions and shape the performance. This paper presents a work domain based approach for modelling performance during cervical spine surgery, based on the idea that anatomical structures delineate the surgical performance. This model was evaluated through an analysis of junior and senior surgeons' actions. METHOD: Twenty-four cervical spine surgeries performed by two junior and two senior surgeons were recorded in real time by an expert surgeon. According to a work domain-based model describing an optimal progression through anatomical structures, the degree of adjustment of each surgical procedure to a statistical polynomial function was assessed. RESULTS: Each surgical procedure showed a significant suitability with the model and regression coefficient values around 0.9. However, the surgeries performed by senior surgeons fitted this model significantly better than those performed by junior surgeons. Analysis of the relative frequencies of actions on anatomical structures showed that some specific anatomical structures discriminate senior from junior performances. CONCLUSION: The work domain-based modelling approach can provide an overall statistical indicator of surgical performance, but in particular, it can highlight specific points of interest among anatomical structures that the surgeons dwelled on according to their level of expertise. PMID- 25735735 TI - Combination of on-line CE assay with MS detection for the study of drug metabolism by cytochromes P450. AB - A new CE-MS method with enzymatic reaction inside the capillary was developed for the study of drug metabolism by cytochromes P450. This automated method, based on the transverse diffusion of laminar flow profiles methodology, is comprised of the injection of substrates and enzyme, their mixing, incubation, and separation of the reaction products, all performed by CE, and their detection, identification, and quantification by MS. The developed and validated method was finally used to conduct a kinetic study of cytochrome P450 isoform 2C9 or human liver microsomes with diclofenac in order to demonstrate its practical functionality. All the estimated kinetic values--apparent Michaelis constants and apparent maximum reaction velocities were in agreement with literature data obtained using other techniques. In addition, the consumption of reactants was in the tens of nL per analysis. The method's usability was further demonstrated on tolbutamide, the other probe substrate of cytochrome P450 isoform 2C9. As a result, the method is conceptually applicable for the screening of any other cytochrome P450 isoform and its substrates and inhibitors after adapting the incubation and separation conditions. PMID- 25735736 TI - Relaxation Kinetic Study of Eudragit(r) NM30D Film Based on Complex Modulus Formalism. AB - This study is aimed at resolving and characterizing the primary (alpha) and secondary relaxations (beta) in Eudragit(r) NM30D film based on apparent activation energies derived from complex modulus formalism using dielectric analysis (DEA). The glass transition (T g) of the film was determined using differential scanning calorimetry (DSC). The alpha relaxation corresponding to T g and the beta relaxations occurring below T g were probed using DEA. The occurrence of alpha and beta relaxations in Eudragit(r) NM30D film was elucidated using the complex modulus of the dielectric response employing loss modulus and permittivity data. Activation energies of these relaxations and the fundamental frequency so determined support the assignment of the relaxation pattern in the Eudragit(r) NM30D film. DEA methodology of the complex modulus formalism is a useful tool for differentiating the alpha and beta relaxation kinetics in Eudragits(r) not easily studied using traditional thermal methods such as DSC. The kinetics associated with alpha and beta relaxations so determined will provide formulation design support for solid orals that incorporate Eudragit(r) polymers. As mobility changes can affect stability and diffusion, the dipolar alpha and beta relaxations revealed through DEA analysis may enable a better correlation to functionality of Eudragit(r) based pharmaceutical dosage forms. PMID- 25735737 TI - History and development of surgical procedures for atrial fibrillation. AB - Cox J.L. devised the Maze procedure as a radical procedure for treating lone atrial fibrillation (AF) based on the multiple re-entry theory proposed by Allessie M.A. recently, Damiano R.J. devised the Cox Maze IV procedure using a bipolar radiofrequency clamp instead of cut-and-sew lines in 2008. In Japan, Kosakai Y. modified the original Maze II procedure using cryoablation in place of cut-and-sew lines in 1994, and Sueda T. reported the efficacy of the left atrial Maze procedure for persistent AF associated with mitral valve disease in 1996. The latter procedure subsequently provided insight regarding the origin of AF for cardiologists, and Haissagierre M. discovered ectopic foci arising the from pulmonary veins as a trigger of paroxysmal AF in 1998. Other procedures, including the radial approach and the biatrial appendage-preserving Maze procedure, were also developed by Japanese surgeons. This paper reviews the history and modifications of the Maze procedure developed to eradicate AF, focusing especially on the contributions of Japanese surgeons in this field. PMID- 25735738 TI - Distribution of interstitial pneumonia: a new radiological predictor of 90-day mortality after resection of lung cancer. AB - BACKGROUND: Surgery for lung cancer complicated by idiopathic interstitial pneumonia (IIP) is associated with a high rate of postoperative mortality. Thus, preoperative predictors of surgical mortality are needed to aid in the selection of suitable surgical candidates. METHODS: The subjects of this retrospective study were 1625 patients who underwent resection of primary lung cancer between 2000 and 2012, 203 (12.5 %) of whom were found to have IIPs. The following radiological findings were also evaluated: presence of honeycombing and the distribution (diffuse or localized) and extension (central extension or peripheral localized) of honeycombing or infiltration. We also investigated clinical factors and conducted multivariate analyses to identify the predictors of surgical mortality. RESULTS: The 30- and 90-day mortality rates were 0.5 and 1.4 % overall and 1.6 and 6.4 % in the IIP patients, respectively. Multivariate analysis revealed that a preoperative pO2 < 70 mmHg (HR 15.3), diffuse distribution and central extension of interstitial pneumonia on computed tomography (HR 9.2), and operative blood loss (ml: HR 1.003) were significant predictors of 90-day mortality. CONCLUSIONS: Diffuse distribution and central extension of IIPs, as well as preoperative hypoxia and operative blood loss, were significant predictors of 90-day mortality. PMID- 25735739 TI - Single-incision laparoscopic surgery for stricturing and penetrating Crohn's disease. AB - PURPOSE: Single-incision laparoscopic surgery (SILS) is a promising new technique that is potentially applicable to Crohn's disease (CD). However, there is no consensus on the application of SILS for penetrating CD due to its complex pathology. METHODS: We investigated the feasibility of SILS in 24 CD patients (12 with stricturing and 12 with penetrating CD) and compared the results between the two groups. RESULTS: There were 17 males and seven females [median age at the time of surgery, 41 (range 20-61) years old] included in the study. Sixteen patients underwent primary surgery, while eight received repeat surgery. Twenty patients had small bowel CD and four patients had ileocolonic CD. The indication for surgery was a fistula/abscess in 12 patients, stenosis in 10 and other indications in two cases. The total length of the operation and blood loss was 171 min (113-221 min) and 230 mL (30-400 mL) in the penetrating CD cases, and 149 min (111-186 min) and 90 mL (20-400 mL) in the stricturing CD cases. There were no significant differences in the length of the operation between the two groups, but the blood loss was significantly greater in the cases of penetrating CD. Conversion to open surgery was required in one patient with penetrating CD. Postoperative complications developed in one patient with stricturing CD. CONCLUSION: SILS could be performed safely not only in patients with stricturing CD, but also in those with penetrating CD. PMID- 25735740 TI - Sugar-sweetened beverages and risk of hypertension and CVD: a dose-response meta analysis. AB - A number of prospective cohort studies have investigated the associations between consumption of sugar-sweetened beverages (SSB) and the risk of hypertension, CHD and stroke, but revealed mixed results. In the present study, we aimed to perform a dose-response meta-analysis of these prospective studies to clarify these associations. A systematic literature search was conducted using the PubMed and Embase databases up to 5 May 2014. Random- or fixed-effects models were used to calculate the pooled relative risks (RR) with 95 % CI for the highest compared with the lowest category of SSB consumption, and to conduct a dose-response analysis. A total of six prospective studies (240 726 participants and 80 411 incident cases of hypertension) from four publications on hypertension were identified. A total of four prospective studies (194 664 participants and 7396 incident cases of CHD) from four publications on CHD were identified. A total of four prospective studies (259 176 participants and 10 011 incident cases of stroke) from four publications on stroke were identified. The summary RR for incident hypertension was 1.08 (95 % CI 1.04, 1.12) for every additional one serving/d increase in SSB consumption. The summary RR for incident CHD was 1.17 (95 % CI 1.10, 1.24) for every serving/d increase in SSB consumption. There was no significant association between SSB consumption and total stroke (summary RR 1.06, 95 % CI 0.97, 1.15) for every serving/d increase in SSB consumption. The present meta-analysis suggested that a higher consumption of SSB was associated with a higher risk of hypertension and CHD, but not with a higher risk of stroke. PMID- 25735741 TI - Sir William Turner (1832-1916) - Lancastrian, anatomist and champion of the Victorian era. AB - Sir William Turner, a Lancastrian, was renowned as a scientist, anatomist and a great reformer of medical education. His students became anatomists at various international institutions, which consequently shaped the future of anatomy as a subject matter both in the United Kingdom and in South Africa. Although Turner's accomplishments have been documented, little is known about the details that determined his career path and the individuals that shaped his future. Here the authors aim to highlight some aspects of Turner's academic achievements and his personal life as well as how he crossed paths with other great minds of the Victorian era including Richard Owen, Charles Darwin, James Paget and Joseph Lister. PMID- 25735742 TI - Caregiving experiences of family members of persons with dementia in south India. AB - This study reports on the first phase of an investigation aimed at adapting The Savvy Caregiver program, a successful family caregiving curriculum developed in the United States, for application in South India. Thirty family members caring for a person with dementia were interviewed regarding their experiences as caregivers (CGs). Qualitative interviews were conducted with the family member at a geriatric clinic, while other diagnostic procedures were being carried out with the person with dementia. Findings from the study revealed that although family members understood the term CG, none could identify a word for CG in his or her language. There was little understanding of dementia as an illness. Family CGs reported feeling distressed, overwhelmed, and frustrated with caregiving. Caregivers were interested in an educational program, but many had unrealistic expectations for what they wanted to learn. The findings provide directions for adapting The Savvy Caregiver curriculum for Indian family CGs. PMID- 25735743 TI - The contribution of cohesin-SA1 to gene expression and chromatin architecture in two murine tissues. AB - Cohesin, which in somatic vertebrate cells consists of SMC1, SMC3, RAD21 and either SA1 or SA2, mediates higher-order chromatin organization. To determine how cohesin contributes to the establishment of tissue-specific transcriptional programs, we compared genome-wide cohesin distribution, gene expression and chromatin architecture in cerebral cortex and pancreas from adult mice. More than one third of cohesin binding sites differ between the two tissues and these show reduced overlap with CCCTC-binding factor (CTCF) and are enriched at the regulatory regions of tissue-specific genes. Cohesin/CTCF sites at active enhancers and promoters contain, at least, cohesin-SA1. Analyses of chromatin contacts at the Protocadherin (Pcdh) and Regenerating islet-derived (Reg) gene clusters, mostly expressed in brain and pancreas, respectively, revealed remarkable differences that correlate with the presence of cohesin. We could not detect significant changes in the chromatin contacts at the Pcdh locus when comparing brains from wild-type and SA1 null embryos. In contrast, reduced dosage of SA1 altered the architecture of the Reg locus and decreased the expression of Reg genes in the pancreas of SA1 heterozygous mice. Given the role of Reg proteins in inflammation, such reduction may contribute to the increased incidence of pancreatic cancer observed in these animals. PMID- 25735744 TI - An LRP16-containing preassembly complex contributes to NF-kappaB activation induced by DNA double-strand breaks. AB - The activation of NF-kappaB has emerged as an important mechanism for the modulation of the response to DNA double-strand breaks (DSBs). The concomitant SUMOylation and phosphorylation of IKKgamma by PIASy and ATM, respectively, is a key event in this mechanism. However, the mechanism through which mammalian cells are able to accomplish these IKKgamma modifications in a timely and lesion specific manner remains unclear. In this study, we demonstrate that LRP16 constitutively interacts with PARP1 and IKKgamma. This interaction is essential for efficient interactions among PARP1, IKKgamma, and PIASy, the modifications of IKKgamma, and the activation of NF-kappaB following DSB induction. The regulation of LRP16 in NF-kappaB activation is dependent on the DSB-specific sensors Ku70/Ku80. These data strongly suggest that LRP16, through its constitutive interactions with PARP1 and IKKgamma, functions to facilitate the lesion-specific recruitment of PARP1 and IKKgamma and, ultimately, the concomitant recruitment of PIASy to IKKgamma in response to DSB damage. Therefore, the study has provided important new mechanistic insights concerning DSB-induced NF-kappaB activation. PMID- 25735745 TI - Crystal structures of the Gon7/Pcc1 and Bud32/Cgi121 complexes provide a model for the complete yeast KEOPS complex. AB - The yeast KEOPS protein complex comprising Kae1, Bud32, Cgi121, Pcc1 and Gon7 is responsible for the essential tRNA threonylcarbamoyladenosine (t(6)A) modification. Deletion of genes coding for the KEOPS subunits also affects telomere elongation and transcriptional regulation. In the present work, the crystal structure of Bud32/Cgi121 in complex with ADP revealed that ADP is bound in the catalytic site of Bud32 in a canonical manner characteristic of Protein Kinase A (PKA) family proteins. We found that Gon7 forms a stable heterodimer with Pcc1 and report the crystal structure of the Pcc1-Gon7 heterodimer. Gon7 interacts with the same Pcc1 region engaged in the archaeal Pcc1 homodimer. We further show that yeast KEOPS, unlike its archaeal counterpart, exists as a heteropentamer in which Gon7, Pcc1, Kae1, Bud32 and Cgi121 also adopt a linear arrangement. We constructed a model of yeast KEOPS that provides structural insight into the role of Gon7. The model also revealed the presence of a highly positively charged crater surrounding the entrance of Kae1 that likely binds tRNA. PMID- 25735746 TI - New insights into stop codon recognition by eRF1. AB - In eukaryotes, translation termination is performed by eRF1, which recognizes stop codons via its N-terminal domain. Many previous studies based on point mutagenesis, cross-linking experiments or eRF1 chimeras have investigated the mechanism by which the stop signal is decoded by eRF1. Conserved motifs, such as GTS and YxCxxxF, were found to be important for termination efficiency, but the recognition mechanism remains unclear. We characterized a region of the eRF1 N terminal domain, the P1 pocket, that we had previously shown to be involved in termination efficiency. We performed alanine scanning mutagenesis of this region, and we quantified in vivo readthrough efficiency for each alanine mutant. We identified two residues, arginine 65 and lysine 109, as critical for recognition of the three stop codons. We also demonstrated a role for the serine 33 and serine 70 residues in UGA decoding in vivo. NMR analysis of the alanine mutants revealed that the correct conformation of this region was controlled by the YxCxxxF motif. By combining our genetic data with a structural analysis of eRF1 mutants, we were able to formulate a new model in which the stop codon interacts with eRF1 through the P1 pocket. PMID- 25735747 TI - The architecture of ArgR-DNA complexes at the genome-scale in Escherichia coli. AB - DNA-binding motifs that are recognized by transcription factors (TFs) have been well studied; however, challenges remain in determining the in vivo architecture of TF-DNA complexes on a genome-scale. Here, we determined the in vivo architecture of Escherichia coli arginine repressor (ArgR)-DNA complexes using high-throughput sequencing of exonuclease-treated chromatin-immunoprecipitated DNA (ChIP-exo). The ChIP-exo has a unique peak-pair pattern indicating 5' and 3' ends of ArgR-binding region. We identified 62 ArgR-binding loci, which were classified into three groups, comprising single, double and triple peak-pairs. Each peak-pair has a unique 93 base pair (bp)-long (+/-2 bp) ArgR-binding sequence containing two ARG boxes (39 bp) and residual sequences. Moreover, the three ArgR-binding modes defined by the position of the two ARG boxes indicate that DNA bends centered between the pair of ARG boxes facilitate the non-specific contacts between ArgR subunits and the residual sequences. Additionally, our approach may also reveal other fundamental structural features of TF-DNA interactions that have implications for studying genome-scale transcriptional regulatory networks. PMID- 25735748 TI - U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish. AB - Mutations in FUS cause amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to neurodegeneration remain obscure. We previously found that U1 snRNP is the most abundant FUS interactor. Here, we report that components of the U1 snRNP core particle (Sm proteins and U1 snRNA), but not the mature U1 snRNP specific proteins (U1-70K, U1A and U1C), co-mislocalize with FUS to the cytoplasm in ALS patient fibroblasts harboring mutations in the FUS nuclear localization signal (NLS). Similar results were obtained in HeLa cells expressing the ALS causing FUS R495X NLS mutation, and mislocalization of Sm proteins is RRM dependent. Moreover, as observed with FUS, knockdown of any of the U1 snRNP specific proteins results in a dramatic loss of SMN-containing Gems. Significantly, knockdown of U1 snRNP in zebrafish results in motor axon truncations, a phenotype also observed with FUS, SMN and TDP-43 knockdowns. Our observations linking U1 snRNP to ALS patient cells with FUS mutations, SMN containing Gems, and motor neurons indicate that U1 snRNP is a component of a molecular pathway associated with motor neuron disease. Linking an essential canonical splicing factor (U1 snRNP) to this pathway provides strong new evidence that splicing defects may be involved in pathogenesis and that this pathway is a potential therapeutic target. PMID- 25735749 TI - Multimerization of Drosophila sperm protein Mst77F causes a unique condensed chromatin structure. AB - Despite insights on the cellular level, the molecular details of chromatin reorganization in sperm development, which involves replacement of histone proteins by specialized factors to allow ultra most condensation of the genome, are not well understood. Protamines are dispensable for DNA condensation during Drosophila post-meiotic spermatogenesis. Therefore, we analyzed the interaction of Mst77F, another very basic testis-specific protein with chromatin and DNA as well as studied the molecular consequences of such binding. We show that Mst77F on its own causes severe chromatin and DNA aggregation. An intrinsically unstructured domain in the C-terminus of Mst77F binds DNA via electrostatic interaction. This binding results in structural reorganization of the domain, which induces interaction with an N-terminal region of the protein. Via putative cooperative effects Mst77F is induced to multimerize in this state causing DNA aggregation. In agreement, overexpression of Mst77F results in chromatin aggregation in fly sperm. Based on these findings we postulate that Mst77F is crucial for sperm development by giving rise to a unique condensed chromatin structure. PMID- 25735750 TI - A positioned +1 nucleosome enhances promoter-proximal pausing. AB - Chromatin distribution is not uniform along the human genome. In most genes there is a promoter-associated nucleosome free region (NFR) followed by an array of nucleosomes towards the gene body in which the first (+1) nucleosome is strongly positioned. The function of this characteristic chromatin distribution in transcription is not fully understood. Here we show in vivo that the +1 nucleosome plays a role in modulating RNA polymerase II (RNAPII) promoter proximal pausing. When a +1 nucleosome is strongly positioned, elongating RNAPII has a tendency to stall at the promoter-proximal region, recruits more negative elongation factor (NELF) and produces less mRNA. The nucleosome-induced pause favors pre-mRNA quality control by promoting the addition of the cap to the nascent RNA. Moreover, the uncapped RNAs produced in the absence of a positioned nucleosome are degraded by the 5'-3' exonuclease XRN2. Interestingly, reducing the levels of the chromatin remodeler ISWI factor SNF2H decreases +1 nucleosome positioning and increases RNAPII pause release. This work demonstrates a function for +1 nucleosome in regulation of transcription elongation, pre-mRNA processing and gene expression. PMID- 25735751 TI - Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis. AB - The loss of photoreceptors is the defining characteristic of many retinal degenerative diseases, but the mechanisms that regulate photoreceptor cell death are not fully understood. Here we have used the 661W cone photoreceptor cell line to ask whether exposure to the terminal complement complex C5b-9 induces cell death and/or modulates the sensitivity of these cells to other cellular stressors. 661W cone photoreceptors were exposed to complete normal human serum following antibody blockade of CD59. Apoptosis induction was assessed morphologically, by flow cytometry, and on western blotting by probing for cleaved PARP and activated caspase-3. Necroptosis was assessed by flow cytometry and Sirtuin 2 inhibition using 2-cyano-3-[5-(2,5-dichlorophenyl)-2-furyl]-N-5 quinolinylacrylamide (AGK2). The sensitivity of 661W cells to ionomycin, staurosporine, peroxide and chelerythrine was also investigated, with or without prior formation of C5b-9. 661W cells underwent apoptotic cell death following exposure to C5b-9, as judged by poly(ADP-ribose) polymerase 1 cleavage and activation of caspase-3. We also observed apoptotic cell death in response to staurosporine, but 661W cells were resistant to both ionomycin and peroxide. Interestingly, C5b-9 significantly increased 661W sensitivity to staurosporine induced apoptosis and necroptosis. These studies show that low levels of C5b-9 on 661W cells can induce apoptosis, and that C5b-9 specifically sensitizes 661W cells to certain apoptotic and necroptotic pathways. Our observations provide new insight into the potential role of the complement system in photoreceptor loss, with implications for the molecular aetiology of retinal disease. PMID- 25735752 TI - Real-time imaging of mitochondrial hydrogen peroxide and pH fluctuations in living cells using a fluorescent nanosensor. AB - Mitochondrial reactive oxygen species (ROS) and pH fluctuations are closely correlated with mitochondrial dysfunctions, which are implicated in various human diseases including neurodegenerative disorders and cancers. Simultaneously monitoring the changes of ROS and pH of mitochondria remains a major challenge in the mitochondrial biology. In this study, we develop a novel mitochondria targeted fluorescent nanosensor for real-time imaging of the fluctuations of hydrogen peroxide (H2O2) and pH in living cells. The fluorescence probes for detecting pH and H2O2 were loaded in the small-sized mesoporous silica nanoparticles (MSN). Then the polyethylenimine was attached to cap the pores of MSN, the triphenylphosphonium was further modified to target mitochondria in living cells. Confocal fluorescence imaging indicated that the nanosensor could effectively target mitochondria and successfully achieved real-time imaging of mitochondrial H2O2 and pH fluctuations in living cells. Notably, this is a single nanosensing system that is capable of visualizing multiple subcellular analytes at the same time and position by multicolor fluorescence imaging. The current approach can provide a promising tool to investigate the interplaying roles of various subcellular analytes in living cells. PMID- 25735753 TI - Evaluation of the Spiritual Well-Being Scale in a Sample of Korean Adults. AB - This study explored the psychometric qualities and construct validity of the Spiritual Well-Being Scale (SWBS; Ellison in J Psychol Theol 11:330-340, 1983) using a sample of 470 Korean adults. Two factor analyses, exploratory factor analysis and confirmatory factor analysis, were conducted in order to test the validity of the SWBS. The results of the factor analyses supported the original two-dimensional structure of the SWBS-religious well-being (RWB) and existential well-being (EWB) with method effects associated with negatively worded items. By controlling for method effects, the evaluation of the two-factor structure of SWBS is confirmed with clarity. Further, the differential pattern and magnitude of correlations between the SWB subscales and the religious and psychological variables suggested that two factors of the SWBS were valid for Protestant, Catholic, and religiously unaffiliated groups except Buddhists. The Protestant group scored higher in RWB compared to the Buddhist, Catholic, and unaffiliated groups. The Protestant group scored higher in EWB compared to the unaffiliated groups. Future studies may need to include more Buddhist samples to gain solid evidence for validity of the SWBS on a non-Western religious tradition. PMID- 25735754 TI - Diabetes: Christian worldview, medical distrust and self-management. AB - To inform the development of a combined diabetes prevention and self-management intervention in partnership with church communities, this study sampled African American church leaders and members (N = 44) to qualitatively study religious beliefs and practices, diabetes prevention and self-management behaviors, and related community actions. Prior to commencing the study, internal review board approval was obtained. Although not required, community consent was officially provided by the church pastors. Individual consent was subsequently obtained from eligible community members who expressed an interest in participating in the study. Following a participatory action research approach, the inquiry group method was used. Qualitative data were analyzed with content analysis. Findings revealed Christian worldview, medical distrust and self-management as prominent themes. Findings suggest that diabetes providers address religious orientation in the provision of care with attention to rebuilding trust with the African American community to improve health outcomes. PMID- 25735755 TI - Lyar Is a New Ligand for Retinal Pigment Epithelial Phagocytosis. AB - Phagocytosis is critical to tissue homeostasis, as highlighted by phagocytosis defect of retinal pigment epithelial (RPE) cells with debris accumulation, photoreceptor degeneration and blindness. Phagocytosis ligands are the key to delineating molecular mechanisms and functional roles of phagocytes, but are traditionally identified in individual cases with technical challenges. We recently developed open reading frame phage display (OPD) for phagocytosis-based functional cloning (PFC) to identify unknown ligands. One of the identified ligands was Ly-1 antibody reactive clone (Lyar) with functions poorly defined. Herein, we characterized Lyar as a new ligand to stimulate RPE phagocytosis. In contrast to its reported nucleolar expression, immunohistochemistry showed that Lyar was highly expressed in photoreceptor outer segments (POSs) of the retina. Cytoplasmic Lyar was released from apoptotic cells, and selectively bound to shed POSs and apoptotic cells, but not healthy cells. POS vesicles engulfed through Lyar-dependent pathway were targeted to phagosomes and colocalized with phagosome marker Rab7. These results suggest that Lyar is a genuine RPE phagocytosis ligand, which in turn supports the validity of OPD/PFC as the only available approach for unbiased identification of phagocytosis ligands with broad applicability to various phagocytes. PMID- 25735757 TI - Surface pre-conditioning with bioactive glass air-abrasion can enhance enamel white spot lesion remineralization. AB - OBJECTIVE: To evaluate the effect of pre-conditioning enamel white spot lesion (WSL) surfaces using bioactive glass (BAG) air-abrasion prior to remineralization therapy. METHODS: Ninety human enamel samples with artificial WSLs were assigned to three WSL surface pre-conditioning groups (n=30): (a) air-abrasion with BAG polyacrylic acid (PAA-BAG) powder, (b) acid-etching using 37% phosphoric acid gel (positive control) and (c) unconditioned (negative control). Each group was further divided into three subgroups according to the following remineralization therapy (n=10): (I) BAG paste (36 wt.% BAG), (II) BAG slurry (100 wt.% BAG) and (III) de-ionized water (negative control). The average surface roughness and the lesion step height compared to intra-specimen sound enamel reference points were analyzed using non-contact profilometry. Optical changes within the lesion subsurface compared to baseline scans were assessed using optical coherence tomography (OCT). Knoop microhardness evaluated the WSLs' mechanical properties. Raman micro-spectroscopy measured the v-(CO3)(2-)/v1-(PO4)(3-) ratio. Structural changes in the lesion were observed using confocal laser scanning microscopy (CLSM) and scanning electron microscopy-energy dispersive X-ray spectrometry (SEM EDX). All comparisons were considered statistically significant if p<0.05. RESULTS: PAA-BAG air-abrasion removed 5.1 +/- 0.6 MUm from the lesion surface, increasing the WSL surface roughness. Pre-conditioning WSL surfaces with PAA-BAG air-abrasion reduced subsurface light scattering, increased the Knoop microhardness and the mineral content of the remineralized lesions (p<0.05). SEM EDX revealed mineral depositions covering the lesion surface. BAG slurry resulted in a superior remineralization outcome, when compared to BAG paste. SIGNIFICANCE: Pre-conditioning WSL surfaces with PAA-BAG air-abrasion modified the lesion surface physically and enhanced remineralization using BAG 45S5 therapy. PMID- 25735756 TI - Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation. AB - Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction like behavior. PMID- 25735758 TI - Wnt/beta-catenin signaling regulates Dental Pulp Stem Cells' responses to pulp injury by resinous monomers. AB - OBJECTIVES: Aim of this study was to investigate whether Dental Pulp Stem Cells DPSCs responses to pulp injury caused by resinous monomers is be mediated through activation of Wnt/beta-catenin signaling. METHODS: DPSCs cultures were established from third molars of healthy donors and characterized for stem cell markers with flow cytometry. Cells were exposed to TEGDMA (T: 0.5-2mM) with or without presence of the Wnt-1 ligand (W:25-100ng/ml) or the GSK3beta inhibitor Lithium (L:1-10mM), used both as activators of Wnt/beta-catenin signaling. Cell viability was evaluated by MTT assay, cell cycle profiles by flow cytometry and expression of key molecules of Wnt/beta-catenin signaling by Real-time PCR and Western Blot. RESULTS: DPSC exposure to TEGDMA caused a concentration-dependent cytotoxicity, accompanied by G1 arrest at lower and G2/M arrest at higher concentrations or after prolonged exposure. Lithium caused a dual effect, by stimulating/inhibiting cell proliferation at lower/higher concentrations respectively and causing a G2/M arrest in a concentration-dependent manner. Wnt signaling could be activated in DPSCs after Lithium or Wnt-1 treatment, as shown by accumulation of beta-catenin, its translocation into the nucleus and enhanced expression of key pathway players, like LEF1 and Cyclin D1. Importantly, exposure to TEGDMA caused a more pronounced activation of the pathway, whereas cumulative effects were observed after T/L or T/W co-treatment, indicating a very strong activation of Wnt signaling after treatment of already "activated" (by Lithium or Wnt-1) cells with TEGDMA. SIGNIFICANCE: These findings highlight the important role of Wnt canonical signaling in pulp repair responses to common injuries. PMID- 25735759 TI - Assessment of defects at tooth/self-adhering flowable composite interface using swept-source optical coherence tomography (SS-OCT). AB - OBJECTIVES: Assessment of adhesive defects of a self-etch adhesive and a self adhering flowable composite at the tooth/composite interface before and after water storage by optical coherence tomography (OCT). METHODS: 16 extracted human molars (n=8 each) with box-shaped, class-V cavities were restored either with an experimental self-adhering flowable composite (EF, DMG) or with the filling system AdperTM PromptTM L-PopTM/FiltekTM Supreme XT Flowable composite (PLP, 3M ESPE). Restorations of both groups were non-invasively imaged using swept-source OCT before and after storage in water. The OCT signal for adhesive defects at the tooth/composite interface was quantified. RESULTS: At enamel, significantly fewer adhesive defects were detected at EF restorations than at PLP restorations, before water storage (4%/48%, p<0.001) and thereafter (8%/49%, p<0.001); in contrast, at dentin more interfacial defects were observed with EF (before water storage: 75%/11%; p<0.001, after water storage: 77%/52%; pi=0.001). In the case of slight initial adhesive defects, water storage caused a statistically verifiable increase in adhesive defects at the enamel interface with EF (before/after storage: 4%/8%; p=0.023) and at dentin with PLP (before/after storage: 11%/52%; p=0.008). SIGNIFICANCE: Given the high proportion of adhesive defects with the experimental self-adhering flowable composite, its use as the definitive restorative material in class-V cavities must be critically scrutinized and clinical indications must be investigated further with in vitro and in vivo trials. PMID- 25735760 TI - Determination of homologous distributions of bisEMA dimethacrylates in bulk-fill resin-composites by GC-MS. AB - OBJECTIVES: Ethoxylated bisphenol A dimethacrylate (bisEMA) is a basis monomer in several dental resin composites. It was the aim of the present study to develop a method allowing detection of bisEMA and its different degrees of ethoxylation eluted from polymerized resin composites. METHODS: High-temperature gas chromatography/mass spectrometry (HT-GC/MS) by direct on-column injection was used to identify ethoxylated bisEMA in ethanol/water (3:1) eluates from polymerized specimen of four bulk-fill resin composites - Venus((r)) bulk fill, Surefil((r)) SDRTM flow, FiltekTM Bulk Fill and Sonic FillTM. Additionally, the unpolymerised pastes were analysed. RESULTS: The developed method allowed identification of a homologous series of bisEMA up to twelve ethoxy groups in the unpolymerised materials. The molecular masses of the homologous bisEMA varied between 452 g/mol and 892 g/mol and were detected for retention times from 9.43 min to 13.36 min. Analysis of eluates from polymerised materials identified bisEMA monomers with less than 6 ethoxy groups. Chromatograms showed larger peak areas for the lower volatile bisEMA with 4-6 ethoxy groups compared with higher volatile bisEMA with 2 or 3 ethoxy groups, thus indicating that the amounts of these homologues in the pastes were higher. SIGNIFICANCE: Ethoxylated bisEMA with up to twelve ethoxy groups can be identified by HT-GC/MS. In all eluates bisEMA was found. The higher the number of ethoxy groups the lower are the peak areas from bisEMA in the gas chromatogram. These findings may be significant for toxicological analysis of resin-composites incorporating bis-EMA. PMID- 25735761 TI - Proanthocyanidin in red rice inhibits MDA-MB-231 breast cancer cell invasion via the expression control of invasive proteins. AB - Proanthocyanidin is one of the main active compounds found in red jasmine rice. We previously reported that red rice extract could reduce cancer cell invasion. However, the direct effect of proanthocyanidin from red rice on the invasion of cancer cells and the exact molecular mechanism remained unclear. Here, we report for the first time that proanthocyanidin-rich fraction from red rice (PRFR) reduced the migration and invasion of MDA-MB-231 human breast cancer cells. The types of proanthocyanidin in PRFR were identified as procyanidins and prodelphinidins by acid hydrolysis. For cancer cell invasion, degradation of the extracellular matrix (ECM) is required. Treatment of the cells with PRFR reduced the expression of ECM degradation-associated proteins, including matrix metalloproteinase-9 (MMP-9), membrane type-1 matrix metalloproteinase, urokinase plasminogen activator, urokinase plasminogen activator receptor and plasminogen activator-1. Moreover, PRFR also reduced the activity of collagenase and MMP-9. Furthermore, PRFR significantly suppressed the expression of intercellular adhesion molecule-1 and interleukin-6. We also found that PRFR reduced the DNA binding activity of nuclear factor kappa B (NF-kappaB), which is the expressed mediator of ECM degradation-associated proteins. These results suggest that proanthocyanidin from red rice mediates MDA-MB-231 breast cancer cell invasion by altering the expression of the invasion-associated proteins, possibly by targeting NF-kappaB activity. PMID- 25735762 TI - Heterozygote deficits in cyst plant-parasitic nematodes: possible causes and consequences. AB - Deviations of genotypic frequencies from Hardy-Weinberg equilibrium (HWE) expectations could reveal important aspects of the biology of populations. Deviations from HWE due to heterozygote deficits have been recorded for three plant-parasitic nematode species. However, it has never been determined whether the observed deficits were due (i) to the presence of null alleles, (ii) to a high level of consanguinity and/or (iii) to a Wahlund effect. The aim of the present work was, while taking into the possible confounding effect of null alleles, to disentangle consanguinity and Wahlund effect in natural populations of those three economically important cyst nematodes using microsatellite markers: Globodera pallida, G. tabacum and Heterodera schachtii, pests of potato, tobacco and sugar beet, respectively. The results show a consistent pattern of heterozygote deficiency in the three nematode species sampled at the spatial scale of the host plant. We demonstrate that the prevalence of null alleles is weak and that heterozygote deficits do not have a single origin. Our results suggested that it is restricted dispersal that leads to heterozygote deficits through both consanguinity and substructure, which effects can be linked to soil movement, cyst density, and the number of generations per year. We discuss potential implications for the durability of plant resistances that are used to protect crops against parasites in which mating between relatives occur. While consanguineous mating leads to homozygosity at all loci, including loci governing avirulence/virulence, which favours the expression of virulence when recessive, the Wahlund effect is expected to have no particular effect on the adaptation of nematodes to resistances. PMID- 25735763 TI - Oxygen and cardiac arrest: the timepoint matters. PMID- 25735764 TI - Carbapenem resistance in cystic fibrosis strains of Pseudomonas aeruginosa as a result of amino acid substitutions in porin OprD. AB - The aim of this work was to investigate the impact of single amino acid substitutions occurring in specific porin OprD on carbapenem resistance of cystic fibrosis (CF) strains of Pseudomonas aeruginosa. A PAO1DeltaoprD mutant was complemented with the oprD genes from five carbapenem-resistant CF strains exhibiting very low amounts of mutated OprD porins in their outer membrane despite wild-type levels of oprD transcripts. Compared with wild-type porin from strain PAO1, single amino acid substitutions S403P (in periplasmic loop 8), Y242H, S278P and L345P (in beta-sheets 10, 12 and 14, respectively) were found to result in reduced amounts of OprD in the outer membrane, increased carbapenem resistance, and slower growth in minimal medium containing gluconate, an OprD substrate, as the sole source of carbon and energy. This indicates that in CF strains of P. aeruginosa, loss of porin OprD may not only result from mutations downregulating the expression of or disrupting the oprD gene, but also from mutations generating deleterious amino acid substitutions in the porin structure. PMID- 25735765 TI - Separation of p-divinylbenzene by selective room-temperature adsorption inside Mg CUK-1 prepared by aqueous microwave synthesis. AB - A new Mg(II) -based version of the porous coordination polymer CUK-1 with one dimensional pore structure was prepared by microwave synthesis in water. Mg-CUK-1 is moisture-stable, thermally stable up to 500 degrees C, and shows unusual reversible soft-crystal behavior: dehydrated single crystals of the material selectively adsorb a range of organic molecules at ambient temperature and pressure. Both polar and apolar aromatic compounds, including pyridine, benzene, p-xylene, and p-divinylbenzene (p-DVB), are all readily adsorbed, while other isomers from complex mixtures of xylenes or DVBs are selectively excluded. The solvent-loaded structures have been studied by single-crystal X-ray diffraction. Time-dependent liquid sorption experiments using commercially available DVB demonstrate a high and rapid selective adsorption of p-DVB and exclusion of m-DVB and ethylvinylbenzene isomers. PMID- 25735766 TI - Protic anions [H(B12X12)]- (X = F, Cl, Br, I) that act as Bronsted acids in the gas phase. AB - The acidity of protic cations and neutral molecules has been studied extensively in the gas phase, and the gas-phase acidity has been established previously as a very useful measure of the intrinsic acidity of neutral and cationic compounds. However, no data for any anionic acids were available prior to this study. The protic anions [H(B12X12)](-) (X = F, Cl, Br, I) are expected to be the most acidic anions known to date. Therefore, they were investigated in this study with respect to their ability to protonate neutral molecules in the gas phase by using a combination of mass spectrometry and quantum-chemical calculations. For the first time it was shown that in the gas phase protic anions are also able to protonate neutral molecules and thus act as Bronsted acids. According to theoretical calculations, [H(B12I12)](-) is the most acidic gas-phase anion, whereas in actual protonation experiments [H(B12Cl12)](-) is the most potent gas phase acidic anion for the protonation of neutral molecules. This discrepancy is explained by ion pairing and kinetic effects. PMID- 25735767 TI - Doing that thing that scientists do: A discovery-driven module on protein purification and characterization for the undergraduate biochemistry laboratory classroom. AB - In traditional introductory biochemistry laboratory classes students learn techniques for protein purification and analysis by following provided, established, step-by-step procedures. Students are exposed to a variety of biochemical techniques but are often not developing procedures or collecting new, original data. In this laboratory module, students develop research skills through work on an original research project and gain confidence in their ability to design and execute an experiment while faculty can enhance their scholarly pursuits through the acquisition of original data in the classroom laboratory. Students are prepared for a 6-8 week discovery-driven project on the purification of the Escherichia coli cytidylate kinase (CMP kinase) through in class problems and other laboratory exercises on bioinformatics and protein structure analysis. After a minimal amount of guidance on how to perform the CMP kinase in vitro enzyme assay, SDS-PAGE, and the basics of protein purification, students, working in groups of three to four, develop a protein purification protocol based on the scientific literature and investigate some aspect of CMP kinase that interests them. Through this process, students learn how to implement a new but perhaps previously worked out procedure to answer their research question. In addition, they learn the importance of keeping a clear and thorough laboratory notebook and how to interpret their data and use that data to inform the next set of experiments. Following this module, students had increased confidence in their ability to do basic biochemistry techniques and reported that the "self-directed" nature of this lab increased their engagement in the project. PMID- 25735768 TI - ROS and oxidative stress in CKD patients: is it the mitochondria that keeps CKD patients in bed? PMID- 25735769 TI - Logical transformation of genome-scale metabolic models for gene level applications and analysis. AB - MOTIVATION: In recent years, genome-scale metabolic models (GEMs) have played important roles in areas like systems biology and bioinformatics. However, because of the complexity of gene-reaction associations, GEMs often have limitations in gene level analysis and related applications. Hence, the existing methods were mainly focused on applications and analysis of reactions and metabolites. RESULTS: Here, we propose a framework named logic transformation of model (LTM) that is able to simplify the gene-reaction associations and enables integration with other developed methods for gene level applications. We show that the transformed GEMs have increased reaction and metabolite number as well as degree of freedom in flux balance analysis, but the gene-reaction associations and the main features of flux distributions remain constant. In addition, we develop two methods, OptGeneKnock and FastGeneSL by combining LTM with previously developed reaction-based methods. We show that the FastGeneSL outperforms exhaustive search. Finally, we demonstrate the use of the developed methods in two different case studies. We could design fast genetic intervention strategies for targeted overproduction of biochemicals and identify double and triple synthetic lethal gene sets for inhibition of hepatocellular carcinoma tumor growth through the use of OptGeneKnock and FastGeneSL, respectively. AVAILABILITY AND IMPLEMENTATION: Source code implemented in MATLAB, RAVEN toolbox and COBRA toolbox, is public available at https://sourceforge.net/projects/logictransformationofmodel. PMID- 25735770 TI - Alternative splicing and co-option of transposable elements: the case of TMPO/LAP2alpha and ZNF451 in mammals. AB - Transposable elements constitute a large fraction of vertebrate genomes and, during evolution, may be co-opted for new functions. Exonization of transposable elements inserted within or close to host genes is one possible way to generate new genes, and alternative splicing of the new exons may represent an intermediate step in this process. The genes TMPO and ZNF451 are present in all vertebrate lineages. Although they are not evolutionarily related, mammalian TMPO and ZNF451 do have something in common-they both code for splice isoforms that contain LAP2alpha domains. We found that these LAP2alpha domains have sequence similarity to repetitive sequences in non-mammalian genomes, which are in turn related to the first ORF from a DIRS1-like retrotransposon. This retrotransposon domestication happened separately and resulted in proteins that combine retrotransposon and host protein domains. The alternative splicing of the retrotransposed sequence allowed the production of both the new and the untouched original isoforms, which may have contributed to the success of the colonization process. The LAP2alpha-specific isoform of TMPO (LAP2alpha) has been co-opted for important roles in the cell, whereas the ZNF451 LAP2alpha isoform is evolving under strong purifying selection but remains uncharacterized. PMID- 25735771 TI - Estimating the proportion of true null hypotheses when the statistics are discrete. AB - MOTIVATION: In high-dimensional testing problems pi0, the proportion of null hypotheses that are true is an important parameter. For discrete test statistics, the P values come from a discrete distribution with finite support and the null distribution may depend on an ancillary statistic such as a table margin that varies among the test statistics. Methods for estimating pi0 developed for continuous test statistics, which depend on a uniform or identical null distribution of P values, may not perform well when applied to discrete testing problems. RESULTS: This article introduces a number of pi0 estimators, the regression and 'T' methods that perform well with discrete test statistics and also assesses how well methods developed for or adapted from continuous tests perform with discrete tests. We demonstrate the usefulness of these estimators in the analysis of high-throughput biological RNA-seq and single-nucleotide polymorphism data. AVAILABILITY AND IMPLEMENTATION: implemented in R. PMID- 25735772 TI - 14-3-3-Pred: improved methods to predict 14-3-3-binding phosphopeptides. AB - MOTIVATION: The 14-3-3 family of phosphoprotein-binding proteins regulates many cellular processes by docking onto pairs of phosphorylated Ser and Thr residues in a constellation of intracellular targets. Therefore, there is a pressing need to develop new prediction methods that use an updated set of 14-3-3-binding motifs for the identification of new 14-3-3 targets and to prioritize the downstream analysis of >2000 potential interactors identified in high-throughput experiments. RESULTS: Here, a comprehensive set of 14-3-3-binding targets from the literature was used to develop 14-3-3-binding phosphosite predictors. Position-specific scoring matrix, support vector machines (SVM) and artificial neural network (ANN) classification methods were trained to discriminate experimentally determined 14-3-3-binding motifs from non-binding phosphopeptides. ANN, position-specific scoring matrix and SVM methods showed best performance for a motif window spanning from -6 to +4 around the binding phosphosite, achieving Matthews correlation coefficient of up to 0.60. Blind prediction showed that all three methods outperform two popular 14-3-3-binding site predictors, Scansite and ELM. The new methods were used for prediction of 14-3-3-binding phosphosites in the human proteome. Experimental analysis of high-scoring predictions in the FAM122A and FAM122B proteins confirms the predictions and suggests the new 14-3-3 predictors will be generally useful. AVAILABILITY AND IMPLEMENTATION: A standalone prediction web server is available at http://www.compbio.dundee.ac.uk/1433pred. Human candidate 14-3-3-binding phosphosites were integrated in ANIA: ANnotation and Integrated Analysis of the 14-3-3 interactome database. PMID- 25735773 TI - Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor-Driven Lung Adenocarcinoma. AB - Somatic mutations in the EGFR kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here, we demonstrate that MIG6 is a tumor suppressor for the initiation and progression of mutant EGFR driven lung adenocarcinoma in mouse models. Mutant EGFR-induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/Y395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for MIG6 to delay mutant EGFR-driven tumor initiation and progression in mouse models. SIGNIFICANCE: This study demonstrates that MIG6 is a potent tumor suppressor for mutant EGFR-driven lung tumor initiation and progression in mice and provides a possible mechanism by which mutant EGFR can partially circumvent this tumor suppressor in human lung adenocarcinoma. PMID- 25735774 TI - Intratumoral heterogeneity in a Trp53-null mouse model of human breast cancer. AB - Intratumoral heterogeneity correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. Such heterogeneity is thought to contribute to radio- and chemoresistance because many treatments may target only certain tumor cell subpopulations. A better understanding of the functional interactions between various subpopulations of cells, therefore, may help in the development of effective cancer treatments. We identified a unique subpopulation of tumor cells expressing mesenchymal-like markers in a Trp53-null mouse model of basal-like breast cancer using fluorescence-activated cell sorting and microarray analysis. Both in vitro and in vivo experiments revealed the existence of cross talk between these "mesenchymal-like" cells and tumor-initiating cells. Knockdown of genes encoding ligands upregulated in the mesenchymal cells and their corresponding receptors in the tumor-initiating cells resulted in reduced tumorigenicity and increased tumor latency. These studies illustrate the non-cell autonomous properties and importance of cooperativity between tumor subpopulations. SIGNIFICANCE: Intratumoral heterogeneity has been considered one important factor in assessing a patient's initial response to treatment and selecting drug regimens to effectively increase tumor response rate. Elucidating the functional interactions between various subpopulations of tumor cells will help provide important new insights in understanding treatment response and tumor progression. PMID- 25735776 TI - Detainees arrested for the first time in French police stations. AB - The psychological impact of incarceration vary from individual to individual and most people first entering prison experience severe stress. Our objective was to describe the characteristics of detainees arrested for the first time and who had medical examination during custody. The study sample included 200 detainees arrested for the first time in 2012 and examined for the second time before May 31, 2013, 200 detainees arrested for the first time in 2012 and who had not a second examination by May 31, 2013, and a control group of 200 individuals who had been arrested before. Collected data related to persons' characteristics, the course of detention, alleged assaults and traumatic injuries. In our sample, victimization was the most frequent motivation for requesting a medical examination and affected 31-46% of patients who requested the examination. The medical examination was less frequently requested by the detainee at the first detention than at subsequent detentions (35% and 31% vs. 51%, P < 0.001). Unremarkable psychic states were found in most cases in all groups. Detainees expressed a good or very good opinion on custody in 40-51% of cases. In 75-89% of cases, detainees were considered to be unconditionally fit for detention. The present findings suggest only minor differences between clinical features of individuals arrested for the first time and their clinical status when they were arrested for the second time. The systematic collection of more detailed description of the detainees' psychic state could be relevant at the time of medical examinations in police cells. PMID- 25735775 TI - Mid-term survival after continuous-flow left ventricular assist device versus heart transplantation. AB - There is a paucity of data about mid-term outcome of patients with advanced heart failure (HF) treated with left ventricular assist device (LVAD) in Europe, where donor shortage and their aging limit the availability and the probability of success of heart transplantation (HTx). The aim of this study is to compare Italian single-centre mid-term outcome in prospective patients treated with LVAD vs. HTx. We evaluated 213 consecutive patients with advanced HF who underwent continuous-flow LVAD implant or HTx from 1/2006 to 2/2012, with complete follow up at 1 year (3/2013). We compared outcome in patients who received a LVAD (n = 49) with those who underwent HTx (n = 164) and in matched groups of 39 LVAD and 39 HTx patients. Patients that were treated with LVAD had a worse risk profile in comparison with HTx patients. Kaplan-Meier survival curves estimated a one-year survival of 75.5 % in LVAD vs. 82.3 % in HTx patients, a difference that was non statistically significant [hazard ratio (HR) 1.46; 95 % confidence interval (CI) 0.74-2.86; p = 0.27 for LVAD vs. HTx]. After group matching 1-year survival was similar between LVAD (76.9 %) and HTx (79.5 %; HR 1.15; 95 % CI 0.44-2.98; p = 0.78). Concordant data was observed at 2-year follow-up. Patients treated with LVAD as bridge-to-transplant indication (n = 22) showed a non significant better outcome compared with HTx with a 95.5 and 90.9 % survival, at 1- and 2-year follow-up, respectively. Despite worse preoperative conditions, survival is not significantly lower after LVAD than after HTx at 2-year follow-up. Given the scarce number of donors for HTx, LVAD therapy represents a valid option, potentially affecting the current allocation strategy of heart donors also in Europe. PMID- 25735777 TI - Drowning-related fatalities during a 5-year period (2008-2012) in South-West Hungary--a retrospective study. AB - The purpose of the present study was to investigate all the drowning-related cases in South-West Hungary between 2008 and 2012. It is a retrospective and descriptive study of 114 drowning-related deaths during that 5-year period. The investigation includes both unintentional and intentional drowning cases. We found that the most considerable risk factor of drowning in this area of Hungary is alcohol consumption, because in more than half of the cases the victims were under the influence of alcohol. We also concluded that more than two third of the cases included males. The cause of drowning in younger victims was mostly accident. In both genders subjects aged 50-70 had the highest risk of drowning in the period investigated. Seniors frequently committed suicide by drowning. Drowning deaths occurred in all types of water, mostly in lakes, rivers, canals and other types of catchment in the vicinity of victims' homes (most commonly in wells). This study might help to understand the circumstances and the causes leading to drowning and it may draw the attention to the possible preventive interventions. PMID- 25735778 TI - Drug-related deaths between 2002 and 2013 with accent to methadone and benzodiazepines. AB - AIM: The aim of the study is to assess the trends of overdose and drug related fatalities in the Republic of Macedonia during the 11 years. MATERIAL AND METHODS: Cross-sectional retrospective survey and reviewed of postmortem toxicological analyses which examined fatal poisonings with illegal drugs in years 2002-2013. Information about gender, age, drug consumption, reported years were analyzed. Narcotics were confirmed with toxicological semi quantitative fluorescence polarization immunoassay (FPIA) in urine (range 250-4000 ng/ml). RESULTS: Total of 165 deaths were observed. Out of them 145 (87.9%) were male. There is statistical significant differences between male and female DRD due to age (Mann-Whitney U Test = 925, Z = -2626, p = 0.0087). For p < 0.05 there is significant differences between genders due to cause of overdose (Pearson Chi square = 9743, df = 4, p = 0.0449). DRD among male were mainly because of overdose due to heroin in 80 (51.17%) cases followed by DRD due to combination of methadone and BZD in 25 (11.72%) cases. Out of all DRD cases 50 (30.3%) are related to polydrug use. For p < 0.01 there is a significant differences between analyzed age groups due to cause of overdose (Pearson Chi-square = 33,886, df = 12, p = 0.0007). CONCLUSIONS: Death cause analysis reveals the difficulties in determining the role of substitution drugs, as many other factors may be involved. The findings also highlight the importance of further enhancing treatment interventions for benzodiazepine misuse among patients on methadone substitution treatment. PMID- 25735779 TI - Morphological changes in palatal rugae patterns following orthodontic treatment. AB - This study investigated the morphometric changes that occur in palatal rugae during orthodontic treatment. The potential impact of these changes on the individuality of the palatal rugae patterns and on the use of palatal rugae patterns in human identification was also explored. Fifty pairs of pre- and post orthodontic treatment dental casts were used. The palatal rugae patterns were compared between each pre-treatment cast and its post-treatment counterpart to reveal any morphometric changes. In addition, the individuality of the pre- and post-treatment sets of the casts was evaluated. Finally, a matching test of the palatal rugae patterns was performed in which the ability to match each post treatment cast with its duplicate was compared with the ability to match that post-treatment cast with its pre-treatment counterpart. Statistical analysis of the results revealed the incidence of several morphometric changes, including segmentation (22%); unification (20%); changes in orientation (6%), shape (6%), and length (28%); anteroposterior displacement of the medial (54%) and lateral (60%) end of the ruga; and mediolateral displacement of the medial end of ruga (20%). The individuality of the palatal rugae patterns was confirmed in both pre- and post-treatment sets of casts. Finally, the mean percentage of correct matches was found to be significantly higher when the post-treatment casts were matched with their duplicates compared to when they were matched with their pre-treatment counterparts. The study revealed that Orthodontic treatment induces various morphometric changes in the palatal rugae patterns. These changes may potentially complicate palatal rugae-based human identification. PMID- 25735780 TI - A forensic-psychiatric study of sexual offenders in Rio de Janeiro, Brazil. AB - Sexual violence is defined as any sexual act forced upon a person who did not give his or her consent. Our objective is to investigate the socio-demographic features, clinical correlates, criminal behaviour characteristics, and the level of penal responsibility of sexual offenders who were referred to forensic psychiatric assessment in the city of Rio de Janeiro, Brazil. This is a cross sectional descriptive study. All written reports made in the year of 2008 by court-appointed psychiatric experts on individuals charged with having committed sexual crimes and referred to the main forensic hospital in the State of Rio de Janeiro, Brazil, for assessment were reviewed. Forty-four expert reports were identified. All alleged offenders were male. Nineteen (43.2%) offenders did not receive any psychiatric diagnostic. Nine offenders (20.4%) were diagnosed with mental retardation. In 16 cases (36.4%), some form of mental or neurological disorder was diagnosed. Thirty-one (70.4%) offenders were considered fully responsible, eight (18.2%) partially responsible, and five (11.4%) not responsible by reason of insanity. The sexual crimes allegedly perpetrated by the offenders were rape (n=14, 32%), attempted rape (n=4, 9%), indecent assault (n=26, 59%), and indecent exposure (n=5, 11.4%). In 10 cases (22.7%), the offender was under alcohol influence at the moment of the crime. The profile of Brazilian sex offenders subject to forensic psychiatric assessment were male, caucasian, single, working part time, with no mental disorder, who perpetrated indecent assault. PMID- 25735781 TI - Restraint in police use of force events: examining sudden in custody death for prone and not-prone positions. AB - Little is understood about the incidence of sudden death, its underlying pathophysiology, or its actual relationship to subject positioning. We report data from 4828 consecutive use of force events (August 2006-March 2013) in 7 Canadian police agencies in Eastern and Western Canada. Consecutive subjects aged >18 years who were involved in a police use of force event were included regardless of outcome. Officers prospectively documented: final resting position of the subject (prone or non-prone), intoxicants and/or emotional distress, presence of features of excited delirium, and the use of all force modalities. Our outcome of interest was sudden in-custody death. Our study has 80% power to detect a difference of 0.5% in sudden death between the positions. In over 3.25 million consecutive police--public interactions; use of force occurred in 4,828 subjects (0.1% of police public interactions; 95% CI = 0.1%, 0.1%). Subjects were usually male (87.5%); median age 32 years; 81.5% exhibited alcohol and/or drug intoxication, and/or emotional distress at the scene. Significantly more subjects remained in a non-prone vs. prone position; but over 2000 subjects remained prone. One individual died suddenly and unexpectedly in the non-prone position with all 10 features of excited delirium. No subject died in the prone position. There was no significant difference in sudden in custody death, in a worst case scenario 99.8% of subjects would be expected to survive being in either the prone or non-prone position following police use of force. PMID- 25735782 TI - Rapid genotyping of 25 autosomal STRs in a Japanese population using fluorescent universal primers containing locked nucleic acids. AB - Amplification of fluorescently labeled products is one of the most popular methods for genotyping genetic variations. Two-step amplification using fluorescent universal primers simultaneously produces multiple targeted fragments labeled with fluorescent dyes, and this strategy is applicable to large-scale, cost-effective genotyping. In this study, we developed a fast PCR-based, multiple short tandem repeat (STR) genotyping method using fluorescent universal primers containing locked nucleic acids (LNAs). Four amplification reactions, each assaying six or seven markers and using 0.5-1.0 ng of genomic DNA, produced obvious Fam-labeled peaks in all 26 loci tested (25 autosomal STRs and amelogenin). The overall amplification time was 37 min. Moreover, fluorescent signals for the 25 STRs obtained from LNA-containing primers were 1.5-9.0 fold higher compared to those from non-LNA primers. Using genomic DNA from 120 Japanese individuals, 16 out of the 25 STRs had observed heterozygosity greater than 0.7. Some of these 25 STRs also had high discriminatory power, similar to that of the 13 core STRs in the Combined DNA Index System dataset. The probability of incorrectly assigning a match based on the accumulated matching probability for these 25 STRs is 1.2 * 10(-22), and their combined use can provide robust information for Japanese forensics. PMID- 25735783 TI - Conjugal violence: a comparison of violence against men by women and women by men. AB - Because few studies demonstrated the types of violence performed by women, the aim of our study was to access violence men against women as well as women against men. A retrospective study was performed based on all the medical certificates for victims who consulted our centre specialized in assault victims. Eleven percent of the victims were men (81 men, 626 women). Episodes of violence were most often repeated against women than men (p < 0.05). Injuring, in most cases mild, were more frequently found in men than women (p < 0.01). They were primarily cutaneous in 66% of cases (85% men, 64% women) and severe in 5% of cases i.e. fractures, with no difference in gender. Three cases of sexual assault and one case of chemical submission was observed in women. Insults were made more often by men than by women (p < 0.002). A psychological impact was more frequently found in women than in men (p < 0.01). The duration of the total incapacity (incapacite totale de travail = ITT) was less than 0-3 days in most cases, and this occurred more often in 91% men than in 65% women (p < 0.01). Consultations for domestic violence occur less frequently in men than in women. Men present more often with injuries that are less severe compared to those observed in women. In contrast, the psychological impact is less frequent in men. Also episodes of violence were most often repeated when the aggressor was a man. PMID- 25735784 TI - Mental health, sexual violence and the work of Sexual Assault Referral centres (SARCs) in England. AB - There is a clear link between mental health status both before and after rape. It is known, for example, that approximately 40% of attendees to a Sexual Assault Referral centre (SARC) are already known to mental health services. Sexual Violence can also lead to the development of a mental illness. SARCs have been established, inter alia, to provide healthcare to the victims of rape where a mental health risk assessment should be undertaken. All 37 SARCs in England where asked to complete a short survey and a response rate of 68% was achieved. A high proportion (40%) of SACRs clients are already known to mental health services, however, only just under half of SARCs routinely assess mental health and when such an assessment is completed this is by an FME and substance misuse issues are not always included. Almost two-thirds of SARC services report problems in referring on to mental health services for a variety of reasons. More research is needed in this important area and NHS England should fully define the skills required to undertake a mental health risk assessment when someone has been the victim of rape. PMID- 25735785 TI - The medico-legal evaluation of injuries from falls in pediatric age groups. AB - Blunt trauma from accidental falls or intentional jumping from great heights occurs frequently in forensic medicine. The goal of this study was to investigate injuries due to falls in children under 19 years of age. Injuries from falls are the leading cause of visits to emergency departments and to deaths due to injuries. Various methods are used in the classification of falls. In this study, we have classified falls as "high-level" (>= 5 m), "low-level" (<5 m) and "ground level". We have retrospectively evaluated 814 boys (61.18%) and 512 girls (38.62%), making up a total of 1326 children (under 19 years old) with the mean age of 7.85 +/- 3.46, that were admitted to State Hospital between January 2009 and December 2013 due to falls from heights and falls on ground-level. Falls were low-level in 738 cases, high-level in 176 cases, and ground-level in 412 cases. Cases were categorized by gender, age, age group, fall height, Glasgow Coma Scale (GCS), injured body part(s), mortality rate, and distribution according to months. In conclusion, falls merit attention because of their high risk of mortality and morbidity, as well as their burden on medical budgets. If the medico-legal aspects of falls were evaluated with regard to preventive event or death, the importance of the topic could be better understood. PMID- 25735786 TI - The effect of supportive emergency department nursing care on pain reduction of patients with Red Sea marine wildlife injuries. AB - INTRODUCTION: The emergency department at Yoseftal hospital in Eilat is on the shore of the Red Sea, and it is visited by patients with marine wildlife injuries. The purpose of this study was to examine the effects of supportive nursing care on the pain level of patients with Red Sea marine wildlife injuries. METHOD: A prospective quantitative study including 102 patients admitted to the emergency department. The study included a study group (N = 50) and a control group (N = 52). Both groups rated their pain level on the VAS before and after receiving treatment. The control group received the usual treatment, and the study group received the usual nursing treatment along with structured patient guidance and support. RESULTS: There was a significant difference in the level of pain after the intervention between the control and the study group. In the study group, the level of pain was significantly reduced compared with the control group (p < 0.001). DISCUSSION: Nursing training and patient guidance contributed to increasing cooperation with patients and pain reduction. Therefore, training interventions should be structured and assimilated as an integral part of nursing practice. PMID- 25735787 TI - The impact of a flow strategy for patients who presented to an Australian emergency department with a mental health illness. AB - OBJECTIVES: To describe and compare characteristics, care delivered, and outcomes of patients who presented to an emergency department (ED) with a mental health illness before and after the implementation of a patient flow strategy. METHODS: This was a retrospective, descriptive study. Health care data of patients who presented to a public teaching hospital ED in Queensland, Australia diagnosed with a mental health illness before (5th September 2011-4th March 2012) and after (5th March 2012-4th September 2012) the implementation of a patient flow strategy were analysed. RESULTS: A total of 3037 (before: n = 1511; after: n = 1526) mental health presentations (4.5% of all ED presentations) were made to the ED. Following the implementation of a patient flow strategy, improvements in ED length of stay, tests performed and nursing observations were seen. These varied by mental health diagnosis. CONCLUSION: Our results indicate that a targeted approach to improving service delivery for a specific cohort of ED patients can make a difference without additional staffing. Further focused refinement of the strategy (such as time waiting for treatment) may be required. PMID- 25735788 TI - Enhanced CO2 electroreduction efficiency through secondary coordination effects on a pincer iridium catalyst. AB - An iridium(III) trihydride complex supported by a pincer ligand with a hydrogen bond donor in the secondary coordination sphere promotes the electrocatalytic reduction of CO2 to formate in water/acetonitrile with excellent Faradaic efficiency and low overpotential. Preliminary mechanistic experiments indicate formate formation is facile while product release is a kinetically difficult step. PMID- 25735790 TI - A synthetic fragment of leptin increase hematopoietic stem cell population and improve its engraftment ability. AB - Several studies have shown the important actions of cytokine leptin that regulates food intake and energy expenditure. Additionally, the ability to modulate hematopoiesis has also been demonstrated. Previous reports have shown that some synthetic sequences of leptin molecules can activate leptin receptor. Herein, decapeptides encompassing amino acids from positions 98 to 122 of the leptin molecule were constructed to evaluate their effects on hematopoiesis. Among them, the synthetic peptide Lep(110-119)-NH2 (LEP F) was the only peptide that possessed the ability to increase the percentage of hematopoietic stem cells (HSC). Moreover, LEP F also produced an increase of granulocyte/macrophage colony forming units and activated leptin receptor. Furthermore, LEP F also improves the grafting of HSC in bone marrow, but did not accelerate the recovery of bone marrow after ablation with 5-fluorouracil. These results show that LEP F is a positive modulator of the in vivo expansion of HSC and could be useful in bone marrow transplantation. PMID- 25735789 TI - Relationship Between Surface-Based Brain Morphometric Measures and Intelligence in Autism Spectrum Disorders: Influence of History of Language Delay. AB - Autism spectrum disorders (ASD) are a group of conditions that show abnormalities in the neuroanatomy of multiple brain regions. The variability in the development of intelligence and language among individuals on the autism spectrum has long been acknowledged, but it remains unknown whether these differences impact on the neuropathology of ASD. In this study, we aimed to compare associations between surface-based regional brain measures and general intelligence (IQ) scores in ASD individuals with and without a history of language delay. We included 64 ASD adults of normal intelligence (37 without a history of language delay and 27 with a history of language delay and 80 neurotypicals). Regions with a significant association between verbal and nonverbal IQ and measures of cortical thickness (CT), surface area, and cortical volume were first identified in the combined sample of individuals with ASD and controls. Thicker dorsal frontal and temporal cortices, and thinner lateral orbital frontal and parieto-occipital cortices were associated with greater and lower verbal IQ scores, respectively. Correlations between cortical volume and verbal IQ were observed in similar regions as revealed by the CT analysis. A significant difference between ASD individuals with and without a history of language delay in the association between CT and verbal IQ was evident in the parieto-occipital region. These results indicate that ASD subgroups defined on the basis of differential language trajectories in childhood can have different associations between verbal IQ and brain measures in adulthood despite achieving similar levels of cognitive performance. PMID- 25735791 TI - A conceptual framework for studying the strength of plant-animal mutualistic interactions. AB - The strength of species interactions influences strongly the structure and dynamics of ecological systems. Thus, quantifying such strength is crucial to understand how species interactions shape communities and ecosystems. Although the concepts and measurement of interaction strength in food webs have received much attention, there has been comparatively little progress in the context of mutualism. We propose a conceptual scheme for studying the strength of plant animal mutualistic interactions. We first review the interaction strength concepts developed for food webs, and explore how these concepts have been applied to mutualistic interactions. We then outline and explain a conceptual framework for defining ecological effects in plant-animal mutualisms. We give recommendations for measuring interaction strength from data collected in field studies based on a proposed approach for the assessment of interaction strength in plant-animal mutualisms. This approach is conceptually integrative and methodologically feasible, as it focuses on two key variables usually measured in field studies: the frequency of interactions and the fitness components influenced by the interactions. PMID- 25735792 TI - Activity of pemetrexed-based regimen as first-line chemotherapy for advanced non small cell lung cancer with asymptomatic inoperable brain metastasis: a retrospective study. AB - This retrospective study was conducted to assess the efficacy of combination of pemetrexed and cisplatin/carboplatin as first-line treatment in inoperable and asymptomatic brain metastasis (BM) from non-small cell lung cancer (NSCLC). A total of 30 patients with adenocarcinoma were included. Nine patients had solitary, and 21 patients had multiple BM. At evaluation after two cycles, the complete response (CR) rate, partial response (PR) rate, and stable disease (SD) for brain lesions was 0, 33.3, and 46.7%, respectively. The overall CR, PR, and SD were 0, 23.3, and 46.7%, respectively. The median time to tumour progression of BM (TTP-BM) was 6.0 months (95% CI 4.068-7.932). The median progression-free survival (PFS) and overall survival (OS) were 5.0 months (95% CI 4.197-5.803) and 11.0 months (95% CI 7.398-14.602), respectively. Pemetrexed has comparable activity on brain lesions as on extracranial tumours in advanced lung adenocarcinoma patients with inoperable and asymptomatic BM. PMID- 25735793 TI - Intracellular Osteopontin Induced by CagA-positive Helicobacter pylori Promotes Beta-catenin Accumulation and Interleukin-8 Secretion in Gastric Epithelial cells. AB - BACKGROUND: Osteopontin, an important immune modulator and oncogenic promoter, is upregulated in H. pylori-infected gastric mucosa. However, the underlying mechanisms and biological significance are poorly understood. We investigated whether osteopontin was upregulated in gastric epithelial cells by H. pylori and the virulence factors involved. Moreover, cellular component changes caused by osteopontin were also investigated. MATERIALS AND METHODS: The gastric epithelial cell line MKN45 was cocultured with wild-type and mutant H. pylori to analyze osteopontin expression. Beta-catenin levels in cell lysate and interleukin-8 levels in supernatant were analyzed. The difference in osteopontin expression levels in both gastric epithelium and plasma was compared between H. pylori infected patients and uninfected controls. RESULTS: H. pylori induced intracellular, but not secretory, osteopontin expression in MKN45 cells. Accordingly, osteopontin expression intensity in gastric epithelium was higher in H. pylori-infected patients than in controls, but osteopontin levels in plasma were similar between both patient groups. H. pylori virulence factor CagA delivered via the type IV secretion system was essential for intracellular osteopontin upregulation. H. pylori induced beta-catenin accumulation and interleukin-8 secretion, whereas osteopontin knockdown completely abrogated these effects, in MKN45 cells. TLR2 antagonist abolished iOPN expression induced by H. pylori gastritis strain, but not by H. pylori cancer strain. CONCLUSIONS: H. pylori is dependent on CagA translocation via the type IV secretion system to induce intracellular osteopontin expression in gastric epithelial cells. Upregulated intracellular osteopontin may promote gastric carcinogenesis via increased beta-catenin accumulation and interleukin-8 secretion. PMID- 25735794 TI - Self-fueled biomimetic liquid metal mollusk. AB - A liquid metal motor that can "eat" aluminum food and then move spontaneously and swiftly in various solution configurations and structured channels for more than 1 h is discovered. Such a biomimetic mollusk is highly shape self-adaptive by closely conforming to the geometrical space it voyages in. The first ever self fueled pump is illustrated as one of its typical practical utilizations. PMID- 25735795 TI - Comparison between bacteremia caused by Acinetobacter pittii and Acinetobacter nosocomialis. AB - BACKGROUND/PURPOSE: Patients with Acinetobacter pittii and Acinetobacter nosocomialis bacteremia have lower mortality rates than those with Acinetobacter baumannii bacteremia. However, it is unknown whether these organisms differ in outcomes of bacteremic patients. We conducted this study to answer this question. METHODS: In this retrospective study conducted at a teaching hospital in Taiwan, we enrolled all 86 patients who had developed A. pittii bacteremia and those with A. nosocomialis bacteremia from 2000 to 2008 while matching for age, sex, Acute Physiology and Chronic Health Evaluation II score, and appropriate antimicrobial therapy. After adjustment, we accessed the clinical characteristics and 14- and 28-day mortalities. RESULTS: We found that the patients with A. pittii bacteremia had multiple comorbidities less often and received invasive procedures less frequently. The 14-day mortality rate of patients with A. pittii or A. nosocomialis bacteremia was 14% and 7%, respectively, whereas their 28-day mortality rate was 17% and 9%, respectively. Using the mortality rate in patients with A. nosocomialis bacteremia as a reference, the odds ratios for the 14- and 28-day crude morality in those with A. pittii were 2.16 [95% confidence interval (CI), 0.77-6.05] and 2.06 (95% CI, 0.82-5.15), respectively, whereas the adjusted odds ratios for 14- and 28-day mortality were 1.89 (95% CI, 0.56-6.14) and 1.67 (95% CI, 0.59-4.78) respectively. CONCLUSION: Our 8-year study showed that the mortality rate of A. pittii bacteremia was higher but the difference was not statistically significant. PMID- 25735796 TI - Clinical analysis of fever of unknown origin in children: A 10-year experience in a northern Taiwan medical center. AB - BACKGROUND: Fever of unknown origin (FUO) was first described in 1961 as fever >38.3 degrees C for at least 3 weeks with no apparent source after 1 week of investigations in the hospital. Infectious disease comprises the majority of cases (40-60%). There is no related research on FUO in children in Taiwan. The aim of this study is to determine the etiologies of FUO in children in Taiwan and to evaluate the relationship between the diagnosis and patient's demography and laboratory data. METHODS: Children under 18 years old with fever >38.3 degrees C for >2 weeks without apparent source after preliminary investigations at Taipei Veterans General Hospital during 2002-2012 were included. Fever duration, symptoms and signs, laboratory examinations, and final diagnosis were recorded. The distribution of etiologies and age, fever duration, laboratory examinations, and associated symptoms and signs were analyzed. RESULTS: A total of 126 children were enrolled; 60 were girls and 66 were boys. The mean age was 6.7 years old. Infection accounted for 27.0% of cases, followed by undiagnosed cases (23.8%), miscellaneous etiologies (19.8%), malignancies (16.6%), and autoimmune disorders (12.7%). Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were the most commonly found pathogens for infectious disease, and Kawasaki disease (KD) was the top cause of miscellaneous diagnosis. CONCLUSIONS: Infectious disease remains the most common etiology. Careful history taking and physical examination are most crucial for making the diagnosis. Conservative treatment may be enough for most children with FUO, except for those suffering from malignancies. PMID- 25735797 TI - Incidence and risk factors of probable and proven invasive fungal infection in adult patients receiving allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: To investigate the incidence and risk factors for the occurrence of proven or probable invasive fungal infection (IFI) in adult patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We retrospectively analyzed 421 patients undergoing HSCT between 2002 and 2013 in our hospital. The risk factors for the occurrence of IFI were analyzed using Cox regression models. RESULTS: Thirty-one patients with the median age of 42 years (range, 19-60 years) developed IFI after HSCT. The post-HSCT IFI incidence was 7.4% and median time from HSCT to the diagnosis of IFI was 139 days (range, 2 1809 days). Of the pretransplant factors, European Group for Blood and Marrow Transplantation (EBMT) risk score > 2 (p = 0.001) and prior history of IFI (p = 0.006) or type 2 diabetes mellitus (DM; p = 0.042) were the significant predictors for post-HSCT IFI in univariate analyses. In multivariate analysis, EBMT risk score > 2 (p = 0.015) and prior history of IFI (p = 0.006) retained significance. Of the post-transplant factors, acute graft-versus-disease (GVHD) overall Grade III-IV (p < 0.001), extensive chronic GVHD (p = 0.002), development of post-transplant lymphoproliferative disorders (p = 0.005), and the use of high dose steroids (p < 0.001) were statistically significant in univariate analyses. After multivariate analysis, high-dose steroids (p < 0.001) and acute GVHD overall Grade III-IV (p = 0.045) retained significance. CONCLUSION: These results suggest that risk group stratification prior to HSCT and monitoring of IFI in patients with severe GVHD receiving high-dose steroids is mandatory to reduce the mortality and morbidity of post-HSCT IFI, especially in those with prior history of IFI. PMID- 25735799 TI - Risk of virological failure in HIV-1-infected patients experiencing low-level viraemia under active antiretroviral therapy (ANRS C03 cohort study). AB - BACKGROUND: We assessed the association of persistent low-level viraemia between 50-199 copies/ml (LLV) with the risk of virological failure (VF) among HIV-1 infected patients receiving combination antiretroviral therapy (ART). METHODS: ART-naive and ART-experienced patients followed up in the ANRS-CO3 Aquitaine Cohort were included if they started two nucleoside reverse transcriptase inhibitors (NRTIs) with either one non-nucleoside reverse transcriptase inhibitor (NNRTI) or one protease inhibitor boosted with ritonavir (PI/r) between 2000 and 2011 and achieved viral load (VL)<200 copies/ml 4-8 months after initiating ART. VF was defined as either two consecutive VL>=200 copies/ml or one VL>=200 followed by a modification of ART. LLV was defined as at least two consecutive VLs between 50-199 copies/ml for at least one month. We used Cox models to estimate the association of LLV with VF. RESULTS: Among 2,374 patients with a median follow-up of 3 years, 205 (8.6%) experienced LLV. LLV was strongly associated with further VF (adjusted hazard ratio [aHR] 2.30, 95% CI 1.65, 3.20). LLV was associated with VF in ART-experienced patients (aHR 3.02, 95% CI 2.10, 4.33) but not in ART-naive patients. Neither type of ART regimen (PI/r- versus NNRTI-based regimen) nor cumulative duration of LLV was associated with VF. CONCLUSIONS: Persistent LLV between 50-199 copies/ml was associated with VF among ART-experienced patients under ART. LLV between 50-199 copies/ml in ART experienced patients should lead, after assessing patient's adherence and checking for drug interactions, to a closer monitoring and to consider ART optimization. PMID- 25735798 TI - Non-thermal plasma with 2-deoxy-D-glucose synergistically induces cell death by targeting glycolysis in blood cancer cells. AB - In this study, we show the selective and efficient anti-cancer effects of plasma (at a low dose) when cell metabolic modifiers are also included. 2-deoxy-D glucose (2-DG), a glycolytic inhibitor, was used with effective doses of non thermal plasma, synergistically attenuating cell metabolic viability and inducing caspase-dependent and independent cell death. The combination treatment decreased the intracellular ATP and lactate production in various types of blood cancer cells in vitro. Taken together, our findings suggest that 2-DG enhances the efficacy and selectivity of plasma and induces the synergistic inhibition of cancer cell growth by targeting glycolysis and apoptosis. Specifically, this treatment strategy demonstrated an enhanced growth inhibitory effect of plasma in the presence of a metabolic modifier that was selective against cancer cells, not non-malignant cells. This is the first study to report the advantage of combining plasma with 2-DG to eradicate blood cancer cells. Finally, we conclude that 2-DG with non-thermal plasma may be used as a combination treatment against blood cancer cells. PMID- 25735800 TI - The synergistic effect of micro-topography and biochemical culture environment to promote angiogenesis and osteogenic differentiation of human mesenchymal stem cells. AB - Critical failures associated with current engineered bone grafts involve insufficient induction of osteogenesis of the implanted cells and lack of vascular integration between graft scaffold and host tissue. This study investigated the combined effects of surface microtextures and biochemical supplements to achieve osteogenic differentiation of human mesenchymal stem cells (hMSCs) and revascularization of the implants in vivo. Cells were cultured on 10MUm micropost-textured polydimethylsiloxane (PDMS) substrates in either proliferative basal medium (BM) or osteogenic medium (OM). In vitro data revealed that cells on microtextured substrates in OM had dense coverage of extracellular matrix, whereas cells in BM displayed more cell spreading and branching. Cells on microtextured substrates in OM demonstrated a higher gene expression of osteoblast-specific markers, namely collagen I, alkaline phosphatase, bone sialoprotein, and osteocalcin, accompanied by substantial amount of bone matrix formation and mineralization. To further investigate the osteogenic capacity, hMSCs on microtextured substrates under different biochemical stimuli were implanted into subcutaneous pockets on the dorsal aspect of immunocompromised mice to study capacity for ectopic bone formation. In vivo data revealed greater expression of osteoblast-specific markers coupled with increased vascular invasion on microtextured substrates with hMSCs cultured in OM. Together, these data represent a novel regenerative strategy that incorporates defined surface microtextures and biochemical stimuli to direct combined osteogenesis and re vascularization of engineered bone scaffolds for musculoskeletal repair and relevant bone tissue engineering applications. PMID- 25735801 TI - Targeted delivery of cisplatin by LHRH-peptide conjugated dextran nanoparticles suppresses breast cancer growth and metastasis. AB - The metastasis of breast cancer is the leading cause of cancer death in women. In this work, an attempt to simultaneously inhibit the primary tumor growth and organ-specific metastasis by the cisplatin-loaded LHRH-modified dextran nanoparticles (Dex-SA-CDDP-LHRH) was performed in the 4T1 orthotopic mammary tumor metastasis model. With the rationally designed conjugation site of the LHRH ligand, the Dex-SA-CDDP-LHRH nanoparticles maintained the targeting function of LHRH and specifically bound to the LHRH-receptors overexpressed on the surface of 4T1 breast cancer cells. Therefore, the Dex-SA-CDDP-LHRH nanoparticles exhibited improved cellular uptake and promoted cytotoxicity, when compared with the non targeted Dex-SA-CDDP nanoparticles. Moreover, both the non-targeted and targeted nanoparticles significantly decreased the systemic toxicity of CDDP and increased the maximum tolerated dose of CDDP from 4 to 30mgkg(-1). Importantly, Dex-SA-CDDP LHRH markedly enhanced the accumulation of CDDP in the injected primary tumor and metastasis-containing organs, and meanwhile significantly reduced the nephrotoxicity of CDDP. Dose-dependent therapeutic effects further demonstrated that the CDDP-loaded LHRH-decorated polysaccharide nanoparticles significantly enhanced the antitumor and antimetastasis efficacy, as compared to the non targeted nanoparticles. These results suggest that Dex-SA-CDDP-LHRH nanoparticles show great potential for targeted chemotherapy of metastatic breast cancer. PMID- 25735802 TI - Characterization of antimicrobial activity and mechanisms of low amphipathic peptides with different alpha-helical propensity. AB - Antimicrobial peptides (AMPs) serve as a defense mechanism within multicellular organisms and are attracting increasing attention because of their potential application in the treatment of multidrug-resistant infections. Amphipathicity has long been believed to be the most important consideration for the structural modification and design of both naturally occurring and synthetic AMPs. Previous studies indicated that disruptive amphipathicity formed by replacing the paired charged amino acid residues on the polar face of an amphipathic helix with tryptophan residues linked with hydrogen bonds on the basis of alpha-helical protein folding principles endowed the AMPs with increased cell selectivity. In an attempt to augment and hone this strategy further, we designed a series of imperfect amphipathic peptides by placing different types of amino acid residues at the hydrogen bond linked positions of alpha-helix structures to characterize their antimicrobial properties and mechanism of action. The d-Trp-substituted sequence (PRW4-d) showed greater antimicrobial potency than Cys-(C4), Asp-(D4), Ile-(I4), and Pro-(P4) substituted sequences, comparable to the l-Trp-substituted parent sequence (PRW4). Furthermore, the total replacement of Lys residues with Arg residues along the peptide sequence (PRW4-R) exhibited enhanced antimicrobial activity and cell selectivity. In addition, no cytotoxicity was observed among these synthetic peptides. PRW4-d and PRW4-R maintained their activities in the presence of physiological salts and human serum. The fluorescence spectroscopy, flow cytometry, and electron microscopy observations indicated that the optimized sequences exhibited excellent antimicrobial potency by inducing cytoplasmic membrane potential loss, membrane permeabilization and disruption. Collectively, the results could be useful for designing short AMPs with great antimicrobial activity and cell selectivity. PMID- 25735803 TI - Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: A systematic review. AB - BACKGROUND: The optimal cumulative dose and timing of cisplatin administration in various concurrent chemoradiotherapy protocols for nonmetastatic head and neck squamous cell carcinoma (HNSCC) has not been determined. METHODS: The absolute survival benefit at 5 years of concurrent chemoradiotherapy protocols versus radiotherapy alone observed in prospective randomized trials reporting on the use of cisplatin monochemotherapy for nonnasopharyngeal HNSCC was extracted. In the case of nonrandomized studies, the outcome results at 2 years were compared between groups of patients receiving different cumulative cisplatin doses. RESULTS: Eleven randomized trials and 7 nonrandomized studies were identified. In 6 definitive radiotherapy phase III trials, a statistically significant association (p = .027) between cumulative cisplatin dose, independent of the schedule, and overall survival benefit was observed for higher doses. CONCLUSION: Results support the conclusion that the cumulative dose of cisplatin in concurrent chemoradiation protocols for HNSCC has a significant positive correlation with survival. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2151 E2158, 2016. PMID- 25735804 TI - A novel mutation in RNU4ATAC in a patient with microcephalic osteodysplastic primordial dwarfism type I. PMID- 25735805 TI - Systematic review and meta-analysis of islet autotransplantation after total pancreatectomy in chronic pancreatitis patients. AB - Islet autotransplantation (IAT) is a viable treatment for patients with severe chronic pancreatitis, this modality may prevent brittle diabetes mellitus after pancreatectomy. This systematic review and meta-analysis was performed to evaluated the outcomes of IAT after TP and discuss the factors that may affect the efficacy of this procedure. MEDLINE, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 1977 to 30 April 2014. Cohort Studies reported patients with IAT after TP were included. The studies and data were identified and extracted by two reviewers independently. Data were analyzed using STATA 12.0 and Comprehensive Meta AnalysisV2 software. Random effects model, meta-regression analysis, sensitivity analysis and publication bias were conducted to improve the comprehensive analysis. Twelve studies reporting the outcomes of 677 patients were included in this review. The insulin independent rate for IAT after TP at last follow-up was 3.72 per 100 person-years (95% CI: 1.00-6.44). The 30-day mortality was 2.1% (95% CI: 1.2 3.8%). The mortality at last follow-up was 1.09 per 100 person-years (95% CI: 0.21-1.97). Factors associated with incidence density of insulin independence in univariate meta-regression analyses included islet equivalents per kg body weight (IEQ/kgBW) (P=0.026). Our systematic review suggests that IAT is a safe modality for patients with CP need to undergo TP. A significant number of patients will achieve insulin independence for a long time after receiving enough IEQ/kgBW. PMID- 25735806 TI - Essential Elements of an Effective Prison Hospice Program. AB - As the number of prison inmates facing end-stage chronic illness grows, more prisons across the U.S. must address the need for end-of-life care. Many will likely need to develop a plan with potentially limited resources and external support. This case study presents one long-running model of care, the Louisiana State Penitentiary Prison Hospice Program. Based on field observations and in depth interviews with hospice staff, inmate volunteers and corrections officers, we identify five essential elements that have contributed to the long-term operation of this program: patient-centered care, an inmate volunteer model, safety and security, shared values, and teamwork. We describe key characteristics of each of these elements, discuss how they align with earlier recommendations and research, and show how their integration supports a sustained model of prison end-of-life care. PMID- 25735807 TI - Disparities Among Those With Advance Directives in a Medicare Supplement Population. AB - Advance directives (ADs) detail patients' end-of-life (EOL) care preferences. We estimated AD prevalence rates among a Medicare Supplement population and determined characteristics associated with having ADs. We also estimated the impact of having an AD on EOL Medicare expenditures among respondents who later died. Survey respondents with an AD (72%) were significantly more likely to be female, older, nonminority, higher income and education, and have more comorbid conditions. Following regression adjustments, EOL expenditures were significantly lower for those with ADs in the last 3 months (-US$11 189) and 1 month (-US$6092) prior to death. Patients with ADs specifying their wishes for EOL care had significantly lower medical expenditures during the last few months of life. However, disparities exist among those with ADs that may warrant interventions. PMID- 25735808 TI - EPA guidance on the role and responsibilities of psychiatrists. AB - Psychiatry is that branch of the medical profession, which deals with the origin, diagnosis, prevention, and management of mental disorders or mental illness, emotional and behavioural disturbances. Thus, a psychiatrist is a trained doctor who has received further training in the field of diagnosing and managing mental illnesses, mental disorders and emotional and behavioural disturbances. This EPA Guidance document was developed following consultation and literature searches as well as grey literature and was approved by the EPA Guidance Committee. The role and responsibilities of the psychiatrist include planning and delivering high quality services within the resources available and to advocate for the patients and the services. The European Psychiatric Association seeks to rise to the challenge of articulating these roles and responsibilities. This EPA Guidance is directed towards psychiatrists and the medical profession as a whole, towards other members of the multidisciplinary teams as well as to employers and other stakeholders such as policy makers and patients and their families. PMID- 25735809 TI - EPA guidance on how to improve the image of psychiatry and of the psychiatrist. AB - Stigma against mental illness and the mentally ill is well known. However, stigma against psychiatrists and mental health professionals is known but not discussed widely. Public attitudes and also those of other professionals affect recruitment into psychiatry and mental health services. The reasons for this discriminatory attitude are many and often not dissimilar to those held against mentally ill individuals. In this Guidance paper we present some of the factors affecting the image of psychiatry and psychiatrists which is perceived by the public at large. We look at the portrayal of psychiatry, psychiatrists in the media and literature which may affect attitudes. We also explore potential causes and explanations and propose some strategies in dealing with negative attitudes. Reduction in negative attitudes will improve recruitment and retention in psychiatry. We recommend that national psychiatric societies and other stakeholders, including patients, their families and carers, have a major and significant role to play in dealing with stigma, discrimination and prejudice against psychiatry and psychiatrists. PMID- 25735810 TI - EPA guidance on the early detection of clinical high risk states of psychoses. AB - The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion 'cognitive disturbances' (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The 'genetic risk and functional decline' UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states. PMID- 25735811 TI - Cost-effectiveness of intensive home treatment enhanced by inpatient treatment elements in child and adolescent psychiatry in Germany: A randomised trial. AB - BACKGROUND: Admission rate to child and adolescent mental health inpatient units in Germany is high (54,467 admissions in 2013), resources for providing necessary beds are scarce. Alternative pathways to care are needed. Objective of this study was to assess the cost-effectiveness of inpatient treatment versus Hot-BITs treatment (Hometreatment brings inpatient-treatment outside), a new supported discharge service offering an early discharge followed by 12 weeks of intensive support. METHODS: Of 164 consecutively recruited children and adolescents, living within families and being in need of inpatient mental health care, 100 patients consented to participate and were randomised via a computer-list into intervention (n=54) and control groups (n=46). Follow-up data were available for 76 patients. Primary outcome was cost-effectiveness. Effectiveness was gathered by therapist-ratings on the Children's Global Assessment Scale (CGAS) at baseline (T1), treatment completion (T2) and an 8-month-follow-up (T3). Cost of service use (health care costs and non-health care costs) was calculated on an intention to-treat basis at T2 and T3. RESULTS: Significant treatment effects were observed for both groups between T1/T2 and T1/T3 (P<0.001). The Hot-BITs treatment, however, was associated with significantly lower costs at T2 (difference: 6900.47?, P=0.013) and T3 (difference: -8584.10?, P=0.007). Bootstrap cost effectiveness ratio indicated that Hot-BITs was less costly and tended to be more effective at T2 and T3. CONCLUSIONS: Hot-BITs may be a feasible cost-effective alternative to long inpatient stays in child and adolescent psychiatry. Further rigorous evaluations of the model are required. ( REGISTRATION NUMBER: ISRCTN02672532, part 1, Current Controlled Trials Ltd, URL: http://www.controlled trials.com). PMID- 25735813 TI - Cycloparaphenylenes and related nanohoops. AB - The first synthesis of a cyclic oligophenylene possessing a radial pi system was reported in 2008. In the short period that has elapsed since, there has been an ever-increasing level of interest in molecules of this type, as evidenced by the volume of publications in this area. This interest has been driven by the highly unusual properties of these molecules in comparison to their linear oligoarene analogues, as well as the diverse array of potential applications for them. Notably, CPPs and related structures were proposed as viable templates for the bottom-up synthesis of single-walled carbon nanotubes (SWCNTs), a proposition which has recently been realised. This review gives a comprehensive and strictly chronological (by date of first online publication) treatment of literature reports from the inception of the field, with emphasis on both synthesis and properties of CPPs and related nanohoops. (The scope of this review is restricted to molecules possessing a radial pi system consisting entirely of subunits which are aromatic in isolation, e.g. CPPs, but not cycloparaphenyleneacetylenes or cyclopolyacetylenes). PMID- 25735812 TI - Pharmacophore-based design of novel oxadiazoles as selective sphingosine-1 phosphate (S1P) receptor agonists with in vivo efficacy. AB - Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2'-(trifluoromethyl)biphenyl-4-yl]-1,2,4 oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5 [2'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS. PMID- 25735814 TI - Basic fibroblast growth factor induces VEGF expression in chondrosarcoma cells and subsequently promotes endothelial progenitor cell-primed angiogenesis. AB - Chondrosarcoma, a common malignant tumour, develops in bone. Effective adjuvant therapy remains inadequate for treatment, meaning poor prognosis. It is imperative to explore novel remedies. Angiogenesis is a rate-limiting step in progression that explains neovessel formation for blood supply in the tumour microenvironment. Numerous studies indicate that EPCs (endothelial progenitor cells) promote angiogenesis and contribute to tumour growth. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis, and correlates with tumorigenesis. However, the role of bFGF in angiogenesis-related tumour progression by recruiting EPCs in human chondrosarcoma is rarely discussed. In the present study, we found that bFGF induced VEGF (vascular endothelial growth factor) expression via the FGFR1 (fibroblast growth factor receptor 1)/c-Src/p38/NF-kappaB (nuclear factor kappaB) signalling pathway in chondrosarcoma cells, thereby triggering angiogenesis of endothelial progenitor cells. Our in vivo data revealed that tumour-secreted bFGF promotes angiogenesis in both mouse plug and chick CAM (chorioallantoic membrane) assays. Xenograft mouse model data, due to bFGF-regulated angiogenesis, showed the bFGF regulates angiogenesis-linked tumour growth. Finally, bFGF was highly expressed in chondrosarcoma patients compared with normal cartilage, positively correlating with VEGF expression and tumour stage. The present study reveals a novel therapeutic target for chondrosarcoma progression. PMID- 25735815 TI - Polymorphism identification in BMP15 and GDF9 genes and their association with egg production in chickens. AB - 1. Mutations in growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are significantly associated with reproductive performance in mammals and the objective of the present study was to identify polymorphic sites and elucidate the association between genotypes in BMP15 and GDF9 and egg production. 2. Polymorphisms in BMP15 exon1 and GDF9 exon2 were detected by DNA sequencing and PCR-RFLP. Three SNPs were detected in each of BMP15 (A111G, C231T and C34T) and GDF9 (G593A, T824C and C896T). C34T leads to the substitution of Leu by Phe, which was predicted to affect protein function. 3. Results of the association analysis indicated that C34T had an effect on total egg production at 300 d of age (EN) and age at first laying (AFE). G593A affected EN and both C231T and C896T influenced AFE. The TGC1TGC1 diplotype in BMP15 had the highest EN. 4. In conclusion, EN may be significantly improved by marker-assisted selection of the BMP15 genotypes in maternal lines of Shaobo hens. PMID- 25735816 TI - Seroepidemiological survey of Rickettsia spp. in dogs from the endemic area of Rickettsia parkeri rickettsiosis in Uruguay. AB - Rickettsia parkeri rickettsiosis is a vector-borne zoonosis that occurs in some countries of the American continent. Following the first description and determination of the pathogenicity to humans in 2004 in USA, this bacterium has been reported in several South American countries. Human cases have been diagnosed in both Uruguay and Argentina in the past years. This study consisted in a serosurvey of 1000 domestic dogs living in the endemic area of rickettsiosis in Uruguay, where Amblyomma triste is the tick vector. Sera were analyzed by Indirect Immunofluorescence Assay (IFA), against antigens of three different rickettsial species: R. rhipicephali, R. felis and R. parkeri. It was determined that 20.3% of the dogs had antibodies that reacted to at least one of the three species tested, taking as cut off >=64 titers. Furthermore, 140 of the seropositive dogs (14%) had a titer at least 4 times higher to R. parkeri than those of any of the other species, thus, it was considered that the immune response was stimulated by that species in particular. This is the first serological survey in primary hosts for adults of A. triste in Uruguay, and therefore the first prevalence values are reported. Adult A. triste ticks collected from the environment as well as from dogs were analyzed by PCR in order to confirm the current circulation of the agent in the area. In this matter, two out of 28 ticks from dogs, and 3 out of 53 ticks from the environment were positive, and the corresponding sequence analysis revealed 100% similarity with R. parkeri strain maculatum. PMID- 25735817 TI - Mechanisms of 1-hydroxy-2-hydroxymethylanthraquinone from Coptosapelta flavescens as an anti-giardial activity. AB - Thai medicinal plants represent a rich source of potential anti-parasitic compounds. 1-hydroxy-2-hydroxymethylanthraquinone (CFQ) purified from Coptosapelta flavescens, a plant commonly used to expel intestinal worms, indicated potential anti-giardial agent as shown in a previous study. This study aims to investigate its mechanism of action. We assessed whether CFQ was involved as an inducer of apoptosis as well as having effects on the fine structure of Giardia intestinalis trophozoites. We observed the consequences of exposing G. intestinalis trophozoites to CFQ and metronidazole, both had an IC50 of 0.42MUg/ml, after 6, 12 and 24h exposure. An apoptosis in trophozoite was confirmed by the AnnexinV-FITC assay and as viewed by flow cytometry. CFQ at its IC50 induced apoptosis as early as 6h after incubation while metronidazole produced little or no apoptosis at its IC50 value. Ultrastructural analyzes at 24h demonstrated that both CFQ and metronidazole induced several physical alterations, including the appearance of wrinkled and rounded cells, membrane blebbing, ventral disc damage, electron dense precipitates in the nuclei, all of which were indicative of cell death. However, membrane rupture was found only in G. intestinalis exposed to CFQ and this proved the induction of apoptosis. Taken together, we have provided a mechanistic explanation of the action of CFQ against G. intestinalis trophozoites. These results have provided further evidence that CFQ is a new compound that has the potential for use to treat infections from G. intestinalis. PMID- 25735818 TI - Isolation and characterization of tri- and tetra-repeat microsatellite loci in the white-spotted charr Salvelinus leucomaenis (Salmonidae). AB - Tri- and tetra-motif repeat microsatellite marker loci were developed for the white-spotted charr Salvelinus leucomaenis. The 454 pyrosequencing was used to discover repeat arrays, and eight microsatellite-primer sets, available for the estimation of polymorphisms, were identified. The number of alleles in a wild population ranged from two to four and the observed and expected heterozygosities were 0.180-0.600 and 0.188-0.599, respectively. PMID- 25735819 TI - Daily affect variability and context-specific alcohol consumption. AB - INTRODUCTION AND AIMS: Research explored the effects of variability in negative and positive affect on alcohol consumption, specifying daily fluctuation in affect as a critical form of emotion dysregulation. Using daily process methodology allows for a more objective calculation of affect variability relative to traditional self-reports. The present study models within-person negative and positive affect variabilities as predictors of context-specific consumption (i.e. solitary vs. social drinking), controlling for mean levels of affect. DESIGN AND METHODS: A community sample of moderate-to-heavy drinkers (n = 47; 49% women) from a US metropolitan area reported on affect and alcohol consumption thrice daily for 30 days via a handheld electronic interviewer. Within-person affect variability was calculated using daily standard deviations in positive and negative affect. RESULTS: Within person, greater negative and positive variabilities are related to greater daily solitary and social consumption. Across study days, mean levels of negative and positive affect variabilities related to greater social consumption between persons; yet, aggregated negative affect variability was related to less solitary consumption. DISCUSSION AND CONCLUSIONS: Results affirm affect variability as a unique predictor of alcohol consumption, independent of mean affect levels. Yet, it is important to differentiate social context of consumption, as well as type of affect variability, particularly at the between-person level. These distinctions help clarify inconsistencies in the self-medication literature regarding associations between average levels of affect and consumption. Importantly, consistent within-person relationships for both variabilities support arguments that both negative and positive affect variabilities are detrimental and reflect an inability to regulate emotional experience. PMID- 25735820 TI - Crystal structure of LptH, the periplasmic component of the lipopolysaccharide transport machinery from Pseudomonas aeruginosa. AB - Lipopolysaccharide (LPS) is the main glycolipid present in the outer leaflet of the outer membrane (OM) of Gram-negative bacteria, where it modulates OM permeability, therefore preventing many toxic compounds from entering the cell. LPS biogenesis is an essential process in Gram-negative bacteria and thus is an ideal target pathway for the development of novel specific antimicrobials. The lipopolysaccharide transport (Lpt) system is responsible for transporting LPS from the periplasmic surface of the inner membrane, where it is assembled, to the cell surface where it is then inserted in the OM. The Lpt system has been widely studied in Escherichia coli, where it consists of seven essential proteins located in the inner membrane (LptBCFG), in the periplasm (LptA) and in the OM (LptDE). In the present study, we focus our attention on the Pseudomonas aeruginosa PAO1 Lpt system. We identified an LptA orthologue, named LptH, and solved its crystal structure at a resolution of 2.75 A. Using interspecies complementation and site-directed mutagenesis of a conserved glycine residue, we demonstrate that P. aeruginosa LptH is the genetic and functional homologue of E. coli LptA, with whom it shares the beta-jellyroll fold identified also in other members of the canonical E. coli Lpt model system. Furthermore, we modeled the N terminal beta-jellyroll domain of P. aeruginosa LptD, based on the crystal structure of its homologue from Shigella flexneri, aiming to provide more general insight into the mechanism of LPS binding and transport in P. aeruginosa. Both LptH and LptD may represent new targets for the discovery of next generation antibacterial drugs, targeting specific opportunistic pathogens such as P. aeruginosa. DATABASE: Coordinates and structure factors have been deposited in the Protein Data Bank under accession number PDB 4uu4. PMID- 25735821 TI - A pilot study of active rehabilitation for adolescents who are slow to recover from sport-related concussion. AB - The purpose of this study was to examine the effectiveness of an active rehabilitation intervention for adolescents who are slow-to-recover after a sport related concussion. Ten adolescents (three girls and seven boys) seen at the Montreal Children's Hospital Concussion Clinic participated in this case series. Adolescents who were symptomatic more than 4 weeks after the injury were provided with an active rehabilitation intervention (M = 7.9 weeks following injury; range = 3.7 to 26.2 weeks). The rehabilitation program includes gradual, closely monitored light aerobic exercise, general coordination exercises, mental imagery, as well as reassurance, normalization of recovery, and stress/anxiety reduction strategies. The program continued until complete symptom resolution and readiness to begin stepwise return to activities. The primary outcome of the study was evolution of post-concussion symptoms. Secondary outcomes included mood, energy, balance, and cognition. After the intervention, post-concussion symptoms significantly decreased for the group of participants. They also had decreased fatigue and improved mood after 6 weeks of initiating the rehabilitation intervention. This case series shows that postconcussive symptoms and functioning in adolescents following sports-related concussion can be improved after participation in an active rehabilitation intervention. The introduction of graded light intensity exercise in the post-acute period following concussion is safe, feasible and appears to have a positive impact on adolescents' functioning. PMID- 25735822 TI - Isolated central vestibular syndrome. AB - Isolated vestibular syndrome may occur all along the vestibular pathways from the peripheral labyrinth to the brain. By virtue of recent developments in clinical neurotology and neuroimaging, however, diagnosis of isolated central vestibulopathy is increasing. Here, we review five distinct syndromes of isolated central vestibular syndrome from lesions restricted to the vestibular nuclei, the nucleus prepositus hypoglossi, the flocculus, the tonsil, and the nodulus, and introduce a new vestibular syndrome from isolated involvement of the inferior cerebellar peduncle. Decreased responses to head impulses do not exclude a central lesion as a cause of isolated vestibular syndrome. Brain imaging, including diffusion-weighted magnetic resonance imaging (MRI), may be falsely negative during the acute phase in patients with isolated vestibular syndrome because of a stroke. Central signs should be sought carefully in patients with isolated vertigo, even when the patients show the features of peripheral vestibulopathy and negative MRIs. Recognition of these isolated central vestibular syndromes would aid in defining the lesions responsible for various vestibular manifestations in central vestibulopathy. PMID- 25735823 TI - A defined alpha-helix in the bifunctional O-glycosylated natriuretic peptide TcNPa from the venom of Tropidechis carinatus. AB - Natriuretic peptides (NP) play important roles in human cardiac physiology through their guanylyl cyclase receptors NPR-A and NPR-B. Described herein is a bifunctional O-glycosylated natriuretic peptide, TcNPa, from Tropidechis carinatus venom and it unusually targets both NPR-A and NPR-B. Characterization using specific glycosidases and ETD-MS identified the glycan as galactosyl-beta(1 3)-N-acetylgalactosamine (Gal-GalNAc) and was alpha-linked to the C-terminal threonine residue. TcNPa contains the characteristic NP 17-membered disulfide ring with conserved phenylalanine and arginine residues. Both glycosylated and nonglycosylated forms were synthesized by Fmoc solid-phase peptide synthesis and NMR analysis identified an alpha-helix within the disulfide ring containing the putative pharmacophore for NPR-A. Surprisingly, both forms activated NPR-A and NPR-B and were relatively resistant towards proteolytic degradation in plasma. This work will underpin the future development of bifunctional NP peptide mimetics. PMID- 25735824 TI - Completing bacterial genome assemblies: strategy and performance comparisons. AB - Determining the genomic sequences of microorganisms is the basis and prerequisite for understanding their biology and functional characterization. While the advent of low-cost, extremely high-throughput second-generation sequencing technologies and the parallel development of assembly algorithms have generated rapid and cost effective genome assemblies, such assemblies are often unfinished, fragmented draft genomes as a result of short read lengths and long repeats present in multiple copies. Third-generation, PacBio sequencing technologies circumvented this problem by greatly increasing read length. Hybrid approaches including ALLPATHS-LG, PacBio corrected reads pipeline, SPAdes, and SSPACE-LongRead, and non-hybrid approaches--hierarchical genome-assembly process (HGAP) and PacBio corrected reads pipeline via self-correction--have therefore been proposed to utilize the PacBio long reads that can span many thousands of bases to facilitate the assembly of complete microbial genomes. However, standardized procedures that aim at evaluating and comparing these approaches are currently insufficient. To address the issue, we herein provide a comprehensive comparison by collecting datasets for the comparative assessment on the above-mentioned five assemblers. In addition to offering explicit and beneficial recommendations to practitioners, this study aims to aid in the design of a paradigm positioned to complete bacterial genome assembly. PMID- 25735825 TI - An ultra-low Pd loading nanocatalyst with efficient catalytic activity. AB - An ultra-low Pd loading nanocatalyst is synthesized by a convenient solution route of photochemical reduction and aqueous chemical growth. The modification of nanocatalyst structures is investigated through changing morphologies of Pd nanoclusters on the surface of ZnO nanorods. A significant enhancement in photocatalytic properties has been achieved by decorating a trace amount of Pd clusters (0.05 at%) on the surface of ZnO nanorods. The reduction of 4 nitrophenol (4-NP) to 4-aminophenol (4-AP) is applied to demonstrate multiple catalytic activities in the Pd-ZnO hybrid nanocatalyst, which also provides a better understanding of the relationship between the unique nanoconfigured structure and catalytic performance. PMID- 25735826 TI - Empirical research and bioethics. PMID- 25735827 TI - Femoral artery access using the US-determined inguinal ligament and femoral head as reliable landmarks: prospective study of usefulness and safety. AB - PURPOSE: To evaluate ultrasound (US)-guided femoral artery access using the US determined inguinal ligament (IL; US-IL) and femoral head as anatomic landmarks to prevent "high stick" (ie, cannulation above the IL) of the common femoral artery (CFA). MATERIALS AND METHODS: Fifty consecutive US-guided femoral artery accesses for embolization of hepatocellular carcinoma (n = 49) or renal angiography (n = 1) between December 2008 and August 2009 were prospectively analyzed. Primary endpoints were evaluation of technical success and major/minor complications during the procedure and follow-up visits. Secondary endpoints were the relative locations of the US-IL, fluoroscopically determined IL (FL-IL), and origin site of the inferior epigastric artery (IEA) on completion angiography. Relationships were evaluated between CFA types and lengths on US, between CFA types on US, and between frequencies of low-lying US-IL on fluoroscopy. Spearman correlation, Student t test, and Fisher exact test were used for statistical analysis. RESULTS: Technical success of CFA access was achieved in all patients (100%), with no high stick of the CFA noted. No complications were noted. On fluoroscopy, US-IL was located significantly lower than FL-IL (P = .002). On fluoroscopy and completion angiography, US-IL was more strongly correlated (rho = 0.823, P < .001) with the IEA origin site than with the FL-IL (rho = 0.287, P = .043). Finally, a "slope-type" CFA was shorter than a "horizontal-type" CFA on US and was more common in patients with low-lying US-IL on fluoroscopy (P = .001). CONCLUSIONS: US-guided CFA access with US-IL and femoral head guidance is safe and useful and can be helpful in preventing high stick. PMID- 25735828 TI - Inter- and intra-individual variability of total antioxidant capacity of bovine seminal plasma and relationships with sperm quality before and after cryopreservation. AB - The aim of the present study was to investigate inter- and intra-individual variability of total antioxidant capacity (TAC) in seminal plasma of bulls. In addition, relationships between TAC and glutathione peroxidase (GPx), superoxide dismutase activities (SOD), and parameters of sperm quality, respectively, were examined. Eight consecutive ejaculates were collected from nine Holstein-Friesian bulls. The percentage of plasma membrane and acrosome intact (PMAI) sperm was measured by using the FITC-PNA/PI assay, the amount of membrane lipid peroxidation (LPO) without and with stimulation(s) of LPO was quantified by using the BODIPY assay before cryopreservation and immediately (0 h) as well as 3h after thawing. The percentage of sperm with a greater DNA fragmentation index was measured by the sperm chromatin structure assay. The amount of TAC differed (P < 0.0001) between bulls but not (P > 0.05) between ejaculates within bulls. The amounts of TAC were not related (P > 0.05) to amounts of SOD and GPx, but were negatively associated with LPO 0 h (r = -0.85; P <= 0.01). The amounts of SOD showed positive relationships with LPO 0 h (r = 0.71; P <= 0.05) and LPO 3h (r = 0.80; P <= 0.05). In conclusion, total antioxidant activity varied among bulls, but not between ejaculates within bulls. While the amounts of antioxidative enzyme GPx was not related to sperm quality and SOD was positively related with lipid peroxidation after thawing of sperm, whereas total antioxidative capacity was negatively correlated with lipid peroxidation of cryopreserved sperm. PMID- 25735829 TI - Identification of differentially expressed microRNAs in placentas of cloned and normally produced calves by Solexa sequencing. AB - Aberrant gene expression caused by aberrant nuclear reprogramming results in developmental abnormalities in cloned animals and ultimately their death. MicroRNAs (miRNAs), a family of ~ 22 nucleotide, non-coding, single-stranded RNA molecules, are considered as key regulators of gene expression. Numerous miRNAs and their expression patterns have been identified in various species. However, the significance of miRNAs in developmental abnormalities in cloned animals is unclear. Small RNA libraries were generated from the placentas of cloned (somatic cell nuclear transfer, SCNT) and normally produced (control) calves. A total of 18,815,541 clean reads were obtained from the SCNT library and 19,329,352 from the control library. In total, 430 conserved bovine miRNAs were identified in bovine placenta. Furthermore, the family, expression predominance, and base substitution of the conserved miRNAs were also analyzed. We found 135 conserved miRNAs that were differentially expressed significantly between the two samples, which suggest that these miRNAs may affect developmental abnormalities in cloned cattle and ultimately their death. The miRNA target prediction, gene ontology, and pathway analysis for these target genes were also carried out. The present study expands the collection of bovine miRNAs and could initiate further studies on the functions of miRNAs in developmental abnormalities and death in cloned animals. PMID- 25735830 TI - Effect of a new device for sustained progesterone release on the progesterone concentration, ovarian follicular diameter, time of ovulation and pregnancy rate of ewes. AB - This study evaluated the effectiveness of a new progesterone intravaginal device (DPR) in ewes through four experiments: Experiment 1 compared the circulating progesterone concentration of ovariectomized ewes that received either a new or a re-used DPR. Experiment 2 compared the progesterone concentration between DPR estrous-synchronized ewes and naturally estrous-cycling ewes. Experiment 3 evaluated the effect of new and re-used DPRs on ovarian follicular dynamics and time of ovulation of estrous cycling ewes. Experiment 4 compared the pregnancy rate after the use of a DPR and Controlled Internal Drug Releasing Device (CIDR). The mean concentration of progesterone released by the DPR device during its first use (New Group: 5.1 +/- 0.5 ng/ml) was greater than that during the second use (Re-used Group: 2.4 +/- 0.3 ng/ml). There was no difference between the animals that received DPR devices for first and second use in terms of ovulatory follicle diameter, follicular wave emergence day for ovulatory follicle and period of ovulatory wave of ovarian follicular development. However, there was a significant difference between groups regarding the time between DPR device removal and first ovulation (New Group: 71.7 +/- 2.5h and Re-Used Group: 63.9 +/- 2.7h). Pregnancy rates were similar between ewes with DPR and CIDR devices. It was concluded that DPR is effective in increasing and maintaining progesterone concentrations, controlling follicular dynamics, promoting synchronized times of ovulation from healthy follicles, promoting development of a competent corpus luteum and when used results in pregnancy rates similar to that with use of the CIDR. PMID- 25735831 TI - Feedback-amplified electrochemical dual-plate boron-doped diamond microtrench detector for flow injection analysis. AB - An electrochemical flow cell with a boron-doped diamond dual-plate microtrench electrode has been developed and demonstrated for hydroquinone flow injection electroanalysis in phosphate buffer pH 7. Using the electrochemical generator collector feedback detector improves the sensitivity by one order of magnitude (when compared to a single working electrode detector). The diffusion process is switched from an analyte consuming "external" process to an analyte regenerating "internal" process with benefits in selectivity and sensitivity. PMID- 25735832 TI - Pushing the boundaries of vinylogous reactivity: catalytic enantioselective mukaiyama aldol reactions of highly unsaturated 2-silyloxyindoles. AB - The first example of catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2-silyloxyindoles is reported. The reaction utilizes a chiral Lewis base-catalyzed Lewis acid-mediated technology to deliver homoallylic 3-polyenylidene 2-oxindoles with extraordinary levels of regio-, enantio-, and geometrical selectivity. This work highlights a subtle yet decisive influence of the indole N-substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the (13) C NMR chemical shifts of the C-omega remote site within homologous silyloxyindole donors enabled rationalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor. PMID- 25735833 TI - Leading change: curriculum reform in graduate education in the biomedical sciences. AB - The Division of Graduate Medical Sciences at the Boston University School of Medicine houses numerous dynamic graduate programs. Doctoral students began their studies with laboratory rotations and classroom training in a variety of fundamental disciplines. Importantly, with 15 unique pathways of admission to these doctoral programs, there were also 15 unique curricula. Departments and programs offered courses independently, and students participated in curricula that were overlapping combinations of these courses. This system created curricula that were not coordinated and that had redundant course content as well as content gaps. A partnership of key stakeholders began a curriculum reform process to completely restructure doctoral education at the Boston University School of Medicine. The key pedagogical goals, objectives, and elements designed into the new curriculum through this reform process created a curriculum designed to foster the interdisciplinary thinking that students are ultimately asked to utilize in their research endeavors. We implemented comprehensive student and peer evaluation of the new Foundations in Biomedical Sciences integrated curriculum to assess the new curriculum. Furthermore, we detail how this process served as a gateway toward creating a more fully integrated graduate experience, under the umbrella of the Program in Biomedical Sciences. PMID- 25735834 TI - Neuroimaging abnormalities in a patient with posterior reversible encephalopathy syndrome due to acute intermittent porphyria. PMID- 25735837 TI - Toward predicting drug-induced liver injury: parallel computational approaches to identify multidrug resistance protein 4 and bile salt export pump inhibitors. AB - Drug-induced liver injury (DILI) is an important cause of drug toxicity. Inhibition of multidrug resistance protein 4 (MRP4), in addition to bile salt export pump (BSEP), might be a risk factor for the development of cholestatic DILI. Recently, we demonstrated that inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. Here, we aimed to develop computational models to delineate molecular features underlying MRP4 and BSEP inhibition. Models were developed using 257 BSEP and 86 MRP4 inhibitors and noninhibitors in the training set. Models were externally validated and used to predict the affinity of compounds toward BSEP and MRP4 in the DrugBank database. Compounds with a score above the median fingerprint threshold were considered to have significant inhibitory effects on MRP4 and BSEP. Common feature pharmacophore models were developed for MRP4 and BSEP with LigandScout software using a training set of nine well characterized MRP4 inhibitors and nine potent BSEP inhibitors. Bayesian models for BSEP and MRP4 inhibition/noninhibition were developed with cross-validated receiver operator curve values greater than 0.8 for the test sets, indicating robust models with acceptable false positive and false negative prediction rates. Both MRP4 and BSEP inhibitor pharmacophore models were characterized by hydrophobic and hydrogen-bond acceptor features, albeit in distinct spatial arrangements. Similar molecular features between MRP4 and BSEP inhibitors may partially explain why various drugs have affinity for both transporters. The Bayesian (BSEP, MRP4) and pharmacophore (MRP4, BSEP) models demonstrated significant classification accuracy and predictability. PMID- 25735838 TI - Activation and deactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by cytochrome P450 enzymes and flavin-containing monooxygenases in common marmosets (Callithrix jacchus). AB - The potential proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like syndromes in common marmosets, other primates, and humans. MPTP is metabolically activated to 1-methyl-4-phenyl-2,3-dihydropyridinium and 1 methyl-4-phenylpyridinium ions (MPDP(+) and MPP(+), respectively) by desaturation reactions. MPTP is deactivated to 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) by N demethylation and is also deactivated to MPTP N-oxide. The roles of cytochrome P450 (P450) enzymes and flavin-containing monooxygenases (FMOs) in the oxidative metabolism of MPTP-treated marmosets are not yet fully clarified. This study aimed to elucidate P450- and FMO-dependent MPTP metabolism in marmoset liver and brain. Rates of MPTP N-oxygenation in liver microsomes were similar to those in brain microsomes from 11 individual marmosets (substrate concentration, 50 MUM) and were correlated with rates of benzydamine N-oxygenation (r = 0.75, P < 0.05); the reactions were inhibited by methimazole (10 MUM). MPTP N-oxygenation was efficiently mediated by recombinantly expressed marmoset FMO3. Rates of PTP formation by MPTP N-demethylation in marmoset liver microsomes were correlated with bufuralol 1'-hydroxylation rates (r = 0.77, P < 0.01) and were suppressed by quinidine (1 MUM), thereby indicating the importance of marmoset CYP2D6 in PTP formation. MPTP transformations to MPDP(+) and MPP(+) were efficiently catalyzed by recombinant marmoset CYP2D6 and human CYP1A2. These results indicated the contributions of multiple drug-metabolizing enzymes to MPTP oxidation, especially marmoset FMO3 in deactivation (N-oxygenation) and marmoset CYP2D6 for both MPTP deactivation and MPTP activation to MPDP(+) and MPP(+). These findings provide a foundation for understanding MPTP metabolism and for the successful production of preclinical marmoset models. PMID- 25735840 TI - Reactive and proactive aggression: Differential links with emotion regulation difficulties, maternal criticism in adolescence. AB - Proactive and reactive functions of aggression are thought to manifest through different familial and emotional processes, even though they often co-occur. We investigated direct and indirect pathways through which maternal criticism and emotion regulation (ER) difficulties relate to reactive and proactive aggression in adolescence. Further, we examined how maternal criticism and emotion dysregulation interrelate, both concurrently and over time. Participants were 482 Dutch adolescents (M = 15.03, SD = 0.45, 57% boys) who self-reported on their ER difficulties, perceived maternal criticism, and reactive/proactive aggression. Cross-lagged panel modeling across four annual measurements revealed direct bidirectional links over time between maternal criticism and emotion dysregulation. Positive links over time from maternal criticism to proactive (but not reactive) aggression were also present. Emotion dysregulation and proactive aggression were linked only indirectly via maternal criticism. Gender did not significantly moderate these links. By revealing differential developmental pathways involving adolescents' ER and maternal criticism, the present study offers support for the dual function model of aggression. Aggr. Behav. 41:214 226, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25735839 TI - Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta-analysis. AB - AIM: The aim was to investigate associations between drugs with anticholinergic effects (DACEs) and cognitive impairment, falls and all-cause mortality in older adults. METHODS: A literature search using CINAHL, Cochrane Library, Embase and PubMed databases was conducted for randomized controlled trials, prospective and retrospective cohort and case-control studies examining the use of DACEs in subjects >=65 years with outcomes on falls, cognitive impairment and all-cause mortality. Retrieved articles were published on or before June 2013. Anticholinergic exposure was investigated using drug class, DACE scoring systems (anticholinergic cognitive burden scale, ACB; anticholinergic drug scale, ADS; anticholinergic risk scale, ARS; anticholinergic component of the drug burden index, DBIAC ) or assessment of individual DACEs. Meta-analyses were performed to pool the results from individual studies. RESULTS: Eighteen studies fulfilled the inclusion criteria (total 124 286 participants). Exposure to DACEs as a class was associated with increased odds of cognitive impairment (OR 1.45, 95% CI 1.16, 1.73). Olanzapine and trazodone were associated with increased odds and risk of falls (OR 2.16, 95% CI 1.05, 4.44; RR 1.79, 95% CI 1.60, 1.97, respectively), but amitriptyline, paroxetine and risperidone were not (RR 1.73, 95% CI 0.81, 2.65; RR 1.80, 95% CI 0.81, 2.79; RR 1.39, 95% CI 0.59, 3.26, respectively). A unit increase in the ACB scale was associated with a doubling in odds of all-cause mortality (OR 2.06, 95% CI 1.82, 2.33) but there were no associations with the DBIAC (OR 0.88, 95% CI 0.55, 1.42) or the ARS (OR 3.56, 95% CI 0.29, 43.27). CONCLUSIONS: Certain individual DACEs or increased overall DACE exposure may increase the risks of cognitive impairment, falls and all-cause mortality in older adults. PMID- 25735841 TI - Placental lesions associated with oligohydramnios in fetal growth restricted (FGR) pregnancies. AB - INTRODUCTION: Aim of the study was to investigate the association between placental pathology and oligohydramnios in pregnancies complicated by fetal growth restriction (FGR). METHODS: Placentas from 221 consecutive FGR pregnancies and 63 healthy controls were studied. Pathological lesions were described according to consensus nomenclature and standardized criteria; both elementary lesions and constellations of lesions (patterns) were considered. Statistics included analysis of linear trends and multinomial logistic regression. RESULTS: Amniotic fluid index (AFI) was normal in 56 (25.3%) FGR pregnancies, whereas mild, moderate and severe oligohydramnios were diagnosed in 32 (14.5%), 44 (19.9%) and 89 (40.3%) subjects, respectively. In FGR pregnancies, after adjustment for potential confounders, membrane meconium staining (chi-square = 28.6, p < 0.001), chronic villous hypoxia pattern (chi-square = 18.8, p < 0.001) and fetal thrombotic vasculopathy pattern (chi-square = 9.2, p = 0.002) were positively and linearly correlated to AFI decrease. Odds ratios of meconium and chronic villous hypoxia were 9.2 (95% CI = 2.6-32.9) and 4.2 (95% CI = 1.3-13.6) in FGR pregnancies with normal AFI and 25.2 (95% CI = 6.9-91.8) and 9.7 (95% CI = 3-31.5) in those with severe oligohydramnios (p = 0.005 and p = 0.023 compared to normal AFI, respectively). DISCUSSION: In FGR pregnancies, reduction of amniotic fluid volume is directly correlated to histological features of placental under perfusion, meconium staining of membranes and fetal vascular damage. These findings support the clinical notion that in FGR pregnancies oligohydramnios is a risk factor of fetal hypoxia and possibly of increased adverse neonatal outcomes. PMID- 25735842 TI - The APGAR rubric for scoring online discussion boards. AB - The World Health Organization has called for a dramatic increase in the number of midwives and supports the use of innovative programs to assist students in achieving midwifery competencies. Online discussion boards are excellent educational tools for stimulating in-depth student engagement. However, complex discussions can be difficult to grade without a well-constructed rubric. The 'discussion-board APGAR' provides clear scoring criteria for discussions of midwifery care. The discussion-board APGAR has 5 components: Application, Professionalism, Group work, Analysis, and Rationale and provides scoring criteria for unacceptable, marginal, and proficient performance. The discussion board APGAR is based on the Core Competencies for Basic Midwifery Practice in the United States (US), consistent with the International Confederation of Midwives Essential Competencies for Basic Midwifery Practice, and can be adjusted to be congruent with other midwifery standards. PMID- 25735843 TI - Adipostatins A-D from Streptomyces sp. 4875 inhibiting Brugia malayi asparaginyl tRNA synthetase and killing adult Brugia malayi parasites. PMID- 25735845 TI - Dental implants in irradiated patients: which factors influence implant survival? PMID- 25735846 TI - Effects of non-enzymatic glycation in human serum albumin. Spectroscopic analysis. AB - Human serum albumin (HSA), transporting protein, is exposed during its life to numerous factors that cause its functions become impaired. One of the basic factors --glycation of HSA--occurs in diabetes and may affect HSA-drug binding. Accumulation of advanced glycation end-products (AGEs) leads to diseases e.g. diabetic and non-diabetic cardiovascular diseases, Alzheimer disease, renal disfunction and in normal aging. The aim of the present work was to estimate how non-enzymatic glycation of human serum albumin altered its tertiary structure using fluorescence technique. We compared glycated human serum albumin by glucose (gHSA(GLC)) with HSA glycated by fructose (gHSA(FRC)). We focused on presenting the differences between gHSA(FRC) and nonglycated (HSA) albumin used acrylamide (Ac), potassium iodide (KI) and 2-(p-toluidino)naphthalene-6-sulfonic acid (TNS). Changes of the microenvironment around the tryptophan residue (Trp-214) of non glycated and glycated proteins was investigated by the red-edge excitation shift method. Effect of glycation on ligand binding was examined by the binding of phenylbutazone (PHB) and ketoprofen (KP), which a primary high affinity binding site in serum albumin is subdomain IIA and IIIA, respectively. At an excitation and an emission wavelength of lambdaex 335nm and lambdaem 420nm, respectively the increase of fluorescence intensity and the blue-shift of maximum fluorescence was observed. It indicates that the glycation products decreases the polarity microenvironment around the fluorophores. Analysis of red-edge excitation shift method showed that the red-shift for gHSA(FRC) is higher than for HSA. Non enzymatic glycation also caused, that the Trp residue of gHSA(FRC) becomes less accessible for the negatively charged quencher (I(-)), KSV value is smaller for gHSA(FRC) than for HSA. TNS fluorescent measurement demonstrated the decrease of hydrophobicity in the glycated albumin. KSV constants for gHSA-PHB systems are higher than for the unmodified serum albumin, while KSV values for gHSA-KP systems are only slightly lower than that obtained for HSA-KP. The affinity of PHB to the glycated HSA is stronger than to the non-glycated in the first class binding sites within subdomain IIA, in the vicinity of Trp-214. Ketoprofen bound to unmodified human serum albumin stronger than for glycated albumin and one class of binding sites is observed (Scatchard linear plots). PMID- 25735844 TI - Linezolid, vancomycin and daptomycin modulate cytokine production, Toll-like receptors and phagocytosis in a human in vitro model of sepsis. AB - Conventional antibiotics exhibit immunomodulatory properties beneficial in the treatment of sepsis. Antibiotic-resistant Gram-positive bacteria have become a problem in sepsis therapy, giving rise to increased use of last-resort antibiotics; for example, linezolid (LIN), vancomycin (VAN) and daptomycin (DAP). As the immunomodulatory properties of these antibiotics in treating sepsis are unknown, this study examined the effect of VAN, LIN and DAP on the immune response under sepsis-like conditions in vitro. Lipopolysaccharide (LPS) activated THP-1 monocytes were incubated with LIN, VAN or DAP. Gene expression of cytokines (TNFalpha, IL-1beta, IL-6, IL-10) and Toll-like receptors (TLR1, 2, 4, 6, 7 and 9) was monitored and phagocytosis was determined following coincubation with E. coli. The antibiotics differentially modulated the gene expression of the investigated cytokines. While LIN and VAN upregulated the expression of all TLRs, DAP downregulated mRNA levels of TLR1, TLR2 and TLR6, which recognize pathogen associated molecular patterns from Gram-positive bacteria. In addition, LIN inhibited, whereas VAN promoted the phagocytic activity of monocytes. Our results suggest that LIN and VAN possess pro-inflammatory properties, whereas DAP might reduce the immune response to Gram-positive bacteria in sepsis. Furthermore, VAN might be beneficial in the prevention of Gram-negative infections by increasing the phagocytosis of E. coli. PMID- 25735847 TI - Antimicrobial susceptibility assays based on the quantification of bacterial lipopolysaccharides via a label free lectin biosensor. AB - A label free lectin biosensor developed in our laboratory that can quantitatively measure the binding between the lectin immobilized at the carbohydrate sensor surface and the lipopolysaccharide (LPS) on Gram-negative bacteria was demonstrated for an antibiotic susceptibility assay. The biosensor utilizes a polythiophene interface containing fused quinone moieties glycosylated to form a carbohydrate platform for the immobilization of Concanavalin A (Con A) and is capable of LPS binding measurements via orthogonal quartz crystal microbalance and electrochemical readouts (EQCM). Such orthogonal transduction provides cross validation, better sensor sensitivity, and a large dynamic range of the measurements. We have applied this label free lectin biosensor for a new antibiotic susceptibility assay by characterizing the antimicrobial activities of various antibiotics (i.e., ciprofloxacin, ceftriaxone, and tetracycline) against Escherichia coli W1485 as a model system. The label free biosensor allows both end point and real time measurements of antibiotic effects on the bacterial cell surface LPS, which is shown to correlate to their antibiotic effects. At the end point, after 18 h incubation of bacterial cells with these three antibiotics respectively, the bacterial LPS binding signal was reduced to 23%, 27%, and 38%, respectively, for the three antibiotics, indicating that ciprofloxacin is the most effective against this E. coli strain. Real time measurements at the 1 h time point showed a similar trend with a reduction of binding to 91%, 93%, and 95%, respectively. From the binding kinetics of these measurements, the relaxation time (tau) was obtained, where higher tau value means slow binding interactions between the lectin and the bacterial LPS. The obtained order of tau, (i.e., tauciprofloxacin > tauceftriaxone > tautetracycline) again indicated that ciprofloxacin has more bactericidal activity than the other two antibiotics with the same concentrations. Thus, we are able to establish that the reduction in the binding of LPS with the lectin Con A sensor upon exposure to various antibiotics has a direct relation with the antibiotic dosages making this label free biosensor assay promising for therapeutic management of these drugs as well as for applications in antibiotic research and development. PMID- 25735848 TI - Inter-rater reliability and validity of two ataxia rating scales in children with brain tumours. AB - OBJECTIVES: This study aimed to investigate the inter-rater reliability and construct validity of the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) in children with posterior fossa tumours. These scales have been developed for adults with genetic ataxias, and the performance of these scales in children with brain tumours has not previously been described. METHODS: The participants, who had undergone surgical resection for a posterior fossa tumour (inclusion criteria age 4-18 years), were recruited from the neuro-oncology service at a tertiary children's hospital. Children were assessed using the SARA, BARS and Paediatric Evaluation of Disability Index (PEDI) mobility domain, a measure of function. Children were independently rated by two therapists to determine the inter-rater reliability of the SARA and BARS. The construct validity was determined by assessing the correlation between the two scales with the PEDI. RESULTS: Forty-four children were recruited. Inter rater reliability was good for both scales, demonstrating the strong correlations (SARA, r = 0.94; BARS, r = 0.91) and the good consistency (93 % of SARA and 90 % of BARS paired scores differing by less than 2 points) between two raters. Both ataxia scales demonstrated a strong negative correlation with the mobility domain of the PEDI (SARA, r = -0.77; BARS, r = -0.76), indicating that more severe ataxia was associated with worse mobility. The mean time for completion of the SARA was 4.5 and 2.7 min for the BARS. CONCLUSIONS: The SARA and BARS are reliable and valid measures and appear to be of equal value in determining the severity of ataxia in children with posterior fossa tumours. PMID- 25735849 TI - Change in optic nerve sheath diameter as a radiological marker of outcome from endoscopic third ventriculostomy in children. AB - PURPOSE: The purpose of this study was to investigate the value of the change in optic nerve sheath diameter (ONSD) as a radiological marker of endoscopic third ventriculostomy (ETV) outcome in children. METHODS: Magnetic resonance imaging (MRI) scans of patients on whom ETVs were performed between the periods of January 2009 and June 2013 were reviewed. ONSD measurements on pre- and post operative images were performed by two blinded observers, and the relationship between the change in these measurements and outcome from ETV were investigated. These findings were then also compared to conventional imaging features associated with ETV outcome. RESULTS: MRI scans of 24 patients were adequate to measure the ONSD pre- and post-operatively. In patients with successful ETV (n = 19), the mean change in ONSD was 0.73 mm and in patients with a failed ETV (n = 5), the mean change in ONSD was 0.18 mm (p = 0.0007). A change in ONSD of 7.5 % of the initial measurement demonstrated a sensitivity of 92.9 % and a sensitivity of 85.7 % for ETV outcome (area under the receiver operating characteristic curve (AUROC) = 0.96). CONCLUSION: Change in ONSD is a useful radiological marker of ETV outcome and may be used in combination with conventional radiological parameters to aid decision-making in this difficult group of patients. PMID- 25735850 TI - Age-related structural and functional changes of low back muscles. AB - During aging declining maximum force capacity with more or less unchanged fatigability is observed with the underlying mechanisms still not fully understood. Therefore, we compared morphology and function of skeletal muscles between different age groups. Changes in high-energy phosphate turnover (PCr, Pi and pH) and muscle functional MRI (mfMRI) parameters, including proton transverse relaxation time (T2), diffusion (D) and vascular volume fraction (f), were investigated in moderately exercised low back muscles of young and late-middle aged healthy subjects with (31)P-MR spectroscopy, T2- and diffusion-weighted MRI at 3T. In addition, T1-weighted MRI data were acquired to determine muscle cross sectional areas (CSA) and to assess fat infiltration into muscle tissue. Except for pH, both age groups showed similar load-induced MR changes and rates of perceived exertion (RPE), which indicates comparable behavior of muscle activation at moderate loads. Changes of mfMRI parameters were significantly associated with RPE in both cohorts. Age-related differences were observed, with lower pH and higher Pi/ATP ratios as well as lower D and f values in the late middle-aged subjects. These findings are ascribed to age-related changes of fiber type composition, fiber size and vascularity. Interestingly, post exercise f was negatively associated with fat infiltration with the latter being significantly higher in late-middle-aged subjects. CSA of low back muscles remained unchanged, while CSA of inner back muscle as well as mean T2 at rest were associated with maximum force capacity. Overall, applying the proposed MR approach provides evidence of age-related changes in several muscle tissue characteristics and gives new insights into the physiological processes that take place during aging. PMID- 25735851 TI - Thrombectomy for acute ischemic stroke: an evidence-based treatment. PMID- 25735852 TI - Unfavorable neurological outcome in diabetic patients with acute ischemic stroke is associated with incomplete recanalization after intravenous thrombolysis. AB - OBJECTIVE: To assess the impact of diabetes on neurological outcome and recanalization in acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). METHODS: Clinical data of 419 consecutive patients with AIS who received IVT between June 2009 and April 2014. Based on the medical history and new diagnosis, the patients were divided into groups with and without diabetes. Neurological outcomes at 24 h, 7 days and 3 months after IVT were evaluated. Favorable outcome was defined as National Institutes of Health Stroke Scale (NIHSS) score decrease >=4 points from baseline or 0 at 24 h, NIHSS decrease >=8 points or 0 at day 7, or modified Rankin scale <=1 at 3 months after IVT. Recanalization on non-invasive imaging was evaluated in patients with large vessel occlusion (LVO) according to thrombolysis in myocardial infarction grades. RESULTS: Among 419 patients, 98 (23.4%) had diabetes. Multivariable analyses showed that comorbidity of diabetes was an independent predictor of unfavorable outcome at 24 h (OR=0.534, 95% CI 0.316 to 0.903, p=0.019), at day 7 (OR=0.382, 95% CI 0.220 to 0.665, p=0.001), and at 3 months (OR=0.464, 95% CI 0.266 to 0.808, p=0.007). In patients with LVO, diabetes was an independent predictor of incomplete recanalization 24 h after IVT (OR=0.268, 95% CI 0.075 to 0.955, p=0.042). CONCLUSIONS: Diabetic patients with AIS had unfavorable neurological outcome, potentially linked to incomplete recanalization after IVT. PMID- 25735854 TI - Initiatives to identify and mitigate medication errors in England. AB - In response to the EU Directive on Pharmacovigilance, the National Health Service (NHS) in England and the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK have formed a partnership to work together to simplify and increase medication error reporting, improve data report quality, maximise learning and guide practice to minimise harm from medication errors by sharing incident data. This initiative will facilitate implementation of new requirements for medication error reporting and reduce the need for duplicate data entry by frontline staff. The initiative is also intended to provide new types of feedback from the National Reporting and Learning System run by the NHS England and from the Yellow Card Scheme run by the MHRA and to improve learning at the local level by clarifying medication safety roles and identifying key safety contacts to allow better communication between local and national levels. Finally, the partnership has established a new National Medication Safety Network to provide a forum for discussing potential and recognised safety issues, and for identifying trends and actions to improve the safe use of medicines. This article describes the initiative, the structure of which may act as a template for other countries. PMID- 25735853 TI - A liaison between mTOR signaling, ribosome biogenesis and cancer. AB - The ability to translate genetic information into functional proteins is considered a landmark in evolution. Ribosomes have evolved to take on this responsibility and, although there are some differences in their molecular make up, both prokaryotes and eukaryotes share a common structural architecture and similar underlying mechanisms of protein synthesis. Understanding ribosome function and biogenesis has been the focus of extensive research since the early days of their discovery. In the last decade however, new and unexpected roles have emerged that place deregulated ribosome biogenesis and protein synthesis at the crossroads of pathological settings, particularly cancer, revealing a set of novel cellular checkpoints. Moreover, it is also becoming evident that mTOR signaling, which regulates an array of anabolic processes, including ribosome biogenesis, is often exploited by cancer cells to sustain proliferation through the upregulation of global protein synthesis. The use of pharmacological agents that interfere with ribosome biogenesis and mTOR signaling has proven to be an effective strategy to control cancer development clinically. Here we discuss the most recent findings concerning the underlying mechanisms by which mTOR signaling controls ribosome production and the potential impact of ribosome biogenesis in tumor development. This article is part of a Special Issue entitled: Translation and Cancer. PMID- 25735855 TI - Expression and characterization of recombinant humanized anti-HER2 single-chain antibody in Pichia pastoris for targeted cancer therapy. AB - OBJECTIVES: The availability of self-targeting and low immunogenic therapeutic agents is critical to efficient cancer therapy. Therefore, the development of humanized therapeutic antibodies is particularly appealing. RESULTS: A humanized single-chain variable fragment (scFv) antibody that can target human epidermal growth factor receptor-2 (HER2)-overexpressing cancer cells was designed and produced via expression in Pichia pastoris. The expression gave a high yield of 8 mg protein/l (with a purity of 92 %) using shake-flask cultures. Functional studies also revealed that the purified recombinant anti-HER2 scFv exhibited anti proliferative activity and could bind efficiently to HER2-overexpressing human breast cancer cell line SKBR3. CONCLUSION: The recombinant scFv offers promising therapeutic and binding efficiencies that are desirable for targeted cancer therapies. PMID- 25735856 TI - Electrocardiographic Left Ventricular Hypertrophy as a Predictor for Nonsignificant Coronary Artery Disease in Patients With Non-ST-Segment Elevation Myocardial Infarction. AB - Left ventricular hypertrophy (LVH) can lead to subendocardial ischemia by altering the coronary blood flow and its transmural myocardial distribution in the setting of increased oxygen demand. We hypothesized that electrocardiographic LVH predicts nonsignificant coronary artery disease (CAD) in patients with non-ST segment elevation myocardial infarction (NSTEMI). We performed a retrospective analysis of 406 consecutive patients with NSTEMI who underwent coronary angiography. The LVH was diagnosed using Sokolow-Lyon and Cornell voltage criteria. Nonsignificant CAD was defined as stenosis less than 50% in the left main and 70% in any other coronary arteries. Of the 406 patients, 100 (25%) patients had electrocardiographic LVH and 99 (24%) patients had nonsignificant CAD. Patients with electrocardiographic LVH had a higher prevalence of nonsignificant CAD (32% vs 22%, P = .04) and a lower rate of in-hospital revascularization (45% vs 69%, P < .001) than those without LVH. On multivariate analysis, electrocardiographic LVH was an independent predictor of nonsignificant CAD (odds ratio 1.94; 95% confidence interval 1.12-3.35; P = .02). In conclusion, electrocardiographic LVH is an independent predictor of nonsignificant CAD and associated with a lower rate of in-hospital revascularization in patients with NSTEMI. PMID- 25735857 TI - Novel jejunoduodenostomy technique for prevention of duodenal stump blowout following gastrectomy. AB - INTRODUCTION: Many patients undergo gastrectomy every year with a risk of duodenal stump blowout. We compared the conventional surgical techniques with a new and simple method of reconstruction to prevent this complication. METHODS: We reviewed the medical records of all the patients who underwent gastrectomy from 2002 to 2013 (total or partial distal gastrectomies with Billroth II, Roux-en-Y, and our new technique of reconstruction) in Shohada Tajrish University hospital, Tehran, Iran. RESULTS: A total of 179 patients were eligible for the study: 101 had undergone the new technique (study group) and 78 had undergone the conventional methods (control group). There were three cases of duodenal stump blowout, all in the control group (4 %, P<0.05). One was fatal (1 %). The post operative hospital stay was significantly shorter in the study group (8.93 vs. 11.51 days, P<0.05). DISCUSSION: Our results show that this new technique can effectively prevent duodenal stump blowout. Other advantages of this technique include the maintenance of physiological passage of food and a safe route for future diagnostic and therapeutic endoscopic interventions. CONCLUSIONS: We present a simple technique that eliminates the risk of duodenal stump blowout. Randomized controlled trials are necessary to confirm our findings. PMID- 25735858 TI - Biomarkers of tobacco smoke exposure. AB - Diseases and death caused by exposure to tobacco smoke have become the single most serious preventable public health concern. Thus, biomarkers that can monitor tobacco exposure and health effects can play a critical role in tobacco product regulation and public health policy. Biomarkers of exposure to tobacco toxicants are well established and have been used in population studies to establish public policy regarding exposure to second-hand smoke, an example being the nicotine metabolite cotinine, which can be measured in urine. Biomarkers of biological response to tobacco smoking range from those indicative of inflammation to mRNA and microRNA patterns related to tobacco use and/or disease state. Biomarkers identifying individuals with an increased risk for a pathological response to tobacco have also been described. The challenge for any novel technology or biomarker is its translation to clinical and/or regulatory application, a process that requires first technical validation of the assay and then careful consideration of the context the biomarker assay may be used in the regulatory setting. Nonetheless, the current efforts to investigate new biomarker of tobacco smoke exposure promise to offer powerful new tools in addressing the health hazards of tobacco product use. This review will examine such biomarkers, albeit with a focus on those related to cigarette smoking. PMID- 25735859 TI - Ethyl glucuronide and ethyl sulfate. AB - Alcohol misuse is associated with significant morbidity and mortality. Although clinical history, examination, and the use of self-report questionnaires may identify subjects with harmful patterns of alcohol use, denial or under-reporting of alcohol intake is common. Existing biomarkers for detecting alcohol misuse include measurement of blood or urine ethanol for acute alcohol consumption, and carbohydrate-deficient transferrin and gamma-glutamyl transferase for chronic alcohol misuse. There is a need for a biomarker that can detect excessive alcohol consumption in the timeframe between 1 day and several weeks. Ethyl glucuronide (EtG) is a direct metabolite of ethanol detectable in urine for up to 90 h and longer in hair. Because EtG has high specificity for excess alcohol intake, it has great potential for use in detecting "binge" drinking. Using urine or hair, this noninvasive marker has a role in a variety of clinical and forensic settings. PMID- 25735860 TI - Ammonia metabolism and hyperammonemic disorders. AB - Human adults produce around 1000 mmol of ammonia daily. Some is reutilized in biosynthesis. The remainder is waste and neurotoxic. Eventually most is excreted in urine as urea, together with ammonia used as a buffer. In extrahepatic tissues, ammonia is incorporated into nontoxic glutamine and released into blood. Large amounts are metabolized by the kidneys and small intestine. In the intestine, this yields ammonia, which is sequestered in portal blood and transported to the liver for ureagenesis, and citrulline, which is converted to arginine by the kidneys. The amazing developments in NMR imaging and spectroscopy and molecular biology have confirmed concepts derived from early studies in animals and cell cultures. The processes involved are exquisitely tuned. When they are faulty, ammonia accumulates. Severe acute hyperammonemia causes a rapidly progressive, often fatal, encephalopathy with brain edema. Chronic milder hyperammonemia causes a neuropsychiatric illness. Survivors of severe neonatal hyperammonemia have structural brain damage. Proposed explanations for brain edema are an increase in astrocyte osmolality, generally attributed to glutamine accumulation, and cytotoxic oxidative/nitrosative damage. However, ammonia neurotoxicity is multifactorial, with disturbances also in neurotransmitters, energy production, anaplerosis, cerebral blood flow, potassium, and sodium. Around 90% of hyperammonemic patients have liver disease. Inherited defects are rare. They are being recognized increasingly in adults. Deficiencies of urea cycle enzymes, citrin, and pyruvate carboxylase demonstrate the roles of isolated pathways in ammonia metabolism. Phenylbutyrate is used routinely to treat inherited urea cycle disorders, and its use for hepatic encephalopathy is under investigation. PMID- 25735861 TI - 5-methylcytosine and its derivatives. AB - Epigenetics has undergone an explosion in the past decade. DNA methylation, consisting of the addition of a methyl group at the fifth position of cytosine (5 methylcytosine, 5-mC) in a CpG dinucleotide, is a well-recognized epigenetic mark with important functions in cellular development and pathogenesis. Numerous studies have focused on the characterization of DNA methylation marks associated with disease development as they may serve as useful biomarkers for diagnosis, prognosis, and prediction of response to therapy. Recently, novel cytosine modifications with potential regulatory roles such as 5-hydroxymethylcytosine (5 hmC), 5-formylcytosine (5-foC), and 5-carboxylcytosine (5-caC) have been discovered. Study of the functions of 5-mC and its oxidation derivatives promotes the understanding of the mechanism underlying association of epigenetic modifications with disease biology. In this respect, much has been accomplished in the development of methods for the discovery, detection, and location analysis of 5-mC and its oxidation derivatives. In this review, we focus on the recent advances for the global detection and location study of 5-mC and its oxidation derivatives 5-hmC, 5-foC, and 5-caC. PMID- 25735862 TI - Circulating microRNAs as Promising Tumor Biomarkers. AB - microRNAs (miRNAs) are small, nonprotein-coding RNAs that function as posttranscriptional regulators of target genes. miRNAs are involved in multiple cell differentiation, proliferation, and apoptosis processes that are closely related to tumorigenesis. Circulating miRNAs are promising cancer biomarkers under development with great translational potential in personalized medicine. Here, we describe the origin and function of circulating miRNAs and compare the current new high-throughput technology applied to miRNA quantitation. The latest publications on circulating miRNAs were summarized, indicating that miRNAs are potential biomarkers of diagnosis, prognosis, and treatment response of major cancer types including prostate, breast, lung, colorectal, and hematological cancers. We addressed the strengths and limitations of applying circulating miRNAs in clinical laboratory and several issues associated with the accurate measurement of circulating miRNAs. PMID- 25735863 TI - Proteomics in transplantation. AB - Proteomics and biochemical profiling have emerged as exciting and powerful tools in clinical biomarker research. In the field of transplantation, proteomics aims not only at developing noninvasive means for immune monitoring but also to gain mechanistic insights into the pathophysiology of the alloimmune response and hence defining new therapeutic targets. This chapter provides an overview of proteomic biomarker-driven approaches and its underlying concepts and discusses the advantages, clinical implications, challenges, and limitations of this novel modality as it relates to solid organ transplantation. PMID- 25735864 TI - Fibulins and their role in cardiovascular biology and disease. AB - Fibulins are a group of extracellular matrix proteins of which many are present in high amounts in the cardiovascular system. They share common biochemical properties and are often found in relation to basement membranes or elastic fibers. Observations in humans with specific mutations in fibulin genes, together with results from genetically engineered mice and data from human cardiovascular tissue suggest that the fibulin family of proteins play important functional roles in the cardiovascular system. Moreover, fibulin-1 circulates in high concentrations in plasma and may function as a cardiovascular disease marker. PMID- 25735865 TI - Preface. PMID- 25735867 TI - A new synthesis strategy for chiral CdS nanotubes based on a homochiral MOF template. AB - We describe for the first time a convenient technique to prepare helical CdS nanotubes, with a MOF as the template. The prepared helical CdS nanotubes were remarkably sensitive to D/L-aspartic acid (Asp) and can be used as a potential sensor for enantioselective recognition of D/L-Asp. PMID- 25735866 TI - Trajectories of Organized Activity Participation Among Urban Adolescents: An Analysis of Predisposing Factors. AB - Organized activity participation provides important opportunities for adolescents to develop assets and resources related to positive youth development. Predisposing factors, in addition to sociodemographics and self-selection factors, may influence how youth participate over time. In this study, we used growth mixture modeling with longitudinal data from African American adolescents attending urban high schools in Flint, MI to identify subgroups of participation trajectories (Wave 1 N = 681, mean age at Wave 1 = 14.86 years, 51% female). We measured activity participation using psychological and behavioral engagement across multiple contexts over the 4 years of high school. We examined how predisposing risk and promotive factors were related to these trajectories, accounting for sociodemographic and self-selection factors. The results indicated three participation trajectories: a low group decreasing over time (74%), a moderate, consistent participation group (21%) and a moderate, increasing group (5%). More substance use was associated with lower odds of being in the moderate/consistent versus low/decreasing participation group. More parental support was associated with lower odds of being in the moderate/increasing versus the moderate/consistent group. Our results suggest that addressing predisposing factors such as substance use may help facilitate participation over time. PMID- 25735868 TI - Relationship between Epicardial Adipose Tissue Thickness and Atrial Electromechanical Delay in Hypertensive Patients. AB - OBJECTIVES: Epicardial adipose tissue (EAT) and atrial electromechanical delay (AEMD) have been shown to be closely linked with atrial fibrillation. In this study, we aimed to investigate the relationship between EAT and AEMD. METHODS: Ninety-six patients were included in this study. Echocardiographic measurements were performed, and laboratory parameters were recorded. Patients were divided into two groups according to their inter-AEMD values. Patients with an inter-AEMD value of <42.6 msec formed group 1 and patients with an inter-AEMD value of >=42.6 msec formed group 2. RESULTS: The EAT thickness (3.7 +/- 1.2 vs. 5.0 +/- 1.6, P < 0.001) and LAVI (20.4 +/- 2.9 vs. 24.5 +/- 6.7, P = 0.001) were significantly higher in group 2. There was a significant positive correlation between AEMD parameters with EAT and LAVI. After multivariate logistic regression analysis, EAT (OR: 1.505; 95% CI: 1.056-2.143, P = 0.023) and LAVI (OR: 1.140; 95% CI: 1.018-1.277, P = 0.023) were found as independent predictors of prolonged AEMD. CONCLUSIONS: We found that EAT thickness was closely related with AEMD, and we also found that EAT and LAVI were independent predictors of prolonged AEMD. These findings may be helpful to explain some pathogenic mechanisms in the development of AF. PMID- 25735869 TI - The HIV care cascade: models, measures and moving forward. AB - INTRODUCTION: This article seeks to identify where delays occur along the adult HIV care cascade ("the cascade"), to improve understanding of what constitutes "delay" at each stage of the cascade and how this can be measured across a range of settings and to inform service delivery efforts. Current metrics are reviewed, measures informed by global guidelines are suggested and areas for further clarification are underscored. DISCUSSION: Questions remain on how best to evaluate late entry into each stage of the cascade. The delayed uptake of HIV testing may be more consistently measured once rapid CD4 testing is administered at the time of HIV testing. For late enrollment, preliminary research has begun to determine how different time intervals for linking to HIV care affect individual health. Regarding treatment, since 2013, the World Health Organization (WHO) and UNAIDS recommend treatment initiation when CD4 <500 cells/mm(3); these guidelines provide a useful albeit evolving threshold to define late treatment initiation. Finally, WHO guidelines for high-, low- and middle-income countries also could be used to standardize measures for achieving viral suppression. CONCLUSIONS: There is no "one size fits all" model as the provision of services may differ based on a range of factors. Nonetheless, measures informed by global guidelines are needed to more consistently evaluate the scope of and factors associated with delays to each stage of the cascade. Doing so will help identify how practitioners can best deliver services and facilitate access to and continued engagement in care. PMID- 25735870 TI - Simultaneous quantification of digoxin, digitoxin, and their metabolites in serum using high performance liquid chromatography-tandem mass spectrometry. AB - The study describes an LC-MS/MS method for simultaneous quantification of the cardiac glycosidic drugs digoxin and digitoxin and several of their metabolites. The assay represents a useful reference method for immunoassay-based tests, which are easily biased by the presence of metabolites of the target analytes or structurally similar substances. PMID- 25735871 TI - Regulation pattern of fish irf4 (the gene encoding IFN regulatory factor 4) by STAT6, c-Rel and IRF4. AB - Interferon regulatory factor 4 (IRF4) plays pivotal roles in both innate and adaptive immune responses in mammals. In fish, there are two homologues of irf4, irf4a and irf4b. In this study, we examined the regulatory patterns of zebrafish irf4a and irf4b by STAT6 and c-Rel. Firstly, expression of irf4a and irf4b was monitored in several tissues at mRNA level. By infection with SVCV, irf4a and irf4b were upregulated in both kidney and spleen, and were immediately induced by treatment with poly I:C in ZF4 cells. Moreover, the activation of irf4a promoter was regulated by overexpression of stat6 and c-rel in a cooperation manner, which could be inhibited by mutation of the putative binding sites of STAT6 and c-Rel in irf4a promoter region. However, irf4b promoter was activated slightly only by STAT6 but not c-Rel. Furthermore, overexpression of irf4a inhibited the activation of its own promoter under induction of STAT6 and c-Rel, which was the result of that IRF4a bound to STAT6 and c-Rel directly. In addition, cellular location analysis showed that IRF4a was located only in nuclear region. These data indicate that fish irf4a can also be upregulated by STAT6 and c-Rel. PMID- 25735872 TI - Molecular characterization of LvAV in response to white spot syndrome virus infection in the Pacific white shrimp (Litopenaeus vannamei). AB - Litopenaeus vannamei is the most important farmed shrimp species globally, but its production is affected by several factors, including infectious disease. White spot syndrome virus (WSSV), in particular, causes significant shrimp losses. To understand the shrimp's immune response against WSSV, we cloned LvAV from L. vannamei and analyzed its expression pattern in different tissues, in addition to its expression following infection. We employed dsRNA and recombinant (r)LvAV to explore the potential role of LvAV in shrimp immunity when infected with WSSV. We find that LvAV is a C-type Lectin composed of 176 amino acids with a signal peptide and a specific C-type Lectin-type domain (CTLD). It shares 81% amino acid similarity with PmAV, an antiviral-like C-type Lectin from Penaeus monodom, and it is highly expressed in the hepatopancreas. Its expression is affected by infection with both WSSV and V. parahaemolyticus. Significantly, injection with rLvAV slowed WSSV replication, while injection with LvAV dsRNA initially led to enhanced virus propagation. Surprisingly, LvAV dsRNA subsequently led to a dramatic decrease in viral load in the later stages of infection, suggesting that LvAV may be subverted by WSSV to enhance viral replication or immune avoidance. Our results indicate that LvAV plays an important, but potentially complex role in the Pacific white shrimp's immune defense. PMID- 25735873 TI - Mammary Branching Morphogenesis Requires Reciprocal Signaling by Heparanase and MMP-14. AB - The development of the mammary gland involves formation of a branched arboreal structure resulting from the penetration and proliferation of epithelial cells into the fat pad. The mammary cells invade by remodeling their surrounding extracellular matrix (ECM), which are rich in proteins, and glycans such as heparan sulfate proteoglycans (HSPGs). There is increasing literature on how the interaction between signaling by ECM and matrix metalloproteinases (MMPs) is relevant to morphogenetic and physiological contexts. Here we sought to understand how heparanase, the sole mammalian heparan sulfate-degrading endoglycosidase may regulate mammary gland development. We found a robust localization of heparanase within growing end buds during branching in vivo. Using three-dimensional (3D) organotypic cultures, we showed that heparanase expression and activity are required for mammary epithelial invasion/branching within dense collagen I gels. Morphometric analysis of glands from both heparanase-overexpressing and knockout mice showed a direct correlation between degree of branching and the heparanase levels, confirming our 3D organotypic culture observations. Finally, we uncovered a reciprocal association between levels of heparanase and MMP14, a membrane-bound MMP, shedding further light on how branching occurs within developing mammary glands. PMID- 25735874 TI - One-step direct-laser metal writing of sub-100 nm 3D silver nanostructures in a gelatin matrix. AB - Developing an ability to fabricate high-resolution, 3D metal nanostructures in a stretchable 3D matrix is a critical step to realizing novel optoelectronic devices such as tunable bulk metal-dielectric optical devices and THz metamaterial devices that are not feasible with alternative techniques. We report a new chemistry method to fabricate high-resolution, 3D silver nanostructures using a femtosecond-laser direct metal writing technique. Previously, only fabrication of 3D polymeric structures or single-/few-layer metal structures was possible. Our method takes advantage of unique gelatin properties to overcome such previous limitations as limited freedom in 3D material design and short sample lifetime. We fabricate more than 15 layers of 3D silver nanostructures with a resolution of less than 100 nm in a stable dielectric matrix that is flexible and has high large transparency that is well-matched for potential applications in the optical and THz metamaterial regimes. This is a single-step process that does not require any further processing. This work will be of interest to those interested in fabrication methods that utilize nonlinear light matter interactions and the realization of future metamaterials. PMID- 25735875 TI - Ontogenetic changes in embryonic and brain gene expression in progeny produced from migratory and resident Oncorhynchus mykiss. AB - Little information has been gathered regarding the ontogenetic changes that contribute to differentiation between resident and migrant individuals, particularly before the onset of gross morphological and physiological changes in migratory individuals. The aim of this study was to evaluate gene expression during early development in Oncorhynchus mykiss populations with different life histories, in a tissue known to integrate environmental cues to regulate complex developmental processes and behaviours. We sampled offspring produced from migrant and resident parents, collecting whole embryos prior to the beginning of first feeding, and brain tissue at three additional time points over the first year of development. RNA sequencing for 32 individuals generated a reference transcriptome of 30 177 genes that passed count thresholds. Differential gene expression between migrant and resident offspring was observed for 1982 genes. The greatest number of differentially expressed genes occurred at 8 months of age, in the spring a full year before the obvious physiological transformation from stream-dwelling parr to sea water-adaptable smolts begins for migrant individuals. Sex and age exhibited considerable effects on differential gene expression between migrants and resident offspring. Differential gene expression was observed in genes previously associated with migration, but also in genes previously unassociated with early life history divergence. Pathway analysis revealed coordinated differential expression in genes related to phototransduction, which could modulate photoperiod responsiveness and variation in circadian rhythms. The role for early differentiation in light sensitivity and biological rhythms is particularly intriguing in understanding early brain processes involved in differentiation of migratory and resident life history types. PMID- 25735876 TI - [SEIP-AEPAP-SEPEAP consensus document on the aetiology, diagnosis and treatment of bacterial skin infections in out-patients]. AB - Skin infections are a common cause for dermatological consultations in the paediatric setting. A review is presented of the clinical manifestations, diagnosis and treatment of the main bacterial skin infections, as well as the diagnosis and treatment of super-infected puncture and bite wounds. The most prevalent bacteria in skin infections are Staphylococcus aureus and Streptococcus pyogenes. Treatment is usually empirical, since microbiological studies are only recommended under certain circumstances or lack of improvement with common therapies. Superficial skin infections can be treated with local antiseptics or antibiotics (mupirocin or fusidic acid). Systemic treatment is usually reserved for patients with extensive or severe disease or with other risk factors. Systemic treatment depends on the suspected infecting bacteria, with penicillin, amoxicillin, amoxicillin-clavulanic acid and first or second generation cephalosporin being the most frequently used drugs. Due to the low incidence of community-acquired methicillin-resistant infection by S. aureus in Spain, the use of clindamycin or co-trimoxazole is only recommended after severe disease, relapses or a clear epidemiological background. PMID- 25735877 TI - 'Do you remember the first time?' Host plant preference in a moth is modulated by experiences during larval feeding and adult mating. AB - In insects, like in other animals, experience-based modulation of preference, a form of phenotypic plasticity, is common in heterogeneous environments. However, the role of multiple fitness-relevant experiences on insect preference remains largely unexplored. For the multivoltine polyphagous moth Spodoptera littoralis we investigated effects of larval and adult experiences on subsequent reproductive behaviours. We demonstrate, for the first time in male and female insects, that mating experience on a plant modulates plant preference in subsequent reproductive behaviours, whereas exposure to the plant alone or plant together with sex pheromone does not affect this preference. When including larval feeding experiences, we found that both larval rearing and adult mating experiences modulate host plant preference. These findings represent the first evidence that host plant preferences in polyphagous insects are determined by a combination of innate preferences modulated by sensory feedback triggered by multiple rewarding experiences throughout their lifetime. PMID- 25735880 TI - Band-like electron transport with record-high mobility in the TCNQ family. AB - The occurrence of extremely pronounced band-like transport with very high electron mobility in fluorinated tetracyanoquinodimethane (F2 -TCNQ) single crystal field-effect transistors is discovered. This finding identifies the Fx TCNQ family as a paradigm to investigate the fundamental aspects of electronic transport in organic crystals. PMID- 25735879 TI - Systematic determination of thyroid volume by ultrasound examination from infancy to adolescence in Japan: the Fukushima Health Management Survey. AB - Although several reports have defined normal thyroid volume depending on either age or body surface, there are no sequential reference values on childhood thyroid volume evaluated by using ultrasonography and epidemiological analysis in Japan. The aim of the present study was to establish updated reference values for thyroid volume by ultrasound examination and epidemiological analysis in 0-19 year-old Japanese children. It is based on a cross-sectional study conducted from October 9, 2011 to March 31, 2012. The subjects were 38,063 children who were examined by ultrasonography as the initial preliminary survey of the Fukushima Health Management Survey in October 9, 2011 to March 31, 2012. The width, thickness, and height of each lobe were measured and the volume of each lobe was calculated by the mean of the elliptical shape volume formula. The values of thyroid volume at the 2.5 and 97.5 percentiles of age and body surface area for each gender group were obtained from 0-19 year-old children. Positive correlation was observed between thyroid volume and either age or body surface. The right lobe was significantly larger than the left lobe. The thyroid volume in females was larger than that in males after adjusting body surface area. The reference values of childhood thyroid for each age or body surface area were obtained by this extensive survey using ultrasound. These reference values may be used to define the normal size of thyroid gland by echosonography in Japanese children, although thyroid volume may be affected by dimorphic factors such as sex hormones. PMID- 25735881 TI - The lower vitamin C plasma concentrations in elderly men compared with elderly women can partly be attributed to a volumetric dilution effect due to differences in fat-free mass. AB - Women show higher vitamin C plasma concentrations than men, but the reasons for this observation still require elucidation. The objective of the present study was to investigate whether sex differences in vitamin C plasma concentrations are present in elderly subjects and whether these differences are due to sex-specific lifestyles, total antioxidant status (TAOS) and/or body composition. Fasting plasma concentrations of vitamin C were assessed by photometric detection in a cross-sectional study of 181 women and eighty-nine men aged 62-92 years. Body composition was determined by bioelectrical impedance analysis. Vitamin C intake was assessed with a 3 d estimated dietary record. Stepwise multiple regression analyses were performed to investigate whether sex is an independent predictor of vitamin C plasma concentrations by controlling for age, vitamin C intake, lifestyle factors, TAOS and body composition. Women showed higher vitamin C plasma concentrations than men (76 v. 62 MUmol/l, P< 0.0001). In the multiple regression analysis, male sex was a negative predictor of vitamin C plasma concentrations (beta = -0.214), as long as absolute fat-free mass (FFM) was not considered as a confounder. When absolute FFM was included, sex was no longer a predictor of vitamin C plasma concentrations, whereas absolute FFM (beta = 0.216), physical activity level (beta = 0.165), intake of vitamin C supplements (beta = 0.164), age (beta = 0.147) and smoking (beta = -0.125) affected vitamin C plasma concentrations. The results indicate that a higher absolute FFM, and thus a higher distribution volume of vitamin C, contributes to lower vitamin C plasma concentrations in men than women. PMID- 25735882 TI - Disseminated Mycobacterium gordonae and Mycobacterium mantenii infection with elevated anti-IFN-gamma neutralizing autoantibodies. AB - A case of disseminated nontuberculous mycobacteria(l) (NTM) infection in a patient with positive neutralizing anti-interferon-gamma (IFN-gamma) autoantibodies involving bone, bronchus, systemic lymph nodes, and skin is reported. The causative NTMs were two different strains: Mycobacterium gordonae, which rarely causes true disease, and Mycobacterium mantenii, which is extremely rare. Anti-mycobacterial treatment successfully ameliorated all disseminated lesions. Although the concentration of anti-IFN-gamma autoantibodies increased during the pre-treatment period, it gradually decreased after anti-mycobacterial treatment was started. PMID- 25735883 TI - Nonparametric estimation of transition probabilities in the non-Markov illness death model: A comparative study. AB - Multi-state models are often used for modeling complex event history data. In these models the estimation of the transition probabilities is of particular interest, since they allow for long-term predictions of the process. These quantities have been traditionally estimated by the Aalen-Johansen estimator, which is consistent if the process is Markov. Several non-Markov estimators have been proposed in the recent literature, and their superiority with respect to the Aalen-Johansen estimator has been proved in situations in which the Markov condition is strongly violated. However, the existing estimators have the drawback of requiring that the support of the censoring distribution contains the support of the lifetime distribution, which is not often the case. In this article, we propose two new methods for estimating the transition probabilities in the progressive illness-death model. Some asymptotic results are derived. The proposed estimators are consistent regardless the Markov condition and the referred assumption about the censoring support. We explore the finite sample behavior of the estimators through simulations. The main conclusion of this piece of research is that the proposed estimators are much more efficient than the existing non-Markov estimators in most cases. An application to a clinical trial on colon cancer is included. Extensions to progressive processes beyond the three state illness-death model are discussed. PMID- 25735884 TI - Assessing the detectability of antioxidants in two-dimensional high-performance liquid chromatography. AB - This paper explores the analytical figures of merit of two-dimensional high performance liquid chromatography for the separation of antioxidant standards. The cumulative two-dimensional high-performance liquid chromatography peak area was calculated for 11 antioxidants by two different methods--the areas reported by the control software and by fitting the data with a Gaussian model; these methods were evaluated for precision and sensitivity. Both methods demonstrated excellent precision in regards to retention time in the second dimension (%RSD below 1.16%) and cumulative second dimension peak area (%RSD below 3.73% from the instrument software and 5.87% for the Gaussian method). Combining areas reported by the high-performance liquid chromatographic control software displayed superior limits of detection, in the order of 1 * 10(-6) M, almost an order of magnitude lower than the Gaussian method for some analytes. The introduction of the countergradient eliminated the strong solvent mismatch between dimensions, leading to a much improved peak shape and better detection limits for quantification. PMID- 25735885 TI - A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is a debilitating condition associated with mild to moderate cognitive impairment and with a prevalence rate of up to 22% in veterans. This systematic review and quantitative meta-analysis explore volumetric differences of three key structural brain regions (hippocampus, amygdala and anterior cingulate cortex (ACC)), all of which have been implicated in dysfunction of both salience network (SN) and default mode network (DMN) in PTSD sufferers. A literature search was conducted in Embase, Medline, PubMed and PsycINFO in May 2013. Fifty-nine volumetric analyses from 44 articles were examined and included (36 hippocampus, 14 amygdala and nine ACC) with n=846 PTSD participants, n=520 healthy controls (HCs) and n=624 traumatised controls (TCs). Nine statistical tests were performed for each of the three regions of interest (ROIs), measuring volume differences in PTSD subjects, healthy and traumatised controls. Hippocampal volume was reduced in subjects with PTSD, with a greater reduction in the left hippocampus. A medium effect size reduction was found in bilateral amygdala volume when compared with findings in healthy controls; however, no significant differences in amygdala volume between PTSD subjects and trauma-exposed controls were found. Significant volume reductions were found bilaterally in the ACC. While often well matched with their respective control groups, the samples of PTSD subjects composed from the source studies used in the meta-analyses are limited in their homogeneity. The current findings of reduced hippocampal volume in subjects with PTSD are consistent with the existing literature. Amygdala volumes did not show significant reductions in PTSD subjects when compared with volumes in trauma-exposed controls-congruous with reported symptoms of hypervigilance and increased propensity in acquisition of conditioned fear memories-but a significant reduction was found in the combined left and right hemisphere volume analysis when compared with healthy controls. Bilateral volume reductions in the ACC may underpin the attentional deficits and inabilities to modulate emotions that are characteristically associated with PTSD patients. PMID- 25735886 TI - Selective EEG activation by the Stroop test in idiopathic generalized epilepsy. PMID- 25735887 TI - Transformation of atmospheric CO2 catalyzed by protic ionic liquids: efficient synthesis of 2-oxazolidinones. AB - Protic ionic liquids (PILs), such as 1,8-diazabicyclo[5.4.0]-7-undecenium 2 methylimidazolide [DBUH][MIm], can catalyze the reaction of atmospheric CO2 with a broad range of propargylic amines to form the corresponding 2-oxazolidinones. The products are formed in high yields under mild, metal-free conditions. The cheaper and greener PILs can be easily recycled and reused at least five times without a decrease in the catalytic activity and selectivity. A reaction mechanism was proposed on the basis of a detailed DFT study which indicates that both the cation and anion of the PIL play key synergistic roles in accelerating the reaction. PMID- 25735888 TI - Alterations in surgical technique after FDA statement on power morcellation. PMID- 25735889 TI - Effect of cottonseed oilcake as a protein source on production of breeding ostriches. AB - 1. South Africa currently produces 70% of the world's ostrich products. The profit margin of South African producers from the sale of ostrich meat, leather and feathers currently stands at 20%, 65% and 15%, respectively. 2. Local producers want to increase the production of ostrich products but keep production costs as low as possible. Maintaining optimal nutrition of breeding stock is necessary to increase the production of ostrich chicks, thereby decreasing the fixed costs per chick. 3. This research examined the impact on ostrich reproduction of replacing soya oilcake (SOC) as a protein supplement with cheaper cottonseed oilcake (CSOC). Although there are no data available on the impact of CSOC feed on ostrich reproduction, it is well known that gossypol, a naturally occurring toxin in cotton plants, negatively affects male reproduction in other monogastric species and that it may also reduce appetite. 4. Ninety-six breeding ostrich pairs were divided into two groups to compare the effects of diet (CSOC and SOC) during the breeding season on ostrich-breeding parameters. The replacement of SOC with CSOC had no significant effect on the number of total eggs produced (47.8 +/- 5.3 versus 48.3 +/- 5.1 per breeding pair, respectively) or infertile eggs (31.5 +/- 3.9 versus 38.0 +/- 5.2, respectively). Also, the number of dead-in-shell chicks did not differ significantly between groups (20.2 +/- 3.3 versus 26.8 +/- 3.8, respectively). 5. Even though none of these breeding parameters differed, the replacement of SOC with CSOC in the diets of breeding birds led to significantly more chicks hatching per hen from breeding birds fed on the SOC (36.1 +/- 4.8) than the CSOC diet (17.2 +/- 3.8). 6. Although it would thus seem that feeding breeding ostriches CSOC instead of SOC as a protein supplement will have a detrimental effect on chick production, more data are required to deliver a definitive answer. PMID- 25735890 TI - dUTPase expression correlates with cell division potential in Drosophila melanogaster. AB - dUTP pyrophosphatase (dUTPase) is a dNTP-sanitizing enzyme that prevents the appearance of potentially harmful uracil bases in DNA by hydrolyzing cellular dUTP. This function of dUTPase is found to be essential in many organisms including Drosophila melanogaster. Previously, we showed that the expression pattern of dUTPase determines the extent of uracil accumulation in the genome of different tissues. We wished to find the regulatory mechanism that eventually leaves a set of tissues with a uracil-free and intact genome. We found that the expression pattern established by the promoter of Drosophila dUTPase overlaps with mRNA and protein expression, excluding the involvement of other post transcriptional contributions. This promoter was found to be active in primordial tissues, such as in the imaginal discs of larvae, in the larval brain and in reproductive organs. In the case of brain and imaginal tissues, we observed that the promoter activity depends on a DNA replication-related element motif, the docking site of DNA replication-related element binding factor, which is known as a transcriptional activator of genes involved in replication and proliferation. These results suggest that dUTPase expression is fine-tuned to meet the requirements of DNA synthesis in tissues where the maintenance of genome integrity is of high importance. PMID- 25735891 TI - Peptide-induced HLA-E expression in human PBMCs is dependent on peptide sequence and the HLA-E genotype. AB - Human Leukocyte Antigen (HLA)-E is a low-polymorphic non-classical HLA class I molecule which plays a crucial role in immune surveillance by presentation of peptides to T and natural killer (NK) cells. HLA-E polymorphism is related to HLA E surface expression and is associated with patient outcome after stem cell transplantation. We aim to investigate the regulation of HLA-E expression level in peripheral blood mononuclear cells (PBMCs) of healthy individuals homozygous for HLA-E*01:01 or HLA-E*01:03, by using a panel of HLA-E binding peptides derived from CMV, Hsp60 and HLA class I. Basal and peptide-induced HLA-E surface expression levels were higher in PBMC from HLA-E*01:03 homozygous subjects as compared to PBMC from HLA-E*01:01 homozygous subjects. HLA-E mRNA levels were comparable between the two genotypes and remained constant after peptide stimulation. HLA-E surface expression seemed to be not only dependent on the HLA E genotype, but also on the sequence of the peptide as evidenced by the profound difference in HLA-E upregulation with the Hsp60 and the B7 peptide. Our results showed that peptide-induced HLA-E expression is regulated at the posttranscriptional level as extracellular peptide stimulation did not influence RNA expression. This study provides new insights in the mechanism by which HLA-E expression is regulated and underlines a new role for extracellular peptides in inducing HLA-E translation, which may represent a defense mechanism against lytic viral infections and necrosis. PMID- 25735892 TI - Synthesis and in vitro antiproliferative activity of amido and amino analogues of the marine alkaloid isogranulatimide. AB - Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study. PMID- 25735893 TI - Partial monosomy of 11q22.2q22.3 including the SDHD gene in individuals with developmental delay. AB - Deletions in the middle portion of 11q are not as well described in the literature as terminal 11q deletions that result in Jacobsen syndrome. One confounding factor in the older literature is that the G-banding pattern of 11q13q21 is very similar to 11q21q23. The advent of fluorescence in situ hybridization and later microarray technologies have allowed for a better resolution of many of these deletions, but genotype-phenotype correlations are still difficult since these deletions are rare events. We present five individuals who presented with developmental delays with de novo 11q22.2q23.3 deletions. Deletions were observed by standard G-banded chromosome analysis with clarification of breakpoints and gene content by SNP microarray analysis. Of note, all individuals had identical distal breakpoints. All deletions include SDHD, which is implicated in hereditary paraganglioma/pheochromocytoma, for which the patients will need to be monitored in adulthood. In spite of the large deletions of 8.6 Mb (Patients 1 and 3), 13.98 Mb (Patient 2), and 12.6 Mb (Patients 4 and 5) all patients show somewhat mild intellectual disability and dysmorphism. PMID- 25735894 TI - Genome-wide mapping reveals conservation of promoter DNA methylation following chicken domestication. AB - It is well-known that environment influences DNA methylation, however, the extent of heritable DNA methylation variation following animal domestication remains largely unknown. Using meDIP-chip we mapped the promoter methylomes for 23,316 genes in muscle tissues of ancestral and domestic chickens. We systematically examined the variation of promoter DNA methylation in terms of different breeds, differentially expressed genes, SNPs and genes undergo genetic selection sweeps. While considerable changes in DNA sequence and gene expression programs were prevalent, we found that the inter-strain DNA methylation patterns were highly conserved in promoter region between the wild and domestic chicken breeds. Our data suggests a global preservation of DNA methylation between the wild and domestic chicken breeds in either a genome-wide or locus-specific scale in chick muscle tissues. PMID- 25735895 TI - Rapid probing of sialylated glycoproteins in vitro and in vivo via metabolic oligosaccharide engineering of a minimal cyclopropene reporter. AB - ManNAc analogues are important chemical tools for probing sialylation dynamically via metabolic oligosaccharide engineering (MOE). The size of N-acyl and the nature of the chemical handle are two determinants of metabolic incorporation efficiency. We demonstrated a minimal, stable, bioorthogonal, and reactive N-Cp (N-(cycloprop-2-ene-1-ylcarbonyl)) group and the imaging of sialylated glycans using Ac4ManNCp in vitro and in vivo. The results revealed that the Cp group can efficiently be incorporated into the cellular sialic acid and detected rapidly by the reaction with FITC-Tz in different cells. The metabolic incorporation efficiency of non-cytotoxic Ac4ManNCp is not only superior to Ac4ManNMCp, but also superior to the widely-used Ac4ManNAz in some cell lines. Moreover, when Ac4ManNCp was administered to mice, a rapid and intense labelling of splenocytes as well as glycoproteins of sera and organs was observed. This is the first reported metabolic labelling of cyclopropene-modified sugars in vivo. Therefore, Ac4ManNCp is a powerful probe for efficient and rapid MOE and it may find wide applications in the labelling of glycans. PMID- 25735896 TI - A method of lyophilizing vaccines containing aluminum salts into a dry powder without causing particle aggregation or decreasing the immunogenicity following reconstitution. AB - Many currently licensed and commercially available human vaccines contain aluminum salts as vaccine adjuvants. A major limitation with these vaccines is that they must not be exposed to freezing temperatures during transport or storage such that the liquid vaccine freezes, because freezing causes irreversible coagulation that damages the vaccines (e.g., loss of efficacy). Therefore, vaccines that contain aluminum salts as adjuvants are formulated as liquid suspensions and are required to be kept in cold chain (2-8 degrees C) during transport and storage. Formulating vaccines adjuvanted with aluminum salts into dry powder that can be readily reconstituted before injection may address this limitation. Spray freeze-drying of vaccines with low concentrations of aluminum salts and high concentrations of trehalose alone, or a mixture of sugars and amino acids, as excipients can convert vaccines containing aluminum salts into dry powder, but fails to preserve the particle size and/or immunogenicity of the vaccines. In the present study, using ovalbumin as a model antigen adsorbed onto aluminum hydroxide or aluminum phosphate, a commercially available tetanus toxoid vaccine adjuvanted with potassium alum, a human hepatitis B vaccine adjuvanted with aluminum hydroxide, and a human papillomavirus vaccine adjuvanted with aluminum hydroxyphosphate sulfate, it was shown that vaccines containing a relatively high concentration of aluminum salts (i.e., up to ~1%, w/v, of aluminum hydroxide) can be converted into a dry powder by thin-film freezing followed by removal of the frozen solvent by lyophilization while using low levels of trehalose (i.e., as low as 2% w/v) as an excipient. Importantly, the thin-film freeze-drying process did not cause particle aggregation, nor decreased the immunogenicity of the vaccines. Moreover, repeated freezing-and-thawing of the dry vaccine powder did not cause aggregation. Thin-film freeze-drying is a viable platform technology to produce dry powders of vaccines that contain aluminum salts. PMID- 25735898 TI - Sinensetin enhances adipogenesis and lipolysis by increasing cyclic adenosine monophosphate levels in 3T3-L1 adipocytes. AB - Sinensetin is a rare polymethoxylated flavone (PMF) found in certain citrus fruits. In this study, we investigated the effects of sinensetin on lipid metabolism in 3T3-L1 cells. Sinensetin promoted adipogenesis in 3T3-L1 preadipocytes growing in incomplete differentiation medium, which did not contain 3-isobutyl-1-methylxanthine. Sinensetin up-regulated expression of the adipogenic transcription factors peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, and sterol regulatory element binding protein 1c. It also potentiated expression of C/EBPbeta and activation of cAMP-responsive element-binding protein. Sinensetin enhanced activation of protein kinase A and increased intracellular cAMP levels in 3T3-L1 preadipocytes. In mature 3T3-L1 adipocytes, sinensetin stimulated lipolysis via a cAMP pathway. Taken together, these results suggest that sinensetin enhances adipogenesis and lipolysis by increasing cAMP levels in adipocytes. PMID- 25735897 TI - Effects of barriers on chemical and biological properties of two dual resin cements. AB - The aim of this study was to investigate the degree of conversion, monomer release, and cytotoxicity of two dual-cure resin cements (Cement-One and SmartCem2), light-cured across two indirect restorative materials in an attempt to simulate in vitro the clinical conditions. The results obtained show that the degree of conversion was influenced by both barriers, but the effect of the composite material was greater than that of the ceramic one. The amount of monomers released from the polymerized materials in the absence of barriers was significantly lower than that released in the presence of either the ceramic or the composite barrier. However, a higher amount of monomers was released in the presence of the ceramic barrier. All materials, in all the experimental conditions employed, induced slight cytotoxicity (5-10%) on human pulp cells. Our examinations showed that the two resin cements had similar chemical and biological properties. The decreased degree of conversion of the dual-curing self adhesive composite showed that the light-curing component of these materials has an important role in the polymerization process. In clinical practice, it is therefore important to pay attention to the thickness of the material used for the reconstruction. PMID- 25735899 TI - Tilt after-effect from high spatial-frequency patterns in the amblyopic eye of adults with anisometropic amblyopia. AB - With abnormal visual cortical development, amblyopia is generally associated with high spatial frequency deficits in spatial vision. In this study, we aim to answer a critical question: How much high spatial frequency information is available to the amblyopic visual system? We measured the tilt after-effect following adaption to perceptually resolvable and unresolvable sinewave gratings, and showed that gratings with spatial frequency up to 1.5 times the cutoff frequency in grating orientation identification can still produce significant tilt after-effects in adults with amblyopia. Our results suggest that neural connections in the amblyopic visual cortex, at least in V1, may have profoundly developed to represent high spatial frequency information. The demonstration of extant neural connections for high spatial frequencies may have important implications for the development of training protocols for amblyopia treatment. Our paradigm may also serve as a non-invasive probe to diagnose the status of neural connections in other visual deficits. PMID- 25735900 TI - alpha-Glucosidase inhibitory activities of fatty acids purified from the internal organ of sea cucumber Stichopus japonicas. AB - alpha-Glucosidase inhibitory activities of the various solvent fractions (n hexane, CHCl3 , EtOAc, BuOH, and water) of sea cucumber internal organ were investigated. 1,3-Dipalmitolein (1) and cis-9-octadecenoic acid (2) with potent alpha-glucosidase inhibitory activity were purified from the n-hexane fraction of sea cucumber internal organ. IC50 values of compounds 1 and 2 were 4.45 and 14.87 MUM against Saccharomyces cerevisiae alpha-glucosidase. These compounds mildly inhibited rat-intestinal alpha-glucosidase. In addition, both compounds showed a mixed competitive inhibition against S. cerevisiae alpha-glucosidase and were very stable at pH 2 up to 60 min. The KI values of compounds 1 and 2 were 0.48 and 1.24 MUM, respectively. Therefore, the internal organ of sea cucumber might be a potential new source of alpha-glucosidase inhibitors suitably used for prevention of obesity and diabetes mellitus. PMID- 25735902 TI - Changes in intracuff pressure of a cuffed endotracheal tube during surgery for congenital heart disease using cardiopulmonary bypass. AB - BACKGROUND: With the development of newer polyurethane cuffed endotracheal tubes (cETTs), there has been a shift in clinical practice among pediatric anesthesiologists. Despite improvements in design, excessive inflation of the cuff can still compromise tracheal mucosal perfusion. Several perioperative factors can affect the intracuff pressure (CP), and there is no consensus on safe CP in pediatric patients undergoing repair of congenital cardiac disease (CHD) utilizing cardiopulmonary bypass (CPB). In the current study, the CP was continuously monitored in pediatric patients undergoing surgery for CHD. METHODS: After IRB approval, this observational study was conducted on pediatric patients who underwent repair of CHD using CPB with a cETT in place. After anesthetic induction and endotracheal intubation, the cuff was inflated using the air leak technique while maintaining a continuous positive airway pressure of 20 cmH2 O. After inflation, the CP was continuously monitored throughout the procedure. In addition, temperature and mean arterial pressure (MAP) were also recorded. RESULTS: The study included 33 patients who ranged in age from 1 month to 15.3 years. Their weight ranged from 4.0 to 83.6 kg. Six patients were excluded from the analysis due to the need to add or remove air from the cuff, leaving 27 patients for data analysis for cuff pressure over time. The baseline CP at the time of inflation was 16.1 +/- 7.6 cmH2 O. With the use of CPB and initiation of hypothermia, when compared to the baseline, the CP decreased by -0.7 +/- 5.8 cmH2 O at 35-37 degrees C, -9.1 +/- 8.4 cmH2 O at 31-33 degrees C, -7.8 +/- 6.2 cmH2 O at 27-29 degrees C, and -11.1 +/- 6.0 cmH2 O at <27 degrees C. With rewarming, the CP increased back to the baseline level (-3.5 +/- 7.0 cmH2 O). CONCLUSION: There was a significant decrease in the CP during CPB and associated hypothermia. This may offer some protection for mucosal perfusion during CPB which is usually associated with lower than normal MAP. However, the decrease in the CP may compromise the tracheal seal which may not offer the intended protection for the airway from aspiration. PMID- 25735901 TI - Reduction in driveline infection rates: Results from the HeartMate II Multicenter Driveline Silicone Skin Interface (SSI) Registry. AB - BACKGROUND: During left ventricular assist device implantation, a surgical tunneling technique to keep the entire driveline (DL) velour portion in the subcutaneous tunnel, resulting in a silicone-skin interface (SSI) at the exit site, has been adopted by many centers. To assess long-term freedom from DL infection associated with this technique, a multicenter SSI registry was initiated. It was hypothesized that the modified tunneling technique is associated with at least 50% reduction in DL infection at 1 year post-implant compared with the velour-to-skin method used in the HeartMate II (HMII) Destination Therapy (DT) trial. METHODS: SSI is a retrospective and prospective registry of patients who have received the HMII device. Results are reported from the retrospective cohort, which consists of 200 patients who were implanted during the period 2009-2012 with the SSI tunneling method and on HMII support for at least 10 months at the time of enrollment. The prevalence and incidence of DL infection after left ventricular assist device implantation in the SSI retrospective cohort were determined and compared with a control group of 201 patients also on HMII support for at least 10 months from the HMII DT clinical trial who were implanted during the period 2007-2009 using the traditional method in which a small section of the velour portion of the DL was externalized. RESULTS: The 1-year and 2-year prevalence rates of DL infection were 9% and 19% in the SSI patient group compared with 23% and 35% in the control group (hazard ratio 0.49, 95% confidence interval 0.33-0.73, p < 0.001). The event-per-patient year was 0.11 and 0.22 for the SSI and control groups, respectively (p < 0.001). Based on a multivariate analysis, age and DL exit side were the only independent variables associated with DL infection. Effects of management changes over the eras were not studied and could have contributed to the findings. CONCLUSIONS: These results suggest that leaving the entire DL velour portion below the skin is associated with 50% reduction in DL infection compared with results from the HMII DT trial. PMID- 25735903 TI - Microchip electrophoresis-single wall carbon nanotube press-transferred electrodes for fast and reliable electrochemical sensing of melatonin and its precursors. AB - In the current work, single-wall carbon nanotube press-transferred electrodes (SW PTEs) were used for detection of melatonin (MT) and its precursors tryptophan (Trp) and serotonin (5-HT) on microchip electrophoresis (ME). SW-PTEs were simply fabricated by press transferring a filtered dispersion of single-wall carbon nanotubes on a nonconductive PMMA substrate, where single-wall carbon nanotubes act as exclusive transducers. The coupling of ME-SW-PTEs allowed the fast detection of MT, Trp, and 5-HT in less than 150 s with excellent analytical features. It exhibited an impressive antifouling performance with RSD values of <=2 and <=4% for migration times and peak heights, respectively (n = 12). In addition, sample analysis was also investigated by analysis of 5-HT, MT, and Trp in commercial samples obtaining excellent quantitative and reproducible recoveries with values of 96.2 +/- 1.8%, 101.3 +/- 0.2%, and 95.6 +/- 1.2% for 5 HT, MT, and Trp, respectively. The current novel application reveals the analytical power of the press-transfer technology where the fast and reliable determination of MT and its precursors were performed directly on the nanoscale carbon nanotube detectors without the help of any other electrochemical transducer. PMID- 25735904 TI - A Preliminary Risk Stratification Model for Individuals with Neck Pain. AB - INTRODUCTION: The aim of the present study was to identify predictive characteristics related to patients with neck impairments who have a high risk of a poor prognosis (lowest functional recovery compared to visit utilization) as well as those who are at low risk of a poor prognosis (highest functional recovery compared to visit utilization). METHODS: A retrospective cohort of 3,137 patients with neck pain who were seen for physiotherapy care was included in the study. All patients were seen at physiotherapy clinics in the United States and were provided with care in a manner in which the physiotherapists felt was appropriate and necessary. Univariate and multivariate multinomial regression analyses were used to identify significant patient characteristics predictive of treatment response. RESULTS: Statistically significant predictors of high-risk categorization included longer duration of symptoms, surgical history and lower comparative levels of disability at baseline. Statistically significant predictors of low-risk categorization were younger age, shorter duration of symptoms, no surgical history, fewer comorbidities and higher comparative disability levels of function at baseline. DISCUSSION: Few studies have analysed risk stratification models for neck pain, and the findings of the present study suggest that predictors of poor success are similar to those in most musculoskeletal prognostic models. Limitations of the study included those inherent in secondary analysis and the inability to identify the diagnoses of the patients. CONCLUSIONS: Future research should continue to examine the variables predictive of treatment response in patients with neck pain. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25735905 TI - Dinuclear palladium complexes with two ligand-centered radicals and a single bridging ligand: subtle tuning of magnetic properties. AB - The facile and tunable preparation of unique dinuclear [(L(?))Pd-X-Pd(L(?))] complexes (X = Cl or N3), bearing a ligand radical on each Pd, is disclosed, as well as their magnetochemistry in solution and solid state is reported. Chloride abstraction from [PdCl(NNO(ISQ))] (NNO(ISQ) = iminosemiquinonato) with TlPF6 results in an unusual monochlorido-bridged dinuclear open-shell diradical species, [{Pd(NNO(ISQ))}2(MU-Cl)](+), with an unusually small Pd-Cl-Pd angle (ca. 93 degrees , determined by X-ray). This suggests an intramolecular d(8)-d(8) interaction, which is supported by DFT calculations. SQUID measurements indicate moderate antiferromagnetic spin exchange between the two ligand radicals and an overall singlet ground state in the solid state. VT EPR spectroscopy shows a transient signal corresponding to a triplet state between 20 and 60 K. Complex 2 reacts with PPh3 to generate [Pd(NNO(ISQ))(PPh3)](+) and one equivalent of [PdCl(NNO(ISQ))]. Reacting an 1:1 mixture of [PdCl(NNO(ISQ))] and [Pd(N3)(NNO(ISQ))] furnishes the 1,1-azido-bridged dinuclear diradical [{Pd(NNO(ISQ))}2(kappa(1)-N;MU-N3](+), with a Pd-N-Pd angle close to 127 degrees (X-ray). Magnetic and EPR measurements indicate two independent S = 1/2 spin carriers and no magnetic interaction in the solid state. The two diradical species both show no spin exchange in solution, likely because of unhindered rotation around the Pd-X-Pd core. This work demonstrates that a single bridging atom can induce subtle and tunable changes in structural and magnetic properties of novel dinuclear Pd complexes featuring two ligand-based radicals. PMID- 25735906 TI - New phenotype and neonatal onset of sodium channel myotonia in a child with a novel mutation of SCN4A gene. AB - Myotonia is rare in newborns, and not well-known. Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including sodium channel myotonias. We reported a 4-year-old female who presented with diffuse stiffness, bilateral clubfoot, hip dislocation, facial dysmorphisms and myotonia at birth. At 4 years of age the neurological examination showed characteristic "Hercules-like appearance" hyporeflexia, mild grip myotonia and bilateral pes cavus. The stiffness was worst at rest and in the early morning which improves with exercise. The clinical features, electromyography findings and diagnostic work-up of this patient and of child's mother were described. The clinical follow-up led us to the diagnosis of sodium channel myotonia with atypical neonatal onset. Mutation analysis in the patient and in child's mother revealed a novel heterozygous p.N1180I mutation in exon 19 of SCN4A gene. We recommend that in newborns with stiffness, peripheral contractures and myotonia, the sequence analysis of SCN4A gene should be performed. PMID- 25735907 TI - Predictive value of paroxysmal EEG abnormalities for future epilepsy in focal febrile seizures. AB - PURPOSE OF THE STUDY: To reassess the predictive role of clinical parameters and epileptiform paroxysmal EEG abnormalities for subsequent epilepsy in patients with febrile seizures. PATIENTS AND METHODS: 179 patients with febrile seizures were included in a prospective study investigating the impact of some clinical parameters and EEG abnormalities that could be important for future epilepsy. EEGs were performed in afebrile patients after hospital discharge. The follow-up period from the first presentation ranged from 2.1 to 9.2 years (mean, 6.6 years). The correlation between the development of epileptic seizures and the presence of epileptiform EEG abnormalities in the two groups was evaluated with the Mann-Whitney and chi-square test. Statistical significance was set at p<0.05. RESULTS: Febrile seizures occurred more than once in 58 (32.5%) patients, with one recurrence in 32 (17.9%) patients and multiple recurrences in 26 (14.5%) patients. The incidence of paroxysmal abnormalities was 16.8%. Of these, 15 patients (50%) showed generalized paroxysms only, while in 15 patients (50%), focal abnormalities were found. Epilepsy developed in 12 patients (6.7%). There were 27 patients with clinically focal features of the first febrile seizure, five (18.5%) of whom developed epilepsy. With focal EEG abnormalities included, the incidence of epilepsy increased to 50%. CONCLUSION: Generalized EEG discharges in patients with febrile seizures are not predictive of later epilepsy, but focal discharges are. PMID- 25735908 TI - Virtual patients: development in cancer nursing education. AB - BACKGROUND: The number of men diagnosed with prostate cancer is increasing and internationally there are high incidence rates. It is important that nurses and healthcare professionals are enabled to provide appropriate care to those men affected by prostate cancer and their families. Despite this need, there is recognition that many professionals feel ill prepared and lack knowledge in a number of areas. This paper presents the development of a Virtual Patient (VP) online resource to support practitioner learning. AIM: To develop five online VP simulation scenarios to meet the learning needs of nurses and health-care professionals caring for men with prostate cancer. METHOD: Topic areas for the VPs were taken from previous work exploring the needs of health care professionals working with men with prostate cancer. An initial scoping exercise involving nursing practitioners, students and a prostate cancer charity confirmed the focus of the case study scenarios. Service users and specialist practitioners reviewed an outline of each case study to ensure fidelity of the simulations scenarios. Cases were entered into UChoose, a web based interactive VP player and authoring tool. The final case studies were reviewed by a sample of both registered and non-registered nurses and nursing students. RESULTS: The majority of respondents reported an increase in knowledge and suggested that they would recommend the resource to others. A number of positive aspects of the resource were highlighted. Respondents also commented about areas of weakness, a number of which have been addressed subsequently. CONCLUSIONS: The VP case studies provided an opportunity to develop knowledge and confidence in caring for men with prostate cancer. The mode of delivery and the content was acceptable for less experienced and knowledgeable staff. PMID- 25735909 TI - Dementia education in Higher Education Institutions. AB - This article is a contemporary issues piece which discusses the challenges in providing dementia education in Higher Education Institutions. PMID- 25735910 TI - Enhancing self-directed learning among Italian nursing students: A pre- and post intervention study. AB - BACKGROUND: In accordance with Knowles's theory, self-directed learning (SDL) may be improved with tutorial strategies focused on guided reflection and critical analysis of the learning process. No evidence on effects on SDL abilities of different tutorial strategies offered to nursing students during the 1st clinical experience is available. OBJECTIVES: To evaluate the effect of different tutorial strategies offered to nursing students on their SDL abilities. DESIGN: A pre-post intervention non-equivalent control group design was adopted in 2013. For the treatment group, structured and intensive tutorial interventions including different strategies such as briefing, debriefing, peer support, Socratic questioning, performed by university tutors were offered during the 1st clinical experience; for the control group, unstructured and non-intensive tutorial strategies were instead offered. SETTING: Two Bachelor of Nursing Degree. PARTICIPANTS: Students awaiting their clinical experience (n=238) were the target sample. Those students who have completed the pre- and the post-intervention evaluation (201; 84.4%) were included in the analysis. METHODS: SDL abilities were measured with the SRSSDL_ITA (Self Rating Scale of Self Directed Learning Italian Version). A multiple linear regression analysis was developed to explore the predictive effect of individual, contextual and intervention variables. RESULTS: Three main factors explained the 36.8% of the adjusted variance in SDL scores have emerged: a) having received a lower clinical nurse-to-student supervision (B 9.086, beta 2.874), b) having received higher level and structured tutorial intervention by university tutors (B 8.011, beta 2.741), and c) having reported higher SDL scores at the baseline (B .550, beta .556). CONCLUSIONS: A lower clinical nurse-to-student ratio (1:4), accompanied by unstructured and non intensive tutorial intervention adopted by university tutors, seemed to be equivalent to an intensive clinical supervision (1:1) accompanied by higher level and structured tutorial strategies activated by the university tutors. PMID- 25735878 TI - A comprehensive review of glycosylated bacterial natural products. AB - A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of 15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts. PMID- 25735912 TI - Low-velocity super-lubrication of sodium-alginate/polyacrylamide ionic-covalent hybrid double-network hydrogels. AB - Structural and frictional behaviours of sodium alginate (SA)/polyacrylamide (PAAm) ionic-covalent hybrid, sequential double-network (DN) hydrogels against glass have been investigated in water, NaCl and CaCl2 aqueous solutions using a rotational rheometer. Dilution of adsorptive elastohydrodynamic friction for the PAAm covalent network with repulsive hydrodynamic lubrication for the minor SA ionic network was found to control the frictional stresses of the SA/PAAm gels within between those of the SA and PAAm single-network gels. A tentative qualitative model was proposed to describe the impact of ionic environmental solution on the frictional behaviour of the hybrid gel by selectively affecting the SA-network structure and friction. It was revealed that strong Debye shielding in the NaCl solution significantly reduced the thickness of the electric double layer for hydrodynamic lubrication of the SA network, which made the SA/PAAm gel's friction the highest among the three solutions. Dramatically increased ionic cross-linking of the SA network in the CaCl2 solution, although effectively mediated by the PAAm-network flexible skeleton, still functioned partially to conserve a portion of the SA fractional boundary-friction at the interface, making the friction of the hybrid gel intermediate among the three solutions. In contrast, extreme hydration of the SA network in water sharply increased the volume fraction of its unshielded hydrodynamic lubrication at the interface, which greatly reduced the SA/PAAm's friction to the lowest among the three solutions. We have thus incorporated for the first time both super lubrication (frictional coefficients of below 10(-2) over low sliding-velocities of 3 * 10(-5) to 2 * 10(-3) m s(-1)) and previously reported high fracture energy (over 9000 J m(-2)) into a single ionic-covalent hybrid DN hydrogel, which is the SA/PAAm (~1/8.5 w/w) gel in water. Effects of inversion of DN-formation sequence further indicated that frictional behaviours (i.e. frictional stress-sliding velocity profiles) of the hybrid sequential DN hydrogels (SA/PAAm and PAAm/SA), respectively, were primarily determined by those of the second networks (PAAm and SA), presumably due to the formation of first-second network "core-shell" structures at the blob scale. Frictional stress of the SA/PAAm gel was increased monotonically with external normal pressure at all of the sliding velocities investigated in the three solutions, which was in agreement with the predictions from the repulsion-adsorption model proposed by Gong et al. PMID- 25735911 TI - Diversity and selectivity in mRNA translation on the endoplasmic reticulum. AB - Pioneering electron microscopy studies defined two primary populations of ribosomes in eukaryotic cells: one freely dispersed through the cytoplasm and the other bound to the surface of the endoplasmic reticulum (ER). Subsequent investigations revealed a specialized function for each population, with secretory and integral membrane protein-encoding mRNAs translated on ER-bound ribosomes, and cytosolic protein synthesis was widely attributed to free ribosomes. Recent findings have challenged this view, and transcriptome-scale studies of mRNA distribution and translation have now demonstrated that ER-bound ribosomes also function in the translation of a large fraction of mRNAs that encode cytosolic proteins. These studies suggest a far more expansive role for the ER in transcriptome expression, where membrane and secretory protein synthesis represents one element of a multifaceted and dynamic contribution to post-transcriptional gene expression. PMID- 25735913 TI - Enhancing FTS (Salirasib) efficiency via combinatorial treatment. AB - The Ras oncogene transmits signals, which regulate various cellular processes including cell motility, differentiation, growth and death. Since Ras signalling is abnormally activated in more than 30% of human cancers, Ras and its downstream signalling pathways are considered good targets for therapeutic interference. Ras is post-translationally modified by the addition of a farnesyl group, which permits its attachment to the plasma membrane. Exploiting this knowledge, a synthetic Ras inhibitor, S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib), was developed. FTS resembles the farnesylcysteine group of Ras, and acts as an effective Ras antagonist. In the present review, the effect of FTS in combination with various other drugs, as tested in vitro and in vivo, and its therapeutic potential are discussed. As reviewed, FTS cooperates with diverse therapeutic agents, which significantly improves treatment outcome. Therefore, combinations of FTS with other agents have a potential to serve as anti-cancer or anti-inflammatory therapies. PMID- 25735914 TI - Aneusomy detected by fluorescence in-situ hybridization has high positive predictive value for Barrett's dysplasia. AB - AIMS: The goal of this study was to pilot a commercial four-colour fluorescence in-situ hybridization (FISH) probe set as a marker of dysplasia in surveillance biopsies. METHODS AND RESULTS: FISH probes to 9p12 (CDKN2A), 17q11.2-12 (HER2), 8q24.12-13 (CMYC) and 20q13.2 (ZNF217) in 20 cases of Barrett's oesophagus. Dysplastic and non-dysplastic mucosa were compared for each case. Two observers independently counted 50 cells in each region of interest (ROI), and the mean score taken. Wilcoxon's signed-rank test was used to determine the significance of differences between dysplastic and non-dysplastic tissue. Predictive power was determined by logistic regression and receiver operator characteristic (ROC) curves were plotted to examine sensitivity and specificity of each gene to detect dysplasia. Interobserver agreement was excellent. HER2, CMYC and ZNF217 showed significant (P < 0.0005) increases in copy number in dysplastic mucosa; CDKN2A had an insignificant (P = 0.852) decrease when compared to non-dysplastic mucosa. While aneusomy was strongly predictive of dysplasia, eusomy did not rule it out. CONCLUSIONS: Increased HER2, CMYC and ZNF217 copy number distinguished dysplastic from non-dysplastic mucosa, but non-detection of aneusomy did not exclude dysplasia. Further studies are justified to determine whether FISH-positive dysplasia might justify earlier treatment by radio-frequency ablation. PMID- 25735915 TI - Pathologic correlates of late gadolinium enhancement cardiovascular magnetic resonance in a heart transplant patient. AB - We report the histopathologic correlates of late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) in a patient with heart transplant who died for graft failure a few months after the scan. Extensive late enhancement was present at CMR, and it correlated with extensive fibrosis at histology. To our knowledge, this is the first time the findings on contrast enhancement CMR are compared to the histology of the whole heart in a heart transplantation patient, and the correspondence between LGE and fibrosis, demonstrated in other cardiac pathologies, is confirmed also in this particular setting. PMID- 25735916 TI - Trajectories of male sexual aggression from adolescence through college: A latent class growth analysis. AB - Approximately 25% of male college students report engaging in some form of sexual coercion by the end of their fourth year of college. White and Smith (2004) found that negative childhood experiences-childhood sexual abuse, childhood physical abuse, and witnessing domestic violence-predicted sexual aggression perpetrated before college, but not during the subsequent college years, a puzzling finding in view of the reasonably consistent rates of sexual aggression from adolescence to the first 2 years of college. The current study takes a person-centered approach to sexual aggression in an attempt to resolve this discrepancy. We examined the possibility of cohesive subgroups of men in terms of their frequency of sexual aggression across the pre-college and college years. A series of latent class growth models were fit to an existing longitudinal dataset of sexual experiences collected across four time points-pre-college through year 3 of college. A four-trajectory model fit the data well, exhibiting significantly better fit than a three-trajectory model. The four trajectories are interpreted as men who perpetrate sexual aggression at (1) low (71.5% of the sample), (2) moderate (21.2%), (3) decreasing (4.2%), and (4) increasing (3.1%) frequencies across time. Negative childhood experiences predicted membership of the decreasing trajectory, relative to the low trajectory, but did not predict membership of the increasing trajectory, explaining the discrepancy uncovered by White and Smith. Implications for primary prevention of sexual aggression are discussed. PMID- 25735917 TI - Outcome of patients with high risk Myelodysplastic Syndrome (MDS) and advanced Chronic Myelomonocytic Leukemia (CMML) treated with decitabine after azacitidine failure. AB - Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0 28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC<13G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1-27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2-5 months) except 1 responder currently ongoing with +11 months follow up. Two non responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting. PMID- 25735918 TI - A multi-centre phase 3 study comparing efficacy and safety of Bemfola((r)) versus Gonal-f((r)) in women undergoing ovarian stimulation for IVF. AB - Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20-38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of +/-2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 +/- 5.11 versus Gonal-f 10.6 +/- 6.06, mean difference: 0.27 oocytes, 95% confidence interval: -1.34, 1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols. PMID- 25735921 TI - Novel Approaches for Vaccination Against HPV-Induced Cancers. AB - To date, more than 5 % of all cancers are as a result of human papillomavirus (HPV) infection, and this incidence is increasing. Early recognition of disease is associated with good survival, but late presentation results in devastating consequences. Prevention is better than cure, and there are now successful prophylactic vaccination programmes in place. We discuss these and the prospect of therapeutic vaccinations in the near future to address a growing need for improved therapeutic options. PMID- 25735919 TI - Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: an ARIA before the tsunami. AB - Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Abeta40 and Abeta42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-E2 overrepresentation and CAAo had an APOE-E4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology. PMID- 25735920 TI - Blood glutamate grabbing does not reduce the hematoma in an intracerebral hemorrhage model but it is a safe excitotoxic treatment modality. AB - Recent studies have shown that blood glutamate grabbing is an effective strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. The purpose of the study was to investigate the effect of two of the most efficient blood glutamate grabbers (oxaloacetate and recombinant glutamate oxaloacetate transaminase 1: rGOT1) in a rat model of intracerebral hemorrhage (ICH). Intracerebral hemorrhage was produced by injecting collagenase into the basal ganglia. Three treatment groups were developed: a control group treated with saline, a group treated with oxaloacetate, and a final group treated with human rGOT1. Treatments were given 1 hour after hemorrhage. Hematoma volume (analyzed by magnetic resonance imaging (MRI)), neurologic deficit, and blood glutamate and GOT levels were quantified over a period of 14 days after surgery. The results observed showed that the treatments used induced a significant reduction of blood glutamate levels; however, they did not reduce the hematoma, nor did they improve the neurologic deficit. In the present experimental study, we have shown that this novel therapeutic strategy is not effective in case of ICH pathology. More importantly, these findings suggest that blood glutamate grabbers are a safe treatment modality that can be given in cases of suspected ischemic stroke without previous neuroimaging. PMID- 25735922 TI - Targeting the HIV RNA genome: high-hanging fruit only needs a longer ladder. AB - Small molecules targeting the enzymes responsible for human immunodeficiency virus (HIV) maturation, DNA synthesis and its subsequent chromosomal integration as ribonucleotide-free double-stranded DNA remain the mainstay of combination antiretroviral therapy. For infected individuals harboring drug-susceptible virus, this approach has afforded complete or near-complete viral suppression. However, in the absence of a curative strategy, the predictable emergence of drug resistant variants requires continued development of improved antiviral strategies, inherent to which is the necessity of identifying novel targets. Regulatory elementsRegulatory elements that mediate transcription, translation, nucleocytoplasmic transport, dimerization, packaging and reverse transcription of the (+) strand RNA genomeRNA genome should now be considered viable targets for small molecule, peptide- and oligonucleotide-based therapeuticsTherapeutics . Where target specificity and cellular penetration and toxicity have been the primary obstacle to successful "macromolecule therapeutics", this chapter summarizes (a) novel approaches targeting RNA motifs whose three-dimensional structure is critical for biological function and consequently may be less prone to resistance-conferring mutations and (b) improved methods for deliveryDelivery . PMID- 25735923 TI - High-yield preparation of recombinant human alpha-thrombin for therapeutic use. AB - In this study, we established stable cell lines producing 1.5 mg/mL recombinant human prothrombin in 400-L fed-batch culture, using CHO DG44 cells as a host cell line. And we also established a recombinant human alpha-thrombin purification process that produces a purified product suitable for use as a biopharmaceutical, by using recombinant ecarin from CHO DG44 cells, achieving a total yield of approximately 27% of prothrombin in culture medium. The establishment of stable cell lines with high expression levels, long-term passage stability and satisfactory scale-up are essential to ensure the stable supply of biopharmaceuticals. Furthermore, biopharmaceuticals must be of high quality to assure safety and effectiveness in target applications. We had previously reported that recombinant human prethrombin-2 expression level in a stable cell line established using the mouse myeloma cells, Sp2/0-Ag14, reached 200 MUg/mL using animal-free materials in 50-L fed-batch culture. However, the productivity was insufficient to completely replace alpha-thrombin in human plasma preparations. By employing CHO DG44 cells as a host cell line, we had established a stable cell line and achieved significant improvements in quality, productivity of recombinant human alpha-thrombin manufacture suitable for use as a biopharmaceutical. PMID- 25735924 TI - Recurrent, spontaneous, postoperative small bowel perforations caused by invasive candidiasis. PMID- 25735925 TI - Nicorandil, an unusual ulcer etiology. PMID- 25735926 TI - Novel application of anal fistula plug for the treatment of chronic anastomotic sinus. PMID- 25735927 TI - Risk factors for acquisition of multidrug-resistant bacteria in patients with anastomotic leakage after colorectal cancer surgery. AB - PURPOSE: The risk factors for acquiring an infection with multidrug-resistant (MDR) bacteria in patients with anastomotic leakage after colorectal cancer surgery are poorly understood. We evaluated the risk factors associated with the initial acquisition of MDR pathogens in patients with anastomotic leakage after colorectal cancer surgery. METHODS: This study was a retrospective review of prospectively collected data at a university affiliated-tertiary referral hospital in South Korea. From January 2009 to April 2013, a total of 6767 consecutive patients with colorectal cancer who underwent surgery were registered. Of these patients, 190 (2.8%) were diagnosed with anastomotic leakage. Finally, 143 (2.1%) patients with culture test results were included in this study. RESULTS: Of the 143 enrolled patients, 46 (32.2%) were classified in the MDR group. The use of antibiotics for more than 5 days before diagnosis of anastomosis site leakage (p = 0.016) and diabetes mellitus (p = 0.028) was identified as independent risk factors for MDR acquisition by multivariate analysis. The rate of adequate initial empirical antibiotic therapy in the MDR group was lower than in the non-MDR group (35 vs. 75%, p < 0.001). Furthermore, the duration of antibiotic administration after the leak was longer in the MDR group (p = 0.013). Patients in the MDR group also had a longer hospital stay (p = 0.012). CONCLUSIONS: The length of antibiotic administration before the diagnosis of anastomotic leakage and diabetes mellitus were risk factors associated with the acquisition of MDR bacteria in patients with anastomotic leakage after colorectal cancer surgery. PMID- 25735928 TI - Colorectal surgery for a centenarian patient. PMID- 25735929 TI - Laboratory-based measurement of standing balance in individuals with knee osteoarthritis: a systematic review. AB - BACKGROUND: Laboratory-based measurement of standing balance is used to assess postural control in people with and without pathology, including knee osteoarthritis. However, no summary of available data has been reported in this patient population. This study aimed to summarize available data and testing methods for individuals with knee osteoarthritis. METHODS: Medline (OvidSP and PubMed), Embase, CINAHL, and Web of Science were searched from 1994 to October 25, 2014 to identify studies containing a quantifiable measure of standing balance. Methodological quality was assessed using a modified 17-item Downs & Black quality index. Studies scoring <50% were eliminated. FINDINGS: The search strategy initially yielded 1523 unique papers; 21 met all inclusion and quality assessment criteria. The variables measured in three or more of the 21 papers were anteroposterior centre of pressure (COP) velocity, mediolateral COP velocity, mean COP velocity, anteroposterior range of COP, mediolateral range of COP, anteroposterior COP standard deviation, mediolateral COP standard deviation, COP path length, COP area, Biodex anteroposterior score, Biodex mediolateral score, and overall Biodex score. In general, people with knee osteoarthritis exhibited worse standing balance compared to healthy controls. However, there remained much discrepancy in testing procedures across studies. INTERPRETATION: These findings indicate that people with knee osteoarthritis exhibit altered postural control. However, no conclusions could be made on the differences between radiographic severities. That said, these findings provide an opportunity for future researchers and clinicians to compare their findings with the currently published data. PMID- 25735930 TI - Does carbonation of steel slag particles reduce their toxicity? An in vitro approach. AB - Mineral carbonation can stabilize industrial residues and, in the steel industry, may contribute to simultaneously valorize CO2 emissions and slag. We hypothesized that, by restricting the leaching of metals of toxicological concern such as Cr and V, carbonation can suppress the toxicity of these materials. The cytotoxic activity (WST1 assay) of slag dusts collected from a stainless and a Linz Donawitz (LD) steel plant, before and after carbonation, was examined in J774 macrophages. The release of Cr, V, Fe, Mn and Ni was measured after incubation in artificial lung fluids mimicking the extracellular and phagolysosomal milieu to which particles are confronted after inhalation. LD slag had the higher Fe, Mn and V content, and was more cytotoxic than stainless steel slag. The cytotoxic activity of LD but not of stainless dusts was reduced after carbonation. The cytotoxic activity of the dusts toward J774 macrophages necessitated a direct contact with the cells and was reduced in the presence of inhibitors of phagocytosis (cytochalasin D) or phagolysosome acidification (bafilomycin), pointing to a key role of metallic constituents released in phagolysosomes. This in vitro study supports a limited reduction of the cytotoxic activity of LD, but not of stainless, steel dusts upon carbonation. PMID- 25735931 TI - Tumor suppressor candidate 3 (TUSC3) prevents the epithelial-to-mesenchymal transition and inhibits tumor growth by modulating the endoplasmic reticulum stress response in ovarian cancer cells. AB - Ovarian cancer is one of the most common malignancies in women and contributes greatly to cancer-related deaths. Tumor suppressor candidate 3 (TUSC3) is a putative tumor suppressor gene located at chromosomal region 8p22, which is often lost in epithelial cancers. Epigenetic silencing of TUSC3 has been associated with poor prognosis, and hypermethylation of its promoter provides an independent biomarker of overall and disease-free survival in ovarian cancer patients. TUSC3 is localized to the endoplasmic reticulum in an oligosaccharyl tranferase complex responsible for the N-glycosylation of proteins. However, the precise molecular role of TUSC3 in ovarian cancer remains unclear. In this study, we establish TUSC3 as a novel ovarian cancer tumor suppressor using a xenograft mouse model and demonstrate that loss of TUSC3 alters the molecular response to endoplasmic reticulum stress and induces hallmarks of the epithelial-to-mesenchymal transition in ovarian cancer cells. In summary, we have confirmed the tumor suppressive function of TUSC3 and identified the possible mechanism driving TUSC3 deficient ovarian cancer cells toward a malignant phenotype. PMID- 25735932 TI - Cadmium-coordinated supramolecule suppresses tumor growth of T-cell leukemia in mice. AB - Cadmium is a toxic pollutant with occupational and environmental significance, due to its diverse toxic effects. Supramolecules that conjugate and decontaminate toxic metals have potential for use in treatment of cadmium intoxication. In addition, metal-coordinating ability has been postulated to contribute to the cytotoxic effects of anti-tumor agents such as cisplatin or bleomycin. Thiacalixarenes, cyclic oligomers of p-alkylphenol bridged by sulfur atoms, are supramolecules known to have potent coordinating ability to metal ions. In this study, we show that cadmium-coordinated thiacalix[4]arene tetrasulfate (TC4ATS Cd) exhibits an anti-proliferative effect against T-cell leukemia cells. Cadmium exhibited cytotoxicity with IC50 values ranging from 36 to 129 MUM against epithelia-derived cancer cell lines, while TC4ATS-Cd elicited no significant cytotoxicity (IC50 > 947 MUM). However, a number of T-cell leukemia cell lines exhibited marked sensitivity to TC4ATS-Cd. In Jurkat cells, toxicity of TC4ATS-Cd occurred with an IC50 of 6.9 MUM, which is comparable to that of 6.5 MUM observed for cadmium alone. TC4ATS-Cd induced apoptotic cell death through activation of caspase-3 in Jurkat cells. In a xenograft model, TC4ATS-Cd (13 mg/kg) treatment significantly suppressed the tumor growth of Jurkat cells in mice. In addition, TC4ATS-Cd-treated mice exhibited significantly less cadmium accumulation in liver and kidney compared to equimolar cadmium-treated mice. These results suggest that cadmium-coordinated supramolecules may have therapeutic potential for treatment of T-cell leukemia. PMID- 25735933 TI - Proximal occlusion versus distal filter for cerebral protection during carotid stenting: updated meta-analysis of randomised and observational MRI studies. AB - AIMS: Proximal occlusion (PO) and distal filter (DF) serve for cerebral embolic protection during carotid artery stenting (CAS). New cerebral lesions at diffusion-weighted magnetic resonance imaging (DW-MRI) represent a surrogate endpoint for embolisation, though their clinical impact is controversial. We performed a meta-analysis of randomised and observational DW-MRI studies comparing PO and DF during CAS. METHODS AND RESULTS: We searched electronic scientific databases. The primary endpoint was the incidence of new cerebral lesions at DW-MRI; secondary endpoints were the incidence of new ipsilateral and new contralateral cerebral lesions at DW-MRI and death/cerebrovascular events (CVE). A total of 392 patients (seven studies) received CAS. At DW-MRI after 48 hours 178 patients (48.3%) presented new cerebral lesions. The use of PO versus DF reduced neither the risk of new cerebral lesions (OR [95% confidence interval] 0.65 [0.28-1.52], p=0.32) nor the risk of death/CVE (0.59 [0.22-1.60], p=0.30). Diabetes, baseline stenosis and symptoms significantly modified the risk estimates for new cerebral lesions. CONCLUSIONS: In this meta-analysis, one half of patients receiving protected CAS developed new embolic cerebral lesions at DW MRI, although the overwhelming majority were asymptomatic. Cerebral protection with PO versus DF neither reduced cerebral embolisation nor impacted on clinical outcomes. PMID- 25735934 TI - Particulates from hydrophilic-coated guiding sheaths embolise to the brain. AB - AIMS: We sought to evaluate the incidence of embolic material in porcine brains following vascular interventions using hydrophilic-coated sheaths. METHODS AND RESULTS: A new self-expanding stent and delivery system (SDS) was deployed through a hydrophilic-coated (Flexor Ansel; Cook Medical, Bloomington, IN, USA) guiding sheath into the iliac and/or carotid arteries of 23 anaesthetised Yucatan mini swine. The animals were euthanised at three, 30, 90 and 180 days and their brains were removed for histological analysis. In an additional single control animal, the guiding sheath was advanced but no SDS was deployed. Advancement of the coated guiding sheath with or without the SDS was associated with frequent foreign material in the arterioles of the brain. The embolic material was amorphous, non-refractile, non-crystalline, non-birefringent and typically lightly basophilic with a slightly stippled appearance on haematoxylin and eosin (H&E) stain. Material was observed at all time points involving 54% of all study animals (i.e., test and control) and in vitro after incubation in 0.9% saline. CONCLUSIONS: The hydrophilic coating on a clinically used guiding sheath readily avulses and embolises to the brain during deployment in a porcine model. Further documentation of this effect and monitoring in clinical scenarios are warranted. PMID- 25735935 TI - Signal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanism. AB - Signal transduction is the process by which external or internal signals exert their intracellular biological effects and by which intracellular communication is regulated. An important component of the signalling pathway is the second messenger, which is produced upon stimulation of the cell and mediates its effects downstream through phosphorylation and dephosphorylation of target proteins. Intracellular accumulation or deficiency of metabolites that serve as second messengers, due to inborn errors of their metabolism, may lead to perturbation of signalling pathways and disruption of the balance between them, serving as a missing link between the genotype, biochemical phenotype and clinical phenotype. The main second messengers that are putatively associated with the pathogenesis of IEM are 'bioactive lipids' (complex lipids and long chain fatty acids), 'calcium', 'stress' (osmotic, reactive oxygen/nitorgen species, misfolded proteins and others) and 'metabolic' (AMP/ATP ratio, leucine, glutamine). They act through protein kinase C, calcium dependent kinases (CamK) and phosphatase (CN), 'stress-mediated' kinases (MAPK) and AMP/ATP-dependent kinase (AMPK). These signalling pathways lead to cell proliferation, inflammatory response, autophagy (and mitophagy) and apoptosis, suggesting that there are only few final common pathways involved in this pathogenetic mechanism. Questions remain regarding the complexity of the effects of the accumulating metabolites on different signalling pathways, and regarding the relative role and origin of 'proxy' second messengers such as reactive oxygen species. A better understanding of the signalling pathways in IEM may enhance the development of novel therapies in situations where normalising intracellular concentrations of the second messenger is impossible or impractical. PMID- 25735936 TI - Whole exome sequencing of suspected mitochondrial patients in clinical practice. AB - Mitochondrial disorders are characterized by a broad clinical spectrum. Identical clinical signs and symptoms can be caused by mutations in different mitochondrial or nuclear genes. Vice versa, the same mutation can lead to different phenotypes. Genetic syndromes and neuromuscular disorders mimicking mitochondrial disorders further complicate the diagnostic process. Whole exome sequencing (WES) is the state of the art next generation sequencing technique to identify genetic defects in mitochondrial disorders. Until recently it has mainly been used as a research tool. In this study, the use of WES in routine diagnostics is described. The WES data of 109 patients, referred under the suspicion of a mitochondrial disorder, were examined in two steps. First, the data were filtered using a virtual gene panel of genes known to be associated with mitochondrial disease. If negative, the entire exome was examined. A molecular diagnosis was achieved in 39% of the heterogeneous cohort, and in 57% of the subgroup of 42 patients with the highest suspicion for a mitochondrial disease. In addition to mutations in genes known to be associated with mitochondrial disorders (e.g. TUFM, MTFMT, FBXL4), in the subgroup of patients with the lowest suspicion for a mitochondrial disorder we found mutations in several genes associated with neuromuscular disorders (e.g. SEPN1, ACTA1) and genetic syndrome (e.g. SETBP1, ARID1B). Our results show that WES technology has been successfully implemented as a state-of-the-art, molecular diagnostic test for mitochondrial disorders as well as for the mimicking disorders in daily clinical practice. It also illustrates that clinical and biochemical phenotyping is essential for successful application of WES to diagnose individual patients. PMID- 25735937 TI - 'Similar to' is not 'identical with', and 'identical with' is not 'the same as'. PMID- 25735938 TI - Community Health Worker Interventions to Improve Glycemic Control in People with Diabetes: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: We set out to review the efficacy of Community Health Worker (CHW) interventions to improve glycemia in people with diabetes. METHODS: Data sources included the Cochrane Central Register of Controlled Trials, Medline, clinicaltrials.gov, Google Scholar, and reference lists of previous publications. We reviewed randomized controlled trials (RCTs) that assessed the efficacy of CHW interventions, as compared to usual care, to lower hemoglobin A1c (A1c). Two investigators independently reviewed the RCTs and assessed their quality. Only RCTs with a follow-up of at least 12 months were meta-analyzed. A random effects model was used to estimate, from unadjusted within-group mean reductions, the standardized mean difference (SMD) in A1c achieved by the CHW intervention, beyond usual care. RESULTS: Thirteen RCTs were included in the narrative review, and nine of them, which had at least 12 months of follow-up, were included in the meta-analysis. Publication bias could not be ruled-out due to the small number of trials. Outcome heterogeneity was moderate (I(2)= 37%). The SMD in A1c (95% confidence interval) was 0.21 (0.11-0.32). Meta-regression showed an association between higher baseline A1c and a larger effect size. CONCLUSIONS: CHW interventions showed a modest reduction in A1c compared to usual care. A1c reduction was larger in studies with higher mean baseline A1c. Caution is warranted, given the small number of studies. PMID- 25735939 TI - Dermatological Manifestations of Infective Endocarditis. PMID- 25735940 TI - Brains for all the ages: structural neurodevelopment in infants and children from a life-span perspective. AB - Magnetic resonance imaging (MRI) is a noninvasive method to measure brain structure and function that may be applied to human participants of all ages. This chapter reviews our recent work creating a life-span Neurodevelopmental MRI Database. It provides age-specific reference data in fine-grained age intervals from 2 weeks through 89 years. The reference data include average MRI templates, segmented tissue priors, and a common stereotaxic atlas for pediatric and adult participants. The database will be useful for neuroimaging research over a wide range of ages and may be used to make life-span comparisons. The chapter reviews the application of this database to the study of neurostructural development, including a new volumetric study of segmented brain tissue over the life span. We also show how this database could be used to create "study-specific" MRI templates for special groups and apply this to the MRIs of Chinese children. Finally, we review recent use of the database in the study of brain activity in pediatric populations. PMID- 25735941 TI - The importance of puberty for adolescent development: conceptualization and measurement. AB - How and why are teenagers different from children and adults? A key question concerns the ways in which pubertal development shapes psychological changes in adolescence directly through changes to the brain and indirectly through the social environment. Empirical work linking pubertal development to adolescent psychological function draws from several different perspectives, often with varying approaches and a focus on different outcomes and mechanisms. The main themes concern effects of atypical pubertal timing on behavior problems during adolescence, effects of pubertal status (and associated hormones) on normative changes in behaviors that can facilitate or hinder development (especially risk taking, social reorientation, and stress responsivity), and the role of puberty in triggering psychopathology in vulnerable individuals. There is also interest in understanding the ways in which changes in the brain reflect pubertal processes and underlie psychological development in adolescence. In this chapter, we consider the ways that puberty might affect adolescent psychological development, and why this is of importance to developmentalists. We describe the processes of pubertal development; summarize what is known about pubertal influences on adolescent development; consider the assumptions that underlie most work and the methodological issues that affect the interpretation of results; and propose research directions to help understand paths from puberty to behavior. Throughout, we emphasize the importance of pubertal change in all aspects of psychological development, and the ways in which puberty represents an opportunity to study the interplay of biological and social influences. PMID- 25735942 TI - Foundations of children's numerical and mathematical skills: the roles of symbolic and nonsymbolic representations of numerical magnitude. AB - Numerical and mathematical skills are critical predictors of academic success. The last three decades have seen a substantial growth in our understanding of how the human mind and brain represent and process numbers. In particular, research has shown that we share with animals the ability to represent numerical magnitude (the total number of items in a set) and that preverbal infants can process numerical magnitude. Further research has shown that similar processing signatures characterize numerical magnitude processing across species and developmental time. These findings suggest that an approximate system for nonsymbolic (e.g., dot arrays) numerical magnitude representation serves as the basis for the acquisition of cultural, symbolic (e.g., Arabic numerals) representations of numerical magnitude. This chapter explores this hypothesis by reviewing studies that have examined the relation between individual differences in nonsymbolic numerical magnitude processing and symbolic math abilities (e.g., arithmetic). Furthermore, we examine the extent to which the available literature provides strong evidence for a link between symbolic and nonsymbolic representations of numerical magnitude at the behavioral and neural levels of analysis. We conclude that claims that symbolic number abilities are grounded in the approximate system for the nonsymbolic representation of numerical magnitude are not strongly supported by the available evidence. Alternative models and future research directions are discussed. PMID- 25735943 TI - Developmental origins of the face inversion effect. AB - A hallmark of adults' expertise for faces is that they are better at recognizing, discriminating, and processing upright faces compared to inverted faces. We investigate the developmental origins of "the face inversion effect" by reviewing research on infants' perception of upright and inverted faces during the first year of life. We review the effects of inversion on infants' face preference, recognition, processing (holistic and second-order configural), and scanning as well as face-related neural responses. Particular attention is paid to the developmental patterns that emerge within and across these areas of face perception. We conclude that the developmental origins of the inversion effect begin in the first few months of life and grow stronger over the first year, culminating in effects that are commonly thought to indicate adult-like expertise. We posit that by the end of the first year, infants' face-processing system has become specialized to upright faces and a foundation for adults' upright-face expertise has been established. Developmental mechanisms that may facilitate the emergence of this upright-face specialization are discussed, including the roles that physical and social development may play in upright faces' becoming more meaningful to infants during the first year. PMID- 25735944 TI - Early testimonial learning: monitoring speech acts and speakers. AB - Testimony provides children with a rich source of knowledge about the world and the people in it. However, testimony is not guaranteed to be veridical, and speakers vary greatly in both knowledge and intent. In this chapter, we argue that children encounter two primary types of conflicts when learning from speakers: conflicts of knowledge and conflicts of interest. We review recent research on children's selective trust in testimony and propose two distinct mechanisms supporting early epistemic vigilance in response to the conflicts associated with speakers. The first section of the chapter focuses on the mechanism of coherence checking, which occurs during the process of message comprehension and facilitates children's comparison of information communicated through testimony to their prior knowledge, alerting them to inaccurate, inconsistent, irrational, and implausible messages. The second section focuses on source-monitoring processes. When children lack relevant prior knowledge with which to evaluate testimonial messages, they monitor speakers themselves for evidence of competence and morality, attending to cues such as confidence, consensus, access to information, prosocial and antisocial behavior, and group membership. PMID- 25735945 TI - Beyond Sally's missing marble: further development in children's understanding of mind and emotion in middle childhood. AB - Research on the development of theory of mind (ToM), the understanding of people in relation to mental states and emotions, has been a vibrant area of cognitive development research. Because the dominant focus has been addressing when children acquire a ToM, researchers have concentrated their efforts on studying the emergence of psychological understanding during infancy and early childhood. Here, the benchmark test has been the false-belief task, the awareness that the mind can misrepresent reality. While understanding false belief is a critical milestone achieved by the age of 4 or 5, children make further advances in their knowledge about mental states and emotions during middle childhood and beyond. Thus, a comprehensive understanding of children's sociocognitive abilities in older age groups is necessary to understand more fully the course of ToM development. The aim of this review is to outline continued development in ToM during middle childhood. In particular, we focus on children's understanding of interpretation-that different minds can construct different interpretations of the same reality. Additionally, we consider children's growing understanding of how mental states (thoughts, emotions, decisions) derive from personal experiences, cohere across time, and interconnect (e.g., thoughts shape emotions). We close with a discussion of the surprising paucity of studies investigating individual differences in ToM beyond age 6. Our hope is that this chapter will invigorate empirical interest in moving the pendulum toward the opposite research direction-toward exploring strengths, limitations, variability, and persistent errors in developing theories of mind across the life span. PMID- 25735946 TI - Television and children's executive function. AB - Children spend a lot of time watching television on its many platforms: directly, online, and via videos and DVDs. Many researchers are concerned that some types of television content appear to negatively influence children's executive function. Because (1) executive function predicts key developmental outcomes, (2) executive function appears to be influenced by some television content, and (3) American children watch large quantities of television (including the content of concern), the issues discussed here comprise a crucial public health issue. Further research is needed to reveal exactly what television content is implicated, what underlies television's effect on executive function, how long the effect lasts, and who is affected. PMID- 25735947 TI - Moral judgments and emotions in contexts of peer exclusion and victimization. AB - Morality is at the core of social development. How individuals treat one another, develop a sense of obligation toward others regarding equality and equity, and understand the emotions experienced by victims and victimizers, are essential ingredients for healthy development, and for creating a just and civil society. In this chapter, we review research on two forms of social exclusion, intergroup exclusion and interpersonal victimization, from a moral development perspective, identifying distinctions as well as areas of overlap and intersections. Intergroup exclusion (defined as exclusion based on group membership, such as gender, race, ethnicity, and nationality) is most often analyzed at the group level in contrast to interpersonal victimization (defined as the repeated infliction of physical and psychological harm on another) which is most often analyzed at the individual level. In this chapter, we assert that research needs to examine both group-level and individual-level factors for intergroup and interpersonal exclusion and that moral development provides an important framework for investigating these phenomena. PMID- 25735948 TI - Preface. PMID- 25735950 TI - Synthesis of pyrroloindolines and furoindolines via cascade dearomatization of indole derivatives with carbenium ion. AB - A highly efficient intermolecular cascade dearomatization of substituted indoles with benzodithiolylium tetrafluoroborate has been developed. This reaction provides a novel strategy to synthesise C3 methyl-substituted pyrroloindolines and furoindolines under mild reaction conditions, the utility of which has been demonstrated by the synthesis of esermethol and physovenine in a highly concise manner. PMID- 25735949 TI - Rosmarinic acid modulates the antioxidant status and protects pancreatic tissues from glucolipotoxicity mediated oxidative stress in high-fat diet: streptozotocin induced diabetic rats. AB - Persistent hyperglycemia and elevated levels of free fatty acids (FFA) contribute to oxidative stress, a proximate cause for the onset and progression of diabetes and its complications. The present study was hypothesized to evaluate the anti diabetic potential of Rosmarinic acid (RA) during high-fat diet (HFD) streptozotocin (STZ)-induced type 2 Diabetes (T2D) in wistar albino rats. Oral administration of RA (100 mg/kg b.w) significantly (p < 0.05) increased the insulin sensitivity index (ISI0,120), while the levels of blood glucose, HbA1c, advanced glycation end products (AGE), TNF-alpha, IL-1beta, IL 6, NO, p-JNK, P38 MAPK and NF-kappaB were significantly reduced, with a concomitant elevation in the plasma insulin levels in diabetic rats. Furthermore, RA treatment significantly (p < 0.05) reduced the levels of triglycerides, FFA and cholesterol in serum, and reduced the levels of lipid peroxides, AOPP's and protein carbonyls in the plasma and pancreas of diabetic rats. The diminished activities of pancreatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) and the decreased levels of plasma ceruloplasmin, vitamin C, vitamin E and reduced glutathione (GSH) in diabetic rats were also significantly (p < 0.05) recovered upon RA treatment denoting its antioxidant potential which was confirmed by Nrf-2, hemeoxyenase (HO-1) levels. Histological, ultrastructural and immunohistochemical data demonstrate that oral administration of RA protects pancreatic beta-cells from oxidative niche in HFD STZ-induced experimental diabetes. Our findings suggest that the oral treatment with RA alleviates pancreatic beta-cell dysfunction and glucolipotoxicity mediated oxidative stress during HFD-STZ-induced T2DM, perhaps through its antioxidant potential. PMID- 25735951 TI - Giant Purulent Pericarditis with Cardiac Tamponade Due to Streptococcus intermedius Rapidly Progressing to Constriction. AB - Purulent pericardial effusion, although rare, is a life-threatening condition usually produced by the extension of a nearby bacterial infection locus or by blood dissemination in the immune-suppressed subjects or in the course of cardiothoracic surgery. Because clinical features of purulent pericardial effusion are often nonspecific, it can cause delay in diagnosis. Therefore, a high index of suspicion is required for timely diagnosis and management. Herein, we describe a case of giant purulent pericardial effusion due to Streptococcus intermedius with the history of bronchiectasis and pneumonia, which was successfully treated with pericardiocentesis via parasternal approach, appropriate antibiotics, and pericardiectomy. PMID- 25735952 TI - The Epstein-Barr Virus Lytic Protein BZLF1 as a Candidate Target Antigen for Vaccine Development. AB - The Epstein-Barr virus (EBV) is an oncogenic, gamma-herpesvirus associated with a broad spectrum of disease. Although most immune-competent individuals can effectivley develop efficient adaptive immune responses to EBV, immunocompromised individuals are at serious risk for developing life-threatening diseases, such as Hodgkin lymphoma and posttransplant lymphoproliferative disorder (PTLD). Given the significant morbidity associated with EBV infection in high-risk populations, there is a need to develop vaccine strategies that restore or enhance EBV specific immune responses. Here, we identify the EBV immediate-early protein BZLF1 as a potential target antigen for vaccine development. Primary tumors from patients with PTLD and a chimeric human-murine model of EBV-driven lymphoproliferative disorder (EBV-LPD) express BZLF1 protein. Pulsing human dendritic cells (DC) with recombinant BZLF1 followed by incubation with autologous mononuclear cells led to expansion of BZLF1-specific CD8(+) T cells in vitro and primed BZLF1-specific T-cell responses in vivo. In addition, vaccination of hu-PBL-SCID mice with BZLF1-transduced DCs induced specific cellular immunity and significantly prolonged survival from fatal EBV-LPD. These findings identify BZLF1 as a candidate target protein in the immunosurveillance of EBV and provide a rationale for considering BZLF1 in vaccine strategies to enhance primary and recall immune responses and potentially prevent EBV associated diseases. PMID- 25735953 TI - The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion. AB - The killer-cell Ig-like receptor (KIR) 2DL4 (CD158d) acts as a receptor for human leukocyte antigen (HLA)-G and is expressed on almost all human natural killer (NK) cells. The expression and function of KIR2DL4 in other hematopoietic cells is poorly understood. Here, we focused on human mast cells, which exhibit cytotoxic activity similar to that of NK cells. KIR2DL4 was detected in all examined human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), the human mast cell line LAD2, and human nonneoplastic mast cells, including those on pathologic specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production by PB-mast and LAD2 cells, by activating Src homology 2-containing protein tyrosine phosphatase (SHP-2). Next, we performed a coculture assay between LAD2 cells and the HLA-G(+) cancer cells, MCF-7 and JEG 3, and showed that KIR2DL4 on LAD2 cells enhanced MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G(+) breast cancer cells and KIR2DL4(+) tissue mast cells (observed in 12 of 36 cases; 33.3%) was statistically correlated with the presence of lymph node metastasis or lymph vascular invasion (observed in 11 of 12 cases; 91.7%; chi(2) = 7.439; P < 0.01; degrees of freedom, 1) in the clinical samples. These findings suggest that the KIR2DL4 on human mast cells facilitates HLA-G-expressing cancer invasion and the subsequent metastasis. PMID- 25735954 TI - IFNgamma Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer. AB - Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress proinflammatory diseases. GPR109A is the receptor for short chain fatty acids. The functions of GPR109A have been the subject of extensive studies; however, the molecular mechanisms underlying GPR109A expression is largely unknown. We show that GPR109A is highly expressed in normal human colon tissues, but is silenced in human colon carcinoma cells. The GPR109A promoter DNA is methylated in human colon carcinoma. Strikingly, we observed that IFNgamma, a cytokine secreted by activated T cells, activates GPR109A transcription without altering its promoter DNA methylation. Colon carcinoma grows significantly faster in IFNgamma-deficient mice than in wild-type mice in an orthotopic colon cancer mouse model. A positive correlation was observed between GPR109A protein level and tumor-infiltrating T cells in human colon carcinoma specimens, and IFNgamma expression level is higher in human colon carcinoma tissues than in normal colon tissues. We further demonstrated that IFNgamma rapidly activates pSTAT1 that binds to the promoter of p300 to activate its transcription. p300 then binds to the GPR109A promoter to induce H3K18 hyperacetylation, resulting in chromatin remodeling in the methylated GPR109A promoter. The IFNgamma-activated pSTAT1 then directly binds to the methylated but hyperacetylated GPR109 promoter to activate its transcription. Overall, our data indicate that GPR109A acts as a tumor suppressor in colon cancer, and the host immune system might use IFNgamma to counteract DNA methylation-mediated GPR109A silencing as a mechanism to suppress tumor development. PMID- 25735956 TI - Making the case for mobile cognition: EEG and sports performance. AB - In the high stakes world of International sport even the smallest change in performance can make the difference between success and failure, leading sports professionals to become increasingly interested in the potential benefits of neuroimaging. Here we describe evidence from EEG studies that either identify neural signals associated with expertise in sport, or employ neurofeedback to improve performance. Evidence for the validity of neurofeedback as a technique for enhancing sports performance remains limited. By contrast, progress in characterizing the neural correlates of sporting behavior is clear: frequency domain studies link expert performance to changes in alpha rhythms, whilst time domain studies link expertise in response evaluation and motor output with modulations of P300 effects and readiness potentials. Despite early promise, however, findings have had relatively little impact for sports professionals, at least in part because there has been a mismatch between lab tasks and real sporting activity. After selectively reviewing existing findings and outlining limitations, we highlight developments in mobile EEG technology that offer new opportunities for sports neuroscience. PMID- 25735955 TI - Birth order and sibship composition as predictors of overweight or obesity among low-income 4- to 8-year-old children. AB - OBJECTIVE: This study aimed to examine the association of birth order and number and sex of siblings with overweight or obesity among 4- to 8-year-olds. METHODS: This is a cross-sectional study involving 273 low-income mother-child dyads. Questionnaires and anthropometry were completed. Multiple logistic regression was used to examine the association of birth order, having younger siblings, having older siblings, having at least one brother and having at least one sister with odds of overweight or obesity. Analyses were repeated to additionally include non biological siblings. Models were adjusted for potential confounders and intermediate variables. RESULTS: Prevalence of child overweight or obesity was 42.5%. Adjusting for covariates, only children and youngest siblings had higher odds of overweight or obesity compared with oldest siblings (odds ratio [OR]: 4.18, 95% confidence interval [CI]: 1.67, 10.46 and OR: 3.21, 95% CI: 1.41, 7.33, respectively). Having one or more younger siblings and having at least one brother were associated with lower odds (OR: 0.38, 95% CI: 0.21, 0.69 and OR: 0.47, 95% CI: 0.28, 0.81, respectively). Including non-biological siblings did not meaningfully change the associations. CONCLUSION: Birth order and sibship composition are associated with overweight or obesity among 4- to 8-year-olds. Future studies identifying the underlying behavioural mechanism can help inform family-based intervention programmes. PMID- 25735957 TI - A reward-centred model of anorexia nervosa: a focussed narrative review of the neurological and psychophysiological literature. AB - This focussed narrative review examines neurobiological and psychophysiological evidence supporting a role for altered reward processes in the development and maintenance of anorexia nervosa (AN). In AN, there does not appear to be a generalised inability to experience reward. Rather, data suggest that a reluctance to gain weight leads to an aversive appraisal of food- and taste related stimuli. As a result, cues compatible with this aberrant mode of thinking become rewarding for the individual. Evidence also suggests that attribution of motivational salience to such cues promotes anorectic behaviours. These findings are consistent with models in which interactions between cognition and reward are important in eliciting the anorectic "habit". A model is proposed which is consistent with elements of other theoretical frameworks, but differs in that its emphasis is towards neural overlaps between AN and addiction. It is consistent with AN being a reward-based learned behaviour in which aberrant cognitions related to eating and shape alter functioning of central reward systems. It proposes that the primary neural problem responsible for the development, maintenance, and treatment resistance is centred in the striatal reward system. This helps shift the emphasis of aetiological models towards reward processing, particularly in the context of illness-compatible cues. Furthermore, it suggests that continuing to explore the utility and valued nature of AN in the patient's life would be a useful inclusion in treatment and prevention models. PMID- 25735958 TI - Reduced ABA Accumulation in the Root System is Caused by ABA Exudation in Upland Rice (Oryza sativa L. var. Gaoshan1) and this Enhanced Drought Adaptation. AB - Lowland rice (Nipponbare) and upland rice (Gaoshan 1) that are comparable under normal and moderate drought conditions showed dramatic differences in severe drought conditions, both naturally occurring long-term drought and simulated rapid water deficits. We focused on their root response and found that enhanced tolerance of upland rice to severe drought conditions was mainly due to the lower level of ABA in its roots than in those of the lowland rice. We first excluded the effect of ABA biosynthesis and catabolism on root-accumulated ABA levels in both types of rice by monitoring the expression of four OsNCED genes and two OsABA8ox genes. Next, we excluded the impact of the aerial parts on roots by suppressing leaf-biosynthesized ABA with fluridone and NDGA (nordihydroguaiaretic acid), and measuring the ABA level in detached roots. Instead, we proved that upland rice had the ability to export considerably more root-sourced ABA than lowland rice under severe drought, which improved ABA-dependent drought adaptation. The investigation of apoplastic pH in root cells and root anatomy showed that ABA leakage in the root system of upland rice was related to high apoplastic pH and the absence of Casparian bands in the sclerenchyma layer. Finally, taking some genes as examples, we predicted that different ABA levels in rice roots stimulated distinct ABA perception and signaling cascades, which influenced its response to water stress. PMID- 25735960 TI - The role of bilirubin and phototherapy in the oxidative/antioxidant balance. PMID- 25735959 TI - Prevalence of psychiatric co-morbidity in treatment-seeking problem gamblers: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of this paper was to systematically review and meta-analyse the prevalence of co-morbid psychiatric disorders (DSM-IV Axis I disorders) among treatment-seeking problem gamblers. METHODS: A systematic search was conducted for peer-reviewed studies that provided prevalence estimates of Axis I psychiatric disorders in individuals seeking psychological or pharmacological treatment for problem gambling (including pathological gambling). Meta-analytic techniques were performed to estimate the weighted mean effect size and heterogeneity across studies. RESULTS: Results from 36 studies identified high rates of co-morbid current (74.8%, 95% CI 36.5-93.9) and lifetime (75.5%, 95% CI 46.5-91.8) Axis I disorders. There were high rates of current mood disorders (23.1%, 95% CI 14.9-34.0), alcohol use disorders (21.2%, 95% CI 15.6-28.1), anxiety disorders (17.6%, 95% CI 10.8-27.3) and substance (non-alcohol) use disorders (7.0%, 95% CI 1.7-24.9). Specifically, the highest mean prevalence of current psychiatric disorders was for nicotine dependence (56.4%, 95% CI 35.7 75.2) and major depressive disorder (29.9%, 95% CI 20.5-41.3), with smaller estimates for alcohol abuse (18.2%, 95% CI 13.4-24.2), alcohol dependence (15.2%, 95% CI 10.2-22.0), social phobia (14.9%, 95% CI 2.0-59.8), generalised anxiety disorder (14.4%, 95% CI 3.9-40.8), panic disorder (13.7%, 95% CI 6.7-26.0), post traumatic stress disorder (12.3%, 95% CI 3.4-35.7), cannabis use disorder (11.5%, 95% CI 4.8-25.0), attention-deficit hyperactivity disorder (9.3%, 95% CI 4.1 19.6), adjustment disorder (9.2%, 95% CI 4.8-17.2), bipolar disorder (8.8%, 95% CI 4.4-17.1) and obsessive-compulsive disorder (8.2%, 95% CI 3.4-18.6). There were no consistent patterns according to gambling problem severity, type of treatment facility and study jurisdiction. Although these estimates were robust to the inclusion of studies with non-representative sampling biases, they should be interpreted with caution as they were highly variable across studies. CONCLUSIONS: The findings highlight the need for gambling treatment services to undertake routine screening and assessment of psychiatric co-morbidity and provide treatment approaches that adequately manage these co-morbid disorders. Further research is required to explore the reasons for the variability observed in the prevalence estimates. PMID- 25735961 TI - On the analysis of heterogeneity within diagnostic meta-analyses based on mixture models. PMID- 25735962 TI - Let-7f Inhibits Glioma Cell Proliferation, Migration, and Invasion by Targeting Periostin. AB - Glioma is one of the most aggressive and malignant tumor types. Despite advances in surgery, imaging, chemotherapy, and radiation, glioma patient prognosis remains poor. Glioma pathogenesis is an urgent problem that must be solved. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that are key post transcriptional regulators of gene expression. miRNA deregulation commonly occurs in human tumorigenesis. In the present study, the expression levels of Let-7f were down-regulated in both glioma tissues and glioma cells. The enhanced expression of Let-7f suppressed glioma cells proliferation, migration, and invasion via direct targeting perisotin oncogenic activity. Experiments with periostin siRNA or over-expression further suggest that Let-7f may serve as tumor suppressors through perisotin signal. These findings provide insights regarding the role and mechanism of Let-7f in regulating biological behavior of glioma cells via the Let-7f/periostin axis, and Let-7f may serve as a potential therapeutic target in glioma. PMID- 25735963 TI - Bloch surface plasmon enhanced blue emission from InGaN/GaN light-emitting diode structures with Al-coated GaN nanorods. AB - InGaN/GaN light-emitting diode structures with Al-coated GaN nanorods were fabricated by using soft ultraviolet nanoimprint lithography. The intensity of light emission was found to be greatly enhanced due to the strong near-fields confined at the interface of Al/GaN and extended to the multiple quantum wells (MQWs) active region. The dynamics of carrier recombination and plasmon-enhanced Raman scattering were also investigated, providing a progressive view on the effective energy transfer between MQWs and surface plasmons. PMID- 25735964 TI - Impact of insulin-like growth factor 1 and insulin-like growth factor binding proteins on outcomes in acute myeloid leukemia. AB - Our objective was to explore associations of circulating factors implicated in insulin-like growth factor- 1 receptor (IGF-1R) signaling with clinical outcomes of patients with acute myeloid leukemia (AML). Pretreatment blood samples from patients with non-M3 AML (n = 30) were collected prospectively and levels of IGF binding proteins (IGFBPs) 1-7 and IGF-1 (free and total) were established at diagnosis and statistically evaluated. Baseline levels of IGFBP-1 and -6 below respective thresholds of 8.8 ng/mL and 237 ng/mL were associated (p = 0.0347 and 0.0099, respectively) with superior progression-free survival, whereas baseline levels of IGFBP -1, -2, -6 and -7 below the respective thresholds of 8.8, 28.8, 237 and 119 ng/mL were strongly associated (p = 0.0004, 0.0085, 0.0031, 2.46 * 10(- 7), respectively) with improved overall survival. These findings provide promising evidence that IGFBP signatures could be used as predictive tools in AML, with applications in remission surveillance and the development of IGFBP directed biologic therapy. PMID- 25735965 TI - Eradication of acquired hemophilia associated with indolent non-Hodgkin lymphoma by a disease specific treatment. PMID- 25735966 TI - Comparison of GC-MS and GC*GC-MS in the analysis of human serum samples for biomarker discovery. AB - We compared the performance of gas chromatography time-of-flight mass spectrometry (GC-MS) and comprehensive two-dimensional gas chromatography mass spectrometry (GC*GC-MS) for metabolite biomarker discovery. Metabolite extracts from 109 human serum samples were analyzed on both platforms with a pooled serum sample analyzed after every 9 biological samples for the purpose of quality control (QC). The experimental data derived from the pooled QC samples showed that the GC*GC-MS platform detected about three times as many peaks as the GC-MS platform at a signal-to-noise ratio SNR >= 50, and three times the number of metabolites were identified by mass spectrum matching with a spectral similarity score Rsim >= 600. Twenty-three metabolites had statistically significant abundance changes between the patient samples and the control samples in the GC MS data set while 34 metabolites in the GC*GC-MS data set showed statistically significant differences. Among these two groups of metabolite biomarkers, nine metabolites were detected in both the GC-MS and GC*GC-MS data sets with the same direction and similar magnitude of abundance changes between the control and patient sample groups. Manual verification indicated that the difference in the number of the biomarkers discovered using these two platforms was mainly due to the limited resolution of chromatographic peaks by the GC-MS platform, which can result in severe peak overlap making subsequent spectrum deconvolution for metabolite identification and quantification difficult. PMID- 25735967 TI - Strategies to create hierarchical self-assembled structures via cooperative non covalent interactions. AB - Cooperative phenomena are common processes involved in the hierarchical self assembly of multiple systems in nature, such as the tobacco mosaic virus and a cell's cytoskeleton. Motivated by the high degree of order exhibited by these systems, a great deal of effort has been devoted in the past two decades to design hierarchical supramolecular polymers by combining different classes of cooperative interactions. In this review, we have classified the field of supramolecular polymers depending on the cooperative non-covalent forces driving their formation, with particular emphasis on recent examples from literature. We believe that this overview would help scientists in the field to design novel self-assembled systems with improved complexity and functionalities. PMID- 25735968 TI - In vivo differences in inputs and spiking between neurons in lobules VI/VII of neocerebellum and lobule X of archaeocerebellum. AB - The cerebellum plays an important role in the coordination and refinement of movements and cognitive processes. Recently, it has been shown that the main output neuron of the cerebellar cortex, i.e., the Purkinje cell, can show a different firing behavior dependent on its intrinsic electrophysiological properties. Yet, to what extent a different nature of mossy fiber inputs can influence the firing behavior of cerebellar cortical neurons remains to be elucidated. Here, we compared the firing rate and regularity of mossy fibers and neurons in two different regions of cerebellar cortex. One region intimately connected with the cerebral cortex, i.e., lobules VI/VII of the neocerebellum, and another one strongly connected with the vestibular apparatus, i.e., lobule X of the archaeocerebellum. Given their connections, we hypothesized that activity in neurons in lobules VI/VII and lobule X may be expected to be more phasic and tonic, respectively. Using whole-cell and cell-attached recordings in vivo in anesthetized mice, we show that the mossy fiber inputs to these functionally distinct areas of the cerebellum differ in that the irregularity and bursty character of their firing is significantly greater in lobules VI/VII than in lobule X. Importantly, this difference in mossy fiber regularity is propagated through the granule cells at the input stage to the Purkinje cells and molecular layer interneurons, ultimately resulting in different regularity of simple spikes. These data show that the firing behavior of cerebellar cortical neurons does not only reflect particular intrinsic properties but also an interesting interplay with the innate activity at the input stage. PMID- 25735969 TI - Women with rigorously managed overt diabetes during pregnancy do not experience adverse infant outcomes but do remain at serious risk of postpartum diabetes. AB - We retrospectively detected overt diabetes during pregnancy (ODMP) using a modified IADPSG definition and assessed whether ODMP increases the risk of developing maternal and neonatal complications and postpartum diabetes in Korean pregnant women. According to the definition of IADPSG, ODMP pregnant women were defined and 71 ODMP, 1781 gestational diabetes mellitus (GDM) and and 463 non-GDM pregnant women were included in a hospital-based study. Their blood glucose levels were tightly regulated by modifying lifestyles and insulin treatment. The pregnancy outcomes and postpartum glucose tolerances were determined among the non-GDM, GDM and ODMP groups. The ODMP women had higher plasma glucose levels after overnight-fasting and at 2 h after 100 g OGTT challenge as well as higher overnight-fasted plasma insulin and HbA1c levels than GDM women. HbA1c levels at delivery were close to the normal range in both GDM and ODMP groups. Most pregnancy outcomes such as Apgar score and the rate of preterm delivery were not significantly different among three groups. Only the rate of large for gestational age (LGA) was greater in the ODMP group than other groups. However, about 73% of ODMP women remained diabetic at 6-8 week postpartum as compared to 4.3% of GDM. The development of postpartum diabetes was also associated with postpartum waist circumferences and duration of breast feeding. In conclusion, ODMP women in this study maintained tight control of glucose homeostasis and did not experience serious adverse outcomes except for LGA infants; however most ODMP women still had postpartum glucose dysregulation. PMID- 25735970 TI - Molecular and morphological characterization of Austrodiplostomum ostrowskiae Dronen, 2009 (Digenea: Diplostomatidae), a parasite of cormorants in the Americas. AB - The diplostomid genus Austrodiplostomum currently contains two species, i.e. A. mordax and A. ostrowskiae. Adults of these species inhabit the intestine of cormorants of the genus Nannopterum, whereas larval forms (metacercariae) are found in the eyes (vitreous humor) of freshwater fishes. Records of both species have been established across a wide geographic range in the Americas. Diplostomid adults and metacercariae were collected from a wide geographical range that spans from south-eastern Mexico, southwards to Central and South America. Even though the diplostomid has been largely reported in Mexico as Diplostomum (Austrodiplostomum) compactum, our specimens were identified morphologically as A. ostrowskiae. Sequences of the mitochondrial gene cytochrome c oxidase (cox 1) were obtained for 86 individuals, including 15 adults recovered from the intestine of Nannopterum brasilianus, in five localities, and 71 metacercariae from the eyes of ten fish species, in 13 localities. Sequences were used to evaluate the genetic diversity, and to test conspecificity of these specimens with the available sequence of A. ostrowskiae. Sequences were aligned with another 12 taxa representing five genera of Diplostomatidae, forming a dataset of 104 taxa with 478 nucleotides. The genetic divergence estimated among the 86 sequenced individuals, and that of A. ostrowskiae from the double-crested cormorant, Nannopterum auritus, in the USA, was very low, ranging from 0 to 0.8%. The maximum likelihood (ML) and Bayesian consensus trees showed that all sequences nested within a monophyletic lineage, with strong bootstrap and Bayesian posterior probability support values (100/1.0). In conclusion, a link between the metacercariae in fish and the adults in cormorants was established, indicating also that a single species is found in the distribution range comprising southern USA, southwards to Venezuela. Previous records of this species, particularly from Mexico, need to be corrected. PMID- 25735971 TI - The Organic Flatland-Recent Advances in Synthetic 2D Organic Layers. AB - Ultrathin, 2D organic layers of sub-ten nanometer thicknesses and high aspect ratios have received a great deal of attention for their graphene-like topological features and emerging properties. Rational synthetic strategies have led to the realization of periodic 2D layers with unprecedented structural precision. Herein, recent progress on the synthesis of 2D organic layers, including methods based on both non-covalent and covalent interactions, is summarized, and potential applications are highlighted. Such 2D organic nanostructures have a brilliant future as prospective multifunctional materials, showing great promise as platforms for engineering novel optoelectronic, interfacial, and bioactive properties. PMID- 25735972 TI - A microextraction procedure based on a task-specific ionic liquid for the separation and preconcentration of lead ions from red lipstick and pine leaves. AB - First, the extraction and preconcentration of ultratrace amounts of lead(II) ions was performed using microliter volumes of a task-specific ionic liquid. The remarkable properties of ionic liquids were added to the advantages of microextraction procedure. The ionic liquid used was trioctylmethylammonium thiosalicylate, which formed a lead thiolate complex due to the chelating effect of the ortho-positioned carboxylate relative to thiol functionality. So, trioctylmethylammonium thiosalicylate played the roles of both chelating agent and extraction solvent simultaneously. Hence, there is no need to use a ligand. The main parameters affecting the efficiency of the method were investigated and optimized. Under optimized conditions, this approach showed a linear range of 2.0 24.0 ng/mL with a detection limit of 0.0010 ng/mL. The proposed method was applied to the extraction and preconcentration of lead from red lipstick and pine leaves samples prior to electrothermal atomic absorption spectroscopic determination. PMID- 25735973 TI - Aminomethylation of enals through carbene and acid cooperative catalysis: concise access to beta(2)-amino acids. AB - A convergent, organocatalytic asymmetric aminomethylation of alpha,beta unsaturated aldehydes by N-heterocyclic carbene (NHC) and (in situ generated) Bronsted acid cooperative catalysis is disclosed. The catalytically generated conjugated acid from the base plays dual roles in promoting the formation of azolium enolate intermediate, formaldehyde-derived iminium ion (as an electrophilic reactant), and methanol (as a nucleophilic reactant). This redox neutral strategy is suitable for the scalable synthesis of enantiomerically enriched beta(2) -amino acids bearing various substituents. PMID- 25735974 TI - Cytotoxicity and transformation of C3H10T1/2 cells induced by areca nut components. AB - BACKGROUND/PURPOSE: Betel quid (BQ) chewing is popular in Taiwan and many other countries. There are about 200-600 million BQ chewers in the world. BQ chewing is one major risk factor of oral cancer and oral submucous fibrosis (OSF). While areca nut (AN), a main component of BQ, exhibits genotoxicity, its transformation capacity and its role in the initiation and promotion stages of carcinogenesis are not fully clear. METHODS: Mouse C3H10T1/2 cells were exposed to AN extract (ANE) for 24 hours. Cytotoxicity was evaluated by colony forming efficiency. For the transformation assay, C3H10T1/2 cells were exposed to ANE for 24 hours and then incubated in medium with/without 12-O-tetradecanolylphorbol-13-acetate (TPA; a tumor promoter) for 42 days. Cells were stained with Giemsa and type II and type III transformed foci were counted for analysis of the transformation capacity of ANE. RESULTS: ANE exhibited cytotoxicity to C3H10T/12 cells at concentrations higher than 320 MUg/mL as shown by a decrease in colony numbers. ANE (80-640 MUg/mL) alone mildly stimulated the transformed foci formation (p > 0.05). In the presence of TPA, ANE (80-640 MUg/mL) markedly stimulated the transformed foci formation. The percentage of dishes with foci increased from 0% in controls to 20% in ANE (80 MUg/mL and 320 MUg/mL)-treated groups and further increased to 65-94% in ANE plus TPA groups. CONCLUSION: These results indicate that ANE is a weak complete carcinogen. ANE is an effective tumor initiator and can induce malignant transformation of C3H10T1/2 cells in the presence of a tumor promoter. ANE may be involved in multistep chemical carcinogenesis by its malignant transformation capacity. PMID- 25735975 TI - Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin. AB - A close relationship between the bone and systemic glucose metabolism has recently been the center of attention, since the uncarboxylated form of osteocalcin (GluOC), a bone-derived protein, but not the gamma-carboxylated form, is involved in glucose metabolism. However, the analysis of GluOC effect using isolated organs and related cell lines are required to understand its roles in a whole systemic metabolic status. In the present study, we examined the effect of GluOC on cell lines derived from skeletal muscle to explore the mechanisms by which GluOC regulates glucose uptake. In the differentiated C2C12 myotubes, GluOC dose-dependently induced the phosphorylation of ERK without affecting intracellular cAMP and Ca(2+) levels. This effect was inhibited by U0126, an inhibitor of ERK kinase (MEK). Additionally, U73122, an inhibitor of phospholipase C tended to inhibit it as well. Furthermore, cell treatment with GluOC for a long period promoted insulin-induced Akt phosphorylation and glucose uptake in the myotubes, which was abolished by ERK signaling inhibition. These results indicate that GluOC does not triggered Akt phosphorylation and glucose uptake by itself but promotes insulin-induced glucose uptake in myotubes, probably by up-regulating Akt signaling through ERK activation. PMID- 25735976 TI - miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia. AB - MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR 664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR 664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. PMID- 25735977 TI - EML4-ALK induces epithelial-mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells. AB - The echinoderm microtubule-associated protein-like 4(EML4)--anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation. PMID- 25735978 TI - A PKM2 signature in the failing heart. AB - A salient feature of the failing heart is metabolic remodeling towards predominant glucose metabolism and activation of the fetal gene program. Sunitinib is a multitargeted receptor tyrosine kinase inhibitor used for the treatment of highly vascularized tumors. In diabetic patients, sunitinib significantly decreases blood glucose. However, a considerable proportion of sunitinib-treated patients develop cardiac dysfunction or failure. We asked whether sunitinib treatment results in shift towards glycolysis in the heart. Glucose uptake by the heart was increased fivefold in mice treated with sunitinib. Transcript analysis by qPCR revealed an induction of genes associated with glycolysis and reactivation of the fetal gene program. Additionally, we observed a shift in the enzyme pyruvate kinase from the adult M1 (PKM1) isoform to the fetal M2 (PKM2) isoform, a hallmark of the Warburg Effect. This novel observation led us to examine whether a similar shift occurs in human heart failure. Examination of tissue from patients with heart failure similarly displayed an induction of PKM2. Moreover, this phenomenon was partially reversed following mechanical unloading. We propose that pyruvate kinase isoform switching represents a novel feature of the fetal gene program in the failing heart. PMID- 25735979 TI - ROZA-XL, an improved FRET based biosensor with an increased dynamic range for visualizing zeta associated protein 70 kD (ZAP-70) tyrosine kinase activity in live T cells. AB - Genetically encoded FRET based biosensors allow one to visualize the spatial and temporal evolution of specific enzyme activities in live cells. We have previously reported the creation of a FRET based biosensor specific for Zeta Associated Protein -70 kD (ZAP-70) (Randriamampita et al., 2008), a Syk family protein tyrosine kinase. ZAP-70 is essential for early T cell receptor (TCR) signaling events, T lymphocyte development and has also been implicated in integrin mediated T lymphocyte migration. In order to facilitate the study of ZAP 70 kinase activity during dynamic phenomena such as immunological synapse formation or cell migration, we have designed and prepared a second generation of ZAP-70 specific biosensors. Here we describe a novel biosensor named ROZA-XL, that displays a 3-4 times greater dynamic range than its predecessor and possesses a robust baseline FRET value when expressed in the Jurkat human T cell line. We demonstrate that the robust behavior of this biosensor allows for rapid analysis of TCR mediated of ZAP-70 kinase activity at a single cell level, as shown in a simple end point assay in which ROZA-XL expressing cells are allowed to interact with stimulatory anti-CD3epsilon coated coverslips. PMID- 25735980 TI - A chemically defined culture medium containing Rho kinase inhibitor Y-27632 for the fabrication of stratified squamous epithelial cell grafts. AB - With the development of a culture method for stratified squamous epithelial cells, tissue-engineered epithelial cell sheets have been successfully applied as clinical cell grafts. However, the implementation of these cell sheets without the use of any animal-derived materials is highly desirable. In this study, Rho associated protein kinase inhibitor Y-27632 was used to develop a chemically defined culture medium for the fabrication of stratified epithelial cell grafts consisting of human epidermal and oral keratinocytes, and the proliferation activity, cell morphology, and gene expressions of the keratinocytes were analyzed. The results of a colorimetric assay indicated that Y-27632 significantly promoted the proliferation of the keratinocytes in culture media both with and without fetal bovine serum (FBS), although there were no indications of Y-27632 efficacy on cell morphology and stratification of the keratinocytes in culture medium without any animal-derived materials. The results of quantitative RT-PCR revealed that gene expressions correlated with cell adhesion, cell-cell junction, proliferation markers, and stem/progenitor markers in cultured keratinocytes were not strongly affected by the addition of Y-27632 to the culture medium. Moreover, gene expressions of differentiation markers in stratified keratinocytes cultured in medium without FBS were nearly identical to those of keratinocytes co-cultured with 3T3 feeder cells. Interestingly, the expressions of differentiation markers in cultured stratified keratinocytes were suppressed by FBS, whereas they were reconstructed by either co-culture of a 3T3 feeder layer or addition of Y-27632 into the culture medium containing FBS. These findings indicate that Y-27632 is a useful supplement for the development of a chemically defined culture medium for fabrication of stratified epithelial cell grafts for clinical applications for the purpose of developing the culture medium with a lower risk of pathogen transmission that might arise from animal-derived materials. PMID- 25735981 TI - Thr160 of Axin1 is critical for the formation and function of the beta-catenin destruction complex. AB - Upon binding of a Wnt ligand to the frizzled (FZD)-low density lipoprotein receptor related protein 5/6 (LRP5/6) receptor complex, the beta-catenin destruction complex, composed of Axin1, adenomatous polyposis coli (APC), glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1), is immediately inactivated, which causes beta-catenin stabilization. However, the molecular mechanism of signal transduction from the receptor complex to the beta-catenin destruction complex is controversial. Here we show that Wnt3a treatment promotes the dissociation of the Axin1-APC complex in glioblastoma cells cultured in serum free medium. Experiments with the GSK3 inhibitor BIO suggest that Axin1-APC dissociation was controlled by phosphorylation. Introduction of a phosphomimetic mutation into Thr160 of Axin1, located in the APC-binding region RGS, abrogated the interaction of Axin1 with APC. Consistent with these observations, the Axin1 phosphomimetic mutant lost the ability to reduce beta-catenin stability and to repress beta-catenin/TCF-dependent transcription. Taken together, our results suggest a novel mechanism of Wnt signaling through the dissociation of the beta catenin destruction complex by Axin1 Thr160 modification. PMID- 25735982 TI - Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen. AB - This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, Fv/Fm, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H2O2 production and greater increases in H2O2-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage. PMID- 25735983 TI - Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance. AB - Although previous studies attributed a pro-survival role to USP9X in human cancer, how USP9X affects B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. Here, we found that USP9X is overexpressed in B-ALL cell lines and human patients. We investigated the role of USP9X in B-ALL and found that USP9X knockdown significantly reduced leukemic cell growth and increased spontaneous apoptosis, thereby improving survival in immunodeficient mice. These effects are partially mediated by the intrinsic apoptotic pathway, as we found that USP9X knockdown leukemic cells displayed MCL1 down-regulation, with decreased BCL-2/BCL XL levels and increased BAX levels. In addition, we demonstrated that USP9X inhibition negatively regulates mTORC1 activity toward its substrate S6K1. Clinically, USP9X inhibition sensitized glucocorticoid-resistant ALL cells to prednisolone; this observation reveals a potential avenue for improving the treatment of drug-resistant relapses. Collectively, our findings suggest that the combination of USP9X targeting and glucocorticoids treatment has attractive utility in B-ALL. This approach represents a potential strategy for promising combination therapies for lymphoid malignancies. PMID- 25735984 TI - Cross talk between Leishmania donovani CpG DNA and Toll-like receptor 9: an immunoinformatics approach. AB - The precise and potential contribution of Toll-like receptors (TLRs) signaling pathways in fighting parasitic infections of Leishmania spp., an intracellular protozoan parasite, has gained significant attention during the last decades. Although it is well established that TLR9 recognizes CpG motifs in microbial genomes, the specificity of the CpG DNA pattern of Leishmania parasite interacting with endosomal TLR9 is still unknown. Hence in our study to identify the CpG DNA pattern of Leishmania donovani acting as ligand for TLR9, consecutive homology searches were performed using known CpG ODN 2216 as initial template until a consistent CpG pattern in L. donovani was found. A reliable model of TLR9 ectodomains (ECDs) as well as CpG DNA patterns was predicted to develop the 3D structural complexes of TLR9 ECD-CpG DNA utilizing molecular modeling and docking approaches. The results revealed the preferential specificity of L. donovani CpG DNA to TLR9 compared to control ODN and other CpG patterns. The interface between TLR9 and L. donovani CpG DNA was also found to be geometrically complementary with the LRR11 region of TLR9, acting as the critical region for ligand recognition. The L. donovani CpG pattern identified can be employed to derive a platform for development of an innate immunomodulatory agent for deadly disease. PMID- 25735985 TI - Hyperbaric oxygen therapy attenuates central sensitization induced by a thermal injury in humans. AB - BACKGROUND: Hyperbaric oxygen (HBO2 ) treatment has in animal experiments demonstrated antinociceptive effects. It was hypothesized that these effects would attenuate secondary hyperalgesia areas (SHAs), an expression of central sensitization, after a first-degree thermal injury in humans. METHODS: Seventeen healthy volunteers were examined during two sessions using a randomized crossover design. Volunteers were studied during control conditions (ambient pressure, FI O2 = 0.21) and during HBO2 (2.4 standard atmosphere, FI O2 = 1.0, 90 min) conditions in a pressure chamber. Quantitative sensory testing, including assessment of SHAs was performed. RESULTS: A statistically significant overall attenuation of SHAs was seen during the HBO2 sessions compared with the control sessions (P = 0.011). In the eight volunteers starting with the HBO2 session, no difference in SHAs compared with control was demonstrated. However, in the nine volunteers starting with the control session, a statistical significant attenuation of SHAs was demonstrated in the HBO2 session (P = 0.004). CONCLUSIONS: The results indicate that HBO2 therapy in humans attenuates central sensitization induced by a thermal skin injury, compared with control. These new and original findings in humans corroborate animal experimental data. The thermal injury model may give impetus to future human neurophysiological studies exploring the central effects of hyperbaric oxygen treatment. PMID- 25735986 TI - Inhibition of neuroinflammation by synthetic androstene derivatives incorporating amino acid methyl esters on activated BV-2 microglia. AB - Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS) activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13 dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-kappaB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases. PMID- 25735987 TI - Long term follow-up in a patient with a de novo microdeletion of 14q11.2 involving CHD8. AB - We identified a de novo deletion of 14q11.2 in a Czech patient with developmental delay, mild autistic features, macrosomy, macrocephaly, orthognathic deformities, and dysmorphic facial features. The clinical follow-up of the patient lasting 14 years documented changes in the facial dysmorphism from infancy to adolescence. The deletion affects approximately 200 kb of DNA with five protein-coding genes and two snoRNA genes. Two of the protein-coding genes, SUPT16H and CHD8, have been proposed as candidate genes for a new microdeletion syndrome. Our patient further supports the existence of this syndrome and extends its phenotypic spectrum, especially points to the possibility that orthognathic deformities may be associated with microdeletions of 14q11.2. CHD8 mutations have been found in patients with neurodevelopmental disorders and macrocephaly. The HNRNPC gene, repeatedly deleted in patients with developmental delay, is another candidate as its 5 end is adjacent to the deletion, and the expression of this gene may be affected by position effect. PMID- 25735988 TI - Pelvic floor muscle function in women with provoked vestibulodynia and asymptomatic controls. AB - INTRODUCTION AND HYPOTHESIS: The purpose of the present study was to assess vaginal resting pressure (VRP), pelvic floor muscle (PFM) strength and endurance, and surface EMG activity in women with and without provoked vestibulodynia (PVD). METHODS: This was an assessor-masked comparison study including 70 women. Exclusion criteria were any previous pregnancy and presence of candida. Sensitivity of the vulvar vestibule was rated at three sites with Q-tip pressure measurement and a numerical rating scale for pain. VRP and PFM strength and endurance were measured with a high precision pressure transducer connected to a vaginal balloon. Pelvic floor muscle activity was measured with surface EMG. The independent samples t test was used to analyze differences between groups. The p value was set to <0.05 RESULTS: The mean age of the participants was 24.3 years (SD 4.7) and mean body mass index (BMI) was 22.0 kg/m(2) (SD 2.6). Q-tip pressure measurement was significantly lower and pain more severe in the PVD group at all sites of the vulvar vestibule. The PVD group had significantly higher VRP: 20.6 cmH2O (SD 7.1) versus controls: 17.3 cmH2O (SD 4.4), p = 0.02. The PVD group had significantly lower muscle activity during a 10-s holding period; PVD: 465.2 MUV (SD 218.4), controls: 591.1 MUV (SD 277.7), p = 0.04. CONCLUSION: Young, nulliparous women with PVD had significantly higher VRP, but this finding was not confirmed by vaginal surface EMG. PMID- 25735989 TI - GHB for cataplexy: Possible mode of action. AB - The sleep disorder narcolepsy is caused by the loss of orexinergic neurones in the lateral hypothalamus. A troublesome symptom of narcolepsy is cataplexy, the sudden loss of muscle tone in response to strong emotions. It can be alleviated by antidepressants and sodium oxybate (gamma-hydroxybutyric acid (GHB)). It is likely that the noradrenergic nucleus locus coeruleus (LC) is involved since it is essential for the maintenance of muscle tone, and ceases to fire during cataplectic attacks. Furthermore, alpha-2 adrenoceptors proliferate in the LC in cataplexy, probably due to 'heterologous denervation supersensitivity' resulting from the loss/weakening of the orexinergic input to the LC. This would lead to the sensitization of the autoinhibition mechanism of LC neurones mediated by inhibitory alpha-2 adrenoceptors ('autoreceptors'). Thus the excitatory input from the amygdala to the LC, activated by an emotional stimulus, would lead to the 'switching off' of LC activity via the supersensitive auto-inhibition mechanism. GHB is an agonist at both gamma-aminobutyric acid (GABA) GABA (B) and GHB receptors that may be a subtype of an extrasynaptic GABA(A) receptor. GHB may prevent a cataplectic attack by dampening the tone of LC neurones via the stimulation of inhibitory extrasynaptic GABA receptors in the LC, and thus increasing the threshold for autoinhibition. PMID- 25735990 TI - Effects of 10 to 30 years of lithium treatment on kidney function. AB - Long-term lithium treatment is associated with end-stage renal disease, but there is little evidence of a clinically significant reduction in renal function in most patients. We previously found that 1.5% of people who took lithium from the 1960s and 1970s developed end-stage renal disease; however, none of the patients who started after 1980 had end-stage renal disease. Here we aimed to study the prevalence and extent of kidney damage during the course of long-term lithium treatment since 1980. We retrieved serum lithium and creatinine levels from 4879 patients examined between 1 January 1981 and 31 December 2010. Only patients who started their lithium treatment during the study period and had at least 10 years of cumulative treatment were included. The study group comprised 630 adult patients (402 women and 228 men) with normal creatinine levels at the start of lithium treatment. There was a yearly increase in median serum creatinine levels already from the first year of treatment. About one-third of the patients who had taken lithium for 10-29 years had evidence of chronic renal failure but only 5% were in the severe or very severe category. The results indicate that a substantial proportion of adult patients who are treated with lithium for more than a decade develop signs of renal functional impairment, also when treated according to modern therapeutic principles. Our results emphasise that lithium treatment requires continuous monitoring of kidney function. PMID- 25735991 TI - Learning ability is a key outcome determinant of GSK-3 inhibition on visuospatial memory in rats. AB - Learning aptitude has never been a focus of visuospatial performance studies, particularly on memory consolidation and reconsolidation. The aim of this study was to determine the consequences of learning ability on memory consolidation/reconsolidation following inhibition of glucose synthase kinase-3 (GSK-3) by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The anxiety-like nature of rats was characterized in the elevated plus maze. The rats were then trained for four days in the Morris water maze (MWM) and classified as 'superior', 'intermediate' or 'inferior' learners. There were no major differences between superior, intermediate or inferior learners with respect to anxiety which might have influenced learning. After training (day-5), TDZD-8 (2.0 mg/kg) was administered and half of the cohort were exposed to a MWM retrieval trial. Ten days later, animals were subjected to repeated MWM learning. TDZD-8 without a retrieval trial impaired subsequent reconsolidation in inferior learners, but enhanced it in superior learners. There was no modification of performance in intermediate learners. In TDZD-8-treated subjects exposed to retrieval, the pattern of outcomes was identical whereby impairment of reconsolidation occurred in inferior learners, enhancement occurred in superior learners but there was no modification of performance in intermediate learners. Thus, learning ability was a key determinant of the qualitative outcome from GSK 3 inhibition on visuospatial memory. PMID- 25735992 TI - Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies. AB - Metabotropic glutamate receptor-2 positive allosteric modulator, JNJ-40411813 (ADX71149), was characterised for clinical effects in healthy volunteers in two phase-1 studies. In study 1, healthy men received 50-, 100-, 150- or 225 mg and women received 100 mg JNJ-40411813 (n=6, each cohort) or placebo (n=2, each cohort) twice daily for seven days; smoking men (n=30) received placebo twice daily on days 1-7, 100 mg JNJ-40411813 (n=20) or placebo (n=10) on days 8-14. In study 2, healthy men received intravenous 0.005 mg/kg S(+) ketamine over 60 min at 3 (n=24; cohort 1), 12 h (n=8; cohort 3), and 24 h (n=8; cohort 2) after a single oral dose of 500 mg JNJ-40411813 or placebo. The pharmacokinetics and effects of JNJ-40411813 on cognition and subjective awareness were evaluated. Plasma JNJ-40411813 exposure was dose-dependent, t max ranged from 3-4 h and t 1/2 19.4-34.2 h across the dose levels. JNJ-40411813 significantly (p=0.02) reduced continuity of attention score (150 mg dose) and ameliorated smoking withdrawal-induced changes in power of attention and quality of episodic memory versus placebo. A modest reduction in alertness was observed at 150-225 mg doses, JNJ-40411813 (500 mg) reduced S(+) ketamine-induced negative symptoms by approximately 43% and 30% in cohorts 1 and 3, respectively. JNJ-40411813 was generally well-tolerated. PMID- 25735993 TI - Prosocial effects of MDMA: A measure of generosity. AB - BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA) produces "prosocial" effects that contribute to its recreational use. Few studies have examined the cognitive and behavioral mechanisms by which MDMA produces these effects. Here we examined the effect of MDMA on a specific prosocial effect, i.e. generosity, using a task in which participants make decisions about whether they or another person will receive money (Welfare Trade-Off Task; WTT). METHODS: The project included one study without drug administration and one with MDMA. In Study 1, we administered the WTT to healthy adults (N = 361) and examined their performance in relation to measures of personality and socioeconomic status. In Study 2, healthy volunteers with MDMA experience (N = 32) completed the WTT after MDMA administration (0, 0.5, or 1.0 mg/kg). RESULTS: As expected, in both studies participants were more generous with a close friend than an acquaintance or stranger. In Study 1, WTT generosity was related to household income and trait Agreeableness. In Study 2, MDMA (1.0 mg/kg) increased generosity toward a friend but not a stranger, whereas MDMA (0.5 mg/kg) slightly increased generosity toward a stranger, especially among female participants. CONCLUSIONS: These data indicate that the WTT is a valuable, novel tool to assess a component of prosocial behavior, i.e. generosity to others. The findings support growing evidence that MDMA produces prosocial effects, but, as with oxytocin, these appear to depend on the social proximity of the relationships. The brain mechanisms underlying the construct of generosity, or the effects of MDMA on this measure, remain to be determined. PMID- 25735994 TI - Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain. AB - The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5 HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5 chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6 chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY 181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression. PMID- 25735995 TI - Dopamine supersensitivity psychosis and dopamine partial agonist: a retrospective survey of failure of switching to aripiprazole in schizophrenia. AB - The administration of aripiprazole (ARI), a dopamine partial agonist, could provoke abrupt psychotic worsening in patients with schizophrenia. We explored the relationship between this psychotic worsening and dopamine supersensitivity psychosis (DSP), which is a clinically vulnerable state. We conducted a retrospective investigation for 264 patients whose treatment medication was switched to ARI from other antipsychotics. We divided the patients into the DSP(+) group with a history of DSP episode(s) (N = 70) and the DSP(-) group without such a history (N = 194), and then compared the clinical factors relevant to the success or failure of the switch to ARI between them. The results revealed that patients in the DSP(+) group experienced psychotic worsening following the switch to ARI with a significant higher rate compared to the DSP(-) group (23% vs. 8%, P < 0.01). Moreover, the dosages of the drugs before the ARI introduction in the patients experiencing the psychotic worsening in the DSP (-) group were higher than those in other patients of the group. Our findings suggest that patients who receive high dosages of antipsychotic drugs form overt or covert DSP and such state is highly associated with psychotic worsening following ARI treatment. PMID- 25735996 TI - Do Arctic breeding geese track or overtake a green wave during spring migration? AB - Geese breeding in the Arctic have to do so in a short time-window while having sufficient body reserves. Hence, arrival time and body condition upon arrival largely influence breeding success. The green wave hypothesis posits that geese track a successively delayed spring flush of plant development on the way to their breeding sites. The green wave has been interpreted as representing either the onset of spring or the peak in nutrient biomass. However, geese tend to adopt a partial capital breeding strategy and might overtake the green wave to accomplish a timely arrival on the breeding site. To test the green wave hypothesis, we link the satellite-derived onset of spring and peak in nutrient biomass with the stopover schedule of individual Barnacle Geese. We find that geese track neither the onset of spring nor the peak in nutrient biomass. Rather, they arrive at the southernmost stopover site around the peak in nutrient biomass, and gradually overtake the green wave to match their arrival at the breeding site with the local onset of spring, thereby ensuring gosling benefit from the peak in nutrient biomass. Our approach for estimating plant development stages is critical in testing the migration strategies of migratory herbivores. PMID- 25735997 TI - Absolute configuration of remisporines A & B. AB - The absolute configuration of remisporine B was determined based on a comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Density functional theory (DFT) was used to calculate the ECD spectra varying the parameter controlling the number of calculated electronic transitions. Mapping the reaction surface provided support for the proposed Diels-Alder dimerization of remisporine A to form remisporine B. PMID- 25735998 TI - TNF-alpha G308A polymorphism and the susceptibility to Alzheimer's disease: an updated meta-analysis. AB - BACKGROUND AND AIMS: Tumor necrosis factor (TNF)-alpha G308A polymorphism has been reported in the association with susceptibility to Alzheimer's disease (AD); however, results have been contradictory. We conducted an updated meta-analysis to evaluate the role of TNF-alpha G308A in the occurrence of AD. METHODS: Relevant articles were retrieved from online databases. The combined odds ratio, odds ratio in different genetic models, and the related 95% confidence intervals were calculated. Publication bias and homogeneity among individual studies were estimated. Subgroup analyses and sensitivity analyses were also performed. RESULTS: In overall analyses, no risk of AD was associated with TNF-alpha G308A under different genetic models. However, in the subgroup analyses, a significant association between TNF-alpha G308A and AD risk was observed in Chinese. In addition, a significant protective effect of TNF-alpha -308A was found in the occurrence of AD among North European populations under a dominant model. CONCLUSIONS: The result of this meta-analysis suggests that TNF-alpha G308A polymorphism may be associated with the increased risk of AD in Chinese and decreased risk of AD in northern European populations. PMID- 25736000 TI - Putting precision medicine on the national agenda. PMID- 25735999 TI - Developing consensus criteria for sarcopenia: an update. AB - Sarcopenia, the age-related loss of muscle mass and strength, is a major cause of impaired physical function, which contributes to mobility disability, falls and hospitalizations in older adults. Lower muscle mass and strength are also associated with lower bone mineral density and greater risk for osteoporotic fractures. Thus, identification of sarcopenia could be important for fracture prevention as it may help improve fracture risk assessment, and muscle mass and strength can be improved with exercise, even among the frailest older adults. Unfortunately, there are no consensus diagnostic criteria for sarcopenia. Consequently there is no guidance to help clinicians identify older adults with clinically meaningful low muscle mass or weakness. Further, development of novel sarcopenia therapies is hindered not only due to the difficulty in identifying participants for clinical trials, and but also because there are no validated, clinically appropriate endpoints for assessment of treatment efficacy. There is currently a major push to establish a consensus definition of sarcopenia, and recent work holds promise that this goal may be within reach. This article discusses the evolution of the definition of sarcopenia, and focuses on the latest recommended diagnostic criteria proposed by the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. While these empirically based cut-points for clinically important low muscle mass and weakness are a significant step forward for the sarcopenia field, important questions remain to be answered before consensus diagnostic criteria can be definitively established. Ongoing work to refine sarcopenia criteria will further advance the field and bring this important contributor to falls, fractures and disability into the mainstream of clinical care and ultimately lead to better quality of life with aging. PMID- 25736001 TI - Evaluating the potential role of PET/CT in the posttreatment surveillance of head and neck cancer. PMID- 25736002 TI - NCCN: evolution in the early years. PMID- 25736004 TI - Leukemic diffuse large B-cell lymphoma in a patient with myeloproliferative disorder. AB - Essential thrombocythemia is well-known to transform to other myeloid disorders, such as leukemia; however, the risk for development of lymphoma is not as well studied. This case report discusses a 76-year-old man with a history of prefibrotic post-essential thrombocythemia myelofibrosis on ruxolitinib, who developed anemia, thrombocytopenia, and leukocytosis with peripheral blasts. Results of a bone marrow biopsy and PET and CT scans revealed stage IV leukemic diffuse large B-cell lymphoma. Several days after cessation of ruxolitinib, the patient developed fevers, hypotension, and low-grade disseminated intravascular coagulation, and subsequently developed spontaneous tumor lysis syndrome, which resulted in death. This case is unique in several aspects: it highlights the rare possibility of lymphomatous transformation of myeloproliferative disorders, an unusual presentation of lymphoma masquerading as leukemia, and the possibility of ruxolitinib withdrawal syndrome. Additionally, this case serves as a reminder that the use of novel therapies should be adopted after a thorough assessment of long-term risks, including those associated with abrupt withdrawal. PMID- 25736003 TI - Myelodysplastic syndromes, version 2.2015. AB - The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care. PMID- 25736005 TI - Abiraterone in metastatic salivary duct carcinoma. AB - Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy with limited evidence guiding standard treatment. SDC is known to overexpress the androgen receptor, with only a handful of cases reporting responses to androgen blockade. This report presents a case of SDC responding to multiple lines of androgen blockade, including a rapid response to abiraterone, a CYP17 inhibitor effective in prostate cancer. This case represents the first published report of SDC responding to abiraterone and illustrates that androgen receptor expressing SDC may be treated with multiple lines of androgen blockade, including newer agents such as abiraterone. This case suggests that SDC may continue to be androgen-dependent after progression on androgen deprivation, which is analogous to prostate cancer. PMID- 25736006 TI - Health behaviors and quality of life among colorectal cancer survivors. AB - PURPOSE: To examine, at the population level, health behaviors, comorbidities, and health-related quality of life among colorectal cancer (CRC) survivors compared with other cancer survivors and persons without cancer. METHODS: We used data from the 2009 and 2010 Behavioral Risk Factor Surveillance System cancer survivor modules. We calculated descriptive statistics, conducted chi-square tests for comparisons, and used multivariable logistic regression analysis to compare CRC survivors with other cancer survivors and persons without cancer. RESULTS: Of the 52,788 cancer survivors included in this analysis, 4001 reported being CRC survivors. When compared with other cancer survivors, CRC survivors reported higher percentages of obesity and lack of physical activity; however, they had lower levels of current smoking. Adjusted results show that CRC survivors were significantly more likely to report lack of physical activity, fair/poor health, and other chronic health conditions compared with persons without a cancer diagnosis. Conversely, CRC survivors reported lower levels of current smoking than persons without cancer. CONCLUSIONS: CRC survivors have a higher proportion of heath conditions and behaviors that may significantly increase their risks for recurrence or development of a second cancer. Targeted interventions to address these health issues should be considered. PMID- 25736007 TI - Association between urologist characteristics and radiation oncologist consultation for patients with locoregional prostate cancer. AB - BACKGROUND: Physicians managing patients with prostate cancer play a critical role in subsequent specialist consultations and initial treatment choice, especially in cases for which no consensus exists regarding optimal treatment strategy. The NCCN Guidelines for Prostate Cancer recommend radiation as a therapy option for patients with locoregional prostate cancer. PURPOSE: The authors examined the association of urologist characteristics with the likelihood that patients would consult radiation oncologists. METHODS: A retrospective cohort of 39,934 patients aged 66 years or older who were diagnosed with locoregional prostate cancer between 2004 and 2007, and the 2405 urologists who performed the patient diagnostic biopsies were constructed using the SEER Medicare linked database and the American Medical Association Physician Masterfile. Logistic multilevel regression analysis was used to evaluate the influence of urologists' characteristics on radiation oncologist consultation within 9 months of locoregional prostate cancer diagnosis. RESULTS: Overall, 24,549 (61.5%) patients consulted a radiation oncologist. After adjusting for patient and urologist characteristics, patients diagnosed by urologists in noninstitutional settings (eg, physician office) were significantly more likely to consult a radiation oncologist (odds ratio [OR], 1.40; 95% CI, 1.17-1.67; P=.0002) compared with those diagnosed by urologists in institutional settings with a major medical school affiliation. In addition, patients diagnosed by urologists older than 57 years were significantly more likely to consult a radiation oncologist (OR, 1.21; 95% CI, 1.07-1.38, P=.003). PMID- 25736008 TI - Challenges of coverage policy development for next-generation tumor sequencing panels: experts and payers weigh in. AB - BACKGROUND: Next-generation tumor sequencing (NGTS) panels, which include multiple established and novel targets across cancers, are emerging in oncology practice, but lack formal positive coverage by US payers. Lack of coverage may impact access and adoption. This study identified challenges of NGTS coverage by private payers. METHODS: We conducted semi-structured interviews with 14 NGTS experts on potential NGTS benefits, and with 10 major payers, representing more than 125,000,000 enrollees, on NGTS coverage considerations. We used the framework approach of qualitative research for study design and thematic analyses and simple frequencies to further describe findings. RESULTS: All interviewed payers see potential NGTS benefits, but all noted challenges to formal coverage: 80% state that inherent features of NGTS do not fit the medical necessity definition required for coverage, 70% view NGTS as a bundle of targets versus comprehensive tumor characterization and may evaluate each target individually, and 70% express skepticism regarding new evidence methods proposed for NGTS. Fifty percent of payers expressed sufficient concerns about NGTS adoption and implementation that will preclude their ability to issue positive coverage policies. CONCLUSIONS: Payers perceive that NGTS holds significant promise but, in its current form, poses disruptive challenges to coverage policy frameworks. Proactive multidisciplinary efforts to define the direction for NGTS development, evidence generation, and incorporation into coverage policy are necessary to realize its promise and provide patient access. This study contributes to current literature, as possibly the first study to directly interview US payers on NGTS coverage and reimbursement. PMID- 25736009 TI - Compliance with gastric cancer guidelines is associated with improved outcomes. AB - BACKGROUND: Limited data are available on the implementation and effectiveness of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer. PURPOSE: We sought to assess rates of compliance with NCCN Guidelines, specifically stage-specific therapy during the initial episode of care, and to determine its impact on outcomes. METHODS: The California Cancer Registry was used to identify cases of gastric cancer from 2001 to 2006. Logistic regression and Cox proportional hazard models were used to predict guideline compliance and the adjusted hazard ratio for mortality. Patients with TNM staging or summary stage (SS) were also analyzed separately. RESULTS: Compliance with NCCN Guidelines occurred in just 45.5% of patients overall. Patients older than 55 years were less likely to receive guideline-compliant care, and compliance was associated with a median survival of 20 versus 7 months for noncompliant care (P<.001). Compliant care was also associated with a 55% decreased hazard of mortality (P<.001). Further analysis revealed that 50% of patients had complete TNM staging versus an SS, and TNM-staged patients were more likely to receive compliant care (odds ratio, 1.59; P<.001). TNM-staged patients receiving compliant care had a median survival of 25.3 months compared with 15.1 months for compliant SS patients. CONCLUSIONS: Compliance with NCCN Guidelines and stage specific therapy at presentation for the treatment of patients with gastric cancer was poor, which was a significant finding given that compliant care was associated with a 55% reduction in the hazard of death. Additionally, patients with TNM-staged cancer were more likely to receive compliant care, perhaps a result of having received more intensive therapy. Combined with the improved survival among compliant TNM-staged patients, these differences have meaningful implications for health services research. PMID- 25736011 TI - Is observation dead in follicular lymphoma? No, but the apoptosis pathway has been activated. AB - Follicular lymphoma (FL), the most common indolent type of non-Hodgkin's lymphoma, presents with a highly variable clinical course and affects the overall survival (OS) of patients. Although observation has been adopted widely by clinicians in the management of patients with FL, the benefits of early treatment must be reviewed in light of the significant progress made in the treatment of symptomatic or higher-tumor-burden FL. When treatment is indicated, a variety of combination chemotherapeutic regimens have proven efficacy and have shown improvements in both progression-free and event-free survival, and the addition of rituximab to these regimens has shown a statistically significant improvement in OS. Additionally, single-agent rituximab has been added to the possible therapeutic options for patients with low-tumor-burden FL. Although a paucity of clinical data exists on the upfront treatment of the low-tumor-burden population, the question of whether early treatment, especially with the newer rituximab containing chemotherapy regimens, would improve OS is thought-provoking. Furthermore, novel targeted therapies with tolerable side effect profiles are rapidly advancing in the treatment of non-Hodgkin's lymphoma. The future for patients with low-tumor-burden FL is brighter than ever before. PMID- 25736012 TI - Is observation dead in follicular lymphoma? Still appropriate. AB - Given the incurable yet indolent nature of follicular lymphoma (FL) and the lack of a survival benefit seen with the early treatment of patients with a low tumor burden, watchful waiting has been the predominant strategy for treating asymptomatic patients with newly diagnosed FL for more than 2 decades. The success and tolerability of rituximab for the treatment of this disease, however, has led to challenges for this treatment paradigm and the consideration of early upfront treatment with rituximab monotherapy, with or without rituximab maintenance. These strategies have resulted in improvements in quality of life with a low incidence of toxicity and have led some to practice changes. However, based on uncertainty about how early treatment affects response to second treatment, the differential cost of treatment, and the lack of a survival benefit, observation remains an appropriate and viable strategy for select patients. PMID- 25736010 TI - Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. AB - Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL. PMID- 25736013 TI - Mimicking MacGyver in the oncology clinic: improvisation and creative solutions, only rarely involving duct tape. PMID- 25736014 TI - CMS oncology care model names NCCN guidelines as high-quality care and evidence based recommendations. PMID- 25736015 TI - Prevention of enzymatic browning of Chinese yam (Dioscorea spp.) using electrolyzed oxidizing water. AB - In this study, the effects of electrolyzed oxidizing water (EOW) on the prevention of enzymatic browning of fresh-cut "Jiu Jinhuang" Chinese yam were investigated. The yams were immersed in the inhibitors for 25 min at 20 degrees C. Compared with the tap water (TW) treatment, the chromatic attributes were significantly different after 72 h of storage (P < 0.05). The activities of polyphenol oxidase (PPO, EC 1.10.3.1), peroxidase (POD, EC 1.11.1.7), and L phenylalanine ammonia lyase (PAL, EC 4.3.1.5) were inhibited when measured at 24 h. The contents of phenolic acids, including gallic and chlorogenic acid, in the group treated with the slightly acidic electrolyzed water (SAEW) were higher than those treated with TW and neutral electrolyzed water (NEW). The group treated with NEW had the highest total phenol content (P < 0.05, at 24 h), while the group treated with SAEW had the highest flavonoid content (P < 0.05) during storage. Without being treated with inhibitors, the Km and Vmax values of yam PPO were 0.0044 mol/L and 0.02627 U/min, respectively, and the Ki of samples treated with SAEW and citric acid (CA) were 15.6607 and 2.3969 MUmol/L, respectively. These results indicate that EOW is beneficial as a browning inhibitor. PMID- 25736016 TI - Recurrent micronucleation through cell cycle progression in the presence of microtubule inhibitors. AB - Although most cell lines undergo mitotic arrest after prolonged exposure to microtubule inhibitors, some cells subsequently exit this state and become tetraploid. Among these cells, limited numbers of rodent cells are known to undergo multinucleation to generate multiple small independent nuclei, or micronuclei by prolonged colcemid treatment. Micronuclei are thought to be formed when cells shift to a pseudo G1 phase, during which the onset of chromosomal decondensation allows individual chromosomes distributed throughout the cell to serve as sites for the reassembly of nuclear membranes. To better define this process, we used long-term live cell imaging to observe micronucleation induced in mouse A9 cells by treating with the microtubule inhibitor colcemid. Our observations confirm that nuclear envelope formation occurs when mitotic-arrested cells shift to a pseudo G1 phase and adopt a tetraploid state, accompanied by chromosome decondensation. Unexpectedly, only a small number of cells containing large micronuclei were formed. We found that tetraploid micronucleated cells proceeded through an additional cell cycle, shifting to a pseudo G1 phase and forming octoploid micronucleated cells that were smaller and more numerous compared with the tetraploid micronucleated cells. Our data suggest that micronucleation occur when cells shift from mitotic arrest to a pseudo G1 phase, and demonstrate that, rather than being a single event, micronucleation is an inducible recurrent process that leads to the formation of progressively smaller and more numerous micronuclei. PMID- 25736017 TI - MR imaging differentiation of malignant soft tissue tumors from peripheral schwannomas with large size and heterogeneous signal intensity. AB - OBJECTIVE: To determine the value of MR imaging features at and near the margin of the tumor in differentiating peripheral schwannomas with large size (maximum diameter >5 cm) and heterogeneous appearance from malignant soft tissue tumors (MSTTs). MATERIALS AND METHODS: We retrospectively reviewed MR images of 25 MSTTs and 15 peripheral schwannomas with heterogeneous appearance on MR imaging and maximum diameter ranged from 5 cm to 11 cm. The soft tissue masses were evaluated for split fat sign, bright rim sign, lobular shape (with two or more deep lobulations), peritumoral edema, and capsule. The Fisher's exact test was used to determine whether these imaging features differed significantly between schwannomas and MSTTs. A nonparametric Mann-Whitney test was used to compare the maximal extent of peritumoral edema of schwannomas and MSTTs. The optimal cutoff value of the maximal extent of peritumoral edema was calculated by means of receiver operating characteristic analysis for distinguishing between schwannomas and MSTTs. Interobserver agreement in the assessment of imaging features was evaluated using Cohen kappa statistic and percentage agreement. RESULTS: The split fat sign, bright rim sign were more common in schwannomas than in MSTTs (P<0.001). The incidence of lobular shape was higher for MSTTs than for schwannomas (P<0.001). The peritumoral edema was present more frequently in MSTTs than in schwannomas (P=0.001). The median (interquartile range) of the maximal peritumoral edema extent was 13 mm (9.5-17 mm) for schwannomas and 46 mm (24-75.5 mm) for MSTTs, respectively (P<0.001). The optimal cutoff value of the maximal peritumoral edema extent calculated to distinguish MSTTs from schwannomas was 18 mm, which had 100% sensitivity, 89% specificity and Youden index 0.89. The frequency of the presence of capsule was not statistically significant between schwannomas and MSTTs (P=0.107). Interobserver agreement as determined by Cohen kappa statistic for the imaging features evaluated in the study was substantial to almost perfect (kappa=0.694-0.942), with percentage agreements ranging 85 97.5%. CONCLUSION: Large schwannomas with heterogeneous appearance on MR imaging can be distinguished from MSTTs by analyzing the imaging features at and near the margin of the mass. The presence of split fat sign and bright rim sign, and the absence of lobular shape and extensive edema (edema with maximal extent larger than 18 mm) favor the diagnosis of schwannoma, especially when two or more of this imaging features coexist. PMID- 25736018 TI - Symmetry classification of electron and phonon states in TiO2 -based nanowires and nanotubes. AB - Procedure for deriving Wyckoff positions for nanowires (NWs) and nanotubes (NTs) from Wyckoff positions of ambient space group is described. It is proposed how to use SITESYM code available on Bilbao Crystallographic Server to calculate representations induced from orbit stabilizers for 1-periodic groups. This procedure is demonstrated on the example of TiO2 rutile-based NWs. General analytic expressions for Line group representations induced from irreps of their orbit stabilizers are obtained. This approach presupposes the use of the standard (crystallographic) factorization of Line groups. Computer construction of orbits and induced representations can be efficiently implemented and the corresponding computer code SITESYML, which can be considered as a certain elaboration of the existing code SITESYM is written. The application of the code is demonstrated on the example of TiO2 anatase-based NTs with the rectangular and hexagonal morphology. PMID- 25736019 TI - Catalytic asymmetric synthesis of enantioenriched heterocycles bearing a C-CF3 stereogenic center. AB - Given the important agricultural and medicinal application of optically pure heterocycles bearing a trifluoromethyl group at the stereogenic carbon center in the heterocyclic framework, the exploration of efficient and practical synthetic strategies to such types of molecules remains highly desirable. Catalytic enantioselective synthesis has one clear advantage that it is more cost-effective than other synthetic methods, but remains limited by challenges in achieving excellent yield and stereoselectivities with a low catalyst loading. Thus far, numerous models of organo- and organometal-catalyzed asymmetric reactions have been exploited to achieve this elusive goal over the past decade. This review article describes recent progress on this research topic, and focuses on an understanding of the catalytic asymmetric protocols exemplified in the catalytic enantioselective synthesis of a wide range of complex enantioenriched trifluoromethylated heterocycles. PMID- 25736021 TI - Gene expression: Putting a stop to BDNF. PMID- 25736020 TI - Macromolecularly crowded in vitro microenvironments accelerate the production of extracellular matrix-rich supramolecular assemblies. AB - Therapeutic strategies based on the principles of tissue engineering by self assembly put forward the notion that functional regeneration can be achieved by utilising the inherent capacity of cells to create highly sophisticated supramolecular assemblies. However, in dilute ex vivo microenvironments, prolonged culture time is required to develop an extracellular matrix-rich implantable device. Herein, we assessed the influence of macromolecular crowding, a biophysical phenomenon that regulates intra- and extra-cellular activities in multicellular organisms, in human corneal fibroblast culture. In the presence of macromolecules, abundant extracellular matrix deposition was evidenced as fast as 48 h in culture, even at low serum concentration. Temperature responsive copolymers allowed the detachment of dense and cohesive supramolecularly assembled living substitutes within 6 days in culture. Morphological, histological, gene and protein analysis assays demonstrated maintenance of tissue specific function. Macromolecular crowding opens new avenues for a more rational design in engineering of clinically relevant tissue modules in vitro. PMID- 25736022 TI - Psychiatric disorders: A zebrafish model of ADHD. PMID- 25736023 TI - Pain: Turning down the heat in pain. PMID- 25736024 TI - Endoscopic Management of Chronic Frontal Sinusitis: Prospective Quality of Life Analysis. AB - BACKGROUND: Previous studies of endoscopic frontal sinus surgery have been primarily retrospective and focused on symptom relief only. OBJECTIVES: To prospectively assess the impact of endoscopic frontal sinus surgery on frontal sinus ostium patency and disease-specific quality of life as measured by the Rhinosinusitis Disability Index (RSDI). STUDY DESIGN: A 60-patient cohort with chronic frontal sinusitis (100 diseased frontal sinuses) was prospectively evaluated using the RSDI, computed tomography (CT) imaging, and endoscopic examination. Image-guided endoscopic frontal sinusotomy (Draf 2a) was performed in each case. Patients were assessed with RSDI and endoscopic assessment at least 6 months postoperatively. RESULTS: At a mean follow-up of 10 months, endoscopic assessment revealed patent frontal recesses in 90 of 100 frontal sinuses (90%), with significant improvement in the total RSDI score (41.98 +/- 26.48 preoperatively to 17.15 +/- 15.66 postoperatively) as well as each of its physical, emotional, and functional subscales from 16.3 +/- 9.03, 12.23 +/- 10.55, 13.45 +/- 9.59 preoperatively to 5.95 +/- 5.71, 5.55 +/- 5.66, 5.65 +/- 5.72 postoperatively, respectively. Similar improvement was seen in patients with asthma, polyps, and those undergoing revision sinus surgeries. CONCLUSIONS: With frontal recess mucosal preservation and meticulous postoperative endoscopic surveillance, endoscopic frontal sinusotomy results in high rates of frontal sinus ostium patency with significant improvement in quality of life. PMID- 25736025 TI - Dynamics of gene expression patterns during early development of the European seabass (Dicentrarchus labrax). AB - Larval and embryonic stages are the most critical period in the life cycle of marine fish. Key developmental events occur early in development and are influenced by external parameters like stress, temperature, salinity, and photoperiodism. Any failure may cause malformations, developmental delays, poor growth, and massive mortalities. Advanced understanding of molecular processes underlying marine larval development may lead to superior larval rearing conditions. Today, the new sequencing and bioinformatic methods allow transcriptome screens comprising messenger (mRNA) and microRNA (miRNA) with the scope of detecting differential expression for any species of interest. In the present study, we applied Illumina technology to investigate the transcriptome of early developmental stages of the European seabass (Dicentrarchus labrax). The European seabass, in its natural environment, is a euryhaline species and has shown high adaptation processes in early life phases. During its embryonic and larval phases the European seabass lives in a marine environment and as a juvenile it migrates to coastal zones, estuaries, and lagoons. Investigating the dynamics of gene expression in its early development may shed light on factors promoting phenotypic plasticity and may also contribute to the improvement and advancement of rearing methods of the European seabass, a species of high economic importance in European and Mediterranean aquaculture. We present the identification, characterization, and expression of mRNA and miRNA, comprising paralogous genes and differentially spliced transcripts from early developmental stages of the European seabass. We further investigated the detection of possible interactions of miRNA with mRNA. PMID- 25736027 TI - Herbert Rackow and Ernest Salanitre: the emergence of pediatric anesthesia as a specialty in the United States. AB - Herbert Rackow and Ernest Salanitre were pediatric anesthesiologists at Babies Hospital at the Columbia-Presbyterian Medical Center in New York whose work spanned three decades beginning in the early 1950s. Their pioneering research included studies of the uptake and elimination of inhalational anesthetics and of the risk of cardiac arrest in infants and children. They were actively involved in the development of pediatric anesthesia as a specialty, and their efforts contributed to inter-disciplinary collaboration and to the formation of the Section on Anesthesiology of the American Academy of Pediatrics. Their 1969 review article, 'Modern Concepts in Pediatric Anesthesiology', provides a fascinating view of pediatric anesthesia 50 years ago. In 1990, they were jointly awarded the Robert M. Smith award by the Section on Anesthesiology of the American Academy of Pediatrics. PMID- 25736026 TI - Insulin sensitivity and arterial stiffness in youth with type 1 diabetes: the SEARCH CVD study. AB - AIMS: Decreased insulin sensitivity is a cardiovascular risk factor (CVRF) in youth with type 1 diabetes (T1D). Whether baseline insulin sensitivity is independently associated with changes in early arterial stiffness (pulse wave velocity (PWV)) over time in youth with T1D is not known. METHODS: Two hundred ninety-eight youth with T1D in the SEARCH CVD study had PWV measured~five years apart. Insulin sensitivity and other CVRFs were measured at baseline. The association between baseline insulin sensitivity with PWV over time was explored using linear mixed models. Models were adjusted for baseline age, sex and race, with subsequent adjustment for CVRFs. RESULTS: There was a significant interaction (p=0.0326) between baseline insulin sensitivity and time on PWV, independent of CVRFs, indicating that higher insulin sensitivity levels were associated with lower rate of change in PWV over time. Other significant predictors of PWV change were baseline age [beta=0.007 (p=0.03) increase in logPWV/year increase in age] and mean arterial blood pressure (MAP) [beta=0.005 (p<0.01) increase in logPWV/mmHg increase in MAP] and smoking status (current vs. never smoker). CONCLUSIONS: Lower insulin sensitivity at baseline appears to be an important risk factor for increased arterial stiffness over time in youth with T1D. This identifies a potentially modifiable therapeutic target. PMID- 25736028 TI - Aflatoxin B1 affects apoptosis and expression of Bax, Bcl-2, and Caspase-3 in thymus and bursa of fabricius in broiler chickens. AB - Aflatoxin B1 is known as a mycotoxin that develops various health problems of animals, the effects of AFB1 on thymus and bursa of Fabricius in chickens are not clear. The objective of this study was to investigate the apoptosis of thymus and bursa of Fabricius in broilers fed with AFB1 . Two hundred Avian broilers were randomly divided into four groups of 50 each, namely control group and three AFB1 groups fed with 0.15 mg, 0.3 mg, and 0.6 mg AFB1 /kg diet, respectively. In this study, flow cytometer and immunohistochemical approaches were used to determine the percentage of apoptotic cells and the expression of Bax, Bcl-2, and Caspase 3. The results showed that consumption of AFB1 diets results in increased percentage of apoptotic cells and increased expression of Caspase-3 in both thymus and bursa of Fabricius. The expression of Bax was increased and the expression of Bcl-2 was decreased in the thymus, but no significant changes in Bax and Bcl-2 expression were observed in the bursa of Fabricius when broilers fed with AFB1 . These findings suggest that adverse effects of AFB1 on thymus and bursa of Fabricius in broilers were confirmed by increased apoptotic cells and abnormal expression of Caspase-3. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1113-1120, 2016. PMID- 25736029 TI - Absence of BRAF V600E in non-infiltrative, non-invasive follicular variant of papillary thyroid carcinoma. PMID- 25736030 TI - Dynapenic abdominal obesity as predictor of mortality and disability worsening in older adults: A 10-year prospective study. AB - There are relatively few prospective studies evaluating the combined effect of abdominal obesity and low muscle strength on worsening disability and on mortality. The study aimed at evaluating prospectively the prognostic value of dynapenic abdominal obesity definition on disability worsening in a 5.5-year follow-up and mortality in a 10-year follow-up. METHODS: In 93 men and 169 women aged between 66 and 78 years, leg isometric strength, waist circumference (WC), BMI, glycemia, HOMA, lipid profile, vitamin D3, albumin, fibrinogen, physical activity level, income, smoking status and comorbidities were evaluated at the baseline. Reported disabilities were measured at baseline, 1-y, 2-y, 3-y and 5.5 y follow-up and mortality rate was evaluated during a 10-y follow-up. The study population was categorized in dynapenic abdominal obese (D/AO), nondynapenic abdominal obese (ND/AO), dynapenic nonabdominal obese (D/NAO), nondynapenic nonabdominal obese (ND/NAO) according to muscle strength/WC tertiles. RESULTS: D/NAO subjects presented a disability worsening risk of 1.69 times (95%CI:1.11 2.57), ND/AO subjects showed a 2-fold increase in risk (95%CI:1.34-2.98), while being D/AO more than trebled the risk, even after considering confounding variables (HR:3.39,95%CI:1.91-6.02). Mortality risk after adjustment for other confounding variables was 1.57 (95%CI:1.16-2.13) for ND/AO and 2.46 (95%CI:1.34 4.52) for D/AO. CONCLUSIONS: Dynapenic abdominal obese subjects are at higher risk of worsening disability and mortality than subjects with dynapenia or central fat distribution only. PMID- 25736031 TI - Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease. AB - BACKGROUND & AIM: Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose induced non-alcoholic fatty liver disease. METHODS: Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. RESULTS: In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. CONCLUSION: While nitrogen supply alone can attenuate fructose induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. PMID- 25736032 TI - Cancer-Related Pain and Pain Management: Sources, Prevalence, and the Experiences of Children and Parents. AB - Advances in treatment mean children are increasingly cared for by their parents at home, leading to a shift in responsibility from health care professionals to parents. Little is known about parents' pain management experiences and the etiology of pain experienced by children with cancer especially when at home. A rapid review of the literature was undertaken investigating children's cancer related pain, with emphasis on the management of pain outside the health care setting. Electronic databases were searched and a quality assessment was conducted. Forty-two articles were included. Despite advances in pain management techniques, children with cancer regularly cite pain as the most prevalent symptom throughout the cancer trajectory. The source of pain is usually treatment side effects or painful procedures. Parents find dealing with their child's pain distressing and demanding and may hold misconceptions about pain management. Findings indicate a need for more robust research into parental pain management leading to the development of effective pain management resources for parents. PMID- 25736033 TI - Testosterone and cortisol in relation to aggression in a non-clinical sample of boys and girls. AB - Testosterone and cortisol have been proposed to jointly regulate aggressive behavior. However, few empirical studies actually investigated this joint relation in humans, and reported inconsistent findings. Also, samples in these studies were small and/or specific, and consisted largely of males. Therefore, in the current study testosterone and cortisol in relation to aggression were investigated in a non-clinical sample of 259 boys and girls (mean age 16.98 years, SD = 0.42, 56% boys). A positive testosterone/cortisol ratio, that is, high testosterone relative to cortisol, was found to be associated with aggressive behavior, explaining 7% of the variance. The interaction between testosterone and cortisol was not related to aggressive behavior and gender differences were not found. The ratio may reflect an imbalance leaving the individual more prone to rewarding aspects, than fearful of negative implications of aggressive behavior. Current findings indicate that this relation can be generalized to aggression in non-clinical adolescents. PMID- 25736034 TI - Wattles in goats are associated with the FMN1/GREM1 region on chromosome 10. AB - The presence of congenital appendages (wattles) on the throat of goats is supposed to be under genetic control with a dominant mode of inheritance. Wattles contain a cartilaginous core covered with normal skin resembling early stages of extremities. To map the dominant caprine wattles (W) locus, we collected samples of 174 goats with wattles and 167 goats without wattles from nine different Swiss goat breeds. The samples were genotyped with the 53k goat SNP chip for a subsequent genome-wide association study. We obtained a single strong association signal on chromosome 10 in a region containing functional candidate genes for limb development and outgrowth. We sequenced the whole genomes of an informative family trio containing an offspring without wattles and its heterozygous parents with wattles. In the associated goat chromosome 10 region, a total of 1055 SNPs and short indels perfectly co-segregate with the W allele. None of the variants were perfectly associated with the phenotype after analyzing the genome sequences of eight additional goats. We speculate that the causative mutation is located in one of the numerous gaps in the current version of the goat reference sequence and/or represents a larger structural variant which influences the expression of the FMN1 and/or GREM1 genes. Also, we cannot rule out possible genetic or allelic heterogeneity. Our genetic findings support earlier assumptions that wattles are rudimentary developed extremities. PMID- 25736035 TI - Building healthcare workers' confidence to work with same-sex parented families. AB - This article reports on a qualitative study of barriers and access to healthcare for same-sex attracted parents and their children. Focus groups were held with same-sex attracted parents to explore their experiences with healthcare providers and identify barriers and facilitators to access. Parents reported experiencing uncomfortable or anxiety-provoking encounters with healthcare workers who struggled to adopt inclusive or appropriate language to engage their family. Parents valued healthcare workers who were able to be open and honest and comfortably ask questions about their relationships and family. A separate set of focus groups were held with mainstream healthcare workers to identity their experiences and concerns about delivering equitable and quality care for same-sex parented families. Healthcare workers reported lacking confidence to actively engage with same-sex attracted parents and their children. This lack of confidence related to workers' unfamiliarity with same-sex parents, or lesbian, gay and bisexual culture, and limited opportunities to gain information or training in this area. Workers were seeking training and resources that offered information about appropriate language and terminology as well as concrete strategies for engaging with same-sex parented families. For instance, workers suggested they would find it useful to have a set of 'door opening' questions they could utilize to ask clients about their sexuality, relationship status or family make-up. This article outlines a set of guidelines for healthcare providers for working with same-sex parented families which was a key outcome of this study. PMID- 25736036 TI - [Benefit of the implementation of a ST-segment elevation myocardial infarction network on women]. AB - OBJECTIVE: The ST-segment elevation myocardial infarction network "Codi Infart" was implemented in Catalonia (Spain) in June 2009. The objective of this study was to evaluate the impact of the implementation of the Codi Infart on women. METHOD: Women referred for primary percutaneous coronary intervention, were divided into two groups according to Codi Infart: Non-Codi Infart group (January 2003 to May 2009) and Codi Infart group (June 2009 to December 2012). Place of first medical contact, time intervals in diagnosis and treatment, treatments received and rate of major cardiovascular adverse events defined as all-cause death, reinfarction or stroke in-hospital, at 30 and 180 days were compared. RESULTS: From a total population of 2,426 patients, 501 (20.7%) were women. One hundred eighty-six women (2.09 cases/month) belonged to Non-Codi Infart group and 315 women (10.16 cases/month) to Codi Infart group. The percentage of women attended increased since the introduction of CI (22.2% vs. 18.5%, P=.028). In addition, the Codi Infart group had a higher percentage of women initially attended outside our institution (84.1% vs. 16.7%, P<.001), and lower total ischemia time (220 [155-380] vs. 272 [196-456], P=.003). However, no differences in 180-day major cardiovascular adverse events were detected (14.2% vs. 15.6%, P=.692). CONCLUSIONS: The implementation of the major cardiovascular adverse events allowed to increase the rate and the percentage of women with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention and reducing total ischemic time. PMID- 25736037 TI - MicroRNAs in rheumatoid arthritis. AB - The role of genetic and epigenetic factors in the development of rheumatic diseases has been an interesting field of research over the past decades all around the world. Research on the role of microRNAs (miRNAs) in rheumatoid arthritis (RA) has been active and ongoing, and investigations have attempted to use miRNAs as biomarkers in disease diagnosis, prognosis, and treatment. This review focuses on experimental researches in the field of miRNAs and RA to present the data available up to this date and includes researches searched by keywords "microRNA" and "rheumatoid arthritis" in PubMed from 2008 to January 2015. All references were also searched for related papers. miRNAs are shown to act as proinflammatory or anti-inflammatory agents in diverse cell types, and their role seems to be regulatory in most instances. Researchers have evaluated miRNAs in patients compared to controls or have investigated their role by overexpressing or silencing them. Multiple targets have been identified in vivo, in vitro, or in silico, and the researches still continue to show their efficacy in clinical settings. PMID- 25736038 TI - Tespa1 is associated with susceptibility but not severity of rheumatoid arthritis in the Zhejiang Han population in China. AB - Observational and experimental studies in animal models have shown that Tespa1 may be associated with B cell function and the onset of rheumatoid arthritis (RA). We hypothesized that Tespa1 may also play an important role in patients with RA. To test this hypothesis, we investigated the expression level, gene polymorphisms, and promoter methylation of the Tespa1 gene in 77 RA patients and 113 matched healthy controls. We found that the expression of Tespa1 is significantly lower in RA patients with both low and moderate-to-high disease activity. Moreover, patients with familial (first-degree siblings) but not sporadic RA have a statistically significant difference at the rs4758993 locus with healthy people. Furthermore, we found seven methylation sites on the Tespa1 promoter, but no evidence of the association between methylation at these sites and RA susceptibility. These data support a potential role for Tespa1 in the pathogenesis of RA. PMID- 25736039 TI - The Construct Validity of the Dutch Personality Inventory for DSM-5 Personality Disorders (PID-5) in a Clinical Sample. AB - The factor structure and the convergent validity of the Personality Inventory for DSM-5 (PID-5), a self-report questionnaire designed to measure personality pathology as advocated in the fifth edition, Section III of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), are already demonstrated in general population samples, but need replication in clinical samples. In 240 Flemish inpatients, we examined the factor structure of the PID-5 by means of exploratory structural equation modeling. Additionally, we investigated differences in PID-5 higher order domain scores according to gender, age and educational level, and explored convergent and discriminant validity by relating the PID-5 with the Dimensional Assessment of Personality Pathology-Basic Questionnaire and by comparing PID-5 scores of inpatients with and without a DSM IV categorical personality disorder diagnosis. Our results confirmed the original five-factor structure of the PID-5. The reliability and the convergent and discriminant validity of the PID-5 proved to be adequate. Implications for future research are discussed. PMID- 25736040 TI - PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. AB - We attempted to develop a highly sensitive and specific method for the detection of circulating tumor DNA (ctDNA) using a digital PCR (dPCR) assay for PIK3CA mutations (i.e., H1047R, E545K, and E542K) in primary breast cancer patients. The sensitivity of the dPCR assay for the mutant alleles was examined using cell lines with PIK3CA mutations and proved to be 0.01 %. Serum samples were collected pre-operatively from 313 stage I-III breast cancer patients, of whom 110 were found to have PIK3CA mutant tumors. The serum samples from these patients with PIK3CA mutant tumors were subjected to the dPCR assay, and 25 (22.7 %) were found to be positive. No PIK3CA mutant ctDNA was detected in the serum samples of 50 healthy women and 30 breast cancer patients with PIK3CA non-mutant tumors. The patients with PIK3CA mutant ctDNA were dichotomized into mutant ctDNA-high (ctDNA(high)) and ctDNA-low (ctDNA(low)) groups based on the median. The ctDNA(high) patients exhibited significantly shorter recurrence-free survival (RFS; P = 0.0002) and overall survival rates (OS; P = 0.0048) compared to those exhibited by the combined ctDNA(low) patient and ctDNA-free patient group. Multivariate analysis revealed that ctDNA(high) status significantly predicted poor RFS and OS and did so independently of conventional histological parameters. These results suggest that dPCR is a highly sensitive and specific method for the detection of PIK3CA mutant ctDNA and that ctDNA(high) but not ctDNA(low) status is a significant and independent prognostic factor for primary breast cancer patients. PMID- 25736041 TI - Meta-analysis compares anticoagulant strategies in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. PMID- 25736042 TI - A novel approach to the determination of clinical decision thresholds. AB - Our objective was to determine the test and treatment thresholds for common acute primary care conditions. We presented 200 clinicians with a series of web-based clinical vignettes, describing patients with possible influenza, acute coronary syndrome (ACS), pneumonia, deep vein thrombosis (DVT) and urinary tract infection (UTI). We randomly varied the probability of disease and asked whether the clinician wanted to rule out disease, order tests or rule in disease. By randomly varying the probability, we obtained clinical decisions across a broad range of disease probabilities that we used to create threshold curves. For influenza, the test (4.5% vs 32%, p<0.001) and treatment (55% vs 68%, p=0.11) thresholds were lower for US compared with Swiss physicians. US physicians had somewhat higher test (3.8% vs 0.7%, p=0.107) and treatment (76% vs 58%, p=0.005) thresholds for ACS than Swiss physicians. For both groups, the range between test and treatment thresholds was greater for ACS than for influenza (which is sensible, given the consequences of incorrect diagnosis). For pneumonia, US physicians had a trend towards higher test thresholds and lower treatment thresholds (48% vs 64%, p=0.076) than Swiss physicians. The DVT and UTI scenarios did not provide easily interpretable data, perhaps due to poor wording of the vignettes. We have developed a novel approach for determining decision thresholds. We found important differences in thresholds for US and Swiss physicians that may be a function of differences in healthcare systems. Our results can also guide development of clinical decision rules and guidelines. PMID- 25736043 TI - Tonsillectomy or adenotonsillectomy reduces the number of sore throats in children; however, insufficient information is available on the effectiveness in adults. PMID- 25736044 TI - The evidence for treating acute pyelonephritis with oral antibiotic therapy and short intravenous treatment is growing for low-risk children. PMID- 25736046 TI - Is It Too Much of a Good Thing? A New Era in Phosphate Binder Therapy in ESRD. PMID- 25736047 TI - Self-Efficacy and Self-Reported Dietary Behaviors in Adolescents at an Urban School With No Competitive Foods. AB - Over one third of U.S. adolescents are overweight. A descriptive, cross-sectional study examined the relationship between student dietary self-efficacy (SE), sugar sweetened beverages, and low-nutrient energy-dense food consumption, and exposure to a healthy school food environment without competitive foods. The sample consisted of 292 urban, primarily African American students aged 11 to 16 years. Mantel-Haenszel chi(2) analyses revealed a significant but weak linear trend for girls between number of school meals and SE to drink less soda, chi(2)(1) = 6.882, p = .008, and between semesters attended with SE to eat more fruits and vegetables, chi(2)(1) = 5.908, p = .015. Obese students had significantly higher scores for two SE items than nonobese students, that is, plan better nutrition, chi(2)(1) = 3.998, p = .045, and eat healthy at a fast-food restaurant, chi(2)(1) = 4.078, p = .043. Further study of adolescent SE for healthy eating and school based, food-focused obesity prevention interventions is needed. PMID- 25736045 TI - Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD. AB - Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1+/-29.35 ng/ml; P<0.001; change in TSAT, 8.62%+/-1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4 47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders. PMID- 25736048 TI - Hypoalbuminaemia predicts outcome in adult patients with congenital heart disease. AB - BACKGROUND: In patients with acquired heart failure, hypoalbuminaemia is associated with increased risk of death. The prevalence of hypoproteinaemia and hypoalbuminaemia and their relation to outcome in adult patients with congenital heart disease (ACHD) remains, however, unknown. METHODS: Data on patients with ACHD who underwent blood testing in our centre within the last 14 years were collected. The relation between laboratory, clinical or demographic parameters at baseline and mortality was assessed using Cox proportional hazards regression analysis. RESULTS: A total of 2886 patients with ACHD were included. Mean age was 33.3 years (23.6-44.7) and 50.1% patients were men. Median plasma albumin concentration was 41.0 g/L (38.0-44.0), whereas hypoalbuminaemia (<35 g/L) was present in 13.9% of patients. The prevalence of hypoalbuminaemia was significantly higher in patients with great complexity ACHD (18.2%) compared with patients with moderate (11.3%) or simple ACHD lesions (12.1%, p<0.001). During a median follow-up of 5.7 years (3.3-9.6), 327 (11.3%) patients died. On univariable Cox regression analysis, hypoalbuminaemia was a strong predictor of outcome (HR 3.37, 95% CI 2.67 to 4.25, p<0.0001). On multivariable Cox regression, after adjusting for age, sodium and creatinine concentration, liver dysfunction, functional class and disease complexity, hypoalbuminaemia remained a significant predictor of death. CONCLUSIONS: Hypoalbuminaemia is common in patients with ACHD and is associated with a threefold increased risk of risk of death. Hypoalbuminaemia, therefore, should be included in risk-stratification algorithms as it may assist management decisions and timing of interventions in the growing ACHD population. PMID- 25736049 TI - Long-term mortality following interhospital transfer for acute myocardial infarction. AB - BACKGROUND: Interhospital transfer of patients admitted with an acute myocardial infarction for specialised care is common and costly. However, the long-term mortality of transferred patients compared with patients solely treated at the presenting hospital has not been evaluated. Here, we assess the long-term mortality of patients who undergo interhospital transfer during their acute myocardial infarction admission. METHODS: We evaluated 40 482 patients with a ICD10-AM diagnosis of acute myocardial infarction admitted to hospitals in New South Wales, Australia, from 2004 to 2008, of whom 10 107 (25%) were transferred. We compared in-hospital and mortality up to 5.5 years postdischarge among transferred and non-transferred patients. We created a 1:1 propensity score matched cohort (n=16 854; 8427 per group) to account for selection bias. RESULTS: In the matched cohort, transferred patients were more likely to undergo revascularisation (55.6% vs 13.7%, RR 4.05; 95% CI 3.83 to 4.29) and had lower mortality at 30 days (3.5% vs 5.7%, HR 0.60; 95% CI 0.52 to 0.70), 1 year (7.5% vs 12.6%, HR 0.58; 95% CI 0.52 to 0.64) and at the end of follow-up (15.3% vs 22.5%, HR 0.65; 95% CI 0.61 to 0.70) than patients treated in presenting hospitals. With the exception of transfers originating from revascularisation capable hospitals, these findings were consistent across a range of subgroups, including patients of all ages, ST-elevation myocardial infarction and non ST elevation myocardial infarction patients, and transfers originating from hospitals in regional and major city areas. Sensitivity analyses showed that these findings are unlikely to be due to survival bias or to confounding by unmeasured variables. CONCLUSIONS: Patients hospitalised for an acute myocardial infarction who are transferred to one or more hospitals for specialised care have higher rates of coronary revascularisation and experience lower long-term mortality. PMID- 25736050 TI - Quantitative autistic traits are transmitted intergenerationally and increase risk for autism spectrum disorders. PMID- 25736051 TI - Unruptured Sinus of Valsalva Aneurysm with Right Ventricular Outflow Tract Obstruction and Ventricular Septal Defect--A Rare Combination. AB - Sinus of Valsalva aneurysms are rare cardiac anomalies that may be acquired or congenital. We describe the case of a patient who had an unruptured sinus of Valsalva aneurysm causing right ventricular outflow obstruction, with an associated subaortic ventricular septal defect. Sinus of Valsalva aneurysms rarely present until rupture occurs. However, the unruptured aneurysm of the right sinus of Valsalva caused significant right ventricular outflow tract obstruction, resulting in exertional dyspnea. Intraoperative multiplane transesophageal echocardiography and color Doppler helped in precise identification of structural anomalies, shunt location, and definitive surgical repair. PMID- 25736052 TI - Construction of a new minicircle DNA carrying an enhanced green florescent protein reporter gene for efficient expression into mammalian cell lines. AB - The presence of a bacterial backbone in conventional eukaryotic expression plasmids may cause undesirable effects by triggering the immune responses in mammals and repression of episomal transgene expression. To avoid these problems, researchers have proposed the use of minicircle DNAs which are episomal vectors that have lost their bacterial backbone using a site-specific recombinase mediated recombination. In the present study, we have constructed a new minicircle DNA vector that carries an enhanced green florescent protein (EGFP) reporter gene using phage PhiC31 integrase-mediated recombination and homing endonuclease ISceI-mediated purification in E. coli. PhiC31 integrase expression was under the control of the araBAD promoter, whereas ISceI endonuclease was controlled by the tac promoter. This vector was transfected into CHO-K1 cells, which showed transient expression of EGFP up to 14 generations. Similar results were obtained upon transient transfection into HEK cells. In addition, PCR results on genomic DNA, demonstrated the EGFP-minicircle was episomal and did not integrate into the host genome. Our constructed parental plasmid expresses EGFP and could be used for the generation of episomal minicircle DNA with intent to carry out transient transfection of interested DNA fragments into the eukaryotic cells for various purposes. PMID- 25736053 TI - Maternal support following childhood sexual abuse: Associations with children's adjustment post-disclosure and at 9-month follow-up. AB - Maternal support has been widely cited as an important predictor of children's adjustment following disclosure of sexual abuse. However, few studies have examined these effects longitudinally. The current study examines the relationships between a multidimensional assessment of maternal support rated by both mothers and children and children's adjustment in various domains (internalizing, externalizing, anger, depression, and posttraumatic stress disorder symptoms) concurrently and longitudinally. Participants were 118 mother child dyads recruited from a Child Advocacy Center where children were determined through a forensic evaluation to be victims of sexual abuse. Child and mother ratings of maternal support and child adjustment were collected shortly after the forensic evaluation and at 9-month follow-up. Results were consistent with findings from past studies that maternal support is significantly related to children's post-disclosure adjustment and extends these findings longitudinally. Additionally, the study sheds light on differential relations between dimensions of maternal support (Emotional Support, Blame/Doubt, Vengeful Arousal, and Skeptical Preoccupation) and child adjustment and suggests the importance of using both child and mother ratings of maternal support in future research. PMID- 25736054 TI - Recent Change in Treatment of Disseminated Intravascular Coagulation in Japan: An Epidemiological Study Based on a National Administrative Database. AB - This study investigated the time trends and hospital factors affecting the use of drugs for infectious disease-associated disseminated intravascular coagulation (DIC) based on a national administrative database. A total of 14 324 patients with infectious disease-associated DIC were referred to 1041 hospitals from 2010 to 2012 in Japan. Patients' data were collected from the administrative database to determine time trends and hospital factors affecting the use of drugs for DIC. Three study periods were established, namely, the fiscal years 2010 (n = 3308), 2011 (n = 5403), and 2012 (n = 5613). The use of antithrombin, heparin, protease inhibitors, and recombinant human soluble thrombomodulin (rhs-TM) for DIC was evaluated. The frequency of use of antithrombin, heparin, and protease inhibitors decreased while that of rhs-TM significantly increased from 2010 to 2012 in Japan (25.1% in 2010, 43.1% in 2011, and 56.8% in 2012; P < .001, respectively). Logistic regression showed that the study period was associated with the use of rhs-TM in patients with DIC. The odds ratio (OR) for 2011 was 2.34 (95% confidence interval [CI], 2.12-2.58; P < .001) whereas that for 2012 was 4.34 (95% CI, 3.94-4.79; P < .001). A large hospital size was the most significant factor associated with the use of rhs-TM in patients with DIC (OR, 3.14; 95% CI, 2.68-3.66; P < .001). The use of rhs-TM has dramatically increased. A large hospital size was significantly associated with the increased use of rhs-TM in patients with DIC from 2010 to 2012 in Japan. PMID- 25736056 TI - Gene Signatures of 1,25-Dihydroxyvitamin D3 Exposure in Normal and Transformed Mammary Cells. AB - To elucidate potential mediators of vitamin D receptor (VDR) action in breast cancer, we profiled the genomic effects of its ligand 1,25-dihydroxyvitamin D3 (1,25D) in cells derived from normal mammary tissue and breast cancer. In non transformed hTERT-HME cells, 483 1,25D responsive entities in 42 pathways were identified, whereas in MCF7 breast cancer cells, 249 1,25D responsive entities in 31 pathways were identified. Only 21 annotated genes were commonly altered by 1,25D in both MCF7 and hTERT-HME cells. Gene set enrichment analysis highlighted eight pathways (including senescence/autophagy, TGFbeta signaling, endochondral ossification, and adipogenesis) commonly altered by 1,25D in hTERT-HME and MCF7 cells. Regulation of a subset of immune (CD14, IL1RL1, MALL, CAMP, SEMA6D, TREM1, CSF1, IL33, TLR4) and metabolic (ITGB3, SLC1A1, G6PD, GLUL, HIF1A, KDR, BIRC3) genes by 1,25D was confirmed in hTERT-HME cells and similar changes were observed in another comparable non-transformed mammary cell line (HME cells). The effects of 1,25D on these genes were retained in HME cells expressing SV40 large T antigen but were selectively abrogated in HME cells expressing SV40 + RAS and in MCF7 cells. Integration of the datasets from hTERT-HME and MCF7 cells with publically available RNA-SEQ data from 1,25D treated SKBR3 breast cancer cells enabled identification of an 11-gene signature representative of 1,25D exposure in all three breast-derived cell lines. Four of these 11 genes (CYP24A1, CLMN, EFTUD1, and SERPINB1) were also identified as 1,25D responsive in human breast tumor explants, suggesting that this gene signature may prove useful as a biomarker of vitamin D exposure in breast tissue. PMID- 25736055 TI - BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer. AB - The BRCA/Fanconi anemia (FA) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer (BTC). We also investigated changes in the CD24(+)/44(+) population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine (GEM)-resistant (GR) cells and evaluated the expression of BRCA/FA pathway components, chemoresistance, and the effect of BRCA/FA pathway inhibition on the CD24(+)/44(+) population. FANCD2 and CD24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA/FA components. The BRCA/FA pathway was upregulated by GEM and cisplatin (CDDP) exposure. Inhibition using siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24(+)/44(+) population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24(+)/44(+) population in MzChA1-GR cells. Thus, high expression of the BRCA/FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD24(+)/44(+) population in BTC. PMID- 25736057 TI - TRAIL and TRAIL receptors splice variants during long-term interferon beta treatment of patients with multiple sclerosis: evaluation as biomarkers for therapeutic response. AB - OBJECTIVE: We aimed to assess the effects of interferon beta (IFNbeta) treatment on the expression of the splice variants of the Tumour necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) and its receptors in different cell subpopulations (CD14+, CD4+ and CD8+) from patients with multiple sclerosis (MS), and to determine whether this expression discriminated responders from non responders to IFNbeta therapy. METHODS: We examined mRNA expression of the TRAIL and TRAIL receptors variants in patients with MS, at baseline and after one year of IFNbeta therapy, according to responsiveness to this drug. RESULTS: Long-term therapy with IFNbeta increased the expression of TRAIL-alpha in T cell subsets exclusively from responders and decreased the expression of the isoform 2 of TRAILR-2 in monocytes from responders as well as non-responders. Lower expression of TRAIL-alpha, and higher expression of TRAIL-beta in monocytes and T cells, was found before the onset of IFNbeta therapy in patients who will subsequently become responders. Baseline expression of TRAILR-1 was also significantly higher in monocytes and CD4+ T cells from responders. CONCLUSIONS: The present study shows that long-term IFNbeta treatment has a direct influence on TRAIL-alpha and TRAILR-2 isoform 2 expression. Besides, receiver operating characteristic analysis revealed that the baseline expression of TRAIL-alpha in monocytes and T cells, and that of TRAILR-1 in monocytes and CD4+ T cells, showed a predictive value of the clinical response to IFNbeta therapy, pointing to a role of TRAIL system in the mechanism of action of IFNbeta in MS that will need further investigation. PMID- 25736058 TI - Phosphatidylinositol 4-phosphate negatively regulates chloroplast division in Arabidopsis. AB - Chloroplast division is performed by the constriction of envelope membranes at the division site. Although constriction of a ring-like protein complex has been shown to be involved in chloroplast division, it remains unknown how membrane lipids participate in the process. Here, we show that phosphoinositides with unknown function in envelope membranes are involved in the regulation of chloroplast division in Arabidopsis thaliana. PLASTID DIVISION1 (PDV1) and PDV2 proteins interacted specifically with phosphatidylinositol 4-phosphate (PI4P). Inhibition of phosphatidylinositol 4-kinase (PI4K) decreased the level of PI4P in chloroplasts and accelerated chloroplast division. Knockout of PI4Kbeta2 expression or downregulation of PI4Kalpha1 expression resulted in decreased levels of PI4P in chloroplasts and increased chloroplast numbers. PI4Kalpha1 is the main contributor to PI4P synthesis in chloroplasts, and the effect of PI4K inhibition was largely abolished in the pdv1 mutant. Overexpression of DYNAMIN RELATED PROTEIN5B (DRP5B), another component of the chloroplast division machinery, which is recruited to chloroplasts by PDV1 and PDV2, enhanced the effect of PI4K inhibition, whereas overexpression of PDV1 and PDV2 had additive effects. The amount of DRP5B that associated with chloroplasts increased upon PI4K inhibition. These findings suggest that PI4P is a regulator of chloroplast division in a PDV1- and DRP5B-dependent manner. PMID- 25736059 TI - The calcium-dependent protein kinase CPK28 regulates development by inducing growth phase-specific, spatially restricted alterations in jasmonic acid levels independent of defense responses in Arabidopsis. AB - Phytohormones play an important role in development and stress adaptations in plants, and several interacting hormonal pathways have been suggested to accomplish fine-tuning of stress responses at the expense of growth. This work describes the role played by the CALCIUM-DEPENDENT PROTEIN KINASE CPK28 in balancing phytohormone-mediated development in Arabidopsis thaliana, specifically during generative growth. cpk28 mutants exhibit growth reduction solely as adult plants, coinciding with altered balance of the phytohormones jasmonic acid (JA) and gibberellic acid (GA). JA-dependent gene expression and the levels of several JA metabolites were elevated in a growth phase-dependent manner in cpk28, and accumulation of JA metabolites was confined locally to the central rosette tissue. No elevated resistance toward herbivores or necrotrophic pathogens was detected for cpk28 plants, either on the whole-plant level or specifically within the tissue displaying elevated JA levels. Abolishment of JA biosynthesis or JA signaling led to a full reversion of the cpk28 growth phenotype, while modification of GA signaling did not. Our data identify CPK28 as a growth phase dependent key negative regulator of distinct processes: While in seedlings, CPK28 regulates reactive oxygen species-mediated defense signaling; in adult plants, CPK28 confers developmental processes by the tissue-specific balance of JA and GA without affecting JA-mediated defense responses. PMID- 25736060 TI - Tudor staphylococcal nuclease links formation of stress granules and processing bodies with mRNA catabolism in Arabidopsis. AB - Tudor Staphylococcal Nuclease (TSN or Tudor-SN; also known as SND1) is an evolutionarily conserved protein involved in the transcriptional and posttranscriptional regulation of gene expression in animals. Although TSN was found to be indispensable for normal plant development and stress tolerance, the molecular mechanisms underlying these functions remain elusive. Here, we show that Arabidopsis thaliana TSN is essential for the integrity and function of cytoplasmic messenger ribonucleoprotein (mRNP) complexes called stress granules (SGs) and processing bodies (PBs), sites of posttranscriptional gene regulation during stress. TSN associates with SGs following their microtubule-dependent assembly and plays a scaffolding role in both SGs and PBs. The enzymatically active tandem repeat of four SN domains is crucial for targeting TSN to the cytoplasmic mRNA complexes and is sufficient for the cytoprotective function of TSN during stress. Furthermore, our work connects the cytoprotective function of TSN with its positive role in stress-induced mRNA decapping. While stress led to a pronounced increase in the accumulation of uncapped mRNAs in wild-type plants, this increase was abrogated in TSN knockout plants. Taken together, our results establish TSN as a key enzymatic component of the catabolic machinery responsible for the processing of mRNAs in the cytoplasmic mRNP complexes during stress. PMID- 25736061 TI - Early results of first versus second generation Amplatzer occluders for left atrial appendage closure in patients with atrial fibrillation. AB - BACKGROUND: Transcatheter left atrial appendage (LAA) occlusion has been proven to be an effective treatment for stroke prophylaxis in patients with atrial fibrillation. For this purpose, the Amplatzer cardiac plug (ACP) was introduced. Its second generation, the Amulet, was developed for easier delivery, better coverage, and reduction of complications. AIM: To investigate the safety and efficacy of first generation versus second generation Amplatzer occluders for LAA occlusion. METHODS: Retrospective analysis of prospectively collected data from the LAA occlusion registries of the Bern and Zurich university hospitals. Comparison of the last consecutive 50 ACP cases versus the first consecutive 50 Amulet cases in patients with non-valvular atrial fibrillation. For safety, a periprocedural combined endpoint, which is composed of death, stroke, cardiac tamponade, and bailout by surgery was predefined. For efficacy, the endpoint was procedural success. RESULTS: There were no differences between the two groups in baseline characteristics. The percentage of associated interventions during LAA occlusion was high in (78% with ACP vs. 70% with Amulet p = ns). Procedural success was similar in both groups (98 vs. 94%, p = 0.61). The combined safety endpoint for severe adverse events was reached by a similar rate of patients in both groups (6 vs. 8%, p = 0.7). Overall complication rate was insignificantly higher in the ACP group, which was mainly driven by clinically irrelevant pericardial effusions (24 vs. 14%, p = 0.31). Death, stroke, or tamponade were similar between the groups (0 vs. 2%, 0 vs. 0%, or 6 vs. 6%, p = ns). CONCLUSION: Transcatheter LAA occlusion for stroke prophylaxis in patients with atrial fibrillation can be performed with similarly high success rates with first and second generations of Amplatzer occluders. According to this early experience, the Amulet has failed to improve results of LAA occlusion. The risk for major procedural adverse events is acceptable but has to be taken into account when selecting patients for LAA occlusion, a preventive procedure. PMID- 25736062 TI - Activation of neuroimmune pathways increases therapeutic effects of radiotherapy on poorly differentiated breast carcinoma. AB - Recent studies document the importance of neuronal dysfunction in cancer development and metastasis. We reported previously that both depletion of neuropeptides in capsaicin-sensitive sensory nerve endings and vagotomy increases metastasis of triple negative breast carcinoma. Of the sensory neuropeptides, Substance P (SP) is distributed widely for regulation of immune functions. We therefore examined the affects of continuous exposure to low doses of SP on brain metastatic cells of the mouse breast carcinoma (4TBM) in the presence of radiotherapy (RT) thought to increase antigenicity of cancer cells. 4TBM cells have a cancer stem cell phenotype and induce extensive visceral metastasis after orthotopic inoculation into the mammary pad. Results demonstrated that SP treatment decreases the number of tumor-infiltrating myeloid-derived suppressor cells as well as the TNF-alpha response to LPS challenge. SP also increased CD4+Cd25(bright) cells in draining lymph nodes of tumor-bearing animals and IFN gamma secretion from leukocyte culture prepared from lymph nodes and spleens of tumor-bearing animals. SP also prevented tumor-induced degeneration of sensory nerve endings and altered release of angiogenic factors from cancer-associated fibroblasts (CAF) and tumor explants. In accordance with these observed immunological effects, combination treatment of continuous SP with a single dose of RT induced complete tumor regression and significantly reduced or prevented metastasis in 50% of the animals while suppressing primary tumor growth and metastasis in the remaining mice. These original findings demonstrate that SP through neuroimmune modulation can prevent formation of immune suppression in the tumor microenvironment, enhance cytotoxic immunity in the presence of RT and prevent metastatic growth. PMID- 25736063 TI - A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the "post-inflammatory brain syndrome" PIBS. AB - Post-concussion syndrome is an aggregate of symptoms that commonly present together after head injury. These symptoms, depending on definition, include headaches, dizziness, neuropsychiatric symptoms, and cognitive impairment. However, these symptoms are common, occurring frequently in non-head injured controls, leading some to question the existence of post-concussion syndrome as a unique syndrome. Therefore, some have attempted to explain post-concussion symptoms as post-traumatic stress disorder, as they share many similar symptoms and post-traumatic stress disorder does not require head injury. This explanation falls short as patients with post-concussion syndrome do not necessarily experience many key symptoms of post-traumatic stress disorder. Therefore, other explanations must be sought to explain the prevalence of post-concussion like symptoms in non-head injury patients. Many of the situations in which post concussion syndrome like symptoms may be experienced such as infection and post surgery are associated with systemic inflammatory responses, and even neuroinflammation. Post-concussion syndrome itself has a significant neuroinflammatory component. In this review we examine the evidence of neuroinflammation in post-concussion syndrome and the potential role systemic inflammation plays in post-concussion syndrome like symptoms. We conclude that given the overlap between these conditions and the role of inflammation in their etiologies, a new term, post-inflammatory brain syndromes (PIBS), is necessary to describe the common outcomes of many different inflammatory insults. The concept of post-concussion syndrome is in its evolution therefore, the new term post inflammatory brain syndromes provides a better understanding of etiology of its wide-array of symptoms and the wide array of conditions they can be seen in. PMID- 25736064 TI - Catecholaminergic-to-cholinergic transition of sympathetic nerve fibers is stimulated under healthy but not under inflammatory arthritic conditions. AB - OBJECTIVE: Density of sympathetic nerve fibers decreases in inflamed arthritic tissue tested by immunoreactivity towards tyrosine-hydroxylase (TH, catecholaminergic key enzyme). Since sympathetic nerve fibers may change phenotype from catecholaminergic to cholinergic (example: sweat glands), loss of nerve fibers may relate to undetectable TH. We aimed to investigate possible catecholaminergic-to-cholinergic transition of sympathetic nerve fibers in synovial tissue of animals with arthritis, and patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and we wanted to find a possible transition factor. METHODS: Nerve fibers were detected by immunofluorescence towards TH (catecholaminergic) and vesicular acetylcholine transporter (cholinergic). Co culture experiments with sympathetic ganglia and lymphocytes or osteoclast progenitors were designed to find stimulators of catecholaminergic-to-cholinergic transition (including gene expression profiling). RESULTS: In mouse joints, an increased density of cholinergic relative to catecholaminergic nerve fibers appeared towards day 35 after immunization, but most nerve fibers were located in healthy joint-adjacent skin or muscle and almost none in inflamed synovial tissue. In humans, cholinergic fibers are more prevalent in OA synovial tissue than in RA. Co-culture of sympathetic ganglia with osteoclast progenitors obtained from healthy but not from arthritic animals induced catecholaminergic-to cholinergic transition. Osteoclast mRNA microarray data indicated that leukemia inhibitory factor (LIF) is a candidate transition factor, which was confirmed in ganglia experiments, particularly, in the presence of progesterone. CONCLUSION: In humans and mice, catecholaminergic-to-cholinergic sympathetic transition happens in less inflamed tissue but not in inflamed arthritic tissue. Under healthy conditions, presence of cholinergic sympathetic nerve fibers may support the cholinergic anti-inflammatory influence recently described. PMID- 25736065 TI - Transgenerational changes of metabolic phenotypes in two selectively bred mouse colonies for different susceptibilities to diet-induced glucose intolerance. AB - We recently established 2 mouse lines with different susceptibilities (prone and resistant) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-prone [SDG P] and -resistant [SDG-R], respectively). In the present study, we analyzed transgenerational changes in metabolic phenotypes in these 2 mouse colonies to explore how the distinct phenotypes have emerged through the repetitive selection. Using C57BL/6, C3H, and AKR as background strains, mice showing inferior and superior glucose tolerance after HFD feeding were selected and bred repetitively over 20 generations to produce SDG-P and SDG-R, respectively. In addition to the blood glucose levels, HFD intake and body weight were also measured over the selective breeding period. As the generations proceeded, SDG-P mice became more susceptible to HFD-induced glucose intolerance and body weight gain, whereas SDG-R mice had gradually reduced HFD intake. The differences in fasting and post-glucose challenge blood glucose levels, body weight, and HFD intake became more evident between the 2 colonies through the selective breeding, mainly due to the HFD-induced glucose metabolism impairment and body weight gain in SDG-P mice and the reduction of HFD intake in SDG-R mice. These transgenerational changes in the metabolic phenotypes suggest that the genetic loci associated with the quantitative traits have been selectively enriched in SDG-P and SDG-R. PMID- 25736066 TI - Clinical, biochemical, and genetic features of non-classical 21-hydroxylase deficiency in Japanese children. AB - Non-classical 21-hydroxylase deficiency (NC21-OHD) is a mild form of 21 hydroxylase deficiency lacking apparent symptoms of androgen excess at birth. Most NC21-OHD cases are diagnosed after the onset of puberty, while a substantial number of patients are not diagnosed during childhood. Previous studies have reported ethnic differences in the prevalence of NC21-OHD. To date, the clinical features of NC21-OHD in Japanese children have not been systemically reported. Thus, we performed 3 independent analyses: retrospective analyses of newborn screening in 2 major Japanese cities (Sapporo and Niigata) and a national surveillance collecting clinical information from pediatric endocrinologists throughout the country. During the last 10 years, one case of NC21-OHD was diagnosed by newborn screening in each city, resulting in incidences of 2.0 (95% confidence interval = 0.0-5.9) and 2.1 (0.0-6.2) per 1,000,000 in Sapporo and Niigata, respectively. We collected information from 85% of the 135 Councilors of Japanese Society of Pediatric Endocrinology. Fifteen NC21-OHD patients were diagnosed during childhood, resulting in the estimated prevalence of 0.58 (0.28 1.1) per 1,000,000. Eleven patients were discovered by newborn screening, 7 patients developed hyperandrogenism symptoms (2-8 years of age, median 7), and 9 patients were treated with hydrocortisone at the time of the survey. Ten out of 13 patients showed compound heterozygosity for the P30L mutation of CYP21A2. Our study suggests that the prevalence/incidence of NC21-OHD is lower than that in Western countries, and that the age for initial onset of androgen excess symptoms varies during the prepubertal period. PMID- 25736067 TI - A case of Cushing's syndrome due to bilateral cortisol-secreting adenomas with unilateral DHEAS oversecretion. AB - A 39-year-old Japanese woman presented with typical clinical symptoms of Cushing's syndrome, including amenorrhea and hirsutism, for 2 years. The results of her initial endocrine evaluation were consistent with ACTH-independent Cushing's syndrome due to bilateral adrenal masses (diameters of 3.1 cm and 2.4 cm on the left and right, respectively). Serum dehydroepiandrosterone levels were 6,901 ng/mL (normal range 230-2,660 ng/mL). Bilateral laparoscopic adrenalectomies were performed (left adrenalectomy first and right adrenalectomy 3 months later). Following the left adrenalectomy, the results of the endocrine evaluations were still consistent with a diagnosis of ACTH-independent Cushing's syndrome. Serum dehydroepiandrosterone sulphate levels, however, were below the normal range (143 ng/mL). Unexpectedly, the patient's menstruation resumed 2.5 months after the left adrenalectomy. Pathological examination of the resected glands showed bilateral adrenocortical adenomas, one on the left with a diameter of 3 cm, and two on the right with diameters of 0.7 cm and 1.3 cm. Immunohistochemical analysis revealed side chain cleavage, 17alpha-hydroxylase, 3beta-hydroxysteroid dehydrogenase, and 21-hydroxylase immunoreactivity in each adenoma. Dehydroepiandrosterone-sulfotransferase immunoreactivity was pronounced in the left adenoma, less pronounced in one of the right adenoma and weak in the other right adenoma. These results were consistent with clinical endocrine findings. Ours is the first case of a patient with bilateral cortisol-secreting adenomas with unilateral oversecretion of dehydroepiandrosterone sulphate. Resumption of menstruation after the correction of the dehydroepiandrosterone sulphate excess, despite persistent cortisol excess, indicates the importance of adrenal androgens for the regulation of the menstrual cycle. PMID- 25736068 TI - Introducing a new radical trifluoromethylation reagent. AB - Perfluoro-3-ethyl-2,4-dimethyl-3-pentyl radical (PPFR) is a persistent radical stable at room temperature, but easily decomposes at 90 degrees C to produce a CF3 radical which is able to react with a variety of aromatic compounds to afford the corresponding trifluoromethyl derivatives, usually as mixtures of regioisomers in good to excellent overall yields. PMID- 25736069 TI - Single center experience in Japanese patients with syncope. AB - BACKGROUND AND PURPOSE: The present diagnostic method and features of syncope in Japan are unclear. Implantable loop recorder (ILR) and head-up tilt tests have recently become available for diagnosing syncope. The examination method and rates of diagnosing syncope may vary. This study aimed to clarify the present diagnostic method and features of syncope in a single Japanese medical center. METHODS AND RESULTS: We retrospectively reviewed the medical records of consecutive patients who were seen at our hospital from January 1, 2009, to December 31, 2012. A total of 547 patients (328 men, 60.4+/-21.5 years) with syncope were seen at our hospital. Reflex syncope was diagnosed in 29.1% of the cases, orthostatic hypotension in 11.7%, cardiac syncope in 34.0%, and unexplained syncope in 23.9% by initial and early evaluations. The number of patients with situational syncope and orthostatic hypotension that could be diagnosed in the initial evaluation of the first examination was significantly greater than that in subsequent evaluations. Forty-three percent of the unexplained syncope patients received an ILR. The consent rate for ILR implantations in the unexplained syncope patients with a suspected arrhythmia nature was 53.1%. The cumulative ILR diagnostic rates were 47% and 65% at 1 and 2 years after the ILR implantation, respectively. The estimated ILR diagnostic rates were significantly greater than that for conventional test without using an ILR. When patients with unexplained syncope could be diagnosed, the recurrent symptoms were greatly reduced. CONCLUSIONS: Syncope is induced by various causes in Japan. It is important that we understand the characteristics of each syncope cause. The consent rate for implanting an ILR in appropriate unexplained syncope patients is low. We need to educate these patients about the importance of making a diagnosis of syncope. PMID- 25736070 TI - Twenty-years experience with de novo metastatic breast cancer. AB - Although new treatments have been widely studied to improve the survival of patients with metastatic breast cancer (BC), prognosis continues to be poor with an average survival time no longer than 3 years. We carried on a population-based study with the purpose of evaluating the outcome of metastatic breast cancer in the province of Modena from 1990 to 2009. We examined the Modena Cancer Registry and evaluated the 5-year overall survival (OS) of women diagnosed with a de novo metastatic breast cancer between 1990 and 2009, defining 5 periods of 4 years each. After a median follow-up time of 29 months, the 5-year OS was 11% for years 1990-1993, 15% for years 1994-1997, 12% for years 1998-2001, 20% for years 2002 2005 and 29% for years 2006-2009 (p = 0.012). Overall, although no OS differences were noted in the first decade analyzed, a real advantage has been shown in the last two cohorts. In a multivariate analysis, the 5-year OS was significantly increased only for hormone receptor positive and HER2+ tumors, whereas chemotherapy treatments were not significant independent predictors of survival in "de novo" metastatic BC (p = 0.08). Our analysis confirms that the prognosis of de novo metastatic breast cancer has improved overtime, particularly in the last decade. Trastuzumab, LH-RH analogues and aromatase inhibitors have determined a significant clinical benefit and cost-effectiveness in metastatic breast cancer treatment. PMID- 25736071 TI - Simultaneous determination of aromatic amino acids in human blood plasma by capillary electrophoresis with UV-absorption detection. AB - Phenylalanine, tyrosine, and tryptophan, also known as aromatic amino acids, are involved in many physiological and pathophysiological conditions and are indicative of the liver and kidney function. In this work, we describe a simple and accurate method for their simultaneous quantification, in a single capillary electrophoresis run. This method requires minimal sample manipulation, no derivatization procedures, and methyl tryptophan as internal standard. The human blood plasma sample was precipitated using sulfosalicylic acid and the supernatant was used for the analysis. All the analytes were baseline resolved within 16 min and detected at 200 nm using Tris phosphate 80 mmol/L at pH 1.4 as the background electrolyte. The proposed method showed good linearity (r = 0.998) and repeatability (intra-assay RSD < 2.78%, interassay RSD < 5.4%) for all the analytes. The limit of quantification was 13 MUmol/L for phenylalanine and 5 MUmol/L for tyrosine and tryptophan. The method suitability was tested measuring aromatic amino acids level in 20 chronic kidney disease patients at basal level and after simvastatin/ezetimibe treatment. PMID- 25736072 TI - A simulator study of adverse wear with metal and cement debris contamination in metal-on-metal hip bearings. AB - OBJECTIVES: Third-body wear is believed to be one trigger for adverse results with metal-on-metal (MOM) bearings. Impingement and subluxation may release metal particles from MOM replacements. We therefore challenged MOM bearings with relevant debris types of cobalt-chrome alloy (CoCr), titanium alloy (Ti6Al4V) and polymethylmethacrylate bone cement (PMMA). METHODS: Cement flakes (PMMA), CoCr and Ti6Al4V particles (size range 5 um to 400 um) were run in a MOM wear simulation. Debris allotments (5 mg) were inserted at ten intervals during the five million cycle (5 Mc) test. RESULTS: In a clean test phase (0 Mc to 0.8 Mc), lubricants retained their yellow colour. Addition of metal particles at 0.8 Mc turned lubricants black within the first hour of the test and remained so for the duration, while PMMA particles did not change the colour of the lubricant. Rates of wear with PMMA, CoCr and Ti6Al4V debris averaged 0.3 mm(3)/Mc, 4.1 mm(3)/Mc and 6.4 mm(3)/Mc, respectively. CONCLUSIONS: Metal particles turned simulator lubricants black with rates of wear of MOM bearings an order of magnitude higher than with control PMMA particles. This appeared to model the findings of black, periarticular joint tissues and high CoCr wear in failed MOM replacements. The amount of wear debris produced during a 500 000-cycle interval of gait was 30 to 50 times greater than the weight of triggering particle allotment, indicating that MOM bearings were extremely sensitive to third-body wear. Cite this article: Bone Joint Res 2015;4:29-37. PMID- 25736073 TI - Alternating copolymerization by nitroxide-mediated polymerization and subsequent orthogonal functionalization. AB - A novel method for the preparation of functionalized alternating copolymers is presented. Nitroxide-mediated polymerization of hexafluoroisopropyl acrylate with 7-octenyl vinyl ether provides the corresponding alternating polymer, which can be chemically modified using two orthogonal polymer-analogous reactions. A thiol ene click reaction followed by amidation provides dual-functionalized alternating copolymers. The potential of this method is illustrated by the preparation of a small library (15 examples) of functionalized alternating copolymers. PMID- 25736074 TI - Antiepileptic drug use during pregnancy: sodium valproate is associated with lower offspring IQ. PMID- 25736075 TI - Hospitalization risk in patients with schizophrenia before and after initiation of risperidone long-acting injection in Japan. PMID- 25736076 TI - Mosaic trisomy 15 in a liveborn infant. AB - With only a small number of cases in the medical literature, mosaic trisomy 15 in liveborn infants is very rare. Despite its rarity, similar features among individuals have been described, including intrauterine growth retardation, craniofacial abnormalities and facial dysmorphisms, cardiac disease, and other organ anomalies. Very few liveborns have survived the first year of life. We report here on a term infant with growth restriction and multiple congenital anomalies who was found to have mosaic trisomy 15. The proband presented with some frequently reported findings such as dysmorphic facies and overlapping fingers, and the uncommon finding of whorled hypopigmentation. Previously unreported findings include abnormal cerebral vasculature and dysplastic kidneys. We add this new phenotypic information to widen the spectrum previously reported and provide a review of the literature to date. PMID- 25736077 TI - Evidence-based management of epistaxis in hereditary haemorrhagic telangiectasia. AB - BACKGROUND: There are currently no guidelines in the UK for the specific management of hereditary haemorrhagic telangiectasia related epistaxis. The authors aimed to review the literature and provide an algorithm for the management of hereditary haemorrhagic telangiectasia related epistaxis. METHOD: The Medline and Embase databases were interrogated on 15 November 2013 using the search items 'hereditary haemorrhagic telangiectasia' (title), 'epistaxis' (title) and 'treatment' (title and abstract), and limiting the search to articles published in English. RESULTS: A total of 46 publications were identified, comprising 1 systematic review, 2 randomised, controlled trials, 27 case series, 9 case reports, 4 questionnaire studies and 3 in vitro studies. CONCLUSION: There is a lack of high-level evidence for the use of many of the available treatments for the specific management of epistaxis in hereditary haemorrhagic telangiectasia. Current management should be based on a multidisciplinary team approach involving both a hereditary haemorrhagic telangiectasia physician and an ENT surgeon, especially when systemic therapy is being considered. The suggested treatment algorithm considers that the severity of epistaxis merits intervention at different levels of the treatment ladder. The patient should be assessed using a reproducible validated assessment tool, for example an epistaxis severity score, to guide treatment. More research is required, particularly in the investigation of topical agents targeting the development and fragility of telangiectasiae in hereditary haemorrhagic telangiectasia. PMID- 25736078 TI - A self-charging power unit by integration of a textile triboelectric nanogenerator and a flexible lithium-ion battery for wearable electronics. AB - A novel integrated power unit realizes both energy harvesting and energy storage by a textile triboelectric nanogenerator (TENG)-cloth and a flexible lithium-ion battery (LIB) belt, respectively. The mechanical energy of daily human motion is converted into electricity by the TENG-cloth, sustaining the energy of the LIB belt to power wearable smart electronics. PMID- 25736079 TI - Cardiorespiratory endurance in relation to body mass in Polish rural children: Preliminary report. AB - Physical fitness is generally viewed as having morphological, muscular, motor, cardiovascular and metabolic components. Cardiorespiratory fitness describes the capacity of the cardiovascular and respiratory systems to carry out prolonged strenuous exercise. It is often considered as the most important indicator of health status. The place of residence is seen as a factor that may influence the feasibility of physically active lifestyles, and thus shaping cardiorespiratory fitness. The study group consisted of 121 children aged 10-16 years, including 60 girls and 61 boys. All of the children lived in rural areas. The investigated group was divided according to age and sex; body height and weight were measured and body mass index (BMI) calculated. All children performed the Cooper's run test and the Ruffier's test. The analysis of BMI for the nutritional status of children in relation to the entire study group demonstrated that 81 children had normal weight, 20 children were overweight and 11 were obese, while 9 children were underweight. The studied group of children showed on average very good and good performance in the Cooper's test, regardless of body weight, whereas the results of the Ruffier's test showed merely weak or medium cardiorespiratory endurance, which was even worse in overweight or obese children. PMID- 25736080 TI - Fabrication of SERS-active substrates using silver nanofilm-coated porous anodic aluminum oxide for detection of antibiotics. AB - We have developed a silver nanofilm-coated porous anodic aluminum oxide (AAO) as a surface-enhanced Raman scattering (SERS)-active substrate for the detection of trace level of chloramphenicol, a representative antibiotic in food systems. The ordered aluminum template generated during the synthesis of AAO serves as a patterned matrix on which a coated silver film replicates the patterned AAO matrix to form a 2-dimensional ordered nanostructure. We used atomic force microscopy and scanning electron microscopy images to determine the morphology of this nanosubstrate, and characterized its localized surface plasmon resonance by ultraviolet-visible reflection. We gauged the SERS effect of this nanosubstrate by confocal micro-Raman spectroscopy (782-nm laser), finding a satisfactory and consistent performance with enhancement factors of approximately 2 * 10(4) and a limit of detection for chloramphenicol of 7.5 ppb. We applied principal component analysis to determine the limit of quantification for chloramphenicol of 10 ppb. Using electromagnetic field theory, we developed a detailed mathematical model to explain the mechanism of Raman signal enhancement of this nanosubstrate. With simple sample pretreatment and separation steps, this silver nanofilm-coated AAO substrate could detect 50 ppb chloramphenicol in milk, indicating good potential as a reliable SERS-active substrate for rapid detection of chemical contaminants in agricultural and food products. PMID- 25736081 TI - Orienting Effect of the Cage Addends: The Case of Nucleophilic Cyclopropanation of C2 -C70 (CF3 )8. AB - C2 -C70 (CF3 )8 was found to be a very promising substrate in the Bingel and the Bingel-Hirsch reactions combining perfect regioselectivity with much higher reactivity compared to its analogs. The reactions with diethyl malonate yield a single isomer of the monoadduct C70 (CF3 )8 [C(CO2 Et)2 ] and a single C2 symmetrical bisadduct C70 (CF3 )8 [C(CO2 Et)2 ]2 . The Bingel-Hirsch variation is particularly interesting in that it additionally affords, in a similar regioselective manner, the unexpected alkylated derivatives C70 (CF3 )8 [CH(CO2 Et)2 ]H and C70 (CF3 )8 [C(CO2 Et)2 ][CH(CO2 Et)2 ]H. The novel compounds have been isolated and structurally characterized by means of (1) H and (19) F NMR spectroscopy as well as single-crystal X-ray diffraction. The mechanistic and regiochemical aspects of the reaction are explained with the aid of DFT calculations. PMID- 25736082 TI - Implant-based immediate breast reconstruction in the previously augmented patient. AB - BACKGROUND: Millions of women have undergone augmentation mammaplasty with implants and breast cancer continuing to be the most common non-cutaneous malignancy in female patients. Reconstructive surgeons will inevitably encounter breast cancer patients with prior augmentation. Implant-based techniques represent the most common form of breast reconstruction overall and remains a common option among those who were previously augmented. OBJECTIVE: The purpose of this study is to evaluate outcomes of implant-based reconstruction in previously augmented women. METHODS: A retrospective review from September 2004 to December 2009 was performed. 38 women (63 breasts) with a history of prior augmentation (PA) who underwent implant-based reconstruction were identified and compared to a non-prior augmented (NPA) control group (77 patients; 138 breasts). Normative data, augmentation details, reconstruction method, complication rates, and revision rates were evaluated. RESULTS: The total complication rate was significantly different between the two groups with 18 complications (28.6%) occurring in 9 PA breasts and 20 complications (14.5%) in 19 NPA breasts (p-value 0.037). When analyzed by specific complication subtypes, capsular contracture was the only complication that bordered significance between the two cohorts (p-value 0.057). Complication rates were otherwise similar regardless of augmentation or reconstruction type. CONCLUSION: Implant-based reconstruction is a safe option for previously augmented patients that is able to provide outcomes similar to non augmented patients. Results are not affected by the location of previous implants or the implant-based reconstruction method. There may be a higher incidence of capsular contracture in the previously augmented patient that warrants further investigation and preoperative discussion. PMID- 25736083 TI - Systematic metabolomic analysis of eicosanoids after omega-3 polyunsaturated fatty acid supplementation by a highly specific liquid chromatography-tandem mass spectrometry-based method. AB - Omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) have beneficial effects in many pathological processes, especially cardiovascular disease, and their protective eicosanoid metabolites are thought to play important roles. However, how omega-3 PUFAs affect the eicosanoid profile has not been elucidated comprehensively. Here, we systematically analyzed the eicosanoid metabolites induced by omega-3 PUFA supplementation. We developed an LC-MS/MS-based method covering 32 arachidonic acid (ARA) metabolites and 37 omega-3 PUFA-derived products. The limits of detection for eicosanoids were between 0.0625 and 1 pg and the detection specificity was optimized. We then quantified eicosanoids in mouse and human plasma and mouse aorta samples after omega-3 PUFA supplementation. Levels of EPA hydroxyl products, 4-HDoHE, 17,18-EEQ, 17,18 DiHETE, TXB2, and LXA4 were significantly changed in both mouse samples, and those of 2-series PGs, EDPs and DHA hydroxyl products were changed in aorta samples. Correlation network analysis of mouse plasma data revealed that some eicosanoids had higher connection degree or betweenness centrality score than others after omega-3 PUFA supplementation. Eicosanoids in human plasma were profiled across five time points after omega-3 PUFA supplementation. Fuzzy c-mean clustering algorithm suggested that the time curves of eicosanoid activity could be described with three kinetic patterns: sustained upregulation, short-term upregulation, and downregulation. This is the first systematic profiling of eicosanoids with omega-3 PUFA supplementation. The highly specific eicosanoid metabolomic and related data analysis methods would be powerful tools for comprehensive eicosanoid study. PMID- 25736085 TI - Ribonucleotides in DNA: hidden in plain sight. PMID- 25736086 TI - Subversive bacteria reveal new tricks in their cytoskeleton-hijacking arsenal. PMID- 25736087 TI - Secondary nucleation wears the BRICHOS in this family. PMID- 25736088 TI - The proteasome gets a grip on protein complexity. PMID- 25736092 TI - Corrigendum: Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7. PMID- 25736093 TI - Corrigendum: Structure of EF-G-ribosome complex in a pretranslocation state. PMID- 25736094 TI - Negative differential conductance and super-Poissonian shot noise in single molecule magnet junctions. AB - Molecular spintroinic device based on a single-molecule magnet is one of the ultimate goals of semiconductor nanofabrication technologies. It is thus necessary to understand the electron transport properties of a single-molecule magnet junction. Here we study the negative differential conductance and super Poissonian shot noise properties of electron transport through a single-molecule magnet weakly coupled to two electrodes with either one or both of them being ferromagnetic. We predict that the negative differential conductance and super Poissonian shot noise, which can be tuned by a gate voltage, depend sensitively on the spin polarization of the source and drain electrodes. In particular, the shot noise in the negative differential conductance region can be enhanced or decreased originating from the different formation mechanisms of negative differential conductance. The effective competition between fast and slow transport channels is responsible for the observed negative differential conductance and super-Poissonian shot noise. In addition, we further discuss the skewness and kurtosis properties of transport current in the super-Poissonian shot noise regions. Our findings suggest a tunable negative differential conductance molecular device, and the predicted properties of high-order current cumulants are very interesting for a better understanding of electron transport through single-molecule magnet junctions. PMID- 25736095 TI - Supramolecular interaction of fullerenes with a curved pi-surface of a monomeric quadruply ring-fused porphyrin. AB - Molecular binding of fullerenes, C60 and C70, with the Zn(II) complex of a monomeric ring-fused porphyrin derivative (2-py) as a host molecule, which has a concave pi-conjugated surface, has been confirmed spectroscopically. The structures of associated complexes composed of fullerenes and 2-py were explicitly established by X-ray diffraction analysis. The fullerenes in the 2:1 complexes, which consist of two 2-py molecules and one fullerene molecule, are fully covered by the concave surfaces of the two 2-py molecules in the crystal structure. In contrast, in the crystal structure of the 1:1 complex consisting of one 2-py molecule and one C60 molecule, the C60 molecule formed a pi-pi stacked pair with a C60 molecule in the neighboring complex using a partial surface, which was uncovered by the 2-py molecule. Additionally, the molecular size of fullerene adopted significantly affects the (1)H NMR spectral changes and the redox properties of 2-py upon the molecular binding. PMID- 25736096 TI - Long-term outcome of liver transplant patients with Budd-Chiari syndrome secondary to myeloproliferative neoplasms. AB - BACKGROUND: A considerable proportion of patients receiving liver transplants for Budd-Chiari syndrome (BCS) suffer from myeloproliferative neoplasms (MPN). This study evaluated the long-term prognosis of liver-transplanted patients with BCS secondary to MPN and the effect of immunosuppression on MPN progression. METHODS: A total of 78 patients with BCS were evaluated between 1982 and 2013. Of those, 40 patients suffered from polycythaemia vera (PV) and essential thrombocythaemia (ET). One patient had primary myelofibrosis (PMF). All patients received the standard immunosuppressive regimen. We retrospectively evaluated the long-term survival, clinical course and laboratory parameters of patients with MPN. RESULTS: Exactly 29/41 patients (71%) with MPN survived >= 3 years [mean age 36 +/- 11 years; females n = 27 (93%)]. Mean follow-up after orthotopic liver transplantation (OLT) was 12.4 +/- 7.3 years (range 3-28 years). Five- and 10 year survival rates were not significantly different in patients with and without MPN (P = 0.81 and P = 0.66 respectively) or in patients with PV and ET (P = 0.29 and P = 0.55 respectively). Thrombosis and bleeding developed in 7/29 (24%) long term MPN survivors with no significant difference between ET and PV (P = 0.18). In the long-term follow-up, there was no evidence of progression to overt myelofibrosis or acute myeloid leukaemia (AML). In the uni- and multivariate Cox regression analyses, MPN did not influence survival after OLT. CONCLUSIONS: Budd Chiari syndrome patients with and without underlying MPN had similar long-term survival rates after OLT. There was no evidence of enhanced progression of MPN after OLT secondary to immunosuppressive therapy. However, major haemorrhage and recurrent thrombosis contributed to morbidity and mortality after OLT in those patients. PMID- 25736097 TI - Hydrogen plasma-mediated modification of the electrical transport properties of ZnO nanowire field effect transistors. AB - We investigated the effects of hydrogen plasma treatment on the electrical transport properties of ZnO nanowire field effect transistors (FETs) with a back gate configuration. After hydrogen plasma treatment of the FET devices, the effective carrier density and mobility of the nanowire FETs increased with a threshold voltage shift toward a negative gate bias direction. This can be attributed to the desorption of oxygen molecules adsorbed on the surface of the nanowire channel, to passivation and to doping effects due to the incorporation of energetic hydrogen ions generated in plasma. PMID- 25736098 TI - Dexmedetomidine-ketamine combination and caudal block for superficial lower abdominal and genital surgery in children. AB - BACKGROUND: The use of dexmedetomidine-ketamine combination to perform different diagnostic and surgical pediatric procedures has increased. The optimal ketamine dose to combine with dexmedetomidine has not been determined. The goal of this study was to determine the ED50 and ED95 of ketamine, which in combination with, dexmedetomidine (1 MUg . kg(-1)) provides an adequate anesthetic effect to perform a caudal block and then the ensuing superficial lower abdominal or genital surgery. MATERIAL AND METHODS: Twenty-five patients, aged 1-8 years, scheduled for superficial lower abdominal or genital surgery, were studied. All patients received an intravenous dose of dexmedetomidine 1 MUg . kg(-1) and a random dose of ketamine from 1 mg . kg(-1) to 2 mg . kg(-1). After ketamine administration, a caudal block was performed and then surgery was initiated. Hemodynamics, respiratory variables, sedation level, and postoperative complications were recorded. The ED50 and ED95 of ketamine were calculated using logistic regression analysis. RESULTS: The ED50 and ED95 of ketamine to perform a caudal block were 1.53 (1.29-1.76) mg . kg(-1) and 2.25 (1.63-2.88) mg . kg(-1), respectively. The ED50 and ED95 of ketamine to perform a caudal block and to complete the entire procedure were 1.76 (1.57-1.95) mg . kg(-1), and 2.21 (1.77 2.64) mg . kg(-1), respectively. Three patients presented mild, self-limited, intraoperative bradycardia. CONCLUSIONS: These results suggest that adding ketamine 2 mg . kg(-1) to dexmedetomidine 1 MUg . kg(-1) should produce an effective anesthetic level to perform a caudal block and the ensuing superficial lower abdominal or genital surgery in children. PMID- 25736099 TI - Health risk assessment to TriCresyl Phosphates (TCPs) in aircraft: A commentary. PMID- 25736100 TI - Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis. AB - Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD(+) )-dependent protein deacetylase. In mice, mSirt1 deficiency causes the onset of fatty liver via regulation of the hepatic nutrient metabolism pathway. In this study, we demonstrate SIRT1 expression, activity and NAD(+) regulation using noncancerous liver tissue specimens from hepatocellular carcinoma patients with non-B non-C (NBNC) hepatitis. SIRT1 expression levels were higher in NBNC patients than in healthy donors, while SIRT1 histone H3K9 deacetylation activity was suppressed in NBNC patients. In the liver of hepatitis patients, decreased NAD(+) amounts and its regulatory enzyme nicotinamide phosphoribosyltransferase expression levels were observed, and this led to inhibition of SIRT1 activity. SIRT1 expression was associated with HIF1 protein accumulation in both the NBNC liver and liver cancer cell lines. These results may indicate that the NBNC hepatitis liver is exposed to hypoxic conditions. In HepG2 cells, hypoxia induced inflammatory chemokines, such as CXCL10 and MCP-1. These inductions were suppressed in rich NAD(+) condition, and by SIRT1 activator treatment. In conclusion, hepatic SIRT1 activity was repressed in NBNC patients, and normalization of NAD(+) amounts and activation of SIRT1 could improve the inflammatory condition in the liver of NBNC hepatitis patients. PMID- 25736101 TI - Effects of propofol or desflurane on post-operative spirometry in elderly after knee surgery: a double-blind randomised study. AB - BACKGROUND: Intravenous or volatile agents reduce respiratory function, which can result in respiratory complications in geriatric patients. We hypothesised that there would be no differences in lung function between anaesthesia established using either drug. METHODS: Elderly patients were randomly assigned to receive either propofol with remifentanil (n = 48) or desflurane (DES) with remifentanil (n = 52) for knee surgery. Spirometry tests including forced expiratory volume in 1 s (FEV1 ), forced vital capacity (FVC), forced mid-expiratory flow (FEF25-75), and FEV1 /FVC ratio were performed preoperatively, and 30 min, 60 min, and 24 h after awakening. Emergence time and post-operative pain scores were also measured. RESULTS: Time to emergence was significantly longer in the propofol than in the DES group (17.0 vs. 12.5 min, P = 0.04). Post-operative FEV1 (1.6 or 1.4 l, P = 0.68 between groups) were significantly lower than preoperative values (2.1 or 2.0 l, P = 0.001 vs. post-operative values, respectively) in both groups. Reduced FEV1 lasted for 24 h after surgery (1.7 or 1.6 l, P = 0.001 vs. preoperative values, respectively). Post-operative FVC or FEF25-75 were lower than preoperative values. FEV1 /FVC ratio did not change during the study period in both groups. There was no difference in FEV1 , FVC, FEF25-75, FEV1 /FVC, and post-operative pain between the two anaesthetic techniques. CONCLUSIONS: Although there is a delay in awakening when using propofol, the effects of propofol on post-operative spirometry parameters are similar to those of DES when anaesthesia duration is approximately 3 h. Decreased respiratory parameters persisted up to 24 h after anaesthesia, irrespective of the choice of anaesthetic. PMID- 25736102 TI - Effects of exercise training on carbohydrate and lipid catabolism in the swimming muscles of Nile tilapia (Oreochromis niloticus). AB - This study aims to determine the effects of exercise training on carbohydrate and lipid catabolism in the swimming muscles of Nile tilapia (Oreochromis niloticus) by measuring the levels of related enzymes, lipids and free fatty acids. We designed one control group and two training groups of fish that were exercised at different training intensities [0, 1 and 1.5 body lengths per second (bl/s)]. The fish in the experimental groups were trained for 12 h/day for 4 weeks. Compared with the control group, the 1 and 1.5 bl/s groups showed significantly increased hexokinase and pyruvate kinase activities in red muscle (p < 0.05). In white muscle, pyruvate kinase activity was significantly higher in the 1.5 bl/s group than in the control group (p < 0.05), and hexokinase activity did not significantly differ between the groups. The activities of hormone-sensitive lipase and carnitine palmitoyltransferase I in both muscle types were significantly lower in the training groups than in the control group (p < 0.05). The plasma-free fatty acid level decreased (p < 0.05), while the lipid percentages increased in red muscle (p < 0.05) after exercise training. These findings clearly indicated that with exercise training, glycolysis increased and lipid oxidation decreased in the swimming muscle of tilapia. PMID- 25736103 TI - Hydroxytyrosol, a dietary phenolic compound forestalls the toxic effects of methylmercury-induced toxicity in IMR-32 human neuroblastoma cells. AB - This study demonstrates the protective potential of hydroxytyrosol (HT), an olive oil phenol, against methylmercury (MeHg)-induced neurotoxicity using IMR-32 human neuroblastoma cell line. HT inhibited MeHg-induced cytotoxicity and genotoxicity as confirmed by MTT, micronucleus, and comet assays. Cells preconditioned with HT showed reduction of MeHg-induced cellular oxidative stress along with the maintenance of glutathione, superoxide dismutase, glutathione-S-tranferase, and catalase. Fluorescence microscopy and DNA ladder assays indicated the inhibitory effect of HT against MeHg-induced apoptosis, which was further established by Western blotting. An effective concentration of 5 uM HT caused downregulation of p53, bax, cytochrome c, and caspase 3 and upregulation of prosurvival proteins including nuclear factor erythroid 2-related factor 2 (Nrf2) and metallothionein. This work indicates the cytoprotective potential of HT against MeHg-induced toxicity primarily by the lowering of oxidative stress, which may be endorsed to its antigenotoxic and antiapoptotic potential, in addition to its free radical scavenging ability. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1264 1275, 2016. PMID- 25736105 TI - [Big Data: the great opportunities and challenges to microbiome and other biomedical research]. AB - With the development of high-throughput technologies, biomedical data has been increasing exponentially in an explosive manner. This brings enormous opportunities and challenges to biomedical researchers on how to effectively utilize big data. Big data is different from traditional data in many ways, described as 3Vs - volume, variety and velocity. From the perspective of biomedical research, here I introduced the characteristics of big data, such as its messiness, re-usage and openness. Focusing on microbiome research of meta analysis, the author discussed the prospective principles in data collection, challenges of privacy protection in data management, and the scalable tools in data analysis with examples from real life. PMID- 25736104 TI - [Cognitive remediation therapy for children: literature data and clinical application in a child and adolescent psychiatry department]. AB - The hypothesis of cerebral plasticity in psychiatric disorders has encouraged clinicians to develop cognitive remediation therapy (CRT), a new therapeutic approach based on attention, memory, planning, and mental flexibility tasks. The first cognitive remediation programs were developed and validated for adults with schizophrenia and were shown to have a positive impact on executive functions as well as on quality of life. In children and adolescents, researchers emphasized the existence of executive dysfunction in neurodevelopmental disorders such as autistic spectrum disorder, attention deficit disorder, and eating disorders. For these disorders, neuropsychological studies suggest that memory, planning, attention and mental flexibility are impaired. Despite the paucity of studies on cognitive remediation (CR) in children, preliminary results have suggested, as in adults with schizophrenia, good compliance and optimization of executive functioning. Consequently, programs dedicated to young subjects were developed in English-speaking countries, and the Department of Child and Adolescent Psychiatry of Sainte Anne Hospital (Paris) developed a new CR program for children with attention deficit disorder, academic problems, or eating disorders. These programs complete the field of CRT proposed by Sainte Anne Hospital's Remediation and Psychosocial Rehabilitation Reference Center, initially designed for adults with schizophrenia. Our team used and adapted validated tools such as Delahunty and Wykes's CRT program (translated and validated in French by Amado and Franck) and Lindvall and Lask's CRT Resource Pack. One program was developed for an adolescent with anorexia nervosa and applied to the subject and her family, but the purpose of this paper is to present a CR approach for children with attention deficit disorder or academic disorder, a 6-month program based on paper-pencil tasks and board and card games. The team was trained in different kinds of cognitive remediation, and the program was applied by a clinical nurse with the supervision of a child and adolescent psychiatrist and the department's neuropsychologists. Paper-pencil tasks were adapted from the CRT program for adults; the card and board games used were geometric figures, illusions, Rush Hour((r)), Set((r)), Jungle Speed((r)), Color Addict((r)), etc. These games are available in stores and the program can be applied at home, which helps families set aside their preoccupations with their child's academic performance. Diagnostic and neuropsychological evaluations were done before the beginning of the therapy and repeated at the end of the 6-month program. This program does not ignore the metapsychological impact of the therapy, and work on self-esteem is also done. The presence of the therapist is necessary, which seems better than a computer program, which cannot encourage the young subject in the same personalized and empathetic way. We therefore conducted the first clinical feasibility trial of cognitive remediation in young subjects and present a clinical case of a 6-year-old boy with attention deficit disorder and academic disorder. The results of neuropsychological evaluations before and after therapy suggest improvement in executive functions and better self-esteem. Satisfaction for the boy and his family was high. Even if these results need to be replicated, cognitive remediation appears to be a new therapeutic tool, complementary to classical approaches used in childhood psychiatric disorders. The Department of Child and Adolescent Psychiatry will submit this program to a research program conducted by the National Health Department to study the impact of this approach in a controlled study. PMID- 25736106 TI - [Induced differentiation of rat kidney stem cells into renal tubular epithelial cells]. AB - OBJECTIVE: To investigate the differentiation capability of kidney stem cells (KSCs) into renal tubular epithelial cells (RTECs). METHODS: KSCs isolated from the renal papilla of 4-week-old SD rats were co-cultured with hypoxia-exposed RTEC in induced medium (containing activin A, BMP-7, and retinoic acid) and renal epithelial cell growth medium (REGM) alternately. The KSCs cultured in MSC medium served as the control. The KSC differentiation rates in both groups were determined using flow cytometry, immunofluorescence assay and qRT-PCR. RESULTS: Flow cytometry showed a CK-18 positive rate of 6.5Percnt; in the control KSC group and of 44.2% in the induced group. Immunofluorescence assay detected the positivity for mature epithelial cell markers CK-18, E-cadherin, and ZO-1 in the induced cells. The results of qRT-PCR showed significantly increased expression of E-cadherin and AQP-1 mRNAs in the induced cells compared with the control cells (P<0.01). CONCLUSION: Rat KSCs can be induced to differentiate into RTECs in vitro. PMID- 25736107 TI - [Preparation and characterization of polyclonal antibodies against rat sodium pump alpha 2 subunit M1-M2 extra membrane fragment]. AB - OBJECTIVE: To prepare polyclonal antibodies against sodium pump alpha 2 subunit M1-M2 extramembrane fragment (NKAalpha2 EM1) for studying the pathogenesis of hypertension. METHODS: According to the GenBank data, the amino acid sequence of NKAalpha2 EM1 was obtained and the target peptide (LAAMEDEPSNDN) was synthesized using a peptide synthesizer with Fmoc method and purified with high-performance liquid chromatography. The synthesized peptide was then coupled to KLH for immunizing New Zealand white rabbits for 4 times to obtain the antiserum. The IgG antibodies against the synthetic peptide, after affinity purification with Protein A, were used for detecting NKAalpha2 EM1 expression in rat aortic vascular smooth muscle cells by enzyme-linked immunosorbent assay and immunocytochemistry (ICC). RESULTS: The synthesized peptide fragment , which consisted of 13 amino acid residues including one derivatized cysteine residue in the N-terminal (LAAMEDEPSNDN-C), had a theoretical relative molecular mass of 1408.48 D with a measured relative molecular mass of 1407.90 D and a purity exceeding 85.5%. The titer of the antiserum was more than 1:512 000, and the purified IgG antibody concentration was 0.965 mg/ml after purification with Protein A. At a 1:1000 dilution (final concentration of 1 ug/ml), the titer of the purified IgG antibody was more than 1:256 000. The purified IgG antibody could be used at 1:100 to 1:200 dilutions for for immunocytological examination of formalin-fixed cells. CONCLUSION: The anti-NKAalpha2 EM1 polyclonal antibodies obtained can be used in ELISA and immunocytochemistry for detecting the sodium pump alpha 2 subunit in formalin-fixed tissue or cells to facilitate investigation of the relationship between sodium pump and hypertension. PMID- 25736108 TI - [Construction of a vector encoding T-cell epitopes of Dermatophagoides pteronyssinus major allergen group 1 as a vaccine delivered by MHC class II pathway]. AB - OBJECTIVE: To construct a vector encoding T-cell epitopes of major allergen group 1 of Dermatophagoides pteronyssinus as a vaccine delivered by MHC class II pathway. METHODS: The nucleotide sequences of the 3 target genes were synthesized, including TAT, IhC and the recombinant fragment of Der p 1 encoding 3 T-cell epitopes. After amplification of the 3 target fragments by PCR and digestion with corresponding restriction endonucleases, the recombinant gene TAT IhC-Der p 1-3T was ligated using T4 DNA ligase and inserted into the prokaryotic expression vector pET28a(+) to construct the recombinant plasmid pET-28a(+)-TAT IhC-Der p 1-3T, which was confirmed by digestion with restriction endonucleases and sequencing. The recombinant vector was transformed into E. coli strain BL21 (DE3) and induced with IPTG, and the induced protein TAT-IhC-Der p 1-3T was detected by SDS-PAGE. After purification, the recombinant protein was confirmed by Western blotting and its allergenicity tested using IgE-binding assay. RESULTS: The recombinant plasmid pET-28a-TAT-IhC-Der p 1-3T was successfully constructed as confirmed by restriction endonuclease digestion and sequencing and the expression of the recombinant protein TAT-IhC-Der p 1-3T was induced in E. coli. Western blotting verified successfull purification of the target protein, which showed a stronger IgE-binding ability than Der p 1. CONCLUSION: We successfully constructed a recombinant expression vector pET-28a-TAT-IhC-Der p 1 3T expressing a T-cell epitope vaccine delivered by MHC II pathway with strong IgE-binding ability, which provides a basis for further study on specific immunotherapy via MHC class II pathway. PMID- 25736109 TI - [Effect of MSX2 interference on epithelial-mesenchymal transitions of pancreatic cancer cell line PANC-1]. AB - OBJECTIVE: To investigate the effect of MSX2 interference on epithelial mesenchymal transitions (EMT) of pancreatic cancer cell line PANC-1. METHODS: Three vectors containing short hairpin RNAs (shRNAs) of MSX2 (shMSX2-1, shMSX2-2, and shMSX2-3) and the empty vector (negative control) were transfected separately into PANC-1 cell line with Lipofectamine2000. Real-time RT-PCR and Western blotting were used to observe changes in the expressions of MSX2, E-cadherin, and vimentin in the cells. CCK-8 assay was used to assess the changes in the cell growth, and wound scratch assay and Transwell assay were employed to evaluate the cell invasion and metastasis after the transfection. RESULTS: Among the 3 shRNA, shMSX2-1 showed the highest interference efficiency. MSX2 knockdown by the specific shRNA of MSX2 significantly increased E-cadherin expressions, lowered vimentin expressions, and suppressed the invasion, metastasis and proliferation of the cells (P<0.05). MSX2 knockdown also resulted in morphological changes of the cells into cobblestone-like cells in close contact. RT-PCR results revealed significantly reduced mRNA expressions of the transcription factors snail and twist (P<0.05) without affecting slug and zeb1 expressions in the cells with MSX2 knockdown. Conclusion MSX2 knockdown can reverse EMT and induce MET in PANC1 cells, in which process the transcription factors snail and twist may play a role. PMID- 25736110 TI - [A proliferation-inducing ligand expression in breast cancer and its relationship with prognosis]. AB - OBJECTIVE: To explore the relationship between a proliferation-inducing ligand (APRIL) expression in primary tumor foci of breast cancer and the patients' prognosis. METHODS: Paraffin sections of surgical specimens were retrospectively collected from 130 stage I-III breast cancer patients who received surgery between January 2000 and December 2002 in our hospital. Immunohistochemistry was used to assess APRIL expression intensity in the tumor cells and density of interstitial APRIL-positive cells, and their association was analyzed with the density of interstitial CD4+ and CD8+ cells and with the histopathologic features, overall survival (OS), and disease-free survival (DFS) of the patients. RESULTS: APRIL positive staining was found in the cytoplasm of the tumor cells, interstitial cells, and the extracellular matrix. APRIL intensity in the tumor cells was positively correlated with the density of interstitial APRIL-positive cells (P=0.009) and Ki67 (P=0.003). The density of interstitial APRIL-positive cells was positively correlated with the density of interstitial CD4+ cells (P<0.001) and CD8+ cells (P<0.001). In hormone receptor negative patients (ER- and PR-), multivariate COX regression identified the density of interstitial APRIL-positive cells as a positive prognostic factor for DFS (HR=0.313, 95% CI=0.107-0.920, P=0.035). CONCLUSIONSl APRIL is widely expressed in the interstitial immune cells in breast cancer. APRIL staining intensity in the tumor cells is positively correlated with tumor proliferation, indicating that the immune cells might promote tumor proliferation by secreting APRIL. A greater density of interstitial APRIL-positive cells is associated with a good prognosis in hormone receptor-negative patients. PMID- 25736111 TI - [Role of KA1 receptor in excitotoxic neurodegeneration in mouse hippocampus triggered by kainic acid- or tunicamycin-induced endoplasmic reticulum stress]. AB - OBJECTIVE: To explore the effect of up-regulation of KA1 subunit of the kainate receptor on endoplasmic reticulum stress (ERS)-induced excitotoxic neurodegeneration in mouse hippocampus. METHODS: Seventy adult male KM mice were subjected to microinjections into the hippocampus of kainic acid (KA) or 500, 1000, or 2000 ug/ml tunicamycin (TM). At 1, 2, 3, 4, 5, 8, and 12 h after the injections, the mice were assessed for Bederson scores and sacrificed for FJB staining and immunofluorescence observation of the brain slices. RESULTS: At 3, 4, 5, and 8 h after KA injection and at 4 and 5 h after of 2000 ug/ml TM injection, the mice showed severe central nervous system dysfunction, and FJB staining revealed increased cell death in the hippocampus, where up-regulated expressions of KA1 receptor and ERS marker P-eIF2alpha were found by immunofluorescence staining (P<0.05). CONCLUSION: Microinjection of KA or TM into the hippocampus causes neuronal death and ERS with up-regulated expression of KA1. In this process of neuronal apoptosis, the membrane receptor KA1 receives the apoptosis signal and transfers it to the inside of the cells to cause cell endoplasmic reticulum dysfunction and ERS response, which ultimately leads to neuronal death. PMID- 25736112 TI - [Expression of CD133 and Notch1 in non-small cell lung cancer and the clinicopathological significance]. AB - OBJECTIVE: To investigate the presence of cancer stem cells (CSCs) exist in non small cell lung cancer (NSCLC) and explore the relationship among the expressions of CD133, Notch1, and vascular endothelial growth factor (VEGF) and their relations with the clinicopathological parameters of the patients. METHODS: A total of 305 specimens of NSCLC and 80 normal lung tissue specimens were analyzed for CD133, Notch1, and VEGF protein expressions by immunohistochemical staining. RESULTS: In NSCLC specimens, the positivity rates of CD133, Notch1, and VEGF were 48.9%, 43.9%, and 45.6%, respectively, significantly higher than those in normal lung tissues (10.0%, 15.0%, and 0%, respectively, P<0.01). The expression levels of CD133, Notch1, and VEGF proteins were significantly correlated with the tumor grades, lymph node metastasis, TNM stages, and postoperative survival time of the patients (P<0.01). A positive correlation was found among the expression levels of CD133, Notch1, and VEGF proteins. Kaplan-Meier survival analysis showed a significantly lower overall mean survival time of the patients positive for CD133, Notch1, and VEGF than that of the negative patients (P<0.001). Cox regression analysis suggested that positive expressions of CD133 and Notch1 were independent prognostic factors of NSCLC (P<0.05). CONCLUSIONS: CD133, Notch1, and VEGF may play important roles in the occurrence, progression, invasion, and metastasis of NSCLC. CD133 and Notch1 have important values for predicting the prognosis and evaluating disease progression of the patients. PMID- 25736113 TI - [Changes in splenocyte proliferation, subsets and cytokine production in mice immunized with recombinant vaccine Bifidobacterium bifidum (pGEX-Sj32) of Schistosoma japonicum]. AB - OBJECTIVE: To observe the dynamic changes of immune responses of splenocytes in mice immunized with recombinant vaccine Bifidobacterium bifidum (pGEX-Sj32) of Schistosoma japonicum and investigate the immunological mechanism of the vaccine. METHODS: Eighty-eight BALB/c mice were randomized for immunization with 106 CFU recombinant vaccine orally or with 105 CFU recombinant vaccine intranasally. Four mice were selected from each group every two weeks to test the responses of the splenocytes to stimulations with SjAWA or ConA. MTT assay and flow cytometry were used to assess splenocyte proliferation and the distribution of CD4+ and CD8+ T cells, respectively; the levels of interleukin-10 (IL-10), IL-12 and tumor necrosis factor-alpha (TNF-alpha) in the cell culture supernatant were detected by ELISA. RESULTS: Regardless of the stimulations, the splencytes showed significantly enhanced proliferation in weeks 2-16 in oral administration group and in weeks 2-18 in intranasal group (P<0.01). CD4+ subsets in both two groups increased obviously in weeks 2-12 (P<0.01) but CD8+ subsets remained stable. In oral administration group, the levels of TNF-alpha, IL-10 and IL-12 increased in weeks 2-14, 2-18 and 2-14, and peaked at week 8, 10 and 6, respectively; in intranasal group, the cytokines increased in weeks 2-14, 2-18 and 2-18, and peaked at week 8, 10 and 8, respectively. CONCLUSION: The recombinant vaccine rBb (pGEX-Sj32) can induce effective immune responses in mice. PMID- 25736114 TI - [18F-FDG PET/CT for predicting outcomes of diffuse large B-cell lymphoma: shall it be performed in the interim versus later phase of chemotherapy?]. AB - OBJECTIVE: To compare the value of 18F-FDG PET/CT performed in the interim and later phase of chemotherapy in predicting the prognosis of diffuse large B-cell lymphoma (DLBCL). METHODS: 18F-FDG PET/CT was performed in 71 patients with DLBCL in the interim phase of chemotherapy (3-4 cycles) and in another 71 patients in the later phase of chemotherapy (5-8 cycles). The patients were followed up for an average of 28.73 months (18-114 months) to compare the progression-free survival (PFS) and the PFS rate. RESULTS: The positive finding rate was similar between 18F-FDG PET/CT performed in the interim and the later phase (36.6% vs 33.8%, X2=12.423, P>0.05). The PFS was much longer in patients with negative findings than in those with positive findings in both the interim (63.56 vs 19.23 months, P=0.000) and later phase groups (65.78 vs 24.32 months, P=0.000), but showed no significant difference between the negative patients (P>0.05) or between the positive patients (P>0.05) in the two groups. The PFS rate was significantly greater in patients with negative than those with positive findings in the interim group (73.3% vs 15.4%, P=0.000) and in the later phase group (74.5% vs 16.7%, P=0.000), but comparable between the negative (P>0.05) and between the positive patients (P>0.05) in the two groups. CONCLUSIONS: 18F-FDG PET/CT in the interim and later phase of chemotherapy has similar value for predicting the prognosis of DLBCL, and we therefore recommend that 18F-FDG PET/CT be performed in the interim but not in the later phase. PMID- 25736115 TI - [Differential expression of miRNAs in myocardial tissues of rats with lipopolysaccharide- induced endotoxemia]. AB - OBJECTIVE: To analyze the differential miRNA expression profile in the myocardium of rats with lipopolysaccharide (LPS)-induced endotoxemia and explore the role of miRNA in endotoxin-induced myocardial injury. METHODS: Twenty male SD rats received intraperitoneal injection of 10 mg/kg LPS (n=10) or an equivalent amount of saline solution (n=10). At 24 h after LPS injection, the rats were sacrificed to detect myocardial expressions of TLR4, TNF-alpha and IL-1beta using real-time PCR and for observing myocardial ultrastructures under transmission electron microscopy. The differentially expressed miRNA in the myocardium were detected using a miRNA array, and the common differentially expressed miRNAs were selected for verifying their actual expressions using real-time PCR. RESULTS: TLR4, TNF alpha and IL-1beta were over-activated in the myocardium of LPS-treated rats, in which mitochondria swelling, structural damaged and cytoplasmic vacuoles were observed. In LPS-challenged rats, miR-194-3p, miR-344a-3p, miR-465-3p, miR-501 5p, miR-3596c, miR-185-3p, and miR-877 were found up-regulated significantly, whereas miR-208b-3p, miR-547-3p, miR-141-3p, miR-28-5p, and miR-3585-5p down regulated in the myocardium. CONCLUSION: Significant differential expression of the miRNAs occurs in the myocardium of LPS-treated rats, suggesting their involvement in endotoxin-induced myocardial injury. PMID- 25736116 TI - [Internal fixation surgery planning for complex tibial plateau fracture based on digital design and 3D printing]. AB - OBJECTIVE: To investigate the application of 3D printing and digital technology in preoperative assessment and planning of internal fixation surgery for complex tibial plateau fracture. METHODS: Complex tibial plateau fractures and commonly used plates for tibial plateau were imaged using computed tomography (CT) to reconstruct the 3D fracture and plate models. The 3D models were used to perform virtual reduction and preoperative planning of internal fixation surgery with the most appropriate plates assisted by the 3D library of plates. According to the optimal plan, the 3D physical models of tibial plateau fractures and plates were 3D printed to simulate internal fixation operation. The effects of internal fixation were compared between the virtual surgery and the simulated surgery based on the 3D models. RESULTS: The effects of internal fixation in the simulated surgery based on the 3D models were consistent with those of the virtual surgery. No significant difference was found in the screw length between the two surgeries. CONCLUSION: The combination of 3D printing and digital design can improve the effects of internal fixation for complex tibial plateau fractures. PMID- 25736117 TI - [High-intensity focused ultrasound inhibits tumor metastasis in a melanoma bearing mouse model]. AB - OBJECTIVE: To investigate the effect of high-intensity focused ultrasound (HIFU) on tumor metastasis in mouse model bearing melanoma xenograft. METHODS: Mice bearing murine melanoma B16-F10 cell xenograft were randomized for sham-HIFU or HIFU exposure when the tumors grew to a maximum diameter of 7-10 mm, and the tumor size was measured every 3 days. The cumulative survival rate of the mice and tumor metastasis rate were calculated, and the circulating melanoma cells were detected using qRT-PCR. At 14 days after HIFU treatment, B16-F10 cells were retransplanted via the tail vein and the pulmonary metastatic nodules were counted. RESULTS: The median survival time of the mice was 19.00 days (95% CI 17.14-20.86 days) in the sham group and 26.00 days (95%CI 24.76-27.25 days) in HIFU group. The cumulative survival rate in the HIFU group was significantly higher than that in sham-HIFU group (P<0.01), and the tumor size was significantly smaller in HIFU group at 20, 23, and 26 days after HIFU treatment (P<0.05). Compared with the sham-HIFU group, HIFU group had significantly lower levels of MAGE-A3, MART1 and PAX3 at 7 days after HIFU (P<0.05) with still lower MAGE-A3 level at 14 days (P<0.05). HIFU group showed a significantly smaller number of pulmonary metastatic nodules following tumor cell retransplantation than in sham-HIFU group (P<0.01) with a metastasis inhibition rate of 42.4%. CONCLUSION: HIFU treatment can inhibit tumor metastasis in melanoma-bearing mice possibly by reducing tumor cell detachment from the primary tumor site and suppressing colonization of the circulating melanoma cells. PMID- 25736118 TI - [Caspase-independent programmed cell death induced by temozolomide in rat glioma C6 cell line]. AB - OBJECTIVE: To investigate programmed cell death induced by temozolomide in rat glioma C6 cell line. METHODS: Rat glioma C6 cell line was treated by temozolomide at different concentrations and for different time lengths. MTT assay was used to evaluate the cell inhibition rate to determine the optimal exposure time and concentration. After the exposure to 400 ug/ml temozolomide for 24 h, the cells were observed for programmed cell death using HE staining, Hochest and Tunnel assay, Western blotting, and immunohistochemistry. RESULTS: MTT, HE staining, and Hochest and Tunnel assay all showed temozolomide-induced apoptosis in rat glioma C6 cell line. Western blotting and immunohistochemistry revealed up-regulation of Bax and down-regulation of Bcl-2 expression in the exposed cells, where the expressions of caspases 3, 8, 9, and 12 remained unchanged. CONCLUSION: Temozolomide induces apoptosis in rat glioma C6 cell line through a caspase- independent pathway. PMID- 25736119 TI - [Analysis of population genetic structure of Anopheles sinensis based on mitochondrial DNA cytochrome oxidase subunit I gene fragment]. AB - OBJECTIVE: To study the population genetic variation, genetic diversity and phylogenesis of Anopheles sinensis in China. METHODS: Anopheles sinensis samples collected from Shandong, Anhui, Jiangsu, Guizhou, and Yunnan Provinces and Guangxi Zhuang Autonomous Region with different geographical conditions between 2010 and 2012 were analyzed by mitochondrial DNA cytochrome oxidase subunit I (mtDNA-COI) gene amplification and sequencing. Bioedit 7.0 and DnaSP 5.0 software was used to compare the gene sequences and analyze the population genetic structure, respectively. Arlequin 3.1 was used to calculate the genetic distance and parameters of population differentiation. The relationship between the geographic and genetic distances was analyzed using IBD Web Service. PHYLIP 3.6 was used to construct the phylogenetic tree. RESULTS: PCR amplification and sequencing was performed successfully for 6 Anopheles sinensis populations containing 123 female mosquitoes. The length of mtDNA-COI gene fragment was 841 bp with an average A+T content of 71.2% and G+C content of 28.8%. High nucleotide diversity and genetic differentiation were observed among the Anopheles sinensis populations based on mtDNA-COI gene. Analysis of the molecular variance revealed a greater variation between populations than that within populations with isolation by distance between the populations. The Anopheles sinensis populations appeared to have undergone expansion, but the Yunnan population constituted an isolated branch in the phylogenetic tree. CONCLUSION: mtDNA-COI can serve as the molecular marker to analyze population genetic variation and phylogenesis of Anopheles sinensis. The Yunnan population shows a phylogenetic difference from the other populations analyzed in this study. PMID- 25736120 TI - [Src kinase inhibitor PP2 protects rat astrocytes from hypoxia/reoxygenation injury in vitro]. AB - OBJECTIVE: To investigate the effect of Src kinase inhibitor PP2 on hypoxia/reoxygenation (H/R) injury in rat astrocytes in vitro. METHODS: In vitro cultured rat astrocytes were exposed to hypoxia for 8 h followed by reoxygenation for 24 h with or without pretreatment with PP2 (10 umol/L) for 24 h before H/R injury. MTT assay and flow cytometry were used to detect the viability and apoptosis of the exposed astrocytes, respectively, and the protein expressions of Src, Bax, and Bcl-2 in the cells were determined using Western blotting. RESULTS: PP2 pretreatment significantly increased the viability and decreased the apoptosis rate of rat astrocytes exposed to H/R injury (P<0.01). Western blotting showed that H/R injury caused increased expression of Src kinase, which was lowered by PP2 pretreatment. The ratio of Bax/bcl-2 in the astrocytes increased after H/R injury, and was significantly decreased by PP2 pretreatment (P<0.01). CONCLUSION: PP2 protects rat astrocytes from H/R injury possibly by inhibiting the expression of Src kinase and activating the anti-apoptotic mechanisms in the cells. PMID- 25736121 TI - [Factors affecting oculomotor nerve function recovery time following balloon embolization for oculomotor nerve palsy caused by traumatic carotid cavernous sinus fistula]. AB - OBJECTIVE: To analyze the factors that affect oculomotor nerve function recovery time in patients receiving balloon embolization for oculomotor nerve palsy caused by traumatic carotid cavernous sinus fistula. METHODS: The clinical data were collected from 87 patients undergoing balloon embolization for oculomotor nerve palsy due to traumatic carotid cavernous sinus fistula from July 2005 to July 2013 and the factors affecting oculomotor nerve function recovery time was analyzed using a self-made questionnaire. RESULTS AND CONLUSION: Oculomotor nerve function recovery time ranged from 1 to 6 months (mean 33.32 +/- 16.76 days) in these patients. Age, severity of preoperative oculomotor nerve paralysis, injury to-treatment time, and number of balloon used were positively correlated with nerve function recovery time, and the flow volume of traumatic carotid cavernous sinus fistula was negatively correlated with the recovery time. PMID- 25736122 TI - [Effects of uterine adenomyosis on clinical outcomes of infertility patients treated with in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET)]. AB - OBJECTIVE: To explore the effects of uterine adenomyosis on the clinical outcomes of infertility patients treated with in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). METHODS: A retrospective study was conducted of 61 IVF/ICSI-ET cycles as the study group, diagnosed with uterine adenomyosis by transvaginal ultrasound, and 164 IVF/ICSI-ET cycles of patients with tubal infertility as the control group. The baseline characteristics, ovary response and clinical outcomes were compared between the two groups. RESULTS: The implantation rate, clinical pregnancy rate and live birth rate decreased significantly in the study group (P<0.05), and early abortion rate increased significantly (P<0.05). For patients with adenomyosis, GnRH-antagonist cycles tended to decrease clinical pregnancy rate and increase abortion rate (25.0% vs 45.0%, P=0.184; 66.7% vs 27.8%, P=0.247), and significantly decrease live birth rate (0% vs 30.8%, P=0.025), compared with GnRHa agonist cycles. CONCLUSION: Uterine adenomyosis decreases implantation rate, clinical pregnancy rate and birth rate, and increases abortion rate significantly in patients with IVF/ICSI ET. GnRH-antagonist cycles have adverse effects on the outcomes of adenomyosis; GnRH agonist long protocol cycles may increase clinical pregnancy rate and decrease abortion rate. PMID- 25736123 TI - [Changes in muscle spindle afferent discharge activities in rat soleus following hindlimb immobilization]. AB - OBJECTIVE: To investigate the changes in the afferent discharge activities of the sensory nerve endings in muscle spindles of rats with hindlimb immobilization. METHODS: Plaster cast was used immobilize the hindllimbs of rats. Using air-gap technique, the spontaneous discharge of the muscle spindles and its responses to perfusion with succinylcholine (0.05 mg/ml) and suspension in an extended position were observed in isolated muscle spindles from rats with hindlimb immobilization for 3, 7, and 14 days. RESULTS: The muscle spindles of rat soleus showed a sharp decrease in spontaneous discharge frequency (P<0.01) and response to succinylcholine perfusion after 3 days of hindlimb immobilization (P<0.05). Significant changes of the firing rate in an extended position was observed in rats after a 14-day immobilization (P<0.01). The duration of individual spikes was significantly prolonged following hindlimb immobilization (P<0.01). CONCLUSION: Muscle spindle discharges decrease significantly in rats following hindlimb immobilization, which might be related to reduced contractile properties of the muscle spindle. PMID- 25736124 TI - [Association of single nucleotide polymorphisms in the promoter of GABAA receptor beta2 subunit gene with schizophrenia]. AB - OBJECTIVE: To investigate the genetic association between schizophrenia and the polymorphism of GABA(A) receptor beta2 subunit (GABRB2) gene. METHODS: A population association analysis was performed of 5 single nucleotide polymorphisms (SNPs) in the proximal promoter of GABRB2 gene by PCR and sequencing of the genomic DNA in a cohort of 172 schizophrenics and 167 controls of Chinese Han nationality. RESULTS: One out of the 5 SNPs, namely rs3811996, was found to be significantly associated with schizophrenia especially in the male cohorts, where the heterozygous genotypes (A/G) and minor allele G displayed lower frequencies in case group than in the controls. CONCLUSION: We found a new risk, SNP rs3811996, for paranoia schizophrenia, which further supports the importance of genetic variations of GABRB2 in the etiology of schizophrenia. PMID- 25736125 TI - [Correction of enhanced dynamic wedge factor and analysis of monitor unit calculation]. AB - OBJECTIVE: To study the correction of algorithm for Varian enhanced dynamic wedge(EDW) factors and compare the dose/monitor unit (MU) deviation measured at the central axis of EDW field with that obtained by manual calculation or using the treatment planning system. METHODS: EDW factors and dose were measured with Thimble ion chamber at 10 cm depth under the water for 6 MV and 10 MV photon on Varian linear accelerator. The corresponding calculations were done with the radiation treatment planning system. An analytic formula, namely the MU Fraction model, was used to calculate the EDW factor, which was corrected with a constant factor. The MU of conventional 2-D planning derived from manual calculating, treatment planning system, and actual measurements were compared. RESULTS: With the measured results as the standard, the corrected manual calculation deviation of EDW factors was significantly reduced. For photon 6 MV, the maximum deviation reduced from 4.2% to 1.3% for 60 degrees symmetry fields was, and from -4.7% to 1.8% for asymmetric fields. For photon 10 MV, the maximum deviation for all EDW fields was reduced from -3.0% to 1.1%. Comparison of the manual calculations with the measured results showed a MU deviation for symmetric fields within 2%, and more than 5% for some asymmetric fields. The deviation between the calculations of the treatment planning and the measured results was less than 1.5%. CONCLUSION: Constant factor correction can effectively reduce the deviation of manual calculation. For MU calculation of EDW field in conventional 2-D dimensional treatment planning, the corrected results of symmetric fields meet clinical requirements. While the minimum distance between the field edge and the central axis was less than 4 cm in asymmetric fields, the corresponding special method, measurement or the treatment planning system should be used to calculate the dose/MU. PMID- 25736126 TI - [Application of dexmedetomidine combined with propofol in patients undergoing painless colonoscopy for colonic polyps resection under Narcotrend monitoring]. AB - OBJECTIVE: This clinical study was conducted to investigate the effects of dexmedetomidine (DEX) combined with propofol on vital signs and anaesthetic depth in patients. METHODS: Ninety patients with ASA 1-2 requiring painless colonoscopy for colonic polyps resection were randomized to receive DEX 0.3 micro;g/kg (group D, n=45) followed by propofol 1 mg/kg or propofol 2 mg/kg (group C, n=45), and according to the body activity and operation time, additional doses of propofol (0.2-0.5 mg/kg) were given. The full recovery time, operation time, consumed dose of propofol, mean arterial pressure (MAP), heart rate (HR), hemoglobin oxygen saturation levels(SPO2) and NTI were recorded. RESULTS: The SPO2recover time and the consumed dose of propofol in group D were decreased compared to those in group C (P<0.01). The rate of the body activity in group D was lower than that in group C (P<0.05). The NTI in group C was lower than that in group D (P<0.05). The HR and MAP were similar in both groups. CONCLUSION: Under Narcotrend monitoring, the value of DEX combined with low dose of propofol in colonoscopy for colonic polyps resection is to reach more reasonable depth of anesthesia to reduce adverse responses and the dose of propofol. PMID- 25736127 TI - [Preparation and characterization of uricase in uricase-catalase liposomes prepared using borate buffer]. AB - OBJECTIVE: To characterize the property of uricase loaded in uricase-catalase liposomes (BUCLPs) prepared using borate buffer. METHODS: BUCLPs were prepared using reverse-phase evaporation, and the physicochemical properties of uricase in the prepared BUCLPs were examined. RESULTS: The optimal temperature of BUCLP and URI was 40 degrees celsius, their optimal pH values were 8.0 and 8.5, and their Michaelis-Menten constants were 14.207 umol/L and 13.623 umol/L, respectively. Fluorescence intensity of nanoliposome-loaded uricase-catalase that bound to FITC was higher than that of uricase-catalase binding directly with FITC; the fluorescence intensity of BUCLP was higher than that of free uricase-catalase at 280 nm. CONCLUSION: Uricase activity is enhanced after loading in uricase and catalase liposomes. PMID- 25736128 TI - [A prognostic model for predicting extracorporeal circuit clotting in patients with continuous renal replacement therapy]. AB - OBJECTIVE: To establish a prognostic model for predicting extracorporeal circulation clotting in patients with continuous renal replacement therapy (CRRT). METHODS: 425 patients with CRRT were involved in the study. We built a predictive risk model of extracorporeal blood clotting with the 302 participants, and 103 participants were used to validate the model. The primary endpoint of CRRT was extracorporeal circulation pipe blockage. RESULTS: We used a score of 0 5 point evaluating system to predict the risk of 24 hours CRRT integral model of cardiopulmonary bypass clogging. The area under the CRRT predictive model of cardiopulmonary bypass clogging integral system ROC curve was 0.790 (95% CI 0.719 0.826) (P<0.001). The evaluating system can determine the blockage of 24 hours CRRT extracorporeal circulation. The results showed that CRRT extracorporeal plugging prediction fitted the integral model and could predict the chance of plugging. The actual plugging rate showed no significant difference from the predicted rate (R2 = 0.301, P=0.232). The cardiopulmonary pipe survival time between the 3 groups(low risk, intermediate risk, and high risk) showed a significant difference (P<0.05). CONCLUSION: We established a continuity extracorporeal blood purification plugging risk score model, to predict plugging risks during CRRT treatment. PMID- 25736129 TI - [Effect of Gold Belt combined with methylprednisolone on motor function and brain derived neurotrophic factor expression in rats following traumatic spinal cord injury]. AB - OBJECTIVE: To study the effects of a Gold Belt (GB, a traditional Chinese herbal medicine) combined with methyl-prednisolone (MP) on the motor function and brain derived neurotrophic factor (BDNF) expression in rats with contusive spinal cord injury (SCI). METHODS: Thirty adult female SD rats were randomly divided into 5 equal groups, namely the sham-operated group, SCI group, SCI with MP treatment group (MP group, with intramuscular injection of 50 mg/kg MP within 8 hours after SCI and then dosage reduced 10 mg/kg daily), SCI with GB treatment group (GB group, with intragastric gavage of GB 50 mg/kg once daily for 7 days), and combined GB and MP treatment group. The Basso, Beattie and Bresnahan (BBB) locomotor scale was used to evaluate the hindlimb motor function of the rats on days 1, 3, 7, 14, 21 and 28 after the injury. After the last evaluation the rats were sacrificed for immunohistochemistry to observe the localization of BDNF in the ventral and dorsal horn of spinal cord. RESULTS: BDNF were distributed mainly in neurons in the spinal cord grey matter ventral horn and dorsal horn of the rats. The number of BDNF-positive neurons and BBB scores in the combined treatment group were significantly higher than those in the other 4 groups (P<0.05). CONCLUSION: GB combined with MP produces better therapeutic effects for treating SCI than GB or MP used alone, and such effects are probably related with enhanced BDNF expression in the spinal cord. PMID- 25736130 TI - [Lentiviral vector-mediated short hairpin RNA targeting survivin inhibits abdominal growth of human endometrium xenograft in nude mice]. AB - OBJEVTIVE: To investigate the inhibitory effect of lentiviral vector-mediated short hairpin RNA targeting survivin (LV-survivin shRNA) on the growth of human endometrium xenograft in the abdominal cavity of nude mice. METHODS: The endometrium xenografts from 8 women with endometriosis were injected into the peritoneal cavities of 45 nude mice. The mice were then randomly assigned to receive intraperitoneal injection of LV-survivin shRNA, pGCL-NC-GFP (negative control) or PBS (blank control). Two weeks later, the number and morphometry of endometriotic lesions were quantified and the expression of survivin protein were detected by immunohistochemistry. RESULTS: The formation of endometriotic lesions was significantly suppressed in mice receiving LV-survivin shRNA injection as compared with those in the two control groups (P/0.001). The mice in LV-survivin shRNA group showed significantly down-regulated expression levels of survivin protein compared with those in the negative and blank control groups, presenting also necrosis in the endometriosis-like lesions in microscopic observation. CONCLUSION: Lentiviral vector-mediated shRNA can effectively inhibit the expression of survivin in human endometrium xengrafts and suppress the formation and growth of endometriotic lesions in the abdominal cavities of nude mice. PMID- 25736131 TI - [Expression of transient receptor potential canonical 1 in ozone-induced inflammatory lung tissues in mice]. AB - OBJECTIVE: To detect the expression of transient receptor potential canonical 1 (TRPC1) in a mouse model of ozone-induced lung inflammation and explore its role in lung inflammation. METHODS: In a mouse model of lung inflammation established by ozone exposure, the expression of TRPC1 in the inflammatory lung tissues was detected by RT-PCR, Wstern blotting and immunohistochemistry. RESULTS: Compared to the control mice, the mice exposed to ozone showed significantly increased expression level of TRPC1 mRNA and protein in the inflammatory lung tissues (P<0.05). Immunohistochemistry showed increased TRPC1 protein expressions in the alveolar epithelial cells, bronchial epithelial cells, and inflammatory cells in the inflammatory lung tissues (P<0.05). The mRNA and protein expression levels of TRPC1 were positively correlated with the counts of white blood cells, macrophages, neutrophils and lymphocytes in the bronchoalveolar lavage fluid of the exposed mice (P<0.01). CONCLUSION: TRPC1 may play a role in ozone-induced lung inflammation in mice. PMID- 25736132 TI - [Application of domestically made endoscopic stapling instrument for laparoscopic assisted rectal cancer resection]. AB - OBJECTIVE: To investigate the safety and feasibility of domestically made endoscopic stapling instrument in laparoscopic assisted rectal cancer resection (Dixon). METHODS: Sixty-four patients with rectal cancer were randomly divided into the research group (35 cases) to receive laparoscopic assisted rectal cancer resection using ENDO RLC general endoscopic linear cutter and single-use loading unit and circular staplers with staples (from REACH medical equipment co.LTD) and the control group (29 cases) to receive surgery with the corresponding products widely used (fom Johnson and Johnson Medical Euipment C.Ltd). The clinical data of the two groups were compared. RESULTS: Satisfactory therapeutic effects were obtained in all the cases. The two groups showed no significant differences in the operative time, intraoperative anastomosis success rate, or postoperative complications (anastomotic bleeding, leakage, or stricture) between the two groups (P>0.05), but the average cost of endoscopic stapling instrument was significantly lower in the research group (6604.31 +/- 699.95 vs 7822.28 +/- 576.98 RMB Yuan, P<0.05). CONCLUSION: The domestic endoscopic stapling instrument is safe, effective and less costly for laparoscopic assisted rectal cancer resection. PMID- 25736133 TI - [Effect of mTOR plasmid transfection on growth of breast cancer MCF-7 cells in vitro]. AB - OBJECTIVE: To investigate the effect of mTOR signal transduction pathway and down regulating anti-oncogene PTEN on the growth of breast cancer MCF-7 cells. METHODS: MCF-7 cells were transfected with the eukaryotic expression plasmid pcDNA3.1-mTOR and non-loaded plasmid, and the expression of mTOR in the cells was detected using Western blotting. Flow cytometry was used to analyze apoptosis and cell cycle of the transfected cells, and the expression of PTEN was detected after transfection. RESULTS: The cells transfected with pcDNA3.1-mTOR showed a increased growth rate than those transfected with the non-loaded plasmid and those without transfection. The expression of the protein PTEN decreased obviously in the cells after mTOR trasnfection. CONCLUSION: mTOR can regulate the expression of PTEN via PI3K/AKT/PTEN pathways through a negative feedback mechanism. Increased mTOR expression promotes MCF-7 cell growth, suggesting the potential value of mTOR specific inhibitor in the treatment of breast cancer. PMID- 25736134 TI - [Effect of intensive pretreatment with atorvastatin calcium on outcomes of percutaneous coronary intervention in elderly patients with coronary heart disease]. AB - OBJECTIVE: To observe the effects of different loading doses of atorvastatin calcium on the outcomes of percutaneous coronary intervention (PCI) in elderly patients with coronary heart disease (CHD). METHODS: A total of 120 CHD patients aged over 80 years were randomly assigned into 3 equal groups to receive intensive pretreatment with statin at the doses of 20, 40, or 60 mg prior to PCI performed within 48 to 72 h after admission. The changes of postoperative cardiac biochemical markers including creatine kinase isoenzyme (CKMB), troponin I (cTNI) and high-sensitivity c-reactive protein (hs-CRP) were observed and the incidence of major adverse cardiac events (MACE, including cardiac death, myocardial infarction, and target vessel revascularization) were recorded within 30 days after PCI. RESULTS: Thirty-four patients in 20 mg statin group, 40 in 40 mg statin group, and 38 in 60 mg statin group completed this study. In all the 3 groups, hs-CRP level significantly increased at 12 and 24 h after PCI compared with the preoperative levels (P<0.05). The patients in 60 mg statin group showed significantly lower levels of CKMB, cTNI, and hs-CRP at 24 h after PCI than those in 20 mg statin group (P<0.05), and had also a significantly lower incidence of total MACE within 30 days after PCI (2.6% vs 26.5%, P=0.003) resulting primarily from significantly reduced myocardial infarction associated with PCI (2.6% vs 20.6%, P=0.016). The adverse drug reactions were comparable among the 3 groups (P>0.05). CONCLUSIONS: Intensive pretreatment with 60 mg/day atorvastatin calcium can significantly reduce myocardial infarction related to PCI with good safety in elderly patients with CHD. PMID- 25736135 TI - [Research progress in the correlation between insulin resistance and pulmonary arterial hypertension]. AB - Pulmonary arterial hypertension (PAH) is a common clinical syndrome characterized by dysfunction of pulmonary arterioles leading to increased vascular resistance and elevated pulmonary artery pressure. Insulin resistance (IR) is recognized as a critical risk factor for cardiovascular disease, but recent evidence suggested an association between IR and PAH. The pathological consequences of IR, such as hyperinsulinemia, dyslipidemia, chronic inflammation, and oxidative stress can cause pulmonary vasoconstriction, endothelial dysfunction and vascular remodeling, which aggravate the progressive course of PAH. Therefore, addressing the molecular mechanisms by which IR promotes the development of pulmonary hypertension and searching for appropriate interventions are important in the management of PAH. PMID- 25736136 TI - [Diagnostic value of hemomyelogram for acute appendicitis]. AB - OBJECTIVE: To analyze the relationship between hemomyelogram and sererity of acute appendicitis and identify the best routine blood test feature for perforation. METHODS: 721 patients were included in this study, all of whom underwent appendectomy for the clinical diagnosis of appendicitis during the years of 2010-2013. The initial preoperative hemomyelogram was evaluated at different stages of appendicitis. The area under the ROC curve was used to assess the clinical feature with greater diagnostic accuracy of perforation. Total lymphocyte counts of 1.83 was used in the prediction of perforative appendicitis. A group of 467 patients was used for validation to confirm the diagnostic value of the cut-off value. RESULTS: The percentage of lymphocytes had the closest association with the evolutionary phase of acute appendicitis. Total lymphocyte counts < or=1.83 indicated perforation, with high sensitivity and low specificity. CONCLUSION: The percentage of lymphocytes and total lymphocyte counts are helpful as a diagnostic paramete for different stages of acute appendicitis. PMID- 25736137 TI - [Spontaneous renal hemorrhage caused by invasive mole: a case report]. AB - Gestational trophoblastic tumors (GTTs) are malignant lesions that often cause abnormal genital bleeding and may present with hemoptysis, intraperitoneal bleeding or acute neurologic deficits. GTTs are generally highly chemosensitive with more favorable outcomes than other comparable malignancies. Here we report a rare case of invasive mole (FIGO stage IV, WHO score16) presenting with renal subcapsular hematoma due to bleeding renal metastasis. The patient had a pretreatment beta-human chorionic gonadotrophin (beta-HCG) level of 462 047 mIU/ml and received combined chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine with also adjuvant surgeries including hysterectomy and nephrectomy. The patient recovered well and the tumor has remained in complete remission for one year and a half. PMID- 25736138 TI - [Ebstein's anomaly with refractory right-sided heart failure and leg ulcers: a case report]. AB - Ebstein malformation is a congenital heart disease characterized pathologically by displacement of the septal leaflet of the tricuspid valve towards the apex of the right ventricle of the heart. Hypoplasia, dysfunction of the right ventricle and tricuspid regurgitation cause an increased volume load of the right heart and result in the clinical manifestations of chest tightness, shortness of breath and fatigue after activities, palpitation, cyanosis and heart failure. We report a case of Ebstein's anomaly with refractory right heart failure and leg ulcers. PMID- 25736139 TI - Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project. AB - The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2 years follow-up (2007-2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4 monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (beta = -0.071), FSH (beta = -0.085), LH (beta = -0.070), and E1 (beta = 0.107) remained significantly associated with BMD loss in multivariate-adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171; hip, n = 44; and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging. PMID- 25736141 TI - Editorial: quadruple therapy for H. pylori eradication is better than triple therapy. PMID- 25736140 TI - Diagnosis and risk stratification in patients with anti-RNP autoimmunity. AB - INTRODUCTION: Anti-RNP autoantibodies occur either in mixed connective tissue disease (MCTD) (with a frequently favorable prognosis), or in systemic lupus erythematosus (SLE) cases with aggressive major organ disease. It is uncertain how to assess for the risk of severe disease in anti-RNP + patients. METHODS: Following institutional review board-approved protocols, clinical data and blood were collected from patients with known or suspected anti-RNP autoimmunity and normal controls in a cohort study. Samples were screened for parameters of immune activation. Groups were compared based on clinical diagnoses, disease classification criteria, disease activity and specific end-organ clinical manifestations. RESULTS: Ninety-seven per cent of patients satisfying Alarcon Segovia MCTD criteria also met Systemic Lupus International Collaborating Clinic (SLICC) SLE criteria, while 47% of the anti-RNP + SLE patients also met MCTD criteria. Among SLICC SLE patients, MCTD criteria were associated with reduced rates of renal disease (odds ratio (OR) 4.3, 95% confidence interval (CI) 1.3 14.0), increased rates of Raynaud's phenomenon (OR 3.5, 95% CI 1.3-9.5) and increased serum B-cell maturation antigen, transmembrane activator and CAML interactor and TNFalpha levels. Circulating immune markers and markers of type I interferon activation were not effective at distinguishing clinical subgroups. CONCLUSIONS: Among anti-RNP patients, the question of MCTD versus SLE is not either/or: most MCTD patients also have lupus. MCTD classification criteria (but not a broad set of immune markers) distinguish a subset of SLE patients at reduced risk for renal disease. PMID- 25736142 TI - Editorial: alcohol and obesity - the double peril. PMID- 25736143 TI - Editorial: quadruple therapy for H. pylori eradication is better than triple therapy - authors' reply. PMID- 25736144 TI - Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea. PMID- 25736145 TI - Editorial: colesevelam effects on faecal bile acids in IBS with diarrhoea - author's reply. PMID- 25736146 TI - Letter: management of portal vein thromboses in cirrhosis. PMID- 25736147 TI - Letter: management of portal vein thromboses in cirrhosis - authors' reply. PMID- 25736148 TI - Letter: body surface area and body muscle parameters may influence adalimumab trough levels. PMID- 25736149 TI - Letter: is there a relationship between length of Barrett's oesophagus and body mass index? PMID- 25736150 TI - Letter: is there a relationship between Barrett's oesophagus length and body mass index? Authors' reply. PMID- 25736151 TI - Letter: volatile metabolomics of exhaled breath or faecal gas? PMID- 25736152 TI - Letter: proton pump inhibitors - severity of liver disease and mortality in patients with cirrhosis. PMID- 25736154 TI - Letter: proton pump inhibitors - severity of liver disease and mortality in patients with cirrhosis - authors' reply. PMID- 25736153 TI - Letter: volatile metabolomics of exhaled breath or faecal gas? - authors' reply. PMID- 25736155 TI - Letter: why treatments of hepatitis C virus are less effective in cirrhosis. PMID- 25736156 TI - Changes in turnover and vacancy rates of care workers in England from 2008 to 2010: panel analysis of national workforce data. AB - The combination of growing demand for long-term care and higher expectations of care staff needs to be set in the context of long-standing concerns about the sustainability of recruitment and retention of front-line staff in the United Kingdom. Organisational and work environment factors are associated with vacancy levels and turnover rates. The aim of the current analysis was to investigate changes in turnover and vacancy rates over time experienced by a sample of social care employers in England. Taking a follow-up approach offers potentially more accurate estimates of changes in turnover and vacancy rates, and enables the identification of any different organisational characteristics which may be linked to reductions in these elements over time. The study constructed a panel of 2964 care providers (employers) using 18 separate data sets from the National Minimum Data Set for Social Care during 2008-2010. The findings indicate slight reductions in vacancy rates but the presence of enduring, high turnover rates among direct care workers over the study period. However, the experience of individual employers varied, with home-care providers experiencing significantly higher turnover rates than other parts of the sector. These findings raise questions around the quality and motivations of new recruits and methods of reducing specific vacancy levels. At a time of increased emphasis on care at home, it is worthwhile examining why care homes appear to have greater stability of staff and fewer vacancies than home-care agencies. PMID- 25736157 TI - Investigations into the decomposition of aminoacyl-substituted monosaccharide scaffolds from a drug discovery library. AB - This study investigated the unexpected decomposition and associated intermediates of compound 1, a specific member of a drug discovery library based on a monosaccharide scaffold. LC/MS and NMR spectroscopic analyses indicated that, under acidic conditions, 1 can be converted into the 4-aminogalactoside 2, due to cleavage of the 4-aminobutanoyl side chain. The reaction occurs most likely through an initial intramolecular amino-amide interaction, followed by an N- to O acyl transfer of the side chain from C-4 to the C-6 position to form an ester intermediate (5), detectable by NMR, and subsequent hydrolysis. Similar decomposition reactions could be induced in selected compounds with similar structures, containing a free hydroxyl group at C-6 and a 4-aminobutanoyl side chain at C-4 of an aminogalactoside. Furthermore, three model compounds were synthesized without a C-6 hydroxyl group and with different length aminoalkanoyl side chains at the C-4 position. The model compounds all decomposed under acidic conditions, but at different rates and much slower when compared with compound 1, suggesting that both the C-6 hydroxyl group and the length of the side chain have an influence on stability. PMID- 25736158 TI - Heterosis and differential gene expression in hybrids and parents in Bombyx mori by digital gene expression profiling. AB - Heterosis is a concern to all breeders, but the mechanism of heterosis remains unknown. In F1 organisms, genetic material is inherited from the two parents and theoretically, heterosis might be caused by differences in gene expression or modification. Differential gene expression was analyzed in hybrids and parents in Bombyx mori. The results showed that there were significant changes in gene expression in the fat body involving biological regulation, cellular and metabolic processes. Consistent trends in expression patterns covering different hybrid combinations were seen in 74 genes. Moreover, these differential gene expression patterns included overdominance, dominance, and additive effects. By correlating these patterns with economic traits, a potential relationship was found. Differential gene expression was seen in different cross combinations and in different sexes. In addition, a regulatory mechanism involving metabolism and ErbB signaling pathways was also found, suggesting that such a network might also be related to heterosis in Bombyx mori. Together, our data provide a comprehensive overview and useful resource for transcriptional analysis of heterosis of Bombyx mori. PMID- 25736159 TI - Comments on Korthoewer and Chandran: osteoporosis management and the utilization of FRAX(r): a survey amongst health care professionals of the Asia-Pacific. PMID- 25736160 TI - Osteoporosis management and the utilization of FRAX(r): a survey amongst health care professionals of the Asia-Pacific--response to comments by Lee and Ha. PMID- 25736161 TI - Cadmium exposure via diet and its implication on the derivation of health-based soil screening values in China. AB - The cadmium (Cd) intake rates via diet of adults from different regions in China were between 0.160 and 0.557 MUg/(kg BW.day), which were less than the provisional tolerable monthly intake (0.833 MUg/(kg BW.day)) issued by Food and Agriculture Organization/World Health Organization in 2010, but higher than the one (0.365 MUg/(kg BW.day)) issued by the European Food Safety Authority in 2011, to protect children, vegetarians and people living in heavily contaminated regions, and the intake rate of children (1.007 MUg/(kg BW.day)) at the national scale was higher than the values recommended by the above institutes and those of adults. Vegetables were the critical contributors, followed by rice, flour, meats and aquatic products. Cd concentration in vegetable was the most sensitive factor in calculating the intake rate, followed by its contents in rice and aquatic products, and the intake rate of flour, indicating that more attention should be given to these parameters in future total diet surveys. When dietary exposure was incorporated, the derived national screening value of Cd under commercial scenario was reduced from 825 to 458 mg/kg, while the values of the north, south, Beijing and Shanghai were reduced to 627, 365, 693 and 489 mg/kg, respectively, indicating that the hazard would be underestimated if dietary exposure was not taken into account, especially for the south. The great variance between the screening values was due to the varied Cd intake rates, which indicated that deriving a screening value for each specific area based on its corresponding exposure characteristics was more appropriate. The national screening level for the residential scenario derived theoretically based on the dietary exposure characteristics of children was a negative value, meaning that the dietary intake rate was above the tolerable value. The method used in the United Kingdom to derive soil guideline values when non-soil exposure accounted for more than half of the maximum tolerable daily intake dose may be an appropriate estimate, but the exact ratio assigned to soil exposure should be assessed comprehensively based on a more sophisticated dietary exposure survey and the corresponding economic implications. PMID- 25736162 TI - Dust metal loadings and the risk of childhood acute lymphoblastic leukemia. AB - We evaluated the relationship between the risk of childhood acute lymphoblastic leukemia (ALL) and the levels of metals in carpet dust. A dust sample was collected from the homes of 142 ALL cases and 187 controls participating in the California Childhood Leukemia Study using a high volume small surface sampler (2001-2006). Samples were analyzed using microwave-assisted acid digestion in combination with inductively coupled plasma mass spectrometry for arsenic, cadmium, chromium, copper, lead, nickel, tin, tungsten, and zinc. Eight metals were detected in at least 85% of the case and control homes; tungsten was detected in <15% of homes. Relationships between dust metal loadings (MUg metal per m(2) carpet) and ALL risk were modeled using multivariable logistic regression, adjusting for the child's age, sex, and race/ethnicity and confounders, including household annual income. A doubling of dust metal loadings was not associated with significant changes in ALL risk (odds ratio (95% confidence interval): arsenic: 0.96 (0.86, 1.07), cadmium: 0.92 (0.81, 1.05), chromium: 1.01 (0.90, 1.14), copper: 0.97 (0.91, 1.03), lead: 1.01 (0.93, 1.10), nickel: 0.95 (0.82, 1.09), tin: 0.96 (0.86, 1.08), and zinc: 0.94 (0.84, 1.05)). Our findings do not support the hypothesis that metals in carpet dust are risk factors for childhood ALL. PMID- 25736163 TI - Challenges for environmental epidemiology research: are biomarker concentrations altered by kidney function or urine concentration adjustment? AB - Biomonitoring has become a standard approach for exposure assessment in occupational and environmental epidemiology. The use of biological effect markers to identify early adverse changes in target organs has also become widely adopted. However, the potential for kidney function to affect biomarker levels in the body and the optimal approach to adjustment of biomarker concentrations in spot urine samples for hydration status are two important but underappreciated challenges associated with biomarker use. Several unexpected findings, such as positive associations between urine nephrotoxicant levels and estimated glomerular filtration rate (eGFR), have been reported recently in research using biomarkers. These and other findings, discussed herein, suggest an impact of kidney glomerular filtration or tubule processing on biomarker levels. This is more commonly raised in the context of decreased kidney filtration, traditionally referred to as reverse causality; however, recent data suggest that populations with normal kidney filtration may be affected as well. Misclassification bias would result if biomarkers reflect kidney function as well as either exposures or early biological effect outcomes. Furthermore, urine biomarker associations with eGFR that differ markedly by approach used to adjust for urine concentration have been reported. Associations between urine measures commonly used for this adjustment, such as urine creatinine, and specific research outcomes could alter observed biomarker associations with outcomes. Research recommendations to address the potential impact of kidney function and hydration status adjustment on biomarkers are provided, including a range of approaches to study design, exposure and outcome assessment, and adjustment for urine concentration. PMID- 25736164 TI - Patient-reported Outcomes for Multicentric Castleman's Disease in a Randomized, Placebo-controlled Study of Siltuximab. AB - BACKGROUND: Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments. METHODS: We analyzed results of a randomized, double-blind trial comparing siltuximab 11 mg/kg every 3 weeks with placebo to treat MCD. Subjects (N = 79) completed the recently developed MCD-Symptom Scale (MCD-SS), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, and the Short Form (SF)-36 at predetermined time points throughout the treatment period. Scores were compared at baseline and over time between the treatment arms and PRO instruments. RESULTS: At baseline, the mean number of symptoms reported was 9.2 (standard deviation 3.76) out of 16 total, as measured by the MCD-SS. Fatigue was a key symptom across all PRO instruments. Siltuximab-treated subjects reported early improvements in symptoms compared with subjects in the placebo arm on both the MCD-SS and FACIT-Fatigue scale. Statistically significant improvements in five SF-36 domains were observed in siltuximab-treated patients, namely role physical, role emotional, vitality, bodily pain, and mental health. CONCLUSIONS: Patients with MCD commonly report impairments in functioning, wellbeing, and fatigue at baseline. Siltuximab-treated patients reported significant improvements in these outcomes after treatment. PMID- 25736165 TI - Suspected adipose tumours of the hand and the potential risk for malignant transformation to sarcoma: a series of 14 patients. AB - INTRODUCTION: Lipomas are associated with a variety of symptoms including neuropathies, local compression of the surrounding tissues, aesthetic complaints and may be graded as liposarcomas histologically. This study was performed to review our surgical management at the level of the hand. MATERIALS AND METHODS: Between 2008 and 2013, 14 patients were referred to our department for suspected adipose tumour of the hand. Preoperative MRI was used to assess tumour and surrounding tissue to plan the surgical therapy. We reviewed the clinical history, MRI findings, surgical approach, and outcomes. RESULTS: Complaints leading to consultation were pain in 11 cases, compression neuropathy in 7 cases, aesthetic concern in 8 cases, and limited wrist range of motion in 2 cases. Magnetic resonance imaging was performed in 13 cases, confirming the diagnosis of adipose tumour in all but two cases. These two cases were diagnosed in one case as a ganglion and the other as an epithelioid sarcoma. An amputation of the fifth digit was performed regarding the latter case and the patient received additional radiotherapy. The mean follow-up period was 32 +/- 20 months. There was no recurrence of lipoma or sarcoma. CONCLUSION: MRI is useful for diagnosing and planning of the surgical intervention performed in the latter case adipose tumours. Rapidly evolving tumours with subfascial localization are absolute surgical indications. Incision biopsy is mandatory for entities of unknown dignity and for malignant tumours. Interdisciplinary tumour board meetings should discuss each patient before surgery is performed. LEVEL OF EVIDENCE AND STUDY TYPE: IV. PMID- 25736167 TI - The ABC of writing a grant proposal. PMID- 25736168 TI - Controlled cutting and hydroxyl functionalization of carbon nanotubes through autoclaving and sonication in hydrogen peroxide. AB - In this study, an eco-friendly process utilizing a low concentration of hydrogen peroxide along with autoclaving and sonication was developed, accomplishing both carbon nanotube size reduction and hydroxyl functionalization. PMID- 25736166 TI - Cortical thinning and progressive cortical porosity in female patients with systemic lupus erythematosus on long-term glucocorticoids: a 2-year case-control study. AB - In this study, we characterized longitudinal changes of volumetric bone mineral density and cortical and trabecular microstructure at the distal radius using HR pQCT in female systemic lupus erythematosus (SLE) patients on long-term glucocorticoids. Cortical thinning and increased cortical porosity are the major features of longitudinal microstructural deterioration in SLE patients. INTRODUCTION: The study aims to characterize longitudinal changes of volumetric bone mineral density (vBMD) and bone microstructure at distal radius in female systemic lupus erythematosus (SLE) patients on long-term glucocorticoids. METHODS: This 2-year case-control study consisted of 166 premenopausal subjects (75 SLE patients and 91 controls) and 79 postmenopausal subjects (44 SLE patients and 35 controls). We obtained areal BMD (aBMD) by dual-energy X-ray absorptiometry at multiple skeletal sites and indices of vBMD and microstructure at distal radius by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline, 12 and 24 months. RESULTS: In either premenopausal or postmenopausal subjects, changes in aBMD did not differ between patients and controls except that decrease in aBMD at total hip at 24 months in premenopausal patients was significantly higher. In premenopausal subjects, decrease in cortical area (-0.51 vs. -0.06 %, p = 0.039) and thickness (-0.63 vs. 0.02 %, p = 0.031) and increase in cortical porosity (21.7 vs. 7.16 %, p = 0.030) over study period were significantly larger in patients after adjustment of age and body mass index. Decreased in trabecular vBMD was significantly less (-0.63 vs. -2.32 %, p = 0.001) with trabecular microstructure better maintained in patients. In postmenopausal subjects, decrease in cortical vBMD (-2.66 vs. -1.56 %, p = 0.039) and increase in cortical porosity (41.6 vs. 16.3 %, p = 0.021) were significantly higher in patients, and there was no group-wise difference in change of trabecular microstructure. CONCLUSION: Longitudinal microstructural deterioration in SLE is characterized by cortical thinning and increased cortical porosity. Cortical bone is an important source of bone loss in SLE patients on glucocorticoids. PMID- 25736170 TI - Ancient mycobacterial lipids: Key reference biomarkers in charting the evolution of tuberculosis. AB - Mycobacterium tuberculosis has a cell envelope incorporating a peptidoglycan linked arabinogalactan esterified by long-chain mycolic acids. A range of "free" lipids are associated with the "bound" mycolic acids, producing an effective envelope outer membrane. The distribution of these lipids is discontinuous among mycobacteria and such lipids have proven potential for biomarker use in tracing the evolution of tuberculosis. A plausible evolutionary scenario involves progression from an environmental organism, such as Mycobacterium kansasii, through intermediate "smooth" tubercle bacilli, labelled "Mycobacterium canettii"; cell envelope lipid composition possibly correlates with such a progression. M. kansasii and "M. canettii" have characteristic lipooligosaccharides, associated with motility and biofilms, and glycosyl phenolphthiocerol dimycocerosates ("phenolic glycolipids"). Both these lipid classes are absent in modern M. tuberculosis sensu stricto, though simplified phenolic glycolipids remain in certain current biotypes. Dimycocerosates of the phthiocerol family are restricted to smaller phthiodiolone diesters in M. kansasii. Diacyl and pentaacyl trehaloses are present in "M. canettii" and M. tuberculosis, accompanied in the latter by related sulfated acyl trehaloses. In comparison with environmental mycobacteria, subtle modifications in mycolic acid structures in "M. canettii" and M. tuberculosis are notable. The probability of essential tuberculosis evolution taking place in Pleistocene megafauna, rather than Homo sapiens, is reemphasised. PMID- 25736171 TI - Constructing a classification of hypersensitivity/allergic diseases for ICD-11 by crowdsourcing the allergist community. AB - The global allergy community strongly believes that the 11th revision of the International Classification of Diseases (ICD-11) offers a unique opportunity to improve the classification and coding of hypersensitivity/allergic diseases via inclusion of a specific chapter dedicated to this disease area to facilitate epidemiological studies, as well as to evaluate the true size of the allergy epidemic. In this context, an international collaboration has decided to revise the classification of hypersensitivity/allergic diseases and to validate it for ICD-11 by crowdsourcing the allergist community. After careful comparison between ICD-10 and 11 beta phase linearization codes, we identified gaps and trade-offs allowing us to construct a classification proposal, which was sent to the European Academy of Allergy and Clinical Immunology (EAACI) sections, interest groups, executive committee as well as the World Allergy Organization (WAO), and American Academy of Allergy Asthma and Immunology (AAAAI) leaderships. The crowdsourcing process produced comments from 50 of 171 members contacted by e mail. The classification proposal has also been discussed at face-to-face meetings with experts of EAACI sections and interest groups and presented in a number of business meetings during the 2014 EAACI annual congress in Copenhagen. As a result, a high-level complex structure of classification for hypersensitivity/allergic diseases has been constructed. The model proposed has been presented to the WHO groups in charge of the ICD revision. The international collaboration of allergy experts appreciates bilateral discussion and aims to get endorsement of their proposals for the final ICD-11. PMID- 25736172 TI - Mucormycosis in a Non-Hodgkin Lymphoma Patient Caused by Syncephalastrum racemosum: Case Report and Review of Literature. AB - Mucormycosis is a rare opportunistic fungal infection caused by saprophytic zygomycetes. These fungal infections are caused by members of the mucorales. The clinical importance of zygomycosis, an emerging and frequently fatal mycotic disease, has increased during recent years, due to several risk factors such as (a) the use of broad-spectrum antibiotic, (b) use of empirical antifungal treatment (mainly triazoles), and (c) aggressive chemotherapy and sustained leucopenia (i.e., peripheral stem cell transplantation). An almost fulminant pneumonia caused by Syncephalastrum racemosum in an immunocompromised patient with an aggressive non-Hodgkin lymphoma (NHL) is described. Despite treatment with amphotericin B, deoxycholate, caspofungin, and surgical resection of fungal bodies from both lungs, and survival of 10 months without relapsing from fungal infection, the patient died due to hematological complications from an unresponsive disease. Herein is the description of the first case of pulmonary infection caused by Syncephalastrum racemosum. PMID- 25736173 TI - Systemic Review of Published Reports on Primary Cutaneous Cryptococcosis in Immunocompetent Patients. AB - Primary cutaneous cryptococcosis (PCC) has been confirmed as a distinct clinical entity with secondary cutaneous cryptococcosis from systematic infection since 2003. Although it has been confirmed as a distinct clinical entity, little has progressed on PCC in immunocompetent hosts compared to their immunocompromised counterpart. We reviewed the literature on cases of PCC in immunocompetent patients from 2004 to 2014, and 21 cases from 16 reports were identified. Males are more likely to develop PCC infections, with a ratio of 17:4 male to female. These patients were found to be almost all senior population except for patients from Asia. Asymptomatic or moderate itching manifesting in a painful nodule is the most common presentation, although there is no typical clinical manifestation recorded. Upper limbs are the most common site of infection, accounting for 71.4 % of all patients. Of the 12 identified isolates, 6 strains are identified as C. neoformans, 5 as C. gattii, and 1 as C.laurentii. Fluconazole was used in 10 cases; however, only 80 % of the 10 cases could confirm that fluconazole was effective in clearing the infections. Interestingly although not approved as a treatment option, Itraconazole was effective in the seven cases it was used to treat cryptococcosis, with a dosage range of 100-400 mg/d and duration from 3 to 6 months. Even though the prognosis of these patients was generally good, more data are need to determine which antifungal azole is the better treatment option and whether primary skin infections could disseminate to systematic infection. PMID- 25736174 TI - Imaging Tuberous Sclerosis: The Incremental Benefit of Three-Dimensional and Speckle Tracking Echocardiography. AB - Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome and multisystem disorder with autosomal dominant inheritance and variable penetrance. Cardiac rhabdomyomas have been reported in 50-64% of patients with TSC and transthoracic echocardiography is established as the primary imaging modality for their detection. The precise functional assessment of the left ventricle in these patients requires clarification. We report a case of a 19-year-old male with known TSC who was referred for outpatient transthoracic echocardiography (TTE) to investigate for the presence of cardiac rhabdomyomas. TTE demonstrated multiple rhabdomyomas with a normal ejection fraction but altered global and regional deformation on speckle tracking. The regional longitudinal strain was notably reduced in the anterior septum (-11%) and inferior septum (-15%). The global circumferential strain (GCS) was significantly reduced at -15.6%. The distribution of regional circumferential strain reduction for the mid-ventricular segment correlated with the location of cardiac rhabdomyomas. PMID- 25736175 TI - (18)F-FDG PET/CT localized valvular infection in chronic Q fever endocarditis. AB - Delayed diagnosis in chronic Q fever endocarditis is fairly common world wide, we present a case where FDG-PET/CT correctly identified the infected valve, showing promise in management. PMID- 25736176 TI - Cardiac sympathetic imaging in the diagnosis of cardiac autonomic neuropathy in pre-diabetes. PMID- 25736177 TI - Comparison of dynamic electromyographic analysis of masticatory capsules with materials of different textures. AB - OBJECTIVES: The aim of this study was to compare the mastication electromyographic indexes of capsules used for the masticatory efficiency evaluation "ME-mastig" and of materials of different textures (gum, raisins, and peanuts). METHODS: Thirty young, healthy, adult subjects, with an average age of 23.46 years old, with no symptoms of temporomandibular dysfunction (TMD), confirmed by the clinical exam, RDC/TMD, and the static test of electromyography (EMG) were chosen. Afterward, dynamic tests were performed (bilateral mastication of the compounds) to determine number of chewing cycles (CYCLES); masticatory frequency (FREQ); SMI (symmetrical masticatory index - corresponding to the value of neuromuscular coordination during mastication); and IMPACT (corresponding to impact - total electromyographic activity performed by the system during chewing). RESULTS: Cycle and frequency were similar. Regarding SMI and IMPACT, the raisin, the capsule, and the peanut were similar between each other, and different from the gum. CONCLUSIONS: Masticatory capsules and the natural foods with different textures had similar results regarding EMG indexes. PMID- 25736178 TI - Comparative analysis of temporal gene expression patterns in the developing ovary of the embryonic chicken. AB - Many genes participate in the process of ovarian germ cell development, while the combined action mechanisms of these molecular regulators still need clarification. The present study was focused on determination of differentially expressed genes and gene functions at four critical time points in chicken ovarian development. Comparative transcriptional profiling of ovaries from embryonic day 5.5 (E5.5), E12.5, E15.5 and E18.5 was performed using an Affymetrix GeneChip chicken genome microarray. Differential expression patterns for genes specifically depleted and enriched in each stage were identified. The results showed that most of the up- and downregulated genes were involved in the metabolism of retinoic acid (RA) and synthesis of hormones. Among them, a higher number of up- and downregulated genes in the E15.5 ovary were identified as being involved in steroid biosynthesis and retinol metabolism, respectively. To validate gene changes, expressions of twelve candidate genes related to germ cell development were examined by real-time PCR and found to be consistent with the of GeneChip data. Moreover, the immunostaining results suggested that ovarian development during different stages was regulated by different genes. Furthermore, a Raldh2 knockdown chicken model was produced to investigate the fundamental role of Raldh2 in meiosis initiation. It was found that meiosis occurred abnormally in Raldh2 knockdown ovaries, but the inhibitory effect on meiosis was reversed by the addition of exogenous RA. This study offers insights into the profile of gene expression and mechanisms regulating ovarian development, especially the notable role of Raldh2 in meiosis initiation in the chicken. PMID- 25736179 TI - What makes migraine a migraine--of the importance of disease classifications in scientific research. PMID- 25736180 TI - Targeting pericranial nerve branches to treat migraine: Current approaches and perspectives. AB - BACKGROUND: Migraine is a highly prevalent neurological disorders and a major individual and societal burden. Migraine is not curable at the present time, but it is amenable to acute symptomatic and preventive pharmacotherapies. SUMMARY: Since the latter are frequently unsatisfactory, other treatment strategies have been used or are being explored. In particular, interventions targeting pericranial nerves are now part of the migraine armamentarium. We will critically review some of them, such as invasive and noninvasive neurostimulation, therapeutic blocks and surgical decompressions. CONCLUSIONS: Although current knowledge on migraine pathophysiology suggests a central nervous system dysfunction, there is some evidence that interventions targeting peripheral nerves are able to modulate neuronal circuits involved in pain control and that they could be useful in some selected patients. Larger, well-designed and comparative trials are needed to appraise the respective advantages, disadvantages and indications of most interventions discussed here. PMID- 25736181 TI - Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies. AB - Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established - but puzzling - findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. PMID- 25736182 TI - Coupling of neurogenesis and angiogenesis after ischemic stroke. AB - Stroke is a leading cause of mortality and severe long-term disability worldwide. Development of effective treatment or new therapeutic strategies for ischemic stroke patients is therefore crucial. Ischemic stroke promotes neurogenesis by several growth factors including FGF-2, IGF-1, BDNF, VEGF and chemokines including SDF-1, MCP-1. Stroke-induced angiogenesis is similarly regulated by many factors most notably, eNOS and CSE, VEGF/VEGFR2, and Ang-1/Tie2. Important findings in the last decade have revealed that neurogenesis is not the stand alone consideration in the fight for full functional recovery from stroke. Angiogenesis has been also shown to be critical in improving post-stroke neurological functional recovery. More than that, recent evidence has shown a highly possible interplay or dependence between stroke-induced neurogenesis and angiogenesis. Moving forward, elucidating the underlying mechanisms of this coupling between stroke-induced neurogenesis and angiogenesis will be of great importance, which will provide the basis for neurorestorative therapy. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25736183 TI - Piloting online WellnessRx learning modules: demonstration of developmental evaluation. AB - WellnessRx is a health initiative focusing on healthy living through education, knowledge translation, and community engagement. Stakeholders of WellnessRx identified web-based education learning modules on nutrition and physical education as a priority to be integrated into existing health sciences curricula, as well as adapted for use by health professionals. Five learning modules were created with essential knowledge, skills, attitudes and resources or tools for health professional students and practitioners. As part of the 'developmental evaluation framework' for WellnessRx, two of these modules were piloted within two health professional student programs. This paper describes the pilot evaluation experience involving student surveys, focus groups and interviews, and faculty perspectives. For both modules, student pre-post knowledge assessments indicated some improvements in post-module knowledge. Post module evaluations by students indicated benefits with the online delivery being flexible for access, self-health, case-based assessments and useful nutrition and physical activity guides. Challenges for students included their time to do the modules and the activity expectations. Instructors felt each module could be better targeted to different years within an undergraduate program. Through developmental evaluation, the pilot results along with recommendations and lessons learned provided the direction needed to further develop the WellnessRx logic model and proposed learning modules. PMID- 25736185 TI - Spectroscopic (vibrational, NMR and UV-vis.) and quantum chemical investigations on 4-hexyloxy-3-methoxybenzaldehyde. AB - In this study, the 4-hexyloxy-3-methoxybenzaldehyde compound as one of the derivatives of vanillin which is a well known flavoring agent, C14H20O3, has been investigated by experimentally and extensively utilizing density functional theory (DFT) at the B3LYP/6-311++G(d,p) level. In this context, the optimized geometry, vibrational frequencies, (1)H and (13)C NMR chemical shifts, UV-vis. (in gas phase and in methanol solvent) spectra, HOMO-LUMO analysis, molecular electrostatic potential (MEP), thermodynamic parameters and atomic charges of 4 hexyloxy-3-methoxybenzaldehyde have been calculated. In addition, theoretically predicted IR, Raman and UV-vis. (in gas phase and in methanol solvent) spectra of the mentioned molecule have been constructed. The results calculated were compared with the experimental data. PMID- 25736184 TI - Statins and breast cancer stage and mortality in the Women's Health Initiative. AB - PURPOSE: To evaluate the association between statins and breast cancer stage and mortality in the Women's Health Initiative. METHODS: The study population included 128,675 postmenopausal women aged 50-79 years, out of which there were 7,883 newly diagnosed cases of in situ (19%), local (61%)-, regional (19%)- and distant (1%)-stage breast cancer and 401 deaths due to breast cancer after an average of 11.5 (SD = 3.7) years of follow-up. Stage was coded using SEER criteria and was stratified into early (in situ and local)- versus late (regional and distant)-stage disease. Information on statins and other risk factors were collected by self- and interviewer-administered questionnaires. Cause of death was based on medical record review. Multivariable-adjusted hazards ratios (HR) and 95% confidence intervals (CIs) evaluating the relationship between statin use (at baseline only and in a time-dependent manner) and diagnosis of late-stage breast cancer and breast cancer-specific mortality were computed from Cox proportional hazards analyses after adjusting for appropriate confounders. RESULTS: Statins were used by 10,474 women (8%) at baseline. In the multivariable adjusted time-dependent model, use of lipophilic statins was associated with a reduction in diagnosis of late-stage breast cancer (HR 0.80, 95% CI 0.64-0.98, p = 0.035) which was also significant among women with estrogen receptor-positive disease (HR 0.72, 95% CI 0.56-0.93, p = 0.012). Breast cancer mortality was marginally lower in statin users compared with nonusers (HR 0.59, 95 % CI 0.32 1.06, p = 0.075). CONCLUSIONS: Prior statin use is associated with lower breast cancer stage at diagnosis. PMID- 25736186 TI - Copper-catalyzed intermolecular carboetherification of unactivated alkenes by alkyl nitriles and alcohols. AB - A three-component carboetherification of unactivated alkenes has been developed allowing the rapid building of complexity from simple starting materials. A wide range of alpha-substituted styrenes underwent smooth reactions with unactivated alkyl nitriles and alcohols to afford gamma-alkoxy alkyl nitriles with concomitant generation of a quaternary carbon center. A radical clock experiment provided clear-cut evidence that the reaction proceeds through a tertiary alkyl radical intermediate. PMID- 25736187 TI - Glycosylated hemoglobin and the risk of periprocedural myocardial infarction in non-diabetic patients. AB - BACKGROUND: Alterations of glucose homeostasis have been reported to occur even in non-diabetic patients, thus increasing the risk of cardiovascular events and worsening the outcome after an acute myocardial infarction (AMI). Still debated is the role of impaired glucose control in patients undergoing percutaneous coronary intervention (PCI), as hyperglycemia, represents an important pro thrombotic stimulus, increasing platelet reactivity and potentially procedural complications. Therefore, the aim of our study was to assess the association between glycosylated hemoglobin and periprocedural myocardial infarction (PMI) in non-diabetic patients undergoing PCI. METHODS: We included patients without history of diabetes undergoing elective PCI. PMI was defined as creatine kinase MB increase by 3 times the upper limit normal or by 50% of an elevated baseline value, whereas periprocedural myonecrosis as Troponin I increase by 3* ULN or 50% of baseline. RESULTS: Our population is represented by 1199 patients, who were divided according to tertile values of glycosylated hemoglobin (HbA1c). Higher HbA1c was associated with ageing (p<0.001), hypertension (p=0.005), previous myocardial infarction (p=0.009), PCI (p<0.001) or CABG (p=0.001), treatment with diuretics (p<0.001), higher levels of glycemia (p<0.001) and white blood cells (p=0.02), multivessel coronary artery disease (p=0.03), higher rate of instent restenosis (p=0.02). HbA1c did not impact on periprocedural myocardial infarction (p=0.85; adjusted OR [95% CI]=0.91 [0.74-1.12], p=0.38) or myonecrosis (p=0.69; adjusted OR [95% CI]=0.95 [0.80-1.13], p=0.56). Similar results were obtained fasting glycemia for PMI (p=0.82, adjusted OR [95% CI]=0.90 [0.71-1.14], p=0.37) and myonecrosis (p=0.21, adjusted OR [95% CI]=1.02 [0.84-1.24], p=0.84) and confirmed in high-risk subsets of patients. CONCLUSIONS: In non-diabetic patients undergoing elective PCI, neither glycosylated hemoglobin levels nor fasting glycemia are associated with the risk of periprocedural myocardial infarction and necrosis. PMID- 25736188 TI - An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation. AB - Patients with microdeletions in the 19p13.2 chromosomal region show developmental delays, overgrowth, and distinctive features with big head appearances. These manifestations are now recognized as Sotos syndrome-like features (Sotos syndrome 2) or Malan syndrome. We identified three female patients with 19p13.2 deletions involving NFIX, a gene responsible for Malan syndrome. We compared the genotypic and phenotypic data of these patients with those of the patients previously reported. The most of the clinical features were found to overlap; however, Chiari malformation type I was observed in two of the three patients evaluated in this study. Because Chiari malformation type I has never been reported in the patients with NSD1-related Sotos syndrome, this finding indicates the possible role of 19p13.2 deletion in patients with mimicking features of Sotos syndrome but have negative NSD1 testing results. PMID- 25736189 TI - Hypogonadism and fertility issues following primary treatment for testicular cancer. AB - BACKGROUND: The majority of testicular cancer (TC) patients are cured and expected to live for decades after treatment, such that knowledge about hypogonadism and fertility issues is particularly important for the group of testicular cancer survivors (TCSs). Hypogonadism and fertility issues are related to treatment intensity. METHODS: In order to give an overview about hypogonadism in testicular cancer survivors (TCSs) the literature was reviewed. Testicular dysfunction was defined as inadequate spermatogenesis, as reflected by increased levels of Follicle Stimulating Hormone (FSH) and reduced fertility and/with or without insufficient testosterone (T) production with or without compensatory increased Luteinizing Hormone (LH) levels. FINDINGS: Hypogonadism may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease (CVD). The hypothesized "Testicular Dysgenesis Syndrome" comprising low sperm counts, hypospadias, cryptorchidism, and finally TC, probably contributes to hypogonadism independent of applied TC treatment. Recently, an increased risk of accelerated hormonal ageing has been reported in TCSs in the very long term, i.e. 20 years after TC treatment. PMID- 25736190 TI - In vitro evaluation of different methods of handling human liposuction aspirate and their effect on adipocytes and adipose derived stem cells. AB - Nowadays, fat tissue transplantation is widely used in regenerative and reconstructive surgery. However, a shared method of lipoaspirate handling for ensuring a good quality fat transplant has not yet been established. The study was to identify a method to recover from the lipoaspirate samples the highest number of human viable adipose tissue-derived stem cells (hADSCs) included in stromal vascular fraction (SVF) cells and of adipocytes suitable for transplantation, avoiding an extreme handling. We compared the lipoaspirate spontaneous stratification (10-20-30 min) with the centrifugation technique at different speeds (90-400-1500 * g). After each procedure, lipoaspirate was separated into top oily lipid layer, liquid fraction, "middle layer", and bottom layer. We assessed the number of both adipocytes in the middle layer and SVF cells in all layers. The histology of middle layer and the surface phenotype of SVF cells by stemness markers (CD105+, CD90+, CD45-) was analyzed as well. The results showed a normal architecture in all conditions except for samples centrifuged at 1500 * g. In both methods, the flow cytometry analysis showed that greater number of ADSCs was in middle layer; in the fluid portion and in bottom layer was not revealed significant expression levels of stemness markers. Our findings indicate that spontaneous stratification at 20 min and centrifugation at 400 * g are efficient approaches to obtain highly viable ADSCs cells and adipocytes, ensuring a good thickness of lipoaspirate for autologous fat transfer. Since an important aspect of surgery practice consists of gain time, the 400 * g centrifugation could be the recommended method when the necessary instrumentation is available. PMID- 25736191 TI - Transitions of care for stroke and TIA. AB - PURPOSE: The purpose of this study was to identify elements of a stroke population that may affect transitions of care (TOC). DATA SOURCES: A retrospective analysis of the demographic characteristics of patients from an urban primary stroke center with an admitting diagnosis of transient ischemic attack, acute ischemic stroke, subarachnoid hemorrhage, or intracerebral hemorrhage was performed over an 8-month period (N = 276). A subset of this patient sample participated in a telephone survey 1 month after discharge. CONCLUSION: Hospital length of stay, age, insurance status, discharge disposition, comorbidities, and readmission rates were identified as important elements affecting TOC for stroke and TIA. Information from patient surveys indicated that emotional health, follow-up with care providers, stroke education, and point of contact are important elements during the transition periods after stroke and TIA. IMPLICATIONS FOR PRACTICE: Both providers and patients should inform the development of a comprehensive TOC program that spans in-hospital to multiple care settings, including the home, which is essential. The advanced practice nurse is ideally suited to successfully lead these programs. PMID- 25736192 TI - Erectile Dysfunction is Common among Men with Acromegaly and is Associated with Morbidities Related to the Disease. AB - INTRODUCTION: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. AIM: The aim of this study was to evaluate sexual function in men with acromegaly. METHODS: Multicenter-based, retrospective analysis of a nonselected series of 57 acromegalic subjects (mean age: 52.7 +/- 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4,000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. MAIN OUTCOME MEASURES: Patients were interviewed using Structured Interview on Erectile Dysfunction (SIEDY) structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile color Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. RESULTS: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events history at enrollment and lower PCDU parameters. CONCLUSIONS: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up. PMID- 25736193 TI - Open tubular capillary electrochromatography with an N-phenylacrylamide-styrene copolymer-based stationary phase for the separation of anomers of glucose and structural isomers of maltotriose. AB - A ligand with a terminal halogen (4-chloromethylphenyl isocyanate) was chemically bound on the inner surface of pretreated silica capillary with 50 MUm internal diameter and 58 cm total and 50 cm effective length in the presence of dibutyl tin dichloride as a catalyst through isocyanate-hydroxyl reaction. Attachment of initiator (sodium diethyl dithiocarbamate) to the bound ligand was carried out and followed by in situ polymerization. Reversible addition-fragmentation chain transfer polymerization was used for the immobilization of N-phenylacrylamide styrene copolymer on the inner surface of capillary column. The resultant open tubular column showed excellent separation performance for derivatized saccharide isomers in capillary electrochromatography. D-Glucose was separated into alpha- and beta-anomers while five structural isomers were separated for derivatized maltotriose with separation efficiency above one million theoretical plates per meter. The effects of pH and acetonitrile composition on the electrochromatographic performance of the derivatized saccharides were studied and the optimized elution condition was found to be 90:10 v/v% acetonitrile/30 mM sodium acetate at pH 6.6. UV absorption at 214 nm was used as detection mode in open tubular capillary electrochromatography separations. PMID- 25736194 TI - Mixed hepatocellular carcinoma and cholangiocarcinoma during pregnancy: a case report. PMID- 25736195 TI - A truncated fragment of Ov-ASP-1 consisting of the core pathogenesis-related-1 (PR-1) domain maintains adjuvanticity as the full-length protein. AB - The Onchocerca volvulus activation-associated secreted protein-1 (Ov-ASP-1) has good adjuvanticity for a variety of antigens and vaccines, probably due to its ability activate antigen-processing cells (APCs). However, the functional domain of Ov-ASP-1 as an adjuvant is not clearly defined. Based on the structural prediction of this protein family, we constructed a 16-kDa recombinant protein of Ov-ASP-1 that contains only the core pathogenesis-related-1 (PR-1) domain (residues 10-153), designated ASPPR. We found that ASPPR exhibits adjuvanticity similar to that of the full-length Ov-ASP-1 (residues 10-220) for various antigens, including ovalbumin (OVA), HBsAg protein antigen, and the HIV peptide 5 (Pep5) antigen, but it is more suitable for vaccine design in ASPPR-antigen fusion proteins, and more stable in PBS than Ov-ASP-1 stored at -70 degrees C. These results suggest that ASPPR might be the functional region of Ov-ASP-1 as an adjuvant, and therefore could be developed as an adjuvant for human use. PMID- 25736196 TI - Critical analysis of olecranon fracture management by pre-contoured locking plates. AB - BACKGROUND: Fractures of the proximal ulna are rare and usually managed surgically. Strong fixation of the harware is essential to obtain good outcomes. We report our experience with pre-contoured locking plate fixation of complex olecranon fractures and present a critical appraisal of the outcomes. HYPOTHESIS: Pre-contoured locking plates provide good outcomes, but their clinical tolerance may be limited in some instances. MATERIALS AND METHODS: From September 2009 to December 2011, 28 patients were managed using a pre-contoured locking compression plate (LCP((r))). Among them, 6 were excluded because of missing data, which left 22 patients (11 males and 11 females) with a mean age of 55.7 years, including 12 who were employed. The fracture was on the dominant side in 11 patients. According to the Mayo Clinic classification, 15 fractures were type II and 7 type III. In addition to the ulnar fracture, a radial head fracture was present in 9 patients and a coronoid process fracture in 5 patients. Functional recovery was assessed using the Broberg-Morrey score and Mayo Elbow Performance Score (MEPS). Radiographs were obtained to evaluate the quality of fracture reduction and fracture healing, as well as to look for ossifications and osteoarthritis. RESULTS: Mean follow-up was 20 months. Flexion was 131 degrees , extension loss was 9.5 degrees , pronation was 79 degrees , and supination was 80.5 degrees . The mean Broberg-Morrey score was 96.7 and the mean MEPS score 96.6. Fracture healing occurred in all patients, within a mean of 10.6 weeks. Evidence of early osteoarthritis was found in 6 patients, ossifications in 3 patients, and synostosis in 1 patient. An infection was successfully treated with lavage and antibiotic therapy in 1 patient. The fixation hardware was removed in 6 patients. No prognostic factors were identified. DISCUSSION-CONCLUSION: Our hypothesis was confirmed. The outcomes are encouraging and comparable to those reported in the literature. The critical issue is the limited clinical tolerance of the plate with a high rate of posterior impingement requiring plate removal (27%). Rigorous technique is essential during plate implantation. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25736197 TI - Biomechanical study of dynamic changes in L4-L5 foramen surface area in flexion and extension after implantation of four interspinous process devices. AB - BACKGROUND: Lumbar spinal stenosis is a major public health issue. Interspinous devices implanted using minimally invasive techniques may constitute an alternative to the reference standard of bony decompression with or without intervertebral fusion. However, their indications remain unclear, due to a paucity of clinical and biomechanical data. Our objective was to evaluate the effects of four interspinous process devices implanted at L4-L5 on the intervertebral foramen surface areas at the treated and adjacent levels, in flexion and in extension. MATERIALS AND METHOD: Six fresh frozen human cadaver lumbar spines (L2-sacrum) were tested on a dedicated spinal loading frame, in flexion and extension, from 0 to 10 N.m, after preparation and marking of the L3 L4, L4-L5, and L5-S1 foramina. Stereoscopic 3D images were acquired at baseline then after implantation at L4-L5 of each of the four devices (Inspace((r)), Synthes; X-Stop((r)), Medtronic; Wallis((r)), Zimmer; and Diam((r)), Medtronic). The surface areas of the three foramina of interest were computed. RESULTS: All four devices significantly opened the L4-L5 foramen in extension. The effects in flexion separated the devices into two categories. With the two devices characterized by fixation in the spinous processes (Wallis((r)) and Diam((r))), the L4-L5 foramen opened only in extension; whereas with the other two devices (X Stop((r)) and Inspace((r))), the L4-L5 foramen opened not only in extension, but also in flexion and in the neutral position. None of the devices implanted at L4 L5 modified the size of the L3-L4 foramen. X-Stop((r)) and Diam((r)) closed the L5-S1 foramen in extension, whereas the other two devices had no effect at this level. CONCLUSION: Our results demonstrate that interspinous process devices modify the surface area of the interspinous foramina in vitro. Clinical studies are needed to clarify patient selection criteria for interspinous process device implantation. LEVEL OF EVIDENCE: Level IV. Investigating an orthopaedic device. PMID- 25736198 TI - Relationship between autologous bone graft osteointegration and correction loss after antero-posterior spondylodesis of traumatic vertebral body fracture. AB - BACKGROUND: A common method to restore the sagittal alignment and stabilize the spinal column is a dorso-ventral spondylodesis. It is assumed that correction loss after posttraumatic spondylodesis results from inadequate incorporation of the autologous iliac crest graft. MATERIALS AND METHODS: Retrospective documentation of patients with unstable vertebral body fractures of the thoracic or lumbar spine with concomitant rupture of at least one adjacent intervertebral disk who received surgical treatment at our institution from 2000 to 2006. Followed by analysis of the computer tomography documentation of a total of 142 patients with unstable vertebral body fracture stabilized by posterior internal fixator and anterior iliac crest spondylodesis. RESULTS: The following mean angle changes were derived from the second series of CT scans performed on average 283 days after anterior spondylodesis: vertebral wedge angle (VWA): 2.1 degrees ; segmental kyphotic angle: 4.9 degrees ; adjusted-SKA: 4.8 degrees ; sagittal index (SI): -0.04; segmental-scoliotic-angle (SSA): 0 degrees ; adjusted-SSA: 0 degrees . Changes in VWA, both SKAs and SI postoperatively and prior to ME, were statistically significant (P<0.05). The McAfee fusion assessment of the graft showed: full fusion: cranial 64%, caudal 47%; partial fusion: cranial 20.5%, caudal 29%; lysis: cranial 8.5%, caudal 17%; graft resorption: 7%. No correlation was found between the above-mentioned angle changes and fusions grade. DISCUSSION: The importance of radiological evidence of fusion deficiency is questionable, because the extent of fusion only has a minimal effect on correction loss. LEVEL OF EVIDENCE: Level IV. PMID- 25736199 TI - Realization of improved efficiency on nanostructured multicrystalline silicon solar cells for mass production. AB - We report the realization of both excellent optical and electrical properties of nanostructured multicrystalline silicon solar cells by a simple and industrially compatible technique of surface morphology modification. The nanostructures are prepared by Ag-catalyzed chemical etching and subsequent NaOH treatment with controllable geometrical parameters and surface area enhancement ratio. We have examined in detail the influence of different surface area enhancement ratios on reflectance, carrier recombination characteristics and cell performance. By conducting a quantitative analysis of these factors, we have successfully demonstrated a higher-than-traditional output performance of nanostructured multicrystalline silicon solar cells with a low average reflectance of 4.93%, a low effective surface recombination velocity of 6.59 m s(-1), and a certified conversion efficiency of 17.75% on large size (156 * 156 mm(2)) silicon cells, which is ~0.3% higher than the acid textured counterparts. The present work opens a potential prospect for the mass production of nanostructured solar cells with improved efficiencies. PMID- 25736200 TI - Corrigendum: Metabolic profiles of prokaryotic and eukaryotic communities in deep sea sponge Neamphius huxleyi indicated by metagenomics. PMID- 25736201 TI - Assessment of microcirculatory perfusion in healthy anesthetized cats undergoing ovariohysterectomy using sidestream dark field microscopy. AB - OBJECTIVE: To: (1) determine the feasibility of using sidestream dark field microscopy (SDM) to measure microcirculatory parameters in healthy, anesthetized cats and (2) determine if surgical tissue manipulation and anesthesia time alter these parameters during ovariohysterectomy. DESIGN: Prospective observational study. SETTING: University teaching hospital. ANIMALS: Eighteen healthy female cats. INTERVENTIONS: Sublingual mucosa microcirculatory videos were obtained under general anesthesia preoperatively, intraoperatively, and postoperatively using an SDM device in healthy cats presenting for ovariohysterectomy. At each video acquisition point, macrovascular parameters (heart rate, blood pressure, pulse oximetry, end-tidal CO2) were recorded. Vascular analysis software was used to calculate standard microcirculatory parameters. Multivariate analysis was performed to compare microvascular and macrovascular parameters, as well as correlation with the effect of surgical manipulation and time under anesthesia. MEASUREMENTS AND MAIN RESULTS: Twelve of 18 cats were included in final video analysis; 6 were removed for poor video quality. Values for total vessel density (TVD, 47.7 +/- 8.39 mm/mm(2)), proportion of perfused vessels (PPV, 88.2 +/- 5.95%), perfused vessel density (PVD, 43.0 +/- 9.00 mm/mm(2)), microcirculatory flow index (MFI, 2.33 +/- 0.33) were determined preoperatively. There were no significant changes in TVD, PPV, and PVD across intervention points. The MFI increased significantly from preoperative to intra- and postoperative data collection points. No correlation between microcirculatory parameters and length of anesthesia or macrocirculatory values was found. CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrated that SDM can be utilized to obtain sublingual microvascular parameters in healthy, anesthetized cats. Limitations include difficulty in obtaining high quality images, presumed need for general anesthesia, and need for off-line video analysis. This technology has potential as a tool in experimental and clinical monitoring of microcirculatory changes in felines. PMID- 25736202 TI - Successful treatment of a mycotic multifocal thoracoabdominal aortic aneurysm as a late sequelae of intravesical bacillus Calmette-Guerin therapy: case report and literature review. AB - Bacillus Calmette-Guerin (BCG) is a live, attenuated strain of Mycobacterium bovis commonly used for the treatment of superficial bladder carcinoma. Intravesical BCG is well tolerated despite side effects that range from hematuria to sepsis syndrome. A very rare complication is vascular infection developing a mycotic BCG aneurysm, especially in the thoracoabdominal aorta (TAAA). These are challenging to diagnose because of their scarcity, nontraditional culture media, slow growth, and are often lethal. We report the first successful repair of a symptomatic, multifocal TAAA secondary to M bovis manifesting 17 months after intravesical BCG therapy and review the literature. PMID- 25736203 TI - A retrospective cohort comparison of expanded polytetrafluorethylene to autologous vein for vascular reconstruction in modern combat casualty care. AB - BACKGROUND: Reconstruction of vascular injury often requires use of a conduit, either autologous vein (AV) or expanded polytetrafluorethylene (ePTFE). The most common anatomic locations for and durability of ePTFE as an adjunct to vascular repair in the combat setting are unknown. The objectives of this study were to characterize the anatomic locations of use of ePTFE during the wars in Afghanistan and Iraq and to compare its effectiveness to AV. METHODS: US service personnel undergoing vascular repair (2002-2012) were identified. Patients in whom ePTFE was used as an interposition conduit (n = 25) were matched with similar patients who received AV (n = 24) reconstruction. Injury and operative factors were assessed, and freedom from graft-related complication was quantified using Kaplan-Meier log-rank test. RESULTS: There was no difference between ePTFE and AV with regard to age, injury severity, or mangled extremity severity score. Follow-up for the ePTFE and AV groups was 71 and 62 months, respectively. In the cohort there was an apparent but not significantly greater freedom from graft related complication for AV compared with ePTFE (65% vs. 17%; P = 0.13). In the carotid, subclavian, and axillary artery positions, ePTFE performed equal to AV with no apparent difference in freedom from graft-related complications (P = 0.90). However, in the periphery, AV demonstrated greater 8-year freedom from graft-related complication than ePTFE (77% vs. 31%, P = 0.044). CONCLUSIONS: AV is a more durable conduit than ePTFE in repair of wartime extremity vascular injury, whereas ePTFE is effective and durable in the carotid, subclavian, and axillary locations. PMID- 25736204 TI - Are the reduction and oxidation properties of nitrocompounds dissolved in water different from those produced when adsorbed on a silica surface? A DFT M05-2X computational study. AB - The reduction and oxidation properties of four nitrocompounds (trinitrotoluene [TNT], 2,4-dinitrotoluene, 2,4-dinitroanisole, and 5-nitro-2,4-dihydro-3H-1,2,4 triazol-3-one [NTO]) dissolved in water as compared with the same properties for compounds adsorbed on a silica surface were studied. To consider the influence of adsorption, cluster models were developed at the M05/tzvp level. A hydroxylated silica (001) surface was chosen to represent a key component of soil. The PCM(Pauling) and SMD solvation models were used to model water bulk influence. The following properties were analyzed: electron affinity, ionization potential, reduction Gibbs free energy, oxidation Gibbs free energy, and reduction and oxidation potentials. It was found that adsorption and solvation decrease gas phase electron affinity, ionization potential, and Gibbs free energy of reduction and oxidation, and thus, promote redox transformation of nitrocompounds. However, in case of solvation, the changes are more significant than for adsorption. This means that nitrocompounds dissolved in water are easier to transform by reduction or oxidation than adsorbed ones. Among the considered compounds, TNT was found to be the most reactive in an electron attachment process and the least reactive for an electron detachment transformation. During ionization, a deprotonation of adsorbed NTO was found to occur. PMID- 25736205 TI - Helicobacter pylori infection can affect energy modulating hormones and body weight in germ free mice. AB - Helicobacter pylori, is an invariably commensal resident of the gut microbiome associated with gastric ulcer in adults. In addition, these patients also suffered from a low grade inflammation that activates the immune system and thus increased shunting of energy to host defense mechanisms. To assess whether a H. pylori infection could affect growth in early life, we determined the expression levels of selected metabolic gut hormones in germ free (GF) and specific pathogen free (SPF) mice with and without the presence of H. pylori. Despite H. pylori infected (SPFH) mice display alteration in host metabolism (elevated levels of leptin, insulin and peptide YY) compared to non-infected SPF mice, their growth curves remained the same. SPFH mice also displayed increased level of eotaxin-1. Interestingly, GF mice infected with H. pylori (GFH) also displayed increased levels of ghrelin and PYY. However, in contrast to SPFH mice, GFH showed reduced weight gain and malnutrition. These preliminary findings show that exposure to H. pylori alters host metabolism early in life; but the commensal microbiota in SPF mice can attenuate the growth retarding effect from H. pylori observed in GF mice. Further investigations of possible additional side effects of H. pylori are highly warranted. PMID- 25736206 TI - Ultrathin pH-sensitive nanoporous membranes for superfast size-selective separation. AB - Stimuli-responsive nanoporous membranes have attracted increasing interest in various fields due to their abrupt changes of permeation/separation in response to the external environment. Here we report ultrathin pH-sensitive nanoporous membranes that are easily fabricated by the self-assembly of poly(acrylic acid) (PAA) in a metal hydroxide nanostrand solution. PAA-adsorbed nanostrands (2.5-5.0 nm) and PAA-Cu(II) nanogels (2.0-2.5 nm) grow competitively during self-assembly. The PAA-adsorbed nanostrands are deposited on a porous support to fabricate ultrathin PAA membranes. The membranes display ultrafast water permeation and good rejection as well as significant pH-sensitivity. The 28 nm-thick membrane has a water flux decrease from 3740 to 1350 L m(-1) h(-1) bar(-1) (pH 2.0 to 7.0) with a sharp decrease at pH 5.0. This newly developed pH-sensitive nanoporous membranes may find a wide range of applications such as controlled release and size- and charge-selective separation. PMID- 25736207 TI - Conducting a two-stage preference trial: utility and challenges. AB - Treatment preferences reflect individuals' choice of therapy and influence their adherence to treatment and achievement of outcomes. The two-stage partially randomized clinical or preference trial (two-stage PRCT) is an appropriate design for examining the contribution of treatment preferences. It involves a two-stage process for assigning participants to treatments, which is useful to dismantle the effects of the treatments from those of treatment preferences. In this paper, we explain the role of treatment preferences in intervention evaluation research, describe the protocol for implementing the two-stage PRCT, and discuss issues in its application. The issues are encountered in the selection of treatments, assignment of participants and assessment of treatment preferences. Lastly, we propose ways to address the issues. PMID- 25736208 TI - MutS HOMOLOG1-derived epigenetic breeding potential in tomato. AB - Evidence is compelling in support of a naturally occurring epigenetic influence on phenotype expression in land plants, although discerning the epigenetic contribution is difficult. Agriculturally important attributes like heterosis, inbreeding depression, phenotypic plasticity, and environmental stress response are thought to have significant epigenetic components, but unequivocal demonstration of this is often infeasible. Here, we investigate gene silencing of a single nuclear gene, MutS HOMOLOG1 (MSH1), in the tomato (Solanum lycopersicum) 'Rutgers' to effect developmental reprogramming of the plant. The condition is heritable in subsequent generations independent of the MSH1-RNA interference transgene. Crossing these transgene-null, developmentally altered plants to the isogenic cv Rutgers wild type results in progeny lines that show enhanced, heritable growth vigor under both greenhouse and field conditions. This boosted vigor appears to be graft transmissible and is partially reversed by treatment with the methylation inhibitor 5-azacytidine, implying the influence of mobile, epigenetic factors and DNA methylation changes. These data provide compelling evidence for the feasibility of epigenetic breeding in a crop plant. PMID- 25736212 TI - Additive effect of nuclear and mitochondrial mutations in a patient with mitochondrial encephalomyopathy. AB - We describe the case of a woman in whom combination of a mitochondrial (MT-CYB) and a nuclear (SDHB) mutation was associated with clinical and metabolic features suggestive of a mitochondrial disorder. The mutations impaired overall energy metabolism in the patient's muscle and fibroblasts and increased cellular susceptibility to oxidative stress. To clarify the contribution of each mutation to the phenotype, mutant yeast strains were generated. A significant defect in strains carrying the Sdh2 mutation, either alone or in combination with the cytb variant, was observed. Our data suggest that the SDHB mutation was causative of the mitochondrial disorder in our patient with a possible cumulative contribution of the MT-CYB variant. To our knowledge, this is the first association of bi genomic variants in the mtDNA and in a nuclear gene encoding a subunit of complex II. PMID- 25736209 TI - Proteomic analysis of lettuce seed germination and thermoinhibition by sampling of individual seeds at germination and removal of storage proteins by polyethylene glycol fractionation. AB - Germination and thermoinhibition in lettuce (Lactuca sativa 'Jianyexianfeng No. 1') seeds were investigated by a proteomic comparison among dry seeds, germinated seeds at 15 degrees C, at 15 degrees C after imbibition at 25 degrees C for 48 h, or at 25 degrees C in KNO3 (all sampled individually at germination), and ungerminated seeds at 25 degrees C, a thermoinhibitory temperature. Before two dimensional gel electrophoresis analysis, storage proteins (greater than 50% of total extractable protein) were removed by polyethylene glycol precipitation, which significantly improved the detection of less abundant proteins on two dimensional gels. A total of 108 protein spots were identified to change more than 2-fold (P<0.05) in abundance in at least one germination treatment. Nineteen proteins increasing and one protein decreasing in abundance during germination had higher abundance in germinated 15 degrees C, 15 degrees C after imbibition at 25 degrees C for 48 h, and 25 degrees C in KNO3 seeds than in ungerminated 25 degrees C seeds. Gene expression of 12 of those proteins correlated well with the protein accumulation. Methionine metabolism, ethylene production, lipid mobilization, cell elongation, and detoxification of aldehydes were revealed to be potentially related to lettuce seed germination and thermoinhibition. Accumulation of three proteins and expression of five genes participating in the mevalonate (MVA) pathway of isoprenoid biosynthesis correlated positively with seed germinability. Inhibition of this pathway by lovastatin delayed seed germination and increased the sensitivity of germination to abscisic acid. MVA pathway-derived products, cytokinins, partially reversed the lovastatin inhibition of germination and released seed thermoinhibition at 25 degrees C. We conclude that the MVA pathway for isoprenoid biosynthesis is involved in lettuce seed germination and thermoinhibition. PMID- 25736213 TI - Germline correction of an epimutation related to Silver-Russell syndrome. AB - Like genetic mutations, DNA methylation anomalies or epimutations can disrupt gene expression and lead to human diseases. However, unlike genetic mutations, epimutations can in theory be reverted through developmental epigenetic reprograming, which should limit their transmission across generations. Following the request for a parental project of a patient diagnosed with Silver-Russell syndrome (SRS), and the availability of both somatic and spermatozoa DNA from the proband and his father, we had the exceptional opportunity to evaluate the question of inheritance of an epimutation. We provide here for the first time evidence for efficient reversion of a constitutive epimutation in the spermatozoa of an SRS patient, which has important implication for genetic counseling. PMID- 25736214 TI - Funding renal replacement therapy in southeast Asia: building public-private partnerships in Singapore, Malaysia, Thailand, and Indonesia. AB - The provision of renal replacement therapy (RRT) in developing economies is limited by lack of financial and other resources. There are no national reimbursement policies for RRT in many countries in Asia. The Southeast Asia countries of Singapore, Malaysia, Thailand, and Indonesia have adopted a strategy of encouraging public-private partnerships to increase the RRT rates in their respective countries. The private organizations include both for-profit and philanthropic bodies. The latter raise funds from ordinary citizens, corporations, and faith-based groups, as well as receive subsidies from the government to support RRT for patients in need. The kidney foundations of these countries play a leadership role in this public-private partnership. Many of the private organizations that support RRT are providers of treatment in addition to offering financial assistance to patients, with hemodialysis being the most frequently supported modality. Public-private partnership in funding RRT is sustainable over the long term with proper organization and facilitated by support from the government. PMID- 25736215 TI - Possible Impact of RET Polymorphism and Its Haplotypic Association Modulates the Susceptibility to Thyroid Cancer. AB - Rearranged during Transfection (RET) gene polymorphisms act to influence thyroid cancer in a polygenic and low-penetrance manner and no study regarding RET alterations in thyroid cancer has undergone from this part of the world (North India). We evaluated RET G691S (rs1799939), L769L (rs1800861), and S904S (rs1800863) polymorphisms to elucidate their possible role as risk factors in papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Polymorphic analysis of RET gene was performed by polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP). In RET G691S polymorphism, the overall distribution of variant alleles (GA + AA) in cases was 62.9% as against 44.5% in controls (P < 0.05) whereas frequency of RET L769L variant alleles (TG + GG) in cases was 70% versus 88% in controls (P < 0.05). In RET S904S, frequency of variant alleles (CG + GG) in cases was 56% versus 44% in controls (P < 0.05). Interestingly, G691S/L769L variant showed increased risk for the non-smokers (P < 0.05). RET S904S variant showed association with benign thyroid disease as against those with no history. The over-representation of homozygotes in G691S and L769L polymorphic variants was not observed, which suggest a "Dominant mode of inheritance." The S904S polymorphism heterozygote lies almost in the middle of the two homozygotes confirming an "Additive mode of inheritance." In conclusion, RET gene G691S/S904S polymorphisms were over represented and L769L polymorphism was under-represented in PTC and FTC patients. RET polymorphic variants could act synergistically in the development or progression of PTC and FTC. PMID- 25736216 TI - Total intravenous general anaesthesia vs. spinal anaesthesia for total hip arthroplasty. PMID- 25736217 TI - Synthesis of anionic phosphorus-containing heterocycles by intramolecular cyclizations involving N-functionalized phosphinecarboxamides. AB - We report that the 2-phosphaethynolate anion (PCO(-)) reacts with propargylamines in the presence of a proton source to afford novel N-derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five- and six-membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5-exo-dig or 6-endo-dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus-containing heterocylic systems that are closely related to known organic molecules with interesting bio-active properties. PMID- 25736218 TI - Sustainable dairy cattle selection in the genomic era. AB - Genomic selection offers considerable flexibility to increase genetic trends in dairy cattle breeding. It is also an opportunity for more sustainable breeding, in terms of breeding goal and genetic variability. With a shorter generation interval, there is a big risk of increasing inbreeding if semen dissemination policy of elite bulls is not changed. However, using a large number of young bulls as service bulls and bull sires is a solution for both maximizing genetic trend while reducing inbreeding trend. Female genotyping is a key challenge for within-herd selection but, more importantly, for selection of new traits and for replacement of current reference populations based upon progeny-tested bulls. Genomic selection also opens new avenues for more customized breeding across herds or production systems. A big challenge is to reduce the dependency of genomic predictions on relationship between candidates and the reference population. A strong effort is presently dedicated to integrating genome sequence information into predictions, to improve their accuracy and persistency. In the longer term, further customization of selection will be possible by accounting for G * E interactions. Important developments are also necessary to decrease loss of favourable alleles through genetic drift. PMID- 25736219 TI - Haemogregarines of freshwater turtles from Southeast Asia with a description of Haemogregarina sacaliae sp. n. and a redescription of Haemogregarina pellegrini Laveran and Pettit, 1910. AB - The uniform morphology of the developmental stages of Haemogregarina species and the insufficient information supplied by the simplistic descriptions of previous authors complicates their differential diagnosis and proper species identification. In this study, we detected Haemogregarina spp. in 6 out of 22 (27.2%) examined turtles originating from Southeast Asia, Malayemys subtrijuga (n = 4), Sacalia quadriocellata (n = 1) and Platysternon megacephalum (n = 1), and compared them with the available literature data. Microscopic analysis of our isolates distinguished 2 morphological species, Haemogregarina pellegrini and one new species, being described in this paper as Haemogregarina sacaliae sp. n. Phylogenetic analyses based on 1210 bp long fragment of 18S rDNA sequences placed both haemogregarines firmly within the monophyletic Haemogregarina clade. Isolates of H. pellegrini from 2 distantly related turtle hosts, M. subtrijuga and P. megacephalum, were genetically identical. Despite the fact that numerous Haemogregarina species of turtles have been described, the incompleteness of the morphological data and relatively low host specificity provides the space for large synonymy within this taxon. Therefore, a complex approach combining microscopic analyses together with molecular-genetic methods should represent the basic standard for all taxonomic studies. PMID- 25736220 TI - Primary osteolysis syndromes: beware of difficult airway. AB - BACKGROUND: Primary osteolysis syndromes represent a number of rare conditions characterized by destruction and resorption of bone that is unrelated to neoplasia, infection, or trauma. AIM: To characterize the periprocedural course of patients with primary osteolysis syndrome undergoing procedures that require anesthesia care. METHODS: The medical records database from our institution was searched from 1976 to 2013 to identify patients with primary osteolysis syndromes who received anesthesia care. We reviewed demographic characteristics, comorbidities, and perioperative course of patients with different forms of primary osteolysis. A systematic review of the literature was performed to identify reports describing the anesthetic management of patients with these conditions. RESULTS: We identified 11 patients with a primary osteolysis syndrome who received 111 anesthetics. The patients' ages at the time of surgery ranged from 3 to 62 years. Difficult airway management was a common finding. On preoperative examination, difficulty with endotracheal intubation was predicted in 8 of 11 patients. Three patients had preexisting tracheostomies. One patient required multiple awake fiberoptic intubations. Another two patients where successfully intubated early in life via direct laryngoscopy, but eventually required awake fiberoptic intubations as the disease process caused progressive distortion of airway structures. Intraoperative complications were absent. In the postoperative period, three patients required prolonged mechanical ventilation due to airway swelling, respiratory failure, and infection. CONCLUSIONS: Airway management may be challenging in patients with primary osteolysis syndromes. Because the osteolytic process advances with aging and craniofacial dysmorphism may progressively worsen, the airway should always be reassessed before surgery with an appropriate strategy for potentially difficult intubation. In all patients with primary osteolysis, a potential for pathologic fracture must be considered and careful intraoperative positioning is warranted. PMID- 25736221 TI - DNA/HSA interaction and nuclease activity of an iron(III) amphiphilic sulfonated corrole. AB - The DNA binding of amphiphilic iron(III) 2,17-bis(sulfonato)-5,10,15 tris(pentafluorophenyl)corrole complex (Fe-SC) was studied using spectroscopic methods and viscosity measurements. Its nuclease-like activity was examined by using pBR322 DNA as a target. The interaction of Fe-SC with human serum albumin (HSA) in vitro was also examined using multispectroscopic techniques. Experimental results revealed that Fe-SC binds to ct-DNA via an outside binding mode with a binding constant of 1.25 * 10(4) M(-1). This iron corrole also displays good activity during oxidative DNA cleavage by hydrogen peroxide or tert butyl hydroperoxide oxidants, and high-valent (oxo)iron(V,VI) corrole intermediates may play an important role in DNA cleavage. Fe-SC exhibits much stronger binding affinity to site II than site I of HSA, indicating a selective binding tendency to HSA site II. The HSA conformational change induced by Fe-SC was confirmed by UV/Vis and CD spectroscopy. PMID- 25736222 TI - Inhibition of lipopolysaccharide-induced gene expression by liver X receptor ligands in macrophages involves interference with early growth response factor 1. AB - Liver X receptors (LXRs) are nuclear receptors that act as ligand-dependent transcription factors forming permissive heterodimers with retinoid X receptors (RXRs). In this study we aimed to assess the effect of LXR/RXR activation on the transcriptional induction of pro-inflammatory genes including cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in activated macrophages. Our study shows that LXR ligands such as oxysterols, GW3965 or TO901317, as well as RXR ligands like 9cis retinoic acid or SR11237, decreased LPS-induced expression of COX-2 and mPGES-1. Consequently, LPS-dependent PGE2 production was substantially reduced in macrophages treated with LXR/RXR ligands. The inhibitory effects of LXR/RXR activation on LPS-induced expression of COX-2 and mPGES-1 in macrophages, occurred by a mechanism involving interference with transcriptional activation of these genes. LXR/RXR activation interfered with the activity of transcription factors essential in the up-regulation of the expression of pro-inflammatory genes in these cells, such as NFkappaB, but also Egr-1, which had not been previously associated with LXR-mediated gene repression. As this transcription factor is involved in the regulation of a variety of genes involved in inflammatory processes, LXR and RXR-mediated interference with Egr-1 signaling could represent an important event mediating the anti-inflammatory effects of these receptors in macrophages. PMID- 25736223 TI - Regulation of the Arabidopsis CBF regulon by a complex low-temperature regulatory network. AB - Exposure of Arabidopsis thaliana plants to low non-freezing temperatures results in an increase in freezing tolerance that involves action of the C-repeat binding factor (CBF) regulatory pathway. CBF1, CBF2 and CBF3, which are rapidly induced in response to low temperature, encode closely related AP2/ERF DNA-binding proteins that recognize the C-repeat (CRT)/dehydration-responsive element (DRE) DNA regulatory element present in the promoters of CBF-regulated genes. The CBF transcription factors alter the expression of more than 100 genes, known as the CBF regulon, which contribute to an increase in freezing tolerance. In this study, we investigated the extent to which cold induction of the CBF regulon is regulated by transcription factors other than CBF1, CBF2 and CBF3, and whether freezing tolerance is dependent on a functional CBF-CRT/DRE regulatory module. To address these issues we generated transgenic lines that constitutively overexpressed a truncated version of CBF2 that had dominant negative effects on the function of the CBF-CRT/DRE regulatory module, and 11 transcription factors encoded by genes that were rapidly cold-induced in parallel with the 'first-wave' CBF genes, and determined the effects that overexpressing these proteins had on global gene expression and freezing tolerance. Our results indicate that cold regulation of the CBF regulon involves extensive co-regulation by other first wave transcription factors; that the low-temperature regulatory network beyond the CBF pathway is complex and highly interconnected; and that the increase in freezing tolerance that occurs with cold acclimation is only partially dependent on the CBF-CRT/DRE regulatory module. PMID- 25736224 TI - Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer. AB - Our previous studies demonstrated that specific inhibition of the BIG3-PHB2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP, a dominant negative peptide inhibitor, leads to suppression of E2-dependent estrogen receptor (ER) alpha activation through the reactivation of the tumor suppressive activity of PHB2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti-estrogen tamoxifen in breast cancer cells. Intrinsic PHB2 released from BIG3 by ERAP effectively disrupted each interaction of membrane-associated ERalpha and insulin-like growth factor 1 receptor beta (IGF-1Rbeta), EGFR, PI3K or human epidermal growth factor 2 (HER2) in the presence of E2 and the growth factors IGF or EGF, followed by inhibited the activation of IGF-1Rbeta, EGFR or HER2, and reduced Akt, MAPK and ERalpha phosphorylation levels, resulting in significant suppression of proliferation of ERalpha-positive breast cancer cells in vitro and in vivo. More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER2 amplification. Taken together, our findings suggest that the specific inhibition of BIG3-PHB2 is a novel potential therapeutic approach for the treatment of tamoxifen-resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women. PMID- 25736225 TI - The design and relevance of a computerized gamified depression therapy program for indigenous maori adolescents. AB - BACKGROUND: Depression is a major health issue among Maori indigenous adolescents, yet there has been little investigation into the relevance or effectiveness of psychological treatments for them. Further, consumer views are critical for engagement and adherence to therapy. However, there is little research regarding indigenous communities' opinions about psychological interventions for depression. OBJECTIVE: The objective of this study was to conduct semistructured interviews with Maori (indigenous New Zealand) young people (taitamariki) and their families to find out their opinions of a prototype computerized cognitive behavioral therapy (cCBT) program called Smart, Positive, Active, Realistic, X-factor thoughts (SPARX), a free online computer game intended to help young persons with mild to moderate depression, feeling down, stress or anxiety. The program will teach them how to resolve their issues on their own using Cognitive Behavioural Therapy as psychotherapeutic approach. METHODS: There were seven focus groups on the subject of the design and cultural relevance of SPARX that were held, with a total of 26 participants (19 taitamarki, 7 parents/caregivers, all Maori). There were five of the groups that were with whanau (family groups) (n=14), one group was with Maori teenage mothers (n=4), and one group was with taitamariki (n=8). The general inductive approach was used to analyze focus group data. RESULTS: SPARX computerized therapy has good face validity and is seen as potentially effective and appealing for Maori people. Cultural relevance was viewed as being important for the engagement of Maori young people with SPARX. Whanau are important for young peoples' well being. Participants generated ideas for improving SPARX for Maori and for the inclusion of whanau in its delivery. CONCLUSIONS: SPARX computerized therapy had good face validity for indigenous young people and families. In general, Maori participants were positive about the SPARX prototype and considered it both appealing and applicable to them. The results of this study were used to refine SPARX prior to it being delivered to taitamariki and non-Maori young people. TRIAL REGISTRATION: The New Zealand Northern Y Regional Ethics Committee; http://ethics.health.govt.nz/home; NTY/09/003; (Archived by WebCite at http://www.webcitation/6VYgHXKaR). PMID- 25736226 TI - Mesenchymal Deletion of Histone Demethylase NO66 in Mice Promotes Bone Formation. AB - Our previous studies indicated that the Jumonji C (JmjC)-domain-containing NO66 is a histone demethylase with specificity for methylated histone H3K4 and H3K36. NO66 binds to the transcription factor Osterix (Osx) and inhibits its transcriptional activity in promoter assays. However, the physiological role of NO66 in formation of mammalian bones is unknown. Here, using a genetically engineered mouse model, we show that during early skeletal development, Prx1-Cre dependent mesenchymal deletion of NO66 promotes osteogenesis and formation of both endochondral as well as intramembranous skeletal elements, leading to a larger skeleton and a high bone mass phenotype in adult mice. The excess bone formation in mice where NO66 was deleted in cells of mesenchymal origin is associated with an increase in the number of preosteoblasts and osteoblasts. Further analysis revealed that in the embryonic limbs and adult calvaria of mice with deletion of NO66 in cells of mesenchymal origin, expression of several genes including bone morphogenetic protein 2 (Bmp2), insulin-like growth factor 1 (Igf1), and osteoclast inhibitor osteoprotegerin was increased, concurrent with an increase in expression of bone formation markers such as osterix (Osx), type I collagen, and bone sialoprotein (Bsp). Taken together, our results provide the first in vivo evidence that NO66 histone demethylase plays an important role in mammalian osteogenesis during early development as well as in adult bone homeostasis. We postulate that NO66 regulates bone formation, at least in part, via regulating the number of bone-forming cells and expression of multiple genes that are critical for these processes. PMID- 25736227 TI - Generation of high-titre virus stocks using BrK.219, a B-cell line infected stably with recombinant Kaposi's sarcoma-associated herpesvirus. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-2-lymphotropic human oncogenic herpesvirus associated with Kaposi's sarcoma (KS) and two B-cell lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KSHV establishes latency soon after infection in vivo and in vitro. Consequently, it is technically difficult to generate high-titre virus stocks required for infection experiments in tissue culture. Currently used methods of KSHV stock production involve induction of the lytic/productive cycle in PEL cell lines or in adherent cell lines harbouring recombinant KSHV genomes. In this study, the BJAB-derived B-cell line BrK.219, which is infected latently with a recombinant KSHV (rKSHV.219), is used to produce high-titre virus stocks. BrK.219 cells enter the lytic KSHV replication cycle upon cross-linking of B-cell receptors (BCRs) with anti-IgM antibodies without the need for additional, potentially toxic chemical inducers. High cell concentrations can be cultured and induced easily in spinner flasks, saving time and resources. The established protocol allows the generation of KSHV virus stocks with titres of up to 10(6) IU/ml in unconcentrated culture supernatants, representing a 10(3)-10(4)-fold improvement compared to conventional methods. PMID- 25736228 TI - Longitudinal 2-point dixon muscle magnetic resonance imaging in becker muscular dystrophy. AB - INTRODUCTION: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). METHODS: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1-year follow-up using a 2 point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. RESULTS: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow-up. The severity of muscle involvement varied between various muscle groups. CONCLUSIONS: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. PMID- 25736229 TI - Sleeve Gastrectomy Reduces Hepatic Steatosis by Improving the Coordinated Regulation of Aquaglyceroporins in Adipose Tissue and Liver in Obese Rats. AB - BACKGROUND: Glycerol constitutes an important metabolite for the control of lipid accumulation and glucose homeostasis. Our aim was to investigate the potential role of aquaglyceroporins, which are glycerol channels mediating glycerol efflux in adipocytes (AQP3 and AQP7) and glycerol influx (AQP9) in hepatocytes, in the improvement of adiposity and hepatic steatosis after sleeve gastrectomy in an experimental model of diet-induced obesity (DIO). METHODS: Male Wistar DIO rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal diet (ND) or a high-fat diet (HFD) or pair-fed to the amount of food eaten by sleeve-gastrectomized animals]. The tissue distribution and expression of AQPs in biopsies of epididymal (EWAT) and subcutaneous (SCWAT) white adipose tissue and liver were analyzed by real-time PCR, Western blot, and immunohistochemistry. RESULTS: Four weeks after surgery, DIO rats undergoing sleeve gastrectomy showed a reduction in body weight, whole body adiposity, and hepatic steatosis. DIO was associated with a tendency towards an increase in EWAT AQP3 and SCWAT AQP7 and a decrease in hepatic AQP9. Sleeve gastrectomy downregulated AQP7 in both fat depots and upregulated AQP3 in EWAT, without changing hepatic AQP9. Aqp7 transcript levels in EWAT and SCWAT were positively associated with adiposity and glycemia, while Aqp9 mRNA was negatively correlated with markers of hepatic steatosis and insulin resistance. CONCLUSION: Our results show, for the first time, that sleeve gastrectomy, a widely applied bariatric surgery procedure, restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, thereby improving whole-body adiposity and hepatic steatosis. PMID- 25736230 TI - Manometry of the Upper Gut Following Roux-en-Y Gastric Bypass Indicates That the Gastric Pouch and Roux Limb Act as a Common Cavity. AB - BACKGROUND: The motility of the upper gut after Roux-en-Y gastric bypass (RYGBP) is underexplored. We aimed to investigate the oesophago-gastro-Roux limb motor activity during fasting and after food intake. METHODS: Eighteen morbidly obese patients were examined at least 2 years after RYGBP. A high-resolution manometry catheter was positioned to straddle the oesophagogastric junction, the gastric pouch and the proximal Roux limb using transmucosal potential difference measurements. Three patients with vertical banded gastroplasty (VBG) were also studied. RESULTS: During the fasting state, the gastric pouch had low or no activity whereas the Roux limb exhibited regular migrating motility complexes (MMCs) being initiated just distal to gastroenteroanastomosis. Median cycle duration was 72 min, and the median propagating velocity of the phase III MMC phase was 2.7 cm/min (n = 8). When patients were asked to eat until they felt comfortably full, intraluminal pressure increased by 6 to 8 cmH2O without any significant difference between gastric pouch and the Roux limb (n = 9). The increased intraluminal pressure following food intake correlated neither to weight loss nor to meal size or rate of eating. CONCLUSIONS: A successful RYGBP is associated with MMC in the Roux limb during fasting. The gastric pouch and the Roux limb behaved as a common cavity during food ingestion. Data do not support the hypothesis that the alimentary limb pressure in response to food intake influences either meal size or weight loss. PMID- 25736231 TI - Indocyanine green-enhanced fluorescence in laparoscopic sleeve gastrectomy. AB - The aim of this study is to present our preliminary experience with indocyanine green fluorescence (IGF) imaging in laparoscopic sleeve gastrectomy. After dissection of the greater curve sleeve, gastrectomy is performed using a linear articulated stapler. Once the stomach is resected, an indocyanine green solution is prepared and injected in a periferic vein. A laparoscopic system with a high definition camera system connected to a laparoscope equipped with a specific filter for optimal detection of the near-infrared fluorescence was used at all times as previously reported in a paper of Boni et al. A methylene blue test is routinely performed after near-infrared fluorescence, and a routine gastrografin upper gastrointestinal study is performed on postoperative day 2. We retrospectively identified 15 patients undergoing laparoscopic sleeve gastrectomy between April and October 2014. IGF imaging was used for all patients. A regular and homogeneous perfusion was observed along the entire gastric sleeve including the esophago-gastric junction. On the contrary, the excised specimen appeared devascularized at IGF imaging as expected. Intraoperative methylene blue test was negative in all cases. The contrast swallow did not document any leak. Neither clinical leak nor other complications occurred postoperatively (minimum follow-up of 2 months). IGF is a recent development in minimally invasive surgery. In this preliminary experience, IGF results resemble to intraoperative methylene blue test and postoperative contrast swallow ones. IGF allows a real-time assessment and gives a direct image of tissue perfusion and vascularization. Moreover, IGF may be helpful to explain the exact pathogenesis of gastric leak. PMID- 25736232 TI - Priorities, concerns and unmet needs among Haitians in Boston after the 2010 earthquake. AB - In January 2010, a massive earthquake struck Haiti. The devastation not only affected those living in Haiti at the time but also those Haitians living in the United States (U.S.). Few studies have assessed the degree of impact of the earthquake in U.S. Haitian communities. The purpose of this study was to elicit information about health priorities, concerns and resources needed to improve the delivery of health and social care for Haitians in Boston, MA. We conducted six focus groups among 78 individuals in the spring of 2011. Participants were recruited through community organisations, including churches, Haitian social service centres, restaurants and by word of mouth. Analysis of qualitative data revealed an enormous psychological, emotional, financial and physical toll experienced by Boston-area Haitians following the earthquake. Participants described increased distress, depressive episodes, headaches and financial hardship. They also noted insufficient resources to meet the increased needs of those living in the U.S., and those who had immigrated after the earthquake. Most participants cited an increased need for mental health services, as well as assistance with finding employment, navigating the immigration system, and balancing the health and financial needs of families in the U.S. and in Haiti. Despite this, many reported that the tragedy created a sense of unity and solidarity within the Haitian community. These findings corroborate the need for culturally and linguistically appropriate mental health services, as well as for employment, immigration and healthcare navigation services. Participants suggested that interventions be offered through Haitian radio and television stations, as well as group events held in churches. Further research should assess the need for and barriers to utilisation of mental health services among the Haitian community. A multi-faceted approach that includes a variety of outreach strategies implemented through multiple channels may offer a means of improving awareness of and access to health and social services. PMID- 25736233 TI - A novel synthetic chemistry approach to linkage-specific ubiquitin conjugation. AB - Ubiquitination is of great importance as the post-translational modification of proteins with ubiquitin, or ubiquitin chains, facilitates a number of vital cellular processes. Herein we present a facile method of preparing various ubiquitin conjugates under mild conditions using michael acceptors based on dibromo-maleimides and dibromo-pyridazinediones. PMID- 25736234 TI - Hypnotherapy for irritable bowel syndrome: an audit of one thousand adult patients. AB - BACKGROUND: Gut-focused hypnotherapy improves the symptoms of irritable bowel syndrome (IBS) with benefits being sustained for many years. Despite this, the technique has not been widely adopted by healthcare systems, possibly due to relatively small numbers in published studies and uncertainty about how it should be provided. AIM: To review the effect of hypnotherapy in a large cohort of refractory IBS patients. METHODS: One thousand IBS patients fulfilling Rome II criteria, mean age 51.6 years (range 17-91 years), 80% female, receiving 12 sessions of hypnotherapy over 3 months, were studied. The primary outcome was a 50 point reduction in the IBS Symptom Severity Score. The fall in scores for Noncolonic Symptoms, Quality of Life and Anxiety or Depression, were secondary outcomes. The Federal Drug Administration's recommended outcome of a 30% or more reduction in abdominal pain was also recorded. RESULTS: Overall, 76% met the primary outcome which was higher in females (females: 80%, males: 62%, P < 0.001) and those with anxiety (anxious: 79%, non-anxious: 71%, P = 0.010). The mean reduction in other scores was: IBS Symptom Severity Score, 129 points (P < 0.001), Noncolonic Symptom Score, 65 (P < 0.001) and Quality of Life Score, 66 (P < 0.001). Sixty-seven per cent reported a 30% or more reduction in abdominal pain scores. Pain days fell from 18 to 9 per month. Patients with anxiety and depression fell from 63% to 34% and 25% to 12% respectively (P < 0.001). Outcome was unaffected by bowel habit subtype. CONCLUSION: These results provide further evidence that gut-focused hypnotherapy is an effective intervention for refractory IBS. PMID- 25736235 TI - Cost effectiveness of dipeptidyl peptidase-4 inhibitors for type 2 diabetes. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs used for treating type 2 diabetes mellitus. While many studies have reported on the cost-effectiveness of DPP-4 inhibitors for treating type 2 diabetes, a systematic review of economic evaluations of DPP-4 inhibitors is currently lacking. OBJECTIVES: The aim of this systematic review was to assess the cost effectiveness of DPP-4 inhibitors for patients with type 2 diabetes. DATA SOURCES: MEDLINE, EMBASE, National Health Service Economic Evaluation Database (NHS EED), Web of Science, EconLit databases, and the Cochrane Library were searched in November 2013. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Studies assessing the cost effectiveness of DPP-4 inhibitors for type 2 diabetes were eligible for analysis. DPP-4 inhibitor monotherapy or combinations with other antidiabetic agents were included in the review. The DPP 4 inhibitors were all marketed drugs. Two reviewers independently reviewed titles, abstracts, and articles sequentially to select studies for data abstraction based on the inclusion and exclusion criteria. Disagreements were resolved by consensus. STUDY APPRAISAL AND SYNTHESIS METHODS: The quality of included studies was assessed according to the 24-item checklist of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. The costs reported by the included studies were converted to US dollars via purchasing power parities (PPP) in the year 2013 using the CCEMG-EPPI-Center Cost Converter. RESULTS: A total of 11 published studies were selected for inclusion; all were cost-utility analyses. Nine studies were conducted from a payer perspective and one used a societal perspective; however, the perspective of the other study was unclear. Four studies were of good quality, six were of moderate quality, and one was of low quality. Of the seven studies comparing DPP-4 inhibitors plus metformin with sulfonylureas plus metformin, six concluded that DPP-4 inhibitors were cost effective in patients with type 2 diabetes who were no longer adequately controlled by metformin monotherapy. Five studies compared DPP 4 inhibitors with thiazolidinediones, and whether DPP-4 inhibitors were cost effective was uncertain. Only two economic evaluations provided data to compare DPP-4 inhibitors versus insulin, and the results favored the use of DPP-4 inhibitors as second-line therapy. LIMITATIONS: Synthesis of the data was impossible because of heterogeneity in the methodology and data sources of the economic evaluations, and the inclusion criteria excluded conference abstracts. It was difficult to find reliable weightings for each of the items of the CHEERS checklist, and the ratings were dichotomous. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This study provides the first systematic evaluation of DPP-4 inhibitors for patients with type 2 diabetes. It found that, in patients with type 2 diabetes who do not achieve glycemic targets with antidiabetic monotherapy, DPP-4 inhibitors as add-on treatment may represent a cost-effective option compared with sulfonylureas and insulin. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed. PMID- 25736237 TI - Reconsidering outdoor temperature and cognition in multiple sclerosis. AB - BACKGROUND: Research in multiple sclerosis (MS) suggests warmer weather plays a role in disease manifestation. OBJECTIVE: This work sought to replicate the finding that warmer outdoor temperatures are significantly associated with poorer cognition in MS. METHODS: Associations between outdoor temperature and cognition were examined in three studies with a total of 263 patients with MS. RESULTS: Contrary to previous research, no significant relationship was found between cognitive performance and outdoor temperature in MS. CONCLUSIONS: The results of the current work underscore the need to better understand if, when, and how cognitive performance may be influenced by seasonal variables in MS. PMID- 25736236 TI - INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia. AB - In this study, we investigated the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4B(high)) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4B(high) was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4B(high) effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4B(high) has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target. PMID- 25736238 TI - Sporadic melanoma in South-Eastern Italy: the impact of melanocortin 1 receptor (MC1R) polymorphism analysis in low-risk people and report of three novel variants. AB - Environmental and genetic risk factors are involved in the development of melanoma. The role of the melanocortin 1 receptor (MC1R) gene has been investigated and differences according to geographic areas have been described. To evaluate the role of some clinical and genetic risk factors in melanoma development, we performed a case-control study involving 101 melanoma patients and 103 controls coming from South-Eastern Italy (Puglia), after achieving informed consent. We confirmed the role of known clinical risk factors for melanoma. Furthermore, 42 MC1R polymorphisms were observed. Three of these variants (L26V, H232L, D294Y) were not previously reported in the literature. Their predicted impact on receptor function was evaluated using bioinformatic tools. We report an overall frequency of MC1R variants in our population higher than in Northern or Central Italy. The most common polymorphism found was V60L, that has been recently reported to spread among South Mediterranean population. This variant influenced phenotypic characteristics of our population while it did not impinge on melanoma risk. An increased risk of melanoma was associated with two or more MC1R variants, when at least one was RHC, compared to people carrying the MC1R consensus sequence or a single MC1R polymorphism. Interestingly, we observed an increased risk of melanoma in subjects with darker skin and lower nevus count, usually considered at low risk, when carrying MC1R polymorphisms. PMID- 25736239 TI - Modeling post-death transmission of Ebola: challenges for inference and opportunities for control. AB - Multiple epidemiological models have been proposed to predict the spread of Ebola in West Africa. These models include consideration of counter-measures meant to slow and, eventually, stop the spread of the disease. Here, we examine one component of Ebola dynamics that is of ongoing concern - the transmission of Ebola from the dead to the living. We do so by applying the toolkit of mathematical epidemiology to analyze the consequences of post-death transmission. We show that underlying disease parameters cannot be inferred with confidence from early-stage incidence data (that is, they are not "identifiable") because different parameter combinations can produce virtually the same epidemic trajectory. Despite this identifiability problem, we find robustly that inferences that don't account for post-death transmission tend to underestimate the basic reproductive number - thus, given the observed rate of epidemic growth, larger amounts of post-death transmission imply larger reproductive numbers. From a control perspective, we explain how improvements in reducing post-death transmission of Ebola may reduce the overall epidemic spread and scope substantially. Increased attention to the proportion of post-death transmission has the potential to aid both in projecting the course of the epidemic and in evaluating a portfolio of control strategies. PMID- 25736241 TI - Metabolome analysis via comprehensive two-dimensional liquid chromatography: identification of modified nucleosides from RNA metabolism. AB - Modified nucleosides derived from the RNA metabolism constitute an important chemical class, which are discussed as potential biomarkers in the detection of mammalian breast cancer. Not only the variability of modifications, but also the complexity of biological matrices such as urinary samples poses challenges in the analysis of modified nucleosides. In the present work, a comprehensive two dimensional liquid chromatography mass spectrometry (2D-LC-MS) approach for the analysis of modified nucleosides in biological samples was established. For prepurification of urinary samples and cell culture supernatants, we performed a cis-diol specific affinity chromatography using boronate-derivatized polyacrylamide gel. In order to establish a 2D-LC method, we tested numerous column combinations and chromatographic conditions. In order to determine the target compounds, we coupled the 2D-LC setup to a triple quadrupole mass spectrometer performing full scans, neutral loss scans, and multiple reaction monitoring (MRM). The combination of a Zorbax Eclipse Plus C18 column with a Zorbax Bonus-RP column was found to deliver a high degree of orthogonality and adequate separation. By application of 2D-LC-MS approaches, we were able to detect 28 target compounds from RNA metabolism and crosslinked pathways in urinary samples and 26 target compounds in cell culture supernatants, respectively. This is the first demonstration of the applicability and benefit of 2D-LC-MS for the targeted metabolome analysis of modified nucleosides and compounds from crosslinked pathways in different biological matrices. PMID- 25736240 TI - Pancreatic adaptive responses in alcohol abuse: Role of the unfolded protein response. AB - The majority of those who drink excessive amounts of alcohol do not develop pancreatic disease. One overarching hypothesis is that alcohol abuse requires additional risk factors, either environmental or genetic, for disease to occur. However, another reason be a result of alcohol-induced activation of adaptive systems that protect the pancreas from the toxic effects of alcohol. We show that mechanisms within the unfolded protein response (UPR) of the endoplasmic reticulum (ER) that can lead to protection of the pancreas from pancreatic diseases with alcohol abuse. The remarkable ability of the pancreas to adapt its machinery to alcohol abuse using UPR systems and continue functioning is the likely reason that pancreatitis from alcohol abuse does not occur in the majority of heavy drinkers. These findings indicate that methods to enhance the protective responses of the UPR can provide opportunities for prevention and treatment of pancreatic diseases. PMID- 25736242 TI - Simultaneous determination of chiral pesticide flufiprole enantiomers in vegetables, fruits, and soil by high-performance liquid chromatography. AB - A simple and reliable method for the simultaneous determination of chiral pesticide flufiprole enantiomers using high-performance liquid chromatography has been established. The separation and determination were performed using reversed phase chromatography on a carbamoyl-cellulose-type chiral stationary phase, a Lux Cellulose-2 column. The effects of different mobile phase composition on separation were discussed. The absolute configuration of flufiprole enantiomers was measured through the combination of experimental and predicted ECD spectra. An Alumina-N solid-phase extraction (SPE) column was used in the cleanup of the vegetables, fruits, and soil samples. The method was evaluated by the specificity, matrix effect, linearity, precision, accuracy and stability. The mean recoveries of two enantiomers ranged from 86.8 to 98.9 %, with 1.1-6.4 % intra-day relative standard deviation (RSD) and 1.2 to 5.8 % inter-day RSD. Good linearity (R (2) > 0.998) was obtained for all analyte matrix calibration curves within the range of 0.2-20 mg L(-1). The limit of detection for two enantiomers in the six matrices was 0.007-0.008 mg kg(-1), whereas the limit of quantification of two enantiomers in fruits, vegetables, and soil was 0.021-0.025 mg kg(-1). The results confirmed that this method was convenient and accurate for the simultaneous determination of flufiprole enantiomers in food and environmental samples. PMID- 25736243 TI - Synthesis of boronic-acid-functionalized magnetic attapulgite for selective enrichment of nucleosides. AB - 2,4-Difluoro-3-formyl-phenylboronic acid (DFFPBA)-modified magnetic attapulgite (ATP-Fe3O4-NH2-DFFPBA) was synthesized and employed to capture and enrich cis diol-containing biomolecules. The resulting material exhibited a high saturation magnetization value of 20.71 emu/g, allowing the absorbent to be conveniently magnetically separated. Combining the Fe3O4 nanoparticles with the high specific surface area of attapulgite yielded a material with a high capture capacity (13.78 mg/g) for adenosine. Furthermore, ATP-Fe3O4-NH2-DFFPBA was found to possess remarkable selectivity for adenosine at a low molar ratio of adenosine/2 deoxyadenosine (1:500). The potential applications of this material were explored by using it to extract five nucleosides from urine samples, and the results demonstrate that it can decrease matrix interference and selectively enrich analytes. PMID- 25736244 TI - Evidence for an N-methyl transfer reaction in phosphatidylcholines with a terminal aldehyde during negative electrospray ionization tandem mass spectrometry. AB - Lipidomic analysis of the complex mixture of lipids isolated from biological systems can be a challenging process that often involves tandem mass spectrometry and interpretation of both precursor ions and product ions relative to the molecular structure of the lipids. Therefore, detailed understanding of the gas phase ion chemistry occurring for each class of phospholipids is critically important for an accurate assignment of lipid structure. Some oxidized phosphatidylcholines are known to be biologically active and responsible for pathological events, and are therefore important targets for detection in lipidomic studies. Modification of fatty acyl chains by oxidation may, however, change the behavior of ion formation and decomposition in the mass spectrometer. In this study, we report on the mass-spectrometric behavior of 1-palmitoyl-2-(9' oxononanoyl)-sn-glycero-3-phosphocholine, a bioactive product of phosphatidylcholine oxidation. In addition to [M-15](-) and the acetate adduct [M+59](-), three additional adduct ions, including [M-H](-), were present in significant abundance in the negative ion electrospray mass spectrum. It was found that this unexpected [M-H](-) ion was formed by the transfer of a methyl group from the choline residue on the polar head group to the aldehyde functionality of the sn-2 substituent, resulting in a 14-Da increase in the mass of the resulting sn-2 carboxylate anion formed by collisional activation of this ion. These results suggest additional rules for understanding the gas-phase ion chemistry of aldehydic phosphatidylcholine molecular species. PMID- 25736246 TI - Analysis of glucuronide and sulfate steroids in urine by ultra-high-performance supercritical-fluid chromatography hyphenated tandem mass spectrometry. AB - Profiling conjugated urinary steroids to detect anabolic-steroid misuse is recognized as an efficient analytical strategy in both chemical-food-safety and anti-doping fields. The relevance and robustness of such profiling rely on the analysis of glucuronide and sulfate steroids, which is expected to have properties including accuracy, specificity, sensitivity, and, if possible, rapidity. In this context, the ability of ultra-high-performance supercritical fluid chromatography (UHPSFC) hyphenated tandem mass spectrometry (MS-MS) to provide reliable and accurate phase II analysis of steroids was assessed. Four stationary phases with sub-2 MUm particles (BEH, BEH 2-ethyl-pyridine, HSS C18 SB, and CSH fluorophenyl) were screened for their capacity to separate several conjugated steroid isomers. Analytical conditions including stationary phase, modifier composition and percentage, back pressure, column temperature, and composition and flow rate of make-up solvent were investigated to improve the separation and/or the sensitivity. Thus, an analytical procedure enabling the analysis of eight glucuronide and 12 sulfate steroids by two different methods in 12 and 15 min, respectively, was optimized. The two procedures were evaluated, and UHPSFC-MS-MS analysis revealed its ability to provide sensitive (limits of quantification: 0.1 ng mL(-1) and 0.5 ng mL(-1) for sulfate and glucuronide steroids, respectively) and reliable quantitative performance (R(2) > 0.995, RSD < 20%, and bias < 30%) through the use of suitable labeled internal standards. Comparison with UHPLC-MS-MS was performed, and UHPSFC-MS-MS obtained better performance in terms of sensitivity. Finally, as a proof of concept, this so called green technology was used in a chemical-food-safety context to profile steroid conjugates in urine samples from bovines treated with estradiol. Graphical Abstract Glucuronide and sulfate steroids analysis in urine by ultra high performance supercritical fluid chromatography hyphenated tandem mass spectrometry. PMID- 25736247 TI - Facet-dependent catalytic activity of MnO electrocatalysts for oxygen reduction and oxygen evolution reactions. AB - This Communication highlights the facet-dependent electrocatalytic activity of MnO nanocrystals for OERs/ORRs. The MnO(100) facets with higher adsorption energy of O species can largely promote the electrocatalytic activity. PMID- 25736245 TI - Effects of pre-analytical processes on blood samples used in metabolomics studies. AB - Every day, analytical and bio-analytical chemists make sustained efforts to improve the sensitivity, specificity, robustness, and reproducibility of their methods. Especially in targeted and non-targeted profiling approaches, including metabolomics analysis, these objectives are not easy to achieve; however, robust and reproducible measurements and low coefficients of variation (CV) are crucial for successful metabolomics approaches. Nevertheless, all efforts from the analysts are in vain if the sample quality is poor, i.e. if preanalytical errors are made by the partner during sample collection. Preanalytical risks and errors are more common than expected, even when standard operating procedures (SOP) are used. This risk is particularly high in clinical studies, and poor sample quality may heavily bias the CV of the final analytical results, leading to disappointing outcomes of the study and consequently, although unjustified, to critical questions about the analytical performance of the approach from the partner who provided the samples. This review focuses on the preanalytical phase of liquid chromatography-mass spectrometry-driven metabolomics analysis of body fluids. Several important preanalytical factors that may seriously affect the profile of the investigated metabolome in body fluids, including factors before sample collection, blood drawing, subsequent handling of the whole blood (transportation), processing of plasma and serum, and inadequate conditions for sample storage, will be discussed. In addition, a detailed description of latent effects on the stability of the blood metabolome and a suggestion for a practical procedure to circumvent risks in the preanalytical phase will be given. PMID- 25736248 TI - Validation of a measure of children's perceptions of their oncology camp experience: a national study. PMID- 25736249 TI - The evaluation of ICHD-3 beta diagnostic criteria for Tolosa-Hunt syndrome: a study of 22 cases of Tolosa-Hunt syndrome. AB - The objective of the study was to evaluate the amended International Classification of Headache Disorders (third edition, beta version, ICHD-3 beta) with a retrospective analysis. A total of 22 patients diagnosed with painful ophthalmoplegia and Tolosa-Hunt syndrome (THS) in our hospital were retrospectively studied. The following clinical data were collected: symptoms, signs, location of inflammatory tissue, time interval of paresis following the onset of pain, pain and signs of resolution, follow-up and relapse. Pain and diplopia were found in 22 (100 %) and 20 cases (91 %). The sympathetic nerve was involved in 6 cases (27 %). Paresis followed the pain for an average of 8 +/- 5.87 days. Serial magnetic resonance imaging (MRI) revealed granulomatous lesion that was visible in 20 patients (91 %). 19 patients (86 %) demonstrated the lesions located in the cavernous sinus, orbital apex or superior orbital fissure. One lesion extended to the intracranial structure. Pain was relieved in 20 cases (91 %) within 72 h and no patient had complete relief from paresis. According to our study, we think the time course of relief should be undefined. Headache location is hard to describe accurately. Normal MRI should be involved in THS diagnoses. The lesion of THS can extend beyond the cavernous sinus and the orbit. The time interval between headache and paresis can exceed 2 weeks. PMID- 25736250 TI - Reversible parkinsonism and cognitive deficits due to vitamin B12 deficiency. PMID- 25736251 TI - Four-dimensional flow magnetic resonance imaging visualizes drastic change in vortex flow in the main pulmonary artery after percutaneous transluminal pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. PMID- 25736252 TI - Management of valvular disease in pregnancy: a global perspective. AB - Valvular heart disease (VHD) in pregnant women, whether due to congenital or acquired aetiologies, poses a challenge to clinicians and their patients. Significant valve disease, which can affect a single valve or several valves, increases the risk of pregnancy to the mother and foetus and requires a careful preconception risk assessment and, subsequently during pregnancy, specialized care to minimize maternal and foetal morbidity and mortality. The goal of this paper is to provide a guide to risk assessment and to give an overview of the optimal cardiac and obstetric management, including surgical intervention, taking into consideration the resources available in higher and lower-to-middle income countries. This manuscript provides a practical approach and is not replacing comprehensive guidelines on the management of VHD or cardiovascular disease in pregnancy. It focuses on common valvular diseases and does not cover the large variety of aortic disease with and without valve disease or complex congenital heart disease in detail. PMID- 25736253 TI - Very late thrombosis observed on optical coherence tomography 22 months after the implantation of a polymer-based bioresorbable vascular scaffold. PMID- 25736254 TI - GroupTracker: Video tracking system for multiple animals under severe occlusion. AB - Quantitative analysis of behaviors shown by interacting multiple animals can provide a key for revealing high-order functions of their nervous systems. To resolve these complex behaviors, a video tracking system that preserves individual identity even under severe overlap in positions, i.e., occlusion, is needed. We developed GroupTracker, a multiple animal tracking system that accurately tracks individuals even under severe occlusion. As maximum likelihood estimation of Gaussian mixture model whose components can severely overlap is theoretically an ill-posed problem, we devised an expectation-maximization scheme with additional constraints on the eigenvalues of the covariance matrix of the mixture components. Our system was shown to accurately track multiple medaka (Oryzias latipes) which freely swim around in three dimensions and frequently overlap each other. As an accurate multiple animal tracking system, GroupTracker will contribute to revealing unexplored structures and patterns behind animal interactions. The Java source code of GroupTracker is available at https://sites.google.com/site/fukunagatsu/software/group-tracker. PMID- 25736255 TI - Glutamate-dependent translational control through ribosomal protein S6 phosphorylation in cultured bergmann glial cells. AB - Glutamate (Glu) the main excitatory neurotransmitter of the central nervous system regulates gene expression at different levels through the activation of specific membrane receptors and transporters expressed in neurons and glia cells. A membrane to nucleus signaling cascade triggered by this neurotransmitter has been described in cultured cerebellar Bergmann glia cells isolated from chick embryos. Furthermore, it has also been described that Glu receptors activation is linked to a modulation of [(35)S]-methionine incorporation into newly synthesized polypeptides. In order to gain insight into the signal transduction cascades that participate in this effect, in the present study we characterized the phosphorylation of a critical component of the translational machinery, namely the ribosomal protein S6. The phosphorylation sites in rpS6 have been mapped to five clustered residues, Ser235, Ser236, Ser240, Ser244 and Ser247. Nevertheless, Ser236 phosphorylation is the primary phosphorylation site. The kinases responsible of this modification are p70(S6K) and p90(RSK). rpS6 phosphorylation increases the affinity of 40s subunit for mRNAs and thus facilitates translational initiation. Glutamate exposure of cultured cerebellar Bergmann glia cells results in a time- and dose-dependent increase in rpS6 phosphorylation. This effect is mainly observed at cytoplasm, and involves the phosphoinositol-3 kinase/protein kinase B pathway. Our results favor the notion of a continuous neuronal signaling to glia cells that regulates the proteome of these cells not only at the transcriptional level but also at the level of protein synthesis. PMID- 25736256 TI - Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep. AB - Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial- and muscular-dependent pathways. This was associated with an enhanced nitric oxide-dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN. PMID- 25736257 TI - Effects of myrrh on the strength of suture materials: an in vitro study. AB - The present in vitro study sought to determine the effects of myrrh-containing solutions on common suture materials used in periodontal surgery. Three commonly used suture materials (silk, polyglactin 910, polytetrafluoroethylene) were immersed in four thermostatically controlled experimental media to simulate daily oral rinsing activity, namely -artificial saliva, normal saline solution with 0.2% Commiphora myrrh, full-concentration (100%) Commiphora myrrh oil, and a myrrh-containing commercial mouthwash. Tensile strength was measured at the end of each day using an Instron tensile testing machine. Silk sutures were susceptible to tensile strength loss when exposed to 0.2% myrrh solution once daily for 5 days. Myrrh-containing commercial mouthwash had no effect on tensile strength, but all three suture materials lost tensile strength when exposed to 100% myrrh oil. For patients that routinely use myrrh mouthwashes postoperatively, findings of this study suggested that silk sutures might not be the optimal material choice. PMID- 25736258 TI - Ultraviolet irradiation enhanced bioactivity and biological response of mesenchymal stem cells on micro-arc oxidized titanium surfaces. AB - This present study investigated the effect of ultraviolet (UV) irradiation on bioactivity of micro-arc oxidized (MAO) titanium surface in vitro by cell culture medium immersion test and interactions with rat-derived mesenchymal stem cells (MSCs). UV-irradiated MAO surface exhibited no obvious changes in surface roughness, morphology, and phase composition when compared with MAO-only surface. However, in cell culture medium immersion test, markedly more bone-like apatite was formed on UV-modified samples than on MAO sample. Rat bone marrow- and adipose tissue-derived MSCs cultured on UV-modified samples displayed accelerated attachment, significant higher levels of alkaline phosphatase (ALP) activity, and up-regulated osteogenesis-related mRNA expression than MAO sample. XPS results provided direct evidence that the amount of basic hydroxyl groups increased with UV irradiation time, which could be one of the key mechanisms underlying their improved bioactivity. PMID- 25736259 TI - Repair bond strength of resin composite to a novel CAD/CAM hybrid ceramic using different repair systems. AB - This study evaluated the repair bond strength of a nanohybrid resin composite to a novel CAD/CAM hybrid ceramic based on four intraoral ceramic repair systems. Vita Enamic (VE) CAD/CAM hybrid ceramic was used in this study. Specimens were divided into five test groups according to the repair method performed on the ceramic surface: Gr C (No treatment; control); Gr CZ (Cimara Zircon); Gr PR (Porcelain Repair); Gr CR (Clearfil Repair); and Gr CS (CoJet system). Nanohybrid resin composite (GrandioSO) was packed onto treated ceramic surfaces for adhesion testing using microtensile bond strength test. Debonded specimens were examined with a stereomicroscope and SEM to determine the fracture mode. Data were analyzed using ANOVA and Tukey's HSD test. PR and CZ repair systems significantly enhanced the bond strength of nanohybrid resin composite to VE CAD/CAM hybrid ceramic when compared with the other tested repair systems. PMID- 25736260 TI - Cytotoxicity evaluation of luting resin cements on bovine dental pulp-derived cells (bDPCs) by real-time cell analysis. AB - To evaluate the cytotoxicity of resin cements on dental pulp-derived cells (bDPCs), Bifix QM (BQM), Choice 2(C2), RelyX U200(RU200), Maxcem Elite(ME), and Multilink Automix(MA) were tested. The materials were incubated in DMEM for 72 h. A real-time cell analyzer was used to evaluate cell survival. The statistical analyses used were one-way ANOVA and Tukey-Kramer tests. BQM, RU200, and ME demonstrated a significant decrease in the bDPCs' index at 24 and 72 h (p<=0.001). These materials were found to be the most toxic resin cements, as compared to the control and other tested materials (C2 and MA). However, C2 and MA showed a better survival rate, compared to BQM, RU200, and ME, and had lower cell index than the control group. The cytotoxic effects of resin cements on pulpa should be evaluated during the selection of proper cements. PMID- 25736261 TI - The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. AB - IL2 and IL15, members of the 4alpha-helix bundle family of cytokines, play pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL2 through maintenance of fitness of regulatory T cells and activation-induced cell death is the elimination of self-reactive T cells to prevent autoimmunity. In contrast with IL2, IL15 is dedicated to the prolonged maintenance of memory T cell responses to invading pathogens. Blockade of IL2 and IL15 using monoclonal antibodies has been reported to be of value in the treatment of patients with leukemia, autoimmune disorders, and in the prevention of allograft rejection. IL2 has been approved by the FDA for the treatment of patients with malignant renal cell cancer and metastatic malignant melanoma. Clinical trials involving recombinant human IL15 given by bolus infusions have been completed, and studies assessing subcutaneous and continuous intravenous infusions are under way in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL15 with IL15Ralpha(+/-) IgFc. PMID- 25736263 TI - The 'sweet' spot of cellular pluripotency: protein glycosylation in human pluripotent stem cells and its applications in regenerative medicine. AB - INTRODUCTION: Human pluripotent stem cells (hPSCs) promise for the future of regenerative medicine. The structural and biochemical diversity associated with glycans makes them a unique type of macromolecule modification that is involved in the regulation of a vast array of biochemical events and cellular activities including pluripotency in hPSCs. The primary focus of this review article is to highlight recent advances in stem cell research from a glycobiological perspective. We also discuss how our understanding of glycans and glycosylation may help overcome barriers hindering the clinical application of hPSC-derived cells. AREAS COVERED: A literature survey using NCBI-PubMed and Google Scholar was performed in 2014. EXPERT OPINION: Regenerative medicine hopes to provide novel strategies to combat human disease and tissue injury that currently lack effective therapies. Although progress in this field is accelerating, many critical issues remain to be addressed in order for cell-based therapy to become a practical and safe treatment option. Emerging evidence suggests that protein glycosylation may significantly influence the regulation of cellular pluripotency, and that the exploitation of protein glycosylation in hPSCs and their differentiated derivatives may lead to transformative and translational discoveries for regenerative medicine. In addition, hPSCs represent a novel research platform for investigating glycosylation-related disease. PMID- 25736262 TI - Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. AB - Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1 (PD-1/PD L1)] at three centers and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P = 0.07), clinical benefit (response + stable disease lasting >= 24 weeks; 50% vs. 31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P = 0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared with other genotypes (8/12 vs. 9/20 samples with >= 1% expression; 6/12 vs. 6/20 samples with >= 5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression. PMID- 25736264 TI - Demands for carbohydrates as major energy substrates depend on the preimplantation developmental stage in pig embryos: differential use of fructose by parthenogenetic diploids before and after the 4-cell stage in the pig. AB - The embryo culture technique has been improving, but the detailed demands for energy substrates such as glucose, fructose, pyruvate and lactate of preimplantation embryos are still unclear. In the present study, the demands of pig preimplantation embryos at each different developmental stage were investigated by use of parthenogenetic diploids as a model of pig preimplantation embryos. Pig parthenogenetic diploids showed different use of glucose and fructose before and after the 4-cell stage. Although glucose supported the development of pig embryos throughout the preimplantation stages and even maintained the expansion and hatching of blastocysts, it suppressed development to the blastocyst stage when glucose coexisted with pyruvate and lactate from 4 h after activation, but not after 48 h (early 4-cell stage). Since ketohexokinase that metabolizes fructose was not expressed in 2-cell and 4-cell diploids, a medium that included only fructose as a major energy substrate did not support early cleavage of pig diploids beyond the 4-cell stage, and almost no diploids developed to the morula stage just as in a medium without carbohydrates. These results may explain the different suppressive effects on pig preimplantation development between glucose and fructose when pyruvate and lactate were present in a medium. In addition, 4-cell diploids that had been cultured in a medium with pyruvate and lactate developed to the expanded blastocyst stage without any carbohydrates as a major energy substrate. These results show that the demands for carbohydrates are different depending on the developmental stage in pig preimplantation embryos. PMID- 25736265 TI - Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection. AB - In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT) VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at different time periods following IANX and resulting in the extraterritorial neuropathic pain in the orofacial region following trigeminal nerve injury. PMID- 25736267 TI - Effects of bentonite and yeast extract as nutrient on decrease in hydraulic conductivity of porous media due to CaCO3 precipitation induced by Sporosarcina pasteurii. AB - The reduction mechanism of hydraulic conductivity was investigated in porous media treated with bentonite and CaCO3 precipitates induced by growing cells of Sporosarcina pasteurii (ATCC 11859). Bentonite, the bacterial cells, and a precipitation solution, composing of 0.5 M CaCl2 and 0.5 M urea with or without 2% weight/volume yeast extract allowing the bacterial growth were sequentially introduced into the continuous-flow columns containing glass beads between 0.05 and 3 mm in diameter. The treatments reduced the hydraulic conductivity of the columns from between 8.4 * 10(-1) and 4.1 * 10(-3) cm/s to between 9.9 * 10(-4) and 2.1 * 10(-6) cm/s as the lowest. With yeast extract, the conductivity continuously decreased during four days of the experiment, while became stable after two days without yeast extract. Introduction of the bacterial cells did not decrease the conductivity. The reduction in hydraulic conductivity was inversely correlated with the volume occupied by the depositions of bentonite and CaCO3 precipitates in column, showing the same efficiency but a larger effect of the CaCO3 precipitates with increasing volume by bacterial growth. The smaller glass beads resulted in larger volume of the depositions. Bentonite increased the deposition of CaCO3 precipitates. Analysis using the Kozeny-Carman equation suggested that without yeast extract, bentonite and the CaCO3 precipitates formed aggregates with glass beads, thus increasing their diameter and consequently decreasing the pore size in the column. With yeast extract, in addition to the aggregates, the individual CaCO3 precipitates formed separately from the aggregates reduced the hydraulic conductivity. PMID- 25736268 TI - Catalytic asymmetric mannich-type reaction of N-alkylidene-alpha aminoacetonitrile with ketimines. AB - Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Bronsted base cooperative catalyst allows for an efficient stereoselective coupling of N-alkylidene-alpha-aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra- and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading. PMID- 25736266 TI - Proteomics of ovarian cancer: functional insights and clinical applications. AB - In the past decade, there has been an increasing interest in applying proteomics to assist in understanding the pathogenesis of ovarian cancer, elucidating the mechanism of drug resistance, and in the development of biomarkers for early detection of ovarian cancer. Although ovarian cancer is a spectrum of different diseases, the strategies for diagnosis and treatment with surgery and adjuvant therapy are similar across ovarian cancer types, increasing the general applicability of discoveries made through proteomics research. While proteomic experiments face many difficulties which slow the pace of clinical applications, recent advances in proteomic technology contribute significantly to the identification of aberrant proteins and networks which can serve as targets for biomarker development and individualized therapies. This review provides a summary of the literature on proteomics' contributions to ovarian cancer research and highlights the current issues, future directions, and challenges. We propose that protein-level characterization of primary lesion in ovarian cancer can decipher the mystery of this disease, improve diagnostic tools, and lead to more effective screening programs. PMID- 25736269 TI - FBN1 contributing to familial congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is a relatively common, life--threatening birth defect. We present a family with recurrent CDH--paraesophageal and central- for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice--FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology. PMID- 25736270 TI - Disability after cardiac surgery is the major predictor of infections occurring in the rehabilitation phase. AB - BACKGROUND: Few data have assessed the incidence, site and predictors of infections following cardiac surgery after discharge, particularly during an early rehabilitation phase. AIM: To assess the epidemiology and predictors of infections occurring after cardiac surgery. METHODS: Data prospectively recorded from 5464 patients, consecutively included in a residential cardiac rehabilitation programme after cardiac surgery, were retrospectively analysed. Major infections were arbitrarily defined as (1) demonstration of bacterial growth in a sample collected to rule out a clinical suspected infection and (2) requiring an intravenous antibiotic treatment. Infections were grouped as (1) surgery-site infections (SSIs), and (2) healthcare associated infections (HCAIs). Barthel index was used as a measure of disability. RESULTS: Major infections occurred in 10.9% of patients, with SSI documented in 4.1% and HCAI in 6.8% of patients. In 50% of the cases, infections were diagnosed within four days from admission, 18 +/- 16 days from intervention. A Barthel index <60 was the strongest independent predictor of SSI or HCAI. An older age, the presence of chronic renal failure or chronic obstructive pulmonary disease were all significantly associated with HCAI but not with SSI. CONCLUSIONS: In a large cohort of patients, residual disability after cardiac surgery was the strongest independent predictor of infections. Disability is readily accessible, and can be used to recognize patients at higher risk of infections. The 10.9% rate of major infections observed after discharge from the surgical department confirms the importance of prolonging infection surveillance after discharge from the cardiac surgery department. PMID- 25736271 TI - Posterior restoration procedures and the long-term results in indicated patients with dilated cardiomyopathy ?. AB - OBJECTIVES: Non-transplant surgery for dilated cardiomyopathy (DCM) has been in the process of development. We performed posterior restoration for dilated akinetic or dyskinetic lesions in patients with DCM and obtained favourable outcomes. The early and long-term results of the procedures are discussed. METHODS: Between 2005 and 2013, posterior restoration procedures (PRPs) for DCM were electively performed in 58 patients (17 with ischaemic and 41 with non ischaemic DCM). There were 45 men and 13 women with a mean age of 56 +/- 12 years old. The mean preoperative ejection fraction was 24% and the preoperative New York Heart Association functional class was Class III in 24 and Class IV in 34 patients with intravenous inotrope support. Indications for PRPs were determined by using speckle-tracking echocardiography of the posterior region of the left ventricle before surgery (GE ultrasound machine, Vivid 7 or Vivid E9). After cardioplegic arrest, mitral surgery or coronary artery bypass grafting (CABG) was performed and the posterior left ventricular (LV) muscle between bilateral papillary muscles was incised or resected. The LV apex was preserved and cryoablation was applied between the cut edge and the posterior mitral annulus. All patients were followed up by transthoracic echocardiography. RESULTS: In addition to PRP, mitral surgery was performed in 56 (plasty 51, replacement 5), tricuspid annuloplasty in 21, CABG in 17, cardiac resynchronization therapy in 6 and LV lead implantation in 27 patients. Perioperative intra-aortic balloon pumping was used in 9 patients and there was no hospital mortality. After the operation, 35 patients (60%) improved their functional class to Class I or II. In the late follow-up, there were 14 cardiac deaths (congestive heart failure 10, ventricular arrhythmia 4). The 3- and 8-year survival rates were 77 or 66%, respectively. CONCLUSIONS: DCM with posterior akinesis or dyskinesis indicated by speckle-tracking echocardiography can be surgically treated with PRP. Our results demonstrated that 60% of the selected patients could avoid heart transplantation with relief of their symptoms. PMID- 25736272 TI - Veno-veno-arterial extracorporeal membrane oxygenation for respiratory failure with severe haemodynamic impairment: technique and early outcomes. AB - OBJECTIVES: Patients with respiratory failure may benefit from veno-venous and veno-arterial extracorporeal membrane oxygenation (ECMO) support. We report on our initial experience of veno-veno-arterial (v-v-a) ECMO in patients with respiratory failure. METHODS: Between January 2012 and February 2014, 406 patients required ECMO support at our institution. Here, we retrospectively analysed the characteristics and outcomes of patients commenced on either veno venous or veno-arterial ECMO due to respiratory failure, and then switched to v-v a ECMO. RESULTS: Ten (2%) patients proceeded to v-v-a ECMO. The underlying conditions were acute respiratory distress syndrome (n = 3), end-stage pulmonary fibrosis (n = 5) and respiratory failure after major thoracic surgery (n = 1) and Caesarean section (n = 1). In all of these patients, ECMO was initially started as veno-venous (n = 9) or veno-arterial (n = 1) ECMO but was switched to a veno veno-arterial (v-v-a) approach after a mean of 2 (range, 0-7) days. Reasons for switching were: haemodynamic instability (right heart failure, n = 5; pericardial tamponade, n = 1; severe mitral valve regurgitation, n = 1; haemodynamic instability following cardiopulmonary resuscitation, n = 1 and evidence of previously unknown atrial septal defect with pulmonary hypertension and Eisenmenger syndrome, n = 1) and upper-body hypoxaemia (n = 1). ECMO-related complications were bleeding (n = 3) and leg ischaemia (n = 2). Seven patients were successfully taken off ECMO with 4 being bridged to recovery and a further 3 to lung transplantation after a mean of 11 (range, 9-18) days. Five patients survived until hospital discharge and all of them were alive at the end of the follow-up. CONCLUSIONS: Veno-veno-arterial ECMO is a technically feasible rescue strategy in treating patients presenting with combined respiratory and haemodynamic failure. PMID- 25736273 TI - Clarifying perspectives: Ethics case reflection sessions in childhood cancer care. AB - BACKGROUND: Childhood cancer care involves many ethical concerns. Deciding on treatment levels and providing care that infringes on the child's growing autonomy are known ethical concerns that involve the whole professional team around the child's care. OBJECTIVES: The purpose of this study was to explore healthcare professionals' experiences of participating in ethics case reflection sessions in childhood cancer care. RESEARCH DESIGN: Data collection by observations, individual interviews, and individual encounters. Data analysis were conducted following grounded theory methodology. PARTICIPANTS AND RESEARCH CONTEXT: Healthcare professionals working at a publicly funded children's hospital in Sweden participated in ethics case reflection sessions in which ethical issues concerning clinical cases were reflected on. ETHICAL CONSIDERATIONS: The children's and their parents' integrity was preserved through measures taken to protect patient identity during ethics case reflection sessions. The study was approved by a regional ethical review board. FINDINGS: Consolidating care by clarifying perspectives emerged. Consolidating care entails striving for common care goals and creating a shared view of care and the ethical concern in the specific case. The inter-professional perspectives on the ethical aspects of care are clarified by the participants' articulated views on the case. Different approaches for deliberating ethics are used during the sessions including raising values and making sense, leading to unifying interactions. DISCUSSION: The findings indicate that ethical concerns could be eased by implementing ethics case reflection sessions. Conflicting perspectives can be turned into unifying interactions in the healthcare professional team with the common aim to achieve good pediatric care. CONCLUSION: Ethics case reflection sessions is valuable as it permits the discussion of values in healthcare-related issues in childhood cancer care. Clarifying perspectives, on the ethical concerns, enables healthcare professionals to reflect on the most reasonable and ethically defensible care for the child. A consolidated care approach would be valuable for both the child and the healthcare professionals because of the common care goals. PMID- 25736274 TI - The Ross procedure in the young: evidence from multicentre registries. PMID- 25736276 TI - The role of screening and monitoring for bleomycin pulmonary toxicity. AB - Bleomycin-induced pulmonary toxicity can have a significant impact on patient outcomes. However, no guidelines for ideal screening and monitoring are available. This paper reviews the literature to identify the best way to monitor and reduce patient risk for bleomycin pulmonary toxicity. We have created evidence-based guidelines to help healthcare professionals identify patient risk factors and provide appropriate assessment and monitoring for patients receiving bleomycin therapy. PMID- 25736275 TI - Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage. AB - Cancer prevention is a cost-effective alternative to treatment. In mice, the mTOR inhibitor rapamycin prevents distinct spontaneous, noninflammatory cancers, making it a candidate broad-spectrum cancer prevention agent. We now show that oral microencapsulated rapamycin (eRapa) prevents skin cancer in dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) carcinogen-induced, inflammation-driven carcinogenesis. eRapa given before DMBA/TPA exposure significantly increased tumor latency, reduced papilloma prevalence and numbers, and completely inhibited malignant degeneration into squamous cell carcinoma. Rapamycin is primarily an mTORC1-specific inhibitor, but eRapa did not reduce mTORC1 signaling in skin or papillomas, and did not reduce important proinflammatory factors in this model, including p-Stat3, IL17A, IL23, IL12, IL1beta, IL6, or TNFalpha. In support of lack of mTORC1 inhibition, eRapa did not reduce numbers or proliferation of CD45(-)CD34(+)CD49f(mid) skin cancer initiating stem cells in vivo and marginally reduced epidermal hyperplasia. Interestingly, eRapa reduced DMBA/TPA-induced skin DNA damage and the hras codon 61 mutation that specifically drives carcinogenesis in this model, suggesting reduction of DNA damage as a cancer prevention mechanism. In support, cancer prevention and DNA damage reduction effects were lost when eRapa was given after DMBA-induced DNA damage in vivo. eRapa afforded picomolar concentrations of rapamycin in skin of DMBA/TPA-exposed mice, concentrations that also reduced DMBA induced DNA damage in mouse and human fibroblasts in vitro. Thus, we have identified DNA damage reduction as a novel mechanism by which rapamycin can prevent cancer, which could lay the foundation for its use as a cancer prevention agent in selected human populations. PMID- 25736277 TI - Nationwide trends in the current management of desmoid (aggressive) fibromatosis. AB - AIMS: The optimal management of desmoid fibromatosis remains unclear, leading to significant variability in patient management. To assess this problem, the current approach of clinicians managing this complex condition in the UK was investigated. MATERIALS AND METHODS: A hypothetical case of intramuscular limb girdle desmoid fibromatosis in a fit 65-year-old patient was devised. Surgical and non-surgical oncology members of the British Sarcoma Group were questioned on how they would manage this case in three scenarios: primary disease with function sparing surgery possible, primary disease with neurovascular involvement and disease recurrence after a previous R0 resection. Initial management, management of symptomatic disease progression, follow-up preferences and any differences in respondents' management choices in a younger case were investigated. RESULTS: The responses from 14 sarcoma surgeons and 23 oncologists (14 clinical, nine medical) were analysed. Desmoid fibromatosis management is generally shared by surgeons and oncologists within sarcoma multidisciplinary teams in the UK. Variation exists in the chosen initial management of primary desmoid fibromatosis in the UK, with function-sparing surgery possible (observation 51%, resection 51%), primary desmoid fibromatosis with neurovascular involvement (hormone therapy with non-steroidal anti-inflammatory drugs 51%, radiotherapy 27%, observation 22%) and for cases of desmoid fibromatosis recurrence (radiotherapy 41%, hormone therapy and non-steroidal anti-inflammatory drugs 27%, observation 24%). There was a clear preference of surgical resection of symptomatic disease progression in cases of primary desmoid fibromatosis without neurovascular involvement (60%). By contrast, radiotherapy was the preferred treatment for progression in cases with neurovascular involvement (47%) or cases of recurrence after a previous R0 resection (34%). Clinical follow-up was selected 3 months after intervention in 68% of scenarios. Follow-up imaging was selected 3 or 6 months after intervention in 57% and 21% of cases, respectively. Most respondents would not change their chosen management in younger patients. DISCUSSION: Several groups have issued formal guidelines for clinicians managing desmoid fibromatosis, including the British Sarcoma Group, the National Comprehensive Cancer Network and the European Society for Medical Oncology. However, these are in some ways contradictory and may not reflect recent publications, potentially explaining the significant variation in the management of desmoid fibromatosis in the UK shown by this survey. We propose a review of current evidence; a national consensus or a desmoid fibromatosis registry may help to standardise desmoid fibromatosis care. PMID- 25736278 TI - Association Between Smoking and p53 Mutation in Oesophageal Squamous Cell Carcinoma: A Meta-analysis. AB - AIMS: Several studies have evaluated the association between smoking and p53 mutation in oesophageal squamous cell carcinoma (ESCC), but the conclusions are inconsistent. The aim of the present study was to carry out a meta-analysis evaluating the relationship between smoking and p53 mutation in patients with ESCC. MATERIALS AND METHODS: Eligible studies were identified through searches in PubMed and EMBASE. The odds ratio with 95% confidence interval was used to assess the association. In total, 20 studies were identified that met the selection criteria; these studies were analysed using STATA 12.0 software. RESULTS: The 20 studies identified comprised 1524 ESCC patients, of whom 72.97% were smokers and 27.03% were non-smokers. The pooled odds ratio of p53 mutation in ESCC for any cigarette smoking versus no smoking was 1.28 (95% confidence interval=0.88-1.88). The estimated odds ratios were 1.06 (95% confidence interval=0.56-2.00, based on five studies, 129 light smokers and 70 non-smokers) for light smoking and 2.01 (95% confidence interval=1.12-3.60, based on five studies, 223 heavy smokers and 73 non-smokers) for heavy smoking. CONCLUSION: The results of our meta-analysis indicate an overall positive relationship between heavy smoking and p53 mutation in ESCC. Heavy smokers with ESCC have a higher risk for p53 mutation than non smokers. Large-scale clinical studies are still needed to draw a more precise conclusion. PMID- 25736279 TI - The Ross procedure in young adults: over 20 years of experience in our Institution. AB - OBJECTIVES: The aim of this study was to evaluate the long-term outcomes following the Ross procedure in young adults in our institution. METHODS: All adult patients who received a Ross operation between 1991 and 2014 were included in the study. Survival analysis and regression analysis were performed. Survival of the Ross cohort was compared with the age-, gender- and calendar year-matched general population. RESULTS: Three hundred-and-six patients (mean age: 41.7 +/- 9.7, male: 74.8%, bicuspid aortic valve: 58.5%, valve stenosis: 68%) were included in the analysis. There were 7 perioperative deaths (2.3%). Nine patients were lost to follow-up from hospital and completeness of the follow-up was 94%. The median follow-up of the remaining 290 patients was 10.6 years. There were 21 late deaths of which only 3 were valve-related. The overall survival at 15 years since surgery is 88 +/- 3% that is comparable with the matched population. Freedom from valve-related deaths was 96.8 +/- 2% at 16 years. Freedom from autograft and pulmonary homograft reoperation was 74.5 +/- 4.3% at 16 years. Preoperative aortic regurgitation was the only significant predictor of autograft failure over time. Freedom from the combined end point of bleeding/thromboembolism/endocarditis/reoperation was 69.2 +/- 4% at 16 years. Perioperative mortality following reoperation was 2.6% and the autograft could be spared in 72% of reinterventions. CONCLUSIONS: The Ross operation in young adults is associated with an excellent survival in the long term that is comparable with the general population. Although there is a risk of reoperation, incidence of other valve-related events is very low. The use of pulmonary autograft should be considered in any young adult patient requiring aortic valve replacement. PMID- 25736280 TI - Effect of three-size too large strong stocking on venous hemodynamics in normal subjects. AB - OBJECTIVES: To study the differences in impact on venous hemodynamics between larger size strong graduated elastic compression stockings (GECS) and appropriate size strong/moderate GECS. METHOD: In healthy legs fitted for a small (Group S; n = 8) and large (Group L; n = 8) GECS, air plethysmography was performed without GECS, with an appropriate size strong GECS (GECS1), with a three-size too large strong GECS (GECS2), and with an appropriate size moderate GECS (GECS3) in this order. RESULTS: In Group S, interface pressure with GECS2 was equal to or higher than that with GECS3. Decreased venous volume, unchanged ejection volume, and decreased residual volume were achieved by GECS, but differences in these parameters among GECS were not observed. Although insignificant, a similar tendency was found in Group L. CONCLUSIONS: A larger size strong GECS seemed to have equivalent interface pressure and impact on venous hemodynamics compared to an appropriate size moderate or strong GECS. PMID- 25736281 TI - Bramah N. Singh, MD, DPhil, DSc: A Tribute. PMID- 25736282 TI - Tanshinone IIA Prevents Rat Basilar Artery Smooth Muscle Cells Proliferation by Inactivation of PDK1 During the Development of Hypertension. AB - Basilar vascular smooth muscle cells (BASMCs) hyperplasia is a prominent feature of cerebrovascular remodeling and stroke during the development of hypertension. Tanshinone IIA (Tan) has been reported to exhibit a protective effect against the pathological features of hypertension. Previous studies have shown that phosphoinostitide-3 kinase (PI3K)/3'-phosphoinostitide dependent kinase (PDK1)/AKT pathway is involved in the regulation of proliferation of various cell types. Therefore, there may be a crosstalk between Tan antihypertension processes and PI3K/PDK1/AKT proliferative effect in BASMCs. To test this hypothesis, we used a 2-kidney, 2-clip hypertension model to examine the effect of Tan on PI3K/PDK1/AKT pathway by cellular, molecular, and biochemical approaches. Our results revealed that the abundance of PDK1 in plasma was paralleled with an increase in blood pressure and the cross-sectional area of basilar artery in hypertensive rats. Tan decreased blood pressure and hypertension-induced PDK1 phosphorylation but produced no effect on the phosphorylation of PI3K. Moreover, Tan attenuated endothelin 1 induced the activation of PDK1/AKT pathway in rat BASMCs. Tan could inhibit cell cycle transition by regulating the expression of cyclin D1 and p27, in turn, prevent proliferation of BASMCs. Our study provides a novel mechanism by which Tan prevents cerebrovascular cell proliferation during hypertension, and thus Tan may be a potential therapeutic agent for cerebrovascular remodeling and stroke. PMID- 25736283 TI - A Multidose Study to Examine the Effect of Food on Evacetrapib Exposure at Steady State. AB - PURPOSE: To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants. METHODS: This was a randomized, 2-period, 2 sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for evacetrapib concentrations and pharmacokinetic parameter estimates including area under the concentration-time curve during a dosing interval (AUCtau), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated. Pharmacodynamic parameters, including cholesteryl ester transfer protein (CETP) activity, high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), total cholesterol, and triglycerides, were also assessed. RESULTS: A total of 34 males and 6 females, mean age 41.5 years and mean body mass index 26.6 kg/m(2), were enrolled. Statistical analysis showed AUCtau was 44% higher (90% confidence interval [CI]: 29%-62%) and Cmax was 51% higher (90% CI: 28%-79%) in the fed state than in the fasted state, indicating an effect of food. Consistent with higher evacetrapib exposure, changes in HDL-C, LDL-C, and CETP activity appeared to be greater in the fed state than in the fasted state. There were no notable changes in total cholesterol or triglycerides following administration in the fed and fasted states. The 130-mg doses of evacetrapib were well tolerated with and without food. CONCLUSION: A high-fat meal increased evacetrapib mean exposure at steady state by 44% in healthy participants. PMID- 25736284 TI - Protective effects of corticosteroids in coronary artery bypass graft surgery alone or combined with valvular surgery: an updated and comprehensive meta analysis and systematic review. AB - This systematic review with meta-analysis sought to determine the protective effects of corticosteroids on clinical outcomes following coronary artery bypass grafting (CABG). Medline, Embase, Elsevier and Sciences online database as well as Google scholar literature were used for selecting appropriate studies with randomized controlled design. The effect sizes measured were odds ratio (OR) for categorical variables and weighted mean difference with 95% confidence interval (CI) for calculating differences between mean values of duration of hospitalization in intervention and control groups. Values of P < 0.1 for Q-test or I(2) > 50% indicated significant heterogeneity between the studies. The literature search of all major databases retrieved 3735 studies. After screening, a total of 45 trials were identified that reported outcomes. Pooled analysis was performed on incidence of atrial fibrillation (OR of 0.71; 95% CI: 0.59-0.86; P = 0.000), stroke (OR of 1.61; 95% CI: 0.63-4.1; P = 0.3), infection (OR of 1.03; 95% CI: 0.68-1.5; P = 0.8), re-infarction (OR of 0.88; 95% CI: 0.47-1.63; P = 0.6), length of ventilation time [weighted mean difference (WMD) of 0.257; 95% CI: 0.10-0.41; P = 0.00], length of hospital stay (WMD of -0.48; 95% CI: -0.66 to -0.3; P = 0.000), amount of blood loss (WMD of -124.05; 95% CI: -147.72 to 100.38; P = 0.00), re-exploration (OR of 1.25; 95% CI: 0.66-2.35; P = 0.4) and mortality (OR of 0.87; 95% CI: 0.46-1.64; P = 0.6). Overall, steroid prophylaxis in patients undergoing CABG could significantly reduce complications such as atrial fibrillation and length of hospital stay, but slightly increased the length of ventilation time. On the other hand, no significant impact on the incidence of infection was observed compared with the placebo. PMID- 25736285 TI - Uniportal video-assisted thoracoscopic lobectomy: an alternative to conventional thoracoscopic lobectomy in lung cancer surgery? AB - OBJECTIVES: Although the standard video-assisted thoracoscopic surgery (VATS) approach is generally performed through two to four incisions, uniportal VATS pulmonary resection has recently been reported to be a promising, less invasive alternative. To evaluate the adequacy of uniportal VATS lobectomy as an alternative to conventional VATS lobectomy in lung cancer, we analysed and compared the outcomes of uniportal and conventional VATS lobectomies. METHODS: Retrospective observational data for patients who underwent VATS lobectomy at Samsung Medical Center between January 2013 and February 2014 due to a diagnosis of lung cancer were collected. Perioperative factors such as operative time, postoperative chest tube duration, postoperative hospital stay, complication rate, conversion rate, reoperation rate and mortality were compared between the uniportal and conventional VATS groups. RESULTS: A total of 90 uniportal VATS lobectomies and 60 conventional VATS lobectomies were attempted. Fifty-eight (64.5%) cases were completed as uniportal VATS lobectomies, and 51 (85%) cases as conventional VATS lobectomies. There were 32 (35.5%) conversions of uniportal VATS lobectomy cases, including four conversions to three-port VATS, 18 to two port VATS and 10 to open thoracotomy. No differences in postoperative complications, postoperative 30-day mortality or reoperation rate were noted between the two groups. There was no difference in operative time, number of removed lymph nodes, chest tube duration or length of postoperative hospital stay between the uniportal VATS group and conventional VATS group. CONCLUSIONS: The similar perioperative results of uniportal VATS lobectomy compared with conventional VATS lobectomy suggest that uniportal VATS is a viable alternative approach to the conventional VATS approach in selected patients, especially in patients with early peripheral lung cancer with good anatomy and in good general condition. PMID- 25736286 TI - Complete thoracoscopic lobectomy for cancer: comparative study of three dimensional high-definition with two-dimensional high-definition video systems ?. AB - OBJECTIVES: Common video systems for video-assisted thoracic surgery (VATS) provide the surgeon a two-dimensional (2D) image. This study aimed to evaluate performances of a new three-dimensional high definition (3D-HD) system in comparison with a two-dimensional high definition (2D-HD) system when conducting a complete thoracoscopic lobectomy (CTL). METHODS: This multi-institutional comparative study trialled two video systems: 2D-HD and 3D-HD video systems used to conduct the same type of CTL. The inclusion criteria were T1N0M0 non-small cell lung carcinoma (NSCLC) in the left lower lobe and suitable for thoracoscopic resection. The CTL was performed by the same surgeon using either a 3D-HD or 2D HD system. Eighteen patients with NSCLC were included in the study between January and December 2013: 14 males, 4 females, with a median age of 65.6 years (range: 49-81). The patients were randomized before inclusion into two groups: to undergo surgery with the use of a 2D-HD or 3D-HD system. We compared operating time, the drainage duration, hospital stay and the N upstaging rate from the definitive histology. RESULTS: The use of the 3D-HD system significantly reduced the surgical time (by 17%). However, chest-tube drainage, hospital stay, the number of lymph-node stations and upstaging were similar in both groups. CONCLUSIONS: The main finding was that 3D-HD system significantly reduced the surgical time needed to complete the lobectomy. Thus, future integration of 3D-HD systems should improve thoracoscopic surgery, and enable more complex resections to be performed. It will also help advance the field of endoscopically assisted surgery. PMID- 25736287 TI - Emergency treatment of haemorrhaging coeliac or mesenteric artery aneurysms and pseudoaneurysms in the era of endovascular management. AB - OBJECTIVES: Patients requiring emergency treatment of visceral artery aneurysms (VAAs) can be treated by endovascular or surgical techniques. Outcomes after failed attempts at endovascular control are unclear as is the present role of surgery. This study reviewed treatment and outcomes of a contemporary cohort of patients with symptomatic VAAs at a tertiary referral centre. METHODS: Patients undergoing emergency treatment of a VAA of the coeliac, mesenteric arteries, or their branches were identified over a 5-year period. Patient variables, treatments, and outcomes were assessed. RESULTS: Forty-eight patients underwent 65 radiological and two surgical procedures. Pseuodaneuryms were present in 45 (94%) of patients. Interventional radiology procedures were the initial treatment in every patient. The initial success was 40 out of 48 (83%). Patients requiring more than one procedure were all successfully treated. Regarding initial failures, if the VAA sac could not be accessed at angiography an alternative procedure to control the VAA was required in every case. If initial endovascular treatment failed, repeating the same procedure was successful in half of the patients. Ultrasound-guided percutaneous VAA embolisation was used in four patients. The 30-day mortality was eight out of 48 (17%). There were four recorded complications including one death directly attributable to VAA treatment. CONCLUSIONS: Patients needing emergency treatment of a VAA could be well served by non-surgical management. When the initial attempt at control of bleeding is unsuccessful it is important to consider non-conventional means of accessing these arteries. The need for surgery, in selected centres, may exist for a small group of patients after initial failed radiological treatment only. PMID- 25736288 TI - Synaptic control of mRNA translation by reversible assembly of XRN1 bodies. AB - Repression of mRNA translation is linked to the formation of specific cytosolic foci such as stress granules and processing bodies, which store or degrade mRNAs. In neurons, synaptic activity regulates translation at the post-synapse and this is important for plasticity. N-methyl-D-aspartate (NMDA) receptor stimulation downregulates translation, and we speculate that this is linked to the formation of unknown mRNA-silencing foci. Here, we show that the 5'-3' exoribonuclease XRN1 forms discrete clusters associated with the post-synapse that are different from processing bodies or stress granules, and we named them synaptic XRN1 bodies (SX bodies). Using primary neurons, we found that the SX-bodies respond to synapse stimulation and that their formation correlates inversely with the local translation rate. SX-bodies increase in size and number upon NMDA stimulation, and metabotropic glutamate receptor activation provokes SX-body dissolution, along with increased translation. The response is specific and the previously described Smaug1 foci and FMRP granules show a different response. Finally, XRN1 knockdown impairs the translational repression triggered by NMDA. Collectively, these observations support a role for the SX-bodies in the reversible masking and silencing of mRNAs at the synapse. PMID- 25736289 TI - A dynamic coordination of flagellum and cytoplasmic cytoskeleton assembly specifies cell morphogenesis in trypanosomes. AB - Plasma membrane-to-plasma membrane connections are common features of eukaryotic cells, with cytoskeletal frameworks below the respective membranes underpinning these connections. A defining feature of Trypanosoma brucei is the lateral attachment of its single flagellum to the cell body, which is mediated by a cytoskeletal structure called the flagellum attachment zone (FAZ). The FAZ is a key morphogenetic structure. Disruption of FAZ assembly can lead to flagellum detachment and dramatic changes in cell shape. To understand this complex structure, the identity of more of its constituent proteins is required. Here, we have used both proteomics and bioinformatics to identify eight new FAZ proteins. Using inducible expression of FAZ proteins tagged with eYFP we demonstrate that the site of FAZ assembly is close to the flagellar pocket at the proximal end of the FAZ. This contrasts with the flagellum, which is assembled at its distal end; hence, these two interconnected cytoskeletal structures have distinct spatially separated assembly sites. This challenging result has many implications for understanding the process of cell morphogenesis and interpreting mutant phenotypes. PMID- 25736290 TI - DNA damage response clamp 9-1-1 promotes assembly of ZMM proteins for formation of crossovers and synaptonemal complex. AB - Formation of crossovers between homologous chromosomes during meiosis is positively regulated by the ZMM proteins (also known as SIC proteins). DNA damage checkpoint proteins also promote efficient formation of interhomolog crossovers. Here, we examined, in budding yeast, the meiotic role of the heterotrimeric DNA damage response clamp composed of Rad17, Ddc1 and Mec3 (known as '9-1-1' in other organisms) and a component of the clamp loader, Rad24 (known as Rad17 in other organisms). Cytological analysis indicated that the 9-1-1 clamp and its loader are not required for the chromosomal loading of RecA homologs Rad51 or Dmc1, but are necessary for the efficient loading of ZMM proteins. Interestingly, the loading of ZMM proteins onto meiotic chromosomes was independent of the checkpoint kinase Mec1 (the homolog of ATR) as well as Rad51. Furthermore, the ZMM member Zip3 (also known as Cst9) bound to the 9-1-1 complex in a cell-free system. These data suggest that, in addition to promoting interhomolog bias mediated by Rad51-Dmc1, the 9-1-1 clamp promotes crossover formation through a specific role in the assembly of ZMM proteins. Thus, the 9-1-1 complex functions to promote two crucial meiotic recombination processes, the regulation of interhomolog recombination and crossover formation mediated by ZMM. PMID- 25736292 TI - Cyclin-A-CDK2-mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication. AB - CIZ1 is a nuclear matrix protein that cooperates with cyclin A2 (encoded by CCNA2) and CDK2 to promote mammalian DNA replication. We show here that cyclin-A CDK2 also negatively regulates CIZ1 activity by phosphorylation at threonines 144, 192 and 293. Phosphomimetic mutants do not promote DNA replication in cell free and cell-based assays, and also have a dominant-negative effect on replisome formation at the level of PCNA recruitment. Phosphorylation blocks direct interaction with cyclin-A-CDK2 and recruitment of endogenous cyclin A to the nuclear matrix. In contrast, phosphomimetic CIZ1 retains the ability to bind to the nuclear matrix, and its interaction with CDC6 is not affected. Phospho-T192 specific antibodies confirm that CIZ1 is phosphorylated during S phase and G2, and show that phosphorylation at this site occurs at post-initiation concentrations of cyclin-A-CDK2. Taken together, the data suggest that CIZ1 is a kinase sensor that promotes initiation of DNA replication at low kinase levels, when in a hypophosphorylated state that is permissive for cyclin-A-CDK2 interaction and delivery to licensed origins, but blocks delivery at higher kinase levels when it is phosphorylated. PMID- 25736291 TI - STIM1L traps and gates Orai1 channels without remodeling the cortical ER. AB - STIM proteins populate and expand cortical endoplasmic reticulum (ER) sheets to mediate store-operated Ca(2+) entry (SOCE) by trapping and gating Orai channels in ER-plasma membrane clusters. A longer splice variant, STIM1L, forms permanent ER-plasma membrane clusters and mediates rapid Ca(2+) influx in muscle. Here, we used electron microscopy, total internal reflection fluorescence (TIRF) microscopy and Ca(2+) imaging to establish the trafficking and signaling properties of the two STIM1 isoforms in Stim1(-/-)/Stim2(-/-) fibroblasts. Unlike STIM1, STIM1L was poorly recruited into ER-plasma membrane clusters and did not mediate store-dependent expansion of cortical ER cisternae. Removal of the STIM1 lysine-rich tail prevented store-dependent cluster enlargement, whereas inhibition of cytosolic Ca(2+) elevations or removal of the STIM1L actin-binding domain had no impact on cluster expansion. Finally, STIM1L restored robust but not accelerated SOCE and clustered with Orai1 channels more slowly than STIM1 following store depletion. These results indicate that STIM1L does not mediate rapid SOCE but can trap and gate Orai1 channels efficiently without remodeling cortical ER cisternae. The ability of STIM proteins to induce cortical ER formation is dispensable for SOCE and requires the lysine-rich tail of STIM1 involved in binding to phosphoinositides. PMID- 25736293 TI - Dynactin and Num1 cooperate to establish the cortical anchoring of cytoplasmic dynein in S. pombe. AB - Chromosome movement during meiosis is crucial for homologous pairing and meiotic recombination. During meiotic prophase in fission yeast, rapid nuclear migration is dependent on cytoplasmic dynein, which is anchored to the cell cortex and pulls microtubules, thereby driving nuclear migration. However, the precise mechanisms underlying dynein localization and activation remain unclear. Here, we identified three subunits of dynactin in fission yeast: Arp1, Mug5 and Jnm1 (also known as Mug1). These subunits transiently colocalized with dynein foci at the cell cortex and were essential for the cortical anchoring of dynein. Cortical factor Num1 (also known as Mcp5), which was also required for dynein anchoring, bound to dynein independently of dynactin. Whereas Num1 suppressed the sliding of dynein foci along the cortex, Arp1, Mug5 and Jnm1 were involved in the regulation of shrinkage and bundling of microtubules. From these data, we propose that dynein anchoring is established by cooperation of transient assembly of dynactin and function of Num1 at the cell cortex. PMID- 25736294 TI - Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast. AB - Spindle pole biogenesis and segregation are tightly coordinated to produce a bipolar mitotic spindle. In yeasts, the spindle pole body (SPB) half-bridge composed of Sfi1 and Cdc31 duplicates to promote the biogenesis of a second SPB. Sfi1 accumulates at the half-bridge in two phases in Schizosaccharomyces pombe, from anaphase to early septation and throughout G2 phase. We found that the function of Sfi1-Cdc31 in SPB duplication is accomplished before septation ends and G2 accumulation starts. Thus, Sfi1 early accumulation at mitotic exit might correspond to half-bridge duplication. We further show that Cdc31 phosphorylation on serine 15 in a Cdk1 (encoded by cdc2) consensus site is required for the dissociation of a significant pool of Sfi1 from the bridge and timely segregation of SPBs at mitotic onset. This suggests that the Cdc31 N-terminus modulates the stability of Sfi1-Cdc31 arrays in fission yeast, and impacts on the timing of establishment of spindle bipolarity. PMID- 25736295 TI - Hsp90alpha and Hsp90beta together operate a hypoxia and nutrient paucity stress response mechanism during wound healing. AB - When tissues are injured and blood vessels clot, the local environment becomes ischemic, meaning that there is a lack of adequate supply of oxygen and glucose delivered to the surrounding cells. The heat shock protein-90 (Hsp90) family proteins protect tissues from various environmental insults and participate in the repair of damaged tissue. Here, we report discovery of a new ischemia responsive mechanism in which the two Hsp90 isoforms Hsp90alpha and Hsp90beta (also known as HSP90AA1 and HSP90AB1, respectively) work together to promote cell motility in wounded skin and accelerate wound closure. We demonstrate that Hsp90alpha and Hsp90beta have distinct and non-exchangeable functions during wound healing. Under hypoxia and when there is a lack of serum factors, Hsp90beta binds to the cytoplasmic tail of the LDL receptor-related protein-1 (LRP-1) and stabilizes the receptor at the cell surface. Hsp90alpha, however, is secreted by the cell into extracellular space where it binds and signals through the LRP-1 receptor to promote cell motility, leading to wound closure. In addition to skin injury, we suggest that this repair mechanism applies broadly to other non cutaneous injured tissues. PMID- 25736296 TI - Recent ecological transitions in China: greening, browning, and influential factors. AB - Ecological conservation and restoration are necessary to mitigate environmental degradation problems. China has taken great efforts in such actions. To understand the ecological transition during 2000-2010 in China, this study analysed trends in vegetation change using remote sensing and linear regression. Climate and socioeconomic factors were included to screen the driving forces for vegetation change using correlation or comparative analyses. Our results indicated that China experienced both vegetation greening (restoration) and browning (degradation) with great spatial heterogeneity. Socioeconomic factors, such as human populations and economic production, were the most significant factors for vegetation change. Nature reserves have contributed slightly to the deceleration of vegetation browning and the promotion of greening; however, a large-scale conservation approach beyond nature reserves was more effective. The effectiveness of the Three-North Shelter Forest Program lay between the two above approaches. The findings of this study highlighted that vegetation trend detection is a practical approach for large-scale ecological transition assessments, which can inform decision-making that promotes vegetation greening via proper socioeconomic development and ecosystem management. PMID- 25736297 TI - Corrigendum to Comparison of the effect of 6% hydroxyethyl starch and gelatine on cardiac and stroke volume index: a randomized, controlled trial after cardiac surgery. PMID- 25736298 TI - Physical examination tests for hip dysfunction and injury. AB - BACKGROUND: Physical examination tests for hip dysfunction and injury of the strongest diagnostic accuracy were identified in a recent systematic review with meta-analysis in BJSM. These tests are described in this article. DISCUSSION: A detailed description of the various different tests is given, with photographs for each test procedure. Diagnostic interpretation of each test requires careful consideration, with special attention to specific variables such as test performance and patient population. PMID- 25736299 TI - Commentary on: Peyronie's disease and autoimmunity-a real-life clinical study and comprehensive review. PMID- 25736300 TI - Blockage of ROS and NF-kappaB-mediated inflammation by a new chalcone L6H9 protects cardiomyocytes from hyperglycemia-induced injuries. AB - Increased oxidative stress and cardiac inflammation have been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). We previously found that a novel chalcone derivative, L6H9, was able to reduce LPS-induced inflammatory response in macrophages. This study was designed to investigate its protective effects on DCM and the underlying mechanisms. H9C2 cells were cultured with DMEM containing 33 mmol/L of glucose in the presence or absence of L6H9. Pretreatment with L6H9 significantly reduced high glucose-induced inflammatory cytokine expression, ROS level increase, mitochondrial dysfunction, cell apoptosis, fibrosis, and hypertrophy in H9c2 cells, which may be mediated by NF-kappaB inhibition and Nrf2 activation. In mice with STZ-induced diabetes, oral administration of L6H9 at 20 mg/kg/day for 8 weeks significantly decreased the cardiac cytokine and ROS level, accompanied by decreasing cardiac apoptosis and hypertrophy, and, finally, improved histological abnormalities and fibrosis, without affecting the hyperglycemia. L6H9 also attenuated the diabetes-induced NF-kappaB activation and Nrf2 decrease in diabetic hearts. These results strongly suggest that L6H9 may have great therapeutic potential in the treatment of DCM via blockage of inflammation and oxidative stress. This study also provides a deeper understanding of the regulatory role of Nrf2 and NF-kappaB in DCM, indicating that they may be important therapeutic targets for diabetic complications. PMID- 25736302 TI - Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell. AB - Pancreatic cancer (PC) is a deadly human malignancy. Dendritic cell (DC)-based immunotherapy with whole tumor antigens demonstrates potential efficiency in cancer treatment. Tumor RNA and tumor fusion hybrid cells are sources of whole tumor antigens for preparing DC tumor vaccines. However, the efficacy of these sources in eliciting immune responses against PC has not yet to be directly compared. In the present study, patient-derived PC cells and DCs were fused (DC tumor hybrids) and primary cultured PC cell-derived total RNA was electroporated into autologous DCs (DC-tumor RNA). The antitumor immune responses induced by DC tumor hybrids and DC-tumor RNA were compared directly. The results showed that both RNA and hybrid methodologies could induce tumor-specific cytotoxic T lymphocyte (CTL) responses, but pulsing DCs with total tumor RNA could induce a higher frequency of activated CTLs and T-helper cells than fusing DCs with autologous tumor cells. In addition, DC-tumor RNA triggered stronger autologous tumor cell lysis than DC-tumor hybrids. It could be concluded that DCs pulsed with whole tumor RNA are superior to those fused with tumor cells in priming anti PC CTL responses. Electroporation with total tumor RNA may be more suitable for DC-based PC vaccination. PMID- 25736301 TI - Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. AB - Fibroblast growth factor 21 (FGF21) is a modulator of energy homeostasis and is increased in human nonalcoholic liver disease (NAFLD) and after feeding of methionine- and choline-deficient diet (MCD), a conventional inducer of murine nonalcoholic steatohepatitis (NASH). However, the significance of FGF21 induction in the occurrence of MCD-induced NASH remains undetermined. C57BL/6J Fgf21-null and wild-type mice were treated with MCD for 1 week. Hepatic Fgf21 mRNA was increased early after commencing MCD treatment independent of peroxisome proliferator-activated receptor (PPAR) alpha and farnesoid X receptor. While no significant differences in white adipose lipolysis were seen in both genotypes, hepatic triglyceride (TG) contents were increased in Fgf21-null mice, likely due to the up-regulation of genes encoding CD36 and phosphatidic acid phosphatase 2a/2c, involved in fatty acid (FA) uptake and diacylglycerol synthesis, respectively, and suppression of increased mRNAs encoding carnitine palmitoyl-CoA transferase 1alpha, PPARgamma coactivator 1alpha, and adipose TG lipase, which are associated with lipid clearance in the liver. The MCD-treated Fgf21-null mice showed increased hepatic endoplasmic reticulum (ER) stress. Exposure of primary hepatocytes to palmitic acid elevated the mRNA levels encoding DNA damage inducible transcript 3, an indicator of ER stress, and FGF21 in a PPARalpha independent manner, suggesting that lipid-induced ER stress can enhance hepatic FGF21 expression. Collectively, FGF21 is elevated in the early stage of MCD induced NASH likely to minimize hepatic lipid accumulation and ensuing ER stress. These results provide a possible mechanism on how FGF21 is increased in NAFLD/NASH. PMID- 25736303 TI - Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis. AB - Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (P < 0.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option. PMID- 25736304 TI - Study of the applicability of non-conventional aqueous two-phase systems in counter-current and centrifugal partition chromatography. AB - Aqueous two-phase systems composed of imidazolium-based ionic liquids and phosphate salts were evaluated for their applicability in liquid-liquid chromatography. The influence of the nature of ionic liquid anion and cation on the partitioning of bovine serum albumin, lysozyme and myoglobin was investigated. A mixture of K2HPO4 and KH2PO4 in a ratio of 1.82:1 wt/wt was used in all of the tested biphasic systems to adjust the pH to a range of 7-8. The results show that more hydrophobic cations decrease the partition coefficients of the proteins in the biphasic systems and outweigh the effect of the anion on the distribution of the macromolecules. Viscosities and densities of the biphasic systems were in a suitable range for liquid-liquid chromatography. Even though the partition coefficients were too high for a conventional batch operation mode, these aqueous two-phase systems show favorable properties for protein capturing in liquid-liquid chromatographic columns. Additionally, the possible application of ionic liquids as modifiers in polyethylene glycol (PEG)-based aqueous two phase systems was investigated. It could be demonstrated that ionic liquids alter the partition coefficients of the proteins. PMID- 25736305 TI - Capillary electrophoresis in an extended nanospray tip-electrospray as an electrophoretic column. AB - Capillary electrophoresis coupled to mass spectrometry (CE/MS) is gaining its space among the most powerful tools in modern (bio)analytical laboratory. The most challenging instrumental aspect in CE/MS is striking the balance between the stability and reproducibility of the signal and sensitivity of the analysis. Several interface designs have been published in the past decade addressing the variety of instrumental aspects and ease of operation. Most of the interfaces can be categorized either into the sheath flow arrangement (considered to be a de facto standard), or sheathless interface, often expected to provide the ultimate sensitivity. In this work we have explored an "interface-free" approach, where the CE/MS analysis was performed in narrow bore (<20 MUm ID) electrospray capillary. The separation capillary and electrospray tip formed one entity and the high voltage, applied at the injection end of the capillary served for both the separation and electrospray ionization. Thus the separation voltage was defined as the product of the electrospray current and resistivity of the separation electrolyte. Optimum conditions for the separation and electrospray ionization were achieved with voltage programming. The performance of this simplest possible CE/MS system was tested on peptide separations from the cytochrome c tryptic digest. The subnanoliter sample consumption and sensitivity in the attomole range predetermines such a system for analysis of limited samples. PMID- 25736306 TI - A portable device for fast analysis of explosives in the environment. AB - A novel portable device for fast and sensitive analysis of explosives in environmental samples is presented. The developed system consists of miniaturized microcolumn liquid chromatograph, photolytic converter and chemiluminescence detector. The device is able to determine selectively nitramine- and nitroester- and most of nitroaromates-based explosives as well as inorganic nitrates at trace concentrations in water or soil extracts in less than 8 min. The device allows to analyze various environmental samples such as soils or water materials without previous preconcentration. Because of internal power supply, the device ensures 12h of continuous operation. Limits of detection of compounds of interest are in the range of concentrations from 5.0 * 10(-9)M to 8.0 * 10(-5)M for a signal-to noise ratio of 3. Limits of quantification are in the range of concentrations from 1.7 * 10(-8)M to 2.7 * 10(-4)M for a signal-to-noise ratio of 10. The repeatability of the method (RSD=2.9-5.6%) was determined by repeated injections (n=10) of the standard samples during 4h. PMID- 25736307 TI - Accuracy of cardiac CT, radionucleotide and invasive ventriculography, two- and three-dimensional echocardiography, and SPECT for left and right ventricular ejection fraction compared with cardiac MRI: a meta-analysis. AB - AIMS: Left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) are important tools in clinical decision-making. We hypothesized that two-dimensional echocardiography (2DE), three-dimensional echocardiography (3DE), radionucleotide ventriculography (RNV), cardiac computed tomography (CT), gated single-photon emission CT (SPECT), and invasive cardiac cine ventriculography (ICV) provide variable accuracy for LVEF and RVEF when using cardiac magnetic resonance imaging (MRI) as a gold standard. METHODS AND RESULTS: We systematically searched published databases for studies comparing LVEF and RVEF measured by CT, 3DE, 2DE, RNV, ICV, and SPECT compared with MRI. We utilized meta-analytic methods to determine the pooled bias (mean weighted difference), limits of agreement (LOA), and correlation coefficient for each modality. For LVEF, 174 studies (7047 patients) were included. For RVEF, 46 studies (1720 patients) were included. Pooled LOA for LVEF were different between modalities: CT and 3DE had smaller LOA than 2DE, SPECT, ICV, and RNV. 2DE showed the largest LOA and a weaker correlation for LVEF (-13.3 to 12.1%, r = 0.660). For RVEF, CT and 3DE have the best data to support their use with a bias <5% and tight LOA and correlation coefficients with (r) >0.75. CONCLUSION: For LVEF, CT and 3DE had the lowest bias and the best agreement with MRI. Compared with MRI, CT and 3DE comparably estimate RVEF and have the most evidence to support their use. PMID- 25736308 TI - Quantification of infarct size and myocardium at risk: evaluation of different techniques and its implications. AB - AIMS: The aim of this study was to evaluate seven methods for quantifying myocardial oedema [2 standard deviation (SD), 3 SD, 5 SD, full width at half maximum (FWHM), Otsu method, manual thresholding, and manual contouring] from T2 weighted short tau inversion recovery (T2w STIR) and also to reassess these same seven methods for quantifying acute infarct size following ST-segment myocardial infarction (STEMI). This study focuses on test-retest repeatability while assessing inter- and intraobserver variability. T2w STIR and late gadolinium enhancement (LGE) are the most widely used cardiovascular magnetic resonance (CMR) techniques to image oedema and infarction, respectively. However, no consensus exists on the best quantification method to be used to analyse these images. This has potential important implications in the research setting where both myocardial oedema and infarct size are increasingly used and measured as surrogate endpoints in clinical trials. METHODS AND RESULTS: Forty patients day 2 following acute reperfused STEMI were scanned for myocardial oedema and infarction (LGE). All patients had a second CMR scan on the same day >6 h apart from the first one. Images were analysed offline by two independent observers using the semi-automated software. Both oedema and LGE were quantified using seven techniques (2 SD, 3 SD, 5 SD, Otsu, FWHM, manual threshold, and manual contouring). Interobserver, intraobserver and test-retest agreement and variability for both infarct size and oedema quantification were assessed. Infarct size and myocardial quantification vary depending on the quantification method used. Overall, manual contouring provided the lowest inter-, intraobserver, and interscan variability for both infarct size and oedema quantification. The FWHM method for infarct size quantification and the Otsu method for myocardial oedema quantification are acceptable alternatives. CONCLUSIONS: This study determines that, in acute myocardial infarction (MI), manual contouring has the lowest overall variability for quantification of both myocardial oedema and MI when analysed by experienced observers. PMID- 25736309 TI - BNP and haematological parameters are markers of severity of Ebstein's anomaly: correlation with CMR and cardiopulmonary exercise testing. AB - AIMS: Ebstein's anomaly (EA) involves a displaced and dysplastic tricuspid valve resulting in an atrialized portion of the right ventricle and an enlargement of the functional right ventricle and right atrium. Biomarkers targeting heart failure such as brain natriuretic peptide (BNP) or haematological parameters [haemoglobin (Hb) and haematocrit (Hct)] are upregulated in states of pulmonary hypoperfusion. We hypothesized that decreased pulmonary perfusion dependent on the stage of right heart failure is a possible mechanism in EA, and that it can be correlated with cardiac magnetic resonance (CMR) parameters. The aim of this study was to investigate the relationship between BNP and haematological parameters with functional parameters from CMR and exercise testing in patients with EA. METHODS AND RESULTS: Twenty-five patients with non-corrected EA were studied prospectively (mean age 26 +/- 14 years). BNP level was increased (74 +/- 127 ng/L), and in 16% markedly above the heart failure cut-off level of 100 ng/L. Hb and Hct were increased above normal levels in 20 and 24% of patients, respectively. BNP and Hct/Hb correlated with CMR [total right/left (R/L)-Volume Index, right atrium-end-diastolic volume index (EDVi), functional right ventricle (fRV)-EDVi, fRV-ejection fraction (EF), tricuspid regurgitation, pulmonary artery flow, and left ventricular EF] and exercise testing [workload/kg, oxygen uptake (VO2), ventilatory response to carbon dioxide production (VE/VCO2), oxygen (O2) pulse, and heart rate reserve]. The higher BNP and haematological parameters, the higher was the disease severity and the more limited was the physical exercise capacity. CONCLUSION: In this EA cohort, BNP levels and haematological parameters correlated well with functional data from CMR and exercise testing. The total R/L Volume-Index and BNP, and to some extent hematological parameters, may be useful as prognostic markers in patients with EA. PMID- 25736310 TI - Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. AB - Memory stem T cells (TSCM) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked TSCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived TSCM are highly enriched early after HSCT. We showed at the antigen-specific and clonal level that TSCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of TSCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting TSCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT. PMID- 25736311 TI - miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. AB - Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B) miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance. PMID- 25736314 TI - Frontline of dermatomycology research is just in front of us! PMID- 25736313 TI - Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. AB - Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide 3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5 phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function. PMID- 25736312 TI - Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities. AB - Lenalidomide is an immunomodulatory drug (IMiD) with activity in lymphoid malignancies occurring primarily through immune modulation (eg, T-cell immune synapse enhancement and NK-cell/T-cell effector augmentation) and antiproliferative effects. Food and Drug Administration-approved for bortezomib resistant, relapsed/refractory mantle-cell lymphoma, lenalidomide has demonstrated efficacy in several additional lymphoma subtypes. There are many ongoing clinical trials examining the use of lenalidomide alone or in combinatorial therapy. It will be important in these studies to delineate reliable, predictive biomarkers to optimally integrate lenalidomide into lymphoma treatment paradigms. PMID- 25736315 TI - Molecular markers useful for epidemiology of dermatophytoses. AB - Dermatophytosis is a very common skin disorder and the most prevalent infectious disease treated by dermatologists. Recent developments in molecular techniques have markedly changed methods of identifying dermatophytes, with these methods showing intraspecies polymorphisms in some molecular markers. Intraspecies subtyping and strain differentiation have made possible the tracking of infections, the identification of common sources of infections and recurrence or reinfection after treatment. This review describes methods of intraspecies differentiation using mitochondrial DNA, random amplification of polymorphic DNA, non-transcribed spacer regions of ribosomal RNA genes and microsatellite markers, as well as their usefulness and limitations. PMID- 25736316 TI - Immunoresponses in dermatomycoses. AB - Contact with fungal pathogens initiates a series of host responses beginning with innate immunity, which leads to fungal recognition and microbial killing. The innate immune system also modulates the adaptive immune responses, leading to the establishment of immunological memory and protection against pathogens. In the case of dimorphic fungi such as Candida albicans and Malassezia, the immune system plays an important role in tolerance and resistance when managing the organisms either as commensal microbiota or invading pathogens, and disruption of this balance can result in pathological consequences for the host. In addition, Malassezia and dermatophytes have immunomodulatory capabilities that allow them to adapt to their environments and they may exert different effects in healthy and diseased skin. Here, we discuss the host immune responses to dermatomycoses caused by dimorphic fungi such as C. albicans and Malassezia as well as dermatophytes such as Trichophyton spp. and Arthroderma benhamiae to gain a better understanding of the mechanisms of the host-dermatomycosis interaction. PMID- 25736317 TI - Trichophyton tonsurans infection in Japan: epidemiology, clinical features, diagnosis and infection control. AB - In this review, we summarize the status of Trichophyton tonsurans infection in Japan in terms of epidemiology, clinical features, diagnosis and infection control. Since approximately 2000, outbreaks of T. tonsurans infections among combat sports club members have been reported frequently, with the infection then spreading to their friends and family members. The most common clinical features of T. tonsurans infection are tinea corporis, which is difficult to differentiate from eczema, and tinea capitis. Tinea capitis is classified as the seborrheic form, kerion celsi form or "black dot" form, although 90% or more of patients are asymptomatic carriers. The diagnosis of symptomatic T. tonsurans infection is established by potassium hydroxide examination and fungal culture. However, because there are many asymptomatic carriers of T. tonsurans infection, tests using the hairbrush culture method are necessary. An increase in asymptomatic carriers of T. tonsurans makes assessment of the current prevalence of the infection challenging and underscores the importance of educational efforts and public awareness campaigns to prevent T. tonsurans epidemics. PMID- 25736318 TI - Malassezia species and their associated skin diseases. AB - Malassezia spp. are lipophilic fungi that occur on all skin surfaces of humans and animals as commensal and pathogenic organisms. In the 2000s, several new species were added to the Malassezia genus by Japanese researchers. The genus Malassezia now includes 14 species of basidiomycetous yeast. Culture-independent molecular analysis clearly demonstrated that the DNA of Malassezia spp. was predominantly detected in core body and arm sites, suggesting that they are the dominant fungal flora of the human body. Malassezia spp. have been implicated in skin diseases including pityriasis versicolor (PV), Malassezia folliculitis (MF), seborrheic dermatitis (SD) and atopic dermatitis (AD). While Malassezia spp. are directly responsible for the infectious diseases, PV and MF, they act as an exacerbating factor in AD and SD. The fatty acids generated by Malassezia lipase can induce inflammation of the skin, resulting in development of SD. Patch and serum immunoglobulin E tests revealed that AD patients were hypersensitive to Malassezia. However, these findings only partially elucidated the mechanism by which Malassezia spp. induce inflammation in the skin; understanding of the pathogenetic role of Malassezia spp. in SD or AD remains incomplete. In this article, the latest findings of Malassezia research are reviewed with special attention to skin diseases. PMID- 25736319 TI - Primary cutaneous mucormycosis caused by Mucor irregularis in an immunocompetent patient. PMID- 25736320 TI - Factors influencing breast cancer screening and risk assessment among young African American women: An integrative review of the literature. AB - PURPOSE: This integrative review was conducted to examine factors that influence mammography screening and use of cancer genetic services among younger African American women at increased risk for developing breast cancer. DATA SOURCES: Research articles were identified using PubMed, CINAHL, PsychINFO, and Cochrane library to find studies published from 2003 to 2013. CONCLUSIONS: Findings from this review indicate that while younger African American women receive mammograms more often than the general population, they are not being referred for genetic testing when appropriate. This is a major concern because African American women tend to experience more aggressive forms of breast cancer at an earlier age than the general population; it is imperative that they undergo genetic testing for optimal management of their breast cancer risk. IMPLICATIONS FOR PRACTICE: Nurse practitioners have a significant role in breast cancer screening and genetic testing of at-risk women, particularly in identifying and referring young women for testing. Further communication efforts are needed to improve young women's knowledge of breast cancer risk and the benefits of genetic testing. Reducing barriers to breast healthcare services requires nursing efforts that focus on populations at greatest risk for poor health outcomes. PMID- 25736321 TI - Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2. AB - BACKGROUND & AIMS: Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor beta receptor II (TGFBR2). TGFbeta signaling therefore is believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGFbeta. We investigated how TGFbeta signaling might continue in MSI H CRC cells. METHODS: We sequenced the 10-adenines microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGFbeta signaling was detected by SMAD2 phosphorylation and through use of a TGFbeta-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells, which do not respond to TGFbeta, and their activities were measured. RESULTS: SMAD2 was phosphorylated in most MSI-H CRC tissues (strong detection in 44% and weak detection in 34% of MSI-H tumors). Phosphorylation of SMAD2 in MSI-H cells required TGFBR2-even the form encoding a frameshift mutation. Transcription and translation of TGFBR2 with a 1-nucleotide deletion at its microsatellite sequence still produced a full-length TGFBR2 protein. However, protein expression required preservation of the TGFBR2 microsatellite sequence; cells in which this sequence was replaced with a synonymous nonmicrosatellite sequence did not produce functional TGFBR2 protein. CONCLUSION: TGFbeta signaling remains active in some MSI-H CRC cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. Strategies to reactivate TGFbeta signaling in colorectal tumors might not be warranted, and the functional effects of mutations at other regions of microsatellite instability should be evaluated. PMID- 25736322 TI - A Comparative Study With In Vitro Ultrasonographic and Histologic Grading of Metatarsal Head Cartilage in Rheumatoid Arthritis. AB - BACKGROUND: Ultrasonography is among the valid methods to assess articular cartilage in the foot. This study aimed to evaluate the validity of ultrasonographic grading to assess metatarsal head articular cartilage for rheumatoid forefoot deformity in vivo and to compare the findings with in vitro ultrasonographic and histologic gradings. METHODS: Participants were 15 patients scheduled to undergo resection arthroplasty of the metatarsal heads of the lesser toes because of rheumatoid arthritis of the metatarsophalangeal joints. Ultrasonographic examination was performed in vivo the day before surgery. Specimens of the second to fifth metatarsal heads taken intraoperatively were graded from in vitro ultrasonographic and histologic evaluations. Correlations among in vivo ultrasonographic, in vitro ultrasonographic, and histologic gradings were analyzed. RESULTS: In 46 metatarsal heads, the distribution of grading ranged from grade 1 to 6 for in vivo ultrasonographic examinations and from grade 1 to 4 for histologic examinations. In vivo ultrasonographic grading showed significant correlation to both in vitro ultrasonographic grading (P < .001, R = 0.74) and histologic grading (P < .001, R = 0.67). CONCLUSIONS: The significant correlations between in vivo ultrasonographic and histologic gradings suggest that a semiquantitative in vivo ultrasonographic assessment of forefoot deformity in rheumatoid arthritis may be possible. Ultrasonographic grading may prove useful for pre- and postoperative evaluation of remaining joint function in rheumatoid forefoot deformity. An ultrasonographic grading system for remaining joint surfaces might be helpful in selecting surgical procedures such as joint sparing osteotomy and metatarsal head resection. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25736323 TI - Remodeling of the Proximal Tibia Subsequent to Bone Graft Harvest: Postoperative CT Study. AB - BACKGROUND: Proximal tibia bone autograft (PTBG) is regularly used in reconstructive foot, ankle, and maxillofacial surgery. Although many surgeons prefer PTBG rather than the conventional iliac crest, little is known about the remodeling capacity of the proximal tibia after harvesting cancellous bone. METHODS: Via bilateral postoperative computed tomography of 17 harvesting sites, comparing the defect side with the healthy side, we measured the repair capacity of the proximal tibia in response to bone defect created by the harvest at medium term follow-up (mean 29 months; range, 7-55 months). RESULTS: 16 of 17 (94%) cortical defects showed complete consolidation. Cancellous remodeling was graded 0 to 3, with 2 defects showing complete remodeling (grade 3), 4 defects partial remodeling (more than 50%), 8 defects partial remodeling (less than 50%) and 3 defects no remodeling at all (grade 0). CONCLUSION: The proximal tibia has the potential to form new cancellous bone after cancellous bone graft harvesting. More data are required to identify possible variables influencing this remodeling capacity. When performing knee surgery, knee surgeons should take into account the relatively small defect size and the consolidation of the cortical window after proximal tibia bone harvesting. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25736324 TI - Use of Negative Pressure Wound Therapy on Closed Surgical Incision After Total Ankle Arthroplasty. AB - BACKGROUND: Wound healing problems of the anterior ankle incision are among the most common complications after total ankle arthroplasty, possibly resulting in exposure of the prostheses and infection. The aim of this study was to investigate the role of negative pressure wound therapy (NPWT) in decreasing the rate of wound healing problems after total ankle arthroplasty. METHODS: This is a retrospective cohort study including consecutive patients who underwent total ankle arthroplasty by a single surgeon at a single institution between 2009 and 2013. The incisional negative pressure dressing was applied to all patients who underwent total ankle arthroplasty between 2012 and 2013 with a continuous application of -80 mm Hg negative pressure for 6 days postoperatively. The control group consisted of patients who underwent total ankle arthroplasty between 2009 and 2012 with a conventional nonadherent gauze dressing. Seventy four patients were involved in this study: 37 in the control group and 37 in the incisional NPWT group. RESULTS: All patients tolerated the incisional NPWT to completion without any dressing failures or skin problems. Both groups showed similar distributions in demographics and perioperative risk factors for wound healing. There were 9 (24%) wound healing problems in the control group and 1 (3%) in the incisional NPWT group. Incisional NPWT was found to reduce wound healing problems with an odds ratio of 0.10 (95% CI, 0.01-0.50; P = .004). CONCLUSIONS: Our study demonstrated that there was a decreased incidence of wound healing problems following total ankle arthroplasty with incisional NPWT dressings. This is the first study evaluating the efficacy of incisional NPWT as an adjunct treatment for wound healing after total ankle arthroplasty. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25736325 TI - Drug Repositioning for Preeclampsia Therapeutics by In Vitro Screening: Phosphodiesterase-5 Inhibitor Vardenafil Restores Endothelial Dysfunction via Induction of Placental Growth Factor. AB - We screened a library of 528 approved drugs to identify candidate compounds with therapeutic potential as preeclampsia treatments via their proangiogenic properties. Using human umbilical vein endothelial cells (HUVECs), we assessed whether the screened drugs induced placental growth factor (PIGF) and restored damaged endothelial cell function. Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure levels of PlGF in conditioned media treated with each drug (100 umol/L) in the drug library. Tube formation assays were performed using HUVECs to evaluate the angiogenic effects of drugs that induced PlGF. We also performed ELISA, quantitative reverse transcription polymerase chain reaction, and tube formation assays after treatment with a range of concentrations of the candidate drug. Of the drugs that induced PlGF, vardenafil was the only compound that significantly facilitated tube formation in comparison with the control cells (P < .01). Treatment with vardenafil at concentrations of 50, 100, and 250 umol/L increased expression of PlGF in a dose-dependent manner. Vardenafil (250 umol/L) significantly improved tube formation which was inhibited in the presence of soluble fms-like tyrosine kinase 1 (100 ng/mL) and/or soluble endoglin (100 ng/mL). Production of PlGF from HUVECs in the presence of sera derived from patients with preeclampsia was significantly elevated by administration of vardenafil (250 umol/L). By assessing drug repositioning through screening a library of approved drugs, we identified vardenafil as a potential protective agent against preeclampsia. The therapeutic mechanism of vardenafil may involve inhibition of the systemic maternal antiangiogenic state that leads to preeclampsia, in addition to its vasodilating effect. As concentrations used are high and unlikely to be useful clinically, further work is needed before testing it in humans. PMID- 25736326 TI - Expression of Myostatin in Intrauterine Growth Restriction and Preeclampsia Complicated Pregnancies and Alterations to Cytokine Production by First-Trimester Placental Explants Following Myostatin Treatment. AB - Preeclampsia (PE) and intrauterine growth restriction (IUGR) are major obstetric health problems. Higher levels of T-helper (Th) 1 (proinflammatory) cytokines have been observed in pregnancies complicated with PE and IUGR; this is in contrast to the predominant Th2 (anti-inflammatory) cytokine environment found in uncomplicated pregnancies. Myostatin is best known as a negative regulator of muscle development and reportedly has a role in fat deposition, glucose metabolism, and cytokine modulation (outside the placenta). Myostatin concentrations in plasma and protein expression in placental tissue are significantly higher in women with PE. Expression of myostatin in IUGR and PE IUGR and the effect of this protein on the cytokine production from the placenta is unknown. In the current study, significant differences were identified in the expression of myostatin in pregnancies complicated with IUGR, PE, and PE with IUGR. Furthermore, cytokine production by first-trimester placental tissues was altered following myostatin treatment. PMID- 25736328 TI - Involvement of miRNAs and Cell-Secreted Vesicles in Mammalian Ovarian Antral Follicle Development. AB - Ovarian follicular development is a controlled series of events culminating with an ovulatory or atretic follicle. MicroRNAs (miRNAs) are small noncoding RNAs involved in translational regulation of genes in different developmental processes. Deletion of Dicer in mice ovaries demonstrated the importance of miRNAs in reproduction, which led to infertility. The miRNAs were thought to act only within host cells; however, these molecules are also present in cell secreted vesicles. These vesicles are present in body fluids such as milk, serum, and ovarian follicular fluid. Vesicles are secreted in extracellular fluids and travel from donor to target cells, mediating transfer of bioactive material. Herein we discuss the role of hormonal-regulated miRNAs within different ovarian follicular cells as well as cell-secreted vesicles participation in mammalian ovarian follicular fluid. Furthermore, we discuss the possibility of miRNAs transference mediated by cell-secreted vesicles present in ovarian follicular fluid, increasing the versatility of miRNA functions during antral follicle development. PMID- 25736327 TI - Tubal Ligation Induces Quiescence in the Epithelia of the Fallopian Tube Fimbria. AB - Tubal ligation keeps the fimbriated end of the fallopian tube intact while interrupting the conduit for sperm and egg between the uterus and ovary. Tubal ligation is associated with an approximately 20% decreased risk of high-grade serous ovarian cancers, which mounting evidence suggests arise from the distal fallopian tube epithelium. We postulated that biological changes at the epithelial cellular level of the distal fallopian tube may account for the surgical procedure's observed risk reduction. We compared the histology, presence of epithelial progenitors (basally located CD44-positive cells), and degree of epithelial proliferation (Ki67-positive cells) of distal fallopian tube from 10 patients with previous tubal ligation and 10 age-matched patients with uncut fallopian tubes. A significantly reduced population of proliferating epithelial progenitors (basally located CD44/Ki67 dual-positive cells) was detected in the tubal ligated specimens (P = .0002). To functionally assess the effect of tubal ligation, a murine model was utilized to compare the growth capacity of distal fallopian tube epithelial cells isolated from either ligated or sham-operated tubal epithelia. Murine fallopian tube epithelial cells isolated after tubal ligation showed a significantly reduced capacity to grow organoids in culture compared to sham-operated controls (P = .002). The findings of this study show that tubal ligation is associated with a reduced presence and decreased proliferation of progenitor cells in the distal fallopian tube epithelium. These compositional and functional changes suggest that tubal ligation induces quiescence of distal fallopian tube epithelial cells. PMID- 25736329 TI - Misuse of fentanyl transdermal patch mixed with acute coronary syndrome. AB - Fentanyl transdermal patches have long been used in the palliative care of patients with chronic pain with a favorable safety profile. However, intoxications secondary to intentional and unintentional misuse have been widely reported. In this study, we report an otherwise healthy woman presented to emergency department who used three patches of fentanyl to alleviate her knee pain and with a picture mimicking acute coronary syndrome. PMID- 25736330 TI - Homocatenation of aluminum: alkane-like structures of Li2Al2 H6 and Li3Al3H8. AB - Invited for the cover of this issue is Alexander I. Boldyrev and co-workers at Utah State University. The image depicts the magician who symbolizes a chemist synthesizing molecules of "aluminum homocatenated ethane and propane" based on the idea of electronic transmutation. Read the full text of the article at 10.1002/chem.201500298. PMID- 25736331 TI - Synthesis, X-ray structure and in vitro cytotoxicity studies of Cu(I/II) complexes of thiosemicarbazone: special emphasis on their interactions with DNA. AB - 4-(p-X-phenyl)thiosemicarbazone of napthaldehyde {where X = Cl (HL1) and X = Br (HL2)}, thiosemicarbazone of quinoline-2-carbaldehyde (HL3) and 4-(p fluorophenyl)thiosemicarbazone of salicylaldehyde (H2L4) and their copper(I) {[Cu(HL1)(PPh3)2Br].CH3CN (1) and [Cu(HL2)(PPh3)2Cl].DMSO (2)} and copper(II) {[(Cu2L32Cl)2(MU-Cl)2].2H2O (3) and [Cu(L4)(Py)] (4)} complexes are reported herein. The synthesized ligands and their copper complexes were successfully characterized by elemental analysis, cyclic voltammetry, NMR, ESI-MS, IR and UV Vis spectroscopy. Molecular structures of all the Cu(I) and Cu(II) complexes have been determined by X-ray crystallography. All the complexes (1-4) were tested for their ability to exhibit DNA-binding and -cleavage activity. The complexes effectively interact with CT-DNA possibly by groove binding mode, with binding constants ranging from 104 to 105 M-1. Among the complexes, 3 shows the highest chemical (60%) as well as photo-induced (80%) DNA cleavage activity against pUC19 DNA. Finally, the in vitro antiproliferative activity of all the complexes was assayed against the HeLa cell line. Some of the complexes have proved to be as active as the clinical referred drugs, and the greater potency of 3 may be correlated with its aqueous solubility and the presence of the quinonoidal group in the thiosemicarbazone ligand coordinated to the metal. PMID- 25736332 TI - Reversible Deterioration in Hypophosphatasia Caused by Renal Failure With Bisphosphonate Treatment. AB - Hypophosphatasia is an inborn error of metabolism caused by mutations in the ALPL gene. It is characterized by low serum alkaline phosphatase (ALP) activity and defective mineralization of bone, but the phenotype varies greatly in severity depending on the degree of residual enzyme activity. We describe a man with compound heterozygous mutations in ALPL, but no previous bone disease, who suffered numerous disabling fractures after he developed progressive renal failure (for which he eventually needed dialysis treatment) and was prescribed alendronate treatment. A bone biopsy showed marked osteomalacia with low osteoblast numbers and greatly elevated pyrophosphate concentrations at mineralizing surfaces. In vitro testing showed that one mutation, T117H, produced an ALP protein with almost no enzyme activity; the second, G438S, produced a protein with normal activity, but its activity was inhibited by raising the media phosphate concentration, suggesting that phosphate retention (attributable to uremia) could have contributed to the phenotypic change, although a pathogenic effect of bisphosphonate treatment is also likely. Alendronate treatment was discontinued and, while a suitable kidney donor was sought, the patient was treated for 6 months with teriparatide, which significantly reduced the osteomalacia. Eighteen months after successful renal transplantation, the patient was free of symptoms and the scintigraphic bone lesions had resolved. A third bone biopsy showed marked hyperosteoidosis but with plentiful new bone formation and a normal bone formation rate. This case illustrates how pharmacological (bisphosphonate treatment) and physiologic (renal failure) changes in the "environment" can dramatically affect the phenotype of a genetic disorder. PMID- 25736333 TI - Center of Excellence to build nursing scholarship and improve health care in Italy. AB - PURPOSE: This article profiles the establishment and initial phase (2010-2014) of a Center of Excellence (CoE) as an instrument to strengthen nursing scholarship and improve health care in Italy. APPROACH: This CoE is unique as a non university-based center. The National Regulatory Board of Registered Nurses, Health Visitors, and Pediatric Nurses (IPASVI) designated substantial administrative and funding support to the CoE for advancing nursing education, clinical practice, research development, and research training. Boyer's Model of Scholarship underpinned the CoE's conceptual framework, and its operational infrastructure was adapted from the U.S. National Institutes of Health P20 program award mechanism. Diverse methods included sponsoring research studies by nurse-led teams, research training courses, nursing education longitudinal studies, evidence-based practice training, and related pilot studies. FINDINGS: Multiple collaborative projects were conducted via the CoE in conjunction with the successful launch of an expansive digital library and communication system accessible to nurses. The introduction of English proficiency courses was also a unique contribution. CONCLUSIONS: The CoE concept is a potential instrument to strengthen nursing scholarship in Italy with potential scalability considerations to other global settings. CLINICAL RELEVANCE: An overlapping focus on research, education, and practice under the umbrella of nursing scholarship within a CoE while engaging all levels of nursing is important to impact healthcare changes. PMID- 25736334 TI - Constitutional chromothripsis involving chromosome 19 in a child with subtle dysmorphic features. PMID- 25736336 TI - Tuning electron donor-acceptor hybrids by alkali metal complexation. AB - A zinc phthalocyanine endowed with four [18]-crown-6 moieties, ZnPcTeCr, has been prepared and self-assembled with either pyridyl-functionalized perylenebisimides (PDI-Py) or fullerenes (C60-Py) to afford a set of novel electron donor-acceptor hybrids. In the case of ZnPcTeCr, aggregation has been circumvented by the addition of potassium or rubidium ions to lead to the formation of monomers and cofacial dimers, respectively. From fluorescence titration experiments, which gave rise to mutual interactions between the electron donors and the acceptors in the excited state, the association constants of the respective ZnPcTeCr monomers and/or dimers with the corresponding electron acceptors were derived. Complementary transient-absorption experiments not only corroborated photoinduced electron transfer from ZnPcTeCr to either PDI-Py or C60-Py within the electron donor-acceptor hybrids, but also the unexpected photoinduced electron transfer within ZnPcTeCr dimers. In the electron donor-acceptor hybrids, the charge separated-state lifetimes were elucidated to be close to 337 ps and 3.4 ns for the two PDI-Pys, whereas the longest lifetime for the photoactive system that contains C60-Py was calculated to be approximately 5.1 ns. PMID- 25736335 TI - Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. AB - 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations. PMID- 25736337 TI - Complications of pre-operative anorexia nervosa in bariatric surgery. AB - It is important to recognise that patients who seek weight loss surgery may have a history of restrictive eating or anorexia nervosa. The following case report describes a woman with a history of anorexia nervosa who underwent Roux-en-Y gastric bypass surgery. Her eating disorder symptoms subsequently reappeared and were largely resistant to treatment. To the best of our knowledge, this is the first case report of a bariatric surgery patient with a prior history of anorexia nervosa. Further research is required to determine how best to select patients for weight loss surgery. PMID- 25736338 TI - Pulmonary tuberculosis caused by Mycobacterium bovis in China. AB - The epidemiology of Mycobacterium bovis infection in humans in China is unknown. In this study, pulmonary tuberculosis caused by M. bovis in China was studied. A total of 4069 clinical strains isolated from sputa during the 2007-2009 nationwide surveillance of drug-resistant tuberculosis in China were analyzed. M. bovis was identified by para-nitrobenzoic acid and thiophen-2-carboxylic acid hydrazide growth tests, spoligotyping and multiplex PCR amplification. In addition, a total of 1828 clinical specimens were recruited from Beijing Chest Hospital (Beijing, China) for Lowenstein-Jensen (LJ) culture, both on standard LJ medium and LJ medium containing 4.5 mg/ml(W/V) sodium pyruvate, the latter being the preferred medium for M. bovis growth. The isolates which demonstrated more vigorous on pyruvate containing medium than on standard LJ medium were then identified by multiplex PCR amplification. Only 1 isolate from the nationwide surveillance was confirmed as M. bovis-BCG. The isolate belonged to a predominant spoligotype SB0120 (ST482). In addition, no M. bovis isolate was acquired by the continuous screening step in Beijing Chest Hospital. M. bovis has a negligible contribution to pulmonary tuberculosis in China, so neither laboratory identification nor clinical treatment of M. bovis infection need be considered in routine work. PMID- 25736339 TI - Plasmon-enhanced photocatalytic hydrogen production over visible-light responsive Cu/TiO2. AB - Cheap and visible-light responsive Cu/TiO2 photocatalysts were fabricated by illuminating ultraviolet (UV) to a mixture of TiO2 nanoparticles (NPs) and Cu2O NPs in an evacuated reaction chamber. The Cu2O NPs were reduced by UV in an oxygen-free reaction chamber, and hence, metallic Cu NPs with size less than 5 nm were uniformly loaded on TiO2. Due to the plasmon resonance of the Cu NPs, the Cu/TiO2 exhibited a good performance of water-splitting hydrogen production under visible light in the presence of glycerol as a hole scavenger. The optimum hydrogen production rate of Cu/TiO2 was 0.24 mmol h(-1) g(-1). The Cu/TiO2 also showed high stability of the photocatalytic performance in the evacuated chamber; however, the visible-light responsive photocatalytic properties dramatically and rapidly decreased when exposed to air. PMID- 25736341 TI - True risks of paracetamol may be underestimated, say researchers. PMID- 25736340 TI - Effectiveness of a Web-based tailored interactive health communication application for patients with type 2 diabetes or chronic low back pain: randomized controlled trial. AB - BACKGROUND: The prevalence of chronic diseases such as type 2 diabetes and chronic low back pain is rising. Patient empowerment is a key strategy in the management of chronic diseases. Patient empowerment can be fostered by Web-based interactive health communication applications (IHCAs) that combine health information with decision support, social support, and/or behavioral change support. Tailoring the content and tone of IHCAs to the needs of individual patients might improve their effectiveness. OBJECTIVE: The main objective was to test the effectiveness of a Web-based, tailored, fully automated IHCA for patients with type 2 diabetes or chronic low back pain against a standard website with identical content without tailoring (control condition) on patients' knowledge and empowerment. METHODS: We performed a blinded randomized trial with a parallel design. In the intervention group, the content was delivered in dialogue form, tailored to relevant patient characteristics. In the control group, the sections of the text were presented in a content tree without any tailoring. Participants were recruited online and offline and were blinded to their group assignments. Measurements were taken at baseline (t0), directly after the first visit (t1), and at 3-month follow-up (t2). The primary hypothesis was that the tailored IHCA would have larger effects on knowledge and patient empowerment (primary outcomes) than the control website. The secondary outcomes were decisional conflict and preparation for decision making. All measurements were conducted by online self-report questionnaires. Intention-to-treat (ITT) and available cases (AC) analyses were performed for all outcomes. RESULTS: A total of 561 users agreed to participate in the study. Of these, 179 (31.9%) had type 2 diabetes and 382 (68.1%) had chronic low back pain. Usage was significantly higher in the tailored system (mean 51.2 minutes) than in the control system (mean 37.6 minutes; P<.001). Three months after system use, 52.4% of the sample was retained. There was no significant intervention effect in the ITT analysis. In the AC analysis, participants using the tailored system displayed significantly more knowledge at t1 (P=.02) and more emotional well-being (subscale of empowerment) at t2 (P=.009). The estimated mean difference between the groups was 3.9 (95% CI 0.5-7.3) points for knowledge and 25.4 (95% CI 6.3 44.5) points for emotional well-being on a 0-100 points scale. CONCLUSIONS: The primary analysis did not support the study hypothesis. However, content tailoring and interactivity may increase knowledge and reduce health-related negative effects in persons who use IHCAs. There were no main effects of the intervention on other dimensions of patient empowerment or decision-related outcomes. This might be due to our tailored IHCA being, at its core, an educational intervention offering health information in a personalized, empathic fashion that merely additionally provides decision support. Tailoring and interactivity may not make a difference with regard to these outcomes. TRIAL REGISTRATION: International Clinical Trials Registry: DRKS00003322; http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00003322 (Archived by WebCite at http://www.webcitation.org/6WPO0lJwE). PMID- 25736343 TI - State-of-the-art nanoplatform-integrated MALDI-MS impacting resolutions in urinary proteomics. AB - Urine proteomics has become a subject of interest, since it has led to a number of breakthroughs in disease diagnostics. Urine contains information not only from the kidney and the urinary tract but also from other organs, thus urinary proteome analysis allows for identification of biomarkers for both urogenital and systemic diseases. The following review gives a brief overview of the analytical techniques that have been in practice for urinary proteomics. MALDI-MS technique and its current application status in this area of clinical research have been discussed. The review comments on the challenges facing the conventional MALDI-MS technique and the upgradation of this technique with the introduction of nanotechnology. This review projects nano-based techniques such as nano-MALDI-MS, surface-assisted laser desorption/ionization, and nanostructure-initiator MS as the platforms that have the potential in trafficking MALDI-MS from the lab to the bedside. PMID- 25736344 TI - Diagnosis of primary pure signet-ring cell carcinoma of the cervix. PMID- 25736345 TI - Targeting lipoprotein (a): an evolving therapeutic landscape. AB - Robust epidemiologic and genetic studies have solidified the role of lipoprotein (a) [Lp(a)] as an independent and causal risk factor for cardiovascular disease. The increased cardiovascular risk of Lp(a) is mediated through both proatherogenic and prothrombotic/antifibrinolytic mechanisms. Several societies recommend Lp(a) screening for patients with high cardiovascular risk, although no consensus exists on the management of patients with elevated Lp(a). However, numerous pharmacologic approaches are being evaluated that have the potential to reduce Lp(a) and will be the focus of this review. The majority of these interventions have been developed for other lipid-lowering indications, but also lower Lp(a). There are also novel therapies in development that specifically target Lp(a). The efficacy of these therapies varies, and their role in the evolving lipoprotein therapeutic landscape has yet to be determined. Nevertheless, targeted Lp(a) reduction is certainly intriguing and will likely continue to be an active area of investigation in the future. PMID- 25736346 TI - HIV testing behaviour and use of risk reduction strategies by HIV risk category among MSM in Vancouver. AB - We carried out an analysis of a serobehavioural study of men who have sex with men >19 years of age in Vancouver, Canada to examine HIV testing behaviour and use of risk reduction strategies by HIV risk category, as defined by routinely gathered clinical data. We restricted our analysis to those who self-identified as HIV-negative, completed a questionnaire, and provided a dried blood spot sample. Of 842 participants, 365 (43.3%) were categorised as lower-risk, 245 (29.1%) as medium-risk and 232 (27.6%) as higher-risk. The prevalence of undiagnosed HIV infection was low (lower 0.8%, medium 3.3%, higher 3.9%; p = 0.032). Participants differed by risk category in terms of having had an HIV test in the previous year (lower 46.5%, medium 54.6%, higher 67.0%; p < 0.001) and in their use of serosorting (lower 23.3%, medium 48.3%, higher 43.1%; p < 0.001) and only having sex with HIV-positive men if those men had low viral loads or were taking HIV medication (lower 5.1%, medium 4.8%, higher 10.9%; p = 0.021) as risk reduction strategies. These findings speak to the need to consider segmented health promotion services for men who have sex with men with differing risk profiles. Risk stratification could be used to determine who might benefit from tailored multiple health promotion interventions, including HIV pre-exposure prophylaxis. PMID- 25736347 TI - Clinical findings and outcomes in patients with possible usual interstitial pneumonia. AB - BACKGROUND: Patients with possible usual interstitial pneumonia (UIP) constitute a substantial group, and their clinical characteristics and outcomes are not well defined. We compared the clinical characteristics and survival between patients with possible UIP and the UIP pattern. METHODS: We evaluated 62 patients with possible UIP and 544 patients with the UIP pattern. Both groups were diagnosed by clinical characteristics and high-resolution computed tomography (HRCT) findings. Two radiologists performed radiological evaluation based on the new idiopathic pulmonary fibrosis (IPF) guidelines. Two risk-stratification methods were used to compare UIP pattern and possible UIP patients. RESULTS: The groups had similar demographic and clinical characteristics. Pulmonary function tests revealed no significant differences in lung volumes between the 2 groups. However, DLCO was significantly lower with the UIP pattern than with possible UIP (p = 0.004). Multivariate analysis showed age, sex, and carbon monoxide diffusing capacity (DLCO) as important independent variables for survival. The UIP HRCT pattern did not affect survival (hazard ratio, 0.83; 95% confidence interval, 0.51-1.24; p = 0.32). Possible UIP was not associated with prognosis when independent predictors for survival rate and propensity score were considered. In the case-control study, the 3-year survival rate was 44.6% in the UIP pattern group and 56.8% in the possible UIP group (p = 0.16). CONCLUSIONS: Clinical characteristics and outcomes were similar in possible UIP and UIP patients, except for differences in DLCO. The UIP pattern itself did not affect survival. PMID- 25736348 TI - Average length of a flaccid and erect penis is published to help counsellors. PMID- 25736349 TI - Paravertebral block in rib fractures. PMID- 25736350 TI - Electrocardiogram changes and prognosis of takotsubo cardiomyopathy. PMID- 25736351 TI - Nonsteroidal anti-inflammatory drugs and venous thromboembolism. PMID- 25736352 TI - Correlation between acute pulmonary embolism and ST elevation inferior myocardial infarction. PMID- 25736353 TI - Left heart abnormalities in connective tissue disease patients with pre-capillary pulmonary hypertension as well as borderline mean pulmonary arterial pressure. AB - OBJECTIVE: To describe co-existence of left heart abnormalities among case series of connective tissue disease (CTD) patients who showed pre-capillary pulmonary hypertension (PH) as well as borderline mean pulmonary arterial pressure (mPAP). METHODS: From 2010 through 2012, 49 CTD patients suspected to have PH by exercise Doppler echocardiography underwent right heart catheterization. We retrospectively searched for left heart diseases from the available data on Doppler echocardiography, cardiac magnetic resonance imaging (MRI), scintigraphy, and endomyocardial biopsy. RESULTS: Among 49 patients, 11 and 2 had pre- and post capillary PH, respectively, and another 10 had borderline mPAP. Six of 11 patients with pre-capillary PH showed low pulmonary vascular resistance (PVR) (<= 240 dynes*sec*cm(- 5)) and low diastolic pulmonary gradient (< 7 mmHg). Seven of 10 patients with borderline mPAP had normal PVR (< 160) suggesting the presence of left heart abnormalities. Other abnormal findings included increased left atrial volume index and E/E' on Doppler echocardiography, delayed contrast enhancement by MRI, patchy area of hypoperfusion on thallium scintigraphy, and fibrosis in endomyocardial biopsy. CONCLUSION: The present case series suggested some contribution of left heart abnormalities to the increase in mPAP among CTD patients with pre-capillary PH as well as borderline mPAP. PMID- 25736354 TI - Corticosteroid- and cyclophosphamide-free treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis using tocilizumab. PMID- 25736355 TI - Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 and innovator infliximab in Japanese patients with rheumatoid arthritis. AB - OBJECTIVES: To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks. METHODS: In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6-16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUC(tau)) (weeks 6-14) and C(max) (week 6) of these drugs, and to compare their efficacy and safety. RESULTS: The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUC(tau) and C(max) values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24 124.29%) and 104.09% (92.12-117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs. CONCLUSION: CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety. PMID- 25736356 TI - Association of IL-1R2 genetic polymorphisms with the susceptibility of ankylosing spondylitis in Northern Chinese Han population. AB - OBJECTIVES: Previous Genome-wide association studies (GWAS) have demonstrated Interleukin-1 receptor 2 (IL-1R2) was strongly associated with susceptibility to ankylosing spondylitis (AS). The aim of this study was to replicate the association of IL-1R2 single-nucleotide polymorphisms (SNPs) with AS in the northern Han Chinese. METHODS: A total of 490 AS patients and 580 matched healthy controls were enrolled in our study. Six tagSNPs in IL-1R2: rs4851526, rs4851527, rs2302589, rs2072476, rs2072472, and rs2310173 were selected and genotyped by Taqman SNP genotyping method. The differences of allele and genotype frequencies were analyzed by use of PLINK 1.07. RESULTS: Logistic regression analysis showed that one tagSNP rs2302589 in IL-1R2 was significantly associated with AS susceptibility (OR 0.77, 95% CI = 0.64-0.92, P = 0.005). However, no significant association was observed on the other tagSNPs for AS risk. The haplotype analysis further showed that the haplotype "GCGCGG" of IL-1R2 was also associated with the increased risk of AS (OR 1.362, P = 0.0207). CONCLUSIONS: This is the first detection that the genetic variation rs2302589 in IL-1R2 gene was associated with AS in Northern Han Chinese. This result confirmed that IL-1R2 may be genetic biomarker for susceptibility to AS. PMID- 25736357 TI - Large-vessel involvement in granulomatosis with polyangiitis successfully treated with rituximab: A case report and literature review. AB - Granulomatosis with polyangiitis (GPA) is primary necrotizing vasculitis, which predominantly affects small to medium vessels. Herein, we describe a case of a 60 year-old female with GPA who developed inflammatory wall thickening localized in the aortic arch, upper abdominal aorta, and pulmonary artery. The wall thickening in the large vessels and other GPA lesions such as lung nodules and orbital mass had failed to respond to high-dose glucocorticoids combined with cyclophosphamide; however, all were successfully treated with rituximab. Our literature review identified 24 cases of large-vessel involvement associated with GPA. Luminal stenosis, occlusion, or wall thickening were observed in 8, periaortitis in 11, and aneurysms in 5 cases. The most commonly affected vessel was the abdominal aorta (12 cases), followed by the thoracic aorta (6 cases), subclavian artery (4 cases), and internal carotid artery (4 cases). Glucocorticoids were used in 23 cases, 20 of which received combination therapy with cyclophosphamide. Surgical or endovascular therapies were performed in 10 cases with aneurysmal dilatation. This is the first case showing the potential efficacy of rituximab for refractory large-vessel involvement associated with GPA. PMID- 25736358 TI - A case developing minimal change disease during the course of IgG4-related disease. AB - We describe a 66-year-old male with immunoglobulin G4-related disease (IgG4-RD) presenting with minimal change disease (MCD). Three years prior to this admission, the patient had been diagnosed with IgG4-RD. The development of sudden massive proteinuria (4+; 16.7 g/gCr) with a weight gain of 8 kg within a two-week period was noted, and nephrotic syndrome was suspected. The patient's serum IgG4 level did not increase and hypocomplementemia was not found. A renal biopsy showed no cellular infiltration in the renal interstitium, and no spiking or bubbling was found on periodic acid methenamine silver staining. On electron microscopy, foot process effacement was seen, but no subepithelial electron-dense deposits were found. The patient was diagnosed with MCD. Ten days after starting prednisolone (60 mg/day), proteinuria was negative. Since IgG4-RD and MCD share a T-helper 2-dominant immunoreaction, the development of MCD in IgG4-RD patients may reflect more than a mere coincidence. PMID- 25736359 TI - Testicular lymphocytic vasculitis treated with prednisolone and azathioprine. AB - Testicular vasculitis is a rare condition and little is known about its morphological features. Herein, we report a case of testicular lymphocytic vasculitis, which is rarely documented, in an elderly man. He presented with left testicular swelling and fever, but without any signs of other organ involvement. He was effectively treated with prednisolone and azathioprine. This case report offers information related to the disease course and the importance of biopsy. PMID- 25736360 TI - Real-world practice of obstetricians in respect of assays for antiphospholipid antibodies. AB - OBJECTIVE: The international classification criteria (CC) for definite antiphospholipid syndrome (APS) recommend confirmation of the sustained presence, for at least 12 weeks, of both lupus anticoagulant (LA), as determined by aPTT and RVVT, and anti beta2glycoprotein I (beta2GPI) or anticardiolipin (aCL) IgG and/or IgM. However, it remains unclear whether obstetricians comply with the aforementioned CC for the diagnosis of APS in daily clinical practice. We performed a nationwide survey to examine the attitudes of Japanese obstetricians toward the use of assays for antiphospholipid antibodies (aPLs). METHODS: A questionnaire was sent to 2,700 obstetric facilities where maternity checkups are carried out. The types of assays conducted for aPLs, ascertainment of persistence of the antibodies for at least 12 weeks, and the cutoff points used for the assays were examined. RESULTS: Of the facilities surveyed, 61.5% carried out the assay(s) only once. In regard to the type of assay performed, 97.1% carried out the assay for aCL IgG and/or beta2GPI-dependent aCL, while 67.9% performed the LA aPTT and/or LA-RVVT assay. Only 8.8% carried out assays for both LA. As for the cutoff points used, 98% of the facilities used lower cutoff points described in the manufacturers' manuals rather than the cutoff values recommended in the CC. CONCLUSION: Thus, only a limited number of facilities adhered precisely to the CC for the diagnosis of APS. Inappropriate treatment and unnecessary expense are potentially major concerns when facilities overdiagnose APS using lower cutoff points or without ascertaining the persistence of the antibodies for at least 12 weeks. On the other hand, some patients miss the opportunity to be treated for APS because of the absence of testing for LA. PMID- 25736361 TI - Operator-independent quantitative chest computed tomography versus standard assessment of interstitial lung disease related to systemic sclerosis: A multi centric study. AB - PURPOSE: Interstitial lung disease (ILD) related to systemic sclerosis (SSc) is assessed with pulmonary functional tests (PFTs) and semi-quantitative scores based on extent of ILD detectable on chest computed tomography (CT). CT quantitative indexes (QCTIs) are promising tools to assess extent of ILD. This study's aim is to evaluate the validity of QCTI compared with that of chest CT standard evaluation and PFTs. Moreover, QCTI differences between patients' subgroups according to prognostic stratifications were investigated. METHODS: ILD SSc of patients from six rheumatological clinics was routinely assessed with chest CT and PFTs. Patients were clustered according to prognosis based on functional and/or radiological examinations. Finally, chest CTs were processed with OsiriX in order to obtain QCTI. RESULTS: Two hundred fifty-seven SSc patients were enrolled. QCTI correlation between extent of ILD and PFTs range from - 0.60 to 0.58 and from - 0.54 to 0.52, respectively. The majority of QCTI have a different distribution in patients' subgroups based on prognosis. Most of QCTI discriminate patients with an ILD severity leading to a poor prognosis. CONCLUSIONS: QCTI assessment of ILD-SSc is comparable to the evaluation based on chest CT and/or PFTs. QCTI values corresponding to severe ILD were identified. QCTIs are excellent candidates for a new and more reliable SSc-ILD assessment. PMID- 25736362 TI - MicroRNA-124 involves in ankylosing spondylitis by targeting ANTXR2. AB - OBJECTIVES: A recent genome-wide association study or GWAS identified that anthrax roxin receptor 2 (ANTXR2) was one of the risk loci for ankylosing spondylitis (AS). Previous study also showed that ANTXR2 could potentially affect new bone formation. This study aimed to investigate the possible mechanisms of ANTXR2 involved in AS pathogenesis. METHODS: The expression level of ANTXR2 and miR-124 in peripheral blood was detected by quantitative real-time polymerase chain reaction or qRT-PCR. ANTXR2 was predicted to be a target gene of miR-124 by TargetScan, which was confirmed by luciferase reporter assays. Western blot analysis was used to further investigate the effect of miR-124 on c-Jun N terminal kinase (JNK) activation and evaluate the activated status of autophagy. RESULTS: We evidenced that ANTXR2 was downregulated and miR-124 was upregulated in peripheral blood from AS patients. Intriguingly, miR-124 targeted ANTXR2 and overexpression of miR-124 in Jurkat cells notably inhibited ANTXR2 expression. ANTXR2 inhibition by miR-124 promoted JNK activation and induced autophagy. CONCLUSIONS: Our results suggested that miR-124 might induce autophagy to participate in AS by targeting ANTXR2, which might be implicated in pathological process of AS. PMID- 25736363 TI - Decreased expression of alpha-enolase inhibits the proliferation of hypoxia induced rheumatoid arthritis fibroblasts-like synoviocytes. AB - OBJECTIVES: To investigate the effect of decreased alpha-enolase (ENO1) expression on rheumatoid arthritis fibroblasts-like synoviocytes (RA-FLSs) proliferation in response to hypoxia, and elucidate the possible mechanisms involved. METHODS: RA-FLSs and osteoarthritis fibroblasts-like synoviocytes (OA FLSs) were cultured in tri-gas incubators with different oxygen concentrations (3% O2, 7% O2, and 21% O2). 3% O2 (hypoxia) and 7% O2 conditions simulated intra articular oxygen concentrations as observed in RA and healthy individual, respectively. 21% O2 represented oxygen condition for normal cell culture. ENO1 knockdown FLSs were established using ENO1-siRNA. The expression level of ENO1 was detected using reverse transcription polymerase chain reaction or RT-PCR and Western blot. Proliferation and apoptosis of RA-FLSs and OA-FLSs were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium or MTS assay and flow cytometry, respectively. Western blot analysis was used to detect key proteins involved in apoptosis. RESULTS: ENO1 gene expression was remarkably upregulated, as well as its translation into protein, in RA-FLSs and OA-FLSs that were cultured in 3% O2 concentration. RA FLSs and OA-FLSs that were cultured under hypoxic conditions hyperproliferated compared with similar cells under normaxic conditions. Neither 7% O2 nor 21% O2 condition had any significant effect on ENO1 expression. ENO1-siRNA-transfected FLSs, but not control-siRNA FLSs, showed markedly decreased proliferation. Additionally, ENO1 expression was found to promote significantly higher expression levels of the anti-apoptotic proteins Bcl-2, surviving, and cyclinB1, but inhibited the expression of cleaved caspase3. CONCLUSION: ENO1 may be crucial in the regulation of the proliferation and survival of synovial fibroblasts. PMID- 25736364 TI - Predicting joint destruction in rheumatoid arthritis with power Doppler, anti citrullinated peptide antibody, and joint swelling. AB - OBJECTIVE: To determine combined evaluation of musculoskeletal ultrasonography (MSUS) and power Doppler (PD) signals, anti-citrullinated peptide antibody (ACPA), and other clinical findings improve the prediction of joint destruction in rheumatoid arthritis (RA). METHODS: We performed a retrospective study of 331 RA patients (female n = 280 and male n = 51, mean age: 57.9 +/- 13.2 years) who underwent MSUS from 2002 to 2012. Correlations with progression of joint destructions in 1,308 2nd and 3rd metacarpophalangeal (MCP) joints and various factors including PD signals of the same joints, clinical findings, age, disease duration at the study entry, gender, observation period, radiographic bone scores according to modified Sharp-van der Heijde methods, ACPA, and rheumatoid factor (RF) were analyzed in patient- and joint-based fashions, using univariate and multivariate logistic regression analyses and generalized linear mixed model. RESULTS: Patients' characteristics were as follows: mean disease duration: 5.7 +/ 7.5 years, observation period: 4.6 +/- 2.6 years, RF positivity: 79.9%, and ACPA positivity: 77.5%. PD-positive 2nd and 3rd joints showed higher rate of joint destruction, especially in ACPA-positive patients. Moreover, PD-positive joints in ACPA-positive patients showed joint destruction even in joints without swelling. Multivariate analysis determined PD, swollen joint (SJ), observation period, basal radiographic bone scores, and ACPA as independent risks for joint destruction. CONCLUSION: PD, SJ, basal radiographic bone scores, and ACPA are independent predictors for the joint destruction of 2nd and 3rd MCPs in RA; thus, considering these factors would be useful in daily practice. PMID- 25736365 TI - A novel rat model of hip pain by intra-articular injection of nerve growth factor characteristics of sensory innervation and inflammatory arthritis. AB - OBJECTIVES: To determine the direct effects of intra-articular injection of nerve growth factor (NGF) into normal rat hips and the time course of pain-related mediator appearance. METHODS: Using 36 numbers of 8-week-old male Sprague-Dawley rats, 30 MUl of 1% Fluoro-Gold solution (FG) (Sham-operated group; n = 12), 30 MUl of 1% FG with 50 MUg/ml NGF (NGF50 group; n = 12), and 30 MUl of 1% FG with 100 MUg/ml NGF (NGF100 group; n = 12) were injected into the left hip joints. Neurons in the dorsal root ganglion (DRG) labeled with FG, and FG and calcitonin gene-related peptide-immunoreactivity (CGRP-IR) were counted. The synovia in the left hip joint was examined histologically. RESULTS: The NGF50 and NGF100 groups showed evidence of synovitis without cartilage degeneration compared with the Sham-operated group. At 7 days, the proportions of CGRP-IR FG-labeled to total FG labeled neurons were 12%, 18%, and 36% in the Sham-operated, NGF50, and NGF100 groups, respectively. At 14 days, the proportions were 13%, 22%, and 35% in the Sham-operated, NGF50, and NGF100 groups, respectively. At 7 and 14 days, the NGF50 and NGF100 groups showed a significantly higher proportion of CGRP-IR FG labeled neurons than the Sham-operated group. CONCLUSIONS: Intra-articular administration of NGF into the hip joint produces a novel rat model for hip pain. PMID- 25736366 TI - Presence of enthesopathy demonstrated with ultrasonography in systemic sclerosis. AB - OBJECTIVE: The aim of this study was to sonographically assess the presence and distribution of enthesopathy in systemic sclerosis (SSc). METHODS: Consecutive patients with SSc and age-matched healthy controls were included in this study. All of the patients met the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc. Six entheses sites were evaluated using gray scale and Doppler ultrasonographies (USs) with a linear transducer and were scored using the Madrid Sonography Enthesitis Index (MASEI). RESULTS: We evaluated 52 patients with SSc (46.10 +/- 13.42 years) and 41 healthy controls (49.59 +/- 9.35 years). Patients with SSc had significantly higher MASEI scores than the healthy controls. Except for plantar aponeurosis, the tendons and ligaments were thicker in the SSc group. In the SSc group, there were 25 (48.1%) diffuse cutaneous SScs and 22 (42.3%) limited cutaneous SScs. Variables such as age, BMI, disease duration, diagnostic delay and MASEI scores were similar in subgroups of SSc. There was a positive correlation between MASEI score and age, modified Rodnan's skin score and dyspnea grade, and a negative correlation with handgrip strength. CONCLUSION: To the best of our knowledge, this is the first study showing the presence of enthesopathy in patients with SSc using US. Enthesopathy should be kept in mind in symptomatic patients with SSc; additionally, it can be easily identified with US. PMID- 25736367 TI - High circulating level of interleukin-18 in patients with primary Sjogren's syndrome is associated with disease activity. PMID- 25736368 TI - Risk of Wernicke's encephalopathy and cardiac disorders in patients with myeloproliferative neoplasm. AB - The objectives of the study were to estimate the incidence of Wernicke's encephalopathy (WE) and cardiac disorders among patients with myeloproliferative neoplasms (MPN), and compare it with those without MPN. A total of 39,761 MPN patients were identified from the US Marketscan database. Approximately 27% of them were 65+ years of age, and 51% were male. Patients with MPN had higher rates of WE, compared to those without MPN (MPN vs. non-MPN: 1.09 vs. 0.39/1000 person year, adjusted HR=2.19, 95%CI 1.43-3.34). Patients with MPN also had higher rates of cardiac events (congestive heart failure: MPN vs. non-MPN: 9.27 vs. 3.70/1000 person-year, adjusted HR=1.64, 95%CI 1.42-1.88; acute myocardial infarction: MPN vs. non-MPN: 10.45 vs. 5.02/1000 person-year, adjusted HR=1.44, 95%CI 1.27, 1.63; cardiac arrhythmia: MPN vs. non-MPN: 106.5 vs. 53.9/1000 person-year, adjusted HR=1.42, 95%CI 1.36-1.48). Physicians who care for patients with MPN should be aware of increased risk of WE and cardiac disorders in this population. PMID- 25736369 TI - Prevalence of an inherited cancer predisposition syndrome associated with the germ line TP53 R337H mutation in Paraguay. AB - The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer, and the germline TP53 R337H mutation is the most common mutation reported to date. However, this mutation is associated with a lower cumulative lifetime cancer risk than other mutations in the p53 DNA-binding domain. A detailed statistical analysis of 171,500 DNA tests in Brazilian neonates found that 0.27% of the general population is positive for this mutation, and some of the estimated 200,000 Brazilian R337H carriers in southern and southeastern Brazil have already developed cancer. The present study was designed to estimate R337H prevalence in neighboring Paraguay. To address this question, 10,000 dried blood samples stored in Guthrie cards since 2008 were randomly selected from the Paraguayan municipalities located at the border with Brazil. These samples were tested for R337H mutation using the PCR-restriction fragment length polymorphism assay. This germline mutation was detected in five samples (5/10,000), indicating that the total number of R337H carriers in Paraguay may be as high as 3500. Previous studies have shown that other countries (i.e., Portugal, Spain, and Germany) presented one family with this mutation, leading us to conclude that, besides Brazil and Paraguay, other countries may have multiple families carrying this mutation, which is an inherited syndrome that is difficult to control. PMID- 25736370 TI - Loci and candidate gene identification for resistance to Sclerotinia sclerotiorum in soybean (Glycine max L. Merr.) via association and linkage maps. AB - Soybean white mold (SWM), caused by Sclerotinia sclerotiorum ((Lib.) W. Phillips), is currently considered to be the second most important cause of soybean yield loss due to disease. Research is needed to identify SWM-resistant germplasm and gain a better understanding of the genetic and molecular basis of SWM resistance in soybean. Stem pigmentation after treatment with oxaloacetic acid is an effective indicator of resistance to SWM. A total of 128 recombinant inbred lines (RILs) derived from a cross of 'Maple Arrow' (partial resistant to SWM) and 'Hefeng 25' (susceptible) and 330 diverse soybean cultivars were screened for the soluble pigment concentration of their stems, which were treated with oxalic acid. Four quantitative trait loci (QTLs) underlying soluble pigment concentration were detected by linkage mapping of the RILs. Three hundred and thirty soybean cultivars were sequenced using the whole-genome encompassing approach and 25 179 single-nucleotide polymorphisms (SNPs) were detected for the fine mapping of SWM resistance genes by genome-wide association studies. Three out of five SNP markers representing a linkage disequilibrium (LD) block and a single locus on chromosome 13 (Gm13) were significantly associated with the soluble pigment content of stems. Three more SNPs that represented three minor QTLs for the soluble pigment content of stems were identified on another three chromosomes by association mapping. A major locus with the largest effect on Gm13 was found both by linkage and association mapping. Four potential candidate genes involved in disease response or the anthocyanin biosynthesis pathway were identified at the locus near the significant SNPs (<60 kbp). The beneficial allele and candidate genes should be useful in soybean breeding for improving resistance to SWM. PMID- 25736371 TI - Amodiaquine-Ciprofloxacin: a potential combination therapy against drug resistant malaria. AB - Emergence of malaria parasites resistant to artemisinin necessitates the need for development of new antimalarial therapies. Ciprofloxacin (CFX) a second generation quinolone antibiotic possesses some antimalarial activities. We investigated the in vivo antimalarial activities of CFX in combination with amodiaquine in mice infected with chloroquine-resistant Plasmodium berghei ANKA. Animals were treated orally with 80 or 160 mg kg-1 body weight of CFX alone given twice daily or in combination with amodiaquine (AQ) 10 mg kg-1 body weight. Parasitological activity and survival of the animals were assessed over 21 days. Peak parasitaemia in the untreated control group was 72.51%. Treatment with AQ alone resulted in clearance of parasitaemia by day 4 while treatment with CFX 80 and 160 mg kg-1 alone suppressed parasitaemia by 13.94-54.64% and 35.6-92.7%, respectively. However, the combination of CFX with AQ significantly enhanced response of infection in the animals to treatment (P < 0.05) resulting in complete resolution of parasitaemia throughout follow up period with CFX 160 mg kg-1, delayed recrudescence time with CFX 80 mg kg-1 and significant increase in survival rate of the animals. The results demonstrate beneficial interaction between AQ and CFX which may provide a clinically relevant antimalarial/antibiotic therapeutic option in the management of malaria. PMID- 25736372 TI - Stimulating new and innovative perspectives on old and persistent problems: a commentary on "Attempters adherers and non-adherers: latent profile analysis of CPAP use with correlates" by Wohlgemuth et al. PMID- 25736373 TI - Magnetic resonance imaging abnormalities of peripheral nerve and muscle are common in amyotrophic lateral sclerosis and share features with multifocal motor neuropathy. AB - INTRODUCTION: Magnetic resonance imaging (MRI) of peripheral nerve and muscle in patients with amyotrophic lateral sclerosis (ALS) may be performed to investigate alternative diagnoses, including multifocal motor neuropathy (MMN). MRI findings of peripheral nerve and muscle are not well described in these conditions, making interpretation of results difficult. METHODS: We examined systematically the peripheral nerve and muscle MRI findings in patients with ALS (n = 60) and MMN (n = 8). RESULTS: In patients with ALS and MMN, abnormal MRIs were common (85% and 75%, respectively), but did not correlate with disease severity. Peripheral nerve MRI abnormalities were similar in frequency (ALS 58%, MMN 63%), with most changes being of mild to moderate severity. Muscle MRI changes were more common in ALS (57% vs. 33%), and no muscle atrophy was seen in patients with MMN. CONCLUSION: MRI abnormalities of peripheral nerve and muscle in ALS and MMN are common and share some features. PMID- 25736374 TI - Polyvinyl pyrrolidone capped fluorescent anthracene nanoparticles for sensing fluorescein sodium in aqueous solution and analytical application for ophthalmic samples. AB - Based on the known complexation ability between polyvinyl pyrrolidone (PVP) and fluorescein sodium (FL Na(+)), fluorescent PVP capped anthracene nanoparticles (PVP-ANPs) were prepared using a reprecipitation method for detection of fluorescein in aqueous solution using the fluorescence resonance energy transfer (FRET) approach. A dynamic light scattering histogram of PVP-ANPs showed narrower particle size distribution and the average particle size was 15 nm. The aggregation-induced enhanced emission (AIEE) of PVP-ANPs was red shifted from its monomer by 1087.22 cm(-1). The maximum emission was seen to occur at 420 nm. The presence of FL Na(+) in the vicinity of PVP-ANPs quenched the fluorescence of PVP ANPs because of its adsorption on the surface of PVP-ANPs in aqueous suspension. The FL Na(+) and PVP-ANPs were brought close enough, typically to 7.89 nm, which was less than the distance of 10 nm that is required between the energy donor acceptor molecule for efficient FRET. The quenching results fit into the Stern Volmer relationship even at temperatures greater than ambient temperatures. The thermodynamic parameters determined from FRET results helped to propose binding mechanisms involving hydrophobic and electrostatic molecular interaction. The fluorescence quenching results were used further to develop an analytical method for estimation of fluorescein sodium from ophthalmic samples available commercially in the market. PMID- 25736375 TI - SIGNing a symbiotic treaty with gut microbiota. AB - Beneficial microbes hold great promise for the treatment of a wide range of immune and inflammatory disorders. In this issue of The EMBO Journal, Lightfoot and colleagues report how the food-grade bacterium Lactobacillus acidophilus helps the immune system to limit experimental colitis in mice through interaction between SIGNR3 and surface layer protein A (SlpA) in L. acidophilus. These results pave the way for future development of novel therapies for inflammatory diseases, including inflammatory bowel disease. PMID- 25736376 TI - Astro-logics with microRNAs. PMID- 25736377 TI - Interrupting synoviolin play at the ER: a plausible action to elevate mitochondrial energetics and silence obesity. AB - Obesity is a global concern, which has been linked to increased risk for cardiovascular disease, type 2 diabetes, atherosclerosis,non-alcoholic fatty liver, and cancer. In this issue of The EMBO Journal,Fujita et al (2015) describe the role of an endoplasmic reticulum (ER)-resident E3ubiquitin ligase, synoviolin, and its ability to control body weight and energy expenditure by targeting PGC-1b, a transcriptional modulator of mitochondrial oxidative metabolism. PMID- 25736378 TI - Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice. AB - In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence associated beta-gal (SA-beta-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, focal adhesion kinase, and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies, which rely on senescence induction by inhibiting Shp2 or controlling its target gene products, may be useful in blocking breast cancer. PMID- 25736379 TI - Blood transfusions caused nearly 9000 cases of HIV in India in past five years. PMID- 25736381 TI - Factors that determine cancer treatment choice among minority groups. PMID- 25736380 TI - OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies. AB - We examined the interaction between OSU-03012 (also called AR-12) with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone glucose-regulated protein (GRP78)/BiP/HSPA5 in the cellular response. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill stem-like GBM cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of GRP78 and other HSP70 and HSP90 family chaperone proteins. Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced PERK-eIF2alpha-ATF4-CHOP signaling and was blocked by GRP78 over-expression. In vivo OSU-03012/sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of ABCB1 and ABCG2 in the normal brain. The combination of OSU-03012/sildenafil synergized with low concentrations of sorafenib to kill tumor cells, and with lapatinib to kill ERBB1 over-expressing tumor cells. In multiplex assays on plasma and human tumor tissue from an OSU-03012/sildenafil treated mouse, we noted a profound reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers for potentially suppressing the killing response. Inhibition of FGFR signaling and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil lethality. PMID- 25736382 TI - Oncology payment reform and drug reimbursement in the proper perspective. PMID- 25736383 TI - Wide Variation in the Diffusion of a New Technology: Practice-Based Trends in Intensity-Modulated Radiation Therapy (IMRT) Use in the State of Michigan, With Implications for IMRT Use Nationally. AB - PURPOSE: To characterize the adoption and variation of intensity-modulated radiation therapy (IMRT) use in the state of Michigan. METHODS: As a certificate of-need state, Michigan requires every radiation oncology facility to report the number of external-beam and IMRT treatments delivered annually. We examined the percentage of treatments delivered using IMRT across centers from 2005 to 2012. We constructed a repeated-measures longitudinal linear regression model to evaluate bivariable and multiple variable associations with IMRT use. RESULTS: The median proportion of treatments delivered with IMRT rose from 16% in 2005 to 42% in 2012. All treatment centers in the state of Michigan possessed the capacity to deliver IMRT as of 2009. The fraction of treatments delivered with IMRT varied between 23% and 96% (standard deviation, 19%) in the lowest- and highest-use centers in 2012. Higher IMRT use was significantly associated with freestanding facilities and year of treatment, with a trend toward higher IMRT use in academic centers and low-volume facilities. CONCLUSION: IMRT use grew significantly across the state of Michigan over time, with four-fold variability among centers, which was related to facility characteristics. These data provide no indication of an ideal or appropriate level of IMRT use. Rather, the wide variation in IMRT use among centers indicates a lack of consensus regarding the situations in which IMRT provides significant clinical benefit. This supports further research and interventions to ensure that patients receive appropriate care, regardless of where they are treated. PMID- 25736384 TI - Reply to M. Thompson et Al. PMID- 25736385 TI - HemOnc.org: A Collaborative Online Knowledge Platform for Oncology Professionals. AB - PURPOSE: Cancer care involves extensive knowledge about numerous chemotherapy drugs and chemotherapy regimens. This information is constantly evolving, and there has been no freely available, comprehensive, centralized repository of chemotherapy information to date. METHODS: We created an online, freely accessible, ad-free, collaborative wiki of chemotherapy information entitled HemOnc.org to address the unmet need for a central repository of this information. This Web site was developed with wiki development software and is hosted on a cloud platform. Chemotherapy drug and regimen information (including regimen variants), as well as other information of interest to hematology/oncology professionals, is housed on the site in a fully referenced and standardized format. Accredited users are allowed to freely contribute information to the site. RESULTS: From its inception in November 2011, HemOnc.org has grown rapidly and most recently has detailed information on 383 drugs and 1,298 distinct chemotherapy regimens (not counting variants) in 92 disease subtypes. There are regularly more than 2,000 visitors per week from the United States and international locations. A user evaluation demonstrated that users find the site useful, usable, and recommendable. CONCLUSION: HemOnc.org is now the largest free source of chemotherapy drug and regimen information and is widely used. Future enhancements, including more metadata about drugs and increasingly detailed efficacy and toxicity information, will continue to improve the value of the resource. PMID- 25736387 TI - Rapid synthesis of flexible conductive polymer nanocomposite films. AB - Polymer nanocomposite films with nanoparticle-specific properties are sought out in novel functional materials and miniaturized devices for electronic and biomedical applications. Sensors, capacitors, actuators, displays, circuit boards, solar cells, electromagnetic shields and medical electrodes rely on flexible, electrically conductive layers or films. Scalable synthesis of such nanocomposite films, however, remains a challenge. Here, flame aerosol deposition of metallic nanosliver onto bare or polymer-coated glass substrates followed by polymer spin-coating on them leads to rapid synthesis of flexible, free-standing, electrically conductive nanocomposite films. Their electrical conductivity is determined during their preparation and depends on substrate composition and nanosilver deposition duration. Accordingly, thin (<500 nm) and flexible nanocomposite films are made having conductivity equivalent to metals (e.g. 5 * 10(4) S cm(-1)), even during repetitive bending. PMID- 25736386 TI - Exploring community pharmacists' experiences of surveying patients for drug utilization research purposes. AB - BACKGROUND: Patient self-reported data are important in drug utilization research, but often logistically difficult to collect. During 2006-2012, 72 Swedish community pharmacies regularly collected such data through structured survey interviews at the pharmacy counter, performed by the dispensing pharmacists. This study is part of a validation of that data acquisition method. OBJECTIVES: (1) To explore the experiences of the pharmacists involved, (2) to explore a random or systematic exclusion of eligible patients by the pharmacists, and (3) to find areas of improvement to the applied method of surveying. SETTING: 72 Swedish community pharmacies, distributed all over the country. METHOD: (a) A questionnaire was distributed to approximately 400 dispensing pharmacists at the pharmacies conducting the patient surveys; (b) semi-structured telephone interviews conducted with 19 pharmacists at 12 of the pharmacies. MAIN OUTCOME MEASURE: Proportions of pharmacists reporting positive and negative experiences of structured survey interviews, the nature of their experiences, proportion of pharmacists reporting to avoid survey interviews and reasons for doing so, and suggested areas of improvement. RESULTS: A total of 126 pharmacists (32 %) completed the questionnaire. A majority (82 %) reported positive experiences of interviewing. In addition to the data generated as the primary goal of surveying, secondary benefits such as an improved patient-pharmacist dialogue and an increased detection and resolution of drug related problems were reported. However, a majority (63 %) of the pharmacists also reported negative experiences related to a perceived lack of time to fulfil one's professional obligations. Almost half of the pharmacists (44 %) in the survey admitted that they occasionally avoided interviewing eligible patients, due to the immediate increase in work load. The limited availability of staff resources was the most apparent area of improvement. CONCLUSION: Under certain conditions, community pharmacies are feasible as a setting for conducting patient surveys in drug utilization research, and dispensing pharmacists suitable for conducting them. When regular dispensing staff perform the survey interviews as a part of the drug dispensing process, additional resources to manage the immediate increase in work load have to be considered. Otherwise, data quality may be compromised. PMID- 25736388 TI - Ultrasound and magnetic resonance imaging of healthy paediatric ankles and knees: a baseline for comparison with haemophilic joints. AB - The study was undertaken to document cartilage and soft tissue changes/findings in ankles and knees of normal children of different age groups to be used for comparison in the assessment of children with haemophilia. Cartilage thickness and soft tissue changes were recorded at predetermined sites of ankles/knees on both US and MRI in healthy boys in three age groups: 7-9; 10-14; and 15-18 years. To assess the validity of the ultrasound and MRI measurements, an ex vivo study was done using agar phantoms with techniques and scanners similar to those applied in vivo. Twenty (48%) knees and 22 (52%) ankles of 42 boys, were evaluated. There was a reduction in the thickness of joint cartilage with age. A difference in cartilage measurements was noted in most sites between the age groups on both US and MRI (P < 0.05 each), but such difference was not noted for joint fluid in ankles or knees (P = 0.20, P = 0.68 or P = 0.75, P = 0.63 for US, MRI, respectively). Although cartilage measurements were smaller on US than on MRI for both ankles and knees (P < 0.05 each), this observation was not recorded for fluid in knees (P = 0.02). For diminutive measurements (2 mm) mean US measurements were smaller than corresponding phantom's measurements, P = 0.02. Age-related measurements were noted for cartilage thickness on US and MRI in ankles and knees. US measurements were smaller than corresponding MRI measurements at most joint sites, which were supported by results on small diameter phantoms. PMID- 25736389 TI - The impact of a brief gratitude intervention on subjective well-being, biology and sleep. AB - This randomised controlled experiment tested whether a brief subjective well being intervention would have favourable effects on cardiovascular and neuroendocrine function and on sleep. We compared 2 weeks of a gratitude intervention with an active control (everyday events reporting) and no treatment conditions in 119 young women. The treatment elicited increases in hedonic well being, optimism and sleep quality along with decreases in diastolic blood pressure. Improvements in subjective well-being were correlated with increased sleep quality and reductions in blood pressure, but there were no relationships with cortisol. This brief intervention suggests that subjective well-being may contribute towards lower morbidity and mortality through healthier biological function and restorative health behaviours. PMID- 25736390 TI - Everyday discrimination and physical health: Exploring mental health processes. AB - Goals of this study were to examine the mental health processes whereby everyday discrimination is associated with physical health outcomes. Data are drawn from a community health survey conducted with 1299 US adults in a low-resource urban area. Frequency of everyday discrimination was associated with overall self-rated health, use of the emergency department, and one or more chronic diseases via stress and depressive symptoms operating in serial mediation. Associations were consistent across members of different racial/ethnic groups and were observed even after controlling for indicators of stressors associated with structural discrimination, including perceived neighborhood unsafety, food insecurity, and financial stress. PMID- 25736391 TI - The relationship between suicidal behaviors and atopic dermatitis in Korean adolescents. AB - Atopic dermatitis is a common skin disease in adolescents, which may have a negative effect on the mental and emotional health. We investigated the relationship between atopic dermatitis and suicidal behaviors in Korean adolescents. Participants included 74,186 adolescents (38,221 boys and 35,965 girls) in middle and high school who completed the Eighth Korea Youth Risk Behavior Web-Based Survey. There were significant associations between atopic dermatitis and suicidal behaviors for girls. The overestimation of weight perception might have an additive impact on suicidal risk among girls. However, there were no significant associations between atopic dermatitis and suicidal behaviors in boys. PMID- 25736392 TI - Preparing for emergencies in a travel medicine context - apps and movies. PMID- 25736393 TI - Competition between cap and basal actin fiber orientation in cells subjected to contact guidance and cyclic strain. AB - In vivo, adhesive cells continuously respond to a complex range of physical cues coming from the surrounding microenvironment by remodeling their cytoskeleton. Topographical and mechanical cues applied separately have been shown to affect the orientation of the actin stress fibers. Here we investigated the combined effects of contact guidance by topographical cues and uniaxial cyclic strain on actin cytoskeleton orientation of vascular derived cells. We devised a modular setup of stretchable circular and elliptic elastomeric microposts, capable to expose the cells to both contact guidance and uniaxial cyclic strain. A competition occurs between these cues when both contact guidance and strain are oriented along the same direction. For the first time we show that this competition originates from the distinct response of perinuclear basal and actin cap fibers: While basal fibers follow the contact guidance cue, actin cap fibers respond to the cyclic strain by strain avoidance. We also show that nuclear orientation follows actin cap fiber orientation, suggesting that actin cap fibers are responsible for cellular reorientation. Taken together, these findings may have broad implications in understanding the response of cells to combined topographical and mechanical cues. PMID- 25736394 TI - Comparison of structural, thermodynamic, kinetic and mass transport properties of Mg(2+) ion models commonly used in biomolecular simulations. AB - The prevalence of Mg(2+) ions in biology and their essential role in nucleic acid structure and function has motivated the development of various Mg(2+) ion models for use in molecular simulations. Currently, the most widely used models in biomolecular simulations represent a nonbonded metal ion as an ion-centered point charge surrounded by a nonelectrostatic pairwise potential that takes into account dispersion interactions and exchange effects that give rise to the ion's excluded volume. One strategy toward developing improved models for biomolecular simulations is to first identify a Mg(2+) model that is consistent with the simulation force fields that closely reproduces a range of properties in aqueous solution, and then, in a second step, balance the ion-water and ion-solute interactions by tuning parameters in a pairwise fashion where necessary. The present work addresses the first step in which we compare 17 different nonbonded single-site Mg(2+) ion models with respect to their ability to simultaneously reproduce structural, thermodynamic, kinetic and mass transport properties in aqueous solution. None of the models based on a 12-6 nonelectrostatic nonbonded potential was able to reproduce the experimental radial distribution function, solvation free energy, exchange barrier and diffusion constant. The models based on a 12-6-4 potential offered improvement, and one model in particular, in conjunction with the SPC/E water model, performed exceptionally well for all properties. The results reported here establish useful benchmark calculations for Mg(2+) ion models that provide insight into the origin of the behavior in aqueous solution, and may aid in the development of next-generation models that target specific binding sites in biomolecules. PMID- 25736395 TI - Lipofuscin in saliva and plasma and its association with age in healthy adults. AB - BACKGROUND AND AIM: To compare blood and salivary levels of lipofuscin in healthy adults and to analyze the relationship between the lipofuscin level and the healthy adults' age. METHODS: One hundred and twenty-two healthy volunteers were recruited and divided into three groups according to their age: young (n = 42, 20 44 years old), middle-aged (n = 51, 45-59 years old), and elderly (n = 29, 60-74 years old). One ml saliva and 5 ml whole blood were collected from each person. An ELISA kit was used to measure both the plasma and salivary lipofuscin levels. The differences between the groups were compared with independent-sample t test, and the relationship between the salivary lipofuscin level and the age was assessed with linear regression analysis. RESULTS: The mean +/- SD of the lipofuscin level in the saliva and plasma of 122 subjects was 68.93 +/- 1.32 and 78.05 +/- 1.75 MUmol/l, respectively. No gender-dependent differences were observed in either the salivary or the plasma lipofuscin level (saliva: p = 0.443, plasma: p = 0.459). The salivary and plasma lipofuscin levels of the elderly subjects were significantly higher than those of the young (saliva: 80.72 +/- 13.53 mmol/l versus 59.12 +/- 1.92 mmol/l, p = 0.0003; plasma: 93.31 +/- 3.14 mmol/l versus 67.43 +/- 2.54 mmol/l, p = 0.0002) and middle-aged (saliva: 80.72 +/- 13.53 mmol/l versus 70.31 +/- 11.17 mmol/l, p = 0.0004; plasma: 93.31 +/- 3.14 mmol/l versus 78.12 +/- 2.40 mmol/l, p = 0.0002) subjects. Similarly, the salivary and plasma lipofuscin levels of the middle-aged subjects were significantly higher than those of the young subjects (saliva: 70.31 +/- 11.17 mmol/l versus 59.12 +/- 1.92 mmol/l, p < 0.0001; plasma: 78.12 +/- 2.40 mmol/l versus 67.43 +/- 2.54 mmol/l, p = 0.0019). The lipofuscin levels in the saliva and plasma were significantly positively correlated with the subject age (r = 0.551, p = 0.0001; r = 0.528, p < 0.0001). Furthermore, the salivary lipofuscin level and plasma lipofuscin level also were found to have a positive correlation (r = 0.621, p < 0.0001). CONCLUSION: No gender-dependent differences were observed in either the salivary or plasma lipofuscin levels. The salivary and plasma lipofuscin levels were positively correlated, and the age is positively correlated with lipofuscin content in saliva. PMID- 25736396 TI - Prediction of one-repetition maximum from submaximal ratings of perceived exertion in older adults pre- and post-training. AB - BACKGROUND: Individual's one-repetition maximum (1-RM) is required to calculate and prescribe intensity for resistance training, while testing protocols enhance the risk of injuries and are time-consuming. AIMS: The aim of the present study was to assess the accuracy of 1-RM prediction from ratings of perceived exertion (RPE) of resistance exercises performed at submaximal sets (intensity and volume) in older adult males before and after a 12-week rehabilitation program. METHODS: 18 untrained subjects (70.4 +/- 4.5 years) first completed a 1-RM direct assessment with a horizontal leg press pre- and post-training. Thereafter, participants performed, in a random order, 2-repetition sets with loads unknown to them (corresponding to 20, 45 and 70 % of 1-RM). The RPE was recorded immediately after the sets. That RPE associated to its corresponding load was subjected to a linear regression analysis to extrapolate the maximal RPE score and its corresponding 1-RM. RESULTS: RPE and relative intensities of sets appeared related pre- [r (2) = 0.59, standard error of estimate (SEE) = 13.3 %] and post-training (r (2) = 0.83, SEE = 8.1 %). Differences between measured and predicted 1-RM were reduced from the beginning to the end of training but standard deviations remained high (17.4 +/- 11.8 vs. 4.2 +/- 11.1 kg). Pre training, 1-RM expressed relatively to body weight was negatively related with the errors of 1-RM predictions (r (2) = 0.39, p = 0.03). CONCLUSIONS: In older subjects, RPE may be used to predict 1-RM; however, the predicted value deviates considerably from the measured one, necessitating cautious application. Importantly, this method allows to capture training-induced change in 1-RM, thus making possible assessing training's effectiveness and allowing its modification if necessary. PMID- 25736397 TI - Efficacy of once-daily administration of udenafil for 24 weeks on erectile dysfunction: results from a randomized multicenter placebo-controlled clinical trial. AB - INTRODUCTION: The method of administration of oral phosphodiesterase-5 inhibitors has been expanded to once-daily repeated administration with lower initial dosage than on-demand administration. AIM: The aim of this study was to evaluate the efficacy and safety of once-daily udenafil as a treatment for erectile dysfunction (ED) for intermediate-term period. METHODS: This multicenter, randomized, double-blind clinical trial included 346 ED patients (placebo, udenafil 50 mg, udenafil 75 mg). Subjects were treated with each medication once daily for 24 weeks. MAIN OUTCOME MEASURES: Subjects were asked to complete the International Index of Erectile Function (IIEF)-erectile function (EF) domain at baseline, 12 weeks, and 24 weeks and the development of adverse drug reactions (ADRs) was inspected. RESULTS: Both dosages of udenafil induced a significant increase in IIEF-EF compared with placebo at both 12 and 24 weeks. When patients were divided according to the severity of baseline EF score, significant improvement was observed only with udenafil 75 mg regardless of the degree of ED. At 24 weeks, the proportions of patients who reported a return to normal EF (IIEF EF over 26) were 39.1% for udenafil 50 mg and 47.0% for udenafil 75 mg. In terms of safety, ADRs were observed in 6.1%, 12.9%, and 17.9% for placebo, udenafil 50 mg, and 75 mg, respectively. Although a statistically higher rate of ADRs was observed in the udenafil 75 mg group (P = 0.024), the majority were mild and recovered without treatment. CONCLUSIONS: Once-daily administration of udenafil 50 mg and 75 mg for 24 weeks resulted in improvement of EF. In particular, udenafil 75 mg improves EF regardless of the baseline degree of ED. PMID- 25736398 TI - 4-Nitro-3-phenylphenol has both androgenic and anti-androgenic-like effects in rats. AB - To investigate the effect of endocrine disruption of 4-nitro-3-phenylphenol (PNMPP) on immature male Wistar-Imamichi rats, the rat pituitary was exposed to PNMPP (10(-5)-10(-9) M) for 24 h with or without gonadotropin-releasing hormone (GnRH) in experiment I. In addition, the Leydig cells (10(-5)-10(-9) M) were exposed to PNMPP for 24 h with or without human chronic gonadotropin (hCG) in experiment II. Our results showed that the PNMPP at 10(-5)-10(-7) M suppressed follicle-stimulating hormone (FSH) and luteinizing hormone (LH) productions from GnRH-stimulated pituitary cells. At the same time, PNMPP 10(-5)-10(-7) M induced an increase in testosterone production from the Leydig cells treated with or without hCG. Based on our results, it can be concluded that that PNMPP might have both androgen agonist action by decreasing FSH and LH production in the pituitary and anti-androgenic action by increasing testosterone production in the Leydig cell. PMID- 25736400 TI - Three cases of severe hyponatremia during a river run in Grand Canyon National Park. AB - We present 3 cases of severe hyponatremia occurring on a commercially guided river rafting trip on the Colorado River in Grand Canyon National Park. All 3 women appeared to have been overhydrating because of concern about dehydration and required evacuation within 24 hours of each other after the staggered onset of symptoms, which included fatigue and emesis progressing to disorientation or seizure. Each was initially transferred to the nearest hospital and ultimately required intensive care. Imaging and laboratory data indicated all 3 patients had hypervolemic hyponatremia. Unlike the well-documented exercise-associated hyponatremia cases commonly occurring in prolonged endurance athletic events, these 3 unique cases of acute hyponatremia were not associated with significant exercise. The cases illustrate the diagnostic and treatment challenges related to acute hyponatremia in an austere setting, and underscore the importance of preventive measures focused on avoidance of overhydration out of concern for dehydration. PMID- 25736401 TI - Development of an improved bone washing and demineralisation process to produce large demineralised human cancellous bone sponges. AB - Shaped demineralised bone matrices (DBM) made from cancellous bone have important uses in orthopaedic and dental procedures, where the properties of the material allow its insertion into confined defects, therefore acting as a void filler and scaffold onto which new bone can form. The sponges are often small in size, <1.0 cm(3). In this study, we report on an improved bone washing and demineralisation process that allows production of larger DBM sponges (3.375 or 8.0 cm(3)) from deceased donor bone. These sponges were taken through a series of warm water washes, some with sonication, centrifugation, 100 % ethanol and two decontamination chemical washes and optimally demineralised using 0.5 N hydrochloric acid under vacuum. Demineralisation was confirmed by quantitative measurement of calcium and qualitatively by compression. Protein and DNA removal was also determined. The DBM sponges were freeze dried before terminal sterilisation with a target dose of 25 kGy gamma irradiation whilst frozen. Samples of the sponges were examined histologically for calcium, collagen and the presence of cells. The data indicated lack of cells, absence of bone marrow and a maximum of 1.5 % residual calcium. PMID- 25736399 TI - In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma. AB - CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [(68)Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [(68)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [(68)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [(18)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34(+) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [(68)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases. PMID- 25736402 TI - Evaluation of serum brain-derived neurotrophic factor levels in type 2 diabetes mellitus patients with and without depressive symptoms. PMID- 25736403 TI - Disturbance of hippocampal H2S generation contributes to CUMS-induced depression like behavior: involvement in endoplasmic reticulum stress of hippocampus. AB - The chronic unpredictable mild stress (CUMS) model is a widely used experimental model of depression. Exogenous stress-induced neuronal cell death in the hippocampus is closely associated with the pathogenesis of depression. Excessive and prolonged endoplasmic reticulum (ER) stress triggers cell death. Hydrogen sulfide (H2S), the third endogenous signaling gasotransmitter, plays an important role in brain functions as a neuromodulator and a neuroprotectant. We hypothesized that the disturbance of endogenous H2S generation and ER stress in the hippocampus might be involved in CUMS-induced depression-like behaviors. Thus, the present study focused on whether CUMS disturbs the generation of endogenous H2S and up-regulates ER stress in the hippocampus and whether exogenous H2S prevents CUMS-induced depressive-like behaviors. Results showed that CUMS-treated rats exhibit depression-like behavior and hippocampal ER stress responses including up-regulated levels of glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and cleaved caspase-12 expression, while the endogenous generation of H2S in the hippocampus is suppressed in CUMS-treated rats. Furthermore, exogenous H2S prevents CUMS-induced depression-like behavior. These data indicated that CUMS-induced depression-like behaviors are related to the disturbance of endogenous H2S generation and ER stress in the hippocampus and suggested that endogenous H2S and ER stress are novel treatment targets of depression. PMID- 25736404 TI - Distribution and expression of Pen-2 in the central nervous system of APP/PS1 double transgenic mice. AB - The gamma-secretase complex catalyzes the final cleavage step of amyloid beta protein precursor (APP) to generate amyloid beta (Abeta) peptide, a pathogenic component of senile plaques in the brain of Alzheimer's disease (AD) patients. Recent studies have shown that presenilin enhancer-2 (Pen-2), presenilin (PS, including PS1 and PS2), nicastrin, and anterior pharynx-defective 1 are essential components of the gamma-secretase. The structure and function of Pen-2 in vitro have been well defined. However, little is known about the neuroanatomical distribution and expression of Pen-2 in the central nervous system (CNS) of AD model mice. We report here, using various methods such as immunohistochemical staining and immunoblotting, that Pen-2 is widely expressed at specific neuronal cells of major areas in AD model mice, including the olfactory bulb, basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum, brainstem, and spinal cord. It is co-expressed with PS1 in specific neuronal cells in mouse brain. Pen-2 is distributed much more extensively than extracellular amyloid deposits, suggesting the importance of other factors in localized amyloid deposition. Pen-2 is localized predominantly in cell membrane and cytoplasma in adult AD mice, but only distributed at cell membrane in controls. At the early stages of postnatal development, the expression level of Pen-2 is relatively high in CNS, but declines, gradually in adult mice. The present study provides an anatomical basis for Pen-2 as a key component of gamma secretase complex in the brain of developing and adult mice, and Pen-2 might be closely related to Abeta burden in aging nervous system. PMID- 25736405 TI - Hypoxia promotes bone marrow-derived mesenchymal stem cell proliferation through apelin/APJ/autophagy pathway. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are a population of multipotent progenitors that have the capacity of proliferation and differentiation into mesenchymal lineage cells. The regulatory peptide apelin is the endogenous ligand for the G protein-coupled receptor APJ. Apelin, which can enhance BMSC proliferation, has mitogenic effects on a wide variety of cell types. We hypothesized that the increased apelin/APJ might be involved in the occurrence and development of hypoxia-induced BMSC proliferation. BMSCs from the bone marrow of 8- to 10-week-old C57BL/6J mice were cultured under either normoxia (21% oxygen) or hypoxia (1% oxygen) condition. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-bromo-2'-deoxyuridine assay. Expressions of hypoxia-inducible factor (HIF) 1alpha, apelin, APJ, Beclin-1, and LC3II/LC3I were detected by western blot analysis. Results suggested that hypoxia enhanced the proliferation of BMSC in a time-dependent manner. The expressions of HIF-1alpha, apelin, APJ, Beclin-1, and LC3II/LC3I were increased in BMSCs induced by hypoxia. Small interfering RNA (siRNA)-HIF-1alpha that inhibited the hypoxia-induced expressions of apelin, APJ, Beclin-1, and LC3II/LC3I prevented hypoxia-induced BMSC proliferation. siRNA-APJ that inhibited the hypoxia-induced expressions of Beclin-1 and LC3II/LC3I reversed hypoxia-induced BMSC proliferation. siRNA-Beclin-1 also abolished hypoxia-induced cell proliferation. These data suggested that the apelin/APJ/autophagy signaling pathway might be involved in hypoxia-induced BMSC proliferation. PMID- 25736406 TI - Identification of biological processes and genes for gestational diabetes mellitus. AB - AIM: Gestational diabetes mellitus (GDM) is one of the most usual complications of pregnancy, while the correlations between genes and their known biological processes need to be further elucidated. METHODS: In the current study, microarray data GSE2956 containing a list of 435 significantly modified genes (differentially expressed genes, DEGs) were used. Genes that correspond to official gene symbols were chosen and were functional annotated for Gene Ontology (GO) and pathway analyses (p <= 0.05). Then, the protein-protein interaction (PPI) network and the sub network were constructed and analyzed (combined score >=0.4). RESULTS: A total of 405 DEGs including 239 up-regulated and 166 down regulated genes were screened, and they were found mainly related to adhesion and motion, stimulus-response, and wound healing, etc. Besides, a PPI network containing 217 nodes and 644 lines was obtained. Hub genes including fibronectin 1 (FN1) and insulin-like growth factor 1 (IGF1) were down-regulated, and leptin (LEP) and calmodulin 1 (CALM1) were up-regulated. Three modules in the PPI network were mined and similar functional terms enriched by DEGs of these modules were obtained. CONCLUSION: GO terms relevant to translation and metabolic process and their related genes CREB1, ribosomal proteins and LEP, still the inflammation related proteins (e.g., IGF1 and CALM1) and cell adhesion-related protein FN1 may work together and be essential for GDM. This study provides insight into the cooperative interactions of metabolism and immune responses and the pathogenesis of GDM. PMID- 25736407 TI - Pterostilbene suppressed irradiation-resistant glioma stem cells by modulating GRP78/miR-205 axis. AB - Glioblastoma multiforme (GBM) is the most aggressive type characterized by relapse and resistance even with the combination of radio- and chemotherapy. The presence of glioma stem cells (GSCs) has been shown to contribute to tumorigenesis, recurrence and treatment resistance. Particularly, CD133-positive glioma cells have been shown to represent the subpopulation that confers glioma radioresistance and suggested to be the source of tumor recurrence after radiation. Thus, a better understanding and the development of agents which target GSCs could potentially lead to a significant improvement in treating GBM patients. Here, we demonstrated that GRP78 (an antistress protein) was highly expressed in GBM cells along with beta-catenin and Notch and correlated to the development of GSCs. CD133+ GSCs exhibited enhanced migration/invasion and self renewal abilities. When GRP78 was silenced, GSC properties were suppressed and the sensitivity towards irradiation increased. In addition, the level of microRNA 205 appeared to be negatively associated with GRP78 expression. Our previous study indicated that pterostilbene (PT) possessed anticancer stem cell properties in hepatocellular carcinoma. Thus, we examined whether PT is also effective against GSCs. We found that PT-treated GSCs exhibited suppressed self-renewal and irradiation-resistant abilities. PT-mediated effects were associated with an increase of miR-205. Finally, we showed that PT treatment suppressed tumorigenesis in GSC xenograft mice. In conclusion, we provided evidence that GRP78/miR-205 axis played an important role in GSC maintenance and irradiation resistance. PT treatment suppressed GSC development via negatively modulating GRP78 signaling. PT may be considered for combined therapeutic agent to enhance irradiation efficacy in GBM patients. PMID- 25736409 TI - Leeuwenhoekiella polynyae sp. nov., isolated from a polynya in western Antarctica. AB - A Gram-stain-negative, motile by gliding, rod-shaped bacterial strain, designated SOJ2014-1(T) was isolated from surface water of a polynya in the Antarctic Ocean. A comparative 16S rRNA gene sequence analysis showed that strain SOJ2014-1(T) belongs to the genus Leeuwenhoekiella and is most closely related to Leeuwenhoekiella marinoflava DSM 3653(T) (97.5% 16S rRNA gene sequence similarity). The G+C content of the genomic DNA of strain SOJ2014-1(T) was 38.8 mol%. Its predominant cellular fatty acids were summed feature 3 (composed of C16 : 1omega6c and/or C16 : 1omega7c), iso-C17 : 0 3-OH, iso-C15 : 0, iso-C15 : 1 G and summed feature 9 (composed of iso-C17 : 1omega9c and/or 10-methyl C16 : 0). DNA-DNA relatedness between strain SOJ2014-1(T) and close relatives, L. marinoflava DSM 3653(T) and Leeuwenhoekiella aequorea LMG 22550(T), was below 49%. The respiratory quinone was MK-6. The major polar lipids were phosphatidylethanolamine, an unidentified aminolipid and two unidentified lipids. The strain grew at 0-35 degrees C (optimum, 25 degrees C) with 0-14.0% (w/v) NaCl (optimum, 1.0-5.0%). It was strictly aerobic and had different carbohydrate utilization traits compared with L. marinoflava DSM 3653(T). Based on the phenotypic, chemotaxonomic and phylogenetic analyses, strain SOJ2014-1(T) is proposed as a representative of a novel species, Leeuwenhoekiella polynyae. The type strain is SOJ2014-1(T) ( =KCTC 42185(T) =JCM 30387(T)). PMID- 25736410 TI - Cautionary tale of using 16S rRNA gene sequence similarity values in identification of human-associated bacterial species. AB - Modern bacterial taxonomy is based on a polyphasic approach that combines phenotypic and genotypic characteristics, including 16S rRNA sequence similarity. However, the 95 % (for genus) and 98.7 % (for species) sequence similarity thresholds that are currently recommended to classify bacterial isolates were defined by comparison of a limited number of bacterial species, and may not apply to many genera that contain human-associated species. For each of 158 bacterial genera containing human-associated species, we computed pairwise sequence similarities between all species that have names with standing in nomenclature and then analysed the results, considering as abnormal any similarity value lower than 95 % or greater than 98.7 %. Many of the current bacterial species with validly published names do not respect the 95 and 98.7 % thresholds, with 57.1 % of species exhibiting 16S rRNA gene sequence similarity rates >=98.7 %, and 60.1 % of genera containing species exhibiting a 16S rRNA gene sequence similarity rate <95 %. In only 17 of the 158 genera studied (10.8 %), all species respected the 95 and 98.7 % thresholds. As we need powerful and reliable taxonomical tools, and as potential new tools such as pan-genomics have not yet been fully evaluated for taxonomic purposes, we propose to use as thresholds, genus by genus, the minimum and maximum similarity values observed among species. PMID- 25736408 TI - Desulfuromonas carbonis sp. nov., an Fe(III)-, S0- and Mn(IV)-reducing bacterium isolated from an active coalbed methane gas well. AB - A novel, mesophilic, obligately anaerobic, acetate-oxidizing, dissimilatory iron , sulfur-, and manganese-reducing bacterium, designated strain ICBM(T), was obtained from an active, coalbed methane gas well in Indiana, USA. Strain ICBM(T) was a Gram-stain-negative, non-spore-forming, rod-shaped, non-motile bacterium that was rich in c-type cytochromes and formed red colonies in solid medium. Strain ICBM(T) conserved energy to support growth from the oxidation of acetate, propionate, pyruvate, malate, fumarate, succinate and dl-lactate, concomitant with dissimilatory iron reduction. Strain ICBM(T) fermented fumarate yielding succinate and acetate. Strain ICBM(T) was able to grow in the temperature range of 10 degrees C to 37 degrees C, NaCl concentration range of 0 to 1.2 M, and pH range of 6.5 to 8.0. The physiological characteristics of strain ICBM(T) indicated that it belongs to the Desulfuromonas cluster. The G+C content of its genomic DNA was 61.2 mol%. The predominant cellular fatty acids were C16 : 0 (39.3%), C16 : 1omega7c and/or iso-C15 : 0 2-OH (36.6%). The closest cultured phylogenetic relative of strain ICBM(T) was Desulfuromonas michiganensis BB1(T) with only 95% 16S rRNA gene sequence similarity. This confirmed that strain ICBM(T) is affiliated with the genus Desulfuromonas . On the basis of phenotypic and genotypic differences between strain ICBM(T) and other taxa of the genus Desulfuromonas , strain ICBM(T) represents a novel species for which the name Desulfuromonas carbonis sp. nov. is proposed (type strain ICBM(T) = DSM 29759(T) = JCM 30471(T)). Strain ICBM(T) is the first Fe(III)-, S(0)-, and Mn(IV)-reducing bacterium that was isolated from a coal bed. PMID- 25736411 TI - Revision of the taxonomic status of type strains of Mesorhizobium loti and reclassification of strain USDA 3471T as the type strain of Mesorhizobiumerdmanii sp. nov. and ATCC 33669T as the type strain of Mesorhizobiumjarvisii sp. nov. AB - The species Mesorhizobim loti was isolated from nodules of Lotus corniculatus and its type strain deposited in several collections. Some of these type strains, such as those deposited in the USDA and ATCC collections before 1990, are not coincident with the original strain, NZP 2213T, deposited in the NZP culture collection. The analysis of the 16S rRNA gene showed that strains USDA 3471T and ATCC 33669T formed independent branches from that occupied by Mesorhizobium loti NZP 2213T and related to those occupied by Mesorhizobium opportunistum WSM2075T and Mesorhizobium huakuii IFO 15243T, respectively, with 99.9 % similarity in both cases. However, the analysis of concatenated recA, atpD and glnII genes with similarities lower than 96, 98 and 94 %, respectively, between strains USDA 3471T and M. opportunistum WSM2075T and between strains ATCC 33669T and M. huakuii IFO 15243T, indicated that the strains USDA 3471T and ATCC 33669T represent different species of the genus Mesorhizobium. These results were confirmed by DNA-DNA hybridization experiments and phenotypic characterization. Therefore, the two strains were reclassified as representatives of the two species Mesorhizobium erdmanii sp. nov. (type strain USDA 3471T = CECT 8631T = LMG 17826t2T) and Mesorhizobium jarvisii sp. nov. (type strain ATCC 33669T = CECT 8632T = LMG 28313T). PMID- 25736412 TI - Stackebrandtia endophytica sp. nov., an actinobacterium isolated from Tripterygium wilfordii. AB - A novel endophytic actinobacterium, designated strain YIM 64602T, was isolated from healthy stems of Tripterygium wilfordii. It grew at 15-40 degrees C, pH 6.0 9.0 and in the presence of 0-3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YIM 64602T belongs to the genus Stackebrandtia. Whole-cell hydrolysates of strain YIM 64602T contained the amino acid meso-diaminopimelic acid with the sugars mannose, rhamnose and glucose, and a trace of ribose. The major polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine and phosphatidylethanolamine. MK-10(H6), MK-10(H4) and MK-11(H4) were the predominant components in the quinone system. The fatty acid pattern was mainly composed of the saturated branched-chain acids iso-C16 : 0, anteiso-C17 : 0, iso-C15 : 0 and iso-C17 : 0. The DNA G+C content was 72.4 mol%. 16S rRNA gene sequence analysis showed the highest pairwise sequence identity (96.0-98.5 %) with the members of the genus Stackebrandtia. Strain YIM 64602T displayed a DNA-DNA relatedness of 43.9+/-0.4 % with the type strain Stackebrandtia albiflava YIM 45751T. Based on evidence from this polyphasic study, strain YIM 64602T ( = BCRC 16954T = DSM 45928T) is considered to represent a novel species of the genus Stackebrandtia, for which the name Stackebrandtia endophytica is proposed. PMID- 25736413 TI - Caloranaerobacter ferrireducens sp. nov., an anaerobic, thermophilic, iron (III) reducing bacterium isolated from deep-sea hydrothermal sulfide deposits. AB - A thermophilic, anaerobic, iron-reducing bacterium (strain DY22619T) was isolated from a sulfide sample collected from an East Pacific Ocean hydrothermal field at a depth of 2901 m. Cells were Gram-stain-negative, motile rods (2-10 um in length, 0.5 um in width) with multiple peritrichous flagella. The strain grew at 40-70 degrees C inclusive (optimum 60 degrees C), at pH 4.5-8.5 inclusive (optimum pH 7.0) and with sea salts concentrations of 1-10 % (w/v) (optimum 3 % sea salts) and NaCl concentrations of 1.5-5.0 % (w/v) (optimum 2.5 % NaCl). Under optimal growth conditions, the generation time was around 55 min. The isolate was an obligate chemoorganoheterotroph, utilizing complex organic compounds, amino acids, carbohydrates and organic acids including peptone, tryptone, beef extract, yeast extract, alanine, glutamate, methionine, threonine, fructose, mannose, galactose, glucose, palatinose, rhamnose, turanose, gentiobiose, xylose, sorbose, pyruvate, tartaric acid, alpha-ketobutyric acid, alpha-ketovaleric acid, galacturonic acid and glucosaminic acid. Strain DY22619T was strictly anaerobic and facultatively dependent on various forms of Fe(III) as an electron acceptor: insoluble forms and soluble forms. It did not reduce sulfite, sulfate, thiosulfate or nitrate. The genomic DNA G+C content was 29.0 mol%. Phylogenetic 16S rRNA gene sequence analyses revealed that the closest relative of strain DY22619T was Caloranaerobacter azorensis MV1087T, sharing 97.41 % 16S rRNA gene sequence similarity. On the basis of physiological distinctness and phylogenetic distance, the isolate is considered to represent a novel species of the genus Caloranaerobacter, for which the name Caloranaerobacterhttp://dx.doi.org/10.1601/nm.4081ferrireducens sp. nov. is proposed. The type strain is DY22619T ( = JCM 19467T = DSM 27799T = MCCC1A06455T). PMID- 25736414 TI - Helicobacter himalayensis sp. nov. isolated from gastric mucosa of Marmota himalayana. AB - A Gram-stain-negative, microaerophilic strain, 80(YS1)T, with a spiral-shaped morphology and 1-2 sheathed flagella at each end of the cells was isolated from the gastric mucosa of Marmota himalayana, the animal reservoir of Yersinia pestis in China, on the Qinghai-Tibet Plateau. The strain grew at 30, 35 and 42 degrees C, but not at 25 degrees C. Growth was in the form of a thinly spreading film on brain heart infusion agar containing 8 % sheep blood under microaerobic conditions. The strain did not hydrolyse urea or hippurate, and did not grow on media containing 1 % glycine. It reduced nitrate to nitrite, and was catalase- and alkaline-phosphatase-positive, susceptible to nalidixic acid and resistant to cefalotin. It was positive for genus-specific PCR for the genus Helicobacter, but could not be classified to any recognized species according biochemical tests results. Therefore, a phylogenetic study based on 16S rRNA, 23S rRNA, 60 kDa heat shock protein (hsp60) and gyrase subunit B (gyrB) genes was conducted. The 16S rRNA gene sequence (1468 bp) analysis showed that strain 80(YS1)T was most closely related to Helicobacter marmotae (96.7 % similarity). The 23S rRNA gene sequence (2879 bp) analysis showed that the strain was most closely related to Helicobacter canis (96 % similarity). The complete gyrB gene sequence (2325 bp) analysis showed that it was related phylogenetically to Helicobacter cinaedi (79.4 % similarity) and H. marmotae (79.1 % similarity). Analysis of the partial sequence of the hsp60 gene of strain 80(YS1)T showed closest similarity to the sequences of Helicobacter equorum (82 %) and H. cinaedi (81 %), respectively. However, there was no hsp60 sequence of H. marmotae available for analysis. The data of morphological, biochemical and phylogenetic characteristics all supported that this strain represents a novel species. The name Helicobacter himalayensis sp. nov. is proposed for this novel species with the type strain 80(YS1)T ( = CGMCC 1.12864T = DSM 28742T). PMID- 25736415 TI - Bifidobacterium lemurum sp. nov., from faeces of the ring-tailed lemur (Lemur catta). AB - Four Gram-positive-staining, microaerophilic, non-spore-forming, fructose-6 phosphate phosphoketolase-positive bacterial strains were isolated from a faecal sample of a 5-year-old ring-tailed lemur (Lemur catta). The strains showed a peculiar morphology, resembling a small coiled snake, a ring shape, or forming a little 'Y' shape. The isolated strains appeared identical, and LMC 13T was chosen as a representative strain and characterized further. Strain LMC 13T showed an A3beta peptidoglycan type, similar to that found in Bifidobacterium longum. The DNA base composition was 57.2 mol% G+C. Almost-complete 16S rRNA, hsp60, rpoB, dnaJ, dnaG, purF, clpC and rpoC gene sequences were obtained, and phylogenetic relationships were determined. Comparative analysis of 16S rRNA gene sequences showed that strain LMC 13T showed the highest similarity to B. longum subsp. suis ATCC 27533T (96.65 %) and Bifidobacterium saguini DSM 23967T (96.64 %). Strain LMC 13T was located in an actinobacterial cluster and was more closely related to the genus Bifidobacteriumthan to other genera in the Bifidobacteriaceae. On the basis of these results, strain LMC 13T represents a novel species within the genus Bifidobacterium, for which the name Bifidobacterium lemurum sp. nov. is proposed; the type strain is LMC 13T ( = DSM 28807T = JCM 30168T). PMID- 25736416 TI - Future of Saatchi bill is uncertain after Liberal Democrats' veto. PMID- 25736417 TI - Screening for depression in older adults on an acute medical ward: the validity of NICE guidance in using two questions. AB - BACKGROUND: depression is common in older people in general hospital settings and associated with poor outcomes. This study aimed to evaluate the validity of two screening questions recommended by the UK National Institute for Health and Clinical Excellence (NICE). METHODS: one hundred and eighteen patients aged over 65 years, admitted to acute medical wards at a teaching hospital, were interviewed in a standardised manner using relevant sections of the Present State Examination-Schedules for Clinical Assessment in Neuropsychiatry to identify depression according to ICD-10 criteria. Subsequently, participants completed the two depression screening questions and the 15-item version of the Geriatric Depression Scale (GDS-15). RESULTS: a threshold of one or more positive responses to the two NICE depression screening questions gave a sensitivity of 100%, specificity of 71%, positive predictive value (PPV) of 49% and negative predictive value (NPV) of 100%. The GDS-15 optimal cut-off was 6/7 with a sensitivity of 80%, specificity of 86%, PPV of 62% and NPV of 94%. A two-stage screening process utilising the NICE two questions followed by the GDS-15 with these cut-offs gave a sensitivity of 80%, specificity of 91%, PPV of 71% and NPV of 94%. CONCLUSION: the two depression questions perform well as an initial screening process for non-cognitively impaired older people in the acute medical setting. A positive response to either question would indicate that further assessment is required by a clinician competent in diagnosing depression in this population, or the possible use of a more detailed instrument such as the GDS-15 to reduce the number of false-positive cases. PMID- 25736418 TI - Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. AB - In normal physiologic responses to injury and infection, inflammatory cells enter tissue and sites of inflammation through a chemotactic process regulated by several families of proteins, including inflammatory chemokines, a family of small inducible cytokines. In neutrophils, chemokines chemokine (CXC motif) ligand 1 (CXCL1) and CXCL8 are potent chemoattractants and activate G protein coupled receptors CXC chemokine receptor 1 (CXCR1) and CXCR2. Several small molecule antagonists of CXCR2 have been developed to inhibit the inflammatory responses mediated by this receptor. Here, we present the data describing the pharmacology of AZD5069 [N-(2-(2,3-difluorobenzylthio)-6-((2R,3S)-3,4 dihydroxybutan-2-yloxy)[2,4,5,6-(13)C4, 1,3-(15)N2]pyrimidin-4-yl)azetidine-1 sulfonamide,[(15)N2,(13)C4]N-(2-(2,3-difluoro-6-[3H]-benzylthio)-6-((2R,3S)-3,4 dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide], a novel antagonist of CXCR2. AZD5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA2 of approximately 9.6, and adhesion molecule expression, with a pA2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. With short incubation times, AZD5069 appeared to have an antagonist profile with insurmountable antagonism of calcium response curves. This behavior was also observed in vivo in an acute lipopolysaccharide-induced lung inflammation model. Altogether, the data presented here show that AZD5069 represents a novel, potent, and selective CXCR2 antagonist with potential as a therapeutic agent in inflammatory conditions. PMID- 25736419 TI - Characterization of a Pachymedusa dacnicolor-Sauvagine analog as a new high affinity radioligand for corticotropin-releasing factor receptor studies. AB - The corticotropin-releasing factor (CRF) peptide family comprises the mammalian peptides CRF and the urocortins as well as frog skin sauvagine and fish urophyseal urotensin. Advances in understanding the roles of the CRF ligand family and associated receptors have often relied on radioreceptor assays using labeled CRF ligands. These assays depend on stable, high-affinity CRF analogs that can be labeled, purified, and chemically characterized. Analogs of several of the native peptides have been used in this context, most prominently including sauvagine from the frog Phyllomedusa sauvageii (PS-Svg). Because each of these affords both advantages and disadvantages, new analogs with superior properties would be welcome. We find that a sauvagine-like peptide recently isolated from a different frog species, Pachymedusa dacnicolor (PD-Svg), is a high-affinity agonist whose radioiodinated analog, [(125)ITyr(0)-Glu(1), Nle(17)]-PD-Svg, exhibits improved biochemical properties over those of earlier iodinated agonists. Specifically, the PD-Svg radioligand binds both CRF receptors with comparably high affinity as its PS-Svg counterpart, but detects a greater number of sites on both type 1 and type 2 receptors. PD-Svg is also ~10 times more potent at stimulating cAMP accumulation in cells expressing the native receptors. Autoradiographic localization using the PD-Svg radioligand shows robust specific binding to rodent brain and peripheral tissues that identifies consensus CRF receptor-expressing sites in a greater number and/or with greater sensitivity than its PS-Svg counterpart. We suggest that labeled analogs of PD-Svg may be useful tools for biochemical, structural, pharmacological, and anatomic studies of CRF receptors. PMID- 25736420 TI - CD133(+) CD44(+) Cells Mediate in the Lung Metastasis of Osteosarcoma. AB - CD133 and CD44 are commonly used markers of cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical value and significance of CD133 and CD44 in lung metastasis of osteosarcoma (OS) remains controversial. The purpose of this study was to investigate whether CD133(+) CD44(+) cells mediates the metastasis of OS. We identified the CD133(+) CD44(+) cells in lung metastatic lesions and OS cell lines, and next demonstrated CD133(+) CD44(+) cells were more aggressive in sphere formation, migration and invasiveness compared with CD133(+) CD44(-) , CD133(-) CD44(+) , or CD133(-) CD44(-) cells. We finally sorted the CD133(+) CD44(+) and CD133(-) CD44(-) cells from Saos-2 cell lines, after intratibial xenograft in nude mice, these cells developed primary tumors, and CD133(+) CD44(+) cells are more potential to form lung metastatic tumors. Thus we concluded that CD133(+) CD44(+) cells may mediate in the lung metastasis of OS. PMID- 25736421 TI - Estimating overdiagnosis in screening for abdominal aortic aneurysm: could a change in smoking habits and lowered aortic diameter tip the balance of screening towards harm? PMID- 25736422 TI - Toward a cultural adaptation of pharmacotherapy: Latino views of depression and antidepressant therapy. AB - Relative to non-Latino Whites, Latinos in the United States with major depressive disorder (MDD) show low engagement in antidepressant therapy, whether engagement is defined as pharmacotherapy access, medication initiation, pill-taking, or treatment retention. One potential reason for this disparity in depression care is the low cultural congruence of pharmacotherapy for this population. To examine Latinos' views of depression and antidepressant therapy, we conducted qualitative interviews with 30 Latino outpatients initiating antidepressants prior to their first treatment visit using the semistructured Treatment Adherence and Retention Questionnaire. These baseline interviews were randomly selected from data collected for a randomized controlled trial testing a novel intervention to enhance engagement by depressed Latino outpatients. Participant narratives were analyzed using open coding and the iterative analytical approach derived from grounded theory. Patient views about depression addressed stigmatizing views held by others in their social circle. Most participants directly refuted these views by providing alternate explanations to depression experiences. Antidepressant therapy narratives also revealed marked stigmatization, but participants tended not to refute these views. Instead, patients expressed concerns about antidepressants and showed marked ambivalence about seeking psychiatric care. Participants, however, did suggest ways in which clinicians and patients might collaborate to address their concerns about antidepressants. Some cultural views, such as concerns about addiction to or dependence on medication, may be negotiable barriers to treatment. Prescribing clinicians should address cultural views and concerns in order to improve Latino engagement in antidepressant therapy. PMID- 25736423 TI - A novel reductive graphene oxide-based magnetic molecularly imprinted poly(ethylene-co-vinyl alcohol) polymers for the enrichment and determination of polychlorinated biphenyls in fish samples. AB - The novel reductive graphene oxide-based magnetic molecularly imprinted poly(ethylene-co-vinyl alcohol) polymers (rGO@m-MIPs) were successfully synthesized as adsorbents for six kinds of polychlorinated biphenyls (PCBs) in fish samples. rGO@m-MIPs was prepared by surface molecular imprinting technique. Besides, Fe3 O4 nanoparticles (NPs) were employed as magnetic supporters, and rGO@Fe3 O4 was in situ synthesis. Different from functional monomer and cross linker in traditional molecularly imprinted polymer, here, 3,4-dichlorobenzidine was employed as dummy molecular and poly(ethylene-co-vinyl alcohol) was adopted as the imprinted polymers. After morphology and inner structure of the magnetic adsorbent were characterized, the adsorbent was employed for disperse solid phase extraction toward PCBs and exhibited great selectivity and high adsorption efficiency. This material was verified by determination of PCBs in fish samples combined with gas chromatography-mass spectrometry (GC-MS) method. According to the detection, the low detection limits (LODs) of PCBs were 0.0035-0.0070 ug l( 1) and spiked recoveries ranged between 79.90 and 94.23%. The prepared adsorbent can be renewable for at least 16 times and expected to be a new material for the enrichment and determination of PCBs from contaminated fish samples. PMID- 25736424 TI - A protease inhibition strategy based on acceleration of autolysis. AB - We report on an iconoclastic strategy for inhibiting proteases via autolysis acceleration. We show that proteases can be concentrated and induced to rapidly self-digest by a biocompatible polymer serving as an efficient catalyst. This new generation of protease inhibitors may find applications in the treatment of various protease-dependent diseases. PMID- 25736425 TI - Primary Care Providers' HIV Prevention Practices Among Older Adults. AB - PURPOSE: To explore primary care providers' HIV prevention practices for older adults. Primary care providers' perceptions and awareness were explored to understand factors that affect their provision of HIV prevention materials and HIV screening for older adults. DESIGN AND METHOD: Data were collected through 24 semistructured interviews with primary care providers (i.e., physicians, physician assistants, and nurse practitioners) who see patients older than 50 years. RESULTS: Results reveal facilitators and barriers of HIV prevention for older adults among primary care providers and understanding of providers' HIV prevention practices and behaviors. Individual, patient, institutional, and societal factors influenced HIV prevention practices among participants, for example, provider training and work experience, lack of time, discomfort in discussing HIV/AIDS with older adults, stigma, and ageism were contributing factors. Furthermore, factors specific to primary and secondary HIV prevention were identified, for instance, the presence of sexually transmitted infections influenced providers' secondary prevention practices. IMPLICATIONS: HIV disease, while preventable, is increasing among older adults. These findings inform future research and interventions aimed at increasing HIV prevention practices in primary care settings for patients older than 50. PMID- 25736426 TI - Overdiagnosis in mammography screening: a 45 year journey from shadowy idea to acknowledged reality. PMID- 25736428 TI - Reactivity and kinetics of vinyl sulfone-functionalized self-assembled monolayers for bioactive ligand immobilization. AB - A new vinyl sulfone (VS) disulfide, 1,2-bis(11-(vinyl sulfonyl)undecyl)disulfane, was synthesized to enable the preparation of VS-presenting self-assembled monolayers (VS SAMs) on Au substrates. The VS SAMs were used as a model system to assess the reaction kinetics of bioactive ligands, i.e., glutathione (GSH), N-(5 amino-1-carboxypentyl)iminodiacetic acid (ab-NTA), and mannose, toward the VS groups on the SAM surface. The VS SAMs and the ligand immobilization were characterized by X-ray photoelectron spectroscopy (XPS), contact angle goniometry, and protein-binding experiments using a quartz crystal microbalance (QCM). Kinetic studies showed that the surface VS groups undergo pseudo-first order reactions with various ligands, with the observed rate constant being 0.057 min(-1) for GSH at pH 7.5, 0.011 min(-1) for ab-NTA at pH 8.5, and 0.009 min(-1) for mannose at pH 10.5. This work advanced our understanding of the reactivity of VS-bearing functional surfaces and further demonstrated the versatile potential of VS chemistry to prepare ligand-immobilized bioactive surfaces. PMID- 25736429 TI - Procedural Learning in Children With Developmental Coordination, Reading, and Attention Disorders. AB - The aim is to assess repetition-based learning of procedures in children with developmental coordination disorder (DCD), reading disorder (RD) and attention deficit hyperactivity disorder (ADHD). Participants included 187 children, studied in 4 groups: (a) DCD comorbid with RD and ADHD (DCD+RD+ADHD) (n = 30); (b) RD comorbid with ADHD (RD+ADHD) (n = 48); (c) ADHD (n = 19); and typically developing children (control group) (n = 90). Two procedural learning tasks were used: Assembly learning and Mirror drawing. Children were tested on 4 occasions for each task: 3 trials were consecutive and the fourth trial was performed after an interference task. Task performance by DCD+RD+ADHD children improved with training (P < .05); however, the improvement was significantly lower than that achieved by the other groups (RD+ADHD, ADHD and controls) (P < .05). In conclusion, children with DCD+RD+ADHD improve in their use of cognitive-motor procedures over a short training period. Aims of intervention in DCD+RD+ADHD should be based on individual learning abilities. PMID- 25736430 TI - Langmuir monolayers of non-ionic polymers: equilibrium or metastability? Case study of PEO and its PPO-PEO diblock copolymers. AB - Stability and reorganization in Langmuir films of PEO in PEO homopolymers and PPO PEO block copolymers were investigated using film balance measurements. The apparent fractional losses of EO segments transferred into the subphase resulting from successive compression-expansion cycles have been estimated. The apparent loss is mainly Gamma(max), M(n) and time-dependent. At surface concentrations Gamma?0.32 mg/m(2), PEO films are in equilibrium. For 0.32?Gamma?0.7 mg/m(2), the losses remain modest. Further compression leads to densification of the monolayer, requiring the interplay of thermodynamics and kinetic factors In the plateau regime, the loss is higher and constant for 1?Gamma(max)?2 mg/m(2) upon maintaining the achieved surface area for 15 min. Similar losses were obtained for PEO homopolymers of high Mn and PPO353-PEO2295. It suggests that the PEO remains anchored in a metastable state at the air-water interface at surface concentration well above the onset of the plateau. Additional losses are incurred for PEO homopolymers for monolayers kept compressed in the plateau for 2 h. For the interpretation of these phenomena a combination of elements from self consistent field theory and scaling is desirable with as a trend an increasing contribution of the latter with increasing surface concentration. PMID- 25736427 TI - 25 years of African trypanosome research: From description to molecular dissection and new drug discovery. AB - The Molecular Parasitology conference was first held at the Marine Biological laboratory, Woods Hole, USA 25 years ago. Since that first meeting, the conference has evolved and expanded but has remained the showcase for the latest research developments in molecular parasitology. In this perspective, I reflect on the scientific discoveries focussed on African trypanosomes (Trypanosoma brucei spp.) that have occurred since the inaugural MPM meeting and discuss the current and future status of research on these parasites. PMID- 25736431 TI - Reprint of: self-assembly of nanoparticles employing polymerization-induced phase separation. AB - Nanoparticles (NPs) may be homogeneously dispersed in the precursors of a polymer (reactive solvent) by an adequate selection of their stabilizing ligands. However, the dispersion can become metastable or unstable in the course of polymerization. If this happens, NP-rich domains can be segregated by a process called polymerization-induced phase separation (PIPS). This occurs mainly due to the decrease in the entropic contribution of the reactive solvent to the free energy of mixing (increase in its average size) and, for a reactive solvent generating a cross-linked polymer, the additional contribution of the elastic energy in the post-gel stage. The extent of PIPS will depend on the competition between phase separation and polymerization rates. It can be completely avoided, limited to a local scale or conveyed to generate different types of NPs' aggregates such as crystalline platelets, self-assembled structures with a hierarchical order and partitioning at the interface, and bidimensional patterns of NPs at the film surface. The use of a third component in the initial formulation such as a linear polymer or a block copolymer, provides the possibility of generating an internal template for the preferential location and self-assembly of phase-separated NPs. Some illustrative examples of morphologies generated by PIPS in solutions of NPs in reactive solvents, are analyzed in this feature article. PMID- 25736432 TI - Inactivated Probiotic Bacteria Stimulate Cellular Immune Responses of Catla, Catla catla (Hamilton) In Vitro. AB - In the present study, we investigated the in vitro immunostimulatory effects of inactivated form of two potential probiotics, Bacillus amyloliquefaciens FPTB16 and B. subtilis FPTB13 in catla (Catla catla). Catla head kidney leukocytes (HK) were incubated with the bacteria alive or inactivated with heat shock (2 h at 60 degrees C), UV light (for 2.5 h) and formalin (1.0%, v/v) treatment (for 24 h at 4 degrees C) at different concentrations (10(7), 10(8) and 10(9) cells ml(-1)). After incubation, different cellular immune parameters such as respiratory burst activity, nitric oxide production, leukocyte peroxidase content and proliferative response were analyzed. The inactivated probiotic preparations stimulated all the cellular immune parameters of catla HK leukocytes in vitro. Among the different inactivated preparations, heat-treated form exhibited the best result. The lowest dose (10(7) cells ml(-1)) of both the strains showed the maximum stimulation. The results collectively suggest the efficacy of inactivated preparations to be used as immunostimulant in aquaculture. PMID- 25736433 TI - Differentiation of functional constipation and constipation predominant irritable bowel syndrome based on Rome III criteria: a population-based study. AB - BACKGROUND: While the Rome III classification recognises functional constipation (FC) and constipation predominant IBS (IBS-C) as distinct disorders, recent evidence has suggested that these disorders are difficult to separate in clinical practice. AIM: To identify whether clinical and lifestyle factors differentiate Rome III-defined IBS-C from FC based on gastrointestinal symptoms and lifestyle characteristics. METHOD: 3260 people randomly selected from the Australian population returned a postal survey. FC and IBS-C were defined according to Rome III. The first model used logistic regression to differentiate IBS-C from FC based on lifestyle, quality-of-life and psychological characteristics. The second approach was data-driven employing latent class analysis (LCA) to identify naturally occurring clusters in the data considering all symptoms involved in the Rome III criteria for IBS-C and FC. RESULTS: We found n = 206 (6.5%; 95% CI 5.7 7.4%) people met strict Rome III FC whereas n = 109 (3.5%; 95% CI 2.8-4.1%) met strict Rome III IBS-C. The case-control approach indicated that FC patients reported an older age at onset of constipation, were less likely to exercise, had higher mental QoL and less health care seeking than IBS-C. LCA yielded one latent class that was predominantly (75%) FC, while the other class was approximately half IBS-C and half FC. The FC-dominated latent class had clearly lower levels of symptoms used to classify IBS (pain-related symptoms) and was more likely to be male (P = 0.046) but was otherwise similar in distribution of lifestyle factors to the mixed class. CONCLUSION: The latent class analysis approach suggests a differentiation based more on symptom severity rather than the Rome III view. PMID- 25736434 TI - Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways. AB - Bone marrow-derived mesenchymal stem cells (MSCs) have been identified as one possible strategy for the treatment of chronic obstructive pulmonary disease (COPD). Our previous studies have demonstrated that MSC administration has therapeutic potential in airway inflammation and emphysema via a paracrine mechanism. We proposed that MSCs reverse the inflammatory process and restore impaired lung function through their interaction with macrophages. In our study, the rats were exposed to cigarette smoke (CS), followed by the administration of MSCs into the lungs for 5 weeks. Here we show that MSC administration alleviated airway inflammation and emphysema through the down-regulation of cyclooxygenase-2 (COX-2) and COX-2-mediated prostaglandin E2 (PGE2) production, possibly through the effect on alveolar macrophages. In vitro co-culture experiments provided evidence that MSCs down-regulated COX-2/PGE2 in macrophages through inhibition of the activation-associated phosphorylation of p38 MAPK and ERK. Our data suggest that MSCs may relieve airway inflammation and emphysema in CS-exposed rat models, through the inhibition of COX-2/PGE2 in alveolar macrophages, mediated in part by the p38 MAPK and ERK pathways. This study provides a compelling mechanism for MSC treatment in COPD, in addition to its paracrine mechanism. PMID- 25736435 TI - Doctors form new pressure group to prevent "marketisation" of NHS. PMID- 25736437 TI - Catching the adaptor-WDFY1, a new player in the TLR-TRIF pathway. AB - The innate immune system detects microbes and abnormal self through pattern recognition receptors (PRRs), which detect molecules that are either specific for microbes (such as lipopolysaccharide), present in much higher concentrations during infection (such as double-stranded RNA), or present in aberrant locations (such as cytosolic DNA) [1]. The Toll-like receptors (TLRs) are the best described set of PRRs. TLRs are membrane-bound receptors localized on the plasma membrane and in endosomes, the ligand-binding regions of which face the extracellular environment and the endosomal lumen, respectively [1]. In this issue of EMBO Reports, Hu and colleagues report that WD-repeat and FYVE-domain containing protein 1 (WDFY1) recruits the signaling adaptor TRIF to TLR3 and TLR4, thereby potentiating signaling from these PRRs (Fig 1); [2]. PMID- 25736436 TI - WDFY1 mediates TLR3/4 signaling by recruiting TRIF. AB - Toll-like receptors (TLRs) are pattern recognition receptors that sense a variety of pathogens, initiate innate immune responses, and direct adaptive immunity. All TLRs except TLR3 recruit the adaptor MyD88 to ultimately elicit inflammatory gene expression, whereas TLR3 and internalized TLR4 use TIR-domain-containing adaptor TRIF for the induction of type I interferon and inflammatory cytokines. Here, we identify the WD repeat and FYVE-domain-containing protein WDFY1 as a crucial adaptor protein in the TLR3/4 signaling pathway. Overexpression of WDFY1 potentiates TLR3- and TLR4-mediated activation of NF-kappaB, interferon regulatory factor 3 (IRF3), and production of type I interferons and inflammatory cytokines. WDFY1 depletion has the opposite effect. WDFY1 interacts with TLR3 and TLR4 and mediates the recruitment of TRIF to these receptors. Our findings suggest a crucial role for WDFY1 in bridging the TLR-TRIF interaction, which is necessary for TLR signaling. PMID- 25736438 TI - A pilot study of rapid hepatitis C virus testing in the Rhode Island Department of Corrections. AB - BACKGROUND: The correctional population bears a heavy burden of hepatitis C virus (HCV) infection necessitating expansion of HCV testing and treatment opportunities. Rapid HCV testing provides point-of-care antibody results and may be ideal for correctional facilities, particularly jails, where persons are often incarcerated for short periods of time, yet feasibility has not been established. METHODS: We conducted a pilot study of a rapid HCV testing algorithm among short term inmates with unknown HCV status. Participants completed a questionnaire, viewed an informational video and underwent rapid HCV testing and confirmatory testing, when indicated. Persons with chronic infection were referred to community care after release. Baseline characteristics, risk behaviors, test results and linkage were examined by descriptive analyses. RESULTS: Two hundred and fifty-two inmates were enrolled and 249 completed all study activities. Twenty-five participants (10%) had reactive rapid tests and 23 (92%) completed confirmatory testing. 15/23 (65%) had detectable HCV RNA, but only 4 linked to care after release. Persons with reactive HCV tests were more likely to be White (P = 0.01) and to have ever injected (P < 0.0001) and/or recently injected (P < 0.0001) drugs. CONCLUSIONS: Rapid HCV testing within jails is feasible, identifies previously unrecognized cases of HCV infection, and implementation should be considered. Low rates of linkage to care after release remain a barrier to care. PMID- 25736439 TI - Late arterial waves: an early warning system for heart failure? PMID- 25736440 TI - Late systolic central hypertension as a predictor of incident heart failure: the Multi-ethnic Study of Atherosclerosis. AB - BACKGROUND: Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure. METHODS AND RESULTS: We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/E(SPTI)) was assessed as a predictor of incident HF during median 8.5 years of follow-up. The L/E(SPTI) was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI=1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI=1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/E(SPTI) was the modifiable factor associated with the greatest improvements in model performance. A high L/E(SPTI) (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI=0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001). CONCLUSIONS: Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population. PMID- 25736441 TI - Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial. AB - BACKGROUND: In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. METHODS AND RESULTS: We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. CONCLUSIONS: TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov. Unique identifier: NCT00403767. PMID- 25736443 TI - Diagnosis and management of irritable bowel syndrome in adults in primary care: summary of NICE guidance. PMID- 25736442 TI - Moderate-to-vigorous physical activity with accelerometry is associated with visceral adipose tissue in adults. AB - BACKGROUND: We examined the relation between objectively measured physical activity with accelerometry and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based sample. METHODS AND RESULTS: We evaluated 1249 participants of the Framingham Third Generation and Omni II cohorts (mean age 51.7 years, 47% women) who underwent assessment of moderate-to vigorous physical activity (MVPA) with accelerometry over 5 to 7 days, and multi detector computed tomography for measurement of SAT and VAT volume; fat attenuation was estimated by SAT and VAT hounsfield units (HU). In women, higher levels of MVPA were associated with decreased SAT (P<0.0001) and VAT volume (P<0.0001). The average decrement in VAT per 30 minute/day increase in MVPA was 453 cm(3) (95% CI -574, -331). The association was attenuated but persisted upon adjustment for BMI (-122 cm(3), P=0.002). Higher levels of MVPA were associated with higher SAT HU (all P<=0.01), a marker of fat quality, even after adjustment for SAT volume. Similar findings were observed in men but the magnitude of the association was less. Sedentary time was not associated with SAT or VAT volume or quality in men or women. CONCLUSIONS: MVPA was associated with less VAT and SAT and better fat quality. PMID- 25736444 TI - Predictive utility of cardiac ultrasound in traumatic cardiac arrest in a combat casualty. AB - We report a case of traumatic cardiac arrest in a combat casualty who was resuscitated to return of spontaneous circulation despite asystole and no visible cardiac activity on initial ultrasound examination. This return of spontaneous circulation suggests that survival may be possible in traumatic cardiac arrest due to exsanguination, even when there is no demonstrable cardiac activity on ultrasound. Cardiac ultrasonography was performed for 10 s only. We suggest that cardiac ultrasonography should be performed for a minimum of 1 min during volume resuscitation. If absence of cardiac activity is confirmed once the heart is full, and there are no other signs of life (including pupillary reaction), then termination of resuscitation should be considered. PMID- 25736445 TI - Lagged Syndesmotic Fixation: Our Clinical Experience. AB - Ankle fractures are very common, and although algorithms are in place for osseous management, consensus has not been reached regarding treatment of associated ligamentous injuries. Although tibiofibular syndesmotic stabilization can be done using different forms of fixation, the biomedical literature has long emphasized the risk of long-term restriction of ankle mobility with the use of lagged transfixation. However, when reduction cannot be maintained with positional fixation, we found that lagging the syndesmotic screw helped to maintain the reduction without causing functional restriction. In this report, we describe our experience with patients who had undergone lagged tibiofibular transfixation and were available for short- to intermediate-term follow-up to assess ankle function. A total of 31 patients (32.63% of 95 consecutive patients) were available at a mean of 34.87 (range 18 to 52) months to complete the American Orthopedic Foot and Ankle Society ankle-hindfoot questionnaire. The mean score was 88.38 (range 42 to 100) points at a mean follow-up interval of 34.87 (range 18 to 52) months. Of 31 patients, 19 had an AOFAS score of 90 points, 9 an AOFAS score of 80 to 89 points, 2 an AOFAS score of 60 to 69 points, and 1 an AOFAS score of <60 points. Because all syndesmotic screws were placed using the lag technique, unrestricted motion compared with the uninjured limb was used as the endpoint. All subjects had unrestricted motion compared with the uninjured limb, refuting the assertion that lagged syndesmotic screw fixation confers more restriction in ankle kinematics than positional syndesmotic fixation. PMID- 25736446 TI - Assessment of Postoperative Tendon Quality in Patients With Achilles Tendon Rupture Using Diffusion Tensor Imaging and Tendon Fiber Tracking. AB - Although pre- and postoperative imaging of Achilles tendon rupture (ATR) has been well documented, radiographic evaluations of postoperative intratendinous healing and microstructure are still lacking. Diffusion tensor imaging (DTI) is an innovative technique that offers a noninvasive method for describing the microstructure characteristics and organization of tissues. DTI was used in the present study for quantitative assessment of fiber continuity postoperatively in patients with acute ATR. The data from 16 patients with ATR from 2005 to 2012 were retrospectively analyzed. The microstructure of ART was evaluated using tendon fiber tracking, tendon continuity, fractional anisotropy, and apparent diffusion coefficient values by way of DTI. The distal and proximal portions were measured separately in both the ruptured and the healthy extremities of each patient. The mean patient age was 41.56 +/- 8.49 (range 26 to 56) years. The median duration of follow-up was 21 (range 6 to 80) months. The tendon fractional anisotropy values of the ruptured Achilles tendon were significantly lower statistically than those of the normal side (p = .001). However, none of the differences between the 2 groups with respect to the distal and proximal apparent diffusion coefficient were statistically significant (p = .358 and p = .899, respectively). In addition, the fractional anisotropy and apparent diffusion coefficient measurements were not significantly different in the proximal and distal regions of the ruptured tendons compared with the healthy tendons. The present study used DTI and fiber tracking to demonstrate the radiologic properties of postoperative Achilles tendons with respect to trajectory and tendinous fiber continuity. Quantifying DTI and fiber tractography offers an innovative and effective tool that might be able to detect microstructural abnormalities not appreciable using conventional radiologic techniques. PMID- 25736447 TI - Infection with haemoplasma species in 22 cats with anaemia. AB - OBJECTIVES: Information regarding the clinical course of natural infection with feline haemotropic mycoplasmas (haemoplasmas) is limited. The objective of the study was to describe the clinical findings and course of disease in naturally infected cats with haemoplasmosis and anaemia. METHODS: A retrospective analysis was performed on patient data from cats presenting with anaemia and haemoplasma infection regarding signalment, clinical signs, laboratory data and course of infection. The diagnosis was confirmed by conventional haemoplasma PCR analysis. RESULTS: Haemoplasma infection was found in 22 anaemic (haematocrit 5-25% [median 17%]; reference interval 30-44%) cats ('Candidatus Mycoplasma haemominutum', n = 12; Mycoplasma haemofelis, n = 3; 'Candidatus Mycoplasma turicensis', n = 2; species not determined, n = 4; coinfection with all three species, n = 1) between 2005 and 2014. Thirteen of the cats had concurrent diseases. All cats underwent antibiotic treatment; 15 cats received blood products. Six cats were euthanased within 11 weeks owing to concurrent disease, persistent severe anaemia or financial constraints. Ten cats underwent follow-up for a period of 14-199 weeks (median 26 weeks). Haemoplasma PCR was negative in 5/7 cases after 3-23 weeks. PCR remained positive in two cases after 18 and 199 weeks, respectively. Reactivation of the haemoplasma infection occurred in two cats, once and three times, respectively, up to 177 weeks after initial presentation. Reactivation was suspected in two further cases. Owing to concurrent disease, four of the 10 follow-up cats were euthanased 14-180 weeks after initial presentation. CONCLUSION AND RELEVANCE: Infection with haemoplasma species is often chronic, can reactivate months later and is rarely a reason for euthanasia. PMID- 25736448 TI - Detection of feline coronavirus in cerebrospinal fluid for diagnosis of feline infectious peritonitis in cats with and without neurological signs. AB - OBJECTIVES: The objective of this study was to evaluate the sensitivity and specificity of a real-time reverse transcriptase polymerase chain reaction (real time RT-PCR) detecting feline coronavirus (FCoV) RNA in cerebrospinal fluid (CSF) of cats with and without neurological and/or ocular signs for the diagnosis of feline infectious peritonitis (FIP). METHODS: This prospective case-control study included 34 cats. Nineteen cats had a definitive histopathological diagnosis of FIP (seven of these with neurological and/or ocular signs), and 15 cats had other diseases but similar clinical signs (three of these with neurological and/or ocular signs). Real-time RT-PCR was performed on the CSF of all cats, and sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were calculated. RESULTS: Real-time RT-PCR of CSF showed a specificity of 100% in diagnosing FIP, a sensitivity of 42.1%, a PPV of 100% and an NPV of 57.7%. The sensitivity of the real-time RT-PCR of CSF in cats with neurological and/or ocular signs was 85.7%. CONCLUSIONS AND RELEVANCE: Although it is known that RT PCR can give false positive results, especially if performed using serum or plasma, this real-time RT-PCR detecting FCoV RNA in CSF can be considered a reliable specific tool for the diagnosis of FIP. If only cats with neurological involvement are evaluated, the sensitivity of this real-time RT-PCR in CSF is also high. PMID- 25736449 TI - Helicobacter pylori interferes with leukocyte migration via the outer membrane protein HopQ and via CagA translocation. AB - The human gastric pathogen Helicobacter pylori is a paradigm for chronic bacterial infections. Persistent colonization of the stomach mucosa is facilitated by several mechanisms of immune evasion and immune modulation, such as avoidance of Toll-like receptor recognition or skewing of effector T cell responses. Interactions of H. pylori with different immune cells have been described with respect to immune cell activation, cytokine release, or oxidative burst induction. We show here that H. pylori infection of human granulocytes, or of HL-60 cells differentiated to a granulocyte-like phenotype (dHL-60 cells) results in inhibition of cell migration under different conditions. Migration of dHL-60 cells in a three-dimensional collagen gel was found to be inhibited independently of the cag pathogenicity island, whereas migration inhibition in an under agarose assay was dependent on the cag pathogenicity island, on its effector protein CagA, and on the outer membrane protein HopQ. CagA translocation into leukocytes is accompanied by its tyrosine phosphorylation and by proteolytic processing into an N-terminal 100 kDa and a C-terminal 35 kDa fragment at a distinct cleavage site. By using complemented H. pylori strains producing either phosphorylation-resistant or cleavage-resistant CagA variants, we show that CagA tyrosine phosphorylation is required for migration inhibition, but CagA processing is not. Our results suggest that direct contact of H. pylori with immune cells subverts not only their activation characteristics, but also their migratory behaviour. PMID- 25736450 TI - Trends in Adolescents Obesity and the Association between BMI and Blood Pressure: A Cross-Sectional Study in 714,922 Healthy Teenagers. AB - BACKGROUND: Seventeen percent of youth in the United States are obese. Obesity has been linked to higher prevalence of hypertension. Past studies were limited by their size and conflicting results. The aim of this study was to analyze trends in adolescents' obesity between 1998 and 2011 and to evaluate the relationship between blood pressure and body mass index (BMI) in healthy adolescents. METHODS: All adolescents who underwent a medical exam in the years 1998-2011 and were found fit for combat duties in the Israeli Defense Force were included. RESULTS: The cohort included 714,922 healthy adolescents with 59% of them being males. The mean age was 17.4+/-0.45 and mean BMI was 22+/-3.5 kg/m(2). The percentage of overweight adolescents (BMI > 25 kg/m(2)) has increased from 13.2% in 1998 to 21% in 2011, P < 0.001. The mean systolic and diastolic blood pressures increased with increasing BMI deciles (systolic blood pressure by 10mm Hg and diastolic blood pressure by 3-4mm Hg from the 1st decile to the 10th decile, P < 0.001 for both). In multivariate analysis, each increase of 1 unit of BMI was associated with an increased risk of systolic blood pressure above 130 mm Hg in both males (OR = 1.108, 95% CI 1.107-1.110, P < 0.001) and females (OR = 1.114, 95% CI 1.139-1.146, P < 0.001). CONCLUSIONS: BMI in adolescents is significantly associated with systolic blood pressure and diastolic blood pressure in both genders and in both the normal weight and overweight groups. There has been consistent trend of increasing BMI values over recent years. PMID- 25736451 TI - Lack of evidence for a role of olfaction on first maturation in farmed sea bass Dicentrarchus labrax. AB - Chemical communication is widespread in the animal kingdom and olfaction constitutes a powerful channel for social and environmental cues. In fish, olfactory stimuli are known to influence physiological processes, including reproduction. Here we investigate the effects of olfaction on puberty in European sea bass Dicentrarchus labrax males. Intact sea bass coming to first maturity (puberty) are able to smell conspecific odours. However, induced anosmia during most of the spermatogenesis period had no effect on the sex ratio, gonad maturation state or gonado-somatic index at the time of reproduction. Furthermore anosmia decreased mRNA expression of brain KISS2 and pituitary LHb and FSHb, but not brain GnRH1 and GnRH3. Thus, although anosmia seems to modify gene expression of key reproduction related genetic factors, it seems to be insufficient to stop or delay growth or gonadal development and maturation. PMID- 25736452 TI - Cloning and expression pattern of gsdf during the first maleness reproductive phase in the protandrous Acanthopagrus latus. AB - Gonadal soma-derived factor (Gsdf) is a new member of the transforming growth factor beta superfamily. As a teleost- and gonad-specific growth factor, several studies indicate that Gsdf plays an important role in early germ cell development. In the present study, for the first time, a 1700-bp long gsdf gene was cloned from a protandrous species, Acanthopagrus latus. We further analyzed the cellular localization and the expression patterns of gsdf in respective testicular and ovarian zones during the first maleness reproductive phase. The results showed that gsdf transcripts were highly expressed in the ovotestis during sex differentiation, and the somatic cells of the testicular zone expressed many more gsdf transcripts than those of the ovarian zone. At the onset of puberty, the gsdf expression levels decreased gradually during spermatogenesis. Conversely, the ovarian zone exhibited a stable increase pattern which was similar to the plasma 17beta-estradiol (E2) levels. These results suggested that Gsdf may participates in early germ cell development, e.g. proliferation and differentiation of spermatogonia and oogonia in A. latus. PMID- 25736453 TI - Flexor carpi radialis surface electromyography electrode placement for evoked and voluntary measures. AB - INTRODUCTION: In this study we evaluated the reliability of bipolar electrode recordings, which allow for undistorted compound muscle action potentials (CMAPs) while minimizing cross-talk during voluntary contractions. METHODS: Twenty-four men completed maximal voluntary wrist flexion contractions in 4 test sessions. Compound muscle action potentials were also evoked during each session. Surface electromyography was recorded from the flexor carpi radialis (FCR) with the recording electrode (G1) placed on the motor point and a second recording electrode (G2) adjacent to G1. Reliability was assessed using intraclass correlational analysis of variance and standard error of measurement. RESULTS: Root-mean-square (RMS) amplitude and mean power frequency (MPF) were highly reliable (R = 0.89 and 0.84, respectively). The CMAPs also exhibited good reliability (R = 0.75). Normalization of RMS amplitude reduced the intraclass reliability coefficient (R = 0.85). CONCLUSION: The electrode placement resulted in reliable measures from voluntary contractions and CMAPs. Normalization can decrease reliability. PMID- 25736454 TI - Visual deterioration during pregnancy due to skull base tumors compressing the optic apparatus. AB - Intracranial tumors may rapidly enlarge during pregnancy. When the tumor abuts the optic apparatus, tumor growth may cause visual deterioration. The decisions regarding the management of these tumors should take into consideration visual function, fetal and maternal safety, and the ability for total resection of the tumor. The objective of the study was to describe our experience and to establish principles for management of intracranial tumors compressing the optic apparatus that present during pregnancy or in the early post partum period. A retrospective case-series review was conducted. Women who presented with visual deterioration either during pregnancy or in the early post partum period due to an intracranial tumor were included. Neurosurgical and obstetrical data were collected from the patients' hospital files and outpatient clinic records. Between 2005 and 2011, nine pregnant women with visual deterioration were diagnosed and treated. Of them, four underwent a neurosurgical procedure during pregnancy. Of the five patients who underwent surgery for tumor resection after delivery, three required urgent cesarean section either due to acute visual deterioration or obstetrical reasons. There was no maternal or fetal mortality and a good overall neonatal outcome was achieved. Improvement in visual acuity and visual fields was achieved in all patients. Postoperative complications included two cases of CSF leak, which resolved after treatment. Visual deterioration during pregnancy due to tumors that compress the optic apparatus requires treatment by a multi disciplinary team. Surgery is well tolerated by mother and fetus during early and midpregnancy; thus, in cases where visual deterioration is detected, delay of surgery is not justified. PMID- 25736455 TI - The current status of 5-ALA fluorescence-guided resection of intracranial meningiomas-a critical review. AB - Meningiomas are the second most common primary tumors affecting the central nervous system. Surgical treatment can be curative in case of complete resection. 5-aminolevulinic acid (5-ALA) has been established as an intraoperative tool in malignant glioma surgery. A number of studies have tried to outline the merits of 5-ALA for the resection of intracranial meningiomas. In the present paper, we review the existing literature about the application of 5-ALA as an intraoperative tool for the resection of intracranial meningiomas. PubMed was used as the database for search tasks. We included articles published in English without limitations regarding publication date. Tumor fluorescence can occur in benign meningiomas (WHO grade I) as well as in WHO grade II and WHO grade III meningiomas. Most of the reviewed studies report fluorescence of the main tumor mass with high sensitivity and specificity. However, different parts of the same tumor can present with a different fluorescent pattern (heterogenic fluorescence). Quantitative probe fluorescence can be superior, especially in meningiomas with difficult anatomical accessibility. However, only one study was able to consistently correlate resected tissue with histopathological results and nonspecific fluorescence of healthy brain tissue remains a confounder. The use of 5-ALA as a tool to guide resection of intracranial meningiomas remains experimental, especially in cases with tumor recurrence. The principle of intraoperative fluorescence as a real-time method to achieve complete resection is appealing, but the usefulness of 5-ALA is questionable. 5-ALA in intracranial meningioma surgery should only be used in a protocolled prospective and long-term study. PMID- 25736456 TI - Nuclear matrix binding protein SMAR1 regulates T-cell differentiation and allergic airway disease. AB - Asthma is a complex airway allergic disease involving the interplay of various cell types, cytokines, and transcriptional factors. Though many factors contribute to disease etiology, the molecular control of disease phenotype and responsiveness is not well understood. Here we report an essential role of the matrix attachment region (MAR)-binding protein SMAR1 in regulating immune response during allergic airway disease. Conditional knockout of SMAR1 in T cells rendered the mice resistant to eosinophilic airway inflammation against ovalbumin (OVA) allergen with low immunoglobulin E (IgE) and interleukin-5 (IL-5) levels. Moreover, a lower IgE/IgG2a ratio and higher interferon-gamma (IFN-gamma) response suggested aberrant skewing of T-cell differentiation toward type 1 helper T cell (Th1) response. We show that SMAR1 functions as a negative regulator of Th1 and Th17 differentiation by interacting with two potential and similar MAR regions present on the promoters of T-bet and IL-17. Thus, we present SMAR1 as a regulator of T-cell differentiation that favors the establishment of Th2 cells by modulating Th1 and Th17 responses. PMID- 25736457 TI - Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine. AB - Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4(+) T cells are poorly understood. Here we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4(+) T cells in the intestinal lamina propria, with T helper type 17 (Th17) cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells constitutively secrete IL 18 that acts directly on IL-18R1-expressing CD4(+) T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1 signaling. In addition, although IL-18R1 is not required for colonic Foxp3(+) regulatory T (Treg) cell differentiation, we found that IL-18R1 signaling was critical for Foxp3(+) Treg cell-mediated control of intestinal inflammation, where it promoted the expression of key Treg effector molecules. Thus IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4(+) T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders. PMID- 25736458 TI - Response to "In vivo attenuation and genetic evolution of a ST247-SCCmecI MRSA clone after 13 years of pathogenic bronchopulmonary colonization in a patient with cystic fibrosis: implications of the innate immune response". PMID- 25736460 TI - Polymersomes prepared from thermoresponsive fluorescent protein-polymer bioconjugates: capture of and report on drug and protein payloads. AB - Polymersomes provide a good platform for targeted drug delivery and the creation of complex (bio)catalytically active systems for research in synthetic biology. To realize these applications requires both spatial control over the encapsulation components in these polymersomes and a means to report where the components are in the polymersomes. To address these twin challenges, we synthesized the protein-polymer bioconjugate PNIPAM-b-amilFP497 composed of thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) and a green-fluorescent protein variant (amilFP497). Above 37 degrees C, this bioconjugate forms polymersomes that can (co-)encapsulate the fluorescent drug doxorubicin and the fluorescent light-harvesting protein phycoerythrin 545 (PE545). Using fluorescence lifetime imaging microscopy and Forster resonance energy transfer (FLIM-FRET), we can distinguish the co-encapsulated PE545 protein inside the polymersome membrane while doxorubicin is found both in the polymersome core and membrane. PMID- 25736459 TI - Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1beta/IL-17A axis. AB - Colitis-associated colorectal cancer (CAC) is the most serious complication of inflammatory bowel disease (IBD). Excessive complement activation has been shown to be involved in the pathogenesis of IBD. However, its role in the development of CAC is largely unknown. Here, using a CAC model induced by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), we demonstrated that complement activation was required for CAC pathogenesis. Deficiency in key components of complement (e.g., C3, C5, or C5a receptor) rendered tumor repression in mice subjected to AOM/DSS. Mechanistic investigation revealed that complement ablation dramatically reduced proinflammatory cytokine interleukin (IL)-1beta levels in the colonic tissues that was mainly produced by infiltrating neutrophils. IL-1beta promoted colon carcinogenesis by eliciting IL 17 response in intestinal myeloid cells. Furthermore, complement-activation product C5a represented a potent inducer for IL-1beta in neutrophil, accounting for downregulation of IL-1beta levels in the employed complement-deficient mice. Overall, our study proposes a protumorigenic role of complement in inflammation related colorectal cancer and that the therapeutic strategies targeting complement may be beneficial for the treatment of CAC in clinic. PMID- 25736461 TI - A contemporary review of management and prognostic factors of upper tract urothelial carcinoma. AB - BACKGROUND: Upper tract urothelial carcinoma (UTUC) accounts for <5% of all urothelial cancers. Although the main treatment is radical nephroureterectomy (NU), oncologic outcomes are not comparable to lower tract urothelial cancers. Identifying prognostic factors can help guide management and potentially improve outcomes. This article systematically reviews current literature on prognostic factors and management options for UTUC. METHODS: A comprehensive literature search was performed to identify all studies examining prognostic factors and management options for UTUC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to November 2014. An updated systematic review was performed. RESULTS: Preoperative prognostic factors for UTUC patients include age, race, performance status, obesity, smoking status, elevated fibrinogen levels, hydronephrosis, tumor size, multi-focality, location, clinical grade and previous/synchronous bladder cancer. Postoperative variables include tumor stage/grade, multifocality, nodal involvement, lympho-vascular invasion, initial ureteral location, necrosis, sessile architecture, variant histologies and presence of tissue ALDH1 and SOX2. Curative treatment of choice is NU, with lymphadenectomy conferring survival benefits. Minimally invasive surgery has equivalent oncologic and better peri-operative outcomes compared to open surgery. Conservative therapy includes adjuvant BCG and intravesical mitomycin C. Two randomized trials investigating postoperative instillation of mitomycin C suggest bladder recurrence benefits. Adjuvant chemo-radiotherapy may be useful for patients with advanced T3/4 and/or N+ disease. CONCLUSION: Gold-standard treatment for UTUC remains NU, increasingly performed using minimally invasive surgery. Nomograms including pre- and post-operative variables can aid prognostication and guide further therapy. PMID- 25736463 TI - Magnetic force microscopy using tip magnetization modulated by ferromagnetic resonance. AB - In magnetic force microscopy (MFM), the tip-sample distance should be reduced to analyze the microscopic magnetic domain structure with high spatial resolution. However, achieving a small tip-sample distance has been difficult because of superimposition of interaction forces such as van der Waals and electrostatic forces induced by the sample surface. In this study, we propose a new method of MFM using ferromagnetic resonance (FMR) to extract only the magnetic field near the sample surface. In this method, the magnetization of a magnetic cantilever is modulated by FMR to separate the magnetic field and topographic structure. We demonstrate the modulation of the magnetization of the cantilever and the identification of the polarities of a perpendicular magnetic medium. PMID- 25736462 TI - Evaluation of surface alterations in different retreatment nickel-titanium files: AFM and SEM study. AB - The aim of this study was to evaluate the surface changes of nickel titanium (Ni Ti) rotary retreatment files after three and five uses. Furthermore, the effects of 2% sodium hypochlorite and chloroform solutions and sterilization procedures on the NiTi rotary retreatment surfaces were investigated. ProTaper Retreatment files, R-endo files, and Mtwo retreatment files were used for this study. The palatinal roots of maxillary molar teeth were obturated with gutta percha and Ah26. Retreatment procedures were performed with these retreatment file systems. The surface changes of untreated NiTi rotary files that were used three and five times, immersed in NaOCl and chloroform and subjected to sterilization procedures were investigated with atomic force microscopy (AFM) and scanning electron microscopy (SEM). The RMS values, three dimensional images and SEM images at various magnifications were obtained. RMS values showed that all three NiTi rotary retreatment file systems showed significant deteriorations after three and five uses. Cracks, damages and spiral construction deteriorations were detected in the SEM images after three and five uses. Furthermore, the Mtwo 15 file was broken off after five uses. AFM data indicated that 2% NaOCl caused significant surface deteriorations on NiTi rotary files and both AFM and SEM evaluation showed that chloroform solution and sterilization procedures did not cause significant surface deteriorations. In conclusion, ProTaper retreatment, R-endo, and Mtwo retreatment files showed surface damages depending on retreatment procedures. Clinicians have to consider that retreatment files always have a tendency to break off after the third time they have been used. PMID- 25736464 TI - A kinetic model for estimating net photosynthetic rates of cos lettuce leaves under pulsed light. AB - Time-averaged net photosynthetic rate (P n) under pulsed light (PL) is known to be affected by the PL frequency and duty ratio, even though the time-averaged photosynthetic photon flux density (PPFD) is unchanged. This phenomenon can be explained by considering that photosynthetic intermediates (PIs) are pooled during light periods and then consumed by partial photosynthetic reactions during dark periods. In this study, we developed a kinetic model to estimate P n of cos lettuce (Lactuca sativa L. var. longifolia) leaves under PL based on the dynamics of the amount of pooled PIs. The model inputs are average PPFD, duty ratio, and frequency; the output is P n. The rates of both PI accumulation and consumption at a given moment are assumed to be dependent on the amount of pooled PIs at that point. Required model parameters and three explanatory variables (average PPFD, frequency, and duty ratio) were determined for the simulation using P n values under PL based on several combinations of the three variables. The model simulation for various PL levels with a wide range of time-averaged PPFDs, frequencies, and duty ratios further demonstrated that P n under PL with high frequencies and duty ratios was comparable to, but did not exceed, P n under continuous light, and also showed that P n under PL decreased as either frequency or duty ratio was decreased. The developed model can be used to estimate P n under various light environments where PPFD changes cyclically. PMID- 25736466 TI - Substandard care at "dysfunctional" Morecambe Bay maternity unit led to unnecessary deaths. PMID- 25736465 TI - Genomic analysis of parallel-evolved cyanobacterium Synechocystis sp. PCC 6803 under acid stress. AB - Experimental evolution is a powerful tool for clarifying phenotypic and genotypic changes responsible for adaptive evolution. In this study, we isolated acid adapted Synechocystis sp. PCC 6803 (Synechocystis 6803) strains to identify genes involved in acid tolerance. Synechocystis 6803 is rarely found in habitants with pH < 5.75. The parent (P) strain was cultured in BG-11 at pH 6.0. We gradually lowered the pH of the medium from pH 6.0 to pH 5.5 over 3 months. Our adapted cells could grow in acid stress conditions at pH 5.5, whereas the parent cells could not. We performed whole-genome sequencing and compared the acid-adapted and P strains, thereby identifying 11 SNPs in the acid-adapted strains, including in Fo F1-ATPase. To determine whether the SNP genes responded to acid stress, we examined gene expression in the adapted strains using quantitative reverse transcription polymerase chain reaction. sll0914, sll1496, sll0528, and sll1144 expressions increased under acid stress in the P strain, whereas sll0162, sll0163, slr0623, and slr0529 expressions decreased. There were no differences in the SNP genes expression levels between the P strain and two adapted strains, except for sll0528. These results suggest that SNPs in certain genes are involved in acid stress tolerance in Synechocystis 6803. PMID- 25736467 TI - Effective provision of a genetic screening program delivered to University students with limited resources. PMID- 25736468 TI - Bone-conduction hearing aids in an elderly population: complications and quality of life assessment. AB - To determine whether an elderly population with hearing impairment can be adequately rehabilitated with a bone-conduction hearing aid and whether the putative relationship between the elderly and an increased complication rate is justified. The study design was a retrospective case note review with a postal and telephone questionnaire, which was carried out in a tertiary centre. All patients aged 60 or over underwent implantation with a bone-conduction aid between 2009 and 2013 for conductive, SSD or mixed hearing loss. Outcome measures were complication rates and quality of life assessment using the Glasgow Benefit Inventory. The influence of patient and surgical factors on the complication rate was assessed. Fifty-one patients were implanted. Mean age was 67 years (range 60 89 years). The mean benefit, satisfaction and global GBI scores were 70 % (range 0-100 %), 70 % (0-100 %) and 82 % (83-100 %), respectively. The residual disability was 18 % (0-25 %). The adverse skin reaction rate was 16 % and the fixture loss rate was 2 %. There was a demonstrable increase in the complication rate with the dermatome (45 %; 5 patients) compared to the Sheffield 'S' (13 %; 2 patients) or linear incision techniques (29 %; 7 patients). The bone-conduction hearing aids are ideal method of hearing rehabilitation in the elderly for all forms of hearing loss. It provides significant benefit with no increased complication rate, which is imperative if social isolation is to be avoided and cognition preserved in this growing elderly population. PMID- 25736469 TI - Clinical proteomics and breast cancer. AB - BACKGROUND: Breast cancer is a heterogeneous disease. Yet, many molecular players and mechanisms behind the complexity of its clinical behaviour remain unknown, and advances in biomedical research are expected to unravel novel molecular discoveries in breast and other cancers. Clinical proteomics is currently experiencing rapid advances in technology that promise new means to improve breast cancer early diagnosis, stratification, and treatment response. METHODS: We reviewed recent literature adopting clinical proteomics in breast cancer research. FINDINGS: This review highlights the principles, advantages, limitations, discoveries and future prospects of recent clinical proteomics discovery efforts in breast cancer research. CONCLUSION: Numerous proteomic studies of breast cancer have been accomplished aiming to aid the development of personalised therapies, increase understanding of post treatment relapse, and help improve prediction of patient prognosis. This has led to the possible identification of profiles refining breast cancer subtypes and the discovery of novel biomarkers pointing towards diagnostic and prognostic potential. PMID- 25736471 TI - Ecology and genetic variation of Amblyomma tonelliae in Argentina. AB - The ecology of Amblyomma tonelliae (Ixodida: Ixodidae), including its seasonal distribution and the development periods of each stage, was investigated during a study carried out over two consecutive years in northwestern Argentina. In addition, the genetic variation of this tick was studied through analyses of 16S rDNA sequences. Amblyomma tonelliae has a 1-year lifecycle characterized by a long pre-moult period in larvae with no development of morphogenetic diapause. Larvae peak in abundance during late autumn and early winter; nymphs peak in abundance in spring, and adults do so from late spring to early summer. Amblyomma tonelliae shows a marked ecological preference for the driest areas of the Chaco ecoregion. In analyses of 16S rDNA sequences in genes from different populations of A. tonelliae, values for nucleotide diversity and the average number of nucleotide differences showed genetic diversity within this species to be low. No significant differences were found in comparisons among populations. PMID- 25736472 TI - Veno-venous extracorporeal CO2 removal improves pulmonary hemodynamics in a porcine ARDS model. AB - BACKGROUND: Protective lung ventilation is recommended in patients with acute respiratory distress syndrome (ARDS) to minimize additional injuries to the lung. However, hypercapnic acidosis resulting from ventilation at lower tidal volume enhances pulmonary hypertension and might induce right ventricular (RV) failure. We investigated if extracorporeal veno-venous CO2 removal therapy could have beneficial effects on pulmonary circulation and RV function. METHODS: This study was performed on an experimental model of ARDS obtained in eight anaesthetized pigs connected to a volume-cycled ventilator. A micromanometer-tipped catheter was inserted into the main pulmonary artery and an admittance micromanometer tipped catheter was inserted into the right ventricle. RV-arterial coupling was derived from RV pressure-volume loops. ARDS was obtained by repeated bronchoalveolar lavage. Protective ventilation was then achieved, and the pigs were connected to a pump-driven extracorporeal membrane oxygenator (PALP, Maquet, Germany) in order to achieve CO2 removal. RESULTS: ARDS induced severe hypercapnic acidosis. Systolic pulmonary artery pressure significantly increased from 29.6+/-1.8 to 43.9+/-2.0 mmHg (P<0.001). After the PALP was started, acidosis was corrected and normocarbia was maintained despite protective ventilation. Pulmonary artery pressure significantly decreased to 31.6+/-3.2 mmHg (P<0.001) and RV-arterial coupling significantly improved (RV-arterial coupling index=1.03+/-0.33 vs. 0.55+/-0.41, P<0.05). CONCLUSION: Veno-venous CO2 removal therapy enabled protective ventilation while maintaining normocarbia during ARDS. CO2 removal decreased pulmonary hypertension and improved RV function. This technique may be an effective lung- and RV-protective adjunct to mechanical ventilation. PMID- 25736470 TI - Radiation-induced motility alterations in medulloblastoma cells. AB - Photon irradiation has been repeatedly suspected of increasing tumor cell motility and promoting locoregional recurrence of disease. This study was set up to analyse possible mechanisms underlying the potentially radiation-altered motility in medulloblastoma cells. Medulloblastoma cell lines D425 and Med8A were analyzed in migration and adhesion experiments with and without photon and carbon ion irradiation. Expression of integrins was determined by quantitative FACS analysis. Matrix metalloproteinase concentrations within cell culture supernatants were investigated by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using Student's t-test. Both photon and carbon ion irradiation significantly reduced chemotactic medulloblastoma cell transmigration through 8-MUm pore size membranes, while simultaneously increasing adherence to fibronectin- and collagen I- and IV-coated surfaces. Correspondingly, both photon and carbon ion irradiation downregulate soluble MMP9 concentrations, while upregulating cell surface expression of proadhesive extracellular matrix protein-binding integrin alpha5. The observed phenotype of radiation-altered motility is more pronounced following carbon ion than photon irradiation. Both photon and (even more so) carbon ion irradiation are effective in inhibiting medulloblastoma cell migration through downregulation of matrix metalloproteinase 9 and upregulation of proadhesive cell surface integrin alpha5, which lead to increased cell adherence to extracellular matrix proteins. PMID- 25736473 TI - Lung cancer stigma as a barrier to medical help-seeking behavior: Practice implications. AB - PURPOSE: The purpose of this study was to examine the relationship of perceived lung cancer stigma and timing of medical help-seeking behavior in symptomatic individuals. DATA SOURCES: A convenience sample was recruited from an academic thoracic oncology clinic and community hospital-based outpatient radiation center in a large city in the southeastern United States. This descriptive, cross sectional study used survey methodology and semistructured interviews to examine the relationship of perceived lung cancer stigma and delayed medical help seeking finding a statistically significant positive correlation. Additional examination revealed positive correlations between the stigma and shame, social isolation, and smoking-related stigma subscales and delay. The discrimination-related subscale was not associated with delay. In addition, smoking status was not related to perceived lung cancer stigma. CONCLUSIONS: Findings support an association between lung cancer stigma and delayed medical help-seeking behavior. Therefore, lung cancer stigma is a potential barrier to timely medical help seeking behavior in lung cancer symptoms, which can have important patient outcome implications. IMPLICATIONS FOR PRACTICE: As primary care nurse practitioners, awareness that lung cancer stigma exists for patients is essential regardless of smoking status and efforts to decrease this barrier to timely health care are important. PMID- 25736474 TI - Nailfold capillary microscopic changes and arterial stiffness in Korean systemic sclerosis patients. PMID- 25736475 TI - Hepatozoon and Theileria species detected in ticks collected from mammals and snakes in Thailand. AB - We report the detection of Hepatozoon and Theileria in 103 ticks from mammals and snakes in Thailand. By using a genus-specific 18S rRNA PCR, Hepatozoon and Theileria spp. were detected in 8% and 18%, respectively, of ticks (n=79) removed from mammals. Of the ticks removed from snakes (n=24), 96% were infected with Hepatozoon spp., but none were infected with Theileria. Phylogenetic analysis revealed that Hepatozoon spp. detected from Dermacentor astrosignatus and Dermacentor auratus ticks from Wild boar (Sus scrofa) formed a phylogenetic group with many isolates of Hepatozoon felis that were distantly related to a species group containing Hepatozoon canis and Hepatozoon americanum. In contrast, a phylogenetic analysis of the Hepatozoon sequences of snake ticks revealed that Hepatozoon spp. from Amblyomma varanense from King cobra (Ophiophagus hannah) and Amblyomma helvolum ticks from Indochinese rat snake (Ptyas korros), and Asiatic water snake (Xenochrophis piscator) are grouped with Hepatozoon spp. recently isolated from Monocellate cobras, Reticulated pythons and Burmese pythons, all of Thai origin, and with Hepatozoon sp. 774c that has been detected from a tick species obtained from Argus monitors in Australia. A phylogenetic analysis demonstrated that Theileria spp. from Rhipicephalus (Boophilus) microplus, Haemaphysalis obesa, and Haemaphysalis lagrangei ticks from Sambar deer (Cervus unicolor) cluster with the Theileria cervi isolates WU11 and 239, and Theileria sp. Iwate 141. We report for the first time a Hepatozoon species that shares genetic similarity with Hepatozoon felis found in Dermacentor astrosignatus and Dermacentor auratus ticks collected from Wild boars in Thailand. In addition, we found the presence of a Theileria cervi-like sp. which suggests the potential role of Haemaphysalis lagrangei as a Theileria vector in Thailand. PMID- 25736476 TI - A newly established real-time PCR for detection of Borrelia miyamotoi in Ixodes ricinus ticks. AB - A total of 350 ticks collected in Austria were analyzed for the presence of DNA sequences of B. miyamotoi. Three ticks gave positive results in a B. miyamotoi specific nested PCR. Results were confirmed by sequencing the amplified glpQ gene from the positive samples. Moreover we developed a real-time PCR which unambiguously detected B. miyamotoi in all positive samples. Further genotyping of the samples found 100% identity of the 16S-23S intergenic spacer region with Swedish B. miyamotoi sequences. This is the first detection of the relapsing fever spirochete Borrelia miyamotoi in hard ticks in Austria. The results consolidate the picture of a European-wide distribution of B. miyamotoi and again underscore the need for clinical awareness to clarify possible involvement of this species in human disease. PMID- 25736478 TI - Detection of urinary biomarkers in reservoir hosts of leptospirosis by capillary electrophoresis-mass spectrometry. AB - PURPOSE: Pathogenic leptospires colonize the renal tubules of reservoir hosts of infection and are excreted via urine into the environment. Asymptomatic reservoir hosts include a wide range of domestic and wild animal species and include cattle, dogs, and rats that can persistently excrete large numbers of pathogenic leptospires over many months. A similar presentation has been observed in humans categorized as "long-term asymptomatic individuals" as they excreted leptospires in the absence of any clinical symptoms or positive serology. EXPERIMENTAL DESIGN: In the current study, the urine of experimentally infected rats, which showed no clinical signs or positive serology, was analyzed by CE-MS to identify urinary biomarkers of chronic infection. RESULTS: A discriminating peptide pattern of 43 polypeptides provided a sensitivity of 93%, a specificity of 83%, and an accuracy of 90% for the identification of urine from chronically infected rats (p < 0.05, AUC > 90%). The majority of discriminating peptides were decreased in abundance in urine of chronically infected rats, including a peptide derived from neprilysin, a membrane metalloendopeptidase, the expression of which has previously been shown to be diminished in infected urine. CONCLUSION AND CLINICAL RELEVANCE: Results highlight the diagnostic capabilities of urinary biomarkers to identify reservoir hosts of leptospirosis using CE coupled to MS. PMID- 25736477 TI - Transcriptome analysis of thermogenic Arum concinnatum reveals the molecular components of floral scent production. AB - Several plant species can generate enough heat to increase their internal floral temperature above ambient temperature. Among thermogenic plants, Arum concinnatum shows the highest respiration activity during thermogenesis. However, an overall understanding of the genes related to plant thermogenesis has not yet been achieved. In this study, we performed de novo transcriptome analysis of flower organs in A. concinnatum. The de novo transcriptome assembly represented, in total, 158,490 non-redundant transcripts, and 53,315 of those showed significant homology with known genes. To explore genes associated with thermogenesis, we filtered 1266 transcripts that showed a significant correlation between expression pattern and the temperature trend of each sample. We confirmed five putative alternative oxidase transcripts were included in filtered transcripts as expected. An enrichment analysis of the Gene Ontology terms for the filtered transcripts suggested over-representation of genes involved in 1-deoxy-D-xylulose 5-phosphate synthase (DXS) activity. The expression profiles of DXS transcripts in the methyl-D-erythritol 4-phosphate (MEP) pathway were significantly correlated with thermogenic levels. Our results suggest that the MEP pathway is the main biosynthesis route for producing scent monoterpenes. To our knowledge, this is the first report describing the candidate pathway and the key enzyme for floral scent production in thermogenic plants. PMID- 25736479 TI - Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats. AB - Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats. PMID- 25736480 TI - Comparative study of behavioural tests in the SOD1G93A mouse model of amyotrophic lateral sclerosis. AB - In preclinical trials, a sensitive functional test is required to detect changes in the motor behaviour of the SOD1G93A mouse model of amyotrophic lateral sclerosis (ALS). We evaluated changes in body weight and motor impairment in behavioural tests, such as the rotarod, the hanging-wire test and the treadmill, of transgenic and wild type mice. We found differences in detection of the onset of symptoms and progression of the disease between the different tests assessed. Moreover, the data showed significant gender differences in the motor behaviour of this mouse model. The rotarod and the hanging-wire test were more sensitive to detect early motor impairment. Moreover, the results suggested that the rotarod and hanging-wire became the most accurate tests rather than treadmill to characterise the ALS disease phenotype. PMID- 25736482 TI - Low-protein diet disrupts the crosstalk between the PKA and PKC signaling pathways in isolated pancreatic islets. AB - Protein restriction in the early stages of life can result in several changes in pancreatic function. These alterations include documented reductions in insulin secretion and in cytoplasmic calcium concentration [Ca(2+)]i. However, the mechanisms underlying these changes have not been completely elucidated and may result, in part, from alterations in signaling pathways that potentiate insulin secretion in the presence of glucose. Our findings suggest that protein restriction disrupts the insulin secretory synergism between Cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and Ca(2+)-dependent protein kinase C (PKC) in isolated islets. Western blot analysis demonstrated reduced levels of both phospho-cAMP response element-binding protein (phospho-CREB) at Ser-133 and substrates phosphorylated by PKCs (Phospho-(Ser) PKC substrate), suggesting that PKA and PKC activity was impaired in islets from rats fed a low protein diet (LP). cAMP levels and global Ca(2+) entry were also reduced in LP islets. In summary, our findings showed that protein restriction altered the crosstalk between PKA and PKC signaling pathways, resulting in the alteration of secretory synergism in isolated islets. PMID- 25736481 TI - Effects of dietary virgin olive oil polyphenols: hydroxytyrosyl acetate and 3, 4 dihydroxyphenylglycol on DSS-induced acute colitis in mice. AB - Hydroxytyrosol, a polyphenolic compound from extra virgin olive oil (EVOO) has exhibited an improvement in a model of DSS-induced colitis. However, other phenolic compounds present such as hydroxytyrosyl acetate (HTy-Ac) and 3,4 dihydroxyphenylglycol (DHPG) need to be explored to complete the understanding of the overall effects of EVOO on inflammatory colon mucosa. This study was designed to evaluate the effect of both HTy-Ac and DHPG dietary supplementation in the inflammatory response associated to colitis model. Six-week-old mice were randomized in four dietary groups: sham and control groups received standard diet, and other two groups were fed with HTy-Ac and DHPG, respectively, at 0.1%. After 30 days, all groups except sham received 3% DSS in drinking water for 5 days followed by a regime of 5 days of water. Acute inflammation was evaluated by Disease Activity Index (DAI), histology and myeloperoxidase (MPO) activity. Colonic expression of iNOS, COX-2, MAPKs, NF-kB and FOXP3 were determined by western blotting. Only HTy-Ac-supplemented group showed a significant DAI reduction as well as an improvement of histological damage and MPO. COX-2 and iNOS protein expression were also significantly reduced. In addition, this dietary group down-regulated JNK phosphorylation and prevented the DSS-induced nuclear translocation level of p65. However, no significant differences were observed in the FOXP3 expression. These results demonstrated, for the first time, that HTy-Ac exerts an antiinflammatory effect on acute ulcerative colitis. We concluded that HTy-Ac supplement might provide a basis for developing a new dietary strategy for the prevention of ulcerative colitis. PMID- 25736483 TI - Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, and suppresses lung metastasis and tumor growth in combination with taxol in tumor xenografted C57BL/6 mice. AB - This study aimed to investigate the anti-metastatic activity of alpha-carotene (AC) in Lewis lung carcinoma (LLC) and in combination with taxol in LLC xenografted C57BL/6 mice. Cell culture studies reveal that AC significantly inhibited invasion, migration and activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator but increased protein expression of tissue inhibitor of MMP (TIMP)-1, -2 and plasminogen activator inhibitor (PAI)-1. These effects of AC are similar to those of beta-carotene at the same concentration (2.5 MUM). AC (2.5 MUM) also significantly inhibited integrin beta1-mediated phosphorylation of focal adhesion kinase (FAK) which then decreased the phosphorylation of MAPK family. Findings from the animal model reveal that AC treatment (5m g/kg) alone significantly decreased lung metastasis without affecting primary tumor growth, whereas taxol treatment (6 mg/kg) alone exhibited significant inhibition on both actions, as compared to tumor control group. AC treatment alone significantly decreased protein expression of integrin beta1 but increased protein expression of TIMP-1 and PAI-1 without affecting protein expression of TIMP-2 and phosphorylation of FAK in lung tissues, whereas taxol treatment alone significantly increased protein expression of TIMP-1, PAI-1 and TIMP-2 but decreased protein expression of integrin beta1 and phosphorylation of FAK. The combined treatment produced stronger actions on lung metastasis and lung tissues protein expression of TIMP-1, TIMP-2 and PAI-1. Overall, we demonstrate that AC effectively inhibits LLC metastasis and suppresses lung metastasis in combination with taxol in LLC-bearing mice, suggesting that AC could be used as an anti-metastatic agent or as an adjuvant for anti-cancer drugs. PMID- 25736484 TI - Ecology of malaria infections in western lowland gorillas inhabiting Dzanga Sangha Protected Areas, Central African Republic. AB - African great apes are susceptible to infections with several species of Plasmodium, including the predecessor of Plasmodium falciparum. Little is known about the ecology of these pathogens in gorillas. A total of 131 gorilla fecal samples were collected from Dzanga-Sangha Protected Areas to study the diversity and prevalence of Plasmodium species. The effects of sex and age as factors influencing levels of infection with Plasmodium in habituated gorilla groups were assessed. Ninety-five human blood samples from the same locality were also analysed to test for cross-transmission between humans and gorillas. According to a cytB PCR assay 32% of gorilla's fecal samples and 43.1% human individuals were infected with Plasmodium spp. All Laverania species, Plasmodium vivax, and for the first time Plasmodium ovale were identified from gorilla samples. Plasmodium praefalciparum was present only from habituated individuals and P. falciparum was detected from human samples. Although few P. vivax and P. ovale sequences were obtained from gorillas, the evidence for cross-species transmission between humans and gorillas requires more in depth analysis. No association was found between malaria infection and sex, however, younger individuals aged <=6 years were more susceptible. Switching between two different Plasmodium spp. was observed in three individuals. Prolonged monitoring of Plasmodium infection during various seasons and recording behavioural data is necessary to draw a precise picture about the infection dynamics. PMID- 25736485 TI - Sequential/parallel production of potential Malaria vaccines--A direct way from single batch to quasi-continuous integrated production. AB - An intensification of pharmaceutical protein production processes can be achieved by the integration of unit operations and application of recurring sequences of all biochemical process steps. Within optimization procedures each individual step as well as the overall process has to be in the focus of scientific interest. This paper includes a description of the development of a fully automated production plant, starting with a two step upstream followed by a four step downstream line, including cell clarification, broth cleaning with microfiltration, product concentration with ultrafiltration and purification with column chromatography. Recursive production strategies are developed where a cell breeding, the protein production and the whole downstream is operated in series but also in parallel, each main operation shifted by one day. The quality and reproducibility of the recursive protein expression is monitored on-line by Golden Batch and this is controlled by Model Predictive Multivariate Control (MPMC). As a demonstration process the production of potential Malaria vaccines with Pichia pastoris is under investigation. PMID- 25736486 TI - Modification of luminescence spectra of CaF2:Eu2+. AB - CaF2:Eu(2+) is a well known phosphor having efficient excitation in the near ultraviolet (NUV) range. Phosphors with NUV excitation are required in newly emerging applications such as photoluminescence liquid crystal displays (PLLCD), solid-state lighting (SSL), and down-conversion for solar cells. However, emission of CaF2:Eu(2+) is around 424 nm. Eye sensitivity drops considerably at these wavelengths. It is thus not useful for display applications for which emission in one of the primary colours (blue - 450 nm, green - 540 nm or red - 610 nm) is required. Efforts were made to modify the Photoluminescence (PL) spectra of CaF2:Eu(2+) to meet these requirements using co-dopants. A Ca0.49 Sr0.50 Eu0.01 F2 phosphor showing better colour coordinates and having an emission maximum around 440 nm was discovered during these studies. PMID- 25736487 TI - 8th Georg Rajka International Symposium on Atopic Dermatitis: meeting report. AB - The 8th Georg Rajka International Symposium on Atopic Dermatitis was held in Nottingham in May 2014. The 3-day meeting featured a number of lectures by experts in the field of atopic dermatitis from around the world, as well as several original research presentations and a question and answer session. This paper aims to summarize the main oral presentations from the meeting, but is not meant to be a substitute for reading the conference proceedings and related references. PMID- 25736488 TI - Middle Holocene daily light cycle reconstructed from the strontium/calcium ratios of a fossil giant clam shell. AB - Insolation is an important component of meteorological data because solar energy is the primary and direct driver of weather and climate. Previous analyses of cultivated giant clam shells revealed diurnal variation in the Sr/Ca ratio, which might reflect the influence of the daily light cycle. We applied proxy method to sample from prehistoric era, a fossil giant clam shell collected at Ishigaki Island in southern Japan. The specimen was alive during the middle Holocene and thus exposed to the warmest climate after the last glacial period. This bivalve species is known to form a growth line each day, as confirmed by the analysis of the Sr enrichment bands using EPMA and facilitated age-model. We analyzed the Sr/Ca, Mg/Ca and Ba/Ca ratios along the growth axis, measuring a 2-MUm spot size at 2-MUm interval using NanoSIMS. The Sr/Ca ratios in the winter layers are characterized by a striking diurnal cycle consisting of narrow growth lines with high Sr/Ca ratios and broad growth bands with low Sr/Ca ratios. These variations, which are consistent with those of the cultivated clam shell, indicate the potential for the reconstruction of the variation in solar insolation during the middle Holocene at a multi-hourly resolution. PMID- 25736489 TI - Corrigendum: Large cities are less green. PMID- 25736490 TI - Biomimetic and nanostructured hybrid bioactive glass. AB - Inspired by nature's toughening mechanisms, we designed a new polyhedral oligomeric silsesquioxane (POSS)-derived hybrid glass (PHG) that has covalent interactions on the molecular scale between the inorganic POSS cage and organic phase. These features allow "elastic deformation" of the inorganic POSS cage in limited scale. The final product is a bulk hybrid material with toughness (3.56 +/- 0.25 MPa.m(1/2)) similar to natural bone (2.4-5.3 MPa.m(1/2)). PHG exhibited excellent bioactivity by promoting the formation of plate-like hydroxyapatite on its surface in simulated body fluid and showed good cell adhesion. PHG also can be a platform to guide adipose tissue-derived mesenchymal stem cells differentiation and mineralization. The key structural features of this material can be used to guide the design of bio-inspired composites with unique toughness, which would be of great benefit to hard tissue engineering. PMID- 25736491 TI - The effects of electrospun substrate-mediated cell colony morphology on the self renewal of human induced pluripotent stem cells. AB - The development of xeno-free, chemically defined stem cell culture systems has been a primary focus in the field of regenerative medicine to enhance the clinical application of pluripotent stem cells (PSCs). In this regard, various electrospun substrates with diverse physiochemical properties were synthesized utilizing various polymer precursors and surface treatments. Human induced pluripotent stem cells (IPSCs) cultured on these substrates were characterized by their gene and protein expression to determine the effects of the substrate physiochemical properties on the cells' self-renewal, i.e., proliferation and the maintenance of pluripotency. The results showed that surface chemistry significantly affected cell colony formation via governing the colony edge propagation. More importantly, when surface chemistry of the substrates was uniformly controlled by collagen conjugation, the stiffness of substrate was inversely related to the sphericity, a degree of three dimensionality in colony morphology. The differences in sphericity subsequently affected spontaneous differentiation of IPSCs during a long-term culture, implicating that the colony morphology is a deciding factor in the lineage commitment of PSCs. Overall, we show that the capability of controlling IPSC colony morphology by electrospun substrates provides a means to modulate IPSC self-renewal. PMID- 25736493 TI - Versatile click alginate hydrogels crosslinked via tetrazine-norbornene chemistry. AB - Alginate hydrogels are well-characterized, biologically inert materials that are used in many biomedical applications for the delivery of drugs, proteins, and cells. Unfortunately, canonical covalently crosslinked alginate hydrogels are formed using chemical strategies that can be biologically harmful due to their lack of chemoselectivity. In this work we introduce tetrazine and norbornene groups to alginate polymer chains and subsequently form covalently crosslinked click alginate hydrogels capable of encapsulating cells without damaging them. The rapid, bioorthogonal, and specific click reaction is irreversible and allows for easy incorporation of cells with high post-encapsulation viability. The swelling and mechanical properties of the click alginate hydrogel can be tuned via the total polymer concentration and the stoichiometric ratio of the complementary click functional groups. The click alginate hydrogel can be modified after gelation to display cell adhesion peptides for 2D cell culture using thiol-ene chemistry. Furthermore, click alginate hydrogels are minimally inflammatory, maintain structural integrity over several months, and reject cell infiltration when injected subcutaneously in mice. Click alginate hydrogels combine the numerous benefits of alginate hydrogels with powerful bioorthogonal click chemistry for use in tissue engineering applications involving the stable encapsulation or delivery of cells or bioactive molecules. PMID- 25736492 TI - Initiation of puberty in mice following decellularized ovary transplant. AB - Clinical interventions to preserve fertility and restore hormone levels in female patients with therapy-induced ovarian failure are insufficient, particularly for pediatric cancer patients. Laparoscopic isolation of cortical ovarian tissue followed by cryopreservation with subsequent autotransplantation has temporarily restored fertility in at least 27 women who survived cancer, and aided in pubertal transition for one pediatric patient. However, reintroducing cancer cells through ovarian transplantation has been a major concern. Decellularization is a process of removing cellular material, while maintaining the organ skeleton of extracellular matrices (ECM). The ECM that remains could be stripped of cancer cells and reseeded with healthy ovarian cells. We tested whether a decellularized ovarian scaffold could be created, recellularized and transplanted to initiate puberty in mice. Bovine and human ovaries were decellularized, and the ovarian skeleton microstructures were characterized. Primary ovarian cells seeded onto decellularized scaffolds produced estradiol in vitro. Moreover, the recellularized grafts initiated puberty in mice that had been ovariectomized, providing data that could be used to drive future human transplants and have broader implications on the bioengineering of other organs with endocrine function. PMID- 25736494 TI - Towards long lasting zirconia-based composites for dental implants. Part I: innovative synthesis, microstructural characterization and in vitro stability. AB - In order to fulfill the clinical requirements for strong, tough and stable ceramics used in dental applications, we designed and developed innovative zirconia-based composites, in which equiaxial alpha-Al2O3 and elongated SrAl12O19 phases are dispersed in a ceria-stabilized zirconia matrix. The composite powders were prepared by an innovative surface coating route, in which commercial zirconia powders were coated by inorganic precursors of the second phases, which crystallize on the zirconia particles surface under proper thermal treatment. Samples containing four different ceria contents (in the range 10.0-11.5 mol%) were prepared by carefully tailoring the amount of the cerium precursor during the elaboration process. Slip cast green bodies were sintered at 1450 degrees C for 1 h, leading to fully dense materials. Characterization of composites by SEM and TEM analyses showed highly homogeneous microstructures with an even distribution of both equiaxial and elongated-shape grains inside a very fine zirconia matrix. Ce content plays a major role on aging kinetics, and should be carefully controlled: sample with 10 mol% of ceria were transformable, whereas above 10.5 mol% there is negligible or no transformation during autoclave treatment. Thus, in this paper we show the potential of the innovative surface coating route, which allows a perfect tailoring of the microstructural, morphological and compositional features of the composites; moreover, its processing costs and environmental impacts are limited, which is beneficial for further scale-up and real use in the biomedical field. PMID- 25736496 TI - Nestin(+) kidney resident mesenchymal stem cells for the treatment of acute kidney ischemia injury. AB - Renal resident mesenchymal stem cells (MSCs) are important regulators of kidney homeostasis, repair or regeneration. However, natural distribution and the starting population properties of these cells remain elusive because of the lack of specific markers. Here, we identified post-natal kidney derived Nestin(+) cells that fulfilled all of the criteria as a mesenchymal stem cell. These isolated Nestin(+) cells expressed the typical cell-surface marker of MSC, including Sca-1, CD44, CD106, NG2 and PDGFR-alpha. They were capable of self renewal, possessed high clonogenic potential and extensive proliferation for more than 30 passages. Under appropriate differentiation conditions, these cells could differentiate into adipocytes, osteocytes, chondrocytes and podocytes. After intravenous injection into acute kidney injury mice, Nestin(+) cells contributed to functional improvement by significantly decreasing the peak level of serum creatinine and BUN, and reducing the damaged cell apoptosis. Furthermore, conditioned medium from Nestin(+) cells could protect against ischemic acute renal failure partially through paracrine factor VEGF. Taken together, our findings indicate that renal resident Nestin(+) MSCs can be derived, propagated, differentiated, and repair the acute kidney injury, which may shed new light on understanding MSCs biology and developing cell replacement therapies for kidney disease. PMID- 25736495 TI - Biomaterials differentially regulate Src kinases and phosphoinositide 3-kinase gamma in polymorphonuclear leukocyte primary and tertiary granule release. AB - In the foreign body response, infiltrating PMNs exocytose granule subsets to influence subsequent downstream inflammatory and wound healing events. In previous studies, we found that PMNs cultured on poly(ethylene glycol) (PEG) containing hydrogels (i.e., PEG and gelatin + PEG hydrogels) had enhanced primary granule release, yet similar tertiary granule release compared with PMNs cultured on polydimethylsiloxane or tissue culture polystyrene. PMN primary granules contain microbicidal proteins and proteases, which can potentially injure bystander cells, degrade the extracellular matrix, and promote inflammation. Here, we sought to understand the mechanism of the enhanced primary granule release from PMNs on PEG hydrogels. We found that primary granule release from PMNs on PEG hydrogels was adhesion mediated and involved Src family kinases and PI3K-gamma. The addition of gelatin to PEG hydrogels did not further enhance PMN primary granule release. Using stable-isotope dimethyl labeling-based shotgun proteomics, we identified many serum proteins - including Ig gamma constant chain region proteins and alpha-1-acid glycoprotein 1 - that were absorbed/adsorbed in higher quantities on PEG hydrogels than on TCPS, and may be involved in mediating PMN primary granule release. Ultimately, this mechanistic knowledge can be used to direct inflammation and wound healing following biomaterial implantation to promote a more favorable healing response. PMID- 25736497 TI - ATP-responsive DNA-graphene hybrid nanoaggregates for anticancer drug delivery. AB - Stimuli-triggered drug delivery systems are primarily focused on the applications of the tumor microenvironmental or cellular physiological cues to enhance the release of drugs at the target site. In this study, we applied adenosine-5' triphosphate (ATP), the primary "energy molecule", as a trigger for enhanced release of preloaded drugs responding to the intracellular ATP concentration that is significantly higher than the extracellular level. A new ATP-responsive anticancer drug delivery strategy utilizing DNA-graphene crosslinked hybrid nanoaggregates as carriers was developed for controlled release of doxorubicin (DOX), which consists of graphene oxide (GO), two single-stranded DNA (ssDNA, denoted as DNA1 and DNA2) and ATP aptamer. The single-stranded DNA1 and DNA2 together with the ATP aptamer serve as the linkers upon hybridization for controlled assembly of the DNA-GO nanoaggregates, which effectively inhibited the release of DOX from the GO nanosheets. In the presence of ATP, the responsive formation of the ATP/ATP aptamer complex causes the dissociation of the aggregates, which promoted the release of DOX in the environment with a high ATP concentration such as cytosol compared with that in the ATP-deficient extracellular fluid. This supports the development of a novel ATP-responsive platform for targeted on-demand delivery of anticancer drugs inside specific cells. PMID- 25736498 TI - Bioactive cell-derived matrices combined with polymer mesh scaffold for osteogenesis and bone healing. AB - Successful bone tissue engineering generally requires an osteoconductive scaffold that consists of extracellular matrix (ECM) to mimic the natural environment. In this study, we developed a PLGA/PLA-based mesh scaffold coated with cell-derived extracellular matrix (CDM) for the delivery of bone morphogenic protein (BMP-2), and assessed the capacity of this system to provide an osteogenic microenvironment. Decellularized ECM from human lung fibroblasts (hFDM) was coated onto the surface of the polymer mesh scaffolds, upon which heparin was then conjugated onto hFDM via EDC chemistry. BMP-2 was subsequently immobilized onto the mesh scaffolds via heparin, and released at a controlled rate. Human placenta-derived mesenchymal stem cells (hPMSCs) were cultured in such scaffolds and subjected to osteogenic differentiation for 28 days in vitro. The results showed that alkaline phosphatase (ALP) activity, mineralization, and osteogenic marker expression were significantly improved with hPMSCs cultured in the hFDM coated mesh scaffolds compared to the control and fibronectin-coated ones. In addition, a mouse ectopic and rat calvarial bone defect model was used to examine the feasibility of current platform to induce osteogenesis as well as bone regeneration. All hFDM-coated mesh groups exhibited a significant increase of newly formed bone and in particular, hFDM-coated mesh scaffold loaded with a high dose of BMP-2 exhibited a nearly complete bone defect healing as confirmed via micro-CT and histological observation. This work proposes a great potency of using hFDM (biophysical) coupled with BMP-2 (biochemical) as a promising osteogenic microenvironment for bone tissue engineering applications. PMID- 25736499 TI - Modulation of integrin and E-cadherin-mediated adhesions to spatially control heterogeneity in human pluripotent stem cell differentiation. AB - Heterogeneity in human pluripotent stem cell (PSC) fates is partially caused by mechanical asymmetry arising from spatial polarization of cell-cell and cell matrix adhesions. Independent studies have shown that integrin and E-cadherin adhesions promote opposing differentiation and pluripotent fates respectively although their crosstalk mechanism in modulating cell fate heterogeneity remains unknown. Here, we demonstrated that spatial polarization of integrin and E cadherin adhesions in a human PSC colony compete to recruit Rho-ROCK activated myosin II to different localities to pattern pluripotent-differentiation decisions, resulting in spatially heterogeneous colonies. Cell micropatterning was used to modulate the spatial polarization of cell adhesions, which enabled us to prospectively determine localization patterns of activated myosin II and mesoendoderm differentiation. Direct inhibition of Rho-ROCK-myosin II activation phenocopied E-cadherin rather than integrin inhibition to form uniformly differentiated colonies. This indicated that E-cadherin was the primary gatekeeper to differentiation progression. This insight allows for biomaterials to be tailored for human PSC maintenance or differentiation with minimal heterogeneity. PMID- 25736500 TI - Healing of massive segmental femoral bone defects in minipigs by allogenic ASCs engineered with FLPo/Frt-based baculovirus vectors. AB - Adipose-derived stem cells (ASCs) hold promise for bone regeneration but possess inferior osteogenesis potential. Allotransplantation of ASCs engineered with the BMP2/VEGF-expressing baculoviruses into rabbits healed critical-size segmental bone defects. To translate the technology to clinical applications, we aimed to demonstrate massive bone healing in minipigs that more closely mimicked the clinical scenarios, using a new hybrid baculovirus system consisting of BacFLPo expressing the codon-optimized FLP recombinase (FLPo) and the substrate baculovirus harboring the transgene flanked by Frt sequences. Co-transduction of minipig ASCs (pASCs) with BacFLPo and the substrate baculovirus enabled transgene cassette excision, recombination and minicircle formation in ~73.7% of pASCs, which substantially prolonged the transgene (BMP2 and VEGF) expression to 28 days. When encoding BMP2, the FLPo/Frt-based system augmented the pASCs osteogenesis. Allotransplantation of the BMP2/VEGF-expressing pASCs into minipigs healed massive segmental bone defects (30 mm in length) at the mid-diaphysis of femora, as evaluated by computed tomography, positron emission tomography, histology, immunohistochemical staining and biochemical testing. The defect size was ~15% of femoral length in minipigs and was equivalent to ~60-70 mm of femoral defect in humans, thus the healing using pASCs engineered with the FLPo/Frt-based baculovirus represented a remarkable advance for the treatment of massive bone defects. PMID- 25736501 TI - Osteogenesis on nanoparticulate mineralized collagen scaffolds via autogenous activation of the canonical BMP receptor signaling pathway. AB - Skeletal regenerative medicine frequently incorporates deliverable growth factors to stimulate osteogenesis. However, the cost and side effects secondary to supraphysiologic dosages of growth factors warrant investigation of alternative methods of stimulating osteogenesis for clinical utilization. In this work, we describe growth factor independent osteogenic induction of human mesenchymal stem cells (hMSCs) on a novel nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC-GAG). hMSCs demonstrated elevated osteogenic gene expression and mineralization on MC-GAG with minimal to no effect upon addition of BMP-2 when compared to non-mineralized scaffolds (Col-GAG). To investigate the intracellular pathways responsible for the increase in osteogenesis, we examined the canonical and non-canonical pathways downstream from BMP receptor activation. Constitutive Smad1/5 phosphorylation with nuclear translocation occurred on MC-GAG independent of BMP-2, whereas Smad1/5 phosphorylation depended on BMP-2 stimulation on Col GAG. When non-canonical BMPR signaling molecules were examined, ERK1/2 phosphorylation was found to be decreased in MC-GAG but elevated in Col-GAG. No differences in Smad2/3 or p38 activation were detected. Collectively, these results demonstrated that MC-GAG scaffolds induce osteogenesis without exogenous BMP-2 addition via endogenous activation of the canonical BMP receptor signaling pathway. PMID- 25736502 TI - Arterial grafts exhibiting unprecedented cellular infiltration and remodeling in vivo: the role of cells in the vascular wall. AB - OBJECTIVE: To engineer and implant vascular grafts in the arterial circulation of a pre-clinical animal model and assess the role of donor medial cells in graft remodeling and function. APPROACH AND RESULTS: Vascular grafts were engineered using Small Intestinal Submucosa (SIS)-fibrin hybrid scaffold and implanted interpositionally into the arterial circulation of an ovine model. We sought to demonstrate implantability of SIS-Fibrin based grafts; examine the remodeling; and determine whether the presence of vascular cells in the medial wall was necessary for cellular infiltration from the host and successful remodeling of the implants. We observed no occlusions or anastomotic complications in 18 animals that received these grafts. Notably, the grafts exhibited unprecedented levels of host cell infiltration that was not limited to the anastomotic sites but occurred through the lumen as well as the extramural side, leading to uniform cell distribution. Incoming cells remodeled the extracellular matrix and matured into functional smooth muscle cells as evidenced by expression of myogenic markers and development of vascular reactivity. Interestingly, tracking the donor cells revealed that their presence was beneficial but not necessary for successful grafting. Indeed, the proliferation rate and number of donor cells decreased over time as the vascular wall was dominated by host cells leading to significant remodeling and development of contractile function. CONCLUSIONS: These results demonstrate that SIS-Fibrin grafts can be successfully implanted into the arterial circulation of a clinically relevant animal model, improve our understanding of vascular graft remodeling and raise the possibility of engineering mural cell-free arterial grafts. PMID- 25736503 TI - Bio-inspired oligovitronectin-grafted surface for enhanced self-renewal and long term maintenance of human pluripotent stem cells under feeder-free conditions. AB - Current protocols for human pluripotent stem cell (hPSC) expansion require feeder cells or matrices from animal sources that have been the major obstacle to obtain clinical grade hPSCs due to safety issues, difficulty in quality control, and high expense. Thus, feeder-free, chemically defined synthetic platforms have been developed, but are mostly confined to typical polystyrene culture plates. Here, we report a chemically defined, material-independent, bio-inspired surface coating allowing for feeder-free expansion and maintenance of self-renewal and pluripotency of hPSCs on various polymer substrates and devices. Polydopamine (pDA)-mediated immobilization of vitronectin (VN) peptides results in surface functionalization of VN-dimer/pDA conjugates. The engineered surfaces facilitate adhesion, proliferation, and colony formation of hPSCs via enhanced focal adhesion, cell-cell interaction, and biophysical signals, providing a chemically defined, xeno-free culture system for clonal expansion and long-term maintenance of hPSCs. This surface engineering enables the application of clinically-relevant hPSCs to a variety of biomedical systems such as tissue-engineering scaffolds and medical devices. PMID- 25736504 TI - Affinity binding of antibodies to supermacroporous cryogel adsorbents with immobilized protein A for removal of anthrax toxin protective antigen. AB - Polymeric cryogels are efficient carriers for the immobilization of biomolecules because of their unique macroporous structure, permeability, mechanical stability and different surface chemical functionalities. The aim of the study was to demonstrate the potential use of macroporous monolithic cryogels for biotoxin removal using anthrax toxin protective antigen (PA), the central cell-binding component of the anthrax exotoxins, and covalent immobilization of monoclonal antibodies. The affinity ligand (protein A) was chemically coupled to the reactive hydroxyl and epoxy-derivatized monolithic cryogels and the binding efficiencies of protein A, monoclonal antibodies to the cryogel column were determined. Our results show differences in the binding capacity of protein A as well as monoclonal antibodies to the cryogel adsorbents caused by ligand concentrations, physical properties and morphology of surface matrices. The cytotoxicity potential of the cryogels was determined by an in vitro viability assay using V79 lung fibroblast as a model cell and the results reveal that the cryogels are non-cytotoxic. Finally, the adsorptive capacities of PA from phosphate buffered saline (PBS) were evaluated towards a non-glycosylated, plant derived human monoclonal antibody (PANG) and a glycosylated human monoclonal antibody (Valortim((r))), both of which were covalently attached via protein A immobilization. Optimal binding capacities of 108 and 117 mg/g of antibody to the adsorbent were observed for PANG attached poly(acrylamide-allyl glycidyl ether) [poly(AAm-AGE)] and Valortim((r)) attached poly(AAm-AGE) cryogels, respectively, This indicated that glycosylation status of Valortim((r)) antibody could significantly increase (8%) its binding capacity relative to the PANG antibody on poly(AAm-AGE)-protien-A column (p < 0.05). The amounts of PA which remained in the solution after passing PA spiked PBS through PANG or Valortim bound poly(AAm AGE) cryogel were significantly (p < 0.05) decreased relative to the amount of PA remained in the solution after passing through unmodified as well as protein A modified poly(AAm-AGE) cryogel columns, indicates efficient PA removal from spiked PBS over 60 min of circulation. The high adsorption capacity towards anthrax toxin PA of the cryogel adsorbents indicated potential application of these materials for treatment of Bacillus anthracis infection. PMID- 25736505 TI - Multifunctional hollow CaF2:Yb(3+)/Er(3+)/Mn(2+)-poly(2-Aminoethyl methacrylate) microspheres for Pt(IV) pro-drug delivery and tri-modal imaging. AB - Combining the multi-modal medical imaging with cancer therapy in one single system has attracted the great interests for theranostic purpose. In this paper, CaF2:Yb(3+)/Er(3+)/Mn(2+)-poly(2-Aminoethyl methacrylate) (UCHNs-PAMA) hybrid microspheres were successfully fabricated. The synthetic route to the nanocomposite based on a facile hydrothermal method for fabrication of hollow upconversion (UC) nanospheres at first and then post-filling the PAMA interiorly through photo-initiated polymerization. The UCHNs showed orange fluorescence under 980 nm near infrared (NIR) laser excitation, which provided the upconverting luminescence (UCL) imaging modality. Meanwhile, the presence of functional Mn(2+) and Yb(3+) offered the enhanced T1-weighted magnetic resonance (MR) and computed tomography (CT) imaging, respectively. Thanks to introducing amine groups-containing PAMA inside the hollow nanospheres, the Pt(IV) pro-drug, c,c,t-Pt(NH3)2Cl2(OOCCH2CH2COOH)2 (DSP), can be conveniently bonded on the polymer network to construct a nanoscale anti-cancer drug carrier. The UCHNs-PAMA Pt(IV) nanocomposite shows effective inhibition for Hela cell line via MTT assay. In contrast, Pt(IV) pro-drug and UCHNs-PAMA microspheres behave little cytotoxicity to Hela cells. This should be attributed the fact that the anti cancer ability can be recovered only when Pt(IV) pro-drug was reduced to Pt(II) drug in cellular environment. Furthermore, the in vivo experiments on small mice also confirm that the hybrid microspheres have relatively low toxic side effects and high tumor inhibition rate. These findings show that the multifunctional hybrid microspheres have potential to be used as UCL/MR/CT tri-modal imaging contrast agent and anti-cancer drug carriers. PMID- 25736506 TI - Porous nanoparticles as delivery system of complex antigens for an effective vaccine against acute and chronic Toxoplasma gondii infection. AB - Development of sub-unit mucosal vaccines requires the use of specific delivery systems or immune-modulators such as adjuvants to improve antigen immunogenicity. Nasal route for vaccine delivery by nanoparticles has attracted much interest but mechanisms triggering effective mucosal and systemic immune response are still poorly understood. Here we study the loading of porous nanoparticles (DGNP) with a total extract of Toxoplasma gondii antigens (TE), the delivery of TE by DGNP into airway epithelial, macrophage and dendritic cells, and the subsequent cellular activation. In vitro, DGNP are able to load complex antigens in a stable and quantitative manner. The outstanding amount of antigen association by DGNP is used to deliver TE in airway mucosa cells to induce a cellular maturation with an increased secretion of pro-inflammatory cytokines. Evaluation of nasal vaccine efficiency is performed in vivo on acute and chronic toxoplasmosis mouse models. A specific Th1/Th17 response is observed in vivo after vaccination with DGNP/TE. This is associated with high protection against toxoplasmosis regarding survival and parasite burden, correlated with an increased delivery of antigens by DGNP in airway mucosa cells. This study provides evidence of the potential of DGNP for the development of new vaccines against a range of pathogens. PMID- 25736508 TI - Single crystal to single crystal (SC-to-SC) transformation from a nonporous to porous metal-organic framework and its application potential in gas adsorption and Suzuki coupling reaction through postmodification. AB - A new amino-functionalized strontium-carboxylate-based metal-organic framework (MOF) has been synthesized that undergoes single crystal to single crystal (SC-to SC) transformation upon desolvation. Both structures have been characterized by single-crystal X-ray analysis. The desolvated structure shows an interesting 3D porous structure with pendent -NH2 groups inside the pore wall, whereas the solvated compound possesses a nonporous structure with DMF molecules on the metal centers. The amino group was postmodified through Schiff base condensation by pyridine-2-carboxaldehyde and palladium was anchored on that site. The modified framework has been utilized for the Suzuki cross-coupling reaction. The compound shows high activity towards the C-C cross-coupling reaction with good yields and turnover frequencies. Gas adsorption studies showed that the desolvated compound had permanent porosity and was microporous in nature with a BET surface area of 2052 m(2) g(-1). The material also possesses good CO2 (8 wt %) and H2 (1.87 wt %) adsorption capabilities. PMID- 25736507 TI - Molecular beacon-based detection and isolation of working-type cardiomyocytes derived from human pluripotent stem cells. AB - Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) provide a potential source of cells to repair injured ventricular myocardium. CM differentiation cultures contain non-cardiac cells and CMs of both nodal and working subtypes. Direct application of such cultures in clinical studies could induce arrhythmias; thus, further purification of working-type CMs from heterogeneous cultures is desirable. Here, we designed 10 molecular beacons (MBs) targeting NPPA mRNA, a marker associated with working-type CMs and highly up-regulated during differentiation. We examined these MBs by solution assays and established their specificity using NPPA-overexpressing CHO cells as well as hPSC-CMs. We selected one MB for subsequent CM subtype isolation using fluorescence-activated cell sorting because the signal-to-background ratio was the highest for this MB in solution assays and a linear correlation was observed between MB signals and the CM purity in differentiation cultures. Compared with cells with low MB signals, cells positively selected based on MB signal had higher expression levels of genes associated with working-type CMs and lower expression levels of genes associated with nodal-type CMs. Therefore, the MB-based method is capable of separating working-type CMs from nodal-type CMs with high specificity and throughput, potentially providing working-type CMs for biomedical applications. PMID- 25736509 TI - SnRK1 from Arabidopsis thaliana is an atypical AMPK. AB - SNF1-related protein kinase 1 (SnRK1) is the plant orthologue of the evolutionarily-conserved SNF1/AMPK/SnRK1 protein kinase family that contributes to cellular energy homeostasis. Functional as heterotrimers, family members comprise a catalytic alpha subunit and non-catalytic beta and gamma subunits; multiple isoforms of each subunit type exist, giving rise to various isoenzymes. The Arabidopsis thaliana genome contains homologues of each subunit type, and, in addition, two atypical subunits, beta(3) and betagamma, with unique domain architecture, that are found only amongst plants, suggesting atypical heterotrimers. The AtSnRK1 subunit structure was determined using recombinant protein expression and endogenous co-immunoprecipitation, and six unique isoenzyme combinations were identified. Each heterotrimeric isoenzyme comprises a catalytic alpha subunit together with the unique betagamma subunit and one of three non-catalytic beta subunits: beta(1), beta(2) or the plant-specific beta(3) isoform. Thus, the AtSnRK1 heterotrimers contain the atypical betagamma subunit rather than a conventional gamma subunit. Mammalian AMPK heterotrimers are phosphorylated on the T-loop (pThr175/176) within both catalytic a subunits. However, AtSnRK1 is insensitive to AMP and ADP, and is resistant to T-loop dephosphorylation by protein phosphatases, a process that inactivates other SNF1/AMPK family members. In addition, we show that SnRK1 is inhibited by a heat labile, >30 kDa, soluble proteinaceous factor that is present in the lysate of young rosette leaves. Finally, none of the three SnRK1 carbohydrate-binding modules, located in the beta(1), beta(2) and betagamma subunits, associate with various carbohydrates, including starch, the plant analogue of glycogen to which AMPK binds in vitro. These data clearly demonstrate that AtSnRK1 is an atypical member of the SNF1/AMPK/SnRK1 family. PMID- 25736510 TI - Functional Neuroanatomical Correlates of The Frontal Assessment Battery Performance in Alzheimer Disease: A FDG-PET Study. AB - BACKGROUND/OBJECTIVES: We aimed to elucidate the functional neuroanatomical correlates of Frontal Assessment Battery (FAB) performances by applying [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) to a large population of patients with Alzheimer disease (AD). METHODS: The FAB was administered to 177 patients with AD, and regional cerebral glucose metabolism (rCMglc) was measured by FDG-PET scan. Correlations between FAB scores and rCMglc were explored using both region-of-interest-based (ROI-based) and voxel-based approaches. RESULTS: The ROI-based analysis showed that FAB scores correlated with the rCMglc of the dorsolateral prefrontal cortices. Voxel-based approach revealed significant positive correlations between FAB scores and rCMglc which were in various cortical regions including the temporal and parietal cortices as well as frontal regions, independent of age, gender, and education. After controlling the effect of global disease severity with Mini-Mental State Examination score, significant positive correlation was found only in the bilateral prefrontal regions. CONCLUSIONS: Although FAB scores are influenced by temporoparietal dysfunction due to the overall progression of AD, it likely reflects prefrontal dysfunction specifically regardless of global cognitive state or disease severity in patients with AD. PMID- 25736511 TI - Association between polymorphisms of the swine MHC-DQA gene and diarrhoea in three Chinese native piglets. AB - Swine leucocyte antigen (SLA) is a highly polymorphic multigene family that plays a crucial role in swine immune response and disease resistance. Here, we identified polymorphisms and gene variations of SLA-DQA exon 2 using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing analysis, and further investigated the correlation between the polymorphisms and piglet diarrhoea in three Chinese native pig breeds (Bamei, Juema and Gansu Black pigs). Consequently, 12 genotypes and 8 alleles including two novel alleles were detected. Nucleotide polymorphism was compared with the actual functional polymorphism in the peptide-binding region (PBR), binding pockets P1, P6 and P9, and the antigen-binding groove, variations in the antigen binding groove of alleles DQA*01xa01, DQA*01xa03, DQA*01xb01, DQA*We02, DQA*03xb03 and DQA*wy06 were higher than alleles DQA*03xa01 and DQA*03xa03, while amino acid variations in peptide-binding pockets of allele DQA*03xa03 were most abundant among all alleles. The results of association analysis showed the diarrhoea score of Gansu Black pigs (-0.08 +/- 0.78) was significantly higher than Bamei and Juema pigs (P < 0.01), and genotype DQA*03xa0103xa01 (0.39 +/- 0.54) was significantly higher relative to other genotypes (P < 0.01), while that of genotype DQA*03xa0303xa03 (-1.31 +/- 0.88) was markedly lower than scores obtained with genotypes DQA*03xa0103xa01 and DQA*03xa0101xa01 (P < 0.01), as well as DQA*01xa0101xa01 (P < 0.05), indicating that amino acid variations in the peptide-binding pockets play a more important role than the antigen-binding groove in piglet diarrhoea resistance. Further studies on other SLA molecules of native pigs are required to validate the link between this gene complex and diarrhoea. PMID- 25736512 TI - Peri-procedural Risk with Urgent Carotid Artery Stenting: A Population based Swedvasc Study. AB - OBJECTIVES: Current European Society for Vascular Surgery guidelines recommend that patients with a symptomatic carotid stenosis should be operated on within 14 days of onset of symptoms. Recent reports indicate that carotid endarterectomy (CEA) within 2 days of a neurological event may be associated with a higher peri procedural risk of stroke. Whether urgent carotid artery stenting (CAS) carries a similar high risk is unclear. The aim of this study was to analyze if urgent CAS increases the peri-procedural risks. METHODS: Retrospective analysis of all CAS registered in Swedvasc, a validated nationwide registry, between January 1, 2005, and March 20, 2014. Only symptomatic patients treated for a stenosis of the internal carotid artery were included. Patients were categorized according to time from index event to surgery; 0-2 days, 3-7 days, 8-14 days, and 15-180 days. Primary outcome was 30 day combined stroke and death rate. RESULTS: 323 patients underwent CAS for symptomatic carotid artery stenosis. The demographic and clinical data were similar in the groups. No procedure related complications or deaths were observed in the urgent CAS group. The 30 day combined stroke and death rate did not differ significantly between the groups; zero of 13 (0%; 95% CI 0-26.6) in the group treated 0-2 days versus four of 85 (4.7%; 95% CI 1.5 11.9), at 3-7 days, five of 80 (6.3%; 95% CI 2.4-14.1) at 8-14 days, and six of 145 (4.1%; 95% CI 1.7-8.9) for the patients treated at 15-180 days (p = .757). Stroke and death were not more frequent for patients treated within 1 week compared with after 1 week: 4 out of 98 (4.1%; 95% CI 1.3-9.0) versus 11/225 (4.9%; 95% CI 2.7-8.6) (p = .751). CONCLUSIONS: In this national registry study, CAS performed within 1 week of the onset of a neurologic event was not associated with an additional risk of a peri-operative complication compared with those treated subsequently. PMID- 25736513 TI - Peripheral artery disease: a marked lack of awareness in Ireland. AB - OBJECTIVES: Patients with symptomatic peripheral artery disease (PAD) have a 30% risk of death within 5 years. However, public awareness of vascular disease has been shown to be low. The aim of this study was to assess awareness regarding risk factors, significance and potential sequelae of PAD in an Irish population. DESIGN: A cross-sectional, anonymous survey of patients and members of the public. MATERIALS: An anonymous questionnaire was developed to collect details on basic demographics, presence of and treatment for risk factors for cardiovascular disease, awareness of PAD and its risk factors and sequelae. The local ethics committee granted ethical approval. METHODS: Two investigators in face-to-face interviews administered the survey with patients and members of the general public, older than 40 years of age, attending a range of outpatient clinics, day care services and in patients. RESULTS: A total of 336 questionnaires were administered. A post-secondary school course had been completed by 32% of respondents. Only 19% of patients reported familiarity with PAD, a figure considerably lower than those reporting familiarity with stroke (94%), coronary artery disease (78%) or diabetes (98%) (Chi Squared p<0.001). The only independent predictor of awareness of PAD was having a post-secondary school course with an odds ratio or 4.2. CONCLUSIONS: This study demonstrates a disturbing lack of awareness of PAD and highlight the need for a meaningful targeted public health awareness campaign on PAD in order to close the gap of knowledge in Irish patients, prior to any prevention campaign. PMID- 25736514 TI - Intra-operative cone beam computed tomography can help avoid reinterventions and reduce CT follow up after infrarenal EVAR. AB - OBJECTIVE/BACKGROUND: Re-interventions after endovascular abdominal aortic aneurysm repair (EVAR) are common and therefore a strict imaging follow up protocol is required. The purpose of this study was to evaluate whether cone beam computed tomography (CBCT) can detect intra-operative complications and to compare this with angiography and the 1 month CT follow up (computed tomography angiography [CTA]). METHODS: Fifty-one patients (44 men) were enrolled in a prospective trial. Patients underwent completion angiography and CBCT during infrarenal EVAR. Contrast was used except when pre-operative renal insufficiency was present or if the maximum contrast dose threshold was reached. CBCT reconstruction included the top of the stent graft to the iliac bifurcation. Endoleaks, kinks, or compressions were recorded. RESULTS: CBCT was technically successful in all patients. Twelve endoleaks were detected on completion digital subtraction angiography (CA). CBCT detected 4/5 type 1 endoleaks, but only one type 2 endoleak. CTA identified eight type 2 endoleaks and one residual type I endoleak. Two cases of stent compression were seen on CA. CBCT revealed five stent compressions and one kink, which resulted in four intra-operative adjunctive manoeuvres. CTA identified all cases of kinks or compressions that were left untreated. Two of them were corrected later. No additional kinks/compressions were found on CTA. Groin closure consisted of 78 fascia sutures, nine cut downs, and 11 percutaneous sutures. Seven femoral artery pseudoaneurysms (<1 cm) were detected on CTA, but no intervention was needed. CONCLUSION: CA is better than CBCT in detecting and categorizing endoleaks but CBCT (with or without contrast) is better than CA for detection of kinks or stentgraft compression. CTA plus CBCT identified all significant complications noted on the 1 month follow up CTA. The use of intra-operative CA and CBCT could replace early CTA after standard EVAR thus reducing overall radiation and contrast use. Technical development might further improve the resolution and usefulness of CBCT. PMID- 25736515 TI - Cumulative incidence of graft infection after primary prosthetic aortic reconstruction in the endovascular era. AB - OBJECTIVE: The introduction of endovascular techniques has had a major impact on the case mix of patients that undergo open aortic reconstruction. Hypothetically, this may also have increased the incidence of aortic graft infection (AGI). The aim of this study was to report on the short and mid-term incidence of AGI after primary open prosthetic aortic reconstruction in the endovascular era. METHODS: From 2000 to 2010, all 514 patients in a tertiary referral university hospital, undergoing primary open prosthetic aortic reconstruction for aneurysmal or occlusive aortic disease with at least one aortic anastomosis were included. Data were obtained by retrospectively analyzing the medical records, by contacting patients or their general practitioner by telephone, and by merging the dataset with the national Cause of Death Register. AGI was defined as proven by cultures or clinically in combination with positive imaging results. The 30 day, 1 year, and 2 year incidence rates were computed using life table analysis and expressed as percentages with 95% confidence intervals (CI). RESULTS: AGI was diagnosed in 23 of the 514 included patients. 56% of the patients underwent elective surgery and 86% underwent surgery for an abdominal aortic aneurysm. The 30 day incidence was 1.6% (95% CI 0.4-2.8%), 1 year incidence was 3.6% (95% CI 1.7-5.5%), and 2 year incidence for AGI was 4.5% (95% CI 2.4-6.6%). The total number of person years (1058) yielded an AGI rate of 2.2 per 100 person years. CONCLUSION: The 2 year cumulative incidence of AGI following primary, open aortic procedures with at least one aortic anastomosis is considerable, at around 1 in 20. PMID- 25736516 TI - Incidence of Acute Kidney Injury (AKI) after Endovascular Abdominal Aortic Aneurysm Repair (EVAR) and Impact on Outcome. AB - BACKGROUND: Acute kidney injury (AKI) is an important post-operative complication that may impact on mortality, morbidity, and cost. The incidence after endovascular aneurysm repair (EVAR) remains unknown, as the current literature has not employed consistent definitions. The aim of this study is to assess the incidence of AKI after elective EVAR and examine the impact of AKI on mortality and cardiovascular morbidity using the current universally accepted definitions. METHODS: This was a cohort study using prospectively collected data, including consecutive patients undergoing elective EVAR for an infrarenal abdominal aortic aneurysm (AAA). Those with end stage renal failure were excluded. The primary endpoint was incidence of AKI as per the "Acute Kidney Injury Network" (AKIN), and "Kidney Disease Improving Global Outcomes" (KDIGO) criteria. Secondary endpoints included AKI stage, drop in estimated glomerular filtration rate (eGFR), and mortality and cardiovascular morbidity. RESULTS: 149 patients were included (16 females, 11%; mean age: 69 +/- 8 years; mean AAA diameter: 6.0 +/- 1.1 cm), 28 (18.8%) of whom developed AKI (26 patients classified as stage 1 and 2 as stage 2). Within 48 hours, those with AKI dropped their eGFR from 61 +/- 20 mL/kg/1.73 m(2) to 51 +/- 20 units (p < .001), and those without from 75 +/- 9 to 74 +/- 10 units (p < .001). None required dialysis during a 33 +/- 11 month follow up. Development of AKI was associated with mortality (HR 0.035, 95% CI: 0.005 to 0.240, p < .001) and cardiovascular morbidity (HR: 0.021, 95% CI: 0.004 to 0.11, p < .001) on adjusted regression analysis. CONCLUSIONS: The incidence of AKI after EVAR is significant and is independently associated with medium-term mortality and morbidity. PMID- 25736517 TI - The Necessity for Routine Pre-operative Ultrasound Mapping Before Arteriovenous Fistula Creation: A Meta-analysis. AB - OBJECTIVE/BACKGROUND: Existing guidelines suggest routine use of pre-operative color Doppler ultrasound (DUS) vessel mapping before the creation of arteriovenous fistulae (AVF); however, there is controversy about its benefit over traditional clinical examination or selective ultrasound use. METHODS: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing routine DUS mapping before the creation of AVF with patients for whom the decision for AVF placement was based on clinical examination and selective ultrasound use. A search of MEDLINE/PubMed, SCOPUS, and the Cochrane Library was carried out in June 2014. The analyzed outcome measures were the immediate failure rate and the early/midterm adequacy of the fistula for hemodialysis. Additionally, assessment of the methodological quality of the included studies was carried out. RESULTS: Five studies (574 patients) were analyzed. A random effects model was used to pool the data. The pooled odds ratio (OR) for the immediate failure rate was 0.32 (95% confidence interval [CI] 0.17-0.60; p < .01), which was significantly in favor of the DUS mapping group. The pooled OR for the early/midterm adequacy for hemodialysis was 0.66 (95% CI 0.42-1.03; p = .06), with a trend in favor of the DUS mapping group; however, subgroup analysis revealed that routine DUS mapping was more beneficial than selective DUS (p < .05). CONCLUSION: The available evidence, based mainly on moderate quality RCTs, suggests that the pre-operative clinical examination should always be supplemented with routine DUS mapping before AVF creation. This policy avoids negative surgical explorations and significantly reduces the immediate AVF failure rate. PMID- 25736518 TI - Switchable Pickering emulsions stabilized by silica nanoparticles hydrophobized in situ with a conventional cationic surfactant. AB - A stable oil-in-water Pickering emulsion stabilized by negatively charged silica nanoparticles hydrophobized in situ with a trace amount of a conventional cationic surfactant can be rendered unstable on addition of an equimolar amount of an anionic surfactant. The emulsion can be subsequently restabilized by adding a similar trace amount of cationic surfactant along with rehomogenization. This destabilization-stabilization behavior can be cycled many times, demonstrating that the Pickering emulsion is switchable. The trigger is the stronger electrostatic interaction between the oppositely charged ionic surfactants compared with that between the cationic surfactant and the (initially) negatively charged particle surfaces. The cationic surfactant prefers to form ion pairs with the added anionic surfactant and thus desorbs from particle surfaces rendering them surface-inactive. This access to switchable Pickering emulsions is easier than those employing switchable surfactants, polymers, or surface-active particles, avoiding both the complicated synthesis and the stringent switching conditions. PMID- 25736519 TI - Liver transplantation with deceased ABO-incompatible donors is life-saving but associated with increased risk of rejection and post-transplant complications. AB - ABO-incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO-compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13-75); 33 patients were transplanted on urgent indications, 13 had malignancy-related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10 86). Forty-four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty-four patients received induction with IL-2 antagonist or anti-CD20 antibody. Median follow-up time was 29 months (range 0-200). The 1-, 3-, 5-, and 10-year Kaplan-Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1-, 3-, 5-, and 10-year GS for A2 grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non-A2 grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A2 grafts is associated with acceptable graft survival and can be used safely in urgent cases. PMID- 25736520 TI - What is the nature of the autism 'spectrum'? PMID- 25736522 TI - Distinct localizations and roles of non-muscle myosin II during proplatelet formation and platelet release. AB - BACKGROUND: At the end of maturation, megakaryocytes (MKs) form long cytoplasmic extensions called proplatelets (PPT). Enormous changes in cytoskeletal structures cause PPT to extend further, to re-localize organelles such as mitochondria and to fragment, leading to platelet release. Two non-muscle myosin IIs (NMIIs) are expressed in MKs; however, only NMII-A (MYH9), but not NMII-B (MYH10), is expressed in mature MKs and is implicated in PPT formation. OBJECTIVES: To provide in vivo evidence on the specific role of NMII-A and IIB in MK PPT formation. METHODS: We studied two transgenic mouse models in which non-muscle myosin heavy chain (NMHC) II-A was genetically replaced either by II-B or by a chimeric NMHCII that combined the head domain of II-A with the rod and tail domains of II-B. RESULTS AND CONCLUSIONS: This work demonstrates that the kinetic properties of NM-IIA, depending on the N-terminal domain, render NMII-A the better NMII candidate to control PPT formation. Furthermore, the carboxyl terminal domain determines myosin II localization in the constriction region of PPT and is responsible for the specific role of NMII in platelet release. PMID- 25736521 TI - Metabolomics specificity of tuberculosis plasma revealed by (1)H NMR spectroscopy. AB - Tuberculosis (TB) is a communicable disease of major global importance and causes metabolic disorder of the patients. In a previous study, we found that the plasma metabolite profile of TB patients differs from that of healthy control subjects based on nuclear magnetic resonance (NMR) spectroscopy. In order to evaluate the TB specificity of the metabolite profile, a total of 110 patients, including 40 with diabetes, 40 with malignancy, and 30 with community-acquired pneumonia (CAP), assessed by NMR spectroscopy, and compared to those of patients with TB. Based on the orthogonal partial least-squares discriminant analysis (OPLS-DA), the metabolic profiles of these diseases were significant different, as compared to the healthy controls and TB patients, respectively. The score plots of the OPLS-DA model demonstrated that TB was easily distinguishable from diabetes, CAP and malignancy. Plasma levels of ketone bodies, lactate, and pyruvate were increased in TB patient compared to healthy control, but lower than CAP and malignancy. We conclude that the metabolic profiles were TB-specific and reflected MTB infection. Our results strongly support the NMR spectroscopy-based metabolomics could contribute to an improved understanding of disease mechanisms and may offer clues to new TB clinic diagnosis and therapies. PMID- 25736523 TI - Fetal laser therapy: applications in the management of fetal pathologies. AB - Fetoscopic coagulation of placental anastomoses is the treatment of choice for severe twin-to-twin transfusion syndrome. In the present day, fetal laser therapy is also used to treat amniotic bands, chorioangiomas, sacrococcygeal teratomas, lower urinary tract obstructions and chest masses, all of which will be reviewed in this article. Amniotic band syndrome can cause limb amputation by impairing downstream blood flow. Large chorioangiomas (>4 cm), sacrococcygeal teratomas or fetal hyperechoic lung lesions can lead to fetal compromise and hydrops by vascular steal phenomenon or compression. Renal damage, bladder dysfunction and lastly death because of pulmonary hypolasia may be the result of megacystis caused by a posterior urethral valve. The prognosis of these pathologies can be dismal, and therapy options are limited, which has brought fetal laser therapy to the forefront. Management options discussed here are laser release of amniotic bands, laser coagulation of the placental or fetal tumor feeding vessels and laser therapy by fetal cystoscopy. This review, largely based on case reports, does not intend to provide a level of evidence supporting laser therapy over other treatment options. Centralized evaluation by specialists using strict selection criteria and long-term follow-up of these rare cases are now needed to prove the value of endoscopic or ultrasound-guided laser therapy. PMID- 25736524 TI - Anti-lipoteichoic acid monoclonal antibody (pagibaximab) studies for the prevention of staphylococcal bloodstream infections in preterm infants. AB - INTRODUCTION: Advances in modern medicine have given very low birth weight (VLBW) infants a better chance of survival; however, these infants remain at high risk for developing nosocomial infections associated with increased morbidity and mortality. The ability of antistaphylococcal immunoglobulins, Altastaph and INH A 2, to augment the neonatal immune system to prevent infections has been studied and evaluated in a 2009 Cochrane review. AREAS COVERED: Our objective is to evaluate the safety and efficacy of a third antistaphylococcal immunoglobulin, pagibaximab, in the prevention of staphylococcal infection in preterm infants. Three studies of pagibaximab, Phases I, II and III, were examined in terms of study design, pharmacokinetics, development of sepsis and adverse effects. EXPERT OPINION: These studies demonstrated safety and tolerability of pagibaximab with no observed reduction in sepsis. Reported adverse events in both treatment and placebo groups were similar and consistent with events commonly observed in VLBW infants. Antistaphylococcal immunoglobulins alone have been unsuccessful in preventing nosocomial infections. Further investigations need to evaluate any potential immunomodulating products in preterm animal models prior to human studies. Future studies are required to determine how to best augment the immature immune system, likely through the use of multiple immunomodulating agents to successfully prevent infections in preterm infants. PMID- 25736525 TI - Unrecognized arterial cannulation due to the backflow feature of the BD InsyteTM AutoguardTM BC cannula. PMID- 25736526 TI - Homochiral coordination cages assembled from dinuclear paddlewheel nodes and enantiopure ditopic ligands: syntheses, structures and catalysis. AB - A series of homochiral metal-organic cages (MOCs) have been obtained from self assembly of Cu(II) salts with chiral N,N'-(bicyclo[2,2,2]oct-7-ene tetracarboxylic)-bis-amino acids. Single-crystal X-ray diffraction analyses reveal that these compounds show a lantern-type cage structure, in which one pair of Cu2(CO2)4 paddlewheels is linked by four diacid ligands. The resulting homochiral cages have been fully characterized by EA, TOF-MS, TGA, VTPXRD, IR, UV, and CD measurements. The catalytic tests reveal that these Cu(II) cages are effective in cyclopropanation with excellent diastereoselectivity (up to 99 : 1 E/Z). In addition, the cage catalysts can promote the aziridination reaction with PhI=NNs. PMID- 25736527 TI - Distribution profile of gadolinium in gadolinium chelate-treated renally-impaired rats: role of pharmaceutical formulation. AB - While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt ("free" Gd) or low stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5 mmol Gd/kg) either alone or after being spiked with either "free" gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01 mmol Gd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of "free", non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in "free" gadolinium salt treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The presence of impurities in the GC pharmaceutical solution may have long-term biological consequences. PMID- 25736528 TI - Orodispersible drug formulations for children and elderly. AB - Various orodispersible drug formulations have been recently introduced into the market. Oral lyophilisates and orodispersible granules, tablets or films have enriched the therapeutic options. In particular, the paediatric and geriatric population may profit from the advantages like convenient administration, lack of swallowing, ease of use. Until now, only a few novel products made it to the market as the development and production usually is more expensive than for conventional oral drug dosage forms like tablets or capsules. The review reports the recent advances, existing and upcoming products, and the significance of formulating patient-friendly oral dosage forms. The preparation of the medicines can be performed both in pharmaceutical industry and in community pharmacies. Recent advances, e.g. drug printing technologies, may facilitate this process for community or hospital pharmacies. Still, regulatory guidelines and pharmacopoeial monographs lack appropriate methods, specifications and global harmonization to foster the development of innovative orodispersible drug dosage forms. PMID- 25736529 TI - mGluR5 in the nucleus accumbens shell regulates morphine-associated contextual memory through reactive oxygen species signaling. AB - Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) critically modulates drug and drug-related behaviors. However, the role of mGluR5 in the opiate-induced contextual memory remains unclear. Here, we found that microinfusion of the mGluR5 antagonist 3-((2-Methyl-1,3-thiazol-4 yl)ethynyl)pyridine (MTEP) into the nucleus accumbens (NAc) shell, but not into the core, significantly attenuated the expression of morphine conditioned place preference (CPP) in rats. Following the expression of morphine CPP, the protein level of membrane mGluR5 was selectively increased in the NAc shell. In primary striatal neurons, we observed that treatment with the mGluR5 agonist CHPG increased the phosphorylation level of extracellular signal-regulated kinase (ERK), which was dependent on the mGluR5-inositol-1,4,5-trisphosphate-reactive oxygen species (ROS) pathway. Moreover, the microinjection of the ROS scavenger Tempol into the NAc shell of rats blocked the expression of morphine CPP. Further, the administration of t-BOOH, a ROS donor, into the NAc shell rescued the retrieval impairment of morphine CPP produced by MTEP. Our previous study demonstrated that the expression of morphine CPP increased the phosphorylation of ERK selectively in the NAc shell. Thus, results of the present study suggest that mGluR5 in the NAc shell, but not in the core, is essential for the retrieval of morphine contextual memory, which is mediated at least in part, through the ROS/ERK signaling pathway. Uncovering the molecular basis of opiate contextual memory will benefit the development of new therapeutic approaches for the treatment of opiate addiction. PMID- 25736530 TI - The pretreatment neutrophil-to-lymphocyte ratio predicts therapeutic response to radiation therapy and concurrent chemoradiation therapy in uterine cervical cancer. AB - BACKGROUND: The aim of this study was to investigate the prognostic role of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a predictive marker prior to treatment of cervical cancer with radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT). METHODS: Fifty-six patients with squamous cell carcinoma (SCC) of the uterine cervix who underwent RT or CCRT from 2005-2013 at the Hirosaki University Hospital were retrospectively identified using electronic databases. Patients were divided into a high NLR group (>=2.5) and a low NLR group (<2.5). The efficacy of RT and CCRT in the two groups was compared. RESULT: Of the 56 patients, 35 were in the high NLR group and 21 were in the low NLR group. In comparison to a high NLR, a low NLR was significantly associated with a complete response (P < 0.001). When cancer was divided into stages I/II and III/IV, patients with a low NLR had a significantly better therapeutic outcome than those with a high NLR (P < 0.05). Multivariate analysis showed that only the NLR was a significant prognostic factor for progression-free survival (PFS) and overall survival (OS). Patients with a high NLR had significantly shorter PFS and OS than those with a low NLR. CONCLUSION: Results showed that a low NLR before treatment could predict a good response to RT or CCRT at all stages of uterine cervical cancer. The NLR may be a promising parameter on which to base the choice of a therapeutic strategy to treat SCC of the uterine cervix. PMID- 25736531 TI - Co-administration of antiresorptive and anabolic agents: a missed opportunity. AB - Co-administration of antiresorptive and anabolic therapies has appeal because these treatments target the two main abnormalities in bone remodeling responsible for bone loss and microstructural deterioration. Antiresorptives reduce the number of basic multicellular units (BMUs) remodeling bone and reduce the volume of bone each BMU resorbs. Intermittent parathyroid hormone (PTH) increases the volume of bone formed by existing BMUs and those generated by PTH administration. PTH also increases bone formation by stimulating the differentiation, maturation, and longevity of osteoblast lineage cells residing upon quiescent bone surfaces. Despite these rationally targeted actions, enthusiasm for this approach waned when combined therapy blunted the increase in areal bone mineral density (aBMD) relative to that produced by PTH. Although many studies have since reported additive effects of combined therapy, whatever the aBMD result (blunting, additive, or null), these outcomes give little, if any, insight into changes in bone's material composition or microstructure and give misleading information concerning the net effects on bone strength. Combined therapy remains a potentially valuable approach to therapy. Because studies of antifracture efficacy comparing combined with single therapy are unlikely to be performed in humans, efforts should be directed toward improving methods of quantifying the net effects of combined therapy on bone's material composition, microarchitecture, and strength. PMID- 25736532 TI - Isaacs syndrome: A review. AB - Isaacs syndrome is a peripheral nerve hyperexcitability (PNH) syndrome that presents as continuous motor activity. Clinical findings include cramps, fasciculations, and myokymia. Electrodiagnosis plays a key role in diagnosis by demonstrating after-discharges on nerve conduction studies, and fasciculation potentials, myokymic discharges, neuromyotonic discharges, and other types of abnormal spontaneous activity on needle examination. Etiopathogenesis involves the interaction of genetic, autoimmune, and paraneoplastic factors, which requires a broad-ranging evaluation for underlying causes. Initial treatment is symptomatic, but immune therapy is often needed and can be effective. The purpose of this review is to describe the syndrome and its pathogenesis, assist the reader in evaluating patients with suspected Isaacs syndrome and distinguishing it from other disorders of PNH, and suggest an approach to management, including both symptomatic and immunomodulating therapy. PMID- 25736534 TI - Too much medicine is not just a problem of rich countries. PMID- 25736533 TI - Transcription Factor Tfe3 Directly Regulates Pgc-1alpha in Muscle. AB - The microphthalmia (MiT) family of transcription factors is an important mediator of metabolism. Family members Mitf and Tfeb directly regulate the expression of the master regulator of metabolism, peroxisome-proliferator activated receptor gamma coactivator-1 alpha (Pgc-1alpha), in melanomas and in the liver, respectively. Pgc-1alpha is enriched in tissues with high oxidative capacity and plays an important role in the regulation of mitochondrial biogenesis and cellular metabolism. In skeletal muscle, Pgc-1alpha affects many aspects of muscle functionally such as endurance, fiber-type switching, and insulin sensitivity. Tfe3 also regulates muscle metabolic genes that enhance insulin sensitivity in skeletal muscle. Tfe3 has not yet been shown to regulate Pgc 1alpha expression. Our results reported here show that Tfe3 directly regulates Pgc-1alpha expression in myotubes. Tfe3 ectopic expression induces Pgc-1alpha, and Tfe3 silencing suppresses Pgc-1alpha expression. This regulation is direct, as shown by Tfe3's binding to E-boxes on the Pgc-1alpha proximal promoter. We conclude that Tfe3 is a critical transcription factor that regulates Pgc-1alpha gene expression in myotubes. Since Pgc-1alpha coactivates numerous biological programs in diverse tissues, the regulation of its expression by upstream transcription factors such Tfe3 implies potential opportunities for the treatment of diseases where modulation of Pgc-1alpha expression may have important clinical outcomes. PMID- 25736535 TI - Sex-related difference in food-anticipatory activity of mice. AB - The expression of food-anticipatory activity (FAA) is induced by restricted feeding (RF), and its entrainment requires food-entrainable oscillators, the neuroanatomical basis of which is currently unclear. Although RF impacts various hormones, sex-related differences in FAA are unclear. 'Here, we report significantly more food-anticipatory wheel-running activity in male than in female mice during RF. In parallel with the sex-related difference in FAA, male and female mice display different food intake and body weight in response to RF. Since gonadal hormones could be involved in the sex-specific difference in FAA, we compared sham and gonadectomized male and female wild-type mice. In gonadectomized mice, the sex difference in FAA was abolished, indicating a role for gonadal hormones in FAA. Further, plasma concentrations of the hormone ghrelin were higher in female than in male mice during ad libitum (AL) feeding, and RF induced a temporal advance in its peak in both sexes. RF also shifted the expression peak of the circadian gene mPer1 in the hippocampus and liver, although no sex difference was found in either the level or the cyclic phase of its expression. Per1(Brdm1) mutant mice were still sexually dimorphic for FAA, but diminished FAA was noted in both male and female Per2(Brdm1) mutant mice. In summary, our results imply that gonadal hormones contribute to the sex difference in FAA, possibly through modulating ghrelin activity. PMID- 25736536 TI - Intralocus tactical conflict: genetic correlations between fighters and sneakers of the dung beetle Onthophagus taurus. AB - Males and females differ in their phenotypic optima for many traits, and as the majority of genes are expressed in both sexes, some alleles can be beneficial to one sex but harmful to the other (intralocus sexual conflict; ISC). ISC theory has recently been extended to intrasexual dimorphisms, where certain alleles may have opposite effects on the fitness of males of different morphs that employ alternative reproductive tactics (intralocus tactical conflict; ITC). Here, we use a half-sib breeding design to investigate the genetic basis for ISC and ITC in the dung beetle Onthophagus taurus. We found positive heritabilities and intersexual genetic correlations for almost all traits investigated. Next, we calculated the intrasexual genetic correlation between males of different morphs for horn length, a sexually selected trait, and compared it to intrasexual correlations for naturally selected traits in both sexes. Intrasexual genetic correlations did not differ significantly between the sexes or between naturally and sexually selected traits, failing to support the hypothesis that horns present a reduction of intrasexual genetic correlations due to ITC. We discuss the implications for the idea of developmental reprogramming between male morphs and emphasize the importance of genetic correlations as constraints for the evolution of dimorphisms. PMID- 25736537 TI - A model for the unique role of factor Va A2 domain extension in the human ternary thrombin-generating complex. AB - An all-atom human ternary model for the prothrombinase-prothrombin complex, including metal ions and post-translationally modified residues, was constructed from existing X-ray crystal structures. The factor Xa-prothrombin interface was taken from an existing ternary model, which locates the active site of factor Xa in the vicinity of prothrombin cleavage positions. The three sulfotyrosine residues at the C-terminal sequence of factor Va A2 domain are accommodated by modelling rational interactions with positively charged patches on the surface of prothrombin. The entire model is then solvent-equilibrated with molecular dynamics. This ternary model for the thrombin-generating complex provides an estimate as to the role of the C-terminus of the factor Va A2 domain: to establish an interface between FXa and prothrombin and to stabilize the orientation of this interface. PMID- 25736538 TI - 7000 year-old tuberculosis cases from Hungary - Osteological and biomolecular evidence. AB - This study derives from the macroscopic analysis of a Late Neolithic population from Hungary. Remains were recovered from a tell settlement at Hodmezovasarhely Gorzsa from graves within the settlement as well as pits, ditches, houses and as stray finds. One of the most important discoveries from these remains was evidence of tuberculosis. Pathological analysis of the seventy-one individuals revealed numerous cases of infections and non-specific stress indicators on juveniles and adults, metabolic diseases on juveniles, and evidence of trauma and mechanical changes on adults. Several cases showed potential signs of tuberculosis and further analyses were undertaken, including biomolecular studies. The five individuals were all very young adults and included a striking case of Hypertrophic Pulmonary Osteopathy (HPO) with rib changes, one case with resorptive lesions on the vertebrae, two cases with hypervascularisation on the vertebrae and periosteal remodelling on the ribs, and one case with abnormal blood vessel impressions and a possible lesion on the endocranial surface of the skull. The initial macroscopic diagnosis of these five cases was confirmed by lipid biomarker analyses, and three of them were corroborated by DNA analysis. At present, these 7000-year-old individuals are among the oldest palaeopathological and palaeomicrobiological cases of tuberculosis worldwide. PMID- 25736539 TI - Novel laboratory diagnostic tests for tuberculosis and their potential role in an integrated and tiered laboratory network. AB - Lack of laboratory capacity in high-burden countries presents a significant barrier in providing diagnosis and treatment to patients infected with HIV/AIDS, tuberculosis (TB), and malaria. Strengthening laboratory services in these settings via implementation of novel diagnostic tests is especially indispensable to battle against TB and MDR/XDR-TB. Novel TB diagnostic assays have to be applicable to field conditions, affordable and accessible to all patients at different levels of the tiered laboratory network. A functional laboratory network should be based on well-developed diagnostic platforms that can provide not only timely and adequate diagnosis but are simple to use, and easy to implement and sustain. The article is overviewing the latest developments of TB laboratory diagnostics such as smear microscopy, rapid growth detection and susceptibility testing and rapid molecular testing with focus on performance and applicability to diagnostic needs at different levels of the diagnostic network. PMID- 25736540 TI - Using a simplified pre-hospital 'MET' score to predict in-hospital care and outcomes. AB - BACKGROUND: Medical emergency team (MET) activation criteria serve as a predictor of serious adverse events on hospital wards and in the emergency department (ED). We aimed to determine whether in-hospital MET activation criteria would be useful in identifying patients at risk in pre-hospital care. METHODS: The data were collected retrospectively from 610 adult patients treated by physician-staffed helicopter emergency medical services. Pre-hospital vital signs were compared with MET activation criteria and scored accordingly to receive a simplified pre hospital 'MET' score. The primary outcome measure was hospital mortality. The secondary outcome measures were admission to intensive care unit and the length of ED stay, intensive care unit (ICU) stay and hospital stay. The simplified pre hospital 'MET' score was also compared with Emergency Severity Index (ESI) used as a triage tool in ED. RESULTS: Higher simplified pre-hospital 'MET' scores were associated with hospital mortality (P<0.001), the need for ICU treatment (P<0.001) and a more urgent ESI class in the ED (P<0.001). Higher simplified pre hospital 'MET' scores were associated with shorter stay in the ED (P<0.001), longer stay in the ICU (P<0.001) and longer hospital stay (P<0.001). A simplified pre-hospital 'MET' score was an independent predictor for hospital mortality (odds ratio 2.42, confidence interval 1.84 3.18, P<0.001), regardless of age or patient's previous overall physical health classified by American Society of Anesthesiologists physical status classification system. CONCLUSION: A simplified pre-hospital 'MET' score is a predictor for patient outcome and could serve as a risk assessment tool for the health care provider on-scene. PMID- 25736541 TI - Biallelic mutations in huntington disease: A new case with just one affected parent, review of the literature and terminology. AB - Patients with biallelic mutations for Huntington disease (HD) are rare. We present a 46-year-old female with two expanded Huntingtin (HTT) alleles with just one known affected parent. This is the first reported patient with molecular studies performed to exclude HTT uniparental disomy (UPD). The proband had biparental inheritance of HTT alleles (42/44 CAG repeats). Given the negative UPD results, the proband's unaffected mother either had a reduced penetrance allele that expanded into the full mutation range during transmission to our patient or an unknown full HTT mutation and died before symptom onset, unlikely given no family history of HD and asymptomatic at age 59. We made the novel observation in our literature review that most patients with biallelic HD did not have two full HTT mutations. Most had one HTT allele that was in the intermediate or reduced penetrance ranges or 40 CAG repeats, the lowest limit of the full mutation range. Although the number of patients is small, when an allele in these size ranges was present, generally the age of HD onset was in the 50s. If the second HTT allele had >45 repeats, then onset was typically 20s-30s. While similar ages of onset have been reported for patients with one or two HTT mutations, patients with biallelic mutations may have later onset if an expanded HTT allele has <=40 CAG repeats. Finally, we propose that "biallelic mutations" or "compound heterozygosity" are more accurate descriptive terms than "homozygosity" when there are two non-identical expanded HTT alleles. PMID- 25736542 TI - Sensitization to Api m 1, Api m 2, and Api m 4: association with safety of bee venom immunotherapy. PMID- 25736543 TI - 12 cases of primary thyroid lymphoma in China. AB - INTRODUCTION: Primary thyroid lymphoma (PTL) is a rare malignant disease, which can be life threatening because of airway obstruction due to a suddenly and rapidly growing mass. Prompt and accurate detection and diagnosis in the early phase of PTL are crucial for the treatment of this disease. However, due to lack of standardized diagnostic procedures and methods, PTL can be easily missed or misdiagnosed. MATERIALS AND METHODS: In this study, we retrospectively reviewed 12 thyroid lymphomas cases to determine the typical clinical and sonographic profiles of thyroid lymphomas. RESULTS: All the patients showed symptoms of rapidly developing neck swelling or mass sensation when they underwent diagnostic procedures. We found that, in sonography, 3 of the 12 patients (25.0 %) showed diffuse heterogeneous hypoechoic parenchyma with intervening echogenic septa-like structures, 8 (66.7 %) showed markedly hypoechoic masses, and 1 (8.3 %) showed a mixed pattern. Histological analysis of the lymphomas using paraffin-embedded sections revealed that all the 12 lymphomas were non-Hodgkin lymphoma with a B cell origin: extranodal marginal zone B cell lymphomas of the mucosa-associated lymphoid tissue lymphoma type in 3 (MALT, 25.0 %), and diffuse large B cell lymphomas in 9 (75.0 %) lymphomas. All the MALT patients had diffuse heterogeneous hypoechoic parenchyma in sonography, but only one of them with diffuse large B cell lymphomas had diffuse heterogeneous hypoechoic parenchyma in sonography. Complete remission was achieved in all patients when they were given CHOP or COP therapy accompanied by local radiotherapy after accurate diagnosis of PTL. CONCLUSION: We analyzed clinical, sonographic and histological features of twelve cases of malignant lymphoma arising in the thyroid gland and proposed a systematic strategy for prompt and accurate diagnosis of PTL. PMID- 25736544 TI - Serum 25-hydroxyvitamin D predict prognosis in radioiodine therapy of Graves' disease. AB - PURPOSE: To investigate serum 25-hydroxyvitamin D 25(OH)D status and assess the predictability of outcome in patients with Graves' disease (GD) who received a patient-specific calculated dose of radioiodine therapy (RIT). METHODS: 128 patients with GD who received RIT from July 2010 to September 2010 were included. Pre-therapy serum levels of 25(OH)D, calcium, phosphorus, parathyroid hormone, free triiodothyronine, free thyroxine, thyroid stimulating hormone and creatinine were measured. 60 age- and BMI-matched healthy subjects were chosen as the normal control group. RESULTS: Post-therapy follow-up results revealed that therapy failed in 25.00 % of the patients. Serum 25(OH)D levels were found to be significantly lower in patients who failed in therapy. The prevalence of vitamin D deficiency in GD patients was significantly higher compared with control subjects (56.25 vs. 10.00 %, P < 0.001), and therapy failed in 27 (37.50 %) of these patients whose serum 25(OH)D levels < 20 ng/ml. Out of the 56 patients (43.75 %) in whom serum 25(OH)D levels >=20 ng/ml, therapy was unsuccessful in only 5 (8.93 %). Cox regression analysis suggested that serum 25(OH)D levels <20 ng/ml might be an independent risk factor for predicting failure of RIT in GD patients (relative risk = 8.83, 95 % confidence interval = 3.34-23.38, P < 0.001). CONCLUSIONS: Serum 25(OH)D levels were lower in patients who failed than in those who succeeded in RIT of GD. Therefore, serum 25(OH)D < 20 ng/ml might be an independent risk factor for predicting failure of RIT in GD patients. PMID- 25736545 TI - Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy. AB - PURPOSE: Recognition of dysthyroid optic neuropathy (DON) requires sensitive diagnostic tools. Clinical assessment may fail to reliably evaluate the acuteness of DON especially if signs for inflammation are missing. Aim of this cross sectional study was to assess the relationship between thyroid-stimulating immunoglobulins (TSI) and onset of DON. METHODS: At a multidisciplinary orbital center, serum TSI levels were measured in 180 consecutive patients with thyroid eye disease (TED) and 302 healthy controls with a FDA-cleared cell-based bioassay using a chimeric TSH receptor and a CRE-dependent luciferase. RESULTS: Thirty of 180 (16.7 %) patients with TED had DON of recent onset or a past history of DON (post-DON). Optic disk swelling was present and visual-evoked potentials were pathologic in all eyes with DON of recent onset, but in one of 13 (7.7 %) with post-DON, only (p = 0.005). 19/20 (96 %) patients with DON of recent onset were TSI-positive. TSI was associated with DON of recent onset (OR: 20.96; 95 % CI 1.064-412.85, p = 0.045). All controls were TSI negative. TSI correlated with the clinical activity score (R = 0.70, p < 0.001) and higher TSI-levels were noted in active vs. inactive TED (485.1 +/- 132.3 vs. 277.7 +/- 143.7 %, cut-off < 140 %; p < 0.001). Six of seven (85.7 %) patients with inactive TED with recent onset DON versus one of four (25 %) with active post-DON were TSI-positive (p = 0.006). A discriminatory cut-point of 377 SRR % for TSI was determined based on a ROC analysis (sensitivity: 0.95, specificity: 0.8). CONCLUSIONS: Serum TSI levels identify patients with DON of recent onset requiring urgent therapy. PMID- 25736546 TI - Friedman tongue position: age distribution and relationship to sleep-disordered breathing. AB - PURPOSE: Friedman tongue position (FTP) may play an important role in the evaluation of children with sleep-related breathing disorders (SRBD), but there are no previous data on FTP distribution by age. The objective of the current study was to determine the distribution of FTP by age and examine the relationship between FTP and snoring in children. METHODS: Prospective cross sectional study of 199 children (mean age, 6.8 years; 59% male) had tongue position assessed by FTP as part of their clinical examination of the oral cavity during routine ENT visits at a tertiary care children's hospital. The FTP and snoring frequency of participants was examined across the entire age range as well as by comparing those older (middle childhood and above) and younger than 5 years of age. RESULTS: Tongue position did not correlate with age or snoring frequency. The proportion of children with FTP III/IV was not significantly different in children younger than five years of age compared to older than five. Habitual snoring was not associated with having a higher FTP. Among children who snored <3 times per week, those who had previously undergone tonsillectomy did have higher FTP compared to those who had not (p=0.007). BMI-%-for-age was significantly correlated with FTP (p=0.003). The percent of children having FTP class III/IV differed significantly between ethnicities (22% of whites, 26% of others, 45% of hispanics, 53% of African-Americans; p=0.011). Inter-rater reliability among pediatric otolaryngologist was excellent (kappa=0.93, p<0.001). CONCLUSIONS: There does not appear to be an association between FTP with age or snoring frequency in children. The excellent inter-rater reliability for FTP among pediatric ENT providers suggests the null findings are not due to rater bias. These findings may serve as an important reference for those studying the role of tongue position in pediatric SRBD and complement previous studies examining FTP among children with known OSA or snoring. PMID- 25736547 TI - Diagnosis of extraesophageal reflux in children with chronic otitis media with effusion using Peptest. AB - INTRODUCTION: The aim of the study was to investigate whether Peptest, an immunoassay used to detect pepsin, could be used to diagnose extraesophageal reflux (EER) in children with chronic otitis media with effusion (OME). The results obtained using this fast, simple and non-expensive method were compared with the results of previous studies. METHODS: Children 1-7 years old who had been diagnosed with OME and who were undergoing myringotomy with insertion of a ventilation tube were included in the prospective study. Middle ear fluid obtained during myringotomy was analyzed with Peptest to determine the presence of pepsin, and hence EER. RESULTS: Bilateral and unilateral myringotomy was performed in 15/44 (34.1%) and 29/44 (65.9%) children, respectively. Pepsin in the middle ear was detected in 14/44 (31.8%) children and in 19/59 (32.2%) middle ear specimens. Serous and mucous samples were positive for pepsin in 11/32 (34.4%) and 6/27 (22.2%) cases, respectively. Pepsin in the middle ear was detected in 3/7 children (42.9%) with bronchial asthma (p=0.662). CONCLUSIONS: Pepsin was detected in 1/3 of middle ear specimens of patients with OME. These patients probably suffer from more severe reflux and therefore would be potential candidates for antireflux therapy. However, this has to be confirmed in further studies. PMID- 25736548 TI - During influenza season: all influenza-like illnesses are not due to influenza: dengue mimicking influenza. AB - BACKGROUND: During influenza season, many patients present to the emergency department (ED) for evaluation with influenza-like illnesses (ILIs). ILIs are commonly due to influenza A or B, but other infections may mimic influenza in their clinical presentation. With the high volume of ILIs presenting to the ED during influenza season, the ED physician should be alert to other infections masquerading as influenza. CASE REPORT: We report an interesting case of a 31 year-old female who presented with an ILI during influenza season. She had recently been in contact with multiple people with influenza. Her nonspecific laboratory tests done in the ED were consistent with influenza, except for a highly elevated serum ferritin level. The serum ferritin level was the key finding that led to the correct diagnosis of dengue fever, which she acquired during a recent trip to Haiti. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: During influenza season, facing high patient volumes of ILIs in the ED, the ED physician needs to be aware of clinical features in ILIs that may suggest a mimic of influenza. PMID- 25736549 TI - Structure-dependent electrical conductivity of protein: its differences between alpha-domain and beta-domain structures. AB - Electron transports in the alpha-domain and beta-domain of proteins have been comprehensively investigated. The structure-dependent electron transport of proteins has been experimentally measured and theoretically simulated, and both the theoretical and experimental results demonstrate significant differences in electrical conductivity between the alpha-domain and beta-domain. By controlling the feedback system of the scanning tunneling microscope (STM), the conductance of a single alpha-domain protein hemoglobin (Hgb) and a beta-domain protein superoxide dismutase enzyme (SOD) were measured, respectively. The current signal of Hgb is obviously stronger, indicating that the alpha-domain is more conductive. To confirm our finding, molecular orbitals of both the beta-domain in SOD and alpha-domain in Hgb have been analyzed based on first-principles calculations. As expected, tunneling transport and hopping in the alpha-domain are both more efficient, indicating that it is easier for electrons to transport through the alpha-domain, which are in great agreement with our experimental data. In order to explain our results, molecular structures of alpha- and beta domains have been carefully analyzed and show that the explanation should lie in the differences in packing mode between the alpha-domain and beta-domain. This research should be very important to application prospects in molecular electronics. PMID- 25736551 TI - Evaluation of the effect of different root canal obturation techniques using two root canal sealers on the fracture resistance of endodontically treated roots. AB - AIM: The aim of this study was to compare the fracture resistance of teeth filled with AH Plus and MTA Fillapex root canal sealers by using different root canal obturation techniques. MATERIALS AND METHODS: One hundred and twenty pieces of single-rooted-and-canalled mandibular premolar teeth were selected. After the crowns were removed from the cemento-enamel junction, they were divided into 10 groups (n = 12). All the root canals except for the Group 1 were shaped until F4 file with ProTaper Nickel- Titanyum (Ni-Ti) rotary system. Group 1: was not instrumented. Group 2: the root canals were shaped but not filled. Group 3: roots were filled with cold lateral condensation technique (CLC) by using AH Plus. Group 4: roots were filled with CLC by using MTA Fillapex. Group 5: roots were filled with single cone technique by using AH Plus. Group 6: roots were filled with single cone technique by using MTA Fillapex. Group 7: roots were filled with AH Plus by using vertical compaction method with continuous heat. Group 8: roots were filled with MTA Fillapex by using vertical compaction method with continuous heat. Group 9: roots were filled with AH Plus by using thermoplastic core carrier method. Group 10: roots were filled with MTA Fillapex by using thermoplastic core carrier method. Before embedding the samples in acrylic resin after standing in an oven at 37 degrees C for 2 weeks for the hardening of the root canal sealers the 5 mm apical portion of the roots were immersed in wax in order to imitate the surrounding tissues. Polyvinyl siloxane impression material was used for the samples which were embedded in acrylic resin in a way that the coronal 8 mm remained outside in order to imitate the periodontal ligament. Lateral force was applied to the samples with 1 mm/min speed in the Universal Tester. The maximum force values (F-max) which cause fractures in the examples were determined and the results were subjected to statistical evaluation by using one-way Anova and Tukey HSD tests with the significance set at (P < 0.05). RESULTS: The control group showed the maximum fracture resistance (P < 0.05). Thermafil group showed higher fracture resistance than single cone technique, cold lateral condensation technique, and system B (P < 0.05). CONCLUSIONS: It was concluded that shaping and widening of the root canals reduced the fracture resistance of teeth while Thermafil increased the resistance of roots against fracture. PMID- 25736550 TI - Glutathione supplementation to semen extender improves the quality of frozen thawed canine spermatozoa for transcervical insemination. AB - The present study was conducted to evaluate whether supplementation of semen extender with glutathione (GSH) can maintain the quality of frozen-thawed canine spermatozoa. Eighteen ejaculates were obtained from 5 dogs and placed in extender (20% egg yolk, Tris, citric acid, lactose, raffinose, antibiotics and 6.5% glycerol) containing 0 (control), 2.5, 5, 7.5 or 10 mM GSH. The samples were cooled to 4 C and then frozen in liquid nitrogen vapor. Motility parameters of the sperm were evaluated at 0, 1, 2, 3, 4, 12 and 24 h after thawing. Sperm motility was higher in the 5 mM GSH group than in the control or 2.5 and 10 mM GSH groups; this effect was observed at 1 to 24 h after thawing (P < 0.05). The 5 mM GSH group had a higher sperm viability index at 12 and 24 h after thawing compared with the other groups (P < 0.05). Acrosome integrity, evaluated at 4 h after thawing, was greater in two of the GSH-treated groups (5 and 10 mM) compared with the control. Lipid peroxidation (LP) levels immediately after thawing were lower in the 5 and 10 mM GSH groups compared with the control, while those at 12 h after thawing did not differ significantly. Frozen-thawed semen in the 5 mM GSH group was used for transcervical insemination of 4 bitches, resulting in delivery of 5 puppies from 2 bitches. These results indicate that supplementation of semen extender with 5 mM GSH was effective in improving motility, longevity and acrosomal integrity and inhibiting LP levels in post-thaw canine spermatozoa, without any adverse impacts on full-term development after transcervical insemination. PMID- 25736552 TI - Otto Poetzl (1877-1962). PMID- 25736553 TI - Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency. PMID- 25736554 TI - Neuroanatomical correlates of severe cardiac arrhythmias in acute ischemic stroke. AB - Neurocardiological interactions can cause severe cardiac arrhythmias in patients with acute ischemic stroke. The relationship between the lesion location in the brain and the occurrence of cardiac arrhythmias is still discussed controversially. The aim of the present study was to correlate the lesion location with the occurrence of cardiac arrhythmias in patients with acute ischemic stroke. Cardiac arrhythmias were systematically assessed in patients with acute ischemic stroke during the first 72 h after admission to a monitored stroke unit. Voxel-based lesion-symptom mapping (VLSM) was used to correlate the lesion location with the occurrence of clinically relevant severe arrhythmias. Overall 150 patients, 56 with right-hemispheric and 94 patients with a left hemispheric lesion, were eligible to be included in the VLSM study. Severe cardiac arrhythmias were present in 49 of these 150 patients (32.7%). We found a significant association (FDR correction, q < 0.05) between lesions in the right insular, right frontal and right parietal cortex as well as the right amygdala, basal ganglia and thalamus and the occurrence of cardiac arrhythmias. Because left- and right-hemispheric lesions were analyzed separately, the significant findings rely on the 56 patients with right-hemispheric lesions. The data indicate that these areas are involved in central autonomic processing and that right-hemispheric lesions located to these areas are associated with an elevated risk for severe cardiac arrhythmias. PMID- 25736556 TI - Self-esteem is associated with perceived stress in multiple sclerosis patients. AB - Previous studies have showed that perceived stress (PS) in patients with multiple sclerosis (MS) constitutes an important factor for disease onset, relapse, symptomatology and psychological adjustment. OBJECTIVES: The aim of this pilot cross-sectional study was to examine the role of self-esteem in PS, after controlling for sociodemographical characteristics, depression and personality in MS patients. METHODS: Sixty-six relapsing-remitting MS patients (66.67% females, mean age of 40 +/- 11.1 years old, mean duration of disease 133.6 +/- 128.8 months) were studied. Perceived stress, self-esteem, depression and personality type were assessed using self-administered questionnaires. Hierarchical multivariate regression modelling was used. RESULTS: Higher education and depression and lower self-esteem were independently and significantly associated with increased PS, accounting for 40.5% of its variance. Univariate analyses revealed that low extroversion and openness and higher neurotism were associated with higher PS, although no significant after adjusting for other factors. DISCUSSION: Although our findings need further confirmation, psychological interventions targetting self-esteem are strongly encouraged. PMID- 25736555 TI - Neurological update: emerging issues in gait disorders. AB - Gait disorders represent a common and diverse challenge in Neurological practice. The literature on this field is expanding and is seeking to address mainstream clinical issues as well as a greater understanding of pathophysiological mechanisms. This update will introduce a range of these concepts. PMID- 25736557 TI - Risk factors for secondary caries in direct composite restorations in primary teeth. AB - BACKGROUND: Secondary caries or caries adjacent to restorations is the most frequent reason for replacement of dental restorations. Though, limited data is available on variables influencing the development of secondary caries in primary teeth. AIM: To investigate risk factors for the development of secondary caries adjacent to direct composite restorations in primary teeth. DESIGN: For this retrospective study, data of 2417 composite restorations, which were placed due to primary carious lesions, were considered. A total of 212 restorations failed due to secondary caries within a maximum observation period of 8 years. A control group was randomly selected. Mann-Whitney U-test, binomial logistic regression with backward elimination and Cox regression with frailty model were performed (P < 0.05). RESULTS: The overall caries experience amounted to 6.3 dmft and 13.3 dmfs. 72.5% of restorations failed within the first 2 years. Older children and children from families with a higher socio-economic status showed a lower risk for secondary caries. Further, the dentist and the adhesive had a significant influence on the longevity. Posterior restorations had a higher risk to fail in comparison with anterior restorations. CONCLUSIONS: Within the limitation of this study, it is concluded that the development of secondary caries is influenced by several factors. Nevertheless, the secondary caries rate was found to be relatively low in this high-risk population. PMID- 25736558 TI - Methylene Blue Attenuates iNOS Induction Through Suppression of Transcriptional Factor Binding Amid iNOS mRNA Transcription. AB - Inducible nitric oxide synthase (iNOS) critically contributes to the development of endotoxin-mediated inflammation. It can be induced by cytokines or endotoxins via distinct signaling pathways. Lipopolysaccharide (LPS) triggers iNOS expression through activation of the inhibitor of kappaB-alpha (IkappaB-alpha) nuclear factor kappaB (NF-kappaB) cascade, whereas interferon-gamma (IFN-gamma) acts primarily through Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1). Methylene blue (MB), an agent used clinically to treat numerous ailments, has been shown to reduce NO accumulation through suppression of iNOS activity. But it remains unclear whether MB affects iNOS induction. This knowledge gap is addressed in the present study using cultured cells and endotoxemic mice. With mouse macrophages, MB treatment prevented the LPS- and/or IFN-gamma-stimulated iNOS protein expression. Real-time PCR experiments showed that iNOS mRNA transcription was robustly blocked by MB treatment. The inhibitory effect of MB on iNOS expression was confirmed in vivo in endotoxemic mice. Further analysis showed that MB had no significant effect on IkappaB-alpha degradation and NF-kappaB or STAT1 phosphorylation in LPS/IFN-gamma-stimulated cells. The nuclear transport of active NF-kappaB or STAT1 was also not affected by MB treatment. But MB treatment markedly reduced the binding of NF-kappaB and STAT1 to their DNA elements. Chromatin immunoprecipitation assays confirmed that MB reduced NF-kappaB and STAT1 bindings to iNOS promoter inside the cell. These studies show that MB attenuates transcriptional factor binding amid iNOS mRNA transcription, providing further insight into the molecular mechanism of MB in disease therapy. PMID- 25736559 TI - Different Factors for Different Causes: Analysis of the Spatial Aggregations of Fire Ignitions in Catalonia (Spain). AB - The present study analyzes the effects of different socioeconomic factors on the frequency of fire ignition occurrence, according to different original causes. The data include a set of documented ignition points in the region of Catalonia for the period 1995-2008. The analysis focused on the spatial aggregation patterns of the ignitions for each specific ignition cause. The point-based data on ignitions were interpolated into municipality-level information using kernel methods as the basis for defining five ignition density levels. Afterwards, the combination of socioeconomic factors influencing the ignition density levels of the municipalities was analyzed for each documented cause of ignition using a principal component analysis. The obtained results confirmed the idea that both the spatial aggregation patterns of fire ignitions and the factors defining their occurrence were specific for each of the causes of ignition. Intentional fires and those of unknown origin were found to have similar spatial aggregation patterns, and the presence of high ignition density areas was related to high population and high unemployment rates. Additionally, it was found that fires originated from forest work, agricultural activities, pasture burning, and lightning had a very specific behavior on their own, differing from the similarities found on the spatial aggregation of ignitions originated from smokers, electric lines, machinery, campfires, and those of intentional or unknown origin. PMID- 25736560 TI - Study on the interaction of a cyanine dye with human serum transferrin. AB - Complexation between the primary carrier of ligands in blood plasma, human serum transferrin (Tf), and a cyanine dye, 3,3'-di(3-sulfopropyl)-4,5,4',5'-dibenzo-9 phenyl-thiacarbocyanine-triethylam monium salt (PTC) was investigated using fluorescence spectra, UV/Vis absorption spectra, synchronous fluorescence spectra, circular dichroism (CD) and molecular dynamic docking. The experimental results demonstrate that the formation of PTC-Tf complex is stabilized by van der Waal's interactions and hydrogen bonds, and the binding constants were found to be 8.55 * 10(6), 8.19 * 10(6) and 1.75 * 10(4) M(-1). Moreover, fluorescence experiments prove that the operational mechanism for the fluorescence quenching is static quenching and non-radiative energy transfer. Structural investigation of the PTC-Tf complexes via synchronous fluorescence spectra and CD showed that the structure of Tf became more stable with a major increase in the alpha-helix content and increased polarity around the tryptophan residues after PTC binding. In addition, molecular modeling highlights the residues located in the N-lobe, which retain high affinity for PTC. The mode of action of the PTC-Tf complex is illustrated by these results, and may provide an effective pathway for the transport and targeted delivery of antitumor agents. PMID- 25736561 TI - Successful ablation of an epicardial ventricular tachycardia by video-assisted thoracoscopy. PMID- 25736563 TI - Radiation risk reduction in cardiac electrophysiology through use of a gridless imaging technique. AB - AIMS: It has been previously demonstrated that use of appropriate frame rates coupled with minimal use of high-dose digital acquisition can limit radiation risk to patients undergoing diagnostic and therapeutic electrophysiology (EP). Imaging without the anti-scatter grid has been proposed as a means of achieving further radiation reduction. We evaluate application of a gridless imaging technique to deliver further reductions in radiation risk to both patients and personnel. METHODS AND RESULTS: Radiation and clinical data for EP procedures performed for 16 months from March 2012 were monitored. The period was divided into three phases: Phase 1 (March 2012-June 2012) provided a performance baseline (radiation output modelling and procedural risk adjustment calibration), Phase 2 (July 2012-September 2012) confirmation of performance with the grid, and Phase 3 (September 2012-June 2013) gridless imaging period. Statistical process control (SPC) charts were used to monitor for changes in radiation use and clinical outcomes (procedural success). Imaging without the grid halved the levels of radiation delivered in undertaking EP procedures. Although there was a perceptible impact on image quality with the grid removed. Review of the SPC chart monitoring procedural outcomes did not identify any discernable adverse impact on success rates. Selected use of the gridless technique is recommended with re-introduction of the grid in larger patients or during aspects of the procedure where image quality is important (e.g. transeptal punctures). CONCLUSION: Use of a gridless imaging technique can contribute to a significant reduction in radiation risk to both patients and operators during cardiac EP procedures. PMID- 25736562 TI - Utility of automated template matching for the interpretation of pace mapping in patients ablated due to outflow tract ventricular arrhythmias. AB - AIMS: One of the disadvantages of classic pace mapping (PM) is the operator's subjective interpretation. The aim of this single-centre retrospective study was to evaluate the value of automated template matching (AMT) in patients ablated due to ventricular outflow tract arrhythmias (OTAs). METHODS AND RESULTS: From an overall group of 105 patients with OTA who were scheduled for transcatheter ablation (TA), AMT was accessible in 42 patients [21 right ventricular outflow tract (RVOT), 21 left ventricular outflow tract (LVOT), 28 women, aged 51.5 +/- 12.7 years]. We used AMT to compare spontaneous arrhythmia ORS (spontQRS) with paced QRS complexes during PM in sites where radiofrequency (RF) applications were successful and in sites where RF applications were unsuccessful. The concordance was presented in per cents as objective matching scores (OMS). Then, at the successful ablation sites, we examined the relationship between OMS and the visual interpretation of PM was presented as electrophysiologists matching scores (EMS). The OMS of PM at sites of successful ablation varied from 78 to 99% (mean 94.1 +/- 3.8) and from 47 to 95% (mean 80.2 +/- 12.6%) at sites of unsuccessful ablation. Pace mapping in unsuccessful RF sites was significantly less similar to spontQRS morphologies than in successful RF sites (P = 0.0001). There was a significant correlation between OMS and EMS (r = 0.82; P < 0.0001). The OMS that indicated optimal ablation site was 89% (sensitivity = 95%; specificity = 80%). The mean OMS for successful sites at RVOT (95.1 +/- 1.8%) and LVOT (93.1 +/- 4.9%) were not different (P = 0.0551). CONCLUSION: This analysis revealed that AMT is a valuable technique for the interpretation of PM and for the identification of successful ablation sites in OTA. PMID- 25736564 TI - Atrial fibrillation cycle length as a predictor for the extent of substrate ablation. AB - AIMS: Atrial fibrillation (AF) cycle length (CL) has been demonstrated to be one of the predictors for termination during ablation for AF. We evaluated the AF CL gradient between right atrium (RA) and left atrium (LA) and their mean AF CL in predicting the extent of substrate ablation. METHODS AND RESULTS: One-hundred and thirty-six patients undergoing first ablation for persistent AF were studied. Stepwise ablation, sequentially in the following order: pulmonary veins (PV), LA, and RA, was performed to achieve AF termination. Stepwise ablation terminated AF in 110 patients (81%). In the AF termination group, AF was terminated by PV isolation (PVI) (Group P), PVI plus LA ablation (Group L), and PVI plus LA plus RA ablation (Group R) in 14 patients (13%), 49 patients (44%), and 47 patients (43%), respectively. Group R had much shorter mean AF CL than Group L (156 +/- 18 vs. 174 +/- 24 ms, P < 0.001) and mean AF CL in Group L was much shorter than Group P (174 +/- 24 vs. 209 +/- 36 ms, P = 0.004). The RA to LA AF CL gradient was not significantly different between left-side ablation (Group P + Group L) and additional RA ablation (Group R) (P = 0.177). Mean AF CL >180.50 ms predicted AF termination by PVI (Group P) with 79% sensitivity and 84% specificity while mean AF CL >165.25 ms predicted AF termination by left-side ablation (Group P + Group L) with 67% sensitivity and 75% specificity. After a mean follow-up of 15 +/- 7 months, freedom from arrhythmia recurrence was significantly higher in left side ablation (Group P + Group L) than additional RA ablation (Group R) (P = 0.024). CONCLUSION: Baseline mean AF CL may identify the subset of patients in whom persistent AF can be terminated by different extent of substrate ablation, which may in turn predict the chance of recurrence. However, baseline RA to LA AF CL gradient cannot predict the need for additional RA ablation. PMID- 25736565 TI - How do viruses control mitochondria-mediated apoptosis? AB - There is no doubt that viruses require cells to successfully reproduce and effectively infect the next host. The question is what is the fate of the infected cells? All eukaryotic cells can "sense" viral infections and exhibit defence strategies to oppose viral replication and spread. This often leads to the elimination of the infected cells by programmed cell death or apoptosis. This "sacrifice" of infected cells represents the most primordial response of multicellular organisms to viruses. Subverting host cell apoptosis, at least for some time, is therefore a crucial strategy of viruses to ensure their replication, the production of essential viral proteins, virus assembly and the spreading to new hosts. For that reason many viruses harbor apoptosis inhibitory genes, which once inside infected cells are expressed to circumvent apoptosis induction during the virus reproduction phase. On the other hand, viruses can take advantage of stimulating apoptosis to (i) facilitate shedding and hence dissemination, (ii) to prevent infected cells from presenting viral antigens to the immune system or (iii) to kill non-infected bystander and immune cells which would limit viral propagation. Hence the decision whether an infected host cell undergoes apoptosis or not depends on virus type and pathogenicity, its capacity to oppose antiviral responses of the infected cells and/or to evade any attack from immune cells. Viral genomes have therefore been adapted throughout evolution to satisfy the need of a particular virus to induce or inhibit apoptosis during its life cycle. Here we review the different strategies used by viruses to interfere with the two major apoptosis as well as with the innate immune signaling pathways in mammalian cells. We will focus on the intrinsic mitochondrial pathway and discuss new ideas about how particular viruses could activately engage mitochondria to induce apoptosis of their host. PMID- 25736568 TI - Enhancing the Exploitation of Functional Nanomaterials through Spatial Confinement: The Case of Inorganic Submicrometer Capsules. AB - Hollow inorganic nanostructures have attracted much interest in the last few years due to their many applications in different areas of science and technology. In this Feature Article, we overview part of our current work concerning the collective use of plasmonic and magnetic nanoparticles located in voided nanostructures and explore the more specific operational issues that should be taken into account in the design of inorganic nanocapsules. Along these lines, we focus our attention on the applications of silica-based submicrometer capsules aiming to stress the importance of creating nanocavities in order to further exploit the great potential of these functional nanomaterials. Additionally, we will examine some of the recent research on this topic and try to establish a perspective for future developments in this area. PMID- 25736569 TI - Enhancement of Cortical Excitability and Lower Limb Motor Function in Patients With Stroke by Transcranial Direct Current Stimulation. AB - BACKGROUND: Motor dysfunction in the lower limbs is a common sequela in stroke patients. OBJECTIVE: We used transcranial magnetic stimulation (TMS) to determine if applying transcranial direct current stimulation (tDCS) to the primary motor cortex helps enhance cortical excitability. Furthermore, we evaluate if combination anodal tDCS and conventional physical therapy improves motor function in the lower limbs. METHODS: Twenty-four patients with early-stage stroke were randomly assigned to 2 groups: 1) the tDCS group, in which patients received 10 sessions of anodal tDCS and conventional physical therapy; and 2) the sham group, in which patients received 10 sessions of sham stimulation and conventional physical therapy. One day before and after intervention, the motor-evoked potential (MEP) of the affected tibialis anterior muscle was evaluated and motor function was assessed using the lower limb subscale of the Fugl-Meyer Assessment (FMA-LE), lower limb Motricity Index (MI-LE), Functional Ambulatory Category (FAC), Berg Balance Scale (BBS), and gait analysis. RESULTS: The MEPs in the tDCS group became shorter in latency and higher in amplitude after intervention in comparison with the sham group. Improvements in FMA-LE and MI-LE were greater in the tDCS group, but no significant differences in FAC or BBS scores were found. Also, the changes observed on the gait analyses did not significantly differ between the tDCS and sham groups. CONCLUSION: Combination anodal tDCS and conservative physical therapy appears to be a beneficial therapeutic modality for improving motor function in the lower limbs in patients with subacute stroke. PMID- 25736566 TI - The structure and functions of coronavirus genomic 3' and 5' ends. AB - Coronaviruses (CoVs) are an important cause of illness in humans and animals. Most human coronaviruses commonly cause relatively mild respiratory illnesses; however two zoonotic coronaviruses, SARS-CoV and MERS-CoV, can cause severe illness and death. Investigations over the past 35 years have illuminated many aspects of coronavirus replication. The focus of this review is the functional analysis of conserved RNA secondary structures in the 5' and 3' of the betacoronavirus genomes. The 5' 350 nucleotides folds into a set of RNA secondary structures which are well conserved, and reverse genetic studies indicate that these structures play an important role in the discontinuous synthesis of subgenomic RNAs in the betacoronaviruses. These cis-acting elements extend 3' of the 5'UTR into ORF1a. The 3'UTR is similarly conserved and contains all of the cis-acting sequences necessary for viral replication. Two competing conformations near the 5' end of the 3'UTR have been shown to make up a potential molecular switch. There is some evidence that an association between the 3' and 5'UTRs is necessary for subgenomic RNA synthesis, but the basis for this association is not yet clear. A number of host RNA proteins have been shown to bind to the 5' and 3' cis-acting regions, but the significance of these in viral replication is not clear. Two viral proteins have been identified as binding to the 5' cis-acting region, nsp1 and N protein. A genetic interaction between nsp8 and nsp9 and the region of the 3'UTR that contains the putative molecular switch suggests that these two proteins bind to this region. PMID- 25736570 TI - High-dose conventional thoracic re-irradiation for lung cancer: updated results. PMID- 25736571 TI - I1171 missense mutation (particularly I1171N) is a common resistance mutation in ALK-positive NSCLC patients who have progressive disease while on alectinib and is sensitive to ceritinib. AB - OBJECTIVES: Acquired resistance mutations to anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib and alectinib have been documented in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangement (ALK+). Of note I1171T/N/S mutations in the ALK kinase domain have recently been described by several groups to confer resistance to alectinib, a second-generation ALK inhibitor. Additionally one of these reports demonstrated one ALK+ NSCLC patient harboring an I1171T acquired mutation has responded to ceritinib, another second generation ALK inhibitor. MATERIALS AND METHODS: We reported the presence of an ALK I1171N resistance mutation from comprehensive genomic profiling from a liver biopsy of a progressing metastatic lesion in an ALK+ patient on alectinib after an initial partial response. The patient then responded to ceritinib 750 mg orally once daily but required dose reduction to 600 mg once daily. She initially had grade 3 elevation of liver enzymes from crizotinib necessitating the original switch to alectinib but experienced no transaminase elevations with alectinib or ceritinib. CONCLUSIONS: This is the fifth patient case to date demonstrating that ALK I1171 mutation confers resistance to alectinib and the second reported case of ALK I1171 mutation being sensitivity to ceritinib. Substitutions of isoleucine at amino acid 1171 in the ALK kinase domain may distinguish which second generation ALK inhibitor will be effective after crizotinib failure. This case also provides evidence that transaminase elevations is likely a unique adverse event associated with crizotinib and unlikely a "class" effect involving all ALK inhibitors. PMID- 25736572 TI - Streets, strolls and spots: sex work, drug use and social space in Detroit. AB - BACKGROUND: In this paper, we explore social spaces related to street sex work and illicit drug use in Detroit. We consider these spaces as assemblages (Duff, 2011, 2013; Latour, 2005) that reflect the larger moral geography (Hubbard, 2012) of the city and fulfill specific functions in the daily lives of drug using sex workers. METHODS: We draw on thirty-one in-depth qualitative interviews with former street sex workers who were recruited through a court-based treatment and recovery program, as well as ethnographic field notes from drug treatment and law enforcement settings. RESULTS: Our interview findings reveal highly organized and routine activities that exist in a relatively stable, symbiotic relationship with law enforcement practices, employment and commuter patterns, and built environments. While the daily life of street sex work involves a good deal of individual agency in terms of moving between spaces and negotiating terms of exchange, daily trajectories were also circumscribed by economics, illicit substance use, and the objective risks of the street and the police. CONCLUSION: We consider the implications of these results for future policy directed at harm reduction in the street setting. PMID- 25736574 TI - Biology-oriented synthesis of a withanolide-inspired compound collection reveals novel modulators of hedgehog signaling. AB - Biology-oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans-hydrindane dehydro-delta-lactone motif defines the characteristic scaffold of the steroid-like withanolides, a plant-derived natural product class with a diverse pattern of bioactivity. A withanolide-inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell-based assays that monitored biological signal-transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened. PMID- 25736573 TI - Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival. AB - The identification of pathways necessary for photoreceptor and retinal pigment epithelium (RPE) function is critical to uncover therapies for blindness. Here we report the discovery of adiponectin receptor 1 (AdipoR1) as a regulator of these cells' functions. Docosahexaenoic acid (DHA) is avidly retained in photoreceptors, while mechanisms controlling DHA uptake and retention are unknown. Thus, we demonstrate that AdipoR1 ablation results in DHA reduction. In situ hybridization reveals photoreceptor and RPE cell AdipoR1 expression, blunted in AdipoR1(-/-) mice. We also find decreased photoreceptor-specific phosphatidylcholine containing very long-chain polyunsaturated fatty acids and severely attenuated electroretinograms. These changes precede progressive photoreceptor degeneration in AdipoR1(-/-) mice. RPE-rich eyecup cultures from AdipoR1(-/-) reveal impaired DHA uptake. AdipoR1 overexpression in RPE cells enhances DHA uptake, whereas AdipoR1 silencing has the opposite effect. These results establish AdipoR1 as a regulatory switch of DHA uptake, retention, conservation and elongation in photoreceptors and RPE, thus preserving photoreceptor cell integrity. PMID- 25736575 TI - Host genetic influences on the anthelmintic efficacy of papaya-derived cysteine proteinases in mice. AB - Eight strains of mice, of contrasting genotypes, infected with Heligmosomoides bakeri were studied to determine whether the anthelmintic efficacy of papaya latex varied between inbred mouse strains and therefore whether there is an underlying genetic influence on the effectiveness of removing the intestinal nematode. Infected mice were treated with 330 nmol of crude papaya latex or with 240 nmol of papaya latex supernatant (PLS). Wide variation of response between different mouse strains was detected. Treatment was most effective in C3H (90.5 99.3% reduction in worm counts) and least effective in CD1 and BALB/c strains (36.0 and 40.5%, respectively). Cimetidine treatment did not improve anthelmintic efficacy of PLS in a poor drug responder mouse strain. Trypsin activity, pH and PLS activity did not differ significantly along the length of the gastro intestinal (GI) tract between poor (BALB/c) and high (C3H) drug responder mouse strains. Our data indicate that there is a genetic component explaining between mouse variation in the efficacy of a standard dose of PLS in removing worms, and therefore warrant some caution in developing this therapy for wider scale use in the livestock industry, and even in human medicine. PMID- 25736576 TI - Insight into bio-metal interface formation in vacuo: interplay of S-layer protein with copper and iron. AB - The mechanisms of interaction between inorganic matter and biomolecules, as well as properties of resulting hybrids, are receiving growing interest due to the rapidly developing field of bionanotechnology. The majority of potential applications for metal-biohybrid structures require stability of these systems under vacuum conditions, where their chemistry is elusive, and may differ dramatically from the interaction between biomolecules and metal ions in vivo. Here we report for the first time a photoemission and X-ray absorption study of the formation of a hybrid metal-protein system, tracing step-by-step the chemical interactions between the protein and metals (Cu and Fe) in vacuo. Our experiments reveal stabilization of the enol form of peptide bonds as the result of protein metal interactions for both metals. The resulting complex with copper appears to be rather stable. In contrast, the system with iron decomposes to form inorganic species like oxide, carbide, nitride, and cyanide. PMID- 25736577 TI - Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities. PMID- 25736578 TI - Study on the hydrocyclonic separation of waste plastics with different density. AB - The recycling of waste plastics is an important aspect in the recycling of solid waste. Based on the difference in density, PET and PVC particles was separated with help of the centrifugal sedimentation and shearing dispersion in a hydrocyclone. Through tests and CFD simulation, the relationship between the separating efficiency and pressure drop and split ratio has been investigated. Test results show that the Newton efficiency can reach above 80%, i.e. the purity of PVC could reach 93.2% while the purity of PET could reach 94.5%. PMID- 25736579 TI - Impacts of policy and market incentives for solid waste recycling in Dhaka, Bangladesh. AB - Solid waste mismanagement in Dhaka, Bangladesh, illustrates a well-known market failure which can be summarized as: waste is a resource in the wrong place. Inorganic materials such as plastic or paper can be used to feed the demand for recycled materials in the industrial sector. Organic materials can be converted and used in the nutrient-starved agricultural sector which is currently heavily depending on chemical fertilizers. They are also a feedstock to generate renewable energy in the form of biogas for this energy-starved country relying on diminishing natural gas reserves and increasing import of coal. Reality however does not capitalize on this potential; instead the waste is a burden for municipal authorities who spend large portions of their budgets attempting to transport it out of the city for discharge into landfills. The major part of these materials still remains uncollected in the residential areas and is discarded indiscriminately in open spaces, polluting the residents' living environment including water, soil and air resources, in the city and beyond. Bangladeshi authorities have, to some extent, recognized this market failure and have developed policies to encourage the development of waste recycling activities. It is also important to note that this market failure is only partial: a large, mostly informal recycling sector has developed in Bangladesh, focusing on inorganic recyclables of market value. The fact that this sector remains largely informal means that these actors perceive significant barriers to formalization. Comparatively, the organic waste recycling sector is less driven by market mechanisms. Competition from chemical fertilizers and fossil fuels is fierce and hinders the development of market opportunities for compost and renewable energy. Nevertheless commercial production of compost and biogas from organic municipal waste is formalized and benefiting from policy incentives. PMID- 25736580 TI - Tracking the composition and transformation of humic and fulvic acids during vermicomposting of sewage sludge by elemental analysis and fluorescence excitation-emission matrix. AB - Sewage sludge (T1) and the mixture of sewage sludge and cattle dung (T2) were vermicomposted with Eisenia fetida, respectively. The transformation of humic acid (HA) and fulvic acid (FA) extracted from these two treatments were evaluated by a series of chemical and spectroscopic methods. Results indicated that the vermicomposting decreased pH, TOC, and C/N ratio, and increased EC, total extractable C, and HA contents. The FA content in treatment T1 was increased significantly, and only slight increasing was observed in treatment T2. Moreover, vermicomposting decreased H content, C/N ratio, proteinaceous and carbohydrates components, and increased the N content, C/H ratio, aromatic compounds and polycondensation structures in HA and FA. In addition, fluorescence spectra and fluorescence regional integration indicated that protein-like groups were degraded and HA compounds were formed. Furthermore, the addition of cattle dung enhanced the humification process and improved the HA quality in spite of no significant effect on the FA. PMID- 25736581 TI - Revisiting the extended producer responsibility program for metal packaging in South Korea. AB - Recently, developed and emerging countries have increasingly adopted the principle of extended producer responsibility (EPR) to reduce waste. In 2003, South Korea replaced the waste deposit recycling (WDR) program with the EPR program. Previous comparative analyses between the WDR and EPR programs have been qualitative evaluations and have not yet quantitatively shown whether the change has increased benefits. The aim of this paper is to explore which program brings larger net benefits. Because of limited data availability, here we focus on metal packaging exclusively. We find that the recycling rate dropped from 59% in 2000 to 40% in 2011 and recycling volume dropped accordingly. Cost-benefit incidence analysis shows that net social benefits decreased by 2.8 billion won (2.5 million US dollars), while the net benefits to producers increased by 1.9 billion won (1.7 million US dollars) under the EPR program compared with the WDR program. The government of South Korea should set an ambitious recycling target and narrow the scope of the exemption from the mandatory recycling requirement. PMID- 25736583 TI - Emerging drugs for bronchiectasis: an update. AB - INTRODUCTION: Recent research has confirmed the increasing burden of bronchiectasis, in affluent and developing countries. Bronchiectasis, the destruction and dilation of airways, is due to a variety of causes and is characterised by a self-perpetuating cycle of airway inflammation, infection and obstruction that results in substantial morbidity and mortality. Improved therapies that address these three components, and the diseases that both cause and result from bronchiectasis are required. AREAS COVERED: In this review, we update our previous summary of the clinical features, pathophysiology and epidemiology of bronchiectasis among adults and children, highlighting the most recent advances in therapeutics. We discuss current treatment strategies and then identify key goals for future research on the causes and treatments of a variety of types of bronchiectasis. EXPERT OPINION: Bronchiectasis remains an orphan disease with respect to the development of new therapies. There has been progress in the recognition and studies but further research is now required on the pathogenesis, prevention, and treatment of bronchiectasis in order to decrease its high burden. Such advances will require a concerted, global effort to coordinate studies of both the pathophysiology and potential treatments of this heterogeneous, chronic disease that affects people of all ages and demographics. PMID- 25736582 TI - Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities. AB - Androgen deprivation therapy (ADT) provides palliation for most patients with advanced prostate cancer (CaP); however, greater than 80% subsequently fail ADT. ADT has been indicated to induce an acute but transient destabilization of the prostate vasculature in animal models and humans. Human re-hydrated lyophilized platelets (hRL-P) were investigated as a prototype for therapeutic agents designed to target selectively the tumour-associated vasculature in CaP. The ability of hRL-P to bind the perturbed endothelial cells was tested using thrombin- and ADP-activated human umbilical vein endothelial cells (HUVEC), as well as primary xenografts of human prostate tissue undergoing acute vascular involution in response to ADT. hRL-P adhered to activated HUVEC in a dose responsive manner. Systemically administered hRL-P, and hRL-P loaded with super paramagnetic iron oxide (SPIO) nanoparticles, selectively targeted the ADT damaged human microvasculature in primary xenografts of human prostate tissue. This study demonstrated that hRL-P pre-loaded with chemo-therapeutics or nanoparticles could provide a new paradigm for therapeutic modalities to prevent the rebound/increase in prostate vasculature after ADT, inhibiting the transition to castration-recurrent growth. PMID- 25736584 TI - Identifying faecal impaction is important for ensuring the timely diagnosis of childhood functional constipation. AB - AIM: Most research on functional constipation has been carried out at a tertiary level. We focused this study on a secondary-level hospital outpatients' department, assessing the distribution of diagnostic criteria for childhood functional constipation and evaluating the consequences of current diagnostic practice based on current guidelines. METHODS: We enrolled 235 children, aged two to 16 years of age, with functional constipation according to the Rome III criteria and assessed them using medical histories and physical examinations, including rectal examinations and ultrasound measurements of rectal diameter. Faecal impaction was a rectal diameter exceeding 3 cm. RESULTS: The most frequently reported symptom was painful bowel movements (72.3%) and 39.1% had faecal incontinence. Rectal examination identified faecal impaction in 149 children (66.2%), and ultrasound showed a mean rectal diameter of 3.4 +/- 0.6 cm, compared to 2.2 +/- 0.6 cm in children without impaction (p < 0.001). Of the 149 children with faecal impaction, 19 (12.8%) only had one additional Rome III criterion. The rectal diameter exceeded 3 cm in 79.9% of cases. CONCLUSION: Identifying faecal impaction is important for ensuring the timely diagnosis of childhood functional constipation at the secondary care level. Ultrasound examination proved a reliable alternative to rectal examination or abdominal radiography when identifying faecal impaction. PMID- 25736585 TI - Effect of midazolam and butorphanol premedication on inhalant isoflurane anesthesia in mice. AB - Isoflurane is a representative inhalant anesthesia used in laboratory animals. However, isoflurane mediates respiratory depression and adverse clinical reactions during induction. In the present study, we established a novel balanced anesthesia method in mice that combined isoflurane anesthesia with midazolam and butorphanol (MB). Thirty-four male C57BL/6J mice received either isoflurane alone or isoflurane with an intra-peritoneal MB premedication (3 mg/kg midazolam and 4 mg/kg butorphanol). The minimum alveolar concentration (MAC) in each group was evaluated. Induction time and adverse clinical reactions were recorded in each group. Core body temperature, heart rate, respiratory rate, and oxygen saturation (SPO(2)) were assessed before and for 1 h after induction. Premedication with MB achieved a significant reduction in MAC compared with isoflurane monoanesthesia (isoflurane, 1.38 +/- 0.15%; isoflurane with MB, 0.78 +/- 0.10%; P<0.05). Induction time was significantly shortened with MB premedication, and adverse reactions such as excitement or incontinence were observed less frequently. Furthermore, isoflurane anesthesia with MB premedication caused increase of respiratory rates compared to isoflurane monoanesthesia. No significant decrease of SPO(2) was observed in MBI anesthesia, while a decrease in SPO(2) was apparent with isoflurane monoanesthesia (baseline, 98.3% +/- 1.1; 10 min after induction, 91.8 +/- 6.4%; P<0.05). In conclusion, premedication with MB was effective for the mitigation of respiratory depression induced by isoflurane in mice, with rapid induction and fewer adverse clinical reactions. PMID- 25736586 TI - Two cases of asymptomatic massive fetomaternal hemorrhage. AB - Evaluation of fetomaternal hemorrhage (FMH) in the immediate postpartum period is critical for the timely administration of Rh immunoglobulin (RhIG) prophylaxis to minimize the risk of alloimmunization in D-negative mothers of D-positive newborns. We report a series of two clinically-unsuspected cases of massive FMHs identified at our university medical center. Retrospective records of two cases of massive FMH were investigated using the electronic medical record. After positive fetal bleed screens, flow cytometric analysis for hemoglobin F was performed to quantify the volume of the hemorrhages in both cases. Flow cytometric enumeration with anti-D was also performed in one case. The two patients had 209.5 and 75 mL of fetal blood in circulation, resulting in 8 and 4 doses of RhIG administered, respectively. For the former patient, flow cytometric analysis with anti-D ruled out hereditary persistence of fetal hemoglobin and supported the fetal origin of the red cells. Due to the clinically-silent nature of both hemorrhages, further evaluation of the newborns' blood was not performed. These cases highlight the importance of rapidly obtaining accurate measurements of fetal blood loss via flow cytometric analysis in cases of FMH, particularly in clinically-unsuspected cases, to ensure timely administration of adequate immunoprophylaxis to D-negative mothers. PMID- 25736587 TI - Translocation of forkhead box O1 to the nuclear periphery induces histone modifications that regulate transcriptional repression of PCK1 in HepG2 cells. AB - Forkhead box O1 (FOXO1) is an important target for insulin. It is widely accepted that insulin-induced phosphorylation of FOXO1 by Akt leads to its nuclear exclusion and results in the inhibition of FOXO1-mediated transcription of the gluconeogenic gene phosphoenolpyruvate carboxykinase 1 (PCK1) in hepatocytes. However, many results that contradict this model have accumulated. Here, we provide a new mechanism for insulin-dependent repression of FOXO1-mediated transcription. We showed insulin-induced translocation of endogenous Ser256 phosphorylated FOXO1, which is essential for regulation of FOXO1-mediated transcription, from nuclear speckles to the nuclear periphery. This insulin dependent translocation of FOXO1 regulated transcriptional repression of PCK1 concomitant with the formation of the FOXO1-euchromatic histone-lysine N methyltransferase2 (EHMT2) complex and histone modifications of the PCK1 promoter region. Notably, our results suggest that FOXO1 uses nucleoporin 98 kDa NUP98 for this transcriptional regulation. These results provide a new insight into various FOXO1-mediated transcriptional regulation and FOXO1-mediated essential biological pathways. PMID- 25736588 TI - A comparison of spinal and epidural anesthesia for cesarean section following epidural labor analgesia: A retrospective cohort study. AB - INTRODUCTION: This study aimed to investigate different types of regional anesthesia for cesarean section (CS) following epidural labor analgesia that could lead to various perioperative and postoperative outcomes. METHODS: We retrospectively included those parturients who received epidural labor analgesia but needed subsequent CS under regional anesthesia in our institution from January 2008 to June 2012. RESULTS: In all, 2341 of 6609 parturients underwent painless labor, and 334 of them converted to CS. Spinal anesthesia (SA) was used with 163 parturients, and epidural anesthesia (EA) with 96; the two groups were then compared. No high-level block or total SA was noted. The primary outcome revealed that the time from anesthesia to surgical incision and the total anesthesia time were shorter, hypotension episodes were more frequent, the rate of perioperative ephedrine administration was higher, and the rate of midazolam was lower in the SA group. With regard to secondary outcomes, the Apgar scores of the neonates recorded at 1 minute and 5 minutes and maternal satisfaction were similar. The neuraxial morphine dose was converted to parenteral morphine equivalent dose (MED), which revealed that the parturients in the spinal morphine group had lower dosages and visual analog scale (VAS) pain scores on postoperative Day 1. CONCLUSION: For parturients with labor epidural analgesia needing CS, the use of SA led to shorter anesthetic time and lower postoperative pain scores, with lower morphine doses compared with EA. However, the high failure rate with both neuraxial techniques needs to be addressed. PMID- 25736589 TI - Fiber type-specific response of skeletal muscle satellite cells to high-intensity resistance training in dialysis patients. AB - INTRODUCTION: The aim of this study was to assess the effect of high-intensity resistance training on satellite cell (SC) and myonuclear number in the muscle of patients undergoing dialysis. METHODS: Patients (n = 21) underwent a 16-week control period, followed by 16 weeks of resistance training 3 times weekly. SC and myonuclear number were determined by immunohistochemistry of vastus lateralis muscle biopsy cross-sections. Knee extension torque was tested in a dynamometer. RESULTS: During training, SCs/type I fibers increased by 15%, whereas SCs/type II fibers remained unchanged. Myonuclear content of type II, but not type I, fibers increased with training. Before the control period, the SC content of type II fibers was lower than that of type I fibers, whereas contents were comparable when normalized to fiber area. Torque increased after training. CONCLUSIONS: Increased myonuclear content of type II muscle fibers of dialysis patients who perform resistance training suggests that SC dysfunction is not the limiting factor for muscle growth. PMID- 25736590 TI - Dual-modal magnetic resonance/fluorescent zinc probes for pancreatic beta-cell mass imaging. AB - Despite the contribution of changes in pancreatic beta-cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic-resonance imaging (MRI) provides a potentially useful technique, targeting MRI-active probes to the beta cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual-modal probes based on transition-metal chelates capable of binding zinc. The first of these, Gd?1, binds Zn(II) directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from lambdaem =410 to 500 nm with an increase in relaxivity from r1 =4.2 up to 4.9 mM(-1) s( 1) . The probe is efficiently accumulated into secretory granules in beta-cell derived lines and isolated islets, but more poorly by non-endocrine cells, and leads to a reduction in T1 in human islets. In vivo murine studies of Gd?1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140 minutes. PMID- 25736591 TI - Bone Tissue Properties Measurement by Reference Point Indentation in Glucocorticoid-Induced Osteoporosis. AB - Glucocorticoids, widely used in inflammatory disorders, rapidly increase bone fragility and, therefore, fracture risk. However, common bone densitometry measurements are not sensitive enough to detect these changes. Moreover, densitometry only partially recognizes treatment-induced fracture reductions in osteoporosis. Here, we tested whether the reference point indentation technique could detect bone tissue property changes early after glucocorticoid treatment initiation. After initial laboratory and bone density measurements, patients were allocated into groups receiving calcium + vitamin D (Ca+D) supplements or anti osteoporotic drugs (risedronate, denosumab, teriparatide). Reference point indentation was performed on the cortical bone layer of the tibia by a handheld device measuring bone material strength index (BMSi). Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA). Although Ca+D-treated patients exhibited substantial and significant deterioration, risedronate-treated patients exhibited no significant change, and both denosumab- and teriparatide treated participants exhibited significantly improved BMSi 7 weeks after initial treatment compared with baseline; these trends remained stable for 20 weeks. In contrast, no densitometry changes were observed during this study period. In conclusion, our study is the first to our knowledge to demonstrate that reference point indentation is sensitive enough to reflect changes in cortical bone indentation after treatment with osteoporosis therapies in patients newly exposed to glucocorticoids. PMID- 25736592 TI - Effects of dance on upper extremity activities in underserved adults. AB - PURPOSE: This secondary analysis examined the immediate and maintaining effects of a 12-week line-dancing intervention on upper and lower extremity activities in underserved adults who receive care from a nurse-managed clinic (NMC). DATA SOURCES: This one-group, repeated measures, feasibility study consisted of 40 participants recruited from an urban apartment complex that housed a NMC. Of the 40 participants, 21 participants completed the 12-week line-dancing intervention. Physical function of the upper and lower extremities was measured with the Late Life Function and Disability Instrument at baseline, 12, and 18 weeks to determine the maintaining effects. CONCLUSIONS: Age ranged from 45 to 87 years (M = 63; SD = 7.8), body mass index (BMI) was 33.4 (SD = 7.8), 92% were female, and 75% were African American. At baseline, participants showed limitations in all aspects of physical function. Significant improvements in upper and lower extremity activities were noted at 12 weeks and maintained at 18 weeks. IMPLICATIONS FOR PRACTICE: Although line-dancing mainly involves the lower body, there were significant improvements in upper extremity activities at 12 weeks, which were maintained at 18 weeks. The maintaining effects support line-dancing as an intervention to improve upper and lower extremity activities needed for independent living. NMCs are important settings for health promotion interventions in underserved adults. PMID- 25736593 TI - Coupled Neel domain wall motion in sandwiched perpendicular magnetic anisotropy nanowires. AB - The operating performance of a domain wall-based magnetic device relies on the controlled motion of the domain walls within the ferromagnetic nanowires. Here, we report on the dynamics of coupled Neel domain wall in perpendicular magnetic anisotropy (PMA) nanowires via micromagnetic simulations. The coupled Neel domain wall is obtained in a sandwich structure, where two PMA nanowires that are separated by an insulating layer are stacked vertically. Under the application of high current density, we found that the Walker breakdown phenomenon is suppressed in the sandwich structure. Consequently, the coupled Neel domain wall of the sandwich structure is able to move faster as compared to individual domain walls in a single PMA nanowire. PMID- 25736595 TI - Impacts of climate change and socio-economic scenarios on flow and water quality of the Ganges, Brahmaputra and Meghna (GBM) river systems: low flow and flood statistics. AB - The potential impacts of climate change and socio-economic change on flow and water quality in rivers worldwide is a key area of interest. The Ganges Brahmaputra-Meghna (GBM) is one of the largest river basins in the world serving a population of over 650 million, and is of vital concern to India and Bangladesh as it provides fresh water for people, agriculture, industry, conservation and for the delta system downstream. This paper seeks to assess future changes in flow and water quality utilising a modelling approach as a means of assessment in a very complex system. The INCA-N model has been applied to the Ganges, Brahmaputra and Meghna river systems to simulate flow and water quality along the rivers under a range of future climate conditions. Three model realisations of the Met Office Hadley Centre global and regional climate models were selected from 17 perturbed model runs to evaluate a range of potential futures in climate. In addition, the models have also been evaluated using socio-economic scenarios, comprising (1) a business as usual future, (2) a more sustainable future, and (3) a less sustainable future. Model results for the 2050s and the 2090s indicate a significant increase in monsoon flows under the future climates, with enhanced flood potential. Low flows are predicted to fall with extended drought periods, which could have impacts on water and sediment supply, irrigated agriculture and saline intrusion. In contrast, the socio-economic changes had relatively little impact on flows, except under the low flow regimes where increased irrigation could further reduce water availability. However, should large scale water transfers upstream of Bangladesh be constructed, these have the potential to reduce flows and divert water away from the delta region depending on the volume and timing of the transfers. This could have significant implications for the delta in terms of saline intrusion, water supply, agriculture and maintaining crucial ecosystems such as the mangrove forests, with serious implications for people's livelihoods in the area. The socio-economic scenarios have a significant impact on water quality, altering nutrient fluxes being transported into the delta region. PMID- 25736594 TI - Recombinant expression, purification, and crystallization of the glutaminyl-tRNA synthetase from Toxoplasma gondii. AB - Aminoacyl tRNA synthetases play a critical role in protein synthesis by providing precursor transfer-RNA molecules correctly charged with their cognate amino acids. The essential nature of these enzymes make them attractive targets for designing new drugs against important pathogenic protozoans like Toxoplasma. Because no structural data currently exists for a protozoan glutaminyl-tRNA synthetase (QRS), an understanding of its potential as a drug target and its function in the assembly of the Toxoplasma multi-aminoacyl tRNA (MARS) complex is therefore lacking. Here we describe the optimization of expression and purification conditions that permitted the recovery and crystallization of both domains of the Toxoplasma QRS enzyme from a heterologous Escherichia coli expression system. Expression of full-length QRS was only achieved after the addition of an N-terminal histidine affinity tag and the isolated protein was active on both cellular and in vitro produced Toxoplasma tRNA. Taking advantage of the proteolytic susceptibility of QRS to cleavage into component domains, N terminal glutathione S-transferase (GST) motif-containing domain fragments were isolated and crystallization conditions discovered. Isolation of the C-terminal catalytic domain was accomplished after subcloning the domain and optimizing expression conditions. Purified catalytic domain survived cryogenic storage and yielded large diffraction-quality crystals over-night after optimization of screening conditions. This work will form the basis of future structural studies into structural-functional relationships of both domains including potential targeted drug-design studies and investigations into the assembly of the Toxoplasma MARS complex. PMID- 25736596 TI - Selective aerobic oxidation of 5-HMF into 2,5-furandicarboxylic acid with Pt catalysts supported on TiO2 - and ZrO2 -based supports. AB - Pt catalysts prepared over different metallic oxide supports were investigated in the oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) in alkaline aqueous solutions with air, to examine the combined effect of the support and base addition. The base (nature and amount) played a significant role in the degradation or oxidation of HMF. Increasing amounts of the weak NaHCO3 base improved significantly the overall catalytic activity of Pt/TiO2 and Pt/ZrO2 by accelerating the oxidation steps, especially for the aldehyde group. This was highlighted by a proposed kinetic model that gave very good concentration-time fittings. Moreover, the promotion of the catalyst with bismuth yielded a Pt?Bi/TiO2 catalytic system with improved activity and stability. Y2 O3 ? and La2 O3 ?ZrO2 -supported catalysts exhibited lower activity than Pt/ZrO2 , which suggests no cooperative effect of the weakly basic properties introduced and the homogeneous base. Quantitative oxidation of HMF (0.1 M) and high yields of FDCA (>99 %) were obtained in less than 5 h by using an HMF/Pt molar ratio of 100 and Na2 CO3 as a weak base over Pt?Bi/TiO2 (Bi/Pt=0.22). PMID- 25736597 TI - MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRgamma. AB - Tamoxifen represents a major adjuvant therapy to those patients with estrogen receptor-alpha positive breast cancer. However, tamoxifen resistance occurs quite often, either de novo or acquired during treatment. To investigate the role of miR-320a in the development of resistance to tamoxifen, we established tamoxifen resistant (TamR) models by continually exposing MCF-7 or T47D breast cancer cells to tamoxifen, and identified microRNA(miRNA)-320a as a down-regulated miRNA in tamoxifen resistant cells. Re-expression of miR-320a was sufficient to sensitize TamR cells to tamoxifen by targeting cAMP-regulated phosphoprotein (ARPP-19) and estrogen-related receptor gamma (ERRgamma) as well as their downstream effectors, c-Myc and Cyclin D1. Furthermore, progesterone (P4) promoted the expression of miR-320a by repressing c-Myc expression, while estrogen (E2) exerted the opposite effect. These results suggest the potential therapeutic approach for tamoxifen resistant breast cancer by restorating miR-320a expression or depleting ARPP 19/ERRgamma expression. PMID- 25736598 TI - Relationship between programmed cell death-1 polymorphisms and clearance of hepatitis B virus. AB - Programmed cell death-1 (PD-1) plays a critical role in regulating T-cell function during hepatitis B virus (HBV) infection. This study investigated the relationship between the polymorphisms of PD-1 gene and the susceptibility to HBV infection. Single nucleotide polymorphisms (SNPs) in PD-1 gene at positions +7146 G>A (guanine to adenine substitution) and +7209 C>T (cytosine to thymine substitution) were analysed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 220 subjects with chronic hepatitis B infection and 165 spontaneous clearance of HBV subjects. However, no statistically significant differences were found in the genotype distributions of the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms among chronic hepatitis B and spontaneous clearance subjects. According to stratified analyses, borderline significance was observed between PD-1 +7146 GA genotype and risk of HBV chronicity in the subgroup of male gender (OR = 1.88, 95% 0.95-3.71; P = 0.07). Our findings demonstrate for the first time that the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms have not been any major role in genetic susceptibility to chronicity of HBV infection, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 25736600 TI - Phenotypic plasticity in haptoral structures of Ligophorus cephali (Monogenea: Dactylogyridae) on the flathead mullet (Mugil cephalus): a geometric morphometric approach. AB - Evaluating phenotypic plasticity in attachment organs of parasites can provide information on the capacity to colonise new hosts and illuminate evolutionary processes driving host specificity. We analysed the variability in shape and size of the dorsal and ventral anchors of Ligophorus cephali from Mugil cephalus by means of geometric morphometrics and multivariate statistics. We also assessed the morphological integration between anchors and between the roots and points in order to gain insight into their functional morphology. Dorsal and ventral anchors showed a similar gradient of overall shape variation, but the amount of localised changes was much higher in the former. Statistical models describing variations in shape and size revealed clear differences between anchors. The dorsal anchor/bar complex seems more mobile than the ventral one in Ligophorus, and these differences may reflect different functional roles in attachment to the gills. The lower residual variation associated with the ventral anchor models suggests a tighter control of their shape and size, perhaps because these anchors seem to be responsible for firmer attachment and their size and shape would allow more effective responses to characteristics of the microenvironment within the individual host. Despite these putative functional differences, the high level of morphological integration indicates a concerted action between anchors. In addition, we found a slight, although significant, morphological integration between roots and points in both anchors, which suggests that a large fraction of the observed phenotypic variation does not compromise the functional role of anchors as levers. Given the low level of genetic variation in our sample, it is likely that much of the morphological variation reflects host-driven plastic responses. This supports the hypothesis of monogenean specificity through host switching and rapid speciation. The present study demonstrates the potential of geometric morphometrics to provide new and previously unexplored insights into the functional morphology of attachment and evolutionary processes of host parasite coevolution. PMID- 25736599 TI - A highly conserved, inhibitable astacin metalloprotease from Teladorsagia circumcincta is required for cuticle formation and nematode development. AB - Parasitic nematodes cause chronic, debilitating infections in both livestock and humans worldwide, and many have developed multiple resistance to the currently available anthelmintics. The protective collagenous cuticle of these parasites is required for nematode survival and its synthesis has been studied extensively in the free-living nematode, Caenorhabditis elegans. The collagen synthesis pathway is a complex, multi-step process involving numerous key enzymes, including the astacin metalloproteases. Nematode astacinsare crucial for C. elegans development, having specific roles in hatching, moulting and cuticle synthesis. NAS-35 (also called DPY-31) is a homologue of a vertebrate procollagen C proteinase and performs a central role in cuticle formation of C. elegans as its mutation causes temperature-sensitive lethality and cuticle defects. The characterisation of DPY-31 from the ovine gastrointestinal nematode Teladorsagia circumcincta and its ability to rescue the C. elegans mutant is described. Compounds with a hydroxamate functional group have previously been shown to be potent inhibitors of procollagen C-proteinases and were therefore examined for inhibitory activity against the T. circumcincta enzyme. Phenotypic screening against T. circumcincta, Haemonchus contortus and C. elegans larval stages identified compounds that caused body morphology phenotypes consistent with the inhibition of proteases involved in cuticle collagen synthesis. These compounds correspondingly inhibited the activity of recombinant T. circumcincta DPY-31, supporting the hypothesis that this enzyme may represent a potentially novel anthelmintic drug target. PMID- 25736601 TI - Transcription rates in DNA brushes. AB - We theoretically predict the rate of transcription (TX) in DNA brushes by introducing the concept of TX dipoles that takes into account the unidirectional motion of enzymes (RNAP) along DNA during transcription as correlated pairs of sources and sinks in the relevant diffusion equation. Our theory predicts that the TX rates dramatically change upon the inversion of the orientation of the TX dipoles relative to the substrate because TX dipoles modulate the concentrations of RNAP in the solution. Comparing our theory with experiments suggests that, in some cases, DNA chain segments are relatively uniformly distributed in the brush, in contrast to the parabolic profile expected for flexible polymer brushes. PMID- 25736602 TI - Nitrogen fixing bacteria in the family Acetobacteraceae and their role in agriculture. AB - For centuries, the Acetobacteraceae is known as a family that harbors many species of organisms of biotechnological importance for industry. Nonetheless, since 1988 representatives of this family have also been described as nitrogen fixing bacteria able to plant growth promotion by a variety of mechanisms. Nitrogen fixation is a biological process that guarantees that the atmospheric N2 is incorporated into organic matter by several bacterial groups. Most representatives of this group, also known as diazotrophic, are generally associated with soil rhizosphere of many plants and also establishing a more specific association living inside roots, leaves, and others plants tissues as endophyte. Their roles as plant growth-promoting microorganisms are generally related to increase in plant biomass, phosphate and other mineral solubilization, and plant pathogen control. Here, we report many of these plant growth-promoting processes related to nitrogen fixing species already described in Acetobacteraceae family, especially Gluconacetobacter diazotrophicus and their importance to agriculture. In addition, a brief review of the state of art of the phylogenetics, main physiological and biochemical characteristics, molecular and functional genomic data of this group of Acetobacteraceae is presented. PMID- 25736603 TI - Correction: Control of selectivity in allylic alcohol oxidation on gold surfaces: the role of oxygen adatoms and hydroxyl species. PMID- 25736604 TI - Structural studies of the C-terminal 19-peptide of serum amyloid A and its Pro -> Ala variants interacting with human cystatin C. AB - Serum amyloid A (SAA) is a multifunctional acute-phase protein whose concentration in serum increases markedly following a number of chronic inflammatory and neoplastic diseases. Prolonged high SAA level may give rise to reactive systemic amyloid A (AA) amyloidosis, where the N-terminal segment of SAA is deposited as amyloid fibrils. Besides, recently, well-documented association of SAA with high-density lipoprotein or glycosaminoglycans, in particular heparin/heparin sulfate (HS), and specific interaction between SAA and human cystatin C (hCC), the ubiquitous inhibitor of cysteine proteases, was proved. Using a combination of selective proteolytic excision and high-resolution mass spectrometry, a hCC binding site in the SAA sequence was determined as SAA(86 104). The role of this SAA C-terminal fragment as a ligand-binding locus is still not clear. It was postulated important in native SAA folding and in pathogenesis of AA amyloidosis. In the search of conformational details of this SAA fragment, we did its structure and affinity studies, including its selected double/triple Pro -> Ala variants. Our results clearly show that the SAA(86-104) 19-peptide has rather unordered structure with bends in its C-terminal part, which is consistent with the previous results relating to the whole protein. The results of affinity chromatography, fluorescent ELISA-like test, CD and NMR studies point to an importance of proline residues on structure of SAA(86-104). Conformational details of SAA fragment, responsible for hCC binding, may help to understand the objective of hCC-SAA complex formation and its importance for pathogenesis of reactive amyloid A amyloidosis. PMID- 25736606 TI - Vitamin D status in patients with knee or hip osteoarthritis in a Mediterranean country. AB - BACKGROUND: Vitamin D plays an important role in bone mineralization, remodeling, and maintenance and therefore its deficiency may be implicated in the pathogenesis of osteoarthritis (OA). Vitamin D status was evaluated in patients with knee or hip OA scheduled for joint replacement. The impact of anthropometric parameters such as gender, age, and body mass index on vitamin D levels was also examined. The study was conducted in a Mediterranean country (Greece). MATERIALS AND METHODS: We included 164 patients with knee or hip OA scheduled for joint replacement in this study. Serum levels of 25-hydroxyvitamin D (vitamin D) were measured in routine blood samples taken from the patients at their pre-admission visit, a week before the operation, using radioimmunoassay. RESULTS: The majority of patients were vitamin D deficient (81.7 %); 15.2 % of them were vitamin D insufficient (hypovitaminosis). Only 3 % of patients were vitamin D sufficient. There was a significantly positive association between vitamin D levels and male gender. CONCLUSION: These findings indicate a large percentage of vitamin D deficient patients with knee or hip OA, which is unexpected considering the high annual insolation in northern Greece. Many other possible predisposing factors for OA should be taken into consideration. Whether treatment with vitamin D supplements may provide beneficial effects to these patients and the stage of disease in which this treatment should commence remains an issue for further scientific investigation. LEVEL OF EVIDENCE: Level IV. PMID- 25736607 TI - Low-Intensity Pulsed Ultrasound Affects Chondrocyte Extracellular Matrix Production via an Integrin-Mediated p38 MAPK Signaling Pathway. AB - Although low-intensity pulsed ultrasound (LIPUS) regulates p38 mitogen-activated protein kinase (MAPK) and promotes cartilage repair in osteoarthritis, the role of integrin-mediated p38 MAPK in the effect of LIPUS on extracellular matrix (ECM) production of normal and OA chondrocytes remains unknown. The aim of this study was to investigate whether LIPUS affects ECM production in normal and OA rabbit chondrocytes through an integrin-p38 signaling pathway. A rabbit model of OA was established by anterior cruciate ligament transection, and chondrocytes were isolated from normal or OA cartilage and cultured in vitro. Chondrocytes were treated with LIPUS and then pre-incubated with the integrin inhibitor GRGDSP or the p38 inhibitor SB203580. Expression of type II collagen, MMP-13, integrin beta1, p38 and phosphorylated p38 was assessed by Western blot analysis. We found that type II collagen and integrin beta1 were upregulated (p < 0.05), whereas MMP 13 was downregulated (p < 0.05) in normal and OA chondrocytes. Furthermore, phosphorylated p38 was upregulated (p < 0.05) in normal chondrocytes, but downregulated (p < 0.05) in OA chondrocytes after LIPUS stimulation. Pre incubation of chondrocytes with the integrin inhibitor disrupted the effects of LIPUS on normal and OA chondrocytes. Pre-incubation of chrondocytes with the p38 inhibitor reduced the effects of LIPUS on normal chondrocytes, but had no impact on OA chondrocytes. Our findings suggest that the integrin-p38 MAPK signaling pathway plays an important role in LIPUS-mediated ECM production in chondrocytes. PMID- 25736608 TI - A Two-Step Segmentation Method for Breast Ultrasound Masses Based on Multi resolution Analysis. AB - Breast ultrasound images have several attractive properties that make them an interesting tool in breast cancer detection. However, their intrinsic high noise rate and low contrast turn mass detection and segmentation into a challenging task. In this article, a fully automated two-stage breast mass segmentation approach is proposed. In the initial stage, ultrasound images are segmented using support vector machine or discriminant analysis pixel classification with a multiresolution pixel descriptor. The features are extracted using non-linear diffusion, bandpass filtering and scale-variant mean curvature measures. A set of heuristic rules complement the initial segmentation stage, selecting the region of interest in a fully automated manner. In the second segmentation stage, refined segmentation of the area retrieved in the first stage is attempted, using two different techniques. The AdaBoost algorithm uses a descriptor based on scale variant curvature measures and non-linear diffusion of the original image at lower scales, to improve the spatial accuracy of the ROI. Active contours use the segmentation results from the first stage as initial contours. Results for both proposed segmentation paths were promising, with normalized Dice similarity coefficients of 0.824 for AdaBoost and 0.813 for active contours. Recall rates were 79.6% for AdaBoost and 77.8% for active contours, whereas the precision rate was 89.3% for both methods. PMID- 25736609 TI - Laplacian normalization and random walk on heterogeneous networks for disease gene prioritization. AB - Random walk on heterogeneous networks is a recently emerging approach to effective disease gene prioritization. Laplacian normalization is a technique capable of normalizing the weight of edges in a network. We use this technique to normalize the gene matrix and the phenotype matrix before the construction of the heterogeneous network, and also use this idea to define the transition matrices of the heterogeneous network. Our method has remarkably better performance than the existing methods for recovering known gene-phenotype relationships. The Shannon information entropy of the distribution of the transition probabilities in our networks is found to be smaller than the networks constructed by the existing methods, implying that a higher number of top-ranked genes can be verified as disease genes. In fact, the most probable gene-phenotype relationships ranked within top 3 or top 5 in our gene lists can be confirmed by the OMIM database for many cases. Our algorithms have shown remarkably superior performance over the state-of-the-art algorithms for recovering gene-phenotype relationships. All Matlab codes can be available upon email request. PMID- 25736610 TI - Oxidative damage and cell-programmed death induced in Zea mays L. by allelochemical stress. AB - The allelochemical stress on Zea mays was analyzed by using walnut husk washing waters (WHWW), a by-product of Juglans regia post-harvest process, which possesses strong allelopathic potential and phytotoxic effects. Oxidative damage and cell-programmed death were induced by WHWW in roots of maize seedlings. Treatment induced ROS burst, with excess of H2O2 content. Enzymatic activities of catalase were strongly increased during the first hours of exposure. The excess in malonildialdehyde following exposure to WHWW confirmed that oxidative stress severely damaged maize roots. Membrane alteration caused a decrease in NADPH oxidase activity along with DNA damage as confirmed by DNA laddering. The DNA instability was also assessed through sequence-related amplified polymorphism assay, thus suggesting the danger of walnut processing by-product and focusing the attention on the necessity of an efficient treatment of WHWW. PMID- 25736611 TI - Herbicide impact on the growth and reproduction of characteristic and rare arable weeds of winter cereal fields. AB - The decline of arable species characteristic of winter cereal fields has often been attributed to different factors related to agricultural intensification but most importantly to herbicide use. Herbicide phytotoxicity is most frequently assessed using short-term endpoints, primarily aboveground biomass. However, short-term sensitivity is usually not sufficient to detect actual effects because plants may or may not recover over time following sublethal herbicide exposures. Therefore, it is important to assess the long-term effects of herbicide applications. Annual species rely on renewable seed production to ensure their persistence; hence, assessment of herbicide sensitivity is more accurately estimated through effects on reproduction. Here we aim to assess the phytotoxicity of two commonly used herbicides: tribenuron and 2,4-D on eight plant species belonging to four families, each with one rare and one more common species. Specifically we examined the pattern of sensitivity using short-term and long-term endpoints (total aboveground biomass, total seed biomass and number of seeds) of these species; we determined the levels of and time to recovery in terms of stem length and fruit number, and assessed whether their rarity relates to their sensitivity to herbicide application. Our results suggest that although differences in herbicide sensitivity are not a direct cause of rarity for all species, it may be an important driver of declining arable plants. PMID- 25736612 TI - The ultrasound-assisted paraspinous approach to lumbar neuraxial blockade: a simplified technique in patients with difficult anatomy. AB - Pre-procedural ultrasound imaging of the spine to identify the interspinous and interlaminar space has been shown to facilitate subsequent performance of lumbar neuraxial blockade. However, adequate visualization of the vertebral canal can be challenging for less-experienced operators, and particularly in subjects with difficult anatomy. In this case report, we describe a simplified technique of ultrasound-assisted neuraxial blockade that addresses these limitations and may thus be a useful fallback option. A pre-procedural scan is performed in which the main ultrasonographic landmarks to be identified are the neuraxial midline and the spinous processes, rather than the posterior and anterior complexes of the vertebral canal. Another key difference is the use of a paraspinous (or paramedian) needle approach rather than a midline approach that is advantageous where the interspinous spaces are narrowed by disease or suboptimal patient positioning. The anatomical basis and technical performance of this novel ultrasound-assisted paraspinous approach are presented in detail. PMID- 25736613 TI - Association of face-to-face handoffs and outcomes of hospitalized internal medicine patients. AB - BACKGROUND: Failures in communication at the time of patient handoff have been implicated as contributing factors to preventable adverse events. OBJECTIVE: Examine the relationship between face-to-face handoffs and the rate of patient outcomes, including adverse events. DESIGN: Retrospective cohort. SETTING: A 1157 bed academic tertiary referral hospital. PATIENTS: There were 805 adult patients admitted to general internal medicine services. INTERVENTION: Retrospective comparison of clinical outcomes, including the rate of adverse events, of patients whose care was transitioned with and without face-to-face handoffs. MEASUREMENTS: Rapid response team calls, code team calls, transfers to a higher level of care, death in hospital, 30-day readmission rate, length of stay, and adverse events (as identified using the Global Trigger Tool). RESULTS: There was no significant difference with respect to the frequency of rapid response team calls, code team calls, transfers to a higher level of care, deaths in hospital, length of stay, 30-day readmission rate, or adverse events between patients whose care was transitioned with or without a face-to-face handoff. CONCLUSIONS: Face to-face handoff of patients admitted to general medical services at a large academic tertiary referral hospital was not associated with a significant difference in measured patient outcomes, including the rate of adverse events, compared to a non-face-to-face handoff. Additional study is needed to determine the qualities of patient handoff that optimize efficiency and safety. PMID- 25736614 TI - Nighttime clinical encounters: how residents perceive and respond to calls at night. AB - BACKGROUND: Care fragmentation is common and contributes to communication errors and adverse events. Handoff tools were developed to reduce the potential for these errors. Despite their widespread adoption, there is little information describing their impact on clinical work. Understanding their impact could be helpful in improving handoffs and transitions. OBJECTIVE: To better understand what clinical work is done overnight, the housestaff perceptions of overnight clinical work, and how handoff instruments support this work. DESIGN: Real-time data collection and survey. PARTICIPANTS: Internal medicine resident physicians. MAIN MEASURES: Data collection measured information related to nighttime clinical encounters, including the information sources and actions taken. Surveys assessed resident perceptions toward care transitions. KEY RESULTS: Of 299 encounters, 289 contained complete data. The tool was used as an information source in 27.7% of encounters, whereas the information source was either the nurse or the chart in 94.4% of encounters. Many encounters resulted in a new order for a medication, whereas 3.8% resulted in documentation. In the survey data, 73.6% residents reported the sign-out procedure was safe. CONCLUSION: These data suggest that a handoff tool is not sufficient to address nighttime clinical issues and suggest that effective care requires more than just the information transfer. It may also reflect that electronic medical records have become a readily available information source at the point of care. Sign-out should support residents' ability to make sense of what is happening and integrate care of day and night teams, rather than solely transfer information. PMID- 25736615 TI - Handoffs: a story in evolution. PMID- 25736616 TI - Adequacy of cervical sampling in hysterectomy specimens for endometrial cancer. AB - AIM: To determine whether sampling one section, which includes the anterior and posterior cervical lips in hysterectomy specimens, provides the best prospect for detecting stromal invasion in hysterectomy specimens for endometrial cancers. METHODS: To assess the most likely section in which cervical stromal invasion was identified in 29 cases. RESULTS: Cervical stromal invasion was detected in first section in 75.8% cases, whereas 24.1% detected in random sections other than first section. CONCLUSION: Cervical stromal invasion is most likely to be identified in one section taken in the midline, which includes anterior and posterior lips. However, in a significant number of cases, this one section missed invasion, which was detected in other random cervical sections. Therefore, sampling of one block (anterior and posterior) from the cervix is insufficient for detecting cervical stromal invasion for endometrial cancer. PMID- 25736617 TI - People's willingness to accept overdetection in cancer screening: population survey. AB - OBJECTIVES: To describe the level of overdetection people would find acceptable in screening for breast, prostate, and bowel cancer and whether acceptability is influenced by the magnitude of the benefit from screening and the cancer specific harms from overdetection. DESIGN: Online survey. Women were presented with scenarios on breast and bowel cancer, men with scenarios on prostate and bowel cancer. For each particular cancer, we presented epidemiological information and described the treatment and its consequences. Secondly, we presented two different scenarios of benefit: one indicating a 10% reduction in cancer specific mortality and the second indicating a 50% reduction. SETTING: Online survey of the population in the United Kingdom. PARTICIPANTS: Respondents were part of an existing panel of people who volunteer for online research and were invited by email or online marketing. We recruited 1000 respondents, representative for age and sex for the UK population. MAIN OUTCOME MEASURES: Number of cases of overdetection people were willing to accept, ranging from 0-1000 (complete screened population) for each cancer modality and each scenario of benefit. RESULTS: There was large variability between respondents in the level of overdetection they would find acceptable, with medians ranging from 113 to 313 cases of overdetection per 1000 people screened. Across all scenarios, 4-7% of respondents indicated they would accept no overdetection at all compared with 7 14% who thought that it would be acceptable for the entire screened population to be overdetected. Acceptability in screening for bowel cancer was significantly lower than for breast and prostate cancer. People aged 50 or over accepted significantly less overdetection, whereas people with higher education levels accepted more; 29% of respondents had heard of overdetection before. CONCLUSIONS: Acceptability of overdetection in cancer screening is variable. Invitations for screening should include clear information on the likelihood and consequences of overdetection to allow people to make an informed choice. PMID- 25736618 TI - Synthetic cannabinoid use in a nationally representative sample of US high school seniors. AB - BACKGROUND: Synthetic cannabinoids are marketed as "legal highs" and have similar effects to cannabis (marijuana). Although prevalence of synthetic cannabinoid use is now declining in the US, use has been associated with tens of thousands of poisonings and hospitalizations, particularly among teens. It is important to examine which teens are at highest risk for use of these new, potentially deleterious drugs as they are understudied and continue to emerge. METHODS: Data were analyzed from a nationally representative sample of high school seniors in the Monitoring the Future study (2011-2013; Weighted N = 11,863; modal age: 18). Bivariable and multivariable models were used to delineate correlates of recent (12-month) synthetic cannabinoid use. RESULTS: Ten percent reported any recent use and 3% reported more frequent use (used >= 6 times). Females were at low odds for use and going out 4-7 evenings per week for fun consistently increased odds of use. Black and religious students were at low odds of use until controlling for other drug use, and higher income increased odds of use until controlling for other drug use. Lifetime use of alcohol, cigarettes and other illicit drugs all robustly increased odds of use, but frequency of lifetime marijuana use was the strongest correlate with more frequent use further increasing odds of synthetic cannabinoid use. Only 0.5% of non-marijuana users reported use of synthetic cannabinoids. CONCLUSIONS: This is among the first national studies to delineate correlates of synthetic cannabinoid use. Results can inform national and local efforts to prevent use and adverse consequences resulting from use. PMID- 25736621 TI - Caution for monitoring the surface modification of dually emitted ZnSe quantum dots by time-resolved photoluminescence. AB - This work wants to give a caution for monitoring the surface modification of dually emitted ZnSe quantum dots (QDs) by using time-resolved photoluminescence (PL). Aqueous ZnSe QDs have two emission bands: namely ZnSe band gap emission centered at 395 nm and ZnSe trap emission centered at 470 nm. By fitting the measured PL spectra by two peaks, serious overlapping of two emission bands can be found in the range of 360-430 nm. As a result, the measured PL lifetimes at 395 nm (the peak position of ZnSe band gap emission) is just an apparent value, composing of both ZnSe band emission (contribution proportion about 80%) and ZnSe trap emission (contribution proportion about 20%). Due to the much smaller PL lifetime of ZnSe band gap emission (less than 20 ns) than that of ZnSe trap emission (about 50-70 ns), the elevated contribution proportion of ZnSe band gap emission at improved QD surface modification will lead to the decreased average PL lifetime at 395 nm. This result is completely opposite to the traditional result where improved QD surface modification leads to increased PL lifetimes on the basis of single emitted QDs. Hence, when time-resolved PL is used for monitoring the surface modification of dually emitted QDs, the emission bands overlapping should be taken into consideration with caution. PMID- 25736619 TI - Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis. AB - BACKGROUND: Alterations in frontal and striatal function are hypothesized to underlie risky decision making in drug users, but how these regions interact to affect behavior is incompletely understood. We used mediation analysis to investigate how prefrontal cortex and ventral striatum together influence risk avoidance in abstinent drug users. METHOD: Thirty-seven abstinent substance dependent individuals (SDI) and 43 controls underwent fMRI while performing a decision-making task involving risk and reward. Analyses of a priori regions-of interest tested whether activity in dorsolateral prefrontal cortex (DLPFC) and ventral striatum (VST) explained group differences in risk avoidance. Whole-brain analysis was conducted to identify brain regions influencing the negative VST risk avoidance relationship. RESULTS: Right DLPFC (RDLPFC) positively mediated the group-risk avoidance relationship (p < 0.05); RDLPFC activity was higher in SDI and predicted higher risk avoidance across groups, controlling for SDI vs. CONTROLS: Conversely, VST activity negatively influenced risk avoidance (p < 0.05); it was higher in SDI, and predicted lower risk avoidance. Whole-brain analysis revealed that, across group, RDLPFC and left temporal-parietal junction positively (p <= 0.001) while right thalamus and left middle frontal gyrus negatively (p < 0.005) mediated the VST activity-risk avoidance relationship. CONCLUSION: RDLPFC activity mediated less risky decision making while VST mediated more risky decision making across drug users and controls. These results suggest a dual pathway underlying decision making, which, if imbalanced, may adversely influence choices involving risk. Modeling contributions of multiple brain systems to behavior through mediation analysis could lead to a better understanding of mechanisms of behavior and suggest neuromodulatory treatments for addiction. PMID- 25736620 TI - Current recommended 25-hydroxyvitamin D targets for chronic kidney disease management may be too low. AB - OBJECTIVE: It is uncertain whether increasing 25-hydroxyvitamin D (25-D) levels in chronic kidney disease (CKD) patients above those recommended by current guidelines result in progressive amelioration of secondary hyperparathyroidism. Our objective was to identify a potential therapeutic 25-D target which optimally lowers plasma parathyroid hormone (PTH) without producing excessive hypercalcemia or hyperphosphatemia in CKD. METHODS: We performed a cross-sectional analysis of 14,289 unselected stage 1-5 CKD patients from US primary care and nephrology practices utilizing a laboratory-based CKD clinical decision support service between September 2008 and May 2012. Estimated glomerular filtration rate (eGFR), plasma PTH, and serum 25-D, calcium, and phosphorus results were analyzed. RESULTS: In CKD stages 3-5, progressively higher 25-D pentiles contained progressively lower mean PTH levels. Regression analysis of log PTH on 25-D was significant in all CKD stages with no evidence of a decreasing effect of 25-D to lower PTH until 25-D levels of 42-48 ng/ml. Progressively higher 25-D concentrations were not associated with increased rates of hypercalcemia or hyperphosphatemia. CONCLUSIONS: We found evidence for an optimal level of 25-D above which suppression of PTH progressively diminishes. This level is more than twice that currently recommended for the general population. We found no association between these higher 25-D levels and hyperphosphatemia or hypercalcemia. Additional prospective trials seem appropriate to test the idea that 25-D levels around 40-50 ng/ml could be a safe and effective treatment target for secondary hyperparathyroidism in CKD. PMID- 25736622 TI - Cell-free extract from porcine induced pluripotent stem cells can affect porcine somatic cell nuclear reprogramming. AB - Pretreatment of somatic cells with undifferentiated cell extracts, such as embryonic stem cells and mammalian oocytes, is an attractive alternative method for reprogramming control. The properties of induced pluripotent stem cells (iPSCs) are similar to those of embryonic stem cells; however, no studies have reported somatic cell nuclear reprogramming using iPSC extracts. Therefore, this study aimed to evaluate the effects of porcine iPSC extracts treatment on porcine ear fibroblasts and early development of porcine cloned embryos produced from porcine ear skin fibroblasts pretreated with the porcine iPSC extracts. The Chariot(TM) reagent system was used to deliver the iPSC extracts into cultured porcine ear skin fibroblasts. The iPSC extracts-treated cells (iPSC-treated cells) were cultured for 3 days and used for analyzing histone modification and somatic cell nuclear transfer. Compared to the results for nontreated cells, the trimethylation status of histone H3 lysine residue 9 (H3K9) in the iPSC-treated cells significantly decreased. The expression of Jmjd2b, the H3K9 trimethylation specific demethylase gene, significantly increased in the iPSC-treated cells; conversely, the expression of the proapoptotic genes, Bax and p53, significantly decreased. When the iPSC-treated cells were transferred into enucleated porcine oocytes, no differences were observed in blastocyst development and total cell number in blastocysts compared with the results for control cells. However, H3K9 trimethylation of pronuclear-stage-cloned embryos significantly decreased in the iPSC-treated cells. Additionally, Bax and p53 gene expression in the blastocysts was significantly lower in iPSC-treated cells than in control cells. To our knowledge, this study is the first to show that an extracts of porcine iPSCs can affect histone modification and gene expression in porcine ear skin fibroblasts and cloned embryos. PMID- 25736624 TI - Examining the Specification Validity of the HEDIS Quality Measures for Substance Use Disorders. AB - Accurate operationalization is a major challenge in developing quality measures for substance use disorder treatment. Specification validity is a term used to describe whether a quality measure is operationalized such that it captures the intended care processes and patients. This study assessed the specification validity of the 2009 Healthcare Effectiveness Data and Information Set (HEDIS(r)) substance use disorder initiation and engagement measures by examining whether encounters assumed to include relevant treatment have corroborating evidence in the clinical progress notes. The positive predictive values were excellent (>90%) for residential and outpatient records selected from addiction treatment programs but more modest for records generated in non-addiction settings, and were highly variable across facilities. Stakeholders using these measures to compare care quality should be mindful of the clinical composition of the data and determine if similar validation work has been conducted on the systems being evaluated. PMID- 25736623 TI - A comparison of three interventions for homeless youth evidencing substance use disorders: results of a randomized clinical trial. AB - While research on homeless adolescents and young adults evidencing substance use disorder is increasing, there is a dearth of information regarding effective interventions, and more research is needed to guide those who serve this population. The current study builds upon prior research showing promising findings of the community reinforcement approach (CRA) (Slesnick, Prestopnik, Meyers, & Glassman, 2007). Homeless adolescents and young adults between the ages of 14 to 20 years were randomized to one of three theoretically distinct interventions: (1) CRA (n = 93), (2) motivational enhancement therapy (MET, n = 86), or (3) case management (CM, n = 91). The relative effectiveness of these interventions was evaluated at 3, 6, and 12 months post-baseline. Findings indicated that substance use and associated problems were significantly reduced in all three interventions across time. Several moderating effects were found, especially for sex and history of childhood abuse. Findings show little evidence of superiority or inferiority of the three interventions and suggest that drop-in centers have choices for addressing the range of problems that these adolescents and young adults face. PMID- 25736625 TI - Factors associated with hospitalization for blood-borne viral infections among treatment-seeking illicit drug users. AB - Blood-borne viral infections (BBVIs) are important health consequences of illicit drug use. This study assessed predictors of inpatient hospital admissions for BBVIs in a cohort of 4817 clients seeking treatment for drug use in Finland. We examined clients' data on hospital admissions registered in the Finnish National Hospital Discharge Register from 1997 to 2010 with diagnoses of BBVIs. Cox proportional hazards regression analyses were separately conducted for each of the three BBVI groups to test for association between baseline variables and hospitalizations. Findings were reported as adjusted hazard ratios (aHRs). Based upon primary discharge diagnoses, 81 clients were hospitalized for HIV, 116 for hepatitis C, and 45 for other types of hepatitis. Compared to those admitted for hepatitis C and other hepatitis, drug users with HIV had higher total number of hospital admissions (294 versus 141 and 50 respectively), higher crude hospitalization rate (7.1 versus 3.4.and 1.2 per 1000 person-years respectively), and higher total length of hospital stay (2857 days versus 279 and 308 respectively). Trends in hospitalization for all BBVI groups declined at the end of follow-up. HIV positive status at baseline (aHR: 6.58) and longer duration of drug use (aHR: 1.11) were independently associated with increased risk for HIV hospitalization. Female gender (aHR: 3.05) and intravenous use of primary drug (aHR: 2.78) were significantly associated with HCV hospitalization. Having hepatitis B negative status at baseline (aHR: 0.25) reduced the risk of other hepatitis hospitalizations. Illicit drug use coexists with blood-borne viral infections. To address this problem, clinicians treating infectious diseases need to also identify drug use in their patients and provide drug treatment information and/or referral. PMID- 25736626 TI - Improving recognition of pain by calling attention to its various faces. AB - BACKGROUND: The ability to accurately recognize facial expressions of pain is known to affect clinical decision making and delivery of care. Although recognition accuracy for facial expressions of pain is well above chance level, substantial shortcomings have also been reported which stress the need to look for methods to improve recognition accuracy. Based on findings that pain is encoded in different facial activity patterns, we wanted to investigate whether training observers to recognize these various faces of pain might improve their ability to accurately recognize pain. METHODS: Participants (55 male, 65 female) were randomly assigned to one of the three training groups: 'different patterns group' (calling attention to the various faces of pain); 'prototypical group' (calling attention to the prototypical expression of pain); and 'control group' (being informed about pain in general). For outcome assessments, participants viewed videos of individuals experiencing either pain, disgust or a neutral condition and had to infer what the individual in the video was experiencing. These videos were presented twice (before and after the training). RESULTS: The 'different patterns group' benefited the most from its training, with recognition accuracy for pain increasing significantly more compared to the other groups. The 'prototypical' group also showed improved recognition accuracy for pain, however, this improved recogntition was cancelled out by decreased recognition accuracy for disgust. CONCLUSIONS: Raising awareness in observers that different combinations of facial movements (different faces of pain) are equivalent signals of pain through a brief training procedure can improve recognition accuracy for pain substantially. PMID- 25736628 TI - Nursing vote could prove crucial in next election. PMID- 25736627 TI - Effects of neurotrophin receptor-mediated MAGE homology on proliferation and odontoblastic differentiation of mouse dental pulp cells. AB - OBJECTIVES: This study aimed to investigate effects of neurotrophin receptor mediated melanoma antigen-encoding gene homology (NRAGE) on proliferation and odontoblastic differentiation of mouse dental pulp cells (mDPCs). MATERIALS AND METHODS: Mouse dental pulp cells were infected with recombinant lentivirus to stably knockdown expression of NRAGE, and biological effects of NRAGE on the cells were detected. Proliferation and odontoblastic differentiation of mDPCs were observed. Simultaneously, mRNA and protein levels of NRAGE and nuclear factor-kappaB (NF-kappaB) protein expression were detected. Immunofluorescence assay was used to detect expression and location of NRAGE and NF-kappaB. RESULTS: NRAGE mRNA and protein levels reduced significantly after mDPC odontoblastic induction. Knockdown of NRAGE inhibited the proliferation of mDPCs. However, knockdown of NRAGE enhanced their odontoblastic differentiation with up-regulated ALPase activity. It also promoted mineral nodule formation as well as mRNA and protein expressions of ALP, DSPP and DMP1. Protein levels of NF-kappaB/p50 significantly increased, whereas NF-kappaB/p105 protein expression decreased in the mDPC/shNRG group. Immunofluorescence revealed that relocation of NF-kappaB was similar to that of NRAGE during odontoblastic induction, in which NF-kappaB translocated from the cytoplasm to the nucleus. CONCLUSION: NRAGE is a potent regulator of proliferation and odontoblastic differentiation of mDPCs, which might be via the NF-kappaB signalling pathway. PMID- 25736629 TI - Psychiatric nurse takes centre stage in new BBC comedy drama. PMID- 25736630 TI - Safe staffing and a decent pay rise top wish lists ahead of election. PMID- 25736631 TI - Teenage Cancer Trust launches L80m nationwide holistic outreach service. PMID- 25736632 TI - RCN takes issue with migration committee verdict. PMID- 25736633 TI - Stress at work affecting nurses' health, survey finds. PMID- 25736634 TI - Trusts must explain how they will protect patients from sexual attacks. PMID- 25736635 TI - Strike called off as midwives accept pay offer. PMID- 25736636 TI - Eye clinics are a first for Wales. PMID- 25736637 TI - Experts urge caution over 12-hour shifts amid doubts about safety. PMID- 25736639 TI - NICE outlines warning signs of understaffing in maternity. PMID- 25736640 TI - Specialist dementia care saves money. PMID- 25736641 TI - Safe staffing is the key to nurses' votes, with many still undecided. PMID- 25736647 TI - Asthma diagnosis. PMID- 25736648 TI - Welcome to an exciting new era. AB - This week we launch RCNi, the new name for RCN Publishing, plus a new website for all nursing staff - rcni.com. Here we explain how the website is tailored to meet the needs of busy nurses who are passionate about their work. Its easy-to navigate format offers comprehensive support with revalidation, exclusive news and information plus a discussion forum. PMID- 25736649 TI - Ready, steady, go. AB - The need to improve the population's health and reduce preventable disease is a major theme in Simon Stevens' NHS Five Year Forward View. The NHS England chief executive calls for 'hardhitting national action' on obesity, smoking and alcohol consumption. Nurses will need new skills to motivate patients to change their lifestyles. PMID- 25736650 TI - 'Throne project' could be a life-changer. AB - Colchester Hospital falls prevention nurse Carrie Tyler has introduced the 'Throne project' and implemented simple, inexpensive changes to the hospital's bathrooms that have reduced the number of serious falls experienced by patients. PMID- 25736658 TI - Atrial Fibrillation Association. PMID- 25736661 TI - The best of the week's health-related TV and radio. PMID- 25736662 TI - Breathing Zone Free app. AB - Breathing Zone Free offers simple guided breathing exercises. This free version for Macs and iPhone is a useful introduction to the health benefits of slower, therapeutic breathing. PMID- 25736663 TI - It is up to our patients to decide when to discuss spiritual needs. PMID- 25736664 TI - Seize the opportunity to lobby MPs on the importance of safe staffing. PMID- 25736665 TI - Integrating health and social care is far from revolutionary. PMID- 25736666 TI - A further registration fee rise would be a slap in the face. PMID- 25736668 TI - "EBOLA NURSE CAFFERKEY SUBJECT OF NMC INVESTIGATION". PMID- 25736669 TI - A new perspective on pain relief after 'health care from a bed'. PMID- 25736670 TI - The NHS may be challenged, but my father's care is praiseworthy. PMID- 25736672 TI - Organisational aspects of care. AB - Organisational aspects of care, the second essential skills cluster, identifies the need for registered nurses to systematically assess, plan and provide holistic patient care in accordance with individual needs. Safeguarding, supporting and protecting adults and children in vulnerable situations; leading, co-ordinating and managing care; functioning as an effective and confident member of the multidisciplinary team; and managing risk while maintaining a safe environment for patients and colleagues, are vital aspects of this cluster. This article discusses the roles and responsibilities of the newly registered graduate nurse. Throughout their education, nursing students work towards attaining this knowledge and these skills in preparation for their future roles as nurses. PMID- 25736673 TI - Introduction to the research series. PMID- 25736674 TI - Stages in the research process. AB - Research should be conducted in a systematic manner, allowing the researcher to progress from a general idea or clinical problem to scientifically rigorous research findings that enable new developments to improve clinical practice. Using a research process helps guide this process. This article is the first in a 26-part series on nursing research. It examines the process that is common to all research, and provides insights into ten different stages of this process: developing the research question, searching and evaluating the literature, selecting the research approach, selecting research methods, gaining access to the research site and data, pilot study, sampling and recruitment, data collection, data analysis, and dissemination of results and implementation of findings. PMID- 25736675 TI - Management of gastroenteritis in children under five years. AB - This article explores the causes and management of gastroenteritis in children under five years. It considers in particular national guidance from the National Institute for Health and Care Excellence. The importance of identifying and assessing dehydration is discussed, as well as its systematic management, carer education and infection prevention. Promoting carer competence, confidence and self-management is emphasised. PMID- 25736676 TI - Measles. AB - Before the introduction of measles vaccination, measles was considered an inevitable part of childhood and occurred in 96-98% of children by the age of 18 years. At that time there were approximately 100 reported deaths per year associated with measles in the UK. PMID- 25736677 TI - Championing diversity. PMID- 25736678 TI - 'It is an enormous privilege to be with people at the end of life'. PMID- 25736680 TI - Student life - rewarding mission. PMID- 25736681 TI - Fluorescent fungus and foliage. PMID- 25736682 TI - Photoactivation of Akt1/GSK3beta Isoform-Specific Signaling Axis Promotes Pancreatic beta-Cell Regeneration. AB - Promotion of insulin-secreting beta-cell regeneration in patients with diabetes is a promising approach for diabetes therapy, which can contribute to rescue the uncontrolled hyperglycemia. Low-power laser irradiation (LPLI) has been demonstrated to regulate multiple physiological processes both in vitro and in vivo through activation of various signaling pathways. In the present study, we showed that LPLI promoted beta-cell replication and cell cycle progression through activation of Akt1/GSK3beta isoform-specific signaling axis. Inhibition of PI3-K/Akt or GSK3 with specific inhibitors dramatically reduced or increased LPLI-induced beta-cell replication, revealing Akt/GSK3 signaling axis was involved in beta-cell replication and survival upon LPLI treatment. Furthermore, the results of shRNA-mediated knock down of Akt/GSK3 isoforms revealed that Akt1/GSK3beta isoform-specific signaling axis regulated beta-cell replication and survival in response to LPLI, but not Akt2/GSK3alpha. The mechanism by which LPLI promoted beta-cell replication through Akt1/GSK3beta signaling axis involved activation of beta-catenin and down-regulation of p21. Taken together, these observations suggest that Akt1/GSK3beta isoform signaling axis play a key role in beta-cell replication and survival induced by LPLI. Moreover, our findings suggest that activation of Akt1/GSK3beta isoform signaling axis by LPLI may provide guidance in practical applications for beta-cell regenerative therapies. PMID- 25736683 TI - Study on interactions of aminoglycoside antibiotics with calf thymus DNA and determination of calf thymus DNA via the resonance Rayleigh scattering technique. AB - A simple and sensitive resonance Rayleigh scattering (RRS) spectra method was developed for the determination of calf thymus DNA (ctDNA). The enhanced RRS signals were based on the interactions between ctDNA and aminoglycoside antibiotics (AGs) including kanamycin (KANA), tobramycin (TOB), gentamicin (GEN) and neomycin (NEO) in a weakly acidic medium (pH 3.3-5.7). Parameters influencing the method were investigated. Under optimum conditions, increments in the scattering intensity (?I) were directly proportional to the concentration of ctDNA over certain ranges. The detection limit ranged from 12.2 to 16.9 ng/mL. Spectroscopic methods, including RRS spectra, absorption spectra and circular dichroism (CD) spectroscopy, coupled with thermo-denaturation experiments were used to study the interactions, indicating that the interaction between AGs with ctDNA was electrostatic binding mode. PMID- 25736684 TI - Bufalin is a steroid receptor coactivator inhibitor-response. PMID- 25736686 TI - Bufalin is a steroid receptor coactivator inhibitor-letter. PMID- 25736685 TI - Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. AB - Mutated KRAS (KRAS*) is a fundamental driver in the majority of pancreatic ductal adenocarcinomas (PDAC). Using an inducible mouse model of KRAS*-driven PDAC, we compared KRAS* genetic extinction with pharmacologic inhibition of MEK1 in tumor spheres and in vivo. KRAS* ablation blocked proliferation and induced apoptosis, whereas MEK1 inhibition exerted cytostatic effects. Proteomic analysis evidenced that MEK1 inhibition was accompanied by a sustained activation of the PI3K-AKT MTOR pathway and by the activation of AXL, PDGFRa, and HER1-2 receptor tyrosine kinases (RTK) expressed in a large proportion of human PDAC samples analyzed. Although single inhibition of each RTK alone or plus MEK1 inhibitors was ineffective, a combination of inhibitors targeting all three coactivated RTKs and MEK1 was needed to inhibit proliferation and induce apoptosis in both mouse and human low-passage PDAC cultures. Importantly, constitutive AKT activation, which may mimic the fraction of AKT2-amplified PDAC, was able to bypass the induction of apoptosis caused by KRAS* ablation, highlighting a potential inherent resistance mechanism that may inform the clinical application of MEK inhibitor therapy. This study suggests that combinatorial-targeted therapies for pancreatic cancer must be informed by the activation state of each putative driver in a given treatment context. In addition, our work may offer explanative and predictive power in understanding why inhibitors of EGFR signaling fail in PDAC treatment and how drug resistance mechanisms may arise in strategies to directly target KRAS. PMID- 25736688 TI - Adipose-derived stems cells and their role in human cancer development, growth, progression, and metastasis: a systematic review. AB - Obesity is a well recognized risk factor for several types of cancers, many of which occur solely or disproportionately in women. Adipose tissue is a rich source of adipose-derived stem cells (ASC), which have received attention for their role in cancer behavior. The purpose of this systematic review is to present the existing literature on the role of ASCs in the growth, development, progression, and metastasis of cancer, with an emphasis on malignancies that primarily affect women. To accomplish this goal, the bibliographic database PubMed was systematically searched for articles published between 2001 and 2014 that address ASCs' relationship to human cancer. Thirty-seven articles on ASCs' role in human cancer were reviewed. Literature suggests that ASCs exhibit cancer promoting properties, influence/are influenced by the tumor microenvironment, promote angiogenesis, and may be associated with pathogenic processes through a variety of mechanisms, such as playing a role in hypoxic tumor microenvironment. ASCs appear to be important contributors to tumor behavior, but research in areas specific to women's cancers, specifically endometrial cancer, is scarce. Also, because obesity continues to be a major health concern, it is important to continue research in this area to improve understanding of the impact adiposity has on cancer incidence. PMID- 25736690 TI - Evaluation of microRNAs-29a, 92a and 145 in colorectal carcinoma as candidate diagnostic markers: An Egyptian pilot study. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant neoplasms in Egypt, and interestingly in young age. Adenomatous polyps and inflammatory bowel diseases (IBD) are considered the commonest pre-malignant lesions for CRC. A possible diagnostic role for different microRNAs on CRC has been suggested by numerous studies. AIM OF WORK: To assess the serum expression of 3 microRNA markers (miR-29a, miR-92a and miR-145) in pre-malignant and malignant colorectal lesions. PATIENTS AND METHODS: The 60 patients studied were divided into 4 groups: CRC group (25 patients), IBD group (11 patients), adenomatous polyps group (14 patients) and control group (10 patients). The serum expression of the 3 markers (miR-29a, miR-92a and miR-145) has been assessed by RT-PCR. RESULTS: All CRCs were sporadic cases. Significant downregulation of miR-145 in CRC group was reported at all levels, i.e. when compared to normal, among the 3 studied groups, and when compared between CRC and non-CRC groups. Significant upregulation of miR-29a in CRC was reported when compared to normal, but no significant difference existed either among the 3 studied groups or between CRC and the other 2 groups. All 3 miRNAs studied were positively inter-correlated. CONCLUSIONS: miR-145 may be considered a promising non-invasive reliable diagnostic marker in CRC. Extended studies are needed to ascertain the diagnostic role of miRNAs in CRC. PMID- 25736687 TI - CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy. AB - Growing evidence suggests that tumor-associated macrophages (TAM) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix remodeling, and immunosuppression. In this study, prostate cancer under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to prostate cancer disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF1 or CSF1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF1 signaling through its receptor, CSF1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared with ABT alone. PMID- 25736691 TI - Cognition and personality: an analysis of an emerging field. AB - It is now well established that individuals can differ consistently in their average levels of behaviour across different contexts. There have recently been calls to apply the same adaptive framework to interindividual differences in cognition. These calls have culminated in the suggestion that variation in personality and cognition should correlate. We suggest that both these appealing notions are conceptually and logistically problematic. We identify the first crucial step for establishing any cognition-personality relationship. This is to determine the degree to which cognitive abilities yield consistent task performance. We then suggest how to establish whether such consistency exists. Finally, we discuss why formulating predictions about how cognition might be related to personality is much more difficult than is currently realised. PMID- 25736692 TI - Associations between life stress and subclinical cardiovascular disease are partly mediated by depressive and anxiety symptoms. AB - BACKGROUND: Stress experienced during childhood or adulthood has been associated with cardiovascular disease (CVD), but it is not clear whether associations are already prevalent on a subclinical cardiovascular level. This study investigates associations between indicators of life stress and subclinical CVD, and whether these are mediated by depression and anxiety. METHODS: Subjects were 650 participants of the Netherlands Study of Depression and Anxiety, aged 20-66 years, with or without (27.5%) depressive and anxiety disorders. Life stress included childhood trauma, negative life events and recently experienced daily hassles or job strain. Subclinical CVD was measured as 1) carotid atherosclerosis (intima-media thickness and the presence of plaques) using B-mode ultrasonography, and 2) central arterial stiffness (heart rate normalized augmentation index) using calibrated radial applanation tonometry. RESULTS: Increased central arterial stiffness was shown in subjects who had experienced childhood trauma (per SD increase: beta=.07; p=.01), or reported recently experienced daily hassles (per SD increase: beta=.06; p=.02), negative life events (per SD increase: beta=.05; p=.03), or job strain (high versus low: beta=.09; p=.01). Associations between life stress and arterial stiffness appeared to be partly mediated by severity of depressive and anxiety symptoms. No significant associations were found for childhood life events, nor between indicators of life stress and carotid atherosclerosis. CONCLUSIONS: Childhood trauma and recent life stress were associated with increased central arterial stiffness. This suggests that life stress - partly via depression and anxiety - might enhance the development and progression of CVD. PMID- 25736693 TI - The prevalence and implications of BK virus replication in non-renal solid organ transplant recipients: A systematic review. AB - The significance of BK viruria and viremia in non-renal solid organ transplants is poorly understood. A systematic review was performed reviewing the incidence and implications of BK virus replication in non-renal solid organ transplants. Ninety-seven studies were identified, of which 18 including lung, heart, liver and pancreas transplants were included. The overall incidence of BK viruria and viremia was 20% and 3% respectively and 17 cases of BK nephropathy were identified. Heart transplant recipients had a higher overall incidence of BK viremia than other non-renal organ types, and the majority of cases of BK virus associated nephropathy were in heart transplant recipients. The incidence of BK viremia was significantly lower in non-renal solid organ transplants than that of renal transplant recipients and BK virus-associated nephropathy was rare. BK virus-associated nephropathy may be considered in heart transplant recipients who have unexplained and persistent renal dysfunction not attributable to other causes. PMID- 25736694 TI - Measuring alloreactivity and drug adherence: making the best of what we have. PMID- 25736696 TI - FDG-PET Predicts Pain Response and Local Control in Palliative Radiotherapy With or Without Systemic Treatment in Patients With Bone Metastasis From Non-small cell Lung Cancer. AB - The purpose of the present study was to evaluate the prognostic value of the maximal standardized uptake value (SUVmax) from serial positron emission tomography scans in patients with bone metastases from non-small-cell lung cancer. The results showed that the pre-RT SUVmax predicted the initial pain severity and local control. Moreover, the change in the SUVmax after palliative radiotherapy predicted the pain response and local control rate. INTRODUCTION: We sought to evaluate the value of fluorine-18 fluorodeoxyglucose positron emission tomography (PET) in predicting the pain severity, pain response, and in-field tumor control after palliative radiotherapy (RT) in patients with non-small-cell lung cancer (NSCLC) bone metastases. MATERIALS AND METHODS: The present retrospective, institutional review board-approved study involved 74 patients with NSCLC and 185 bone metastatic lesions. All patients had undergone PET computed tomography (CT) scans before and after RT. The pain scores were determined using a numerical rating scale, and the maximal standardized uptake value (SUVmax) at each location was recorded. The pain scores and responses to RT were compared using the pre-RT SUVmax and SUVmax changes after RT. Cox regression analyses were performed to identify the prognostic factors for in-field progression-free survival (PFS) and in-field event-free survival (EFS). RESULTS: The pre-RT SUVmax correlated with the initial pain scores (r = 0.885, P < .001), and the decrease in the SUVmax after RT was associated with the pain response to RT (P = .001). During the follow-up period, 47.03% and 38.92% of the lesions showed in-field tumor radiographic progression and in-field events, respectively. The Cox regression analyses showed that a higher pre-RT SUVmax (>= 8.2) was an independent prognostic factor of worse in-field PFS and worse in-field EFS (hazard ratio [HR] 1.42 and 1.46; P = .044 and P = .005, respectively) and that a greater SUVmax decrease (>= 28.3%) after RT was an independent prognostic factor of better in-field PFS and better in-field EFS (HR 0.59 and 0.60, respectively; P < .001 for both). CONCLUSION: In patients with NSCLC osseous metastasis treated with palliative RT, the pre-RT SUVmax predicted the initial pain severity and local control. Moreover, the change in the SUVmax after RT predicted the pain response and local control. PMID- 25736695 TI - Glycine decarboxylase deficiency causes neural tube defects and features of non ketotic hyperglycinemia in mice. AB - Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism. GLDC mutations cause a rare recessive disease non-ketotic hyperglycinemia (NKH). Mutations have also been identified in patients with neural tube defects (NTDs); however, the relationship between NKH and NTDs is unclear. We show that reduced expression of Gldc in mice suppresses glycine cleavage system activity and causes two distinct disease phenotypes. Mutant embryos develop partially penetrant NTDs while surviving mice exhibit post-natal features of NKH including glycine accumulation, early lethality and hydrocephalus. In addition to elevated glycine, Gldc disruption also results in abnormal tissue folate profiles, with depletion of one-carbon-carrying folates, as well as growth retardation and reduced cellular proliferation. Formate treatment normalizes the folate profile, restores embryonic growth and prevents NTDs, suggesting that Gldc deficiency causes NTDs through limiting supply of one-carbon units from mitochondrial folate metabolism. PMID- 25736697 TI - Photoinduced postsynthetic polymerization of a metal-organic framework toward a flexible stand-alone membrane. AB - Metal-organic frameworks (MOFs) are a promising class of nanoporous polymeric materials. However, the processing of such fragile crystalline powders into desired shapes for further applications is often difficult. A photoinduced postsynthetic polymerization (PSP) strategy was now employed to covalently link MOF crystals by flexible polymer chains, thus endowing the MOF powders with processability and flexibility. Nanosized UiO-66-NH2 was first functionalized with polymerizable functional groups, and its subsequent copolymerization with monomers was easily induced by UV light under solvent-free and mild conditions. Because of the improved interaction between MOF particles and polymer chains, the resulting stand-alone and elastic MOF-based PSP-derived membranes possess crack free and uniform structures and outstanding separation capabilities for Cr(VI) ions from water. PMID- 25736698 TI - Piperine inhibit inflammation, alveolar bone loss and collagen fibers breakdown in a rat periodontitis model. AB - BACKGROUND AND OBJECTIVE: Piperine exhibits anti-inflammatory activity, and has a long history of medicinal use. The objective of this study was to investigate the protective effects of piperine on inflammation, alveolar bone and collagen fibers in experimental periodontitis. We evaluated the related expression of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, matrix metalloproteinase (MMP)-8 and MMP-13 to enhance insight into these effects. MATERIAL AND METHODS: Thirty two Wistar rats were divided into four groups of eight animals each: control group, periodontitis group, periodontitis plus 50 mg/kg piperine group and periodontitis plus 100 mg/kg piperine group. Histopathologic changes were detected by hematoxylin and eosin staining. Alveolar bone loss and trabecula microstructures were evaluated by micro-computed tomography. Changes in collagen fibers were assessed by picrosirius red staining. Western blot analysis was conducted to determine the levels of IL-1beta, TNF-alpha, MMP-8 and MMP-13. RESULTS: Piperine clearly inhibited alveolar bone loss and reformed trabecula microstructures in a dose-dependent manner. Histological staining showed that piperine significantly reduced the infiltration of inflammation in soft tissues. Both doses of piperine limited the fractions of degraded areas in collagen fibers. Piperine (100 mg/kg) significantly downregulated the expressions of IL 1beta, MMP-8 and MMP-13 in periodontitis, but not that of TNF-alpha. CONCLUSION: Piperine displays significantly protective effects on inflammation, alveolar bone loss, bone microstructures and collagen fiber degradation in experimental periodontitis. The effects may be ascribed to its inhibitory activity on the expressions of IL-1beta, MMP-8 and MMP-13. PMID- 25736699 TI - Form and function in early clause-combining. AB - The study characterizes developmental trends in early Hebrew clause-combining (CC) by analyzing the interplay between linguistic form and communicative function in different interactional settings. Analysis applied to all utterances produced by three children aged 2; 0-3 ;0 who combined two or more clauses, either self-initiated or on the basis of adult input. Ten types of CC were analyzed for marking by connectives (e.g., the Hebrew equivalents of 'and', 'that', 'so'). Four shared consecutive developmental phases emerged: non-marking; partial marking by 'and' and 'that'; use of 'but' and 'because', favored significantly in interlocutor-supported contexts; marking of adverbial relations and more varied use of se- 'that'. These CC processes are interpreted as reflecting general properties of language development, in the form of gradually increasing specification of form-function relations under the impact of interlocutor-child interactive support combined with Hebrew-particular typological factors. PMID- 25736700 TI - Halloysite nanotubes capturing isotope selective atmospheric CO2. AB - With the aim to capture and subsequent selective trapping of CO2, a nanocomposite has been developed through selective modification of the outer surface of the halloysite nanotubes (HNTs) with an organosilane to make the nanocomposite a novel solid-phase adsorbent to adsorb CO2 from the atmosphere at standard ambient temperature and pressure. The preferential adsorption of three major abundant isotopes of CO2 ((12)C(16)O2, (13)C(16)O2, and (12)C(16)O(18)O) from the ambient air by amine functionalized HNTs has been explored using an optical cavity enhanced integrated cavity output spectroscopy. CO2 adsorption/desorption cycling measurements demonstrate that the adsorbent can be regenerated at relatively low temperature and thus, recycled repeatedly to capture atmospheric CO2. The amine grafted halloysite shows excellent stability even in oxidative environments and has high efficacy of CO2 capture, introducing a new route to the adsorption of isotope selective atmospheric CO2. PMID- 25736703 TI - Editorial overview: Food biotechnology: microbial ecosystem management: strategies to adapt ecosystems to improve performance and health impact. PMID- 25736702 TI - Preventability of adverse effects of analgesics: analysis of spontaneous reports. AB - OBJECTIVES: The aims of this study were to determine the patterns of analgesic adverse drug reactions (ADRs) and to assess their preventability and contributing factors. METHODS: This is a retrospective, descriptive study conducted on ADRs of analgesics and other drugs indicated as analgesics, spontaneously reported to the Bordeaux pharmacovigilance center from January 2011 to June 2012. RESULTS: The 141 cases selected for the analysis included 16 cases of medication errors (11.3%) and 15 addiction cases (10.6%). In total, 214 ADRs were registered, for which 173 analgesic medicines were suspected. The most frequent ADRs reported were nervous system disorders (26.6%), psychiatric disorders (15.0%), and skin and subcutaneous tissue disorders (12.1%). Tramadol alone or in combination (17.3%), followed by morphine (15%), fentanyl (9.8%), and paracetamol (8.7%) were the most frequently involved analgesics. More than half of the cases (54.6%) were serious and led to hospitalization or prolonged hospitalization. Preventability was determined for 134 cases (95%): 51.5% were considered as preventable, 26.1% not preventable, and 22.4% not assessable. The main contributing factors for the preventable cases included negligence of recommendations for analgesic use and failure to consider patients' risk factors when prescribing. CONCLUSIONS: A significant number of analgesic ADRs could be prevented, and being aware of their contributing factors promotes efficient analgesia with minimum risks to the patients. PMID- 25736701 TI - Changes in comorbid conditions after prolonged exposure for PTSD: a literature review. AB - Prolonged exposure (PE) is an effective psychological treatment for patients who suffer from PTSD. The majority of PTSD patients have comorbid psychiatric disorders, and some clinicians are hesitant to use PE with comorbid patients because they believe that comorbid conditions may worsen during PE. In this article, we reviewed the evidence for this question: what are the effects of PE on comorbid symptoms and associated symptomatic features? We reviewed findings from 18 randomized controlled trials of PE that assessed the most common comorbid conditions (major depression, anxiety disorders, substance use disorders, personality disorders, and psychotic disorders) and additional symptomatic features (suicidality, dissociation, negative cognitions, negative emotions, and general health and work/social functioning). Although systematic research is not available for all comorbid populations, the existing research indicates that comorbid disorders and additional symptomatic features either decline along with the PTSD symptoms or do not change as a result of PE. Therefore, among the populations that have been studied to date, there is no empirical basis for excluding PTSD patients from PE due to fear of increases in comorbid conditions or additional symptomatic features. Limitations of the existing research and recommendations for future research are also discussed. PMID- 25736704 TI - Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK. AB - Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed. PMID- 25736705 TI - Do we foresee new emerging drugs to treat malignant hyperthermia? AB - Malignant hyperthermia (MH) is a life-threatening genetic sensitivity of skeletal muscles to volatile anesthetics and depolarizing neuromuscular blocking drugs occurring during or after anesthesia. Mortality of MH has been significantly reduced by using the skeletal muscle relaxant dantrolene. However, pharmacological disadvantages are known. By approval of a nanocrystalline dantrolene sodium suspension (DSS), a new product enters the market. DSS is a promising substance, but clinical data are lacking up to now. Especially with regard to newer knowledge on MH and its associated clinical presentations, there might be an increasing interest on DSS. PMID- 25736706 TI - Incidence and morbidity of urinary tract infection in a prospective cohort of children. AB - AIM: Information on the epidemiology of childhood urinary tract infections (UTIs) is scarce and mostly based on retrospective data. This study investigated incidence rates, morbidity and risk factors for UTIs in a prospective cohort of children. METHODS: We explored UTIs in a representative cohort of 1049 neonates from birth to 6 years of age, using maternal interviews that were verified by hospital records. The majority (88.2%) completed the first-year, and more than half (56.2%) completed the 6-year follow-up. RESULTS: By 6 years of age, more than 10% of our sample had been affected by UTIs. The cumulative incidence for the first year of life was 3.77%, without significant differences between genders, and for one to 6 years, it was 6.81% and 5.7 times higher in girls than boys. Clinical information was available for 63 children: 25 were hospitalised, 16 suffered recurrences, 10 received prophylaxis, eight had urinary tract malformations, three required surgery, and two had impaired renal function. CONCLUSION: UTIs affected approximately 4% and 10% of children by the ages of one and 6 years, respectively, and their incidence was related to gender and age. Morbidity was considerable, recurrences were common, and despite advances in management, long-term consequences may still be encountered. PMID- 25736707 TI - Chick embryo chorioallantoic membrane (CAM): an alternative predictive model in acute toxicological studies for anti-cancer drugs. AB - The chick embryo chorioallantoic membrane (CAM) is a preclinical model widely used for vascular and anti-vascular effects of therapeutic agents in vivo. In this study, we examine the suitability of CAM as a predictive model for acute toxicology studies of drugs by comparing it to conventional mouse and rat models for 10 FDA-approved anticancer drugs (paclitaxel, carmustine, camptothecin, cyclophosphamide, vincristine, cisplatin, aloin, mitomycin C, actinomycin-D, melphalan). Suitable formulations for intravenous administration were determined before the average of median lethal dose (LD50) and median survival dose (SD(50)) in the CAM were measured and calculated for these drugs. The resultant ideal LD(50) values were correlated to those reported in the literature using Pearson's correlation test for both intravenous and intraperitoneal routes of injection in rodents. Our results showed moderate correlations (r(2)=0.42 - 0.68, P<0.005 0.05) between the ideal LD(50) values obtained using the CAM model with LD(50) values from mice and rats models for both intravenous and intraperitoneal administrations, suggesting that the chick embryo may be a suitable alternative model for acute drug toxicity screening before embarking on full toxicological investigations in rodents in development of anticancer drugs. PMID- 25736708 TI - Effect of hypochlorous acid solution on the eradication and prevention of Pseudomonas aeruginosa infection, serum biochemical variables, and cecum microbiota in rats. AB - In this study, hypochlorous acid solution, a weak acid, provided as drinking water to rats, was evaluated for its ability to eradicate and prevent Pseudomonas aeruginosa infection, while monitoring its simultaneous effect on serum biochemical variables and microbiota in the rat cecum. The results suggest that the solution could not eliminate the bacteria in the experimentally infected rats; however, the administration of a 10-parts-per-million (ppm) hypochlorous acid solution as drinking water was effective in inhibiting horizontal spread of P. aeruginosa infection among cage mates. Additionally, exposure to hypochlorous solution did not have any effect on serum biochemical variables of the rat including levels of total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin, total bilirubin, lipase, amylase, urea nitrogen, total protein, calcium (Ca), phosphorus (P), sodium (Na), chlorine (Cl), except for potassium (K) levels. The most frequently isolated bacteria in the rat cecum included species belonging to Bacteroidales, Lactobacillus, Clostridiales, Erysipelotrichaceae, Akkermansia, Coriobacteriales, and Firmicutes. The ratio of the terminal restriction fragment length polymorphism (T-RFLP) peaks did not differ across rats administered with 5 and 10 ppm weak acid solution as compared to the control group for any of the bacteria, except for Erysipelotrichaceae and Firmicutes, where the ratio of T-RFLP peaks was higher in the 5 ppm group for Erysipelotrichaceae and in the 10 ppm group for Firmicutes than that in the control group (P<0.01). The results suggest that the weak acid hypochlorous solution could not eradicate P. aeruginosa completely from rats. The solution was effective in preventing infection without affecting serum biochemical variables; however, some of bacterial microbiota may have changed due to administration of the solution. PMID- 25736709 TI - A nonsense nucleotide substitution in the oculocutaneous albinism II gene underlies the original pink-eyed dilution allele (Oca2(p)) in mice. AB - The original pink-eyed dilution (p) on chromosome 7 is a very old spontaneous mutation in mice. The oculocutaneous albinism II (Oca2) gene has previously been identified as the p gene. Oca2 transcripts have been shown to be absent in the skin of SJL/J mice with the original p mutant allele (Oca2(p)); however, the molecular genetic lesion underlying the original Oca2(p) allele has never been reported. The NCT mouse (commonly known as Nakano cataract mouse) has a pink-eyed dilution phenotype, which prompted us to undertake a molecular genetic analysis of the Oca2 gene of this strain. Our genetic linkage analysis suggests that the locus for the pink-eyed dilution phenotype of NCT is tightly linked to the Oca2 locus. PCR cloning and nucleotide sequence analysis indicates that the NCT mouse has a nonsense nucleotide substitution at exon 7 of the Oca2 gene. Examination of three mouse strains (NZW/NSlc, SJL/J, and 129X1/SvJJmsSlc) with the original Oca2(p) allele revealed the presence of a nonsense nucleotide substitution identical to that in the NCT strain. RT-PCR analysis revealed that the Oca2 transcripts were absent in the skin of NCT mice, suggesting intervention of the nonsense-mediated mRNA decay pathway. Collectively, the data in this study indicate that the nonsense nucleotide substitution in the Oca2 gene underlies the Oca2(p) allele. Our data also indicate that the NCT mouse can be used not only as a cataract model, but also as a model for human type II oculocutaneous albinism. PMID- 25736711 TI - Military intervention: The last option for polio eradication in Pakistan? PMID- 25736710 TI - Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin. AB - The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes mellitus, diabetic microvascular complications, including nephropathy, peripheral neuropathy and retinopathy, are observed at young ages. In the present study, blood glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective SGLT inhibitor, to examine whether and how these complications are caused by hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic nephropathy. These renal parameters tended to decrease with phlorizin; however, effects were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in electroretinograms) and histopathological eye abnormalities, including retinal folding and mature cataracts were also observed. Both nerve and eye disorders were prevented with phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic complications in SDT fatty rats. However, other factors, such as hyperlipidemia and hypertension, may affect diabetic nephropathy. These characteristics of diabetic complications will become helpful in evaluating new drugs for diabetic complications using SDT fatty rats. PMID- 25736712 TI - International Journal of Language & Communication Disorders. Editorial. PMID- 25736713 TI - Congenital multiple cranial neuropathies: Relevance of orofacial electromyography in infants. AB - INTRODUCTION: The aim of this study was to assess diagnoses and outcomes of infants with 2 or more cranial neuropathies identified using orofacial electromyography (EMG). METHODS: This retrospective study involved 90 patients. Diagnoses took into account clinical, radiological, and genetic data. EMG examined the orbicularis oculi, genioglossus, and levator veli palatini muscles, and blink responses. To evaluate outcome, neurological disability, respiratory complications, and feeding difficulties were recorded. RESULTS: The patients had malformation syndromes (59), encephalopathies (29), or no underlying disorders (2). Neurogenic EMG signs were detected in a mean of 4 muscles, reflecting a mean of 3 affected nerves. EMG identified a higher number of neuropathies than clinical examination alone (82 vs. 31, facial; 56 vs. 2, pharyngeal; 25 vs. 3, hypoglossal). Poor outcome and death were more frequent when EMG identified >=4 affected nerves (P = 0.02). CONCLUSION: EMG highlights multiple cranial neuropathies that can be clinically silent in infants with malformation syndromes or encephalopathies. PMID- 25736714 TI - Chemical versus electrochemical synthesis of carbon nano-onion/polypyrrole composites for supercapacitor electrodes. AB - The development of high-surface-area carbon electrodes with a defined pore size distribution and the incorporation of pseudo-active materials to optimize the overall capacitance and conductivity without destroying the stability are at present important research areas. Composite electrodes of carbon nano-onions (CNOs) and polypyrrole (Ppy) were fabricated to improve the specific capacitance of a supercapacitor. The carbon nanostructures were uniformly coated with Ppy by chemical polymerization or by electrochemical potentiostatic deposition to form homogenous composites or bilayers. The materials were characterized by transmission- and scanning electron microscopy, differential thermogravimetric analyses, FTIR spectroscopy, piezoelectric microgravimetry, and cyclic voltammetry. The composites show higher mechanical and electrochemical stabilities, with high specific capacitances of up to about 800 F g(-1) for the CNOs/SDS/Ppy composites (chemical synthesis) and about 1300 F g(-1) for the CNOs/Ppy bilayer (electrochemical deposition). PMID- 25736716 TI - A review of the safety and efficacy of bariatric surgery in adults over the age of 60: 2002-2013. AB - PURPOSE: The purpose of this review is to compare outcomes of bariatric surgery in adults over 60 to younger patients. This analysis is important to determine if nurse practitioners (NPs) and other providers should recommend bariatric surgery to obese older adults. DATA SOURCES: This review included 15 studies published between 2002 and 2013. CONCLUSIONS: Although older adults seem to experience less weight loss, bariatric surgery has potential benefits for these patients. Significant improvements in hypertension, diabetes, and, to a lesser extent, dyslipidemia are noted. Mortality and surgical complications in older adults are low, while differences in length of hospital stay are inconclusive. IMPLICATIONS FOR PRACTICE: The risks of bariatric surgery in older adults need to be carefully evaluated based on individual medical condition. Overall the evidence suggests that bariatric surgery can be safely performed in older adults but more research is needed to determine which older adult patients are the best candidates for bariatric surgery. As bariatric surgery among older adults increases, interdisciplinary teams will continue to serve an important role in the management of bariatric surgery patients. NPs must be aware of trends in this emerging population of bariatric surgery patients. PMID- 25736715 TI - Distinct Tissue Mineral Density in Plate- and Rod-like Trabeculae of Human Trabecular Bone. AB - Trabecular bone quality includes both microstructural and intrinsic tissue mineralization properties. However, the tissue mineralization in individual trabeculae of different trabecular types and orientations has not yet been investigated. The aim of this study was to develop an individual trabecula mineralization (ITM) analysis technique to determine tissue mineral density (TMD) distributions in plate- and rod-like trabeculae, respectively, and to compare the TMD of trabeculae along various orientations in micro-computed tomography (MUCT) images of trabecular bone samples from the femoral neck, greater trochanter, and proximal tibia. ITM analyses indicated that trabecular plates, on average, had significantly higher TMD than trabecular rods. In addition, the distribution of TMD in trabecular plates depended on trabecular orientation with the lowest TMD in longitudinal plates and the highest TMD in transverse plates. Conversely, there was a relatively uniform distribution of TMD among trabecular rods, with respect to trabecular orientation. Further analyses of TMD distribution revealed that trabecular plates had higher mean and peak TMD, whereas trabecular rods had a wider TMD distribution and a larger portion of low mineralized trabeculae. Comparison of apparent Young's moduli derived from micro-finite element models with and without heterogeneous TMD demonstrated that heterogeneous TMD in trabecular plates had a significant influence on the elastic mechanical property of trabecular bone. In conclusion, this study revealed differences in TMD between plate- and rod-like trabeculae and among various trabecular orientations. The observation of less mineralized longitudinal trabecular plates suggests interesting implications of these load-bearing plates in bone remodeling. The newly developed ITM analysis can be a valuable technique to assess the influence of metabolic bone diseases and their pharmaceutical treatments on not only microstructure of trabecular bone but also the microarchitectural heterogeneity of tissue mineralization. PMID- 25736718 TI - Relaxation dynamics of a quantum emitter resonantly coupled to a coherent state of a localized surface plasmon. AB - We investigate the relaxation dynamics of a quantum dipole emitter (QDE), e.g., a molecule or quantum dot, located near a metal nanoparticle (MNP) exhibiting a dipolar localized surface plasmon (LSP) resonance at the frequency of the QDE radiative transition. A generic three-level QDE, which is pumped with an external laser pulse and thereby brought into an optically active excited state, is considered to be weakly coupled to the resonant LSP described by a coherent state. It is shown that, under the condition of the QDE-MNP characteristic relaxation time being much shorter than that of the QDE in free space but much longer than the LSP lifetime, the QDE relaxation dynamics can be described analytically and feature, in general, non-exponential decay with complicated transient behaviour. The main physical consequence of this relaxation process is that the emission, being largely determined by the MNP, comes out with a substantial delay. It is also shown that energy dissipation in the QDE-MNP system is relatively weak with the probability of the photon emission being ~0.75, a number which, rather surprisingly, does not explicitly depend on the metal absorption characteristics. A large number of QDE-MNP system parameters in our analytical description open new possibilities for controlling quantum emitter dynamics. PMID- 25736717 TI - betaA3/A1-crystallin is a critical mediator of STAT3 signaling in optic nerve astrocytes. AB - We have previously reported that in the Nuc1 rat, which has a spontaneous mutation in Cryba1 (the gene encoding betaA3/A1-crystallin), astrocytes exhibit decreased Notch signaling, leading to reduced promoter activity for glial fibrillary acidic protein (GFAP). Interestingly, in both Nuc1 astrocytes and in wild type astrocytes following knockdown of Cryba1, vascular endothelial growth factor (VEGF) secretion is decreased. This has led us to explore signaling mediators that could be regulated by betaA3/A1-crystallin to modulate both GFAP and VEGF. Several studies have shown that the signal transducer and activator of transcription 3 (STAT3) is involved in the co-regulation of GFAP and VEGF. We show that STAT3 and betaA3/A1-crystallin may co-regulate each other in astrocytes. Such co-regulation would create a positive feedback circuit; i.e., in the cytosol of astrocytes, betaA3/A1-crystallin is necessary for the phosphorylation of STAT3, which then dimerizes and translocates to the nucleus to form DNA-binding complexes, activating transcription of Cryba1. This stoichiometric co-regulation of STAT3 and Cryba1 could potentiate expression of GFAP and secretion of VEGF, both of which are essential for maintaining astrocyte and blood vessel homeostasis in the retina. Consistent with this idea, Cryba1 knockout mice exhibit an abnormal astrocyte pattern and defective remodeling of retinal vessels. PMID- 25736719 TI - Potential of sustainable hierarchical zeolites in the valorization of alpha pinene. AB - In the valorization of alpha-pinene, which is an important biomass intermediate derived from turpentine oil, hierarchical (mesoporous) zeolites represent a superior class of catalysts. Hierarchical USY, ZSM-5, and beta zeolites have been prepared, characterized, and catalytically evaluated, with the aim of combining the highest catalytic performance with the most sustainable synthetic protocol. These zeolites are prepared by alkaline treatment in aqueous solutions of NH4 OH, NaOH, diethylamine, and NaOH complemented with tetrapropylammonium bromide. The hierarchical USY zeolite is the most attractive catalyst of the tested series, and is able to combine an overall organic-free synthesis with an up to sixfold activity enhancement and comparable selectivity over the conventional USY zeolite. This superior performance relates to a threefold greater activity than that of the commercial standard, namely, H2 SO4 /TiO2 . Correlation of the obtained benefits to the amount of solid lost during the postsynthetic modifications highlights that the highest activity gains are obtained with minor leaching. Furthermore, a highly zeolitic character, as determined by bulk XRD, is beneficial, but not crucial, in the conversion of alpha-pinene. The alkaline treatments not only result in a higher overall activity, but also a more functional external surface area, attaining up to four times the pinene conversions per square nanometer. The efficiency of the hierarchical USY zeolite is concomitantly demonstrated in the conversion of limonene and turpentine oil, which emphasizes its industrial potential. PMID- 25736720 TI - White spot syndrome virus VP51 interact with ribosomal protein L7 of Litopenaeus vannamei. AB - The interaction between viral structural proteins and host plays key functions in viral infection. In previous studies, most research have been undertaken to explore the interaction of envelope structural proteins with host molecules. However, how the nucleocapsid proteins of WSSV interacted with host molecules remained largely unknown. In this study, the interaction of nucleocapsid protein VP51 and ribosomal protein L7 of Litopenaeus vannamei (LvRPL7) was reported. Furthermore, the mRNA transcriptional response of LvRPL7 to WSSV was investigated. The results showed that LvRPL7 was widely distributed in all analyzed tissues of L. vannamei. The high expression levels of LvRPL7 were found in the tissues of muscle and gills. The temporal expression of LvRPL7 in WSSV challenged shrimp showed that LvRPL7 was up-regulated (P < 0.5) in the muscle at 8 h and 24 h post WSSV challenge and then restored to the normal levels. But the LvRPL7 expression was up-regulated (P < 0.5) in the hepatopancreas at 8 h post WSSV challenge and down-regulated at 12 h and 24 h post WSSV challenge. Indirect immunofluorescence assay indicated that LvRPL7 was mainly located on the surface and cytoplasm of hemocytes. Far-Western blotting showed that VP51 bound with LvRPL7. Moreover, ELISA results appeared that LvRPL7 interacted with VP51 in concentration dependent manner. Neutralization assay in vivo showed that anti LvRPL7 antibody significantly delayed WSSV infection. Our results reveal that LvRPL7 was involved in WSSV infection. PMID- 25736721 TI - Microreactor array device. AB - We report a device to fill an array of small chemical reaction chambers (microreactors) with reagent and then seal them using pressurized viscous liquid acting through a flexible membrane. The device enables multiple, independent chemical reactions involving free floating intermediate molecules without interference from neighboring reactions or external environments. The device is validated by protein expressed in situ directly from DNA in a microarray of ~10,000 spots with no diffusion during three hours incubation. Using the device to probe for an autoantibody cancer biomarker in blood serum sample gave five times higher signal to background ratio compared to standard protein microarray expressed on a flat microscope slide. Physical design principles to effectively fill the array of microreactors with reagent and experimental results of alternate methods for sealing the microreactors are presented. PMID- 25736722 TI - Inhibition of Acetylcholinesterase (AChE): A Potential Therapeutic Target to Treat Alzheimer's Disease. AB - A new series of icariin derivatives were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. Most of the tested compounds exhibited high AChE inhibition and low toxicity, and among which compounds 1, 2, and 10 were the most potent (IC50 = 71.52 +/- 22.43, 8.28 +/- 1.45, 5.830 +/- 1.78 nm, respectively). PMID- 25736723 TI - Interatrial septal thickness is associated with the extent of left atrial complex fractionated atrial electrograms and acute procedural outcome in patients with persistent atrial fibrillation. AB - AIMS: The interatrial septal thickness (IAST) reflects the changes of the atrial wall in patients with atrial fibrillation (AF). Complex fractionated atrial electrograms (CFAEs) were consistently positioned on the interatrial septum, especially in the remodelled left atrium (LA). We sought to characterize the relationship between IAST and LA CFAE area, as well as the acute procedural and clinical outcomes of catheter ablation in persistent AF patients. METHODS AND RESULTS: This study included 71 patients who underwent catheter ablation for drug refractory persistent AF. A stepwise ablation approach included circumferential pulmonary vein isolation followed by LA and right atrial CFAE-guided ablation. Interatrial septal thickness was measured 1 cm inferior to the fossa ovalis on cardiac computed tomography (CT). The extent of LA CFAEs was assessed by CFAE area and index (CFAE area/LA surface area * 100). Patients were grouped into tertiles according to the value of IAST. The mean IAST of the first, second, and third tertile was 4.69 +/- 0.79, 6.44 +/- 0.45, and 9.12 +/- 1.42 mm, respectively (P < 0.001). The mean CFAE areas (5.6 +/- 6.9, 18.5 +/- 20.3, and 24.3 +/- 26.6 mm(2), P = 0.005) and CFAE indexes (3.1 +/- 4.2, 9.2 +/- 10.7, and 11.8 +/- 15.3, P = 0.025) in LA were significantly different among the three groups. More patients in the highest IAST tertile did not terminate AF during catheter ablation (12.5% vs. 26.1% vs. 37.5%, P = 0.048). CONCLUSIONS: Interatrial septal thickness measured by cardiac CT is associated with the extent of CFAE area within the LA and is related to acute procedural success of catheter ablation. These findings suggest that IAST reflects the degree of atrial substrate and remodelling in patients with persistent AF. PMID- 25736724 TI - Ablation of typical atrial flutter using a non-fluoroscopic catheter tracking system vs. conventional fluoroscopy--results from a prospective randomized study. AB - AIMS: Reduction of radiation exposure using a sensor-based non-fluoroscopic catheter tracking (NFCT) system (MediGuideTM, St Jude Medical, Inc.) was recently demonstrated by retrospective comparisons. We aimed to prospectively compare the effects of using NFCT vs. standard fluoroscopy on procedural parameters in patients undergoing radiofrequency ablation of typical atrial flutter. METHODS AND RESULTS: We prospectively randomized 40 patients undergoing cavotricuspid isthmus ablation for typical atrial flutter to either NFCT (n = 20) or conventional fluoroscopy (CONV, n = 20). Procedural parameters such as fluoroscopy time, radiation dose, and procedure duration, as well as periprocedural complications were compared. There were no statistically significant differences in baseline characteristics between the two groups. Bidirectional isthmus block was achieved in all patients. Fluoroscopy time was significantly reduced in the NFCT group {0.3 [inter-quartile range (IQR) 0.2; 0.48] min} when compared with CONV [5.7 (IQR 4.2; 11.5) min] (P < 0.001). This resulted in a significant reduction in radiation dose in patients randomized to NFCT [17.4 (IQR 11; 206.6) cGy cm(2)] vs. the CONV group [418.4 (IQR 277; 812.2) cGy cm(2)] (P < 0.001). There were no significant differences in procedure duration between the NFCT group [49.5 (IQR 37; 65) min] when compared with the CONV group [33.5 (IQR 26.3; 55.5) min] (P = 0.053). No adverse events were recorded. Freedom from atrial flutter at 6 months of follow-up was 19/20 (95%) in the NFCT and 18/20 (90%) in the CONV group (n.s.). CONCLUSION: In this first prospective randomized study, by comparing NFCT with standard fluoroscopy in patients undergoing radiofrequency ablation of typical atrial flutter, NFCT significantly reduced both radiation dose and fluoroscopy time with no effects on procedural duration. These findings support the incorporation of NFCT in routine clinical use. PMID- 25736725 TI - Pulmonary vein isolation by radiosurgery: implications for non-invasive treatment of atrial fibrillation. AB - AIMS: Electrical isolation of the pulmonary veins (PVs) has been established in clinical routine as a curative treatment for atrial fibrillation (AF). While catheter ablation carries procedural risks, radiosurgery might be able to non invasively induce lesions at the PV ostia to block veno-atrial electrical conduction. This porcine feasibility and dose escalation study determined the effect of radiosurgery on electrophysiologic properties of the left atrial-PV junction. METHODS AND RESULTS: Eight adult Goettingen mini-pigs underwent electrophysiological voltage mapping in the left atrium and the upper right PV. Radiation was delivered with a conventional linear accelerator. A single homogeneous dose ranging from 22.5 to 40 Gy was applied circumferentially to the target vein antrum. Six months after radiosurgery, electrophysiological mapping was repeated and a histological examination performed. Voltage mapping consistently showed electrical potentials in the upper right PV at baseline. Pacing the target vein prompted atrial excitation, thus proving veno-atrial electrical conduction. After 6 months, radiation had reduced PV electrogram amplitudes. This was dose dependent with a mean interaction effect of -5.8%/Gy. Complete block of atrio-venous electrical conduction occurred after 40 Gy dose application. Histology revealed transmural scarring of the targeted PV musculature with doses >30 Gy. After 40 Gy, it spanned the entire circumference in accordance with pulmonary vein isolation. CONCLUSION: Pulmonary vein isolation to treat AF can be achieved by radiosurgery with a conventional linear accelerator. Yet, it requires a high radiation dose which might limit clinical applicability. PMID- 25736726 TI - Binding analysis of Bacillus thuringiensis Cry1 proteins in the sugarcane borer, Diatraea saccharalis (Lepidoptera: Crambidae). AB - Sugarcane borer (Diatraea saccharalis, F.) is an important corn pest in South America and United States. The aim of the present study was to analyze the susceptibility and binding interactions of three Cry1A proteins and Cry1Fa in a Brazilian D. saccharalis population. The results showed that Cry1Ab was the most active, followed by Cry1Ac, Cry1Fa and Cry1Aa. All Cry1-biotinylated proteins tested bound specifically to the D. saccharalis brush border membrane vesicles (BBMV). Heterologous competition assays showed shared binding sites for all Cry1A proteins and another one shared by Cry1Fa and Cry1Ab. Thus, pyramiding Cry1Aa/Cry1Ac and Cry1F proteins would be a recommended strategy for managing this pest. PMID- 25736727 TI - Development and application of an analytical method for curdione quantification in pregnant Sprague-Dawley rats by LC-MS/MS. AB - The vaginal administration route suffers from relatively low absorption efficiency, which may hinder the identification of the toxicokinetics of curdione in pregnant women. A sensitive analytical method for determining the plasma concentration of curdione was developed and applied in the determination of curdione in pregnant Sprague-Dawley rats as a simulated model. Glimepiride was used as an internal standard and chromatographic separation was achieved on a Capcell Pak C18 MGIII column. A gradient elution profile with 0.5% formic acid (A)-0.5% formic acid-acetonitrile (B) was selected as mobile phase. The selected reaction monitoring mode was used for quantification based on the target fragment ions m/z 237.2 to m/z 135.1 for curdione and m/z 491.3 to m/z 352.1 for the glimepiride. The standard curve was linear over the range of 0.5-500 ng/mL for curdione in rat plasma and yielded a consistent peak pattern, even at the lower limit of quantitation of 0.5 ng/mL. The retention times of curdione and IS were 6.55 and 6.59 min, respectively. The mean recovery of curdione in rat plasma was 95.5-101.1%. The intra-day and inter-day precisions were between 2.35 and 9.08%. This LC-MS/MS method provides a simple and sensitive means for determining the plasma concentration. PMID- 25736729 TI - A remarkable enhancement in Am3+/Eu3+ selectivity by an ionic liquid based solvent containing bis-1,2,4-triazinyl pyridine derivatives: DFT validation of experimental results. AB - Mutual separation of trivalent actinide (An(3+)) and lanthanide (Ln(3+)) using several soft (N) donor ligands (bis(5,6-dialkyl-1,2,4-triazinyl)pyridine (R-BTP)) is attempted for the first time in room temperature ionic liquid (RTIL) medium. The results indicate a spectacular enhancement in the selectivity as compared to that in molecular diluents with a separation factor (S.F.) of >3000 for Am(3+) over Eu(3+) using the methyl derivative (Me-BTP) in RTIL medium using [C(n)mim].[NTf2] as the diluents (where n = 2, 3, 4, 6 or 8). Such a high S.F. value has never been reported before with any of the R-BTP derivatives in molecular diluents. An opposite trend in the distribution ratio values of both Am(3+) and Eu(3+) with the increasing size of the alkyl (R) group is observed in RTIL medium when compared with that in molecular diluents. The differences in the extraction behaviour of R-BTPs in RTILs vis-a-vis molecular diluents are explained on the basis of the difference in the nature of complexes extracted in these two distinctly different media as supported by the time resolved fluorescence (TRFS) study. An unusually high extractability and selectivity for Am(3+) over Eu(3+) with Me-BTP was attributed to the formation of a 1 : 4 complex for Am(3+), which was never reported earlier with any of the R-BTP derivatives in molecular diluents. DFT studies indicated higher metal 'd' and 'f' orbital participation (covalence) in the bonding with R-BTP in the case of Am(3+) complexes as compared to that in the case of Eu(3+) complexes, which resulted in the selectivity of these classes of ligands. The observed results may have a great significance in the radioactive waste management involving the partitioning and transmutation strategy. PMID- 25736731 TI - Molecular and physiological mechanisms regulating tissue reunion in incised plant tissues. AB - Interactions among the functionally specialized organs of higher plants ensure that the plant body develops and functions properly in response to changing environmental conditions. When an incision or grafting procedure interrupts the original organ or tissue connection, cell division is induced and tissue reunion occurs to restore physiological connections. Such activities have long been observed in grafting techniques, which are advantageous not only for agriculture and horticulture but also for basic research. To understand how this healing process is controlled and how this process is initiated and regulated at the molecular level, physiological and molecular analyses of tissue reunion have been performed using incised hypocotyls of cucumber (Cucumis sativus) and tomato (Solanum lycopersicum) and incised flowering stems of Arabidopsis thaliana. Our results suggest that leaf gibberellin and microelements from the roots are required for tissue reunion in the cortex of the cucumber and tomato incised hypocotyls. In addition, the wound-inducible hormones ethylene and jasmonic acid contribute to the regulation of the tissue reunion process in the upper and lower parts, respectively, of incised Arabidopsis stems. Ethylene and jasmonic acid modulate the expression of ANAC071 and RAP2.6L, respectively, and auxin signaling via ARF6/8 is essential for the expression of these transcription factors. In this report, we discuss recent findings regarding molecular and physiological mechanisms of the graft union and the tissue reunion process in wounded tissues of plants. PMID- 25736732 TI - Changing Trends in Surgical Management of Prostate Cancer: The End of Overtreatment? AB - The use of prostate-specific antigen (PSA) for screening or early detection of prostate cancer (PCa) results in significant stage migration toward more favorable stages and a proven decrease in PCa mortality but is accompanied by substantial rates of overdiagnosis and overtreatment. Acknowledgement of these downsides and endeavors to avoid them have led to substantial changes in treatment patterns. Many centers have reported dramatic changes, with increases in active surveillance (AS) of early cancers and local treatment of advanced disease. To estimate the impact of this development on our radical prostatectomy (RP) series, we analyzed changes in cancer and patient selection over the past 15 yr. Despite a trend toward decreased utilization of RP in Germany, the annual caseload at our institution increased due to regionalization, from 382 RPs in 2000 to 2145 in 2011, and has been stable for the past 3 yr (2106 RPs in 2014). The rate of RPs performed in patients with low-risk PCa, AS candidates, or men with a pure Gleason 6 pattern in the RP specimen dropped from 60%, 38.2%, and 56.2%, respectively, in 2004 to 27%, 14.7%, and 10%, respectively, in 2011-2013. Patients undergoing RP with solely Gleason 6 cancer were younger on average (aged 61 yr) than patients in higher risk groups (aged 65 yr). The rate of histologically insignificant PCa was low, ranging from 1% to 8.8% depending on the definition used. Patient selection is the other important tool used to avoid overtreatment. Long-term other-cause mortality (OCM) should be low in adequately selected RP candidates, and after a minimum follow-up of 15 yr, overall OCM was 14.8%. The OCM rate was 10.2% in men aged <65 yr and 24.3% in men aged >=65 yr. The current analysis documents a clear shift in utilization of RP toward significant PCa in men with long life expectancy. Based on patient and cancer selection as described, the long-standing discussion of overtreatment with RP might become invalid. PATIENT SUMMARY: Discussion of possible overtreatment has led to dramatic changes in indication for radical prostatectomy (RP). We analyzed a large European patient cohort and found that RP is rarely done in early cancers but is used more for aggressive tumors. Those who underwent RP had long life expectancy and benefit from surgery. With this change in application, overtreatment with RP is unlikely. PMID- 25736733 TI - High-dose-rate brachytherapy as a monotherapy for prostate cancer--Single institution results of the extreme fractionation regimen. AB - PURPOSE: We report a single-institution retrospective analysis of the outcomes, disease control, and toxicity of high-dose-rate (HDR) brachytherapy used as the only treatment modality (monotherapy) for localized prostate cancer. METHODS: Between 2006 and 2012, 77 patients with diagnosed prostate cancer were treated with HDR brachytherapy as a monotherapy. The prescribed dose was 45 Gy in three separate implants 21 days apart, with single fraction per implant. Of the 77 patients, 67 (87%) received hormonal therapy. Prostate-specific antigen failure was defined according to Phoenix consensus, as nadir + 2 ng/mL. Toxicity was scored according to Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: The median followup time was 57 months (4.75 years). The 5-year actuarial overall survival was 98.7%, biochemical control 96.7%, local control 96.9%, and metastasis-free survival 98.4%. Younger age at the beginning of brachytherapy predicted the onset of bounce phenomenon. There were no Grade 3 or higher acute toxicities detected, and Grade 2 genitourinary acute toxicity developed in 19 patients (24.6%). There were no Grade 2 gastrointestinal complications. No Grade 4 or 5 late toxicity was detected. There were also no Grade 3 gastrointestinal toxicities detected. One patient (1.3%) underwent transurethral resection of the prostate because of Grade 3 urethral stenosis and urinary retention. A total of 26 patients (33.8%) developed Grade 2 late toxicity. CONCLUSIONS: HDR brachytherapy as monotherapy for localized prostate cancer was feasible, effective, and had acceptable toxicity profile. PMID- 25736734 TI - Urinary stones as a novel matrix for human biomonitoring of toxic and essential elements. AB - Monitoring of body burden of toxic elements is usually based on analysis of concentration of particular elements in blood, urine and/or hair. Analysis of these matrices, however, predominantly reflects short- or medium-term exposure to trace elements or pollutants. In this work, urinary stones were investigated as a matrix for monitoring long-term exposure to toxic and essential elements. A total of 431 samples of urinary calculi were subjected to mineralogical and elemental analysis by infrared spectroscopy and inductively coupled plasma mass spectrometry. The effect of mineralogical composition of the stones and other parameters such as sex, age and geographical location on contents of trace and minor elements is presented. Our results demonstrate the applicability of such approach and confirm that the analysis of urinary calculi can be helpful in providing complementary information on human exposure to trace metals and their excretion. Analysis of whewellite stones (calcium oxalate monohydrate) with content of phosphorus <0.6 % has been proved to be a promising tool for biomonitoring of trace and minor elements. PMID- 25736738 TI - A longitudinal study of constipation and laxative use in a community-dwelling elderly population. AB - BACKGROUND: Little is known about laxative use, the association of constipation with laxative use, risk factors for constipation and how each of these changes over time in the community-dwelling elderly. OBJECTIVE: The aim was to explore the prevalence of laxative use and of self-reported constipation, and identify risk factors (including age) associated with constipation, in a cohort of community-dwelling elderly residents. METHODS: Data from the Australian Longitudinal Study of Ageing (ALSA) was used to compare differences in constipation and laxative use in the community-dwelling elderly between 1992-1993 and 2003-2004. RESULTS: Relevant data was available for 239 ALSA participants. The prevalence of self-reported constipation increased from 14% in 1992-1993 to 21% in 2003-2004. There was a corresponding increase in the prevalence of laxative use from 6% to 15% over the same period. At both time points, females reported a higher prevalence of both constipation and laxative use however the female:male prevalence ratios decreased over time indicating higher increases in the prevalence of each among males. Persistent chronic constipation occurred in 9% of the cohort. The association between laxative use and self-reported constipation was poor and laxative use was associated with self-reported constipation in less than a third of cases. CONCLUSION: The prevalence of both constipation and laxative use increases with age in the elderly, and these increases are greater for males than for females. Discrepancies between self reported constipation and laxative use may suggest sub-optimal management of constipation in the community-dwelling elderly and further work is needed to fully understand this. PMID- 25736739 TI - Influence of surface stresses on indentation response. AB - Surface stresses lead to an effective change in the elastic constants of thin films and at surfaces. The development of modern scanning probe techniques like contact resonance atomic force microscopy empowers the experimenter to measure at scales where these effects become increasingly relevant. In this paper we employ a computational multiscale approach where we compare density functional theory (DFT) and molecular dynamics simulations as tools to calculate the thin film/surface elastic behavior for silicon and strontiumtitanate. From the surface elastic constants gained by DFT calculations we develop a continuum finite element multilayer model to study the impact of surface stresses on indentation experiments. In general the stress field of an indenter and thus the impact of surface stresses on the indentation modulus depends on its contact radius and on its particular shape. We propose an analytical model that describes the behavior of the indentation modulus as a function of the contact radius. We show that this model fits well to simulation results gained for a spherical and a flat punch indenter. Our results demonstrate a surface-stress-induced reduction of the indentation modulus of about 5% for strontiumtitanate and 6% for silicon for a contact radius of [Formula: see text], irrespective of the indenter shape. PMID- 25736740 TI - Electrophoretic mobility shift assay analysis of NF-kappaB DNA binding. AB - The discovery and characterization of the nuclear factor-kappa B (NF-kappaB) family of transcription factors was predicated on the technical ability to detect protein binding to defined sequences of DNA. Proteins capable of binding to specific sequences of nucleic acid are detected through the use of the electrophoretic mobility shift assay (EMSA), also called a gel shift assay. While newer techniques, including chromatin immunoprecipitation (ChIP), are widely used to assess NF-kappaB binding to the promoters and enhancers of specific genes, the EMSA remains a powerful experimental tool to quickly test for the presence of NF kappaB that is capable of binding DNA. In this way, the EMSA is a useful general readout of the activation state of the NF-kappaB pathway and an essential tool for the investigation of this important transcription factor family. PMID- 25736741 TI - Detection of IkappaB degradation dynamics and IkappaB-alpha ubiquitination. AB - The NF-kappaB signaling pathway is a primary regulator of inflammation that has been implicated in the pathogenesis of immune disorders and cancer. This signaling network is strictly regulated; in a nonactivated state, NF-kappaB transcription factors are sequestered in the cytoplasm by the IkappaB family of proteins. Various pro-inflammatory stimuli result in the phosphorylation and subsequent ubiquitination of IkappaBs. These events lead to rapid degradation of IkappaB and allow translocation of the transcription factors to the nucleus. Therefore, ubiquitination and degradation of IkappaBs are critical steps in NF kappaB pathway activation and can serve as a quantitative parameter to assess pathway activation. In this article, we present a detailed protocol for the quantification of in vivo ubiquitination and turnover of IkappaB-alpha in response to a variety of cellular stimuli. PMID- 25736742 TI - Measurement of NF-kappaB transcriptional activity and identification of NF-kappaB cis-regulatory elements using luciferase assays. AB - The NF-kappaB family of transcription factors is activated in response to numerous environmental stimuli and coordinates the transcriptional response to immunoreceptors such as the Toll-like receptors, cytokine receptors, and antigen receptors, growth factors, survival factors, and stress signals such as ultraviolet irradiation and oxidative stress. The transcriptional targets of these various pathways include approximately 500 experimentally indentified genes, and it is highly likely that many others remain to be discovered. A genome wide analysis of NF-kappaB-chromatin interactions has revealed a surprisingly large number of NF-kappaB binding sites across the entire genome, many of which are found in intergenic regions and many more do not appear to be associated with changes in transcription of nearby genes. Assessing the consequences of NF-kappaB binding at genomic sites is therefore essential to determine the functional role of NF-kappaB in regulating the expression of specific genes. Luciferase-based reporter assays provide a robust and flexible method to test the contribution of specific NF-kappaB sites to the regulation of gene transcription. The methods described in this chapter may be applied to any promoter sequence and used in a variety of cell lines and conditions to provide critical information on the regulation of gene expression by NF-kappaB. PMID- 25736743 TI - Assessing sites of NF-kappaB DNA binding using chromatin immunoprecipitation. AB - The NF-kappaB transcription factor is in fact a family of related proteins which dimerize to form at least 12 distinct complexes which regulate the expression of hundred of genes of importance to a range of physiological and pathological processes. The binding of NF-kappaB to the regulatory regions and promoters of target genes is influenced by a number of factors including the sequence of DNA binding sites, the posttranslational modification of NF-kappaB, and the interaction of cofactors and co-regulators of transcription. In addition, the binding of NF-kappaB to promoters is highly dynamic and the recruitment of specific subunits to specific binding sites may occur with distinct kinetics. Moreover, genome-wide analysis of NF-kappaB chromatin binding indicates that the majority of DNA-binding events are not associated with changes in transcriptional activity. Thus, the analysis of NF-kappaB recruitment and activity at specific binding sites is of critical importance in understanding the regulation of transcription. In this chapter we describe a chromatin immunoprecipitation assay to investigate the in situ binding of NF-kappaB to specific sites in the genome. PMID- 25736744 TI - IKK kinase assay for assessment of canonical NF-kappaB activation in neurons. AB - Nuclear factor kappa B (NF-kappaB) is a potent transcription factor highly expressed in the central nervous system (CNS) where it has been shown to be required for multiple behavioral paradigms of learning and memory in both mammalian and invertebrate systems. NF-kappaB dimers are found in neuronal cell bodies, are also present at synapses, and can participate in the activity dependent regulation of gene expression in response to excitatory neurotransmission. Multiple serine-directed phosphorylation events are critical in the canonical NF-kappaB activation pathway, including activation of the IkappaB kinase complex (IKK) and phosphorylation and degradation of the inhibitor of NF-kappaB (IkappaB). In this chapter, we describe methods for immunoprecipitation (IP) of the IKK complex from dissociated cultured murine hippocampal neurons, followed by in vitro kinase assay to evaluate excitatory neurotransmission-induced IKK activation by monitoring phosphorylation of a GST IkappaBalpha substrate. These methods can also be successfully implemented in subcellular-reduced brain preparations, such as biochemically isolated synapses. PMID- 25736745 TI - Analysis of epidermal growth factor-induced NF-kappaB signaling. AB - The nuclear factor kappaB (NF-kappaB) is a family of transcription factors that control cell survival, cell proliferation, cell differentiation, inflammatory responses, and innate and adaptive immune responses. Its activation is tightly regulated, and incorrect regulation of NF-kappaB has been linked to a variety of pathological diseases, including cancer initiation and progression. NF-kappaB is often constitutively activated in cancer cells to promote cell survival, proliferation, migration, and/or epithelial-to-mesenchymal transition (EMT). Although the mechanism of constitutive NF-kappaB activation in cancer cells is not fully understood, it has been shown that mutation or aberrant expression of epidermal growth factor receptor (EGFR) contributes to this, and the NF-kappaB activation, in turn, contributes to cell proliferation, survival, metastasis, and drug resistance in various cancers. Recent study from our lab indicates that CARMA3, similar to the function of CARMA1 in mediating antigen receptor-mediated NF-kappaB activation, plays an essential role in mediating EGFR-induced NF-kappaB activation. However, the mechanism on how EGFR induces NF-kappaB activation is not clearly understood. In this chapter, we describe the methods required to test and characterize the role of a potential signaling component in EGFR-induced NF kappaB activation. PMID- 25736746 TI - Methods to assess the activation of the alternative (noncanonical) NF-kappaB pathway by non-death TNF receptors. AB - The alternative or noncanonical NF-kappaB pathway regulates the generation of p52 containing NF-kappaB dimers (e.g., p52/RelB) through a partial degradation (called processing) of the precursor p100 into p52. This pathway is activated by a subset of non-death TNF receptor members, which ultimately activate two kinases: NIK (NF-kappaB-Inducing Kinase) and IKKalpha (Inhibitor of kappaB Kinase alpha). These kinases create a phosphodegron for the E3 ligase SCF-beta-TrCP that covalently binds K48-linked polyubiquitin chain onto p100 prior to its proteasomal processing. The resulting p52-containing complexes translocate into the nucleus to activate target genes involved in secondary lymphoid organ development, B cell survival or in osteoclastogenesis. We describe in this chapter straightforward methods to monitor the activation of the alternative NF kappaB pathway. These methods uncover cytosolic and nuclear biochemical modifications of key proteins of the alternative NF-kappaB pathway required prior to the transcription of NF-kappaB target genes. PMID- 25736747 TI - Systematic detection of noncanonical NF-kappaB activation. AB - In unstimulated cells, NF-kappaB dimers usually exist as latent complexes in the cytoplasm with the IkappaB (inhibitor of NF-kappaB) proteins or IkappaB-like protein p100, the precursor of NF-kappaB2 mature form p52. Accordingly, there are two major mechanisms leading to NF-kappaB activation: inducible degradation of IkappaBs and processing of p100 to generate p52 (selective degradation of the C terminal IkappaB-like sequence of p100), which are termed the canonical and noncanonical NF-kappaB pathways, respectively. While activation of the canonical NF-kappaB pathway plays critical roles in a wide range of biological processes, the noncanonical NF-kappaB pathway has important but more restricted roles in both normal and pathological processes. Systematic detection of the noncanonical NF-kappaB pathway activation is very important for understanding the physiological role of this pathway in biological processes, and for the diagnosis, prevention, and treatment of related diseases. We describe here the methods we employ to detect noncanonical NF-kappaB activation in cells and tissues. These methods are immunoblotting, co-immunoprecipitation, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation (ChIP) analysis, and electrophoretic mobility shift assay (EMSA). Noncanonical NF-kappaB induced gene expression changes can be determined by gene array analysis and quantitative real-time PCR. PMID- 25736748 TI - Noncanonical NF-kappaB activation and SDF-1 expression in human endothelial cells. AB - NF-kappaB is a family of transcription factors regulated through two distinct signaling cascades, the classical and the Noncanonical NF-kappaB pathways. Noncanonical NF-kappaB plays important roles in the immune system, as it is necessary for lymphoid organogenesis and B-cell survival and differentiation, as well as osteoclastogenesis. In the last few years, there has been an increased number of studies focusing on both identifying the upstream events that regulate the noncanonical NF-kappaB pathway as well as determining the physiological roles of noncanonical NF-kappaB in normal and disease pathologies, such as cancer and autoimmune diseases. Dysregulation of noncanonical NF-kappaB has now been associated with the pathogenesis of several types of lymphomas and autoimmune diseases and is believed to contribute to chronic inflammatory diseases, including ulcerative colitis. These studies suggest that targeting the Noncanonical pathway, similar to classical NF-kappaB, may have some therapeutic potential in the future; however, there is still quite a bit about the regulation of the noncanonical signaling that remains to be defined. In this chapter we describe the use of HUVEC, as an in vitro model for examining noncanonical NF kappaB signaling in response to different stimuli. We demonstrate two different methods to measure noncanonical NF-kappaB activation: the processing of p100 to p52, and noncanonical NF-kappaB-dependent gene expression of CXCL12. The first method examines a key regulatory requirement for noncanonical NF-kappaB activation, by which p100 undergoes proteolytic cleavage to relieve the inhibition of NF-kappaB dimers for nuclear translocation and activation of gene transcription. The latter demonstrates the downstream effects of activated noncanonical NF-kappaB in response to stimuli. PMID- 25736749 TI - Stable reconstitution of IKK-deficient mouse embryonic fibroblasts. AB - Retroviral transduction is an invaluable technique in molecular biology used to express proteins encoded by nonviral genes in mammalian cells. A key feature of this technique is the ability to create cell lines that stably express the protein of interest and can be cultured long term. Here we describe a retroviral transduction procedure for mouse embryonic fibroblasts (MEFs) that uses Platinum E cells to rapidly package high-titer, helper-free retrovirus. This technique is useful to study the role of key signaling kinases in the NF-kappaB signal transduction pathway. PMID- 25736750 TI - Dissecting NF-kappaB signaling induced by genotoxic agents via genetic complementation of NEMO-deficient 1.3E2 cells. AB - The transcription factor NF-kappaB regulates expression of a diverse set of genes to modulate multiple biological and pathological processes. Among these, NF kappaB activation in response to genotoxic agents has received considerable attention due to its role in regulating cancer cell resistance to chemo- and radiation therapy. Furthermore, induction of this pathway by endogenous damage is further implicated in normal developmental processes, such as B cell development, and premature aging, among others. This pathway also serves as a signaling model in which nuclear initiated signals (DNA damage) are communicated to a cytoplasmic target (IkappaB kinase and NF-kappaB). Several of the critical molecular events of this nuclear to cytoplasmic NF-kappaB signaling cascade were discovered, in part, by genetic complementation analyses of the NEMO-deficient 1.3E2 mouse pre-B cell line. This chapter describes methods used to generate and analyze such reconstitution cell systems and certain caveats that are critical for proper interpretation of NEMO mutant defects. PMID- 25736751 TI - Visualizing TCR-induced POLKADOTS formation and NF-kappaB activation in the D10 T cell clone and mouse primary effector T cells. AB - T cells are an immune cell lineage that play a central role in protection against pathogen infection. Antigen, in the form of pathogen-derived peptides, stimulates the T-cell receptor (TCR), leading to activation of the transcription factor, nuclear factor kappa B (NF-kappaB). The subsequent NF-kappaB-dependent gene expression program drives expansion and effector differentiation of antigen specific T cells, leading to the adaptive anti-pathogen immune response. The cell surface TCR transmits activating signals to cytosolic NF-kappaB by a complex signaling cascade, in which the adapter protein Bcl10 plays a key role. We have previously demonstrated that TCR engagement leads to the formation of cytosolic Bcl10 clusters, called POLKADOTS, that provide a platform for the assembly of the terminal signaling complex that ultimately mediates NF-kappaB activation. In this chapter, we describe the methods utilized to visualize the formation of TCR induced POLKADOTS and to study the temporal association between POLKADOTS formation and nuclear translocation of the NF-kappaB subunit, RelA/p65. PMID- 25736752 TI - Detection of recombinant and cellular MALT1 paracaspase activity. AB - MALT1 (mucosa-associated lymphoid tissue protein 1) is a key regulator of antigen induced NF-kappaB activation in the adaptive immune response. Activation of proteolytic activity of the MALT1 paracaspase was shown to boost the immune response. Additionally, MALT1 proteolytic activity is essential for the survival of MALT1-dependent lymphoma, such as the activated B-cell type (ABC) of diffuse large B-cell lymphoma (DLBCL) or MALT lymphoma. The functional impact of MALT1 paracaspase on T-cell activation and lymphomagenesis suggests that MALT1 is a promising therapeutic target for the treatment of autoimmune diseases and distinct lymphoma entities. To evaluate the requirement of MALT1 in further detail, direct measurement of its activity status is of great importance. We have established a fluorogenic cleavage assay which can be used to measure activity of recombinant and cellular MALT1. Here we describe the basis of the cleavage assay and include a detailed protocol for recombinant production of MALT1 and also the cellular immunoprecipitation of endogenous MALT1 to determine its proteolytic activity. PMID- 25736753 TI - TRAF protein function in noncanonical NF-kappaB signaling. AB - Nuclear factor-kappaB (NF-kappaB) signaling is classified into the canonical and noncanonical pathways. We describe in this chapter the methods used to study the noncanonical pathway, including derivation of primary cells, pathway stimulation, and immunoblotting. PMID- 25736754 TI - Roles of c-IAP proteins in TNF receptor family activation of NF-kappaB signaling. AB - Precise regulation of survival and signaling pathways is essential for proper maintenance of organismal homeostasis, development, and immune defense. Inhibitor of apoptosis (IAP) proteins are evolutionarily conserved regulators of cell death and immune signaling that impact numerous cellular processes. Initially characterized as inhibitors of apoptosis, the ubiquitin ligase activity of IAP proteins is critical for modulating various signaling pathways (e.g., NF-kappaB, MAPK) and cellular fate. Cellular IAP1 and IAP2 regulate the pro-survival canonical NF-kappaB pathway by ubiquitinating RIP1 and enabling recruitment of kinase (IKK) and E3 ligase (LUBAC) complexes. On the other hand, c-IAP1 and c IAP2 are negative regulators of noncanonical NF-kappaB signaling by promoting ubiquitination and consequent degradation of the NF-kappaB-inducing kinase NIK. In this article, we describe the involvement of c-IAP1 and c-IAP2 in NF-kappaB signaling and provide detailed methodology for examining how c-IAPs exert their functional roles. PMID- 25736755 TI - Elucidating dynamic protein-protein interactions and ubiquitination in NF-kappaB signaling pathways. AB - The Nuclear factor-kappaB (NF-kappaB) family of transcription factors plays critical roles in inflammatory responses and host defense; however, uncontrolled NF-kappaB activation can be deleterious by promoting autoimmune diseases and cancers. Lysine K63 (K63)-linked polyubiquitination has emerged as an important regulatory mechanism in NF-kappaB signaling by regulating dynamic protein-protein interactions that trigger NF-kappaB signaling. RIP1 and TRAF6 serve as key substrates of K63-linked polyubiquitin chains in tumor necrosis factor receptor (TNFR) and interleukin-1 receptor (IL-1R) pathways respectively as a mechanism to recruit TAK1 and IKK kinases by associated ubiquitin-binding adaptor molecules. Activation of IKKbeta by TAK1 induces IkappaBalpha phosphorylation, degradation, and downstream NF-kappaB activation. The ubiquitin-editing enzyme A20 maintains transient NF-kappaB activation by opposing the K63-linked polyubiquitination of RIP1 and TRAF6. A20 inducibly interacts with the adaptor molecule TAX1BP1 and the E3 ligases Itch and RNF11 to form an A20 ubiquitin-editing enzyme complex. Notably, loss-of-function somatic mutations or polymorphisms in human A20 are associated with B-cell lymphomas or a variety of autoimmune diseases as a result of dysregulated NF-kappaB activation. In this chapter, we summarize the protocols routinely used in our laboratories to examine ubiquitination and NF-kappaB signaling. PMID- 25736756 TI - Immunoblot analysis of linear polyubiquitination of NEMO. AB - Stimulation with inflammatory cytokines such as TNF-alpha and IL-1 activates the canonical NF-kappaB pathway through the activation of the IKK complex. The mechanism underlying IKK activation has been extensively studied and the involvement of the ubiquitin system has been well documented. We have recently reported that a novel ubiquitin ligase complex, LUBAC is involved in the activation of the IKK complex. LUBAC consists of one catalytic subunit, HOIP and two accessory molecules, HOIL-1L and SHARPIN and activates the IKK complex by conjugating the linear polyubiquitin chains to NEMO (IKKgamma), the regulatory subunit of IKK complex. In this chapter, we describe the protocol for the detection of the linear polyubiquitination of NEMO by the immunoblotting using anti-linear ubiquitin antibody. PMID- 25736757 TI - In vitro detection of NEMO-ubiquitin binding using DELFIA and microscale thermophoresis assays. AB - Canonical NF-kappaB signaling in response to various stimuli converges at the level of the IkappaB kinase (IKK) complex to ultimately activate NF-kappaB. To achieve this, the IKK complex uses one of its regulatory subunit (IKKgamma/NEMO) to sense ubiquitin chains formed by upstream complexes. Various studies have shown that different Ubiquitin chains are involved in the binding of NEMO and thereby the activation of NF-kappaB. We have utilized two distinct biochemical methods, i.e., Dissociation-Enhanced Lanthanide Fluorescence Immunoassay (DELFIA) and Microscale Thermophoresis (MST), to detect the interaction of NEMO to linear and K63-linked Ubiquitin chains, respectively. Here, we describe the brief basis of the methods and a detailed underlying protocol. PMID- 25736758 TI - Use of fluorescence spectroscopy for quantitative investigations of ubiquitin interactions with the ubiquitin-binding domains of NEMO. AB - Ubiquitin serves as a signal for a variety of cellular processes and its specific interaction with ubiquitin-binding domain (UBD) regulates key cellular events including protein degradation, cell-cycle control, DNA repair, and kinase activation. Several binding mechanisms for isolated UBDs have been reported in recent years. However, little is known about the mechanism through which proteins containing multiple-UBDs achieve specificity for a particular oligomer of polyUb. The NF-kappaB essential modulator (NEMO, also known IKKgamma), which plays a key role in the NF-kappaB signaling pathway, belongs to the latter family of proteins since it contains two distal NOA (also known UBAN/CC2-LZ/NUB) and ZF UBDs, separated by an unstructured proline-rich linker of about 40 residues in length. Here, we show a new procedure for fast purification of this bipartite domain. We also describe the use of intrinsic fluorescence spectroscopy for quantitative investigations of ubiquitin interactions between two distal ubiquitin-binding domains of NEMO (NOA and ZF). This spectroscopic method has many advantages over other techniques like GST pulldown and Biacore's SPR for monitoring avid interactions between two UBDs, especially when UBDs are located at significant distance from each other within the protein. PMID- 25736759 TI - Generation of a proteolytic signal: E3/E2-mediated polyubiquitination of IkappaBalpha. AB - A key regulatory node in NF-kappaB signaling is the removal of the IkappaBalpha inhibitor, whose levels are tightly controlled by the ubiquitin-proteasome system. In response to signal activation and transmission, ubiquitin E1, E2, and E3 enzymes are employed to generate a lysine 48-linked ubiquitin chain that triggers degradation of IkappaBalpha by the proteasome. In this chapter we describe an in vitro biochemical approach to reconstitute the ubiquitination system. To do so, we detail methods for the preparation of the relevant enzymes and substrate, as well as for the execution of the reaction with high efficiency. This sensitive and highly reproducible readout can be applied to the study of proteins, small molecules, and other factors that modulate IkappaBalpha ubiquitination, thereby producing outcomes that impact NF-kappaB signaling to advance the course of improving human health. PMID- 25736760 TI - Control of NF-kappaB subunits by ubiquitination. AB - NF-kappaB is an essential regulator of inflammation and is also required for normal immune development and homeostasis. The inducible activation of NF-kappaB by a wide range of immuno-receptors such as the toll-like receptors (TLR), Tumour Necrosis Factor receptor (TNFR), and antigen T cell and B cell receptors requires the ubiquitin-triggered proteasomal degradation of IkappaBalpha to promote the nuclear translocation and transcriptional activity of NF-kappaB dimers. More recently, an additional role for ubiquitination and proteasomal degradation in the control of NF-kappaB activity has been uncovered. In this case, it is the ubiquitination and proteasomal degradation of the NF-kappaB subunits that play a critical role in the termination of the NF-kappaB-dependent transcriptional response induced by receptor activation. The primary trigger of NF-kappaB ubiquitination is DNA binding by NF-kappaB dimers and is further controlled by specific phosphorylation events which regulate the interaction of NF-kappaB with the E3 ligase complex and the deubiquitinase enzyme USP7. It is the balance between ubiquitination and deubiquitination that shapes the NF-kappaB-mediated transcriptional response. This chapter describes methods for the analysis of NF kappaB ubiquitination. PMID- 25736761 TI - Methodology to study NF-kappaB/RelA ubiquitination in vivo. AB - Nuclear factor-kappa B (NF-kappaB) is a family of transcription factors that regulate immune responses, cell proliferation, differentiation, and survival. Activity of the NF-kappaBeta pathway on a cellular level is tightly controlled through various mechanisms, one of which is the ubiquitin-dependent degradation of chromatin-bound NF-kappaB subunits. In general, the ubiquitination of NF kappaB regulates the duration of gene transcription activated in response to inflammatory signals. In this article, we present protocols to examine the in vivo ubiquitination status of RelA, a critical protein of the NF-kappaB family. PMID- 25736762 TI - Using sequential immunoprecipitation and mass spectrometry to identify methylation of NF-kappaB. AB - Posttranslational modifications have long been known to play an essential role in the regulation of NF-kappaB activity. In the past few years, in addition to more traditional modifications such as phosphorylation, the p65 subunit of NF-kappaB has been found to be methylated at multiple sites. Here, we describe procedures for using immunoprecipitation and mass spectrometry to identify the methylation sites of p65. PMID- 25736763 TI - Methods to detect NF-kappaB acetylation and methylation. AB - Posttranslational modifications of NF-kappaB, including acetylation and methylation, have emerged as an important regulatory mechanism for determining the duration and strength of NF-kappaB nuclear activity as well as its transcriptional output. Within the seven NF-kappaB family proteins, the RelA subunit of NF-kappaB is the most studied for its regulation by lysine acetylation and methylation. Acetylation or methylation at different lysine residues modulates distinct functions of NF-kappaB, including DNA-binding and transcription activity, protein stability, and its interaction with NF-kappaB modulators. Here, we describe the experimental methods to monitor the in vitro and in vivo acetylated or methylated forms of NF-kappaB. These methods include radiolabeling the acetyl or methyl groups and immunoblotting with pan- or site specific acetyl- or methyl-lysine antibodies. Radiolabeling is useful in the initial validation of the modifications. Immunoblotting with antibodies provides a rapid and powerful approach to detect and analyze the functions of these modifications in vitro and in vivo. PMID- 25736764 TI - A method for the quantitative analysis of stimulation-induced nuclear translocation of the p65 subunit of NF-kappaB from patient-derived dermal fibroblasts. AB - Developmental and immune-mediated disease has been linked to genetic mutation of key signaling components involved in NF-kappaB activation that leads to impaired activation or regulation of the canonical IKK complex. We identify patients with suspected or known defects of the NF-kappaB signaling pathway through clinical phenotyping and genetic sequencing. To help understand how mutations cause disease, we quantitate the kinetics and dose-response of NF-kappaB activation signaling events in their cells. Following activation of the canonical IKK complex, phosphorylation of the inhibitor of NF-kappaB proteins (IkappaB) leads to their degradation and the subsequent translocation of NF-kappaB family members from the cell cytoplasm to the nucleus. Here, we provide a method to obtain patient-derived dermal fibroblasts and quantitatively assess the integrity of the signal transduction pathway from receptor activation to nuclear p65 translocation. PMID- 25736765 TI - Methods for assessing the in vitro transforming activity of NF-kappaB transcription factor c-Rel and related proteins. AB - Among NF-kappaB transcription factors, c-Rel and c-Rel-derived proteins, including v-Rel, are the only ones that have shown consistent and frank transforming activity in cell culture. In particular, viral, chicken, mouse, and human Rel proteins can rapidly transform primary chicken spleen and bone marrow cells. Overexpression of a human Rel protein missing a C-terminal transactivation domain can also enhance the transformed state of the human B-lymphoma cell line BJAB. As described in this chapter, these in vitro assays can be used to quantitatively assess the transforming activity of Rel proteins. PMID- 25736766 TI - Using RNA interference in lung cancer cells to target the IKK-NF-kappaB pathway. AB - RNA interference-based gene silencing has become a widely used technology to evaluate how inhibition of expression of individual proteins affects biological readout. Through the use of this technology, a lot has been learned about how different proteins function in a wide variety of biological contexts, including cancer. In this context, RNA interference-mediated gene silencing has contributed to further our understanding of how different proteins in the NF-kappaB signaling pathway (including the NF-kappaB members themselves) contribute to cancer. Here, we describe two RNA interference-based protocols in lung cancer cells targeting upstream activators of NF-kappaB transcription factor: the catalytic subunits of the IKK complex. The first protocol is designed to evaluate the impact of IKKalpha or IKKbeta inhibition on NF-kappaB transcriptional activity, whereas the second protocol is designed to evaluate how siRNA-mediated IKK inhibition affects lung cancer cell proliferation. PMID- 25736767 TI - Immunohistochemical analysis of NF-kappaB in human tumor tissue. AB - Immunohistochemistry is a valuable molecular technique based upon the principle of antibody specificity for target antigens in tissues with subsequent development of an amplified colorimetric signal. When staining specificity is ensured with the use of an isotype control, it allows for semiquantitative comparisons, tissue/cellular localization, and inference regarding activation status of proteins of interest. Here we describe a protocol for immunohistochemical analysis of NF-kappaB family members in fresh frozen human tumor samples. PMID- 25736768 TI - Assessment of canonical NF-kappaB activity in canine diffuse large B-cell lymphoma. AB - Companion dogs with spontaneous malignancies are clinically relevant models in which to study the corresponding human diseases and potential therapies. In both dogs and people, non-Hodgkin's lymphoma (NHL) is the most common hematopoietic malignancy. Diffuse large B-cell lymphoma (DLBCL) is the most common NHL subtype in dogs and people, sharing similar biologic, behavioral, genetic, and molecular characteristics in both species. One such molecular characteristic is the constitutive activation of the canonical NF-kappaB pathway, which in health regulates the expression of target genes that control cellular proliferation, survival, and immune and inflammatory responses as well as multidrug resistance. We found that canine and human DLBCL patients share similar NF-kappaB activity profiles. Using the cell-permeable NBD peptide, which blocks NF-kappaB signaling, we inhibited constitutive NF-kappaB activity and induced apoptosis of primary canine malignant B cells in vitro. In addition, we found that NBD peptide administration to dogs with relapsed B-cell lymphoma inhibited the expression of NF-kappaB target genes and reduced tumor burden. In this chapter, we describe our methods for processing canine malignant lymphoid tissue. We also describe our methods for treating the lymphocytes isolated from this tissue with NBD peptide and evaluating constitutive canonical NF-kappaB activity in these cells via immunoblot and electrophoretic mobility shift assay (EMSA). We highlight the nuances of working with canine primary cells. PMID- 25736769 TI - NEMO-binding domain peptide inhibition of inflammatory signal-induced NF-kappaB activation in vivo. AB - NF-kappaB comprises a family of transcription factors that regulate the expression of diverse gene families essential for inflammatory and immune responses as well as cell survival and cell death pathways. Aberrant NF-kappaB transcriptional activity plays pivotal roles in a large number of human pathologies, including a variety of cancers and chronic inflammatory diseases. Therefore, there has been a large increase in studies aimed at identifying and testing drugs or small molecule inhibitors that would specifically block NF kappaB activation in inflammatory diseases and cancer. In this chapter, we describe an in vivo system to test the inhibitory effects of the NEMO-binding domain (NBD) peptide on NF-kappaB activation specifically in the vascular endothelium and lymphocytes in mice. We demonstrate that pretreatment of mice with the NBD peptide reduces the NF-kappaB induced gene expression of cell adhesion molecules and DNA-binding activity following systemic LPS stimulation. These methods can be further used to test alternate inhibitors for effects on NF kappaB signaling in murine endothelium and immune cells. PMID- 25736770 TI - Regulation of NF-kappaB signaling in osteoclasts and myeloid progenitors. AB - The transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is crucial for immune responses and skeletal development. Work in recent years has shown that various members of the NF-kappaB family are viable targets to regulate activity and survival of bone cells and hence bone metabolism. In this regard, deletion of upstream kinases or distal NF-kappaB subunits resulted with bone deformities. Thus, it has become increasingly apparent that detailed investigation of NF-kappaB in bone cells may provide opportunities to design new therapeutic modalities. In this chapter we present modified methodology describing efficient approaches to regulate the NF-kappaB pathway in vitro and in vivo to assess its function in bone cells and tissues. PMID- 25736771 TI - NF-kappaB activation with aging: characterization and therapeutic inhibition. AB - Aging is a condition characterized by progressive decline in tissue homeostasis due, at least in part, to the accumulation of replicative, oxidative, and genotoxic stress over time. The activity of the transcription factor NF-kappaB is upregulated in both naturally aged mice and multiple progeroid mouse models of accelerated aging. Suppressing NF-kappaB activity genetically or pharmacologically has been shown to delay the onset and progression of aging pathology and therefore prolong the healthspan in progeroid mouse models. Here, we describe the methods for measuring aging endpoints along with NF-kappaBeta activation in mice, as well as after pharmacologic intervention to prevent NF kappaB activation using a NEMO-binding domain (NBD)-protein transduction domain (PTD) fusion peptide. PMID- 25736772 TI - The "sneaking-ligand" approach: cell-type specific inhibition of the classical NF kappaB pathway. AB - The intracellular delivery of molecules across the plasma membrane represents a major obstacle. The conjugation of cell-permeable peptides (CPPs) to proteins promotes the uptake and internalization. However, uptake of CPPs is receptor independent and not cell-type specific. Recently, we established the "sneaking ligand" approach which is based on multimodular recombinant fusion proteins that consist of three modules connected with serine-glycine linkers. Module one is responsible for receptor-mediated endocytosis; module two supports translocation into the cytoplasm so that the effector module three can interact with its binding partner in the cytoplasm. For NF-kappaB inhibition, we described an NF kappaB inhibitor that targets selectively the activated endothelium via an oligopeptide motif. Upon E-selectin-mediated endocytosis, the Pseudomonas exotoxin A domain II (ETAII) translocates the NEMO-binding peptide to the cytoplasm interfering with IkappaB kinase complex assembly. Inflammatory autoimmune diseases are triggered, but also resolved by a variety of cell types. Therefore, the inhibition of NF-kappaB should be restricted to those cells that are crucially involved in the pathogenesis of inflammatory diseases. A general blockade of NF-kappaB may result in severe immunosuppression and possibly in organ dysfunction or damage. The "sneaking-ligand" approach could minimize the risks of therapeutic interventions and identify disease-relevant cell types. Here we describe the recombinant expression and purification of the E-selectin specific "sneaking-ligand construct" (SLC1) and its ability to inhibit cytokine induced NF-kappaB activation in vitro. PMID- 25736773 TI - Sneaking-ligand fusion proteins attenuate serum transfer arthritis by endothelium targeted NF-kappaB inhibition. AB - The nuclear transcription factor kappaB (NF-kappaB) is a crucial mediator of the inflammatory and immune response. The contribution of dysregulated NF-kappaB is established in the pathogenesis of arthritis. Accordingly, NF-kappaB represents an attractive molecular target for the development of therapeutic interventions in inflammatory diseases. However, ubiquitous pharmacologic suppression of NF kappaB activity is limited by the hazards of toxic side effects and profound immunosuppression. Cell type-specific NF-kappaB inhibition with the "sneaking ligand" approach could identify disease-relevant cell types and improve risk benefit ratios of therapeutic interventions. Vascular endothelial cells act as a gatekeeper and are crucial for leukocyte recruitment into sites of inflammation. The endothelium-specific NF-kappaB inhibitor SLC1 ameliorates serum transfer arthritis in mice and protects against inflammation and cartilage destruction. In this chapter, we describe the SLC1 treatment schedule in the K/BxN serum transfer arthritis and present the evaluation system to analyze arthritis severity and histopathological alterations. PMID- 25736774 TI - Analysis of NF-kappaB activation in mouse intestinal epithelial cells. AB - Nuclear factor kappa B (NF-kappaB) is a key transcription factor controlling inflammation, innate immunity, and tissue integrity. NF-kappaB is activated by IkappaB kinase (IKK) in response to pro-inflammatory stimuli but is also found to be chronically activated in many inflammatory diseases accompanied by tissue destruction. To study the effects of chronic NF-kappaB activation in intestinal epithelium, we generated IKKbeta(EE)(IEC) transgenic mice which express constitutively active form of IKKbeta in their intestinal epithelial cells (IEC). In this chapter, we describe three different methods that we applied for analysis of NF-kappaB activation in IEC of IKKbeta(EE)(IEC) transgenic mice: immunohistochemistry (IHC), nuclear fractionation, and chromatin immunoprecipitation (ChIP). These methods can be also applied to analyze NF kappaB activation in mouse intestinal tissue in general. PMID- 25736775 TI - Characterizing the DNA binding site specificity of NF-kappaB with protein-binding microarrays (PBMs). AB - NF-kappaB transcription factors control a wide array of important cellular and organismal processes in eukaryotes. All NF-kappaB transcription factors bind to DNA target sites as dimers. In vertebrates, there are five NF-kappaB subunits, p50, p52, RelA (p65), c-Rel, and RelB, that can form almost all combinations of homodimers and heterodimers, which recognize distinct, but overlapping, target sequences. In this chapter, we describe the use of protein-binding microarrays (PBMs), a high-throughput method to measure the binding of proteins to different DNA sequences. PBM datasets allow for sensitive comparisons of NF-kappaB dimer DNA-binding differences and can aid in the computational and experimental prediction of NF-kappaB target genes. PMID- 25736776 TI - Methods for analyzing the evolutionary relationship of NF-kappaB proteins using free, web-driven bioinformatics and phylogenetic tools. AB - Phylogenetic analysis enables one to reconstruct the functional evolution of proteins. Current understanding of NF-kappaB signaling derives primarily from studies of a relatively small number of laboratory models-mainly vertebrates and insects-that represent a tiny fraction of animal evolution. As such, NF-kappaB has been the subject of limited phylogenetic analysis. The recent discovery of NF kappaB proteins in "basal" marine animals (e.g., sponges, sea anemones, corals) and NF-kappaB-like proteins in non-metazoan lineages extends the origin of NF kappaB signaling by several hundred million years and provides the opportunity to investigate the early evolution of this pathway using phylogenetic approaches. Here, we describe a combination of bioinformatic and phylogenetic analyses based on menu-driven, open-source computer programs that are readily accessible to molecular biologists without formal training in phylogenetic methods. These phylogenetically based comparisons of NF-kappaB proteins are powerful in that they reveal deep conservation and repeated instances of parallel evolution in the sequence and structure of NF-kappaB in distant animal groups, which suggest that important functional constraints limit the evolution of this protein. PMID- 25736777 TI - Studying NF-kappaB signaling with mathematical models. AB - Mathematical modeling of NF-kappaB signaling can be employed to understand how the network of molecular interactions leads to signaling phenomena observed experimentally. Model construction is a challenging process; however, existing models can be utilized and can provide a great deal of insight quickly and inexpensively. The simulation of various inputs and the identification of potential therapeutic targets using the mathematical model are detailed here. PMID- 25736778 TI - Association between outdoor ozone and compensated acute respiratory diseases among workers in Quebec (Canada). AB - Respiratory effects of ozone in the workplace have not been extensively studied. Our aim was to explore the relationship between daily average ozone levels and compensated acute respiratory problems among workers in Quebec between 2003 and 2010 using a time-stratified case-crossover design. Health data came from the Workers' Compensation Board. Daily concentrations of ozone were estimated using a spatiotemporal model. Conditional logistic regressions, with and without adjustment for temperature, were used to estimate odds ratios (ORs, per 1 ppb increase of ozone), and lag effects were assessed. Relationships with respiratory compensations in all industrial sectors were essentially null. Positive non statistically significant associations were observed for outdoor sectors, and decreased after controlling for temperature (ORs of 0.98; 1.01 and 1.05 at Lags 0, 1 and 2 respectively). Considering the predicted increase of air pollutant concentrations in the context of climate change, closer investigation should be carried out on outdoor workers. PMID- 25736779 TI - Accelerations relevant to blunt trauma: theory and data. AB - Maximum acceleration and the head injury criterion (HIC) are both used as indicators of likely head injury severity. A dataset has previously been published of impacts of an instrumented missile on four ground surfaces having a layer of between 0 and 16 cm of sand. The dataset is compared with recently developed theory that predicts power-function dependence of maximum acceleration and HIC on drop height. That prediction was supported by the data. The surfaces differed in respect of the exponents estimated. PMID- 25736780 TI - Suprarenal versus infrarenal stent graft fixation on renal complications after endovascular aneurysm repair. AB - OBJECTIVE: The effect of stent graft fixation type on renal function after endovascular aneurysm repair (EVAR) remains controversial. This systematic review and meta-analysis was conducted to determine whether suprarenal (SR) or infrarenal (IR) fixation influences the risk of renal complications after EVAR. METHODS: We searched MEDLINE and EMBASE with no date or language restrictions for comparative studies evaluating EVAR with SR vs IR fixation on renal dysfunction, renal artery stenosis, renal artery occlusion, renal infarction, and new need for hemodialysis. For each outcome, we calculated the absolute risk difference (RD) with a random effects meta-analysis and performed assessments of heterogeneity and publication bias. Post hoc subgroup analyses explored the influence of individual moderator variables. RESULTS: A total of 21 nonrandomized studies comparing SR vs IR fixation representing 4474 unique patients (SR, 1949; IR, 2525) were included. Baseline patient characteristics were similar between the SR and IR groups. Median patient follow-up was 12 months in each group. There were no statistically significant differences in the risk of any renal complication between SR and IR fixation groups. The absolute RD between the SR and IR fixation groups was <1%, with no evidence of heterogeneity or publication bias for renal dysfunction, renal artery stenosis, renal artery occlusion or new need for hemodialysis after EVAR. Renal infarction occurred in 6.4% of SR patients and in 2.5% of IR patients (P = .09), with evidence of heterogeneity (I(2) = 85%) and publication bias (Egger P = .08). Subgroup analyses revealed that older studies (median treatment period before 2000) reported greater risks of renal infarction with SR fixation (RD, 6.2%; P = .01). However, more contemporary studies (median treatment period after 2000) demonstrated no difference between SR and IR fixation on renal infarction risk (RD, 0.2%; P = .75). CONCLUSIONS: There is no difference in the risk of postoperative renal complications when comparing stent grafts using SR vs IR fixation, particularly with newer-generation devices. Contemporary comparative studies with longer-term follow-up are warranted to further elucidate the influence of SR and IR fixation on renal complications. PMID- 25736781 TI - Clinical outcome and morphologic determinants of mural thrombus in abdominal aortic endografts. AB - OBJECTIVE: Endograft mural thrombus has been associated with stent graft or limb thrombosis after endovascular aneurysm repair (EVAR). This study aimed to identify clinical and morphologic determinants of endograft mural thrombus accumulation and its influence on thromboembolic events after EVAR. METHODS: A prospectively maintained database of patients treated by EVAR at a tertiary institution from 2000 to 2012 was analyzed. Patients treated for degenerative infrarenal abdominal aortic aneurysms and with available imaging for thrombus analysis were considered. All measurements were performed on three-dimensional center-lumen line computed tomography angiography (CTA) reconstructions. Patients with thrombus accumulation within the endograft's main body with a thickness >2 mm and an extension >25% of the main body's circumference were included in the study group and compared with a control group that included all remaining patients. Clinical and morphologic variables were assessed for association with significant thrombus accumulation within the endograft's main body by multivariate regression analysis. Estimates for freedom from thromboembolic events were obtained by Kaplan-Meier plots. RESULTS: Sixty-eight patients (16.4%) presented with endograft mural thrombus. Median follow-up time was 3.54 years (interquartile range, 1.99-5.47 years). In-graft mural thrombus was identified on 30-day CTA in 22 patients (32.4% of the study group), on 6-month CTA in 8 patients (11.8%), and on 1-year CTA in 17 patients (25%). Intraprosthetic thrombus progressively accumulated during the study period in 40 patients of the study group (55.8%). Overall, 17 patients (4.1%) presented with endograft or limb occlusions, 3 (4.4%) in the thrombus group and 14 (4.1%) in the control group (P = .89). Thirty-one patients (7.5%) received an aortouni-iliac (AUI) endograft. Two endograft occlusions were identified among AUI devices (6.5%; overall, 0.5%). None of these patients showed thrombotic deposits in the main body, nor were any outflow abnormalities identified on the immediately preceding CTA. Estimated freedom from thromboembolic events at 5 years was 95% in both groups (P = .97). Endograft thrombus accumulation was associated with >25% proximal aneurysm neck thrombus coverage at baseline (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3), neck length <= 15 mm (OR, 2.4; 95% CI, 1.3-4.2), proximal neck diameter >= 30 mm (OR, 2.4; 95% CI, 1.3-4.6), AUI (OR, 2.2; 95% CI, 1.8-5.5), or polyester-covered stent grafts (OR, 4.0; 95% CI, 2.2-7.3) and with main component "barrel-like" configuration (OR, 6.9; 95% CI, 1.7-28.3). CONCLUSIONS: Mural thrombus formation within the main body of the endograft is related to different endograft configurations, main body geometry, and device fabric but appears to have no association with the occurrence of thromboembolic events over time. PMID- 25736782 TI - Proteomic and network analysis of proteins regulated by REX1 in human embryonic stem cells. AB - Recent studies have suggested that REX1 (reduced expression 1) plays an important role in pluripotency, proliferation, and differentiation. However, the molecular mechanisms involved in REX1-dependent regulation of diverse cellular processes remain unclear. To elucidate the regulatory functions of REX1 in human embryonic stem cells (hESCs), comparative proteomic analysis was performed on REX1 RNAi specifically silenced hESCs. Analysis of the proteome via nano-LC-MS/MS identified 140 differentially expressed proteins (DEPs) displaying a >2-fold difference in expression level between control and REX1 knockdown (KD) hESCs, which were then compared with transcriptome data and validated by quantitative real-time RT-PCR and Western blotting. These DEPs were analyzed by GO, pathway, and functional clustering analyses to determine the molecular functions of the proteins and pathways regulated by REX1. The REX1 KD-mediated DEPs mapped to major biological processes involved in the regulation of ribosome-mediated translation and mitochondrial function. Functional network analysis revealed a highly interconnected network among these DEPs and indicated that these interconnected proteins are predominantly involved in translation and the regulation of mitochondrial organization. These findings regarding REX1-mediated regulatory network have revealed the contributions of REX1 to maintaining the status of hESCs and have improved our understanding of the molecular events that underlie the fundamental properties of hESCs. PMID- 25736783 TI - Repeated muscle damage blunts the increase in heat strain during subsequent exercise heat stress. AB - PURPOSE: Exercise-induced muscle damage (EIMD) has recently been shown to increase heat strain during exercise heat stress (HS), and represents a risk factor for exertional heat illness (EHI). We hypothesised that a repeated bout of EIMD blunts the increase in rectal temperature (T re) during subsequent endurance exercise in the heat. METHODS: Sixteen non-heat-acclimated males were randomly allocated to EIMD (n = 9) or control (CON, n = 7). EIMD performed a downhill running treatment at -10 % gradient for 60 min at 65 % [Formula: see text]O2max in 20 degrees C, 40 % RH. CON participants performed the same treatment but at +1 % gradient. Following treatment, participants rested for 30 min, then performed HS (+1 % gradient running for 40 min at 65 % [Formula: see text]O2max in 33 degrees C, 50 % RH) during which thermoregulatory measures were assessed. Both groups repeated the treatment and subsequent HS 14 days later. Isometric quadriceps strength was assessed at baseline, and 48 h post-treatment. RESULTS: The decrease in leg strength 48 h post-EIMD trial 1 (-7.5 %) was absent 48 h post EIMD trial 2 (+2.9 %) demonstrating a repeated bout effect. Final T re during HS was lower following EIMD trial 2 (39.25 +/- 0.47 degrees C) compared with EIMD trial 1 (39.59 +/- 0.49 degrees C, P < 0.01), with CON showing no difference. Thermal sensation and the T re threshold for sweating onset were also lower during HS on EIMD trial 2. CONCLUSION: The repeated bout effect blunted the increase in heat strain during HS conducted after EIMD. Incorporating a muscle damaging bout into training could be a strategy to reduce the risk of EHI and improve endurance performance in individuals undertaking heavy exercise with an eccentric component in the heat. PMID- 25736784 TI - MiRNAs in primary cutaneous lymphomas. AB - Primary cutaneous lymphomas (PCL) compose a heterogeneous disease with still unknown aetiology and mechanisms of development. MicroRNAs (miRNAs) have recently been discovered as one of the crucial players in PCL carcinogenesis through post transcriptional regulation of gene expression. miRNAs have been reported to be frequently deregulated in PCLs and their biological significance has been further confirmed in multiple functional experiments. Such studies help us understand molecular pathogenesis of PCL. In this review, we summarize expression of miRNAs and their corresponding roles in different subtypes of PCL. With expression and functional role of miRNAs revealed, investigation of their possible clinical use as biomarkers for diagnosis, prediction of prognosis and target for therapies, will be a promising area in the future. PMID- 25736785 TI - Association Between Systemic Hypertension and Macular Thickness Measured by Optical Coherence Tomography. AB - PURPOSE: This study aimed to evaluate an association between hypertension and macular thickness. METHODS: A total of 827 Korean adults composed of 163 pairs of twins and their family members were included in this population-based cross sectional study. Macular thickness was measured with optical coherence tomography at nine macular subfields defined by the Early Treatment of Diabetic Retinopathy Study. Cardiometabolic risk factors, including body mass index (BMI), hypertension, diabetes, lipid profiles, and smoking status, were assessed. Linear mixed regression analysis was conducted with consideration of familial correlations and adjustment for covariates. RESULTS: Age-, sex-, and axial length adjusted analysis showed that systemic hypertension was associated with a significant change in macular thickness in most subfields except for the fovea. Compared with normotensive subjects, macular thickness was lower in subjects with systemic hypertension (P <= 0.05), with the highest difference (2.52%) in the outer temporal region and the lowest difference (1.44%) in the inner temporal region. This association persisted even after adjusting for other cardiometabolic risk factors. Other cardiometabolic risk factors were not independently associated with macular thickness in any subfields. Stratified analysis showed that the inverse association between macular thickness and hypertension was stronger in the group with elevated fasting glucose compared with the group with normal fasting glucose (P for interaction <= 0.05). CONCLUSIONS: Systemic hypertension was inversely associated with macular thickness in most macular subfields, particularly in subjects with an elevated fasting glucose level. This finding suggests that it may be necessary to consider the presence of hypertension when macular thickness and pericentral macular area volume are evaluated. PMID- 25736788 TI - Changing material properties of the tree shrew sclera during minus lens compensation and recovery. AB - PURPOSE: To estimate two collagen-specific material properties (crimp angle and elastic modulus of collagen fibrils) of the remodeling tree shrew sclera during monocular -5 diopter (D) lens wear and recovery. METHODS: Tensile tests were performed on scleral strips obtained from juvenile tree shrews exposed to three different visual conditions: normal, monocular -5 D lens wear to induce myopia, and recovery. Collagen fibrils are crimped in the unloaded sclera and uncrimp as the tissue stiffens under load. Inverse numerical analyses were performed to estimate the (unloaded) crimp angle and elastic modulus of collagen fibrils using a microstructure-based constitutive model. RESULTS: Compared with the control eye, the crimp angle was significantly higher in the treated eye after 2 days and remained significantly higher until 21 days of lens wear (P < 0.05). The difference between the crimp angle of the treated and control eye rapidly vanished during recovery in concert with the changes in axial elongation rate. A rapid and extensive increase in the elastic modulus was seen in both eyes after starting and stopping the lens wear. CONCLUSIONS: The estimated change in the crimp of scleral collagen fibrils is temporally associated with the change in axial elongation rate during myopia development and recovery. This finding suggests that axial elongation may be controlled by a remodeling mechanism that modulates the collagen fibril crimp. The observed binocular changes in scleral stiffness are not temporally associated with the axial elongation rate, indicating that scleral stiffening may not be causally related to myopia. PMID- 25736789 TI - The Role of Thrombin and Cell Contractility in Regulating Clustering and Collective Migration of Corneal Fibroblasts in Different ECM Environments. AB - PURPOSE: We previously reported that extracellular matrix composition (fibrin versus collagen) modulates the pattern of corneal fibroblast spreading and migration in 3-D culture. In this study, we investigate the role of thrombin and cell contractility in mediating these differences in cell behavior. METHODS: To assess cell spreading, corneal fibroblasts were plated on top of fibrillar collagen and fibrin matrices. To assess 3-dimensional cell migration, compacted collagen matrices seeded with corneal fibroblasts were embedded inside acellular collagen or fibrin matrices. Constructs were cultured in serum-free media containing platelet-derived growth factor (PDGF), with or without thrombin, the Rho kinase inhibitor Y-27632, and/or the myosin II inhibitor blebbistatin. We used 3-dimensional and 4-dimensional imaging to assess cell mechanical behavior, connectivity and cytoskeletal organization. RESULTS: Thrombin stimulated increased contractility of corneal fibroblasts. Thrombin also induced Rho kinase dependent clustering of cells plated on top of compliant collagen matrices, but not on rigid substrates. In contrast, cells on fibrin matrices coalesced into clusters even when Rho kinase was inhibited. In nested matrices, cells always migrated independently through collagen, even in the presence of thrombin. In contrast, cells migrating into fibrin formed an interconnected network. Both Y 27632 and blebbistatin reduced the migration rate in fibrin, but cells continued to migrate collectively. CONCLUSIONS: The results suggest that while thrombin induced actomyosin contraction can induce clustering of fibroblasts plated on top of compliant collagen matrices, it does not induce collective cell migration inside 3-D collagen constructs. Furthermore, increased contractility is not required for clustering or collective migration of corneal fibroblasts interacting with fibin. PMID- 25736790 TI - Impact of reticular pseudodrusen on microperimetry and multifocal electroretinography in intermediate age-related macular degeneration. AB - PURPOSE: To examine the influence of reticular pseudodrusen (RPD) on retinal and visual function in intermediate AMD using multifocal electroretinography (mfERG) and microperimetry. METHODS: In a prospective cross-sectional study, microperimetry and mfERG testing, followed by color fundus photography, near infrared reflectance imaging and spectral-domain optical coherence tomography (SD OCT) scans were performed in 120 eyes from 60 participants with bilateral intermediate AMD. The number of subfields with pigmentary changes and RPD within the central 3-mm diameter of the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and drusen cube root volume within the central 3-mm diameter was determined. The influence of these pathological features on microperimetry and mfERG in this region were examined. RESULTS: Microperimetric sensitivity was not significantly associated with the presence and extent of RPD (P = 0.068), but with drusen volume and extent of pigmentary changes (P < 0.001 for both). However, the presence and extent of RPD was independently and significantly associated with mfERG implicit time, along with drusen volume and the extent of pigmentary changes (P <= 0.023). The mfERG response amplitude was not significantly associated with the presence and extent of RPD (P = 0.130). CONCLUSIONS: The presence and extent of RPD was associated with functional changes on mfERG implicit time, but not mfERG response amplitude or microperimetry. These findings suggest that the presence of RPD in eyes with intermediate AMD has a significant influence on cone-mediated neuroretinal function, without a significant influence on mesopic visual function as determined on microperimetry. PMID- 25736791 TI - Collagen microstructural factors influencing optic nerve head biomechanics. AB - PURPOSE: Previous studies have suggested that the lamina cribrosa (LC) and its surrounding sclera are biomechanically important in the pathogenesis of glaucoma, but many were limited by assumptions of tissue isotropy and homogeneity. Here, we used an improved biomechanical model driven by experimental measurements of scleral and LC collagen fiber organization to more accurately evaluate optic nerve head (ONH) biomechanics. METHODS: Collagen fiber organization was quantitatively mapped across human ONH cryosections (three normal and three glaucomatous) using small-angle light scattering (SALS) and fed into two dimensional finite element models loaded under biaxial stress to simulate raised intraocular pressure. Effects of artificial variations in collagen fiber microstructure and stiffness on LC and scleral strains were also investigated. RESULTS: Scleral collagen fibers were circumferential and exhibited the highest alignment in a region not immediately adjacent to, but at a distance (400-500 MUm) away from, the LC. In models, such a fiber arrangement yielded rings of low strain (second principal and effective) in the scleral region immediately adjacent to the LC. Further sensitivity analyses showed that scleral fiber alignment was crucial in determining LC strain levels. Moderate scleral anisotropy (as observed physiologically) was more effective than isotropy or high anisotropy in limiting LC and scleral strain magnitude. CONCLUSIONS: The presence of a heterogeneous collagen fiber organization in the peripapillary sclera appears effective in limiting LC strain and is able to reduce strain levels at the scleral canal boundary: a transition zone prone to LC disinsertion, focal lamina cribrosa defects, and optic disc hemorrhages in glaucoma. PMID- 25736792 TI - Disorganized retinal lamellar structures in nonperfused areas of diabetic retinopathy. AB - PURPOSE: To investigate morphologic changes on spectral-domain optical coherence tomography (SD-OCT) images in nonperfused areas (NPAs) in diabetic retinopathy (DR). METHODS: One hundred eight consecutive eyes of 80 patients with diabetic ischemic maculopathy were retrospectively reviewed. The boundary between the nerve fiber layer (NFL) and the ganglion cell layer (GCL)/inner plexiform layer (IPL) and the status of Henle's layer were characterized on the vertical sectional images of SD-OCT. These findings were compared with the NPAs on the FA images and the logMAR visual acuity (VA). RESULTS: The SD-OCT images showed that most areas of capillary nonperfusion had an indistinct boundary between the NFL and GCL/IPL in DR, regardless of high or moderate OCT reflectivity. The total transverse length of the NPAs was correlated positively with that of the areas with no boundary between these layers in all 108 eyes (R = 0.860, P < 0.001). Sixty-four eyes that had center-involved diabetic macular edema (DME) also had a significant association between them (R = 0.764, P < 0.001), and the most significant correlation was seen in eyes without DME (R = 0.955, P < 0.001). The macular transverse length of the areas with no boundary between the NFL and GCL/IPL was associated modestly with the logMAR VA (R = 0.334, P < 0.001). The indistinct Henle's layer on SD-OCT images often was delineated specifically in the NPAs rather than in the perfused areas. CONCLUSIONS: Nonperfused areas were associated significantly with the absence of a boundary between the NFL and GCL/IPL on SD-OCT images in DR. PMID- 25736793 TI - Mouse slc9a8 mutants exhibit retinal defects due to retinal pigmented epithelium dysfunction. AB - PURPOSE: As part of a large scale systematic screen to determine the effects of gene knockout mutations in mice, a retinal phenotype was found in mice lacking the Slc9a8 gene, encoding the sodium/hydrogen ion exchange protein NHE8. We aimed to characterize the mutant phenotype and the role of sodium/hydrogen ion exchange in retinal function. METHODS: Detailed histology characterized the pathological consequences of Slc9a8 mutation, and retinal function was assessed by electroretinography (ERG). A conditional allele was used to identify the cells in which NHE8 function is critical for retinal function, and mutant cells analyzed for the effect of the mutation on endosomes. RESULTS: Histology of mutant retinas reveals a separation of photoreceptors from the RPE and infiltration by macrophages. There is a small reduction in photoreceptor length and a mislocalization of visual pigments. The ERG testing reveals a deficit in rod and cone pathway function. The RPE shows abnormal morphology, and mutation of Slc9a8 in only RPE cells recapitulates the mutant phenotype. The NHE8 protein localizes to endosomes, and mutant cells have much smaller recycling endosomes. CONCLUSIONS: The NHE8 protein is required in the RPE to maintain correct regulation of endosomal volume and/or pH which is essential for the cellular integrity and subsequent function of RPE. PMID- 25736795 TI - A Novel Method Using Quantum Dots for Testing the Barrier Function of Cultured Epithelial Cell Sheets. AB - PURPOSE: The corneal epithelium provides a barrier to protect the deeper structures of the eye from any particles or pathogens. Cultured epithelial cell sheets are used in transplantation surgery for corneal repair or regeneration. The purpose of this study was to develop a novel method using fluorescent quantum dot nanoparticles for validating the quality and barrier function of cultured epithelial cell sheets. METHODS: Human function epithelial cell sheets, cultured from oral mucosal or corneal limbal cells, were incubated in either normal calcium-containing medium or medium containing no calcium with a calcium chelator. Also contained in the media were suspensions of two different sizes of quantum dots. Following incubation, analysis of quantum dot penetration was carried out using confocal microscopy. RESULTS: In contrast to the cell sheets incubated in calcium-containing medium, removal of extracellular calcium resulted in the disruption of tight junctions, compromising the cell sheet's barrier function. This caused a reduction in transepithelial electrical resistance and deeper, more ubiquitous penetration of the quantum dots into the paracellular space and interior of the cell sheet. CONCLUSIONS: This method provides easy to interpret qualitative and quantitative data on the functionality of a cell sheet's tight junctions, as well as nanoscale and microscale structural information on its surface and interior morphology, and any localized areas of damage or abnormality. This novel technique could be used as part of the validation system for cultured epithelial cell sheets for use in transplantation. PMID- 25736794 TI - TRP Channels Localize to Subdomains of the Apical Plasma Membrane in Human Fetal Retinal Pigment Epithelium. AB - PURPOSE: Calcium regulates many functions of the RPE. Its concentration in the subretinal space and RPE cytoplasm is closely regulated. Transient receptor potential (TRP) channels are a superfamily of ion channels that are moderately calcium-selective. This study investigates the subcellular localization and potential functions of TRP channels in a first-passage culture model of human fetal RPE (hfRPE). METHODS: The RPE isolated from 15- to 16-week gestation fetuses were maintained in serum-free media. Cultures were treated with barium chloride (BaCl2) in the absence and presence of TRP channel inhibitors and monitored by the transepithelial electrical resistance (TER). The expression of TRP channels was determined using quantitative RT-PCR, immunoblotting, and immunofluorescence confocal microscopy. RESULTS: Barium chloride substantially decreased TER and disrupted cell-cell contacts when added to the apical surface of RPE, but not when added to the basolateral surface. The effect could be partially blocked by the general TRP inhibitor, lanthanum chloride (LaCl3, ~75%), or an inhibitor of calpain (~25%). Family member-specific inhibitors, ML204 (TRPC4) and HC-067047 (TRPV4), had no effect on basal channel activity. Expression of TRPC4, TRPM1, TRPM3, TRPM7, and TRPV4 was detected by RT-PCR and immunoblotting. The TRPM3 localized to the base of the primary cilium, and TRPC4 and TRPM3 localized to apical tight junctions. The TRPV4 localized to apical microvilli in a small subset of cells. CONCLUSIONS: The TRP channels localized to subdomains of the apical membrane, and BaCl2 was only able to dissociate tight junctions when presented to the apical membrane. The data suggest a potential role for TRP channels as sensors of [Ca(2+)] in the subretinal space. PMID- 25736796 TI - Inflammation but not obesity or insulin resistance is associated with increased plasma fibroblast growth factor 23 concentration in the elderly. AB - BACKGROUND: Fibroblast growth factor 23 (FGF23) is a hormone involved in calcium phosphate homoeostasis. The data of recently published studies suggest that FGF 23 may also play a role in some metabolic processes beyond mineral metabolism, such as insulin resistance or energy homoeostasis. The aim of the study was to attempt the relationships between plasma cFGF-23 (C-terminal) and iFGF-23 (intact) concentrations and the occurrence of obesity, insulin resistance and inflammation in elderly population. MATERIALS AND METHODS: The analysis included 3115 elderly subjects (1485 women). During three visits, a questionnaire survey, comprehensive geriatric assessment and anthropometric measurements were performed as well as blood and urine samples were collected by trained nurses. Serum phosphorus, calcium, intact parathormone (iPTH), 25(OH)D3 , iFGF-23 and cFGF-23, insulin, glucose, albumin (also in urine), creatinine, hs-CRP, interleukin-6 and NT-proBNP concentrations were assessed. HOMA-IR was calculated according to the standard formula. RESULTS: Both forms of FGF23, iPTH and 25-OH-D3 levels were not related to the occurrence of obesity and insulin resistance. Increase in phosphorus, iPTH and NT-proBNP concentrations is associated with rise in plasma iFGF23 and cFGF23 levels. Additionally, increase in hs-CRP explained the elevated plasma iFGF23 levels. In multiple regression models, circulating iFGF23 and cFGF23 level's variability in elderly population were explained by changes in serum phosphorus, iPTH, eGFR, hs-CRP and NT-proBNP levels but not by BMI and HOMA IR values. CONCLUSION: In conclusion, our study shows that increased levels of both circulating Fibroblast growth factor 23 forms in elderly subjects are associated with inflammation but not obesity or insulin resistance per se. PMID- 25736797 TI - Recovery, as Experienced by Women with Borderline Personality Disorder. AB - Studies examining recovery through the service users' perspectives have mainly included persons with schizophrenia or bipolar disorder. Giving voice to those with borderline personality disorder (BPD) would enrich our understanding of recovery, as their specific experiences may bring new dimensions, obstacles and facilitators. The objective of this study was to qualitatively capture the experience of recovery in women with BPD. Participants were women between 18 and 65 years old who had a diagnosis of BPD and completed at least 2 years in a program for persons with BPD. During the first meeting, they produced a picture collage, followed by an interview on their experience of recovery. The second meeting was a phone interview to discuss new thoughts. In addition, their medical records were reviewed. A thematic analysis of the interviews was conducted and organized with the Person-Environment-Occupation model. Although recovery was not the best term to name their experience, they all talked about a process towards stability and wellbeing (n = 12). Dimensions of recovery included, for example, letting go of the past (person), being involved in meaningful activities (occupation) and having healthy relationships (environment). Facilitators included social support and participation in a specialized therapy program. The main obstacle was unstable family relationships. The findings from this study showed similar dimensions to previous recovery studies, new perspectives on certain dimensions, as well as new ones. They also reinforced the importance to incorporate intervention outcomes that target the person with BPD, their social environment and meaningful occupations. PMID- 25736798 TI - Psychometric Validation of the Chinese Compulsive Internet Use Scale (CIUS) with Taiwanese High School Adolescents. AB - The recent development of internet infrastructure has fuelled a popular concern that young Asian internet users are experiencing Internet addiction due to excessive Internet use. In order to understand the phenomenon, psychometric validation of a 14-item Compulsive Internet Use Scale (CIUS), with 417 Chinese adolescents has been performed. Compared to other instruments for use with Chinese populations, e.g. the 20-item Internet Addiction Test (IAT) and the 26 item Chen Internet Addiction Scale, the CIUS is relatively concise, and easy to use for measuring and diagnosing Internet addiction. The present psychometric validation has found good factorial stability with a one-factor solution for the CIUS. The internal consistency and model fit indices were very good, and even better than any previous CIUS validations. The Chinese CIUS is a valid and reliable self-reporting instrument for examining compulsive Internet use among Chinese adolescents. Other findings included: male adolescents tend to experience more compulsive Internet use than their female counterparts, and CIUS scores were positively correlated with the daily Internet use time and negatively correlated with the academic performance of the participants. No significant relationships between the CIUS, ICT accessibility, family economic condition, parental occupation or religion were found. PMID- 25736799 TI - Schizophrenia and Employment: Evaluation From Professionals Point of View. AB - Schizophrenia is a severe and chronic disorder requiring long-lasting and comprehensive treatment. Because of this disorder patients are socially isolated. Consequently, schizophrenia has a significant economic burden both in a group of direct and indirect costs. The aim was to analyse experts' opinions in the field of psychiatry concerning work possibilities among people with schizophrenia and to present the importance of employment for more effective treatment. A worldwide study was conducted between June 2011 and June 2013 using a questionnaire consisting of six open-closed questions and a short metrics. The questionnaire was delivered to experts and spread all over the world by post and via the internet. Over 3000 questionnaires were sent and the addressed specialists were requested to return them. From received 403 questionnaires 320 were included into the study, based on adopted inclusion and exclusion criteria. Although patients are afraid of looking for a job, respondents indicated that they crave for employment. The number of people that are able to work during remission of schizophrenia is considerably higher (50.35 %) than the number of actually employed (15.85 %). Non-pharmacological therapies were indicated as important to improve patients' chances of finding a job during remission of schizophrenia. The number of people that can work during remission of schizophrenia is considerably higher than the number of affected people employed. Patients crave for a job and supported employment should be treated as priority by health-care decision makers. PMID- 25736800 TI - EGF Protects Cells Against Dox-Induced Growth Arrest Through Activating Cyclin D1 Expression. AB - It has been reported that the antitumor drug doxorubicin (Dox) exerts its toxic effects via GATA-4 depletion and that over-expression of GATA-4 reverses Dox induced toxicity and apoptosis; however, the precise mechanisms remain unclear. In this study, we observed, for the first time, that EGF protects cells against Dox-mediated growth arrest, G2/M-phase arrest, and apoptosis. Additionally, EGF expression was down-regulated in Dox-treated cells and up-regulated in GATA-4 over-expressing cells. Utilizing real-time PCR and western blotting analysis, we found that the expression of the cell cycle-associated protein cyclin D1 was inhibited in GATA-4-silenced cells and Dox-treated cells and was enhanced in GATA 4 over-expressing cells and EGF-treated cells. Furthermore, EGF treatment reversed the inhibited expression of cyclin D1 that was mediated by GATA-4 RNAi or Dox. Our results indicate that EGF, as a downstream target of Dox, may be involved in Dox-induced toxicity as well as in the protective role of GATA-4 against toxicity induced by Dox via regulating cyclin D1 expression, which elucidates a new molecular mechanism of Dox toxicity with important clinical implications. PMID- 25736801 TI - History of family violence, childhood behavior problems, and adolescent high-risk behaviors as predictors of girls' repeated patterns of dating victimization in two developmental periods. AB - This study aims to document the prevalence of repeated patterns of dating victimization and to examine, within the frameworks of an ecological model and lifestyle/routine activities theories, associations between such patterns and family, peer, and individual factors. Dating victimization in adolescence (age 15) and early adulthood (age 21) was evaluated in 443 female participants. Multinomial logistic regression analyses revealed that history of family violence, childhood behavior problems, and adolescent high-risk behaviors were associated with an increased risk for girls of being victimized (psychologically and/or physically/sexually) in their dating relationships, either in adolescence or early adulthood, or at both developmental periods. PMID- 25736802 TI - Summer's death. PMID- 25736803 TI - Commentary on Summer's death. PMID- 25736805 TI - Expression of Kit and Etv1 in restricted brain regions supports a brain-cell progenitor as an origin for cranial germinomas. AB - Mismigrating germ-cell progenitors have historically been accepted as the cell of origin for central nervous system (CNS) germinomas. However, an alternative hypothesis suggests that CNS germinomas arise from a brain-cell progenitor. Germinomas often acquire Kit signaling pathway mutations, and there is evidence for an oncogenic relationship between KIT and the ETV1 transcription factor. KIT appears to be necessary to stabilize ETV1, and ETV1 then activates oncogenesis associated genes. ETV1 expression is not increased by KIT, so ETV1 already needs to be expressed in order for KIT to have an oncogenic function. Therefore, if brain-cell progenitors are the cell of origin for germinomas, those cells would already need to coexpress ETV1 and KIT. We examined Kit and Etv1 in situ hybridization data from the Allen Brain Atlas, for mouse brain tissue at various stages of development. Both Kit and Etv1 were expressed in the regions where germinomas most commonly arise, and in the medulla oblongata. All human cases of germinomas correlated to the regions where ETV1 and KIT are coexpressed. We therefore postulate that germinomas in the brain share a similar mechanism with other KIT-driven cancers, which supports the hypothesis that germinomas arise from a brain-cell progenitor. PMID- 25736806 TI - Digital media interventions for sexual health promotion-opportunities and challenges: a great way to reach people, particularly those at increased risk of sexual ill health. PMID- 25736807 TI - Season of birth, the dopamine D4 receptor gene and emotional eating in males and females. Evidence of a genetic plasticity factor? AB - Emotional eating has a female preponderance and an understanding of possible genetic and environmental underpinnings is still in the early stages. The current study focuses on the possible role of the dopamine D4 receptor (DRD4) 'plasticity' gene in emotional eating and the possible moderator effects of sex and season of birth therein. We tested this in two samples (n = 93 and n = 586) of male and female Caucasian adults by genotyping DRD4 and assessing self reported emotional eating. Participants were defined as high risk carriers if they had at least one long (7-repeat) allele, which confers hypo-function to DRD4. We also ran analyses that grouped 2- and 7-repeat carriers together. In the first sample there only was a moderator effect of sex. In the second sample there also was a 3 way interaction between season of birth, sex and genotype. In line with the idea that the Drd4 gene functions as a plasticity gene that affects the sensitivity to environmental influences, the moderator effect of sex was only found for the participants born in fall. Only in females the hypo-functional variants of DRD4 were associated with significantly higher degrees of emotional eating. Furthermore, the sex * genotype effects were somewhat stronger when the 2 repeat allele was grouped together with the 7-repeat allele. Our data suggest that DRD4 hypo-functional genetic variants are associated with emotional eating, only in females. PMID- 25736808 TI - Combining sieving and washing, a way to treat MSWI boiler fly ash. AB - Municipal Solid Waste Incineration (MSWI) fly ashes contain some compounds that could be extracted and valorised. A process based on wet sieving and washing steps has been developed aiming to reach this objective. Such unique combination in MSWI fly ash treatment led to a non-hazardous fraction from incineration fly ashes. More specifically, MSWI Boiler Fly Ash (BFA) was separately sampled and treated. The BFA finer particles (13wt%) were found to be more contaminated in Pb and Zn than the coarser fractions. After three washing steps, the coarser fractions presented leaching concentrations acceptable to landfill for non hazardous materials so that an eventual subsequent valorisation may be foreseen. At the contrary, too much Pb leached from the finest particles and this fraction should be further treated. Wet sieving and washing permit thus to reduce the leachability of MSWI BFA and to concentrate the Pb and Zn contamination in a small (in particle size and volume) fraction. Such combination would therefore constitute a straightforward and efficient basis to valorise coarse particles from MSWI fly ashes. PMID- 25736809 TI - [Multiple evanescent white dot syndrome associated with tuberous sclerosis: case report]. PMID- 25736810 TI - Ketamine for status epilepticus: canadian physician views and time to push forward. PMID- 25736811 TI - Fe(II) spin-crossover phenomenon in the pentadecanuclear {Fe9[Re(CN)8]6} spherical cluster. AB - The self-assembly of iron(II) ions with rare octacyanidorhenate(V) metalloligands in a methanolic solution results in the formation of a nanometric pentadecanuclear {Fe(II) 9 [Re(V) (CN)8 ]6 (MeOH)24 }?10 MeOH (1) molecule with a six-capped body-centered cubic topology. The cluster demonstrates a thermally induced spin-crossover phase transition at T1/2 =195 K which occurs selectively for a single Fe(II) ion embedded in the center of a cluster core. PMID- 25736812 TI - The natural history of pulmonary function in Duchenne muscular dystrophy. PMID- 25736813 TI - The challenges in developing effective canine infectious respiratory disease vaccines. AB - OBJECTIVES: Canine infectious respiratory disease (CIRD) is a disease of multifactorial aetiology, where multiple pathogens act sequentially or synergistically to cause disease. It is common within large dog populations, such as those in re-homing or training kennels. Vaccines are vital in its management of CIRD, but they often fail to prevent disease. Recently, a number of novel pathogens have been identified in CIRD outbreaks and represent new targets for vaccination. KEY FINDINGS: Innate immune responses provide a vital first line of defence against the infectious agents involved in the development of CIRD. Once breeched, adaptive mucosal immunity is necessary to prevent infection and limit spread. Current vaccines target only a few of the agents involved in CIRD. Evidence, from the limited amount of published data, indicates that although vaccinating against these agents reduces infection rates, duration of shedding and severity of disease, it does not induce sterilising immunity; and this has important consequences for the management of the disease, and the future of CIRD vaccine development. SUMMARY: In the process of considering the development of novel CIRD vaccines, this paper focuses on the immunological mechanisms that provide protection for the respiratory tract, the current recommendations for canine vaccination, and the challenges surrounding existing CIRD vaccines, and their future development. PMID- 25736814 TI - Improving environmental assessments by integrating Species Sensitivity Distributions into environmental modeling: examples with two hypothetical oil spills. AB - A three dimensional (3D) trajectory model was used to simulate oil mass balance and environmental concentrations of two 795,000 L hypothetical oil spills modeled under physical and chemical dispersion scenarios. Species Sensitivity Distributions (SSD) for Total Hydrocarbon Concentrations (THCs) were developed, and Hazard Concentrations (HC) used as levels of concern. Potential consequences to entrained water column organisms were characterized by comparing model outputs with SSDs, and obtaining the proportion of species affected (PSA) and areas with oil concentrations exceeding HC5s (Area ? HC5). Under the physically-dispersed oil scenario ? 77% of the oil remains on the water surface and strands on shorelines, while with the chemically-dispersed oil scenario ? 67% of the oil is entrained in the water column. For every 10% increase in chemical dispersion effectiveness, the average PSA and Area ? HC5 increases (range: 0.01-0.06 and 0.50-2.9 km(2), respectively), while shoreline oiling decreases (? 2919 L/km). Integrating SSDs into modeling may improve understanding of scales of potential impacts to water column organisms, while providing net environmental benefit comparison of oil spill response options. PMID- 25736815 TI - Effect of historical residual hexachlorocyclohexanes and dichlorodiphenyltrichloroethane on bacterial communities in sediment core collected from an estuary in northeastern China by next-generation sequencing. AB - In this study, we evaluate the influence of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethane (DDT) on bacterial communities of sediment core from an estuary formed during the period of 1960-2011. Canonical correspondence analysis showed that o,p'-DDT, o,p'-DDD (mitotane), and depth had important influences on bacterial community distributions (p<0.05). Furthermore, our results found variance explained by all variables was 82.9%, while that by o,p' DDD was 24.4%, and that of o,p'-DDT was 9.8%, indicating that o,p'-DDD had a greater influence on sediment-dwelling bacteria than o,p'-DDT. Also, bacterial diversity was affected and the Shannon index was significantly negatively correlated with total HCHs (r=-0.579, p<0.05) and total DDTs (r=-0.607, p<0.01), respectively. Furthermore, our results showed that Flavobacteria and Clostridia content can be considered an indicator of pollution of HCHs and DDTs in sediment core samples. PMID- 25736816 TI - Potentiation of ciprofloxacin action against Gram-negative bacterial biofilms by a nitroxide. AB - We previously showed that soluble nitroxides (nitric oxide analogues) mimicked the well-established ability of nitric oxide to cause biofilm dispersal and further showed that these compounds could prevent biofilm formation. Here, we investigated the effect of the nitroxide carboxy-TEMPO in combination with sub MUg/ml concentrations of ciprofloxacin on pre-formed flow cell biofilms formed by Gram-negative bacteria. Combination therapy led to substantial eradication of existing biofilms formed by Pseudomonas aeruginosa PA14 (99.3%) and Escherichia coli O157 (93%). PMID- 25736817 TI - Valinomycin as a Classical Anionophore: Mechanism and Ion Selectivity. AB - In the present study, we use theory and modeling to investigate K(+) carrier valinomycin (Vln) as a classical anionophore. We discuss formation of the ion pair VlnK(+), Cl(-) versus encapsulation of the anion into VlnCl(-) complex as two alternative mechanisms that could account for surprisingly high anionophoretic activity of the cyclic peptide (Riddell and Zhou in J Inorg Biochem 55:55-279, 1994), meanwhile constructing kinetic models to help distinguish between the two. The study is guided by the idea to create "valinomycin for anions" and in this respect the selectivity problem is at the heart, as synthetic anionophores are expected to have the same issues with the counterion translocation as Vln has. The study helps to understand what Vln really is and so what "valinomycin for anions" has to be. Furthermore, using recent examples, we explore how Vln has been utilized as a tool for research in the two different fields, with an aim to illustrate advantages and potential of basic scientific methods over supramolecular way, celebrating victory of science over commonsense. PMID- 25736819 TI - Cilostazol research in Asia: can it be applied to European and American patients? AB - Cilostazol is an antiplatelet drug often used in Asian countries like Korea, Japan, and China. However, it is rarely used in the west. Cilostazol inhibits phosphodiesterase, increases cyclic AMP concentrations, and consequently inhibits platelet aggregation. Interestingly, it also has vasodilatory activity, inhibits vascular smooth muscle proliferation, and protects the endothelium. Studies in Asia have shown that cilostazol is effective in the secondary prevention of stroke. Moreover, it is significantly less likely to cause bleeding complications than aspirin. Additional trials have shown that cilostazol is effective in the prevention of intracranial atherosclerosis progression. Unfortunately, cilostazol has rarely been studied in non-Asian stroke patients and, accordingly, the benefits of cilostazol are less well appreciated in Europe and America than in Asia. Although further studies are required, we suggest that at least some stroke patients (e.g., patients prone to bleeding, patients with intracranial atherosclerosis, etc.) may readily benefit from cilostazol regardless of ethnicity. PMID- 25736818 TI - Are we ready to predict late effects? A systematic review of clinically useful prediction models. AB - BACKGROUND: After completing treatment for cancer, survivors may experience late effects: consequences of treatment that persist or arise after a latent period. PURPOSE: To identify and describe all models that predict the risk of late effects and could be used in clinical practice. DATA SOURCES: We searched Medline through April 2014. STUDY SELECTION: Studies describing models that (1) predicted the absolute risk of a late effect present at least 1 year post-treatment, and (2) could be used in a clinical setting. DATA EXTRACTION: Three authors independently extracted data pertaining to patient characteristics, late effects, the prediction model and model evaluation. DATA SYNTHESIS: Across 14 studies identified for review, nine late effects were predicted: erectile dysfunction and urinary incontinence after prostate cancer; arm lymphoedema, psychological morbidity, cardiomyopathy or heart failure and cardiac event after breast cancer; swallowing dysfunction after head and neck cancer; breast cancer after Hodgkin lymphoma and thyroid cancer after childhood cancer. Of these, four late effects are persistent effects of treatment and five appear after a latent period. Two studies were externally validated. Six studies were designed to inform decisions about treatment rather than survivorship care. Nomograms were the most common clinical output. CONCLUSION: Despite the call among survivorship experts for risk stratification, few published models are useful for risk-stratifying prevention, early detection or management of late effects. Few models address serious, modifiable late effects, limiting their utility. Cancer survivors would benefit from models focused on long-term, modifiable and serious late effects to inform the management of survivorship care. PMID- 25736820 TI - Year in review 2014: Lung cancer, pleural diseases, respiratory infections and tuberculosis, bronchoscopic intervention and imaging. PMID- 25736821 TI - Repetitive genomic insertion of gene-sized dsDNAs by targeting the promoter region of a counter-selectable marker. AB - Genome engineering can be used to produce bacterial strains with a wide range of desired phenotypes. However, the incorporation of gene-sized DNA fragments is often challenging due to the intricacy of the procedure, off-target effects, and low insertion efficiency. Here we report a genome engineering method enabling the continuous incorporation of gene-sized double-stranded DNAs (dsDNAs) into the Escherichia coli genome. DNA substrates are inserted without introducing additional marker genes, by synchronously turning an endogenous counter selectable marker gene ON and OFF. To accomplish this, we utilized lambda Red protein-mediated recombination to insert dsDNAs within the promoter region of a counter-selectable marker gene, tolC. By repeatedly switching the marker gene ON and OFF, a number of desired gene-sized dsDNAs can be inserted consecutively. With this method, we successfully inserted approximately 13 kb gene clusters to generate engineered E. coli strains producing 1,4-butanediol (1,4-BDO). PMID- 25736822 TI - From admission to death: prevalence and course of pain, agitation, and shortness of breath, and treatment of these symptoms in nursing home residents with dementia. AB - OBJECTIVES: Burdensome symptoms frequently develop as part of the dementia trajectory and influence quality of life. We explore the course of symptoms and their treatment during nursing home stay to help target adequate symptom management. DESIGN: Data were collected as part of the Dutch End of Life in Dementia study, a longitudinal observational study with up to 3.5 years of follow up. Physicians performed assessments at baseline, semiannually, and shortly after death of pain, agitation, shortness of breath, and treatment provided for these symptoms. SETTING: Long-term care facilities (28) in the Netherlands. PARTICIPANTS: Newly admitted nursing home residents (372) in variable stages of dementia. MEASUREMENTS: We described prevalence and course of symptoms, and treatment provided for these symptoms. We used generalized estimating equations to evaluate the longitudinal change in symptoms and their treatment, and the associations between the symptoms of pain and agitation, as well as between stage of dementia and symptoms. RESULTS: Pain was common (varying from 47% to 68% across the semiannual assessments) and frequently persistent (36%-41% of all residents); it increased to 78% in the last week of life. Agitation was the most common symptom (57%-71%), and also frequently persistent (39%-53%), yet it decreased to 35% in the last week of life. Shortness of breath was less common (16%-26%), but it increased to 52% at the end of life. Pain was not significantly associated with agitation. Advanced dementia was associated with more pain only. Treatment changed in particular at the end of life. Pain was treated mostly with acetaminophen (34%-52%), and at the end of life with parenteral opioids (44%). Agitation was mostly treated nonpharmacologically (78%-92%), and at the end of life anxiolytics were the most frequently prescribed treatment (62%). Overall, aerosolized bronchodilators were the most frequently prescribed treatment for shortness of breath (29%-67%), but at the end of life, this was morphine (69%). CONCLUSION: Pain and agitation were common and frequently persisted in residents with dementia during nursing home stay, but symptom management intensified only at the end of life. Symptom control may be suboptimal from admission, and a stronger focus on symptom control is needed at an earlier stage than the end of life. PMID- 25736823 TI - 10.5% efficient polymer and amorphous silicon hybrid tandem photovoltaic cell. AB - Thin-film solar cells made with amorphous silicon (a-Si:H) or organic semiconductors are considered as promising renewable energy sources due to their low manufacturing cost and light weight. However, the efficiency of single junction a-Si:H or organic solar cells is typically <10%, insufficient for achieving grid parity. Here we demonstrate an efficient double-junction photovoltaic cell by employing an a-Si:H film as a front sub-cell and a low band gap polymer:fullerene blend film as a back cell on planar glass substrates. Monolithic integration of 6.0% efficienct a-Si:H and 7.5% efficient polymer:fullerene blend solar cells results in a power conversion efficiency of 10.5%. Such high-efficiency thin-film tandem cells can be achieved by optical management and interface engineering of fully optimized high-performance front and back cells without sacrificing photovoltaic performance in both cells. PMID- 25736824 TI - Controllable fabrication and magnetic properties of double-shell cobalt oxides hollow particles. AB - Double-shell cobalt monoxide (CoO) hollow particles were successfully synthesized by a facile and effective one-pot solution-based synthetic route. The inner architecture and outer structure of the double-shell CoO hollow particles could be readily created through controlling experimental parameters. A possible formation mechanism was proposed based on the experimental results. The current synthetic strategy has good prospects for the future production of other transition-metal oxides particles with hollow interior. Furthermore, double-shell cobalt oxide (Co3O4) hollow particles could also be obtained through calcinating corresponding CoO hollow particles. The magnetic measurements revealed double shell CoO and Co3O4 hollow particles exhibit ferromagnetic and antiferromagnetic behaviour, respectively. PMID- 25736825 TI - Surgical repair of aorta-right atrial tunnel in an adult. PMID- 25736826 TI - Evolving practice: X-linked agammaglobulinemia and lung transplantation. AB - X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD). PMID- 25736827 TI - Analytical solution for the anisotropic Rabi model: effects of counter-rotating terms. AB - The anisotropic Rabi model, which was proposed recently, differs from the original Rabi model: the rotating and counter-rotating terms are governed by two different coupling constants. This feature allows us to vary the counter-rotating interaction independently and explore the effects of it on some quantum properties. In this paper, we eliminate the counter-rotating terms approximately and obtain the analytical energy spectrums and wavefunctions. These analytical results agree well with the numerical calculations in a wide range of the parameters including the ultrastrong coupling regime. In the weak counter rotating coupling limit we find out that the counter-rotating terms can be considered as the shifts to the parameters of the Jaynes-Cummings model. This modification shows the validness of the rotating-wave approximation on the assumption of near-resonance and relatively weak coupling. Moreover, the analytical expressions of several physics quantities are also derived, and the results show the break-down of the U(1)-symmetry and the deviation from the Jaynes-Cummings model. PMID- 25736828 TI - Feeding behavior and aggression in wild Siberut macaques (Macaca siberu) living under low predation risk. AB - Investigating which factors influence feeding competition is crucial for our understanding of the diversity of social relationships. Socio-ecological models differ in their predictions whether predation risk directly influences feeding competition and which factors exactly predict contest competition. We investigated feeding competition in Siberut macaques (Macaca siberu), a species endemic to Siberut Island (West Sumatra, Indonesia). Siberut macaques experience low predation risk, as major predators (felids, raptors) are absent. They are therefore appropriate subjects to test the prediction that low predation risk reduces feeding competition. To estimate contest potential, we quantified size, spatial distribution and density of food plants, and the availability of alternative resources. We recorded behavior in food patches using a modified focal tree method. Food patches, sorted by decreasing average feeding group size, included large trees (40% of focal plant observations), lianas/strangler (16%), medium trees (9%), small (palm) trees (20%), and rattan (15%). Most food patches were clumped but occurred at low densities relative to the area of average group spread. Thus, availability of alternative food patches was low. Although food patch characteristics indicate high contest potential, the observed aggression rate (0.13 bouts between adults/h) was low relative to other primates. Average feeding group size was small relative to total group size, and feeding group size matched crown volume. Perceived predation risk was low, based on spatial and feeding behavior of juveniles. Together, these results suggest that predation risk may influence feeding competition. Social and temporal factors (patch feeding time), but not ecological factors (fruit abundance in patch and forest, alternative resources) predicted aggression frequency in food patches. Overall, comparative data are still relatively scarce, and researchers should collect more data on group spread, sub-grouping, perceived predation risk, and aggression in food patches before we can draw final conclusions about the role of predation risk for feeding competition. PMID- 25736829 TI - The causes of falls: views of older people with visual impairment. AB - BACKGROUND: Sight impairment increases with age and, compared with the general older population, older people with sight impairment are more likely to fall. There is a growing body of evidence on the views and perceptions of older people about falls, but little is published on the views of older people with sight impairment. OBJECTIVE: To explore what older people with sight impairment believe to be the causes of falls. DESIGN: A qualitative design was used, incorporating focus groups and interviews in which participants discussed falls and falls prevention. Framework analysis was employed to identify themes arising from participants' discussions of the causes of falls. SETTING AND PARTICIPANTS: Fifty four community dwelling men and women with sight impairment, aged 65 and over, were recruited from across Greater Manchester, UK. RESULTS: Five types of factors were identified that were believed to cause falls: (i) health issues and changes in balance caused by ageing; (ii) cognitive and behavioural factors; (iii) the impact of sight impairment on getting around the home; (iv) the impact of sight impairment on negotiating the environment away from home; and (v) unexplained falls. DISCUSSION AND CONCLUSIONS: Older people with sight impairment reported many researched risk factors previously identified by older people without sight impairment but also described many perceived risks unique to people with sight impairment. There are few interventions to prevent falls aimed at older people with sight impairment, and the results of this study allow further tailoring of such interventions based on views of older people with sight impairment. PMID- 25736831 TI - Exploratory assessment of groundwater vulnerability to pollution in Abi, southeastern Nigeria, using geophysical and geological techniques. AB - The geophysical-based integrated electrical conductivity (IEC) and the groundwater hydraulic confinement-overlying strata-depth to water table (GOD) techniques were used to assess vulnerability levels of aquifers and the extent of aquifer protection in Abi, Nigeria. The IEC indices was generated from constrained one dimensional (1D) inversion of vertical electrical sounding (VES) and two dimensional (2D) electrical resistivity tomography (ERT) data, acquired randomly in the area. The GOD indices were sourced from existing geologic data within the area. Results showed that IEC values vary from <0.1 S in the weakly protected areas to >2.0 S in the strongly protected areas. The GOD indices vary from <0.3 in the lowly vulnerable areas to 0.6 in the highly vulnerable areas. Thus, the groundwater resources in the area need to be properly managed for sustainability and such management practices have been suggested. PMID- 25736830 TI - Estimation of toxic elements in the samples of different cigarettes and their effect on the essential elemental status in the biological samples of Irish smoker rheumatoid arthritis consumers. AB - Cigarette smoking interferes with the metal homeostasis of the human body, which plays a crucial role for maintaining the health. A significant flux of heavy metals, among other toxins, reaches the lungs through smoking. In the present study, the relationship between toxic element (TE) exposure via cigarette smoking and rheumatoid arthritis incidence in population living in Dublin, Ireland, is investigated. The trace {zinc (Zn), copper (Cu), manganese (Mn), and selenium (Se)} and toxic elements arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) were determined in biological (scalp hair and blood) samples of patients diagnosed with rheumatoid arthritis, who are smokers living in Dublin, Ireland. These results were compared with age- and sex-matched healthy, nonsmoker controls. The different brands of cigarette (filler tobacco, filter, and ash) consumed by the studied population were also analyzed for As, Cd, Hg, and Pb. The concentrations of trace and TEs in biological samples and different components of cigarette were measured by inductively coupled plasma mass spectrophotometer after microwave-assisted acid digestion. The validity and accuracy of the methodology were checked using certified reference materials. The recovery of all the studied elements was found to be in the range of 96.4-99.8% in certified reference materials. The filler tobacco of different branded cigarettes contains Hg, As, Cd, and Pb concentrations in the ranges of 9.55-12.4 ng, 0.432-0.727 MUg, 1.70-2.12 MUg, and 0.378-1.16 MUg/cigarette, respectively. The results of this study showed that the mean values of As, Cd, Hg, and Pb were significantly higher in scalp hair and blood samples of rheumatoid arthritis patients as compare to healthy controls, while Zn, Cu, Mn, and Se concentrations were found to be lower in rheumatoid arthritis patients, the difference was significant in the case of smoker patients (p<0.001). The levels of four toxic elements were 2-3-folds higher in scalp hair and blood samples of nonrheumatoid arthritis smoker subjects as compared to nonsmoker controls. The high exposure of toxic metals as a result of cigarette smoking may be synergistic with risk factors associated with rheumatoid arthritis. PMID- 25736832 TI - Robotic Nudges: The Ethics of Engineering a More Socially Just Human Being. AB - Robots are becoming an increasingly pervasive feature of our personal lives. As a result, there is growing importance placed on examining what constitutes appropriate behavior when they interact with human beings. In this paper, we discuss whether companion robots should be permitted to "nudge" their human users in the direction of being "more ethical". More specifically, we use Rawlsian principles of justice to illustrate how robots might nurture "socially just" tendencies in their human counterparts. Designing technological artifacts in such a way to influence human behavior is already well-established but merely because the practice is commonplace does not necessarily resolve the ethical issues associated with its implementation. PMID- 25736833 TI - Trophy hunters' willingness to pay for wildlife conservation and community benefits. AB - In the face of fundamental land-use changes, the potential for trophy hunting to contribute to conservation is increasingly recognized. Trophy hunting can, for example, provide economic incentives to protect wildlife populations and their habitat, but empirical studies on these relationships are few and tend to focus on the effects of benefit-sharing schemes from an ex post perspective. We investigated the conditions under which trophy hunting could facilitate wildlife conservation in Ethiopia ex ante. We used a choice experiment approach to survey international trophy hunters' (n = 224) preferences for trips to Ethiopia, here operationalized as trade-offs between different attributes of a hunting package, as expressed through choices with an associated willingness to pay. Participants expressed strong preferences and, consequently, were willing to pay substantial premiums for hunting trips to areas with abundant nontarget wildlife where domestic livestock was absent and for arrangements that offered benefit sharing with local communities. For example, within the range of percentages considered in the survey, respondents were on average willing to pay an additional $3900 for every 10 percentage points of the revenue being given to local communities. By contrast, respondents were less supportive of hunting revenue being retained by governmental bodies: Willingness to pay decreased by $1900 for every 10 percentage points of the revenue given to government. Hunters' preferences for such attributes of hunting trips differed depending on the degree to which they declared an interest in Ethiopian culture, nature conservation, or believed Ethiopia to be politically unstable. Overall, respondents thus expressly valued the outcomes of nature conservation activities--the presence of wildlife in hunting areas--and they were willing to pay for them. Our findings highlight the usefulness of insights from choice modeling for the design of wildlife management and conservation policies and suggest that trophy hunting in Ethiopia could generate substantially more financial support for conservation and be more in line with conservation objectives than is currently the case. PMID- 25736834 TI - Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety. AB - INTRODUCTION: Antidepressants (ADs) are widely used among elderly persons, making AD-related safety an important issue. AREAS COVERED: This review highlights safety considerations related to AD use including risks associated with inappropriate and off-label use. The age-related pharmacokinetic and pharmacodynamic changes underlying safety concerns connected to ADs are outlined. Drug-drug interactions as a cause of AD-related adverse drug reactions (ADRs) are also discussed. We reviewed scientific evidence concerning three important safety outcomes related to ADs in elderly persons: cardiac arrhythmias, hyponatraemia and falls/fractures. EXPERT OPINION: Several AD-related ADRs in elderly people are likely to be preventable. Current evidence suggests that selective serotonin re-uptake inhibitors (SSRIs) are best avoided particularly in persons with kidney disease due to the risk of hyponatraemia. The use of tricyclic antidepressants (TCAs) should be limited in the elderly due to anticholinergic adverse effects. TCAs should also be avoided in elderly persons at high risk of cardiovascular events due to a risk of cardiac arrhythmia. Emerging evidence suggests that SSRIs also have arrhythmogenic potential. Both TCAs and SSRIs should be used cautiously in elderly persons at risk of falls. Future research in this area should aim to investigate the lowest effective dose of AD possible, the relationship between AD dose and adverse effects, and which elderly subgroups are most prone to develop severe ADRs. PMID- 25736835 TI - Efficient, chemical-catalytic approach to the production of 3-hydroxypropanoic acid by oxidation of biomass-derived levulinic acid with hydrogen peroxide. AB - 3-Hydroxypropanoic acid (HPA), a precursor to acrylic acid, can be produced in high yield by oxidation of the biomass-derived platform chemical levulinic acid. While treatment of levulinic acid with H2 O2 under acidic conditions gives predominantly succinic acid, a remarkable reversal of selectivity is observed under basic conditions, leading either directly to HPA or, under modified conditions, initially to 3-(hydroperoxy)propanoic acid, which can be quantitatively hydrogenated to HPA. PMID- 25736836 TI - The molecular relationships between apoptosis, autophagy and necroptosis. AB - Cells are constantly subjected to a vast range of potentially lethal insults, which may activate specific molecular pathways that have evolved to kill the cell. Cell death pathways are defined partly by their morphology, and more specifically by the molecules that regulate and enact them. As these pathways become more thoroughly characterized, interesting molecular links between them have emerged, some still controversial and others hinting at the physiological and pathophysiological roles these death pathways play. We describe specific molecular programs controlling cell death, with a focus on some of the distinct features of the pathways and the molecular links between them. PMID- 25736838 TI - Coronal fistula repair under the glans without reoperative hypospadias glansplasty or urinary diversion. AB - BACKGROUND: Coronal fistulas present a potential dilemma in management. Successful closure requires reoperative glansplasty when there is only a thin band of tissue separating the urethral meatus from the fistula, indicating glans dehiscence. However, we avoided reoperative glansplasty during coronal fistula repair when the glans wings remained well-fused, given the increased risk for complications, including recurrent fistula, following reoperative glansplasty. PURPOSE: We report coronal fistula closure without reoperative glansplasty in patients with preserved fusion of the glans wings. We also compare this closure done with versus without postoperative urinary diversion. The primary outcome was recurrent fistula. MATERIALS: Consecutive patients with coronal fistula and no glans dehiscence (Figure) underwent repair by dissecting the fistula tract under the glans rather than re-opening the glans wings. A midline incision facilitated creation of a ventral dartos barrier flap, used in all cases, as well as selective skin revision when needed. Initial patients had postoperative urinary diversion, whereas later consecutive patients did not. Data was recorded prospectively at the time of service into a database. RESULTS: WS performed 122 fistula repairs from 2001 to 2013, of which 78 were coronal. Of these, 33 had glans dehiscence with only a thin band of skin separating the fistula from the distal meatus and underwent reoperative hypospadias repair. The other 45 met inclusion criteria with maintained glans wings fusion and had only fistula closure. These 45 patients all had fistulas 100 MUm, (4) multinuclearity, (5) syncytial morphology, (6) unusually large cytoplasmic projections, and (7) apparent haemophagocytosis. RESULTS: All analysed patients showed 22-40% GCs with atypical cytomorphology (median 29%). The median number of atypical features of GCs was 10 per patient (range 6-13). Multinuclearity was the most common atypical feature of GCs, followed by erythrophagocytosis and foamy cytoplasm. There was a strong positive correlation between erythrophagocytosis and foamy cytoplasm in GCs (Spearman's rank correlation coefficient: 0.9). Although majority of atypical GCs had one atypical feature, there was a considerable amount of GCs presenting >= 2 atypical features. CONCLUSIONS: Untreated patients with GD1 often show a considerable proportion of GCs with atypical cytomorphology. The knowledge of possible atypical variant forms of GCs can contribute to a quicker and accurate diagnosis of GD, and minimize the risk for misdiagnosis. To the best of our knowledge, this is the first published report on atypical cytomorphology of GCs in untreated patients with GD1. PMID- 25736846 TI - Two-step spin transition in a 1D Fe(II) 1,2,4-triazole chain compound. AB - A thermochromic 1D spin crossover coordination (SCO) polymer [Fe(betaAlatrz)3](BF4)2?2 H2O (1?2 H2O), whose precursor betaAlatrz, (1,2,4 triazol-4-yl-propionate) has been tailored from a beta-amino acid ester is investigated in detail by a set of superconducting quantum interference device (SQUID), (57)Fe Mossbauer, differential scanning calorimetry, infrared, and Raman measurements. An hysteretic abrupt two-step spin crossover (T1/2(?) = 230 K and T1/2(?) = 235 K, and T1/2(?) = 172 K and T1/2(?) = 188 K, respectively) is registered for the first time for a 1,2,4-triazole-based Fe(II) 1D coordination polymer. The two-step SCO configuration is observed in a 1:2 ratio of low spin/high-spin in the intermediate phase for a 1D chain. The origin of the stepwise transition was attributed to a distribution of chains of different lengths in 1?2 H2O after First Order Reversal Curves (FORC) analyses. A detailed DFT analysis allowed us to propose the normal mode assignment of the Raman peaks in the low-spin and high-spin states of 1?2 H2O. Vibrational spectra of 1?2 H2O reveal that the BF4(-) anions and water molecules play no significant role on the vibrational properties of the [Fe(betaAlatrz)3](2+) polymeric chains, although non-coordinated water molecules have a dramatic influence on the emergence of a step in the spin transition curve. The dehydrated material [Fe(betaAlatrz)3](BF4)2 (1) reveals indeed a significantly different magnetic behavior with a one-step SCO which was also investigated. PMID- 25736848 TI - Re: High-intensity focused ultrasound applied to the placenta using a toroidal transducer: a preliminary ex-vivo study. J. Caloone, C. Huissoud, J. Vincenot, A. Kocot, C. Dehay, J. Y. Chapelon, R. C. Rudigoz and D. Melodelima. Ultrasound Obstet Gynecol 2015; 45: 313-319. PMID- 25736847 TI - Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre eclampsia in singleton pregnancy: implications for clinical practice. PMID- 25736849 TI - Re: Single fetal demise in monochorionic pregnancies: incidence and patterns of cerebral injury. J. M. M. van Klink, A. van Steenis, S. J. Steggerda, L. Genova, M. Sueters, D. Oepkes and E. Lopriore. Ultrasound Obstet Gynecol 2015; 45: 294 300. PMID- 25736850 TI - Re: Prenatal diagnosis of isolated butterfly vertebra. PMID- 25736851 TI - Reply: To PMID 25044258. PMID- 25736852 TI - Innovative ultrasound techniques for diagnosis of deep pelvic endometriosis: more confusion or a possible solution to the dilemma? PMID- 25736853 TI - Reply: New ultrasound technologies to classify deep pelvic endometriosis. PMID- 25736854 TI - High-mobility group box 1-mediated heat shock protein beta 1 expression attenuates mitochondrial dysfunction and apoptosis. AB - AIMS: Apoptosis of cardiomyocytes is thought to account for doxorubicin cardiotoxicity as it contributes to loss of myocardial tissue and contractile dysfunction. Given that high-mobility group box 1 (HMGB1) is a nuclear DNA binding protein capable of inhibiting apoptosis, we aimed to clarify the role of HMGB1 in heat shock protein beta 1 (HSPB1) expression during doxorubicin-induced cardiomyopathy. METHODS AND RESULTS: Mitochondrial damage, cardiomyocyte apoptosis, and cardiac dysfunction after doxorubicin administration were significantly attenuated in mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) compared with wild type (WT) -mice. HSPB1 levels after doxorubicin administration were significantly higher in HMGB1-Tg mice than in WT mice. Transfection with HMGB1 increased the expression of HSPB1 at both the protein and mRNA levels, and HMGB1 inhibited mitochondrial dysfunction and apoptosis after exposure of cardiomyocytes to doxorubicin. HSPB1 silencing abrogated the inhibitory effect of HMGB1 on cardiomyocyte apoptosis. Doxorubicin increased the binding of HMGB1 to heat shock factor 2 and enhanced heat shock element promoter activity. Moreover, HMGB1 overexpression greatly enhanced heat shock element promoter activity. Silencing of heat shock factor 2 attenuated HMGB1-dependent HSPB1 expression and abrogated the ability of HMGB1 to suppress cleaved caspase-3 accumulation after doxorubicin stimulation. CONCLUSIONS: We report the first in vivo and in vitro evidence that cardiac HMGB1 increases HSPB1 expression and attenuates cardiomyocyte apoptosis associated with doxorubicin-induced cardiomyopathy. Cardiac HMGB1 increases HSPB1 expression in cardiomyocytes in a heat shock factor 2-dependent manner. PMID- 25736855 TI - Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100. AB - Natriuretic peptide receptor 3 (NPR3) is the clearance receptor for the cardiac natriuretic peptides (NPs). By modulating the level of NPs, NPR3 plays an important role in cardiovascular homeostasis. Although the physiological functions of NPR3 have been explored, little is known about its regulation in health or disease. MicroRNAs play an essential role in the post-transcriptional expression of many genes. Our aim was to investigate potential microRNA-based regulation of NPR3 in multiple models. Hypoxic challenge elevated levels of NPPB and ADM mRNA, as well as NT-proBNP and MR-proADM in human left ventricle derived cardiac cells (HCMa), and in the corresponding conditioned medium, as revealed by qRT-PCR and ELISA. NPR3 was decreased while NPR1 was increased by hypoxia at mRNA and protein levels in HCMa. Down-regulation of NPR3 mRNA was also observed in infarct and peri-infarct cardiac tissue from rats undergoing myocardial infarction. From microRNA microarray analyses and microRNA target predictive databases, miR-100 was selected as a candidate regulator of NPR3 expression. Further analyses confirmed up-regulation of miR-100 in hypoxic cells and associated conditioned media. Antagomir-based silencing of miR-100 enhanced NPR3 expression in HCMa. Furthermore, miR-100 levels were markedly up-regulated in rat hearts and in peripheral blood after myocardial infarction and in the blood from heart failure patients. Results from this study point to a role for miR-100 in the regulation of NPR3 expression, and suggest a possible therapeutic target for modulation of NP bioactivity in heart disease. PMID- 25736856 TI - Somatosensory temporal discrimination in essential tremor and isolated head and voice tremors. AB - The aim of this study was to investigate the somatosensory temporal discrimination threshold in patients with essential tremor (sporadic and familial) and to evaluate whether somatosensory temporal discrimination threshold values differ depending on the body parts involved by tremor. We also investigated the somatosensory temporal discrimination in patients with isolated voice tremor. We enrolled 61 patients with tremor: 48 patients with essential tremor (31 patients with upper limb tremor alone, nine patients with head tremor alone, and eight patients with upper limb plus head tremor; 22 patients with familial vs. 26 sporadic essential tremor), 13 patients with isolated voice tremor, and 45 healthy subjects. Somatosensory temporal discrimination threshold values were normal in patients with familial essential tremor, whereas they were higher in patients with sporadic essential tremor. When we classified patients according to tremor distribution, somatosensory temporal discrimination threshold values were normal in patients with upper limb tremor and abnormal only in patients with isolated head tremor. Temporal discrimination threshold values were also abnormal in patients with isolated voice tremor. Somatosensory temporal discrimination processing is normal in patients with familial as well as in patients with sporadic essential tremor involving the upper limbs. By contrast, somatosensory temporal discrimination is altered in patients with isolated head tremor and voice tremor. This study with somatosensory temporal discrimination suggests that isolated head and voice tremors might possibly be considered as separate clinical entities from essential tremor. PMID- 25736857 TI - A Heuristic Automatic and Robust ROI Detection Method for Medical Image Warermarking. AB - This paper presents an automatic region of interest (ROI) segmentation method for application of watermarking in medical images. The advantage of using this scheme is that the proposed method is robust against different attacks such as median, Wiener, Gaussian, and sharpening filters. In other words, this technique can produce the same result for the ROI before and after these attacks. The proposed algorithm consists of three main parts; suggesting an automatic ROI detection system, evaluating the robustness of the proposed system against numerous attacks, and finally recommending an enhancement part to increase the strength of the composed system against different attacks. Results obtained from the proposed method demonstrated the promising performance of the method. PMID- 25736858 TI - The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics. AB - Dietary oxysterols are cholesterol auto-oxidation products widely present in cholesterol-rich foods. They are thought to affect the intestinal barrier function, playing a role in gut inflammation. This study has characterized specific cell signals that are up-regulated in differentiated CaCo-2 colonic epithelial cells by a mixture of oxysterols representative of a hyper cholesterolemic diet. p38 MAPK activation plays a major role, while other signal branches, i.e. the JNK and ERK pathways, make minor contributions to the intestinal inflammation induced by dietary oxysterols. p38 transduction might be the missing link connecting the known NADPH oxidase activation, and the induction of NF-kappaB-dependent inflammatory events related to oxysterols' action in the intestine. A NOX1/p38 MAPK/NF-kappaB signaling axis was demonstrated by the quenched inflammation observed on blocking individual branches of this signal with specific chemical inhibitors. Furthermore, all these signaling sites were prevented when CaCo-2 cells were pre-incubated with phenolic compounds extracted from selected wines made of typical Sardinian grape varieties: red Cannonau and white Vermentino. Notably, Cannonau was more effective than Vermentino. The effect of Sardinian wine extracts on intestinal inflammation induced by dietary oxysterols might mainly be due to their phenolic content, more abundant in Cannonau than in Vermentino. Furthermore, among different phenolic components of both wines, epicatechin and caffeic acid exerted the strongest effects. These findings show a major role of the NOX1/p38 MAPK/NF-kappaB signaling axis in the activation of oxysterol-dependent intestinal inflammation, and confirm the concept that phenolics act as modulators at different sites of pro-oxidant and pro-inflammatory cell signals. PMID- 25736860 TI - Lifestyle factors and small intestine adenocarcinoma risk: A systematic review and meta-analysis. AB - BACKGROUND: Although the incidence of small intestinal adenocarcinoma (SIA) is low, rates are increasing and little information regarding modifiable lifestyle risk factors is available. AIM: To provide a systematic review of lifestyle factors and SIA risk. METHODS: Ovid MEDLINE, EMBASE and Web of science were searched from inception to week 1 October 2013. Nine publications that reported on SIA risk in relation to alcohol intake (n=6), tobacco smoking (n=6), diet (n=5), body mass (n=3), physical activity (n=1), hormone use (n=1) and/or socio economic status (n=3) were retrieved. Results for alcohol, smoking and SIA risk were pooled using random-effects meta-analyses to produce relative risks (RR) and 95% confidence intervals (CI). RESULTS: The summary RR for individuals consuming the highest versus lowest category of alcohol intake was 1.51 (95% CI 0.83-2.75; n=5 studies) with significant increased risks emerging in sensitivity analysis with reduced heterogeneity (RR: 1.82, 95% CI: 1.05-3.15; n=4 studies). The pooled SIA RR for individuals in the highest versus lowest category of smoking was 1.24 (95% CI 0.71-2.17; n=5 studies). In relation to dietary factors, high fibre intakes and normal body weight may be protective, while high intakes of red/processed meat and sugary drinks may increase SIA risk. Evidence on socio economic status and SIA risk was equivocal. Data on other factors were too sparse to draw any conclusions. CONCLUSIONS: Alcohol may be associated with an increased risk of SIA. Further investigation of lifestyle factors, particularly alcohol, smoking and diet, in the aetiology of this cancer is warranted in large consortial studies. PMID- 25736861 TI - Detection in and circulation of Bluetongue virus among domestic ruminants in Madagascar. AB - So far, no published data was available concerning the circulation of Bluetongue virus (BTV) in Madagascar. During a survey on Rift Valley Fever, we were able to detect a virus belonging to BTV. Therefore, we conducted a study aiming at characterizing molecularly the BTV isolated and assess the importance of circulation of BTV in Madagascar. A total of 4393 sera from ruminants selected randomly by stratification and sampled in 30 districts of Madagascar were tested for BTV. Moreover, 175 cattle were followed during 11 months. Phylogenetic analyses were performed from virus isolated from unfed pools of mosquitoes. Overall, the estimated mean seroprevalence of infection at the national level was 95.9% (95% CI: [95.2-96.5]) in cattle and 83.7% (95% CI: [81.4-85.9]) in small ruminants. Estimation of incidence rate was 54 per 100 cattle-years assuming that the incidence rate is constant all year along. Phylogenetic analyses revealed that BTV detected belong to serotype 2. In conclusion, our results showed that BTV is endemic in Madagascar and highly prevalent among cattle. In our study we did not work on the vector involved in transmission of BTV in cattle. Thus, research should be conducted to better describe epidemiology of BTV in Madagascar including vectors and assess economic impact of the disease associated to BTV infections. PMID- 25736862 TI - GWIPS-viz as a tool for exploring ribosome profiling evidence supporting the synthesis of alternative proteoforms. AB - The boundaries of protein coding sequences are more difficult to define at the 5' end than at the 3' end due to potential multiple translation initiation sites (TISs). Even in the presence of phylogenetic data, the use of sequence information only may not be sufficient for the accurate identification of TISs. Traditional proteomics approaches may also fail because the N-termini of newly synthesized proteins are often processed. Thus ribosome profiling (ribo-seq), producing a snapshot of the ribosome distribution across the entire transcriptome, is an attractive experimental technique for the purpose of TIS location exploration. The GWIPS-viz (Genome Wide Information on Protein Synthesis visualized) browser (http://gwips.ucc.ie) provides free access to the genomic alignments of ribo-seq data and corresponding mRNA-seq data along with relevant annotation tracks. In this brief, we illustrate how GWIPS-viz can be used to explore the ribosome occupancy at the 5' ends of protein coding genes to assess the activity of AUG and non-AUG TISs responsible for the synthesis of proteoforms with alternative or heterogeneous N-termini. The presence of ribo-seq tracks for various organisms allows for cross-species comparison of orthologous genes and the availability of datasets from multiple laboratories permits the assessment of the technical reproducibility of the ribosome densities. PMID- 25736863 TI - Phenotypic analysis of familial breast cancer: comparison of BRCAx tumors with BRCA1-, BRCA2-carriers and non-familial breast cancer. AB - AIMS: Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetime. However, only about 20% of familial breast cancer is attributed to mutations in BRCA1 and BRCA2, while a further 5-10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. We aim to analyze the pathology of familial cases of which no pathogenic mutation is yet identified. METHODS: We compared the pathological phenotype of BRCA1/BRCA2 negative familial breast cancer (BRCAx) to BRCA1-positive, BRCA2-positive and sporadic cases without a family history. Age-adjusted analysis is summarized in odd's ratios and confidence intervals for tumor type, grade, lymph node, ER and HER2 status. RESULTS: We found non-familial cases to be more likely to be ER positive (P = 0.041) as compared with BRCAx tumors. More cases of lobular carcinoma were found with BRCAx as compared to BRCA1 tumors (P = 0.05). After multivariate logistic regression analysis, BRCAx tumors are more likely ER positive (P = 0.001) and HER2 positive (P = 0.047) in comparison to BRCA1. Conversely, BRCAx cases are less likely to be ER positive (P = 0.02) but more likely to be HER2 positive (P = 0.021) as compared with BRCA2 tumors. CONCLUSION: Our findings suggest that BRCA1, BRCA2 and BRCAx tumors differ in phenotype from non-familial and familial BRCA1-positive and BRCA2-positive tumors. Further studies will need to be performed in this important population in order to develop strategies for early detection and prevention. PMID- 25736864 TI - Population dynamics of cyanomyovirus in a tropical eutrophic reservoir. AB - Samples from three stations in Kranji Reservoir, Singapore (n = 21) were collected and analyzed for cyanomyovirus abundance and diversity. A total of 73 different g20 (viral capsid assembly protein genes) amino acid sequences were obtained from this study. A phylogenetic analysis revealed that the 73 segments were distributed in six major clusters (alpha to zeta), with four unique subclusters, which were identified as KRM-I, KRM-II, KRM-III, and KRM-IV. The cyanophage community in Kranji Reservoir exhibited a large degree of diversity; the clones obtained in this study showed similarities to those from many different environments, including oceans, lakes, bays, and paddy floodwater, as well as clones from paddy field soils. However, the sequences in this study were generally found to be more closely related to the g20 sequences of freshwaters and brackish waters than those from marine environments. The rarefaction curves and Chao 1 indices from this study showed that the diversity of the cyanomyovirus community was greater during the Inter-monsoon periods than the Southwest and Northeast Monsoons. A few seasonal changes in the taxa were observed: (i) Cluster zeta was absent during the Southwest Monsoon, and (ii) most of the samples fell into Group 3 in the PCA score plot during the Northeast Monsoon, and the fraction of Cluster E increased significantly. PMID- 25736865 TI - Insecticide-degrading Burkholderia symbionts of the stinkbug naturally occupy various environments of sugarcane fields in a Southeast island of Japan. AB - The stinkbug Cavelerius saccharivorus, which harbors Burkholderia species capable of degrading the organophosphorus insecticide, fenitrothion, has been identified on a Japanese island in farmers' sugarcane fields that have been exposed to fenitrothion. A clearer understanding of the ecology of the symbiotic fenitrothion degraders of Burkholderia species in a free-living environment is vital for advancing our knowledge on the establishment of degrader-stinkbug symbiosis. In the present study, we analyzed the composition and abundance of degraders in sugarcane fields on the island. Degraders were recovered from field samples without an enrichment culture procedure. Degrader densities in the furrow soil in fields varied due to differences in insecticide treatment histories. Over 99% of the 659 isolated degraders belonged to the genus Burkholderia. The strains related to the stinkbug symbiotic group predominated among the degraders, indicating a selection for this group in response to fenitrothion. Degraders were also isolated from sugarcane stems, leaves, and rhizosphere in fields that were continuously exposed to fenitrothion. Their density was lower in the plant sections than in the rhizosphere. A phylogenetic analysis of 16S rRNA gene sequences demonstrated that most of the degraders from the plants and rhizosphere clustered with the stinkbug symbiotic group, and some were identical to the midgut symbionts of C. saccharivorus collected from the same field. Our results confirmed that plants and the rhizosphere constituted environmental reservoirs for stinkbug symbiotic degraders. To the best of our knowledge, this is the first study to investigate the composition and abundance of the symbiotic fenitrothion degraders of Burkholderia species in farmers' fields. PMID- 25736866 TI - Environmental factors shaping the community structure of ammonia-oxidizing bacteria and archaea in sugarcane field soil. AB - The effects of environmental factors such as pH and nutrient content on the ecology of ammonia-oxidizing bacteria (AOB) and archaea (AOA) in soil has been extensively studied using experimental fields. However, how these environmental factors intricately influence the community structure of AOB and AOA in soil from farmers' fields is unclear. In the present study, the abundance and diversity of AOB and AOA in soils collected from farmers' sugarcane fields were investigated using quantitative PCR and barcoded pyrosequencing targeting the ammonia monooxygenase alpha subunit (amoA) gene. The abundances of AOB and AOA amoA genes were estimated to be in the range of 1.8 * 10(5)-9.2 * 10(6) and 1.7 * 10(6)-5.3 * 10(7) gene copies g dry soil(-1), respectively. The abundance of both AOB and AOA positively correlated with the potential nitrification rate. The dominant sequence reads of AOB and AOA were placed in Nitrosospira-related and Nitrososphaera-related clusters in all soils, respectively, which varied at the level of their sub-clusters in each soil. The relationship between these ammonia oxidizing community structures and soil pH was shown to be significant by the Mantel test. The relative abundances of the OTU1 of Nitrosospira cluster 3 and Nitrososphaera subcluster 7.1 negatively correlated with soil pH. These results indicated that soil pH was the most important factor shaping the AOB and AOA community structures, and that certain subclusters of AOB and AOA adapted to and dominated the acidic soil of agricultural sugarcane fields. PMID- 25736867 TI - Childhood adversities and adult-onset chronic pain: Results from the World Mental Health Survey, Japan. AB - BACKGROUND: Childhood adversities (CAs) have been associated with adult-onset chronic pain. However, to date, most single country studies on this association have been undertaken in Western countries. This study examined the association in Japan where information is scarce. METHODS: Data were drawn from the World Mental Health Survey Japan, a population-based cross-sectional survey undertaken in 11 areas of Japan in 2002-2006. We analyzed data from adults aged >=20 years who provided information on CAs occurring before age 18 years and chronic pain (n = 1740). Cox proportional hazard models were used to estimate the risk for different forms of adult-onset chronic pain (arthritis/rheumatism, neck/back pain, headache and any pain) as a function of the presence of 11 different types of CA and the number of CAs. RESULTS: In the adjusted models, significant associations were observed between: physical abuse and neck/back pain (HR 2.55) and any pain (HR 1.88); sexual abuse and any pain (HR 2.84). Significant dose dependent relationships were also observed between a greater number of CAs and some adult-onset chronic pain conditions (neck/back and any pain). CONCLUSIONS: The results of this study suggest that in Japan, some forms of CA may be associated with certain types of adult-onset chronic pain, in particular neck/back pain. PMID- 25736869 TI - Molecular responses in the telomere-mitochondrial axis of ageing in the elderly: a candidate gene approach. AB - Experimental evidence shows that telomere shortening induces mitochondrial damage but so far studies in humans are scarce. Here, we investigated the association between leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in elderly and explored possible intermediate mechanisms by determining the gene expression profile of candidate genes in the telomere-mitochondrial axis of ageing. Among 166 non-smoking elderly, LTL, leukocyte mtDNA content and expression of candidate genes: sirtuin1 (SIRT1), tumor protein p53 (TP53), peroxisome proliferator-activated receptor gamma-coactivator1alpha (PGC-1alpha), peroxisome proliferator-activated receptor gamma-coactivator1beta (PGC-1beta), nuclear respiratory factor 1 (NRF1) and nuclear factor, erythroid 2 like 2 (NRF2), using a quantitave real time polymerase chain assay (qPCR). Statistical mediation analysis was used to study intermediate mechanisms of the telomere mitochondrial axis of ageing. LTL correlated with leukocyte mtDNA content in our studied elderly (r = 0.23, p = 0.0047). SIRT1 gene expression correlated positively with LTL (r = 0.26, p = 0.0094) and leukocyte mtDNA content (r = 0.43, p < 0.0001). The other studied candidates showed significant correlations in the telomere-mitochondrial interactome but not independent from SIRT1. SIRT1 gene expression was estimated to mediate 40% of the positive association between LTL and leukocyte mtDNA content. The key finding of our study was that SIRT1 expression plays a pivotal role in the telomere-mitochondrial interactome. PMID- 25736868 TI - Keratin 17 is co-expressed with 14-3-3 sigma in oral carcinoma in situ and squamous cell carcinoma and modulates cell proliferation and size but not cell migration. AB - Expression of keratin (K) 13 is replaced with that of K17 when squamous cells of the oral mucosa transform from normal and dysplastic epithelia to carcinoma in situ (CIS) and squamous cell carcinoma (SCC). Since 14-3-3 sigma is functionally associated with K17, we examined possible relationships between expression of K17 and 14-3-3 sigma in oral CIS and SCC tissues by immunohistochemistry. We furthermore examined whether or not K17 expression or knockdown by small interfering RNA (siRNA) modulates the behavior of SCC cells in culture in terms of cell proliferation and migration. In tissue specimens of oral SCC and CIS, the pattern of cytoplasmic expression of 14-3-3 sigma and K17 was similar but neither was expressed in normal or dysplastic epithelia. Both proteins were demonstrated in the cytoplasm of control oral SCC ZK-1 cells, but expression of 14-3-3 sigma changed from cytoplasmic to nuclear upon knockdown of K17. In carcinoma cells, therefore, cytoplasmic localization of 14-3-3 sigma seems to accompany expression of K17. In K17-knockdown cells, proliferation was significantly suppressed at 4 days after seeding. In addition, the cell size of K17-knockdown cells was significantly smaller than that of control cells; as a result of which in the migration experiments, we found delayed closure of scratch wounds but migration as such was not affected. We conclude that K17 expression promotes SCC cell growth and cell size but does not affect cell migration. K17 expression is accompanied by cytoplasmic expression of 14-3-3 sigma, indicative of their functional relationship. PMID- 25736870 TI - Neonatal liver abscesses due to Candida infection in a preterm infant, secondary to malpositioned umbilical lines--a rare entity. AB - Neonatal liver abscess is an uncommon seen condition in neonatology and it holds a very high neonatal mortality because of difficulty in diagnosis and treatment. Till today, only few instances are reported that too are mainly in preterm. Its diagnosis requires a high index of suspicion. Fungal hepatic abscess is very rare and in medical literature very few case reports are there in the medical literature. Here, we report a case of Candida albicans liver abscess in a preterm neonate, secondary to malpositioned umbilical lines that presented with respiratory difficulty and other clinical features of sepsis that was managed medically and discharged successfully. PMID- 25736871 TI - MicroRNA in intervertebral disc degeneration. AB - Aetiology of intervertebral disc degeneration (IDD) is complex, with genetic, developmental, biochemical and biomechanical factors contributing to the disease process. It is becoming obvious that epigenetic processes influence evolution of IDD as strongly as the genetic background. Deregulated phenotypes of nucleus pulposus cells, including differentiation, migration, proliferation and apoptosis, are involved in all stages of progression of human IDD. Non-coding RNAs, including microRNAs, have recently been recognized as important regulators of gene expression. Research into roles of microRNAs in IDD has been very active over the past 5 years. Our review summarizes current research enlightenment towards understanding roles of microRNAs in regulating nucleus pulposus cell functions in IDD. These exciting findings support the notion that specific modulation of microRNAs may represent an attractive approach for management of IDD. PMID- 25736872 TI - Preface. PMID- 25736873 TI - Foreword. PMID- 25736874 TI - Metabolic profiling in Prader-Willi syndrome and nonsyndromic obesity: sex differences and the role of growth hormone. AB - OBJECTIVES: To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. METHODS: We compared amino acids, fatty acids and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated with ghrelin, peptide YY and markers of insulin sensitivity (adiponectin and HOMA-IR). RESULTS: Compared with obese controls (OC), children with PWS had fasting hyperghrelinaemia, hyperadiponectinaemia, hypoinsulinaemia and increased ghrelin/PYY. Hyperghrelinaemia, hyperadiponectinaemia and hypoinsulinaemia were more striking in PWS females than males, and decreases in BCAA were detected only in PWS females. GH-treated PWS subjects had lower leptin and higher IGF-1 and adiponectin than untreated subjects; fasting ghrelin, PYY and insulin levels were comparable. Ghrelin correlated inversely with BCAA in PWS but not OC. Adiponectin correlated negatively with BMIz and HOMA-IR in PWS; in contrast, adiponectin correlated more strongly with BCAA than BMIz or HOMA-IR in OC. CONCLUSIONS: BCAA levels were lower in PWS females than OC females and correlated inversely with ghrelin. Low BCAA in PWS females may promote hyperghrelinaemia and hyperphagia, while hyperadiponectinaemia may maintain insulin sensitivity despite excess weight gain. GH treatment may reduce leptin and increase adiponectin, but does not affect fasting ghrelin or PYY. PMID- 25736875 TI - Effect of fermentation and subsequent pasteurization processes on amino acids composition of orange juice. AB - The fermentation of fruit produces significant changes in their nutritional composition. An orange beverage has been obtained from the controlled alcoholic fermentation and thermal pasteurization of orange juice. A study was performed to determine the influence of both processes on its amino acid profile. UHPLC-QqQ MS/MS was used for the first time for analysis of orange juice samples. Out of 29 amino acids and derivatives identified, eight (ethanolamine, ornithine, phosphoethanolamine, alpha-amino-n-butyric acid, hydroxyproline, methylhistidine, citrulline, and cystathionine) have not previously been detected in orange juice. The amino acid profile of the orange juice was not modified by its processing, but total amino acid content of the juice (8194 mg/L) was significantly increased at 9 days of fermentation (13,324 mg/L). Although the pasteurization process produced partial amino acid degradation, the total amino acid content was higher in the final product (9265 mg/L) than in the original juice, enhancing its nutritional value. PMID- 25736876 TI - Inhibition of platelet function with clopidogrel, as measured with a novel whole blood impedance aggregometer in horses. AB - This study aimed to validate a loading and maintenance clopidogrel dosing scheme for the inhibition of platelet function, measured by whole blood impedance aggregometry in healthy adult horses. Ten Warmblood horses received oral clopidogrel once daily. Doses were based on 50 kg weight categories and resulted in one loading dose of 6-6.5 mg/kg bodyweight and maintenance doses of 1.2-1.4 mg/kg over the next 4 days. Platelet function was measured via whole blood multiple electrode impedance aggregometry prior to (T0) and at 6, 12, 24, 48, 72, 96, 144, 192 and 240 h following the loading dose. Aggregometries for collagen (COLtest), arachidonic acid (ASPItest), adenosine diphosphate (ADPtest) and ADP with prostaglandin E1 (ADPtestHS) were performed. Statistical analyses included one way repeated measures ANOVAs and subsequent Dunnett's tests. Platelet aggregation induced by collagen remained unchanged. There were significant inhibitions in the ASPItest (P <0.01 at 192 h, and P <0.05 at 240 h) and the ADPtest and ADPtestHS (P < 0.01, with the exception of 240 h). The loading dose of clopidogrel induced rapid inhibition of platelet function within hours, and the low dose was suitable for maintaining the inhibition over the 4 days of therapy. Recovery of platelet function was restored 6 days after the cessation of medication, determined with the ADPtest and ADPtestHS, but remained inhibited with the ASPItest. The prolonged effect of clopidogrel may indicate differences in the activation of platelets between horses and humans that were previously unknown. PMID- 25736878 TI - High magnetic hardness for the canted antiferromagnetic, ferroelectric, and ferroelastic layered perovskite-like (C2H5NH3)2[Fe(II)Cl4]. AB - An unusual high magnetic hardness for the layered perovskite-like (C2H5NH3)2[Fe(II)Cl4], in addition to its already found canted antiferromagnetism, ferroelasticity, and ferroelectricity, which are absent for (CH3NH3)2[Fe(II)Cl4], has been observed. The additional CH2 in the ethylammonium compared to methylammonium allows more degrees of freedom and therefore numerous phase transitions which have been characterized by single-crystal structure determinations from 383 to 10 K giving the sequence from tetragonal to orthorhombic to monoclinic (I4/mmm <-> P42/ncm <-> Pccn <-> Pcab <-> C2/c) accompanied by both tilting and rotation of the FeCl6 octahedra. The magnetic properties on single crystal and powder samples at high temperature are similar for both compounds, but at TN (C2H5NH3)2[Fe(II)Cl4] is a proper canted antiferromagnet unlike the hidden canting observed for (CH3NH3)2[Fe(II)Cl4]. The canting angle is 0.6 degrees toward the c-axis, and thus the moments lie in the easy plane of the iron-chloride layer defined by a critical exponent beta = 0.18. The isothermal magnetizations for the field along the three orthogonal crystallographic axes show wider hysteresis for H ? c and is present at all temperature below 98 K. The coercive field increases as the temperature is lowered, and at T < 20 K it is difficult to reverse all the moments with the available 50 kOe of the SQUID for both single crystal and powder samples. The shape of the virgin magnetization after zero-field-cool (ZFC) indicates that the high coercive field is due to domain wall pinning. Thus, there are unusual associated anomalies such as asymmetric hysteresis and history dependence. The difference in magnetic hardness of the two compounds suggests that magnetic, electric, and elastic domains are intricately manifested and therefore raise the key question of how the different domains interact. PMID- 25736877 TI - Protocadherin20 Acts as a Tumor Suppressor Gene: Epigenetic Inactivation in Nasopharyngeal Carcinoma. AB - Genetic alterations of 13q21 (PCDH 8,9,17, and 20) are frequently observed in multiple tumors, suggesting the presence of critical tumor suppressor genes (TSGs). Protocadherin20 (PCDH20), located at 13q21.2, belongs to the delta1 protocadherins, which constitutes one of the largest subgroup within the adherin superfamily. Frequent downregulation/silencing of PCDH20 was found in NPC cell lines using semiquantitative PCR. PCDH20 mRNA was broadly expressed in normal nasopharyngeal tissues and cell lines. Promoter methylation of PCDH20 was observed in 80% (4/5) of NPC cell lines and 78.4% (40 of 51) of primary tumors by methylation-specific PCR, but rarely in normal nasopharygeal tissues and nasopharyngeal epithelial cell line (NP69). The silencing of PCDH20 can be reversed by pharmacological demethylation, indicating an epigenetic mechanism. Restoration of PCDH20 expression in NPC cells strongly suppressed cell numbers and colony formation. Overexpression of PCDH20 antagonized Wnt/beta-catenin signaling pathway and promoted beta-catenin to translocate from nucleus to cytoplasm and membrane. PCDH20 significantly inhibited the migration and invasion ability of NPC cells. PCDH20 also inhibited epithelial-mesenchymal transition (EMT) through enhanced expression of E-cadherin. Our study identified PCDH20 as a functional tumor suppressor and an important antagonist of Wnt/beta-catenin signaling and EMT, with frequent epigenetic inactivation in NPC. PMID- 25736879 TI - MR imaging of arrhythmogenic right ventricular dysplasia: What the radiologist needs to know. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart muscle disease that predominantly affects the right ventricle. Clinical manifestations are related to severe ventricular arrhythmia that may lead to sudden death, mostly in young patients. Magnetic resonance imaging (MRI), included in the new diagnostic criteria since 2010, aims to detect segmental and global wall motion abnormalities, reduced ejection fraction, right ventricular dilatation and right ventricular diastolic/systolic dysfunction. An MRI assessment of the right ventricle is often challenging, partly because the MRI diagnostic criteria have some limitations, and also because it requires a significant learning curve due to the low prevalence of the disease. Therefore, this article aims to review the pathophysiology of the disease, the cardiac MRI protocol, images of the various stages of this affection as well as the differential diagnosis. PMID- 25736880 TI - Convergent adaptation in the dominant global hospital clone ST239 of methicillin resistant Staphylococcus aureus. AB - Infections caused by highly successful clones of hospital-associated methicillin resistant Staphylococcus aureus (HA-MRSA) are a major public health burden. The globally dominant sequence type 239 (ST239) HA-MRSA clone has persisted in the health care setting for decades, but the basis of its success has not been identified. Taking a collection of 123 ST239 isolates spanning 32 years, we have used population-based functional genomics to investigate the evolution of this highly persistent and successful clone. Phylogenetic reconstruction and population modeling uncovered a previously unrecognized distinct clade of ST239 that was introduced into Australia from Asia and has perpetuated the epidemic in this region. Functional analysis demonstrated attenuated virulence and enhanced resistance to last-line antimicrobials, the result of two different phenomena, adaptive evolution within the original Australian ST239 clade and the introduction of a new clade displaying shifts in both phenotypes. The genetic diversity between the clades allowed us to employ genome-wide association testing and identify mutations in other essential regulatory systems, including walKR, that significantly associate with and may explain these key phenotypes. The phenotypic convergence of two independently evolving ST239 clades highlights the very strong selective pressures acting on HA-MRSA, showing that hospital environments have favored the accumulation of mutations in essential MRSA genes that increase resistance to antimicrobials, attenuate virulence, and promote persistence in the health care environment. Combinations of comparative genomics and careful phenotypic measurements of longitudinal collections of clinical isolates are giving us the knowledge to intelligently address the impact of current and future antibiotic usage policies and practices on hospital pathogens globally. IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for innumerable drug-resistant health care-associated infections globally. This study, the first to investigate the evolutionary response of hospital-associated MRSA (HA-MRSA) over many decades, demonstrates how MRSA can persist in a region through the reintroduction of a previously unrecognized distinct clade. This study also demonstrates the crucial adaptive responses of HA MRSA to the highly selective environment of the health care system, the evolution of MRSA isolates to even higher levels of antibiotic resistance at the cost of attenuated virulence. However, in vivo persistence is maintained, resulting in a clone of HA-MRSA able to resist almost all antimicrobial agents and still cause invasive disease in the heavily compromised hosts found in modern health care settings. PMID- 25736881 TI - Structural basis for metallic-like conductivity in microbial nanowires. AB - Direct measurement of multiple physical properties of Geobacter sulfurreducens pili have demonstrated that they possess metallic-like conductivity, but several studies have suggested that metallic-like conductivity is unlikely based on the structures of the G. sulfurreducens pilus predicted from homology models. In order to further evaluate this discrepancy, pili were examined with synchrotron X ray microdiffraction and rocking-curve X-ray diffraction. Both techniques revealed a periodic 3.2-A spacing in conductive, wild-type G. sulfurreducens pili that was missing in the nonconductive pili of strain Aro5, which lack key aromatic acids required for conductivity. The intensity of the 3.2-A peak increased 100-fold when the pH was shifted from 10.5 to 2, corresponding with a previously reported 100-fold increase in pilus conductivity with this pH change. These results suggest a clear structure-function correlation for metallic-like conductivity that can be attributed to overlapping pi-orbitals of aromatic amino acids. A homology model of the G. sulfurreducens pilus was constructed with a Pseudomonas aeruginosa pilus model as a template as an alternative to previous models, which were based on a Neisseria gonorrhoeae pilus structure. This alternative model predicted that aromatic amino acids in G. sulfurreducens pili are packed within 3 to 4 A, consistent with the experimental results. Thus, the predictions of homology modeling are highly sensitive to assumptions inherent in the model construction. The experimental results reported here further support the concept that the pili of G. sulfurreducens represent a novel class of electronically functional proteins in which aromatic amino acids promote long distance electron transport. IMPORTANCE: The mechanism for long-range electron transport along the conductive pili of Geobacter sulfurreducens is of interest because these "microbial nanowires" are important in biogeochemical cycling as well as applications in bioenergy and bioelectronics. Although proteins are typically insulators, G. sulfurreducens pilus proteins possess metallic-like conductivity. The studies reported here provide important structural insights into the mechanism of the metallic-like conductivity of G. sulfurreducens pili. This information is expected to be useful in the design of novel bioelectronic materials. PMID- 25736882 TI - Finding the sweet spot: how human fungal pathogens acquire and turn the sugar inositol against their hosts. AB - Inositol is an essential nutrient with important structural and signaling functions in eukaryotes. Its role in microbial pathogenesis has been reported in fungi, protozoans, and eubacteria. In a recent article, Porollo et al. [mBio 5(6):e01834-14, 2014, doi:10.1128/mBio.01834-14] demonstrated the importance of inositol metabolism in the development and viability of Pneumocystis species- obligate fungal pathogens that remain unculturable in vitro. To understand their obligate nature, the authors used innovative comparative genomic approaches and discovered that Pneumocystis spp. are inositol auxotrophs due to the lack of inositol biosynthetic enzymes and that inositol insufficiency is a contributing factor preventing fungal growth in vitro. This work is in accord with other studies suggesting that inositol plays a conserved role in microbial pathogenesis. Inositol uptake and metabolism therefore may represent novel antimicrobial drug targets. Using comparative genomics to analyze metabolic pathways offers a powerful tool to gain new insights into nutrient utilization in microbes, especially obligate pathogens. PMID- 25736883 TI - Switching from a unicellular to multicellular organization in an Aspergillus niger hypha. AB - Pores in fungal septa enable cytoplasmic streaming between hyphae and their compartments. Consequently, the mycelium can be considered unicellular. However, we show here that Woronin bodies close ~50% of the three most apical septa of growing hyphae of Aspergillus niger. The incidence of closure of the 9th and 10th septa was even >=94%. Intercompartmental streaming of photoactivatable green fluorescent protein (PA-GFP) was not observed when the septa were closed, but open septa acted as a barrier, reducing the mobility rate of PA-GFP ~500 times. This mobility rate decreased with increasing septal age and under stress conditions, likely reflecting a regulatory mechanism affecting septal pore diameter. Modeling revealed that such regulation offers effective control of compound concentration between compartments. Modeling also showed that the incidence of septal closure in A. niger had an even stronger impact on cytoplasmic continuity. Cytoplasm of hyphal compartments was shown not to be in physical contact when separated by more than 4 septa. Together, data show that apical compartments of growing hyphae behave unicellularly, while older compartments have a multicellular organization. IMPORTANCE: The hyphae of higher fungi are compartmentalized by porous septa that enable cytosolic streaming. Therefore, it is believed that the mycelium shares cytoplasm. However, it is shown here that the septa of Aspergillus niger are always closed in the oldest part of the hyphae, and therefore, these compartments are physically isolated from each other. In contrast, only part of the septa is closed in the youngest part of the hyphae. Still, compartments in this hyphal part are physically isolated when separated by more than 4 septa. Even open septa act as a barrier for cytoplasmic mixing. The mobility rate through such septa reduces with increasing septal age and under stress conditions. Modeling shows that the septal pore width is set such that its regulation offers maximal control of compound concentration levels within the compartments. Together, we show for the first time that Aspergillus hyphae switch from a unicellular to multicellular organization. PMID- 25736884 TI - Antibiotic tolerance and combination therapy. PMID- 25736885 TI - Correction for Herrera et al., The Vibrio cholerae VprA-VprB two-component system controls virulence through endotoxin modification. PMID- 25736886 TI - RIG-I ATPase activity and discrimination of self-RNA versus non-self-RNA. AB - Many RNA viruses are detected by retinoic acid-inducible gene i (RIG-I), a cytoplasmic sensor that triggers an antiviral response upon binding non-self-RNA that contains a stretch of double-stranded RNA (dsRNA) bearing a base-paired 5' ppp nucleotide. To gain insight into how RIG-I discriminates between self-RNA and non-self-RNA, we used duplexes whose complementary bottom strand contained both ribo- and deoxynucleotides. These duplexes were examined for their binding to RIG I and their relative abilities to stimulate ATPase activity, to induce RIG-I dimerization on the duplex, and to induce beta interferon (IFN-beta) expression. We show that the chemical nature of the bottom strand is not critical for RIG-I binding. However, two key ribonucleotides, at positions 2 and 5 on the bottom strand, are minimally required for the RIG-I ATPase activity, which is necessary but not sufficient for IFN-beta stimulation. We find that duplexes with shorter stretches of dsRNA, as model self-RNAs, bind less stably to RIG-I but nevertheless have an enhanced ability to stimulate the ATPase. Moreover, ATPase activity promotes RIG-I recycling on RIG-I/dsRNA complexes. Since pseudo-self RNAs bind to RIG-I less stably, they are preferentially recycled by ATP hydrolysis that weakens the helicase domain binding of dsRNA. Our results suggest that one function of the ATPase is to restrict RIG-I signaling to its interaction with non-self-RNA. A model of how this discrimination occurs as a function of dsRNA length is presented. IMPORTANCE: The innate immune response to pathogens is based on the discrimination between self-RNA and non-self-RNA. The main determinants of this detection for RNA viruses are specific pathogen-associated molecular patterns (PAMPs) of RNA, which are detected by dedicated cytoplasmic pattern recognition receptors (PRRs). RIG-I is a PRR that specifically detects short viral dsRNAs amid a sea of cellular RNAs. Here we study the determinants of this discrimination and how RIG-I ATPase activity, the only enzymatic activity of this sensor, contributes to its activation in a manner restricted to its interaction with non-self-RNAs. We also show how the innate immune response evolves during infection via IFN expression, from a state in which discrimination of self-RNA from non-self-RNA is most important to one in which this discrimination is sacrificed for the effectiveness of the antiviral response. PMID- 25736887 TI - Glycan engagement dictates hydrocephalus induction by serotype 1 reovirus. AB - Receptors expressed on the host cell surface adhere viruses to target cells and serve as determinants of viral tropism. Several viruses bind cell surface glycans to facilitate entry, but the contribution of specific glycan moieties to viral disease is incompletely understood. Reovirus provides a tractable experimental model for studies of viral neuropathogenesis. In newborn mice, serotype 1 (T1) reovirus causes hydrocephalus, whereas serotype 3 (T3) reovirus causes encephalitis. T1 and T3 reoviruses engage distinct glycans, suggesting that glycan-binding capacity contributes to these differences in pathogenesis. Using structure-guided mutagenesis, we engineered a mutant T1 reovirus incapable of binding the T1 reovirus-specific glycan receptor, GM2. The mutant virus induced substantially less hydrocephalus than wild-type virus, an effect phenocopied by wild-type virus infection of GM2-deficient mice. In comparison to wild-type virus, yields of mutant virus were diminished in cultured ependymal cells, the cell type that lines the brain ventricles. These findings suggest that GM2 engagement targets reovirus to ependymal cells in mice and illuminate the function of glycan engagement in reovirus serotype-dependent disease. IMPORTANCE: Receptor utilization strongly influences viral disease, often dictating host range and target cell selection. Different reovirus serotypes bind to different glycans, but a precise function for these molecules in pathogenesis is unknown. We used type 1 (T1) reovirus deficient in binding the GM2 glycan and mice lacking GM2 to pinpoint a role for glycan engagement in hydrocephalus caused by T1 reovirus. This work indicates that engagement of a specific glycan can lead to infection of specific cells in the host and consequent disease at that site. Since reovirus is being developed as a vaccine vector and oncolytic agent, understanding reovirus-glycan interactions may allow manipulation of reovirus glycan-binding properties for therapeutic applications. PMID- 25736888 TI - Glycan-foraging systems reveal the adaptation of Capnocytophaga canimorsus to the dog mouth. AB - Capnocytophaga canimorsus is known to form two kinds of cells on blood agar plates (coccoid and bacillary), evoking phase variation. When grown in coculture with animal cells these bacteria appeared only as bacilli, but in the presence of vancomycin they were round, indicating that coccoid shapes likely result from weakening of the peptidoglycan layer. Polysaccharide utilization locus 5 (PUL5) and sialidase mutant bacteria, unable to retrieve glycans from glycoproteins, grew less than wild-type bacteria and also appeared polymorphic unless GlcNAc was added, suggesting that C. canimorsus is unable to synthesize GlcNAc, an essential component of peptidoglycan. Accordingly, a genome analysis was conducted and revealed that C. canimorsus strain 5 lacks the GlmM and GlmU enzymes, which convert glucosamine into GlcNAc. Expression of the Escherichia coli GlmM together with the acetyltransferase domain of GlmU allowed PUL5 mutant bacteria to grow normally, indicating that C. canimorsus is a natural auxotroph that relies on GlcNAc harvested from the host N-glycoproteins for peptidoglycan synthesis. Mucin, a heavily O-glycosylated protein abundant in saliva, also rescued growth and the shape of PUL5 mutant bacteria. Utilization of mucin was found to depend on Muc, a Sus-like system encoded by PUL9. Contrary to all known PUL-encoded systems, Muc cleaves peptide bonds of mucin rather than glycosidic linkages. Thus, C. canimorsus has adapted to build its peptidoglycan from the glycan-rich dog's mouth glycoproteins. IMPORTANCE: Capnocytophaga canimorsus is a bacterium that lives as a commensal in the dog mouth and causes severe infections in humans. In vitro, it forms two kinds of cells (coccoid and bacillary), evoking phase variation. Here, we show that cell rounding likely results from weakening of the peptidoglycan layer due to a shortage of N-acetylglucosamine (GlcNAc). C. canimorsus cannot synthesize GlcNAc because of the lack of key enzymes. In its niche, the dog mouth, C. canimorsus retrieves GlcNAc by foraging glycans from salivary mucin and N-linked glycoproteins through two different apparatuses, Muc and Gpd, both of which are related to the Bacteroides starch utilization system. The Muc system is peculiar in the sense that the enzyme of the complex is a protease and not a glycosylhydrolase, as it cleaves peptide bonds in order to capture glycan chains. This study provides a molecular genetic demonstration for the complex adaptation of C. canimorsus to its ecological niche, the oral cavity of dogs. PMID- 25736889 TI - "Mycobacterium indicus pranii" is a strain of Mycobacterium intracellulare. PMID- 25736890 TI - Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. AB - No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE: We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals. PMID- 25736892 TI - Reproductive safety evaluation of L-Ergothioneine. AB - L-Ergothioneine is a naturally occurring histidine-derived betaine (CAS No: 497 30-3) synthesized by bacteria and fungi, and found ubiquitously in plants and animals. It is present in many human foodstuffs. We evaluated the potential reproductive toxicity of L-Ergothioneine in Sprague-Dawley rats. L-Ergothioneine was administered at concentrations of 0.1, 0.3 or 0.9% in diet to F0 males (for 10 weeks before pairing and 3 weeks during pairing) and F0 females (for 13 weeks before pairing, during pairing and gestation, and until day 5 of lactation). Systemic exposure increased with dose-level, but not dose proportionally, suggesting saturation of uptake mechanisms. No clinical signs of toxicity were observed and there were no effects of L-Ergothioneine treatment on mating and reproductive performance or parameters of fertility. All animals mated within a similar number of days and pregnancy rates were uniformly high in control and treated groups. There were no effects of treatment with L-Ergothioneine on the duration of gestation, pre- and post-implantation losses, number of pups delivered and viability index, or on litter parameters (litter size, clinical signs, body weight or sex ratio) and the repartition of found dead/cannibalized pups. In conclusion, L-Ergothioneine was well tolerated and without adverse effects on the reproductive parameters evaluated. PMID- 25736891 TI - Shigella flexneri regulation of ARF6 activation during bacterial entry via an IpgD-mediated positive feedback loop. AB - Entry into cells is critical for virulence of the human bacterial pathogens Shigella spp. Shigella spp. induce membrane ruffle formation and macropinocytic uptake, but the events instigating this process are incompletely understood. The host small GTPase ADP-ribosylation factor 6 (ARF6) functions in membrane trafficking at the plasma membrane and activates membrane ruffle formation. We demonstrate that ARF6 is required for efficient Shigella flexneri entry, is activated by S. flexneri dependent on the phosphatase activity of the type III secreted effector IpgD, and depends on cytohesin guanine nucleotide exchange factors (GEFs) for recruitment to entry sites. The cytohesin GEF ARF nucleotide binding site opener (ARNO) is recruited to these sites, also dependent on IpgD phosphatase activity. ARNO recruitment is independent of ARF6, indicating that, in addition to the described recruitment of ARNO by ARF6, ARNO is recruited upstream of ARF6. Our data provide evidence that ARF6, IpgD, phosphoinositide species, and ARNO constitute a previously undescribed positive feedback loop that amplifies ARF6 activation at bacterial entry sites, thereby promoting efficient S. flexneri uptake. IMPORTANCE: Shigella spp. cause diarrhea and dysentery by infection of epithelial cells in the human colon. Critical to disease is the ability of Shigella to enter into cells, yet the mechanisms involved in entry are incompletely understood. We demonstrate that the small GTPase ADP-ribosylation factor 6 (ARF6) is required for efficient cellular entry of Shigella flexneri and that activation of ARF6 depends on the phosphatase activity of the Shigella protein IpgD, which is introduced into cells via the bacterial type III secretion system. We further show that IpgD phosphatase activity is required for recruitment of the ARF6 guanine nucleotide exchange factor (GEF) ARF nucleotide binding site opener (ARNO) to bacterial entry sites and that ARNO lies upstream of ARF6 activation. These relationships define a positive feedback loop that contributes to activation of ARF6 at S. flexneri entry sites and leads to local amplification of signals that promote bacterial entry. PMID- 25736893 TI - Influence of mixotrophic growth on rhythmic oscillations in expression of metabolic pathways in diazotrophic cyanobacterium Cyanothece sp. ATCC 51142. AB - This study investigates the influence of mixotrophy on physiology and metabolism by analysis of global gene expression in unicellular diazotrophic cyanobacterium Cyanothece sp. ATCC 51142 (henceforth Cyanothece 51142). It was found that Cyanothece 51142 continues to oscillate between photosynthesis and respiration in continuous light under mixotrophy with cycle time of ~ 13 h. Mixotrophy is marked by an extended respiratory phase compared with photoautotrophy. It can be argued that glycerol provides supplementary energy for nitrogen fixation, which is derived primarily from the glycogen reserves during photoautotrophy. The genes of NDH complex, cytochrome c oxidase and ATP synthase are significantly overexpressed in mixotrophy during the day compared to autotrophy with synchronous expression of the bidirectional hydrogenase genes possibly to maintain redox balance. However, nitrogenase complex remains exclusive to nighttime metabolism concomitantly with uptake hydrogenase. This study throws light on interrelations between metabolic pathways with implications in design of hydrogen producer strains. PMID- 25736894 TI - Local heat activation of single myosins based on optical trapping of gold nanoparticles. AB - Myosin is a mechano-enzyme that hydrolyzes ATP in order to move unidirectionally along actin filaments. Here we show by single molecule imaging that myosin V motion can be activated by local heat. We constructed a dark-field microscopy that included optical tweezers to monitor 80 nm gold nanoparticles (GNP) bound to single myosin V molecules with nanometer and submillisecond accuracy. We observed 34 nm processive steps along actin filaments like those seen when using 200 nm polystyrene beads (PB) but dwell times (ATPase activity) that were 4.5 times faster. Further, by using DNA nanotechnology (DNA origami) and myosin V as a nanometric thermometer, the temperature gradient surrounding optically trapped GNP could be estimated with nanometer accuracy. We propose our single molecule measurement system should advance quantitative analysis of the thermal control of biological and artificial systems like nanoscale thermal ratchet motors. PMID- 25736895 TI - Targeted fluorination with the fluoride ion by manganese-catalyzed decarboxylation. AB - We describe the first catalytic decarboxylative fluorination reaction based on the nucleophilic fluoride ion. The reported method allows the facile replacement of various aliphatic carboxylic acid groups with fluorine. Moreover, the potential of this method for PET imaging has been demonstrated by the successful (18) F labeling of a variety of carboxylic acids with radiochemical conversions up to 50 %, representing a targeted decarboxylative (18) F labeling method with no-carrier-added [(18) F]fluoride. Mechanistic probes suggest that the reaction proceeds through the interaction of the manganese catalyst with iodine(III) carboxylates formed in situ from iodosylbenzene and the carboxylic acid substrates. PMID- 25736896 TI - Improving outpatient antibiotic prescribing for respiratory tract infections: results of new algorithms used in European trials. PMID- 25736898 TI - Modified semitendinosus muscle transposition to repair ventral perineal hernia in 14 dogs. AB - OBJECTIVES: To describe a modified technique of semitendinosus muscle transposition for the repair of ventral perineal hernia. MATERIALS AND METHODS: Retrospective review of case records of dogs with ventral perineal hernia that were treated by transposing the medial half of the longitudinally split semitendinosus muscle of one limb. The transposition of the internal obturator muscle was used when uni- or bilateral rectal sacculation was also present in addition to ventral perineal hernia; colopexy and vas deferens pexy were also performed. RESULTS: Fourteen dogs were included. In addition to ventral perineal hernia, unilateral and bilateral perineal hernia was also present in five and six of the dogs, respectively. The mean follow-up time was 890 days. Ventral perineal hernia was successfully managed by the modified semitendinosus muscle transposition with minor complications in all the dogs included in the study. CLINICAL SIGNIFICANCE: Despite the small number of dogs included, the unilateral transposition of the medial half of the longitudinally split semitendinosus muscle consistently supported the ventral rectal enlargement in perineal hernia without obvious adverse effects. PMID- 25736897 TI - Impact of supramolecular interactions of dextran-beta-cyclodextrin polymers on invertase activity in freeze-dried systems. AB - beta-Cyclodextrin (beta-CD)-grafted dextrans with spacer arms of different length were employed to evaluate the impact of supramolecular interactions on invertase activity. The modified dextrans were used as single additives or combined with trehalose in freeze-dried formulations containing invertase. Enzyme activity conservation was analyzed after freeze-drying and thermal treatment. The change of glass transition temperature (Tg ) was also evaluated and related to effective interactions. Outstanding differences on enzyme stability were mainly related to the effect of the spacer arm length on polymer-enzyme interactions, since both the degree of substitution and the molecular weight were similar for the two polymers. This change of effective interactions was also manifested in the pronounced reduction of Tg values, and were related to the chemical modification of the backbone during oxidation, and to the attachment of the beta-CD units with spacer arms of different length on dextran. PMID- 25736899 TI - Seasonality of fatigue among young adults in the primary care setting. PMID- 25736900 TI - Prevalence of cardio-metabolic syndrome in Nigeria: a systematic review. AB - OBJECTIVE: This is a systematic review of the distribution of cardiometabolic syndrome (CMS) in Nigeria, the clinical definitions widely used and how it affects the proposition of a national prevalence of CMS that will advise management interventions. STUDY DESIGN: Systematic review of literature. METHODS: To present a comprehensive report of the distribution of CMS in Nigeria, extensive searches was carried out on PubMed, African Journals Online (AJOL), SCOPUS, EBSCOhost (CINAHL Plus), Google Scholar and Science Direct using terms: Nigeria, metabolic syndrome, cardio-metabolic syndrome, syndrome X, World Health Organization, International Diabetic Federation, National Cholesterol Education Program Adult Treatment Panel III, European Group for study on Insulin Resistance, American Association of Clinical Endocrinologist, American Heart Association/National Heart, Lung and Blood Institute. All published data between January 2002 and December 2013 were collated into a database. Information gathered and recorded for each source were the population sampled, age and number of population, locality, clinical definition used, longitude and latitude, and period of the study. RESULTS: Out of 32 studies, 9 (28.1%) adopted the WHO classification, 19 (59.4%) used the ATPIII definition, while the remaining 10 (31.3%) studies used the IDF definitions. Twenty (62.5%) were hospital-based studies on diabetic, hypertensive, HIV, asthmatic and thyroid disorder patients. The remaining 12 (37.5%) studies were population-based studies in urban, suburb and rural settings. The mean overall prevalence of CMS in Nigeria is 31.7%, 27.9% and 28.1% according to the WHO, ATPIII and IDF definitions, respectively. Most of the studies were from the Southern region. Age groups mostly studied were those from >=35 years. CONCLUSION: The report of this review provides an essential overview on the current distribution of CMS in Nigeria. It provides an insight to direct future studies such as the need to (1) study rural communities where lifestyles are not westernized as in the urban areas, and (2) young adults, as well as (3) develop a consensus on the definition of CMS among the Sub-Saharan African populations. PMID- 25736901 TI - What hopes for the NHS: the election and beyond? PMID- 25736902 TI - Occurrence and Source Appraisal of Polycyclic Aromatic Hydrocarbons (PAHs) in Surface Waters of the Almendares River, Cuba. AB - In this work, 14 polycyclic aromatic hydrocarbons (PAHs) included in the United States Environmental Protection Agency pollutant priority list were analyzed in the surface water of the upper urbanized part of Almendares River, the most important water course in Havana, Cuba. Surface water from five sampling sites was collected at the end of dry season and analyzed by high-performance liquid chromatography-fluorescence detection method after solid phase extraction procedure. Total PAHs concentrations varied from 836 to 15 811 ng L(-1) with a geometric mean value of 2512 ng L(-1). PAH typology was dominated by low molecular-weight PAHs (2- to 3-ring components). Pollutant source appraisal was determined by diagnostic ratios method in five sampling sites. Factor analysis of normalized samples was used to concentration identified two factors as the main significant pollutant sources and to cluster similar sampling sites corresponding to petrogenic and combustion inputs, respectively. Ecological risks were considered. For animal aquatic life, acute toxicity values exceed the permissible values in the more-polluted sampling sites. PMID- 25736904 TI - Applied potentials regulate recovery of residual hydrogen from acid-rich effluents: Influence of biocathodic buffer capacity over process performance. AB - An absolute biological microbial electrolysis cell (MEC) was operated for a prolonged period under different applied potentials (Eapp, -0.2V to -1.0V) and hydrogen (H2) production was observed using acid-rich effluent. Among these potentials, an optimal voltage of -0.6 V influenced the biocathode by which maximum H2 production of 120 +/- 9 ml was noticed. This finding was corroborated with dehydrogenase activity (1.8 +/- 0.1 MUg/ml) which is the key enzyme for H2 production. The in situ biocathode regulated buffer overpotentials which was remarkably observed by the change in peak heights of dissociation value (pKa) from the titration curve. Substrate degradation analysis gave an estimate of coulombic efficiency of about 72 +/- 5% when operated at optimal voltage. Evidently, the electron transfer from solid carbon electrode to biocathode was analyzed by cyclic voltammetry and its derivatives showed the involvement of redox mediators. Despite, the MEC endures certain activation overpotentials which were estimated from the Tafel slope analysis. PMID- 25736903 TI - Biomineralization of azo dye bearing wastewater in periodic discontinuous batch reactor: Effect of microaerophilic conditions on treatment efficiency. AB - The present study illustrates the influence of microaerophilic condition on periodic discontinuous batch reactor (PDBR) operation in treating azo dye containing wastewater. The process performance was evaluated with the function of various dye load operations (50-750 mg/l) by keeping the organic load (1.6 kg COD/m(3)-day) constant. Initially, lower dye operation (50mg dye/l) resulted in higher dye [45 mg dye/l (90%)] and COD [SDR: 1.29 kg COD/m(3)-day (92%)] removal efficiencies. Higher dye load operation (750 mg dye/l) also showed non-inhibitory performance with respect to dye [600 mg dye/l (80%)] and COD [1.25 kg COD/m(3) day (80%)] removal efficiencies. Increment in dye load showed increment in azo reductase and dehydrogenase activities (39.6 U; 4.96 MUg/ml; 750 mg/l). UV-Vis spectroscopy (200-800 nm), FTIR and (1)H NMR studies revealed the disappearance of azo bond (-NN-). First derivative cyclic voltammogram supported the involvement of various membrane bound redox shuttlers, viz., cytochrome-C, cytochrome-bc1 and flavoproteins (FAD (H)). PMID- 25736905 TI - Lipid metabolism in response to individual short chain fatty acids during mixotrophic mode of microalgal cultivation: Influence on biodiesel saturation and protein profile. AB - Critical influence of different short chain fatty acids as organic carbon source, during growth (GP) and nutrient stress lipogenic phase (NSLP) was investigated on biomass and lipid productivity, in mixotrophic fed-batch microalgae cultivation. Nutrient deprivation induced physiological stress stimulated highest lipid productivity with acetate (total/neutral lipids, 35/17) with saturation index of 80.53% by the end of NSLP followed by butyrate (12/7%; 78%). Biomass growth followed the order of acetate (2.23 g/l) >butyrate (0.99 g/l) >propionate (0.77 g/l). VFA removal (as COD) was maximum with acetate (87%) followed by butyrate (55.09%) and propionate (10.60%). Palmitic acid was the most dominant fatty acid found in the fatty acid composition of all variants and butyrate fed system yielded a maximum of 44% palmitic acid. Protein profiling illustrated prominence of acetyl CoA-synthetase activity in acetate system. Thus, fatty acids provide a promising alternative feedstock for biodiesel production with integrated microalgae-biorefinery. PMID- 25736906 TI - Screening executive function and global cognition with the Nine-Card Sorting Test: healthy participant studies and ageing implications. AB - BACKGROUND: The Nine-Card Sorting Test provides valid and reliable scores when screening executive function, intelligence, and academic achievement. It is also useful for detecting cognitive impairment and dementia in the elderly and for assessing disease evolution and treatment effectiveness. It deals with three non verbal sorting principles, individually and in pairs. The presence of risk in the ability to discover and organize visual logical stimuli is explored. OBJECTIVES: This study aimed to describe performance on the Nine-Card Sorting Test in a non clinical sample, to analyze the effect of demographic variables, and to propose suitable (i.e. the simplest and most homogeneous) cut-off points for possible deficits. Combinations in pairs (double arrays) were assessed (range: 0-3). RESULTS: Significant effects of age and education were observed, but no interactions among the demographic variables were seen. Differences between the second and third levels of education and between men and women were not significant. The simplest cut-off points were as follows: (i) the median for people younger than 45 years old was 2, independent of educational level; (ii) the median for people older than 74 years old was 1, independent of educational level; and (iii) the median for people aged 45-74 years old was 1 for the first level of education and 2 for higher levels of education. CONCLUSION: By considering both the statistical nature of the present dependent variable (number of completed categories) and the clear-cut performance of the different samples studied, this neuropsychological test can be defined as a categorical screening for executive function and global cognition. This is advantageous for reporting risk. Of the whole sample, the 25th percentile (score = 1) represented a valid index for possible deficits. Ageing questions are highlighted. The test is also fruitful for studies on visuospatial organization and its facilitatory and inhibitory mechanisms. PMID- 25736907 TI - The anti-fibrotic effects of mesenchymal stem cells on irradiated lungs via stimulating endogenous secretion of HGF and PGE2. AB - Radiation-induced pulmonary fibrosis is a common disease and has a poor prognosis owing to the progressive breakdown of gas exchange regions in the lung. Recently, a novel strategy of administering mesenchymal stem cells for pulmonary fibrosis has achieved high therapeutic efficacy. In the present study, we attempted to use human adipose tissue-derived mesenchymal stem cells to prevent disease in Sprague Dawley rats that received semi-thoracic irradiation (15 Gy). To investigate the specific roles of mesenchymal stem cells in ameliorating radiation-induced pulmonary fibrosis, we treated control groups of irradiated rats with human skin fibroblasts or phosphate-buffered saline. After mesenchymal stem cells were infused, host secretions of hepatocyte growth factor (HGF) and prostaglandin E2 (PGE2) were elevated compared with those of the controls. In contrast, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF beta1) levels were decreased after infusion of mesenchymal stem cells. Consequently, the architecture of the irradiated lungs was preserved without marked activation of fibroblasts or collagen deposition within the injured sites. Moreover, mesenchymal stem cells were able to prevent the irradiated type II alveolar epithelial cells from undergoing epithelial-mesenchymal transition. Collectively, these data confirmed that mesenchymal stem cells have the potential to limit pulmonary fibrosis after exposure to ionising irradiation. PMID- 25736908 TI - The chest X-ray features of chronic respiratory disease in HIV-infected children- a review. AB - Several features of human immunodeficiency virus (HIV) infection contribute to the development of chronic respiratory disease in children. These include the frequency and severity of acute chest infections, as well as the increased risk of pulmonary tuberculosis, aspiration, cardiovascular disease, lymphocytic interstitial pneumonitis or pulmonary neoplasia. The chest radiograph (CXR) remains the most accessible investigation for respiratory disease and plays an important role in the baseline assessment and follow-up. This review focuses on the CXR abnormalities of HIV-related chronic respiratory disease in children. The most commonly documented chronic CXR abnormalities are homogeneous opacification and pulmonary nodules, with pulmonary tuberculosis and lymphocytic interstitial pneumonitis the leading respective causes. Deficiencies in radiographic reporting methodology and relative paucity of radiographic data contribute to current limitations in knowledge and understanding of this field. The review highlights the need for standardised terminology and systematic reporting methodology in future studies. Prospective research on the natural history of lymphocytic interstitial pneumonitis, response to anti-tuberculous therapy, the impact of anti-retroviral therapy and HIV-associated bronchiectasis are needed. PMID- 25736909 TI - Enhancing and inhibiting stimulated Brillouin scattering in photonic integrated circuits. AB - On-chip nonlinear optics is a thriving research field, which creates transformative opportunities for manipulating classical or quantum signals in small-footprint integrated devices. Since the length scales are short, nonlinear interactions need to be enhanced by exploiting materials with large nonlinearity in combination with high-Q resonators or slow-light structures. This, however, often results in simultaneous enhancement of competing nonlinear processes, which limit the efficiency and can cause signal distortion. Here, we exploit the frequency dependence of the optical density-of-states near the edge of a photonic bandgap to selectively enhance or inhibit nonlinear interactions on a chip. We demonstrate this concept for one of the strongest nonlinear effects, stimulated Brillouin scattering using a narrow-band one-dimensional photonic bandgap structure: a Bragg grating. The stimulated Brillouin scattering enhancement enables the generation of a 15-line Brillouin frequency comb. In the inhibition case, we achieve stimulated Brillouin scattering free operation at a power level twice the threshold. PMID- 25736910 TI - Early administration of non-vitamin K antagonist oral anticoagulants for acute ischemic stroke patients with atrial fibrillation in comparison with warfarin mostly combined with heparin. AB - BACKGROUND: This study evaluated the rates of new lesions on diffusion-weighted images (DWIs) of magnetic resonance imaging (MRI) and hemorrhagic transformation (HT) during 2 weeks after acute ischemic stroke (AIS) in patients with atrial fibrillation (Af) who were given one of the non-vitamin K antagonist oral anticoagulants (NOACs); this was then compared with those who were given warfarin. METHODS AND RESULTS: Consecutive AIS patients with Af were enrolled between January 2008 and June 2013, and those selected were patients who had a MRI that included DWIs both on admission and after 2 weeks, and those given only wafrarin (warfarin group) or only one of the NOACs (NOAC group) within 2 weeks of admission. Of all 257 enrolled patients, 50 patients were selected for the NOAC group (median age of 80.0 years) and 125 patients for the warfarin group (median age of 80.0 years). Both NOAC and warfarin were started at a median of the second day after admission. There was no significant difference in the rates of new lesions on DWIs (26.0% vs. 28.0%, P=0.7888) and HT (30.0% vs. 39.2%, P=0.2536) between the NOAC and warfarin groups. The NOAC group had a lower rate of concomitant use of heparin (44.0% vs. 92.8%, P<0.0001) than the warfarin group. CONCLUSIONS: This study suggests that NOACs are suitable for AIS patients with Af, perhaps even better than warfarin, given their simplicity. PMID- 25736911 TI - Identification of the optic recess region as a morphogenetic entity in the zebrafish forebrain. AB - Regionalization is a critical, highly conserved step in the development of the vertebrate brain. Discrepancies exist in how regionalization of the anterior vertebrate forebrain is conceived since the "preoptic area" is proposed to be a part of the telencephalon in tetrapods but not in teleost fish. To gain insight into this complex morphogenesis, formation of the anterior forebrain was analyzed in 3D over time in zebrafish embryos, combining visualization of proliferation and differentiation markers, with that of developmental genes. We found that the region containing the preoptic area behaves as a coherent morphogenetic entity, organized around the optic recess and located between telencephalon and hypothalamus. This optic recess region (ORR) makes clear borders with its neighbor areas and expresses a specific set of genes (dlx2a, sim1a and otpb). We thus propose that the anterior forebrain (secondary prosencephalon) in teleosts contains three morphogenetic entities (telencephalon, ORR and hypothalamus), instead of two (telencephalon and hypothalamus). The ORR in teleosts could correspond to "telencephalic stalk area" and "alar hypothalamus" in tetrapods, resolving current inconsistencies in the comparison of basal forebrain among vertebrates. PMID- 25736912 TI - International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial. AB - Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort. PMID- 25736913 TI - The role of binding site on the mechanical unfolding mechanism of ubiquitin. AB - We apply novel atomistic simulations based on potential energy surface exploration to investigate the constant force-induced unfolding of ubiquitin. At the experimentally-studied force clamping level of 100 pN, we find a new unfolding mechanism starting with the detachment between beta5 and beta3 involving the binding site of ubiquitin, the Ile44 residue. This new unfolding pathway leads to the discovery of new intermediate configurations, which correspond to the end-to-end extensions previously seen experimentally. More importantly, it demonstrates the novel finding that the binding site of ubiquitin can be responsible not only for its biological functions, but also its unfolding dynamics. We also report in contrast to previous single molecule constant force experiments that when the clamping force becomes smaller than about 300 pN, the number of intermediate configurations increases dramatically, where almost all unfolding events at 100 pN involve an intermediate configuration. By directly calculating the life times of the intermediate configurations from the height of the barriers that were crossed on the potential energy surface, we demonstrate that these intermediate states were likely not observed experimentally due to their lifetimes typically being about two orders of magnitude smaller than the experimental temporal resolution. PMID- 25736914 TI - A series of conditional shuttle vectors for targeted genomic integration in budding yeast. AB - The capacity of Saccharomyces cerevisiae to repair exposed DNA ends by homologous recombination has long been used by experimentalists to assemble plasmids from DNA fragments in vivo. While this approach works well for engineering extrachromosomal vectors, it is not well suited to the generation, recovery and reuse of integrative vectors. Here, we describe the creation of a series of conditional centromeric shuttle vectors, termed pXR vectors, that can be used for both plasmid assembly in vivo and targeted genomic integration. The defining feature of pXR vectors is that the DNA segment bearing the centromere and origin of replication, termed CEN/ARS, is flanked by a pair of loxP sites. Passaging the vectors through bacteria that express Cre recombinase reduces the loxP-CEN/ARS loxP module to a single loxP site, thereby eliminating the ability to replicate autonomously in yeast. Each vector also contains a selectable marker gene, as well as a fragment of the HO locus, which permits targeted integration at a neutral genomic site. The pXR vectors provide a convenient and robust method to assemble DNAs for targeted genomic modifications. PMID- 25736915 TI - Detecting treatment-covariate interactions using permutation methods. AB - The primary objective of a Randomized Clinical Trial usually is to investigate whether one treatment is better than its alternatives on average. However, treatment effects may vary across different patient subpopulations. In contrast to demonstrating one treatment is superior to another on the average sense, one is often more concerned with the question that, for a particular patient, or a group of patients with similar characteristics, which treatment strategy is most appropriate to achieve a desired outcome. Various interaction tests have been proposed to detect treatment effect heterogeneity; however, they typically examine covariates one at a time, do not offer an integrated approach that incorporates all available information, and can greatly increase the chance of a false positive finding when the number of covariates is large. We propose a new permutation test for the null hypothesis of no interaction effects for any covariate. The proposed test allows us to consider the interaction effects of many covariates simultaneously without having to group subjects into subsets based on pre-specified criteria and applies generally to randomized clinical trials of multiple treatments. The test provides an attractive alternative to the standard likelihood ratio test, especially when the number of covariates is large. We illustrate the proposed methods using a dataset from the Treatment of Adolescents with Depression Study. PMID- 25736916 TI - Next-generation sequencing as a powerful motor for advances in the biological and environmental sciences. AB - Next-generation sequencing (NGS) provides unprecedented insight into (meta)genomes, (meta)transcriptomes (cDNA) and (meta)barcodes of individuals, populations and communities of Archaea, Bacteria and Eukarya, as well as viruses. This special issue combines reviews and original papers reporting technical and scientific advances in genomics and transcriptomics of non-model species, as well as quantification and functional analyses of biodiversity using NGS technologies of the second and third generations. In addition, certain papers also exemplify the transition from Sanger to NGS barcodes in molecular taxonomy. PMID- 25736917 TI - Low-intensity pulsed ultrasound enhances bone repair in a rabbit model of steroid associated osteonecrosis. AB - BACKGROUND: Steroids are a leading cause of femoral head osteonecrosis. Currently there are no medications available to prevent and/or treat steroid-associated osteonecrosis. Low-intensity pulsed ultrasound (LIPUS) was approved by the FDA for treating delayed union of bone fractures. Some studies have reported that LIPUS can enhance bone formation and local blood flow in an animal model of fracture healing. However, whether the effect of osteogenesis and neovascularization by LIPUS can enhance the repair progress in steroid-associated osteonecrosis is unknown. QUESTIONS/PURPOSES: We hypothesized that LIPUS may facilitate osteogenesis and neovascularization in the reparative processes of steroid-associated osteonecrosis. Using a rabbit animal model, we asked whether LIPUS affects (1) bone strength and trabecular architecture; (2) blood vessel number and diameter; and (3) BMP-2 and VEGF expression. METHODS: Bilateral femoral head necrosis was induced by lipopolysaccharide and methylprednisolone in 24 rabbits. The left femoral heads of rabbits received LIPUS therapy (200 mW/cm(2)) for 20 minutes daily and were classified as the LIPUS group. The right femoral heads of the same rabbits did not receive therapy and were classified as the control group. All rabbits were euthanized 12 weeks after LIPUS therapy. Micro-CT, biomechanical testing, histologic evaluation, immunohistochemistry, quantitative real-time PCR, and Western blot were used for examination of the effects of LIPUS. RESULTS: Twelve weeks after LIPUS treatment, the loading strength in the control group was 355 +/- 38 N (95% CI, 315-394 N), which was lower (p = 0.028) than that in the LIPUS group (441 +/- 78 N; 95% CI, 359-524 N). The bone tissue volume density (bone volume/total volume) in the LIPUS group (49.29% +/- 12.37%; 95 % CI, 36.31%-62.27%) was higher (p = 0.022) than that in the control group (37.93% +/- 8.37%; 95 % CI, 29.15%-46.72%). The percentage of empty osteocyte lacunae in the LIPUS group (17% +/- 4%; 95% CI, 15%-20%) was lower (p = 0.002) than that in the control group (26% +/- 9%; 95% CI, 21%-32%). The mineral apposition rate (MUm/day) in the LIPUS group (2.3 +/- 0.8 MUm/day; 95% CI, 1.8 2.8 MUm/day) was higher (p = 0.001) than that in the control group (1.6 +/- 0.3 MUm/day; 95% CL, 1.4-1.8 MUm/day). The number of blood vessels in the LIPUS group (7.8 +/- 3.6/mm(2); 95% CI, 5.5-10.1 mm(2)) was greater (p = 0.025) than the number in the control group (5.7 +/- 2.6/mm(2); 95% CI, 4.0-7.3 mm(2)). Messenger RNA (mRNA) and protein expression of BMP-2 in the LIPUS group (75 +/- 7, 95% CI, 70-79; and 30 +/- 3, 95% CI, 28-31) were higher (both p < 0.001) than those in the control groups (46 +/- 5, 95% CI, 43-49; and 15 +/- 2, 95% CI, 14-16). However, there were no differences (p = 0.114 and 0.124) in mRNA and protein expression of vascular endothelial growth factor between the control (26 +/- 3, 95% CI, 24-28; and 22 +/- 6, 95% CI, 18-26) and LIPUS groups (28 +/- 2, 95% CI, 26-29; and 23 +/- 6, 95% CI, 19-27). CONCLUSIONS: The results of this study indicate that LIPUS promotes osteogenesis and neovascularization, thus promoting bone repair in this steroid-associated osteonecrosis model. CLINICAL RELEVANCE: LIPUS may be a promising modality for the treatment of early-stage steroid-associated osteonecrosis. Further research, including clinical trials to determine whether LIPUS has a therapeutic effect on patients with early-onset steroid-associated osteonecrosis may be warranted. PMID- 25736919 TI - Limits to captive breeding of mammals in zoos. AB - Captive breeding of mammals in zoos is the last hope for many of the best-known endangered species and has succeeded in saving some from certain extinction. However, the number of managed species selected is relatively small and focused on large-bodied, charismatic mammals that are not necessarily under strong threat and not always good candidates for reintroduction into the wild. Two interrelated and more fundamental questions go unanswered: have the major breeding programs succeeded at the basic level of maintaining and expanding populations, and is there room to expand them? I used published counts of births and deaths from 1970 to 2011 to quantify rates of growth of 118 captive-bred mammalian populations. These rates did not vary with body mass, contrary to strong predictions made in the ecological literature. Most of the larger managed mammalian populations expanded consistently and very few programs failed. However, growth rates have declined dramatically. The decline was predicted by changes in the ratio of the number of individuals within programs to the number of mammal populations held in major zoos. Rates decreased as the ratio of individuals in programs to populations increased. In other words, most of the programs that could exist already do exist. It therefore appears that debates over the general need for captive-breeding programs and the best selection of species are moot. Only a concerted effort could create room to manage a substantially larger number of endangered mammals. PMID- 25736918 TI - Femoroacetabular Impingement: Prevalent and Often Asymptomatic in Older Men: The Osteoporotic Fractures in Men Study. AB - BACKGROUND: The epidemiology of femoroacetabular impingement (FAI) is important but incompletely understood, because most reports arise from symptomatic populations. Investigating the prevalence of FAI in a community-based cohort could help us better understand its epidemiology and in particular the degree to which it might or might not be associated with hip pain. QUESTIONS/PURPOSES: The purposes of this study were (1) to evaluate the proportion of older (>=65 years of age) men with morphologic abnormalities consistent with FAI; and (2) to assess the association of the morphologic abnormalities with prevalent radiographic hip osteoarthritis (OA) and hip pain. METHODS: Anteroposterior radiographs were obtained in 4140 subjects (mean age+/-SD, 77+/-5 years) from the Osteoporotic Fractures in Men study. We assessed each hip for cam, pincer, and mixed FAI types using validated radiographic definitions. Both intra- and interobserver reproducibility were >0.9. Radiographic hip OA was assessed by an expert reader (intraobserver reproducibility, 0.7-0.8) using validated methods, and summary grades of 2 or greater (on a scale from 0 to 4) were used to define radiographic hip OA. Covariates including hip pain in the last 30 days were collected by questionnaires that were answered by all patients included in this report. Logistic regressions with generalized estimating equations were performed to evaluate the association of radiographic features of FAI and arthrosis. RESULTS: Pincer, cam, or mixed types of radiographic FAI had a prevalence of 57% (1748 of 3053), 29% (886 of 3053), and 14% (419 of 3053), respectively, in this group of older men. Both pincer and mixed types of FAI were associated with arthrosis but not with hip pain (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.25 2.13; p<0.001 for pincer and OR, 2.49; 95% CI, 1.65-3.76; p<0.001 for mixed type). Patients with hips characterized by cam-type FAI had slightly reduced hip pain without the presence of arthrosis compared with hips without FAI (OR, 0.82; 95% CI, 0.68-0.99; p=0.037). A center-edge angle>39 degrees and a caput-collum diaphyseal angle<125 degrees were associated with arthrosis (OR, 1.53; 95% CI, 1.22-1.94; p<0.001 and OR, 2.09; 95% CI, 1.24-3.51; p=0.006, respectively), but not with hip pain (OR, 0.89; 95% CI, 0.77-1.03; p<0.108 and OR, 0.99; 95% CI, 0.67-1.45; p=0.945, respectively). An impingement angle<70 degrees was associated with less hip pain compared with hips with an impingement angle>=70 degrees (OR, 0.76; 95% CI, 0.61-0.95; p=0.015). CONCLUSIONS: FAI is common in older men and represents more of an anatomic variant rather than a symptomatic disease. This finding should raise questions on how age, activities, and this anatomic variant each contribute to result in symptomatic disease. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25736920 TI - In diabetic foot infections antibiotics are to treat infection, not to heal wounds. AB - INTRODUCTION: Diabetic foot ulcers, especially when they become infected, are a leading cause of morbidity and may lead to severe consequences, such as amputation. Optimal treatment of these diabetic foot problems usually requires a multidisciplinary approach, typically including wound debridement, pressure off loading, glycemic control, surgical interventions and occasionally other adjunctive measures. AREAS COVERED: Antibiotic therapy is required for most clinically infected wounds, but not for uninfected ulcers. Unfortunately, clinicians often prescribe antibiotics when they are not indicated, and even when indicated the regimen is frequently broader spectrum than needed and given for longer than necessary. Many agents are available for intravenous, oral or topical therapy, but no single antibiotic or combination is optimal. Overuse of antibiotics has negative effects for the patient, the health care system and society. Unnecessary antibiotic therapy further promotes the problem of antibiotic resistance. EXPERT OPINION: The rationale for prescribing topical, oral or parenteral antibiotics for patients with a diabetic foot wound is to treat clinically evident infection. Available published evidence suggests that there is no reason to prescribe antibiotic therapy for an uninfected foot wound as either prophylaxis against infection or in the hope that it will hasten healing of the wound. PMID- 25736921 TI - Tongue and hyoid musculature and functional morphology of a neonate gray whale (Cetacea, Mysticeti, Eschrichtius robustus). AB - Little is known about the anatomy and musculature of the gray whale (Eschrichtius robustus), especially related to the anatomy of the tongue and hyoid region. The recovery of an extremely fresh head of a neonatal female gray whale provided an opportunity to conduct the first in-depth investigation of the musculoskeletal features of the tongue and hyoid apparatus. Unlike other mysticetes, the gray whale tongue is strong, muscular, and freely mobile inside the buccal cavity. In particular, the genioglossus and hyoglossus muscles are extremely large and robust making up the majority of the body of the tongue. In addition, the genioglossus had a unique position and fiber orientation in the tongue compared to other mammals. The structure of the hyoid apparatus differs between E. robustus and other mysticete species, although there are similarities among individual elements. We provide the first documentation of fungiform papillae that may be associated with taste buds in Mysticeti. The highly mobile, robust tongue and the presence of well-defined tongue and hyoid musculature are in keeping with observations of gray whale feeding that suggest this group of whales utilize oral suction to draw benthic prey into the buccal cavity. PMID- 25736922 TI - Identification of putative negative regulators of yeast signaling through a screening for protein phosphatases acting on cell wall integrity and mating MAPK pathways. AB - The lack of signaling through MAPK pathways leads to a defective cellular response to the corresponding stimulus, but an improper hyperactivation of these routes results in deleterious effects as well. Protein phosphorylation is an activating modification for signal transmission through components of MAPK pathways and thus, protein phosphatases are key negative regulators of these cellular routes by limiting excessive signaling activity. However, in contrast to most of the protein kinases operating in MAPK pathways, protein phosphatases usually exhibit redundancy and promiscuity, which has limited the identification of their function. In order to identify new putative phosphatases operating in Saccharomyces cerevisiae MAPK signaling, we have taken advantage of growth inhibition promoted by overproduction of constitutively active components of the mating and cell wall integrity (CWI) pathways to perform a screen with a collection of 43 protein phosphatases or phosphatase-regulatory proteins. The phosphatases able to alleviate the induced growth inhibition when overproduced were further studied by testing their capacity to downregulate expression of mating and CWI responsive promoters and the consequences of their removal on MAPK signaling. Epistasis analysis placed the Ser/Thr protein phosphatase Ppq1 as a regulator of the mating MAPK module downstream the MAPKKK Ste11. The dual specificity phosphatase Yvh1 was found to be important for the maintenance of cell wall integrity and appropriate signaling through the CWI pathway. Moreover, we have found that Ptc2 and Ptc4 bind to the CWI MAPK Slt2. Together with known phosphatases of the mating and CWI pathway, as Msg5 or Ptp2, other putative negative regulators of both pathways that came up in the screening were Ptc2, Oca2 and Ptp1. We show that Ptp1 physically interacts with Slt2 and the mating MAPK Fus3. Elimination of Ptp1 results in increased signaling through these pathways, suggesting that this tyrosine phosphatase, like Ptp2 and Ptp3, plays a downregulatory role on both MAPKs. PMID- 25736923 TI - A link between cold environment and cancer. AB - Many risk factors such as smoking and change of life style have been shown to promote genetic and adaptive epigenetic changes responsible for tumorigenesis. This study brings environmental temperature as a cancer causing factor to light. The cancer mortality rate (CMR) of a country was correlated with 17 different variables. Multivariate analysis of a total of 188 countries found that the average annual temperature (AAT) of a country might have a significant contribution to cancer death when compared with other factors such as alcohol and meat consumption. Univariate analysis found a negative correlation between AAT and CMR. All these countries were categorized into three temperature zones (zone I, -2 to 11.5 degrees C; number of countries, 38; zone II, 11.6 to 18.6 degrees C; number of countries, 32; and zone III, 18.7 to 30 degrees C; number of countries, 118). Out of the top-most 50 countries having the highest CMR, 26 (68.42 %), 10 (31.25 %), and 14 (11.66 %) belong to zone I, zone II, and zone III, respectively. Out of the least 50 countries having the lowest CMR, 1 (2.63 %), 4 (12.5 %), and 45 (37.5 %) belong to zone I, zone II, and zone III, respectively. CMR is low in those countries situated near to the Torrid zone (33( degrees ) N to 23.5( degrees )S), but it is high for those countries situated away from these two latitudes. These data indicate that cold temperature may have a contribution in increasing tumorigenesis. High metabolic stress, which is the result of maintaining our body temperature against a cold environment, could be the possible cause for the higher cancer mortality. PMID- 25736924 TI - Depletion of ALX1 causes inhibition of migration and induction of apoptosis in human osteosarcoma. AB - Osteosarcoma is the most common primary malignant tumor in children and young adults, and the molecular regulation of the invasion of osteosarcoma (OS) remains unknown. In this study, we found that increased expression of ALX1 was associated with the progression of osteosarcoma and that ALX1 protein levels were significantly elevated in matched distant metastases. High ALX1 levels also predict shorter overall survival of osteosarcoma patients. We investigated the therapeutic potential of targeting ALX1 expression using the technique of RNA silencing via short hairpin RNA (shRNA). Synthetic shRNA duplexes against ALX1 were introduced to downregulate the expression of ALX1 in a highly malignant osteosarcoma cell line, U2OS. The results obtained indicated that shRNA targeting of ALX1 could lead to an efficient and specific inhibition of endogenous ALX1 activity. Furthermore, we found that depletion of ALX1 caused a dramatic cell cycle arrest, followed by massive apoptotic cell death, and eventually resulted in a significant decrease in migration and invasion of the osteosarcoma cell line studied. PMID- 25736925 TI - C6orf106 enhances NSCLC cell invasion by upregulating vimentin, and downregulating E-cadherin and P120ctn. AB - Chromosome 6 open reading frame 106 (C6orf106) is a newly discovered protein; its expression and clinical pathological significance in human tumors remains unclear. Immunohistochemistry, Western blot, and immunofluorescence were performed to assess C6orf106 expression in non-small cell lung cancer (NSCLC). In addition, the relationships between subcellular localization and clinical pathological factors were analyzed. Through C6orf106 overexpression and repression, respectively, in lung cancer cell lines, we explored the effect of this molecule on NSCLC invasion abilities. C6orf106 was highly expressed in the cytoplasm of lung cancer tissue cells (60.4 %, 75/124), compared with adjacent normal lung tissues (15.2 %, 7/46, p < 0.001). In addition, its expression was positively correlated with differentiation (p = 0.001), TNM stage (p = 0.011), lymph node metastasis (p = 0.018), and poor prognosis (p = 0.006). Furthermore, C6orf106 overexpression enhanced NSCLC cell invasion. Moreover, C6orf106 was shown to increase vimentin expression, while decreasing E-cadherin and P120ctn. C6orf106 is highly expressed in NSCLC and correlates with clinical and pathological factors, as well as poor prognosis. C6orf106 promotes invasion in NSCLC cells. Finally, C6orf106 upregulates vimentin, and downregulates E-cadherin and P120ctn. PMID- 25736926 TI - Cannabis smoke can be a major risk factor for early-age laryngeal cancer--a molecular signaling-based approach. AB - Epidermal growth factor receptor (EGFR) and its downstream elements are overexpressed in most cases of the head and neck squamous cell carcinoma. This study investigated the expression pattern of key proteins linked to the EGFR pathway in laryngeal carcinoma patients with a history of cannabis smoking. We selected 83 male glottic cancer patients, aged between 45 to 75 years with three distinct populations-nonsmoker, cigarette smoker, and cannabis smoker. Immunohistochemical staining was performed for EGFR, protein kinase B (PKB or Akt), nuclear factor kappa B p50 (NF-KB), and cyclooxygenase-2 (COX-2) followed by boolean scoring for statistical analysis. Experimental data showed upregulation of the selected EGFR cascade in tumor cells, stromal expression of EGFR, and nuclear localization of COX-2 in metaplastic gland cells of laryngeal cancer tissue sample. Statistical analyses indicated that overexpression of the EGFR cascade is significantly correlated to cannabis smoking. Cannabis smokers had higher expression (p < 0.01) of these onco-proteins with respect to both nonsmokers as well as cigarette smokers. Risk factor analysis showed high risk of these proteins expression in age <60 years (odds ratio (OR) > 1.5) as the lower age group had relatively higher number of cannabis smokers. This study provides evidence for a direct association between cannabis smoking and increased risk of laryngeal cancer. Higher expression of the EGFR cascade in cannabis smokers revealed that cannabis smoking may be a major cause for the early onset of aggressive laryngeal cancer. PMID- 25736927 TI - Oncolytic adenovirus-mediated short hairpin RNA targeting MYCN gene induces apoptosis by upregulating RKIP in neuroblastoma. AB - The amplification of MYCN is a typical characteristic of aggressive neuroblastomas, whereas acquired mutations of p53 lead to refractory and relapsed cases. We had previously examined the applicability of the replication-competent oncolytic adenovirus, ZD55-shMYCN, to deliver a short hairpin RNA targeting MYCN gene for p53-null and MYCN-amplified neuroblastoma cell line LA1-55N. Our data have shown that ZD55-shMYCN has an additive tumor growth inhibitory response through shRNA-mediated MYCN knockdown and ZD55-mediated cancer cell lysis. In this regard, ZD55-shMYCN can downregulate MYCN and perform anticancer effects, thereby acquiring significance in the administration of MYCN-amplified and p53 null neuroblastomas. Hence, we further investigated the anticancer properties of ZD55-shMYCN in neuroblastomas. Our data showed that ZD55-shMYCN induced G2/M arrest via decreasing the levels of cyclin D1 and cyclin B1 irrespective of p53 status. ZD55-shMYCN effectively induced apoptosis in neuroblastomas through activation of caspase-3 and enhancing PARP cleavage. Furthermore, ZD55-shMYCN could downregulate phosphoinositide 3-kinase and pAkt and upregulate RKIP levels. Similarly, pro-apoptosis was revealed by the histopathologic examination of paraffin-embedded section of resected tumors of mice xenograft. In vitro and in vivo studies, we elucidate the apoptosis properties and mechanisms of action of ZD55-shMYCN, which provide a promising approach for further clinical development. PMID- 25736928 TI - Cancerous inhibitor of protein phosphatase 2A promotes premature chromosome segregation and aneuploidy in prostate cancer cells through association with shugoshin. AB - Yeast two-hybrid (Y2H) studies have shown that cancerous Inhibitor of protein phosphatase 2A (CIP2A) interacted with several proteins, including leucine-rich repeat-containing protein 59 (LRRC59), suggesting that CIP2A may interact with the chromosome maintenance protein, shugoshin (Sgol1). We previously showed that LRRC59 interacted with CIP2A, which was required for CIP2A nuclear localization. Thus, we predicted that CIP2A and Sgol1 may also interact. Sgol1 is a nuclear protein that regulates chromosome segregation during cell division via protection of cohesin ring proteins. Here, we demonstrated that Sgol1 and the C-terminus of CIP2A interact in prostate carcinoma cell lines in a protein phosphatase 2A (PP2A)-dependent manner. Moreover, we demonstrated that depletion of CIP2A in PC 3 cells decreases premature chromosome segregation, whereas overexpression of CIP2A in an immortalized prostate cell line increases premature chromosome segregation. Importantly, we further showed that CIP2A depletion decreases the incidence of aneuploidy and stabilizes cohesin complex proteins, while overexpression of CIP2A destabilizes Sgol1. Thus, our findings strongly suggest that CIP2A promotes cell cycle progression, premature chromosome segregation, and aneuploidy, possibly through a novel interaction with Sgol1. PMID- 25736929 TI - Immunotherapy for lung cancer: for whom the bell tolls? AB - Lung cancer is the leading cause of cancer-related death and accounts for approximately 30% of all cancer deaths. Despite the recent developments in personalized therapy, the prognosis in lung cancer is still very poor. Immunotherapy is now emerging as a new hope for patients with lung cancer. It is well known that standard chemotherapeutic regimens have devastating effects for the patient's immune system. Therefore, the aim of immunotherapy is to specifically enhance the immune response against the tumour. Recently, many trials addressed the role of such therapies for metastatic non-small cell lung cancer (NSCLC) treatment: ipilimumab, tremelimumab, nivolumab and pembrolizumab are immunotherapeutic agents of high relevance in this field. Anti-tumour vaccines, as well as dendritic cell-based therapies, have emerged as potent inducers of immune response against the tumour. Herein, we will review some of the most promising cancer immunotherapies, highlighting their advantages and try to understand, in an immunological perspective, the missteps associated with the current treatments for cancer. PMID- 25736931 TI - Bipartisan, bicameral bill would add pharmacist services to Medicare. PMID- 25736930 TI - Helper component-proteinase enhances the activity of 1-deoxy-D-xylulose-5 phosphate synthase and promotes the biosynthesis of plastidic isoprenoids in Potato virus Y-infected tobacco. AB - Virus-infected plants show strong morphological and physiological alterations. Many physiological processes in chloroplast are affected, including the plastidic isoprenoid biosynthetic pathway [the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway]; indeed, isoprenoid contents have been demonstrated to be altered in virus-infected plants. In this study, we found that the levels of photosynthetic pigments and abscisic acid (ABA) were altered in Potato virus Y (PVY)-infected tobacco. Using yeast two-hybrid assays, we demonstrated an interaction between virus protein PVY helper component-proteinase (HC-Pro) and tobacco chloroplast protein 1-deoxy-D-xylulose-5-phosphate synthase (NtDXS). This interaction was confirmed using bimolecular fluorescence complementation (BiFC) assays and pull down assays. The Transket_pyr domain (residues 394-561) of NtDXS was required for interaction with HC-Pro, while the N-terminal region of HC-Pro (residues 1-97) was necessary for interaction with NtDXS. Using in vitro enzyme activity assays, PVY HC-Pro was found to promote the synthase activity of NtDXS. We observed increases in photosynthetic pigment contents and ABA levels in transgenic plants with HC-Pro accumulating in the chloroplasts. During virus infection, the enhancement of plastidic isoprenoid biosynthesis was attributed to the enhancement of DXS activity by HC-Pro. Our study reveals a new role of HC-Pro in the host plant metabolic system and will contribute to the study of host-virus relationships. PMID- 25736932 TI - Medicare updates pharmacy practice expectations for critical access hospitals. PMID- 25736933 TI - ASHP engages on compounding. PMID- 25736934 TI - Whitney Award recipient Bernard Mehl dies at 81. PMID- 25736935 TI - Hints for success in ASHP's Clinical Skills Competition. PMID- 25736936 TI - Where does AJHP go next? PMID- 25736937 TI - Bosutinib for the treatment of chronic myeloid leukemia. AB - PURPOSE: The pharmacology, pharmacokinetics, efficacy, and safety of the tyrosine kinase inhibitor (TKI) bosutinib in the management of chronic myeloid leukemia (CML) are reviewed. SUMMARY: Although clinical outcomes are favorable in patients wth Philadelphia chromosome (Ph)-positive CML who receive first-line TKI therapy with imatinib, dasatinib, and nilotinib, disease progression or relapse may occur. Thus, effective second-line agents are crucial. Bosutinib (Bosulif, Pfizer Inc.) is a second-generation TKI approved for the treatment of patients with Ph positive chronic-, accelerated-, or blast-phase CML who are intolerant or resistant to other TKIs. Bosutinib inhibits a tyrosine kinase oncogene and Src kinases responsible for CML pathogenesis. Bosutinib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4; therefore, concomitant use of strong or moderate CYP3A4 inhibitors and inducers should be avoided. Bosutinib is effective in cases involving most imatinib-resistant mutations (not including the T315I and V299L mutations). Clinical trials demonstrated bosutinib's efficacy in inducing durable hematologic and cytogenetic responses, as well as high rates of progression-free and overall survival, in patients with CML who had developed resistance or intolerance to other TKIs. However, bosutinib was not found to be superior to imatinib for inducing cytogenetic responses in cases of newly diagnosed CML and is thus not indicated for use in TKI-naive patients. The most common adverse events among bosutinib-treated patients in clinical trials were diarrhea, nausea, and vomiting, which were generally transient and self-limited. CONCLUSION: Bosutinib is a safe and effective second-line treatment option for select patients with Ph-positive CML who were intolerant or resistant to prior TKI therapy. PMID- 25736938 TI - Probable boceprevir-induced hyponatremia in a patient with chronic hepatitis C. AB - PURPOSE: A probable case of severe drug-induced hyponatremia associated with boceprevir use is reported. SUMMARY: A 55-year-old woman was started on boceprevir (800 mg orally thrice daily) during week 5 of triple therapy for chronic hepatitis C. Her serum sodium concentration the morning before starting boceprevir use was 140 mmol/L. After the fourth dose of boceprevir, the patient developed progressive dizziness leading to eventual loss of consciousness. She was taken to the emergency department (ED), where her serum sodium concentration was measured as 126 mmol/L; boceprevir use was temporarily discontinued. The patient's symptoms improved with infusion of 0.9% sodium chloride injection, and she was discharged home the same day. After resuming boceprevir use that evening, the woman developed extreme dizziness and headache upon awakening the next morning. On her return to the ED later that day, she had a serum sodium value of 134 mmol/L and was admitted to the hospital for monitoring and evaluation. Over the next three days, her symptoms improved with additional infusion therapy and discontinuation of boceprevir. The patient continued to receive dual therapy (peginterferon alfa-2a and ribavirin) without further documented serum sodium instability. Using the adverse drug reaction probability scale of Naranjo et al., the case was assigned a score of 5, indicating a probable reaction to boceprevir. CONCLUSION: Soon after initiating boceprevir use as part of hepatitis C triple therapy, a woman required hospitalization for probable drug-induced hyponatremia, which resolved with discontinuation of the medication. PMID- 25736939 TI - Pharmacist-led medication management program within a patient-centered medical home. AB - PURPOSE: The impact of a clinical pharmacist-led medication management program (MMP) within a patient-centered medical home (PCMH) was evaluated. METHODS: This retrospective analysis included patients in Sutter Health's electronic health records who (1) were seen by the MMP clinical pharmacist within the PCMH (MMP cohort), (2) were within the PCMH but were not referred to the MMP pharmacist (PCMH cohort), or (3) received usual care at two non-PCMH primary care clinics (usual care cohort). Patients were matched on their propensity for receiving medication management. The primary outcome measure was healthcare resource use (i.e., ambulatory care visits, emergency department [ED] visits, and hospitalizations). RESULTS: MMP patients had a higher percentage of ambulatory care visits relative to PCMH patients (p = 0.004) but a lower rate of hospitalizations (p = 0.003). The MMP group had a lower frequency of hospitalizations (p < 0.001) and ED visits (p = 0.014) relative to patients in the usual care group. No differences in healthcare resource use were observed between the PCMH and usual care cohorts. Glycosylated hemoglobin, blood pressure, or low-density-lipoprotein cholesterol at goal did not significantly differ among the three cohorts. CONCLUSION: Patients in a pharmacist-led MMP had a significantly higher estimated rate of ambulatory care visits but a lower rate of hospitalizations than did patients who attended the same clinic but were not in the MMP. MMP patients had a similar rate of ambulatory care visits but significantly lower rates of hospitalizations and ED visits than patients receiving usual care. PMID- 25736940 TI - Starting from the bottom. PMID- 25736941 TI - Pharmacist-driven antimicrobial stewardship program in an institution without infectious diseases physician support. AB - PURPOSE: Improved drug-utilization and cost outcomes achieved by a pharmacist-led antimicrobial stewardship program (ASP) are described. SUMMARY: Pharmacists may be tasked to lead ASP development and implementation with little or no support from an infectious diseases (ID) physician and other hospital personnel whose involvement on ASP teams is recommended (e.g., clinical microbiologists, infection control specialists, hospital epidemiologists). Several years ago, Intermountain Healthcare's 325-bed McKay-Dee Hospital in Utah implemented an ASP led by an antimicrobial stewardship pharmacist. In addition to reviewing patient profiles and meeting with physicians to discuss cases daily (Monday-Friday), the pharmacist was available to provide afterhours phone consultations; support was provided by an infection prevention nurse, two physician ASP champions, the pharmacy leadership, pharmacy informatics and hospital laboratory personnel, and the chief medical officer. In the program's first 33 months, the pharmacist made a total of 2,457 interventions or recommendations, with an acceptance rate of 91.8%. Comparison of selected outcomes during one-year periods before and after ASP implementation indicated substantial decreases in the utilization of four commonly used antimicrobial agents and classes (carbapenems, daptomycin, echinocandins, and levofloxacin) in the postimplementation period, with a significant decline in the average length of stay for community-acquired pneumonia (mean +/- S.D., 2.69 +/- 0.10 days versus 3.40 +/- 0.23 days; p = 0.03). Two years after ASP implementation, annual cost savings attributed to the program were estimated at $355,000. CONCLUSION: In the absence of ID physician support and oversight, the pharmacist-led ASP achieved substantial reductions in antimicrobial utilization and associated expenditures. PMID- 25736942 TI - Addressing innovative off-label medication use at an academic medical center. AB - PURPOSE: A large hospital's systematic and evidence-based approach to adjudicating, monitoring, and ensuring the safety of off-label medication use is described. SUMMARY: In 2003 the University of Pittsburgh Medical Center (UPMC) Presbyterian implemented a policy that created a formal process for the systematic evaluation of formulary requests and drug-utilization patterns indicating or suggesting off-label use. Explicit criteria were developed for differentiating "innovative off-label use" (i.e., use based on a reasonable rationale yet lacking definitive scientific support in the form of fully published randomized controlled trials) from medication use more appropriately classified as clinical research. The UPMC-Presbyterian policy also outlined a process for the development, implementation, and evaluation of guidelines on innovative off-label use, including the collection of efficacy and safety outcomes. As of October 2012, 31 proposals for off-label medication use had been evaluated by the medical center's pharmacy and therapeutics committee and formulary subcommittee. Thirteen requests resulted in a determination of innovative off-label use and the development of prescribing guidelines, and 10 prompted the extension of an agent's current formulary status; in 6 cases, proposed off-label uses were determined to constitute clinical research. In some instances, innovative off-label medication use generated safety and outcomes data that led to changes in local standards of care. An algorithm to guide decision making with regard to requests and proposals for off-label medication use is provided. CONCLUSION: The UPMC-Presbyterian experience indicates that off-label medication use can be effectively managed using evidence-based principles and peer review mechanisms. PMID- 25736943 TI - Stability of frozen 1% voriconazole ophthalmic solution. AB - PURPOSE: The physicochemical stability of frozen 1% voriconazole ophthalmic solution was evaluated. METHODS: Multiple batches of voriconazole 10-mg/mL eye drops were aseptically prepared in a laminar-airflow cabinet. One batch was analyzed immediately after preparation, and the rest were stored at -20 degrees C and analyzed using high-performance liquid chromatography at 30, 60, and 90 days to test their physicochemical stability and sterility. All samples were analyzed in triplicate. Additional analyses were performed to determine the solution's in vitro activity once thawed. The sterility of the 1% voriconazole solution was evaluated using blood-agar media and thioglycollate broth. Samples were incubated for 14 days and checked daily for signs of growth. Stability was defined as the absence of particles, color variation, or changes in pH and a remaining antifungal concentration of 90-110% of the initial concentration. RESULTS: All solutions remained clear and colorless throughout the study, and no precipitation or turbidity was observed in any of the batches, regardless of solution temperature. The pH and osmolarity of all batches remained essentially unchanged during storage at -20 degrees C and after thawing. No significant differences in concentration were observed during the storage at -20 or 5 degrees C. The voriconazole concentration remained within 10% of the initial concentration during the 90-day period of storage at -20 degrees C. The percentage of recovery was also optimal after thawing. CONCLUSION: Voriconazole 1% solution prepared for ophthalmic use was stable and retained antifungal activity when stored at -20 degrees C for 90 days. After thawing, this extemporaneously prepared formulation was stable at 5 degrees C for 14 days. PMID- 25736944 TI - Physical compatibility of cisatracurium with selected drugs during simulated Y site administration. AB - PURPOSE: The physical compatibility of cisatracurium with selected drugs during simulated Y-site administration was studied. METHODS: Study drugs were selected based on the lack of physical compatibility data with cisatracurium and their use in intensive care units. Test admixtures were prepared by mixing 2.5-mL samples of varying concentrations of calcium gluconate, diltiazem, esomeprazole, regular insulin, nicardipine, pantoprazole, and vasopressin with either 2.5 mL of normal saline 0.9% (control) or 2.5 mL of cisatracurium (experimental) to simulate a 1:1 Y-site ratio. Drug infusions were prepared at the maximum concentrations used clinically. Physical compatibility of the admixtures was determined by visual and turbidimetric assessments performed in triplicate immediately after mixing and at 15, 30, and 60 minutes. Visual incompatibility was defined as a change in color, the formation of haze or precipitate, the presence of particles, or the formation of gas in the experimental groups compared with the controls. Disturbances invisible to the naked eye were determined by assessing changes in turbidity of experimental admixtures compared with the controls. RESULTS: None of the admixtures exhibited visual changes when mixed with cisatracurium. Six of the seven admixtures exhibited turbidimetric compatibility with cisatracurium. Pantoprazole admixtures demonstrated a significant difference in turbidimetric assessment between the control and experimental groups when mixed with cisatracurium (p < 0.001). CONCLUSION: Calcium gluconate, diltiazem hydrochloride, esomeprazole, regular insulin, nicardipine hydrochloride, and vasopressin demonstrated physical compatibility with cisatracurium over 60 minutes during simulated Y-site administration. Cisatracurium and pantoprazole should not be coadministered due to a significant difference in turbidity between control and experimental samples. PMID- 25736945 TI - Pharmacist provision of patient medication education groups. PMID- 25736946 TI - How mobile devices are changing pharmacy practice. PMID- 25736947 TI - An outbreak of viral conjunctivitis in an Irish military deployment to Liberia. PMID- 25736948 TI - The novel neuropeptide phoenixin is highly co-expressed with nesfatin-1 in the rat hypothalamus, an immunohistochemical study. AB - The hypothalamus regulates a number of autonomic functions essential for homeostasis; therefore, investigations concerning hypothalamic neuropeptides and their functions and distribution are of great importance in contemporary neuroscience. Recently, novel regulatory factors expressed in the hypothalamus have been discovered, of which nesfatin-1 and phoenixin (PNX), show intriguing similarities in their brain distributions. There are currently few studies characterizing PNX expression, so it is imperative to accurately trace its localization, with particular attention to the hypothalamic nuclei and nesfatin-1 co-expression. Using fluorescence and classical immunohistochemical stainings on adult rat brain, we visualized the potential co-expression of nesfatin-1 and PNX immunoreactive cells. We have demonstrated a distinct PNX-immunoreactivity in 21 32% of cells in the arcuate nucleus, paraventricular nucleus, ventromedial and lateral hypothalamus. Nesfatin-1 expression reached 45-68% of all neurons in the same sites, while co-expression was strikingly seen in the vast majority (70-86%) of PNX-immunoreactive neurons in the rat hypothalamic nuclei. Our results demonstrate for the first time, a wide distribution of PNX in the hypothalamus which could implicate a potential functional relationship with nesfatin-1, possibly in the regulation of the hypothalamic-pituitary-gonadal axis or other autonomic functions, which require further study. PMID- 25736949 TI - Neural mechanism of facial expression perception in intellectually gifted adolescents. AB - The current study investigated the relationship between general intelligence and the three stages of facial expression processing. Two groups of adolescents with different levels of general intelligence were required to identify three types of facial expressions (happy, sad, and neutral faces), which were presented with either inverted or upright orientation. Participants' response times and accuracy were measured and event-related potentials (ERPs) were recorded to evaluate neural dynamic processes. The behavioral results showed that high IQ adolescents exhibited shorter response times than average IQ adolescents during the facial expression identification task. The electrophysiological responses showed that no significant IQ-related differences were found for P1 responses during the early visual processing stage. During the middle processing stage, high IQ adolescents had faster structural encoding of inverted faces (shorter N170 latencies) compared to their average IQ peers, and they also showed better structural encoding of sad faces, with larger vertex positive potential (VPP) amplitudes than for neutral faces. During the late processing stage, adolescents with high IQ showed better attentional modulation, with larger late positive potential (LPP) amplitudes compared to adolescents with average IQ. The current study revealed that adolescents with different intellectual levels used different neural dynamic processes during these three stages in the processing of facial expressions. PMID- 25736950 TI - Early microlesion of viral encephalitis confirmed by galectin-3 expression after a virus inoculation. AB - Galectin-3 is a beta-galactosidase-binding lectin which is important in cell proliferation and apoptotic regulation. Encephalomyocarditis virus (EMCV), which includes the Enterovirus genus, can cause not only acute myocarditis but also neuronal degeneration of central nervous system in various animals including mice. The pathophysiological role of galectin-3 in central nervous system following acute viral infection is not fully understood. The goal of this study is to determine the localization and time-course of galectin-3 expression after acute viral inoculation with EMCV. Galectin-3 is up-regulated in degenerated lesions of brain area including cerebellum, hippocampus, thalamus and cerebral hemisphere, 96 h after EMCV inoculation. At the same time, Iba-1 positive microglia was morphologically activated within and around the focus of infection. Interestingly, in cerebellum, the microlesions containing a few galectin-3 cells were detected in the immediate-early phase of infection, as early as 48 h after EMCV inoculation. Thus, our results indicate that galectin-3 expression may be a key mediator between viral infection and neuronal degeneration in central nervous system including cerebellum. Furthermore, detection of galectin-3 might be an early diagnostic method for neuronal degeneration after virus infection. PMID- 25736951 TI - Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis. AB - Optic neuritis is inflammation of the optic nerve and is strongly associated with multiple sclerosis (MS), an inflammatory demyelinating syndrome of the central nervous system. It leads to retinal ganglion cell (RGC) death and can cause severe vision loss. Brimonidine (BMD) is a selective alpha2-adrenergic receptor agonist that is used clinically for the treatment of glaucoma. BMD lowers intraocular pressure, but recent evidence suggests that its therapeutic efficacy may also mediate through mechanisms independent of modulation of intraocular pressure. In this study, we examined the effects of topical administration of BMD on retinal degeneration during optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE was induced with MOG35-55 in C57BL/6J mice and BMD eyedrops were applied daily. In the EAE retina, the number of RGCs was significantly decreased and this effect was suppressed with BMD treatment. Consistent with histological analyses, the visual impairment observed in EAE mice was inhibited with BMD treatment, indicating the functional significance of the neuroprotective effect of BMD. Furthermore, BMD increased the expression level of basic fibroblast growth factor in the EAE retina, particularly in Muller glial cells and RGCs. Our findings suggest that topical administration of BMD may be available for RGC protection during optic neuritis, as well as for glaucoma. PMID- 25736952 TI - The prevalence and risk factors of low back pain in the eastern Black Sea region of Turkey. AB - BACKGROUND: Low back pain (LBP) is a public health problem commonly seen in all societies. OBJECTIVE: The aim of this study was to determine the prevalence and specific risk factors of low back pain (LBP) in the central and outlying districts of the province of Trabzon, a Black Sea region of Turkey. METHOD: A random sample of 7897 (4006 men and 3789 women) adults was collected by using sampling techniques of stratification. In this study questionnaires were completed at face-to-face interviews with participants selected on the basis of place of residence, gender and age group. The used variables in this study were: use of cigarettes, status of marriage, level of education, and presence of chronic disease, the prevalence of lifetime LBP and of LBP in the preceding year. Chronic LBP was determined as being present for more than 6 weeks. RESULTS: The lifetime prevalence of LBP in the general population was determined at 62.1%. Prevalence in the preceding year was 46.1%, and that of LBP lasting more than six week was 18.1%. Lifetime prevalence of LBP, prevalence of LBP in the preceding year and prevalence of pain lasting more than six week were all statistically significantly higher in women (p< 0.001). Use of cigarettes, female gender, marriage, a low level of education and presence of chronic disease were identified as independent risk factors for LBP (p< 0.001). CONCLUSION: Lower back pain is a common public health problem. Recommendations were made for local health services to prevent LBP, including health education through combating chronic diseases, reducing cigarette consumption, improvement of working environments and life styles. PMID- 25736953 TI - Selective recruitment of the thoracic erector spinae during prone trunk-extension exercise. AB - OBJECTIVE: This study examined the effect of modified prone trunk-extension (PTE) exercises on selective activity of the thoracic erector spinae. METHODS: Thirty nine healthy subjects performed four modified PTE exercises, involving location of the edge of the table (iliac crests [IC] vs. xiphoid process [XP]) and the degree of trunk extension (horizontal vs. hyperextension). Electromyography signals were collected bilaterally from the longissimus thoracis (LT), iliocostalis thoracis (ICT), and iliocostalis lumborum (ICL). Normalized LT:ICL and ICT:ICL ratios were calculated. The data were analyzed using a repeated measures two-way analysis of variance. RESULTS: The LT:ICL and ICT:ICL ratios were significantly higher under the XP than the IC condition (p < 0.05); however, the degree of trunk extension did not affect the ratio (p > 0.05). Activity in the lumbar erector spinae and left ICT muscles was greater when subjects were in the hyperextended position than in the horizontal position. Moreover, activity in the thoracic erector spinae was greater when the table edge was aligned with the IC compared with the XP (p < 0.05). CONCLUSIONS: Our findings suggest that PTE exercise with the XP aligned with the table edge increased the selective activation of the thoracic erector spinae muscles. PMID- 25736954 TI - Effects of William training on lumbosacral muscles function, lumbar curve and pain. AB - BACKGROUND: There are many types of treatments and recommendations for restoring back deformities depending on doctors' knowledge and opinions. The purpose of the exercises is to reduce pain and to ensure stability of the lower trunk by toning the abdominal muscles, buttocks and hamstrings. Given the duration of flares and relapses rate, it is important to apply an efficient and lasting treatment. OBJECTIVE: To evaluate the effects of 8 weeks of William's training on flexibility of lumbosacral muscles and lumbar angle in females with Hyperlordosis. METHODS: Forty female students with lumbar lordosis more than normal degrees (Hyperlordotic) that were randomly divided into exercise and control groups were selected as the study sample. The lumbar lordosis was measured using a flexible ruler, flexibility of hamstring muscles was measured with the active knee extension test, the hip flexor muscles strength was measured using Thomas test, the lumbar muscles flexibility measures by Schober test, abdominal muscles strength measured by Sit-Up test and back pain was measured using McGill's Visual Analogue Scales (VAS) questionnaire. Data were compared before and post-test using independent and paired t-testes. RESULTS: Results showed that 8 weeks of William's exercise led to significant decreases in lumbar angle and back pain, increases in flexibility of hamstring muscles, hip flexor muscles flexibility, lumbar extensor muscles flexibility and abdominal muscles strength. CONCLUSION: The findings show that William's corrective training can be considered as a useful and valid method for restoring and refining back deformities like as accentuated back-arc and became wreaked muscles' performance in lumbar areas. PMID- 25736955 TI - Do psychological states associate with pain and disability in chronic neck pain patients? AB - BACKGROUND: Chronic neck pain is one of the most usual neuromusculoskeletal pain conditions which can lead patients to chronic disability. Similarly to other pain conditions, the changed psychological status of these patients is believed to be associated with their pain condition and disability. However, the association between the psychological status of patients with idiopathic neck pain and their pain intensity and disability is minimally explored. OBJECTIVE: This study was aimed at investigating the association between psychological states (anxiety, depression, kinesiophobia, catastrophizing) of patients with chronic idiopathic neck pain and self-reported pain and disability. METHODS: Forty five patients with idiopathic chronic neck pain (more than 6 months, at least once a week) participated. Their psychological states were assessed by using the Hospital Anxiety and Depression scale, Pain Catastrophizing scale and Tampa Scale for Kinesiophobia. Self-reported disability was recorded with the Neck Disability Index. Pain intensity was recorded by using a visual analog scale. RESULTS: Neck pain intensity was significantly correlated with anxiety (p< 0.05). Disability was significantly correlated with anxiety, depression and catastrophizing (p< 0.05). Multiple regression analysis showed that pain-induced disability can be significantly predicted by anxiety and catastrophizing (p< 0.05). CONCLUSIONS: It can be concluded that anxiety, depression and catastrophizing of patients with chronic neck pain is associated with their self-reported disability, whereas anxiety is also associated with their pain intensity. Anxiety and catastrophizing may be important predicting markers of patients' self-reported disability. PMID- 25736956 TI - Musculoskeletal system problems and quality of life of mothers of children with cerebral palsy with different levels of disability. AB - OBJECTIVE: The objective of this study is to investigate musculoskeletal system problems and quality of life of mothers of children with cerebral palsy with different levels of disability. METHODS: 100 children (37 girls and 63 boys) with cerebral palsy (CP) and their mothers were included in this study. Functional levels of children with CP were assessed by using the Gross Motor Function Classification System (GMFCS) and the Pediatric Functional Independence Measure (WeeFIM). Quality of life of mothers regarding health was assessed by using the Nottingham Health Profile (NHP). Musculoskeletal system problems of mothers were assessed by using the Neck Disability Index (NDI) and the Roland-Morris Disability Questionnaire (RMDQ). RESULTS: No statistical significance was found when GMFCS levels of children with CP and the NHP, DASH-T, RMDQ, NDI and the BAE values of mothers were compared in an inter-group way (p> 0.05). When the NHP parameters and the existence of lower and arm pains of mothers were compared with their BAI, NDI, RMDQ and DASH-T scores, a statistically significant relationship was found among them (p< 0.05). CONCLUSION: As functional levels of children with CP get worse, upper extremity, lower back and neck problems and anxiety levels of mothers increase and this situation negatively affects mothers' quality of life. PMID- 25736957 TI - Effectiveness of targeted home-based hip exercises in individuals with non specific chronic or recurrent low back pain with reduced hip mobility: A randomised trial. AB - BACKGROUND: The relationship between low back pain (LBP) and reduced hip rotation has been well established. However, there is a lack of studies investigating the effect of treatment targeted at the hip in people with LBP. OBJECTIVE: The aim of this study was to assess the level of effectiveness that different types of exercises targeted at the hip had on pain and function in individuals with non specific chronic or recurrent LBP with concurrent reduced hip rotation. METHOD: Thirty participants were assigned to one of three exercise groups: hip rotation stretching, multi-directional hip stretching and hip strengthening. All groups participated in a six week home exercise program. Pain (numerical rating scale), functional disability (Modified Oswestry Disability Questionnaire; MOD), and hip rotation measurements were assessed at baseline and post intervention. RESULTS: Results revealed that all exercise groups were effective in improving pain and function (MOD) (P< 0.05). Between group comparisons revealed that hip strengthening was more effective than hip rotation exercises in improving functional disability (P= 0.03). The majority of participants in all groups (60 70%) demonstrated clinical improvements in pain, but only the hip strengthening group had the majority of participants (80%) exhibit clinical improvements in function. CONCLUSION: In individuals with non-specific LBP and reduced hip rotation, clinical intervention of providing exercises targeted at the hip can be beneficial in improving pain and function, with strengthening exercises most beneficial for improving function. PMID- 25736958 TI - Laboratory evaluation of suspected motor neuron disease: A survey of physicians. AB - INTRODUCTION: The clinical diagnosis of amyotrophic lateral sclerosis (ALS) relies on exclusion of mimic syndromes, but there are no specific guidelines regarding the extent of laboratory testing required. METHODS: A survey was sent to 274 physicians listed in the Neuromuscular Section of the American Academy of Neurology. The survey asked how often they order 21 different laboratory tests in patients suspected of having ALS. RESULTS: Ninety-nine responses were received (36% response rate). Greater than 75% ordered serum creatine kinase, chemistry panel, and thyroid functions often or always. Fewer than 25% tested for serum complement, hexosaminidase A, spinal muscular atrophy, Kennedy disease, heavy metals, or human T-cell lymphotrophic virus often or always. Twelve other tests had intermediate responses. CONCLUSIONS: There is a lack of consensus among respondents regarding the laboratory evaluation of suspected ALS. Prospective studies are needed to define the diagnostic yield and cost-effectiveness of laboratory testing in this population. PMID- 25736959 TI - [On-call burnout in the family physician]. PMID- 25736960 TI - Long-term kinetics of AA amyloidosis and effects of inflammatory restimulation after disappearance of amyloid depositions in mice. AB - Amyloid A (AA) amyloidosis is characterized by extracellular pathogenic deposition of insoluble fibril protein in various body organs. Deposited amyloid generally remains in a variety of organs for long periods, but its disappearance has been reported after the precursor protein is diminished. The kinetics of AA deposition are not completely understood and, in particular, the roles of cells and cytokines in the deposition and clearance of amyloid remain unclear. In this study, we investigated the disappearance of amyloid depositions in mice over a 1 year period. AA amyloidosis was induced experimentally in mice by injecting amyloid-enhancing factor (AEF) and silver nitrate. Mice were killed at different time-points to examine the occurrence and disappearance of amyloid depositions. Maximum levels of amyloid depositions were observed at 20 days after inoculation. Clearance of amyloid depositions was observed from the 40th day onwards, with only minute traces of amyloid present by 240 days. A second inflammatory stimulus consisting of AEF and silver nitrate was given at 330 or 430 days, after amyloid depositions had disappeared almost completely. After that, serum amyloid A was overproduced and redeposition of amyloid was observed, indicating that all mice were primed for aggressive amyloid depositions. After administration of the inflammatory stimuli, the proinflammatory environment was found to have increased levels of interleukin (IL)-6, while anti-inflammatory conditions were established by IL-10 as regression of amyloid deposition occurred. These results suggest that the proinflammatory and anti-inflammatory status have key roles in both amyloid deposition and clearance. PMID- 25736961 TI - STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma. AB - Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Go6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Go6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3 S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705 negative GBM could be a relevant approach to improve radiation therapy. PMID- 25736962 TI - Measurement of empathy among Argentine cardiologists: Psychometrics and differences by age, gender, and subspecialty. AB - BACKGROUND: Cardiologists are involved in the management of patients with multiple cardiovascular risk factors and chronic heart diseases, so empathy is a necessary feature to deal with them. The aim of the study was to evaluate the validity and reliability of the Spanish version of the Jefferson Scale of Physician Empathy (JSPE) among Argentine cardiologists and to explore the potential differences by age, gender, and subspecialty. METHODS: Between August and September 2012, we performed a survey in a non-randomized sample of 566 Spanish-speaking cardiologists of Argentina. A Principle Component Analysis (PCA) was used to explore the link between observed variables and latent variables in order to identify the factor structure. The PCA criteria for identifying the factor structure were examined with the Kaiser-Meyer-Olkin (KMO) analysis. RESULTS: The KMO measure of sampling adequacy was 0.86 and Bartlett's test of sphericity was highly significant (p = 0.000), determining the suitability of the data set for factor analysis. The PCA of 20 items yielded a three factor model that accounted for 40.6% of the variance. The JSPE mean rank score for women was 307.9 vs. 275.0 for men (p = 0.017). The comparison of mean rank score according to age (quartiles) showed a significant relation between older age and empathy. No difference was found when the mean rank scores were compared by respondent subspecialty. CONCLUSIONS: JSPE provides a valid and reliable scale to measure Argentine cardiologists' attitudes towards empathy. Female cardiologists seem to be more empathic than their male colleagues, and a positive relationship between age and empathy was found. PMID- 25736963 TI - Anemia and renal dysfunction: Two different conditions but same results in cardiovascular disease. PMID- 25736964 TI - Authors' response. PMID- 25736965 TI - Comparison of the electronic and vibrational optical activity of a europium(III) complex. AB - The geometry and the electronic structure of chiral lanthanide(III) complexes are traditionally probed by electronic methods, such as circularly polarised luminescence (CPL) and electronic circular dichroism (ECD) spectroscopy. The vibrational phenomena are much weaker. In the present study, however, significant enhancements of vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectral intensities were observed during the formation of a chiral bipyridine-Eu(III) complex. The ten-fold enhancement of the vibrational absorption and VCD intensities was explained by a charge-transfer process and the dominant effect of the nitrate ion on the spectra. A much larger enhancement of the ROA and Raman intensities and a hundred-fold increase of the circular intensity difference (CID) ratio were explained by the resonance of the lambda = 532 nm laser light with the (7)F0 -> (5)D0 transitions. This phenomenon is combined with a chirality transfer, and mixing of the Raman and luminescence effects involving low-energy (7)F states of europium. The results thus indicate that the vibrational optical activity (VOA) may be a very sensitive tool for chirality detection and probing of the electronic structure of Eu(III) and other coordination compounds. PMID- 25736966 TI - Applications of a versatile modelling approach to 3D atom probe simulations. AB - The article addresses application examples of a flexible simulation approach, which is based on an irregular mesh of Voronoi cells. The detailed atomic structure of APT field emitters is represented by Wigner-Seitz cells. In this way, arbitrary crystal structures can be modelled. The electric field results from the solution of the Poisson equation. The evaporation sequence of atoms from the emitter surface is enabled by calculation of the field-induced force, which acts on the surface cells. Presented examples show simulated field desorption maps of a cubic fcc <111> structure in comparison to the close-packed hcp <0001> structure. Additionally, the desorption maps of the cubic sc, bcc, and fcc lattices in <011> orientation are presented. The effect of inhomogeneous evaporation conditions on the emitter apex curvature is demonstrated. Reconstructions derived from the simulation of Sigma5 GBs differently inclined with respect to the emitter axis are analyzed. Finally, the stress exerted on an embedded nano-particle during the simulated evaporation with inhomogeneous evaporation thresholds is estimated. PMID- 25736967 TI - Synthesis, characterization and investigation of the photophysical and photochemical properties of highly soluble novel metal-free, zinc(II), and indium(III) phthalocyanines substituted with 2,3,6-trimethylphenoxy moieties. AB - This work presents the synthesis and characterization of metal-free, zinc(II), and indium(III)acetate phthalocyanines substituted with 2,3,6-trimethylphenoxy groups at the peripheral and non-peripheral positions. The photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen generation and photodegradation under light irradiation) properties of these novel phthalocyanines and unsubstituted zinc(II) and indium(III)acetate phthalocyanines were investigated in dimethylformamide solution. The effects of the types of substituents and their positions and the variety of central metal ions on the phthalocyanine core on their spectroscopic, photophysical and photochemical properties were also determined. The studied 2,3,6-trimethylphenoxy substituted metal-free, zinc(II) and indium(III)acetate phthalocyanines especially indium(III)acetate derivatives exhibited appropriate photophysical and photochemical properties such as high singlet oxygen generation and these phthalocyanines can be potential Type II photosensitizers for photodynamic therapy in cancer applications. PMID- 25736968 TI - How reliable are sympathetic skin responses in subjects with spinal cord injury? AB - OBJECTIVE: To determine the test-retest reliability of sympathetic skin responses (SSR) in individuals with spinal cord injury (SCI). METHODS: Fourteen men and four women with traumatic SCI (age: 44 +/- 18 years; C2-T11; AIS A-D; 1-383 months post-injury) participated in two electrophysiological testing sessions separated by an average of 1 day. During each session, sudomotor function was tested supine by recordings of SSRs in both hands and feet. Two stimulation approaches were chosen: median nerve stimulation and a deep breath maneuver. SSR recordings were analyzed as SSR scores representing the presence or absence of responses. In addition, SSR amplitude and latencies were calculated. Test-retest reliability for the SSR score was calculated by the intraclass correlation coefficient (ICC) and its confidence interval. Coefficient of variation (CV) was calculated for SSR amplitudes and latencies. RESULTS: SSR score to median nerve stimulation demonstrated 'almost perfect' reliability with ICCs of 0.97 and 0.96, for both hands and feet, respectively. The SSR score to deep breath maneuver was slightly lower, such as 0.89 and 0.74 for hands and feet. The CV of SSR amplitudes to median nerve stimulation was 48 and 18% for hands and feet, respectively, and 7 and 12% for the latency. INTERPRETATION: The qualitative interpretation of SSR by its presence or absence is a reliable way to assess sudomotor function in individuals with SCI. Although methodical procedures try to standardize SSR testings, quantitative SSR outcomes (amplitude, latency) are still highly variable. PMID- 25736969 TI - Characterization of lysophosphatidylcholine-induced changes of intracellular calcium in Drosophila S2 cells. AB - AIMS: Lysophosphatidylcholine (LPC), a bioactive lipid, regulates a wide array of biological processes. LPC could be deacylated to form glycerophosphocholine by neuropathy target esterase (NTE)/Swiss cheese protein (SWS). Although NTE/SWS is important in maintaining Ca(2+) homeostasis, the role of LPC in regulating the intracellular calcium concentration ([Ca(2+)]i) in Drosophila remains poorly understood. We aimed to study the mechanism of LPC-induced [Ca(2+)]i changes in Drosophila S2 cells. MAIN METHODS: The [Ca(2+)]i of Drosophila S2 cells was measured by fluorescence spectrophotometry after loading the cells with the calcium-sensitive fluorescent probe Fura-2/AM. KEY FINDINGS: Our results demonstrated that LPC could cause a rapid, dose-dependent increase in the [Ca(2+)]i in the presence of external calcium ([Ca(2+)]e). The LPC-induced [Ca(2+)]i increase was reduced by 60.7% in the absence of [Ca(2+)]e. Furthermore, the Ca(2+) influx was inhibited by 37.3% after the cells were preincubated with an L-type Ca(2+) channel blocker. In the Ca(2+)-free medium, the LPC-induced [Ca(2+)]i increase was completely blocked using an inositol triphosphate receptor (IP3R) inhibitor. However, a ryanodine receptor (RyR) inhibitor had no effect on the LPC-induced [Ca(2+)]i increase. SIGNIFICANCE: The LPC-induced [Ca(2+)]i increase in S2 cells was dependent on both the release of Ca(2+) stored in the endoplasmic reticulum and [Ca(2+)]e influx. Both L-type Ca(2+) channels and IP3R might be involved in this process. The LPC-induced [Ca(2+)]i increase in S2 cells characterized in this study may shed light on the study of NTE/SWS protein function in general because the enzyme is responsible for the deacylation of LPC. PMID- 25736970 TI - Depression is associated with increased vagal withdrawal during unpleasant emotional imagery after cardiac surgery. AB - BACKGROUND: The aim of this study was to examine the influence of depression on heart rate and heart rate variability (HRV) during emotional imagery in patients after cardiac surgery. METHODS: Based on the scores of the Center for Epidemiological Studies of Depression (CES-D) scale, 28 patients after cardiac surgery were assigned either to the group with depression (CES-D scores >= 16; N = 14) or the one without depression (CES-D scores<16; N = 14). Each patient completed a rest period and an emotional imagery including pleasant, neutral and unpleasant scripts. Inter-beat intervals (IBIs) and HRV were measured during the entire protocol. RESULTS: Compared to nondepressed patients, those with depression had greater reductions in high frequency expressed in normalized units (HF n.u.) during the imaging of the unpleasant script (p = .003, Cohen's d = 1.34). Moreover, HF n.u. were lower during the imaging of the unpleasant script than the pleasant one in depressed patients only (p = .020, Cohen's d = 0.55). CES-D scores were also inversely correlated with residualized changes in IBIs (r = -.38, p = .045) and HF n.u. (r = -.49, p = .008) from rest to the imaging of the unpleasant script. CONCLUSIONS: The relationship between depression and increased vagal withdrawal during unpleasant emotional imagery extends to patients after cardiac surgery. The present study suggests that increased vagal withdrawal to negative emotions in patients after cardiac surgery may mediate the conferral of cardiac risk by depression. PMID- 25736971 TI - Diminished event-related cortical arousals and altered heart rate response in Parkinson's disease. AB - OBJECTIVES: In Parkinson's disease (PD), partial neuronal loss occurs in several arousal-promoting structures, but the effects on arousability have not yet been studied. METHODS: Polysomnographic analysis of 70 PD patients and 70 control subjects matched for age, sex, body mass index, apnea-hypopnea index (AHI), and periodic limb movements in sleep index (PLMSI). RESULTS: In PD patients, arousal frequency was diminished by 50% compared with controls (9.1 +/- 7.6 vs. 18.6 +/- 22.9/h; P < 0.001), and the correlations with AHI (rho = 0.266 vs. 0.503, P = 0.004) and PLMSI (rho = 0.082 vs. 0.354, P = 0.006) were weaker. Hoehn & Yahr stage was an independent negative predictor of arousal index (beta = -0.297, P = 0.015). Normalization of heart rate increase after cortical arousals was prolonged in PD patients compared with controls (P = 0.003). CONCLUSION: Our findings indicate that the neurodegenerative process in PD is associated with an attenuated arousability to respiratory and motor events, and with an alteration of the heart rate pattern accompanying arousals. PMID- 25736973 TI - Subacute sclerosing panencephalitis with parkinsonian features in a child: A case report. AB - BACKGROUND: Subacute sclerosing panencephalitis (SSPE) can present with atypical clinical signs which may result in delayed diagnosis and treatment. We present a child with SSPE whose initial manifestation was parkinsonism. PATIENT: This 12 year-old boy presented with the complaint of difficulty in standing up and walking for 2 months. Neurological examination revealed generalized rigidity, bradykinesia, impaired postural reflexes, and a mask-like facies. The initial diagnosis of Juvenile Parkinson Disease was made. He had no improvement with levodopa, trihexyphenidyl, tetrabenazine and clonazepam. The EEG showed irregular background activity with generalized slow waves which were not suppressed with diazepam injection. SSPE was considered and the diagnosis was confirmed with the identification of measles antibodies in cerebrospinal fluid. CONCLUSION: SSPE should be considered in children and adolescents with parkinsonian symptoms, particularly in the absence of a history of vaccination against measles. PMID- 25736974 TI - Mixed movements disorders as an initial feature of pediatric lupus. AB - Systemic lupus erythematosus (SLE) is an immunologic disease of the early adulthood. In children, SLE is rare and neurological onset is uncommon. We report on an observation of pediatric lupus in heterozygous twins revealed by mixed movement disorders. CASE REPORT: An 8-year-old boy, born to non consanguineous parents, with a family history of depression and a personal history of macular eruption, inflammatory polyarthralgias and a recurrent angina presented with acute movement and mood disorders. Neurological exam showed mild generalized choreic movements with motor and vocal tics. Antinuclear antibodies were positive. Brain MRI was normal. One year after, his twin brother presented with the same features. DISCUSSION: Movement disorders are described in pediatric lupus but are unusual as inaugural features of the disease. In SLE, movement disorders such as chorea are usually reported. However, Tics seem to be exceptional. Pathophysiology remains unclear. Early onset and familial form support genetic implication in the pathogenesis of lupus. CONCLUSION: Immune mediated movement disorders such as in SLE are an established cause of acute movement disorders in child. PMID- 25736975 TI - Impact of metformin on anti-Mullerian hormone in women with polycystic ovary syndrome: a secondary analysis of a randomized controlled trial. AB - Conclusions on the effect of metformin on circulating anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) are ambiguous. We performed a secondary analysis of a randomized, double-blind, placebo-controlled cross-over trial. Fifty-six women with hyperandrogenemic PCOS were included. Each woman served as her own control receiving a daily dose of either 1700 mg metformin or placebo for 6 months. After a 3-month wash-out period they received the opposite treatment. The decrease in AMH from a median of 49.5 to 46.9 pmol/L after 6 months on metformin was overall not significant (p = 0.81), nor were changes in obese women (from 49.5 to 38.2 pmol/L; p = 0.53). Comparing individual metformin/placebo AMH values, a small absolute decrease of 9.3 pmol/L (p = 0.03) was observed in obese women after 6 months relative to baseline, suggesting a trend towards decreasing values after metformin treatment, mainly in obese women. PMID- 25736976 TI - Cowpea-Meloidogyne incognita interaction: Root proteomic analysis during early stages of nematode infection. AB - Cowpea (Vigna unguiculata L. Walp) is an important legume species well adapted to low fertility soils and prolonged drought periods. One of the main problems that cause severe yield losses in cowpea is the root-knot nematode Meloidogyne incognita. The aim of this work was to analyze the differential expression of proteins in the contrasting cultivars of cowpea CE 31 (highly resistant) and CE 109 (slightly resistant) during early stages of M. incognita infection. Cowpea roots were collected at 3, 6, and 9 days after inoculation and used for protein extraction and 2-DE analysis. From a total of 59 differential spots, 37 proteins were identified, mostly involved in plant defense, such as spermidine synthase, patatin, proteasome component, and nitrile-specifier protein. A follow-up study was performed by quantitative RT-PCR analysis of nine selected proteins and the results revealed a very similar upregulation trend between the protein expression profiles and the corresponding transcripts. This study also identified ACT and GAPDH as a good combination of reference genes for quantitative RT-PCR analysis of the pathosystem cowpea/nematode. Additionally, an interactome analysis showed three major pathways affected by nematode infection: proteasome endopeptidase complex, oxidative phosphorylation, and flavonoid biosynthesis. Taken together, the results obtained by proteome, transcriptome, and interactome approaches suggest that oxidative stress, ubiquitination, and glucosinolate degradation may be part of cowpea CE 31 resistance mechanisms in response to nematode infection. PMID- 25736977 TI - Persistence of smoking-cessation decision support use in a dental practice. AB - INTRODUCTION: A computer-assisted tobacco decision support tool increased dental practitioners' (dentists and dental hygienists) advice to quit smoking and referral to a quitline during a group randomized trial. The purpose of this study is to document the extent to which use persisted after the trial. METHODS: Electronic dental record (EDR) data from 2010 to 2013 were analyzed in 2014 for use of computer-assisted tobacco intervention tool advice scripts and referral to a quitline during four periods: during the trial and post-trial when only intervention clinic dental practitioners had access to the tool, and during full deployment, both before and after an EDR modification. RESULTS: Intervention clinic dental practitioners (18.5 dentist full-time equivalents [FTEs] and 27.8 dental hygienist FTEs practicing in seven clinics) referred 19.0% of 1,368 smokers to a quitline during the trial and referred 15.4% of 4,011 smokers post trial. After full tool deployment but pre-EDR change, these dental practitioners referred 15.6% of 2,214 intervention clinic smokers, whereas 18.3 dentist FTEs and 29.7 dental hygienist FTEs practicing in eight clinics referred 8.5% of 2,113 smokers. Post-EDR change, dental practitioners referred 12.2% of 2,214 intervention clinic smokers and 8.1% of 2,399 control clinic smokers to a quitline. In the last three quarters of observation, clinic script use ranged from 15.4% to 65.8% and referral to a quitline ranged from 2.0% to 18.7% of visits. CONCLUSIONS: Although EDR design affected rates of referral, dental practitioners persisted in using a computer-assisted tobacco intervention tool to refer smokers to a quitline. PMID- 25736978 TI - Rising suicide among adults aged 40-64 years: the role of job and financial circumstances. AB - INTRODUCTION: Suicide rates among middle-aged men and women in the U.S. have been increasing since 1999, with a sharp escalation since 2007. PURPOSE: To examine whether suicides with circumstances related to economic crises increased disproportionately among the middle-aged between 2005 and 2010. METHODS: This study used the National Violent Death Reporting System (NVDRS) in 2014 to explore trends and patterns in circumstance and method among adults aged 40-64 years. RESULTS: Suicide circumstances varied considerably by age, with those related to job, financial, and legal problems most common among individuals aged 40-64 years. Between 2005 and 2010, the proportion of suicides where these circumstances were present increased among this age group, from 32.9% to 37.5% of completed suicides (p<0.05). Further, suffocation is a method more likely to be used in suicides related to job, economic, or legal factors, and its use increased disproportionately among the middle-aged. The number of suicides using suffocation increased 59.5% among those aged 40-64 years between 2005 and 2010, compared with 18.0% for those aged 15-39 years and 27.2% for those aged >65 years (p<0.05). CONCLUSIONS: The growth in the importance of external circumstances and increased use of suffocation jointly pose a challenge for prevention efforts designed for middle-aged adults. Suffocation is a suicide method that is highly lethal, requires relatively little planning, and is readily available. Efforts that target employers and workplaces as important stakeholders in the prevention of suicide and link the unemployed to mental health resources are warranted. PMID- 25736980 TI - Distribution and evolution of nitrogen fixation genes in the phylum Bacteroidetes. AB - Diazotrophs had not previously been identified among bacterial species in the phylum Bacteroidetes until the rapid expansion of bacterial genome sequences, which revealed the presence of nitrogen fixation (nif) genes in this phylum. We herein determined the draft genome sequences of Bacteroides graminisolvens JCM 15093(T) and Geofilum rubicundum JCM 15548(T). In addition to these and previously reported 'Candidatus Azobacteroides pseudotrichonymphae' and Paludibacter propionicigenes, an extensive survey of the genome sequences of diverse Bacteroidetes members revealed the presence of a set of nif genes (nifHDKENB) in strains of Dysgonomonas gadei, Dysgonomonas capnocytophagoides, Saccharicrinis fermentans, and Alkaliflexus imshenetskii. These eight species belonged to and were distributed sporadically within the order Bacteroidales. Acetylene reduction activity was detected in the five species examined, strongly suggesting their diazotrophic nature. Phylogenetic analyses showed monophyletic clustering of the six Nif protein sequences in the eight Bacteroidales species, implying that nitrogen fixation is ancestral to Bacteroidales and has been retained in these species, but lost in many other lineages. The identification of nif genes in Bacteroidales facilitates the prediction of the organismal origins of related sequences directly obtained from various environments. PMID- 25736981 TI - Temperature alone does not explain phenological variation of diverse temperate plants under experimental warming. AB - Anthropogenic climate change has altered temperate forest phenology, but how these trends will play out in the future is controversial. We measured the effect of experimental warming of 0.6-5.0 degrees C on the phenology of a diverse suite of 11 plant species in the deciduous forest understory (Duke Forest, North Carolina, USA) in a relatively warm year (2011) and a colder year (2013). Our primary goal was to dissect how temperature affects timing of spring budburst, flowering, and autumn leaf coloring for functional groups with different growth habits, phenological niches, and xylem anatomy. Warming advanced budburst of six deciduous woody species by 5-15 days and delayed leaf coloring by 18-21 days, resulting in an extension of the growing season by as much as 20-29 days. Spring temperature accumulation was strongly correlated with budburst date, but temperature alone cannot explain the diverse budburst responses observed among plant functional types. Ring-porous trees showed a consistent temperature response pattern across years, suggesting these species are sensitive to photoperiod. Conversely, diffuse-porous species responded differently between years, suggesting winter chilling may be more important in regulating budburst. Budburst of the ring-porous Quercus alba responded nonlinearly to warming, suggesting evolutionary constraints may limit changes in phenology, and therefore productivity, in the future. Warming caused a divergence in flowering times among species in the forest community, resulting in a longer flowering season by 10-16 days. Temperature was a good predictor of flowering for only four of the seven species studied here. Observations of interannual temperature variability overpredicted flowering responses in spring-blooming species, relative to our warming experiment, and did not consistently predict even the direction of flowering shifts. Experiments that push temperatures beyond historic variation are indispensable for improving predictions of future changes in phenology. PMID- 25736979 TI - Molecular characterization of viable Legionella spp. in cooling tower water samples by combined use of ethidium monoazide and PCR. AB - Viable Legionella spp. in environmental water samples were characterized phylogenetically by a clone library analysis combining the use of ethidium monoazide and quantitative PCR. To examine the diversity of Legionella spp., six cooling tower water samples and three bath water samples were collected and analyzed. A total of 617 clones were analyzed for their 16S rRNA gene sequences and classified into 99 operational taxonomic units (OTUs). The majority of OTUs were not clustered with currently described Legionella spp., suggesting the wide diversity of not-yet-cultured Legionella groups harbored in cooling tower water environments. PMID- 25736983 TI - Which instruments to support diagnosis of depression have sufficient accuracy? A systematic review. AB - BACKGROUND: Instruments are frequently used in case finding, diagnosis and severity grading of major depression, but the evidence supporting their utility is weak. AIM: To systematically review the specificity and sensitivity of instruments used to diagnose and grade the severity of depression. METHODS: MEDLINE, PsycInfo, Embase and the Cochrane Library databases were searched until April 2014. Fifty studies fulfilled the inclusion criteria. Risk of bias was assessed with QUADAS. The average sensitivity and specificity of each instrument was estimated with hierarchical summary receiver operating characteristics analyses and the confidence in the estimates was evaluated using GRADE. Minimum acceptable sensitivity/specificity, with structured interview as the reference, was 80%/80% for structured interviews and 80%/70% for case-finding instruments. The minimum acceptable standard for severity measures was a correlation of 0.7 with DSM-IV classification. RESULTS: Twenty instruments were investigated. The average sensitivity/specificity was 85%/92% for the Structured Clinical Interview for DSM-IV-Axis-I Disorders (SCID-I), 95%/84% for the Mini International Neuropsychiatric Interview (MINI), < 70%/85% for the Primary Care Evaluation of Mental Disorders (PRIME-MD), 88%/78% for the Patient Health Questionnaire-9 (PHQ 9) with a cut-off score of 10, 69%/95% for PHQ-9 as a diagnostic algorithm and 70%/83% for the Hospital Anxiety and Depression Scale (HADS) with a cut-off score of 7. The confidence in the estimates for the other instruments was very low. CONCLUSIONS: Only the SCID-I, MINI and PHQ-9 with a cut-off score of 10 fulfilled the minimum criteria for sensitivity and specificity. The use of the PRIME-MD and HADS is not supported by current evidence. PMID- 25736982 TI - Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology. AB - PURPOSE: This review aims to summarize the evidence that Notch signaling is associated with prostate development, tumorigenesis and prostate tumor progression. METHODS: Studies in PubMed database were searched using the keywords of Notch signaling, prostate development and prostate cancer. Relevant literatures were identified and summarized. RESULTS: The Notch pathway plays an important role in determining cell fate, proliferation, differentiation and apoptosis. Recent findings have highlighted the involvement of Notch signaling in prostate development and in the maintenance of adult prostate homeostasis. Aberrant Notch expression in tissues leads to dysregulation of Notch functions and promotes various neoplasms, including prostate cancer. High expression of Notch has been implicated in prostate cancer, and its expression increases with higher cancer grade. However, the precise role of Notch in prostate cancer has yet to be clearly defined. The roles of Notch either as an oncogene or tumor suppressor in prostate cancer hallmarks such as cell proliferation, apoptosis and anoikis, hypoxia, migration and invasion, angiogenesis as well as the correlation with metastasis are therefore discussed. CONCLUSIONS: Notch signaling is a complicated signaling pathway in modulating prostate development and prostate cancer. Understanding and manipulating Notch signaling could therefore be of potential therapeutic value in combating prostate cancer. PMID- 25736984 TI - 'Being a conduit' between hospital and home: stakeholders' views and perceptions of a nurse-led Palliative Care Discharge Facilitator Service in an acute hospital setting. AB - AIMS AND OBJECTIVES: To explore and critically examine stakeholders' views and perceptions concerning the nurse-led Palliative Care Discharge Service in an acute hospital setting and to inform sustainability, service development and future service configuration. BACKGROUND: The drive in policy and practice is to enable individuals to achieve their preferred place of care during their last days of life. However, most people in UK die in acute hospital settings against their wishes. To facilitate individuals' preferred place of care, a large acute hospital in northeast England implemented a pilot project to establish a nurse led Macmillan Palliative Care Discharge Facilitator Service. DESIGN: A pluralistic evaluation design using qualitative methods was used to seek stakeholders' views and perceptions of this service. METHODS: In total, 12 participants (five bereaved carers and seven health professionals) participated in the evaluation. Semi-structured interviews were conducted with bereaved carers who used this service for their relatives. A focus group and an individual interview were undertaken with health professionals who had used the service since its inception. Individual interviews were also conducted with the Discharge Facilitator and service manager. Analysis of all data was guided by Framework Analysis. RESULTS: Four key themes emerged relating to the role of the Discharge Facilitator Service: achieving preferred place of care; the Discharge Facilitator as the 'conduit' between hospital and community settings; delays in hospital discharge and stakeholders' perceptions of the way forward for the service. CONCLUSION: The Discharge Facilitator Service acted as a reliable resource and support for facilitating the fast-tracking of end-of-life patients to their preferred place of care. RELEVANCE TO CLINICAL PRACTICE: Future planning for hospital-based palliative care discharge facilitating services need to consider incorporating strategies that include: increased profile of the service, expansion of service provision and the Discharge Facilitator's earlier involvement in the discharge process. PMID- 25736985 TI - Effects of Pregnancy-associated Malaria on T Cell Cytokines in Cameroonian Women. AB - Although Th17 cells subsets improve immunity against extra and intracellular pathogens, and in modulating Th1 and other immune responses, its role on pregnancy-associated malaria (PAM) is unknown. This study aims to investigate the effects of PAM on Th1 (IFN-gamma, TNF-alpha), IL-10 family (IL-10, IL-19, IL-22), Th17 (IL-17A, IL-23) cytokines and on CXCL-10 chemokine profiles in pregnant women. Between 2010 and 2011, venous blood specimens from 107 volunteer pregnant Cameroonian women was used to determine parasitaemia microscopically and haemoglobin levels using HemoCue analyzer. Plasma levels of the biomarkers were determined by ELISA. Parasitaemia was higher in women with low haemoglobin levels, parity and mother's age. IL-10 and CXCL-10 plasma levels were higher in the malaria infected and in anaemic women while IFN-gamma and IL-17A levels were higher in malaria non-infected and in non-anaemic women. Parasitaemia correlated positively with IL-10 and CXCL-10 levels but inversely with IFN-gamma and IL-17A. Haemoglobin levels were higher in women with low IL-10 and CXCL-10 levels, and in group with high IFN-gamma, IL-17A and IL-23 levels. Only IL-10 levels associated negatively with parity. Positive correlations were observed between Th17 (IL-17A) and Th1 (IFN-gamma, TNF-alpha), IL-10 family (IL-19 and IL-22) and Th17 (IL-23) cytokines. Multivariate analysis showed association between: mother's age and IFN gamma levels, parasitaemia and IL-10 and CXCL-10 levels and haemoglobin levels, gestational age and IL-17A levels. In conclusion, during PAM, CXCL-10 and IL-10 responses are implicated in the pathogenesis while Th17 and Th1 immune responses, via IL-17A and IFN-gamma might play protective roles. PMID- 25736986 TI - High dose subcutaneous unfractionated heparin for prevention of venous thromboembolism in overweight neurocritical care patients. AB - Timing and dosing of chemical venous thromboembolism (VTE) prophylaxis in brain injury is controversial. Risk of bleeding while using high dose unfractionated heparin (UFH) in overweight patients to prevent VTE is also unknown. The purpose of this study was to describe the use of subcutaneous heparin 7500 units for VTE prophylaxis in overweight patients. This was a retrospective study comparing patients over 100 kg who received either 7500 units Q8 h (n = 141) (high dose group, HDG), or 5000 units Q8 h (n = 257) (traditional dose group, TDG), of UFH subcutaneously. Both groups had similar rates of bleeding complications. The incidence of drop in hemoglobin by two points in any 24 h was 14 % (20/141) HDG versus 11 % (28/257) TDG; P = 0.33. Hemoglobin drop by two points from baseline was 57 % (81/141) HDG versus 51 % (132/257) TDG; P = 0.24. The need for pRBC transfusion was 26 % (36/141) HDG versus 20 % (52/257) TDG; P = 0.22. An increase in aPTT from baseline by two times was 4 % (5/141) HDG versus 4 % (9/257) TDG, P = 0.59. Discontinuation of heparin therapy for association with progressive bleeding was not documented in any patients. No differences in minor bleeding complications were observed. There was no difference in the incidence of VTE: 5.7 % (8/141) HDG versus 9.3 % (24/257) TDG; P = 0.2. In univariate and multivariable logistic regression analysis, only the time of the initiation of heparin after admission was associated with the occurrence of VTE (median, IQR) 46 h (17-86) HDG versus 105 h (56-167) TDG; OR 1.2 (1.1-1.3); P < 0.001. High dose subcutaneous UFH was not associated with an increased risk of bleeding, nor did it decrease the incidence of VTE in overweight patients. PMID- 25736987 TI - Oral syphilis: report of three cases and characterization of the inflammatory cells. AB - Syphilis is a sexually transmitted infectious disease caused by Treponema pallidum. This study reports 3 cases of syphilis and highlights the importance of identifying oral lesions for its final diagnosis. Case 1: a 48-year-old male patient presented with a bleeding ulcer in the lower lip. Overall clinical examination revealed patchy alopecia and skin target lesions. Case 2: a 61-year old male patient presented with white spots on the lateral tongue and nodules on the dorsum of the tongue. Overall clinical examination showed erythematous target lesions on the abdomen, forearm, palms of the hand, and soles of the feet. Case 3: a 17-year-old male patient presented with an ulcerated lesion on the tongue and lymph node involvement. The following serologic tests were requested: Venereal Disease Research Laboratory, fluorescent treponemal antibody-absorption, anti-HIV-1 and anti-HIV-2, and anti-hepatitis C virus. An incisional biopsy revealed epithelial hyperplasia associated with intense and diffuse mononuclear inflammatory cell infiltration consisting mainly of plasma cells, in a perivascular and perineural distribution. The final diagnosis in the 3 patients was syphilis. Treatment consisted of 1 weekly dose of penicillin (2.4 million units, intramuscular) for 2 or 3 weeks. Immunohistochemical reactions for XIIIa, CD3, CD20, CD68, CD163, S100, CD1a, CD11c, CD83, CD138, and CD208 were performed. Clinicians should be familiarized with oral syphilis lesions in order to be able to diagnose this emerging infectious disease of variable clinical presentation. PMID- 25736988 TI - PTEN Inhibits High Glucose-Induced Phenotypic Transition in Podocytes. AB - Accumulating evidence has suggested that podocytes undergo epithelial-mesenchymal transition (EMT) in diabetic nephropathy (DN). However, the underlying mechanisms of EMT in podocyte are not well understood. PI3K/Akt pathway is involved in the progression of DN. In the present study, we demonstrated that PI3K/Akt pathway was activated in podocytes exposed to high glucose conditions, accompanied by down-regulation of the podocalyxin (PCX) and nephrin expression and up-regulation of the desmin and alpha-smooth muscle actin (alpha-SMA) expression. Inhibition of PI3K/Akt pathway by chemical LY294002 or Phosphase and tensin homology deleted on chromosome ten (PTEN) prevented the phenotypic transition. These findings indicate that PTEN/PI3K/Akt pathway mediates high glucose-induced phenotypic transition in podocytes. PMID- 25736989 TI - A series of simple oligomer-like small molecules based on oligothiophenes for solution-processed solar cells with high efficiency. AB - A series of acceptor-donor-acceptor simple oligomer-like small molecules based on oligothiophenes, namely, DRCN4T-DRCN9T, were designed and synthesized. Their optical, electrical, and thermal properties and photovoltaic performances were systematically investigated. Except for DRCN4T, excellent performances were obtained for DRCN5T-DRCN9T. The devices based on DRCN5T, DRCN7T, and DRCN9T with axisymmetric chemical structures exhibit much higher short-circuit current densities than those based on DRCN6T and DRCN8T with centrosymmetric chemical structures, which is attributed to their well-developed fibrillar network with a feature size less than 20 nm. The devices based on DRCN5T/PC71BM showed a notable certified power conversion efficiency (PCE) of 10.10% under AM 1.5G irradiation (100 mW cm(-2)) using a simple solution spin-coating fabrication process. This is the highest PCE for single-junction small-molecule-based organic photovoltaics (OPVs) reported to date. DRCN5T is a rather simpler molecule compared with all of the other high-performance molecules in OPVs to date, and this might highlight its advantage in the future possible commercialization of OPVs. These results demonstrate that a fine and balanced modification/design of chemical structure can make significant performance differences and that the performance of solution processed small-molecule-based solar cells can be comparable to or even surpass that of their polymer counterparts. PMID- 25736990 TI - Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo controlled, phase 3 trials. AB - BACKGROUND: Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. METHODS: We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per MUL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3.0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patient's body weight and randomly assigned treatment group. Additionally, the sponsor's clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2). FINDINGS: Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0.50 [95% CI 0.37-0.67]; study 2: 0.41 [0.28-0.59]; both p<0.0001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study. INTERPRETATION: These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. FUNDING: Teva Branded Pharmaceutical Products R&D. PMID- 25736991 TI - Protective effect of arjunolic acid against atorvastatin induced hepatic and renal pathophysiology via MAPK, mitochondria and ER dependent pathways. AB - 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin (ATO), is a highly effective drug used for the treatment of hypercholesterolemia and hypertriglyceridemia. Its application is restricted now-a-days due to several acute and chronic side effects. ATO induced anti hypercholesterolemia and hepatic tissue toxicity has been reported to follow different mechanisms. The present study has been carried out to investigate the protective role of arjunolic acid (AA) against ATO induced oxidative impairment and cell death in hepatic and renal tissue in mice. Administration of ATO (at a dose 30 mg/kg/day for 8 weeks) enhanced serum markers, increased reactive oxygen species (ROS) production and altered the pro oxidant-antioxidant status of liver and kidney tissues. Our experimental evidence suggests that ATO exposure induces apoptotic cell deathby the activation of caspase-3 and reciprocal regulation of Bcl-2/Bax with the concomitant reduction of mitochondrial membrane potential and increased level of cytosolic cytochrome c, Apaf1, caspase-9. Besides, ATO markedly increased the phosphorylation of MAPKs, enhanced caspase-12 and calpain level. Histological studies and DNA fragmentation analysis also support the toxic effect of ATO in these organs pathophysiology. Post treatment with AA (at a dose of 20 mg/kg body weight for 4 days), however, reduced ATO-induced oxidative stress and suppressed all these apoptotic events. Results suggest that AA could effectively and extensively counteract these adverse effects and might protect liver and kidney from ATO-induced severe tissue toxicity. PMID- 25736992 TI - Detection of orphan domains in Drosophila using "hydrophobic cluster analysis". AB - INTRODUCTION: Comparative genomics has become an important strategy in life science research. While many genes, and the proteins they code for, can be well characterized by assigning orthologs, a significant amount of proteins or domains remain obscure "orphans". Some orphans are overlooked by current computational methods because they rapidly diverged, others emerged relatively recently (de novo). Recent research has demonstrated the importance of orphans, and of de novo proteins and domains for development of new phenotypic traits and adaptation. New approaches for detecting novel domains are thus of paramount importance. RESULTS: The hydrophobic cluster analysis (HCA) method delineates globular-like domains from the information of a protein sequence and thereby allows bypassing some of the established methods limitations based on conserved sequence similarity. In this study, HCA is tested for orphan domain detection on 12 Drosophila genomes. After their detection, the oprhan domains are classified into two categories, depending on their presence/absence in distantly related species. The two categories show significantly different physico-chemical properties when compared to previously characterized domains from the Pfam database. The newly detected domains have a higher degree of intrinsic disorder and a particular hydrophobic cluster composition. The older the domains are, the more similar their hydrophobic cluster content is to the cluster content of Pfam domains. The results suggest that, over time, newly created domains acquire a canonical set of hydrophobic clusters but conserve some features of intrinsically disordered regions. CONCLUSION: Our results agree with previous findings on orphan domains and suggest that the physico-chemical properties of domains change over evolutionary long time scale. The presented HCA-based method is able to detect domains with unusual properties without relying on prior knowledge, such as the availability of homologs. Therefore, the method has large potential for complementing existing strategies to annotate genomes, and for better understanding how molecular features emerge. PMID- 25736993 TI - Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs. AB - Two series of C-8 substituted guanine derivatives were synthesized, one bearing 2 amino substitutions and the other bearing 2-acetamide substitutions. Biological activity tests showed that almost all of them possessed some extent of antitumor activities, and were with lower toxicity against normal human liver HL7702 cells than AZD4547 (the positive control). Among them, N-[8-(4-bromo-1H-indol-3-yl)-6 hydroxy-9H-purin-2-yl]-acetamide exhibited a relatively satisfied inhibition against FGFR1 kinase with IC50 of 1.56 MUM and specifically against A549 cells with IC50 of 8.28 MUM and B16-F10 cells with IC50 of 6.59 MUM. Above all, the introduction of large substituents such as indolyl groups at 8-position of the guanine scaffold probably achieves higher selectivity for FGFR1 as compared with AZD4547. PMID- 25736994 TI - Synthesis of novel pleuromutilin derivatives. Part 1: preliminary studies of antituberculosis activity. AB - The worldwide threat from tuberculosis (TB) has resulted in great demand for new drugs, particularly those that can treat multidrug-resistant TB. We synthesized novel pleuromutilin derivatives with N-benzylamine side chain substituted at the C14 position and evaluated their activity in vitro against a virulent strain of Mycobacterium tuberculosis (H37Rv). The primary assay results showed that five compounds inhibited the H37Rv at 20MUM, with a MIC of one of the analogues as low as 7.2MUM. PMID- 25736995 TI - A coumarin lignanoid from the stems of Kadsura heteroclita. AB - Coumarinlignan (1), possessing a unique coumarin-containing lignan skeleton, was isolated from the stems of Kadsura heteroclita. Its structure and absolute configuration were determined by spectroscopic techniques, especially 2D NMR and X-ray crystallographic data analyses. The proposed biosynthetic pathway is discussed. This new compound showed good anti-HBV activity against HBeAg and HBsAg, and moderate anti-fibrotic and neuroprotective activities. PMID- 25736996 TI - Novel beta-amyloid aggregation inhibitors possessing a turn mimic. AB - Amyloid beta peptide, the main component of senile plaques found in the brain of Alzheimer disease (AD) patients, is a molecular target for AD therapeutic intervention. A number of potential AD therapeutics have been reported, including inhibitors of beta-secretase, gamma-secretase, and Abeta aggregation, and anti amyloid agents, such as neprilysin, insulin degrading enzyme (IDE), and Abeta antibodies. Recently, we reported potent small-sized beta-secretase (BACE1) inhibitors, which could serve as anti-AD drugs. However AD is a progressive disorder, where dementia symptoms gradually worsen over several decades, and therefore may require many years to get cured. One possible way to achieve a greater therapeutic effect is through simultaneous administration of multiple drugs, similar to those used in Highly Active Anti-Retroviral Therapy (HAART) used to treat AIDS. In order to overcome AD, we took a drug discovery approach to evaluate, novel beta-amyloid aggregation inhibitors. Previously, we reported that a tong-type compound possessing a turn mimic as the inhibitor of HIV-1 protease dimerization. Oligomerized amyloid beta peptides contain a turn structure within the molecule. Here, we designed and synthesized novel beta-amyloid aggregation inhibitors with a turn-mimic template, based on the turn conformer of the oligomerized amyloid beta peptides. PMID- 25736997 TI - Nine new diterpenes from the leaves of plantation-grown Cunninghamia lanceolata. AB - Nine new diterpenes named lanceolatanol hydroperoxide (1), epilanceolatanol hydroperoxide (2), lanceolatanoic acid hydroperoxide (3), epilanceolatanoic acid hydroperoxide (4), lanceolatanol (5), lanceolatanoic acid (6), 11 acetoxylanceolatanoic acid (7), 11-acetoxylanceolatanoic acid methyl ester (8) and epoxyhinokiol (13) were characterized from the leaves of plantation-grown Cunninghamia lanceolata along with twelve known compounds. The compounds were evaluated for their growth inhibitory activities against the human prostate cell line (PC-3). PMID- 25736998 TI - Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors. AB - In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5 disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development. PMID- 25736999 TI - Asymmetric aldol reaction of allenoates: regulation for the selective formation of isomeric allenyl or alkynyl aldol adduct. AB - A highly stereoselective synthesis of 3-butynyl-threo-aldol adducts is achieved from the reaction of allyl allenoate with a chiral bromoborane in the presence of iPr2NEt, followed by addition of BF3.OEt2 as an additive to scavenge excess base and then aldehydes, whereas isomeric allenyl aldol adducts are formed in the absence of a Lewis acid additive from methyl allenoate. PMID- 25737000 TI - Current concepts in congenital portosystemic shunts. AB - Congenital portosystemic shunts (CPSS) are vascular abnormalities that allow portal blood to bypass the liver and join systemic circulation. Laboratory and imaging studies are performed preoperatively to diagnose CPSS and hopefully identify an anatomic location of the shunt. CPSS can be found in different locations in both small and large breed dogs. Most CPSS are best managed surgically. The goal of surgical management of CPSS is to slowly redirect blood from the shunting vessel through the portal vasculature while avoiding portal hypertension. Many surgical management methods are available, including open and less invasive procedures, such as laparoscopy and embolization. PMID- 25737002 TI - Surgical approach to a rare case of double-outlet right ventricle and aortopulmonary window. AB - Although the spectrum of physiology seen in infants and children with double outlet right ventricle is broad, this anatomy in combination with an aortopulmonary window is extremely rare. We present an interesting case of an infant prenatally diagnosed with this rare CHD. To our knowledge, this is the first report of complete repair in the neonatal period for such a combination of defects. PMID- 25737001 TI - Ruthenium(II)-catalyzed C-H activation/alkyne annulation by weak coordination with O2 as the sole oxidant. AB - Aerobic oxidative C?H functionalizations of weakly coordinating benzoic acids have been accomplished with versatile ruthenium(II) biscarboxylates under ambient oxygen or air. Mechanistic studies identified the key factors controlling the elementary step of the oxidation of the ruthenium(0) complex. PMID- 25737003 TI - Purification, characterization, and biological activities of broccolini lectin. AB - Plant lectins have displayed a variety of biological activities. In this study, for the first time, a 27 kDa arabinose- and mannose-specific lectin from Broccolini (Brassica oleracea Italica * Alboglabra), named as BL (Broccolini lectin), was purified by an activity-driven protocol. Mass spectrometry analysis and database search indicated that no matches with any plant lectin were found, but BL contained some peptide fragments (QQQGQQGQQLQQVISR, QQGQQQGQQGQQLQQVISR and VCNIPQVSVCPF QK). BL exhibited hemagglutinating activity against chicken erythrocytes at 4 ug/mL. BL retained full hemagglutinating activity at pH 7-8 and temperature 30-40 degrees C, and had an optimal activity in Ca(2+) solution. Bioactivity assay revealed that BL exhibited dose-dependent inhibition activity on 5 bacterial species with IC50 values of 143.95-486.33 MUg/mL, and on 3 cancer cells with IC50 values of 178.82-350.93 MUg/mL. Notably, 5-fold reduction in IC50 values was observed on normal L-O2 vs cancerous HepG-2 cells (924.35 vs. 178.82 MUg/mL). This suggests that BL should be promising in food and medicine. PMID- 25737004 TI - The diversity of mechanisms influenced by transthyretin in neurobiology: development, disease and endocrine disruption. AB - Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs). TTR synthesised in the liver is secreted into the bloodstream and distributes THs around the body, whereas TTR synthesised in the choroid plexus is involved in movement of thyroxine from the blood into the cerebrospinal fluid and the distribution of THs in the brain. This is important because an adequate amount of TH is required for normal development of the brain. Nevertheless, there has been heated debate on the role of TTR synthesised by the choroid plexus during the past 20 years. We present both sides of the debate and how they can be reconciled by the discovery of TH transporters. New roles for TTR have been suggested, including the promotion of neuroregeneration, protection against neurodegeneration, and involvement in schizophrenia, behaviour, memory and learning. Recently, TTR synthesis was revealed in neurones and peripheral Schwann cells. Thus, the synthesis of TTR in the central nervous system (CNS) is more extensive than previously considered and bolsters the hypothesis that TTR may play wide roles in neurobiological function. Given the high conservation of TTR structure, function and tissue specificity and timing of gene expression, this implies that TTR has a fundamental role, during development and in the adult, across vertebrates. An alarming number of 'unnatural' chemicals can bind to TTR, thus potentially interfering with its functions in the brain. One role of TTR is delivery of THs throughout the CNS. Reduced TH availability during brain development results in a reduced IQ. The combination of the newly discovered sites of TTR synthesis in the CNS, the increasing number of neurological diseases being associated with TTR, the newly discovered functions of TTR and the awareness of the chemicals that can interfere with TTR biology render this a timely review on TTR in neurobiology. PMID- 25737005 TI - Minimally invasive versus open total mesorectal excision for rectal cancer: Long term results from a case-matched study of 633 patients. AB - BACKGROUND: This study compared the long-term oncologic outcomes of patients with rectal cancer who underwent either laparoscopic or robotic total mesorectal excision (TME) via minimally invasive surgery (MIS) to those patient who underwent open TME. METHODS: This study was a retrospective, case-control study; patients in the 2 groups were matched according to age, sex, MIS vs open operation, body mass index, tumor location, pathologic TNM stage (ie, tumor-node metastasis), neoadjuvant treatment, and adjuvant treatment. RESULTS: A total of 633 patients (MIS, n = 211; open, n = 422) were assessed. The median follow-up period was 64 (2-124) months. Patient characteristics did not differ between the groups. Overall postoperative complication rates did not differ between the groups (16.0% [MIS]; 17.0% [open]; P = .76). Rates of the involvement of the circumferential resection margin did not differ between the groups (4.0% [MIS]; 5.0% [open]; P = .84). The 5-year overall survival, disease-specific survival, disease-free survival, and local recurrence rates were not different between the MIS and open groups (overall survival = 88.4% vs 85.3%, P = .23; disease-specific survival = 88.8% vs 87.4%, P = .53, disease-free survival = 80.7% vs 78.4%, P = .74; local recurrence = 5.7% vs 5.1%, P = .95). In subgroup analysis, no differences were found in terms of the long-term, oncologic outcomes, oncologic adequacy, and postoperative complications among 3 groups. CONCLUSION: We found no differences in the oncologic outcomes between MIS and open surgery, suggesting that MIS for rectal cancer is a safe option for rectal cancer that does not increase the risk of serious complications. PMID- 25737006 TI - The association of noise and surgical-site infection in day-case hernia repairs. AB - INTRODUCTION: Surgical-site infections (SSIs) are associated with an increased duration of hospital stay, poorer quality of life, and an marked increase in cost to the hospital. Lapses in compliance with aseptic principles are a substantial risk factor for SSI, which may be attributable to distractions such as noise during the operation. The aims of this study were to assess whether noise levels in the operating room are associated with the development of SSI and to elucidate the extent to which these levels affect the financial burden of surgery. METHODS: Prospective data collection from elective, day-case male patients undergoing elective hernia repairs was undertaken. Patients were included if they were fit and at low risk for SSI. Sound levels during procedures was measured via a decibel meter and correlated with the incidence of SSI. Data analysis was performed with IBM SPSS (IBM, Armonk, NY). RESULTS: Noise levels were substantially greater in patients with SSI from time point of 50 minutes onwards, which correlated to when wound closure was occurring. Additional hospital costs for these patients were L243 per patient based on the National Health Service 2013 reference costing. CONCLUSION: Decreasing ambient noise levels in the operating room may aid in reducing the incidence of SSIs, particularly during closure, and decrease the associated financial costs of this complication. PMID- 25737008 TI - Isolation, synthesis and anti-hepatitis B virus evaluation of p hydroxyacetophenone derivatives from Artemisia capillaris. AB - p-Hydroxyacetophenone (p-HAP), as a main hepatoprotective and choleretic constituent of Artemisia capillaris, was revealed with anti-hepatitis B virus (HBV) effects in recent investigation. In addition to p-HAP, four derivatives of p-HAP were also isolated from A. capillaris by various chromatographic methods. Subsequent structural modification on p-HAP and its glycoside led to the synthesis of 28 additional derivatives, of which 13 compounds showed activity inhibiting hepatitis B surface antigen (HBsAg) secretion; and 18 compounds possessed inhibition on HBV DNA replication. The primary structure-activity relationships (SARs) suggested that the conjugated derivatives of p-HAP glycoside and substituted cinnamic acids (2a-2i) obviously enhanced the activity against HBV DNA replication with IC50 values ranged from 5.8 to 74.4 MUM. PMID- 25737007 TI - Asymmetric Dimethyl-L-Arginine is a Biomarker for Disease Stage and Follow-Up of Pulmonary Hypertension Associated with Congenital Heart Disease. AB - This study investigated the clinical value of plasma asymmetrical dimethyl-L arginine (ADMA) level in the diagnosis, staging, and treatment response in congenital heart disease (CHD) patients with pulmonary arterial hypertension (PAH). This was a single-center prospective observational study in 80 CHD patients. Plasma ADMA levels were measured by enzyme-linked immunosorbent assay. Plasma ADMA levels were significantly increased in CHD patients with PAH compared with CHD patients without PAH (P < 0.01) and healthy controls (P < 0.001). In CHD patients with severe PAH, plasma ADMA levels were significantly higher in patients with Eisenmenger's syndrome (ES) than in patients exhibiting low pulmonary vascular resistance (P < 0.001). The plasma ADMA levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (P < 0.001) in patients with CHD. Severe PAH was identified by plasma ADMA with a cutoff value of 0.485 MUmol/L (P < 0.001) with a specificity of 82.8 % and a sensitivity of 90 %. ES was identified by plasma ADMA with a cutoff value of 0.85 MUmol/L (P < 0.05) with a specificity of 85.2 % and a sensitivity of 64.3 %. ADMA levels were significantly decreased after sildenafil therapy for 6 months compared with before therapy levels (0.91 +/- 0.22 vs. 0.57 +/- 0.30, P < 0.01). Our study suggests that plasma ADMA level may be used as a biomarker for identifying PAH in patients with CHD, assessing pulmonary vascular remodeling, and evaluating the treatment response of CHD patients with PAH to sildenafil. PMID- 25737009 TI - Synthesis of erythrocentaurin derivatives as a new class of hepatitis B virus inhibitors. AB - Twenty-four derivatives of erythrocentaurin (ET) were synthesized and evaluated for their anti-HBV activities on HepG 2.2.15 cell line in vitro. Eight compounds 1, 2, 5, 8, 9, 1e, 1k, and 1m increased activity against HBV DNA replication with the SI values higher than 11. In particular, derivatives 1e and 1k exhibited the most potent inhibition on HBV DNA replication with the IC50 values of 0.026 mM (SI>70.8) and 0.045 mM (SI>36.0), respectively. The primary structure-activity relationships (SARs) of ET derivatives were summarized for exploring potent anti HBV agents. PMID- 25737010 TI - Mesophilic versus thermophilic anaerobic digestion of cattle manure: methane productivity and microbial ecology. AB - In this study, productivity and physicochemical and microbiological (454 sequencing) parameters, as well as environmental criteria, were investigated in anaerobic reactors to contribute to the ongoing debate about the optimal temperature range for treating animal manure, and expand the general knowledge on the relation between microbiological and physicochemical process indicators. For this purpose, two reactor sizes were used (10 m(3) and 16 l), in which two temperature conditions (35 degrees C and 50 degrees C) were tested. In addition, the effect of the hydraulic retention time was evaluated (16 versus 20 days). Thermophilic anaerobic digestion showed higher organic matter degradation (especially fiber), higher pH and higher methane (CH4) yield, as well as better percentage of ultimate CH4 yield retrieved and lower residual CH4 emission, when compared with mesophilic conditions. In addition, lower microbial diversity was found in the thermophilic reactors, especially for Bacteria, where a clear intensification towards Clostridia class members was evident. Independent of temperature, some similarities were found in digestates when comparing with animal manure, including low volatile fatty acids concentrations and a high fraction of Euryarchaeota in the total microbial community, in which members of Methanosarcinales dominated for both temperature conditions; these indicators could be considered a sign of process stability. PMID- 25737011 TI - Autopsy-confirmed hippocampal-sparing Alzheimer's disease with delusional jealousy as initial manifestation. AB - Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD. PMID- 25737013 TI - PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145. AB - The human genome encodes a family of nine protein arginine methyltransferases (PRMT1-9), whose members can catalyse three distinct types of methylation on arginine residues. Here we identify two spliceosome-associated proteins-SAP145 and SAP49-as PRMT9-binding partners, linking PRMT9 to U2 snRNP maturation. We show that SAP145 is methylated by PRMT9 at arginine 508, which takes the form of monomethylated arginine (MMA) and symmetrically dimethylated arginine (SDMA). PRMT9 thus joins PRMT5 as the only mammalian enzymes capable of depositing the SDMA mark. Methylation of SAP145 on Arg 508 generates a binding site for the Tudor domain of the Survival of Motor Neuron (SMN) protein, and RNA-seq analysis reveals gross splicing changes when PRMT9 levels are attenuated. These results identify PRMT9 as a nonhistone methyltransferase that primes the U2 snRNP for interaction with SMN. PMID- 25737014 TI - Creating, Synthesizing, and Sharing: The Management of Knowledge in Public Health. AB - OBJECTIVES: To better understand the applicability of knowledge management (KM) in public health (PH) as a strategy to improve planning and decision making. DESIGN AND SAMPLE: The study was designed as a narrative inquiry; a form of storytelling research. Qualitative data were collected through interviews designed to gain participants' stories about planning processes. Twenty-four participants from six PH Units in Ontario, Canada. MEASURES: We performed a secondary analysis to better understand the use of KM strategies, techniques, and approaches. Findings were compared to a preliminary KM framework supporting knowledge processes within a dynamic, interactive context. RESULTS: Analysis showed that while KM strategies are supported informally, it is most often done in an ad hoc manner. Participants acknowledged a gap in their knowledge sharing practices. CONCLUSION: PH professionals are ready to apply KM in PH as an approach to facilitate planning and decision making. The proposed KM framework incorporates partnerships to adapt to the realities of PH context. Consideration of KM strategies can improve information organization, partnerships and decision making, as well as contribute to current PH reforms aimed at strengthening the health care system. This presents an opportunity to integrate formalized methods of knowledge use and knowledge sharing among PH employees using a KM approach. PMID- 25737012 TI - In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features. AB - Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas compared with normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24-72 h) increased GH and ACTH secretion, Ca(2+) and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors. PMID- 25737015 TI - Comparison of the physiological characteristics of transgenic insect-resistant cotton and conventional lines. AB - The introduction of transgenic insect-resistant cotton into agricultural ecosystems has raised concerns regarding its ecological effects. Many studies have been conducted to compare the differences in characteristics between transgenic cotton and conventional counterparts. However, few studies have focused on the different responses of transgenic cotton to stress conditions, especially to the challenges of pathogens. The aim of this work is to determine the extent of variation in physiological characteristics between transgenic insect-resistant cotton and the conventional counterpart infected by cotton soil borne pathogens. The results showed that the difference in genetic backgrounds is the main factor responsible for the effects on biochemical characteristics of transgenic cotton when incubating with cotton Fusarium oxysporum. However, genetic modification had a significantly greater influence on the stomatal structure of transgenic cotton than the effects of cotton genotypes. Our results highlight that the differences in genetic background and/or genetic modifications may introduce variations in physiological characteristics and should be considered to explore the potential unexpected ecological effects of transgenic cotton. PMID- 25737016 TI - Percutaneous antegrade mitral paravalvular leak closure through porcelain atrial septum- first percutaneous paravalvular leak closure in Japan. PMID- 25737018 TI - The impact of the israeli transplantation law on the socio-demographic profile of living kidney donors. AB - The Israeli transplantation law of 2008 stipulated that organ trading is a criminal offense, and banned the reimbursement of such transplants by insurance companies, thus decreasing dramatically transplant tourism from Israel. We evaluated the law's impact on the number and the socio-demographic features of 575 consecutive living donors, transplanted in the largest Israeli transplantation center, spanning 5 years prior to 5 years after the law's implementation. Living kidney donations increased from 3.5 +/- 1.5 donations per month in the pre-law period to 6.1 +/- 2.4 per month post-law (p < 0.001). This was mainly due to a rise in intra-familial donations from 2.1 +/- 1.1 per month to 4.6 +/- 2.1 per month (p < 0.001). In unrelated donors we found a significant change in their socio-demographic characteristics: mean age increased from 35.4 +/- 7.4 to 39.9 +/- 10.2 (p = 0.001), an increase in the proportion of donors with college level or higher education (31.0% to 63.1%; p < 0.001) and donors with white collar occupations (33.3% to 48.3%, p = 0.023). In conclusion, the Israeli legislation that prohibited transplant tourism and organ trading in accordance with Istanbul Declaration, was associated with an increase in local transplantation activity, mainly from related living kidney donors, and a change in the profile of unrelated donors into an older, higher educated, white collar population. PMID- 25737017 TI - Pioglitazone increases circulating microRNA-24 with decrease in coronary neointimal hyperplasia in type 2 diabetic patients- optical coherence tomography analysis. AB - BACKGROUND: Aberrant expression of microRNAs is associated with neointimal hyperplasia (NIH) in type 2 diabetes. We prospectively compared the effects of pioglitazone on coronary NIH and changes in microRNAs according to NIH status in type 2 diabetic patients during 9-month follow-up. METHODS AND RESULTS: Type 2 diabetic patients were randomly assigned to the pioglitazone (n=36) or control groups (n=36) after coronary stenting. Primary endpoint was the comparison of changes in neointimal volume on OCT and in the level of circulating microRNA-17, 24,-92a,-126 and -145 during 9-month follow-up. Secondary endpoint was the comparison of changes in brachial artery flow-mediated dilation and inflammatory markers such as IL-6, TNF-alpha, hsCRP, adiponectin, sICAM-1, and sVCAM-1 between the 2 groups. Neointimal volume was significantly lower in the pioglitazone group (25.02+/-17.78 mm(3)vs. 55.10+/-30.01 mm(3), P<0.001) with significant increases in circulating microRNA-24 (0.264+/-0.084 vs. 0.006+/-0.030, P<0.001) during follow-up. FMD was significantly greater in the pioglitazone than control group at 9 months (0.47+/-0.14 mm vs. 0.28+/-0.18 mm, P<0.05, respectively). Decreases in inflammatory markers such as IL-6, TNF-alpha, and sVCAM-1 were significantly greater in the pioglitazone than the control group during the follow-up. CONCLUSIONS: Pioglitazone significantly decreased NIH with increases in circulating microRNA-24 at 9-month follow-up. The decrease in microRNA-24 could be used as a potential predictor of increases in NIH in type 2 diabetic patients. PMID- 25737019 TI - Co-occurring Psychiatric Disorders in Preschool and Elementary School-Aged Children with Autism Spectrum Disorder. AB - We employed a clinical sample of young children with ASD, with and without intellectual disability, to determine the rate and type of psychiatric disorders and possible association with risk factors. We assessed 101 children (57 males, 44 females) aged 4.5-9.8 years. 90.5% of the sample met the criteria. Most common diagnoses were: generalized anxiety disorder (66.5%), specific phobias (52.7%) and attention deficit hyperactivity disorder (59.1%). Boys were more likely to have oppositional defiant disorder (OR 3.9). Higher IQ was associated with anxiety disorders (OR 2.9) and older age with agoraphobia (OR 5.8). Night terrors was associated with parental psychological distress (OR 14.2). Most young ASD children met the criteria for additional psychopathology. PMID- 25737020 TI - Efficacy of the ADEC in Identifying Autism Spectrum Disorder in Clinically Referred Toddlers in the US. AB - The Autism Detection in Early Childhood (ADEC) is a brief, play-based screening tool for the assessment of autism spectrum disorder (ASD) in children aged 12-36 months. We examined the psychometric properties of the ADEC in a clinical sample of toddlers (n = 114) referred to a US pediatric hospital for assessment due to concerns of developmental delay or ASD. The ADEC (cutoff = 11) returned good sensitivity (.93-.94) but poorer specificity (.62-.64) for best estimate clinical diagnosis of ASD, and compared favorably with the ADOS-2. Internal consistency was acceptable, alpha = .80, and inter-rater reliability was high, ICC = .95. Results support the use of the ADEC as a clinical screen for ASD. PMID- 25737021 TI - Naturalistic Developmental Behavioral Interventions: Empirically Validated Treatments for Autism Spectrum Disorder. AB - Earlier autism diagnosis, the importance of early intervention, and development of specific interventions for young children have contributed to the emergence of similar, empirically supported, autism interventions that represent the merging of applied behavioral and developmental sciences. "Naturalistic Developmental Behavioral Interventions (NDBI)" are implemented in natural settings, involve shared control between child and therapist, utilize natural contingencies, and use a variety of behavioral strategies to teach developmentally appropriate and prerequisite skills. We describe the development of NDBIs, their theoretical bases, empirical support, requisite characteristics, common features, and suggest future research needs. We wish to bring parsimony to a field that includes interventions with different names but common features thus improving understanding and choice-making among families, service providers and referring agencies. PMID- 25737023 TI - Lentivirus-Mediated Knockdown of TCTN1 Inhibits Glioma Cell Proliferation. AB - Tectonic-1, also named as TCTN1 or TECT1, which belongs to a family of signal sequence-containing secreted and transmembrane proteins evolutionarily conserved among eukaryotes, was reported to be involved in central nervous system development and ciliogenesis. In this paper, we found that TCTN1 is extensively expressed in human glioma cell lines. To clarify the role of TCTN1 in glioma, we employed lentivirus-mediated short hairpin RNA to knock down TCTN1 expression in U251 and U87MG glioma cells. Knockdown of TCTN1 potently inhibited cell proliferation, as determined by MTT and colony formation assays. Cell cycle analysis showed depletion of TCTN1 led to both U251 and U87MG cells arrested in the G0/G1 phase. These data suggest TCTN1 is essential for glioma cell viability, and dysregulation of TCTN1 may play a key role in glioma tumorigenesis. PMID- 25737022 TI - Improving prediction of prostate cancer recurrence using chemical imaging. AB - Precise Outcome prediction is crucial to providing optimal cancer care across the spectrum of solid cancers. Clinically-useful tools to predict risk of adverse events (metastases, recurrence), however, remain deficient. Here, we report an approach to predict the risk of prostate cancer recurrence, at the time of initial diagnosis, using a combination of emerging chemical imaging, a diagnostic protocol that focuses simultaneously on the tumor and its microenvironment, and data analysis of frequent patterns in molecular expression. Fourier transform infrared (FT-IR) spectroscopic imaging was employed to record the structure and molecular content from tumors prostatectomy. We analyzed data from a patient cohort that is mid-grade dominant - which is the largest cohort of patients in the modern era and in whom prognostic methods are largely ineffective. Our approach outperforms the two widely used tools, Kattan nomogram and CAPRA-S score in a head-to-head comparison for predicting risk of recurrence. Importantly, the approach provides a histologic basis to the prediction that identifies chemical and morphologic features in the tumor microenvironment that is independent of conventional clinical information, opening the door to similar advances in other solid tumors. PMID- 25737024 TI - Characterization of a potential beta-lactamase inhibitory metabolite from a marine Streptomyces sp. PM49 active against multidrug-resistant pathogens. AB - Actinobacteria is a prolific producer of complex natural products; we isolated a potential marine Streptomyces sp. PM49 strain from Bay of Bengal coastal area of India. The strain PM49 exhibited highly efficient antibacterial properties on multidrug-resistant pathogens with a zone of inhibition of 14-17 mm. SSF was adopted for the production of the secondary metabolites from PM49 with ISP2; utilizing agricultural wastes for compound extraction was also attempted. Bioactive fraction of Rf value 0.69 resolved using chloroform and ethyl acetate (1:1, v/v) was obtained and subjected to further analysis. Based on UV, IR, ESI MS, and (1)H and (13)C NMR spectral analysis, it was revealed that the compound is closely similar to cyslabdan with a molecular mass of 467.66 corresponding to the molecular formula C25H41NO5S. ESBL and MBL production was screened in the hospital test isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus. PCR amplification in the phenotypically positive strains was positive for bla IMP, bla SHV, bla CTX-M, and mec genes. The beta-lactamase enzyme from tested strains had cephalosporinase activity with a 31-kDa protein and isolated compound from the strain possessing beta-lactamase inhibitory potential. MIC of the active fraction was 16-32 MUg/ml on ATCC strains; the ceftazidime and meropenem sensitive and resistant test strains showed MIC of 64-256 MUg/ml. The Streptomyces sp. PM49 aerial mycelium was rectiflexibile; the 16S rRNA showed 99 % identity with Streptomyces rochei and submitted at Genbank with accession no JX904061.1. PMID- 25737025 TI - Automated centrifugal-microfluidic platform for DNA purification using laser burst valve and coriolis effect. AB - We report a fully automated DNA purification platform with a micropored membrane in the channel utilizing centrifugal microfluidics on a lab-on-a-disc (LOD). The microfluidic flow in the LOD, into which the reagents are injected for DNA purification, is controlled by a single motor and laser burst valve. The sample and reagents pass successively through the micropored membrane in the channel when each laser burst valve is opened. The Coriolis effect is used by rotating the LOD bi-directionally to increase the purity of the DNA, thereby preventing the mixing of the waste and elution solutions. The total process from the lysed sample injection into the LOD to obtaining the purified DNA was finished within 7 min with only one manual step. The experimental result for Salmonella shows that the proposed microfluidic platform is comparable to the existing devices in terms of the purity and yield of DNA. PMID- 25737026 TI - Bayesian hierarchical modelling of continuous non-negative longitudinal data with a spike at zero: An application to a study of birds visiting gardens in winter. AB - The development of methods for dealing with continuous data with a spike at zero has lagged behind those for overdispersed or zero-inflated count data. We consider longitudinal ecological data corresponding to an annual average of 26 weekly maximum counts of birds, and are hence effectively continuous, bounded below by zero but also with a discrete mass at zero. We develop a Bayesian hierarchical Tweedie regression model that can directly accommodate the excess number of zeros common to this type of data, whilst accounting for both spatial and temporal correlation. Implementation of the model is conducted in a Markov chain Monte Carlo (MCMC) framework, using reversible jump MCMC to explore uncertainty across both parameter and model spaces. This regression modelling framework is very flexible and removes the need to make strong assumptions about mean-variance relationships a priori. It can also directly account for the spike at zero, whilst being easily applicable to other types of data and other model formulations. Whilst a correlative study such as this cannot prove causation, our results suggest that an increase in an avian predator may have led to an overall decrease in the number of one of its prey species visiting garden feeding stations in the United Kingdom. This may reflect a change in behaviour of house sparrows to avoid feeding stations frequented by sparrowhawks, or a reduction in house sparrow population size as a result of sparrowhawk increase. PMID- 25737027 TI - Incentivizing biodiversity conservation in artisanal fishing communities through territorial user rights and business model innovation. AB - Territorial user rights for fisheries are being promoted to enhance the sustainability of small-scale fisheries. Using Chile as a case study, we designed a market-based program aimed at improving fishers' livelihoods while incentivizing the establishment and enforcement of no-take areas within areas managed with territorial user right regimes. Building on explicit enabling conditions (i.e., high levels of governance, participation, and empowerment), we used a place-based, human-centered approach to design a program that will have the necessary support and buy-in from local fishers to result in landscape-scale biodiversity benefits. Transactional infrastructure must be complex enough to capture the biodiversity benefits being created, but simple enough so that the program can be scaled up and is attractive to potential financiers. Biodiversity benefits created must be commoditized, and desired behavioral changes must be verified within a transactional context. Demand must be generated for fisher created biodiversity benefits in order to attract financing and to scale the market model. Important design decisions around these 3 components-supply, transactional infrastructure, and demand-must be made based on local social ecological conditions. Our market model, which is being piloted in Chile, is a flexible foundation on which to base scalable opportunities to operationalize a scheme that incentivizes local, verifiable biodiversity benefits via conservation behaviors by fishers that could likely result in significant marine conservation gains and novel cross-sector alliances. PMID- 25737028 TI - Incorporation of future costs in health economic analysis publications: current situation and recommendations for the future. AB - Future costs are not usually included in economic evaluations. The aim of this study was to assess the extent of published economic analyses that incorporate future costs. A systematic review was conducted of economic analyses published from 2008 to 2013 in three general health economics journals: PharmacoEconomics, Value in Health and the European Journal of Health Economics. A total of 192 articles met the inclusion criteria, 94 of them (49.0%) incorporated future related medical costs, 9 (4.2%) also included future unrelated medical costs and none of them included future nonmedical costs. The percentage of articles including future costs increased from 2008 (30.8%) to 2013 (70.8%), and no differences were detected between the three journals. All relevant costs for the perspective considered should be included in economic evaluations, including related or unrelated, direct or indirect future costs. It is also advisable that pharmacoEconomic guidelines are adapted in this sense. PMID- 25737029 TI - Morphometrics and structure of complete baleen racks in gray whales (Eschrichtius robustus) from the Eastern North Pacific Ocean. AB - Mysticetes have evolved a novel filter feeding apparatus-baleen-an epidermal keratinous tissue composed of keratin that grows as a serial arrangement of transverse cornified laminae from the right and left sides of the palate. The structure and function of baleen varies among extant mysticete clades and this variation likely can be viewed as adaptations related to different filter feeding strategies. In one of the first morphometric studies of the full baleen apparatus, we describe the morphology of complete baleen racks in neonate, yearling and adult gray whales (Eschrichtius robustus), and note morphometric variations between age groups as well as within individual racks. Morphometric data and detailed descriptions were collected from the full baleen apparatus of three frozen specimens of E. robustus using previously derived ecologically significant and broad scale measurements of baleen. Additionally, characters of the baleen apparatus were described based on visible patterns of baleen laminae and plates on the dorsal root of the rack. Results indicate that the longest, widest, and thickest plates and laminae are found toward the posterior half of the rack, resulting in the greatest surface area for filtration of prey occurring in this region. Ontogenetic changes were also documented that reveal a progressive increase in the filter surface area of the developing baleen apparatus as baleen laminae and main plates grow in length and width. Also noted was a progressive posterior shift in the position of greatest filtration area. Histological examination of the epithelial base (Zwischensubstanz) and laminae showed basic epidermal layers, as well as gapping between layers and vacuoles. PMID- 25737030 TI - Rapid regulation of blood parameters under acute hypoxia in the Amazonian fish Prochilodus nigricans. AB - Prochilodus nigricans, locally known as curimata, is an Amazonian commercial fish that endures adverse environmental conditions, in particular low dissolved oxygen, during its migration. Poorer environmental conditions are expected in the near future. Prochilodus nigricans overcomes current seasonal and diurnal changes in dissolved oxygen by adjusting erythrocytic levels of ATP and GTP, modulators of Hb-O2 affinity. Will this fish species be endangered under more extreme environmental conditions as hypoxia and acidification tend to occur in a shorter period of time? As P. nigricans does not exhibit any apparent morphological alterations to exploit the air-water interface, it must rely on fast adjustments of blood properties. To investigate this aspect, basic hematology indices, pHe, pHi, plasma lactate, erythrocytic levels of ATP and GTP and functional properties of the hemolysate of P. nigricans were analyzed over a period of 6h in hypoxia and subsequent recovery in normoxia. The levels of erythrocytic GTP were four times higher than ATP and were reduced to 1/4 of the original level after 3h under hypoxia. Erythrocytic levels of ATP were unaffected over the experimental period. All other analyzed blood parameters exhibited a time-course change in animals under hypoxia and returned to normoxic levels. Considering the hemolysate functional properties and the ability to regulate the above mentioned blood characteristics, P. nigricans is able to endure short-term changes in dissolved oxygen. PMID- 25737031 TI - Obestatin partially suppresses ghrelin stimulation of appetite in "high responders" grass carp, Ctenopharyngodon idellus. AB - Ghrelin and obestatin are two gastrointestinal peptides obtained by post translational processing of a common precursor, preproghrelin. The effect of obestatin on food intake is still controversial. The aim of the present study was to investigate the effects of ghrelin and obestatin on food intake in grass carp, Ctenopharyngodon idellus. Fish received intraperitoneal (IP) injection of saline, ghrelin (100 ng g(-1)BW), obestatin-like (25 ng g(-1)BW) and ghrelin in combination with obestatin-like. Ghrelin stimulation of food intake varied considerably among individual fish with 70.8% eliciting a robust response. In these high-responders, food intake was significantly increased by IP ghrelin within 2 h. Co-administration of ghrelin and obestatin-like resulted in a decrease in food intake, indicating that obestatin was able to antagonize the effect of ghrelin. However, IP obestatin-like alone could not regulate food intake in grass carp. RT-PCR analysis demonstrated that IP ghrelin peptide led to a significant increase in mRNA abundance of NPY, Y8a and Y8b genes compared to saline injected fish, while in combination with obestatin-like peptide decreased ghrelin-induced gene expressions of these three genes. IP sole obestatin-like peptide did not modify the expression levels of NPY, Y8a, Y8b, CART and POMC compared to the control group. Therefore, IP administration of obestatin-like peptide, partially blocking the ghrelin-induced appetite, investigated the possible involvement of obestatin as a mediator of the ghrelin stimulatory action on food intake, at least in "high-responders" grass carp. PMID- 25737032 TI - Metabolic behavior prediction of pazopanib by cytochrome P450 (CYP) 3A4 by molecular docking. AB - Metabolism-mediated drug adverse effects (e.g., drug-drug interaction, bioactivation, etc.) strongly limit the utilization of clinical drugs. The present study aims to predict the metabolic capability of cytochrome P450 (CYP) 3A4 toward pazopanib which is an excellent drug exhibiting therapeutic role toward various cancers especially for ovarian cancer. Pazopanib can be well docked into the activity cavity of CYP3A4, and the interaction structure in pazopanib was methyl group located besides nitrogen in the five-membered ring. The distance between the hydrogen atom in methyl group and active center is 3.64 A. The interaction amino acid is Glu374. Furthermore, both pazopanib and ketoconazole were docked into the activity cavity of CYP3A4 to compare their binding potential. The distance between ketoconazole and activity center (2.10 A) is closer than the distance between pazopanib and activity center of CYP3A4, indicating the easy influence of CYP3A4 inhibitor toward the metabolism of pazopanib. All these data were helpful for the clinical application of pazopanib, and R&D of other tinib drug candidates as new anti-tumor drugs. PMID- 25737033 TI - Risk factors of incident type 2-diabetes mellitus over a 3-year follow-up: Results from a large Australian sample. AB - AIMS: To describe the incidence of type 2 diabetes mellitus (T2DM) among middle aged and older Australian adults and to examine a broad range of risk factors of T2DM. METHODS: A large cohort of Australian adults aged 45 and up was sampled from the general population and was followed up for approximately 3 years (n=60,404). Physician-diagnosed T2DM was self-reported at baseline (2006-2008) and follow-up (2010). Incident T2DM was determined as not reporting T2DM at baseline, but reporting T2DM at follow-up. A broad range of risk factors, including socio-demographic characteristics, health status, family history, and lifestyle behaviors were examined at baseline. Multiple logistic regression was used for selecting potential predictors of incident T2DM, and age and reported family history of T2DM were tested as potential effect modifiers. RESULTS: Of the 54,997 without T2DM at baseline, 888 reported T2DM at follow-up (cumulative incidence 1.6% over 3.4 years, annual incidence rate 0.44%). Adjusted for other risk factors, being male, older age, higher relative socio-economic disadvantage, being born in Asia, lower educational attainment, medical history of hypertension and dyslipidemia, family history of T2DM, overweight/obese, smoking, long sleeping hours, and psychological distress were significantly associated with higher odds of developing T2DM. Particularly, hypertension, dyslipidemia, and overweight/obesity were stronger predictors of T2DM among middle-aged than older adults (>=60 years). CONCLUSIONS: Understanding risk factors for incident T2DM could help identify at-risk populations and develop upstream preventive strategies to combat the epidemic of diabetes. PMID- 25737034 TI - Comparison of HbA1c, blood pressure, and cholesterol (ABC) control in type 2 diabetes attending general medical clinics and specialist diabetes clinics in Thailand. AB - AIMS: The aim of this study was to compare the achievement of clinical targets for patients with type 2 diabetes mellitus (T2DM) in general medical clinics (GMCs) and specialist diabetes clinics (SDCs) for different hospital types (regional, provincial and community) in Thailand. METHODS: We used the medical records of patients (n=26,860) with T2DM from 595 hospitals (26 regional, 70 provincial and 499 community) across all 77 provinces in Thailand. Generalized linear mixed models were used to conduct multi-level modeling to evaluate the achievement of individual outcomes (A - glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol), B - Blood Pressure (BP) <140/80 mmHg and C - LDL-Cholesterol <100mg/dL) and aggregated outcomes (AllABC - achieved all three of the targets, AnyABC - achieved at least one target, ABCcount - the number of targets achieved: 0, 1, 2 or 3). RESULTS: Neither clinic types (SDCs or GMCs) were consistency superior across all hospital types. For regional hospitals, SDCs were associated with higher odds of achieving BP, AnyABC, and ABCcount (OR=1.55, 95%CI: 1.25 1.92, p<0.001; OR=1.35, 95%CI: 1.02-1.79; p=0.04; RR=1.10, 95%CI: 1.01-1.20, p=0.03, respectively). For provincial hospitals, SDCs exhibited higher achievement of BP and LDL-C (OR=1.52, 95%CI: 1.23-1.87, p<0.001; OR=1.28, 95%CI: 1.04-1.58, p=0.02, respectively). For community hospitals, however GMCs demonstrated higher achievement of BP and AnyABC (OR=0.81, 95%CI: 0.67-0.98, p=0.03; OR=0.74, 95%CI: 0.56-0.97, p=0.03, respectively). CONCLUSIONS: In larger (regional and provincial) hospitals, SDCs outperform GMCs in several (but not all) clinical targets. In contrast, in community hospital, where most patients with T2DM are serviced, GMCs were shown to have superior performance. PMID- 25737035 TI - The space-time continuum: the effects of elevated CO2 and temperature on trees and the importance of scaling. AB - To predict how forests will respond to rising temperatures and atmospheric CO2 concentrations, we need to understand how trees respond to both of these environmental factors. In this review, we discuss the importance of scaling, moving from leaf-level responses to those of the canopy, and from short-term to long-term responses of vegetation to climate change. While our knowledge of leaf level, instantaneous responses of photosynthesis, respiration, stomatal conductance, transpiration and water-use efficiency to elevated CO2 and temperature is quite good, our ability to scale these responses up to larger spatial and temporal scales is less developed. We highlight which physiological processes are least understood at various levels of study, and discuss how ignoring differences in the spatial or temporal scale of a physiological process impedes our ability to predict how forest carbon and water fluxes forests will be altered in the future. We also synthesize data from the literature to show that light respiration follows a generalized temperature response across studies, and that the light compensation point of photosynthesis is reduced by elevated growth CO2. Lastly, we emphasize the need to move beyond single factorial experiments whenever possible, and to combine both CO2 and temperature treatments in studies of tree performance. PMID- 25737036 TI - A Qualitative Assessment of the Practice Experiences of Certified Diabetes Educator Pharmacists. AB - OBJECTIVE: To describe the practice experiences of Certified Diabetes Educator (CDE) pharmacists in Saskatchewan and determine what impact the CDE designation has had on their personal practices. METHODS: A qualitative research approach was used. All pharmacists in Saskatchewan were e-mailed about the study, and eventually, a purposive sampling method was used to select a range of CDE pharmacists. Semistructured, in-person interviews were performed. An interview guide was developed to assess the work activities performed, the benefits of becoming a CDE and the challenges and resultant solutions that optimize their CDE designations. All interviews were transcribed verbatim and coded using deductive thematic analysis to identify the main themes that described the experiences of respondents, with the aid of QSR NVivo. RESULTS: A total of 14 CDE pharmacists from various communities and work settings chose to participate. All of the participants indicated they were engaging in increased diabetes-related activities since becoming CDEs. All participants indicated they were happy with their decisions to become CDEs and described numerous benefits as a direct result of achieving this designation. Although some solutions were offered, participants still face challenges in optimizing their role as CDEs, such as devoting enough time to diabetes management and remuneration for providing diabetes services. CONCLUSIONS: CDE pharmacists in Saskatchewan report performing enhanced diabetes related activities subsequent to becoming CDEs and that obtaining this designation has had a positive impact on their personal practices. A larger, cross-country study is necessary to determine whether these results are consistent amongst all pharmacists in Canada. PMID- 25737037 TI - Phenotypic variability of CMT4C in a French-Canadian kindred. AB - INTRODUCTION: Charcot-Marie-Tooth type 4C (CMT4C) is an autosomal recessive dysmyelinating neuropathy characterized by precocious and rapidly progressive scoliosis. METHODS: Patients in a French-Canadian kindred were evaluated with clinical examination, electrophysiologic study, and genomic DNA extraction. RESULTS: Six of 10 siblings were clinically symptomatic with supportive electrophysiologic features. The proband presented with regional side-to-side sensorimotor asymmetry, typical pes cavus without obvious scoliosis, and unremarkable plain films of the spine. Affected siblings all share symptoms of foot deformity but have variable onset of neuropathic symptoms, degree of extremity weakness, progression of symptoms, and, most notably, evidence of scoliosis. DNA sequence analysis revealed a novel combination of 2 known recessive mutations, p.R904X and p.R954X, in the SH3TC2 gene. CONCLUSIONS: A broad spectrum of phenotypes should be considered in the possible diagnosis of CMT4C. The absence of scoliosis or late-onset symptoms should not exclude SH3TC2 from the list of candidate genes under consideration. Age of onset and clinical features were variable and suggest that polygenic factors contribute to the final phenotype. PMID- 25737038 TI - Prosthetic joint infection due to Enterococcus sp treated with debridement, antibiotics and retention of the implant (DAIR). PMID- 25737039 TI - The influence of paediatric HIV infection on circulating B cell subsets and CXCR5(+) T helper cells. AB - Antiretroviral therapy (ART) only partially restores HIV-induced alterations in lymphocyte populations. We assessed B and T cell phenotypes in a cohort of children from a single centre in the United Kingdom with perinatally acquired HIV compared to healthy controls. The majority of HIV infected children (44 of 56) were on fully suppressive combination ART. Children with perinatally acquired HIV had significantly lower memory B and CD4(+) CD45RO(+) CXCR5(+) [follicular T helper cell (Tfh)-like] T cell percentages. Detectable viraemia was associated with higher CD21(-) (activated and exhausted/tissue-like memory) B cells. A greater proportion of life spent on suppressive ART was associated with higher memory B cell percentages. These results suggest that early and sustained suppressive ART may preserve B and T cell phenotypes in perinatally acquired HIV and limit deficits in humoral immunity. A lower proportion of circulating Tfh like cells in HIV infected children appears to be independent of HIV treatment history and ongoing HIV viraemia and warrants further investigation. PMID- 25737040 TI - Body Mass Index and Mortality Rate in Korean Patients with Alzheimer's Disease. AB - BACKGROUND: A relationship between body weight, cognitive impairment, and the onset of Alzheimer's disease (AD) was recently reported. However, to our knowledge, no studies have investigated the relationship between body weight and mortality in Asian AD patients. OBJECTIVE: We evaluated the relationship between body mass index (BMI) and mortality rate in Korean AD cohorts. METHODS: Participants were consecutively included from two Korean representative registries: 579 AD patients from Samsung Medical Center and 1911 AD patients from the Clinical Research Center for Dementia of South Korea study. We combined these two AD cohorts to evaluate the association between BMI and mortality. BMI was used to categorize the participants into underweight, normal-weight, overweight, and obesity subgroups. All deaths were confirmed through the nationwide mortality database of Statistics Korea. RESULTS: 53 of 181 (29.3%), 208 of 1,127 (18.5%), 88 of 626 (14.1%), and 115 of 556 (20.7%) patients died in the underweight, normal-weight, overweight, and obese subgroups during 43.7 months of follow-up. The time-dependent cox proportional hazards model showed that, relative to the normal-weight subgroup, the underweight group had higher mortality (HR 1.82 (95% CI, 1.07-3.09)) while overweight group had lower mortality rate (HR 0.60 (95% CI, 0.38-0.95)) The effects of underweight and overweight were prominent in younger and older elderly group, respectively. However, there were no interactive effects of dementia severity or gender and BMI on survival rate. CONCLUSION: Relative to AD patients of normal weight, those who were underweight had an increased mortality rate, and overweight predicted decreased mortality in AD patients. Furthermore, our findings may help facilitate mortality stratification in AD patients by using baseline BMI. PMID- 25737041 TI - Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease. AB - The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID- 25737042 TI - Decreased Neurotrophic Support is Associated with Cognitive Decline in Non Demented Subjects. AB - BACKGROUND: There is evidence of decreased neurotrophic support in Alzheimer's disease (AD), including its prodromal stages, but it is not clear whether this abnormality represents a marker of this process. OBJECTIVE: To determine serum concentrations of a panel of neurotrophic factors (BDNF, NGF, and GDNF) in a cross-section of elderly patients with mild cognitive impairment (MCI) and AD compared to cognitively healthy controls, and to evaluate whether abnormal levels of these factors at baseline predict the transition from MCI to dementia. METHODS: A total of 134 older adults were enrolled in this study. Twenty-six patients with mild to moderate AD, 62 with MCI, and 46 cognitively healthy older adults (controls) were subjected to a clinical evaluation including several cognitive tests. Peripheral blood was drawn and serum levels of BDNF, NGF, and GDNF were measured by enzyme-linked immunosorbent assay. APOE genotyping was performed by PCR assays. RESULTS: Serum concentrations of BDNF, NGF, and GDNF were significantly reduced in cognitively impaired subjects (i.e., MCI and AD) as compared to controls, although only the former two remained statistically different after controlling for age, gender, and cognitive performance (p = 0.05 and p = 0.01, respectively). Lower BDNF and NGF levels were also observed in the sub-sample of MCI patients who progressed to dementia upon follow-up (p = 0.02 and p = 0.002, respectively). CONCLUSION: Abnormalities in neurotrophic systems are observed at early stages of AD and may represent a marker of cognitive deterioration. PMID- 25737043 TI - Pregnancy Zone Protein is Increased in the Alzheimer's Disease Brain and Associates with Senile Plaques. AB - Increased levels of pregnancy zone protein (PZP) were found in the serum of persons who later developed Alzheimer's disease (AD) in comparison to controls who remained dementia free. We suggested that this increase is due to brain derived PZP entering the blood stream during the early phase of the disease. Here we investigate the possible involvement of PZP in human AD pathogenesis. We observed increased PZP immunoreactivity in AD postmortem brain cortex compared to non-demented controls. In the AD cortex, PZP immunoreactivity localized to microglial cells that interacted with senile plaques and was occasionally observed in neurons. Our data link the finding of elevated serum PZP levels with the characteristic AD pathology and identify PZP as a novel component in AD. PMID- 25737044 TI - APOE Genotype Alters Immunoglobulin Subtypes in Knock-In Mice. AB - Apolipoprotein E (APOE) alleles are strongly related to the risk of Alzheimer's disease (AD). APOE genotype also affects inflammatory processes in response to damage. We tested whether APOE genotype affected the levels of specific immunoglobulins in healthy, uninfected APOE knock-in mice. We measured specific immunoglobulins in brain, spleen, and plasma. Levels of total IgG in brain and spleen were highest in APOE-E3 mice, significantly higher than in APOE-E2 and APOE-E4 mice; no differences were observed for levels of total IgG in plasma. We also measured specific subtypes of IgG. IgG1 was only detectable in plasma and did not differ by APOE genotype. IgG3 was detectable in plasma and spleen, and also did not differ by APOE genotype. IgG2b showed the same pattern as levels of total IgG by APOE genotype, with the highest levels of IgG2b in brain, spleen, and plasma of APOE-E3 mice. IgG2a showed an entirely different pattern, with significantly higher levels in spleen and plasma of APOE-E4 mice compared to APOE E2 and APOE-E3 mice. We also measured IgM and IgA in spleens and plasma of these mice. In spleen, APOE-E4 mice had the lowest IgA levels and the highest levels of IgM; both being significantly different from APOE-E2 mice. In total, murine IgG2a and IgM were highest in APOE-E4 mice, while total IgG and Ig2b were highest in APOE-E3 mice. These dramatically different distributions of immunoglobulins could allow for human AD risk biomarkers based on specific immunoglobulin subtypes. PMID- 25737045 TI - Neuropsychological Correlates of the Alzheimer's Questionnaire. AB - Informant-based assessments of cognition and function are commonly used to differentiate individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) from those who are cognitively normal. However, determining the extent to which informant-based measures correlate to objective neuropsychological tests is important given the widespread use of neuropsychological tests in making clinical diagnoses of aMCI and AD. The aim of the current study is to determine how well the Alzheimer's Questionnaire (AQ) correlates with objective neuropsychological tests. The study utilized data from 300 individuals participating in a brain and body donation program. Individuals diagnosed with aMCI (n = 83) and AD (n = 67) were matched on age, gender, and education to a control individual (n = 150). The average age for the entire sample was 83.52+/-6.51 years with an average education level of 14.57+/-2.55 years. Results showed that the AQ correlated strongly with the Mini-Mental State Exam (r =-0.71, p < 0.001) and the Mattis Dementia Rating Scale-2 (r =-0.72, p < 0.001), and moderate correlations were noted for the AQ with memory function (Rey Auditory Verbal Learning Test Delayed Recall, r =-0.61, p < 0.001) and executive function (Trails B, r = 0.53, p < 0.001). The findings of this study suggest that the AQ correlates well with several neuropsychological tests and lend further support to the validity of the AQ as a screening instrument for cognitive impairment. PMID- 25737046 TI - Activation of the 5'-AMP-Activated Protein Kinase in the Cerebral Cortex of Young Senescence-Accelerated P8 Mice and Association with GSK3beta- and PP2A-Dependent Inhibition of p-tau396 Expression. AB - The 5'-AMP-activated protein kinase (AMPK), which is a sensor of cellular energy, regulates neuronal survival and energy homeostasis. However, the roles of AMPK in the pathogenesis of Alzheimer's disease (AD) are unclear. The senescence accelerated mouse prone 8 (SAMP8) strain is characterized by deficits in learning and memory, exhibits pathological characteristics of AD as early as 5 months of age, and is being increasingly recognized as a model of AD. Here, we investigated the relationship between AMPK activation and phosphorylation of the tau protein in the brain of young (2-month-old) SAMP8 animals and in differentiated SH-SY5Y cells. Upregulation of p-AMPK, p-ACC, and p-GSK3betaS9 and downregulation of p tau396 and sirtuin 1 (Sirt1) were observed in the cerebral cortex of young SAMP8 mice compared with that of age-matched SAMR1 animals. The hippocampal levels of p AMPK and p-tau396 in SAMP8 animals were not significantly different from those of SAMR1, whereas upregulation of p-GSK3betaS9 and downregulation of sirt1 was observed in the hippocampus of SAMP8 mice. Consistent with in vivo findings in the cortex, AMPK activation in SH-SY5Y cells upregulated p-GSK3betaS9 but downregulated p-tau396, whereas it had no significant effect on p-tau262 expression. In addition, the AMPK-mediated inhibition of p-tau396 expression was attenuated by okadaic acid, a protein phosphatase 2A (PP2A) inhibitor. Taken together, our data showed that AMPK activation inhibits p-tau396 expression in a GSK3beta- and PP2A-dependent manner, and suggest that differential regulation of tau phosphorylation in young SAMP8 mice by AMPK plays a compensatory role against accelerated senescence in this AD animal model. PMID- 25737047 TI - Oxidative Stress and Aberrant Cell Cycle in Alzheimer's Disease Lymphocytes: Diagnostic Prospects. AB - In Alzheimer's disease (AD), molecular changes are observed not only in patients' neurons but also in peripheral cells, such as blood lymphocytes. These include changes in the level of oxidative stress markers, mitochondria impairment, and aberrant cell cycle regulation in AD blood lymphocytes. While the concepts of early causes of AD are currently highly controversial, these findings provide support for the cell cycle hypothesis of AD pathomechanism and emphasize the systemic nature of the disease. Moreover, because of difficulties in studying dynamic processes in the human brain, lymphocytes seem to be useful for readout of AD molecular mechanisms. In addition, lymphocytes as easily accessible human cells have potential diagnostic value. We summarize current perspectives for the development of new therapeutic strategies based on oxidative stress and cell cycle dysregulation in AD, and for diagnostic methodologies involving new markers in AD lymphocytes. PMID- 25737048 TI - The consensus model for regulation of APRNs: Implications for nurse practitioners. AB - Purpose: To examine the Consensus Model for APRN Regulation as a proposed solution to simplify and unify regulation of advanced nursing practice with respect to licensure, certification, accreditation, and educational standards. Data sources: Policy statements and reports issued by national organizations of nursing professionals and discussion within the scholarly literature provided an overview of regulatory differences among the 50 U.S. states, their impacts on advanced practice registered nurse (APRN) practice, and discussion of the Consensus Model as a potential solution. Conclusions: Major organizations of nursing professionals have endorsed the Consensus Model, indicating the importance of this significant step toward standards and consistent quality in APRN education and practice. Diverse regulatory criteria, such as variable accreditation standards, disparate certification and licensing requirements, inconsistent population foci, and scopes of practice, represent barriers to optimized APRN function within today's complex healthcare system and, ultimately, reduced access to safe, quality care for patients. Implications for practice: The Consensus Model for APRN Regulation promises to unify APRN education, practice, and licensure, promoting greater mobility among nursing professionals. Elimination of inconsistencies in APRN licensure, education, certification, and accreditation requirements will promote greater value and mobility for the APRN within the healthcare system. PMID- 25737049 TI - Physical rehabilitation for critical illness myopathy and neuropathy. AB - BACKGROUND: Intensive care unit (ICU) acquired or generalised weakness due to critical illness myopathy (CIM) and polyneuropathy (CIP) are major causes of chronically impaired motor function that can affect activities of daily living and quality of life. Physical rehabilitation of those affected might help to improve activities of daily living. OBJECTIVES: Our primary objective was to assess the effects of physical rehabilitation therapies and interventions for people with CIP and CIM in improving activities of daily living such as walking, bathing, dressing and eating. Secondary objectives were to assess effects on muscle strength and quality of life, and to assess adverse effects of physical rehabilitation. SEARCH METHODS: On 16 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register and on 14 July 2014 we searched CENTRAL, MEDLINE, EMBASE and CINAHL Plus. In July 2014, we searched the Physiotherapy Evidence Database (PEDro, http://www.pedro.org.au/) and three trials registries for ongoing trials and further data about included studies. There were no language restrictions. We also handsearched relevant conference proceedings and screened reference lists to identify further trials. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs and randomised controlled cross-over trials of any rehabilitation intervention in people with acquired weakness syndrome due to CIP/CIM. DATA COLLECTION AND ANALYSIS: We would have extracted data, assessed the risk of bias and classified the quality of evidence for outcomes in duplicate, according to the standard procedures of The Cochrane Collaboration. Outcome data collection would have been for activities of daily living (for example, mobility, walking, transfers and self care). Secondary outcomes included muscle strength, quality of life and adverse events. MAIN RESULTS: The search strategy retrieved 3587 references. After examination of titles and abstracts, we retrieved the full text of 24 potentially relevant studies. None of these studies met the inclusion criteria of our review. No data were suitable to be included in a meta-analysis. AUTHORS' CONCLUSIONS: There are no published RCTs or quasi-RCTs that examine whether physical rehabilitation interventions improve activities of daily living for people with CIP and CIM. Large RCTs, which are feasible, need to be conducted to explore the role of physical rehabilitation interventions for people with CIP and CIM. PMID- 25737050 TI - Two-dimensional crystals from reduced symmetry analogues of trimesic acid. AB - The two-dimensional assembly of multicarboxylated arenes is explored at the liquid-graphite interface using scanning tunneling microscopy. Symmetry variations were introduced via phenylene spacer addition and the influence of these perturbations on the formation of hydrogen-bonded motifs from an alkanoic acid solvent is observed. This work demonstrates the importance of symmetry in 2D crystal formation and draws possible links of this behavior to prediction of coordination modes in three-dimensional coordination polymers. PMID- 25737051 TI - First isolation of Toxoplasma gondii from cats of Colima, Mexico: tissue distribution and genetic characterization. AB - Toxoplasma gondii is among the commonest zoonotic infectious agents worldwide. It infects many warm-blooded animals, including felines, the definitive hosts. This parasite is now classified in 15 haplogroups spread out around the world. Few reports reveal a predominance of genotypes I and III in Mexico, although recombinant and atypical variants have also been found in humans and animals. The aim of this study was to detect, isolate and genotype T. gondii from cats of Colima Mexico, and to analyze tissue distribution of the parasite. IgG specific antibodies were investigated in 48 serum samples from unwanted and stray cats by indirect ELISA. Isolation in mice and molecular characterization by PCR-RFLP and sequencing were attempted using pools of brain, heart, liver, lung, spleen and brachiocephalic muscle samples of seropositive cats. Fourteen animals (29.2%) were seropositive, the frequency ranged between 27.3 and 40% among the different localities. Ten seropositive animals were euthanized, eight of them were positive for the B1 gene by conventional PCR. More frequently infected tissues were the brachiocephalic muscle (75.0%) the brain (63.0%) and the spleen (63.0%). Genotype III was determined for the SAG3 locus of the parasite infecting an unwanted cat. Tachyzoites were isolated from the peritoneal cavity of two mice inoculated with the tissue pool of one kitten. Type I alleles were found in SAG1, SAG2, SAG3, BTUB, GRA6, c29-2 and PK1 loci, while c22-8 was type II, and L358 and Apico were type III. This genotype corresponds to ToxoDB genotype #28. This is the first T. gondii isolate genetically characterized in Colima, Mexico and is different to other isolations of the country. PMID- 25737053 TI - Modeling the extrinsic incubation of Dirofilaria immitis in South America based on monthly and continuous climatic data. AB - The spread and recrudescence of dirofilariosis across several regions, either caused by Dirofilaria immitis or D. repens, responds to many factors. Building upon the temperature model by Slocombe et al. (1989), a number of studies have been performed to generate predictive models for dirofilariosis. These studies have demonstrated the length of transmission periods and the number of Dirofilaria generations supported throughout several regions of the world (either at large or at small-scale). The usual procedure have proved to be extremely time consuming, as it appears impractical when assessing potential transmission at large scale, such as at a country or large-scale level. Due to the increasing need to suggest standardized surveillance protocols and apply adequate preventive measures at national and regional levels, a model for calculation of Dirofilaria HDUs based on monthly data was adapted for large-scale regional use. The models proposed are based on both point data (meteorological stations) and interpolated climate data layers (WorldClim). Three different models (daily and monthly models based on point data, and monthly model based on continuous data) were developed and compared statistically. When compared with the results from the classical daily model, the monthly models proposed accurately predicted the locations were extrinsic incubation was possible. These models proved to be adequate for the regional analysis of the extrinsic incubation of D. immitis and, hence, the relative risk of transmission in South America. Further, these models confirm that favorable temperatures for heartworm transmission in South America are present in most of the countries. D. immitis extrinsic incubation follows a seasonal pattern in Argentina, Chile, Uruguay, eastern Paraguay and southeastern Brazil; while in northern half of South America (less than 25 degrees S) transmission may occur year-round. Moreover, high risk areas suitable for dirofilariasis transmission are not geographically constant throughout the year. The validation procedures indicate that the predicted HDU and HG maps are good predictors of dirofilariosis potential distribution, but estimating dirofilariosis prevalences based on them might not be completely accurate. The resulting distribution and seasonal maps would be useful for heartworm prevention by chemoprophylaxis in different regions known to be endemic for canine dirofilariasis. The information here provided can be an important tool in veterinary public health, as well as a guide for future research. PMID- 25737054 TI - Probing a new approach for warm white light generation in lanthanide doped nanophosphors. AB - Lanthanides are among the most acceptable activator ions for cool white light emission; however, solid state lighting for some applications requires a warm white light. Herein, the present work probes a new approach for color temperature tuning in such systems to get a warm white light. The idea is that the additional use of red spectral components in cool white light, to a certain extent, may lead to a perfect warm white light, which can be achieved by making use of the surface oxygen defects mediated red emission from ZnO. To realize this noble concept, white light was initially produced in Y(1.993)Dy(0.001)Tm(0.006)O3 and then further ZnO was added. The study includes detailed structural and optical (steady state and time domain) characterization, chromaticity coordinates (CIE) calculation and correlated color temperature (CCT) analysis. The results show that, initially, at low ZnO concentration, Zn(2+) ions prefer to go into the interstitial sites, due to the mismatch of ionic radius between Y(3+) (0.90 A) and Zn(2+) (0.75 A). However, beyond a 10 mol% concentration of ZnO, the solubility limit of Zn(2+) ions in the Y2O3 matrix is reached, which results in the development of a Y2O3-ZnO composite. The presence of the ZnO phase gives rise to defect level induced red emission, which tunes the color temperature from 6072 K to 3898 K, which is reasonably good warm white light for solid state lighting applications. This idea can also be generalized in other similar hosts for developing potential warm white light sources. PMID- 25737055 TI - Cooperative rescue and predator fatality involving a group-living strepsirrhine, Coquerel's sifaka (Propithecus coquereli), and a Madagascar ground boa (Acrantophis madagascariensis). AB - The interactions between primates and their snake predators are of interest because snakes have influenced the evolution of primate visual systems and predation has driven the evolution of primate behaviour, including group living. However, there are few accounts of primate-snake interactions in the wild. We report an incident from Northwest Madagascar in which a large female Madagascar ground boa (Acrantophis madagascariensis) captured an adult female Coquerel's sifaka (Propithecus coquereli); upon capture, the prey's group members proceeded to bite and scratch the snake until it released the prey, which survived. However, a broken mandible suffered by the boa during the incident led to its death by starvation 2 months later. Our observations demonstrate that, in addition to improved predator detection and deterrence (i.e., mobbing), active defence against some predators may provide an additional benefit to group living in Coquerel's sifaka, and suggest that predation on group-living primates may be more costly for predators than attacking a solitary species of similar body size. PMID- 25737052 TI - An update on Sarcocystis neurona infections in animals and equine protozoal myeloencephalitis (EPM). AB - Equine protozoal myeloencephalitis (EPM) is a serious disease of horses, and its management continues to be a challenge for veterinarians. The protozoan Sarcocystis neurona is most commonly associated with EPM. S. neurona has emerged as a common cause of mortality in marine mammals, especially sea otters (Enhydra lutris). EPM-like illness has also been recorded in several other mammals, including domestic dogs and cats. This paper updates S. neurona and EPM information from the last 15 years on the advances regarding life cycle, molecular biology, epidemiology, clinical signs, diagnosis, treatment and control. PMID- 25737056 TI - Non-rigid, but not rigid, motion interferes with the processing of structural face information in developmental prosopagnosia. AB - There is growing evidence to suggest that facial motion is an important cue for face recognition. However, it is poorly understood whether motion is integrated with facial form information or whether it provides an independent cue to identity. To provide further insight into this issue, we compared the effect of motion on face perception in two developmental prosopagnosics and age-matched controls. Participants first learned faces presented dynamically (video), or in a sequence of static images, in which rigid (viewpoint) or non-rigid (expression) changes occurred. Immediately following learning, participants were required to match a static face image to the learned face. Test face images varied by viewpoint (Experiment 1) or expression (Experiment 2) and were learned or novel face images. We found similar performance across prosopagnosics and controls in matching facial identity across changes in viewpoint when the learned face was shown moving in a rigid manner. However, non-rigid motion interfered with face matching across changes in expression in both individuals with prosopagnosia compared to the performance of control participants. In contrast, non-rigid motion did not differentially affect the matching of facial expressions across changes in identity for either prosopagnosics (Experiment 3). Our results suggest that whilst the processing of rigid motion information of a face may be preserved in developmental prosopagnosia, non-rigid motion can specifically interfere with the representation of structural face information. Taken together, these results suggest that both form and motion cues are important in face perception and that these cues are likely integrated in the representation of facial identity. PMID- 25737058 TI - Relationship of age of onset and family history in Parkinson disease. AB - BACKGROUND: The aim of this study was to determine whether age of onset of Parkinson disease (PD) is associated with differences in PD risk and PD age of onset in parents and siblings. METHODS: Clinical and detailed family history data were available for 1,114 PD probands. RESULTS: Proband age of onset was not associated with differences in PD prevalence or PD age of onset in parents. Proband age of PD onset <50, compared with >= 50 years, was associated with significantly greater risk of PD in siblings (hazard ratio: 2.4; P=0.002; 95% confidence interval: 1.4, 4.1), and proband age of onset was significantly correlated with sibling age of onset (Somer's D=0.20; P=0.018). CONCLUSIONS: Proband age of PD onset is not associated with differences in parental PD risk. Siblings of PD patients with onset before age 50 are at increased risk of PD and are more likely to have early-onset disease. PMID- 25737059 TI - Correction: Programming macro-materials from DNA-directed self-assembly. PMID- 25737057 TI - Eukaryotic DNA polymerase zeta. AB - This review focuses on eukaryotic DNA polymerase zeta (Pol zeta), the enzyme responsible for the bulk of mutagenesis in eukaryotic cells in response to DNA damage. Pol zeta is also responsible for a large portion of mutagenesis during normal cell growth, in response to spontaneous damage or to certain DNA structures and other blocks that stall DNA replication forks. Novel insights in mutagenesis have been derived from recent advances in the elucidation of the subunit structure of Pol zeta. The lagging strand DNA polymerase delta shares the small Pol31 and Pol32 subunits with the Rev3-Rev7 core assembly giving a four subunit Pol zeta complex that is the active form in mutagenesis. Furthermore, Pol zeta forms essential interactions with the mutasome assembly factor Rev1 and with proliferating cell nuclear antigen (PCNA). These interactions are modulated by posttranslational modifications such as ubiquitination and phosphorylation that enhance translesion synthesis (TLS) and mutagenesis. PMID- 25737060 TI - The imaging features of neurologic complications of left atrial myxomas. AB - BACKGROUND: Neurologic complications may be the first symptoms of atrial myxomas. Understanding the imaging features of neurologic complications of atrial myxomas can be helpful for the prompt diagnosis. OBJECTIVE: To identify neuroimaging features for patients with neurologic complications attributed to atrial myxoma. METHODS: We retrospectively reviewed the medical records of 103 patients with pathologically confirmed atrial myxoma at Xiangya Hospital from January 2009 to January 2014. The neuroimaging data for patients with neurologic complications were analyzed. RESULTS: Eight patients with atrial myxomas (7.77%) presented with neurologic manifestations, which constituted the initial symptoms for seven patients (87.5%). Neuroimaging showed five cases of cerebral infarctions and three cases of aneurysms. The main patterns of the infarctions were multiplicity (100.0%) and involvement of the middle cerebral artery territory (80.0%). The aneurysms were fusiform in shape, multiple in number (100.0%) and located in the distal middle cerebral artery (100.0%). More specifically, high-density in the vicinity of the aneurysms was observed on CT for two patients (66.7%), and homogenous enhancement surrounding the aneurysms was detected in the enhanced imaging for two patients (66.7%). CONCLUSION: Neurologic complications secondary to atrial myxoma consist of cerebral infarctions and aneurysms, which show certain characteristic features in neuroimaging. Echocardiography should be performed in patients with multiple cerebral infarctions, and multiple aneurysms, especially when aneurysms are distal in location. More importantly, greater attention should be paid to the imaging changes surrounding the aneurysms when myxomatous aneurysms are suspected and these are going to be the relevant features in our article. PMID- 25737063 TI - Label-free mass spectrometric analysis of the mdx-4cv diaphragm identifies the matricellular protein periostin as a potential factor involved in dystrophinopathy-related fibrosis. AB - Proteomic profiling plays a decisive role in the identification of novel biomarkers of muscular dystrophy and the elucidation of new pathobiochemical mechanisms that underlie progressive muscle wasting. Building on the findings of recent comparative analyses of tissue samples and body fluids from dystrophic animals and patients afflicted with Duchenne muscular dystrophy, we have used here label-free MS to study the severely dystrophic diaphragm from the not extensively characterized mdx-4cv mouse. This animal model of progressive muscle wasting exhibits less dystrophin-positive revertant fibers than the conventional mdx mouse, making it ideal for the future monitoring of experimental therapies. The pathoproteomic signature of the mdx-4cv diaphragm included a significant increase in the fibrosis marker collagen and related extracellular matrix proteins (asporin, decorin, dermatopontin, prolargin) and cytoskeletal proteins (desmin, filamin, obscurin, plectin, spectrin, tubulin, vimentin, vinculin), as well as decreases in proteins of ion homeostasis (parvalbumin) and the contractile apparatus (myosin-binding protein). Importantly, one of the most substantially increased proteins was identified as periostin, a matricellular component and apparent marker of fibrosis and tissue damage. Immunoblotting confirmed a considerable increase of periostin in the dystrophin-deficient diaphragm from both mdx and mdx-4cv mice, suggesting an involvement of this matricellular protein in dystrophinopathy-related fibrosis. PMID- 25737062 TI - [Prevalence of Clostridium difficile infection in hospitalized patients with diarrhea: results of a French prospective multicenter bi-annual point prevalence study]. AB - BACKGROUND: Clostridium difficile infections represent the major cause of healthcare-associated diarrhea. The objective of the study was to determine the incidence of C. difficile infection (CDI) in 2012 and to assess the under estimation of the disease in France. METHODS: Seventy healthcare facilities participated in a prospective point prevalence study. Each laboratory was requested to send all the diarrheal stool samples from hospitalized patients during 2 days (one in December 2012 and one in July 2013) to the National Reference Laboratory (NRL) for C. difficile, irrespective of a medical request for C. difficile. At the NRL, stool samples were analyzed using the Quik Chek Complete assay (Alere). Positive samples for glutamate deshydrogenase or toxins were confirmed by the toxigenic culture. Results obtained by the NRL were then compared to those given by each healthcare facility. Incidence of CDI in 2012 was provided by each healthcare facility through a specific questionnaire. RESULTS: Mean incidence of CDI reported in 2012 by the HCF was 3.6 +/- 2.9 per 10,000 patient-days; the incidence was positively correlated to the density testing (defined by the number of tests per 10,000 patient-days), which varied across the HCF (median 29.0 per 10,000 patient-days, IQR 19-50). During the bi-annual point prevalence survey, 651 stool samples were included and 90 were positive for C. difficile in culture. The overall prevalence of patients infected by a toxigenic C. difficile strain was 9.7% (63/651) and the prevalence of patients colonized by a non-toxigenic strain was 4.2% (27/651). Among the 65 cases of CDI detected by the NRL, 35 (55.6%) were missed by the participating HCF because of a lack of sensitivity of the methods used for the diagnosis (16/63, 25.4%) or because of a lack of clinical suspicion (19/63, 30.2%). CONCLUSION: The incidence of CDI in 2012 has increased in France compared to that of 2009 but is still underestimated because of a lack of clinical suspicion or a lack of sensitivity of methods used for toxin detection. PMID- 25737064 TI - Arterial Stiffness Predicts Cognitive Decline in Japanese Community-dwelling Elderly Subjects: A One-year Follow-up Study. AB - AIM: The purpose of this study was to determine whether arterial stiffness can be used to predict one-year changes in the cognitive function in Japanese community dwelling elderly subjects. METHODS: A total of 103 Japanese community-dwelling elderly patients joined this study. Information regarding the age, height, weight, gender and past medical history of each participant was obtained. Additionally, arterial stiffness was determined according to the cardio-ankle vascular index (CAVI), and the cognitive function was assessed with the Mini Mental State Examination (MMSE). One year later, we performed the MMSE in the same subjects. After dividing the cohort according to the 80th percentile of the CAVI (normal and arterial stiffness [AS] groups), we examined whether the degree of cognitive decline, as determined using the pre- and post-MMSE, was significantly different based on the severity of arterial stiffness, adjusted for age, BMI, gender and the pre-MMSE scores. RESULTS: Of the 103 subjects who participated in the pre-data collection, 74 (38 men and 36 women, 73.4+/-4.0 years) joined the post-data collection. We found a significant difference in the change in the post-MMSE scores between the normal and AS groups (pre-MMSE: normal group [27.4+/-2.1] and AS group [26.9+/-2.4] and post-MMSE: normal group [27.2+/ 2.1] and AS group [25.5+/-2.3], F=5.95, p=0.02). For each domain of the MMSE, the changes in MMSE-attention-and-calculation (F=5.11, p=0.03) and MMSE-language (F=4.32, p=0.04) were significantly different according to an ANCOVA. CONCLUSIONS: We found that arterial stiffness predicts cognitive decline in Japanese community-dwelling elderly subjects regardless of the initial level of the global cognitive function. This finding indicates the potential use of the degree of arterial stiffness as an indicator for preventing or delaying the onset of dementia in the elderly. PMID- 25737069 TI - Legal and policy foundations for global generic competition: Promoting affordable drug pricing in developing societies. AB - The so-called 'TRIPS flexibilities' restated in 2001 by the World Trade Organization's Doha Declaration on TRIPS and Public Health offer a variety of policy avenues for promoting global price-based competition for essential medicines, and thus for improving access to affordable medicines in the developing world. In recent years, developing countries and international organisations alike have begun to explore the potentialities of global generic markets and competition generally, and also of using compulsory licensing to remedy anti-competitive practices (e.g. excessive pricing) through TRIPS compatible antitrust enforcement. These and other 'pro-competitive' TRIPS flexibilities currently available provide the critical leverage and policy space necessary to improve access to affordable medicines in the developing world. PMID- 25737070 TI - Patients' perceptions of their postoperative recovery for one month. AB - AIMS AND OBJECTIVES: To explore orthopaedic and general surgery patients' perceptions of their postoperative recovery for one month. BACKGROUND: In general, nursing research in the postoperative context has been directed towards a single symptom or area, which is valuable. However, there is a lack of studies of orthopaedic and general surgery patients' perceptions of postoperative recovery from a short-term perspective. DESIGN: A quantitative approach with a longitudinal design was used. METHODS: A total of 180 patients participated in the study. Data were collected using a standardised questionnaire, the Postoperative Recovery Profile, for self-assessment of recovery. Descriptive statistics reported as proportions were used for the categorical variables. Analytic statistics were used to identify statistically significant differences. Mean values and t-tests were used for quantity variables, and Mann-Whitney U tests and Chi-squared tests were used for nonparametric variables. RESULTS: Overall, the orthopaedic patients were substantially less recovered than the general surgery patients. Two-thirds of the orthopaedic patients and half of the general surgery patients perceived severe or moderate pain in the acute recovery phase. Within the general surgery group, there were significant differences in the recovery between the Gastric Bypass patients and colon/ileum surgery patients. The gastric bypass patients were overall more recovered than the other groups of patients. The Gastric Bypass patients reported that they had improved after one month compared to their own status prior to surgery. CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: Nursing support for orthopaedic patients must be improved, especially after they are discharged from the hospital. To structure and monitor individual recovery, a top-five priority profile of the most important problems should be used during follow-up calls after the patient is discharged from the hospital. Postoperative pain continues to represent a clinical problem that requires attention. Heterogeneity in the perceptions of recovery within the general surgery group was indicated, which may depend on the surgical procedure as well as the patients' expectations and comparisons with their lives before surgery. Rather than return to their preoperative levels, certain patients tend to continue towards a new or different life postoperatively. PMID- 25737071 TI - Immunological profiling of haemodialysis patients and young healthy individuals with implications for clinical regulatory T cell sorting. AB - With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients. PMID- 25737072 TI - Use of oestrogen-containing medication is not associated with renal angiomyolipoma in tuberous sclerosis: findings from a survey. PMID- 25737073 TI - Risk factors for formation of steinstrasse after extracorporeal shock wave lithotripsy for pediatric renal calculi: a multivariate analysis model. AB - OBJECTIVES: To define various stone, renal and therapy factors that could affect steinstrasse (SS) formation after extracorporeal shock wave lithotripsy (SWL) for pediatric kidney stones. Thus, SS could be anticipated and prophylactically avoided METHODS: From January 1999 through December 2012, 317 children underwent SWL with Dornier Lithotripter S for the treatment of renal stones. Univariate and multivariate statistical analyses of patients, stones and therapy characteristics in relation to the incidence of SS were performed to detect the factors that had a significant impact on SS formation. RESULTS: The overall incidence of SS was 8.5%. The steinstrasse was in the pelvic ureter in 74.1% of the cases, lumbar ureter in 18.5% and iliac ureter in 7.4%. Steinstrasse incidence significantly correlated with stone size, site and age of child. Steinstrasse was more common with increasing stone length and stones located in renal pelvis or upper calyx with the age below 4 years. A statistical model was constructed to estimate the risk of steinstrasse formation accurately. The equation for logistic regression is Z = -4.758 + B for age + B for size stone X length in mm + B for stone site. CONCLUSIONS: The stone size, site and age are the most important risk factors responsible for SS formation in children. Our regression analysis model can help with prospective identification of children who will be at risk of SS formation. Those children at high risk of SS formation should be closely monitored or treated by endoscopic maneuvers from the start. PMID- 25737074 TI - A fatal case of iliopsoas abscess caused by Salmonella enterica serovar Choleraesuis that heterogeneously formed mucoid colonies. AB - Salmonella enterica subsp. enterica serovar Choleraesuis, an organism highly adapted to swine, rarely causes invasive human infection. We describe a fatal case of Salmonella ser. Choleraesuis infection developing iliopsoas abscess. A part of organisms recovered from the blood formed mucoid colonies, which became reactive to anti-O antigen antisera after either heat treatment or subculture through semisolid agar. PMID- 25737075 TI - Sirt1 Regulates Microtubule Dynamics Through Negative Regulation of Plk1 in Mitosis. AB - Although loss of Sirt1 leads to chromosome aneuploidy, which accounts for higher tumor susceptibility, the molecular mechanisms remain unclear. Herein, we demonstrate that Sirt1 directly regulates Plk1, of which activity is critical for mitotic progression and spindle dynamics. Depletion or inhibition of Sirt1 significantly perturbs the formation of the mitotic spindle, leading to defective chromosome segregation. Elevated depolymerization of the mitotic spindle following loss of Sirt1 was associated with the deregulation of Plk1 activity. Thus, we conclude that Sirt1 may contribute to a mitotic regulator that controls spindle dynamics through Plk1 activity, resulting in fine-tuning of Plk1 dependent microtubule dynamics. PMID- 25737076 TI - Photoinduced hole injection into a self-assembled pi-extended G-quadruplex. AB - We have prepared a G-quadruplex (GQ-1) that incorporates an 8-(4' aminophenylethynyl)guanine (GEAn) electron donor covalently attached to a 4 aminonaphthalene-1,8-imide (ANI) chromophore and a naphthalene-1,8:4,5 bis(dicarboximide) (NDI) electron acceptor (GEAn-ANI-NDI, 1). In the presence of KPF6 in tetrahydrofuran (THF), 1 self-assembles into a monodisperse, C4-symmetric GQ-1 with small spatial intraquadruplex overlap between the ANI-NDI units. Photoexcitation of monomeric 1 induces the two-step charge transfer GEAn-(1)*ANI NDI -> GEAn(+*)-ANI(-*)-NDI -> GEAn(+*)-ANI-NDI(-*) that occurs in tau(CS1) = 5 ps and tau(CS2) = 330 ps, respectively, while charge recombination in ca. 300 ns. Sharpening of the GEAn(+*) transient absorption and a shift of the ethynyl vibrational frequency in 1 were observed, concomitant with the stepwise electron transfer from ANI(-*) to NDI. Formation of GQ-1 from 1 in THF increases the secondary charge-shifting rate (tau(CS2) = 110 ps) and results in no change in ethynyl vibrational frequency. Charge recombination in GQ-1 is slowed by enhanced radical-pair intersystem crossing driven by the greater number of hyperfine couplings in the assembly. Moreover, time-resolved EPR spectroscopy shows that the spin-spin-exchange interaction (J) between the radicals of GEAn(+*)-ANI-NDI( *) within GQ-1 is smaller than that of 1, suggesting that the spin (charge) density in GEAn(+*) is more dispersed in GQ-1. The spectroscopic results are consistent with hole sharing among the guanines within the G-quadruplex that is kinetically competitive with the formation of GEAn(+*). This suggests that G quadruplexes can serve as effective hole conduits in ordered donor-acceptor assemblies. PMID- 25737077 TI - Adverse birth outcomes in women exposed to Syrian chemical attack. PMID- 25737078 TI - A call for international accountability--preserving hope amid false protection. PMID- 25737079 TI - Neuroprognostication after cardiac arrest in Europe: new timings and standards. PMID- 25737080 TI - The association between manual mode defibrillation, pre-shock pause duration and appropriate shock delivery when employed by basic life support paramedics during out-of-hospital cardiac arrest. AB - BACKGROUND: Pre-shock pause duration of <20s is associated with improved survival after cardiac arrest. Manual mode defibrillation has been associated with the shortest duration of pre-shock pause but is largely practiced by advanced life support paramedics (ALS) whereas defibrillator only paramedics (basic life support or BLS) routinely use the defibrillator in automatic mode. OBJECTIVE: We sought to explore the relationship between manual mode defibrillation, pre-shock pause duration and rate of inappropriate shocks when defibrillation is provided by ALS vs. BLS trained in manual mode defibrillation. METHODS: We performed a retrospective review of all treated non-traumatic adult out-of-hospital cardiac arrest (OHCA) presenting in a shockable rhythm over a one year period beginning January 1, 2012. Our primary outcome measure was the proportion of manual mode shocks delivered by BLS with pre-shock pause duration of <20s when compared to ALS. Our secondary outcome measures were the duration of pre-, post- and peri shock pause and the proportion of appropriate shocks (defined as correct identification and shock delivery to patients in a shockable rhythm) delivered by either level of paramedic. This study had a power of 90% to detect an absolute difference of 15% between paramedic levels in proportion of shocks delivered with pre-shock pause duration <20s. RESULTS: Among 2019 treated OHCA, 335 (20%) presented in a shockable rhythm. Manual defibrillation was performed in 155 (46%) of these cases (196 shocks by ALS, 143 shocks by BLS). There were no differences in the proportion of shocks delivered with pre-shock pause duration <20s (ALS 82.8% vs. BLS 84.8%, p=.65) nor pre-shock pause duration (s) (median, Q1, Q3); ALS: 12.0 (7.0,17.0) vs. BLS: 11.0 (5.0,17.0), p=.13 while BLS had a significantly shorter peri-shock pause duration (s) (median, Q1, Q3); ALS: 17.0 (12.0, 23.0) vs. BLS: 15.0 (9.0, 22.0), p=.05. There were no differences in the rate of inappropriate shocks (ALS 1.0% vs. BLS 0.7%), p=1.0 between levels of paramedics. CONCLUSIONS: Manual mode defibrillation by BLS paramedics produced similar measures of pre-shock pause duration when compared to ALS paramedics without increasing the incidence of inappropriate shocks. Further study is required to determine the potential impact of BLS manual mode defibrillation on clinical outcomes. PMID- 25737081 TI - Intramuscolar epinephrine during neonatal resuscitation. PMID- 25737083 TI - Blowing hot or cold? Oxygenation and temperature after paediatric cardiac arrest. PMID- 25737082 TI - Neurocognitive outcomes following successful resuscitation from cardiac arrest. AB - INTRODUCTION: Cardiac arrest commonly results in varying degrees of cognitive injury. Standard outcome measures used in the cardiac arrest cohort do not rigorously evaluate for these injury patterns. We examined the utility of the Computerized Assessment for Mild Cognitive Injury (CAMCI) in cardiac arrest (CA) survivors. We hypothesized that cognitive deficits would be more severe in patients who were comatose on hospital arrival. METHODS: Prospective cohort of CA survivors at a single tertiary care facility where participants received neurocognitive testing using CAMCI. CAMCI results were subdivided into memory, attention, and executive functions. Scores between subjects who were initially comatose and were not comatose following resuscitation were compared using the Mann-Whitney test. RESULTS: Of 72 subjects included, the majority (N=44) were initially comatose following resuscitation with mean age of 54 (+/-14) years. The majority experienced a good neurologic outcome based on Cerebral Performance Category (N=47; 66%) and Modified Rankin Scale (N=38; 53%). Time from resuscitation to CAMCI testing was not associated with total CAMCI score in this cohort (Pearson's r(2) value -0.1941, p=0.20). Initially comatose and not comatose subjects did not differ in their CAMCI overall scores (p=0.33), or in any subtest areas. The not comatose cohort had 1 subtest for which there was a Moderate Risk for mild cognitive impairment (Nonverbal Accuracy), and 2 for which there was a Moderately Low Risk (Verbal Accuracy and Executive Accuracy). The Comatose cohort had 4 subtests, which were deemed Moderately Low Risk for cognitive impairment (Verbal Accuracy, Attention Accuracy, Executive Accuracy and Nonverbal Accuracy). CONCLUSIONS: In-hospital CAMCI testing suggests memory, attention and executive impairment are commonly in patients following resuscitation from cardiac arrest. Outcome evaluations should test for deficits in memory, attention, and executive function. PMID- 25737084 TI - Internalization of staphylococcal leukotoxins that bind and divert the C5a receptor is required for intracellular Ca(2+) mobilization by human neutrophils. AB - A growing number of receptors, often associated with the innate immune response, are being identified as targets for bacterial toxins of the beta-stranded pore forming family. These findings raise the new question of whether the receptors are activated or merely used as docking points facilitating the formation of a pore. To elucidate whether the Staphylococcus aureus Panton-Valentine leukocidin and the leukotoxin HlgC/HlgB act through the C5a receptor (C5aR) as agonists, antagonists or differ from the C5a complement-derived peptide, their activity is explored on C5aR-expressing cells. Both leukotoxins equally bound C5aR in neutrophils and in stable transfected U937 cells and initiated mobilization of intracellular Ca(2+) . HlgC/HlgB requires the presence of robust intracellular acidic Ca(2+) stores in order to evoke a rise in free [Ca(2+) ]i , while the LukS PV/LukF-PV directly altered reticular Ca(2+) stores. Intracellular target specificity is conferred by the F-subunit associated to the S-subunit binding the receptor. Furthermore, internalization of the two leukotoxin components (S- and F subunits) associated to C5aR is required for the initiation of [Ca(2+) ]i mobilization. Electrophysiological recordings on living cells demonstrated that LukS-PV/LukF-PV does not alter the membrane resistance of C5aR-expressing cells. The present observations suggest that part of the pore-forming process occurs in distinct intracellular compartments rather than at the plasma membrane. PMID- 25737085 TI - Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists. AB - Structure-affinity relationship (SAR) and structure-kinetics relationship (SKR) studies were combined to investigate a series of biphenyl anthranilic acid agonists for the HCA2 receptor. In total, 27 compounds were synthesized and twelve of them showed higher affinity than nicotinic acid. Two compounds, 6g (IC50=75nM) and 6z (IC50=108nM) showed a longer residence time profile compared to nicotinic acid, exemplified by their kinetic rate index (KRI) values of 1.31 and 1.23, respectively. The SAR study resulted in the novel 2-F, 4-OH derivative (6x) with an IC50 value of 23nM as the highest affinity HCA2 agonist of the biphenyl series, although it showed a similar residence time as nicotinic acid. The SAR and SKR data suggest that an early compound selection based on binding kinetics is a promising addition to the lead optimization process. PMID- 25737086 TI - The short way to chiral compounds with hexahydrofluoreno[9,1-bc]furan framework: synthesis and cytotoxic activity. AB - A simple and efficient method for synthesizing chiral heterocyclic compounds with the hexahydrofluoreno[9,1-bc]furan framework via interaction between trans-4 hydroxymethyl-2-carene and aromatic aldehydes containing methoxy and hydroxyl moieties in the presence of montmorillonite clay was found. One of the synthesized compounds exhibited a high cytotoxic activity against lymphoblastoid cell line MT-4 (CTD50 0.9MUM), which was higher than that of the comparative drug Doxorubicin. Death of cancer cells in this case substantially occurs via induction of apoptosis. PMID- 25737087 TI - Identification of Bacillus anthracis PurE inhibitors with antimicrobial activity. AB - N(5)-carboxy-amino-imidazole ribonucleotide (N(5)-CAIR) mutase (PurE), a bacterial enzyme in the de novo purine biosynthetic pathway, has been suggested to be a target for antimicrobial agent development. We have optimized a thermal shift method for high-throughput screening of compounds binding to Bacillus anthracis PurE. We used a low ionic strength buffer condition to accentuate the thermal shift stabilization induced by compound binding to Bacillus anthracis PurE. The compounds identified were then subjected to computational docking to the active site to further select compounds likely to be inhibitors. A UV-based enzymatic activity assay was then used to select inhibitory compounds. Minimum inhibitory concentration (MIC) values were subsequently obtained for the inhibitory compounds against Bacillus anthracis (DeltaANR strain), Escherichia coli (BW25113 strain, wild-type and DeltaTolC), Francisella tularensis, Staphylococcus aureus (both methicillin susceptible and methicillin-resistant strains) and Yersinia pestis. Several compounds exhibited excellent (0.05 0.15MUg/mL) MIC values against Bacillus anthracis. A common core structure was identified for the compounds exhibiting low MIC values. The difference in concentrations for inhibition and MIC suggest that another enzyme(s) is also targeted by the compounds that we identified. PMID- 25737088 TI - Synthesis and biological activity evaluation of hydrazone derivatives based on a Troger's base skeleton. AB - We report the design and synthesis of novel anticancer agents based on bis hydrazones separated by a rigid Troger's base skeleton. This novel approach combines a biologically active moiety (hydrazone) with this scaffold (Troger's base) to construct DNA intercalators. Evaluation of the anticancer activity of these agents using seven cancer cell lines and two healthy cell lines found that several derivatives had potent anticancer activity and excellent selectivity indexes toward cancer cells. The antimicrobial activities were tested on a set of thirteen bacterial stains, but the prepared compounds were not active. Complexation studies using biologically important metal ions demonstrated that these compounds are able to bind Cu(2+), Fe(3+), Co(2+), Ni(2+) and Zn(2+). DNA intercalation studies showed that the compounds themselves do not interact with DNA, but their metallocomplexes do interact, most likely via intercalation into DNA. PMID- 25737089 TI - Synthesis of air- and moisture-stable dibenzogallepins: control of planarity of seven-membered rings in solid states by coordination to gallium atoms. AB - Air- and moisture-stable dibenzo[b,f]gallepins with planar seven-membered rings have been designed and synthesized. From X-ray single-crystal analyses, the effects of the coordination numbers were evaluated at the gallium atom on the planarity of the seven-membered rings with a series of the synthesized complexes. Accordingly, it was shown that the seven-membered ring of dibenzogallepin involving a three-coordinated gallium atom presented the highest planarity compared to other dibenzogallepins with four- or five-coordinated gallium atoms. In addition, from theoretical calculations, it was proposed that the electronic states of the gallium atom in the complexes contributed to the energy levels of LUMOs+1. PMID- 25737090 TI - Standard precautions: what is meant and what is not. PMID- 25737091 TI - Role of data warehousing in healthcare epidemiology. AB - Electronic storage of healthcare data, including individual-level risk factors for both infectious and other diseases, is increasing. These data can be integrated at hospital, regional and national levels. Data sources that contain risk factor and outcome information for a wide range of conditions offer the potential for efficient epidemiological analysis of multiple diseases. Opportunities may also arise for monitoring healthcare processes. Integrating diverse data sources presents epidemiological, practical, and ethical challenges. For example, diagnostic criteria, outcome definitions, and ascertainment methods may differ across the data sources. Data volumes may be very large, requiring sophisticated computing technology. Given the large populations involved, perhaps the most challenging aspect is how informed consent can be obtained for the development of integrated databases, particularly when it is not easy to demonstrate their potential. In this article, we discuss some of the ups and downs of recent projects as well as the potential of data warehousing for antimicrobial resistance monitoring. PMID- 25737092 TI - Multidrug-resistant Gram-negative bacteria: a product of globalization. AB - Global trade and mobility of people has increased rapidly over the last 20 years. This has had profound consequences for the evolution and the movement of antibiotic resistance genes. There is increasing exposure of populations all around the world to resistant bacteria arising in the emerging economies. Arguably the most important development of the last two decades in the field of antibiotic resistance is the emergence and spread of extended-spectrum beta lactamases (ESBLs) of the CTX-M group. A consequence of the very high rates of ESBL production among Enterobacteriaceae in Asian countries is that there is a substantial use of carbapenem antibiotics, resulting in the emergence of plasmid mediated resistance to carbapenems. This article reviews the emergence and spread of multidrug-resistant Gram-negative bacteria, focuses on three particular carbapenemases--imipenem carbapenemases, Klebsiella pneumoniae carbapenemase, and New Delhi metallo-beta-lactamase--and highlights the importance of control of antibiotic use. PMID- 25737093 TI - Nickel-catalyzed asymmetric transfer hydrogenation of hydrazones and other ketimines. AB - We report the use of nickel catalysts for the catalytic transfer hydrogenation of hydrazones and other ketimines with formic acid. Strongly donating bisphosphines must be used to support the catalysts. As in enzymatic catalysis, attractive weak interactions may be important for stereochemical control by the nickel/binapine catalyst. PMID- 25737094 TI - Effect of different levels of rapeseed meal and sunflower meal and enzyme combination on the performance, digesta viscosity and carcass traits of broiler chickens fed wheat-based diets. AB - The aim of the present experiment was to examine the effect of different levels of rapeseed meal (RSM) and sunflower meal (SFM) and enzyme combination (endoxylanase and beta-glucanase) on the production performance, carcass quality, gizzard development and digesta viscosity of broiler chickens. The experimental design was a 3*2 factorial arrangement of treatments evaluating three diet types containing different levels of RSM and SFM (low (L), medium (M) and high (H)) and two levels of enzyme inclusion (0 or 100 g/tonne diet to provide 1220 U xylanase and 152 U beta-glucanase per kg diet). Broiler starter and grower/finisher diets were formulated, based on wheat and soya bean meal and containing 50, 50 and 80 g/kg RSM and 0, 50 and 60 g/kg SFM for L, M and H treatments, respectively, during starter period and 80, 80 and 120 g/kg RSM and 0, 80 and 100 g/kg SFM for L, M and H, respectively, during grower/finisher period, and each diet was fed ad libitum to eight pens of 20 male broilers each. During the starter period (1 to 21 days), birds fed the H treatment had lower (P0.05) on feed conversion ratio (FCR). During the grower/finisher phase (22 to 42 day) and over the entire period (1 to 42 day) birds fed the H treatment had lower (P0.05) between RSM and SFM inclusion level and enzyme supplementation were observed for any of the measured parameters at any period. Diet type and enzyme supplementation had no effect (P>0.05) on carcass traits, abdominal fat pad, breast meat yield and jejunal digesta viscosity. Diet type influenced (P=0.05) relative empty gizzard weight, where the H treatment had higher relative empty gizzard weight compared with the L treatment. Enzyme supplementation tended (P=0.10) to increase relative empty gizzard weight. The present data suggest that high inclusion of SFM and RSM negatively influenced broiler performance. Enzyme supplementation improved FCR at all levels of RSM and SFM included in this study, but did not recover the reduction in weight gain caused by high inclusion of RSM and SFM. PMID- 25737095 TI - Engineering superactive granulocyte macrophage colony-stimulating factor transferrin fusion proteins as orally-delivered candidate agents for treating neurodegenerative disease. AB - Intravenously injected granulocyte macrophage colony-stimulating factor (GM-CSF) has shown efficacy in Alzheimer's Disease (AD) and Parkinson's Disease (PD) animal studies and is undergoing clinical evaluation. The likely need for dosing of GM-CSF to patients over months or years motivates pursuit of avenues for delivering GM-CSF to circulation via oral administration. Flow cytometric screening of 37 yeast-displayed GM-CSF saturation mutant libraries revealed residues P12, H15, R23, R24, and K72 as key determinants of GM-CSF's CD116 and CD131 GM-CSF receptor (GM-CSFR) subunit binding affinity. Screening combinatorial GM-CSF libraries mutated at positions P12, H15, and R23 yielded variants with increased affinities toward both CD116 and CD131. Genetic fusion of GM-CSF to human transferrin (Trf), a strategy that enables oral delivery of other biopharmaceuticals in animals, yielded bioactive wild type and variant cytokines upon secretion from cultured Human Embryonic Kidney cells. Surface plasmon resonance (SPR) measurements showed that all evaluated variants possess decreases in CD116 and CD131 binding KD values of up to 2.5-fold relative to wild type. Improved affinity led to increased in vitro bioactivity; the most bioactive variant, P12D/H15L/R23L, had a leukocyte proliferation assay EC50 value 3.5-fold lower than the wild type GM-CSF/Trf fusion. These outcomes are important first steps toward our goal of developing GM-CSF/Trf fusions as orally available AD and PD therapeutics. PMID- 25737096 TI - Navigating the labyrinth: a guide to sequence-based, community ecology of arbuscular mycorrhizal fungi. AB - Data generated from next generation sequencing (NGS) will soon comprise the majority of information about arbuscular mycorrhizal fungal (AMF) communities. Although these approaches give deeper insight, analysing NGS data involves decisions that can significantly affect results and conclusions. This is particularly true for AMF community studies, because much remains to be known about their basic biology and genetics. During a workshop in 2013, representatives from seven research groups using NGS for AMF community ecology gathered to discuss common challenges and directions for future research. Our goal was to improve the quality and accessibility of NGS data for the AMF research community. Discussions spanned sampling design, sample preservation, sequencing, bioinformatics and data archiving. With concrete examples we demonstrated how different approaches can significantly alter analysis outcomes. Failure to consider the consequences of these decisions may compound bias introduced at each step along the workflow. The products of these discussions have been summarized in this paper in order to serve as a guide for any researcher undertaking NGS sequencing of AMF communities. PMID- 25737098 TI - MR detection of retinal hemorrhages: correlation with graded ophthalmologic exam. AB - BACKGROUND: Dilated fundoscopic exam is considered the gold standard for detecting retinal hemorrhage, but expertise in obtaining this exam is not always immediately available. MRI can detect retinal hemorrhages, but correlation of the grade or severity of retinal hemorrhage on dilated fundoscopic exam with retinal hemorrhage visibility on MRI has not been described. OBJECTIVE: To determine the value of standard brain protocol MRI in detecting retinal hemorrhage and to determine whether there is any correlation with MR detection of retinal hemorrhage and the dilated fundoscopic exam grade of hemorrhage. MATERIALS AND METHODS: We conducted a retrospective chart review of 77 children <2 years old who were seen for head trauma from April 2007 to July 2013 and had both brain MRI and dilated fundoscopic exam or retinal camera images. A staff pediatric radiologist and radiology resident reviewed the MR images. Retinal hemorrhages were graded by a chief ophthalmology resident on a 12-point scale based on the retinal hemorrhage type, size, location and extent as seen on review of retinal camera images and detailed reports by ophthalmologists. Higher scores indicated increased severity of retinal hemorrhages. RESULTS: There was a statistically significant difference in the median grade of retinal hemorrhage examination between children who had retinal hemorrhage detected on MRI and children who did not have retinal hemorrhage detected on MRI (P = 0.02). When examination grade was categorized as low-grade (1-4), moderate-grade (5-8) or high-grade (>8) hemorrhage, there was a statistically significant association between exam grade and diagnosis based on MRI (P = 0.008). For example, only 14% of children with low-grade retinal hemorrhages were identified on MRI compared to 76% of children with high-grade hemorrhages. MR detection of retinal hemorrhage demonstrated a sensitivity of 61%, specificity of 100%, positive predictive value of 100% and negative predictive value of 63%. Retinal hemorrhage was best seen on the gradient recalled echo (GRE) sequences. CONCLUSION: MRI using routine brain protocol demonstrated 61% sensitivity and 100% specificity in detecting retinal hemorrhage. High-grade hemorrhage was more often detected on MRI than low-grade hemorrhage, 76% vs. 14%. GRE images were the most sensitive for detection of retinal hemorrhages. A dilated fundoscopic exam can be difficult to obtain in infancy, especially in critically ill or non-sedated children. MRI is a useful modality for added documentation of retinal hemorrhage and can be used as an alternative exam when ophthalmologic expertise or retinal camera images are unavailable. Additionally, identification of retinal hemorrhage on MRI can raise the possibility of abuse in children presenting with nonspecific findings. PMID- 25737097 TI - The medial prefrontal cortex: coordinator of autonomic, neuroendocrine and behavioural responses to stress. AB - Responding to real or potential threats in the environment requires the coordination of autonomic, neuroendocrine and behavioural processes to promote adaptation and survival. These diverging systems necessitate input from the limbic forebrain to integrate and modulate functional output in accordance with contextual demand. In the present review, we discuss the potential role of the medial prefrontal cortex (mPFC) as a coordinator of behavioural and physiological stress responses across multiple temporal and contextual domains. Furthermore, we highlight converging evidence from rodent and human research indicating the necessity of the mPFC for modulating physiological energetic systems to mobilise or limit energetic resources as needed to ultimately promote behavioural adaptation in the face of stress. We review the literature indicating that glucocorticoids act as one of the primary messengers in the reallocation of energetic resources having profound effects locally within the mPFC, as well as shaping how the mPFC acts within a network of brain structures to modulate responses to stress. Finally, we discuss how both rodent and human studies point toward a critical role of the mPFC in the coordination of anticipatory responses to stress and why this distinction is an important one to make in stress neurobiology. PMID- 25737099 TI - Family support, anticipated support, negative interaction, and psychological well being of older parents in Thailand. AB - BACKGROUND: A number of studies have consistently indicated that family support has a powerful impact on older parents' well-being, but little is known about the effects of anticipated support and negative interaction on psychological well being. The present study attempted to examine the relationships between family support, negative interaction, and psychological well-being in older Thai parents. METHODS: The sample included 578 elderly parents aged 60 years and older. Multiple regression models were employed to determine whether received support, anticipated support, and negative interaction influence older parents' well-being. RESULTS: Findings revealed that greater emotional and instrumental support received from family members and anticipated support were significantly associated with a greater sense of older parents' psychological well-being. However, psychological well-being was lower for those with more negative family interactions. CONCLUSION: The results suggest that filial piety and family solidarity should be considered when developing elder care policy and interventions to promote psychological well-being. PMID- 25737100 TI - Characterization of wheat straw-degrading anaerobic alkali-tolerant mixed cultures from soda lake sediments by molecular and cultivation techniques. AB - Alkaline pretreatment has the potential to enhance the anaerobic digestion of lignocellulosic biomass to biogas. However, the elevated pH of the substrate may require alkalitolerant microbial communities for an effective digestion. Three mixed anaerobic lignocellulolytic cultures were enriched from sediments from two soda lakes with wheat straw as substrate under alkaline (pH 9) mesophilic (37 degrees C) and thermophilic (55 degrees C) conditions. The gas production of the three cultures ceased after 4 to 5 weeks, and the produced gas was composed of carbon dioxide and methane. The main liquid intermediates were acetate and propionate. The physiological behavior of the cultures was stable even after several transfers. The enrichment process was also followed by molecular fingerprinting (terminal restriction fragment length polymorphism) of the bacterial 16S rRNA gene and of the mcrA/mrtA functional gene for methanogens. The main shift in the microbial community composition occurred between the sediment samples and the first enrichment, whereas the structure was stable in the following transfers. The bacterial communities mainly consisted of Sphingobacteriales, Clostridiales and Spirochaeta, but differed at genus level. Methanothermobacter and Methanosarcina genera and the order Methanomicrobiales were predominant methanogenes in the obtained cultures. Additionally, single cellulolytic microorganisms were isolated from enrichment cultures and identified as members of the alkaliphilic or alkalitolerant genera. The results show that anaerobic alkaline habitats harbor diverse microbial communities, which can degrade lignocellulose effectively and are therefore a potential resource for improving anaerobic digestion. PMID- 25737101 TI - Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test. AB - BACKGROUND: Neuroglucopenic hypoglycemia might be an underestimated threat for roux-en-Y gastric bypass (RYGB) patients leading to fatigue, syncope, seizures or even accidental deaths. Different measurements can assess hypoglycemia such as a finger-stick glucometer, an Oral Glucose Tolerance Test, a Mixed Meal-Test (MMT) or, as introduced recently, continuous glucose monitoring (CGM). SETTING: University Hospital, Austria. METHODS: To assess the incidence of hypoglycemic episodes under real life conditions, 5-day CGM was performed in a series of 40 patients at a mean of 86 months after RYGB. The detection rates were compared to a mixed meal-test. RESULTS: CGM detected hypoglycemic episodes of <55 mg/dL or <3.05 mmol/L in 75% of the patients, while MMT indicated hypoglycemia in 29% of the patients. CGM also detected nocturnal hypoglycemic episodes in 15 (38%) of the patients. A mean of 3+/-1 hypoglycemic episodes per patient with a mean duration of 71+/-25 minutes were observed by CGM. CONCLUSIONS: Assessed under real life conditions by CGM, post-RYGB hypoglycemia was found more frequently than expected. CGM revealed hypoglycemic episodes in 75% of the patients while MMT had a lower detection rate. Thus, CGM may have a role for screening but also for the evaluation of dietary modifications, drug therapy or surgical intervention for hypoglycemia after RYGB. PMID- 25737102 TI - Lipopolysaccharide and lipopolysaccharide-binding protein levels and their relationship to early metabolic improvement after bariatric surgery. AB - BACKGROUND: Bariatric surgery usually results in metabolic improvements within a few days from intervention, but the underlying mechanism is not completely understood and may vary depending on the bariatric procedure. Lipopolysaccharides (LPS) from gut microbiota have been proposed as a triggering factor for the inflammatory state in obesity. Roux-en-Y Gastric Bypass (RYGB) leads to a LPS decrease in the medium-term. OBJECTIVE: To analyze LPS and LPS-binding protein (LBP) in normoglycemic (NG) and diabetic morbidly obese patients in the short term after 2 different bariatric surgery procedures. SETTING: University Hospital, Spain. METHODS: Fifty morbidly obese patients underwent bariatric surgery: 24 with sleeve gastrectomy (SG) and 26 with biliopancreatic diversion (BPD). Patients were classified according to their glycemic status as NG or prediabetic/diabetic. LPS and LBP levels and biochemical and anthropometric variables were determined before and at days 15 and 90 after surgery. RESULTS: A significant LPS reduction was seen only in the prediabetic/diabetic patients at 90 days after SG. LBP levels rose at 15 days after BPD but at 90 days returned to baseline in both NG and prediabetic/diabetic patients. At 90 days after SG, LBP levels significantly decreased compared to baseline in NG and prediabetic/diabetic patients. After multivariate analysis only the change in BMI was independently associated with the change in LBP levels at 90 days. None of the changes in biochemical or anthropometrical variables were significantly associated with the changes in LPS levels at 15 days or 90 days. CONCLUSION: This is the first study showing that the short-term LPS decrease after bariatric surgery depends on the surgical procedure used as well as on the previous glycemic status of the patient, with SG having the greatest short-term effect on LPS and LBP levels. LBP is closely related to anthropometric variables and may be an inflammatory marker in bariatric surgery patients. PMID- 25737103 TI - Laparoscopic hand sewn regastrojejunostomy for complicated Roux-en-Y gastric bypass. PMID- 25737104 TI - Sexual functioning in men who underwent bariatric surgery: far beyond sex hormones. PMID- 25737105 TI - Family members' experiences of being cared for by nurses and physicians in Norwegian intensive care units: a phenomenological hermeneutical study. AB - OBJECTIVES: When patients are admitted to intensive care units, families are affected. This study aimed to illuminate the meaning of being taken care of by nurses and physicians for relatives in Norwegian intensive care units. RESEARCH METHODOLOGY/DESIGN: Thirteen relatives of critically ill patients treated in intensive care units in southern Norway were interviewed in autumn 2013. Interview data were analysed using a phenomenological hermeneutical method inspired by the philosopher Paul Ricoeur. RESULTS: Two main themes emerged: being in a receiving role and being in a participating role. The receiving role implies experiences of informational and supportive care from nurses and physicians. The participating role implies relatives' experiences of feeling included and being able to participate in caring activities and decision-making processes. CONCLUSION: The meaning of being a relative in ICU is experienced as being in a receiving role, and at the same time as being in a participating role. Quality in relations is described as crucial when relatives share their experiences of care by nurses and physicians in the ICU. Those who experienced informational and supportive care, and who had the ability to participate, expressed feelings of gratitude and confidence in the healthcare system. In contrast, those who did not experience such care, especially in terms of informational care expressed feelings of frustration, confusion and loss of confidence. However, patient treatment and care outweighed relatives' own feelings. PMID- 25737106 TI - Tuning locality of pair coherence in graphene-based Andreev interferometers. AB - We report on gate-tuned locality of superconductivity-induced phase-coherent magnetoconductance oscillations in a graphene-based Andreev interferometer, consisting of a T-shaped graphene bar in contact with a superconducting Al loop. The conductance oscillations arose from the flux change through the superconducting Al loop, with gate-dependent Fraunhofer-type modulation of the envelope. We confirm a transitional change in the character of the pair coherence, between local and nonlocal, in the same device as the effective length to-width ratio of the device was modulated by tuning the pair-coherence length xiT in the graphene layer. PMID- 25737107 TI - Startle-response based tasks and laboratory measures of impulsivity in abstinent alcoholic patients. AB - AIMS: It is well known that impulsivity is a risk factor for the development of Addictive Disorders, and more specifically Alcohol Use Disorders (AUD). Recently, the Startle-Response Based Tasks (SRBT) and its different forms of plasticity have been found to be impaired in the alcoholic population. This is the first study to explore the correlation between impulsivity laboratory tasks and the SRBT test, in order to determine whether impulsivity and startle response (SR) could be related and in turn, explain their association with Alcohol Dependence (AD). METHODS: SUBJECTS: 40 men, who met DSM-IV criteria for AD and had been abstinent for at least one month. Impulsivity was assessed using three laboratory tests: Continuous Performance Test (CPT), Stop-Signal Task (SST) and Differential Reinforcement for Low-Rate Responding (DRL6). Patients also underwent the SR test. They were compared to 40 matched controls. RESULTS: Impulsivity laboratory measures tasks (SST and commissions of the CPT) correlated positively with the magnitude of SR (P < 0.05) and with habituation (P < 0.05). Scores on DRL6 correlated negatively with the magnitude of SR (P < 0.05). This was not found in the control group. CONCLUSIONS: The fact that impulsivity laboratory measures and the SR are correlated in patients but not in controls, could imply the existence of a common link for these two measures in alcoholic patients. Our findings support the hypothesis of the existence of two different vulnerability pathways for the development of AUD: anxiety and disinhibitory behaviour. PMID- 25737108 TI - Controlling superconductivity by tunable quantum critical points. AB - The heavy fermion compound CeRhIn5 is a rare example where a quantum critical point, hidden by a dome of superconductivity, has been explicitly revealed and found to have a local nature. The lack of additional examples of local types of quantum critical points associated with superconductivity, however, has made it difficult to unravel the role of quantum fluctuations in forming Cooper pairs. Here, we show the precise control of superconductivity by tunable quantum critical points in CeRhIn5. Slight tin-substitution for indium in CeRhIn5 shifts its antiferromagnetic quantum critical point from 2.3 GPa to 1.3 GPa and induces a residual impurity scattering 300 times larger than that of pure CeRhIn5, which should be sufficient to preclude superconductivity. Nevertheless, superconductivity occurs at the quantum critical point of the tin-doped metal. These results underline that fluctuations from the antiferromagnetic quantum criticality promote unconventional superconductivity in CeRhIn5. PMID- 25737110 TI - Isovolumic acceleration measurement at the lateral tricuspid annulus: a promising parameter in pediatric right heart function determination. PMID- 25737111 TI - Reply: To PMID 25039533. PMID- 25737113 TI - Genome engineering and direct cloning of antibiotic gene clusters via phage phiBT1 integrase-mediated site-specific recombination in Streptomyces. AB - Several strategies have been used to clone large DNA fragments directly from bacterial genome. Most of these approaches are based on different site-specific recombination systems consisting of a specialized recombinase and its target sites. In this study, a novel strategy based on phage phiBT1 integrase-mediated site-specific recombination was developed, and used for simultaneous Streptomyces genome engineering and cloning of antibiotic gene clusters. This method has been proved successful for the cloning of actinorhodin gene cluster from Streptomyces coelicolor M145, napsamycin gene cluster and daptomycin gene cluster from Streptomyces roseosporus NRRL 15998 at a frequency higher than 80%. Furthermore, the system could be used to increase the titer of antibiotics as we demonstrated with actinorhodin and daptomycin, and it will be broadly applicable in many Streptomyces. PMID- 25737114 TI - Evolving perspectives of mTOR complexes in immunity and transplantation. AB - Since the discovery of Rapamycin (RAPA) and its immunosuppressive properties, enormous progress has been made in characterizing the mechanistic target of rapamycin (mTOR). Use of RAPA and its analogues (rapalogs) as anti-rejection agents has been accompanied by extensive investigation of how targeting of mTOR complex 1 (mTORC1), the principal target of RAPA, and more recently mTORC2, affects the function of immune cells, as well as vascular endothelial cells, that play crucial roles in regulation of allograft rejection. While considerable knowledge has accumulated on the function of mTORC1 and 2 in T cells, understanding of the differential roles of these complexes in antigen-presenting cells, NK cells and B cells/plasma cells is only beginning to emerge. Immune cell specific targeting of mTORC1 or mTORC2, together with use of novel, second generation, dual mTORC kinase inhibitors (TORKinibs) have started to play an important role in elucidating the roles of these complexes and their potential for targeting in transplantation. Much remains unknown about the role of mTOR complexes and the consequences of mTOR targeting on immune reactivity in clinical transplantation. Here we address recent advances in understanding and evolving perspectives of the role of mTOR complexes and mTOR targeting in immunity, with extrapolation to transplantation. PMID- 25737115 TI - Diversity of Duodenal and Rectal Microbiota in Biopsy Tissues and Luminal Contents in Healthy Volunteers. AB - The diverse microbial communities that colonize distinct segments of the gastrointestinal tract are intimately related to aspects of physiology and the pathology of human health. However, most recent studies have focused on the rectal or fecal microbiota, and the microbial signature of the duodenum is poorly studied. In this study, we compared the microbiota in duodenal and rectal samples to illustrate the characteristic microbial signatures of the duodenum in healthy adults. Nine healthy volunteers donated biopsies and luminal contents from the duodenum and rectum. To determine the composition and diversity of the microbiota, 454- pyrosequencing of bacterial 16S rRNA was performed and multiple bioinformatics analyses were applied. The alpha-diversity and phylogenetic diversity of the microbiota in the duodenal samples were higher than those of the rectal samples. There was higher biodiversity among the microbiota isolated from rectal biopsies than feces. Proteobacteria were more highly represented in the duodenum than in the rectum, both in the biopsies and in the luminal contents from the healthy volunteers (38.7% versus 12.5%, 33.2% versus 5.0%, respectively). Acinetobacter and Prevotella were dominant in the duodenum, whereas Bacteroides and Prevotella were dominant in the rectum. Additionally, the percentage of OTUs shared in biopsy groups was far higher than in the luminal group (43.0% versus 26.8%) and a greater number of genera was shared among the biopsies than the luminal contents. Duodenal samples demonstrated greater biological diversity and possessed a unique microbial signature compared with the rectum. The mucosa-associated microbiota was more relatively conserved than luminal samples. PMID- 25737116 TI - Proteomic Analysis of Erythritol-Producing Yarrowia lipolytica from Glycerol in Response to Osmotic Pressure. AB - Osmotic pressure is a critical factor for erythritol production with osmophilic yeast. Protein expression patterns of an erythritol-producing yeast, Yarrowia lipolytica, were analyzed to identify differentially-expressed proteins in response to osmotic pressure. In order to analyze intracellular protein levels quantitatively, two-dimensional gel electrophoresis was performed to separate and visualize the differential expression of the intracellular proteins extracted from Y. lipolytica cultured under low (3.17 osmol/kg) and high (4.21 osmol/kg) osmotic pressures. Proteomic analyses allowed identification of 54 differentially expressed proteins among the proteins distributed in the range of pI 3-10 and 14.4-97.4 kDa molecular mass between the osmotic stress conditions. Remarkably, the main proteins were involved in the pathway of energy, metabolism, cell rescue, and stress response. The expression of such enzymes related to protein and nucleotide biosynthesis was inhibited drastically, reflecting the growth arrest of Y. lipolytica under hyperosmotic stress. The improvement of erythritol production under high osmotic stress was due to the significant induction of a range of crucial enzymes related to polyols biosynthesis, such as transketolase and triosephosphate isomerase, and the osmotic stress responsive proteins like pyridoxine-4-dehydrogenase and the AKRs family. The polyols biosynthesis was really related to an osmotic response and a protection mechanism against hyperosmotic stress in Y. lipolytica. Additionally, the high osmotic stress could also induce other cell stress responses as with heat shock and oxidation stress responses, and these responsive proteins, such as the HSPs family, catalase T, and superoxide dismutase, also had drastically increased expression levels under hyperosmotic pressure. PMID- 25737117 TI - What Can Proteomics Tell Us about Tuberculosis? AB - Tuberculosis (TB) is an infectious disease transmitted by aerosol droplets and characterized by forming granulomatous lesions. Although the number of people infected in the population is high, the vast majority does not exhibit symptoms of active disease and only 5-10% develop the disease after a latent period that can vary from weeks to years. The bases of the immune response for this resistance are unknown, but it depends on a complex interaction between the environment, the agent, and the host. The analysis of cellular components of M. tuberculosis shows important host-pathogen interactions, metabolic pathways, virulence mechanisms, and mechanisms of adaptation to the environment. However, the M. tuberculosis proteome still remains largely uncharacterized in terms of virulence and pathogenesis. Here, we summarize some of the major proteomic studies performed to scrutinize all the mycobacterial components. PMID- 25737118 TI - Morphological, Molecular, and Biochemical Characterization of Monounsaturated Fatty Acids-Rich Chlamydomonas sp. KIOST-1 Isolated from Korea. AB - Microalgae hold promise as producers of sustainable biomass for the production of biofuels and other biomaterials. However, the selection of strains with efficient and robust production of desirable resources remains challenging. In this study, we isolated a green microalga from Korea and analyzed its morphological, molecular, and biochemical characteristics. Microscopic and phylogenetic analyses demonstrated that the isolate could be classified into the genus Chlamydomonas, and we designated the isolate Chlamydomonas s p. K IOST -1. Compositions of protein, lipid, and carbohydrate in the microalgal cells were estimated to be 58.8 +/- 0.2%, 22.7 +/- 1.2%, and 18.5 +/- 1.0%, respectively. Similar to other microalgae belonging to Chlorophyceae, the dominant amino acid and monosaccharide in Chlamydomonas sp. KIOST-1 were glutamic acid and glucose. On the other hand, the proportions of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids clearly differed from other species in the genus Chlamydomonas, and monounsaturated fatty acids accounted for a large portion (41.3%) of the total fatty acids in the isolate. Based on these results, Chlamydomonas sp. KIOST-1 has advantageous characteristics for biomass production. PMID- 25737120 TI - Mitotic cohesin subunit Mcd1 regulates the progression of meiotic recombination in budding yeast. AB - The cohesin complex holds sister chromatids together and prevents premature chromosome segregation until the onset of anaphase. Mcd1 (also known as Scc1), the alpha-kleisin subunit of cohesin, is a key regulatory subunit of the mitotic cohesin complex and is required for maintaining sister chromatid cohesion, chromosome organization, and DNA repair. We investigated the function of Mcd1 in meiosis by ectopically expressing Mcd1 during early meiotic prophase I in Saccharomyces cerevisiae. Mcd1 partially regulated the progression of meiotic recombination, sister chromatid separation, and nuclear division. DNA physical analysis during meiotic recombination showed that Mcd1 induced double-strand breaks (DSBs) but negatively regulated homologous recombination during DSB repair; Mcd1 expression delayed post-DSB stages, leading to inefficiencies in the DSB-to-joint molecule (JM) transition and subsequent crossover formation. These findings indicate that meiotic cells undergo Mcd1-mediated DSB formation during prophase I, and that residual Mcd1 could regulate the progression of JM formation during meiotic recombination. PMID- 25737119 TI - Green Chemistry Approach for the Synthesis of Gold Nanoparticles Using the Fungus Alternaria sp. AB - The synthesis of gold nanoparticles has gained tremendous attention owing to their immense applications in the field of biomedical sciences. Although several chemical procedures are used for the synthesis of nanoparticles, the release of toxic and hazardous by-products restricts their use in biomedical applications. In the present investigation, gold nanoparticles were synthesized biologically using the culture filtrate of the filamentous fungus Alternaria sp. The culture filtrate of the fungus was exposed to three different concentrations of chloroaurate ions. In all cases, the gold ions were reduced to Au(0), leading to the formation of stable gold nanoparticles of variable sizes and shapes. UV-Vis spectroscopy analysis confirmed the formation of nanoparticles by reduction of Au(3+) to Au(0). TEM analysis revealed the presence of spherical, rod, square, pentagonal, and hexagonal morphologies for 1 mM chloroaurate solution. However, quasi-spherical and spherical nanoparticles/heart-like morphologies with size range of about 7-13 and 15-18 nm were observed for lower molar concentrations of 0.3 and 0.5 mM gold chloride solution, respectively. The XRD spectrum revealed the face-centered cubic crystals of synthesized gold nanoparticles. FT-IR spectroscopy analysis confirmed the presence of aromatic primary amines, and the additional SPR bands at 290 and 230 nm further suggested that the presence of amino acids such as tryptophan/tyrosine or phenylalanine acts as the capping agent on the synthesized mycogenic gold nanoparticles. PMID- 25737121 TI - Fast determination of multiple-reaction intermediates for long-chain dicarboxylic Acid biotransformation by gas chromatography-flame ionization detector. AB - For the analysis of multiple-reaction intermediates for long-chain dicarboxylic acid biotransformation, simple and reproducible methods of extraction and derivatization were developed on the basis of gas chromatography with flame ionization detector (GC-FID) instead of mass spectrometry. In the derivatization step, change of the ratio of pyridine to MSTFA from 1:3 to 9:1 resulted in higher peak intensity (p = 0.021) and reproducibility (0.6%CV) when analyzing 32 g/l ricinoleic acid (RA). Extraction of RA and omega-hydroxyundec- 9-enoic acid with water containing 100 mM Tween 80 showed 90.4-99.9% relative extraction efficiency and 2-7%CV compared with those with hydrophobic ethyl acetate. In conclusion, reduction of the pyridine content and change of the extraction solvent to water with Tween 80 provided compatible derivatization and extraction methods to GC-FID based analysis of longchain carboxylic acids. PMID- 25737123 TI - Improving Protein Production on the Level of Regulation of both Expression and Secretion Pathways in Bacillus subtilis. AB - The well-characterized gram-positive bacterium Bacillus subtilis is an outstanding industrial candidate for protein expression owing to its single membrane and high capacity of secretion, simplifying the downstream processing of secretory proteins. During the last few years, there has been continuous progress in the illustration of secretion mechanisms and application of this robust host in various fields of life science, such as enzyme production, feed additives, and food and pharmaceutical industries. Here, we review the developments of Bacillus subtilis as a highly promising expression system illuminating strong chemical- and temperatureinducible and other types of promoters, strategies for ribosome binding-site utilization, and the novel approach of signal peptide selection. Furthermore, we outline the main steps of the Sec pathway and the relevant elements as well as their interactions. In addition, we introduce the latest discoveries of Tat-related complex structures and functions and the countless applications of this full-folded protein secretion pathway. This review also lists some of the current understandings of ATP-binding cassette transporters. According to the extensive knowledge on the genetic modification strategies and molecular biology of Bacillus subtilis, we propose some suggestions and strategies for improving the yield of intended productions. We expect this to promote striking future developments in the optimization and application of this bacterium. PMID- 25737122 TI - Secretory Expression and Characterization of an Acidic Endo-Polygalacturonase Gene from Aspergillus niger SC323 in Saccharomyces cerevisiae. AB - The endo-polygalacturonase gene (endo-pgaA) was cloned from DNA of Aspergillus niger SC323 using the cDNA synthesized by overlapping PCR, and successfully expressed in Saccharomyces cerevisiae EBY100 through fusing the alpha-factor signal peptide of yeast. The full-length cDNA consists of 1,113 bp and encodes a protein of 370 amino acids with a calculated molecular mass of 38.8 kDa. After induction by galactose for 48 h, the activity of recombinant endo-PgaA in the culture supernatant can reach up to 1,448.48 U/mg. The recombinant protein was purified to homogeneity by ammonium sulfate precipitation and gel filtration column chromatography and subsequently characterized. The optimal pH and temperature of the purified recombinant enzyme were 5.0 and 50 degrees C, respectively. The Michaelis-Menten constant (Km) and maximal velocity (Vmax) of the enzyme for pectin were 88.54 MUmol/ml and 175.44 MUmol/mg/min, respectively. The enzyme activity was enhanced by Ca(2+), Cu(2+), and Na(+), and strongly inhibited by Pb(2+) and Mn(2+). The pectin hydrolysates were mainly galacturonic acid and other oligo-galacturonates. Therefore, these characteristics suggest that the recombinant endo-PgaA may be of potential use in the food and feed industries. PMID- 25737124 TI - Production of Biopharmaceuticals in E. coli: Current Scenario and Future Perspectives. AB - Escherichia coli is the most preferred microorganism to express heterologous proteins for therapeutic use, as around 30% of the approved therapeutic proteins are currently being produced using it as a host. Owing to its rapid growth, high yield of the product, cost-effectiveness, and easy scale-up process, E. coli is an expression host of choice in the biotechnology industry for large-scale production of proteins, particularly non-glycosylated proteins, for therapeutic use. The availability of various E. coli expression vectors and strains, relatively easy protein folding mechanisms, and bioprocess technologies, makes it very attractive for industrial applications. However, the codon usage in E. coli and the absence of post-translational modifications, such as glycosylation, phosphorylation, and proteolytic processing, limit its use for the production of slightly complex recombinant biopharmaceuticals. Several new technological advancements in the E. coli expression system to meet the biotechnology industry requirements have been made, such as novel engineered strains, genetically modifying E. coli to possess capability to glycosylate heterologous proteins and express complex proteins, including full-length glycosylated antibodies. This review summarizes the recent advancements that may further expand the use of the E. coli expression system to produce more complex and also glycosylated proteins for therapeutic use in the future. PMID- 25737125 TI - Achievement of developmental milestones in young adults after liver transplantation in childhood. AB - Little is known about the achievement of developmental milestones (i.e., COL) after pediatric liver transplantation. The aim of this study was to examine the COL of young adults who underwent a liver transplantation during childhood and to compare it to healthy peers. Furthermore, we studied factors possibly related to their COL. COL was assessed using the CLQ, which assesses the achievement of developmental milestones (autonomy, psychosexual, social, and antisocial development) and risk behavior (substance abuse and gambling). Sociodemographic characteristics and clinical data were collected using the prospective institutional liver transplantation database. A total of 39 young adults who underwent a liver transplantation at the UMCG in their childhood completed the CLQ. They achieved fewer milestones with regard to autonomy, psychosexual, and social development compared to healthy peers, and they reported less risk behavior. Neither age at the time of study nor age at the time of transplantation was significantly correlated with any of the COL subscales. Young adults show delay in reaching developmental milestones in every dimension after a liver transplantation during their childhood. PMID- 25737126 TI - Ti-O-N/Ti composite coating on Ti-6Al-4V: surface characteristics, corrosion properties and cellular responses. AB - To enhance the corrosion resistance of Ti-6Al-4V and extend its lifetime in medical applications, Ti-O-N/Ti composite coating was synthesized on the surface via plasma immersion ion implantation and deposition (PIIID). Surface morphology and cross sectional morphology of the composite coating were characterized using atomic force microscopy and scanning electron microscopy, respectively. Although X-ray photoelectron spectroscopic analysis revealed that the Ti-O-N/Ti composite coating was composed of non-stoichiometric titanium oxide, titanium nitride and titanium oxynitride, no obvious characteristic peak corresponding to the crystalline phases of them was detected in the X-ray diffraction pattern. In accordance with Owens-Wendt equation, surface free energy of the uncoated and coated samples was calculated and compared. Moreover, the corrosion behavior of uncoated and coated samples was evaluated by means of electrochemical impedance spectroscopy measurement, and an equivalent circuit deriving from Randles model was used to fit Bode plots and describe the electrochemical processes occurring at the sample/electrolyte interface. On the basis of the equivalent circuit model, the resistance of the composite coating was 4.7 times higher than that of the passive layer on uncoated samples, indicating the enhanced corrosion resistance after PIIID treatment. Compared to uncoated Ti-6Al-V, Ti-O-N/Ti-coated samples facilitated ostoblast proliferation within 7 days of cell culture, while there was no statistically significant difference in alkaline phosphate activity between uncoated and coated samples during 21 days of cell culture. PMID- 25737127 TI - Biocorrosion properties of antibacterial Ti-10Cu sintered alloy in several simulated biological solutions. AB - Ti-10Cu sintered alloy has shown strong antibacterial properties against S. aureus and E. coli and good cell biocompatibility, which displays potential application in dental application. The corrosion behaviors of the alloy in five different simulated biological solutions have been investigated by electrochemical technology, surface observation, roughness measurement and immersion test. Five different simulated solutions were chosen to simulate oral condition, oral condition with F(-) ion, human body fluids with different pH values and blood system. It has been shown that Ti-10Cu alloy exhibits high corrosion rate in Saliva pH 3.5 solution and Saliva pH 6.8 + 0.2F solution but low corrosion rate in Hank's, Tyrode's and Saliva pH 6.8 solutions. The corrosion rate of Ti-10Cu alloy was in a order of Hank's, Tyrode's, Saliva pH 6.8, Saliva pH 3.5 and Saliva pH 6.8 + 0.2F from slow to fast. All results indicated acid and F(-) containing conditions prompt the corrosion reaction of Ti-Cu alloy. It was suggested that the Cu ion release in the biological environments, especially in the acid and F(-) containing condition would lead to high antibacterial properties without any cell toxicity, displaying wide potential application of this alloy. PMID- 25737128 TI - Chitosan and composite microsphere-based scaffold for bone tissue engineering: evaluation of tricalcium phosphate content influence on physical and biological properties. AB - In the hereby presented work the authors describe a technique of high-compression resistant biodegradable bone scaffold preparation. The methodology is based on the agglomeration of chitosan (CH) and chitosan/beta-tricalcium phosphate (CH/TCP) microspheres and represents a novel approach to 3D matrices design for bone tissue engineering application. The materials were prepared from high deacetylation degree chitosan. The authors describe the method for scaffold fabrication, essential properties of the materials manufactured and the influence of various TCP concentrations on material morphology, mechanical properties (for dry and hydrated materials) and preliminary study on the interaction between CH or CH/TCP scaffolds and within cultured MG-63 osteoblast-like cells. The properties of the obtained materials were significantly affected by the calcium phosphate content, which had a particular influence on the granule microstructure, size distribution and inner biomaterial pore size. The water uptake ability was found to be lower for the materials enriched with the inorganic phase and tended to decrease with the increasing calcium phosphate concentration. The evaluation of mechanical properties has revealed that scaffolds produced with the usage of granule-based technology display a potential to be used as a load-bearing material since the Young's modulus values were limited to the range of 200-500 MPa for dry materials and 15-20 MPa for the hydrated state of the scaffolds. The cell number, identified in three time points (48 h, 7 and 14 days) by Pico Green assay, was lower for the materials enriched with inorganic phase (75 % of control), however cell distribution, when compared to CH only biomaterial, was acknowledged as steadier on the surface of the material containing the highest calcium phosphate concentration. PMID- 25737129 TI - A potential platform for developing 3D tubular scaffolds for paediatric organ development. AB - Children suffer from damaged or loss of hollow organs i.e. trachea, oesophagus or arteries from birth defects or diseases. Generally these organs possess an outer matrix consisting of collagen, elastin, and cells such as smooth muscle cells (SMC) and a luminal layer consisting of endothelial or epithelial cells, whilst presenting a barrier to luminal content. Tissue engineering research enables the construction of such organs and this study explores this possibility with a bioabsorbable nanocomposite biomaterial, polyhedral oligomeric silsesquioxane poly(epsilon-caprolactone) urea urethane (POSS-PCL).Our established methods of tubular graft extrusion were modified using a porogen-incorporated POSS-PCL and a new lamination method was explored. Porogen (40, 60 or 105 um) were introduced to POSS-PCL, which were fabricated into a bilayered, dual topography matching the exterior and luminal interior of tubular organs. POSS-PCL with different amounts of porogen were tested for their suitability as a SMC layer by measuring optimal interactions with human adipose derived stem cells. Angiogenesis potential was tested with the chorioallantoic membrane assay. Tensile strength and burst pressures of bilayared tubular grafts were determined. Scaffolds made with 40 um porogen demonstrated optimal adipose derived stem cell integration and the scaffolds were able to accommodate angiogenesis. Mechanical properties of the grafts confirmed their potential to match the relevant physiological and biophysical parameters. This study presents a platform for the development of hollow organs for transplantation based on POSS-PCL. These bilayered-tubular structures can be tailor-made for cellular integration and match physico mechanical properties of physiological systems of interest. More specific luminal cell integration and sources of SMC for the external layer could be further explored. PMID- 25737131 TI - Diagnostic Value of (18)F-FDG PET/CT in Detecting Local Recurrent Colorectal Cancer: A Pooled Analysis of 26 Individual Studies. AB - Fluorine 18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) has emerged as a new modality for colorectal cancer (CRC) patients. The aim of this meta-analysis was to assess the diagnostic value of (18)F-FDG PET/CT in detecting local recurrence in patients with CRC. We searched PubMed, Medline, Embase, and ISI databases to collect articles in English that evaluated the diagnostic value of (18)F-FDG PET/CT in patients with CRC. Two reviewers independently assessed the methodological quality of each study using the quality assessment of diagnostic accuracy studies tool. The data were analyzed using Meta-Disc (Version 1.4) and Stata (Version 12.0) software. We estimated the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC). A total of 26 studies were included. When all the eligible studies included, the pooled sensitivity and specificity for (18)F FDG PET/CT in detecting CRC were 0.94 (95 % confidence interval [CI] 0.92-0.96) and 0.94 (95 % CI 0.93-0.95), respectively. The pooled PLR and NLR were 14.39 (95 % CI 7.37-28.09) and 0.08 (95 % CI 0.06-0.12), respectively. The DOR was 208.67 (95 % CI 109.56-397.44) and the area under the SROC curve was 0.9776. The overall diagnostic accuracy (Q* index) was 0.9329. (18)F-FDG PET/CT has good diagnostic performance in detecting local recurrence in patients with CRC. Further larger prospective studies are needed to establish its value for detecting local recurrence of CRC cancer patients. PMID- 25737130 TI - Indirect protein quantification of drug-transforming enzymes using peptide group specific immunoaffinity enrichment and mass spectrometry. AB - Immunoaffinity enrichment of proteotypic peptides, coupled with selected reaction monitoring, enables indirect protein quantification. However the lack of suitable antibodies limits its widespread application. We developed a method in which multi-specific antibodies are used to enrich groups of peptides, thus facilitating multiplexed quantitative protein assays. We tested this strategy in a pharmacokinetic experiment by targeting a group of homologous drug transforming proteins in human hepatocytes. Our results indicate the generic applicability of this method to any biological system. PMID- 25737132 TI - Optimization Studies on Prokaryotic Cell Expression of the Human Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL). AB - The aim of the study was to optimize the in vitro induction and expression of the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and also study the processes of its denaturation, renaturation, and purification. The pGEX 6P-1/TRAIL114-281 plasmid was induced by isopropyl-beta-D-1-thiogalactopyranoside (IPTG) in Escherichia coli BL21 (DE3), and the expressed target protein was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The protein expressed in the form of inclusion body was first denaturalized and then renaturalized by dilution and dialysis technique. GST-rTRAIL114-281 fusion protein was purified by Glutathione-Superflow Resin affinity chromatography and confirmed by Western blot. The molecular weight of GST-rTRAIL expressed in E. coli BL21 (DE3) was approximately 40 kDa. GST-rTRAIL was mainly expressed in the form of inclusion bodies. An optimum expression was induced by IPTG at a concentration of 0.2 mM for 8 h at 37 degrees C. Glutathione-Superflow Resin affinity chromatography yielded the purified GST-rTRAIL protein which was confirmed by Western blot using anti-GST mouse monoclonal antibody. The optimum prokaryotic cell expression of the human GST-rTRAIL was obtained by 0.2 mM IPTG induction for 8 h at 37 degrees C. The denatured inclusion body protein can be refolded by dilution and dialysis and purified by Glutathione-Superflow Resin affinity chromatography. PMID- 25737133 TI - Cardiac Arrhythmias: Diagnosis, Symptoms, and Treatments. AB - The cardiac arrhythmia is characterized by irregular rhythm of heartbeat which could be either too slow (<60 beats/min) or too fast (>100 beats/min) and can happen at any age. The use of pacemaker and defibrillators devices has been suggested for heart arrhythmias patients. The antiarrhythmic medications have been reported for the treatment of cardiac arrhythmias or irregular heartbeats. The diagnosis, symptoms, and treatments of cardiac arrhythmias as well as the radiofrequency ablation, tachycardia, Brugada syndrome, arterial fibrillation, and recent research on the genetics of cardiac arrhythmias have been described here. PMID- 25737134 TI - Minimizing the cost of translocation failure with decision-tree models that predict species' behavioral response in translocation sites. AB - The high number of failures is one reason why translocation is often not recommended. Considering how behavior changes during translocations may improve translocation success. To derive decision-tree models for species' translocation, we used data on the short-term responses of an endangered Australian skink in 5 simulated translocations with different release conditions. We used 4 different decision-tree algorithms (decision tree, decision-tree parallel, decision stump, and random forest) with 4 different criteria (gain ratio, information gain, gini index, and accuracy) to investigate how environmental and behavioral parameters may affect the success of a translocation. We assumed behavioral changes that increased dispersal away from a release site would reduce translocation success. The trees became more complex when we included all behavioral parameters as attributes, but these trees yielded more detailed information about why and how dispersal occurred. According to these complex trees, there were positive associations between some behavioral parameters, such as fight and dispersal, that showed there was a higher chance, for example, of dispersal among lizards that fought than among those that did not fight. Decision trees based on parameters related to release conditions were easier to understand and could be used by managers to make translocation decisions under different circumstances. PMID- 25737135 TI - On the anatomy of the temporomandibular joint and the muscles that act upon it: observations on the gray whale, Eschrichtius robustus. AB - The temporomandibular joint and its associated musculature are described in a neonate gray whale (Eschrichtius robustus) and serve as the basis for direct anatomical comparisons with the temporomandibular region in other clades of baleen whales (Mysticeti). Members of the right whale/bowhead whale clade (Balaenidae) are known to possess a synovial lower jaw joint, while members of the rorqual clade (Balaenopteridae) have a nonsynovial temporomandibular joint characterized by a highly flexible fibrocartilaginous pad and no joint capsule. In contrast, the gray whale possesses a modified temporomandibular joint (intermediate condition), with a vestigial joint cavity lacking a fibrous capsule, synovial membrane, and articular disk. In addition, the presence of a rudimentary fibrocartilaginous pad appears to be homologous to that seen in balaenopterid mysticetes. The intrinsic temporomandibular musculature in the gray whale was found to include a multibellied superficial masseter and a single bellied deep masseter. The digastric and internal pterygoid muscles in E. robustus are enlarged relative to the condition documented in species of Balaenoptera. A relatively complex insertion of the temporalis muscle on the dentary is documented in the gray whale and the low, knob-like process on the gray whale dentary is determined to be homologous with the prominent coronoid process of rorquals. Comparison with the anatomy of the temporomandibular musculature in rorquals reveals an increased importance of alpha rotation of the dentary in the gray whale. This difference in muscular morphology and lines of muscle action is interpreted as representing adaptations for suction feeding. PMID- 25737136 TI - Regulation of the fatty acid synthase promoter by liver X receptor alpha through direct and indirect mechanisms in goat mammary epithelial cells. AB - Fatty acid synthase (FASN) is a central enzyme of milk fat synthesis in the ruminant mammary gland. However, the mechanisms regulating goat FASN transcription remain elusive. The objective of this study was to investigate the mechanisms by which liver X receptor alpha (LXRalpha) regulates the FASN promoter in goat mammary epithelial cells (GMECs). In this study, T0901317 (T09), an agonist for LXRalpha, significantly enhanced the mRNA expression and promoter activity of FASN. Cloning of the dairy goat FASN promoter revealed the presence of one LXR response element (LXRE) and two sterol regulatory elements (SREs). Deletion or mutation of the FASN promoter LXRE reduced, but did not eliminate the transcriptional response of FASN to T09. While the LXRE and the SREs were both disrupted, basal transcription was severely reduced and there was no response to T09 treatment. This suggested that a complete response required one LXRE and two SREs. Knockdown of LXRalpha by siRNA did not alter the basal or T09-induced transcriptional activity of FASN. However, when sterol regulatory binding protein 1 (SREBP1) was knocked down, T09 significantly increased FASN transcription by wild-type GMECs, but had no effect on cells with LXRE-mutant promoters. The results suggested that LXR regulates FASN promoter activity through direct interaction with the LXRE as well as through increasing SREBP1 abundance. The present study provides insight into the transcriptional regulatory mechanisms controlling de novo fatty acid synthesis in GMECs. PMID- 25737137 TI - Genome-wide identification of allele-specific expression in response to Streptococcus suis 2 infection in two differentially susceptible pig breeds. AB - Although allele expression imbalance has been recognized in many species, and strongly linked to diseases, no whole transcriptome allele imbalance has been detected in pigs during pathogen infections. The pathogen Streptococcus suis 2 (SS2) causes serious zoonotic disease. Different pig breeds show differential susceptibility/resistance to pathogen infection, but the biological insight is little known. Here we analyzed allele-specific expression (ASE) using the spleen transcriptome of four pigs belonging to two phenotypically different breeds after SS2 infection. The comparative analysis of allele specific SNPs between control and infected animals revealed 882 and 1096 statistically significant differentially expressed allele SNPs (criteria: ratio ? 2 or ? 0.5) in Landrace and Enshi black pig, respectively. Twenty nine allelically imbalanced SNPs were further verified by Sanger sequencing, and later six SNPs were quantified by pyrosequencing assay. The pyrosequencing results are in agreement with the RNA seq results, except two SNPs. Looking at the role of ASE in predisposition to diseases, the discovery of causative variants by ASE analysis might help the pig industry in long term to design breeding programs for improving SS2 resistance. PMID- 25737138 TI - Obtaining chicken primordial germ cells used for gene transfer: in vitro and in vivo results. AB - Recently, several attempts have been made to create a generation of transgenic chickens via chimeric intermediates produced by primordial germ cells (PGCs) transfer. This study aimed to compare the influences of different chicken PGCs isolated from circulating blood (bPGCs) or gonads (gPGCs), purification (ACK, Percoll or trypsin) and transfection methods (electroporation or lipofection) on the expression of transgenes in vitro and the migration of modified donor cells to the recipient gonads. The highest average frequency of pEGFP-N1 plasmid transfected bPGCs (75.8%) was achieved with Percoll density gradient centrifugation and electroporation. After ammonium chloride-potassium (ACK) treatment and lipofection, in vitro transgene expression was only detected in 35.2% of bPGCs. Chimeric chickens were produced from these purified, transfected and cultured cells, and the transgene was detected in the gonads of 44 and 42% of the recipient embryos that had been injected with bPGCs and gPGCs, respectively. These data confirmed that the combination of PGC purification via Percoll centrifugation and electroporation was an effective method for producing transgenic chickens. Subsequently, we used this method with expression vectors for gene hIFNalpha 2a/hepatitis B virus surface antigen (HBsAg) under the control of the ovalbumin promoter to generate G0 transgenic chickens. Consequently, we observed that 4.9% of the hens and 3.5% of the roosters carried the hIFNalpha 2a gene, whereas 16.7% of the hens and 2.4% of the roosters carried the HBsAg gene, thus undisputedly confirming the exceptional effectiveness of the applied methods. PMID- 25737139 TI - Money doesn't grow on trees: municipal solid waste management programmes must be effective, efficient, and affordable. PMID- 25737140 TI - Valorisation of biodiesel production wastes: Anaerobic digestion of residual Tetraselmis suecica biomass and co-digestion with glycerol. AB - One of the principal opportunity areas in the development of the microalgal biodiesel industry is the energy recovery from the solid microalgal biomass residues to optimise the fuel production. This work reports the cumulative methane yields reached from the anaerobic digestion of the solid microalgal biomass residues using different types of inocula, reporting also the improvement of biogas production using the co-digestion of microalgal biomass with glycerol. Results demonstrate that the solid microalgal biomass residues showed better biogas production using a mesophilic inoculum, reaching almost two-fold higher methane production than under thermophilic conditions. Furthermore, the solid microalgal biomass residues methane production rate showed an increase from 173.78 +/- 9.57 to 438.46 +/- 40.50 mL of methane per gram of volatile solids, when the co-digestion with glycerol was performed. These results are crucial to improve the energy balance of the biodiesel production from Tetraselmis suecica, as well as proposing an alternative way to treat the wastes derived from the microalgae biodiesel production. PMID- 25737141 TI - Enhancing engagement with community sector organisations working in sustainable waste management: A case study. AB - Voluntary and community sector organisations are increasingly being viewed as key agents of change in the shifts towards the concepts of resource efficiency and circular economy, at the community level. Using a meta-analysis and questionnaire surveys across three towns in the East Midlands of England, namely Northampton, Milton Keynes and Luton, this study aimed to understand public engagement with these organisations. The findings suggest that these organisations play a significant and wide-spread role, not only with regard to sustainable environmental management, but also a social role in community development and regeneration. The surveys indicated that there were generally high levels of awareness of the organisations and strong engagement with them. Clothes were the items most donated. Key reasons for engagement included the financial value offered and the perception that it helped the environment. However, potential limitations in future public engagement were also determined and recommendations for addressing these suggested. PMID- 25737142 TI - Corrigendum. AB - Characteristics and management of domestic waste in the rural area of Southwest China by Zhiyong Han et al., Waste Manag Res January 2015 33: 39-47, doi:10.1177/0734242X14558668. PMID- 25737143 TI - Risk of Pneumonitis After Stereotactic Body Radiation Therapy in Patients With Previous Anatomic Lung Resection. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) has emerged as a standard treatment of early-stage, medically inoperable lung cancer. Limited data have evaluated the radiation pneumonitis (RP) risk with SBRT after previous anatomic lung resection (ALR). We assessed the incidence of RP and all pulmonary toxicity (PT) in patients who underwent lung SBRT after ALR and compared them with those of patients without previous ALR. MATERIALS AND METHODS: We reviewed the medical records of 84 consecutively treated patients with stage T1-T2b non-small-cell lung cancer (NSCLC) treated with 88 courses of SBRT for 94 lung tumors from January 2007 to December 2014, including 17 patients with previous ALR. The rates of RP and all PT were compared between the patients with and without previous ALR. RESULTS: At a median follow-up duration of 18.3 months (range, 1.8-85.6 months), the crude grade 2+ RP rate was 5.9% and 2.8% for patients with and without previous ALR, respectively (P = .51). The corresponding 2-year estimates of freedom from RP were 89% and 97% (P = .51). The crude rate of all grade 2+ PT was 11.8% and 2.8% for those with and without previous ALR (P = .11), with 2-year estimates of freedom from PT of 97% and 84% (P = .11), respectively. The 2 cohorts were well matched by the mean lung dose, percentage of lung volume receiving 20 Gy (P = .86), and prescribed dose (P = .75). The 2-year estimates of local control, cause-specific survival, and overall survival were similar between the 2 cohorts. CONCLUSION: The observed rates of PT were low among all patients, with a trend toward increased grade 2 and 3 lung toxicity among patients with previous ALR. Previous ALR did not increase the risk of grade 4 and 5 RP, and SBRT appears safe and effective in this population. PMID- 25737144 TI - Light-harvesting superstructures of green plant chloroplasts lacking photosystems. AB - The light-harvesting antenna of higher plant photosystem II (LHCII) is the major photosynthetic membrane component encoded by an entire family of homologous nuclear genes. On the contrary, the great majority of proteins of photosystems and electron transport components are encoded by the chloroplast genome. In this work, we succeeded in gradually inhibiting the expression of the chloroplast genes that led to the disappearance of the photosystem complexes, mimicking almost total photoinhibition. The treated plants, despite displaying only some early signs of senescence, sustained their metabolism and growth for several weeks. The only major remaining membrane component was LHCII antenna that formed superstructures - stacks of dozens of thylakoids or supergrana. Freeze-fracture electron microscopy revealed specific organization, directly displaying frequently bifurcated membranes with reduced or totally absent photosystem II (PSII) reaction centre complexes. Our findings show that it is possible to accumulate large amounts of light-harvesting membranes, organized into three dimensional structures, in the absence of reaction centre complexes. This points to the reciprocal role of LHCII and PSII in self-assembly of the three dimensional matrix of the photosynthetic membrane, dictating its size and flexible adaptation to the light environment. PMID- 25737145 TI - The composition of cellular infiltrates in anti-HMG-CoA reductase-associated myopathy. AB - INTRODUCTION: To characterize cellular infiltrates in muscle biopsies from patients with anti-3-hydroxy-3-methyl-gulatryl-CoA reductase (HMGCR)-associated myopathy. METHODS: Biopsies from 18 anti-HMGCR myopathy and 7 control dermatomyositis patients were analyzed. RESULTS: CD4+ and CD8+ T-cells were scattered within the endomysium in 50% of anti-HMGCR biopsies. All anti-HMGCR biopsies included increased endomysial and/or perivascular CD163+ M2 macrophages; CD11c+ M1 macrophages were present in 18.8%. CD123+ plasmacytoid dendritic (PD) cells were observed within the endomysium and perivascular spaces in 62.5% of anti-HMGCR biopsies. Membrane attack complex was deposited on endothelial cells in 50% and on the sarcolemma of nonnecrotic muscle fibers in 85.7% of anti-HMGCR cases. Major histocompatibility complex class I antigen was up-regulated in 87.5% of the anti-HMGCR cases. CONCLUSIONS: In addition to necrosis, scattered CD4+, CD8+, and PD cells are characteristic of anti-HMGCR myopathy. Predominant M2 polarization suggests infiltrating macrophages are more likely to be involved with tissue repair than destruction. PMID- 25737146 TI - Secondary metabolite profiles and antifungal drug susceptibility of Aspergillus fumigatus and closely related species, Aspergillus lentulus, Aspergillus udagawae, and Aspergillus viridinutans. AB - The incidence of Aspergillus infection has been increasing in the past few years. Also, new Aspergillus fumigatus-related species, namely Aspergillus lentulus, Aspergillus udagawae, and Aspergillus viridinutans, were shown to infect humans. These fungi exhibit marked morphological similarities to A. fumigatus, albeit with different clinical courses and antifungal drug susceptibilities. The present study used liquid chromatography/time-of-flight mass spectrometry to identify the secondary metabolites secreted as virulence factors by these Aspergillus species and compared their antifungal susceptibility. The metabolite profiles varied widely among A. fumigatus, A. lentulus, A. udagawae, and A. viridinutans, producing 27, 13, 8, and 11 substances, respectively. Among the mycotoxins, fumifungin, fumiquinazoline A/B and D, fumitremorgin B, gliotoxin, sphingofungins, pseurotins, and verruculogen were only found in A. fumigatus, whereas auranthine was only found in A. lentulus. The amount of gliotoxin, one of the most abundant mycotoxins in A. fumigatus, was negligible in these related species. In addition, they had decreased susceptibility to antifungal agents such as itraconazole and voriconazole, even though metabolites that were shared in the isolates showing higher minimum inhibitory concentrations than epidemiological cutoff values were not detected. These strikingly different secondary metabolite profiles may lead to the development of more discriminative identification protocols for such closely related Aspergillus species as well as improved treatment outcomes. PMID- 25737147 TI - Applications of the pharmacokinetic/pharmacodynamic (PK/PD) analysis of antimicrobial agents. AB - The alarming increase of resistance against multiple currently available antibiotics is leading to a rapid lose of treatment options against infectious diseases. Since the antibiotic resistance is partially due to a misuse or abuse of the antibiotics, this situation can be reverted when improving their use. One strategy is the optimization of the antimicrobial dosing regimens. In fact, inappropriate drug choice and suboptimal dosing are two major factors that should be considered because they lead to the emergence of drug resistance and consequently, poorer clinical outcomes. Pharmacokinetic/pharmacodynamic (PK/PD) analysis in combination with Monte Carlo simulation allows to optimize dosing regimens of the antibiotic agents in order to conserve their therapeutic value. Therefore, the aim of this review is to explain the basis of the PK/PD analysis and associated techniques, and provide a brief revision of the applications of PK/PD analysis from a therapeutic point-of-view. The establishment and reevaluation of clinical breakpoints is the sticking point in antibiotic therapy as the clinical use of the antibiotics depends on them. Two methodologies are described to establish the PK/PD breakpoints, which are a big part of the clinical breakpoint setting machine. Furthermore, the main subpopulations of patients with altered characteristics that can condition the PK/PD behavior (such as critically ill, elderly, pediatric or obese patients) and therefore, the outcome of the antibiotic therapy, are reviewed. Finally, some recommendations are provided from a PK/PD point of view to enhance the efficacy of prophylaxis protocols used in surgery. PMID- 25737148 TI - Erratum. Intraocular Pharmacokinetics of Ranibizumab in Vitrectomized Versus Nonvitrectomized Eyes. PMID- 25737149 TI - CNGB3-Achromatopsia Clinical Trial With CNTF: Diminished Rod Pathway Responses With No Evidence of Improvement in Cone Function. PMID- 25737150 TI - Severity of vision loss interacts with word-specific features to impact out-loud reading in glaucoma. AB - PURPOSE: To assess the impact of glaucoma-related vision loss on measures of out loud reading, including time to say individual words, interval time between consecutive words, lexical errors, skipped words, and repetitions. METHODS: Glaucoma subjects (n = 63) with bilateral visual field loss and glaucoma suspect controls (n = 57) were recorded while reading a standardized passage out loud. A masked evaluator determined the start and end of each recorded word and identified reading errors. RESULTS: Glaucoma subjects demonstrated longer durations to recite individual words (265 vs. 243 ms, P < 0.001), longer intervals between words (154 vs. 124 ms, P < 0.001), and longer word/post-word interval complexes (the time spanned by the word and the interval following the word; 419 vs. 367 ms, P < 0.001) than controls. In multivariable analyses, each 0.1 decrement in log contrast sensitivity (logCS) was associated with a 15.0 ms longer word/post-interval complex (95% confidence interval [CI] = 9.6-20.4; P < 0.001). Contrast sensitivity was found to significantly interact with word length, word frequency, and word location at the end of a line with regards to word/post-word interval complex duration (P < 0.05 for all). Glaucoma severity was also associated with more lexical errors (Odds ratio = 1.20 for every 0.1 logCS decrement; 95% CI = 1.02-1.39, P < 0.05), but not with more skipped or repeated words. CONCLUSIONS: Glaucoma patients with greater vision loss make more lexical errors, are slower in reciting longer and less frequently used words, and more slowly transition to new lines of text. These problem areas may require special attention when designing methods to rehabilitate reading in patients with glaucoma. PMID- 25737151 TI - Heat-Shock Proteins 70 Induce Pro-Inflammatory Maturation Program in Decidual CD1a(+) Dendritic Cells. AB - PROBLEM: The aim of the study was to assess possible binding of a mixture of constitutive Hsc70 and inducible Hsp70 forms (HSP70) to Toll-like receptor (TLR) 4 and CD91 receptors on decidual CD1a(+) dendritic cells (DCs) and their influence on DCs maturation status. METHOD OF STUDY: Immunohistology and immunofluorescence of paraffin-embedded first trimetester and term pregnancy decidua were performed together with flow cytometry detection of antigens in DCs after stimulation of decidual mononuclear cells with HSP70. RESULTS: Hsc70 and Hsp70 labeling revealed intracellular and nuclear staining in trophoblast cells. The numbers of Hsc70(+) and Hsp70(+) cells of decidual tissue were higher in early pregnancy decidua than in decidua at term. HSP70 binds CD91 and TLR4 receptors on CD1a(+) DCs and increased the expression of CD83, HLA-DR, CD80, and CD86, but decreased CC receptor (CCR) 5. HSP70 increased CC ligand (CCL) 3 and CCL22. HSP70 in the concentration of 1 MUg/mL increased the percentage of interferon-gamma and interleukin (IL)-15-expressing cells over the cells expressing IL-4. CONCLUSION: HSP70 binds CD91 and TLR4 on decidual CD1a(+) DCs, causes their maturation, and increases IL-15 in the context of Th1 cytokine/chemokine domination, which could support immune response harmful for ongoing pregnancy. PMID- 25737152 TI - Non-pharmacological management for patients with frontotemporal dementia: a systematic review. AB - Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by changes in behavior and language caused by focal degeneration of the frontal and anterior temporal lobes. The behavioral symptoms are distressing to patients and their caregivers. Non-pharmacological management is important as no disease specific pharmacological treatment for FTD is currently available. The primary objective is to review the literature on non-pharmacological management for FTD and to propose directions for future research, with reference to findings. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included "frontotemporal dementia", and words related to non-pharmacological management, and it identified a total of 858 articles. Results revealed that very few randomized controlled trials exist on non-pharmacological management interventions for FTD. These interventions have been proposed by literature based on clinical experience. A small number of studies have supported behavioral management techniques that exploit disease-specific behaviors and preserved functions in patients with FTD, along with the management of caregivers' distress. These limitations warrant well-designed large-scale research to examine effects of non-pharmacological interventions on behavioral symptoms of FTD. PMID- 25737153 TI - C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype-phenotype correlation study. PMID- 25737155 TI - Single-channel recording of glutamate receptors. AB - Highlighted in this unit are issues that should be considered when recording glutamate receptors at the single-channel level, including some commonly encountered problems and their remedies. "UNIT 11.17, Single-Channel Analysis of Glutamate Receptors" describes analysis techniques used to characterize the recorded single-channel properties. PMID- 25737156 TI - Single-channel analysis of glutamate receptors. AB - This is a companion to UNIT 11.16: Single-Channel Recording of Glutamate Receptors. Described here are techniques for analyzing single-channel currents recorded from glutamate receptors to characterize their properties. In addition, issues that need to be taken into account when analyzing glutamate receptor single-channel recording results are discussed. PMID- 25737157 TI - Generation of human acute lymphoblastic leukemia xenografts for use in oncology drug discovery. AB - The establishment of reproducible mouse models of acute lymphoblastic leukemia (ALL) is necessary to provide in vivo therapeutic test systems that recapitulate human ALL, and for amplification of limited amounts of primary tumor material. A popular assay is the primary xenograft model that utilizes immunocompromised mice. The protocol includes injection of primary patient tumor specimens into mice with subsequent serial passaging of the tumors by retransplants of cells harvested from the mouse bone marrow and spleen. The tumors generated are then used for genomic profiling, ex vivo compound testing, mechanistic studies and retransplantation. Detailed in this unit are procedures for the establishment and maintenance of primary ALL xenograft panels for use in basic research and translational studies. PMID- 25737159 TI - Al(III) -catalysed formation of poly(limonene)carbonate: DFT analysis of the origin of stereoregularity. AB - Amino-triphenolate derived Al(III) complexes combined with suitable nucleophiles have been investigated as binary catalysts for the coupling of limonene oxide and carbon dioxide to afford alternating polycarbonates. These catalysts are able to produce stereoregular, perfectly alternating trans-polymers from cis-limonene oxide, whereas the pure trans isomer and cis/trans mixture give rise to lower degrees of stereoregularity. The best Al(III) catalyst shows the potential to mediate the conversion of both stereoisomers of limonene oxide with high conversion levels of up to 71 % under neat conditions, indicating the high degree of robustness and atom-efficiency of this catalytic process. Computational studies have revealed unique features of the binary catalyst system, among which is the preferred nucleophilic attack on the quaternary carbon centre in the limonene oxide substrate. PMID- 25737158 TI - Arrestin-3-Dependent Activation of c-Jun N-Terminal Kinases (JNKs). AB - Only one out of four mammalian arrestin subtypes, arrestin-3, facilitates the activation of JNK family kinases. Here we describe two different protocols used for elucidating the mechanisms involved. One is based on reconstitution of signaling modules from purified proteins: arrestin-3, MKK4, MKK7, JNK1, JNK2, and JNK3. The main advantage of this method is that it unambiguously establishes which effects are direct because only intended purified proteins are present in these assays. The key drawback is that the upstream-most kinases of these cascades, ASK1 or other MAPKKKs, are not available in purified form, limiting reconstitution to incomplete two-kinase modules. The other approach is used for analyzing the effects of arrestin-3 on JNK activation in intact cells. In this case, signaling modules include ASK1 and/or other MAPKKKs. However, as every cell expresses thousands of different proteins their possible effects on the readout cannot be excluded. Nonetheless, the combination of in vitro reconstitution from purified proteins and cell-based assays makes it possible to elucidate the mechanisms of arrestin-3-dependent activation of JNK family kinases. PMID- 25737160 TI - Glabridin, an isoflavan from licorice root, downregulates iNOS expression and activity under high-glucose stress and inflammation. AB - SCOPE: In females, hyperglycemia abolishes estrogen-vascular protection, leading to inflammation and oxidative stress that are related to diabetes-associated cardiovascular complications. Such knowledge led us to examine the potential of glabridin, as a replacement of estrogen anti-inflammatory activity under high glucose conditions. METHODS AND RESULTS: In macrophage-like cells, chronic glucose stress (28 and 44 mM) upregulated inducible nitric oxide synthase (iNOS) mRNA expression by 42 and 189%, respectively. Pretreatment with glabridin, under chronic glucose stress, downregulated the LPS-induced nitric oxide secretion and nitrotyrosine formation, by 39 and 21%, respectively. Pretreatment with estradiol did not prevent the LPS-induced nitrotyrosine formation. Furthermore, glabridin, brought about a decrease in the LPS-induced iNOS mRNA expression by 48%, as compared to cells pretreated with estradiol. Glabridin decreased protein levels of liver iNOS by 69% in adult mouse offspring which developed hyperglycemia after early fetal exposure to a saturated fatty acid-enriched maternal diet. Glabridin also decreased liver nitrotyrosine levels in offspring of regular diet-fed mothers after further receiving high-fat diet. CONCLUSION: Such results indicate that glabridin retains anti-inflammatory abilities to regulate the synthesis and activity of iNOS under high-glucose levels, implying that a glabridin supplement may serve as an anti-inflammatory agent in diabetes-related vascular dysfunction. PMID- 25737161 TI - Morphology control in biphasic hybrid systems of semiconducting materials. AB - Simple blends of inorganic nanocrystals and organic (semiconducting) polymers usually lead to macroscopic segregation. Thus, such blends typically exhibit inferior properties than expected. To overcome the problem of segregation, polymer coated nanocrystals (nanocomposites) have been developed. Such nanocomposites are highly miscible within the polymer matrix. In this Review, a summary of synthetic approaches to achieve stable nanocomposites in a semiconducting polymer matrix is presented. Furthermore, a theoretical background as well as an overview concerning morphology control of inorganic NCs in polymer matrices are provided. In addition, the morphologic behavior of highly anisotropic nanoparticles (i.e. liquid crystalline phase formation of nanorod composites) and branched nanoparticles (spatial orientation of tetrapods) is described. Finally, the morphology requirements for the application of inorganic/organic hybrid systems in light emitting diodes and solar cells are discussed, and potential solutions to achieve the required morphologies are provided. PMID- 25737162 TI - Ni-Pt nanoparticles growing on metal organic frameworks (MIL-96) with enhanced catalytic activity for hydrogen generation from hydrazine at room temperature. AB - Well-dispersed bimetallic Ni-Pt nanoparticles (NPs) with different compositions have been successfully grown on the MIL-96 by a simple liquid impregnation method using NaBH4 as the reducing agent. Powder X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectroscopy, N2 adsorption desorption, and inductively coupled plasma-atomic emission spectroscopy measurements were employed to characterize the NiPt/MIL-96. Catalytic activity of NiPt/MIL-96 catalysts was tested in the hydrogen generation from the aqueous alkaline solution of hydrazine at room temperature. These catalysts are composition dependent on their catalytic activity, while Ni64Pt36/MIL-96 exhibits the highest catalytic activity among all the catalysts tested, with a turnover frequency value of 114.3 h(-1) and 100% hydrogen selectivity. This excellent catalytic performance might be due to the synergistic effect of the MIL-96 support and NiPt NPs, while NiPt NPs supported on other conventional supports, such as SiO2, carbon black, gamma-Al2O3, poly(N-vinyl-2-pyrrolidone) (PVP), and the physical mixture of NiPt and MIL-96, all of them exhibit inferior catalytic activity compared to that of NiPt/MIL-96. PMID- 25737163 TI - In vitro hydrodynamic, transient, and overtime performance of a miniaturized valve for hydrocephalus. AB - Reliable cerebrospinal fluid (CSF) draining methods are needed to treat hydrocephalus, a chronic debilitating brain disorder. Current shunt implant treatments are characterized by high failure rates that are to some extent attributed to their length and multiple components. The designed valve, made of hydrogel, steers away from such protracted schemes and intends to provide a direct substitute for faulty arachnoid granulations, the brain's natural CSF draining valves, and restore CSF draining operations within the cranium. The valve relies on innate hydrogel swelling phenomena to strengthen reverse flow sealing at idle and negative pressures thereby alleviating common valve failure mechanisms. In vitro measurements display operation in range of natural CSF draining (cracking pressure, PT ~ 1-110 mmH2O and outflow hydraulic resistance, Rh ~ 24-152 mmH2O/mL/min), with negligible reverse flow leakage (flow, QO > -10 uL/min). Hydrodynamic measurements and over-time tests under physically relevant conditions further demonstrate the valve's operationally-reproducible properties and strengthen its validity for use as a chronic implant. PMID- 25737164 TI - Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes. AB - Honokiol is a bioactive neolignan compound isolated from the species of Magnolia. This study was designed to elucidate the cellular mechanism by which honokiol alleviates the development of non-alcoholic steatosis. HepG2 cells were treated with honokiol for 1h, and then exposed to 1mM free fatty acid (FFA) for 24h to simulate non-alcoholic steatosis in vitro. C57BL/6 mice were fed with a high-fat diet for 28days, and honokiol (10mg/kg/day) was daily treated. Honokiol concentration-dependently attenuated intracellular fat overloading and triglyceride (TG) accumulation in FFA-exposed HepG2 cells. These effects were blocked by pretreatment with an AMP-activated protein kinase (AMPK) inhibitor. Honokiol significantly inhibited sterol regulatory element-binding protein-1c (SREBP-1c) maturation and the induction of lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) in FFA-exposed HepG2 cells, but these effects were blocked by pretreatment of an AMPK inhibitor. Honokiol induced AMPK phosphorylation and subsequent acetyl-CoA carboxylase (ACC) phosphorylation, which were inhibited by genetic deletion of liver kinase B1 (LKB1). Honokiol stimulated LKB1 phosphorylation, and genetic deletion of LKB1 blocked the effect of honokiol on SREBP-1c maturation and the induction of SCD-1 and FAS proteins in FFA-exposed HepG2 cells. Honokiol attenuated the increases in hepatic TG and lipogenic protein levels and fat accumulation in the mice fed with high-fat diet, while significantly induced LKB1 and AMPK phosphorylation. Taken together, our findings suggest that honokiol has an anti-lipogenic effect in hepatocytes, and this effect may be mediated by the LKB1-AMPK signaling pathway, which induces ACC phosphorylation and inhibits SREBP-1c maturation in hepatocytes. PMID- 25737165 TI - Cystic fibrosis microbiology: Advances in antimicrobial therapy. AB - Much of the improvement in the survival of individuals with cystic fibrosis (CF) is due to advancements in antimicrobial treatments. New aerosolized antibiotic formulations have recently been introduced (such as inhaled aztreonam), and others are in development (inhaled levofloxacin and liposomal amikacin). Licensed dry powder formulations include tobramycin inhalation powder and dry powder colistimethate (available in Europe). Although inhaled antibiotics have the advantage of being able to deliver high intrapulmonary concentrations of drug, antimicrobial resistance can still develop and is a concern in CF. Antimicrobial resistance might be mitigated by using non-antibiotic treatments, antibiotic adjuvants, which have activity against bacteria. Examples include agents such as gallium, antimicrobial peptides and anti-biofilm compounds such as alginate oligosaccharides (OligoG) and garlic. Vaccination strategies and antibody therapy (IgY) against Pseudomonas aeruginosa have also been attempted to prevent initial infection with this organism in CF. Although aggressive and long-term use of antibiotics has been crucial in slowing lung function decline and improving survival in people with CF, it has added a significant burden of care and associated toxicities in these individuals. Careful surveillance and the use of preventative strategies for antibiotic related toxicity (such as nephrotoxicity and ototoxicity) are essential. Continued development of effective antimicrobial agents that can function in the conditions encountered in the CF lung, such as against bacterial biofilm growth and under anaerobic conditions, is needed. PMID- 25737167 TI - CD44 as a potential diagnostic tumor marker. AB - CD44 is a cellular protein that has been intensively studied in relation to carcinogenesis over the last decade. It is altered during inflammatory responses and cellular malfunctioning during tumor progression. Tumors of epithelial origin express CD44 in multiple isoforms called variants; some isoforms are related to specific cancer cells. An increase of CD44 specific isoforms is detected in certain leukemic proliferations. Most published data indicates a partial involvement of CD44 in cancer cells, either in invasiveness or self-renewability. However, there is still uncertainty regarding the exact mechanism by which CD44 participates in growth of cancer or the inflammatory response. This review focuses on CD44 prevalence in cancer cell. It considers tumorigenic behavior of cells that highly express CD44 as an early marker for neoplastic stem cell proliferation. We will discuss multiple examples of tumor in this paper, with an emphasis of 2 solid tumors; namely, breast and colon cancer. PMID- 25737166 TI - Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson's disease. AB - This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson's disease (PD). BACKGROUND: Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS. METHODS: Parkinson's Progression Markers Initiative (PPMI) is a multi-site study of early, untreated PD patients and healthy controls (HCs), the latter with normal cognition. At baseline, participants were assessed with a neuropsychological battery and for symptoms of depression, anxiety, impulse control disorders (ICDs), psychosis, and apathy. RESULTS: Baseline data of 423 PD patients and 196 HCs yielded no between-group differences in demographic characteristics. Twenty-two percent of PD patients met the PD-recommended screening cutoff for CI on the Montral Cognitive Assessment (MoCA), but only 9% met detailed neuropsychological testing criteria for mild cognitive impairment (MCI)-level impairment. The PD patients were more depressed than HCs (P < 0.001), with twice as many (14% vs. 7%) meeting criteria for clinically significant depressive symptoms. The PD patients also experienced more anxiety (P < 0.001) and apathy (P < 0.001) than HCs. Psychosis was uncommon in PD (3%), and no between-group difference was seen in ICD symptoms (P = 0.51). CONCLUSIONS: Approximately 10% of PD patients in the early, untreated disease state met traditional criteria of CI, which is a lower frequency compared with previous studies. Multiple dopaminergic-dependent NPS are also more common in these patients compared with the general population, but others associated with dopamine replacement therapy are not or are rare. Future analyses of this cohort will examine biological predictors and the course of CI and NPS. (c) 2015 International Parkinson and Movement Disorder Society. PMID- 25737168 TI - Clinical characteristics and needle aspiration management of Bacillus Calmette Guerin lymphadenitis in children. AB - OBJECTIVES: To describe characteristics of children developing Bacillus Calmette Guerin (BCG) lymphadenitis, and to evaluate needle aspiration treatment. METHODS: Children developing BCG lymphadenitis following BCG vaccination in Al-Rass General Hospital, Al-Rass, Saudi Arabia were prospectively studied from October 2008 to September 2013. Non-suppurative BCG lymphadenitis was conservatively managed, while suppurative lymphadenitis was treated by needle aspiration. RESULTS: The mean (SD) age of children (n=23) was 4.1 (1.4) months, and symptoms duration was 2.08 (1.38) months. Fifteen (65.2%) children had suppurative, whereas 8 (34.8%) had non-suppurative lymphadenitis. Age, gender, birth weight, and duration of symptoms were not significantly different between children with suppurative and non-suppurative lymphadenitis (p>0.05). Children with suppurative adenitis had higher weight, and larger size of the involved lymph nodes compared with those with non-suppurative nodes (p=0.001). Most (91.3%) had axillary lesions; with a mean lymph node size of 3.2 cm. Abscesses were detected by ultrasound in 8 (80%). Non-suppurative lymphadenitis was conservatively managed, while suppurative was aspirated. The mean duration for resolution was 3.25 months. Lymph nodes aspirate were positive for acid and alcohol fast bacilli in 10 patients (66.6%), and 3 of them grew Staphylococcus aureus. CONCLUSION: Bacillus Calmette-Guerin adenitis occurs in young children, mainly as unilocular suppurative left axillary group with a mean size of 3.2 cm. Needle aspiration is safe in treatment of suppurative lymphadenitis. Mycobacteria stained positive in most of the suppurative lesions. Excision is not needed. PMID- 25737169 TI - The effects of probiotics on treatment of Helicobacter pylori eradication in children. AB - OBJECTIVES: To investigate the eradication rates and side effects of probiotics added in standard triple therapy for the treatment of Helicobacter pylori (H. pylori). METHODS: A prospective open study was performed in the outpatient clinics of the Department of Pediatric Gastroenterology, School of Medicine, Suleyman Demirel University, Isparta, Turkey between March 2012 and May 2013. Sixty-one symptomatic children (range 7-18 years) with H. pylori infection were randomized to 2 groups: group 1 received standard triple therapy (lansoprazole, amoxicillin, and clarithromycin for 14 days), group 2 received the standard triple therapy plus probiotics (Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacterium lactis). Side effects of the drugs were recorded. The 14C urea breath test was performed for 6 weeks after discontinuation of the therapy. RESULTS: Helicobacter pylori infection was detected in 61 of 95 (64.2%) children. Fifty-six patients (38 girls and 18 boys) completed the study. Their mean age was 13.9 +/- 2.7 years. Helicobacter pylori eradication rate was 68.9% in group 1, and 66.6% in group 2 (p=0.78). No statistically significant difference was observed between the 2 groups in terms of side effects. CONCLUSION: We found no evidence in terms of eradication of H. pylori, or impact on adverse effects obtained after the addition of probiotics to standard treatment. Larger randomized controlled investigations are needed to clearly understand the effects of probiotics on H. pylori eradication. PMID- 25737170 TI - Oral steroid treatment for idiopathic sudden sensorineural hearing loss. AB - OBJECTIVES: To describe the efficacy of long-term oral steroids in idiopathic sudden sensorineural hearing loss (ISSHL), and to explore potential prognosis factors, the relationship of hearing recovery outcome, and the recovery time course in ISSHL. METHODS: In this retrospective study, we analyzed 215 cases diagnosed with idiopathic unilateral sudden deafness between January 2003 and December 2012 at a regional hospital in southern Taiwan. All of them received oral steroid therapy and were followed for at least 3 months. RESULTS: Young age, the presence of no other disease (diabetes, hypertension, or cardiovascular disease), treatment within 7 days of the onset of ISSHL, mild hearing loss, and audiograms with ascending curves had a statistically significant better hearing recovery. The average pure-tone audiometry (PTA) was 67.8+/-23.9 dB initially, and was improved between one month (51.6+/-28.7 dB) and 2 months post treatment (49.7+/-28.6 dB). The average last-visit PTA was 49.9+/-29.2 dB. CONCLUSION: Approximately one third of patients had full recovery in hearing, one third had partial recovery, and approximately one third did not recover from hearing loss. In addition, the hearing level remained relatively stable following 2 months of treatment. More than 2 months of oral steroid therapy for ISSHL is not recommended because no additional benefits were evidenced. PMID- 25737171 TI - Management of treatment-naive limited-stage small cell esophagus carcinoma. AB - OBJECTIVES: To identify the problems and principles of treatment decisions in treatment-naive limited-stage small cell esophagus carcinoma (LD-SCEC). METHODS: Clinical data from 39 patients with LD-SCEC treated in the Chinese People's Liberation Army General Hospital, Beijing, China between 2000 and 2013 were retrospectively collected with regard to pathologic characteristics, overall survival (OS), and relevant prognostic factors. RESULTS: The median OS was 21.1 months (95% confidence interval [CI]: 12.4-29.7 months). The one-year OS was 76%, 3-year was 25%, and the 5-year OS was 8%. Depth of invasion, lymph metastasis status, and chemotherapy were independent prognostic factors. Of the 39 cases, only 38.4% (15 cases) were diagnosed as SCEC by the biopsy specimen. Eight of the 15 patients (group A) received chemotherapy and/or radiotherapy, while the remaining 7 patients (group B) and the other 24 patients (group C) received surgery as initial treatment. The one-year survival of group A was 87%, of group B was 69%, and of group C was 74% (p=0.037). The accuracy of the biopsy diagnosis influenced the treatment decisions and prognosis. CONCLUSION: Small cell esophagus carcinoma is a systemic disease, with depth of invasion, lymph metastasis status, and chemotherapy as independent prognostic factors. Systemic therapy based on chemotherapy is recommended. The top priority is to improve the accuracy of diagnosis before deciding on the initial treatment option. PMID- 25737172 TI - The desire to utilize postmastectomy breast reconstruction in Saudi Arabian women. Predictors and barriers. AB - OBJECTIVES: To study factors that influence the desire to utilize breast reconstruction after mastectomy, and to investigate the barriers to reconstruction among women in Saudi Arabia. METHODS: We conducted a cross sectional study at 2 surgical centers in Jeddah, Saudi Arabia. A self administered questionnaire was distributed to all breast cancer patients attending the surgery clinics for follow-up after mastectomy between January and March 2013. Ninety-one patients met the study inclusion criteria. The first part of the questionnaire covered the demographic and socioeconomic information regarding factors that might influence the desire to utilize breast reconstruction including possible barriers. Multivariate logistic regression was used to determine the significant predictors of the desire to undergo reconstruction. RESULTS: Overall, 16.5% of patients underwent breast reconstruction after mastectomy. Young age and high educational attainment were significantly associated with an increased desire to undergo reconstruction. The main barriers to reconstruction were the lack of adequate information on the procedure (63%), concerns on the complications of the procedure (68%), and concerns on the reconstruction interfering with the detection of recurrence (54%). CONCLUSION: Age and educational level were significant predictors of the desire to utilize breast reconstruction. Furthermore, modifiable barriers included the lack of knowledge and misconceptions on the procedure. Addressing these issues may increase the rate of breast reconstruction in Saudi Arabia. PMID- 25737173 TI - Sublingual varices in relation to smoking, cardiovascular diseases, denture wearing, and consuming vitamin rich foods. AB - OBJECTIVES: To identify potential risk factors such as smoking, cardiovascular diseases (CVD), denture wearing, and consuming vitamin rich foods, and its relation to the development of sublingual varices (SLV). METHODS: This cross sectional observational study was conducted on patients who attended the Department of Dentistry at The University of Jordan Hospital, Amman, Jordan between February and May 2013. Clinical examinations and inspections of 391 patients (203 males and 188 females), 13-74 years of age were conducted to determine the presence of SLV. Sublingual varices were classified into 2 categories: grade 0 (few or none visible), and grade one (moderate or severe). Frequency distributions of both SLV and risk factors were obtained. Multiple logistic regression analysis and Chi-square test were used to analyze the influence of individual risk factors on the incidence of SLV. RESULTS: There were 88 subjects (22.5%) who had SLV. In the multivariate logistic regression model, SLV were significantly associated with age (odds ratio [OR]: 2.27, p=0.008) with highest occurrences in the eighth decade of life, gender (OR: 2.74, p=0.001), smoking (OR: 2.93, p=0.002), denture wearing (OR: 2.03, p=0.044), and CVD (OR: 4.01, p=0.00). CONCLUSION: The presence of SLV could be indicative of some potential risk factors including old age, female gender, and denture wearing, and may alert the dental clinician to recognize underlying systemic conditions, particularly CVD. PMID- 25737174 TI - Pattern of drugs use and association with anti-mutated citrullinated vimentin antibody in rheumatoid arthritis. AB - OBJECTIVES: To demonstrate the pattern of disease-modifying antirheumatic drugs (DMARDs) use in Saudi and non-Saudi rheumatoid arthritis (RA) patients, and to evaluate the association of DMARDs use with anti-mutated citrullinated vimentin (anti-MCV) positivity and other factors. METHODS: Retrospectively, for a period of 7 years (2007-2014), we studied 205 RA patients, at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. All patients used DMARDs. Pattern of use for all 6 DMARDs was almost the same among Saudis and non-Saudis with no significant difference (p>0.05) for each DMARD; MTX was the most commonly used DMARD (71-76%). RESULTS: There was no association between anti-MCV positivity and different DMARDs use. Methotrexate was used 76 times as combination, scoring the highest in this respect. There was a significant correlation (p<0.05) between Plaquenil with Methotrexate and with Sulfasalazine; Leflunomide with anti-TNF and with Prednisolone; age with Methotrexate and with Plaquenil; anti-MCV positivity with Prednisolone. Saudi/non-Saudi status showed no correlation with all factors or drugs. There was no significant association between DMARDs and comorbidity. CONCLUSION: Similar to worldwide results, MTX was the most commonly used DMARD; with the addition of anti-TNF to increase the effect, and folic acid to minimize the side effects. In this cohort, the pattern of use for all DMARDs was similar among Saudis and non-Saudis; treatment depended neither on anti-MCV positivity nor on the presence of comorbid conditions. A study of the association of DMARDs with disease activity is recommended. PMID- 25737175 TI - Epidemiology of infant burn in Eastern Saudi Arabia. AB - OBJECTIVES: To identify the epidemiology, pattern, outcome, and impact of infant burns in Eastern Saudi Arabia. METHODS: We conducted a retrospective review of admitted infants charts over 4 years (2008-2013) at the Burn Unit of King Fahad Hospital, Hofuf, Al-Ahsa, Saudi Arabia. The charts were reviewed for age, gender, etiology, site of injury, total body surface area (TBSA), depth of burn, hospital stay, and discharge status. RESULTS: The total number of admissions to the Burn Unit was 510 cases. Out of these cases, 84 were infants, constituting 16.5% of total admissions. Scald burn was the most common etiology affecting 73 infants (86.9%). The highest percentage of total body surface area was between 5-10%, which occurred in 41 infants (48.8%). The average hospital stay was 10 days. No infant mortality was reported during this period. CONCLUSION: The prevalence of burns among infants in our hospital is high, and preventive measures must be implemented to decrease the occurrence of burns in this age group. PMID- 25737176 TI - Self-medication in Central Saudi Arabia. Community pharmacy consumers' perspectives. AB - OBJECTIVES: To determine the prevalence of self-medication and assess the knowledge, attitudes, and perception of consumers toward self-medication. METHODS: This cross-sectional survey was conducted over 4 weeks in May 2011 in Riyadh city, Kingdom of Saudi Arabia. Community pharmacies within 5 areas of the city (North, South, West, East, and Middle) were randomly selected for the study. All consumers were approached to participate in the study, with the exception of those buying cosmetic and medicinal equipments. A validated self-administered questionnaire was used to collect the data. RESULTS: A total of 538 out of 707 consumers attending community pharmacies in Riyadh city, agreed to participate in the study. Most responders were male (73%), 23-33 years old (35%), and college graduates (42%). A total of 285 medications were bought without a prescription. Of these, 149 (49%) medications should be dispensed by prescription only, and 155 (51%) were over the counter medications. The most common prescription medications dispensed without prescriptions were antibiotics (22%) and analgesics/antipyretics (19%). The most common reasons for buying medications without a prescription were that the symptoms were too minor to visit a doctor (54%), time saving (40%), and minor illnesses for which the participants knew the required treatment (40%). Overall, most participants had poor knowledge, and negative perceptions regarding self-medication. More than 68% of participants did not know whether the medicine they bought is a prescription-only or over the counter medication. CONCLUSION: Irresponsible self-medication is common in Saudi Arabia. Future studies should focus on improving the consumers' awareness of self medication and the proper use of medications. PMID- 25737177 TI - The preparedness of private dental offices and polyclinics for medical emergencies. A survey in Western Saudi Arabia. AB - OBJECTIVES: To assess preparedness for medical emergencies in private dental offices in Jeddah, Kingdom of Saudi Arabia (KSA). METHODS: In this cross sectional study, a survey was distributed to 70 dental offices and polyclinics in Jeddah, Saudi Arabia between October 2013 and January 2014. The questionnaire gathered information on the prevention of medical emergencies, the preparedness of the office personnel, and availability of emergency drugs and equipment. RESULTS: For prevention, 92% (n=65) of the offices reported that they obtain a thorough medical history prior to treatment; however, only 11% (n=8) obtain vital signs for each visit. Using a preparedness percent score (0 to 100), the mean level of preparedness of the office personnel in all surveyed dental offices was 55.2+/-20. The availability of emergency drugs was 35+/-35, and equipment was 19+/-22. CONCLUSION: We found a deficiency in personnel training, availability of drugs, and emergency equipment in the surveyed dental clinics. More stringent rules and regulations for emergency preparedness must be reinforced to avoid disasters in these clinics. PMID- 25737178 TI - Students' perception towards the problem based learning tutorial session in a system-based hybrid curriculum. AB - OBJECTIVES: To evaluate students' perception towards the problem based learning (PBL) session in a system-based hybrid curriculum. METHODS: We conducted a cross sectional study in the College of Medicine, King Saud University, Saudi Arabia at the end of the 2012-2013 academic year. The survey questionnaire was self administered, and examined perceptions of PBL session benefits, appropriate running of sessions, and tutor's roles. RESULTS: Out of 510 students, 275 (53.9%) completed the questionnaire. Most of the students reported that PBL sessions were helpful in understanding basic sciences concepts (p=0.04). In addition, they agreed that PBL sessions increased their knowledge of basic sciences (p=0.01). Most students reported that PBL sessions encouraged self-directed learning, collaborative learning, and improved decision making skills. However, 54.5% of students reported lack of proper training before starting the PBL sessions, and only 25.1% of students agreed that the teaching staff are well prepared to run the sessions. Most students used the internet (93.1%), lecture notes (76.7%), and books (64.4%) as learning resources. Most students reported repetition of topics between PBL sessions and lectures (p=0.07). CONCLUSION: The study highlighted the significant role of PBL in a system-based hybrid curriculum and helped students improve their knowledge and different learning skills. Students and staff training is required before the utilizing the PBL as an instructional method. PMID- 25737179 TI - Relationship between the learning style preferences of medical students and academic achievement. AB - OBJECTIVES: To investigate the relationship between the learning style preferences of Saudi medical students and their academic achievements. METHODS: A cross-sectional study was conducted among 600 medical students at King Saud University in Riyadh, Kingdom of Saudi Arabia from October 2012 to July 2013. The Visual, Aural, Read/Write, and Kinesthetic questionnaire (VARK) questionnaire was used to categorize learning style preferences. Descriptive and analytical statistics were used to identify the learning style preferences of medical students and their relationship to academic achievement, gender, marital status, residency, different teaching curricula, and study resources (for example, teachers' PowerPoint slides, textbooks, and journals). RESULTS: The results indicated that 261 students (43%) preferred to learn using all VARK modalities. There was a significant difference in learning style preferences between genders (p=0.028). The relationship between learning style preferences and students in different teaching curricula was also statistically significant (p=0.047). However, learning style preferences are not related to a student's academic achievements, marital status, residency, or study resources (for example, teachers' PowerPoint slides, textbooks, and journals). Also, after being adjusted to other studies' variables, the learning style preferences were not related to GPA. CONCLUSION: Our findings can be used to improve the quality of teaching in Saudi Arabia; students would be advantaged if teachers understood the factors that can be related to students' learning styles. PMID- 25737180 TI - A rare case of multilocus brain abscess due to Entamoeba histolytica infection in a child. AB - Brain abscess due to Entamoeba histolytica (E. histolytica) may pose a diagnostic problem or a therapeutic challenge, as evidenced by the paucity of papers reporting complete recovery after treatment. An 11-year-old girl presented with progressive drowsiness, diminished movements of the left upper limb, and swallowing problems. Cranial MRI showed multiple, contrast-dense masses with fluid content. She was started on meropenem. Surgical drainage was performed. No bacterial or fungal growth was observed in drainage samples. Entamoeba histolytica trophozoites were detected in the tissue sample. Intravenous metronidazole was started and continued for 6 weeks, at the end of which abscesses were found and to have shrunk considerably. Intravenous therapy was switched to oral metronidazole, which was continued for 2 weeks. She regained all her preexisting abilities. Multiple brain abscesses due to E. histolytica is a very rare occurrence, and histopathologic evaluation is important in diagnosis. PMID- 25737181 TI - Bilateral synchronous male breast cancer. AB - Bilateral synchronous breast cancer is extremely rare. A 75-year-old man presented with a right breast mass, which ulcerated and a lump in the left breast. Right breast examination revealed a breast ulcer 7x10cm with everted edges and complete nipple destruction. The left breast showed a hard lump measuring 4x5cm in the nipple-areolar area, unattached to skin, or underlying structure. There was no palpable axillary lymph node bilaterally. A wedge biopsy of right breast ulcer and excision of the left breast lump confirmed bilateral invasive ductal carcinoma - Grade 2 tumor in both breasts. He had bilateral simple mastectomy and chemotherapy; defaulted for 18 months during treatment, and re-presented with bilateral tumor recurrence. The importance of this case report is to create more awareness that breast cancer can occur in males just as in females, though the incidence is rare in males. Early presentation and compliance with treatment modality provide a better outcome. PMID- 25737182 TI - Successful treatment and follow-up of a case of recurrent pseudosarcomatous myofibroblastic proliferation. AB - This report describes a case of recurrent pseudosarcomatous myofibroblastic proliferation (PMP) of the bladder with a satisfactory clinical course after a 3.5-year follow-up. There is a lack of reports of successful treatment experiences on recurrent PMP of the bladder in adults. For the primary lesion, a transurethral resection of the bladder tumor (TUR-BT) was performed; for the recurrent lesion, a combination regime of TUR-BT and intravesical mitomycin C proved effective treatment. The patient did not suffer local recurrence or distal metastasis during the 3.5-year follow-up. Our experience may serve as treatment reference to urologists who encounter similar cases. PMID- 25737183 TI - Traumatic female urethral avulsion. AB - Traumatic female urethral avulsion in the absence of a pelvic fracture is an exceedingly rare entity, with no consensus on its' management. Here, we present a 35-year-old pregnant woman with severe anterior vaginal wall laceration and complete urethral avulsion secondary to straddle injury. Management consisted of primary urethral and vaginal repair. PMID- 25737184 TI - Fertility after oophorectomy due to torsion. AB - OBJECTIVES: To investigate the prevalence of infertility in patients who underwent salpingo-oophorectomy due to adnexal torsion (AT). METHODS: All adult women admitted to the Teaching Institution of the University of Dammam, Dammam, Saudi Arabia who underwent surgery due to AT between January 2001 and 2010 were included. Complete data was collected from the time of admission to the follow up. The data was entered into the database and analyzed. RESULTS: The data of 26 patients was available for analysis. The mean age (+/-standard deviation) at presentation was 22.19+/-4.4 years, and average age at follow up was 34.81+/-5.75 years. The average delay in presentation was 37.76+/-47 hours, and the surgery was performed at 45.07+/-48.57 hours. The right side was involved in 13 (53.8%) of the cases. Fourteen (53.9%) women presented with infertility. Eleven (78.57%) were treated for infertility, and 5 (45.5%) conceived. Patients who were younger at the time of torsion fared better with regard to pregnancy (p<0.03, 95% confidence interval:-6.85; <0.58). CONCLUSION: Patients who undergo salpingo oophorectomy for AT have an increased risk of infertility and should be warned of this impending complication. PMID- 25737185 TI - Screening for urine abnormalities among preschool children in Western Saudi Arabia. PMID- 25737186 TI - Epidemiology of neural tube defects. PMID- 25737187 TI - Population differentiation determined from putative neutral and divergent adaptive genetic markers in Eulachon (Thaleichthys pacificus, Osmeridae), an anadromous Pacific smelt. AB - Twelve eulachon (Thaleichthys pacificus, Osmeridae) populations ranging from Cook Inlet, Alaska and along the west coast of North America to the Columbia River were examined by restriction-site-associated DNA (RAD) sequencing to elucidate patterns of neutral and adaptive variation in this high geneflow species. A total of 4104 single-nucleotide polymorphisms (SNPs) were discovered across the genome, with 193 putatively adaptive SNPs as determined by F(ST) outlier tests. Estimates of population structure in eulachon with the putatively adaptive SNPs were similar, but provided greater resolution of stocks compared with a putatively neutral panel of 3911 SNPs or previous estimates with 14 microsatellites. A cline of increasing measures of genetic diversity from south to north was found in the adaptive panel, but not in the neutral markers (SNPs or microsatellites). This may indicate divergent selective pressures in differing freshwater and marine environments between regional eulachon populations and that these adaptive diversity patterns not seen with neutral markers could be a consideration when determining genetic boundaries for conservation purposes. Estimates of effective population size (N(e)) were similar with the neutral SNP panel and microsatellites and may be utilized to monitor population status for eulachon where census sizes are difficult to obtain. Greater differentiation with the panel of putatively adaptive SNPs provided higher individual assignment accuracy compared to the neutral panel or microsatellites for stock identification purposes. This study presents the first SNPs that have been developed for eulachon, and analyses with these markers highlighted the importance of integrating genome-wide neutral and adaptive genetic variation for the applications of conservation and management. PMID- 25737188 TI - The value of the urinary protein:creatinine ratio for the detection of significant proteinuria in women with suspected preeclampsia. AB - To explore the correlation between urinary protein:creatinine ratio and 24-h excretion of protein, we studied 149 women referred to a day assessment unit for investigations for suspected preeclampsia. Paired samples were obtained for measurement of urinary protein:creatinine ratio and 24-h protein excretion. Collection of a 24-h urine sample was validated by the daily creatinine excretion. The outcome measure was proteinuria of 300 mg/day or more. Inaccurate 24-h collection was observed in 17% of women. All women (n = 56) with a protein:creatinine ratio >60 mg/mM had significant proteinuria. No woman with protein:creatinine ratio <18 mg/mM (n = 20) had significant proteinuria. We recommend that a dual cut-off should be used for excluding and "ruling in" the diagnosis of significant proteinuria. A 24-h urine collection should be used only for urinary protein:creatinine ratio values between 18 and 60 mg/mM in the detection of significant proteinuria. PMID- 25737189 TI - [Tracheobronchial prosthesis in Mounier-Kuhn syndrome: New perspectives]. AB - INTRODUCTION: Mounier-Kuhn syndrome or tracheobronchomegaly is a rare congenital condition, the management of which is complex. We report the case of a patient who was treated with interventional endoscopy. OBSERVATION: We describe the case of a 74-year-old man with a diagnosis of tracheobronchomegaly who was admitted in 2003 with a background of deteriorating respiratory status and the occurrence of postural syncope. He initially received a tracheobronchial silicone Y prosthesis, extended with metal prostheses at the tracheal and bronchial level. This arrangement remained stable until 2011. He then began to develop episodes of asphyxia related to posterior dislocation of the tracheobronchial prosthesis, after breakage of the metallic mesh tracheal prosthesis. A new tracheobronchial prosthesis Y was then placed, custom-made from a 3D model of the airways. This was clinically and functionally effective. DISCUSSION: This case describes the management of a patient with Mounier-Kuhn syndrome by interventional bronchoscopy, with the adaptation of prosthetic materials, on an individual basis, to the anatomy of the patient's airway. PMID- 25737190 TI - Phosphoproteomics of the goat milk fat globule membrane: New insights into lipid droplet secretion from the mammary epithelial cell. AB - Mechanisms of milk lipid secretion are highly controversial. Analyzing the fine protein composition of the "milk fat globule membrane" (MFGM), the triple-layered membrane surrounding milk lipid droplets (LDs) can provide mechanistic clues to better understand LD biosynthesis and secretion pathways in mammary epithelial cells (MECs). We therefore combined a high-sensitive Q-Exactive LC-MS/MS analysis of MFGM-derived peptides to the use of an in-house database intended to improve protein identification in the goat species. Using this approach, we performed the identification of 442 functional groups of proteins in the MFGM from goat milk. To get a more dynamic view of intracellular mechanisms driving LD dynamics in the MECs, we decided to investigate for the first time whether MFGM proteins were phosphorylated. MFGM proteins were sequentially digested by lysine-C and trypsin proteases and the resulting peptides were fractionated by a strong cation exchange chromatography. Titanium beads were used to enrich phosphopeptides from strong cation exchange chromatography eluted fractions. This approach lets us pinpoint 271 sites of phosphorylation on 124 unique goat MFGM proteins. Enriched GO terms associated with phosphorylated MFGM proteins were protein transport and actin cytoskeleton organization. Gained data are discussed with regard to lipid secretory mechanisms in the MECs. All MS data have been deposited in the ProteomeXchange with identifier PXD001039 (http://proteomecentral.proteomexchange.org/dataset/PXD001039). PMID- 25737191 TI - Atheroma Progression in Obese Early-stage Diabetic Japanese Patients in Response to Glycemic Control: Sub-analysis from the DIANA Study. AB - AIM: Diabetes is accompanied by abdominal obesity, which produces various metabolic abnormalities. While metabolic factors have been considered to promote the development of coronary atherosclerosis in the early-stage of diabetes, it remains unknown whether the presence of obesity in early-stage diabetics affects the natural history of coronary atherosclerosis. We herein investigated the characteristics of the disease substrate in obese early-stage diabetics. METHODS: The DIANA (DIAbetes and diffuse coronary NArrowing) study was a serial evaluation of angiographic disease progression in early-stage diabetics with coronary artery disease. A total of 252 study subjects were stratified into non-obese (n=168) and obese groups (n=84). Obesity in Japanese subjects was defined as a body mass index >=25 kg/m(2) according to the statement about Japanese obesity from the Japan Society for the Study of Obesity. Coronary atherosclerotic changes were evaluated by a quantitative computed analysis. The total lesion length (TLL=total length of all atherosclerotic lesions) was compared between the groups. RESULTS: The obese patients were younger (p=0.0002) and had higher levels of fasting (p=0.002) and postprandial insulin (p=0.01), and higher triglyceride levels (p=0.02). On serial angiographic evaluations, obese patients had greater disease progression, reflected by a larger percent change in the TLL (24.7+/-13.7 vs. 7.4+/-10.0%, p=0.04). However, the improvement of abnormal glucose tolerance was associated with a slowing of disease progression in both non-obese (-0.9+/-10.7 vs. +15.0+/-11.2%, p=0.04) and obese (+4.2+/-22.8 vs. +55.5+/-26.5%, p=0.005) patients. CONCLUSIONS: Obese patients with early-stage diabetes exhibit profound disease progression. Glycemic control attenuated the progression of their coronary atherosclerosis. Our findings indicate progressive but modifiable disease in obese early-stage diabetics under optimal glycemic management. PMID- 25737192 TI - Randomized, Double-Blind, Dose-Finding, Phase II Study of Prasugrel in Japanese Patients Undergoing Elective Percutaneous Coronary Intervention. AB - AIM: Prasugrel is a novel platelet P2Y12 receptor blocker with a faster onset of action and greater platelet inhibition with less response variability than clopidogrel. Our objective was to determine the optimal prasugrel dose in Japanese patients undergoing elective percutaneous coronary intervention (PCI) with respect to the incidence of bleeding and platelet inhibition. METHODS: A total of 422 patients were randomly assigned to receive clopidogrel or prasugrel in two strata (standard group: <75 years of age and body weight >50 kg, n=312; high-risk group: >=75 years of age and/or body weight <=50 kg, n=110). The standard group received 20/3.75 or 20/5mg (loading/maintenance doses for three months) of prasugrel or 300/75mg of clopidogrel, while the high-risk group received 20/2.5 or 20/3.75mg of prasugrel or 300/75mg of clopidogrel. RESULTS: The rates of TIMI major and minor bleeding (primary endpoint) were similar among the three treatment arms in the standard group (20/5mg of prasugrel: 0%; 20/3.75mg of prasugrel: 3.8%; 300/75mg of clopidogrel: 2.9%) and the high-risk group (20/3.75mg of prasugrel: 2.7%; 20/2.5mg of prasugrel: 0%; 300/75mg of clopidogrel: 2.8%). VerifyNow assays revealed sufficient levels of platelet inhibition at Weeks 4 and 12 in both the prasugrel arms of the standard group and the 20/3.75mg of prasugrel arm in the high-risk group. Platelet inhibition was not affected by the CYP2C19 phenotype in the prasugrel groups. CONCLUSIONS: The prasugrel dosing regimen of 20/3.75mg has strong antiplatelet effects and the risk of bleeding events is low in Japanese patients undergoing PCI. PMID- 25737193 TI - Effects of Body Mass Index on the Lipid Profile and Biomarkers of Inflammation and a Fibrinolytic and Prothrombotic State. AB - AIM: Both an overweight status and obesity are associated with high cardiovascular morbidity and mortality. The aim of this study was to examine the effects of obesity on different underlying mechanisms, i.e. inflammation, fibrinolysis and a prothrombotic state, in a young high-risk population in the Mediterranean area. METHODS: The study population included 237 subjects (median age: 44 years). We recorded the presence of cardiovascular risk factors and premature ischaemic heart disease and performed weight stratification using the body mass index (BMI) according to the established World Health Organization (WHO) criteria. We also measured the serum/plasma lipid, fibrinogen, D-dimer, von Willebrand factor, tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor-1 antigen (PAI-1) and high-sensitivity C-reactive protein (CRP-hs) levels in samples of peripheral blood. RESULTS: The subjects with premature ischaemic heart disease and hypertension had higher BMI values (p<0.01), and the subjects with an increased weight showed an unadjusted detrimental lipid profile, with a proinflammatory, prothrombotic state and abnormal fibrinolytic parameters. According to a multivariate analysis, the HDL cholesterol (r(2)=0.176; p<0.001), t-PA antigen (r(2)=0.235; p<0.001), PAI-1 antigen (r(2)=0.164; p<0.001) and CRP-hs (r(2)=0.096; p=0.019) levels were significantly related to the weight stratification. CONCLUSIONS: A high BMI is a common finding in young populations at high risk of cardiovascular disease. In the current study, the patients with an increased BMI demonstrated an unhealthy lipid profile, as well as a proinflammatory and prothrombotic state and abnormal fibrinolytic parameters. PMID- 25737194 TI - Echolucent Carotid Plaque is Associated with Future Renal Dysfunction in Patients with Stable Coronary Artery Disease. AB - AIM: Functional and structural abnormalities of the peripheral arteries are associated with renal dysfunction, independent of the presence of renal artery stenosis. This study investigated whether echolucent carotid plaque is associated with a future decline in the renal function in patients with coronary artery disease (CAD). METHODS: Ultrasound assessments of carotid plaque echolucency with integrated backscatter (IBS) analyses were performed in 327 patients with stable CAD and carotid plaque who exhibited a normal renal function (estimated glomerular filtration rate [eGFR] >=60 mL/min/1.73 m(2)) at baseline. A lower IBS value reflects the presence of echolucent and lipid-rich unstable plaque. All patients were followed up for 36 months or until the occurrence of renal dysfunction, defined as an eGFR of <45 mL/min/1.73 m(2). RESULTS: During the follow-up period, 39 patients developed renal dysfunction. A multivariate logistic regression analysis showed that the presence of carotid plaque with a low IBS value was significantly associated with progression to renal dysfunction (odds ratios 0.48; 95% CI 0.30-0.78, p= 0.003). In addition, carotid plaque with a low IBS value had a significant incremental effect on the predictive value of known risk factors for renal dysfunction in analyses using c-statistics (AUC of the baseline risk model with and without IBS: 0.83 vs. 0.79, respectively, p=0.04), net reclassification improvement (index=0.549, p=0.001) and integrated discrimination improvement (index=0.068, p=0.002). CONCLUSIONS: Echolucency of the carotid arteries is associated with future renal dysfunction in patients with stable CAD, indicating that the mechanisms related to plaque instability may be involved in the onset of renal dysfunction. PMID- 25737195 TI - Metal-catalyzed "on-demand" production of carbonyl sulfide from carbon monoxide and elemental sulfur. AB - The group 6 molybdenum(II) cyclopentadienyl amidinate (CPAM) bis(carbonyl) complex [Cp*Mo{N(iPr)C(Ph)N(iPr)}(CO)2] (Cp*=eta(5)-C5Me5) serves as a precatalyst for the high-yielding photocatalytic production of COS from CO and S8 under near-ambient conditions (e.g., 10 psi, 25 degrees C). Further documented is the isolation and structural characterization of several key transition-metal intermediates which collectively support a novel molybdenum(IV)-based catalytic cycle as being operative. Finally, in the presence of an excess amount of a primary amine, it is demonstrated that this catalytic system can be successfully used for the "on-demand" generation and utilization of COS as a chemical reagent for the synthesis of ureas. PMID- 25737197 TI - 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose increases a population of T regulatory cells and inhibits IgE production in ovalbumin-sensitized mice. AB - 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose (PGG) is a gallotannin isolated from various plants. In a previous study, it was reported that PGG suppressed interleukin (IL)-4 induced signal pathway in B cell which is indispensable for immunoglobulin E (IgE) production. However, the suppressive effect of PGG on IgE production in allergen-sensitized mice remains unclear. Therefore, the aim of this study was to investigate the inhibitory effect of PGG on IgE production in ovalbumin (OVA)-sensitized mice. Mice orally administered PGG showed a decrease in total and OVA-specific IgE levels in serum. Oral administration of PGG strongly suppressed production of type 2 T helper (IL-4 and IL-13), type 1 T helper (IFN-gamma), and pro-inflammatory cytokines (TNF-alpha and IL-6), but not anti-inflammatory cytokine (IL-10) from splenocytes of OVA-sensitized mice against OVA re-stimulation. A population of T regulatory (Treg) cells with immunosuppressive properties was increased in mesenteric lymph nodes and spleen of PGG-fed mice. PGG administration not only reduced expression levels of eotaxin, tissue inhibitors of metalloproteinases-1, and TNF-alpha, which assisted with IgE production, but also increased the expression of insulin-like growth factor binding protein-3 which inhibits IgE production. Additionally, PGG increased the levels of Treg cell-inducing factors such as IL-2, IL-10 and platelet factor-4 in serum. These data suggest that the inhibitory effect of PGG on IgE production could be partially caused by increasing a population of Treg cells in conjunction with Treg-inducing factors. PMID- 25737196 TI - The effect of prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement on swallowing and swallow-related outcomes in patients undergoing radiotherapy for head and neck cancer: a systematic review. AB - Patients undergoing radiotherapy for head and neck cancer (HNC) often experience malnutrition and dehydration during treatment. As a result, some centres place PEG tubes prophylactically (pPEG) to prevent these negative consequences. However, recent research has suggested that pPEG use may negatively affect swallowing physiology, function and/or quality of life, especially in the long term. The purpose of this study was to systematically review the literature on pPEG use in HNC patients undergoing radiotherapy and to determine its impact on swallowing-related outcomes. The following electronic databases were searched for all relevant primary research published through February 24, 2014: AMED, CINAHL, the Cochrane Library, Embase, Healthstar, Medline, and PsycINFO. Main search terms included HNC, radiotherapy, deglutition disorders, feeding tube(s), and prophylactic or elective. References for all accepted papers were hand searched to identify additional relevant research. Methodological quality was assessed using Cochrane's Risk of Bias. At all levels, two blinded raters provided judgments. Discrepancies were resolved by consensus. The search retrieved 181 unique citations. Twenty studies met our inclusion criteria. Quality assessment revealed that all studies were at risk for bias due to non-randomized sampling and unreported or inadequate blinding. Ten studies demonstrated selection bias with significant baseline differences between pPEG patients and controls. Results regarding the frequency and severity of dysphagia and swallowing-related outcomes were varied and inconclusive. The impact of pPEG use on swallowing and swallowing related outcomes remains unclear. Well-controlled, randomized trials are needed to determine if pPEG places patients at greater risk for developing long-term dysphagia. PMID- 25737198 TI - Molecular attributes of conjugate antigen influence function of antibodies induced by anti-nicotine vaccine in mice and non-human primates. AB - Anti-nicotine vaccines aim to prevent nicotine entering the brain, and thus reduce or eliminate the reward that drives nicotine addiction. Those tested in humans to date have failed to improve quit rates over placebo, possibly because antibody (Ab) responses were insufficient to sequester enough nicotine in the blood in the majority of subjects. We have previously shown in mice that the carrier, hapten and linker used in the nicotine conjugate antigen each influence the function (nicotine-binding capacity) of the Ab induced. Herein we have evaluated immunogenicity in mice of 27 lots of NIC7-CRM, a conjugate of 5 aminoethoxy-nicotine (Hapten 7) and a mutant nontoxic form of diphtheria toxin (CRM197), that differed in three antigen attributes, namely hapten load (number of haptens conjugated to each molecule of CRM197), degree of conjugate aggregation and presence of adducts (small molecules attached to CRM197 via a covalent bond during the conjugation process). A range of functional responses (reduced nicotine in the brain of immunized animals relative to non-immunized controls) were obtained with the different conjugates, which were adjuvanted with aluminum hydroxide and CpG TLR9 agonist. Trends for better functional responses in mice were obtained with conjugates having a hapten load of 11 to 18, a low level of high molecular mass species (HMMS) (i.e., not aggregated) and a low level of adducts and a more limited testing in cynomolgus monkeys confirmed these results. Thus hapten load, conjugate aggregation and presence of adducts are key antigen attributes that can influence Ab function induced by NIC7-CRM. PMID- 25737199 TI - The impact of immunomodulator compound from the group of substituted thiadiazines on the course of stress reaction. AB - A significant role of the stress response to many different diseases prompted a search for new specialized and non-specialized anti-stress agents. This study examines the effect of the compound L17 from the group of 5-phenyl substituted-6H 1,3,4-thiadiazine-2-amines, on the manifestations of the stress response. The authors used a standard model of immobilization stress, in which an animal was immobilized on its back for 6h a day. Parameters of the morphological and functional states of the organs studied were measured and biochemical and enzyme immunoassays were carried out on the first and second days. This study reveals that the main mechanism by which the L17 compound mediates of its anti-stress was by activation of macrophages on the second day of the experiments and the inhibition of apoptosis in the thymus. The results enable us to suggest that the compound L17 does not improve resistance to stress; however, it does lower the reaction to stress. PMID- 25737200 TI - Intimate partner violence in the Caribbean: State, activist and media responses. AB - Violence in the Caribbean is a major public health and criminal justice problem. In some Caribbean countries, women's share of morbidity and mortality due to violence outstrips men's, which demonstrates a reversal in how gender and violence have been typically and globally understood. This morbidity and mortality among women is frequently a consequence of intimate partner violence (IPV). Using qualitative analysis and feminist discourse and narrative analysis on data from Guyana, St. Vincent and the Grenadines and Barbados, the authors of this paper contribute to the growing research on IPV. The central organising questions are how do state, activist and media responses reproduce and/or challenge asymmetrical relations of power and gender, and what does this mean for women's agency in the context of violent relationships. State, activist and media responses reveal how assumptions about gender and IPV contribute to a contradictory context in which women navigate their desired outcomes. PMID- 25737201 TI - Balancing hope with reality: how neonatal nurses manage the uncertainty of caring for extremely premature babies. AB - AIMS AND OBJECTIVES: This article aims to explore the ways in which neonatal nurses manage the uncertainty associated with the treatment and outcomes of extremely premature babies. BACKGROUND: Current literature suggests that survival rates of extremely premature babies have increased; however, the incidence of long-term problems has not decreased among survivors. The outcomes can often not be predicted; therefore, there is much uncertainty associated with survival and outcomes. Neonatal nurses care for babies and families during these times of uncertainty. This article will focus on how neonatal nurses manage and survive the challenges associated with uncertainty when caring for extremely premature babies. DESIGN: Qualitative. METHODS: This article used a series of interviews in a qualitative study informed by phenomenological insights. The analysis of the interview data involved the discovery of thematic statements and the analysis of the emerging themes. RESULTS: Three themes captured the experience of working with uncertainty from the perspective of the neonatal nurses: 'Everything is fine, then they crash': When the honeymoon is over; '"I don't know which one is going to be fine": it's like a lottery' and 'Balancing hope with reality'. CONCLUSION: Uncertainty had both positive and negative aspects, because while ever there was uncertainty, there was room for hope. While initial uncertainty of the baby's prognosis and outcome gave the nurses hope, certainty of diagnosis and poor outcome could take that hope away. RELEVANCE TO CLINICAL PRACTICE: Increasing survival of extremely premature babies will see neonatal nurses caring for more babies <=24 weeks gestation. Prematurity has risks associated with life sustaining treatments. Uncertainty is a reality of life for these babies, their families and the nursing and medical teams who care for them. It is important to recognise the challenges associated with uncertainty. PMID- 25737202 TI - Induction of Local Secretory IgA and Multifunctional CD4+ T-helper Cells Following Intranasal Immunization with a H5N1 Whole Inactivated Influenza Virus Vaccine in BALB/c Mice. AB - Avian influenza subunit vaccines have been shown to be poorly immunogenic, leading to the re-evaluation of the immunogenic and dose-sparing potential of whole virus vaccines. In this study, we investigated the immune responses after one or two doses of intramuscular or intranasal whole inactivated influenza H5N1 virus vaccine in BALB/c mice. Serum samples and nasal washings were collected weekly post-vaccination and analysed using enzyme-linked immunosorbent assay (ELISA). Sera were also analysed by the haemagglutination inhibition (HI) assay. Antibody-secreting cells were measured in lymphocytes from spleen and bone marrow via enzyme-linked immunospot (ELISPOT). Splenocytes were stimulated in vitro, and T-helper profiles were measured through multiplex bead assay in the supernatants, or intracellularly by multiparametric flow cytometry. Both vaccine routes induced high HI titres following the second immunization (intramuscular = 370, intranasal = 230). Moreover, the intramuscular group showed significantly higher levels of serum IgG (P < 0.01), IgG1 (P < 0.01) and IgG2a (P < 0.01) following the second vaccine dose, while the intranasal group exhibited significantly higher levels of serum IgA (P < 0.05) and local IgA (P < 0.01) in the nasal washings. Also, IgA antibody-secreting cells were found in significantly higher numbers in the intranasal group in both the spleen (P < 0.01) and the bone marrow (P < 0.01). Moreover, Th1 (TNF-alpha, IL-2, IFN-gamma) and Th2 (IL-4, IL-5, IL-10) cytokines were expressed by both groups, yet only the intranasal group expressed the Th17 marker IL-17. As the intranasal vaccines induce local IgA and are easily administered, we suggest the intranasally administered whole virus vaccine as a promising candidate for a pandemic H5N1 vaccine. PMID- 25737203 TI - Isolation and characterisation of Bacillus spp. antagonistic to Vibrio parahaemolyticus for use as probiotics in aquaculture. AB - Acute gastroenteritis caused by pathogenic Vibrio parahaemolyticus is one of the major factors affecting the development of aquaculture and the safety of seafood. Using the antagonism of probiotics against pathogens is an alternative strategy to antibiotics and a common trend to control food-borne pathogenic bacteria. In this study, a total of 249 isolates were isolated from four types of seafood (Litopenaeus vannamei, Oratosquilla oratoria, Mactra veneriformis and Portunus trituberculatus) and coastal sediment from Liaodong Bay in the Bohai Sea, China with five different separation agars. The most isolates came from the sample of coastal sediment and on agar of 2216E, which accounted for 36.14 and 54.62 % respectively. Twenty-four among 249 isolates displayed direct antimicrobial activity to V. parahaemolyticus with spot inoculation. Sixteen active isolates were selected for extracellular antimicrobial activity using the Oxford cup method. Only strains of B16 and J7 showed extracellular antimicrobial activity and were identified as Bacillus pumilus and Bacillus mojavensis respectively based on the physiological identification and 16S rRNA sequence analysis. Both of the strains B16 and J7 exhibited extracellular hydrolytic enzyme activity and antagonism against more than one indicator bacteria in vitro, which indicates that the two strains have broad potential application as suitable probiotic candidates in aquaculture while B. mojavensis was first reported to inhibit pathogenic Vibrio spp. in vitro. There is no particular trait as to antagonism of B. pumilus B16 or B. mojavensis J7 to Gram-positive or Gram-negative indicator bacteria. PMID- 25737204 TI - Repetitive transcranial magnetic stimulation plus standardized suggestion of benefit for functional movement disorders: an open label case series. AB - BACKGROUND: We studied suggestion of benefit combined with motor cortex and premotor cortex repetitive transcranial magnetic stimulation (rTMS) in chronic (>2 years) FMDs. METHODS: Patients were identified from our patient records who had clinically definite FMDs and had undergone neuropsychiatric evaluation. Those with chronic FMDs were offered open-label rTMS over the dominant motor cortex. If they failed to improve they received dominant premotor cortex rTMS. The primary outcome was change from baseline to post-rTMS in quality of life measured by the World Health Organization Quality of Life Brief (WHOQOL-BREF) scale. Secondary outcomes were subject and investigator global impression of change (GIC), blinded Rush psychogenic movements rating scale, Barbers suggestibility scale, baseline expectation of benefit scale, and adverse effects. RESULTS: Six subjects were enrolled. For the primary outcome, there was significant improvement in the physical domain scores but significant reduction in psychological domain scores after premotor cortex rTMS compared to baseline and after motor cortex rTMS. There was no significant change between baseline and motor cortex rTMS or in any other domain after premotor cortex rTMS. Secondary outcome measures showed no meaningful change. Transient headache and worsening of FMD symptoms were the most common adverse effects observed. CONCLUSION: rTMS combined with strong suggestion of benefit provided dissonant results after premotor cortex rTMS with improvement in physical quality of life but reduction in psychological quality of life. These results serve to underscore the complex nature of FMDs where the overt physical manifestation is but one part of a comprehensive neuropsychological syndrome. PMID- 25737205 TI - Measuring the burden and mortality of hospitalisation in Parkinson's disease: A cross-sectional analysis of the English Hospital Episodes Statistics database 2009-2013. AB - BACKGROUND: Patients with Parkinson's disease have higher hospital admission rates than the general population. We examined the reasons for admission, length of stay, costs, and in-hospital mortality in a national sample of Parkinson's disease patients. METHODS: We used hospital admission data from the English Hospital Episodes Statistics database (2009-2013). Patients with Parkinson's disease or Parkinson's disease dementia and aged over 35 years were compared to all other admissions, excluding the above, with the same age criteria. We examined reasons for admissions (ICD-10), length of stay and in-hospital mortality. We used indirect standardisation and Poisson modelling to derive proportional ratios adjusting for age group and sex. RESULTS: There were 324,055 Parkinson's disease admissions in 182,859 patients over 4 years which included 232,905 non-elective admissions (72%). This resulted in expenditure of L907 million (L777 million for non-elective admissions). The main reasons for admission were pneumonia (13.5%), motor decline (9.4%), urinary tract infection (9.2%), and hip fractures (4.3%). These conditions occurred 1.5 to 2.6 times more frequently in patients than controls. Patients with Parkinson's disease were almost twice as likely to stay in hospital for more than 3 months (ratio 1.90, 95% CI 1.83, 1.97) and even more likely die in hospital (ratio 2.46, 95% CI 2.42, 2.49). CONCLUSIONS: Parkinson's disease patients in England have higher rates of emergency admissions with longer hospital stays, higher costs and in-hospital mortality. Urgent attention should be given to developing cost-effective interventions to reduce the burden of hospitalisation for patients, carers and healthcare systems. PMID- 25737206 TI - In memoriam: Paul J. Bedard, MD PhD (1942-2014). PMID- 25737207 TI - The timecourse of apoptotic cell death during postnatal remodeling of the mouse cochlea and its premature onset by triiodothyronine (T3). AB - Apoptosis underlies various forms of tissue remodeling during development. Prior to the onset of hearing, thyroid hormone (T3) promotes cochlear remodeling, which involves regression of the greater epithelial ridge (GER), a transient structure of columnar cells adjacent to the mechanosensory hair cells. We investigated the timecourse of apoptosis in the GER and the influence of ectopic T3 on apoptosis. In saline-treated mice, activated caspase 3-positive cells were detected in the GER between postnatal days 7 and 13 and appeared progressively along the cochlear duct from base to apex over developmental time. T3 given on P0 and P1 advanced the overall program of apoptosis and remodeling by ~4 days. Thyroid hormone receptor beta was required for these actions, suggesting a receptor-mediated process of initiation of apoptosis. Finally, T3 given only at P0 or P1 resulted in deafness in adult mice, thus revealing a transient period of susceptibility to long-term damage in the neonatal auditory system. PMID- 25737208 TI - NGF promotes mouse granulosa cell proliferation by inhibiting ESR2 mediated down regulation of CDKN1A. AB - Nerve growth factor (NGF) is known to play key roles in ovarian follicular development, such as the assembly of early follicles and follicular ovulation through its high-affinity receptor, tyrosine kinase receptor A (trkA). Herein, the molecular mechanism controlling NGF-induced granulosa cell (GC) proliferation was not clear. In this study, we found that NGF is abundant in preantral GCs and knockdown of trkA in GCs attenuated NGF-induced GC proliferation and further decreased the levels of phosphorylated extracellular regulated protein kinases 1/2 (ERK1/2). Cyclin-dependent kinase inhibitor 1A (CDKN1A), also named p21, a factor which could be either a negative or a positive regulator via transformation related protein 53 (TRP53, also named p53)-dependent or independent pathways in cell proliferation, was up-regulated during the process of NGF-induced GC proliferation. Blockade of trkA (K252alpha) and ERK1/2 (U0126) in GCs decreased NGF-induced expression of CDKN1A and did not alter the expression of TRP53, indicating that NGF stimulates CDKN1A expression via the trkA-ERK1/2 pathway in a TRP53-independent manner. Meanwhile, ESR2, a tumor suppressor which is exclusively expressed in GCs, was suppressed in NGF-induced GC proliferation, and this effect was abrogated by U0126. Blockade of ESR2 (ICI182,780) caused the promotion of GC proliferation and CDKN1A expression, indicating that ESR2 may be downstream of the ERK1/2 pathway in mediating the effect of CDKN1A on NGF-induced GC proliferation. Therefore, ESR2 may be involved in the integration of intracellular signal cascades and cell cycle proteins in affecting GC proliferation. Here, we provide mechanistic insights into the roles of CDKN1A in NGF-induced GC proliferation. Understanding potential cross-points between CDKN1A and ESR2 affecting GC proliferation will help in the discovery of new therapeutic targets in some female infertility disorders. PMID- 25737209 TI - Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis. AB - Iron is an essential component of erythropoiesis and its metabolism is tightly regulated by a variety of internal and external cues including iron storage, tissue hypoxia, inflammation and degree of erythropoiesis. There has been remarkable improvement in our understanding of the molecular mechanisms of iron metabolism past decades. The classical model of iron metabolism with iron response element/iron response protein (IRE/IRP) is now extended to include hepcidin model. Endogenous and exogenous signals funnel down to hepcidin via wide range of signaling pathways including Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3), Bone Morphogenetic Protein/Hemojuvelin/Mothers Against Decapentaplegic Homolog (BMP/HJV/SMAD), and Von Hippel Lindau/Hypoxia-inducible factor/Erythropoietin (VHL/HIF/EPO), then relay to ferroportin, which directly regulates intra- and extracellular iron levels. The successful molecular delineation of iron metabolism further enhanced our understanding of common genetic and acquired disorder, hemochromatosis. The majority of the hereditary hemochromatosis (HH) patients are now shown to have mutations in the genes coding either upstream or downstream proteins of hepcidin, resulting in iron overload. The update on hepcidin centered mechanisms of iron metabolism and their clinical perspective in hemochromatosis will be discussed in this review. PMID- 25737210 TI - Cost-effectiveness of Out-of-Hospital Continuous Positive Airway Pressure for Acute Respiratory Failure. AB - STUDY OBJECTIVE: We determine the cost-effectiveness of out-of-hospital continuous positive airway pressure (CPAP) compared with standard care for adults presenting to emergency medical services with acute respiratory failure. METHODS: We developed an economic model using a United Kingdom health care system perspective to compare the costs and health outcomes of out-of-hospital CPAP to standard care (inhospital noninvasive ventilation) when applied to a hypothetical cohort of patients with acute respiratory failure. The model assigned each patient a probability of intubation or death, depending on the patient's characteristics and whether he or she had out-of-hospital CPAP or standard care. The patients who survived accrued lifetime quality-adjusted life-years (QALYs) and health care costs according to their age and sex. Costs were accrued through intervention and hospital treatment costs, which depended on patient outcomes. All results were converted into US dollars, using the Organisation for Economic Co-operation and Development purchasing power parities rates. RESULTS: Out-of hospital CPAP was more effective than standard care but was also more expensive, with an incremental cost-effectiveness ratio of L20,514 per QALY ($29,720/QALY) and a 49.5% probability of being cost-effective at the L20,000 per QALY ($29,000/QALY) threshold. The probability of out-of-hospital CPAP's being cost effective at the L20,000 per QALY ($29,000/QALY) threshold depended on the incidence of eligible patients and varied from 35.4% when a low estimate of incidence was used to 93.8% with a high estimate. Variation in the incidence of eligible patients also had a marked influence on the expected value of sample information for a future randomized trial. CONCLUSION: The cost-effectiveness of out-of-hospital CPAP is uncertain. The incidence of patients eligible for out-of hospital CPAP appears to be the key determinant of cost-effectiveness. PMID- 25737211 TI - Confusion About Infusion: Rational Volume Limits for Intravenous Lipid Emulsion During Treatment of Oral Overdoses. PMID- 25737212 TI - Animal and management factors influencing grower and finisher pig performance and efficiency in European systems: a meta-analysis. AB - A meta-analysis on the effects of management and animal-based factors on the performance and feed efficiency of growing pigs can provide information on single factor and interaction effects absent in individual studies. This study analysed the effects of such factors on average daily gain (ADG), feed intake (FI) and feed conversion ratio (FCR) of grower and finisher pigs. The multivariate models identified significant effects of: (1) bedding (P<0.01), stage of growth (P<0.001) and the interaction bedding*lysine (P<0.001) on ADG. ADG was higher on straw compared with no bedding (710 v. 605 g/day). (2) FI was significantly affected by stage of growth (P<0.01), bedding (P<0.01), group composition (P<0.05), group size (P<0.01), feed CP content (P<0.01), ambient temperature (P<0.01) and the interaction between floor space and feed energy content (P<0.001). Pigs housed on straw had a lower FI in comparison with those without (1.44 v. 2.04 kg/day); a higher FI was seen for pigs separated by gender in comparison with mixed groups (2.05 v. 1.65 kg/day); FI had a negative linear relationship with group size, the CP content of the feed and ambient temperature. (3) Stage of growth (P<0.001), feed CP (P<0.001) and lysine content (P<0.001), ambient temperature (P<0.001) and feed crude fibre (CF) content (P<0.01) significantly affected FCR; there were no significant interactions between any factors on this trait. There was an improvement in FCR at higher ambient temperatures, increased feed CP and lysine content, but a deterioration of FCR at higher CF contents. For ADG, the interaction of bedding*lysine was caused by pigs housed without bedding (straw) having higher ADG when on a feed lower in lysine, whereas those with bedding had a higher ADG when on a feed higher in lysine. Interaction effects on FI were caused by animals with the least amount of floor space having a higher FI when given a feed with a low metabolisable energy (ME) content, in contrast to all other pigs, which showed a higher FI with increased ME content. The meta-analysis confirmed the significant effect of several well known factors on the performance and efficiency of grower and finisher pigs, the effects of some less established ones and, importantly, the interactions between such factors. PMID- 25737213 TI - Correction. PMID- 25737215 TI - Correction. PMID- 25737214 TI - Correction. PMID- 25737216 TI - Correction. PMID- 25737217 TI - Embolisation of pheochromocytoma to stabilise and wean a patient in cardiogenic shock from emergency extracorporeal life support. AB - Pheochromocytoma is a catecholamine-secreting tumour associated with varying symptoms ranging from episodic headache, sweating, paroxysmal hypertension and tachycardia to intractable cardiogenic shock. Cardiogenic shock is rare but well described and the timing of correct management is crucial since mortality is high. Fifty per cent of pheochromocytomas are diagnosed on autopsy. We report on a case of embolisation of the adrenal artery during ongoing extracorporeal life support (ECLS) in order to stabilise and wean the patient from ECLS as a bridge to final surgery. PMID- 25737218 TI - Correction. PMID- 25737219 TI - The unmasking of a pyopericardium. AB - Pyopericardium is a rare condition with a high mortality rate in which infection propagates in the pericardial space, leading to a pus filled pericardial effusion and cardiac tamponade, which can cause cardiogenic shock and death. We present a case of a previously healthy woman of 52, who was admitted with a severe lower respiratory tract infection that eventually led to a pyopericardium. The diagnosis of pyopericardium was delayed due to masking of symptoms by her underlying infection, sepsis and an upper gastrointestinal bleed that the patient suffered during the admission, requiring an emergency gastroscopy. The pyopericardium was considered when ST elevation was seen on an ECG and an ECHO discovered a large pericardial effusion causing tamponade. An emergency pericardiocentesis drained frank pus. Treatment with intravenous antibiotics, frequent pericardial drainage and a pericardectomy led to an excellent outcome, and a full recovery. PMID- 25737220 TI - Surgical management of subcutaneous Colletotrichum gloeosporioides. AB - A 52-year-old male patient with a history of sarcoidosis and over 10 years of chronic low-dose glucocorticoid use, cirrhosis and type 2 diabetes mellitus presented with two painful, enlarging subcutaneous nodules ultimately identified as Colletotrichum gloeosporioides. Two attempts at needle aspiration of the larger nodule resulted in rapid reaccumulation. Complete surgical excision of both nodules resulted in complete resolution without the use of any concomitant antifungals. Patient had no recurrence at 2 years of follow-up. PMID- 25737221 TI - Endoscopic mucosal resection of early stage colon neuroendocrine carcinoma. AB - Early stage colorectal neuroendocrine carcinoma is rare. A small colon tumour was found in a 56-year-old man during diagnostic colonoscopy performed after a positive faecal occult blood test, and he was referred for treatment. A slightly reddish superficial elevated lesion with a shallow depression 10 mm in size was found in the transverse colon. Magnifying narrow-band imaging revealed disrupted irregular microvessels and the absence of a surface pattern in the depressed area. En bloc endoscopic mucosal resection (EMR) of the tumour was undertaken. The tumour was positive for chromogranin A and synaptophysin, and had a mitotic rate of >20/10 high-power fields and a Ki-67 proliferative index of >50%; it was diagnosed as a neuroendocrine carcinoma. The tumour minimally invaded the submucosa (300 MUm) without lymphovascular involvement. The patient was followed up carefully, and at 1 year after EMR, no recurrence was found using colonoscopy and CT scans. PMID- 25737222 TI - Undescended parathyroid adenoma. AB - Undescended parathyroid adenomas are rare, representing 0.08% of all parathyroid adenomas; however, they make up 7% of the underlying cause of failed cervical exploration in patients with persistent primary hyperparathyroidism. A 43-year old woman with no significant medical or family history presented with fatigue and was diagnosed with primary hyperparathyroidism; however, preoperative imaging including sestamibi scan and ultrasound was unable to identify the hyperfunctioning gland. She underwent a neck exploration and hemithyroidectomy and partial parathyroidectomy with failure of resolution of her disease. Subsequent work up including a CT of the neck demonstrated a 1.9 cm mass adjacent to the left submandibular gland. This was removed with postoperative normalisation of the patient's serum calcium and parathyroid hormone levels. PMID- 25737224 TI - Correction. PMID- 25737223 TI - Retinal astrocytic hamartoma in a patient with Leber's congenital amaurosis. PMID- 25737225 TI - An uncommon cause for compressive myelopathy. PMID- 25737226 TI - Covalent and stable CuAAC modification of silicon surfaces for control of cell adhesion. AB - Stable primary functionalization of metal surfaces plays a significant role in reliable secondary attachment of complex functional molecules used for the interfacing of metal objects and nanomaterials with biological systems. In principle, this can be achieved through chemical reactions either in the vapor or liquid phase. In this work, we compared these two methods for oxidized silicon surfaces and thoroughly characterized the functionalization steps by tagging and fluorescence imaging. We demonstrate that the vapor-phase functionalization only provided transient surface modification that was lost on extensive washing. For stable surface modification, a liquid-phase method was developed. In this method, silicon wafers were decorated with azides, either by silanization with (3 azidopropyl)triethoxysilane or by conversion of the amine groups of an aminopropylated surface by means of the azido-transfer reaction. Subsequently, D amino acid adhesion peptides could be immobilized on the surface by use of Cu(I) catalyzed click chemistry. This enabled the study of cell adhesion to the metal surface. In contrast to unmodified surfaces, the peptide-modified surfaces were able to maintain cell adhesion during significant flow velocities in a microflow reactor. PMID- 25737227 TI - The dynamics of cereal cyst nematode infection differ between susceptible and resistant barley cultivars and lead to changes in (1,3;1,4)-beta-glucan levels and HvCslF gene transcript abundance. AB - Heterodera avenae (cereal cyst nematode, CCN) infects the roots of barley (Hordeum vulgare) forming syncytial feeding sites. In resistant host plants, relatively few females develop to maturity. Little is known about the physiological and biochemical changes induced during CCN infection. Responses to CCN infection were investigated in resistant (Rha2) and susceptible barley cultivars through histological, compositional and transcriptional analysis. Two phases were identified that influence CCN viability, including feeding site establishment and subsequent cyst maturation. Syncytial development progressed faster in the resistant cultivar Chebec than in the susceptible cultivar Skiff, and was accompanied by changes in cell wall polysaccharide abundance, particularly (1,3;1,4)-beta-glucan. Transcriptional profiling identified several glycosyl transferase genes, including CELLULOSE SYNTHASE-LIKE F10 (HvCslF10), which may contribute to differences in polysaccharide abundance between resistant and susceptible cultivars. In barley, Rha2-mediated CCN resistance drives rapid deterioration of CCN feeding sites, specific changes in cell wall-related transcript abundance and changes in cell wall composition. During H. avenae infection, (1,3;1,4)-beta-glucan may influence CCN feeding site development by limiting solute flow, similar to (1,3)-beta-glucan during dicot cyst nematode infections. Dynamic transcriptional changes in uncharacterized HvCslF genes, possibly involved in (1,3;1,4)-beta-glucan synthesis, suggest a role for these genes in the CCN infection process. PMID- 25737228 TI - Astrocyte and microglial control of glutamatergic signalling: a primer on understanding the disruptive role of chronic stress. AB - It is now well established that chronic stress can induce significant structural remodelling of astrocytes and microglia. Until recently, however, the full significance of these morphological disturbances has remained unclear. Clues to the significance of astroglial re-organisation following stress are beginning to emerge from a compelling literature describing how astrocytes contribute to glutamatergic neurotransmission. The present review briefly summarises these two fields of research, identifies points of overlap and, in doing so, pin-points future research directions for stress neurobiology. Ultimately, understanding how chronic stress can disrupt the interactions of astrocytes and microglia with neurones has the potential in the future to improve the development of therapeutics designed to treat stress-related illnesses such as depression. PMID- 25737229 TI - Acoustic emission detection for mass fractions of materials based on wavelet packet technology. AB - Materials are often damaged during the process of detecting mass fractions by traditional methods. Acoustic emission (AE) technology combined with wavelet packet analysis is used to evaluate the mass fractions of microcrystalline graphite/polyvinyl alcohol (PVA) composites in this study. Attenuation characteristics of AE signals across the composites with different mass fractions are investigated. The AE signals are decomposed by wavelet packet technology to obtain the relationships between the energy and amplitude attenuation coefficients of feature wavelet packets and mass fractions as well. Furthermore, the relationship is validated by a sample. The larger proportion of microcrystalline graphite will correspond to the higher attenuation of energy and amplitude. The attenuation characteristics of feature wavelet packets with the frequency range from 125 kHz to 171.85 kHz are more suitable for the detection of mass fractions than those of the original AE signals. The error of the mass fraction of microcrystalline graphite calculated by the feature wavelet packet (1.8%) is lower than that of the original signal (3.9%). Therefore, AE detection base on wavelet packet analysis is an ideal NDT method for evaluate mass fractions of composite materials. PMID- 25737230 TI - Gallic acid-based alkyl esters synthesis in a water-free system by celite-bound lipase of Bacillus licheniformis SCD11501. AB - Gallic acid (3, 4, 5- trihydroxybenzoic acid) is an important antioxidant, anti inflammatory, and radical scavenging agent. In the present study, a purified thermo-tolerant extra-cellular lipase of Bacillus licheniformis SCD11501 was successfully immobilized by adsorption on Celite 545 gel matrix followed by treatment with a cross-linking agent, glutaraldehyde. The celite-bound lipase treated with glutaraldehyde showed 94.8% binding/retention of enzyme activity (36 U/g; specific activity 16.8 U/g matrix; relative increase in enzyme activity 64.7%) while untreated matrix resulted in 88.1% binding/retention (28.0 U/g matrix; specific activity 8.5 U/g matrix) of lipase. The celite-bound lipase was successfully used to synthesis methyl gallate (58.2%), ethyl gallate (66.9%), n propyl gallate (72.1%), and n-butyl gallate (63.8%) at 55(o) C in 10 h under shaking (150 g) in a water-free system by sequentially optimizing various reaction parameters. The low conversion of more polar alcohols such as methanol and ethanol into their respective gallate esters might be due to the ability of these alcohols to severely remove water from the protein hydration shell, leading to enzyme inactivation. Molecular sieves added to the reaction mixture resulted in enhanced yield of the alkyl ester(s). The characterization of synthesised esters was done through fourier transform infrared (FTIR) spectroscopy and (1) H NMR spectrum analysis. PMID- 25737231 TI - Biological electric fields and rate equations for biophotons. AB - Biophoton intensities depend upon the squared modulus of the electric field. Hence, we first make some general estimates about the inherent electric fields within various biosystems. Generally, these intensities do not follow a simple exponential decay law. After a brief discussion on the inapplicability of a linear rate equation that leads to strict exponential decay, we study other, nonlinear rate equations that have been successfully used for biosystems along with their physical origins when available. PMID- 25737232 TI - Binding of hemin, hematoporphyrin, and protoporphyrin with erythroid spectrin: fluorescence and molecular docking studies. AB - Free heme has toxic effects, for example lipid peroxidation, DNA damage, and protein aggregation. In severe hemolysis, which occurs during pathological states, for example sickle cell disease, ischemia reperfusion, and malaria, levels of free heme increase inside erythrocytes. The purpose of this study was to investigate whether spectrin, the major erythroid cytoskeleton protein, is involved as an acceptor of free heme. We compared the interactions of three heme derivatives, hemin chloride, hematoporphyrin, and protoporphyrin-IX, with dimeric and tetrameric spectrin. The dissociation constants (K d) for binding to spectrin dimer and tetramer were 0.57 and 1.16 uM respectively. Thermodynamic data associated with this binding revealed the binding to be favored by a positive change in entropy. Although molecular docking studies identified the SH3 domain as the unique binding site of these heme derivatives to erythroid spectrin, experimental results indicated a binding stoichiometry of 1 heme attached to both dimeric and tetrameric spectrin, indicating the common self-associating domain to be the unique binding site. We also noticed heme-induced structural changes in the membrane skeletal protein. Erythroid spectrin could thus act as a potential acceptor of heme, particularly relevant under disease conditions. PMID- 25737233 TI - Relationship between dementia severity and behavioural and psychological symptoms in early-onset Alzheimer's disease. AB - BACKGROUND: The features of behavioural and psychological symptoms of dementia (BPSD) are influenced by dementia stage. In early-onset Alzheimer's disease (EOAD), the association between BPSD and dementia stage remains unclear because of the difficulty of recruiting subjects with a wide range of disease severity. We used a combination of community-based and hospital-based approaches to investigate the relationship between dementia severity and BPSD in EOAD patients. METHODS: Sixty-three consecutive EOAD outpatients and 29 EOAD patients from a community-based survey were divided into three dementia severity groups according to the Clinical Dementia Rating scale (CDR): mild (CDR 0.5-1, n = 55), moderate (CDR 2, n = 17), and severe (CDR 3, n = 20). BPSD were rated using the Neuropsychiatric Inventory. RESULTS: Scores of the Neuropsychiatric Inventory subscales agitation, euphoria, apathy, disinhibition, irritability, and aberrant motor behaviour increased significantly with increased dementia severity. Hallucinations were greater in the moderate group than in the mild group. For delusions, depression, and anxiety, no significant differences were observed among the three severity groups. CONCLUSIONS: The pattern of apathy, agitation, disinhibition, irritability, and aberrant motor behaviour worsening with severity progression in EOAD is similar to the pattern in late-onset Alzheimer's disease. In contrast, hallucinations, depression, and anxiety showed different patterns in EOAD. PMID- 25737234 TI - Fentanyl, an agonist at the mu opioid receptor, depresses pupillary unrest. AB - Pupillary unrest is a chaotic fluctuation in pupil size that is observed in darkness with the onset of drowsiness, and in ambient light. The mechanism of pupillary unrest in darkness as well as in ambient light is unknown but studies suggest that it is caused by fluctuating activity in the Edinger-Westphal (E.W.) nucleus. Neurons in the periaqueductal gray with oscillating firing patterns that are inhibitory to the E.W. nucleus have been described in the cat. We theorized that such oscillating neurons produce pupillary unrest in light and would be depressed by agents, such as opioids, known to depress inhibitory pathways in the midbrain. An infrared pupillometer was used to measure the effect of light on pupillary unrest in eight volunteer subjects, and on 20 patients scheduled for knee arthroscopy who received fentanyl as premedication. Pupillary unrest was quantified through spectral analysis of fast Fourier transforms. Sixteen-second measurements of pupil size at 33 Hz were filtered to eliminate blink artifacts and baseline drift. Pupillary unrest was augmented by excitation of the E.W. nucleus by light and was depressed by 40 +/- 20% after the administration of the moderate dose of 1 mcg/kg of fentanyl. Recovery from the drug effect was observed. Based upon the data from this study we propose that pupillary unrest in light originates within oscillating inhibitory neurons that intermittently depress the E. W. nucleus. PMID- 25737235 TI - Training conditions that best reproduce the joint powers of unsupported walking. AB - OBJECTIVE: To identify the clinically relevant combinations of body weight support and speed that best reproduce the joint powers of unsupported walking. METHODS: Timing and magnitude of lower extremity joint powers were calculated for 8 neurologically intact volunteers (4M/4F) walking with 0%, 30% and 50% body weight support at three speeds (slow, comfortable, and fast). Lower extremity joint power absorption was analyzed during weight acceptance and forward propulsion. In addition, power generation was analyzed during forward propulsion. Timings and magnitudes of joint powers per condition were evaluated to identify the training combinations of body weight support and speed that best preserved the powers of unsupported walking at slow, comfortable and fast speeds. RESULTS: For all speeds examined, increasing body weight support to 30% without changing speed provided the best match. In general, changes in speed disrupted the joint power magnitudes and timings more than application of body weight support. Increasing body weight support when faster training speeds were used proved a viable method for reproducing the joint powers of slow, unsupported walking. CONCLUSIONS: These data provide a reference for understanding the effect of potential training conditions on power absorption and generation within the lower extremity joints during walking. It is possible to reproduce the joint powers of unsupported walking with certain combinations of body weight support and speed. We recommend applying adequate levels of BWS when training speeds are faster than the overground speed goal, as occurs during treadmill-based locomotor rehabilitation of individuals with incomplete spinal cord injury. PMID- 25737236 TI - Interpretation of postural control may change due to data processing techniques. AB - Postural control is commonly assessed by quantifying center of pressure (CoP) variability during quiet stance. CoP data is traditionally filtered prior to analysis. However, some researchers suggest filtering may lead to undesirable consequences. Further, sampling frequency may also affect CoP analysis, as filtering CoP signals of different sampling frequencies may influence variability metrics. This study examined the influence of sampling frequency and filtering on metrics that index the magnitude and structure of variability in CoP displacement and velocity. Healthy adults (N=8, 27.4+/-2.6 years) balanced on their right foot for 60s on a force plate. CoP data recorded at 100Hz was then downsampled and/or filtered (2nd order dual-pass 10Hz low-pass Butterworth) to create six different CoP time series for each participant: (1) original, (2) filtered, (3) downsampled to 50Hz, (4) downsampled to 25Hz, (5) downsampled to 50Hz and filtered, and (6) down-sampled to 25Hz and filtered. Data were then analyzed using four common variability metrics (standard deviation [SD], root mean square [RMS], detrended fluctuation analysis alpha [DFA alpha], and sample entropy [SampEn]). Data processing techniques did not influence the magnitude of variability (SD and RMS), but did influence the structure of variability (DFA alpha and SampEn) in CoP displacement. All metrics were influenced by data processing techniques in CoP velocity. Thus, when interpreting changes in CoP variability, one must be careful to identify how much change is driven by the neuromotor system and how much is a function of data processing technique. PMID- 25737237 TI - Force plate targeting has no effect on spatiotemporal gait measures and their variability in young and healthy population. AB - Force plate targeting has been referenced as a confounding factor in gait research, but the literature is sparse. Asking participants to target force plates is a convenient strategy to increase the number of acceptable trials, but may inadvertently alter the motor control of gait and limit external validity. This study aimed to investigate the effect of visual targeting on spatiotemporal, kinematic, and kinetic measures of gait and their variability. Young healthy participants were asked to traverse a walkway with three embedded hidden force plates. Starting from a participant-specific initial position and leading with the same foot each time, participants performed series of natural walking trials (no targeting and unaware of the hidden force plates), followed by targeting walking trials. For the targeting trials, participants were asked to step completely within the bounds of a tape outline (~50cm*45cm), which coincided with the position of the last hidden force plate. The results demonstrated evidence of targeting during targeting trials; compared to natural walking trials, mean heel target distance variability for targeting trials decreased progressively for the steps approaching the targeting step, reaching significance (p<0.05) for the target (41%), and post-target steps (39%). Despite visual targeting, no significant differences between targeting and natural trials were detected in spatiotemporal, kinematic, and kinetic gait measures, or the variability of the measures. When the experimental set-up was tailored to the individual participant's gait variables (step/stride length), visual targeting of the force plates appeared to have no effect on the magnitude or variability of any gait measures. PMID- 25737238 TI - Analysis of intestinal microbiota in hybrid house mice reveals evolutionary divergence in a vertebrate hologenome. AB - Recent evidence suggests that natural selection operating on hosts to maintain their microbiome contributes to the emergence of new species, that is, the 'hologenomic basis of speciation'. Here we analyse the gut microbiota of two house mice subspecies, Mus musculus musculus and M. m. domesticus, across their Central European hybrid zone, in addition to hybrids generated in the lab. Hybrid mice display widespread transgressive phenotypes (that is, exceed or fall short of parental values) in a variety of measures of bacterial community structure, which reveals the importance of stabilizing selection operating on the intestinal microbiome within species. Further genetic and immunological analyses reveal genetic incompatibilities, aberrant immune gene expression and increased intestinal pathology associated with altered community structure among hybrids. These results provide unique insight into the consequences of evolutionary divergence in a vertebrate 'hologenome', which may be an unrecognized contributing factor to reproductive isolation in this taxonomic group. PMID- 25737240 TI - Analysis of risk factors for acute kidney injury after ascending aortic replacement combined with open placement of triple-branched stent graft in type A aortic dissection: a new technique versus the traditional method in a single Chinese center. AB - BACKGROUND: We aimed to analyze the risk factors and prognosis of acute kidney injury (AKI) after aortic arch repair in type A aortic dissection. MATERIAL AND METHODS: We included 155 patients undergoing arch repair surgery for type A aortic dissection from January 2009 to January 2014 in our hospital. Ninety-three patients underwent ascending aortic replacement combined with open placement of triple-branched stent graft and 62 underwent arch replacement with 4-branched Dacron graft combined with stented elephant trunk implantation into the descending aorta. Univariate analysis and multiple logistic regression were performed to evaluate possible parameters associated with AKI according to the AKI Network (AKIN). RESULTS: Postoperative AKI occurred in 56 patients, with a morbidity of 36.13%. Advanced age (OR=2.32 per decade, 95% CI; range, 1.47-3.67); aortic arch replacement with 4-branched Dacron graft combined with stented elephant trunk implantation (OR=3.29, 95% CI; range, 1.12-9.67); cardiopulmonary bypass time >180 min (OR=3.91, 95% CI; range, 1.35-11.35) and packed red blood cells >10 U (OR=4.88, 95% CI; range, 2.03-11.76) were independent risk factors. CONCLUSIONS: AKI is a complication after arch repair in type A aortic dissection. Advanced age; aortic arch replacement with 4-branched Dacron graft combined with stented elephant trunk implantation; cardiopulmonary bypass time >180 min; and packed red blood cells >10 U were independent risk factors for AKI. Ascending aortic replacement combined with open triple-branched stent graft placement could reduce the occurrence of AKI and protect renal function. PMID- 25737239 TI - HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation. AB - Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL. PMID- 25737243 TI - Real-time pure shift 15N HSQC of proteins: a real improvement in resolution and sensitivity. AB - Spectral resolution in proton NMR spectroscopy is reduced by the splitting of resonances into multiplets due to the effect of homonuclear scalar couplings. Although these effects are often hidden in protein NMR spectroscopy by low digital resolution and routine apodization, behind the scenes homonuclear scalar couplings increase spectral overcrowding. The possibilities for biomolecular NMR offered by new pure shift NMR methods are illustrated here. Both resolution and sensitivity are improved, without any increase in experiment time. In these experiments, free induction decays are collected in short bursts of data acquisition, with durations short on the timescale of J-evolution, interspersed with suitable refocusing elements. The net effect is real-time (t 2) broadband homodecoupling, suppressing the multiplet structure caused by proton-proton interactions. The key feature of the refocusing elements is that they discriminate between the resonances of active (observed) and passive (coupling partner) spins. This can be achieved either by using band-selective refocusing or by the BIRD element, in both cases accompanied by a nonselective 180 degrees proton pulse. The latter method selects the active spins based on their one-bond heteronuclear J-coupling to (15)N, while the former selects a region of the (1)H spectrum. Several novel pure shift experiments are presented, and the improvements in resolution and sensitivity they provide are evaluated for representative samples: the N-terminal domain of PGK; ubiquitin; and two mutants of the small antifungal protein PAF. These new experiments, delivering improved sensitivity and resolution, have the potential to replace the current standard HSQC experiments. PMID- 25737244 TI - NMR data-driven structure determination using NMR-I-TASSER in the CASD-NMR experiment. AB - NMR-I-TASSER, an adaption of the I-TASSER algorithm combining NMR data for protein structure determination, recently joined the second round of the CASD-NMR experiment. Unlike many molecular dynamics-based methods, NMR-I-TASSER takes a molecular replacement-like approach to the problem by first threading the target through the PDB to identify structural templates which are then used for iterative NOE assignments and fragment structure assembly refinements. The employment of multiple templates allows NMR-I-TASSER to sample different topologies while convergence to a single structure is not required. Retroactive and blind tests of the CASD-NMR targets from Rounds 1 and 2 demonstrate that even without using NOE peak lists I-TASSER can generate correct structure topology with 15 of 20 targets having a TM-score above 0.5. With the addition of NOE-based distance restraints, NMR-I-TASSER significantly improved the I-TASSER models with all models having the TM-score above 0.5. The average RMSD was reduced from 5.29 to 2.14 A in Round 1 and 3.18 to 1.71 A in Round 2. There is no obvious difference in the modeling results with using raw and refined peak lists, indicating robustness of the pipeline to the NOE assignment errors. Overall, despite the low-resolution modeling the current NMR-I-TASSER pipeline provides a coarse-grained structure folding approach complementary to traditional molecular dynamics simulations, which can produce fast near-native frameworks for atomic level structural refinement. PMID- 25737245 TI - Synchrotron X-ray imaging of pulmonary alveoli in respiration in live intact mice. AB - Despite nearly a half century of studies, it has not been fully understood how pulmonary alveoli, the elementary gas exchange units in mammalian lungs, inflate and deflate during respiration. Understanding alveolar dynamics is crucial for treating patients with pulmonary diseases. In-vivo, real-time visualization of the alveoli during respiration has been hampered by active lung movement. Previous studies have been therefore limited to alveoli at lung apices or subpleural alveoli under open thorax conditions. Here we report direct and real time visualization of alveoli of live intact mice during respiration using tracking X-ray microscopy. Our studies, for the first time, determine the alveolar size of normal mice in respiration without positive end expiratory pressure as 58 +/- 14 (mean +/- s.d.) MUm on average, accurately measured in the lung bases as well as the apices. Individual alveoli of normal lungs clearly show heterogeneous inflation from zero to ~25% (6.7 +/- 4.7% (mean +/- s.d.)) in size. The degree of inflation is higher in the lung bases (8.7 +/- 4.3% (mean +/- s.d.)) than in the apices (5.7 +/- 3.2% (mean +/- s.d.)). The fraction of the total tidal volume allocated for alveolar inflation is 34 +/- 3.8% (mean +/- s.e.m). This study contributes to the better understanding of alveolar dynamics and helps to develop potential treatment options for pulmonary diseases. PMID- 25737246 TI - Sarcoidosis: a Critical Review of History and Milestones. AB - Sarcoidosis is a chronic systemic disease of unknown origin and uncertain prognosis that most commonly affects young adults, and frequently presents with bilateral hilar lymphadenopathy, pulmonary infiltrates and ocular and skin lesions. The diagnosis is established when characteristic clinical-radiological features are supported by compatible histopathology of epithelioid cell granulomas, following exclusion of known causes of granulomatous inflammation. Indeed, sarcoidosis belongs to a large family of disorders that share granuloma formation as common denominator. Since its first description by Jonathan Hutchinson in 1869, sarcoidosis has generated enormous interest and considerable controversy. In Hutchinson's day, it was considered a dermatological condition, which gradually evolved into a multisystem disorder associated in the majority of cases with respiratory abnormalities. With time, it has also become clear that sarcoidosis occurs throughout the world, affecting individuals of both genders and all races, although its prevalence varies widely across ethnic and racial groups. In recent years, advances in different disciplines, particularly biochemistry, genetics, immunology and molecular biology, have improved dramatically our understanding of the disease. Yet, the critical questions regarding who gets sarcoidosis and whether it has an infectious origin remain unanswered. Sarcoidosis has a distinguished medical history that covers the last 150 years. Right from the time of seminal contributions by Hutchinson, Besnier and Boeck medical discussion on sarcoidosis has always been animated and to a certain extent emotional. Such discussions will inevitable continue until the true cause of the disease has been found, hopefully in the near future. PMID- 25737248 TI - Semiparametric regression models for a right-skewed outcome subject to pooling. AB - Pooling specimens prior to performing laboratory assays has various benefits. Pooling can help to reduce cost, preserve irreplaceable specimens, meet minimal volume requirements for certain lab tests, and even reduce information loss when a limit of detection is present. Regardless of the motivation for pooling, appropriate analytical techniques must be applied in order to obtain valid inference from composite specimens. When biomarkers are treated as the outcome in a regression model, techniques applicable to individually measured specimens may not be valid when measurements are taken from pooled specimens, particularly when the biomarker is positive and right skewed. In this paper, we propose a novel semiparametric estimation method based on an adaptation of the quasi-likelihood approach that can be applied to a right-skewed outcome subject to pooling. We use simulation studies to compare this method with an existing estimation technique that provides valid estimates only when pools are formed from specimens with identical predictor values. Simulation results and analysis of a motivating example demonstrate that, when appropriate estimation techniques are applied to strategically formed pools, valid and efficient estimation of the regression coefficients can be achieved. PMID- 25737247 TI - Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. AB - A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naive patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33-68%) and the 5-year OS was 85% (95% CI 73-97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL. PMID- 25737249 TI - Introduction to the anatomy of the head of a neonate gray whale (Mysticeti, Eschrichtius robustus). AB - The gray whale (Eschrichtius robustus) is the sole living representative of the mysticete (baleen whale) family Eschrichtiidae. Previous anatomical work on gray whales has been limited owing, in part, to difficulties of specimen access. These contributions to the anatomy of the gray whale head based on dissection of a stranded specimen from northern California include detailed investigation of internal and external features that confirm existing information and provide new evidence for their functional roles, particularly in thermoregulation and feeding. PMID- 25737251 TI - Reply to: Diagnostic power of fecal calprotectin in inflammatory and functional intestinal disorders. PMID- 25737250 TI - Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle. AB - Oxidative stress, caused by excess reactive oxygen species (ROS), has been hypothesized to cause or exacerbate skeletal muscle wasting in a number of diseases and chronic conditions. ROS, such as hydrogen peroxide, have the potential to affect signal transduction pathways such as the phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3 K)/Akt pathway that regulates protein synthesis. Previous studies have found contradictory outcomes for the effect of ROS on the PI3K/Akt signaling pathway, where oxidative stress can either enhance or inhibit Akt phosphorylation. The apparent contradictions could reflect differences in experimental cell types or types of ROS treatments. We replicate both effects in myotubes of cultured skeletal muscle C2C12 cells, and show that increased oxidative stress can either inhibit or enhance Akt phosphorylation. This differential response could be explained: thiol oxidation of Akt, but not the phosphatases PTEN or PP2A, caused a decline in Akt phosphorylation; whereas the thiol oxidation of Akt, PTEN and PP2A increased Akt phosphorylation. These observations indicate that a more complete understanding of the effects of oxidative stress on a signal transduction pathway comes not only from identifying the proteins susceptible to thiol oxidation, but also their relative sensitivity to ROS. PMID- 25737252 TI - Mental state attribution and the gaze cueing effect. AB - Theory of mind is said to be possessed by an individual if he or she is able to impute mental states to others. Recently, some authors have demonstrated that such mental state attributions can mediate the "gaze cueing" effect, in which observation of another individual shifts an observer's attention. One question that follows from this work is whether such mental state attributions produce mandatory modulations of gaze cueing. Employing the basic gaze cueing paradigm, together with a technique commonly used to assess mental-state attribution in nonhuman animals, we manipulated whether the gazing agent could see the same thing as the participant (i.e., the target) or had this view obstructed by a physical barrier. We found robust gaze cueing effects, even when the observed agent in the display could not see the same thing as the participant. These results suggest that the attribution of "seeing" does not necessarily modulate the gaze cueing effect. PMID- 25737254 TI - Cross-Modal Associations between Color and Haptics. AB - The objective of the present study was to explore cross-modal associations between color and tactile sensation while using haptically rendered virtual stimuli with substance properties of roughness/smoothness, hardness/softness, heaviness/lightness, elasticity/inelasticity, and adhesiveness/nonadhesiveness. The stimuli with the indicated properties were rendered with the aid of SensAble PHANTOM OMNI(r) haptic device. The experimental setup required the participants to use exploratory procedures typical to real object interaction, and select a color from the HSV color space that matched the experienced sensation. The findings of our investigation reveal systematic mapping between color characteristics and intensity of the haptic stimuli. Qualitatively different haptic sensations, however, produced relatively similar patterns of cross-modal associations. PMID- 25737255 TI - Developmental trends in interpolation and its spatial constraints: A comparison of subjective and occluded contours. AB - We examined interpolation in 6- and 9-year-old children and in adults, in the two most common forms of fragmentation: subjective and partially occluded contours. Experiment 1 examined the effects on adults' interpolation of contour geometry, specifically, the effect of a scale-dependent factor (i.e., retinal size) and a scale-independent factor (i.e., support ratio). For both subjective and partially occluded contours, interpolation was affected more by support ratio than absolute size. However, subjective contours were less precisely interpolated and their interpolation was affected more by support ratio than was the case for partial occlusion. Experiment 2 used a subset of retinal size and support ratio levels in children and adults. Interpolation of both subjective and occluded contours improved significantly with age, with the two types of contours equally affected by spatial constraints during early childhood. However, while interpolation of occluded contours became more precise with age and less dependent on support ratio by adulthood, interpolation of subjective contours was less improved and became even more tied to support ratio in adulthood. The implications of these differential age-related changes in the spatial constraints on interpolation of the two types of contours for the mechanisms of perceptual completion are discussed. PMID- 25737253 TI - Different developmental trajectories across feature types support a dynamic field model of visual working memory development. AB - Research on visual working memory has focused on characterizing the nature of capacity limits as "slots" or "resources" based almost exclusively on adults' performance with little consideration for developmental change. Here we argue that understanding how visual working memory develops can shed new light onto the nature of representations. We present an alternative model, the Dynamic Field Theory (DFT), which can capture effects that have been previously attributed either to "slot" or "resource" explanations. The DFT includes a specific developmental mechanism to account for improvements in both resolution and capacity of visual working memory throughout childhood. Here we show how development in the DFT can account for different capacity estimates across feature types (i.e., color and shape). The current paper tests this account by comparing children's (3, 5, and 7 years of age) performance across different feature types. Results showed that capacity for colors increased faster over development than capacity for shapes. A second experiment confirmed this difference across feature types within subjects, but also showed that the difference can be attenuated by testing memory for less familiar colors. Model simulations demonstrate how developmental changes in connectivity within the model-purportedly arising through experience-can capture differences across feature types. PMID- 25737256 TI - Does perceptual confidence facilitate cognitive control? AB - Our visual perception is typically accompanied by a sense of subjective confidence. Since perceptual confidence is related to prefrontal activity, higher perceptual confidence may enhance cognitive control functions. To examine this interaction, we developed a novel method to selectively manipulate perceptual confidence while keeping stimulus discrimination accuracy constant. In a behavioral experiment, grating stimuli with different orientations were presented as go/no-go signals. Surprisingly, the results showed that confidence in visual discrimination of the signals on its own did not facilitate response inhibition, since when participants were presented with stimuli that yielded higher confidence, they were no better at performing a go/no-go task. These results were replicated with different (dot motion) stimuli, ruling out alternative explanations based on stimulus idiosyncrasy. In a different experiment, when the grating stimuli were presented as cues for task set preparation, we found that higher perceptual confidence also did not enhance task set preparation efficiency. This result was again replicated with dot motion stimuli. Since confidence may relate to perceptual awareness (Peirce & Jastrow, 1885), our findings may put current dominant theories in question, since these theories often suppose the critical involvement of consciousness in cognitive control. As a proof of concept, our method may also provide a new and powerful way to examine other functions of consciousness in future studies. PMID- 25737257 TI - Attentional guidance by working memory differs by paradigm: an individual differences approach. AB - The contents of working memory (WM) have been repeatedly found to guide the allocation of visual attention; in a dual-task paradigm that combines WM and visual search, actively holding an item in WM biases visual attention towards memory-matching items during search (e.g., Soto et al., Journal of Experimental Psychology: Human Perception and Performance, 31(2), 248-261, 2005). A key debate is whether such memory-based attentional guidance is automatic or under strategic control. Generally, two distinct task paradigms have been employed to assess memory-based guidance, one demonstrating that attention is involuntarily captured by memory-matching stimuli even at a cost to search performance (Soto et al., 2005), and one demonstrating that participants can strategically avoid memory matching distractors to facilitate search performance (Woodman & Luck, Journal of Experimental Psychology: Human Perception and Performance, 33(2), 363-377, 2007). The current study utilized an individual-differences approach to examine why the different paradigms--which presumably tap into the same attentional construct- might support contrasting interpretations. Participants completed a battery of cognitive tasks, including two types of attentional guidance paradigms (see Soto et al., 2005; Woodman & Luck, 2007), a visual WM task, and an operation span task, as well as attention-related self-report assessments. Performance on the two attentional guidance paradigms did not correlate. Subsequent exploratory regression analyses revealed that memory-based guidance in each task was differentially predicted by visual WM capacity for one paradigm, and by attention related assessment scores for the other paradigm. The current results suggest that these two paradigms--which have previously produced contrasting patterns of performance--may probe distinct aspects of attentional guidance. PMID- 25737258 TI - Contextual cueing: implicit memory of tactile context facilitates tactile search. AB - In visual search, participants detect and subsequently discriminate targets more rapidly when these are embedded in repeatedly encountered distractor arrangements, an effect termed contextual cueing (Chun & Jiang Cognitive Psychology, 36, 28-71, 1998). However, whereas previous studies had explored contextual cueing exclusively in visual search, in the present study we examined the effect in tactile search using a novel tactile search paradigm. Participants were equipped with vibrotactile stimulators attached to four fingers on each hand. A given search array consisted of four stimuli (i.e., two items presented to each hand), with the target being an odd-one-out feature singleton that differed in frequency (Exps. 1 and 2) or waveform (Exp. 3) from the distractor elements. Participants performed a localization (Exps. 1 and 2) or discrimination (Exp. 3) task, delivering their responses via foot pedals. In all three experiments, reaction times were faster when the arrangement of distractor fingers predicted the target finger. Furthermore, participants were unable to explicitly discriminate repeated from nonrepeated tactile configurations (Exps. 2 and 3). This indicates that the tactile modality can mediate the formation of configural representations and use these representations to guide tactile search. PMID- 25737259 TI - Stimulus set size modulates the sex-emotion interaction in face categorization. AB - Previous research has shown that invariant facial features-for example, sex-and variant facial features-for example, emotional expressions-interact during face categorization. The nature of this interaction is a matter of dispute, however, and has been reported as either asymmetrical, such that sex cues influence emotion perception but emotional expressions do not affect the perception of sex, or symmetrical, such that sex and emotion cues each reciprocally influence the categorization of the other. In the present research, we identified stimulus set size as the critical factor leading to this disparity. Using faces drawn from different databases, in two separate experiments we replicated the finding of a symmetrical interaction between face sex and emotional expression when larger sets of posers were used. Using a subset of four posers, in the same setups, however, did not provide evidence for a symmetrical interaction, which is also consistent with prior research. This pattern of results suggests that different strategies may be used to categorize aspects of faces that are encountered repeatedly. PMID- 25737260 TI - Lean in healthcare: A comprehensive review. AB - BACKGROUND: Lean seems to be the next revolution for a better, improved, value based healhcare. In the last 15 years Lean has been increasingly adapted and adopted in healthcare. Accordingly, Lean healthcare has been developing into a major strand of research since the early 2000s. The aim of this work is to present a comprehensive overview of the main issues highlighted by research on implementation of Lean in a complex contest such as the healthcare one. METHOD: Comprehensive literature review was conducted in order to identify empirical and theoretical articles published up to September 2013. Thematic analysis was performed in order to extract and synthesis data. FINDINGS: 243 articles were selected for analysis. Lean is best understood as a means to increase productivity. Hospital is the more explored setting, with emergency and surgery as the pioneer departments. USA appears to be the leading country for number of applications. The theoretical works have been focused mainly on barriers, challenges and success factors. Sustainability, framework for measurement and critical appraisal remain underestimated themes. Evaluations of "system wide approach" are still low in number. CONCLUSION: Even though Lean results appear to be promising, findings so far do not allow to draw a final word on its positive impacts or challenges when introduced in the healthcare sector. Scholars are called to explore further the potentiality and the weaknesses of Lean, above all as for the magnitude of investments required and for the engagement of the whole organization it represents increasingly strategic choice, whilst health professionals, managers and policy makers could and should learn from research how to play a pivotal role for a more effective implementation of lean in different health contexts. PMID- 25737261 TI - Nonpharmacologic Interventions to Heal Pressure Ulcers in Older Patients: An Overview of Systematic Reviews (The SENATOR-ONTOP Series). AB - BACKGROUND: Pressure ulcers (PUs) are more frequent in older patients, and the healing process is usually challenging. Nonpharmacologic interventions may play a role in the treatment of older people with PUs, but most systematic reviews (SRs) have not addressed this specific population using convincing outcome measures. OBJECTIVE: To summarize and critically appraise the evidence from SRs of the primary studies on nonpharmacologic interventions to treat PUs in older patients. DESIGN: SR and meta-analysis of comparative studies. METHODS: PubMed, Cochrane Database of Systematic Reviews, EMBASE, and CINHAL (from inception to October 2013) were searched. A new search for updates in the Cochrane Database was launched in July 2014. SRs that included at least 1 comparative study evaluating any nonpharmacologic intervention to treat PUs in older patients, in any health care setting, were included. Any primary study with experimental design was then identified and included. From each primary study, quality assessment was undertaken as specified by the Cochrane Collaboration and the Grading of Recommendations Assessment, Development and Evaluation working group. Interventions were identified and compared among different studies to explore the possibility of performing a meta-analysis, using complete ulcer healing as the outcome measure. RESULTS: One hundred ten SRs with 45 primary studies satisfied the inclusion criteria. The most frequent interventions explored in these trials were support surfaces (13 studies), nutrition (8), and electrotherapy (6). High or moderate quality of evidence was found in none of the interventions, mainly because of the very serious risk of bias of most studies and imprecision in the treatment effect. Evidence grade is very low or insufficient to support the use of any support surface, nutrition intervention, multicomponent interventions, repositioning or other adjunctive therapy (ultrasound, negative pressure, laser, electromagnetic, light, shock wave, hydrotherapy, radiofrequency, or vibration therapy) to increase the rates of PU healing in older patients. Electrotherapy showed some beneficial effect in the treatment of PUs, although the quality of evidence is low. CONCLUSIONS: In older patients with PUs, evidence to use any nonpharmacologic therapy to increase the rates of wound healing is inconclusive, except for low quality evidence that supports the use of electrotherapy. This situation is especially alarming for interventions that are usually standard clinical practice (repositioning, support surfaces). Although there is some evidence in younger populations and other types of ulcers, studies in older populations with PUs using sound methodology are needed. PMID- 25737262 TI - Risk of subsequent dementia among patients with bipolar disorder or major depression: a nationwide longitudinal study in Taiwan. AB - BACKGROUND: Both major depression and bipolar disorder are associated with an increased risk of developing dementia. However, the differential risk of dementia between major depression and bipolar disorder is rarely investigated. METHODS: Using the Taiwan National Health Insurance Research Database, a total of 2291 patients aged >= 55 years (major depression: 1946 and bipolar disorder: 345) and 2291 age-and sex-matched controls were enrolled between 1998 and 2008, and followed to the end of 2011. Participants who developed dementia during the follow-up were identified. RESULTS: Both patients with bipolar disorder [hazard ratio (HR) 5.58, 95% confidence interval (CI) 4.26-7.32] and those with major depression (HR 3.02, 95% CI 2.46-3.70) had an increased risk of developing dementia in later life, after adjusting for demographic data and medical comorbidities. The sensitivity tests after excluding the 1-year (bipolar disorder: HR 4.73, 95% CI 3.50-6.35; major depression: HR 2.62, 95% CI 2.11-3.25) and 3-year (HR 3.92, 95% CI 2.78-5.54; HR 2.21, 95% CI 1.73-2.83, respectively) follow-up duration also revealed consistent findings. Furthermore, patients with bipolar disorder were associated with an 87% increased risk (HR 1.87, 95% CI 1.48 2.37) of subsequent dementia compared with patients with major depression. CONCLUSIONS: Midlife individuals with bipolar disorder or major depression were associated with an elevated risk of developing dementia in later life. Further studies may be required to clarify the underlying mechanisms among major depression, bipolar disorder, and dementia, and to investigate whether prompt intervention may decrease this risk. PMID- 25737264 TI - Freezing avoidance by supercooling in Olea europaea cultivars: the role of apoplastic water, solute content and cell wall rigidity. AB - Plants can avoid freezing damage by preventing extracellular ice formation below the equilibrium freezing temperature (supercooling). We used Olea europaea cultivars to assess which traits contribute to avoid ice nucleation at sub-zero temperatures. Seasonal leaf water relations, non-structural carbohydrates, nitrogen and tissue damage and ice nucleation temperatures in different plant parts were determined in five cultivars growing in the Patagonian cold desert. Ice seeding in roots occurred at higher temperatures than in stems and leaves. Leaves of cold acclimated cultivars supercooled down to -13 degrees C, substantially lower than the minimum air temperatures observed in the study site. During winter, leaf ice nucleation and leaf freezing damage (LT50 ) occurred at similar temperatures, typical of plant tissues that supercool. Higher leaf density and cell wall rigidity were observed during winter, consistent with a substantial acclimation to sub-zero temperatures. Larger supercooling capacity and lower LT50 were observed in cold-acclimated cultivars with higher osmotically active solute content, higher tissue elastic adjustments and lower apoplastic water. Irreversible leaf damage was only observed in laboratory experiments at very low temperatures, but not in the field. A comparative analysis of closely related plants avoids phylogenetic independence bias in a comparative study of adaptations to survive low temperatures. PMID- 25737263 TI - Frailty as a predictor of the incidence and course of depressed mood. AB - BACKGROUND: Late-life depression and physical frailty are supposed to be reciprocally associated, however, longitudinal studies are lacking. OBJECTIVES: This study examines whether physical frailty predicts a higher incidence of depression, as well as a less favorable course of depression. METHODS: A population-based cohort study of 888 people aged 65 years and over with follow-up measures at 3, 6, and 9 years. Cox proportional hazards models adjusted for age, sex, education, smoking, alcohol usage, and global cognitive functioning were applied to calculate the incidence of depressed mood in those nondepressed at baseline (n = 699) and remission in those with depressed mood at baseline (n = 189). Depressed mood onset or remission was defined as crossing the cut-off score of 20 points on the Center for Epidemiological Studies-Depression Scale combined with a relevant change in this score. Physical frailty was based on the presence of >= 3 out of 5 components (ie, weight loss, weakness, slowness, exhaustion, and low physical activity level). RESULTS: A total of 214 out of 699 (30.6%) nondepressed persons developed depressed mood during follow-up. Physical frailty predicted the onset of depressed mood with a hazard rate of 1.26 (95% confidence interval 1.09-1.45, P = .002). Of the 189 persons with depressed mood at baseline, 96 (50.8%) experienced remission during follow-up. Remission was less likely in the presence of a higher level of physical frailty (hazard rate = 0.72, 95% confidence interval 0.58-0.91, P = .005). CONCLUSIONS: Because physical frailty predicts both the onset and course of late-life depressed mood, physical frailty should receive more attention in mental health care planning for older persons as well as its interference with treatment. Future studies into the pathophysiological mechanisms may guide the development of new treatment opportunities for these vulnerable patients. PMID- 25737265 TI - Diagnostic use of surface EMG in a patient with spinal muscular atrophy. PMID- 25737266 TI - Acanthamoeba castellanii Proteases are Capable of Degrading Iron-Binding Proteins as a Possible Mechanism of Pathogenicity. AB - Acanthamoeba castellanii, a free-living amoeba, is an amphizoic organism that can behave as an opportunistic pathogen, causing granulomatous amoebic encephalitis in immunocompromised patients or infecting immunocompetent individuals via cutaneous lesions, sinusoidal infections, or amoebic keratitis. Therefore, this amoeba could be in contact with different iron-binding proteins, such as lactoferrin in tears and mucosa and transferrin and hemoglobin in blood. Iron is a vital and necessary element for host metabolism but also for parasite survival. Accordingly, parasites have developed iron uptake mechanisms, one of which is the utilization of proteases to degrade host iron-binding proteins. In this work, we performed a partial biochemical characterization of A. castellanii proteases at different pHs and utilizing protease inhibitors with 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and copolymerized with different iron-binding proteins. We describe for the first time the presence of several cysteine proteases in a total A. castellanii crude extract and in conditioned culture medium precipitated with ethanol. These amoebic peptidases degraded human holo lactoferrin, holo-transferrin, hemoglobin, and horse spleen ferritin; some of these proteases were substrate specific, and others degraded multiple substrates. These proteases could be considered virulence factors that promote iron acquisition from the host. PMID- 25737267 TI - Patterns of Tau and alpha-Synuclein Pathology in the Visual System. AB - BACKGROUND: Spreading of misfolded proteins has been suggested for neurodegenerative diseases. The hierarchical distribution of protein deposits in Alzheimer's (AD) and Parkinson's disease (PD) supports this concept. OBJECTIVES: To evaluate alpha-synuclein and tau-deposition in the optic pathway as an excellent anatomical model, which follows a strict trajectory including a cortico geniculate feedback connection. METHODS: We immunostained the optic nerve, lateral geniculate nucleus (LGN), and occipital cortex for AT8 (phosphorylated tau), alpha-synuclein, and disease-associated prion protein (PrP) in 47 cases with tau pathology (AD type, argyrophilic grain disease, or progressive supranuclear palsy), 16 PD, and 5 Creutzfeldt-Jakob disease (CJD) cases, respectively. RESULTS: We detected immunoreactivity for all proteins along the optic pathway. The optic nerve showed immunopositivity only in cases with tau (6/8, 75%) or alpha-synuclein (5/7, 71%) pathology. The LGN was involved also frequently (tau: 22/47, 46.8% ; alpha-synuclein: 15/16, 93.7% ; PrP 5/5, 100%). The occipital cortex was variably affected by tau or alpha-synuclein pathology, but always showed PrP immunoreactivity in the CJD cases. Tau pathology in the LGN correlated with tau immunoreactivity in the occipital cortex and Braak stages of neurofibrillary degeneration. In tauopathies, which do not involve the occipital cortex, like argyrophilic grain disease or progressive supranuclear palsy, tau pathology was more frequently astrocytic in the LGN. CONCLUSIONS: Our results have implications 1) for the understanding of disease spreading along neural pathways and 2) for the diagnostic evaluation of the visual system in neurodegenerative proteinopathies as a potential biomarker to evaluate disease progression or subgrouping of cases. PMID- 25737268 TI - Non-derivatized glycan analysis by reverse phase liquid chromatography and ion mobility-mass spectrometry. AB - A simple method for the analysis of non-derivatized glycans using a reverse phase column on a liquid chromatography-ion mobility-mass spectrometry (LC-IM-MS) instrument. The methodology supports both glycomic and proteomic work flows without the necessity of switching columns. PMID- 25737269 TI - Metastasectomy on the rise across several cancer types. PMID- 25737270 TI - The challenge of deciphering linkage isomers in mixtures of oligomeric complexes derived from 9-methyladenine and trans-(NH3)2Pt(II) units. AB - Metal coordination to N9-substituted adenines, such as the model nucleobase 9 methyladenine (9MeA), under neutral or weakly acidic pH conditions in water preferably occurs at N1 and/or N7. This leads, not only to mononuclear linkage isomers with N1 or N7 binding, but also to species that involve both N1 and N7 metal binding in the form of dinuclear or oligomeric species. Application of a trans-(NH3)2Pt(II) unit and restriction of metal coordination to the N1 and N7 sites and the size of the oligomer to four metal entities generates over 50 possible isomers, which display different feasible connectivities. Slowly interconverting rotamers are not included in this number. Based on (1)H NMR spectroscopic analysis, a qualitative assessment of the spectroscopic features of N1,N7-bridged species was attempted. By studying the solution behavior of selected isolated and structurally characterized compounds, such as trans [PtCl(9MeA-N7)(NH3)2]ClO4?2H2O or trans,trans-[{PtCl(NH3)2}2(9MeA N1,N7)][ClO4]2?H2O, and also by application of a 9MeA complex with an (NH3)3Pt(II) entity at N7, [Pt(9MeA-N7)(NH3)3][NO3]2, which blocks further cross link formation at the N7 site, basic NMR spectroscopic signatures of N1,N7 bridged Pt(II) complexes were identified. Among others, the trinuclear complex trans-[Pt(NH3)2{MU-(N1-9MeA-N7)Pt(NH3)3}2][ClO4]6?2H2O was crystallized and its rotational isomerism in aqueous solution was studied by NMR spectroscopy and DFT calculations. Interestingly, simultaneous Pt(II) coordination to N1 and N7 acidifies the exocyclic amino group of the two 9MeA ligands sufficiently to permit replacement of one proton each by a bridging heterometal ion, Hg(II) or Cu(II), under mild conditions in water. PMID- 25737271 TI - Validation of the German version of the Burn Specific Health Scale-Brief (BSHS B). AB - BACKGROUND: The Burn Specific Health Scale-Brief (BSHS-B) is recognized as a valid self-rating scale to evaluate quality of life after burn. AIM: To validate the translated German version of the BSHS-B. METHOD: One hundred and forty one burn survivors (65.2% men) with a mean age of 49.62 years (SD=15.16) and a mean duration after burn of 45.01 months (SD=26.18) answered the BSHS-B. Factor structure was tested by using confirmatory factor analysis, reliability (internal consistency) of the scales was determined by means of Cronbach's alpha. Construct validity was explored through correlations between the BSHS-B and the Short-Form 8 Health Survey (SF-8). In addition, the know-groups technique was used to determine to which degree the BSHS-B discriminates between patients with low and high burn severity based on the abbreviated burn severity index (ABSI). The Hospital Anxiety and Depression Scale (HADS) was used to examine criterion validity. RESULTS: The nine BSHS-B subscales showed good internal consistency. A second-order confirmatory factor analysis revealed the following main components: (1) Affect and Relationship, (2) Function and (3) Skin Involvement. The second order factors were positively correlated with the SF-8 and negatively correlated with symptoms of anxiety and depression. Patients with low ABSI scored higher on all three BSHS-B domains than those with high ABSI. CONCLUSIONS: The results indicate good psychometric properties of the German BSHS-B. Further studies are needed to investigate the utility of the questionnaire in clinical routine practice, evaluation of burn management programs, and burn-specific research. PMID- 25737272 TI - Maternal high-salt diets affected pressor responses and microvasoconstriction via PKC/BK channel signaling pathways in rat offspring. AB - SCOPE: High-salt (HS) intake is linked to hypertension, and prenatal exposure to maternal HS diets may have long-term impact on cardiovascular systems. The relationship between HS diets and cardiovascular disease has received extensive attention. This study determined pressor responses and microvessel functions in the adult offspring rats exposed to prenatal HS. METHODS AND RESULTS: The offspring of 5-month old as young adults in rats were used. Blood pressure, vascular tone, intracellular Ca(2+), and BK channels in mesenteric arteries were measured in the offspring. Phenylephrine (Phe)-induced pressor responses were significantly higher in the prenatal HS offspring. Vessel tension and intracellular Ca(2+) concentrations associated with Phe-induced pressor responses were increased in the mesenteric arteries of the HS offspring. PKC alpha- and delta-isoforms were upregulated in mesenteric arteries of the HS offspring. The enhanced Phe-mediated vascular activity was linked to the altered PKC-modulated BK channel functions. CONCLUSION: The results suggested that prenatal exposure to HS altered microvascular activity probably via changes in PKC/BK signaling pathways, which may lead to increased risks of hypertension in the offspring. PMID- 25737273 TI - Fabrication of functional nanofibers through post-nanoparticle functionalization. AB - A facile method is developed to functionalize nanofiber surfaces with nanoparticles (NPs) through dithiocarbamate chemistry. Gold nanoparticles (AuNPs) and quantum dots (QDs) are immobilized on the nanofiber surface. These surfaces provide scaffolds for further supramolecular functionalization, as demonstrated through the Forster resonance energy transfer (FRET) pairing of QD-decorated fibers and fluorescent proteins. PMID- 25737274 TI - Genetically modified bacteria as a tool to detect microscopic solid tumor masses with triggered release of a recombinant biomarker. AB - Current tomographic methods of cancer detection have limited sensitivity and are unable to detect malignant masses smaller than half a centimeter in diameter. Mortality from tumor recurrence and metastatic disease would be reduced if small lesions could be detected earlier. To overcome this limitation, we created a detection system that combines the specificity of tumor-targeting bacteria with the sensitivity of a synthetic biomarker. Bacteria, specifically Salmonella, preferentially accumulate in tumors and microscopic metastases as small as five cell layers thick. To create tumor detecting bacteria, an attenuated strain of Salmonella was engineered to express and release the fluorescent protein ZsGreen. A single-layer antibody method was developed to measure low concentrations of ZsGreen. Engineered bacteria were administered to a microfluidic tumor-on-a-chip device to measure protein production. In culture, half of produced ZsGreen was released by viable bacteria at a rate of 87.6 fg bacterium(-1) h(-1). Single layer antibody dots were able to detect bacterially produced ZsGreen at concentrations down to 4.5 ng ml(-1). Bacteria colonized in 0.12 mm(3) of tumor tissue in the microfluidic device released ZsGreen at a rate of 23.9 MUg h(-1). This release demonstrates that ZsGreen readily diffuses through tissue and accumulates at detectable concentrations. Based on a mathematical pharmacokinetic model, the measured rate of release would enable detection of 0.043 mm(3) tumor masses, which is 2600 times smaller than the current limit of tomographic techniques. Tumor-detecting bacteria would provide a sensitive, minimally invasive method to detect tumor recurrence, monitor treatment efficacy, and identify the onset of metastatic disease. PMID- 25737275 TI - Rasch analysis of professional behavior in medical education. AB - The use of students' "consumer feedback" to assess faculty behavior and improve the process of medical education is a significant challenge. We used quantitative Rasch measurement to analyze pre-categorized student comments listed by 385 graduating medical students. We found that students differed little with respect to the number of comments they provided and that their comments indeed form a probabilistic Rasch hierarchy. However, different hierarchies were found across medical departments and faculty. An analysis of these interactions provides valuable, detailed, and quantitative information that can augment qualitative research approaches. In addition, we suggest how the Rasch scaling of student comments can assist researchers in the design and implementation of new faculty evaluation instruments. Finally, the interactions between student and department identified a subset of behaviors that appear to guide and possibly elicit students' comments. PMID- 25737277 TI - A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage specific regulator of leukemia cell growth. AB - We performed a genome-scale shRNA screen for modulators of B-cell leukemia progression in vivo. Results from this work revealed dramatic distinctions between the relative effects of shRNAs on the growth of tumor cells in culture versus in their native microenvironment. Specifically, we identified many "context-specific" regulators of leukemia development. These included the gene encoding the zinc finger protein Phf6. While inactivating mutations in PHF6 are commonly observed in human myeloid and T-cell malignancies, we found that Phf6 suppression in B-cell malignancies impairs tumor progression. Thus, Phf6 is a "lineage-specific" cancer gene that plays opposing roles in developmentally distinct hematopoietic malignancies. PMID- 25737276 TI - The yin and yang of kidney development and Wilms' tumors. AB - Wilms' tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms' tumor in the context of renal development. Many of the genes implicated in Wilms' tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general and specific miRNAs in particular-in normal kidney development that still await further analysis. The recent identification of Wilms' tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions. PMID- 25737278 TI - Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. AB - Hereditary cancers derive from gene defects that often compromise DNA repair. Thus, BRCA-associated cancers are sensitive to DNA-damaging agents such as cisplatin. The efficacy of cisplatin is limited, however, by the development of resistance. One cisplatin resistance mechanism is restoration of homologous recombination (HR), which can result from BRCA reversion mutations. However, in BRCA2 mutant cancers, cisplatin resistance can occur independently of restored HR by a mechanism that remains unknown. Here we performed a genome-wide shRNA screen and found that loss of the nucleosome remodeling factor CHD4 confers cisplatin resistance. Restoration of cisplatin resistance is independent of HR but correlates with restored cell cycle progression, reduced chromosomal aberrations, and enhanced DNA damage tolerance. Suggesting clinical relevance, cisplatin resistant clones lacking genetic reversion of BRCA2 show de novo loss of CHD4 expression in vitro. Moreover, BRCA2 mutant ovarian cancers with reduced CHD4 expression significantly correlate with shorter progression-free survival and shorter overall survival. Collectively, our findings indicate that CHD4 modulates therapeutic response in BRCA2 mutant cancer cells. PMID- 25737279 TI - The DREAM complex promotes gene body H2A.Z for target repression. AB - The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle genes, but its mechanism of action is poorly understood. Here we show that Caenorhabditis elegans DREAM targets have an unusual pattern of high gene body HTZ-1/H2A.Z. In mutants of lin-35, the sole p130/Rb-like gene in C. elegans, DREAM targets have reduced gene body HTZ-1/H2A.Z and increased expression. Consistent with a repressive role for gene body H2A.Z, many DREAM targets are up-regulated in htz-1/H2A.Z mutants. Our results indicate that the DREAM complex facilitates high gene body HTZ-1/H2A.Z, which plays a role in target gene repression. PMID- 25737280 TI - Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt. AB - Cellular morphology is an essential determinant of cellular function in all kingdoms of life, yet little is known about how cell shape is controlled. Here we describe a molecular program that controls the early morphology of neurons through a metazoan-specific zinc finger protein, Unkempt. Depletion of Unkempt in mouse embryos disrupts the shape of migrating neurons, while ectopic expression confers neuronal-like morphology to cells of different nonneuronal lineages. We found that Unkempt is a sequence-specific RNA-binding protein and identified its precise binding sites within coding regions of mRNAs linked to protein metabolism and trafficking. RNA binding is required for Unkempt-induced remodeling of cellular shape and is directly coupled to a reduced production of the encoded proteins. These findings link post-transcriptional regulation of gene expression with cellular shape and have general implications for the development and disease of multicellular organisms. PMID- 25737281 TI - A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation. AB - The transcriptional activator MyoD serves as a master controller of myogenesis. Often in partnership with Mef2 (myocyte enhancer factor 2), MyoD binds to the promoters of hundreds of muscle genes in proliferating myoblasts yet activates these targets only upon receiving cues that launch differentiation. What regulates this off/on switch of MyoD function has been incompletely understood, although it is known to reflect the action of chromatin modifiers. Here, we identify KAP1 (KRAB [Kruppel-like associated box]-associated protein 1)/TRIM28 (tripartite motif protein 28) as a key regulator of MyoD function. In myoblasts, KAP1 is present with MyoD and Mef2 at many muscle genes, where it acts as a scaffold to recruit not only coactivators such as p300 and LSD1 but also corepressors such as G9a and HDAC1 (histone deacetylase 1), with promoter silencing as the net outcome. Upon differentiation, MSK1-mediated phosphorylation of KAP1 releases the corepressors from the scaffold, unleashing transcriptional activation by MyoD/Mef2 and their positive cofactors. Thus, our results reveal KAP1 as a previously unappreciated interpreter of cell signaling, which modulates the ability of MyoD to drive myogenesis. PMID- 25737282 TI - The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses. AB - Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Kruppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs. PMID- 25737283 TI - Cyclin-dependent kinase regulates the length of S phase through TICRR/TRESLIN phosphorylation. AB - S-phase cyclin-dependent kinases (CDKs) stimulate replication initiation and accelerate progression through the replication timing program, but it is unknown which CDK substrates are responsible for these effects. CDK phosphorylation of the replication factor TICRR (TopBP1-interacting checkpoint and replication regulator)/TRESLIN is required for DNA replication. We show here that phosphorylated TICRR is limiting for S-phase progression. Overexpression of a TICRR mutant with phosphomimetic mutations at two key CDK-phosphorylated residues (TICRR(TESE)) stimulates DNA synthesis and shortens S phase by increasing replication initiation. This effect requires the TICRR region that is necessary for its interaction with MDM two-binding protein. Expression of TICRR(TESE) does not grossly alter the spatial organization of replication forks in the nucleus but does increase replication clusters and the number of replication forks within each cluster. In contrast to CDK hyperactivation, the acceleration of S-phase progression by TICRR(TESE) does not induce DNA damage. These results show that CDK can stimulate initiation and compress the replication timing program by phosphorylating a single protein, suggesting a simple mechanism by which S-phase length is controlled. PMID- 25737284 TI - Characterization of submicron (0.1-1 MUm) particles in therapeutic proteins by nanoparticle tracking analysis. AB - The importance of 0.1-1 MUm submicron particles characterization in therapeutic proteins, which was limited because of a lack of suitable methods, has been recognized recently. An application of nanoparticle tracking analysis (NTA) for characterization of 18 lots of recombinant fusion protein (rP1) drug product presentation along with stressed samples of this material exposed to heat at 50 degrees C, agitation, and UV light was studied. In addition, monodisperse polystyrene standards with nominal sizes of 60-800 nm and rP1 samples spiked with 100-400 nm polystyrene standards were analyzed. The NTA technique was capable of demonstrating good sizing of monodisperse polystyrene standards, detect small particle size population in 800 nm standard, and resolve three size populations in the mixture of four standards (60-400 nm). The NTA was also capable of resolving 400 nm polystyrene standard from the main rP1 peak, but was not able to resolve 100 and 200 um standards because of the particle distribution profiles overlap. A characterization of 0.1-1 MUm submicron particles in rP1 showed a relatively diverse range of mean particle diameters, D90, and size distributions, which was not linked to the lots storage duration prior to analysis. The size distribution profile of rP1was specific for a single lot and did not show significant variability, which allowed detection of larger particle population in stressed samples compared with a control. Overall, the NTA technique is suitable for characterization of submicron particles in a studied therapeutic protein. However, the NTA can only be used as a semiquantitative methodology, because frequent sample dilution is required to achieve optimal particle concentration. PMID- 25737285 TI - Effects of spatiotemporal consistencies on visual learning dynamics and transfer. AB - Spatiotemporal interactions affect visual performance under repeated stimulation conditions, showing both incremental (commonly related to learning) and decremental (possibly sensory adaptation) effects. Here we examined the role of spatiotemporal consistencies on learning dynamics and transfer. The backward masked texture-discrimination paradigm was used, with stimulus onset asynchrony (SOA) controlling the observers' performance level. Temporal consistencies were examined by modifying the order in which SOA was varied during a training session: gradually reduced SOA (high consistencies) versus randomized SOA (low consistencies). Spatial consistencies were reduced by interleaving standard target trials with oriented 'dummy' trials containing only the background texture (no target, oriented 45 degrees relative to the target's orientation). Our results showed reduced improvement following training with gradual SOA, as compared with random SOA. However, this difference was eliminated by randomizing SOA only at the initial and final segments of training, revealing a contaminating effect of temporal consistencies on threshold estimation rather than on learning. Inserting the 'dummy' trials (reduced spatial consistencies) facilitated both the learning and the subsequent transfer of learning, but only when sufficient pre training was provided. These results indicate that visual sensitivity depends on a balance between two opposing processes, perceptual learning and sensory adaptation, both of which depend on spatiotemporal consistencies. Reducing spatiotemporal consistencies during training reduces the short-term spatiotemporal interactions that interfere with threshold estimation, learning, and generalization of learning. We consider the results within a theoretical framework, assuming an adaptable low-level network and a readout mechanism, with orientation and location-specific low-level adaptation interfering with the readout learning. PMID- 25737286 TI - Sepsis is a more important risk factor for cytomegalovirus colitis in human immunodeficiency virus-negative adults with chronic kidney disease. PMID- 25737287 TI - Novel compound heterozygous mutations in PRKRA cause pure dystonia. PMID- 25737288 TI - [Mechanical support in cardiogenic shock]. AB - Treatment of patients in cardiogenic shock (CS) presenting with acute myocardial infarction (AMI) is still a challenge and mortality rates remain high, approaching 50 %. Hemodynamic stabilization before and/or after early revascularization remains the primary goal in these patients. In addition to hemodynamic support by inotropes and vasopressors, support with mechanical devices such as intra-aortic balloon pumping (IABP), percutaneous left ventricular assist devices (LVAD) and complete extracorporeal life support (ECLS) with extracorporeal membrane oxygenation (ECMO) may be considered. The use of IABP cannot be recommended anymore on a routine basis. Unfortunately, there are no large randomized data from studies evaluating treatment with mechanical support systems compared to standard treatment with respect to the clinical outcome of patients and no head-to-head comparison of different devices is available. Another important open question to be answered is which subgroups of patients may have a benefit from LVAD therapy. Guidelines discourage the routine use of mechanical support as a first-line treatment in CS patients and emphasize that the application should be restricted to those patients with refractory shock. This article gives an overview of the different devices for percutaneous mechanical support in CS and describes the available evidence and guideline recommendations. PMID- 25737289 TI - [New therapy concepts for heart failure with preserved ejection fraction]. AB - The management of patients with heart failure and preserved ejection fraction (HFpEF) remains challenging and requires an accurate diagnosis. Although currently no convincing therapy that can prolong survival in patients with HFpEF has been established, treatment of fluid retention, heart rate and control of comorbidities are important cornerstones to improve the quality of life and symptoms. In recent years many new therapy targets have been tested for development of successful interventional strategies for HFpEF. Insights into new mechanisms of HFpEF have shown that heart failure is associated with dysregulation of the nitric oxide-cyclic guanosine monophosphate-protein kinase (NO-cGMP-PK) pathway. Two new drugs are currently under investigation to test whether this pathway can be significantly improved by either the neprilysin inhibitor LCZ 696 due to an increase in natriuretic peptides or by the soluble guanylate cyclase stimulator vericiguat, which is also able to increase cGMP. In addition, several preclinical or early phase studies which are currently investigating new mechanisms for matrix, intracellular calcium and energy regulation including the role of microRNAs and new devices are presented and discussed. PMID- 25737290 TI - Activities of ceftazidime, ceftaroline, and aztreonam alone and combined with avibactam against isogenic Escherichia coli strains expressing selected single beta-lactamases. AB - Avibactam is a novel beta-lactamase inhibitor that restores the activity of otherwise hydrolyzed beta-lactams against Gram-negative bacteria expressing different classes of serine beta-lactamases. In the last decade, beta-lactam avibactam combinations were tested against a variety of clinical isolates expressing multiple commonly encountered beta-lactamases. Here, we analyzed isogenic Escherichia coli strains expressing selected single beta-lactamase genes that were not previously tested or were not characterized in an isogenic background. The activities of ceftazidime, ceftaroline, and aztreonam alone and in combination with 4 mg/L of avibactam, as well as comparator agents, were assessed against a unique collection of isogenic strains of E. coli carrying selected extended-spectrum, inhibitor-resistant, and/or carbapenem-hydrolyzing bla genes. When combined with avibactam, ceftazidime, ceftaroline, or aztreonam MICs were reduced for 91.4%, 80.0%, and 80.0% of isolates, respectively. The data presented add to our understanding of the microbiologic spectrum of these beta lactams with avibactam and serve as a reference for further studies. PMID- 25737291 TI - LDL apheresis in the treatment of familial hypercholesterolemia: experience of Hospital Santo Antonio, Porto. AB - INTRODUCTION: High plasma levels of low-density lipoprotein (LDL) cholesterol are a risk factor for the development of premature atherosclerosis. Direct adsorption of lipoproteins (DALI) is an apheresis technique by which LDL cholesterol is selectively removed from whole blood. OBJECTIVE: The present study describes our experience with DALI LDL apheresis in severely hypercholesterolemic patients. METHODS: Three hypercholesterolemic patients suffering from atherosclerotic complications were treated fortnightly by DALI apheresis, in a total of 308 sessions between December 2008 and January 2013. All patients were on the highest tolerated dose of statins and other lipid-lowering drugs. RESULTS: The sessions were essentially uneventful, adverse events being recorded in only 3.6% of them. A mean 63.3% acute reduction in LDL cholesterol was obtained. CONCLUSION: DALI apheresis proved to be a simple, safe and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid-lowering therapy. PMID- 25737292 TI - The surgical management of recurrent stress urinary incontinence: a systematic review. AB - BACKGROUND: Despite a wide spectrum of interventions, surgical treatments of recurrent stress urinary incontinence (SUI) are associated with high failure rates. OBJECTIVES: To systematically review current evidence on the effectiveness of surgical interventions for recurrent SUI. DATA SOURCES: An electronic database search was undertaken (1980-2014). Keywords were: "stress urinary incontinence," "failure," "recurrence," "treatment." References of identified studies and abstracts from conferences were considered. STUDY SELECTION: We restricted the search to female patients and currently used surgical procedures, including studies with five or more cases. After the initial yield, studies were selected following title screening, abstract and full text scrutiny. RESULTS: The pooled objective cure rates of colposuspension for recurrent SUI are 76% (95% CI +/ 5.04), whereas rates for midurethral sling procedures are 68.5% (95% CI +/-3.11). Repeat midurethral sling procedures have pooled success rates of 66.2% (95% CI +/ 4) but those of the transobturator approach appear lower than retropubic procedures. Pubovaginal slings for recurrent SUI have pooled success of 79.3% (95% CI +/-6.54). Success rates for adjustable continence therapy and adjustable slings for recurrent SUI are 53.8% (95% CI +/-5.28), whereas for midurethral sling fixation procedures the pooled success is 61% (95% CI +/-10.56). Urethral bulking injections have success rates of 38% (95% CI +/-10.7). Laparoscopic two team sling procedures, salvage spiral slings, and artificial urinary sphincter have shown promising results, but there are limited data on recurrent cases. CONCLUSION: There is a wide spectrum of surgical interventions reported for secondary or tertiary treatment of SUI. A common characteristic for all recurrent procedures is a lower success rate compared with those reported following primary procedures. PMID- 25737293 TI - Automated measurement of site-specific N-glycosylation occupancy with SWATH-MS. AB - Asparagine-linked glycosylation is a common post-translational modification of proteins catalyzed by oligosaccharyltransferase that is important in regulating many aspects of protein function. Analysis of protein glycosylation, including glycoproteomic measurement of the site-specific extent of glycosylation, remains challenging. Here, we developed methods combining enzymatic deglycosylation and protease digestion with SWATH-MS to enable automated measurement of site-specific occupancy at many glycosylation sites. Deglycosylation with peptide endoglycosidase H, leaving a remnant N-acetylglucosamine on asparagines previously carrying high-mannose glycans, followed by trypsin digestion allowed robust automated measurement of occupancy at many sites. Combining deglycosylation with the more general peptide-N-glycosidase F enzyme with AspN protease digest allowed robust automated differentiation of nonglycosylated and deglycosylated forms of a given glycosylation site. Ratiometric analysis of deglycosylated peptides and the total intensities of all peptides from the corresponding proteins allowed relative quantification of site-specific glycosylation occupancy between yeast strains with various isoforms of oligosaccharyltransferase. This approach also allowed robust measurement of glycosylation sites in human salivary glycoproteins. This method for automated relative quantification of site-specific glycosylation occupancy will be a useful tool for research with model systems and clinical samples. PMID- 25737294 TI - Electron flow in reaction mechanisms--revealed from first principles. AB - The "curly arrow" of Robinson and Ingold is the primary tool for describing and rationalizing reaction mechanisms. Despite this approach's ubiquity and stellar success, its physical basis has never been clarified and a direct connection to quantum chemistry has never been found. Here we report that the bond rearrangements expressed by curly arrows can be directly observed in ab initio computations, as transformations of intrinsic bond orbitals (IBOs) along the reaction coordinate. Our results clarify that curly arrows are rooted in physical reality-a notion which has been challenged before-and show how quantum chemistry can directly establish reaction mechanisms in intuitive terms and unprecedented detail. PMID- 25737295 TI - Influence of body mass index on postoperative outcomes after laparoscopic liver resection. AB - BACKGROUND: Despite the increasing prevalence of obesity, the impact of body weight on postoperative outcomes of laparoscopic liver resection (LLR) still remains poorly evaluated. The present study aimed to explore the impact of body mass index (BMI) on perioperative outcomes in patients undergoing LLR. STUDY DESIGN: All patients undergoing LLR from January 2008 to December 2013 were retrospectively reviewed. BMI was subdivided into normal weight (<24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)), and obese (>=30.0 kg/m(2)). These three groups were compared in terms of demographic data, intraoperative factors, and postoperative outcomes. Logistic regression was used to determine odds ratios with 95% confidence intervals and evaluate BMI as an independent risk factor for morbidity. RESULTS: Among 228 selected patients, 83 (36.4%) patients were overweight and 32 (14.0%) were obese. Despite higher rates of diabetes mellitus, hypertension, and ischemic heart disease with an increase in BMI, no significant difference in operative time, blood loss, and conversion rate was observed in the three groups. There were no significant differences in postoperative mortality rate between the groups (0.9 vs. 1.2 vs. 0%). The rate of overall complications (31.0 vs. 31.3 vs. 40.6%) and major complications (14.2 vs. 9.6 vs. 18.8%) did not differ in the three groups. Major hepatectomy (HR 6.810, CI 1.437-32.267, p = 0.016) and operative time >180 min (HR 2.639, CI 1.179-5.908, p = 0.018) were independently associated with postoperative complications. CONCLUSIONS: The present study demonstrated that BMI does not negatively affect the postoperative short-term outcomes. Therefore, obesity and overweight should not be a contraindication for LLR. PMID- 25737296 TI - Isolation, identification, and formation conditions of a novel Maillard yellowish pigment, pyrrolothiazolate. AB - We isolated a novel yellow pigment from a model Maillard reaction system containing l-cysteine, l-lysine, and glucose and identified it as 6-hydroxy 3[R],7a[S]-dimethyl-7-oxo-2,3-dihydropyrrolo[2,1-b]thiazole-3-calboxylic acid. This compound was a novel pyrrolothiazole derivative carrying a carboxy group and was named pyrrolothiazolate. This compound showed the absorption maxima at 300 and 360 nm under acidic and neutral conditions, while 320 and 400 nm did under alkaline conditions. Pyrrolothiazolate formed from cysteine and glucose was the major low-molecular-weight Maillard pigment in the reaction mixture, and its formation was stimulated by adding lysine to the reaction cocktail. After heating at 110 degrees C for 2 h, 1-2 mg/mL of pyrrolothiazolate was formed in a reaction mixture containing 100 mM cysteine, 200 mM lysine, and 300 mM glucose dissolved in 0.5 m acetate buffer (pH 6.0) or 0.5 m phosphate buffer (pH 6.5). PMID- 25737298 TI - Different outcomes after intracytoplasmic sperm injection without oocyte activation in two patients with different types of globozoospermia. AB - Different outcomes after intracytoplasmic sperm injection (ICSI) without oocyte activation in two patients with different types of round-headed spermatozoa (globozoospermia) are reported. After controlled ovarian hyperstimulation and oocyte pick-up, retrieved oocytes were underwent ICSI without oocyte activation and a 33.33% (4/12) fertilisation rate was obtained in the first case, whereas an abnormal fertilisation was achieved in the second case. The transfer of two grade II embryos in the first couple resulted in clinical pregnancy with a healthy livebirth. It was concluded that the main problem of cases with globozoospermia was a low fertilisation rate or failure fertilisation, and even though ICSI and artificial oocyte activation have been employed to increase this rate, it is not necessarily needed to achieve a pregnancy. PMID- 25737299 TI - Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed Alagille syndrome. PMID- 25737297 TI - Phylogenetic distribution of symbiotic bacteria from Panamanian amphibians that inhibit growth of the lethal fungal pathogen Batrachochytrium dendrobatidis. AB - The introduction of next-generation sequencing has allowed for greater understanding of community composition of symbiotic microbial communities. However, determining the function of individual members of these microbial communities still largely relies on culture-based methods. Here, we present results on the phylogenetic distribution of a defensive functional trait of cultured symbiotic bacteria associated with amphibians. Amphibians are host to a diverse community of cutaneous bacteria and some of these bacteria protect their host from the lethal fungal pathogen Batrachochytrium dendrobatidis (Bd) by secreting antifungal metabolites. We cultured over 450 bacterial isolates from the skins of Panamanian amphibian species and tested their interactions with Bd using an in vitro challenge assay. For a subset of isolates, we also completed coculture experiments and found that culturing isolates with Bd had no effect on inhibitory properties of the bacteria, but it significantly decreased metabolite secretion. In challenge assays, approximately 75% of the bacterial isolates inhibited Bd to some extent and these inhibitory isolates were widely distributed among all bacterial phyla. Although there was no clear phylogenetic signal of inhibition, three genera, Stenotrophomonas, Aeromonas and Pseudomonas, had a high proportion of inhibitory isolates (100%, 77% and 73%, respectively). Overall, our results demonstrate that antifungal properties are phylogenetically widespread in symbiotic microbial communities of Panamanian amphibians and that some functional redundancy for fungal inhibition occurs in these communities. We hope that these findings contribute to the discovery and development of probiotics for amphibians that can mitigate the threat of chytridiomycosis. PMID- 25737300 TI - Frequent sputum production is associated with disturbed night's rest and impaired sleep quality in patients with COPD. AB - PURPOSE: In this study, we measured night's rest parameters measured with an accelerometer and sleep quality in mild to very severe patients with COPD. Furthermore, our aim was to investigate the association between night's rest parameters and clinical variables and the association between sleep quality and quality of life or health status. METHODS: Mild to very severe COPD patients were recruited from general practitioners and outpatient clinics of general hospitals to participate in a cross-sectional study on physical activity in patients with COPD. A total of 103 patients (mean age 65 years, 67 % male) wore the accelerometer during night's rest for at least four nights and were included in the analyses. RESULTS: No significant associations were found between objectively measured body movements during night's rest or subjective sleep quality and lung function, dyspnoea severity, body composition and physical activity during the day. Patients with frequent sputum production during the day had a higher number of sitting transitions during the night (5.3 vs 4.3 sitting transitions) and more frequently got out of bed compared to patients who hardly ever produced sputum during the day (1.0 vs 0.8 times per night). Furthermore, these patients also reported worse sleep quality (Pittsburgh sleep quality index (PSQI) score 4 vs 3). CONCLUSIONS: Our results indicate that objectively measured body movements during night's rest like body postures and transitions are not related to sleep quality in patients with COPD. We did find an association between frequent sputum production and disturbances during night's rest and sleep quality. Future studies should investigate whether the treatment of mucus hypersecretion leads to improved night's rest. PMID- 25737301 TI - Daytime cardiac repolarization in patients with obstructive sleep apnea. AB - PURPOSE: Obstructive sleep apnea (OSA) has been implicated in complications of cardiovascular disease, including arrhythmias and sudden cardiac death (SCD). Prolonged QT interval is associated with arrhythmias and SCD in patients with cardiovascular disease and apparently healthy humans. Apneic episodes during sleep in OSA patients are associated with QT prolongation due to increased vagal activity, but it is not understood whether chronic QT prolongation persists during normoxic daytime wakefulness. METHODS: To determine whether daytime QT intervals in OSA patients are prolonged compared to control subjects, we recruited 97 (76 male, 21 female) newly diagnosed patients with OSA [apnea hypopnea index (AHI) >=5 events/h] and 168 (100 male, 68 female) healthy volunteers (AHI <5 events/h) and measured daytime resting QT and RR intervals from the electrocardiograms to determine QT prolongation corrected for heart rate (QTc). RESULTS: All subjects with OSA were older and heavier, with increased heart rate, significantly increased AHI and arousal index, and reduced oxygen saturation (SpO2) during sleep, and spent less time in sleep with >90 % SpO2 compared to respective controls. QTc in patients with OSA (410 +/- 3.3 for male and 433 +/- 5.6 for female) was significantly increased compared to respective control groups (399 +/- 2.9 for male and 417 +/- 2.9 for female), after adjustment for age and body mass index. CONCLUSIONS: Our data show that OSA in either men or women is associated with a significant increase in resting daytime QTc. The propensity for ventricular arrhythmias in patients with OSA may be a result of abnormalities in resting cardiac repolarization. PMID- 25737302 TI - Preventing Persons Affected by Serious Mental Illnesses from Obtaining Firearms: The Evolution of Law, Policy, and Practice in Massachusetts. AB - A history of commitment to a mental health facility disqualifies applicants for gun licenses. Identifying such a history has become increasingly complex as the locus of confinement has become more diversified and privatized. In Massachusetts, prior to 2014, the databases used to identify individuals who would be disqualified on such grounds had not contemporaneously matched the evolution of the state's mental health systems. A survey of Massachusetts police chiefs, who, as in many jurisdictions, are charged with certifying qualification, indicates that some have broadened the scope of their background checks to include the experience of their officers with respect to certain applicants. The survey identifying these patterns, conducted in 2014, preceded by one month significant legislative reforms that mandate the modification of the reporting into a centralized database commitments to all types of mental health and substance use facilities, thus allowing identification of all commitments occurring in the state. The anticipated utilization of a different database mechanism, which has parallels in several other states, potentially streamlines the background check process, but raises numerous concerns that need to be addressed in developing and using such databases. PMID- 25737303 TI - Bortezomib enhances the therapeutic efficacy of dasatinib by promoting c-KIT internalization-induced apoptosis in gastrointestinal stromal tumor cells. AB - Dasatinib-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of dasatinib target proteins, such as c-KIT and PDGFRbeta, attenuates the therapeutic efficiency of dasatinib. Combination therapy which inhibits the activation of dasatinib target proteins may enhance the cytotoxicity of dasatinib in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of dasatinib-treated GIST-T1 cells, whereas GIST-T1 cells showed little dasatinib cytotoxicity when treated with dasatinib alone, as the upregulation of c-KIT caused by dasatinib itself interfered with the inhibition of c-KIT and PDGFRbeta phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf 1, which was originally bound to the c-KIT-Hsp90beta-Apaf-1 complex, induced primary apoptosis in GIST-T1 cells. Combined treatment with bortezomib plus dasatinib caused cell cycle arrest in the G1 phase through inactivation of PDGFRbeta and promoted bortezomib-induced apoptosis in GIST-T1 cells. Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs. PMID- 25737304 TI - Molecular and phenotypic characterization of methicillin-resistant Staphylococcus aureus isolates causing bacteremia at a major hospital in southern Mississippi. AB - Staphylococcus aureus is the predominant cause of bacteremia worldwide. We assessed the molecular epidemiology and antibiotic resistance of methicillin resistant S aureus isolates causing bacteremia in southern Mississippi. Diverse genetic backgrounds in terms of staphylococcal cassette chromosome mec, pulsed field gel electrophoresis, and multilocus sequence typing types of methicillin resistant S aureus were identified as causing bacteremia in Mississippi. A strong association of Panton-Valentine leukocidin genes with elevated vancomycin minimum inhibitory concentration is one of the important findings of our study. PMID- 25737305 TI - Three-year prospective, observational study of central line-associated bloodstream infections in a 600-bed Japanese acute care hospital. AB - BACKGROUND: Central line-associated bloodstream infection (CLABSI) is an important concern associated with central venous catheter (CVC) use. The objective of this study was to determine the influences of CVC access sites, CVC types, and presumed causative microorganisms on CLABSI occurrence in an acute care hospital. METHODS: We conducted a prospective, observational study of CLABSI occurrence for 3 consecutive years in a 600-bed Japanese acute care hospital. Data collected included patient characteristics, CVC access sites, CVC types, and microorganisms isolated by blood culture. RESULTS: For 1,650 CVCs used for 1,237 patients, 39 cases of infection were identified. Most infections had occurred within 1 month of CVC insertion. Maximal sterile barrier precautions had been used for most cases (97.3%). The average CLABSI occurrence days with internal jugular vein access were shorter than those with subclavian vein access and femoral vein access. CLABSI rates were 1.1 and 0.7 for single- and multilumen CVCs, respectively. CLABSI occurrence tended to be shorter when gram-positive cocci were isolated and tended to be longer when fungi (Candida spp) were isolated. CONCLUSION: Most CLABSI cases had occurred within 1 month of CVC insertion. Longer CVC duration increased chance of fungal infection. PMID- 25737308 TI - Risk of Rh (D) alloimmunisation after Rh (D) positive platelet transfusions in patients undergoing haematopoietic stem cell transplantation. PMID- 25737306 TI - Structures of the Apo and FAD-bound forms of 2-hydroxybiphenyl 3-monooxygenase (HbpA) locate activity hotspots identified by using directed evolution. AB - The FAD-dependent monooxygenase HbpA from Pseudomonas azelaica HBP1 catalyses the hydroxylation of 2-hydroxybiphenyl (2HBP) to 2,3-dihydroxybiphenyl (23DHBP). HbpA has been used extensively as a model for studying flavoprotein hydroxylases under process conditions, and has also been subjected to directed-evolution experiments that altered its catalytic properties. The structure of HbpA has been determined in its apo and FAD-complex forms to resolutions of 2.76 and 2.03 A, respectively. Comparisons of the HbpA structure with those of homologues, in conjunction with a model of the reaction product in the active site, reveal His48 as the most likely acid/base residue to be involved in the hydroxylation mechanism. Mutation of His48 to Ala resulted in an inactive enzyme. The structures of HbpA also provide evidence that mutants achieved by directed evolution that altered activity are comparatively remote from the substrate-binding site. PMID- 25737307 TI - Reflections of the Veterans Administration Puget Sound Health Care System Regional Nurse Practitioner Residency Forum. AB - PROBLEM: There is a proliferation of advanced practice residency programs. However, there is no uniform model of developing and evaluating program success. METHODS: An information forum was convened by Veterans Health Administration Puget Sound Health Care System's Center for Primary Care Education on September 17, 2013, in Seattle, Washington, to explore critical aspects of residency models. The three objectives of this forum were to develop a shared understanding of key elements needed to support nurse practitioner residencies; define the unique needs of nurse practitioner trainees who are interested in applying for a residency; and examine the viability of designing a replicable nurse practitioner residency model benchmarking stakeholder best practices. FINDINGS: This article describes the organization of the forum and summarizes the presentations during the program. The companion article explores key recommendations from the forum related to future development of residency "toolkits" to aid in future evaluation and accreditation. CONCLUSION: As nurse practitioner residencies continue to develop and evolve, more is needed in the area of structure and alignment. PMID- 25737309 TI - Economic analysis of Royalactin production under uncertainty: Evaluating the effect of parameter optimization. AB - Royalactin is a protein with several different potential uses in humans. Research, in insects and in mammalian cells, has shown that it can accelerate cell division and prevent apoptosis. The method of action is through the use of the epidermal growth factor receptor, which is present in humans. Potential use in humans could be to lower cholesterolemic levels in blood, and to elicit similar effects to those seen in bees, e.g., increased lifespan. Mass production of Royalactin has not been accomplished, though a recent article presented a Pichia pastoris fermentation and recovery by aqueous two-phase systems at laboratory scale as a possible basis for production. Economic modelling is a useful tool with which compare possible outcomes for the production of such a molecule and in particular, to locate areas where additional research is needed and optimization may be required. This study uses the BioSolve software to perform an economic analysis on the scale-up of the putative process for Royalactin. The key parameters affecting the cost of production were located via a sensitivity analysis and then evaluated by Monte Carlo analysis. Results show that if titer is not optimized the strategy to maintain a low cost of goods is process oriented. After optimization of this parameter the strategy changes to a product-oriented and the target output becomes the critical parameter determining the cost of goods. This study serves to provide a framework for the evaluation of strategies for future production of Royalactin, by analyzing the factors that influence its cost of manufacture. PMID- 25737310 TI - The opossum MHC genomic region revisited. AB - The gray short-tailed opossum Monodelphis domestica is one of the few marsupial species for which a high quality whole genome sequence is available and the major histocompatibility complex (MHC) region has been annotated. Previous analyses revealed only a single locus within the opossum MHC region, designated Modo-UA1, with the features expected for encoding a functionally classical class I alpha chain. Nine other class I genes found within the MHC are highly divergent and have features usually associated with non-classical roles. The original annotation, however, was based on an early version of the opossum genome assembly. More recent analyses of allelic variation in individual opossums revealed too many Modo-UA1 sequences per individual to be accounted for by a single MHC class I locus found in the genome assembly. A reanalysis of a later generation assembly, MonDom5, revealed the presence of two additional loci, now designated Modo-UA3 and UA4, in a region that was expanded and more complete than in the earlier assembly. Modo-UA1, UA3, and UA4 are all transcribed, although Modo-UA4 transcripts are rarer. Modo-UA4 is also relatively non-polymorphic. Evidence presented support the accuracy of the later assembly and the existence of three related class I genes in the opossum, making opossums more typical of mammals and most tetrapods by having multiple apparent classical MHC class I loci. PMID- 25737311 TI - Chicken major histocompatibility complex polymorphism and its association with production traits. AB - Major histocompatibility complex (MHC) is the best characterized genetic region controlling disease resistance and immune responses in chicken. MHC genes are also involved in various non-immune functions such as productive traits and reproductive success. The genetic diversity of MHC in an Iranian indigenous chicken (Khorasan) was studied, and association of the MHC alleles with production traits was determined. The MHC polymorphism was ascertained by genotyping the LEI0258 microsatellite locus by PCR-based fragment analysis. LEI0258 microsatellite marker is a genetic indicator for MHC, which is located on microchromosome 16 and strongly associated with serologically defined MHC haplotypes. A total of 25 different LEI0258 alleles (185-493 bp) and 76 genotypes were identified in 313 chickens. An allele of 361 bp had the highest frequency (26.44%), and alleles of 207 and 262 bp had the lowest (0.16%). High level of heterozygosity (87%) and good genotype frequency fit to the Hardy-Weinberg equilibrium was observed in this population (P = 0.238). The association study also revealed a significant influence of MHC alleles on body weight, egg weight, egg laying intensity, and weight of sexual maturity in Khorasan population (P < 0.05). The information obtained from this study indicates a high MHC genetic diversity and the association of MHC alleles with important production traits in Khorasan chicken. These data would be applicable in designing breeding and genetic resource conservation for indigenous chicken populations. PMID- 25737312 TI - Evaluation of regional cerebral blood flow in patient with atypical senile dementia with asymmetrical calcification. AB - We report an 83-year-old woman with atypical senile dementia with Fahr-type calcification. Brain computed tomography demonstrated asymmetrical calcification predominant in the basal ganglia on the right side and pronounced diffuse cortical atrophy in the frontotemporal areas. The patient was clinically diagnosed with diffuse neurofibrillary tangles with calcification. Brain single photon emission computed tomography findings revealed that cerebral blood flow was reduced on the right side, as compared with the left side, in widespread areas. Hemispheric asymmetry in both calcification and cerebral blood flow suggests a relationship between calcification and vascular changes. PMID- 25737313 TI - Tricuspid Annular Plane Systolic Excursion Is Reduced in Infants with Pulmonary Hypertension: Value of Tricuspid Annular Plane Systolic Excursion (TAPSE) to Determine Right Ventricular Function in Various Conditions of Pediatric Pulmonary Hypertension. PMID- 25737314 TI - Carotid intima-media thickness is associated with the progression of cognitive impairment in older adults. AB - BACKGROUND AND PURPOSE: We investigated the association between cardiovascular risk factors, including carotid intima-media thickness (CIMT), and future risk of mild cognitive impairment (MCI) and dementia in elderly subjects. METHODS: We conducted a population-based prospective study as a part of the Korean Longitudinal Study on Health and Aging. Our study included 348 participants who were nondemented at the baseline (mean age, 71.7+/-6.3 years) and underwent cognitive evaluation at the 5-year follow-up. Baseline cardiovascular risk factors were compared according to the development of MCI or dementia during the study period. RESULTS: At the baseline evaluation, 278 subjects were cognitively normal and 70 subjects had MCI. Diagnoses of cognitive function either remained unchanged or improved during the study period in 292 subjects (nonprogression group), whereas 56 subjects showed progression of cognitive impairment to MCI or dementia (progression group). The progression group exhibited a higher prevalence of hypertension and greater CIMT compared with the nonprogression group. Other baseline cardiovascular risk factors, including sex, body mass index, diabetes mellitus, insulin resistance, total cholesterol, waist-to-hip ratio, visceral fat, pulse wave velocity, and ankle-brachial index, were not significantly different between 2 groups. The association between greater baseline CIMT and the progression of cognitive impairment was maintained after adjustment for conventional baseline risk factors of cognitive impairment. Greater baseline CIMT was also independently associated with the development of MCI in the subjects whose baseline cognitive function was normal. CONCLUSIONS: Greater baseline CIMT was independently associated with the risk of cognitive impairment, such as MCI and dementia in elderly subjects. PMID- 25737315 TI - Association of short-term use of nonsteroidal anti-inflammatory drugs with stroke in patients with hypertension. AB - BACKGROUND AND PURPOSE: Limited studies have investigated the risk of cerebrovascular events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects at high risk. We examined the short-term (defined as 30-day period) effect of selective and nonselective NSAIDs use on the risk of ischemic and hemorrhagic stroke in patients with hypertension. METHODS: We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan. We identified 1653 hypertensive subjects with stroke (defined as International Classification of Diseases-Ninth Revision-CM-codes: 433.x, 434.x, and 436.x for ischemic stroke; 430 and 431 for hemorrhagic stroke) in 2010. We investigated the transient effect of NSAIDs use on stroke using conditional logistic regressions with the adjustment of potential confounders. RESULTS: The results suggested that NSAIDs use during the 30 days before stroke was associated with a 1.57-fold increased risk of ischemic stroke, but not of hemorrhagic stroke (adjusted odds ratio, 1.57; 95% confidence interval, 1.26-1.97 for ischemic stroke; and adjusted odds ratio, 1.38; 95% confidence interval, 0.79 2.40 for hemorrhagic stroke). When classifying NSAIDs into selective and nonselective groups, nonselective NSAIDs use significantly increased the risk of ischemic stroke (adjusted odds ratio, 1.55; 95% confidence interval, 1.24-1.94), but not of hemorrhagic stroke (adjusted odds ratio, 1.56; 95% confidence interval, 0.90-2.73). CONCLUSIONS: The results demonstrate an increased risk of stroke, specifically ischemic stroke among hypertensive subjects with NSAIDs use. It would be important to closely monitor the transient effect of initial NSAIDs treatment, particularly in patients with hypertension. PMID- 25737316 TI - Association of white matter integrity and cognitive functions in patients with subcortical silent lacunar infarcts. AB - BACKGROUND AND PURPOSE: Silent lacunar infarct (SLI) is a risk factor for dementia. This study investigated the white matter integrity abnormality and its relationship to the cognition impairments in SLI patients. METHODS: Between 27 patients with SLI in basal ganglia and 30 healthy controls, we assessed the difference in a batter of neuropsychological tests and in white matter integrity measurements, fractional anisotropy, and mean diffusivity, using tract-based spatial statistics. RESULTS: Compared with healthy controls, SLI patients performed worse in general mental status, memory, executive function, and language ability. They also had reduced fractional anisotropy and increase mean diffusivity in brain regions such as the body and genu of corpus callosum, the forceps minor, the bilateral superior and bilateral anterior corona radiate, and the left external capsule. Furthermore, we found that in SLI patients, fractional anisotropy measure in left external capsule was positively correlated to the performance in memory and language ability. CONCLUSIONS: SLI in basal ganglia leads to local and remote white matter integrity damages and to the cognition impairments. PMID- 25737317 TI - Application and interpretation of high-sensitivity cardiac troponin assays in patients with acute ischemic stroke. PMID- 25737318 TI - In-hospital stroke recurrence and stroke after transient ischemic attack: frequency and risk factors. AB - BACKGROUND AND PURPOSE: We aimed to assess the risk of recurrent ischemic events during hospitalization for stroke or transient ischemic attack (TIA) with optimal current management and to identify associated risk factors. METHODS: We performed a retrospective analysis of all patients treated for acute ischemic stroke or TIA in 3 stroke units between 2010 and 2013. Recurrent stroke was defined as new persisting (>=24 hours) neurological deficit occurring >24 hours after the index event and not attributable to other causes of neurological deterioration. Cox proportional hazard regression identified risk factors associated with recurrent stroke. RESULTS: The study included 5106 patients. During a median length of stay of 5 days (interquartile range, 4-8), stroke recurrence (or stroke after TIA) occurred in 40 patients (0.8%) and was independently associated with history of TIA, symptomatic carotid stenosis (>=70%), or other determined etiology. Patients with recurrent stroke and other determined etiology had cervical arterial dissection (n=2), primary angiitis of the central nervous system (n=1), giant cell arteritis (n=1), and lung cancer with nonbacterial thrombotic endocarditis (n=1). In patients with initial TIA or minor stroke (National Institutes of Health Stroke Scale <=5) recurrence was associated additionally with pneumonia after the inciting ischemic event but before stroke recurrence. Patients with initial stroke and aphasia had a lower stroke recurrence rate and there were no recurrences in patients with lacunar stroke. Recurrence was associated with significantly higher in-hospital mortality (17.5% versus 3.1%; P<0.001). CONCLUSIONS: In-hospital stroke recurrence was low with optimal current management. Patients with a history of TIA, severe symptomatic carotid stenosis, or uncommon causes of stroke were at higher risk. Pneumonia was associated with a higher risk of stroke recurrence in patients with initial TIA or minor stroke but not in the overall population studied. Aphasia may bias the detection rate by concealing new neurological symptoms. PMID- 25737320 TI - Ontogenetic asymmetry modulates population biomass production and response to harvest. AB - Patterns in biomass production are determined by resource input (productivity) and trophic transfer efficiency. At fixed resource input, variation in consumer biomass production has been related to food quality, metabolic type and diversity among species. In contrast, intraspecific variation in individual body size because of ontogenetic development, which characterizes the overwhelming majority of taxa, has been largely neglected. Here we show experimentally in a long-term multigenerational study that reallocating constant resource input in a two-stage consumer system from an equal resource delivery to juveniles and adults to an adult-biased resource delivery is sufficient to cause more than a doubling of total consumer biomass. We discuss how such changes in consumer stage-specific resource allocation affect the likelihood for alternative stable states in harvested populations as a consequence of stage-specific overcompensation in consumer biomass and thereby the risk of catastrophic collapses in exploited populations. PMID- 25737319 TI - Arthroscopic fragment fixation using hydroxyapatite/poly-L-lactate Acid thread pins for treating elbow osteochondritis dissecans. AB - BACKGROUND: Various procedures, such as arthroscopic debridement, osteochondral transplantation, and bone plug fixation, have been described for the treatment of osteochondritis dissecans (OCD) of the humeral capitellum. However, the use of hydroxyapatite/poly-L-lactate acid (HA/PLLA) thread pins to fix the osteochondral fragment in an OCD lesion is a recent development. HYPOTHESIS: Adolescent throwing athletes would return to preinjury levels of function after arthroscopic osteochondral fragment fixation using HA/PLLA thread pins. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Enrolled in this prospective cohort study were 18 adolescent baseball players (mean age, 14.2 years; range 12-16, years) with elbow OCD who underwent arthroscopic fragment fixation with HA/PLLA thread pins between 2006 and 2009. All patients were affected on their dominant side. Plain radiographs taken before surgery showed an open physis in 13 patients (72%) and a closed physis in 5 patients (28%). During surgery, the condition of the OCD lesion was evaluated by use of the International Cartilage Research Society (ICRS) classification system; there were 5 grade II, 11 grade III, and 2 grade IV cases. Outcomes were assessed after 3 years (mean, 39 months; range, 36-50 months). Elbow function was measured using the Timmerman and Andrews score and the Mayo Elbow Performance Index. Return to sports activity was assessed as higher than preinjury, same level, lower level, or no return to sports. RESULTS: The mean Timmerman and Andrews score improved significantly from 126.6+/-6.5 to 197.5+/-1.5, and the mean Mayo Elbow Performance Index improved significantly from 68.0+/-2.1 to 98.06+/-0.9 (P=.0001 for both). Mean elbow extension improved significantly from -10 degrees +/-10.4 degrees to -0.8 degrees +/-5.2 degrees (P=.006), and mean flexion improved significantly from 123.1 degrees +/-17.9 degrees to 138.6 degrees +/-6.1 degrees (P=.001). Three patients had a loss of extension greater than 5 degrees . Five patients returned to a higher level of sports activity, 10 patients returned to the same level, and 2 patients returned to a lower level. A remaining patient did not return to baseball. In one patient, the lesion did not heal, resulting in fragmentation at 1 year after surgery. This patient consequently underwent revision arthroscopy to remove the lesion, and he eventually returned to sports at the same level of activity. CONCLUSION: Arthroscopic fragment fixation using HA/PLLA thread pins provides a beneficial clinical outcome to adolescent baseball players with humeral capitellar OCD. PMID- 25737321 TI - Bronchogenic carcinoma presented as Foville's syndrome. PMID- 25737322 TI - Cardiac CT in an aberrant right coronary artery. PMID- 25737323 TI - Detection Times of Carboxylic Acid Metabolites of the Synthetic Cannabinoids JWH 018 and JWH-073 in Human Urine. AB - Over the past years, use of synthetic cannabinoids has become increasingly popular. To draw the right conclusions regarding new intake of these substances in situations of repeated urinary drug testing, knowledge of their elimination rate in urine is essential. We report data from consecutive urine specimens from five subjects after ingestion of synthetic cannabinoids. Urinary concentrations of the carboxylic acid metabolites JWH-018-COOH and JWH-073-COOH were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) with a limit of quantification of 0.1 ng/mL. In these subjects, specimens remained positive over a period of 20-43 (mean 27) days for JWH-018-COOH and over a period of 11-25 (mean 19) days for JWH-073-COOH. Detection times were shorter for subjects that appeared to have ingested only one, or a few, doses prior to urine collection in the study. Creatinine-normalized concentrations (CN concentrations) slowly declined throughout the follow-up period in all subjects, suggesting that no new intake had taken place during this period. Mean elimination half-lives in urine were 14.0 (range 4.4-23.8) days for CN-JWH-018 COOH and 9.3 (range 3.6-16.8) days for CN-JWH-073-COOH. These data show that urine specimens could be positive for JWH-018-COOH for more than 6 weeks and JWH 073-COOH for more than 3 weeks after ingestion. However, such long detection periods require a low limit of quantification. PMID- 25737324 TI - X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome. AB - X-linked inhibitor of apoptosis (XIAP) deficiency (also known as X-linked lymphoproliferative syndrome type 2, XLP-2) is a rare primary immunodeficiency. Since the disease was first described in 2006, more than 70 patients suffering from XIAP-deficiency have been reported, thus extending the clinical presentations of the disease. The main clinical features of XLP-2 are (i) elevated susceptibility to hemophagocytic lymphohistiocytosis (HLH, frequently in response to infection with Epstein-Barr virus (EBV)), (ii) recurrent splenomegaly and (iii) inflammatory bowel disease (IBD) with the characteristics of Crohn's disease. XIAP deficiency is now considered to be one of the genetic causes of IBD in infancy. Although XIAP is an anti-apoptotic molecule, it is also involved in many other pathways, including the regulation of innate immunity and inflammation. XIAP is required for signaling through the Nod-like receptors NOD1 and 2, which are intracellular sensors of bacterial infection. XIAP-deficient T cells (including innate natural killer T cells and mucosal-associated invariant T cells) are overly sensitive to apoptosis. NOD2 function is impaired in XIAP deficient monocytes. However, the physiopathological mechanisms underlying the clinical phenotypes in XIAP deficiency, notably the HLH and the EBV susceptibility, are not well understood. Here, we review the clinical aspects, molecular etiology and physiopathology of XIAP deficiency. PMID- 25737325 TI - Dose levels in particulate-containing formulations impact anti-drug antibody responses to murine monoclonal antibody in mice. AB - Dosage levels and particulate contents of therapeutic protein formulations are potential factors that impact immunogenicity of protein therapeutics. Here, we evaluated the effect of dose levels on the immunogenicity of protein particulates formed by adsorbing a murine monoclonal IgG2c/kappa antibody (mAb1) onto silicone oil microdroplets, glass, or aluminum hydroxide (Alhydrogel) microparticles. Immune responses to these particulate-containing preparations were compared against responses to solutions of mAb1 that had been ultracentrifuged to minimize particle levels. Formulations containing 5 or 500 MUg of adsorbed mAb1 were administered subcutaneously to C57BL/6J or BALB/c mice. Antidrug antibodies (ADAs) were detected using an isotype-specific enzyme-linked immunosorbent assay (ELISA) method or a chemiluminescence method. Sera from BALB/c mice showed greater ADA responses to administration of particles at the 5-MUg dose level than at the 500-MUg dose level. In sera from C57BL/6J mice, ADA levels detected by ELISA were independent of the particle dose levels tested. ADAs were not detected in sera from C57BL/6J mice performing the chemiluminescence technique. In conclusion, mice administered formulations of a murine antibody adsorbed onto silicone oil microdroplets, glass microparticles, or Alhydrogel((r)) showed greater ADA responses that those that received particle-free mAb1 preparations, and responses were greater for formulations containing lower doses of antibody. . PMID- 25737326 TI - Soil warming increased whole-tree water use of Pinus cembra at the treeline in the Central Tyrolean Alps. AB - This study quantified the effect of soil warming on sap flow density (Qs) of Pinus cembra L. at the treeline in the Central Tyrolean Alps. To enhance soil temperature we installed a transparent roof construction above the forest floor around six trees. Six other trees served as controls in the absence of any manipulation. Roofing enhanced growing season mean soil temperature by 1.6, 1.3 and 1.0 degrees C at 5, 10 and 20 cm soil depth, respectively, while soil water availability was not affected. Sap flow density (using Granier-type thermal dissipation probes) and environmental parameters were monitored throughout three growing seasons. During the first year of treatment, no warming effect was detected on Qs. However, soil warming caused Qs to increase significantly by 11 and 19% above levels in control trees during the second and third year, respectively. This effect appeared to result from warming-induced root production, a reduction in viscosity and perhaps an increase also in root hydraulic conductivity. Hardly affected were leaf-level net CO2 uptake rate and conductance for water vapour, so that water-use efficiency stayed unchanged as confirmed by needle delta(13)C analysis. We conclude that tree water loss will increase with soil warming, which may alter the water balance within the treeline ecotone of the Central Austrian Alps in a future warming environment. PMID- 25737327 TI - Tailoring nano-catalysts: turning gold nanoparticles on bulk metal oxides to inverse nano-metal oxides on large gold particles. AB - Highly active/stable inverse catalysts of nano-oxides on large gold particles are designed and tailored. For the gas-phase oxidation of alcohols as a model reaction, the experimental and theoretical results verify that the catalyst activity depends on the gold-oxide interface, and the anti-sintering feature of such an inverse structure endows the catalyst with high stability. PMID- 25737328 TI - Molecular evolution and species-specific expansion of the NAP members in plants. AB - The NAP (NAC-Like, Activated by AP3 /PI) subfamily is one of the important plant specific transcription factors, and controls many vital biological processes in plants. In the current study, 197 NAP proteins were identified from 31 vascular plants, but no NAP members were found in eight non-vascular plants. All NAP proteins were phylogenetically classified into two groups (NAP I and NAP II), and the origin time of the NAP I group might be relatively later than that of the NAP II group. Furthermore, species-specific gene duplications, caused by segmental duplication events, resulted in the expansion of the NAP subfamily after species divergence. Different groups have different expansion rates, and the NAP group preference was found during the expansion in plants. Moreover, the expansion of NAP proteins may be related to the gain and loss of introns. Besides, functional divergence was limited after the gene duplication. Abscisic acid (ABA) might play an important role in leaf senescence, which is regulated by NAP subfamily. These results could lay an important foundation for expansion and evolutionary analysis of NAP subfamily in plants. PMID- 25737329 TI - Improving cell-free protein synthesis through genome engineering of Escherichia coli lacking release factor 1. AB - Site-specific incorporation of non-standard amino acids (NSAAs) into proteins opens the way to novel biological insights and applications in biotechnology. Here, we describe the development of a high yielding cell-free protein synthesis (CFPS) platform for NSAA incorporation from crude extracts of genomically recoded Escherichia coli lacking release factor 1. We used genome engineering to construct synthetic organisms that, upon cell lysis, lead to improved extract performance. We targeted five potential negative effectors to be disabled: the nuclease genes rna, rnb, csdA, mazF, and endA. Using our most productive extract from strain MCJ.559 (csdA(-) endA(-)), we synthesized 550+/-40 MUg mL(-1) of modified superfolder green fluorescent protein containing p-acetyl-L phenylalanine. This yield was increased to ~1300 MUg mL(-1) when using a semicontinuous method. Our work has implications for using whole genome editing for CFPS strain development, expanding the chemistry of biological systems, and cell-free synthetic biology. PMID- 25737330 TI - Increased and mistimed sex hormone production in night shift workers. AB - BACKGROUND: Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. METHODS: We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6 sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. RESULTS: Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17-2.32] and androgens (GMR: 1.44; 95% CI, 1.03-2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6 sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46). CONCLUSIONS: We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers. IMPACT: The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers. PMID- 25737332 TI - Validity of expert assigned retrospective estimates of occupational polychlorinated biphenyl exposure. AB - Assessment of retrospective exposures based on expert judgment in case-control studies is usually of unknown validity because of the difficulty in finding gold standards for comparison. We investigated the relationship between expert assigned retrospective occupational polychlorinated biphenyl (PCB) exposure estimates and serum PCB concentrations. Analyses were conducted on a subset of cases (n = 94) and controls (n = 96) in the multi-center National Cancer Institute, Surveillance, Epidemiology, and End Results Case-Control Study of non Hodgkin lymphoma. Based on the subjects' lifetime work histories, an industrial hygienist assigned each job a probability of PCB exposure [<5% (unexposed), 5 <50% (possibly exposed), >=50% (probably exposed)]. Ordinary least squares regression was used to investigate associations between the probability rating and log-transformed lipid-adjusted serum levels of 14 PCB congeners and total PCBs (GammaPCBs). Compared to unexposed participants (n = 163), those with a probably exposed job (n = 7) had serum levels that were 87% higher for GammaPCBs (95% confidence interval: 1.33-2.62) and 38% of serum level variability was explained by the probability rating. Statistically significant associations between probability ratings and serum levels for 12 of 14 individual congeners were also observed. In summary, the observed contrast in PCB serum levels by probability rating provides support for the occupational PCB exposure assessment. PMID- 25737331 TI - High-Risk Human Papillomavirus (HPV) Infection and Cervical Cancer Prevention in Britain: Evidence of Differential Uptake of Interventions from a Probability Survey. AB - BACKGROUND: The third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3) provides an opportunity to explore high-risk human papillomavirus (HR HPV) and uptake of cervical screening and HPV vaccination in the general population. METHODS: Natsal-3, a probability sample survey of men and women ages 16 to 74, resident in Britain, interviewed 8,869 women in 2010 to 2012. We explored risk factors for HR-HPV (in urine from 2,569 sexually experienced women ages 16 to 44), nonattendance for cervical screening in the past 5 years, and noncompletion of HPV catch-up vaccination. RESULTS: HR-HPV was associated with increasing numbers of lifetime partners, younger age, increasing area-level deprivation, and smoking. Screening nonattendance was associated with younger and older age, increasing area-level deprivation (age-adjusted OR 1.91, 95% confidence interval, 1.48-2.47 for living in most vs. least deprived two quintiles), Asian/Asian British ethnicity (1.96, 1.32-2.90), smoking (1.97, 1.57 2.47), and reporting no partner in the past 5 years (2.45, 1.67-3.61 vs. 1 partner) but not with HR-HPV (1.35, 0.79-2.31). Lower uptake of HPV catch-up vaccination was associated with increasing area-level deprivation, non-white ethnicity, smoking, and increasing lifetime partners. CONCLUSIONS: Socioeconomic markers and smoking were associated with HR-HPV positivity, nonattendance for cervical screening, and noncompletion of catch-up HPV vaccination. IMPACT: The cervical screening program needs to engage those missing HPV catch-up vaccination to avoid a potential widening of cervical cancer disparities in these cohorts. As some screening nonattenders are at low risk for HR-HPV, tailored approaches may be appropriate to increase screening among higher-risk women. PMID- 25737333 TI - Evaluation of the dark-medium objective lens in counting asbestos fibers by phase contrast microscopy. AB - A Japanese round-robin study revealed that analysts who used a dark-medium (DM) objective lens reported higher fiber counts from American Industrial Hygiene Association (AIHA) Proficiency Analytical Testing (PAT) chrysotile samples than those using a standard objective lens, but the cause of this difference was not investigated at that time. The purpose of this study is to determine any major source of this difference by performing two sets of round-robin studies. For the first round-robin study, 15 AIHA PAT samples (five each of chrysotile and amosite generated by water-suspended method, and five chrysotile generated by aerosolization method) were prepared with relocatable cover slips and examined by nine laboratories. A second round-robin study was then performed with six chrysotile field sample slides by six out of nine laboratories who participated in the first round-robin study. In addition, two phase-shift test slides to check analysts' visibility and an eight-form diatom test plate to compare resolution between the two objectives were examined. For the AIHA PAT chrysotile reference slides, use of the DM objective resulted in consistently higher fiber counts (1.45 times for all data) than the standard objective (P-value < 0.05), regardless of the filter generation (water-suspension or aerosol) method. For the AIHA PAT amosite reference and chrysotile field sample slides, the fiber counts between the two objectives were not significantly different. No statistically significant differences were observed in the visibility of blocks of the test slides between the two objectives. Also, the DM and standard objectives showed no pattern of differences in viewing the fine lines and/or dots of each species images on the eight-form diatom test plate. Among various potential factors that might affect the analysts' performance of fiber counts, this study supports the greater contrast caused by the different phase plate absorptions as the main cause of high counts for the AIHA PAT chrysotile slides using the DM objective. The comparison of fiber count ratios (DM/standard) between the AIHA PAT chrysotile samples and chrysotile field samples indicates that there is a fraction of fibers in the PAT samples approaching the theoretical limit of visibility of the phase-contrast microscope with 3-degree phase-shift. These fibers become more clearly visible through the greater contrast from the phase plate absorption of the DM objective. However, as such fibers are not present in field samples, no difference in counts between the two objectives was observed in this study. The DM objective, therefore, could be allowed for routine fiber counting as it will maintain continuity with risk assessments based on earlier phase-contrast microscopy fiber counts from field samples. Published standard methods would need to be modified to allow a higher aperture specification for the objective. PMID- 25737334 TI - Fatal foreign-body granulomatous pulmonary embolization due to microcrystalline cellulose in a patient receiving total parenteral nutrition: all crystals are not what they seem. AB - Pulmonary foreign-body granulomatous embolization has been described secondary to crystal precipitation in total parenteral nutrition (TPN) as well as when pharmaceutical tablets are crushed and injected intravenously. Extensive granulomatous embolization may cause pulmonary hypertension and death due to acute cor pulmonale. We report the case of a 34-year old woman who had been receiving TPN post-operatively secondary to complications of a paraesophageal hernia repair. During and following receiving TPN, she experienced episodes of hypoxia, tachycardia, fever, and hypotension. Computed tomography scans of the thorax showed centrilobular nodules, tree-in-bud and ground-glass opacities, as well as findings of pulmonary hypertension. Following an episode of hypoxia she was found unresponsive and died despite resuscitative efforts. Microscopic examination of the lungs following post-mortem examination revealed occlusive granulomatous inflammation of the pulmonary arterial vasculature by crystalline material. The morphologic and histochemical patterns of the crystals were suggestive of microcrystalline cellulose, a finding that was confirmed by energy dispersive X-spectroscopy and infrared spectroscopy. Ancillary tests did not support that the crystalline material was the result of TPN precipitation. Foreign-body granulomatous embolization leading to acute core pulmonale may occur as a complication of both intravenous injection of oral medications as well as of TPN crystallization. The source of crystalline material may be difficult to discern based solely on morphological assessment or by histochemical staining. Ancillary studies such as energy dispersive X-spectroscopy or infrared spectroscopy should be performed to definitively discern the two entities. PMID- 25737335 TI - Seasonal variation of postmortem microbial communities. AB - Body-associated microbes were recently shown to change significantly during decomposition, undergoing an ecological succession in experimental conditions using rodent and swine models. We investigated microbial succession in soils associated with swine carcasses under experimental field conditions in summer and winter. We demonstrate that these postmortem microbial communities change in a specific, reproducible fashion, and that soil microbes represent a significant component of the postmortem microbial community, contrary to widespread belief in forensic science. However, the effects of decomposition on soil microbial communities were different in summer and winter. We suggest that the microbial ecological succession will be useful in medicolegal death investigation; however, observations in winter might not be applicable to summer, which indicates a need for a greater understanding of the seasonality of decomposition. PMID- 25737336 TI - Professor Johannes Myren. PMID- 25737337 TI - Remote ischemic conditioning: a novel way to treat ischemia-related injury of limbs. AB - Remote ischemic conditioning (RIC) including remote ischemic preconditioning (RIPC) and remote ischemic postconditioning (RIPostC) is widely reported to be able to prevent many organs, such as heart, brain, and skeletal muscle from ischemia-related injury. However, the clinical application of RIC is confined to treating myocardial infarction and stroke. Since RIC could prevent skeletal muscle from ischemia-related injury, and was effective in heart and brain treatments, we hypothesized RIC could treat ischemia-related injury of limbs, such as diabetic foot, Buerger's disease, plantation of severed limb, and crush injury. As we know, many researches not only proved the promising clinical applications of RIC, but also researched the mechanisms in animal models. Our hypothesis could be confirmed by these researches. PMID- 25737338 TI - HPLC-MS-MS Determination of ZCZ-011, A Novel Pharmacological Tool for Investigation of the Cannabinoid Receptor in Mouse Brain Using Clean Screen FAStTM Column Extraction. AB - A high-performance liquid chromatography tandem mass spectrometry method was developed for the detection and quantification of 6-methyl-3-(2-nitro-1-(thiophen 2-yl)propyl)-2-phenyl-1H-indole (ZCZ-011) using 2-phenylindole as the internal standard (ISTD). ZCZ-011 was synthesized as a possible positive allosteric modulator with the CB1 cannabinoid receptor. The analytical method employs a rapid extraction technique using Clean Screen FAStTM columns with a Positive Pressure Manifold. FAStTM columns were originally developed for urine drug analysis but we have successfully adapted them to the extraction of brain tissue. Chromatographic separation was performed on a Restek Allure Biphenyl 5 u, 100 * 3.2 mm column (Bellefonte, PA). The mobile phase consisted of 1:9 deionized water with 10 mmol ammonium acetate and 0.1% formic acid-methanol. The following transition ions (m/z) were monitored for ZCZ-011: 363 > 207 and 363 > 110 and for the ISTD: 194 > 165 and 194 > 89. The FAStTM columns lowered and stabilized the ion suppression over the linear range of the assay (40-4,000 ng/g). The method was evaluated for recovery, ion suppression, accuracy/bias, intraday and interday precision, bench-top stability, freeze-thaw and post-preparative stability. The method was successfully applied to brain tissue from C57BL/6J mice that received intraperitoneal (i.p.) injections with 40 mg/kg of ZCZ-011 or vehicle. PMID- 25737339 TI - A Fatal Case of Pentedrone and alpha-Pyrrolidinovalerophenone Poisoning. AB - We report a fatal case of combined alpha-pyrrolidinovalerophenone (alpha-PVP) and 2-(methylamino)-1-phenylpentan-1-one (pentedrone) poisoning. A 28-year-old man was taken to hospital in asystole. Despite resuscitation efforts over 30 min, he died. The forensic autopsy showed pulmonary edema and moderately advanced atherosclerotic lesions of the arteries. Microscopic observation revealed chronic changes in the heart. Confirmation of the presence of pentedrone, alpha-PVP, and its metabolite 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-ol (OH-alpha-PVP) in tissues and fluids were achieved using gas chromatography-mass spectrometry analysis after liquid-liquid extraction. A quantitative validated liquid chromatography mass spectrometry method was used to determine the concentrations of the above designer drugs in postmortem samples. Pentedrone, alpha-PVP, and OH-alpha-PVP concentrations were 8,794, 901 and 185 ng/mL in whole blood, respectively; 100,044, 2,610 and 2,264 ng/g in the liver, respectively; 22,102, 462 and 294 ng/g in the kidney, respectively; 13,248, 120 and 91 ng/g in the brain, respectively and 500,534, 4,190 and 47 ng/g in the stomach contents, respectively. This is the first known reported death attributed to the combined use of alpha-PVP and pentedrone. Additionally, this article is the first to report the distribution of pentedrone in postmortem human samples. PMID- 25737340 TI - Inferior cancer outcomes more common for uninsured and Medicaid patients. PMID- 25737341 TI - Pressure-induced zigzag phosphorus chain and superconductivity in boron monophosphide. AB - We report on the prediction of the zinc-blende structure BP into a novel C2/m phase from 113 to 208 GPa which possesses zigzag phosphorus chain structure, followed by another P42/mnm structure above 208 GPa above using the particle swarm search method. Strong electron-phonon coupling lambda in compressed BP is found, in particular for C2/m phase with the zigzag phosphorus chain, which has the highest lambda (0.56-0.61) value among them, leading to its high superconducting critical temperature Tc (9.4 K-11.5 K), which is comparable with the 4.5 K to 13 K value of black phosphorus phase I (orthorhombic, Cmca). This is the first system in the boron phosphides which shows superconductivity from the present theoretical calculations. Our results show that pressure-induced zigzag phosphorus chain in BP exhibit higher superconducting temperature TC, opening a new route to search and design new superconductor materials with zigzag phosphorus chains. PMID- 25737342 TI - Transition, part 2. PMID- 25737343 TI - Implementation of an academic adult primary care clinic for adolescents and young adults with complex, chronic childhood conditions. AB - PURPOSE: For the growing population of adolescents and young adults with chronic childhood conditions (AYACCC), the transition from pediatric to adult health care contains many barriers and appropriate adult-based health care options are few. In 2005, the Transition Medicine Clinic (TMC), affiliated with Baylor College of Medicine, was established in Houston, Texas. It is one of the first clinics of its kind and serves AYACCC by providing a medical home in the adult health care system. This article describes the development and implementation of the TMC, its patient population and their resource needs, and lessons learned along the way. METHODS: We retrospectively examined the electronic health records of 332 patients that established care in the TMC prior to July, 2011. Data were collected describing multiple facets of the patient population and their resource utilization, both in aggregate and for several subgroups. RESULTS: The most common primary diagnoses were cerebral palsy, spina bifida, Down syndrome, genetic conditions, and autism. Patient characteristics demonstrated the unique challenges faced by the clinic: more than 80% received Medicaid, 65% had an intellectual disability, 41% used a wheelchair, and most had multiple secondary diagnoses. Compared to typical adult primary care practices, a larger amount of clinical resources, medical technology, and specialists were used, especially for those with the most medically fragile conditions. CONCLUSIONS: The results suggest that a clinic serving AYACCC requires physicians and support staff familiar with the aforementioned issues that are willing to spend a considerable amount of time and effort outside of routine office visits in health care coordination. Because many of these patients are covered by publicly funded health insurance, enhanced reimbursement must be considered to keep clinics like the TMC self-sustaining. Future research is needed to demonstrate adult-based care delivery models, develop clinical care guidelines, and evaluate key clinical outcomes. PMID- 25737344 TI - The relationship of health care transition readiness to disease-related characteristics, psychosocial factors, and health care outcomes: preliminary findings in adolescents with chronic kidney disease. AB - PURPOSE: The current study utilized the Disability-Stress-Coping Model to conceptualize how disease-related risk factors (disease severity, age of diagnosis, and disease burden) and psychosocial resilience factors (coping efficacy, family cohesion, and quality of life) influence health care transition (HCT) readiness when controlling for age and disease severity [1]. Additionally, the impact of low HCT readiness on emergency room visits and medication adherence was examined. METHODS: The sample was comprised of 41 adolescents with chronic kidney disease (CKD) who ranged in age from 13 to 18 years (Mean=15.7). Multiple regression analyses were conducted. RESULTS: None of the disease-related factors were associated with HCT readiness. Of the psychosocial factors, only family cohesion was a significant predictor and accounted for 10% unique variance. Transition readiness was significantly related to both the number of self reported emergency room visits and medication adherence such that high readiness was related to fewer visits to the emergency room and better medication adherence; these variables accounted for 6.4% and 14.9% of the unique variance respectively. CONCLUSION: These findings suggest that disease-related risk factors may be less critical to predicting transition readiness than resilience factors such as family cohesion. Additionally, when adolescents have low transition readiness they are likely to experience significant negative health outcomes. PMID- 25737345 TI - Transition outcomes for young adults with disabilities. AB - PURPOSE: Transition to adulthood can be very challenging for children with special health care needs (CSHCN) especially for those with disabilities who experience functional limitations in activities at home, in school, and in the community. The study examined the transition outcomes in areas of health, education, and independent living for young adult with special health care needs (YASHCN) with disabilities. METHOD: The study is a secondary data analysis of the 2007 Survey of Adult Transition and Health (SATH). Multivariate logistic regression analysis assessed the association between having disabilities and the transition outcomes. RESULTS: Overall, YASHCN with disabilities reported favorable health related transition outcomes with improved access to primary care, care coordination, and physician engagement in transition discussions and connection to mentors. Furthermore, YASCHN with disabilities had higher odds of receiving Medicaid or other insurance for low income or disabilities as an adult (AOR=5.26, 95% CI=3.74, 7.04). However, they were less likely to report having control over personal finances, making friends, and obtaining a high school diploma. CONCLUSION: The findings suggest that YASHCN with disabilities may be among the small proportion of CSHCNs who had a positive transition to adult health care services. However, transition outcomes related to independent living still need more improvements. PMID- 25737346 TI - Health care transition preparation in youth with chronic conditions: working towards translational evidence with a patient perspective. AB - Research in the health care transition (HCT) field has increasingly expanded in the last few decades. However, structured and more intensive examination of this field is needed to provide the best health care practices for youth with chronic health conditions. This commentary includes the views of a young adult with a chronic condition who has graduated to adult-focused services, his parent, and a group of interdisciplinary health providers. We examined the current evidence in the field and suggest prioritizing future directions for research and practice. The key factors in HCT are discussed, along with the current initiatives that are guiding policy, and propose suggestions for how to integrate the current research into practice. PMID- 25737347 TI - Transitioning youth to adult healthcare: new tools from the Illinois Transition Care Project. AB - PURPOSE: To improve youths' transition to adult healthcare, especially for youth with disabilities, The Illinois Transition Care Project created separate, yet complementary, curricula for pediatric and adult-oriented providers. METHODS: Content from the curricula was tested by practicing physicians. The project created a library of skill worksheets with functional goals for patients. All methods included opportunities to teach life skills to patients to independently manage their conditions. The curricula used Maintenance of Certification (MOC) Part 4 credit as an incentive for physician participation. RESULTS: Pediatric pilot data indicate improvement across all sites and activities. Adult medicine results indicate increased perceived importance and feasibility of accepting young adult patients with childhood conditions. Patient/parent reviewers indicate the tools are understandable, interesting, and effective. CONCLUSIONS: Findings suggest the curricula, with MOC Part 4 credit for physicians, are effective in improving transition care. Project results provided new information on population management for transitioning youth and on the use of MOC Part 4 credit as an incentive. Findings have implications for primary care and specialty physicians, team-based care, teaching self-management skills to patients and methods for engaging adult-oriented physicians in the transition process. PMID- 25737348 TI - Health care transition from pediatric care to adult care: opportunities and challenges under the Affordable Care Act. AB - Enrollment of young adults is foundational to the success of the Affordable Care Act (ACA). This article analyzes the implications for young adults transitioning from pediatric to adult care with the implementation of the ACA. We review the key characteristics of this population relevant to health care utilization and access as well as the impact of private insurance market reforms, health insurance marketplaces, Medicaid expansion, and workforce development provisions on this population. We then analyze how reform is impacting and will continue to impact specific populations of young adults, including individuals with disabilities, college students, immigrants, young adults who age out of the foster care system and individuals involved with the criminal justice system. Finally, we look at the socio-economic and political factors influencing outreach efforts, and make recommendations to maximize the benefits of the law for young adults to empower them to have access to care and financial security. PMID- 25737351 TI - Steady-State Spectroscopy of the 2-(N-methylacetimidoyl)-1-naphthol Molecule. AB - The steady-state spectroscopy of 2-(N-methylacetimidoyl)-1-naphthol (MAN) reveals composite absorption and emission spectra from 298 to 193 K in hexane. The ground electronic state (So) absorption can be assigned to the sum of three molecular structures: the OH normal tautomer, and two NH proton transfer tautomers. The NH structures are the most stable ones in equilibrium with the OH tautomer for the S0 state. On photoexcitation of the OH tautomer the excited state intramolecular proton transfer is undergone, and the corresponding NH emission is monitored at 470 nm. On photoexcitation of the NH tautomers the previous emission is monitored in addition to another emission at 600 nm, which is ascribed to intramolecular hydrogen-bonded (IHB) nonplanar NH structures generated from the IHB planar NH tautomers. A Jablonski diagram is introduced which gathers all the experimental evidence as well as the theoretical calculations executed at the DFT-B3LYP and TD DFT levels. The MAN molecule is compared with other analogs such as 1-hydroxy-2 acetonaphthone (HAN), 2-(1'-hydroxy-2'-naphthyl)benzimidazole and methyl 1 hydroxy-2-naphthoate to validate the theoretical calculations. Photoexcitation of MAN generates two emission bands at longer wavelengths than that of the emission band of HAN. The MAN molecule exhibits a great photostability in hydrocarbon solution which depends on the photophysics of the NH tautomers (keto forms). PMID- 25737352 TI - Blood Oxygen Saturation After Ischemia is Altered With Abnormal Microvascular Reperfusion. AB - OBJECTIVE: We have previously described a distinct abnormality in the cutaneous microcirculation that is characterized by an abnormal reperfusion response following an ischemic stimulus. We investigated the physiological significance of this abnormality; by measuring microvascular perfusion and blood oxygen saturation in groups stratified by three distinct reperfusion responses. METHODS: Cutaneous microvascular reperfusion after four minutes of arterial occlusion above the ankle was measured on the foot using laser Doppler fluximetry and optical reflectance spectroscopy in almost 400 adults. Individuals were stratified into three groups according to the microvascular reperfusion response: normal and two abnormal patterns (DEP and NDEP). RESULTS: Our main findings were that abnormal microvascular reperfusion responses (DEP and NDEP) had a higher baseline oxygen saturation (p = 0.005), a lower plateau in oxygen saturation (p < 0.0001 and <0.0001, respectively), lower oxygen saturation area under the curve (p < 0.0001 and <0.0001), a longer time to reach oxygen saturation plateau (p = 0.002 and 0.001), and a longer time to initiate an increase in oxygen saturation (p = 0.007 and 0.001) compared to normal. Differences remained after adjustment for confounding variables. CONCLUSIONS: Individuals with abnormal microvascular reperfusion had a markedly altered pattern of oxygen increase during reperfusion. We propose that this may represent dysfunctional microvascular autoregulation that is clinically important in the etiopathology of target organ damage. PMID- 25737356 TI - Soft matter: from structure to functionality. PMID- 25737362 TI - Subependymoma of septum pellucidum presenting with cough and exertional headache: a case report of spontaneous regression after incomplete surgical removal. PMID- 25737363 TI - Isolated intramedullary cervical spinal cord metastasis from colon cancer: a surgical or medical challenge? PMID- 25737364 TI - Transnasal andtransoral approach to the clivus and the craniovertebral junction. AB - Endoscopy represents a useful complement to the standard microsurgical approach to the anterior cranioveretebral junction CVJ and can be used by transnasal, transoral and transcervical routes; it provides information for a better decompression with no need for soft palate splitting, hard palate resection, or extended maxillotomy. Although neuronavigation allows a better orientation on the surgical field, intraoperative fluoroscopy helps to recognize residual compression. Virtually, in normal anatomic conditions, no surgical limitations exist for endoscopically assisted transoral approach, compared with the pure endonasal and transcervical endoscopic approaches. According to the personal experience in the cadaver lab, the endoscope deserves an interesting role as "support" to the standard transoral microsurgical approach, since 30 degrees angulated endoscopy strongly increase the surgical area exposed over the posterior pharyngeal wall and the extent of the clivus. Moreover, compared to the pure transnasal endoscopic procedure, it deserves the main role due to the wider linear and angled surgical route exposure. PMID- 25737365 TI - Mixing with herringbone-inspired microstructures: overcoming the diffusion limit in co-laminar microfluidic devices. AB - Enhancing mixing is of uttermost importance in many laminar microfluidic devices, aiming at overcoming the severe performance limitation of species transport by diffusion alone. Here we focus on the significant category of microscale co laminar flows encountered in membraneless redox flow cells for power delivery. The grand challenge is to achieve simultaneously convective mixing within each individual reactant, to thin the reaction depletion boundary layers, while maintaining separation of the co-flowing reactants, despite the absence of a membrane. The concept presented here achieves this goal with the help of optimized herringbone flow promoting microstructures with an integrated separation zone. Our electrochemical experiments using a model redox couple show that symmetric flow promoter designs exhibit laminar to turbulent flow behavior, the latter at elevated flow rates. This change in flow regime is accompanied by a significant change in scaling of the Sherwood number with respect to the Reynolds number from Sh ~ Re(0.29) to Sh ~ Re(0.58). The stabilized continuous laminar flow zone along the centerline of the channel allows operation in a co-laminar flow regime up to Re ~325 as we demonstrate by micro laser-induced fluorescence (MULIF) measurements. Micro particle image velocimetry (MUPIV) proves the maintenance of a stratified flow along the centerline, mitigating reactant cross over effectively. The present work paves the way toward improved performance in membraneless microfluidic flow cells for electrochemical energy conversion. PMID- 25737366 TI - Monohydroxylated polycyclic aromatic hydrocarbons influence spicule formation in the early development of sea urchins (Hemicentrotus pulcherrimus). AB - We previously demonstrated that monohydroxylated polycyclic aromatic hydrocarbons (OHPAHs), which are metabolites of polycyclic aromatic hydrocarbons (PAHs), act on calcified tissue and suppress osteoblastic and osteoclastic activity in the scales of teleost fish. The compounds may possibly influence other calcified tissues. Thus, the present study noted the calcified spicules in sea urchins and examined the effect of both PAHs and OHPAHs on spicule formation during the embryogenesis of sea urchins. After fertilization, benz[a]anthracene (BaA) and 4 hydroxybenz[a]anthracene (4-OHBaA) were added to seawater at concentrations of 10(-8) and 10(-7) M and kept at 18 degrees C. The influence of the compound was given at the time of the pluteus larva. At this stage, the length of the spicule was significantly suppressed by 4-OHBaA (10(-8) and 10(-7) M). BaA (10(-7) M) decreased the length of the spicule significantly, while the length did not change with BaA (10(-8) M). The expression of mRNAs (spicule matrix protein and transcription factors) in the 4-OHBaA (10(-7) M)-treated embryos was more strongly inhibited than were those in the BaA (10(-7) M)-treated embryos. This is the first study to demonstrate that OHPAHs suppress spicule formation in sea urchins. PMID- 25737367 TI - Development of inductive generalization with familiar categories. AB - Inductive generalization is ubiquitous in human cognition. In the developmental literature, two different theoretical accounts of this important process have been proposed: a naive theory account and a similarity-based account. However, a number of recent findings cannot be explained within the existing theoretical accounts. We describe a revised version of the similarity-based account of inductive generalization with familiar categories. We tested the novel predictions of this account in two reported studies with 4-year-old children (N = 57). The reported studies include the first short-term longitudinal investigation of the development of children's induction with familiar categories, and it is the first study to explore the role of individual differences in semantic organization, general intelligence, working memory, and inhibition in children's induction. PMID- 25737368 TI - Recent developments in the trifluoromethylation of alkynes. AB - In the last few years, the development of versatile methodologies to incorporate trifluoromethyl groups into organic molecules has attracted significant attention in synthetic chemistry. This review gives an overview over the development on the trifluoromethylation of alkynes, which have not been solely discussed before. Formation of diverse C(sp, sp(2) , sp(3) )-CF3 bonds are all covered in this review. PMID- 25737369 TI - AnaSP: a software suite for automatic image analysis of multicellular spheroids. AB - Today, more and more biological laboratories use 3D cell cultures and tissues grown in vitro as a 3D model of in vivo tumours and metastases. In the last decades, it has been extensively established that multicellular spheroids represent an efficient model to validate effects of drugs and treatments for human care applications. However, a lack of methods for quantitative analysis limits the usage of spheroids as models for routine experiments. Several methods have been proposed in literature to perform high throughput experiments employing spheroids by automatically computing different morphological parameters, such as diameter, volume and sphericity. Nevertheless, these systems are typically grounded on expensive automated technologies, that make the suggested solutions affordable only for a limited subset of laboratories, frequently performing high content screening analysis. In this work we propose AnaSP, an open source software suitable for automatically estimating several morphological parameters of spheroids, by simply analyzing brightfield images acquired with a standard widefield microscope, also not endowed with a motorized stage. The experiments performed proved sensitivity and precision of the segmentation method proposed, and excellent reliability of AnaSP to compute several morphological parameters of spheroids imaged in different conditions. AnaSP is distributed as an open source software tool. Its modular architecture and graphical user interface make it attractive also for researchers who do not work in areas of computer vision and suitable for both high content screenings and occasional spheroid-based experiments. PMID- 25737370 TI - Characterization of oxygenated metabolites of ginsenoside Rb1 in plasma and urine of rat. AB - Oxygenated metabolites have been suggested as the major circulating metabolites of ginsenosides. In the current study, 10 oxygenated metabolites of ginsenoside Rb1 in plasma and urine of rat following iv dose were characterized by comparison with chemically synthesized authentic compounds as quinquenoside L16 (M1 and M2), notoginsenoside A (M3), ginsenoside V (M4 and M7), epoxyginsenoside Rb1 (M5 and M9), notoginsenoside K (M6), and notoginsenoside C (M8 and M10), 9 of which were detected as in vivo metabolites for the first time. After oral administration of ginsenoside Rb1, M3, M4, and M7 were observed as major circulating metabolites and presented in the bloodstream of rat for 24 h. Characterization of the exact chemical structures of these circulating metabolites could contribute greatly to our understanding of chemical exposure of ginsenosides after consumption of ginseng products and provide valuable information for explaining multiple bioactivities of ginseng products. PMID- 25737371 TI - Psychopharmacologic treatment of children prenatally exposed to drugs of abuse. AB - OBJECTIVE: This pilot study compared the pharmacologic treatment history and clinical outcomes observed in pediatric outpatients with psychiatric disorders exposed to drugs of abuse in utero to those of an age-matched, sex-matched and psychiatric disorder-matched, non-drug-exposed group. METHODS: In this matched cohort study, medical records of children treated at an academic, child and adolescent psychiatry outpatient clinic were reviewed. Children with caregiver reported history of prenatal drug exposure were compared with a non-drug-exposed control group being cared for by the same providers. Patients were rated with the Clinical Global Impressions-Severity scale (CGI-S) throughout treatment. The changes in pre-treatment and post-treatment CGI-S scores and the total number of medication trials were determined between groups. RESULTS: The drug-exposed group (n = 30) had a higher total number of lifetime medication trials compared with the non-drug-exposed group (n = 28) and were taking significantly more total medications, at their final assessment. Unlike the non-drug-exposed group, the drug-exposed group demonstrated a lack of clinical improvement. CONCLUSIONS: These results suggest that in utero drug-exposed children may be more treatment refractory to or experience greater side effects from the pharmacologic treatment of psychiatric disorders than controls, although we cannot determine if early environment or drugs exposure drives these findings. PMID- 25737372 TI - The psychosocial response to the ebola health emergency: experience in Madrid, Spain. PMID- 25737373 TI - As far as travelers' risk of acquiring resistant intestinal microbes is considered, no antibiotics (absorbable or nonabsorbable) are safe. PMID- 25737374 TI - Impact of the Timing of Initiation of Antiretroviral Therapy During Primary HIV-1 Infection on the Decay of Cell-Associated HIV-DNA. AB - BACKGROUND: Combined antiretroviral therapy (cART) initiation during primary human immunodeficiency virus (HIV) infection (PHI) yields a larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the timing of cART initiation on CA-HIV-DNA decay. METHODS: We included patients enrolled during PHI in the Agence Nationale de Recherche sur le Sida PRIMO cohort, treated within the month following enrollment and achieving sustained virologic response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation. RESULTS: Three hundred twenty-seven patients were included, accounting for 1305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (interquartile range, 33-54 days). Median follow-up under cART was 2.3 years (range, 0.4-16.6 years). The timing of cART initiation had significant impact on the first slope of decrease: The earlier cART was initiated after HIV infection, the faster CA-HIV-DNA level decreased during the first 8 months of cART: -0.171, 0.131, and -0.068 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs) per month when cART was initiated 15 days, 1 month, and 3 months after infection, respectively (P < .0001). The predicted mean CA-HIV-DNA level achieved after 5 years of successful cART was 1.62 and 2.24 log10 copies/10(6) PBMCs when cART was initiated 15 days and 3 months after infection, respectively (P = .0006). CONCLUSIONS: This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection. PMID- 25737375 TI - Effectiveness of gentamicin-containing collagen sponges for prevention of surgical site infection after hip arthroplasty: a multicenter randomized trial. AB - BACKGROUND: Surgical site infection (SSI) is a feared complication in hip arthroplasty, especially following femoral neck fracture in the elderly, associated with substantially increased morbidity, mortality, and costs. Gentamicin-containing collagen sponges are widely used for prevention of SSIs, but their effectiveness in joint replacement surgery remains unclear. METHODS: We performed a multicenter, randomized trial between February 2011 and July 2013. Eligible patients with femoral neck fracture undergoing hemiarthroplasty were randomly assigned to receive either intravenous antimicrobial prophylaxis alone or with the addition of 2 gentamicin-containing collagen sponges into the hip joint perioperatively. The primary end point was SSI according to the Centers for Disease Control and Prevention criteria within 30 days after surgery. RESULTS: Seven hundred thirty-nine patients were randomly assigned, 684 of whom were included in the modified intention-to-treat analysis. There was no statistical significant difference in SSI between the gentamicin-collagen group (16 of 329 patients [4.9%]) and the control group (19 of 355 patients [5.4%]) (relative risk [RR], 0.91 [95% confidence interval, .48-1.79]; P = .77). No significant differences were observed between the groups in superficial SSI (2 of 329 [0.6%] vs 3 of 355 [0.8%]; P = .99) and deep SSI (14 of 329 [4.3%] vs 16 of 355 [4.5%]; P = .87). There were no significant differences between the groups regarding type of bacteria isolated. CONCLUSIONS: Locally administered gentamicin-collagen sponges did not reduce the incidence of SSI in elderly patients treated with a hemiarthroplasty because of femoral neck fracture. CLINICAL TRIALS REGISTRATION: NCT01287780. PMID- 25737376 TI - Antibody concentrations against the infecting serotype in vaccinated and unvaccinated children with invasive pneumococcal disease in the United Kingdom, 2006-2013. AB - BACKGROUND: This study aimed to estimate, following invasive pneumococcal disease (IPD), the proportion of children with protective immunoglobulin G (IgG) concentrations against the infecting serotype compared with other vaccine serotypes, and to assess risk of recurrent IPD. METHODS: Pneumococcal antibody concentrations were available for 413 children with vaccine-type IPD diagnosed during 2006-2013. We compared serotype-specific IgG concentrations against the infecting vs other vaccine serotypes, after adjusting for confounders such as age using multilevel analyses. RESULTS: After IPD, a higher proportion of vaccine naive children had IgG concentrations >=0.35 ug/mL against their infecting serotype than other vaccine serotypes (51% vs 36%; P < .001). In contrast, among children immunized with pneumococcal conjugate vaccine (PCV) both before and after IPD, the proportion with IgG concentrations >=0.35 ug/mL against the infecting serotype was lower compared with other vaccine serotypes (71% vs 98%; P < .001). These children also had lower IgG geometric mean concentrations (GMCs) against the infecting serotype (2.22 ug/mL) vs other vaccine serotypes (15.64 ug/mL) in multilevel models (IgG GMC ratio, 0.24; 95% confidence interval, .18 .32), although their IgG GMC was higher compared with vaccine-naive children. Vaccinated children with IgG concentrations <0.35 ug/mL against their infecting serotype generally remained unresponsive despite further vaccine doses. However, recurrent IPD with the same infecting serotype was rare (7/3030 children [0.2%]) and not associated with unresponsiveness. CONCLUSIONS: Vaccination with PCV before and/or after IPD was associated with lower IgG concentrations against the infecting serotype compared with other vaccine serotypes, but recurrent IPD was rare. Further studies are needed to understand this phenomenon in immunized children. PMID- 25737377 TI - Implementation of integrated therapies for comorbid post-traumatic stress disorder and substance use disorders in community substance abuse treatment programs. AB - ISSUES: The high prevalence of trauma and post-traumatic stress disorder (PTSD) in individuals with substance use disorders (SUDs) presents a number of treatment challenges for community treatment providers and programs in the USA. Although several evidence-based, integrated therapies for the treatment of comorbid PTSD/SUD have been developed, rates of utilisation of such practices remain low in community treatment programs. APPROACH: The goal of this article was to review the extant literature on common barriers that prevent adoption and implementation of integrated treatments for PTSD/SUD among substance abuse community treatment programs. KEY FINDINGS: Organisational, provider-level and patient-level factors that drive practice decisions were discussed, including organisational philosophy of care policies, funding and resources, as well as provider and patient knowledge and attitudes related to implementation of new integrated treatments for comorbid PTSD and SUD. IMPLICATIONS AND CONCLUSIONS: Understanding and addressing these community treatment challenges may facilitate use of evidence based integrated treatments for comorbid PTSD and SUD. PMID- 25737378 TI - Carbon ion beam treatment in patients with primary and recurrent sacrococcygeal chordoma. AB - PURPOSE: The purpose of this work was to evaluate the results of high-dose radiation treatment using carbon ion therapy, alone or combined with intensity modulated radiation treatment (IMRT), in patients with sacral chordoma. MATERIALS AND METHODS: Between 2009 and 2012, 56 patients with sacral chordoma were treated in our center. The tumor was located above S3 in 33 patients and in S3 or below in 23 patients. In all, 41 patients received radiation therapy for the primary tumor, while 15 patients were treated for the recurrent tumor. Toxicity was measured using NCI CTCAE v.4.03. Local control (LC) and overall survival (OS) were evaluated with the Kaplan-Meier method. RESULTS: A total of 23 patients were irradiated with carbon ions in combination with photon IMRT, while 33 received carbon ion therapy only. Forty-three patients had a macroscopic tumor at treatment start with a median tumor size (GTV) of 244 ml (range 5-1188 ml). The median total dose was 66 Gy (range 60-74 Gy; RBE). After a median follow-up time of 25 months, the 2- and 3-year local control probability was 76 % and 53 %, respectively. The overall survival rate was 100 %. Treatment for primary tumor and male patients resulted in significant better local control. No higher toxicity occurred within the follow-up time. CONCLUSION: High-dose photon/carbon ion beam radiation therapy is safe and, especially for primary sacral chordomas, highly effective. A randomized trial is required to evaluate the role of primary definitive hypofractionated particle therapy compared with surgery with or without adjuvant radiotherapy. PMID- 25737379 TI - Forecasting the Effect of the Change in Timing of the ABR Diagnostic Radiology Examinations: Results of the ACR Survey of Practice Leaders. AB - The results of a survey sent to practice leaders in the ACR Practice of Radiology Environment Database show that the majority of responding groups will continue to hire recently trained residents and fellows even though they have been unable to take the final ABR diagnostic radiology certifying examination. However, a significant minority of private practice groups will not hire these individuals. The majority of private practices expect the timing change for the ABR certifying examinations to affect their groups' function. In contrast, the majority of academic medical school practices expect little or no impact. Residents and fellows should not expect work time off or protected time to study for the certifying examination or for their maintenance of certification examinations in the future. PMID- 25737380 TI - Lynch syndrome: five unanswered questions. PMID- 25737382 TI - Passive restriction of blood flow and counter-current heat exchange via lingual retia in the tongue of a neonatal gray whale Eschrichtius robustus (Cetacea, Mysticeti). AB - Retia mirabilia play broad roles in cetacean physiology, including thermoregulation during feeding and pressure regulations during diving. Vascular bundles of lingual retia are described within the base of the tongue of a neonatal female gray whale (Eschrichtius robustus). Each rete consists of a central artery surrounded by four to six smaller veins. The retia and constituent vessels decrease in diameter as they extend anteriorly within the hyoglossus muscle from a position anterior to the basihyal cartilage toward the apex of the tongue. The position of the retia embedded in the hyoglossus and the anterior constriction of the vessels differs from reports of similar vascular bundles that were previously identified in gray whales. The retia likely serve as a counter current heat exchange system to control body temperature during feeding. Cold blood flowing toward the body center within the periarterial veins would accept heat from warm blood in the central artery flowing toward the anterior end of the tongue. Although thermoregulatory systems have been identified within the mouths of a few mysticete species, the distribution of such vascular structures likely is more widespread among baleen whales than has previously been described. PMID- 25737381 TI - Climate change alters leaf anatomy, but has no effects on volatile emissions from Arctic plants. AB - Biogenic volatile organic compound (BVOC) emissions are expected to change substantially because of the rapid advancement of climate change in the Arctic. BVOC emission changes can feed back both positively and negatively on climate warming. We investigated the effects of elevated temperature and shading on BVOC emissions from arctic plant species Empetrum hermaphroditum, Cassiope tetragona, Betula nana and Salix arctica. Measurements were performed in situ in long-term field experiments in subarctic and high Arctic using a dynamic enclosure system and collection of BVOCs into adsorbent cartridges analysed by gas chromatography mass spectrometry. In order to assess whether the treatments had resulted in anatomical adaptations, we additionally examined leaf anatomy using light microscopy and scanning electron microscopy. Against expectations based on the known temperature and light-dependency of BVOC emissions, the emissions were barely affected by the treatments. In contrast, leaf anatomy of the studied plants was significantly altered in response to the treatments, and these responses appear to differ from species found at lower latitudes. We suggest that leaf anatomical acclimation may partially explain the lacking treatment effects on BVOC emissions at plant shoot-level. However, more studies are needed to unravel why BVOC emission responses in arctic plants differ from temperate species. PMID- 25737383 TI - Biological sulphide removal from anaerobically treated domestic sewage: reactor performance and microbial community dynamics. AB - We developed a biological sulphide oxidation system and evaluated two reactors (shaped similar to the settler compartment of an up-flow anaerobic sludge blanket [UASB] reactor) with different support materials for biomass retention: polypropylene rings and polyurethane foam. The start-up reaction was achieved using microorganisms naturally occurring on the open surface of UASB reactors treating domestic wastewater. Sulphide removal efficiencies of 65% and 90% were achieved with hydraulic retention times (HRTs) of 24 and 12 h, respectively, in both reactors. However, a higher amount of elemental sulphur was formed and accumulated in the biomass from reactor 1 (20 mg S(0) g(-1) VTS) than in that from reactor 2 (2.9 mg S(0) g(-1) VTS) with an HRT of 24 h. Denaturing gradient gel electrophoresis (DGGE) results revealed that the the pink and green biomass that developed in both reactors comprised a diverse bacterial community and had sequences related to phototrophic green and purple-sulphur bacteria such as Chlorobium sp., Chloronema giganteum, and Chromatiaceae. DGGE band patterns also demonstrated that bacterial community was dynamic over time within the same reactor and that different support materials selected for distinct bacterial communities. Taken together, these results indicated that sulphide concentrations of 1-6 mg L(-1) could be efficiently removed from the effluent of a pilot-scale UASB reactor in two sulphide biological oxidation reactors at HRTs of 12 and 24 h, showing the potential for sulphur recovery from anaerobically treated domestic wastewater. PMID- 25737384 TI - Patellar Fracture Following Patellofemoral Arthroplasty. AB - This study aims to report the incidence of patellar fracture after patellofemoral arthroplasty (PFA) and to determine associated factors as well as outcomes of patients with and without this complication. 77 knees in 59 patients with minimum two-year follow-up were included. Seven (9.1%) patients experienced a patellar fracture at a mean of 34 (range 16-64) months postoperatively. All were treated nonoperatively. Lower BMI (P = 0.03), change in patellar thickness (P < 0.001), amount of bone resected (P = 0.001), and larger trochlear component size (P = 0.01) were associated with a greater incidence of fracture. Fewer fractures occurred when the postoperative patellar height exceeded the preoperatively measured height. No statistically significant differences were found in outcome scores between groups at mean four-year follow-up. PMID- 25737385 TI - Updating Cost Effectiveness Analyses in Orthopedic Surgery: Resilience of the $50,000 per QALY Threshold. AB - Attention is being paid in the United States (U.S.) to defining and measuring the value of interventions in healthcare. Traditionally, $50,000 per QALY gained has been the accepted "cost-effectiveness threshold" with which cost effectiveness is defined. The validity of this threshold has been called into question largely due to inexact origins; absence of inflationary adjustments and lack of consideration for high gross domestic product of the U.S. POPULATION: There is an opportunity to reassess how we interpret cost utility analyses and the ratios published therein. Orthopedic surgery has typically lagged behind other fields of medicine in self-advocacy and the adoption/implementation of health economic theory. We argue for tiered QALY thresholds of $50,000, $100,000 and $150,000 corresponding respectively to Governmental, Societal and Health systems analysis perspectives. PMID- 25737386 TI - A High Prevalence of Corrosion at the Head-Neck Taper with Contemporary Zimmer Non-Cemented Femoral Hip Components. AB - Mechanically assisted crevice corrosion (MACC) occurs at metal/metal modular junctions in which at least one of the components is fabricated from cobalt chromium alloy and may lead to adverse local tissue reaction (ALTR) in patients with metal-on-polyethylene (MoP) total hip arthroplasty. This type of reaction has been previously described in hips with head/neck modularity, but the prevalence is unknown. We found a prevalence of 1.1 percent in a consecutive series of 1356 contemporary Zimmer non-cemented femoral hip components followed for a minimum of 2years. The average time to presentation was 3.7years (range, 9 105months); delay in treatment led to irreversible soft tissue damage in three patients. We recommend usage of ceramic heads until this problem is further understood. PMID- 25737387 TI - The Time Course of Knee Swelling Post Total Knee Arthroplasty and Its Associations with Quadriceps Strength and Gait Speed. AB - This study examines the time course of knee swelling post total knee arthroplasty (TKA) and its associations with quadriceps strength and gait speed. Eighty-five patients with unilateral TKA participated. Preoperatively and on post-operative days (PODs) 1, 4, 14, and 90, knee swelling was measured using bioimpedance spectrometry. Preoperatively and on PODs 14 and 90, quadriceps strength was measured using isokinetic dynamometry while fast gait speed was measured using the timed 10-meter walk. On POD1, knee swelling increased ~35% from preoperative levels after which, knee swelling reduced but remained at ~11% above preoperative levels on POD90. In longitudinal, multivariable analyses, knee swelling was associated with quadriceps weakness (P<0.01) and slower gait speed (P=0.03). Interventions to reduce post-TKA knee swelling may be indicated to improve quadriceps strength and gait speed. PMID- 25737388 TI - The Valgus Stress Radiograph Does Not Determine the Full Extent of Correction of Deformity Prior to Medial Unicompartmental Knee Arthroplasty. AB - Routine preoperative stress radiographs have been advocated, in part, to determine "full correctability" of deformities before proceeding with unicompartmental knee arthroplasty (UKA) despite limited data supporting their utility. Fifty consecutive patients undergoing medial UKA with robotic navigation were studied. In 20 degrees of flexion, significantly greater correctability was achieved after removal of osteophytes by an additional 1.8 degrees , with a mean corrected alignment of 2.5 degrees varus. Seventy-four percent of knees were not correctable to neutral alignment or more. In conclusion, preoperative stress radiographs have overstated value in patients undergoing medial UKA since the full extent of correctability of varus deformity cannot be determined until after removal of osteophytes and since most deformities are not fully correctable to neutral in UKA. PMID- 25737389 TI - Bilateral Total Hip Arthroplasty has Similar Complication Rates to Unilateral Total Hip Arthroplasty. AB - Simultaneous bilateral THA has several advantages over staged THA, however its safety has not been well examined. This study reports a statewide 15-year experience of simultaneous bilateral THA and compares its complications to those of unilateral THA. Logistic regression was used to determine the role of bilateral surgery as a predictor of complications while correcting for patient comorbidities. Of 202,986 patients, 1.1% underwent bilateral THA. Bilateral THA was more commonly performed in males, younger patients, those with private insurance, and at higher volume hospitals. There was no difference in 30-day readmissions or revision surgeries. There was a higher rate of sepsis in the bilateral group but no difference in other complications. This study demonstrates that THA is a safe option in appropriately selected patients. PMID- 25737390 TI - Synthesis of a platinum diketonate-containing polymer showing oxygen-resistant phosphorescence. AB - The synthesis of a platinum diketonate-based alternating copolymer containing a fluorene unit and its oxygen-resistant phosphorescence are reported. The polymerization is executed via palladium-catalyzed Suzuki-Miyaura coupling reaction. The synthesized polymer shows good solubility in common organic solvents and processability to form homogeneous films. By optical measurements it is found that the synthesized polymer shows phosphorescence from a triplet pi-pi* ligand-centered transition, and interestingly, the emission is hardly influenced by oxygen. Phosphorescence is observed from both solution and film samples under aerobic conditions. The new idea of obtaining emissive materials based on conjugated polymers showing oxygen-resistant phosphorescence is presented here. PMID- 25737391 TI - A retrospective study of medical comorbidities in psychogeriatric patients. AB - BACKGROUND: This study contributes further research into the assessment and treatment of older psychiatric patients with medical comorbidities. METHODS: A retrospective file audit was conducted at the acute inpatient psychogeriatric unit of St Vincent's Aged Mental Health Service, Melbourne, in order to determine the prevalence of certain medical comorbidities and the nature of medical interventions provided for psychogeriatric inpatients. RESULTS: This study, investigating 165 admissions into an acute inpatient psychogeriatric unit, highlights that psychiatric and medical comorbidities are routine in this population: the vast majority (91.5%) of all inpatients had at least one medical comorbidity. CONCLUSIONS: As the population ages, psychogeriatric wards are likely to see more of the oldest-olds, who are likely to have comorbid medical illnesses. Currently, appropriate detection, investigation, and management of these illnesses are often suboptimal and can affect quality of life, increase mortality, and complicate treatment. This paper adds to the literature about the need for integrating medical and psychiatric care to create a more comprehensive strategy for treating the older person with psychiatric illness. PMID- 25737392 TI - Role of morality in the experience of guilt and shame within the armed forces. AB - OBJECTIVE: Despite advances in our understanding of mental health issues among military forces, a large proportion of military personnel continue to exhibit deployment-related psychological issues. Recent work has identified symptoms of guilt and shame related to moral injury as contributing significantly to combat related mental health issues. This systematic scoping review explores the association between morality and symptoms of guilt and shame within military forces. METHOD: A search of the literature pertaining to guilt, shame and morality within military samples was conducted. RESULTS: Nineteen articles were selected for review. There is strong evidence linking exposure to and the perceived perpetration of moral transgressions with experiences of guilt and shame. Critically, symptoms of guilt and shame were related to adverse mental health outcomes, particularly the onset of post-traumatic stress disorder (PTSD). No studies have explored moral judgment in conjunction with assessments of guilt or moral injury. CONCLUSION: These findings have important implications for the prevention and treatment of PTSD-related symptoms in military samples. By measuring moral judgment prior to deployment, it may be possible to predict the likelihood of incurring moral injuries and the development of associated symptoms. Early intervention programmes aimed at ameliorating guilt and shame are required to prevent the long-term development of deployment-related psychological distress. PMID- 25737393 TI - Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2. AB - BACKGROUND: Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. METHODS AND RESULTS: We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5*10(-8); rs12143842, P=4.8*10(-7); and rs2880058, P=8.6*10(-7)) were strongly associated with the QTc interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3*10(-4)) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5*10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS(NOS1AP)) uncovered a strong linear relationship between GRS(NOS1AP) and the QTc-interval (P=4.2*10(-7)). Furthermore, patients with a GRS(NOS1AP) in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039). CONCLUSIONS: We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome. PMID- 25737395 TI - Thrombocytopenia due to hypersplenism in oncological disease: partial splenic embolization during palliative treatment. AB - Hypersplenism is excess activity of the spleen, resulting in peripheral pancytopenia that predominates in platelet cell lines. Pancytopenia can be limited by reducing the volume of the functional spleen. However, in patients in very poor general condition, a splenectomy may not be possible, due to the risks of surgery and postoperative infection. Another therapeutic alternative in these patients is to reduce the volume of the spleen by super selective percutaneous splenic embolization. We report three cases of peripheral thrombocytopenia due to hypersplenism with a platelet count between 60,000 and 80,000/mm(3), which made it impossible to continue or start a chemotherapy protocol in these patients. For these patients, super selective partial embolization of the splenic parenchyma, with uncharged microspheres (250 microns) quickly resulted in a platelet count above 150,000/mm(3) so that chemotherapy could be continued or initiated. PMID- 25737394 TI - Prognostic implications of low level cardiac troponin elevation using high sensitivity cardiac troponin T. AB - BACKGROUND: High-sensitivity cardiac troponin T (hsTnT) is used in many countries, but is not available in the United States. Prior evidence has been viewed as inconclusive as to whether low cardiac troponin T (cTnT) concentrations detected with hsTnT are prognostically meaningful compared with fourth-generation cTnT. HYPOTHESIS: The aim of this study was to assess the prognostic performance of low-level cTnT elevations using the hsTnT assay compared with the assay (fourth-generation) currently available in the United States. METHODS: We measured serum cTnT in 4160 patients with non-ST-elevation acute coronary syndrome using both the hsTnT and fourth-generation assays. Patients were stratified at the 99th percentile cut point for each assay. RESULTS: Patients with baseline hsTnT >=14 ng/L (n = 3697) vs <14 ng/L were at higher 30-day risk of cardiovascular death (CVD) or myocardial infarction (MI) (9.1% vs 1.9%, P < 0.0001). After adjusting for all other elements of the Thrombolysis In Myocardial Infarction risk score, hsTnT >=14 carried a 5.2-fold higher risk of CVD/MI (95% confidence interval [CI]: 2.6-10.1, P < 0.0001). Low levels of hsTnT (14-50 ng/L) also revealed increased risk (CVD/MI: 6.4%, P = 0.002). Importantly, patients with negative fourth-generation cTnT but positive hsTnT were at 4.5-times higher risk of CVD/MI (95% CI: 1.9-11.0, P = 0.0008) than patients with negative hsTnT. In contrast, patients with a negative hsTnT but positive fourth-generation cTnT result had a lower rate of CVD/MI than with a positive hsTnT (1.3% vs 8.2%, P = 0.0005). CONCLUSIONS: Low-level increases in cTnT detected using the hsTnT assay identified patients at a meaningfully higher risk and who might otherwise be missed, and improves upon risk stratification using the cTnT assay currently available in the United States. PMID- 25737396 TI - Polymeric micelle assembly with inorganic nanosheets for construction of mesoporous architectures with crystallized walls. AB - Here we propose a novel way to construct mesoporous architectures through evaporation-induced assembly of polymeric micelles with crystalline nanosheets. As a model study, we used niobate nanosheets exfoliated by the direct reaction of K4Nb6O17?3 H2O crystals with an aqueous solution of propylamine. The electrostatic interaction between negatively charged nanosheets and positively charged polymeric micelles enable us to form composite micelles with the nanosheets. Removal of the micelles by calcination results in robust mesoporous oxides with the original crystalline structure. PMID- 25737397 TI - Alginate microparticles loaded with lipopolysaccharide subunit antigen for mucosal vaccination against Klebsiella pneumoniae. AB - Klebsiella pneumoniae (K. pneumoniae) is one of the commonest causes of nosocomial infections in human beings. Since K. pneumoniae infections are air borne type, controlling it by mucosal vaccination through nasal and pulmonary route could be a promising approach in order to simulate the natural infection. New vaccines such as subunit vaccines are safer than traditional vaccines, but they are less immunogenic. Therefore to enhance their immunogenicity, there is a need to develop potent and safe adjuvants and delivery systems. It has been established that micro-particles are one of the most potent adjuvants available for mucosal delivery of vaccines and they do so by improving uptake of encapsulated antigen by antigen presenting cells (APCs). Lipopolysaccharide (LPS), the antigenic fraction was extracted from K. pneumoniae by hot phenol extraction method. LPS loaded sodium alginate microparticles were prepared by emulsion ionic gelation method. Microparticles with particle size less than 5 MUm were obtained. Loading efficiency of the LPS loaded microparticles ranged from 76 to 82 %. Comparative in vivo immunogenicity studies were carried for free LPS and encapsulated LPS, administered via intramuscular, intratracheal and intranasal routes in Swiss albino mice. The study revealed that LPS encapsulated microparticles exhibit greater efficacy when administered by intra-tracheal route as compared to free LPS vaccine. PMID- 25737399 TI - Mosaic overgrowth with fibroadipose hyperplasia due to AKT1 mutation. PMID- 25737398 TI - Biomarkers of cognitive decline in Parkinson's disease. AB - Cognitive impairment is a frequent and devastating non-motor symptom of Parkinson's disease (PD). Impaired cognition has a major impact on either quality of life or mortality in patients with PD. Notably, the rate of cognitive decline and pattern of early cognitive deficits in PD are highly variable between individuals. Given that the underlying mechanisms of cognitive decline or dementia associated with PD remain unclear, there is currently no mechanism-based treatment available. Identification of biological markers, including neuroimaging, biofluids and common genetic variants, that account for the heterogeneity of PD related cognitive decline could provide important insights into the pathological processes that underlie cognitive impairment in PD. These combined biomarker approaches will enable early diagnosis and provide indicators of cognitive progression in PD patients. This review summarizes recent advances in the development of biomarkers for cognitive impairments in PD. PMID- 25737400 TI - Synthesis, structural analysis and antitumor activity of novel 17alpha-picolyl and 17(E)-picolinylidene A-modified androstane derivatives. AB - The heterocyclic ring at C-17 position of the androstane compounds plays an important role in biological activity. The aim of the present study was to synthesize and evaluate potential antitumor activity of different A-modified 17alpha-picolyl and 17(E)-picolinylidene androstane derivatives. In several synthetic steps, novel derivatives bearing the hydroximino, nitrile or lactame functions in A-ring were synthesized and characterized according to the spectral data, by mass analysis as well as XRD analysis (compounds 6, 13 and 15). The structurally most promising compounds 6, 11-17 were investigated as antitumor agents. The in vitro antiproliferative activity was evaluated against six human cancer cell lines: estrogen receptor negative (ER-) breast adenocarcinoma (MDA-MB 231); estrogen receptor positive (ER+) breast adenocarcinoma (MCF-7); prostate cancer (PC-3); human cervical carcinoma (HeLa); lung adenocarcinoma (A549) and colon adenocarcinoma (HT-29) using MTT assay. The results of the 48h incubation time in vitro tests showed that compound 15 was the most effective against PC-3 (IC50 6.6MUM), compound 17 against MCF-7 (IC50 7.9MUM) cells, while compound 16 exhibited strong antiproliferative effect against both, MCF-7 (IC50 1.7MUM) and PC-3 (IC50 8.7MUM) cancer cells. It was also found that compounds 16 and 17 induced apoptosis in MCF-7 cells (dicyano derivative 17 stronger then dioxime 16 and reference formestane), with no distinct changes in the cell cycle of MCF-7 cells. PMID- 25737401 TI - Dry eye specific quality of life in veterans using glaucoma drops. AB - PURPOSE: To evaluate the frequency of ocular surface symptoms and their potential impact on dry eye specific quality of life (QoL) in patients using versus not using glaucoma medications. MATERIAL AND METHODS: The study was a single-center, cross-sectional survey of patients seen at the Miami Veterans Affairs (VA) ophthalmology and optometry clinics from June to August, 2010. Patients were invited to complete the Dry Eye Questionnaire 5 (DEQ5) and the Impact of Dry Eye on Everyday Life (IDEEL) at their visit. Of 1348 patients seen in the Miami VA eye clinics during this three-month period, 467 patients completed the DEQ5 and 391 responded to both questionnaires. Outcome measures comprised ocular surface symptoms and their impact on dry eye specific QoL in patients using versus not using glaucoma drops. RESULTS: An increasing number of glaucoma drops was significantly associated with an increased percentage of severe dry eye symptoms: no medications, 25% (n=89/353); 1 or 2 medications, 27% (n=17/62); 3 or more medications, 40% (n=21/52); p=0.03 (Armitage's test for linear-trend in proportions). There was an association between increasing number of drops and decreasing emotional well-being scores (linear p<0.001; quadratic p=0.029). Black patients had higher dry eye symptoms and lower emotional QoL scores compared to white patients at every level of medication use. CONCLUSION: An increasing number of glaucoma medications were associated with an increased frequency of severe dry eye symptoms and decreased emotional QoL. Additionally, dry eye specific emotional QoL was more severely affected in black versus white patients. PMID- 25737402 TI - Intra-articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF-2alpha. AB - We investigated the feasibility of the intra-articular injection of resveratrol for preventing the progression of existing cartilage degeneration in a mouse model of osteoarthritis (OA). The effects of resveratrol on the expression of silent information regulator 2 type 1 (SIRT1), hypoxia-inducible factor-2alpha (HIF-2alpha) and catabolic factors in OA cartilage was explored. OA was induced in the mouse knee via destabilization of the medial meniscus (DMM). Resveratrol was injected weekly into the operated knee beginning 4 weeks after surgery. The OA phenotype was evaluated via histological and immunohistochemical analyses at 8 weeks after DMM. Western blot analysis was performed to identify whether resveratrol modulated the interleukin (IL)-1beta-induced expression of HIF-2alpha in human chondrocytes. Histologically, resveratrol treatment preserved the structural homeostasis of the articular cartilage and the subchondral bone. Following resveratrol injection, the expression of collagen type II was retained, but the expression of inducible nitric oxide synthase and matrix metalloproteinase-13 was reduced in OA cartilage. Moreover, the administration of resveratrol significantly induced the activation of SIRT1 and the inhibition of HIF-2alpha expression in mouse OA cartilage and in IL-1beta-treated human chondrocytes. These findings indicate that the intra-articular injection of resveratrol significantly prevents the destruction of OA cartilage by activating SIRT1 and thereby suppressing the expression of HIF-2alpha and catabolic factors. PMID- 25737403 TI - Cancer during pregnancy and the postpartum period: A population-based study. AB - BACKGROUND: The purpose of this study was to assess patterns of cancer occurrence during pregnancy and the postpartum period. METHODS: This was a register-based study using data from the Swedish Multi-Generation Register and the National Cancer Register from 1963 to 2007. Pregnancy-associated cancer (PAC) was defined as a malignancy detected during pregnancy or within 2 years of delivery and was assessed in 7 time windows: pregnancy, trimesters 1-3, 0-6 months, 7-12 months, and second year postpartum. Population incidence rates by 5-year age groups and periods were used to estimate the expected number of PACs for each site. The observed versus the expected (O/E) number of cases was estimated with 95% confidence intervals (CI). RESULTS: The 3 most common malignancies during pregnancy were melanoma (n = 232), breast (n = 139) and cervical cancer (n = 139). With a slightly different rank order, these cancers are also the most common in women of childbearing age. The number of observed cases during pregnancy was lower than expected for all cancers, with a combined O/E ratio for all sites of 0.46 (95% CI, 0.43-0.49). The O/E ratio was close to 1 during all postpartum intervals, including 0-6 months (0.93; 95% CI, 0.88-0.98), 7-12 months (0.96; 95% CI, 0.91-1.01), and during the second year after delivery (0.95; 95% CI, 0.92-0.99). CONCLUSIONS: The rate of cancer during pregnancy was lower than expected for all sites, a finding that could not be explained entirely by delayed diagnosis. A rebound in the number of observed cases after delivery was restricted to melanoma, nervous system malignancies, and breast and thyroid cancer. PMID- 25737404 TI - Apamin inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration through suppressions of activated Akt and Erk signaling pathway. AB - The increased proliferation and migration of vascular smooth muscle cells (VSMC) are key process in the development of atherosclerosis lesions. Platelet-derived growth factor (PDGF) initiates a multitude of biological effects that contribute to VSMC proliferation and migration. Apamin, a component of bee venom, has been known to block the Ca(2+)-activated K(+) channels. However, the effects of apamin in the regulation PDGF-BB-induced VSMC proliferation and migration has not been identified. In this study, we investigate the inhibitory effect of apamin on PDGF BB-induced VSMC proliferation and migration. Apamin suppressed the PDGF-BB induced VSMC proliferation and migration with no apparent cytotoxic effect. In accordance with these findings, apamin induced the arrest of cell cycle progression at G0/G1 phase. Apamin also decreased the expressions of G0/G1 specific regulatory proteins including proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin-dependent kinases (CDK) 4, cyclin E and CDK2, as well as increased the expression of p21(Cip1) in PDGF-BB-induced VSMC. Moreover, apamin inhibited PDGF-BB-induced phosphorylation of Akt and Erk1/2. These results suggest that apamin plays an important role in prevention of vascular proliferation and migration through the G0/G1 cell cycle arrest by PDGF signaling pathway. Thus, apamin may be a promising candidate for the therapy of atherosclerosis. PMID- 25737405 TI - Naturally occurring PDGF receptor inhibitors with potential anti-atherosclerotic properties. AB - Platelet-derived growth factor (PDGF) represents one of the most prominent inducer of smooth muscle cell (SMC) migration and proliferation. Homo- and heterodimers of PDGF-A, PDGF-B, PDGF-C and PDGF-D subunits act by binding to homo or heterodimers of the PDGF tyrosine kinase receptors, PDGFR-alpha and PDGFR beta. The essential role of PDGFR signaling on restenosis post-angioplasty or atherosclerosis has been demonstrated by using blocking antibodies to PDGF or the tyrosine kinase inhibitor imatinib. More specifically, molecular studies have defined the intracellular signaling pathways activated by PDGF, inducing the cell cycle progression and the migration of SMCs. Considering the relevant role of PDGF in atherogenesis, several studies have been performed to investigate the effect of naturally occurring compounds on both in vitro and in vivo experimental models of atherogenesis. The present review will briefly summarize the pathophysiological role of PDGF and the studies of natural inhibitors tested in in vivo experimental models of restenosis in response to vascular injury and/or atherosclerosis. PMID- 25737406 TI - Limited role of functional differentiation in early diversification of animals. AB - The origin of most animal phyla and classes during the Cambrian explosion has been hypothesized to represent an 'early burst' of evolutionary exploration of functional ecological possibilities. However, the ecological history of marine animals has yet to be fully quantified, preventing an assessment of the early burst model for functional ecology. Here we use ecological assignments for 18,621 marine animal genera to assess the relative timing of functional differentiation versus taxonomic diversification from the Cambrian to the present day. We find that functional diversity increased more slowly than would be expected given the history of taxonomic diversity. Contrary to previous inferences of rapid ecological differentiation from the early appearances of all well-fossilized phyla and classes, explicit coding of functional characteristics demonstrates that Cambrian genera occupied comparatively few modes of life. Functional diversity increased in the Ordovician and, especially, during the recoveries from the end-Permian and end-Cretaceous mass extinctions. Permanent shifts in the relationship between functional and taxonomic diversity following the era bounding extinctions indicates a critical role for these biotic crises in coupling taxonomic and functional diversity. PMID- 25737407 TI - Consequence of cerebral embolism after transcatheter aortic valve implantation compared with contemporary surgical aortic valve replacement: effect on health related quality of life. AB - BACKGROUND: Incidence of cerebral microinfarcts is higher after transcatheter aortic valve implantation (TAVI) compared with surgical aortic valve replacement (SAVR). It is unknown whether these lesions persist and what direct impact they have on health-related quality of life. The objective was to identify predictors of cerebral microinfarction and measure their effect on health-related quality of life during 6 months after TAVI when compared with SAVR. METHODS AND RESULTS: Cerebral MRI was conducted at baseline, post procedure, and 6 months using diffusion-weighted imaging. Health-related quality of life was measured at baseline, 30 days, and 6 months with short form-12 health outcomes and EuroQol 5 dimensions questionnaires. One hundred eleven patients (TAVI, n=71; SAVR, n=40) were studied. The incidence (54 [77%] versus 17 [43%]; P=0.001) and number (3.4+/ 4.9 versus 1.2+/-1.8; P=0.001) of new microinfarcts were greater after TAVI than after SAVR. The total volume per microinfarct was smaller in TAVI than in SAVR (0.23+/-0.24 versus 0.76+/-1.8 mL; P=0.04). The strongest associations for microinfarction were: TAVI (arch atheroma grade: r=0.46; P=0.0001) and SAVR (concomitant coronary artery bypass grafting: r=-0.33; P=0.03). Physical component score in TAVI increased after 30 days (32.1+/-6.6 versus 38.9+/-7.0; P<0.0001) and 6 months (40.4+/-9.3; P<0.0001); the improvement occurred later in SAVR (baseline: 34.9+/-10.6; 30 days: 35.9+/-10.2; 6 months: 42.8+/-11.2; P<0.001). After TAVI, there were no differences in the short form-12 health outcome scores according to the presence or size of new cerebral infarction. CONCLUSIONS: Cerebral microinfarctions are more common after TAVI compared with SAVR but seem to have no negative effect on early (30 days) or medium term (6 months) health-related quality of life. Aortic atheroma (TAVI) and concomitant coronary artery bypass grafting (SAVR) are independent risk factors for cerebral microinfarction. PMID- 25737411 TI - Anterior chamber depth measurement using ultrasound to assess elevated intraocular pressure. PMID- 25737412 TI - Admissions of critically ill patients to the ED intensive care unit. AB - INTRODUCTION: Many emergency departments (EDs) have established units capable of providing critical care because of increasing need for critical care, called as ED intensive care unit (EDICU). However, prolonged critical care leads to crowding, resulting in poor quality of care and high mortality rates. We aimed to determine which type of critically ill patients play a main role for crowding in the EDICU, and how to manage these patients. METHOD: Patients aged older than 18 years who presented to the ED and presented for consultation to the ICU were eligible for inclusion in this study. Patients were classified into 4 priority groups by the Society of Critical Care Medicine. RESULT: Four hundred medical patients were enrolled in the study. Sixty-one patients were not admitted to hospital (15.2% of all patients) and were treated in the EDICU. These patients were older (mean age, 66.6 years) and had a higher percentage belonging to the priority 3 group (82.0%-unstable with reduced likelihood of recovery due to chronic illness) in comparison with other ICUs patients (mean age, 60.4 years and 11.9%, respectively) (P < .05). In priority 3 patients, the length of stay was median 120 hours, and also, length of invasive mechanical ventilations duration was median 19 hours in the EDICU. CONCLUSIONS: Emergency department intensive care unit occupancy appears driven by categorized as "reduced benefit" patients, and these units tend to become alternative dumping grounds for palliative care services. Hospitals and health care administrators should take special care to develop policies for improving the management of these patients. PMID- 25737413 TI - Think ultrasound first for peritonsillar swelling. AB - Peritonsillar abscess (PTA) is one of the most common deep neck space infections that can potentially have life-threatening complications if inadequately diagnosed and not treated promptly. The ability of clinicians to reliably differentiate PTA from peritonsillar cellulitis by physical examination alone is limited and blind needle aspiration, the typical method of diagnosis of PTA, is also unreliable. We review the available evidence supporting the use of ultrasound, either intraoral ultrasound or transcutaneous ultrasound to be the initial imaging modality of choice for evaluation of PTA and be used for real time needle guidance. PMID- 25737414 TI - Diagnosing acute pulmonary embolism masquerading as inferior myocardial infarction. PMID- 25737415 TI - Successful fluid resuscitation in a patient with high extravascular lung water index by restricted fluid infusion strategy under pulse indicator continuous cardiac output monitoring. PMID- 25737416 TI - Photosensitized oxidation of 9,10-dimethylanthracene with singlet oxygen by using a safranin O/silica composite under visible light. AB - The photosensitized oxidation of 9,10-dimethylanthracene with singlet oxygen in acetonitrile was investigated using a safranin O/silica composite as an heterogeneous delivery system of the photosensitizer. The only detected product was the corresponding endoperoxide (9,10-endoperoxianthracene) and its formation rate depended on the initial concentration of DMA, the light intensity and the amount of the composite. The kinetics of this reaction was compared with that of the reported kinetic model of photosensitized oxidations of organic compounds in homogeneous reactions. It was found that both reactions followed the same model, suggesting that the actual reaction between photoproduced singlet oxygen and 9,10 dimethylanthracene was performed in homogeneous media and the surface of the composite was not involved in the reaction. PMID- 25737417 TI - Epidemiology and risk factors for exocrine pancreatic cancer in a Northern African population. AB - BACKGROUND: The etiology of pancreatic cancer remains largely unknown. Although epidemiological studies have reported that many environmental factors may contribute to the development of pancreatic cancer, only age and cigarette smoking have been established as consistent risk factors for the disease. OBJECTIVE: Studying the biological clinical and histological features of patients with pancreatic cancer in order to assess the possible risk factors for pancreatic cancer in a North African population. METHODS: An epidemiological retrospective descriptive study has been performed at the level of surgery department of the university hospital of Sidi bel Abbes region, western Algeria, from 2007 to 2013. RESULTS: A total of 87 patients were diagnosed with cancer of the pancreas (55 males and 32 females) with a mean age of 63.1 years, ranging from 16 to 96 years old, and a sex ratio of 1.71. In 92 % of cases, pancreatic tumors were located at the head of the pancreas; the most predominant histological type was the adenocarcinoma; cigarette smokers represented the rate of 24.3 % and alcoholics 13.5 %. The most recorded disease among patients medical history was diabetes mellitus (25.28 %). About 35.63 % was the prominent rate of patients who underwent cholecystectomy and was diagnosed with pancreatic cancer after an average duration of 5.23 years. Our patients were mostly diagnosed with cancer at M1 and T3 stages. CONCLUSION: According to our results, cholecystectomy could possibly be a risk factor for pancreatic cancer in Algerian population. PMID- 25737418 TI - Superovulation induces alterations in the epigenome of zygotes, and results in differences in gene expression at the blastocyst stage in mice. AB - Gamete and embryo manipulations can result in alterations to the epigenome, and are associated with altered gene expression. The initial objective of this study was to determine the transcript level of several epigenetic modifiers in embryos that had been cultured from the 2-cell stage until the late-blastocyst stage in four culture conditions. Cultured embryos were compared to control, in vivo produced late blastocysts to ascertain if differences in gene expression existed among the culture conditions; none were observed. As all of the embryos used were produced in females that had undergone superovulation, we next compared the transcript level of the same epigenetic modifiers between superovulated, in vivo produced embryos and embryos produced from natural ovulation. Following in vitro culturing, expression of the genes analyzed was increased in all superovulation groups. We therefore hypothesized that the superovulation procedure-used to increase the number of embryos obtained for experimentation-may have caused an inappropriate acquisition of epigenetic modifications in the maternal genome prior to ovulation, which in turn caused misexpression of genes at the blastocyst stage. To test this hypothesis, we compared the level of global DNA methylation and histone 3 lysine-9 or -14 acetylation in zygotes obtained by natural- or superovulation. Indeed, superovulation decreased global DNA methylation on the maternal pronucleus of zygotes, which inversely correlated with H3K9/14 acetylation. In conclusion, superovulation alters the epigenome of the oocyte, resulting in the dysregulation of gene expression at the blastocyst stage. PMID- 25737419 TI - Insights into the mechanism and catalysis of oxime coupling chemistry at physiological pH. AB - The dynamic covalent-coupling reaction involving alpha-effect nucleophiles has revolutionized bioconjugation approaches, due to its ease and high efficiency. Key to its success is the discovery of aniline as a nucleophilic catalyst, which made this reaction feasible under physiological conditions. Aniline however, is not so effective for keto substrates. Here, we investigate the mechanism of aniline activation in the oxime reaction with aldehyde and keto substrates. We also present carboxylates as activating agents that can promote the oxime reaction with both aldehyde and keto substrates at physiological pH. This rate enhancement circumvents the influence of alpha-effect by forming H-bonds with the rate-limiting intermediate, which drives the reaction to completion. The combination of aniline and carboxylates had a synergistic effect, resulting in a ~14-31-fold increase in reaction rate at pD 7.4 with keto substrates. The biocompatibility and efficiency of carboxylate as an activating agent is demonstrated by performing cell-surface oxime labeling at physiological pH using acetate, which showed promising results that were comparable with aniline. PMID- 25737420 TI - An optimization approach for mapping and measuring the divergence and correspondence between paths. AB - Many domains of empirical research produce or analyze spatial paths as a measure of behavior. Previously, approaches for measuring the similarity or deviation between two paths have either required timing information or have used ad hoc or manual coding schemes. In this paper, we describe an optimization approach for robustly measuring the area-based deviation between two paths we call ALCAMP (Algorithm for finding the Least-Cost Areal Mapping between Paths). ALCAMP measures the deviation between two paths and produces a mapping between corresponding points on the two paths. The method is robust to a number of aspects in real path data, such as crossovers, self-intersections, differences in path segmentation, and partial or incomplete paths. Unlike similar algorithms that produce distance metrics between trajectories (i.e., paths that include timing information), this algorithm uses only the order of observed path segments to determine the mapping. We describe the algorithm and show its results on a number of sample problems and data sets, and demonstrate its effectiveness for assessing human memory for paths. We also describe available software code written in the R statistical computing language that implements the algorithm to enable data analysis. PMID- 25737424 TI - Current status of PET imaging of differentiated thyroid cancer with second generation radiopharmaceuticals. AB - Although the prognosis of differentiated thyroid cancer (DTC) is favorable, some histotypes show worst clinical outcome and higher risk of recurrence. Serum thyroglobulin (Tg) levels and 131I-whole-body-scan (WBS), together with neck ultrasound (US), represent the golden standard for DTC follow-up. Nevertheless, the relatively high frequency of patients with high Tg levels and negative WBS requires further investigations by using new imaging modalities. The availability of whole body positron emission tomography (PET) methods, in parallel with the advances in radiochemistry, offer a wide substrate for many solutions. To this day 18F-fluoro-deoxy-glucose (18F-FDG) PET/CT still represents the imaging of choice in follow-up of patients with high serum Tg and negative 131I-WBS but in the last decades the research has focused on finding "second generation" radiopharmaceuticals for PET imaging, with both diagnostic and prognostic purposes, aiming to change the way to image thyroid cancer. Moreover, the use of various PET radiopharmaceuticals, that offer the possibility to explore different pathways involved in thyroid cancer, could find important applications in the near future for clinical decision making in order to program tailored treatments and follow-up. It would be desirable to use the same radiopharmaceutical for both imaging and dosimetric purpose to achieve a tailored therapy. Many efforts are focused in this direction and 124I-PET/CT is now emerging as a valid tool in restaging and therapy management of DTC with promising results. Although the preliminary data available in literature require a confirmation in larger studies with longer follow-up, we think that in next future 124I-PET/CT could gain an important role for management of DTC. The aim of this review was to perform a systematic analysis of literature describing the state of art of "second generation" PET-radiopharmaceuticals for imaging DTC. Discussion is focused on the utility of 124I-PET/CT, but we also mention the pathways explored by 68Gallium-somatostatin analogues, 18F-FLT and 11C-MET and their applications in this clinical setting. PMID- 25737423 TI - Applications of PET imaging with the proliferation marker [18F]-FLT. AB - [18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease. PMID- 25737425 TI - New approaches to image thyroid cancer cells and microenvironment. AB - Poorly differentiated thyroid cancer (PDTC) and undifferentiated thyroid cancer (UDTC) are still life-threatening pathologies, because of the lack of well established diagnostic and therapeutic approaches. In the past, many attempts have been made to develop radiopharmaceutical to diagnose or treat radioactive iodine (RAI)-refractory metastases or recurrences, with limited results. Indeed, it was not possible to find a specific and overexpressed marker to be used as target of radiopharmaceuticals or targeted therapies. Nowadays, with novel advances in the field of tumor microenvironment, many new markers are available to be used as suitable targets for targeted therapies interfering with signalling pathways of cells involved in the mechanisms that favour tumor growth and metastatization. This opened new perspective in the use of radiopharmaceuticals targeting components of tumor microenvironment for early diagnosis, pre-operative staging or therapy planning and follow up with targeted drugs. In the present review we present the state of novel approaches to image thyroid cancer and its microenvironment, focusing on RAI-refractory thyroid cancer as a real clinical problem to be solved. PMID- 25737427 TI - Nanocapsules templated on liquid cores stabilized by graft amphiphilic polyelectrolytes. AB - A surfactant-free method of preparation of nanocapsules templated on liquid cores using amphiphilic graft polyelectrolytes was developed. A model photoactive copolymer, poly(sodium 2-acrylamido-2-methyl-1-propanesulfonate) with grafted poly(vinylnaphthalene) chains (PAMPS-graft-PVN) was used to stabilize toluene droplets in an aqueous emulsion. The macromolecules, due to their amphiphilic character and the presence of strong ionic groups, tend to undergo intramolecular aggregation in water but at the water-oil interface less compact conformation is preferred with PVN grafts anchoring in the oil phase and the charged PAMPS main chains residing in the aqueous phase, thus stabilizing the nanoemulsion droplets. Formation of such nanocapsules was confirmed by dynamic light scattering measurements as well as SEM and cryo-TEM imaging. Grafting density and content of the chromophores in the graft copolymers were varied in order to achieve high stability of the coated nanodroplets. It was shown that the capsules are better stabilized by the copolymers with many short hydrophobic grafts than with fewer but longer ones. Use of photoactive polyelectrolytes enabled spectroscopic investigation of the relationship between conformation of the macromolecules and stabilization of the oil-core nanocapsules. Long-term stability of the nanocapsules was achieved and further increased by multilayer shell formation using polyelectrolytes deposited via the layer-by-layer approach. The obtained capsules served as efficient nanocontainers for a hydrophobic fluorescent probe. The proposed strategy of nanocapsule preparation may be easily extended to biologically relevant polymers and applied to fabricate liquid core nanodelivery systems without the need of using low molecular weight additives which may have adverse effects in numerous biomedical applications. PMID- 25737426 TI - Subjective memory impairment and well-being in community-dwelling older adults. AB - BACKGROUND: The relationship between subjective memory impairment (SMI), future cognitive decline, and negative health status provides an opportunity for interventions to reduce memory complaints in high-risk groups. This study aimed to examine the relationship between SMI and indicators of well-being in older adults enrolled in an exercise trial. Additionally, the study examined whether two different modes of exercise training, aerobic walking and non-aerobic flexibility, toning, and balance, differentially influenced subjective memory across the trial. METHODS: Community-dwelling older adults (n = 179, mean age = 66.4 years) were randomly assigned to a walking or flexibility, toning, and balance group for 12 months. Subjective memory, happiness, perceived stress, and symptom reporting were measured at baseline, 6 months, and 12 months. RESULTS: A main effect of subjective memory indicated that individuals with the fewest memory complaints had lower perceived stress (P < 0.001), lower physical symptom reporting (P < 0.001), and higher happiness levels (P < 0.001) across all measurement occasions. Both main and interaction effects of time and group on SMI were not significant, suggesting SMI remained stable across the intervention and was not significantly impacted by participation in exercise training. CONCLUSIONS: SMI was not responsive to exercise interventions, and the relationship between SMI and negative well-being demonstrates a need for interventions to reduce memory complaints in high-risk groups. PMID- 25737428 TI - Effects of ligand binding upon flexibility of proteins. AB - Binding of a ligand on a protein changes the flexibility of certain parts of the protein, which directly affects its function. These changes are not the same at each point, some parts become more flexible and some others become stiffer. Here, an equation is derived that gives the stiffness map for proteins. The model is based on correlations of fluctuations of pairs of points in proteins, which may be evaluated at different levels of refinement, ranging from all atom molecular dynamics to general elastic network models, including the simplest case of isotropic Gaussian Network Model. The latter is used, as an example, to evaluate the changes of stiffness upon dimerization of ACK1. PMID- 25737429 TI - Reconstruction of a composite nasal columella defect: A four-step technique. PMID- 25737430 TI - Comparative evaluation of root canal preparations of maxillary first molars with self-adjusting file, reciproc single file, and revo-s rotary file: A micro computed tomography study. AB - This study was aimed to use micro-computed tomography (MU-CT) to evaluate the canal shaping properties of three nickel-titanium instruments, Self-Adjusting File (SAF), Reciproc, and Revo-S rotary file, in maxillary first molars. Thirty maxillary molars were scanned preoperatively by using micro-computed tomography (MU-CT) scans at 13,68 MUm resolution. The teeth were randomly assigned to three groups (n = 10). The root canals were shaped with SAF, Reciproc, and Revo-S, respectively. The shaped root canals were rescanned. Changes in canal volumes and surface areas were compared with preoperative values. The data were analyzed using Kruskal-Wallis and Conover's post hoc tests, with p < .05 denoting a statistically significant difference. Preoperatively canal volumes and surface area were statistically similar among the three groups (p > .05). There were statistically significant differences in all measures comparing preoperative and postoperative canal models (p = 0.0001). These differences occurred after instrumentation among the three experimental groups showed no statistically significant difference for volume (p > .05). Surface area showed the similar activity in buccal canals in each of the three techniques whereas no statistically significant difference was detected among surface area, the SAF, and the Revo-S in the palatal (P) canal. Each of three shaping system showed the similar volume activity in all canals, but SAF and Revo-S provided more effectively root planning in comparison with Reciproc in P canal. PMID- 25737431 TI - Eye, nose, hair, and throat: external anatomy of the head of a neonate gray whale (Cetacea, Mysticeti, Eschrichtiidae). AB - Information is scarce on gray whale (Eschrichtius robustus) anatomy and that of mysticetes in general. Dissection of the head of a neonatal gray whale revealed novel anatomical details of the eye, blowhole, incisive papilla with associated nasopalatine ducts, sensory hairs, and throat grooves. Compared to a similar sized right whale calf, the gray whale eyeball is nearly twice as long. The nasal cartilages of the gray whale, located between the blowholes, differ from the bowhead in having accessory cartilages. A small, fleshy incisive papilla bordered by two blind nasopalatine pits near the palate's rostral tip, previously undescribed in gray whales, may be associated with the vomeronasal organ, although histological evidence is needed for definitive identification. Less well known among mysticetes are the numerous elongated, stiff sensory hairs (vibrissae) observed on the gray whale rostrum from the ventral tip to the blowhole and on the mandible. These hairs are concentrated on the chin, and those on the lower jaw are arranged in a V-shaped pattern. We confirm the presence of two primary, anteriorly converging throat grooves, confined to the throat region similar to those of ziphiid and physeteroid odontocetes. A third, shorter groove occurs lateral to the left primary groove. The throat grooves in the gray whale have been implicated in gular expansion during suction feeding. PMID- 25737432 TI - Hesperetin induces the apoptosis of hepatocellular carcinoma cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species, ATP and calcium. AB - Hesperetin, a flavonoid from citrus fruits, has been proved to possess biological activity on various types of human cancers. However, few related studies on hepatocellular carcinoma are available. In this study, we aimed to investigate the effect of hesperetin on hepatocellular carcinoma cells in vitro and in vivo and clarify its potentially specific mechanism. Compared with the control group, the proliferations of hepatocellular carcinoma cells in hesperetin groups were significantly inhibited (P < 0.05), and a dose- and time-dependent inhibition of cell viability was observed. When pretreated with H2O2 (1 mM) or N-acetyl-L cysteine (5 mM), the inhibition of cell viability by hesperetin was enhanced or reduced, respectively (P < 0.05). Similarly, the levels of intracellular ROS, ATP and Ca(2+) changed in different groups (P < 0.05). The results of Hoechst 33258 staining showed that the percentages of apoptotic cells in hesperetin groups are remarkably higher than that in control group (P < 0.05). And the results of Western blot showed that hesperetin caused an increase in the levels of cytosolic AIF, cytosolic Apaf-1, cytosolic Cyt C, caspase-3, caspase-9 and Bax and a decrease in that of Bcl-2, mitochondrial AIF, mitochondrial Apaf-1 and mitochondrial Cyt C (P < 0.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors. Our study suggests that hesperetin could inhibit the proliferation and induce the apoptosis of hepatocellular carcinoma via triggering the activation of the mitochondrial pathway by increasing the levels of intracellular ROS, ATP and Ca(2+). PMID- 25737433 TI - Combined treatment of carfilzomib and z-VAD-fmk inhibits skeletal proteolysis and apoptosis and ameliorates cancer cachexia. AB - The purpose of the study was to evaluate the therapeutic benefit of treatments with carfilzomib (CFZ) and z-VAD-fmk in a mouse model of cancer-induced cachexia. The model of cancer-associated cachexia was generated by injecting murine C26 adenocarcinoma cells into BALB/C mice. CFZ and z-VAD-fmk were administered individually or in combination at 5 and 12 days after inoculation. Changes in body weight, gastrocnemius muscle mass, tumor burden, spontaneous activity, survival, and metabolic profiles were noted. Also evaluated were the circulatory levels of renin and angiotensin II, and levels of apoptotic, proteolytic, and renin-angiotensin system-associated markers and transcription factor 2 (ATF2) in gastrocnemius muscle. The CFZ and z-VAD-fmk treatments were associated with less muscle wasting, reduced tumor burden, modulated metabolism, higher levels of glucose, albumin, and total proteins, and lower levels of triglyceride fatty acids, more spontaneous physical activity, and longer survival in C26-inoculated mice compared with PBS-treated cachectic mice. CFZ and z-VAD-fmk treatments resulted in higher levels of caspase-3 and BAX and lower level of BCL-XL in gastrocnemius muscles and altered the level of proteins in the renin-angiotensin system. The combined treatment administered 5 days after C26 inoculation was more effective than other regimens. Combined treatment with CFZ and z-VAD-fmk early in the development of cachexia was associated with signs of less proteolysis and apoptosis and less severe cachexia in a mouse model of cancer-induced cachexia. PMID- 25737434 TI - Increased Sushi repeat-containing protein X-linked 2 is associated with progression of colorectal cancer. AB - Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel chondroitin sulfate proteoglycan overexpressed in gastrointestinal cancer. Its role in tumor biology remains unknown. The aim of this study was to investigate the expression of SRPX2 in colorectal cancer and its potential association with cancer progression. The expression of SRPX2 and its clinicopathological significance was evaluated using immunohistochemistry in a tissue microarray including 88 colon cancer and pairing normal tissues. The impact of SRPX2 on behavior of colorectal cancer cells and possible mechanism was explored using gene transfection and silencing. Strong staining of SRPX2 was noted in 71 (80.7 %) of 88 colon cancer specimen and 30 (34.1 %) of 88 adjacent normal tissues (P < 0.001). The expression of SRPX2 was significantly correlated with histological differentiation grade (P = 0.003), infiltration depth (P = 0.003), and clinical stage (P = 0.006). The expression of SRPX2 was significantly higher in HCT116 than in HT29 and SW480 cells. Suppression of endogenous SRPX2 expression by small interfering ribonucleic acid (siRNA) in HCT116 cells resulted in significant reduction in the ability of cell proliferation, adhesion, migration, and invasion. Up-regulation of endogenous SRPX2 in SW480 cells significantly promoted the migration and invasion of SW480 cells. In addition, inhibition of SRPX2 by siRNA led to notable down-regulation of beta-catenin, matrix metalloproteinase (MMP)-2, and MMP-9. These findings indicate that overexpressed SRPX2 exerts an oncogenic role in colorectal cancer. SRPX2 may promote the invasion of colorectal cancer through MMP-2 and MMP-9 modulated by Wnt/beta-catenin pathway. PMID- 25737435 TI - [UV-irradiation-induced skin cancer as a new occupational disease]. AB - With the revision of the German Ordinance on Occupational Diseases, skin cancer due to UV irradiation was amended as a new occupational disease to the list of occupational diseases in Germany. The new occupational disease BK 5103 has the following wording: "Squamous cell carcinoma or multiple actinic keratosis of the skin caused by natural UV irradiation". Actinic keratoses are to be considered as multiple according to this new occupational diseases if they occur as single lesions of more than five annually, or are confluent in an area > 4 cm(2) (field cancerization). It is estimated that more than 2.5 million employees are exposed to natural UV irradiation due to their work (outdoor workers) in Germany and therefore have an increased risk of skin cancer. In this article the medical and technical prerequisites which have to be fulfilled for this new occupational disease in Germany are introduced. PMID- 25737436 TI - White and blue light induce reduction in susceptibility to minocycline and tigecycline in Acinetobacter spp. and other bacteria of clinical importance. AB - Minocycline (MIN) and tigecycline (TIG) are antibiotics currently used for treatment of multidrug-resistant nosocomial pathogens. In this work, we show that blue light, as well as white light, modulates susceptibility to these antibiotics in a temperature-dependent manner. The modulation of susceptibility by light depends on the content of iron; an increase in iron results in a reduction in antibiotic susceptibility both under light and in the dark, though the effect is more pronounced in the latter condition. We further provide insights into the mechanism by showing that reduction in susceptibility to MIN and TIG induced by light is likely triggered by the generation of (1)O2, which, by a yet unknown mechanism, would ultimately lead to the activation of resistance genes such as those coding for the efflux pump AdeABC. The clinical relevance of these results may lie in surface-exposed wound infections, given the exposure to light in addition to the relatively low temperatures recorded in this type of lesion. We further show that the modulation of antibiotic susceptibility occurs not only in Acinetobacter baumannii but also in other micro-organisms of clinical relevance such as Escherichia coli and Staphylococcus aureus. Overall, our findings allow us to suggest that MIN and TIG antibiotic treatments may be improved by the inclusion of an iron chelator, in addition to keeping the wounds in the dark, a condition that would increase the effectiveness in the control of infections involving these micro-organisms. PMID- 25737437 TI - The Association between Food Insecurity and Obesity in Children-The National Health and Nutrition Examination Survey. AB - BACKGROUND: Food insecurity can put children at greater risk of obesity because of altered food choices and nonuniform consumption patterns. OBJECTIVE: We examined the association between obesity and both child-level food insecurity and personal food insecurity in US children. DESIGN: Data from 9,701 participants in the National Health and Nutrition Examination Survey, 2001-2010, aged 2 to 11 years were analyzed. Child-level food insecurity was assessed with the US Department of Agriculture's Food Security Survey Module based on eight child specific questions. Personal food insecurity was assessed with five additional questions. Obesity was defined, using physical measurements, as body mass index (calculated as kg/m2) greater than or equal to the age- and sex-specific 95th percentile of the Centers for Disease Control and Prevention growth charts. Logistic regressions adjusted for sex, race/ethnic group, poverty level, and survey year were conducted to describe associations between obesity and food insecurity. RESULTS: Obesity was significantly associated with personal food insecurity for children aged 6 to 11 years (odds ratio=1.81; 95% CI 1.33 to 2.48), but not in children aged 2 to 5 years (odds ratio=0.88; 95% CI 0.51 to 1.51). Child-level food insecurity was not associated with obesity among 2- to 5 year-olds or 6- to 11-year-olds. CONCLUSIONS: Personal food insecurity is associated with an increased risk of obesity only in children aged 6 to 11 years. Personal food-insecurity measures may give different results than aggregate food insecurity measures in children. PMID- 25737438 TI - Retention Interval and Prompts: Creation and Cross-Sectional Pilot-Testing of Eight Interview Protocols to Obtain 24-Hour Dietary Recalls from Fourth-Grade Children. AB - BACKGROUND: Any 24-hour dietary recall (24hDR) has a retention interval and prompts. No research has investigated their combined effect. OBJECTIVE: Eight 24hDR protocols, constructed by crossing two retention intervals (prior-24-hour recall obtained in afternoon and previous-day recall obtained in morning) with four prompts (forward [distant-to-recent], reverse [recent-to-distant], meal-name [eg, breakfast, lunch, etc], and open [no instructions]), were pilot-tested. DESIGN: Via a cross-sectional design, children were interviewed once, using one of eight 24hDR protocols. PARTICIPANTS/SETTING: Forty-eight fourth-grade children (79% black; 50% girls; six per protocol) were randomly selected from two schools during spring 2011. Protocol assignment was random. Analyses excluded one interview due to protocol deviation. STATISTICAL ANALYSES PERFORMED: Multivariate analysis of variance (MANOVA) with four nonaccuracy-related response variables was conducted, with independent variables retention interval, prompt, and their interaction. The significance level was 0.10 due to the study's exploratory nature. RESULTS: The response variable set differed across retention intervals (P=0.0003) and prompts (P=0.045) but not their interaction (P=0.11). Follow-up analysis of variance for each of four variables showed differences by retention interval for three and prompt for two: Interview length (minutes) differed by retention interval (prior-24-hour-afternoon=21.8, previous-day-morning=16.1; P<0.0008) and prompt (open=20.3, reverse=20.0, forward=19.1, and meal-name=16.3; P=0.079). Number of school meals reported eaten during the target period did not depend on retention interval or prompt, but was greater using meal-name prompts (1.7) than the other three prompts (1.3; P=0.055; contrast t test). Number of 10 possible meal components reported eaten at school meals differed by retention interval (prior-24-hour-afternoon=4.1, previous-day-morning=2.9; P=0.048). Weighted number of items (condiment=0.33, combination entree=2.0, and else=1.0) reported eaten at school meals differed by retention interval (prior-24-hour afternoon=5.8, previous-day-morning=4.1; P=0.079) and prompt (forward=6.2, meal name=5.3, reverse=4.9, and open=3.3; P=0.093). CONCLUSIONS: Children's nonaccuracy-related responses to eight 24hDR protocols varied as hypothesized. The selected protocols will be useful in a planned validation study to investigate differences by protocol in children's recall accuracy. PMID- 25737439 TI - Should sphincterotomy be performed before placement of metal stents for biliary obstruction in patients with unresectable pancreatic cancer? PMID- 25737440 TI - Reply: To PMID 24993367. PMID- 25737441 TI - A More Focused Approach to Pharmacoprevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis. PMID- 25737442 TI - Associations of Serum Adiponectin and Leptin With Barrett's Esophagus. AB - BACKGROUND & AIMS: Central adiposity is a risk factor for Barrett's esophagus (BE). Serum levels of adiponectin and leptin are deregulated in obese states and are implicated as putative mediators in the pathophysiology of esophageal columnar metaplasia. We describe associations between serum adiponectin and leptin levels with BE. METHODS: Patients were recruited prospectively for a case control study. Fasting serum levels of adiponectin and leptin were measured in 135 patients with BE and compared with 2 separate control groups: 133 subjects with gastroesophageal reflux disease (GERD) and 1157 colon screening controls. RESULTS: Multivariate analyses adjusted for age, race, and waist-to-hip ratio showed that patients within the highest tertile of serum adiponectin level had decreased odds of BE compared with screening colonoscopy controls (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.22-0.80). This effect was more pronounced in men (OR, 0.35; 95% CI, 0.17-0.74) compared with women (OR, 0.71; 95% CI, 0.17-3.03). In comparisons of BE cases with GERD controls, subjects within the highest tertile of serum adiponectin level showed decreased odds of BE (OR, 0.65; 95% CI, 0.31-1.36), however, this was not statistically significant. Patients in the highest tertile of serum leptin level did not have a significantly increased risk of BE in comparison with GERD (OR, 1.32; 95% CI, 0.61-2.88) or screening colonoscopy controls (OR, 1.57; 95% CI, 0.82-3.04) in analyses including both sexes. Based on sex-specific analyses, sex did not significantly alter the association of leptin with odds of BE. CONCLUSIONS: Serum adiponectin was associated inversely with BE and this effect was more pronounced in men, whereas serum leptin showed no evidence of association with BE in comparisons with multiple control groups. The exact mechanism, if any, by which these adipokines promote metaplasia in the esophagus needs to be explored further. PMID- 25737443 TI - Muscle Cramps in Cirrhosis: A Moving Target. PMID- 25737444 TI - Reply: To PMID 24035776. PMID- 25737445 TI - Racial and Ethnic Disparities in Colonoscopic Examination of Individuals With a Family History of Colorectal Cancer. AB - BACKGROUND & AIMS: Guidelines recommend that persons with a high-risk family history of colorectal cancer (CRC) undergo colonoscopy examinations every 5 years, starting when they are 40 years old. We investigated factors associated with colonoscopy screening of individuals with a family history of CRC, focusing on race and ethnicity. METHODS: In a retrospective study, we analyzed data from the 2009 California Health Interview Survey on persons 40-80 years old with a first-degree relative (mother, father, sibling, or child) with CRC who had visited a physician within the past 5 years. Our study included an unweighted and population-weighted sample of 2539 and 870,214 individuals with a family history of CRC, respectively. We performed a survey-weighted logistic regression analysis to adjust for relevant demographic and socioeconomic variables and used estimates to calculate relative risks and 95% confidence intervals (CIs) for colonoscopy examination within the past 5 years. RESULTS: In the weighted sample, 60.0% of subjects received a colonoscopy within the past 5 years. A physician recommendation for CRC screening increased the odds that an individual would undergo colonoscopy examination (relative risk, 1.89; 95% CI, 1.61-2.24). Latinos were 31% less likely to receive colonoscopies than whites (95% CI, 7%-55%). Among individuals 40-49 years old, blacks were 71% less likely to have had a colonoscopy than whites (95% CI, 13%-96%). CONCLUSION: On the basis of an analysis of data from the California Health Interview Survey, less than two thirds of individuals with a family history of CRC reported receiving guideline recommended colonoscopy examinations within the past 5 years. We observed racial and ethnic disparities in colonoscopy screening of this high-risk group; Latinos and blacks were less likely to have had a colonoscopy than whites. PMID- 25737446 TI - Strategies for correcting very long chain acyl-CoA dehydrogenase deficiency. AB - Very long acyl-CoA dehydrogenase (VLCAD) deficiency is a genetic pediatric disorder presenting with a spectrum of phenotypes that remains for the most part untreatable. Here, we present a novel strategy for the correction of VLCAD deficiency by increasing mutant VLCAD enzymatic activity. Treatment of VLCAD deficient fibroblasts, which express distinct mutant VLCAD protein and exhibit deficient fatty acid beta-oxidation, with S-nitroso-N-acetylcysteine induced site specific S-nitrosylation of VLCAD mutants at cysteine residue 237. Cysteine 237 S nitrosylation was associated with an 8-17-fold increase in VLCAD-specific activity and concomitant correction of acylcarnitine profile and beta-oxidation capacity, two hallmarks of the disorder. Overall, this study provides biochemical evidence for a potential therapeutic modality to correct beta-oxidation deficiencies. PMID- 25737447 TI - MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence. AB - MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility, and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and panobinostat (LBH589), two broad-spectrum HDAC inhibitors up-regulate hsa-miR-31 (miR-31). The up-regulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein BMI1 and induction of cellular senescence. We further show that inhibition of miR-31 overcomes the senescence-inducing effect of HDACi, and restores expression of the PcG protein BMI1. Interestingly, BMI1 also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and BMI1. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the aging process. PMID- 25737448 TI - Fully Human VH Single Domains That Rival the Stability and Cleft Recognition of Camelid Antibodies. AB - Human VH single domains represent a promising class of antibody fragments with applications as therapeutic modalities. Unfortunately, isolated human VH domains also generally display poor biophysical properties and a propensity to aggregate. This has encouraged the development of non-human antibody domains as alternative means of antigen recognition and, in particular, camelid (VHH) domains. Naturally devoid of light chain partners, these domains are characterized by favorable biophysical properties and propensity for cleft binding, a highly desirable characteristic, allowing the targeting of cryptic epitopes. In contrast, previously reported structures of human VH single domains had failed to recapitulate this property. Here we report the engineering and characterization of phage display libraries of stable human VH domains and the selection of binders against a diverse set of antigens. Unlike "camelized" human domains, the domains do not rely on potentially immunogenic framework mutations and maintain the structure of the VH/VL interface. Structure determination in complex with hen egg white lysozyme revealed an extended VH binding interface, with complementarity-determining region 3 deeply penetrating into the active site cleft, highly reminiscent of what has been observed for camelid domains. Taken together, our results demonstrate that fully human VH domains can be constructed that are not only stable and well expressed but also rival the cleft binding properties of camelid antibodies. PMID- 25737449 TI - Structural basis for penetration of the glycan shield of hepatitis C virus E2 glycoprotein by a broadly neutralizing human antibody. AB - Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. A challenge for HCV vaccine development is to identify conserved epitopes able to elicit protective antibodies against this highly diverse virus. Glycan shielding is a mechanism by which HCV masks such epitopes on its E2 envelope glycoprotein. Antibodies to the E2 region comprising residues 412-423 (E2(412-423)) have broadly neutralizing activities. However, an adaptive mutation in this linear epitope, N417S, is associated with a glycosylation shift from Asn 417 to Asn-415 that enables HCV to escape neutralization by mAbs such as HCV1 and AP33. By contrast, the human mAb HC33.1 can neutralize virus bearing the N417S mutation. To understand how HC33.1 penetrates the glycan shield created by the glycosylation shift to Asn-415, we determined the structure of this broadly neutralizing mAb in complex with its E2(412-423) epitope to 2.0 A resolution. The conformation of E2(412-423) bound to HC33.1 is distinct from the beta-hairpin conformation of this peptide bound to HCV1 or AP33, because of disruption of the beta-hairpin through interactions with the unusually long complementarity determining region 3 of the HC33.1 heavy chain. Whereas Asn-415 is buried by HCV1 and AP33, it is solvent-exposed in the HC33.1-E2(412-423) complex, such that glycosylation of Asn-415 would not prevent antibody binding. Furthermore, our results highlight the structural flexibility of the E2(412-423) epitope, which may serve as an immune evasion strategy to impede induction of antibodies targeting this site by reducing its antigenicity. PMID- 25737450 TI - Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells. AB - All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells. We reason that, in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal hematopoietic stem/progenitor cells. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, whereas ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with retinoic acid receptor alpha and modulates ATRA target gene expression. SALL4 is shown to recruit lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, coinhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy. PMID- 25737451 TI - Obstructor A organizes matrix assembly at the apical cell surface to promote enzymatic cuticle maturation in Drosophila. AB - Assembly and maturation of the apical extracellular matrix (aECM) is crucial for protecting organisms, but underlying molecular mechanisms remain poorly understood. Epidermal cells secrete proteins and enzymes that assemble at the apical cell surface to provide epithelial integrity and stability during developmental growth and upon tissue damage. We analyzed molecular mechanisms of aECM assembly and identified the conserved chitin-binding protein Obst-A (Obstructor A) as an essential regulator. We show in Drosophila that Obst-A is required to coordinate protein and chitin matrix packaging at the apical cell surface during development. Secreted by epidermal cells, the Obst-A protein is specifically enriched in the apical assembly zone where matrix components are packaged into their highly ordered architecture. In obst-A null mutant larvae, the assembly zone is strongly diminished, resulting in severe disturbance of matrix scaffold organization and impaired aECM integrity. Furthermore, enzymes that support aECM stability are mislocalized. As a biological consequence, cuticle architecture, integrity, and function are disturbed in obst-A mutants, finally resulting in immediate lethality upon wounding. Our studies identify a new core organizing center, the assembly zone that controls aECM assembly at the apical cell surface. We propose a genetically conserved molecular mechanism by which Obst-A forms a matrix scaffold to coordinate trafficking and localization of proteins and enzymes in the newly deposited aECM. This mechanism is essential for maturation and stabilization of the aECM in a growing and remodeling epithelial tissue as an outermost barrier. PMID- 25737452 TI - Neurons and glia modify receptor protein-tyrosine phosphatase zeta (RPTPzeta)/phosphacan with cell-specific O-mannosyl glycans in the developing brain. AB - Protein O-mannosylation is a glycan modification that is required for normal nervous system development and function. Mutations in genes involved in protein O mannosyl glycosylation give rise to a group of neurodevelopmental disorders known as congenital muscular dystrophies (CMDs) with associated CNS abnormalities. Our previous work demonstrated that receptor protein-tyrosine phosphatase zeta (RPTPzeta)/phosphacan is hypoglycosylated in a mouse model of one of these CMDs, known as muscle-eye-brain disease, a disorder that is caused by loss of an enzyme (protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1) that modifies O mannosyl glycans. In addition, monoclonal antibodies Cat-315 and 3F8 were demonstrated to detect O-mannosyl glycan modifications on RPTPzeta/phosphacan. Here, we show that O-mannosyl glycan epitopes recognized by these antibodies define biochemically distinct glycoforms of RPTPzeta/phosphacan and that these glycoforms differentially decorate the surface of distinct populations of neural cells. To provide a further structural basis for immunochemically based glycoform differences, we characterized the O-linked glycan heterogeneity of RPTPzeta/phosphacan in the early postnatal mouse brain by multidimensional mass spectrometry. Structural characterization of the O-linked glycans released from purified RPTPzeta/phosphacan demonstrated that this protein is a significant substrate for protein O-mannosylation and led to the identification of several novel O-mannose-linked glycan structures, including sulfo-N-acetyllactosamine containing modifications. Taken together, our results suggest that specific glycan modifications may tailor the function of this protein to the unique needs of specific cells. Furthermore, their absence in CMDs suggests that hypoglycosylation of RPTPzeta/phosphacan may have different functional consequences in neurons and glia. PMID- 25737453 TI - Compatibility of an Ultraselective Microcatheter and Epirubicin Loaded 300-500 MUm DC Bead in Ex Vivo Study. AB - PURPOSE: The purpose of this study is to examine whether epirubicin loaded DC Bead 300-500 MUm in size can pass through a 1.8-Fr ultraselective microcatheter in ex vivo study. METHODS: Epirubicin (25 mg/1 mL) loaded 100-300 and 300-500 MUm DC Bead were tested. Both sizes were diluted 5, 10, and 30 times using contrast material. Ultraselective microcatheter with the outer diameter of 1.8 Fr and the inner diameter of .017 inch (431.8 MUm) was used. The diluted DC Bead was injected at a speed of 1 mL/min, and the pressure was continuously measured. The microspheres' shapes after ejection were observed by a stereomicroscope. RESULTS: The maximum pressure of contrast material alone was 8.40 +/- 0.21 psi. The maximum pressure in 5, 10, and 30 times dilution groups of 100-300 MUm were 9.67 +/- 1.18, 9.25 +/- 0.25, and 9.71 +/- 0.28 psi, respectively, whereas 21.10 +/- 10.2, 10.48 +/- 2.14, 10.09 +/- 0.37 psi, respectively in 300-500 MUm groups. The maximum pressure in 5 times dilution group of 300-500 MUm was significantly higher than the other groups (P < 0.05). In 300-500 MUm, 4 of 10 measurements showed high pressure over 24 psi (the maximum value was 43.5 psi) in 5 times dilution group, whereas in 10 times and 30 times dilution groups, all measurements showed less than 12 psi. No damages of microspheres were found. CONCLUSIONS: Epirubicin loaded DC Bead 300-500 MUm in size can pass through a 1.8 Fr ultraselective microcatheter. To avoid high resistance due to microspheres' aggregation, dilution more than 10 times is needed. PMID- 25737454 TI - An Aberrant Left Bronchial Artery Originating from the Proximal Ascending Aorta. AB - The origin of the bronchial arteries (BAs) has numerous anatomical variations. It is important to recognize these variations when performing interventional radiologic procedures in the thorax. We report the case of a 71-year-old man who underwent transarterial infusion chemotherapy for squamous cell carcinoma of the upper lobe of the left lung via a feeding left BA that originated from the proximal ascending aorta. After two cycles of transarterial infusion chemotherapy, the tumor significantly decreased in size. To the best of our knowledge, this is the first report of an aberrant BA originating from this site. PMID- 25737455 TI - Cranial Nerve Dysfunction Associated with Cavernous Dural Arteriovenous Fistulas After Transvenous Embolization with Onyx. AB - PURPOSE: Cranial nerve dysfunction (CND) is not uncommon in patients with cavernous dural arteriovenous fistulas (cDAVFs), and may represent an initial manifestation or a complication after endovascular treatment. This study evaluated the outcome of CND associated with cDAVFs after transvenous embolization (TVE) using Onyx. MATERIALS AND METHODS: Forty-one patients with cDAVFs were treated with TVE in our department between April 2009 and October 2013. For each patient, clinical and radiologic records were retrospectively reviewed and evaluated, with an emphasis placed on evaluating the outcomes of the pre-existing cDAVF-induced CND and the TVE-induced CND. RESULTS: Of the 41 cases, 25 had a history of preoperative CND. Postoperatively, gradual remission to complete recovery (CR) within 8 months was observed in 17 of these cases, transient aggravation in 7, and significant improvement to be better than preoperative function but no CR in 1. All aggravation of CND occurred immediately or within 1 day after TVE and resolved completely within 5 months. Nine patients developed new CND after TVE. New CND occurred during the perioperative period in 8 cases, but all cases resolved completely within 15 days-6 months. Delayed CND was observed in 3 cases with a time lag of 3-25 months after TVE. Two of these completely resolved within 20 days-1 month and the remaining case significantly improved. CONCLUSION: Both the pre-existing cDAVF-induced CND and the TVE-induced new or aggravated CND completely resolved in almost all cases after embolization with Onyx. PMID- 25737456 TI - Endovascular Therapy as a Primary Revascularization Modality in Acute Mesenteric Ischemia. AB - PURPOSE: To evaluate endovascular therapy (EVT) as the primary revascularization method for acute mesenteric ischemia (AMI). METHODS: A retrospective review was performed on all consecutive patients treated for AMI during a 5-year period (January 2009 to December 2013). EVT was attempted in all patients referred for emergent revascularization. Surgical revascularization was performed selectively after failure of EVT. Patient characteristics, clinical presentation, and outcomes were studied. Failures and complications of EVT were recorded. RESULTS: Fifty patients, aged 79 +/- 9 years (mean +/- SD), out of 66 consecutive patients with AMI secondary to embolic or thrombotic obstruction of the superior mesenteric artery were referred for revascularization. The etiology of AMI was embolism in 18 (36 %) and thrombosis in 32 (64 %) patients. EVT was technically successful in 44 (88 %) patients. Mortality after successful or failed EVT was 32 %. The rates of emergency laparotomy, bowel resection, and EVT-related complication were 40, 34, and 10 %, respectively. Three out of six patients with failure of EVT were treated with surgical bypass. EVT failure did not significantly affect survival. CONCLUSIONS: EVT is feasible in most cases of AMI, with favorable patient outcome and acceptable complication rate. PMID- 25737457 TI - Embolization by Direct Puncture with a Transpedicular Approach Using an Isocenter Puncture (ISOP) Method in a Patient with a Type II Endoleak After Endovascular Aortic Repair (EVAR). AB - BACKGROUND: Endovascular aortic repair (EVAR) requires further intervention in 20 30 % of cases, often due to type II endoleak (T2EL). Management options for T2EL include transarterial embolization, direct puncture (DP), or transcaval embolization. We report the case of an 80-year-old man with T2EL who successfully underwent DP embolization. METHODS: Embolization by DP was performed with a transpedicular approach using an isocenter puncture (ISOP) method. An isocenter marker (ICM) was placed at a site corresponding to the aneurysm sac on fluoroscopy in two directions (frontal and lateral views). A vertebroplasty needle was inserted tangentially to the ICM under fluoroscopy and advanced to the anterior wall of the vertebral body. A 20 cm-length, 20-G-PTCD needle was inserted through the outer needle of the 13-G needle and advanced to the ICM. Sac embolization using 25 % N-buty-2-cyanoacrylate diluted with Lipiodol was performed. After complete embolization, rotational DA confirmed good filling of the sac with Lipiodol. The outer cannula and 13-G needle were removed and the procedure was completed. RESULTS: The patient was discharged the next day. Contrast-enhanced computed tomography 1 and 8 months later showed no Lipiodol washout in the aneurysm sac, no endoleak recurrence, and no expansion of the excluded aneurysm. CONCLUSION: DP with a transpedicular approach using ISOP may be useful when translumbar and transabdominal approaches prove difficult. PMID- 25737458 TI - Endovascular Treatment of an Aneurysmal Aberrant Systemic Artery Supplying a Pulmonary Sequestrum. AB - An aberrant systemic artery originating from the abdominal aorta supplying a pulmonary sequestration is a rare congenital malformation. This causes a left-to left shunt. Symptoms include recurrent pneumonias, hemoptysis, and, in the long term, heart failure. Aneurysm of the aberrant vessel is rarely seen. Traditionally, treatment of pulmonary sequestrations includes ligation of the feeding vessel and lobectomy. A new promising treatment is an endovascular approach. Only a few cases describe endovascular treatment of pulmonary sequestration. This is the first published case of a giant aneurysmal branch from the abdominal aorta to the normal basal segments of the lung, successfully occluded with an Amplatzer Vascular Plug II (AVP II, St.Jude Medical, MN, USA) alone. PMID- 25737459 TI - A Rare Anomaly: Recurrent Congenital Aorto-Azygos Fistula After Two Procedure of Transcatheter Occlusion. PMID- 25737460 TI - Disparities in mobile phone access and maternal health service utilization in Nigeria: a population-based survey. AB - BACKGROUND: Mobile communication technologies may reduce maternal health disparities related to cost, distance, and infrastructure. However, the ability of mHealth initiatives to accelerate maternal health goals requires in part that women with the greatest health needs have access to mobile phones. OBJECTIVE: This study examined if women with limited mobile phone access have differential odds of maternal knowledge and health service utilization as compared to female mobile phone users who are currently eligible to participate in maternal mHealth programs. METHODS: Using household survey data from Nigeria, multivariable logistic regressions were used to examine the odds of maternal knowledge and service utilization by mobile phone strata. RESULTS: Findings showed that in settings with unequal access to mobile phones, mHealth interventions may not reach women who have the poorest maternal knowledge and care-seeking as these women often lacked mobile connectivity. As compared to mobile users, women without mobile phone access had significantly lower odds of antenatal care utilization (OR=0.48, 95%CI: 0.36-0.64), skilled delivery (OR=0.56, 95%CI: 0.45 0.70), and modern contraceptive use (OR=0.50, 95%CI: 0.33-0.76) after adjusting for demographic characteristics. They also had significantly lower knowledge of maternal danger signs (OR=0.69, 95%CI: 0.53-0.90) and knowledge of antenatal (OR=0.46, 95%CI: 0.36-0.59) and skilled delivery care benefits (OR=0.62, 95%CI: 0.47-0.82). No differences were observed by mobile phone strata in uptake of emergency obstetric care, postnatal services, or breastfeeding. CONCLUSIONS: As maternal mHealth strategies are increasingly utilized, more efforts are needed to improve women's access to mobile phones and minimize potential health inequities brought on by health systems and technological barriers in access to care. PMID- 25737461 TI - Neoadjuvant endocrine therapy and window of opportunity trials: new standards in the treatment of breast cancer? AB - Until recently, the use of neoadjuvant endocrine therapy was mainly restricted to those patients whose general frailty or comorbidities were contraindications to surgery. There is now increased evidence that certain patient populations (i.e. older patients with hormone-receptor positive disease) can gain as good a pathologic response, with considerably less toxicity, from neoadjuvant endocrine therapy than from neoadjuvant chemotherapy. Optimization of neoadjuvant endocrine therapy is therefore an important therapeutic goal. However, possibly of greater importance in the overall management of breast cancer, is the increased interest in exploring the effects of brief periods of endocrine therapy on in vivo biomarkers, in so called window of opportunity trials. These trials can not only be used to identify the mechanisms of action of novel agents but also to predict optimal subsequent adjuvant therapy for individual patients. While this paper will briefly review the history of neoadjuvant endocrine therapy, more emphasis will be on the evaluation of pivotal window of opportunity trials that will likely lead to a long awaited paradigm shift in the management of breast cancer. PMID- 25737462 TI - Canadian sociological association outstanding contribution lecture: the fading of redistributive politics in Canada. AB - Are redistributive politics in Canada fading or merely in abeyance? In this essay, I examine the empirical evidence for the "fading" metaphor, examine new, neoliberal lenses that have shaped recent policy developments, and identify changes in the role of political actors and policy-making institutions that have facilitated the redistributive weakening. Ever the optimist, however, I conclude on an upbeat note on future democratic possibilities for a fairer and more just Canada. PMID- 25737463 TI - John porter lecture: waves of protest--direct action, deliberation, and diffusion. AB - The book Direct Action, Deliberation and Diffusion: Collective Action After the WTO Protests in Seattle argues that the process of diffusion is dependent on social processes in the receiving context. The most important in social movements is an egalitarian and reflexive deliberation among diverse actors. The book traces the direct action tactics associated with the Seattle protests against the World Trade Organization in 1999 and how these spread to activists in Toronto and New York City. It shows how the structure of the political field, racial and class inequalities, identity boundaries, and organizational and conversational dynamics limited deliberation among activists, and thus limited the diffusion of the Seattle tactics. By constraining the spread of the Seattle tactics, this slowed the global justice movement's wave of protest. In this paper, I explore the application of and implications of this model of protest tactic diffusion to the recent Idle No More mobilizations. PMID- 25737464 TI - [In Process Citation]. AB - The increase in available student placements at colleges and universities, the implementation of provincial and federal postsecondary education policies, and the rise of the educational aspirations of families and individuals have all led to the massification of Canadian higher education. Based on Merle's typology of the forms of democratization, this article attempts to revisit the theory of equality of opportunities by critically analyzing the link between massification of higher education and social equity. The results of an analysis of longitudinal data from the (YIT) Youth in Transition Survey show that at the age of 24 in 2008, approximately 77% of young Canadians have pursued studies in a college or university. If access to postsecondary education is now higher, to what extent has it improved social equity? The article shows, in light of the Merle's typology, that mass university education is achieved in part under the seal of a segregative democratization, while college education tends to be egalitarian. PMID- 25737465 TI - Family Structure and Children's Socioeconomic Attainment: A Canadian Sample. AB - With the proliferation of different family forms in many western countries over the last few decades, research investigating the influence of family structure on children's socioeconomic status attainment has expanded dramatically, especially in the United States. The purpose of this study was to estimate the relative influence of family structure, maternal resources, and family mental health on predicting socioeconomic attainment in young adulthood. Data for this study were derived from a case-comparison, three-wave panel study of single-parent, and two parent families living in London, Ontario, with interviews conducted in 1993 (wave 1), 1994 (wave 2), and between 2005 and 2008 (wave 3). There were virtually no differences in status attainment by family structure. Unexpectedly, however, we found that children raised in temporally stable single-parent families, and those whose mothers transitioned from a single-parent family to a two-parent family had higher socioeconomic status occupations for their longest job held than did children raised in temporally stable two-parent families. Maternal education was positively related to the likelihood that children would graduate from college/university. For those concerned with social policy, this implies that greater attention ought to be paid to addressing disparities in education and family income than to concerns with the kinds of families in which children grow up. PMID- 25737466 TI - The Enduring Influence of Parent's Voluntary Involvement on Their Children's Volunteering in Later Life. AB - This study investigates the effect of parent's voluntary involvement on their children's volunteering in later life, and examines the degree to which this effect persists across older age cohorts. To accomplish this, we make use of retrospective questions from the 2010 Canada Survey of Giving, Volunteering and Participating that ask respondents about their experiences in their school-age years. The results show that parental voluntary involvement is positively related to adult voluntary participation, and that the effect of parental voluntary involvement on later volunteerism appears to persist well into adulthood. The implications of these findings for volunteering in Canada are discussed. PMID- 25737467 TI - To bloom or not to bloom: role of microRNAs in plant flowering. AB - During the course of their life cycles, plants undergo various morphological and physiological changes underlying juvenile-to-adult and adult-to-flowering phase transitions. To flower or not to flower is a key step of plasticity of a plant toward the start of its new life cycle. In addition to the previously revealed intrinsic genetic programs, exogenous cues, and endogenous cues, a class of small non-coding RNAs, microRNAs (miRNAs), plays a key role in plants making the decision to flower by integrating into the known flowering pathways. This review highlights the age-dependent flowering pathway with a focus on a number of timing miRNAs in determining such a key process. The contributions of other miRNAs which exist mainly outside the age pathway are also discussed. Approaches to study the flowering-determining miRNAs, their interactions, and applications are presented. PMID- 25737468 TI - Role of the bridge in photoinduced electron transfer in porphyrin-fullerene dyads. AB - The role of pi-conjugated molecular bridges in through-space and through-bond electron transfer is studied by comparing two porphyrin-fullerene donor-acceptor (D-A) dyads. One dyad, ZnP-Ph-C60 (ZnP = zinc porphyrin), incorporates a phenyl bridge between D and A and behaves very similarly to analogous dyads studied previously. The second dyad, ZnP-EDOTV-C60, introduces an additional 3,4 ethylenedioxythienylvinylene (EDOTV) unit into the conjugated bridge, which increases the distance between D and A, but, at the same time, provides increased electronic communication between them. Two essential outcomes that result from the introduction of the EDOTV unit in the bridge are as follows: 1) faster charge recombination, which indicates enhanced electronic coupling between the charge separated and ground electronic states; and 2) the disappearance of the intramolecular exciplex, which mediates photoinduced charge separation in the ZnP Ph-C60 dyad. The latter can be interpreted as a gradual decrease in electronic coupling between locally excited singlet states of D and A when introducing the EDOTV unit into the D-A bridge. PMID- 25737469 TI - An ATF4-Signal-Modulating Machine Other Than GADD34 Acts in ATF4-to-CHOP Signaling to Block CHOP Expression in ER-Stress-Related Autophagy. AB - Cells respond to ER-stress via ER-stress sensors, leading to the UPR and subsequent apoptosis; however, occasionally, they activate autophagy without subsequent apoptosis in response to ER-stress. We previously showed that the induction of apoptosis by ER-stress was related to the presence or absence of CHOP expression; nevertheless, how ATF4 expression is elicited without downstream CHOP expression is unknown. We studied the role of GADD34 on the induction of autophagy and/or apoptosis by NaF- or tunicamycin-induced ER-stress in HepG2 cells transfected with GADD34 siRNA. Although NaF and tunicamycin both induced PERK activation followed by eIF2alpha phosphorylation and ATF4 expression, CHOP expression was only induced by tunicamycin. Concomitant with the signaling change, autophagy was activated both by NaF and tunicamycin, and apoptosis was induced only by tunicamycin. After 4 h, GADD34 mRNA expression was also increased by NaF and tunicamycin. Suppression of GADD34 by GADD34 siRNA increased ATF4 expression in both NaF- and tunicamycin-treated cells. The GADD34 siRNA increased CHOP expression, which corresponded to increased ATF4 in tunicamycin-treated cells; however, the increased ATF4 did not induce CHOP expression in NaF-treated cells. In concert with signal changes, siRNA treatment additively increased the autophagic activity of both NaF- and tunicamycin-treated cells; however, apoptosis was produced and accelerated only for tunicamycin-treated cells. These findings indicate that GADD34 expression induced by ER-stress delays CHOP expression and retards apoptotic cell death, and that an ATF4-signal-modulating machine other than GADD34 acts on ATF4-to-CHOP signaling to block ATF4-induced CHOP expression in ER-stress related autophagy. PMID- 25737470 TI - A (gray) whale of a tale: a rare view inside one of nature's majestic animals. PMID- 25737471 TI - Impaired Limb Proprioception in Adults With Spasmodic Dysphonia. AB - OBJECTIVES: Focal dystonia of the head and neck are associated with a loss of kinesthetic acuity at muscles distant from the dystonic sites. That is, while the motor deficits in focal dystonia are confined, the associated somatosensory deficits are generalized. This is the first systematic study to examine, if patients diagnosed with spasmodic dystonia (SD) show somatosensory impairments similar in scope to other forms of focal dystonia. METHODS: Proprioceptive acuity (ability to discriminate between two stimuli) for forearm position and motion sense was assessed in 14 spasmodic dystonia subjects and 28 age-matched controls using a passive motion apparatus. Psychophysical thresholds, uncertainty area (UA), and a proprioceptive acuity index (AI) were computed based on the subjects' verbal responses. RESULTS: The main findings are as follows: first, the SD group showed significantly elevated thresholds and UAs for forearm position sense compared with the control group. Second, 9 of 14 dystonia subjects (64%) exhibited an AI for position sense above the control group maximum. Three SD subjects had a motion sense AI above the control group maximum. CONCLUSIONS: The results indicate that impaired limb proprioception is a common feature of SD. Like other forms of focal dystonia, spasmodic dystonia does affect the somatosensation of nondystonic muscle systems. That is, SD is associated with a generalized somatosensory deficit. PMID- 25737472 TI - Laryngeal Electromyography: Are the Results Reproducible? AB - Laryngeal electromyography (LEMG) is an auxiliary diagnostic technique that is used to study neurologic diseases that affect the larynx. This study aimed to verify the reproducibility and accordance of LEMG findings obtained by different approaches applied to the same intrinsic laryngeal muscle in patients with neurologic disorders of the larynx. STUDY DESIGN: This study is prospective, blind, randomized, and controlled. METHODS: Forty subjects (20 males and 20 females) aged between 21 and 78 years underwent LEMG of the thyroarytenoid muscles by different techniques, with a total of 120 insertion sites for analysis. The electrophysiological findings were grouped as follows: (1) equal LEMG findings; (2) different LEMG findings but in agreement on the same electromyographic pattern; and (3) different LEMG findings and in discord on the same electromyographic pattern. RESULTS: We found 5% discordance in the LEMG findings between the sites analyzed. CONCLUSIONS: LEMG is an important and useful technique, but caution must be taken to avoid misinterpretation and the wrong muscle approach. PMID- 25737473 TI - Occupational Vocal Health of Elite Sports Coaches: An Exploratory Pilot Study of Football Coaches. AB - OBJECTIVE: To explore the occupational voice use and vocal health of elite football coaches. STUDY DESIGN: This pilot study explored coaches' voice use patterns and vocal demands across workplace environments. Each coach's experiences of voice symptoms and voice problems were also investigated. METHODS: Twelve Australian professional football coaches participated in a mixed-methods data collection approach. Data were collected through acoustic voice measurement (Ambulatory Phonation Monitor), semistructured interviews, and a voice symptom questionnaire (Voice Capabilities Questionnaire). RESULTS: Acoustic measures suggested heavy vocal loads for coaches during player training. All participants reported experiencing voice symptoms. They also suggested that the structure of their working week, workplace tasks, and vocal demands impacted on their voices. Despite this, participants reported little previous reflection or awareness of what impacted on their voices. Coaches typically did not consider how to support their voices during daily work and discussed experiencing voice symptoms as an inevitable part of their jobs. CONCLUSIONS: This study demonstrates that occupational vocal demands may negatively impact on sports coaches' vocal health. This is particularly important, considering coaches' heavy vocal loads across coaching tasks and reported negative occupational vocal health experience. Furthermore, coaches' limited insight into voice use and vocal health management may impact on their vocal performance and health. Given the exploratory nature of this study, further research into coaches' occupational vocal health is warranted. PMID- 25737474 TI - The Comparison of Thyroarytenoid Muscle Myectomy and Type II Thyroplasty for Spasmodic Dysphonia. AB - OBJECTIVE: Surgical treatments for adductor spasmodic dysphonia include bilateral thyroarytenoid muscle myectomy (TAM) and type II thyroplasty (TPII), both of which are commonly performed. The present study aimed to compare the effects of TAM and TPII. STUDY DESIGN: Retrospective study. METHODS: Subjects were 30 and 35 patients who underwent TAM and TPII, between March 2008 and November 2012. Voice quality was evaluated based on "voice handicap index 10 (VHI10)" and auditory impressions before and 6 months after surgery using five parameters: "strangulation," "interruption," "tremor," "grade," and "breathiness." RESULTS: Comparison of the two procedures revealed significant improvements in VHI10, strangulation, interruption, and tremor, and a significant decline in breathiness after surgery. In particular, VHI10 was improved by more than six points in 90% of patients with TAM, and 96% with TPII. No significant difference was observed between the severities of two procedures preoperatively. Comparison of each postoperative score between the two procedures revealed that TAM significantly improved strangulation, interruption, and tremor, and significantly worsened breathiness, with no significant difference in VHI10. Scatter plots (x: preoperative scores; y: postoperative scores) and regression lines of evaluation items demonstrated that TAM is more effective than TPII in severe cases. CONCLUSIONS: Compared with TPII, TAM tends to improve strangulation, interruption, and tremor; however, it tends to worsen breathiness postoperatively. Postoperative VHI10 scores did not differ significantly between the two procedures. Given favorable improvement rates, both surgical procedures were considered effective. PMID- 25737475 TI - Vocal Fold Vibration in Vocal Fold Atrophy: Quantitative Analysis With High-Speed Digital Imaging. AB - INTRODUCTION: Vocal fold vibrations of vocal fold atrophy (VFA), a rapidly increasing voice disorder owing to worldwide societal aging, have not been clarified by high-speed digital imaging (HSDI). METHODS: The HSDI method was performed on 46 patients (33 males and 13 females) with VFA and 20 vocally healthy subjects (8 males and 12 females), and the obtained data were quantitatively evaluated by frame-by-frame analysis, laryngotopography, single- and multi-line kymography, and glottal area waveform. RESULTS: Overall, patients with VFA revealed larger open quotients, larger lateral phase difference, larger integral glottal width (the average glottal width over a glottal cycle), and smaller speed index than vocally healthy subjects. Some gender difference was noted: in males, lateral phase difference was not significant; and in females, integral glottal width and speed index were not significant. Correlation study revealed moderate correlations between HSDI-derived parameters and conventional acoustic or aerodynamic parameters. CONCLUSIONS: The combination of multiple HSDI analysis methods was effective in documenting the characteristics of vocal fold vibrations in VFA. The knowledge of general vibratory characteristics and gender difference is beneficial for the appropriate clinical care of VFA. PMID- 25737476 TI - Gender Differences in the Prevalence of Vocal Symptoms in Smokers. AB - OBJECTIVES: The purpose of the present study was to explore possible gender differences in the occurrence of vocal symptoms in smokers. METHODS: A total of 1728 respondents, 68% women and 32% men completed a "Speech, language and voice" questionnaire. The questions concerning six vocal symptoms along with questions concerning smoking habits were used as the main data source for the present study. RESULTS: About 24% of the men and 22% of the women were smokers. Male smokers did not differ from male nonsmokers in reporting vocal symptoms. In contrast, female smokers were more likely than female nonsmokers to report having vocal symptoms. Smoking seemed to have a significant effect on four of the six vocal symptoms in the female smokers. CONCLUSIONS: There appears to be a difference in the effects of smoking between men and women. The female vocal folds may be more vulnerable to cigarette smoke, probably due to anatomical and physiological differences. Nevertheless, it is yet to be demonstrated that the vocal symptoms in female smokers are causally related to smoking. It could be meaningful to use gender specific strategies when informing smokers about the risks for voice problems. PMID- 25737477 TI - Hermann Gutzmann (1865-1922): The Father of Phoniatrics, an Independent Specialty. PMID- 25737478 TI - Measurement of Voice Quality, Anxiety and Depression Symptoms After Speech Therapy. AB - OBJECTIVE: To verify changes in vocal behavior of dysphonia patients and components of anxiety and depression symptoms before and after voice therapy. STUDY DESIGN: It is an uncontrolled clinical trial on individuals with dysphonia who attended voice therapy at the outpatient clinic of a hospital in southern Brazil. METHODS: Statistical analysis was carried out using descriptive statistics, Mann-Whitney and Wilcoxon tests, assuming maximum significance level of 5% (P <= 0.05), SPSS 16.0. All patients underwent otorhinolaryngologic assessment for laryngeal disorder diagnosis. Perceptual-auditory voice assessment (GRBAS scale) and the Hospital Anxiety and Depression Scale were applied before and after voice therapy. RESULTS: Sixty-eight patients, 23 of whom were men (33.82%), mean age of 49 years (standard deviation +/- 19.14). The number of voice therapy sessions varied according to each case, with a mean of 10.31 (standard deviation +/- 5.32). The comparisons between psychological or psychiatric referral and participants' age revealed statistical significance, suggesting that younger people were referred to the specialties because they were suspected potential clinical cases. Comparisons between voice parameters, anxiety and depression scores before and after voice therapy showed statistically significant findings. CONCLUSIONS: This study identified the presence of emotional symptoms in dysphonia patients and indicated that voice therapy is effective to improve voice quality and to early detect and help reduce anxiety and depression symptoms. It also highlights the influence of psychological and psychiatric referral on emotional symptoms. The need for controlled trials and the importance of interdisciplinary interventions in this area for the complete care of individuals with dysphonia is pointed out. PMID- 25737479 TI - MQAPsingle: A quasi single-model approach for estimation of the quality of individual protein structure models. AB - We present a Model Quality Assessment Program (MQAP), called MQAPsingle, for ranking and assessing the absolute global quality of single protein models. MQAPsingle is quasi single-model MQAP, a method that combines advantages of both "pure" single-model MQAPs and clustering MQAPs. This approach results in higher accuracy compared to the state-of-the-art single-model MQAPs. Notably, the prediction for a given model is the same regardless if this model is submitted to our server alone or together with other models. Proteins 2016; 84:1021-1028. (c) 2015 Wiley Periodicals, Inc. PMID- 25737481 TI - New insight into the photoheterotrophic growth of the isocytrate lyase-lacking purple bacterium Rhodospirillum rubrum on acetate. AB - Purple non-sulfur bacteria are well known for their metabolic versatility. One of these bacteria, Rhodospirillum rubrum S1H, has been selected by the European Space Agency to ensure the photoheterotrophic assimilation of volatile fatty acids in its regenerative life support system, MELiSSA. Here, we combined proteomic analysis with bacterial growth analysis and enzymatic activity assays in order to better understand acetate photoassimilation. In this isocitrate lyase lacking organism, the assimilation of two-carbon compounds cannot occur through the glyoxylate shunt, and the citramalate cycle has been proposed to fill this role, while, in Rhodobacter sphaeroides, the ethylmalonyl-CoA pathway is used for acetate assimilation. Using proteomic analysis, we were able to identify and quantify more than 1700 unique proteins, representing almost one-half of the theoretical proteome of the strain. Our data reveal that a pyruvate : ferredoxin oxidoreductase (NifJ) could be used for the direct assimilation of acetyl-CoA through pyruvate, potentially representing a new redox-balancing reaction. We additionally propose that the ethylmalonyl-CoA pathway could also be involved in acetate assimilation by the examined strain, since specific enzymes of this pathway were all upregulated and activity of crotonyl-CoA reductase/carboxylase was increased in acetate conditions. Surprisingly, we also observed marked upregulation of glutaryl-CoA dehydrogenase, which could be a component of a new pathway for acetate photoassimilation. Finally, our data suggest that citramalate could be an intermediate of the branched-chain amino acid biosynthesis pathway, which is activated during acetate assimilation, rather than a metabolite of the so-called citramalate cycle. PMID- 25737480 TI - Loss of Egr-1 sensitizes pancreatic beta-cells to palmitate-induced ER stress and apoptosis. AB - Pancreatic beta-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how beta-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr 1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue beta-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic beta-cells to translate fatty acid stimuli into a cellular adaptation mechanism. KEY MESSAGE: PA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2 Elk-1 cascade. Egr-1 attenuates PA-induced ER stress and apoptosis. Egr-1 maintains Akt survival pathway to protect beta-cells from PA-induced apoptosis. Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis. Human EGR1 expression correlates with genes for ER stress and anti-apoptosis. PMID- 25737482 TI - Comparative genomic analysis of coffee-infecting Xylella fastidiosa strains isolated from Brazil. AB - Strains of Xylella fastidiosa constitute a complex group of bacteria that develop within the xylem of many plant hosts, causing diseases of significant economic importance, such as Pierce's disease in North American grapevines and citrus variegated chlorosis in Brazil. X. fastidiosa has also been obtained from other host plants, in direct correlation with the development of diseases, as in the case of coffee leaf scorch (CLS)--a disease with potential to cause severe economic losses to the Brazilian coffee industry. This paper describes a thorough genomic characterization of coffee-infecting X. fastidiosa strains, initially performed through a microarray-based approach, which demonstrated that CLS strains could be subdivided in two phylogenetically distinct subgroups. Whole genomic sequencing of two of these bacteria (one from each subgroup) allowed identification of ORFs and horizontally transferred elements (HTEs) that were specific to CLS-related X. fastidiosa strains. Such analyses confirmed the size and importance of HTEs as major mediators of chromosomal evolution amongst these bacteria, and allowed identification of differences in gene content, after comparisons were made with previously sequenced X. fastidiosa strains, isolated from alternative hosts. Although direct experimentation still needs to be performed to elucidate the biological consequences associated with such differences, it was interesting to verify that CLS-related bacteria display variations in genes that produce toxins, as well as surface-related factors (such as fimbrial adhesins and LPS) that have been shown to be involved with recognition of specific host factors in different pathogenic bacteria. PMID- 25737483 TI - Analysis of the Peltigera membranacea metagenome indicates that lichen-associated bacteria are involved in phosphate solubilization. AB - Although lichens are generally described as mutualistic symbioses of fungi and photosynthetic partners, they also harbour a diverse non-phototrophic microbiota, which is now regarded as a significant part of the symbiosis. However, the role of the non-phototrophic microbiota within the lichen is still poorly known, although possible functions have been suggested, including phosphate solubilization and various lytic activities. In the present study we focus on the bacterial biota associated with the foliose lichen Peltigera membranacea. To address our hypotheses on possible roles of the non-phototrophic microbiota, we used a metagenomic approach. A DNA library of bacterial sequence contigs was constructed from the lichen thallus material and the bacterial microbiota DNA sequence was analysed in terms of phylogenetic diversity and functional gene composition. Analysis of about 30,000 such bacterial contigs from the P. membranacea metagenome revealed significant representation of several genes involved in phosphate solubilization and biopolymer degradation. PMID- 25737485 TI - Reporting and replicating trials of exercise-based cardiac rehabilitation: do we know what the researchers actually did? AB - BACKGROUND: Complete reporting of all components of complex interventions is essential for translation of research evidence into clinical practice. Previous work has highlighted deficiencies in the reporting of nonpharmacological interventions; however, the reporting quality of exercise-based interventions for coronary heart disease has not been examined. METHODS AND RESULTS: A systematic search strategy was used to identify randomized controlled trials of exercise based cardiac rehabilitation published until December 2013. Fifty-seven trials were included, reporting on 74 interventions. Intervention description completeness was assessed using the Template for Intervention Description and Replication checklist. Missing intervention details were then sought from additional published material and also by emailing corresponding authors. Only 6 interventions (8%) sufficiently described all required items within the main publication; this increased to 11 (15%) after searching for additional published material and 32 (43%) after contacting trial authors. Although location/setting and duration were consistently well reported in publications, complete descriptions of the exercise schedule, as well as details about its tailoring and progression, were missing for over half of interventions (complete for 42% and 36% of interventions, respectively). Although some authors (25/61) were able to provide missing intervention details when contacted, others could not be located (20) or did not respond (16). CONCLUSIONS: Inadequate reporting of cardiac rehabilitation interventions is a substantial problem, with essential information frequently missing, and for almost half of all interventions, unobtainable after publication. A conscientious effort to address this problem could facilitate an improvement in the quality of cardiac rehabilitation delivered in clinical practice. PMID- 25737484 TI - The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge. AB - BACKGROUND: The HEART Pathway is a decision aid designed to identify emergency department patients with acute chest pain for early discharge. No randomized trials have compared the HEART Pathway with usual care. METHODS AND RESULTS: Adult emergency department patients with symptoms related to acute coronary syndrome without ST-elevation on ECG (n=282) were randomized to the HEART Pathway or usual care. In the HEART Pathway arm, emergency department providers used the HEART score, a validated decision aid, and troponin measures at 0 and 3 hours to identify patients for early discharge. Usual care was based on American College of Cardiology/American Heart Association guidelines. The primary outcome, objective cardiac testing (stress testing or angiography), and secondary outcomes, index length of stay, early discharge, and major adverse cardiac events (death, myocardial infarction, or coronary revascularization), were assessed at 30 days by phone interview and record review. Participants had a mean age of 53 years, 16% had previous myocardial infarction, and 6% (95% confidence interval, 3.6%-9.5%) had major adverse cardiac events within 30 days of randomization. Compared with usual care, use of the HEART Pathway decreased objective cardiac testing at 30 days by 12.1% (68.8% versus 56.7%; P=0.048) and length of stay by 12 hours (9.9 versus 21.9 hours; P=0.013) and increased early discharges by 21.3% (39.7% versus 18.4%; P<0.001). No patients identified for early discharge had major adverse cardiac events within 30 days. CONCLUSIONS: The HEART Pathway reduces objective cardiac testing during 30 days, shortens length of stay, and increases early discharges. These important efficiency gains occurred without any patients identified for early discharge suffering MACE at 30 days. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01665521. PMID- 25737486 TI - The cards I was dealt: my life with familial hypercholesterolemia. PMID- 25737487 TI - Self-blood pressure monitoring in an urban, ethnically diverse population: a randomized clinical trial utilizing the electronic health record. AB - BACKGROUND: Hypertension is a leading risk factor for cardiovascular disease. Although control rates have improved over time, racial/ethnic disparities in hypertension control persist. Self-blood pressure monitoring, by itself, has been shown to be an effective tool in predominantly white populations, but less studied in minority, urban communities. These types of minimally intensive approaches are important to test in all populations, especially those experiencing related health disparities, for broad implementation with limited resources. METHODS AND RESULTS: The New York City Health Department in partnership with community clinic networks implemented a randomized clinical trial (n=900, 450 per arm) to investigate the effectiveness of self-blood pressure monitoring in medically underserved and largely black and Hispanic participants. Intervention participants received a home blood pressure monitor and training on use, whereas control participants received usual care. After 9 months, systolic blood pressure decreased (intervention, 14.7 mm Hg; control, 14.1 mm Hg; P=0.70). Similar results were observed when incorporating longitudinal data and calculating a mean slope over time. Control was achieved in 38.9% of intervention and 39.1% of control participants at the end of follow-up; the time-to-event experience of achieving blood pressure control in the intervention versus control groups were not different from each other (logrank P value =0.91). CONCLUSIONS: Self-blood pressure monitoring was not shown to improve control over usual care in this largely minority, urban population. The patient population in this study, which included a high proportion of Hispanics and uninsured persons, is understudied. Results indicate these groups may have additional meaningful barriers to achieving blood pressure control beyond access to the monitor itself. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov. Unique Identifier: NCT01123577. PMID- 25737488 TI - Cardiology and accountable care. PMID- 25737489 TI - Finding the holy grail is not a short-term project. PMID- 25737490 TI - Situs inversus with levocardia, infrahepatic interruption of the inferior vena cava, and azygos continuation: a case report. AB - Situs inversus incompletus is a rare congenital condition in which the major abdominal organs are reversed or mirrored from their normal positions. It is often associated with multiple congenital anomalies. We present the case of a 38 year-old woman with dyspnea and a clinical history of chronic kidney disease and kidney transplantation. Echocardiography showed a right atrial mass, and analysis of multidetector computed tomography angiography revealed the interruption of the inferior vena cava with an increase of the azygos vein and azygos continuation. These congenital malformations are often associated with deep vein thrombosis and/or pulmonary thromboembolism and explained the occurrence of dyspnea. Cardiac magnetic resonance with contrast medium confirmed the presence of the right atrial mass, the characteristics of which were attributed to interatrial thrombus, which was further confirmed by the success of thrombolytic therapy and the remission of symptoms. In conclusion, we described a case of situs inversus with levocardia in association with infrahepatic interruption of the inferior vena cava, and azygos continuation with cardiac thrombus and chronic renal failure. PMID- 25737491 TI - Nonadaptive Amino Acid Convergence Rates Decrease over Time. AB - Convergence is a central concept in evolutionary studies because it provides strong evidence for adaptation. It also provides information about the nature of the fitness landscape and the repeatability of evolution, and can mislead phylogenetic inference. To understand the role of adaptive convergence, we need to understand the patterns of nonadaptive convergence. Here, we consider the relationship between nonadaptive convergence and divergence in mitochondrial and model proteins. Surprisingly, nonadaptive convergence is much more common than expected in closely related organisms, falling off as organisms diverge. The extent of the convergent drop-off in mitochondrial proteins is well predicted by epistatic or coevolutionary effects in our "evolutionary Stokes shift" models and poorly predicted by conventional evolutionary models. Convergence probabilities decrease dramatically if the ancestral amino acids of branches being compared have diverged, but also drop slowly over evolutionary time even if the ancestral amino acids have not substituted. Convergence probabilities drop-off rapidly for quickly evolving sites, but much more slowly for slowly evolving sites. Furthermore, once sites have diverged their convergence probabilities are extremely low and indistinguishable from convergence levels at randomized sites. These results indicate that we cannot assume that excessive convergence early on is necessarily adaptive. This new understanding should help us to better discriminate adaptive from nonadaptive convergence and develop more relevant evolutionary models with improved validity for phylogenetic inference. PMID- 25737492 TI - [Psychotherapeutic and psychosocial interventions in cancer]. AB - Every cancer patient and also other family members should have the chance to utilize psychosocial support facilities. Nowadays, there are well-defined data for estimating the needs for psychosocial support measures and also empirical evidence demonstrating the effectiveness of the most important psychotherapeutic interventions. However, the implementation of these measures within the healthcare system still has many difficulties. The reasons for this are the complexity and the problems to identify those patients who are in need of psychotherapeutic support. Therefore, there are national and international recommendations to screen every individual cancer patient for psychosocial distress and unmet support needs. The presence of a psychiatric diagnosis is not a sufficient criterion. The most important interventions vary between psychoeducation and supplying information, counseling and psychotherapy. In psychotherapy supportive-expressive as well as cognitive-behavioral interventions have proved their value. Of increasing importance are time-limited (approximately 10 sessions) interventions focusing on specific problems, e.g. fear of disease progression or interventions within palliative care. PMID- 25737493 TI - [Comorbid depressive and anxiety disorders in patients with cancer]. AB - Patients with cancer face a high risk of comorbid depressive and anxiety disorders that have to be paradigmatically considered within a complex biopsychosocial context. Several conceptual challenges have to be mastered in arriving at a correct clinical diagnosis. Coexistent affective and anxiety disorders in cancer patients include a more dramatic subjective suffering, reduced psychological coping, possible negative interference with somatic treatment and rehabilitation, impaired quality of life and higher grades of psychosocial disability. They may also lead to an overall increased risk of somatic morbidity, a more rapid progression of cancer and a higher cancer-related mortality in the course of the disease. Manifold psychological, psychosocial and existential, cancer and treatment-related stressors have to be considered with respect to common neurobiological, especially neuroendocrine and neuroinflammatory mechanisms. Complex psychosomatic, somatopsychic and somato somatic effects must always be considered. Evidence-based approaches in psychotherapy and pharmacotherapy exist for the integrative treatment of comorbid depressive and anxiety disorders in cancer. PMID- 25737494 TI - [Treatment of depression in coronary heart disease]. AB - Depression and coronary heart disease (CHD) are leading causes of disability and show a high comorbidity. Furthermore, depression is an independent risk factor for an unfavorable course and increased mortality in patients with CHD. In contrast, successful treatment of depression can reduce the risk of cardiac events. Currently, there are several treatment options for the management of depression in CHD, including self-management strategies, psychotherapy, pharmacotherapy and collaborative care models. This article provides an overview of the epidemiology of depression in CHD, the mechanisms of association and the current state of evidence with respect to the different treatment options. PMID- 25737496 TI - Population risk prediction models for incident heart failure: a systematic review. AB - BACKGROUND: The prevalence of heart failure is expected to significantly rise unless high-risk patients are effectively screened and appropriate, cost effective prevention interventions are implemented. METHODS AND RESULTS: We performed a systematic review to evaluate the prediction characteristics of the published heart failure risk prediction models as of August 2014 using MEDLINE and EMBASE databases. Eligible studies reported the development, validation, or impact assessment of a model. Two investigators performed independent review to extract data on study design and characteristics, risk predictors, discrimination, calibration, and reclassification ability of models, as well as validation and impact analysis. We included 13 publications reporting on 28 heart failure risk prediction models. Models had acceptable-to-good discriminatory ability (c-statistics, >0.70) in the derivation sample. Calibration was less commonly assessed, but was acceptable when it was. Only 2 models were externally validated more than once, displaying modest-to-acceptable discrimination (c statistics, 0.61-0.79). When assessed, novel blood and imaging markers modestly improved risk prediction. One model assessed the prediction properties in race based subgroups, whereas 2 models evaluated sex-based subgroups. Impact analysis found none of the models recommended for use in any clinical practice guideline. CONCLUSIONS: Incident heart failure risk prediction remains at an early stage. The discrimination ability of current models is acceptable in derivation data sets but most models have not been externally validated. It remains unclear which models are cost-effective and best suit population screening needs. The effects of models on clinical and preventative care requires further study. PMID- 25737495 TI - G Protein-Coupled Receptor (GPCR) Expression in Native Cells: "Novel" endoGPCRs as Physiologic Regulators and Therapeutic Targets. AB - G protein-coupled receptors (GPCRs), the largest family of signaling receptors in the human genome, are also the largest class of targets of approved drugs. Are the optimal GPCRs (in terms of efficacy and safety) currently targeted therapeutically? Especially given the large number (~ 120) of orphan GPCRs (which lack known physiologic agonists), it is likely that previously unrecognized GPCRs, especially orphan receptors, regulate cell function and can be therapeutic targets. Knowledge is limited regarding the diversity and identity of GPCRs that are activated by endogenous ligands and that native cells express. Here, we review approaches to define GPCR expression in tissues and cells and results from studies using these approaches. We identify problems with the available data and suggest future ways to identify and validate the physiologic and therapeutic roles of previously unrecognized GPCRs. We propose that a particularly useful approach to identify functionally important GPCRs with therapeutic potential will be to focus on receptors that show selective increases in expression in diseased cells from patients and experimental animals. PMID- 25737497 TI - Chronic administration of the nitroxyl donor 1-nitrosocyclo hexyl acetate limits left ventricular diastolic dysfunction in a mouse model of diabetes mellitus in vivo. AB - BACKGROUND: Nitroxyl (HNO), a redox congener of nitric oxide (NO.), is a novel regulator of cardiovascular function, combining concomitant positive inotropic, lusitropic, and vasodilator properties. Moreover, HNO exhibits myocardial antihypertrophic and superoxide-suppressing actions. Despite these favorable actions, the impact of chronic HNO administration has yet to be reported in the context of cardiomyopathy. Diabetic cardiomyopathy is characterized by early diastolic dysfunction and adverse left ventricular (LV) structural remodeling, with LV superoxide generation playing a major causal role. We tested the hypothesis that the HNO donor 1-nitrosocyclohexylacetate (1-NCA) limits cardiomyocyte hypertrophy and LV diastolic dysfunction in a mouse model of diabetes mellitus in vivo. METHODS AND RESULTS: Diabetes mellitus was induced in male FVB/N mice using streptozotocin. After 4 weeks, diabetic and nondiabetic mice were allocated to 1-NCA therapy (83 mg/kg per day IP) or vehicle and followed up for a further 4 weeks. Diabetes mellitus-induced LV diastolic dysfunction was evident on echocardiography-derived E and A wave velocities, E:A ratio, deceleration, and isovolumic relaxation times; LV systolic function was preserved. Increased LV cardiomyocyte size, hypertrophic and profibrotic gene expression, and upregulation of LV superoxide were also evident. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as an HNO donor was demonstrated by sensitivity of acute 1-NCA to l-cysteine but not to hydroxocobalamin in the normal rat heart ex vivo. CONCLUSIONS: Our studies provide the first evidence that HNO donors may represent a promising strategy for treatment of diabetic cardiomyopathy and implies therapeutic efficacy in settings of chronic heart failure. PMID- 25737498 TI - Effect of estimated plasma volume reduction on renal function for acute heart failure differs between patients with preserved and reduced ejection fraction. AB - BACKGROUND: The prognostic relevance of plasma volume reduction (PVR) in acute heart failure patients remains unclear because of the confounding hemodynamic effect of left ventricular ejection fraction impairment on kidney function. METHODS AND RESULTS: Subjects enrolled in the West Tokyo Heart Failure Registry were examined. The PV at admission and discharge was estimated from the subjects' body weight and its deviation from the ideal body weight. Patients in the top tertile of estimated PVR were classified as PVR+. Of the 381 patients with acute heart failure, 181 (47.5%) had heart failure with preserved ejection fraction (HFpEF). Estimated PVR was associated with worsening renal function in the HFpEF (odds ratio, 3.28; 95% confidence interval, 1.55-6.96; P=0.002) but not in the heart failure with reduced ejection fraction cohort (odds ratio, 1.22; 95% confidence interval, 0.61-2.42; P=0.57). This association in the HFpEF cohort remained significant after adjusting for a history of hypertension and diabetes mellitus and the estimated glomerular filtration rate (odds ratio, 3.34; 95% confidence interval, 1.52-7.33; P=0.003). The use of intravenous diuretics was a significant predictor of PVR in the HFpEF and heart failure with reduced ejection fraction groups. CONCLUSIONS: The effect of estimated PVR differs by HF type, and the estimated PVR during hospitalization is a predictor of worsening renal function in patients with HFpEF but not in heart failure with reduced ejection fraction. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index j.html. Unique identifier: UMIN000001549. PMID- 25737500 TI - News feature: A matter of timing. PMID- 25737499 TI - Nonvenous origin of dermal lymphatic vasculature. AB - RATIONALE: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. OBJECTIVE: We aimed to clarify the origin of the murine dermal lymphatic vasculature. METHODS AND RESULTS: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. CONCLUSIONS: Our results demonstrate a significant contribution of nonvenous derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration. PMID- 25737502 TI - Porcelain aorta: a comprehensive review. PMID- 25737504 TI - Progression of electroanatomic substrate and electric storm recurrence in a patient with Brugada syndrome. PMID- 25737505 TI - Asymptomatic progression of an atherosclerotic giant right coronary artery aneurysm over 12 years: characterization using cardiovascular magnetic resonance and computed tomography imaging. PMID- 25737506 TI - Coarctation of the aorta. PMID- 25737507 TI - Immunohistochemical Loss of LKB1 Is a Biomarker for More Aggressive Biology in KRAS-Mutant Lung Adenocarcinoma. AB - PURPOSE: LKB1 loss is common in lung cancer, but no assay exists to efficiently evaluate the presence or absence of LKB1. We validated an IHC assay for LKB1 loss and determined the impact of LKB1 loss in KRAS-mutant non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We optimized and validated an IHC assay for LKB1 (clone Ley37D/G6) using a panel of lung cancer cell lines and tumors with known LKB1 mutations, including 2 patients with Peutz-Jeghers syndrome (PJS) who developed lung adenocarcinoma. We retrospectively analyzed tumors for LKB1 using IHC from 154 KRAS-mutant NSCLC patients, including 123 smokers and 31 never smokers, and correlated the findings with patient and tumor characteristics and clinical outcome. RESULTS: LKB1 expression was lost by IHC in 30% of KRAS-mutant NSCLC (smokers 35% vs. never-smokers 13%, P = 0.017). LKB1 loss did not correlate with a specific KRAS mutation but was more frequent in tumors with KRAS transversion mutations (P = 0.029). KRAS-mutant NSCLC patients with concurrent LKB1 loss had a higher number of metastatic sites at the time of diagnosis (median 2.5 vs. 2, P = 0.01), higher incidence of extrathoracic metastases (P = 0.01), and developed brain metastasis more frequently (48% vs. 25%, P = 0.02). There was a nonsignificant trend to worse survival in stage IV KRAS-mutant NSCLC patients with LKB1 loss. CONCLUSIONS: LKB1 IHC is a reliable and efficient assay to evaluate for loss of LKB1 in clinical samples of NSCLC. LKB1 loss is more common in smokers, and is associated with a more aggressive clinical phenotype in KRAS-mutant NSCLC patients, accordingly to preclinical models. PMID- 25737508 TI - Robotic surgery: edge of tomorrow? PMID- 25737509 TI - A nerve too far? PMID- 25737510 TI - Robotic surgery in trauma and orthopaedics: a systematic review. AB - The use of robots in orthopaedic surgery is an emerging field that is gaining momentum. It has the potential for significant improvements in surgical planning, accuracy of component implantation and patient safety. Advocates of robot assisted systems describe better patient outcomes through improved pre-operative planning and enhanced execution of surgery. However, costs, limited availability, a lack of evidence regarding the efficiency and safety of such systems and an absence of long-term high-impact studies have restricted the widespread implementation of these systems. We have reviewed the literature on the efficacy, safety and current understanding of the use of robotics in orthopaedics. PMID- 25737511 TI - Early surveillance of ceramic-on-metal total hip arthroplasty. AB - Ceramic-on-metal (CoM) is a relatively new bearing combination for total hip arthroplasty (THA) with few reported outcomes. A total of 287 CoM THAs were carried out in 271 patients (mean age 55.6 years (20 to 77), 150 THAs in female patients, 137 in male) under the care of a single surgeon between October 2007 and October 2009. With the issues surrounding metal-on-metal bearings the decision was taken to review these patients between March and November 2011, at a mean follow-up of 34 months (23 to 45) and to record pain, outcome scores, radiological analysis and blood ion levels. The mean Oxford Hip Score was 19.2 (12 to 53), 254 patients with 268 hips (95%) had mild/very mild/no pain, the mean angle of inclination of the acetabular component was 44.8(o) (28(o) to 63(o)), 82 stems (29%) had evidence of radiolucent lines of > 1 mm in at least one Gruen zone and the median levels of cobalt and chromium ions in the blood were 0.83 MUg/L (0.24 MUg/L to 27.56 MUg/L) and 0.78 MUg/L (0.21 MUg/L to 8.84 MUg/L), respectively. The five-year survival rate is 96.9% (95% confidence interval 94.7% to 99%). Due to the presence of radiolucent lines and the higher than expected levels of metal ions in the blood, we would not recommend the use of CoM THA without further long-term follow-up. We plan to monitor all these patients regularly. PMID- 25737512 TI - The validity of a novel radiological method for measuring femoral stem version on anteroposterior radiographs of the hip after total hip arthroplasty. AB - Femoral stem version has a major influence on impingement and early post operative stability after total hip arthroplasty (THA). The main objective of this study was to evaluate the validity of a novel radiological method for measuring stem version. Anteroposterior (AP) radiographs and three-dimensional CT scans were obtained for 115 patients (female/male 63/72, mean age 62.5 years (50 to 75)) who had undergone minimally invasive, cementless THA. Stem version was calculated from the AP hip radiograph by rotation-based change in the projected prosthetic neck-shaft (NSA*) angle using the mathematical formula ST = arcos [tan (NSA*) / tan (135)]. We used two independent observers who repeated the analysis after a six-week interval. Radiological measurements were compared with 3D-CT measurements by an independent, blinded external institute. We found a mean difference of 1.2 degrees (sd 6.2) between radiological and 3D-CT measurements of stem version. The correlation between the mean radiological and 3D-CT stem torsion was r = 0.88 (p < 0.001). The intra- (intraclass correlation coefficient >= 0.94) and inter-observer agreement (mean concordance correlation coefficient = 0.87) for the radiological measurements were excellent. We found that femoral tilt was associated with the mean radiological measurement error (r = 0.22, p = 0.02). The projected neck-shaft angle is a reliable method for measuring stem version on AP radiographs of the hip after a THA. However, a highly standardised radiological technique is required for its precise measurement. PMID- 25737513 TI - Revision total hip arthroplasty in patients with extensive proximal femoral bone loss using a fluted tapered modular femoral component. AB - Revision total hip arthroplasty (THA) is challenging when there is severe loss of bone in the proximal femur. The purpose of this study was to evaluate the clinical and radiographic outcomes of revision THA in patients with severe proximal femoral bone loss treated with a fluted, tapered, modular femoral component. Between January 1998 and December 2004, 92 revision THAs were performed in 92 patients using a single fluted, tapered, modular femoral stem design. Pre-operative diagnoses included aseptic loosening, infection and peri prosthetic fracture. Bone loss was categorised pre-operatively as Paprosky types III-IV, or Vancouver B3 in patients with a peri-prosthetic fracture. The mean clinical follow-up was 6.4 years (2 to 12). A total of 47 patients had peri operative complications, 27 of whom required further surgery. However, most of these further operations involved retention of a well-fixed femoral stem, and 88/92 femoral components (97%) remained in situ. Of the four components requiring revision, three were revised for infection and were well fixed at the time of revision; only one (1%) was revised for aseptic loosening. The most common complications were post-operative instability (17 hips, 19%) and intra-operative femoral fracture during insertion of the stem (11 hips, 12%). Diaphyseal stress shielding was noted in 20 hips (22%). There were no fractures of the femoral component. At the final follow-up 78% of patients had minimal or no pain. Revision THA in patients with extensive proximal femoral bone loss using the Link MP fluted, tapered, modular stem led to a high rate of osseointegration of the stem at mid-term follow-up. Cite this article: Bone Joint J 2015; 97-B:312-17. PMID- 25737514 TI - Treatment of osteochondral lesions in the knee using a cell-free scaffold. AB - The treatment of osteochondral lesions is of great interest to orthopaedic surgeons because most lesions do not heal spontaneously. We present the short term clinical outcome and MRI findings of a cell-free scaffold used for the treatment of these lesions in the knee. A total of 38 patients were prospectively evaluated clinically for two years following treatment with an osteochondral nanostructured biomimetic scaffold. There were 23 men and 15 women; the mean age of the patients was 30.5 years (15 to 64). Clinical outcome was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Tegner activity scale and a Visual Analgue scale for pain. MRI data were analysed based on the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system at three, 12 and 24 months post-operatively. There was a continuous significant clinical improvement after surgery. In two patients, the scaffold treatment failed (5.3%) There was a statistically significant improvement in the MOCART precentage scores. The repair tissue filled most of the defect sufficiently. We found subchondral laminar changes in all patients. Intralesional osteophytes were found in two patients (5.3%). We conclude that this one-step scaffold-based technique can be used for osteochondral repair. The surgical technique is straightforward, and the clinical results are promising. The MRI aspects of the repair tissue continue to evolve during the first two years after surgery. However, the subchondral laminar and bone changes are a concern. PMID- 25737515 TI - Prevention of graft-tunnel mismatch during anatomical anterior cruciate ligament reconstruction using a bone-patellar tendon-bone graft. AB - Graft-tunnel mismatch of the bone-patellar tendon-bone (BPTB) graft is a major concern during anatomical anterior cruciate ligament (ACL) reconstruction if the femoral tunnel is positioned using a far medial portal technique, as the femoral tunnel tends to be shorter compared with that positioned using a transtibial portal technique. This study describes an accurate method of calculating the ideal length of bone plugs of a BPTB graft required to avoid graft-tunnel mismatch during anatomical ACL reconstruction using a far medial portal technique of femoral tunnel positioning. Based on data obtained intra-operatively from 60 anatomical ACL reconstruction procedures, we calculated the length of bone plugs required in the BPTB graft to avoid graft-tunnel mismatch. When this was prevented in all the 60 cases, we found that the mean length of femoral bone plug that remained in contact with the interference screw within the femoral tunnel was 14 mm (12 to 22) and the mean length of tibial bone plug that remained in contact with the interference screw within the tibial tunnel was 23 mm (18 to 28). These results were used to validate theoretical formulae developed to predict the required length of bone plugs in BPTB graft during anatomical ACL reconstruction using a far medial portal technique. PMID- 25737516 TI - A self-centring osteotomy of the tibial tubercle for patellar maltracking or instability: results with ten-years' follow-up. AB - An increased tibial tubercle-trochlear groove (TT-TG) distance is related to patellar maltracking and instability. Tibial tubercle transfer is a common treatment option for these patients with good short-term results, although the results can deteriorate over time owing to the progression of osteoarthritis. We present a ten-year follow-up study of a self-centring tibial tubercle osteotomy in 60 knees, 30 with maltracking and 30 with patellar instability. Inclusion criteria were a TT-TG >= 15 mm and symptoms for > one year. One patient (one knee) was lost to follow-up and one required total knee arthroplasty because of progressive osteoarthritis. Further patellar dislocations occurred in three knees, all in the instability group, one of which required further surgery. The mean visual analogue scores for pain, and Lysholm and Kujala scores improved significantly and were maintained at the final follow-up (repeated measures, p = 0.000, intergroup differences p = 0.449). Signs of maltracking were found in only a minority of patients, with no difference between groups (p > 0.05). An increase in patellofemoral osteoarthritis was seen in 16 knees (31%) with a maximum of grade 2 on the Kellgren-Lawrence scale. The mean increase in grades was 0.31 (0 to 2) and 0.41 (0 to 2) in the maltracking and instability groups respectively (p = 0.2285) This self-centring tibial tubercle osteotomy provides good results at ten years' follow-up without inducing progressive osteoarthritis. PMID- 25737517 TI - Effect of one-year post-operative alendronate treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomised controlled trial of 26 patients. AB - Total knee arthroplasty (TKA) is known to lead to a reduction in periprosthetic bone mineral density (BMD). In theory, this may lead to migration, instability and aseptic loosening of the prosthetic components. Bisphosphonates inhibit bone resorption and may reduce this loss in BMD. We hypothesised that treatment with bisphosphonates and calcium would lead to improved BMD and clinical outcomes compared with treatment with calcium supplementation alone following TKA. A total of 26 patients, (nine male and 17 female, mean age 67 years) were prospectively randomised into two study groups: alendronate and calcium (bisphosphonate group, n = 14) or calcium only (control group, n = 12). Dual energy X-ray absorptiometry (DEXA) measurements were performed post-operatively, and at three months, six months, one, two, four, and seven years post-operatively. Mean femoral metaphyseal BMD was significantly higher in the bisphosphonate group compared with controls, up to four years following surgery in some areas of the femur (p = 0.045). BMD was observed to increase in the lateral tibial metaphysis in the bisphosphonate group until seven years (p = 0.002), and was significantly higher than that observed in the control group throughout (p = 0.024). There were no significant differences between the groups in the central femoral metaphyseal, tibial medial metaphyseal or diaphyseal regions of interest (ROI) of either the femur or tibia. Bisphosphonate treatment after TKA may be of benefit for patients with poor bone quality. However, further studies with a larger number of patients are necessary to assess whether this is clinically beneficial. PMID- 25737518 TI - Long-term follow-up of flexor digitorum longus transfer and calcaneal osteotomy for stage II posterior tibial tendon dysfunction. AB - Flexor digitorum longus transfer and medial displacement calcaneal osteotomy is a well-recognised form of treatment for stage II posterior tibial tendon dysfunction. Although excellent short- and medium-term results have been reported, the long-term outcome is unknown. We reviewed the clinical outcome of 31 patients with a symptomatic flexible flat-foot deformity who underwent this procedure between 1994 and 1996. There were 21 women and ten men with a mean age of 54.3 years (42 to 70). The mean follow-up was 15.2 years (11.4 to 16.5). All scores improved significantly (p < 0.001). The mean American Orthopedic Foot and Ankle Society (AOFAS) score improved from 48.4 pre-operatively to 90.3 (54 to 100) at the final follow-up. The mean pain component improved from 12.3 to 35.2 (20 to 40). The mean function score improved from 35.2 to 45.6 (30 to 50). The mean visual analogue score for pain improved from 7.3 to 1.3 (0 to 6). The mean Short Form-36 physical component score was 40.6 (sd 8.9), and this showed a significant correlation with the mean AOFAS score (r = 0.68, p = 0.005). A total of 27 patients (87%) were pain free and functioning well at the final follow-up. We believe that flexor digitorum longus transfer and calcaneal osteotomy provides long-term pain relief and satisfactory function in the treatment of stage II posterior tibial tendon dysfunction. PMID- 25737519 TI - The management of chronic rupture of the Achilles tendon: minimally invasive peroneus brevis tendon transfer. AB - We hypothesised that a minimally invasive peroneus brevis tendon transfer would be effective for the management of a chronic rupture of the Achilles tendon. In 17 patients (three women, 14 men) who underwent minimally invasive transfer and tenodesis of the peroneus brevis to the calcaneum, at a mean follow-up of 4.6 years (2 to 7) the modified Achilles tendon total rupture score (ATRS) was recorded and the maximum circumference of the calf of the operated and contralateral limbs was measured. The strength of isometric plantar flexion of the gastrocsoleus complex and of eversion of the ankle were measured bilaterally. Functional outcomes were classified according to the four-point Boyden scale. At the latest review, the mean maximum circumference of the calf of the operated limb was not significantly different from the pre-operative mean value, (41.4 cm, 32 to 50 vs 40.6 cm, 33 to 46; p = 0.45), and not significantly less than that of the contralateral limb (43.1 cm, 35 to 52; p = 0.16). The mean peak torque (244.6 N, 125 to 367) and the strength of eversion of the operated ankle (149.1 N, 65 to 240) were significantly lower (p < 0.01) than those of the contralateral limb (mean peak torque 289, 145 to 419; strength of eversion: 175.2, 71 to 280). The mean ATRS significantly improved from 58 pre-operatively (35 to 68) to 91 (75 to 97; 95% confidence interval 85.3 to 93.2) at the time of final review. Of 13 patients who practised sport at the time of injury, ten still undertook recreational activities. This procedure may be safely performed, is minimally invasive, and allows most patients to return to pre-injury sport and daily activities. PMID- 25737520 TI - The effect of severing a normal S1 nerve root to use for reconstruction of an avulsed contralateral lumbosacral plexus: a pilot study. AB - The aim of this study was to evaluate the feasibility of using the intact S1 nerve root as a donor nerve to repair an avulsion of the contralateral lumbosacral plexus. Two cohorts of patients were recruited. In cohort 1, the L4 S4 nerve roots of 15 patients with a unilateral fracture of the sacrum and sacral nerve injury were stimulated during surgery to establish the precise functional distribution of the S1 nerve root and its proportional contribution to individual muscles. In cohort 2, the contralateral uninjured S1 nerve root of six patients with a unilateral lumbosacral plexus avulsion was transected extradurally and used with a 25 cm segment of the common peroneal nerve from the injured leg to reconstruct the avulsed plexus. The results from cohort 1 showed that the innervation of S1 in each muscle can be compensated for by L4, L5, S2 and S3. Numbness in the toes and a reduction in strength were found after surgery in cohort 2, but these symptoms gradually disappeared and strength recovered. The results of electrophysiological studies of the donor limb were generally normal. Severing the S1 nerve root does not appear to damage the healthy limb as far as clinical assessment and electrophysiological testing can determine. Consequently, the S1 nerve can be considered to be a suitable donor nerve for reconstruction of an avulsed contralateral lumbosacral plexus. PMID- 25737521 TI - A comparison of patient-reported outcome measures after spinal surgery. AB - Minimal clinically important differences (MCID) in the scores of patient-reported outcome measures allow clinicians to assess the outcome of intervention from the perspective of the patient. There has been significant variation in their absolute values in previous publications and a lack of consistency in their calculation. The purpose of this study was first, to establish whether these values, following spinal surgery, vary depending on the surgical intervention and their method of calculation and secondly, to assess whether there is any correlation between the two external anchors most frequently used to calculate the MCID. We carried out a retrospective analysis of prospectively gathered data of adult patients who underwent elective spinal surgery between 1994 and 2009. A total of 244 patients were included. There were 125 men and 119 women with a mean age of 54 years (16 to 84); the mean follow-up was 62 months (6 to 199) The MCID was calculated using three previously published methods. Our results show that the value of the MCID varies considerably with the operation and its method of calculation. There was good correlation between the two external anchors. The global outcome tool correlated significantly better. We conclude that consensus needs to be reached on the best method of calculating the MCID. This then needs to be defined for each spinal procedure. Using a blanket value for the MCID for all spinal procedures should be avoided. PMID- 25737522 TI - Recovery of health-related quality of life in a United Kingdom hip fracture population. The Warwick Hip Trauma Evaluation--a prospective cohort study. AB - Hip fracture is a global public health problem. The National Hip Fracture Database provides a framework for service evaluation in this group of patients in the United Kingdom, but does not collect patient-reported outcome data and is unable to provide meaningful data about the recovery of quality of life. We report one-year patient-reported outcomes of a prospective cohort of patients treated at a single major trauma centre in the United Kingdom who sustained a hip fracture between January 2012 and March 2014. There was an initial marked decline in quality of life from baseline measured using the EuroQol 5 Dimensions score (EQ-5D). It was followed by a significant improvement to 120 days for all patients. Although their quality of life improved during the year after the fracture, it was still significantly lower than before injury irrespective of age group or cognitive impairment (mean reduction EQ-5D 0.22; 95% confidence interval (CI) 0.17 to 0.26). There was strong evidence that quality of life was lower for patients with cognitive impairment. There was a mean reduction in EQ-5D of 0.28 (95% CI 0.22 to 0.35) in patients < 80 years of age. This difference was consistent (and fixed) throughout follow-up. Quality of life does not improve significantly during recovery from hip fracture in patients over 80 years of age (p = 0.928). Secondary measures of function showed similar trends. Hip fracture marks a step down in the quality of life of a patient: it accounts for approximately 0.22 disability adjusted life years in the first year after fracture. This is equivalent to serious neurological conditions for which extensive funding for research and treatment is made available. PMID- 25737523 TI - The determinants of mortality and morbidity during the year following fracture of the hip: a prospective study. AB - Several studies have reported the rate of post-operative mortality after the surgical treatment of a fracture of the hip, but few data are available regarding the delayed morbidity. In this prospective study, we identified 568 patients who underwent surgery for a fracture of the hip and who were followed for one year. Multivariate analysis was carried out to identify possible predictors of mortality and morbidity. The 30-day, four-month and one-year rates of mortality were 4.3%, 11.4%, and 18.8%, respectively. General complications and pre operative comorbidities represented the basic predictors of mortality at any time interval (p < 0.01). In-hospital, four-month and one-year general complications occurred in 29.4%, 18.6% and 6.7% of patients, respectively. After adjusting for confounding variables, comorbidities and poor cognitive status determined the likelihood of early and delayed general complications, respectively (p < 0.001). Operative delay was the main predictor of the length of hospital stay (p < 0.001) and was directly related to in-hospital (p = 0.017) and four-month complications (p = 0.008). PMID- 25737524 TI - The stability of fixation of proximal femoral fractures: a radiostereometric analysis. AB - The aim of this study was to quantify the stability of fracture-implant complex in fractures after fixation. A total of 15 patients with an undisplaced fracture of the femoral neck, treated with either a dynamic hip screw or three cannulated hip screws, and 16 patients with an AO31-A2 trochanteric fracture treated with a dynamic hip screw or a Gamma Nail, were included. Radiostereometric analysis was used at six weeks, four months and 12 months post-operatively to evaluate shortening and rotation. Migration could be assessed in ten patients with a fracture of the femoral neck and seven with a trochanteric fracture. By four months post-operatively, a mean shortening of 5.4 mm (-0.04 to 16.1) had occurred in the fracture of the femoral neck group and 5.0 mm (-0.13 to 12.9) in the trochanteric fracture group. A wide range of rotation occurred in both types of fracture. Right-sided trochanteric fractures seem more rotationally stable than left-sided fractures. This prospective study shows that migration at the fracture site occurs continuously during the first four post-operative months, after which stabilisation occurs. This information may allow the early recognition of patients at risk of failure of fixation. PMID- 25737525 TI - Sliding hip screw versus sliding helical blade for intertrochanteric fractures: a propensity score-matched case control study. AB - The spiral blade modification of the Dynamic Hip Screw (DHS) was designed for superior biomechanical fixation in the osteoporotic femoral head. Our objective was to compare clinical outcomes and in particular the incidence of loss of fixation. In a series of 197 consecutive patients over the age of 50 years treated with DHS-blades (blades) and 242 patients treated with conventional DHS (screw) for AO/OTA 31.A1 or A2 intertrochanteric fractures were identified from a prospectively compiled database in a level 1 trauma centre. Using propensity score matching, two groups comprising 177 matched patients were compiled and radiological and clinical outcomes compared. In each group there were 66 males and 111 females. Mean age was 83.6 (54 to 100) for the conventional DHS group and 83.8 (52 to 101) for the blade group. Loss of fixation occurred in two blades and 13 DHSs. None of the blades had observable migration while nine DHSs had gross migration within the femoral head before the fracture healed. There were two versus four implant cut-outs respectively and one side plate pull-out in the DHS group. There was no significant difference in mortality and eventual walking ability between the groups. Multiple logistic regression suggested that poor reduction (odds ratio (OR) 11.49, 95% confidence intervals (CI) 1.45 to 90.9, p = 0.021) and fixation by DHS (OR 15.85, 95%CI 2.50 to 100.3, p = 0.003) were independent predictors of loss of fixation. The spiral blade design may decrease the risk of implant migration in the femoral head but does not reduce the incidence of cut-out and reoperation. Reduction of the fracture is of paramount importance since poor reduction was an independent predictor for loss of fixation regardless of the implant being used. Cite this article: Bone Joint J 2015;97 B:398-404. PMID- 25737526 TI - Ultrasound-guided gradual reduction using flexion and abduction continuous traction for developmental dysplasia of the hip: a new method of treatment. AB - We describe our experience in the reduction of dislocation of the hip secondary to developmental dysplasia using ultrasound-guided gradual reduction using flexion and abduction continuous traction (FACT-R). During a period of 13 years we treated 208 Suzuki type B or C complete dislocations of the hip in 202 children with a mean age of four months (0 to 11). The mean follow-up was 9.1 years (five to 16). The rate of reduction was 99.0%. There were no recurrent dislocations, and the rate of avascular necrosis of the femoral head was 1.0%. The rate of secondary surgery for residual acetabular dysplasia was 19.2%, and this was significantly higher in those children in whom the initial treatment was delayed or if other previous treatments had failed (p = 0.00045). The duration of FACT-R was significantly longer in severe dislocations (p = 0.001) or if previous treatments had failed (p = 0.018). This new method of treatment is effective and safe in these difficult cases and offers outcomes comparable to or better than those of standard methods. PMID- 25737527 TI - The treatment of an unstable slipped capital femoral epiphysis by either intracapsular cuneiform osteotomy or pinning in situ: a comparative study. AB - We undertook a retrospective comparative study of all patients with an unstable slipped capital femoral epiphysis presenting to a single centre between 1998 and 2011. There were 45 patients (46 hips; mean age 12.6 years; 9 to 14); 16 hips underwent intracapsular cuneiform osteotomy and 30 underwent pinning in situ, with varying degrees of serendipitous reduction. No patient in the osteotomy group was lost to follow-up, which was undertaken at a mean of 28 months (11 to 48); four patients in the pinning in situ group were lost to follow-up, which occurred at a mean of 30 months (10 to 50). Avascular necrosis (AVN) occurred in four hips (25%) following osteotomy and in 11 (42%) following pinning in situ. AVN was not seen in five hips for which osteotomy was undertaken > 13 days after presentation. AVN occurred in four of ten (40%) hips undergoing emergency pinning in situ, compared with four of 15 (47%) undergoing non-emergency pinning. The rate of AVN was 67% (four of six) in those undergoing pinning on the second or third day after presentation. Pinning in situ following complete reduction led to AVN in four out of five cases (80%). In comparison, pinning in situ following incomplete reduction led to AVN in 7 of 21 cases (33%). The rate of development of AVN was significantly higher following pinning in situ with complete reduction than following intracapsular osteotomy (p = 0.048). Complete reduction was more frequent in those treated by emergency pinning and was strongly associated with AVN (p = 0.005). Non-emergency intracapsular osteotomy may have a protective effect on the epiphyseal vasculature and should be undertaken with a delay of at least two weeks. The place of emergency pinning in situ in these patients needs to be re-evaluated, possibly in favour of an emergency open procedure or delayed intracapsular osteotomy. Non-emergency pinning in situ should be undertaken after a delay of at least five days, with the greatest risk at two and three days after presentation. Intracapsular osteotomy should be undertaken after a delay of at least 14 days. In our experience, closed epiphyseal reduction is harmful. Cite this article: Bone Joint J 2015;97-B:412-19. PMID- 25737528 TI - Validation of the translated Oxford ankle foot questionnaire in 82 Danish children aged between five and 16 years. AB - We present the validation of a translation into Danish of the Oxford ankle foot questionnaire (OxAFQ). We followed the Isis Pros guidelines for translation and pilot-tested the questionnaire on ten children and their parents. Following modifications we tested the validity of the final questionnaire on 82 children (36 boys and 45 girls) with a mean age of 11.7 years (5.5 to 16.0) and their parents. We tested the reliability (repeatability (test-retest), child-parent agreement, internal consistency), feasibility (response rate, time to completion, floor and ceiling effects) and construct validity. The generic child health questionnaire was used for comparison. We found good internal consistency for the physical and the school and play domains, but lower internal consistency for the emotional domain. Overall, good repeatability was found within children and parents as well as agreement between children and parents. The OxAFQ was fast and easy to complete, but we observed a tendency towards ceiling effects in the school and play and emotional domains. To our knowledge this is the first independent validation of the OxAFQ in any language. We found it valid and feasible for use in the clinic to assess the impact on children's lives of foot and/or ankle disorders. It is a valuable research tool. PMID- 25737529 TI - A positive bacterial culture from allograft bone at implantation does not correlate with subsequent surgical site infection. AB - Fresh-frozen allograft bone is frequently used in orthopaedic surgery. We investigated the incidence of allograft-related infection and analysed the outcomes of recipients of bacterial culture-positive allografts from our single institute bone bank during bone transplantation. The fresh-frozen allografts were harvested in a strict sterile environment during total joint arthroplasty surgery and immediately stored in a freezer at -78o to -68o C after packing. Between January 2007 and December 2012, 2024 patients received 2083 allografts with a minimum of 12 months of follow-up. The overall allograft-associated infection rate was 1.2% (24/2024). Swab cultures of 2083 allografts taken before implantation revealed 21 (1.0%) positive findings. The 21 recipients were given various antibiotics at the individual orthopaedic surgeon's discretion. At the latest follow-up, none of these 21 recipients displayed clinical signs of infection following treatment. Based on these findings, we conclude that an incidental positive culture finding for allografts does not correlate with subsequent surgical site infection. Additional prolonged post-operative antibiotic therapy may not be necessary for recipients of fresh-frozen bone allograft with positive culture findings. PMID- 25737530 TI - Errata. AB - D F Hamilton, R Burnett, J T Patton, C R Howie, M Moran, A H R W Simpson, P Gaston: Implant design influences patient outcome after total knee arthroplasty. Bone Joint J 2015;97-B:64-70. The authors regret that labelling on figure 2 was incorrect. The correct figure is published below. PMID- 25737531 TI - Does neighbourhood composition modify the association between acculturation and unhealthy dietary behaviours? AB - OBJECTIVE: Studies have shown that immigrants' acculturation is associated with numerous unhealthy behaviours. Yet, the role of environmental factors in modifying the effect of acculturation on health behaviours has received little attention. This study aims to create a more nuanced understanding of the health effects of acculturation by examining how neighbourhood immigrant composition modifies the association between individuals' eating patterns and acculturation. METHODS: Cross-sectional Data from Los Angeles County Health Survey 2007 adult sample were linked to data on retail food establishments and US Census 2000 neighbourhood characteristics. Acculturation was measured by language spoken at home and years stayed in the US. Eating fast food more than once per week and eating zero serving of fruit or vegetables during the previous day were used as proxy indicators for unhealthy dietary behaviour. Multilevel logistic regression models were performed in the full sample and in the sample with only Latino adults. RESULTS: Immigrants' lack of acculturation and living in a neighbourhood with a high percentage immigrants were associated with healthier dietary behaviour. We also identified that lack of acculturation conveyed a significantly stronger protective effect on regular fast-food consumption for immigrants living in neighbourhoods with higher percentage immigrants (OR: 0.34, 95% CI: 0.12 to 0.93). CONCLUSIONS: Among immigrants in Los Angeles County, living in a neighbourhood with a high density of other immigrants attenuates the negative effects of acculturation on healthy eating behaviours. Healthy eating promotion efforts should build on this protective effect in outreach to acculturating immigrant communities. PMID- 25737533 TI - Performance of 10 systems for self-monitoring of blood glucose by trained healthcare professionals and in the hands of the users. PMID- 25737532 TI - Turgor and the transport of CO2 and water across the cuticle (epidermis) of leaves. AB - Leaf photosynthesis relies on CO2 diffusing in while water vapour diffuses out. When stomata close, cuticle waxes on the epidermal tissues increasingly affect this diffusion. Also, changes in turgor can shrink or swell a leaf, varying the cuticle size. In this study, the properties of the cuticle were investigated while turgor varied in intact leaves of hypo stomatous grape (Vitis vinifera L.) or amphistomatous sunflower (Helianthus annuus L.). For grape, stomata on the abaxial surface were sealed and high CO2 concentrations outside the leaf were used to maximize diffusion through the adaxial, stoma-free cuticle. For sunflower, stomata were closed in the dark or with abscisic acid to maximize the cuticle contribution to the path. In both species, the internal CO2 concentration was measured directly and continuously while other variables were determined to establish the cuticle properties. The results indicated that stomatal closure diminished the diffusion of both gases in both species, but for CO2 more than for water vapour. Decreasing the turgor diminished the movement of both gases through the cuticle of both species. Because this turgor effect was observed in the adaxial surface of grape, which had no stomata, it could only be attributed to cuticle tightening. Comparing calculated and measured concentrations of CO2 in leaves revealed differences that became large as stomata began to close. These differences in transport, together with turgor effects, suggest calculations of the CO2 concentration inside leaves need to be viewed with caution when stomata begin to close. PMID- 25737534 TI - Impact of leading presenting symptoms on the diagnostic performance of high sensitivity cardiac troponin T and on outcomes in patients with suspected acute coronary syndrome. AB - BACKGROUND: Diagnostic performance of high-sensitivity cardiac troponin T (hs cTnT) varies depending on presenting symptoms in patients with suspected acute coronary syndrome (ACS). METHODS: We compared performance measures of hs-cTnT among patients admitted to the emergency department with typical chest pain (angina), dyspnea, and atypical symptoms and assessed outcomes by leading presenting symptoms. RESULTS: A total of 658 patients suspected of ACS and presenting with typical chest pain (n = 241, 36.6%), dyspnea (n = 142, 21.6%), or atypical symptoms (n = 275, 41.8%) were included. Diagnostic accuracy of hs-cTnT on admission was higher among patients with typical chest pain compared to those with atypical symptoms [area under the curve (AUC) 0.823 vs AUC 0.776 vs AUC 0.705, P > 0.05 and P = 0.04]. Absolute concentration changes within 6 h improved accuracy among all subgroups, with the smallest added benefit in typical chest pain and dyspnea (DeltaAUC, 0.078; P = 0.02 and 0.05, P > 0.05). During 1-year follow-up, dyspnea was associated with a higher risk of death (hazard ratio, 2.36; 95% CI, 1.26-4.43, P = 0.008) and death/AMI (hazard ratio, 2.23; 95% CI, 1.21-4.11, P = 0.01) compared to typical chest pain. Optimal discriminating values for hs-cTnT were higher among patients presenting with dyspnea compared to those with typical chest pain (91.2 vs 14.1 ng/L, P < 0.001). CONCLUSION: The diagnostic performance of hs-cTnT in patients with suspected ACS depends on the leading presenting symptom. Patients admitted with dyspnea represent a high-risk cohort in which the diagnosis of ACS is less frequent and with inferior performance of serial hs-cTnT measurements. Higher hs-cTnT cutoffs at baseline and absolute changes after 6 h help to identify non-STEMI (ST segment elevation myocardial infarction) in this population. PMID- 25737535 TI - Investigation of 2 models to set and evaluate quality targets for hb a1c: biological variation and sigma-metrics. AB - BACKGROUND: A major objective of the IFCC Task Force on Implementation of HbA1c Standardization is to develop a model to define quality targets for glycated hemoglobin (Hb A1c). METHODS: Two generic models, biological variation and sigma metrics, are investigated. We selected variables in the models for Hb A1c and used data of external quality assurance/proficiency testing programs to evaluate the suitability of the models to set and evaluate quality targets within and between laboratories. RESULTS: In the biological variation model, 48% of individual laboratories and none of the 26 instrument groups met the minimum performance criterion. In the sigma-metrics model, with a total allowable error (TAE) set at 5 mmol/mol (0.46% NGSP), 77% of the individual laboratories and 12 of 26 instrument groups met the 2sigma criterion. CONCLUSIONS: The biological variation and sigma-metrics models were demonstrated to be suitable for setting and evaluating quality targets within and between laboratories. The sigma-metrics model is more flexible, as both the TAE and the risk of failure can be adjusted to the situation-for example, requirements related to diagnosis/monitoring or international authorities. With the aim of reaching (inter)national consensus on advice regarding quality targets for Hb A1c, the Task Force suggests the sigma metrics model as the model of choice, with default values of 5 mmol/mol (0.46%) for TAE and risk levels of 2sigma and 4sigma for routine laboratories and laboratories performing clinical trials, respectively. These goals should serve as a starting point for discussion with international stakeholders in the field of diabetes. PMID- 25737536 TI - Noninvasive in vivo imaging reveals differences between tectorial membrane and basilar membrane traveling waves in the mouse cochlea. AB - Sound is encoded within the auditory portion of the inner ear, the cochlea, after propagating down its length as a traveling wave. For over half a century, vibratory measurements to study cochlear traveling waves have been made using invasive approaches such as laser Doppler vibrometry. Although these studies have provided critical information regarding the nonlinear processes within the living cochlea that increase the amplitude of vibration and sharpen frequency tuning, the data have typically been limited to point measurements of basilar membrane vibration. In addition, opening the cochlea may alter its function and affect the findings. Here we describe volumetric optical coherence tomography vibrometry, a technique that overcomes these limitations by providing depth-resolved displacement measurements at 200 kHz inside a 3D volume of tissue with picometer sensitivity. We studied the mouse cochlea by imaging noninvasively through the surrounding bone to measure sound-induced vibrations of the sensory structures in vivo, and report, to our knowledge, the first measures of tectorial membrane vibration within the unopened cochlea. We found that the tectorial membrane sustains traveling wave propagation. Compared with basilar membrane traveling waves, tectorial membrane traveling waves have larger dynamic ranges, sharper frequency tuning, and apically shifted positions of peak vibration. These findings explain discrepancies between previously published basilar membrane vibration and auditory nerve single unit data. Because the tectorial membrane directly overlies the inner hair cell stereociliary bundles, these data provide the most accurate characterization of the stimulus shaping the afferent auditory response available to date. PMID- 25737537 TI - Salient features of otoacoustic emissions are common across tetrapod groups and suggest shared properties of generation mechanisms. AB - Otoacoustic emissions (OAEs) are faint sounds generated by healthy inner ears that provide a window into the study of auditory mechanics. All vertebrate classes exhibit OAEs to varying degrees, yet the biophysical origins are still not well understood. Here, we analyzed both spontaneous (SOAE) and stimulus frequency (SFOAE) otoacoustic emissions from a bird (barn owl, Tyto alba) and a lizard (green anole, Anolis carolinensis). These species possess highly disparate macromorphologies of the inner ear relative to each other and to mammals, thereby allowing for novel insights into the biomechanical mechanisms underlying OAE generation. All ears exhibited robust OAE activity, and our chief observation was that SFOAE phase accumulation between adjacent SOAE peak frequencies clustered about an integral number of cycles. Being highly similar to published results from human ears, we argue that these data indicate a common underlying generator mechanism of OAEs across all vertebrates, despite the absence of morphological features thought essential to mammalian cochlear mechanics. We suggest that otoacoustic emissions originate from phase coherence in a system of coupled oscillators, which is consistent with the notion of "coherent reflection" but does not explicitly require a mammalian-type traveling wave. Furthermore, comparison between SFOAE delays and auditory nerve fiber responses for the barn owl strengthens the notion that most OAE delay can be attributed to tuning. PMID- 25737538 TI - Prevention of early HIV transmissions might be more important in emerging or generalizing epidemics. PMID- 25737539 TI - Correction for Midde et al., Multimodular biosensors reveal a novel platform for activation of G proteins by growth factor receptors. PMID- 25737540 TI - Polytypism, polymorphism, and superconductivity in TaSe(2-x)Te(x). AB - Polymorphism in materials often leads to significantly different physical properties--the rutile and anatase polymorphs of TiO2 are a prime example. Polytypism is a special type of polymorphism, occurring in layered materials when the geometry of a repeating structural layer is maintained but the layer-stacking sequence of the overall crystal structure can be varied; SiC is an example of a material with many polytypes. Although polymorphs can have radically different physical properties, it is much rarer for polytypism to impact physical properties in a dramatic fashion. Here we study the effects of polytypism and polymorphism on the superconductivity of TaSe2, one of the archetypal members of the large family of layered dichalcogenides. We show that it is possible to access two stable polytypes and two stable polymorphs in the TaSe(2-x)Te(x) solid solution and find that the 3R polytype shows a superconducting transition temperature that is between 6 and 17 times higher than that of the much more commonly found 2H polytype. The reason for this dramatic change is not apparent, but we propose that it arises either from a remarkable dependence of Tc on subtle differences in the characteristics of the single layers present or from a surprising effect of the layer-stacking sequence on electronic properties that are typically expected to be dominated by the properties of a single layer in materials of this kind. PMID- 25737541 TI - Cation-induced kinetic heterogeneity of the intron-exon recognition in single group II introns. AB - RNA is commonly believed to undergo a number of sequential folding steps before reaching its functional fold, i.e., the global minimum in the free energy landscape. However, there is accumulating evidence that several functional conformations are often in coexistence, corresponding to multiple (local) minima in the folding landscape. Here we use the 5'-exon-intron recognition duplex of a self-splicing ribozyme as a model system to study the influence of Mg(2+) and Ca(2+) on RNA tertiary structure formation. Bulk and single-molecule spectroscopy reveal that near-physiological M(2+) concentrations strongly promote interstrand association. Moreover, the presence of M(2+) leads to pronounced kinetic heterogeneity, suggesting the coexistence of multiple docked and undocked RNA conformations. Heterogeneity is found to decrease at saturating M(2+) concentrations. Using NMR, we locate specific Mg(2+) binding pockets and quantify their affinity toward Mg(2+). Mg(2+) pulse experiments show that M(2+) exchange occurs on the timescale of seconds. This unprecedented combination of NMR and single-molecule Forster resonance energy transfer demonstrates for the first time to our knowledge that a rugged free energy landscape coincides with incomplete occupation of specific M(2+) binding sites at near-physiological M(2+) concentrations. Unconventional kinetics in nucleic acid folding frequently encountered in single-molecule experiments are therefore likely to originate from a spectrum of conformations that differ in the occupation of M(2+) binding sites. PMID- 25737543 TI - Retroviral vectors elevate coexpressed protein levels in trans through cap dependent translation. AB - Retroviruses cause immunodeficiency and cancer but also are used as vectors for the expression of heterologous genes. Nevertheless, optimal translation of introduced genes often is not achieved. Here we show that transfection into mammalian cells of lentiviral or gammaretroviral vectors, including those with specific shRNAs, increased expression of a cotransfected gene relative to standard plasmid vectors. Levels of most endogenous cellular proteins were unchanged. Transfer of lentiviral vector sequences into a standard plasmid conferred the ability to give increased expression of cotransfected genes (superinduction). Superinduction by the retroviral vector was not dependent on the cell type or species, the type of reporter gene, or the method of transfection. No differences were detected in the IFN, unfolded protein, or stress responses in the presence of retroviral vectors. RT-PCRs revealed that RNA levels of cotransfected genes were unchanged during superinduction, yet Western blotting, pulse labeling, and the use of bicistronic vectors showed increased cap dependent translation of cointroduced genes. Expression of the mammalian target of rapamycin (mTOR) kinase target 4E-BP1, but not the mTOR inhibitor Torin 1, preferentially inhibited superinduction relative to basal protein expression. Furthermore, transcription of lentiviral vector sequences from a doxycycline inducible promoter eliminated superinduction, consistent with a DNA-triggered event. Thus, retroviral DNA increased translation of cointroduced genes in trans by an mTOR-independent signaling mechanism. Our experiments have broad applications for the design of retroviral vectors for transfections, DNA vaccines, and gene therapy. PMID- 25737542 TI - Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. AB - BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC. PMID- 25737544 TI - Atg13 HORMA domain recruits Atg9 vesicles during autophagosome formation. AB - During autophagosome formation, autophagosome-related (Atg) proteins are recruited hierarchically to organize the preautophagosomal structure (PAS). Atg13, which plays a central role in the initial step of PAS formation, consists of two structural regions, the N-terminal HORMA (from Hop1, Rev7, and Mad2) domain and the C-terminal disordered region. The C-terminal disordered region of Atg13, which contains the binding sites for Atg1 and Atg17, is essential for the initiation step in which the Atg1 complex is formed to serve as a scaffold for the PAS. The N-terminal HORMA domain of Atg13 is also essential for autophagy, but its molecular function has not been established. In this study, we searched for interaction partners of the Atg13 HORMA domain and found that it binds Atg9, a multispanning membrane protein that exists on specific cytoplasmic vesicles (Atg9 vesicles). After the Atg1 complex is formed, Atg9 vesicles are recruited to the PAS and become part of the autophagosomal membrane. HORMA domain mutants, which are unable to interact with Atg9, impaired the PAS localization of Atg9 vesicles and exhibited severe defects in starvation-induced autophagy. Thus, Atg9 vesicles are recruited to the PAS via the interaction with the Atg13 HORMA domain. Based on these findings, we propose that the two distinct regions of Atg13 play crucial roles in distinct steps of autophagosome formation: In the first step, Atg13 forms a scaffold for the PAS via its C-terminal disordered region, and subsequently it recruits Atg9 vesicles via its N-terminal HORMA domain. PMID- 25737545 TI - Locating landmarks on high-dimensional free energy surfaces. AB - Coarse graining of complex systems possessing many degrees of freedom can often be a useful approach for analyzing and understanding key features of these systems in terms of just a few variables. The relevant energy landscape in a coarse-grained description is the free energy surface as a function of the coarse grained variables, which, despite the dimensional reduction, can still be an object of high dimension. Consequently, navigating and exploring this high dimensional free energy surface is a nontrivial task. In this paper, we use techniques from multiscale modeling, stochastic optimization, and machine learning to devise a strategy for locating minima and saddle points (termed "landmarks") on a high-dimensional free energy surface "on the fly" and without requiring prior knowledge of or an explicit form for the surface. In addition, we propose a compact graph representation of the landmarks and connections between them, and we show that the graph nodes can be subsequently analyzed and clustered based on key attributes that elucidate important properties of the system. Finally, we show that knowledge of landmark locations allows for the efficient determination of their relative free energies via enhanced sampling techniques. PMID- 25737546 TI - Correction for Chen et al., Plasma butyrylcholinesterase regulates ghrelin to control aggression. PMID- 25737547 TI - Modeling memory consolidation during posttraining periods in cerebellovestibular learning. AB - Long-term depression (LTD) at parallel fiber-Purkinje cell (PF-PC) synapses is thought to underlie memory formation in cerebellar motor learning. Recent experimental results, however, suggest that multiple plasticity mechanisms in the cerebellar cortex and cerebellar/vestibular nuclei participate in memory formation. To examine this possibility, we formulated a simple model of the cerebellum with a minimal number of components based on its known anatomy and physiology, implementing both LTD and long-term potentiation (LTP) at PF-PC synapses and mossy fiber-vestibular nuclear neuron (MF-VN) synapses. With this model, we conducted a simulation study of the gain adaptation of optokinetic response (OKR) eye movement. Our model reproduced several important aspects of previously reported experimental results in wild-type and cerebellum-related gene manipulated mice. First, each 1-h training led to the formation of short-term memory of learned OKR gain at PF-PC synapses, which diminished throughout the day. Second, daily repetition of the training gradually formed long-term memory that was maintained for days at MF-VN synapses. We reproduced such memory formation under various learning conditions. Third, long-term memory formation occurred after training but not during training, indicating that the memory consolidation occurred during posttraining periods. Fourth, spaced training outperformed massed training in long-term memory formation. Finally, we reproduced OKR gain changes consistent with the changes in the vestibuloocular reflex (VOR) previously reported in some gene-manipulated mice. PMID- 25737548 TI - Avoided valence transition in a plutonium superconductor. AB - The d and f electrons in correlated metals are often neither fully localized around their host nuclei nor fully itinerant. This localized/itinerant duality underlies the correlated electronic states of the high-Tc cuprate superconductors and the heavy-fermion intermetallics and is nowhere more apparent than in the 5f valence electrons of plutonium. Here, we report the full set of symmetry-resolved elastic moduli of PuCoGa5--the highest Tc superconductor of the heavy fermions (Tc = 18.5 K)--and find that the bulk modulus softens anomalously over a wide range in temperature above Tc. The elastic symmetry channel in which this softening occurs is characteristic of a valence instability--therefore, we identify the elastic softening with fluctuations of the plutonium 5f mixed valence state. These valence fluctuations disappear when the superconducting gap opens at Tc, suggesting that electrons near the Fermi surface play an essential role in the mixed-valence physics of this system and that PuCoGa5 avoids a valence transition by entering the superconducting state. The lack of magnetism in PuCoGa5 has made it difficult to reconcile with most other heavy-fermion superconductors, where superconductivity is generally believed to be mediated by magnetic fluctuations. Our observations suggest that valence fluctuations play a critical role in the unusually high Tc of PuCoGa5. PMID- 25737549 TI - Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. AB - Alternative splicing (AS) dramatically expands the complexity of the mammalian brain transcriptome, but its atlas remains incomplete. Here we performed deep mRNA sequencing of mouse cortex to discover and characterize alternative exons with potential functional significance. Our analysis expands the list of AS events over 10-fold compared with previous annotations, demonstrating that 72% of multiexon genes express multiple splice variants in this single tissue. To evaluate functionality of the newly discovered AS events, we conducted comprehensive analyses on central nervous system (CNS) cell type-specific splicing, targets of tissue- or cell type-specific RNA binding proteins (RBPs), evolutionary selection pressure, and coupling of AS with nonsense-mediated decay (AS-NMD). We show that newly discovered events account for 23-42% of all cassette exons under tissue- or cell type-specific regulation. Furthermore, over 7,000 cassette exons are under evolutionary selection for regulated AS in mammals, 70% of which are new. Among these are 3,058 highly conserved cassette exons, including 1,014 NMD exons that may function directly to control gene expression levels. These NMD exons are particularly enriched in RBPs including splicing factors and interestingly also regulators for other steps of RNA metabolism. Unexpectedly, a second group of NMD exons reside in genes encoding chromatin regulators. Although the conservation of NMD exons in RBPs frequently extends into lower vertebrates, NMD exons in chromatin regulators are introduced later into the mammalian lineage, implying the emergence of a novel mechanism coupling AS and epigenetics. Our results highlight previously uncharacterized complexity and evolution in the mammalian brain transcriptome. PMID- 25737550 TI - L596-W733 bond between the start of the S4-S5 linker and the TRP box stabilizes the closed state of TRPV4 channel. AB - Unlike other cation channels, each subunit of most transient receptor potential (TRP) channels has an additional TRP-domain helix with an invariant tryptophan immediately trailing the gate-bearing S6. Recent cryo-electron microscopy of TRP vanilloid subfamily, member 1 structures revealed that this domain is a five-turn amphipathic helix, and the invariant tryptophan forms a bond with the beginning of the four-turn S4-S5 linker helix. By homology modeling, we identified the corresponding L596-W733 bond in TRP vanilloid subfamily, member 4 (TRPV4). The L596P mutation blocks bone development in Kozlowski-type spondylometaphyseal dysplasia in human. Our previous screen also isolated W733R as a strong gain-of function (GOF) mutation that suppresses growth when the W733R channel is expressed in yeast. We show that, when expressed in Xenopus oocytes, TRPV4 with the L596P or W733R mutation displays normal depolarization-induced activation and outward rectification. However, these mutant channels have higher basal open probabilities and limited responses to the agonist GSK1016790A, explaining their biological GOF phenotypes. In addition, W733R current fails to inactivate during depolarization. Systematic replacement of W733 with amino acids of different properties produced similar electrophysiological and yeast phenotypes. The results can be interpreted consistently in the context of the homology model of TRPV4 molecule we have developed and refined using simulations in explicit medium. We propose that this bond maintains the orientation of the S4-S5 linker to keep the S6 gate closed. Further, the two partner helices, both amphipathic and located at the polar-nonpolar interface of the inner lipid monolayer, may receive and integrate various physiological stimuli. PMID- 25737551 TI - Glutathione and multidrug resistance protein transporter mediate a self-propelled disposal of bismuth in human cells. AB - Glutathione and multidrug resistance protein (MRP) play an important role on the metabolism of a variety of drugs. Bismuth drugs have been used to treat gastrointestinal disorder and Helicobacter pylori infection for decades without exerting acute toxicity. They were found to interact with a wide variety of biomolecules, but the major metabolic pathway remains unknown. For the first time (to our knowledge), we systematically and quantitatively studied the metabolism of bismuth in human cells. Our data demonstrated that over 90% of bismuth was passively absorbed, conjugated to glutathione, and transported into vesicles by MRP transporter. Mathematical modeling of the system reveals an interesting phenomenon. Passively absorbed bismuth consumes intracellular glutathione, which therefore activates de novo biosynthesis of glutathione. Reciprocally, sequestration by glutathione facilitates the passive uptake of bismuth and thus completes a self-sustaining positive feedback circle. This mechanism robustly removes bismuth from both intra- and extracellular space, protecting critical systems of human body from acute toxicity. It elucidates the selectivity of bismuth drugs between human and pathogens that lack of glutathione, such as Helicobacter pylori, opening new horizons for further drug development. PMID- 25737552 TI - AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. AB - The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-TolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies. PMID- 25737553 TI - Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing. AB - The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based on proteins that modulate splice site selection. EWS FLI1 is an Ewing sarcoma (ES) oncoprotein with an interactome that we demonstrate to have multiple partners in spliceosomal complexes. We evaluate the effect of EWS-FLI1 on posttranscriptional gene regulation using both exon array and RNA seq. Genes that potentially regulate oncogenesis, including CLK1, CASP3, PPFIBP1, and TERT, validate as alternatively spliced by EWS-FLI1. In a CLIP-seq experiment, we find that EWS-FLI1 RNA-binding motifs most frequently occur adjacent to intron-exon boundaries. EWS-FLI1 also alters splicing by directly binding to known splicing factors including DDX5, hnRNP K, and PRPF6. Reduction of EWS-FLI1 produces an isoform of gamma-TERT that has increased telomerase activity compared with wild-type (WT) TERT. The small molecule YK-4-279 is an inhibitor of EWS-FLI1 oncogenic function that disrupts specific protein interactions, including helicases DDX5 and RNA helicase A (RHA) that alters RNA splicing ratios. As such, YK-4-279 validates the splicing mechanism of EWS-FLI1, showing alternatively spliced gene patterns that significantly overlap with EWS FLI1 reduction and WT human mesenchymal stem cells (hMSC). Exon array analysis of 75 ES patient samples shows similar isoform expression patterns to cell line models expressing EWS-FLI1, supporting the clinical relevance of our findings. These experiments establish systemic alternative splicing as an oncogenic process modulated by EWS-FLI1. EWS-FLI1 modulation of mRNA splicing may provide insight into the contribution of splicing toward oncogenesis, and, reciprocally, EWS-FLI1 interactions with splicing proteins may inform the splicing code. PMID- 25737554 TI - Structure and dynamics of the MKK7-JNK signaling complex. AB - Signaling specificity in the mitogen-activated protein kinase (MAPK) pathways is controlled by disordered domains of the MAPK kinases (MKKs) that specifically bind to their cognate MAPKs via linear docking motifs. MKK7 activates the c-Jun N terminal kinase (JNK) pathway and is the only MKK containing three motifs within its regulatory domain. Here, we characterize the conformational behavior and interaction mechanism of the MKK7 regulatory domain. Using NMR spectroscopy, we develop an atomic resolution ensemble description of MKK7, revealing highly diverse intrinsic conformational propensities of the three docking sites, suggesting that prerecognition sampling of the bound-state conformation is not prerequisite for binding. Although the different sites exhibit similar affinities for JNK1, interaction kinetics differ considerably. Importantly, we determine the crystal structure of JNK1 in complex with the second docking site of MKK7, revealing two different binding modes of the docking motif correlating with observations from NMR exchange spectroscopy. Our results provide unique insight into how signaling specificity is regulated by linear motifs and, in general, into the role of conformational disorder in MAPK signaling. PMID- 25737555 TI - Disruption of hierarchical predictive coding during sleep. AB - When presented with an auditory sequence, the brain acts as a predictive-coding device that extracts regularities in the transition probabilities between sounds and detects unexpected deviations from these regularities. Does such prediction require conscious vigilance, or does it continue to unfold automatically in the sleeping brain? The mismatch negativity and P300 components of the auditory event related potential, reflecting two steps of auditory novelty detection, have been inconsistently observed in the various sleep stages. To clarify whether these steps remain during sleep, we recorded simultaneous electroencephalographic and magnetoencephalographic signals during wakefulness and during sleep in normal subjects listening to a hierarchical auditory paradigm including short-term (local) and long-term (global) regularities. The global response, reflected in the P300, vanished during sleep, in line with the hypothesis that it is a correlate of high-level conscious error detection. The local mismatch response remained across all sleep stages (N1, N2, and REM sleep), but with an incomplete structure; compared with wakefulness, a specific peak reflecting prediction error vanished during sleep. Those results indicate that sleep leaves initial auditory processing and passive sensory response adaptation intact, but specifically disrupts both short-term and long-term auditory predictive coding. PMID- 25737556 TI - Quorum-sensing Salmonella selectively trigger protein expression within tumors. AB - Salmonella that secrete anticancer proteins have the potential to eliminate tumors, but nonspecific expression causes damage to healthy tissue. We hypothesize that Salmonella, integrated with a density-dependent switch, would only express proteins in tightly packed colonies within tumors. To test this hypothesis, we cloned the lux quorum-sensing (QS) system and a GFP reporter into nonpathogenic Salmonella. Fluorescence and bacterial density were measured in culture and in a tumor-on-a-chip device to determine the critical density necessary to initiate expression. QS Salmonella were injected into 4T1 tumor bearing mice to quantify GFP expression in vivo using immunofluorescence. At densities below 0.6 * 10(10) cfu/g in tumors, less than 3% of QS Salmonella expressed GFP. Above densities of 4.2 * 10(10) cfu/g, QS Salmonella had similar expression levels to constitutive controls. GFP expression by QS colonies was dependent upon the distance to neighboring bacteria. No colonies expressed GFP when the average distance to neighbors was greater than 155 um. Calculations of autoinducer concentrations showed that expression was sigmoidally dependent on density and inversely dependent on average radial distance. Based on bacterial counts from excised tissue, the liver density (0.0079 * 10(10) cfu/g) was less than the critical density (0.11 * 10(10) cfu/g) necessary to initiate expression. QS Salmonella are a promising tool for cancer treatment that will target drugs to tumors while preventing damage to healthy tissue. PMID- 25737557 TI - Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. AB - Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. PMID- 25737558 TI - Quantum technologies with hybrid systems. AB - An extensively pursued current direction of research in physics aims at the development of practical technologies that exploit the effects of quantum mechanics. As part of this ongoing effort, devices for quantum information processing, secure communication, and high-precision sensing are being implemented with diverse systems, ranging from photons, atoms, and spins to mesoscopic superconducting and nanomechanical structures. Their physical properties make some of these systems better suited than others for specific tasks; thus, photons are well suited for transmitting quantum information, weakly interacting spins can serve as long-lived quantum memories, and superconducting elements can rapidly process information encoded in their quantum states. A central goal of the envisaged quantum technologies is to develop devices that can simultaneously perform several of these tasks, namely, reliably store, process, and transmit quantum information. Hybrid quantum systems composed of different physical components with complementary functionalities may provide precisely such multitasking capabilities. This article reviews some of the driving theoretical ideas and first experimental realizations of hybrid quantum systems and the opportunities and challenges they present and offers a glance at the near- and long-term perspectives of this fascinating and rapidly expanding field. PMID- 25737559 TI - In memoriam: Albert Z. Kapikian, MD, 1930-2014. PMID- 25737560 TI - Comments on Leishmania major in Gorilla Feces. PMID- 25737561 TI - Reply to Bastien et al. PMID- 25737562 TI - A Tick Vector Transmission Model of Monocytotropic Ehrlichiosis. AB - BACKGROUND: Ehrlichioses are emerging, tick-borne diseases distributed worldwide. Previously established animal models use needle inoculation as a mode of infection; however, there is limited representation of natural transmission in artificially inoculated models compared with transmission by the tick vector. The objective of this study was to develop a tick vector transmission animal model of ehrlichial infection using a human pathogen, Ehrlichia muris-like agent (EMLA). METHODS: Ixodes scapularis larvae were fed on EMLA-infected mice, and after molting, infected nymphs were used to infest naive animals. RESULTS: Ehrlichiae were acquired by 90%-100% of feeding larvae. The majority of animals fed upon by infected nymphs developed sublethal infection with 27% lethality. Bacteria disseminated to all tissues tested with greatest bacterial loads in lungs, but also spleen, lymph nodes, liver, kidneys, brain, and bone marrow. Numerous foci of cellular infiltration, mitoses, and hepatocellular death were observed in liver. Mice infected by tick transmission developed higher antiehrlichial antibody levels than needle-inoculated animals. Tick-feeding-site reactions were observed, but there was no observed difference between animals infested with infected or uninfected ticks. CONCLUSIONS: For the first time we were able to develop a tick transmission model with an Ehrlichia that is pathogenic for humans. PMID- 25737563 TI - The Fall of a Dogma? Unexpected High T-Cell Memory Response to Staphylococcus aureus in Humans. AB - INTRODUCTION: Though Staphylococcus aureus is a major pathogen, vaccine trials have failed. In contrast, class-switched antibodies specific to S. aureus are common, implying immune memory formation and suggesting a large pool of S. aureus reactive helper T-cells. OBJECTIVE: To elucidate the cellular arm of S. aureus specific immune memory, the T-cell response in humans was characterized. METHODS: The proliferative response of human peripheral blood mononuclear cells (PBMCs) to S. aureus antigens and the frequency of S. aureus-specific T-cells were quantified by (3)H-thymidine incorporation; cytokine release was measured by flow cytometry. RESULTS: Staphylococcus aureus particles and extracellular proteins elicited pronounced proliferation in PBMCs of healthy adults. This reflected a memory response with high frequencies of T-cells being activated by single S. aureus antigens. The whole S. aureus-specific T-cell pool was estimated to comprise 3.6% of T-cells with 35-fold differences between individuals (range, 0.2%-5.7%). When exposed to S. aureus antigens, the T-cells released predominantly but not solely T helper (Th)1/Th17 cytokines. CONCLUSIONS: The large number of S. aureus antigen-reactive memory T-lymphocytes is likely to influence the course of S. aureus infection. To enable rational vaccine design, the naturally acquired human T-cell memory needs to be explored at high priority. PMID- 25737564 TI - Impact of an electronic consultant system on hypersensitivity reactions to iodinated radiocontrast media: an observational study. AB - OBJECTIVE: To evaluate the impact of an electronic consultation support system on the incidence of hypersensitivity reactions to iodinated radiocontrast media (RCM). MATERIALS AND METHODS: A retrospective observational study was conducted before and after the introduction of the consultation support system. The 1-year study period was divided into two 6-month periods: before and after 1 December 2012 (baseline and intervention periods, respectively), which was when our consultation support system was introduced. Data from examinations were collected retrospectively from the hospital information centre and problem reporting sheets in the radiology department. The primary outcome was the incidence of RCM reactions before and after the introduction of the consultation support system. Generalised estimating equations were used to account for the correlation between the same patients measured on multiple occasions. RESULTS: There were 317/20,179 (1.6%) and 186/19,873 (0.9%) hypersensitivity reactions during the baseline and intervention periods, respectively. The consultation support system significantly decreased the odds of the occurrence of a RCM reaction (OR=0.59, 95% CI 0.49 to 0.71, p<0.001) compared with baseline. There was also a twofold increase in the premedication rate after initiation of the consultation support system (OR=2.05, 95% CI 1.16 to 3.65 p=0.01). However, there was no significant difference in the recurrence rate between the periods (OR=0.97, 95% CI 0.58 to 1.65, p<0.93). CONCLUSIONS: The introduction of the consultation support system reduced the incidence of hypersensitivity reactions to RCM and increased the use of premedication in patients with known hypersensitivity to RCM. PMID- 25737565 TI - The Coalition for Sustainable Egg Supply project: An introduction. AB - In the United States, empirical information on the sustainability of commercial scale egg production is lacking. The passage of state regulations specific to hen housing created urgency to better understand the effects of different housing systems on the sustainability of the egg supply, and stimulated the formation of a coalition, the Coalition for a Sustainable Egg Supply (CSES), to conduct research on this topic. The CSES is a multi-stakeholder group with 27 members, including food manufacturers, research institutions, scientists, restaurants, food service, retail food companies, egg suppliers, and nongovernmental organizations. A commercial-scale study was developed to better understand the effect of 3 housing systems (conventional cage, enriched colony, and cage-free aviary) on 5 areas related to a sustainable egg supply. These 5 sustainability areas represent effects on people, animals, and the environment: animal health and well-being, environment, food safety, worker health and safety, and food affordability. Five teams of scientists, each associated with a sustainability area, conducted an integrated field study at a commercial site in the upper Midwest through 2 flock cycles in 3 housing systems. This paper provides a brief overview of the CSES project to serve as an introduction for the papers that follow in this volume of Poultry Science. PMID- 25737566 TI - Comparative evaluation of three egg production systems: Housing characteristics and management practices. AB - This paper is an integral part of the special publication series that arose from the multidisciplinary and multi-institutional project of the Coalition for Sustainable Egg Supply (CSES). The CSES project involves 3 housing systems for egg production at the same research farm site in the Midwest, USA, namely, a conventional cage (CC) house, an aviary (AV) house, and an enriched colony (EC) house. The CC house (141.4 m L*26.6 m W*6.1 m H) had a nominal capacity of 200,000 hens (6 hens in a cage at a stocking density of 516 cm2/hen), and the cages were arranged in 10 rows, 8 tiers per cage row, with a perforated aisle walkway at 4-tier height. The AV house (154.2 m L*21.3 m W*3.0 m H) and the EC house (154.2 m L*13.7 m W*4.0 m H) each had a nominal capacity of 50,000 hens. The AV house had 6 rows of aviary colonies, and the EC house had 5 rows of 4-tier enriched colonies containing perches, nestbox, and scratch pads (60 hens per colony at a stocking density of 752 cm2/hen). The overarching goal of the CSES project, as stated in the opening article of this series, was to comprehensively evaluate the 3 egg production systems from the standpoints of animal behavior and well-being, environmental impact, egg safety and quality, food affordability, and worker health. So that all the area-specific papers would not have to repeat a detailed description of the production systems and the management practices, this paper is written to provide such a description and to be used as a common reference for the companion papers. PMID- 25737567 TI - Environmental assessment of three egg production systems--Part I: Monitoring system and indoor air quality. AB - To comprehensively assess conventional vs. some alternative laying-hen housing systems under U.S. production conditions, a multi-institute and multi disciplinary project, known as the Coalition for Sustainable Egg Supply (CSES) study, was carried out at a commercial egg production farm in the Midwestern United States over two single-cycle production flocks. The housing systems studied include a conventional cage house (200,000 hen capacity), an aviary house (50,000 hen capacity), and an enriched colony house (50,000 hen capacity). As an integral part of the CSES project, continual environmental monitoring over a 27 month period described in this paper quantifies indoor gaseous and particulate matter concentrations, thermal environment, and building ventilation rate of each house. Results showed that similar indoor thermal environments in all three houses were maintained through ventilation management and environmental control. Gaseous and particulate matter concentrations of the enriched colony house were comparable with those of the conventional cage house. In comparison, the aviary house had poorer indoor air quality, especially in wintertime, resulting from the presence of floor litter (higher ammonia levels) and hens' activities (higher particulate matter levels) in it. Specifically, daily mean indoor ammonia concentrations had the 95% confidence interval values of 3.8 to 4.2 (overall mean of 4.0) ppm for the conventional cage house; 6.2 to 7.2 (overall mean of 6.7) ppm for the aviary house; and 2.7 to 3.0 (overall mean of 2.8) ppm for the enriched colony house. The 95% confidence interval (overall mean) values of daily mean indoor carbon dioxide concentrations were 1997 to 2170 (2083) ppm for the conventional cage house, 2367 to 2582 (2475) ppm for the aviary house, and 2124 to 2309 (2216) ppm for the enriched colony house. Daily mean indoor methane concentrations were similar for all three houses, with 95% confidence interval values of 11.1 to 11.9 (overall mean of 11.5) ppm. The 95% confidence interval values (overall mean) of daily mean PM10 and PM2.5 concentrations, in mg/m3, were, respectively, 0.57 to 0.61 (0.59) and 0.033 to 0.037 (0.035) for the conventional cage house, 3.61 to 4.29 (3.95) and 0.374 to 0.446 (0.410) for the aviary house, and 0.42 to 0.46 (0.44) and 0.054 to 0.059 (0.056) for the enriched colony house. Investigation of mitigation practices to improve indoor air quality of the litter-floor aviary housing system is warranted. PMID- 25737568 TI - Environmental assessment of three egg production systems--Part II. Ammonia, greenhouse gas, and particulate matter emissions. AB - As an integral part of the Coalition for Sustainable Egg Supply (CSES) Project, this study simultaneously monitored air emissions of 3 commercially operated egg production systems at the house level and associated manure storage over 2 single cycle flocks (18 to 78 wk of age). The 3 housing systems were 1) a conventional cage house (CC) with a 200,000-hen capacity (6 hens in a cage at a stocking density of 516 cm2/hen), 2) an enriched colony house (EC) with a 50,000-hen capacity (60 hens per colony at a stocking density of 752 cm2/hen), and 3) an aviary house (AV) with a 50,000-hen capacity (at a stocking density of 1253 to 1257 cm2/hen). The 3 hen houses were located on the same farm and were populated with Lohmann white hens of the same age. Indoor environment and house-level gaseous (ammonia [NH3] and greenhouse gasses [GHG], including carbon dioxide [CO2], methane [CH4], and nitrous oxide [N2O]) and particulate matter (PM10, PM2.5) emissions were monitored continually. Gaseous emissions from the respective manure storage of each housing system were also monitored. Emission rates (ERs) are expressed as emission quantities per hen, per animal unit (AU, 500 kg live BW), and per kilogram of egg output. House-level NH3 ER (g/hen/d) of EC (0.054) was significantly lower than that of CC (0.082) or AV (0.112) (P<0.05). The house-level CO2 ER (g/hen/d) was lower for CC (68.3) than for EC and AV (74.4 and 74.0, respectively), and the CH4 ER (g/hen/d) was similar for all 3 houses (0.07 to 0.08). The house-level PM ER (mg/hen/d), essentially representing the farm-level PM ER, was significantly higher for AV (PM10 100.3 and PM2.5 8.8) than for CC (PM10 15.7 and PM2.5 0.9) or EC (PM10 15.6 and PM2.5 1.7) (P<0.05). The farm-level (house plus manure storage) NH3 ER (g/hen/d) was significantly lower for EC (0.16) than for CC (0.29) or AV (0.30) (P<0.05). As expected, the magnitudes of GHG emissions were rather small for all 3 production systems. Data from this study enable comparative assessment of conventional vs. alternative hen housing systems regarding air emissions and enhance the U.S. national air emissions inventory for farm animal operations. PMID- 25737570 TI - Pulmonary function testing and outcomes in subjects with heart failure listed for heart transplantation. AB - BACKGROUND: Impaired spirometric parameters have been reported in patients with stage C heart failure and portend worse outcomes in these patients. The impact of spirometric parameters on outcomes in patients with stage D heart failure listed for heart transplantation is unknown. METHODS: We collected data on consecutive subjects listed for heart transplantation and examined the association of FEV1, FVC, and FEV1/FVC with (1) death or left ventricular assist device implantation (primary end point) and (2) death, left ventricular assist device implantation, or urgent transplantation (secondary end point). In a secondary analysis, we examined the association of baseline spirometry with post-transplant outcomes. RESULTS: Among 187 subjects (53 +/- 10 y old, 17.1% women, 69.5% white subjects, 28.9% black subjects), there were 19 deaths, 28 left ventricular assist device implantations, and 74 urgent transplantations (primary end point of 25.1%, secondary end point of 64.7%) after a median of 5.5 months (interquartile range of 2.3-15.2). For FEV1, the hazard ratios for the primary and secondary end points were 0.93 (95% CI 0.61-1.41, P = .72) and 0.94 (95% CI 0.72-1.21, P = .62) per L, respectively. The hazard ratios of FVC were 0.90 (95% CI 0.65-1.25, P = .52) and 0.92 (95% CI 0.76-1.13, P = .43) per L, respectively. Impairment patterns (obstructive, restrictive, mixed) were not associated with risk for events. There was no interaction of spirometric parameters with smoking or lung disease for outcomes. Baseline spirometry was not associated with perioperative 30-d mortality (1.4%) and 1-y post-transplant survival (97.1%). CONCLUSIONS: In contrast to stage C subjects with heart failure, spirometric parameters were not associated with outcomes in this homogeneous stage D heart failure population. PMID- 25737569 TI - Marker expression reveals heterogeneity of spermatogonia in the neonatal mouse testis. AB - Prospermatogonia transition to type A spermatogonia, which provide the source for the spermatogonial stem cell (SSC) pool. A percentage of these type A spermatogonia then differentiate to enter meiosis as spermatocytes by ~P10. It is currently unclear as to when these distinct populations are initially formed in the neonatal testis, and when the expression of markers both characteristic of and required for the adult undifferentiated and differentiating states is established. In this study, we compared expression of known spermatogonial cell fate markers during normal development and in response to the differentiation signal provided by retinoic acid (RA). We found that some markers for the undifferentiated state (ZBTB16/PLZF and CDH1) were expressed in nearly all spermatogonia from P1 through P7. In contrast, differentiation markers (STRA8 and KIT) appeared in a subset of spermatogonia at P4, coincident with the onset of RA signaling. GFRA1, which was present in nearly all prospermatogonia at P1, was only retained in STRA8/KIT- spermatogonia. From P4 through P10, there was a great deal of heterogeneity in the male germ cell population in terms of expression of markers, as markers characteristic of the undifferentiated (except GFRA1) and differentiating states were co-expressed through this interval. After P10, these fate markers diverged to mark distinct populations of undifferentiated and differentiating spermatogonia, and this pattern was maintained in juvenile (P18) and adult (P>60) testes. Taken together, these results reveal that the spermatogonia population is heterogeneous during the first wave of spermatogenesis, and indicate that neonatal spermatogonia may not serve as an ideal substitute for studying the function of adult spermatogonia. PMID- 25737571 TI - Reliability of Apnea-Hypopnea Index Measured by a Home Bi-Level Pressure Support Ventilator Versus a Polysomnographic Assessment. AB - BACKGROUND: Ventilators designed for home care provide clinicians with built-in software that records items such as compliance, leaks, average tidal volume, total ventilation, and indices of residual apnea and hypopnea. Recent studies have showed, however, an important variability between devices regarding reliability of data provided. In this study, we aimed to compare apnea-hypopnea indices (AHI) provided by home ventilators (AHINIV) versus data scored manually during polysomnography (AHIPSG) in subjects on noninvasive ventilation (NIV) for obesity-hypoventilation syndrome. METHODS: Stable subjects with obesity hypoventilation syndrome on NIV, all using the same device, underwent 3 consecutive polysomnographic sleep studies with different backup breathing frequencies (spontaneous mode, low and high backup breathing frequencies). During each recording, AHINIV was compared with AHIPSG. RESULTS: Ten subjects (30 polysomnogram tracings) were analyzed. For each backup breathing frequency (spontaneous mode, low and high backup breathing frequencies), AHI values were 62 +/- 7/h, 26 +/- 7/h, and 17 +/- 5/h (mean +/- SD), respectively. Correlation between AHINIV and AHIPSG was highly significant (r(2) = 0.89, P < .001). As determined by Bland-Altman analysis, mean bias was 6.5 events/h, and limits of agreement were +26.0 and -12.9 events/h. Bias increased significantly with higher AHI values. Using a threshold AHI value of 10/h to define appropriate control of respiratory events, the ventilator software had a sensitivity of 90.9%, a specificity and positive predictive value of 100%, and a negative predictive value of 71%. CONCLUSIONS: In stable subjects with obesity-hypoventilation syndrome, the home ventilator software tested was appropriate for determining if control of respiratory events was satisfactory on NIV or if further testing or adjustment of ventilator settings was required. (ClinicalTrials.gov registration NCT01130090.). PMID- 25737572 TI - Effect of Aerosol Devices and Administration Techniques on Drug Delivery in a Simulated Spontaneously Breathing Pediatric Tracheostomy Model. AB - BACKGROUND: This study was conducted to compare the efficiency of jet nebulizers, vibrating mesh nebulizers, and pressurized metered-dose inhalers (pMDI) during assisted and unassisted administration techniques using a simulated spontaneously breathing pediatric model with a tracheostomy tube (TT). METHODS: An in vitro breathing model consisting of an uncuffed TT (4.5-mm inner diameter) was attached to a collecting filter (Respirgard) connected to a dual-chamber test lung and a ventilator (Hamilton Medical) to simulate breathing parameters of a 2-y-old child (breathing frequency, 25 breaths/min; tidal volume, 150 mL; inspiratory time, 0.8 s; peak inspiratory flow, 20 L/min). Albuterol sulfate was administered using a jet nebulizer (MicroMist, 2.5 mg/3 mL), vibrating mesh nebulizer (Aeroneb Solo, 2.5 mg/3 mL), and pMDI (ProAir HFA, 432 MUg). Each device was tested 5 times with an unassisted technique (direct administration of aerosols with simulated spontaneous breathing) and with an assisted technique (using a manual resuscitation bag in conjunction with an aerosol device and synchronized with inspiration). Drug collected on the filter was analyzed by spectrophotometry. RESULTS: With the unassisted technique, the pMDI had the highest inhaled mass percent (IM%, 47.15 +/- 7.82%), followed by the vibrating mesh nebulizer (19.77 +/- 2.99%) and the jet nebulizer (5.88 +/- 0.77%, P = .002). IM was greater with the vibrating mesh nebulizer (0.49 +/- .07 mg) than with the pMDI (0.20 +/- 0.03 mg) and the jet nebulizer (0.15 +/- 0.01 mg, P = .007). The trend of lower deposition with the assisted versus unassisted technique was not significant for the jet nebulizer (P = .46), vibrating mesh nebulizer (P = .19), and pMDI (P = .64). CONCLUSIONS: In this in vitro pediatric breathing model with a TT, the pMDI delivered the highest IM%, whereas the vibrating mesh nebulizer delivered the highest IM. The jet nebulizer was the least efficient device. Delivery efficiency was similar with unassisted and assisted administration techniques. PMID- 25737573 TI - Guidelines, pathways, bundles, and protocols: clinical recipes for success. PMID- 25737574 TI - Raising professional presence through team leadership in the critical care setting. PMID- 25737575 TI - Hypercapnia From Hyperoxia in COPD: Another Piece of the Puzzle or Another Puzzle Entirely? PMID- 25737576 TI - Double lumen endotracheal tube for percutaneous tracheostomy? PMID- 25737577 TI - Double lumen endotracheal tube for percutaneous tracheostomy-reply. PMID- 25737579 TI - Whole-genome mapping of 5' RNA ends in bacteria by tagged sequencing: a comprehensive view in Enterococcus faecalis. AB - Enterococcus faecalis is the third cause of nosocomial infections. To obtain the first snapshot of transcriptional organizations in this bacterium, we used a modified RNA-seq approach enabling to discriminate primary from processed 5' RNA ends. We also validated our approach by confirming known features in Escherichia coli. We mapped 559 transcription start sites (TSSs) and 352 processing sites (PSSs) in E. faecalis. A blind motif search retrieved canonical features of SigA- and SigN-dependent promoters preceding transcription start sites mapped. We discovered 85 novel putative regulatory RNAs, small- and antisense RNAs, and 72 transcriptional antisense organizations. Presented data constitute a significant insight into bacterial RNA landscapes and a step toward the inference of regulatory processes at transcriptional and post-transcriptional levels in a comprehensive manner. PMID- 25737581 TI - Risk of eye lens radiation exposure for members of the public. AB - In 2011, the International Commission on Radiological Protection (ICRP) reviewed its recommendation concerning the equivalent dose limit for the eye lens, lowering it to 20 mSv in a year, for occupational exposure in planned exposure situations. The ICRP's statement does not contain any explicit recommendations regarding the organ dose limit for the eye lens for public exposure. For the moment, no change is proposed. But, to be coherent in the overall approach, the current equivalent limit for the public might be lowered. A similar yardstick than in the former recommendation may be used, that is to say a reduction of 10 times lower than that for occupational exposure. In this context, additional data on potential scenarios for public exposure of the eye lens are necessary. This paper, mainly based on a literature study, aims to provide, as far as possible, an exhaustive list of the situations in which members of the public can be exposed at the level of the eye lens. Once these situations have been defined, some calculations, made to assess the associated doses to the eye lens, are presented. This literature study did not reveal any current situations where members of the public would receive significant radiation doses to the eye lens. Indeed, the situations in which the dose to the eye lens might reach around 1 mSv per year for the public are extremely rare. PMID- 25737580 TI - A second essential function of the Est1-binding arm of yeast telomerase RNA. AB - The enzymatic ribonucleoprotein telomerase maintains telomeres in many eukaryotes, including humans, and plays a central role in aging and cancer. Saccharomyces cerevisiae telomerase RNA, TLC1, is a flexible scaffold that tethers telomerase holoenzyme protein subunits to the complex. Here we test the hypothesis that a lengthy conserved region of the Est1-binding TLC1 arm contributes more than simply Est1-binding function. We separated Est1 binding from potential other functions by tethering TLC1 to Est1 via a heterologous RNA protein binding module. We find that Est1-tethering rescues in vivo function of telomerase RNA alleles missing nucleotides specifically required for Est1 binding, but not those missing the entire conserved region. Notably, however, telomerase function is restored for this condition by expressing the arm of TLC1 in trans. Mutational analysis shows that the Second Essential Est1-arm Domain (SEED) maps to an internal loop of the arm, which SHAPE chemical mapping and 3D modeling suggest could be regulated by conformational change. Finally, we find that the SEED has an essential, Est1-independent role in telomerase function after telomerase recruitment to the telomere. The SEED may be required for establishing telomere extendibility or promoting telomerase RNP holoenzyme activity. PMID- 25737582 TI - Energy response of GR-200A thermoluminescence dosemeters to 60Co and to monoenergetic synchrotron radiation in the energy range 28-40 keV. AB - The response of LiF:Mg,Cu,P thermoluminescence dosemeters (type GR-200A) to monoenergetic radiation of energy 28, 35, 38 and 40 keV was evaluated with respect to irradiation with a calibrated (60)Co gamma-ray source. High-precision measurements of the relative air kerma response performed at the SYRMEP beamline of the ELETTRA synchrotron radiation facility (Trieste, Italy) showed a significant deviation of the average response to low-energy X-rays from that to (60)Co, with an over-response from 6 % (at 28 keV) to 22 % (at 40 keV). These data are not consistent with literature data for these dosemeters, where model predictions gave deviation from unity of the relative air kerma response of about 10 %. The authors conclude for the need of additional determinations of the low energy relative response of GR-200A dosemeters, covering a wider range of monoenergetic energies sampled at a fine energy step, as planned in future experiments by their group at the ELETTRA facility. PMID- 25737583 TI - Focus issue: Inflammatory mechanisms. AB - Research published in Science Signaling identifies previously uncharacterized regulators of the inflammatory response, characterizes feedback mechanisms that modulate inflammation, and demonstrates potential therapies to resolve inflammatory diseases in vivo. PMID- 25737584 TI - Integrating p38alpha MAPK immune signals in nonimmune cells. AB - A study by Huang et al. in this issue of Science Signaling highlights key roles for the mitogen-activated protein kinase p38alpha and the phosphatase MK1 in mediating interleukin-17-dependent pathology in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. PMID- 25737585 TI - Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. AB - Cytosolic Ca2+ signals, generated through the coordinated translocation of Ca2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca2+ is important for mitochondrial function, and when cytosolic Ca2+ concentration becomes too high, mitochondria function as cellular Ca2+ sinks. By measuring mitochondrial Ca2+ currents, we found that mitochondrial Ca2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP3R), which releases Ca2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca2+ -permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca2+ stores. The abundance of MCU, the pore-forming subunit of the mitochondrial Ca2+ uniporter, was reduced in cells deficient in IP3R, STIM1, or Orai1. Chromatin immunoprecipitation and promoter reporter analyses revealed that the Ca2+ -regulated transcription factor CREB (cyclic adenosine monophosphate response element-binding protein) directly bound the MCU promoter and stimulated expression. Lymphocytes deficient in IP3R, STIM1, or Orai1 exhibited altered mitochondrial metabolism, indicating that Ca2+ released from the ER and SOCE-mediated signals modulates mitochondrial function. Thus, our results showed that a transcriptional regulatory circuit involving Ca2+ dependent activation of CREB controls the Ca2+ uptake capability of mitochondria and hence regulates mitochondrial metabolism. PMID- 25737587 TI - Viral entry route determines how human plasmacytoid dendritic cells produce type I interferons. AB - Although plasmacytoid dendritic cells (pDCs) represent a rare immune cell type, they are the most important source of type I interferons (IFNs) upon viral infection. Phagocytosed RNA viruses and RNA virus-infected cells are detected by pDCs with the endosomal pattern recognition receptor (PRR) toll-like receptor 7 (TLR7). We showed that replication of the yellow fever live vaccine YF-17D in human pDCs and pDC-like cell lines stimulated type I IFN production through RIG-I (retinoic acid-inducible gene I), a member of the RIG-I-like receptor (RLR) family of cytosolic PRRs. Thus, human pDCs sense replicative viral RNA. In contrast, direct contact between pDCs and YF-17D-infected cells stimulated a TLR7 dependent, viral replication-independent production of type I IFN. We also showed that the RLR pathway was dampened by the activities of interleukin-1 receptor associated kinases 1 and 4 (IRAK1 and IRAK4), which are downstream effectors of the TLR7 pathway, suggesting that both kinases play opposing roles downstream of specific PRRs. Together, these data suggest that a virus can stimulate either TLR or RLR signaling in the same cell, depending on how its nucleic acid content is delivered. PMID- 25737586 TI - Control of IL-17 receptor signaling and tissue inflammation by the p38alpha-MKP-1 signaling axis in a mouse model of multiple sclerosis. AB - T helper 17 (T(H)17) cells, a subset of CD4+ T cells that secrete the proinflammatory cytokine interleukin-17 (IL-17), play a key pathogenic role in autoimmune diseases. Through inducible and tissue-specific deletion systems, we described the time- and tissue-specific roles of the mitogen-activated protein kinase (MAPK) p38alpha in mediating T(H)17 cell-induced tissue inflammation. Inducible deletion of Mapk14 (which encodes p38alpha) after the onset of experimental autoimmune encephalomyelitis (EAE), a murine model for human multiple sclerosis, protected mice from inflammation. Furthermore, the severity of EAE was markedly reduced in mice with specific loss of p38alpha in neuroectoderm-derived cells, including astrocytes, an effect that was associated with defective production of chemokines and decreased infiltration of the target tissue by immune cells. p38alpha linked IL-17 receptor (IL-17R) signaling to the expression of genes encoding proinflammatory chemokines and cytokines. Mice that lacked MAPK phosphatase 1 (MKP-1), an inhibitor of p38alpha, had exacerbated EAE and enhanced expression of IL-17R-dependent genes. Our results suggest that the p38alpha-MKP-1 signaling axis links IL-17R signaling in tissue-resident cells to autoimmune inflammation dependent on infiltrating T(H)17 cells. PMID- 25737588 TI - Combined procedure of heart transplantation and ascending aorta replacement. AB - Concomitant heart transplantation and ascending aorta replacement is infrequent. In the few cases where this simultaneous procedure was performed, most patients were diagnosed with Marfan syndrome. We report the combined procedure of heart transplantation and ascending aorta replacement using the donor's ascending aorta, in a 70-year-old man who was not diagnosed with Marfan syndrome. This combined procedure can be performed successfully, providing a potentially life saving heart transplant for patients with aortic disease of different etiologies. PMID- 25737589 TI - Mitral valve repair for traumatic mitral regurgitation. AB - Mitral valve injury after blunt chest trauma is a rare clinical condition. We describe a case of mitral valve repair for severe mitral regurgitation due to blunt chest trauma 5 years previously. A 22-year-old man was referred to our hospital for surgical correction of severe mitral regurgitation. Echocardiography demonstrated a partial tear of the anterolateral papillary muscle which lacerated to the apex. The entire anterolateral part of the mitral valve including the anterior commissure and posterior leaflets had prolapsed. Reimplantation of the papillary muscle to the posterior left ventricular wall and ring annuloplasty were successfully performed without residual regurgitation. PMID- 25737590 TI - Methods for solving reasoning problems in abstract argumentation - A survey. AB - Within the last decade, abstract argumentation has emerged as a central field in Artificial Intelligence. Besides providing a core formalism for many advanced argumentation systems, abstract argumentation has also served to capture several non-monotonic logics and other AI related principles. Although the idea of abstract argumentation is appealingly simple, several reasoning problems in this formalism exhibit high computational complexity. This calls for advanced techniques when it comes to implementation issues, a challenge which has been recently faced from different angles. In this survey, we give an overview on different methods for solving reasoning problems in abstract argumentation and compare their particular features. Moreover, we highlight available state-of-the art systems for abstract argumentation, which put these methods to practice. PMID- 25737591 TI - Introducing the Consolidated Species Concept to resolve species in the Teratosphaeriaceae. AB - The Teratosphaeriaceae represents a recently established family that includes numerous saprobic, extremophilic, human opportunistic, and plant pathogenic fungi. Partial DNA sequence data of the 28S rRNA and RPB2 genes strongly support a separation of the Mycosphaerellaceae from the Teratosphaeriaceae, and also provide support for the Extremaceae and Neodevriesiaceae, two novel families including many extremophilic fungi that occur on a diversity of substrates. In addition, a multi-locus DNA sequence dataset was generated (ITS, LSU, Btub, Act, RPB2, EF-1alpha and Cal) to distinguish taxa in Mycosphaerella and Teratosphaeria associated with leaf disease of Eucalyptus, leading to the introduction of 23 novel genera, five species and 48 new combinations. Species are distinguished based on a polyphasic approach, combining morphological, ecological and phylogenetic species concepts, named here as the Consolidated Species Concept (CSC). From the DNA sequence data generated, we show that each one of the five coding genes tested, reliably identify most of the species present in this dataset (except species of Pseudocercospora). The ITS gene serves as a primary barcode locus as it is easily generated and has the most extensive dataset available, while either Btub, EF-1alpha or RPB2 provide a useful secondary barcode locus. PMID- 25737592 TI - Moniliellomycetes and Malasseziomycetes, two new classes in Ustilaginomycotina. AB - Ustilaginomycotina (Basidiomycota, Fungi) has been reclassified recently based on multiple gene sequence analyses. However, the phylogenetic placement of two yeast like genera Malassezia and Moniliella in the subphylum remains unclear. Phylogenetic analyses using different algorithms based on the sequences of six genes, including the small subunit (18S) ribosomal DNA (rDNA), the large subunit (26S) rDNA D1/D2 domains, the internal transcribed spacer regions (ITS 1 and 2) including 5.8S rDNA, the two subunits of RNA polymerase II (RPB1 and RPB2) and the translation elongation factor 1-alpha (EF1-alpha), were performed to address their phylogenetic positions. Our analyses indicated that Malassezia and Moniliella represented two deeply rooted lineages within Ustilaginomycotina and have a sister relationship to both Ustilaginomycetes and Exobasidiomycetes. Those clades are described here as new classes, namely Moniliellomycetes with order Moniliellales, family Moniliellaceae, and genus Moniliella; and Malasseziomycetes with order Malasseziales, family Malasseziaceae, and genus Malassezia. Phenotypic differences support this classification suggesting widely different life styles among the mainly plant pathogenic Ustilaginomycotina. PMID- 25737593 TI - Novel Curvularia species from clinical specimens. AB - The fungal genus Curvularia includes numerous plant pathogens and some emerging opportunistic pathogens of humans. In a previous study we used morphology and sequences of the nuclear ribosomal internal transcribed spacer region (ITS) and the glyceraldehyde-3-phosphate dehydrogenase (gpd) gene to identify species within a set of 99 clinical Curvularia isolates from the USA. Seventy-two isolates could be identified while the remaining 27 isolates belonged in three unclassified clades that were tentatively labelled Curvularia sp. I, II and III. In the present study, we further assess the taxonomic placement of these isolates using sequences of ITS, gpd, the large subunit rDNA, and the second largest subunit of RNA polymerase II. DNA sequence comparisons with a set of 87 isolates representing 33 Curvularia spp. and members of the closely-related genera Bipolaris and Exserohilum revealed that Curvularia sp. I, II and III represent novel lineages in Curvularia. These lineages are morphologically different from the currently accepted species. In the phylogenetic tree, Curvularia sp. I and sp. III were each split into two distinct lineages. Morphology and phylogeny supported the proposal of five new species, to be named C. americana, C. chlamydospora, C. hominis, C. muehlenbeckiae and C. pseudolunata. The concatenated 4-locus phylogeny revealed the existence of six clades in Curvularia, which are associated with particular morphological features. They were named after representative species, namely americana, eragrostidis, hominis, lunata, spicifera and trifolii. PMID- 25737594 TI - Stilbosporaceae resurrected: generic reclassification and speciation. AB - Following the abolishment of dual nomenclature, Stilbospora is recognised as having priority over Prosthecium. The type species of Stilbospora, S. macrosperma, is the correct name for P. ellipsosporum, the type species of Prosthecium. The closely related genus Stegonsporium is maintained as distinct from Stilbospora based on molecular phylogeny, morphology and host range. Stilbospora longicornuta and S. orientalis are described as new species from Carpinus betulus and C. orientalis, respectively. They differ from the closely related Stilbospora macrosperma, which also occurs on Carpinus, by longer, tapering gelatinous ascospore appendages and by distinct LSU, ITS rDNA, rpb2 and tef1 sequences. The asexual morphs of Stilbospora macrosperma, S.longicornuta and S. orientalis are morphologically indistinguishable; the connection to their sexual morphs is demonstrated by morphology and DNA sequences of single spore cultures derived from both ascospores and conidia. Both morphs of the three Stilbospora species on Carpinus are described and illustrated. Other species previously recognised in Prosthecium, specifically P.acerophilum, P. galeatum and P. opalus, are determined to belong to and are formally transferred to Stegonsporium. Isolates previously recognised as Stegonsporium pyriforme (syn. Prosthecium pyriforme) are determined to consist of three phylogenetically distinct lineages by rpb2 and tef1 sequence data, two of which are described as new species (S. protopyriforme, S. pseudopyriforme). Stegonsporium pyriforme is lectotypified and this species and Stilbospora macrosperma are epitypified. Based on DNA sequence data, the North American Stegonsporium acerophilum is recorded from Europe for the first time, and new hosts from Acer sect. Acer are reported for S. opalus and S. pyriforme. Stilbospora and Stegonsporium are classified within the revived family Stilbosporaceae. Prosthecium appendiculatum, P. auctum and P. innesii are shown to be unrelated to the Stilbosporaceae and are recognised in three distinct genera, Phaeodiaporthe appendiculata, Alnecium auctum n. gen. and Calosporella innesii within Diaporthaceae, Gnomoniaceae and Sydowiellaceae, respectively. The generic types of these three monotypic genera are briefly described, illustrated and lecto- and epitypfied. PMID- 25737595 TI - The Colletotrichum gigasporum species complex. AB - In a preliminary analysis, 21 Colletotrichum strains with large conidia preserved in the CBS culture collection clustered with a recently described species, C. gigasporum, forming a clade distinct from other currently known Colletotrichum species complexes. Multi-locus phylogenetic analyses (ITS, ACT, TUB2, CHS-1, GAPDH) as well as each of the single-locus analyses resolved seven distinct species, one of them being C. gigasporum. Colletotrichum gigasporum and its close allies thus constitute a previously unknown species complex with shared morphological features. Five of the seven species accepted in the C. gigasporum species complex are described here as novel species, namely C. arxii, C. magnisporum, C. pseudomajus, C. radicis and C. vietnamense. A species represented by a single sterile strain, namely CBS 159.50, was not described as novel species, and is treated as Colletotrichum sp. CBS 159.50. Furthermore, C. thailandicum is reduced to synonymy with C. gigasporum. PMID- 25737596 TI - The largest type study of Agaricales species to date: bringing identification and nomenclature of Phlegmacium (Cortinarius) into the DNA era. AB - Cortinarius is a species-rich and morphologically challenging genus with a cosmopolitan distribution. Many names have not been used consistently and in some instances the same species has been described two or more times under separate names. This study focuses on subg. Phlegmacium as traditionally defined and includes species from boreal and temperate areas of the northern hemisphere. Our goals for this project were to: i) study type material to determine which species already have been described; ii) stabilize the use of Friesian and other older names by choosing a neo- or epitype; iii) describe new species that were discovered during the process of studying specimens; and iv) establish an accurate ITS barcoding database for Phlegmacium species. A total of 236 types representing 154 species were studied. Of these 114 species are described only once whereas 40 species had one ore more synonyms. Of the names studied only 61 were currently represented in GenBank. Neotypes are proposed for 21 species, and epitypes are designated for three species. In addition, 20 new species are described and six new combinations made. As a consequence ITS barcodes for 175 Cortinarius species are released. PMID- 25737597 TI - Revision of agents of black-grain eumycetoma in the order Pleosporales. AB - Eumycetoma is a chronic fungal infection characterised by large subcutaneous masses and the presence of sinuses discharging coloured grains. The causative agents of black-grain eumycetoma mostly belong to the orders Sordariales and Pleosporales. The aim of the present study was to clarify the phylogeny and taxonomy of pleosporalean agents, viz. Madurella grisea, Medicopsis romeroi (syn.: Pyrenochaeta romeroi), Nigrograna mackinnonii (syn. Pyrenochaeta mackinnonii), Leptosphaeria senegalensis, L. tompkinsii, and Pseudochaetosphaeronema larense. A phylogenetic analysis based on five loci was performed: the Internal Transcribed Spacer (ITS), large (LSU) and small (SSU) subunit ribosomal RNA, the second largest RNA polymerase subunit (RPB2), and translation elongation factor 1-alpha (TEF1) gene. In addition, the morphological and physiological characteristics were determined. Three species were well resolved at the family and genus level. Madurella grisea, L. senegalensis, and L. tompkinsii were found to belong to the family Trematospheriaceae and are reclassified as Trematosphaeria grisea comb. nov., Falciformispora senegalensis comb. nov., and F. tompkinsii comb. nov. Medicopsis romeroi and Pseudochaetosphaeronema larense were phylogenetically distant and both names are accepted. The genus Nigrograna is reduced to synonymy of Biatriospora and therefore N. mackinnonii is reclassified as B. mackinnonii comb. Nov. Mycetoma agents in Pleosporales were phylogenetically quite diverse despite their morphological similarity in the formation of pycnidia, except for the ascosporulating genus Falciformispora (formerly in Leptosphaeria). Most of the species diagnosed from human mycetoma were found to be related to waterborne or marine fungi, suggesting an association of the virulence factors with oligotrophism or halotolerance. PMID- 25737598 TI - Confronting the constraints of morphological taxonomy in the Botryosphaeriales. AB - Identification of fungi and the International Code of Nomenclature underpinning this process, rests strongly on the characterisation of morphological structures. Yet, the value of these characters to define species in many groups has become questionable or even superfluous. This has emerged as DNA-based techniques have increasingly revealed cryptic species and species complexes. This problem is vividly illustrated in the present study where 105 isolates of the Botryosphaeriales were recovered from both healthy and diseased woody tissues of native Acacia spp. in Namibia and South Africa. Thirteen phylogenetically distinct groups were identified based on Internal Transcribed Spacer (ITS) rDNA PCR-RFLP and translation elongation factor 1-alpha (TEF1-alpha) sequence data, two loci that are known to be reliable markers to distinguish species in the Botryosphaeriales. Four of these groups could be linked reliably to sequence data for formerly described species, including Botryosphaeria dothidea, Dothiorella dulcispinae, Lasiodiplodia pseudotheobromae and Spencermartinsia viticola. Nine groups, however, could not be linked to any other species known from culture and for which sequence data are available. These groups are, therefore, described as Aplosporella africana, A. papillata, Botryosphaeria auasmontanum, Dothiorella capri-amissi, Do. oblonga, Lasiodiplodia pyriformis, Spencermartinsia rosulata, Sphaeropsis variabilis and an undescribed Neofusicoccum sp. The species described here could not be reliably compared with the thousands of taxa described in these genera from other hosts and regions, where only morphological data are available. Such comparison would be possible only if all previously described taxa are epitypified, which is not a viable objective for the two families, Botryosphaeriaceae and Aplosporellaceae, in the Botryosphaeriales identified here. The extent of diversity of the Botryosphaeriales revealed in this and other recent studies is expected to reflect that of other undersampled regions and hosts, and illustrates the urgency to find more effective ways to describe species in this, and indeed other, groups of fungi. PMID- 25737599 TI - Stripe smuts of grasses: one lineage or high levels of polyphyly? AB - Stripe smut of grasses, Ustilago striiformis s.l., is a complex of smut fungi widely distributed over temperate and subtropical regions. The disease results in the shredding and death of leaf tissue following the rupture of elongated sori. Nearly 100 different grass species in more than 30 genera are infected by stripe smut. During the last two centuries more than 30 smut taxa have been described from members of this complex. The present study attempts to clarify the taxonomy and phylogeny of stripe smuts on grasses by analysing both morphological and molecular data. More than 200 specimens from different continents and host plants were examined. DNA was extracted from teliospores of 23 specimens from different hosts collected in Europe, Asia, and North America. The ITS and LSU regions of ribosomal DNA were amplified and used in phylogenetic analyses. The results of Maximum Parsimony and Bayesian analyses demonstrated that there are several lineages of stripe smut fungi. Analyses of morphological characters assessed with light and scanning electron microscopy showed high support for the differentiation of two clades as distinct from U. striiformis s.l., i.e., U. nunavutica sp. nov. and U. bromina. Two additional clades, U. striiformis s.str. on Holcus and a clade containing specimens from Elymus, were identified with molecular data although morphological differences were not apparent. Descriptions are given for each species. PMID- 25737600 TI - Persistent hamathecial threads in the Nectriaceae, Hypocreales: Thyronectria revisited and re-instated. AB - Based on type studies and freshly collected material we here re-instate the genus Thyronectria (Nectriaceae, Hypocreales). Species of this genus were recently for the most part classified in the genera Pleonectria (Nectriaceae) or Mattirolia (Thyridiaceae), because Thyronectria and other genera had been identified as members of the Thyridiaceae due to the presence of paraphyses. Molecular phylogenies based on several markers (act, ITS, LSU rDNA, rpb1, rpb2, tef1, tub) revealed that the Nectriaceae contain members whose ascomata are characterised by long, more or less persistent, apical paraphyses. All of these belong to a single genus, Thyronectria, which thus has representatives with hyaline, rosy, green or even dark brown and sometimes distoseptate ascospores. The type species of Thyronectria, T. rhodochlora, syn. T. patavina, syn. T. pyrrhochlora is re described and illustrated. Within the Nectriaceae persistent, apical paraphyses are common in Thyronectria and rarely also occur in Nectria. The genus Mattirolia is revised and merged with Thyronectria and also Thyronectroidea is regarded as a synonym of Thyronectria. The three new species T. asturiensis, T. caudata and T. obscura are added to the genus. Species recently described in Pleonectria as well as some species of Mattirolia are combined in the genus, and a key to Thyronectria is provided. Five species are epitypified. The type species of the genus Thyridium (Thyridiaceae), T. vestitum, is included in phylogenetic analyses to illustrate the phylogenetic distance of Thyronectria from the Thyridiaceae. PMID- 25737602 TI - Bringing 'Light, Life and Happiness': British American Tobacco and musicsponsorship in sub-Saharan Africa. AB - This article aims to provide a review of music sponsorship to market cigarettes in sub-Saharan Africa. Using analysis of previously secret corporate documents from British American Tobacco (BAT) and focusing on two separate case studies of sponsorship in Africa, Nigeria and South Africa, the paper illustrates how tobacco companies have sought to undermine health legislation from 1990 to 2001. Both case studies suggest that music is an important marketing tool in Africa because it can effectively target young consumers; has a universal appeal; transcends barriers to communication imposed by limited literacy and language barriers; has a long-term appeal and can be successful in undermining tobacco control measures. The case studies highlight the limitations of national regulatory efforts and reinforce the significance of the implementation of the WHO's Framework Convention on Tobacco Control in Africa, a critical region for the convention's success. PMID- 25737603 TI - Toxicity of Ayurveda medicines and safety concerns: The need to revive the branch of toxicology in Ayurveda. PMID- 25737601 TI - Fungal Planet description sheets: 281-319. AB - Novel species of fungi described in the present study include the following from South Africa: Alanphillipsia aloeicola from Aloe sp., Arxiella dolichandrae from Dolichandra unguiscati, Ganoderma austroafricanum from Jacaranda mimosifolia, Phacidiella podocarpi and Phaeosphaeria podocarpi from Podocarpus latifolius, Phyllosticta mimusopisicola from Mimusops zeyheri and Sphaerulina pelargonii from Pelargonium sp. Furthermore, Barssia maroccana is described from Cedrus atlantica (Morocco), Codinaea pini from Pinus patula (Uganda), Crucellisporiopsis marquesiae from Marquesia acuminata (Zambia), Dinemasporium ipomoeae from Ipomoea pes-caprae (Vietnam), Diaporthe phragmitis from Phragmites australis (China), Marasmius vladimirii from leaf litter (India), Melanconium hedericola from Hedera helix (Spain), Pluteus albotomentosus and Pluteus extremiorientalis from a mixed forest (Russia), Rachicladosporium eucalypti from Eucalyptus globulus (Ethiopia), Sistotrema epiphyllum from dead leaves of Fagus sylvatica in a forest (The Netherlands), Stagonospora chrysopyla from Scirpus microcarpus (USA) and Trichomerium dioscoreae from Dioscorea sp. (Japan). Novel species from Australia include: Corynespora endiandrae from Endiandra introrsa, Gonatophragmium triuniae from Triunia youngiana, Penicillium coccotrypicola from Archontophoenix cunninghamiana and Phytophthora moyootj from soil. Novelties from Iran include Neocamarosporium chichastianum from soil and Seimatosporium pistaciae from Pistacia vera. Xenosonderhenia eucalypti and Zasmidium eucalyptigenum are newly described from Eucalyptus urophylla in Indonesia. Diaporthe acaciarum and Roussoella acacia are newly described from Acacia tortilis in Tanzania. New species from Italy include Comoclathris spartii from Spartium junceum and Phoma tamaricicola from Tamarix gallica. Novel genera include (Ascomycetes): Acremoniopsis from forest soil and Collarina from water sediments (Spain), Phellinocrescentia from a Phellinus sp. (French Guiana), Neobambusicola from Strelitzia nicolai (South Africa), Neocladophialophora from Quercus robur (Germany), Neophysalospora from Corymbia henryi (Mozambique) and Xenophaeosphaeria from Grewia sp. (Tanzania). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa. PMID- 25737604 TI - Role of indigenous herbs in the management of Alzheimer's disease. AB - Ageing is a natural phenomenon and decline of physiological and structural changes are incurable in advancing years of human life. When such degenerative changes occur in the brain they may lead to dementia and other memory related conditions. The Ayurvedic classics identified the importance of higher faculties dealing with memory and introduced a separate group of drugs namely Medhya Rasayanas. Regular intake of such drugs will help to prevent the onset of degenerative changes in the brain prematurely. Ayurveda can play a useful role in the management of such geriatric conditions. The current review has been done with a view to update documented Ayurvedic therapeutic modalities for certain geriatric conditions suggested by Ayurvedic classics in the management of diseases called Vatavyadhi (nervous system disorders), which also include conditions related to memory functions. Recent studies have started validating the claims recorded in Ayurvedic texts. The pathogenesis and remedies for Vatavyadhi documented in Ayurvedic classics have been reviewed with special emphasis on disorders related to dementia. A review of recent researches on the herbs mentioned in management of vata disorders including dementia have been done to understand their role in management of Alzheimer's disease (AD). There are many herbs of ethno-medicinal source studied experimentally for their potential in treatment of AD. A judicious combination of modern research methodology and Ayurvedic principles could go a long way in the management and care of AD which is going to be a heavy burden on the society in the future. PMID- 25737605 TI - Proposed correlation of modern processing principles for Ayurvedic herbal drug manufacturing: A systematic review. AB - Quality Ayurvedic herbal medicines are potential, low-cost solutions for addressing contemporary healthcare needs of both Indian and global community. Correlating Ayurvedic herbal preparations with modern processing principles (MPPs) can help develop new and use appropriate technology for scaling up production of the medicines, which is necessary to meet the growing demand. Understanding the fundamental Ayurvedic principles behind formulation and processing is also important for improving the dosage forms. Even though Ayurvedic industry has adopted technologies from food, chemical and pharmaceutical industries, there is no systematic study to correlate the traditional and modern processing methods. This study is an attempt to provide a possible correlation between the Ayurvedic processing methods and MPPs. A systematic literature review was performed to identify the Ayurvedic processing methods by collecting information from English editions of classical Ayurveda texts on medicine preparation methods. Correlation between traditional and MPPs was done based on the techniques used in Ayurvedic drug processing. It was observed that in Ayurvedic medicine preparations there were two major types of processes, namely extraction, and separation. Extraction uses membrane rupturing and solute diffusion principles, while separation uses volatility, adsorption, and size-exclusion principles. The study provides systematic documentation of methods used in Ayurveda for herbal drug preparation along with its interpretation in terms of MPPs. This is the first step which can enable improving or replacing traditional techniques. New technologies or use of existing technologies can be used to improve the dosage forms and scaling up while maintaining the Ayurvedic principles similar to traditional techniques. PMID- 25737606 TI - Phytochemical analysis and a study on the antiestrogenic antifertility effect of leaves of Piper betel in female albino rat. AB - OBJECTIVE: To study the effect of graded doses of the aqueous and methanolic extract of the leaves of Piper betel (PB) Linn (PBL) on the estrous cycle of female albino rats. MATERIALS AND METHODS: Both the extracts were tested for their effect on the estrous cycle at three dose levels of 500, 1000 and 1500 mg/kg/day and the vaginal smears were examined daily microscopically for the different phases of the estrous cycle for a period of 30 days. RESULT: The estrous cycle was irregular and prolonged in the treated groups indicating anestrus condition, which would result in infertility. Both types of the extract showed a significant decrease in the duration of proestrus and estrus with a prolonged diestrus at 1000 mg/kg/day and 1500 mg/kg/day doses as compared with control. However, no change was seen in the metestrus phase. The rats treated with PB showed a significant (P < 0.05), dose-dependent decrease in the estrus phase, in comparison to the control group, the effect was more with the methanolic extract. Large, cornified cells appeared after proestrus phase with decreased number of cornified cells. There was a significant reduction in the number of the estrous cycle, in the PBL treated group. Anestrus phase appeared in all the rats treated with the aqueous and methanolic PB extract, which was not observed in the control group. However, the aqueous extract at a dose of 500 mg/kg/day had no effect either on the estrous cycle or on its different phases. The observed effect of PB leaves could be due to the flavonoids and saponin contents, which also contributes to its antiestrogenic mechanism of action. CONCLUSION: Both the aqueous and methanolic extract of PBL possesses antifertility effect in female albino rats. PMID- 25737607 TI - Antidiabetic antihyperlipidemic and hepato-protective effect of Gluconorm-5: A polyherbal formulation in steptozotocin induced hyperglycemic rats. AB - BACKGROUND: The antidiabetic, antihyperlipidemic, and hepato-protective effect of Gluconorm-5, was studied in steptozotocin (STZ) induced hyperglycemic rats. MATERIALS AND METHODS: The hypoglycemic effect of single dose of Gluconorm-5 (150, 300 and 600 mg/kg body weight) made up of five plants namely Camellia sinensis, Punica granatum, Macrotyloma uniflorum, Foeniculum vulgare and Trigonella foenum-graecum was studied in normal, glucose loaded normal and diabetes-induced rats. The extent of antihyperlipidemic and liver-protective effect was studied by estimating the lipid profile, and the liver marker enzymes. Histopathological studies of the pancreatic tissue were also carried out with glibenclamide as standard antihyperglycemic agent. RESULTS: Fifteen days of oral feeding of the Gluconorm-5 (300 and 600 mg/kg) to diabetic rats resulted in a significant (P < 0.01) reduction of blood glucose, lipid profile, liver weight and marker enzymes as compared to those rats in whom STZ induced toxicity was untreated. The diabetic rats treated with the drug showed expanded islets as compared to the untreated diabetic rats, which showed the shrunken islets. The animals that received 300 mg/kg of Gluconorm-5 showed pronounced antidiabetic, antihyperlipidemic and hepato-protective effect in the present study, which was comparable with glibenclamide, a standard drug. CONCLUSION: Gluconorm-5 exerts potent antidiabetic antihyperlipidemic and hepato-protective effect, which can be used as adjuvant in the treatment of diabetes mellitus. PMID- 25737608 TI - In vitro evaluation of anti-herpes simplex-1 activity of three standardized medicinal plants from Lamiaceae. AB - BACKGROUND: Rosmarinic acid (RA) is a phenolic acid with antioxidant and anti viral effects. We have studied anti-herpes simplex virus type 1 (HSV-1) effect of three medicinal plants from Lamiaceae family which have been standardized on the basis of RA content. MATERIALS AND METHODS: Methanolic extract of Teucrium polium, Ziziphora clinopoides, and Salvia rhytidea was prepared by maceration method and RA content of the plants was determined using a spectrophotometric method. Maximum nontoxic concentration (MNTC) of the extracts was determined using neutral red method. Serial dilutions of extracts up to MNTC were examined on Vero cells for anti-HSV-1 effect by plaque assay in comparison to acyclovir as a positive control. RESULTS: Among the tested extracts, T. polium contained the highest percentage of RA (1.8%w/w) and exhibited the least toxicity (MNTC = 1000 MUg/ml). The greatest anti-HSV-1 was shown by T. polium and Z. clinopoides extracts which exhibited both time and concentration-dependent plaque inhibition. CONCLUSION: Considering the low toxicity and significant anti-viral effect of T. polium extract, this plant would prove valuable as an active anti-viral drug. PMID- 25737609 TI - Evaluation of anthelmintic activity and in silico PASS assisted prediction of Cordia dichotoma (Forst.) root extract. AB - BACKGROUND: Worm infection and associated complications are severe problems that afflict a large population worldwide. Failure of synthetic drugs in worm infections because of drug resistance has made alternative drug therapy desirable. Cordia dichotoma (Forst.) is an ethnomedicinal plant which is rich in several secondary metabolites. Traditionally, the plant has been claimed to have high medicinal properties including antimicrobial activity and cytotoxicity. MATERIALS AND METHODS: The study begun with an aim to explore plant-based natural anthelmintic agents against Pheretima posthuma, an Indian earthworm. Methanol extract of the drug was obtained by successive soxhlet extraction. The extract was tested for different phytochemicals. Worms were exposed to 10 mg/ml, 25 mg/ml, 50 mg/ml, and 75 mg/ml concentrations of extract and standard drug, albendazole. A software-based tool, prediction of activity spectra for substances was used to estimate anthelmintic efficacy of plant metabolites. RESULT: The phytochemical analysis revealed presence of alkaloids, tannins, glycosides, saponins, flavonoids, and phenols. The extract showed dose-dependent effects, affecting worm motility, viability, and mortality. It was also found that the biological activity spectrum of the plant phytoconstituents such as octacosanol, lupeol, caffeic acid, and hentricontanol were >0.5 (probable activity > 0.5). CONCLUSION: The findings of the present work suggest that the extract of C. dichotoma significantly interferes with motility pattern of P. posthuma. The paralysis and mortality of P. posthuma might be due to the combined effects different phytoconstituents. The extract of C. dichotoma promises natural sources to control worm infection. PMID- 25737610 TI - Anti-inflammatory activity of roots of Cichorium intybus due to its inhibitory effect on various cytokines and antioxidant activity. AB - BACKGROUND: Cichorium intybus L. commonly known as chicory is one of the important medicinal plants commonly used in Ayurvedic system of medicine. It is commonly used for the treatment of diseases involving a khapa and pitta doshas. Traditionally, C. intybus is used for the treatment of inflammatory conditions, but there are only few in vitro studies reporting the anti-inflammatory activity of roots of chicory. OBJECTIVE: Evaluation of anti-inflammatory activity of roots of chicory and mechanisms involved in it using in vivo models of inflammation. MATERIALS AND METHODS: Albino Wistar rats of either sex weighing 150-200 g were used. Ethanolic and aqueous extracts of roots of chicory were prepared with the help of Soxhlet's apparatus. The anti-inflammatory activity was studied using carrageenan-induced paw edema method and cotton pellet granuloma method. Levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL 6), and IL-1 and activity of antioxidant enzymes such as catalase (CAT) and glutathione peroxidase (GPx) were estimated. RESULTS: Chicory roots demonstrated significant dose-dependent decrease in paw edema in carrageenan-induced paw edema method. Chicory roots diminished the serum TNF-alpha, IL-6, and IL-1 levels. They also significantly attenuated the malonylaldehyde levels and increased the activities of CAT and GPx in paw tissue. Similarly, chicory roots demonstrated a significant decrease in granuloma formation in cotton pellet induced granuloma method. CONCLUSION: Chicory roots possess anti-inflammatory activity, and this might be due to the inhibition of various cytokines, antioxidant effects, and their free radical scavenging activity. PMID- 25737611 TI - Syringing method as an alternative to Srnga therapy in Vatakantaka. AB - Calcaneus forms the bone of the foot. Due to abnormal pressures, foot muscles and ligaments are stretched beyond their normal limits that lead to chronic plantar heel pain, among which calcaneal spur tops the list. In Ayurveda, it can be correlated to "Vatakantaka" (pricking sensation in the foot)-a painful condition of heel caused by its improper placement on the ground. To assess the effect of syringing method (modified Srnga) in the treatment of Vatakantaka. A 10 ml syringe was for ease, hygiene, and to enable the case to be managed in the outpatient department. A diagnosed case of calcaneal spurs with pain, tenderness, and swelling visited KLE University's Shri BMK Ayurveda Hospital and Research Centre, Belgaum, Karnataka, India. After Snigdha Patrapottali sveda (a form of sudation therapy), bloodletting was performed by syringing method. In total procedure was performed for 4 times on the patient. Marked subjective relief was observed. Pain from 8 visual analog scale (VAS) came to 2 visual analog scale (VAS) and tenderness and swelling relived completely. PMID- 25737612 TI - Ayurvedic management of postlumbar myelomeningocele surgery: A case study. AB - A 11-year-old male child presented with the complaints of urinary incontinence, passing hard stools associated with weakness in lower limbs, deformity of feet, reduced sensation below ankle joint since he was 5 years of age as noticed by parents. The clinical features were seen as postlumbar myelomeningocele surgery and child had congenital talipus equinovarus. For this, he was administered anulomana, sarvanga abhyanga (oleation / massage), sangraha cikitsa, avagaha sveda (sudation) and matra basti (type of oleaginous enema). After the treatment, child was able to get control over his bladder, he started feeling sense the fullness of the bladder, there was a desire to void urine and a reduction in a number of voids in daytime and a reduced degree of wetness. PMID- 25737614 TI - Human Uterus Transplantation: Have We Opened a Pandora's Box? PMID- 25737613 TI - Albumin-to-alkaline phosphatase ratio: a novel prognostic index for hepatocellular carcinoma. AB - Prognosis of patients with hepatocellular carcinoma (HCC) depends on both tumour extent and hepatic function reserve. Liver function test (LFT) is a basic routine blood test to evaluate hepatic function. We first analysed LFT components and their associated scores in a training cohort of 217 patients who underwent curative surgery to identify LFT parameters with high performance (discriminatory capacity, homogeneity, and monotonicity of gradient). We derived a novel index, albumin-to-alkaline phosphatase ratio (AAPR), which had the highest c-index (0.646) and chi(2) (24.774) among other liver biochemical parameters. The AAPR was an independent prognostic factor for overall and disease-free survival. The adjusted hazard ratio of death and tumour relapse was 2.36 (P = 0.002) and 1.85 (P = 0.010), respectively. The independent prognostic significance of AAPR on top of 5 commonly used and well established staging systems was further confirmed in 2 independent cohorts of patients receiving surgical resection (n = 256) and palliative therapy (n = 425). In summary, the AAPR is a novel index readily derived from a simple low-cost routine blood test and is an independent prognostic indicator for patients with HCC regardless of treatment options. PMID- 25737615 TI - Progesterone vaginal ring for luteal support. AB - Progesterone supplementation is universally used and has been shown to be beneficial in supplementation of the luteal phase in IVF. There are multiple options and the most commonly used include intramuscular and vaginal progesterone. A progesterone vaginal ring is a novel system for luteal support with advantages of controlled release with less frequent dosing. This review examines options for progesterone luteal support focusing on the rationale for a progesterone vaginal ring. Pub-med search of the literature. A weekly vaginal ring, although not yet FDA approved, is an effective and safe alternative for luteal supplementation in IVF. Large prospective clinical trials are needed to determine the best protocols for replacement cycles. PMID- 25737616 TI - Treatment of endometriosis in women desiring fertility. AB - Endometriosis is a common condition affecting a significant proportion of women in their reproductive age. Apart from the impact of endometriosis on the quality of life of these patients, it also can have an impact on the potential of these women to have a family. The options for treating women with endometriosis desiring a family include surgery or assisted reproduction techniques. The choice of treatment will depend on the stage of disease and the characteristics of the couple seeking help. We review here the latest evidence on the management of endometriosis in women desiring fertility and describe our current practice. PMID- 25737617 TI - Intravenous paracetamol infusion versus intramuscular tramadol as an intrapartum labor analgesic. AB - OBJECTIVES: To compare intravenous paracetamol and intramuscular tramadol as labor analgesics. METHODS: This prospective-randomized study conducted in 200 primigravidae in active labor, distributed into two groups of 100 women each with one receiving intravenous 1,000 mg Paracetamol and other 100 mg intramuscular tramadol. Pain intensity is recorded by McGills scale before, one and 3 h after drug administration. Perinatal outcome is recorded. RESULTS: No difference in pain intensity is seen before drug administration. After 1 h of drug administration, in paracetamol group, 4 % women had horrible pain, and 29 % had distressing pain, while in tramadol group, 30 % women had horrible pain, and 60 % had distressing pain. After 3 h of drug administration, in paracetamol group, 26 % had distressing pain, while in tramadol group, 51 % women had horrible pain, and 35 % had distressing pain. Labor duration in paracetamol and tramadol group was 4.3 and 5.9 h, respectively. In paracetamol group, nausea is seen in 2.2 % and vomiting in 1.1 %, while in tramadol group, nausea is seen in 6.4 % and vomiting in 4.3 %. CONCLUSIONS: Intravenous paracetamol is more effective labor analgesic with fewer maternal adverse effects and shortens labor as compared to intramuscular tramadol. PMID- 25737618 TI - Evaluation of severe maternal outcomes to assess quality of maternal health care at a tertiary center. AB - BACKGROUND: Maternal mortality and near-miss index reflect the quality of care provided by a health facility. The World Health Organization recently published near-miss approach where strict near- miss criteria based on markers of organ dysfunction are defined. OBJECTIVES: The aim of the study was to determine the frequency of severe maternal complications, maternal near-miss cases and maternal deaths, to analyze causes of near-miss and maternal mortality and to determine the values of maternal near-miss indicators. METHODS: This was a prospective observational study conducted at a tertiary care centre in North India from January 2012 - March 2013. WHO's near-miss approach was implemented for evaluation of severe maternal outcomes and to assess the quality of maternal health care. RESULTS: The number of women attending our facility with severe maternal complications was low (205 in 6,767 live births); as a result maternal near-miss ratio (MNMR) was low; 3.98/1,000 live births; Overall Maternal near miss mortality ratio (MNM:1MD) was also low, 3.37:1, because of strict criterion of labeling near-miss and delay in referral to the hospital. Hypertensive disorder (37.5 %) was the commonest underlying cause for maternal mortality. CONCLUSION: Basic implementation of WHO near-miss approach helped in the systematic identification and evidence-based management of severe maternal complications thereby improving the quality of maternal health in a developing country. PMID- 25737619 TI - Palonosetron Versus Ramosetron Prophylaxis for Control of Postoperative Nausea and Vomiting after Cesarean Delivery under Spinal Anesthesia. AB - PURPOSE: Postoperative nausea and vomiting (PONV) after spinal anesthesia for cesarean delivery are distressing to both patients and surgeons. This study was designed to evaluate the efficacy and safety of palonosetron and ramosetron (both newer and highly potent 5HT3 receptor antagonists) in nausea and vomiting in cesarean delivery after spinal anesthesia. METHODS: In this randomized, double blind study, 109 women received either palonosetron (0.075 mg) or ramosetron (0.3 mg) intravenously immediately after clamping of the fetal umbilical cord. Nausea, vomiting, adverse events, and overall satisfaction were then observed for 48 h after administration of spinal anesthesia. RESULTS: A complete response (defined as no postoperative nausea and vomiting) during first 0-2 h postoperative after administration of spinal anesthesia was achieved in 85.5 % of patients with palonosetron and in 83.3 % of patients with ramosetron (p > 0.05). However, the corresponding incidence during 2 to 24 h was 70.9 and 53.7 %, respectively (p < 0.05), while it was 63.3 and 44.4 % at 24-48 h after anesthesia (p < 0.05). Along with a more complete response, the severity of nausea was also lesser with palonosetron during the corresponding study periods (2-24 and 24-48 h, respectively; p < 0.05). Patients who received palonosetron were also more satisfied than those who received ramosetron (p < 0.05). No difference in adverse events was observed in any of the groups. CONCLUSION: To conclude, prophylactic therapy with palonosetron is more effective than prophylactic therapy with ramosetron for the long-term prevention of PONV after cesarean section. PMID- 25737621 TI - Deciding the route for hysterectomy: Indian triage system. AB - OBJECTIVES: To review the limitations, major complications, and conversion rates associated with non-descent vaginal hysterectomy (NDVH); and develop a scoring system to predict the possibility of successful NDVH. METHODS: The risk analysis of conversion rates from vaginal to abdominal route while attempting NDVH was applied to formulate a scoring system for the assessment of successful NDVH. Parameters were selected based on Kovacs guidelines to determine the route of hysterectomy. RESULTS: From April 2005 to December 2008, NDVH was attempted in 364/1,378 women undergoing hysterectomy for benign conditions (Gp-I). Eight out of 364 cases (2.1 %) either had to be converted to the abdominal route or had major complication. Endometriosis and repeated sections had the highest risk. Scoring system was developed based on the risk analysis. Validity of this scoring system was tested in 1,177 women from January 2009 to September 2012 (Gp-II). 460 women with a score of 16 or less underwent NDVH successfully with a conversion rate of 0.2 %. CONCLUSION: Careful assessment by a simple scoring system can help in deciding the feasibility of performing NDVH. PMID- 25737620 TI - Ovarian masses: changing clinico histopathological trends. AB - OBJECTIVE: To study the clinical and histopathological presentation of ovarian masses. METHOD: Retrospective analysis of 205 cases from May 2009 to June 2013. RESULTS: Incidence of ovarian masses was 6.9 %. Among 205 cases, 68 % were neoplastic. Among the neoplasms, 87.8 % were benign, 10 % malignant, and 2.2 % borderline. Mean ages of malignant and benign neoplasm were 41 and 39 years, respectively. 42.9 % malignant tumors presented with non-specific abdominal and constitutional symptoms. Serous cystadenoma was the commonest benign tumor (67 %) followed by Mucinous (19 %) and Dermoid (11.6 %). Most common malignant ovarian tumor was Serous cystadenocarcinoma (42.9 %). Out of the malignant cases, all were primary except one secondary deposit from Non-Hodgkin's Lymphoma. Only 28.6 % presented at stage I, remaining presented at stage III/IV. CONCLUSION: Ovarian neoplasms have twice the incidence of non-neoplasms. Mean age of malignant tumors is decreased. Rising trend in Mucinous cystadenoma is noted. PMID- 25737622 TI - Lower Genital Tract Infections in HIV-Infected Women: Can We Afford to Miss? AB - OBJECTIVES: To study prevalence of lower genital tract infections (LGTI) (bacterial vaginosis, trichomoniasis, and candidiasis) in HIV-seropositive women and correlation with CD4 counts and antiretroviral therapy (ART). METHODS: Cross sectional study conducted in 200 HIV-1-seropositive women (18 to 45 years) attending ART clinic of PGIMS, Rohtak. Vaginal samples sent for laboratory diagnosis of bacterial vaginosis, trichomoniasis, and candidiasis, CD4 count determined and data analyzed using Chi-square method. RESULTS: Prevalence of bacterial vaginosis, candidiasis, and trichomoniasis was 47.7, 43.2, and 8.8 % respectively, 30 % women with CD4 counts <200 cells/MUl had LGTI, and 17.4 % women with CD4 >200 Cell/MUl had LGTI. Of 70 women not on ART, 18.6 % had LGTI and 30 of 130 on ART had LGTI. CONCLUSIONS: HIV-seropositive women had higher prevalence of LGTI especially at lower CD4 counts and women on ART did not have a lower prevalence of LGTI and should be screened for LGTI to decrease HIV transmission. PMID- 25737623 TI - Spontaneous Late Onset OHSS in Singleton Pregnancy in 2nd Trimester: A Rare Case. PMID- 25737624 TI - Copper-T migration into stomach: a laparoscopic management. PMID- 25737625 TI - Symptomatic Chronic Uterine Dehiscence: A Different Approach, Non-surgical Successful Closure. PMID- 25737626 TI - Isolated endometrial calcification presenting as primary amenorrhoea. PMID- 25737627 TI - Comment on residual adherent placenta with bladder injury: can we use methotrexate. PMID- 25737628 TI - Torsion of gravid uterus: alternate management options. PMID- 25737629 TI - Erratum to: Should We be More "Open" About Publishing Research? AB - [This corrects the article DOI: 10.1007/s13224-014-0624-2.]. PMID- 25737632 TI - Retraction statement. AB - [This retracts the article on p. 22 in vol. 33, PMID: 24843232.]. PMID- 25737630 TI - Photoreceptor cells display a daily rhythm in the orphan receptor Esrrbeta. AB - PURPOSE: Nuclear orphan receptors are critical for the development and long-term survival of photoreceptor cells. In the present study, the expression of the nuclear orphan receptor Esrrbeta--a transcriptional regulator of energy metabolism that protects rod photoreceptors from dystrophy--was tested under daily regulation in the retina and photoreceptor cells. METHODS: The daily transcript and protein amount profiles were recorded in preparations of the whole retina and microdissected photoreceptor cells using quantitative PCR (qPCR) and western blot analysis. RESULTS: Esrrbeta displayed a daily rhythm with elevated values at night in the whole retina and enriched photoreceptor cells. Daily regulation of Esrrbeta mRNA depended on light input but not on melatonin, and evoked a corresponding rhythm in the Esrrbeta protein. CONCLUSIONS: The data presented in this study indicate that daily regulation of Esrrbeta in photoreceptor cells may contribute to their adaptation to 24-h changes in metabolic demands. PMID- 25737631 TI - Observation of total VEGF level in hyperglycemic mouse eyes after intravitreal injection of the novel anti-VEGF drug conbercept. AB - PURPOSE: Conbercept (KH902), a novel recombinant, soluble vascular endothelial growth factor (VEGF) receptor-IgG fusion protein, has been developed as a new drug for ocular neovascularization and macular edema. The present study aims to clarify the changes in conbercept levels, VEGF, and intraocular pressure (IOP) after the intravitreal injection of conbercept into diabetic mouse eyes. METHODS: Five-week-old C57BL/6 mice were injected with streptozotocin to induce diabetes. Total VEGF and conbercept levels in the eyes were detected using an ELISA kit at 2 h, 1 h, 1 d, 4 d, 8 d, 16 d, 28 d, and 34 d after intravitreal injection of conbercept into diabetic and control mice. IOP was measured with a noninvasive TonoLab tonometer 7 d after intravitreal conbercept injection. RESULTS: The concentration of conbercept in the treated eyes increased immediately after injection and remained at high levels for 4 d (29.77+/-27.19 ng/ml, 20.28+/-28.85 ng/ml, and 42.43+/-36.51 ng/ml for days 1, 2, and 4, respectively). The concentration of conbercept in the untreated fellow eyes increased from day 2 to day 4 after injection with a level of about 1% of that in the injected eyes. Conbercept concentrations in both the treated and fellow eyes decreased from day 7 after intravitreal injection. The concentration of VEGF in the treated eyes increased significantly 1 h after injection when compared with the baseline measured 2 h before injection in both the diabetic and control mice (645.91+/ 86.47 pg/ml versus 296.10+/-76.11 pg/ml and 860.50+/-201.47 pg/ml versus 377.69+/ 70.72 pg/ml, respectively). VEGF concentration reached its peak 24 h after injection and then decreased thereafter. At day 7 after intravitreal injection, the difference in IOP between mice that received conbercept and mice that received PBS injections was not significant (p>0.05). CONCLUSIONS: Conbercept and total VEGF levels in the mouse eyes were elevated after intravitreal injection of conbercept. Increased VEGF levels likely reflect VEGF sequestered by conbercept. These data could be helpful in understanding the metabolism of anti-VEGF drugs in the eye and for determining the protocol of multiple intravitreal injections of conbercept in patients. PMID- 25737633 TI - Patient-provider communication, self-reported medication adherence, and race in a postmyocardial infarction population. AB - OBJECTIVES: Our objectives were to: 1) describe patient-reported communication with their provider and explore differences in perceptions of racially diverse adherent versus nonadherent patients; and 2) examine whether the association between unanswered questions and patient-reported medication nonadherence varied as a function of patients' race. METHODS: We conducted a cross-sectional analysis of baseline in-person survey data from a trial designed to improve postmyocardial infarction management of cardiovascular disease risk factors. RESULTS: Overall, 298 patients (74%) reported never leaving their doctor's office with unanswered questions. Among those who were adherent and nonadherent with their medications, 183 (79%) and 115 (67%) patients, respectively, never left their doctor's office with unanswered questions. In multivariable logistic regression, although the simple effects of the interaction term were different for patients of nonminority race (odds ratio [OR]: 2.16; 95% confidence interval [CI]: 1.19-3.92) and those of minority race (OR: 1.19; 95% CI: 0.54-2.66), the overall interaction effect was not statistically significant (P=0.24). CONCLUSION: The quality of patient provider communication is critical for cardiovascular disease medication adherence. In this study, however, having unanswered questions did not impact medication adherence differently as a function of patients' race. Nevertheless, there were racial differences in medication adherence that may need to be addressed to ensure optimal adherence and health outcomes. Effort should be made to provide training opportunities for both patients and their providers to ensure strong communication skills and to address potential differences in medication adherence in patients of diverse backgrounds. PMID- 25737634 TI - Fat- and fiber-related diet behavior among type 2 diabetes patients from distinct regions. AB - PURPOSE: Diet and eating habits are of key importance in patients with type 2 diabetes mellitus (T2DM). The purpose of this comparative study was to analyze fat- and fiber-related behavior (FFB) in patients with T2DM from distinct cultural areas. PATIENTS AND METHODS: Observational study was carried out in the Czech Republic (CR) (n=200), the US (n=207), and Yemen (n=200). Patients completed the Fat- and Fiber-related Diet Behavior Questionnaire (FFBQ). RESULTS: Differences in all aspects of FFB among countries were found (P<0.05). The best fat-related behavior reported was from patients from the CR. Patients from the US showed the worst fat-related behavior in total. On the other hand, patients from the US reported the best fiber-related behavior. Patients from Yemen reached the worst scores in all fat-related domains. Patients from all studied countries reported the best results in the "modify meat" and "avoid fat as flavoring" and the worst in the "substitute high fiber" subscales. CONCLUSION: Professionals involved in the diet education of T2DM patients should be aware of the specificity of diet in their country when advising patients keeping general recommendations. We suggest them to be as specific as possible and concentrate on fiber-related behavior. PMID- 25737635 TI - The effectiveness of cognitive behavioral therapy with respect to psychological symptoms and recovering autobiographical memory in patients suffering from post traumatic stress disorder. AB - OBJECTIVES: Given the persistence of post-traumatic stress disorder (PTSD) and its major impact on everyday life, it is important to identify effective treatments. In additional to pharmacological treatments, psychotherapeutic treatments are also highly effective. The aim of the present study was to investigate, among a sample of patients suffering from PTSD, the influence of an additional cognitive behavioral therapy (CBT) intervention on their symptoms of PTSD, depression, and anxiety, and on autobiographical memory. METHODS: A total of 40 patients suffering from PTSD (mean age: 31.64 years; 78.6% female patients) and under psychopharmacological treatment were randomly assigned to an intervention or control condition. The intervention consisted of ten group sessions (one 60-90 minute session per week) of CBT. At baseline and 10 weeks later, a series of self-rating and experts'-rating questionnaires were completed. RESULTS: Over time, symptoms of PTSD, depression, and anxiety decreased; however, greater improvement was observed in the experimental than the control condition. Likewise, as a general pattern of results, memory performance improved over time, though again this improvement was greater in the experimental condition. CONCLUSION: Compared to a control condition, additional CBT improves the treatment of PTSD, with respect to both symptoms and autobiographical memory. PMID- 25737636 TI - Untreated depression in the first trimester of pregnancy leads to postpartum depression: high rates from a natural follow-up study. AB - BACKGROUND: This is a natural follow-up study that presents the postpartum results of women who experienced depression during pregnancy. METHODS: This study involved 78 women diagnosed with depression in the first trimester of pregnancy. All patients were diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) in the first trimester and all were referred to a psychiatric center for treatment. Of the 78, 73 were contacted postpartum and reassessed by SCID-I. Treatment anamnesis was evaluated retrospectively. RESULTS: The women were divided into two groups at the postpartum evaluation according to anamnesis of psychiatric treatment. Twenty-one of the 73 (28.7%) had received treatment during pregnancy (treated group). Fifty-two women had not been treated (untreated group). In the treated group, no postpartum depression was determined (0%). In the untreated group, 92% (n=48) of women had a depressive disorder postpartum (P<0.01). In addition, scores regarding depression, functionality, and perceived social support were worse postpartum for the untreated group. CONCLUSION: Untreated depression during pregnancy is an important predictor of postpartum depression. This natural follow-up study is important because it presents very striking rates of postpartum depression. Referral of patients with depression during pregnancy to psychiatric treatment should be provided and is strongly encouraged. PMID- 25737637 TI - Coexistence of anxiety sensitivity and psychiatric comorbidities in patients with chronic tinnitus. AB - BACKGROUND: Tinnitus refers to the objective or subjective perception of a series of sounds most frequently described as ringing in the ear or within the head itself. Anxiety and depressive disorders frequently accompany this complaint. In this study, we aimed to investigate the presence of psychiatric symptoms and the degree of anxiety sensitivity in patients with chronic tinnitus. METHODS: Fifty patients with chronic tinnitus who had been followed up for at least 6 months or longer were enrolled in this study. All subjects completed the Anxiety Sensitivity Index-3 (ASI-3), Stait-Trait Anxiety Inventory (STAI), and Symptom Check List-90-Revised (SCL-90-R) questionnaires. Fifty healthy volunteers were given the same tests and a statistical comparison of the psychometric outcome data was done for subjects with and without chronic tinnitus. RESULTS: Patients with chronic tinnitus demonstrated higher statistically meaningful scores than the healthy group. Comparison between chronic tinnitus group and control group scores showed that patient group has a high rate of statistically significant results than controls; ASI-3, STAI-2, SCL-90-R GSI, SCL-90-R Somatization, SCL-90 R Depression, SCL-90-R Anxiety (z=-8.00, P<0.01), SCL-90-R Phobic Anxiety. CONCLUSION: Higher scores for anxiety sensitivity and other psychiatric symptoms in patients with chronic tinnitus reflects the prevalence of psychiatric disorders such as depression, anxiety, somatoform disorder, and chronic tinnitus. The finding of more psychiatric comorbidity in patients with chronic tinnitus indicates that planning and follow-up in both otolaryngology and psychiatry is necessary to improve the overall results of treatment. PMID- 25737638 TI - Effect of vitamin D therapy on interleukin-6, visfatin, and hyaluronic acid levels in chronic hepatitis C Egyptian patients. AB - OBJECTIVES: We aimed to compare serum levels of interleukin-6, visfatin, and hyaluronic acid in chronic hepatitis C Egyptian patients who received standard of care (SOC) therapy for chronic hepatitis C virus (HCV) consisting of pegylated interferon (PEG-IFN) and ribavirin (RBV) and in those who received SOC with vitamin D (vit D) for 48 weeks in HCV genotype 4a subjects. DESIGN AND METHODS: One hundred chronic HCV patients were classified into two groups: study 50 patients received SOC therapy PEG-IFN/RBV + vit D and control 50 patients received SOC PEG-IFN/RBV without vit D. Both groups were followed up at 12 weeks, 24 weeks, and 48 weeks of treatment. RESULTS: Results showed a significant elevation in vit D levels in the group treated with SOC and vit D compared to SOC group and a reduction in HCV RNA from the 12th week to reach zero level in the 24th week. Interleukin-6, visfatin, and hyaluronic acid levels were also reduced significantly. Alanine transaminase and aspartate transaminase biomarkers were significantly reduced, indicating decreased liver injury. CONCLUSION: SOC PEG IFN/RBV + vit D therapy for chronic HCV led to reduced interleukin-6, visfatin, and hyaluronic acid levels and follow up liver biochemical biomarkers as aspartate transaminase and alanine transaminase indicates proper liver healing and monitoring. PMID- 25737639 TI - Astroblastoma: beside being a tumor entity, an occasional phenotype of astrocytic gliomas? AB - The diagnosis of astroblastoma is based on a typical histological aspect with perivascular distribution of cells sending cytoplasmic extensions to the vessels and vascular hyalinization. These criteria are useful for standardizing the identification of the tumor, but, in spite of this, there are discrepancies in the literature concerning the age distribution and the benign or malignant nature of the tumor. Three cases are discussed in this study: Case 1 was a typical high grade astroblastoma; Case 2 was an oligodendroglioma at the first intervention and an oligoastrocytoma at the second intervention with typical perivascular arrangements in the astrocytic component; Case 3 was a gemistocytic glioma with malignant features and typical perivascular arrangements. Genetic analysis showed genetic alterations that are typical of gliomas of all malignancy grades. Using the neurosphere assay, neurospheres and adherent cells were found to have developed in Case 1, while adherent cells only developed in Case 2, in line with the stemness potential of the tumors. The cases are discussed in relation to their diagnostic assessment as astroblastoma, and it is hypothesized that the typical perivascular distribution of cells may not indicate a separate and unique tumor entity, but may be a peculiarity that can be acquired by astrocytic gliomas when an unknown cause from the tumor microenvironment influences the relationship between vessels and tumor cells. PMID- 25737640 TI - Drug-eluting stents with biodegradable polymer for the treatment of patients with diabetes mellitus: clinical outcome at 2 years in a large population of patients. AB - OBJECTIVE: This study investigates the safety and efficacy of a third-generation drug-eluting stent (DES) with biodegradable polymer in the complex patient population of diabetes mellitus (DM). CLINICAL TRIAL REGISTRATION: ISRCTN81649913. BACKGROUND: Percutaneous coronary interventions in patients with DM are associated with a higher incidence of death, restenosis, and stent thrombosis as compared to non-diabetic patients. The use of a DES has been shown to improve outcomes in diabetic patients. METHODS: Out of 3,067 patients, enrolled in 126 centers worldwide in the NOBORI 2 registry, 888 patients suffered from DM, 213 of them (14%) being insulin-dependent DM (IDDM). Two years' follow up has been completed in this study. RESULTS: At 1- and 2-year follow-up, 97% and 95% of the patients, respectively, were available. The reported target lesion failure (TLF) rates at 1- and 2-year follow-up were 6.0% and 7.2% in the DM group, respectively, and 3.0% and 4.2% in the non-DM group, respectively (P<0.001 for both years). Inside the DM group, the TLF rates of 9.9% and 11.7% at the 1- and 2-year follow-ups, respectively, in patients with IDDM were significantly higher than the TLF rates of 4.7% and 5.8%, respectively, in the non-IDDM subgroup (P<0.01 for both years). The rate of stent thrombosis at the 2-year follow-up was 1.0% in the DM group and 0.7% in non-DM patients. There were no cases of late, or very late stent thrombosis in IDDM patients. CONCLUSION: The Nobori DES performed well in patients with DM. As expected, patients with DM, particularly those with IDDM, had worse outcomes. However, the absence of late, and very late stent thrombosis in IDDM patients merits further investigation, as this finding might have significant clinical value. PMID- 25737642 TI - Soil salinity: A serious environmental issue and plant growth promoting bacteria as one of the tools for its alleviation. AB - Salinity is one of the most brutal environmental factors limiting the productivity of crop plants because most of the crop plants are sensitive to salinity caused by high concentrations of salts in the soil, and the area of land affected by it is increasing day by day. For all important crops, average yields are only a fraction - somewhere between 20% and 50% of record yields; these losses are mostly due to drought and high soil salinity, environmental conditions which will worsen in many regions because of global climate change. A wide range of adaptations and mitigation strategies are required to cope with such impacts. Efficient resource management and crop/livestock improvement for evolving better breeds can help to overcome salinity stress. However, such strategies being long drawn and cost intensive, there is a need to develop simple and low cost biological methods for salinity stress management, which can be used on short term basis. Microorganisms could play a significant role in this respect, if we exploit their unique properties such as tolerance to saline conditions, genetic diversity, synthesis of compatible solutes, production of plant growth promoting hormones, bio-control potential, and their interaction with crop plants. PMID- 25737643 TI - Factors affecting efficient in vitro micropropagation of Muscari muscarimi Medikus using twin bulb scale. AB - Endemic Muscari muscarimi Medikus is the most fragrant plant among Muscari species and has a high ornamental potential. The natural populations of M. muscarimi, are severely affected by increased environmental pollution and urbanization. There is a need to develop a micropropagation method that should serve effectively for commercial propagation and conservation. Therefore, the study targeted to set up a strategy for efficient in vitro bulblet regeneration system of M. muscarimi using twin scale bulb explants on 1.0 * MS medium containing 4.44, 8.88, 17.76 MUM BAP (6-Benzylaminopurine) plus 2.685, 5.37, 10.74 MUM NAA (alpha-Naphthalene acetic acid). Maximum number of 19 daughter axillary bulblets and 16 daughter adventitious bulblets per twin bulb scale explant was regenerated on 1.0 * MS medium containing 17.76 MUM BAP plus 10.74 MUM NAA and 17.76 MUM BAP plus 2.685 MUM NAA respectively. The daughter bulblets regenerated on twin bulb scales on 8 out of 9 regeneration treatment could be easily rooted on 1.0 * MS medium containing 4.9 MUM IBA (Indole-3-butyric acid). The daughter bulblets regenerated on 9th treatment (1.0 * MS medium containing 17.76 MUM BAP plus 10.74 MUM NAA) were transferred to 1.0 * MS medium containing 30 g/l sucrose to break negative carry over effect of this dose of BAP-NAA, where they grew 2-3 roots of variable length. Daughter bulblet diameter was increased by culturing them on 1.0 * MS medium containing 4.44 MUM BAP plus 5.37 MUM NAA. The results verified that both age and the source of explants had significant effect on regeneration. In another set of experiments, twin scales were obtained from in vitro regenerated daughter bulblets, although they induced bulblets, yet their bulblet regeneration percentage, mean number of bulblets per explant and their diameter were significantly reduced. In vitro regenerated bulblets were acclimatized in growth chamber under ambient conditions of temperature and humidity on peat moss, where they flowered. The study provides important information about selection of suitable micropropagation medium, strategies to improve bulblet diameter and rooting of M. muscarimi which offers a scope for commercial propagation. PMID- 25737641 TI - Recent trends in the gene therapy of beta-thalassemia. AB - The beta-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult beta-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for beta-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from beta-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most significant developments in beta-thalassemia gene therapy over the last decade, with a strong emphasis on the most recent findings, for beta-thalassemia model systems; for beta-, gamma-, and anti-sickling beta-globin gene addition and combinatorial approaches including the latest results of clinical trials; and for novel approaches, such as transgene-mediated activation of gamma-globin and genome editing using designer nucleases. PMID- 25737644 TI - Investigation on the effect of different levels of dried sweet orange (Citrus sinensis) pulp on performance, carcass characteristics and physiological and biochemical parameters in broiler chicken. AB - Utilization of agricultural by-products in animal nutrition is a matter of great concern. Dried sweet orange (Citrus sinensis) pulp (DCSP) is a potential source of valuable nutrients and natural antioxidants for poultry feed. In the experiment, a feeding trial was conducted in order to investigate the effect of different levels of dried orange residues in diet on broiler growth performance, carcass characteristics, blood metabolites, humoral immunity, and cecum microbial population. A total of 200 one day experimental broiler chicks were distributed into a completely randomized design (CRD) which included 5 dietary treatments with 4 replicates per each treatment and 10 birds fed in each replicate. The experimental treatments consist of a control group (without additive), 0.5%, 1.0%, 1.5%, and 2% of DCSP (residue) in diet. Weight gain, feed intake and feed conversion ratio (FCR) were measured. Blood parameters and carcass traits were measured in the postnatal 35th day. The highest level of dried orange residues in treatment 5 (T5) had significantly increased the feed intake and body weight of broilers in groups and overall during the rearing period (P > 0.05). Different levels of dried orange residues had no significant effect on chicken FCR. Using of dried orange residues significantly decreased the liver and abdominal fat of broilers (P < 0.05). T5 has also significantly lower level of triglyceride than the control (T1) and treatment 2 (T2) (P < 0.05). In conclusion, the use of dried orange residues improved some performance (e.g. feed intake and body weight gain), decreased liver and abdominal fat and also serum triglyceride level in broiler chicken. PMID- 25737645 TI - Effect of nickel on nutrient removal by selected indigenous protozoan species in wastewater systems. AB - Nutrient and heavy metal pollutions are major concern worldwide. This study aimed at comparing the effect of Ni(2+) on nutrient removal efficiency of four indigenous wastewater protozoan species (Aspidisca sp., Paramecium sp., Peranema sp., Trachelophyllum sp.). Specific physicochemical parameters and microbial growth/die-off were measured using standard methods. The results revealed that protozoan species were able to simultaneously remove phosphate, nitrate and Ni(2+) at concentrations ranging between 66.4-99.36%, 56.19-99.88% and 45.98 85.69%, respectively. Peranema sp. appeared to be the isolates with the highest removal of nutrients (Phosphate-99.36% and Nitrate-99.88%) while Paramecium sp. showed higher removal of Ni(2+) at 85.69% and low removal of nutrients. Aspidisca sp. was the most sensitive isolate to Ni(2+) but with significant nutrient removal (Phosphate-66.4% and Nitrate-56.19%) at 10 mg-N(2+)/L followed by an inhibition of nutrient removal at Ni(2+) concentration greater than 10 mg/L. Significant correlation between the growth rate and nutrient removal (r = 0.806/0.799, p < 0.05 for phosphate and nitrate, respectively) was noted. Except for Peranema sp. which revealed better nutrient removal ability at 10 mg Ni(2+)/L, an increase in Ni(2+) concentration had a significant effect on nutrient removal efficiency of these indigenous protozoan species. This study suggests that although Ni(2+) appeared to be toxic to microbial isolates, its effect at a low concentration (10 mg-Ni(2+)/L) towards these isolates can be used to enhance the wastewater treatment process for the removal of nutrients. Peranema sp., which was able to remove both Ni(2+) and nutrients from wastewater mixed-liquor, can also be used for bioremediation of wastewater systems. PMID- 25737646 TI - Influence of olive and rosemary leaves extracts on chemically induced liver cirrhosis in male rats. AB - The current study was undertaken to evaluate the protective activity of olive and rosemary leaves extracts on experimental liver cirrhosis induced by thioacetamide (TAA) in Wistar male rats. Highly significant decline in the values of body weight gain and highly statistically increase of liver/body weight ratio were noted in rats treated with TAA. Furthermore, the levels of serum alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, alkaline phosphatase and total bilirubin were statistically increased. Additionally, light microscopic examination of liver sections from rats treated with TAA showed a marked increase in the extracellular matrix collagen content and bridging fibrosis was prominent. There were bundles of collagen surrounding the lobules that resulted in large fibrous septa and distorted tissue architecture. Interestingly, the findings of this experimental study indicated that the extracts of olive and rosemary leaves and their combination possess hepatoprotective properties against TAA-induced hepatic cirrhosis by inhibiting the physiological and histopathological alterations. Moreover, these results suggest that the hepatoprotective effects of these extracts may be attributed to their antioxidant activities. PMID- 25737647 TI - Development and characterisation of nine polymorphic microsatellite markers for Tephrosia calophylla Bedd. (Fabaceae). AB - Tephrosia calophylla Bedd. (Fabaceae) is an endangered tropical plant endemic to southwestern Ghats, India. The objective of this study was to contribute to the characterisation of the diversity of this rare species, which is necessary for its future conservation. Accordingly, microsatellite markers were designed, and their ability to detect polymorphisms was determined. Nine microsatellite markers were developed using genomic libraries, and all of the markers were successfully amplified in 42 individuals. Three to nine alleles per locus were observed, and the heterozygosity of the loci ranged from 0.381 to 0.905. The nine newly developed polymorphic markers recognise a sufficient number of varying loci to perform further studies on the conservation and breeding of this medicinal cultivar. PMID- 25737648 TI - Assessment of antioxidant activities in roots of Miswak (Salvadora persica) plants grown at two different locations in Saudi Arabia. AB - Traditionally, in Middle Eastern countries, many cultures use chewing sticks of arak for medicinal purposes especially, for oral cleanliness care. It was used by Muslims for treatment of teeth and highly recommended to be used by Muslims during the whole day. Therefore, the present work aimed to determine the total phenolic content and total flavonoids in two Miswak extracts obtained from arak roots collected from two different localities in Saudi Arabia. They were extracted with aqueous ethanol (80%) and used to estimate in vitro their antioxidative abilities. The new findings showed that the two tested extracts contained significantly different amounts of both total phenolic content and total flavonoids. According to the increase of total phenolic contents and total flavonoids obtained from the two extracts, Miswak collected from the southern region was found to contain more contents than those collected from the middle region. The results of antioxidant activities of Miswak root extract obtained by using different in vitro methods were varied depending on the technique used. According to the malondialdehyde (MDA) method, hydrogen peroxide (H2O2) scavenging ability and 1,1-diphenyl-2-picrylhydrazyl (DPPH) methods, the two Miswak extracts exhibited to have high to very high antioxidant activities. Mostly, the values of antioxidant activities of Southern region have been shown to be always the highest. PMID- 25737649 TI - Potential for aflatoxin B1 and B2 production by Aspergillus flavus strains isolated from rice samples. AB - In this study, we investigated the potential for aflatoxin B1 (AFB1) and B2 (AFB2) production in rice grain by 127 strains of Aspergillus flavus isolated from rice grains collected from China. These strains were inoculated onto rice grains and incubated at 28 degrees C for 21 days. AFB1 and AFB2 were extracted and quantified by high-performance liquid chromatography coupled with fluorescence detection. Among the tested strains, 37% produced AFB1 and AFB2 with levels ranging from 175 to 124 101 MUg kg(-1) for AFB1 and from not detected to 10 329 MUg kg(-1) for AFB2. The mean yields of these isolates were 5884 MUg kg( 1) for AFB1 and 1968 MUg kg(-1) for AFB2. Overall, most of the aflatoxigenic strains produced higher levels of AFB1 than AFB2 in rice. The obtained information is useful for assessing the risk of aflatoxin contamination in rice samples. PMID- 25737650 TI - Biodiversity characteristics of Teucrium polium species in Saudi Arabia. AB - Teucrium (Lamiaceae) is a large and polymorphic genus distributed mainly in Europe, North Africa and in the temperate parts of Asia. In this study, the anatomical features of the leaf and stem of Teucrium polium are investigated. Teucrium has 19 taxa in Iran, which mainly grow in the Irano-Turanian region between 700 and 2000 m above sea level. T. polium belonging to sect. Polium, is a perennial herb growing on Lorestan province. The leaves clearly exhibit xeromorphy due to features such as thick cuticle layer, thick outer epidermal cell wall, high density of trichomes and thick palisade layer of the mesophyll. Anatomical studies on T. polium revealed that the stem shares the general characteristics of the Labiatae family. The aim of our approach was to study the morphological and taxonomical parameters for T. polium in Saudi Arabia. The results of this study showed that there was no influence of environment on the structure of stomata and trichomes as studying species with T . polium. In conclusion our study shows we have studied the geographical distribution of the species in Saudi Arabia and in the world. PMID- 25737651 TI - Genetic diversity of Moringa peregrina species in Saudi Arabia with ITS sequences. AB - The genus Moringa was the family of Moringaceae and Moringa oleifera and Moringa peregrina are the most famous species of Moringa. M. peregrina is widely grown in Saudi Arabia, Iran and India. Therefore, based on these reports, this study aimed to investigate the first systematic attempt to regulate the genetic diversity of the species M. peregrina in Saudi Arabian samples collected from several geographic locations using internal transcribed sequences. Genomic DNA was separated by CTAB extraction method and PCR was performed. Later on, DNA sequencing was performed for PCR products with ITS. In conclusion, the present study affords the first report on genetic stability of M. peregrina using ITS analysis in Saudi Arabia. Further studies are suggested in order to study in different regions. PMID- 25737652 TI - Screening of ethnic medicinal plants of South India against influenza (H1N1) and their antioxidant activity. AB - Antiviral activity against H1N1 influenza was studied using ethnic medicinal plants of South India. Results revealed that Wrightia tinctoria (2.25 MUg/ml) was one of the best antidotes against H1N1 virus in terms of inhibitory concentration of 50% (IC50) whereas the control drug Oseltamivir showed 6.44 MUg/ml. Strychnos minor, Diotacanthus albiflorus and Cayratia pedata showed low cytotoxicity (>100) to the MDCK (Malin darby canine kidney) cells by cytotoxicity concentration of 50% (CC50) and possessed antiviral activity suggesting that these plants can be used as herbal capsules for H1N1 virus. W. tinctoria and S. minor showed high therapeutic indexes (TI) such as 12.67 and 21.97 suggesting that those plants can be used for anti-viral drug development. The CC50 values of Eugenia singampattiana (0.3 MUg/ml), Vitex altissima (42 MUg/ml), Salacia oblonga (7.32 MUg/ml) and Salacia reticulata (7.36 MUg/ml) resulted in cytotoxicity of the MDCK cells, due to their high phenolic content. Findings from this study state that the plant W. tinctoria can be a potent source for third generation anti-viral drug development against H1N1. PMID- 25737653 TI - Snake bite envenomation in Riyadh province of Saudi Arabia over the period (2005 2010). AB - The present investigation is a retrospective review of snake bites in Riyadh province over the period (2005-2010). A total of 1019 cases of bites admitted to the Ministry of Health medical centers in Riyadh province were analyzed on the basis of age, sex, time of bite and its site on the body, outcome of treatment, antiserum dose and type of snake. Bites occurred throughout the six years with the highest frequency in 2005 and least in 2006 where most of the bite cases were mild and all evolved to cure except four patients who died following the administration of antivenom during 24 h after snake bite. Most of the patients were males (81.7%) and the most attacked age was within the range of 11-30 years (51.5%). All the bites were mainly in the exposed limbs and the most frequently bitten anatomical regions were the lower limbs (427 cases, 41.9%), principally the feet. The study incriminates Cerastes cerastes gasperettii in most of the bites indicating it as the snake of medical importance in Riyadh province. Also, the study indicates low degree of threat in spite of high rate of snake bites as a result of the availability of the medical facilities and the antivenin use in medical centers in Riyadh province. PMID- 25737654 TI - Bacterial-biota dynamics of eight bryophyte species from different ecosystems. AB - Despite the importance of bryophyte-associated microorganisms in various ecological aspects including their crucial roles in the soil-enrichment of organic mass and N2 fixation, nonetheless, little is known about the microbial diversity of the bryophyte phyllospheres (epi-/endophytes). To get insights into bacterial community structures and their dynamics on the bryophyte habitats in different ecosystems and their potential biological roles, we utilized the 16S rRNA gene PCR-DGGE and subsequent phylogenetic analyses to investigate the bacterial community of eight bryophyte species collected from three distinct ecosystems from western Japan. Forty-two bacterial species belonging to gamma proteobacteria and Firmicutes with 71.4% and 28.6%, respectively, were identified among 90 DGGE gel band population. These DGGE-bands were assigned to 13 different genera with obvious predomination the genus Clostridium with 21.4% from the total bacterial community. These analyses provide new insights into bryophyte associated bacteria and their relations to the ecosystems. PMID- 25737655 TI - Antiviral activity of Thuja orientalis extracts against watermelon mosaic virus (WMV) on Citrullus lanatus. AB - Watermelon mosaic potyvirus (WMV) is considered as an important virus infecting watermelon and causing adverse effects on crop productivity. To overcome this problem one of the main objectives of plant breeders is to make these strains less effective in the ability to infect plants by treatment with plant extracts. Due to the advantages of plant tissue culture, in vitro, in the process of the selection of different cultivars under biotic stress, this study was conducted to achieve this aim by evaluating the effect of three concentrations of Thuja extract on the multiplication of WMV in watermelon by measuring callus fresh weight and soluble proteins (mg g(-1) fresh weight) of healthy and infected hypocotyl explants. Also, WMV was isolated from naturally infected watermelon and characterized as potyvirus by serological and molecular analyses. The isolated virus gave a positive reaction with WMV antiserum compared with other antibodies of CMV, ZYMV and SqMV using DAS-ELISA. RT-PCR, with the specific primer for WMV cp. gene, yielded 825 base pair DNA fragments. The results that belong to soluble protein analysis indicated that infected hypocotyl explants treated with 6 g L( 1) recorded the highest rate in the number of soluble protein bands compared with the rest of treatments. As a conclusion of these results, we can recommend to apply the Thuja extract at 6 g L(-1) as a optimum dosage to decrease the infection caused by watermelon mosaic potyvirus. PMID- 25737656 TI - Characterization and evaluation of an arbitrary primed Polymerase Chain Reaction (PCR) product for the specific detection of Brucella species. AB - Laboratory detection of Brucella is based largely on bacterial isolation and phenotypic characterization. These methods are lengthy and labor-intensive and have been associated with a heightened risk of laboratory-acquired infection. Antibody based indirect detection methods also suffer from limitations in proper diagnosis of the organism. To overcome these problems, nucleic acid amplification has been explored for rapid detection and confirmation of the presence of Brucella spp. PCR-based diagnostics is useful for screening large populations of livestock to identify infected individuals and confirms the presence of the pathogen. Random Amplification of Polymorphic DNA (RAPD) was performed and identified a 1.3 kb PCR fragment specifically amplifiable from DNA isolated from Brucella. A BLAST search revealed no significant homology with the reported sequences from species other than the members of Brucella. The isolated fragment seems to be a part of d-alanine-d-alanine ligase gene in Brucella sp. Translational BLAST revealed certain degree of homology of this sequence with orthologs of this gene reported from other microbial species at the deduced amino acid level. The sequence information was used to develop PCR based assays to detect Brucella sp. from various samples. The minimum detection limit of Brucella from blood and milk samples spiked with Brucella DNA was found to be 1 ng/ml and 10 ng/ml, respectively. In conclusion, we demonstrated that the PCR based detection protocol was successfully used for the detection of Brucella from various organs and spiked samples of diseased sheep. Diagnosis of Brucellosis by PCR based method reported in this study is relatively rapid, specific and simple. PMID- 25737657 TI - Molecular and biochemical investigations on the effect of quercetin on oxidative stress induced by cisplatin in rat kidney. AB - The present study was aimed to investigate the ability of quercetin (QE) to ameliorate adverse effects of cisplatin (Cis.) on the renal tissue antioxidants by investigating the kidney antioxidant gene expression and the antioxidant enzymes activity. Forty rats divided into. Control rats. QE treated rats were orally administered 100 mg QE/kg for successive 30 days. Cis. injected rats were administered i.p. Cis. (12 mg/kg b.w.) for 5 mutual days. Cis. + QE rats were administered Cis. i.p. (12 mg/kg) and orally administered 100 mg QE/kg for consecutive 30 days. The obtained results indicated that Cis. induced oxidative stress in the renal tissue. That was through induction of free radical production, inhibition of the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) as well their genes expression. At the same time, vitamin E, vitamin C and reduced glutathione (GSH) levels were decreased. QE had the ability to overcome cisplatin-induced oxidative stress through the reduction of free radical levels. The antioxidant genes expression and antioxidant enzymes activity were induced. Finally the vitamin E, vitamin C and GSH levels were increased. Our work, proved the renoprotective effects of QE against oxidative stress induced by cisplatin. PMID- 25737658 TI - Penicillium ochrochloron MTCC 517 chitinase: An effective tool in commercial enzyme cocktail for production and regeneration of protoplasts from various fungi. AB - Penicillium ochrochloron MTCC 517 is a potent producer of chitinolytic enzymes. Novozyme 234, traditional enzyme cocktail for protoplast generation is not available in the market. So, new enzyme cocktail is prepared for protoplast formation from various filamentous fungi which consists of 5 mg ml(-1) lysing enzymes from Trichoderma harzianum, 0.06 mg ml(-1) beta-glucuronidase from Helix pomatia and 1 mg ml(-1) P. ochrochloron chitinase. The greatest number of protoplasts could be produced from most of the fungi in 0.8 M sorbitol and by incubation for about 2 h at 37 degrees C, but the number was decreased by incubation for more than 3 h. About twice as many protoplasts were produced from different species of fungi by involvement of P. ochrochloron chitinase than with combined commercial enzymes. PMID- 25737659 TI - Stress response of biomolecules (carbohydrate, protein and lipid profiles) in fish Channa punctatus inhabiting river polluted by Thermal Power Plant effluent. AB - Qualitative and quantitative assessment of heavy metals in the Thermal Power Plant effluent was performed to study the impact of their toxic effects on various biomarkers (carbohydrate, protein and lipid profiles). Heavy metals present in the water were in the order Fe > Cu > Zn > Mn > Ni > Co > Cr. Fe and Ni exceeded and Cr was equal to the USA standards set by UNEPGEMS. Glycogen in liver (p < 0.001) and muscle (p < 0.01) depleted significantly. Insignificant (p < 0.05) decline in blood glucose (-21.0%) and significant (p < 0.05) elevation in both total protein and globulin in serum, liver and muscle was noted. Albumin decreased significantly (p < 0.01) in serum but showed significant (p < 0.05) increase in liver and muscle. Thus A:G ratio fell in serum and rose in liver and muscle. Similarly lipid profile also gets altered where significant elevation in serum total lipid (p < 0.01), total cholesterol (p < 0.01), phospholipid (p < 0.05), triglycerides (p < 0.001), LDL (p < 0.01) was observed but significant (p < 0.05) decline in VLDL was recorded. These biomarkers suggested that fish become hypoglycemic, hyperlipidemic and hypercholesterolemic. Heavy metals also provoked immune response as evident from the rise in globulin. In conclusion the Thermal Power Plant wastewater containing heavy metals induced stress, making fish weak and vulnerable to diseases. PMID- 25737660 TI - Scenario simulations of future salinity and ecological consequences in the Baltic Sea and adjacent North Sea areas-implications for environmental monitoring. AB - Substantial ecological changes occurred in the 1970s in the Northern Baltic during a temporary period of low salinity (S). This period was preceded by an episodic increase in the rainfall over the Baltic Sea watershed area. Several climate models, both global and regional, project an increase in the runoff of the Northern latitudes due to proceeding climate change. The aim of this study is to model, firstly, the effects on Baltic Sea salinity of increased runoff due to projected global change and, secondly, the effects of salinity change on the distribution of marine species. The results suggest a critical shift in the S range 5-7, which is a threshold for both freshwater and marine species distributions and diversity. We discuss several topics emphasizing future monitoring, modelling, and fisheries research. Environmental monitoring and modelling are investigated because the developing alternative ecosystems do not necessarily show the same relations to environment quality factors as the retiring ones. An important corollary is that the observed and modelled S changes considered together with species' ranges indicate what may appear under a future climate. Consequences could include a shift in distribution areas of marine benthic foundation species and some 40-50 other species, affiliated to these. This change would extend over hundreds of kilometres, in the Baltic Sea and the adjacent North Sea areas. Potential cascading effects, in coastal ecology, fish ecology and fisheries would be extensive, and point out the necessity to develop further the "ecosystem approach in the environmental monitoring". PMID- 25737661 TI - Complex cervical spine surgery at the hospital for special surgery: editorial. PMID- 25737662 TI - Revision surgery for failed cervical spine reconstruction: review article. AB - BACKGROUND: As the number of cervical spine procedures performed continues to increase, the need for revision surgery is also likely to increase. Surgeons need to understand the etiology of post-surgical changes, as well as have a treatment algorithm when evaluating these complex patients. QUESTIONS/PURPOSES: This study aims to review the rates and etiology of revision cervical spine surgery as well as describe our treatment algorithm. METHODS: We used a narrative and literature review. We performed a MEDLINE (PubMed) search for "cervical" and "spine" and "revision" which returned 353 articles from 1993 through January 22, 2014. Abstracts were analyzed for relevance and 32 articles were reviewed. RESULTS: The rates of revision surgery on the cervical spine vary by the type and extent of procedure performed. Patient evaluation should include a detailed history and review of the indication for the index procedure, as well as lab work to rule out infection. Imaging studies including flexion/extension radiographs and computed tomography are obtained to evaluate potential pseudarthrosis. Magnetic resonance imaging is helpful to evaluate the disc, neural elements, soft tissue, and to differentiate scar from infection. Sagittal alignment should be corrected if necessary. CONCLUSIONS: Recurrent or new symptoms after cervical spine reconstruction can be effectively treated with revision surgery after identifying the etiology, and completing the appropriate workup. PMID- 25737663 TI - Modern instrumentation of the pediatric occiput and upper cervical spine: review article. AB - BACKGROUND: Rigid screw rod techniques for cervical stabilization are widely used in adults. The benefits of rigid internal fixation include increased fusion rates, improvements in deformity correction, and diminished immobilization requirements. Applications of these techniques in children are challenging due to size constraints and the pathologic conditions encountered which require instrumented cervical fusions. Preparation as well as thorough understanding of the anatomy and surgical techniques is paramount to surgical safety in pediatric patients. QUESTIONS/PURPOSES: This review article serves as an educational tool regarding the use of modern posterior instrumentation techniques for pediatric cervical deformity. METHODS: Expert review based on clinical expertise and literature review. RESULTS: The use of rigid screw rod instrumentation for the pediatric occiput and upper cervical spine is discussed. Preoperative imaging requirements for pediatric patients undergoing cervical spine surgery are reviewed. Anatomy, morphologic studies, and surgical techniques are discussed for each area of instrumentation. CONCLUSIONS: Modern posterior cervical instrumentation techniques can be safely applied to the majority of pediatric patients who require an instrumented posterior cervical fusion. Patient safety revolves around thorough preoperative imaging tests, understanding of upper cervical anatomy, and meticulous surgical technique. Modern instrumentation leads to an improvement in fusion rates and a diminishment in immobilization requirements. PMID- 25737664 TI - Anterior surgical treatment of cervical spondylotic myelopathy: review article. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM) is a common indication for cervical spine surgery. Surgical options include anterior, posterior, or combined procedures each with specific advantages and disadvantages. QUESTIONS/PURPOSES: This article will provide a description of the various anterior alternatives and discuss the available evidence used in guiding the surgical decision making process with the aim of answering the following questions: (1) What anatomical/disease related factors favor anterior over posterior surgeries? (2) What are the common anterior procedures and how safe and effective are they? (3) What are the most effective options for multilevel CSM? (4) Is there a role for motion preservation? An additional objective is to discuss technical advances that have improved success rates for anterior procedures. METHODS: The PubMed database was searched. Keywords were CSM and anterior surgery. Three hundred eighty two articles were found one hundred three were reviewed. Articles describing anterior cervical techniques were selected along with studies describing the various anterior techniques or comparisons of anterior to posterior techniques. RESULTS: Anterior decompression and fusion procedures are more effective than posterior procedures for patients with primarily ventrally located compression especially in the presence of cervical kyphosis. ACDF, ACCF, and hybrid combinations are safe and effective treatment options for multilevel CSM. Anterior procedures may be more cost effective and result in significantly improved postoperative quality of life and health-related quality of life measures compared to posterior procedures. CONCLUSION: Anterior cervical decompression techniques are safe and effective in the treatment of CSM. Anterior surgeries may be preferable to posterior approaches, when considering health related quality of life measures and cost effectiveness. PMID- 25737665 TI - Iatrogenic contributions to cervical adjacent segment pathology: review article. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is widely accepted as a predictably excellent procedure. On the other hand, adjacent level pathology following ACDF is a well-known phenomenon which undercuts surgical outcome. However, the extent to which ACDF accelerates this phenomenon in the naturally degenerating cervical spine is still to be understood. QUESTIONS/PURPOSES: To summarize the current evidence concerning adjacent segment pathology in the light of biomechanics, natural history, postoperative course, and comparison between ACDF and total disc replacement (TDR). METHODS: This is a study of published articles. Articles were searched by the topic of adjacent disc pathology in cervical spine through Google Scholar and Pubmed. After review, 37 published articles were deemed suitable for the subject of this study. RESULTS: Biomechanical and clinical data strongly suggest that ASP is a presentation of the iatrogenically accelerated natural aging process of cervical spine. However, power study analysis with assumption showed that current RCTs are unlikely to prove this suggestion. CONCLUSION: Available data suggests that iatrogenic factors play a significant role in adjacent segment pathology following ACDF. PMID- 25737666 TI - Considerations for prophylactic surgery in asymptomatic severe cervical stenosis: review article. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM) is a devastating pathology that can severely impair quality of life. The symptoms in CSM progress slowly and often do not manifest until they become severe and potentially irreversible. There is a consensus that surgical intervention is warranted in symptomatic patients. The recovery of the neurologic deficit after surgical decompression of the spinal cord varies, and halting the progression of the disease remains the principle aim of surgery. QUESTIONS/PURPOSES: The aim of this review is to address the key question of whether or not to intervene in cases that have radiographic evidence of significant cervical stenosis yet are asymptomatic or exhibit minimal symptoms? METHODS: The PubMed databases for publications that addressed asymptomatic cervical spondylotic myelopathy were reviewed. The relevant articles were selected after screening all the resulting abstracts. The references of the relevant articles were then reviewed, and cross references with titles discussing CSM were picked up for review. RESULTS: The search identified 14 papers which were reviewed. Seven articles were found to be relevant to the subject in question. Going through the references of the relevant articles, three articles were found to be directly related to the topic in study. CONCLUSION: There is paucity of evidence to support for or against surgery in the setting of asymptomatic cervical spondylotic myelopathy despite radiographic evidence of severe stenosis. Patient factors such as age, level of activity, and risk of injury should be considered in formulating a management plan. Moreover, the patient should play an integral role in the process of decision making. PMID- 25737667 TI - Posterior surgical treatment of cervical spondylotic myelopathy: review article. AB - BACKGROUND: Cervical spondylosis is now recognised as the leading cause of myelopathy and spinal cord dysfunction worldwide. Chronic spinal cord compression results in chronic inflammation, cellular apoptosis, and microvacular insufficiency, which are thought to the biologic basis for cervical spondylotic myelopathy (CSM). QUESTIONS/PURPOSES: Our purpose was to address the key principles of CSM, including natural history and presentation, pathogenesis, optimal surgical approach, results and complication rates of posterior surgical approaches for CSM so that the rationale for addressing CSM by a posterior approach can be fully understood. METHODS: We conducted a systematic search of PubMed/MEDLINE and the Cochrane Collaboration Library for literature published through February 2014 to identify articles that evaluated CSM and its management. Reasons for exclusion included patients with ossification of the posterior longitudinal ligament (OPLL), patients with degenerative disc disease without CSM, and patients with spine tumor, trauma and infection. Meeting abstracts/proceedings, white articles and editorials were additionally excluded. RESULTS: The search strategy yielded 1,292 articles, which was reduced to 52 articles, after our exclusion criteria were introduced. CSM is considered to be a surgical disorder due to its progressive nature. There is currently no consensus in the literature whether multilevel spondylotic compression is best treated via an anterior or posterior surgical approach. CONCLUSION: Multilevel CSM may be safely and effectively treated using a posterior approach, either by laminoplasty or with a laminectomy and fusion technique. PMID- 25737668 TI - Onlay tibial implants appear to provide superior clinical results in robotic unicompartmental knee arthroplasty. AB - BACKGROUND: Unicompartmental knee arthroplasty (UKA) is an increasingly popular option for the treatment of single-compartment knee osteoarthritis (OA) in adults. Two options for tibial resurfacing during UKA are (1) all-polyethylene inlays and (2) metal-backed onlays. QUESTIONS/PURPOSES: The aim of this study was to determine whether there are any differences in clinical outcomes with inlay versus onlay tibial components. PATIENTS AND METHODS: We identified 39 inlays and 45 onlays, with average 2.7- and 2.3-year follow-up, respectively, from a prospective robotic-assisted surgery database. The primary outcome was the Western Ontario and McMaster University Arthritis Index (WOMAC), subcategorized by the pain, stiffness, and function subscores, at 2 years postoperatively. The secondary outcome was the need for secondary or revision surgery. RESULTS: Postoperative WOMAC pain score was 3.1 for inlays and 1.6 for onlays (p = 0.03). For 25 inlays and 30 onlays with both preoperative and postoperative WOMAC data, pain score improved from 8.3 to 4.0 for inlays versus from 9.2 to 1.7 for onlays (p = 0.01). Function score improved from 27.5 to 12.5 for inlays versus from 32.1 to 7.3 for onlays (p = 0.03). Four inlays and one onlay required a secondary or revision procedure (p = 0.18). CONCLUSIONS: We advise using metal-backed onlays during UKA to improve postoperative clinical outcomes. PMID- 25737669 TI - Ceramic liner fracture and impingement in total hip arthroplasty. AB - BACKGROUND: Ceramic-on-ceramic bearing surfaces were developed to provide an alternate to metal-on-polyethylene to decrease wear-induced osteolysis in total hip arthroplasty patients. In an effort to decrease the risk of ceramic acetabular component fracture or damage during implantation, a raised metal rim was added. QUESTIONS/PURPOSES: How many fractures or impingements have occurred in our population of patients with ceramic liners with raised rims? METHODS: With IRB-approved consent, a case series was reviewed from a single center registry and 4 of 169 patients were identified who had revision hip surgery with the ceramic liner with a raised metal rim: one for ceramic liner fracture and three for metallosis, pain, and squeaking. Implant alignment and operative findings were reviewed. RESULTS: One ceramic liner fracture and three cases of metallosis from impingement of the femoral neck on the posterior elevated metal rim of the acetabular liner were observed at revision. The femoral neck in each patient had a divot that corresponded to a divot in the posterosuperior liner rim. Three of the four patients had audible squeaking or clicking prior to revision. A total of 3% of patients in this series had clinically significant impingement with this implant type. CONCLUSION: Acoustic phenomenon in a ceramic on ceramic bearing surface should be investigated with a cross-table lateral radiograph to evaluate component position. If symptomatic impingement is demonstrated, revision should be considered to avoid failure from metallosis or fracture. PMID- 25737670 TI - Intra-articular Analgesia and Discharge to Home Enhance Recovery Following Total Knee Replacement. AB - BACKGROUND: The increasing demand for total knee arthroplasty (TKR) and the initiatives to reduce health care spending have put the responsibility for efficient care on hospitals and providers. Multidisciplinary care pathways have been shown to shorten length of stay and result in improved short-term outcomes. However, common problems such as post-op nausea, orthostasis, and quad weakness remain, while reliance on discharge to rehabilitation facilities may also prolong hospital stay. QUESTIONS/PURPOSES: Our aim was to document that combined modifications of our traditional clinical pathway for unilateral TKR could lead to improved short-term outcomes. We pose the following research questions. Can pathway modifications which include intra-articular infusion and saphenous nerve block (SNB) provide adequate pain relief and eliminate common side effects promoting earlier mobilization? Can planning for discharge to home avoid in patient rehab stays? Can these combined modifications decrease length of stay even in patients with complex comorbidities indicated by higher ASA class? Will discharge to home incur an increase in complications or a failure to achieve knee range of motion? PATIENTS AND METHODS: A retrospective review was performed and identified two cohorts. Group A included 116 patients that underwent unilateral TKR for osteoarthritis between August 2009 and August 2010. Group B included 171 patients that underwent unilateral TKR for osteoarthritis between February 2012 to February 2013. Group A patients were treated with spinal anesthesia with patient-controlled epidural analgesia (PCEA)/femoral nerve block (FNB) for the first 48 h after surgery. Discharge planning was initiated after admission. Group B had spinal anesthesia with SNB and received a continuous intra-articular infusion of 0.2% ropivicaine for 48 h post-op. Discharge planning was initiated with a case manager prior to hospitalization and discharge to home was declared the preferred approach. An intensive home PT program was made available through a program with our local home care agency. Outcomes assessed and compared between groups included length of stay, incidence of post-op nausea, dizziness, in hospital falls, occurrence of complications including wound infection and the recovery of range of motion at 6 weeks, 3 months, and 1 year post-op. RESULTS: Pain control was similar between the groups but Group B had fewer side effects. With the new pathway, length of stay (LOS) was reduced from 4.32 to 3.64 days with a similar LOS reduction across all ASA classes. There was no increase in Group B wound or other complications. Return of ROM was similar between groups. CONCLUSIONS: Our findings suggest that replacing PCEA and FNB with intra articular analgesia with a SNB allows for improved early recovery following TKR. That, combined with pre-op discharge planning and initiation of an intensive home PT program, reduced average length of stay. PMID- 25737671 TI - Acetabular Version Measurement in Total Hip Arthroplasty: the Impact of Inclination and the Value of Multi-Planar CT Reformation. AB - BACKGROUND: The orientation of the acetabular cup component of a total hip arthroplasty can be evaluated in a number of ways, utilizing a myriad of imaging techniques and measurement parameters, including intraoperative surgical estimates, postoperative radiographs, and cross-sectional imaging such as computed tomography (CT) and magnetic resonance imaging (MRI). QUESTIONS/PURPOSES: How do traditional versus corrected measurements of acetabular version vary from one another based on the inclination of the cup? What is the reliability of the corrected acetabular version measurements based on interobserver and intraobserver consistency? PATIENTS AND METHODS: Two fellowship trained musculoskeletal radiologists reviewed CT scans on 60 total hip arthroplasties. Acetabular inclination, traditional CT acetabular version, and CT acetabular version corrected for inclination (by utilizing multi-planar reformations to measure in the plane of the cup face) were each measured. The difference was then calculated between the "traditional" axial CT and "corrected" acetabular version measurements, and the association between this difference and the acetabular inclination was assessed. RESULTS: The "traditional" axial CT and "corrected" acetabular version measurements differed from one another in every case, with the traditional method yielding a version measurement that was on average 9.5 degrees higher than the corrected technique. However, as the acetabular cup inclination angle decreased, the "traditional" measurement became more variable and increasingly discordant with the "corrected" version measurement. CONCLUSIONS: There is inherent variability between the many methods utilized for defining and measuring acetabular version, with axial CT measurements often used as an accepted proxy for true cup anteversion. However, the variability between different measurement techniques is correlated with acetabular inclination, and this variability is most pronounced when acetabular inclination is low, ultimately leading to potential confusion in measurement terminology. The increasingly widespread availability of multi-planar CT reformations provides an opportunity to standardize methodology, eliminate the impact of inclination on acetabular version measurements, and potentially provide a more reliable comparison of the impact of cup orientation on surgical outcomes. PMID- 25737672 TI - Preoperative predictors of postoperative opioid usage, pain scores, and referral to a pain management service in total knee arthroplasty. AB - BACKGROUND: Little is known about preoperative predictors of postoperative pain and referral to a recuperative pain management service after total knee arthroplasty (TKA). QUESTIONS/PURPOSES: We sought to identify the preoperative predictors of postoperative pain scores, referral to a pain management service, and narcotic usage in patients undergoing primary total knee arthroplasty. METHODS: We performed a prospective cohort study of 97 TKAs from a single surgeon. Pre and 6-week postoperative WOMAC, visual analog pain scale (VAS) scores, narcotic usage, and catastrophizing pain scores were collected. RESULTS: After adjusting for all other variables, higher age and catastrophizing pain scores were associated with lower odds of postoperative opioid usage. Increasing age and BMI were associated with lower odds of being referred to pain management. There was no relationship between self-reported preoperative pain tolerance and postoperative change in WOMAC or VAS pain scores. CONCLUSIONS: This information may help surgeons advise their patients preoperatively and set expectations during the recovery period. PMID- 25737673 TI - A Report on Three Consecutive Cases using Computer Tomography 3D Preoperative Planning for Conversion of Arthrodesed Hips to Total Hip Replacements. AB - BACKGROUND: Conversion of an arthrodesed hip to a total hip arthroplasty (THA) is a technically demanding procedure with high complication rates. One important issue is that determining the amount of correction for a leg length discrepancy (LLD) can be difficult at the planning stage. QUESTIONS/PURPOSES: The aim of this study is to assess the reliable use of computer tomography (CT)-based three dimensional (3D) preoperative planning for the conversion of arthrodesed hips to THAs. PATIENTS AND METHODS: CT-based preoperative 3D planning was used to convert three arthrodesed hips to THAs. The efficacy of the planning was evaluated with postoperative radiographic measurements involving the amount of correction for LLD, position of components, difference between targeted and actual values, and ratio of the moment arms. The clinical assessment was performed with the Japanese Orthopaedic Association (JOA) hip score before and after THA. RESULTS: The mean amount of LLD correction and median LLD after THA were 16 mm (range, 15-17 mm) and 4 mm (range, 1-10 mm), respectively. The components were implanted close to the positions recommended by the preoperative simulation. The ratio of the moment arms indicated that the converted hips were reconstructed in a biomechanically correct manner. The implants for the conversion to THA were successfully positioned with respect to anatomy and functional outcome. The median JOA hip score improved from 50 points (range, 30-66 points) preoperatively to 79 points (range, 72-86 points) at the latest follow-up. CONCLUSIONS: CT-based preoperative 3D planning could be a powerful guidance tool for conversion of arthrodesed hips to THAs. PMID- 25737674 TI - Interdisciplinary Care Improves Functional Mobility in an Individual with Type IX Osteogenesis Imperfecta. PMID- 25737675 TI - Trunnion corrosion as a cause of recurrent pseudotumor. PMID- 25737676 TI - Ultrasound-guided percutaneous long head of the biceps tenotomy. PMID- 25737677 TI - Reply to letter to the editor: ultrasound-guided percutaneous long head of the biceps tenotomy. PMID- 25737678 TI - Serum neutrophil gelatinase-associated lipocalin levels and aortic stiffness in noncritical coronary artery disease. AB - AIM: The aim of this study was to establish the degree of aortic stiffness and levels of neutrophil gelatinase-associated lipocalin (NGAL) in patients with stable ischemic heart disease. MATERIALS AND METHODS: Patients who were found to have stable, noncritical lesions on coronary angiography were included in the study [noncritical coronary artery disease (CAD)]. The control group consisted of those patients who had similar risk profiles and metabolic parameters without atherosclerosis on angiography. RESULTS: A total of 101 patients were included in the study of which 56 had noncritical CAD. Whereas the aortic strain (9.11 +/- 3.4 vs. 14.01 +/- 4.1%, p < 0.001) and aortic distensibility (3.98 +/- 1.9 10(-6) cm(2)/dyn vs. 6.33 +/- 2.3 10(-6) cm(2)/dyn, p < 0.001) were lower in the noncritical CAD group, the aortic stiffness index was higher (6.34 +/- 3.9 vs. 3.37 +/- 2.4, p < 0.001) as compared to controls. Serum NGAL levels were higher in the noncritical CAD group (79.29 +/- 38.8 vs. 48.05 +/- 21.4 ng/ml, p < 0.001). NGAL levels were negatively correlated with aortic strain (p < 0.01, r = 0.57) and distensibility (p < 0.001, r = 0.62), but positively correlated with the aortic stiffness index (p < 0.001, r = 0.72). CONCLUSION: We show that in patients with noncritical CAD, the degree of aortic stiffness and NGAL levels are higher. These markers can be used as tools for further risk stratification of patients with noncritical CAD. PMID- 25737679 TI - Usefulness of urine output criteria for early detection of acute kidney injury after transcatheter aortic valve implantation. AB - BACKGROUND: Previous studies demonstrated that acute kidney injury (AKI) following transcatheter aortic valve implantation (TAVI) is frequent and associated with adverse outcomes. However, these studies only applied the serum creatinine (sCr) criteria while ignoring the urine output criteria. We hypothesized that adding the urine output criteria might contribute to an earlier diagnosis of AKI. METHODS: We included 143 patients with severe aortic stenosis who underwent transfemoral TAVI between December 2012 and April 2014. Urine output was assessed hourly for at least 24 h following TAVI, and sCr was assessed at least daily until discharge. Based on the Valve Academic Research Consortium-2 (VARC-2), AKI was determined using both sCr and urine output criteria. We compared the incidence of AKI and time to AKI diagnosis based on these two methods. RESULTS: The mean age was 81 +/- 6 years (range 61-94) and 56% were male. AKI occurred in 27 (19%) patients, 13 (9%) of whom had AKI defined by sCr criteria. Twenty (14%) patients had AKI defined by urine output criteria, only 6 of whom had AKI also defined by sCr criteria. The use of urine output criteria resulted in earlier identification of AKI (18 +/- 4 vs. 64 +/- 57 h, p = 0.02) and was associated with lower sCr elevation in patients having AKI defined by only urine output criteria (0.03 +/- 0.12 vs. 0.37 +/- 0.06 mg/dl, p < 0.001). CONCLUSION: The use of the VARC-2 urine output criteria significantly increased the incidence of AKI and shortened the time to AKI diagnosis. PMID- 25737680 TI - Vascular compliance in lean, obese, and diabetic children and adolescents: a cross-sectional study in a minority population. AB - BACKGROUND: In adults, both obesity and type 2 diabetes mellitus (T2DM) are positively correlated with cardiovascular disease mortality and arterial stiffness. Several studies of adults have shown that both obesity and T2DM are independently associated with increased arterial stiffness. However, little is known about the relationship between arterial compliance and cardiovascular disease risk in children. We assessed whether large and small arterial compliance is impaired in obese and diabetic pubertal children. METHODS: One hundred children of African-Caribbean ethnicity, aged 14-16 years, including 21 lean children (between the 25th and 75th percentile), 40 obese children (>95th percentile), and 39 children with T2DM diagnosed by American Diabetes Association criteria were studied. Arterial compliance of the large (C1) and small (C2) vessels was measured using radial arterial diastolic pulse wave contour analysis. RESULTS: C1 did not differ significantly between lean, obese, and T2DM subjects. C2 was significantly greater in obese and T2DM subjects (10.9 +/- 1 and 10.4 +/- 0.7 ml/mm Hg * 100 ml, respectively) compared to lean subjects (7.8 +/- 0.8 ml/mm Hg * 100 ml; p < 0.05). C2 was also significantly greater in T2DM subjects receiving antihypertensive drug therapy than in diabetic subjects not on antihypertensive treatment. CONCLUSION: Increased compliance in diabetic and obese children compared to lean subjects could be secondary to premature maturation of the vascular system; whether this early maturation can translate into a subsequent rise in the incidence of cardiovascular events related to diabetes and obesity can only be determined by long-term follow-up of these patients. PMID- 25737681 TI - Left ventricular hypertrophy and chronic renal insufficiency in the elderly. AB - BACKGROUND: The global population is aging. Cardiovascular disease is the leading cause of death in both men and women older than 65 years. In particular, elderly patients have an increased prevalence of left ventricular hypertrophy (LVH) and chronic kidney disease (CKD), both of which predict increased cardiovascular morbidity and mortality. LVH and CKD frequently coexist in the elderly, and LVH is a powerful predictor of mortality in patients with end-stage renal disease. KEY MESSAGES: Several hemodynamic factors contribute to LVH and CKD in the elderly. Increased arterial stiffness in the elderly is associated with LVH and CKD. Studies using noninvasive measures of arterial stiffening have shown a correlation between these measures and LVH in patients with CKD. Hypertensive patients with an altered circadian blood pressure pattern such as nondippers have an increased incidence of LVH and CKD. Anemia is a risk factor for LVH in patients in all stages of CKD, and studies have shown correlations between age, anemia and LV mass. Nonhemodynamic factors include chronic inflammation, increased oxidative stress, and reduced autophagy, all of which are present in the elderly. Disordered mineral metabolism in the elderly with reduced levels of vitamin D and elevated levels of parathyroid hormone and phosphorus is associated with LVH and CKD. CONCLUSIONS: Multiple pathophysiologic mechanisms contribute to the development of LVH and CKD in the elderly. Future research should be directed at interfering with this development and reducing the burden of cardiovascular and renal diseases in this growing population. PMID- 25737682 TI - Management of the cardiorenal syndrome in decompensated heart failure. AB - BACKGROUND: The management of the cardiorenal syndrome (CRS) in decompensated heart failure (HF) is challenging, with high-quality evidence lacking. SUMMARY: The pathophysiology of CRS in decompensated HF is complex, with glomerular filtration rate (GFR) and urine output representing different aspects of kidney function. GFR depends on structural factors (number of functional nephrons and integrity of the glomerular membrane) versus hemodynamic alterations (volume status, renal perfusion, arterial blood pressure, central venous pressure or intra-abdominal pressure) and neurohumoral activation. In contrast, urine output and volume homeostasis are mainly a function of the renal tubules. Treatment of CRS in decompensated HF patients should be individualized based on the underlying pathophysiological processes. KEY MESSAGES: Congestion, defined as elevated cardiac filling pressures, is not a surrogate for volume overload. Transient decreases in GFR might be accepted during decongestion, but hypotension must be avoided. Paracentesis and compression therapy are essential to remove fluid overload from third spaces. Increasing the effective circulatory volume improves renal function when cardiac output is depressed. As mechanical support is invasive and inotropes are related to increased mortality, afterload reduction through vasodilator therapy remains the preferred strategy in patients who are normo- or hypertensive. Specific therapies to augment renal perfusion (rolofylline, dopamine or nesiritide) have rendered disappointing results, but recently, serelaxin has been shown to improve renal function, even with a trend towards reduced all-cause mortality in selected patients. Diuretic resistance is associated with worse outcomes, independent of the underlying GFR. Combinational diuretic therapy, with ultrafiltration as a bail-out strategy, is indicated in case of diuretic resistance. PMID- 25737683 TI - Association between the Hemoglobin Level and Cardiothoracic Ratio in Patients on Incident Dialysis. AB - BACKGROUND/AIM: The present study explores associations between hemoglobin (Hb) levels and patients with cardiac enlargement in end-stage kidney disease (ESKD) to help prevent cardiac remodeling during the predialysis phase of chronic kidney disease (CKD). METHODS: This cross-sectional study included 2,249 patients with ESKD (age, 67 +/- 13 years; male, 67%; diabetic kidney disease, 41%) who started hemodialysis (HD) between January 2006 and October 2013 at eight participating hospitals. We examined associations between Hb levels immediately before the first HD session and cardiothoracic ratios (CTRs). Clinical factors associated with the CTR were also assessed. RESULTS: The mean Hb level was 8.7 +/- 1.6 g/dl, and the mean and median CTRs were 55.0 and 54.7%, respectively. The correlation between the Hb level and the CTR was linear and negative (r = -0.129, p < 0.001). The mean CTR and the prevalence of patients with a CTR >50% obviously decreased with increasing Hb levels (both p < 0.001 for trend). Univariate logistic regression analysis revealed an approximately 20% reduction in the odds ratio for complicating CTRs >50% per 1 g/dl increase in Hb. Hb levels of <9 g/dl were significantly associated with CTRs >50%. Numerical and categorical Hb remained significantly associated with CTRs >50% after adjusting for confounding variables. CONCLUSIONS: Lower Hb levels participate in progressive CTR enlargement in patients with ESKD, and maintaining Hb levels of >9 g/dl might help prevent cardiac remodeling during the predialysis phase of CKD. PMID- 25737684 TI - Acute kidney injury after valvular heart surgery and early changes in cardiac function and structure. AB - BACKGROUND: Acute kidney injury (AKI) following heart surgery is associated with long-term risk of heart failure. It is not known if AKI following valvular heart surgery is associated with early changes in cardiac function or structure. METHODS: A cohort study was conducted on 201 patients with AKI and 201 patients without AKI after valvular heart surgery, who were matched for age, sex, left ventricular function, and estimated glomerular filtration rate. AKI was defined as an increase in postoperative serum creatinine of >=26 MUmol/l (>=0.3 mg/dl) or a relative increase of >=50%. The two primary outcomes were changes in post compared with preoperative left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD) assessed by echocardiography. RESULTS: The mean age was 72 years, and 33% were female. Aortic valve surgery was the most frequent procedure. The mean time from surgery to the postoperative echocardiographic examination was 4.9 days (SD 3.7). There was no significant change in postoperative mean LVEF (-3.6 vs. -4.3%; p = 0.58) or mean LVEDD (-4.7 vs. -3.9 mm; p = 0.31) in patients with AKI compared to those without AKI. CONCLUSION: We found no acute changes in cardiac function or structure assessed by echocardiography in patients with AKI compared to those without AKI after valvular heart surgery. PMID- 25737685 TI - Sleep duration and chronic kidney disease: analysis of the national health interview survey. AB - BACKGROUND: Patients with chronic kidney disease (CKD) have a high prevalence of sleep disorders. The association between sleep duration and self-reported CKD was examined in a population of Americans who participated in a national survey over a 3-year period. STUDY DESIGN: A cross-sectional study using survey data from the National Health Interview Survey (NHIS) from the year 2004-2006 was carried out. A retrospective examination of data from a community-based survey of 128,486 noninstitutionalized US civilian residents over the age of 18 years was conducted. Self-reported CKD was defined as having 'weak or failing kidneys'. The sleep duration was defined by a self-reported estimate of habitual sleep duration. RESULTS: The prevalence of participants self-reporting kidney disease was higher in those with short (<=6 h per night) and long (>=8 h per night) sleep durations when compared to those sleeping 7 h per night. Self-reported information about sleep, demographic information, and information on comorbidities were assessed using standardized validated questionnaires which reported no kidney disease. A multivariate logistic regression analysis showed increased odds of self-reported kidney disease in study participants with both short and long sleep durations compared to healthy sleepers (sleeping >7-8 h per night). Observational data do not permit examination of causality, although possible confounders in observations of interest can be adjusted. CONCLUSION: Among Americans surveyed in the NHIS (2004-2006), those with short or long sleep duration had higher odds of reporting that they had CKD. PMID- 25737686 TI - Oral active vitamin d treatment and mortality in maintenance hemodialysis patients. AB - AIMS: To analyze the relationship between oral active vitamin D treatment and mortality in maintenance hemodialysis (MHD) patients. METHODS: We examined the association of oral calcitriol treatment with mortality in 156 MHD patients (80 men and 76 women; mean age: 59 +/- 15 years). The survival analysis of all-cause and cardiovascular mortality was performed using the Kaplan-Meier survival and Cox proportional-hazards analyses. RESULTS: In all, 108 of the 156 patients received active vitamin D treatment. The intact parathyroid hormone level was obviously lower in the patients who received active vitamin D treatment than in those who did not. Throughout the whole follow-up, overall mortality was 16.7% (26 deaths, 13 in each group). The cardiovascular mortality rates were 14.6% (8/48) in the control group and 4.6% (5/108) in the calcitriol group. The crude analysis of all-cause and cardiovascular mortality using the Kaplan-Meier curve showed a significant reduction in mortality risk for patients who received oral active vitamin D compared with those who did not receive it (p = 0.015 and 0.026, respectively). Cox's regression analysis showed that active vitamin D treatment was associated with a significantly lower risk of all-cause mortality (RR = 0.399, 95% CI 0.185-0.862, p = 0.019) and cardiovascular mortality (RR = 0.295, 95% CI 0.094-0.93, p = 0.037). However, after adjusting for potential confounding variables, oral active vitamin D therapy was no longer clearly associated with a lower risk of either all-cause or cardiovascular mortality. CONCLUSION: Oral active vitamin D treatment was associated with improved survival in MHD patients. However, this survival benefit was smaller than previously reported, and a large cohort study should be performed. PMID- 25737687 TI - Reasons for discontinuation of lipid-lowering medications in patients with chronic kidney disease. AB - BACKGROUND/AIMS: Many patients with chronic kidney disease (CKD) do not receive lipid-lowering therapy despite their high cardiovascular risk. The reasons for this are unknown. METHODS: We have conducted a retrospective cohort study of discontinuation of lipid-lowering drugs in patients with CKD stage 3 and higher treated in practices affiliated with two academic medical centers between 2000 and 2010. Information on medication discontinuation and its reasons was obtained from electronic medical records, including natural language processing of electronic notes using previously validated software. RESULTS: Out of 14,034 patients in the study cohort, 10,072 (71.8%) stopped their lipid-lowering drugs at least once, and 2,444 (17.4%) stopped them for at least 1 month. Patients who had a comorbidity associated with higher cardiovascular risk were less likely to stop lipid-lowering drugs. Insurance request was the most common explicitly documented reason for discontinuation, and adverse reactions were the most common reason for long-term discontinuation. In a multivariable analysis, patients were more likely to stop a lipid-lowering drug because of an insurance request if they had government insurance and they were also more likely to stop a lipid-lowering drug because of adverse reactions if they had a history of multiple adverse reactions to other medications. There was no significant relationship between CKD stage and the reason for discontinuation of lipid-lowering drugs. CONCLUSIONS: Patients with CKD frequently stop lipid-lowering drugs. Insurance requests and adverse reactions are common reasons for the discontinuation. Further research is needed to ensure appropriate lipid-lowering therapy for these individuals at high cardiovascular risk. PMID- 25737688 TI - Echocardiographic changes in patients with stage 3-5 chronic kidney disease and left ventricular diastolic dysfunction. AB - BACKGROUND: Left ventricular (LV) diastolic dysfunction in chronic kidney disease (CKD) patients frequently leads to the development of congestive heart failure. We evaluated changes in echocardiographic parameters among CKD patients with LV diastolic dysfunction. METHODS: We examined 70 ambulatory patients with CKD at stages 3-5 and 26 patients without CKD as a control group. Standard echocardiography and tissue Doppler imaging were performed on all patients. Patients with CKD were divided into two groups according to the results of lateral mitral early diastolic velocity (EmLVlat): a group with diastolic dysfunction (DD group; EmLVlat <8 cm/s) and a group without diastolic dysfunction (WDD group; EmLVlat >=8 cm/s). RESULTS: Compared to the patients in the WDD group, those in the DD group were characterized by lower values of mitral annular plane systolic excursion [MAPSE; 13 (11-17) vs. 14 (11-16) mm, p < 0.0001] and lateral mitral annular systolic velocity [SmLVlat; 7 (5-14) vs. 8 (5-13) cm/s, p = 0.006]. The area under the receiver operating characteristic (ROC) curve of the MAPSE level for the detection of LV diastolic dysfunction was 0.801 [95% CI 0.684 0.890, p < 0.0001], whereas a ROC-derived MAPSE value of <=13 mm was characterized by a sensitivity of 84.4% and a specificity of 75.8% for diagnosing LV diastolic dysfunction. The only independent variable predicting LV diastolic dysfunction was MAPSE [OR = 0.39; 95% CI 0.21-0.74, p = 0.003]. CONCLUSION: We showed that reduced MAPSE, but not SmLVlat, is an independent predictive factor for LV diastolic dysfunction in CKD patients. PMID- 25737689 TI - Insulin resistance and skeletal muscle vasculature: significance, assessment and therapeutic modulators. AB - Overnutrition and sedentarism are closely related to the alarming incidence of obesity and type 2 diabetes mellitus (DM2) in the Western world. Resistance to the actions of insulin is a common occurrence in conditions such as obesity, hypertension and DM2. In the skeletal muscle vasculature, insulin promotes vasodilation and its own transport across the vascular wall to reach its target tissue. Furthermore, insulin resistance (IR) in the skeletal muscle vasculature results in impaired skeletal muscle glucose uptake and altered whole-body glucose homeostasis. The development of different invasive and noninvasive techniques has allowed the characterization of the actions of insulin and other vasoactive hormones in the skeletal muscle vasculature in both health and disease. Current treatment strategies for DM2 do not necessarily address the impaired effect of insulin in the vasculature. Understanding the effects of insulin and other metabolically active hormones in the vasculature should facilitate the development of new therapeutic strategies targeted at the modulation of IR and improvement of whole-body glucose tolerance. PMID- 25737690 TI - Patients with cardiorenal syndrome revealed increased neurohormonal activity, tubular and myocardial damage compared to heart failure patients with preserved renal function. AB - BACKGROUND: Cardiorenal syndrome (CRS) is associated with increased cardiovascular morbidity and mortality; still, its biomarker pattern has been poorly evaluated so far. The aim of this study was to measure the inflammatory activation, neurohormonal status and kidney and myocardial damage in patients with CRS compared to patients with heart failure (HF) without renal impairment (RI). METHODS: We analyzed 246 patients on the basis of renal function (group 1: 120 HF patients without RI; group 2: 126 CRS patients). In each group, interleukin-6, tumor necrosis factor-alpha, B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), troponin T (TnT), osteoprotegerin and blood urea nitrogen (BUN) were measured. The diagnostic power of all laboratory parameters to detect CRS was evaluated by the receiver operating characteristic (ROC) curve and logistic regression analysis. RESULTS: A significant increase in BNP [626.4 pg/ml, confidence interval (CI) 518-749 vs. 487.8 pg/ml, CI 411-578; p < 0.05], NGAL (156 ng/ml, CI 129-186 vs. 89.1 ng/ml, CI 72-109; p < 0.0001), BUN (108.9 mg/dl, CI 98-120 vs. 51 mg/dl, CI 46-55; p < 0,0001) and TnT (0.62 ng/ml, CI 0.51-0.75 vs. 0.21 ng/ml, CI 0.15-0.28; p < 0.001) was seen in CRS patients compared to HF patients without RI. ROC curve analysis showed that only NGAL, BUN, BUN/creatinine ratio and TnT can discriminate patients with CRS from patients without RI. CONCLUSIONS: In CRS patients, renal tubular damage and neurohormonal and cardiac injury activation are increased compared to patients without RI. The current biomarker pattern could be used for an early diagnosis of RI in acute and chronic HF. PMID- 25737691 TI - Endothelial nitric oxide synthase gene expression is associated with hypertension in autosomal dominant polycystic kidney disease. AB - BACKGROUND/AIMS: Early occurrence of hypertension is the prominent feature of autosomal dominant polycystic kidney disease (ADPKD). The role of angiotensin converting enzyme (ACE) gene polymorphism and endothelial nitric oxide synthase (eNOS) gene polymorphism in the clinical course of ADPKD is not well understood. However, data about the expression of these genes are lacking. Thus, we aimed to investigate the polymorphisms and expressions of both the ACE and eNOS genes that affect hypertension in ADPKD. METHODS: Whole blood samples were obtained from all participants. ACE and eNOS gene polymorphisms and their expressions were analyzed in 78 ADPKD patients and 30 controls. Gene expressions were assessed by quantitative real-time PCR. Twenty-four-hour blood pressure monitoring was performed for the diagnosis of hypertension in all study participants. RESULTS: eNOS expression and the estimated glomerular filtration rate were found to be significantly higher in ADPKD patients without hypertension than in those with hypertension. Each unit of increase in eNOS expression led to a 0.88-fold decrease (95% CI: 0.80-0.96) in the risk of hypertension in multiple logistic regression analysis. CONCLUSIONS: eNOS gene expression is independently predictive of hypertension in the ADPKD population. This study showed, for the first time, a novel link between eNOS gene expression and hypertension in ADPKD. PMID- 25737692 TI - Increased arterial stiffness after coronary artery revascularization correlates with serious coronary artery lesions and poor clinical outcomes in patients with chronic kidney disease. AB - OBJECTIVES: This study aimed to clarify the relationship between arterial stiffness and coronary artery lesions as well as their influence on long-term outcomes after coronary artery revascularization in patients with chronic kidney disease (CKD). METHODS: A total of 205 patients who had a coronary angiography and received coronary artery revascularization on demand were enrolled and followed up for 5 years. Demographic and clinical indicators, arterial stiffness indexes, angiographic characteristics and the Gensini score (GS) were recorded at baseline. Major adverse cardiac events (MACE), including cardiac death and repeat coronary artery revascularization, that occurred during the 5 years of follow-up were also recorded. RESULTS: All indexes reflecting the degree of arterial stiffness, including PWV, C1, C2, CSBP, CDBP, AP and Aix, were significantly higher in CKD than in non-CKD patients (all p < 0.05). Patients with CKD also had a higher rate of coronary artery disease and a higher GS (p < 0.05 and p < 0.01, respectively). Logistic regression analysis revealed CKD to be an independent risk factor for increased arterial stiffness (OR = 2.508, 95% CI 1.308-4.808, p = 0.006). During follow-up, CKD patients with PWV >13 m/s or Aix@75 >30 had a significantly higher MACE occurrence rate after coronary artery revascularization (both p < 0.05). CONCLUSION: These results highlight that CKD and arterial stiffness correlate with the severity of coronary artery lesions. CKD patients with impaired arterial stiffness have poor clinical outcomes, suggesting a further clinical use of the arterial stiffness index as a surrogate of worse cardiovascular prognosis in CKD than in non-CKD patients. PMID- 25737693 TI - Dose-dependent and combined effects of N-methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine on the survival of retinal ganglion cells in adult hamsters. AB - This study investigated the effects of daily intraperitoneal injections of N methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine (L-NA) on the survival of retinal ganglion cells (RGCs) at 1 and 2 weeks after unilateral optic nerve transection in adult hamsters. The left optic nerves of all animals were transected intraorbitally 1 mm from the optic disc and RGCs were retrogradely labeled with Fluorogold before they received different daily dosages of single MK-801 or L-NA as well as daily combinational treatments of these two chemicals. All experimental and control animals survived for 1 or 2 weeks after optic nerve transection. Our results revealed that the mean numbers of surviving RGCs increased and then decreased when the dosage of MK 801 (1.0, 3.0 and 4.5 mg/kg) and L-NA (1.5, 3.0, 4.5 and 6.0 mg/kg) increased at both 1 and 2 weeks survival time points. Daily combinational use of 1.0 mg/kg MK 801 and 1.5 mg/kg L-NA lead to a highest RGC number that was even higher than the sum of the RGC numbers in 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA subgroups at 2 weeks. These findings indicated that both MK-801 and L-NA can protect axotomized RGCs in a dose-dependent manner and combinational treatment of these chemicals possesses a potentiative and protective effect. PMID- 25737694 TI - Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist inhibits apoptosis of retinal ganglion cells in a rabbit model of optic nerve injury. AB - A rabbit model of traumatic optic nerve injury, established by occlusion of the optic nerve using a vascular clamp, was used to investigate the effects of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist GYKI 52466 on apoptosis of retinal ganglion cells following nerve injury. Hematoxylin-eosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that retinal ganglion cells gradually decreased with increasing time of optic nerve injury, while GYKI 52466 could inhibit this process. The results demonstrate that following acute optic nerve injury, apoptosis of retinal ganglion cells is a programmed process, which can be inhibited by the alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. PMID- 25737695 TI - X-box-binding protein 1-modified neural stem cells for treatment of Parkinson's disease. AB - X-box-binding protein 1-transfected neural stem cells were transplanted into the right lateral ventricles of rats with rotenone-induced Parkinson's disease. The survival capacities and differentiation rates of cells expressing the dopaminergic marker tyrosine hydroxylase were higher in X-box-binding protein 1 transfected neural stem cells compared to non-transfected cells. Moreover, dopamine and 3,4-dihydroxyphenylacetic acid levels in the substantia nigra were significantly increased, alpha-synuclein expression was decreased, and neurological behaviors were significantly ameliorated in rats following transplantation of X-box-binding protein 1-transfected neural stem cells. These results indicate that transplantation of X-box-binding protein 1-transfected neural stem cells can promote stem cell survival and differentiation into dopaminergic neurons, increase dopamine and 3,4-dihydroxyphenylacetic acid levels, reduce alpha-synuclein aggregation in the substantia nigra, and improve the symptoms of Parkinson's disease in rats. PMID- 25737696 TI - Transplantation of human umbilical cord blood mesenchymal stem cells to treat a rat model of traumatic brain injury. AB - In the present study, human umbilical cord blood mesenchymal stem cells were injected into a rat model of traumatic brain injury via the tail vein. Results showed that 5-bromodeoxyuridine-labeled cells aggregated around the injury site, surviving up to 4 weeks post-transplantation. In addition, transplantation related death did not occur, and neurological functions significantly improved. Histological detection revealed attenuated pathological injury in rat brain tissues following human umbilical cord blood mesenchymal stem cell transplantation. In addition, the number of apoptotic cells decreased. Immunohistochemistry and in situ hybridization showed increased expression of brain-derived neurotrophic factor, nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor, along with increased microvessel density in surrounding areas of brain injury. Results demonstrated migration of transplanted human umbilical cord blood mesenchymal stem cells into the lesioned boundary zone of rats, as well as increased angiogenesis and expression of related neurotrophic factors in the lesioned boundary zone. PMID- 25737697 TI - Electrophysiological functional recovery in a rat model of spinal cord hemisection injury following bone marrow-derived mesenchymal stem cell transplantation under hypothermia. AB - Following successful establishment of a rat model of spinal cord hemisection injury by resecting right spinal cord tissues, bone marrow stem cells were transplanted into the spinal cord lesions via the caudal vein while maintaining rectal temperature at 34 +/- 0.5 degrees C for 6 hours (mild hypothermia). Hematoxylin-eosin staining showed that astrocytes gathered around the injury site and formed scars at 4 weeks post-transplantation. Compared with rats transplanted with bone marrow stem cells under normal temperature, rats transplanted with bone marrow stem cells under hypothermia showed increased numbers of proliferating cells (bromodeoxyuridine-positive cells), better recovery of somatosensory-evoked and motor-evoked potentials, greater Basso, Beattie, and Bresnahan locomotor rating scores, and an increased degree of angle in the incline plate test. These findings suggested that hypothermia combined with bone marrow mesenchymal stem cells transplantation effectively promoted electrical conduction and nerve functional repair in a rat model of spinal cord hemisection injury. PMID- 25737699 TI - Basic fibroblast growth factor increases the number of endogenous neural stem cells and inhibits the expression of amino methyl isoxazole propionic acid receptors in amyotrophic lateral sclerosis mice. AB - This study aimed to investigate the number of amino methyl isoxazole propionic acid (AMPA) receptors and production of endogenous neural stem cells in the SOD1(G93AG1H) transgenic mouse model of amyotrophic lateral sclerosis, at postnatal day 60 following administration of basic fibroblast growth factor (FGF 2). A radioligand binding assay and immunohistochemistry were used to estimate the number of AMPA receptors and endogenous neural stem cells respectively. Results showed that the number of AMPA receptors and endogenous neural stem cells in the brain stem and sensorimotor cortex were significantly increased, while motor function was significantly decreased at postnatal days 90 and 120. After administration of FGF-2 into mice, numbers of endogenous neural stem cells increased, while expression of AMPA receptors decreased, whilst motor functions were recovered. At postnatal day 120, the number of AMPA receptors was negatively correlated with the number of endogenous neural stem cells in model mice and FGF 2-treated mice. Our experimental findings indicate that FGF-2 can inhibit AMPA receptors and increase the number of endogenous neural stem cells, thus repairing neural injury in amyotrophic lateral sclerosis mice. PMID- 25737698 TI - Uric acid promotes neuronal differentiation of human placenta-derived mesenchymal stem cells in a time- and concentration-dependent manner. AB - Uric acid is an important, naturally occurring serum antioxidant. The present study investigates the use of uric acid for promoting proliferation and neuronal differentiation of mesenchymal stem cells derived from human placenta tissue. Human placenta-derived mesenchymal stem cells were pre-induced in the presence of either 0, 0.2, 0.4 or 0.8 mM uric acid in combination with 1 mM beta mercaptoethanol for 24 hours, followed by exposure to identical uric acid concentrations and 5 mM beta-mercaptoethanol for 6 and 10 hours. Cells developed a neuronal-like morphology, with formation of interconnected process extensions, typical of neural cells. Immunocytochemistry and immunofluorescence staining showed neuron specific enolase positive cells were present in each group except the control group. A greater number of neuron specific enolase positive cells were observed in 0.8 mM uric acid in combination with 5 mM beta-mercaptoethanol at 10 hours. After 24 hours of induction, Nissl bodies were detected in the cytoplasm of all differentiated cell groups except the control group and Nissl body numbers were greatest in human placenta-derived mesenchymal stem cells grown in the presence of 0.8 mM uric acid and 5 mM beta-mercaptoethanol. These results suggest uric acid accelerates differentiation of human placenta-derived mesenchymal stem cells into neuronal-like cells in a time- and concentration dependent manner. PMID- 25737700 TI - Olfactory route for cerebrospinal fluid drainage into the cervical lymphatic system in a rabbit experimental model. AB - The present study analyzed the anatomical association between intracranial subarachnoid space and the cervical lymphatic system. X-ray contrast medium and Microfil((r)) (Microfil compounds fill and opacify microvascular and other spaces of non-surviving animals and post-mortem tissue under physiological injection pressure) were injected into the cisterna magna of the rabbit, and perineural routes of cerebrospinal fluid outflow into the lymphatic system were visualized. Under a surgical operating microscope, Microfil was found within the subarachnoid space and along the olfactory nerves. At the nasal mucosa, a lymphatic network was identified near the olfactory nerves, which crossed the nasopharyngeal region and finally emptied into the superficial and deep cervical lymph nodes. Under a light microscope, Microfil was visible around the olfactory nerves and within lymphatic vessels. These results suggested that cerebrospinal fluid drained from the subarachnoid space along the olfactory nerves to nasal lymphatic vessels, which in turn, emptied into the cervical lymph nodes. This anatomical route, therefore, allowed connection between the central nervous system and the lymphatic system. PMID- 25737701 TI - Calcium-mediated paired pulse depression in juvenile rat dorsal striatum. AB - As the major division of the basal ganglia, neostriatum forms mutual connections with multiple brain areas and is critically involved in motor control and learning/memory. Long-term synaptic plasticity has been widely studied in different species recently. However, there are rare reports about the short-term synaptic plasticity in neostratium. In the present study, using field excitatory postsynaptic potentials recording, we reported one form of short-term synaptic plasticity that is paired pulse depression in juvenile rat dorsal striatum slices induced by stimuli of the white matter. The field excitatory postsynaptic potentials could be abolished by alpha-amino-3-hydroxy-5-methylizoxazole-4 propionic acid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, but not by gamma-aminobutyric acid type A receptor antagonist bicuculline or dopamine D1 receptor antagonist SKF-81297. The paired pulse depression in the corticostratial pathway was different from paired pulse facilitation in the hippocampal CA1 synapse. In addition, the paired pulse depression was not affected by bath application of gamma-aminobutyric acid type A receptor antagonist or dopamine D1 receptor antagonist. However, low calcium and high magnesium could attenuate the paired pulse depression. These findings suggest a more complicated plasticity form in the dorsal striatum of juvenile rats that is different from that in the hippocampus, which is related with extracellular calcium. PMID- 25737702 TI - Increased hypoxia-inducible factor 1alpha expression in rat brain tissues in response to aging. AB - The present study observed changes in rat neural cells at various ages (3, 18, 24, and 30 months). With age, neural cells became large and were sparsely arranged, and the number of Nissl bodies decreased. In addition, hypoxia inducible factor 1alpha expression increased with increasing age in hippocampal CA1 and CA3 regions, motor cortex, and the first subfolium, especially from 3 to 18 months. In the open-field test, grid crossing decreased with increasing age, especially from 18 months. The number of rearings reached a peak in the 18 months group, and then subsequently decreased. The results suggested that hypoxia inducible factor 1alpha played an important role in the nervous system aging process. PMID- 25737703 TI - Research progress in muscle-derived stem cells: Literature retrieval results based on international database. AB - OBJECTIVE: To identify global research trends of muscle-derived stem cells (MDSCs) using a bibliometric analysis of the Web of Science, Research Portfolio Online Reporting Tools of the National Institutes of Health (NIH), and the Clinical Trials registry database (ClinicalTrials.gov). DATA RETRIEVAL: We performed a bibliometric analysis of data retrievals for MDSCs from 2002 to 2011 using the Web of Science, NIH, and ClinicalTrials.gov. SELECTION CRITERIA: INCLUSION CRITERIA: (1) Web of Science: (a) peer-reviewed articles on MDSCs that were published and indexed in the Web of Science. (b) Type of articles: original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material and news items. (c) Year of publication: 2002-2011. (d) Citation databases: Science Citation Index-Expanded (SCI-E), 1899-present; Conference Proceedings Citation Index-Science (CPCI-S), 1991-present; Book Citation Index-Science (BKCI-S), 2005-present. (2) NIH: (a) Projects on MDSCs supported by the NIH. (b) Fiscal year: 1988-present. (3) ClinicalTrials.gov: All clinical trials relating to MDSCs were searched in this database. EXCLUSION CRITERIA: (1) Web of Science: (a) Articles that required manual searching or telephone access. (b) We excluded documents that were not published in the public domain. (c) We excluded a number of corrected papers from the total number of articles. (d) We excluded articles from the following databases: Social Sciences Citation Index (SSCI), 1898-present; Arts & Humanities Citation Index (A&HCI), 1975-present; Conference Proceedings Citation Index - Social Science & Humanities (CPCI-SSH), 1991-present; Book Citation Index - Social Sciences & Humanities (BKCI-SSH), 2005-present; Current Chemical Reactions (CCR-EXPANDED), 1985 present; Index Chemicus (IC), 1993-present. (2) NIH: (a) We excluded publications related to MDSCs that were supported by the NIH. (b) We limited the keyword search to studies that included MDSCs within the title or abstract. (3) ClinicalTrials.gov: (a) We excluded clinical trials that were not in the ClinicalTrials.gov database. (b) We excluded clinical trials that dealt with stem cells other than MDSCs in the ClinicalTrials.gov database. MAIN OUTCOME MEASURES: (1) Type of literature; (2) annual publication output; (3) distribution according to journals; (4) distribution according to country; (5) distribution according to institution; (6) top cited authors over the last 10 years; (7) projects financially supported by the NIH; and (8) clinical trials registered. RESULTS: (1) In all, 802 studies on MDSCs appeared in the Web of Science from 2002 to 2011, almost half of which derived from American authors and institutes. The number of studies on MDSCs has gradually increased over the past 10 years. Most papers on MDSCs appeared in journals with a particular focus on cell biology research, such as Experimental Cell Research, Journal of Cell Science, and PLoS One. (2) Eight MDSC research projects have received over US$6 billion in funding from the NIH. The current project led by Dr. Johnny Huard of the University of Pittsburgh-"Muscle-Based Tissue Engineering to Improve Bone Healing"-is supported by the NIH. Dr. Huard has been the most productive and top-cited author in the field of gene therapy and adult stem cell research in the Web of Science over last 10 years. (3) On ClinicalTrials.gov, "Muscle Derived Cell Therapy for Bladder Exstrophy Epispadias Induced Incontinence" Phase 1 is registered and sponsored by Johns Hopkins University and has been led by Dr. John P. Gearhart since November 2009. CONCLUSION: From our analysis of the literature and research trends, we found that MDSCs may offer further benefits in regenerative medicine. PMID- 25737704 TI - Scientific literature addressing detection of monosialoganglioside: A 10-year bibliometric analysis. AB - OBJECTIVE: The study was undertaken to explore a bibliometric approach to quantitatively assess the research on detection of monosialoganglioside from 2002 to 2011. DATA RETRIEVAL: A bibliometric analysis based on the publications on Web of Science was performed using key words such as "monosialoganglioside", "colloidal gold", "high performance liquid chromatography" and "detection". SELECTION CRITERIA: (1) Research articles on the detection of monosialoganglioside; (2) researches on human and animal fundamentals, clinical trials and case reports; (3) article types: article, review, proceedings paper, note, letter, editorial material, discussion, book chapter; (4) Publication year: 2002-2011. EXCLUSION CRITERIA: (1) unrelated articles; (2) type of articles: correction; (3) articles from following databases: all databases related to social science and arts & humanities in Web of Science were excluded. MAIN OUTCOME MEASURES: (1) distribution of subject areas; (2) number of publications annually; (3) document type and language of publications; (4) distribution of institutions; (5) distribution of output in journals; (6) the number of countries in which the article is published; (7) top cited paper. RESULTS: Overall population stands at 1 880 research articles addressing detection of monosialoganglioside in Web of Science during the study period. Articles (1 599) were the most frequently used document type comprising 85.05%, followed by meeting abstracts, reviews and proceedings papers. The distribution of subject categories showed that monosialoganglioside research covered both clinical and basic science research. The USA, Japan, and Italy were the three most productive countries, and the publication numbers in the USA were highest with 559 papers. The University of Milan, Nagoya University, and Kinki University are the most productive institutions regarding detection of monosialoganglioside. In 559 articles published by Americans, Medical College of Georgia ranked the first with 30 articles, followed by University of Medicine and Dentistry of New Jersey (28 articles), Cornell University (24 articles) and Johns Hopkins University (24 articles). In 442 articles published by Japanese, Nagoya University ranked the first with 40 articles, followed by Kinki University (36 articles), and Dokkyo University (31 articles). Though the total number of publications by Japanese is smaller than Americans, the top three institutions published more publications than American institutions. There is a markedly increase in the number of publications on the subject detection of monosialoganglioside in 2004, which the peak in the past 10 years. The valley bottom of the subject appeared in 2005. In total, the research is increased with time prolonged. Journal of Neurochemistry, Journal of Biological Chemistry and Journal of Neuroimmunology were core subject journals in monosialoganglioside studies. CONCLUSION: This study highlights the topics in detection of monosialoganglioside research that are being published around the world. PMID- 25737705 TI - Biotinylated dextran amine anterograde tracing of the canine corticospinal tract. AB - In this study, biotinylated dextran amine (BDA) was microinjected into the left cortical motor area of the canine brain. Fluorescence microscopy results showed that a large amount of BDA-labeled pyramidal cells were visible in the left cortical motor area after injection. In the left medulla oblongata, the BDA labeled corticospinal tract was evenly distributed, with green fluorescence that had a clear boundary with the surrounding tissue. The BDA-positive corticospinal tract entered into the right lateral funiculus of the spinal cord and descended into the posterior part of the right lateral funiculus, close to the posterior horn, from cervical to sacral segments. There was a small amount of green fluorescence in the sacral segment. The distribution of BDA labeling in the canine central nervous system was consistent with the course of the corticospinal tract. Fluorescence labeling for BDA gradually diminished with time after injection. Our findings indicate that the BDA anterograde tracing technique can be used to visualize the localization and trajectory of the corticospinal tract in the canine central nervous system. PMID- 25737706 TI - Telomerase expression in the glial scar of rats with spinal cord injury. AB - A rat model of spinal cord injury was established using the weight drop method. A cavity formed 14 days following spinal cord injury, and compact scar tissue formed by 56 days. Enzyme-linked immunosorbent assay and polymerase chain reaction enzyme-linked immunosorbent assay results demonstrated that glial fibrillary acidic protein and telomerase expression increased gradually after injury, peaked at 28 days, and then gradually decreased. Spearman rank correlation showed a positive correlation between glial fibrillary acidic protein expression and telomerase expression in the glial scar. These results suggest that telomerase promotes glial scar formation. PMID- 25737707 TI - A non-opioid pathway for dynorphin-caused spinal cord injury in rats. AB - Intrathecal injection of dynorphin into rats via subarachnoid catheter induces damage to spinal cord tissue and motor function. Injection of the kappa opioid receptor antagonist nor-binaltorphine, or the excitatory amino acid N-methyl-D aspartate receptor antagonist MK-801 into rats alleviated the pathological changes of dynorphin-caused spinal cord tissue injury and reduced the acid phosphatase activity in the spinal cord. The experimental findings indicate that there are opioid and non-opioid pathways for dynorphin-induced spinal cord injury, and that the non-opioid receptor pathway may be mediated by the excitatory amino acid N-methyl-D-aspartate receptor. PMID- 25737708 TI - Hippocampal expression of synaptic structural proteins and phosphorylated cAMP response element-binding protein in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. AB - The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries. At 60 days after modeling, escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group. In addition, the number of accurate crossings over the original platform significantly decreased, hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased, cAMP response element-binding protein expression remained unchanged, and phosphorylated cAMP response element-binding protein expression significantly decreased. Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion. PMID- 25737709 TI - Propofol effectively inhibits lithium-pilocarpine- induced status epilepticus in rats via downregulation of N-methyl-D-aspartate receptor 2B subunit expression. AB - Status epilepticus was induced via intraperitoneal injection of lithium pilocarpine. The inhibitory effects of propofol on status epilepticus in rats were judged based on observation of behavior, electroencephalography and 24-hour survival rate. Propofol (12.5-100 mg/kg) improved status epilepticus in a dose dependent manner, and significantly reduced the number of deaths within 24 hours of lithium-pilocarpine injection. Western blot results showed that, 24 hours after induction of status epilepticus, the levels of N-methyl-D-aspartate receptor 2A and 2B subunits were significantly increased in rat cerebral cortex and hippocampus. Propofol at 50 mg/kg significantly suppressed the increase in N methyl-D-aspartate receptor 2B subunit levels, but not the increase in N-methyl-D aspartate receptor 2A subunit levels. The results suggest that propofol can effectively inhibit status epilepticus induced by lithium-pilocarpine. This effect may be associated with downregulation of N-methyl-D-aspartate receptor 2B subunit expression after seizures. PMID- 25737710 TI - Ketamine inhibits c-Jun protein expression in mouse hippocampus following cerebral ischemia/reperfusion injury. AB - A model of cerebral ischemia and reperfusion was established in mice. Mice were treated with ketamine via intraperitoneal injection immediately following ischemia or ischemia/reperfusion. Ketamine did not remarkably change infarct volume in mice immediately following ischemia, but injection immediately following ischemia/reperfusion significantly decreased infarct volume. Ketamine injection immediately after ischemia or ischemia/reperfusion inhibited c-Jun protein expression in mouse hippocampus, but nuclear factor kappa B expression was unaltered. In addition, the Longa scale score for neural impairment was not reduced in mice following cerebral ischemia/reperfusion. These results indicate that ketamine can protect mice against cerebral ischemia and reperfusion injury by modulating c-Jun protein expression in mouse hippocampus. PMID- 25737711 TI - Propofol inhibits inflammation and lipid peroxidation following cerebral ischemia/reperfusion in rabbits. AB - The present study established a rabbit model of global cerebral ischemia using the 'six-vessel' method, which was reperfused after 30 minutes of ischemia. Rabbits received intravenous injection of propofol at 5 mg/kg prior to ischemia and 20 mg/kg per hour after ischemia until samples were prepared. Results revealed that propofol inhibited serum interleukin-8, endothelin-1 and malondialdehyde increases and promoted plasma superoxide dismutase activity after cerebral ischemia/reperfusion. In addition, cerebral cortex edema was attenuated with little neuronal nuclear degeneration and pyknosis with propofol treatment. The cross-sectional area of neuronal nuclei was, however, increased following propofol treatment. These findings suggested that propofol could improve anti oxidant activity and inhibit synthesis of inflammatory factors to exert a protective effect on cerebral ischemia/reperfusion injury. PMID- 25737712 TI - The role of microtubule-associated protein 1B in axonal growth and neuronal migration in the central nervous system. AB - In this review, we discuss the role of microtubule-associated protein 1B (MAP1B) and its phosphorylation in axonal development and regeneration in the central nervous system. MAP1B exhibits similar functions during axonal development and regeneration. MAP1B and phosphorylated MAP1B in neurons and axons maintain a dynamic balance between cytoskeletal components, and regulate the stability and interaction of microtubules and actin to promote axonal growth, neural connectivity and regeneration in the central nervous system. PMID- 25737713 TI - Does repair of spinal cord injury follow the evolutionary theory? AB - Lower vertebrates, such as fish and amphibians, and higher vertebrates in embryonic development can acquire complete regeneration of complex body structures, including the spinal cord, an important part of the central nervous system. However, with species evolution and development, this regenerative capacity gradually weakens and even disappears, but the cellular and molecular mechanisms remain poorly understood. We explored the differences in mechanisms of spinal cord regeneration capability between lower and higher vertebrates, investigated differences in their cellular and molecular mechanisms and between the spinal cord structures of lower vertebrates and mammals, such as rat and monkey, to search for theoretical evidence and therapeutic targets for nerve regeneration in human spinal cord. PMID- 25737714 TI - Effect of age on click-evoked otoacoustic emission: A systematic review. AB - OBJECTIVE: The aims of this study were to investigate the changes of the total intensity of transient evoked otoacoustic emission (TEOAE) and signal-to-noise ratio in various frequency bands as a function of aging, and to explore the role of age-related decline of cochlear outer hair cells. DATA SOURCES: The literature was searched using the PubMed database using 'transient-evoked otoacoustic emissions' as a keyword. Articles were limited as follows: Species was 'Humans'; languages were 'English and Chinese'; publication date between 1990-01-01 and 2010-12-31. The references of the found were also searched to obtain additional articles. DATA SELECTION: INCLUSION CRITERIA: (1) Articles should involve the total TEOAE level or signal-to-noise ratio. (2) The measurement and analysis system used was Otodynamics ILO analysis system (ILO88, ILO92, ILO96 or ILO292). (3) Studies involved groups of greater than 10 subjects and TEOAE results were from normally hearing ears. (4) If more papers from the same author or laboratory analyzed the same subjects, only one was used. MAIN OUTCOME MEASURES: The correlations of the age scale with the total level and signal-to-noise ratio of TEOAE was determined, respectively. RESULTS: (1) TEOAE total level gradually increased until 2 months of age, and then decreased with increasing age. Significant negative correlations between total TEOAE level and age were found (r = -0.885, P = 0.000). (2) The most rapid decrease of TEOAE amplitude occurred at 1 year old. The total TEOAE level decreased about 4.25 dB SPL between 2 months to 1 year old, then about 0.26-0.52 dB SPL from 1 year to 10 years old, about 0.23 dB SPL from 11 years to 25 years old, and about 0.14 dB SPL from 26 years to 60 years old. (3) The signal-to-noise ratio in the frequency bands centered at 1.5, 2, 3 and 4 kHz decreased with increasing age after 2 months of age. Significant negative correlations between the signal-to-noise ratio and age were found for frequency bands ranging from 1.5 kHz to 4 kHz, with the highest correlations at 4 kHz (r = -0.890, P < 0.01), then at 3 kHz (r = -0.889, P < 0.01), at 2 kHz (r = 0.850, P < 0.01) and at 1.5 kHz (r = -0.705, P < 0.05). Conversely, a positive correlation between the signal-to-noise ratio centered at 1 kHz and age was found, but was not statistically significant (r = 0.298, P = 0.374). CONCLUSION: The total TEOAE response level decreased with increasing age after the first 2 months of age. The signal-to-noise ratio also decreased with increasing age in frequency bands above 1.5 kHz. The signal-to-noise ratio in higher frequencies decreased faster than in lower frequencies, leading to the maximum signal-to noise ratio shift form 3.2-4.0 kHz in neonates to 1.5 kHz in adults, and further decreasing the total TEOAE response level. The age-related TEOAE spectrum peak shift is most likely because the outer hair cells functioning in higher frequencies are more prone to damage than those for lower frequencies. PMID- 25737715 TI - Effect of tumor necrosis factor inhibitors on rheumatoid arthritis-induced peripheral neuropathy: A cohort study. AB - In this historical cohort study, 236 patients with primary rheumatoid arthritis were treated with the tumor necrosis factor inhibitors, etanercept or infliximab (n = 80), or by conventional methods (n = 156). Results revealed that 11 patients developed varying types of peripheral neuropathy at 1-2 years post-treatment (mean 16 months). The incidence of peripheral neuropathy in the tumor necrosis factor inhibitors treatment group was 8.8% (7/80), which was significantly higher than the conventional treatment group (2.6%; 4/156). The relative risk of developing peripheral neuropathy in the tumor necrosis factor inhibitors treatment group was 3.41 (95% confidence interval: 1.03-11.31). Comparison of the tumor necrosis factor inhibitors revealed that etanercept and infliximab had no significant difference in terms of inducing peripheral neuropathy. Experimental findings indicate that tumor necrosis factor inhibitors may increase the risk of peripheral neuropathy. PMID- 25737716 TI - Remodeling of motor cortex function in acute cerebral infarction patients following human urinary kallidinogenase: A functional magnetic resonance imaging evaluation after 6 months. AB - A total of 29 patients were treated within 48 hours after acute subcortical cerebral infarction with Xuesaitong or Xuesaitong plus human urinary kallidinogenase for 14 days. Neurological deficits, activity of daily living, and evaluations of distal upper limb motor functions at the 6-month follow-up showed that patients treated with Xuesaitong plus human urinary kallidinogenase recovered better than with Xuesaitong alone. In addition, functional MRI revealed that activation sites were primarily at the ipsilesional side of injury in all patients. Human urinary kallidinogenase induced hyperactivation of the ipsilesional primary sensorimotor cortex, premotor cortex, supplementary motor area, and contralesional posterior parietal cortex. Results showed that human urinary kallidinogenase improved symptoms of neurological deficiency by enhancing remodeling of long-term cortical motor function in patients with acute cerebral infarction. PMID- 25737717 TI - Levels of soluble delta-like ligand 1 in the serum and cerebrospinal fluid of tuberculous meningitis patients. AB - In this study, the levels of soluble delta-like ligand 1 in cerebrospinal fluid and serum of 50 patients with tuberculous meningitis, 30 patients with viral meningitis, 20 patients with purulent meningitis and 40 subjects without central nervous system disease were determined using an enzyme-linked immunosorbent assay. The mean levels of soluble delta-like ligand 1 in both cerebrospinal fluid and serum from patients with tuberculous meningitis were significantly higher compared with those from patients with viral meningitis or purulent meningitis or from subjects without central nervous system disease. Meanwhile, the level of soluble delta-like ligand 1 gradually decreased as tuberculous meningitis patients recovered. If patients deteriorated after treatment, the level of soluble delta-like ligand 1 in cerebrospinal fluid gradually increased. There was no correlation between the level of soluble delta-like ligand 1 and the protein level/cell number in cerebrospinal fluid. Our findings indicate that the levels of soluble delta-like ligand 1 in cerebrospinal fluid and serum are reliable markers for the diagnosis of tuberculous meningitis and for monitoring treatment progress. At the same time, this index is not influenced by protein levels or cell numbers in cerebrospinal fluid. PMID- 25737718 TI - Association between Virulence Factors and TRAF1/4-1BB/Bcl-xL Expression in Gastric Mucosa Infected with Helicobacter pylori. AB - Objective. CagA+/vacAs1+/vacAm1+ Helicobacter pylori upregulates the expression of tumor necrosis factor receptor-associated factor 1 (TRAF1), tumor necrosis factor receptor superfamily member 9 (4-1BB), and B-cell lymphoma-extra large (Bcl-xL) in human gastric epithelial cells. We investigated the correlation between cagA/vacAs1/vacAm1 and TRAF1/4-1BB/Bcl-xL expression in gastric mucosal tissue of patients with gastric disorders. Methods. We collected gastric mucosa samples from 35 chronic, nonatrophic gastritis (CG) patients, 41 atrophic gastritis patients, 44 intestinal metaplasia with atypical hyperplasia (IM) patients, and 28 gastric carcinoma (Ca) patients. The expression of TRAF1, 4 1BB, and Bcl-xL was determined using western blotting. The expression of cagA, vacAs1, and vacAm1 in H. pylori was examined with polymerase chain reaction. Results. The expression of TRAF1, 4-1BB, and Bcl-xL was significantly upregulated in IM and Ca patients (P < 0.05 compared with CG). There were more cases of cagA+/vacAs1+/vacAm1+ H. pylori infection in samples with elevated TRAF1, 4-1BB, or Bcl-xL expression (P < 0.05). Additionally, there were a remarkably large number of samples with upregulated TRAF1/4-1BB/Bcl-xL expression in cases of cagA+/vacAs1+/vacAm1+ H. pylori infection (44 cases, 67.7%; P < 0.05). Conclusions. The pathogenesis of IM and Ca may be promoted by cagA+/vacAs1+/vacAm1+ H. pylori, possibly via upregulated TRAF1, 4-1BB, and Bcl xL in gastric mucosal tissue. PMID- 25737719 TI - Altered chemokine signalling in endothelial progenitor cells from acute ulcerative colitis patients. AB - Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory bowel disease, characterized by alternating stages of clinically active and inactive disease. UC exhibits several inflammatory characteristics, including immune activation, leukocyte infiltration, and altered vascular density. In UC, many of the upregulated inflammatory cytokines are proangiogenic and are released by diverse cell populations, such as infiltrating immune cells and endothelial cells (EC). Increasing evidences suggest that neovascularisation may involve also endothelial progenitor cells (EPCs). In this study we evaluated EPCs recruitment and homing, assessed by CXCR4 expression, in both acute and remitting phase of UC. We report an overall decrease of EPCs in UC patients (controls = 97,94 +/- 37,34 cells/mL; acute = 31,10 +/- 25,38 cells/mL; remitting = 30,33 +/- 19,02 cells/mL; P < 0.001 for both UC groups versus controls). Moreover CXCR4(+)-EPCs, committed to home in inflammatory conditions, were found to be reduced in acute UC patients compared to both remitting patients and controls (acute = 3,13 +/- 4,61 cells/mL; controls = 20,12 +/- 14,0; remitting = 19,47 +/- 12,83; P < 0,001). Interestingly, we found that administration of anti-inflammatory drugs in acute UC is associated with an increase in circulating EPCs, suggesting that this therapy may exert a strong influence on the progenitor cells response to inflammatory processes. PMID- 25737720 TI - Semantic annotation for biological information retrieval system. AB - Online literatures are increasing in a tremendous rate. Biological domain is one of the fast growing domains. Biological researchers face a problem finding what they are searching for effectively and efficiently. The aim of this research is to find documents that contain any combination of biological process and/or molecular function and/or cellular component. This research proposes a framework that helps researchers to retrieve meaningful documents related to their asserted terms based on gene ontology (GO). The system utilizes GO by semantically decomposing it into three subontologies (cellular component, biological process, and molecular function). Researcher has the flexibility to choose searching terms from any combination of the three subontologies. Document annotation is taking a place in this research to create an index of biological terms in documents to speed the searching process. Query expansion is used to infer semantically related terms to asserted terms. It increases the search meaningful results using the term synonyms and term relationships. The system uses a ranking method to order the retrieved documents based on the ranking weights. The proposed system achieves researchers' needs to find documents that fit the asserted terms semantically. PMID- 25737721 TI - Treatment of prolactinomas in low-income countries. AB - Purpose. In low-income countries, prolactinomas are difficult to manage with dopamine agonists (DA). We compared the effectiveness of DA in microprolactinomas as a first line treatment and as adjuvant therapy for residual macroprolactinomas treated surgically. Methods. Our retrospective study analyzed 78 patients, 38 with microprolactinomas and 40 with macroprolactinomas. Microprolactinomas were treated with DA. Macroprolactinomas were treated with microsurgical or endoscopic adenomectomies and adjuvant DA. Surgical remission was defined as normoprolactinemia three months postoperatively, and long-term remission as normoprolactinemia at the last control. Results. Surgical remission was achieved in 9 patients (23%). Postsurgical tumor mass was reduced by 50% (34-68). Residual macroprolactinoma size was greater than microprolactinoma size prior to treatment (10 mm versus 4 mm, P < 0.001). Both groups received similar doses of DA. Long term remission occurred in 68% of microprolactinomas and 43% of macroprolactinomas (P = 0.102). Prolactin (PRL) levels at the last control were similar in both groups (23.1 versus 32.9 mcg/L, P = 0.347). Conclusion. Comparable remission rates and PRL levels were reached in microprolactinomas and macroprolactinomas using similar doses of DA. Although complete tumor resection is the goal of surgery, our study suggests that even partial surgical removal has a role in treatment of prolactinomas since it may enhance the response to DA. PMID- 25737722 TI - Clinical characteristics and treatment outcome of 485 patients with nonfunctioning pituitary macroadenomas. AB - Background. Nonfunctioning pituitary adenomas (NFPAs) are the most common benign lesions of the pituitary gland. Objective. To describe our experience with the management of NFPA. Study Design and Methods. Retrospective evaluation of NFPA patients managed between 2008 and 2013. We analyzed data regarding clinical presentation, imaging diagnosis, hormonal status, surgical, radiotherapeutic, and pharmacological treatment, and outcome. Results. 485 patients (54% men, mean age 53 +/- 14 years) were followed for a median of 6.5 years. Visual field abnormalities and headaches were the presenting complaints in 87% and 66%, respectively. The diagnosis of NFPA was made incidentally in 6.2%, and 8% presented with clinical evidence of apoplexy. All patients harbored macroadenomas, with a median volume of 10306 mm(3); 57.9% had supra- or parasellar invasion and 19.6% had tumors larger than 4 cm. Central hypothyroidism, hypogonadism, and hypocortisolism were present in 47.2%, 35.9%, and 27.4%, respectively. Surgical resection was performed at least once in 85.7%. Tumor persistence was documented in 27% and was related to the size and invasiveness of the lesion. In selected cases, radiotherapy proved to be effective in controlling or preventing tumor growth. Conclusions. The diagnosis and treatment of NFPA are complex and require a multidisciplinary approach. PMID- 25737723 TI - Morphological study of palatal rugae in a Sudanese population. AB - Palatal rugae patterns have unique characteristics and have been proposed as an alternative method to establish identity when other means, such as fingerprints and dental records, are not attainable. This study was conducted to determine the morphological characteristics of palatine rugae and to assess the existence of side asymmetry in them in Sudanese Arabs. It also assesses the possibility of determining sex using logistic regression. One hundred dental casts for 50 males and 50 females aged between 18 and 23 were studied for palatal rugae dimensions, shapes, and orientations, as well as sexual dimorphism and side symmetry. The most predominant rugae were primary, and the most prevalent shapes in both sexes were wavy, curved, and straight forms. The predominant orientation was forward. Side asymmetry existed more in the orientations than in the shapes, but no side asymmetry was recorded in the dimensions. There was no significant sexual dimorphism in the rugae dimensions, shapes, and orientations, except for forward directed rugae (P < 0.037). A predictive value of 60% was obtained in assigning sex using dimensions and orientations and of 58% using shapes alone. Therefore, the palatal rugae are not recommended for assigning sex effectively among Sudanese Arabs unless it is the only means available. PMID- 25737724 TI - A new technique for quantitative determination of dexamethasone in pharmaceutical and biological samples using kinetic spectrophotometric method. AB - Dexamethasone is a type of steroidal medications that is prescribed in many cases. In this study, a new reaction system using kinetic spectrophotometric method for quantitative determination of dexamethasone is proposed. The method is based on the catalytic effect of dexamethasone on the oxidation of Orange G by bromate in acidic media. The change in absorbance as a criterion of the oxidation reaction progress was followed spectrophotometrically. To obtain the maximum sensitivity, the effective reaction variables were optimized. Under optimized experimental conditions, calibration graph was linear over the range 0.2-54.0 mg L(-1). The calculated detection limit (3s b/m) was 0.14 mg L(-1) for six replicate determinations of blank signal. The interfering effect of various species was also investigated. The present method was successfully applied for the determination of dexamethasone in pharmaceutical and biological samples satisfactorily. PMID- 25737725 TI - Histopathological, histomorphometrical, and radiographical evaluation of injectable glass-ceramic-chitosan nanocomposite in bone reconstruction of rat. AB - Background. Bone defects following tumor resection and osteolysis due to bone lesions, periodontal tissue disorders, and bone reconstruction are challenges that surgeons face. Gass-ceramic-chitosan nanocomposite contains chitosan, a derivative of crustaceans' exoskeleton. Methods. Thirty-two 6-8-week-old male Wistar rats were chosen. One hole on each right and left tibia was made. The right tibia holes were filled with injectable glass-ceramic-chitosan nanocomposite, and the left tibia holes were left empty. After 7, 14, 28, and 60 days, histopathological, histomorphometrical, and radiographical assessments were performed. Results. Radiographic density on days 7 and 14 was significantly higher in the right tibias than in the left tibias. Trabecular bone thickness, which was higher in the right tibias, increased from day 7 to day 60 in both right and left tibias, although not significantly. Conclusions. Glass-ceramic chitosan nanocomposite is suggested for use in bone repair in cases of bone loss. More histopathological, histomorphometrical, and radiographical assessments are also recommended. PMID- 25737726 TI - Asymptomatic atherosclerosis in egyptian rheumatoid arthritis patients and its relation to disease activity. AB - Aim. To detect the frequency of subclinical atherosclerosis in rheumatoid arthritis patients without clinically evident atherosclerosis and to correlate its presence with the disease activity. Patients and Methods. Our study includes 112 RA patients (group 1) and 40 healthy controls (group 11). All patients and controls were subjected to full history taking, clinical examination, and laboratory investigations. Carotid intima media wall thickness (IMT) and carotid plaques were measured in both groups by B-mode ultrasonography; also color duplex Doppler ultrasound of the brachial artery was done to detect endothelial function. Results. There is atherosclerosis in 31.3% of asymptomatic RA patients compared with only 5% in controls (P = 0.003(**)). A significant difference was detected in patients with and without atherosclerosis regarding duration of the disease (P = 0.0001(***)) and patient's age (P = 0.01(*)). There is highly statistical significant correlation between atherosclerosis and disease activity index. Conclusion. The frequency of subclinical atherosclerosis was high in long term active RA patients. PMID- 25737727 TI - Opinion toward living liver donation of hospital personnel from units related to organ donation and transplantation: a multicenter study from Spain and latin america. AB - BACKGROUND: Hospital personnel of services related to donation and transplantation process play a fundamental role in the development of transplantation. OBJECTIVES: The aim of this study was to investigate the attitude toward living liver donation (LLD) among hospital personnel from services related to donation and transplantation in hospital centers in Spain and Latin America. MATERIALS AND METHODS: Eight hospitals within the "International Donor Collaborative Project" were selected, three in Spain, three in Mexico and two in Cuba. The study was performed in transplant-related services, using a randomized sample, which was stratified by the type of service and job category. RESULTS: In total, 878 workers were surveyed of which 82% (n = 720) were in favor of related LLD, 10% (n = 90) were against and 8% (n = 68) undecided. Attitudes toward related LLD were more favorable in the following groups: the Latin Americans (86% in favor vs. 77% among the Spanish; P = 0.007); younger people (37 vs. 40 years, P = 0.002); those in favor of either deceased donation (P < 0.001) or living kidney donation (P < 0.001); those who believed that they might need a transplant in the future (P < 0.001); those who would accept a liver from a living donor (P < 0.001); those who discussed the subject of donation and transplantation with their families (P = 0.040); and those whose partner was in favor of donation and transplantation (P = 0.044). CONCLUSIONS: Personnel from donation and transplantation-related units had a favorable attitude toward LLD. This attitude was not affected by psychosocial factors, although it was influenced by factors directly and indirectly related to the donation and transplantation process. PMID- 25737728 TI - S gene mutants occurrence among hepatitis B carriers in malaysia. AB - BACKGROUND: The S gene region of the hepatitis B virus (HBV) codes for surface antigen (HBs Ag) and is responsible for classification of HBV strains. OBJECTIVES: The current study aimed to identify important mutations in the S gene in Hepatitis B virus (HBV) isolated from Malaysian HBV carriers. MATERIALS AND METHODS: Isolated HBV DNAs were subjected for PCR amplification and sequencing of HBV full genome. RESULTS: A total of 76 HBV full genome and 17 partial genome sequences were obtained from the 93 sequenced sera samples Genotyping of the full genome sequences by HEPSEQ software revealed a distribution of 49.46%, 48.39% and 2.15% of genotypes C, B, and D, respectively; whereas phylogenetic and jumping profile Hidden Markov Model (jpHMM) analysis identified six (7.89%) recombinant B/C strains. The distribution of sub-genotypes were B2 (78.79%) and B3 (21.21%) for genotype B, sub genotype D2 (100%) for genotype D and sub genotype C1 (75.76%), C2 (15.15%), C3 (6.06%) and C5 (3.13%) for genotype C. Mutation analysis in the S gene demonstrated two significant mutations which were W182 stop codon and deletion at open reading frame (ORF) of pre-S1 with the frequency occurrence of 2.2% (2/93) and 5.4% (5/93), respectively. The two patients with W182 stop codon were both male, infected with HBV genotype C and one showed progression of liver disease to hepatocellular carcinoma (HCC). CONCLUSIONS: Association with sex, genotype and clinical symptoms revealed that the pre-S1 ORF deletion occurred in 40% , 40%,and 20% of genotypes B,C, and D respectively, and 80% of the female population, of which all but one were diagnosed with chronic hepatitis B. Additionally, several mutations were found in the BCP region with the following incidence rate; C1653 T (8.6%), A1752 G (10.8%),1762 AGG--TGA 1764 (26.9%), C1766T(2.2%),T1768 A (10.8%), C1858 T (64.5%), G1896 A (25.8%). PMID- 25737729 TI - Association of Periodontal Diseases and Liver Fibrosis in Patients With HCV and/or HBV infection. AB - BACKGROUND: Periodontal disease and systemic health are closely associated. However, there is no data supporting the association between periodontal disease and patients with liver diseases associated with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) infection. OBJECTIVES: The aim of this study was to evaluate the association between periodontitis and progression of liver diseases in patients with HCV and/or HBV infection. PATIENTS AND METHODS: In this retrospective study, 351 patients with HCV- and/or HBV-related liver diseases underwent screening for periodontal disease using the Salivaster(r) salivary occult blood test from February 2010 to June 2014. Furthermore, we examined the prevalence of fimbrillin (fimA) genotype of Porphyromonas gingivalis (P. gingivalis) in 28 HCV-infected patients visited at our hospital between January 2013 and June 2014. P. gingivalis with fimA genotype with types I to V was further detected using a PCR method. RESULTS: Of 351 patients, 76 patients (group 1) had a strong positive result for salivary occult blood test and 275 patients (group 2) had weak positive or negative test results. Significant factors between the groups were obesity, level of AST, ALT, LDH, ALP, Alb, D.Bil, T.cho, AFP, platelets (Plt), IRI, HOMA-IR, current interferon (IFN) treatment and the daily frequency of tooth brushing. Between-groups analysis indicated that total protein (T.pro) level and liver fibrosis were significant factors. According to multivariate analysis, five factors were associated with periodontal disease as Plt count below 80000, brushing teeth only once a day, current IFN treatment, aged 65 years or older and obesity. The adjusted odds ratios for these five factors were 5.80, 3.46, 2.87, 2.50 and 2.33, respectively, and each was statistically significant. Twenty-eight saliva specimens had positive results for P. gingivalis with fimA genotype types I to V. The prevalence of fimA genotype II was higher in 14 patients with liver cirrhosis or a history of hepatocellular carcinoma treatment (group B, 50.00%) than 14 patients with only hepatitis C (group A, 21.43%). CONCLUSIONS: Periodontitis might be associated with progression of viral liver disease; hence, controlling oral disease is essential for the prevention and management of liver fibrosis. PMID- 25737730 TI - The role of interleukin-6 and interleukin-8 gene polymorphisms in non-alcoholic steatohepatitis. AB - BACKGROUND: Genetic polymorphisms may play role in the pathophysiology of nonalcoholic steatohepatitis (NASH). OBJECTIVES: We purposed to assess the role of interleukin 6 (IL 6) and interleukin 8 (IL 8) gene polymorphisms in the pathogenesis of NASH. PATIENTS AND METHODS: Consecutive patients with biopsy proven NASH and age- and gender-matched healthy individuals with normal liver function tests and normal ultrasonography were enrolled in the study. Histopathological findings were recorded according to nonalcoholic fatty liver disease activity score (NAS). Patients were classified according to fibrosis scores as fibrosis score < 2 (mild fibrosis group) and fibrosis score >= 2 (significant fibrosis group). Blood samples were collected and genomic DNA isolation kit was used to evaluate genetic polymorphisms. RESULTS: Of thirty eight patients, 27 (71%) were in mild fibrosis group and 11 (29%) in significant fibrosis group. Thirty-eight age- and gender-matched healthy controls were enrolled in the study. The frequencies of genotypes G/C and G/G of IL 6 among the NASH group and healthy controls were 39.5% and 60.5% vs. 53.6% and 46.4%, respectively (P = 0.32). The frequencies of the genotypes of IL 8 among the NASH group were 47.2%, 44.6%, and 8.2% for T/T, A/T, and A/A, and in healthy controls were 50%, 28.6% and 21.4%, respectively, (P = 0.568). The differences between IL 8 gene T/A and T/T genotypes were not significant statistically (P > 0.05). However, the frequency of A/A genotype in significant fibrosis group was higher than the mild fibrosis group (P = 0.0016). The differences of -251 A/T polymorphism in the IL 8 and -174 C/G polymorphism in the IL 6 were not statistically significant between fibrosis groups (P > 0.05). CONCLUSIONS: IL6 and IL8 gene polymorphisms have no role in NASH pathogenesis and liver fibrosis process, but presence of the A/A genotype in the IL8 gene is associated with disease progression. PMID- 25737731 TI - Management of liver hemangioma using trans-catheter arterial embolization. AB - BACKGROUND: Hemangioma, a congenital vascular malformation, is the most common benign liver lesion that is usually remain stable subsequently requiring not treatment; however, complications such as abdominal pain or fullness, coagulation disturbances, and inflammatory syndrome may occur, demanding a specific treatment of hemangioma. OBJECTIVES: To assess the safety, feasibility and efficacy of trans-catheter arterial embolization (TAE) for the treatment of Liver hemangioma. PATIENTS AND METHODS: TAE was performed on 20 patients with liver hemangioma. The embolic agent used was polyvinyl alcohol (PVA) particles (300-400 micron, Jonson and Johnson Cordis, USA). All patients were followed up for 6 months. Imaging was carried out and patients were also evaluated symptomatically through telephone interview by a physician. RESULTS: Twenty patients aged from 21 to 63 years (mean: 46.8, SD: 10.26) were included in this study. Post embolization syndrome, including abdominal pain, fever, and leukocytosis occurred in one patient 1 week after TAE and lasted for 3 days. No serious adverse event and TAE-related death was observed. None of the patient underwent another intervention including surgery. During follow up interval, decreased episode of abdominal pain was documented in all patients who had pain. Tumor enlargement was also stopped during the follow up. The average diameter of tumors was 97.00 mm (range: 25-200 SD: 47.85) and 88.95 mm (range: 23-195 SD: 43.27) before and after embolization, respectively. Comparison of images before and after TAE revealed statistically significant decrease in the size of lesion (P value: 0.004, t: 3.31). CONCLUSIONS: Our findings indicate that TAE is a safe and efficient procedure for the treatment of liver hemangioma. Further studies with larger sample sizes are required to support therapeutic effects of TAE. PMID- 25737732 TI - Transcatheter arterial chemoembolization therapy for patients with unresectable hepatocellular carcinoma. AB - BACKGROUND: Although transcatheter arterial chemoembolization (TACE) has been widely used as a palliative treatment for unresectable hepatocellular carcinoma (HCC), its actual efficacy and prognostic usefulness have not been clarified in past studies. OBJECTIVES: The aim of the study is to investigate the efficacy, complications, and prognostic factors of the TACE in unresectable HCC patients. PATIENTS AND METHODS: Thirty-two patients with unresectable HCC were treated with TACE. The procedure was performed with a combination of Lipiodol, doxorubicin, and cytomycin followed by gelatin-sponge particles embolization. CT-scan imaging and liver function tests (AST, ALT, ALP, BIL, and PT) were performed before and after the TACE. All patients were followed-up for 6-months. RESULTS: Of all patients, 1 and 11 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, CR+PR, 44%). Data have shown that tumor size, number of lesions and number of involved segments are significantly reduced after the TACE performance (P < 0.05). No significant clinical adverse effect was observed in patients after the intervention. Also, liver function tests including AST, ALT, ALP, BIL, and PT did not significantly differ before and after the intervention (P > 0.05). The 6-month cumulative survival rates of the 32 patients were 78.1 %, respectively. Univariate analysis showed that survival correlated significantly with the following factors: tumor size; >= 8 cm versus < 8 cm (P < 0.010), serum ALP level; < 300 versus >= 300 (P < 0.043), and number of liver involved segments; < 2 versus >= 2 (P < 0.020). CONCLUSIONS: We showed that in treatment of patients with unresectable hepatocellular carcinoma, TACE significantly improved the disease and the overall survival rate. Also, we introduce the tumor size, serum ALP level, and number of liver involved segments as prognostic factors of the procedure. Finally, TACE can be recommended as the initial treatment for unresectable HCC patients. PMID- 25737733 TI - Oral conditions might cause severe outcomes in patients with viral hepatitis infection. PMID- 25737734 TI - Flavonoid 4'-O-Methylkuwanon E from Morus alba Induces the Differentiation of THP 1 Human Leukemia Cells. AB - Aims. In this work we studied cytodifferentiation effects of newly characterized prenyl flavonoid 4'-O-methylkuwanon E (4ME) isolated from white mulberry (Morus alba L.). Main Methods. Cell growth and viability were measured by dye exclusion assay; cell cycle and surface antigen CD11b were monitored by flow cytometry. For the cytodifferentiation of cells the NBT reduction assay was employed. Regulatory proteins were assessed by western blotting. Key Findings. 4ME induced dose dependent growth inhibition of THP-1 cells, which was not accompanied by toxic effect. Inhibition of cells proliferation caused by 4ME was associated with the accumulation in G1 phase and with downregulation of hyperphosphorylated pRb. Treatment with 4ME led to significant induction of NBT-reducing activity of PMA stimulated THP-1 cells and upregulation expression of differentiation-associated surface antigen CD11b. Our results suggest that monocytic differentiation induced by 4ME is connected with up-regulation of p38 kinase activity. Significance. Our study provides the first evidence that 4ME induces the differentiation of THP-1 human monocytic leukemia cells and thus is a potential cytodifferentiating anticancer agent. PMID- 25737735 TI - Antiosteoporosis Activity of New Oriental Medicine Preparation (Kyungokgo Mixed with Water Extract of Hovenia dulcis) on the Ovariectomized Mice. AB - Protective effect of new oriental medicine (Kyungokgo mixed with water extract of Hovenia dulcis, KOGHD) was assessed on the bone loss induced mice by ovariectomy. In the in vivo experiments, antiosteoporosis effect of KOGHD was investigated using ovariectomized osteoporosis mice model. After 6 weeks of treatment, the mice were euthanized, and the effect of Kyungokgo (KOG) and KOGHD on body weight, spleen weigh, thymus weight, uterine weight, serum biochemical indicators, bone weight and length, immune cell population, bone morphometric parameters, and histological stains was observed. Our results showed that KOGHD prevented the deterioration of trabecular microarchitecture caused by ovariectomy, which were accompanied by the lower levels of bone turnover markers and immune cell population as evidenced by the inhibition of RANKL-mediated osteoclast differentiation without cytotoxic effect on bone marrow derived macrophages (BMMs). Therefore, these results suggest that the Hovenia dulcis (HD) supplementation in the KOG may also prevent and treat bone loss. PMID- 25737736 TI - Pharmacological properties of protocatechuic Acid and its potential roles as complementary medicine. AB - This paper reviews the reported pharmacological properties of protocatechuic acid (PCA, 3,4-dihydroxy benzoic acid), a type of phenolic acid found in many food plants such as olives and white grapes. PCA is a major metabolite of anthocyanin. The pharmacological actions of PCA have been shown to include strong in vitro and in vivo antioxidant activity. In in vivo experiments using rats and mice, PCA has been shown to exert anti-inflammatory as well as antihyperglycemic and antiapoptotic activities. Furthermore, PCA has been shown to inhibit chemical carcinogenesis and exert proapoptotic and antiproliferative effects in different cancerous tissues. Moreover, in vitro studies have shown PCA to have antimicrobial activities and also to exert synergistic interaction with some antibiotics against resistant pathogens. This review aims to comprehensively summarize the pharmacological properties of PCA reported to date with an emphasis on its biological properties and mechanisms of action which could be therapeutically useful in a clinical setting. PMID- 25737737 TI - Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression. AB - Shikonin, a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, has been reported to suppress growth of various cancer cells. This study was aimed to investigate whether this chemical could also inhibit cell growth of lung cancer cells and, if so, works via what molecular mechanism. To fulfill this, A549 lung cancer cells were treated with shikonin and then subjected to microscopic, biochemical, flow cytometric, and molecular analyses. Compared with the controls, shikonin significantly induced cell apoptosis and reduced proliferation in a dose-dependent manner. Specially, lower concentrations of shikonin (1-2.5 MUg/mL) cause viability reduction; apoptosis and cellular senescence induction is associated with upregulated expressions of cell cycle- and apoptotic signaling-regulatory proteins, while higher concentrations (5-10 MUg/mL) precipitate both apoptosis and necrosis. Treatment of cells with pifithrin-alpha, a specific inhibitor of p53, suppressed shikonin-induced apoptosis and premature senescence, suggesting the role of p53 in mediating the actions of shikonin on regulation of lung cancer cell proliferation. These results indicate the potential and dose-related cytotoxic actions of shikonin on A549 lung cancer cells via p53-mediated cell fate pathways and raise shikonin a promising adjuvant chemotherapeutic agent for treatment of lung cancer in clinical practice. PMID- 25737738 TI - Pulmonary alveolar proteinosis induced by hydrofluoric acid exposure during fire extinguisher testing. AB - INTRODUCTION: Automatic fire suppression systems use hydrofluorocarbons (HF) to extinguish fires chemically. At high temperatures, HF can release hydrofluoric acid (HFA), a toxic, potentially lethal gas. CASE REPORT: A 52-year-old male visited our Pulmonary Division with dyspnea of 8-months duration. He had been working at a facility that manufactured fire extinguishers. Bronchoscopy was performed and a transbronchial lung biopsy was taken from the right lower lobe. After the patient was diagnosed with pulmonary alveolar proteinosis (PAP), whole lung lavage was performed. In this case, fire extinguisher gas induced pulmonary alveolar proteinosis. This material should be used with care and investigated further. DISCUSSION: HFA is corrosive and penetrates organic materials, including body tissues. Depending on the mode of exposure, skin ulceration, pulmonary injury, or even systemic shock can result. This report describes PAP that developed after chronic, repeated exposure to fire extinguisher spray. Hydrofluoric acid can induce pulmonary disorders such as PAP. PMID- 25737739 TI - A spatial shape constrained clustering method for mammographic mass segmentation. AB - A novel clustering method is proposed for mammographic mass segmentation on extracted regions of interest (ROIs) by using deterministic annealing incorporating circular shape function (DACF). The objective function reported in this study uses both intensity and spatial shape information, and the dominant dissimilarity measure is controlled by two weighting parameters. As a result, pixels having similar intensity information but located in different regions can be differentiated. Experimental results shows that, by using DACF, the mass segmentation results in digitized mammograms are improved with optimal mass boundaries, less number of noisy patches, and computational efficiency. An average probability of segmentation error of 7.18% for well-defined masses (or 8.06% for ill-defined masses) was obtained by using DACF on MiniMIAS database, with 5.86% (or 5.55%) and 6.14% (or 5.27%) improvements as compared to the standard DA and fuzzy c-means methods. PMID- 25737741 TI - Development of self-image and its components during a one-year follow-up in non referred adolescents with excess and normal weight. AB - BACKGROUND: The proportion of overweight and obese youths is high. The present study aimed to investigate the development of self-image and its components during a one-year follow-up among non-referred adolescents with excess and normal weight. Furthermore, we separately analyzed the data for girls and boys. METHODS: Altogether 86 8(th) grades (41 girls and 45 boys) with a relative weight of 26% or more above the median and 91 controls (43 girls and 48 boys) with normal weight participated the follow-up. The Offer Self-Image Questionnaire, Revised (OSIQ-R) was used to assess self-image at baseline and on follow-up. In the OSIQ R, a low total raw score implies positive adjustment, while a high raw score implies poor adjustment and a negative self-image. The study design was doubly correlated (pairs and time), and a linear mixed model was used in the statistical analysis. RESULTS: In OSIQ-R total scores, a comparative improvement was observed in girls with normal weight. Among these girls, significant change scores compared to zero were seen in impulse control, social functioning, vocational attitudes, self-confidence, self-reliance, body image, sexuality, and ethical values. In girls with excess weight, none of the change scores compared to zero were statistically significant. When the girls with normal and excess weight were compared, the difference in change scores was largest in sexuality and vocational attitudes. Change scores compared to zero were significant in sexuality and idealism for boys with excess weight, and in impulse control, mental health, self reliance, and sexuality for normal weight boys. When the boys with excess and normal weight were compared, no statistically significant differences emerged in change scores. CONCLUSION: In mid-adolescent girls, the influence of overweight and obesity on the development of self-image is substantial. Weight management programs directed at overweight adolescent girls should include psychological interventions aiming to diminish self-image distress, especially that associated with feelings, attitudes, and behavior towards the opposite sex, as well as future career plans. PMID- 25737740 TI - Genotypic distribution of human papillomavirus (HPV) and cervical cytology findings in 5906 Thai women undergoing cervical cancer screening programs. AB - BACKGROUND: Cervical cancer is the major cause of morbidity and mortality in Thai women. Nevertheless, the preventive strategy such as HPV vaccination program has not been implemented at the national level. This study explored the HPV prevalence and genotypic distribution in a large cohort of Thai women. METHODS: A hospital-based cervical cancer screening program at Chulabhorn Hospital, Bangkok and a population-based screening program at a rural Pathum Thani Province were conducted using liquid-based cytology and HPV genotyping. RESULTS: Of 5906 women aged 20-70 years, Pap smear was abnormal in 4.9% and the overall HPV prevalence was 15.1%, with 6.4% high-risk (HR), 3.5% probable high-risk (PR), and 8.4% low risk (LR) HPV. The prevalence and genotypic distribution were not significantly different between the two cohorts. Among HR-HPV genotypes, HPV52 was the most frequent (1.6%), followed by HPV16 (1.4%), HPV51 (0.9%), HPV58 (0.8%), HPV18 (0.6%), and HPV39 (0.6%). Among LR-HPV genotypes, HPV72 and HPV62 were the most frequent while HPV6 and HPV11 were rare. HPV infection was found to be proportionately high in young women, aged 20-30 years (25%) and decreasing with age (11% in women aged >50). The more severe abnormal cytology results, the higher positivity of HR-HPV infection was observed. CONCLUSIONS: In conclusion, HPV52, HPV16, and HPV51 were identified as the most common HR-HPV genotypes in Thai women. This study contributes genotypic evidence that should be essential for the development of appropriate HPV vaccination program as part of Thailand's cervical cancer prevention strategies. PMID- 25737743 TI - Cost-effectiveness of steroid (methylprednisolone) injections versus anaesthetic alone for the treatment of Morton's neuroma: economic evaluation alongside a randomised controlled trial (MortISE trial). AB - BACKGROUND: Morton's neuroma is a common foot condition affecting health-related quality of life. Though its management frequently includes steroid injections, evidence of cost-effectiveness is sparse. So, we aimed to evaluate whether steroid injection is cost-effective in treating Morton's neuroma compared with anaesthetic injection alone. METHODS: We undertook incremental cost-effectiveness and cost-utility analyses from the perspective of the National Health Service, alongside a patient-blinded pragmatic randomised trial in hospital-based orthopaedic outpatient clinics in Edinburgh, UK. Of the original randomised sample of 131 participants with Morton's neuroma (including 67 controls), economic analysis focused on 109 (including 55 controls). Both groups received injections guided by ultrasound. We estimated the incremental cost per point improvement in the area under the curve of the Foot Health Thermometer (FHT-AUC) until three months after injection. We also conducted cost-utility analyses using European Quality of life-5 Dimensions-3 Levels (EQ-5D-3L), enhanced by the Foot Health Thermometer (FHT), to estimate utility and thus quality-adjusted life years (QALYs). RESULTS: The unit cost of an ultrasound-guided steroid injection was L149. Over the three months of follow-up, the mean cost of National Health Service resources was L280 for intervention participants and L202 for control participants - a difference of L79 [bootstrapped 95% confidence interval (CI): L18 to L152]. The corresponding estimated incremental cost-effectiveness ratio was L32 per point improvement in the FHT-AUC (bootstrapped 95% CI: L7 to L100). If decision makers value improvement of one point at L100 (the upper limit of this CI), there is 97.5% probability that steroid injection is cost-effective. As EQ-5D-3L seems unresponsive to changes in foot health, we based secondary cost utility analysis on the FHT-enhanced EQ-5D. This estimated the corresponding incremental cost-effectiveness ratio as L6,400 per QALY. Over the recommended UK threshold, ranging from L20,000 to L30,000 per QALY, there is 80%-85% probability that steroid injection is cost-effective. CONCLUSIONS: Steroid injections are effective and cost-effective in relieving foot pain measured by the FHT for three months. However, cost-utility analysis was initially inconclusive because the EQ 5D-3L is less responsive than the FHT to changes in foot health. By using the FHT to enhance the EQ-5D, we inferred that injections yield good value in cost per QALY. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13668166. PMID- 25737742 TI - Long-term follow-up of females with unbalanced X;Y translocations-reproductive and nonreproductive consequences. AB - BACKGROUND: Females with Xp;Yq translocations manifest short stature and normal fertility, but rarely have follow-up. The study purpose was to define the phenotype of a family with t(X;Y)(p22.3;q11.2), determine long-term reproductive function, and compare to all reported female cases. METHODS: Comprehensive clinical and molecular analyses were performed on the female proband, who had regular menses, normal endocrine function, and three pregnancies spanning seven years--a normal liveborn male and two with unbalanced translocations (liveborn female and stillborn male). RESULTS: The translocation truncated KAL1 and deleted 44 genes on der(X). Our report constitutes the longest follow-up of an X;Y translocation female. She had no evidence of Kallmann syndrome, gonadoblastoma, or cardiovascular disease. Detailed analysis of 50 published female cases indicated a uniform lack of follow-up and significant morbidity-intellectual disability (10%), facial dysmorphism (28%), eye abnormalities (14%), and skeletal defects (28%). CONCLUSIONS: Our findings indicate normal ovarian function to date in a woman with an t(X;Y)(p22.3;q11.2). However, additional published studies in the literature suggest careful follow-up is necessary and contradict the generalization that females with Xp;Yq translocations are usually normal except for short stature. PMID- 25737744 TI - Increasing forest disturbances in Europe and their impact on carbon storage. AB - Disturbances from wind, bark beetles, and wildfires have increased in Europe's forests throughout the 20th century 1. Climatic changes were identified as a main driver behind this increase 2, yet how the expected continuation of climate change will affect Europe's forest disturbance regime remains unresolved. Increasing disturbances could strongly impact the forest carbon budget 3,4, and are hypothesized to contribute to the recently observed carbon sink saturation in Europe's forests 5. Here we show that forest disturbance damage in Europe has continued to increase in the first decade of the 21st century. Based on an ensemble of climate change scenarios we find that damage from wind, bark beetles, and forest fires is likely to increase further in coming decades, and estimate the rate of increase to +0.91.106 m3 of timber per year until 2030. We show that this intensification can offset the effect of management strategies aiming to increase the forest carbon sink, and calculate the disturbance-related reduction of the carbon storage potential in Europe's forests to be 503.4 Tg C in 2021 2030. Our results highlight the considerable carbon cycle feedbacks of changing disturbance regimes, and underline that future forest policy and management will require a stronger focus on disturbance risk and resilience. PMID- 25737745 TI - The effects of human amniotic fluid and different bone grafts on vertebral fusion in an experimental rat model. AB - OBJECTIVE: The high risk of nonunion represents a challenge in vertebral surgery, thus stimulating new strategies to improve fusion rates. We investigated the effect of 2 different bone grafts and amniotic fluid application on radiologically and histologically evaluated vertebral fusion in an experimental rat model. MATERIALS AND METHODS: Forty-eight 24-week-old Sprague Dawley rats were included and assigned into 1 of 4 groups: allograft group, allograft plus human amniotic fluid group, demineralized bone matrix (DBM) group, or DBM plus human amniotic fluid group. After decortication and L4-L6 spinal fusion, study treatments were applied. Fusion in each rat was examined radiologically and histologically 8 weeks after the intervention. RESULTS: The group that received only allograft had better radiologic scores (median = 3.5; range = 3-4) when compared with the group that received only DBM (median = 2; range = 1-4) (P = 0.002); however, histologic scores did not differ. When amniotic fluid was added to the grafting, allograft-based treatments performed better than DBM-based treatments both on radiologic (median = 4; range = 3-4 vs median = 3; range = 3 4; P = 0.003) and histologic (median = 7; range = 6-7 vs median = 5; range = 3-6; P < 0.001) evaluation. Addition of amniotic fluid did not result in better outcomes in the rats that received DBM-based treatments but based on histologic evaluation, rats that received allograft-based treatments benefited from this application. CONCLUSIONS: Amniotic fluid seems to have an enhancing effect on posterior spinal fusion, particularly when combined with allograft. PMID- 25737746 TI - Antibiotic stewardship in urologic surgery. PMID- 25737748 TI - [Not Available]. PMID- 25737747 TI - Our strategy moving forward. PMID- 25737749 TI - CUA Guidelines on antibiotic prophylaxis for urologic procedures. PMID- 25737750 TI - 2015 CUA Practice guidelines for erectile dysfunction. PMID- 25737751 TI - A critical analysis of the 2014 CUA guidelines for erectile dysfunction: Is there more that can be done? PMID- 25737752 TI - Development and incorporation of hybrid simulation OSCE into in-training examinations to assess multiple CanMEDS competencies in urologic trainees. AB - INTRODUCTION: As residency training requirements increasingly emphasize a competency-based approach, novel tools to directly evaluate Canadian Medical Education Directives for Specialists (CanMEDS) competencies must be developed. Incorporating simulation allows residents to demonstrate knowledge and skills in a safe, standardized environment. We describe a novel hybrid simulation station for use in a urology resident in-training Objective Structured Clinical Exam (OSCE) to assess multiple CanMEDS competencies. METHODS: An OSCE station was developed to assess Communicator, Health Advocate, Manager, and Medical Expert (including technical skills) CanMEDS roles. Residents interviewed a standardized patient, interacted with a nurse, performed flexible cystoscopy and attempted stent removal using a novel bladder/stent model. Communication was assessed using the Calgary-Cambridge Observational Guide, knowledge was assessed using a checklist, and technical skills were assessed using a previously validated global rating scale. Video debriefing allowed residents to review their performance. Face and discriminative validity were assessed, and feasibility was determined through qualitative post-examination interviews and cost analysis. RESULTS: All 9 residents (postgraduate years [PGY] 3, 4, 5) completed the OSCE in 15 minutes. Communicator and knowledge scores were similar among all PGYs. Scores in technical skills were higher in PGY-5 compared with PGY-3/4 reside nts (mean score 79% vs. 73%). Residents and exam personnel felt the OSCE station allowed for realistic demonstration of competencies. Equipment cost was $218 for the exam station. CONCLUSIONS: We developed and implemented a hybrid simulation-based OSCE station to assess multiple CanMEDS roles. This approach was feasible and cost effective; it also provided a framework for future development of similar OSCE stations to assess resident competencies across multiple domains. PMID- 25737753 TI - From papayas to practice: Surgical simulation and the future of urology training. PMID- 25737754 TI - The association between renal tumour scoring system components and complications of partial nephrectomy. AB - INTRODUCTION: We evaluate the associations between 3 renal tumour scoring systems and their components with perioperative complications of partial nephrectomy. METHODS: A consecutive cohort of partial nephrectomy patients was analyzed. Patient characteristics were abstracted from medical records. PADUA scores (preoperative aspects and dimensions used for anatomic classification), RENAL (radius exophyic/endophytic nearness anterior/posterior location scoring) nephrometry scores, and Centrality index (C-index) were determined from preoperative axial images by 2 independent reviewers. Cases were evaluated for postoperative complications up to 30 days after surgery. Pre-specified complication definitions were used for 33 potential medical and surgical complications. Unadjusted and adjusted associations between overall scores, individual components, and complications were determined using log binomial regression. RESULTS: In total, 118 patients were included in the study. Of these, 36 (30.5%) surgical complications occurred in 27 (22.9%) patients. Fourteen (11.9%) were Clavien grade >=3. Overall PADUA score was significantly associated with surgical and overall complications after adjusting for potential confounders. Among all components of the 3 scoring systems, only tumour diameter and exophytic/endophytic nature of the tumour were significantly associated with complications after adjusting for the other components of the respective scoring system (p < 0.05). CONCLUSIONS: Renal tumour scoring systems may help predict the risk of complications after partial nephrectomy. Further refinement of current systems is required. A first step would be to include only components that are significantly associated with complications. PMID- 25737755 TI - Renal tumour scoring systems: How useful are they? PMID- 25737756 TI - Laparo-endoscopic single site surgery in pediatrics: Feasibility and surgical outcomes from a preliminary prospective Canadian experience. AB - INTRODUCTION: Laparo-endoscopic single-site surgery (LESS) is becoming an alternative to standard laparoscopic surgery. Proposed advantages include enhanced cosmesis and faster recovery. We assessed the early post-operative surgical outcomes of LESS surgery utilizing different instruments in the pediatric urological population in Canada. METHODS: We prospectively captured data on all patients undergoing LESS at our institution between February 2011 and August 2012. This included patient age, operative time, length of stay, complications and short-term surgical outcomes. Different instruments/devices were used to perform the procedures. Access was achieved through a transumbilical incision. RESULTS: A total of 16 LESS procedures were performed, including seven pyeloplasties, four unilateral and one bilateral varicocelectomies, two simple nephrectomies, one renal cyst decortication and one pyelolithotomy. There was no statistical difference in the operative times, hospital length of stay and cost (pyeloplasty only) in patients undergoing pyeloplasty and varicocelectomy using the LESS technique when compared to an age matched cohort of patients managed with the traditional laparoscopic approach. One pyeloplasty in the LESS group required conversion to open due to a small intra-renal pelvis. There were no immediate or short term post-operative complications; however, one patient experienced a decrease in renal function status post LESS pyeloplasty. Since all procedures were performed by a vastly experienced surgeon at a tertiary center, the generalizability of the results cannot be assessed. CONCLUSIONS: There are only a few series that have assessed the role of LESS in pediatric urological surgery. Although our experience is limited by a heterogeneous group of patients with a short follow-up period, the present cohort demonstrates the safety and feasibility of LESS. Further evaluation with randomized studies is required to better assess the role of LESS in pediatric urology. PMID- 25737757 TI - LESS is more for the patient. PMID- 25737758 TI - On-table urethral catheterisation during laparoscopic appendicectomy: Is it necessary? AB - INTRODUCTION: Laparoscopic appendicectomy (LA) is the most commonly performed surgical emergency procedure. The aim of this study was to highlight a series of iatrogenic bladder injuries during LA and suggest a simple method of prevention. METHODS: A retrospective review was carried out of all LA performed in a university teaching hospital over a two year period 2012-2013. Iatrogenic visceral injuries were identified and operative notes examined. RESULTS: During the study period 1124 appendicectomies were performed. Four iatrogenic bladder injuries occurred related to secondary trocar insertion. No patient was catheterised preoperatively. One of the injuries was identified intra operatively, another in the early postoperative period where as two re-presented acutely unwell post-discharge from hospital. Three were repaired by laparotomy and one laparoscopically. CONCLUSION: Iatrogenic secondary trocar induced bladder injuries are a rare but preventable and potentially serious complication of LA. Urethral catheterisation during LA is a safe and simple method which can prevent this complication. PMID- 25737759 TI - Simultaneous bilateral laparoscopic nephrectomy in a child with peritoneal catheter dialysis using a 4-port trans-abdominal technique. AB - We present the case of an 11-year-old girl with end-stage renal disease and a previously-inserted peritoneal dialysis catheter who underwent a bilateral transperitoneal laparoscopic nephrectomy for hypertension refractory to medical treatment. We employed a 4-port transperitoneal technique using the first detached kidney to occlude the ipsilateral abdominal wall access port during the contralateral nephrectomy to avoid gas/fluid leak and to facilitate location of the first kidney at the end of the surgery. The patient had no morbidity and was able to resume use of the peritoneal dialysis catheter 5 days after the surgery. PMID- 25737760 TI - Advanced testicular cancer associated with life-threatening tumour lysis syndrome and choriocarcinoma syndrome. AB - Tumour lysis syndrome (TLS) and choriocarcinoma syndrome (CS) are severe complications of chemotherapy for testicular cancer. They are rare, but can be life-threatening. A 37-year-old man complaining of persisting cough was referred to our hospital. A computed tomography (CT) scan revealed huge tumours that occupied the peritoneal cavity, with multiple lung, liver, and para-aortic metastases. Although there was no abnormal finding in the testes, serum testicular tumor markers showed marked elevation. A CT-guided biopsy for the peritoneal tumours revealed extragonadal germ cell tumour (GCT), including yolk sac tumour and choriocarcinoma. Chemotherapy with bleomycin, etoposide, and cisplatin (BEP) was started after admission. The morning after the beginning of BEP, the patient developed hemorrhagic shock, in addition to acute pulmonary and renal failure, because of TLS and massive hemorrhage at bilateral lung metastases. He was intubated and resuscitated. Despite appropriate therapy, his renal function did not recover and hemodialysis was started. The patient eventually died of severe respiratory distress syndrome and infection. To our knowledge, this is the first case report of TLS and CS as complications of hemorrhage at the lung metastases of advanced testicular cancer leading to death. PMID- 25737761 TI - Hypogonadism: Easy to define, hard to diagnose, and controversial to treat. PMID- 25737762 TI - Safety, efficacy and outcomes of the new GreenLight XPS 180W laser system compared to the GreenLight HPS 120W system for the treatment of benign prostatic hyperplasia in a prospective nonrandomized single-centre study. AB - INTRODUCTION: We compare and evaluate the safety, efficacy, and short-term outcomes of the new GreenLight XPS 180W (GL-XPS) laser system with the former generation GreenLight HPS 120W (GL-HPS) system for the treatment of benign prostatic hyperplasia (BPH) in a prospective nonrandomized single-centre study. METHODS: From May 2012 to June 2013, 161 consecutive patients with lower urinary tract symptoms secondary to BPH were included: 88 patients were treated with the GL-HPS system and 73 were treated with the GL-XPS system. The perioperative variables International Prostate Symptom Score (IPSS), quality of life (QOL), and maximum flow rate (Qmax) were recorded at baseline, at one month and 6 months. Serum prostate-specific antigen (PSA) was assessed at baseline. RESULTS: The mean age was 70.2 years in the GL-HPS group and 68.6 years in the GL-XPS group. Prostate volumes were 62.3 mL and 61.3 mL, respectively. Both groups showed significant postoperative improvement in the IPSS, QOL, Qmax variables compared to baseline levels. There were no significant differences in improvement in IPSS and QOL between groups. However, both operating and catheterization times were shorter in patients in the GL-XPS group. The overall postoperative complication rate was similar in both groups. CONCLUSION: Both GreenLight systems provide safe, effective tissue vaporization with significant clinical relief of BPH obstruction. The GL-XPS system appears more favourable with regard to reduced operating and hospitalization time, suggesting more cost-effective and efficient tissue removal. PMID- 25737763 TI - Assessment of photoselective vaporization of prostate skills during Urology Objective Structured Clinical Examinations (OSCE). AB - INTRODUCTION: We evaluated the use of the GreenLight Simulator (GL-SIM) (American Medical Systems, Guelph, ON) in the skill assessment of postgraduate trainees (PGTs) in photoselective vaporization of the prostate (PVP). We also sought to determine whether previous PVP experience or GL-SIM practice improved performance. METHODS: PGTs in postgraduate years (PGY-3 to PGY-5) from all 4 Quebec urology training programs were recruited during 2 annual Objective Structured Clinical Examinations (OSCEs). During a 20-minute OSCE station, PGTs were asked to perform 2 exercises: (1) identification of endoscopic landmarks and (2) a PVP of a 30-g normal prostate. Grams vaporized, global scores, and number of correct anatomical landmarks were recorded and correlated with PGY level, practice on the GL-SIM, and previous PVP experience. RESULTS: In total, 25 PGTs were recruited at each OSCE, with 13 PGTs participating in both OSCEs. When comparing scores from the first and second OSCEs, there was a significant improvement in the number of grams vaporized (2.9 vs. 4.3 g; p = 0.003) and global score (100 vs. 165; p = 0.03). There was good correlation between the number of previously performed PVPs and the global score (r = 0.4, p = 0.04). Similarly, PGTs with previous practice on the GL-SIM had significantly higher global score (100.6 vs. 162.6; p = 0.04) and grams vaporized (3.1 vs. 4.1 g; p = 0.04) when compared with those who did not practice on GL-SIM. Furthermore, there were significantly more competent PGTs among those who had previously practiced on the GL-SIM (32.7% vs. 10.2%; p = 0.009). PGY level did not significantly affect grams vaporized or global score (p > 0.05). CONCLUSION: Performance on the GL-SIM at OSCEs significantly correlated with previous practice on the GL-SIM and previous PVP experience rather than PGY level. Furthermore, there were significantly more competent PGTs among those who had previously practiced on the GL-SIM. PMID- 25737764 TI - Strain elastography in the characterization of renal cell carcinoma and angiomyolipoma. AB - INTRODUCTION: We evaluate the diagnostic performance of strain elastography to differentiate renal cell carcinoma (RCC) from angiomyolipoma (AML). METHODS: Strain elastography was performed in 65 patients (mean age 55.5 years; range: 32 81) who had renal lesions (24 AMLs and 41 RCCs) prospectively. Lesions were classified according to lesion size and histological subtypes. The strain ratios of the RCCs and AMLs were evaluated by a radiologist. The area under the curve and the cut-off point were used to assess diagnostic performance. Sensitivity, specificity, and positive and negative predictive values were obtained. RESULTS: In assessing the mean strain ratio, we divided the groups in 3 according to size: (1) <20-mm lesions; (2) 20- to 40-mm lesions; and (3) >40-mm lesions; the respective mean strain ratios were: 1.5 +/- 0.5 (range: 0.06-5.92), 2.8 +/- 0.4 (range: 0.17-9.92), 2.7 +/- 0.3 (range: 0.08-6.15). When RCCs and AMLs were compared, there was a statistically significant difference in the strain ratio among the 3 groups divided per lesion size (p < 0.01). For the strain ratio, the mean +/- standard deviation was 1.1 +/- 0.1 for AMLs and 3.4 +/- 0.3 for RCCs (p < 0.01). When lesion subtypes were compared, there was a statistically significant difference in the strain ratio between the AML and clear cell RCC (p < 0.01). CONCLUSIONS: For assessing renal lesions, strain elastography and strain ratio values may be useful in differentiating RCCs from AMLs. PMID- 25737765 TI - Early experience with microsurgical spermatic cord denervation for chronic orchialgia at a Canadian centre. AB - INTRODUCTION: Microsurgical spermatic cord denervation (MSCD) is an effective surgical technique to manage chronic orchalgia, but it has not been readily adopted by Canadian urosurgeons. This paper reviews the early experience of a single urosurgeon in Canada. METHODS: Nine consecutive testicular units underwent MSCD over a 24 month period. These patients underwent MSCD after ruling out reversible causes and after a successful diagnostic spermatic cord block. RESULTS: Of these patients, 77% (7/9) had a complete resolution and 22% (2/9) had a partial resolution of their pain symptoms following MSCD. There were no failures or complications. CONCLUSIONS: MSCD is an effective, safe, and reproducible surgical technique that should be included in the treatment armamentarium for chronic orchalgia. PMID- 25737766 TI - Adult adrenal ganglioneuroblastoma: A rare case report. AB - Ganglioneuroblastoma is an uncommon malignant tumour, and it is extremely rare in adults. A 27-year-old woman was admitted to hospital complaining of commitment left loin pain for 7 months accompanied with fever for 1 day. Computed tomography (CT) scan shows a huge cystic solid mass among the rear of the pancreatic body and tail, inside of the spleen, and the top of the left kidney. Hormone examinations showed that the serum levels of glucocorticoid, aldosterone, norepinephrine, and epinephrine were normal. However, neuron-specific enolase (NSE) was significantly higher (289.46 ng/mL, normal level <16.3 ng/mL). Adrenal mass resection was scheduled. However, intraoperative separation was very difficult and adrenal tumour resection, resection of the pancreatic body and tail, left nephrectomy, and splenectomy were carried out. Pathological diagnosis was ganglioneuroblastoma. PMID- 25737767 TI - Lumbar plexopathy as a complication of percutaneous nephrolithotomy in a horseshoe kidney. AB - Treatment of nephrolithiasis in horseshoe kidneys can be challenging due to anomalies in renal position, collecting system anatomy and vascular supply. We report on a patient who was referred after a failed percutaneous nephrolithotomy for a left moiety staghorn calculus in a horseshoe kidney. Two punctures had been performed involving upper and middle posterior calyces. Both were very medially placed and inadvertently traversed the psoas muscle, resulting in lumbar plexopathy with permanent deficit. This complication presented postoperatively with left leg weakness, paresthesia, and pain which impaired independent ambulation. The patient went on to be successfully treated for her stone disease with robotic-assisted laparoscopic pyelolithotomy. PMID- 25737768 TI - [Not Available]. PMID- 25737769 TI - Factors affecting complications according to the modified Clavien classification in complete supine percutaneous nephrolithotomy. AB - INTRODUCTION: An increase in percutaneous nephrolithotomy (PCNL) has been accompanied by an increase in complications. We identified the parameters affecting the severity of complications using the modified Clavien classification (MCC). METHODS: From 2008 to 2013, 330 patients underwent complete supine PCNL using subcostal access, one-shot dilation, rigid nephroscopy, and pneumatic lithotripsy. We assessed the impact of the following factors on complication severity based on the MCC: age, gender, body mass index, hypertension, diabetes, previous stone surgery and extracorporeal shock wave lithotripsy, preoperative hemoglobin, renal dysfunction (creatinine >1.4 mg/dL), preoperative urinary tract infection, anatomic upper urinary tract abnormality (AUUTA), significant (moderate-severe) hydronephrosis, stone-related parameters (opacity, number, burden, location, staghorn, complex stones), anesthesia type, kidney side, imaging and calyx for access, tract number, tubeless approach, operative time, postoperative hemoglobin, and hemoglobin drop and stone-free results. RESULTS: The complication rate was 19.7% (MCC: 0=80.3%, I=6.4%, II=11.2%, >=III=2.1%). On univariate analyses, only the following factors affected MCC: gender, preoperative hemoglobin, AUUTA, significant hydronephrosis, imaging for access, calyx for access, tract number, postoperative hemoglobin, hemoglobin drop and stone-free result. Renal dysfunction was accompanied by higher complications, yet the results were not statistically significant. Multivariate logistic regression analysis demonstrated renal dysfunction, absence of significant hydronephrosis, AUUTA, multiple tracts, lower postoperative hemoglobin, and higher postoperative hemoglobin drop as the significant parameters which affected MCC and predicted higher grades. The paper's limitations include a low number of cases in the higher Clavien grades and some subgroups of variables, and not applying some techniques due to surgeon preference. INTERPRETATION: Many of the complete supine PCNL complications were in the lower Clavien grades and major complications were uncommon. Renal dysfunction, AUUTA, significant hydronephrosis, tract number, postoperative hemoglobin, and hemoglobin drop were the only factors affecting MCC. PMID- 25737770 TI - Predictors of early continence following robot-assisted radical prostatectomy. AB - INTRODUCTION: Functional outcomes after robot-assisted radical prostatectomy (RARP) greatly influence patient quality of life. Data regarding predictors of early continence, especially 1 month following RARP, are limited. Previous reports mainly address immediate or 3-month postoperative continence rates. We examine preoperative predictors of pad-free continence recovery at the first follow-up visit 1 month after RARP. METHODS: Between January 2007 and January 2013, preoperative and follow-up data were prospectively collected for 327 RARP patients operated on by 2 fellowship-trained surgeons (AEH and KCZ). Patient and operative characteristics included age, body mass index (BMI), staging, preoperative prostate-specific antigen (PSA), prostate weight, International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM) score and type of nerve-sparing performed. Continence was defined by 0-pad usage at 1 month follow-up. Univariate and multivariate logistic regression models were used to assess for predictors of early continence. RESULTS: Overall, 44% of patients were pad-free 1 month post-RARP. In multivariate regression analysis, age (odds ratio [OR] 0.946, confidence interval [CI] 95%: 0.91, 0.98) and IPSS (OR: 0.953, CI 95%: 0.92, 0.99) were independent predictors of urinary continence 1 month following RARP. Other variables (BMI, staging, preoperative PSA, SHIM score, prostate weight and type of nerve-sparing) were not statistically significant predictors of early continence. Limitations of this study include missing data for comorbidities, patient use of pelvic floor exercises and patient maximal activity. Moreover, patient-reported continence using a 0-pad usage definition represents a semiquantitative and subjective measurement. CONCLUSION: In a broad population of patients who underwent RARP at our institution, 44% of patients were pad-free at 1 month. Age and IPSS were independent predictors of early continence after surgery. Men of advanced age and those with significant lower urinary tract symptoms prior to RARP should be counselled on the increased risk of urinary incontinence in the early stages. PMID- 25737771 TI - Attitudes of Turkish Medical and Law Students towards the Organ Donation. AB - BACKGROUND: Attitudes of medical and law personnel towards organ donation are very important. OBJECTIVE: To compare the attitudes of the medical and law students towards organ donation. METHODS: 498 students in the 1(st) and 4(th) grades of the medical and law faculties of Erciyes University, Kayseri, Turkey, in 2011-12 academic year, were included in this study. A questionnaire consisting of 31 questions on socio-demographic characteristics of the students and their attitudes towards organ donation and transplantation was administered to the participants. RESULTS: The percentage of the students who donated organs was 1%. Approximately, 48% of the medical students and 34% of the law students stated that they think to donate organs. The percentage of the students with a positive attitude towards organ donation was found significantly higher among the medical students than the law students, and higher among the 4th grade compared to the 1(st) grade. CONCLUSION: The percentages of the students who have donated organs and think to donate are rather low. Medical students' attitude towards organ donation was more positive than the law students. PMID- 25737772 TI - Relationship between Serum Soluble Interleukin-2 Receptor and Renal Allograft Rejection: A Hospital-Based Study in KashmirValley. AB - BACKGROUND: Even after adequate immunosuppression therapy, acute rejection continues to be the single most important cause of graft dysfunction after renal transplantation. Renal allograft biopsy continues to be the reference standard, though certain clinical and biochemical parameters are helpful in assessment of these patients. Renal allograft rejection is mediated by T lymphocytes, expressing cell surface interleukin-2 receptors (IL-2R) which has been suggested as a marker of acute rejection episodes after organ transplantation. OBJECTIVE: To determine the pre- and post-transplantation serum soluble IL-2R levels in live related kidney transplant patients to predict acute rejection episodes. METHODS: Serial serum samples from 75 recipients and 41 healthy controls were assessed for soluble IL-2R levels by ELISA. The outcome of the graft was also determined for each recipient. RESULTS: The mean+/-SD serum soluble IL-2R levels in renal allograft recipients with rejection were significantly (p<0.001) higher than those without rejection (329.85+/-59.22 vs 18.12+/-11.22 pg/mL). The elevation of serum soluble IL-2R was evident in acute rejection episodes and found before elevation of serum creatinine. The higher values of serum soluble IL-2R in the rejection group were significantly reduced after recovery of allograft function by adequate anti-rejection therapy. 36.4% of patients in the rejection group had proven positive biopsies for the rejection and higher creatinine values, which was found to be statistically significant (p<0.001). A cohort of 41 healthy controls showed significantly (p<0.05) lower serum soluble IL-2R concentrations (15.27+/-7.79 pg/mL) when compared with the rejection group. CONCLUSION: Serum soluble IL-2R concentrations showed significant correlation with the acute rejection episodes in the renal allograft recipients. Prediction of soluble IL-2R levels might help the early detection of rejection episodes, which may pave way for the management of immunosuppression regimes and better graft functioning. PMID- 25737774 TI - Parents' education level and mortality and morbidity of children after liver transplantation. AB - BACKGROUND: So far numerous post-transplant outcome predictors have been studied to decrease the loss of resources and grafts after organ transplantation. The role of education, as a predictor, in liver transplantation outcome has so far been studied in several articles. However, in most of the studies it was evaluated as a surrogate for socioeconomic status or other variants. The absolute impact of parents' education has rarely been studied. Adult patients are their own caregivers whereas pediatric liver transplantation recipients are mostly cared by their parents. OBJECTIVE: To evaluate the effect of level of patients' education on the mortality and morbidity of pediatric liver transplant recipients. METHODS: We studied a group of 91 children who had undergone liver transplantation in our center from March 21, 2012 to July 21, 2013. In this retrospective study, patients' medical charts and questionnaire were used to collect the necessary data. Post-transplantation mortality and complications were divided into two categories: Early (<6 months after liver transplantation), and late (>=6 months after the transplantation). Parents' educational level was also categorized into 5 groups. RESULTS: Multivariate analysis of all groups showed that paternal education is an independent predictor of the late post transplantation complications (p=0.024). Educational level of children's mothers had no significant correlation with the late post-transplantation complications (p=0.45). Neither maternal (p=0.59) nor paternal (p=0.607) education had significant effect on the late post-transplantation mortality. CONCLUSION: Paternal educational level of liver transplanted children is associated with the late post-transplantation complications. PMID- 25737773 TI - Polymorphism of Transcription Factor-7-Like 2 (TCF7L2) Gene and New-Onset Diabetes after Liver Transplantation. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is a serious complication in transplant recipients. Transcription factor-7-like 2 (TCF7L2) is a Wnt signaling-associated transcription factor that plays an important role in beta-cell proliferation and insulin secretion. The association between TCF7L2 SNP rs7903146 and NODAT was documented in renal transplant patients. OBJECTIVE: To determine the association between TCF7L2 rs7903146 variants and the risk of NODAT after liver transplantation. METHODS: This study was conducted on 140 liver transplant recipients who had received tacrolimus-based immunosuppressive drugs. The patients were divided into NODAT (n=70) and non-NODAT (n=70) groups and were genotyped using PCR-RFLP. In addition, 100 normal subjects were considered as the comparison group. RESULTS: There was a significant difference (p<0.05) between the two study groups regarding donor and recipient age, recipient body mass index, and recipient fasting plasma glucose before the transplantation. No significant relationship was observed between TCF7L2 rs7903146 genotypes and development of NODAT. No significant difference was also found between the two groups in terms of the tacrolimus and mycophenolate mofetil daily dosage as well as tacrolimus blood level. However, the prednisolone daily dosage was significantly (p=0.01) higher in the NODAT group compared to those without NODAT. The majority of the patients in the NODAT group also had an episode of acute rejection. Furthermore, a significant difference was found between the transplant recipients and the comparison subjects regarding T allele (p<0.001, OR=1.96) and TT genotype (p<0.001, OR=3.47) frequencies. CONCLUSION: No correlation was found between TCF7L2 genotypes and development of NODAT. Acute rejection and prednisolone pulse therapy predisposed the susceptible patients to NODAT. PMID- 25737775 TI - Intra-operative Ultrasound-guided Thrombectomy and Thrombolysis for Post operative Portal Vein Thrombosis in Living Liver Donors. AB - There are few reports of portal vein thrombosis among living donor liver transplant donors and no published data on the management of this event. In this report, we present our experience in the diagnosis and management of this rare complication in two living donor liver transplantation donors who developed post operative portal vein thrombosis. Both cases were successfully managed with intra operative ultrasound-guided thrombectomy, vein patch venoplasty, and catheter directed thrombolysis. The two donors are symptom-free two years after the event. PMID- 25737776 TI - Living related donor liver transplantation with atrio-caval anastomosis of inferior vena cava graft stored in deep-freeze for budd-Chiari syndrome. AB - We have previously reported our experience in inferior vena cava resection and reconstruction techniques during liver transplantation for Budd-Chiari syndrome. Herein, we present on a case that demonstrates the importance of experience in complex vascular reconstruction techniques for living donor liver transplantation. A 15-year-old boy was scheduled for living donor liver transplantation for Budd-Chiari syndrome. Venous occlusion was extended up to the right atrial orifice of the supra-hepatic vena cava. Retro- and supra-hepatic segments of the vena cava was resected. Inferior vena cava graft stored in deep freeze was available. Venous reconstruction was performed with end-to-end atrio caval anastomosis. Surgical treatment was completed with the implantation of the right liver lobe donated by the patient's mother. Post-surgical course was uneventful. PMID- 25737777 TI - Analytical model for macromolecular partitioning during yeast cell division. AB - BACKGROUND: Asymmetric cell division, whereby a parent cell generates two sibling cells with unequal content and thereby distinct fates, is central to cell differentiation, organism development and ageing. Unequal partitioning of the macromolecular content of the parent cell - which includes proteins, DNA, RNA, large proteinaceous assemblies and organelles - can be achieved by both passive (e.g. diffusion, localized retention sites) and active (e.g. motor-driven transport) processes operating in the presence of external polarity cues, internal asymmetries, spontaneous symmetry breaking, or stochastic effects. However, the quantitative contribution of different processes to the partitioning of macromolecular content is difficult to evaluate. RESULTS: Here we developed an analytical model that allows rapid quantitative assessment of partitioning as a function of various parameters in the budding yeast Saccharomyces cerevisiae. This model exposes quantitative degeneracies among the physical parameters that govern macromolecular partitioning, and reveals regions of the solution space where diffusion is sufficient to drive asymmetric partitioning and regions where asymmetric partitioning can only be achieved through additional processes such as motor-driven transport. Application of the model to different macromolecular assemblies suggests that partitioning of protein aggregates and episomes, but not prions, is diffusion-limited in yeast, consistent with previous reports. CONCLUSIONS: In contrast to computationally intensive stochastic simulations of particular scenarios, our analytical model provides an efficient and comprehensive overview of partitioning as a function of global and macromolecule specific parameters. Identification of quantitative degeneracies among these parameters highlights the importance of their careful measurement for a given macromolecular species in order to understand the dominant processes responsible for its observed partitioning. PMID- 25737779 TI - Lessons from 2012: What the NHS Can Learn from Britain's Olympic Success. AB - The 2012 London Olympic and Paralympic Games were widely regarded as an organisational and sporting success for the United Kingdom. Therefore, it is prudent to consider what other large, public endeavours might learn from the Games' success. Team GB worked to develop a positive team culture based around shared values. This is something the National Health Service (NHS) could learn from, as an organisation which can appear to lack this culture. The NHS should also work harder to adopt evidence-based practices, and to adopt them quickly, as is often the case in sport. Sport is the ultimate example of transparent results reporting, and the NHS ought to consider systematic reporting of risk-adjusted performance data, which may drive improved performance. The NHS should pay attention to the experiences of successful Olympic sports with centralised centres of excellence, and to medical data which suggests that better outcomes result from centres of excellence. The NHS and wider government should look to Olympic athletes and place more emphasis on prevention of disease by encouraging positive lifestyle choices. Finally, the NHS should develop private sector partnerships carefully. We must look to gather knowledge and ideas from every area of life in pursuit of excellence in the NHS. Experience of the Olympics offers a number of instructive lessons. PMID- 25737778 TI - Simulation tools for particle-based reaction-diffusion dynamics in continuous space. AB - Particle-based reaction-diffusion algorithms facilitate the modeling of the diffusional motion of individual molecules and the reactions between them in cellular environments. A physically realistic model, depending on the system at hand and the questions asked, would require different levels of modeling detail such as particle diffusion, geometrical confinement, particle volume exclusion or particle-particle interaction potentials. Higher levels of detail usually correspond to increased number of parameters and higher computational cost. Certain systems however, require these investments to be modeled adequately. Here we present a review on the current field of particle-based reaction-diffusion software packages operating on continuous space. Four nested levels of modeling detail are identified that capture incrementing amount of detail. Their applicability to different biological questions is discussed, arching from straight diffusion simulations to sophisticated and expensive models that bridge towards coarse grained molecular dynamics. PMID- 25737780 TI - Medical publishing triage - chronicling predatory open access publishers. AB - This editorial examines the problem of predatory publishers and how they have negatively affected scholarly communication. Society relies on high-quality, peer reviewed articles for public policy, legal cases, and improving the public health. Researchers need to be aware of how predatory publishers operate and need to avoid falling into their traps. The editorial examines the recent history of predatory publishers and how they have become prominent in the world of scholarly journals. PMID- 25737781 TI - Commentary on: Misrepresentation of Randomized Controlled Trials in Press Releases and News coverage: A Cohort Study. PMID- 25737782 TI - Estimating the basic reproductive ratio for the Ebola outbreak in Liberia and Sierra Leone. AB - BACKGROUND: Ebola virus disease has reemerged as a major public health crisis in Africa, with isolated cases also observed globally, during the current outbreak. METHODS: To estimate the basic reproductive ratio R0, which is a measure of the severity of the outbreak, we developed a SEIR (susceptible-exposed-infected recovered) type deterministic model, and used data from the Centers for Disease Control and Prevention (CDC), for the Ebola outbreak in Liberia and Sierra Leone. Two different data sets are available: one with raw reported data and one with corrected data (as the CDC suspects under-reporting). RESULTS: Using a deterministic ordinary differential equation transmission model for Ebola epidemic, the basic reproductive ratio R0 for Liberia resulted to be 1.757 and 1.9 for corrected and uncorrected case data, respectively. For Sierra Leone, R0 resulted to be 1.492 and 1.362 for corrected and uncorrected case data, respectively. In each of the two cases we considered, the estimate for the basic reproductive ratio was initially greater than unity leading to an epidemic outbreak. CONCLUSION: We obtained robust estimates for the value of R0 associated with the 2014 Ebola outbreak, and showed that there is close agreement between our estimates of R0. Analysis of our model also showed that effective isolation is required, with the contact rate in isolation less than one quarter of that for the infected non-isolated population, and that the fraction of high-risk individuals must be brought to less than 10% of the overall susceptible population, in order to bring the value of R0 to less than 1, and hence control the outbreak. PMID- 25737783 TI - The value of serum midkine level in diagnosis of hepatocellular carcinoma. AB - Background and Aim. Identification of sensitive biomarkers to improve early diagnosis of HCC is needed. We aimed to evaluate serum midkine (MDK) as a biomarker for HCC diagnosis. Patients and Methods. 40 HCCs, 30 liver cirrhosis patients, and 30 healthy subjects were enrolled. Serum MDK using ELISA was measured in all included subjects. Results. Serum MDK was significantly elevated in HCC group compared to cirrhotic and healthy control groups (0.625 versus 0.15 and 0.125 ng/mL), respectively. No significant association was found between MDK and either BCLC stage, tumor diameter, tumor number, or AFP level. Receiver operating characteristic curve showed that best cutoff for MDK and AFP was 0.387 and 88.5 ng/mL, respectively. Area under the curve of MDK was significantly larger than that of AFP (0.941 versus 0.671). The sensitivity of MDK at 0.387 ng/mL for HCC diagnosis was significantly higher than that of AFP at cutoffs 20, 88.5, and 200 ng/mL (92.5 versus 62.5, 40, and 25%), respectively. Sensitivity of MDK reached 93.3% in patients with AFP <20 ng/mL. Moreover, MDK at 0.387 ng/mL had significant better sensitivity than AFP at 20 ng/mL in distinguishing HCC from BCLC 0/A (90 versus 40%). Conclusion. Serum MDK might be a potential diagnostic marker for HCC particularity in its early stages. PMID- 25737784 TI - Successful stent graft insertion for endovascular aneurysm repair and closure of patent ductus arteriosus in an adult patient. AB - Patent ductus arteriosus (PDA) is sometimes undetected until adulthood, and surgical closure of a PDA is dangerous because of the calcification of the ductus. Percutaneous approaches such as coil embolization and use of a PDA occluder are less invasive; however, these devices are not suitable for PDA with thoracic aortic aneurysm (TAA). We present the case of a 72-year-old female patient who underwent successful stent graft insertions for PDA with TAA. PMID- 25737785 TI - Clinical strategies for complete denture rehabilitation in a patient with Parkinson disease and reduced neuromuscular control. AB - The dentist has a large role in geriatric health care for the ever increasing elder population with associated physical and neurological disorders. The Parkinson disease is progressive neurological disorder with resting tremor, bradykinesia, akinesia, and postural instability. The psychological components of disease include depression, anxiety, and cognitive deficiency. Poor oral hygiene, increased susceptibility for dental caries, and periodontal diseases predispose them to early edentulism. The number of Parkinson affected patients visiting dental clinic seeking complete denture is growing. This case report explains the steps involved in the complete denture rehabilitation of Parkinson patient. The effective prosthesis will help in alleviating functional, aesthetic, and psychological disabilities of the patient. PMID- 25737786 TI - Abdominal tumor in a 14-year-old adolescent: imperforate hymen, resulting in hematocolpos-a case report and review of the literature. AB - Background. Abdominal masses in female adolescents are uncommon. A rare cause of this condition is hematocolpos due to imperforate hymen. Case. We present a case of an unusually massive asymptomatic abdominal bulk in a 14-year-old female patient, who sought for medical advice after unusual abdominal pain lasting for few weeks. The patient was otherwise asymptomatic, apart from an unusual dramatic expansion of her abdominal wall during the last month. We describe the surgical management and the follow-up of the patient. Summary and Conclusion. Clinicians should keep in mind that an imperforate hymen can cause abdominal growth due to hematocolpos and include it in the differential diagnosis of such a clinical entity in female adolescents. 2D ultrasound is usually efficient for the confirmation of the diagnosis of hematocolpos, but 3D ultrasound is more accurate. Wide excision should be undertaken, as an initial approach, to avoid recurrence. PMID- 25737787 TI - Extremely rare case of vulvar myxoid epithelioid sarcoma. AB - Epithelioid sarcoma is a distinct sarcoma type with specific morphology and immunophenotype. An epithelioid sarcoma of the vulva is an extremely rare and aggressive tumor and most commonly occurs on the labia majora in women of reproductive age. Only few cases have been reported, especially with the presence of focal myxoid changes. Early diagnosis is difficult because of its benign appearance as a painless subcutaneous nodule. Optimal treatment is not well established due to its rarity. We report a successfully approached case of vulvar epithelioid sarcoma that occurred in a 34-year-old female patient, treated with wide local excision, and review of the current medical literature. PMID- 25737788 TI - Alternative therapy for epstein-barr virus related hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal condition characterized by excessive immune activation. HLH can occur as a familial or sporadic acquired disorder. Acquired HLH is more frequently found in adults and is commonly secondary to infections, malignancies, or autoimmune diseases. Diagnosing HLH is challenging because of the rare occurrence, variable presentation, and nonspecific findings of this disorder. Diagnosis of HLH can be based on the diagnostic criteria which were used in the HLH-2004 trial. Given the rarity of this disease, protocols for its treatment have developed slowly, and obtaining adequate short-term and long-term control of the disease continues to be a challenge. Conventional induction therapy for HLH is dexamethasone and etoposide (VP-16), followed by or with cyclosporine. Intrathecal methotrexate +/- hydrocortisone is given to those with central nervous system disease. We are reporting a patient who was diagnosed with Epstein-Barr virus (EBV) related HLH. He achieved complete remission with rituximab alone. To our knowledge, this is the first case of an adult patient with EBV related HLH who went into remission with rituximab therapy alone, without using the conventional chemotherapy. PMID- 25737789 TI - Unilateral pedicle stress fracture in a long-term hemodialysis patient with isthmic spondylolisthesis. AB - Most unilateral pedicle stress fractures occur on the contralateral side of patients with unilateral spondylolysis. However, there are few reports of unilateral pedicle stress fractures in patients with bilateral spondylolysis and spondylolisthesis. We report a unique case of unilateral pedicle stress fracture in a long-term hemodialysis patient with isthmic spondylolisthesis. A 65-year-old man who had undergone hemodialysis presented with lower back pain that had persisted for several years. The patient experienced severe right lower extremity pain with no history of trauma. Computed tomography revealed unilateral pedicle fracture with bilateral L5 spondylolysis and spondylolisthesis with progression of scoliosis. The patient underwent Gill laminectomy of L5 with pedicle screw fixation at L4-S1 and interbody fusion at L5-S1. The patient's leg pain ceased immediately, and he began walking without leg pain. In our present patient, development of scoliosis caused by destructive spondyloarthropathy may have contributed to a unilateral pedicle fracture. PMID- 25737790 TI - Hip arthroplasty in a patient with transfemoral amputation: a new tip. AB - Femoral fractures in amputation stump are challenging injuries to manage. The authors describe a case of a 51-year-old patient with a right above knee amputation, who had a right hip femoral neck fracture. In this technical note, we describe a technical and surgical procedure with intraoperative tips and tricks, in which we use commonly available materials, for the safe management in such clinical situations. PMID- 25737791 TI - Arthroscopic Removal of a Wire Fragment from the Posterior Septum of the Knee following Tension Band Wiring of a Patellar Fracture. AB - Tension band wiring with cerclage wiring is most widely used for treating displaced patellar fractures. Although wire breakage is not uncommon, migration of a fragment of the broken wire is rare, especially migration into the knee joint. We describe here a rare case of migration of a wire fragment into the posterior septum of the knee joint after fixation of a displaced patellar fracture with tension band wiring and cerclage wiring. Although it was difficult to determine whether the wire fragment was located within or outside the knee joint from the preoperative plain radiographs or three-dimensional computed tomography (3D CT), we found it arthroscopically through the posterior transseptal portal with assistance of intraoperative fluoroscopy. Surgeons who treat such cases should bear in mind the possibility that wire could be embedded in the posterior septum of the knee joint. PMID- 25737792 TI - Ipsilateral hip dysplasia in patients with sacral hemiagenesis: a report of two cases. AB - Sacral agenesis (SA) is a rare condition consisting of the imperfect development of any part of the sacrum. This paper describes two cases of the rare cooccurrence of ipsilateral SA and developmental dysplasia of the hip (DDH) and analyzes possible contributory factors for SA and DDH. Each of a 16-year-old female and 13-year-old female visited our hospital for left hip pain and limping. The findings of physical examinations showed a lower limb length discrepancy (left side) in both cases, as well as left hip pain without limitations of the range of motion or neurological deficits. Initial radiographs demonstrated left subluxation of the left hip with associated acetabular dysplasia and partial left sacral agenesis. MRI revealed a tethering cord with a fatty filum terminale, and periacetabular osteotomy combined with allogeneic bone grafting was performed. After the surgery, the patients experienced no further pain, with no leg length discrepancy and were able to walk without a limp, being neurologically normal with a normal left hip range of motion. The cooccurrence of SA and DDH suggests a plausible hypothesis to explain the embryogenic relationship between malformation of the sacrum and hip. PMID- 25737793 TI - Multicentric Castleman's Disease in a Child Revealed by Chronic Diarrhea. AB - Multicentric Castleman's disease is a rare benign and unexplained lymphoproliferative disorder that is extremely uncommon in children. It presents with fever, systemic symptoms, generalized lymphadenopathy, and laboratory markers of inflammation. Its treatment is not standardized and its prognosis is poor. We report a novel case of multicentric Castleman's disease in a 13-year-old girl who had presented with chronic diarrhea as the only initial presenting symptom. The diagnosis of celiac or inflammatory bowel diseases was suspected, but two and a half years later, the diagnosis of multicentric Castleman's disease was brought following the appearance of abdominal mass whose biopsy revealed Castleman's disease in the plasma cell form. The outcome was favorable after treatment by corticosteroid, chemotherapy, and surgery. The occurrence of diarrhea as the initial symptom of multicentric Castleman's disease without lymph node involvement is very rare. This case report underlines the diagnostic difficulties and the long interval between onset and diagnosis when diarrhea occurs first. PMID- 25737794 TI - Embryonal rhabdomyosarcoma of the adult urinary bladder: a rare case report of misclassification as inflammatory myofibroblastic tumor. AB - Embryonal rhabdomyosarcoma (ERMS) of the adult urinary bladder is a rare malignant tumour. Inflammatory myofibroblastic tumour (IMT) of the bladder is a benign genitourinary tumour that may appear variable histologically but usually lacks unequivocal malignant traits. Techniques like flow cytometry and immunohistochemistry may be used to differentiate these two tumours. Our patient, a 46-year-old male, had rapidly recurring lower urinary tract symptoms after two transurethral resections of the prostate. He subsequently underwent a transvesical prostatectomy which showed IMT on histology. However, his symptoms did not resolve and an open resection done at our institution revealed a 6 cm tumour arising from the right bladder neck. This time, histology was ERMS with diffuse anaplasia of the bladder. Rapid recurrence of urinary symptoms with prostate regrowth after surgery is unusual. Differential diagnoses of uncommon bladder malignancies should be considered if there is an inconsistent clinical course as treatment approaches are different. PMID- 25737795 TI - Is an Incidental Meckel's Diverticulum Truly Benign? AB - Meckel's diverticulum is the most common congenital abnormality of the gastrointestinal tract and it is found to affect nearly 2 percent of the population. Interestingly, the surgical management of an asymptomatic Meckel's diverticulum remains widely controversial in the adult population. Review of the literature finds the overall risk of Meckel's diverticulum becoming symptomatic to be low; however, the risk accompanying its resection also proves to be minimal thus perpetuating the question of its proper management. We report our experience with an elderly patient who required an emergent operative intervention and was incidentally found to have Meckel's diverticulum. Review of final pathology found Meckel's diverticulum to contain a carcinoid tumor. In our review, the presence of a carcinoid tumor within Meckel's diverticulum is a rare finding, but its incidence may further support the resection of incidentally found asymptomatic Meckel's diverticulum in patients of all ages. PMID- 25737796 TI - Omental infarction mimicking cholecystitis. AB - Omental infarction can be difficult to diagnose preoperatively as imaging may be inconclusive and patients often present in a way that suggests a more common surgical pathology such as appendicitis. Here, a 40-year-old Caucasian man presented to casualty with shortness of breath and progressive right upper abdominal pain, accompanied with right shoulder and neck pain. Exploratory laparoscopy was eventually utilised to diagnose an atypical form of omental infarction that mimics cholecystitis. The vascular supply along the long axis of the segment was occluded initiating necrosis. In this case, the necrotic segment was adherent with the abdominal wall, a pathology not commonly reported in cases of omental infarction. PMID- 25737797 TI - The personal and professional legacy of John Edwin Scarff. PMID- 25737798 TI - Morality and ethics without religion. PMID- 25737799 TI - Emergent cervical surgical embolectomy to rescue total monocular blindness due to simultaneous cervical internal and external carotid artery occlusion by cardiogenic emboli. AB - BACKGROUND: Central retinal artery occlusion (CRAO) is a stroke of the retina and is associated with extremely poor prognosis. Although the pathophysiology of CRAO is diverse, including autoimmune or hematological disorders, neurosurgeons can perform carotid endarterectomy for the causal internal carotid artery stenosis or perform acute recanalization of the extra- or intracranial artery occlusion due to cardiogenic embolism. CASE DESCRIPTION: A 78-year-old male with a history of atrial fibrillation (Af) visited our hospital with a chief complaint of right monocular blindness. Magnetic resonance imaging revealed occlusion of the right internal and external carotid arteries. We performed emergent cervical surgical embolectomy for restoration of vision. Recanalization was accomplished within 8 h after onset, and the patient regained practical vision within 4 months. CONCLUSION: In the diagnosis and treatment of CRAO, occlusion of the internal and/or external carotid artery due to large cardiac emboli should be taken in consideration, especially when the patient has a history of Af, since acute recanalization might restore vision. PMID- 25737800 TI - Prostate dural metastasis presenting as chronic subdural hematoma. A case report and review of the literature. AB - BACKGROUND: Malignant disease metastasising to the cranial dura is rare. Dural metastases manifesting as a subdural fluid collection and presenting as a chronic subdural hematoma is an uncommon entity with unknown pathophysiology. CASE DESCRIPTION: We present a patient with known prostate cancer metastasising to the cranial dura masquerading as a chronic subdural hematoma. The patient presented with bilateral subdural collections manifesting with confusion and dysphasia. Initial drainage of the larger, symptomatic left side improved only temporarily patient's symptoms. A second drainage of the collection was performed on the same side 5 days later and dural biopsies taken during the same procedure revealed prostate metastases. The patient improved slowly and was discharged to a hospice for palliative care management. CONCLUSIONS: Prostate dural metastases should be suspected in patients with known prostate cancer presenting with a subdural collection in the absence of cranial trauma. If decision to drain the subdural collection is taken, then biopsies can be taken the same time as they can pose a diagnostic challenge. PMID- 25737801 TI - Identifying Hypertrophic Cardiomyopathy Patients by Classifying Individual Heartbeats from 12-lead ECG Signals. AB - Test based on electrocardiograms (ECG) that record the heart electrical activity can help in early detection of patients with hypertrophic cardiomyopathy (HCM) where the heart muscle is partially thickened and blood flow is (potentially fatally) obstructed. This paper presents a cardiovascular-patient classifier we developed to identify HCM patients using standard 10-seconds, 12-lead ECG signals. Patients are classified as having HCM if the majority of the heartbeats are recognized as HCM. Thus, the classifier's underlying task is to recognize individual heartbeats segmented from 12-lead ECG signals as HCM beats, where heartbeats from non-HCM cardiovascular patients are used as controls. We extracted 504 morphological and temporal features - both commonly used and newly developed ones - from ECG signals for heartbeat classification. To assess classification performance, we trained and tested a random forest classifier and a support vector machine classifier using 5-fold cross validation. The patient classification precision and F-measure of both classifiers are close to 0.85. Recall (sensitivity) and specificity are approximately 0.90. We also conducted feature selection experiments by gradually removing the least informative features; the results show that a relatively small subset of 304 highly informative features can achieve performance measures comparable to that achieved by using the complete set of features. PMID- 25737802 TI - High-resolution Genomic Surveillance of 2014 Ebolavirus Using Shared Subclonal Variants. AB - BACKGROUND: Viral outbreaks, such as the 2014 ebolavirus, can spread rapidly and have complex evolutionary dynamics, including coinfection and bulk transmission of multiple viral populations. Genomic surveillance can be hindered when the spread of the outbreak exceeds the evolutionary rate, in which case consensus approaches will have limited resolution. Deep sequencing of infected patients can identify genomic variants present in intrahost populations at subclonal frequencies (i.e. <50%). Shared subclonal variants (SSVs) can provide additional phylogenetic resolution and inform about disease transmission patterns. METHODS: We use metrics from population genetics to analyze data from the 2014 ebolavirus outbreak in Sierra Leone and identify phylogenetic signal arising from SSVs. We use methods derived from information theory to measure a lower bound on transmission bottleneck size. RESULTS AND CONCLUSIONS: We identify several SSV that shed light on phylogenetic relationships not captured by consensus-based analyses. We find that transmission bottleneck size is larger than one founder population, yet significantly smaller than the intrahost effective population. Our results demonstrate the important role of shared subclonal variants in genomic surveillance. PMID- 25737803 TI - Estimating drivers of autochthonous transmission of chikungunya virus in its invasion of the americas. AB - Background Chikungunya is an emerging arbovirus that has caused explosive outbreaks in Africa and Asia for decades and invaded the Americas just over a year ago. During this ongoing invasion, it has spread to 45 countries where it has been transmitted autochthonously, infecting nearly 1.3 million people in total. Methods Here, we made use of weekly, country-level case reports to infer relationships between transmission and two putative climatic drivers: temperature and precipitation averaged across each country on a monthly basis. To do so, we used a TSIR model that enabled us to infer a parametric relationship between climatic drivers and transmission potential, and we applied a new method for incorporating a probabilistic description of the serial interval distribution into the TSIR framework. Results We found significant relationships between transmission and linear and quadratic terms for temperature and precipitation and a linear term for log incidence during the previous pathogen generation. The lattermost suggests that case numbers three to four weeks ago are largely predictive of current case numbers. This effect is quite nonlinear at the country level, however, due to an estimated mixing parameter of 0.74. Relationships between transmission and the climatic variables that we estimated were biologically plausible and in line with expectations. Conclusions Our analysis suggests that autochthonous transmission of Chikungunya in the Americas can be correlated successfully with putative climatic drivers, even at the coarse scale of countries and using long-term average climate data. Overall, this provides a preliminary suggestion that successfully forecasting the future trajectory of a Chikungunya outbreak and the receptivity of virgin areas may be possible. Our results also provide tentative estimates of timeframes and areas of greatest risk, and our extension of the TSIR model provides a novel tool for modeling vector-borne disease transmission. PMID- 25737804 TI - CYLD GeneticTesting for Brooke-Spiegler Syndrome, Familial Cylindromatosis and Multiple Familial Trichoepitheliomas. AB - The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations in the tumour suppressor gene CYLD (OMIM 605018). Brooke-Spiegler Syndrome (BSS), familial cylindromatosis (FC) and multiple familial trichoepitheliomas (MFT) (OMIM #605041, #132700, #601606 respectively) differ due to the types of other skin appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of CYLD . The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most commonly on the head and neck. CYLD testing can be performed using PCR and Sanger sequencing for patients with: 1. Multiple cylindromas, spiradenomas or trichoepitheliomas. 2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours. 3. An asymptomatic family member at 50% risk with a known mutation in the family. PMID- 25737805 TI - Assessing the direct effects of the ebola outbreak on life expectancy in liberia, sierra leone and Guinea. AB - BACKGROUND: An EVD outbreak may reduce life expectancy directly (due to high mortality among EVD cases) and indirectly (e.g., due to lower utilization of healthcare and subsequent increases in non-EVD mortality). In this paper, we investigated the direct effects of EVD on life expectancy in Liberia, Sierra Leone and Guinea (LSLG thereafter). METHODS: We used data on EVD cases and deaths published in situation reports by the World Health Organization (WHO), as well as data on the age of EVD cases reported from patient datasets. We used data on non EVD mortality from the most recent life tables published prior to the EVD outbreak. We then formulated three scenarios based on hypotheses about a) the extent of under-reporting of EVD cases and b) the EVD case fatality ratio. For each scenario, we re-estimated the number of EVD deaths in LSLG and we applied standard life table techniques to calculate life expectancy. RESULTS: In Liberia, possible reductions in life expectancy resulting from EVD deaths ranged from 1.63 year (low EVD scenario) to 5.56 years (high EVD scenario), whereas in Sierra Leone, possible life expectancy declines ranged from 1.38 to 5.10 years. In Guinea, the direct effects of EVD on life expectancy were more limited (<1.20 year). CONCLUSIONS: Our high EVD scenario suggests that, due to EVD deaths, life expectancy may have declined in Liberia and Sierra Leone to levels these two countries had not experienced since 2001-2003, i.e., approximately the end of their civil wars. The total effects of EVD on life expectancy may however be larger due to possible concomitant increases in non-EVD mortality during the outbreak. PMID- 25737806 TI - Temporal Changes in Ebola Transmission in Sierra Leone and Implications for Control Requirements: a Real-time Modelling Study. AB - BACKGROUND: Between August and November 2014, the incidence of Ebola virus disease (EVD) rose dramatically in several districts of Sierra Leone. As a result, the number of cases exceeded the capacity of Ebola holding and treatment centres. During December, additional beds were introduced, and incidence declined in many areas. We aimed to measure patterns of transmission in different regions, and evaluate whether bed capacity is now sufficient to meet future demand. METHODS: We used a mathematical model of EVD infection to estimate how the extent of transmission in the nine worst affected districts of Sierra Leone changed between 10th August 2014 and 18th January 2015. Using the model, we forecast the number of cases that could occur until the end of March 2015, and compared bed requirements with expected future capacity. RESULTS: We found that the reproduction number, R, defined as the average number of secondary cases generated by a typical infectious individual, declined between August and December in all districts. We estimated that R was near the crucial control threshold value of 1 in December. We further estimated that bed capacity has lagged behind demand between August and December for most districts, but as a consequence of the decline in transmission, control measures caught up with the epidemic in early 2015. CONCLUSIONS: EVD incidence has exhibited substantial temporal and geographical variation in Sierra Leone, but our results suggest that the epidemic may have now peaked in Sierra Leone, and that current bed capacity appears to be sufficient to keep the epidemic under-control in most districts. PMID- 25737807 TI - The FVB Background Does Not Dramatically Alter the Dystrophic Phenotype of Mdx Mice. AB - The mdx mouse is the most frequently used animal model for Duchenne muscular dystrophy (DMD), a fatal muscle disease caused by the loss of dystrophin. Mdx mice are naturally occurring dystrophin-null mice on the C57BL/10 (BL10) background. We crossed black mdx to the white FVB background and generated mdx/FVB mice. Compared to that of age- and sex-matched FVB mice, mdx/FVB mice showed characteristic limb muscle pathology similar to that of original mdx mice. Further, the forelimb grip strength and limb muscle (tibialis anterior and extensor digitorum longus) specific force of mdx/FVB mice were significantly lower than that of wild type FVB mice. Consistent with what has been reported in original mdx mice, mdx/FVB mice also showed increased susceptibility to eccentric contraction-induced force loss and elevated serum creatine kinase. Our results suggest that the FVB background does not dramatically alter the dystrophic phenotype of mdx mice. PMID- 25737808 TI - Insight into Shiga toxin genes encoded by Escherichia coli O157 from whole genome sequencing. AB - The ability of Shiga toxin-producing Escherichia coli (STEC) to cause severe illness in humans is determined by multiple host factors and bacterial characteristics, including Shiga toxin (Stx) subtype. Given the link between Stx2a subtype and disease severity, we sought to identify the stx subtypes present in whole genome sequences (WGS) of 444 isolates of STEC O157. Difficulties in assembling the stx genes in some strains were overcome by using two complementary bioinformatics methods: mapping and de novo assembly. We compared the WGS analysis with the results obtained using a PCR approach and investigated the diversity within and between the subtypes. All strains of STEC O157 in this study had stx1a, stx2a or stx2c or a combination of these three genes. There was over 99% (442/444) concordance between PCR and WGS. When common source strains were excluded, 236/349 strains of STEC O157 had multiple copies of different Stx subtypes and 54 had multiple copies of the same Stx subtype. Of those strains harbouring multiple copies of the same Stx subtype, 33 had variants between the alleles while 21 had identical copies. Strains harbouring Stx2a only were most commonly found to have multiple alleles of the same subtype (42%). Both the PCR and WGS approach to stx subtyping provided a good level of sensitivity and specificity. In addition, the WGS data also showed there were a significant proportion of strains harbouring multiple alleles of the same Stx subtype associated with clinical disease in England. PMID- 25737809 TI - The effects of venting and decompression on Yellow Tang (Zebrasoma flavescens) in the marine ornamental aquarium fish trade. AB - Each year, over 45 countries export 30 million fish from coral reefs as part of the global marine ornamental aquarium trade. This catch volume is partly influenced by collection methods that cause mortality. Barotrauma in fish resulting from forced ascent from depth can contribute to post-collection mortality. However, implementing decompression stops during ascent can prevent barotrauma. Conversely, venting (puncturing the swim bladder to release expanded internal gas) following ascent can mitigate some signs of barotrauma like positive buoyancy. Here, we evaluate how decompression and venting affect stress and mortality in the Yellow Tang (Zebrasoma flavescens). We examined the effects of three ascent treatments, each with decompression stops of varying frequency and duration, coupled with or without venting, on sublethal effects and mortality using histology and serum cortisol measurements. In fish subjected to ascent without decompression stops or venting, a mean post-collection mortality of 6.2% occurred within 24 h of capture. Common collection methods in the fishery, ascent without decompression stops coupled with venting, or one long decompression stop coupled with venting, resulted in no mortality. Histopathologic examination of heart, liver, head kidney, and swim bladder tissues in fish 0d and 21d post collection revealed no significant barotrauma- or venting-related lesions in any treatment group. Ascent without decompression stops resulted in significantly higher serum cortisol than ascent with many stops, while venting alone did not affect cortisol. Future work should examine links in the supply chain following collection to determine if further handling and transport stressors affect survivorship and sublethal effects. PMID- 25737810 TI - Concordance and discordance of sequence survey methods for molecular epidemiology. AB - The post-genomic era is characterized by the direct acquisition and analysis of genomic data with many applications, including the enhancement of the understanding of microbial epidemiology and pathology. However, there are a number of molecular approaches to survey pathogen diversity, and the impact of these different approaches on parameter estimation and inference are not entirely clear. We sequenced whole genomes of bacterial pathogens, Burkholderia pseudomallei, Yersinia pestis, and Brucella spp. (60 new genomes), and combined them with 55 genomes from GenBank to address how different molecular survey approaches (whole genomes, SNPs, and MLST) impact downstream inferences on molecular evolutionary parameters, evolutionary relationships, and trait character associations. We selected isolates for sequencing to represent temporal, geographic origin, and host range variability. We found that substitution rate estimates vary widely among approaches, and that SNP and genomic datasets yielded different but strongly supported phylogenies. MLST yielded poorly supported phylogenies, especially in our low diversity dataset, i.e., Y. pestis. Trait associations showed that B. pseudomallei and Y. pestis phylogenies are significantly associated with geography, irrespective of the molecular survey approach used, while Brucella spp. phylogeny appears to be strongly associated with geography and host origin. We contrast inferences made among monomorphic (clonal) and non-monomorphic bacteria, and between intra- and inter-specific datasets. We also discuss our results in light of underlying assumptions of different approaches. PMID- 25737811 TI - Significance and value of non-traded ecosystem services on farmland. AB - Background. Ecosystem services (ES) generated within agricultural landscapes, including field boundaries, are vital for the sustainable supply of food and fibre. However, the value of ES in agriculture has not been quantified experimentally and then extrapolated globally. Methods. We quantified the economic value of two key but contrasting ES (biological control of pests and nitrogen mineralisation) provided by non-traded non-crop species in ten organic and ten conventional arable fields in New Zealand using field experiments. The arable crops grown, same for each organic and conventional pair, were peas (Pisum sativum), beans (Phaseolus vulgaris), barley (Hordeum vulgare), and wheat (Triticum aestivum). Organic systems were chosen as comparators not because they are the only forms of sustainable agriculture, but because they are subject to easily understood standards. Results. We found that organic farming systems depended on fewer external inputs and produced outputs of energy and crop dry matter generally less than but sometimes similar to those of their conventional counterparts. The economic values of the two selected ES were greater for the organic systems in all four crops, ranging from US$ 68-200 ha(-1) yr(-1) for biological control of pests and from US$ 110-425 ha(-1)yr(-1) for N mineralisation in the organic systems versus US$ 0 ha(-1)yr(-1) for biological control of pests and from US$ 60-244 ha(-1)yr(-1) for N mineralisation in the conventional systems. The total economic value (including market and non-market components) was significantly greater in organic systems, ranging from US$ 1750 4536 ha(-1)yr(-1), with US$ 1585-2560 ha(-1)yr(-1) in the conventional systems. The non-market component of the economic value in organic fields was also significantly higher than those in conventional fields. Discussion. To illustrate the potential magnitude of these two ES to temperate farming systems and agricultural landscapes elsewhere, we then extrapolate these experimentally derived figures to the global temperate cropping area of the same arable crops. We found that the extrapolated net value of the these two services provided by non-traded species could exceed the combined current global costs of pesticide and fertiliser inputs, even if utilised on only 10% of the global arable area. This approach strengthens the case for ES-rich agricultural systems, provided by non-traded species to global agriculture. PMID- 25737812 TI - X-to-autosome expression and msl-2 transcript abundance correlate among Drosophila melanogaster somatic tissues. AB - In Drosophila melanogaster, the male-specific lethal (MSL) complex has been studied extensively for its role in upregulating male X-linked genes. Recent advances in high-throughput technologies have improved our understanding of how the MSL complex mediates dosage compensation through chromosome-wide chromatin modifications. Most studies, however, have focused on cell line models that cannot reflect any potential heterogeneity of in vivo dosage compensation. Comparisons between cell line and organismal gene-level dosage compensation upregulation suggest the possibility of variation in MSL complex activity among somatic tissues. We hypothesize the degree, up to but not exceeding 2-fold, to which the MSL complex upregulates male X-linked genes varies quantitatively by tissue type. In this model, MSL complex abundance acts as a rheostat to control the extent of upregulation. Using publicly available expression data, we provide evidence for our model in Drosophila somatic tissues. Specifically, we find X-to autosome expression correlates with the tissue-specific expression of msl-2 which encodes an essential male-specific component of the MSL complex. This result suggests MSL complex mediated dosage compensation varies quantitatively by tissue type. Furthermore, this result has consequences for models explaining the organismal-scale molecular and evolutionary consequences of MSL-mediated dosage compensation. PMID- 25737814 TI - Your wish is my command! The influence of symbolic modelling on preschool children's delay of gratification. AB - The ability of children to delay gratification is correlated with a range of positive outcomes in adulthood, showing the potential impact of helping young children increase their competence in this area. This study investigated the influence of symbolic models on the self-control of 3-year old children. Eighty three children were randomly assigned to one of three modelling conditions: personal storytelling, impersonal storytelling, and control. Children were tested on the delay-of-gratification maintenance paradigm both before and after being exposed to a symbolic model or control condition. Repeated measures ANOVA revealed no significant differences between the two storytelling groups and the control group, indicating that the symbolic models did not influence children's ability to delay gratification. A serendipitous finding showed a positive relationship between the ability of children to wait and their production and accurate use of temporal terms, which was more pronounced in girls than boys. This finding may be an indication that a higher temporal vocabulary is linked to a continuous representation of the self in time, facilitating a child's representation of the future-self receiving a larger reward than what the present self could receive. PMID- 25737813 TI - Comprehensive, structurally-informed alignment and phylogeny of vertebrate biogenic amine receptors. AB - Biogenic amine receptors play critical roles in regulating behavior and physiology in both vertebrates and invertebrates, particularly within the central nervous system. Members of the G-protein coupled receptor (GPCR) family, these receptors interact with endogenous bioamine ligands such as dopamine, serotonin, and epinephrine, and are targeted by a wide array of pharmaceuticals. Despite the clear clinical and biological importance of these receptors, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality sequence alignment of vertebrate biogenic amine receptors. In particular, we have integrated a traditional multiple sequence approach with robust structural domain predictions to ensure that alignment columns accurately capture the highly conserved GPCR structural domains, and we demonstrate how ignoring structural information produces spurious inferences of homology. Using this alignment, we have constructed a structurally-partitioned maximum-likelihood phylogeny from which we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors. PMID- 25737816 TI - Early archosauromorph remains from the Permo-Triassic Buena Vista Formation of north-eastern Uruguay. AB - The Permo-Triassic archosauromorph record is crucial to understand the impact of the Permo-Triassic mass extinction on the early evolution of the group and its subsequent dominance in Mesozoic terrestrial ecosystems. However, the Permo Triassic archosauromorph record is still very poor in most continents and hampers the identification of global macroevolutionary patterns. Here we describe cranial and postcranial bones from the Permo-Triassic Buena Vista Formation of northeastern Uruguay that contribute to increase the meagre early archosauromorph record from South America. A basioccipital fused to both partial exoccipitals and three cervical vertebrae are assigned to Archosauromorpha based on apomorphies or a unique combination of characters. The archosauromorph remains of the Buena Vista Formation probably represent a multi-taxonomic assemblage composed of non archosauriform archosauromorphs and a 'proterosuchid-grade' animal. This assemblage does not contribute in the discussion of a Late Permian or Early Triassic age for the Buena Vista Formation, but reinforces the broad palaeobiogeographic distribution of 'proterosuchid grade' diapsids in Permo Triassic beds worldwide. PMID- 25737815 TI - Body image, visual working memory and visual mental imagery. AB - Body dissatisfaction (BD) is a highly prevalent feature amongst females in society, with the majority of individuals regarding themselves to be overweight compared to their personal ideal, and very few self-describing as underweight. To date, explanations of this dramatic pattern have centred on extrinsic social and media factors, or intrinsic factors connected to individuals' knowledge and belief structures regarding eating and body shape, with little research examining links between BD and basic cognitive mechanisms. This paper reports a correlational study in which visual and executive cognitive processes that could potentially impact on BD were assessed. Visual memory span and self-rated visual imagery were found to be predictive of BD, alongside a measure of inhibition derived from the Stroop task. In contrast, spatial memory and global precedence were not related to BD. Results are interpreted with reference to the influential multi-component model of working memory. PMID- 25737817 TI - First record of multi-species synchronous coral spawning from Malaysia. AB - Knowledge about the timing and synchrony of coral spawning has important implications for both the ecology and management of coral reef ecosystems. Data on the timing of spawning and extent of synchrony, however, are still lacking for many coral reefs, particularly from equatorial regions and from locations within the coral triangle. Here we present the first documentation of a multi-species coral spawning event from reefs around Pulau Tioman, Peninsular Malaysia, a popular diving and tourist destination located on the edge of the coral triangle. At least 8 coral species from 3 genera (Acropora, Montipora and Porites) participated in multi-species spawning over five nights in April 2014, between two nights before and two nights after the full moon. In addition, two Acropora species were witnessed spawning one night prior to the full moon in October 2014. While two of the Acropora species that reproduced in April (A. millepora and A. nasuta) exhibited highly synchronous spawning (100% of sampled colonies), two other common species (A. hyacinthus and A. digitifera) did not contain visible eggs in the majority of colonies sampled (i.e., <15% of colonies) in either April or October, suggesting that these species spawn at other times of the year. To the best of our knowledge, this is the first detailed documented observation of multi-species coral spawning from reefs in Malaysia. These data provide further support for the contention that this phenomenon is a feature of all speciose coral assemblages, including equatorial reefs. More research is needed, however, to determine the seasonal cycles and extent of spawning synchrony on these reefs and elsewhere in Malaysia. PMID- 25737818 TI - Computational analysis of the LRRK2 interactome. AB - LRRK2 was identified in 2004 as the causative protein product of the Parkinson's disease locus designated PARK8. In the decade since then, genetic studies have revealed at least 6 dominant mutations in LRRK2 linked to Parkinson's disease, alongside one associated with cancer. It is now well established that coding changes in LRRK2 are one of the most common causes of Parkinson's. Genome-wide association studies (GWAs) have, more recently, reported single nucleotide polymorphisms (SNPs) around the LRRK2 locus to be associated with risk of developing sporadic Parkinson's disease and inflammatory bowel disorder. The functional research that has followed these genetic breakthroughs has generated an extensive literature regarding LRRK2 pathophysiology; however, there is still no consensus as to the biological function of LRRK2. To provide insight into the aspects of cell biology that are consistently related to LRRK2 activity, we analysed the plethora of candidate LRRK2 interactors available through the BioGRID and IntAct data repositories. We then performed GO terms enrichment for the LRRK2 interactome. We found that, in two different enrichment portals, the LRRK2 interactome was associated with terms referring to transport, cellular organization, vesicles and the cytoskeleton. We also verified that 21 of the LRRK2 interactors are genetically linked to risk for Parkinson's disease or inflammatory bowel disorder. The implications of these findings are discussed, with particular regard to potential novel areas of investigation. PMID- 25737819 TI - Bird conservation would complement landslide prevention in the Central Andes of Colombia. AB - Conservation and restoration priorities often focus on separate ecosystem problems. Inspired by the November 11th (2011) landslide event near Manizales, and the current poor results of Colombia's Article 111 of Law 99 of 1993 as a conservation measure in this country, we set out to prioritize conservation and restoration areas where landslide prevention would complement bird conservation in the Central Andes. This area is one of the most biodiverse places on Earth, but also one of the most threatened. Using the case of the Rio Blanco Reserve, near Manizales, we identified areas for conservation where endemic and small range bird diversity was high, and where landslide risk was also high. We further prioritized restoration areas by overlapping these conservation priorities with a forest cover map. Restoring forests in bare areas of high landslide risk and important bird diversity yields benefits for both biodiversity and people. We developed a simple landslide susceptibility model using slope, forest cover, aspect, and stream proximity. Using publicly available bird range maps, refined by elevation, we mapped concentrations of endemic and small-range bird species. We identified 1.54 km(2) of potential restoration areas in the Rio Blanco Reserve, and 886 km(2) in the Central Andes region. By prioritizing these areas, we facilitate the application of Article 111 which requires local and regional governments to invest in land purchases for the conservation of watersheds. PMID- 25737820 TI - Diagnosis of bacterial vaginosis by a new multiplex peptide nucleic acid fluorescence in situ hybridization method. AB - Bacterial vaginosis (BV) is one of most common vaginal infections. However, its diagnosis by classical methods reveals low specificity. Our goal was to evaluate the accuracy diagnosis of 150 vaginal samples with research gold standard methods and our Peptide Nucleic Acid (PNA) probes by Fluorescence in situ Hybridization (FISH) methodology. Also, we described the first PNA-FISH methodology for BV diagnosis, which provides results in approximately 3 h. The results showed a sensitivity of 84.6% (95% confidence interval (CI), from 64.3 to 95.0%) and a specificity of 97.6% (95% CI [92.6-99.4%]), demonstrating the higher specificity of the PNA-FISH method and showing false positive results in BV diagnosis commonly obtained by the classical methods. This methodology combines the specificity of PNA probes for Lactobacillus species and G. vaginalis visualization and the calculation of the microscopic field by Nugent score, allowing a trustful evaluation of the bacteria present in vaginal microflora and avoiding the occurrence of misleading diagnostics. Therefore, the PNA-FISH methodology represents a valuable alternative for BV diagnosis. PMID- 25737821 TI - Spatial patterning and floral synchrony among trillium populations with contrasting histories of herbivory. AB - We investigated the spatial patterning and floral synchrony within and among populations of a non-clonal, forest understory herb, Trillium catesbaei. Two populations of T. catesbaei within Great Smoky Mountains National Park were monitored for five years: Cades Cove (high deer abundance) and Whiteoak Sink (low deer abundance). All individuals within each population were mapped during year one and five. Only flowering and single-leaf juveniles were mapped during intervening years. Greater distances between flowering plants (plants currently in flower) and substantially lower population densities and smaller patch sizes were observed at Cades Cove versus Whiteoak Sink. However, with the exception of flowering plants, contrasting histories of herbivory did not appear to fundamentally alter the spatial patterning of the T. catesbaei population at Cades Cove, an area with a long and well-documented history of deer overabundance. Regardless of browse history, non-flowering life stages were significantly clustered at all spatial scales examined. Flowering plants were clustered in all years at Whiteoak Sink, but more often randomly distributed at Cades Cove, possibly as a result of their lower abundance. Between years, however, there was a positive spatial association between the locations of flowering plants at both sites. Flowering rate was synchronous between sites, but lagged a year behind favorable spring growing conditions, which likely allowed plants to allocate photosynthate from a favorable year towards flowering the subsequent year. Collectively, our results suggest that chronically high levels of herbivory may be associated with spatial patterning of flowering within populations of a non-clonal plant. They also highlight the persistence of underlying spatial patterns, as evidenced by high levels of spatial clustering among non-flowering individuals, and the pervasive, although muted in a population subjected to chronic herbivory, influence of precipitation and temperature on flowering in long-lived forest herbs. PMID- 25737823 TI - Doing mathematics with aftermath of pandemic influenza 2009. PMID- 25737824 TI - TEM and SHV Genes in Klebsiella pneumoniae Isolated from Cockroaches and Their Antimicrobial Resistance Pattern. AB - OBJECTIVES: Klebsiella pneumoniae is a gram-negative rod bacterium, a known cause of community-acquired bacterial pneumonia and is an important hospital-acquired pathogen that causes severe morbidity and mortality. The aim of this study was to identify the TEM and SHV genes in K. pneumoniae isolated from cockroaches obtained from hospitals. METHODS: In this study, 250 cockroaches were collected from different hospitals in the province of Chaharmahal Va Bakhtiari, which is located in southwest Iran. The samples were examined for the presence of K. pneumoniae by plating onto a combination of culture media, and the antimicrobial susceptibility patterns of isolated K. pneumoniae from samples were evaluated using the disk diffusion test. In addition, from the culture, genomic bacterial DNA was extracted, and sequence-specific targets (TEM and SHV genes) were amplified using the polymerase chain reaction (PCR) method. RESULTS: Out of 250 cockroach samples collected from various hospitals, 179 samples (71.60%) were positive for K. pneumoniae. PCR reaction was performed using specific oligonucleotide primers (TEM-F, TEM-R and SHV-F, SHV-R) for the amplification of each gene, and amplified products were visualized on 1% agarose gel electrophoresis. Of all the specimens amplified by PCR in this research, 32 samples (17.87%) were positive for TEM and 15 samples (8.37%) were positive for SHV. CONCLUSION: Detection of TEM and SHV genes using molecular methods and their pattern of antimicrobial resistance can provide useful information about the epidemiology of and risk factors associated with K. pneumoniae infection. PMID- 25737822 TI - Parcellating connectivity in spatial maps. AB - A common goal in biological sciences is to model a complex web of connections using a small number of interacting units. We present a general approach for dividing up elements in a spatial map based on their connectivity properties, allowing for the discovery of local regions underlying large-scale connectivity matrices. Our method is specifically designed to respect spatial layout and identify locally-connected clusters, corresponding to plausible coherent units such as strings of adjacent DNA base pairs, subregions of the brain, animal communities, or geographic ecosystems. Instead of using approximate greedy clustering, our nonparametric Bayesian model infers a precise parcellation using collapsed Gibbs sampling. We utilize an infinite clustering prior that intrinsically incorporates spatial constraints, allowing the model to search directly in the space of spatially-coherent parcellations. After showing results on synthetic datasets, we apply our method to both functional and structural connectivity data from the human brain. We find that our parcellation is substantially more effective than previous approaches at summarizing the brain's connectivity structure using a small number of clusters, produces better generalization to individual subject data, and reveals functional parcels related to known retinotopic maps in visual cortex. Additionally, we demonstrate the generality of our method by applying the same model to human migration data within the United States. This analysis reveals that migration behavior is generally influenced by state borders, but also identifies regional communities which cut across state lines. Our parcellation approach has a wide range of potential applications in understanding the spatial structure of complex biological networks. PMID- 25737825 TI - Preparation and Evaluation of a New Lipopolysaccharide-based Conjugate as a Vaccine Candidate for Brucellosis. AB - OBJECTIVES: Development of an efficacious vaccine against brucellosis has been a challenge for scientists for many years. At present, there is no licensed vaccine against human brucellosis. To overcome this problem, currently, antigenic determinants of Brucella cell wall such as Lipopolysaccharide (LPS) are considered as potential candidates to develop subunit vaccines. METHODS: In this study, Brucella abortus LPS was used for conjugation to Neisseria meningitidis serogroup B outer membrane vesicle (OMV) as carrier protein using carbodiimide and adipic acid-mediated coupling and linking, respectively. Groups of eight BALB/c mice were injected subcutaneously with 10 MUg LPS alone, combined LPS + OMV and conjugated LPS-OMV on 0 days, 14 days, 28 days and 42 days. Anti-LPS IgG was measured in serum. RESULTS: The yield of LPS to OMV in LPS-OMV conjugate was 46.55%, on the basis of carbohydrate content. The ratio for LPS to OMV was 4.07. The LPS-OMV conjugate was the most immunogenic compound that stimulated following the first injection with increased IgG titer of ~5-fold and ~1.3-fold higher than that produced against LPS and LPS in noncovalent complex to OMV (LPS + OMV), respectively. The highest anti-LPS IgG titer was detected 2 weeks after the third injection (Day 42) of LPS-OMV conjugate. The conjugated compound elicited higher titers of IgG than LPS + OMV, that showed a 100-120-fold rise of anti-LPS IgG in mice. CONCLUSION: These results indicate that our conjugated LPS-OMV can be used as a brucellosis vaccine, but further investigation is required. PMID- 25737826 TI - Evaluation of the Mechanical Properties and Drug Permeability of Chitosan/Eudragit RL Composite Film. AB - OBJECTIVES: The aim of this study was to design and evaluate a chitosan-based film that has properties required for successful wound dressing, and can control drug penetration and maintenance time in the location. METHODS: Several formulations of a film containing chitosan (3%) and different concentrations of Eudragit RL (0.5%, 1%, and 1.5%) were prepared using the casting/solvent evaporating technique. Mechanical properties, water vapor transmission rate (WVTR), oxygen permeability, water uptake, and nitrofurazone permeability through the films were investigated. RESULTS: The study results showed that by increasing the Eudragit RL content of composite films, their thickness and tensile strength were enhanced, while their elongation was decreased. No significant difference was observed between the oxygen permeability, WVTR, and water uptake results of pure chitosan films and different composite films containing Eudragit RL. Nitrofurazone permeability of chitosan films was increased by the inclusion of Eudragit RL in composite films, while by increasing the concentration of Eudragit RL, the permeation rate of drug was decreased. CONCLUSION: In conclusion, addition of Eudragit RL can improve mechanical properties of chitosan films without any undesirable effect on their water uptake, oxygen permeability, and WVTR qualities. The permeation rate of drugs through the composite films can be modified by changing Eudragit RL/chitosan ratio. PMID- 25737827 TI - Health status of the residents in occidental mindoro, Philippines: a way to make a healthy community. AB - OBJECTIVES: Even though Philippines is widely known as exporters of health workers in the world, the Occidental Mindoro province suffers from a lack of health workers compared with the total population of each municipality. The aim of this study was to observe, identify, and understand the persisting health status, knowledge, and practices among the three selected communities in Occidental Mindoro, Philippines. METHODS: The study applied a survey using basic questions with three key topics, with relevance to the health condition of the villagers, such as demographics (social capital and regional characteristics), lifestyle (healthy living, and healthy lifestyle and behavior), and status or position in the society (general demographics, and personal behavior and attitudes), with a random sample of 256 adult respondents. RESULTS: Only about 54.3% rated themselves as fair/moderately healthy, and a total of 17.2% suffered from chronic diseases such as diabetes mellitus, cancers, chronic obstructive pulmonary disease, and cardiovascular disease, while 9% have been diagnosed with tuberculosis in the past 6 months. Respondents mostly have low income and low education. CONCLUSION: The majority of the respondents have only primary and secondary education, and a very low average income; these suggest that respondents were afflicted with poverty and low educational attainment. Respondents who are deprived of their rights to obtain a higher education also have a higher chance of having less knowledge on their well-being. Health programs do not guarantee a healthy individual and a healthy society, but a combination of health programs and socioeconomic support can help in creating a healthy community. PMID- 25737828 TI - Comparative study of the impact of intoxication on injuries in china and Korea. AB - OBJECTIVES: Alcohol misuse has been widely studied as a substantial contributor to injured patients' visits to emergency departments. The current research studied differences in alcohol-related injury variables in China and Korea. METHODS: Data were collected from a sample of 4,509 patients (2,862 males and 1,667 females) reporting at emergency departments in China and Korea using the World Health Organization collaborative study on alcohol and injuries protocol. RESULTS: More injuries were reported by men, young people aged 25-34 years, employed individuals, and persons who had at least a high-school education. The proportion of injury cases among intoxicated patients was 14% for Chinese and 20% for Koreans. The odds of intentional injuries to intoxicated patients increased significantly when the perpetrator had been drinking, especially for severely intoxicated victims in both countries. The odds of injuries for intoxicated persons in both countries were high during sports and leisure activities; odds ratio (OR) = 3.93, 95% confidence interval (CI) = 2.76-5.59 for Chinese and OR = 10.97, 95% CI = 6.06-19.85 for Koreans. CONCLUSION: These findings are a contribution to research in the two Asian countries about the effect of intoxication on injuries especially when both victim and perpetrator are intoxicated. PMID- 25737829 TI - Evaluation of Mycobacterium tuberculosis Early Secreted Antigenic Target 6 Recombinant Protein as a Diagnostic Marker in Skin Test. AB - OBJECTIVES: Tuberculosis (TB) is the leading infectious disease in the developing world. Delayed-type hypersensitivity skin test diagnoses TB using tuberculin purified protein derivative (PPD), but this test is incapable of distinguishing Mycobacterium tuberculosis (MTB) infection from bacillus Calmette-Guerin (BCG) vaccination or an infection caused by nontuberculous mycobacteria (NTM). This study was performed to evaluate the use of recombinant early secretory antigenic target 6 (rESAT-6), a secretory protein found only in MTB, Mycobacterium bovis, and few other mycobacterial species, as a skin marker for MTB in guinea pigs. METHODS: We prepared recombinant MTB ESAT-6 and evaluated its use as a specific antigen for MTB in guinea pigs. RESULTS: Our results show that the purified MTB rESAT-6 antigen is capable of inducing a positive reaction only in guinea pigs sensitized to MTB. No such reaction was observed in the animals sensitized to M. bovis, BCG vaccination, or NTM (Mycobacterium avium). CONCLUSION: Our study results confirm that the ESAT-6 antigen is more specific to MTB infection than PPD and could be used in more specific skin tests for detection of MTB in large animals and in humans. PMID- 25737830 TI - Isolation and identification of endosulfan-degrading bacteria and evaluation of their bioremediation in kor river, iran. AB - OBJECTIVES: Endosulfan is a lipophilic insecticide, which causes severe health issues due to its environmental stability, toxicity, and biological reservation in organisms. It is found in the atmosphere, soil, sediments, surface waters, rain, and food in almost equal proportions. The aim of this study was to isolate and identify endosulfan-degrading bacteria from the Kor River and evaluate the possibility of applying bioremediation in reducing environmental pollution in the desired region. METHODS: Samples of surface sediments and water were collected from three different stations in two seasons (summer and autumn), as these are areas with high agricultural activity. Isolated bacteria were identified by various biochemical tests and morphological characteristics. The amounts of degradation of endosulfan isomers and metabolites produced as a result of biodegradation were then analyzed using gas chromatography/mass spectrometry. RESULTS: In this study, the following five bacterial genera were able to degrade endosulfan: Klebsiella, Acinetobacter, Alcaligenes, Flavobacterium, and Bacillus. During biodegradation, metabolites of endosulfan diol, endosulfan lactone, and endosulfan ether were also produced, but these had lesser toxicity compared with the original compound (i.e., endosulfan). CONCLUSION: The five genera isolated can be used as a biocatalyst for bioremediation of endosulfan. PMID- 25737831 TI - Assessment of intensive vaccination and antiviral treatment in 2009 influenza pandemic in Korea. AB - OBJECTIVES: We characterized and assessed public health measures, including intensive vaccination and antiviral treatment, implemented during the 2009 influenza pandemic in the Republic of Korea. METHODS: A mathematical model for the 2009 influenza pandemic is formulated. The transmission rate, the vaccination rate, the antiviral treatment rate, and the hospitalized rate are estimated using the least-squares method for the 2009 data of the incidence curves of the infected, vaccinated, treated, and hospitalized. RESULTS: The cumulative number of infected cases has reduced significantly following the implementation of the intensive vaccination and antiviral treatment. In particular, the intensive vaccination was the most critical factor that prevented severe outbreak. CONCLUSION: We have found that the total infected proportion would increase by approximately six times under the half of vaccination rates. PMID- 25737832 TI - Complete sequence analysis and antiviral screening of medicinal plants for human coxsackievirus a16 isolated in Korea. AB - OBJECTIVES: Coxsackievirus A group 16 strain (CVA16) is one of the predominant causative agents of hand, foot, and mouth disease (HFMD). METHODS: Using a specimen from a male patient with HFMD, we isolated and performed sequencing of the Korean CVA16 strain and compared it with a G10 reference strain. Also, we were investigated the effects of medicinal plant extract on the cytopathic effects (CPE) by CPE reduction assay against Korean CVA16. RESULTS: Phylogenetic analysis showed that the Korean CVA16 isolate belonged to cluster B-1 and was closely related to the strain PM-15765-00 isolated in Malaysia in 2000. The Korean CVA16 isolate showed 73.2% nucleotide identity to the G10 prototype strain and 98.7% nucleotide identity to PM-15765-00. Next, we assessed whether the Korean CVA16 isolate could be used for in vitro screening of antiviral agents to treat HFMD infection. Vero cells infected with the Korean CVA16 isolate showed a cytopathic effect 2 days after the infection, and the treatment of cells with Cornus officinalis, Acer triflorum, Pulsatilla koreana, and Clematis heracleifolia var. davidiana Hemsl extracts exhibited strong antiviral activity against CVA16. CONCLUSION: Collectively, our work provides potential candidates for the development of vaccine and novel drugs to treat the CVA16 strain isolated from a Korean patient. PMID- 25737833 TI - Experiences in healthy dieting of male college students with obesity in Korea. AB - OBJECTIVES: The purpose of this study was to describe and understand experiences of healthy dieting in male college students with obesity. METHODS: The interview data were collected from nine male students and analyzed by using descriptive phenomenology of Colaizzi. The procedural steps described the phenomenon of interest, collected participants' descriptions of the phenomenon, extracted the meaning of significant statements, organized the meanings into clusters, wrote exhaustive descriptions, and then incorporated data into an exhaustive description. RESULTS: The findings in 246 restatements, 47 constructed meanings, 31 themes, eight theme clusters, and four categories were deduced. The four categories were "Uneasiness at interpersonal relationships", "Developing durability in dieting strategies", "Practicing healthy diets based on information", and "Perceived on healthy diets as a whole health support strategies". CONCLUSION: This study described experiences in healthy dieting of male college students who were discharged from military services. These findings have important implications for understanding healthy dieting in young men and must be considered in developing health promotion in youth. PMID- 25737834 TI - Ovicidal and Oviposition Deterrent Activities of Medicinal Plant Extracts Against Aedes aegypti L. and Culex quinquefasciatus Say Mosquitoes (Diptera: Culicidae). AB - OBJECTIVES: To evaluate the ovicidal and oviposition deterrent activities of five medicinal plant extracts namely Aegle marmelos (Linn.), Limonia acidissima (Linn.), Sphaeranthus indicus (Linn.), Sphaeranthus amaranthoides (burm.f), and Chromolaena odorata (Linn.) against Culex quinquefasciatus and Aedes aegypti mosquitoes. Three solvents, namely hexane, ethyl acetate, and methanol, were used for the preparation of extracts from each plant. METHODS: Four different concentrations-62.5 parts per million (ppm), 125 ppm, 250 ppm, and 500 ppm-were prepared using acetone and tested for ovicidal and oviposition deterrent activities. One-way analysis of variance (ANOVA) was used to determine the significance of the treatments and means were separated by Tukey's test of comparison. RESULTS: Among the different extracts of the five plants screened, the hexane extract of L. acidissima recorded the highest ovicidal activity of 79.2% and 60% at 500 ppm concentration against the eggs of Cx. quinquefasciatus and Ae. aegypti, respectively. Similarly, the same hexane extract of L. acidissima showed 100% oviposition deterrent activity at all the tested concentrations against Cx. quinquefasciatus and Ae. aegypti adult females. CONCLUSION: It is concluded that the hexane extract of L. acidissima could be used in an integrated mosquito management program. PMID- 25737835 TI - The SH3 regulatory domain of the hematopoietic cell kinase Hck binds ELMO via its polyproline motif. AB - Eukaryotic EnguLfment and cell MOtility (ELMO) proteins form an evolutionary conserved family of regulators involved in small GTPase dependent actin remodeling processes that regulates the guanine exchange factor activity of some of the Downstream Of CrK (DOCK) family members. Gathered data strongly suggest that DOCK activation by ELMO and the subsequent signaling result from a subtle balance in the binding of partners to ELMO. Among its putative upward modulators, the Hematopoietic cell kinase (Hck), a member of the Src kinase superfamily, has been identified as a binding partner and a specific tyrosine kinase for ELMO1. Indeed, Hck is implicated in distinct molecular signaling pathways governing phagocytosis, cell adhesion, and migration of hematopoietic cells. Although ELMO1 has been shown to interact with the regulatory Src Homology 3 (SH3) domain of Hck, no direct evidence indicating the mode of interaction between Hck and ELMO1 have been provided in the literature. In the present study, we report convergent pieces of evidence that demonstrate the specific interaction between the SH3 domain of Hck and the polyproline motif of ELMO1. Our results also suggest that the tyrosine-phosphorylation state of ELMO1 tail might act as a putative modulator of Hck kinase activity towards ELMO1 that in turn participates in DOCK180 activation and further triggers subsequent signaling towards actin remodeling. PMID- 25737836 TI - MutT from the fish pathogen Aliivibrio salmonicida is a cold-active nucleotide pool sanitization enzyme with unexpectedly high thermostability. AB - Upon infection by pathogenic bacteria, production of reactive oxygen species (ROS) is part of the host organism's first line of defence. ROS damage a number of macromolecules, and in order to withstand such a harsh environment, the bacteria need to have well-functioning ROS scavenging and repair systems. Herein, MutT is an important nucleotide-pool sanitization enzyme, which degrades 8-oxo dGTP and thus prevents it from being incorporated into DNA. In this context, we have performed a comparative biochemical and structural analysis of MutT from the fish pathogen Aliivibrio salmonicida (AsMutT) and the human pathogen Vibrio cholerae (VcMutT), in order to analyse their function as nucleotide sanitization enzymes and also determine possible cold-adapted properties of AsMutT. The biochemical characterisation revealed that both enzymes possess activity towards the 8-oxo-dGTP substrate, and that AsMutT has a higher catalytic efficiency than VcMutT at all temperatures studied. Calculations based on the biochemical data also revealed a lower activation energy (E a) for AsMutT compared to VcMutT, and differential scanning calorimetry experiments showed that AsMutT displayed an unexpected higher melting temperature (T m) value than VcMutT. A comparative analysis of the crystal structure of VcMutT, determined to 2.42 A resolution, and homology models of AsMutT indicate that three unique Gly residues in loops of VcMutT, and additional long range ion-pairs in AsMutT could explain the difference in temperature stability of the two enzymes. We conclude that AsMutT is a stable, cold-active enzyme with high catalytic efficiency and reduced E a, compared to the mesophilic VcMutT. PMID- 25737837 TI - Regulation of a serine protease homolog by the JNK pathway during thoracic development of Drosophila melanogaster. AB - The importance of the Jun N-terminal Kinase (JNK) pathway during normal development and tumor invasion has been well documented in Drosophila. Here, this pathway plays important roles in epithelial morphogenesis, wound healing, apoptosis, immunity and regulation of lifespan. However, which downstream molecules facilitate these effects is not very well elucidated. In this study, data are presented on a serine protease homolog (SPH), scarface. These data show that scarface is under regulatory control of the JNK pathway and that this pathway is both necessary and sufficient for its expression within the context of thoracic development. Consequently, down-regulation of scarface results in a thoracic-cleft phenotype that phenocopies the JNK pathway defect. A possible role of scarface during thoracic development in Drosophila is discussed. PMID- 25737839 TI - Cleft and Craniofacial anomalies. PMID- 25737838 TI - NADH oxidase and alkyl hydroperoxide reductase subunit C (peroxiredoxin) from Amphibacillus xylanus form an oligomeric assembly. AB - The NADH oxidase-peroxiredoxin (Prx) system of Amphibacillus xylanus reduces hydroperoxides with the highest turnover rate among the known hydroperoxide scavenging enzymes. The high electron transfer rate suggests that there exists close interaction between NADH oxidase and Prx. Variant enzyme experiments indicated that the electrons from beta-NADH passed through the secondary disulfide, Cys128-Cys131, of NADH oxidase to finally reduce Prx. We previously reported that ionic strength is essential for a system to reduce hydroperoxides. In this study, we analyzed the effects of ammonium sulfate (AS) on the interaction between NADH oxidase and Prx by surface plasmon resonance analysis. The interaction between NADH oxidase and Prx was observed in the presence of AS. Dynamic light scattering assays were conducted while altering the concentration of AS and the ratio of NADH oxidase to Prx in the solutions. The results revealed that the two proteins formed a large oligomeric assembly, the size of which depended on the ionic strength of AS. The molecular mass of the assembly converged at approximately 300 kDa above 240 mM AS. The observed reduction rate of hydrogen peroxide also converged at the same concentration of AS, indicating that a complex formation is required for activation of the enzyme system. That the complex generation is dependent on ionic strength was confirmed by ultracentrifugal analysis, which resulted in a signal peak derived from a complex of NADH oxidase and Prx (300 mM AS, NADH oxidase: Prx = 1:10). The complex formation under this condition was also confirmed structurally by small-angle X ray scattering. PMID- 25737840 TI - Measurement error of 3D cranial landmarks of an ontogenetic sample using Computed Tomography. AB - BACKGROUND/AIM: Computed Tomography (CT) is a powerful tool in craniofacial research that focuses on morphological variation. In this field, an ontogenetic approach has been taken to study the developmental sources of variation and to understand the basis of morphological evolution. This work aimed to determine measurement error (ME) in cranial CT in diverse developmental stages and to characterize how this error relates to different types of landmarks. MATERIAL AND METHODS: We used a sample of fifteen skulls ranging from 0 to 31 years. Two observers placed landmarks in each image three times. Measurement error was assessed before and after Generalized Procrustes Analysis. RESULTS: The results indicated that ME is larger in neurocranial structures, which are described mainly by type III landmarks and semilandmarks. In addition, adult and infant specimens showed the same level of ME. These results are specially relevant in the context of craniofacial growth research. CONCLUSION: CT images have become a frequent evidence to study cranial variation. Evaluation of ME gives insight into the potential source of error in interpreting results. Neural structures present higher ME which is mainly associated to landmark localization. However, this error is irrespective of age. If landmarks are correctly selected, they can be analyzed with the same level of reliability in adults and subadults. PMID- 25737841 TI - Chlorhexidine-thymol varnish as an adjunct to scaling and root planing: A clinical observation. AB - AIM: To evaluate the efficacy of chlorhexidine-thymol varnish (Cervitec Plus((r))) as an adjunct to scaling and root planing in the improvement of periodontal parameters. MATERIAL AND METHODS: A split mouth randomized clinical trial was conducted in 25 subjects with chronic periodontitis receiving scaling and root planing alone and as an adjunct to chlorhexidine-thymol varnish (Cervitec Plus((r))) and chlorhexidine-thymol varnish (Cervitec Plus((r))) alone. Clinical examinations were performed at baseline, 1 month and 3 months. RESULTS: Short term advantages were observed in the clinical parameters in subjects receiving scaling and root planing and an adjunct, chlorhexidine-thymol varnish (Cervitec Plus((r))) who showed the greatest improvement in the periodontal parameters at 3 months. CONCLUSION: Subjects with chronic periodontitis significantly benefit from scaling and root planing when used with an adjunct, chlorhexidine-thymol varnish (Cervitec Plus((r))). PMID- 25737842 TI - Randomized control trial of non-vascularized fibular and iliac crest graft for mandibular reconstruction. AB - BACKGROUND: Mandibular reconstruction of segmental defects caused by trauma or tumor excision is a challenge despite numerous advances in surgical and fixation techniques. Bone grafts from fibula or iliac crest are most frequently used to reconstruct mandible. METHODS: A prospective randomized study was performed in 20 patients with benign mandibular pathology, to compare non-vascularized fibular and iliac crest bone graft for graft success, improvement in esthetics and function, and any associated donor site complications. RESULTS: No significant difference in graft success, esthetics, function, or donor site complication were found between the two groups. Function improvement was significantly higher in fibula group as compared to iliac crest. An interesting finding of positive association between length of defect and complication was seen irrespective of the graft used, implying that patients with larger defects had higher complication rates. CONCLUSION: Non-vascularized fibular bone graft is as better as iliac crest for reconstruction of mandibular defects of optimal length. PMID- 25737843 TI - Effects of first premolar extraction on maxillary and mandibular third molar angulation after orthodontic therapy. AB - BACKGROUND/AIMS: To compare the change in the angulation of developing mandibular third molar in both first premolar extraction and non-extraction cases and to determine whether premolar extraction results in a more mesial movement of the mandibular buccal segment and causes favorable rotational changes in the mandibular third molar tilt, which can enhance later eruption of the third molars. MATERIALS AND METHODS: Pretreatment (T1) and post treatment (T2) panoramic radiographs were taken of 25 subjects (age 14-19 years) who had been treated by the extraction of all the first premolars and 25 subjects who had been treated with non-extraction. The horizontal reference plane was used to measure and compare the changes in the angles of the developing mandibular third molars. RESULTS: The mean uprighting of the maxillary third molars seen in the extraction group was 4 +/- 9 degrees on the left side and -17 +/- 13 degrees on the right side following treatment (T2 _ T1). For the non-extraction group the mean difference was -16 +/- 12 degrees on the left side and 2 +/- 13 degrees on the right side. There was a statistically significant difference between the groups (P _ 0.021 on the right side and P _ 0.041 on the left side). Mandibular 3rd molars in extraction group showed no statistical significant change in the angulation. CONCLUSION: Premolar extractions had a positive influence on the developing maxillary third molar angulations both on right and left. Mandibular 3rd molar have shown change in the angulation but not statistically significant. Non-extraction therapy did not have any adverse effect. PMID- 25737844 TI - Comparative evaluation of apical extrusion of debris and irrigant with three rotary instruments using crown down technique - An in vitro study. AB - AIMS AND OBJECTIVE: The purpose of this study was to evaluate and compare the apical extrusion of debris and irrigant using various rotary instruments with crown down technique in the instrumentation of root canals. MATERIAL AND METHOD: Thirty freshly extracted human permanent straight rooted mandibular premolars with minimum root curvature of 0-10 degrees were divided in three groups with 10 teeth in each group. Each group was instrumented using one of the three rotary instrumentation systems: Rotary Hero shapers, Rotary ProTaper and Rotary Mtwo. One ml of sterile water was used as an irrigant after using each instrument. Debris extruded was collected in pre weighed glass vials and the extruded irrigant was measured quantitatively by Myers and Montgomery method and was later evaporated. The weight of the dry extruded debris was calculated by comparing the pre and post instrumentation weight of glass vials for each group. STATISTICAL ANALYSIS: Statistical analysis was done by using by a Kruskal-Wallis One-way ANOVA test. RESULTS: Statistical analysis showed that all the rotary instruments used in this study caused apical extrusion of debris and irrigant. A Statistically significant difference was observed with Rotary ProTaper and Rotary Mtwo groups when compared with Rotary Hero shapers. But no significant difference was observed between Rotary ProTaper and Rotary Mtwo groups. CONCLUSION: After instrumentation with different rotary instruments, Hero shapers showed a less apical extrusion of debris and irrigant. PMID- 25737845 TI - Can early exposure to probiotics in children prevent dental caries? A current perspective. AB - BACKGROUND: Probiotics are supplements or foods that contain viable microorganisms which cause alterations of the microflora of the host. Probiotics have already been established in the treatment and prevention of various gastrointestinal system. Recently, role of probiotics has become an important issue for research in dentistry in the era of increased antibiotic resistance. MATERIALS AND METHODS: The basis of the paper is the clinical studies and research done in relation to probiotics on oral health using PUBMED search database. RESULTS AND CONCLUSIONS: Although many clinical studies have demonstrated positive outcome in preventing caries and periodontal diseases, the data is still scarce in recommending probiotics for the oral health. Moreover, since initial colonization of oral cavity of the newborn is very important for developing immunity and prevention of future diseases. Hence, measures should be directed towards its preventive use in infants and children. The formulations produced for oral cavity should also be within reach of common man especially in underdeveloped and developing countries. This review endeavors to compile the research of probiotics on oral cavity and throws a light on its evolving status in developing countries. It also evaluates its use in children for a long-term benefit. PMID- 25737846 TI - Crouzon syndrome with primary optic nerve atrophy and normal brain functions: A case report. AB - BACKGROUND: This report and review of literature aimed to assess an unusual case of Crouzon syndrome characterized by distinctive disfigurement of craniofacial skeletal and soft tissue structures with primary optic nerve atropy. METHODS: We present a case of a 12-year-old girl with Crouzon syndrome displaying classic facial abnormalities with reduced vision and hearing loss. CONCLUSION: Crouzon syndrome should be managed as early as possible as it results in airway obstruction, decreased vision, mental retardation and poor cosmetic appearance. PMID- 25737847 TI - Clinically obscure venous malformation in the sub mandibular triangle: A rare presentation. AB - Vascular lesions have been classified as hemangiomas or vascular malformations depending on the presence of cellular proliferation. These lesions have been known to cause significant morbidity and even mortality in both children and adults. Confusing nomenclature, relative rarity of these lesions, inappropriate diagnosis, lack of precise imaging studies and deficiency of multidisciplinary approach are some of the factors which result in ineffective treatment of such patients. Here, we report a rare case of venous vascular malformation presenting as a mass in the sub mandibular region with no clinical stigmata which was diagnosed with the help of various imaging techniques and subsequently treated by surgery. PMID- 25737848 TI - Wide alveolar cleft and midface distraction: Report of a case. AB - BACKGROUND: Cleft lip and palate patients often present wide alveolar cleft and midface hypoplasia. Closure of such wide alveolar clefts may be difficult using bone graft. Traditional orthognathic surgery for midface advancement shows relapse. Distraction osteogenesis (DO) as a modality for midface advancement has shown good results with external distractors. Use of internal distractor (ID) further improves patient compliance, causes minimal discomfort and offers the advantage of limiting relapse. The purpose of this study was to evaluate the versatility of intraoral distracters in midface advancement in cases with alveolar cleft. METHOD: A 16 years old young girl with midface deficiency and alveolar cleft visited our outpatient clinic for aesthetic improvement and midface distraction was planned. After Le Fort I osteotomy, internal distractor was fixed. A latency period of 5 days was allowed and then distraction was started at the rate of 1 mm per day in two installments. Evaluation was done for closure of cleft, ease of the procedure, stability, and complications. Lateral cephalograms were evaluated at three stages: predistraction; post-distraction; and 1 year post-distraction. RESULTS: Complete closure of alveolar cleft was observed with 17 mm midface advancement and bone formation at the pterygomaxillary region. Maxillary position improved in relation to the cranial base. The results were stable even at 1 year follow-up. CONCLUSION: Distraction osteogenesis using intraoral distractors was successful in alveolar cleft closure, as well as midface advancement in terms of stability of results and patient compliance with minimal complications. PMID- 25737849 TI - Clinical considerations for prosthodontic rehabilitation of intermediate form of osteopetrosis: A report of two cases. AB - INTRODUCTION: Osteopetrosis is a rare autosomal hereditary disorder characterized by abnormal functioning of osteoclasts, which leads to delayed wound healing. Hence chances of infection are increased even after minor surgical procedures. This paper aims to describe clinical features, and prosthodontic management of two patients who presented with clinical features of intermediate form of osteopetrosis and missing teeth. CASE REPORT: A 27-year-old patient having intermediate osteopetrosis presented with difficulty in chewing food and swallowing, due to edentulous maxillary and mandibular arches with large antral cavities, which developed secondary to tooth extraction. Another case discussed is a 25-year-old female patient who reported with chief complaints of difficulty in chewing due to resected left side of lower jaw. In these case reports, importance of avoiding extractions, preservation of remaining teeth and conservative management with minimum number of patients' visits has been emphasized. CONCLUSION: Efforts should be made to avoid dental extraction in such cases as chances of bone infection and fracture are more. If patient is partially or completely edentulous only removable type of prosthesis is advisable as bones are hypocalcified and maintenance of oral hygiene is easy with removable prosthesis. PMID- 25737850 TI - Treatment of multiple adjacent gingival recessions in a single surgical approach with expanded subepithelial connective tissue graft - An innovative approach. AB - BACKGROUND: Gingival recession on anterior teeth compromises facial esthetics and is associated with dentinal hypersensitivity. Multiple teeth recession requires multiple surgeries for adequate coverage. METHODS: Six anterior mandibular teeth were treated with single Subepithelial Connective Tissue Graft (SCTG) expanded with the use of alternate vertical incisions. A brief review of SCTG is included. RESULTS: 90 days evaluation revealed adequate recession coverage. Patient was satisfied with the esthetic results. CONCLUSION: The present technique may be an innovative approach for single surgical harvesting and placement of SCTG over long expanse multiple adjacent gingival recessions. This technique prevents multiple surgical traumas to the patient and enhances esthetics. PMID- 25737851 TI - Free gingival autograft for augmentation of keratinized tissue in apical to gingival recession - A case report. AB - BACKGROUND: The treatment of the mucogingival problem is one of the main objectives of the periodontal therapy. The insufficient or absent attached gingiva increases the risk of development of gingival recessions. METHOD: One patient with Miller class II gingival recession and small vestibule depth in the frontal mandibular region was selected for treatment. Autogenous free gingival grafts harvested from the palatal mucosa were used to gain the attached gingiva. RESULT: The initial healing completed in 2 weeks without complication. The augmentation of the attached gingival tissue using the free gingival graft technique led to gain of attached gingiva in the treated regions. CONCLUSION: The limitations of the apical mucosal flap displacement for preparation of recipient site in situations with inadequate vestibule depth and small alveolar bone height require a graft with small width. The result from the presented case report with application of the free gingival graft indicates that it could be applied when augmentation of the attached gingiva tissue. PMID- 25737852 TI - Rare association of dens invaginatus with impacted mesiodens - A case report. AB - Mesiodens is a supernumerary tooth occupying the position in the maxillary anterior region. This additional tooth structure may cause disturbance in eruption or position of the adjacent teeth. About 8-25% of supernumerary teeth in the anterior region erupt spontaneously. Un-erupted supernumerary teeth are incidentally identified on a routine radiographic examination. Dens invaginatus is a rare tooth malformation showing an in-folding of enamel and dentine of affected tooth sometimes extending deep into the pulp cavity and the root portion. We report a case of un-erupted mesiodens causing midline diastema of permanent teeth subsequently corrected following extraction of mesiodens. Dens invaginatus was identified affecting the un-erupted mesiodens. It is rare to find dens invaginatus associated with a supernumerary tooth and only 10 such instances of dens invaginatus affecting supernumerary teeth have been reported in the English literature. PMID- 25737853 TI - The path less taken. PMID- 25737854 TI - Management of temporomandibular joint disorders. PMID- 25737855 TI - Anatomical vagaries in maxillo-facial region. PMID- 25737856 TI - Reconstruction of ramus-condyle unit with transport distraction osteogenesis: Report of eight cases and review of literature. AB - BACKGROUND/AIMS: This report and review of literature aimed to assess the feasibility of condylar distraction in humans and its esthetic and functional outcome. METHODS: We present a case series of eight TMJ ankylosis patients, where after a gap arthroplasty, ramus condyle unit was reconstructed using transport distraction to analyze its feasibility, esthetic and functional outcome and success. RESULTS: All patients had satisfactory mouth opening, and minimal pain in their follow-up period. CONCLUSION: Condylar transport distraction osteogenesis holds promise for successful TMJ reconstruction and should be the method of choice as it does not involve secondary surgery or need for an alloplast. PMID- 25737857 TI - Evaluation of carotid artery atheromatous plaques using digital panoramic radiographs with Doppler sonography as the ground truth. AB - OBJECTIVES: The objective of the study was to determine whether digital panoramic radiography is a reliable method to detect calcified carotid artery atheromatous plaques (CCAAP) as compared to ultrasonography. STUDY DESIGN: Digital panoramic radiographs were obtained from 50 patients who also underwent carotid ultrasound examination. The images were interpreted by trained maxillofacial radiologist for the presence or absence of calcified atheromatous plaques. The extent of carotid calcification on carotid ultrasonography was determined by a trained sonologist which was considered as gold standard assessment. RESULTS: Digital panoramic radiographs had sensitivity of 76% and specificity of 98.66% in determining calcified carotid artery atheromatous plaques. There was a high level of agreement between diagnoses, with a kappa value of 0.8. CONCLUSION: To conclude, digital panoramic radiographs had good sensitivity and high specificity in detecting calcified carotid artery atheromatous plaques. If properly trained, dentists can detect such plaques and can refer patients to physician for timely medical treatment. PMID- 25737858 TI - Fractures of angle of mandible - A retrospective study. AB - AIMS: This retrospective study was done to evaluate the efficacy of single miniplate osteosynthesis at superior border of angle of mandible. MATERIAL AND METHODS: In this study 50 patients were treated by single miniplate osteosynthesis according to Champy's principle. Bite force generated was used as a parameter for judging the efficacy of internal fixation. In this article we present our experience over the years in the management of the fractures of angle of mandible based on this model. RESULTS: Most patients were of 21-30 yrs of age with unilateral angle fracture of mandible except one patient who had isolated bilateral angle fracture. The patients were treated successfully according to Champy's principle of osteosynthesis. There was a progressive improvement in the bite force generated after osteosynthesis. CONCLUSIONS: The angle of the mandible is an anatomically weak and an area susceptible to fracture. The presence of an impacted or partially erupted third molar tooth further weakens it. Angle of mandible is the most common site for fracture however, bilateral angle fracture is very rare and uncommon. Osteosynthesis according to Champy's model led to an early functional improvement as demonstrated by the bite force generated. PMID- 25737859 TI - Effect of tobacco, alcohol, and smoking habits in oral precancer with histological proven epithelial dysplasia. AB - OBJECTIVES: To assess the effect of risk factors tobacco, alcohol, and smoking habits in oral precancer patients with epithelial dysplasia status. MATERIAL AND METHODS: The study sample included biopsy proven cases of 29 oral submucous fibrosis (OSMF) and 43 cases of clinical leukoplakia. Histopathological diagnosis was made from formalin fixed paraffin embedded tissues as per WHO criteria. The relevant clinical and demographic details were recorded after interviewing the patients. Risk for tobacco, alcohol and smoking was determined by logistic regression analysis by SPSS software. RESULTS: Presence of epithelial dysplasia was significantly associated with tobacco in OSMF & both tobacco and smoking habits in leukoplakia. In OSMF tobacco was associated with 14.16-fold (95% CI, 1.36-147.07; p < 0.026) and in leukoplakia tobacco was associated with 4.66-fold (95% CI, 1.00-21.63; p < 0.047) and smoking was associated with 9.20-fold (95% CI, 1.65-51.28; p < 0.011) increased risk of epithelial dysplasia. CONCLUSION: Tobacco consumption was independent risk factor for epithelial dysplasia in OSMF and both tobacco and cigarette smoking were independent factors for epithelial dysplasia in leukoplakia. PMID- 25737860 TI - Oral verrucous lesions: Controversies in diagnosis and management. AB - AIMS: Oral verrucous lesions, typically presenting as slowly enlarging, grey or white, warty, exophytic overgrowths on the buccal mucosa or gingiva may be verrucous carcinoma (VC), verrucous hyperplasia (VH), proliferative verrucous leukoplakia (PVL), or may show the conventional invasive pattern of squamous cell carcinoma (SCC). This study was undertaken with the aim to report the demography of different types of oral verrucous lesions and evaluate their long-term outcome. MATERIAL & METHODS: This clinical study comprised 15 patients with verrucous lesions of the oral cavity who underwent biopsy for confirmation of diagnosis. RESULTS: Among these, 12 (80%) were male and only three (20%) were female. The age distribution ranged from 32 to 74 years with a median age of 45 years at the time of diagnosis. The most common site of VC within the oral cavity was the buccal mucosa (46.7%). 5 were proven cases of VC, 3 PVL and 7 VH. All cases of VH, PVL were managed by surgical excision, while VC was managed by surgical excision with superficial ostectomy followed by two cycles of chemotherapy additionally, if micro-invasion was observed on histopathological examination. The 2-year overall survival and tumour control rate was 93.4%. Recurrence was not seen in any patient till the time of analysis at a follow up of 3-5 years. CONCLUSION: Accurate diagnosis of the verrucous lesions is important and should be differentiated from grade I squamous cell carcinoma. Management should be based upon the nature, behaviour and malignant potential of the lesion. PMID- 25737861 TI - Sterilization of extracted human teeth: A comparative analysis. AB - BACKGROUND: Extracted human teeth are regularly used for practice and educational purposes in dental institutions at undergraduate and postgraduate levels. Different materials and methods are used for sterilizing extracted teeth to avoid infection from them. AIMS: The present study was done to determine the efficacy of some frequently used methods for disinfection/sterilization of extracted human teeth. MATERIALS AND METHODS: A total of 120 intact, non-carious teeth extracted due to periodontal or orthodontic purpose were divided randomly into 8 groups consisting of 15 teeth in each group. Agents used for sterilization included 10% formalin, 0.1% thymol in distilled water, 5.25% sodium hypochlorite, 2% glutaraldehyde, 3% hydrogen peroxide, boiled in water (100 degrees C), autoclave (121 degrees C, 15 lbs psi), normal saline. Samples were collected with the help of inoculating loop and then streaked over the surface of Mc-Conkey agar medium and Blood agar medium. The media were then incubated at 37 degrees C for 24 h. No visible growth in the culture medium was considered as the method of effective sterilization. RESULTS: 10% formalin, autoclaving, 5.25% sodium hypochlorite could be efficiently used for sterilization and disinfection of extracted human teeth. CONCLUSION: Extracted teeth should be handled with extreme care as these are potential source of infection and need to be disinfected before they are used in the laboratories. PMID- 25737862 TI - Efficiency of traditional chewing stick (miswak) as an oral hygiene aid among Muslim school children in Lucknow: A cross-sectional study. AB - BACKGROUND: Oral hygiene practices vary from country to country and from culture to culture. 'Miswak' as an oral hygiene aid is a pre-Islamic custom contributed to ritual purity. The beneficial effects of miswak in respect to oral hygiene and dental health are attributed to its mechanical and pharmacological actions. AIM: The aim of the present study was to assess and compare the oral hygiene status and gingival conditions in Muslim school children of Lucknow city. MATERIALS & METHOD: Study population comprised of 297 individuals in age group of 12-15 years from residential and non-residential Islamic institutions in Lucknow city. Oral hygiene status was assessed using the Gingival Index (1963), Oral Hygiene Index Simplified (1964) and Plaque Index (1964). RESULTS: Statistically significant difference of mean gingival index score was observed among miswak and toothbrush & toothpaste users. Miswak users had lower mean gingival index score. Mean plaque score was lowest among combined users of toothbrush and miswak. CONCLUSION: Miswak users exhibited a better mean gingival score as compared to toothbrush & toothpaste users, while the mean plaque score was lowest among the combined users of toothbrush and miswak. PMID- 25737863 TI - Oral microbial habitat a dynamic entity. AB - Oral microbial habitat is composed of wide variety of species. These species play a significant role in maintaining the well being of the oral cavity by contributing in various ways. However the proper functioning of these oral microbes can be detrimental for the human oral cavity if the conditions are not suitable such as redox potential (Eh), pH of a site, the activity of the host defenses, and the presence of antimicrobial agents. The oral microbial community represents the best-characterized group associated with the human host. There are strong correlations between the qualitative composition of the oral microbiota and clinically healthy or diseased states. Amongst the bacteria of more than 700 species now identified within the human oral microbiota, it is the streptococci that are numerically predominant. Interactions between mucosal surfaces and microbial microbiota are key to host defense, health, and disease. These surfaces are exposed to high numbers of microbes and must be capable of distinguishing between those that are beneficial or avirulent and those that will invade and cause disease. Our understanding of the mechanisms involved in these discriminatory processes has recently begun to expand as new studies bring to light the importance of epithelial cells and novel immune cell subsets such as T(h)17 T cells in these processes. In this review article we have tried to find out the factors responsible for maintaining oral microbial habitat intact and the reasons which cause changes in its composition. PMID- 25737864 TI - Trigeminal neuralgia: An insight into the current treatment modalities. AB - Trigeminal neuralgia (TN) is one of the most excruciating pain syndromes afflicting the orofacial region. Trigeminal neuralgia may be primary i.e. idiopathic or secondary, resulting from trauma or a CNS lesion. Considering the agonizing nature of the disease and TN being the commonest of the neural maladies affecting the orofacial region it is important for the oral physician to be aware of all available treatment options. This article makes an attempt to present a brief insight into the current treatment modalities that are on hand to treat this condition. From the perspective of the oral physician the pharmacotherapy constitutes the cornerstone in the management of TN. At the same time, it is also important to be aware and updated of the role of the oral surgeon and radiologist in the application of the array of interventional procedures available for treating TN. PMID- 25737865 TI - Novel registration technique to register neutral zone. AB - INTRODUCTION: The three dimensional volume of complete dentures optimally occupies an edentulous space that is substantial, in the light of the progressive changes that accompany edentulism and functional dynamics. The paper discusses current knowledge of neutral zone registration and presents a novel technique for this registration. MATERIAL AND METHODS: Fabricate maxillary and mandibular occlusal rims over conventional record bases using high fusing impression compound. Register the maxillary and mandibular neutral zone separately by swallowing method and after try in of complete denture; remove the wax apical to the tooth surfaces and recording will be completed with putty and light body impression material. RESULTS: Complete dentures are a biomechanical device that must be designed in harmony with normal neuromuscular function to get stability and proper function. Improper teeth positioning and polished surface contour will result in compromised stability of denture. CONCLUSIONS: This article describes a preview of facio-lingual positioning of denture teeth along with a novel approach of recording the neutral zone with an elastomeric impression material. PMID- 25737866 TI - Ameloblastoma - An enigma. AB - Ameloblastoma remains an enigmatic group of oral tumors, inspite of being so frequently encountered and widely discussed. Out of the total ameloblastomas reported, 81% cases have been in the mandible, of which 70% are in the molar ramus area. We report two cases of ameloblastoma with misguiding radiographic and clinical pictures, which made us ponder that common oral lesions are sometimes, the most tough and confusing to diagnose. PMID- 25737867 TI - Adenocarcinoma of the sublingual salivary gland - A case report. AB - BACKGROUND: This report and review of literature aimed to assess a case of adenocarcinoma of sublingual salivary gland. METHOD: We present a case of a 52 year-old female with adenocarcinoma of sublingual salivary gland displaying painful swelling in the floor of the mouth, which was affecting her speech and mastication. CONCLUSION: Surgery is the treatment of choice for malignant sublingual gland tumors, but the type of surgical intervention depends on the extent of the primary tumor itself. Even though the tumors of the sublingual salivary gland are rare, they are a diagnostic challenge to every head and neck surgeon. PMID- 25737868 TI - Management of wooden foreign bodies in craniofacial region. AB - Even though variety of foreign bodies has been reported in a various locations in the craniofacial region, wooden foreign bodies are uncommon. Appropriate management of wooden foreign bodies is considered essential because of their infectious complications and difficulty in radiographic localization. Even though literature is replete with articles on management of foreign bodies in the craniofacial region, specific management of wooden foreign bodies are rarely reported. The purpose of this article is to report two cases of deeply placed wooden foreign body and a protocol for managing them in the maxillofacial region. PMID- 25737869 TI - Full mouth rehabilitation of hypomaturation type amelogenesis imperfecta: A clinical report. AB - PROBLEM CONSIDERED: This clinical report describes the prosthodontic treatment of an 18-year-old female diagnosed with amelogenesis imperfecta. MATERIALS AND METHOD: The specific objectives of the treatment were to restore esthetics and masticatory function. Metal-ceramic fixed partial dentures were fabricated at the existing vertical dimension of occlusion utilizing the PMS occlusal scheme. RESULTS: Clinical examination of the patient 12 months after treatment revealed no evidence of disease or degeneration of the restored teeth. CONCLUSION: The patient's esthetic and functional expectations were satisfied. PMID- 25737870 TI - Strengthening oral care. PMID- 25737871 TI - Robotic surgery. PMID- 25737872 TI - Alveolar bone graft with Platelet Rich Plasma in cleft alveolus. AB - INTRODUCTION: Cleft of the lip, palate and alveolus are the commonest congenital anomaly to affect the orofacial region. Currently, there is great interest in the alveolar bone grafting procedures that involve use of platelet-rich-plasma (PRP), to enhance bone formation and specifically to promote bone graft healing. MATERIALS AND METHODS: 20 patients with residual alveolar cleft, in the age group of 9-29 years, having unilateral or bilateral cleft lip and palate were selected. They were randomly assigned in either group A (with PRP) or group B (without PRP). RESULTS: Primary healing was observed in 90% patients in group A. Secondary healing was seen in 30% patients in group B. There was no graft rejection in group A but was seen in one patient (10%) in group B. Pain and swelling persisted longer in group B then group A. Bone grafts with added PRP presented with increased bone density (1028.00 +/- 11.30 HU) in comparison to grafts without PRP (859.50 +/- 27.73 HU) at end of 6-month postoperative. However, the mean bone density (as determined by the Dentascan image analyzer software) was 1.04 times more in the PRP group than non PRP group at 3-month and 1.2 times more at 6 months. CONCLUSION: We conclude that on preliminary investigations, PRP seems to enhance bone formation in alveolar clefts when admixed with autologous cancellous bone harvested from the iliac crest. PMID- 25737873 TI - Dimensional changes in maxillary sinus of mouth breathers. AB - AIMS: Nose being the primary mode of air intake in humans can be obstructed in certain conditions and mouth takes over the process of breathing. As a result, there is a reduced or complete loss of function of nose, which shows underdevelopment or stunted growth (change in form). This can lead to impaired pneumatization that can result in dimensional changes in the sinus. OBJECTIVE: To assess volume alterations in maxillary sinus as secondary and as compensatory mechanism to altered functional matrices by comparing overall maxillary sinus volume of mouth breathers with normal breathers in the age group 12-14 years and to evaluate effect of gender on maxillary sinus volume. MATERIAL AND METHOD: Maxillary sinus volume calculated using manual segmentation method from CBCT scans of 25 normal breathers and 25 mouth breathers were compared. RESULTS: Mean maxillary sinus volume of mouth breathers was significantly less than normal breathers (p < 0.05). CONCLUSION: Mouth breathers showed lesser maxillary sinus volume but it is still uncertain whether the reduction in the volume of maxillary sinus is because the form of the maxillary sinus is affected due to improper functioning of nasal cavity or due to the underlying pathological condition resulting in poorly growing sinus. PMID- 25737874 TI - Anchor lag screw vs conventional lag screw in mandibular fractures: A series of 30 cases. AB - Lag screw osteosynthesis is a well proven technique. Its application is limited by the fact that the spherical head of the screw act as wedge. Combining this screw with a bioconcave washer has broadened the range of applications for lag screw osteosynthesis in the maxillofacial region. PURPOSE: The aim of the study was to compare the efficacy of anchor lag screw with conventional lag screw in anterior mandibular fractures. PATIENTS AND METHOD: Thirty patients with anterior mandible fractures with no concomitant fractures, infection or extraoral communication, who visited our outpatient Department of Oral and Maxillofacial Surgery, were included in the study after obtaining their informed consent. Patients were randomly divided into two groups; where Group A underwent fixation using conventional lag screw and Group B anchor lag screw. The fixation system used included 2 mm titanium lag screws of sizes 25 mm, 27 mm and 30 mm and 3 mm titanium bioconcave washer. At each follow up visit, clinical data was collected detailing clinical presentation of healing and radiographic findings. RESULTS: Radiographic features at post surgery evaluation indicated loss of bone contact around the screw head and bone resorption in five patients of Group A, thus causing loosening of lag screw whereas none of the patient in Group B, was found to have any such complication. CONCLUSIONS: The findings support the hypothesis that bioconcave washer aids in holding up the farthest fragment at the interface of the fracture fragment. Application of bioconcave washer provides easy loading of lag screw. PMID- 25737875 TI - Retrospective study of absorbable gelatin sponge soaked in triamicinolone acetonide as interpositioning material in temporomandibular joint ankylosis in 350 patients. AB - AIM: To evaluate the feasibility and usefulness of absorbable gelatin sponge soaked in triamcinolone acetonide as an interposition material in the treatment of temporomandibular joint (TMJ) ankylosis. MATERIALS AND METHODS: This retrospective study was conducted in 350 patients of TMJ ankylosis who visited our outpatient department between 2000 and 2010, and were treated by the same surgeon. Patients were randomly divided into two groups, where in group 1, absorbable gelatin sponge soaked with triamcinolone acetonide was interposed in the surgical gap created after arthroplasty and in group 2, temporalis fascia was interposed. Preoperative assessment included history and physical examination, along with cause of ankylosis, Postoperative observation were undertaken for maximum mouth opening (MMO), facial nerve paralysis and recurrence. RESULTS: At one year follow-up, in group 1 MMO ranged from 35 to 45 mm with no case of re ankylosis while in the other group 25-43 mm, with re-ankylosis in 20 patients (13.69%). CONCLUSION: The findings of this study showed successful management of TMJ ankylosis using absorbable gelatin sponge soaked in triamcinolone acetonide in cases which did not require condylar reconstruction. PMID- 25737876 TI - Dental complications and management of patients on bisphosphonate therapy: A review article. AB - Bisphosphonates are group of drugs that inhibit bone resorption and are used to treat a range of pathologies including Paget's disease, osteoporosis, multiple myeloma and metastasis associated with breast or prostate cancer. The most common complication in patients on bisphosphonate therapy is osteonecrosis of jaw (ONJ) which can occur after any surgical dental procedure and the risk for the development of osteonecrosis of jaw is higher in patients receiving intravenous bisphosphonate therapy than in patients receiving oral bisphosphonate therapy. Typical presentation is in the form of non-extraction socket, presence of exposed bone, gingival swelling or purulent discharge, when local debridement and antibiotics are ineffective. At present, there is no effective treatment for bisphosphonate induced osteonecrosis, so prevention is extremely important. Maximum precautions should be taken in patients who are at the risk of development of ONJ especially when any dental surgical procedure like extractions, retrograde apicoectomies, periodontal surgery and implant placement is contemplated. Dentists and oral or maxillofacial surgeon must keep up to date with the latest approaches or guidelines to prevention and the risk factors, particularly when treating patients who are on bisphosphonates, or who will be taking bisphosphonates. PMID- 25737877 TI - Mixture tetracycline citric acid and detergent - A root canal irrigant. A review. AB - BACKGROUND: Root canal irrigants play an indispensable role for the complete disinfection of the root canal system, in particular those areas of the root canal that are not accessible for instrumentation. Sodium hypochlorite, ethylene diamine tetra acetic acid, hydrogen peroxide and chlorhexidine are the most commonly used root canal irrigants in endodontic practice, but they do not satisfy all the properties of an ideal root canal irrigant. Mixture tetracycline, citric acid and detergent, a root canal irrigant, is commercially available as BioPure MTAD (Dentsply, Tulsa Dental, Tulsa, OK). METHODOLOGY: The literature was searched for root canal irrigants used in the last 3 decades in PubMed. Data showed 83 relevant articles, of which 24 were found most suitable on the basis of description of properties, advantages and disadvantages of MTAD, hence were included. The aim of this study was to evaluate the properties of MTAD for its antibacterial efficiency, biocompatibility, chelating action with removal of endodontic smear layer and compare it with other commonly used root canal irrigants like sodium hypochlorite, ethylene diamine tetra acetic acid, hydrogen peroxide, chlorhexidine. RESULTS: MTAD was found to be highly effective intracanal irrigant compared to other commonly used root canal irrigants with excellent disinfection of the entire root canal system. CONCLUSION: MTAD is biocompatible with superior antimicrobial efficiency compared to other commonly used root canal irrigants. PMID- 25737878 TI - Management of chronic parotid fistula with sodium tetradecyl sulfate. AB - A parotid fistula is a rare, extremely unpleasant disease. It may be due to chronic pathologies of the facial soft tissues, trauma (tangential injury to face), infection or congenital. Various treatment modalities including surgical and conservative management are present to treat this disease. Conservative management plays a vital role in patients who are systemically compromised and unfit for surgery. In the present case report an alternative conservative technique of parotid fistula management has been described in a 28-year-old girl who was severe anemic with parotid fistula since last 25 yrs. PMID- 25737879 TI - Treatment of recurrent TMJ dislocation in geriatric patient by autologous blood - A technique revisited. AB - A number of techniques have been advocated for the treatment of recurrent temporomandibular joint dislocation. Autologous blood injection around the articular capsule and/or into the articular cavity, which is one of the treatment modality, was recently reintroduced. We report a case of 82-year-old female with bilateral recurrent temporomandibular joint dislocation, treated by technique of autologous blood injection. The outcome was successful and required no further treatment in eight months follow up, thus the procedure had proven to be safe, simple, minimally invasive and cost effective. PMID- 25737880 TI - Pressure appliance to prevent the recurrence of auricular seroma: A new clinical trial. AB - STATEMENT OF PROBLEM: Auricular swellings significantly affect the facial aesthetics. Swelling affecting the pinna can lead to overt disfigurement and change the entire appeal of the face. Gross deformity can occur because of a delay in diagnosis and mismanagement. In our clinical trial fabrication of a simple, effective innovative pressure appliance for auricular seroma is presented to prevent such changes. METHOD: Our case report comprises of a new clinical trial on a patient with auricular seroma referred from the department of ENT, M.S. Ramaiah medical hospital, Bangalore, Karnataka. A 19-gauge stainless steel wire (Leo wire, Leone, Italy) and chemically cure resin was used to fabricate the pressure appliance to prevent the recurrence of auricular seroma. RESULT: Patient was successfully treated with the help of pressure appliance after 8 weeks of follow up. CONCLUSION: This appliance is a masked alternative to conventional pressure dressing after drainage of auricular seroma which does not pose embarrassment for patient to apply. The use of such an appliance will ensure patient compliance, thereby preventing long term auricular deformity. PMID- 25737881 TI - Two interesting cases of EEC syndrome. AB - AIM: To report two cases of EEC syndrome with oral involvement to highlight the fact that the dental surgeon may be among the first to recognise the condition. INTRODUCTION: The EEC syndrome, a rare congenital syndrome is characterised by ectodermal dysplasia, distal limb anomaly, cleft lip and palate and lachrymal duct anomalies although the term oligosymptomatic EEC syndrome has been suggested for cases in which ectrodactyly may be absent and that such cases should not be deprived of the EEC syndrome diagnosis. It is usually inherited as an autosomal dominant trait with variable expressivity and penetrance and all these features rarely coexist in a single individual. CONCLUSION: Both our cases had all three characteristic features of the EEC syndrome. Other syndromes with overlapping features such as the Rapp-Hodgkin syndrome and the AEC syndrome should be considered in the differential diagnosis of incomplete forms of EEC syndrome. CLINICAL SIGNIFICANCE: It is important to follow an interdisciplinary approach to attain the greatest degree of success possible in the treatment of such cases. PMID- 25737882 TI - Advances in maxillofacial trauma management. PMID- 25737883 TI - Tissue engineering. PMID- 25737884 TI - Periodontal plastic pioneering procedures revisited. AB - BACKGROUND: Various periodontal plastic procedures are available for treatment of localized gingival recessions. However, in the mirage of newer techniques and materials available, it is difficult for clinicians to decide on the treatment modality. Pioneering techniques provide a cost effective and effective means of maintaining esthetics in recession cases. MATERIALS AND METHODS: Twenty-two subjects with localized gingival recessions were divided in equal groups and treated with lateral pedicle graft (Group A) and Free mucosal graft (Group B). Clinical parameters of length and width of recession and apico coronal length of keratinized gingiva (ACKG) was measured at baseline, 30 and 90 days. Root coverage percentage was calculated. RESULTS: Both groups were effective in recession coverage and gain in ACKG. Root coverage gained in Group A was 65.0 +/- 25.2% and for Group B was 61.6 +/- 20.5%. CONCLUSION: Lateral pedicle graft and Free mucosal graft provide not only effective means of gaining in root coverage of localized gingival recession cases but also result in gain of ACKG. These techniques remain an important part of periodontal plastic surgery. PMID- 25737885 TI - Laser vs bur for bone cutting in impacted mandibular third molar surgery: A randomized controlled trial. AB - BACKGROUND: The aim of this study was to assess the feasibility of Er: YAG laser in bone cutting for removal of impacted lower third molar teeth and compare its outcomes with that of surgical bur. MATERIALS & METHODS: The study comprised 40 subjects requiring removal of impacted mandibular third molar, randomly categorized into two equal groups of 20 each, who had their impacted third molar removed either using Er: YAG laser or surgical bur as per their group, using standard methodology of extraction of impacted teeth. Clinical parameters like pain, bleeding, time taken for bone cutting, postoperative swelling, trismus, wound healing and complications were compared for both groups. OBSERVATION & RESULT: Clinical parameters like pain, bleeding and swelling were lower in laser group than bur group, although the difference was statistically not significant. However, postoperative swelling showed significant difference in the two groups. Laser group required almost double the time taken for bone cutting with bur. Trismus persisted for a longer period in laser group. Wound healing and complications were assessed clinically and there was no significant difference in both the groups. CONCLUSION: Based on the results of our study, the possibility of bone cutting using lasers is pursued, the osteotomy is easily performed and the technique is better suited to minimally invasive surgical procedures. The use of Er: YAG laser may be considered as an alternative tool to surgical bur, specially in anxious patients. PMID- 25737886 TI - Comparative evaluation of fracture resistance of various post systems using different luting agents under tangential loading. AB - OBJECTIVE: The purpose of this in vitro study was to evaluate the fracture resistance of various post system using different luting agents under tangential loading after wet thermocycling. MATERIAL & METHODS: Seventy freshly extracted maxillary central incisors were endodontically treated and post-spaces were prepared to receive different post system. They were assigned to 7 groups. Composite resin was used as core material in all the groups. Three type of post system: prefabricated post system (ParaPost((r)) XPTM), fibre post (ParaPost((r)) fiber LuxTM), cast nickel-chromium alloy post and two type of luting cements dual cure resin cement (ParaCem((r)), Whaledent) and glass ionomer cement (Fuji I, GC) were used. The specimens were thermocycled and subjected to tangential loading at a crosshead speed of 1.5 mm/min. The failure loads were recorded and data were statistically analyzed with one-way ANOVA (p < 0.05) and Student's t tests (p < 0.001). RESULTS: Significant differences of fracture resistance were detected among groups (p < 0.001). The greatest number of repairable fracture mode was recorded in fibre posts and resin cement system. CONCLUSIONS: Within the limitations of this in vitro study, it can be stated that fibre posts can be recommended as a better alternative to the cast post and cores and prefabricated metallic posts in the anterior region and resin cement might give additional fracture resistance when used for post and crown cementation. PMID- 25737887 TI - Efficacy of two gingival retraction systems on lateral gingival displacement: A prospective clinical study. AB - PURPOSE: Gingival management is a substantive procedure in fixed dental prosthesis treatment. Various new retraction cord systems are available and used. This study aimed to compare the efficacy of a new retraction cord (Stay-Put, Coltene Whaledent AG) and a conventional retraction cord (Ultrapak, Ultradent Products Inc., South Jordan, Utah) on lateral gingival displacement in continuation with the treatment protocol of the subjects fixed dental prosthesis for various partial edentulous conditions requiring fixed dental prosthesis. METHOD: Thirty subjects were selected who needed bilateral fixed dental restoration. In selected subjects both gingival retraction cords were placed bilaterally buccolingually by simple randomization method. After removing the cords, impressions were made and undamaged definitive casts were retrieved. The abutment teeth were sectioned buccolingually at the buccal ridge followed by decimal measurement of the width (in millimeter) of the retracted gingival sulcus, under a traveling microscope. RESULTS: Data was analyzed using SPSS version. Paired "t" test was used to compare the difference between the displaced gingival width in two retraction group (p > 0.05). CONCLUSION: Although mean gingival retraction in Stay-Put system (0.528 +/- 0.12 mm) was higher as compared to that in Ultrapak (0.487 +/- 0.10 mm), the difference between the two systems (0.041 +/- 0.11) was not significant statistically (p = 0.057). PMID- 25737888 TI - Comparative evaluation of vertical dimension at rest before extraction, after extraction and after rehabilitation with complete denture - A Cephalometric study. AB - INTRODUCTION: The determination of physiologic rest position of the mandible to the maxillae is of paramount importance in almost all fields of dentistry. The stability of vertical dimension at rest has been controversial if the rest position of mandible remains constant throughout life or not. Despite of several studies on the rest position of the mandible and facial vertical dimension, certain fundamental disagreements remain unresolved. The present study aims to compare the vertical dimension at rest, before and after extraction and after rehabilitation with complete denture. MATERIAL & METHODS: This study was conducted in a total of ten randomly selected patients, who had some natural teeth present with one or more opposing posterior teeth with vertical occlusal stops but were advised for extraction because of poor prognosis. Digital lateral cephalograms were done and measurements recorded at three stages: prior to extraction of remaining natural teeth, post extraction and after complete denture rehabilitation. RESULTS: Vertical dimension at rest was found to be greatest in post rehabilitation followed by pre-extraction than post extraction state. The differences in changes were found to be statistically significant. CONCLUSION: Vertical dimension at rest shows a decrease following extraction of natural teeth, the occlusal stops, and an increase on rehabilitation. It can be stated that vertical dimension at rest is not stable position and varies following extraction of natural teeth and rehabilitation. PMID- 25737889 TI - Salivary defense system alters in vegetarian. AB - PURPOSE: The aim of this research was investigating antimicrobial and enzymatic antioxidant activities in salivary fluids of vegetarians as compared to normal subjects. MATERIAL & METHODS: Antimicrobial activity of the saliva samples was evaluated against four clinically important bacteria. The biological activities of three of the main antioxidant enzymes of saliva were measured using appropriate methods of enzyme assay in both groups. RESULTS: According to the results, saliva obtained from vegetarians showed a reduced inhibitory effect on growth of Staphylococcus aureus, Klebsiella oxytoca, Pseudomonas aeruginosa and Escherichia coli as compared to those obtained from the non-vegetarian subjects. The activity of salivary peroxidase, catalase and superoxide dismutase showed a statistically marked decrease in vegetarian group. CONCLUSIONS: According to our literature survey, this is the first report on the antibacterial and antioxidant capacity in saliva of vegetarians. Results obtained from the present study have opened a new line of research with the basis of saliva as a research tool. PMID- 25737890 TI - Salivary enzymes in peptic ulcer disease. AB - AIM: Peptic ulcer, the common disease of the upper gastro-intestinal tract, occurs in about 5-10% of the world's population. Therefore, diagnosis of trace disease progression with a noninvasive method is of prime importance in the field of healthcare research. The aim of this study was to evaluate the validity of salivary enzymes as noninvasive biomarkers for peptic ulcer. MATERIALS AND METHODS: In practice, 34 peptic ulcer patients and 30 healthy subjects donated their un-stimulated saliva samples after 8 h of fasting. The activity of some selected enzymes was measured using appropriate enzymatic assay methods. RESULTS: The results indicated an overall alternation in enzymatic activity of saliva in patients suffering from peptic ulcer. Biological activity of a-amylase, peroxidase and lactate dehydrogenase, showed significantly higher values in almost all patients as compared to control subjects. CONCLUSIONS: Based on the results of salivary enzyme activity, it was concluded that besides the influence of their peptic ulcer on enzyme activity of saliva, the considerably higher activity of a-amylase could also be related to the major role of the enzyme on physiological oxidative stress. PMID- 25737891 TI - Identification of a person with the help of bite mark analysis. AB - Forensic dentistry is an essential part of Forensic science, mainly involves the identification of an assailant by comparing a record of their dentition (set of teeth) with a record of a bite mark left on a victim. Other uses in law for dentists include the identification of human remains, medico-legal assessment of trauma to oral tissues, and testimony about dental malpractice. While the practice of human identification is well established, validated and proven to be accurate, the practice of bite mark analysis is less well accepted. The principle of identifying an injury as a bite mark is complex and, depending on severity and anatomical location, highly subjective. Following the identification of an injury as a bite mark, the comparison of the pattern produced to a suspect's dentition is even more contentious and an area of great debate within contemporary odontological practice. Like fingerprints and DNA, bite marks are unique to an individual - such as distance and angles between teeth, missing teeth, fillings and dental work. This type of impression evidence can be left in the skin of a victim and also can be in food, chewing gum and other miscellaneous items such as pens and pencils. The advent of DNA analysis and its recovery from bite marks has offered an objective method of bite mark analysis. PMID- 25737892 TI - Bone density and its importance in orthodontics. AB - BACKGROUND: Researchers have generally focused on tissue reactions occurring within the periodontal ligament and bone to find possible explanation for various clinical phenomena, with less attention being paid to the inherent bone density. Recently, regional differences in jaw anatomy and bone structure including bone density have become important issue to explain some of the variation in clinical practice with respect to tooth movement, implant success rate, anchorage loss etc. MATERIALS AND METHODS: The intent of this review is to discuss various methods and classification proposed to determine bone density in particular area and its importance in field of orthodontia. Various clinical studies and research done in relation to bone density were searched using PubMed. RESULTS AND CONCLUSION: This review endeavours to compile the research of bone density in maxilla and mandible. Many clinical studies have demonstrated relation between bone density and various clinical phenomena in dentistry. Knowledge of bone density in particular area of oral cavity may help the clinician to plan proper site for implant placement and various anchorage augmentation techniques in order to increase success rate of the treatment. PMID- 25737893 TI - Miswak in oral cavity - An update. AB - Miswak, scientifically known as Salvadora persica, is a species of Salvadora belonging to family Salvadoraceae. It is considered as "Nature's little toothbrush" as it is a popular chewing stick throughout Indian subcontinent. In India, it is commonly known as arak tree, meswak, peelu, kharjal or jhank. It also serves as a natural toothpaste with antibacterial, anti-caries, anti periopathic disinfectant having anti-plaque and anti-fungal properties. Miswak sticks are being used by majority of people who cannot afford to buy the commercial western toothbrush and toothpaste mainly in rural areas of developing countries. The present review is an attempt to define the potential of the miswak in preventing and treating the common diseases of oral cavity and teeth. PMID- 25737894 TI - A simplified technique to fabricate tissue bolus device to manage dose distribution in maxillectomy patient with orbital exenteration. AB - The primary goal of radiotherapy is to deliver maximum dose to tumor but minimal dose to normal tissues. Irregular surfaces along with cavities sometimes make it difficult to deliver a homogenous radiation dose. Data incorporated in the delivery of prescribed dose are measured from the dosimetric system which are homogenous in nature, hence the exposed medium (i.e. tumor) should posses the same property in constituents and nature. At the inference of two different mediums, such as in case of cavity in the treatment field; there occurs build up and build down effects in dose delivery that may result into hot spot and cold spot. These cold spot may result in recurrences. The aim of this paper is to fabricate a simple, cost effective tissue bolus device, which may be filled with normal saline to reproduce homogenous and regular medium at the time of radiotherapy. PMID- 25737895 TI - Extra-articular ankylosis after zygoma fracture; A case report & review of literature. AB - Extra-articular temporomandibular bony ankylosis between the coronoid process and the zygoma is quite uncommon. In this paper we present a case of fusion of the left coronoid to the zygomatic bone in a 23-year-old male. This bony ankylosis was the result of five-week-old untreated zygomatic complex fracture. Ankylosis developed secondary to heterotopic bone formation following trauma. Zygomatico coronoid ankylosis of the mandible is a complication which rarely occurs if fractures of the middle third of the facial skeleton have been adequately treated. The patient was treated by intraoral coronoidectomy. The rationale for clinical and radiographic diagnosis and treatment is reviewed. PMID- 25737896 TI - TMJ osteoarthritis and early diagnosis. PMID- 25737897 TI - Temporomandibular disorders. PMID- 25737898 TI - Evaluation of efficacy of arthrocentesis (with normal saline) with or without sodium hyaluronate in treatment of internal derangement of TMJ - A prospective randomized study in 20 patients. AB - PURPOSE: To compare the outcome of arthrocentesis alone and arthrocentesis with sodium hyaluronate in internal derangement of TMJ. MATERIALS AND METHODS: 20 patients of disc displacement with reduction of TMJ were randomized into 2 experimental groups. Control group of patients received arthrocentesis alone and study group of patients received arthrocentesis with sodium hyaluronate. Patients TMJ status and clinical symptoms were evaluated for 6 months follow up. The clinical parameter recorded were maximal mouth opening (MMO), lateral excursions (right and left side), protrusive movement, joint noises, and pain (at rest, at function). RESULTS: When 2 groups are compared there was no statistically significant difference in terms of inter-incisal opening, lateral excursion, protrusive movement, joint noises and pain however the group with sodium hyaluronidase has shown better results than the control group. CONCLUSION: Both study and control group found to be statistically insignificant but patient who were in the group of arthrocentesis with admission of sodium hyaluronidase had better results. PMID- 25737899 TI - The TN Chawla Lecture - The current management of midfacial trauma. AB - The management of mid-facial trauma has changed very little in the last decade with minor modifications related to orbital trauma and minimal access approaches particularly related to secondary reconstruction. In the UK the introduction of major trauma centres has tended to concentrate the management of polytrauma patients to individual regional sites. From a maxillofacial perspective this increases craniofacial cases treated in these units. It also requires a collaborative team approach and a thorough understanding of ATLS principles. Imaging has progressed to include rapid CT scans, individualised CBCT scans and the use of rapid prototyping models to aid in both visualisation, planning and construction of customised implants. Finally the industry has managed to develop smaller implants with equal strength to facilitate low profile fixation which is less likely to be prominent in the midface. These also facilitate the use of endoscopic assisted procedures, which tend to be used in secondary reconstruction of the upper 1/3 and osteotomy surgery. PMID- 25737900 TI - TMJ pain and cryoanalgesia. AB - Temporomandibular (TMJ) joint pain is a complex issue involving several factors in a spectrum including myofascial pain, internal derangement and degenerative disease, all of which are reciprocally affected by psychological factors. Current assessment of TMD (temporomandibular disorder) can be assisted by standardised protocols, but often there is a combination of disease processes which each need to be addressed. Initial management should always be conservative with a preference for non-invasive measures which do no harm and have evidential support. Subsequent management of myofascial pain could involve tricyclic anti depressants or botulinum injection into areas of muscle spasm. Joint related pain is diagnosed by relief of pain following intra-articular local analgesia. Where this is successful arthroscopy/arthrocentesis are successful in relieving the pain in up to 90% of cases. In addition arthroscopy is an accurate diagnostic tool. Where this fails, open surgery is less successful and ultimately joint replacement may be required. Where the latter are not indicated, but pain is relieved by LA, cryoanalgesia to the joint capsule may be beneficial. PMID- 25737901 TI - Rationale of arthroscopic surgery of the temporomandibular joint. AB - Arthroscopic surgery has been widely used for treatment of temporomandibular joint (TMJ) internal derangements and diseases for the last 40 years. Although 626 articles have been hit by Pubmed search in terms of "TMJ arthroscopic surgery", this review article is described based on distinguished publishing works and on my experiences with TMJ arthroscopic surgery and related research with an aim to analyse the rationale of arthroscopic surgeries of the temporomandibular joint. With arthrocentesis emerging as an alternative, less invasive, treatment for internal derangement with closed lock, the primary indication of arthroscopic surgery seems to be somewhat limited. However, the value of endoscopic inspection and surgery has its position for both patient and physician with its long-term reliable results. PMID- 25737902 TI - Alloplastic or autogenous reconstruction of the TMJ. AB - Reconstruction of the irreparably damaged temporomandibular joint (TMJ) is dependent on the cause of damage and the patient's age. In childhood the current preference is for autogenous reconstruction which can potentially "grow" with the child. This is either with soft tissue interposition (temporalis fascial interposition), local osteotomy, distraction osteogenesis, non-vascularised tissue (costochondral, sternoclavicular) or vascularised tissue (second metatarsal). Current debate centres around the possibility of alloplastic reconstruction particularly where autogenous tissue has failed. The resultant failure of growth - if this occurs, can be dealt with in late adolescence with either osteotomy, distraction osteogenesis or replacement of the condylar component of the prosthesis. In the adult the choice is currently in favour of alloplastic reconstruction as this gives a more stable long term result and facilitates early mobilisation. Initial cost is clearly an issue, but when weighted against the reduced length of stay and reduced morbidity, often the costs are equivalent in the short term and come to benefit alloplasts in the medium term. Their long term outcomes beyond 15 years are however not clear. PMID- 25737905 TI - Chronic candidal osteomyelitis of mid face: A therapeutic dilemma. AB - Numerous explanations have been proposed for the increase in fungal infections including the use of broad-spectrum antibiotics, antineoplastic agents and prosthetic devices. Also increase in proportion of immunocompromised population predisposed to fungal infection might be a contributory factor. Candida albicans is a part of normal flora of the oral cavity. However, it is rarely implicated in maxillary osteomyelitis. Diagnosis of Candida infection is challenging as most symptoms are non-specific and cultures may only become positive late in the course of the infection. Due to scarcity of literature, there are no robust guidelines regarding the most appropriate therapeutic regimens to be employed in such cases. A case of candidal osteomyelitis of mid face is reported suggesting the need for more multicentric long-term studies to formulate and establish appropriate treatment regimens. PMID- 25737903 TI - TMJ Bioengineering: A review. AB - Regeneration using scaffolds, growth factors, and stem cells is being investigated worldwide. Pubmed search for scaffolds for condyle resulted in 102 articles, of which 24 analyzed Temporomandibular joint (TMJ) scaffolds and only 6 evaluated hydroxyapatite scaffolds. 17 articles report studies on TMJ disc regeneration. The ideal bone construct for repair should be able to replicate the lost structure, restore function, be harmless, reliable and biodegradable. Scaffolds act as carriers for mesenchymal stem cells and/or growth factors and are useful for cell adhesion, migration, proliferation, and differentiation. Gene therapy has also led to the accelerated effective bone regeneration. The major materials used as scaffolds are natural or synthetic polymers, ceramics, composite materials, and electrospun nanofibers. Mesenchymal stem cells are responsible for the formation of virtually all dental, oral, and craniofacial structures. Tissue-engineered bone can possess the customized shape and dimensions. It has the potential for the biological replacement of craniofacial bones. PMID- 25737904 TI - Neuromuscular dentistry: Occlusal diseases and posture. AB - Neuromuscular dentistry has been a controversial topic in the field of dentistry and still remains debatable. The issue of good occlusion and sound health has been repeatedly discussed. Sometimes we get complains of sensitive teeth and sometimes of tired facial muscles on getting up in the morning. Owing to the intimate relation of masticatory apparatus with the cranium and cervico-scapular muscular system, the disorders in any system, draw attention from concerned clinicians involved in management, to develop an integrated treatment protocol for the suffering patients. There may be patients reporting to the dental clinics after an occlusal restoration or extraction, having pain in or around the temporomandibular joint, headache or neck pain. Although their esthetic demands must not be undermined during the course of treatment plan, whenever dental treatment of any sort is planned, occlusion/bite should be given prime importance. Very few dentist are able to diagnose the occlusal disease and of those who diagnose many people resort to aggressive treatment modalities. This paper aims to report the signs of occlusal disease, and discuss their association with TMDs and posture. PMID- 25737906 TI - Peripheral and central aggressive form of Pindborg tumor of mandible - A rare case report. AB - INRODUCTION: The calcifying epithelial odontogenic tumor (CEOT), or Pindborg tumor, is a rare and benign odontogenic neoplasm that affects the jaw. Calcifying epithelial odontogenic tumor can be divided into 2 clinico-topographic variants: Intraosseous (central) or Extraosseous (peripheral), with an incidence of 94% and 6%, respectively. The intraosseous tumors have a predilection for the mandible, and most tumors arise in the molar and premolar region of the mandible. When present, extraosseous tumors are often located in the anterior jaw and involve the gingiva. PURPOSE: In this article we present a unique rare variety of Pindborg tumor of mandible with both intraosseous & extraosseous presentation and also locally aggressive behavior. CASE REPORT: A 35 year old man presented with Pindborg tumor (CEOT) of mandible with both intraosseous and extraosseous variant in a single lesion, extending from right premolar region to the left molar region. DISCUSSION: CEOT is an uncommon neoplasm accounting for less than 1% of all odontogenic tumors. Although CEOT is considered less aggressive clinically than typical infiltrating ameloblastoma, but our case is a rarity which was aggressive and also rapidly progressive in short duration, with intra and extraosseous presentation. Hence it was managed surgically similar to a malignant lesion. CONCLUSION: Presentation of two different variants of an odontogenic tumor in a single lesion and aggressive behavior of rather slow growing tumor, mimicking malignant lesion definitely shows possibility of rare variations in different magnitude. Hence proper diagnosis for management with better prognosis of these kinds of tumors is very much essential. PMID- 25737907 TI - Some doubts on fractures of angle of mandible - A retrospective study. PMID- 25737908 TI - Reply to letter to the editor. PMID- 25737909 TI - Can technology conquer biology in craniofacial surgery for malignant tumors. PMID- 25737910 TI - Editorial. PMID- 25737911 TI - Additional cytosine inside mitochondrial C-tract D-loop as a progression risk factor in oral precancer cases. AB - INTRODUCTION: Alterations inside Polycytosine tract (C-tract) of mitochondrial DNA (mtDNA) have been described in many different tumor types. The Poly-Cytosine region is located within the mtDNA D-loop region which acts as point of mitochondrial replication origin. A suggested pathogenesis is that it interferes with the replication process of mtDNA which in turn affects the mitochondrial functioning and generates disease. METHODOLOGY: 100 premalignant cases (50 leukoplakia & 50 oral submucous fibrosis) were selected and the mitochondrial DNA were isolated from the lesion tissues and from the blood samples. Polycytosine tract in mtDNA was sequenced by direct capillary sequencing. RESULTS: 40 (25 leukoplakia & 15 oral submucous fibrosis) patients harbored lesions that displayed one additional cytosine after nucleotide thymidine (7CT6C) at nt position 316 in C-tract of mtDNA which were absent in corresponding mtDNA derived from blood samples. CONCLUSION: Our results show an additional cytosine in the mtDNA at polycytosine site in oral precancer cases. It is postulated that any increase/decrease in the number of cytosine residues in the Poly-Cytosine region may affect the rate of mtDNA replication by impairing the binding of polymerase and other transacting factors. By promoting mitochondrial genomic instability, it may have a central role in the dysregulation of mtDNA functioning, for example alterations in energy metabolism that may promote tumor development. We, therefore, report and propose that this alteration may represent the early development of oral cancer. Further studies with large number of samples are needed in to confirm the role of such mutation in carcinogenesis. PMID- 25737912 TI - Prevalence of oral submucous fibrosis among habitual gutkha and areca nut chewers in Moradabad district. AB - BACKGROUND: To determine the prevalence and severity of oral submucous fibrosis (OSMF) among habitual gutkha, areca nut and pan chewers of Moradabad, India. METHOD: A survey was conducted for a period of one year in east, west, north and south zones of Moradabad district, Uttar Pradesh. One thousand habitual chewers were selected as study participants, using a stratified random sampling technique, between the ages of 11-40 yrs, with a habit of chewing gutkha, areca nut, pan for over a year. A detailed history was recorded and meticulous clinical examination was conducted. Evaluation of taste sensation, hearing, interincisal distance, clinical staging was done in the OSMF patients found amongst habitual chewers. The obtained data was statistically analyzed using an SPSS 16.5 version soft ware. RESULTS: The prevalence of OSMF was 6.3% (63/1000) and gutkha chewing was the most common abusive habit (42/63) amongst OSMF patients. Stage 1, Stage 2, Stage 3 OSMF was seen in 28, 19 and 16 patients respectively. Restricted mouth opening, altered taste perception and defective hearing was observed in 37/63 (58.7%), 24/63 (38.09%) and 14/63 (22.22%) respectively. CONCLUSION: Our study shows a prevalence of 6.3% OSMF among habitual chewers of Moradabad. Prevalence and severity were more in urban and rural patients respectively. PMID- 25737913 TI - Insight to a tobacco user's mouth: An epidemiological study in Bhopal. AB - BACKGROUND: The rampant tobacco abuse is escalating the Indian health sector towards a future overburdened with high prevalence of cancer and potentially malignant conditions. Thus manifestations of tobacco abuse have become a widely recognized but poorly tackled public health issue. To understand the same, a study was conducted in a dental college of Bhopal, India. METHODOLOGY: A hospital based cross sectional study was done over a period of 1.5 years. Patients giving history of deleterious habits were included in the study. The form of tobacco/areca nut used, duration and frequency of usage and awareness regarding their ill-effects were recorded. All documented data was subjected to statistical analysis using chi-square test. RESULTS: Out of 2033 individuals studied 21% were below the age of 25 years, 53% in 26-50 years, 20% in 51-75 years and 6% above 76 years of age with 85% being males. 67% used smokeless form, 21% smoked and 12% used tobacco in both smokeless and smoking form. 58% of the individuals had tobacco associated lesions, of which oral submucous fibrosis (OSMF) was the most prevalent. The relation between duration and frequency of abuse and occurrence of lesion was found to be statistically significant (p < 0.05). CONCLUSION: The smokeless form was most widely abused in this part of the country especially the younger population. OSMF, a premalignant condition with debilitating effects on the lifestyle, was the most prevalent lesion associated with tobacco use. These findings call for early and aggressive intervention methods be put into action. PMID- 25737914 TI - Inhibitory activity of Salvadora persica extracts against oral bacterial strains associated with periodontitis: An in-vitro study. AB - AIMS: The use of natural plant extracts in pharmacology, medicine and dental hygiene has found a growing interest in modern scientific research. Salvadora persica is a natural tree whose fibrous branches have been approved by the World Health Organization for oral hygiene. Periodontitis is a highly prevalent adult gingival disease that leads to bone destruction and connective tissue attachment loss. The aim of this research was assessment the antimicrobial activities of methanolic extract of Salvadora persica (miswak) on isolated strains from the oral fluid. METHODS: In practical section, 50 female university students (21.4 +/ 1 year) participated in the study. Based on examination by a periodontist, they were grouped into (Group I, n = 21) and (Group II, n = 29) i.e. with and without periodontitis respectively. Their un-stimulated saliva samples were obtained in sterile tubes. While three bacterial genera, Staphylococcus, Streptococcus and Lactobacillus were identified in all subjects, Enterococcus and Escherichia were only detected in Group I. RESULTS: A statistically significant difference in colonization levels between the two groups was observed. The effect of methanolic extract of S. persica against oral bacterial strains isolated from saliva was investigated using agar disc diffusion and microdilution methods. Although methanolic extract of S. persica was effective on growth inhibition of all strains, it was significantly more effective on Gram positive bacteria than Gram negative ones. CONCLUSIONS: Effective substances present in S. persica extracts, exhibit a broad range of antibacterial activity and affect almost all bacterial species regardless of the Gram-staining nature. PMID- 25737915 TI - Salivary enzymes and flow rate: Markers of peptic ulcer. AB - AIM: Peptic ulcers are among the most common and most costly diseases known to human. Its diagnosis in the early stages would have great benefit in treatment of the disease. The aim of this study was to compare alternations of enzymes activity in salivary fluid between patients with peptic ulcer disease and healthy controls. MATERIALS AND METHODS: Two groups each composed of 26 subjects (13 male and 13 female) patients with peptic and healthy controls entered. Activities of selective salivary enzymes were assayed by a spectrophotometeric method. RESULTS: The results showed significant increased activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as total salivary protein (TSP) concentration in peptic ulcer patients as compared to control group. However, the enzymatic activity of alkaline phosphatase (ALP) also increased in peptic ulcer patients as compared to healthy control, but not statistically significant. CONCLUSIONS: Based on the obtained results it was concluded that peptic ulcer may be early diagnosed by detecting activity of salivary enzymes. Therefore the saliva can be suggested as a diagnostic fluid. PMID- 25737916 TI - Shear punch strength evaluation of nanocomposite and compomer, post-conditioning in dietary solvents - An in-vitro study. AB - BACKGROUND: Perpetual research in esthetic dentistry has stupendously contributed in improving the mechanical and esthetic properties of restorative materials. Recently introduced nanocomposite claim to possess higher optimized esthetic and mechanical properties superior to other esthetic restorative materials in clinical use. It has been highlighted in many studies that intraoral degradation of composites is a consequence of both mechanical factors and chemical degradation. Thus, this in-vitro study was conducted to determine the strength of commonly used esthetic restorative materials after conditioning them in dietary solvents, thereby, simulating the intraoral environment. AIM: Evaluation of shear punch strength of nanocomposite and compomer, post-conditioning in dietary solvents. MATERIALS AND METHODS: Two test groups mentioned above, each containing sixty preconditioned samples, divided into four subgroups of fifteen samples each and conditioned in different dietary solvents, were subjected to shear punch test in custom designed shear punch apparatus in Universal Testing Machine. RESULTS: Among the dietary solvents, citric acid caused maximum decrease in the strength while conditioning in heptane showed increase in strength of the test restorative materials. CONCLUSION: Nanocomposite revealed to have higher strength, thereby indicating its better application universally. PMID- 25737917 TI - Comparative evaluation of cephalometric measurements of monitor-displayed images by Nemoceph software and its hard copy by manual tracing. AB - OBJECTIVE: The aim of this study was to evaluate and compare the cephalometric measurements obtained from computerized tracing of direct digital radiographs and hand tracing of their digital radiographic printouts. MATERIAL AND METHODS: The soft- and hard-copies of pre-treatment lateral cephalograms of 40 subjects (both males and females) within the age group of 10-30 years, irrespective of the type of malocclusion were taken. Total 26 measurements (13 linear and 13 angular) were obtained using both the manual and the digital technique. RESULTS: Amongst the linear measurements, Anterior facial height (AFH), Posterior facial height (PFH), Upper lip length (ULL), Lower lip length (LLL), Anterior cranial base length (ACBL), Posterior cranial base length (PCBL), Maxillary length (MxL), Mandibular length (MdL), Lower incisor to NB line (L1 to NB) and Lower lip protrusion (LLP) showed statistically significant difference between the two techniques but were clinically acceptable (difference between the digital and manual technique were less than 2 units (1 unit = 1 mm for linear measurements and 1 degrees for angular measurements). While amongst the angular measurements, only occlusal plane angle showed statistically significant difference between the two techniques that was not clinically acceptable. CONCLUSION: Digital measurements obtained from monitor-displayed images (soft copy) were found to be reproducible and comparable to the manual method done on its hard copy, for all the measurements except occlusal plane angle (SN-occlusal plane). PMID- 25737918 TI - Cystatin C: Its role in pathogenesis of OSMF. AB - Oral Submucous Fibrosis (OSF) is a chronic disorder characterized by fibrosis of the mucosa lining the upper digestive tract involving the oral cavity, oro- and hypopharynx and the upper third of the oesophagus. The alkaloids from areca nut are the most important chemical constituents biologically, in producing this lesion. These chemicals appear to interfere with the molecular processes of deposition and/or degradation of extracellular matrix molecules such as collagen. Increased collagen synthesis or reduced collagen degradation have been considered as a possible mechanism in the development of the disease. Increased and continuous deposition of extracellular matrix may also take place as a result of disruption of the equilibrium between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMP). Arecoline a product of areca nut was found to elevate Cystatin C mRNA (CST3) and protein expression in a dose dependent manner. Cystatin C expression was significantly higher in OSF specimens and expressed mainly by fibroblasts, endothelial cells, and inflammatory cells. Cross-links between the molecules are essential for the tensile strength of collagen fibres. These areas are resistant to attack by collagenases but can be attacked by a number of other serine and cysteine proteinases. CST3 encoding a cysteine proteinase inhibitor might contribute to the stabilization of collagen fibrils in OSMF. Treatment directed against Cystatin C may serve as a novel treatment for submucous fibrosis and also in preventing its transformation into malignancy. PMID- 25737919 TI - Dental fluorosis and periodontium: A game of shadows? AB - Dental fluorosis is a condition which is said to be present when the morphologic features of a tooth are altered clinically, in the form of discoloration or anatomic malformation which is attributed to the developmental changes induced by excess fluoride levels in plasma at the time of tooth formation. In India, an estimated 60 million people are at risk and 6 million people are disabled due to fluorosis. Lack of understanding into the effects of fluorosis on periodontium has left a blind spot in the vision of management of periodontitis in such patient groups. This article suggests the important connection these two conditions can have and emphasize research in this study field. PMID- 25737920 TI - Oral sciences: History and future research. PMID- 25737921 TI - Profile changes after conventional and chin shield genioplasty. AB - INTRODUCTION: The aim of this study was to compare the profile changes after conventional and chin shield genioplasty. MATERIAL AND METHOD: 20 patients with retruded chin were randomly allocated to two different groups. The experimental group had chin shield osteotomy with interposition of hydroxyapatite collagen graft soaked in platelet rich plasma, while the controls had a conventional genioplasty. The outcome variables evaluated were lip seal, chin thickness, mandibular base length, SNB, labiomental angle, anterior lower facial height, transverse chin shift, and complications. RESULTS: There was an increase in chin thickness among all, but a significant increase in anterior lower facial height was seen in the experimental group only. There was no statistically significant difference in satisfaction score in both groups. CONCLUSION: Chin shield genioplasty provides horizontal as well as vertical lengthening of chin without deepening of the mentolabial fold. Hydroxyapatite collagen bone graft and platelet rich plasma promote healing, induce bone formation and reduce bone resorption. PMID- 25737922 TI - Incidence of impacted third molars: A radiographic study in People's Hospital, Bhopal, India. AB - OBJECTIVES: The aim of this study is to evaluate the position of impacted third molars based on the classifications of Pell & Gregory and Winter in a sample of Bhopal patients. STUDY DESIGN: In this retrospective study, up to 1100 orthopantomograms (OPG) of the patients who were reported to the MaxilloFacial Department of PDA and Chowdhary hospital from January 2011 to December 2012 were evaluated. RESULTS: Among 1100 patients, 730 were male and 370 were female patients. Of the 1100 OPGs studied, 3,910 third molars were noticed either impacted or erupted and 490 third molars were missing. The most common angulation of impaction in the mandible was in vertical position (41.4%) followed by mesioangular impaction (33.3%) and the most common angulation of impaction in the maxilla was the vertical (67.4%) which was followed by 15.2% in distoangular impaction. The level of eruption of impacted third molar was found to be 43.9% at level A, 34.8% at level B and 21.3% at level C. There was no significant difference between the right and left sides in both the jaws. CONCLUSION: The pattern of third molar impaction in the region of Bhopal is characterized by a high prevalence of impaction, especially in the mandible. The most common angulation was the vertical in the mandible as well as in the maxilla. The most common level of impaction in mandible was level A and in maxilla is level C and there was no any significant difference between the right and left sides in both jaws. PMID- 25737923 TI - Prevalence of cysts and tumors around the retained and unerupted third molars in the Indian population. AB - AIM: Tooth impaction is a frequent phenomena and surgical removal of these teeth are the commonest of the dental surgical procedures. The debate over the removal of asymptomatic impacted third molars still continues. The aim of this retrospective study was to determine the incidence of development of cysts and tumors around the retained and unerupted third molars in the Indian population. MATERIAL AND METHODS: 5486 impacted third molars of 4133 patients were studied through the panoramic radiographs for the presence of associated cysts and tumors. The ages of the patients ranged from 17 to 67 years, with a mean of 33.7 years. The results were evaluated using the Pearson chi-square test. P-values less than 0.05 were considered to be statistically significant. RESULTS: There were 134 cysts (2.24%) and 63 tumors (1.16%) found that were associated with impacted third molars, of which 3 were malignant (0.05%). 143 patients had symptoms such as swelling or pain due to cystic or neoplastic lesions. The remainder 54 patients had no symptoms suggestive of pathology. The most common cyst was dentigerous cyst and the most common tumor was ameloblastoma. CONCLUSION: The results indicate that cysts and tumors do develop in a relatively small but still considerable minority of patients. The fact that a considerable number of patients had no signs or symptoms indicating pathology is certainly worth considering. Consultation should be sought from dental specialists if there are symptoms in the third molar region. PMID- 25737924 TI - Cephalometric skeletal evaluation of patients with Incontinentia Pigmenti. AB - PURPOSE: The aim of this study was to evaluate the skeletal characteristics of patients with the rare genetic disease of Incontinentia Pigmenti, by lateral cephalometric analysis on the antero-posterior plane and by frontal cephalometric analysis on the horizontal plane. METHODS: Lateral skeletal cephalometric analyses were performed according to Steiner for evaluation of antero-posterior direction, and frontal skeletal cephalometric analyses according to Ricketts for evaluation of horizontal direction in 9 patients with IP. Left and right facial widths at the level of the zygomatic arch were also evaluated. The Student t-test was used for paired to a 5% level of significance data. RESULTS: The lateral skeletal cephalometric findings were not statistically significant, but the Class II was the most frequent finding (44.4%), followed by Class III (33.3%) and Class I (22.2%). The right maxillo-mandibular width was significantly lower than normal values, and the right facial width was significantly higher than the left, at the level of the zygomatic arch. CONCLUSIONS: Patients with IP showed more skeletal discrepancies of Class II and III than Class I malocclusion, and had significant horizontal facial skeletal asymmetries. This should alert health professionals to route these patients for orthodontic assessment and possible therapeutic interventions. However, larger samples are needed to better elucidate if these cephalometric findings can be specifically related to IP. PMID- 25737925 TI - Cephalometric norms for orthognathic surgery in North Indian population using Nemoceph software. AB - BACKGROUND: Cephalometric norms, useful in providing guidance to orthodontist during diagnosis and treatment planning are subjected to variability in morphologic characteristics in different ethnic and racial groups, hence norms established for one population group are not applicable for all. AIMS AND OBJECTIVES: To compare and correlate the established hard tissue cephalometric norms for orthognathic surgery (COGS analysis) given by Legan and Burstone with norms obtained for North Indian population. METHODS: Pre-treatment digital lateral cephalograms of 100 orthodontically untreated subjects having pleasing profile and normal occlusion in the age range of 18-25 yrs (mean age of 21 +/- 2.62 years) were selected. 16 linear and 6 angular hard tissue parameters of COGS analysis were analyzed using nemoceph software for the males and females separately. The data obtained were compared with previously established norms for Orthognathic Surgery using SPSS Version 15.0. RESULTS: North Indian males and females had smaller anterior cranial base length with prognathic maxilla and mandible, protrusive chin with poor chin form, decreased facial height, decreased posterior maxillary height with anticlockwise rotation of mandible, increased anterior and posterior maxillary dental heights, decreased ramal and corpus length, clockwise rotation of occlusal plane, presence of sagittal discrepancy between maxillary and mandibular denture bases in comparison to Caucasian males and females respectively. North Indian females had more proclination of mandibular incisors than Caucasian females. Sexual dimorphism was also evident in the present study with males exhibiting significantly larger cranial base length, greater middle third facial height and posterior maxillary height, counterclockwise rotation of mandibular plane, greater anterior and posterior mandibular dental heights and longer ramal and corpus length in comparison to females. CONCLUSION: North Indian population showed significant differences in facial morphology as compared to Caucasians population. Sexual dimorphism was also evident in North Indian populations. Thus the need to develop separate Orthognathic Surgical norms for better treatment planning of North Indian population is justified. PMID- 25737926 TI - Remineralizing potential of various agents on dental erosion. AB - AIM: The purpose of this study is to compare the effect of casein phosphopeptide amorphous calcium phosphate (CPP-ACP, Tooth Mousse) containing and casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF, Tooth Mousse Plus) containing pastes on dental erosion. MATERIALS AND METHODS: Thirty permanent non-carious premolars indicated for orthodontic extraction were included in this study and were sectioned in mesiodistal direction vertically. After immersion in the carbonated drink for 14 min, samples were treated with various remineralizing pastes which were CPP-ACP containing paste (Tooth Mousse) and CPP-ACPF containing paste (Tooth Mousse Plus) according to the manufacturer's instructions. Vickers Microhardness was recorded at baseline, after exposure to erosive drink and after treatment with remineralizing pastes. Data obtained was statistically analysed using Student t-test with a level of significance set at p < 0.05. RESULTS: CPP-ACP (Tooth Mousse) and CPP-ACP with fluoride (Tooth Mousse Plus) resulted in 30.52% and 38.98% increase in post-erosion microhardness values respectively. The remineralizing potential of CPP-ACP with fluoride containing paste (Tooth Mousse Plus) was significantly better than that of CPP-ACP containing paste (Tooth Mousse) (p < 0.05). CONCLUSION: Casein phosphopeptide amorphous calcium phosphate with fluoride (CPP-ACPF, Tooth Mousse Plus) can be recommended to be used in preventing erosive tooth wear from acidic beverages. PMID- 25737927 TI - Mitochondrial DNA from archived tissue samples kept in formalin for forensic odontology studies. AB - BACKGROUND: Samples used for DNA isolation to be used for forensic odontology studies are often limited. The possibility to use tissue samples stored in formalin for a prolonged period, which contains nucleic acids of questionable quality, opens exciting possibilities for genetic and molecular biology studies useful in speciality of forensic odontology. AIM: The present study defines substantial modification of existing protocols for total genomic isolation including mitochondrial DNA and proves the utility of such obtained mitochondrial DNA in microsatellite analyses. METHODS: 50 dental tissue samples which were kept in neutral buffered formalin liquid bottles were taken for DNA isolation and subsequent analysis. For the isolation of total genomic DNA from tissue samples, a new protocol with substantial modifications from routine ones was adopted by us. Total genomic DNA from matched blood samples were extracted using standard phenol-chloroform extraction method. RESULTS: Polymerase Chain Reaction and Sequencing of such extracted DNA samples for mitochondrial D loop region were successful and the results were comparable with DNA extracted from normal sources of samples. CONCLUSION: The present study reports for the first time that nucleic acids extracted from human dental tissue samples under prolonged formalin fixation times can be used for forensic odontology studies using the described methodology. PMID- 25737928 TI - Clinical evaluation of 3 Mix and Other Mix in non-instrumental endodontic treatment of necrosed primary teeth. AB - PROBLEM CONSIDERED: The objective was to evaluate and compare the clinical and radiographic efficacy of two different combinations of antibacterial drugs when used in non-instrumental endodontic treatment of necrosed primary teeth. MATERIALS AND METHOD: Forty teeth were randomly divided into two groups, viz. groups A and B having 20 teeth each. In Group A, 3 Mix (ciprofloxacin, metronidazole, and minocycline) and in Group B, Other Mix (ciprofloxacin, ornidazole, and minocycline) mixed with propylene glycol were used. Medication cavities of Group-A and B were filled with 3 Mix and Other Mix respectively followed by restoration of teeth. Clinical evaluation was done at 3 months whereas, clinical and radiographic evaluation was done at 6 and 12 months, respectively. RESULTS: Both the groups showed 100% clinical success whereas, radiographic success rate was 81% with 3 Mix and 92% with Other Mix but, was not statistically significant. CONCLUSIONS: Both the antibacterial pastes can be used effectively in non instrumental endodontic treatment of necrosed primary teeth and require more clinical trials to prove its efficacy. PMID- 25737929 TI - Randomized testing of taste discrimination in a case of congenital aglossia. AB - AIMS: Isolated Congenital Aglossia (ICA) is a rare syndrome where an individual is born without a tongue. A few anecdotal reports have identified taste as a sensation experienced by the person with congenital aglossia (PWCA). To date no systematic investigations have been reported. This study aimed to systematically determine gustatory function in a PWCA. METHODS: The current study utilized a randomized, double-blinded, controlled trial that tested the five basic tastes: sweet (sucrose), sour (acetic acid), salty (sodium chloride), bitter (caffeine), and umami (monosodium glutamate, MSG) in a 44 year old female PWCA. Five concentration levels (three for salty) were tested in triplicate for each stimulus. A nose clip was used to exclude contribution by olfactory detection. Contingency tables were constructed to determine relationships between identification accuracy and stimulus or concentration level. RESULTS: The sweet (17.1 g/L), salty (0.58 g/L), and bitter (0.02 g/L) stimuli were detected at comparable concentrations to those reported in non-randomized trials, while sour (0.02 g/L) was detected at a lower concentration. The most common substitution was salty for umami (n = 7). Identification accuracy was significantly associated with taste stimuli chi (2) = 12.634, p = 0.013. Concentration level was significantly associated with identification accuracy only for salty, chi (2) = 9.000, p = 0.011. CONCLUSION: This study has demonstrated the perception of different tastes in a PWCA. This is the first known report of umami being identified as a unique taste in a PWCA. Variations in threshold taste concentrations compared to normal individuals indicate certain gustatory dysfunction. PMID- 25737930 TI - A review: Immunological markers for malignant salivary gland tumors. AB - Salivary gland cancers are rare. Around 8 out of 10 salivary gland tumors (80%) are in the parotid. Just fewer than 2 out of 10 salivary gland cancers develop in the other two salivary glands - the submandibular or sublingual glands. Fewer than 1 in 10 cancers start in the minor salivary glands. There are many different types of salivary gland cancers. The most common is mucoepidermoid carcinoma (MEC). Just over 3 out of 10 (25-35%) salivary gland cancers (SGT, SGC) are of this type. The others include adenoid cystic carcinoma (ACC), acinic cell carcinoma, carcinoma ex-pleomorphic adenoma (Ca-PA), polymorphous low grade adenocarcinoma (PLGA) and some newly discovered salivary gland tumors. Because of the infrequency of salivary gland tumors and their complex histopathological diagnosis, it is difficult to exactly predict their clinical course by means of its recurrence, malignant progression or metastasis. Salivary gland tumors always pose problems in diagnosis. This review provides an insight into the recent concepts and immunohistochemical markers to diagnose the malignant salivary gland tumors (SGT), thus guiding the Ear, Nose and Throat specialists, Oral and Maxillofacial Surgeons, General Pathologists and other medical and dental specialists thereby enabling them to make correct diagnosis and provide the appropriate treatment. PMID- 25737931 TI - Ectrodactyly-ectodermal dysplasia clefting syndrome (EEC syndrome). AB - Ectrodactyly-ectodermal dysplasia- clefting syndrome (also k/a. split hand- split foot malformation /split hand-split foot ectodermal dysplasia- cleft syndrome/ectodermal dysplasia cleft lip/cleft palate syndrome) a rare form of ectodermal dysplasia, is an autosomal dominant disorder inherited as a genetic trait and characterized by a triad of (i) ectrodactyly, (ii) ectodermal dysplasia and, (iii) & facial clefts. PMID- 25737932 TI - Prosthetic rehabilitation of a child with velopharyngeal dysfunction - A case report. AB - The speech of person is a unique mode of expression for an individual. Alterations or deviation from normal speech leading to nasal and unintelligible speech have enormous effects on the psychological well being of a person as it hampers social interactions. The anatomic or functional anomalies occurring as a result of congenital or traumatic defects leading to velopharyngeal dysfunctions influence the speech by making it completely atypical. The cleft palate patients may have residual velopharyngeal inadequacy even after surgical repair. A removable palatal lift appliance in conjuction with speech therapy is a viable treatment option for such patients as it is economical, easy to fabricate and easy to use. PMID- 25737933 TI - Platelet rich fibrin: A new covering material for oral mucosal defects. AB - In the current oral and maxillofacial surgery practice, the use of PRF membrane is limited to bony lesions and gingival defects. We have used it for reconstruction of benign hyperkeratotic lesion of oral mucosa in a healthy adult male and have found good healing clinically. It is suggested that the use of PRF membrane could be tried for various other superficial oral mucosal lesions. PMID- 25737934 TI - Peripheral calcifying epithelial odontogenic tumor - Case report. AB - The calcifying epithelial odontogenic tumor (CEOT), Pindborg tumor is a benign, slow growing, but locally invasive neoplasm. It is known to have a common intraosseous variant and a very rare extraosseous variant. We report an unusual case of an extraosseous variant of CEOT of unusual large size and maxillary anterior location, the treatment was planned considering the clinical, radiological and histological features. Though peripheral types are less aggressive and had no recurrence, in our case regular follow up is required considering the aggressiveness of the lesion and its proximity to important adjacent structures. PMID- 25737935 TI - Two dimensional alveolar ridge augmentation using particulate hydroxyapatite and collagen membrane: A case report. AB - BACKGROUND: Ridge augmentation procedures require bone regeneration outside of the existing bony walls or housing and are therefore often considered to be the most challenging surgical procedures. The bony deficiencies can be managed with GBR techniques involving bone grafting material and membrane while vertical augmentation may require the use of space-creating support mechanisms. Non degradable membranes have been used for ridge augmentation with encouraging results however; requirement of second surgery for its removal and associated infection on exposure may compromise the desired results. These problems can be overcome by employing resorbable collagen membranes. Different bone graft materials are also used in combination with resorbable membranes, for prevention of membrane collapse and maintenance of space, as they lack sufficient rigidity. Particulate hydroxyapatite bone graft may be better alternative, because it treats the underlying bone defect to restore the natural support of the tissue architecture. Moreover, its use avoids potential donor site complications associated with autogenous block grafts. METHOD: Patient described in this report presented with missing right maxillary incisor with ridge deficiency. A treatment approach involving localised ridge augmentation with particulate hydroxyapatite and collagen membrane was used. RESULT: Six month post-operative periapical radiograph demonstrated a significant vertical bone fill. CONCLUSION: The clinical and radiographic findings of the present case suggests that HA in conjunction with a resorbable collagen membrane may be an acceptable alternative to the autogenous block graft and non-resorbable membrane in the treatment of compromised alveolar ridge deficiencies. PMID- 25737937 TI - Dentistry: Changing paradigm with growth of basic sciences. PMID- 25737936 TI - Maxillary canine transposition - A literature review with case report. AB - Tooth transposition is a severe disturbance of tooth eruptive position and their sequence, which involve certain teeth occurring at any of several specific sites in the mouth. Tooth transposition is of several types and their classification depends on the teeth involved. The review of literature aims to discuss the incidence and identifying factors related to occurrence of this dental anomaly. The present study aims to discuss about the prosthetic treatment of a patient with unilateral maxillary canine - lateral incisor transposition with the absence of permanent lateral incisor. PMID- 25737938 TI - Comparative study of different centrifugation protocols for a density gradient separation media in isolation of osteoprogenitors from bone marrow aspirate. AB - INTRODUCTION: Human bone marrow contains osteoprogenitors capable of differentiating into osteoblasts. Density gradient centrifugation (DGC) is a commonly used method to isolate osteoprogenitors from bone marrow. Numerous studies used different dilution and centrifugation protocols, which might affect cell yields and quality. Moreover, the relative isolation efficiencies of the different separation protocols have not been investigated. This study compares the enrichment efficacy of the two different centrifugation protocols for a commonly used DGC media in isolation of osteoprogenitors. MATERIAL AND METHOD: Bone marrow was aspirated from human anterior iliac crests. Osteoprogenitors are isolated with Ficoll DGC media. A centrifugal force of 400 g and 1:1 dilution was compared with the centrifugal force of 1000 g after three dilution times with a buffer. RESULTS: The average numbers of isolated cells were significantly higher when using lower centrifugal force with 1:1 dilution, however, there was no detectable difference between Colony-forming unit-fibroblast (CFU-F) forming capacity, STRO-1 positivity, osteogenic differentiation or mineralization abilities between protocols. CONCLUSION: Both protocols could isolate competent and functional osteoprogenitors, while a lower centrifugal force (400 g) with 1:1 dilution produced recovery of more osteoprogenitors. PMID- 25737939 TI - Comparison of curcumin with intralesional steroid injections in Oral Submucous Fibrosis - A randomized, open-label interventional study. AB - INTRODUCTION: Oral Submucous Fibrosis (OSMF) is precancerous condition caused by areca nut chewing characterized by restricted mouth opening, burning sensation and stiffness & blanching of oral mucosa. Complete regression of the condition had not been achieved in all cases with any of the present treatment regimens. Curcumin is (diferuloylmethane), a yellow pigment in curry powder, exhibits anti oxidant, anti-inflammatory, and pro-apoptotic activities. Hence an interventional study was undertaken to establish the efficacy of curcumin in OSMF patients. SETTINGS & DESIGN: A randomized open label, interventional study was conducted in forty patients with clinically and histologically proven Oral Submucous Fibrosis. MATERIALS & METHODS: Forty patients with clinically and histologically proven Oral Submucous Fibrosis were selected for the study and were randomly divided into 2 groups. The first group was treated with weekly intralesional injection of 4 mg Dexamethasone & 1500 I.U Hyaluronidase and the second group by oral administration of two Curcumin tablets (Turmix 300 mg) per day for 3 months each. Improvement of burning sensation, interincisal distance and tongue protrusion was evaluated on a weekly basis. RESULTS: Burning sensation improved in both the groups from early to late stages. Complete resolution of burning sensation was noted with turmix. The mean increase in interincisal distance was 3.13 mm and 1.25 mm respectively in groups 1 &2. The interincisal distance improved in both the groups, with significant results at the end of first month. Tongue protrusion showed greater recovery at the end of 1st month in group 1 when compared with group 2. CONCLUSION: Turmix is beneficial and effective in reducing burning sensation in early OSMF patients. PMID- 25737940 TI - Minor salivary gland tumors in the Indian population: A series of cases over a ten year period. AB - PROBLEM CONSIDERED: Minor salivary glands are found in the sino-nasal cavities, oropharynx, larynx and trachea with the majority being found in the oral cavity. 80% or more of minor salivary gland tumors are malignant and they tend to have a great variation in presentation and histology. We sought out to compare the presentation of various minor salivary gland tumors (MSGT's) in the Indian population as compared to that reported in different races and regions. METHODS: We report a clinical case series in which 17 patients with biopsy proven minor salivary gland tumors both benign and malignant at various intraoral sites viz the palate, cheek, retromolar trigone and floor of the mouth were operated upon and followed up over a span of 10 years from 2001 to 2011. RESULTS: 15 patients were treated timely with complete removal of the lesions by wide local excision and as confirmed by histopathology; one patient with adenoid cystic carcinoma delayed in seeking treatment and expired within a month and another with salivary duct carcinoma presented with advanced disease and regional metastases in the form of multiple ipsilateral enlarged lymph nodes and distant metastases in the liver. He was given palliative radiotherapy but he died after six weeks of receiving treatment. CONCLUSION: the results that we obtained for Indians were comparable to the various population studies done around the world. PMID- 25737941 TI - Comparative evaluation of antimicrobial substantivity of different concentrations of chlorhexidine as a root canal irrigant: An in vitro study. AB - INTRODUCTION: The aim of this in vitro study was to evaluate and compare the antimicrobial substantivity of different concentrations of chlorohexidine as root canal irrigant by microbiological assay using mitis salivarius bacitracin streptomycin, MSBS agar plate. METHODS: Extracted single rooted permanent human teeth were selected as samples and randomly divided into four groups (three experimental, one control). The samples of the three experimental groups used different concentration of chlorhexidine, CHX (0.1%, 1% and 2%), deionized water used as an irrigant served as control. In each group the apices of teeth were sealed with composite and mounted on plaster blocks. Root canals were prepared using step back technique and enlarged upto no 80. With each change in the file size the corresponding irrigant was used and final irrigation was done with deionized water. Samples were taken with paper points at 12 h, 1 day, 2 days and 3 days respectively and stored in sterile phials which were then arranged on MSBS agar plates for microbiological assay. RESULTS AND CONCLUSION: Results were analysed by ANOVA and Tukey's HSD test showed that antibacterial substantivity of 2% CHX was best followed by 1% CHX and 0.1% CHX in decreasing order respectively. PMID- 25737942 TI - A comparative study of different intrusion methods and their effect on maxillary incisors. AB - INTRODUCTION: To evaluate and compare the rate of intrusion and root resorption of maxillary incisors by three different intrusion techniques: Rickett's utility arch, Kalra's Simultaneous Intrusion & Retraction arch and arch with Reverse Curve of Spee. METHODS: The study was conducted over 30 patients aged between 14 and 25 yrs with deep bite requiring at least 2-4 mm intrusion of maxillary incisors. These patients were equally divided into three groups based on intrusion technique used, Rickets utility arch (Group I), K-SIR arch (Group II) and RCS arch (Group III). For each patient, amount of intrusion and root resorption occurring during intrusion was measured. Seven angular and six linear cephalometric measurements were made to evaluate skeletal and dental changes before and after incisor intrusion. RESULTS: The mean true incisor intrusion achieved with utility arch was 1.6 mm, with K-SIR, 1.25 mm and with RCS, 0.70 mm respectively. The rate of intrusion of utility arch was 0.44 mm/month, K-SIR - 0.33 mm/month, RCS - 0.35 mm/month, the difference was not statistically significant (p = 0.451). Utility arch had significantly higher mean root resorption of 1.56 mm as compared to K-SIR of 1.08 mm and RCS of 0.96 mm. CONCLUSION: Both the intrusion rate and root resorption is more by utility arch while with K-SIR arch, though the rate of intrusion is almost same; the root resorption is much less. PMID- 25737943 TI - Evaluation of canine retraction following periodontal distraction using NiTi coil spring and implants - A clinical study. AB - OBJECTIVE: To evaluate the amount of canine retraction with periodontal distraction using miniscrew implants and NiTi coil spring. MATERIAL AND METHOD: Sample comprised of 25 patients who were scheduled for all 1st premolar extraction (13 males and 12 females), in the age range of 16-22 years with mean age 18.8 +/- 2.7 years. For each patient left side served as control side (Group I) and right side as experimental side (Group II). At the time of first premolar extraction, periodontal distraction was performed only on the experimental side, followed by retraction of canine from mini-implant by closed NiTi coil spring on both the sides. "Nemotech" software was used to evaluate the amount of canine retraction for a period of 3 months. RESULTS: Significantly higher amount of tooth movement was seen from T0-T1 and from T1-T2 in Group II for the maxillary parameters 3C-5C, 6CF-3C, 3C-I/3C-J and for the mandibular parameter 6CF"-3C". Whereas no significant amount of tooth movement was observed for maxillary and mandibular parameters between T2-T3 except for 6CF"-3C" (p <= 0.01) which was significantly higher for the Group II. CONCLUSION: There was accelerated canine retraction on the periodontal distraction side as compared to the control side, with negligible anchorage loss. PMID- 25737944 TI - Finite element analysis: A boon to dentistry. AB - The finite element analysis (FEA) is an upcoming and significant research tool for biomechanical analyses in biological research. It is an ultimate method for modeling complex structures and analyzing their mechanical properties. In Implantology, FEA has been used to study the stress patterns in various implant components and also in the peri-implant bone. It is also useful for studying the biomechanical properties of implants as well as for predicting the success of implants in clinical condition. FEA of simulated traumatic loads can be used to understand the biomechanics of fracture. FEA has various advantages compared with studies on real models. The experiments are repeatable, there are no ethical considerations and the study designs may be modified and changed as per the requirement. There are certain limitations of FEA too. It is a computerized in vitro study in which clinical condition may not be completely replicated. So, further FEA research should be supplemented with clinical evaluation. PMID- 25737945 TI - A technique for using short term soft liners as complete dentures final impression material. AB - Tissue conditioners can be used to condition abused tissues, record functional impressions, make temporary relining for surgical splints and obturators, and for other clinical applications, mainly because of their specific viscoelasticity. Their function in complete denture fabrication is debatable but their use as a functional impression material has been proved. The present article describes a technique for using tissue conditioners as functional impression materials. Correct method of usage, manipulation, specific properties as impression materials and precautions in different situations for obtaining accurate impressions has been highlightened. PMID- 25737946 TI - Osteochondroma of the mandibular condyle - Report of an atypical case and the importance of computed tomography. AB - Osteochondroma is a rare tumor of the mandibular condyle. Much confusion seems to exist in the literature in differentiating these tumors from chondromas as well as condylar hyperplasias. Due to considerable overlapping features between chondromas and condylar hyperplasia, it is likely to get misdiagnosed, thereby resulting in inadvertent errors in the treatment. A case report of a 35 year old male patient with mandibular deviation and malocclusion is presented here. He initially went unnoticed for features of an osteochondroma of the mandibular condyle but was subsequently treated for the same. PMID- 25737947 TI - Long term dento-facial effects of radiotherapy in a treated patient of retinoblastoma. AB - Newer cancer treatment modalities have increased patient survival rate and longevity. Craniofacial and dental abnormalities occurring after radiation therapy and surgery in cancer patients may lead to severe cosmetic or functional sequelae, which may require surgical or orthodontic intervention later on. We, present a case; who was treated for retinoblastoma with enucleation of left eye and external beam radiotherapy at 26 months of age. As a result of radiotherapy there was hypoplasia of the maxilla. This case validates Von-Limborg's theory that states that local epigenetic factor like the developing eye has an important influence on the growth of adjacent structures, as with this patient there was hypoplasia of left orbit. Certain dental anomalies were also seen in the maxillary arch. PMID- 25737948 TI - Decreased expression of hepatic glucokinase in type 2 diabetes. AB - BACKGROUND/OBJECTIVES: Increased endogenous glucose production is a hallmark of type 2 diabetes. Evidence from animal models has suggested that a likely cause of this is increased mRNA expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase (encoded by G6PC, PCK1 and PCK2). But another contributing factor may be decreased liver glucokinase (encoded by GCK). METHODS: We examined expression of these enzymes in liver biopsies from 12 nondiabetic and 28 diabetic individuals. Diabetic patients were further separated into those with HbA1c lower or higher than 7.0. RESULTS: In diabetic subjects with HbA1c > 7.0, we found that gluconeogenic enzymes were expressed normally, but GCK was suppressed more than 60%. Moreover, HbA1c and fasting glucose were negatively correlated with GCK, but showed no correlation with G6PC, PCK1, or PCK2. CONCLUSION: These findings suggest an underlying dysregulation of hepatic GCK expression during frank diabetes, which has implications for the therapeutic use of glucokinase activators in this population. PMID- 25737949 TI - Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. AB - OBJECTIVE: Leptin alleviates hyperglycemia in rodent models of Type 1 diabetes by activating leptin receptors within the central nervous system. Here we delineate whether non-canonical leptin signaling through the Creb-regulated transcriptional coactivator 1 (Crtc1) contributes to leptin-dependent improvements in diabetic glucose metabolism. METHODS: We employed mice with a targeted genetic disruption of Crtc1, tracer dilution techniques and neuroanatomical studies to interrogate whether Crtc1 enables leptin to improve glucose metabolism in streptozotocin induced (STZ) diabetes. RESULTS: Here we show that leptin improves diabetic glucose metabolism through Crtc1-dependent and independent mechanisms. We find that leptin reduces diabetic hyperglycemia, hepatic gluconeogenic gene expression and selectively increases glucose disposal to brown adipose tissue and heart, in STZ-diabetic Crtc1 (WT) mice but not Crtc1 (+/-) mice. By contrast, leptin decreases circulating glucagon levels in both STZ-diabetic Crtc1 (WT) and Crtc1 (+/-) mice. We also demonstrate that leptin promotes Crtc1 nuclear translocation in pro-opiomelanocortin (Pomc) and non-Pomc neurons within the hypothalamic arcuate nucleus (ARC). Accordingly, leptin's ability to induce Pomc gene expression in the ARC is blunted in STZ-diabetic Crtc1 (+/-) mice. CONCLUSIONS: Our study reveals that Crtc1 functions as a conduit for leptin's glucoregulatory actions in insulin-dependent diabetes. This study also highlights a new role for Crtc1 in modulating peripheral glucose metabolism. PMID- 25737950 TI - SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes. AB - OBJECTIVE: During pregnancy, women normally increase their food intake and body fat mass, and exhibit insulin resistance. However, an increasing number of women are developing metabolic imbalances during pregnancy, including excessive gestational weight gain and gestational diabetes mellitus. Despite the negative health impacts of pregnancy-induced metabolic imbalances, their molecular causes remain unclear. Therefore, the present study investigated the molecular mechanisms responsible for orchestrating the metabolic changes observed during pregnancy. METHODS: Initially, we investigated the hypothalamic expression of key genes that could influence the energy balance and glucose homeostasis during pregnancy. Based on these results, we generated a conditional knockout mouse that lacks the suppressor of cytokine signaling-3 (SOCS3) only in leptin receptor expressing cells and studied these animals during pregnancy. RESULTS: Among several genes involved in leptin resistance, only SOCS3 was increased in the hypothalamus of pregnant mice. Remarkably, SOCS3 deletion from leptin receptor expressing cells prevented pregnancy-induced hyperphagia, body fat accumulation as well as leptin and insulin resistance without affecting the ability of the females to carry their gestation to term. Additionally, we found that SOCS3 conditional deletion protected females against long-term postpartum fat retention and streptozotocin-induced gestational diabetes. CONCLUSIONS: Our study identified the increased hypothalamic expression of SOCS3 as a key mechanism responsible for triggering pregnancy-induced leptin resistance and metabolic adaptations. These findings not only help to explain a common phenomenon of the mammalian physiology, but it may also aid in the development of approaches to prevent and treat gestational metabolic imbalances. PMID- 25737951 TI - Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes. AB - OBJECTIVE: Dysregulated muscle metabolism is a cardinal feature of human insulin resistance (IR) and associated diseases, including type 2 diabetes (T2D). However, specific reactions contributing to abnormal energetics and metabolic inflexibility in IR are unknown. METHODS: We utilize flux balance computational modeling to develop the first systems-level analysis of IR metabolism in fasted and fed states, and varying nutrient conditions. We systematically perturb the metabolic network to identify reactions that reproduce key features of IR-linked metabolism. RESULTS: While reduced glucose uptake is a major hallmark of IR, model-based reductions in either extracellular glucose availability or uptake do not alter metabolic flexibility, and thus are not sufficient to fully recapitulate IR-linked metabolism. Moreover, experimentally-reduced flux through single reactions does not reproduce key features of IR-linked metabolism. However, dual knockdowns of pyruvate dehydrogenase (PDH), in combination with reduced lipid uptake or lipid/amino acid oxidation (ETFDH), does reduce ATP synthesis, TCA cycle flux, and metabolic flexibility. Experimental validation demonstrates robust impact of dual knockdowns in PDH/ETFDH on cellular energetics and TCA cycle flux in cultured myocytes. Parallel analysis of transcriptomic and metabolomics data in humans with IR and T2D demonstrates downregulation of PDH subunits and upregulation of its inhibitory kinase PDK4, both of which would be predicted to decrease PDH flux, concordant with the model. CONCLUSIONS: Our results indicate that complex interactions between multiple biochemical reactions contribute to metabolic perturbations observed in human IR, and that the PDH complex plays a key role in these metabolic phenotypes. PMID- 25737952 TI - NPY signalling in early osteoblasts controls glucose homeostasis. AB - OBJECTIVE: The skeleton has recently emerged as an additional player in the control of whole-body glucose metabolism; however, the mechanism behind this is not clear. METHODS: Here we employ mice lacking neuropeptide Y, Y1 receptors solely in cells of the early osteoblastic lineage (Y1f3.6Cre), to examine the role of osteoblastic Y1 signalling in glycaemic control. RESULTS: Y1f3.6Cre mice not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis; significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance. The reduced glucose tolerance and elevated bone mass was corrected in Y1f3.6Cre mice by bone marrow transplant from wildtype animals, reinforcing the osteoblastic nature of this pathway. Importantly, when fed a high fat diet, Y1f3.6Cre mice, while equally gaining body weight and fat mass compared to controls, showed significantly improved glucose and insulin tolerance. Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway. Importantly, osteocalcin a secreted osteoblastic factor previously identified as a modulator of insulin secretion was not altered in the Y1f3.6Cre model. CONCLUSION: This study identifies the existence of other osteoblast-derived regulators of pancreas function and insulin secretion and illustrates a mechanism by which NPY signalling in bone tissue is capable of regulating pancreatic function and glucose homeostasis. PMID- 25737953 TI - Genetic determination of the cellular basis of the ghrelin-dependent bone remodeling. AB - OBJECTIVE: Bone mass is maintained through a balance of bone formation and resorption. This homeostatic balance is regulated by various systems involving humoral and local factors. The discovery that the anorexigenic hormone leptin regulates bone mass via neuronal pathways revealed that neurons and neuropeptides are intimately involved in bone homeostasis. Ghrelin is a stomach-derived orexigenic hormone that counteracts leptin's action. However, the physiological role of ghrelin in bone homeostasis remains unknown. In this study, through the global knockout of ghrelin receptor (Ghsr) followed by tissue-specific re expression, we addressed the molecular basis of the action of ghrelin in bone remodeling in vivo. METHODS: We performed molecular, genetic and cell biological analyses of Ghsr-null mice and Ghsr-null mice with tissue specific Ghsr restoration. Furthermore, we evaluated the molecular mechanism of ghrelin by molecular and cell-based assays. RESULTS: Ghsr-null mice showed a low bone mass phenotype with poor bone formation. Restoring the expression of Ghsr specifically in osteoblasts, and not in osteoclasts or the central nervous system, ameliorated bone abnormalities in Ghsr-null mice. Cell-based assays revealed ghrelin induced the phosphorylation of CREB and the expression of Runx2, which in turn accelerated osteoblast differentiation. CONCLUSIONS: Our data show that ghrelin regulates bone remodeling through Ghsr in osteoblasts by modulating the CREB and Runx2 pathways. PMID- 25737954 TI - High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene. AB - OBJECTIVE: Association between prostate cancer and obesity remains controversial. Allelic deletions of PTEN, a tumor suppressor gene, are common in prostate cancer in men. Monoallelic Pten deletion in mice causes low prostatic intraepithelial neoplasia (mPIN). This study tested the effect of a hypercaloric diet on prostate cancer in Pten (+/-) mice. METHODS: 1-month old mice were fed a high-calorie diet deriving 45% calories from fat for 3 and 6 months before prostate was analyzed histologically and biochemically for mPIN progression. Because Pten (+/-) mice are protected against diet-induced insulin resistance, we tested the role of insulin on cell growth in RWPE-1 normal human prostatic epithelial cells with siRNA knockdown of PTEN. RESULTS: In addition to activating PI3 kinase/Akt and Ras/MAPkinase pathways, high-calorie diet causes neoplastic progression, angiogenesis, inflammation and epithelial-mesenchymal transition. It also elevates the expression of fatty acid synthase (FAS), a lipogenic gene commonly elevated in progressive cancer. SiRNA-mediated downregulation of PTEN demonstrates increased cell growth and motility, and soft agar clonicity in addition to elevation in FAS in response to insulin in RWPE-1 normal human prostatic cells. Downregulating FAS in addition to PTEN, blunted the proliferative effect of insulin (and IL-6) in RWPE-1 cells. CONCLUSION: High calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis. PMID- 25737955 TI - Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis. AB - OBJECTIVE: Disruption of the genes encoding either seipin or 1-acylglycerol-3 phosphate O-acyltransferase 2 (AGPAT2) causes severe congenital generalized lipodystrophy (CGL) in humans. However, the function of seipin in adipogenesis remains poorly defined. We demonstrated recently that seipin can bind the key adipogenic phosphatidic acid (PA) phosphatase lipin 1 and that seipin forms stable dodecamers. As AGPAT2 generates PA, the substrate for lipin 1, we investigated whether seipin might bind both enzymes of this lipid biosynthetic pathway, which is required for adipogenesis to occur. METHODS: We employed co immunoprecipitation and immunofluorescence methods to determine whether seipin can interact with AGPAT2 and the consequences of this in developing adipocytes. Atomic force microscopy was used to determine whether these interactions involved direct association of the proteins and to define the molecular architecture of these complexes. RESULTS: Our data reveal that seipin can bind AGPAT2 during adipogenesis and that stabilizing this interaction during adipogenesis can increase the nuclear accumulation of PPARgamma. Both AGPAT2 and lipin 1 can directly associate with seipin dodecamers, and a single seipin complex can simultaneously bind both AGPAT2 and lipin with a defined orientation. CONCLUSIONS: Our study provides the first direct molecular link between seipin and AGPAT2, two proteins whose disruption causes CGL. Moreover, it provides the first example of an interaction between seipin and another protein that causally influences a key aspect of adipogenesis. Together our data suggest that the critical role of seipin in adipogenesis may involve its capacity to juxtapose important regulators of this process in a multi-protein complex. PMID- 25737957 TI - Increased biogenesis of glucagon-containing secretory granules and glucagon secretion in BIG3-knockout mice. AB - OBJECTIVE: Although both insulin and glucagon are intimately involved in the regulation of glucose homeostasis, the intrinsic control of glucagon secretion, including the biogenesis and exocytosis of glucagon-containing granules, is far less understood compared with that of insulin. As Brefeldin A-inhibited guanine nucleotide exchange protein 3 (BIG3) is a negative regulator of insulin-granule biogenesis and insulin secretion, we investigated whether BIG3 plays any role in alpha-cells and glucagon secretion. METHODS: We examined the expression of BIG3 in islet cells by immuno-fluorescence and confocal microscopy, and measured glucagon production and secretion in BIG3-depleted and wild-type mice, islets and cells. RESULTS: BIG3 is highly expressed in pancreatic alpha-cells in addition to beta-cells, but is absent in delta-cells. Depletion of BIG3 in alpha-cells leads to elevated glucagon production and secretion. Consistently, BIG3-knockout (BKO) mice display increased glucagon release under hypoglycemic conditions. CONCLUSIONS: Together with our previous studies, the current data reveal a conserved role for BIG3 in regulating alpha- and beta-cell functions. We propose that BIG3 negatively regulates hormone production at the secretory granule biogenesis stage and that such regulatory mechanism may be used in secretory pathways of other endocrine cells. PMID- 25737956 TI - Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation. AB - OBJECTIVE: Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous system (CNS) neuropeptide Y (NPY); in fact, a single intracerebroventricular (icv) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion and does so, in large part, via signaling through the CNS NPY Y1 receptor. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism. METHODS: Chow-fed Zucker fatty (ZF) rats were pair-fed by matching their caloric intake to that of lean controls and effects on body weight, plasma TG, and liver content of TG and phospholipid (PL) were compared to ad-libitum (ad-lib) fed ZF rats. Additionally, lean 4-h fasted rats with intact or disrupted hepatic sympathetic innervation were treated with icv NPY or NPY Y1 receptor agonist to identify novel hepatic mechanisms by which NPY promotes VLDL particle maturation and secretion. RESULTS: Manipulation of plasma TG levels in obese ZF rats, through pair-feeding had no effect on liver TG content; however, hepatic PL content was substantially reduced and was tightly correlated with plasma TG levels. Treatment with icv NPY or a selective NPY Y1 receptor agonist in lean fasted rats robustly activated key hepatic regulatory proteins, stearoyl-CoA desaturase-1 (SCD-1), ADP-ribosylation factor-1 (ARF-1), and lipin-1, known to be involved in remodeling liver PL into TG for VLDL maturation and secretion. Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation. CONCLUSIONS: These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is dependent on the Y1 receptor and sympathetic signaling to the liver. PMID- 25737958 TI - White matter disruption in moderate/severe pediatric traumatic brain injury: advanced tract-based analyses. AB - Traumatic brain injury (TBI) is the leading cause of death and disability in children and can lead to a wide range of impairments. Brain imaging methods such as DTI (diffusion tensor imaging) are uniquely sensitive to the white matter (WM) damage that is common in TBI. However, higher-level analyses using tractography are complicated by the damage and decreased FA (fractional anisotropy) characteristic of TBI, which can result in premature tract endings. We used the newly developed autoMATE (automated multi-atlas tract extraction) method to identify differences in WM integrity. 63 pediatric patients aged 8-19 years with moderate/severe TBI were examined with cross sectional scanning at one or two time points after injury: a post-acute assessment 1-5 months post-injury and a chronic assessment 13-19 months post-injury. A battery of cognitive function tests was performed in the same time periods. 56 children were examined in the first phase, 28 TBI patients and 28 healthy controls. In the second phase 34 children were studied, 17 TBI patients and 17 controls (27 participants completed both post-acute and chronic phases). We did not find any significant group differences in the post-acute phase. Chronically, we found extensive group differences, mainly for mean and radial diffusivity (MD and RD). In the chronic phase, we found higher MD and RD across a wide range of WM. Additionally, we found correlations between these WM integrity measures and cognitive deficits. This suggests a distributed pattern of WM disruption that continues over the first year following a TBI in children. PMID- 25737959 TI - Patterns of brain structural connectivity differentiate normal weight from overweight subjects. AB - BACKGROUND: Alterations in the hedonic component of ingestive behaviors have been implicated as a possible risk factor in the pathophysiology of overweight and obese individuals. Neuroimaging evidence from individuals with increasing body mass index suggests structural, functional, and neurochemical alterations in the extended reward network and associated networks. AIM: To apply a multivariate pattern analysis to distinguish normal weight and overweight subjects based on gray and white-matter measurements. METHODS: Structural images (N = 120, overweight N = 63) and diffusion tensor images (DTI) (N = 60, overweight N = 30) were obtained from healthy control subjects. For the total sample the mean age for the overweight group (females = 32, males = 31) was 28.77 years (SD = 9.76) and for the normal weight group (females = 32, males = 25) was 27.13 years (SD = 9.62). Regional segmentation and parcellation of the brain images was performed using Freesurfer. Deterministic tractography was performed to measure the normalized fiber density between regions. A multivariate pattern analysis approach was used to examine whether brain measures can distinguish overweight from normal weight individuals. RESULTS: 1. White-matter classification: The classification algorithm, based on 2 signatures with 17 regional connections, achieved 97% accuracy in discriminating overweight individuals from normal weight individuals. For both brain signatures, greater connectivity as indexed by increased fiber density was observed in overweight compared to normal weight between the reward network regions and regions of the executive control, emotional arousal, and somatosensory networks. In contrast, the opposite pattern (decreased fiber density) was found between ventromedial prefrontal cortex and the anterior insula, and between thalamus and executive control network regions. 2. Gray-matter classification: The classification algorithm, based on 2 signatures with 42 morphological features, achieved 69% accuracy in discriminating overweight from normal weight. In both brain signatures regions of the reward, salience, executive control and emotional arousal networks were associated with lower morphological values in overweight individuals compared to normal weight individuals, while the opposite pattern was seen for regions of the somatosensory network. CONCLUSIONS: 1. An increased BMI (i.e., overweight subjects) is associated with distinct changes in gray-matter and fiber density of the brain. 2. Classification algorithms based on white-matter connectivity involving regions of the reward and associated networks can identify specific targets for mechanistic studies and future drug development aimed at abnormal ingestive behavior and in overweight/obesity. PMID- 25737960 TI - White matter integrity in small vessel disease is related to cognition. AB - Cerebral small vessel disease, including white matter hyperintensities (WMH) and lacunes of presumed vascular origin, is common in elderly people and is related to cognitive impairment and dementia. One possible mechanism could be the disruption of white matter tracts (both within WMH and normal-appearing white matter) that connect distributed brain regions involved in cognitive functions. Here, we investigated the relation between microstructural integrity of the white matter and cognitive functions in patients with small vessel disease. The Radboud University Nijmegen Diffusion tensor and Magnetic resonance Cohort study is a prospective cohort study among 444 independently living, non-demented elderly with cerebral small vessel disease, aged between 5500 and 85 years. All subjects underwent magnetic resonance imaging and diffusion tensor imaging scanning and an extensive neuropsychological assessment. We showed that loss of microstructural integrity of the white matter at specific locations was related to specific cognitive disturbances, which was mainly located in the normal-appearing white matter (p < 0.05, FWE-corrected for multiple comparisons). The microstructural integrity in the genu and splenium showed the highest significant relation with global cognitive function and executive functions, in the cingulum bundle with verbal memory performance. Associations between diffusion tensor imaging parameters and most cognitive domains remained present after adjustment for WMH and lacunes. In conclusion, cognitive disturbances in subjects with cerebral small vessel disease are related to microstructural integrity of multiple white matter fibers (within WMH and normal-appearing white matter) connecting different cortical and subcortical regions. PMID- 25737961 TI - Language lateralization in a patient with temporal lobe epilepsy and callosal agenesis. AB - The corpus callosum has been proposed as a mechanism of interhemispheric inhibition that allows language dominance to develop [1]. Callosal agenesis or dysgenesis provides a test of this hypothesis, as patients lacking a normal corpus callosum should also lack normal language lateralization [2]. We report pre- and postoperative functional magnetic resonance imaging (fMRI) and neuropsychological testing in a patient with partial callosal agenesis who underwent a right temporal lobectomy for medically refractory seizures. PMID- 25737962 TI - Subdural electrode recording of generalized photoepileptic responses. AB - We evaluated the spatiotemporal distribution of photic driving (PDR), photoparoxysmal (PPR), and photoconvulsive (PCR) responses recorded by intracranial electrodes (ic-EEG) in a patient with generalized photosensitivity and right frontal lobe cortical dysplasia. Intermittent light stimulation (ILS) was performed thirteen times in nine days. Cortical responses to ILS recorded by ic-EEG were reviewed and classified as PDRs, PPRs, and PCRs. Photic driving responses were restricted to the occipital lobe at ILS frequencies below 9 Hz, spreading to the parietal and central regions at > 9 Hz. Photoparoxysmal responses commonly presented as focal, medial occipital, and parietal interictal epileptic discharges (IEDs), the latter propagating to the sensorimotor cortices. Generalized IEDs were also generated in the setting of PPRs. Photoconvulsive responses, characterized by repetitive bilateral upper extremity myoclonus sustained until the end of the stimulus, were associated with propagation of the medial parieto-occipital discharge to the primary sensorimotor and supplementary area cortices, while generalized myoclonic seizures were associated with a generalized spike-and-wave discharge with an interhemispheric posterior cingulate onset sparing the sensorimotor cortices. Both types of PCR could occur during the same stimulus. Regardless of the pathway, PCRs only occurred when PDRs involved the parietal cortices. While there may be more than one pathway underlying PCRs, parietal lobe association cortices appear to be critical to their generation. PMID- 25737963 TI - Nonconvulsive status epilepticus in the elderly associated with newer antidepressants used at therapeutic doses: A report of three cases. AB - Classic antidepressants have been known to induce convulsive seizures and nonconvulsive status epilepticus (NCSE). On the other hand, many reports have emphasized the safety of novel antidepressants. However, we encountered three cases of NCSE in the elderly associated with the use of newer antidepressants at therapeutic doses. All three patients were male and were 73 years of age or older. One patient was recently diagnosed with temporal lobe epilepsy and treated with low-dose lamotrigine. In all patients, newer antidepressants were initiated because of depressive symptoms. After titrating to therapeutic doses (paroxetine 20 mg/day, sertraline 50 mg/day, and combination of sertraline 50 mg/day and mirtazapine 30 mg/day in one patient each), impaired consciousness appeared. Electroencephalography (EEG) showed generalized slow waves with intermittent spike-slow-wave complexes. Intravenous injection of antiepileptic drugs improved EEG findings and clinical symptoms. After discontinuance of the abovementioned antidepressants, NCSE did not recur in any of patients. These reports raise the question of whether the newer antidepressants, like classic antidepressants, might also induce NCSE in the elderly, even when used at therapeutic doses. Physicians should consider monitoring for possible NCSE when using newer antidepressants in patients who may have low drug tolerability. Active continuous video-EEG monitoring is essential when behavioral and psychological symptoms or change in consciousness level is suspected. PMID- 25737964 TI - Panayiotopoulos syndrome presenting with respiratory arrest: A case report and literature review. AB - We describe a child with Panayiotopoulos syndrome (PS) who presented with autonomic status epilepticus and developed respiratory arrest requiring intubation and mechanical ventilation. Because of that life-threatening episode and the risk of developing a similar event in subsequent seizures, we decided to initiate our patient on AED treatment. Such life-threatening complications were previously reported in only four children with PS. Although PS is considered to be a benign childhood epilepsy syndrome usually not requiring treatment with antiepileptic drugs, our case and the small number of similar cases in the literature show it is important to realize that it can rarely be associated with life-threatening complications. It is our opinion that children with PS who develop an episode of autonomic status epilepticus and those living in remote areas with no quick access to emergency departments should be initiated on AED therapy to minimize the risk of experiencing a subsequent potentially fatal seizure. We further suggest that the use of benzodiazepines in this syndrome should only be administered during the early stage of the seizure, since administration of this class of drugs during an established autonomic status epilepticus can result in further respiratory depression. PMID- 25737965 TI - First case report of Rett syndrome in the Azeri Turkish population and brief review of the literature. AB - Rett syndrome is a dominant X-linked male-lethal disorder largely caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). Clinical manifestations include neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and abnormal electroencephalograms. Afflicted females show normal development until the age of 6 to 18 months, followed by gradual loss of speech abilities, microcephaly, social impairment, ataxia, and stereotypic hand movements. We report a 7-year-old girl who was born of a nonconsanguineous marriage presenting with mental retardation and delayed development. Physical examination revealed loss of speech, repetitive hand-wringing movement, short stature (120 cm), strabismus, microcephaly, and autistic behavior. The diagnosis was confirmed by sequencing MECP2 gene with heterozygous mutation C385A in exon 2. The current study aimed to report the first case of Rett syndrome in the Azeri Turkish population. PMID- 25737966 TI - Variation of Axial Ocular Dimensions with Age, Sex, Height, BMI-and Their Relation to Refractive Status. AB - BACKGROUND: Myopia is one of the most common causes of visual impairment worldwide.It is proved in earlier studies that the eye shape is different in myopic and nonmyopic children even at a very young age, with the former manifesting asymmetric axial globe elongation and the latter global expansion but limited information is available regarding hypermetropia. AIM: To find out the variations of axial ocular dimensions in relation to age, sex, height and to demonstrate any possible correlation of body mass index (BMI) in myopic hypermetropic and emmetropic patients. SETTINGS: It is a cross-sectional observational study. MATERIALS AND METHODS: All the patients attending eye OPD in the Regional Institute of Ophthalmology (R.I.O.), Medical College, Kolkata, West Bengal, India from June2010 to May 2011.Axial dimensions were measured by B-mode USG. Refractive status was measured.Age, gender, height and BMI were also observed. After collecting all the data,all the variables were summarised by descriptive statistics followed by correlation testing by Pearson's Correlation Coefficient r. RESULTS: Height was positively correlated with axial length, anterior chamber depth, vitreous chamber depth ;age was positively correlated with axial length, vitreous chamber depth and negatively correlated with anterior chamber depth. Subjects with higher BMI tended to had refractions that were more hypermetropic. CONCLUSION: The findings of the present study can highlight not only the normal range of the different ocular parameters namely axial length, anterior chamber depth, vitreous chamber depth and lens thickness but their variation with age, gender, height and weight. PMID- 25737967 TI - Isolated single umbilical artery in twin pregnancies and its adverse pregnancy outcomes - a case report and review of literature. AB - Single umbilical artery is the most common congenital abnormality of the umbilical cord and is seen in 4-11% of twin pregnancies. It is usually associated with intrauterine growth retardation, preterm labour, small-for-dates and other structural anomalies. There is no significant difference in the incidence between monochorionic and dichorionic twins. The left artery is usually absent more commonly than the right. The female co-twin was predominantly more affected than their male counterparts. Single umbilical artery is found twice more common in white women than in Afro-Asians and Americans. The hemodynamic disturbances occur early in the embryonic development, influence greatly in the development of single umbilical artery. Genetic and environmental factors also play a major role in the development of this anomaly. The pregnancies with single umbilical artery were classified as high risk group, because the overall perinatal mortality rate was estimated to be as high as 20%. There is a significant increase in the occurrence of single umbilical artery in pregnancies due to artificial reproductive technologies, as well as in spontaneous miscarriages. Prenatal ultrasonography is the principal diagnostic technique employed to identify single umbilical artery during 3(rd) trimester of pregnancy. The present case, reports the presence of a single umbilical artery in a monozygotic, monochorionic twin pregnancy, which is acardiac-acephalic fetus, small for dates, female sex, associated with other major structural anomalies, and was still born. Authors analyse its incidence, clinical presentations and pregnancy outcome and also review the pertinent literature. PMID- 25737968 TI - An unusual variation of axillary artery: a case report. AB - An unusual unilateral variation was observed in branching pattern and course of branches of the axillary artery of the left upper limb in an adult male cadaver. The superior thoracic branch of axillary artery had a very unusual course as it passed between the two divisions of the lateral cord of the brachial plexus and then descended down towards the first two intercostal spaces. A common trunk was seen arising from the third part of the axillary artery which divided into anterior and posterior circumflex humeral, subscapular and Profunda brachii artery. The ulnar and radial collaterals arose from the Profunda brachii artery rather than the brachial artery. The knowledge about such variations becomes essential and of utmost significance in various clinical procedures performed by the vascular surgeons, radiologists and clinical anatomists. Moreover, the injuries of the brachial plexus are quite common and require exploration and repair. During such repair surgeries the abnormal arterial branch may be a matter of definite concern if its presence is not kept in mind. PMID- 25737970 TI - Effect of bacopa monniera on cold stress induced neurodegeneration in hippocampus of wistar rats: a histomorphometric study. AB - INTRODUCTION: Bacopa monniera/ Brahmi,is used over centuries in Ayurvedic medicine for memory development, learning, concentration and other mental illnesses such as nervousness and poor cognition. The present study aims to evaluate the effect of Bacopa monniera (Brahmi, BM) on cold stress induced histological changes in hippocampus of Wistar rats. MATERIALS AND METHODS: Total 24 male rats divided into four groups were used (n=6) for this study. Group I was control in which rats were kept under ideal laboratory conditions, Group II was given 40 mg/kg of BM extract, Group III was cold water swim stress in which rats were forced to swim in the cold water maintained at 18+/-2(o)C till it started to sink for a period of one month and Group IV in which cold water swim stress given for a month followed by oral administration of BM extracts 40mg/kg treatment for a month. The whole study was carried out for a period of 60 d. The animals were sacrificed next day and their brains dissected out for histomorphometric analysis. The diameter, packing density and total number of neurons were calculated from stained histological section by using micrometry in the CA-1 region of the hippocampus. STATISTICAL ANALYSIS: The analysis and plotting of graphs were carried out using Sigma Plot 12 (Systat Software Inc., USA). Values are expressed as Mean +/- SEM (n = 6). One way analysis of variance followed by Student-Newman-Keul's multiple comparisons test was used for the comparison of means. A probability of 0.05 and less was taken as statistically significant. RESULTS: The results showed that there is no significant difference in the diameter of the cells between the groups but total number of the cells in Group II was statistically significant when compared with the others groups. Student Newman-Keuls method showed that Group II and Group IV are statistically significant when compared to Group III (p<0.05). CONCLUSION: RESULTS indicates that when BM extracts administered orally produce neuroprotective effect in cold stress induced hippocampal neurodegeneration of rats. Hence, the herb BM can possibly be used as an adjuvant to improve memory to combat stress in our day to day life. PMID- 25737969 TI - The Nuclear Maturation and Embryo Development of Mice Germinal Vesicle Oocytes with and without Cumulus Cell after Vitrification. AB - BACKGROUND: Cryobiology is an essential tool in assisted reproductive technology. Research in this area focuses on the possibility of restoring fertility in women with reproductive problems or after cancer treatments. AIM: The purpose of this study was to evaluate viability of oocytes, In vitro maturation and embryo development in vitrified germinal vesicle oocytes with and without cumulus cell after single and stepwise vitrification procedure. MATERIALS AND METHODS: Germinal vesicle oocytes with or without cumulus cells were obtained from 4 weeks old female mice 48h after intraperitoneal injection of 7.5 IU pregnant mare serum gonadotropin (PMSG). For vitrification collected oocytes vitrification were exposed to cryoprotectant, which was composed of 30% (v/v) ethylene glycol, 18% (w/v) Ficoll-70, and 0.3 M sucrose, either by single step or in a step-wise way. After exposure to cryoprotectant and immerged in liquid nitrogen, the oocytes were thawed and washed in medium TCM199 two times. Then the oocytes transferred to IVM medium for maturation and embryo development to blastocyst. RESULTS: The oocytes survival rates after vitrifying-warming, maturation rate, the capacity of fertilization and embryonic development to blastocyst were examined in vitro. The oocytes survival, maturation to MII, fertilization developmental rate in the step wise exposure and with cumulus cell was significantly higher (p<0.05) as compared with corresponding rate in the single step procedure without cumulus cell. CONCLUSION: The results of present study indicated that oocytes vitrified with cumulus cells and stepwise procedure had positive effect on maturation and developmental rate to blastocyst than oocytes without cumulus cell and single step procedure. PMID- 25737971 TI - Relationship of Caffeine with Adiponectin and Blood Sugar Levels in Subjects with and without Diabetes. AB - INTRODUCTION: Coffee though not usually thought of as healthy food but can be treated as one of the beneficial drink. Many researchers have found strong evidence that coffee reduces the risk of several serious ailments, including diabetes, heart disease, cirrhosis of the liver, etc. The long term beneficial effect of coffee on diabetes is now understood to be more influential and obliging. MATERIALS AND METHODS: This study comprised 220 healthy subjects of which 143 consumed coffee and 77 did not. These were matched with 90 diabetic subjects. Among the 90 diabetics, 48 consumed coffee and 42 did not consume coffee. RESULTS: The mean adiponectin value was significantly higher in coffee consumed normal and diabetic subjects than the subjects who did not consume coffee. The decrease in fasting blood sugar and HbA1c values were also observed in normal and diabetic subjects who consumed coffee than the other groups who did not consume coffee. Significant difference (p<0.05) in mean FBG, PPBS, HbA1c and adiponectin were observed between coffee consumed and no coffee consumed groups. CONCLUSION: The long term use of caffeine is more efficient on blood sugar and adiponectin levels, which needed in the prevention of complications in diabetic subjects. PMID- 25737973 TI - Evaluating estradiol levels in male patients with colorectal carcinoma. AB - BACKGROUND: Globally more than 1 million people suffer from colorectal cancer (CRC) per annum, resulting in about 0.5 million deaths. The role of estrogen in CRC is being researched with great interest; expression of estrogen receptors (alfa and beta) is being explored. AIMS AND OBJECTIVE: Our objective was to compare the serum estradiol levels in diagnosed male patients of CRC, with age matched controls; and to study the estradiol levels across the different stages of CRC. SETTING AND DESIGN: A cross-sectional study was conducted from January, 2012 to March, 2013 at a tertiary care hospital in north India. MATERIALS AND METHODS: Fifty one male preoperative CRC patients were enrolled along with 50 age matched male controls. Ethical approval and informed written consent from each participant were duly obtained. CRC patients were staged as per TNM (T- Tumour, N Node, M- Metastasis; I, II, III and IV) criteria. Serum estradiol level was measured by Chemiimmunofluroscence method (normal = 11.6 - 41.2 pg/ml). STATISTICAL ANALYSIS USED: We used student's t test and ANOVA (analysis of variance) to analyse the data (SPSS version 17.0, SPSS, Inc., Chicago, Illinois) Result: The mean serum estradiol level among CRC patients (43.4, sd=27.1) was significantly more than that among controls (mean=24.7, sd=17.5), (p<0.0001). Across the four TNM stages of CRC patients, mean estradiol level was highest in Stage II (55.9, sd=15.5); followed by Stages III (44.1, sd=24.9), IV (36.3, sd=30.0) and I (26.4, sd=38.8). However, significant difference was obtained only between Stages I and II. CONCLUSION: Our study revealed increased levels of serum estradiol in Indian male CRC patients. Further research is warranted to corroborate this finding, and to understand the role of estradiol across different TNM stages of CRC. PMID- 25737972 TI - The evaluation of serum levels of testosterone in type 2 diabetic men and its relation with lipid profile. AB - INTRODUCTION AND AIM: Type 2 diabetes mellitus (T2DM) is the predominant form of diabetes worldwide and much is known about its patho-physiology. Yet, newer aspects related to it are being constantly explored. For ages, testosterone has been known to men as the male sex hormone but now it has been shown by certain studies that it might have a role in the development of metabolic disorders like type 2 diabetes. This study was carried out to determine the relation of testosterone levels with type 2 diabetes mellitus and lipid profile in North East Indian men aged 31 to 73 years. MATERIALS AND METHODS: This case control study comprised of 40 type 2 diabetic men and 40 age matched non diabetic healthy men. Testosterone, SHBG levels and lipid profile were evaluated in both the groups along with anthropometric measurements and were statistically analysed. RESULTS: Serum total and free testosterone and Sex Hormone Binding Globulin were significantly lower in the test group than in the control group. Prevalence of type 2diabetes was five times higher in men having a total testosterone less than 8nmol/L and 5.57 times higher in those having a free testosterone of less than 0.225nmol/L. Fasting blood glucose showed a strong negative correlation with total and free testosterone. Glycated haemoglobin correlated negatively with SHBG but no such correlation was seen with total or free testosterone. Serum total and LDL cholesterol showed significant negative correlation with total testosterone and SHBG but no significant correlation was found with free testosterone. Serum VLDL, HDL and triglycerides did not show any significant correlation with total or free testosterone and SHBG levels. CONCLUSION: Low testosterone might have a role in the development of type 2 DM and to the associated altered lipid profile. This study, though a small one is among the few of its kind in India and it thrives to assist other studies related to the matter. PMID- 25737974 TI - A novel way to monitor urine concentration: fluorescent concentration matrices. AB - BACKGROUND: The amount of water found in urine is important diagnostic information; nevertheless it is not yet directly determined. Indirectly, the water content in urine is expressed by its density (specific gravity). However, without the diuresis value it is not possible to determine whether the increase in density of urine is due to a decrease in water secretion or an increase in the concentration of secreted substances. This problem can be solved by the use of fluorescent concentration 3D-matrices which characterise urine concentration through the pphi (or -logphi) value of the first fluorescence centre. MATERIALS AND METHODS: The urine fluorescent concentration 3D-matrix was created by the alignment of the synchronous spectra of the dilution series of urine starting from undiluted (pphi = 0) to 1000-fold diluted urine (pphi = 3). RESULTS: Using the fluorescence concentration 3D-matrix analysis of the urine samples from healthy individuals, a reference range was established for the value pphi, determining the normal, concentrated or diluted type of urine. The diagnostic potential of this approach was tested on urine samples from two patients with a chronic glomerulonephritis. CONCLUSION: The pphi value of the urine fluorescence concentration 3D-matrix analysis determines whether the urine sample falls within the normal, concentrated or diluted type of urine. This parameter can be directly utilised in sportsmen's hydration state monitoring, as well as in the diagnosis and treatment of serious diseases. An important advantage of this novel diagnostic approach is that a 12/24 h urine collection is not required, which predetermines it for use especially within paediatrics. PMID- 25737975 TI - Evaluation of serum prolactin level in patients of subclinical and overt hypothyroidism. AB - BACKGROUND: Prolactin secretion is controlled by prolactin inhibitor factor that is secreted from hypothalamus; factors like vasoactive inhibitory peptide (VIP) and thyroid releasing hormone (TRH) lead to increase in prolactin secretion. Hyperprolactinemia is a common condition that can result from a number of causes including hypothyroidism. Objective of the study was to determine correlation between serum levels of prolactin and thyroid hormones in euthyroid, subclinical and overt hypothyroid cases. MATERIALS AND METHODS: Consecutive patients presenting for various thyroid related problems were segregated into two groups subclinical and overt hypothyroidism according to their diagnosis based on history and clinical examination, laboratory reports, inclusion and exclusion criteria. Newly diagnosed 75 patients in each group were finally enrolled. Similar number of age and sex matched controls were selected. All subjects filled a predesigned questionnaire for the evaluation of hypothyroid symptoms. Thyroid profile for T3, T4 (total and free), TSH and prolactin were determined in all the subjects and analyzed. RESULTS: Prolactin elevation was found in 16 patients (21.33 %) with overt hypothyroidism, and in six patients (8%) with subclinical hypothyroidism. The control group and subclinical hypothyroid patients exhibited no significant difference in terms of total and free T3, total and free T4. For TSH and prolactin on the other hand, a statistically significant elevation was found in patients with overt hypothyroidism when compared with subclinical hypothyroidism; and in patients with subclinical hypothyroidism when compared to the controls. A significant statistical difference was observed between the two groups of hypothyroid patients for all hypothyroid symptoms except alopecia and hirsuitism. CONCLUSION: The incidence of hyperprolactinemia in hypothyroidism was found to be higher when compared with normal controls. Serum prolactin assessment should be performed on all patients with hypothyroidism (overt and subclinical) before performing further tests. PMID- 25737976 TI - Plasma Fibrinogen in Type 2 Diabetic Patients with Metabolic Syndrome and its Relation with Ischemic Heart Disease (IHD) and Retinopathy. AB - INTRODUCTION: Metabolic syndrome or Syndrome X is characterized by hyperlipidemia, increased blood pressure, abdominal obesity and hyperglycemia, which increases the risk of cardiovascular complications. In addition to these, it is also associated with nontraditional risk factor like C- reactive protein, Plasminogen activator and fibrinogen. Various studies have documented association of these nontraditional risk factor, in Type 2 diabetes mellitus. Thus patients with diabetes mellitus are higher risk of developing micro and macro vascular complications like ischemic heart disease (IHD) and diabetic retinopathy. Diabetic retinopathy is the leading cause of decreased visual acuity, which is associated with maculopathy and profierative complications of it. Chronic hyperglycemia and its associated nonenzymatic glycation play an important role in the development of microangiopathy. AIMS AND OBJECTIVES: To study the prevalence of the metabolic syndrome in type 2 diabetes mellitus. To study the plasma fibrinogen and its relationship with IHD and retinopathy in type 2 Diabetes mellitus patients with metabolic syndrome. MATERIALS AND METHODS: Patients of type 2 diabetes Mellitus were recruited based on the inclusion and exclusion criteria. History of IHD and ECG evidence of ischemia was obtained. Retinopathy was diagnosed by direct opthalmoscopy. Fasting glucose, lipid profile and plasma fibrinogen were analyzed. Stastical analysis was carried by Chi square test and student't' test. RESULTS: The prevalence of metabolic syndrome in study population of 100 type 2 diabetic patients is 58% and is significantly associated with duration of the disease (p<0.001). Fifty eight patients have hyperfibrinogenemia and mean fibrinogen level is significantly high in diabetic patients with metabolic syndrome when compared to diabetic patients without metabolic syndrome (p<0.001). Diabetic patient with metabolic syndrome and hyperfibrinogenemia have higher prevalence of IHD and retinopathy in comparison with diabetic patients without metabolic syndrome (p<0.05). CONCLUSION: The prevalence of metabolic syndrome is higher in type 2 Diabetes mellitus patients. The combination of metabolic syndrome and hyperfibrinogenemia increases the risk of developing micro and macro vascular complications. PMID- 25737977 TI - Utility of Heart-type Fatty Acid Binding Protein as a New Biochemical Marker for the Early Diagnosis of Acute Coronary Syndrome. AB - INTRODUCTION: Acute coronary syndrome (ACS) refers to a constellation of clinical symptoms caused by acute myocardial ischemia. Cardiovascular diseases (CVDs) are major and growing contributors to mortality and disability in India. AIMS AND OBJECTIVES: Especially patients with non-ACS-related troponin elevations have an adverse outcome and require careful patient management. So, we look forward for another marker Heart-type Fatty Acid Binding Protein (H-FABP) that reliably detects myocardial ischemia in the absence of necrosis and would be useful for initial identification and for differentiating patients with chest pain of aetiology other than coronary ischemia. MATERIALS AND METHODS: The study was done on 88 subjects of whom 34 subjects were with ischemic chest pain, 29 were with non-ischemic chest pain and 25 were normal subjects. RESULTS: Receiver operating characteristic (ROC) curve analysis was done which showed that area under the curve (AUC) for H-FABP was 0.885(0.79-0.94) and that of high-sensitive Troponin T (hs-TnT) in initial six hours was 0.805(0.70-0.88). The specificity of H-FABP was higher compare to hs-TnT while sensitivity was comparable during 0-6 h of presentation of chest pain. CONCLUSION: H-FABP can be used as an additional marker to hs-TnT in diagnosis of myocardial infarction (MI) and for exclusion of non-AMI (acute myocardial infarction) patients. PMID- 25737978 TI - Serum levels of metal ions in female patients with breast cancer. AB - BACKGROUND: Breast cancer is the second commonest form of cancer among women. Several studies have been conducted to identify potential risk factors. However, role of trace elements or metals in causing breast cancer has not been studied to great extent. AIMS: To estimate the serum levels of calcium, copper, magnesium, iron, phosphorus and zinc and determine their role in causing breast cancer in female patients. SETTINGS AND DESIGN: A case-control study on female patients with breast cancer was conducted in a private superspecialty hospital and Cancer centre situated in Southern part of India. MATERIALS AND METHODS: Newly diagnosed female patients with breast cancer in the age group of 30-60 y attending Oncology clinic were included in the study. These cases were selected irrespective of type and stage of the disease. The age matched control subjects were drawn from apparently healthy women attending master health check at superspecialty hospital. The patients or controls suffering from co-morbid conditions which affect serum levels of metal ions and other malignancies, and those undergoing treatment for breast cancer were excluded from the study. Serum was separated and tests were performed according to standard procedure for each metal ion on the same day. The estimation of metal ions was done by UV-Visible Spectrophotometer CHEM 7. STATISTICAL ANALYSIS: Independent Samples T-test was used to calculate difference between the two means. The p-value of <0.05 was considered as significant. RESULTS: The study was conducted on 54 female patients with breast cancer and 54 female controls with mean age of 47.2+/-8.14 y and 46.8+/-8.4 y respectively. There was statistically significant increase in serum levels of calcium, copper, iron and phosphorus in patients with breast cancer when compared to controls. The increase in serum levels of magnesium was insignificant. A statistically significant decrease in serum zinc levels was observed in patient with breast cancer when compared to controls. CONCLUSION: The present study highlights the role of calcium, copper, iron, phosphorus, magnesium and zinc in the pathogenesis of breast cancer. The estimation of serum levels of these metal ions has a potential role in early detection and monitoring of breast cancer. PMID- 25737979 TI - Assessment of lecture strategy with different teaching AIDS. AB - BACKGROUND AND OBJECTIVES: Medical/dental colleges in Northern India cater to students with diverse backgrounds, mother tongues, levels of comprehending English, and intelligence levels. This study was conducted to identify lecture strategy and teaching aid best suited for North Indian dental and medical students. It was conducted in two parts - 1. Survey of teachers' and students' opinion to obtain their preferences in teaching-learning practices followed in a conventional lecture, and 2. Comparison of students' performances after a single trial lecture with different groups of students, using different teaching aids (TAs). MATERIALS AND METHODS: Opinions of 33 faculty teaching first year dental/ medical students and 506 volunteer students (320 female) were compiled. Students were divided into four groups. A single trial lecture was held with each group (on the same topic, using identical lesson plan, by the same teacher) using a different teaching aid with each group. Lecture strategy was designed according to students' preferences (as obtained from opinion survey) regarding language of instruction and the number of mental breaks. TAs used with different groups were chalk and board (C&B), PowerPoint (PPT), overhead projector (OHP), and a combination of C&B and PPT. Pre- and post-tests using multiple choice questions were conducted with each group. RESULTS of post-test questionnaire and feedback from faculty attending the lecture were assessed for students' satisfaction and attentiveness in all four groups. RESULTS: Survey results indicated that although 97.6% students believed they had good/fair proficiency in English, 83.6% preferred being taught in a combination of English and Hindi; 44.3% students preferred C&B, 40.1% preferred PPT and 15.6% preferred the use of OHP as TA. After conducting a trial lecture with different TAs with each group, more than 90% students expressed satisfaction with the TA used for that group. Significantly better performance was observed in the post-lecture test when C&B was used. CONCLUSION: The needs of students in India are different from those of their Western counterparts, and should be considered during didactic lectures to improve the students' understanding. Post-test results were better when C&B was used, as more students were attentive and/or took notes. PMID- 25737980 TI - Heart rate variability in overweight health care students: correlation with visceral fat. AB - BACKGROUND AND OBJECTIVES: Increased sympathetic activity, decreased parasympathetic activity and sympathovagal imbalance (SVI) has been reported in obese individuals. However, the SVI and its association with visceral fat in overweight health care students have not been explored. Therefore, in the present study, we have assessed heart rate variability (HRV) and its association with visceral fat in overweight health care students. MATERIALS AND METHODS: Frequency domain parameters of HRV, body fat distribution and baseline anthropometric parameters were recorded in the control (n=40) and overweight (n=40) individuals. Further, the association of visceral fat with HRV was analysed. RESULTS: There was no significant difference in age and height of overweight group and control group (p = 0.732). The baseline heart rate and blood pressure (p<0.001) were higher in the overweight group. Total body fat, subcutaneous fat and visceral fat were higher in the overweight group (p<0.001). Among frequency domain parameter of HRV, LFnu and LF: HF were more in the overweight group (p<0.001). Further, HFnu was less in the overweight group (p<0.001). CONCLUSION: Sympathovagal imbalance due to increased sympathetic activity and its association with visceral fat was observed in overweight individuals. PMID- 25737981 TI - Posterior reversible encephalopathy syndrome with involvement of the cervical cord and medulla: a case report. AB - Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state, which is associated with symmetrical subcortical areas of vasogenic oedema that are preferentially parieto-occipital, and it typically resolves within a few weeks after appropriate treatment, We hereby report a case of a female with adrenal tumour presenting with PRES, who was featured by a very rare neuroimaging manifestation, the involvement of cervical cord and medulla. PMID- 25737982 TI - Taste pathway: what do we teach? PMID- 25737983 TI - Correlation of RAPD-PCR Profiles with ESBL Production in Clinical Isolates of Klebsiella pneumoniae in Tehran. AB - BACKGROUND: Multidrug resistant K. pneumoniae, particularly the extended-spectrum beta-lactamase (ESBL) producing strains, are often responsible for the failure of antibiotic treatment in nosocomial infections. Employing molecular methods to distinguish between ESBL and non-ESBL producing isolates can help quick identification of these multidrug resistant pathogens and thereby initiating appropriate antibiotic therapy. The aim of this study was to employ RAPD-PCR to distinguish the genetic fingerprints of ESBL producing clinical isolates of K. pneumoniae from ESBL negative strains. MATERIALS AND METHODS: Antibacterial susceptibility of 104 K. pneumoniae clinical isolates was determined to 13 antibacterial agents by disc diffusion. ESBL production was measured by the double disc synergy test followed by phenotypic confirmatory tests. Genetic fingerprinting was carried out by RAPD-PCR. RESULTS: All isolates were susceptible to imipenem. Antibiotic resistance rates were: piperacillin (100%), ceftazidime (62.5%), cefotaxime (57.6%), aztreonam (52.8%), cefepime (51.9%), kanamycin (50.9%), gentamicin (41.3%), ciprofloxacin (37.5%), nitrofurantoin (30.6%), nalidixic acid (22.1%), piperacillin/tazobactam (21.1%) and amikacin (9.6%). ESBL production was observed in 14 isolates (13.4%). Genetic fingerprinting performed on 43 isolates (14 ESBL positive and 29 ESBL negative) by RAPD-PCR, showed that 46.5% of the isolates belonged to a single profile (genotype 1), of which, the majority (62.1%) were non-ESBL producers. CONCLUSION: RAPD-PCR results showed heterogeneity among the isolates. There was no association between ESBL production with any specific genetic fingerprint. PMID- 25737984 TI - Comparative Evaluation of Disc Diffusion and E-test with Broth Micro-dilution in Susceptibility testing of Amphotericin B, Voriconazole and Caspofungin against Clinical Aspergillus isolates. AB - BACKGROUND: Clinical importance of Aspergillus has increased over the past few decades because of rise in immunosuppressive drugs and immune-modulating diseases. Antifungal susceptibility of Aspergillus is rarely performed by clinical laboratories because of lack of easier method. This study has investigated and compared susceptibility pattern of Aspergillus isolates by disc diffusion, E-test and broth micro-dilution for amphotericin B, voriconazole and caspofungin. MATERIALS AND METHODS: Disk diffusion (DD) method of antifungal susceptibility (AFS) was evaluated for three different classes of antifungals: amphotericin B (AMB), voriconazole (VCZ) and caspofungin (CAS). Forty four clinical isolates of Aspergillus were selected; these included 34 A.fumigatus, 8 A.flavus and 2 A. terreus. AFS by DD and E-test was done on non-supplemented Mueller Hinton Agar (MHA) and was compared to Clinical Laboratory Standard Institute(CLSI) broth micro-dilution (BMD) method of AFS. RESULTS: Disk diffusion method for amphotericin B showed 87.5% agreement while E-test showed 93.8% agreement with broth micro-dilution. The agreement with broth micro-dilution was similar for both disk diffusion and E-test in case of voriconazole (93.8%) and caspofungin (100%). 31.8% and 9.1% Aspergillus isolates were found to have amphotericin B and voriconazole MIC values above epidemiological cut off value (ECV) respectively. All isolates were within ECV for caspofungin. CONCLUSION: CLSI method of DD promises to be easier, reproducible and cost effective method of susceptibility testing, but this method must be interpreted with caution in case of amphotericin B susceptibility testing. E-test correlates better than DD with BMD. PMID- 25737985 TI - Biofilm Producing Multidrug Resistant Acinetobacter baumannii: An Emerging Challenge. AB - AIM: To study the quantitative method for biofilm formation and examine the correlation between biofilm formation and antibiotic resistance among the clinical isolates of Acinetobacter baumannii. MATERIALS AND METHODS: A total of 72 A. baumannii isolates from different clinical specimens were processed and confirmed by conventional microbiological methods. Antimicrobial susceptibility testing was performed by Kirby Bauer disc diffusion method using six antibiotics. Biofilm formation was studied by microtitre plate assay. RESULTS: Forty five (62.5%) of 72 isolates produced biofilm. Resistance to ampicillin-sulbactam was least. 36.1% isolates were resistant to imipenem, 66.6% to ceftazidime, 72.2% to ciprofloxacin, 80.5% to amikacin and 84.7% to piperacillin. Biofilm formers showed greater resistance to ampicillin- sulbactam, amikacin, ciprofloxacin and ceftazidime as compared to imipenem and piperacillin. In all 65 (90.3%) isolates showed multiple drug resistance. Correlation between multidrug resistance and biofilm formation was analysed statistically and p-value was found to be significant (p-value =0.0004; p-value < 0.05 is significant by Chi - Square Test). CONCLUSION: The study concludes that there a positive correlation between biofilm formation and multiple drug resistance in A. baumannii. PMID- 25737986 TI - Performance of a rapid strip test for the serologic diagnosis of latent tuberculosis in children. AB - BACKGROUND: The serodiagnostic tests for tuberculosis (TB) present a high variability in terms of sensitivity and specificity. Data on patients with latent TB infection (LTBI) and children in high prevalence settings are still limited. The present study aimed to evaluate an in-house strip test for detection of anti M. tuberculosis antibodies in TB patients, mostly children aged under 15 y, grouped into four diagnostic categories: active TB, LTBI, healthy TB contacts, and other non-TB diseases. MATERIALS AND METHODS: The diagnostic performance of strip test was compared with the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). Sensitivity and specificity were assessed for all three diagnostic tests. The detection accuracy among the tests was calculated by using a receiver operating characteristic analysis. RESULTS: TST and IGRA could diagnose the active TB cases correctly (100%). The sensitivity of strip test for active TB was 58.3% and 37.5% for LTBI, while the sensitivities of TST and IGRA for LTBI were 90.3% and 37.5%, respectively. The overall specificities of strip test and IGRA were 91.5% and 95.7%, respectively, which were superior to that of TST (68.1%). CONCLUSION: The strip test did not appear to be useful for diagnosis of active TB in comparison with the current diagnostic standard. The assay may be particularly significant in situations where TB is clinically difficult to diagnose like LTBI and could be a meaningful tool in terms of high specificity and simplicity for ruling in pediatric TB in countries with high TB infection rate. Further studies are needed to determine whether strip test can be improved in its sensitivity and should be implemented into routine clinical practice. PMID- 25737987 TI - Prospective Analysis of 55 Cases of Tuberculosis Meningitis (TBM) in North India. AB - INTRODUCTION: To assess the clinical profile, laboratory and neuroimaging data of adult tuberculous meningitis (TBM) patients and to determine the predictors of mortality. MATERIALS AND METHODS: A total of 55 TBM patients and 60 controls were enrolled in this prospective study. Detailed clinical, radiological, biochemical and microbiological evaluation was performed. STATISTICAL ANALYSIS: Done using SPSS 15.0 for Windows. P value of <0.05 was considered to be significant. RESULTS: 61.8% were males and majority of the study subjects belonged to age group of 21-40 years. Duration of symptoms in all cases was >14 days and commonly included fever, headache, neck rigidity, altered sensorium and vomiting. Biochemical features of cerebrospinal fluid (CSF) showed significant results where 94.5%, 85.45%,83.63% and 81.81% of patients showed CSF sugar levels <2/3 corresponding blood sugar, proteins>100mg%, CSF total leucocyte count of >20 cells/mm(3) and ADA >9.5IU/L respectively while neuroimaging revealed hydrocephalus, basal exudates and meningeal enhancement as significant findings. More than half of TBM patients presented in stage II of disease and overall mortality was 43.63%. A model for prediction of mortality in TBM cases was framed which included variables of age>40 years, past history of tuberculosis (TB), presence of basal exudates and hydrocephalus. CONCLUSION: TBM is a serious extrapulmonary form of TB and should arise suspicion in mind of clinician based on clinical, laboratory and radiologic results. Further, a model for prediction of mortality in such patients may be helpful for early intervention and better prognosis. PMID- 25737988 TI - Ibuprofen-mediated reversal of fluconazole resistance in clinical isolates of Candida. AB - INTRODUCTION: In view of the increasing prevalence of invasive Candidiasis in today's health-care scenario and the emergence of fluconazole resistance among clinical isolates of Candida, we sought to determine if Ibuprofen could elicit a reversal of fluconazole resistance and thereby offer a potential therapeutic breakthrough in fluconazole-resistant Candidiasis. MATERIALS AND METHODS: We selected 69 clinical isolates of Candida, which demonstrated an MIC of >32 MUg/ml for fluconazole, and subjected them to broth microdilution in presence and absence of Ibuprofen. RESULTS: Forty two of the 69 isolates (60.9%) demonstrated reversal of Fluconazole resistance with concomitant use of Ibuprofen. This was characterized by significant species-wise variation (p=0.00008), with all the C. albicans isolates and none of the C. glabrata isolates demonstrating such reversal. Only 22.2% and 37.7% of C. krusei and C. tropicalis isolates respectively showed Ibuprofen-mediated reversal of Fluconazole resistance. CONCLUSION: Since Ibuprofen is a known efflux pump inhibitor, our findings hint at the possible mechanism of Fluconazole resistance in most of our Candida isolates and suggest a potential therapeutic alternative that could be useful in the majority of Fluconazole-resistant clinical isolates of Candida. PMID- 25737989 TI - Surgical Site Infection Caused by Aeromonas hydrophila in a Patient with Underlying Malignancy. AB - Aeromonas skin and soft tissue infections in cancer patients can lead to serious life threatening conditions such as cellulitis, necrotizing fasciitis and myonecrosis. We report here a case of surgical site infection, post radical mastectomy, in a 58-year-old female with carcinoma breast. Cultures of exudates from the wound grew Aeromonas hydrophila on repeated occasions. Recovery was uneventful following targeted antimicrobial therapy and regular dressing of the wound. Early suspicion, diagnosis, and treatment with potent antibiotics are needed to prevent any further complications resulting from infection by this emerging pathogen. PMID- 25737990 TI - Appendicitis in a Child due to Streptococcus Pneumoniae: A Rare Case Report. AB - A variety of bacterial species play a major role in appendicitis. Both aerobic and anaerobic gram positive and gram negative bacteria such as, Bacteroides fragilis, Streptococcus species, Escherichia coli, Klebsiella species and Citrobacter freundii cause appendicitis. Appendicitis is usually polymicrobial. The case assumes importance because of single aetiological agent i.e. unimicrobial and no predisposing factors are present to cause infection. We report a rare case of appendicitis due to Streptococcus pneumoniae in child. This case emphasizes that Streptococcus pneumoniae can cause wide spectrum of disease like appendicitis. PMID- 25737991 TI - Optimizing the Roche LightCycler(R) for Single-Tube Multiplexed RT-PCR Assays. PMID- 25737992 TI - The importance of cytokeratin 19 expression in the differentiation of Basal cell carcinoma and trichoepithelioma. AB - INTRODUCTION: Basal cell carcinoma (BCC) is the most common skin neoplasm reported in human. On the other hand, trichoepithelioma (TE) is a rare, benign tumour of skin adnexa. The differentiation of BCC and TE may be difficult since their morphological findings are similar. In a few studies, it has been determined that undifferentiated basaloid cells are highly positively stained with cytokeratin 19. AIM: The aim of this study was the comparison of cytokeratin 19 expression in cases of BCC and TE. MATERIALS AND METHODS: Sections of skin tissues of 17 TE, 25 BCC and 12 non-neoplastic cases were used for cytokeratin 19 (CK19) immunohistochemical staining. RESULTS: Staining with CK19 of the BCC cases gave 15(60%) diffuse, 7 (28%) focal and 3 (12%) negative staining. On the other hand, among TE cases, 2 (12%) gave diffuse, 5 (29%) focal and 10 (59%) negative staining with CK19. In the non-neoplastic skin tissue samples, while positive staining with cytokeratin 19 in the outer root sheath of hair follicles and sweat glands were observed, there was no staining in basal layers. CONCLUSION: CK19 expression may be helpful in the differential diagnosis of BCC and TE especially in small skin biopsy samples in which morphologic differentiation is difficult. PMID- 25737993 TI - Angiogenesis in Breast Cancer and its Correlation with Estrogen, Progesterone Receptors and other Prognostic Factors. AB - PURPOSE: The aim of study is to evaluate angiogenesis using CD34, in estrogen, progesterone positive and negative breastcancer and to correlate the microvessel density with known histological prognostic factors, morphological type of breast carcinoma and lymph node metastasis. MATERIALS AND METHODS: Twenty eight untreated cases of breast cancer were included in the study and paraffin embedded sections were obtained from representative mastectomy specimen of breast cancer patient. The sections were stained with hematoxylin and eosin stain and immunohistochemistry was performed using CD34, estrogen, progesterone, cytokeratin and epithelial membrane antigen antibody. Angiogenesis was analysed using CD 34 antibody. For statistical analysis, cases were grouped into estrogen, progesterone positive and negative receptors. RESULTS: Mean microvessel density in ER-/PR-, ER-/ PR+, ER+/PR-, ER+/PR+ was 15.45, 14.83, 11, 10.89 respectively. A significant correlation was found between ER receptors and mean vascular density with p-value (< 0.05). A significant difference was observed in mean vascular density between the four groups comprising (p-value < 0.05). Infiltrating duct carcinoma (NOS) grade III has got the highest mean microvessel density (14.17) followed by grade II (12.93) and grade I (12.33). CONCLUSION: Information about prognostic factors in breast cancer patients may lead to better ways to identify those patients at high risk who might benefit from adjuvant therapies. PMID- 25737994 TI - Paediatric surgical pathology - a profile of cases from Western India and review of literature. AB - AIM: The paediatric surgical pathology specimens manifest a wide spectrum of morphological and histological features. The present work has been undertaken to know the prevalence and to describe the profile of paediatric surgical pathology specimens from western India as seen in Ahmedabad, India from 2008 to 2010. MATERIALS AND METHODS: We reviewed 140 paediatric surgical specimens, 118 specimens rendered definitive diagnosis were included for the analysis. Cases were divided in two groups, one of developmental and congenital conditions and another of acquired lesions. RESULTS: This study included 118 patients of which 79.3 % were male and 20.7 % were female. Age range of the patients was one day to twelve years. Children of one month to one year age group (infants) were the most vulnerable (31.3% cases). Group of developmental and congenital conditions consisted of 45.7% cases where as 55.3 % cases were of acquired lesions. Gastrointestinal tract was most frequently affected organ (43.2%) followed by head and neck region (14.4%) and testis (7.6%). Hirschsprung's disease (HD) cases (6.7%) were commonest among the group of developmental and congenital conditions followed by juvenile polyps of colon (5%), Meckel's diverticulum of small intestine (5%) and neural tube defect (5%). In acquired lesions, Appendicitis was the most frequent lesion (21.2%) followed by haemorrhagic infarct of testis due to torsion (5%) and intussuception of intestine (5%). Malignant cases were (4.2%) and the most common cancer was yolk sac tumour. CONCLUSION: Paediatric surgical specimens, unlike adults, represent significant number of developmental and congenital conditions in addition to acquired lesions; accounting for wide spectrum of morphological and histological features. Study provides insight into the trends of paediatric surgical lesions in the western region of India. PMID- 25737995 TI - Inexplicable Co- Existence of Eccrine Spiradenoma and Lichen Planus in an old Case of Basal Cell Carcinoma. AB - Eccrine spiradenoma is a rare benign adnexal tumour usually seen in the head, neck or upper trunk in young adults. It is rare in the lower extremities and in the elderly. Co- existence of eccrine spiradenoma with other lesions like cylindroma, trichoepithelioma, hidradenoma and chondroid syringoma has been documented in literature. But, concomitant occurrence of eccrine spiradenoma with a non- neoplastic lesion like lichen planus in an old and treated case of basal cell carcinoma has not been documented in literature till date. We present a rare case of eccrine spiradenoma occurring on the right thigh in an elderly female along with lichen planus over the left breast. The lady had been diagnosed with basal cell carcinoma 10 years ago and treated with wide local excision. A brief review of literature is also included. PMID- 25737996 TI - Metastases of squamous cell carcinoma of uterine cervix to duodenum: a case report. AB - We report a case of squamous cell carcinoma of uterine cervix metastasizing to the duodenum through lymphatics. Para-aortic group of lymph nodes were involved which ultimately infiltrated the duodenum. On endoscopic examination, peri ampullary growth was noted. Endoscopic biopsy from the growth was studied by routine histopathology and metastasis of squamous cell carcinoma involving duodenum was reported. PMID- 25737997 TI - Pancreatic heterotopia of small intestine with tubercular ileitis. AB - Pancreatic heterotopia is defined as pancreatic tissue outside the boundary of pancreas that lacks an anatomic and vascular connection to it. Till today, no case of pancreatic heterotopia along with tubercular ileitis has been reported. We report one such case that presented in our institution. PMID- 25737998 TI - A Rare Case of Multple Myeloma (Mm) Presented With Pancytopaenia in A Patient of HIV - At Very Early Age. AB - Non-hodgkin's lymphoma (NHL) is the most common haematological malignancy which is seen in HIV infected patients. Among NHLs, immunoblastic lymphomas are most common and a majority of these are diffuse large B-cell lymphomas. Multiple myeloma is a disease of the elderly. It is extremely rare below 30 years of age. On the other hand, in HIV infected individuals, the average age of presentation with plasma cell disorders is 33 years, which is far younger than the average age of presentation in general population. The incidence of AIDS defining malignancies has declined markedly, whereas non-AIDS defining cancers are being increasingly diagnosed in patients with HIV infection during the HAART-era and they may be the presenting manifestations of AIDS. Multiple myeloma, however, usually is not a first presenting feature of AIDS. The usual clinical presentation of multiple myeloma is bone pain and pallor. Pancytopaenia is a rare presenting feature of multiple myeloma. Here, we are reporting a case of pancytopaenia which occurred in a 28-year-old, newly diagnosed, HIV-1 positive female, who with the help of bone marrow examination and further investigations, was subsequently diagnosed as multiple myeloma. PMID- 25737999 TI - Blastic Phase of CML with Microfilaria: A Rare Case Report. AB - Filariasis is a major public health concern in tropical and subtropical countries including India. There have been very few case reports of incidental filariasis in the bone marrow aspirate smears in patients with hematological malignancies. We present a case of blastic phase of chronic myeloid leukemia (CML) with associated filariasis with monocytosis. Such an association, to the best of our knowledge, is hitherto unreported. Moreover, eosinophilia was not a feature in our case. A 37-year-old male, diagnosed case of CML, presented with low grade fever, weight loss and abdominal distension for one month. Physical examination revealed massive splenomegaly and hepatomegaly. However, there was no lymphadenopathy. His hemoglobin was 10.5 g/dl, total leukocyte count was 52.31x 109 / L with platelet count of 30x 109/L .Differential leukocyte count on peripheral smear showed 21% blasts, 30% polymorphs, 16% lymphocytes, 1% myelocyte, 1%metamyelocyte, 30%monocytoid cells and 1% eosinophils. Bone marrow aspirate smears were diluted with peripheral blood and showed blasts and monocytoid cells constituting 25% and 15% of marrow nucleated cells respectively. In addition, occasional microfilaria of Wuchereria bancrofti were also seen both in the peripheral blood and aspirate smears. Based on the above findings, a diagnosis of blastic phase of CML with monocytosis with microfilaria of W.bancrofti. Hence this was an unusual case of CML blastic phase which was associated with filariasis. Moreover, inspite of having filariasis and CML, patient lacked eosinophilia and instead showed monocytosis, which is hitherto unreported. PMID- 25738000 TI - A rare case of disseminated cutaneous rhinosporidiosis. PMID- 25738001 TI - Comparative trial to study the effectiveness of clonidine hydrochloride and buprenorphine-naloxone in opioid withdrawal - a hospital based study. AB - OBJECTIVES: Prevalence of opioid addiction has alarmingly increased over the recent years. In South Asian region alone there are more than 10 million opioid abusers amounting to 2% of world population. Detoxification remains to be the first step for the successful treatment of opioid addiction. The present study was carried out to compare the relative efficacy and safety of buprenorphine naloxone and clonidine hydrochloride in the detoxification of opioid-dependents. MATERIALS AND METHODS: Present trial was conducted at De- addiction centre of Institute of Mental and Neurosciences (IMNS), GMC Srinagar. Fifty four (54) treatment seeking subjects, 15-50 years of age, fulfilling DSM-1V TR (American Psychiatric association's Mental Disorders-1V text revision) criteria for opioid dependence were included and randomized into two groups. The groups received either clonidine hydrochloride (Group A) or buprenorphine- naloxone (Bup-Nax) (Group B) for the duration of 10 days. The efficacy of the two drugs in controlling the opioid withdrawal was evaluated by Clinical Opioid Withdrawal Scale (COWS) and their effect on the desire for the abused substance was measured by Visual Analogue Scale (VAS). The safety of the two drugs was measured by taking the side effect profile of the two compared drugs into consideration. RESULTS: There was significant difference of COWS-score between the two groups which was evident from day 3 (14.85 +/- 3.43 vs. 11.67 +/- 2.40, p<0.005) and continued till day 6 (2.56 +/- 1.40 vs. 0.30 +/- 0.61, p<0.005), for Group A and group B respectively. The effect of two drugs in controlling the craving for the abused substance also showed significant difference from day 2 (66.30 +/- 10.80 vs. 47.40 +/- 12.90, p<0.005) till day 5 (7.78 +/- 6.41 vs. 1.85 +/- 6.22, p<0.005), for Group A and Group B respectively. CONCLUSION: Administration of buprenorphine-naloxone was more efficient in reducing the signs and symptoms of opioid withdrawal and in controlling the craving for the abused substance during the first few days of detoxification. PMID- 25738002 TI - Oxcarbazepine induced maculopapular rash - a case report. AB - Unlike carbamazepine, newer anti epileptic drug like oxcarbazepine, reports fewer side effects. In this report we describe a case of oxcarbazepine induced maculopapular rash probably happened because of a drug interaction with isoniazid, and a brief review of the existing literature is presented herewith. A 40-year-old male patient received oxcarbazepine 300mg twice daily along with other anti-tubercular drugs including isoniazid (300mg) once daily since two days. Extensive cutaneous rash with intense itching developed which subsided on discontinuation of oxcarbazepine. This case highlights the fact that there is a potential possibility of drug-drug interaction between oxcarbazepine and isoniazid and concomitant use of these two drugs should better be avoided during clinical practice. PMID- 25738003 TI - Evaluation of anti-inflammatory activity of aqueous extract of leaves of solanum melongena linn. In experimental animals. AB - INTRODUCTION: Aqueous extract of leaves of Solanum melongena Linn was investigated for its anti-inflammatory activity. MATERIALS AND METHODS: Acute oral toxicity study according to OECD425 guidelines was done to find out the LD50 of test drug. Carrageenan induced paw oedema method in Wistar Albino rats were used in this study. Aspirin in the dose of 300mg/kg was used as the standard drug and three doses of aqueous extract of leaves of Solanum melongena L. (100mg/kg, 200mg/kg, 400mg/kg b.w.) was used as the test drug. The results were measured at 1(st) h, 3(rd) h, and 5(th) h after the carrageenan injection. RESULTS: In acute oral toxicity study none of the animals died at the dose of 2000mg/kg. Aqueous extract of Solanum melongena Linn leaf in the dose of 200mg/kg showed significant anti-inflammatory activity (p <0.05) at 3(rd) hr and highly significant anti inflammatory activity (p<0.001) at 5(th) hr; in the dose of 400 mg/kg, test drug showed p<0.01 at 3(rd) and p<0.001 at 5(th) hr and in the dose of 100mg/kg it showed significant (p<0.05) anti-inflammatory activity at 5(th) hr. In doses of 200mg/kg and 400 mg/kg of aqueous extract of S. melongena L showed the percentage of inhibition of 42.62% which is less than the standard drug aspirin which showed 64.5% inhibition. CONCLUSION: Aqueous extract of leaves of Solanum melongena Linn has anti-inflammatory activity. PMID- 25738004 TI - To Evaluate the Effect of Edrophonium on Blood Glucose Levels in Euglycemic Albino Rats Through OGTT. AB - OBJECTIVE: To evaluate the effect of Edrophonium on blood glucose levels in euglycemic albino rats through OGTT. MATERIALS AND METHODS: Twelve Swiss albino rats weighing around 150-200 gms of either sex were randomly selected from the central animal facility, JSSMC, Mysore and divided into two groups. The control group received distilled water (25ml/kg body wt.) per orally, test groups received Edrophonium (6.3mg/kg/day) intravenously for five days. On the fifth day, following overnight fasting, half an hour after drug administration in all the groups of rats Oral Glucose Tolerance Test was performed, by administering oral glucose in dose of 0.6gm/kg body weight. The capillary blood glucose levels were measured at 0, 60 and 150 min, by rat tail snipping method using (ACCUCHEK) glucometer. RESULTS: The Capillary Blood Glucose levels of Edrophonium group was less when compared to control group at all-time intervals. CONCLUSION: Edrophonium showed the hypoglycemic activity when given for five days intravenously in euglycemic albino rats through Oral Glucose Tolerance Test. PMID- 25738005 TI - Risk of cardiovascular effects with azithromycin. PMID- 25738006 TI - Robertsonian translocation T (21; 21) in a female born to normal parents: a case report. AB - Downs syndrome (DS) occurs due to an extra copy of chromosome 21. About 3% of cases of Downs syndrome occur due to Robertsonian translocation, most commonly t (14; 21), other types of translocations are very rare cause of the syndrome. A 10 year-old patient with mental retardation was admitted following road traffic accident. Patient had flabby muscles, had delayed mile stones, stunted growth for the age, slanting of eyes, flat nasal bridge, and ineligible speech. On cytogenetic analysis the patient had karyotype showing one normal chromosome 21 and one Robertsonian translocation t (21; 21). Parents and siblings of the patient were phenotypically normal. Robertsonian translocation t (21; 21), can occur by transmission from carrier parent, due to ovarian mosaicism for Robertsonian translocation or may appear de novo. In the present case as the parents had normal karyotype and siblings were phenotypically normal, Robertsonian translocation probably have arisen de novo. The present case was a case of Downs syndrome with Robertsonian translocation t (21;21) probably arising de novo. PMID- 25738007 TI - Non viral vectors in gene therapy- an overview. AB - Non-viral vectors are simple in theory but complex in practice. Apart from intra cellular and extracellular barriers, number of other challenges also needs to be overcome in order to increase the effectiveness of non-viral gene transfer. These barriers are categorized as production, formulation and storage. No one-size-fits all solution to gene delivery, which is why in spite of various developments in liposome, polymer formulation and optimization, new compounds are constantly being proposed and investigated. In this review, we will see in detail about various types of non-viral vectors highlighting promising development and recent advances that had improved the non-viral gene transfer efficiency of translating from "Bench to bedside". PMID- 25738008 TI - Accuracy of four dental age estimation methods in southern Indian children. AB - INTRODUCTION: For various forensic investigations of both living and dead individuals, the knowledge of the actual age or date of birth of the subject is of utmost importance. In recent years, age estimation has gained importance for a variety of reasons, including identifying criminal and legal responsibility, and for many other social events such as birth certificate, marriage, beginning a job, joining the army and retirement. Developing teeth are used to assess maturity and estimate age in number of disciplines; however the accuracy of different methods has not been assessed systematically. The aim of this study was to determine the accuracy of four dental age estimation methods. MATERIALS AND METHODS: Digital Orthopantomographs (OPGS) of South Indian children between the ages of 6 and 16 y who visited the department of Department of Oral medicine and Radiology of GITAM Dental College, Visakhapatnam, Andhra Pradesh, India with similar ethnic origin were assessed. Dental age was calculated using Demirjian, Willems, Nolla, and adopted Haavikko methods and the difference between estimated dental age and chronological age were compared with paired t-test and Wilcoxon signed rank test. RESULTS: An overestimation of the dental age was observed by using Demirjian and Nolla methods (0.1+/-1.63, 0.47+/-0.83 years in total sample respectively) and an underestimation of dental age was observed by using Willems and Haavikko methods (-0.4+/-1.53, -2.9+/-1.41 years respectively in total sample). CONCLUSION: Nolla's method was more accurate in estimating dental age compared to other methods. Moreover, all the four methods were found to be reliable in estimating age of individuals of unknown chronological age in South Indian children. PMID- 25738009 TI - Community medicine teaching and evaluation: scope of betterment. AB - There have been rapid and extensive changes in the way assessment is conducted in medical education. Assessment brings about standardization of the manner in which the syllabus is to be implemented and also gives guidelines regarding the teaching pattern, especially when the student is going to rotate through various departments in a medical college. Community Medicine is an important branch of medicine concerned with the health of populations. Existing forms of assessment of community medicine education mainly consists of internal [formative] assessment and final (summative) examination. Advantages of the present system is the similarity of the methods used for internal assessments and final examinations and is relatively easily done since only the knowledge application and recall ability of the student in theory and practical are assessed. Disadvantages in the current evaluation system are neglecting the assessment of psychomotor, affective and communication skills. Evaluation systems can be improved by implementing techniques to assess psychomotor skills, presentation and communication skills, organizational skills and the student's ability to work in a team. Regular feedback from students should be taken periodically for the betterment of Community Medicine education. This article is meant to sensitise the academic experts in medical education to plan better need based methods of assessment in the subject of Community Medicine, in relation to the new MCI 2012 Regulations, in order to make it a better learning experience for the students. PMID- 25738010 TI - Share of tobacco related cancers: gender and time gaps-Indian scenario. AB - INTRODUCTION: Cancer is one of the leading causes of mortality in Indian population with control approach of varied kind which the health system of the country needs to prioritize. The tobacco related cancer which account for major share of all the cancers could be largely controlled through primary prevention a strategy effective in terms of resources hence take priority in terms of cancer control activities. It would be worthwhile to study the cancer of sites and relative magnitude of the cancers which are tobacco related and are amenable for prevention. MATERIALS AND METHODS: The age specific cancer incidence rates of cancer as available from the consolidated reports of the National Cancer Registry Program of Indian Council of Medical Research for the years 1990-96 an 2001-04 were utilized for computing proportion of tobacco related cancers which included population based cancer registries at Bangalore, Bhopal, Barshi a rural registry in Maharashtra, Chennai, Delhi and Mumbai. As defined cancer of the sites oral cavity, lip, tongue, oropharynx, hypopharnx, pharynx, oesophagus, larynx, lung, urinary bladder were considered as tobacco related cancers. The statistical evaluation of proportion of tobacco related cancers between two time periods under consideration was carried out by proportion test. RESULTS: There was a significant decline of proportion of tobacco related cancers from 1990-96 to 2003 for all the registries except Bhopal where around 50% of the total cancers attributed to tobacco habits for the two time periods under consideration. The Barshi also reported a decline but was not statistically significant. In females the proportion of tobacco related cancers ranged between 17% in Bangalore 10% in Delhi for the two time periods under review. All the registries showed significant decline in proportion of tobacco related cancers for the periods under consideration, except Delhi and Bhopal, while rural registry at Barshi revealed an increase of 3.3 %. The gender difference of the proportion of tobacco related cancers ranges between 19.8% to 34% during the period 1990-96, while it was 18.5% to 35% for the period 2001-03. While examining the difference between gender gap between the two time periods, the results from Mumbai registry revealed significant decline. PMID- 25738011 TI - Anaemia in Relation to Body Mass Index (BMI) and Socio-Demographic Characteristics in Adult Nigerians in Ebonyi State. AB - INTRODUCTION: Anaemia, a multifactorial health challenge has been found to affect every stage of human development with negative health impacts. Providing information on the factors associated with Anaemia will help in formulating mitigating strategies against this important public health problem. OBJECTIVE: To determine the prevalence of Anaemia and its relationship with body mass index (BMI) and sociodemographic characteristics in adult Nigerians in Ebonyi State, South-eastern Nigeria. MATERIALS AND METHODS: Adults (n=428) aged >= 18 y (mean=38.4+/-13.7 y) randomly selected from 130 political wards from the 13 Local Government Areas of the state were studied. Sociodemographic data was collected with questionnaire while blood samples were collected for hemoglobin determination using colorimetric cyanmethemoglobin method. Data was analysed using statistical package for social sciences (SPSS((r)) for Windows((r)) ver. 16). RESULTS: In general, 21.7% of the subjects were anemic with Anaemia prevalence of 9.9%, 15.8% and 39.8% in male, non-pregnant and pregnant female, respectively. About four percent (3.7%) of the subjects were underweight, while 37.6% had excess weight with hemoglobin concentration having no relationship with BMI and sociodemographic parameters. CONCLUSION: It may be conclude that the Anaemia in adult Nigerians in Ebonyi State has no definite relationship with BMI and sociodemographic characteristics studied. Further studies are needed to document other factors that may be associated with Anaemia among adults in the State. PMID- 25738012 TI - Adenoid Cystic Carcinoma- A rare Differential Diagnosis for a mass in the External Auditory Canal. AB - Primary external auditory canal malignancies are very rare; in which, adenoid cystic carcinoma is extremely rare tumour accounting for approximately 5%. Majority of the patients presents with unilateral severe or dull aching constant ear pain of prolonged duration, reduced hearing and mass in the External Ear. These tumours are treated with aggressive surgical excision and adjuvant radiotherapy. Despite this, the overall prognosis is poor due to recurrences and distant metastasis. We report a rare case of adenoid cystic carcinoma in a 36 year-old female, who presented with right ear pain for the last one year. She was treated with wide local excision of the mass followed by adjuvant radiotherapy. PMID- 25738013 TI - Meningoencephalocoele in a mastoid cavity: a case report and review of literature. AB - A young adult male presented to us with a discharging mastoid cavity. Clinical and radiological examination revealed cholesteatoma recidivism along with a meningoencephalocoele (ME) which was managed successfully. Two year follow-up revealed no recurrence of the pathology. PMID- 25738014 TI - Comparison of ranolazine and trimetazidine on glycemic status in diabetic patients with coronary artery disease - a randomized controlled trial. AB - INTRODUCTION: Cardiovascular diseases have become the leading cause of death around the globe and diabetes mellitus (DM) is considered to be a coronary artery disease (CAD) risk equivalent. Ranolazine, an anti anginal drug has been found to reduce Glycated haemoglobin (HbA1c) in diabetes patients with chronic angina. However the effect of another antianginal drug trimetazidine, on glycemic status is not clear. AIM: To compare the effect of ranolazine and trimetazidine on glycemic status in diabetic patients with CAD. SETTINGS AND DESIGN: Patients diagnosed with CAD and diabetes mellitus attending Cardiology Out Patient Department (OPD), Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India were recruited for this randomized open label parallel arm trial. MATERIALS AND METHODS: The study conducted from January 2012 to April-2013 had 47 eligible patients diagnosed with CAD and diabetes mellitus. They were randomized to receive either ranolazine 500 mg BD or trimetazidine 35 mg BD for 12 weeks. HbA1c levels, fasting blood glucose (FBG), lipid profile, QT and QTc intervals were measured at baseline and after 12 weeks. STATISTICAL ANALYSIS: Unpaired t-test was used to compare the baseline characteristics of between the groups while comparison within the groups were done using Paired t-test. Wilcoxon and Mann Whitney U-tests were used for non parametric data. Graph pad instat version-3 was used for statistical analysis. Values were expressed as mean +/- SD. A p < 0.05 was considered statistically significant. RESULTS: The study could not find any change in HbA1c levels in both ranolazine and trimetazidine groups. The adverse effects reported from patients on ranolazine include angina, constipation, postural hypotension, headache, dizziness, nausea and weakness while patients on trimetazidine complained of constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort, joint pain, etc. CONCLUSION: In patients with chronic angina and diabetes mellitus Ranolazine 500mg BD and Trimetazidine 35mg BD did not show any effect on HbA1c and fasting blood glucose lebel. PMID- 25738015 TI - An Analysis of Global Research Trends in Cardiology Over the Last two Decades. AB - INTRODUCTION: Heart disease today is a major cause of morbidity and mortality plaguing mankind worldwide. AIM: The present research was undertaken to ascertain global research trends in clinical trials in Cardiology involving human subjects over the last two decades. MATERIALS AND METHODS: Cross-sectional study. A detailed search strategy was employed in December 2013, using the PubMed database. All papers published in 1993-2013 were evaluated. The research trends of various cardiologic subspecialties in the United States and worldwide have been analysed and detailed statistical analysis was done. RESULTS: United States had maximum number of researches. Clinical trials involving infarction were maximum followed by coronary angiography and coronary angioplasty in that order. The year 2013 had the most researches. The United States was the top country and Boston was the top city. Author Christodoulos Stefanadis had the greatest number of researches in this field. American Journal of Cardiology was the most favored journal and Circulation was the journal with the highest impact factor. This effort may help funding agencies, prospective job seekers, fellowship applicants, policymakers and patients Conclusion: The research output in cardiology has increased and improved significantly over past decade. The publication per diplomat is more in transplant cardiology, Also more clinical trials involving coronary restenosis have to be done to know in depth to add to current knowledge and database. PMID- 25738016 TI - N-acetyl cysteine in the management of rodenticide consumption - life saving? AB - BACKGROUND AND AIM OF STUDY: Rodenticide is a commonly ingested poison in India. Many rodenticides contain hepatotoxic agents and can cause acute liver failure (ALF). There is no antidote for rodenticide poison, and consumption is often fatal. The Role of N acetyl cysteine (NAC) in acetaminophen induced ALF is well established. Additionally some studies have shown that it may be useful in non acetaminophen induced ALF also. Cases with ALF secondary to suicidal rodenticide consumption have been reported, and some reports show that NAC is beneficial in these cases. Our study was a retrospective analysis of patients admitted with rodenticide consumption, comparing outcomes in those receiving standard of care management and those who were treated with NAC also. MATERIALS AND METHODS: Case sheets of all inpatients of a tertiary medical college hospital between January 2010 and December 2012 admitted with an alleged history of rodenticide consumption were surveyed and data was extracted and analysed. STATISTICAL ANALYSIS: Patients were analysed with respect to age, sex, mode of presentation, interval between consumption of rodenticide and starting NAC; the outcome in patients treated with acetylcysteine was compared to outcomes in those not treated with acetylcysteine RESULTS: A total of 100 patients were studied out of which 18 died. Sixteen of the deaths were in patients who had not been treated with NAC. We found that patients who had received NAC had lower mortality, lower peak values of AST/ALT, and shorter hospital stay. CONCLUSION: NAC may have a role in the management of ALF associated with rodenticide consumption. PMID- 25738017 TI - Surrogate markers of the kidney and liver in the assessment of gestational diabetes mellitus and fetal outcome. AB - INTRODUCTION: To investigate whether serum levels of butyrylcho-linesterase activity, cystatin C, and pre-albumin has the potential value as gamma-glutamyl transferase in reflecting gestational diabetes mellitus and its fetal outcome. MATERIALS AND METHODS: Seventy-six gestational diabetes mellitus women and 76 pregnancies with normal glucose tolerance in the second trimester were enrolled. Maternal serum parameters of butyrylcholinesterase activity, gamma-glutamyl transferase, cystatin C, and pre-albumin were detected and evaluated. The pregnant complications and fetal outcome were also evaluated. RESULTS: Levels of butyrylcholinesterase activity, gamma-glutamyl transferase, cystatin C, pre albumin and glycemic variables were higher in the gestational diabetes mellitus patients than in the controls. Levels of butyrylcholinesterase activity were significantly correlated to the levels of fasting plasma glucose, cystatin C, and gamma- glutamyl transferase (p < 0.05) in the gestational diabetes mellitus group. There were statistical differences in cases of preterm delivery, preeclampsia and postpartum hemorrhage. Higher levels of gamma-glutamyl transferase and pre-albumin were risk markers for gestational diabetes mellitus (p < 0.05). The diagnosis curve demonstrated that gamma-glutamyl transferase had a significant advantage over other markers (p < 0.001) but no significance compared with pre-albumin (p = 0.096). None of the detected markers showed predictive value for fetal outcome. CONCLUSION: Serum levels of butyrylcholinesterase activity, gamma-glutamyl transferase, cystatin C and pre albumin were correlated with gestational diabetes mellitus status but not with the fetal outcome. Pre-albumin can be equivalent as gamma-glutamyl transferase in reflecting the presence of gestational diabetes mellitus. PMID- 25738018 TI - Left Ventricular Diastolic Dysfunction (LVDD) & Cardiovascular Autonomic Neuropathy (CAN) in Type 2 Diabetes Mellitus (DM): A Cross-Sectional Clinical Study. AB - INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) is one of the major complications of Diabetes Mellitus (DM) seen in a significant number of patients, which is often ignored and is also least frequently diagnosed. It can be diagnosed by performing five standard non-invasive bedside autonomic function tests based on Cardiovascular reflexes, which are quite cumbersome. Studies have revealed an increase in mortality in the diabetic patients with CAN due to silent cardiac ischemia, sudden cardiac death, arrhythmias. The precursor of diabetic cardiomyopathy is Left ventricular diastolic dysfunction (LVDD). In the present study we are studying the association between LVDD and CAN, in order to identify high mortality risk patients by performing 2D Echo and looking at LVDD instead of performing the cumbersome bedside cardiovascular autonomic function tests. AIMS AND OBJECTIVES: To study the association between LVDD and CAN in patients with Type 2 DM. MATERIALS AND METHODS: This study is a cross-sectional observational study with a sample size of 100. Both outpatients and inpatients between 35 y and 65 y of age with Type 2 DM coming to Department of General Medicine, KIMS hospital, Bangalore were studied from November 2011 to October 2013.Patients with macrovascular complications, Hypertension, congenital & acquired heart diseases etc. were excluded from the study. The standard five autonomic function tests based on cardiovascular reflexes and 2D Echo were performed. Individual scores for each of the five tests were added to produce Ewing's score. Ewing's score of >2.5 is positive for CAN. STATISTICAL ANALYSIS: Chi-square/ Fisher Exact test has been. RESULTS: There was a significant association between individual non invasive bedside tests of Ewing's score and LVDD. Significant association was also seen between LVDD and positive Ewing's score. CONCLUSION: Positive Ewing's score is strongly associated with LVDD in patients with Type 2 DM in this study .This suggests that patients with LVDD have CAN and hence, are at increased risk of sudden cardiac death. As bedside tests are cumbersome, patients with LVDD on 2D Echo can be concluded to have CAN. PMID- 25738019 TI - A curious case of Fever and hyperpigmentation. AB - Megaloblastic anaemia as a cause of pyrexia is a rare entity. Similarly, hyperpigmentation of skin has rarely been reported as the presenting manifestation of folate and/or vitamin B12 deficiency. The author reports the case of a patient who presented with fever and hyperpigmentation and was diagnosed to have megaloblastic anaemia secondary to vitamin B12 and folate deficiency after other infective, inflammatory/autoimmune, endocrine causes of pyrexia and hyperpigmentation were excluded by appropriate investigations. The patient responded remarkably well to the treatment with vitamin B12 and folic acid supplementation. Although presentation of megaloblastic anaemia as isolated fever or hyperpigmentation are noted in literature, simultaneous fever and hyperpigmentation as its initial presentation is exceedingly rare. PMID- 25738020 TI - Successful transradial percutaneous coronary intervention in a patient with dextrocardia and situs inversus. AB - Dextrocardia with situs inversus is a rare clinical entity with an estimated incidence ranges from 1 in 8000 to 1 in10,000. Percutaneous intervention in patient with dextrocardia and situs inversus is clinically challenging due to abnormal orientation of coronary geometry and the intervention requires appropriate use of guiding catheters, engagement technique, appropriate radiological angles as well as views. In this case-report, we describe percutaneous intervention with stenting in 48-year-old male patient with dextrocardia and situs inversus. We successfully deployed drug-eluting stents in right coronary artery and left circumflex artery. PMID- 25738021 TI - Intracranial Fungal Granulomas Mimicking High Grade Gliomas. A Decisive Role of Squash Cytology (SC): A Report of Two Cases. AB - Intracranial fungal granulomas can be misdiagnosed clinically and radiologically as neoplastic lesions. They also rarely occur without any history of immunodeficiency or diabetes. We report two such cases of fungal granulomas that were unsuspected clinically and radiologically but were detected on intraoperative squash cytology (SC) and later confirmed on histopathology. Timely intervention was hence possible and patient was saved from the hazards of unnecessary removal of eloquent areas of brain and was shifted on proper medical management. SC remains an indispensible tool for the neurosurgeon to get a provisional intraoperative diagnosis and in such surprising scenarios, change the surgical management of the patient, save the resection of eloquent brain areas and begin immediate postoperative medical management. These cases are being presented for their rarity and for highlighting the importance of SC as a regular tool for intraoperative neurosurgical consultation of intracranial mass lesions. PMID- 25738022 TI - Limb Girdle Muscular Dystrophy (LGMD): Case Report. AB - We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower's sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID- 25738023 TI - Hodgkin's Disease Presenting with Chronic Pruritis and Cutaneous Involvement. PMID- 25738024 TI - Acquired Jejunal Atresia in a 2-Month-old Infant. AB - Acquired intestinal atresia in non-necrotizing enterocolitis affected patients is very rare. We report a 2 month old male infant who presented with bilious vomiting, abdominal distension and constipation. He was exclusively breast fed, gained weight and was asymptomatic till six weeks of age. Exploratory laparotomy revealed blind-ended, dilated proximal segment and collapsed distal segment of jejunum at approximately 30 cms from duedeno-jejunal flexure, with a V-shaped mesentery defect resembling a type III-a congenital jejunal atresia. PMID- 25738025 TI - Management of a case of ruptured pseudoaneurysm and stenosis of femoral artery caused by femoral osteochondroma. AB - We present a rare case of ruptured pseudoaneurysm of distal femoral artery due to osteochondroma in a 21-year- old male. The patient was initially treated for osteochondroma as ruptured pseudoaneurysm was not suspected. Diagnosis of ruptured pseudoaneurysm could only be made intraoperatively when rent in the femoral artery was found along with surrounding hematoma and obstruction in the distal femoral artery. Patient underwent multiple surgeries (resection of osteochondroma and femoro-popliteal bypass) and recovered well with palpable pulsations in the operated limb. PMID- 25738026 TI - Gastroduodenal intussusception due to pedunculated polypoid gastrointestinal stromal tumour (gist ): a rare case. AB - Gastrointestinal stromal tumours (GISTs) account for less than 3% of all gastrointestinal tract tumours and 5.7% of all sarcomas, and the majority of these tumours are gastric in origin. Patients commonly present with gastrointestinal bleeding or abdominal pain with 10-30% of patients presenting with symptoms of gastrointestinal obstruction. We report a rare case clinically presenting as gastric outlet obstruction, gastroscopy suspecting it to be organo axial gastric volvulus, CECT(Contrast Enhanced Computerised Tomography) suggesting features of gastric malignancy (leiomyosarcoma) keeping the possibility of differential diagnosis of GIST. Eventually on exploratory laparotomy we discovered gastric outlet obstruction due to transpylorically herniated pedunculated polypoid GIST leading to gastroduodenal inussusception. PMID- 25738027 TI - Stercoral perforation of the sigmoid colon in a schizophrenic patient. AB - Stercoral perforation of the colon is a life threatening condition, due to pressure necrosis by hard fecaloma which, are commonly found in chronic constipated patients. We report the case of a 45-year-old schizophrenic woman, under psychiatric treatment for two years, presenting with a 10-day history of absolute obstipation and distension. On physical examination the patient had signs of generalized peritonitis. Preoperative diagnostic workup gave no clear cut clues about diagnosis. Emergency laparotomy revealed a single perforation over the antimesentric border of the sigmoid colon with hard fecal matter protruding through perforation margin. A segmental resection of the sigmoid colon with colonic lavage and end to end anastomosis was performed. The patient made an uneventful recovery. We have discussed the diagnostic work-up, and the management of this rare entity. Patient was on antipsychotic, anticholenergic and NSAID'S drugs for long time with longstanding immobilisation and poor oral intake. Association of these etiological factors with chronic constipation which ultimately leads to stercoral perforation have been corroborated. PMID- 25738028 TI - Transvaginal small bowel evisceration in known case of uterine prolapse due to trauma. AB - Spontaneous transvaginal bowel evisceration is a rare surgical emergency with only a few cases reported and particularly postmenopausal, posthysterectomy, multiparous elderly women are considered to be at higher risk for development of bowel evisceration. It is difficult to manage such a patient for any surgeon and poses significant challenges especially intraoperatively. Here, we report a case of vaginal vault rupture with small bowel evisceration through the vagina in a known case of uterine prolapse and highlight the risk factors, clinical presentation, and treatment options for this rare surgical emergency. PMID- 25738029 TI - Benign paravertebral ancient neurilemmoma in a young adult: a rare occurrence. AB - Neurilemmoma is a benign neurogenic tumour arising from Schwann cells of the peripheral nerve sheath, which is commonly seen in women in the 5th decade. It rarely arises in the retroperitoneum, being more common in the head and neck region and extremities. Ancient variety of schwannoma is a long-standing tumour, is seen in the middle age and elderly age groups, and is associated with secondary degenerative changes. Herein, we report a case of benign retroperitoneal paravertebral ancient neurilemmoma occurring in a young male adult. PMID- 25738030 TI - Large congenital nevus scalp managed by tissue expansion- a case report. AB - Tissue expansion is an emerging trend in the reconstruction of various defects of the human body when there is insufficient adjacent tissue for direct closure of the defect or repair with a local tissue transfer. It is the most important armamentarium for aesthetic hair-bearing scalp reconstruction in cases of congenital or acquired defects. In this case, a large linear verrucous epidermal nevus is excised and covered with expanded hair-bearing scalp tissue. PMID- 25738031 TI - Accidental intra-arterial injection of diclofenac -case report. AB - Diclofenac sodium is a very common drug used in medical practice for analgesia and is freely available over the counter without any medical prescription. The drug is also the most commonly used or misused by quacks working all over India. Many case reports have been published on upper limb catastrophe of unintentional intra-arterial injection of barbiturates, thiopental sodium, narcotics, and tranquilizers but only two cases of inadvertent intra-arterial injection of diclofenac have been reported till date. Potential serious complication of inadvertent intra-arterial injection of diclofenac sodium leading to gangrene has been recently reported in medical literature. It is a medical emergency and literature has shown that timely diagnosis with early intervention can salvage the limb. We hereby report a case of accidental intra-arterial injection of diclofenac sodium in the ulnar artery by a quack for pain abdomen leading to gangrene of the distal part of affected little, ring and part of middle finger of right hand. PMID- 25738032 TI - An unusual presentation of neurofibroma masquerading as a vascular hamartoma, post-iatrogenic intervention. AB - Neurofibroma is a localized discrete mass of benign nerve sheath tumour in the peripheral nervous system. Mostly present as skin lesions. Solitary neurofibroma may occur in deep soft tissue or subcutaneous plane in rare cases associated with syndromes like NF1. The neurofibroma most commonly present as skin lesions as isolated soft papules or nodules arising in any cutaneous site. Present case depicts unusual presentation of a neurofibroma as a vascular hamartoma post an iatrogenic intervention. PMID- 25738033 TI - Small bowel obstruction- a surprise. AB - Trans - omental hernia is very rare, accounting to 1-4% of all internal hernias which is an unusual cause of small bowel obstruction. Here we present a case report of a small bowel obstruction in a female due to trans - omental hernia presenting with central abdominal pain, distension and bilious vomiting. She had no previous history of trauma, surgery. Plain X-ray abdomen erect showed multiple air fluid levels with dilated small bowel loops. Emergency laparotomy revealed a segment of congested small bowel loop (ileum) through a defect in greater omentum. On table the herniated bowel loop was reduced and the defect in greater omentum was closed primarily. There was no necessity for bowel resection as it regained normal colour after reduction. Postoperative period was uneventful with complete resolution of symptoms. This case is presented for its rarity and its importance in clinical differential diagnosis of acute abdomen due to small bowel obstruction. PMID- 25738034 TI - Giant submucosal lipomatous polyp causing perforation of sigmoid colon: a case report and review of literature. AB - Colonic lipomas are rare benign tumours that are usually asymptomatic. Large colonic lipomas can present with symptoms such as constipation, abdominal pain, bleeding per rectum, and intussusception. We report the case of an 82-year-old man presenting with sudden onset lower abdomen pain and features of peritonitis. An exploratory laparotomy revealed a perforation of sigmoid colon with a fleshy mass protruding through the perforation. No case of spontaneous perforated sigmoid colon by submucous giant lipoma is reported yet in the literature. We discuss the details of first such case, our management, the outcome and also briefly review the literature. PMID- 25738035 TI - Unusual Ventriculoperitoneal (VP) Shunt Tube Extrusion through Anus in a Child with Dandy Walker Malformation: A Rare Case Report. AB - Aim of this paper is to report a case of extrusion of Ventriculo peritoneal shunt tube through anus in a one year female child ( k/c/o dandy walker malformation ) treated with placement of ventriculo peritoneal shunt for post operative hydrocephalus after excision of Subtorcular occipital meningocoel. The exact cause of such extrusion is not known. Unusual migration of distal catheter tip of VP shunt is a rare and bowel perforation is reported to occur between 0.1% and 0.7%. The possible factors responsible for this complication are thin bowel wall in children, sharp and stiff end of the VP shunt, use of trocar by some surgeons, chronic irritation by the shunt, previous surgery, infection and silicone allergy. In view of the potential for meningitis prompt and aggressive management is essential to avoid morbidity and mortality. PMID- 25738036 TI - A rare case of malignant fibrous histiocytoma/ pleomorphic undifferentiated sarcoma of the kidney. AB - Malignant Fibrous Histiocytoma (MFH) usually arises from the extremities with the retroperitoneum being the second most common site. We present the case report of a 58-year-old man presenting with fever and was detected to have a renal mass on evaluation. He underwent a radical nephrectomy with a preoperative diagnosis of renal cell carcinoma. But the final histopathological report was MFH. Primary renal MFH is extremely rare and is usually diagnosed on histopathology with the aid of immunohistochemistry. PMID- 25738037 TI - Combined gastric and duodenal perforation through blunt abdominal trauma. AB - Blunt abdominal traumas are uncommonly encountered despite their high prevalence, and injuries to the organ like duodenum are relatively uncommon (occurring in only 3%-5% of abdominal injuries) because of its retroperitoneal location. Duodenal injury combined with gastric perforation from a single abdominal trauma impact is rarely heard. The aim of this case report is to present a rare case of blunt abdominal trauma with combined gastric and duodenal injuries. PMID- 25738038 TI - Is It Safe to Provide Abortion Pills over the Counter? A Study on Outcome Following Self-Medication with Abortion Pills. AB - BACKGROUND: Medical abortion is a safe method of termination of pregnancy when performed as per guidelines with a success rate of 92-97 %. But self administration of abortion pills is rampant throughout the country due to over the counter availability of these drugs and complications are not uncommon due to this practice. The society perceives unsupervised medical abortion as a very safe method of termination and women use this as a method of spacing. AIM OF THE STUDY: The aim of this study was to study the implications of self-administration of abortion pills by pregnant women. MATERIALS AND METHODS: Retrospective observational study done in Sri Manakula Vinayagar Medical College & Hospital between the period of July 2013 to June2014. Case sheets were analysed to obtain data regarding self-administration of abortion pills and complications secondary to its administration. The following data were collected. Age, marital status, parity, duration of pregnancy as perceived by the women, confirmation of pregnancy, duration between pill intake and visit to hospital, whether any intervention done elsewhere, any known medical or surgical complications, Hb level on admission, whether patient was in shock, USG findings, evidence of sepsis, blood transfusion, treatment given and duration of hospital stay. Descriptive analysis of the collected data was done. RESULTS: Among the 128 cases of abortion in the study period, 40 (31.25%) patients had self-administered abortion pills. Among these 40 patients 27.5% had consumed abortion pills after the approved time period of 63 days of which 17.5% had consumed pills after 12 weeks of gestation. The most common presentation was excessive bleeding (77.5%) Severe anaemia was found in 12.5% of the patients and 5% of patients presented with shock. The outcome was as follows : 62.5% of the patients were found to have incomplete abortion, 22.5% had failed abortion and 7.5% of patients had incomplete abortion with sepsis. Surgical evacuation was performed in 67.5% of the patients whereas 12.5% of the patients required surgical evacuation with blood transfusion. Medical methods were used in 15% of the patients whereas 2.5% required transfusion along with medical methods. CONCLUSION: Unsupervised medical abortion can lead to increased maternal morbidity and mortality. To curtail this harmful practice, strict legislations are required to monitor and also to restrict the sales of abortion pills over the counter and access to abortion pills for the public should be only through centers approved for MTP. Large scale prospective studies are required to assess the actual magnitude of this problem. PMID- 25738039 TI - Using Wood's Light as a Diagnostic Tool for Vaginal Atrophy. AB - INTRODUCTION: Wood's light lamp is a device that emits ultraviolet (UV) light and is a useful diagnostic tool for dermatologic disorders. The change in the thickness of vaginal mucosa, in vaginal atrophy, causes a change in its colour under Wood's light. We wanted to assess the feasibility of Wood's light (WL) as a diagnostic tool for vaginal atrophy. MATERIALS AND METHODS: The study was conducted at the Department of Obstetrics and Gynaecology from 1 March 2013 to 1 September 2014. We evaluated 45 healthy postmenopausal women with atrophic vaginitis (study group) and 45 healthy, reproductive-aged women as a control group. All patients underwent WL and routine gynaecological examinations for this study. RESULTS: Ninety patients were selected for this study: 45 postmenopausal women suffering atrophic vaginitis symptoms like vaginal dryness, dyspareunia, vulvar pruritus, and signs like pale, smooth, dry, fragile vaginal epithelium, areas of petechiae, and rash, and 45 healthy reproductive-aged women without vaginal atrophy. Thirty-six of the postmenopausal women's vaginal mucosa appeared pale royal green under WL indicative of vaginal atrophy. Thirty-nine of reproductive-aged women's (n: 45) vaginal mucosa were not visualized as pale royal green fluorescent images under the WL. CONCLUSION: Using Wood's light to diagnose vaginal atrophy is a new use for the old device and may be a reliable, and cheap tool for diagnosing vaginal atrophy. Diagnostic accuracy and cost effectiveness of Wood's light will be better optimized in further trials. PMID- 25738040 TI - Fallopian tube choriocarcinoma presenting as ovarian tumour: a case report. AB - Choriocarcinoma of the fallopian tube is a rare form of gestational trophoblastic disease. It can be gestational or non gestational choriocarcinoma, based on the origin. Fallopian tube choriocarcinoma has been reported commonly after ectopic pregnancy. Choriocarcinomas are germ cell tumours formed by trophoblastic elements. A 26-year-old lady presented with pain and mass abdomen of 15 days duration. Clinical examination revealed a ovarian tumour with elevated beta HCG. The working diagnosis was ovarian choriocarcinoma. Patient was also found to be having pulmonary artery hypertension due to the metastasis to lungs. Staging laparotomy was done. Histopathology revealed it to be metastatic gestational choriocarcinoma of fallopian tube with vascular emboli. The stage was stage III and WHO scoring of 15. She received Etoposide, Methotrexate, Actinomicin, Cyclophosphamide and Oncovin therapy. Following treatment there was a significant drop in the beta HCG. Patient tolerated the chemotherapy well. This is a rare presentation of choriocarcinoma with good prognosis. PMID- 25738041 TI - A rare case of foreign body causing recurrent vaginal discharge in prepubertal child. AB - Vaginal discharge in prepubertal children is mainly due to hypoestrogenic state of vaginal mucosa making it thin and alkaline leading to mucosal invasion by pathogen. In a paediatric case with persistent foul smelling , blood stained vaginal discharge not responding to medical therapy, vaginal foreign body should always be ruled out. Here, we report a 3 -year -old girl with complaint of recurrent vaginal discharge occasionally blood stained not relieved despite few antibiotics courses. On X -ray pelvis, a radioopaque foreign body hair clip was seen. Under sedation foreign body was removed by forceps following which child became asymptomatic. PMID- 25738042 TI - Misdiagnosis of abdominal pain in pregnancy: acute pancreatitis. AB - We report a case of acute pancreatitis in a pregnant woman who presented to our emergency department with complaints of severe abdominal pain, was misdiagnosed as scar dehiscence and underwent emergency repeat caesarean section at 33 wks for fetal distress. The preterm baby developed severe respiratory distress and succumbed on the second postnatal day. Persistent severe pain in the postoperative period in the mother prompted further evaluation which led to a diagnosis of acute pancreatitis. Conservative and supportive management was instituted leading to an eventual favourable maternal outcome. PMID- 25738043 TI - Incidental intravascular lipoleiomyomatosis in a hysterectomy specimen: how to manage? AB - Leiomyomas are common benign tumors in female gynaecologic surgery. They are originated from smooth muscle cells of the uterus and/or sometimes of the uterine vessels. Intravascular lipoleiomyomatosis is a very rare form of leiomyomas which grow within veins and can extend up to vena cava inferior and right heart chamber with cardiac symptoms and is diagnosed by cardiovascular surgeons. We report a case of incidental intravascular lipoleiomyomatosis which was confined to the uterus being diagnosed after a total abdominal hysterectomy by pathology and its management strategy. PMID- 25738044 TI - Cerebral venous sinus thrombosis and posterior reversible encephalopathy syndrome in a preeclamptic woman. AB - Cerebral venous sinus thrombosis (CVST) and posterior reversible encephalopathy syndrome (PRES) are two rare diseases which may present with similar symptoms and signs. We report a case with coexisting PRES and CVST in a preeclamptic woman. A 24-year-old woman, G2 P1, at 33 wk and 5 d of pregnancy presented with headache. Her blood pressure was 180/120 mmHg and urinary test revealed +3proteinuria. Cesarean section was performed with indications of severe preeclampsia, intrauterine growth retardation and fetal distress. Cranial MR venography of the patient revealed thrombiin superior sagittal sinus, confluenssinuum, right transverse and right sigmoid sinus and diffusion MRI showed increased signal intensity (vasogenicoedema) in cortical and subcortical areas of parietooccipital and posterior frontal lobes.The patient was treated with magnesium sulfate and heparin successfully. After treatment period, control cranial MRI and diffusion MRI were normal. Thrombi within the sinuses were totally regressed. Albeit rare, these two diseases should be kept in mind especially in preeclamptic/eclamptic patients that present with neurological symptom and/or sign. PMID- 25738045 TI - Diagnostic Dilemma in Cornual Pregnancy- 3D Ultrasonography may Aid!! AB - Interstitial or cornual pregnancy is a rare and dangerous type of ectopic gestation. It poses a diagnostic difficulty and differentiating from eccentrically located intrauterine pregnancy may be challenging. We are reporting a case of nulliparous woman diagnosed as having interstitial pregnancy on three dimensional ultrasonography. We managed the patient successfully with weekly intramuscular doses of methotrexate. The beta HCG levels were high throughout the therapy (89,000 to 1,48,000 IU/ml). The patient was admitted throughout the course of treatment. After three doses of methotrexate, the beta-HCG levels began to fall. Weekly monitoring was done thereafter till normal values of beta-HCG were reported. Early and prompt diagnosis and treatment of interstitial pregnancy is important to prevent catastrophic hemorrhagic complications. Three-dimensional sonography is an important diagnostic tool as it may impart better anatomical orientation and precise location of the gestational sac as compared to other imaging modalities. Methotrexate therapy may be considered in selected cases. PMID- 25738046 TI - Intercondylar humerus fracture- parallel plating and its results. AB - BACKGROUND: Intercondylar fracture of humerus is one of the commonest fractures of young adult and counts for about 30% of all elbow fractures. The treatment of these fractures continues to present challenges despite advances in internal fixation. Although orthogonal plating use to provid adequate functional results in these fractures, parallel plating is said to be mechanically more stable construct thus allowing early mobilization and better range of motion. AIM: AIM of the study is to assess the clinical as well functional results of these fractures treated with parallel plating. STUDY AND DESIGN: Prospective study in a tertiary care hospital. MATERIALS AND METHODS: A total of 23 fresh patients of intercondylar fracture of humerus from Jan 2013 to May 2014 were included in the study and were treated with parallel plating. These patients were followed at 3, 6, 12, 24 weeks and at 1year of follow up and assessed in terms of time for union, range of motion, MAYO score, DASH score and complication rate. RESULTS: At final follow up Mayo score was 96.32+/-04.96 from 5.00+/-01.26 and DASH SCORE was 31.42+/-2.04 which dropped from 150+/-05.34, Range of motion improved from 21.38+/-05.70 to 116.1+/-07.92 with 100% union rate and complications less than 19%. CONCLUSION: Parallel plating for intercondylar fracture of humerus is excellent method of fixation and results are similar to those treated with orthogonal plating. PMID- 25738047 TI - Idiopathic eosinophilic synovitis of the knee joint with peripheral eosinophilia a rare case report. AB - Synovitis, presenting as a synovial effusion is common. The most common cause include tuberculosis, osteoarthritis. Here with, presenting a rare case of monoarticular synovitis with synovial fluid and peripheral blood eosinophilia of unknown aetiology in an 18-year-old male. We review the clinical and pathological features and impress the need for synovial fluid examination in all cases. PMID- 25738048 TI - Isolated plexiform neurofibroma of arm with unusual presentation - a rare case report. AB - Plexiform neurofibroma (PNF) arises as a diffuse mass from nerve trunk and leads to overgrowth of cutis and subcutis structure. This is a case report of 20-year old male, presented to our hospital with a giant ulcerated swelling over his left arm. Differential diagnosis of sarcoma, neurofibroma, hemangioma and angiolipoma was made but biopsy confirmed the diagnosis of plexiform neurofibroma. Isolated PNF with ulceration of overlying skin over arm is a rare presentation and here we are presenting it as a perusal of rare entity. PMID- 25738049 TI - Bipolar hemiarthroplasty for primary abductor deficiency with femoral neck fracture. PMID- 25738050 TI - Study of serum zinc in low birth weight neonates and its relation with maternal zinc. AB - OBJECTIVE: Assessment of serum Zinc in LBW (Low Birth Weight) and appropriate for gestational age (AGA) neonates in relation to their maternal zinc level. MATERIALS AND METHODS: A prospective study was conducted in a tertiary care teaching hospital of central India between August 2011 to July 2012. Serum samples were collected from the eligible LBW (preterm & term IUGR) and term AGA healthy neonates and their mothers for zinc level estimation. Serum zinc was measured by atomic absorption spectrophotometer. Newborn of mothers having any medical illness, on any medication, with anaemia (Hb <10 gm/dl) were excluded from the study. Neonates with any perinatal insult were also excluded. RESULTS: Out of 100 newborn-mother pairs enrolled in the study, 46 newborns (18 preterm and 28 term IUGR) with birth weight <2.5kg comprised the case group and rest 54 term AGA newborns (birth weight >2.5kg) were categorized as control group. Mean serum zinc level was significantly low in LBW neonates (83.45+/-16.74 MUg/dl) in comparison to term AGA newborns (93.74+/-19.95 MUg/dl), (p-value <0.05). Similarly, zinc level was also low in mothers of LBW babies (67.02+/-15.99 MUg/dl) in comparison to mothers of term AGA newborns (83.59+/-18.46 MUg/dl), (p value < 0.05). Low maternal zinc levels were significant correlated with lower serum zinc in LBW neonates (Pearson correlation value - 0.938). However, maternal zinc levels have shown no significant correlation with neonatal serum zinc levels in term AGA (0.029). CONCLUSION: LBW neonates and their mothers have significant zinc deficiency as compared to term AGA neonates and their mothers and this deficiency is correlated with zinc deficiency in mothers of these LBW neonates. PMID- 25738051 TI - Effect of Family-centered Care on Improving Parental Satisfaction and Reducing Readmission among Premature Infants: A Randomized Controlled Trial. AB - INTRODUCTION: Healthcare quality is usually evaluated through analysing medical outcomes including neonatal readmission and patient and family satisfaction. Parental involvement in neonatal care is considered as one of the most important factors, which directly affects these outcomes. The aim of the present study was to determine the effect of family-centered care including maternal participation, presence, and information about neonatal care, on maternal satisfaction and neonatal readmission; the care services were provided by the primiparous mothers of preterm infants. MATERIALS AND METHODS: One hundred and ten primiparous mothers with preterm infants participated in this clinical trial. All samples were randomly divided into family-centered care (FCC) and control groups, through simple random sampling. The FCC program, which consisted of information about neonatal care, maternal presence, and participation in the care process, was implemented in the FCC group, while the control group was provided with routine care. Data were obtained using demographic and satisfaction questionnaires and readmission checklist. RESULTS: In the FCC group, the mean score of satisfaction increased after the implementation of the program (22.36 and 59.28 before and after the program, respectively) (p<0.001); however, this increase in the control group was not significant. The obtained results regarding the different aspects of satisfaction indicated that mothers in the FCC group were more satisfied with maternal presence in the neonatal intensive care unit (NICU), compared with aspects of information and participation. In addition, the number of neonatal readmission was less in the FCC group compared with the control group, and the mean duration of hospitalization was 6.96 and 12.96 days in the FCC and control groups, respectively (p<0.001). CONCLUSION: FCC program seems to be effective in increasing maternal satisfaction and decreasing neonatal readmission. Therefore, it seems necessary that healthcare authorities of the departments of obstetrics and gynecology in Iran provide the opportunity for the implementation of such programs in clinical environments, which follow the policy of parental absence and participation in the intensive care units. PMID- 25738052 TI - Guillain-barre syndrome: a clinical study of twenty children. AB - BACKGROUND: Guillain-Barre Syndrome (GBS) is an acute monophasic demyelinating neuropathy characterized by progressive motor weakness of limbs with areflexia. AIM: To study the clinical pattern and outcome of children with Guillain-Barre syndrome. MATERIALS AND METHODS: It was a cross-sectional study conducted in a pediatric unit of tertiary care hospital over a period of 18 months. We assessed the clinical manifestations, results of electro-diagnostic tests, functional status, treatment instituted and outcome of 20 children diagnosed with GBS. RESULTS: Of the 20 (male to female ratio = 2.3:1) children studied, all had motor weakness, 5 (25%) had sensory loss, 4 (20 %) had cranial nerve palsies and 4 (20%) had autonomic disturbances. Respiratory paralysis was found in 7 (35%) children requiring assisted ventilation. Antecedent illness preceding GBS was recorded in 50% children. The GBS subtype distribution as per electrodiagnostic studies was as follows: acute motor axonal neuropathy (AMAN) in 7 (38.9%), acute motor sensory axonal neuropathy (AMSAN) in 4 (22.2%), acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in 4 (22.2%) and both axonal and demyelinating neuropathy in 3 (16.7%). Intravenous immunoglobulins (IVIG) constituted the treatment given in majority of the patients. Plasmapharesis was performed in one child in view of poor response to IVIG. Complete recovery was observed in 14 children and the remaining 3 children experienced only incomplete recovery. CONCLUSION: Male preponderance and presence of antecedent illness in a majority of subjects was observed in our study. Regardless of the severity of illness at admission and electrophysiological subtypes, a majority achieved full recovery. Intravenous Immunoglobulin and supportive care form the cornerstone of management in childhood GBS. PMID- 25738053 TI - Clinico-radiological correlation in a cohort of cervical myelopathy patients. AB - OBJECTIVE: Though both clinical evaluation and MRI are complimentary in detection and precise localization of the level of lesion in patients with cervical myelopathy, there is paucity of data comparing segment specific clinical features with the MRI abnormalities in cervical myelopathy. MATERIALS AND METHODS: Thirty one patients with cervical myelopathy and abnormal MRI of the cervical spine (signal changes in the cord) admitted to the neurology and neurosurgery wards during the study period were included in the study. The patients were prospectively evaluated by a detailed neurological examination. Clinically, the site of lesion was determined by highest of the pyramidal, sensory or segmental features of involvement. The MRI lesions were categorized based on the vertebral level at which the abnormalities were seen. The patients were divided into three groups according to the site of lesion on MRI: (1) cervico-medullary (foramen magnum to C1) lesions (2) upper cervical (C2-C4) lesions and (3) lower cervical (C5-T1) lesions. Comparisons of clinical symptoms, signs and level of lesion with MRI abnormalities were done and the level of significance was set at p < 0.05. RESULTS: Clinical evaluation showed limb weakness in all, sensory loss in 90%, sphincter disturbances in 67.7%, scissoring gait in 32.2%, diaphragmatic weakness in 12.9% of patients. Based on clinical examination the site of lesion was cervico-medullary in 9, upper cervical region in 4 and lower cervical region of involvement in five patients. The maximal antero-posterior extent of the lesion and neurological deficits were concordant (p-0.05). As compared to pyramidal signs or sensory abnormalities, segmental features - segmental sensory loss, weakness, wasting or 'reflex' loss - were most concordant with the MRI level of lesion (p - 0.03). Among 'motor', 'sensory' and 'reflex' levels, the 'reflex (DTR)' levels were most concordant with the MRI level of lesion (p - 0.04). CONCLUSION: Segmental features form the foundation for clinical localization of the level of lesion. Though the clinical level of lesion and MRI level of lesion were discordant in 14 patients, clinical evaluation may still provide useful information. PMID- 25738054 TI - Differentiation of Leptomeningeal and Vascular Enhancement on Post-contrast FLAIR MRI Sequence: Role in Early Detection of Infectious Meningitis. AB - OBJECTIVE: To qualitatively and quantitatively differentiate leptomeningeal and vascular enhancement on Post-contrast Fluid Attenuated Inversion Recovery (PCFLAIR) sequence compared to post-contrast T1-weighted (PCT1W) sequence with fat suppression (FS) and evaluate its role in early detection of infectious meningitis. MATERIALS AND METHODS: Thirty-one patients with diagnosis of meningitis were evaluated with pre and post-contrast FLAIR and T1-weighted sequences with fat suppression (FS). Qualitative assessment was done by two observers for presence, absence or equivocal status of leptomeningeal enhancement. Further, quantitative estimation of single pixel signal intensities (SPSI) for meningeal and vascular enhancement was undertaken. A statistical comparison was performed using Kappa coefficient and t-test. RESULTS: The overall qualitative accuracy was 90.3% for PCFLAIR compared to 54.8% for PCT1W with FS sequence. PCFLAIR was found to be 100% accurate in the detection of tubercular and pyogenic meningitis and 70% accurate in the detection of viral meningitis while PCT1W with FS sequence showed the corresponding accuracy to be 76.2% and 0% respectively. Both observers rated PCFLAIR images better than PCT1W with FS at detecting meningitis (p<0.05). The quantitative assessment revealed that the SPSI difference between the average meningeal and vascular enhancement on PCFLAIR was significantly greater than that on PCT1W with FS sequence (t= 6.31, p<0.01). CONCLUSION: PCFLAIR sequence has insignificant component of vascular enhancement compared to meningeal enhancement. This makes meningeal inflammation easily discernable and aids in early detection of infectious meningitis. PMID- 25738055 TI - Comparative study of pineapple juice as a negative oral contrast agent in magnetic resonance cholangiopancreatography. AB - OBJECTIVES: The aim of this study was to compare the image quality of magnetic resonance Cholangiopancreatography (MRCP) using Pineapple Juice (PJ) or ranitidine as negative oral contrast agents and no agent. MATERIALS AND METHODS: MRCP images of patients administered PJ (n = 117) or Ranitidine (n = 110) at random, and patients without an agent (n = 50) were evaluated. The subjective image quality of the overall, extra hepatic bile duct and pancreatic duct and the degree of elimination of gastrointestinal fluid were scored by two blinded radiologists. RESULTS were compared using Mann-Whitney's U-test. RESULTS: The degrees of elimination of gastro duodenal fluid of PJ and ranitidine were significantly better than those without an agent (p < 0.01 and p < 0.01, respectively). The subjective image quality of PJ of the overall and extra hepatic bile duct were significantly better, although no significant differences for ranitidine were observed compared with those without an agent (p < 0.01 and p =0.23, p = 0.025 and p = 0.18). There were no significant differences for the pancreatic duct (p = 0.13 and p = 0.20), nor were there any significant differences in the evaluations between PJ and ranitidine (p = 0.21 and p = 0.96). CONCLUSION: PJ showed better performance compared to that of conventional ranitidine in terms of pancreatic and biliary depiction and safety. PMID- 25738056 TI - Categorization of Pathology Causing Low Back Pain using Magnetic Resonance Imaging (MRI). AB - BACKGROUND: Low backache is the most common ailment flooding the orthopaedic clinic. Most of the population at least once seek medical attention for low back ache. Magnetic Resonance Imaging (MRI) is a non invasive, commonly used diagnosing modality and accurate in diagnosing pathology causing low back ache. AIM: To classify and quantify the causes of low back pain referred to radiology department by MRI. MATERIALS AND METHODS: Patients with back pain referred to radiology department were subjected to single MRI scan after ruling out any contraindications using the following sequences: T1W Turbo Spin Echo, T2W Turbo Spin Echo, Gradient-echo, Myelogram and short TI inversion recovery (STIR), in all imaging planes. Gadolinium enhanced T1W turbo spin echo sequence was used wherever necessary. RESULTS: Data were analysed using Excel 2007, SPSS 14, Students t-test. Degenerative disc diseases were the commonest pathology followed by congenital and traumatic lesions. Neoplastic lesions were the least common. Commonest herniation type being the disc bulge (79%) followed by disc protrusion (15%), disc extrusion (6%) and disc sequestration (<1%). The posterolateral disc herniation as the commonest and foraminal the least. Sacralisation was the most common congenital spinal anomaly, followed by lumbar scoliosis and perineural cyst. There is no sex difference in disc protrusion but male preponderance in disc extrusion with subligmentous extrusion. CONCLUSION: MRI is useful in classifying the spinal lesions which again influences the treatment modality and clinical outcome. Degenerative disc disease is the single most common category which accounts for most the Low Back Ache for which a preventing strategy should be drafted. PMID- 25738057 TI - Magnetic resonance imaging (MRI) evaluation of developmental delay in pediatric patients. AB - INTRODUCTION: Developmental delay is defined as significant delay in one or more developmental domains. Magnetic Resonance Imaging (MRI) is the best modality to investigate such patients. Evaluation of a child with developmental delay is important not only because it allows early diagnosis and treatment but also helpful for parental counseling regarding the outcome of their child and to identify any possible risk of recurrence in the siblings. Thus this study was undertaken to evaluate the developmental delay in Indian children which will help the clinicians in providing an estimation of the child's ultimate developmental potential and organize specific treatment requirement and also relieve parental apprehension. AIMS AND OBJECTIVES: To study the prevalence of normal and abnormal MRI in pediatric patients presenting with developmental delay and further categorize the abnormal MRI based on its morphological features. MATERIALS AND METHODS: It is a prospective, observational & descriptive study of MRI Brain in 81 paediatric patients (46 Males and 35 Females), aged between three months to 12 years; presenting with developmental delay in Deccan College of Medical Sciences, Hyderabad; over a period of three years (Sept 2011 to Sept 2014). MRI brain was done on 1.5T Siemens Magnetom Essenza & 0.35T Magnetom C with appropriate sequences and planes after making the child sleep/sedated/ anesthetized. Various anatomical structures like Ventricles, Corpus callosum, etc were systematically assessed. The MRI findings were divided into various aetiological subgroups. RESULTS: Normal MRI findings were seen in 32% cases and 68% had abnormal findings of which the proportion of Traumatic/ Neurovascular Diseases, Congenital & Developmental, Metabolic and Degenerative, neoplastic and non specific were 31%, 17%, 10%, 2.5% and 7.5% respectively. The ventricles and white matter mainly the corpus callosum were the most commonly affected anatomical structures. The diagnostic yield was found to be 68% and higher yield was seen in patients presenting with developmental delay plus. CONCLUSION: The clinical diagnosis of developmental delay should not be the end point, but rather a springboard for an effective search for causal factors. MRI is the best investigation with a high yield in such patients. PMID- 25738058 TI - Magnetic resonance imaging characteristics of persistent vegetative state due to prolonged hypoglycemia. AB - Hypoglycemia is the sudden decrease in serum glucose level <50mg/dL. Neurological manifestations complicating profound and prolonged hypoglycemia range from reversible focal deficits and transient encephalopathy to irreversible coma. Here, we report magnetic resonance imaging characteristics of a patient with prolonged hypoglylicemia. A 47-year-old woman with a history of insulin dependent diabetes mellitus has been brought to the emergency room by her relatives. She used mistakenly overdose insulin injection and probably stayed 11 hours with low level blood glucose. The initial blood sugar level was 39.6 mg/dL at the emergency department visit, which was recovered urgently by 50% dextrose. MR imaging revealed high intensities at the bilateral posterior parietal cortices, corona radiata and hippocampus, but not in the basal ganglia. Seventy-two hour after admission, confluent lesions in the posterior parietal, temporal, frontal cortices and splenium of corpus callosum were more prominent on DWI and FLAIR, and did not match typical arterial territories. None of the lesions were enhanced on contrast-enhanced T1-weighted images. The prognosis or neurologic sequelae of hypoglycemic encephalopathy may depend on the severity and duration of hypoglycemia and persistent, diffuse involvement of the cerebral cortex, basal ganglia, or hippocampus on the following MR imaging. MR imaging findings in hypoglycemic vegetative state can be helpful in the differential diagnosis distinguishing from other neurologic conditions. PMID- 25738059 TI - Congenital kyphosis in thoracic spine secondary to absence of two thoracic vertebral bodies. AB - Congenital thoracic kyphosis at D6-D7 vertebral body level has been encountered in an 18-month-old boy without neurological deficit. The constellation of the spine malformation complex such as incomplete development of the vertebral bodies associated with defective ossification of the thoracic pedicles causing effectively the development of spinal cord injury at the kyphotic level of D6-D7 were present. Congenital kyphosis in thoracic spine secondary to absence of two thoracic vertebral bodies has been reported in a few studies. It is the absence and asymmetry of growth plates that may contribute to a congenital defect. Congenital Kyphosis refers to the normal convex curvature of the spine as it occurs in the thoracic and sacral regions since birth. Congenital kyphosis is an uncommon, but potentially devastating anomaly of the spine. It is one of the important aetiology for spinal cord compression leading to further neurological complications. Congenital kyphosis although rare, is more associated with neurological complication. Early identification not only helps in understanding its natural history but also helps in deciding its management. PMID- 25738060 TI - A new variant of choledochal cyst diagnosed on magnetic resonance cholangiopancreatography. AB - Choledochal cysts (CDC) have been traditionally classified into five types and subtypes based on the pattern and location of involvement of intra and extra hepatic biliary tree. Herein, we describe a new variant of choledochal cyst which has not been previously described in the English-language medical literature. PMID- 25738061 TI - Idiopathic subareolar breast abscess in a male patient. AB - We present a case of left breast abscess in a young male patient who presented with acute onset swelling left breast. Imaging studies helped in accurate diagnosis and the case was managed by subareolar incision and drainage. Subareolar breast abscess is an uncommon entity in male and should be kept as a differential diagnosis for male breast swellings. PMID- 25738062 TI - Comparision between bupivacaine and ropivacaine in patients undergoing forearm surgeries under axillary brachial plexus block: a prospective randomized study. AB - CONTEXT: Brachial plexus block is a suitable alternative to general anaesthesia for patient undergoing upper extremity surgery. Ropivacaine the S-enantiomer emerged as a possible replacement of Bupivacaine without undesirable toxic effects. It provides similar duration of sensory analgesia with early recovery of motor block. AIMS: Comparision of onset, duration of sensory- motor block and any adverse effects between 0.5% Bupivacaine and 0.5% Ropivacaine in axillary brachial plexus block. SETTINGS AND DESIGN: Prospective randomized study. MATERIALS AND METHODS: This study was carried out in 50 patients between 18-55 y, comparable in demographic variables was randomly allocated to two groups of 25 each. Group I received 30ml 0.5% Bupivacaine, Group II received 30 ml 0.5% Ropivacaine in axillary brachial plexus block for forearm surgeries. Onset, Duration of sensory-motor block, Heart rate, Blood pressure, Oxygen saturation and Respiratory rate were recorded. STATISTICAL ANALYSIS: Statistical analysis used was Statistical Package for Social Sciences version 15.0, Chi-square test was used to evaluate the proportional data. Odds ratio/risk ratios have been calculated wherever necessary. Parametric data has been evaluated using Student t test while non-parametric data has been evaluated using Mann-Whitney U-test. RESULTS: Onset of motor blockade was earlier in ropivacaine group (5 min) as compared to bupivacaine group (20 min), Higher levels of motor blockade, Mean onset time for motor block was significantly shorter in ropivacaine group (14.88+/-3.35 min) as compared to bupivacaine group (22.92+/-3.79 min), Mean duration of block was significantly longer in bupivacaine group (408.40+/-50.39 min) as compared to ropivacaine group (365.60+/-34.29 min) (p=0.001), Onset of sensory block was observed from 5 min itself in ropivacaine group as compared to bupivacaine group (10 min), Duration of sensory block was significantly longer in bupivacaine group (450.40+/-54.50 min) as compared to ropivacaine group (421.20+/ 38.33 min) . CONCLUSION: On the basis of present study, conclusions were drawn that onset of action of sensory, motor block was early in Ropivacaine group with faster recovery of motor functions as compared to Bupivacaine group. No adverse effects were noted in either groups. This study suggests that Ropivacaine is a suitable alternative to Bupivacaine for forearm surgeries under Brachial Plexus Block. PMID- 25738063 TI - Incidental hypoglycemia with suspected high spinal in a case for emergency caesarian. AB - Spinal anaesthesia is a suitable choice for emergency LSCS (lower segment caesarian section). High spinal is common in parturients. We report a case of 25 year-old primigravida with cephalo pelvic disproportion coming for emergency LSCS with no comorbidities. The patient became unresponsive after 5 min of Sub Arachnoid Block (SAB), managed as a case of high spinal. Still the patient remained unresponsive at the end of surgery, 50 min after SAB. Patient started responding to oral commands after correction of hypoglycemia with 25% dextrose infusion. PMID- 25738064 TI - Accidental subclavian artery catheterization during attempted internal jugular central venous catheter placement: a case report. AB - Central venous catheter placement has been routinely employed for anesthetic and intensive care management. Despite proper technique used and expertise complications do occur; some of which are related to catheter misplacements. We report a case in which subclavian artery was accidently catheterized during attempted internal jugular venous cannulation. PMID- 25738065 TI - Delayed recovery from anaesthesia in a patient with optimised hypothyroidism and incidental hypokalemia. AB - Delayed recovery/awakening/ emergence can occur under anaesthesia and is multifactorial, could be drug or non drug related. Similarly, we report a case of delayed recovery in a 68-year-old patient, for laparoscopic cholecystectomy, a known case of hypertension, bronchial asthma and hypothyroidism. Preoperatively, she was optimised for her medical disorders; however, she had delayed recovery from general anaesthesia. The delayed recovery, often, would be expected in a case of hypothyroidism, however in our patient it was found to be associated with inadvertent hypokalemia. PMID- 25738066 TI - Haemangioma, thrombocytopenia and coagulopathy- kasabach merritt syndrome: an appraisal for anaesthesiologists. PMID- 25738067 TI - Homosexual Obsessive Compulsive Disorder (HOCD): A Rare Case Report. AB - Homosexual Obsessive Compulsive Disorder (HOCD) is marked by excessive fear of becoming or being homosexual. The subjects often experience intrusive, unwanted mental images of homosexual behaviour. The excessive uncontrolled thoughts/doubts are very distressing and lead to compulsions in form of checking. We present a rare such case who was suffering from HOCD. PMID- 25738068 TI - Morphological Pattern of Cutaneous Adverse Drug Reactions due to Antiepileptic Drugs in Eastern India. AB - INTRODUCTION: Cutaneous manifestations of adverse drug reactions are a common occurrence and need to be differentiated from other causes of similar manifestations. Antiepileptic drugs (AED) usually are responsible for severe cutaneous adverse drug reactions (CADR) like Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophillia and systemic symptoms (DRESS). There is paucity of published research regarding morphological pattern of CADR due to various antiepileptic drugs AED. OBJECTIVE: To study the morphological patterns of CADR due to AED and common anticonvulsant drugs implicated particularly in severe CADR such as SJS/TEN and DRESS in a tertiary care teaching hospital in eastern India. MATERIALS AND METHODS: A prospective, observational study was conducted over a period of 4 years from August 2009 to July 2013 after the approval of the Institutional Ethics Committee using self reporting method for selection of cases. SETTINGS: All patients with CADR after AED consumption for various conditions presenting to the Dermatology outpatient department (OPD) and Pediatric OPD and Indoor patients of a tertiary care teaching hospital located in Rohtas district of Bihar were included in this study. RESULTS: During the study period, 64 cases of severe CADRs were included in this study. Out of 64 patients, 28 were male and 36 were female with mean age 36.1 years (range 6 years to 72 years). Most common AED implicated for CADR was Phenytoin. Maculopapular rash was the most common cutaneous manifestation of ADRs (42.85%). Serious CADR like TEN and SSJS were more likely in patients prescribed Phenytoin and Carbemazepine simultaneously. CONCLUSION: CADRs are a common occurrence and awareness about the same is essential for diagnosis and prevention. This study identified combined use of phenytoin and carbamezepine as a most important risk factor for serious CADR like SJS and TEN. PMID- 25738069 TI - Tretinoin Nanogel 0.025% Versus Conventional Gel 0.025% in Patients with Acne Vulgaris: A Randomized, Active Controlled, Multicentre, Parallel Group, Phase IV Clinical Trial. AB - BACKGROUND: Conventional topical tretinoin formulation is often associated with local adverse events. Nanogel formulation of tretinoin has good physical stability and enables good penetration of tretinoin into the pilo-sebaceous glands. AIM: The present study was conducted to assess the efficacy and safety of a nanogel formulation of tretinoin as compared to its conventional gel formulation in the treatment of acne vulgaris of the face. MATERIALS AND METHODS: This randomized, active controlled, multicentric, phase IV clinical trial evaluated the treatment of patients with acne vulgaris of the face by the two gel formulations locally applied once daily at night for 12 wk. Acne lesion counts (inflammatory, non-inflammatory & total) and severity grading were carried out on the monthly scheduled visits along with the tolerability assessments. RESULTS: A total of 207 patients were randomized in the study. Reductions in the total (72.9% vs. 65.0%; p = 0.03) and inflammatory (78.1% vs. 66.9%; p = 0.02) acne lesions were reported to be significantly greater with the nanogel formulation as compared to the conventional gel formulation. Local adverse events were significantly less (p = 0.04) in the nanogel group (13.3%) as compared to the conventional gel group (24.7%). Dryness was the most common adverse event reported in both the treatment groups while peeling of skin, burning sensation and photosensitivity were reported in patients using the conventional gel only. CONCLUSION: In the treatment of acne vulgaris of the face, tretinoin nanogel formulation appears to be more effective and better tolerated than the conventional gel formulation. PMID- 25738070 TI - Primary ewings sarcoma of the lung. AB - Extraosseous ewings sarcoma is an extremely rare neuroectodermal tumour. We report the case of a 30-year-old female who presented with right sided pulmonary mass. Radiology, histopathology and immunohistochemistry confirmed the diagnosis of primary pulmonary Ewings sarcoma. This case highlights the fact that Ewings sarcoma should be considered in differential diagnosis of patients presenting with pulmonary mass. PMID- 25738071 TI - ALK Positive Anaplastic Large Cell Lymphoma Presenting as Extensive Bone Involvement. AB - Anaplastic lymphoma kinase (ALK) positive Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all Non-Hodgkin's lymphomas that commonly involves nodal as well as a wide variety of extra nodal sites, as skin, soft tissue, bones and lungs, although primary or secondary involvement of bone is rare. Herein, we report a case of 14-year-old female child presented as extensive bony involvement with a clinical diagnosis of bone tumour/ small round cell tumour, which was proved to be ALK positive ALCL on histopathological examination. PMID- 25738072 TI - A rare collision tumour of infiltrating ductal carcinoma and squamous cell carcinoma of skin overlying breast: a case report. AB - Collision tumour is the concrescence of two neighbouring independent neoplasm occurring in the same site. Collision tumours are rare and are reported in various organs. Collision tumours in breast are reported in various combinations. The treatment of these tumours is not tailored and prognosis depends on the histologic type and pathologic stage of the most aggressive component. We report a rare case of breast collision tumour of infiltrating ductal carcinoma and squamous cell carcinoma of skin overlying breast in a 44-year-old female. PMID- 25738073 TI - Extradural Spinal Metastasis of Adenoid Cystic Carcinoma (ACC): A Case Report. AB - Adenoid cystic carcinoma (ACC) is a rare malignant tumour of the major salivary glands. It accounts for 10-15% of all salivary gland tumours and 1% of all head and neck tumours. Surgical resection followed by radiation is the choice of treatment for ACC. However, late loco-regional recurrence and metastasis is often seen emphasizing the importance of long-term follow-up. We report an unusual case of extradural metastasis of ACC in the dorsal spine. The primary submandibular gland tumour was resected 11 y back. A recurrence had been detected two years prior to the occurrence of spinal metastasis. Surgical decompression was done which was followed by palliative radiotherapy. Patient is symptomatically better, ambulant and on regular follow-up. PMID- 25738074 TI - Can Aspirin and Cancer Prevention be Ageless Companions? AB - Over the past few decades, the rate of cancer diagnosis has increased worldwide due to the increase in population and average life expectancy, and also, due to the advances in diagnostic medical technology that facilitate early cancer detection and recognition. Nonetheless, the treatment options have not been developed proportional to this increase, with a huge number of patients frequently being diagnosed with different types of fatal cancer. This has prompted different health organizations to search for novel strategies to prevent cancer, or even halt its progression. Having failed to provide optimum vascular protection benefits, especially with the introduction of relatively superior antiplatelets, such as adenosine diphosphate (ADP) receptor inhibitors; clopidogrel and ticagrelor, regular aspirin use was proposed to reduce the risk of common cancers like colorectal cancer, gastric cancer, breast cancer, lung cancer, prostate cancer and haematological malignancies, as suggested by epidemiological studies. However, it is difficult to draw any firm conclusions on such weak data, as this could raise false hopes among patients and physicians and could potentially mislead scientific research. Clearly, current evidence highlights a gap in medical research and emphasizes the need to carry out interventional studies in high risk for cancer patients using specific aspirin doses in order to validate the data. This should also shed some light on the risk benefit profile in view of the potential for bleeding complications, especially with the higher doses. PMID- 25738075 TI - Comparative evaluation of advanced and conventional diagnostic AIDS for endodontic management of periapical lesions, an in vivo study. AB - AIM: To evaluate efficacy of Colour Doppler ultrasonography (CDUSG), direct digital radiography (DDR) and conventional radiography (CR) in diagnosis of periapical lesions and to clinically correlate treatment plan of periapical diseases. MATERIALS AND METHODS: Thirty patients which were diagnosed with periapical lesions in anterior region by using both conventional and digital radiography were examined using colour doppler ultrasound imaging at the site of lesion. The images of each lesion were analysed by two endodontists and by an expert oral radiologist. A tentative differential diagnosis was agreed upon, based on certain principles discussed in article, then a diagnosis between cyst, granuloma and mixed lesions was made. Periapical lesions diagnosed as mixed lesions by colour doppler ultrasonography (CDUSG) were treated non-surgically whereas other periapical lesions were treated surgically. Tissues obtained during endodontic surgery were processed and examined for histopathological findings, and compared with the diagnosis made by ultrasound images. Statistical analysis was done with Chi-Square test and using one-way-Anova. RESULTS: The periapical lesions which were diagnosed as granuloma by ultrasonographic findings, was confirmed by the results of histopathological examination in all 16 surgically treated cases. The lesions in rest of the 14 cases which showed vascularity and were diagnosed as mixed lesions by ultrasonography, were treated non-surgically and had a favourable prognosis. CONCLUSION: CR and DDR facilitate diagnosis of the presence of periapical disease, but do not provide and information of its nature. CDUSG imaging facilitates accurate information on the pathological nature of the lesion and hence can lead to predictable treatment planning. PMID- 25738076 TI - Evaluation of Cytotoxicity of Silorane and Methacrylate based Dental Composites using Human Gingival Fibroblasts. AB - AIM: The effects of leached substances from the restorative dental materials may induce local and systemic adverse effects. Thus the biological and toxic properties of the restorative dental materials must be compatible with the oral tissues or with general health. Therefore, the need for biocompatible restorative dental material implies the necessity of toxicity testing. It was the purpose of this investigation to determine and compare the possible toxic effect of silorane based composite (Filtek P90) on human gingival fibroblast (HGF) in vitro using cytotoxicity measuring parameters (MTT assay) in comparison with its methacrylate counterpart (Z100) for their viability, proliferation rate. MATERIALS AND METHODS: Fresh healthy biopsy specimens of human gingival tissue of patients were obtained. For HGF, cells were cultured in Dulbecco's modified Eagle medium and grown to sub confluent monolayers. After attaining confluence, cells were treated with different doses of the Filtek P90 or Z 100 for different time point. HGF cells were observed for their proliferation, viability by MTT assay. RESULTS: The results of the cytotoxicity assay showed that, the percentage of viable cells was very good in the first 24h and marginally decreased in the next 48h period in all groups. However, the proliferation rate was never below 84% in all the groups, at any given concentration. Filtek P90 and Z100 treated cells exhibited insignificant decrease in the cell proliferation both in 24h and 48h exposure when compared to significant decrease in the cell survival rate in the positive control (Mitomycin C 250 MUg/ml).) Comparison of the toxicity between Filtek P90 and Z100 in 24h & 48h separately showed that there was no significant difference (p<0.05) between these two composites in 24h and 48h' time period at all concentrations of the composites. CONCLUSION: To conclude, the new silorane based restorative composite showed comparable cytotoxic characteristics to clinically successful dimethacrylate composites suggesting the non-toxic nature in the oral environment and hence contributing to clinical success of these new restorative materials. PMID- 25738077 TI - In vitro evaluation of shear bond strength of nanocomposites to dentin. AB - AIMS: To compare the shear bond strength of nanocomposites to dentin using three different types of adhesive systems; and to test few specimens under Scanning Electron Microscope (SEM) for analysing whether the bond failure is adhesive or cohesive. MATERIALS AND METHODS: Sixty human premolar teeth were selected and were randomly grouped, with 20 specimens in each group: group 1 - fluoride releasing dentin bonding agent; group 2 - antibacterial containing dentin bonding agent; and group 3 - one step conventional self etch adhesive. Each group was treated with its respective bonding agents, composite resin build up was done, and shear bond strengths were tested using Instron Universal testing machine. Few of the specimens were tested under SEM. RESULTS: The results were statistically analysed using One-way ANOVA and paired t-test. It was observed that group 3 has the highest shear bond strength followed by group 2, and then group 1. Adhesive failures and mixed failures were most frequent types of failures as seen under SEM. CONCLUSION: Addition of antimicrobial agent decreases the bond strength of dentin bonding agent and addition of fluoride further decreases the bond strength. From SEM results it can be concluded that the zone of failure could not be defined and also that the failure mode was independent of the dentin bonding agent used. PMID- 25738078 TI - Colour stability of heat and cold cure acrylic resins. AB - INTRODUCTION: To evaluate the colour stability of heat and cold cure acrylic resins under simulated oral conditions with different colorants. MATERIALS AND METHODS: Three different brands of heat cure acrylic resin and two rapid cure auto polymerizing acrylic resin of commercial products such as Trevelon Heat Cure (THC), DPI Heat cure (DHC), Pyrax Heat Cure (PHC), DPI Cold cure (DCC) and Acralyn-R-Cold cure (ACC) have been evaluated for discoloration and colour variation on subjecting it to three different, commonly employed food colorants such as Erythrosine, Tartarizine and Sunset yellow. In order to simulate the oral condition the food colorants were diluted with artificial saliva to the samples taken up for the study. These were further kept in an incubator at 37 degrees C +/- 1 degrees C. The UV-visible spectrophotometer has been utilized to evaluate the study on the basis of CIE L* a* b* system. The prepared samples for standard evaluation have been grouped as control group, which has been tested with a white as standard, which is applicable for testing the colour variants. RESULTS: The least colour changes was found to be with Sunset Yellow showing AE* value of 3.55 with heat cure acrylic resin branded as PHC material and the highest colour absorption with Tartarizine showing AE* value of 12.43 in rapid cure autopolymerzing acrylic resin material branded as ACC material. CONCLUSION: ACC which is a self cure acrylic resin shows a higher colour variation to the tartarizine food coloration. There were not much of discoloration values shown on the denture base resins as the food colorants are of organic azodyes. PMID- 25738079 TI - Cephalometric appraisal of tongue and related soft tissues in normal and open bite subjects at rest. AB - AIM: To compare the tongue position of normal and open bite subjects at rest and to study if there is any difference in the hyoid bone and posterior pharyngeal wall positions in normal and open bite subjects. MATERIALS AND METHODS: Sample size consisted of 48 individuals with 24 subjects having normal occlusion and 24 subjects having open bite malocclusion within the age range of 16 to 25 y. Standardized Lateral cephalograms were taken for all the subjects. The subjects were asked to protrude their tongue as much as possible. The dorsum of the tongue was then coated with a palatable suspension of Barium Sulphate (MICROBAR). The subjects were asked to swallow on command, after 10 sec of the swallow, lateral cephalograms were taken. STATISTICAL ANALYSIS: t-test RESULTS: The antero posterior relationship of maxilla and mandible to the cranial base is normal in both the groups. The open bite subjects had a larger over jet and as compared to the normal subjects, and had steeper mandibular planes.It was also seen that as the total tongue occupancy area increased so did the partial tongue occupancy area. CONCLUSION: A significant positive correlation was found between the horizontal position of the tongue tip and the lower incisor position in the normal group, also for the ratio of total tongue area to total oral area & the ratio of upper tongue area to the anterior oral area in the normal and openbite groups. There was no difference in the position of the tongue, hyoid bone and posterior wall in the normal and openbite groups. The mandibular plane angle and palatal plane - mandibular plane angles were found to be larger in the openbite subjects as compared to normal subjects. Supra-eruption of the maxillary molars was seen in the openbite group leading to a downward and backward rotation of the mandible. The maxillary and mandibular incisors were more proclinated in the normal as well as openbite groups. PMID- 25738080 TI - Sizing the shape: understanding morphometrics. AB - PURPOSE: One of the most fundamental limitations associated with the conventional cephalometrics is its inability to delineate size from shape as it depends mainly on linear and angular measurements. However, the biological structures warrant greater description in terms of shape and form for better comparison of variation in a particular population. To overcome these shortcomings, morphometrics are now being employed for describing the biological structures in terms of quantifying the shape and form. Also, statistical analysis is being applied to find the variability of this form in the population. The present paper assesses the use of the Procuste superimposition technique and the subsequent form analysis by the principal component analysis (PCA). MATERIALS AND METHODS: The lateral cephalograms of 10 adult females were taken from existing records, traced & digitized & then superimposed by means of procuste superimposition. A comparison was made with the conventional superimposition methods based on arbitrary reference planes like cranial base, FHP, SN. The statistical analysis for assessment of shape variability of the structures seen on the lateral cephalogram was done by calculating the principal components for 3 out of these 10 samples. RESULTS: The conventional superimposition methods do not provide realistic picture of variation in the biological structures as they themselves are prone to variability even in a particular population. CONCLUSION: Concepts in Morphometrics can be applied for the purpose of orthodontic assessment of a particular patient with regards to his craniofacial morphology. With the help of morphometrics, norms for a population can be determined based on all the kinds of variations present naturally in that particular population & individuals can thus be compared more realistically regarding the morphological variations. PMID- 25738081 TI - Shear Bond Strength Evaluation of Resin Composite Bonded to GIC Using Different Adhesives. AB - AIM: To evaluate the bonding of composite to glass ionomer cement (GIC) using two different bonding systems. MATERIALS AND METHODS: The occlusal surface of 30 teeth was flattened and they were divided into three groups. In Group A, composite (Filtek" Z350 XT, 3M ESPE, USA) was bonded to GIC (Fuji II, GC Corporation, Japan) after initial setting of the GIC being employed as a total etch adhesive(AdperSinglebond 2, 3M ESPE, USA). In Group B and C, self-etch primer(Adper" Easy One, 3M ESPE, USA) was employed to bond composite to GIC before and after initial setting of GIC respectively. Shear bond strength and nature of fracture of specimens was determined. STATISTICAL ANALYSIS: One-way analysis of variance (ANOVA) was used. RESULTS: Group B showed higher bond strength than Group A & Group C (p<0.01). Group C showed the least bond strength. CONCLUSION: Bond strength of composite to GIC was significantly higher for self etch primer group employed on unset GIC. PMID- 25738082 TI - A qualitative analysis to compare the effects of surface machining of conventional denture base resin and two soft liners: a scanning electron microscopic study. AB - INTRODUCTION: The denture base acrylic resins require adjustments for various reasons. During this process there is an alteration in the surface characteristics of the denture base. Rough surfaces promote the bacterial adhesion and plaque accumulation; therefore it is important to know the character of the surface left by instrumentation on denture base materials. This study evaluated the surface characteristics of the machined surfaces of heat-cured acrylic denture base resin, GC supersoft and Permasoft softliners. MATERIALS AND METHODS: Thirty 15*15*1.5mm acrylic resin specimens were fabricated with each of three acrylic resins: Lucitone 199 denture base resin (Group I), GC supersoft (Group II) and Permasoft (Group III) softliners. They were further divided into three sub Groups A, B and C, in which Sub Group A was control group that is smooth produced against the glass. Sub Group B was produced by machining with the tungsten carbide bur and Sub group C is machined with the stone bur. Each surface was evaluated by a Scanning electron microscope and data were analyzed by analysis of variance followed by Tukey's HSD test. RESULTS: Stone bur produced smoother surface (Ra 3.6681MUm+/- 0.254) on Lucitone199 than the tungsten carbide bur (Ra 5.3881MUm +/- 0.3373). Carbide bur produced a smoother surface on the GC super soft (Ra 1.617097MUm +/- 0.191767) and Permasoft softliners (Ra 2.237419MUm +/- 0.354259). Whereas stone bur produced rougher surface on GC supersoft(Ra 2.6MUm) and Permasoft (Ra 4.184839MUm +/- 0.409869) softliners. CONCLUSION: The present study shows each type of rotary instrument produces its own characteristic surface on each type of denture base materials and that care is needed when selecting the most appropriate instrument to adjust denture base materials. These results can have a significant clinical implication. While using Lucitone 199 stone bur can be used for chair side adjustments. Tungsten carbide bur can be used for GC supersoft and Permasoft softliners to achieve smoother surface. PMID- 25738083 TI - Effectiveness of outreach program: a three year follow-up study among 12 years school students in lucknow. AB - AIM: To assess the effectiveness of outreach program in the 12 years school going children during a three year follow up period of Lucknow city. MATERIALS AND METHODS: A random sample of 298 school going children of age 12 years was drawn from adopted schools of Lucknow. Three years later the same population was re examined with a population of 242 children of 15 y age group. The oral health status of these children was accessed by using WHO 1997 profoma. RESULTS: Significantly (p<0.001) higher proportion of children had healthy gingival, healthy periodontal status after three years. The difference in regard to crowding in the incisal segment in 2010 and 2013 was statistically highly significant (p<0.001). CONCLUSION: The findings of the study showed that after providing regular dental check up and treatment camps in the three adopted schools after three year follow up study from 2010-2013 showed positive impact on the children oral hygiene status and has been estimated to be on the more positive aspect in future also. PMID- 25738084 TI - Co Relation between PUFA Index and Oral Health Related Quality of Life of a Rural Population in India: A Cross-Sectional Study. AB - INTRODUCTION: A new measuring system called PUFA index had been identified to quantify the consequences of untreated dental caries. The co relation between PUFA index and oral health related quality of life has not been documented so far in India and thereby the need for this study Design: Cross-sectional observational study. MATERIALS AND METHODS: Sample size of 212 subjects, who are the residents of a town in Rangareddy district were included to be a part of this study. The subjects were interviewed for the OHIP score and the clinical examination done to record the PUFA scores. RESULTS: The main objective of this study was to find out if there was any correlation between the OHIP scores and the study subjects and using the Pearson' s co relation coefficient, there was a significant correlation between the OHIP and the PUFA scores.(Pearson' s correlation= 0.31) CONCLUSION: The mean OHIP and PUFA scores of the study subjects were 2.21 and 0.40 respectively. There is a positive correlation between the OHIP score and the PUFA score among the study population i.e. with the PUFA scores increasing, it has a detrimental effect on the oral health related quality of life of the individual. PMID- 25738085 TI - High levels of physical inactivity amongst dental professionals: a questionnaire based cross sectional study. AB - INTRODUCTION: A Dentist plays an important role in providing health education (General and Oral) to the community. Questions arise regarding their own health, which in turn affects their patients' counselling for leading a healthy and a physically active life. AIM: To measure and compare the amount of physical activity present amongst dental professionals with the general population of Greater Noida. MATERIALS AND METHODS: The International Physical Activity Questionnaire (IPAQ) was used to measure physical activity and statistical significance was calculated using SPSS version 21.0. Statistical significance was kept as p <.05. RESULTS: Compared to the general population, Dentists were more obese and reported increased levels of low physical activity. Dentists had an increased and significant transportation and leisure time activity (p= .03 and .01) whereas, the general population had a higher level of vigorous activity(p = <.01). The MET hour/week for dentists and general population was 33.72 and 36.24 respectively, which was quite low as compared to European population. CONCLUSION: The results indicate that dentists report a lower level of physical activity as compared to the general population of Greater Noida. However, on a global scale, the physical inactiveness of dentists and general population alike could pose a serious health hazard and if kept unchecked, shall increase the global burden of chronic disease. PMID- 25738086 TI - Effect of unintentional periapical extrusion of metapex in immature teeth- a case report. AB - The paper discusses a case of an immature premolar tooth with a large periapical lesion, in which Metapex (calcium hydroxide paste containing iodoform and barium sulphate as a radiopacifier) was used. There was an un-intentional extrusion of calcium hydroxide during application. The patient was evaluated for periapical healing at 12 and 24 months. The follow up revealed that the accidental extrusion of metapex did not have any detrimental effect on periapical healing. However, delayed resorption of Metapex as well as healing of the periapical lesion may be attributed to the presence of BaSO4 and iodoform as compared to plain Calcium hydroxide. PMID- 25738087 TI - Histogenesis and clinical analysis of 2 cases of congenital gingival granular cell tumour. AB - Dentistry for babies aims to contribute to the formation of a generation with fewer dental problems, higher quality of oral health and more aware of the importance of prevention. The congenital gingival granular cell tumour (CGCT) is a rare benign soft tissue tumour in the newborn that can lead to respiratory difficulties and feeding. The aim of this work was to report two cases of CGCT in babies and discuss the clinical and histological differential diagnosis and their treatment, as well as the importance of knowledge of this pathology for dentists. Clinical features and treatment approaches are presented and discussed. The surgical approach improved the child quality of life and restored the parent's confidence and emotional stability. Knowledge of this pathology helps in better diagnosis and treatment, which lead to a better quality of life of children and return confidence and emotional stability to parents. PMID- 25738088 TI - Surgical management of fractured orthodontic mini- implant- a case report. AB - The idea of absolute anchorage has always been an elusive goal for clinicians. Orthodontic mini-implants or temporary anchorage devices allow tooth movements previously thought to be impossible or difficult. Although extensive literature exists on use of temporary anchorage devices, their failures have been hardly focused upon, especially implant fracture. The following case report describes successful management of fractured orthodontic mini-implant. PMID- 25738089 TI - Giant central ossifying fibroma of the maxilla presenting with a pus discharging intra-oral sinus. AB - Central ossifying fibroma (COF) is a rare benign fibro-osseous neoplasm which has a predilection for mandible and is encountered in middle aged women. It arises from mesenchymal blast cells of the periodontal ligament, and with a potential to form fibrous tissue, cementum and bone. It is a well circumscribed lesion mainly comprising of fibrous tissue with varying amounts of bone or cementum or osteo cementum like tissue. We present an uncommon case of COF of the maxilla in a 35 year-old male who presented with a pus discharging sinus in the maxilla. Due to the bizarre size of the lesion we have termed as 'giant' COF. There is extensive facial asymmetry on the right side with obliteration of the maxillary antrum, deviation of the nose and upward displacement of the orbit. PMID- 25738090 TI - Gingival veneer: a novel technique of masking gingival recession. AB - One of the most distressing aspects of periodontitis is the unesthetic appearance of maxillary and mandibular anteriors. The elongation of the crowns due to root exposure and increased interdental spacing results in unesthetic appearance. Surgical procedures for gingival recession coverage do not have acceptable results in cases of severe gingival recession. So nonsurgical methods like gingival veneers should be considered as a treatment modality in such cases. This article aims to revisit the gingival veneer: its uses, advantages, disadvantages, and its fabrication. The case discussed here highlight clinical situation where the gingival veneer prosthesis helped in achieving optimum esthetics and patient satisfaction thus proving to be a feasible and simple treatment modality in certain clinical cases. This may offer a good interim solution for patients who may wish to have time to consider their options of more advanced and complex treatment. PMID- 25738091 TI - Osteomyelitis in pycnodysostosis - report of 2 clinical cases. AB - Pycnodysostosis is a rare craniofacial syndrome characterized by dwarfism, cranial anomalies, diffuse osteosclerosis where multiple fracture of long bones and osteomyelitis of jaw are frequent complications. This clinical entity was first described in 1962 by Maroteaux and Lamy. This article presents two clinical cases of pycnodysostosis with their clinical and radiological characteristics. PMID- 25738092 TI - Ultrasonics: a novel approach for retrieval of separated instruments. AB - An instrument fracture within the root canal interferes and hinders the outcome of the successful root canal treatment. Fracture of endodontic instrument often results from incorrect use or overuse. This article reports a case of retrieval of separated endodontic instrument with help of ultrasonic and discusses the factors influencing the removal of fractured instrument. PMID- 25738093 TI - Facial asymmetry in young adults with condylar hyperplasia-unusual changes in the facial bones. AB - Facial asymmetry can be caused by various pathological conditions, condylar hyperplasia (CH) is one of such condition, characterized by unilateral or bilateral mandibular condylar overgrowth, causing facial asymmetry, mandibular deviation, malocclusion and functional impairment. Advanced imaging and scintigraphic methods, helps the clinicians in diagnosing and monitoring its macroscopic aspects. Here we report three interesting and illustrative cases of facial asymmetry with unilateral CH discussing the unusual changes in the facial bones. PMID- 25738094 TI - Management of large preiapical lesion with the combination of second generation platelet extract and hydroxyapatite bone graft: a report of three cases. AB - The pulp tissue necrosis and extensive periodontal diseases leads to the development of the inflammatory periapical lesion which causes a local response of bone around the apex of the tooth. Depends upon the nature of wound and available biological growth factors the outcome will be either regeneration or repair. Being a rich source of growth factors, platelet rich fibrin (PRF) posses many advantages in bone regeneration. The purpose of this case report is to present an attempt to evaluate the healing potential of the combination of PRF and Hydroxyapatite bone graft as opposed to using these materials alone. A periapical endodontic surgery was performed on three patients with a large periapical inflammatory lesion and a large bony defect. The defect was then filled with a combination of PRF and Hydroxyapatite bone graft crystals. Clinical examination exhibited uneventful wound healing. The HA crystals have been replaced by new bone radiographically at the end of two years in Case 1 and Case 2, Case 3 were followed upto one year. On the basis of our cases outcome, we conclude the use of PRF in combination with HA crystals might have accelerate the bone regeneration. PMID- 25738095 TI - Hand schuller christian disease: a rare case report with oral manifestation. AB - Langerhan's Cell Histiocytosis (LCH) is disorders which include abnormalities that result from abnormal proliferation of langerhan's cells or their precursors. LCH is clinically classified into three types-eosinophilic granuloma, Hand Schuller Christian disease and Abt-Letterer- Siwe disease. It is usually manifested in childhood as well as in adulthood. The clinical manifestations are the result of the accumulation and infilteration of the langerhan cells in organs and tissues. Here is a rare case report of 6-year-old boy with extraoral manifestation of exopthalmic right eye and oral manifestation of mobility of teeth and with typical radiological findings. Basing on the clinical, radiological and histopathological examination the diagnosis of Hand Schuller Christian Disease was given. PMID- 25738096 TI - Drug induced gingival overgrowth: a rare case report. AB - Gingival overgrowth is well documented side effect associated with three major classes of drugs viz, anticonvulsants, calcium channel blockers, and immunosuppressants. Despite our greater understanding of pathogenesis of Drug induced Gingival Overgrowth (DIGO), its treatment still remains a challenge for the periodontists and treatment is still largely limited to maintenance of improved level of oral hygiene and surgical removal of overgrown tissue. Dental Surgeons need to discuss this issue with their medical colleagues and to practice care while prescribing the drugs associated with gingival overgrowth. The aim of present article is to report a rare case where even after extraction of all teeth; the enlargement did not subsided for one month. PMID- 25738097 TI - Unilateral Ankylosis of Temporomandibular Joint (TMJ) with Contralateral Condylar Aplasia and Related Orthopedic Deformity - Syndromic or Nonsyndromic? AB - Condylar aplasia which means "failure of development" is a rare condition and can be unilateral or bilateral. Mandibular condylar Aplasia without any association with syndrome is extremely rare. Temporomandibular joint (TMJ) ankylosis results from trauma, infection and inadequate surgical treatment of the condylar area. Congenital cases are very rare. We report case of congenital unilateral aplasia of left mandibular condyle with ankylosis of right condyle, with an associated orthopedic deformity in a nine-year-old male patient, which may be a part of some unreported syndrome that has not been mentioned so far in literature. As per our best knowledge, no other case including such clinical features has been reported. PMID- 25738098 TI - Oral rehabilitation and management of mentally retarded. AB - High level of periodontal problems of dental caries are frequently observed in mentally handicapped children. This group of patients presents various problems when they face dental treatments. Identification of such population and providing them affordable oral health care is the new concept. A systematic method for identification and screening of persons with mental retardation has been developed and is being followed. Cost and fear are the most commonly cited barriers to dental care. Physical or mental may lead to deterioration in self care, and oral care state have a low priority. Risk factors are inter-related and are often barriers to oral health. With advancements in today's world sufficient information and support is available for each and every individual to lead a healthy life which include the access to the oral health care. Factors such as fear, anxiety and dental phobia plays a vital role in acceptance of dental care and also the delaying of dental care. Lack of knowledge of oral and dental disease, awareness or oral need, oral side-effects of medication and organization of dental services are highlighted in the literature. All health personnel should receive training to support the concept of primary oral health care. Training about dealing with such mentally handicapped people should be addressed urgently among the health professionals. PMID- 25738099 TI - Bonebiomarkers in periodontal disease: a review article. AB - Periodontitis, is an inflammatory state of the tooth supporting structures and if left untreated, the disease continues to progressive bone destruction and subsequent tooth loss. The increasing prevelance of periodontal disease paved way to the development of new diagnostic tests that could detect the presence of active disease,the course of the disease and its response to treatment. Bone is a metabolically active tissue and undergo continuous remodelling, a process that largely relies on the activity of osteoclasts to remove bone and of osteoblasts to form bone. In health ,bone resorption and formation are coupled to each other and its long term maintenance of skeletal balance is brought about by the systemic hormones and local mediators.In contrasts,during disease there is a pronounced in balance in bone turnover. Bone biomarkers which are produced either in health or in disease state are tell tale markers which would be used to monitor the health status. This review highlights, the recent advances in the use of biomarkers of bone remodelling,that could facilitate the screening, diagnosis and management of periodontal diseases. PMID- 25738100 TI - Localization of impacted canines. AB - Impaction of maxillary canines is a frequently encountered clinical problem. The impaction of canine can be prevented in some situationsif the canine displacement is diagnosed in the early mixed dentition period and this would be extremely useful for the clinician. Hence,it is very important to focus on the means of early diagnosis and interception of this clinical situation. In the present article, the differentmodalities used to diagnose the impacted canine are reviewed with an insight into current 3-D modalities. PMID- 25738101 TI - Occlusion calculator. AB - Start with end in mind' is a popular cliche in orthodontics. This aptly applies to the therapeutic occlusion the orthodontist strives to achieve. Predicting the post treatment occlusion is an essential component of treatment planning. When no extractions or symmetric extractions are done predicting the final occlusion is somewhat easy. Prediction is challenging when we do unconventional and/or asymmetric extractions. To aid this decision Kesling proposed the 'Kesling Setup'. Though it serves the purpose acceptably; it is time, energy and money consuming. We have developed a model which can help us visualize the final occlusion in matter of seconds. Although this model is primarily intended for orthodontic postgraduate teaching, it can be of considerable use even to a seasoned orthodontist. The regular use of "Orthodontic Calculator" in our department is a testimony to its usefulness. PMID- 25738102 TI - A simplified method of fabricating a habit breaking appliance. PMID- 25738103 TI - Head Strap Double Fluid Level Device: An Innovative and User Friendly Design to Record Natural Head Position (NHP). AB - Head positions can be oriented in a standardized position when the patient stands upright and focusses his/her eyes into a point in infinity. This is the natural head position. This position offers the maximum reproducibility and correlates well with the clinical picture offered to the diagnostician. This article describes an innovative and user friendly method to record natural head position using the head strap double fluid level device, a design modified from the popular fluid level device by Showfety, Vig and Matteson. PMID- 25738104 TI - Bilateral supplemental maxillary incisors with both dens invaginatus and dens evaginatus in a non syndromic patient: a rare case report. PMID- 25738105 TI - Impacted love: mandibular kissing molars advisable to remove or not. PMID- 25738106 TI - An Eagle's Eye on 'Gutkha Ban Legislation' in India. PMID- 25738107 TI - Oral malignant melanoma. PMID- 25738108 TI - Gastric pouch after simple or radical cystectomy for benign and malignant bladder disease. AB - BACKGROUND: There is a controversy regarding the use of gastric pouch for benign and malignant bladder diseases. OBJECTIVES: The aim of this retrospective study was to report our experience, mostly on gastric neobladder (not gastrocystoplasty) for benign and malignant bladder diseases, its complications, outcomes and follow-up results. MATERIALS AND METHODS: In this retrospective case series, we described our experience on seven gastric pouches (2 gastrocystoplasty and 5 gastric neobladders). RESULTS: Postoperative complications were rare. Continence was defined as bladder capacity over 400 mL. Their follow-up period ranged from five months up to writing the article. One of the studied cases is still alive and awaiting renal transplantation. CONCLUSIONS: Gastric pouch is a suitable segment for bladder cystoplasty and neobladder. Continence is mostly related to the capacity of pouch. PMID- 25738109 TI - Protean faces of infective endocarditis in renal transplant recipients. PMID- 25738110 TI - Von Willebrand factor-cleaving protease activity in thrombotic microangiopathy: first report from iran. AB - BACKGROUND: Thrombotic microangiopathy (TMA) is a rare but devastating small vessels disorder that is characterized by intravascular platelet thrombi, thrombocytopenia, and various degrees of organ ischemia and anemia, which is due to erythrocyte fragmentation in microcirculation. OBJECTIVES: The Aim of this study was to determine the von Willebrand factor-cleaving protease (ADAMTS13) activity during the acute phase of TMA. We also investigated inhibiting antibodies against ADAMTS13 in these patients. PATIENTS AND METHODS: In a collaborative work with Mario-Negro institute of pharmacological research in Bergamo-Italy, we registered the clinical and laboratory data, collected the serum samples, and transferred the samples to the laboratories. Serum samples were taken before the start of plasmapheresis or at least 15 days after the final exchange. RESULTS: We recruited 40 patients (14 males and 26 females) with the mean age of 46.12 +/- 17.26 years. The mean activity of ADAMTS13 was 34.58% +/- 21.83%. Two patients had inhibitory antibodies against ADAMTS13 with profound deficiency of ADAMTS13 activity (< 6%). Infectious diseases were the most common underlying condition, followed by systemic lupus erythematous. CONCLUSIONS: Majority of patients had an underlying condition and had various ADAMTS13 activity. The presence of inhibiting antibodies and accompanied complete deficiency of ADAMTS13 activity is an indicator of severity. PMID- 25738111 TI - Delivery of huge bladder stone in a thirty-five-year-old man. AB - INTRODUCTION: Bladder stone is the most common form of lower urinary tract stones and constitutes 5% of all urinary tract stones. The giant bladder stones are very rare and our report was the first one in Iran and in the world. CASE PRESENTATION: The patient was a 35-year-old man who was referred to our urology clinic with the lower urinary tract symptoms. Irritative symptoms were dominant without obstructive symptoms. During a physical examination, hard mass was palpated in suprapubic area. On ultrasonography, a huge stone with 110-mm diameter was revealed in the bladder. CONCLUSIONS: A unique point in this patient was the absence of any history or current conditions such as bladder outlet obstruction or foreign body, which might predispose bladder to stone formation. Another unique point was the heavy weight (826 g) of one-piece-stone filling all bladder space. In majority of reported bladder stones, the weight was lower and the stones were in multiple pieces. PMID- 25738112 TI - Membranous Nephropathy With MPO-ANCA-Associated Crescentic GN. AB - INTRODUCTION: Antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (GN) is characterized by necrotizing and crescentic GN with paucity of immunoglobulin (Ig) and complement deposition, which is also known as pauci-immune crescentic GN. Membranous nephropathy (MN) is characterized by the formation of subepithelial immune deposit with resultant changes in glomerular basement membrane (GBM), most notably spike formation. CASE PRESENTATION: A 48 year-old man presented with marked proteinuria, hypoalbuminemia, and renal dysfunction with positive results for myeloperoxidase (MPO) and ANCA. Renal biopsy revealed crescents and thick GBM with subepithelial spikes along with IgG deposition on immunofluorescent staining. The condition was diagnosed as MN with MPO-ANCA-associated crescentic GN. He was treated with intravenous methylprednisolone and cyclophosphamide. After one-month follow-up, antibody level and renal function did not improve. CONCLUSIONS: Coexistence of MN with MPO ANCA crescentic GN is very rare and should be managed aggressively. PMID- 25738113 TI - Erectile dysfunction in chronic hemodialysis patients in dakar: a cross-sectional study in 2012. AB - BACKGROUND: Patients with chronic kidney disease (CKD) experience multiple complications including erectile dysfunction (ED). It involves more than 50% of patients on dialysis or transplant. In Africa, the true extent of ED in CKD is unknown although some studies have been done in this regard. OBJECTIVES: This study aimed to determine the prevalence and identify risk factors of ED in patients on hemodialysis. PATIENTS AND METHODS: This cross-sectional multicenter study was conducted from January 2, 2012 through April 30, 2012 in four hemodialysis centers in Dakar. We included all patients on chronic hemodialysis who aged >= 18 years old and freely consented to participate in the study. Sociodemographic, clinical, and hemodialysis data were collected through a questionnaire. Erectile function was assessed by a short version of International Index of Erectile Function (IIEF-5). RESULTS: Among a target of 80 patients, 73 met the inclusion criteria and were included in this study. Mean dialysis vintage was 27.3 months (range, 1-156). Their mean age was 53.81 +/- 12.52 years, with a higher proportion of age group of 50 to 69 years old. Fifty-six patients were married (37 monogamous and 19 polygamous) and six were singles. Overall prevalence of ED was 84.9% and it was severe in 14 patients (19.2%). Hypertension and diabetes were the most frequent etiologies and antihypertensive treatment was used in 95.5%. The main factors associated with ED were age > 50 years old and polygamy. CONCLUSIONS: ED is a common problem among patients on hemodialysis in Dakar with a high prevalence. Aging and diabetes represent most common causes. More efforts are needed for its early detection, prevention, and multidisciplinary management. PMID- 25738114 TI - Nontraditional cardiovascular biomarkers and estimation of cardiovascular risk in predialysis chronic kidney disease patients and their correlations with carotid intima media thickness. AB - BACKGROUND: Cardiovascular biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T (cTnT), hs-CRP (high sensitivity C reactive protein), and albuminuria predict underlying heart disease in the general population as well as CKD patients. OBJECTIVES: We aimed to study the association of NT-proBNP, cTnT, hs-CRP, and spot urine albumin creatinine ratio with carotid intima media thickness (CIMT) for cardiovascular risk estimation in predialysis CKD (chronic kidney disease) patients. PATIENTS AND METHODS: This cross-sectional study included a total of 120 adult predialysis CKD patients. Forty patients were allocated in each predialysis CKD group of stages 3, 4, and 5. Serum cTnT and hs-CRP, plasma NT-proBNP, and single spot urine albumin creatinine ratio (ACR) were measured. Ultrasonographic examination of carotid artery was done with 7.5 MHz linear probe in B mode ultrasonography and carotid intima media thickness was measured. RESULTS: Mean values +/- standard deviation of plasma NT-proBNP (pg/mL), serum hs-CRP (mg/L), spot urine ACR (mg/g of creatinine), and CIMT (mm) were 585.68 +/- 514.84, 5.96 +/- 2.52, 719.37 +/- 411.36, and 0.78 +/- 0.15, respectively in predialysis CKD patients (n = 120). Serum cTnT level was high in 40% of predialysis CKD patients. Among cardiovascular biomarkers, plasma NT-proBNP had maximum strength of correlation (Spearman Rho correlation coefficient; r = 0.575 and P < 0.0001) with the carotid intima media thickness followed by serum cTnT (Spearman Rho correlation coefficient; r = 0.419 and P < 0.0001), spot urine albumin creatinine ratio (Spearman Rho correlation coefficient; r = 0.322 and P < 0.0001), and serum hs CRP (Spearman Rho correlation coefficient; r = 0.246 and P = 0.007). CONCLUSIONS: Nontraditional cardiovascular biomarkers such as plasma NT-proBNP, serum cTnT, serum hs-CRP, and spot urine ACR significantly correlate with CIMT. These biomarkers can estimate the cardiovascular risk in a predialysis CKD population with expected high cardiac morbidity and mortality. PMID- 25738115 TI - Association of micro albuminuria with diastolic function in obese normotensive no diabetic individuals. AB - BACKGROUND: Recently, an association between impaired diastolic function and increased urinary albumin excretion has been hypothesized. OBJECTIVES: We tried to assess the association between diastolic function and micro albuminuria in normotensive no diabetic obese individuals. PATIENTS AND METHODS: This cross sectional study was conducted on 186 consecutive obese normotensive no diabetic individuals who were older than 18 years and attended the outpatient health clinic at the Tehran Municipality in 2011. Systolic and diastolic blood pressures were measured using a standard mercury sphygmomanometer. Micro albuminuria was defined as abnormal urinary albumin to creatinine ratio (UACR) between 30 and 300 mg/g/d. RESULTS: An adverse significant linear correlations was found between the UACR measurement and diastolic function (r = -0.184 and P = 0.012); however, this correlation was insignificant for systolic function (r = 0.007 and P = 0.926). Multivariable linear regression analysis showed that UACR index had a significant reverse correlation with diastolic function (Standardized Beta = -0.218 and P = 0.006). CONCLUSIONS: Our study obtained some evidences on the association of micro albuminuria with diastolic dysfunction in obese normotensive no diabetic individuals. Nonetheless, more assessment is necessary for obtaining a causal relationship between micro albuminuria and diastolic dysfunction. PMID- 25738116 TI - Isolation and molecular identification of Mycoplasma hominis in infertile female and male reproductive system. AB - BACKGROUND: Infection of urogenital system with Mycoplasma potentially affect reproductive system and increases infants mortalities. Therefore, detection of these organisms is an important issue that should be considered and appropriate diagnostic methods should be used to identify these microorganisms. In the female reproductive system, infection can affect different parts of the cervix, endometrium, and fallopian tube. The extent of this infection in different diseases and its pathogenesis might be related to anatomic site of involvement. Some infections can lead to infertility in both males and females. Genital infection with Mycoplasmas have devastating effects on reproductive organs and cause fertility disorders and mortality in infants. In recent years, many studies have been conducted to isolate these pathogens; however, the isolates have not been identified so far. OBJECTIVES: The aim of this study was to determine the molecular identity of Mycoplasma hominis isolated from infertile female and male reproductive system in the Infertility Center of Kerman. MATERIALS AND METHODS: This descriptive study was performed purposefully on 100 infertile females and 100 infertile males who were referred to the Infertility Center of Kerman during a six-month period. The collected samples of semen and vaginal swabs were examined for the presence of M. hominis by PCR. The samples with positive results in PCR were selected for molecular identification. Alignment of samples sequence was performed using MEGA 5 software through Neighbor-joining method. RESULTS: Among 100 samples from infertile males, the presence of genus Mycoplasma was confirmed in 45 cases of which 15 cases were infected with M. hominis. Among 100 samples from infertile female, the presence of genus Mycoplasma was confirmed in 43 cases of which 18 case were infected with M. hominis. The positive samples were sequenced and the phylogenetic tree was plotted. CONCLUSIONS: The results showed that 37.5% of infertile males and females were infected with M. hominis. Analysis of the nucleotide sequences of the study isolates indicates a particular variety among these isolates. In comparing the isolates in the study, a very little genotypic similarity was found among some of them. PMID- 25738117 TI - Major barriers responsible for malnutrition in hemodialysis patients: challenges to optimal nutrition. AB - BACKGROUND: Nutritional barriers may contribute to malnutrition in hemodialysis (HD) patients. Higher rates of morbidity and mortality rates have been reported in malnourished HD patients. These patients are faced with different challenges affecting their nutritional status. OBJECTIVES: The aim of this cross-sectional study was to identify most important barriers responsible for malnutrition in HD patients. PATIENTS AND METHODS: We randomly selected 255 of 800 stable HD patients from three HD centers with an age range of 18-85 years, who had been on hemodialysis for at least three months without any acute illness. Each patient was interviewed to evaluate malnutrition [subjective global assessment (SGA), malnutrition inflammation score (MIS)], and potential medical, behavioral and socioeconomic barriers. Body composition of patients was checked through bioelectrical impedance analysis (BIA). Routine clinical markers of malnutrition such as serum albumin and total protein were measured using standard automated techniques. Binary logistic regression model was used to find the association between nutritional markers and potential barriers. RESULTS: Patients with higher SGA had lower knowledge about general nutrition [odds ratio (OR), 1.3], potassium (OR, 1.89), difficulty chewing (OR, 1.16), and shopping (OR, 1.16). Those with greater MIS scores had poor appetite (OR, 1.3), depression (OR, 1.21), and difficulty with cooking (OR, 1.15). Lower BCM (body cell mass) was associated with poor appetite (OR, 0.92) and needed help for cooking (OR, 0.88). Patients with higher BFMI (body fat mass index) had insufficient general nutrition (OR, 1.15), and protein (OR, 1.27) knowledge, and needed help for shopping (OR, 1.14). Moreover, patients with higher SGA scores were those with older age and longer duration of HD. CONCLUSIONS: Three medical barriers (poor appetite, depression and difficulty chewing), one behavioral barrier (poor total nutrition, protein, and potassium knowledge), and one socioeconomic barrier (needing help for shopping and cooking) were independently associated with nutritional markers. PMID- 25738118 TI - Bilateral Renal Lymphangiectasia in a Thirty-two-Year-Old Woman. AB - INTRODUCTION: Renal lymphangiectasia is a rare disorder of the lymphatic system that might be confused with various other renal cystic diseases and urinoma. Clinical presentation is non-specific and characteristic findings in radiologic imaging are the mainstay of diagnosis. CASE PRESENTATION: We reported a case of bilateral lymphangiectasia in a 32-year-old woman who presented with flank pain and hypertension. DISCUSSION: Renal lymphangiectasia is an uncommon benign condition. Most of the cases improve with conservative treatment. Surgery is rarely required, except in cases such as those with persistent pain refractory to medication. PMID- 25738119 TI - Massive vesical calculi formation as a complication of augmentation cystoplasty. AB - INTRODUCTION: Here we report an unusual case of massive stone formation in augmented urinary bladder. CASE PRESENTATION: A 25-year-old man presented with recurrent urinary tract infection ten years after augmentation cystoplasty after a complex pelvic fracture urethral distraction defect. On evaluation by ultrasonography, X-ray, and computed tomography of abdomen showed large burden of stones in the urinary bladder. Patent underwent an open cystolithotomy and forty stones weighing about 1400 g were removed. It was one of the largest reported stone burdens following augmented cystoplasty until now. DISCUSSION: Even though stone formation is a common complication after augmentation cystoplasty, it can be prevented by regular bladder wash and good follow-up. PMID- 25738120 TI - Global scientific vision with local vigilance: renal transplantation in developing countries. AB - CONTEXT: Renal Transplantation is the most effective treatment for patients with end-stage renal disease, which is fortunately available in the developing countries, even for poor people. Nonetheless, the way forward should be the implementation of advanced science of transplantation, allograft monitoring abilities, knowledge about the epidemiology of renal disease in any specific region, awareness about the influence of ethenic and genetic factors immunosuppressant bioavailability, and post-transplant complications all strongly affecting the patients and allograft survival. EVIDENCE ACQUISITIONS: In this process we searched mainly in PubMed, Web of Science and Google Scholar data bases for key words of renal allograft monitoring, post-transplant infections, renal/kidney transplantation and Iran. We followed the cross articles to follow our main idea to find a connection between modern advancement in renal allograft monitoring and our practice in developing countries. Another focus was on the special infectious and non-infection complication that do exist in specific region and need specific considerations. RESULTS: Implementation of modern techniques of immune monitoring, allograft function, awareness about the specific infectious and non-infectious disease in each region improves the quality of renal transplantation. CONCLUSIONS: We need to combine the advance scientific vision with local vigilance to achieve the best outcome in renal allograft recipients. PMID- 25738121 TI - Isolated anti-hbc and occult HBV infection in dialysis patients. AB - BACKGROUND: Occult Hepatitis B virus (HBV) infection (OBI) is defined as the presence of HBV-DNA in the liver or serum with undetectable hepatitis B surface antigen (HBsAg). Hemodialysis (HD) patients are at risk of acquiring parenterally transmitted infections. OBJECTIVES: The aim of this study was to assess the prevalence of OBI in HD patients. PATIENTS AND METHODS: A hundred HBsAg negative HD patients were included in this study from main dialysis units in Tehran, Iran. HBsAg, hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti HBc) and liver enzymes levels were examined in all subjects. The presence of HBV DNA was determined in plasma samples using real-time PCR. RESULTS: A hundredpatients with a mean age of 58.5 +/- 16.1 years were enrolled in this study. In total, 56.7% were male and 43.3% female. Anti-HBs, anti-HBc, anti-HCV and anti-HIV were detected in 56.7%, 2%, 5.2% and 1% of patients, respectively. Isolated anti-HBc was detected in 2% of cases. HBV-DNA was detected in 1% of HBsAg negative patients. CONCLUSIONS: This study showed a low rate of isolated anti-HBc and occult HBV infection in HD patients. It can be due to improvement of people's knowledge about HBV transmission routes, HBV vaccination of HD patients and regular surveillance of HBV infection. PMID- 25738122 TI - Association between body mass index and urinary tract infection in adult patients. AB - BACKGROUND: Overweight and obesity have become a global public health over the last decades. Obesity has been suggested to be a risk factor for some infections, but studies often showed controversial findings. Few studies examined the relationship between body mass index (BMI) and urinary tract infection (UTI), showing inconsistent results. OBJECTIVES: The purpose of this study was to determine the relationship between BMI and UTI in adult patients. PATIENTS AND METHODS: Adult patients (>= 18 years old) who were referred to clinics or admitted in hospital with diagnosis of UTI were considered for participation in the study. Control group were selected from healthy adult normal population whom underwent medical check-ups at the same hospital and without history of UTI. Data about age, gender, history of diabetes mellitus and BMI were registered for individuals who met inclusion criteria. RESULTS: A total of 116 patients with UTI and 156 people as the control group were included in the study. Two groups were matched for age, gender and history of diabetes mellitus. Mean BMI +/- SD of patients was 25.2 +/- 4.0 kg/m(2) and the controls was 25.1 +/- 3.6 kg/m(2). There was no significant correlation between BMI and UTI (P = 0.757). Mean BMI +/ SD of patients with upper UTI was 25.6 +/- 4.1 kg/m(2) and for lower UTI was 24.9 +/- 4.0 kg/m(2). There was no significant difference between BMI of controls and patients with any type of UTI (P = 0.573). CONCLUSIONS: Our findings did not found an association between BMI and UTI and does not support obesity as a risk factor for UTI in adult patients. PMID- 25738123 TI - Translation and psychometric properties of the persian version of the dialysis symptom index in hemodialysis patients. AB - BACKGROUND: Hemodialysis patients have a high physical and psychosocial symptom burden. There is no valid and reliable tool for assessing symptoms of hemodialysis patients in Iran. OBJECTIVES: The aim of this study was to determine psychometric properties of the Persian version of the dialysis symptom index (DSI). PATIENTS AND METHODS: The forward-backward procedure was applied to translate the DSI from English into Persian (Iranian language). The scale (Persian Version) was tested with a convenience sample of 95 patients with end stage renal disease referred to main hemodialysis centers from December 2012 to June 2013. Validity was assessed using content, face and convergent validity. To test reliability, the kappa values were calculated for test-retest stability and the Cronbach alpha coefficients were also calculated for internal consistency. RESULTS: The mean age of patients was 50.4 (SD = 15.72) years and % 61.1 of patients were male. The most commonly reported symptoms were fatigue, being irritable and nervous. Divergent validity was mostly supported by the pattern of association between DSI and SF-36 (r = -0.18- -0.48, P< 0.05). Cronbach's alpha of the DSI was 0.90 and the weighted kappa ranged from 0.21 to 0.93, and it was greater than 0.4 for 25 of the 30 items. CONCLUSIONS: The Iranian version of the DSI had good psychometric properties and can be used to assess symptoms of hemodialysis patients. PMID- 25738124 TI - Association between plasma Beta-2 microglobulin level and cardiac performance in patients with chronic kidney disease. AB - BACKGROUND: Beta-2 microglobulin (B2M) is considered as a surrogate marker for middle molecule uremic toxins and a key component in dialysis-related amyloidosis. However, few studies have evaluated role of B2M in patients with chronic kidney disease (CKD). OBJECTIVES: The purpose of this study was to evaluate the association of plasma B2M level with some metabolic and cardiac performance factors in patients with CKD. PATIENTS AND METHODS: In this case control study, we measured plasma B2M level in 86 patients with different stages of CKD and 78 age- and sex-matched individuals, as healthy control group. Then we investigated the association between plasma B2M level and left ventricular hypertrophy, ejection fraction (EF), and left ventricular end-diastolic diameter (LVEDD) in echocardiography and some inflammatory and metabolic factors in patients with CKD. RESULTS: Mean plasma B2M level was significantly higher in patients with CKD than in control group (P < 0.001). It was directly correlated with serum C-reactive protein (r = 0.167, P < 0.001), phosphate (r = 0.112, P < 0.001) levels, and left ventricular mass index (r = 0.438, P < 0.001) and LVEDD (r = 0.275, P < 0.001) in echocardiography. It was also inversely correlated with glomerular filtration rate (r = -0.033, P < 0.001), albumin (r = -0.521, P < 0.001), hemoglobin (r = -0.748, P < 0.001), and EF (r = -0.625, P < 0.001). CONCLUSIONS: Our findings suggested that plasma B2M level is inversely associated with GFR and EF and directly correlated with some metabolic and cardiac performance factors. PMID- 25738126 TI - Leiomyosarcoma of the Spermatic Cord in a Seventy-Five-Year-Old man. AB - INTRODUCTION: Leiomyosarcoma is a malignant soft tissue tumor that can arise from any tissue containing smooth muscle. Leiomyosarcomas of the spermatic cord are rare tumors of non-testicular origin, which drain into the retroperitoneal lymph nodes and have been reported in less than 150 cases in the literature until now. Radical inguinal orchiectomy and high ligation of the cord is the standard primary surgical procedure in spermatic cord leiomyosarcoma. CASE PRESENTATION: Here we reported a 75-year-old man who presented with a painless lump in the right hemiscrotum. A right radical orchiectomy was performed. Histopathology confirmed a neoplastic tissue with mesenchymal origin in spermatic cord; further evaluation revealed a leiomyosarcoma of the spermatic cord. The patient was followed up for 1-year and shows no signs of recurrence. CONCLUSIONS: Preoperative diagnosis of spermatic cord leiomyosarcma is difficult and commonly made by histological examination and immunochemical staining. PMID- 25738125 TI - Sleep quality among Iranian hemodialysis patients: a multicenter study. AB - BACKGROUND: Sleep disorders are prevalent complication in patients with end-stage renal disease undergoing hemodialysis (HD). The factors affecting sleep quality (SQ) of patients on HD have not been completely recognized yet. In addition, some studies have shown that poor SQ increases the risk of mortality in patients on HD. OBJECTIVES: This study aimed to identify the prevalence of poor SQ and its associated risk factors in Iranian patients on HD. PATIENTS AND METHODS: This cross-sectional and multicenter study was conducted on 6878 patients on HD from 132 dialysis centers in Iran. Sleep domain of disease specific core of KDCS-SF questionnaire and generic core of this questionnaire (SF-36) were used to assess patients' SQ and quality of life (QoL), respectively. A poor SQ was defined as a score of <= 61.2. Logistic and linear regression analyses were applied to assess predictors of SQ and their associations. RESULTS: The mean age of patients was 54.4 +/- 17.1 years and 39.7% of patients were > 60 years old. The majority of our patients had poor SQ (60.6%). Patients with diabetes mellitus were significantly more likely to have poor quality of sleep (63.4%). In logistic regression analysis, there were significant correlation between good SQ and younger age, shorter dialysis vintage, less muscle cramp, high QoL, high cognitive function score, and high sexual function. In addition, linear regression showed a significant association among SQ, QoL, and hospital stay as an outcome. CONCLUSIONS: With improving some factors and QoL of patients on HD, we can promote SQ in these patients that it might lead to reduction in length of hospital stay. PMID- 25738127 TI - Rare adrenal gland emergencies: a case series of giant myelolipoma presenting with massive hemorrhage and abscess. AB - INTRODUCTION: Adrenal Myelolipoma is a rare benign neoplasm, which contains mature adipose tissue and variable amounts of haematopoietic elements. Most lesions are small and asymptomatic, discovered incidentally during autopsy or imaging studies performed for other reasons. CASE PRESENTATION: Here we reported a series of two cases of giant myelolipomas of the adrenal gland; first one the largest tumor reported so far presented with massive hemorrhage and the second case introduced with its rare unreported presentation of adrenal myelolipomas i.e. a large abscess. DISCUSSION: Adrenal myelolipoma is a rare and asymptomatic tumor usually discovered incidentally in less than 1% of population on autopsy or imaging performed for other reasons. There is an increasing incidence of large adrenal myelolipoma (> 10 cm) presenting with life threatening and recurrent retroperitoneal hemorrhage along with other complications as abscess. To avoid such a life-threatening situation, authors recommend close monitoring and consideration of urgent surgical intervention for tumors larger than 4 cm at presentation or increase in size or change in appearance during follow-up. PMID- 25738128 TI - The impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. AB - BACKGROUND: Patients with end stage renal disease (ESRD) can be sustained with dialysis therapy. OBJECTIVES: In this study, we followed up the effect of early acute and late acute rejections on survival rates of patients' grafts. PATIENTS AND METHODS: We investigated the timing and frequency of acute rejection episodes related to long-term patient-graft survival in Taleghani hospital between 1990 and 2011. Recipients were divided into three groups as Group-1 (no rejection), Group-2 (early acute rejection [EAR]: less than 3-months) and Group-3 (late acute rejection [LAR]: after 3 months of transplant). RESULTS: One and five-year patient's survival rates were 94.87% and 93.8%, and graft survival (GS) rates were 92.6% and 81.9%. EAR and LAR occurred in 125 (18.8%) and 77 (11.7%) patients, respectively. Graft and patient survival rates at one and five years were as follows; Group-1 (Graft 96.7% and 94.5% patient: 97.4% and 96.8%), Group 2 (Graft: 72% and 61%, patient: 85.6% and 84%), Group-3 (Graft: 84.4% and 36.8%, patient: 92.2% and 89.4%). Recipient age, type and length of dialysis, number of transplantations and the status of panel reactivity antibody (PRA) had no effect on the type of rejection. LAR was more commonly associated with males (P = 0.001) and donors' age was associated with rejection (P = 0.0002). Five-year GS rate among the three groups was lower in the LAR group (P < 0.0001). CONCLUSIONS: LAR had a negative impact on long-term renal allograft survival and the risk of chronic graft dysfunction increased in patients with a history of LAR. PMID- 25738129 TI - Association between metabolic syndrome and coronary heart disease in patients on hemodialysis. AB - BACKGROUND: The metabolic syndrome (MeS) is a common risk factor for coronary heart disease (CHD) in the general population. OBJECTIVES: We examined the association between MeS and its risk in terms of CHD in patients on hemodialysis (HD). PATIENTS AND METHODS: This study was conducted on 300 patients on HD in six HD centers during March 2012. Patients were divided in two groups regarding presence of MeS. The rate of CHD were evaluated in each group and compared with each other. RESULTS: A total of 300 patients on HD, 173 males and 127 females with mean age of 61.7 +/- 14.2, were enrolled in the study. Prevalence of MeS was 50.3%; hypertension, 83.7%; diabetes mellitus, 52%; high triglyceride level, 34%, low HDL cholesterol, 48.3%; and abdominal obesity, 41.3%. During the study, the CHD was more frequent in patients with MeS (27.8%) than was in those without MeS (14.1%) (P = 0.004). In addition, stroke happened more frequently in the MeS group than in those without MeS (30.5% vs. 17.4%; P = 0.008). The mean number of criteria for MeS was not significantly associated with mortality causes (CHD, 2.7 +/- 1.3; stroke, 2.8 +/- 0.9; other causes, 2.9 +/- 1.3 P = 0.78). However, hypertension (89.3%) and diabetes mellitus (53.8%) were associated with increased risk for mortality. In the group of MeS, CHD were not significantly associated with serum albumin, calcium, phosphate, blood urea nitrogen, creatinine, ferritin, C-reactive protein, and KT/V; but there was significant association with white blood cells count (P < 0.0002). CONCLUSIONS: These findings suggested MeS might be an important risk factor for CHD, but not for mortality due to CHD in patients on HD. PMID- 25738131 TI - The Ruled-out Scaphoid Fracture on Computed Tomography Prevalence and the Therapeutic Management of Other Carpal Fractures. PMID- 25738130 TI - Correlation between health-related quality of life in veterans with chronic spinal cord injury and their caregiving spouses. AB - BACKGROUND: Recently, investigations have indicated that caring of a chronically ill family member strongly influences the health status and the quality of life (QOL) of the caregiving family members. OBJECTIVES: The purpose of this study was to examine the relationship between health-related QOL of veterans with chronic spinal cord injury and their caregiving spouses. PATIENTS AND METHODS: We designed a cross-sectional study including two groups; veterans with chronic spinal cord injury and their caregiving wives who were living in the city of Mashhad, Iran. The patients with spinal cord injury were veterans from the Iran Iraq war (1980-1988). All the participants filled out the short form 36 (SF-36) health survey questionnaire. A Pearson correlation coefficient was calculated for the scales of the two groups. RESULTS: The mean age and standard deviation of veterans and their spouses were 48.5 +/- 5.9 and 44.8 +/- 7.2, respectively and their number of children ranged between 0-6. Our data analysis showed that there was a significant difference between the two groups in some domains of the SF-36, including PF, MH, PCS, MCS, BP and GH (P < 0.05), but there was no significant difference in RP, VT, SF and RE between the two groups. CONCLUSIONS: The results indicate that a decrease in health status level of veterans, physically and mentally, can affect the health-related QOL of their caregiving spouses. PMID- 25738132 TI - Waiting times in emergency department after using the emergency severity index triage tool. AB - BACKGROUND: Hospital emergency departments (EDs) are as barometers of the health care system. Crowded EDs threaten delivery of timely care. Prolonged ED wait times reduce the quality of care and increase adverse and sometimes irreversible events. OBJECTIVES: The purpose of this study was to determine the patients' waiting time at Namazi and Shahid Faghihi hospitals in Shiraz, Iran. PATIENTS AND METHODS: This analytical cross-sectional study was conducted in two phases from December 2012 to May 2013. First, the researcher attended the EDs of the two hospitals and recorded the information of 900 patients who entered the ED, including arrival time, level of triage, and time of first visit by physician. Then, among patients admitted to the ED units, 273 were followed and waiting times for the first physician order in the referral unit and the commencement of clinical interventions (defined as check time by the nurse) were recorded. RESULTS: The median waiting time from arrival to first visit by physician for the 900 patients included in the study was 8 (5-14) minutes [median (interquartile range)]. For the patients admitted to referral units, waiting time was 84 (43 145) minutes for the physician order and 85 (45-147) minutes for the commencement of first clinical intervention; 75% of the patients in triage level I, 84.6% in triage level II, and 95.6% in triage level III were visited within the target time limit. CONCLUSIONS: Waiting time for commencement of clinical action in patients admitted to the EDs was considerably high for patients with higher priorities; so, rapid care of critically ill patients, identified during the triage process, should be emphasized. PMID- 25738133 TI - Comparing the interpretation of traumatic chest x-ray by emergency medicine specialists and radiologists. AB - BACKGROUND: Discrepancy between X-ray readings of emergency physicians (EPs) versus radiologists was reported between 0.95% and 16.8% in different studies. The discordance was even higher when specific studies such as chest X-rays (CXR) were probed. OBJECTIVES: This prospective study was conducted to assess the discrepancies between emergency and radiology departments with respect to interpretation of the traumatic chest X-rays. PATIENTS AND METHODS: This prospective study was conducted in Shohadaye Tajrish Hospital, Tehran, Iran, from March to April 2014. Based on Advanced Trauma Life Support (ATLS) guidelines, plain chest radiography (CXR) was ordered for all patients in two standard views of posterior-anterior and lateral. All CXRs were interpreted by a corresponding emergency medicine specialist and a radiologist blind to the clinical findings of the patients. Finally, the results of two interpretations were compared. Accuracy, sensitivity, specificity, and predictive values of traumatic CXR interpretation were calculated by EPs with 95% of confidence interval (CI). RESULTS: The evaluation of EPs was identical to that of the radiologists in 89.5% of the cases. Ninety-eight percent (98%) indicated total agreement and 1.5 percent total disagreement. CONCLUSIONS: There is a high agreement between EPs and radiologists in CXR interpretations in Shohadaye Tajrish Hospital. Thus, EPs can substitute radiologists in the emergency department. More improvements are recommended to achieve the standard level of agreement. PMID- 25738134 TI - The burning questions of heterotopic ossification. PMID- 25738135 TI - Research, evidence, and ethics: new technology or grey medicine. AB - Major pioneering advances of medicine in history tend to manifest in two directions that seem divergent but actually unified with dialectics: one is the important biological principle revealed by in-depth studies from the clinic to the laboratory based on individual cases; the other is the colonial generality displayed by epidemiologic data from large-scale samples. Although advances predominated, we human beings were paying dearly for it due to serious incidents of endangering ourselves and defects of restrictions of laws and ethics. Subsequently, the Nuremberg Code, Declaration of Helsinki and Belmont Report came into light and constrained human experiments and clinical trials. However, the development of such laws and regulations in China is lagging behind and renders China as a breeding ground for gray medicine. There are three lessons we can learn from painful histories and apply to individualized treatment of lung cancer. Firstly, the abuse of Avastin beyond its indications reflected the similar situation of tyrosine kinase inhibitors in lung cancer due to different molecular types and stages of tumors; secondly, the black market of stem cell therapy in China reminds us how to identify the boundaries of clinical trials and clinical treatment, in similar to the cellular immunotherapy of tumors; thirdly, the theory of Xiao's Reflex Arc emerged us to rethink the level of the validity of clinical evidences, which can provide hints related to video-assisted thoracoscopic surgeries (VATSs). In conclusion, clinical applications of new techniques and treatment regimens should follow three points: identify indications and contraindications clearly, obtain informed consent and permission of patients and supervise effectively according to laws and ethics. PMID- 25738136 TI - Significance of (99m)Tc-GSA liver scintigraphy in liver surgery and transplantation. PMID- 25738137 TI - (99m)Tc-GSA SPECT/CT fused images for assessment of hepatic function and hepatectomy planning. AB - To assure safe hepatectomy, accurate estimation of the functional reserve of the future remnant liver is crucial. The combination of indocyanine green retention rate at 15 min and CT volumetry is widely used in deciding on the extent of hepatectomy. On the other hand, there are quantitative indices calculated from (99m)Tc-GSA scintigraphy that reflect the number and function of hepatocytes. Therefore, there are many indices calculated from (99m)Tc-GSA scintigraphy that have been reported. In recent Annals of Surgical Oncology on Oct. 2014 the Uptake Index (UI) calculated from (99m)Tc-GSA scintigraphy was reported to be useful for hepatectomy planning and postoperative liver failure prediction. In this paper, we report on the usefulness and limits of quantitative indices calculated from (99m)Tc-GSA SPECT/CT for preoperative simulation. PMID- 25738138 TI - Will the 40-gene expression classifier predict responders to EGFR targeted chemotherapy for the invasive bladder cancer patients? PMID- 25738139 TI - Optimizing lung cancer screening: nodule size, volume doubling time, morphology and evaluation of other diseases. PMID- 25738140 TI - New therapies for reducing post-myocardial left ventricular remodeling. PMID- 25738141 TI - Probability of lung cancer based on the size threshold and volume-doubling time for lung nodules detected in low-dose CT screening. PMID- 25738142 TI - Glucan supplementation enhances the immune response against an influenza challenge in mice. AB - BACKGROUND: The strong immunostimulating potential of beta-glucans has been well established in numerous diseases. However, the effects on viral infection were less studied. METHODS: In our study, we focused on possible effects of a special combined glucan formulation on immunosuppression caused by influenza infection. RESULTS: We found that a 2-week oral feeding with glucan mixture significantly reduced the effects of influenza infection in total mortality. Our study was focused on phagocytosis, cytokine levels, antibody response and cytotoxicity assay. CONCLUSIONS: Based on our data, we concluded that these effects are caused by stimulation of both cellular and humoral immune reaction resulting in lower viral load. PMID- 25738143 TI - The role of chemokine receptor 4 and its ligand stromal cell derived factor 1 in breast cancer. AB - Breast tumour cells express the chemokine receptor C-X-C chemokine receptor type 4 (CXCR4) and frequently metastasize to organs with an abundant source of CXCR4 ligand, stromal cell derived factor1 (SDF1). For this reason, CXCR4/SDF1 has garnered much interest as a target for therapeutic intervention. The present study is an attempt to correlate the CXCR4/SDF1 expression patterns with clinicopathological factors, patient survival, and its coexistence and response to 17-beta estradiol (E2) and 4-hydoxytamoxifen (4OHT) in breast cancer cells. Immunohistochemistry and Reverse Transcriptase-Polymerase Chain Reaction were performed to assess the protein and gene level expressions of CXCR4 and SDF1 in normal and tumour breast tissue. The effect of E2 and 4OHT on expression of CXCR4 and SDF1 in breast cancer cells were assessed using RT-PCR, Immunofluorescence microscopy and colocalization. The CXCR4 and SDF1 were over expressed and have a significant correlation with each other as well as with histological grade, tumour size and poor survival of patients. The study also showed a modulatory effect of E2 and 4OHT on the expression and colocalization of CXCR4/SDF1 in breast cancer cells. The correlation of CXCR4/SDF1 with other parameters and modulatory effect of E2 and 4OHT on the expression and colocalization of CXCR4/SDF1 in breast cancer cells are likely to open up new avenues for the successful management of this malignancy. PMID- 25738144 TI - Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research. AB - This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few available targeted therapies that is FDA approved and provides promising results in metastatic disease. However, its resistance at an early stage is of great concern. Recent implementation of combinational therapies including "targeted therapy", immunotherapy, and biological agents has appealed many researchers to define the adjunctive role of available therapies and their limitations in advanced stage and metastatic melanoma. This commends the need for future multi institutional studies to confirm the clinical validity of different therapeutic strategies on a large scale population. PMID- 25738145 TI - Surgery or stereotactic ablative radiation therapy: how will be treated operable patients with early stage not small cell lung cancer in the next future? AB - Lung neoplasm is the most influent cause of death for cancer. With the increasing of life expectancy in elderly patients and with the intensification of lung cancer screening by low-dose computed tomography, a further rise of the number of new non-small cell lung cancer (NSCLC) cases has been shown. Standard of care of early stage NSCLC patients is lobectomy but approximately 20% of them are not fit for surgery for comorbidities. Due to the high local control rates and the little adverse effects, stereotactic body radiation therapy (SBRT) also called stereotactic ablative radiation therapy (SABR), has rapidly replaced the conventional radiotherapy in not operable patients with stage I NSCLC. We review the evidence for use of SABR in medically inoperable patients with stage I NSCLC, and its possible extension of use to operable patients, from the perspectives of radiation oncologists and thoracic surgeons. Until the results of large randomized trials will be available, the multidisciplinary management, balancing during discussion the advantages/disadvantages of each treatment modality, could be the coming soon best approach for medically operable early-stage NSCLC. As a result, the minimally invasive thoracic surgery advantages and the SABR innovations will be translated into real clinical benefits. PMID- 25738146 TI - Lung cancer is a global epidemic and requires a global effort. PMID- 25738147 TI - Prof. Jacek Jassem: we should be more aggressive about tobacco control in fighting against lung cancer. PMID- 25738148 TI - The voice of the patient: a venue for all of our voices in Annals of Translational Medicine. PMID- 25738149 TI - PEGylated carbon nanotubes impair retrieval of contextual fear memory and alter oxidative stress parameters in the rat hippocampus. AB - Carbon nanotubes (CNT) are promising materials for biomedical applications, especially in the field of neuroscience; therefore, it is essential to evaluate the neurotoxicity of these nanomaterials. The present work assessed the effects of single-walled CNT functionalized with polyethylene glycol (SWCNT-PEG) on the consolidation and retrieval of contextual fear memory in rats and on oxidative stress parameters in the hippocampus. SWCNT-PEG were dispersed in water at concentrations of 0.5, 1.0, and 2.1 mg/mL and infused into the rat hippocampus. The infusion was completed immediately after training and 30 min before testing of a contextual fear conditioning task, resulting in exposure times of 24 h and 30 min, respectively. The results showed that a short exposure to SWCNT-PEG impaired fear memory retrieval and caused lipid peroxidation in the hippocampus. This response was transient and overcome by the mobilization of antioxidant defenses at 24 h. These effects occurred at low and intermediate but not high concentration of SWCNT-PEG, suggesting that the observed biological response may be related to the concentration-dependent increase in particle size in SWCNT-PEG dispersions. PMID- 25738150 TI - Adventitial alterations are the main features in pulmonary artery remodeling due to long-term chronic intermittent hypobaric hypoxia in rats. AB - Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, n = 9) and long term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, n = 10) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, n = 10). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer. PMID- 25738151 TI - Evaluation of antibacterial activity of some traditionally used medicinal plants against human pathogenic bacteria. AB - The worldwide increase of multidrug resistance in both community- and health-care associated bacterial infections has impaired the current antimicrobial therapy, warranting the search for other alternatives. We aimed to find the in vitro antibacterial activity of ethanolic extracts of 16 different traditionally used medicinal plants of Nepal against 13 clinical and 2 reference bacterial species using microbroth dilution method. The evaluated plants species were found to exert a range of in vitro growth inhibitory action against the tested bacterial species, and Cynodon dactylon was found to exhibit moderate inhibitory action against 13 bacterial species including methicillin-resistant Staphylococcus aureus, imipenem-resistant Pseudomonas aeruginosa, multidrug-resistant Salmonella typhi, and S. typhimurium. The minimum inhibitory concentration (MIC) values of tested ethanolic extracts were found from 31 to >25,000 MUg/mL. Notably, ethanolic extracts of Cinnamomum camphora, Curculigo orchioides, and Curcuma longa exhibited the highest antibacterial activity against S. pyogenes with a MIC of 49, 49, and 195 MUg/mL, respectively; whereas chloroform fraction of Cynodon dactylon exhibited best antibacterial activity against S. aureus with a MIC of 31 MUg/mL. Among all, C. dactylon, C. camphora, C. orchioides, and C. longa plant extracts displayed a potential antibacterial activity of MIC < 100 MUg/mL. PMID- 25738152 TI - Sample entropy analysis of EEG signals via artificial neural networks to model patients' consciousness level based on anesthesiologists experience. AB - Electroencephalogram (EEG) signals, as it can express the human brain's activities and reflect awareness, have been widely used in many research and medical equipment to build a noninvasive monitoring index to the depth of anesthesia (DOA). Bispectral (BIS) index monitor is one of the famous and important indicators for anesthesiologists primarily using EEG signals when assessing the DOA. In this study, an attempt is made to build a new indicator using EEG signals to provide a more valuable reference to the DOA for clinical researchers. The EEG signals are collected from patients under anesthetic surgery which are filtered using multivariate empirical mode decomposition (MEMD) method and analyzed using sample entropy (SampEn) analysis. The calculated signals from SampEn are utilized to train an artificial neural network (ANN) model through using expert assessment of consciousness level (EACL) which is assessed by experienced anesthesiologists as the target to train, validate, and test the ANN. The results that are achieved using the proposed system are compared to BIS index. The proposed system results show that it is not only having similar characteristic to BIS index but also more close to experienced anesthesiologists which illustrates the consciousness level and reflects the DOA successfully. PMID- 25738153 TI - Left ventricle: fully automated segmentation based on spatiotemporal continuity and myocardium information in cine cardiac magnetic resonance imaging (LV-FAST). AB - CMR quantification of LV chamber volumes typically and manually defines the basal most LV, which adds processing time and user-dependence. This study developed an LV segmentation method that is fully automated based on the spatiotemporal continuity of the LV (LV-FAST). An iteratively decreasing threshold region growing approach was used first from the midventricle to the apex, until the LV area and shape discontinued, and then from midventricle to the base, until less than 50% of the myocardium circumference was observable. Region growth was constrained by LV spatiotemporal continuity to improve robustness of apical and basal segmentations. The LV-FAST method was compared with manual tracing on cardiac cine MRI data of 45 consecutive patients. Of the 45 patients, LV-FAST and manual selection identified the same apical slices at both ED and ES and the same basal slices at both ED and ES in 38, 38, 38, and 41 cases, respectively, and their measurements agreed within -1.6 +/- 8.7 mL, -1.4 +/- 7.8 mL, and 1.0 +/- 5.8% for EDV, ESV, and EF, respectively. LV-FAST allowed LV volume-time course quantitatively measured within 3 seconds on a standard desktop computer, which is fast and accurate for processing the cine volumetric cardiac MRI data, and enables LV filling course quantification over the cardiac cycle. PMID- 25738154 TI - Prevalence and possible risk factors of low bone mineral density in untreated female patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation. Different studies have shown decreased bone mineral density (BMD) in patients with SLE. The objective of this study was to investigate the prevalence and possible risk factors of low BMD in untreated female patients with SLE in Chinese population. A total of 119 untreated female patients with SLE were included. BMD was measured at lumbar spine and at total hip by dual-energy X-ray absorptiometry. The associations between decreased BMD and demographic variables, clinical variables, and bone metabolism variables were analyzed. These SLE patients had the following characteristics: mean age was 32.6 +/- 11.9 years, mean disease duration was 22.1 +/- 34.5 months, and mean SLEDAI was 11.4 +/- 5.4. Osteopenia was present in 31.1% of the patients and osteoporosis in 8.5%. A significant negative association between low density lipoprotein cholesterol (LDL c) and BMD at the lumbar spine (correlation coefficient = -0.242; P = 0.023) and total hip (correlation coefficient = -0.259; P = 0.019) was shown. These results seem to indicate that increased LDL-c may be an important risk factor for low BMD at lumbar spine and total hip in untreated female SLE patients. PMID- 25738155 TI - Acoustic-frequency vibratory stimulation regulates the balance between osteogenesis and adipogenesis of human bone marrow-derived mesenchymal stem cells. AB - Osteoporosis can be associated with the disordered balance between osteogenesis and adipogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). Although low-frequency mechanical vibration has been demonstrated to promote osteogenesis, little is known about the influence of acoustic-frequency vibratory stimulation (AFVS). BM-MSCs were subjected to AFVS at frequencies of 0, 30, 400, and 800 Hz and induced toward osteogenic or adipogenic-specific lineage. Extracellular matrix mineralization was determined by Alizarin Red S staining and lipid accumulation was assessed by Oil Red O staining. Transcript levels of osteogenic and adipogenic marker genes were evaluated by real-time reverse transcription-polymerase chain reaction. Cell proliferation of BM-MSCs was promoted following exposure to AFVS at 800 Hz. Vibration at 800 Hz induced the highest level of calcium deposition and significantly increased mRNA expression of COL1A1, ALP, RUNX2, and SPP1. The 800 Hz group downregulated lipid accumulation and levels of adipogenic genes, including FABP4, CEBPA, PPARG, and LEP, while vibration at 30 Hz supported adipogenesis. BM-MSCs showed a frequency dependent response to acoustic vibration. AFVS at 800 Hz was the most favorable for osteogenic differentiation and simultaneously suppressed adipogenesis. Thus, acoustic vibration could potentially become a novel means to prevent and treat osteoporosis. PMID- 25738157 TI - Ginsenoside-Rb1 Inhibition of VEGF Release - Structure and Activity Relations (SAR) Perspective. PMID- 25738156 TI - Using regional homogeneity to reveal altered spontaneous activity in patients with mild cognitive impairment. AB - Most patients with mild cognitive impairment (MCI) are thought to be in an early stage of Alzheimer's disease (AD). Resting-state functional magnetic resonance imaging reflects spontaneous brain activity and/or the endogenous/background neurophysiological process of the human brain. Regional homogeneity (ReHo) rapidly maps regional brain activity across the whole brain. In the present study, we used the ReHo index to explore whole brain spontaneous activity pattern in MCI. Our results showed that MCI subjects displayed an increased ReHo index in the paracentral lobe, precuneus, and postcentral and a decreased ReHo index in the medial temporal gyrus and hippocampus. Impairments in the medial temporal gyrus and hippocampus may serve as important markers distinguishing MCI from healthy aging. Moreover, the increased ReHo index observed in the postcentral and paracentral lobes might indicate compensation for the cognitive function losses in individuals with MCI. PMID- 25738158 TI - Lung cancer and eye metastases. AB - It has been observed that lung cancer either non-small cell or small cell is responsible for eye metastases. This form of metastases in several cases was the first manifestation of the disease and further investigation led to the diagnosis of the underlying malignancy. Both types of lung cancer are equally responsible for this demonstration. Furthermore; both chemotherapy and tyrosine kinase inhibitors have shown equal positive results in treating the exophalmos manifestation. Up to date information will be presented in our current work. PMID- 25738160 TI - An Overview of Rare and Unusual Clinical Features of Bietti's Crystalline Dystrophy. AB - Bietti's crystalline dystrophy (BCD) is a rare disease presenting with the appearance of intraretinal crystalline deposits and varying degrees of chorioretinal atrophy commencing at the posterior pole. Within time, intraretinal crystals gradually disappear and chorioretinal atrophy extends beyond the macula even resulting in complete chorioretinal atrophy. Concomitant corneal crystals can be noted in 1/2 - 1/3 of the patients, and the presence of corneal crystals is not a must for establishing the diagnosis. For the past decade, genetic evaluations and newer imaging modalities expand our knowledge about the disease. CYP4V2 gene is found to be the gene responsible for the disease process and new mutations are still being described. Modern imaging modalities, such as a spectral domain optical coherence tomography (SD-OCT) shed light on the anatomic features of the disease. By this, we reiterate the rare and unusual clinical features of BCD. PMID- 25738159 TI - An Overview of Nd:YAG Laser Capsulotomy. AB - It has been revealed that posterior capsule opacification (PCO) is the most common delayed complication of cataract surgery. On the other hand, Nd:YAG laser capsulotomy is accepted as standard treatment for PCO. Although, Nd:YAG laser capsulotomy is a noninvasive and safe treatment it carries risk of some complications. Using less total energy and performing smaller capsulotomies are effective choices to decrease complications after Nd:YAG capsulotomy. The purpose of this review is to look through the complications associated with Nd:YAG laser capsulotomy, and the effect of capsulotomy size and used total energy on such complications. PMID- 25738161 TI - Omental transposition in treatment of severe ocular surface alkaline burn: an experimental study. AB - Since alkaline substances can rapidly penetrate into the cornea and subsequently damage limbal stem cells, another source of stem cells may be necessary to reconstruct the ocular surface. Omentum has some such characteristics like ability to regenerate tissue as well as anti-inflammatory capacity. Presence of adult stem cells and pluripotent embryonic cell markers make it suitable in wound healing; therefore, it seems reasonable to evaluate whether omentum can be helpful to restoration of ocular surface in severe alkaline burn. In this experimental trial, two groups of dogs (5 in each) were assigned. Following ethics approval, ocular surface alkaline burn was induced in both groups by placing filter papers soaked with NaOH (0.5 mol/l) on the cornea of one eye. Subsequently, group 1 (n=5) was treated only by conventional therapy; group 2 (n=5) was treated with omental elongation and transposition to the injured eye immediately following injury. Both groups were followed for six months. Ocular surface was evaluated by slit lamp microscope and corneal clarity was assessed and graded. At the end of six months, corneal opacity and vascularization were significantly reduced in group 2 (p-values of 0.009, 0.049, and 0.032 for corneal opacity, fluorescein staining, and vascularization grades, respectively). We have concluded that transposition of omental pedicle may be an effective treatment for severe ocular surface alkaline burn although more studies might be required. PMID- 25738162 TI - Geographic altitude, ocular diseases and injuries. PMID- 25738163 TI - Disease exacerbation after rituximab induction in neuromyelitis optica. PMID- 25738164 TI - Observations on the evolving fields of neuroimmunology and neuroinflammation. PMID- 25738165 TI - Unmasking and provoking severe disease activity in a patient with NMO spectrum disorder. PMID- 25738166 TI - Rasmussen encephalitis: Response to early immunotherapy in a case of immune mediated encephalitis. PMID- 25738167 TI - Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens. AB - OBJECTIVE: To evaluate immune responses to neoantigen and recall antigens in healthy subjects treated with teriflunomide. METHODS: This was a randomized, double-blind, placebo-controlled study. Subjects received oral teriflunomide (70 mg once daily for 5 days followed by 14 mg once daily for 25 days) or placebo for 30 days. Antibody responses were evaluated following rabies vaccination (neoantigen) applied at days 5, 12, and 31 of the treatment period. Occurrence of delayed-type hypersensitivity (DTH) to Candida albicans, Trichophyton, and tuberculin (recall antigens) was assessed before and at the end of treatment to investigate cellular memory response. Safety and pharmacokinetics were evaluated. RESULTS: Forty-six randomized subjects were treated (teriflunomide, n = 23; placebo, n = 23) and completed the rabies vaccination. Geometric mean titers for rabies antibodies were lower with teriflunomide at days 31 and 38 than with placebo. However, all subjects achieved sufficient seroprotection following rabies vaccination (titers well above the 0.5 IU/mL threshold). Overall, the DTH response to recall antigens in the teriflunomide group did not notably differ from responses in the placebo group. CONCLUSIONS: Following vaccination, geometric mean titers for rabies antibodies were lower with teriflunomide than with placebo. However, teriflunomide did not limit the ability to achieve seroprotective titers against this neoantigen. Evaluation of DTH showed that teriflunomide had no adverse impact on the cellular memory response to recall antigens. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in normal subjects treated with teriflunomide, antibody titer responses to rabies vaccination are lower than with placebo but sufficient for seroprotection. PMID- 25738168 TI - High natural killer cell number might identify stroke patients at risk of developing infections. AB - OBJECTIVE: To investigate early changes in leukocyte subsets and autonomic function as predictors of the development of poststroke infections. METHODS: We assessed the time course of leukocyte subsets in the blood of 59 patients with acute ischemic stroke. We divided the patients into 2 groups: those who developed infections during the first 7 days after stroke onset and those who did not. We measured urinary norepinephrine and epinephrine concentrations and pulse rate variability indices within 24 hours of admission. RESULTS: We found that the number of circulating natural killer (NK) cells within the first hours after stroke was higher in stroke patients who developed infections (mean 435 cells/mL; 95% confidence interval [CI] 321-588) than in stroke patients who did not develop infections (mean 236 cells/mL; 95% CI 186-300; p = 0.001). This was followed by a decrease in all lymphocyte subsets from admission to day 1, varying between 22% and 40%, which was not seen in patients without poststroke infection (mean increase varied between 2% and 23%; all p < 0.005). In the group that developed infections, pulse rate variability revealed a decreased high frequency component. These findings all remained significant after adjustment for age and stroke volume. CONCLUSIONS: High circulating NK cell count within the first hours after ischemic stroke onset followed by a drop in all lymphocyte subsets identified patients who developed infections and may be caused by a sympathovagal imbalance with sympathetic overweight. These findings need to be validated in larger studies. PMID- 25738169 TI - GABAA receptor and LGI1 antibody encephalitis in a patient with thymoma. PMID- 25738170 TI - Varicella-zoster virus encephalitis mimicking toxoplasmosis relapse. PMID- 25738171 TI - Complement-associated neuronal loss in a patient with CASPR2 antibody-associated encephalitis. PMID- 25738172 TI - Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. AB - OBJECTIVE: To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of multiple sclerosis (MS) on leukocyte and lymphocyte subsets. METHODS: Peripheral blood leukocyte and lymphocyte subsets, including CD3(+), CD4(+), and CD8(+) T cells; CD19(+) B cells; and CD56(+) natural killer (NK) cells, were obtained at baseline and monitored at 3 months, 6 months, and 12 months after initiation of DMF treatment. RESULTS: Total leukocyte and lymphocyte counts diminished after 6 months of DMF therapy. At 12 months, lymphocyte counts had decreased by 50.1% (p < 0.0001) and were below the lower limit of normal (LLN) in one-half of patients. CD3(+) T lymphocyte counts fell by 44.2% (p < 0.0001). Among subsets, CD8(+) T cell counts declined by 54.6% (p < 0.0001), whereas CD4(+) T cell counts decreased by 39.2% (p = 0.0006). This disproportionate reduction of CD8(+) T cells relative to CD4(+) T cells was significant (p = 0.007) and was reflected by a 35.5% increase in the CD4/CD8 ratio (p = 0.007). A majority of CD8(+) T cell counts, but not CD4(+) T cell counts, were below the LLN even when total lymphocyte counts were greater than 500 cells/MUL. CD19(+) B cell counts were reduced by 37.5% (p = 0.035). Eosinophil levels decreased by 54.1% (p = 0.006), whereas levels of neutrophils, monocytes, basophils, and NK cells were not significantly altered. CONCLUSION: Subsets of peripheral blood leukocytes and lymphocytes are differentially affected by DMF treatment of MS. Reduction of CD8(+) T cells is more pronounced than that of CD4(+) T cells. These findings may have implications for cell mediated antiviral immunity during DMF treatment. PMID- 25738173 TI - The in vitro modulatory effect of TNFalpha on the mRNA expression and protein levels of zinc finger protein ZNF334 in CD4(+) lymphocytes of healthy people. AB - We have shown before that the expression of ZNF334 gene, coding for a newly described zinc finger protein of as yet unknown function, is extremely reduced in CD4(+) lymphocytes of rheumatoid arthritis (RA) patients regardless of their age, and thus can be considered a new molecular marker of the disease. Based on the promoter sequence of the gene we speculated that it might be regulated by TNFalpha. Here we have tested that hypothesis, studying the in vitro influence of TNFalpha on the ZNF334 gene expression and protein levels in resting and stimulated CD4(+) cells of healthy volunteers. We have confirmed that treatment with TNFalpha modifies the levels of ZNF334 expression in the CD4(+) cells ex vivo; however, the effect varied for different individuals and reduction of expression was seen only for those cell samples that initially exhibited high transcriptional activity of the gene, while for those exhibiting initially very low expression, some increase in the transcriptional activity was observed. Incubation with TNFalpha significantly reduced the amounts of two isoforms of ZNF334 protein (initially high in all subjects) in parallel to the reduced transcription. Finally, the expression of ZNF334 in CD4(+) lymphocytes isolated after various periods of anti-CD3 stimulation generally increased with longer culture times, and the effect of TNFalpha treatment was negligible. Concluding, our results obtained in vitro for helper lymphocytes of healthy individuals seem to mimic the regulatory effect of TNFalpha on the expression of ZNF334 in the cells of RA patients. PMID- 25738174 TI - Expression of RUNX2 and its signaling partners TCF7, FGFR1/2 in cleidocranial dysplasia. AB - RUNX2 is a member of the PEBP2/CBF transcription factors family controlling the expression of genes whose products are essential for bone formation. Mutations in the RUNX2 gene may be associated with cleidocranial dysplasia (CCD), a rare skeletal disease characterized by stature aberrations, delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and multiple dental abnormalities. As RUNX2 is involved in many signaling pathways, we hypothesize that CCD may be associated with their changes. We determined the expression of RUNX2 and its signaling partners TCF7, involved in canonical Wnt signaling, and fibroblast growth factor receptors, FGFR1 and FGFR2 in periodontum of CCD patients and control individuals. We did not observe any differences between the level of RUNX2, TCF7 and FGFR1/2 mRNA, determined by real-time PCR, in CDD patients and controls. Therefore, RUNX2 signaling pathways with their partners TCF7 and FGFR1/2 may not be involved in CCD pathogenesis. PMID- 25738175 TI - Editorial: a tribute to Professor Per-Ingvar Branemark. PMID- 25738176 TI - Efficacy of surgical and non-surgical interventions on accelerating orthodontic tooth movement: a systematic review. AB - PURPOSE: To conduct a systematic review of randomised controlled trials (RCTs) evaluating the effect of surgical and non-surgical procedures on the acceleration of orthodontic tooth movement (OTM) as an adjunct to orthodontic therapy (OT) in order to estimate the efficacy of these procedures and the benefit of their use in everyday orthodontic practice. MATERIALS AND METHODS: Literature search was performed on PubMed, Scopus, Web of Science and Cochrane databases up to July 2014. Inclusion criteria were: (1) RCTs; (2) orthodontic therapy on permanent dentition; (3) application of adjunctive surgical or non-surgical procedures for accelerating OTM; (4) measurement of tooth movement. The primary outcome measure was tooth movement expressed as cumulative tooth movement (CTM), rate of tooth movement (RTM) or time of tooth movement (TTM). Pain and discomfort, periodontal health, anchorage loss, bone and root changes, and undesired tooth movement were evaluated as secondary outcomes. RESULTS: Literature research identified 184 studies. After screening of titles, abstracts and full-text studies, fifteen fulfilled the inclusion criteria and were included in this review. Six of the included studies investigated the effect of corticotomies, one of interseptal bone reduction, four of lowlevel laser therapy (LLLT), three of intraoral/extraoral devices releasing extracorporeal shock waves (ESWT), pulsed electromagnetic field (PEMF) and electrical current, respectively, and one of injected substances (relaxin) as an adjunct to OT. Three studies resulted of high methodological quality, six of medium, and six of low quality. Interseptal bone reduction was reported to increase RTM during the first 2 months (P = 0.002) and CTM at 3 months (P = 0.003). Studies investigating corticotomy reported significantly increased RTM (up to 2.3 times) during the first months after intervention, whereas results on TTM and CTM were quite controversial ranging from non-significant to highly significant (up to three times of TTM increase). The heterogeneity between studies investigating corticotomy could not allow for quantitative synthesis of the findings. Out of four studies investigating LLLT three reported positive effect on OT. Due to inadequate statistical analysis of data from original articles, results could not be summarised in meta-analyses. Effects of both electrical current devices and PEMF devices on CTM were reported to be larger on the experimental sides than on the control sides (P < 0.001). The other interventions were reported to be of no statistical or clinical relevance. CONCLUSIONS: In the short term, corticotomy can accelerate OTM whereas long-term effects are questionable, thus no firm conclusions can be made on its efficacy and benefit of clinical use. There is some evidence that LLLT can slightly accelerate OTM but this result is not significant and the effect estimated is not clinically relevant. The very limited research-based evidence suggesting beneficial effects of interseptal bone reduction, electrical current and PEMF on OTM does not allow for solid conclusions. More high quality clinical research is required in order to estimate the efficacy of adjunctive interventions on accelerating OTM and their potential clinical use. PMID- 25738177 TI - Immediate loading of fixed cross-arch prostheses supported by flapless-placed supershort or long implants: 1-year results from a randomised controlled trial. AB - PURPOSE: To compare the outcome of cross-arch prostheses supported either by supershort (5 mm) or long (11.5 mm) implants, placed flapless and immediately restored with metal-resin screw-retained cross-arch prostheses. MATERIALS AND METHODS: Thirty patients with edentulous (or to be rendered edentulous) mandibles and 30 with edentulous maxillas, who had sufficient bone to allow the placement of four and six implants respectively, which were at least 11.5 mm-long, were randomised according to a parallel group design into 2 equal groups, where they received either 5 mm or 11.5 mm-long implants at one centre. Implants with a diameter of 5 mm, were to be placed flapless with an insertion torque of at least 50 Ncm. Mandibles received four implants between the mental foramina. Implants were to be immediately loaded with metal-resin-definitive prostheses on the same day of implant placement. Patients were followed up to 1 year after loading and the outcome measures were: prosthesis and implant failures, complications, and peri-implant marginal bone level changes. RESULTS: No patients dropped-out. Two prostheses were remade, one on short maxillary implants and one on long mandibular implants. Two 5 mm maxillary implants which did not achieve 50 Ncm torque in soft bone of one patient, but were immediately loaded anyway, failed after 3 weeks compared to one mandibular 11.5 mm-long implant that failed after 60 days. Two complications occurred in each group. There were no statistically significant differences for prosthesis failures, implant failures and complications. Patients with mandibular short implants lost on average 0.08 mm of peri-implant bone at 1 year and patients with long mandibular implants lost 0.51 mm. Patients with short maxillary implants lost on average 0.15 mm of peri implant bone at 1 year and patients with long maxillary implants lost 0.62 mm. Short implants showed less bone loss when compared to long implants and the differences up to 1 year were statistically significant both in maxillae (mean difference = 0.48 mm, 95% CI 0.22 to 0.73, P = 0.0011) and in mandibles (mean difference = 0.44 mm, 95% CI 0.21 to 0.66, P = 0.0009). CONCLUSIONS: Flapless placed 5 mm-long implants achieved similar results as 11.5 mm-long implants when supporting immediately loaded cross-arch prostheses both in maxillae and mandibles up to 1 year after loading. These preliminary results must be confirmed by other trials, and 5- to 10-year post-loading data is necessary before making reliable recommendations. PMID- 25738178 TI - Postextraction socket preservation using epithelial connective tissue graft vs porcine collagen matrix. 1-year results of a randomised controlled trial. AB - PURPOSE: To compare epithelial connective tissue graft vs porcine collagen matrix for sealing postextraction sockets grafted with deproteinised bovine bone. MATERIALS AND METHODS: A total of 30 patients, who needed a maxillary tooth to be extracted between their premolars and required a delayed, fixed, single implant supported restoration, had their teeth atraumatically extracted and their sockets grafted with deproteinised bovine bone. Patients were randomised according to a parallel group design into two arms: socket sealing with epithelial connective tissue graft (group A) vs porcine collagen matrix (group B). Outcome measures were: implant success and survival rate, complications, horizontal and vertical alveolar bone dimensional changes measured on Cone Beam computed tomography (CBCT) scans at three levels localised 1, 3, and 5 mm below the most coronal aspect of the bone crest (levels A, B, and C); and between the palatal and buccal wall peaks (level D); and peri-implant marginal bone level changes measured on periapical radiographs. RESULTS: 15 patients were randomised to group A and 15 to group B. No patients dropped out. No failed implants or complications were reported 1 year after implant placement. Five months after tooth extraction there were no statistically significant differences between the 2 groups for both horizontal and vertical alveolar bone dimensional changes. At level A the difference was 0.13 +/- 0.18; 95% CI 0.04 to 0.26 mm (P = 0.34), at level B it was 0.08 +/- 0.23; 95% CI -0.14 to 0.14 (P = 0.61), at level C it was 0.05 +/- 0.25; 95% CI -0.01 to 0.31 mm (P = 0.55) and at level D it was 0.13 +/- 0.27; 95% CI -0.02 to 0.32 mm (P = 0.67). One year after implant placement there were no statistically significant differences between the 2 groups for peri-implant marginal bone level changes (difference: 0.07 +/- 0.11 mm; 95% CI -0.02 to 0.16; P = 0.41). CONCLUSIONS: When teeth extractions were performed atraumatically and sockets were filled with deproteinised bovine bone, sealing the socket with a porcine collagen matrix or a epithelial connective tissue graft showed similar outcomes. The use of porcine collagen matrix allowed simplification of treatment because no palatal donor site was involved. PMID- 25738179 TI - Immediate loading with a novel implant featured by variable-threaded geometry, internal conical connection and platform shifting: three-year results from a prospective cohort study. AB - PURPOSE: To evaluate the clinical and radiological performance of an immediately loaded novel implant design over a 3-year period. MATERIALS AND METHODS: This prospective study includes 54 consecutive partially edentulous patients treated between December 2010 and October 2011. Outcome measures were: implant and prosthetic failures; biological and mechanical complications; marginal bone loss (MBL); sulcus bleeding index (SBI); and plaque score (PS). RESULTS: A total of 118 (29 narrow platform, 70 regular platform and 19 wide platform) NobelReplace Conical Connection implants were placed in both post-extraction sockets and healed sites and immediately loaded. The mean insertion torque was 63.4 +/- 7.1 Ncm. One hundred out of 118 implants (84.7%) were inserted with a torque ranging between 55 and 70 Ncm. Each patient received a single prosthesis. At the 3-year follow-up, no patient dropped out and only two post-extractive implants failed (1.7%) in two patients (3.7%). The only complication (1.9%) observed was an event of periimplantitis, consisting of a mean mesiodistal peri-implant bone loss of 3.2 mm reported in a healed site of a smoker patient at the 2-year follow-up examination. No prosthesis failures were detected. The cumulative mean MBL between implant placements at the 3-year follow-up was 0.68 mm (95% CI: 0.44, 0.92). At the 3-year follow-up session, the SBI and PS were 5.7% and 15.4%, respectively. CONCLUSIONS: The NobelReplace Conical Connection implant can be considered as a valuable treatment option for immediate implant placement and loading in the partially edentulous patients over a 3-year period. Insertion torques ranging between 55 and 70 Ncm are not detrimental to osseointegration. PMID- 25738181 TI - Cross-sectional study on the prevalence and risk indicators of peri-implant diseases. AB - PURPOSE: To evaluate the prevalence of peri-implant diseases in a university patient sample and to analyse possible risk variables associated with their occurrence. MATERIALS AND METHODS: One hundred and eighty-six patients with 597 implants were examined clinically and radiographically. The mean period of function was 5.5 years (range 1 to 16.5 years). A subgroup analysis was performed for implants with a minimum function time of 5 years. Outcome measures were implant failures, prevalence and risk indicators of peri-implant diseases. In order to identify statistically significant risk indicators of peri-implant mucositis and peri-implantitis multi-level logistic regression models were constructed. RESULTS: The prevalence of peri-implantitis and peri-implant mucositis on patient levels were 12.9% (13.3% for >= 5 years) and 64.5% (64.4% for >= 5 years), respectively. Multi-level analysis showed that a high plaque score (OR = 1.365; 95% CI: 1.18 to 1.57, P < 0.001) was a risk indicator for periimplant mucositis, while augmentation of the hard or soft tissue at implant sites had a protective effect (OR = 0.878 95% CI: 0.79 to 0.97, P = 0.01). It was also shown that the odds ratio for having peri-implant mucositis increased with the increase of plaque score in a dose-dependent manner. With respect to peri implantitis, loss of the last tooth due to periodontitis (OR = 1.063; 95% CI: 1.00 to 1.12, P = 0.03) and location of the implants in the maxilla (OR = 1.052, 95% CI: 1.00 to 1.09, P = 0.02) were identified as statistically significant risk indicators. CONCLUSIONS: Within the limitations of this study, the history of periodontal disease was the most significant risk indicator for peri-implantitis and the level of oral hygiene was significantly associated with peri-implant mucositis. PMID- 25738180 TI - How do peri-implant mucositis and gingivitis respond to supragingival biofilm control - an intra-individual longitudinal cohort study. AB - PURPOSE: This single-arm study to compare the gingival with peri-implant mucosal inflammatory response to a mechanical supragingival-supramucosal biofilm control program. MATERIALS AND METHODS: Twenty-two participants (55.7 +/- 11.2 years) with both gingivitis and periimplant mucositis were examined at days 0, 30 and 390 (full mouth/6 sites per tooth/implant [TTH/IMPL]) for visible plaque (VPI), gingival bleeding (GBI), modified plaque (mPlI) and bleeding indexes (mBI), probing depth (PD) and bleeding on probing (BOP). The biofilm control was carried out weekly in the first month and every 3 months thereafter. An intention-to treat analysis was performed (drop-out rate = 8) and linear models were used against comparisons in order to look at the clustering of TTH/IMPL by each individual. RESULTS: VPI/mPlI and GBI/mBI reduced from day 0 onwards. Intra-group reductions (P < 0.05) were observed at day 30. PD values (in mm) were higher (P < 0.001) for IMPL than for TTH [mean difference (95% CI) at day 0: -1.10 (-1.58 to 0.63); day 30: -0.88 (-1.28 to -0.48); and day 390: -0.60 (-0.84 to -0.33)], where both groups showed reductions (P < 0.05) throughout the study. BOP was greater (P = 0.00001) for IMPL at baseline [mean difference (95% CI): -0.24 ( 0.31 to -0.17)] but reduced (P = 0.00001) and showed similar levels to TTH from day 30 onwards. With regard to sites with the greatest PD, BOP reduced (P < 0.05) in both IMPL and TTH, with greater PD reductions observed for IMPL (P = 0.00001). CONCLUSIONS: The supragingival-supramucosal biofilm control benefited both teeth and implants. PMID- 25738183 TI - Enhanced FTIR bench-top imaging of single biological cells. AB - A new optical system has recently been developed that enables infrared images to be obtained with a pixel resolution of 1 micron on a bench-top instrument using a thermal source. We present here imaging data from two contrasting cellular systems that represent different challenges. Renal carcinoma cells cytospun onto CaF2 have a largely rounded morphology and thus suffer from strong resonant Mie scattering. Skin fibroblast cells, cultured onto CaF2 on the other hand are very spread out so scatter less strongly but are so thin they deliver extremely weak signals. Using suitable pre-processing methods, including PCA noise reduction and RMieS correction, we demonstrate that useful high resolution images can be obtained from either sample. PMID- 25738184 TI - Applications of tunable resistive pulse sensing. AB - Tunable resistive pulse sensing (TRPS) is an experimental technique that has been used to study and characterise colloidal particles ranging from approximately 50 nm in diameter up to the size of cells. The primary aim of this Review is to provide a guide to the characteristics and roles of TRPS in recent applied research. Relevant studies reflect both the maturation of the technique and the growing importance of submicron colloids in fields such as nanomedicine and biotechnology. TRPS analysis of extracellular vesicles is expanding particularly swiftly, while TRPS studies also extend to on-bead assays using DNA and aptamers, drug delivery particles, viruses and bacteria, food and beverages, and superparamagnetic beads. General protocols for TRPS measurement of particle size, concentration and charge have been developed, and a summary of TRPS technology and associated analysis techniques is included in this Review. PMID- 25738185 TI - A gold nanorod-based localized surface plasmon resonance platform for the detection of environmentally toxic metal ions. AB - Gold nanorods (Au NRs) are elongated nanoparticles with unique optical properties which depend on their shape anisometry. The Au NR-based longitudinal localized surface plasmon resonance (longitudinal LSPR) band is very sensitive to the surrounding local environment and upon the addition of target analytes, the interaction between the analytes and the surface of the Au NRs leads to a change in the longitudinal LSPR band. This makes it possible to devise Au NR probes with application potential to the detection of toxic metal ions with an improved limit of detection, response time, and selectivity for the fabrication of sensing devices. The effective surface modification of Au NRs helps in improving their selectivity and sensitivity toward the detection of toxic metal ions. In this review, we discuss different methods for the preparation of surface modified Au NRs for the detection of toxic metal ions based on the LSPR band of the Au NRs and the types of interactions between the surface of Au NRs and metal ions. We summarize the work that has been done on Au NR-based longitudinal LSPR detection of environmentally toxic metal ions, sensing mechanisms, and the current progress in various modified Au NR-based longitudinal LSPR sensors for toxic metal ions. Finally, we discuss the applications of Au NR-based longitudinal LSPR sensors to real sample analysis and some of the future challenges facing longitudinal LSPR based sensors for the detection of toxic metal ions toward commercial devices. PMID- 25738186 TI - Importance of platinum particle size for complete oxidation of toluene over Pt/ZSM-5 catalysts. AB - Size-controllable Pt nanoparticles ranging from 1.3 to 2.3 nm were successfully loaded onto ZSM-5 (Pt-x/ZSM-5, where x is the mean diameter of the Pt nanoparticles). Catalytic tests in complete oxidation of toluene as a model for VOC removal show that Pt-1.9/ZSM-5 has the highest activity, due to a balance of Pt dispersion and Pt(0) proportion. PMID- 25738187 TI - Highly efficient regioselective hydrosilylation of allenes using a [(3IP)Pd(allyl)]OTf catalyst; first example of allene hydrosilylation with phenyl and diphenylsilane. AB - A [(3IP)Pd(allyl)]OTf complex was shown to function efficiently and regioselectively in allene hydrosilylation with phenyl- and diphenylsilane. The catalyst also proved to be highly active for allene hydrosilylation employing a wide range of silanes, each of which produced a single regioisomer. PMID- 25738188 TI - Highly specific enrichment of N-glycoproteome through a nonreductive amination reaction using Fe3O4@SiO2-aniline nanoparticles. AB - A novel method based on the conjunction of aldehydes from oxidized glycopeptides to aniline groups on magnetic nanoparticles via nonreductive amination is reported for the highly selective enrichment of N-glycopeptides. For the first time, a nonreductive amination reaction has been introduced into N-glycoproteome extraction, and correspondingly a new type of aniline-functionalized nanoparticle has been designed and synthesized. PMID- 25738189 TI - Fluorescence and Forster resonance energy transfer investigations on DNA oligonucleotide and PAMAM dendrimer packing interactions in dendriplexes. AB - Considering the importance of short oligonucleotide packing in dendriplex mediated gene delivery, a direct insight into the 14-mer oligonucleotide and dendrimer interactions using fluorescence and FRET techniques is the focus of this study. Fluorometric titrations of various fluorophore-tagged oligonucleotides with the first three PAMAM dendrimer generations showed a decrease in the fluorescence intensity with two break points, namely Z and Z, for each titration. The first break point for each dendrimer was identical to the neutralization point observed by basic biophysical studies for the corresponding dendrimer generations. Additionally, FRET studies on dual tagged oligonucleotide (DFT) molecules revealed a third break point at the charge ratio (Z) where there was the highest fluorescence energy transfer from the donor to the acceptor fluorophores. Altogether, dendriplex formation was considered to take place via three steps with an increase in the dendrimer concentration, where initially there was monomeric complexation at the neutralization point (Z) followed by loosely held molecular aggregation of the dendrimer (Z). In the final step, dendrimer molecular aggregates were held tightly together for the closest possible packing of the oligonucleotide molecules onto their surface. The effective molecular packing is identified by the highest FRET intensity for the dendrimer of generation 2 at a charge ratio of 0.34 (Z+/-). PMID- 25738190 TI - Intramolecular charge transfer character in tetrathiafulvalene-annulated porphyrinoids: effects of core modification and protonation. AB - The synthesis, characterization, and photophysical and electrochemical properties of a novel tetrathiafulvalene (TTF)-annulated core-modified porphyrin (1) and its expanded rubyrin analogue (2) are described. The sulfur core modifications in 1 and 2 allow a feasible intramolecular charge transfer from the TTF fragments to the central conjugated core as inferred from comparative spectroscopic and electrochemical measurements. DFT calculations also support the intramolecular charge transfer nature of 1 and 2 upon excitation. Further the electronic perturbation of the TTF-annulated porphyrins was achieved by protonation, giving rise to a drastic change in the optical features with an extremely low energy band in the NIR region. The pronounced electron accepting ability of the macrocyclic core of the dicationic species (H21(2+) and H22(2+)) resulted in the thermally excited electron transfer occurring at room temperature as elucidated by EPR spectroscopy. PMID- 25738191 TI - Plasmonic resonance of Ag nanoclusters diffused in soda-lime glasses. AB - Silver nanoclusters were prepared in a soda-lime glass matrix through the ion exchange (Ag(+)<-> Na(+)) method followed by thermal annealing in an air atmosphere. The nanoscale patterning of Ag nanoclusters embedded in a soda lime glass matrix in an air atmosphere at different annealing temperatures has been investigated. During annealing, Ag(+) is reduced to Ag(0) and subsequently forms silver nanoparticles inside the glass matrix. A blue shift of 20 nm has been observed as a function of the post annealing temperature. The photoluminescence intensity is highest for an annealing temperature of 500 degrees C for 1 h and continuously decreases as annealing temperature increases up to 600 degrees C. The presence of spherical nanoparticles with a maximum particle size of 7.2 nm has been observed after annealing at 600 degrees C for 1 hour, which is consistent with Mie theory based results. PMID- 25738192 TI - Rate coefficients for the reaction of OH radicals with cis-3-hexene: an experimental and theoretical study. AB - The kinetics of the cis-3-hexene + OH reaction were investigated by an experimental relative rate method and at the density functional theory level. The experimental set-up consisted of a 200 L Teflon bag, operated at atmospheric pressure and 298 K. OH radicals were produced by the photolysis of H2O2 at 254 nm. Relative rate coefficients were determined by comparing the decays of the cis 3-hexene and reference compounds (cyclohexene, 2-buten-1-ol and allyl ether). The mean second-order rate coefficient value found was (6.27 +/- 0.66) * 10(-11) cm(3) molecule(-1) s(-1), the uncertainty being estimated by propagation of errors. Theoretical calculations for the addition reaction of OH to cis-3-hexene have also been performed, at the BHandHLYP/aug-cc-pVDZ level, in order to investigate the reaction mechanism, to clarify the experimental observations and to model the reaction kinetics. Different conformations of the reactants, pre barrier complexes and saddle points were considered in our calculations. The individual rate coefficients, calculated for each conformer of the reactant, at 298 K, using a microcanonical variational transition state method, are 4.19 * 10( 11) and 1.23 * 10(-10) cm(3) molecule(-1) s(-1). The global rate coefficient was estimated from the Boltzmann distribution of the conformers to be 8.10 * 10(-11) cm(3) molecule(-1) s(-1), which is in agreement with the experimental value. Rate coefficients calculated over the temperature range from 200-500 K are also given. Our results suggest that the complex mechanism, explicitly considering different conformations for the stationary points, must be taken into account for a proper description of the reaction kinetics. PMID- 25738193 TI - An unknown ruptured hepatic aneurysm and successful endovascular stent-graft. PMID- 25738194 TI - Who is the expert for the evaluation of work ability? PMID- 25738195 TI - Environmental (nongenetic) factors in gynecological cancers: update and future perspectives. AB - Globally, gynecological cancers comprise three of the seven most common female cancers and are responsible for more than 1,000,000 new cases and 500,000 deaths annually. This review summarizes current knowledge regarding the role of environmental factors in gynecological cancer etiology and survival, focusing on those that are potentially amenable to intervention. Strong associations with use of exogenous hormones are countered by opposing risks of breast cancer, thus current hormonal preparations are not an option for prevention. Weight control would reduce risk of endometrial cancer but this and other lifestyle modifications are unlikely to have a major effect on gynecological cancer mortality rates. There is little information regarding the potential for lifestyle changes to improve outcomes for women with gynecological cancer. PMID- 25738196 TI - Reply: To PMID 24052007. PMID- 25738197 TI - Response: good learning experiences emerge from unfortunate necessity. PMID- 25738198 TI - PET/CT in prostate cancer: an unmet clinical need. PMID- 25738199 TI - 18F-NaF PET/CT and 11C-Choline PET/CT for the initial detection of metastatic disease in prostate cancer: overview and potential utilization. AB - With the rapid increase in new therapies to treat advanced prostate cancer, improved diagnosis tools are necessary to help refine patient management throughout the entire disease course. Many radiopharmaceuticals, most of which are imaged using positron emission tomography/computed tomography (PET/CT), are in development; two of these newer radiopharmaceuticals are 18F-sodium fluoride (NaF) and radiolabeled choline. Compared with traditional imaging, use 18F-NaF has been shown to improve sensitivity and specificity, and radiolabeled choline has been shown to detect recurrent and metastatic disease earlier. We briefly review these two imaging technologies and provide potential utilization strategies based on available data. PMID- 25738200 TI - [T.O.B. Aasen & J. Kongerud reply]. PMID- 25738201 TI - Aristo Vojdani, PhD: environmental factors and autoimmune disease. PMID- 25738202 TI - The authors' reply. PMID- 25738203 TI - AMSSM: increasingly valuable for primary care sports and exercise medicine physicians. PMID- 25738204 TI - Evolution of musculoskeletal and non-musculoskeletal sports ultrasound. PMID- 25738205 TI - Sports ultrasound: a fundamental skill for sports medicine fellows moving forward. PMID- 25738206 TI - Ultrasonographic assessment of fractures: a break in tradition? PMID- 25738207 TI - Detection and characterization of SiO2 and TiO2 nanostructures in dietary supplements. AB - Nanomaterials are beginning to enter our daily lives through various consumer products as the result of technology commercialization. The development of methodologies to detect the presence of nanomaterials in consumer products is an essential element in understanding our exposure. In this study, we have developed methods for the separation and characterization of silicon dioxide (SiO2) and titanium dioxide (TiO2) nanostructures in dietary supplements marketed in products specifically targeted for women. A total of 12 commercial products claiming the inclusion of SiO2 and TiO2, but not making any claims regarding the particle size, were randomly selected for purchase through various retailers. To isolate nanostructures from these products, a simple methodology that combines acid digestion and centrifugation was utilized. Once isolated, the chemical composition, size, morphology, and crystal structure were characterized using mass spectroscopy, light scattering, electron microscopy, and X-ray diffraction techniques. SiO2 and TiO2 nanostructures were detected in 11 of 12 products using these methods. Many of the isolated nanoscale materials showed a high degree of aggregation; however, identified individual structures had at least one dimension below 100 nm. These robust methods can be used for routine monitoring of commercial products for nanoscale oxides of silica and titanium. PMID- 25738208 TI - Heteroaggregation between PEI-coated magnetic nanoparticles and algae: effect of particle size on algal harvesting efficiency. AB - Colloidal interactions between magnetic nanoparticles (NPs) and algal cells are of paramount significance to magnetophoretic separation of algal biomass from water. This study evaluated the size effect of magnetic NPs (MNPs) coated with polyethylenimine (PEI) on the separation efficiency of Scenedesmus dimorphus as well as on the recovery efficiency of MNPs from algal biomass. Results showed that algal harvesting efficiency (HE) increased from ca. 60% to 85% as the diameter of PEI-coated MNPs increased from 9 to 53 nm. Likewise, algal recovery capacity (algae/MNPs, w/w) also showed the same size dependence. But a large size (247 nm) led to a decline of algal HE, which was correctly interpreted by a settling model that predicts large sizes of MNPs could eventually reduce the settling velocity under magnetophoresis. The extended Derjaguin-Landau-Verwey Overbeek theory revealed that the particle size and PEI coating both influenced the interaction energies (e.g., energy barrier) between MNPs and algae. Particularly, PEI coating significantly reduced the energy barrier between MNPs and algae and thereby increased their heteroaggregation and algal HE. Moreover, PEI-coated MNPs were recovered from the harvested algae biomass through a chemical-free ultrasonic method, and the recovery efficiency appeared to be higher for larger MNPs. Overall, the synthesized sizes of applied MNPs will not only affect algal HE but also have economic implications on magnetophoretic algal separation technologies. PMID- 25738209 TI - Preprocessing of NMR metabolomics data. AB - Metabolomics involves the large scale analysis of metabolites and thus, provides information regarding cellular processes in a biological sample. Independently of the analytical technique used, a vast amount of data is always acquired when carrying out metabolomics studies; this results in complex datasets with large amounts of variables. This type of data requires multivariate statistical analysis for its proper biological interpretation. Prior to multivariate analysis, preprocessing of the data must be carried out to remove unwanted variation such as instrumental or experimental artifacts. This review aims to outline the steps in the preprocessing of NMR metabolomics data and describe some of the methods to perform these. Since using different preprocessing methods may produce different results, it is important that an appropriate pipeline exists for the selection of the optimal combination of methods in the preprocessing workflow. PMID- 25738210 TI - Three new secoiridoid glycosides from the rhizomes and roots of Gentiana scabra and their anti-inflammatory activities. AB - Three new (1-3) and 17 known (4-20) iridoid and secoiridoid glycosides were isolated from a methanol extract of the rhizomes and roots of Gentiana scabra. Their chemical structures were elucidated from 1D and 2D NMR, IR absorption, and HR-ESI-MS spectra, as well as comparisons of these data with reported values. The effects of the isolated compounds on lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells were investigated. Compounds 6, 10 and 20 exhibited significant inhibitory effects on LPS-induced IL-12 p40 and IL-6 production with IC50 values of 1.62-14.29 MUM. Compound 10 also showed a strong inhibitory effect on the LPS-stimulated production of TNF-alpha with an IC50 value of 10.45 MUM. PMID- 25738211 TI - Rapid detection of Cyprinid herpesvirus-3 (CyHV-3) using a gold nanoparticle based hybridization assay. AB - Cyprinid herpesvirus-3 (CyHV-3) is a highly infectious pathogen that causes fatal disease in common and koi carp Cyprinus carpio L. CyHV-3 detection is usually based on virus propagation or amplification of the viral DNA using the PCR or LAMP techniques. However, due to the limited susceptibility of cells used for propagation, it is not always possible to successfully isolate CyHV-3 even from tissue samples that have high virus titres. All previously described detection methods including PCR-based assays are time consuming, laborious and require specialized equipment. To overcome these limitations, gold nanoparticles (AuNPs) have been explored for direct and sensitive detection of DNA. In this study, a label-free colorimetric nanodiagnostic method for direct detection of unamplified CyHV-3 DNA using gold nanoparticles is introduced. Under appropriate conditions, DNA probes hybridize with their complementary target sequences in the sample DNA, which results in aggregation of the gold nanoparticles and a concomitant colour change from red to blue, whereas test samples with non complementary DNA sequences remain red. In this study, gold nanoparticles were used to develop and evaluate a specific and sensitive hybridization assay for direct and rapid detection of the highly infectious pathogen termed Cyprinid herpesvirus-3. PMID- 25738212 TI - Effects of Calcium Plus Vitamin D Supplementation on Anthropometric Measurements and Blood Pressure in Vitamin D Insufficient People with Type 2 Diabetes: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Up to 75% of the risk of type 2 diabetes is attributable to obesity. Therefore, finding a way to control obesity can be useful for management of diabetes. OBJECTIVE: This study was performed to assess the effects of vitamin D3 and calcium supplementation on anthropometric measurements and blood pressure in vitamin D insufficient people with type 2 diabetes. METHODS: One hundred eighteen patients with diabetes were enrolled in this randomized placebo-controlled clinical trial. All subjects were randomly assigned into 4 groups receiving (1) 50,000 IU/wk vitamin D3 plus (equal to 7143 IU/d) calcium placebo; (2) 1000 mg/d calcium plus vitamin D3 placebo; (3) 50,000 IU/wk vitamin D3 (equal to 7143 IU/d) plus 1000 mg/d calcium; or (4) vitamin D3 placebo plus calcium placebo for 8 weeks. Anthropometric measurements and blood pressure were assessed at study baseline and after 8 weeks of intervention. RESULTS: A greater reduction in body mass index was observed in calcium plus vitamin D group than other groups (p = 0.03). Comparison of changes in waist circumference among 4 groups revealed no significant difference in crude model (p = 0.21) and when the effect of confounders was taken into account (p = 0.08). Calcium supplementation resulted in a significant reduction in hip circumference compared to other groups (p <0.001). Systolic blood pressure significantly decreased in the calcium plus vitamin D group compared to placebo (-7.3 +/- 8.7 mmHg vs 0.5 +/- 8.2 mmHg; p = 0.001). However, calcium and vitamin D supplementation had no significant effects on diastolic blood pressure. CONCLUSION: Calcium-vitamin D3 cosupplementation can have beneficial effect on body mass index (BMI), hip circumference, and systolic blood pressure in vitamin D-insufficient type 2 diabetics. PMID- 25738213 TI - The impact of diabetes and diabetes medications on bone health. AB - Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures despite increased body weight and normal or higher bone mineral density. The mechanisms by which T2DM increases skeletal fragility are unclear. It is likely that a combination of factors, including a greater risk of falling, regional osteopenia, and impaired bone quality, contributes to the increased fracture risk. Drugs for the treatment of T2DM may also impact on the risk for fractures. For example, thiazolidinediones accelerate bone loss and increase the risk of fractures, particularly in older women. In contrast, metformin and sulfonylureas do not appear to have a negative effect on bone health and may, in fact, protect against fragility fracture. Animal models indicate a potential role for incretin hormones in bone metabolism, but there are only limited data on the impact of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists on bone health in humans. Animal models also have demonstrated a role for amylin in bone metabolism, but clinical trials in patients with type 1 diabetes with an amylin analog (pramlintide) have not shown a significant impact on bone metabolism. The effects of insulin treatment on fracture risk are inconsistent with some studies showing an increased risk and others showing no effect. Finally, although there is limited information on the latest class of medications for the treatment of T2DM, the sodium-glucose co-transporter-2 inhibitors, these drugs do not seem to increase fracture risk. Because diabetes is an increasingly common chronic condition that can affect patients for many decades, further research into the effects of agents for the treatment of T2DM on bone metabolism is warranted. In this review, the physiological mechanisms and clinical impact of diabetes treatments on bone health and fracture risk in patients with T2DM are described. PMID- 25738214 TI - The Chewing Lice (Insecta: Phthiraptera: Ischnocera: Amblycera) of Japanese Pigeons and Doves (Columbiformes), with Descriptions of Three New Species. AB - The chewing louse fauna of pigeons and doves in Japan is reviewed based on published records and new collections. An updated checklist of the chewing lice of Japanese pigeons and doves is provided, and 3 new species are described: Columbicola asukae n. sp. and Coloceras nakamurai n. sp., both from Columba janthina Temminck, 1830 (Japanese wood pigeon), and Columbicola lemoinei n. sp. from Treron formosae permagnus Stejneger, 1887, and Treron formosae medioximus (Bangs, 1901) (whistling green-pigeons). This checklist includes data on the first records of Coloceras chinense (Kellogg and Chapman, 1902), Coloceras piriformis ( Tendeiro, 1969 ), and Columbicola guimaraesi Tendeiro, 1965, in Japan. New host records of Hohorstiella sp. from Columba janthina and Treron formosae permagnus, and Coloceras sp. from Treron sieboldii sieboldii (Temminck, 1835) (white-bellied green-pigeon) are provided. PMID- 25738215 TI - Ethical issues when using social media for health outside professional relationships. AB - Social media have the potential to revolutionize health and healthcare, but fulfilling this potential requires attention to the ethical issues social media may raise. This article reviews the major ethical issues arising when social media are used for research, public health, mobile health applications, and global health. It focuses on social media use outside fiduciary relationships between healthcare professionals and patients. Emphasis is given to the potential of social media in these contexts, the ethical issues relatively unique to each, and where possible how existing ethical principles and frameworks could help navigate these issues. In some cases social media create the circumstance for particular ethical issues but also facilitate managing them, such as in informed consent for research. In other cases, disagreement exists about whether social media - despite their potential - should be used for certain purposes, such as in public health surveillance (where confidentiality represents a significant ethical concern). In still others, ethical uncertainty exists about how social media will affect ethical issues, such as inequality in global health. As social media technologies continue to develop, identifying and managing the ethical issues they raise will be critical to their success in improving health while preserving fundamental ethical values. PMID- 25738216 TI - Signalling pathways involved in oocyte growth, acquisition of competence and activation. AB - The oocyte's primary function is to be fertilised by a spermatozoon in order to create a viable embryo. Oocyte growth and development are initiated during embryogenesis and occur in parallel to follicular development. Factors produced by the oocyte bind to receptors on follicular cells, ensuring follicular development. Oocytes begin meiosis during foetal development and are arrested in prophase I by elevated levels of cyclic adenosine monophosphate (cAMP). Activation of mitogen-activated protein kinases triggers degradation of cAMP, allowing oocyte maturation to proceed. The production of progesterone and prostaglandins during the ovulation process ultimately activates proteases, whose action helps to release the oocyte into the Fallopian tube. Oocyte activation depends on fertilisation and is induced by changes in intracellular calcium levels. Dysregulation of these pathways is involved in the pathogenesis of several diseases including the syndrome of oocyte maturation failure. PMID- 25738217 TI - The complete mitogenome of the endangered white-clawed freshwater crayfish Austropotamobius pallipes (Lereboullet, 1858) (Crustacea: Decapoda: Astacidae). AB - The Austropotamobius pallipes complete mitogenome has been recovered using Next Gen sequencing. Our sample of A. pallipes has a mitogenome of 15,679 base pairs (68.44% A + T content) made up of 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs, and a 877 bp non-coding AT-rich region. This is the first mitogenome sequenced for a crayfish from the family Astacidae and the 4(th) for northern hemisphere genera. PMID- 25738218 TI - Base composition of the Danio chrysotaenitus complete mitochondrial genome. AB - In this study, 16 sets of primers were used to amplify contiguous, overlapping segments of the complete mitochondrial DNA (mtDNA) of Danio chrysotaenitus in order to characterize and compare their mitochondrial genomes. The total length of the mitochondrial genome is 16,608 bp and deposited in the GenBank with accession numbers KP407138. The organization of the mitochondrial genomes was similar to those reported from other Mountain carp fishes mitochondrial genomes containing 37 genes (13 protein-coding genes, 2 ribosomal RNA, and 22 transfer RNAs) and a major non-coding control region (D-loop region). Most genes were encoded on the H-strand, except for the ND6 and 8 tRNA genes, encoding on the L strand. The nucleotide skewness for the coding strands of Danio chrysotaenitus (AT-skew = 0.10, GC-skew = -0.25) is biased toward T and G. The complete mitogenome may provide important date set for the study of genetic mechanism of Danio chrysotaenitus. PMID- 25738219 TI - Mitochondrial genome of Boleophthalmus sp. nov. (Osteichthyes: Gobiidae). AB - Boleophthalmus is a genus that consists of six valid species and possesses a number of specializations in terms of amphibious life. The complete mtDNA sequence of Boleophthalmus sp. nov. (17,113 bp in length) has 13 protein-coding genes, 22 tRNA genes, two rRNA genes (12S and 16 S rRNA), and one control region. By comparing the COI sequences, Boleophthalmus sp. nov. is closely related of B. pectinirostris but exhibits 8.93% genetic distance with B. pectinirostris and 13.26% with B. boddarti. This finding may fill some gaps remaining on the taxonomy and biodiversity of this taxon and contribute to the understanding of the phylogeographic relationships between the continental coast and Southeast Asia. PMID- 25738221 TI - Patients Selected for Definitive Concurrent Chemoradiation at High-volume Facilities Achieve Improved Survival in Stage III Non-Small-Cell Lung Cancer. AB - BACKGROUND: The relationship between provider experience and clinical outcomes is poorly defined in radiation oncology. This study examined the impact of facility case volume on overall survival in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive concurrent chemoradiation therapy (CCRT). METHODS: Using the National Cancer Data Base, we identified clinical stage III NSCLC patients diagnosed in 2004 to 2006 who were treated with definitive CCRT to 59.4-74.0 Gy. High-volume facilities (HVF) were defined as those in the ninetieth percentile of annual CCRT volume (>=12 cases/year). Independent predictors of receiving CCRT at HVF were identified using multivariable logistic regression. Overall survival based on receiving CCRT at HVF was assessed using Kaplan-Meier analysis, Cox proportional hazards regression, and propensity score matching. RESULTS: Among 10,072 included patients, 1207 (12.0%) were treated at HVF. Patients in HVF were more likely to have a higher Charlson-Deyo comorbidity score, more advanced nodal stage, higher doses, and 3D-conformal or intensity modulated radiotherapy. When controlling for demographic and clinical covariates including academic affiliation, treatment at HVF was independently associated with a significantly decreased risk of death (hazards ratio = 0.93; 95% confidence interval: 0.87-0.99; p = 0.03). Propensity score matching showed that these findings were robust (hazards ratio = 0.91; 95% confidence interval: 0.84 0.99; p = 0.04). CONCLUSIONS: Our findings suggest that treatment at HVF is associated with improved overall survival among stage III NSCLC patients receiving definitive CCRT, independent of academic affiliation. Further research is needed to determine whether or not efforts supporting centralization of radiotherapy at HVF will improve population-based survival, toxicities, and costs. PMID- 25738220 TI - Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience. AB - INTRODUCTION: Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing and clinicopathologic correlations are presented. METHODS: Mutation testing in at least one of the eight genes (epidermal growth factor receptor [EGFR], KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, and PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing+/- peptide nucleic acid and/or sizing assays, along with anaplastic lymphoma kinase (ALK) and/or MET fluorescence in situ hybridization, were performed in six labs on 1007 patients from 14 institutions. RESULTS: In all, 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared with 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22%, 25%, 8.5%, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never-smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never smoking status and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never-smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK, or MET. CONCLUSION: Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations. PMID- 25738223 TI - Nonfilling carbon coating of porous silicon micrometer-sized particles for high performance lithium battery anodes. AB - Silicon is widely recognized as one of the most promising anode materials for lithium-ion batteries due to its 10 times higher specific capacity than graphite. Unfortunately, the large volume change of Si materials during their lithiation/delithiation process results in severe pulverization, loss of electrical contact, unstable solid-electrolyte interphase (SEI), and eventual capacity fading. Although there has been tremendous progress to overcome these issues through nanoscale materials design, improved volumetric capacity and reduced cost are still needed for practical application. To address these issues, we design a nonfilling carbon-coated porous silicon microparticle (nC-pSiMP). In this structure, porous silicon microparticles (pSiMPs) consist of many interconnected primary silicon nanoparticles; only the outer surface of the pSiMPs was coated with carbon, leaving the interior pore structures unfilled. Nonfilling carbon coating hinders electrolyte penetration into the nC-pSiMPs, minimizes the electrode-electrolyte contact area, and retains the internal pore space for Si expansion. SEI formation is mostly limited to the outside of the microparticles. As a result, the composite structure demonstrates excellent cycling stability with high reversible specific capacity (~1500 mAh g(-1), 1000 cycles) at the rate of C/4. The nC-pSiMPs contain accurate void space to accommodate Si expansion while not losing packing density, which allows for a high volumetric capacity (~1000 mAh cm(-3)). The areal capacity can reach over 3 mAh cm(-2) with the mass loading 2.01 mg cm(-2). Moreover, the production of nC pSiMP is simple and scalable using a low-cost silicon monoxide microparticle starting material. PMID- 25738222 TI - The Association Between Stimulant, Opioid, and Multiple Drug Use on Behavioral Health Care Utilization in a Safety-Net Health System. AB - BACKGROUND: Prior studies show an association between drug use and health care utilization. The relationship between specific drug type and emergent/urgent, inpatient, outpatient, and behavioral health care utilization has not been examined. We aimed to determine if multiple drug use was associated with increased utilization of behavioral health care. METHODS: To assess health care utilization, we conducted a retrospective cohort study of patients who accessed health care at a safety-net medical center and affiliated clinics. Using electronic health records, we categorized patients who used stimulants, opioids, or multiple drugs based on urine toxicology screening tests and/or International Classification of Diseases, 9th Revision (ICD-9). Remaining patients were categorized as patients without identified drug use. Health care utilization by drug use group and visit type was determined using a negative binomial regression model. Associations were reported as incidence rate ratios. Utilization was described by rates of health care-related visits for inpatient, emergent/urgent, outpatient, and behavioral health care among patients who used drugs, categorized by drug types, compared with patients without identified drug use. RESULTS: Of 95,198 index visits, 4.6% (n=4340) were by patients who used drugs. Opioid and multiple drug users had significantly higher rates of behavioral health care visits than patients without identified drug use (opioid incidence rate ratio [IRR]=7.2; 95% confidence interval [CI]: 3.8-13.8; multiple drug use IRR=5.6, 95% CI: 3.3-9.7). Patients who used stimulants were less likely to use behavioral health services (IRR=1.3, 95% CI: 0.9-2.0) when compared with opioid and multiple drug users, but were more likely to use inpatient (IRR=1.6, 95% CI: 1.4-1.8) and emergent/urgent care (IRR=1.4, 95% CI: 1.3-1.5) services as compared with patients without identified drug use. CONCLUSIONS: Integrated medical and mental health care and drug treatment may reduce utilization of costly health care services and improve patient outcomes. How to capture and deliver primary care and behavioral health care to patients who use stimulants needs further investigation. PMID- 25738224 TI - Magnetism and electronic structure calculation of SmN. AB - The results of the electronic structure calculations performed on SmN by using the LDA+U method with and without including the spin-orbit coupling are presented. Within the LDA+U approach, a N(2p) band polarization of about 0.3 MUB is induced by Sm(4f)-N(2p) hybridization, and a half-metallic ground state is obtained. By including spin-orbit coupling the magnetic structure was shown to be antiferromagnetic of type II, with Sm spin and orbital moments nearly cancelling. This results into a semiconducting ground state, which is in agreement with experimental results. PMID- 25738225 TI - Evaluation of the open time of calcium channels at variation potential generation in wheat leaf cells. AB - The role of ions in the generation and mechanism of propagation of variation potential (VP) has been widely investigated. It is likely that Ca(2+) influx via calcium channels is an initial stage of VP; however, development of long-term membrane depolarization requires prolonged open times of calcium channels. We investigated depolarization time in the present study. It was shown that local burning induced VP in wheat seedling and the electrical response was suppressed under EGTA presence. Depolarization formation, which may indicate open time of calcium channels at VP generation, was observed up to 30 s after reaction induction when calcium ions were added to initially calcium-free medium. Long term calcium channel open time may be the reason for long membrane depolarization at VP and may also be connected with the type of channels participating in wound reaction propagation. PMID- 25738226 TI - Antipodal crambescin A2 homologues from the marine sponge Pseudaxinella reticulata. Antifungal structure-activity relationships. AB - Investigation of antifungal natural products from the marine sponge Pseudaxinella reticulata from the Bahamas led to the discovery of new crambescin homologues (1, 2) and enantiomers (3, 4) of known natural products. The cyclic-guanidine structures were solved through analysis of 2D NMR, MS-MS, and CD data. The absolute configurations of 1-4 were established as 13R-opposite of known homologues reported from Crambe crambe obtained from the Mediterranean Sea-by comparison of their CD spectra with predicted Cotton effects obtained from DFT calculations. Antifungal activities of 1-4 against the pathogenic strains Candida albicans and Cryptococcus sp. were observed to correlate potency (MIC50 and MIC90) with the length of the alkyl side chain. PMID- 25738228 TI - A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. AB - Huntington's disease (HD) represents an important model for neurodegenerative disorders and proteinopathies. It is mainly caused by cytotoxicity of the mutant huntingtin protein (Htt) with an expanded polyQ stretch. While Htt is ubiquitously expressed, HD is characterized by selective neurodegeneration of the striatum. Here we report a striatal-enriched orphan G protein-coupled receptor(GPCR) Gpr52 as a stabilizer of Htt in vitro and in vivo. Gpr52 modulates Htt via cAMP-dependent but PKA independent mechanisms. Gpr52 is located within an intron of Rabgap1l, which exhibits epistatic effects on Gpr52-mediated modulation of Htt levels by inhibiting its substrate Rab39B, which co-localizes with Htt and translocates Htt to the endoplasmic reticulum. Finally, reducing Gpr52 suppresses HD phenotypes in both patient iPS-derived neurons and in vivo Drosophila HD models. Thus, our discovery reveals modulation of Htt levels by a striatal enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies. PMID- 25738229 TI - Tuning myosin-driven sorting on cellular actin networks. AB - Myosin V and VI are antagonistic motors that cohabit membrane vesicles in cells. A systematic study of their collective function, however, is lacking and forms the focus of this study. We functionally reconstitute a two-dimensional actin myosin interface using myosin V and VI precisely patterned on DNA nanostructures, in combination with a model keratocyte actin meshwork. While scaffolds display solely unidirectional movement, their directional flux is modulated by both actin architecture and the structural properties of the myosin lever arm. This directional flux can be finely-tuned by the relative number of myosin V and VI motors on each scaffold. Pairing computation with experimental observations suggests that the ratio of motor stall forces is a key determinant of the observed competitive outcomes. Overall, our study demonstrates an elegant mechanism for sorting of membrane cargo using equally matched antagonistic motors, simply by modulating the relative number of engagement sites for each motor type. PMID- 25738231 TI - Maytansinoid-BODIPY Conjugates: Application to Microscale Determination of Drug Extinction Coefficients and for Quantification of Maytansinoid Analytes. AB - Determining drug to antibody ratios (DAR) for antibody-drug conjugates (ADCs) in early research and development can be hampered by difficulties in accurate weighing of the effector payload and subsequent determination of its extinction coefficient. Two maytansinoids, DM1 and DM4, potent antimitotic agents used in clinical ADCs, were derivatized with the compact fluorophore BODIPY FL using two different linker designs. We identified DM1-mal-BODIPY as a conjugate with little through-space interaction between the maytansinoid and BODIPY chromophores. The 1:1 stoichiometry between the maytansinoid and BODIPY makes the molar concentration of both components equal and the extinction coefficient of the maytansinoid in proportion with the known BODIPY chromophore according to Beer's Law. By only derivatizing 50 MUg of unpurified DM1 and analyzing about 25 MUg of DM1-mal-BODIPY by UV-vis, we determined epsilonDM1 252 nm and epsilonDM1 280 nm as 26 355 +/- 360 and 5230 +/- 160 cm(-1) M(-1), respectively. These values are nearly identical to those accepted for DM1 based on weighing >100 mg of pure sample. Surprisingly, some of the maytansinoid-BODIPY conjugates that were synthesized were partially or completely fluorescence-quenched. The green fluorescence of quenched DM4-acetamide-BODIPY could be fully restored in the presence of an antibody designed to tightly bind maytansine. We exploited this observation to develop a simple "mix and read" fluorogenic immunoassay for detection of nanogram quantities of maytansinoids. PMID- 25738233 TI - Transition-metal-free direct anti-carboboration of alkynes with boronic acids to produce alkenylheteroarenes. AB - The transition-metal-free intermolecular direct 1,2-carboboration reaction of heteroarylacetylenes using boronic acids as reagents is achieved by utilizing tartaric acid as promoter. The reaction proceeds with excellent regioselectivity and anti stereoselectivity to afford boroxole frameworks. The resulting compounds are of use for the stereoselective preparation of polysubstituted alkenylheteroarenes. PMID- 25738230 TI - Mitochondrial dynamics in diabetic cardiomyopathy. AB - SIGNIFICANCE: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca(2+) handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. RECENT ADVANCES: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. CRITICAL ISSUES: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. FUTURE DIRECTIONS: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. PMID- 25738234 TI - A Pilot Test of the Additive Benefits of Physical Exercise to CBT for OCD. AB - The majority of "responders" to first-line cognitive-behavioural therapy (CBT) and pharmacological treatments for obsessive-compulsive disorder (OCD) are left with residual symptoms that are clinically relevant and disabling. Therefore, there is pressing need for widely accessible efficacious alternative and/or adjunctive treatments for OCD. Accumulating evidence suggests that physical exercise may be one such intervention in the mood and anxiety disorders broadly, although we are aware of only two positive small-scale pilot studies that have tested its clinical benefits in OCD. This pilot study aimed to test the feasibility and preliminary efficacy of adding a structured physical exercise programme to CBT for OCD. A standard CBT group was delivered concurrently with a 12-week customized exercise programme to 11 participants. The exercise regimen was individualized for each participant based on peak heart rate measured using an incremental maximal exercise test. Reports of exercise adherence across the 12 week regimen exceeded 80%. A paired-samples t-test indicated very large treatment effects in Yale-Brown Obsessive-Compulsive Scale scores from pre- to post treatment in CBT group cohorts led by expert CBT OCD specialists (d = 2.55) and junior CBT clinician non-OCD specialists (d = 2.12). These treatment effects are very large and exceed effects typically observed with individual and group-based CBT for OCD based on leading meta-analytic reviews, as well as previously obtained treatment effects for CBT using the same recruitment protocol without exercise. As such, this pilot work demonstrates the feasibility and significant potential clinical utility of a 12-week aerobic exercise programme delivered in conjunction with CBT for OCD. PMID- 25738232 TI - Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample. AB - IMPORTANCE: Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. OBJECTIVES: To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. DESIGN, SETTING, AND PARTICIPANTS: We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs). MAIN OUTCOMES AND MEASURES: Participants underwent screening using a population based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis. RESULTS: On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%]). CONCLUSIONS AND RELEVANCE: The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD. PMID- 25738235 TI - Global consensus on keratoconus and ectatic diseases. AB - BACKGROUND: Despite extensive knowledge regarding the diagnosis and management of keratoconus and ectatic corneal diseases, many controversies still exist. For that reason, there is a need for current guidelines for the diagnosis and management of these conditions. PURPOSE: This project aimed to reach consensus of ophthalmology experts from around the world regarding keratoconus and ectatic diseases, focusing on their definition, concepts, clinical management, and surgical treatments. METHODS: The Delphi method was followed with 3 questionnaire rounds and was complemented with a face-to-face meeting. Thirty-six panelists were involved and allocated to 1 of 3 panels: definition/diagnosis, nonsurgical management, or surgical treatment. The level of agreement considered for consensus was two thirds. RESULTS: Numerous agreements were generated in definitions, methods of diagnosing, and management of keratoconus and other ectatic diseases. Nonsurgical and surgical treatments for these conditions, including the use of corneal cross-linking and corneal transplantations, were presented in a stepwise approach. A flowchart describing a logical management sequence for keratoconus was created. CONCLUSIONS: This project resulted in definitions, statements, and recommendations for the diagnosis and management of keratoconus and other ectatic diseases. It also provides an insight into the current worldwide treatment of these conditions. PMID- 25738236 TI - Pythium insidiosum keratitis: clinical profile and role of DNA sequencing and zoospore formation in diagnosis. AB - PURPOSE: To report the molecular and microbiological diagnosis and clinical profile of 13 patients with Pythium insidiosum keratitis. METHODS: Phase 1 of the study consisted of DNA sequencing of the ITS region of the rDNA of 162 stocked morphologically unidentified nonconsecutive fungal isolates from corneal scraping of patients with keratitis (2010-2012). Blast and phylogenetic analyses of the sequences showed 9 to be P. insidiosum. A retrospective review of archived photographs of colony and direct microscopy of corneal scrapings and clinical records of the cases were performed. Phase 2 began in 2014, in which a simple method of zoospore formation was used for fungal colonies resembling those of P. insidiosum followed by DNA sequencing. RESULTS: The prevalence of P. insidiosum among unidentified fungal isolates from keratitis was 9/162 (5.5%) in phase 1. In phase 2, 4/102 cases (3.9%) of fungal keratitis were identified as P. insidiosum (January-February, 2014). Phylogenetic analysis of all 13 fungal isolates confirmed the identification of P. insidiosum. Corneal infiltrates exhibited hyphate edges, tentacle-like extensions, and dot-like infiltrates surrounding the main infiltrate. Response to topical 5% natamycin eye drops with or without oral antifungals was poor (penetrating keratoplasty: 9 and evisceration: 2) with a mean follow-up period of 82 days. CONCLUSIONS: P. insidiosum keratitis needs to be considered in the differential diagnosis of severe fungal keratitis. It can be identified using the zoospore formation method and confirmed by ITS DNA sequencing. Lack of response to currently used antifungal drugs calls for evaluation of newer drugs for medical therapy and consideration for early penetrating keratoplasty. PMID- 25738237 TI - All sweeping may not be equal. A comment on "factors affecting DSAEK graft lenticle adhesion: an in vitro experimental study". PMID- 25738238 TI - The many etiologies of neonatal hypocalcemic seizures. AB - Seizures during the neonatal period have a broad differential diagnosis. Unlike in developing countries where hypovitaminosis D and hypocalcemia constitutes a major cause of infantile seizures, the number of neonatal seizures attributed to hypocalcemia in developed countries has decreased dramatically due to the improvement of infant formulas and vitamin D supplementation. In these countries, most infants that present with hypocalcemic seizures have underlying endocrinological etiologies rather than dietary insufficiencies. Here, we describe 3 cases of neonatal seizures due to hypocalcemia. Although the symptoms and calcium concentrations at presentation were similar in all 3 cases, the course of the disease and the final diagnosis for each were distinct. The cases are presented along with a brief review of the pathophysiology, differential diagnosis, and treatment of neonatal hypocalcemia. PMID- 25738239 TI - Gastric adenocarcinoma presenting with thromboembolism in a 13-year-old boy. AB - Abdominal pain is a frequent complaint in the pediatric emergency department. A 13-year-old boy presented with complaints of abdominal pain, hematemesis, headache, and leg pain. Further investigation revealed an advanced-stage gastric adenocarcinoma with multiple thromboembolism including the greater saphenous vein and nonbacterial thrombotic endocarditis. This case points out the challenges of diagnosing this rare condition and treating the primary tumor and thromboembolism in the setting of both hypercoagulable state and gastrointestinal bleeding. PMID- 25738240 TI - An unusual presentation of hydrochloric acid ingestion: a mystery unraveled. AB - BACKGROUND: Unintentional acid ingestion is less commonly encountered than alkali ingestion. The injury develops for hours to days after ingestion and often results in progressively increasing difficulty in airway management. However, gastric perforation is rare. CASE: A 3-year-old boy presented to us with an orotonsillopharyngeal membrane and severe upper airway obstruction. Subsequently, he was diagnosed with a case of gastric perforation due to unintentional hydrochloric acid ingestion. He was treated with partial gastrectomy and feeding jejunostomy, and the recovery was good. CONCLUSIONS: Unintentional hydrochloric acid ingestion is rare in children. The manifestations masquerade many other clinical conditions, and the diagnosis is difficult in cases in which history of ingestion is not available. Treatment is symptomatic, and emergency surgery is indicated in case of gastrointestinal perforation. PMID- 25738241 TI - Fishhook injury to the eyelid: case report and review of removal methods. AB - Fishhook injuries are most commonly seen among adult and adolescent anglers. However, children can also be injured by fishhooks. We present the case of an 11 year-old boy with an eyelid fishhook injury that was successfully managed in the emergency department. We review a variety of procedures that can be used to remove embedded fishhooks, including the suitability, advantages, and disadvantages of each method. PMID- 25738242 TI - Pediatric emergency medicine: legal briefs. PMID- 25738243 TI - A 12-year-old girl with seizures after intentional drug overdose. Bupropion overdose. PMID- 25738244 TI - A 3-year-old boy with ataxia. AB - Complications that arise secondary to functional malabsorptive conditions, such as short bowel syndrome, can present with a wide variety of symptoms. One in particular, D-lactic acidosis, causes a neurologic syndrome characterized by altered mental status, slurred speech, and ataxia, typically after a large carbohydrate meal. The neurologic deterioration can mimic inebriation and has therefore been dually named D-lactate encephalopathy. We present a case of D lactic acidosis in a 3-year-old patient with short bowel syndrome. Although relatively rare, physicians must remain vigilant in their clinical suspicion of this syndrome whenever neurologic symptoms develop in patients with functional malabsorptive conditions. PMID- 25738245 TI - Point-of-care ultrasound detection of acute scaphoid fracture. AB - In cases of traumatic wrist pain, emergency physicians must maintain a high index of suspicion for scaphoid fractures due to their potential for serious complications. A growing body of literature supports the use of point-of-care ultrasonography by emergency physicians in the evaluation of potential fractures. We report a case of a pediatric scaphoid fracture that was initially not visualized on x-ray and was subsequently detected using point-of-care ultrasound in the ED. PMID- 25738246 TI - Os odontoideum. PMID- 25738247 TI - ECGs in the ED. PMID- 25738249 TI - Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1. AB - Pemetrexed is a multitargeted antifolate used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). However, the mechanism by which pemetrexed induces apoptosis remains unclear. In the present study, we investigated the involvement of reactive oxygen species (ROS) and sirtuin 1 (SIRT1) in pemetrexed-induced apoptosis in MSTO-211 malignant mesothelioma cells and A549 NSCLC cells. Pemetrexed enhanced caspase-dependent apoptosis, induced intracellular ROS generation, and downregulated SIRT1 in the MSTO-211 and A549 cells. Pemetrexed-induced apoptosis, which was prevented by pretreatment with N acetyl-cysteine (NAC), was mediated by effects on the mitochondria, including mitochondrial membrane potential transition (MPT) and cytosolic release of cytochrome c, and also involved regulation of SIRT1 expression. Interference with SIRT1 expression using siRNA enhanced pemetrexed-induced apoptosis through mitochondrial dysfunction and ROS generation, whereas resveratrol, an activator of SIRT1, protected against pemetrexed-induced apoptosis. These results show that pemetrexed induces apoptosis in MSTO-211 mesothelioma cells and A549 NSCLC cells through mitochondrial dysfunction mediated by ROS accumulation and SIRT1 downregulation. PMID- 25738251 TI - Now or never? The case for cell-based immunosuppression in kidney transplantation. AB - By exploiting mechanisms of immunological regulation against donor alloantigen, it may be possible to reduce the dependence of kidney transplant recipients upon calcineurin inhibitor-based maintenance immunosuppression. One means to strengthen regulatory responses is treating recipients with preparations of regulatory cells obtained by ex vivo manipulation. This strategy, which is a well established experimental method, has been developed to the point that early-phase clinical trials in kidney transplantation are now feasible. Cell-based therapies represent a radical departure from conventional treatment, so what grounds are there for this new approach? This article offers a three-part justification for trialing cell-based therapies in kidney transplantation: first, a clinical need for alternatives to standard immunosuppression is identified, based on the inadequacies of calcineurin inhibitor-based regimens in preventing late allograft loss; second, a mechanistic explanation of how cell-based therapies might address this clinical need is given; and third, the possible benefit to patients is weighed against the potential risks of cell-based immunosuppressive therapy. It is concluded that the safety of cell-based immunosuppressive therapy will not be greatly improved by further basic scientific and preclinical development. Only trials in humans can now tell us whether cell-based therapy is likely to benefit kidney transplant recipients, but these should be conservative in design to minimize any potential harm to patients. PMID- 25738250 TI - Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report. AB - Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1beta (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease. PMID- 25738252 TI - The diffuse extent of peritubular capillaritis in renal allograft rejection is an independent risk factor for graft loss. AB - By the Banff classification, the score of peritubular capillaritis, its extent, and its cellular composition should normally be reported in renal allograft pathology. While the score represents an important diagnostic and prognostic variable, the clinical value of capillaritis extent or composition has yet to be resolved. In a retrospective study of 749 renal transplant recipients subjected to 1322 indication biopsies, we found that prevalence scores of 1, 2, or 3 in the biopsy specimens were 10.7, 11.6, and 2.6%, respectively. Focal and diffuse peritubular capillaritis (inflammation over 50% of cortical peritubular capillaries) was diagnosed in 10.5 or 14.4% of cases, respectively. Mononuclear, granulocytic, and mixed peritubular capillaritis was present in 13.1, 3.3, and 8.5%, respectively. While peritubular capillaritis without further subclassification was not related to higher allograft loss rates, a score of 3 (hazard ratio 2.57 (CI: 1.25-5.28)) and diffuse peritubular capillaritis (1.67 (1.1-2.54)) were significant impartial risk factors for allograft loss. Diffuse peritubular capillaritis was independently associated with features of chronic antibody-mediated rejection and greater eGFR decline after 3 years. In contrast, detailed report of leukocytic composition in peritubular capillaritis did not confer additional prognostic information. Thus, in contrast to typing the infiltrating inflammatory cells, the score and extent of peritubular capillaritis in kidney allograft pathology is essential to assess transplant prognosis. PMID- 25738253 TI - Novel in vivo techniques to visualize kidney anatomy and function. AB - Intravital imaging using multiphoton microscopy (MPM) has become an increasingly popular and widely used experimental technique in kidney research over the past few years. MPM allows deep optical sectioning of the intact, living kidney tissue with submicron resolution, which is unparalleled among intravital imaging approaches. MPM has solved a long-standing critical technical barrier in renal research to study several complex and inaccessible cell types and anatomical structures in vivo in their native environment. Comprehensive and quantitative kidney structure and function MPM studies helped our better understanding of the cellular and molecular mechanisms of the healthy and diseased kidney. This review summarizes recent in vivo MPM studies with a focus on the glomerulus and the filtration barrier, although select, glomerulus-related renal vascular and tubular functions are also mentioned. The latest applications of serial MPM of the same glomerulus in vivo, in the intact kidney over several days, during the progression of glomerular disease are discussed. This visual approach, in combination with genetically encoded fluorescent markers of cell lineage, has helped track the fate and function (e.g., cell calcium changes) of single podocytes during the development of glomerular pathologies, and provided visual proof for the highly dynamic, rather than static, nature of the glomerular environment. Future intravital imaging applications have the promise to further push the limits of optical microscopy, and to advance our understanding of the mechanisms of kidney injury. Also, MPM will help to study new mechanisms of tissue repair and regeneration, a cutting-edge area of kidney research. PMID- 25738254 TI - MicroRNA-494 promotes cervical cancer proliferation through the regulation of PTEN. AB - The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway appears to be a key regulator in cervical carcinogenesis. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is principally involved in the homeostatic maintenance of PI3K/Akt signaling and PTEN has been identified to play an important role in the occurrence and development of cervical cancer. MicroRNA (miRNA)-494 has been proven to be involved in the carcinogenesis and development of various types of cancer by directly targeting PTEN. However the role, mechanism and clinical significance of miR-494 in cervical cancer have not been further reported. In the present study, we analyzed the expression of miR-494 in with PTEN expression and clinicopathological data of cervical cancer patients. The results showed that miR-494 expression was significantly upregulated in human cervical cancer cell lines and tissues. miR-494 upregulation was significantly associated with PTEN downregulation, adverse clinicopathological characteristics, poor overall and progression-free survival and poor prognosis. In vitro experiments showed that inhibition of miR-494 suppressed cell proliferation and growth by directly targeting the 3'-untranslated region (3'-UTR) of PTEN mRNA. These findings identified a novel molecular mechanism involved in the regulation of PTEN expression and cervical cancer progression. Results of the present study indicated that miR-494 may have an essential role in the carcinogenesis and progression of cervical cancer and targeting miR-494 may be a promising therapeutic strategy for the treatment of cervical cancer. PMID- 25738255 TI - Ligustrazine attenuates the platelet-derived growth factor-BB-induced proliferation and migration of vascular smooth muscle cells by interrupting extracellular signal-regulated kinase and P38 mitogen-activated protein kinase pathways. AB - The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) leads to intimal thickening of the aorta and is, therefore, important in the development of arteriosclerosis. As a result, the use of antiproliferative and antimigratory agents for VSMCs offers promise for the treatment of vascular disorders. Although several studies have demonstrated that ligustrazine may be used to treat heart and blood vessel diseases, the detailed mechanism underlying its actions remain to be elucidated. In the present study, the inhibitory effect of ligustrazine on platelet-derived growth factor (PDGF)-BB-stimulated VSMC proliferation and migration, and the underlying mechanisms were investigated. The findings demonstrated that ligustrazine significantly inhibited PDGF-BB stimulated VSMC proliferation. VSMCs dedifferentiated into a proliferative phenotype under PDGF-BB stimulation, which was effectively reversed by the administration of ligustrazine. In addition, ligustrazine also downregulated the production of nitric oxide and cyclic guanine monophosphate, induced by PDGF-BB. Additionally, ligustrazine significantly inhibited PDGF-BB-stimulated VSMC migration. Mechanistic investigation indicated that the upregulation of cell cycle-associated proteins and the activation of the extracellular signal regulated kinase (ERK) and P38 mitogen-activated protein kinase (MAPK) signaling induced by PDGF-BB was suppressed by the administration of ligustrazine. In conclusion, the present study, demonstrated for the first time, to the best of our knowledge, that ligustrazine downregulated PDGF-BB-induced VSMC proliferation and migration partly, at least, through inhibiting the activation of the ERK and P38 MAPK signaling. PMID- 25738256 TI - From vesicles to protocells: the roles of amphiphilic molecules. AB - It is very challenging to construct protocells from molecular assemblies. An important step in this challenge is the achievement of vesicle dynamics that are relevant to cellular functions, such as membrane trafficking and self reproduction, using amphiphilic molecules. Soft matter physics will play an important role in the development of vesicles that have these functions. Here, we show that simple binary phospholipid vesicles have the potential to reproduce the relevant functions of adhesion, pore formation and self-reproduction of vesicles, by coupling the lipid geometries (spontaneous curvatures) and the phase separation. This achievement will elucidate the pathway from molecular assembly to cellular life. PMID- 25738257 TI - Mechanisms of High Temperature Resistance of Synechocystis sp. PCC 6803: An Impact of Histidine Kinase 34. AB - Synechocystis sp. PCC 6803 is a widely used model cyanobacterium for studying responses and acclimation to different abiotic stresses. Changes in transcriptome, proteome, lipidome, and photosynthesis in response to short term heat stress are well studied in this organism, and histidine kinase 34 (Hik34) is shown to play an important role in mediating such response. Corresponding data on long term responses, however, are fragmentary and vary depending on parameters of experiments and methods of data collection, and thus are hard to compare. In order to elucidate how the early stress responses help cells to sustain long-term heat stress, as well as the role of Hik34 in prolonged acclimation, we examined the resistance to long-term heat stress of wild-type and DeltaHik34 mutant of Synechocystis. In this work, we were able to precisely control the long term experimental conditions by cultivating Synechocystis in automated photobioreactors, measuring selected physiological parameters within a time range of minutes. In addition, morphological and ultrastructural changes in cells were analyzed and western blotting of individual proteins was used to study the heat stress-affected protein expression. We have shown that the majority of wild type cell population was able to recover after 24 h of cultivation at 44 degrees C. In contrast, while DeltaHik34 mutant cells were resistant to heat stress within its first hours, they could not recover after 24 h long high temperature treatment. We demonstrated that the early induction of HspA expression and maintenance of high amount of other HSPs throughout the heat incubation is critical for successful adaptation to long-term stress. In addition, it appears that histidine kinase Hik34 is an essential component for the long term high temperature resistance. PMID- 25738259 TI - Erratum to "Doubling Down on the PI3K-AKTmTOR Pathway Enhances the Antitumor Efficacy of PARP Inhibitor in Triple Negative Breast Cancer Model beyond BRCA ness" [Neoplasia 16 (2014) 43-72]. AB - [This corrects the article DOI: 10.1593/neo.131694.]. PMID- 25738260 TI - Peculiar terminals in light at the extreme. AB - Materials with both relative permeability and permittivity near zero offer unprecedented features in light-matter interactions. Here, we explore how terminal endings involving bound regions of such materials may exhibit unusual electromagnetic behaviour. Physical intuitions and potential implications of such peculiar effects are also discussed. PMID- 25738258 TI - Immune-enhancing effect of nano-DNA vaccine encoding a gene of the prME protein of Japanese encephalitis virus and BALB/c mouse granulocyte-macrophage colony stimulating factor. AB - Plasmid-encoded granulocyte-macrophage colony-stimulating factor (GM-CSF) is an adjuvant for genetic vaccines; however, how GM-CSF enhances immunogenicity remains to be elucidated. In the present study, it was demonstrated that injection of a plasmid encoding the premembrane (prM) and envelope (E) protein of Japanese encephalitis virus and mouse GM-CSF (pJME/GM-CSF) into mouse muscle recruited large and multifocal conglomerates of macrophages and granulocytes, predominantly neutrophils. During the peak of the infiltration, an appreciable number of immature dendritic cells (DCs) appeared, although no T and B-cells was detected. pJME/GM-CSF increased the number of splenic DCs and the expression of major histocompatibility complex class II (MHCII) on splenic DC, and enhanced the antigenic capture, processing and presentation functions of splenic DCs, and the cell-mediated immunity induced by the vaccine. These findings suggested that the immune-enhancing effect by pJME/GM-CSF was associated with infiltrate size and the appearance of integrin alphax (CD11c)+cells. Chitosan-pJME/GM-CSF nanoparticles, prepared by coacervation via intramuscular injection, outperformed standard pJME/GM-CSF administrations in DC recruitment, antigen processing and presentation, and vaccine enhancement. This revealed that muscular injection of chitosan-pJME/GM-CSF nanoparticles may enhance the immunoadjuvant properties of GM-CSF. PMID- 25738261 TI - ACK1 promotes hepatocellular carcinoma progression via downregulating WWOX and activating AKT signaling. AB - Several studies have revealed that ACK1 is upregulated in various cancers and promotes tumor progression. However, the role and mechanism of ACK1 in hepatocellular carcinoma (HCC) remains unknown. In this study, the expression of ACK1 was assessed in several cell lines and 150 pairs of HCC and adjacent noncancerous liver tissues. The protein expression of p-ACK1 and WWOX were detected by immunohistochemistry to evaluate their correlation with ACK1. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay, MTT assay and Transwell assay were used to detect apoptosis, proliferation, invasion and migration of HCC cells. The regulatory effect of ACK1 on WWOX, AKT, p-AKT, MMP2 and MMP9 in HCC cells was confirmed by immuno-blotting. We found that ACK1 was more highly expressed in HCC tissues than in non-HCC tissues, and over-expression of ACK1 was correlated with clinicopathological features of poor prognosis. Clinical analysis demonstrated that ACK1 is an independent prognostic marker for predicting overall survival and disease-free survival of HCC patients. Pearson's correlation coefficient analysis indicated that ACK1 was positively associated with p-ACK1 and was negatively associated with WWOX expression. In vitro studies showed that knockdown of ACK1 promoted HCC cell apoptosis and repressed HCC cells invasion, migration and proliferation. Furthermore, knockdown of ACK1 resulted in upregulation of WWOX and inactivation of AKT signaling. In this study, we also found that knockdown of ACK1 resulted in the downregulation of MMP2 and MMP9 in HCC. Our results indicate that ACK1 is an independent prognostic marker and promotes HCC progression via downregulating WWOX and activating AKT signaling. PMID- 25738262 TI - Protective effect of ixerisoside A against UVB-induced pro-inflammatory cytokine production in human keratinocytes. AB - Human skin is the first line of defense for the protection of the internal organs of the body from different stimuli. Ultraviolet B (UVB), one of the harmful radiations for skin, is widely known to induce abnormally increased cytokine release from keratinocytes leading to inflammatory skin disorders. IL-6 and IL-8 induce an acute-phase response and stimulate leukocyte infiltration in the skin. Previous studies have shown that chronic exposure to UVB radiation increases cyclooxygenase-2 (COX-2) expression through various cell signaling pathways, resulting in skin cancer. Recent studies have shown that the activation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPK is strongly correlated with acute inflammation and development of skin cancer caused by an increased expression of COX-2. Ixerisoside A (IXA) is an active constituent of Ixeris dentata of the Compositae (Asteraceae) family. The effect of IXA on skin inflammation has yet to be elucidated. To determine the anti-inflammatory effects of IXA, we examined its effect on UVB-induced pro inflammatory cytokine production in human keratinocytes (HaCaT cells) by observing these cells in the presence or absence of IXA. In this study, pro inflammatory cytokine production was determined by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (rt-pcr), and western blot analysis to evaluate the activation of mitogen-activated protein kinases (MAPKs). IXA inhibited UVB-induced production of the pro-inflammatory cytokines IL-6 and IL-8 in a dose-dependent manner. Moreover, IXA inhibited the expression of COX-2, ERK, JNK, and p38 MAPKs, indicating that the secretion of the pro-inflammatory cytokines IL-6 and IL-8, and COX-2 expression was inhibited by blocking MAPK phosphorylation. These results indicated that IXA potentially protects against UVB-induced skin inflammation. PMID- 25738263 TI - Identification and validation of reference genes for the detection of serum microRNAs by reverse transcription-quantitative polymerase chain reaction in patients with bladder cancer. AB - Serum microRNAs (miRNAs) have been proposed as novel non-invasive biomarkers for the early detection of cancer. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the most commonly used method for investigating miRNA expression levels, however, the interpretation of RT-qPCR results depends largely on normalization to an appropriate endogenous control. The present study involved 129 patients with non-muscle-invasive bladder cancer (NMIBC), 121 patients with muscle-invasive bladder cancer (MIBC) and 158 healthy controls. The aim of the present study was to determine the most stable reference genes for the investigations of serum miRNA in bladder cancer (BC). MiSeq sequencing was performed and the expression levels of 10 miRNAs and U6 were then measured using RT-qPCR. Following RT-qPCR, five genes (hsa-miR-193a-5p, hsa-miR-16-5p, U6, hsa miR-191-5p and hsa-let-7d-3p) were selected for stability analysis using geNorm and NormFinder software. These algorithms identified hsa-miR-193a-5p and hsa-miR 16-5p as the most stably expressed reference genes. The availability of hsa-miR 193a-5p and hsa-miR-16-5p was confirmed in an additional cohort. One-way analysis of variance indicated that no significant differences were present in the expression levels among the three groups. Furthermore, miR-148b-3p was selected as a target miRNA to determine the effect of hsa-miR-193a-5p and hsa-miR-16-5p on miRNA quantification. The combined use of hsa-miR-193a-5p and hsa-miR-16-5p enabled the detection of a significant upregulation of miR-148b-3p in the BC serum. The results of the present study demonstrated that normalization of miRNA data, using a combination of hsa-miR-193a-5p and hsa-miR-16-5p as reference genes, may produce reliable and accurate results for the detection of serum miRNAs in BC. PMID- 25738264 TI - Testosterone enhances lipopolysaccharide-induced interleukin-6 and macrophage chemotactic protein-1 expression by activating the extracellular signal-regulated kinase 1/2/nuclear factor-kappaB signalling pathways in 3T3-L1 adipocytes. AB - Low-grade chronic inflammation is commonly found in patients with polycystic ovary syndrome (PCOS) who exhibit hyperandrogenism or hyperandrogenemia. Clinical studies have shown that hyperandrogenemia is closely correlated with low-grade chronic inflammation. However, the mechanism underlying this correlation remains unclear. Recent studies have suggested that adipocytes increase the production of proinflammatory mediators such as interleukin-6 (IL-6) and macrophage chemotactic protein-1 (MCP-1) when the inflammatory signal transduction cascade system is activated by external stimuli. The present study aimed to evaluate the effects of testosterone on the innate signalling and expression of proinflammatory mediators in 3T3-L1 adipocytes, which were or were not induced by lipopolysaccharide (LPS). The effects of testosterone on the expression of proinflammatory mediators, nuclear factor-kappaB (NF-kappaB), and extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathways were investigated using an enzyme-linked immunosorbent assay, reverse transcriptase-polymerase chain reaction, western blot analysis and an electrophoresis mobility shift assay. Testosterone induces IL-6 and MCP-1, and enhances LPS-induction of IL-6 and MCP-1. However, the effects are not simply additive, testosterone significantly enhanced the effects of LPS-induced inflammation factors. Testosterone induces the phosphorylation of ERK1/2 and NF-kappaB. The effect of testosterone on the expression of IL-6 and MCP-1 is inhibited by PD98059 , an ERK1/2 inhibitor, and PDTC, an NF-kappaB inhibitor. The results indicate that testosterone enhances LPS-induced IL-6 and MCP-1 expression by activating the ERK1/2/NF-kappaB signalling pathways in 3T3-L1 adipocytes. PMID- 25738265 TI - SLC6A2 and SLC6A4 variants interact with venlafaxine serum concentrations to influence therapy outcome. PMID- 25738266 TI - Dietary inference from upper and lower molar morphology in platyrrhine primates. AB - The correlation between diet and dental topography is of importance to paleontologists seeking to diagnose ecological adaptations in extinct taxa. Although the subject is well represented in the literature, few studies directly compare methods or evaluate dietary signals conveyed by both upper and lower molars. Here, we address this gap in our knowledge by comparing the efficacy of three measures of functional morphology for classifying an ecologically diverse sample of thirteen medium- to large-bodied platyrrhines by diet category (e.g., folivore, frugivore, hard object feeder). We used Shearing Quotient (SQ), an index derived from linear measurements of molar cutting edges and two indices of crown surface topography, Occlusal Relief (OR) and Relief Index (RFI). Using SQ, OR, and RFI, individuals were then classified by dietary category using Discriminate Function Analysis. Both upper and lower molar variables produce high classification rates in assigning individuals to diet categories, but lower molars are consistently more successful. SQs yield the highest classification rates. RFI and OR generally perform above chance. Upper molar RFI has a success rate below the level of chance. Adding molar length enhances the discriminatory power for all variables. We conclude that upper molar SQs are useful for dietary reconstruction, especially when combined with body size information. Additionally, we find that among our sample of platyrrhines, SQ remains the strongest predictor of diet, while RFI is less useful at signaling dietary differences in absence of body size information. The study demonstrates new ways for inferring the diets of extinct platyrrhine primates when both upper and lower molars are available, or, for taxa known only from upper molars. The techniques are useful in reconstructing diet in stem representatives of anthropoid clade, who share key aspects of molar morphology with extant platyrrhines. PMID- 25738267 TI - Honorary and ghost authorship. PMID- 25738269 TI - Polymylagia rheumatica: common disease, elusive diagnosis. AB - Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease with little known about its etiology or incidence. Frequently found in older adult women, this disease can be debilitating, painful, and dangerous. Diagnosing PMR can be elusive due to lack of specific laboratory tests, and treatment with use of long-term glucocorticoids can be difficult due to side effects. The following article describes the pathophysiology, diagnosis, signs and symptoms, and treatment of PMR, as well as implications for home healthcare. PMID- 25738271 TI - Methotrexate. AB - The purpose of this article is to educate healthcare professionals about the many uses of the drug Methotrexate. Information regarding dosing, action, contraindications, adverse effects, drug interactions, as well as tips for patient education are included. PMID- 25738272 TI - The 2nd International Home Care Nurses Organization conference. AB - The International Home Care Nurses Organization, a grass-roots movement, held its 2nd annual conference in Singapore in September 2014. This article describes the highlights of the conference. PMID- 25738273 TI - Dementia and the home healthcare clinician. AB - As record number of individuals move into their retirement years, home healthcare clinicians are witnessing an increase in the number of patients and families struggling to cope with the complex symptoms of dementia. Unlike other terminal conditions such as cancer, the course of this terminal and debilitating disease can span several decades. Home healthcare clinicians will be caring for greater numbers of these patients and their families in the community. PMID- 25738274 TI - Interactions between parents of technology-dependent children and providers: an integrative review. AB - This article is a review of the literature on the experiences of parents and their interactions with healthcare providers while caring for their technology dependent child(ren) in their homes. Results are presented in the following themes: information needs, respect and partnership with healthcare providers, care coordination, and experiences with home healthcare nurses. Parents needed information and guidance and felt supported when providers recognized parents' expertise with the child's care, and offered reassurance and confirmation about their practices. Home healthcare clinicians provided supportive care in the home, but their presence created challenges for the family. By acknowledging and valuing the parents' expertise, healthcare providers can empower parents to confidently care for their child. PMID- 25738275 TI - Diabetes standards for older adults. PMID- 25738276 TI - Providing patients with ISMP consumer leaflets can help prevent hospital readmissions. PMID- 25738277 TI - Infection prevention: single- and multidose vial management. PMID- 25738278 TI - A day in the life of a pediatric home care nurse. PMID- 25738279 TI - The importance of reconciling nonprescription products. PMID- 25738280 TI - Addressing the needs of our aging population through managed long-term care. PMID- 25738281 TI - Against all odds. PMID- 25738282 TI - Purpuric Lesions on Acral Sites. Type I cryoglobulinemia associated with multiple myeloma. PMID- 25738283 TI - Association of genetic polymorphisms in the telomerase reverse transcriptase gene with prostate cancer aggressiveness. AB - Telomerase reverse transcriptase (TERT), encoded by the TERT gene, is an essential component of telomerase, essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality. The aim of the present study was to evaluate the association between common genetic variations across the TERT gene region and prostate cancer (PCa) aggressiveness in a Chinese population. A total of 12 TERT tagging single-nucleotide polymorphisms (SNPs) were genotyped on the Sequenom Mass-ARRAY iPLEX(r) platform in a case-case study with 1,210 Chinese patients with PCa. Unconditional logistic regression was used to investigate the association of genotypes with PCa aggressiveness, Gleason grade and risk of developing early-onset PCa. It was observed that the C allele of the TERT intron 2 SNP (rs2736100) was significantly associated with reduced risk of PCa aggressiveness [odds ratio (OR)=0.81; 95% confidence interval (CI): 0.66-0.99; P=0.037]. This allele was also significantly correlated with a reduced risk of developing a tumor with a high Gleason score (>7; OR=0.83; 95% CI: 0.70 0.99; P=0.039). The T allele of the intron 4 SNP (rs10069690) was found to be significantly associated with a decreased risk for an aggressive form of PCa (OR=0.76; 95% CI: 0.59-0.97; P=0.030). In addition, the A allele of rs10078761 located at the 3' end of the TERT gene exhibited a statistically significant association with the reduced risk of developing a higher grade disease (OR=0.48; 95% CI: 0.28-0.81; P=0.006). However, no association between TERT polymorphisms and age at diagnosis was observed in the present study. The present findings demonstrated for the first time, to the best of our knowledge, that genetic variations across the TERT gene are associated with PCa aggressiveness in a Chinese Han population. PMID- 25738284 TI - Antioxidant activity is required for the protective effects of cyclophilin A against oxidative stress. AB - Cyclophilin (Cyp) belongs to a group of proteins that have peptidyl-prolyl cis trans isomerase (PPIase) activity. CypA is the major cellular target for the immunosuppressive drug cyclosporin A and mediates its actions. Previous studies have demonstrated that CypA has diverse cellular functions and have suggested that CypA may function as an antioxidant. The present study investigated the antioxidant activity of CypA and its association with PPIase activity. The purified CypA/wild-type (WT) and CypA/P16S mutant proteins were active in PPIase assays. A total antioxidant capacity assay revealed that the purified CypA/WT protein had significantly higher antioxidant activity, whereas the CypA/P16S mutant was defective in its antioxidant activity. To confirm the importance of CypA antioxidant activity, CypA/P16S was overexpressed in Chang human liver cells and the rate of cell death was measured following treatment with cisplatin or H2O2. Overexpression of CypA/WT protected the cells against cisplatin or H2O2 induced oxidative damage, however, the CypA/P16S mutant had no effect. These findings suggested that CypA exhibits a protective antioxidant effect. PMID- 25738285 TI - Biochemical characterization of three BLT receptors in zebrafish. AB - The leukotriene B4 (LTB4) receptor 1 (BLT1) is a high affinity receptor for LTB4, a chemotactic and inflammatory eicosanoid. The LTB4 receptor 2 (BLT2) was originally identified as a low affinity receptor for LTB4, and, more recently, as a high affinity receptor for 12-hydroxyheptadecatrienoic acid (12-HHT). The zebrafish BLT receptors have not been previously identified and the in vivo functions of these receptors have been unknown. In this paper, we describe one zebrafish BLT1-like receptor, Blt1, and two zebrafish BLT2-like receptors, Blt2a and Blt2b. Cells expressing Blt1 exhibited LTB4-induced intracellular [Ca2+] increases, inhibition of cAMP production, ligand-dependent [35S]GTPgammaS binding, and transforming growth factor-alpha (TGFalpha) shedding activity in a dose-dependent manner, similar to human BLT1. Cells expressing Blt2a and Blt2b exhibited 12-HHT- and LTB4-induced intracellular [Ca2+] increases, inhibition of cAMP production, [35S]GTPgammaS binding, and TGFalpha shedding activity, with a dose-dependency similar to human BLT2. Reverse transcription (RT)-PCR analysis and whole-mount in situ hybridization revealed that blt1, blt2a, blt2b, zebrafish LTA4 hydrolase (lta4h), and zebrafish 5-lipoxiganase (5lo) are expressed in zebrafish embryos. Knockdown of blt1 by morpholino antisense oligonucleotides resulted in delayed epiboly at gastrulation. Consistently, knockdown of lta4h, an enzyme mediating LTB4 production, induced a phenotype similar to knockdown of blt1. These results suggest that the LTB4-BLT1 axis is involved in epiboly in zebrafish development. PMID- 25738286 TI - Ecuador's mangrove forest carbon stocks: a spatiotemporal analysis of living carbon holdings and their depletion since the advent of commercial aquaculture. AB - In this paper we estimate the living carbon lost from Ecuador's mangrove forests since the advent of export-focused shrimp aquaculture. We use remote sensing techniques to delineate the extent of mangroves and aquaculture at approximately decadal periods since the arrival of aquaculture in each Ecuadorian estuary. We then spatiotemporally calculate the carbon values of the mangrove forests and estimate the amount of carbon lost due to direct displacement by aquaculture. Additionally, we calculate the new carbon stocks generated due to mangrove reforestation or afforestation. This research introduces time and LUCC (land use / land cover change) into the tropical forest carbon literature and examines forest carbon loss at a higher spatiotemporal resolution than in many earlier analyses. We find that 80 percent, or 7,014,517 t of the living carbon lost in Ecuadorian mangrove forests can be attributed to direct displacement of mangrove forests by shrimp aquaculture. We also find that IPCC (Intergovernmental Panel on Climate Change) compliant carbon grids within Ecuador's estuaries overestimate living carbon levels in estuaries where substantial LUCC has occurred. By approaching the mangrove forest carbon loss question from a LUCC perspective, these findings allow for tropical nations and other intervention agents to prioritize and target a limited set of land transitions that likely drive the majority of carbon losses. This singular cause of transition has implications for programs that attempt to offset or limit future forest carbon losses and place value on forest carbon or other forest good and services. PMID- 25738287 TI - Recombination between homologous chromosomes induced by unrepaired UV-generated DNA damage requires Mus81p and is suppressed by Mms2p. AB - DNA lesions caused by UV radiation are highly recombinogenic. In wild-type cells, the recombinogenic effect of UV partially reflects the processing of UV-induced pyrimidine dimers into DNA gaps or breaks by the enzymes of the nucleotide excision repair (NER) pathway. In this study, we show that unprocessed pyrimidine dimers also potently induce recombination between homologs. In NER-deficient rad14 diploid strains, we demonstrate that unexcised pyrimidine dimers stimulate crossovers, noncrossovers, and break-induced replication events. The same dose of UV is about six-fold more recombinogenic in a repair-deficient strain than in a repair-proficient strain. We also examined the roles of several genes involved in the processing of UV-induced damage in NER-deficient cells. We found that the resolvase Mus81p is required for most of the UV-induced inter-homolog recombination events. This requirement likely reflects the Mus81p-associated cleavage of dimer-blocked replication forks. The error-free post-replication repair pathway mediated by Mms2p suppresses dimer-induced recombination between homologs, possibly by channeling replication-blocking lesions into recombination between sister chromatids. PMID- 25738289 TI - Evaluating sustainability of cropland use in Yuanzhou county of the Loess plateau, China using an emergy-based ecological footprint. AB - Evaluating the sustainability of cropland use is essential for guaranteeing a secure food supply and accomplishing agriculture sustainable development. This study was conducted in the ecologically vulnerable Loess Plateau region of China to evaluate the sustainability of cropland use based on an ecological footprint model that integrates emergy analysis. One modified method proposed in 2005 is known as the emergetic ecological footprint (EEF). We enhanced the method by accounting for both the surface soil energy in the carrying capacity calculation and the net topsoil loss for human consumption in the EF calculation. This paper evaluates whether the cropland of the study area was overloaded or sustainably managed during the period from 1981 to 2009. Toward this end, the final results obtained from EEF were compared to conventional EF and previous methods. The results showed that the cropland of Yuanzhou County has not been used sustainably since 1983, and the conventional EF analysis provided similar results. In contrast, a deficit did not appear during this time period when previous calculation methods of others were used. Additionally, the ecological sustainable index (ESI) from three models indicated that the recently used cropland system is unlikely to be unsustainable. PMID- 25738288 TI - Effect of dietary gluten on dendritic cells and innate immune subsets in BALB/c and NOD mice. AB - The innate immune system is known to play an important role in oral tolerance to dietary antigens. This is important in development of celiac disease (CD) but may also be important in type 1 diabetes (T1D), and could potentially explain the reduced incidence of T1D in mice receiving a gluten-free (GF) diet. The direct in vivo effect of gluten on innate cells, and particularly dendritic cells (DC) is not sufficiently clarified. Therefore, we wished to investigate the innate cell populations of spontaneous diabetic NOD mice and healthy BALB/c mice kept on a GF or a standard (STD) gluten containing diet. We studied, by flow cytometry and reverse transcription-quantitative polymerase chain reaction (qRT-PCR), if dietary gluten induces changes in the activation of DCs and distribution of selected innate cells in lymphoid, pancreatic and intestinal tissues in BALB/c and NOD mice. We found that a GF diet increased the percentage of macrophages in BALB/c spleen and of CD11c+ DCs in BALB/c and NOD spleen. Strictly gluten-free (SGF) diet increased the percentage of CD103+ DCs in BALB/c mice and decreased percentages of CD11b+ DCs in mesenteric and pancreatic lymph nodes in BALB/c mice. SGF diet in BALB/c mice also decreased DC expression of CD40, CCR7 and MHC II in pancreatic lymph nodes. In conclusion, GF diet changes the composition of the innate immune system in BALB/c and NOD mice and increases expression of DC activation markers in NOD mice. These results contribute to the explanation of the low diabetes incidence in GF NOD mice. This mechanism may be important in development of type 1 diabetes, celiac disease and non-celiac gluten sensitivity. PMID- 25738290 TI - Interactive video game cycling leads to higher energy expenditure and is more enjoyable than conventional exercise in adults. AB - BACKGROUND: Despite the widely accepted health benefits of regular physical activity, only a small percentage of the population meets the current recommendations. The reasons include a wide use of technology and a lack of enjoyment while exercising. The purpose of this study was to compare the physiological, perceptual and enjoyment responses between a single bout of (I) conventional cycling and (II) interactive cycling video game at a matched workload. METHODS: A cross-sectional study in 34 healthy participants was performed. Initially, participants completed an incremental maximal cycling test to measure peak oxygen uptake and to determine ventilatory threshold. In random order, participants carried out a 30 min interactive cycling trial and a 30 min conventional cycling trial at 55% of peak power output. During the trials, oxygen uptake and energy expenditure were measured by open-circuit spirometry and heart rate was measured by radiotelemetry. RPE and enjoyment were measured every 10 minutes with Borg scale and a modified PACES scale. RESULTS: Interactive cycling resulted in a significantly greater %VO2Reserve (68.2% +/- 9.2% vs 64.7% +/- 8.1%), rate of energy expenditure (505.8+/-75.2 vs 487.4+/-81.2 j.kg-1.min-1), and enjoyment (63.4% +/- 17 vs 42% +/- 13.6), P<0.05. Participants were working at a higher intensity in relation to the individual's ventilatory threshold during the interactive cycling video game trial (M = 11.86, SE = 3.08) than during the Conventional cycling trial (M = 7.55, SE = 3.16, t(33) = -2.69, P<0.05, r = .42). No significant differences were found for heart rate reserve (72.5 +/- 10.4 vs 71.4+/-10.1%) and RPE (13.1 +/- 1.8 vs 13.2 +/- 1.7). CONCLUSION: Interactive cycling games can be a valid alternative to conventional exercise as they result in a higher exercise intensity than conventional cycling and a distraction from aversive cognitive and physiological states at and above the ventilatory threshold. PMID- 25738291 TI - Interactions of cultures and top people of Wikipedia from ranking of 24 language editions. AB - Wikipedia is a huge global repository of human knowledge that can be leveraged to investigate interwinements between cultures. With this aim, we apply methods of Markov chains and Google matrix for the analysis of the hyperlink networks of 24 Wikipedia language editions, and rank all their articles by PageRank, 2DRank and CheiRank algorithms. Using automatic extraction of people names, we obtain the top 100 historical figures, for each edition and for each algorithm. We investigate their spatial, temporal, and gender distributions in dependence of their cultural origins. Our study demonstrates not only the existence of skewness with local figures, mainly recognized only in their own cultures, but also the existence of global historical figures appearing in a large number of editions. By determining the birth time and place of these persons, we perform an analysis of the evolution of such figures through 35 centuries of human history for each language, thus recovering interactions and entanglement of cultures over time. We also obtain the distributions of historical figures over world countries, highlighting geographical aspects of cross-cultural links. Considering historical figures who appear in multiple editions as interactions between cultures, we construct a network of cultures and identify the most influential cultures according to this network. PMID- 25738293 TI - T cell-activated signaling pathways and locally produced cytokines as potential targets in celiac disease. AB - Celiac disease (CD) is an autoimmune disease induced by an autoimmune reaction to indigested gluten, which occurs in genetically predisposed population. The etiology of CD is linked to innate and adaptive immunity, mostly mediated by lymphocytes, especially T cells, infiltrating into the small intestinal wall. The subpopulations of T cells that infiltrate inflamed intestinal tissues comprise various CD4+ T cells and CD8+ T cells. The plethora of T cell subtypes activated in CD leads to simultaneous activation of different signaling cascades including GATA1, NF-kB, JAK or STAT5 the activity of which may be modified by diet or drugs. It was recently showed that food allergens may accelerate CD by altering the interaction between IL-15 and CD4+ T cells in the activation of CD8+ T cells. Increased levels of cytokines like IL-15 are considered to play a role in CD development. Furthermore it was showed that some drugs like tofacitinib or ruxolitinib may influence CD by blocking IL-15 signaling and CD8+ T cell activity. This mini-review will summarize the current knowledge on the role of CD4+ T cell and CD8+ T cell in clinical and experimental CD and will describe how T cell-activated signaling pathways and locally released proteins may be influenced by dietary factors and drugs used in CD treatment. PMID- 25738292 TI - The pathogenesis of cardiomyopathy in Friedreich ataxia. AB - Friedreich ataxia (FA) is an autosomal recessive disease with a complex neurological phenotype, but the most common cause of death is heart failure. This study presents a systematic analysis of 15 fixed and 13 frozen archival autopsy tissues of FA hearts and 10 normal controls (8 frozen) by measurement of cardiomyocyte hypertrophy; tissue frataxin assay; X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn) in polyethylene glycol-embedded samples of left and right ventricular walls (LVW, RVW) and ventricular septum (VS); metal quantification in bulk digests by inductively-coupled plasma optical emission spectrometry (ICP OES); Fe histochemistry; and immunohistochemistry and immunofluorescence of cytosolic and mitochondrial ferritins and of the inflammatory markers CD68 and hepcidin. FA cardiomyocytes were significantly larger than normal and surrounded by fibrotic endomysium. Frataxin in LVW was reduced to less than 15 ng/g wet weight (normal 235.4 +/- 75.1 ng/g). All sections displayed characteristic Fe reactive inclusions in cardiomyocytes, and XRF confirmed significant regional Fe accumulation in LVW and VS. In contrast, ICP-OES analysis of bulk extracts revealed normal total Fe levels in LVW, RVW, and VS. Cardiac Zn remained normal by XRF and assay of bulk digests. Cytosolic and mitochondrial ferritins exhibited extensive co-localization in cardiomyocytes, representing translational and transcriptional responses to Fe, respectively. Fe accumulation progressed from a few small granules to coarse aggregates in phagocytized cardiomyocytes. All cases met the "Dallas criteria" of myocarditis. Inflammatory cells contained CD68 and cytosolic ferritin, and most also expressed the Fe-regulatory hormone hepcidin. Inflammation is an important factor in the pathogenesis of FA cardiomyopathy but may be more evident in advanced stages of the disease. Hepcidin-induced failure of Fe export from macrophages is a likely contributory cause of damage to the heart in FA. Frataxin replacement and anti-inflammatory agents are potential therapies in FA cardiomyopathy. PMID- 25738294 TI - Motility disorders, functional gastrointestinal disorders, inflammatory bowel disease and cardiac rhythm disturbances - is there a link? Review of literature. AB - Gastrointestinal disorders are frequently accompanied by symptoms exceeding gastrointestinal tract. This is at least partially connected with the involvement of autonomic nervous system in pathophysiology of diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) or spectrum of motility disorders. In light of the above, involvement of cardiovascular system in natural history of gastrointestinal disorders seems to be of interest. On the other hand, available data regarding the prevalence of cardiac rhythm disturbances in IBD, IBS and motility disorders is limited. What is more, pharmacotherapy of the mentioned diseases includes drugs with possible arrhythmogenic potential. In this review we present current experiences and observations concerning gastrointestinal disorders and cardiac rhythm disturbances. PMID- 25738295 TI - Immunomodulatory Drugs: IMiDs in Acute Myeloid Leukemia (AML). AB - AML patients have an aberrant and dysfunctional immune state, paving the way for novel agents targeting pathways that integrate with immune signaling, function, and response. Small molecule immunomodulatory drugs (IMiDs) represent a class of agents derived from the parent compound, thalidomide. There are currently 3 IMiDs approved for a variety of malignancies: thalidomide, lenalidomide, and the newest agent, pomalidomide. IMiDs lead to a multitude of immunobiologic effects such as cytokine modulation, co-stimulation of T cells, down-regulation of co-inhibitory molecules, enhancing natural killer cell activity, inhibition of regulatory T cells, and repairing perturbed synapse formation on T cells. IMiDs have been extensively studied in various AML settings with promising clinical activity. This review discusses the immunologic effects of IMiDs, the rationale for studying IMiDs in AML, and the published and ongoing clinical trials investigating IMiD activity in AML. PMID- 25738296 TI - Hemoglobin Degrading Proteases of Plasmodium falciparum as Antimalarial Drug Targets. AB - Plasmepsins, falcipains and aminopeptidases are Plasmodium falciparum proteases involved in human host hemoglobin degradation and other processes like erythrocyte invasion and rupture. Antimalarial drug resistance and natural selection in parasite are important reasons that create the urgent need of novel targets and lead compounds to overcome the burden of malaria. This report explored progress of the study covering proteases and their inhibitors specific to hemoglobin degradation. Additionally, in silico predicted antimalarial targets, balancing selection and drug-protein interaction are included. PMID- 25738297 TI - Do We Need Full Donor Chimerism? How Alloreactive Cell Therapies without Substantial Engraftment Might Treat Hematologic Cancers. AB - "Alloreactive cell therapy without substantial engraftment"; (ACT-WiSE) refers to adoptive transfer of natural ("non-engineered") human leukocyte antigen mismatched lymphocytes to mediate anti-neoplastic alloreactivity in recipients without employing pharmacologic immunosuppression. By definition, ACT-WiSE entails subsequent rejection of most, if not all, donor cells. Macrochimerism is transient and microchimerism may be either short-lived or persistent. This strategy harnesses the anticancer potency of alloreactivity without incurring significant risk of graft-versus-host disease. "Microtransplantation" refers to a form of ACT-WiSE where the donor cell product contains hematopoietic progenitor cells. Microtransplantation therefore accelerates hematopoietic recovery and its immunomodulatory effects may differ from other forms of ACT-WiSE. Recent studies suggest that various forms of ACT-WiSE, including microtransplantation, may improve chemosensitivity in patients with myeloid malignancies, resulting in higher complete remission rates and increased survival. Microtransplantation has also demonstrated promising pilot results in relapsed or refractory Non-Hodgkin and Hodgkin lymphoma. ACT-WiSE and microtransplantation may establish a new class of allogeneic cell therapy of particular relevance to persons not considered candidates for traditional allogeneic hematopoietic cell transplantation (AHCT). Open questions include the optimal timing and cell dose of ACT-WiSE, which donor factors contribute to efficacy, and whether these remissions are durable after eradication of donor cells. We extrapolate from lessons learned in the course of traditional and haploidentical AHCT to propose ways of optimizing ACT-WiSE. We divide these into donor-related strategies (including rational donor selection and boosting NK-cell and T-cell alloreactivity) and patient- related strategies (that may favor development of autologous NK-cell and T-cell mediated anticancer cytotoxicity in the post-ACT-WiSE window). PMID- 25738298 TI - Nitroso-Redox Balance and Modulation of Basal Myocardial Function: An Update from the Italian Society of Cardiovascular Research (SIRC). AB - Reactive oxygen species and reactive nitrogen species are produced endogenously by cardiomyocytes and are fundamental signaling molecules that regulate cellular function. Production of ROS and RNS is finely tuned to maintain proper myocardial function, but is altered in many pathophysiological conditions, therefore contributing to worsening myocardial dysfunction and ultimately heart failure. Indeed, an excess of ROS and RNS is central in many pathways leading to cardiac hypertrophy and failure, and the correct regulation of the nitroso-redox balance is fundamental for the function of the main components of the EC-coupling machinery. Broad antioxidant therapies have been proposed to improve myocardial function, but these therapies blunt even physiological ROS and RNS signaling, bringing limited, if any, beneficial effect. On the other hand, more targeted interventions on specific sources or pathways may produce promising results. PMID- 25738299 TI - Metformin for Prevention and Treatment of Colon Cancer: A Reappraisal of Experimental and Clinical Data. AB - In the 70-80th of last century, it has been shown that the antidiabetic biguanide drugs phenformin (PF) and buformin (BF) can exert an inhibitory action on carcinogenesis in animal models and increase from 5 to 10-years survival of cancer patients. Since 2005, after first evidence publication of the capacity of metformin (MF), another biguanide, to prevent development of malignant tumors in individuals with type 2 diabetes (T2D) and suppress tumorigenesis in mice, the burst of studies started in this field focused on breast, pancreas, prostatic, endometrial and some other cancers. Colorectal cancer (CRC) is the most prevalent among digestive system cancers. In this mini-review are presented the available data on the capacity of antidiabetic biguanide drugs to prevent colorectal carcinogenesis and growth in vitro and in vivo in experimental models and clinical observations. PMID- 25738300 TI - The burden of acute disease in Mahajanga, Madagascar - a 21 month study. AB - BACKGROUND: Efforts to develop effective and regionally-appropriate emergency care systems in sub-Saharan Africa are hindered by a lack of data on both the burden of disease in the region and on the state of existing care delivery mechanisms. This study describes the burden of acute disease presenting to an emergency unit in Mahajanga, Madagascar. METHODS AND FINDINGS: Handwritten patient registries on all emergency department patients presenting between 1 January 2011 and 30 September 2012 were reviewed and data entered into a database. Data included age, sex, diagnosis, and disposition. We classified diagnoses into Clinical Classifications Software (CCS) multi-level categories. The population was 53.5% male, with a median age of 31 years. The five most common presenting conditions were 1) Superficial injury; contusion, 2) Open wounds of head; neck; and trunk, 3) Open wounds of extremities, 4) Intracranial injury, and 5) Unspecified injury and poisoning. Trauma accounted for 48%, Infectious Disease for 15%, Mental Health 6.1%, Noncommunicable 29%, and Neoplasms 1.2%. The acuity seen was high, with an admission rate of 43%. Trauma was the most common reason for admission, representing 19% of admitted patients. CONCLUSIONS: This study describes the burden of acute disease at a large referral center in northern Madagascar. The Centre Hopitalier Universitaire de Mahajanga sees a high volume of acutely ill and injured patients. Similar to other reports from the region, trauma is the most common pathology observed, though infectious disease was responsible for the majority of adult mortality. Typhoid fever other intestinal infections were the most lethal CCS-coded pathologies. By utilizing a widely understood classification system, we are able to highlight contrasts between Mahajanga's acute and overall disease burden as well as make comparisons between this region and the rest of the globe. We hope this study will serve to guide the development of context-appropriate emergency medicine systems in the region. PMID- 25738301 TI - The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity. AB - The interferon-inducible transmembrane (IFITM) proteins inhibit a wide range of viruses. We previously reported the inhibition of human immunodeficiency virus type 1 (HIV-1) strain BH10 by human IFITM1, 2 and 3. It is unknown whether other HIV-1 strains are similarly inhibited by IFITMs and whether there exists viral countermeasure to overcome IFITM inhibition. We report here that the HIV-1 NL4-3 strain (HIV-1NL4-3) is not restricted by IFITM1 and its viral envelope glycoprotein is partly responsible for this insensitivity. However, HIV-1NL4-3 is profoundly inhibited by an IFITM1 mutant, known as Delta(117-125), which is deleted of 9 amino acids at the C-terminus. In contrast to the wild type IFITM1, which does not affect HIV-1 entry, the Delta(117-125) mutant diminishes HIV-1NL4 3 entry by 3-fold. This inhibition correlates with the predominant localization of Delta(117-125) to the plasma membrane where HIV-1 entry occurs. In spite of strong conservation of IFITM1 among most species, mouse IFITM1 is 19 amino acids shorter at its C-terminus as compared to human IFITM1 and, like the human IFITM1 mutant Delta(117-125), mouse IFITM1 also inhibits HIV-1 entry. This is the first report illustrating the role of viral envelope protein in overcoming IFITM1 restriction. The results also demonstrate the importance of the C-terminal region of IFITM1 in modulating the antiviral function through controlling protein subcellular localization. PMID- 25738303 TI - Correction: paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration. PMID- 25738302 TI - Differential induction of Ly6G and Ly6C positive myeloid derived suppressor cells in chronic kidney and liver inflammation and fibrosis. AB - CD11b+Gr1+ myeloid derived suppressor cells (MDSC) are known to be very potent suppressors of T cell immunity and can be further stratified into granulocytic MDSC and monocytic MDSC in mice based on expression of Ly6G or Ly6C, respectively. Here, using these markers and functional assays, we aimed to identify whether MDSC are induced during chronic inflammation leading to fibrosis in both kidney and liver and whether additional markers could more specifically identify these MDSC subsets. In an adenine-induced model of kidney inflammation/fibrosis suppressive Ly6Gpos MDSC were induced. The suppressive function within the Ly6G+ MDSC population was exclusively present in IFNgammaRbeta expressing cells. In contrast, in chronic inflammation in the liver induced by bile duct ligation, suppressive capacity was exclusively present in the Ly6Cpos MDSC subset. Gene expression analyses confirmed the differential origins and regulation of those MDSC subsets. Additionally, depletion of MDSC in either kidney or liver fibrosis enhanced fibrosis markers, indicating a protective role for MDSC in organ fibrosis. Thus, our data demonstrate that during liver inflammation and kidney fibrosis MDSC with similar function arise bearing a distinct marker profile and arising from different cell populations. PMID- 25738305 TI - Correction: a long non-coding RNA is required for targeting centromeric protein A to the human centromere. PMID- 25738306 TI - Photoresponsive carbohydrate-based giant surfactants: automatic vertical alignment of nematic liquid crystal for the remote-controllable optical device. AB - Photoresponsive carbohydrate-based giant surfactants (abbreviated as CELAnD-OH) were specifically designed and synthesized for the automatic vertical alignment (VA) layer of nematic (N) liquid crystal (LC), which can be applied for the fabrication of remote-controllable optical devices. Without the conventional polymer-based LC alignment process, a perfect VA layer was automatically constructed by directly adding the 0.1 wt % CELA1D-OH in the N-LC media. The programmed CELA1D-OH giant surfactants in the N-LC media gradually diffused onto the substrates of LC cell and self-assembled to the expanded monolayer structure, which can provide enough empty spaces for N-LC molecules to crawl into the empty zones for the construction of VA layer. On the other hand, the CELA3D-OH giant surfactants forming the condensed monolayer structure on the substrates exhibited a planar alignment (PA) rather than a VA. Upon tuning the wavelength of light, the N-LC alignments were reversibly switched between VA and PA in the remote controllable LC optical devices. Based on the experimental results, it was realized that understanding the interactions between N-LC molecules and amphiphilic giant surfactants is critical to design the suitable materials for the automatic LC alignment. PMID- 25738304 TI - Overexpression of the transcription factor Sp1 activates the OAS-RNAse L-RIG-I pathway. AB - Deregulated expression of oncogenes or transcription factors such as specificity protein 1 (Sp1) is observed in many human cancers and plays a role in tumor maintenance. Paradoxically in untransformed cells, Sp1 overexpression induces late apoptosis but the early intrinsic response is poorly characterized. In the present work, we studied increased Sp1 level consequences in untransformed cells and showed that it turns on an early innate immune transcriptome. Sp1 overexpression does not activate known cellular stress pathways such as DNA damage response or endoplasmic reticulum stress, but induces the activation of the OAS-RNase L pathway and the generation of small self-RNAs, leading to the upregulation of genes of the antiviral RIG-I pathway at the transcriptional and translational levels. Finally, Sp1-induced intrinsic innate immune response leads to the production of the chemokine CXCL4 and to the recruitment of inflammatory cells in vitro and in vivo. Altogether our results showed that increased Sp1 level in untransformed cells constitutes a novel danger signal sensed by the OAS RNase L axis leading to the activation of the RIG-I pathway. These results suggested that the OAS-RNase L-RIG-I pathway may be activated in sterile condition in absence of pathogen. PMID- 25738307 TI - Unravelling kinetic and thermodynamic effects on the growth of gold nanoplates by liquid transmission electron microscopy. AB - The growth of colloidal nanoparticles is simultaneously driven by kinetic and thermodynamic effects that are difficult to distinguish. We have exploited in situ scanning transmission electron microscopy in liquid to study the growth of Au nanoplates by radiolysis and unravel the mechanisms influencing their formation and shape. The electron dose provides a straightforward control of the growth rate that allows quantifying the kinetic effects on the planar nanoparticles formation. Indeed, we demonstrate that the surface-reaction rate per unit area has the same dose-rate dependent behavior than the concentration of reducing agents in the liquid cell. Interestingly, we also determine a critical supply rate of gold monomers for nanoparticle faceting, corresponding to three layers per second, above which the formation of nanoplates is not possible because the growth is then dominated by kinetic effects. At lower electron dose, the growth is driven by thermodynamic and the formation and shape of nanoplates are directly related to the twin-planes formed during the growth. PMID- 25738308 TI - Uptake of cadmium by rice grown on contaminated soils and its bioavailability/toxicity in human cell lines (Caco-2/HL-7702). AB - Cadmium (Cd) enters the food chain from polluted soils via contaminated cereals and vegetables; therefore, an understanding of Cd bioaccessibility, bioavailability, and toxicity in humans through rice grain is needed. This study assessed the Cd bioaccessibility, bioavailability, and toxicity to humans from rice grown on Cd-contaminated soils using an in vitro digestion method combined with a Caco-2/HL-7702 cell model. Cadmium bioaccessibility (18.45-30.41%) and bioavailability (4.04-8.62%) were found to be significantly higher in yellow soil (YS) rice than calcareous soil (CS) rice with the corresponding values of 6.89 11.43 and 1.77-2.25%, respectively. Toxicity assays showed an initial toxicity in YS rice at 6 mg kg(-1) Cd, whereas CS rice did not show any significant change due to low Cd concentrations. The acidic soils of Cd-contaminated areas can contribute to a higher dietary intake of Cd. Therefore, it is imperative to monitor Cd concentration in rice to minimize human health risk. PMID- 25738309 TI - In situ fabrication of highly conductive metal nanowire networks with high transmittance from deep-ultraviolet to near-infrared. AB - We have developed a facile and compatible method to in situ fabricate uniform metal nanowire networks on substrates. The as-fabricated metal nanowire networks show low sheet resistance and high transmittance (2.2 Omega sq(-1) at T = 91.1%), which is equivalent to that of the state-of-the-art metal nanowire networks. We demonstrated that the transmittance of the metal networks becomes homogeneous from deep-ultraviolet (200 nm) to near-infrared (2000 nm) when the size of the wire spacing increases to micrometer size. Theoretical and experimental analyses indicated that we can improve the conductivity of the metal networks as well as keep their transmittance by increasing the thickness of the metal films. We also carried out durability tests to demonstrate our as-fabricated metal networks having good flexibility and strong adhesion. PMID- 25738310 TI - Sorafenib-irinotecan sequential therapy augmented the anti-tumor efficacy of monotherapy in hepatocellular carcinoma cells HepG2. AB - The current study aimed to evaluate the efficacy of sorafenib-based combined therapy against hepatocellular carcinoma (HCC). HepG2 cells were exposed to sorafenib, irinotecan, and oxaliplatin and then subjected to MTT assay to determine chemosensitivity. Flow cytometry was used to examine cell cycle distribution and cell apoptosis. Levels of cleaved caspase-8, -3, and PARP were determined by Western blot. Real-time PCR and Western blot were used to determine p53 expression, respectively. The efficacy of combined therapy were verified in nude mice bearing HepG2 xenografts. HepG2 cells used in the current study were sensitive to sorafenib, irinotecan, and oxaliplatin. Sorafenib arrested cell cycle in S phase and the peak effect appeared at 30 h post treatment. Sorafenib exposure for 30 h followed by irinotecan exposure for 48 h synergistically induced cell apoptosis in HepG2 cells. On the other hand, sorafenib-oxaliplatin sequential exposure for the same time only acted an additive effect in soliciting cell apoptosis. Sorafenib and irinotecan sequential treatment significantly increased the levels of cleaved caspase-8, -3, and PARP in HepG2 cells. Sorafenib suppressed p53 expression at both mRNA and protein levels, which might contribute to cell cycle arrest and sensitize tumor cells to irinotecan. Sorafenib and irinotecan sequential therapy was obviously superior to monotherapy in suppressing the growth of HepG2 xenografts. Sorafenib-irinotecan sequential treatment augmented the efficacy of either drug used alone in soliciting HepG2 cells apoptosis in vitro and in suppressing the growth of HepG2 xenografts in vivo. KEYWORDS: hepatocellular carcinoma, irinotecan, sorafenib, synergistic effect. PMID- 25738311 TI - The endoplasmic reticulum stress response is associated with insulin resistance mediated drug resistance in HepG2 cells. AB - Insulin resistance has a close relationship with tumorigenesis, tumor progression, and cancer prognosis. Importantly, the liver is the main target tissue of insulin, and the resistance to chemotherapeutic agents has been reported in hepatocarcinoma. However, little is known about the relationship between drug resistance and insulin resistance in hepatocarcinoma. Therefore, we treated HepG2 cells (a human hepatoma cell line) with high concentrations of insulin to establish a cell-based model of insulin resistance (HepG2/IR cells) to define the relationship between insulin resistance and the resistance to chemotherapy. We identified that HepG2/IR cells exhibited stable insulin resistance, with decreased glucose consumption, reduced glycogen synthesis, and decreased expression of the insulin receptor gene. HepG2/IR cells also exhibited endoplasmic reticulum (ER) dilatation and degranulation. Molecular markers of endoplasmic reticulum stress, including glucose-regulated protein78 (GRP78) and phosphorylated protein kinase R-like ER kinase (p-PERK), increased significantly, which was accompanied by increased reactive oxygen metabolism and decreased mitochondrial membrane potential. In addition, HepG2/IR cells were resistant to the chemotherapy agent Adriamycin, which was accompanied by the upregulation of multidrug resistance gene 1/ P-glycoprotein (P-gp; an endoplasmic reticulum chaperone that plays a role in ER stress), and enhanced drug efflux. These data suggest that the endoplasmic reticulum (ER) stress response was active in HepG2/IR cells, and that insulin resistance was related to drug resistance in HepG2 cells. Interestingly, the ER stress and chemotherapy resistance observed in HepG2/IR cells could be reversed by treatment with the insulin sensitizer pioglitazone. Therefore, our study suggests that there is a close relationship between the resistance to chemotherapy and insulin resistance in HepG2 cells, and that the ER stress response play a role in insulin resistance-mediated drug resistance in hepatocarcinoma cells. KEYWORDS: Insulin resistance, drug resistance, P-gp, endoplasmic reticulum stress, HepG2 cells. PMID- 25738312 TI - Noninternalizing targeted cytotoxics for cancer therapy. AB - Conventional cancer chemotherapy is limited by the fact that small organic cytotoxic agents typically do not preferentially localize at the tumor site, causing unwanted toxicities to normal organs and limiting dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the tumor environment. While traditionally internalizing ligands have been used for such targeting applications, increasing experimental evidence suggests that the ligand based delivery of anticancer drugs to the extracellular space in the tumor, followed by suitable release strategies, may mediate a potent anticancer activity. In this review, we outline the main requirements for the development of noninternalizing targeted cytotoxics. PMID- 25738313 TI - BAG3 increases the invasiveness of uterine corpus carcinoma cells by suppressing miR-29b and enhancing MMP2 expression. AB - Approximately 30% of uterine corpus carcinomas are diagnosed at an advanced stage and have a poor prognosis. Our previous study indicated that BCL2-associated athanogene 3 (BAG3) enhances matrix metalloproteinase-2 (MMP2) expression and binds to MMP2 to positively regulate the process of cell invasion in ovarian cancer cells. Recently, altered miRNA expression patterns were observed in several groups of patients with endometrial cancers. One of the altered miRNAs, miR-29b, reportedly reduces tumor invasiveness by suppressing MMP2 expression. Our aim in the present study was to examine the relationships among BAG3, miR-29b and MMP2 in endometrioid adenocarcinoma cells. We found that BAG3 suppresses miR 29b expression and enhances MMP2 expression, which in turn increases cell motility and invasiveness. Moreover, restoration of miR-29b through BAG3 knockdown reduced MMP2 expression, as well as cell motility and invasiveness. Collectively, our findings indicate that BAG3 enhances MMP2 expression by suppressing miR-29b, thereby increasing the metastatic potential of endometrioid adenocarcinomas. PMID- 25738314 TI - MicroRNA-125b is involved in atherosclerosis obliterans in vitro by targeting podocalyxin. AB - Cardiovascular disease associated with oxidative stress, including atherosclerosis, is the leading cause of mortality worldwide. The accelerated proliferation and migration of vascular smooth muscle cells are the predominant characteristics of atherogenesis, and endothelial dysfunction is a major risk factor for the pathogenesis of atherosclerosis. Podocalyxin (PODXL), a type I member of the cluster of differentiation 34 family of sialomucins, functions as a pro-adhesive molecule. Emerging evidence has revealed the importance of micro (mi)RNAs in the cardiovascular system. The present study demonstrated that there was an inverse association between miRNA (miR)-125b and PODXL in human umbilical vein endothelial cells and human aortic vascular smooth muscle cells (HAVSMCs) treated with oxidized low-density lipoprotein (LDL) and platelet derived growth factor. Additionally, miR-125b had a suppressive function in cell proliferation and migration, at least partially via targeting PODXL in the HAVSMCs. Furthermore, the data suggested that the functions of miR-125b in arteriosclerosis obliterans may be associated with transgelin, lectin-type oxidized LDL receptor-1, vascular endothelial-cadherin, intercellular adhesion molecule-1, interleukin-6 and monocyte chemotactic protein-1. In conclusion, miR 125b was found to be important in arteriosclerosis obliterans by suppressing the expression of PODXL and may serve as a potential therapeutic target for the treatment of arteriosclerosis obliterans. PMID- 25738315 TI - A plea for male contraception. PMID- 25738316 TI - Maternal migration and autism risk: systematic analysis. AB - Autism (AUT) is one of the most prevalent developmental disorders emerging during childhood, and can be amongst the most incapacitating mental disorders. Some individuals with AUT require a lifetime of supervised care. Autism Speaks reported estimated costs for 2012 at L34 billion in the UK; and $3.2 million-$126 billion in the US, Australia and Canada. Ethnicity and migration experiences appear to increase risks of AUT and relate to underlying biological risk factors. Sociobiological stress factors can affect the uterine environment, or relate to stress-induced epigenetic changes during pregnancy and delivery. Epigenetic risk factors associated with AUT also include poor pregnancy conditions, low birth weight, and congenital malformation. Recent studies report that children from migrant communities are at higher risk of AUT than children born to non-migrant mothers, with the exception of Hispanic children. This paper provides the first systematic review into prevalence and predictors of AUT with a particular focus on maternal migration stressors and epigenetic risk factors. AUT rates appear higher in certain migrant communities, potentially relating to epigenetic changes after stressful experiences. Although AUT remains a rare disorder, failures to recognize its public health urgency and local community needs continue to leave certain cultural groups at a disadvantage. PMID- 25738317 TI - Red wine consumption is associated with fecal microbiota and malondialdehyde in a human population. AB - OBJECTIVES: Red wine intake has been associated with a lower risk of cardiovascular disease; its polyphenol content is the primary cause of antioxidant and anti-inflammatory properties attributed to this beverage. However, the way in which these activities are exerted is not yet clear, although some authors have proposed that intestinal microbiota could be implicated. METHODS: The association between red wine intake, inflammation, and oxidative stress parameters and fecal microbial populations has been explored in 38 adult volunteers. Food intake was recorded by means of an annual food frequency questionnaire (FFQ). Energy, cholesterol, and ethanol intake were analyzed using the nutrient Food Composition Tables developed by Centro de Ensenanza Superior de Nutricion y Dietetica (CESNID) and polyphenol intake was obtained from the Phenol Explorer Database. Fecal levels of Akkermansia, Bacteroides, Bifidobacterium, Blautia coccoides group, Clostridium leptum group, Lactobacillus group, and Faecalibacterium prausnitzii were determined by quantitative polymerase chain reaction. Serum concentrations of C-reactive protein (CRP), malondialdehyde (MDA), total antioxidant capacity (TAC), cholesterol, triglycerides and glucose were analyzed by standard methods. RESULTS: Subjects with regular consumption of red wine (mean = 100 ml/day) had lower serum concentrations of MDA and lower fecal levels of B. coccoides, C. leptum, Bifidobacterium, and Lactobacillus. A positive association between MDA levels and B. coccoides and Lactobacillus was also found. CONCLUSION: Regular consumption of red wine appears to be associated with a reduced serum lipoperoxidation in which the intestinal microbiota may be involved. PMID- 25738318 TI - Abeliaside, a new phenolic glucoside from Abelia triflora. AB - A new phenolic glucoside, abeliaside, along with four known compounds, 5,6,7,4' tetrahydroxy flavones, caffeic acid, 4-O-caffeoylquinic acid and caffeic acid glucoside, was isolated from the leaves of Abelia triflora R. Br. (Caprifoliaceae). The structure of the new compound was elucidated by different spectroscopic techniques. Compounds 1-5 were assayed for their anticancer activities against two cancerous human cell lines, MCF-7 and PC-3 cells, and normal Vero cell line using the crystal violet staining method. From the results it could be seen that caffeic acid possessed the highest anticancer effect against MCF-7 (IC50: 17 MUg/mL) and PC-3 (IC50: 20.1 MUg/mL) compared to vinblastine sulphate as reference drug (IC50: 4.6, 2.8 MUg/mL). The other compounds showed weak anticancer activity on both cell lines. PMID- 25738319 TI - Expression and Functional Roles of the Pepper Pathogen-Induced bZIP Transcription Factor CabZIP2 in Enhanced Disease Resistance to Bacterial Pathogen Infection. AB - A pepper bZIP transcription factor gene, CabZIP2, was isolated from pepper leaves infected with a virulent strain of Xanthomonas campestris pv. vesicatoria. Transient expression analysis of the CabZIP2-GFP fusion protein in Nicotiana benthamiana revealed that the CabZIP2 protein is localized in the cytoplasm as well as the nucleus. The acidic domain in the N-terminal region of CabZIP2 that is fused to the GAL4 DNA-binding domain is required to activate the transcription of reporter genes in yeast. Transcription of CabZIP2 is induced in pepper plants inoculated with virulent or avirulent strains of X. campestris pv. vesicatoria. The CabZIP2 gene is also induced by defense-related hormones such as salicylic acid, methyl jasmonate, and ethylene. To elucidate the in vivo function of the CabZIP2 gene in plant defense, virus-induced gene silencing in pepper and overexpression in Arabidopsis were used. CabZIP2-silenced pepper plants were susceptible to infection by the virulent strain of X. campestris pv. vesicatoria, which was accompanied by reduced expression of defense-related genes such as CaBPR1 and CaAMP1. CabZIP2 overexpression in transgenic Arabidopsis plants conferred enhanced resistance to Pseudomonas syringae pv. tomato DC3000. Together, these results suggest that CabZIP2 is involved in bacterial disease resistance. PMID- 25738320 TI - Feasibility of Implementing Shared Medical Appointments (SMAs) for Office-Based Opioid Treatment With Buprenorphine: A Pilot Study. AB - BACKGROUND: Shared medical appointments (SMAs) are designed to improve patient satisfaction and increase access to treatment. In a typical SMA, 6-12 patients with similar diagnoses attend a group appointment with their health care providers, often lasting 60-120 minutes. All components of an individual visit are completed, and additional time is spent providing education and facilitating peer support. The aim of this study was to report on patient and program outcomes after implementation of SMA-based office-based opioid treatment with buprenorphine. METHODS: The study was conducted at a hospital-based outpatient psychiatric clinic that previously did not offer any office-based opioid treatment with buprenorphine. Demographic and clinical data (treatment retention, depression, anxiety, craving scores, and urine toxicology results) were extracted from the medical records. Patients were recruited to complete a survey assessing their experience. RESULTS: Ninety-three patients enrolled in the program, and 52.7% remained in treatment at 6 months. The proportion of aberrant opioid urine results, depression, anxiety, and craving decreased significantly from baseline to 6 months. Twenty-two patients completed the survey, who generally agreed that the SMA format allowed for more time with physicians, more support from peers, better coordination of care, and more predictable times for visits. CONCLUSIONS: Implementation of an SMA-based buprenorphine program was feasible, with treatment outcomes comparable to traditional models of care. More research is needed to explore the impact of SMA on buprenorphine treatment. PMID- 25738321 TI - Helminth Parasites of the Juvenile Hawksbill Turtle Eretmochelys imbricata (Testudines: Cheloniidae) in Brazil. AB - The helminth fauna of 31 juvenile specimens of Eretmochelys imbricata from the Brazilian coast was examined. Seventeen individuals were infected with helminths (54.8%). The helminths found were: Diaschistorchis pandus, Cricocephalus albus, Metacetabulum invaginatum, Pronocephalus obliquus (Pronocephalidae), Cymatocarpus solearis (Brachycoeliidae), Styphlotrema solitaria (Styphlotrematidae), Carettacola stunkardi, Amphiorchis caborojoensis (Spirorchiidae), Orchidasma amphiorchis (Telorchiidae), and Anisakis nematode larvae. This report is the first analysis of parasite communities in this host. PMID- 25738322 TI - MCM2 is a therapeutic target of lovastatin in human non-small cell lung carcinomas. AB - Human non-small cell lung carcinoma (NSCLC) is one of the most common cancer worldwide. In previous studies, lovastatin, acting as an inhibitor of 3-hydroxy-3 methylglutaryl Co A (HMG-CoA) reductase, exhibited significant antitumor activity during tumorigenesis. However, whether or not this effect is mediated through changes in minichromosome maintenance (MCM) 2 expression remains unclear. The present study investigated whether lovastatin inhibits proliferation due to MCM2 in NSCLCs. We first assessed the effects of lovastatin on cell anti proliferation, cell cycle progression and apoptosis in NSCLC cells. We found, by quantitative RT-PCR and western blot analysis, that lovastatin treatment markedly and consistently inhibited the expression of MCM2. Then, to further explore the anticancer mechanism of lovastatin involving MCM2, we silenced MCM2 by siRNA in two cell lines (A549 and GLC-82). Silencing of MCM2 triggered G1/S arrest. Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest. In addition, siMCM2 induced apoptosis. Finally, lovastatin treatment increased p-JNK, which is involved in the downregulation of MCM2. In conclusion, our data suggest that MCM2 may be a novel therapeutic target of lovastatin treatment in NSCLCs. PMID- 25738324 TI - Global income and production impacts of using GM crop technology 1996-2013. AB - This paper provides an economic assessment of the value of using genetically modified (GM) crop technology in agriculture at the farm level. It follows and updates earlier annual studies which examined economic impacts on yields, key costs of production, direct farm income and effects, and impacts on the production base of the 4 main crops of soybeans, corn, cotton and canola. The commercialisation of GM crops has continued to occur at a rapid rate since the mid 1990s, with important changes in both the overall level of adoption and impact occurring in 2013. This annual updated analysis shows that there continues to be very significant net economic benefits at the farm level amounting to $20.5 billion in 2013 and $133.4 billion for the 18 years period (in nominal terms). These economic gains have been divided roughly 50% each to farmers in developed and developing countries. About 70% of the gains have derived from yield and production gains with the remaining 30% coming from cost savings. The technology have also made important contributions to increasing global production levels of the 4 main crops, having added 138 million tonnes and 273 million tonnes respectively, to the global production of soybeans and maize since the introduction of the technology in the mid 1990s. PMID- 25738323 TI - Role of transgene regulation in ex vivo lentiviral correction of artemis deficiency. AB - Artemis is a single-stranded endonuclease, deficiency of which results in a radiation-sensitive form of severe combined immunodeficiency (SCID-A) most effectively treated by allogeneic hematopoietic stem cell (HSC) transplantation and potentially treatable by administration of genetically corrected autologous HSCs. We previously reported cytotoxicity associated with Artemis overexpression and subsequently characterized the human Artemis promoter with the intention to provide Artemis expression that is nontoxic yet sufficient to support immunodevelopment. Here we compare the human Artemis promoter (APro) with the moderate-strength human phosphoglycerate kinase (PGK) promoter and the strong human elongation factor-1alpha (EF1alpha) promoter to regulate expression of Artemis after ex vivo lentiviral transduction of HSCs in a murine model of SCID A. Recipient animals treated with the PGK-Artemis vector exhibited moderate repopulation of their immune compartment, yet demonstrated a defective proliferative T lymphocyte response to in vitro antigen stimulation. Animals treated with the EF1alpha-Artemis vector displayed high levels of T lymphocytes but an absence of B lymphocytes and deficient lymphocyte function. In contrast, ex vivo transduction with the APro-Artemis vector supported effective immune reconstitution to wild-type levels, resulting in fully functional T and B lymphocyte responses. These results demonstrate the importance of regulated Artemis expression in immune reconstitution of Artemis-deficient SCID. PMID- 25738325 TI - Negative phototropism is seen in Arabidopsis inflorescences when auxin signaling is reduced to a minimal level by an Aux/IAA dominant mutation, axr2. AB - Inflorescences of a dominant mutant of Arabidopsis Aux/IAA7, axr2, showed negative phototropism with a similar fluence response curve to the positive phototropism of wild-type stems. Application of a synthetic auxin, NAA, and an inhibitor of polar auxin transport, NPA, increased and decreased respectively the magnitude of the phototropic response in the wild type, while in axr2 application of NAA reduced the negative phototropic response and NPA had no effect. Decapitation of the apex induced a small negative phototropism in wild-type stems, and had no effect in axr2 plants. Inflorescences of the double mutants of auxin transporters, pgp1 pgp19, showed no phototropic response, while decapitation resulted in a negative phototropic response. These results suggest that negative phototropism can occur when the level of auxin or of auxin signaling is reduced to a minimal level, and that in plant axial organs the default phototropic response to unilateral blue light may be negative. Expression of axr2 protein by an endodermis-specific promoter resulted in agravitropism of inflorescences in a similar way to that of axr2, but phototropism was normal, confirming that the endodermis does not play a critical role in phototropism. PMID- 25738327 TI - Bioactive isopimarane diterpenes from the fungus, Epicoccum sp. HS-1, associated with Apostichopus japonicus. AB - One new isopimarane diterpene (1), together with two known compounds, 11 deoxydiaporthein A (2) and iso-pimara-8(14),15-diene (3) were isolated from the culture of Epicoccum sp., which was associated with Apostichopus japonicus. Their structures were determined by the analysis of 1D and 2D NMR, as well as mass spectroscopic data. The absolute configuration of Compound 1 was deduced by a single-crystal X-ray diffraction experiment using CuKalpha radiation. In the bioactivity assay, both Compounds 1 and 2 exhibited alpha-glucosidase inhibitory activity with IC50 values of 4.6 +/- 0.1 and 11.9 +/- 0.4 MUM, respectively. This was the first report on isopimarane diterpenes with alpha-glucosidase inhibitory activity. PMID- 25738329 TI - Emergence and epidemiology of ciguatera in the coastal cities of southern China. AB - In the present review of 23 published case studies, the main objective is to report the emergence and epidemiology of ciguatera in the coastal cities of southern China. There was a sudden surge in ciguatera outbreaks in 2004. Ciguatera mostly occurred in the Guangdong Province. In Shenzhen, the incidence of ciguatera in 2004 was estimated to be over 7.5 per million people. In Foshan and Zhongshan, three large outbreaks each affecting over 100-200 subjects (caused by tiger grouper served at banquets) accounted for the much higher incidence of ciguatera in 2004 (>48.7 and >129.9 per million people). Humphead wrasse and areolated coral grouper were the other important ciguatoxic fish. In some subjects, risk factors for increased likelihood of (severe) ciguatera were present, namely concomitant alcohol consumption and ingestion of large reef fishes and CTX-rich fish parts. To prevent large outbreaks and severe illness, large apex predators from coral reefs should never be served at banquets and the public should realize the increased risk of severe symptoms due to ingestion of CTX-rich fish parts with alcohol. The systematic collection of accurate details, implementation of risk assessment process and continuing education for the public on prevention are of obvious importance. PMID- 25738326 TI - How exercise may amend metabolic disturbances in diabetic cardiomyopathy. AB - SIGNIFICANCE: Over-nutrition and sedentary lifestyle has led to a worldwide increase in obesity, insulin resistance, and type 2 diabetes (T2D) associated with an increased risk of development of cardiovascular disorders. Diabetic cardiomyopathy, independent of hypertension or coronary disease, is induced by a range of systemic changes and may through multiple processes result in functional and structural cardiac derangements. The pathogenesis of this cardiomyopathy is complex and multifactorial, and it will eventually lead to reduced cardiac working capacity and increased susceptibility to ischemic injury. RECENT ADVANCES: Metabolic disturbances such as altered lipid handling and substrate utilization, decreased mechanical efficiency, mitochondrial dysfunction, disturbances in nonoxidative glucose pathways, and increased oxidative stress are hallmarks of diabetic cardiomyopathy. Interestingly, several of these disturbances are found to precede the development of cardiac dysfunction. CRITICAL ISSUES: Exercise training is effective in the prevention and treatment of obesity and T2D. In addition to its beneficial influence on diabetes/obesity related systemic changes, it may also amend many of the metabolic disturbances characterizing the diabetic myocardium. These changes are due to both indirect effects, exercise-mediated systemic changes, and direct effects originating from the high contractile activity of the heart during physical training. FUTURE DIRECTIONS: Revealing the molecular mechanisms behind the beneficial effects of exercise training is of considerable scientific value to generate evidence-based therapy and in the development of new treatment strategies. PMID- 25738328 TI - Chitin and chitosan preparation from marine sources. Structure, properties and applications. AB - This review describes the most common methods for recovery of chitin from marine organisms. In depth, both enzymatic and chemical treatments for the step of deproteinization are compared, as well as different conditions for demineralization. The conditions of chitosan preparation are also discussed, since they significantly impact the synthesis of chitosan with varying degree of acetylation (DA) and molecular weight (MW). In addition, the main characterization techniques applied for chitin and chitosan are recalled, pointing out the role of their solubility in relation with the chemical structure (mainly the acetyl group distribution along the backbone). Biological activities are also presented, such as: antibacterial, antifungal, antitumor and antioxidant. Interestingly, the relationship between chemical structure and biological activity is demonstrated for chitosan molecules with different DA and MW and homogeneous distribution of acetyl groups for the first time. In the end, several selected pharmaceutical and biomedical applications are presented, in which chitin and chitosan are recognized as new biomaterials taking advantage of their biocompatibility and biodegradability. PMID- 25738330 TI - Biotransfer of beta-N-methylamino-L-alanine (BMAA) in a eutrophicated freshwater lake. AB - beta-N-Methylamino-L-alanine (BMAA), a neurotoxic non-protein amino acid, plays a significant role as an environmental risk factor in neurodegenerative diseases, such as amyotrophic lateral sclerosis. BMAA producers occur globally, colonizing almost all habitats and represent species from distinct phytoplanktonic groups, i.e., cyanobacteria, diatoms, and dinoflagellates. Bioaccumulation of BMAA in invertebrate and vertebrate organisms has also been registered around the globe. In the Baltic Sea, BMAA has been detected in several commercial fish species, raising the question of the bioaccumulation of BMAA in Swedish limnic systems. Here we find the presence of BMAA in water samples from Lake Finjasjon and identify its bioaccumulation patterns in both plankti-benthivorous and piscivorous fish, according to fish species, total weight, gender, and season of collection. For the first time, a large number of fish individuals were used in order to draw conclusions on BMAA bioaccumulation in a closed ecological community based on a statistical approach. We may, therefore, conclude that feeding patterns (plankti-benthivorous) and increased age of fish may lead to a higher tissue concentration of BMAA. PMID- 25738331 TI - Combination of cytokinin and auxin induces apoptosis, cell cycle progression arrest and blockage of the Akt pathway in HeLa cells. AB - Plant cytokinins and auxins have recently been proposed as novel cancer therapies, which proceed via different mechanisms; however, their combined use has not been investigated. To the best of our knowledge, the present study was the first to show that the cytokinin ortho-methoxytopolin-riboside (MeoTR) strongly inhibited the proliferation of HeLa cells, the effect of which was synergistically enhanced by auxin indole-3-acetic acid (IAA), while IAA demonstrated to have no cytotoxic effects on cells. MeoTR was found to activate intrinsic and extrinsic caspase-dependent pathways, and IAA potentiated this activation. In addition, these effects were blocked by Z-Val-Ala-Asp fluoromethylketone (Z-VAD-FMK), a pan-specific-caspase-inhibitor. IAA increased the MeoTR- induced inhibition of B cell lymphoma 2 (Bcl-2) and survivin, whereas IAA-only decreased Bcl-2 expression. MeoTR downregulated phosphorylated (p) pyruvate dehydrogenase kinase 1, p-Akt and p-glycogen synthase kinase 3beta, the effect of which was more potent in combination with IAA, despite the weak effect of IAA alone. LY294002, an Akt-inhibitor, was able to increase the inhibition of p-Akt through MeoTR and combination treatment. IAA and MeoTR increased the proportion of cells in S phase independently. However, the combination treatment induced a further increase. In addition, IAA and MeoTR treatment downregulated protein levels of cyclin A, cyclin-dependent kinase 2 (CDK2) and p-CDK2, and upregulated protein levels of p21 and p27. Furthermore, the combination treatment enhanced these effects, indicating that IAA potentiated the inhibitory effect of MeoTR on HeLa cells via cell cycle progression arrest and accumulation in S phase, coupled with the negative regulation of Bcl-2. In conclusion, the results of the present study suggested that treatment with these two phytohormones in combination, may offer a novel therapeutic strategy for the treatment of malignant cervical cancer. PMID- 25738332 TI - Lithium chloride induces mesenchymal-to-epithelial reverting transition in primary colon cancer cell cultures. AB - Epithelial-to-mesenchymal transition (EMT) confers stem cell-like phenotype and more motile properties to carcinoma cells. During EMT, the expression of E cadherin decreases, resulting in loss of cell-cell adhesion and increased migration. Expression of Twist1 and other pleiotropic transcription factors, such as Snail, is known to activate EMT. We established primary colon cancer cell cultures from samples of operated patients and validated cultures by cytogenetic and molecular biology approaches. Western blot assay, quantitative real-time PCR and immunofluorescence were performed to investigate the expression of E cadherin, vimentin, beta-catenin, cytokeratin-20 and -18, Twist1, Snail, CD44, cyclooxygenase-2 (COX2), Sox2, Oct4 and Nanog. Moreover, cell differentiation was induced by incubation with LiCl-containing medium for 10 days. We observed that these primary colorectal cancer (CRC) cells lost expression of the E-cadherin epithelial marker, which was instead expressed in cancer and normal colon mucosa of the same patient, while overexpressed vimentin (mesenchymal marker), Twist1, Snail (EMT markers) and COX2. Cytokeratin-18 was expressed both in tissues and cell cultures. Expression of stem cell markers, such as CD44, Oct4 and Nanog, were also observed. Following differentiation with the glycogen synthase kinase 3beta (GSK3beta) inhibitor LiCl, the cells began to express E-cadherin and, at once, Twist1 and Snail expression was strongly downregulated, suggesting a MET reverting process. In conclusion, we established primary colon mesenchymal cancer cell cultures expressing mesenchymal and epithelial biomarkers together with high level of EMT transcription factors. We propose that they could represent a good model for studying EMT and its reverting mechanism, the mesenchymal-to-epithelial transition (MET). Our observation indicates that LiCl, a GSK3beta inhibitor, induces MET in vitro, suggesting that LiCl and GSK3beta could represent, respectively, interesting drug, and target for CRC therapy. PMID- 25738333 TI - Discontinuation of disease-modifying anti-rheumatic drugs and clinical outcomes in the Rheumatoid Arthritis DMARD Intervention and Utilisation Study 2 (RADIUS 2). AB - OBJECTIVES: The purpose of this analysis was to examine discontinuation and reasons for discontinuation from disease-modifying anti-rheumatic (DMARD) therapies in the RADIUS 2 registry, a long-term, open-label, observational study of patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patients who participated in RADIUS 2 initiated etanercept (ETN) therapy at study entry and were followed for 5 years. In this post hoc analysis, patients who had received ETN continuously from entry to month 4 were categorised by treatment at month 4: ETN monotherapy, ETN+methotrexate (MTX), ETN+MTX+other DMARDs (OTH), or ETN+OTH. Outcomes were assessed at month 4 and at the time of any subsequent treatment change, and included Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: Of 3,484 patients analysed (982 ETN; 1,356 ETN+MTX; 537 ETN+MTX+OTH; 609 ETN+OTH), baseline demographic and clinical characteristics were similar across treatments. No treatment change occurred in 62.3%, 49.9%, 33.3%, and 37.1% of ETN, ETN+MTX, ETN+MTX+OTH, and ETN+OTH patients, respectively. The mean time on therapy from month 4 was longer for patients receiving ETN (23.3 months) or ETN+MTX (23.7 months) than those receiving ETN+MTX+OTH (18.0 months) or ETN+OTH (18.3 months). The greatest improvements in CDAI and HAQ-DI were seen in patients who continued on ETN. The most common reasons for discontinuing DMARD therapy were cost and ineffective treatment. CONCLUSIONS: Most patients who had received >=4 months of ETN continued on ETN throughout the 5-year observation period. Patients with greatest clinical and disability improvements tended to continue on ETN. PMID- 25738334 TI - 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginsenoside Rb1, enhances the production of hyaluronic acid through the activation of ERK and Akt mediated by Src tyrosin kinase in human keratinocytes. AB - The aim of the present study was to determine the mechanisms through which 20-O beta-D-glucopyranosyl-20(S)-protopanaxadiol (20GPPD) promotes the production of hyaluronic acid (HA) in human keratinocytes. 20GPPD is the primary bioactive metabolite of Rb1, a major ginsenoside found in ginseng (Panax ginseng). We sought to elucidate the underlying mechanisms behind the 20GPPD-induced production of HA. We found that 20GPPD induced an increase in HA production by elevating hyaluronan synthase 2 (HAS2) expression in human keratinocytes. The phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was also enhanced by 20GPPD in a dose-dependent manner. The pharmacological inhibition of ERK (using U0126) or Akt (using LY294002) suppressed the 20GPPD-induced expression of HAS2, whereas treatment with an epidermal growth factor receptor (EGFR) inhibitor (AG1478) or an intracellular Ca2+ chelator (BAPTA/AM) did not exert any observable effects. The increased Src phosphorylation was also confirmed following treatment with 20GPPD in the human keratinocytes. Following pre-treatment with the Src inhibitor, PP2, both HA production and HAS2 expression were attenuated. Furthermore, the 20GPPD-enhanced ERK and Akt signaling decreased following treatment with PP2. Taken together, our results suggest that Src kinase plays a critical role in the 20GPPD-induced production of HA by acting as an upstream modulator of ERK and Akt activity in human keratinocytes. PMID- 25738335 TI - Esthetic outcomes in relation to implant-abutment interface design following a standardized treatment protocol in a multicenter randomized controlled trial--a cohort of 12 cases at 1-year follow-up. AB - The design of an implant-abutment interface may have an impact on the peri implant soft tissue esthetics. In an ongoing randomized controlled trial (RCT) with 141 participants, the authors evaluated the peri-implant tissue responses around three different implant-abutment interface designs used to replace single teeth in the esthetic zone. The aim of this report is to describe the treatment protocol utilized in this ongoing RCT by (1) demonstrating in detail a clinical case treated under this protocol and (2) reporting peri-implant soft tissue responses in a cohort of 12 representative cases from the RCT at 1-year follow up. Male and female adults requiring single implants in the anterior maxilla were enrolled in the RCT according to the study protocol. Five months following any required extraction and/or socket bone grafting/ridge augmentation, one of the following three implant-abutment interfaces was placed and immediately provisionalized: (1) conical interface (CI; OsseoSpeed, Dentsply Implants), n = 4; (2) flat-to-flat interface (FI; NobelSpeedy Replace, Nobel Biocare), n = 4; or (3) platform-switch interface (PS; NanoTite Certain Prevail, Biomet 3i), n = 4. Twelve weeks later, definitive crowns were delivered. Throughout the treatment, peri-implant buccal gingival zenith height and mesial/distal papilla height were measured on stereotactic device photographs, and pink esthetic scores (PES) were determined. The demographics of the participants in each of the three implant abutment interface groups were very similar. All 12 study sites had ideal ridge form with a minimum width of 5.5 mm following implant site development performed according to the described treatment protocol. Using this treatment protocol for single-tooth replacement in the anterior maxilla, the clinicians were able to obtain esthetic peri-implant soft tissue outcomes with all three types of implant abutment interface designs at 1-year follow-up as shown by the Canfield data and PES. The proposed treatment protocol for single-tooth replacement in the esthetic zone provides a reliable method to obtain and assess the esthetic outcome as a function of implant-abutment interface design and is now in its fifth year of follow-up. PMID- 25738336 TI - Combined piezosurgery and selective distraction osteogenesis to correct malpositioned implants: a case report. AB - This case report shows the combined use of piezosurgical and orthodontic procedures to successfully relocate two severely malpositioned implants in the anterior maxilla by moving them separately, with the objective of attaining functional prosthetic restoration and acceptable esthetics. PMID- 25738337 TI - Partial lateralization of the nasopalatine nerve at the incisive foramen for ridge augmentation in the anterior maxilla prior to placement of dental implants: a retrospective case series evaluating self-reported data and neurosensory testing. AB - The objective of this study was to assess implant therapy after a staged guided bone regeneration procedure in the anterior maxilla by lateralization of the nasopalatine nerve and vessel bundle. Neurosensory function following augmentative procedures and implant placement, assessed using a standardized questionnaire and clinical examination, were the primary outcome variables measured. This retrospective study included patients with a bone defect in the anterior maxilla in need of horizontal and/or vertical ridge augmentation prior to dental implant placement. The surgical sites were allowed to heal for at least 6 months before placement of dental implants. All patients received fixed implant supported restorations and entered into a tightly scheduled maintenance program. In addition to the maintenance program, patients were recalled for a clinical examination and to fill out a questionnaire to assess any changes in the neurosensory function of the nasopalatine nerve at least 6 months after function. Twenty patients were included in the study from February 2001 to December 2010. They received a total of 51 implants after augmentation of the alveolar crest and lateralization of the nasopalatine nerve. The follow-up examination for questionnaire and neurosensory assessment was scheduled after a mean period of 4.18 years of function. None of the patients examined reported any pain, they did not have less or an altered sensation, and they did not experience a "foreign body" feeling in the area of surgery. Overall, 6 patients out of 20 (30%) showed palatal sensibility alterations of the soft tissues in the region of the maxillary canines and incisors resulting in a risk for a neurosensory change of 0.45 mucosal teeth regions per patient after ridge augmentation with lateralization of the nasopalatine nerve. Regeneration of bone defects in the anterior maxilla by horizontal and/or vertical ridge augmentation and lateralization of the nasopalatine nerve prior to dental implant placement is a predictable surgical technique. Whether or not there were clinically measurable impairments of neurosensory function, the patients did not report them or were not bothered by them. PMID- 25738338 TI - The use of a xenogeneic collagen matrix at the time of implant placement to increase the volume of buccal soft tissue. AB - The purpose of this study was to evaluate the efficacy of Mucograft (MG; a porcine-derived purified collagen membrane) to increase the thickness and height of the buccal soft tissue when placed at the time of implant placement in patients with thin or deficient keratinized tissue (KT). The primary endpoint of the study was the change in thickness and height of the buccal KT. Secondary endpoints included stability of the midbuccal soft tissue level; clinician rating of color, texture, and contour of treatment site; probing pocket depths (PPDs); assessment of satisfaction outcome; and patient assessment of pain/discomfort. Thirty-two patients were enrolled and 31 patients completed the study. There were no statistically significant (SS) differences between the MG and control groups for height measures. There was no SS difference for KT thickness (P = .117) between the groups at the final measurement (3 months postsurgery). However, there was an SS difference (P = .009) in favor of the MG group when comparing the difference in presurgical KT thickness to that 3 months postsurgery. Thus, MG was successful (compared to the control) in increasing the buccal KT. There were no SS differences between the groups for any of the other endpoints, including color, texture, contour, and pain assessment at any visit or successful outcome between the treatment group and the control. More cases and longer follow-up of implants placed with MG are needed to verify the results of this randomized prospective study. PMID- 25738339 TI - Soft tissue contour changes at immediate postextraction single-tooth implants with immediate restoration: a 12-month prospective cohort study. AB - In the maxillary arch from premolar to premolar, 26 single dental implants were inserted in fresh extraction sockets and immediately provisionalized. The bone-to implant gap was grafted with a bovine bone mineral. After 3 months, definitive ceramic crowns were placed. At baseline and after 1 year, the soft tissue horizontal width, mesiodistal papillary level, midfacial gingival level, and pink esthetic score were evaluated. No statistical differences were found between baseline and 1 year for all parameters. Immediate single-tooth implants, with immediate restoration, are capable of maintaining the soft tissue contour and esthetics compared to the pretreatment status. PMID- 25738340 TI - A customized zirconia abutment design combined with a CAD/CAM laminate veneer: a clinical report. AB - An alternative prosthetic treatment approach for single implants in the maxillary esthetic zone with an improper implant axis, limited interocclusal distance, inadequate abutment retention, and screw holes located at the labial surface is presented in this clinical report. The gingiva and soft tissues were contoured with provisional composite restorations to mimic the emergence profile of lateral incisors. Prefabricated zirconia abutments were customized with laminate veneer preparations by appropriate ceramic build-up with reference from the reshaped gingiva to avoid labiolingual overcontour. The laminate veneers were fabricated by computer-aided design/ computer-assisted manufacture to cover the screw hole of the angulated abutment at the labial surface. Preliminary results revealed improvement in esthetics; however, long-term clinical follow-up should be performed. PMID- 25738341 TI - Surface roughness of restoration margin preparations: a comparative analysis of finishing techniques. AB - This study compared the margin profile and surface roughness created by the tips of four different finishing instruments: fine diamond, dura white stone, tungsten carbide, and ultrasonic diamond-coated tips (UDTs). The aim was to determine which of these instruments produced the smoothest finish and created the most evenly contoured margin characteristics. It was hypothesized that UDTs would produce a rougher dentin surface than a fine diamond bur, that a tungsten carbide bur would provide a smoother finish than a fine diamond, and that the dura white stone would produce an intermediate finish. Forty extracted premolars were divided into two groups. For the first group, a 1.5 x 3.0-mm dentin slot was prepared in 30 teeth using a control 50-MUm diamond bur, followed by one of the four finishing instruments. The surface roughness (Ra) was then measured using a surface profilometer and a one-way analysis of variance followed by a post hoc Bonferroni test to assess whether any statistical difference existed among the Ra values. For the second group, shoulder margins were prepared in 10 teeth. They were then refined with one of the four finishing instruments and examined with scanning electron microscopy (SEM). The fine diamond bur created a significantly smoother surface than the control diamond (P < .001), UDTs (P < .007), and tungsten carbide bur (P < .010). The fine diamond was not found to be significantly smoother than the dura white stone. SEM images of the fine diamond showed divoting on the margin floor. The dura stone showed a well-defined, undamaged margin. The tungsten carbide bur created frequent chipping in enamel margins. The UDT specimens showed an inconsistent finish and discrete patches of open dentinal tubules. The fine diamond created the lowest Ra values; however, the dura stone offered efficient finishing and less damage to the margin profile. PMID- 25738342 TI - Effect of restorative, endodontic, and fatigue treatments on the cuspal deflection of maxillary premolars subjected to different cyclic occlusal forces: an in vitro study. AB - This study aimed to determine the effect of adhesive direct composite restorations, endodontic treatments, and fatigue treatments on the cuspal deflection of maxillary premolars subjected to different cyclic occlusal forces. Thirty intact maxillary second premolars were selected. Ten teeth were left untreated (group IN), 10 teeth were subjected to endodontic and restorative treatment (group FL), and the remaining 10 teeth were subjected to endodontic, restorative, and fatigue treatments (group FT). All teeth were subjected to 5 occlusal compressive loading forces (98, 147, 196, 245, and 294 N) with a universal testing device. A total of 15 experimental groups were obtained with 3 tooth conditions (IN, FL, FT) and 5 different occlusal loading values. Deflection amounts (MUm) were measured with laser sensors and recorded, and obtained data were statistically analyzed with one-way analysis of variance at a significance level of .05. Mean cuspal deflection values (MUm) and SDs of experimental groups ranged as follows: IN-98 (24.4 +/- 19.8), IN-147 (34.8 +/- 28.9), IN-196 (43.8 +/ 34.7), IN-245 (54.5 +/- 46.4), IN-294 (60.3 +/- 50.6), FL-98 (56 +/- 49.1), FL 147 (62.6 +/- 49.6), FL-196 (72.4 +/- 52.1), FL-245 (81.3 +/- 56), FL-294 (92.2 +/- 60.9), FT-98 (77.2 +/- 80.9), FT-147 (83.4 +/- 81.3), FT-196 (92.6 +/- 83.7), FT-245 (102.7 +/- 85.4), and FT-294 (124.2 +/- 89.5). Mean values of three main experimental groups were as follows: IN (43.5 MUm), FL (72.9 MUm) and FT (96.0 MUm). Significant differences were found between the three main groups and relevant subgroups (P < .001). Highest cuspal deflection values (CDV) were obtained in FT groups. Lowest CDV were obtained in IN groups. FL groups showed higher deflection values than IN groups. CDV increased progressively as the teeth were restored and subjected to fatigue treatment. PMID- 25738343 TI - Surgical combined approach for alveolar ridge augmentation with titanium mesh and rhPDGF-BB: a 3-year clinical case series. AB - The purpose of this case series was to report the clinical outcomes and histologic findings of vertical ridge augmentation using a combination of titanium mesh and recombinant human platelet-derived growth factor BB (rhPDGF BB). Two patients were included, and anorganic bovine bone particles were used. The bone graft was mixed with rhPDGF-BB and loaded onto the bony defect up to the level of the adjacent alveolar crest. A preadapted titanium mesh was placed over the grafted region; no areas of the grafted region were exposed. Postoperative healing was without complications. During reentry surgery for removal of the titanium mesh, all implants could be placed according to the prosthetic design. This report demonstrates the remarkable efficacy of guided bone regeneration using a combination of titanium mesh and rhPDGF for vertical ridge augmentation, thus expanding the indications for implant therapy and allowing recovery of the three-dimensional esthetic architecture in a severely resorbed alveolar ridge. PMID- 25738344 TI - Immediate functional loading of posterior implants placed in partially edentulous patients: a preliminary report on a prospective clinical study. AB - The goal of this study was to investigate outcomes of implants placed in the partially edentulous posterior maxilla and mandible and restored with two- to four-unit fixed prostheses that were functionally loaded immediately after implant placement. Forty-nine patients were treated, and 63 fixed prostheses were inserted on 140 implants. After an average of 8.6 months of follow-up, 2 implants failed-a cumulative success rate of 98.6%. These preliminary results support other findings that suggest patients with maxillary and mandibular partial posterior edentulism can confidently be treated with immediately loaded dental implants. PMID- 25738345 TI - Evaluation of root coverage with and without connective tissue graft for the treatment of single maxillary gingival recession using an image analysis system: a randomized controlled clinical trial. AB - The aim of this prospective randomized clinical study was to evaluate, by means of an image analysis system, the efficacy of two different surgical procedures for the treatment of Miller Class I and II maxillary gingival recession. Patients treated for maxillary gingival recession were recruited and randomly divided into two groups: patients who received a coronally advanced flap with connective tissue graft (CAF + CTG) or CAF alone. Outcome parameters included complete root coverage, recession reduction, and keratinized tissue amount. Twenty-five patients completed the 12-month follow-up period. Patients in the CAF + CTG group showed a better primary outcome- gingival recession at 12 months-than CAF patients (P = .0001). Gingival recession at 12 months had a median of 0.5 (interquartile range [IQR] 0.5 to 0.6) in the CAF + CTG group and a median of 1.0 (IQR 0.9 to 1.1) in the CAF group. CAF + CTG and CAF groups had similar complete root coverage at 6 and 12 months. Recession and keratinized tissue width significantly decreased over time (P < .0001), with no effect of treatment or of treatment over time. Buccal probing depth had similar values over time (P = .28) and in the two groups (P = .52). Buccal clinical attachment level had similar values in the two groups (P = .87); moreover, mesial and distal clinical attachment levels did not show any variation over time (P = .88 and P = .68, respectively). By means of a computerized image analysis system better outcomes in terms of recession reduction after 12 months of follow-up were measured for maxillary gingival recessions treated with CAF and CTG. Adjunctive application of a CTG under a CAF increased the probability of achieving complete root coverage in maxillary Miller Class I and II defects (61.5% versus 83.3%; P = .38). Both treatments were equally effective in providing a consistent reduction of the baseline recession. PMID- 25738346 TI - A double-layer technique using an acellular dermal matrix for the treatment of Miller Class I and II gingival recession defects: 1-year results of 50 consecutive cases. AB - The aim of this study was to evaluate the performance of a double-layer technique using an acellular dermal matrix (ADM) in conjunction with a coronally advanced flap (CAF) in treating Miller Class I and II gingival recession defects. A total of 50 patients with isolated Class I and II gingival recession defects were treated. At 52 weeks, the mean recession defect decreased from 3.8 +/- 0.9 mm to 0.2 +/- 0.5 mm. This represents 94.7% root coverage. Complete root coverage was achieved in 80.0% of the cases. Statistical improvements also were found with probing depths and clinical attachment levels. These results support the use of a double-layer technique using ADM in conjunction with a CAF in treating Class I and II recession defects. PMID- 25738347 TI - MMP-9 -1562 C>T (rs3918242) promoter polymorphism as a susceptibility factor for multiple gingival recessions. AB - The objective of this pilot study was to investigate the potential role of -1562 C>T single nucleotide polymorphism (SNP) in the promoter region of the matrix metalloproteinase-9 (MMP-9) gene as a risk modulator in the development of multiple gingival recessions (MGRs) in young adults in the Serbian population. The study sample comprised 161 systemically healthy people: 60 with MGRs and 101 controls with healthy periodontal tissues. Genotyping was done using polymerase chain reaction/restriction fragment length polymorphism approach on DNA obtained from buccal swabs. Clinical measurements included vertical recession depth (VRD), clinical attachment level (CAL), keratinized gingival width (KGW), visible plaque index (PI), and bleeding on probing (BOP). Heterozygotes (CT) were significantly more frequent in the MGRs group than in the control group (P = .005) and carriers of the T allele had an approximately threefold increase of MGRs risk. Patients with the CT genotype exhibited significantly higher values of VRD and CAL and significantly lower values of KGW than patients with the wildtype genotype. Associations among different genotypes and periodontal biotypes in the MGRs group remained insignificant because all participants exhibited thin biotype. The -1562 C>T SNP in the promoter region of MMP-9 appears to be a risk factor for MGR development and a potential predictor of more severe clinical phenotype. PMID- 25738348 TI - Prospective comparative study of tapered implants with SLA surfaces in the maxillary posterior area according to 3- and 6-month loading time. AB - The purpose of this study was to demonstrate clinical outcomes of sandblasted, large-grit, acid-etched (SLA)-surfaced tapered implants when early loaded in partially edentulous spaces in the maxilla. SLA-surfaced implants were placed in participants in the maxillary posterior edentulous area. At the time of definitive restoration, participants were allocated either to group 1 (3-month loading group) or group 2 (6-month loading group). A total of 36 participants (18 people [35 implants] in group 1 and 18 [33 implants] in group 2) were analyzed. Clinical outcomes, including survival rate and peri-implant parameters such as marginal bone loss were measured 1 year after loading. The survival rate was 97.0% in group 1 and 100% in group 2. Marginal bone loss was 0.22 +/- 0.34 mm in group 1 and 0.17 +/- 0.25 mm in group 2 at 1 year after loading (P = .488). There were no significant differences between groups in keratinized mucosal width (P = .206), Plaque Index (P = .677), or Gingival Index (P = .558). With adequate remaining bone height and primary implant stability achieved, the 3-month early loading of SLA-surface tapered implants may be a viable choice when restoring posterior maxillary edentulous areas. PMID- 25738349 TI - Association of salivary lipid peroxidation levels, antioxidant enzymes, and chronic periodontitis. AB - This study assessed the activities of antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR), and catalase (CAT) and free radical damage marker malondialdehyde (MDA) levels in saliva of 30 patients with chronic periodontitis (CP) compared to 30 healthy controls by spectrophotometry. MDA levels were significantly elevated in the CP group, whereas the SOD, CAT, and GR activities were significantly reduced compared to healthy controls. MDA levels demonstrated a significant direct correlation with all periodontal parameters, whereas all antioxidant enzymes studied (SOD, CAT, and GR) showed an inverse correlation. These findings support the idea that oxidative stress has a role in periodontal disease pathogenesis. PMID- 25738350 TI - Reconstruction of an atrophied posterior mandible with the inlay technique and allograft block versus allograft particulate: a case report. AB - This case report describes the bilateral reconstruction of a severely atrophic posterior mandible in a 30-year-old woman using allograft block versus particulate grafting in the inlay technique. Three months later, four dental implants were placed and bone core biopsy specimens were taken for histologic evaluation. During implant placement, the grafted sites were stable with good clinical osseointegration. The histologic analysis showed the presence of compact bone revealing areas of demarcation between grafted bone, newly formed bone, and bone-regenerated areas. Allografts might serve as an alternative to autogenous and heterologous grafting in posterior mandible augmentation using the inlay technique. PMID- 25738351 TI - Comparison of expression levels of RANKL and interleukin-17A in male and female orthodontic patients with and without appliances. AB - During orthodontic treatment, mechanical forces may change the components of gingival crevicular fluid (GCF), which reflects the cellular response in the periodontium. The objective of this study was to investigate the expressions of receptor activator of nuclear factor-kappa beta ligand (RANKL) and interleukin- 17A (IL-17A) in GCF in subjects with or without orthodontic appliances, the correlation between them, their gender predominance, and their relationship with treatment time. GCF was collected from 72 young people to detect the expressions of RANKL and IL-17A. Cytokine analysis was done with the help of enzyme-linked immunosorbent assay. Results showed that the expressions of RANKL and IL-17A were higher in the treatment group than the nontreatment group (P < .05) and higher in males than in females (P < .05). Their increments were well correlated with each other (r = 0.788, P = < .01) but were not time dependent. The authors concluded that these proteins increased in the treatment group and more in the young male orthodontic patients than in the female patients. The proteins were well correlated with each other. PMID- 25738352 TI - Correlation between the expression of DNMT1, and GSTP1 and APC, and the methylation status of GSTP1 and APC in association with their clinical significance in prostate cancer. AB - The aim of the present study was to investigate the correlation between the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1), glutathione S transferase-P1 (GSTP1) and adenomatous polyposis coli (APC), and the methylation status of GSTP1 and APC in prostate cancer (PCa) and benign prostatic hyperplasia (BPH), and to examine its clinical significance. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of DNMT1, GSTP1 and APC in 56 samples of PCa tissue and 10 samples of BPH tissue. Methylation-specific-PCR was used to detect the methylation status of the CpG island promoters of GSTP1 and APC. The positive rate of expression of DNMT1 in poorly-differentiated PCa, moderately-differentiated PCa, well differentiated PCa and BPH was 86.7%, 70.6%, 55.6% and 30.0%, respectively (P<0.05); for GSTP1, the positive rate was 13.3%, 29.4%, 44.4% and 90.0%, respectively (P<0.05); and for APC, the positive rate was 23.3%, 47.6%, 55.6% and 70.0%, respectively (P<0.05). The correlation coefficient for the association between the expression of DNMT1 and GSTP1 was -0.891 (P<0.05). Between the expression of DNMT1 and APC, the correlation coefficient was -0.721 (P<0.05). GSTP1 and APC were hypermethylated in the majority of PCa tissue samples. The positive rate of methylation of these genes in poorly-differentiated PCa was 83.3% and 73.3%, respectively. By contrast, hypomethylation (or demethylation) was observed in BPH samples, in which the positive rate of methylation was 10.0% and 20.0%, respectively (P<0.05). The increased expression of DNMT1, and the reduced expression of GSTP1 and APC have an important role in the development of PCa. Due to the high expression of DNMT1 mRNA, it is likely that the hypermethylation of CpG islands contributed to the silencing of GSTP1 and APC in PCa tissues. PMID- 25738353 TI - [Fractures of the tibial shaft]. AB - The tibia shaft is the most often fractured long bone of human beings. Among others traffic accidents (37.5 %), falls (17.8 %), sport accidents (30.9 %) and assaults (4.5 %) are typical mechanisms. A brief clinical examination including the correct classification of the fracture pattern and even more important the degree of the soft tissue damage are the most crucial factors for the following therapeutic cascade. This follows a defined algorithm based on the degree of soft tissue damage. As biplanar X-ray diagnostics are obligatory, CT scans are subject to complex fracture patterns and accompanying intraarticular pathologies.The treatment of tibial shaft fractures is the preserve of operative stabilization, which should be done primarily depending on the degree of the soft tissue injury. Here intramedullary methods - especially intramedullary nailing - are the golden standard.The most serious complication of these fractures is the development of a compartment syndrome. This requires rapid diagnosis and an adequate surgical management in order to avoid extensive muscle necrosis with ischaemic contractures and irreversible neurovascular deficits. Apart from postoperative infections, which are the predominant complication especially in open injuries, non union provide typical and late complications which are partly difficult to treat. These should, depending on their type, follow a dedicated treatment algorithm. PMID- 25738354 TI - Cluster of differentiation 147 is a key molecule during hepatocellular carcinoma cell-hepatic stellate cell cross-talk in the rat liver. AB - The cross-talk between hepatocellular carcinoma (HCC) cells and activated hepatic stellate cells (HSCs) is considered to be important for modulating the biological behavior of tumor cells. However, the molecular links between inflammation and cancer in the activation of HSCs remain to be elucidated. The present study demonstrated that cluster of differentiation (CD)147 is a key molecule involved in the interaction between HCC cells and HSCs. The effects of conditioned medium from human HCC cells on the activation of the human HSC line, LX-2, were assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blotting, RT-qPCR and gelatin zymography were also used to investigate the effects of CD147 on the activation of LX-2. The expression levels of alpha-smooth muscle actin (alpha-SMA) and CD147 were assessed in a co-culture system of LX-2 and FHCC-98 cells by immunofluorescence staining and immunoblotting. In hepatic tissues from a rat model of fibrosis, immunohistochemistry and immunoblotting were performed to detect the expression levels of alpha-SMA and CD147. Tumor-conditioned medium and CD147 promoted cell proliferation, activated LX-2 cells, increased the expression levels of alpha SMA, collagen I and tissue inhibitor of metalloproteinase-1 (TIMP-1), and increased the secretion of matrix metalloproteinase (MMP)-2. The HSCs, which were induced in the co-culture system of HCC cells and HSCs exhibited marked expression levels of CD147. In the hepatic tissue of rat models of fibrosis induced by CCl4, marked expression levels of CD147 were observed in the activated HSCs. Therefore, CD147 promoted the activation of HSCs and was a key molecule during HCC cell-HSC cross-talk in the rat liver. PMID- 25738355 TI - Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. AB - Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production. PMID- 25738356 TI - Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells. AB - The antitumor enzyme asparaginase, which targets essential amino acid L asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML. PMID- 25738357 TI - Tamoxifen improves cytopathic effect of oncolytic adenovirus in primary glioblastoma cells mediated through autophagy. AB - Oncolytic gene therapy using viral vectors may provide an attractive therapeutic option for malignant gliomas. These viral vectors are designed in a way to selectively target tumor cells and spare healthy cells. To determine the translational impact, it is imperative to assess the factors that interfere with the anti-glioma effects of the oncolytic adenoviral vectors. In the current study, we evaluated the efficacy of survivin-driven oncolytic adenoviruses pseudotyping with adenoviral fiber knob belonging to the adenoviral serotype 3, 11 and 35 in their ability to kill glioblastoma (GBM) cells selectively without affecting normal cells. Our results indicate that all recombinant vectors used in the study can effectively target GBM in vitro with high specificity, especially the 3 knob-modified vector. Using intracranial U87 and U251 GBM xenograft models we have also demonstrated that treatment with Conditionally Replicative Adenovirus (CRAd-S-5/3) vectors can effectively regress tumor. However, in several patient-derived GBM cell lines, cells exhibited resistance to the CRAd infection as evident from the diminishing effects of autophagy. To improve therapeutic response, tumor cells were pretreated with tamoxifen. Our preliminary data suggest that tamoxifen sensitizes glioblastoma cells towards oncolytic treatment with CRAd-S-5/3, which may prove useful for GBM in future experimental therapy. PMID- 25738358 TI - C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis. AB - The SMYD3 histone methyl transferase (HMTase) and the nuclear chaperone, HSP90, have been independently implicated as proto-oncogenes in several human malignancies. We show that a degenerate tetratricopeptide repeat (TPR)-like domain encoded in the SMYD3 C-terminal domain (CTD) mediates physical interaction with HSP90. We further demonstrate that the CTD of SMYD3 is essential for its basal HMTase activity and that the TPR-like structure is required for HSP90 enhanced enzyme activity. Loss of SMYD3-HSP90 interaction leads to SMYD3 mislocalization within the nucleus, thereby losing its chromatin association. This results in reduction of SMYD3-mediated cell proliferation and, potentially, impairment of SMYD3's oncogenic activity. These results suggest a novel approach for blocking HSP90-driven malignancy in SMYD3-overexpressing cells with a reduced toxicity profile over current HSP90 inhibitors. PMID- 25738360 TI - CCAAT/enhancer binding protein beta induces motility and invasion of glioblastoma cells through transcriptional regulation of the calcium binding protein S100A4. AB - We have previously shown that decreased expression of CCAAT/enhancer binding protein beta (C/EBPbeta) inhibits the growth of glioblastoma cells and diminishes their transformation capacity and migration. In agreement with this, we showed that C/EBPbeta depletion decreases the mRNA levels of different genes involved in metastasis and invasion. Among these, we found S100 calcium binding protein A4 (S100A4) to be almost undetectable in glioblastoma cells deficient in C/EBPbeta. Here, we have evaluated the possible role of S100A4 in the observed effects of C/EBPbeta in glioblastoma cells and the mechanism through which S100A4 levels are controlled by C/EBPbeta. Our results show that C/EBPbeta suppression significantly reduced the levels of S100A4 in murine GL261 and human T98G glioblastoma cells. By employing an S100A4-promoter reporter, we observed a significant induction in the transcriptional activation of the S100A4 gene by C/EBPbeta. Furthermore, overexpression of S100A4 in C/EBPbeta-depleted glioblastoma cells reverses the enhanced migration and motility induced by this transcription factor. Our data also point to a role of S100A4 in glioblastoma cell invasion and suggest that the C/EBPbeta gene controls the invasive potential of GL261 and T98G cells through direct regulation of S100A4. Finally, this study indicates a role of C/EBPbeta on the maintenance of the stem cell population present in GL261 glioblastoma cells. PMID- 25738361 TI - Cytoplasmic TRAF4 contributes to the activation of p70s6k signaling pathway in breast cancer. AB - Tumor necrosis factor receptor associated factor 4 (TRAF4) is an important adaptor protein that plays a significant role in several signaling pathways. By studying the relationship between TRAF4 and 70 kDa ribosomal protein S6 kinase (p70s6k) in vivo, we demonstrated that cytoplasmic TRAF4 was correlated with the activation of p70s6k in breast cancer. Moreover, we found that cytoplasmic TRAF4 expression in breast cancer patients was significantly associated with a poor prognosis. To determine the exact mechanism, we analyzed the interaction between TRAF4 and p70s6k and identified the Zinc fingers domain of TRAF4 was responsible for their interaction in MCF7 cells. Furthermore, we found that activation of p70s6k/S6 signaling pathway by TRAF4 requires the mammalian target of rapamycin (mTOR) activity; TRAF4 acted as a sensitizer. Tumor necrosis factor receptor associated factor 2 (TRAF2), as a binding partner of TRAF4, could also promoted activation of p70s6k signaling via upregulating cytoplasm expression of TRAF4 and played a critical role in TNFa-induced activation of p70s6k/S6 pathway. Finally, we demonstrated p70s6k/S6 signaling pathway played an important role in the promoting function of TRAF4 on cell proliferation. In summary, our work suggests a new direction for understanding the oncogenic function of TRAF4 in breast cancer. PMID- 25738359 TI - Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells. AB - Alterations of the EGFR/ERK and Hippo/YAP pathway have been found in non-small cell lung cancer (NSCLC). Herein, we show that ERK1 and ERK2 have an effect on the Hippo/YAP pathway in human NSCLC cells. Firstly, inhibition of ERK1/2 by siRNA or small-molecular inhibitors decreased the YAP protein level, the reporter activity of the Hippo pathway, and the mRNA levels of the Hippo downstream genes, CTGF, Gli2, and BIRC5. Secondly, degradation of YAP protein was accelerated after ERK1/2 depletion in NSCLC cell lines, in which YAP mRNA level was not decreased. Thirdly, forced over-expression of the ERK2 gene rescued the YAP protein level and Hippo reporter activity after siRNA knockdown targeting 3'UTR of the ERK2 gene in NSCLC cells. Fourthly, depletion of ERK1/2 reduced the migration and invasion of NSCLC cells. Combined depletion of ERK1/2 had a greater effect on cell migration than depletion of either one separately. Finally, the MEK1/2 inhibitor Trametinib decreased YAP protein level and transcriptional activity of the Hippo pathway in NSCLC cell lines. Our results suggest that ERK1/2 inhibition participates in reducing YAP protein level, which in turn down-regulates expression of the downstream genes of the Hippo pathway to suppress migration and invasion of NSCLC cells. PMID- 25738362 TI - WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression. AB - Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by poor prognosis and a low survival rate. VEGF-A is the most established angiogenic factor involved in the angiogenic-regulated tumor progression. WISP-1/CCN4 is an extracellular matrix-related protein that belongs to the Cyr61, CTGF, Nov (CCN) family and regulates many biological functions, such as angiogenesis. Previous studies indicated the role of WISP-1 in tumor progression. However, the angiogenic property of WISP-1 in the cancer microenvironment has never been discussed. Here, we provide novel insights regarding the role of WISP-1 in the angiogenesis through promoting VEGF-A expression. In this study, the correlation of WISP-1 and VEGF-A was confirmed by IHC staining of specimens from patients with OSCC. In vitro results indicated that WISP-1 induced VEGF-A expression via the integrin alphavbeta3/FAK/c-Src pathway, which transactivates the EGFR/ERK/HIF1-alpha signaling pathway in OSCC. This pathway in turn induces the recruitment of endothelial progenitor cells and triggers the neovascularization in the tumor microenvironment. Our in vivo data revealed that tumor-secreted WISP-1 promoted the angiogenesis through VRGF expression and increased angiogenesis-related tumor growth. Our study offers new information that highlights WISP-1 as a potential novel therapeutic target for OSCC. PMID- 25738363 TI - Progression of naive intraepithelial neoplasia genome to aggressive squamous cell carcinoma genome of uterine cervix. AB - Although cervical intraepithelial neoplasia (CIN) is considered a neoplasia, its genomic alterations remain unknown. For this, we performed whole-exome sequencing and copy number profiling of three CINs, a microinvasive carcinoma (MIC) and four cervical squamous cell carcinomas (CSCC). Both total mutation and driver mutation numbers of the CINs were significantly fewer than those of the MIC/CSCCs (P = 0.036 and P = 0.018, respectively). Importantly, PIK3CA was altered in all MIC/CSCCs by either mutation or amplification, but not in CINs. The CINs harbored significantly lower numbers of copy number alterations (CNAs) than the MIC/CSCCs as well (P = 0.036). Pathway analysis predicted that the MIC/CSCCs were enriched with cancer-related signalings such as cell adhesion, mTOR signaling pathway and cell migration that were depleted in the CINs. The mutation-based estimation of evolutionary ages identified that CIN genomes were younger than MIC/CSCC genomes. The data indicate that CIN genomes harbor unfixed mutations in addition to human papilloma virus infection but require additional driver hits such as PIK3CA, TP53, STK11 and MAPK1 mutations for CSCC progression. Taken together, our data may explain the long latency from CIN to CSCC progression and provide useful information for molecular diagnosis of CIN and CSCC. PMID- 25738364 TI - Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model. AB - Artesunate (ART), a semi-synthetic derivative of artemisinin, is one of the most commonly used anti-malarial drugs. Also, ART possesses anticancer potential albeit through incompletely understood molecular mechanism(s). Here, the effect of ART on various protein kinases, associated gene products, cellular response, and apoptosis was investigated. The in vivo effect of ART on the growth of human CML xenograft tumors in athymic nu/nu mice was also examined. In our preliminary experiments, we first observed that phosphorylation of p38, ERK, CREB, Chk-2, STAT5, and RSK proteins were suppressed upon ART exposure. Interestingly, ART induced the expression of SOCS-1 protein and depletion of SOCS-1 using siRNA abrogated the STAT5 inhibitory effect of the drug. Also various dephosphorylations caused by ART led to the suppression of various survival gene products and induced apoptosis through caspase-3 activation. Moreover, ART also substantially potentiated the apoptosis induced by chemotherapeutic agents. Finally, when administered intraperitoneally, ART inhibited p38, ERK, STAT5, and CREB activation in tumor tissues and the growth of human CML xenograft tumors in mice without exhibiting any significant adverse effects. Overall, our results suggest that ART exerts its anti-proliferative and pro-apoptotic effects through suppression of multiple signaling cascades in CML both in vitro and in vivo. PMID- 25738365 TI - Identification of a microRNA signature associated with risk of distant metastasis in nasopharyngeal carcinoma. AB - PURPOSE: Despite significant improvement in locoregional control in the contemporary era of nasopharyngeal carcinoma (NPC) treatment, patients still suffer from a significant risk of distant metastasis (DM). Identifying those patients at risk of DM would aid in personalized treatment in the future. MicroRNAs (miRNAs) play many important roles in human cancers; hence, we proceeded to address the primary hypothesis that there is a miRNA expression signature capable of predicting DM for NPC patients. METHODS AND RESULTS: The expression of 734 miRNAs was measured in 125 (Training) and 121 (Validation) clinically annotated NPC diagnostic biopsy samples. A 4-miRNA expression signature associated with risk of developing DM was identified by fitting a penalized Cox Proportion Hazard regression model to the Training data set (HR 8.25; p < 0.001), and subsequently validated in an independent Validation set (HR 3.2; p = 0.01). Pathway enrichment analysis indicated that the targets of miRNAs associated with DM appear to be converging on cell-cycle pathways. CONCLUSIONS: This 4-miRNA signature adds to the prognostic value of the current "gold standard" of TNM staging. In-depth interrogation of these 4-miRNAs will provide important biological insights that could facilitate the discovery and development of novel molecularly targeted therapies to improve outcome for future NPC patients. PMID- 25738366 TI - Rapamycin inhibits mSin1 phosphorylation independently of mTORC1 and mTORC2. AB - Current knowledge indicates that the mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2, regulating cell growth, proliferation, survival, differentiation, and motility. Recently mSin1 has been identified as a critical component of mTORC2, which is essential for phosphorylation of Akt and other signaling molecules. Studies have shown that rapamycin inhibits phosphorylation of mSin1. However, the underlying mechanism is unknown. Here we found that rapamycin inhibited phosphorylation of mSin1 potently and rapidly. Expression of rapamycin-resistant mutant of mTOR (mTOR-T), but not rapamycin-resistant and kinase dead mutant of mTOR (mTOR-TE), prevented rapamycin from inhibiting mSin1 phosphorylation, suggesting that rapamycin-induced dephosphorylation of mSin1 is mTOR-dependent. Surprisingly, ectopic expression of rapamycin-resistant and constitutively active p70 S6 kinase 1 (S6K1) did not confer resistance to rapamycin-induced dephosphorylation of mSin1. Furthermore, disruption of mTORC1 and mTORC2 by silencing raptor and rictor, respectively, or downregulation of S6K1 or Akt did not induce the dephosphorylation of mSin1 as rapamycin did. However, silencing mTOR or mLST8 mimicked the effect of rapamycin, inhibiting mSin1 phosphorylation. Our findings suggest that rapamycin inhibits mSin1 phosphorylation, which is independent of mTORC1 and mTORC2, but is possibly dependent on a new mTOR complex, which at least contains mTOR and mLST8. PMID- 25738368 TI - Molecular mechanism underlying the anticancer effect of simvastatin on MDA-MB-231 human breast cancer cells. AB - Breast carcinoma is the leading cause of cancer-associated mortality in female individuals worldwide. Previous studies have investigated the pro-apoptotic and antimetastatic effects of statins, and have demonstrated that simvastatin exhibits antitumor activity and potent chemopreventive effects. However, the mechanism underlying the effects of simvastatin in breast cancer remains to be elucidated. The present study demonstrated that simvastatin inhibited the proliferation of MDA-MB-231 human breast cancer cells in a dose-dependent manner, decreased the protein expression of B cell lymphoma 2 (Bcl-2) and increased the protein expression of Bcl-2-associated X protein in time- and dose-dependent manners. In addition, simvastatin arrested cells in the G0/G1 phase of the cell cycle, downregulated the protein expression levels of cyclin D1 and cyclin dependent kinase (CDK)2, mediated the mitochondria-dependent caspase cascade by increasing the protein expression levels of caspase-3, -8 and -9, and downregulated the protein expression of X-linked inhibitor of apoptosis, which induced cell apoptosis. In addition, simvastatin decreased the protein expression of matrix metalloproteinase (MMP)-2 and suppressed the activation of nuclear factor (NF)-kappaB in the MDA-MB-231 cells. Taken together, these results demonstrated that the antitumor effect of simvastatin in the human MDA-MB-231 breast cancer cell line was via the inhibition of cell proliferation, affecting the cell cycle, downregulating the expression levels of cyclin D1 and CDKs, inducing apoptosis and decreasing the expression of MMP-2, possibly by inhibiting the activation of NF-kappaB. Statin treatment may provide a novel therapeutic approach for the treatment of breast cancer. PMID- 25738367 TI - MicroRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma. AB - MicroRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion. PMID- 25738369 TI - Short hairpin RNA targeting AKT1 and PI3K/p85 suppresses the proliferation and self-renewal of lung cancer stem cells. AB - The aim of the present study was to investigate the effect of short hairpin (sh)RNA targeting AKT1 and phosphatidylinositol 3-kinase (PI3K)/p85 on the proliferation and self-renewal of lung cancer stem cells (LCSCs). The recombinant adenovirus expression vector, which contained shRNA targeting open reading frames of AKT1 and PI3K/p85, was transfected into LCSCs. It was found that AKT1 and PI3K/p85 expression was upregulated in LCSCs compared with that in the primary lung cancer cells. Recombinant adenovirus vector rAd5-siAKT1-siPI3K/p85 significantly downregulated AKT1 and PI3K/p85 mRNA and protein expression in LCSCs. The downstream factors, proliferating cell nuclear antigen (PCNA) and cyclin D1 were also downregulated, while p53 was upregulated. Following silencing of AKT1 and PI3K/p85, cell proliferation, tumor sphere formation and tumor formation in NOD/SCID mice were also reduced. According to the present results, it was hypothesized that the PI3K/Akt signaling pathway is important in the self renewal and proliferation of LCSCs, and that targeting the PI3K/Akt signaling pathway decreases the rate of tumor formation in vivo. PMID- 25738371 TI - A twin study of the trough plasma steady-state concentration of metformin. AB - OBJECTIVE: The aim of this study was to determine the intrapair similarity in trough steady-state plasma concentrations of metformin in monozygotic and dizygotic twin pairs. METHODS: We included 16 twin pairs (eight monozygotic and eight dizygotic twin pairs) for this study after contacting 524 twin pairs. They were dosed with metformin to steady state (1 g twice daily) for 6 days and on day 7, the trough concentration of metformin was determined 12 h after the last dose. RESULTS: There was no strong intrapair similarity in trough steady-state plasma concentrations of metformin in either dizygotic or monozygotic twin pairs. CONCLUSION: The trough steady-state plasma concentration of metformin does not appear to be tightly genetically regulated. The interpretation of this finding is limited by the small sample size. PMID- 25738370 TI - The influence of human GSTZ1 gene haplotype variations on GSTZ1 expression. AB - BACKGROUND/OBJECTIVES: The zeta-1 family isoform of GST biotransforms the investigational drug dichloroacetate (DCA) and certain other halogenated carboxylic acids. Haplotype variability in GSTZ1 influences the kinetics and, possibly, the toxicity of DCA. DCA metabolism correlates with expression of the GSTZ1 protein, so it is important to document variables that affect expression. Following up on a limited previous study, we tested the hypothesis that a coding single nucleotide polymorphism (SNP), the lysine (K) amino acid (E32>K) in GSTZ1 haplotypes linked to a promoter region SNP results in lower hepatic expression of GSTZ1. MATERIALS AND METHODS: The influence of K carrier and non-K carrier haplotypes on GSTZ1 expression was determined by analyzing 78 liver samples from individuals aged 7-84 years of various racial and ethnic backgrounds. GSTZ1 expression data were analyzed on the basis of the presence or absence of lysine 32. RESULTS: GSTZ1 protein expression differed significantly between K carrier and non-K carrier haplotypes (P=0.001) in Whites, but not in African-Americans (P=0.277). We attribute this difference in GSTZ1 expression among K carrier haplotypes in Whites to the linkage disequilibrium between the K or A allele from the G>A SNP (rs7975), within the promoter G>A-1002 SNP (rs7160195) A allele. There is no linkage disequilibrium between these two polymorphisms in African Americans. CONCLUSION: We conclude that the lower expression of GSTZ1 in Whites who possess the K carrier haplotype results in lower enzymatic activity and slower metabolism of DCA, compared with those who possess the non-K carrier haplotype. These results further define safe, genetics-based dosing regimens for chronic DCA administration. PMID- 25738372 TI - Disease activity assessment in IBD: clinical indices and biomarkers fail to predict endoscopic remission. AB - BACKGROUND: In the current management paradigm, mucosal healing is preferred over clinical remission as a therapeutic end point in inflammatory bowel disease (IBD) because of the benefits engendered with respect to durability of remission. Colonoscopy, however, is not suitable for regular disease monitoring, and routine clinical assessment is often inaccurate with respect to endoscopic disease activity. The current investigation set out to characterize the relationship that exists between endoscopically determined IBD activity and clinical and biochemical measures of disease severity and to determine clinically useful thresholds for use in clinical practice. METHODS: Patients attending for colonoscopy with known or suspected IBD were recruited. Clinical disease activity was recorded as per the Harvey-Bradshaw Index for Crohn's disease or the simple clinical colitis activity index for ulcerative colitis. Endoscopic activity was recorded using the simple endoscopic score for Crohn's disease or the modified Baron score for ulcerative colitis. Receiver operating characteristic analysis determined the predictive value and optimal predictive thresholds for clinical and biomarker data. RESULTS: The Harvey-Bradshaw Index was not able to distinguish active from inactive Crohn's disease. The sensitivity, specificity, and positive and negative predictive values of simple clinical colitis activity index to detect endoscopic active disease were 43%, 96%, 94%, and 51%, respectively. Any elevation of C-reactive protein or fecal calprotectin was predictive of active mucosal disease, however, no lower threshold could be identified that predicted disease in remission. CONCLUSIONS: C-reactive protein and fecal calprotectin are useful for the identification of endoscopically active IBD, but normal results do not confirm endoscopic remission. PMID- 25738373 TI - Hydrogen sulfide protects from colitis and restores intestinal microbiota biofilm and mucus production. AB - BACKGROUND: Microbiota dysbiosis and impaired barrier function are among the most prominent features of inflammatory bowel disease. In the gastrointestinal tract, hydrogen sulfide (H(2)S) is an important regulator of mucosal homeostasis. We hypothesized that H(2)S promotes resolution of colonic inflammation through actions on microbiota biofilm and the mucus barrier. METHODS: We used mice genetically deficient for a key enzyme for H(2)S production (cystathionine gamma lyase) and pharmacologically inhibited that enzyme during colitis in wild-type mice. We tested the effects of administering an H(2)S donor (diallyl disulfide) to rodents during hapten-induced colitis. Colonic microbiota biofilm was visualized by fluorescent in situ hybridization, and mucus granules were quantified with periodic acid-alcian blue staining. We exposed human microbiota biofilms and planktonic bacteria to H(2)S donors ex vivo to determine changes in their growth, viability, and biomass. RESULTS: Intestinal microbiota formed linear biofilms in the colon of healthy rodents. During colitis, microbiota biofilms were fragmented and mucus granule production decreased. Endogenous production of H(2)S had beneficial effects on establishment of microbiota biofilms and colonic mucus production. Therapeutic delivery of H(2)S into the colon reduced inflammation, restored the microbiota biofilm, and increased the production of mucus granules. In ex vivo human microbiota, H(2)S not only promoted biofilm formation but also reduced growth of planktonic bacteria. CONCLUSIONS: Our results suggest that H(2)S donors could be used therapeutically during colitis, facilitating correction of microbiota biofilm dysbiosis and mucus layer reconstitution. PMID- 25738374 TI - ATG16L1 and IL23R variants and genetic susceptibility to crohn's disease: mode of inheritance based on meta-analysis of genetic association studies. AB - BACKGROUND: Autophagy and regulation of IL-23 signaling pathways have been implicated in the pathogenesis of Crohn's disease (CD). We studied the mode of inheritance and reviewed the association of 2 polymorphic variants of ATG16L1 and IL23R with CD. METHODS: We searched the PubMed and ISI Web of Science databases (up to May 2014) for pertinent articles. We included all studies that had a case control design, with cases having CD and controls being healthy and reported full genotype frequencies for the ATG16L1 and/or IL23R variant of interest. We quantified the relative genetic risk using the model-free approach of the generalized odds ratio metric (ORG) and reported 95% precision estimates. Also, we explored the mode of inheritance using the degree of dominance h-index. RESULTS: Fifty-one studies fulfilled these requirements and were included in the analysis. These studies involved 12,762 patients and 16,735 controls evaluating the association of ATG16L1 (rs2241880 p.Thr300Ala) and 8110 patients and 11,900 controls evaluating the association of IL23R (rs11209026 p.Arg381Gln) with CD. The ATG16L1 variant rs2241880 was associated with increased susceptibility to CD (combined ORG = 1.38; 95% confidence interval, 1.29-1.48) and a nondominant mode of inheritance (suggesting that the effect of heterozygosity lies exactly in the middle of extreme homozygotes, h = 0). The IL23R variant rs11209026 was associated with significant protection (ORG = 0.46; 95% confidence interval, 0.41 0.53) and a recessive mode of inheritance, indicating that the effect of a heterozygous genotype would lie close to the wild-type homozygous genotype. In subgroup analysis, the significant effects persisted across Caucasian ancestry studies and pediatric populations but were lacking across studies in Asian populations. CONCLUSIONS: The ATG16L1 variant rs2241880 was associated with 38% increase in the risk for CD for higher mutational load, whereas IL23R variant rs11209026 decreased the risk by 54% for higher mutational load. The mode of inheritance for ATG16L1 variant demonstrated perfect additivity for genetic risk, whereas it showed recessiveness for the IL23R variant. This analysis permits risk stratification for CD based on the mutational status and highlight the need for additional studies in certain populations. PMID- 25738375 TI - Factors associated with mucosal healing in patients with ulcerative colitis in clinical remission. AB - BACKGROUND: Mucosal healing (MH) has been associated with improved outcomes in ulcerative colitis but factors associated with MH are not well defined. METHODS: Consecutive patients with ulcerative colitis in clinical remission (Mayo symptomatic subscore = 0) who had at least 1 colonoscopy since diagnosis from 6 centers were included. For patients who had at least 2 colonoscopies during follow-up, each colonoscopy was reviewed to define whether they had early MH (Mayo endoscopic subscore reduced to 0 within 3 yr of clinical remission). Factors associated with MH and early MH were determined using logistic regression. RESULTS: Two hundred thirty-seven patients with ulcerative colitis (mean age 50.39 +/- 14.10 yr; 56.5% male) were included. Independent factors for MH were clinical remission >3 years (odds ratio [OR] 4.0; 95% confidence interval [CI], 1.2-13.1), mild/moderate mucosal inflammation (OR 3.3; 95% CI, 1.3-8.5), and immunosuppressant use (OR 4.6; 95% CI, 1.5-14.6). Among patients who had >=2 of above factors, 74% achieved MH, whereas only 39% with <2 factors achieved MH (P < 0.001). Of patients in clinical remission <1 year, 1 to 3 years and >3 years, 30%, 45.9%, and 62.9% achieved MH, respectively. Immunosuppressant therapy was associated with early MH (P = 0.025). In multivariate analysis, patients with previous mild inflammation were more likely to achieve early MH than those with moderate/severe inflammation (OR 2.8; 95% CI, 1.2-6.2). CONCLUSIONS: A longer disease remission, previous less severe mucosal inflammation, and immunosuppressant use are associated with MH. Severity of mucosal inflammation and use of immunosuppressant are also associated with early MH. PMID- 25738376 TI - Health Care utilization in elderly onset inflammatory bowel disease: a population based study. AB - BACKGROUND: There is an increasing burden of inflammatory bowel disease (IBD) among the elderly. We sought to characterize health care utilization of elderly onset IBD. METHODS: We identified incident IBD cases in Ontario, Canada between 1999 and 2008 and categorized subjects by age at diagnosis as young (18-40 yr), middle-age (41-64 yr), and elderly (>=65 yr). We compared IBD-specific health utilization indicators, including outpatient visits, emergency department visits, and hospitalizations. RESULTS: The elderly accounted for 8.1% (N = 725) and 11.6% (N = 1749) of incident Crohn's disease (CD) and ulcerative colitis (UC), respectively. They were less likely than young adults to have any IBD-specific gastroenterology visit in the first year after diagnosis (CD, 63% versus 71%, P < 0.001; UC, 63% versus 69%, P < 0.001). They less frequently received continuous gastroenterology care (CD, 36% versus 46%, P < 0.001; UC, 33% versus 43%, P < 0.001). Elderly patients with IBD were less likely than young adults to require an IBD-specific emergency department visit in the first year (CD, 8.8% versus 18.5%, P < 0.001; UC, 7.8% versus 11.6%, P < 0.001). Similarly, elderly patients with CD exhibited lower hospitalization rates (incidence rate ratio, 0.62; 95% confidence interval, 0.59-0.65). Hospitalization rates were modestly higher among those elderly patients with UC compared with young adults during the first year (incidence rate ratio, 1.14; 95% confidence interval: 1.02-1.28), but this association reversed thereafter (incidence rate ratio, 0.64; 95% confidence interval: 0.57-0.71). CONCLUSIONS: Elderly patients with IBD exhibited lower IBD specific health care utilization than young adults, which may reflect a multitude of factors including more benign disease and differential health care access. PMID- 25738377 TI - MyD88 mediates the protective effects of probiotics against the arteriolar thrombosis and leukocyte recruitment associated with experimental colitis. AB - Several studies in patients with IBD and in animal models of IBD have revealed a protective effect of probiotics in reducing clinical symptoms of disease and in blunting the gut inflammation that accompanies this condition. However, the mechanism underlying the therapeutic effect of probiotics is currently unknown. Furthermore, the ability of probiotics to influence the enhanced thrombus development that accompanies IBD has not been studied. This study addresses whether the enhanced extraintestinal thrombosis (induced by light/dye injury) associated with experimental colitis is altered by oral treatment with the probiotic preparation VSL#3 or by the absence of microbiota. Colitis was induced by DSS 3% in Swiss Webster mice, germ-free mice, C57BL/6 WT, or Myd88 mice. In some experiments, mice received VSL#3 for 8 days before and during DSS feeding. Swiss Webster mice were also subjected to a chronic model of DSS colitis, and the effect of VSL#3 was evaluated. VSL#3 treatment significantly attenuated the accelerated thrombus formation observed in both acute and chronic models of colitis. VSL#3-treated mice also exhibited attenuated inflammatory response and injury in the colon. The protective effects of VSL#3 on colitis-associated thrombogenesis and inflammation were not evident in MyD88-deficient mice. Our results suggest that improved control of the enteric microflora in IBD may afford protection against the hypercoagulable prothrombotic state that follows this condition. PMID- 25738378 TI - A microRNA signature in pediatric ulcerative colitis: deregulation of the miR 4284/CXCL5 pathway in the intestinal epithelium. AB - BACKGROUND: Twenty to 25% of the patients with inflammatory bowel disease (IBD) present the disease before the age of 18 to 20, with worse extent and severity, compared with adult-onset IBD. We sought to identify the differential expression of microRNAs in pediatric ulcerative colitis (UC) and their association with different clinical phenotypes. METHODS: MicroRNA expression analysis was performed in colonic tissues derived from pediatric patients with UC and controls without IBD. MiR-4284 levels were verified by real-time quantitative polymerase chain reaction in 2 additional cohorts of pediatric patients with UC. Bioinformatics analysis was performed to predict the targets of miR-4284. In vitro experiments using luciferase reporter assays and real-time polymerase chain reaction evaluated the direct effect of miR-4284 on CXCL5 mRNA. In vivo experiments were performed in 2 mouse models of experimental colitis. RESULTS: A 24-microRNA signature was identified in colonic tissues derived from pediatric patients with UC. The most downregulated microRNA in the tissue of pediatric patients UC, relative to non-IBD controls, was miR-4284. In situ hybridization revealed that miR-4284 is present in colonic epithelial cells, and its levels correlate with the disease activity. Furthermore, we found that miR-4284 regulates CXCL5 mRNA expression through binding to its 3'UTR. CXCL5 had increased mRNA levels in colonic tissue from pediatric patients with UC and correlated with disease activity. Furthermore, we found an inverse correlation between miR-4284 and CXCL5 levels in the colonic pediatric UC tissues and in 2 mouse models of experimental colitis. CONCLUSIONS: Our data reveal a novel microRNA pediatric UC signature and provide evidence that miR-4284 directly regulates CXCL5 and correlates with the disease activity. PMID- 25738380 TI - Guidelines for the surgical treatment of Crohn's perianal fistulas. PMID- 25738381 TI - Estimating subgroup effects using the propensity score method: a practical application in outcomes research. AB - OBJECTIVE: Our aim was to demonstrate the feasibility of the univariate and generalized propensity score (PS) method in subgroup analysis of outcomes research. METHODS: First, to estimate subgroup effects, we tested the performance of 2 different PS methods, using Monte Carlo simulations: (1) the univariate PS with additional adjustment on the subgroup; and (2) the generalized PS, estimated by crossing the treatment options with a subgroup variable. The subgroup effects were estimated in a linear regression model using the 2 PS adjustments. We further explored whether the subgroup variable should be included in the univariate PS. Second, the 2 methods were compared using data from a large effectiveness study on psychotherapy in personality disorders. Using these data we tested the differences between short-term and long-term treatment, with the severity of patients' problems defining the subgroups of interest. RESULTS: The Monte Carlo simulations showed minor differences between both PS methods, with the bias and mean squared error overall marginally lower for the generalized PS. When considering the univariate PS, the subgroup variable can be excluded from the PS estimation and only adjusted for in the outcome equation. When applied to the psychotherapy data, the univariate and generalized PS estimations gave similar results. CONCLUSION: The results support the use of the generalized PS as a feasible method, compared with the univariate PS, to find certain subgroup effects in nonrandomized outcomes research. PMID- 25738379 TI - Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. AB - BACKGROUND: Commensal gut microbiota play an important role in regulating metabolic and inflammatory conditions. Reshaping intestinal microbiota through pharmacologic means may be a viable treatment option. We sought to delineate the functional characteristics of glucocorticoid-mediated alterations on gut microbiota and their subsequent repercussions on host mucin regulation and colonic inflammation. METHODS: Adult male C57Bl/6 mice, germ-free, Muc2 heterozygote (+/-), or Muc2-knockout (-/-) were injected with dexamethasone, a synthetic glucocorticoid, for 4 weeks. Fecal samples were collected for gut microbiota analysis through 16S rRNA terminal restriction fragment length polymorphism and amplicon sequencing. Intestinal mucosa was collected for mucin gene expression studies. Germ-free mice were conventionalized with gut microbes from treated and nontreated groups to determine their functional capacities in recipient hosts. RESULTS: Exposure to dexamethasone in wild-type mice led to substantial shifts in gut microbiota over a 4-week period. Furthermore, a significant downregulation of colonic Muc2 gene expression was observed after treatment. Muc2-knockout mice harbored a proinflammatory environment of gut microbes, characterized by the increase or decrease in prevalence of specific microbiota populations such as Clostridiales and Lactobacillaceae, respectively. This colitogenic phenotype was transmissible to IL10-knockout mice, a genetically susceptible model of colonic inflammatory disorders. Microbiota from donors pretreated with dexamethasone, however, ameliorated symptoms of inflammation. CONCLUSIONS: Commensal gut bacteria may be a key mediator of the anti inflammatory effects observed in the large intestine after glucocorticoid exposure. These findings underscore the notion that intestinal microbes comprise a "microbial organ" essential for host physiology that can be targeted by therapeutic approaches to restore intestinal homeostasis. PMID- 25738382 TI - VHL: Cullin-g the hypoxic response. AB - Hypoxia inducible factor (HIF)-mediated response to hypoxic conditions is turned off by VHL-mediated ubiquitination of HIFalpha. To achieve this, VHL binds HIFalpha and recruits it to a specific E3 ubiquitin ligase complex, a Cullin-RING ligase. In this issue of Structure, Nguyen et al. provide a structural view of how VHL engages the ligase in order to inhibit the hypoxic response. PMID- 25738383 TI - Helix-helix interactions: is the medium the message? AB - In this issue of Structure, Zhang and colleagues compare the helix-helix interaction spaces of an extensive database of soluble and membrane proteins. Intriguingly, the resultant clusters show similar helix interaction geometries between the protein classes, differing in detail only by patterns of local interactions and inter-helical distances. PMID- 25738384 TI - Simulations move toward a cure for viral diseases. AB - In this issue of Structure, Reddy and colleagues combined various experimental data to build a realistic near-atomic model of the complete lipidic influenza A virion. Here, we illustrate the advances made by this pioneering simulation study and discuss ongoing challenges. PMID- 25738385 TI - Yolk bishell Mn(x)Co(1-x)Fe2O4 hollow microspheres and their embedded form in carbon for highly reversible lithium storage. AB - The yolk-shell hollow structure of transition metal oxides has many applications in lithium-ion batteries and catalysis. However, it is still a big challenge to fabricate uniform hollow microspheres with the yolk bishell structure for mixed transition metal oxides and their supported or embedded forms in carbon microspheres with superior lithium storage properties. Here we report a new approach to the synthesis of manganese cobalt iron oxides/carbon (MnxCo1-xFe2O4 (0 <= x <= 1)) microspheres through carbonization of Mn(2+)Co(2+)Fe(3+)/carbonaceous microspheres in N2, which can be directly applied as high-performance anodes with a long cycle life for lithium storage. Furthermore, uniform hollow microspheres with a MnxCo1-xFe2O4 yolk bishell structure are obtained by annealing the above MnxCo1-xFe2O4/carbon microspheres in air. As demonstrated, these anodes exhibited a high reversible capacity of 498.3 mAh g(-1) even after 500 cycles for Mn0.5Co0.5Fe2O4/carbon microspheres and 774.6 mAh g(-1) over 100 cycles for Mn0.5Co0.5Fe2O4 yolk bishell hollow microspheres at the current density of 200 mA g(-1). The present strategy not only develops a high-performance anode material with long cycle life for lithium ion batteries but also demonstrates a novel and feasible technique for designed synthesis of transition metal oxides yolk bishell hollow microspheres with various applications. PMID- 25738386 TI - The Use of Task-Evoked Pupillary Response as an Objective Measure of Cognitive Load in Novices and Trained Physicians: A New Tool for the Assessment of Expertise. AB - PURPOSE: Task-evoked pupillary responses (TEPRs), or changes in pupil size, correlate with changes in cognitive processing demands. The magnitude of this change is a reliable marker of cognitive load. The authors used TEPRs to compare cognitive load between novices and trained physicians as they answered clinical knowledge questions. METHOD: In 2013, 20 emergency medicine trainees were recruited and divided into novice (n = 10) and trained physician (n = 10) groups. The authors used mobile eye-tracking glasses to assess changes in pupil diameter as participants answered arithmetic questions, general knowledge questions, and clinical emergency medicine questions in a controlled setting. Questions were categorized by difficulty a priori. RESULTS: Difficult arithmetic questions caused greater changes in TEPRs than easy ones (P = .024). TEPRs were similar between groups when answering general knowledge questions (P = .383) but were significantly greater for novices than trained physicians when answering clinical questions (P < .001). TEPRs in trained physicians were significantly greater when answering difficult clinical questions than easy ones (P < .001), whereas TEPRs in novices were similar (P = .291). For those clinical questions answered correctly by both groups, TEPRs in novices were greater than those in trained physicians despite all participants answering correctly (P < .001). CONCLUSIONS: Novices require more mental effort to answer clinical questions than trained physicians, even when both respond correctly. Measuring TEPRs has the potential to be a valuable assessment tool by providing objective measures of expertise and is worthy of further study. PMID- 25738387 TI - Health Systems Innovation at Academic Health Centers: Leading in a New Era of Health Care Delivery. AB - Challenged by demands to reduce costs and improve service delivery, the U.S. health care system requires transformational change. Health systems innovation is defined broadly as novel ideas, products, services, and processes-including new ways to promote healthy behaviors and better integrate health services with public health and other social services-which achieve better health outcomes and/or patient experience at equal or lower cost. Academic health centers (AHCs) have an opportunity to focus their considerable influence and expertise on health systems innovation to create new approaches to service delivery and to nurture leaders of transformation. AHCs have traditionally used their promotions criteria to signal their values; creating a health systems innovator promotion track could be a critical step towards creating opportunities for innovators in academic medicine. In this Perspective, the authors review publicly available promotions materials at top-ranked medical schools and find that while criteria for advancement increasingly recognize systems innovation, there is a lack of specificity on metrics beyond the traditional yardstick of peer-reviewed publications. In addition to new promotions pathways and alternative evidence for the impact of scholarship, other approaches to fostering health systems innovation at AHCs include more robust funding for career development in health systems innovation, new curricula to enable trainees to develop skills in health systems innovation, and new ways for innovators to disseminate their work. AHCs that foster health systems innovation could meet a critical need to contribute both to the sustainability of our health care system and to AHCs' continued leadership role within it. PMID- 25738388 TI - The Facilitatory Effect of Casearia sylvestris Sw. (guacatonga) Fractions on the Contractile Activity of Mammalian and Avian Neuromuscular Apparatus. AB - Many natural products influence neurotransmission and are used clinically. In particular, facilitatory agents can enhance neurotransmission and are potentially useful for treating neuromuscular diseases in which muscular weakness is the major symptom. In this work, we investigated the facilitatory effect of apolar to polar fractions of Casearia sylvestris Sw. (guacatonga) on contractility in mouse phrenic nerve-diaphragm (PND) and chick biventer cervicis (BC) neuromuscular preparations exposed to indirect (via the nerve; 3 V stimuli) and direct (30 V stimuli) muscle stimulation in the absence and presence of pharmacological antagonists. Methanolic and ethyl acetate fractions, but not hexane or dichloromethane fractions, exerted a facilitatory effect on PND (indirect stimulation). The methanolic fraction was chosen for further assays to assess the involvement of: 1) presynaptic sites (axons or nerve terminals), 2) postsynaptic sites (cholinergic receptors, sarcolemma or T-tubules), and 3) the synaptic cleft (acetylcholinesterase enzyme). In preparations treated with d-tubocurarine, the methanolic fraction did not cause facilitation in response to direct stimuli; this fraction was also unable to reverse dantrolene-induced blockade (indirect stimulation). In curarized preparations, the methanolic fraction either restored neuromuscular transmission (mimicking the effect of neostigmine) or failed to cause any recovery of neurotransmission. In the presence of 3,4-diaminopyridine (3,4-DAP), the methanolic fraction decreased twitch amplitude, whereas at a high frequency of stimulation (40 Hz) there was an increase in tetanic tension. In BC preparations, the methanolic fraction did not affect contractures to exogenous acetylcholine or potassium chloride. Incubation with atropine showed there was certain modulation by prejunctional nicotinic receptors, whereas treatment with nifedipine showed that the neurofacilitation required the entry of extracellular calcium. Tetrodotoxin did not prevent the facilitatory effect of 3,4-DAP or neostigmine, but antagonized the response to the methanolic fraction. These findings indicate that neuronal sodium channels have an important role in the facilitatory response to the methanolic fraction, with extracellular calcium entry via calcium channels modulating this neurofacilitation. Possible modulation of prejunctional cholinoceptors was not excluded, particularly in view of certain antagonism by the methanolic fraction at muscarinic receptors. Since facilitation by the methanolic fraction involved enhanced acetylcholine release, use of this fraction could be potentially beneficial in neuromuscular diseases and in the reversal of residual paralysis in the post-operative period or after local anaesthesia. PMID- 25738389 TI - Primary Characterization and Evaluation of Anti Ulcerogenic Activity of an Aqueous Extract from Callus Culture of Cereus peruvianus Mill. (Cactaceae). AB - In the current study we reported cultivation, extraction procedure, analysis and preliminary characterization of the aqueous extract from Cereus peruvianus callus culture and evaluated its anti ulcerogenic activity in vivo models of experimental ulcers in Wistar rats. The obtained aqueous extract from callus (AC) was dialyzed and subjected to freeze-thaw process, providing a possible polysaccharide. The carbohydrate and protein contents of the aqueous extract were estimated at 53.4% and 0.66%, respectively, composed primarily of galactose, arabinose and galacturonic acid, with minor amounts of glucose. This appeared heterogeneous when analyzed by high-performance size-exclusion chromatography and a multi-angle laser light scattering detector (HPSEC-MALLS). The AC was found to be significantly effective against ethanol-induced lesions but was ineffective against indomethacin-induced lesions. The callus culture of C. peruvianus is an alternative source for the synthesis of substances originally produced by plants. The calluses grown indefinitely in vitro under controlled conditions are stable tissues, and the aqueous extract from calluses may be used instead of fully developed plants using the protocols described in this study. PMID- 25738390 TI - Inhibitory Mechanisms of CME-1, a Novel Polysaccharide from the Mycelia of Cordyceps sinensis, in Platelet Activation. AB - Objective: CME-1 is a polysaccharide purified from the mycelia of medicinal mushroom Cordyceps sinensis, its molecular weight was determined to be 27.6 kDa by using nuclear magnetic resonance and gas chromatography-mass spectrometry. The initiation of arterial thromboses is relevant to various cardiovascular diseases (CVDs) and is believed to involve platelet activation. Our recent study exhibited that CME-1 has potent antiplatelet activity via the activation of adenylate cyclase/cyclic AMP ex vivo and in vivo. Methods: The aggregometry, and immunoblotting were used in this study. Results: In this study, the mechanisms of CME-1 in platelet activation is further investigated and found that CME-1 inhibited platelet aggregation as well as the ATP-release reaction, relative intracellular [Ca+2] mobilization, and the phosphorylation of phospholipase C (PLC)gamma2 and protein kinase C (PKC) stimulated by collagen. CME-1 has no effects on inhibiting either convulxin, an agonist of glycoprotein VI, or aggretin, an agonist of integrin alpha2beta1 stimulated platelet aggregation. Moreover, this compound markedly diminished thrombin and arachidonic acid (AA) induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 2, c-Jun N-terminal kinase 1, and Akt. Treatment with SQ22536, an inhibitor of adenylate cyclase, markedly diminished the CME-1-mediated increasing of cyclic AMP level and reversed prostaglandin E1- or CME-1-mediated inhibition of platelet aggregation and p38 MAPK and Akt phosphorylation stimulated by thrombin or AA. Furthermore, phosphodiesterase activity of human platelets was not altered by CME-1. Conclusion: The crucial finding of this study is that the antiplatelet activity of CME-1 may initially inhibit the PLCgamma2-PKC-p47 cascade, and inhibit PI3-kinase/Akt and MAPK phosphorylation through adenylate cyclase/cyclic AMP activation, then inhibit intracellular [Ca+2] mobilization, and, ultimately, inhibit platelet activation. The novel role of CME-1 in antiplatelet activity indicates that this compound exhibits high therapeutic potential for treating or preventing CVDs. PMID- 25738391 TI - Generation of Transgenic Energy Cane Plants with Integration of Minimal Transgene Expression Cassette. AB - Lignocellulosic biomass has the potential to serve as feedstock and direct replacement for petrochemicals in the fuel, chemical, pharmaceutical and material industries. Energy cane has been identified by the U.S. Department of Energy (DOE) as prime lignocellulosic feedstock as it produces record biomass yields and is able to grow on low-value land with reduced inputs. Molecular improvement of energy cane is an essential step toward the development of a high-value crop and may contribute to improved biomass conversion to value added products. Such improvements require a development of an efficient regeneration and transformation system for the vegetatively propagated energy cane varieties. In this report, an efficient biolistic gene delivery protocol for energy canes (genotype L 79-1002 and Ho 00-961) has been established with immature leaf rolls as explants. Embryonic calli, developed approximately 6 weeks after culture initiation and was used as target for biolistic transfer of a minimum expression cassette of P-ubi::nptII::35S polyA derived from plasmid pJFNPTII. Putative transgenic clones of callus were obtained after selection on callus induction medium supplemented with 30 mg l-1 geneticin. Regeneration was carried out on NB medium, which is modified from MS supplemented with 1.86 mg l-1 naphthaleneacetic acid (NAA) and 0.1mg l-1, 6-benzylaminopurine (BAP) and 20mg l-1 paromomycin. Shoots growing on selection media were transferred to hormone free medium with 20 mg l-1 paromomycin. Putative transgenic lines were first analyzed by PCR. Transgene integration was confirmed by Southern blot analysis. ELISA (Enzyme Linked Immunosorbent Assay) and Immunochromathography assays confirmed transgene expression. PMID- 25738392 TI - Homogeneous edge-plane carbon as stationary phase for reversed-phase liquid chromatography. AB - Carbon stationary phases have been widely used in HPLC due to their unique selectivity and high stability. Amorphous carbon as a stationary phase has at least two sites of interaction with analytes: basal-plane and edge-plane carbon sites. The polarity and adsorptivity of the two sites are different. In this work, the edge-plane carbon stationary phase is prepared by surface-directed liquid crystal assembly. Specific precursor polymers form discotic liquid crystal phases during the pyrolysis process. By using silica as the substrate to align the discotic liquid crystal, edge-plane carbon surfaces were formed. Similar efficiencies as observed for Hypercarb were observed in chromatograms. The column efficiency was studied as a function of linear flow rate. A minimum reduced plate height of 6 was observed in these studies. To evaluate the performance of the homogeneous edge-plane carbon stationary phase, linear solvation energy relationships were used to compare these ordered carbon surfaces to commercially available carbon stationary phases, including Hypercarb. Reversed-phase separations of nucleosides, nucleotides, and amino acids and derivatives were demonstrated using the ordered carbon surfaces, respectively. The column batch-to batch reproducibility was also evaluated. The retention times for the analytes were reproducible within 1-6% depending on the analyte. PMID- 25738393 TI - Ab initio molecular dynamics of high-temperature unimolecular dissociation of gas phase RDX and its dissociation products. AB - Unimolecular dynamics of gas-phase hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and its dissociation products were simulated using density functional theory (DFT) at the M06-L level. The simulations of RDX at 2000 K showed that dissociation proceeds from multiple conformers, mostly via homolytic fission of an N-N bond with a minor contribution from elimination of HONO, in agreement with previous transition state theory calculations. However, the simulations of the fission and elimination products revealed that secondary N-N fission is facile and, at the simulated temperature of 1750 K, dominant over other mechanisms. The simulations of the resulting intermediates revealed a number of new unimolecular pathways that have not been previously considered. The transition structures and minimal energy paths were calculated for all reactions to confirm these observations. Based on these findings, a revised set of the unimolecular reactions contributing to gas-phase RDX decomposition is proposed. PMID- 25738394 TI - Sensitive ELISA Method for the Measurement of Catabolites of Antibody-Drug Conjugates (ADCs) in Target Cancer Cells. AB - A new, sensitive ELISA method has been developed which measures catabolites in cells and media upon processing of antibody-drug conjugates (ADCs) by target cancer cells. This ELISA method, exemplified for maytansinoid ADCs, uses competitive inhibition by a maytansinoid analyte of the binding of biotinylated antimaytansine antibody to an immobilized BSA-maytansinoid conjugate. Synthetic standards of several maytansinoid catabolites derived from ADCs with different linkers were tested and showed similar inhibition curves, with an EC50 of about 0.1 nM (0.03 pmol in an assay volume of 0.25 mL). This high sensitivity allowed quantification of catabolites from a methanolic cell extract and from the medium, generated from an ADC in 1 day using only about 1 million cells. The processing of anti-EpCAM and anti-CanAg ADCs with noncleavable linker (SMCC-DM1), disulfide linker (SPDB-DM4), and charged sulfonate-bearing disulfide linker (sulfo-SPDB DM4), each containing an average of about four maytansinoid molecules per antibody, were compared in colon cancer cell lines (COLO 205 and HT-29). An 8-10 fold higher total level of catabolite was observed for anti-CanAg ADCs than for anti-EpCAM ADCs upon processing by COLO 205 cells, consistent with a higher cell surface expression of CanAg. In a multidrug resistant HCT-15 colon cancer cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was not cytotoxic and showed a significantly lower level of catabolite within cells compared to that in medium, presumably due to Pgp-mediated efflux of the nonpolar DM4 catabolite. In contrast, sulfo-SPDB-DM4 and SMCC-DM1 linker conjugates were cytotoxic, which correlated with higher amounts of catabolites found within the HCT-15 cells relative to amounts in medium. In a nonmultidrug resistant HT-29 cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was cytotoxic, with most of the catabolite found in cells and little in the medium. In conclusion, this highly sensitive ELISA method for measurement of ADC catabolite is convenient for screening multiple ADC parameters such as linkers and antibodies in a number of cell lines, does not require concentration of sample or extraction of media, and is complementary to other reported methods such as radiolabeling of ADCs or mass spectrometry. PMID- 25738396 TI - Half-life of DISC1 protein and its pathological significance under hypoxia stress. AB - DISC1 (disrupted in schizophrenia 1) is an intracellular scaffolding molecule which regulates multiple signaling pathways for neural cell differentiation and function. Many biological studies utilizing animal models of DISC1 have indicated that loss of DISC1 functions are associated with pathological psychiatric conditions. Thus, DISC1 protein stability is a prerequisite to its goal in governing neural function, and modulating the protein stability of DISC1 may be a key target for understanding underlying pathology, as well promising drug discovery strategies. Nonetheless, a half-life of DISC1 protein has remained unexplored. Here, we determine for the first time the half-life of DISC1, which are regulated by ubiquitin-proteasome cascade. Overexpression of PDE4B2, a binding partner of DISC1, prolonged the half-life of DISC1, whereas NDEL1 does not alter DISC1 protein stability. Notably, the half-life of DISC1 is diminished under hypoxia stress by increasing protein degradation of DISC1, suggesting that alteration of DISC1 stability may be involved in hypoxia stress-mediated pathological conditions, such as ischemic stroke. PMID- 25738398 TI - B-cell lymphoma 2 and beta-catenin expression in colorectal cancer and their prognostic role following surgery. AB - The prognosis of colorectal cancer depends on the stage of the disease. However, even within the same stage there may be different outcomes in terms of recurrence and survival. Therefore, it is clear that as well as pathological stage, novel biomarkers that are capable of improving risk stratification and therapeutic decision-making are required. The present study aimed to evaluate the potential roles of two previously proposed biomarkers of tumour status: B-cell lymphoma 2 (Bcl-2) and beta-catenin. A total of 412 patients undergoing surgery for primary colorectal cancer were studied. Tumour specimens of the patients were collected, fixed and processed for immunohistochemical detection of Bcl-2 and beta-catenin. The data were then analyzed in relation to disease-free survival and overall survival. Pathological stage was the only variable that was significantly correlated with both disease-free and overall survival. The expression levels of neither Bcl-2 nor beta-catenin were able to accurately predict prognosis. However, there was a clear association between nuclear beta-catenin expression levels and disease-free survival in the three tumour stages. There was an increased hazard ratio in stage I and II nuclear beta-catenin positive tumours, whereas there was a marked decrease in risk in stage III positive tumours. A similar effect was also observed with regards to overall survival, however this finding was not significant. The results of the present study suggest that conventional pathological tumour staging is the only accurate prognostic method. Neither Bcl-2 or beta-catenin were shown to be useful biomarkers for the prognosis of colorectal cancer. However, the heterogeneous behaviour of nuclear beta-catenin expression in the various tumour stages may indicate a possible role in predicting the response of patients to chemotherapy. Therefore, nuclear beta catenin expression may be a biomarker for the prediction of improved responses to chemotherapy. PMID- 25738397 TI - Blood pressure, left ventricular geometry, and systolic function in children exposed to inorganic arsenic. AB - BACKGROUND: Inorganic arsenic (iAs) is a ubiquitous element present in the groundwater worldwide. Cardiovascular effects related to iAs exposure have been studied extensively in adult populations. Few epidemiological studies have been focused on iAs exposure-related cardiovascular disease in children. OBJECTIVE: In this study we investigated the association between iAs exposure, blood pressure (BP), and functional and anatomical echocardiographic parameters in children. METHODS: A cross-sectional study of 161 children between 3 and 8 years was conducted in Central Mexico. The total concentration of arsenic (As) species in urine (U-tAs) was determined by hydride generation-cryotrapping-atomic absorption spectrometry and lifetime iAs exposure was estimated by multiplying As concentrations measured in drinking water by the duration of water consumption in years (LAsE). BP was measured by standard protocols, and M-mode echocardiographic parameters were determined by ultrasonography. RESULTS: U-tAs concentration and LAsE were significantly associated with diastolic (DBP) and systolic blood pressure (SBP) in multivariable linear regression models: DBP and SBP were 0.013 (95% CI: 0.002, 0.024) and 0.021 (95% CI: 0.004, 0.037) mmHg higher in association with each 1-ng/mL increase in U-tAs (p < 0.025), respectively. Left ventricular mass (LVM) was significantly associated with LAsE [5.5 g higher (95% CI: 0.65, 10.26) in children with LAsE > 620 compared with < 382 MUg/L-year; p = 0.03] in an adjusted multivariable model. The systolic function parameters left ventricular ejection fraction (EF) and shortening fraction were 3.67% (95% CI: 7.14, -0.20) and 3.41% (95% CI: -6.44, -0.37) lower, respectively, in children with U-tAs > 70 ng/mL compared with < 35 ng/mL. CONCLUSION: Early-life exposure to iAs was significantly associated with higher BP and LVM and with lower EF in our study population of Mexican children. PMID- 25738399 TI - Spontaneous pneumomediastinum, pneumopericardium and epidural pneumatosis: insights on clinical management. AB - Spontaneous pneumomediastinum is a benign condition that has been reported, however the association with epidural pneumatosis is much less common. A 27-year old male presented with concomitant air in the epidural space, mediastinum and pericardium after illicit drug use and engagement in sexual activity. The patient was hemodynamically stable. Non-invasive tests ruled out aerodigestive injury. The patient was discharged after a short observation without intervention. Invasive and potentially risky diagnostic tests may be safely avoided in patients who remain asymptomatic with this unique presentation. PMID- 25738400 TI - A systematic review of pathways to and processes associated with radicalization and extremism amongst Muslims in Western societies. AB - Following the terrorist attacks of 9/11 in the USA and 7/7 in the UK, academic interest in factors involved in radicalization and terrorism has increased dramatically. Many related social and psychological theories have been put forward, however terrorism literature still lacks empirical research. In particular, little is known about the early processes and pathways to radicalization. Our aim is to investigate original research on pathways and processes associated with radicalization and extremism amongst people of Muslim heritage living in Western societies, that is, the group prioritized by counter terrorism policy. Studies included in the review were original qualitative or quantitative primary research published in peer-reviewed journals, identified by searching research databases. All disciplines of journals were included. No single cause or pathway was implicated in radicalization and violent extremism. Individuals may demonstrate vulnerabilities that increase exposure to radicalization; however, the only common characteristic determined that terrorists are generally well-integrated, 'normal' individuals. Engagement in such activity is dependent on a wide range of interacting variables influenced by personal, localized and externalized factors. Further research should examine broader determinants of radicalization in susceptible populations. Future policy should follow this public health approach rather than constructing from perpetrators already committed to engaging in terrorism. PMID- 25738401 TI - Coffee extracts suppress tryptophan breakdown in mitogen-stimulated peripheral blood mononuclear cells. AB - OBJECTIVES: Coffee consumption is considered to exert an influence on mood, the immune system, cardiovascular disease, and cancer development, but the mechanisms of action of coffee and its compounds are only partly known and understood. METHODS: Immunomodulatory effects of filtered extracts of coffee and decaffeinated coffee as well as coffee compounds were investigated in human peripheral blood mononuclear cells (PBMCs) stimulated with mitogen phytohemagglutinin (PHA). The activation of PBMCs was monitored by the breakdown of tryptophan to kynurenine via enzyme indoleamine 2,3-dioxygenase (IDO) and the production of the immune activation marker neopterin by GTP-cyclohydrolase I (GCH1). Both of these biochemical pathways are induced during cellular immune activation in response to the Th1-type cytokine interferon-gamma (IFN-gamma). RESULTS: Filtered extracts of coffee and decaffeinated coffee both suppressed tryptophan breakdown and neopterin formation in mitogen-stimulated PBMCs efficiently and in a dose-dependent manner. Of 4 coffee compounds tested individually, only gallic acid and less strong also caffeic acid had a consistent suppressive influence but also affected cell viability, whereas pure caffeine and chlorogenic acid exerted no relevant effect in the PBMC assay. CONCLUSION: The parallel influence of extracts on tryptophan breakdown and neopterin production shows an anti-inflammatory and immunosuppressive property of coffee extracts and some of its compounds. When extrapolating the in vitro results to in vivo, IFN gamma-mediated breakdown of tryptophan could be counteracted by the consumption of coffee or decaffeinated coffee. This may increase tryptophan availability for the biosynthesis of the neurotransmitter 5-hydroxytryptamine (serotonin) and thereby improve mood and quality of life. PMID- 25738402 TI - Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells. AB - Molecular-targeted therapy has shown promise as a treatment for advanced osteosarcoma (OS). Sorafenib (SOR), a multikinase inhibitor, is the approved systemic drug of choice for OS, but has demonstrated limited benefits due to its toxicity and other adverse effects. Therapy strategies for reducing toxicity include using lower doses of SOR in combination with other complementary agents. Cisplatin (CDDP) has been shown to be a promising anticancer drug against various types of cancer including OS. In the present study, SOR was combined with CDDP to determine whether this combinatorial treatment suppressed tumor growth thereby simultaneously reducing doses of the two drugs for the treatment of OS. Human Saos-2 OS cells were treated with SOR and CDDP, alone and in combination, and the effect of these treatments on cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion, and involvement in receptor signaling, as well as tumor growth ability in nude mice was determined. It was found that the combination of low concentrations of SOR and CDDP significantly suppressed the cell proliferation, colony formation, migration and invasion, and induced cell apoptosis and cell cycle arrest in the G0/G1 stage, and suppressed tumor growth in a nude mouse model compared to the actions of either agent alone. The results also showed that SOR in combination with CDDP significantly suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), which may contribute to the inhibition of tumor growth. These results suggested that SOR in combination with CDDP acts synergistically in the treatment of OS. PMID- 25738404 TI - Electronic transport of recrystallized freestanding graphene nanoribbons. AB - The use of graphene and other two-dimensional materials in next-generation electronics is hampered by the significant damage caused by conventional lithographic processing techniques employed in device fabrication. To reduce the density of defects and increase mobility, Joule heating is often used since it facilitates lattice reconstruction and promotes self-repair. Despite its importance, an atomistic understanding of the structural and electronic enhancements in graphene devices enabled by current annealing is still lacking. To provide a deeper understanding of these mechanisms, atomic recrystallization and electronic transport in graphene nanoribbon (GNR) devices are investigated using a combination of experimental and theoretical methods. GNR devices with widths below 10 nm are defined and electrically measured in situ within the sample chamber of an aberration-corrected transmission electron microscope. Immediately after patterning, we observe few-layer polycrystalline GNRs with irregular sp(2)-bonded edges. Continued structural recrystallization toward a sharp, faceted edge is promoted by increasing application of Joule heat. Monte Carlo-based annealing simulations reveal that this is a result of concentrated local currents at lattice defects, which in turn promotes restructuring of unfavorable edge structures toward an atomically sharp state. We establish that intrinsic conductance doubles to 2.7 e(2)/h during the recrystallization process following an almost 3-fold reduction in device width, which is attributed to improved device crystallinity. In addition to the observation of consistent edge bonding in patterned GNRs, we further motivate the use of bonded bilayer GNRs for future nanoelectronic components by demonstrating how electronic structure can be tailored by an appropriate modification of the relative twist angle of the bonded bilayer. PMID- 25738403 TI - Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) due to placental insufficiency is a leading cause of perinatal complications for which there is no effective prenatal therapy. We have previously demonstrated that intraplacental injection of adenovirus-mediated insulin-like growth factor-1 (Ad-IGF-1) corrects fetal weight in a murine IUGR model induced by mesenteric uterine artery branch ligation. This study investigated the effect of intraplacental Ad-IGF-1 gene therapy in a rabbit model of naturally occurring IUGR (runt) due to placental insufficiency, which is similar to the human IUGR condition with onset in the early third trimester, brain sparing, and a reduction in liver weight. Laparotomy was performed on New Zealand White rabbits on day 21 of 30 days of gestation and litters were divided into five groups: Control (first position)+phosphate-buffered saline (PBS), control+Ad-IGF-1, runt (third position)+PBS, runt+Ad-IGF-1, and runt+Ad-LacZ. The effect of IGF-1 gene therapy on fetal, placental, liver, heart, lung, and musculoskeletal weights of the growth-restricted pups was examined. Protein expression after gene transfer was seen along the maternal-fetal placenta interface (n=12) 48 hr after gene therapy. There was minimal gene transfer detected in the pups or maternal organs. At term, compared with the normally grown first-position control, the runted third-position pups demonstrated significantly lower fetal, placental, liver, lung, and musculoskeletal weights. The fetal, liver, and musculoskeletal weights were restored to normal by intraplacental Ad-IGF-1 gene therapy (p<0.01), with no change in the placental weight. Intraplacental gene therapy is a novel strategy for the treatment of IUGR caused by placental insufficiency that takes advantage of an organ that will be discarded at birth. Development of nonviral IGF-1 gene delivery using placenta specific promoters can potentially minimize toxicity to the mother and fetus and facilitate clinical translation of this novel therapy. PMID- 25738405 TI - Antimalarial and cytotoxic constituents of Xylaria cf. cubensis PK108. AB - Xylaria cf. cubensis PK108 was identified by its distinctive morphological characteristics and its internal transcribed spacers sequence analysis. The chromatographic separation and structural elucidation based on spectroscopic analysis of fungal crude extracts led to 10 compounds; tryptoquivaline L (1), fiscalin C (2), epi-fiscalin C (3), cytochalasin D (4), ergosterol (5), ergosterol peroxide (6), chevalone C (7), xylaranol B (8), helvolic acid (9) and cyclo-(L-Pro-L-Leu) (10). The bioassay screening showed that 4 displayed cytotoxicity against KB and NCI-H187 cancer cell lines with IC50 values of 3.25 and 5.95 MUg mL(-1). 6 exhibited cytotoxicity against NCI-H187 with an IC50 value of 5.81 MUg mL(-1). 7 and 9 showed antimalarial activity with IC50 values of 25.00 and 6.25 MUg mL(-1), respectively. This result establishes Xylaria as broad spectrum bioactive compound producers. PMID- 25738406 TI - Base-promoted cross-dehydrogenative coupling of quinoline N-oxides with 1,3 azoles. AB - An efficient cross-dehydrogenative coupling of quinoline N-oxides and 1,3-azoles has been developed under external oxidant and metal free conditions. The desired products were isolated in good to excellent yields for 26 examples. This methodology provides a practical pathway to biheteroaryls and features high practicality, high efficiency, and environmental friendliness. PMID- 25738408 TI - Mast cells influence the proliferation rate of myeloma plasma cells. AB - In multiple myeloma (MM), mast cells (MCs) modify bone marrow microenvironment. In order to estimate whether MC density (MCD) in active MM bone marrows relates to the proliferative activity of plasma cells, we estimated in 42 patients MCD, microvascular density (MVD), and the Ki-67 proliferation index (PI) (immunohistochemical expression of tryptase, CD31, and Ki-67). MCD correlated with Ki-67 PI (p < .001), suggesting the important participation of MCs in MM biology and growth; MCs enhance angiogenesis and produce cytokines with growth effects on myeloma cells. Therefore, MCs could be valuable targets for therapeutic interventions. PMID- 25738409 TI - Glioma-derived thrombospondin-1 modulates cd14+ cell tolerogenic properties. AB - Thrombospondin-1 (TSP1) plays a role in the immune tolerance, and is involved in the pathogenesis of glioma. This study aims to investigate the role of the glioma derived TSP1 in the induction of the tumor immune tolerance. The results showed that the primary human glioma cells expressed high levels of TSP1. Glioma cells enhanced the expression of transforming growth factor (TGF)-beta in CD4+ CD16- naive monocytes (Mos). The TGF-beta+ Mos showed inhibitory effect on CD8+ T cell proliferation. We conclude that glioma cell-derived TSP1 facilitates the induction of TGF-beta in Mos. The TSP1 may be a potential therapeutic target of glioma. PMID- 25738410 TI - Effects of thionation and fluorination on cis-trans isomerization in tertiary amides: an investigation of N-alkylglycine (peptoid) rotamers. AB - Peptoids constitute a class of peptidomimetics with potential as protease resistant, biologically active ligands. To harness the full potential of such compounds, however, detailed predictive insight into their propensity to adopt well-defined secondary structures is highly desirable. In this work we present an investigation of the effects of thioamides and/or fluorides in peptoid monomer model systems using chemical synthesis, NMR spectroscopy, and X-ray crystallography. We find that the steric environment surrounding the tertiary amide bonds is the key promoter of conformational preference, and X-ray crystallographic interrogation of our model systems did not suggest the presence of stabilizing n -> pi* interactions unless the carbonyls were altered electronically by alpha-halogenation or thioamide formation. In addition to the function as an investigative tool, these two types of modification may thus be utilized as stabilizers of secondary structure in future oligomer designs, such as the cis-amide-based polypeptoid helices that resemble the polyproline type-I helix. PMID- 25738411 TI - New insights into the mechanism of F-box proteins in colorectal cancer (Review). AB - Colorectal cancer (CRC) is one of the most common cancers worldwide with a high incidence and mortality rate. Integrative studies including systematic sequencing of colorectal tumors have provided an unprecedented insight into the molecular basis of CRC. Recently, evidence indicates that F-box proteins (FBPs) play a critical role in the oncogenesis, invasion, metastasis and prognostic assessment of CRC. Therefore, this review discusses the recent literature regarding the function and regulation of FBPs in the pathogenesis of CRC. Furthermore, we highlight that FBPs may represent an attractive therapeutic target for CRC. PMID- 25738412 TI - Potential for Increase in Gabapentin Associated Complications with Its Increased Availability. PMID- 25738413 TI - Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin. AB - Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD. PMID- 25738414 TI - Co-culture with bone marrow stromal cells protects PC12 neuronal cells from tumor necrosis factor-alpha-induced apoptosis by inhibiting the tumor necrosis factor receptor/caspase signaling pathway. AB - Bone marrow stromal cells (BMSCs), derived from the mesoderm, have been applied in the repair and reconstruction of injured tissues. The present study was conducted to explore the effects of BMSCs on cell viability of tumor necrosis factor-alpha (TNF-alpha)-stimulated PC12 cells. PC12 cells were co-cultured with BMSCs under TNF-alpha treatment, with normal PC12 cells as controls. Results from an MTT assay indicated that BMSCs significantly increased cell growth and proliferation of TNF-alpha-treated PC12 cells (survival rates were 56.71 and 76.86% for the positive control (PC) and co-culture group, respectively). Furthermore, Annexin V/propidium iodide staining and flow cytometric analysis demonstrated that TNF-alpha increased PC12-cell apoptosis from 3.49 to 40.74% in the negative control and PC group, and the apoptotic rate was significantly reduced upon co-culture with BMSCs to 16.97%. In addition, data from reverse transcription-quantitative polymerase chain reaction and western blot analyses illustrated that TNF-alpha-induced upregulation in TNF receptor (TNFR)-1 (TNFR1) and caspase-8 expression in PC12 cells were partially reversed by co-culture with BMSCs. In conclusion, the present study suggested that BMSCs protect PC12 cells against stimulation with TNF-alpha, which is partially mediated through the TNFR/caspase signaling pathway. The results of the present study also suggested a therapeutic use of BMSCs in clinical neurodegenerative diseases. PMID- 25738415 TI - Dynamic three-dimensional pore-scale imaging of reaction in a carbonate at reservoir conditions. AB - Quantifying CO2 transport and average effective reaction rates in the subsurface is essential to assess the risks associated with underground carbon capture and storage. We use X-ray microtomography to investigate dynamic pore structure evolution in situ at temperatures and pressures representative of underground reservoirs and aquifers. A 4 mm diameter Ketton carbonate core is injected with CO2-saturated brine at 50 degrees C and 10 MPa while tomographic images are taken at 15 min intervals with a 3.8 MUm spatial resolution over a period of 2(1/2) h. An approximate doubling of porosity with only a 3.6% increase in surface area to volume ratio is measured from the images. Pore-scale direct simulation and network modeling on the images quantify an order of magnitude increase in permeability and an appreciable alteration of the velocity field. We study the uniform reaction regime, with dissolution throughout the core. However, at the pore scale, we see variations in the degree of dissolution with an overall reaction rate which is approximately 14 times lower than estimated from batch measurements. This work implies that in heterogeneous rocks, pore-scale transport of reactants limits dissolution and can reduce the average effective reaction rate by an order of magnitude. PMID- 25738416 TI - Probing nanoscale chemical segregation and surface properties of antifouling hybrid xerogel films. AB - Over the past decade there has been significant development in hybrid polymer coatings exhibiting tunable surface morphology, surface charge, and chemical segregation-all believed to be key properties in antifouling (AF) coating performance. While a large body of research exists on these materials, there have yet to be studies on all the aforementioned properties in a colocalized manner with nanoscale spatial resolution. Here, we report colocalized atomic force microscopy, scanning Kelvin probe microscopy, and confocal Raman microscopy on a model AF xerogel film composed of 1:9:9 (mol:mol:mol) 3 aminopropyltriethoxysilane (APTES), n-octyltriethoxysilane (C8), and tetraethoxysilane (TEOS) formed on Al2O3. This AF film is found to consist of three regions that are chemically and physically unique in 2D and 3D across multiple length scales: (i) a 1.5 MUm thick base layer derived from all three precursors; (ii) 2-4 MUm diameter mesa-like features that are enriched in free amine (from APTES), depleted in the other species and that extend 150-400 nm above the base layer; and (iii) 1-2 MUm diameter subsurface inclusions within the base layer that are enriched in hydrogen-bonded amine (from APTES) and depleted in the other species. PMID- 25738417 TI - A 3D co-culture of three human cell lines to model the inflamed intestinal mucosa for safety testing of nanomaterials. AB - Oral exposure to nanomaterials is a current concern, asking for innovative biological test systems to assess their safety, especially also in conditions of inflammatory disorders. Aim of this study was to develop a 3D intestinal model, consisting of Caco-2 cells and two human immune cell lines, suitable to assess nanomaterial toxicity, in either healthy or diseased conditions. Human macrophages (THP-1) and human dendritic cells (MUTZ-3) were embedded in a collagen scaffold and seeded on the apical side of transwell inserts. Caco-2 cells were seeded on top of this layer, forming a 3D model of the intestinal mucosa. Toxicity of engineered nanoparticles (NM101 TiO2, NM300 Ag, Au) was evaluated in non-inflamed and inflamed co-cultures, and also compared to non inflamed Caco-2 monocultures. Inflammation was elicited by IL-1beta, and interactions with engineered NPs were addressed by different endpoints. The 3D co culture showed well preserved ultrastructure and significant barrier properties. Ag NPs were found to be more toxic than TiO2 or Au NPs. But once inflamed with IL 1beta, the co-cultures released higher amounts of IL-8 compared to Caco-2 monocultures. However, the cytotoxicity of Ag NPs was higher in Caco-2 monocultures than in 3D co-cultures. The naturally higher IL-8 production in the co-cultures was enhanced even further by the Ag NPs. This study shows that it is possible to mimic inflamed conditions in a 3D co-culture model of the intestinal mucosa. The fact that it is based on three easily available human cell lines makes this model valuable to study the safety of nanomaterials in the context of inflammation. PMID- 25738418 TI - Thiocyanate as a local probe of ultrafast structure and dynamics in imidazolium based ionic liquids: water-induced heterogeneity and cation-induced ion pairing. AB - Ultrafast two-dimensional infrared spectroscopy (2D-IR) of thiocyanate ([SCN]-) in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C4C1im][NTf2]) and 1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide ([C4C1C1(2)im][NTf2]) ionic liquids probes local structure and dynamics as a function of the water content, solute counterion, and solute concentration. The 2D-IR spectra of the water-saturated ionic liquids resolve two distinct kinds of dynamics. This dynamical heterogeneity is explained as two subensembles, one with and one without a water molecule in the first solvation shell. When the countercation is K+, ion pairs between K+ and [SCN]- that persist for >100 ps are detected by long-lasting vibrational frequency correlations. The observed dynamics are invariant to [SCN]- concentration, which indicates that the [SCN]- does not cluster in ionic liquid solution. Taken together, these results are consistent with a picture of thiocyanate as a local probe that can interrogate ultrafast structure and dynamics at a small spatial scale in ionic liquids. PMID- 25738419 TI - Catalytic chemo-, regio-, and enantioselective bromochlorination of allylic alcohols. AB - Herein we describe a highly chemo-, regio-, and enantioselective bromochlorination reaction of allylic alcohols, employing readily available halogen sources and a simple Schiff base as the chiral catalyst. The application of this interhalogenation reaction to a variety of substrates, the rapid enantioselective synthesis of a bromochlorinated natural product, and preliminary extension of this chemistry to dibromination and dichlorination are reported. PMID- 25738420 TI - Immunogenicity and safety of vaccination against seasonal 2012 influenza virus among patients with psoriatic arthritis and psoriasis. AB - OBJECTIVES: We aimed to assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) and psoriasis (Pso) patients. METHODS: Patients with PsA or Pso and healthy controls were vaccinated with the Sanofi Pasteur vaccine recommended by the WHO in 2012. Clinical and laboratory assessments were performed on the day of the vaccination and 4-6 weeks later. The immunogenicity of the vaccine was evaluated by haemagglutination inhibition assay. RESULTS: The study included 63 consecutive PsA patients and 4 Pso patients (mean age 50.1, 37 females, 30 males, 55.2% treated with tumour necrosis factor alpha blockers [TNF-alpha], 31.3% on disease-modifying anti rheumatic drugs [DMARDs]) and 30 healthy controls. The geometric mean titers increased significantly in all participants for each of the subtypes tested. A substantial and similar proportion of patients in both groups responded to the vaccine. The response rate was not affected by parameters such as age, gender, disease activity or the use of TNF-alpha blockers or DMARDs. There were no significant changes in the patients' 68 tender and 66 swollen joint counts, dactylitis, PASI, global evaluation of the patient and physician and ESR, while there was a rise in CRP levels. CONCLUSIONS: Vaccination against seasonal influenza is safe and induces an appropriate response in patients with PsA, similar to healthy controls. PMID- 25738421 TI - Tetraparesis as clinical correlate of subacute cervical flexion myelopathy. AB - CONTEXT: We report the case of a 20-year-old woman who underwent tracheal resection with postoperative chin-to-chest suture for 10 days, presenting with severe tetraparesis at our institution. Similar cases have been reported previously, however, not yet in the pathophysiological context of chronic cervical flexion myelopathy (Hirayama syndrome). FINDINGS: Extensive myelopathy at cervical level is the consequence of the fixed cervical spine position due to chin-to-chest suture. Predominantly affected young individuals (age range from 20 25 years) without evidence of degenerated spine disease suggest a similar mechanism as described in Hirayama syndrome-displacement of the dura with consecutive compression of the spinal cord vasculature. CONCLUSIONS: Subacute flexion myelopathy represents a serious complication of operative/postoperative fixed cervical spine positions, warranting particular attention by respective surgeons. PMID- 25738422 TI - Health Care Utilization, Patient Costs, and Access to Care in US Adults With Eczema: A Population-Based Study. AB - IMPORTANCE: Little is known about the health burden of adult eczema in the United States. OBJECTIVE: To study the out-of-pocket costs, health care access and utilization in adult eczema in the United States. DESIGN, SETTING, AND PARTICIPANTS: Two US population-based studies, the 2010 and 2012 National Health Interview Surveys, surveyed 27 157 and 34 613 adults (ages 18-85 years). EXPOSURES: History of eczema. MAIN OUTCOMES AND MEASURES: The out-of-pocket costs, lost workdays, days in bed, and access to care. RESULTS: Adults with eczema had $371 to $489 higher out-of-pocket costs per person-year compared with those without eczema, with higher odds of increased out-of-pocket costs (survey multinomial logistic regression, adjusted odds ratios [ORs] [95% CIs] for NHIS 2012, <$1 to 499: OR, 1.27; 95% CI, 1.05-1.54; $500 to $1999: OR, 1.49; 95% CI, 1.22-1.81; $2000-$2999: OR, 1.74; 95% CI, 1.36-2.21; $3000-$4999: OR, 2.07; 95% CI, 1.56-2.73; >=$5000: OR, 1.74; 95% CI, 1.34-2.27; P < .001). Adults with eczema were significantly more likely to have at least 6 lost workdays from all causes (OR, 1.53; 95% CI, 1.26-1.84), 1 to 2 half-days (OR, 1.31; 95% CI, 1.14 1.51); 3 to 5 half-days (OR, 1.84; 95% CI, 1.54-2.20), and at least 6 half-days (OR, 2.24; 95% CI, 1.92-2.62) in bed and increased health care utilization with more physician visits (1-3 visits: OR, 1.70; 95% CI, 1.40-2.07; 4-9 visits: OR, 2.45; 95% CI, 2.00-3.00; and >=10 visits: OR, 3.33; 95% CI, 2.69-4.12), urgent or emergency care visits (1-3 visits: OR, 1.46; 95% CI, 1.29-1.66; 4-9 visits: OR, 1.81; 95% CI, 1.27-2.57; and >=10 visits: OR, 2.43; 95% CI, 1.19-4.99) and hospitalizations (OR, 1.37; 95% CI, 1.17-1.60). Adults with eczema had significantly limited access to care with inability to afford prescription medications (OR, 2.36; 95% CI, 1.92-2.81), were unable to get an appointment soon enough (OR, 2.04; 95% CI, 1.73-2.41), had to wait too long to see a physician (OR, 1.59; 95% CI, 1.28-1.97), had delayed care (OR, 1.73; 95% CI, 1.49-2.01), and were not able to get care (OR, 1.66; 95% CI, 1.40-1.97) because of worry about the related costs. CONCLUSIONS AND RELEVANCE: This study demonstrates a large health burden of eczema in adults and suggests substantial out-of-pocket costs, indirect costs from lost workdays and sick days, and increased health care utilization. PMID- 25738423 TI - Solubility enhancement and in vitro evaluation of PEG-b-PLA micelles as nanocarrier of semi-synthetic andrographolide analogue for cholangiocarcinoma chemotherapy. AB - BACKGROUND: Semi-synthetic andrographolide analogue (19-triphenylmethyl ether andrographolide, AG 050) is a C-19 substituted andrographolide which is the major constituent from Andrographis Paniculata Nees (Acanthaceae). The analogue has previously been reported to be highly cytotoxic against several cancer cell lines. Nevertheless, its poor water solubility limits clinical applications of this compound. OBJECTIVES: To improve the aqueous solubility and bioavailability of AG 050 by protonation and encapsulation in poly(ethylene glycol)-b-poly(d,l lactide) (PEG-b-PLA) polymeric micelles. MATERIALS AND METHODS: PEG-b-PLA micelle was employed as a nanocarrier for AG 050. The physicochemical properties and in vitro cytotoxicity against cholangiocarcinoma (CCA) (KKU-M213) cell line were done in this study. RESULT AND DISCUSSION: Hydrochloride salt of AG 050 (AG 050 P) greatly enhanced the solubility of this compound (15-fold). PEG-b-PLA was able to encapsulate AG 050-P in hydrophobic core with a significant increase in the amount of AG 050-P in aqueous solution (280-fold). Film sonication method provided greater results in drug-loading study as compared to micelles via solvent evaporation. In addition, the encapsulated AG 050-P exhibited sustained release pattern and excellent cytotoxicity activity against KKU-M213 with IC50 of 3.33 uM. CONCLUSION: Nanoencapsulation of AG 050-P implicated its potential development for clinical use in CCA treatment. PMID- 25738425 TI - Planar microfluidic drop splitting and merging. AB - Open droplet microfluidic platforms offer attractive alternatives to closed microchannel devices, including lower fabrication cost and complexity, significantly smaller sample and reagent volumes, reduced surface contact and adsorption, as well as drop scalability, reconfigurability, and individual addressability. For these platforms to be effective, however, they require efficient schemes for planar drop transport and manipulation. While there are many methods that have been reported for drop transport, it is far more difficult to carry out other drop operations such as dispensing, merging and splitting. In this work, we introduce a novel alternative to merge and, more crucially, split drops using laterally-offset modulated surface acoustic waves (SAWs). The energy delivery into the drop is divided into two components: a small modulation amplitude excitation to initiate weak rotational flow within the drop followed by a short burst in energy to induce it to stretch. Upon removal of the SAW energy, capillary forces at the center of the elongated drop cause the liquid in this capillary bridge region to drain towards both ends of the drop, resulting in its collapse and therefore the splitting of the drop. This however occurs only below a critical Ohnesorge number, which is a balance between the viscous forces that retard the drainage and the sufficiently large capillary forces that cause the liquid bridge to pinch. We show the possibility of reliably splitting drops into two equal sized droplets with an average deviation in their volumes of only around 4% and no greater than 10%, which is comparable to the 7% and below splitting deviation obtained with electrowetting drop splitting techniques. In addition, we also show that it is possible to split the drop asymmetrically to controllably and reliably produce droplets of different volumes. Such potential as well as the flexibility in tuning the device to operate on drops of different sizes without requiring electrode reconfiguration, i.e., the use of different devices, as is required in electrowetting-therefore makes the present method an attractive alternative to electrowetting schemes. PMID- 25738424 TI - Circuit- and Diagnosis-Specific DNA Methylation Changes at gamma-Aminobutyric Acid-Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder. AB - IMPORTANCE: Dysfunction related to gamma-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis- and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in schizophrenia and bipolar disorder. OBJECTIVE: To investigate the hypothesis that aberrant DNA methylation contributes to circuit- and diagnosis-specific abnormal expression of GAD1 regulatory network genes in psychotic illness. DESIGN, SETTING, AND PARTICIPANTS: This epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with schizophrenia, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing. MAIN OUTCOMES AND MEASURES: Methylation levels at 1308 GAD1 regulatory network-associated CpG loci were assessed both as individual sites to identify differentially methylated positions and by sharing information among colocalized probes to identify differentially methylated regions. RESULTS: A total of 146 differentially methylated positions with a false detection rate lower than 0.05 were identified across all 6 groups (2 circuit locations in each of 3 diagnostic categories), and 54 differentially methylated regions with P < .01 were identified in single-group comparisons. Methylation changes were enriched in MSX1, CCND2, and DAXX at specific loci within the hippocampus of patients with schizophrenia and bipolar disorder. CONCLUSIONS AND RELEVANCE: This work demonstrates diagnosis- and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in schizophrenia and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus. PMID- 25738427 TI - Diagnostic delay and survival in high-grade gliomas - evidence of the 'waiting time paradox'? AB - INTRODUCTION: We present a retrospective single-centre study to determine whether delays in diagnosis of high-grade glioma (HGG) impact on overall survival (OS). MATERIAL AND METHODS: Consecutive patients diagnosed with HGG at a single neuroscience centre in 2011 were reviewed. Route of referral and time from initial presentation to diagnosis were analysed and correlated with OS. RESULTS: 118 patients were studied - 92 patients with glioblastoma (GBM). Diagnosis of GBM in patients presenting to emergency services was quicker than that through outpatients (8 days vs. 26 days, p < 0.0001), but these patients had significantly worse OS (181 days vs. 386 days p = 0.0075). This trend was observed for the whole cohort (Grade III and GBM), with OS 278 days in patients presenting to emergency services compared with 423 days for patients presenting via outpatients (p = 0.0034). Patients presenting to outpatients were younger (median age: 54 years) compared with patients presenting to emergency services (median age: 62.5 years) (p = 0.0106). There were no other differences between the two groups with respect to the nature of presenting symptoms. CONCLUSION: Earlier diagnosis is paradoxically associated with a worse OS in GBM. An 'aggressive' phenotype with rapid symptomatic deterioration and hence emergency presentation is a poor prognostic factor not influenced by earlier diagnosis. PMID- 25738426 TI - Advances in electronic-nose technologies for the detection of volatile biomarker metabolites in the human breath. AB - Recent advancements in the use of electronic-nose (e-nose) devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to point-of-care clinical disease diagnoses. This exciting new area of electronic disease detection and diagnosis promises to yield much faster and earlier detection of human diseases and disorders, allowing earlier, more effective treatments, resulting in more rapid patient recovery from various afflictions. E-nose devices are particularly suited for the field of disease diagnostics, because they are sensitive to a wide range of volatile organic compounds (VOCs) and can effectively distinguish between different complex gaseous mixtures via analysis of electronic aroma sensor-array output profiles of volatile metabolites present in the human breath. This review provides a summary of some recent developments of electronic-nose technologies, particularly involving breath analysis, with the potential for providing many new diagnostic applications for the detection of specific human diseases associated with different organs in the body, detectable from e-nose analyses of aberrant disease-associated VOCs present in air expired from the lungs. PMID- 25738428 TI - Rice immune regulator, OsPti1a, is specifically phosphorylated at the plasma membrane. AB - OsPti1a (Pto-interacting protein 1a) has important roles in the regulation of immune responses in rice. Phosphorylation of a conserved threonine in OsPti1a is necessary to activate defense responses; however, the regulatory mechanism of OsPti1a-mediated immune responses is still obscure. Recently, we revealed that OsPti1a forms protein complex(es) at the plasma membrane and this localization is required for its function. Here, we show that membrane-localized OsPti1a was selectively phosphorylated. Additionally, phosphorylation was not required for the localization of OsPti1a at the membrane. These results suggest that OsPti1a protein is selectively regulated by its phosphorylation after OsPti1a localizes to the plasma membrane. PMID- 25738429 TI - Ribonucleotide reductase M2 is a promising molecular target for the treatment of oral squamous cell carcinoma. AB - In our previous study, ribonucleotide reductase M2 (RRM2) was identified as a cancer-related gene commonly overexpressed in human oral squamous cell carcinoma (OSCC) cell lines. Herein, we attempted to determine whether targeting RRM2 may be a plausible therapeutic approach for the treatment of patients with OSCC. First, we examined the expression levels of RRM2 in human OSCC cell lines and tissues. Overexpression of RRM2 in OSCC was confirmed by western blot analysis. Subsequently, we investigated the effects of a synthetic small interfering RNA specific for RRM2 and gemcitabine (GEM), an inhibitor of RRM2 enzymatic activity, on the growth of human OSCC cell lines and primary cultured cells. Targeting RRM2 by RNA interference almost completely suppressed the expression of RRM2 and markedly suppressed the growth of both types of cells by >54.8%. GEM also reduced the growth rate of these cells by >83.0%. Finally, we evaluated the antitumor effects of GEM, cisplatin (CDDP), 5-fluorouracil (5-FU), and docetaxel (DOC) against OSCC cells using the collagen gel droplet embedded culture drug sensitivity test. OSCC cells were more sensitive to GEM and DOC than to CDDP and 5-FU, regardless of the expression level of RRM2 mRNA. These results suggested that RRM2 supported the growth of human OSCC cells and that targeting of RRM2, e.g., via GEM treatment, may be a promising therapeutic strategy for OSCC. PMID- 25738430 TI - Anion and cation dynamics of sulfonylamide-based ionic liquids and the solid liquid transitions. AB - Some of the important factors that characterise room-temperature ionic liquids (RTILs) are the variety of conformations adopted by the constituent ions and their flexibility. Using 1,3-dimethylimidazolium bis(fluorosulfonyl)amide ([C1mim][FSA]) and 1,3-dimethylimidazolium bis(trifluoromethylsulfonyl)amide ([C1mim][NTf2]) as samples, the longitudinal and transverse relaxation times (T1 and T2) for (19)F and (1)H were determined as a function of temperature and were correlated with the dynamics of the phase behaviours of the two RTILs. Because the anions and cations in the two compounds have (19)F and (1)H nuclei, respectively, their dynamics can be independently investigated and the relationships between them can be discussed. For [C1mim][FSA], the only observed phase changes included melting and crystallisation. The temperature dependences of T1 and T2 for (19)F were similar to those of T1 and T2 for (1)H, indicating similar dynamics due to the formation of strong anion-cation interactions. For [C1mim][NTf2], the T1 and T2 values for both (19)F and (1)H discontinuously changed at same temperatures, which were assigned to the crystallisation and melting points. However, the T1 curves for (19)F and (1)H were different in the crystalline region, suggesting independent dynamics for the anions and cations in [C1mim][NTf2]. In the crystalline state for each salt, the cation dynamics was distinctly separated into the framework movement of the imidazolium ring and the movement of the methyl groups, while the anion dynamics was characterised by the movement of the entire anion. The influence of the crystal structure on the dynamics of each salt was also considered. PMID- 25738431 TI - A comparative study of the proliferation and osteogenic differentiation of human periodontal ligament cells cultured on beta-TCP ceramics and demineralized bone matrix with or without osteogenic inducers in vitro. AB - The repair of bone defects that result from periodontal diseases remains a clinical challenge for periodontal therapy. beta-tricalcium phosphate (beta-TCP) ceramics are biodegradable inorganic bone substitutes with inorganic components that are similar to those of bone. Demineralized bone matrix (DBM) is an acid extracted organic matrix derived from bone sources that consists of the collagen and matrix proteins of bone. A few studies have documented the effects of DBM on the proliferation and osteogenic differentiation of human periodontal ligament cells (hPDLCs). The aim of the present study was to investigate the effects of inorganic and organic elements of bone on the proliferation and osteogenic differentiation of hPDLCs using three-dimensional porous beta-TCP ceramics and DBM with or without osteogenic inducers. Primary hPDLCs were isolated from human periodontal ligaments. The proliferation of the hPDLCs on the scaffolds in the growth culture medium was examined using a Cell-Counting kit-8 (CCK-8) and scanning electron microscopy (SEM). Alkaline phosphatase (ALP) activity and the osteogenic differentiation of the hPDLCs cultured on the beta-TCP ceramics and DBM were examined in both the growth culture medium and osteogenic culture medium. Specific osteogenic differentiation markers were examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). SEM images revealed that the cells on the beta-TCP were spindle-shaped and much more spread out compared with the cells on the DBM surfaces. There were no significant differences observed in cell proliferation between the beta-TCP ceramics and the DBM scaffolds. Compared with the cells that were cultured on beta-TCP ceramics, the ALP activity, as well as the Runx2 and osteocalcin (OCN) mRNA levels in the hPDLCs cultured on DBM were significantly enhanced both in the growth culture medium and the osteogenic culture medium. The organic elements of bone may exhibit greater osteogenic differentiation effects on hPDLCs than the inorganic elements. PMID- 25738432 TI - [Single Centre Study: Results of Transanal Endoscopic Microsurgery of Rectal Tumors since 2003 vs. Results of Endoscopic Submucosal Dissection Reported in the Literature]. AB - BACKGROUND: Due to the variety of methods for local ablation of sessile rectal polyps and low-risk T1 rectal cancer, a retrospective study by transanal local excision, the endoscopic microsurgery (TEM) was performed. The results of the TEM were compared with literature-based results of endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: 174 patients who had received a TEM during the period from March 2003 to October 2011 for a removal of a rectal polyp or low risk cancer were included in the study. The evaluation included the en bloc and R0 resection rate, duration of surgery, the postoperative hospitalisation, postoperative complications and recurrence rate. RESULTS: The en bloc-resection rate was 87.5 % (152 of 174) and the R0 resection was achieved in 84.5 % (147 of 174) of the cases. The average surgery duration was 33 (5-121) min, with an average specimen size of 4 (1.2-13) cm. The average postoperative length of stay included 5 (1-15) d. The postoperative complication rate was 3 % (4 of 174) and the recurrence rate was 4 % (7 of 174) with an average follow-up of 36 (6-108) months. CONCLUSION: Compared to the Japanese results of ESD in the rectum based on literature results, we show equal or better results for the TEM. Compared to the European results of the ESD, the results of the TEM show advantages in terms of higher en bloc and R0 resection rates, shorter intervention times also with larger specimen sizes and a lower postoperative complication rate. PMID- 25738433 TI - [Assessment of bovine pericardium (tutomesh(r)) and coated polypropylene (proceed(r)) in the para-oesophageal position in a pig model]. AB - BACKGROUND: Hiatal hernias are nowadays increasingly treated with meshes. Often, biological implants are being used for this application. Oesophageal perforations have been reported as rare but serious complications from the application of synthetic meshes at the oesophageal hiatus. The role of the different mesh types has not been clearly established by experimental research so far. In the present large animal model, we investigated two implant types (Tutomesh(r) and Proceed(r)) with respect to their biocompatibility and mechanical stability. MATERIAL AND METHODS: We used 12 domestic pigs aged three months. Tutomesh(r) and Proceed(r) were implanted in 6 animals each for bridging at the oesophageal hiatus. After a follow-up of 3 months, the experiment was terminated. We performed endoscopy and intraoperative macroscopic evaluation of the situs. In representative histological sections, established histopathological and immunohistochemical parameters of biocompatibility were investigated and tensile strength testing was performed on standardised tissue samples. RESULTS: One animal of the Proceed(r) group had grade 2 oesophagitis. None of the animals had an oesophagus arrosion. The analysis of adhesions revealed slightly less adhesions in the Tutomesh(r) group. There was no significant difference with respect to the investigated inflammation response and immune response between both meshes. The most substantial finding of the mechanical analysis was a loss of tear strength of the Tutomesh(r)-tissue-complex of 30 % as compared to native tissue and more than 50 % compared to Tutomesh(r) prior to implantation, respectively. CONCLUSIONS: After 3 months, there was no significant difference between the two implant types with respect to the inflammatory response. The loss of tear strength of the Tutomesh(r)-tissue-complex at the oesophageal hiatus is probably clinically not relevant and may be explained by the so-called biological remodeling of biological materials. The remodeling depends on the extent of the cross-linking of the respective material. It is expected that biological hernia implants, such as Tutomesh(r), may have a marked potential for avoiding complications at the oesophageal hiatus in the long run. This potential cannot be proven after 3 months from our data. Further experimental investigations are necessary to clarify this issue, in particular with respect to the long-term results. PMID- 25738434 TI - Identification of DXCF cyanobacteriochrome lineages with predictable photocycles. AB - Diverse organisms use phytochrome photoreceptors to measure the ratio of red to far-red light in their respective environments. In addition to red/far-red phytochromes, many cyanobacteria contain distantly related cyanobacteriochrome (CBCR) photosensors that also use photoisomerization of a covalently bound linear tetrapyrrole (bilin) chromophore to measure multiple colors of light. CBCRs exhibit a remarkable variety of photocycles spanning the near ultraviolet and the entire visible spectrum. One group of CBCRs, distinguished by the presence of a conserved Asp-Xaa-Cys-Phe (DXCF) motif or variations thereon, includes members with violet/green, blue/teal, blue/green, blue/yellow, blue/orange, green/blue and green/teal photocycles. To date, it has not proven possible to predict such photocycles from primary amino acid sequence. We here use site-directed mutagenesis, phylogenetic analysis, and characterization of six new CBCRs to probe structure/function relationships in DXCF CBCRs. This approach has defined two groups of DXCF CBCRs with specialized green/blue and blue/orange photocycles that are robustly predictable from primary sequence data. Such knowledge facilitates the use of CBCRs for synthetic photobiological applications and informs approaches to understand the roles of CBCRs in cyanobacterial photobiology. PMID- 25738435 TI - Identification of a mutation in the WISP3 gene in three unrelated families with progressive pseudorheumatoid dysplasia. AB - Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disease, which is caused by the functional loss or abnormality of Wntl inducible signaling pathway protein 3 [WISP3 protein (also termed CCN6, OMIM #603400)]. WISP3 is a member of the cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed protein family. Mutations in WISP3 may result in continuous degeneration and loss of articular cartilage. The present study collected clinical data from three patients with PPD from three unrelated families, and WISP3 mutations were detected by polymerase chain reaction and direct sequencing. Overall, five mutations were identified, which consisted of two missense mutations, two nonsense mutations and one duplication mutation, which spanned exons 2, 4 and 5 of WISP3. In family 1, a compound heterozygosity mutation of WISP3 was detected, and the proband was shown to carry a novel missense mutation: c.667T>G (p.Cys223Gly) and a nonsense mutation: c.857C>G (p.Ser286*). The other three mutations: c.342T>G (p.Cys114Trp), c.136C>T (p.Gln46*) and c.866dupA (p.Ser290Glufs*13) had previously been identified. Overall, the three patients had similar clinical phenotypes, and no specific correlation between genotype and phenotype was detected. The results of the present study expand the WISP3 mutation spectrum that is associated with PPD and aid in further elucidating the function of WISP3. PMID- 25738436 TI - Estrogen receptor alpha mediates the effects of notoginsenoside R1 on endotoxin induced inflammatory and apoptotic responses in H9c2 cardiomyocytes. AB - Estrogen receptors (ERs) are important for preventing endotoxin-induced myocardial dysfunction. Therefore, plant-derived phytoestrogens, which target ERs may also affect endotoxin-induced toxicity in cardiomyocytes. Our previous study revealed that notoginsenoside-R1 (NG-R1), a predominant phytoestrogen from Panax notoginseng, protects against cardiac dysfunction. However, the effects of NG-R1 on cardiomyocytes and the precise cellular/molecular mechanisms underlying its action remain to be elucidated. In the present study, pretreatment with NG-R1 suppressed the lipopolysaccharide (LPS)-induced degradation of inhibitor of nuclear factor-kappaB (NF-kappaB) alpha, the activation of NF-kappaB and caspase 3, and the subsequent myocardial inflammatory and apoptotic responses in H9c2 cardiomyocytes. An increase in the mRNA and protein expression of ERalpha was also observed in the NG-R1-treated cardiomyocytes. However, the expression pattern of ERbeta remained unaltered. Furthermore, the cardioprotective properties of NG-R1 against LPS-induced apoptosis and the inflammatory response in cardiomyocytes were attenuated by ICI 182780, a non-selective ERalpha antagonist, and methyl-piperidino-pyrazole, a selective ERalpha antagonist. These findings suggested that NG-R1 reduced endotoxin-induced cardiomyocyte apoptosis and the inflammatory response via the activation of ERalpha. Therefore, NG-R1 exerted direct anti-inflammatory and anti-apoptotic effects on the cardiomyocytes, representing a potent agent for the treatment of myocardial inflammation during septic shock. PMID- 25738437 TI - Pirfenidone inhibits proliferation, arrests the cell cycle, and downregulates heat shock protein-47 and collagen type I in rat hepatic stellate cells in vitro. AB - Pirfenidone (esbiret) is an established anti-fibrotic and anti-inflammatory drug used to treat idiopathic pulmonary fibrosis. In the present study, the dose dependent effects of pirfenidone on the cell cycle, proliferation and expression of heat shock protein (HSP)-47 and collagen type I in a cultured rat hepatic stellate cell line (HSC-T6) were investigated. Following pirfenidone treatment, cell proliferation was determined using the cell counting kit-8 assay and the cell cycle was measured using flow cytometry. HSP-47 expression was estimated using western blot analysis and collagen type I mRNA was assessed using reverse transcription quantitative polymerase chain reaction. Pirfenidone induced significant dose-dependent inhibition of proliferation in HSC-T6 cells. Cell viability was unaffected by treatment with pirfenidone (0, 10 or 100 uM) for 24 and 72 h. However, after 24 h, HSC-T6 cells exhibited dose-dependent decreases in HSP-47 protein and collagen I mRNA levels. In conclusion, pirfenidone inhibited HSC-T6 cell proliferation, arrested the cell cycle and reduced the expression of HSP-47 and collagen type I, indicating that pirfenidone may be a promising drug in the treatment of liver fibrosis. PMID- 25738438 TI - Optimism and recovery after acute coronary syndrome: a clinical cohort study. AB - OBJECTIVE: Optimism is associated with reduced cardiovascular mortality, but its impact on recovery after acute coronary syndrome (ACS) is poorly understood. We hypothesized that greater optimism would lead to more effective physical and emotional adaptation after ACS and would buffer the impact of persistent depressive symptoms on clinical outcomes. METHODS: This prospective observational clinical study took place in an urban general hospital and involved 369 patients admitted with a documented ACS. Optimism was assessed with a standardized questionnaire. The main outcomes were physical health status, depressive symptoms, smoking, physical activity, and fruit and vegetable consumption measured 12 months after ACS, and composite major adverse cardiac events (cardiovascular death, readmission with reinfarction or unstable angina, and coronary artery bypass graft surgery) assessed over an average of 45.7 months. RESULTS: We found that optimism predicted better physical health status 12 months after ACS independently of baseline physical health, age, sex, ethnicity, social deprivation, and clinical risk factors (B = 0.65, 95% confidence interval [CI] = 0.10-1.20). Greater optimism also predicted reduced risk of depressive symptoms (odds ratio = 0.82, 95% CI = 0.74-0.90), more smoking cessation, and more fruit and vegetable consumption at 12 months. Persistent depressive symptoms 12 months after ACS predicted major adverse cardiac events over subsequent years (odds ratio = 2.56, 95% CI = 1.16-5.67), but only among individuals low in optimism (optimism * depression interaction; p = .014). CONCLUSIONS: Optimism predicts better physical and emotional health after ACS. Measuring optimism may help identify individuals at risk. Pessimistic outlooks can be modified, potentially leading to improved recovery after major cardiac events. PMID- 25738439 TI - Modulation of Food Reward by Endocrine and Environmental Factors: Update and Perspective. AB - OBJECTIVE: Palatable foods are frequently high in energy density. Chronic consumption of high-energy density foods can contribute to the development of cardiometabolic pathology including obesity, diabetes, and cardiovascular disease. This article reviews the contributions of extrinsic and intrinsic factors that influence the reward components of food intake. METHODS: A narrative review was conducted to determine the behavioral and central nervous system (CNS) related processes involved in the reward components of high-energy density food intake. RESULTS: The rewarding aspects of food, particularly palatable and preferred foods, are regulated by CNS circuitry. Overlaying this regulation is modulation by intrinsic endocrine systems and metabolic hormones relating to energy homeostasis, developmental stage, or gender. It is now recognized that extrinsic or environmental factors, including ambient diet composition and the provocation of stress or anxiety, also contribute substantially to the expression of food reward behaviors such as motivation for, and seeking of, preferred foods. CONCLUSIONS: High-energy density food intake is influenced by both physiological and pathophysiological processes. Contextual, behavioral, and psychological factors and CNS-related processes represent potential targets for multiple types of therapeutic intervention. PMID- 25738440 TI - Use of the Behavior Rating Inventory of Executive Function and Child Behavior Checklist in Ugandan Children with HIV or a History of Severe Malaria. AB - OBJECTIVE: To assess the structural overlap between the Behavior Rating Inventory of Executive Function (BRIEF) and Achenbach Child Behavior Checklist (CBCL) among children in Uganda. METHODS: Caregiver ratings for the BRIEF and CBCL were obtained for 2 independent samples of school-aged children: 106 children (5-12 years old, 50% males) with a history of severe malaria and on 144 HIV-infected children (5-12 years old, 58% males) in Uganda. Exploratory factor analysis was used to evaluate the factor structure of the 8 subscales for the BRIEF and the 8 scales of the CBCL to determine correlation. RESULTS: Overall, children in the severe malaria group had higher (increased symptom) BRIEF and CBCL scores than those in the HIV-infected group. Three factors that provided a reasonable fit to the data and could be characterized as 3 specific domains were identified: (1) Metacognition, which consisted of the scales in the BRIEF Metacognition domain, (2) Behavioral Adjustment, which comprised of the scales in the BRIEF Behavioral Regulation domain and the Externalizing Symptoms scales in the CBCL, and (3) Emotional Adjustment, which mainly consisted of the Internalizing Symptoms scales in the CBCL. The BRIEF Behavior Regulation and CBCL Externalizing Symptoms scales, however, did overlap in terms of assessing similar behavior symptoms. These findings were consistent across the severe malaria and HIV-infected samples of children. CONCLUSION: The BRIEF and CBCL instruments offer distinct, yet complementary, assessments of behavior in clinical pediatric populations in the Ugandan context, supporting the use of these measures for similar research settings. PMID- 25738441 TI - Commentary on "Optical coherence tomography for planning of follicular unit extraction". PMID- 25738442 TI - Outcomes of basal cell carcinomas directly invading the parotid gland. AB - BACKGROUND: Parotid involvement by basal cell carcinoma (BCC) is rare, and therefore management is controversial. OBJECTIVE: To review the treatment and outcomes of patients with BCC involving the parotid by direct infiltration. METHODS AND MATERIALS: The authors performed a retrospective chart review of BCC cases involving the parotid. RESULTS: From 1994 to 2007, there were 19 cases of BCC involving the parotid gland by direct extension. Nine were primary tumors, and 10 recurrent (nonprimary). Eight tumors were treated with Mohs micrographic surgery (MMS), and 11 with wide local excision (WLE). One patient died of unrelated causes 5 months after treatment, and 2 did not follow up. The remaining 16 cases had an average follow-up of 55.2 months (range, 18-112 months). No primary BCC recurred after treatment. Six of 10 nonprimary BCC (60%) recurred, 2 of 10 metastasized, and 1 of 10 died of metastatic BCC. Two recurrences occurred after MMS, and 4 occurred after WLE with or without parotidectomy. CONCLUSION: Mohs micrographic surgery or WLE with intra-operative margin control seems to be an acceptable first-line treatment for primary BCC involving the parotid. Recurrent BCC involving the parotid gland through direct infiltration has high rates of future recurrence, and adjuvant treatment may be required. PMID- 25738443 TI - Commentary on Trends in Mohs surgery from 1995 to 2010. PMID- 25738444 TI - The suspension (Frost) suture: experience and applications. AB - BACKGROUND: The Frost suture is a well-known surgical technique for providing upward tension on the lower lid to prevent or correct ectropion after surgical interventions in the periorbital area. Despite its relatively common use, comprehensive information on executing this technique is not readily available. OBJECTIVE: To review eyelid anatomy, indications, and proper technique for performing the Frost suture, as well as potential complications. MATERIALS AND METHODS: A review of the literature on Frost sutures was performed. Cadaveric dissection was performed to demonstrate placement of the Frost suture. RESULTS AND CONCLUSION: The Frost suture is a useful method to reduce the risk of ectropion after surgery near the lower eyelid. Downward pull on the lid can occur with normal wound contracture even if ectropion is not present with the initial repair, reinforcing the need for preventive measures. Potential complications of this technique include superficial skin erosion of the upper lid, corneal abrasion, and blockage of the field of vision while the suture is in place. PMID- 25738445 TI - "Cotton nail cast": a simple solution for mild and painful lateral and distal nail embedding. AB - BACKGROUND: Onychocryptosis is one of the most common painful nail conditions. Conservative treatment may take a long time to obtain effective results. OBJECTIVE: The purpose of this study is to show the effectiveness of a conservative treatment of ingrown nails that shows rapid results. METHODS AND MATERIALS: Patients with painful Stage 1 to 2 onychocryptosis who were not candidates or refused surgery were treated with the cotton cast. The severity and cause of onychocryptosis was clinically evaluated during a 2-month period. A questionnaire was applied to all patients to evaluate pain, final treatment, and possible complications. RESULTS: All patients noticed results in less than 72 hours. Pain subsided in less than 24 hours in half of the patients and before 72 hours in 100% of the patients without the need of other treatments. The use of the cast prevented surgery and the accompanying morbidities in most of the patients (80%). CONCLUSION: The "cotton nail cast" is an effective conservative method for mild nail embedding. It is easy to apply, inexpensive, relieves pain rapidly, and avoids surgery in most patients. PMID- 25738446 TI - Histomorphometric analysis of collagen architecture of auricular keloids in an Asian population. AB - BACKGROUND: Keloids are a pathologic condition of the reparative process, which present as excessive scar formation that involves various cells and cytokines. Many studies focusing on the histologic feature of keloids, however, have shown discordant results without consideration of architectural aspect of collagen structure. OBJECTIVE: The purpose of this study was to demonstrate a schematic illustration of collagen architecture of keloids, specifically auricular keloids, and to analyze each part on the histomorphologic and morphometric basis. MATERIALS AND METHODS: Thirty-nine surgically excised auricular keloids were retrieved from the file of Kangbuk Samsung Hospital. After exhaustive histomorphologic analysis, 3 distinctive structural parts, keloidal collagen, organizing collagen, and proliferating core collagen, were identified and mapped in every case. Cellularity of fibroblasts, blood vessel density, degree of inflammatory cell infiltration, and mast cells counts using Masson trichrome stain, Van Gieson stain, toluidine blue stain, and immunohistochemical stains for CD31 and smooth muscle actin were analyzed in each part of each case. Morphometric analysis on these parameters using ImageJ software was performed using 3 representative images of each part. RESULTS: Three parts were histomorphologically distinct by shape and array of collagen bundles, fibroblasts cellularity, blood vessel density, degree of inflammatory cells, and mast cell infiltration. Morphometric analysis revealed statistically significant difference between each part in fibroblasts cellularity, blood vessel density, degree of inflammatory cell infiltration, and mast cells count. All parameters were exceedingly high in whorling hypercellular fibrous nodules in proliferating core collagen showing simultaneous changes in other parts. CONCLUSION: Morphologically and morphometrically, 3 distinctive parts were identified in auricular keloids. Mast cell infiltrations, blood vessel density, and fibroblast cellularity are simultaneously increased or decreased according to these parts. Proliferating core collagen might serve as a proliferating center of keloids and might be a key portion for tumor growth and recurrence. PMID- 25738447 TI - Scrotal hidradenitis suppurativa with secondary lymphedema and lymphangiomata: successful management with carbon dioxide laser excision and marsupialization. PMID- 25738448 TI - Vismodegib for the treatment of aggressive basal cell carcinoma in a patient unable to swallow pills. PMID- 25738449 TI - An improved needle holder for the cutaneous surgeon. PMID- 25738450 TI - Metabolic switches linked to pluripotency and embryonic stem cell differentiation. AB - Embryonic stem cells (ESCs) manifest a unique metabolism that is intimately linked to their pluripotent state. In this issue, Moussaieff et al. (2015) find that ESCs utilize glycolysis to fuel high rates of cytosolic acetyl-CoA synthesis to maintain the histone acetylation required for pluripotency. PMID- 25738451 TI - Modifying mitochondrial tRNAs: delivering what the cell needs. AB - Protein synthesis is critically dependent on transfer (t)-RNAs, but the factors regulating tRNA function are poorly understood. In this issue of Cell Metabolism, Wei et al. (2015) show that Cdk5 regulatory subunit-associated protein-like-1 synchronizes mitochondrial and cytosolic translation in response to external stress, providing key insight into the pathogenesis of a common inherited mitochondrial disease. PMID- 25738452 TI - FFAR out new targets for diabetes. AB - Dyslipidemia has long been associated with beta cell dysfunction in the development of diabetes. Tang et al. (2015) have now revealed that beta cell short-chain fatty acid receptors FFA2 and FFA3 are activated in an autocrine fashion and reduce insulin secretion in type 2 diabetes models. PMID- 25738453 TI - A mitochondrially encoded hormone ameliorates obesity and insulin resistance. AB - MOTS-c, a mitochondrially encoded open reading frame-derived peptide recently discovered by Lee et al. 2015 (this issue of Cell Metabolism) promotes biosynthesis of an endogenous AMP analog, AICAR. As AICAR activates AMPK, the discovery of MOTS-c offers an unexpected therapeutic option to be exploited toward the prevention of type 2 diabetes and delaying of the aging processes. PMID- 25738454 TI - GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. AB - Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L cells promotes nutrient disposal via the incretin effect. However, the majority of L cells are localized to the distal gut, suggesting additional biological roles for GLP-1. Here, we demonstrate that GLP-1 receptor (GLP-1R) signaling controls mucosal expansion of the small bowel (SB) and colon. These actions did not require the epidermal growth factor (EGF) or intestinal epithelial insulin-like growth factor (IGF1) receptors but were absent in Glp1r(-/-) mice. Polyp number and size were increased in SB of exendin-4-treated Apc(Min/+) mice, whereas polyp number was reduced in SB and colon of Glp1r(-/-):Apc(Min/+) mice. Exendin-4 increased fibroblast growth factor 7 (Fgf7) expression in colonic polyps of Apc(Min/+) mice and failed to increase intestinal growth in mice lacking Fgf7. Exogenous exendin 4 and Fgf7 regulated an overlapping set of genes important for intestinal growth. Thus, gain and loss of GLP-1R signaling regulates gut growth and intestinal tumorigenesis. PMID- 25738455 TI - Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. AB - Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation. Metabolic and transcriptional analyses showed that pluripotent cells produced acetyl-CoA through glycolysis and rapidly lost this function during differentiation. Importantly, modulation of glycolysis blocked histone deacetylation and differentiation in human and mouse embryonic stem cells. Acetate, a precursor of acetyl-CoA, delayed differentiation and blocked early histone deacetylation in a dose-dependent manner. Inhibitors upstream of acetyl-CoA caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our results show a metabolic switch causing a loss of histone acetylation and pluripotent state during the first hours of differentiation. Our data highlight the important role metabolism plays in pluripotency and suggest that a glycolytic switch controlling histone acetylation can release stem cells from pluripotency. PMID- 25738456 TI - Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. AB - Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis. PMID- 25738457 TI - The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism. AB - ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We report an essential role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage, and demonstrate that mutations in this enzyme cause an autosomal recessive neurometabolic disorder and mtDNA depletion syndrome (MDS). We describe a family with encephalomyopathic MDS caused by a homozygous missense mutation in ABAT that results in elevated GABA in subjects' brains as well as decreased mtDNA levels in subjects' fibroblasts. Nucleoside rescue and co-IP experiments pinpoint that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Pharmacological inhibition of ABAT through the irreversible inhibitor Vigabatrin caused depletion of mtDNA in photoreceptor cells that was prevented through addition of dNTPs in cell culture media. This work reveals ABAT as a connection between GABA metabolism and nucleoside metabolism and defines a neurometabolic disorder that includes MDS. PMID- 25738458 TI - Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. AB - Transfer RNAs (tRNAs) contain a wide variety of posttranscriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms(2)) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms(2) modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms(2) modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms(2) modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease. PMID- 25738459 TI - The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. AB - Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16 amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome. PMID- 25738460 TI - A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. AB - Long non-coding RNAs (lncRNAs) constitute a significant portion of mammalian genome, yet the physiological importance of lncRNAs is largely unknown. Here, we identify a liver-enriched lncRNA in mouse that we term liver-specific triglyceride regulator (lncLSTR). Mice with a liver-specific depletion of lncLSTR exhibit a marked reduction in plasma triglyceride levels. We show that lncLSTR depletion enhances apoC2 expression, leading to robust lipoprotein lipase activation and increased plasma triglyceride clearance. We further demonstrate that the regulation of apoC2 expression occurs through an FXR-mediated pathway. LncLSTR forms a molecular complex with TDP-43 to regulate expression of Cyp8b1, a key enzyme in the bile acid synthesis pathway, and engenders an in vivo bile pool that induces apoC2 expression through FXR. Finally, we demonstrate that lncLSTR depletion can reduce triglyceride levels in a hyperlipidemia mouse model. Taken together, these data support a model in which lncLSTR regulates a TDP 43/FXR/apoC2-dependent pathway to maintain systemic lipid homeostasis. PMID- 25738461 TI - Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation. AB - Maximal exercise-associated oxidative capacity is strongly correlated with health and longevity in humans. Rats selectively bred for high running capacity (HCR) have improved metabolic health and are longer-lived than their low-capacity counterparts (LCR). Using metabolomic and proteomic profiling, we show that HCR efficiently oxidize fatty acids (FAs) and branched-chain amino acids (BCAAs), sparing glycogen and reducing accumulation of short- and medium-chain acylcarnitines. HCR mitochondria have reduced acetylation of mitochondrial proteins within oxidative pathways at rest, and there is rapid protein deacetylation with exercise, which is greater in HCR than LCR. Fluxomic analysis of valine degradation with exercise demonstrates a functional role of differential protein acetylation in HCR and LCR. Our data suggest that efficient FA and BCAA utilization contribute to high intrinsic exercise capacity and the health and longevity benefits associated with enhanced fitness. PMID- 25738462 TI - Translational tolerance of mitochondrial genes to metabolic energy stress involves TISU and eIF1-eIF4GI cooperation in start codon selection. AB - Protein synthesis is a major energy-consuming process, which is rapidly repressed upon energy stress by AMPK. How energy deficiency affects translation of mRNAs that cope with the stress response is poorly understood. We found that mitochondrial genes remain translationally active upon energy deprivation. Surprisingly, inhibition of translation is partially retained in AMPKalpha1/AMPKalpha2 knockout cells. Mitochondrial mRNAs are enriched with TISU, a translation initiator of short 5' UTR, which confers resistance specifically to energy stress. Purified 48S preinitiation complex is sufficient for initiation via TISU AUG, when preceded by a short 5' UTR. eIF1 stimulates TISU but inhibits non-TISU-directed initiation. Remarkably, eIF4GI shares this activity and also interacts with eIF1. Furthermore, eIF4F is released upon 48S formation on TISU. These findings describe a specialized translation tolerance mechanism enabling continuous translation of TISU genes under energy stress and reveal that a key step in start codon selection of short 5' UTR is eIF4F release. PMID- 25738464 TI - SnapShot: Osteoimmunology. AB - Bone and the immune system interact with each other and share molecular mechanisms to maintain the homeostasis. The paradigm of the osteoimmune system is required for both bone biology and immunology, providing an essential framework for understanding the physiology and pathology of metabolic bone diseases and immunological disorders. PMID- 25738463 TI - Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense. AB - Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection. PMID- 25738465 TI - Trophoblast glycoprotein promotes pancreatic ductal adenocarcinoma cell metastasis through Wnt/planar cell polarity signaling. AB - Trophoblast glycoprotein (TPBG), a 72 kDa glycoprotein was identified using a monoclonal antibody, which specifically binds human trophoblast. The expression of TPBG in normal tissues is limited; however, it is upregulated in numerous types of cancer. When TPBG is expressed at a high level, this usually indicates a poor clinical outcome. In the present study, it was demonstrated that TPBG was more commonly observed in human pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissue. Immunohistochemical analysis of PDAC tissue microarrays indicated that the expression of TPBG in PDAC tissues was closely correlated with the tumor-node-metastasis stage of the tumor. Silencing of TPBG in PDAC cell lines resulted in a decreased ability of cancer cell migration and invasion. Further investigation demonstrated that the Wnt/planar cell polarity signaling pathway was suppressed, as the expression of Wnt5a and the activation of c-Jun N-terminal kinase was inhibited following TPBG knockdown. In conclusion, the present study provided evidence that TPBG is involved in PDAC metastasis, and that TPBG and its associated signaling pathways may be a suitable target for PDAC therapy. PMID- 25738466 TI - Sporadic and reversible chromothripsis in chronic lymphocytic leukemia revealed by longitudinal genomic analysis. PMID- 25738467 TI - Attitudes Concerning Clinical Molecular Testing Among Dermatology Trainees at a Single Institution. PMID- 25738468 TI - Coating of Nafion membranes with polyelectrolyte multilayers to achieve high monovalent/divalent cation electrodialysis selectivities. AB - Electrodialysis (ED) membranes typically exhibit modest selectivities between monovalent and divalent ions. This paper reports a dramatic enhancement of the monovalent/divalent cation selectivities of Nafion 115 membranes through coating with multilayer poly(4-styrenesulfonate) (PSS)/protonated poly(allylamine) (PAH) films. Remarkably, K(+)/Mg(2+) ED selectivities reach values >1000, and similar monovalent/divalent cation selectivities occur with feed solutions containing K(+) and Ca(2+). For comparison, the corresponding K(+)/Mg(2+) selectivity of bare Nafion 115 is only 1.8 +/- 0.1. However, with 0.01 M KNO3 and 0.01 M Mg(NO3)2 in the source phase, as the applied current density increases from 1.27 to 2.54 mA cm(-2), the K(+)/Mg(2+) selectivities of coated membranes decrease from >1000 to 22. Water-splitting at strongly overlimiting current densities may lead to a local pH increase close to the membrane surface and alter film permeability or allow passage of Mg(OH)x species to decrease selectivity. When the source phase contains 0.1 M KNO3 and 0.1 M Mg(NO3)2, the K(+) transference number approaches unity and the K(+)/Mg(2+) selectivity is >20,000, presumably because the applied current is below the limiting value for K(+) and H(+) transport is negligible at this high K(+) concentration. The high selectivities of these membranes may enable electrodialysis applications such as purification of salts that contain divalent or trivalent ions. PMID- 25738469 TI - NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients. AB - Recent studies show that NOTCH3 is involved in the glioma development and it is also a prognostic factor for glioma patients. However, the gene polymorphism of NOTCH3 in gliomas prognosis remains unknown.A total of 266 patients were enrolled into this study. The NOTCH3 gene polymorphism at 3 loci, including C>T polymorphism at nucleotide 381, C>A polymorphism at 474 and G>A polymorphism at 684 were determined. All patients received the surgical treatment and/or chemotherapy and/or radiotherapy.We found that the 684G>A polymorphism affects the tumor NOTCH3 expression level and is closely associated with a higher tumor grade, poorer tumor differentiation, and karnofsky performance score in these glioma patients. More importantly, the 684G>A polymorphism is significantly associated with the prognosis of these patients regardless of their treatment manner.Our study indicates that the NOTCH3 gene 684G>A polymorphism may be used as a prognosis marker for gliomas. PMID- 25738470 TI - Emergency department companions of stroke patients: implications on quality of care. AB - Acute care of stroke victims largely relies on the rapid identification and timely clinical and radiological assessment. We evaluated the effect of the number of patient companions on the efficiency of the diagnostic process in the emergency department (ED).Consecutive stroke patients admitted to the ED between August 2011 and October 2012 were evaluated. Clinical, epidemiological, and timeline data (symptoms onset, ED arrival, computed tomography [CT] scanning, and recombinant tissue plasminogen activator infusion), as well as the number of accompanying persons in the ED were prospectively recorded. We used multivariate Poisson log linear models to analyze the association of number of companions adjusted and door-to-CT times and logistic regression for the analysis of the successful identification of stroke patient by ED triage nurse.Out of a total of 724 stroke patients admitted, data regarding number of ED companions were available for 610 (84.3%) patients. Number of companions was associated with higher National Institute of Health Stroke Scale and speech disturbances. It was found to be independently associated with shorter time to CT scanning adjusted for the stroke severity, sex, and speech disturbances (no companions as a reference group, relative risks 0.82, 0.73, and 0.70 for 1, 2, and >=3 companions, respectively, all P < 0.001). Similarly, number of companions was associated with higher rates of stroke recognition by the triage nurse adjusted for covariates (odds ratios 2.11, 2.62, and 4.11, respectively, all P < 0.05).Our findings suggest that the family members and other companions could serve as facilitators of faster and more effective ED management of stroke patients, possibly improving their outcome. PMID- 25738471 TI - Increased cerebellar-default-mode-network connectivity in drug-naive major depressive disorder at rest. AB - The default-mode network (DMN) has been implicated in the neurobiology of major depressive disorder (MDD), and the cerebellum is suggested to be involved in high order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN alterations remains equivocal. This study was conducted to examine the cerebellar-DMN connectivity in drug-naive MDD directly by using the cerebellum Crus I as seeds.Forty-four drug-naive MDD patients and 44 healthy controls participated in the resting-state scan. Functional connectivity (FC) was applied to analyze the images.Significantly increased FCs were observed between the right Crus I and the right inferior frontal cortex (orbital part)/superior temporal pole, bilateral MPFC (orbital part), and left middle temporal gyrus in the patients compared with the controls. There was a significantly positive correlation between the z values of the right Crus I-bilateral MPFC (orbital part) connectivity and the scores of Automatic Thoughts Questionnaire in the patients (r = 0.329, P = 0.029).The findings reveal that depressed patients have increased cerebellar-DMN connectivity with clinical significance, and thus highlight the contribution of the cerebellum to the DMN alterations in neurobiology of MDD. PMID- 25738472 TI - Atypical regressive corneal endothelial cysts in long-term confocal follow-up: a case report. AB - Corneal endothelium is formed of 1 layer of mitochondria-rich cubic cells whose main role is to maintain corneal transparency. Corneal endothelial disorders represent group of both inherited and noninherited and may affect proper vision.A 36-year-old male patient with suspicion of corneal endothelial dystrophy underwent visual acuity, intraocular pressure, the basic slit-lamp examination, anterior segment optical coherence tomography (AS-OCT) (Visante, Carl Zeiss Meditec, Dublin, CA), and corneal confocal microscopy in vivo (Rostock Cornea Module, Heidelberg Engineering Retina Tomograph III, Heidelberg, Germany). During the 3-year observation the patient reported symptoms mainly in the right eye. Slit-lamp examination revealed endothelial changes, much more pronounced in the right eye. Examination by the AS-OCT Visante showed hyperreflective dots within the right corneal endothelium. In order to assess endothelial cell morphology, analysis using corneal confocal microscopy in vivo was performed. Scans revealed presence of single endothelial deposits and severe cell changes of different morphology in both eyes. In the right eye, less pronounced changes of the polymorphic structure-polygonal guttas in different stages, linear and branched loss with "nuclear-like" formations and accompanying sediments. In the left eye, severe homomorphous polygonal "guttas-like" changes with "nuclear-like" formations were observed. Endothelial cysts' features were dynamically changing during follow-up time with different effects on the patient's clinical state.Corneal confocal microscopy allows accurate imaging of the endothelial cells and their detailed characteristics. Structural changes within the endothelial cells are not always proportional to visual acuity and slit-lamp image. The presented case is an example of an unusual corneal endothelial syndrome with probably nondystrophic background due to observed dynamic state with regressive tendency. PMID- 25738473 TI - C-reactive protein and white blood cell count as triage test between urgent and nonurgent conditions in 2961 patients with acute abdominal pain. AB - The purpose of this article is to assess the diagnostic accuracy of C-reactive protein (CRP) and white blood cell (WBC) count to discriminate between urgent and nonurgent conditions in patients with acute abdominal pain at the emergency department, thereby guiding the selection of patients for immediate diagnostic imaging.Data from 3 large published prospective cohort studies of patients with acute abdominal pain were combined in an individual patient data meta-analysis. CRP levels and WBC counts were compared between patients with urgent and nonurgent final diagnoses. Parameters of diagnostic accuracy were calculated for clinically applicable cutoff values of CRP levels and WBC count, and for combinations.A total of 2961 patients were included of which 1352 patients (45.6%) had an urgent final diagnosis. The median WBC count and CRP levels were significantly higher in the urgent group than in the nonurgent group (12.8 *10/L; interquartile range [IQR] 9.9-16) versus (9.3 *10/L; IQR 7.2-12.1) and (46 mg/L; IQR 12-100 versus 10 mg/L; IQR 7-26) (P < 0.001).The highest positive predictive value (PPV) (85.5%) and lowest false positives (14.5%) were reached when cutoff values of CRP level >50 mg/L and WBC count >15 *10/L were combined; however, 85.3% of urgent cases was missed.A high CRP level (>50 mg/L) combined with a high WBC count (>15 *10/L) leads to the highest PPV. However, this applies only to a small subgroup of patients (8.7%). Overall, CRP levels and WBC count are insufficient markers to be used as a triage test in the selection for diagnostic imaging, even with a longer duration of complaints (>48 hours). PMID- 25738475 TI - Visceral adipose tissue area as an independent risk factor for elevated liver enzyme in nonalcoholic fatty liver disease. AB - Chronic elevations in alanine aminotransferase (ALT) levels are associated with body composition. The aim of this study was to evaluate the relationship between elevated liver enzyme levels and the visceral tissue area in subjects with and without nonalcoholic fatty liver disease (NAFLD).An observational cohort study was conducted with subjects undergoing general health examinations. To evaluate the visceral and subcutaneous abdominal adipose tissue area, a computed tomography scan was performed. NAFLD was diagnosed if a person demonstrated fatty liver on ultrasonography without a history of significant alcohol consumption or chronic liver disease. Abnormal liver enzyme levels were based on ALT elevations according to the updated Asian definition.Of the 5100 subjects, 3712 (72.8%) met the inclusion criteria, and NAFLD was found in 1185 subjects. Elevated ALT values were positively correlated with body mass index, waist circumference, and subcutaneous and visceral adipose tissue area. These relationships were attenuated, although they remained significant in a dose-dependent manner, after adjusting for multiple liver injury risk factors. In addition, when body mass index and subcutaneous and visceral tissue areas were finally considered in combination, only visceral adipose tissue remained independently associated with elevated ALT levels in the ultrasonographically diagnosed NAFLD group (P for trend <0.001 for men and women).Elevated ALT levels were independently and dose dependently associated with visceral fat accumulation in the healthy general population, especially in ultrasonographically diagnosed NAFLD patients. These results reemphasize the importance of visceral fat in the pathogenesis of NAFLD. PMID- 25738474 TI - Relations of plasma polyunsaturated Fatty acids with blood pressures during the 26th and 28th week of gestation in women of Chinese, Malay, and Indian ethnicity. AB - Observational and intervention studies have reported inconsistent results of the relationship between polyunsaturated fatty acids (PUFAs) and hypertension during pregnancy. Here, we examined maternal plasma concentrations of n-3 and n-6 PUFAs between the 26th and the 28th week of gestation in relation to blood pressures and pregnancy-associated hypertension.We used data from a birth cohort study of 751 Chinese, Malay, and Indian women. Maternal peripheral systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken from the brachial arm, and central SBP and pulse pressures (PPs) were derived from radial artery pressure waveforms between the 26th and the 28th week of gestation. Pregnancy-associated hypertension (including gestational hypertension and preeclampsia) was ascertained from medical records. Plasma phosphatidylcholine n-3 and n-6 PUFAs were measured by gas chromatography and expressed as percentage of total fatty acids.Peripheral SBP was inversely associated with total n-3 PUFAs [-0.51 (95% confidence interval, CI, -0.89 to -0.13) mm Hg] and long-chain n-3 PUFAs [-0.52 (CI -0.92 to -0.13) mmHg]. Similar but weaker associations were observed for central SBP and PP. Dihomo-gamma-linolenic acid was marginally positively associated with peripheral SBP, central SBP, and PP, whereas linoleic acid and total n-6 PUFAs showed no significant associations with blood pressures. We identified 28 pregnancy-associated hypertension cases, and 1% increase in total n 3 PUFAs was associated with a 24% lower odds of pregnancy-associated hypertension (odds ratio 0.76; 95% CI 0.60 to 0.97). Maternal ethnicity modified the PUFAs blood pressure relations, with stronger inverse associations with n-3 PUFAs in Chinese women, and stronger positive associations with n-6 PUFAs in Indian women (P values for interaction ranged from 0.02 to 0.07).Higher n-3 PUFAs at midgestation are related to lower maternal blood pressures and pregnancy associated hypertension in Asian women, and the ethnicity-related variation between PUFAs and blood pressures deserves further investigation. PMID- 25738476 TI - Histopathological diagnostic value of the IgG4+/IgG+ ratio of plasmacytic infiltration for IgG4-related diseases: a PRISMA-compliant systematic review and meta-analysis. AB - This article aims to perform a meta-analysis to evaluate the diagnostic value of the immunoglobulin G (IgG)4/IgG ratio of plasmacytic infiltration for IgG4 related diseases.Four databases-EMBASE, ISI Web of Knowledge, PubMed, and the Cochrane Library-were systematically searched. Approximately 200 participants from several studies were included in this research. STATA 11.2 software (Stata Corporation, College Station, TX) and Meta-DiSc 1.4 (Unit of Clinical Biostatistics, Ramon y Cajal Hospital, Madrid, Spain) were used to perform the meta-analysis.Nine studies were included in the meta-analysis. The pooled diagnostic odds ratio was 18.94 [95% confidence interval (CI), 2.89-124.30]. The sensitivity was 58.80% (95% CI, 50.90-66.30) and the specificity was 90.20% (95% CI, 81.20-95.80). The positive and negative likelihood ratios were 3.12 (95% CI, 1.07-9.16) and 0.26 (95% CI, 0.09-0.70), respectively. The area under the curve of the summary receiver-operating characteristic was 0.88.To conclude, the IgG4/IgG ratio of plasmacytic infiltration is modestly effective in diagnosing IgG-related disease. PMID- 25738477 TI - Heat sink effect on tumor ablation characteristics as observed in monopolar radiofrequency, bipolar radiofrequency, and microwave, using ex vivo calf liver model. AB - Thermal ablation of liver tumors near large blood vessels is affected by the cooling effect of blood flow, leading to incomplete ablation. Hence, we conducted a comparative investigation of heat sink effect in monopolar (MP) and bipolar (BP) radiofrequency ablation (RFA), and microwave (MW) ablation devices.With a perfused calf liver, the ablative performances (volume, mass, density, dimensions), with and without heat sink, were measured. Heat sink was present when the ablative tip of the probes were 8.0 mm close to a major hepatic vein and absent when >30 mm away. Temperatures (T1 and T2) on either side of the hepatic vein near the tip of the probes, heating probe temperature (T3), outlet perfusate temperature (T4), and ablation time were monitored.With or without heat sink, BP radiofrequency ablated a larger volume and mass, compared with MP RFA or MW ablation, with latter device producing the highest density of tissue ablated. MW ablation produced an ellipsoidal shape while radiofrequency devices produced spheres.Percentage heat sink effect in Bipolar radiofrequency : Mono-polar radiofrequency : Microwave was (Volume) 33:41:22; (mass) 23:56:34; (density) 9.0:26:18; and (relative elipscity) 5.8:12.9:1.3, indicating that BP and MW devices were less affected.Percentage heat sink effect on time (minutes) to reach maximum temperature (W) = 13.28:9.2:29.8; time at maximum temperature (X) is 87:66:16.66; temperature difference (Y) between the thermal probes (T3) and the temperature (T1 + T2)/2 on either side of the hepatic vessel was 100:87:20; and temperature difference between the (T1 + T2)/2 and temperature of outlet circulating solution (T4), Z was 20.33:30.23:37.5.MW and BP radiofrequencies were less affected by heat sink while MP RFA was the most affected. With a single ablation, BP radiofrequency ablated a larger volume and mass regardless of heat sink. PMID- 25738478 TI - Growth retardation, general hypotonia, and loss of acquired neuromotor skills in the infants of mothers with cobalamin deficiency and the possible role of succinyl-CoA and glycine in the pathogenesis. AB - Vitamin B12 (cobalamin, Cbl) deficiency can cause metabolic, hematological, and neurological abnormalities. Adequate levels of succinyl-coenzyme A (CoA) cannot be synthesized from methylmalonyl-CoA because of the decreased activity of the methylmalonyl-CoA mutase enzyme that uses Cbl as the cofactor. Succinyl-CoA synthesis deficiency leads to decreased heme synthesis and gluconeogenesis. The reason of growth retardation can be gluconeogenesis deficiency together with heme synthesis deficiency whereas the reason of the neurological abnormalities can be glycine increase in the tissue due to decreased heme synthesis. We present 7 infants diagnosed with severe nutritional Cbl deficiency and discuss the role of succinyl-CoA and glycine in the possible pathogenesis in this article. Patients brought to our clinic with a complaint of growth retardation and diagnosed with nutritional Cbl deficiency were included in the study. There were 5 females and 2 males. The mean age was 11 +/- 2.30 (range 6-13) months. All patients had general muscular hypotonia and 4 had growth retardation. Neuromotor growth retardation was found in 4 of the children who had previously shown normal neuromotor development for age. The mean Cbl level was 83.8 +/- 27.6 (45.6-114) pg/mL. The mean Cbl level of the mothers was 155 +/- 56.6 (88-258) pg/mL. Six of the patients had anemia and 1 had thrombocytopenia. Mean corpuscular volume value was 91.5 +/- 12.2 fL. Following treatment, the muscle tonus of the patients improved, the anemia and growth retardation decreased, and the lost neuromotor abilities were recovered. Severe nutritional Cbl deficiency is an important nutritional disease where complications can be prevented with early treatment. When evaluating the pathogenesis, it should be noted that nutritional Cbl deficiency is a succinyl-CoA synthesis deficiency. PMID- 25738479 TI - Solitary perihepatic splenosis mimicking liver lesion: a case report and literature review. AB - Hepatic splenosis, one type of manifestation of ectopic spleen tissue, is rarely reported. It cannot be distinguished from hepatic malignancies because of lack of significant radiological features. By means of this case report and 31 literature reviews, potential treatment modalities concerning clinical diagnostics, patient's management could be discussed.The report presents the case of a 33-year old man with a liver lesion. Finally, after a mini-incision laparotomy, the lesion was resected and the diagnosis confirmed it as hepatic splenosis. A literature search for case reports published between January 1, 1900, and August 1, 2014, was performed on PubMed.Approximately 80% (27/34) of patients diagnosed with hepatic splenosis had a history of splenectomy. The mean time interval between splenectomy and hepatic splenosis detection was 25 (1.5-47) years. The median size of reported hepatic splenosis is 30 mm in diameter. Technetium-99m labeled heat denatured red-blood-cells scintigraphy or superparamagnetic iron oxide-enhanced magnetic resonance imaging is now considered to be the optimal method of diagnosing splenosis.Hepatic splenosis requires no treatment in most cases. Operation should be performed if it is accompanied by hypersplenism in hematological diseases. When the diagnosis remains unclear, further biopsy or laparoscopy is recommended. If hepatic splenosis is confirmed, careful follow-up is beneficial. PMID- 25738480 TI - Effect of hypertension on outcomes of high-risk patients after BCG-treated bladder cancer: a single-institution long follow-up cohort study. AB - Immunotherapy with Bacillus Calmette-Guerin (BCG) is the most efficacious treatment for high-risk bladder cancer (BC) (Ta/T1 or carcinoma in situ) to reduce the risk of recurrence. Our aim was to evaluate whether hypertension and diabetes influence the outcome of patients with noninvasive BC treated with BCG instillations.In order to collect homogeneous data, we considered as "hypertensive" only those patients who had previous diagnosed hypertension and a history of taking medical therapy with antihypertensive drugs (AHT), and as "diabetic" only those prescribed oral antidiabetics or insulin (ADT).We analyzed 343 high-risk BC patients undergoing BCG (1995-2010) with a median follow-up of 116 months (range 48-238). The distribution of various kinds of AHT and antidiabetic drugs was homogeneous, with no significant differences (p > 0.05).In both univariate and multivariate analyses, the only statistically significant parameter prognostic for recurrence after BCG treatment was AHT. Recurrence-free survival curves showed a significant correlation with AHT (p = 0.0168, hazards ratio [HR] 1.45, 95% confidence interval [CI] 1.0692-1.9619); there was no correlation (p = 0.9040) with ADT (HR 0.9750, 95% CI 0.6457-1.4721). After stratification of AHT and ADT according to drug(s) prescribed, there were no significant differences in the BC recurrence rate (p > 0.05).In this study with a very long-term follow-up, hypertension alone (evaluated by AHT) revealed the increased risk of BC recurrence after BCG treatment.Several hypotheses have been formulated to support these findings, but further prospective studies are needed to both evaluate the real influence of hypertension and identify a possible prognostic factor to be used in selecting poor-prognosis BC patients as early candidates for surgical treatment. PMID- 25738481 TI - Cost-utility of angiotensin-converting enzyme inhibitor-based treatment compared with thiazide diuretic-based treatment for hypertension in elderly Australians considering diabetes as comorbidity. AB - The objective of this study was to examine the cost-effectiveness of angiotensin converting enzyme inhibitor (ACEI)-based treatment compared with thiazide diuretic-based treatment for hypertension in elderly Australians considering diabetes as an outcome along with cardiovascular outcomes from the Australian government's perspective.We used a cost-utility analysis to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained. Data on cardiovascular events and new onset of diabetes were used from the Second Australian National Blood Pressure Study, a randomized clinical trial comparing diuretic-based (hydrochlorothiazide) versus ACEI-based (enalapril) treatment in 6083 elderly (age >=65 years) hypertensive patients over a median 4.1-year period. For this economic analysis, the total study population was stratified into 2 groups. Group A was restricted to participants diabetes free at baseline (n = 5642); group B was restricted to participants with preexisting diabetes mellitus (type 1 or type 2) at baseline (n = 441). Data on utility scores for different events were used from available published literatures; whereas, treatment and adverse event management costs were calculated from direct health care costs available from Australian government reimbursement data. Costs and QALYs were discounted at 5% per annum. One-way and probabilistic sensitivity analyses were performed to assess the uncertainty around utilities and cost data.After a treatment period of 5 years, for group A, the ICER was Australian dollars (AUD) 27,698 (&OV0556; 18,004; AUD 1-&OV0556; 0.65) per QALY gained comparing ACEI-based treatment with diuretic-based treatment (sensitive to the utility value for new-onset diabetes). In group B, ACEI-based treatment was a dominant strategy (both more effective and cost-saving). On probabilistic sensitivity analysis, the ICERs per QALY gained were always below AUD 50,000 for group B; whereas for group A, the probability of being below AUD 50,000 was 85%.Although the dispensed price of diuretic-based treatment of hypertension in the elderly is lower, upon considering the potential enhanced likelihood of the development of diabetes in addition to the costs of treating cardiovascular disease, ACEI-based treatment may be a more cost-effective strategy in this population. PMID- 25738482 TI - Clinical and pathological findings of a fatal systemic capillary leak syndrome (Clarkson disease): a case report. AB - Systemic capillary leak syndrome (SCLS) is a rare disorder with episodes of hypotension, hypoalbuminemia, and hemoconcentration. During attacks endothelial hyperpermeability results in leakage of plasma proteins into the interstitial space. Attacks vary in severity and may be lethal.A 49-year-old previously healthy man was admitted to hospital for hypovolemic shock, anasarca with pleuropericardial effusion, muscle fatigue, and oliguria occurring after a flu like syndrome. Laboratory data showed an increase in hematocrit (65%), leucocytes (24.590 MU/L), creatinine (2.5 mg/dL), creatine phosphokinase (10.000 U/L), and a decrease in serum albumin (17 g/L) without proteinuria. Immunoglobulins of class G/lambda monoclonal gammopathy were detected (1.3 g/L). The initial suspicions addressed to a protein-loosing syndrome or to an effort-related rhabdomyolysis. Initial therapy was based on steroids, albumin, and high molecular weight plasma expanders (hydroxyethyl starch). Because of high hematocrit, phlebotomy was also performed. The patient had complete clinical remission and a diagnosis of SCLS was finally made. He received prophylactic therapy with verapamil and theophylline that was self-stopped for intolerance (hypotension and tachycardia). He had a new crisis 2 days after a physical effort, and was admitted in intensive care unit. The patient died for severe hypovolemic shock with multiorgan failure and sudden cardiac arrest 15 hours after hospital admission. Postmortem investigation revealed massive interstitial edema of main organs with myocardial hyperacute ischemia.Studies on SCLS are limited for the rarity of the disease and its unpredictable course. Both prophylactic and acute crisis treatments are empirical and optimal management of severe attacks is still lacking. PMID- 25738483 TI - Vitamin D deficiency is an independent risk factor for urinary tract infections after renal transplants. AB - Vitamin D deficiency is frequently found in patients with renal transplants (RTxs). Because vitamin D plays indispensable roles in the immune system, there may be an association between vitamin D deficiency and infection in these patients, but this has not been fully elucidated. Therefore, this study investigated the impact of pre-RTx vitamin D deficiency on urinary tract infection (UTI) development after RTx.We measured 25-hydroxyvitamin D3 (25(OH)D3) levels in 410 patients 2 weeks before they underwent RTx. Vitamin D deficiency was defined as 25(OH)D3 <10 ng/mL. The primary outcome was UTI occurrence after RTx. Cox proportional hazard analysis determined whether vitamin D deficiency was independently associated with UTI.The mean 25(OH)D3 level was 12.8 +/- 6.9 ng/mL, and 171 patients (41.7%) were vitamin D deficient. During a median follow-up duration of 7.3 years, the UTI incidence was significantly higher in vitamin D deficient patients (52 patients, 30.4%) compared with vitamin D-nondeficient patients (40 patients, 16.7%) (P = 0.001). Moreover, multivariate Cox proportional hazard analysis showed that vitamin D deficiency was an independent predictor of UTI after RTx (hazard ratio 1.81, 95% confidence interval 1.11-2.97, P = 0.02).Vitamin D deficiency was an independent risk factor for UTI after RTx; hence, determining 25(OH)D3 levels might help to predict infectious complications after RTx. PMID- 25738484 TI - Serosal invasion strongly associated with recurrence after curative hepatic resection of hepatocellular carcinoma: a retrospective study of 214 consecutive cases. AB - The purpose of this study was to clarify the individual prognostic factors after curative and primary resection of hepatocellular carcinoma (HCC).Reliable prognostic factors and tumor staging for HCC have been required to predict an appropriate prognosis. However, in HCC, no staging system has received universal acceptance, and several tumor factors seem to relate to HCC prognosis, but they are not definitive. At present, few studies have mentioned the importance of serosal invasion as a prognostic factor.A retrospective search of our database identified 214 consecutive patients who underwent primary and curative hepatectomy for HCC at our department between January 1998 and December 2011. Risk factors for recurrence-free survival (RFS) and overall survival (OS) were analyzed with Cox proportional hazard model, Kaplan-Meier method, and log-rank tests.Multivariate analyses showed that serosal invasion (hazard ratio [HR], 2.75; P = 0.0005) and vascular invasion (HR, 1.71; P = 0.0331) were independently correlated with RFS. Serosal invasion was significantly correlated with HCC recurrence (P = 0.0230). The Kaplan-Meier method and log-rank tests revealed that the patients with serosal invasion showed significantly worse prognosis both in RFS (P < 0.0001) and OS (P = 0.0016).Serosal invasion should be regarded as a strong independent predictor for recurrence in curatively resected HCC cases. PMID- 25738485 TI - Long-term risk of acute coronary syndrome in splenectomized patients due to splenic injury. AB - We aimed to assess the magnitude and duration of risk of acute coronary syndrome (ACS) associated with splenectomy for splenic injury.We identified 5139 splenectomized patients (the splenectomy cohort) to compare with 2 other cohorts for assessing the magnitude and risk of ACS: the first cohort comprising subjects without splenic injury and without splenectomy (control cohort), and the second cohort comprising nonsplenectomized patients with splenic injury (nonsplenectomy cohort; n = 6391). For each splenic injury patient (n = 11530), 4 control comparisons were frequency-matched by the year of index date, age, and sex (n = 46120).The adjusted risk of ACS was significantly higher in the splenectomy group than in the control group (2.08 vs 1.68 per 1000 person-years; adjusted hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.01-1.68). The sex-specific data showed that the adjusted HR for the splenectomy group, compared with the control group, was 1.29 in men (95% CI, 0.97-1.73) and 1.36 in women (95% CI, 0.79-2.33). The age-specific analyses failed to demonstrate a significantly higher adjusted HR of ACS in the splenectomized patients in any age subgroup, compared with their counterparts in the control group. Furthermore, no difference in the risk of ACS was detected between the splenectomy and nonsplenectomy cohorts within the splenic injury patients.In comparison with the control cohort, patients undergoing splenectomy for splenic injury exhibited an elevated risk of ACS. PMID- 25738486 TI - Graphene oxide-assisted nucleic acids assays using conjugated polyelectrolytes based fluorescent signal transduction. AB - In this work, we investigated the interactions between graphene oxide (GO) and conjugated polyelectrolytes (CPEs) with different backbone and side chain structures. By studying the mechanism of fluorescence quenching of CPEs by GO, we find that the charge and the molecular structure of CPEs play important roles for GO-CPEs interactions. Among them, electrostatic interaction, pi-pi interaction, and cation-pi bonding are dominant driving forces. By using a cationic P2, we have developed a sensitive homogeneous sensor for DNA and RNA detection with a detection limit of 50 pM DNA and RNA, which increased the sensitivity by 40-fold as compared to GO-free CPE-based sensors. This GO-assisted CPE sensing strategy is also generic and shows a high potential for biosensor designs based on aptamers, proteins, peptides, and other biological probes. PMID- 25738487 TI - Geometry dependence of electronic and energetic properties of one-dimensional peanut-shaped fullerene polymers. AB - In the present study, we investigate different types of 1D peanut-shaped fullerene polymers (PSFPs) using density functional theory to understand the electronic states and the energetic stability of curved carbon nanomaterials. We generated 53 different models of the 1D PSFPs by means of the generalized Stone Wales transformations and performed structural optimization for each model. Band structures of the 1D PSFPs exhibit either metallic or semiconducting property according to the geometrical structures. We find that the energetic stability of the 1D PSFPs depends on the geometry: the more octagon and pentagon-octagon pairs (heptagons and hexagon-heptagon pairs) in their geometrical structures, the more stable (unstable) the 1D PSFPs. PMID- 25738488 TI - The first example of Tb3-containing metallopolymer-type hybrid materials with efficient and high color-purity green luminescence. AB - In the series of homo-leptic trinuclear complexes {[Ln3(L)4Cl4(MeOH)(H2O)].Cl} (Ln = La, 1; Ln = Eu, 2; Ln = Tb, 3 or Ln = Gd, 4) self-assembled from the allyl modified benzimidazole-type ligand HL (4-allyl-2-(1H-benzo[d]imidazol-2-yl)-6 methoxyphenol) and LnCl3.6H2O, a suitable energy level match endows efficient green luminescence (Phi(overall) = 72%) of Tb3-arrayed complex 3. The copolymerization between each of these complex monomers 1-4 and C=C-containing MMA (methyl methacrylate) or NBE (norbornene) shows that degradative chain transfer of the terminal four flexible allyl groups within restrains their radical polymerization with MMA while it does not hinder their effective ring opening metathesis polymerization (ROMP) with NBE. Thus, two kinds of PMMA supported doping hybrid materials 1@PMMA, 2@PMMA, 3@PMMA and 4@PMMA and PNBE supported metallopolymer-type hybrid materials Poly(NBE-1), Poly(NBE-2), Poly(NBE 3) and Poly(NBE-4) are obtained, respectively. Especially for both 3@PMMA and Poly(NBE-3) with high color-purity characteristic green emission of Tb(3+) ions, improved physical properties including significantly enhanced luminescence (Phi(overall) = 76% or 83%) are observed, and covalent-bonding endows a higher concentration self-quenching as compared to physical doping. PMID- 25738489 TI - Continuous and semi-continuous cell culture for production of blood clotting factors. AB - Recombinant clotting factors are important biotherapeutics that Pfizer has produced and marketed for over fifteen years. Owing to the complexity of the structure and function of these blood factors, it can be challenging to achieve the required product quality and manufacturing productivity. The article highlights the semi-continuous and continuous cell culture processes employed by Pfizer for the production of BeneFIX and ReFacto AF. The benefits of such processes, the challenges of maintaining an aseptic production culture for extended periods, and batch definition are discussed in this article. PMID- 25738490 TI - Understanding the physical and chemical nature of the warfarin drug binding site in human serum albumin: experimental and theoretical studies. AB - Human serum albumin (HSA) is one of the major carrier proteins in the body and constitutes approximately half of the protein found in blood plasma. It plays an important role in lipid metabolism, and its ability to reversibly bind a large variety of pharmaceutical compounds makes it a crucial determinant of drug pharmacokinetics and pharmacodynamics. This review deals with one of the protein's major binding sites "Sudlow I" which includes a binding pocket for the drug warfarin (WAR). The binding nature of this important site can be characterized by measuring the spectroscopic changes when a ligand is bound. Using several drugs, including WAR, and other drug-like molecules as ligands, the results emphasize the nature of Sudlow I as a flexible binding site, capable of binding a variety of ligands by adapting its binding pockets. The high affinity of the WAR pocket for binding versatile molecular structures stems from the flexibility of the amino acids forming the pocket. The binding site is shown to have an ionization ability which is important to consider when using drugs that are known to bind in Sudlow I. Several studies point to the important role of water molecules trapped inside the binding site in molecular recognition and ligand binding. Water inside the protein's cavity is crucial in maintaining the balance between the hydrophobic and hydrophilic nature of the binding site. Upon the unfolding and refolding of HSA, more water molecules are trapped inside the binding site which cause some swelling that prevents a full recovery from the denatured state. Better understanding of the mechanism of binding in macromolecules such as HSA and other proteins can be achieved by combining experimental and theoretical studies which produce significant synergies in studying complex biochemical phenomena. PMID- 25738491 TI - Understanding the interaction between human serum albumin and anti-bacterial/ anti-cancer compounds. AB - Human serum albumin (HSA) is the most important carrier of exogenous and endogenous molecules in human plasma. Understanding and characterizing the interaction of drugs with HSA has attracted enormous research interests from decades. The nature and magnitude of these bindings have direct consequence on drug delivery, pharmacokinetics, pharmacodynamics, therapeutic efficacy and drug designing. An overview of HSA and antibacterial/ anti-cancer ligands interaction is the need of the hour as these drugs together constitute more than half of the total drug consumption in the world. In this review, the information on the number of binding sites, binding strength, the nature of binding interactions and the location of binding sites of such drugs on the HSA are summarised. The effect of such drugs on the overall conformation, stability and function of HSA is also reviewed. This review will help to gain useful insights into the significance of the binding of anti-bacterial and anti-cancer drugs with plasma protein and the effect of binding on its overall distribution and pharmacological activities. PMID- 25738492 TI - Validation of the Spanish version of the Pediatric Asthma Caregiver Quality of Life Questionnaire (PACQLQ) in a population of Hispanic children. AB - OBJECTIVE: The Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ) is intended to measure the impact of children's asthma on their parents/caregiver's QoL. However, there are no formal validation studies of the Spanish version of PACQLQ. METHODS: In a prospective cohort validation study, asthmatic children aged between 7 and 17 years and their parents, attended both a baseline and a follow-up visit 2-6 weeks later. In these two visits, we gathered the necessary data for assessing the criterion validity, construct validity, test retest reliability, sensitivity to change, internal consistency and usability of the PACQLQ. RESULTS: At baseline, PACQLQ scores were significantly different between patients with controlled, partly controlled and uncontrolled asthma (median [IQR] 78.0 [61.0-85.0], 71.0 [37.0-76.0] and 48.0 [40.7-55.0], respectively, p < 0.001), and also between patients for whom this visit resulted in a step-up versus no change or a step-down in therapy (50.0 [40.0-60.0] versus 78.0 [61.0-85.0]; p < 0.001). PACQLQ scores at baseline were significantly lower than those obtained in the follow-up visit in patients with change for the better in the global rating of change questionnaire (median [IQR] 50.0 [42.5-56.0] versus 80.0 [78.5-85.0]; p < 0.001). The intraclass correlation coefficient of the measurements was 0.839 (95%CI: 0.735-0.902). The Cronbach alpha was 0.914 for the questionnaire as a whole. CONCLUSIONS: The Spanish version of the PACQLQ has adequate construct validity, adequate sensitivity to change, good internal consistency, excellent test-retest reliability and good usability when employed in children aged between 7 and 17 years with physician-diagnosed asthma. PMID- 25738493 TI - Diastolic hypotension in pediatric patients with asthma receiving continuous albuterol. AB - OBJECTIVES: Concerns have been raised regarding cardiac side effects of continuous high-dose albuterol nebulization in status asthmaticus management. Our study goal was to determine prevalence and potential risk factors for hypotension development during continuous albuterol administration in pediatric patients. METHODS: A retrospective cohort study was conducted at Children's Memorial Hermann Hospital from 1 January 2011 to 31 August 2012. A total of 152 patients admitted to pediatric intensive or intermediate care units who received continuous albuterol nebulization for management of status asthmaticus were analyzed. RESULTS: Diastolic hypotension, defined as a value < 50 mmHg or <5th percentile of normal for age, developed in 90% of patients and a positive correlation with increasing doses of albuterol was demonstrated. The overall median time to onset of hypotension was 4 h (interquartile range (IQR): 2-6.5) and was significantly lower among patients admitted to the intensive care unit rather than intermediate care (p = 0.005). The odds of hypotension were 82% lower among patients who received fluid boluses prior to continuous albuterol nebulization. None of the potential risk factors demonstrated statistical significance. CONCLUSIONS: Diastolic hypotension is a common occurrence among patients who receive continuous albuterol nebulization for status asthmaticus. Total albuterol dose appeared to be directly related to risk of developing diastolic hypotension. Administration of supplemental fluid boluses before continuous nebulized albuterol appeared to provide a significant protective effect. The clinical impact and the significance of diastolic hypotension and the importance of prophylactic administration of intravenous fluid boluses in patients experiencing status asthmaticus are yet to be determined. PMID- 25738494 TI - MiR-486 regulates lactation and targets the PTEN gene in cow mammary glands. AB - Mammary gland development is controlled by several genes. Although miRNAs have been implicated in mammary gland function, the mechanism by which miR-486 regulates mammary gland development and lactation remains unclear. We investigated miR-486 expression in cow mammary gland using qRT-PCR and ISH and show that miR-486 expression was higher during the high-quality lactation period. We found that miR-486 targets phosphoinositide signaling in the cow mammary gland by directly downregulating PTEN gene expression and by altering the expression of downstream genes that are important for the function of the mammary gland, such as AKT, mTOR. We analyzed the effect of beta-casein, lactose and triglyceride secretion in bovine mammary gland epithelial cells (BMECs) transfected by an inhibitor and by mimics of miR-486. Our results identify miR-486 as a downstream regulator of PTEN that is required for the development of the cow mammary gland. PMID- 25738495 TI - Metabolic effects of cholecystectomy: gallbladder ablation increases basal metabolic rate through G-protein coupled bile acid receptor Gpbar1-dependent mechanisms in mice. AB - BACKGROUND & AIMS: Bile acids (BAs) regulate energy expenditure by activating G protein Coupled Bile Acid Receptor Gpbar1/TGR5 by cAMP-dependent mechanisms. Cholecystectomy (XGB) increases BAs recirculation rates resulting in increased tissue exposure to BAs during the light phase of the diurnal cycle in mice. We aimed to determine: 1) the effects of XGB on basal metabolic rate (BMR) and 2) the roles of TGR5 on XGB-dependent changes in BMR. METHODS: BMR was determined by indirect calorimetry in wild type and Tgr5 deficient (Tgr5-/-) male mice. Bile flow and BAs secretion rates were measured by surgical diversion of biliary duct. Biliary BAs and cholesterol were quantified by enzymatic methods. BAs serum concentration and specific composition was determined by liquid chromatography/tandem mass spectrometry. Gene expression was determined by qPCR analysis. RESULTS: XGB increased biliary BAs and cholesterol secretion rates, and elevated serum BAs concentration in wild type and Tgr5-/- mice during the light phase of the diurnal cycle. BMR was ~25% higher in cholecystectomized wild type mice (p <0.02), whereas no changes were detected in cholecystectomized Tgr5-/- mice compared to wild-type animals. CONCLUSION: XGB increases BMR by TGR5 dependent mechanisms in mice. PMID- 25738496 TI - Human footprint variation while performing load bearing tasks. AB - Human footprint fossils have provided essential evidence about the evolution of human bipedalism as well as the social dynamics of the footprint makers, including estimates of speed, sex and group composition. Generally such estimates are made by comparing footprint evidence with modern controls; however, previous studies have not accounted for the variation in footprint dimensions coming from load bearing activities. It is likely that a portion of the hominins who created these fossil footprints were carrying a significant load, such as offspring or foraging loads, which caused variation in the footprint which could extend to variation in any estimations concerning the footprint's maker. To identify significant variation in footprints due to load-bearing tasks, we had participants (N = 30, 15 males and 15 females) walk at a series of speeds carrying a 20kg pack on their back, side and front. Paint was applied to the bare feet of each participant to create footprints that were compared in terms of foot length, foot width and foot area. Female foot length and width increased during multiple loaded conditions. An appreciation of footprint variability associated with carrying loads adds an additional layer to our understanding of the behavior and morphology of extinct hominin populations. PMID- 25738497 TI - Inhibition of methyltransferases accelerates degradation of cFLIP and sensitizes B-cell lymphoma cells to TRAIL-induced apoptosis. AB - Non-Hodgkin lymphomas (NHLs) are characterized by specific abnormalities that alter cell cycle regulation, DNA damage response, and apoptotic signaling. It is believed that cancer cells are particularly sensitive to cell death induced by tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL). However, many cancer cells show blocked TRAIL signaling due to up-regulated expression of anti-apoptotic factors, such as cFLIP. This hurdle to TRAIL's tumor cytotoxicity might be overcome by combining TRAIL-based therapy with drugs that reverse blockages of its apoptotic signaling. In this study, we investigated the impact of a pan-methyltransferase inhibitor (3-deazaneplanocin A, or DZNep) on TRAIL induced apoptosis in aggressive B-cell NHLs: mantle cell, Burkitt, and diffuse large B-cell lymphomas. We characterized TRAIL apoptosis regulation and caspase activation in several NHL-derived cell lines pre-treated with DZNep. We found that DZNep increased cancer cell sensitivity to TRAIL signaling by promoting caspase-8 processing through accelerated cFLIP degradation. No change in cFLIP mRNA level indicated independence of promoter methylation alterations in methyltransferase activity induced by DZNep profoundly affected cFLIP mRNA stability and protein stability. This appears to be in part through increased levels of cFLIP-targeting microRNAs (miR-512-3p and miR-346). However, additional microRNAs and cFLIP-regulating mechanisms appear to be involved in DZNep-mediated enhanced response to extrinsic apoptotic stimuli. The capacity of DZNep to target cFLIP expression on multiple levels underscores DZNep's potential in TRAIL-based therapies for B-cell NHLs. PMID- 25738498 TI - Enhanced CD8 T cell responses through GITR-mediated costimulation resolve chronic viral infection. AB - Chronic infections are characterized by the inability to eliminate the persisting pathogen and often associated with functional impairment of virus-specific T-cell responses. Costimulation through Glucocorticoid-induced TNFR-related protein (GITR) can increase survival and function of effector T cells. Here, we report that constitutive expression of GITR-ligand (GITRL) confers protection against chronic lymphocytic choriomeningitis virus (LCMV) infection, accelerating recovery without increasing pathology. Rapid viral clearance in GITRL transgenic mice coincided with increased numbers of poly-functional, virus-specific effector CD8+ T cells that expressed more T-bet and reduced levels of the rheostat marker PD-1. GITR triggering also boosted the helper function of virus-specific CD4 T cells already early in the infection, as was evidenced by increased IL-2 and IFNgamma production, and more expression of CD40L and T-bet. Importantly, CD4 depletion experiments revealed that the expanded pool of virus-specific effector CD8 T cells and the ensuing viral clearance in LCMV-infected GITRL tg mice was entirely dependent on CD4 T cells. We found no major differences for NK cell and regulatory T cell responses, whereas the humoral response to the virus was increased in GITRL tg mice, but only in the late phase of the infection when the virus was almost eradicated. Based on these findings, we conclude that enhanced GITR-triggering mediates its protective, anti-viral effect on the CD8 T cell compartment by boosting CD4 T cell help. As such, increasing costimulation through GITR may be an attractive strategy to increase anti-viral CTL responses without exacerbating pathology, in particular to persistent viruses such as HIV and HCV. PMID- 25738499 TI - Scabies and impetigo prevalence and risk factors in Fiji: a national survey. AB - BACKGROUND: Scabies is recognised as a major public health problem in many countries, and is responsible for significant morbidity due to secondary bacterial infection of the skin causing impetigo, abscesses and cellulitis, that can in turn lead to serious systemic complications such as septicaemia, kidney disease and, potentially, rheumatic heart disease. Despite the apparent burden of disease in many countries, there have been few large-scale surveys of scabies prevalence or risk factors. We undertook a population-based survey in Fiji of scabies and impetigo to evaluate the magnitude of the problem and inform public health strategies. METHODOLOGY/PRINCIPAL FINDINGS: A total of 75 communities, including villages and settlements in both urban and rural areas, were randomly selected from 305 communities across the four administrative divisions, and all residents in each location were invited to participate in skin examination by trained personnel. The study enrolled 10,887 participants. The prevalence of scabies was 23.6%, and when adjusted for age structure and geographic location based on census data, the estimated national prevalence was 18.5%. The prevalence was highest in children aged five to nine years (43.7%), followed by children aged less than five (36.5%), and there was also an indication of prevalence increasing again in older age. The prevalence of scabies was twice as high in iTaukei (indigenous) Fijians compared to Indo-Fijians. The prevalence of impetigo was 19.6%, with a peak in children aged five to nine years (34.2%). Scabies was very strongly associated with impetigo, with an estimated 93% population attributable risk. CONCLUSIONS: As far as we are aware, this is the first national survey of scabies and impetigo ever conducted. We found that scabies occurs at high levels across all age groups, ethnicities, and geographical locations. Improved strategies are urgently needed to achieve control of scabies and its complications in endemic communities. PMID- 25738500 TI - Sex distribution of study samples reported in American Society of Biomechanics annual meeting abstracts. AB - BACKGROUND: Study samples should be appropriately selected to maximize generalizability of results. Excluding one sex from studies of conditions that affect both sexes is problematic and has received attention as a public policy issue in the United States, resulting in legislation and recommendations made by the National Institutes of Health to address this deficiency of study designs. It is unknown to what extent biomechanical studies have inappropriately excluded one sex. The objective of this study was to provide objective data on this question. METHODS: A retrospective review of random samples of abstracts presented at American Society of Biomechanics annual meetings from 1983 to 2013 was conducted to assess reporting of sex of study samples and whether the study samples were approximately balanced with respect to sex. FINDINGS: We did not find a statistically significant increasing trend in the percentage of abstracts reporting sex over time. However, increasing trends were noted in the percentage of abstracts including both sexes (p < 0.05) and percentage of abstracts having an "approximately balanced" study sample containing 50 +/- 20% females (p > 0.05). In 2013 the percentage of abstracts reporting studies having approximately balanced study samples was only 28%, far from the ideal level of 100%. INTERPRETATION: While there has been modest change since 1983, there remains significant room for improvement in the reporting and composition of experimental studies reported at American Society of Biomechanics annual meetings. PMID- 25738501 TI - Intake of hydrolyzed casein is associated with reduced body fat accretion and enhanced phase II metabolism in obesity prone C57BL/6J mice. AB - The amount and form of dietary casein have been shown to affect energy metabolism and lipid accumulation in mice, but the underlying mechanisms are not fully understood. We investigated 48 hrs urinary metabolome, hepatic lipid composition and gene expression in male C57BL/6J mice fed Western diets with 16 or 32 energy% protein in the form of extensively hydrolyzed or intact casein. LC-MS based metabolomics revealed a very strong impact of casein form on the urinary metabolome. Evaluation of the discriminatory metabolites using tandem mass spectrometry indicated that intake of extensively hydrolyzed casein modulated Phase II metabolism associated with an elevated urinary excretion of glucuronic acid- and sulphate conjugated molecules, whereas glycine conjugated molecules were more abundant in urine from mice fed the intact casein diets. Despite the differences in the urinary metabolome, we observed no differences in hepatic expression of genes involved in Phase II metabolism, but it was observed that expression of Abcc3 encoding ATP binding cassette c3 (transporter of glucuronic acid conjugates) was increased in livers of mice fed hydrolyzed casein. As glucuronic acid is derived from glucose and sulphate is derived from cysteine, our metabolomic data provided evidence for changes in carbohydrate and amino acid metabolism and we propose that this modulation of metabolism was associated with the reduced glucose and lipid levels observed in mice fed the extensively hydrolyzed casein diets. PMID- 25738502 TI - Decreased prefrontal lobe interhemispheric functional connectivity in adolescents with internet gaming disorder: a primary study using resting-state FMRI. AB - PURPOSES: Recent neuroimaging studies have shown that people with Internet gaming disorder (IGD) have structural and functional abnormalities in specific brain areas and connections. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (rsFC) in participants with IGD. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric rsFC of the whole brain in participants with IGD. METHODS: We compared interhemispheric rsFC between 17 participants with IGD and 24 healthy controls, group-matched on age, gender, and education status. All participants were provided written informed consent. Resting-state functional and structural magnetic resonance images were acquired for all participants. The rsFC between bilateral homotopic voxels was calculated. Regions showing abnormal VMHC in IGD participants were adopted as regions of interest for correlation analyses. RESULTS: Compared to healthy controls, IGD participants showed decreased VMHC between the left and right superior frontal gyrus (orbital part), inferior frontal gyrus (orbital part), middle frontal gyrus and superior frontal gyrus. Further analyses showed Chen Internet Addiction Scale (CIAS)-related VMHC in superior frontal gyrus (orbital part) and CIAS (r = -0.55, p = 0.02, uncorrected). CONCLUSIONS: Our findings implicate the important role of altered interhemispheric rsFC in the bilateral prefrontal lobe in the neuropathological mechanism of IGD, and provide further supportive evidence for the reclassification of IGD as a behavioral addiction. PMID- 25738503 TI - National trends in the ambulatory treatment of hypertension in the United States, 1997-2012. AB - IMPORTANCE: Hypertension is common and costly. Over the past decade, new antihypertensive therapies have been developed, several have lost patent protection and additional evidence regarding the safety and effectiveness of these agents has accrued. OBJECTIVE: To examine trends in the use of antihypertensive therapies in the United States between 1997 and 2012. DESIGN, SETTING AND PARTICIPANTS: We used nationally representative audit data from the IMS Health National Disease and Therapeutic Index to examine the ambulatory pharmacologic treatment of hypertension. OUTCOME MEASURES: Our primary unit of analysis was a visit where hypertension was a reported diagnosis and treated with a pharmacotherapy (treatment visit). We restricted analyses to the use of six therapeutic classes of antihypertensive medications among individuals 18 years or older. RESULTS: Annual hypertension treatment visits increased from 56.9 million treatment visits (95% confidence intervals [CI], 53.9-59.8) in 1997 to 83.3 million visits (CI 79.2-87.3) in 2008, then declined steadily to 70.9 million visits (CI 66.7-75.0) by 2012. Angiotensin receptor blocker utilization increased substantially from 3% of treatment visits in 1997 to 18% by 2012, whereas calcium channel blocker use decreased from 27% to 18% of visits. Rates of diuretic and beta-blocker use remained stable and represented 24%-30% and 14-16% of visits, respectively. Use of direct renin inhibitor accounted for fewer than 2% of annual visits. The proportion of visits treated using fixed-dose combination therapies increased from 28% to 37% of visits. CONCLUSIONS: Several important changes have occurred in the landscape of antihypertensive treatment in the United States during the past decade. Despite their novel mechanism of action, the adoption rate of direct renin inhibitors remains low. PMID- 25738504 TI - Circulating microRNA-196a as a candidate diagnostic biomarker for chronic hepatitis C. AB - Previous studies have demonstrated the inhibitory effect of microRNA (miR)-196a on hepatitis C virus (HCV) expression in human hepatocytes. However, the clinical implications of aberrant miR-196a expression and the application of circulating miR-196a in the diagnosis and management of chronic hepatitis C (CHC) require further investigation. The present study aimed to examine the possibility of using serum miR-196a as a biomarker for CHC. The Affymetrix miRNA array platform was used for miRNA expression profiling in adenovirus (Ad)-HCV core-infected (HepG2-HCV) and Ad-enhanced green fluorescence protein (EGFP)-infected HepG2 cells (HepG2-control). miR-196a downregulation and levels were analyzed using stem-loop reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis of the sera of 43 patients with CHC and 22 healthy controls. A total of six miRNAs were identified as significantly different (>= 1.5 fold; P <= 0.05) between the two groups. Of note, significant miR-196a downregulation was observed in HepG2-HCV as compared with HepG2-EGFP. Furthermore, as compared with that of the healthy control group, serum miR-196a was demonstrated to be significantly lower in patients with CHC. In addition, analysis of the receiver operating characteristic (ROC) curve for serum miR-196a revealed an area under the ROC curve of 0.849 (95% confidence interval, 0.756-0.941; P<0.001) with 81.8% sensitivity and 76.7% specificity in discriminating chronic HCV infection from healthy controls at a cut-off value of 6.115 x 10(-5), demonstrating significant diagnostic value for CHC. However, no correlation was identified between serum miR-196a and alanine aminotransferase, aspartate aminotransferase or HCV-RNA. In conclusion, the present study identified circulating miR-196a as a specific and noninvasive candidate biomarker for the diagnosis of CHC. PMID- 25738505 TI - Variation in the frequency and extent of hybridization between Leucosceptrum japonicum and L. stellipilum (Lamiaceae) in the Central Japanese Mainland. AB - Variations in the frequency and extent of hybridization among mixed populations located in the same contact zone provide natural laboratories for the study of extrinsic reproductive isolation maintaining species integrity. In this study, we examined the pattern of hybridization between L. japonicum and L. stellipilum among mixed populations in different localities of a contact zone. The genetic structures from three sympatric populations and six mixed populations in the hybrid zone, and five reference populations far from the contact zone, were characterized using 10 neutral nuclear microsatellite markers. Evidence from genetic distance-based clustering analysis, the frequency distribution of admixture proportion values, and the hybrid category assignment approaches indicated that the frequency and extent of hybridization varied considerably among populations in the contact zone between L. japonicum and L. stellipilum. One likely explanation is that variation in exogenous (ecological) selection among populations might contribute to differences in frequency and extent of hybridization. The present study will facilitate future research exploring the evolution of reproductive isolation between L. japonicum and L. stellipilum. PMID- 25738506 TI - A specific nuclear DNA background is required for high frequency lymphoma development in transmitochondrial mice with G13997A mtDNA. AB - We previously found that mouse mitochondrial DNA (mtDNA) with a G13997A mutation (G13997A mtDNA) controls not only the transformation of cultured lung carcinoma cells from poorly metastatic into highly metastatic cells, but also the transformation of lymphocytes into lymphomas in living C57BL/6 (B6) mice. Because the nuclear genetic background of the B6 strain makes the strain prone to develop lymphomas, here we examined whether G13997A mtDNA independently induces lymphoma development even in mice with the nuclear genetic background of the A/J strain, which is not prone to develop lymphomas. Our results showed that the B6 nuclear genetic background is required for frequent lymphoma development in mice with G13997A mtDNA. Moreover, G13997A mtDNA in mice did not enhance the malignant transformation of lung adenomas into adenocarcinomas or that of hepatocellular carcinomas from poorly metastatic into highly metastatic carcinomas. Therefore, G13997A mtDNA enhances the frequency of lymphoma development under the abnormalities in the B6 nuclear genome, and does not independently control tumor development and tumor progression. PMID- 25738507 TI - Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity. AB - BACKGROUND: Neurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment. OBJECTIVE: The objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH. METHODS: CSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses. RESULTS: CSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95). CONCLUSIONS: Herein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant. PMID- 25738508 TI - Risky sexual behaviors among female youth in Tiss Abay, a semi-urban area of the Amhara Region, Ethiopia. AB - BACKGROUND: Little is known about sexual risks and associated factors about female youths in semi-urban areas of Ethiopia. This study aimed to describe the nature and magnitude of risky sexual behaviors, and the socio-demographic and behavioral determinants among female youths in Tiss Abay, a semi-urban area on the outskirts of Bahir Dar City of the Amhara Region in northern Ethiopia. METHODS: A cross-sectional census type study was conducted among female youths who were unmarried and aged 15-29 years in September 2011. RESULTS: 711 female youths participated in the study, with the mean age of initiation of sex of 78.6% being16.73+/-2.53 years. Only 52(9.3%) used condom during the first sex. Within the last 12 months, 509(71.6%) had sexual intercourse and 278(54.6%) had two or more sex partners, and 316(62.1%) did not use condom during their last sex. Sex under the influence of substances was reported by 350(68.8%), and a third of the recent sexes were against the will of participants. One or more risky sexual practices were reported by 503(70.3%) participants, including: multiple sexual partnerships, inconsistently using or not using condoms, sex under the influence of alcohol and/or sex immediately after watching pornography. Age group, current marital status, drinking homemade alcohol, chewing 'khat', watching pornography and using any form of stimulant substances were the predictors of risky sexual behavior. Watching pornography before sex and sex for transaction were the predicators of not using condom during most recent sex. CONCLUSIONS: Risky sexual behaviors were very common among the female youths in Tiss Abay. Initiation of context-based interventions, such as raising awareness about the risks, safer sex practices, condom promotion and integration of gender issues in the programs are recommended. PMID- 25738509 TI - Combining PM2.5 Component Data from Multiple Sources: Data Consistency and Characteristics Relevant to Epidemiological Analyses of Predicted Long-Term Exposures. AB - BACKGROUND: Regulatory monitoring data have been the exposure data resource most commonly applied to studies of the association between long-term PM2.5 components and health. However, data collected for regulatory purposes may not be compatible with epidemiological studies. OBJECTIVES: We studied three important features of the PM2.5 component monitoring data to determine whether it would be appropriate to combine all available data from multiple sources for developing spatiotemporal prediction models in the National Particle Component and Toxicity (NPACT) study. METHODS: The NPACT monitoring data were collected in an extensive monitoring campaign targeting cohort participant residences. The regulatory monitoring data were obtained from the Chemical Speciation Network (CSN) and the Interagency Monitoring of Protected Visual Environments (IMPROVE). We performed exploratory analyses to examine features that could affect our approach to combining data: comprehensiveness of spatial coverage, comparability of analysis methods, and consistency in sampling protocols. In addition, we considered the viability of developing spatiotemporal prediction models given a) all available data, b) NPACT data only, and c) NPACT data with temporal trends estimated from other pollutants. RESULTS: The number of CSN/IMPROVE monitors was limited in all study areas. The different laboratory analysis methods and sampling protocols resulted in incompatible measurements between networks. Given these features we determined that it was preferable to develop our spatiotemporal models using only the NPACT data and under simplifying assumptions. CONCLUSIONS: Investigators conducting epidemiological studies of long-term PM2.5 components need to be mindful of the features of the monitoring data and incorporate this understanding into the design of their monitoring campaigns and the development of their exposure prediction models. PMID- 25738512 TI - Site-specific chemical modification of peptide and protein by thiazolidinediones. AB - A direct aldol reaction employing 2,4-thiazolidinediones as nucleophilic donors was performed to modify peptides and protein under mild conditions. Various functional groups could be readily introduced into protein without conformation change. PMID- 25738513 TI - A rapid expansion of HIV-1 CRF63_02A1 among newly diagnosed HIV-infected individuals in the Tomsk Region, Russia. AB - The prevalence of HIV infection in different Russian regions is nonuniform. In the Tomsk region (TR), 2020 HIV new infection cases were recorded in 2013, the morbidity having increased 5.9-fold as compared to 2012. In total, 64 blood plasma samples from primary HIV cases have been examined. HIV-specific fragments of the pol gene have been obtained for 61 samples (of protease for 58 and of integrase for 23) and of the env gene V3 region for 40 samples. Phylogenetic analysis of the determined HIV-1 sequences has detected CRF63_02A1 in 55 (90.2%) cases, whereas HIV subtype A1, characteristic of Russia, has been observed in only three (4.9%) patients. Three (4.9%) cases contain CRF63_02A1/A recombinant variants. This article demonstrates that a drastic activation of the epidemic in the Tomsk region is accompanied by a rapid spreading of the recently described HIV-1 CRF63_02A1, which we detected in the Novosibirsk region outbreak of 2008. PMID- 25738514 TI - Incorporating Bacteria as a Living Component in Supramolecular Self-Assembled Monolayers through Dynamic Nanoscale Interactions. AB - Supramolecular assemblies, formed through noncovalent interactions, has become particularly attractive to develop dynamic and responsive architectures to address living systems at the nanoscale. Cucurbit[8]uril (CB[8]), a pumpkin shaped macrocylic host molecule, has been successfully used to construct various self-assembled architectures for biomedical applications since it can simultaneously bind two aromatic guest molecules within its cavity. Such architectures can also be designed to respond to external stimuli. Integrating living organisms as an active component into such supramolecular architectures would add a new dimension to the capabilities of such systems. To achieve this, we have incorporated supramolecular functionality at the bacterial surface by genetically modifying a transmembrane protein to display a CB[8]-binding motif as part of a cystine-stabilized miniprotein. We were able to confirm that this supramolecular motif on the bacterial surface specifically binds CB[8] and forms multiple intercellular ternary complexes leading to aggregation of the bacterial solution. We performed various aggregation experiments to understand how CB[8] interacts with this bacterial strain and also demonstrate that it can be chemically reversed using a competitor. To confirm that this strain can be incorporated with a CB[8] based architecture, we show that the bacterial cells were able to adhere to CB[8] self-assembled monolayers (SAMs) on gold and still retain considerable motility for several hours, indicating that the system can potentially be used to develop supramolecular bacterial biomotors. The bacterial strain also has the potential to be combined with other CB[8] based architectures like nanoparticles, vesicles and hydrogels. PMID- 25738515 TI - A subset of circulating microRNAs is expressed differently in patients with myocardial infarction. AB - The objective of the present study was to analyze the differences in the plasma microRNA (miRNA) expression profiles between patients with myocardial infarction (MI) (with or without heart failure) and individuals in a normal control group using an miRNA array. Specific miRNAs were selected to explore novel circulating markers for MI and heart failure. A total of 15 patients with heart failure and 10 patients without heart failure following acute MI (AMI) were recruited as the AMI with heart failure (AMHF) and with no heart failure (AMNHF) groups, respectively. In addition, 10 patients with an older (>= 1 year) MI with heart failure were selected as the old MI and heart failure (OMHF) group. Finally, 10 patients with normal coronary angiograms were recruited as the control (N) group. The plasma of peripheral venous blood was collected for miRNA array detection. In the AMHF group, the expression of 17 miRNAs was upregulated and the expression of 21 miRNAs was downregulated by >1.5-fold compared with that in the AMNHF group. Compared with the N group, the expression of miRNAs in the AMNHF group was upregulated in 38 and downregulated in 48 cases by >1.5-fold. Compared with the OMHF group, 13 miRNAs were upregulated and 43 were downregulated by >1.5-fold in the AMHF group. Significant differences in the miRNA expression profiles were observed between patients with different stages of heart failure following MI and individuals in the normal control group. These differences were determined using miRNA array analysis methods based on the peripheral blood plasma. Thus, the specific miRNAs identified in this study may be novel circulating markers for MI and heart failure. PMID- 25738516 TI - Respiratory protection for firefighters--evaluation of CBRN canisters for use during overhaul. AB - In the United States, there are approximately 366,600 structural fires each year. After visible flames are extinguished, firefighters begin the overhaul stage of firefighting to smother remaining hot spots and initiate investigations. Typically during overhaul significant ambient concentrations of chemical contaminants remain. However, previous research suggests that the use of air purifying respirators (APR) fitted with chemical, biological, radiological, and nuclear (CBRN) canisters may reduce occupational respiratory exposures. This pilot study used large-scale prescribed burns of representative structural materials to perform simultaneous, side-by-side, filtering and service-life evaluations of commercially available CBRN filters. Three types of CBRN canisters and one cartridge were challenged in repetitive post live-fire overhaul exposure tests using a sampling manifold apparatus. At a flow rate of 80 L/min, nine tests were conducted in the breathing zone for three different exposure durations (0-15 min, 0-30 min, and 0-60 min). Fifty different chemicals were identified for evaluation and results indicate that 21 of the 50 chemicals tested were in the air of the overhaul environment. Respirable particles and formaldehyde were consistently present above the American Conference of Governmental Industrial Hygienists (ACGIH(r)) recommended exposure level (REL) and threshold limit ceiling value (TLVc), respectively. Each filter effectively reduced concentrations for respirable particulates below the maximum recommended level. Formaldehyde was reduced, but not consistently filtered below the TLVc. These results were consistent across all exposure durations. This study indicates that, regardless of brand, CBRN filters provide protection from the vast majority of particle and gas-phase contaminants. However, due to formaldehyde breakthrough, CBRN filters do not provide complete protection during firefighter overhaul. PMID- 25738517 TI - Coupled oscillators for tuning fluorescence properties of squaraine dyes. AB - Combining a squaraine (S) and a BODIPY (B) chromophore in a heterodimer (SB) and two heterotrimers (BSB and SBS) by alkyne bridges leads to the formation of coupled oscillators whose fluorescence properties are superior compared to the parent squaraine chromophore. The lowest energy absorption and emission properties of these superchromophores are mainly governed by the squaraine part and are shifted by more than 1000 cm(-1) to the red by excitonic interaction between the squaraine and the BODIPY dye. Employing polarization-dependent transient absorption and fluorescence upconversion measurements, we could prove that the lowest energy absorption in SB and BSB is caused by a single excitonic state but by two for SBS. Despite the spectral red-shift of their lowest absorption band, the fluorescence quantum yields increase for SB and BSB compared to the parent squaraine chromophore SQA. This is caused by intensity borrowing from the BODIPY states, which increases the squared transition moments of the lowest energy band dramatically by 29% for SB and 63% for BSB compared to SQA. Thereby, exciton coupling leads to a substantial enhancement of fluorescence quantum yield by 26% for SB and by 46% for BSB and shifts the emission from the red into the near-infrared. In this way, the BODIPY-squaraine conjugates combine the best properties of each class of dye. Thus, exciton coupling in heterodimers and -trimers is a valuable alternative to tuning fluorescence properties by, e.g., attaching substituents to chromophores. PMID- 25738519 TI - Two new compounds from cultures of the basidiomycete Antrodiella albocinnamomea. AB - A new linear triterpene (1), and a new sesquiterpene (2), together with a known compound methyl indole-3-carboxylate (3) were isolated from the crude extract of Antrodiella albocinnamomea. The structures of the new compounds 1-2 were determined by comprehensive spectroscopic analysis. Compound 1 exhibited significant inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 value of 1.0 MUg/mL. PMID- 25738520 TI - miR-182 promotes cell growth and invasion by targeting forkhead box F2 transcription factor in colorectal cancer. AB - Forkhead box F2 transcription factor (FoxF2) has been described to promote organ development, extracellular matrix (ECM) synthesis and epithelial-mesenchymal interaction. Although recent studies reported decreased FoxF2 expression in several types of cancers, indicating its potential role in carcinogenesis, the mechanistic role of FoxF2 is yet to be explored. MicroRNAs (miRNAs) are strongly implicated in carcinogenesis. The oncogenetic properties of miR-182 have been described in multiple cancers. In the present study, we aimed to investigate the role of miR-182 in colorectal cancer (CRC) and identify the regulation of FoxF2 by miR-182. Bioinformatic analyses on gene expression profiling datasets showed decreased FoxF2 expression in colorectal adenomas, primary tumors compared to normal colon epithelial and a negative association between FoxF2 and beta-catenin expression. Restoration of FoxF2 in CRC cells suppressed beta-catenin expression and simultaneously inhibited cell growth and invasion. Furthermore, we observed that miR-182 was aberrantly upregulated in CRC. Knockdown of miR-182 in CRC cells impeded cell growth and invasion. The direct binding of miR-182 to the 3' untranslated region (3'UTR) of FoxF2 mRNA was confirmed using a luciferase reporter gene assay. Importantly, elevated FoxF2 expression was observed in miR 182-knockdown cells with a simultaneous reduction in beta-catenin. In conclusion, the present study describes a potential mechanism underlying an miR-182/FoxF2 link contributing to CRC development. miR-182-induced downregulation of FoxF2 partly accounts for increased activity of beta-catenin signaling. Inhibition of miR-182 represents a potential strategy against CRC. PMID- 25738521 TI - Pilot study for detection of early changes in tissue associated with heterotopic ossification: moving toward clinical use of Raman spectroscopy. AB - Over 60% of combat-wounded patients develop heterotopic ossification (HO). Nearly 33% of them require surgical excision for symptomatic lesions, a procedure that is both fraught with complications and can delay or regress functional rehabilitation. Relative medical contraindications limit widespread use of conventional means of primary prophylaxis, such as nonspecific nonsteroidal anti inflammatory medications and radiotherapy. Better methods for risk stratification are needed to both mitigate the risk of current means of primary prophylaxis as well as to evaluate novel preventive strategies currently in development. We asked whether Raman spectral changes, measured ex vivo, could be associated with histologic evidence of the earliest signs of HO formation and substance P (SP) expression in tissue biopsies from the wounds of combat casualties. In this pilot study, we compared normal muscle tissue, injured muscle tissue, very early HO lesions (< 16 d post-injury), early HO lesions (> 16 d post-injury) and mature HO lesions. The Raman spectra of these tissues demonstrate clear differences in the Amide I and III spectral regions of HO lesions compared to normal tissue, denoted by changes in the Amide I band center (p < 0.01) and the 1340/1270 cm(-1) (p < 0.05) band area and band height ratios. SP expression in the HO lesions appears to peak between 16 and 30 d post-injury, as determined by SP immunohistochemistry of corresponding tissue sections, potentially indicating optimal timing for administration of therapeutics. Raman spectroscopy may therefore prove a useful, non-invasive and early diagnostic modality to detect HO formation before it becomes evident either clinically or radiographically. PMID- 25738522 TI - Distribution of mesoscale elastic properties and mass density in the human femoral shaft. AB - Cortical bone properties are determined by tissue composition and structure at several hierarchical length scales. In this study, the spatial distribution of micro- and mesoscale elastic properties within a human femoral shaft has been investigated. Microscale tissue degree of mineralization (DMB), cortical vascular porosity Ct.Po and the average transverse isotropic stiffness tensor C(Micro) of cylindrical-shaped samples (diameter: 4.4 mm, N = 56) were obtained from cortical regions between 20 and 85% of the total femur length and around the periphery (anterior, medial, posterior and lateral quadrants) by means of synchrotron radiation uCT (SRuCT) and 50-MHz scanning acoustic microscopy (SAM). Within each cylinder, the volumetric bone mineral density (vBMD) and the mesoscale stiffness tensor C(Meso) were derived using a numerical homogenization approach. Moreover, microelastic maps of the axial elastic coefficient c33 measured by SAM at distinct cross-sectional locations along the femur were used to construct a 3-D multiscale elastic model of the femoral shaft. Variations of vBMD (6.1%) were much lower than the variations of mesoscale elastic coefficients (11.1-21.3%). The variation of DMB was only a minor predictor for variations of the mesoscale elastic properties (0.05 <= R(2) <= 0.34). Instead, variations of the mesoscale elastic properties could be explained by variations of cortical porosity and microscale elastic properties. These data were suitable inputs for numerical evaluations and may help to unravel the relations between structure and composition on the elastic function in cortical bone. PMID- 25738524 TI - The International Nucleome Consortium. AB - The eukaryotic genome adopts in the cell nucleus a 3-dimensional configuration that varies with cell types, developmental stages and environmental condition as well as between normal and pathological states. Understanding genome function will therefore require the elucidation of the structure-function relationship of the cell nucleus as a complex, dynamic biological system, referred to as the nucleome. This exciting and timely task calls for a multi-faceted, interdisciplinary and multi-national effort. We propose the establishment of an International Nucleome Consortium to coordinate this effort worldwide. PMID- 25738523 TI - Articular cartilage zonal differentiation via 3D Second-Harmonic Generation imaging microscopy. AB - PURPOSE: The collagen structure throughout the patella has not been thoroughly investigated by 3D imaging, where the majority of the existing data come from histological cross sections. It is important to have a better understanding of the architecture in normal tissues, where this could then be applied to imaging of diseased states. METHODS: To address this shortcoming, we investigated the combined use of collagen-specific Second-Harmonic Generation (SHG) imaging and measurement of bulk optical properties to characterize collagen fiber orientations of the histologically defined zones of bovine articular cartilage. Forward and backward SHG intensities of sections from superficial, middle and deep zones were collected as a function of depth and analyzed by Monte Carlo simulations to extract the SHG creation direction, which is related to the fibrillar assembly. RESULTS: Our results revealed differences in SHG forward backward response between the three zones, where these are consistent with a previously developed model of SHG emission. Some of the findings are consistent with that from other modalities; however, SHG analysis showed the middle zone had the most organized fibril assembly. While not distinct, we also report bulk optical property values for these different zones within the patella. CONCLUSIONS: Collectively, these results provide quantitative measurements of structural changes at both the fiber and fibril assembly of the different cartilage zones and reveals structural information not possible by other microscope modalities. This can provide quantitative insight to the collagen fiber network in normal cartilage, which may ultimately be developed as a biomarker for osteoarthritis. PMID- 25738525 TI - Acacia ferruginea inhibits inflammation by regulating inflammatory iNOS and COX 2. AB - Inflammation is a local defensive reaction of a host to cellular injury or infection. Prolonged inflammation can contribute to pathogenesis of many disorders. Identification of naturally occurring phytoconstituents that can suppress inflammatory mediators can lead to the discovery of anti-inflammatory therapeutics. Acacia ferruginea is used traditionally to treat numerous ailments including hemorrhage, irritable bowel syndrome and leprosy. The present study evaluated the anti-inflammatory activity of A. ferruginea extract against acute (carrageenan) and chronic (formaldehyde) inflammation in Balb/c mice. Pre treatment with A. ferruginea extract (10 mg/kg BW) for 5 consecutive days via intraperitonial (IP) administration significantly inhibited subsequent induction of paw edema in both models; the effects were comparable to that of the standard drug indomethacin. The results also showed the A. ferruginea extract significantly inhibited nitric oxide (NO) synthesis and iNOS expression (as measured in serum), diminished inflammation in - and neutrophil infiltration to - the paw tissues and led to a reduction in the number of COX-2(+) immunoreative cells (as evidenced by histologic and immunohistochemical analyses) in the paws relative to those in paws of mice that received the irritants only. Further, in vitro studies showed the extract could significantly scavenge free radicals generated as in DPPH and NO radical generating assays. Taken together, the results showed that A. ferruginea extract imparted potent anti-oxidant and inflammatory effects, in part by maintaining oxidative homeostasis, inhibiting NO synthesis and suppressing iNOS and COX-2 expression and so could potentially be exploited as a potential plant-based medication against inflammatory disorders. PMID- 25738526 TI - Reductions in indoor black carbon concentrations from improved biomass stoves in rural India. AB - Deployment of improved biomass burning cookstoves is recognized as a black carbon (BC) mitigation measure that has the potential to achieve health benefits and climate cobenefits. Yet, few field based studies document BC concentration reductions (and resulting human exposure) resulting from improved stove usage. In this paper, data are presented from 277 real-world cooking sessions collected during two field studies to document the impacts on indoor BC concentrations inside village kitchens as a result of switching from traditional stoves to improved forced draft (FD) stoves. Data collection utilized new low-cost cellphone methods to monitor BC, cooking duration, and fuel consumption. A cross sectional study recorded a reduction of 36% in BC during cooking sessions. An independent paired sample study demonstrated a statistically significant reduction of 40% in 24 h BC concentrations when traditional stoves were replaced with FD stoves. Reductions observed in these field studies differ from emission factor reductions (up to 99%) observed under controlled conditions in laboratory studies. Other nonstove sources (e.g., kerosene lamps, ambient concentrations) likely offset the reductions. Health exposure studies should utilize reductions determined by field measurements inside village kitchens, in conjunction with laboratory data, to assess the health impacts of new cooking technologies. PMID- 25738527 TI - Evaluation of the benefits of sequential addition of leflunomide in patients with polyarticular course juvenile idiopathic arthritis failing standard dose methotrexate. AB - OBJECTIVES: To evaluate the benefits of the addition of leflunomide (LEF) in children with polyarticular course juvenile idiopathic arthritis (JIA), non responsive to standard dose parenteral methotrexate (MTX). METHODS: In an observational study, 32 children with polyarticular course JIA failing standard dose MTX (up to 15 mg/m2/week sc for at least 3 and up to 6 months) received additional LEF. Permitted concomitant drugs included pulse steroids for flares and/or low bridging dose of prednisolone, intra-articular steroids and non steroidal anti-inflammatory drugs. No other DMARDs had been used before enrolment. Patients underwent 8-12 weekly assessment. At each visit, core set of outcome variables and laboratory parameters, viz. haemogram and liver enzymes were recorded. The primary efficacy outcome was the ACR Pedi 30 criteria. At the last follow up, Wallace's criteria were used to determine children achieving remission. RESULTS: 25 of 32 children who followed up for at least 3 months were analysed. Mean follow up duration following addition of LEF was 1.61 years (range: 0.29 to 3.0 years). At 3 months, 68% of the patients met the ACR Pedi 30 response. 17 of the 20 children (85%) showed an ACR Pedi 30 response at 6 months and 16 out of 18 (88.8%) at 1 year. Of the 18 children followed up till the end of the study, 12 (66.6%) met the ACR Pedi 30 criteria and 9 (50%) were in clinical remission on medications (off steroids). Adverse effects were observed in 2 children (gastritis in one and elevated liver enzymes in the other). CONCLUSIONS: Our findings support further study of the role of this combination in the management of polyarticular course JIA refractory to standard dose MTX, especially in resource challenged settings where biologicals are unaffordable. The open observational nature of the study is its limitation. PMID- 25738528 TI - Is any job better than no job? Labor market experiences and depressive symptoms in people living with HIV. AB - The purpose of this study is to determine the relationship between the psychosocial work environment and labor market experiences (including unemployment) on mental health among adults living with HIV. We used data provided by 538 participants at clinical and community sites across Ontario, Canada. Generalized estimating equation models showed that employment was associated with lower depressive symptoms. For employed participants, adverse psychosocial work conditions, specifically job insecurity, psychological demands, and decision authority were associated with depressive symptoms. For the entire sample, the number of adverse psychosocial work conditions was associated with higher depressive symptoms while participants working in poor quality jobs reported similar levels of depressive symptoms than those who were unemployed or not in the labor force. This study showed that poor quality employment (as assessed by having a high number of adverse psychosocial work exposures) was associated with a similar level of depressive symptoms as unemployment, suggesting that "bad jobs" may not offer the same mental health benefits as "good jobs." Policies to improve employment outcomes should take the quality of employment into account to maximize mental health benefits as better employment may lead to better mental health. PMID- 25738529 TI - Depression and suicide among physician trainees: recommendations for a national response. PMID- 25738530 TI - Genome-wide analysis of histone modifications by ChIP-chip to identify silenced genes in gastric cancer. AB - The present study aimed to identify novel histone modification markers in gastric cancer (GC) by chromatin immunoprecipitation microarray (ChIP-chip) analysis and to determine whether these markers were able to discriminate between normal and GC cells. We also tested for correlations with DNA methylation. We probed a human CpG island microarray with DNA from a GC cell line (MKN45) by chromatin immunoprecipitation (ChIP). ChIP-reverse-transcriptase quantitative polymerase chain reaction PCR (RT-qPCR) was used to validate the microarray results. Additionally, mRNA expression levels and the DNA methylation of potential target genes were evaluated by RT-qPCR and methylation-specific PCR (MSP). The moults showed that 134 genes exhibited the highest signal-to-noise ratio of H3-K9 trimethylation over acetylation and 46 genes exhibited the highest signal-to noise ratio of H3-K9 trimethylation over H3-K4 trimethylation in MKN45 cells. The ChIP-qPCR results agreed with those obtained from the ChIP-chip analysis. Aberrant DNA methylation status and mRNA expression levels were also identified for selected genes (PSD, SMARCC1 and Vps37A) in the GC cell lines. The results suggest that CpG island microarray coupled with ChIP (ChIP-chip) can identify novel targets of gene silencing in GC. Additionally, ChIP-chip is the best approach for assessing the genome-wide status of epigenetic regulation, which may allow for a broader genomic understanding compared to the knowledge that has been accumulated from single-gene studies. PMID- 25738531 TI - Specific binding at the cellulose binding module-cellulose interface observed by force spectroscopy. AB - The need for effective enzymatic depolymerization of cellulose has stimulated an interest in interactions between protein and cellulose. Techniques utilized for quantitative measurements of protein-cellulose noncovalent association include microgravimetry, calorimetry, and atomic force microscopy (AFM), none of which differentiate between specific protein-cellulose binding and nonspecific adhesion. Here, we describe an AFM approach that differentiates nonspecific from specific interactions between cellulose-binding modules (CBMs) and cellulose. We demonstrate that the "mismatched" interaction between murine galectin-3, a lectin with no known affinity for cellulose, and cellulose shows molecular recognition force microscopy profiles similar to those observed during the interaction of a "matched" clostridial CBM3a with the same substrate. We also examine differences in binding probabilities and rupture profiles during CBM-cellulose binding experiments in the presence and absence of a blocking agent-a substrate specific for CBM that presumably blocks binding sites. By comparison of the behavior of the two proteins, we separate specific (i.e., blockable) and nonspecific adhesion events and show that both classes of interaction exhibit nearly identical rupture forces (45 pN at ~0.4 nN/s). Our work provides an important caveat for the interpretation of protein-carbohydrate binding by force spectroscopy; delineation of the importance of such interactions to other classes of binding warrants further study. PMID- 25738532 TI - Nanoscopic dynamics of phospholipid in unilamellar vesicles: effect of gel to fluid phase transition. AB - The dynamics of phospholipids in unilamellar vesicles (ULVs) is of interest in biology, medical, and food sciences, since these molecules are widely used as biocompatible agents and a mimic of cell membrane systems. We have investigated the nanoscopic dynamics of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) phospholipid in ULVs as a function of temperature using elastic and quasielastic neutron scattering (QENS). The dependence of the signal on the scattering momentum transfer, which is a critical advantage of neutron scattering techniques, allows the detailed analysis of the lipid motions that cannot be carried out by other means. In agreement with a differential scanning calorimetry measurement, a sharp rise in the elastic scattering intensity below ca. 296 K indicates a phase transition from the high-temperature fluid phase to the low temperature solid gel phase. The microscopic lipid dynamics exhibits qualitative differences between the solid gel phase (in a measurement at 280 K) and the fluid phase (in a measurement at a physiological temperature of 310 K). The analysis of the data demonstrates the presence of two types of distinct motions: the entire lipid molecule motion within a monolayer, also known as lateral diffusion, and the relatively faster internal motion of the DMPC molecule. The lateral diffusion of the entire lipid molecule is Fickian in character, whereas the internal lipid motions are of localized character, which is consistent with the structure of the vesicles. The lateral motion slows down by an order of magnitude in the solid gel phase, whereas for the internal motion not only the time scale but also the character of the motion changes upon the phase transition. In the solid gel phase, the lipids are more ordered and undergo uniaxial rotational motion. However, in the fluid phase, the hydrogen atoms of the lipid tails undergo confined translation diffusion rather than uniaxial rotational diffusion. The translational, but spatially localized, diffusion of the hydrogen atoms of the lipid tails is a manifestation of the flexibility of the chains acquired in the fluid phase. Because of this flexibility, both the local diffusivity and the confinement volume for the hydrogen atoms increase in the linear fashion from near the lipid's polar headgroup to the end of its hydrophobic tail. Our results present a quantitative and detailed picture of the effect of the gel-fluid phase transition on the nanoscopic lipid dynamics in ULVs. The data analysis approach developed here has a potential for probing the dynamic response of lipids to the presence of additional cell membrane components. PMID- 25738533 TI - Buprenorphine-Naloxone Treatment in Physicians and Nurses With Opioid Dependence. PMID- 25738534 TI - Synthesis, larvicidal activities and antifungal activities of novel chlorantraniliprole derivatives and their target in the ryanodine receptor. AB - In order to identify novel chlorantraniliprole derivatives as potential insecticides or fungicides, 25 analogues of chlorantraniliprole were synthesized. The insecticidal activities against oriental armyworm and the antifungal activities against five typical fungi of these derivatives were tested. Compounds 2u, 2x and 2y exhibited good activities against oriental armyworm, especially compounds 2u and 2x which showed higher larvicidal activities than indoxacarb. Moreover, all of the tested compounds exhibited activities against five typical fungi. The Ki values of all synthesized compounds were calculated using AutoDock4. The relationship between the Ki values and the results of insecticidal activities against oriental armyworm further indicated that the membrane-spanning domain protein of the ryanodine receptor might contain chlorantraniliprole binding sites. PMID- 25738535 TI - Rational drug design and synthesis of molecules targeting the angiotensin II type 1 and type 2 receptors. AB - The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Alphang II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases. PMID- 25738537 TI - Exploring the effects of pulsed electric field processing parameters on polyacetylene extraction from carrot slices. AB - The effects of various pulsed electric field (PEF) parameters on the extraction of polyacetylenes from carrot slices were investigated. Optimised conditions with regard to electric field strength (1-4 kV/cm), number of pulses (100-1500), pulse frequency (10-200 Hz) and pulse width (10-30 MUs) were identified using response surface methodology (RSM) to maximise the extraction of falcarinol (FaOH), falcarindiol (FaDOH) and falcarindiol-3-acetate (FaDOAc) from carrot slices. Data obtained from RSM and experiments fitted significantly (p < 0.0001) the proposed second-order response functions with high regression coefficients (R2) ranging from 0.82 to 0.75. Maximal FaOH (188%), FaDOH (164.9%) and FaDOAc (166.8%) levels relative to untreated samples were obtained from carrot slices after applying PEF treatments at 4 kV/cm with 100 number of pulses of 10 MUs at 10 Hz. The predicted values from the developed quadratic polynomial equation were in close agreement with the actual experimental values with low average mean deviations (E%) ranging from 0.68% to 3.58%. PMID- 25738538 TI - Metabolites software-assisted flavonoid hunting in plants using ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry. AB - Plant secondary metabolism drives the generation of metabolites used for host plant resistance, as biopesticides and botanicals, even for the discovery of new therapeutics for human diseases. Flavonoids are one of the largest and most studied classes of specialized plant metabolites. To quickly identify the potential bioactive flavonoids in herbs, a metabolites software-assisted flavonoid hunting approach was developed, which mainly included three steps: firstly, utilizing commercial metabolite software, a flavonoids database was established based on the biosynthetic pathways; secondly, mass spectral data of components in herbs were acquired by ultra-high performance liquid chromatography quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF-MS); and finally, the acquired LC-MS data were imported into the database and the compounds in the herbs were automatically identified by comparison of their mass spectra with the theoretical values. As a case study, the flavonoids in Smilax glabra were profiled using this approach. As a result, 104 flavonoids including 27 potential new compounds were identified. To our knowledge, this is the first report on profiling the components in the plants utilizing the plant metabolic principles with the assistance of metabolites software. This approach can be extended to the analysis of flavonoids in other plants. PMID- 25738536 TI - Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. AB - Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility. PMID- 25738539 TI - The synthetic antimicrobial peptide pexiganan and its nanoparticles (PNPs) exhibit the anti-helicobacter pylori activity in vitro and in vivo. AB - The aim of this study was to probe the potential anti-H. pylori activity of the synthetic antimicrobial peptide pexiganan, which is an analog of the peptide magainin, and its nanoparticles (PNPs) that were prepared in our laboratory. To compare their antibacterial effects in vitro and in vivo, studies of H. pylori growth inhibition, kinetics and resistance assays were undertaken. The gastric mucoadhesive efficiency and H. pylori clearance efficiency of pexiganan and PNPs were evaluated in rats and mice infected with H. pylori. The eradication of H. pylori was determined using urease tests and a microbial culture method. We observed that PNPs adhered to gastric mucosa more effectively owing to a prolonged stay in the stomach, which resulted in a more effective H. pylori clearance. In addition, PNPs had greater anti-H. pylori effect than pexiganan in infected mice. The amount of pexiganan required to eradicate H. pylori was significantly less using PNPs than the corresponding pexiganan suspension. The results confirmed that PNPs improved peptide stability in the stomach and more effectively eradicated H. pylori from mice stomachs than pexiganan. PMID- 25738540 TI - Volatile compounds and antioxidant capacity of the bio-oil obtained by pyrolysis of Japanese red pine (pinus densiflora siebold and zucc.). AB - In the present study, sawdust bio-oil (SBO) manufactured by fast pyrolysis of Japanese red pine (Pinus densiflora Siebold and Zucc.) sawdust was analyzed for its volatile chemical compound composition and evaluated for its free radical scavenging potential, inhibition of lipid peroxidation and reducing power. Gas chromatography and mass spectroscopy revealed 29 volatile compounds, comprising 97.6% of the total volatile compounds in SBO. The antioxidant potential of SBO in terms of IC50 values was 48.44 ug/mL for hydroxyl radical scavenging, 89.52 ug/mL for 1,1-diphenyl-2-picrylhydraxyl radical scavenging, 94.23 ug/mL for 2,2'-azino bis[3-ethylbenzothiazoline-6-sulphonic acid] radical scavenging, and 136.06 ug/mL for superoxide radical scavenging activity. The total phenol content in SBO was 5.7% gallic acid equivalent. Based on the composition of its volatile compounds, high free radical scavenging potential and antioxidant properties, SBO could be used as a source of antioxidant compounds, flavoring agents and nutraceuticals in the food, pharmaceutical, and cosmetic industries. PMID- 25738541 TI - Urinary retention and episodic paresthesias. PMID- 25738542 TI - Market-based solutions to antitrust threats--the rejection of the Partners settlement. PMID- 25738543 TI - Establishment of Tsc2-deficient rat embryonic stem cells. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by TSC1 or TSC2 mutations. TSC causes the development of tumors in various organs such as the brain, skin, kidney, lung, and heart. The protein complex TSC1/2 has been reported to have an inhibitory function on mammalian target of rapamycin complex 1 (mTORC1). Treatment with mammalian target of rapamycin (mTOR) inhibitors has demonstrated tumor-reducing effects in patients with TSC but is also associated with various adverse effects. In recent years, experiments involving in vivo differentiation of pluripotent stem cells have been reported as useful in elucidating mechanisms of pathogenesis and discovering new therapeutic targets for several diseases. To reveal the molecular basis of the pathogenesis caused by the Tsc2 mutation, we derived embryonic stem cells (ESCs) from Eker rats, which have the Tsc2 mutation and develop brain lesions and renal tumors. Although several studies have reported the necessity of Tsc1 and Tsc2 regulation to maintain ESCs and hematopoietic stem cells, we successfully established not only Tsc2+/+ and Tsc2+/- ESCs but also Tsc2-/- ESCs. We confirmed that these cells express pluripotency markers and retain the ability to differentiate into all three germ layers. Comprehensive gene expression analysis of Tsc2+/+ and Tsc2+/- ESCs revealed similar profiles, whereas the profile of Tsc2-/- ESCs was distinct from these two. In vitro differentiation experiments using these ESCs combined with in vivo experiments may reveal the mechanism of the tissue-specific pathogenesis caused by the Tsc2 mutation and identify specific new therapeutic targets. PMID- 25738544 TI - Electrochemical layer-by-layer approach to fabricate mechanically stable platinum black microelectrodes using a mussel-inspired polydopamine adhesive. AB - OBJECTIVE: Platinum black (PtBK) has long been used for microelectrode fabrication owing to its high recording performance of neural signals. The porous structure of PtBK enlarges the surface area and lowers the impedance, which results in background noise reduction. However, the brittleness of PtBK has been a problem in practice. In this work, we report mechanically stable PtBK microelectrodes using a bioinspired adhesive film, polydopamine (pDA), while maintaining the low impedance of PtBK. APPROACH: The pDA layer was incorporated into the PtBK structure through electrochemical layer-by-layer deposition. Varying the number of layers and the order of materials, multi-layered pDA-PtBK hybrids were fabricated and the electrical properties, both impedance and charge injection limit, were evaluated. MAIN RESULTS: Multilayered pDA-PtBK hybrids had electrical impedances as low as PtBK controls and charge injection limit twice larger than controls. For the 30 min-ultrasonication agitation test, impedance levels rarely changed for some of the pDA-PtBK hybrids indicating that the pDA improved the mechanical property of the PtBK structures. The pDA-PtBK hybrid microelectrodes readily recorded neural signals of cultured hippocampal neurons, where background noise levels and signal-to-noise were 2.43 ~ 3.23 MUVrms and 28.4 ~ 69.1, respectively. SIGNIFICANCE: The developed pDA-PtBK hybrid microelectrodes are expected to be applicable to neural sensors for neural prosthetic studies. PMID- 25738545 TI - Reliability of the sit-up test in individuals with spinal cord injury. AB - OBJECTIVE: To determine the day-to-day reliability of blood pressure responses during a sit-up test in individuals with a traumatic spinal cord injury (SCI). DESIGN: Within-subject, repeated measures design. SETTING: Community outpatient assessments at a research laboratory at the University of British Columbia. PARTICIPANTS: Five men and three women with traumatic SCI (age: 31 +/- 6 years; C4-T11; American Spinal Injury Association Impairment Scale A-B; 1-17 years post injury). OUTCOME MEASURE: Maximum change in systolic (DeltaSBP) and diastolic (DeltaDBP) blood pressure upon passively moving from a supine to seated position. RESULTS: The average values for DeltaSBP were -11 +/- 13 mmHg (range -38 to 3 mmHg) for visit 1, and -12 +/- 8 mmHg (range -26 to -1 mmHg) for visit 2. The average values for DeltaDBP were -9 +/- 8 mmHg (range -21 to 0 mmHg) for visit 1, and -13 +/- 8 mmHg (range -29 to -3 mmHg) for visit 2. The DeltaSBP demonstrated substantial reliability with an intraclass correlation coefficient of 0.79 (P = 0.006; 95% CI 0.250-0.953), while the DeltaDBP demonstrated almost perfect reliability with an intraclass correlation coefficient of 0.92 (P < 0.001; 95% CI 0.645-0.983). The smallest detectable differences in DeltaSBP and DeltaDBP were 7 mmHg and 6 mmHg, respectively. CONCLUSION: Blood pressure responses to the sit-up test are reliable in individuals with SCI, which supports its implementation as a practical bedside assessment for orthostatic hypotension in this at risk population. PMID- 25738546 TI - microRNA-214 enhances the invasion ability of breast cancer cells by targeting p53. AB - Breast cancer (BC) is the foremost cause of cancer-related mortality in women worldwide. An increasing number of studies has confirmed that microRNAs (miRNAs or miRs) play an important role in the development and progression of BC. microRNA-214 (miR-214), a member of the miRNA family, has been demonstrated to function as both a tumor suppressor and oncogene in various types of human cancer. However, the biological function of miR-214 in BC remains unclear. The present study was designed to investigate the potential role of miR-214 in the development and progression of BC. Our results revealed that miR-214 expression was significantly increased in the BC tissues compared with the adjacent benign tissues, and that the upregulation of miR-214 was significantly associated with the invasion ability of the BC cells. Furthermore, p53, which has been reported to be downregulated in BC, was predicted to be the target gene of miR-214 using bioinformatics software programs. Moreover, luciferase reporter vectors were constructed and it was confirmed that p53 is a target of miR-214. Following the transfection of miR-214 into BC cells, we found that the overexpression of miR 214 markedly enhanced cell invasion through the downregulation of p53 expression. By contrast, the overexpression of p53 abrogated the effects of miR-214. In conclusion, this study demonstrates that miR-214 functions as an oncogene in BC, at least partly by promoting cell invasion through the downregulation of p53. Therefore, miR-214 may be a potential therapeutic target for the treatment of BC. PMID- 25738548 TI - Palladium-catalyzed enantioselective Heck alkenylation of acyclic alkenols using a redox-relay strategy. AB - We report a highly enantioselective intermolecular Heck reaction of alkenyl triflates and acyclic primary or racemic secondary alkenols. The mild reaction conditions permit installation of a wide range of alkenyl groups at positions beta, gamma, or delta to a carbonyl group in high enantioselectivity. The success of this reaction is attributed to the use of electron-withdrawing alkenyl triflates, which offer selective beta-hydride elimination followed by migration of the catalyst through the alkyl chain to give the alkenylated carbonyl products. The synthetic utility of the process is demonstrated by a two-step modification of a reaction product to yield a tricyclic core structure, present in various natural products. PMID- 25738547 TI - Gibberellin driven growth in elf3 mutants requires PIF4 and PIF5. AB - The regulatory connections between the circadian clock and hormone signaling are essential to understand, as these two regulatory processes work together to time growth processes relative to predictable environmental events. Gibberellins (GAs) are phytohormones that control many growth processes throughout all stages of the plant life cycle, including germination and flowering. An increasing number of examples demonstrate that the circadian clock directly influences GA biosynthesis and signaling. EARLY FLOWERING 3 (ELF3) participates in a tripartite transcriptional complex known as the Evening Complex (EC). In this capacity, ELF3 is fundamental to core circadian clock activity, as well as time-of-day specific regulation of genes directly responsible for growth control, namely the PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PIF5 genes. Here we show that the GA biosynthesis inhibitor paclobutrazol substantially reduces the long hypocotyl and petiole phenotypes of Arabidopsis elf3 mutants. In addition, loss of ELF3 activity causes upregulation of the key GA biosynthesis genes GA20ox1 and GA20ox2. Moreover, GA20ox1 and GA20ox2 expression depends strongly on the redundant activities of PIF4 and PIF5. These findings indicate that the defining growth phenotypes of elf3 mutants arise from altered GA biosynthesis due to misregulation of PIF4 and PIF5. These observations agree with recent work linking increased GA production with the elongated growth phenotypes of the barley elf3 mutant. Thus, the role of the EC in regulation of GA biosynthesis and signaling in eudicots is shared with monocots and, therefore, is a highly conserved mechanism for growth control. PMID- 25738549 TI - Changes in the Antioxidant System in Soybean Leaves Infected by Corynespora cassiicola. AB - Considering the importance of target spot, caused by the fungus Corynespora cassiicola, to reduce soybean yield in Brazil and that more basic information regarding the soybean-C. cassiicola interaction is needed, the present study aimed to investigate whether the cellular damage caused by C. cassiicola infection could activate the antioxidant system and whether a more efficient antioxidant system could be associated with an increase in soybean resistance to target spot. The activities of the antioxidant enzymes superoxide dismutase, catalase, peroxidase, ascorbate peroxidase, glutathione peroxidase, glutathione reductase, glutathione S-transferase as well as the concentrations of ascorbate (AsA), hydrogen peroxide (H2O2), superoxide (O2*-), and malondialdehyde (MDA) were measured in soybean plants from two cultivars differing in resistance to the pathogen. The number of lesions per square centimeter was significantly reduced by 14% in plants from cultivar Fundacep 59 compared with plants from cultivar TMG 132. The area under the disease progress curve was significantly lower, by 15%, in plants from Fundacep 59 than in plants from TMG 132. Generally, antioxidant enzyme activities and AsA concentration significantly increased in response to C. cassiicola infection in plants from both cultivars, however more prominent increases were recorded for plants from Fundacep 59. The concentrations of MDA, H2O2, and O2*- also increased, particularly for plants from TMG 132. The results from this study highlight the importance of a more efficient antioxidative system in the removal of reactive oxygen species generated in soybean plants during C. cassiicola infection, contributing to the resistance to target spot. PMID- 25738550 TI - Population Structure of the Late Blight Pathogen Phytophthora infestans in a Potato Germplasm Nursery in Two Consecutive Years. AB - As the causal agent of late blight on potato, Phytophthora infestans is one of the most destructive plant pathogens worldwide and widely known as the Irish potato famine pathogen. Understanding the genetic structure of P. infestans populations is important both for breeding and deployment of resistant varieties and for development of disease control strategies. Here, we investigate the population genetic structure of P. infestans in a potato germplasm nursery in northwestern China. In total, 279 isolates were recovered from 63 potato varieties or lines in 2010 and 2011, and were genotyped by mitochondrial DNA haplotypes and a set of nine simple-sequence repeat markers. Selected isolates were further examined for virulence on a set of differential lines containing each resistance (R) gene (R1 to R11). The overall P. infestans population was characterized as having a low level of genetic diversity and resistance to metalaxyl, and containing a high percentage of individuals that virulent to all 11 R genes. Both A1 and A2 mating types as well as self-fertile P. infestans isolates were present but there was no evidence of sexual reproduction. The low level of genetic differentiation in P. infestans populations is probably due to the action of relatively high levels of migration as supported by analysis of molecular variance (P < 0.01). Migration and asexual reproduction were the predominant mechanisms influencing the P. infestans population structure in the germplasm nursery. Therefore, it is important to ensure the production of pathogen-free potato seed tubers to aid sustainable production of potato in northwestern China. PMID- 25738551 TI - Grapevine Red Blotch-Associated Virus, an Emerging Threat to the Grapevine Industry. AB - Grapevine red blotch-associated virus (GRBaV) is a newly identified virus of grapevines and a putative member of a new genus within the family Geminiviridae. This virus is associated with red blotch disease that was first reported in California in 2008. It affects the profitability of vineyards by substantially reducing fruit quality and ripening. In red-berried grapevine cultivars, foliar disease symptoms consist of red blotches early in the season that can expand and coalesce across most of the leaf blade later in the season. In white-berried grapevine cultivars, foliar disease symptoms are less conspicuous and generally involve irregular chlorotic areas that may become necrotic late in the season. Determining the GRBaV genome sequence yielded critical information for the design of primers for polymerase chain reaction-based diagnostics. To date, GRBaV has been reported in the major grape-growing areas in North America and two distinct phylogenetic clades have been described. Spread of GRBaV is suspected in certain vineyards but a vector of epidemiological significance has yet to be identified. Future research will need to focus on virus spread, the production of clean planting stocks, and the development of management options that are effective, economical, and environmentally friendly. PMID- 25738552 TI - Xylella fastidiosa Isolates from Both subsp. multiplex and fastidiosa Cause Disease on Southern Highbush Blueberry (Vaccinium sp.) Under Greenhouse Conditions. AB - Xylella fastidiosa is a xylem-limited gram-negative plant pathogen that affects numerous crop species, including grape, citrus, peach, pecan, and almond. Recently, X. fastidiosa has also been found to be the cause of bacterial leaf scorch on blueberry in the southeastern United States. Thus far, all X. fastidiosa isolates obtained from infected blueberry have been classified as X. fastidiosa subsp. multiplex; however, X. fastidiosa subsp. fastidiosa isolates are also present in the southeastern United States and commonly cause Pierce's disease of grapevines. In this study, seven southeastern U.S. isolates of X. fastidiosa, including three X. fastidiosa subsp. fastidiosa isolates from grape, one X. fastidiosa subsp. fastidiosa isolate from elderberry, and three X. fastidiosa subsp. multiplex isolates from blueberry, were used to infect the southern highbush blueberry 'Rebel'. Following inoculation, all isolates colonized blueberry, and isolates from both X. fastidiosa subsp. multiplex and X. fastidiosa subsp. fastidiosa caused symptoms, including characteristic stem yellowing and leaf scorch symptoms as well as dieback of the stem tips. Two X. fastidiosa subsp. multiplex isolates from blueberry caused more severe symptoms than the other isolates examined, and infection with these two isolates also had a significant impact on host mineral nutrient content in sap and leaves. These findings have potential implications for understanding X. fastidiosa host adaptation and expansion and the development of emerging diseases caused by this bacterium. PMID- 25738553 TI - Silicon-Induced Systemic Defense Responses in Perennial Ryegrass Against Infection by Magnaporthe oryzae. AB - Sustainable integrated disease management for gray leaf spot of perennial ryegrass may involve use of plant defense elicitors with compatible traditional fungicides to reduce disease incidence and severity. Silicon (Si) has previously been identified as a potential inducer or modulator of plant defenses against different fungal pathogens. To this end, perennial ryegrass was inoculated with the causal agent of gray leaf spot, Magnaporthe oryzae, when grown in soil that was nonamended or amended with three different levels of calcium silicate (1, 5, or 10 metric tons [t]/ha). When applied at a rate of 5 t/ha, calcium silicate was found to significantly suppress gray leaf spot in perennial ryegrass, including a significant reduction of disease incidence (39.5%) and disease severity (47.3%). Additional studies observed nonpenetrated papillae or cell-wall appositions harboring callose, phenolic autofluorogens, and lignin-associated polyphenolic compounds in grass grown in the Si-amended soil. Regarding defense-associated enzyme levels, only following infection did grass grown in Si-amended soil exhibit greater activities of peroxidase and polyphenol oxidase than equivalent inoculated control plants. Also following infection with M. oryzae, grass levels of several phenolic acids, including chlorogenic acid and flavonoids, and relative expression levels of genes encoding phenylalanine ammonia lyase (PALa and PALb) and lipoxygenase (LOXa) significantly increased in Si-amended plants compared with that of nonamended control plants. These results suggest that Si mediated increase of host defense responses to fungal pathogens in perennial ryegrass has a great potential to be part of an effective integrated disease management strategy against gray leaf spot development. PMID- 25738554 TI - The Multi-Resistant Reaction of Drought-Tolerant Coffee 'Conilon Clone 14' to Meloidogyne spp. and Late Hypersensitive-Like Response in Coffea canephora. AB - Root-knot nematodes (RKN), Meloidogyne spp., have major economic impact on coffee production in Central and South America. Genetic control of RKN constitutes an essential part for integrated pest management strategy. The objective of this study was to evaluate the resistance of Coffea canephora genotypes (clones) to Meloidogyne spp. Sensitive and drought-tolerant coffee genotypes were used to infer their resistance using nematode reproduction factor and histopathology. Eight clonal genotypes were highly resistant to M. paranaensis. 'Clone 14' (drought-tolerant) and 'ESN2010-04' were the only genotypes highly resistant and moderately resistant, respectively, to both M. incognita races 3 and 1. Several clones were highly resistant to both avirulent and virulent M. exigua. Clone 14 and ESN2010-04 showed multiple resistance to major RKNs tested. Roots of 'clone 14' (resistant) and 'clone 22' (susceptible) were histologically studied against infection by M. incognita race 3 and M. paranaensis. Reduction of juvenile (J2) penetration in clone 14 was first seen at 2 to 6 days after inoculation (DAI). Apparent early hypersensitive reaction (HR) was seen in root cortex between 4 and 6 DAI, which led to cell death and prevention of some nematode development. At 12 to 20 DAI, giant cells formed in the vascular cylinder, besides normal development into J3/J4. From 32 to 45 DAI, giant cells were completely degenerated. Late, intense HR and cell death were frequently observed around young females and giant cells reported for the first time in coffee pathosystem. These results provide rational bases for future studies, including prospection, characterization, and expression profiling of genomic loci involved in both drought tolerance and resistance to multiple RKN species. PMID- 25738555 TI - Triangular platinum(II) metallacycles: syntheses, photophysics, and nonlinear optics. AB - Three triangular platinum(II) diimine metallacycles incorporating large cyclic oligo(phenylene-ethynylene) (OPE) bisacetylide ligands are synthesized, and their photophysical properties are studied. Two types of triplet excited states with ligand/metal-to-ligand charge-transfer and acetylide-ligand-centered characteristics respectively, are exhibited by these complexes depending on the size (conjugation length) and electronic features of the cyclic OPE ligands. When the energy levels of the two excited states are close to each other, the lowest triplet state is found to switch between the two in varied solvents, resulting from their relative energy inversion induced by solvent polarity change. Density functional theory and time-dependent density functional theory calculations provide corroborative evidence for such experimental conclusions. More importantly, the designed metallacycles show impressive two-photon absorption (2PA) and two-photon excitation phosphorescing abilities, and the 2PA cross section reaches 1020 GM at 680 nm and 670 GM at 1040 nm by two different metallacycles. Additionally, pronounced reverse saturable absorptions are observed with these metallacycles by virtue of their strong transient triplet state absorptions. PMID- 25738557 TI - Differences between scintigraphic reflux studies in gastrointestinal reflux disease and laryngopharyngeal reflux disease and correlation with symptoms. AB - OBJECTIVES: Gastro-oesophageal reflux disease (GERD) is poorly defined at best. Symptoms can be variable, ranging from none to heartburn, regurgitation and chest pain. When the reflux extends to the oropharynx [laryngopharyngeal reflux (LPR)], the symptoms can be protean and include cough and sore throat. We present the scintigraphic findings in two broad groups classified by symptoms as either GERD or LPR. PATIENTS AND METHODS: Patients with an established diagnosis of GERD or LPR by standard methods (95%) or high clinical pretest probability (5%) were scanned in the upright and supine position after swallowing (99m)Tc-DTPA. A delayed image was obtained at 2 h to evaluate the possibility of lung aspiration. RESULTS: Studies were obtained in 285 patients (168 females, 117 males), with a mean age of 54 years. Of these, 80 had typical symptoms of GERD and 205 had LPR. The group with GERD had pharyngeal contamination in 49 and 14% showed pulmonary aspiration. The group with LPR had pharyngeal contamination in 65 and 23% had lung aspiration. Pharyngeal contamination was more common in the supine than in the upright position (P=0000). Lung aspiration was correlated with upper oesophageal activity. CONCLUSION: Scintigraphic reflux studies are a good screening test for GERD and LPR as they can detect oropharyngeal reflux and lung aspiration in an unsuspected proportion of patients in both groups. The oropharynx and lung are sites that are out of reach of the current standards of investigation such as pH studies, manometry and impedance monitoring. PMID- 25738558 TI - Estimation of skin dose rate from a catheter bag filled with P-32 solution. AB - Patients attending for therapy with phosphorus-32 (P-32) may have problems with urinary continence requiring the use of a urinary catheter. P-32 is excreted renally and the contents of the catheter bag will impart a dose to the skin with which the bag is in contact. We simulated a catheter bag filled with P-32 contaminated urine and measured the dose rate per unit activity from the bag. A volume of 25 MBq of P-32 was added to a 500 ml bag of saline and mixed thoroughly. A personal dosimetry badge was fixed to the surface of the bag and left for 48 h before being sent for processing. To account for decay, the cumulative activity in the bag over the 48 h period was calculated and the shallow [Hp(0.07)] dose measured by the badge was divided by the cumulative activity to yield a dose rate per MBq of activity. The measured Hp(0.07) dose was 192.8 mSv, which corresponds to a dose rate per MBq of 169 MUSv/h/MBq. This study has shown that the dose rate per MBq from a simulated catheter bag of radioactive phosphorus differs from the dose rates published for other containers. This value may be useful in the risk assessment of P-32 therapy in catheterized patients. PMID- 25738559 TI - Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging. AB - PURPOSE: The aim of the study was to evaluate the diagnostic value of the prostate-specific membrane antigen (PSMA) ligand (68)Ga-HBED-CC (PSMA PET/CT) in patients with prostate cancer and evaluate the value of early imaging of the pelvis. MATERIALS AND METHODS: The files of 28 patients were retrospectively evaluated. All patients had a histopatological confirmation of prostate cancer. PSMA PET/CT images were obtained at 5 and 60 min after injection from all patients. RESULTS: Intense pathologic radiotracer uptake was observed in 23 patients (77%) at the site of primary tumour. Lymph node metastases were detected in 10 patients (36%) and bone metastases were detected in seven patients (25%). Bone scan (n=25) results revealed metastatic bone lesions in four patients, equivocal results in nine patients and normal results in 12 patients. PSMA PET/CT confirmed bone metastases in all four patients. Pathologic radiotracer uptake in PSMA PET/CT scans was observed only in one patient among those who had equivocal bone scans. PSMA PET/CT showed additional bone lesions in two patients who had a normal bone scan. When we compared early and late pelvic images we found no difference in the number of lesions detected. The maximum standardized uptake value (SUV(max)) for primary tumour, lymph nodes and bone metastases was significantly higher in late images. CONCLUSION: PSMA PET/CT imaging seems to be a valuable imaging modality for evaluation of primary prostate cancer and it seems to have potential for the detection of lymph node and bone metastases. Early images 5 min p.i. can help to better distinguish between urinary bladder (before tracer accumulation occurs) and tumour lesions. PMID- 25738560 TI - The predictive value of C-reactive protein and erythrocyte sedimentation rate for 18F-FDG PET/CT outcome in patients with fever and inflammation of unknown origin. AB - OBJECTIVES: The objective of this study was to determine the predictive value of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to a positive fluorine-18 fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (CT) result in patients with inflammation of unknown origin and fever of unknown origin. PATIENTS AND METHODS: Individual data of 498 patients were retrieved from three retrospective studies. Receiver operating characteristic derived areas under the curve were used to assess (18)F-FDG PET/CT versus age, CRP, and ESR. The discriminative value of age, CRP, and ESR related to (18)F-FDG PET/CT was examined using the net reclassification improvement (NRI). RESULTS: A diagnosis was established in 331 patients; (18)F-FDG PET/CT had a diagnostic accuracy of 89%. (18)F-FDG PET/CT had the highest area under the curve (0.89, P<0.001). The addition of (18)F-FDG PET/CT to a diagnosis prediction model including age, CRP, and ESR resulted in an NRI of 42% (P<0.001). In the same model with CRP values below 20 mg/l or ESR values below 20 mm/h, the NRI was 64% (P<0.001) and 29% (P=0.059), respectively. In 30 of 91 patients with CRP less than 10 mg/l, a diagnosis could be established; (18)F-FDG PET/CT was 100% true negative only in patients with CRP levels less than 5 mg/l. CONCLUSION: In patients with fever of unknown origin or inflammation of unknown origin, compared with elevated ESR levels, elevated CRP levels more often indicate a true positive (18)F-FDG PET/CT outcome.In addition, (18)F-FDG PET/CT, compared with CRP and ESR, shows the highest discrimination of patients with possible disabling disease. PMID- 25738561 TI - Estimation of radioactivity in single-photon emission computed tomography for sentinel lymph node biopsy in a torso phantom study. AB - OBJECTIVE: The number of lymph nodes to be removed is determined from residual counts. Advance estimation of residual radioactivity in lymphatic nodes before a biopsy is useful for reducing surgical operation time. The purpose of this study was to estimate the total radioactivity of a small hotspot in single-photon emission computed tomography (SPECT) of a torso phantom. METHODS: A cross calibration study was performed to convert counts in SPECT images to radioactivity. A simulation study was performed to estimate the size of the volume of interest (VOI) covering a hotspot corrupted with full-width at half maximum between 8 and 16 mm. The estimation of total radioactivity was validated in a torso phantom study using small sources. RESULTS: True radioactivity was approximately equal to integrated values of hotspots using the VOI with a diameter of 40 mm in our simulation study. The difference was less than 18% in cases of more than 9.4 kBq. CONCLUSION: The total radioactivity in small sources simulating a typical sentinel node was estimated from SPECT images using a VOI of 40 mm in a torso phantom study. Because the difference from actual values was less than 10% on average when radioactivities were more than 9.4 kBq, the total radioactivity of a lymph node can be estimated in a clinical examination. PMID- 25738562 TI - Nanofiber-based Drug Design, Delivery and Application. PMID- 25738564 TI - Cytotoxic T lymphocyte-associated antigen 4 inhibition increases the antitumor activity of adoptive T-cell therapy when carried out with naive rather than differentiated T cells. AB - Although treatment with an antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) combined with multiple therapeutic interventions has been explored, the effect of combination therapy with CTLA-4 inhibition and adoptive T cell therapy has not been determined. In the present study, our aim was to determine whether CTLA-4 inhibition, combined with adoptive transfer of T cells at different stages of differentiation, exhibits synergistic antitumor effects in a murine colon cancer model. Mice bearing subcutaneous tumors were administered adoptive T-cell transfer of CD62Lhigh or CD62Llow cells combined with an anti CTLA-4 antibody (alpha-CTLA-4) or control immunoglobulin G. Subcutaneous tumors were harvested, and the antitumor effects and helper T-cell polarization were analyzed. CTLA-4 inhibition combined with CD62Lhigh cell administration showed the strongest antitumor effect. Combination therapy increased the number of CD3+ cells within the tumor. Moreover, CTLA-4 inhibition induced polarization of T cells infiltrating the tumor toward the T helper 1 lineage, and suppressed the frequency of regulatory T cells within the tumor, particularly in combination with CD62Lhigh T-cell transfer. This is the first report demonstrating that the efficacy of alpha-CTLA-4 and adoptive T-cell transfer combination therapy depends on the state of differentiation of the transferred T cells. Our data support the notion that a combination of alpha-CTLA-4 and adoptive T-cell transfer containing an abundance of naive phenotype cells could potentially exert antitumor effects in a clinical setting. PMID- 25738563 TI - Apolipoprotein epsilon4 is associated with lower brain volume in cognitively normal Chinese but not white older adults. AB - Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The epsilon4 allele of apolipoprotein E (APOE epsilon4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE epsilon4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE epsilon4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE epsilon4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE epsilon4 and being Chinese. The APOE epsilon4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE epsilon4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE epsilon4 effects on the brain in diverse populations. PMID- 25738565 TI - Flower bud transcriptome analysis of Sapium sebiferum (Linn.) Roxb. and primary investigation of drought induced flowering: pathway construction and G-quadruplex prediction based on transcriptome. AB - Sapium sebiferum (Linn.) Roxb. (Chinese Tallow Tree) is a perennial woody tree and its seeds are rich in oil which hold great potential for biodiesel production. Despite a traditional woody oil plant, our understanding on S. sebiferum genetics and molecular biology remains scant. In this study, the first comprehensive transcriptome of S. sebiferum flower has been generated by sequencing and de novo assembly. A total of 149,342 unigenes were generated from raw reads, of which 24,289 unigenes were successfully matched to public database. A total of 61 MADS box genes and putative pathways involved in S. sebiferum flower development have been identified. Abiotic stress response network was also constructed in this work, where 2,686 unigenes are involved in the pathway. As for lipid biosynthesis, 161 unigenes have been identified in fatty acid (FA) and triacylglycerol (TAG) biosynthesis. Besides, the G-Quadruplexes in RNA of S. sebiferum also have been predicted. An interesting finding is that the stress induced flowering was observed in S. sebiferum for the first time. According to the results of semi-quantitative PCR, expression tendencies of flowering-related genes, GA1, AP2 and CRY2, accorded with stress-related genes, such as GRX50435 and PRXII39562. This transcriptome provides functional genomic information for further research of S. sebiferum, especially for the genetic engineering to shorten the juvenile period and improve yield by regulating flower development. It also offers a useful database for the research of other Euphorbiaceae family plants. PMID- 25738566 TI - Multi-Ligand-Binding Flavoprotein Dodecin as a Key Element for Reversible Surface Modification in Nano-biotechnology. AB - In this paper the multiple (re)programming of protein-DNA nanostructures comprising generation, deletion, and reprogramming on the same flavin-DNA modified surface is introduced. This work is based on a systematic study of the binding affinity of the multi-ligand-binding flavoprotein dodecin on flavin terminated DNA monolayers by surface plasmon resonance and quartz crystal microbalance with dissipation (QCM-D) measurements, surface plasmon fluorescence spectroscopy (SPFS), and dynamic AFM force spectroscopy. Depending on the flavin surface coverage, a single apododecin is captured by one or more surface immobilized flavins. The corresponding complex binding and unbinding rate constants kon(QCM) = 7.7 * 10(3) M(-1).s(-1) and koff(QCM) = 4.5 * 10(-3) s(-1) (Kd(QCM) = 580 nM) were determined by QCM and were found to be in agreement with values for koff determined by SPFS and force spectroscopy. Even though a single apododecin-flavin bond is relatively weak, stable dodecin monolayers were formed on flavin-DNA-modified surfaces at high flavin surface coverage due to multivalent interactions between apododecin bearing six binding pockets and the surface-bound flavin-DNA ligands. If bi- or multivalent flavin ligands are adsorbed on dodecin monolayers, stable sandwich-type surface-DNA-flavin apododecin-flavin ligand arrays are obtained. Nevertheless, the apododecin flavin complex is easily and quantitatively disassembled by flavin reduction. Binding and release of apododecin are reversible processes, which can be carried out alternatingly several times to release one type of ligand by an external redox trigger and subsequently replace it with a different ligand. Hence the versatile concept of reprogrammable functional biointerfaces with the multi-ligand-binding flavoprotein dodecin is demonstrated. PMID- 25738567 TI - A disintegrin and metalloprotease 17 promotes microglial cell survival via epidermal growth factor receptor signalling following spinal cord injury. AB - Tumour necrosis factor-alpha (TNF-alpha) converting enzyme (TACE), also termed a disintegrin and metalloprotease 17 (ADAM17), is involved in multiple cell signalling pathways. Through the secretion of epidermal growth factor receptor (EGFR) ligands, ADAM17 can activate the EGFR and is involved in various downstream signalling pathways. The present study aimed to investigate whether ADAM17-induced EGFR transactivation is involved in microglial cell survival following spinal cord injury (SCI). Reverse transcription quantitative polymerase chain reaction and western blot analysis revealed that ADAM17 was overexpressed in a mouse model following SCI. A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay demonstrated that the viability of human microglia and oligodendrocytes were significantly reduced in a time- and dose dependent manner following treatment with the ADAM17 antagonist, TNF protease inhibitor 2. Hoechst 33258 staining and flow cytometric analysis revealed that inhibiting ADAM17 increased the rate of cellular apoptosis in neuronal and glial cell cultures, which was accompanied by increased cleavage of caspase-3. Western blot analysis demonstrated that inhibiting ADAM17 resulted in a reduction in the phosphorylation of the EGFR signalling pathway components and thereby impaired functional recovery, inhibited cell viability and prompted microglial apoptosis following SCI. Pre-treatment with the EGFR inhibitor, AG1478, rescued the ADAM17 mediated proliferation of microglial cells. These data demonstrated that ADAM17 contributed to microglial cell survival, predominantly by EGFR signalling, following SCI. PMID- 25738568 TI - Leishmania infantum modulates host macrophage mitochondrial metabolism by hijacking the SIRT1-AMPK axis. AB - Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis. PMID- 25738569 TI - Unilateral Vocal Cord Motion Impairment After 1 Dose of Vincristine: Case Report and Literature Review. AB - Vocal cord paralysis after administration of the chemotherapeutic agent vincristine is a rare occurrence. Most occurrences are bilateral. Of the 24 cases referenced in this article, 19 are children. In all the reported cases, symptoms have occurred after multiple doses of vincristine have been administered. The authors report a case of a 39-year-old woman with unilateral vocal cord motion impairment occurring 3 days after the administration of the first dose of vincristine. This is the first case of vocal cord motion impairment reported after the administration of only 1 dose of this drug. PMID- 25738570 TI - A Systematic Review on the Efficacy of Amlodipine in the Treatment of Patients With Hypertension With Concomitant Diabetes Mellitus and/or Renal Dysfunction, When Compared With Other Classes of Antihypertensive Medication. AB - The long-term cardiovascular (CV) effects of calcium channel blockers, with special focus on amlodipine, were compared with other classes of antihypertensive medications in high-risk hypertensive patient subgroups. A systematic literature review and meta-analysis was undertaken of 38 unique randomized, active controlled, parallel-group trials comparing amlodipine/calcium channel blockers with diuretics, beta-blockers, alpha-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, with >=6-month follow-up, and which had included assessment of blood pressure (BP) and CV events [all-cause death, CV death, myocardial infarction (MI), stroke, congestive heart failure (CHF), or major CV events (MACE: MI, CHF, stroke, and CV death)], in hypertensive patients (baseline systolic/diastolic BP >=140/>=90 mm Hg) with either concomitant diabetes and/or renal dysfunction. In hypertensive patients with diabetes, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, and MI; a decrease in stroke risk, and an increase in CHF risk, was seen. In hypertensive patients with renal dysfunction, no difference was found for amlodipine versus comparators with respect to all cause death, CV death, MACE, MI, and CHF; a decrease in stroke risk was seen. Amlodipine was found to be at least as efficacious as all the other classes of antihypertensive agents in reducing systolic and diastolic BP. Long-term control of BP is critical for avoiding complications of hypertension in high-risk patients, particularly CV and cerebrovascular events such as stroke. This analysis has provided evidence that amlodipine is an appealing therapeutic option in the long-term management of hypertension in both diabetic and renal dysfunction patients. PMID- 25738571 TI - Association of VEGFR-2 Gene Polymorphisms With Clopidogrel Resistance in Patients With Coronary Heart Disease. AB - Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a central role in atherogenesis. We investigated the correlation between VEGFR-2 polymorphisms and the risk of clopidogrel resistance (CR) in patients with coronary heart disease (CHD). The study involved 275 patients with CHD undergoing percutaneous coronary intervention and on antiplatelet clopidogrel therapy. The participants were divided into CR group (n = 59) and non-CR group (NCR, n = 216) based on maximum platelet aggregation measurements. VEGFR-2 gene polymorphisms, +1192C>T (rs2305948), +1416T>A (rs1870377), and -271A>G (rs7667298), were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay was used to measure serum transforming growth factor, beta receptor 2 levels. CR was found in 59 patients (20.45%). A significantly higher proportion of patients in the CR group had a history of diabetes mellitus compared with the NCR group (P < 0.05). Genotype and allele frequency of VEGFR-2 +1192C>T (rs2305948) was significantly higher in the CR group than in the NCR group (all P < 0.01). In the VEGFR-2 +1192C>T (rs2305948), the angina pectoris, recurrent myocardial infarction, and combined end point events were significantly more prevalent in the TT carriers than in the CC + CT carriers. In VEGFR-2 271A>G (rs7667298), the GG carriers had a lower proportion of target lesion revascularization and angina pectoris in contrast to the AA + AG carriers (all P < 0.05). Based on our results, VEGFR-2 +1192C>T (rs2305948) polymorphism is strongly associated with increased CR and main adverse cardiovascular event incidence in patients with CHD undergoing percutaneous coronary intervention. Additionally, patients with CHD with diabetes mellitus history were more likely to develop CR. The associations of +1416T>A (rs1870377) and -271A>G (rs7667298) polymorphisms with CR were inconclusive and will need to be examined further. PMID- 25738572 TI - Air and Bone Conduction Click and Tone-Burst Auditory Brainstem Thresholds Using Kalman Adaptive Processing in Nonsedated Normal-Hearing Infants. AB - OBJECTIVES: To study normative thresholds and latencies for click and tone-burst auditory brainstem response (TB-ABR) for air and bone conduction in normal infants and those discharged from neonatal intensive care units, who passed newborn hearing screening and follow-up distortion product otoacoustic emission. An evoked potential system (Vivosonic Integrity) that incorporates Bluetooth electrical isolation and Kalman-weighted adaptive processing to improve signal to noise ratios was employed for this study. Results were compared with other published data. DESIGN: One hundred forty-five infants who passed two-stage hearing screening with transient-evoked otoacoustic emission or automated auditory brainstem response were assessed with clicks at 70 dB nHL and threshold TB-ABR. Tone bursts at frequencies between 500 and 4000 Hz were used for air and bone conduction auditory brainstem response testing using a specified staircase threshold search to establish threshold levels and wave V peak latencies. RESULTS: Median air conduction hearing thresholds using TB-ABR ranged from 0 to 20 dB nHL, depending on stimulus frequency. Median bone conduction thresholds were 10 dB nHL across all frequencies, and median air-bone gaps were 0 dB across all frequencies. There was no significant threshold difference between left and right ears and no significant relationship between thresholds and hearing loss risk factors, ethnicity, or gender. Older age was related to decreased latency for air conduction. Compared with previous studies, mean air conduction thresholds were found at slightly lower (better) levels, while bone conduction levels were better at 2000 Hz and higher at 500 Hz. Latency values were longer at 500 Hz than previous studies using other instrumentation. Sleep state did not affect air or bone conduction thresholds. CONCLUSIONS: This study demonstrated slightly better wave V thresholds for air conduction than previous infant studies. The differences found in the present study, while statistically significant, were within the test step size of 10 dB. This suggests that threshold responses obtained using the Kalman weighting software were within the range of other published studies using traditional signal averaging, given step size limitations. Thresholds were not adversely affected by variable sleep states. PMID- 25738573 TI - Effects of a Dual Sensory Loss Protocol on Hearing Aid Outcomes: A Randomized Controlled Trial. AB - OBJECTIVES: Dual sensory loss (DSL; concurrent vision and hearing loss) negatively affects quality of life. As speechreading is hampered, use of hearing aids (HAs) is important for older adults with DSL. However, due to vision loss, use of small and complex HAs is assumed to be difficult. An integrative DSL protocol that addresses rehabilitative care for older adults with DSL, including proper HA use, was implemented in low vision rehabilitation centers. The present study aims to evaluate the effectiveness of the DSL protocol among HA owners on HA outcomes (i.e., HA use, benefit, satisfaction with HAs, and hearing with HAs). DESIGN: In a randomized controlled trial, the DSL protocol was compared to a waiting list control group among clients (aged >=50 years) of low vision rehabilitation centers with DSL. The International Outcome Inventory for Hearing Aids (IOI-HA) and the HA Fitting Questionnaire (HAFQ) were administered at baseline and 3 months follow-up. Participants (n = 128) were randomly allocated to either the intervention (n = 63) or control group (n = 65). RESULTS: Intention to-treat analyses showed a near significant effect on IOI-HA Residual problems (effect size, 0.35; p = 0.063). Per-protocol analyses showed similar (nonsignificant) results on the main outcomes, and a ceiling effect was found on the HAFQ. Significant effects were found in subgroups of patients: among patients with low HAFQ scores (HAFQ-Use: effect size = 0.56, p = 0.046; HAFQ-Hearing with HAs: effect size = 0.64, p = 0.019), male participants (effect size = 0.80; p = 0.003), and those with moderate hearing loss (effect size = 0.72; p = 0.028), significantly better IOI-HA scores were found in the intervention group at 3 months follow-up. CONCLUSIONS: Although the per-protocol and subgroup analyses need to be interpreted with caution, DSL patients who experience HA difficulties could benefit from the DSL protocol by making better use of their HAs. The increasing prevalence and impact of DSL on a person's independence and social participation call for more awareness of concurrent sensory impairments in both low vision and audiology rehabilitation. Interdisciplinary training for rehabilitation professionals could be an important step, followed by integration of vision and hearing services using the DSL protocol. PMID- 25738574 TI - Effect of Channel Envelope Synchrony on Interaural Time Difference Sensitivity in Bilateral Cochlear Implant Listeners. AB - OBJECTIVES: For a periodic acoustic input signal, the channel envelopes coded by current bilateral cochlear implant sound processors can be asynchronous. The effect of this asynchrony on sensitivity to interaural time differences (ITDs) was assessed. DESIGN: ITD sensitivity was measured in six bilateral cochlear implant listeners for single- and three-electrode stimuli. The three-electrode stimuli contained envelope modulations, either synchronous or asynchronous across electrodes, with delays of 1.25 up to 5.00 ms. Each individual electrode carried the same ITD. Either neighboring electrodes were chosen or a separation of four electrodes to investigate the effect of electrode distance. RESULTS: With synchronous envelopes, no difference in ITD sensitivity was found among single electrode, adjacent three-electrode, and spaced three-electrode stimuli. A decrease in ITD sensitivity was found with increasing across-channel envelope asynchrony, which was consistent with the use of the across-electrode aggregate stimulation pattern rather than individual information channels for ITDs. No consistent effect of electrode separation was found. CONCLUSIONS: While the binaural system was resilient to small delays between envelopes, larger delays significantly deceased ITD sensitivity, both for adjacent and further spaced electrodes. PMID- 25738575 TI - Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics. AB - BACKGROUND: T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-alpha), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. METHODS: PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-alpha. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. RESULTS: Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. CONCLUSION: Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases. PMID- 25738576 TI - Astragaloside IV protects against isoproterenol-induced cardiac hypertrophy by regulating NF-kappaB/PGC-1alpha signaling mediated energy biosynthesis. AB - We previously reported that Astragaloside IV (ASIV), a major active constituent of Astragalus membranaceus (Fisch) Bge protects against cardiac hypertrophy in rats induced by isoproterenol (Iso), however the mechanism underlying the protection remains unknown. Dysfunction of cardiac energy biosynthesis contributes to the hypertrophy and Nuclear Factor kappaB (NF-kappaB)/Peroxisome Proliferator-Activated Receptor-gamma Coactivator 1alpha (PGC-1alpha) signaling gets involved in the dysfunction. The present study was designed to investigate the mechanism by which ASIV improves the cardiac hypertrophy with focuses on the NF-kappaB/PGC-1alpha signaling mediated energy biosynthesis. Sprague-Dawley (SD) rats or Neonatal Rat Ventricular Myocytes (NRVMs) were treated with Iso alone or in combination with ASIV. The results showed that combination with ASIV significantly attenuated the pathological changes, reduced the ratios of heart weight/body weight and Left ventricular weight/body weight, improved the cardiac hemodynamics, down-regulated mRNA expression of Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), increased the ratio of ATP/AMP, and decreased the content of Free Fat Acid (FFA) in heart tissue of rats compared with Iso alone. In addition, pretreatment with ASIV significantly decreased the surface area and protein content, down-regulated mRNA expression of ANP and BNP, increased the ratio of ATP/AMP, and decreased the content of FFA in NRVMs compared with Iso alone. Furthermore, ASIV increased the protein expression of ATP5D, subunit of ATP synthase and PGC-1alpha, inhibited translocation of p65, subunit of NF-kappaB into nuclear fraction in both rats and NRVMs compared with Iso alone. Parthenolide (Par), the specific inhibitor of p65, exerted similar effects as ASIV in NRVMs. Knockdown of p65 with siRNA decreased the surface areas and increased PGC-1alpha expression of NRVMs compared with Iso alone. The results suggested that ASIV protects against Iso-induced cardiac hypertrophy through regulating NF-kappaB/PGC-1alpha signaling mediated energy biosynthesis. PMID- 25738577 TI - Apogossypolone induces reactive oxygen species accumulation and controls cell cycle progression in Raji Burkkit's lymphoma cells. AB - Burkitt's lymphoma (BL) is a highly aggressive type of non-Hodgkin's lymphoma, with marked rates of proliferation and metabolism. The expression levels of the translocated cellular Myc (c-Myc) oncogene and Epstein-Barr virus infection have an oncogenic role in facilitating tumor progression and maintaining a malignant phenotype in BL Raji cells. The present study identified that more reactive oxygen species (ROS) were produced in Raji cells compared with other types of malignant B cells. Cells exhibiting higher ROS levels suggested facilitation of the induction of cell death by ROS-induction compounds. In the present study, apogossypolone (ApoG2) was observed to induce marked accumulation in the levels of ROS in the Raji cells, which damaged the cells and suppressed cell proliferation. Within 12 h following ApoG2 treatment, the Raji cells were prominently arrested in the G1 phase of the cell cycle. Immunoblotting analysis indicated that the chromodomain-helicase-DNA-binding protein 1, checkpoint kinase 1 and c-Myc proteins were significantly downregulated at 3, 6 and 12 h, respectively, following treatment. Following treatment with ApoG2 for 48 h, ApoG2 induced significant apoptosis in the Raji cells. This findings, together with our previous studies, which demonstrated ApoG2 as a potent inhibitor of anti apoptotic B cell lymphoma 2 proteins, indicated that the ROS stimulatory effect of ApoG2 increased the antitumor activity of ApoG2. PMID- 25738578 TI - The relationship between bipolar disorder and cannabis use in daily life: an experience sampling study. AB - OBJECTIVES: Although cannabis use is common in bipolar disorder and may contribute to worse clinical outcomes, little is understood about the relationship between this drug and bipolar disorder over the course of daily life. The aim of study was to examine the effect of cannabis on affect and bipolar symptoms in a group of individuals with bipolar disorder. METHODS: Twenty four participants with bipolar disorder type I or type II completed diaries for 6 days using Experience Sampling Methodology to investigate the temporal associations between cannabis, affect and bipolar disorder symptoms. RESULTS: The results indicated that higher levels of positive affect increase the odds of using cannabis (OR:1.25 ,CI:1.06-1.47, P=0.008). However, neither negative affect, manic nor depressive symptoms predicted the use of cannabis. Cannabis use was associated with subsequent increases in positive affect (beta=0.35, CI:0.20 0.51, P=0.000), manic symptoms (beta=0.20,CI:0.05-0.34, P=0.009) and depressive symptoms (beta= 0.17,CI:0.04-0.29, P=0.008). CONCLUSION: The findings indicate that cannabis use is associated with a number of subsequent psychological effects. However there was no evidence that individuals with BD were using cannabis to self-medicate minor fluctuations in negative affect or bipolar disorder symptoms over the course of daily life. The findings in relation to existing literature and clinical implications are discussed. PMID- 25738579 TI - How old do you feel? The role of age discrimination and biological aging in subjective age. AB - Subjective age, or how young or old individuals experience themselves to be relative to their chronological age, is a crucial construct in gerontology. Subjective age is a significant predictor of important health outcomes, but little is known about the criteria by which individuals' subjectively evaluate their age. To identify psychosocial and biomedical factors linked to the subjective evaluation of age, this study examined whether perceived age discrimination and markers of biological aging are associated with subjective age. Participants were 4776 adults (Mage = 68) from the 2008 and 2010 waves of the Health and Retirement Study (HRS) who completed measures of subjective age, age discrimination, demographic variables, self-rated health and depression, and had physical health measures, including peak expiratory flow, grip strength, waist circumference, systolic and diastolic blood pressure. Telomere length was available for a subset of participants in the 2008 wave (n = 2214). Regression analysis indicated that perceived age discrimination, lower peak expiratory flow, lower grip strength, and higher waist circumference were associated with an older subjective age, controlling for sociodemographic factors, self-rated health, and depression. In contrast, blood pressure and telomere length were not related to subjective age. These findings are consistent with the hypothesis that how old a person feels depends in part on psychosocial and biomedical factors, including the experiences of ageism and perceptible indices of fitness and biological age. PMID- 25738581 TI - The Pneumovirinae fusion (F) protein: A common target for vaccines and antivirals. AB - The Pneumovirinae fusion (F) protein mediates fusion of the virus and cell membrane, an essential step for entry of the viral genome in the cell cytoplasm and initiation of a new infectious cycle. Accordingly, potent inhibitors of virus infectivity have been found among antibodies and chemical compounds that target the Pneumovirinae F protein. Recent developments in structure-based vaccines have led to a deeper understanding of F protein antigenicity, unveiling new conformations and epitopes which should assist in development of efficacious vaccines. Similarly, structure-based studies of potent antiviral inhibitors have provided information about their mode of action and mechanisms of resistance. The advantages and disadvantages of the different options to battle against important pathogens, such as human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are summarized and critically discussed in this review. PMID- 25738582 TI - Viroids, the simplest RNA replicons: How they manipulate their hosts for being propagated and how their hosts react for containing the infection. AB - The discovery of viroids about 45 years ago heralded a revolution in Biology: small RNAs comprising around 350 nt were found to be able to replicate autonomously-and to incite diseases in certain plants-without encoding proteins, fundamental properties discriminating these infectious agents from viruses. The initial focus on the pathological effects usually accompanying infection by viroids soon shifted to their molecular features-they are circular molecules that fold upon themselves adopting compact secondary conformations-and then to how they manipulate their hosts to be propagated. Replication of viroids-in the nucleus or chloroplasts through a rolling-circle mechanism involving polymerization, cleavage and circularization of RNA strands-dealt three surprises: (i) certain RNA polymerases are redirected to accept RNA instead of their DNA templates, (ii) cleavage in chloroplastic viroids is not mediated by host enzymes but by hammerhead ribozymes, and (iii) circularization in nuclear viroids is catalyzed by a DNA ligase redirected to act upon RNA substrates. These enzymes (and ribozymes) are most probably assisted by host proteins, including transcription factors and RNA chaperones. Movement of viroids, first intracellularly and then to adjacent cells and distal plant parts, has turned out to be a tightly regulated process in which specific RNA structural motifs play a crucial role. More recently, the advent of RNA silencing has brought new views on how viroids may cause disease and on how their hosts react to contain the infection; additionally, viroid infection may be restricted by other mechanisms. Representing the lowest step on the biological size scale, viroids have also attracted considerable interest to get a tentative picture of the essential characteristics of the primitive replicons that populated the postulated RNA world. PMID- 25738580 TI - Diarrheagenic Escherichia coli carrying supplementary virulence genes are an important cause of moderate to severe diarrhoeal disease in Mexico. AB - Diarrheagenic Escherichia coli (DEC) cause acute and persistent diarrhoea worldwide, but little is known about their epidemiology in Mexico. We determined the prevalence of bacterial enteropathogens in 831 children with acute diarrhoea over a four-year period in Yucatan, Mexico. Six DEC supplementary virulence genes (SVG), mainly associated with enteroaggregative E. coli (EAEC), were sought in 3100 E. coli isolates. DEC was the most common bacterial enteropathogen (28%), surpassing Salmonella (12%) and Shigella (9%). Predominant DEC groups were diffusely adherent E. coli (DAEC) (35%), EAEC (24%), and enteropathogenic E. coli (EPEC) (19%). Among children with DEC infections, 14% had severe illness mainly caused by EPEC (26%) and DAEC (18%); 30% had moderate diarrhoea mainly caused by DAEC (36%), mixed DEC infections (33%) and EAEC (32%). DAEC was most prevalent during spring, while ETEC, EAEC and EPEC predominated in summer. EAEC was more frequent in children 6-24 months old than in those younger than 6 months of age (P = 0.008, OR = 4.2, 95% CI, 1.3-13.9). The presence of SVG dispersin, (aatA), dispersin-translocator (aatA), enteroaggregative heat-stable toxin 1 (astA), plasmid encoded toxin (pet), cytolethal distending toxin (cdt) was higher in DEC than non-DEC strains, (36% vs 26%, P <0.0001, OR = 1.5, 95% CI, 1.3-1.8). 98% of EAEC-infected children harboured strains with SVG; 85% carried the aap-aatA gene combination, and 33% of these also carried astA. 28% of both EPEC and ETEC, and 6% of DAEC patients had strains with SVG. 54% of EPEC patients carried pet positive strains alone or in combination with astA; only this DEC group harboured cdt-positive isolates. All ETEC patients carried astA- or astA-aap-positive strains. astA and aap were the most common SVG in DAEC (3% and 2%) and non-DEC strains (21% and 13%). DEC carrying SVG are an important cause of moderate to severe bacterial diarrhoea in Mexican children. PMID- 25738583 TI - Full regeneration of segmental bone defects using porous titanium implants loaded with BMP-2 containing fibrin gels. AB - Regeneration of load-bearing segmental bone defects is a major challenge in trauma and orthopaedic surgery. The ideal bone graft substitute is a biomaterial that provides immediate mechanical stability, while stimulating bone regeneration to completely bridge defects over a short period. Therefore, selective laser melted porous titanium, designed and fine-tuned to tolerate full load-bearing, was filled with a physiologically concentrated fibrin gel loaded with bone morphogenetic protein-2 (BMP-2). This biomaterial was used to graft critical sized segmental femoral bone defects in rats. As a control, porous titanium implants were either left empty or filled with a fibrin gels without BMP-2. We evaluated bone regeneration, bone quality and mechanical strength of grafted femora using in vivo and ex vivo uCT scanning, histology, and torsion testing. This biomaterial completely regenerated and bridged the critical-sized bone defects within eight weeks. After twelve weeks, femora were anatomically re shaped and revealed open medullary cavities. More importantly, new bone was formed throughout the entire porous titanium implants and grafted femora regained more than their innate mechanical stability: torsional strength exceeded twice their original strength. In conclusion, combining porous titanium implants with a physiologically concentrated fibrin gels loaded with BMP-2 improved bone regeneration in load-bearing segmental defects. This material combination now awaits its evaluation in larger animal models to show its suitability for grafting load-bearing defects in trauma and orthopaedic surgery. PMID- 25738584 TI - Local origins impart conserved bone type-related differences in human osteoblast behaviour. AB - Osteogenic behaviour of osteoblasts from trabecular, cortical and subchondral bone were examined to determine any bone type-selective differences in samples from both osteoarthritic (OA) and osteoporotic (OP) patients. Cell growth, differentiation; alkaline phosphatase (TNAP) mRNA and activity, Runt-related transcription factor-2 (RUNX2), SP7-transcription factor (SP7), bone sialoprotein II (BSP-II), osteocalcin/bone gamma-carboxyglutamate (BGLAP), osteoprotegerin (OPG, TNFRSF11B), receptor activator of nuclear factor-kappabeta ligand (RANKL, TNFSF11) mRNA levels and proangiogenic vascular endothelial growth factor-A (VEGF A) mRNA and protein release were assessed in osteoblasts from paired humeral head samples from age-matched, human OA/OP (n = 5/4) patients. Initial outgrowth and increase in cell number were significantly faster (p < 0.01) in subchondral and cortical than trabecular osteoblasts, in OA and OP, and this bone type-related differences were conserved despite consistently faster growth in OA. RUNX2/SP7 levels and TNAP mRNA and protein activity were, however, greater in trabecular than subchondral and cortical osteoblasts in OA and OP. BSP-II levels were significantly greater in trabecular and lowest in cortical osteoblasts in both OA and OP. In contrast, BGLAP levels showed divergent bone type-selective behaviour; highest in osteoblasts from subchondral origins in OA and trabecular origins in OP. We found virtually identical bone type-related differences, however, in TNFRSF11B:TNFSF11 in OA and OP, consistent with greater potential for paracrine effects on osteoclasts in trabecular osteoblasts. Subchondral osteoblasts (OA) exhibited highest VEGF-A mRNA levels and release. Our data indicate that human osteoblasts in trabecular, subchondral and cortical bone have inherent, programmed diversity, with specific bone type-related differences in growth, differentiation and pro-angiogenic potential in vitro. PMID- 25738585 TI - Osteoblasts with impaired spreading capacity benefit from the positive charges of plasma polymerised allylamine. AB - Bone diseases such as osteoporosis, osteoarthritis and rheumatoid arthritis, impinge on the performance of orthopaedic implants by impairing bone regeneration. For this reason, the development of effective surface modifications supporting the ingrowth of implants in morbid bone tissue is essential. Our study is designed to elucidate if cells with restricted cell-function limiting adhesion processes benefit from plasma polymer deposition on titanium. We used the actin filament disrupting agent cytochalasin D (CD) as an experimental model for cells with impaired actin cytoskeleton. Indeed, the cell's capacity to adhere and spread was drastically reduced due to shortened actin filaments and vinculin contacts that were smaller. The coating of titanium with a positively charged nanolayer of plasma polymerised allylamine (PPAAm) abrogated these disadvantages in cell adhesion and the CD-treated osteoblasts were able to spread significantly. Interestingly, PPAAm increased spreading by causing enhanced vinculin number and contact length, but without significantly reorganising actin filaments. PPAAm with the monomer allylamine was deposited in a microwave-excited low-pressure plasma-processing reactor. Cell physiology was monitored by flow cytometry and confocal laser scanning microscopy, and the length and number of actin filaments was quantified by mathematical image processing. We showed that biomaterial surface modification with PPAAm could be beneficial even for osteoblasts with impaired cytoskeleton components. These insights into in vitro conditions may be used for the evaluation of future strategies to design implants for morbid bone tissue. PMID- 25738586 TI - Reductions of oxygen, carbon dioxide, and acetonitrile by the magnesium(II)/magnesium(I) couple in aqueous media: theoretical insights from a nano-sized water droplet. AB - Reductions of O2, CO2, and CH3CN by the half-reaction of the Mg(II)/Mg(I) couple (Mg(2+) + e(-) -> Mg(+*)) confined in a nanosized water droplet ([Mg(H2O)16](*+)) have been examined theoretically by means of density functional theory based molecular dynamics methods. The present works have revealed many intriguing aspects of the reaction dynamics of the water clusters within several picoseconds or even in subpicoseconds. The reduction of O2 requires an overall doublet spin state of the system. The reductions of CO2 and CH3CN are facilitated by their bending vibrations and the electron-transfer processes complete within 0.5 ps. For all reactions studied, the radical anions, i.e., O2(*-), CO2(*-), and CH3CN(* ), are initially formed on the cluster surface. O2(*-) and CO2(*-) can integrate into the clusters due to their high hydrophilicity. They are either solvated in the second solvation shell of Mg(2+) as a solvent-separated ion pair (ssip) or directly coordinated to Mg(2+) as a contact-ion pair (cip) having the (1)eta [MgO2](*+) and (1)eta-[MgOCO](*+) coordination modes. The (1)eta-[MgO2](*+) core is more crowded than the (1)eta-[MgOCO](*+) core. The reaction enthalpies of the formation of ssip and cip of [Mg(CO2)(H2O)16](*+) are -36 +/- 4 kJ mol(-1) and 30 +/- 9 kJ mol(-1), respectively, which were estimated based on the average temperature changes during the ion-molecule reaction between CO2 and [Mg(H2O)16](*+). The values for the formation of ssip and cip of [Mg(O2)(H2O)16](*+) are estimated to be -112 +/- 18 kJ mol(-1) and -128 +/- 28 kJ mol(-1), respectively. CH3CN(*-) undergoes protonation spontaneously to form the hydrophobic [CH3CN, H](*). Both CH3CN and [CH3CN, H](*) cannot efficiently penetrate into the clusters with activation barriers of 22 kJ mol(-1) and ~40 kJ mol(-1), respectively. These results provide fundamental insights into the solvation dynamics of the Mg(2+)/Mg(*+) couple on the molecular level. PMID- 25738587 TI - Is ultrasound a better target than clinical disease activity scores in rheumatoid arthritis with fibromyalgia? A case-control study. AB - OBJECTIVES: Our goal is to study the correlations among gray-scale seven-joint ultrasound score (GS-US7), power Doppler seven-joint ultrasound score (PD-US7), disease activity score-28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI) in patients with and without fibromyalgia (FM). METHODS: A matched case-control study included all patients consecutively seen in the Rheumatoid Arthritis (RA) Clinic. Participants were allocated into one of two groups: RA with FM and RA without FM. Ultrasound (US) and clinical scoring were blinded for the presence of FM. Medians and proportions were compared by Mann-Whitney's test and McNemar's test, respectively. Spearman's rank correlation coefficients (rs) were calculated among clinical and US scores and differences were tested by r-to-z transformation test. RESULTS: Seventy-two women were included, out of 247 RA patients, mostly white, with median (IQR) age of 57.5 (49.3-66.8) years, with RA symptoms for 13.0 (6.0-19.0) years and FM symptoms for 6.0 (2.0-15.0) years. Disease-modifying antirheumatic drugs, non steroidal anti-inflammatory drugs and prednisone use was comparable between groups. Objective activity parameters were not different between groups. RA patients with FM had greater DAS28, SDAI and CDAI but similar GS-US7 and PD-US7. GS-US7 correlated with DAS28, SDAI and CDAI in patients with and without FM (rs = 0.36-0.57), while PD-US7 correlated with clinical scores only in patients without FM (rs = 0.35-0.38). CONCLUSION: To our knowledge, this is the first study to demonstrate that ultrasound synovitis scores are not affected by FM in RA patients. PD-US7 performed better than GS-US7 in long-standing RA patients with DAS28, SDAI or CDAI allegedly overestimated due to FM. Since sonographic synovitis predicts erosion better than swollen joint count, C-reactive protein and erythrocyte sedimentation rate, US should be considered a promising treatment target in RA patients with FM. PMID- 25738588 TI - Temporal relationship between vitamin D status and parathyroid hormone in the United States. AB - BACKGROUND: Interpretation of parathyroid hormone (iPTH) requires knowledge of vitamin D status that is influenced by season. OBJECTIVE: Characterize the temporal relationship between 25-hydroxyvitamin D3 levels [25(OH)D3] and intact iPTH for several seasons, by gender and latitude in the U.S. and relate 25 hydrovitamin D2 [25(OH)D2] levels with PTH levels and total 25(OH)D levels. METHOD: We retrospectively determined population weekly-mean concentrations of unpaired [25(OH)D2 and 25(OH)D3] and iPTH using 3.8 million laboratory results of adults. The 25(OH)D3 and iPTH distributions were normalized and the means fit with a sinusoidal function for both gender and latitudes: North >40, Central 32 40 and South <32 degrees. We analyzed PTH and total 25(OH)D separately in samples with detectable 25(OH)D2 (>=4 ng/mL). FINDINGS: Seasonal variation was observed for all genders and latitudes. 25(OH)D3 peaks occurred in September and troughs in March. iPTH levels showed an inverted pattern of peaks and troughs relative to 25(OH)D3, with a delay of 4 weeks. Vitamin D deficiency and insufficiency was common (33% <20 ng/mL; 60% <30 ng/mL) as was elevated iPTH levels (33%>65 pg/mL). The percentage of patients deficient in 25(OH)D3 seasonally varied from 21% to 48% and the percentage with elevated iPTH reciprocally varied from 28% to 38%. Patients with detectable 25(OH)D2 had higher PTH levels and 57% of the samples with a total 25(OH)D > 50 ng/mL had detectable 25(OH)D2. INTERPRETATION: 25(OH)D3 and iPTH levels vary in a sinusoidal pattern throughout the year, even in vitamin D2 treated patients; 25(OH)D3, being higher in the summer and lower in the winter months, with iPTH showing the reverse pattern. A large percentage of the tested population showed vitamin D deficiency and secondary hyperparathyroidism. These observations held across three latitudinal regions, both genders, multiple-years, and in the presence or absence of detectable 25(OH)D2, and thus are applicable for patient care. PMID- 25738590 TI - Clomiphene citrate for treatment of acromegaly not controlled by conventional therapies. AB - CONTEXT: Oral estrogens, alone or in combination with somatostatin receptor ligands, have been shown to control acromegaly in women. Selective estrogen receptor modulators resulted in similar effects in both genders. Clomiphene citrate (CC), a selective estrogen receptor modulator that increases LH and FSH secretion, improves hypogonadism and fertility outcomes. OBJECTIVE: To assess the impact of CC on serum IGF-1 and T levels in male acromegalic patients not controlled by surgery, radiotherapy, and/or medical treatment. STUDY DESIGN: In this prospective, open-label, single-center trial, CC (50 mg/d) was added to previous medical treatment for 3 months. Hormonal assessment was performed before and during the intervention. PATIENTS: Sixteen male patients (median age, 52.8 y; range, 36-79 y) met the following criteria: IGF-1 above the upper limit of normal range for at least 1 year despite the use of available medical therapies, and T levels within or below the third inferior tertile of normality. RESULTS: Serum IGF-1 levels decreased by 41% (mean +/- SD, 424 +/- 108 to 250 +/- 83 ng/mL; P < .0004), leading 44% (seven of 16) of the patients to achieve normal IGF-1 levels. Total serum T levels increased by 209% (282 +/- 201 to 497 +/- 310 ng/dL), reaching normal levels in 67% (four of six) of those patients considered hypogonadal. CONCLUSIONS: Addition of CC should be considered an option in male acromegaly patients not controlled by current available options, with a considerable cost-saving benefit. Furthermore, improvement of T levels can be obtained in those patients with concurrent central hypogonadism. PMID- 25738589 TI - The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium. AB - AIMS: We recently published that the positive inotropic response (PIR) to levosimendan can be fully accounted for by phosphodiesterase (PDE) inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD), levosimendan and other PDE inhibitors. METHODS: Contractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors. RESULTS: OR-1896 evoked a maximum PIR of 33 +/- 10% above basal at 1 MUM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89 +/- 14%) and absent in the presence of the PDE3 inhibitors cilostamide (0.5 +/- 5.3%) or milrinone (3.2 +/- 4.4%). The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of beta AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to beta-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the alpha1-AR response. CONCLUSION: The observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic) effect of levosimendan, nor of its main metabolite OR-1896. PMID- 25738591 TI - Serum dehydroepiandrosterone sulphate concentration is not a predictive factor in IVF outcomes before the first cycle of GnRH agonist administration in women with normal ovarian reserve. AB - OBJECTIVE: The aim of our study was to determine whether serum dehydroepiandrosterone sulphate (DHEAS) concentration and the models incorporating it could help clinicians to predict IVF outcomes in women with normal ovarian reserve undergoing their first long protocol. STUDY DESIGN: We performed a retrospective analysis of 459 women undergoing cycles of intracytoplasmic sperm injection (ICSI) for the first time in a long GnRH agonist protocol. RESULTS: Embryo transfer was performed in 407 women (88.7%). The fertilisation rate was 78.6%. The clinical pregnancy rate was 44.8% per started cycle and 50.6% per embryo transfer. Our univariate model revealed that the best predictors of clinical pregnancy were the number of mature oocytes, the number of embryos transferred and the number of good quality embryos, account for the clinical parameters that reflect ovarian reserve the best being AMH level and AFC. DHEAS did not predict clinical pregnancy (OR 1.001, 95% CI, 0.999-1.004). After adjusting for the number of embryos transferred and class of embryos in a multivariate model, the best predictors were age (OR 0.918, 95% CI, 0.867-0.972) and AFC (OR 1.022, 95% CI, 0.992-1.053). Serum DHEAS levels were positively correlated with AFC (r = 0.098, P<0.039) and testosterone levels (r = 0.371, P<0.001), as well as the number of mature oocytes (r = 0.109, P<0.019); serum DHEAS levels were negatively correlated with age (r = -0.220, P<0.001), follicle stimulating hormone (FSH), (r = -0.116, P<0.015) and sex hormone-binding globulin (SHBG), (r = -0.193, P<0.001). CONCLUSIONS: DHEAS concentration (in addition to the known factors of ovarian reserve) does not predict clinical pregnancy in women with normal ovarian reserve who are undergoing ICSI. PMID- 25738592 TI - Persistence of a pKPN3-like CTX-M-15-encoding IncFIIK plasmid in a Klebsiella pneumonia ST17 host during two years of intestinal colonization. AB - OBJECTIVES: To characterize the CTX-M-15-encoding plasmid in a Klebsiella pneumoniae ST17 strain, responsible for an outbreak at a Norwegian neonatal intensive care unit and subsequent colonization of affected children for up to two years. To identify plasmid-mediated features relevant for the outbreak dynamics, and to investigate the plasmids capability of horizontal transfer, its segregational stability and plasmid-mediated fitness costs. METHODS: Plasmid profiling was performed by S1-nuclease PFGE, PCR-based replicon typing and Southern blot-hybridization. The complete sequence of the CTX-M-15-encoding plasmid was obtained by 454 sequencing. Plasmid self-transferability was investigated by broth- and filter mating, segregational stability was explored by serial passage, and plasmid-conferred fitness costs were examined in pairwise head-to-head competitions and by growth rate comparisons. RESULTS: CTX-M-15 was encoded by a ~180 kb IncFIIK plasmid in K. pneumoniae ST17. S1-nuclease PFGE profiles of the first and the last CTX-M-15-producing K. pneumoniae isolates, recovered from the four children colonized the longest, suggested that the plasmid was stably maintained during intestinal carriage of up to two years. The DNA sequence of the pKPN3-like plasmid, pKp848CTX, uncovered a Tn3-like antibiotic resistance region and multiple heavy metal- and thermoresistance determinants. Plasmid pKp848CTX could not be transferred to Escherichia coli in vitro and we found no evidence to support horizontal plasmid transfer in vivo. Segregational plasmid loss ranging from 0.83% to 17.5% was demonstrated in evolved populations in vitro, but only minor fitness costs were associated with plasmid-carriage. CONCLUSIONS: Plasmid pKp848CTX encodes phenotypic traits, which may have had an impact on the fitness and survival of the K. pneumoniae ST17 strain in the outbreak setting. The antibiotic resistance plasmid pKp848CTX was stably maintained during two years of intestinal colonization, conferring negligible fitness cost to its host, and thus seem well adapted to its K. pneumoniae host. PMID- 25738594 TI - Current response for a single redox moiety trapped in a closed generator collector system: the role of capacitive coupling. AB - A theoretical model is proposed to describe the steady-state average limiting current associated with a single redox moiety (ox or red) trapped in a closed generator-collector system along with excess supporting electrolyte. By "closed" we mean that neither solvent nor solutes can enter or leave the system. The potential difference, EOE - ERE, between the oxidizing electrode (OE) and the reducing electrode (RE) is maintained constant with the values of EOE and ERE chosen so that the operative faradaic electrode processes are very fast, i.e., red = ox + nETe(-) (kox = infinity) at the OE and ox + nETe(-) = red (kred = infinity) at the RE. Because there is only a single redox moiety the faradaic process occurs at only one electrode at a time while current at the other electrode is purely capacitive (we refer to this as capacitive coupling). We propose that a two-step process is required to transfer nETqe coulombs (qe is the absolute value of the elemental electronic charge). The first step is associated with diffusion (approximated as a random walk) of a single red moiety to the OE where it is oxidized to ox with a concomitant transfer of qstep1 (= nETqe/(1 + AOECOE/ARECRE)) coulombs; the second step is associated with the diffusion (random walk) of the newly formed single ox moiety to the RE with the concomitant transfer of qstep2 (= nETqe/(1 + ARECRE/AOECOE)) coulombs (ARE,AOE andCRE,COEare the areas (cm(2)) and differential capacitances (farads cm(-2)) of the corresponding electrodes). The total charge transferred in the two steps is nETqe(= qstep1 + qstep2). Transport of the redox moiety from one electrode to the other is accomplished by a random walk. The probability density function (pdf) and cumulative density function (CDF) for the duration of a full redox cycle are presented as the analytical solution to a 1-dimensional bounded random-walk problem (confirmed by numerical simulation). These show that tfull, the average time for the full redox cycle (step 1 + step 2), is equal to L(2)/D where L is the intraelectrode distance and D is the diffusion coefficient. The average steady-state limiting current is shown to be described by the familiar expression for a generator-collector system: ilim = (qstep1 + qstep2)/tfull = nETqe/tfull = nETqeD/L(2). PMID- 25738593 TI - Lack of pupil reflex and loss of consciousness predict 30-day neurological sequelae in patients with carbon monoxide poisoning. AB - BACKGROUND: Predicting the neurological sequelae of carbon monoxide poisoning (COP) has not been well studied. We investigated the independent predictors of neurological sequelae in patients with COP and combined these predictors to predict the prognosis. METHODS: This study was conducted at four hospitals in Shandong Province, China. Data were retrospectively collected from 258 patients with COP between November 1990 and October 2011. Thirty-day neurological sequelae were the primary endpoints. RESULTS: A lack of pupil reflex and a loss of consciousness appear to be independent predictors for neurological sequelae in patients with COP. The presence of either one had a sensitivity of 77.0% (95% confidence interval [CI]: 69.3-83.2), a specificity of 47.1% (95% CI: 38.3-56.0), positive predictive value (PPV) of 62.9% (95% CI: 55.2-70.1), and a negative predictive value (NPV) of 63.6% (95% CI: 52.6-73.4). With both predictors present, the sensitivity was 11.5% (95% CI: 6.9 to 18.3), the specificity was 99.2 (95% CI: 94.7-100.0), the PPV was 94.1% (95% CI: 69.2-99.7), and the NPV was 49.0% (95% CI: 42.5-55.5). CONCLUSIONS: The risk for neurological sequelae apparently increased with the number of independent predictors. In patients with both predictors, the risk for neurological sequelae was 94.1%. Almost all (99.2%) patients with neither predictor had no neurological sequelae. This finding may help physicians make decisions about and dispositions for patients with COP. For patients with a higher risk, earlier treatment and more appropriate utilization of health care services, including hyperbaric oxygen, should be considered. PMID- 25738595 TI - All-trans-retinoic acid inhibits chondrogenesis of rat embryo hindlimb bud mesenchymal cells by downregulating p53 expression. AB - Despite the well-established role of all-trans-retinoic acid (ATRA) in congenital clubfoot (CCF)-like deformities in in vivo models, the essential cellular and molecular targets and the signaling mechanisms for ATRA-induced CCF-like deformities remain to be elucidated. Recent studies have demonstrated that p53 and p21, expressed in the hindlimb bud mesenchyme, regulate cellular proliferation and differentiation, contributing to a significant proportion of embryonic CCF-like abnormalities. The objective of the present study was to investigate the mechanisms for ATRA-induced CCF, by assessing ATRA-regulated chondrogenesis in rat embryo hindlimb bud mesenchymal cells (rEHBMCs) in vitro. The experimental study was based on varying concentrations of ATRA exposure on embryonic day 12.5 rEHBMCs in vitro. The present study demonstrated that ATRA inhibited the proliferation of cells by stimulating apoptotic cell death of rEHBMCs. It was also observed that ATRA induced a dose-dependent reduction of cartilage nodules compared with the control group. Reverse transcription polymerase chain reaction and western blotting assays revealed that the mRNA and protein expression of cartilage-specific molecules, including aggrecan, Sox9 and collagen, type II, alpha 1 (Col2a1), were downregulated by ATRA in a dose dependent manner; the mRNA levels of p53 and p21 were dose-dependently upregulated from 16 to 20 h of incubation with ATRA, but dose-dependently downregulated from 24 to 48 h. Of note, p53 and p21 were regulated at the translational level in parallel with the transcription with rEHBMCs treated with ATRA. Furthermore, the immunofluorescent microscopy assays indicated that proteins of p53 and p21 were predominantly expressed in the cartilage nodules. The present study demonstrated that ATRA decreases the chondrogenesis of rEHBMCs by inhibiting cartilage-specific molecules, including aggrecan, Sox9 and Col2al, via regulating the expression of p53 and p21. PMID- 25738597 TI - The absence of the embryo in the pseudopregnant uterus alters the deposition of some ECM molecules during decidualization in mice. AB - The embryo-implantation promotes deep changes in the uterus resulting in the formation of a new structure at the maternal-fetal interface, the decidua. Decidualization can also be induced in pseudopregnant rodents resulting in a structure called deciduoma that is morphologically and functionally similar to the decidua. Previous studies from our and other laboratories demonstrate that in rodents, decidualization of the endometrium requires remarkable remodeling of the endometrial extracellular matrix (ECM) that is mainly coordinated by estradiol and progesterone. The influence of the embryo in this process, however, has not yet been investigated. To enlarge the knowledge on this subject, the present study investigates the behavior of a set of ECM molecules, in the absence of paracrine cues originated from the embryo. For that deciduoma was induced in pseudopregnant Swiss mice, and the distribution of collagen types I, III, IV, V and the proteoglycans decorin and biglycan was investigated by immunolabeling from the fifth to the eighth day of pseudopregnancy. It was observed the deposition of collagen types III and IV as well as decorin and biglycan was similar to that previously described by our group in the decidua. However, in the absence of the embryo, some differences occur in the distribution of collagen types I and V, suggesting that beside the major role of ovarian hormones on the endometrial ECM remodeling, molecular signals originated from the conceptus may influence this process. PMID- 25738596 TI - In utero and childhood polybrominated diphenyl ether exposures and body mass at age 7 years: the CHAMACOS study. AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are lipophilic flame retardants that bioaccumulate in humans. Child serum PBDE concentrations in California are among the highest worldwide. PBDEs may be associated with obesity by disrupting endocrine systems. OBJECTIVE: In this study, we examined whether pre- and postnatal exposure to the components of pentaBDE mixture was associated with childhood obesity in a population of Latino children participating in a longitudinal birth cohort study in the Salinas Valley, California. METHODS: We measured PBDEs in serum collected from 224 mothers during pregnancy and their children at 7 years of age, and examined associations with body mass index (BMI) at age 7 years. RESULTS: Maternal PBDE serum levels during pregnancy were associated with higher BMI z-scores in boys (BMI z-score betaadjusted = 0.26; 95% CI: -0.19, 0.72) but lower scores in girls (BMI z-score betaadjusted = -0.41; 95% CI: -0.87, -0.05) at 7 years of age (pinteraction = 0.04). In addition, child's serum BDE-153 concentration (log10), but not other pentaBDE congeners, demonstrated inverse associations with BMI at age 7 years (BMI z-score betaadjusted = -1.15; 95% CI: -1.53, -0.77), but there was no interaction by sex. CONCLUSIONS: We estimated sex-specific associations with maternal PBDE levels during pregnancy and BMI at 7 years of age, finding positive associations in boys and negative associations in girls. Children's serum BDE-153 concentrations were inversely associated with BMI at 7 years with no difference by sex. Future studies should examine the longitudinal trends in obesity with PBDE exposure and changes in hormonal environment as children transition through puberty, as well as evaluate the potential for reverse causality. PMID- 25738598 TI - Chondrocyte miRNAs 221 and 483-5p respond to loss of matrix interaction by modulating proliferation and matrix synthesis. AB - AIM: The purpose of this study was to identify the microRNAs that regulate the response of chondrocytes to loss of matrix interaction. MATERIALS AND METHODS: MicroRNA and gene expression was compared in bovine cartilage and isolated chondrocytes using array analysis. Those microRNAs showing more than three-fold change in expression were verified by quantitative PCR after a stem-loop reverse transcription in bovine and human cartilage, and chondrocytes. Their function was investigated using target gene reporter construct expression, quantification of cell proliferation, and analysis of gene expression and matrix synthesis after transfection with microRNA mimics. RESULTS: Only four microRNAs were confirmed to have a greater than three-fold change in expression after isolation of bovine or human chondrocytes from their extracellular matrix; miRs-221, -222 and -21 showed increased expression and miR-483-5p showed decreased expression. Transfection with a miR-221 mimic was shown to suppress expression of the cyclin-dependent kinase inhibitor p27 leading to the stimulation of chondrocyte proliferation. Transfection of chondrocytes with a miR-483-5p mimic was shown to suppress several members of the mitogen activated protein kinase (MAPK) pathway; a likely explanation of the increased matrix production observed. CONCLUSIONS: microRNAs 221 and 483-5p respond to the loss of chondrocyte matrix interaction by respectively stimulating proliferation by suppression of inhibitors of cell division and suppression of matrix production possibly by release of inhibition of the MAPK pathway. PMID- 25738599 TI - [4 + 2] cycloaddition of in situ generated 1,2-diaza-1,3-dienes with simple olefins: facile approaches to tetrahydropyridazines. AB - A catalyst-free [4 + 2] annulation process between in situ generated 1,2-diaza 1,3-butadienes and simple olefins has been developed. Under mild conditions, the reactions afforded 1,4,5,6-tetrahydropyridazines, which feature a wide range of bioactive compounds, with high yields (up to 99% yield). PMID- 25738601 TI - Correction: Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion. PMID- 25738600 TI - Overexpression of caudal type homeobox transcription factor 2 inhibits the growth of the MGC-803 human gastric cancer cell line in vivo. AB - Caudal type homeobox transcription factor 2 (CDX2) is important in intestinal cell fate specification and multiple lines of evidence have substantiated that CDX2 is important in carcinogenesis of the digestive tract. The CDX2 regulatory network is intricate and remains to be fully elucidated in gastric cancer. The aim of the present study was to examine the effects of CDX2 on the growth of the MGC-803 human gastric cancer cell line in vivo, and to elucidate the mechanism involved. The effects of the overexpression of CDX2 in xenograft tumors of MGC 803 cells was investigated in nude mice through the injection of CDX2 recombinant lentiviral vectors. The tumor size was measured using vernier callipers. The expression levels of CDX2, survivin, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cyclin D1, s-phase kinase-associated protein 2 (Skp2) and c-Myc in the tumor cells were analyzed by western blotting and semi-quantitative reverse transcription polymerase chain reaction. The apoptotic rates were determined using a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The overexpression of CDX2 was observed in the group subjected to the injection of CDX2 recombinant lentiviral vectors. CDX2 had an inhibitory effect on the MGC-803 human gastric cancer cell line and promoted tumor cell apoptosis in vivo. Furthermore, the overexpression of CDX2 upregulated the expression of Bax and downregulated the expression levels of survivin, Bcl-2, cyclin D1, Skp2 and c-Myc in the tumor tissues. These results indicated that CDX2 may serve as a tumor suppressor in gastric cancer, and inhibits gastric cancer cell growth by suppressing the nuclear factor-kappaB signaling pathway. PMID- 25738602 TI - Occupational Exposure to Airborne Nanomaterials: An Assessment of Worker Exposure to Aerosolized Metal Oxide Nanoparticles in Semiconductor Wastewater Treatment. AB - This study characterized potential inhalation exposures of workers to nanometal oxides associated with industrial wastewater treatment processes in a semiconductor research and development facility. Exposure assessment methodology was designed to capture aerosolized engineered nanomaterials associated with the chemical mechanical planarization wafer polishing process that were accessible for worker contact via inhalation in the on-site wastewater treatment facility. The research team conducted air sampling using a combination of filter-based capture methods for particle identification and characterization and real-time direct-reading instruments for semi-quantitation of particle number concentration. Filter-based samples were analyzed using electron microscopy and energy-dispersive x-ray spectroscopy while real-time particle counting data underwent statistical analysis. Sampling conducted over 14 months included 5 discrete sampling series events for 7 job tasks in coordination with on-site employees. The number of filter-based samples captured for analysis by electron microscopy was: 5 from personal breathing zone, 4 from task areas, and 3 from the background. Direct-reading instruments collected data for 5 sample collection periods in the task area and the background, and 2 extended background collection periods. Engineered nanomaterials of interest (Si, Al, Ce) were identified by electron microscopy in filter-based samples from all areas of collection, existing as agglomerates (>500 nm) and nanoparticles (100 nm-500 nm). Particle counts showed an increase in number concentration during and after selected tasks above background. While additional data is needed to support further statistical analysis and determine trends, this initial investigation suggests that nanoparticles used or generated by chemical mechanical planarization become aerosolized and may be accessible for inhalation exposures by workers in wastewater treatment facilities. Additional research is needed to further quantify the level of exposure and determine the potential human health impacts. PMID- 25738604 TI - Analysis of miRNAs Targeting 3'UTR of H2AFX Gene: a General in Silico Approach. AB - MiRNAs are gene (post-transcriptional) regulators that bind the 3'UTR of target genes. Single-nucleotide polymorphisms (SNPs) located within a miRNA binding site can impact miRNAdependent gene regulation by weakening or reinforcing the microRNA:mRNA bond. We present a general in silico approach enabling researchers to "predict" which of the several SNPs of 3'UTR of H2AFX gene can mainly affect its regulation. H2AFX gene encodes a member of the H2A histone family which is central in the detection of and response to DNA double-strand breaks. All the 17 common SNPs located within the 3'UTR of H2AFX gene were analyzed for putative miRNA-binding sites by using different databases (such as dbSNP and miRBase) and pre-existing algorithms (such as MicroSNiPer and RNAcofold) in order to calculate the minimum free energies of hybridization of the microRNA:mRNA duplex, for both the wild-type and mutant alleles. The difference in these energies was also calculated. Since in each tissue one target sequence can bind only one miRNA at a time, the sum of all the difference of energies can be considered a relevant parameter for predicting the importance of a SNP with respect to miRNA regulation. We used tertiles to classify the SNPs and provide a priority list based on their theoretically strongest impact on miRNA binding. By using the described approach, we provided the basis for a reasoned, user-friendly algorithm driven selection of SNPs impacting miRNA biology. The proposed method is helpful for selecting SNPs having a more powerful (putative) biological function, minimizing workflow and costs for experimental and clinical investigations. PMID- 25738603 TI - How does anodal transcranial direct current stimulation of the pain neuromatrix affect brain excitability and pain perception? A randomised, double-blind, sham control study. AB - BACKGROUND: Integration of information between multiple cortical regions of the pain neuromatrix is thought to underpin pain modulation. Although altered processing in the primary motor (M1) and sensory (S1) cortices is implicated in separate studies, the simultaneous changes in and the relationship between these regions are unknown yet. The primary aim was to assess the effects of anodal transcranial direct current stimulation (a-tDCS) over superficial regions of the pain neuromatrix on M1 and S1 excitability. The secondary aim was to investigate how M1 and S1 excitability changes affect sensory (STh) and pain thresholds (PTh). METHODS: Twelve healthy participants received 20 min a-tDCS under five different conditions including a-tDCS of M1, a-tDCS of S1, a-tDCS of DLPFC, sham a-tDCS, and no-tDCS. Excitability of dominant M1 and S1 were measured before, immediately, and 30 minutes after intervention respectively. Moreover, STh and PTh to peripheral electrical and mechanical stimulation were evaluated. All outcome measures were assessed at three time-points of measurement by a blind rater. RESULTS: A-tDCS of M1 and dorsolateral prefrontal cortex (DLPFC) significantly increased brain excitability in M1 (p < 0.05) for at least 30 min. Following application of a-tDCS over the S1, the amplitude of the N20-P25 component of SEPs increased immediately after the stimulation (p < 0.05), whilst M1 stimulation decreased it. Compared to baseline values, significant STh and PTh increase was observed after a-tDCS of all three stimulated areas. Except in M1 stimulation, there was significant PTh difference between a-tDCS and sham tDCS. CONCLUSION: a-tDCS of M1 is the best spots to enhance brain excitability than a tDCS of S1 and DLPFC. Surprisingly, a-tDCS of M1 and S1 has diverse effects on S1 and M1 excitability. A-tDCS of M1, S1, and DLPFC increased STh and PTh levels. Given the placebo effects of a-tDCS of M1 in pain perception, our results should be interpreted with caution, particularly with respect to the behavioural aspects of pain modulation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials, ACTRN12614000817640, http://www.anzctr.org.au/. PMID- 25738605 TI - Optimized codon usage enhances the expression and immunogenicity of DNA vaccine encoding Taenia solium oncosphere TSOL18 gene. AB - Cysticercosis due to larval cysts of Taenia solium, is a serious public health problem affecting humans in numerous regions worldwide. The oncospheral stage specific TSOL18 antigen is a promising candidate for an anti-cysticercosis vaccine. It has been reported that the immunogenicity of the DNA vaccine may be enhanced through codon optimization of candidate genes. The aim of the present study was to further increase the efficacy of the cysticercosis DNA vaccine; therefore, a codon optimized recombinant expression plasmid pVAX1/TSOL18 was developed in order to enhance expression and immunogenicity of TSOL18. The gene encoding TSOL18 of Taenia solium was optimized, and the resulting opt-TSOL18 gene was amplified and expressed. The results of the present study showed that the codon-optimized TSOL18 gene was successfully expressed in CHO-K1 cells, and immunized mice vaccinated with opt-TSOL18 recombinant expression plasmids demonstrated opt-TSOL18 expression in muscle fibers, as determined by immunohistochemistry. In addition, the codon-optimized TSOL18 gene produced a significantly greater effect compared with that of TSOL18 and active spleen cells were markedly stimulated in vaccinated mice. 3H-thymidine incorporation was significantly greater in the opt-TSOL18 group compared with that of the TSOL18, pVAX and blank control groups (P<0.01). In conclusion, the eukaryotic expression vector containing the codon-optimized TSOL18 gene was successfully constructed and was confirmed to be expressed in vivo and in vitro. The expression and immunogenicity of the codon-optimized TSOL18 gene were markedly greater compared with that of the un-optimized gene. Therefore, these results may provide the basis for an optimized TSOL18 gene vaccine against cysticercosis. PMID- 25738606 TI - Short Communication: Low Expression of Activation and Inhibitory Molecules on NK Cells and CD4(+) T Cells Is Associated with Viral Control. AB - Chronic HIV-1 infection induces severe immune alterations, including hyperactivation, exhaustion, and apoptosis. In fact, viral control has been associated with low frequencies of these processes. Here, we evaluated the expression of activation and inhibitory molecules on natural killer (NK) and CD4(+) T cells and plasma levels of proinflammatory cytokines in individuals exhibiting viral control: a cohort of HIV-1-exposed-seronegative individuals (HESN) and a cohort of HIV controllers. There was lower expression of CD69, LAG 3, PD-1, and TIM-3 in both cohorts when compared to a low-risk population or HIV progressors. In addition, HIV controllers exhibited lower plasma levels of proinflamatory molecules TNF-alpha and IP-10. These findings suggest that individuals exhibiting viral control have lower basal expression of markers associated with cellular activation and particularly immune exhaustion. PMID- 25738607 TI - Reciprocal interaction of Wnt and RXR-alpha pathways in hepatocyte development and hepatocellular carcinoma. AB - Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal development. We found a major shift in expression of Wnt and RXR-alpha pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-alpha gene signature categorized HCCs into two subtypes (high Wnt, low RXR-alpha and low Wnt, high RXR alpha), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-alpha levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-alpha achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR alpha, in part via Wnt signaling, plays a key functional role in the hepatocyte like subtype and potentially could serve as a selective therapeutic target. PMID- 25738610 TI - Beyond the line - military and veteran health research. PMID- 25738609 TI - Hierarchical porous carbon materials with high capacitance derived from Schiff base networks. AB - A type of hierarchical porous carbon material was prepared using a Schiff-base network as the precursor and ZnCl2 as the activation agent, and their electrochemical performances were investigated in acid and alkaline aqueous solutions, respectively. The as-prepared materials have high surface areas, appropriate distributions of hierarchical pore sizes, and various forms of nitrogen/oxygen derivatives. These structural advantages guarantee the outstanding performances of such carbon materials as electrodes for supercapacitors, which include high specific capacitances, fast current responses, and high cycling stabilities. PMID- 25738608 TI - Diminished reovirus capsid stability alters disease pathogenesis and littermate transmission. AB - Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral sigma3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing sigma3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, sigma3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing sigma3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with sigma3 Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses. PMID- 25738611 TI - TGFbeta1 genetic variants are associated with an increased risk of acute brucellosis. AB - OBJECTIVE: Cytokines play a critical role in the regulation of the immune response against brucellosis infection, and mediate production of many pro- and anti-inflammatory signals. Transforming growth factor-beta 1 (TGFbeta1), a powerful suppressive cytokine, inhibits macrophage activation and modulates T cell function, and plays crucial roles in regulation of microbial replication and host responses to brucella. METHODS: The association of three polymorphisms in the TGFbeta1 gene (-509 C/T [rs1800469], + 868 C/T [rs1800470], and + 913 G/C [rs1800471]) in promoter, codons 10 and 25, respectively, with brucellosis infection was evaluated. This case-control study was performed on a total of 281 Iranian subjects including 153 patients with active brucellosis and 128 age- and sex-matched healthy individuals as controls. Genotyping for the TGFbeta1 -509 C/T and + 868 C/T variants was performed using tetra amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). Also, the + 913 G/C polymorphism was genotyped using an allele-specific PCR. RESULTS: The results demonstrated that the TGFbeta1 + 868 C/T mutant homozygote genotype (TT vs CC), was a risk factor for developing brucellosis in the co-dominant and recessive models (odds ratio (OR) = 2.60, p = 0.023; OR = 2.602, p = 0.014, respectively). Additionally, the diplotype analyses revealed that TGFbeta1 codon 10 and 25 diplotype, TT/GG, was associated with an increased risk of brucellosis (OR = 2.49, p = 0.038). Other TGFbeta1 variants did not increase the risk of brucellosis infection. CONCLUSIONS: Our findings propose that TGFbeta1 + 868 TT genotype and TT/GG diplotype may confer increased risk of brucellosis in the examined population. PMID- 25738612 TI - Screening for diabetes mellitus in tuberculosis patients in a referral center in Iran. AB - BACKGROUND: A significant link between diabetes mellitus (DM) and tuberculosis (TB) has been widely demonstrated. DM increases the risk of TB in all aspects. The aims of this study were to assess the prevalence of DM among newly diagnosed TB patients, to screen these patients for DM, and to determine the number needed to screen (NNS) to diagnose new cases of DM. METHODS: A prospective cohort descriptive study was carried out in Iranian adults admitted to the National Research Institute of Tuberculosis and Lung Disease from 2012 to 2013 with a new diagnosis of TB. Glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) were measured for all patients. RESULTS: Of the 293 patients included, 101 (34.5%) had DM. DM was newly diagnosed in 45 (19%) patients. The number needed to screen was 5 to identify one new DM case. Age >= 40 years was associated with DM in this population (odds ratio (OR) = 3.91, 95% confidence interval (CI) = 1.47-10.38). CONCLUSION: Screening for DM should be performed routinely in patients with TB and may improve treatment outcomes. PMID- 25738613 TI - Long-term neuropsychiatric consequences of aseptic meningitis in adult patients. AB - Aseptic meningitis is considered a benign and self-limiting clinical condition. In contrast to viral encephalitis and bacterial meningitis, the prognosis is usually good. The existing literature is scarce on the potential long-term neuropsychiatric consequences of aseptic meningitis. Previous studies have primarily been retrospective and differences in methodologies make it difficult to draw conclusions regarding the prevalence and nature of neuropsychiatric manifestations. However, studies have reported decreased psychomotor speed and impaired executive and visuo-constructive functions following aseptic meningitis. Larger controlled prospective studies are urgently needed to elucidate the neuropsychiatric complications of aseptic meningitis. PMID- 25738614 TI - Using serum alpha-fetoprotein for prognostic prediction in patients with hepatocellular carcinoma: what is the most optimal cutoff? AB - BACKGROUND AND AIMS: The prognostic ability of alpha-fetoprotein (AFP) for patients with hepatocellular carcinoma (HCC) was examined by using different cutoff values. The optimal AFP cutoff level is still unclear. METHODS: A total of 2579 HCC patients were consecutively enrolled in Taiwan, where hepatitis B is the major etiology of chronic liver disease. Four frequently used AFP cutoff levels, 20, 200, 400, 1000 ng/mL, were investigated. One-to-one matched pairs between patients having AFP higher and lower than the cutoffs were selected by using the propensity model. The adjusted hazard ratios of survival difference were calculated with Cox proportional hazards model. RESULTS: Patients with a higher AFP level were associated with more severe cirrhosis, more frequent vascular invasion, higher tumor burden and poorer performance status (all p<0.0001). In the propensity model, 4 groups of paired patients were selected, and there was no difference found in the comparison of baseline characteristics (all p>0.05). Patients with AFP <20 ng/mL had significantly better long-term survival than patients with AFP ?20 ng/mL (p<0.0001), and patients with AFP <400 ng/mL had significantly better overall outcome than patients with AFP ?400 ng/mL (p = 0.0186). There was no difference of long-term survival between patients divided by AFP levels of 200 and 1000 ng/mL. The adjusted hazard ratios of AFP ?20 ng/mL and AFP ?400 ng/mL were 1.545 and 1.471 (95% confidence interval: 1.3-1.838 and 1.178-1.837), respectively. CONCLUSIONS: This study shows the independently predictive ability of baseline serum AFP level in HCC patients. AFP levels of 20 and 400 ng/mL are considered feasible cutoffs to predict long-term outcome in unselected HCC patients. PMID- 25738615 TI - Interactions between Hofmeister anions and the binding pocket of a protein. AB - This paper uses the binding pocket of human carbonic anhydrase II (HCAII, EC 4.2.1.1) as a tool to examine the properties of Hofmeister anions that determine (i) where, and how strongly, they associate with concavities on the surfaces of proteins and (ii) how, upon binding, they alter the structure of water within those concavities. Results from X-ray crystallography and isothermal titration calorimetry show that most anions associate with the binding pocket of HCAII by forming inner-sphere ion pairs with the Zn(2+) cofactor. In these ion pairs, the free energy of anion-Zn(2+) association is inversely proportional to the free energetic cost of anion dehydration; this relationship is consistent with the mechanism of ion pair formation suggested by the "law of matching water affinities". Iodide and bromide anions also associate with a hydrophobic declivity in the wall of the binding pocket. Molecular dynamics simulations suggest that anions, upon associating with Zn(2+), trigger rearrangements of water that extend up to 8 A away from their surfaces. These findings expand the range of interactions previously thought to occur between ions and proteins by suggesting that (i) weakly hydrated anions can bind complementarily shaped hydrophobic declivities, and that (ii) ion-induced rearrangements of water within protein concavities can (in contrast with similar rearrangements in bulk water) extend well beyond the first hydration shells of the ions that trigger them. This study paints a picture of Hofmeister anions as a set of structurally varied ligands that differ in size, shape, and affinity for water and, thus, in their ability to bind to-and to alter the charge and hydration structure of-polar, nonpolar, and topographically complex concavities on the surfaces of proteins. PMID- 25738616 TI - Exploring the important role of nanocrystals orientation in TiO2 superstructure on photocatalytic performances. AB - Efficient charge separation has been widely accepted as one of the important factors responsible for the photocatalytic water splitting, organic oxidation, and solar cell, etc. TiO2 mesocrystal is a superstructure which could largely enhance charge separation, where TiO2 nanocrystals with parallel crystallographic alignment assemble in a form of oriented aggregation. Here, the intercrystal misorientation in TiO2 superstructure was first concerned and evaluated on the influence of photocatalytic efficiency. Our results showed that the intercrystal misorientation in TiO2 superstructures had a harmful effect on the charge separation efficiency. PMID- 25738617 TI - (18)F-Fluorothymidine PET-CT for resected malignant gliomas before radiotherapy: tumor extent according to proliferative activity compared with MRI. AB - OBJECTIVE: To compare the presence of post-operative residual disease by magnetic resonance imaging (MRI) and [18F]fluorothymidine (FLT)-positron emission tomography (PET)-computer tomography (CT) in patients with malignant glioma and to estimate the impact of 18F-FLT PET on the delineation of post-operative target volumes for radiotherapy (RT) planning. METHODS: Nineteen patients with post operative residual malignant gliomas were enrolled in this study. For each patient, 18F- FLT PET-CT and MRI were acquired in the same week, within 4 weeks after surgery but before the initiation of RT. The PET-CT and MRI data were co registered based on mutual information. The residual tumor volume defined on the 18F-FLT PET (Vol-PET) was compared with that of gadolinium [Gd] enhancement on T1 weighted MRI (Vol-T1) and areas of hyperintensity on T2-weighted MRI (Vol-T2). RESULTS: The mean Vol-PET (14.61 cm3) and Vol-T1 (13.60 cm3) were comparable and smaller than the mean Vol-T2 (32.93 cm3). The regions of 18F-FLT uptake exceeded the contrast enhancement and the hyperintense area on the MRI in 14 (73.68%) and 8 patients (42.11%), respectively. In 5 (26.32%) of the 19 patients, Vol-PET extended beyond 25 mm from the margin of Vol-T1; in 2 (10.53%) patients, Vol-PET extended 20 mm from the margin of Vol-T2. Vol-PET was detected up to 35 mm away from the edge of Vol-T1 and 24 mm away from the edge of Vol-T2. In 16 (84.21%) of the 19 patients, the Vol-T1 extended beyond the Vol-PET. In all of the patients, at least some of the Vol-T2 was located outside of the Vol-PET. CONCLUSIONS: The volumes of post-operative residual tumor in patients with malignant glioma defined by 18F-FLT uptake on PET are not always consistent with the abnormalities shown on post-operative MRI. Incorporation of 18F-FLT-PET in tumor delineation may have the potential to improve the definition of target volume in post operative radiotherapy. PMID- 25738618 TI - Reliability concepts and methods: special focus section. PMID- 25738619 TI - Evaluation of dynamic weight bearing for measuring nonevoked inflammatory hyperalgesia in mice. AB - BACKGROUND: Animal models in pain research have suggested that inclusion of both evoked and nonevoked behavioral measures is needed to better reflect the human pain experience. Individuals with chronic pain are known to experience spontaneous pain, in addition to pain after exposure to an external stimulus. Recently, the dynamic weight bearing (DWB) apparatus was developed to assess for nonevoked hyperalgesia by capturing weight bearing and surface distribution in the paws of mice after acute inflammation. OBJECTIVES: The aim of this study was to evaluate the DWB test as a measure of nonevoked hyperalgesia. METHODS: The experimental group received an intraplantar injection in the left hind paw of the inflammatory agent--complete Freund's adjuvant (CFA)--whereas the vehicle control group received a saline injection and the naive control group had no treatment. Calipers and a plethysmometer were used to verify inflammation and the hot-plate test was used as a measure for stimulus-evoked hyperalgesia. Data were collected at baseline; 3 hours; and 1, 3, and 7 days after injection. RESULTS: Mice injected with CFA showed a statistically significant higher mean paw thickness and volume displacement compared with the vehicle and naive control groups. In the hot-plate testing, CFA-treated mice showed lower response temperature at 7 days compared with the other groups. On the DWB test, CFA-treated mice showed a reduction in the ipsilateral paw load and surface area compared with the contralateral paw load at Days 1, 3, and 7. DISCUSSION: Mice with inflammation showed alterations in weight bearing as well as increased thermal hyperalgesia in comparison with control groups. These findings support the use of the DWB test as a tool for measuring nonevoked inflammatory hyperalgesia in a mouse model. PMID- 25738620 TI - Barthel Index of activities of daily living: item response theory analysis of ratings for long-term care residents. AB - BACKGROUND: The Barthel Index (BI) is a frequently used measure of independence in the activities of daily living (ADLs). Item functioning of various versions of the BI have been examined using Rasch analysis. Item response theory (IRT) models for ordered polytomous responses may provide more insight into item functioning across levels of independence in ADLs. OBJECTIVES: To compare the fit and appropriateness of the one-parameter logistic model (1PL), the partial credit model (PCM), and the extension of the generalized partial credit model implemented in ConQuest (GPCM-CQ) for the 15-item BI. METHODS: This article is a secondary analysis of baseline BI data obtained from four randomized controlled trials for 788 residents from multiple long-term care facilities. Parameters of three different IRT-based models (1PL Rasch model, PCM, and GPCM-CQ) were estimated. Fit of items and response vectors was assessed. Overall fit was compared across the three models. RESULTS: Item difficulties were similar for all three models. Most of the 15 items were located at a moderate level of functional independence. In all three models, "don brace" was the easiest ADL but had poor discrimination; "climbing stairs" was the most difficult ADL. Multiple items showed misfit in both 1PL and PCM. Item parameters and person proficiency estimates were highly correlated for the PCM and GPCM-CQ models. The difference in deviance between the PCM and GPCM-CQ was significant. In the GPCM-CQ, most items showed good discrimination, but several had negative or very low discrimination parameters. DISCUSSION: GPCM-CQ results suggested that further revision of the BI may be warranted. Because some items showed poor discrimination, caution should be used when measuring ADL independence with the BI item set. PMID- 25738621 TI - Multilevel drivers of human immunodeficiency virus/acquired immune deficiency syndrome among Black Philadelphians: exploration using community ethnography and geographic information systems. AB - BACKGROUND: Unequal human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) distribution is influenced by certain social and structural contexts that facilitate HIV transmission and concentrate HIV in disease epicenters. Thus, one of the first steps in designing effective community-level HIV/AIDS initiatives is to disentangle the influence of individual, social, and structural factors on HIV risk. Combining ethnographic methodology with geographic information systems mapping can allow for a complex exploration of multilevel factors within communities that facilitate HIV transmission in highly affected areas. OBJECTIVES: We present the formative comparative community-based case study findings of an investigation of individual-, social-, and structural level factors that contribute to the HIV/AIDS epidemic among Black Philadelphians. METHODS: Communities were defined using census tracts. The methodology included ethnographic and geographic information systems mapping, observation, informal conversations with residents and business owners, and secondary analyses of census tract-level data in four Philadelphia neighborhoods. RESULTS: Factors such as overcrowding, disadvantage, permeability in community boundaries, and availability and accessibility of health-related resources varied significantly. Furthermore, HIV/AIDS trended with social and structural inequities above and beyond the community's racial composition. DISCUSSION: This study was a first step to disentangle relationships between community-level factors and potential risk for HIV in an HIV epicenter. The findings also highlight stark sociodemographic differences within and across racial groups and further substantiate the need for comprehensive, community-level HIV prevention interventions. These findings from targeted U.S. urban communities have potential applicability for examining the distribution of HIV/AIDS in broader national and international geosocial contexts. PMID- 25738622 TI - Diabetes self-management: using the Colored Eco-Genetic Relationship Map to assess social support. AB - BACKGROUND: The positive association between individual social support and diabetes health outcomes is well established. However, most tools for assessing social support are highly structured and are rarely used in clinical settings and/or clinical outcomes research. A novel tool that has been shown to engage patients in the identification and use of their social networks is the Colored Eco-Genetic Relationship Map (CEGRM). OBJECTIVE: The purpose of this pilot study was to explore the feasibility of using the CEGRM adapted for eliciting information about how individuals with diabetes use their social networks to support their self-management efforts. METHODS: A sample of 18 adult patients with diabetes completed the newly created diabetes-CEGRM (D-CEGRM) alongside structured questions regarding social support for diabetes self-management. RESULTS: Whereas structured questions elicited information about participants' use of social networks, the D-CEGRM expanded on answers from structured questions by identifying both positive and negative aspects of social support, additional individual and community-based resources, and nuanced interpersonal information about the individuals involved. DISCUSSION: The D-CEGRM appears to be feasible and useful in assessing the social networks of adults with diabetes and how they are used to support tasks related to self-management. The information elicited by completing the D-CEGRM expanded on information collected through structured questions about social support in a way that might better address research questions and inform clinical decision making. PMID- 25738623 TI - Prenatal care in Oregon and Washington: policy and utilization for vulnerable women. AB - BACKGROUND: In the prenatal period, women can have sustained contact with nurses and other clinicians, forming relationships that are likely to be health enhancing for both the woman and her unborn child. Yet, first trimester care use in Oregon dropped noticeably over the past decade. In comparison with Washington state, Oregon has not shown substantial recovery. OBJECTIVE: The aim of this study was to explore potential reasons for the declining prenatal trend in Oregon. METHODS: We collated county-level birth data from all Oregon and Washington counties from 2000 to 2010. A descriptive, observational, time-series regression analysis for both states assessed the influence of maternal determinants known to impact first trimester care utilization. RESULTS: In Oregon, two factors were significantly associated with declining first trimester care: Medicaid funding (p<.01) and maternal Hispanic ethnicity (p=.02). In Washington, there was no significant association between any assessed determinant and first trimester care. DISCUSSION: In Oregon, over the period of our study, women dependent on Medicaid and women of Hispanic origin were less likely to utilize first trimester care. A similar trend for these variables was not observed in Washington. At the time of our study, both states had different policy approaches, which may explain some of the observable patterns. Amid current healthcare reforms and rising immigration, our findings suggest the need for strong advocacy for those less able to access or utilize care. PMID- 25738624 TI - Conceptions of reliability revisited and practical recommendations. AB - We discuss reliability definitions from the perspectives of classical test theory, factor analysis, and generalizability theory. For each method, we discuss the rationale, the estimation of reliability, and the goodness of fit of the model that defines the reliability coefficient to the data. Similarities and differences in the three approaches are highlighted. Finally, we provide a computational example using generated data to illustrate the differences among the different reliability methods. PMID- 25738625 TI - Response to Sijtsma and van der Ark (2015): "Conceptions of reliability revisited and practical recommendations". AB - Sijtsma and van der Ark present a broad set of models and methods for reliability estimation, and their discussion of similarities and differences provides clear information for nurse researchers to move forward in their instrument development projects. In particular, we applaud the authors' clear exposition of the factor analytic model and its utility for providing a framework for unifying reliability and validity. However, we do not want to be constrained only to the point estimates. We also need to ascertain the uncertainty in the point estimate usually in the form of a 95% confidence interval-or, as the Bayesians refer to, a credible interval. Another issue not discussed by Sijtsma and van der Ark is conditional standard errors of measurement along the score scale measuring latent traits or true scores. In our response, practical tools for estimating intervals and a brief discussion of conditional standard errors of measurement are presented. PMID- 25738626 TI - The problem with Cronbach's Alpha: comment on Sijtsma and van der Ark (2015). AB - Knowledge of a scale's dimensionality is an essential preliminary step to the application of any measure of reliability derived from classical test theory--an approach commonly used is nursing research. The focus of this article is on the applied aspects of reliability and dimensionality testing. Throughout the article, the Self-Care of Heart Failure Index is used to exemplify real-world data challenges of quantifying reliability and to provide insight into how to overcome such challenges. PMID- 25738627 TI - Further discussion on reliability: the art of reliability estimation. AB - Sijtsma and van der Ark (2015) focused in their lead article on three frameworks for reliability estimation in nursing research: classical test theory (CTT), factor analysis (FA), and generalizability theory. We extend their presentation with particular attention to CTT and FA methods. We first consider the potential of yielding an overly negative or an overly positive assessment of reliability based on coefficient alpha. Next, we discuss other CTT methods for estimating reliability and how the choice of methods affects the interpretation of the reliability coefficient. Finally, we describe FA methods, which not only permit an understanding of a measure's underlying structure but also yield a variety of reliability coefficients with different interpretations. On a more general note, we discourage reporting reliability as a two-choice outcome--unsatisfactory or satisfactory; rather, we recommend that nursing researchers make a conceptual and empirical argument about when a measure might be more or less reliable, depending on its use. PMID- 25738628 TI - The many issues in reliability research: choosing from a horn of plenty. AB - We respond to three commentaries on our discussion article on different conceptions of test score reliability. First, we discuss the use of standard errors for reliability estimates. Second, we discuss the desirability not to confuse issues pertaining to the dimensionality of the test data (closely related to construct validity) and the degree to which measurement values are repeatable under the same circumstances (i.e., the reliability issue). Third, we discuss a new reliability estimation method that is almost unbiased irrespective of the dimensionality of the test data. PMID- 25738630 TI - Accurate calculation of (31)P NMR chemical shifts in polyoxometalates. AB - We search for the best density functional theory strategy for the determination of (31)P nuclear magnetic resonance (NMR) chemical shifts, delta((31)P), in polyoxometalates. Among the variables governing the quality of the quantum modelling, we tackle herein the influence of the functional and the basis set. The spin-orbit and solvent effects were routinely included. To do so we analysed the family of structures alpha-[P2W18-xMxO62](n-) with M = Mo(VI), V(V) or Nb(V); [P2W17O62(M'R)](n-) with M' = Sn(IV), Ge(IV) and Ru(II) and [PW12-xMxO40](n-) with M = Pd(IV), Nb(V) and Ti(IV). The main results suggest that, to date, the best procedure for the accurate calculation of delta((31)P) in polyoxometalates is the combination of TZP/PBE//TZ2P/OPBE (for NMR//optimization step). The hybrid functionals (PBE0, B3LYP) tested herein were applied to the NMR step, besides being more CPU-consuming, do not outperform pure GGA functionals. Although previous studies on (183)W NMR suggested that the use of very large basis sets like QZ4P were needed for geometry optimization, the present results indicate that TZ2P suffices if the functional is optimal. Moreover, scaling corrections were applied to the results providing low mean absolute errors below 1 ppm for delta((31)P), which is a step forward in order to confirm or predict chemical shifts in polyoxometalates. Finally, via a simplified molecular model, we establish how the small variations in delta((31)P) arise from energy changes in the occupied and virtual orbitals of the PO4 group. PMID- 25738631 TI - Chemical composition, antioxidant and antimicrobial activity of the essential oil from the leaves of Macleaya cordata (Willd) R. Br. AB - The essential oil from the leaves of Macleaya cordata R.Br. obtained by hydrodistillation was analysed by gas chromatography/mass spectrometry. Sixty eight compounds consisting of up to 92.53% of the essential oil were identified. Antioxidant activities of the essential oil were evaluated by using DPPH radical scavenging and beta-carotene-linoleic acid assays. The essential oil showed moderate antioxidant activity. In addition, the essential oil exhibited potential antimicrobial activity against all tested microorganisms, with diameters of inhibition zones ranging from 8.7 +/- 0.5 to 17.2 +/- 1.2 mm and minimum inhibitory concentration values from 125 to 500 MUg/mL. We selected the most sensitive bacterium Staphylococcus aureus as model to observe of the action of essential oils of M. cordata on the membrane structure by scanning electron microscopy. The treated cell membranes were damaged severely. The results presented here indicate that the essential oil of M. cordata may be potential sources of antioxidant and antimicrobial agents in the future. PMID- 25738632 TI - Evaluation of clinical measurements and development of new diagnostic criteria for Takayasu arteritis in a Chinese population. AB - OBJECTIVES: Takayasu arteritis (TA) is a chronic granulomatous large-vessel vasculitis. When diagnosing TA, the criteria designed by the American College of Rheumatology (ACR) are used commonly but they were just classification criteria. There is an urgent need for a new set of diagnostic criteria. METHODS: One hundred and thirty-one TA patients and 132 control patients with other types of vascular disease were enrolled and both groups were distributed into a "training set" and a "validation set". All general information as well as clinical, laboratory and imaging data were collected. After comparing all the medical records of two groups in the training set, logistic regression and clinical judgment were used to form the new criteria for TA. The new criteria were tested by the validation set. RESULTS: New TA diagnostic criteria within total score 26 include age (<40 years), female, chest pain/chest distress, amaurosis, vascular bruits, a decreased/absent pulse, involvement of the aortic arch or its major branches, and involvement of the abdominal aorta or its branches. Patients with a score >= 8 were diagnosed as TA. The sensitivity and specificity of our new criteria were 91.92% and 93.94%, respectively, higher than those of the ACR criteria (75.76%, 85.86%) and the Ishikawa criteria (56.57%, 94.95%). The areas under the ROC curves of the new criteria and ACR criteria were 0.981 and 0.868, respectively (p<0.001). Sensitivity and specificity tested in the validation set were 90.63% and 96.97%, respectively. CONCLUSIONS: The new diagnostic criteria exhibited high sensitivity and specificity and have demonstrated to be feasible in the diagnosis of TA. PMID- 25738634 TI - Correction to "Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators". PMID- 25738633 TI - Emotional noun processing: an ERP study with rapid serial visual presentation. AB - Reading is an important part of our daily life, and rapid responses to emotional words have received a great deal of research interest. Our study employed rapid serial visual presentation to detect the time course of emotional noun processing using event-related potentials. We performed a dual-task experiment, where subjects were required to judge whether a given number was odd or even, and the category into which each emotional noun fit. In terms of P1, we found that there was no negativity bias for emotional nouns. However, emotional nouns elicited larger amplitudes in the N170 component in the left hemisphere than did neutral nouns. This finding indicated that in later processing stages, emotional words can be discriminated from neutral words. Furthermore, positive, negative, and neutral words were different from each other in the late positive complex, indicating that in the third stage, even different emotions can be discerned. Thus, our results indicate that in a three-stage model the latter two stages are more stable and universal. PMID- 25738635 TI - Exogenous hydrogen sulfide exerts proliferation/anti apoptosis/angiogenesis/migration effects via amplifying the activation of NF kappaB pathway in PLC/PRF/5 hepatoma cells. AB - Hydrogen sulfide (H2S) takes part in a diverse range of intracellular pathways and hss physical and pathological properties in vitro and in vivo. However, the effects of H2S on cancer are controversial and remain unclear. The present study investigates the effects of H2S on liver cancer progression via activating NF kappaB pathway in PLC/PRF/5 hepatoma cells. PLC/PRF/5 hepatoma cells were pretreated with 500 umol/l NaHS (a donor of H2S) for 24 h. The expression levels of CSE, CBS, phosphosphorylate (p)-NF-kappaB p65, caspase-3, COX-2, p-IkappaB and MMP-2 were measured by western blot assay. Cell viability was detected by cell counter kit 8 (CCK-8). Apoptotic cells were observed by Hoechst 33258 staining assay. The production level of H2S in cell culture medium was measured by using the sulfur-sensitive electrode method. The production of vascular endothelial growth factor (VEGF) was tested by enzyme-linked immunosorbent assay (ELISA). Our results showed that the production of H2S was dramatically increased in the PLC/PRF/5 hepatoma cells, compared with human LO2 hepatocyte cells group, along with the overexpression levels of CSE and CBS. Treatment of PLC/PRF/5 hepatoma cells with 500 umol/l NaHS (a donor of H2S) for 24 h markedly increased the expression levels of CSE, CBS, p-IkappaB and NF-kappaB activation, leading to COX 2 and MMP-2 overexpression, and decreased caspase-3 production, as well as increased cell viability and decreased number of apoptotic cells. Otherwise, the production level of H2S and VEGF were also significantly increased. Furthermore, co-treatment of PLC/PRF/5 hepatoma cells with 500 umol/l NaHS and 200 umol/l PDTC for 24 h significantly overturned these indexes. The findings of the present study provide evidence that the NF-kappaB is involved in the NaHS-induced cell proliferation, anti-apoptisis, angiogenesis, and migration in PLC/PRF/5 hepatoma cells, and that the PDTC against the NaHS-induced effects were by inhibition of the NF-kappaB pathway. PMID- 25738636 TI - Effects of the knockdown of death-associated protein 3 expression on cell adhesion, growth and migration in breast cancer cells. AB - The death-associated protein 3 (DAP3) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP3 expression and clinicopathological parameters of human breast cancer. In the present study, we intended to determine the role of DAP3 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sub-lines of MCF7 and MDA-MB-231, and performed growth, adhesion, invasion assays and electric cell-substrate impedance sensing (ECIS) studies of post-wound migration of the cells. In addition, we studied the mRNA expression of caspase 8 and 9, death ligand signal enhancer (DELE), IFN-beta promoter stimulator 1 (IPS1), cyclin D1 and p21 in the control and knockdown sub lines. The knockdown sub-lines of MCF7 and MDA-MB-231 had significantly increased adhesion and decreased growth when compared to the controls. Furthermore, invasion and migration were significantly increased in the MDA-MB-231DAP3kd cells vs. the controls. The expression of caspase 9 and IPS1, known components of the apoptosis pathway, were significantly reduced in the MCF7DAP3kd cells (p=0.05 and p=0.003, respectively). We conclude that DAP3 silencing contributes to breast carcinogenesis by increasing cell adhesion, migration and invasion. It is possible that this may be due to the activity of focal adhesion kinase further downstream of the anoikis pathway. Further research in this direction would be beneficial in increasing our understanding of the mechanisms underlying human breast cancer. PMID- 25738637 TI - Syntaxin1A-mediated Resistance and Hypersensitivity to Isoflurane in Drosophila melanogaster. AB - BACKGROUND: Recent evidence suggests that general anesthetics activate endogenous sleep pathways, yet this mechanism cannot explain the entirety of general anesthesia. General anesthetics could disrupt synaptic release processes, as previous work in Caenorhabditis elegans and in vitro cell preparations suggested a role for the soluble NSF attachment protein receptor protein, syntaxin1A, in mediating resistance to several general anesthetics. The authors questioned whether the syntaxin1A-mediated effects found in these reductionist systems reflected a common anesthetic mechanism distinct from sleep-related processes. METHODS: Using the fruit fly model, Drosophila melanogaster, the authors investigated the relevance of syntaxin1A manipulations to general anesthesia. The authors used different behavioral and electrophysiological endpoints to test the effect of syntaxin1A mutations on sensitivity to isoflurane. RESULTS: The authors found two syntaxin1A mutations that confer opposite general anesthesia phenotypes: syxH3-C, a 14-amino acid deletion mutant, is resistant to isoflurane (n = 40 flies), and syxKARRAA, a strain with two amino acid substitutions, is hypersensitive to the drug (n = 40 flies). Crucially, these opposing effects are maintained across different behavioral endpoints and life stages. The authors determined the isoflurane sensitivity of syxH3-C at the larval neuromuscular junction to assess effects on synaptic release. The authors find that although isoflurane slightly attenuates synaptic release in wild-type animals (n = 8), syxH3-C preserves synaptic release in the presence of isoflurane (n = 8). CONCLUSION: The study results are evidence that volatile general anesthetics target synaptic release mechanisms; in addition to first activating sleep pathways, a major consequence of these drugs may be to decrease the efficacy of neurotransmission. PMID- 25738638 TI - Effects of RNA interference-mediated NRP-1 silencing on the proliferation and apoptosis of breast cancer cells. AB - Lentiviral expression vectors carrying human NRP-1 short hairpin RNA (shRNA) were constructed and selected to present highly efficient NRP-1/shRNA interference sequences, in order to investigate the effects of RNA interference (RNAi) mediated NRP-1 silencing on the biological activities of breast cancer cells. Three pairs of human NRP-1 targeted specific interference sequences and one pair of non-specific control sequences were designed, synthesized and subcloned into pLB lentiviral vectors, which were further identified by polymerase chain reaction (PCR) and sequencing. Recombinant and lentiviral packaging plasmids were co-transfected into 293FT cell lines in order to produce lentiviral particles and to infect breast cancer cells with high NRP-1 expression. Flow cytometry was used to sort green fluorescent protein-positive cells. Fluorescence quantitative reverse transcription-PCR and western blot analysis were employed to identify the interference silencing sequence with the most efficient silencing profile. A cell counting kit-8 assay and an Annexin V-propidium iodide method in combination with flow cytometry were used to examine the effects of RNA interference-mediated NRP 1 gene silencing on cell proliferation, apoptosis and sensitivity to chemotherapy. The recombinant lentiviral plasmid pLB-NRP-1/shRNA was constructed successfully, as confirmed by PCR and sequencing. After the infection of recombinant lentiviral plasmids, the expression profiles of NRP-1 mRNA, and proteins of MCF-7 and SK-BR-3 cell-specific interference group (pLB-NRP-1/shRNA3) were significantly lower than that of the control group (P<0.05). Compared with the control group, the MCF-7 and SK-BR-3 cell-specific interference group (pLB NRP-1/shRNA3) showed lower optical density values and higher apoptotic rates at 48, 72 and 96 h; these differences were statistically significant (P<0.05). EPI administration resulted in increased apoptosis in the MCF-7 and SK-BR-3 cell specific interference groups compared with the control group (P<0.05). Lentiviral vectors encoding the human NRP-1 gene were constructed successfully and highly efficient NRP-1/shRNA interference sequences were selected. Furthermore, RNA interference (RNAi)-mediated NRP-1 silencing may induce proliferation suppression, apoptosis promotion, as well as enhanced sensitivity to chemotherapeutic agents. PMID- 25738639 TI - Diversity and abundance of arsenic biotransformation genes in paddy soils from southern China. AB - Microbe-mediated arsenic (As) biotransformation in paddy soils determines the fate of As in soils and its availability to rice plants, yet little is known about the microbial communities involved in As biotransformation. Here, we revealed wide distribution, high diversity, and abundance of arsenite (As(III)) oxidase genes (aioA), respiratory arsenate (As(V)) reductase genes (arrA), As(V) reductase genes (arsC), and As(III) S-adenosylmethionine methyltransferase genes (arsM) in 13 paddy soils collected across Southern China. Sequences grouped with As biotransformation genes are mainly from rice rhizosphere bacteria, such as some Proteobacteria, Gemmatimonadales, and Firmicutes. A significant correlation of gene abundance between arsC and arsM suggests that the two genes coexist well in the microbial As resistance system. Redundancy analysis (RDA) indicated that soil pH, EC, total C, N, As, and Fe, C/N ratio, SO4(2-)-S, NO3(-)-N, and NH4(+)-N were the key factors driving diverse microbial community compositions. This study for the first time provides an overall picture of microbial communities involved in As biotransformation in paddy soils, and considering the wide distribution of paddy fields in the world, it also provides insights into the critical role of paddy fields in the As biogeochemical cycle. PMID- 25738640 TI - Proteomics profiling of chikungunya-infected Aedes albopictus C6/36 cells reveal important mosquito cell factors in virus replication. AB - Chikungunya virus (CHIKV) is the only causative agent of CHIKV fever with persistent arthralgia, and in some cases may lead to neurological complications which can be highly fatal, therefore it poses severe health issues in many parts of the world. CHIKV transmission can be mediated via the Aedes albopictus mosquito; however, very little is currently known about the involvement of mosquito cellular factors during CHIKV-infection within the mosquito cells. Unravelling the neglected aspects of mosquito proteome changes in CHIKV-infected mosquito cells may increase our understanding on the differences in the host factors between arthropod and mammalian cells for successful replication of CHIKV. In this study, the CHIKV-infected C6/36 cells with differential cellular proteins expression were profiled using two-dimensional gel electrophoresis (2DE) coupled with the use of matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS). 2DE analysis on CHIKV-infected C6/36 cells has shown 23 mosquito cellular proteins that are differentially regulated, and which are involved diverse biological pathways, such as protein folding and metabolic processes. Among those identified mosquito proteins, spermatogenesis associated factor, enolase phosphatase e-1 and chaperonin-60kD have been found to regulate CHIKV infection. Furthermore, siRNA-mediated gene knockdown of these proteins has demonstrated the biological importance of these host proteins that mediate CHIKV infection. These findings have provided an insight to the importance of mosquito host factors in the replication of CHIKV, thus providing a potential channel for developing novel antiviral strategies against CHIKV transmission. PMID- 25738641 TI - Early event-related brain potentials and hemispheric asymmetries reveal mind wandering while reading and predict comprehension. AB - The electroencephalogram (EEG) of mind-wandering (MW) was examined in event related potentials (ERPs) and pre-stimulus alpha (8-12 Hz), over lateral posterior sites of left and right brain hemispheres, while individuals read text passages. After controlling for individual differences in general intelligence (g), P1-asymmetry was greater (right-minus- left) and N1 amplitudes were more negative, when individuals were not MW (i.e., they were reading attentively). Approximately 82% of variance in reading comprehension was accounted for by the predictors: g, pre-stimulus alpha, left- and right-hemisphere P1, and left hemisphere N1 (when individuals were not MW). Together, individual differences in MW-sensitive ERPs uniquely accounted for approximately 38% of the variance in reading comprehension, over and above prediction by g and pre-stimulus alpha. The within-person effect of MW on P1-asymmetry was estimated to account for an additional 4.6% of criterion variance. Implications for EEG/ERP research into attention, language processing, hemispheric asymmetries, and individual differences are discussed. PMID- 25738642 TI - Nuclear mechanotransduction: forcing the nucleus to respond. AB - Cell phenotype and fate are driven by the mechanical properties of their surrounding environment. Changes in matrix rigidity or application of force have been shown to impact profoundly cell behavior and phenotype, demonstrating that the molecular mechanisms which "sense" and transduce these signals into biochemical pathways are central in cell biology. In this commentary, we discuss recent evidence showing that mechanotransduction mechanisms occur in the nucleus, allowing dynamic regulation of the nucleoskeleton in response to mechanical stress. We will review this nucleoskeletal response and its impact on both nuclear structure and function. PMID- 25738643 TI - Chromosome conformation of human fibroblasts grown in 3-dimensional spheroids. AB - In the study of interphase chromosome organization, genome-wide chromosome conformation capture (Hi-C) maps are often generated using 2-dimensional (2D) monolayer cultures. These 2D cells have morphological deviations from cells that exist in 3-dimensional (3D) tissues in vivo, and may not maintain the same chromosome conformation. We used Hi-C maps to test the extent of differences in chromosome conformation between human fibroblasts grown in 2D cultures and those grown in 3D spheroids. Significant differences in chromosome conformation were found between 2D cells and those grown in spheroids. Intra-chromosomal interactions were generally increased in spheroid cells, with a few exceptions, while inter-chromosomal interactions were generally decreased. Overall, chromosomes located closer to the nuclear periphery had increased intra chromosomal contacts in spheroid cells, while those located more centrally had decreased interactions. This study highlights the necessity to conduct studies on the topography of the interphase nucleus under conditions that mimic an in vivo environment. PMID- 25738644 TI - Gene-rich chromosomal regions are preferentially localized in the lamin B deficient nuclear blebs of atypical progeria cells. AB - More than 20 mutations in the gene encoding A-type lamins (LMNA) cause progeria, a rare premature aging disorder. The major pathognomonic hallmarks of progeria cells are seen as nuclear deformations or blebs that are related to the redistribution of A- and B-type lamins within the nuclear lamina. However, the functional significance of these progeria-associated blebs remains unknown. We have carried out an analysis of the structural and functional consequences of progeria-associated nuclear blebs in dermal fibroblasts from a progeria patient carrying a rare point mutation p.S143F (C428T) in lamin A/C. These blebs form microdomains that are devoid of major structural components of the nuclear envelope (NE)/lamina including B-type lamins and nuclear pore complexes (NPCs) and are enriched in A-type lamins. Using laser capture microdissection and comparative genomic hybridization (CGH) analyses, we show that, while these domains are devoid of centromeric heterochromatin and gene-poor regions of chromosomes, they are enriched in gene-rich chromosomal regions. The active form of RNA polymerase II is also greatly enriched in blebs as well as nascent RNA but the nuclear co-activator SKIP is significantly reduced in blebs compared to other transcription factors. Our results suggest that the p.S143F progeria mutation has a severe impact not only on the structure of the lamina but also on the organization of interphase chromatin domains and transcription. These structural defects are likely to contribute to gene expression changes reported in progeria and other types of laminopathies. PMID- 25738645 TI - Protective mechanism of Korean Red Ginseng in cisplatin-induced ototoxicity through attenuation of nuclear factor-kappaB and caspase-1 activation. AB - Cisplatin is an effective anti-cancer drug; however, one of its side effects is irreversible sensorineural hearing damage. Korean Red Ginseng (KRG) has been used clinically for the treatment of various diseases; however, the underlying mechanism of KRG treatment of ototoxicity has not been studied extensively. The present study aimed to further investigate the mechanism of KRG on cisplatin induced toxicity in auditory HEI-OC1 cells in vitro, as well as in vivo. The pharmacological effects of KRG on cisplatin-induced changes in the hearing threshold of mice were determined, as well as the effect on the impairment of hair cell arrays. In addition, in order to elucidate the protective mechanisms of KRG, the regulatory effects of KRG on cisplatin-induced apoptosis-associated gene levels and nuclear factor-kappaB (NF-kappaB) activation were investigated in auditory cells. The results revealed that KRG prevented cisplatin-induced alterations in the hearing threshold of mice as well as the destruction of hair cell arrays in rat organ of Corti primary explants. In addition, KRG inhibited cisplatin-mediated cell toxicity, reactive oxygen species generation, interleukin 6 production, cytochrome c release and activation of caspases-3 in the HEI-OC1 auditory cell line. Furthermore, the results demonstrated that KRG inhibited the activation of NF-kappaB and caspase-1. In conclusion, these results provided a model for the pharmacological mechanism of KRG and provided evidence for potential therapies against ototoxicity. PMID- 25738647 TI - Is high weight status associated with pediatric forearm fractures requiring anatomic reduction? AB - BACKGROUND: High weight status is associated with increased forearm fracture risk but its relationship to severity of fracture has not been evaluated. We compared the epidemiology of children's forearm fractures treated with fracture reduction to those not treated with reduction, hypothesizing that high weight status would be significantly associated with need for reduction. METHODS: This is a case control study including Washington, DC children, ages 2 to 17 years, treated for isolated forearm fractures in an urban, tertiary care pediatric emergency department from 2003 to 2006. Descriptive statistics and logistic regression were conducted to compare patients with forearm fracture reductions to nonintervention controls. RESULTS: Of 888 forearm fractures, 330 (37.2%) required reduction (cases) whereas 558 (64.8%) did not (controls). Cases were more likely than controls to be male [adjusted odds ratio, 1.67 (95% confidence interval, 1.11 2.50)] and to have experienced a more severe mechanism of trauma [adjusted odds ratio, 2.11 (95% confidence interval, 1.14-3.90)]. The groups did not differ in weight status, age, or race/ethnicity. CONCLUSIONS: The need for reduction among children with forearm fractures is significantly associated with male sex and major mechanisms of trauma but not with high weight status. Strategies to reduce severe forearm fractures should focus on preventing major mechanisms of trauma. PMID- 25738646 TI - Bacterial Adaptation during Chronic Respiratory Infections. AB - Chronic lung infections are associated with increased morbidity and mortality for individuals with underlying respiratory conditions such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The process of chronic colonisation allows pathogens to adapt over time to cope with changing selection pressures, co-infecting species and antimicrobial therapies. These adaptations can occur due to environmental pressures in the lung such as inflammatory responses, hypoxia, nutrient deficiency, osmolarity, low pH and antibiotic therapies. Phenotypic adaptations in bacterial pathogens from acute to chronic infection include, but are not limited to, antibiotic resistance, exopolysaccharide production (mucoidy), loss in motility, formation of small colony variants, increased mutation rate, quorum sensing and altered production of virulence factors associated with chronic infection. The evolution of Pseudomonas aeruginosa during chronic lung infection has been widely studied. More recently, the adaptations that other chronically colonising respiratory pathogens, including Staphylococcus aureus, Burkholderia cepacia complex and Haemophilus influenzae undergo during chronic infection have also been investigated. This review aims to examine the adaptations utilised by different bacterial pathogens to aid in their evolution from acute to chronic pathogens of the immunocompromised lung including CF and COPD. PMID- 25738648 TI - Persistence of cardiovascular risk factors in women with previous preeclampsia: a long-term follow-up study. AB - BACKGROUND: Preeclampsia is a cardiovascular (CV) disease risk factor, and lifestyle modifications are recommended. It was suggested that preeclampsia may increase the prevalence of various CV disease risk factors such as metabolic syndrome, hypertension, insulin resistance, microalbuminuria, and endothelial dysfunction, among others. Here, we investigate the role of serum uric acid in preeclampsia in the development of CV complications. MATERIALS AND METHODS: This was an observational case-control study that compared women with history of preeclampsia (n = 25) with age-matched controls with uncomplicated pregnancies (n = 20) who were followed for at least 5 years. Measurements included clinical and ambulatory blood pressure monitoring, ultrasound-measured flow-mediated dilatation (FMD), microalbuminuria, carotid intima-media thickness (CIMT) and serum uric acid, as well as clinical and demographic features. Cardiovascular disease risk factors were compared in women with and without previous preeclampsia. RESULTS: At the time of index gestation, preeclamptic women had higher serum uric acid values (4.36 +/- 0.61 vs 2.27 +/- 0.38 mg/dL, P < 0.001). Five years after pregnancy, the patients who had preeclampsia were more likely to have hypertension and had higher serum uric acid levels, higher microalbuminuria and CIMT levels, and lower FMD values than did the patients who did not have preeclampsia. The 2 groups were similar with regard to various ambulatory blood pressure parameters. Univariate associates of FMD were history of preeclampsia and the current hypertension status. Microalbuminuria correlated with gestational uric acid levels (coefficient of correlation of 0.40, P = 0.01 for FMD and coefficient of correlation of 0.37, P = 0.01 for CIMT, respectively). CONCLUSIONS: Preeclampsia might be a risk factor for the development of cardiovascular risk factors at least 5 years after index pregnancy. Serum uric acid and microalbuminuria may be mechanistic mediators of heightened risk, along with impaired endothelial function in preeclampsia. PMID- 25738649 TI - Renal elasticity quantification by acoustic radiation force impulse applied to the evaluation of kidney diseases: a review. AB - For centuries, clinicians have used palpation to evaluate abdominal organs. After exploring almost all the different methods of interaction between x-rays, ultrasound, and magnetic fields on tissues, recent interest has focused on the evaluation of their mechanical properties.Acoustic radiation force impulse (ARFI) is a recent, established ultrasound-based diagnostic technique that allows physicians to obtain a measure of the elastic properties of an organ. Shear wave velocity, obtained by the ARFI technique, depends on the elasticity of tissues.To date, there are studies on the ARFI technique applied to normal kidneys, chronic kidney diseases, and kidney transplants. Mechanical properties of the kidney, such as stiffness and deformity, depend on various conditions that alter its histology, in particular the amount of fibrosis in the renal parenchyma; urinary pressure and renal blood perfusion may be other important contributing factors. Unfortunately, the ARFI technique applied to native renal pathologies is still limited, and not all studies are comparable because they used different methods. Therefore, the results reported in recent literature encourage further improvement of this method and the drawing up of standardized guidelines of investigation. PMID- 25738650 TI - Nb-C nanocomposite films with enhanced biocompatibility and mechanical properties for hard-tissue implant applications. AB - One of the key challenges in engineering of orthopedic implants is to "bioactivate" their surface by using different surface techniques and materials. Carbon, especially amorphous (a-C) and diamond-like carbon down (DLC) films have attracted much attention in biomedical fields due to their biocompatibility and low coefficient of friction. However, they are unsuitable for uses as a "bioactivity enhancer" of orthopedic implants due to their bioinertness. In this work, we use the nonreactive magnetron sputtering technique to produce a-C films including the biocompatible niobium (Nb) element to alter the surface chemistry and nanotopography of the a-C films with the purpose of bioactivating the a-C film coated implants. Results show that the nanocomposite films (Nb-C) formed by the addition of Nb into the a-C films not only have improved corrosion resistance, but also possess enhanced mechanical properties (nanohardness, Young's modulus and superelastic recovery). Preosteoblasts (MC3T3-E1) cultured on the Nb-C films have enhanced adhesion and upregulated alkaline phosphatase (ALP) activity, compared to those cultured on the a-C film and TiO2 films used as a control, which are thought to be ascribed to the combined effects of the changes in surface chemistry and the refinement of the nanotopography caused by the addition of Nb. PMID- 25738651 TI - NFATc1 activation promotes the invasion of U251 human glioblastoma multiforme cells through COX-2. AB - Recent studies have revealed that the nuclear factor of activated T-cells (NFAT) is a transcription factor that is highly expressed in aggressive cancer cells and tissues, and mediates invasion through the transcriptional induction of pro invasion and pro-migration genes. However, the mechanisms through which nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), in particular, translocates to the nucleus and regulates the invasion of human glioblastoma multiforme (GBM) cells have not yet been fully elucidated. In the present study, to investigate the role of NFATc1 in GBM cells, we established a U251 cell line expressing a constitutively active form of NFATc1 (CA-NFATc1). On the other hand, RNA interference was used to knock down NFATc1 expression in the U251 cell line. Our results demonstrated that the expression of CA-NFATc1 promoted cancer cell invasion, while small interfering RNA (siRNA) against NFATc1 successfully inhibited the invasion ability of the U251 cell line. Moreover, we demonstrated that NFATc1 promoted U251 cell invasion through the induction of cyclooxygenase-2 (COX-2). NFAT transcriptionally regulates the induction of COX-2 induction in U251 cells and binds to the promoter. We also demonstrated that a large proportion of GBM specimens expressed NFATc1. NFATc1 expression increased according to the histopathological grade of the glioma. However, no NFATc1 staining was observed in the non-neoplastic brain tissues. These findings suggest that the inhibition of the activation of the NFATc1 pathway is an effective therapeutic strategy for the clinical management of GBM. PMID- 25738652 TI - Targeting FoxM1 inhibits proliferation, invasion and migration of nasopharyngeal carcinoma through the epithelial-to-mesenchymal transition pathway. AB - High expression levels of the forkhead box M1 (FoxM1) transcription factor are associated with metastasis and poor prognosis of malignancies. However, little is known concerning its function in nasopharyngeal carcinoma (NPC). The present study aimed to investigate the impact of FoxM1 inhibition on the migration and invasion of NPC cells and the potential mechanisms. The effects of FoxM1 inhibitor treatment and FoxM1 silencing on the proliferation, migration and invasion of NPC CNE-1 and CNE-2 cells were examined by CCK-8, Transwell migration/invasion and colony formation assays. The effects of stable FoxM1 silencing on the growth and lung metastasis of implanted NPC were evaluated. The relative levels of FoxM1, zinc finger E-box binding homeobox 2 (ZEB2), Snail2 and E-cadherin in the different groups of NPC cells and tumors were determined by quantitative real-time PCR, western blotting and immunohistochemical assays. Treatment with thiostrepton, FoxM1 inhibitor, significantly reduced the survival of NPC cells. Treatment with thiostrepton and/or knockdown of FoxM1 inhibited the anchorage-independent proliferation, migration and invasion of NPC cells. Inhibition of FoxM1 also increased the relative levels of E-cadherin, but reduced ZEB2 and Snail2 expression in NPC cells. Stable FoxM1 silencing inhibited the growth and lung metastasis of implanted NPC in vivo, which was associated with increased levels of E-cadherin, but decreased ZEB2 and Snail2 expression in the NPC tumors. In conclusion, our data clearly indicate that knockdown of FoxM1 inhibited the growth and metastasis of human NPC by modulating epithelial-to mesenchymal transition (EMT), and FoxM1 may be a potential target for the intervention of NPC. PMID- 25738653 TI - Children's recall of fast food television advertising-testing the adequacy of food marketing regulation. AB - BACKGROUND AND AIM: In the United States, the fast food companies McDonald's and Burger King participate in marketing self-regulation programs that aim to limit emphasis on premiums and promote emphasis of healthy food choices. We determine what children recall from fast food television advertisements aired by these companies. METHODS: One hundred children aged 3-7 years were shown McDonald's and Burger King children's (MDC & BKC) and adult (MDA & BKA) meal ads, randomly drawn from ads that aired on national US television from 2010-11. Immediately after seeing the ad, children were asked to recall what they had seen and transcripts evaluated for descriptors of food, healthy food (apples or milk), and premiums/tie-ins. RESULTS: Premiums/tie-ins were common in children's but rarely appeared in adult ads, and all children's ads contained images of healthy foods (apples and milk). Participants were significantly less likely to recall any food after viewing the children's vs. the adult ad (MDC 32% [95% confidence interval 23, 41] vs. MDA 68% [59, 77]) p <0.001; BKC 46% [39, 56] vs. BKA 67% [58, 76] respectively, p = 0.002). For children's ads alone and for both restaurants, recall frequency for all food was not significantly different from premium/tie ins, and participants were significantly more likely to recall other food items than apples or milk. Moreover, premiums/tie-ins were recalled much more frequently than healthy food (MDC 45% [35, 55] vs. 9% [3, 15] p<0.001; BKC 54% [44, 64] vs. 2% [0, 5] respectively, p<0.001). CONCLUSIONS: Children's net impressions of television fast food advertising indicate that industry self regulation failed to achieve a de-emphasis on toy premiums and tie-ins and did not adequately communicate healthy menu choices. The methods devised for this study could be used to monitor and better regulate advertising patterns of practice. PMID- 25738654 TI - Genetic stratigraphy of key demographic events in Arabia. AB - At the crossroads between Africa and Eurasia, Arabia is necessarily a melting pot, its peoples enriched by successive gene flow over the generations. Estimating the timing and impact of these multiple migrations are important steps in reconstructing the key demographic events in the human history. However, current methods based on genome-wide information identify admixture events inefficiently, tending to estimate only the more recent ages, as here in the case of admixture events across the Red Sea (~8-37 generations for African input into Arabia, and 30-90 generations for "back-to-Africa" migrations). An mtDNA-based founder analysis, corroborated by detailed analysis of the whole-mtDNA genome, affords an alternative means by which to identify, date and quantify multiple migration events at greater time depths, across the full range of modern human history, albeit for the maternal line of descent only. In Arabia, this approach enables us to infer several major pulses of dispersal between the Near East and Arabia, most likely via the Gulf corridor. Although some relict lineages survive in Arabia from the time of the out-of-Africa dispersal, 60 ka, the major episodes in the peopling of the Peninsula took place from north to south in the Late Glacial and, to a lesser extent, the immediate post-glacial/Neolithic. Exchanges across the Red Sea were mainly due to the Arab slave trade and maritime dominance (from ~2.5 ka to very recent times), but had already begun by the early Holocene, fuelled by the establishment of maritime networks since ~8 ka. The main "back-to Africa" migrations, again undetected by genome-wide dating analyses, occurred in the Late Glacial period for introductions into eastern Africa, whilst the Neolithic was more significant for migrations towards North Africa. PMID- 25738655 TI - Engagement in HIV care and sexual transmission risk behavior among men who have sex with men using online social/sexual networking in Latin America. AB - HIV/AIDS in Latin America is concentrated among men who have sex with men (MSM). However, accurate estimates of engagement in HIV care in this population can be difficult to ascertain because many do not self-identify as MSM. Given evidence of decreased HIV transmissibility in the context of antiretroviral therapy (ART) adherence, identifying individuals not in care who are engaging in HIV transmission risk behavior is crucial for secondary prevention. Primary aims of this study were to examine engagement in care from testing to ART adherence among MSM using online social/sexual networking across Latin America, and whether individuals not in care at each step reported greater sexual transmission risk behavior than those in care. In the overall sample (n=28,779), approximately 75% reported ever being tested for HIV, and 9% reported having received an HIV diagnosis. Among known HIV-infected individuals, 20% reported not being in care, 30% reported not taking ART, and 55% reported less than 100% ART adherence. Over one-third of HIV-infected individuals reported sexual HIV transmission risk behavior, defined as unprotected anal intercourse (UAI) with a male partner of different/unknown HIV serostatus in the past three months. HIV-infected individuals not engaged in care more often reported UAI compared to those in care (OR=1.29; 95% CI=1.01-1.66). Although not statistically significant, HIV-infected individuals not on ART more often reported UAI compared to those on ART (OR=1.18; 95% CI=0.94-1.47). Individuals who reported less than 100% ART adherence more often reported UAI compared to individuals with 100% adherence (OR=1.55; 95% CI=1.26-1.90). Findings demonstrate that a substantial portion of HIV-infected MSM in Latin America who are likely not virologically suppressed from lack of ART use or adherence report sexual HIV transmission risk. Tailoring secondary HIV prevention for MSM in Latin America who are not in HIV care or adherent to ART may be warranted. PMID- 25738656 TI - Early 1900 s detection of Batrachochytrium dendrobatidis in Korean amphibians. AB - The pathogenic fungus Batrachochytrium dendrobatidis (Bd) is a major conservation concern because of its role in decimating amphibian populations worldwide. We used quantitative PCR to screen 244 museum specimens from the Korean Peninsula, collected between 1911 and 2004, for the presence of Bd to gain insight into its history in Asia. Three specimens of Rugosa emeljanovi (previously Rana or Glandirana rugosa), collected in 1911 from Wonsan, North Korea, tested positive for Bd. Histology of these positive specimens revealed mild hyperkeratosis - a non-specific host response commonly found in Bd-infected frogs - but no Bd zoospores or zoosporangia. Our results indicate that Bd was present in Korea more than 100 years ago, consistent with hypotheses suggesting that Korean amphibians may be infected by endemic Asian Bd strains. PMID- 25738658 TI - A call to action for pre-end-stage renal disease care. PMID- 25738657 TI - Bowel function and quality of life after colostomy in individuals with spinal cord injury. AB - OBJECTIVE: To evaluate the effect of colostomy on bowel function and quality of life (QoL) in individuals with spinal cord injury (SCI). DESIGN: Cross-sectional descriptive study. SETTING: Department for Spinal Cord Injuries and Departments of Gastroenterology and Radiology, Rigshospitalet. PARTICIPANTS: Eighteen individuals with SCI and a colostomy performed post injury, 12 males, 6 females, 8 with tetraplegia and 10 with paraplegia. Median age at time of study was 49.9 years, years since lesion was 3-56 years, and time since colostomy was performed 0.5 to 20 years. INTERVENTIONS: Questionnaires and measurement of gastrointestinal transit time (GITT). OUTCOME MEASURES: Retrospective data collection from patient records, a questionnaire on bowel management pre and post colostomy, quality of life (QoL) by SF-36, and GITT. RESULTS: Seventy-two percent significantly reduced their use of time on bowel emptying after the colostomy. All but one reported being content with the colostomy. Thirty-nine percent reported one or more problems related to the colostomy. Seventy-five percent had a GITT within normal range for able-bodied populations. When disregarding the physical component, QoL was not significantly lower in the total study group compared to a Danish norm group, but significantly lower when compared the subgroup of persons with tetraplegia. CONCLUSION: A colostomy reduces the time necessary for bowel management. The majority of individuals with SCI and a colostomy did not perceive bowel management as being a problem. The results indicate that colostomy is a favourable option for individuals with SCI, who spend long hours on bowel management and for whom non-invasive procedures did not improve the situation enough. PMID- 25738659 TI - Functions of autobiographical memory in Taiwanese and American emerging adults. AB - The study addresses cultural and person-level factors contributing to emerging adult's use of memory to serve adaptive functions. The focus is on three functions: self-continuity, social-bonding and directing-behaviour. Taiwanese (N = 85, 52 women) and American (N = 95, 51 women) emerging adults completed the Thinking about Life Experiences scale, and measures of trait personality, self concept clarity and future time perspective. Findings show that individuals from both cultures use memory to serve these three functions, but Taiwanese individuals use memory more frequently than Americans to maintain self continuity. Culture also interacted with person-level factors: in Taiwan, but not America, memory is more frequently used to create self-continuity in individuals high in conscientiousness. Across cultures, having lower self-concept clarity was related to greater use of memory to create self-continuity. Findings are discussed in terms of how memory serves functions in context and specific aspects of the Taiwanese and American cultural context that may predict the functional use of memory in emerging adulthood. PMID- 25738660 TI - Empowerment in the process of health messaging for rural low-income mothers: an exploratory message design project. AB - Rural, low-income mothers face challenges to their health equal to or greater than those of low-income mothers from urban areas. This study put health message design into the hands of low-income rural mothers. The current study filled a research gap by analyzing a participatory process used to design health messages tailored to the everyday lives of rural low-income mothers. A total of forty three mothers participated in nine focus groups, which were held from 2012 to 2013, in eight states. The mothers were from different racial and ethnic backgrounds. Participants discussed food security, physical activity, and oral health information. They created messages by considering several elements: visuals, length of message, voice/perspective, self-efficacy and personal control, emotional appeals, positive and negative reinforcements, and steps to health behavior change. This study was innovative in its focus on empowerment as a key process to health message design. PMID- 25738662 TI - Red phosphorus-single-walled carbon nanotube composite as a superior anode for sodium ion batteries. AB - Sodium ion batteries (SIBs) have been considered as a top alternative to lithium ion batteries due to the earth abundance and low cost of sodium compared with lithium. Among all proposed anode materials for SIBs, red phosphorus (P) is a very promising candidate because it has the highest theoretical capacity (~2600 mAh/g). In this study, a red P-single-walled carbon nanotube (denoted as red P SWCNT) composite, in which red P is uniformly distributed between tangled SWCNTs bundles, is fabricated by a modified vaporization-condensation method. Benefiting from the nondestructive preparation process, the highly conductive and mechanically strong SWCNT network is preserved, which enhances the conductivity of the composite and stabilizes the solid electrolyte interphase. As a result, the red P-SWCNT composite presents a high overall sodium storage capacity (~700 mAh/gcomposite at 50 mA/gcomposite), fast rate capability (~300 mAh/gcomposite at 2000 mA/gcomposite), and stable long-term cycling performance with 80% capacity retention after 2000 sodiation-desodiation cycles. The red P-SWCNT composite fabricated by the vaporization-condensation method significantly extends the cycling stability of P/carbon composite from current ~100 cycles to ~2000 cycles. PMID- 25738661 TI - Kinetics of exchange between zero-, one-, and two-hydrogen-bonded states of methyl and ethyl acetate in methanol. AB - It has recently been shown that the ester carbonyl stretching vibration can be used as a sensitive probe of local electrostatic field in molecular systems. To further characterize this vibrational probe and extend its potential applications, we studied the kinetics of chemical exchange between differently hydrogen-bonded (H-bonded) ester carbonyl groups of methyl acetate (MA) and ethyl acetate (EA) in methanol. We found that, while both MA and EA can form zero, one, or two H-bonds with the solvent, the population of the 2hb state in MA is significantly smaller than that in EA. Using a combination of linear and nonlinear infrared measurements and numerical simulations, we further determined the rate constants for the exchange between these differently H-bonded states. We found that for MA the chemical exchange reaction between the two dominant states (i.e., 0hb and 1hb states) has a relaxation rate constant of 0.14 ps(-1), whereas for EA the three-state chemical exchange reaction occurs in a predominantly sequential manner with the following relaxation rate constants: 0.11 ps(-1) for exchange between 0hb and 1hb states and 0.12 ps(-1) for exchange between 1hb and 2hb states. PMID- 25738663 TI - A precious jewel--the role of general practice in the English NHS. AB - General practice, long considered the jewel in the crown of the English National Health Service, is being criticized for its small scale, isolation, and lack of accountability. There is growing concern that many general practices cannot respond to new expectations. PMID- 25738664 TI - Making hepatitis E a vaccine-preventable disease. AB - A hepatitis E vaccine could become a powerful new tool in the prevention and control of hepatitis E virus transmission and disease. Most immediately, it can have a role in curbing outbreaks of hepatitis E in humanitarian crises. PMID- 25738665 TI - On taking notice--learning mindfulness from (Boston) Brahmins. AB - Although the great physicians of past centuries might have called it something else, proficiency at promoting mindfulness has always been and should remain part of a doctor's clinical toolkit. PMID- 25738666 TI - Association of improved air quality with lung development in children. AB - BACKGROUND: Air-pollution levels have been trending downward progressively over the past several decades in southern California, as a result of the implementation of air quality-control policies. We assessed whether long-term reductions in pollution were associated with improvements in respiratory health among children. METHODS: As part of the Children's Health Study, we measured lung function annually in 2120 children from three separate cohorts corresponding to three separate calendar periods: 1994-1998, 1997-2001, and 2007-2011. Mean ages of the children within each cohort were 11 years at the beginning of the period and 15 years at the end. Linear-regression models were used to examine the relationship between declining pollution levels over time and lung-function development from 11 to 15 years of age, measured as the increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) during that period (referred to as 4-year growth in FEV1 and FVC). RESULTS: Over the 13 years spanned by the three cohorts, improvements in 4-year growth of both FEV1 and FVC were associated with declining levels of nitrogen dioxide (P<0.001 for FEV1 and FVC) and of particulate matter with an aerodynamic diameter of less than 2.5 MUm (P= 0.008 for FEV1 and P<0.001 for FVC) and less than 10 MUm (P<0.001 for FEV1 and FVC). These associations persisted after adjustment for several potential confounders. Significant improvements in lung-function development were observed in both boys and girls and in children with asthma and children without asthma. The proportions of children with clinically low FEV1 (defined as <80% of the predicted value) at 15 years of age declined significantly, from 7.9% to 6.3% to 3.6% across the three periods, as the air quality improved (P = 0.001). CONCLUSIONS: We found that long-term improvements in air quality were associated with statistically and clinically significant positive effects on lung-function growth in children. (Funded by the Health Effects Institute and others.). PMID- 25738667 TI - Long-term efficacy of a hepatitis E vaccine. AB - BACKGROUND: Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined. METHODS: In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years. RESULTS: During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis, rather than (95% confidence interval, 71 to 84) [corrected]. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups. CONCLUSIONS: Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.). PMID- 25738668 TI - Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. AB - BACKGROUND: Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS: We randomly assigned 257 premenopausal women with operable hormone-receptor negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS: At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05). CONCLUSIONS: Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.). PMID- 25738669 TI - Valganciclovir for symptomatic congenital cytomegalovirus disease. AB - BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.). PMID- 25738671 TI - Clinical management of potential bioterrorism-related conditions. AB - The agents most likely to be used in bioterrorism attacks are reviewed, along with the clinical syndromes they produce and their treatment. PMID- 25738672 TI - Images in clinical medicine: Segmental neurofibromatosis. AB - A 4-year-old girl presented for evaluation of cutaneous nodules that had been present on the left side of her trunk since birth. Physical examination revealed numerous soft, nontender papules and nodules across the left upper abdomen and wrapping around to the back. PMID- 25738673 TI - Clinical problem solving: Itching for a diagnosis. AB - A 58-year-old woman presented with a 2-week history of generalized pruritus. She also reported having fatigue, dizziness, and decreased appetite. A week before the onset of symptoms, a mild upper respiratory tract infection had developed. PMID- 25738670 TI - Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. AB - BACKGROUND: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. METHODS: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression free survival. RESULTS: After a median follow-up of 40 months, median progression free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR CAP group. CONCLUSIONS: VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.). PMID- 25738674 TI - Cleaner air, bigger lungs. PMID- 25738675 TI - Epigenetic signatures of obesity. AB - A study in drosophila shows that the progeny of male flies briefly fed a diet with abnormally high or low sugar levels are more susceptible to obesity. The data suggest that epigenetic susceptibility factors are at play not only in flies but in humans and mice as well. PMID- 25738676 TI - Blood pressure in early autosomal dominant polycystic kidney disease. PMID- 25738677 TI - Blood pressure in early autosomal dominant polycystic kidney disease. PMID- 25738678 TI - Blood pressure in early autosomal dominant polycystic kidney disease. PMID- 25738679 TI - Blood pressure in early autosomal dominant polycystic kidney disease. PMID- 25738680 TI - Atenolol versus Losartan in Marfan's Syndrome. PMID- 25738681 TI - Atenolol versus Losartan in Marfan's Syndrome. PMID- 25738682 TI - Atenolol versus Losartan in Marfan's Syndrome. PMID- 25738683 TI - Atenolol versus Losartan in Marfan's Syndrome. PMID- 25738684 TI - Case 38-2014: A man with sore throat, hoarseness, fatigue, and dyspnea. PMID- 25738685 TI - Case 38-2014: A man with sore throat, hoarseness, fatigue, and dyspnea. PMID- 25738686 TI - Infection with a chlorophyllic eukaryote after a traumatic freshwater injury. AB - Infections with chlorophyllic algae are uncommon. Invasive infection with Desmodesmus armatus developed in two patients independently after they each sustained a penetrating freshwater injury. PMID- 25738687 TI - Images in clinical medicine: African tick-bite fever after a game-hunting expedition. AB - A 15-year-old girl was admitted to the hospital with a persistent fever, headache, and myalgia. A solitary, painful, black, crusted ulcer with a peripheral erythematous halo was noted in the left popliteal fossa; the ulcer had begun as an asymptomatic erythematous papule 1 week previously. PMID- 25738692 TI - Adverse childhood experiences and military service. PMID- 25738688 TI - Meta-analysis on vitamin D receptor and cancer risk: focus on the role of TaqI, ApaI, and Cdx2 polymorphisms. AB - Vitamin D plays a significant role in our health, including cancer incidence and mortality. Vitamin D receptor (VDR) single-nucleotide polymorphisms (SNPs) may affect its activity, influencing the risk of cancer. Several studies have investigated VDR SNPs, but the association with the risk of cancer is controversial. Here, we present a meta-analysis to assess the association of TaqI, ApaI, and Cdx2 SNPs with the risk of cancer. A systematic literature search was performed following a predefined protocol and using validated search strategies. This meta-analysis shows the summary odd ratio (SOR) overall, by cancer sites and by ethnicity. Up to January 2014, we identified 73 independent studies with 35 525 cases and 38 675 controls. The meta-analysis of Cdx2 gg versus GG showed a significant 12% increased risk for all cancers [SOR=1.12; 95% confidence interval (CI): 1.00-1.25]. The other SNPs analyzed did not show an overall significant association with the risk of cancer: SOR=0.98 (95% CI: 0.90 1.07) and 1.06 (95% CI: 0.95-1.19) for TaqI tt versus TT and ApaI aa versus AA, respectively. TaqI shows a significant 43% increased risk for colorectal cancer (SOR=1.43; 95% CI: 1.30-1.58 for tt vs. TT). Strong frequency variations are present among different ethnic groups. This meta-analysis showed an overall increased risk of cancer associated with Cdx2 SNP and a specific higher risk of colorectal cancer associated with the TaqI polymorphism. The VDR genotype might become more relevant when clustered in a specific haplotype, associated with other SNPs of genes involved in vitamin D metabolism, or for specific tumors and/or patient characteristics. PMID- 25738693 TI - Adverse childhood experiences and military service--reply. PMID- 25738695 TI - 3D-printed microfluidic automation. AB - Microfluidic automation - the automated routing, dispensing, mixing, and/or separation of fluids through microchannels - generally remains a slowly-spreading technology because device fabrication requires sophisticated facilities and the technology's use demands expert operators. Integrating microfluidic automation in devices has involved specialized multi-layering and bonding approaches. Stereolithography is an assembly-free, 3D-printing technique that is emerging as an efficient alternative for rapid prototyping of biomedical devices. Here we describe fluidic valves and pumps that can be stereolithographically printed in optically-clear, biocompatible plastic and integrated within microfluidic devices at low cost. User-friendly fluid automation devices can be printed and used by non-engineers as replacement for costly robotic pipettors or tedious manual pipetting. Engineers can manipulate the designs as digital modules into new devices of expanded functionality. Printing these devices only requires the digital file and electronic access to a printer. PMID- 25738696 TI - Differences in abuse potential of ADHD drugs measured by contrasting poison centre and therapeutic use data. AB - CONTEXT: Atomoxetine (ATX) is the treatment of choice for attention deficit hyperactivity disorders with co-morbid risk of drug abuse, although its abuse potential needs to be qualified. The purpose of this study is to analyse ATX misuse in relation to therapeutic use and compare our results with that of methylphenidate (MPH). METHODS AND MATERIALS: Data on enquiries were extracted from the Danish Poison Information Centre database (January 2006 to June 2012), while data on therapeutic use were provided by the Danish State Serum Institute (2007-2011). RESULTS: The study included 28 ATX and 394 MPH enquiries. Frequency of ATX enquiries did not show a significant correlation to either sale or number of treated patients but for MPH, both correlations were significant (p = 0.001 and p = 0.0008, respectively). The enquiries/number of treated patients relationship differed significantly between ATX and MPH (p = 0.018), but not the enquiries/sale relationship. The proportion of exposures motivated by recreational drug use was significantly lower for ATX (19%) than that for MPH (40%) (p = 0.038). DISCUSSION AND CONCLUSION: These results suggest that ATX is used by adults for non-medical purposes including recreational use, but to a lesser extent than MPH. PMID- 25738697 TI - "My child ate poop!"--how one poison center established its social media presence. PMID- 25738698 TI - The impact of predation by marine mammals on patagonian toothfish longline fisheries. AB - Predatory interaction of marine mammals with longline fisheries is observed globally, leading to partial or complete loss of the catch and in some parts of the world to considerable financial loss. Depredation can also create additional unrecorded fishing mortality of a stock and has the potential to introduce bias to stock assessments. Here we aim to characterise depredation in the Patagonian toothfish (Dissostichus eleginoides) fishery around South Georgia focusing on the spatio-temporal component of these interactions. Antarctic fur seals (Arctocephalus gazella), sperm whales (Physeter macrocephalus), and orcas (Orcinus orca) frequently feed on fish hooked on longlines around South Georgia. A third of longlines encounter sperm whales, but loss of catch due to sperm whales is insignificant when compared to that due to orcas, which interact with only 5% of longlines but can take more than half of the catch in some cases. Orca depredation around South Georgia is spatially limited and focused in areas of putative migration routes, and the impact is compounded as a result of the fishery also concentrating in those areas at those times. Understanding the seasonal behaviour of orcas and the spatial and temporal distribution of "depredation hot spots" can reduce marine mammal interactions, will improve assessment and management of the stock and contribute to increased operational efficiency of the fishery. Such information is valuable in the effort to resolve the human-mammal conflict for resources. PMID- 25738699 TI - The Impact of Laparoscopic Approaches on Short-term Outcomes in Patients Undergoing Liver Surgery for Metastatic Tumors. AB - PURPOSE: To compare the perioperative outcomes associated with open and laparoscopic (LAP) surgical approaches for liver metastases. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all adult patients who underwent surgical therapy for metastatic liver tumors between 2006 and 2012 (N=7684). Patients who underwent >1 procedure were excluded. Logistic regression after matching on propensity scores was used to assess the association between surgical approaches and perioperative outcomes. RESULTS: A total of 4555 patients underwent open resection, 387 LAP resection, 297 open radiofrequency ablation (RFA), and 265 LAP RFA. In propensity-matched samples (over 95% of patients successfully matched), there was no significant difference between LAP resection and LAP RFA in perioperative complications and length of stay and both compared favorably with their open counterparts. DISCUSSION: Minimally invasive approaches for secondary hepatic malignancies were associated with improved postoperative morbidity and length of stay and should be preferred in appropriate patients. PMID- 25738700 TI - Laparoscopic-assisted Peritoneal Shunt Insertion for Ventriculoperitoneal and Lumboperitoneal Shunt Placement: An Institutional Experience of 53 Consecutive Cases. AB - PURPOSE: The purpose of this study was to describe operative times, complication rates, and outcomes following laparoscopic placement of the peritoneal catheter in ventriculoperitoneal (VP) and lumboperitoneal (LP) shunt insertion. METHODS: A retrospective review was performed of those who underwent laparoscopic-assisted VP or LP shunt insertion from July 2007 to August 2011. RESULTS: The study included 53 consecutive patients (35 women and 18 men). Mean age was 51 years (range, 16 to 83 y), mean BMI was 27.6 (range, 16 to 54), and 35.8% of the patients had previous abdominal surgery. Mean operative time for VP shunt placement was 68.2 +/- 19.0 minutes, and for LP shunt placement 84 +/- 12.4 minutes. There were no intraoperative complications, and conversion to minilaparotomy was 0%. There were 2 distal catheter-associated complications. CONCLUSIONS: Laparoscopic-assisted VP/LP shunt placement is associated with a low incidence of distal catheter malfunction. Direct visualization of shunt placement into the peritoneal cavity is a major advantage making it a viable alternative over traditional techniques. PMID- 25738701 TI - Feasibility and safety of endoscopic submucosal dissection for large colorectal tumors. AB - PURPOSE: Recently, endoscopic submucosal dissection (ESD) has been applied for superficial colorectal neoplasms and the number of publications about it has been increasing, but little is known about the outcomes of colorectal ESD for the lesions > 50 mm. In this study, we evaluated the feasibility and safety of colorectal ESD for the lesions > 50 mm compared with the lesions < 50 mm. METHODS: A total of 674 superficial colorectal neoplasms in 629 patients treated by ESD at Kobe University Hospital from July 2008 to July 2013 were included in the analysis. RESULTS: The median operation time (range) in the large lesion group (>= 5 cm) was 109 (37 to 596) minutes, and it was 55 (6 to 248) minutes in the small lesion group (< 5 cm). Median procedure speed (range) in the large lesion group was 0.28 (0.06 to 0.83) cm2/min, and it was 0.19 (0.04 to 0.83) cm2/min in the small lesion group. The en bloc resection rate and the curative resection rate in the small lesion group was 98.7% and 96.0%, and those were 95.7% and 91.4% in the large lesion group, respectively. In terms of adverse events, perforation, muscle damage, and postoperative bleeding occurred at similar frequency in both groups. CONCLUSIONS: ESD on colorectal lesions > 50 mm takes longer operation time; however, it is resected time effectively without increasing the risk of adverse events compared with smaller lesions by ESD. PMID- 25738702 TI - Construction and validation of a low-cost surgical trainer based on iPhone technology for training laparoscopic skills. AB - In this article, we describe the construction and validation of a laparoscopic trainer using an iPhone 5 and a plastic document holder case. The abdominal cavity was simulated with a clear plastic document holder case. On 1 side of the case, 2 holes for entry of laparoscopic instruments were drilled. We added a window to place the camera of the iPhone, which works as our camera of the trainer. Twenty residents carried out 4 tasks using the iPhone Trainer and a physical laparoscopic trainer. The time of all tasks were analyzed with a simple paired t test. The construction of the trainer took 1 hour, with a cost of 65 years of age is 13% and ~66 million individuals in this age group undergo surgery annually under anesthesia. It is therefore important to determine whether commonly used inhaled anesthetics induce cytotoxicity, which may lead to neurodegeneration. Findings from several studies suggest that the anesthetics, isoflurane, sevoflurane and desflurane, may activate caspases, increase the synthesis and accumulation of beta-amyloid (Abeta) protein, and induce hyperphosphorylation of tau proteins, all of which are cellular responses consistent with the neuropathogenesis of AD. Other studies have arrived at different and occasionally contradictory conclusions. The present review attempts to resolve this discrepancy by reviewing previous studies, which have investigated the effects of commonly used inhaled anesthetics on the synthesis and accumulation of Abeta, tau pathology and cognitive function. The possible underlying mechanism was also reviewed. However, several aspects of this phenomenon remain to be elucidated. Further studies are required to fully examine anesthesia-induced neurotoxicity and elucidate the effect of inhaled anesthetics on the onset and progression of AD. PMID- 25738736 TI - Estimating influenza disease burden from population-based surveillance data in the United States. AB - Annual estimates of the influenza disease burden provide information to evaluate programs and allocate resources. We used a multiplier method with routine population-based surveillance data on influenza hospitalization in the United States to correct for under-reporting and estimate the burden of influenza for seasons after the 2009 pandemic. Five sites of the Influenza Hospitalization Surveillance Network (FluSurv-NET) collected data on the frequency and sensitivity of influenza testing during two seasons to estimate under-detection. Population-based rates of influenza-associated hospitalization and Intensive Care Unit admission from 2010-2013 were extrapolated to the U.S. population from FluSurv-NET and corrected for under-detection. Influenza deaths were calculated using a ratio of deaths to hospitalizations. We estimated that influenza-related hospitalizations were under-detected during 2010-11 by a factor of 2.1 (95%CI 1.7 2.9) for age < 18 years, 3.1 (2.4-4.5) for ages 18-64 years, and 5.2 (95%CI 3.8 8.3) for age 65+. Results were similar in 2011-12. Extrapolated estimates for 3 seasons from 2010-2013 included: 114,192-624,435 hospitalizations, 18,491-95,390 ICU admissions, and 4,915-27,174 deaths per year; 54-70% of hospitalizations and 71-85% of deaths occurred among adults aged 65+. Influenza causes a substantial disease burden in the U.S. that varies by age and season. Periodic estimation of multipliers across multiple sites and age groups improves our understanding of influenza detection in sentinel surveillance systems. Adjusting surveillance data using a multiplier method is a relatively simple means to estimate the impact of influenza and the subsequent value of interventions to prevent influenza. PMID- 25738737 TI - Correction to "Manganese catalysts with bulky bipyridine ligands for the electrocatalytic reduction of carbon dioxide: eliminating dimerization and altering catalysis". PMID- 25738738 TI - Deregulated microRNA species in the plasma and placenta of patients with preeclampsia. AB - Emerging evidence indicates that microRNAs (miRNAs), a class of small non-coding RNAs, are involved in a number of biological processes. The results of SOLiDTM sequencing were used to analyze differentially expressed miRNA profiles in the plasma and placenta of patients with preeclampsia (PE) and a subject who had had a pregnancy without complications. miRNAs were identified that were consistently expressed in the placenta, following normalization of the raw data. miRNAs that had increased and differential expression were selected, as defined by percentage >0.02% and a log2 fold change >= |1.2|, respectively. This process was repeated in the plasma. Twenty such miRNAs were identified. These were: miR-126, miR-126*, miR-130a, miR-135b, miR-142-3p, miR-149, miR-188-5p, miR-18a, miR-18b, miR-203, miR-205, miR-224, miR-27a, miR-29a, miR-301a, miR-517c, miR-518-3p, miR-518e, miR 519d and miR-93. These miRNAs belonged to 13 clusters or families. However, only four clusters or families involved two or more of these miRNAs. These were the mir-16 cluster, the mir-17 family, the mir-130 family and the mir-517 family. These abnormally-expressed miRNAs and miRNA gene clusters or families are known to be involved in a number of biological processes. Gene enrichment analysis was used to investigate the pathways involved in the development of PE. In conclusion, the miRNAs identified in this study as being abnormally expressed in PE, may be useful as non-invasive diagnostic biomarkers. Co-regulated mRNAs and possible causal pathways involved in the pathogenesis of PE were also identified. PMID- 25738739 TI - Design of electrophoretic and biocompatible poly(2-oxazoline)s initiated by perfluoroalkanesulfoneimides and electrophoretic deposition with bioactive glass. AB - N-Methyl bis[(nonafluorobutane)sulfonyl]imide (Nf2NMe) was synthesized to serve as an initiator for polymerization of 2-oxazolines and the polymerization activity and control of molecular weight were compared with conventional methyl triflate (TfOMe). Ring-opening polymerization of the vinyl-containing 2 oxazoline, 2-(3-butenyl)-2-oxazoline, and a subsequent thiol-ene click reaction and oxidation resulted in the successful synthesis of electrophoretic poly(2 oxazoline)s containing pendent sulfone. It was possible to coat the polymeric sulfones obtained via oxone oxidation (conversion, >99%) on a stainless-steel anode selectively. Furthermore, hybridization of the poly(2-oxazoline)s with bioactive glass (Bioglass45S5) by electrophoretic deposition (EPD) was investigated, and the biocompatibility of the hybrid was also evaluated. PMID- 25738740 TI - Orthodontic marketing through social media networks: the patient and practitioner's perspective. AB - OBJECTIVE: To (1) assess orthodontic patient and practitioner use of and preferences for social media and (2) investigate the potential benefit of social media in marketing and communication strategies in orthodontic practices. MATERIALS AND METHODS: A survey was developed and randomly distributed to orthodontists via the American Association of Orthodontists and to patients/parents via private practices throughout the United States. Participants were asked to answer questions related to their use of social media and their perceptions of the use of social media in the orthodontic practice. RESULTS: Of the participants, 76% of orthodontists and 89% of patients/parents use social media. Furthermore, Facebook was the social media platform that was most preferred. Social media use was more common in female and younger adult participants. Orthodontists posted information more often in the morning (40%) and afternoon (56%), and patients/parents used social media mainly in the evening (76%). The most commonly used marketing strategies in the orthodontic practices were social media (76%) and a practice website (59%). Social media and practice websites were positively related with new patient starts (P = .0376, P = .0035, respectively). CONCLUSIONS: Most orthodontists and patients/parents used social media. Social media may be an effective marketing and communication tool in an orthodontic practice. PMID- 25738742 TI - To apply or not to apply: a survey analysis of grant writing costs and benefits. AB - We surveyed 113 astronomers and 82 psychologists active in applying for federally funded research on their grant-writing history between January, 2009 and November, 2012. We collected demographic data, effort levels, success rates, and perceived non-financial benefits from writing grant proposals. We find that the average proposal takes 116 PI hours and 55 CI hours to write; although time spent writing was not related to whether the grant was funded. Effort did translate into success, however, as academics who wrote more grants received more funding. Participants indicated modest non-monetary benefits from grant writing, with psychologists reporting a somewhat greater benefit overall than astronomers. These perceptions of non-financial benefits were unrelated to how many grants investigators applied for, the number of grants they received, or the amount of time they devoted to writing their proposals. We also explored the number of years an investigator can afford to apply unsuccessfully for research grants and our analyses suggest that funding rates below approximately 20%, commensurate with current NIH and NSF funding, are likely to drive at least half of the active researchers away from federally funded research. We conclude with recommendations and suggestions for individual investigators and for department heads. PMID- 25738741 TI - An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein. AB - A monoclonal antibody (mAb) that binds to a transient intermediate may act as a catalyst for the corresponding reaction; here we show this principle can extend on a macro molecular scale to the induction of mutant-like oligomerization in a wild-type protein. Using the common pathogenic E342K (Z) variant of alpha1 antitrypsin as antigen-whose native state is susceptible to the formation of a proto-oligomeric intermediate-we have produced a mAb (5E3) that increases the rate of oligomerization of the wild-type (M) variant. Employing ELISA, gel shift, thermal stability and FRET time-course experiments, we show that mAb5E3 does not bind to the native state of alpha1-antitrypsin, but recognizes a cryptic epitope in the vicinity of the post-helix A loop and strand 4C that is revealed upon transition to the polymerization intermediate, and which persists in the ensuing oligomer. This epitope is not shared by loop-inserted monomeric conformations. We show the increased amenity to polymerization by either the pathogenic E342K mutation or the binding of mAb5E3 occurs without affecting the energetic barrier to polymerization. As mAb5E3 also does not alter the relative stability of the monomer to intermediate, it acts in a manner similar to the E342K mutant, by facilitating the conformational interchange between these two states. PMID- 25738743 TI - Comparative digestibility of energy and nutrients in diets fed to sows and growing pigs. AB - The objective of this research was to compare values for digestible energy (DE) and metabolisable energy (ME) and apparent total tract digestibility (ATTD) of nutrients in 11 diets fed to both growing pigs and gestating sows. Three diets were based on corn, wheat or sorghum and eight diets were based on a combination of corn and soybean meal, canola meal, conventional distillers' dried grains with solubles, low-fat distillers' dried grains with solubles, corn germ meal, corn bran, wheat middlings or soybean hulls. A total of 88 gestating sows (252 +/- 24.2 kg BW; parity two to six) and 88 growing barrows (40 +/- 4.7 kg BW) were used and randomly allotted to the 11 diets with eight replicate sows or pigs per diet. Faecal and urine samples were collected for 4 d following a 19 d adaptation period. The DE, ME and ATTD of gross energy (GE), acid detergent fibre (ADF), neutral detergent fibre (NDF) and crude protein (CP) in the 11 diets were calculated. Gestating sows had greater (p < 0.05) ATTD of GE and CP and DE values for all diets compared with growing pigs. Gestating sows also had greater (p < 0.05) ME values than growing pigs for the three grain diets and the diets containing wheat middlings and soybean hulls. No differences were observed in ATTD of ADF and NDF between gestating sows and growing pigs for any of the diets, except that gestating sows had greater (p < 0.05) ATTD of NDF than growing pigs when they were fed the four protein diets. The ATTD of GE and CP and DE values in gestating sows may be predicted by using equations generated from the values of ATTD of GE and CP and DE values obtained in growing pigs. Results of this research indicate that ATTD values of CP and GE obtained in gestating sows are greater than the values obtained in growing pigs, but values for ATTD of ADF obtained in growing pigs are not different from values in gestating sows. PMID- 25738745 TI - Routine outcome measures in Canada. AB - Canada is a federal country of 10 provinces and three territories. High level information on mental health conditions and service use has mostly been generated from administrative data collected by provinces and territories. These include four major types - hospital admissions and discharges, physician billings, ambulatory care services, and drug databases. At the national level, the Canadian Institute for Health Information brings together this information to produce indicators of outcome. Although these data provide information on patient and health system characteristics, they do not capture the full spectrum of formal and informal mental healthcare. These include changes in health status, functioning, community integration and quality of life. As a result, some jurisdictions have begun to implement more standardized measures of outcome such as the clinician-rated Health of the Nation Outcome Scales or the inpatient Resident Assessment Instrument - Mental Health. In this paper we provide an overview of mental-health-related data sources in Canada, highlight some of the more progressive practices beginning to emerge, and conclude with some thoughts about how the routine measurement and reporting of mental health outcomes in Canada might be advanced including efforts at engaging both clinicians and decision-makers. PMID- 25738744 TI - Interaction between the type III effector VopO and GEF-H1 activates the RhoA-ROCK pathway. AB - Vibrio parahaemolyticus is an important pathogen that causes food-borne gastroenteritis in humans. The type III secretion system encoded on chromosome 2 (T3SS2) plays a critical role in the enterotoxic activity of V. parahaemolyticus. Previous studies have demonstrated that T3SS2 induces actin stress fibers in various epithelial cell lines during infection. This stress fiber formation is strongly related to pathogenicity, but the mechanisms that underlie T3SS2 dependent actin stress fiber formation and the main effector have not been elucidated. In this study, we identified VopO as a critical T3SS2 effector protein that activates the RhoA-ROCK pathway, which is an essential pathway for the induction of the T3SS2-dependent stress fiber formation. We also determined that GEF-H1, a RhoA guanine nucleotide exchange factor (GEF), directly binds VopO and is necessary for T3SS2-dependent stress fiber formation. The GEF-H1-binding activity of VopO via an alpha helix region correlated well with its stress fiber inducing capacity. Furthermore, we showed that VopO is involved in the T3SS2 dependent disruption of the epithelial barrier. Thus, VopO hijacks the RhoA-ROCK pathway in a different manner compared with previously reported bacterial toxins and effectors that modulate the Rho GTPase signaling pathway. PMID- 25738746 TI - Interfacial and bulk nanostructure of liquid polymer nanocomposites. AB - Liquid polymer nanocomposites (l-PNCs) have been prepared using silica nanoparticles with diameters of 15 nm (l-PNC-15) and 24 nm (l-PNC-24), and Jeffamine M-2070, an amine-terminated ethylene oxide/propylene oxide (PEO/PPO, ratio 31/10) copolymer. Jeffamine M-2070 was used as the host liquid in which the particles were suspended and was also grafted onto the particle surface to prevent aggregation. The grafting density of Jeffamine M-2070 on the particle surfaces was ~0.75 chains nm(-2). When the total polymer content (surface layer + host) was greater than ~30 wt %, the PNC was a liquid, while at lower polymer volume fractions the PNC was solid. In this work, the bulk and surface structures of l-PNCs with ~70 wt % polymer and 30% silica are characterized and compared. Small-angle neutron scattering (SANS) was used to probe the bulk structure of the l-PNCs and revealed that the particles are well-dispersed with minor clustering in l-PNC-15 and substantial clustering in l-PNC-24. This is attributed to stronger van der Waals attractions between particles due to the larger particle size in l-PNC-24. Corresponding effects were revealed using tapping mode atomic force microscopy (TM-AFM) at the l-PNC-air interface; clustering was minimal on the surface of l-PNC-15 but significant for l-PNC-24 droplets. In regions of the l-PNC where the particles were well-dispersed, the spacing between particles is consistent with their volume fractions. This is the first time that the distribution of polymer and particles within l-PNCs has been imaged in situ. PMID- 25738747 TI - Engineering of unsubstituted quinoid-like frameworks enabling 2 V vs. Li(+)/Li redox voltage tunability and related derivatives. AB - A criterion for redox voltage tuning (0.96-2.96 V vs. Li(+)/Li) was derived from DFT calculations on quinoneazine and analogues (C/O replacing N). As rationalized through spin-charge distributions and energetic criteria, high-low voltage implying a bridge with delocalized-localized bond nature mainly originates from ring stabilization. Established guidelines serve to propose optimal derivatives. PMID- 25738748 TI - A metal-organic tetrahedron as a redox vehicle to encapsulate organic dyes for photocatalytic proton reduction. AB - The design of artificial systems that mimic highly evolved and finely tuned natural photosynthetic systems is a subject of intensive research. We report herein a new approach to constructing supramolecular systems for the photocatalytic generation of hydrogen from water by encapsulating an organic dye molecule into the pocket of a redox-active metal-organic polyhedron. The assembled neutral Co4L4 tetrahedron consists of four ligands and four cobalt ions that connect together in alternating fashion. The cobalt ions are coordinated by three thiosemicarbazone NS chelators and exhibit a redox potential suitable for electrochemical proton reduction. The close proximity between the redox site and the photosensitizer encapsulated in the pocket enables photoinduced electron transfer from the excited state of the photosensitizer to the cobalt-based catalytic sites via a powerful pseudo-intramolecular pathway. The modified supramolecular system exhibits TON values comparable to the highest values reported for related cobalt/fluorescein systems. Control experiments based on a smaller tetrahedral analogue of the vehicle with a filled pocket and a mononuclear compound resembling the cobalt corner of the tetrahedron suggest an enzymatic dynamics behavior. The new, well-elucidated reaction pathways and the increased molarity of the reaction within the confined space render these supramolecular systems superior to other relevant systems. PMID- 25738749 TI - Terpenoids of Linaria alpina (L.) Mill. from Dolomites, Italy. AB - This paper reports the first phytochemical analysis of Linaria alpina (L.) Mill., collected in Dolomites (Italy), a species characteristic of mountain environment. Besides aucubin (4), which is rare in the subgenus Antirrhineae of Plantaginaceae, mainly acidic compounds were found, i.e. oleanolic acid (1), ursolic acid (2) maslinic acid (3) and shikimic acid (5). The pentacyclic triterpenes of L. alpina resulted in relatively high content, whereas flavonoids resulted in low content. PMID- 25738750 TI - Discovery and optimization of a novel series of Dyrk1B kinase inhibitors to explore a MEK resistance hypothesis. AB - Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response. PMID- 25738752 TI - Knockdown of flotillin-2 impairs the proliferation of breast cancer cells through modulation of Akt/FOXO signaling. AB - Lipid rafts, specialized domains in cell membranes, function as physical platforms for various molecules to coordinate a variety of signal transduction processes. Flotillin-2 (FLOT2), a marker of lipid rafts, is involved in the progression of cancer, yet the precise mechanism remains unclear. In the present study, we examined the effect of FLOT2 on cell proliferation and found that silencing endogenous FLOT2 with shRNAs inhibited proliferation of breast cancer cells. Furthermore, the antiproliferative effect of silencing FLOT2 on breast cancer cells was associated with upregulation of cyclin-dependent kinase (CDK) inhibitors p21Cip1 and p27Kip1. Moreover, we further demonstrated that the silencing of FLOT2 enhanced the transcriptional activity of FOXO factors by decreasing its phosphorylation through inhibiting the PI3K/Akt signaling pathway. Taken together, our results provide the first demonstration of a novel mechanism by which FLOT2 induces proliferation of breast cancer cells, and our findings suggest that FLOT2 plays an important role in oncogenesis of breast cancer and thereby may be a potential target for human breast cancer treatment. PMID- 25738751 TI - Endogenous interferon-beta-inducible gene expression and interferon-beta treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis. AB - Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-beta is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-beta inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-beta. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-beta-inducible genes in peripheral blood mononuclear cells and interferon-beta-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-beta-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-beta-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-beta are associated with reduced myelin basic protein-induced T cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-beta-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10. PMID- 25738753 TI - Cardiovascular manifestations of Erdheim-Chester disease. AB - Erdheim-Chester disease (ECD) is a rare inflammatory disorder of unknown etiology, characterised by diffuse organ infiltration of CD68-positive, CD1a negative, S100-low/negative foamy histiocytes. It is a non-Langerhans cell histiocytosis which invariably involves bones (96% of cases). Extraskeletal involvement is observed in about 50% of cases. Cardiovascular involvement affects more than 20% of patients and associates with poor prognosis, conferring a reduced response to treatment. Frequent findings are pericardial effusion (24% of patients), "coated aorta", a perivascular circumferential thickening of the aorta, and pericardial thickening. Other typical features include right atrial mass with pseudo-tumoural appearance and histiocytes' infiltration of right atrial walls, atrioventricular sulcus and interatrial septum. After the recent introduction of cardiac cine MRI in the clinical assessment of patients affected by ECD, a growing body of case reports and retrospective data showed that cardiovascular involvement is present more frequently than previously thought and that it is relatively often asymptomatic. Hence, clinicians should systematically screen ECD patients for occult cardiovascular involvement by means of highly sensitive imaging tools. Despite these recent novelties, comprehensive literature reviews focusing on ECD cardiovascular involvement and its imaging assessment in the last decade are lacking. PMID- 25738754 TI - Tricetin, a dietary flavonoid, suppresses benzo(a)pyrene-induced human non-small cell lung cancer bone metastasis. AB - This is the first study to demonstrate that benzo(a)-pyrene (BaP) was able to enhance the production of parathyroid hormone-related protein (PTHrP) by human non-small cell lung cancer H460 cells. Such effect would further contribute to bone metastasis of lung cancer by increasing osteoclastogenesis. This study is also the first to reveal that tricetin (TCN), a flavonoid derivative found in Myrtaceae pollen and Eucalyptus honey, was able to reverse BaP-mediated bone resorption activity of lung cancer cells. Human non-small cell lung cancer H460 cells were treated with BaP to generate conditioned medium. When osteoblasts were cultured with BaP-H460-CM, their expression of osteoclastogenesis activator macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL) was increased. BaP-H460-CM reduced the production of osteoprotegerin (OPG), an osteoclastogenesis inhibitor, in osteoblasts. Osteoclastogenesis and bone resorption activity of H460 cells were increased by BaP-H460-CM. With BaP-mediated PTHrP upregulation, IL-8 secretion in H460 cells was increased contributing to human non-small cell lung cancer-mediated osteoclast differentiation and bone resorption. Moreover, TCN suppressed BaP mediated bone resorption. Therefore, TCN may be a novel agent for treatment of non-small cell lung cancer patients with bone metastasis. PMID- 25738755 TI - Exciton dispersion in molecular solids. AB - The investigation of the exciton dispersion (i.e. the exciton energy dependence as a function of the momentum carried by the electron-hole pair) is a powerful approach to identify the exciton character, ranging from the strongly localised Frenkel to the delocalised Wannier-Mott limiting cases. We illustrate this possibility at the example of four prototypical molecular solids (picene, pentacene, tetracene and coronene) on the basis of the parameter-free solution of the many-body Bethe-Salpeter equation. We discuss the mixing between Frenkel and charge-transfer excitons and the origin of their Davydov splitting in the framework of many-body perturbation theory and establish a link with model approaches based on molecular states. Finally, we show how the interplay between the electronic band dispersion and the exchange electron-hole interaction plays a fundamental role in setting the nature of the exciton. This analysis has a general validity holding also for other systems in which the electron wavefunctions are strongly localized, as in strongly correlated insulators. PMID- 25738757 TI - Synergistic effects of combined treatment with simvastatin and exemestane on MCF 7 human breast cancer cells. AB - Breast cancer is associated with high levels of incidence, morbidity and mortality; therefore, the identification of effective chemopreventive strategies is crucial. It is important for clinicians to be able to identify the populations at risk who would benefit from chemoprevention, and the interventions that are effective and safe. The aim of the present study was to investigate the combined effects of simvastatin and exemestane on MCF-7 human breast cancer cells. The anti-proliferative effects of simvastatin and exemestane, alone and in combination, on the growth of MCF-7 human breast cancer cells were assessed by MTT assay. The synergism between the two drugs was determined in vitro using the combination index (CI) analysis. Cell cycle distribution and apoptosis were analyzed by flow cytometry, and alterations to the signaling pathway in MCF-7 cells were examined by immunoblotting following treatment with various regimens. The results of the MTT assay indicated that the combined treatment of simvastatin and exemestane significantly decreased the viability of MCF-7 estrogen receptor positive (ER+) human breast cancer cells, as compared with those that were treated with the individual drugs (CI<1). In addition, coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug-treated cells. Furthermore, the results of the present study indicated that these synergistic effects may be associated with the B-cell lymphoma 2 (Bcl-2)/Bcl-2 associated X protein apoptotic pathway and the mitogen-activated protein kinase/mammalian target of rapamycin/p70S6 kinase growth pathway. The combination of exemestane and simvastatin generated synergistic effects on MCF-7 ER+ breast cancer cells, indicating that the combination of these drugs may be a potential therapeutic strategy for the treatment of hormone-dependent breast cancer. The combination of the two inhibitors markedly increased the efficacy, as compared with the single-agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer. The results of the present study suggested that this combination of drugs has therapeutic potential, and requires further mechanistic and biomarker investigations in clinical trials. PMID- 25738756 TI - Hepatic oxidative stress, genotoxicity and vascular dysfunction in lean or obese Zucker rats. AB - Metabolic syndrome is associated with increased risk of cardiovascular disease, which could be related to oxidative stress. Here, we investigated the associations between hepatic oxidative stress and vascular function in pressurized mesenteric arteries from lean and obese Zucker rats at 14, 24 and 37 weeks of age. Obese Zucker rats had more hepatic fat accumulation than their lean counterparts. Nevertheless, the obese rats had unaltered age-related level of hepatic oxidatively damaged DNA in terms of formamidopyrimidine DNA glycosylase (FPG) or human oxoguanine DNA glycosylase (hOGG1) sensitive sites as measured by the comet assay. There were decreasing levels of oxidatively damaged DNA with age in the liver of lean rats, which occurred concurrently with increased expression of Ogg1. The 37 week old lean rats also had higher expression level of Hmox1 and elevated levels of DNA strand breaks in the liver. Still, both strain of rats had increased protein level of HMOX-1 in the liver at 37 weeks. The external and lumen diameters of mesenteric arteries increased with age in obese Zucker rats with no change in media cross-sectional area, indicating outward re-modelling without hypertrophy of the vascular wall. There was increased maximal response to acetylcholine-mediated endothelium-dependent vasodilatation in both strains of rats. Collectively, the results indicate that obese Zucker rats only displayed a modest mesenteric vascular dysfunction, with no increase in hepatic oxidative stress-generated DNA damage despite substantial hepatic steatosis. PMID- 25738758 TI - Complex interaction of deferasirox and Pythium insidiosum: iron-dependent attenuation of growth in vitro and immunotherapy-like enhancement of immune responses in vivo. AB - Pythium insidiosum iron acquisition mechanisms are unknown. We previously showed that the iron chelator deferasirox had weak activity in vitro and in rabbits with experimental pythiosis. Here we show that deferasirox causes damage to P. insidiosum hyphae in vitro, but that activity is diminished in the presence of exogenous iron. The tissue activity of the proinflammatory enzyme adenosine deaminase and the histological pattern observed in pythiosis lesions of rabbits treated with deferasirox were similar to the ones in animals treated with immunotherapy. PMID- 25738759 TI - Examination of cocaine dose in a preclinical model of natural reward devaluation by cocaine. AB - In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution before 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared with day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e. the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e. gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose. PMID- 25738760 TI - Memantine improves observational learning in day-old chicks. AB - Evidence of observational learning (social learning) is present in many species. One such task is the one-trial taste-avoidance task, in which Actor chicks peck a bead coated with an aversant substance. Observer chicks learn to avoid beads that are similar in appearance to the one presented to the Actors. It has been firmly established that active learning of the one-trial taste-avoidance task is dependent on a constrained level of glutamate receptor activation. The current study examined the effects of memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, on the learning by Observers. Memantine produced an inverted U-shaped dose-dependent response curve; 1.0 mmol/l memantine produced significant improvement. These results demonstrate that memantine influences memory formation for observational learning in the day-old chick and support the hypothesis that memantine can improve memories by altering levels of glutamate during memory formation. PMID- 25738761 TI - Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models. AB - The treatment and prevention of hypoxic/ischemic brain injury in stroke patients remain a severe and global medical issue. Numerous clinical studies have resulted in a failure to develop chemical neuroprotection for acute, ischemic stroke. Over 150 estimated clinical trials of ischemic stroke treatments have been done, and more than 200 drugs and combinations of drugs for ischemic and hemorrhagic strokes have been developed. Billions of dollars have been invested for new scientific breakthroughs with only limited success. The revascularization of occluded cerebral arteries such as anti-clot treatments of thrombolysis has proven effective, but it can only be used in a 3-4.5h time frame after the onset of a stroke, and not for every patient. This review is about novel insights on how to resist tissue hypoxia from unconventional animal models. Ability to resist tissue hypoxia is an extraordinary ability that is not common in many laboratory animals such as rat and mouse models. For example, we can learn from a naked mole rat, Chrysemys picta, how to actively regulate brain metabolic activity to defend the brain against fluctuating oxygen tension and acute bouts of oxidative stress following the onset of a stroke. Additionally, a euthermic arctic ground squirrel can teach us how the brain of a stroke patient can remain well oxygenated during tissue hypoxia with no evidence of cellular stress. In this review, we discuss how these animals provide us with a system to gain insight into the possible mechanisms of tissue hypoxia/ischemia. This issue is of clinical significance to stroke patients. We describe specific physiological and molecular adaptations employed by different animals' models of hypoxia tolerance in aquatic and terrestrial environments. We highlight how these adaptations might provide potential clues on strategies to adapt for the clinical management of tissue hypoxia during conditions such as stroke where oxygen demand fails to match the supply. PMID- 25738762 TI - Enantioselective syntheses of sulfoxides in octahedral ruthenium(II) complexes via a chiral-at-metal strategy. AB - The preparation of chiral 2-(alkylsulfinyl)phenol compounds by enantioselective coordination-oxidation of the thioether ruthenium complexes with a chiral-at metal strategy has been developed. The enantiomerically pure sulfoxide complexes Delta-[Ru(bpy)2{(R)-LO-R}](PF6) (bpy is 2,2'-bipyridine, HLO-R is 2 (alkylsulfinyl)phenol, R = Me (Delta-1a), Et (Delta-2a), iPr (Delta-3a), Bn (Delta-4a), and Nap (Delta-5a)) and Lambda-[Ru(bpy)2{(S)-LO-R}](PF6) (R = Me (Lambda-1a), Et (Lambda-2a), iPr (Lambda-3a), Bn (Lambda-4a), and Nap (Lambda 5a)) have been synthesized by the reaction of Delta-[Ru(bpy)2(py)2](2+) or Lambda [Ru(bpy)2(py)2](2+) with the prochiral thioether ligands 2-(alkylthio)phenol (HL R), followed by enantioselective oxidation with m-CPBA as oxidant. The X-ray crystallography was used to verify the stereochemistry of ruthenium complexes and sulfur atoms. The configurations of the ruthenium complexes are stable during the coordination and oxidation reactions. Moreover, the chiral sulfoxide ligands are enantioselectively generated by controlling of the configuration of ruthenium centers in the course of oxidation reaction. That is, the Lambda configuration at the ruthenium center generates the S sulfoxide ligand; on the contrary, the Delta configuration of the ruthenium complex originates the R sulfoxide ligand. Acidolysis of Lambda-[Ru(bpy)2{(R)-LO-R}](PF6) and Delta-[Ru(bpy)2{(S)-LO R}](PF6) complexes in the presence of TFA-MeCN afforded the chiral ligands (R) HLO-R and (S)-HLO-R in 96-99% ee values, respectively. Importantly, the chiral ruthenium complexes can be recycled as Delta/Lambda-[Ru(bpy)2(MeCN)2](PF6)2 and reused in a next reaction cycle with complete retention of the configurations at ruthenium centers. PMID- 25738763 TI - Vector graph assisted pedestrian dead reckoning using an unconstrained smartphone. AB - The paper presents a hybrid indoor positioning solution based on a pedestrian dead reckoning (PDR) approach using built-in sensors on a smartphone. To address the challenges of flexible and complex contexts of carrying a phone while walking, a robust step detection algorithm based on motion-awareness has been proposed. Given the fact that step length is influenced by different motion states, an adaptive step length estimation algorithm based on motion recognition is developed. Heading estimation is carried out by an attitude acquisition algorithm, which contains a two-phase filter to mitigate the distortion of magnetic anomalies. In order to estimate the heading for an unconstrained smartphone, principal component analysis (PCA) of acceleration is applied to determine the offset between the orientation of smartphone and the actual heading of a pedestrian. Moreover, a particle filter with vector graph assisted particle weighting is introduced to correct the deviation in step length and heading estimation. Extensive field tests, including four contexts of carrying a phone, have been conducted in an office building to verify the performance of the proposed algorithm. Test results show that the proposed algorithm can achieve sub meter mean error in all contexts. PMID- 25738764 TI - Sub-sampling framework comparison for low-power data gathering: a comparative analysis. AB - A key design challenge for successful wireless sensor network (WSN) deployment is a good balance between the collected data resolution and the overall energy consumption. In this paper, we present a WSN solution developed to efficiently satisfy the requirements for long-term monitoring of a historical building. The hardware of the sensor nodes and the network deployment are described and used to collect the data. To improve the network's energy efficiency, we developed and compared two approaches, sharing similar sub-sampling strategies and data reconstruction assumptions: one is based on compressive sensing (CS) and the second is a custom data-driven latent variable-based statistical model (LV). Both approaches take advantage of the multivariate nature of the data collected by a heterogeneous sensor network and reduce the sampling frequency at sub-Nyquist levels. Our comparative analysis highlights the advantages and limitations: signal reconstruction performance is assessed jointly with network-level energy reduction. The performed experiments include detailed performance and energy measurements on the deployed network and explore how the different parameters can affect the overall data accuracy and the energy consumption. The results show how the CS approach achieves better reconstruction accuracy and overall efficiency, with the exception of cases with really aggressive sub-sampling policies. PMID- 25738765 TI - A high speed CMOS image sensor with a novel digital correlated double sampling and a differential difference amplifier. AB - In order to increase the operating speed of a CMOS image sensor (CIS), a new technique of digital correlated double sampling (CDS) is described. In general, the fixed pattern noise (FPN) of a CIS has been reduced with the subtraction algorithm between the reset signal and pixel signal. This is because a single slope analog-to-digital converter (ADC) has been normally adopted in the conventional digital CDS with the reset ramp and signal ramp. Thus, the operating speed of a digital CDS is much slower than that of an analog CDS. In order to improve the operating speed, we propose a novel digital CDS based on a differential difference amplifier (DDA) that compares the reset signal and the pixel signal using only one ramp. The prototype CIS has been fabricated with 0.13 um CIS technology and it has the VGA resolution of 640 * 480. The measured conversion time is 16 us, and a high frame rate of 131 fps is achieved at the VGA resolution. PMID- 25738766 TI - Detection of bird nests during mechanical weeding by incremental background modeling and visual saliency. AB - Mechanical weeding is an important tool in organic farming. However, the use of mechanical weeding in conventional agriculture is increasing, due to public demands to lower the use of pesticides and an increased number of pesticide resistant weeds. Ground nesting birds are highly susceptible to farming operations, like mechanical weeding, which may destroy the nests and reduce the survival of chicks and incubating females. This problem has limited focus within agricultural engineering. However, when the number of machines increases, destruction of nests will have an impact on various species. It is therefore necessary to explore and develop new technology in order to avoid these negative ethical consequences. This paper presents a vision-based approach to automated ground nest detection. The algorithm is based on the fusion of visual saliency, which mimics human attention, and incremental background modeling, which enables foreground detection with moving cameras. The algorithm achieves a good detection rate, as it detects 28 of 30 nests at an average distance of 3.8 m, with a true positive rate of 0.75. PMID- 25738767 TI - Opportunistic mobility support for resource constrained sensor devices in smart cities. AB - A multitude of wireless sensor devices and technologies are being developed and deployed in cities all over the world. Sensor applications in city environments may include highly mobile installations that span large areas which necessitates sensor mobility support. This paper presents and validates two mechanisms for supporting sensor mobility between different administrative domains. Firstly, EAP Swift, an Extensible Authentication Protocol (EAP)-based sensor authentication protocol is proposed that enables light-weight sensor authentication and key generation. Secondly, a mechanism for handoffs between wireless sensor gateways is proposed. We validate both mechanisms in a real-life study that was conducted in a smart city environment with several fixed sensors and moving gateways. We conduct similar experiments in an industry-based anechoic Long Term Evolution (LTE) chamber with an ideal radio environment. Further, we validate our results collected from the smart city environment against the results produced under ideal conditions to establish best and real-life case scenarios. Our results clearly validate that our proposed mechanisms can facilitate efficient sensor authentication and handoffs while sensors are roaming in a smart city environment. PMID- 25738768 TI - Biosignal analysis to assess mental stress in automatic driving of trucks: palmar perspiration and masseter electromyography. AB - Nowadays insight into human-machine interaction is a critical topic with the large-scale development of intelligent vehicles. Biosignal analysis can provide a deeper understanding of driver behaviors that may indicate rationally practical use of the automatic technology. Therefore, this study concentrates on biosignal analysis to quantitatively evaluate mental stress of drivers during automatic driving of trucks, with vehicles set at a closed gap distance apart to reduce air resistance to save energy consumption. By application of two wearable sensor systems, a continuous measurement was realized for palmar perspiration and masseter electromyography, and a biosignal processing method was proposed to assess mental stress levels. In a driving simulator experiment, ten participants completed automatic driving with 4, 8, and 12 m gap distances from the preceding vehicle, and manual driving with about 25 m gap distance as a reference. It was found that mental stress significantly increased when the gap distances decreased, and an abrupt increase in mental stress of drivers was also observed accompanying a sudden change of the gap distance during automatic driving, which corresponded to significantly higher ride discomfort according to subjective reports. PMID- 25738769 TI - A guided wave sensor based on the inverse magnetostrictive effect for distinguishing symmetric from asymmetric features in pipes. AB - The magnetostrictive guided wave sensor with a single induced winding cannot distinguish axially symmetric from non-axially symmetric features in a pipe, because it is impossible for the sensor to detect the non-axially symmetric mode waves. When we study the effect of the change of the magnetic field in the air zone for receiving the longitudinal guided wave mode, we find that the change of the magnetic flux in the air zone is almost equivalent to the change of the flux in the pipe wall, but in opposite directions. Based on this phenomenon, we present a sensor that can detect the flexural-mode waves in pipes based on the inverse magnetostrictive effect. The sensor is composed of several coils that are arranged evenly on the outside of pipes. The coils induce a change in magnetic flux in the air to detect the flexural-mode waves. The waves can be determined by adding a phase delay to the induced signals. The symmetric and asymmetric features of a pipe can be distinguished using the sensor. A prototype sensor that can detect F(1,3) and F(2,3) mode waves is presented. The function of the sensor is verified by experiments. PMID- 25738770 TI - Coinjection with TLR2 agonist Pam3CSK4 reduces the pathology of leishmanization in mice. AB - Cutaneous leishmaniasis caused by Leishmania major is an emergent, uncontrolled public health problem and there is no vaccine. A promising prophylactic approach has been immunotherapy with Toll-like receptor (TLR) agonists to enhance parasite specific immune responses. We have previously reported that vaccination of C57BL/6 mice with live L. major plus the TLR9 agonist CpG DNA prevents lesion development and confers immunity to reinfection. Our current study aims to investigate whether other TLR agonists can be used in leishmanization without induction of lesion formation. We found that live L. major plus the TLR2 agonist Pam3CSK4 reduced the pathology in both genetically resistant (C57BL/6) and susceptible (BALB/c) mouse strains. The addition of Pam3CSK4 activated dermal dendritic cells and macrophages to produce greater amounts of proinflammatory cytokines in both mouse strains. Both Th1 and Th17 responses were enhanced by leishmanization with L. major plus Pam3CSK4 in C57BL/6 mice; however, Th17 cells were unchanged in BALB/c mice. The production of IL-17 from neutrophils was enhanced in both strains infected with L. major plus Pam3CSK4. However, the sustained influx of neutrophils in sites of infection was only observed in BALB/c mice. Our data demonstrate that the mechanism behind leishmanization with TLR agonists may be very different depending upon the immunological background of the host. This needs to be taken into account for the rational development of successful vaccines against the disease. PMID- 25738771 TI - UNC50 prompts G1/S transition and proliferation in HCC by regulation of epidermal growth factor receptor trafficking. AB - BACKGROUND: UNC50 has long been recognized as a Golgi apparatus protein in yeast, and is involved in nicotinic receptor trafficking in Caenorhabditis elegans, but little is known about UNC50 gene function in human biology despite it being conserved from yeast to high eukaryotes. OBJECTIVES: We investigated the relation between UNC50 and human hepatocellular carcinoma (HCC) and the potential mechanisms underlying HCC development. METHODS: UNC50 mRNA expression patterns in 12 HCC and adjacent non-cancerous tissues determined using northern blotting were confirmed by real-time PCR in another 44 paired tissues. Microarray experiments were used to screen for global effects of UNC50 knockdown in the Hep3B cell line, and were confirmed by real-time PCR, western blotting, flow cytometry, and tetrazolium assay in both UNC50 overexpression and knockdown Hep3B cells. RESULTS: UNC50 expression levels were upregulated in HCC tissues in comparison with the adjacent non-cancerous tissues. UNC50 knockdown reduced mRNA levels of the downstream targets of the epidermal growth factor receptor (EGFR) pathway: cyclin D1 (CCND1), EGF, matrix metalloproteinase-7 (MMP7), aldose reductase-like 1 (AKR1B10), cell surface-associated mucin 1 (MUC1), and gastrin (GAST). Moreover, UNC50 influenced EGF, inducing cell cycle entry by affecting cell surface EGFR amounts. CONCLUSIONS: UNC50 may plays some roles in HCC progression by affecting the EGFR pathway. PMID- 25738772 TI - Clinical pathology reference intervals for an in-water population of juvenile loggerhead sea turtles (Caretta caretta) in Core Sound, North Carolina, USA. AB - The loggerhead sea turtle (Caretta caretta) is found throughout the waters of the Atlantic, Pacific, and Indian Oceans. It is a protected species throughout much of its range due to threats such as habitat loss, fisheries interactions, hatchling predation, and marine debris. Loggerheads that occur in the southeastern U.S. are listed as "threatened" on the U.S. Endangered Species List, and receive state and federal protection. As part of an on-going population assessment conducted by the National Marine Fisheries Service, samples were collected from juvenile loggerhead sea turtles in Core Sound, North Carolina, between 2004 and 2007 to gain insight on the baseline health of the threatened Northwest Atlantic Ocean population. The aims of the current study were to establish hematologic and biochemical reference intervals for this population, and to assess variation of the hematologic and plasma biochemical analytes by season, water temperature, and sex and size of the turtles. Reference intervals for the clinical pathology parameters were estimated following Clinical Laboratory Standards Institute guidelines. Season, water temperature, sex, and size of the turtles were found to be significant factors of variation for parameter values. Seasonal variation could be attributed to physiological effects of decreasing photoperiod, cooler water temperature, and migration during the fall months. Packed cell volume, total protein, and albumin increased with increasing size of the turtles. The size-related differences in analytes documented in the present study are consistent with other reports of variation in clinical pathology parameters by size and age in sea turtles. As a component of a health assessment of juvenile loggerhead sea turtles in North Carolina, this study will serve as a baseline aiding in evaluation of trends for this population and as a diagnostic tool for assessing the health and prognosis for loggerhead sea turtles undergoing rehabilitation. PMID- 25738773 TI - Modeling photoionization of aqueous DNA and its components. AB - Radiation damage to DNA is usually considered in terms of UVA and UVB radiation. These ultraviolet rays, which are part of the solar spectrum, can indeed cause chemical lesions in DNA, triggered by photoexcitation particularly in the UVB range. Damage can, however, be also caused by higher energy radiation, which can ionize directly the DNA or its immediate surroundings, leading to indirect damage. Thanks to absorption in the atmosphere, the intensity of such ionizing radiation is negligible in the solar spectrum at the surface of Earth. Nevertheless, such an ionizing scenario can become dangerously plausible for astronauts or flight personnel, as well as for persons present at nuclear power plant accidents. On the beneficial side, ionizing radiation is employed as means for destroying the DNA of cancer cells during radiation therapy. Quantitative information about ionization of DNA and its components is important not only for DNA radiation damage, but also for understanding redox properties of DNA in redox sensing or labeling, as well as charge migration along the double helix in nanoelectronics applications. Until recently, the vast majority of experimental and computational data on DNA ionization was pertinent to its components in the gas phase, which is far from its native aqueous environment. The situation has, however, changed for the better due to the advent of photoelectron spectroscopy in liquid microjets and its most recent application to photoionization of aqueous nucleosides, nucleotides, and larger DNA fragments. Here, we present a consistent and efficient computational methodology, which allows to accurately evaluate ionization energies and model photoelectron spectra of aqueous DNA and its individual components. After careful benchmarking, the method based on density functional theory and its time-dependent variant with properly chosen hybrid functionals and polarizable continuum solvent model provides ionization energies with accuracy of 0.2-0.3 eV, allowing for faithful modeling and interpretation of DNA photoionization. The key finding is that the aqueous medium is remarkably efficient in screening the interactions within DNA such that, unlike in the gas phase, ionization of a base, nucleoside, or nucleotide depends only very weakly on the particular DNA context. An exception is the electronic interaction between neighboring bases which can lead to sequence-specific effects, such as a partial delocalization of the cationic hole upon ionization enabled by presence of adjacent bases of the same type. PMID- 25738774 TI - Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity. AB - Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as 'strains' in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called 'variants', dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI(+)] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1. Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored. PMID- 25738776 TI - Isoform switch of pyruvate kinase M1 indeed occurs but not to pyruvate kinase M2 in human tumorigenesis. AB - Muscle type of pyruvate kinase (PKM) is one of the key mediators of the Warburg effect and tumor metabolism. Due to alternative splicing, there are at least 12 known isoforms of the PKM gene, of which PKM1 and PKM2 are two major isoforms with only a 23 amino acid sequenced difference but quite different characteristics and functions. It was previously thought the isoform switch from PKM1 to PKM2 resulted in high PKM2 expression in tumors, providing a great advantage to tumor cells. However, this traditional view was challenged by two recent studies; one study claimed that this isoform switch does not occur during the Warburg effect; the other study asserted that the isoform switch is tissue specific. Here, we re-analyzed the RNA sequencing data of 25 types of human tumors from The Cancer Genome Atlas Data Portal, and confirmed that PKM2 was the major isoform in the tumors and was highly elevated in addition to the entire PKM gene. We further demonstrated that the expression level of PKM1 significantly declined even though there was substantially increased expression of the entire PKM gene. The proportion of PKM1 in total transcript variants also significantly declined in tumors but the proportion of PKM2 did not change accordingly. Therefore, we conclude that the isoform switch of PKM1 does indeed occur, but it switches to other isoforms rather than PKM2. Considering the change in the expression levels of PKM1, PKM2 and the entire PKM gene, we propose that the upregulation of PKM2 is primarily due to elevated transcriptional levels of the entire PKM gene, instead of the isoform switch. PMID- 25738779 TI - A case of an anaplastic meningioma metastasizing to the mediastinal lymph nodes. AB - CONTEXT: Grade II and III (World Health Organization classification) meningiomas rarely develop in the spinal cord. However, we experienced a case with an anaplastic meningioma that developed in the spinal cord at the cervicothoracic junction and metastasized to the mediastinal lymph nodes. No such cases have previously been reported. FINDINGS: The patient was a 68-year-old man who developed back pain that did not affect his daily living. He developed left lower limb paralysis, and was admitted after magnetic resonance imaging (MRI) revealed an intramedullary tumor at the level of cervical vertebra 7 and thoracic vertebra 1. Positron emission tomography revealed tracer uptake in the intramedullary tumor and the mediastinal lymph nodes, suggesting a metastatic spinal cord tumor or malignant lymphoma. A lymph node biopsy was then performed. Although the tumor was highly malignant, its primary site was not identified. Detailed examinations by several other departments revealed no abnormalities. On hospital day 30, his left lower limb paralysis deteriorated, and MRI revealed that the tumor had grown. Thus, laminaplasty, laminectomy, and tumor resection were performed. The tumor was an anaplastic meningioma that resembled mediastinal lymph node tissue, and other tumor lesions were not found. These findings suggested that an anaplastic meningioma had metastasized to the mediastinal lymph nodes. The patient did not respond to radiotherapy, and he was transferred to another hospital. CONCLUSION: In cases of intramedullary spinal tumors with metastasis without other potential primary tumor lesions, early diagnosis and treatment should be performed while considering anaplastic meningioma. PMID- 25738780 TI - Voluntary medical male circumcision for HIV prevention and early resumption of sexual activity: a literature review. AB - A number of programs have focused on scale-up and implementation research regarding voluntary medical male circumcision; however, there is limited research with regard to factors and strategies related to abstinence compliance and the effects of resuming sex during the wound healing period (42-day post circumcision). We searched the literature for peer-reviewed articles examining early resumption of sex during this period. This review identifies factors that may predispose a client to engage in sex during the 42-day postoperative period, examines how early resumption of sex can inhibit wound healing and increase seroconversion, and reviews strategies that may increase adherence to abstinence during the wound healing period. We found that the most common factor that may predispose a client to engage in sex before the end of the postoperative period is marriage or cohabitation with a sexual partner. With regard to the effect of sex during the postoperative period on wound healing and seroconversion, we found that adverse events incurred were mild, and there was an increased risk of seroconversion. The only strategy studied to increase compliance to abstinence during the postoperative period utilized text messaging, and the trial results indicate that text messaging did not increase abstinence compliance. PMID- 25738781 TI - Thromboxane synthase deficiency improves insulin action and attenuates adipose tissue fibrosis. AB - Thromboxane A2, an arachidonic acid-derived eicosanoid generated by thromboxane synthase (TBXAS), plays critical roles in hemostasis and inflammation. However, the contribution of thromboxane A2 to obesity-linked metabolic dysfunction remains incompletely understood. Here, we used in vitro and mouse models to better define the role of TBXAS in metabolic homeostasis. We found that adipose expression of Tbxas and thromboxane A2 receptor (Tbxa2r) was significantly upregulated in genetic and dietary mouse models of obesity and diabetes. Expression of Tbxas and Tbxa2r was detected in adipose stromal cells, including macrophages. Furthermore, stimulation of macrophages with interferon-gamma or resistin factors known to be upregulated in obesity induced Tbxas and Tbxa2r expression. Mice lacking Tbxas had similar weight gain, food intake, and energy expenditure. However, loss of Tbxas markedly enhanced insulin sensitivity in mice fed a low-fat diet. Improvement in glucose homeostasis was correlated with the upregulated expression of multiple secreted metabolic regulators (Ctrp3, Ctrp9, and Ctrp12) in the visceral fat depot. Following a challenge with a high-fat diet, Tbxas deficiency led to attenuated adipose tissue fibrosis and reduced circulating IL-6 levels without adipose tissue macrophages being affected; however, these changes were not sufficient to improve whole body insulin action. Together, our results highlight a novel, diet-dependent role for thromboxane A2 in modulating peripheral tissue insulin sensitivity and adipose tissue fibrosis. PMID- 25738782 TI - Sex and depot differences in ex vivo adipose tissue fatty acid storage and glycerol-3-phosphate acyltransferase activity. AB - Adipose tissue fatty acid storage varies according to sex, adipose tissue depot, and degree of fat gain. However, the mechanism(s) for these variations is not completely understood. We examined whether differences in adipose tissue glycerol 3-phosphate acyltransferase (GPAT) might play a role in these variations. We optimized an enzyme activity assay for total GPAT and GPAT1 activity in human adipose tissue and measured GPAT activity. Omental and subcutaneous adipose tissue was collected from obese and nonobese adults for measures of GPAT and GPAT1 activities, ex vivo palmitate storage, acyl-CoA synthetase (ACS) and diacylglycerol-acyltransferase (DGAT) activities, and CD36 protein. Total GPAT and GPAT1 activities decreased as a function of adipocyte size in both omental (r = -0.71, P = 0.003) and subcutaneous (r = -0.58, P = 0.04) fat. The relative contribution of GPAT1 to total GPAT activity increased as a function of adipocyte size, accounting for up to 60% of GPAT activity in those with the largest adipocytes. We found strong, positive correlations between ACS, GPAT, and DGAT activities for both sexes and depots (r values 0.58-0.91) and between these storage factors and palmitate storage rates into TAG (r values 0.55-0.90). We conclude that: 1) total GPAT activity decreases as a function of adipocyte size; 2) GPAT1 can account for over half of adipose GPAT activity in hypertrophic obesity; and 3) ACS, GPAT, and DGAT are coordinately regulated. PMID- 25738783 TI - Adrenergically stimulated blood flow in brown adipose tissue is not dependent on thermogenesis. AB - Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen and for the distribution of the generated heat to the rest of the body. Therefore, it is fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here, we present high resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel noninvasive method to detect BAT perfusion, we demonstrate that adrenergically stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and therefore, it is not a reliable parameter for the estimation of BAT activation and heat generation. PMID- 25738784 TI - Hypoenergetic diet-induced reductions in myofibrillar protein synthesis are restored with resistance training and balanced daily protein ingestion in older men. AB - Strategies to enhance weight loss with a high fat-to-lean ratio in overweight/obese older adults are important since lean loss could exacerbate sarcopenia. We examined how dietary protein distribution affected muscle protein synthesis during energy balance (EB), energy restriction (ER), and energy restriction plus resistance training (ER + RT). A 4-wk ER diet was provided to overweight/obese older men (66 +/- 4 yr, 31 +/- 5 kg/m(2)) who were randomized to either a balanced (BAL: 25% daily protein/meal * 4) or skewed (SKEW: 7:17:72:4% daily protein/meal; n = 10/group) pattern. Myofibrillar and sarcoplasmic protein fractional synthetic rates (FSR) were measured during a 13-h primed continuous infusion of l-[ring-(13)C6]phenylalanine with BAL and SKEW pattern of protein intake in EB, after 2 wk ER, and after 2 wk ER + RT. Fed-state myofibrillar FSR was lower in ER than EB in both groups (P < 0.001), but was greater in BAL than SKEW (P = 0.014). In ER + RT, fed-state myofibrillar FSR increased above ER in both groups and in BAL was not different from EB (P = 0.903). In SKEW myofibrillar FSR remained lower than EB (P = 0.002) and lower than BAL (P = 0.006). Fed-state sarcoplasmic protein FSR was reduced similarly in ER and ER + RT compared with EB (P < 0.01) in both groups. During ER in overweight/obese older men a BAL consumption of protein stimulated the synthesis of muscle contractile proteins more effectively than traditional, SKEW distribution. Combining RT with a BAL protein distribution "rescued" the lower rates of myofibrillar protein synthesis during moderate ER. PMID- 25738785 TI - Point Prevalence, Clinical Characteristics, and Treatment Variation for Infants with Severe Bronchopulmonary Dysplasia. AB - OBJECTIVES: Despite improvements in survival of preterm infants, bronchopulmonary dysplasia (BPD) remains a persistent morbidity. The incidence, clinical course, and current management of severe BPD (sBPD) remain to be defined. To address these knowledge gaps, a multicenter collaborative was formed to improve outcomes in this population. STUDY DESIGN: We performed a "snapshot" in eight neonatal intensive care units (NICUs) on December 17, 2013. A standardized clinical data form for each inpatient born at < 32 weeks was completed and collated centrally for analysis. sBPD was defined as receiving >= 30% supplemental oxygen and/or receiving positive pressure ventilation at 36 weeks postmenstrual age (PMA). RESULTS: Of a total census of 710 inpatients, 351 infants were born at < 32 weeks and 128 of those (36.5%) met criteria for sBPD. The point prevalence of sBPD varied between centers (11-58%; p < 0.001). Among infants with sBPD there was a variation among centers in the use of mechanical ventilation at 28 days of life (p < 0.001) and at 36 weeks PMA (p = 0.001). We observed differences in the use of diuretics (p = 0.018), inhaled corticosteroids (p < 0.001), and inhaled beta agonists (p < 0.001). CONCLUSION: The high point prevalence of sBPD and variable management among NICUs emphasizes the lack of evidence in guiding optimal care to improve long-term outcomes of this high-risk, understudied population. PMID- 25738786 TI - Active Warming during Cesarean Delivery: Should We SCIP It? AB - BACKGROUND: The purpose of this open, cluster randomized controlled trial was to evaluate whether use of a fiber optic-regulated warming mattress would decrease the incidence of hypothermia in women undergoing cesarean delivery. PATIENTS AND METHODS: A total of 484 women were randomized via the cluster method on a rotating weekly basis allocating participants to either use of the warming mattress or the standard method of warming at Parkland Hospital (heat-retaining caps, warmed intravenous and irrigation fluids, and warmed blankets). The primary outcome of interest was maternal hypothermia. Surgical site infections and neonatal outcomes were also assessed. RESULTS: The incidence of maternal hypothermia at the conclusion of the surgery was decreased in the warming mattress group, 67 versus 80% in the standard method group (p = 0.013). There were no significant differences in maternal hypothermia at delivery or on arrival to the postanesthesia care unit. The difference in surgical site infections and neonatal outcomes were nonsignificant. CONCLUSION: Use of a warming mattress reduced the incidence of maternal hypothermia at the conclusion of surgery; however, on admission to the postanesthesia care unit, these effects had dissipated. PMID- 25738787 TI - Improving the Quality of Radiographs in Neonatal Intensive Care Unit Utilizing Educational Interventions. AB - OBJECTIVE: We aimed to develop an educational tool to improve the radiograph quality, sustain this improvement overtime, and reduce the number of repeat radiographs. STUDY DESIGN: A three phase quality control study was conducted at a tertiary care NICU. A retrospective data collection (phase1) revealed suboptimal radiograph quality and led to an educational intervention and development of X ray preparation checklist (primary intervention), followed by a prospective data collection for 4 months (phase 2). At the end of phase 2, interim analysis revealed a gradual decline in radiograph quality, which prompted a more comprehensive educational session with constructive feedback to the NICU staff (secondary intervention), followed by another data collection for 6 months (phase 3). RESULTS: There was a significant improvement in the quality of radiographs obtained after primary educational intervention (phase 2) compared with phase 1 (p < 0.001). During interim analysis after phase 2, radiograph quality declined but still remained significantly better than phase 1. Secondary intervention resulted in significant improvement in radiograph quality to > 95% in all domains of image quality. No radiographs were repeated in phase 3, compared with 5.8% (16/277) in phase 1. CONCLUSION: A structured, collaborated educational intervention successfully improves the radiograph quality and decreases the need for repeat radiographs and radiation exposure in the neonates. PMID- 25738788 TI - Evaluation of Early Transcutaneous Bilirubinometry to Predict Subsequent Hyperbilirubinemia in Neonates Admitted to a Well-Baby Nursery. AB - OBJECTIVE: The aim of this study is to determine whether a transcutaneous bilirubin (TcB) value obtained within 6 hours of birth (early transcutaneous bilirubin [ETcB]) either alone, or used to calculate an early rate of rise (E ROR) in TcB, will identify those neonates who are at a higher risk for subsequent jaundice. STUDY DESIGN: ETcB values were obtained from a convenience sample of neonates admitted to the newborn nursery. E-ROR was calculated as the average hourly increase between ETcB and subsequent TcB obtained at 18 to 36 hours of age. TcB percentile values at various ages were obtained from a previously published and cross-validated nomogram. The predictive values relating ETcB, E ROR, and TcB at 18 to 36 hours of age to TcB at 42 to 66 hours of age were determined, and receiver-operator characteristic curves were compared. RESULTS: A total of 516 late preterm and term neonates were studied. ETcB was higher (p = 0.003) in those neonates who subsequently received phototherapy (n = 15), and negative predictive value was always >= 0.96; positive predictive value (PPV) ranged from 0.04 to 0.06. Compared with ETcB, TcB at 18 to 36 hours was more likely to predict significant jaundice at 42 to 66 hours of age. CONCLUSION: Given the observed low PPV, ETcB is not useful in identifying infants who develop subsequent hyperbilirubinemia. However, it may be helpful in identifying those neonates at a low risk of subsequent hyperbilirubinemia. PMID- 25738789 TI - Tidal Volume Requirement in Mechanically Ventilated Infants with Meconium Aspiration Syndrome. AB - OBJECTIVE: The aim of the study is to test the hypothesis that increased physiologic dead space and functional residual capacity seen in meconium aspiration syndrome (MAS) results in higher tidal volume (VT) requirement to achieve adequate ventilation. STUDY DESIGN: Retrospective review of infants with MAS admitted to our hospital from 2000 to 2010 managed with conventional ventilation. Demographics, ventilator settings, VT, respiratory rate (RR), and blood gas values were recorded. Minute ventilation (MV) was calculated as RR * VT. Only VT values with corresponding partial pressure of carbon dioxide (Paco 2) between 35 and 60 mm Hg were included. Mean VT/kg and MV/kg were calculated for each patient. Forty infants ventilated for lung disease other than MAS or pulmonary hypoplasia served as controls. RESULTS: Birth weights of the 28 MAS patients and 40 control infants were similar (3,330 +/- 500 g and 3,300 +/- 640 g). Two patients in each group required extracorporeal membrane oxygenation. Infants with MAS required 26% higher VT and 42% higher MV compared with controls to maintain equal Paco 2. CONCLUSION: Infants with MAS require larger VT and higher total MV to achieve similar alveolar ventilation, consistent with pathophysiology of MAS. Our findings provide the first reference data to guide selection of VT in infants with MAS. PMID- 25738791 TI - Oxidative Stress-Mediated Damage in Newborns with Necrotizing Enterocolitis: A Possible Role of Melatonin. AB - BACKGROUND: Necrotizing enterocolitis is a gastrointestinal surgical emergency in premature neonates. Free radicals have been linked to the development of the disease in infants. Ischemia, hypoxia-reperfusion, infection, and inflammation produce elevated levels of reactive oxygen species, impairing the redox balance and shifting cells into a state of oxidative stress. Melatonin, an effective direct free-radical scavenger and indirect antioxidant agent, exerts pleiotropic action on the human body. Several studies have tested the efficacy of melatonin in counteracting oxidative injury in diseases of newborns. Melatonin has been widely used in newborns including cases of asphyxia, respiratory distress syndrome, and sepsis, and no significant toxicity or treatment-related side effects with long-term melatonin therapy have been reported. CONCLUSION: Therefore, melatonin, besides standard therapies, could be considered as a potentially safe approach to prevent and treat necrotizing enterocolitis in premature infants. This review summarizes what is known about the role of oxidative stress, and potentially beneficial effects of antioxidants, such as melatonin, in necrotizing enterocolitis. PMID- 25738790 TI - Preventing Preterm Birth with Progesterone in Women with a Short Cervical Length from a Low-Risk Population: A Multicenter Double-Blind Placebo-Controlled Randomized Trial. AB - OBJECTIVE: The objective of this study was to evaluate the effectiveness of vaginal progesterone in reducing adverse neonatal outcome due to preterm birth (PTB) in low-risk pregnant women with a short cervical length (CL). STUDY DESIGN: Women with a singleton pregnancy without a history of PTB underwent CL measurement at 18 to 22 weeks. Women with a CL <= 30 mm received vaginal progesterone or placebo. Primary outcome was adverse neonatal outcome, defined as a composite of respiratory distress syndrome, bronchopulmonary dysplasia, intracerebral hemorrhage > grade II, necrotizing enterocolitis > stage 1, proven sepsis, or death before discharge. Secondary outcomes included time to delivery, PTB before 32, 34, and 37 weeks of gestation. Analysis was by intention to treat. RESULTS: Between 2009 and 2013, 20,234 women were screened. A CL of 30 mm or less was seen in 375 women (1.8%). In 151 women, a CL <= 30 mm was confirmed with a second measurement and 80 of these women agreed to participate in the trial. We randomly allocated 41 women to progesterone and 39 to placebo. Adverse neonatal outcomes occurred in two (5.0%) women in the progesterone and in four (11%) women in the control group (relative risk [RR], 0.47; 95% confidence interval [CI], 0.09-2.4). The use of progesterone resulted in a nonsignificant reduction of PTB < 32 weeks (2.0 vs. 8.0%; RR, 0.33; 95% CI, 0.04-3.0) and < 34 weeks (7.0 vs. 10%; RR, 0.73; 95% CI, 0.18-3.1) but not on PTB < 37 weeks (15 vs. 13%; RR, 1.2; 95% CI, 0.39-3.5). CONCLUSION: In women with a short cervix, who are otherwise low risk, we could not show a significant benefit of progesterone in reducing adverse neonatal outcome and PTB. PMID- 25738792 TI - Patient expectations of emergency hospital admission: a cross-sectional questionnaire survey. AB - OBJECTIVES: Emergency admissions are rising, but little is known about the patient perspective. We aimed to explore the views of patients assessed for admission in terms of (i) whether they expected to be admitted, (ii) the comfort, convenience and safety of admission and (iii) whether satisfaction with care was influenced by expectations of admission being met. PATIENTS AND METHODS: We undertook a cross-sectional survey of 200 patients who arrived by emergency ambulance and were assessed for the need for admission. Patients completed a questionnaire that recorded their expectations of hospital admission before a decision was made to admit or discharge and their satisfaction with the decision when it was made. RESULTS: The study population was 63% (127/200) female, with a mean age of 61 years. Around 45 of 200 (22.5%) patients expected themselves to be admitted, whereas 85/200 (42.5%) were actually admitted. Responses indicated that 74.5% [95% confidence interval (CI) 68.0-80.0%] agreed or strongly agreed that they felt safer in hospital than at home, 47.5% (95% CI 40.7-54.4%) felt more comfortable in hospital and 86.0% (95% CI 81.1-90.6%) agreed that it would be easier to provide treatment for them if they were admitted. We found no evidence of an association between patient satisfaction and expectations being met in those expecting admission (P=0.301) or expecting discharge home (P=0.885). CONCLUSION: Most patients being assessed for admission do not expect to be admitted, but most report positive views about the safety, comfort and convenience of hospital admission. We found no evidence of reduced satisfaction if expectations about admission are not met. PMID- 25738793 TI - Individualized rescuer change by a team leader during uninterrupted cardiopulmonary resuscitation: comparison with rescuer change in 2-min intervals. AB - OBJECTIVE: Currently recommended cardiopulmonary resuscitation (CPR) guidelines to change rescuers in 2-min intervals do not consider the differences in the physical capability of individual rescuers. We compared the quality of chest compressions between the conventional rescuer rotation method (RC2, rescuers changed in 2-min intervals) and the novel rescuer rotation method (RCL, rescuers changed by a team leader's decision on the basis of gross assessment of the quality of chest compression). METHODS: Ninety-six rescuers (48 pairs) were recruited and the sequence of the two-rescuer change methods (RC2 and RCL) was randomized. Forty-eight teams performed 8 min of uninterrupted two-rescuer CPR on a manikin with Skill-Reporter during two consecutive days (one method for each day). RESULTS: The RCL method achieved deeper compression depth (mm) (52.6+/-3.8 vs. 49.5+/-4.7, P=0.002) and a higher number of correct chest compressions per minute (96.3+/-41.2 vs. 77.6+/-52.7, P<0.0001) than the RC2 method. However, the RCL method showed a longer total interruption time (s) than the RC2 method (21.1+/-3.9 vs. 14.8+/-1.0, P<0.0001) during 8 min of uninterrupted CPR. CONCLUSION: The quality of chest compression was better with RCL than the conventional RC2 method in terms of compression depth and proportions of correct compressions. RCL may be a practical alternative rescuer change strategy during uninterrupted chest compressions, especially when objective parameters to monitor the quality of chest compression are not readily available. PMID- 25738796 TI - Downregulation of NIT2 inhibits colon cancer cell proliferation and induces cell cycle arrest through the caspase-3 and PARP pathways. AB - Colorectal cancer, also known as colon cancer is the most devastating malignancy worldwide. Previous studies have reported that Nit2, a member of the nitrilase superfamily, is a potential tumor suppressor, although its function remains elusive in colon cancer. In the present study, we employed an RNA interference lentivirus system to silence endogenous NIT2 expression in the colon cancer cell line, HCT116. The knockdown efficiency was determined by RT-qPCR and western blot analysis. The depletion of NIT2 markedly inhibited colon cancer cell proliferation and colony formation and induced cell cycle arrest in the G0/G1 phase, as shown by MTT assay, colony formation assay and flow cytometric analysis, respectively. Further investigation with an intracellular signaling array demonstrated that the depletion of NIT2 triggered the apoptosis of colon cancer cells through the caspase-3 and poly(ADP-ribose) polymerase (PARP) pathways. Our findings suggest that NIT2 may be an oncogene in human colon cancer and may thus serve as a promising therapeutic target for the treatment of colon cancer. PMID- 25738797 TI - Germanium Nanowires-in-Graphite Tubes via Self-Catalyzed Synergetic Confined Growth and Shell-Splitting Enhanced Li-Storage Performance. AB - Despite the high theoretical capacity, pure Ge has various difficulties such as significant volume expansion and electron and Li(+) transfer problems, when applied as anode materials in lithium ion battery (LIB), for which the solution would finally rely on rational design like advanced structures and available hybrid. Here in this work, we report a one-step synthesis of Ge nanowires-in graphite tubes (GNIGTs) with the liquid Ge/C synergetic confined growth method. The structure exhibits impressing LIB behavior in terms of both cyclic stability and rate performance. We found the semiclosed graphite shell with thickness of ~50 layers experience an interesting splitting process that was driven by electrolyte diffusion, which occurs before the Ge-Li alloying plateau begins. Two types of different splitting mechanism addressed as "inside-out"/zipper effect and "outside-in" dominate this process, which are resulted from the SEI layer growing longitudinally along the Ge-graphite interface and the lateral diffusion of Li(+) across the shell, respectively. The former mechanism is the predominant way driving the initial shell to split, which behaves like a zipper with SEI layer as invisible puller. After repeated Li(+) insertion/exaction, the GNIGTs configuration is finally reconstructed by forming Ge nanowires-thin graphite strip hybrid, both of which are in close contact, resulting in enormous enchantment to the electrons/Li(+) transport. These features make the structures perform well as anode material in LIB. We believe both the progress in 1D assembly and the structure evolution of this Ge-C composite would contribute to the design of advanced LIB anode materials. PMID- 25738795 TI - Rapid HIV testing and counseling for residents in domestic violence shelters. AB - Over one million Americans live with the human immunodeficiency virus (HIV), and roughly 20 percent of those living with HIV are unaware of their status. One way to decrease this epidemic is community-based rapid testing with high-risk populations. One high-risk population that has received limited attention is victims of intimate partner violence who seek shelter. In an effort to gain foundational information to implement rapid HIV testing and counseling services in domestic violence shelters, the current study conducted a series of focus groups with eighteen residents and ten staff of local shelters from October 15 to December 12, 2012. Participants provided valuable insight into how HIV rapid testing and counseling might be best implemented given the resources and constraints of shelter life. Despite identifying some potential barriers, most believed that the promise of quick results, the convenience and support afforded by the shelter venue, and the timing of the intervention at a point when women are making life changes would render the intervention acceptable to residents. Further insights are discussed in the article. PMID- 25738794 TI - Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage (STITCH[Trauma]): The First Randomized Trial. AB - Intraparenchymal hemorrhages occur in a proportion of severe traumatic brain injury TBI patients, but the role of surgery in their treatment is unclear. This international multi-center, patient-randomized, parallel-group trial compared early surgery (hematoma evacuation within 12 h of randomization) with initial conservative treatment (subsequent evacuation allowed if deemed necessary). Patients were randomized using an independent randomization service within 48 h of TBI. Patients were eligible if they had no more than two intraparenchymal hemorrhages of 10 mL or more and did not have an extradural or subdural hematoma that required surgery. The primary outcome measure was the traditional dichotomous split of the Glasgow Outcome Scale obtained by postal questionnaires sent directly to patients at 6 months. The trial was halted early by the UK funding agency (NIHR HTA) for failure to recruit sufficient patients from the UK (trial registration: ISRCTN19321911). A total of 170 patients were randomized from 31 of 59 registered centers worldwide. Of 82 patients randomized to early surgery with complete follow-up, 30 (37%) had an unfavorable outcome. Of 85 patients randomized to initial conservative treatment with complete follow-up, 40 (47%) had an unfavorable outcome (odds ratio, 0.65; 95% confidence interval, CI 0.35, 1.21; p=0.17), with an absolute benefit of 10.5% (CI, -4.4-25.3%). There were significantly more deaths in the first 6 months in the initial conservative treatment group (33% vs. 15%; p=0.006). The 10.5% absolute benefit with early surgery was consistent with the initial power calculation. However, with the low sample size resulting from the premature termination, we cannot exclude the possibility that this could be a chance finding. A further trial is required urgently to assess whether this encouraging signal can be confirmed. PMID- 25738798 TI - Fish biodiversity of the Vitoria-Trindade Seamount Chain, southwestern Atlantic: an updated database. AB - Despite a strong increase in research on seamounts and oceanic islands ecology and biogeography, many basic aspects of their biodiversity are still unknown. In the southwestern Atlantic, the Vitoria-Trindade Seamount Chain (VTC) extends ca. 1,200 km offshore the Brazilian continental shelf, from the Vitoria seamount to the oceanic islands of Trindade and Martin Vaz. For a long time, most of the biological information available regarded its islands. Our study presents and analyzes an extensive database on the VTC fish biodiversity, built on data compiled from literature and recent scientific expeditions that assessed both shallow to mesophotic environments. A total of 273 species were recorded, 211 of which occur on seamounts and 173 at the islands. New records for seamounts or islands include 191 reef fish species and 64 depth range extensions. The structure of fish assemblages was similar between islands and seamounts, not differing in species geographic distribution, trophic composition, or spawning strategies. Main differences were related to endemism, higher at the islands, and to the number of endangered species, higher at the seamounts. Since unregulated fishing activities are common in the region, and mining activities are expected to drastically increase in the near future (carbonates on seamount summits and metals on slopes), this unique biodiversity needs urgent attention and management. PMID- 25738799 TI - Ginsenoside Rg3 sensitizes human non-small cell lung cancer cells to gamma radiation by targeting the nuclear factor-kappaB pathway. AB - At present, it is elusive how non-small cell lung cancer (NSCLC) develops resistance to gamma-radiation; however, the transcription factor nuclear factor kappaB (NF-kappaB) and NF-kappaB-regulated gene products have been proposed as mediators. Ginsenoside Rg3 is a steroidal saponin, which was isolated from Panax ginseng. Ginsenoside Rg3 possesses high pharmacological activity and has previously been shown to suppress NF-kappaB activation in various types of tumor cell. Therefore, the present study aimed to determine whether Rg3 could suppress NF-kappaB activation in NSCLC cells and sensitize NSCLC to gamma-radiation, using an NSCLC cell line and NSCLC xenograft. A clone formation assay and lung tumor xenograft experiment were used to assess the radiosensitizing effects of ginsenoside Rg3. NF-kappaB/inhibitor of NF-kappaB (IkappaB) modulation was ascertained using an electrophoretic mobility shift assay and western blot analysis. NF-kappaB-regulated gene products were monitored by western blot analysis. The present study demonstrated that ginsenoside Rg3 was able to sensitize A549 and H1299 lung carcinoma cells to gamma-radiation and significantly enhance the efficacy of radiation therapy in C57BL/6 mice bearing a Lewis lung carcinoma cell xenograft tumor. Furthermore, ginsenoside Rg3 suppressed NF-kappaB activation, phosphorylation of IkappaB protein and expression of NF-kappaB-regulated gene products (cyclin D1, c-myc, B-cell lymphoma 2, cyclooxygenase-2, matrix metalloproteinase-9 and vascular endothelial growth factor), a number of which were induced by radiation therapy and mediate radioresistance. In conclusion, the results of the present study suggested that ginsenoside Rg3 may potentiate the antitumor effects of radiation therapy in NSCLC by suppressing NF-kappaB activity and NF-kappaB-regulated gene products, leading to the inhibition of tumor progression. PMID- 25738800 TI - Both food restriction and high-fat diet during gestation induce low birth weight and altered physical activity in adult rat offspring: the "Similarities in the Inequalities" model. AB - We have previously described a theoretical model in humans, called "Similarities in the Inequalities", in which extremely unequal social backgrounds coexist in a complex scenario promoting similar health outcomes in adulthood. Based on the potential applicability of and to further explore the "similarities in the inequalities" phenomenon, this study used a rat model to investigate the effect of different nutritional backgrounds during gestation on the willingness of offspring to engage in physical activity in adulthood. Sprague-Dawley rats were time mated and randomly allocated to one of three dietary groups: Control (Adlib), receiving standard laboratory chow ad libitum; 50% food restricted (FR), receiving 50% of the ad libitum-fed dam's habitual intake; or high-fat diet (HF), receiving a diet containing 23% fat. The diets were provided from day 10 of pregnancy until weaning. Within 24 hours of birth, pups were cross-fostered to other dams, forming the following groups: Adlib_Adlib, FR_Adlib, and HF_Adlib. Maternal chow consumption and weight gain, and offspring birth weight, growth, physical activity (one week of free exercise in running wheels), abdominal adiposity and biochemical data were evaluated. Western blot was performed to assess D2 receptors in the dorsal striatum. The "similarities in the inequalities" effect was observed on birth weight (both FR and HF groups were smaller than the Adlib group at birth) and physical activity (both FR_Adlib and HF_Adlib groups were different from the Adlib_Adlib group, with less active males and more active females). Our findings contribute to the view that health inequalities in fetal life may program the health outcomes manifested in offspring adult life (such as altered physical activity and metabolic parameters), probably through different biological mechanisms. PMID- 25738801 TI - A novel assay reveals hygrotactic behavior in Drosophila. AB - Humidity is one of the most important factors that determines the geographical distribution and survival of terrestrial animals. The ability to detect variation in humidity is conserved across many species. Here, we established a novel behavioral assay that revealed the thirsty Drosophila exhibits strong hygrotactic behavior, and it can locate water by detecting humidity gradient. In addition, exposure to high levels of moisture was sufficient to elicit proboscis extension reflex behavior in thirsty flies. Furthermore, we found that the third antennal segment was necessary for hygrotactic behavior in thirsty flies, while arista was required for the avoidance of moist air in hydrated flies. These results indicated that two types of hygroreceptor cells exist in Drosophila: one located in the third antennal segment that mediates hygrotactic behavior in thirst status, and the other located in arista which is responsible for the aversive behavior toward moist air in hydration status. Using a neural silencing screen, we demonstrated that synaptic output from the mushroom body alpha/beta surface and posterior neurons was required for both hygrotactic behavior and moisture aversive behavior. PMID- 25738803 TI - Development of real time PCR to study experimental mixed infections of T. congolense Savannah and T. b. brucei in Glossina morsitans morsitans. AB - Tsetse flies are able to acquire mixed infections naturally or experimentally either simultaneously or sequentially. Traditionally, natural infection rates in tsetse flies are estimated by microscopic examination of different parts of the fly after dissection, together with the isolation of the parasite in vivo. However, until the advent of molecular techniques it was difficult to speciate trypanosomes infections and to quantify trypanosome numbers within tsetse flies. Although more expensive, qPCR allows the quantification of DNA and is less time consuming due to real time visualization and validation of the results. The current study evaluated the application of qPCR to quantify the infection load of tsetse flies with T. b. brucei and T. congolense savannah and to study the possibility of competition between the two species. The results revealed that the two qPCR reactions are of acceptable efficiency (99.1% and 95.6%, respectively), sensitivity and specificity and can be used for quantification of infection load with trypanosomes in experimentally infected Glossina morsitans morsitans. The mixed infection of laboratory Glossina species and quantification of the infection suggests the possibility that a form of competition exists between the isolates of T. b. brucei and T. congolense savannah that we used when they co exist in the fly midgut. PMID- 25738804 TI - Association of six genetic variants with myocardial infarction. AB - Although various genes that confer susceptibility to myocardial infarction (MI) have been identified for Caucasian populations in genome-wide association studies (GWAS), genetic variants related to this condition in Japanese individuals have not been identified definitively. The aim of the present study was to examine an association of MI in Japanese individuals with 29 polymorphisms identified as susceptibility loci for MI or coronary artery disease in Caucasian populations by meta-analyses of GWAS. The study subjects comprised 1,824 subjects with MI and 2,329 controls. Genotypes of the polymorphisms were determined by Luminex bead based multiplex assay. To compensate for multiple comparisons, we adopted the criterion of a false discovery rate (FDR) of <0.05 for statistical significance for association. Comparisons of allele frequencies by the chi(2) test revealed that rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1, FDR=0.0007), rs4977574 of the CDKN2B antisense RNA 1 gene (CDKN2B-AS1, FDR=0.0038), rs264 of the lipoprotein lipase gene (LPL, FDR=0.0061), rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1, FDR=0.0118), rs9319428 of the fms-related tyrosine kinase 1 gene (FLT1, FDR=0.0118) and rs12413409 of the cyclin and CBS domain divalent metal cation transport mediator 2 gene (CNNM2, FDR=0.0300) were significantly associated with MI. Multivariate logistic regression analysis with adjustment for covariates revealed that rs9369640 (P=0.0005; odds ratio, 0.89), rs4977574 (P=0.0001; odds ratio, 1.50), rs264 (P=0.0405; odds ratio, 0.85), rs599839 (P=0.0003; odds ratio, 0.68), rs9319428 (P=0.0155; odds ratio, 1.20) and rs12413409 (P=0.0076; odds ratio, 0.66) were significantly (P<0.05) associated with MI. PHACTR1, CDKN2B-AS1, LPL, PSRC1, FLT1 and CNNM2 may thus be susceptibility loci for MI in Japanese individuals. PMID- 25738805 TI - Distractions during resident handoffs: incidence, sources, and influence on handoff quality and effectiveness. AB - IMPORTANCE: Handoffs have significantly increased in number following Accreditation Council for Graduate Medical Education (ACGME) work-hour restrictions. Studies have shown correlations between the number of handoffs and errors/patient harm. Distractions are common during handoffs and may interfere with handoff quality and effectiveness. OBJECTIVE: To examine the frequency of distractions and their impact on handoff quality. DESIGN, SETTING, AND PARTICIPANTS: In this prospective observational study, a total of 214 surgical resident handoffs (residents = 184; Bay area residents [moonlighters] = 30) were observed over 18 months (July 11, 2012-December 19, 2014) by 2 independent observers in 3 teaching hospitals (university, county, and veterans). MAIN OUTCOMES AND MEASURES: Handoff quality (both giver and receiver) was assessed using a standardized scoring system. The number and types of distractions were recorded. RESULTS: Pages were the most common distraction (37.5%), followed by telephone calls (32.8%), residents/medical students (9.3%), talking (5.2%), and noise (4.1%). Distractions from attending physicians, electronics, nursing, consults, and room changes were less common (collectively 11%, each <3%). Distractions were present in 102 resident handoffs (48%) (16% with 1 distraction; 15% with 2; 6% with 3, and 11% with >=4). Distractions occurred in 54% of junior resident handoffs (mean, 1.4/handoff), 30% of moonlighter handoffs (mean, 0.5/handoff), and 38% of senior resident handoffs (mean, 0.89/handoff) (P = .01, junior vs moonlighter/senior). Distractions were more common during evening than morning handoffs (52% vs 36%; P = .045) and during team vs individual handoffs (58% vs 44%; P < .10). Handoffs without distractions were shorter in length (13.2 minutes without distractions vs 21.5 minutes with distractions; P < .001) and minutes per patient (1.78 without vs 2.15 with distractions; P = .04). Handoff quality was not diminished by distractions, as measured by handoff giver score (15.41 without vs 15.47 with distractions; P = .90) and receiver score (7.42 without vs 7.25 with distractions; P = .45). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest study of distractions during surgical resident handoffs. Distractions were very common during handoffs; they were more common in the evening when junior residents more commonly performed the handoff and they increased the handoff length. However, distractions did not negatively affect the quality of resident handoffs. This may demonstrate the resilience of surgical residents to distractions. PMID- 25738802 TI - Bacterial iron-sulfur cluster sensors in mammalian pathogens. AB - Iron-sulfur clusters act as important cofactors for a number of transcriptional regulators in bacteria, including many mammalian pathogens. The sensitivity of iron-sulfur clusters to iron availability, oxygen tension, and reactive oxygen and nitrogen species enables bacteria to use such regulators to adapt their gene expression profiles rapidly in response to changing environmental conditions. In this review, we discuss how the [4Fe-4S] or [2Fe-2S] cluster-containing regulators FNR, Wbl, aconitase, IscR, NsrR, SoxR, and AirSR contribute to bacterial pathogenesis through control of both metabolism and classical virulence factors. In addition, we briefly review mammalian iron homeostasis as well as oxidative/nitrosative stress to provide context for understanding the function of bacterial iron-sulfur cluster sensors in different niches within the host. PMID- 25738806 TI - The precision-recall plot is more informative than the ROC plot when evaluating binary classifiers on imbalanced datasets. AB - Binary classifiers are routinely evaluated with performance measures such as sensitivity and specificity, and performance is frequently illustrated with Receiver Operating Characteristics (ROC) plots. Alternative measures such as positive predictive value (PPV) and the associated Precision/Recall (PRC) plots are used less frequently. Many bioinformatics studies develop and evaluate classifiers that are to be applied to strongly imbalanced datasets in which the number of negatives outweighs the number of positives significantly. While ROC plots are visually appealing and provide an overview of a classifier's performance across a wide range of specificities, one can ask whether ROC plots could be misleading when applied in imbalanced classification scenarios. We show here that the visual interpretability of ROC plots in the context of imbalanced datasets can be deceptive with respect to conclusions about the reliability of classification performance, owing to an intuitive but wrong interpretation of specificity. PRC plots, on the other hand, can provide the viewer with an accurate prediction of future classification performance due to the fact that they evaluate the fraction of true positives among positive predictions. Our findings have potential implications for the interpretation of a large number of studies that use ROC plots on imbalanced datasets. PMID- 25738807 TI - Downregulation of matrix metalloproteinase 9 by small interfering RNA inhibits the tumor growth of ovarian epithelial carcinoma in vitro and in vivo. AB - Matrix metalloproteinase 9 (MMP-9) is upregulated in various types of malignancy, including human ovarian carcinomas. It promotes invasion, metastasis, growth and the survival of malignant cells. However, relatively little is known about the role of MMP9 in epithelial ovarian carcinoma. Therefore, the aim of the present study was to determine the effects of targeting this molecule on ovarian carcinoma progression. A plasmid, psi-MMP-9, carrying a short hairpin RNA against MMP-9 gene expression was constructed and transfected into the human ovarian cancer cell line SKOV3 using a human U6 promoter-driven DNA template approach to determine the effect of MMP-9 gene RNA interference (RNAi) on the proliferation, apoptosis, migration, invasion and tumorigenicity of the human ovarian carcinoma cells. The results demonstrated that siRNA-mediated knockdown of MMP-9 in the human ovarian cancer cell line SKOV3 inhibited cell proliferation, migration and invasion in vitro. The results also demonstrated that downregulation of MMP-9 led to cell apoptosis in SKOV3 cells, inhibited the expression of anti-apoptotic molecules, including B cell lymphoma-2, survivin and X-linked inhibitor of apoptosis protein, and enhanced the activity of capsase-3 and caspase-8. In addition, knockdown of MMP-9 inhibited tumorigenicity in nude mice. Taken together, MMP-9 gene RNAi in ovarian carcinoma cells inhibited proliferation, migration and invasion, induced cell apoptosis in vitro and suppressed tumor growth in nude mice. These results suggest that MMP-9 is an ovarian cancer associated gene and is a potential target for therapeutic anti-cancer drugs. PMID- 25738808 TI - Easy and rapid binding assay for functional analysis of disulfide-containing peptides by a pull-down method using a puromycin-linker and a cell-free translation system. AB - Constrained peptides are an attractive class as affinity reagents or drug leads owing to their excellent binding properties. Many kinds of these peptides, such as cyclic peptides containing disulfide bridges, are found in nature or designed artificially by directed evolution. However, confirming the binding properties of the disulfide-rich peptides can be generally difficult, because of oxidative folding problems in the preparation steps. Therefore, a method for evaluating the binding properties of such peptides rapidly and easily is required. Here, we report an easy and rapid method for preparing biotin-attached peptides containing disulfide bridges or a chemical cross-linker using a cell-free translation system and a puromycin-linker, which is applicable to pull-down assays for protein (or peptide) molecular interaction analysis. PMID- 25738809 TI - Effects of anodal transcranial direct current stimulation on visually guided learning of grip force control. AB - Anodal transcranial Direct Current Stimulation (tDCS) has been shown to be an effective non-invasive brain stimulation method for improving cognitive and motor functioning in patients with neurological deficits. tDCS over motor cortex (M1), for instance, facilitates motor learning in stroke patients. However, the literature on anodal tDCS effects on motor learning in healthy participants is inconclusive, and the effects of tDCS on visuo-motor integration are not well understood. In the present study we examined whether tDCS over the contralateral motor cortex enhances learning of grip-force output in a visually guided feedback task in young and neurologically healthy volunteers. Twenty minutes of 1 mA anodal tDCS were applied over the primary motor cortex (M1) contralateral to the dominant (right) hand, during the first half of a 40 min power-grip task. This task required the control of a visual signal by modulating the strength of the power-grip for six seconds per trial. Each participant completed a two-session sham-controlled crossover protocol. The stimulation conditions were counterbalanced across participants and the sessions were one week apart. Performance measures comprised time-on-target and target-deviation, and were calculated for the periods of stimulation (or sham) and during the afterphase respectively. Statistical analyses revealed significant performance improvements over the stimulation and the afterphase, but this learning effect was not modulated by tDCS condition. This suggests that the form of visuomotor learning taking place in the present task was not sensitive to neurostimulation. These null effects, together with similar reports for other types of motor tasks, lead to the proposition that tDCS facilitation of motor learning might be restricted to cases or situations where the motor system is challenged, such as motor deficits, advanced age, or very high task demand. PMID- 25738811 TI - Monitoring of the manufacturing process for ambroxol hydrochloride tablet using NIR-chemometric methods: compression effect on content uniformity model and relevant process parameters testing. AB - This study aimed at using near-infrared (NIR) spectroscopy to monitor compaction pressure for simultaneously determining the tensile strength and content uniformity, as well as moisture and mean particle size of ambroxol hydrochloride tablets. The content uniformity, compression force and tensile strength of the laboratory samples were obtained by pressing a mixture of active principle and excipient components into tablets. To reduce the spectral baseline shift of the laboratory samples, the compaction pressure applied to the mixture was assessed by a variable pressure test. Production samples were added to the test and subjected to principal component analysis. The expanded partial least-squares (PLS) calibration model used to quantify the active content was more accurate than the model constructed from laboratory samples using the production tablets included in the calibration set. The model showed good predictability, with correlation coefficient (R) 0.9977. The validation and reliability of the content model were evaluated to determine trueness and reliability for the measurement of individual production tablets and the laboratory tablets with drug content ranging from 24 to 36 mg. The PLS calibration models for compression force and tensile strength were constructed using the same spectral set assuming both were highly related. These models yielded high R values (0.9955 and 0.9910). The R values of the moisture and mean particle size were 0.9994 and 0.9919, respectively. This study demonstrated that NIR spectroscopy combined with chemometric techniques can be successfully used to quantitatively monitor the tablet manufacturing process in the pharmaceutical industry. PMID- 25738810 TI - Sequence features and transcriptional stalling within centromere DNA promote establishment of CENP-A chromatin. AB - Centromere sequences are not conserved between species, and there is compelling evidence for epigenetic regulation of centromere identity, with location being dictated by the presence of chromatin containing the histone H3 variant CENP-A. Paradoxically, in most organisms CENP-A chromatin generally occurs on particular sequences. To investigate the contribution of primary DNA sequence to establishment of CENP-A chromatin in vivo, we utilised the fission yeast Schizosaccharomyces pombe. CENP-ACnp1 chromatin is normally assembled on ~10 kb of central domain DNA within these regional centromeres. We demonstrate that overproduction of S. pombe CENP-ACnp1 bypasses the usual requirement for adjacent heterochromatin in establishing CENP-ACnp1 chromatin, and show that central domain DNA is a preferred substrate for de novo establishment of CENP-ACnp1 chromatin. When multimerised, a 2 kb sub-region can establish CENP-ACnp1 chromatin and form functional centromeres. Randomization of the 2 kb sequence to generate a sequence that maintains AT content and predicted nucleosome positioning is unable to establish CENP-ACnp1 chromatin. These analyses indicate that central domain DNA from fission yeast centromeres contains specific information that promotes CENP-ACnp1 incorporation into chromatin. Numerous transcriptional start sites were detected on the forward and reverse strands within the functional 2 kb sub-region and active promoters were identified. RNAPII is enriched on central domain DNA in wild-type cells, but only low levels of transcripts are detected, consistent with RNAPII stalling during transcription of centromeric DNA. Cells lacking factors involved in restarting transcription TFIIS and Ubp3-assemble CENP-ACnp1 on central domain DNA when CENP-ACnp1 is at wild-type levels, suggesting that persistent stalling of RNAPII on centromere DNA triggers chromatin remodelling events that deposit CENP-ACnp1. Thus, sequence encoded features of centromeric DNA create an environment of pervasive low quality RNAPII transcription that is an important determinant of CENP-ACnp1 assembly. These observations emphasise roles for both genetic and epigenetic processes in centromere establishment. PMID- 25738813 TI - Stress with parents and peers: how adolescents from 18 nations cope with relationship stress. AB - BACKGROUND AND OBJECTIVES: We investigated how adolescents from five regions around the world perceived and coped with parent- and peer-related stress. DESIGN: The study comprised N = 4957 adolescents (mean age of 15.2 years) from 18 countries. METHODS: The study used self-report measures for stress perception and coping style. RESULTS: Across countries, adolescents perceived parent-related stress to be considerably greater than peer-related stress. They coped less actively with parent-related stress than with peer-related stress. Significant differences emerged with respect to geographic region and key demographic indicators. Adolescents from Eastern European and Western countries had generally quite low levels of stress. Adolescents from Southern Europe exhibited the highest stress levels and the greatest coping activity in dealing with stress in both domains, whereas adolescents from Southern Emerging and Asian countries reported high levels of parent-related stress and dealt much less actively with parent-related stress than with peer-related stress. CONCLUSIONS: Adolescents from all countries were remarkably competent in dealing with relationship stressors. Cultural and regional differences have a stronger effect on stress perception and coping style than gender. PMID- 25738812 TI - Development and characterization of folate anchored Saquinavir entrapped PLGA nanoparticles for anti-tumor activity. AB - OBJECTIVE: Saquinavir (SQV) is a US-FDA approved HIV protease inhibitor (HPI) for HIV cure. The purpose of the present investigation was to develop and characterize the anticancer potential of the SQV-loaded folic acid (FA) conjugated PEGylated and non-PEGylated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) (SQV-Fol-PEG-PLGA and SQV-Fol-PLGA) employing PC-3 (human prostate) and MCF-7 (human breast) cancer cell lines. MATERIALS AND METHODS: Developed NPs were characterized by IR, NMR, DSC, XRD, size, charge and further tested for drug loading and cellular uptake properties. RESULT: The entrapment efficiency was found to be 56 +/- 0.60 and 58 +/- 0.80 w/v for SQV-Fol-PEG-PLGA and SQV-PLGA NPs, respectively. The obtained results of SQV-Fol-PEG-PLGA showed enhanced cytotoxicity and cellular uptake and were most preferentially taken up by the cancerous cells via folate receptor-mediated endocytosis (RME) mechanism. At 260 uM concentration, SQV-PLGA NPs and SQV-Fol-PEG-PLGA NPs showed 20%, 20% and 23% cell growth inhibition in PC-3 cells, respectively whereas in MCF-7 cells it was 12%, 15% and 14% cell growth inhibition, respectively. CONCLUSIONS: Developed targeted SQV-Fol-PEG-PLGA NPs were superior anticancer potential as compared to non-targeted SQV-PLGA NPs. Thus, these targeted NPs provide another option for anticancer drug delivery scientists. PMID- 25738814 TI - Recombinant interleukin 6 with M cell-targeting moiety produced in Lactococcus lactis IL1403 as a potent mucosal adjuvant for peroral immunization. AB - Development and application of safe and effective mucosal adjuvants are important to improve immunization efficiency in oral vaccine. Here, we report a novel mucosal adjuvant, IL-6-CKS9, a recombinant cytokine generated by conjugating an M cell-targeting peptide (CKS9) with c-terminus of the murine interleukin 6 (IL-6), which facilitated enhancement of mucosal immune response. Lactococcus lactis IL1403, a food-grade strain of lactic acid bacteria (LAB) which is widely used in dairy industry, was used as a host cell to express and secrete the IL-6-CKS9 for a mucosal vaccine adjuvant. The recombinant L. lactis IL1403 secreting IL-6-CKS9 was orally administered with a model antigen protein, M-BmpB (Brachyspira membrane protein B conjugated with CKS9), to BALB/c mice for mucosal immunization. ELISA analyses showed consistent enhancement tendencies in induction of anti-M-BmpB antibody levels both with mucosal (IgA) and systemic (IgG) immune responses in IL-6-CKS9-LAB treated group compared with other groups tested by conducting two separated mice immunization assays. In addition, we characterized that the oral administration of model protein antigen with live LAB producing IL-6-CKS9 could induce both Th1 and Th2 type immune responses by analysis of the specific anti-BmpB IgG1 and IgG2a isotypes in the sera and also investigated possible oral tolerance in our vaccine strategy. Collectively, our results showed successful production and secretion of recombinant murine IL-6 with M cell-targeting moiety (IL-6-CKS9) from L. lactis IL1403 and demonstrated the live recombinant LAB producing IL-6-CKS9 could have a potential to be used as an efficient adjuvant for peroral vaccination. PMID- 25738815 TI - Laboratory investigations of vaccinated patients with varicella. AB - BACKGROUND: Accompanying varicella vaccination in children in Germany recommended with one (2004) and two (2009) doses, sentinel surveillance of varicella with a sample (n~900) of private physicians was established in 2005. Physicians reported monthly aggregated data on all varicella cases and case-based on vaccinated patients, of whom skin lesion samples were laboratory investigated to identify varicella-zoster virus (VZV). We analyzed the impact of vaccination frequency on the number of cases and on laboratory results within the sentinel. METHODS: Swabs were obtained with a Teflon tip and sent together with a case-based questionnaire to the reference laboratory. VZV wild-type and vaccine-type was identified by polymerase chain-reaction (PCR) and pyrosequencing methods. Case-based data and laboratory results were analyzed descriptively. RESULTS: From April 2005 to March 2014, of all monthly reported cases (n=111,456) 4789 were vaccinated and eligible for further analysis. No differences were found between laboratory investigated and not investigated cases (1017 vs. 3772) except that the proportion of cases vaccinated twice was higher in lab-cases (29.4% vs. 16.1%). PCR remained negative in 69.6% (197/283) of breakthrough-cases vaccinated twice, in comparison to 22.7% (147/649) breakthrough-cases vaccinated once. VZV was confirmed in 500 (81) patients with breakthrough varicella after one (two) vaccination(s); identification of VZV wild-type, vaccine-type, or no further differentiation was possible in 485 (72), 5 (6), and 10 (3) cases, respectively. CONCLUSION: Varicella breakthrough disease is rare in Germany and suspected clinical cases require laboratory confirmation. The lower confirmation rate of VZV after two vaccine doses suggests a better protection compared to one dose. PMID- 25738816 TI - Outer membrane proteins preferentially load MHC class II peptides: implications for a Chlamydia trachomatis T cell vaccine. AB - CD4 T cell immune responses such as interferon-gamma and tumor necrosis factor alpha secretion are necessary for Chlamydia immunity. We used an immunoproteomic approach in which Chlamydia trachomatis and Chlamydia muridarum-derived peptides presented by MHC class II molecules on the surface of infected dendritic cells (DCs) were identified by tandem mass spectrometry using bone marrow derived DCs (BMDCs) from mice of different MHC background. We first compared the C. muridarum immunoproteome in C3H mice to that previously identified in C57BL/6 mice. Fourteen MHC class II binding peptides from 11 Chlamydia proteins were identified from C3H infected BMDCs. Two C. muridarum proteins overlapped between C3H and C57B/6 mice and both were polymorphic membrane proteins (Pmps) which presented distinct class II binding peptides. Next we studied DCs from C57BL/6 mice infected with the human strain, C. trachomatis serovar D. Sixty MHC class II binding peptides derived from 27 C. trachomatis proteins were identified. Nine proteins were orthologous T cell antigens between C. trachomatis and C. muridarum and 2 of the nine were Pmps which generated MHC class II binding epitopes at distinct sequences within the proteins. As determined by antigen specific splenocyte responses outer membrane proteins PmpF, -G and -H and the major outer membrane protein (MOMP) were antigenic in mice previously infected with C. muridarum or C. trachomatis. Furthermore a recombinant protein vaccine consisting of the four Pmps (PmpEFGH) with MOMP formulated with a Th1 polarizing adjuvant significantly accelerated (p<0.001) clearance in the C57BL/6 mice C. trachomatis transcervical infection model. We conclude that Chlamydia outer membrane proteins are important T cell antigens useful in the development of a C. trachomatis subunit vaccine. PMID- 25738817 TI - Naturally occurring bactericidal antibodies specific for Haemophilus influenzae lipooligosaccharide are present in healthy adult individuals. AB - Nontypeable Haemophilus influenzae (NTHi), a typical mucosal pathogen largely responsible for respiratory infections and pediatric otitis media, has been increasingly recognized as a significant cause of invasive disease, especially in immunocompromised individuals. Lipooligosaccharide (LOS) is a conserved molecule with an important role in H. influenzae virulence and immune evasion, and it may be considered as a vaccine candidate. However, abilities of H. influenzae LOS to induce protective immune response are poorly understood. The goal of this study was to determine whether antibodies against LOS isolated from H. influenzae strains Eagan, Rd and NTHi 375 are present in the sera of normal individuals. Antigen specific IgG and IgM were studied in sera of 71 and 30 healthy adults, respectively. IgG specific for LOS of all three strains was ubiquitously present in our sample population while IgM specific for Eagan, Rd and NTHi 375 LOS compounds was detected in 37%, 63%, and 40% of samples, respectively. All tested serum samples exhibited bactericidal activity against all three H. influenzae strains; the removal of anti-LOS antibodies from the sera resulted in significant increases in bacterial survival of the corresponding strain. NTHi 375 exhibited the highest serum resistance, whereas the Rd strain was the least resistant. Serum bactericidal activity of anti-LOS antibody was mediated via the classical complement pathway. These findings suggest that in healthy adults, naturally acquired complement-activating anti-LOS antibodies significantly contribute to the overall serum bactericidal activity against both encapsulated and non encapsulated strains of H. influenzae. PMID- 25738818 TI - Consequences of warming and resource quality on the stoichiometry and nutrient cycling of a stream shredder. AB - As a result of climate change, streams are warming and their runoff has been decreasing in most temperate areas. These changes can affect consumers directly by increasing their metabolic rates and modifying their physiology and indirectly by changing the quality of the resources on which organisms depend. In this study, a common stream detritivore (Echinogammarus berilloni Catta) was reared at two temperatures (15 and 20 degrees C) and fed Populus nigra L. leaves that had been conditioned either in an intermittent or permanent reach to evaluate the effects of resource quality and increased temperatures on detritivore performance, stoichiometry and nutrient cycling. The lower quality (i.e., lower protein, soluble carbohydrates and higher C:P and N:P ratios) of leaves conditioned in pools resulted in compensatory feeding and lower nutrient retention capacity by E. berilloni. This effect was especially marked for phosphorus, which was unexpected based on predictions of ecological stoichiometry. When individuals were fed pool-conditioned leaves at warmer temperatures, their growth rates were higher, but consumers exhibited less efficient assimilation and higher mortality. Furthermore, the shifts to lower C:P ratios and higher lipid concentrations in shredder body tissues suggest that structural molecules such as phospholipids are preserved over other energetic C rich macromolecules such as carbohydrates. These effects on consumer physiology and metabolism were further translated into feces and excreta nutrient ratios. Overall, our results show that the effects of reduced leaf quality on detritivore nutrient retention were more severe at higher temperatures because the shredders were not able to offset their increased metabolism with increased consumption or more efficient digestion when fed pool-conditioned leaves. Consequently, the synergistic effects of impaired food quality and increased temperatures might not only affect the physiology and survival of detritivores but also extend to other trophic compartments through detritivore-mediated nutrient cycling. PMID- 25738820 TI - Anomalous ligand effect in gold(I)-catalyzed intramolecular hydroamination of alkynes. AB - We analyzed the ligand electronic effect in a gold(I)-catalyzed intramolecular alkyne hydroamination, through a DFT and charge-displacement function (CDF) study. We found that, in the presence of pi-electron conjugation between the alkyne and the nucleophilic functionality, electron poor ligands modify the coordination mode and the geometric parameters of the substrate in such a way that, contrary to expectations, the activation barrier of the nucleophilic attack increases. This remarkable effect is due to the competition between alkyne activation and nucleophile deactivation. The general relevance of these findings is highlighted. PMID- 25738819 TI - Adhesive fiber stratification in uropathogenic Escherichia coli biofilms unveils oxygen-mediated control of type 1 pili. AB - Bacterial biofilms account for a significant number of hospital-acquired infections and complicate treatment options, because bacteria within biofilms are generally more tolerant to antibiotic treatment. This resilience is attributed to transient bacterial subpopulations that arise in response to variations in the microenvironment surrounding the biofilm. Here, we probed the spatial proteome of surface-associated single-species biofilms formed by uropathogenic Escherichia coli (UPEC), the major causative agent of community-acquired and catheter associated urinary tract infections. We used matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) to analyze the spatial proteome of intact biofilms in situ. MALDI-TOF IMS revealed protein species exhibiting distinct localizations within surface associated UPEC biofilms, including two adhesive fibers critical for UPEC biofilm formation and virulence: type 1 pili (Fim) localized exclusively to the air exposed region, while curli amyloid fibers localized to the air-liquid interface. Comparison of cells grown aerobically, fermentatively, or utilizing an alternative terminal electron acceptor showed that the phase-variable fim promoter switched to the "OFF" orientation under oxygen-deplete conditions, leading to marked reduction of type 1 pili on the bacterial cell surface. Conversely, S pili whose expression is inversely related to fim expression were up-regulated under anoxic conditions. Tethering the fim promoter in the "ON" orientation in anaerobically grown cells only restored type 1 pili production in the presence of an alternative terminal electron acceptor beyond oxygen. Together these data support the presence of at least two regulatory mechanisms controlling fim expression in response to oxygen availability and may contribute to the stratification of extracellular matrix components within the biofilm. MALDI IMS facilitated the discovery of these mechanisms, and we have demonstrated that this technology can be used to interrogate subpopulations within bacterial biofilms. PMID- 25738821 TI - Antiepileptic drugs as prophylaxis for post-craniotomy seizures. AB - BACKGROUND: The incidence of seizures following supratentorial craniotomy for non traumatic pathology has been estimated to be between 15% to 20%; however, the risk of experiencing a seizure may vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials (RCTs). OBJECTIVES: To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective. SEARCH METHODS: Searches were run for the original review in January 2012. We performed subsequent searches in September 2012 and up to 04 August 2014. We searched the Cochrane Epilepsy Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE. We did not apply any language restrictions. SELECTION CRITERIA: We included RCTs of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons. Trials with adequate randomisation methods and concealment were included; these could either be blinded or unblinded parallel trials. We did not stipulate a minimum treatment period, and we included trials using active drugs or placebo as a control group. DATA COLLECTION AND ANALYSIS: Two review authors (JP and JG) independently selected trials for inclusion and performed data extraction and risk of bias assessments. We resolved any disagreements through discussion. Outcomes investigated included the number of patients experiencing seizures (early - occurring within first week following craniotomy, and late - occurring after first week following craniotomy), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, we did not combine data from the included trials in a meta-analysis; we presented the findings of the review in narrative format. MAIN RESULTS: We included eight RCTs (N = 1602), which were published between 1983 and 2013. Three trials compared a single AED (phenytoin) with a placebo or no treatment. One three-arm trial compared two AEDs (carbamazepine, phenytoin) with no treatment. A second three-arm trial compared phenytoin, phenobarbital and no treatment. Three other trials were head-to-head trials of AEDs (phenytoin vs. valproate; zonisamide vs. phenobarbital) and levetiracetam vs. phenytoin. Of the five trials comparing AEDs with controls, only one trial reported a significant difference between AED treatment and controls for early seizure occurrence. All other comparisons were non-significant. Of the head-to-head trials, none reported statistically significant differences between treatments for either early or late seizures. One head-to-head trial showed an increase in the number of deaths following one AED treatment compared to another AED treatment. Incidences of adverse effects of treatment were poorly reported, and the most trials reported no significant differences between treatment groups. However data on adverse events were limited. AUTHORS' CONCLUSIONS: There is little evidence to suggest that AED treatment administered prophylactically is effective or not effective in preventing post-craniotomy seizures. The current evidence base is limited due to the differing methodologies employed in the trials and inconsistencies in reporting of outcomes. Further evidence from good-quality, contemporary trials is required in order to assess the effectiveness of prophylactic AED treatment compared to control groups or other AEDs in preventing post-craniotomy seizures properly. PMID- 25738822 TI - A Pilot Assessment of Occupational Health Hazards in the US Electronic Scrap Recycling Industry. AB - The National Institute for Occupational Safety and Health (NIOSH) surveyed a randomly selected sample of electronic scrap (e-scrap) recycling facilities nationwide to characterize work processes, exposures, and controls. Despite multiple attempts to contact 278 facilities, only 47 responded (17% response rate). Surveyed facilities reported recycling a wide variety of electronics. The most common recycling processes were manual dismantling and sorting. Other processes included shredding, crushing, and automated separation. Many facilities reported that they had health and safety programs in place. However, some facilities reported the use of compressed air for cleaning, a practice that can lead to increased employee dust exposures, and some facilities allowed food and drinks in the production areas, a practice that can lead to ingestion of contaminants. Although our results may not be generalizable to all US e-scrap recycling facilities, they are informative regarding health and safety programs in the industry. We concluded that e-scrap recycling has the potential for a wide variety of occupational exposures particularly because of the frequent use of manual processes. On-site evaluations of e-scrap recyclers are needed to determine if reported work processes, practices, and controls are effective and meet current standards and guidelines. Educating the e-scrap recycling industry about health and safety best practices, specifically related to safe handling of metal dust, would help protect employees. PMID- 25738823 TI - WITHDRAWN:Expression of the angiotensin II, rac GTPase activating protein 1, signal transducer and activator of transcription 3 signaling pathway in patients with permanent atrial fibrillation and rheumatic heart disease. AB - Ahead of Print article withdrawn by publisher. PMID- 25738824 TI - Some metabolic issues should not be neglected when using citrate for continuous renal replacement therapy! PMID- 25738826 TI - A tin-free route to trans-diels-alder motifs by visible light photoredox catalysis. AB - A tin-free trans-Diels-Alder paradigm for the stereoselective synthesis of trans fused polycyclic systems was developed through the photocatalytic reductive dehalogenation of alpha-haloketones promoted by visible light. Good to excellent diastereoselectivities were observed in the stereoselective construction of trans fused octalone derivatives under mild reaction conditions. PMID- 25738825 TI - Tenascin C in metastasis: A view from the invasive front. AB - The extracellular matrix protein tenascin C (TNC) is a large glycoprotein expressed in connective tissues and stem cell niches. TNC over-expression is repeatedly observed in cancer, often at the invasive tumor front, and is associated with poor clinical outcome in several malignancies. The link between TNC expression and poor survival in cancer patients suggests a role for TNC in metastatic progression, which is responsible for the majority of cancer related deaths. Indeed, functional studies using mouse models are revealing new roles of TNC in cancer progression and underscore its important contribution to the development of metastasis. TNC has a pleiotropic role in advancing metastasis by promoting migratory and invasive cell behavior, angiogenesis and cancer cell viability under stress. TNC is an essential component of the metastatic niche and modulates stem cell signaling within the niche. This may be crucial for the fitness of disseminated cancer cells confronted with a foreign environment in secondary organs, that can exert a strong selective pressure on invading cells. TNC is a compelling example of how an extracellular matrix protein can provide a molecular context that is imperative to cancer cell fitness in metastasis. PMID- 25738827 TI - Human serum amyloid A3 (SAA3) protein, expressed as a fusion protein with SAA2, binds the oxidized low density lipoprotein receptor. AB - Serum amyloid A3 (SAA3) possesses characteristics distinct from the other serum amyloid A isoforms, SAA1, SAA2, and SAA4. High density lipoprotein contains the latter three isoforms, but not SAA3. The expression of mouse SAA3 (mSAA3) is known to be up-regulated extrahepatically in inflammatory responses, and acts as an endogenous ligand for the toll-like receptor 4/MD-2 complex. We previously reported that mSAA3 plays an important role in facilitating tumor metastasis by attracting circulating tumor cells and enhancing hyperpermeability in the lungs. On the other hand, human SAA3 (hSAA3) has long been regarded as a pseudogene, which is in contrast to the abundant expression levels of the other isoforms. Although the nucleotide sequence of hSAA3 is very similar to that of the other SAAs, a single oligonucleotide insertion in exon 2 causes a frame-shift to generate a unique amino acid sequence. In the present study, we identified that hSAA3 was transcribed in the hSAA2-SAA3 fusion transcripts of several human cell lines. In the fusion transcript, hSAA2 exon 3 was connected to hSAA3 exon 1 or hSAA3 exon 2, located approximately 130kb downstream from hSAA2 exon 3 in the genome, which suggested that it is produced by alternative splicing. Furthermore, we succeeded in detecting and isolating hSAA3 protein for the first time by an immunoprecipitation-enzyme linked immune assay system using monoclonal and polyclonal antibodies that recognize the hSAA3 unique amino acid sequence. We also demonstrated that hSAA3 bound oxidized low density lipoprotein receptor (oxLDL receptor, LOX-1) and elevated the phosphorylation of ERK, the intracellular MAP-kinase signaling protein. PMID- 25738828 TI - Two-dimensional gel electrophoresis analysis of the leiomyoma interstitial fluid reveals altered protein expression with a possible involvement in pathogenesis. AB - Uterine leiomyoma is the most common smooth benign neoplasm. In the present study, we analyzed the global interstitial fluid (IF) profile of leiomyoma vs. normal myometrium to identify protein dysregulation involved in leiomyoma pathogenesis. Two-dimensional gel electrophoresis and mass spectrometry were used to generate and compare the global interstitial fluid profiles of the leiomyoma and of the normal tissue. Two proteins were validated by immunohistochemistry. By comparing the interstitial fluid profile of the leiomyoma with that of the normal myometrium, the levels of seven proteins were found to be significantly different: four structural organization proteins (desmin, prelamin-A/C, transgelin and alpha-actinin-1), an inflammatory response (alpha1-antitrypsin), a response to oxidative stress (peroxiredoxin-2), and a folding protein (heat shock 70 kDa protein 1A/1B). Desmin, alpha1-antitrypsin and peroxiredoxin-2 were upregulated in the leiomyoma, whereas heat shock 70 kDa protein 1A/1B, alpha actinin-1, prelamin-A/C and transgelin were downregulated. Desmin and alpha1 antitrypsin were further validated by immunohistochemistry. By identifying proteins with altered expression levels compared to the myometrium from several pathways of the leiomyoma pathogenesis, we found the leiomyoma interstitial fluid to have a characteristic proteomic profile. A better appreciation of the pathophysiology of the disease can be useful in the development of conservative treatments that serve as viable alternatives to hysterectomy. PMID- 25738829 TI - Expression of connective tissue growth factor in male breast cancer: clinicopathologic correlations and prognostic value. AB - Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of secreted proteins that are believed to play an important role in the development of neoplasia. In particular, CTGF has been reported to play an important role in mammary tumorigenesis and to have prognostic value in female breast cancer (FBC). The aim of the present study was to investigate clinicopathologic correlations and prognostic value of CTGF in male breast cancer (MBC) and to compare these findings with FBC. For this, we studied CTGF protein expression by immunohistochemistry in 109 MBC cases and 75 FBC cases. In MBC, stromal CTGF expression was seen in the majority of the cases 78% (85/109) with high expression in 31/109 cases (28.4%), but expression in tumor cells was only seen in 9.2% (10/109) of cases. High stromal CTGF expression correlated with high grade and high proliferation index (>15%) assessed by MIB-1 immunohistochemical staining. CTGF expression in tumor epithelial cells did not correlate with any of the clinicopathologic features. In FBC, stromal CTGF expression positively correlated with mitotic count and tumor CTGF expression was associated with triple negative status of the tumor (p = 0.002). Neither stromal nor tumor epithelial cell CTGF expression had prognostic value in MBC and FBC. In conclusion, stromal CTGF expression was seen in a high percentage of MBC and was correlated with high grade and high proliferation index. In view of the important role of the microenvironment in cancer progression, this might suggest that stromal CTGF could be an interesting target for novel therapies and molecular imaging. However, the lack of association with prognosis warrants caution. The potential role of CTGF as a therapeutic target for triple negative FBC deserves to be further studied. PMID- 25738831 TI - Correction to assembling multiporphyrin stacks inside the DNA double helix. PMID- 25738830 TI - Acute inflammatory responses of nanoparticles in an intra-tracheal instillation rat model. AB - Exposure to hard metal tungsten carbide cobalt (WC-Co) "dusts" in enclosed industrial environments is known to contribute to the development of hard metal lung disease and an increased risk for lung cancer. Currently, the influence of local and systemic inflammation on disease progression following WC-Co exposure remains unclear. To better understand the relationship between WC-Co nanoparticle (NP) exposure and its resultant effects, the acute local pulmonary and systemic inflammatory responses caused by WC-Co NPs were explored using an intra-tracheal instillation (IT) model and compared to those of CeO2 (another occupational hazard) NP exposure. Sprague-Dawley rats were given an IT dose (0-500 MUg per rat) of WC-Co or CeO2 NPs. Following 24-hr exposure, broncho-alveolar lavage fluid and whole blood were collected and analyzed. A consistent lack of acute local pulmonary inflammation was observed in terms of the broncho-alveolar lavage fluid parameters examined (i.e. LDH, albumin, and macrophage activation) in animals exposed to WC-Co NP; however, significant acute pulmonary inflammation was observed in the CeO2 NP group. The lack of acute inflammation following WC-Co NP exposure contrasts with earlier in vivo reports regarding WC-Co toxicity in rats, illuminating the critical role of NP dose and exposure time and bringing into question the potential role of impurities in particle samples. Further, we demonstrated that WC-Co NP exposure does not induce acute systemic effects since no significant increase in circulating inflammatory cytokines were observed. Taken together, the results of this in vivo study illustrate the distinct differences in acute local pulmonary and systemic inflammatory responses to NPs composed of WC-Co and CeO2; therefore, it is important that the outcomes of pulmonary exposure to one type of NPs may not be implicitly extrapolated to other types of NPs. PMID- 25738832 TI - Mothers' acceptance of human papillomavirus (HPV) vaccination for daughters in a country with a high prevalence of HPV. AB - Cervical cancer is the second most common cancer among women in Argentina and the mortality rate is not declining despite opportunistic screening. Free-of-charge human papillomavirus (HPV) vaccination of 11-year-old girls was introduced in 2011. Parental acceptance of HPV vaccination is considered to be of great importance for HPV vaccine uptake. However, little is known regarding this factor in Argentina. The aim of the present study was to explore maternal HPV vaccination acceptance, willingness to pay for HPV vaccination and correlates of this willingness, awareness of HPV and HPV-associated disease and behaviors and attitudes associated with HPV vaccination acceptance. A total of 180 mothers of girls aged 9-15 years comprised this quantitative, cross-sectional, survey-based study, conducted at two hospitals in the Mendoza Province. Correlates of willingness to pay for HPV vaccination were obtained using multivariable logistic regression models. Maternal HPV vaccination acceptance was 90%, and 60% of mothers were willing to pay for HPV vaccination. Mothers who were gainfully employed and had a higher disposable household income were significantly more willing to pay for HPV vaccination [odds ratio (OR)=2.54, 95% confidence interval (CI) 1.01-6.38; OR=3.28, 95% CI 1.36-7.94, respectively], as were mothers who were aware of cervical cancer prior to the study (OR=3.22, 95% CI 1.02-10.14). Only one in 10 mothers were informed that HPV vaccination does not offer complete protection against cervical cancer. In conclusion, the present study showed high maternal HPV vaccination acceptance, although acceptance decreased when vaccination was not free-of-charge. Continuous public education campaigns are needed to improve knowledge of HPV, HPV vaccines and HPV-associated disease. PMID- 25738833 TI - Controlled high-fidelity navigation in the charge stability diagram of a double quantum dot. AB - We propose an efficient control protocol for charge transfer in a double quantum dot. We consider numerically a two-dimensional model system, where the quantum dots are subjected to time-dependent electric fields corresponding to experimental gate voltages. Our protocol enables navigation in the charge stability diagram from a state to another through controllable variation of the fields. We show that the well-known adiabatic Landau-Zener transition-when supplemented with a time-dependent field tailored with optimal control theory-can remarkably improve the transition speed. The results also lead to a simple control scheme obtained from the experimental charge stability diagram that requires only a single parameter. Eventually, we can achieve the ultrafast performance of the composite pulse protocol that allows the system to be driven at the quantum speed limit. PMID- 25738834 TI - Punch card programmable microfluidics. AB - Small volume fluid handling in single and multiphase microfluidics provides a promising strategy for efficient bio-chemical assays, low-cost point-of-care diagnostics and new approaches to scientific discoveries. However multiple barriers exist towards low-cost field deployment of programmable microfluidics. Incorporating multiple pumps, mixers and discrete valve based control of nanoliter fluids and droplets in an integrated, programmable manner without additional required external components has remained elusive. Combining the idea of punch card programming with arbitrary fluid control, here we describe a self contained, hand-crank powered, multiplex and robust programmable microfluidic platform. A paper tape encodes information as a series of punched holes. A mechanical reader/actuator reads these paper tapes and correspondingly executes operations onto a microfluidic chip coupled to the platform in a plug-and-play fashion. Enabled by the complexity of codes that can be represented by a series of holes in punched paper tapes, we demonstrate independent control of 15 on-chip pumps with enhanced mixing, normally-closed valves and a novel on-demand impact based droplet generator. We demonstrate robustness of operation by encoding a string of characters representing the word "PUNCHCARD MICROFLUIDICS" using the droplet generator. Multiplexing is demonstrated by implementing an example colorimetric water quality assays for pH, ammonia, nitrite and nitrate content in different water samples. With its portable and robust design, low cost and ease of-use, we envision punch card programmable microfluidics will bring complex control of microfluidic chips into field-based applications in low-resource settings and in the hands of children around the world. PMID- 25738835 TI - Enantioselective direct functionalization of indoles by Pd/sulfoxide-phosphine catalyzed N-allylic alkylation. AB - A general and efficient Pd/sulfoxide-phosphine complex-catalyzed direct asymmetric N-allylic alkylation of indoles has been developed to allow for the preparation of various N-allylated indoles in generally good yields with excellent enantioselectivities. This catalytic system could also be extended to other N-containing heterocycles with good results. PMID- 25738836 TI - Pyrethroid treatment of cattle for tsetse control: reducing its impact on dung fauna. AB - BACKGROUND: African trypansomiases of humans and animals can be controlled by attacking the vectors, various species of tsetse fly. Treatment of cattle with pyrethroids to kill tsetse as they feed is the most cost-effective method. However, such treatments can contaminate cattle dung, thereby killing the fauna which disperse the dung and so play an important role in soil fertility. Hence there is a need to identify cost-effective methods of treating cattle with minimal impact on dung fauna. METHODOLOGY/PRINCIPAL FINDINGS: We used dung beetles to field bioassay the levels of dung contamination following the use of spray and pour-on formulations of deltamethrin, applied to various parts of the body of cattle in Zimbabwe. Results suggested that dung was contaminated by contact with insecticide on the body surface as the cattle defecated, and by ingestion of insecticide as the cattle licked themselves. Death of dung beetles was reduced to negligible levels by using only the spray and applying it to the legs and belly or legs alone, i.e., places where most tsetse feed. CONCLUSION/SIGNIFICANCE: The restricted applications suitable for minimising the impact on dung fauna have the collateral benefits of improving the economy and convenience of cattle treatments for tsetse control. The demonstration of collateral benefits is one of the surest ways of promoting environmentally friendly procedures. PMID- 25738837 TI - Sulfation of melatonin: enzymatic characterization, differences of organs, species and genders, and bioactivity variation. AB - Exogenous melatonin (Mel) is widely used in clinic for multiple therapeutic purposes. In metabolism pathways of Mel, 6-hydroxymelatonin-sulfate (S-O-Mel) and N-acetylserotonin sulfate (S-NAS) are the most abundant metabolites account for over 90% of total Mel metabolites in humans, indicating that sulfation plays an important role in reflecting the functions and clearance of Mel in vivo. In the present study, we characterized Mel sulfation using various human organ cytosols (liver, lung, kidney, small intestine and brain), liver cytosols from five different animal species, and cDNA-expressed human sulfotransferase (SULT) for the first time. Our results demonstrated that liver, lung, kidney and small intestine of humans had high catalytic efficiency for Mel sulfation, however, brain contained a very low reaction rate. Interestingly, organ cytosols prepared from females exhibited higher sulfation activity than those of males. SULT isoforms 1A1, 1A2, 1A3, 1B1 and 1E1 exhibited metabolic activities toward Mel. According to kinetic parameters (Km and Vmax), chemical inhibition, correlation analysis, molecular docking and sulfation assays with recombinant human SULTs isoforms, SULT1A1 was determined as the major enzyme responsible for Mel sulfation. Furthermore, considerable species differences in Mel sulfation were observed, and the total intrinsic clearance rate of Mel sulfation was as follows: monkey>rat>dog>human>pig>mouse. Additionally, the anti-inflammatory effects of Mel and its sulfated metabolites were evaluated by inhibiting nitric oxide (NO) production in RAW264.7 cells, and S-O-Mel as a bioactive form, exhibited potent bioactivity. Our investigation provided a global view of the enzyme-dependent sulfation of Mel that can guide biomedical research on Mel. PMID- 25738838 TI - Fate of antibiotic resistant bacteria and genes during wastewater chlorination: implication for antibiotic resistance control. AB - This study investigated fates of nine antibiotic-resistant bacteria as well as two series of antibiotic resistance genes in wastewater treated by various doses of chlorine (0, 15, 30, 60, 150 and 300 mg Cl2 min/L). The results indicated that chlorination was effective in inactivating antibiotic-resistant bacteria. Most bacteria were inactivated completely at the lowest dose (15 mg Cl2 min/L). By comparison, sulfadiazine- and erythromycin-resistant bacteria exhibited tolerance to low chlorine dose (up to 60 mg Cl2 min/L). However, quantitative real-time PCRs revealed that chlorination decreased limited erythromycin or tetracycline resistance genes, with the removal levels of overall erythromycin and tetracycline resistance genes at 0.42 +/- 0.12 log and 0.10 +/- 0.02 log, respectively. About 40% of erythromycin-resistance genes and 80% of tetracycline resistance genes could not be removed by chlorination. Chlorination was considered not effective in controlling antimicrobial resistance. More concern needs to be paid to the potential risk of antibiotic resistance genes in the wastewater after chlorination. PMID- 25738839 TI - Early resolved acute syphilitic posterior placoid chorioretinitis. AB - PURPOSE: Acute syphilitic posterior placoid chorioretinitis (ASPPC) is a rare ocular manifestation of syphilis, and its natural course is not well understood. We herein present two unusual cases of ASPPC in which there was almost total resolution of the fundus and optical coherence tomography (OCT) findings during the early presentation before treatment was initiated. CASE REPORTS: Patient 1: A 44-year-old man presented with a 4-day history of decreased visual acuity in his left eye. Dilated fundus examination revealed a yellowish subretinal placoid lesion in the posterior pole, and OCT images showed subretinal fluid and irregular or granular hyperreflectivity of the retinal pigment epithelium. Ten days later, the yellowish placoid lesion had dramatically improved and the OCT findings showed absence of the subretinal fluid and hyperreflective lesion without any treatment. Patient 2: A 35-year-old man presented with a 3-day history of decreased visual acuity in his right eye. Dilated fundus examination showed a yellow submacular placoid lesion, and OCT images showed a small amount of subretinal fluid with disruption of the inner segment/outer segment junction. Four days after presentation, the fundus and OCT findings had markedly resolved without definitive treatment. In both cases, serologic test results confirmed the diagnosis of syphilis, and the patients were referred to the Department of Infectious Disease for systemic antibiotic treatment. After treatment, the patients' visual acuities were improved, but the disruption of the inner segment/outer segment junction on OCT images remained. CONCLUSIONS: In patients with ASPPC, fundus and OCT findings can spontaneously recover during the early clinical course before treatment. PMID- 25738840 TI - Sutureless artificial iris after phacoemulsification in congenital aniridia. AB - PURPOSE: This article reports the first case of a sutureless artificial iris prosthesis used in combination with cataract surgery for congenital aniridia with successful visual and cosmetic results. CASE REPORT: A 15-year-old woman with congenital bilateral partial aniridia, cataracts, and intense photophobia presented to the Cornea and Refractive Surgery Unit of the Ophthalmology Department. She was managed with an artificial iris implant (ArtificialIris, Dr. Schmidt Intraocularlinsen GmbH, Human Optics) fixed in the ciliary sulcus without any sutures after small-incision cataract surgery. At the 1-year follow-up, subjective complaints of glare and photophobia as well as binocular near visual acuity improved significantly. The cosmetic result was excellent. No postoperative complications have been recorded within this period. CONCLUSIONS: The ArtificialIris is a promising device for treating photophobia in congenital aniridia. ArtificialIris does not require suture fixation with adequate capsular support and iris remnants. PMID- 25738842 TI - Vismodegib as a neoadjuvant treatment to Mohs surgery for aggressive basal cell carcinoma. AB - BACKGROUND: Vismodegib, a hedgehog pathway inhibitor has been recently introduced as an oral therapy for locally advanced and metastatic basal cell carcinoma. Although treatment of patients with basal cell carcinoma with vismodegib has been associated with partial or complete clinical response, it is still unclear if it is also associated with histological cure. PATIENTS: Two patients with 3 large and aggressive basal cell carcinomas were treated with Vismodegib for 6 months. The treatment was followed by Mohs micrographic surgery. RESULTS: Two tumors disappeared clinically and one was reduced dramatically in its size following treatment with vismodegib. Mohs surgery in all three tumors revealed residual islands of BCC although margins were cleared at the end of surgery. CONCLUSIONS: Neoadjuvant therapy with vismodegib for 6 months prior to Mohs surgery was effective in reducing the size of primary and recurrent aggressive basal cell carcinoma. However, residual tumor nests were found during surgery. Further larger studies are needed to evaluate the efficacy of Vismodegib as a neoadjuvant treatment prior to Mohs surgery. PMID- 25738841 TI - Identifying prognostic features by bottom-up approach and correlating to drug repositioning. AB - BACKGROUND: Traditionally top-down method was used to identify prognostic features in cancer research. That is to say, differentially expressed genes usually in cancer versus normal were identified to see if they possess survival prediction power. The problem is that prognostic features identified from one set of patient samples can rarely be transferred to other datasets. We apply bottom up approach in this study: survival correlated or clinical stage correlated genes were selected first and prioritized by their network topology additionally, then a small set of features can be used as a prognostic signature. METHODS: Gene expression profiles of a cohort of 221 hepatocellular carcinoma (HCC) patients were used as a training set, 'bottom-up' approach was applied to discover gene expression signatures associated with survival in both tumor and adjacent non tumor tissues, and compared with 'top-down' approach. The results were validated in a second cohort of 82 patients which was used as a testing set. RESULTS: Two sets of gene signatures separately identified in tumor and adjacent non-tumor tissues by bottom-up approach were developed in the training cohort. These two signatures were associated with overall survival times of HCC patients and the robustness of each was validated in the testing set, and each predictive performance was better than gene expression signatures reported previously. Moreover, genes in these two prognosis signature gave some indications for drug repositioning on HCC. Some approved drugs targeting these markers have the alternative indications on hepatocellular carcinoma. CONCLUSION: Using the bottom up approach, we have developed two prognostic gene signatures with a limited number of genes that associated with overall survival times of patients with HCC. Furthermore, prognostic markers in these two signatures have the potential to be therapeutic targets. PMID- 25738843 TI - Onychomycosis: epidemiology, diagnosis, and treatment in a changing landscape. AB - Onychomycosis is an often overlooked and/or undertreated disease. This may be in part due to an under appreciation among both physicians and patients of its impact on quality of life and the potential for significant complications, from tinea corporis and cruris, to bacterial superinfection. Some health care providers are unaware of the effective low-risk treatments currently available. Changing demographic characteristics such as the relative aging of the population; the increasing prevalence of diabetes and peripheral vascular disease, and widespread iatrogenic immunosuppression; and changes in lifestyle practices such as earlier and greater participation in sports, are likely to lead to an increased prevalence of onychomycosis in both adults and children. Two topical onychomycosis treatments, efinaconazole 10% solution, and tavaborole 5% solution were recently approved by the FDA. This article reviews the state of knowledge and describes, briefly, these new treatment options. PMID- 25738844 TI - Leflunomide: an immune modulating drug that may have a role in controlling secondary infections with review of its mechanisms of action. AB - BACKGROUND: Leflunomide (LEF) is an immune modulator used most commonly for rheumatoid arthritis (RA). The mechanisms of action of LEF also include anti microbial effects, particularly anti-viral effects. OBSERVATIONS: We present three patients with atopic dermatitis on azathioprine therapy who had multiple verrucae and in two molluscum contagiosum (MC) that were resistant to repeated conventional therapies. These patients were switched to LEF, and all the patients showed complete resolution of their verrucae and MC within 2 months of starting therapy. In addition, all three patients showed equivalent to better control of their atopic dermatitis with LEF. CONCLUSIONS: LEF has previously been reported to be a useful immune modulator for the treatment of severe atopic dermatitis. The spectrum of anti-viral effects previously seen with leflunomide did appear beneficial in these patients in clearing verrucae and MC, which had been resistant to conventional therapies while the patients were on azathioprine. PMID- 25738845 TI - The use of a reliable, ubiquitous, inexpensive, and user-friendly tablet-based system to track target lesion improvements in subjects with plaque psoriasis treated with clobetasol propionate 0.05% spray. AB - Ubiquitous electronic devices, such as smartphones and tablets, have the potential to enable a fundamental shift in the paradigm of healthcare as these devices may allow patients and health care providers (HCPs) to rapidly and remotely communicate with each other. Once fully realized, these devices may facilitate interactions between patients and HCPs. While these devices hold much promise, much work remains in assessing their viability in various diseases. A pilot study was conducted to investigate the use of a tablet-based numeric rating scale to assess improvements in a plaque psoriasis target lesion treated with clobetasol propionate 0.05% spray (CPS). Twenty-eight subjects with plaque psoriasis enrolled and were treated with CPS twice daily for 15 days. Target lesion severity (scale of 0 [no psoriasis] to 10 [very severe psoriasis]) and effectiveness scores (scale of 0 [none] to 3 [severe]) were recorded using a tablet-based system by the investigator and subjects. The tablet was also used to take photos of the target lesion to capture photographic evidence of improvement. Investigator and subject assessed target lesion severity and effectiveness scores improved during the study from baseline to day 15; in addition subjects indicated a high level of satisfaction with CPS treatment. Very few technological failures were reported and captured photographs were consistent visit to visit and of high quality. Taken together, this study supports the use of a tablet-based system to measure and track plaque psoriasis disease progression and also confirmed that CPS is an effective and safe treatment for plaque psoriasis. PMID- 25738846 TI - Next-generation biologics in the management of plaque psoriasis: a literature review of IL-17 inhibition. AB - Advances in the understanding of the pathogenesis of psoriasis have led to the development of biologic agents that target T cells and cytokines that play a specific role in the underlying inflammation associated with psoriasis (eg, tumor necrosis factor-alpha inhibitors, interleukin [IL]-12/23 inhibitors). In this review, evidence for the central role of IL-17 in the pathophysiology of psoriasis is presented, along with available clinical trial data on the selective IL-17 inhibitors in development. Three biologic agents that target IL-17 are currently in clinical development: secukinumab, ixekizumab, and brodalumab. Clinical studies to date suggest a favorable safety profile and the potential for better efficacy over the previous generation of agents, with Psoriasis Area Severity Index 75 response rates of up to 80% or greater. Fully published results of phase III studies of these agents are eagerly awaited. PMID- 25738847 TI - Polypodium leucotomos extract: a status report on clinical efficacy and safety. AB - Various extracts of polypodium leucotomos (PLE) applied topically or taken orally have been shown to have several beneficial antioxidant, photoprotectant, antimutagenic, and immunoregulatory effects. Modern studies have evaluated the efficacy of PLE orally as a photoprotective agent and for use in several photo aggravated dermatologic disorders such as polymorphous light eruption, other photodermatoses, and melasma. No articles have been published evaluating the safety of PLE. We performed a PUBMED search for any randomized clinical trials related to PLE, or anapsos, a synonym. The primary safety endpoint of the review was any mention of an adverse event, side effect, or toxicity. Overall, 19 human and 6 basic science studies were included spanning over 40 years of research. Oral PLE was administered at daily doses ranging from 120 mg to 1080 mg. No adverse effects were reported in laboratory studies. In humans, side effects (gastrointestinal complaints and pruritus) were mild to moderate and found only in very small numbers of patients overall (16/1016 [2%]). This review concludes PLE is well tolerated at all doses administered and associated with a negligible risk of side effects. PMID- 25738848 TI - Evolving perspectives on the etiology and pathogenesis of acne vulgaris. AB - As the pathophysiology of acne is complex and multifactorial, the continued influx of new basic science and clinical information requires careful analysis before drawing conclusions about what truly contributes to the development and progression of this chronic disease. Our objective is to review the latest evidence and highlight a number of important perspectives on the pathophysiology of acne. An improved understanding of acne pathogenesis should lead to more rational therapy and a better understanding of the role of P acnes opens new perspectives for the development of new treatments and management. Further research may be directed at targeting receptors, adhesion molecules, cytokines, chemokines or other pro-inflammatory targets implicated in the activation of immune detection and response (i.e., toll-like receptors [TLRs], protease activated receptors [PARs]) that appear to contribute to the pathophysiology of acne. Therapeutic options that reduce the need for topical and/or oral antibiotic therapy for acne are welcome as bacterial resistance to antibiotics is a clinically relevant concern both in the United States and globally. PMID- 25738849 TI - One-year topical stabilized retinol treatment improves photodamaged skin in a double-blind, vehicle-controlled trial. AB - BACKGROUND: Retinol, a precursor of retinoic acid, has great potentials as a topical anti-aging molecule; however, only a handful of clinical investigations have been published to date. OBJECTIVE: This study aimed to assess the efficacy and safety of 0.1% stabilized retinol on photodamaged skin during a one-year treatment. METHODS: The investigation included two 52-week, double-blind, vehicle controlled studies. In the main study, 62 subjects applied either a stabilized retinol formulation or its vehicle to the full face. A second exploratory study evaluated histological/histochemical markers in 12 subjects after 52 weeks of either retinol or vehicle use on contralateral dorsal forearms. RESULTS: The retinol group showed significant photodamage improvement over vehicle at all timepoints during the study. After 52 weeks, retinol had improved crow's feet fine lines by 44%, and mottled pigmentation by 84%, with over 50% of subjects showing +2 grades of improvement in many parameters. Additionally, at week 52, histochemical data confirmed the clinical results, showing increased expression of type I procollagen, hyaluronan, and Ki67 as compared to vehicle. CONCLUSION: This study confirms that a stabilized retinol (0.1%) formulation can significantly improve the signs of photoaging, and improvements in photodamage continue with prolonged use. PMID- 25738850 TI - A phase I safety and pharmacokinetic study of ATX-101: injectable, synthetic deoxycholic acid for submental contouring. AB - ATX-101 (deoxycholic acid [DCA] injection) is a proprietary formulation of pure synthetic DCA. When injected into subcutaneous fat, ATX-101 results in focal adipocytolysis, the targeted destruction of fat cells. ATX-101 is undergoing investigation as an injectable drug for contouring the submental area by reducing submental fat (SMF). The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of the maximal therapeutic dose of ATX-101 (100 mg total dose). Following PK evaluation of endogenous DCA, subjects (N=24) received subcutaneous injections of ATX-101 (2 mg/cm2, with or without 0.9% benzyl alcohol) into SMF; PK evaluation was repeated periodically over 24 hours. Endogenous DCA plasma concentrations measured prior to injection were highly variable within and between subjects. Similarly, following ATX-101 injection, DCA plasma concentrations were highly variable, peaked rapidly, and returned to the range observed for endogenous values by 24 hours postdose. All subjects experienced at least 1 adverse event (AE). No death, serious AE, or AE-related discontinuations occurred. The majority of AEs were transient, associated with the area treated, and of mild or moderate severity. No clinically significant changes were reported for laboratory test results, vital signs, or Holter electrocardiograms postdosing. These data support the favorable safety and efficacy observations of ATX-101 as an injectable drug to reduce SMF. PMID- 25738851 TI - 12-month effects of stabilized hyaluronic acid gel compared with saline for rejuvenation of aging hands. AB - In this evaluator-blind, placebo-controlled study, microinjections of stabilized hyaluronic acid (HA) gel for rejuvenation of aging hands were evaluated. Patients received three injections of 1.0 ml HA gel (20 mg/ml HA) in the dorsum of one hand and 1.0 ml saline in the other, over 3 months (M). Treatments were compared up to M03; comparisons with Day 1 (D01) were made up to M05 and M12 (extension study). Efficacy was evaluated by patients and investigators using the Global Aesthetic Improvement Scale (GAIS). Self-assessment questionnaires, biomechanical measurements, and adverse events (AEs) were analyzed. Thirty women (mean age: 53 years) provided data up to M05. At M03, HA gel treatment improved hand skin condition in all patients versus D01, according to the GAIS; improvements were sustained to M12. Mean patient scores at M01-M03 were significantly higher for HA gel than for saline (P<0.05). Self-assessment questionnaire grades up to M03 were generally significantly better for HA gel versus saline (P<0.05); grades were maintained to M12. Statistically significant improvements with HA gel in hydration and elasticity was demonstrated at M03, compared with D01 and saline (P<0.05), and in terms of skin roughness versus D01. Maximum roughness (P<0.05) and waviness (P<0.01) were significantly improved versus saline. All AEs were mild and anticipated, with no serious AEs. Overall, HA gel injections were generally well tolerated and efficacious for rejuvenation of aging hands compared with saline. Sustained improvements at 12 months compared with baseline indicate that efficacy could be maintained long term. PMID- 25738852 TI - DNA repair enzymes: an important role in skin cancer prevention and reversal of photodamage--a review of the literature. AB - The incidence of skin cancer continues to increase annually despite preventative measures. Non-melanoma skin cancer affects more than 1,000,000 people in the United States every year.1 The current preventative measures, such as sunscreens and topical antioxidants, have not shown to be effective in blocking the effects of UV radiation based on these statistics. The level of antioxidants contained in the majority of skin creams is not sufficient to majorly impact free radical damage. Sunscreens absorb only a portion of UV radiation and often are not photostable. In this review article, we present the novel use of exogenous DNA repair enzymes and describe their role in combating photocarcinogenesis and photoaging. Topical application of these enzymes serves to supplement intrinsic DNA repair mechanisms. The direct repair of DNA damage by endogenous repair enzymes lessens rates of mutagenesis and strengthens the immune response to tumor cells. However, these innate mechanisms are not 100% efficient. The use of exogenous DNA repair enzymes presents a novel way to supplement intrinsic mechanisms and improve their efficacy. Several DNA repair enzymes critical to the prevention of cutaneous malignancies have been isolated and added to topical preparations designed for skin cancer prevention. These DNA repair enzymes maximize the rate of DNA repair and provide a more efficient response to carcinogenesis. PMID- 25738853 TI - Intraoperative localized urticarial reaction during Q-switched Nd:YAG laser tattoo removal. AB - Q-switched lasers, such as the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, are the gold standard for tattoo removal. Allergy to tattoo pigment is well documented, but adverse allergic reactions during or shortly after laser tattoo removal are rare with few reports in the medical literature. Here we describe an intraoperative, localized urticarial reaction that developed during treatment of a tattoo using a 1064-nm Nd:YAG laser. As laser tattoo removal becomes increasingly popular amongst our patients, it is important for dermatologists to be aware of urticarial allergic reactions as well as their management. We outline our recommendations for medical management of this condition and hope that these guidelines will facilitate patient care by dermatologists who encounter this immune skin reaction to laser tattoo removal PMID- 25738854 TI - Autonomic nervous system activity as risk predictor in the medical emergency department: a prospective cohort study. AB - OBJECTIVES: To evaluate heart rate deceleration capacity, an electrocardiogram based marker of autonomic nervous system activity, as risk predictor in a medical emergency department and to test its incremental predictive value to the modified early warning score. DESIGN: Prospective cohort study. SETTING: Medical emergency department of a large university hospital. PATIENTS: Five thousand seven hundred thirty consecutive patients of either sex in sinus rhythm, who were admitted to the medical emergency department of the University of Tubingen, Germany, between November 2010 and March 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Deceleration capacity of heart rate was calculated within the first minutes after emergency department admission. The modified early warning score was assessed from respiratory rate, heart rate, systolic blood pressure, body temperature, and level of consciousness as previously described. Primary endpoint was intrahospital mortality; secondary endpoints included transfer to the ICU as well as 30-day and 180-day mortality. One hundred forty-two patients (2.5%) reached the primary endpoint. Deceleration capacity was highly significantly lower in nonsurvivors than survivors (2.9 +/- 2.1 ms vs 5.6 +/- 2.9 ms; p < 0.001) and yielded an area under the receiver-operator characteristic curve of 0.780 (95% CI, 0.745-0.813). The modified early warning score model yielded an area under the receiver-operator characteristic curve of 0.706 (0.667-0.750). Implementing deceleration capacity into the modified early warning score model led to a highly significant increase of the area under the receiver-operator characteristic curve to 0.804 (0.770-0.835; p < 0.001 for difference). Deceleration capacity was also a highly significant predictor of 30-day and 180-day mortality as well as transfer to the ICU. CONCLUSIONS: Deceleration capacity is a strong and independent predictor of short-term mortality among patients admitted to a medical emergency department. PMID- 25738855 TI - Management of apixaban-associated subdural hematoma: a case report on the use of factor eight inhibitor bypassing activity. AB - OBJECTIVE: We report a case of a patient receiving apixaban who developed a spontaneous subdural hematoma and declining mental status that improved after administration of a single dose of factor eight inhibitor bypassing activity. DESIGN: Case report. SETTING: Comprehensive Stroke Center, Neurocritical Care Unit. PATIENT: A 76-year-old man presented to an outside facility with a chief complaint of headache and pain behind his right eye. A CT scan of his head revealed a subdural hematoma. The patient was transferred to our facility with worsening clinical status. INTERVENTIONS: After a confirmatory cranial CT scan revealed a worsening subdural hematoma with midline shift, a single dose of factor VIII inhibitor bypassing activity (25 U/kg) was administered. MEASUREMENTS AND MAIN RESULTS: Coagulation tests following the administration of factor VIII inhibitor bypassing activity and a follow-up CT scan confirmed hemostasis. The patient was discharged home with no focal deficits. CONCLUSIONS: Factor VIII inhibitor bypassing activity may be a viable, nonspecific reversal agent for life threatening bleeding associated with apixaban. PMID- 25738856 TI - Lipid paradox in acute myocardial infarction-the association with 30-day in hospital mortality. AB - OBJECTIVES: Elevated low-density lipoprotein cholesterol and triglycerides are major risk factors for coronary artery disease. However, fatty acids from triglycerides are a major energy source, low-density lipoprotein cholesterol is critical for cell membrane synthesis, and both are critical for cell survival. This study was designed to clarify the relationship between lipid profile, morbidity as assessed by Killip classification, and 30-day mortality in patients with acute myocardial infarction. DESIGN: A noninterventional observational study. SETTING: Coronary care unit in a university hospital. PATIENTS: Seven hundred twenty-four patients with acute myocardial infarction in the coronary care program of the Bureau of Health Promotion were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Low-density lipoprotein cholesterol and triglyceride levels were significantly lower in high-Killip (III+IV) patients compared with low-Killip (I+II) patients and in those who died compared with those who survived beyond 30 days (both p<0.001). After adjustment for risk factors, low-density lipoprotein cholesterol less than 62.5 mg/dL and triglycerides less than 110 mg/dL were identified as optimal threshold values for predicting 30-day mortality and were associated with hazard ratios of 1.65 (95% CI, 1.18-2.30) and 5.05 (95% CI, 1.75-14.54), and the actual mortality rates were 23% in low low-density lipoprotein, 6% in high low-density lipoprotein, 14% in low triglycerides, and 3% in high triglycerides groups, respectively. To test the synergistic effect, high-Killip patients with triglycerides less than 62.5 mg/dL and low-density lipoprotein cholesterol less than 110 mg/dL had a 10.9-fold higher adjusted risk of mortality than low-Killip patients with triglycerides greater than or equal to 62.5 mg/dL and low-density lipoprotein cholesterol greater than or equal to 110 mg/dL (p<0.001). The lipid paradox also improved acute myocardial infarction short-term outcomes prediction on original Killip and thrombolytic in myocardial infarction scores. CONCLUSIONS: Low low-density lipoprotein cholesterol, low triglycerides, and high Killip severity were associated with significantly higher 30-day in-hospital mortality in patients presenting with acute myocardial infarction. The initial lipid profile of patients with acute myocardial infarction may therefore hold prognostic value. PMID- 25738858 TI - Extracorporeal membrane oxygenation for the support of adults with acute myocarditis. AB - OBJECTIVES: To characterize survival outcomes for adult patients with acute myocarditis supported with extracorporeal membrane oxygenation and identify risk factors for in-hospital mortality. DESIGN: Retrospective review of Extracorporeal Life Support Organization registry database. SETTING: Data reported to Extracorporeal Life Support Organization by 230 extracorporeal membrane oxygenation centers. PATIENTS: Patients 16 years old or older supported with extracorporeal membrane oxygenation for myocarditis during 1995 to 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 150 separate runs of extracorporeal membrane oxygenation for 147 patients with a diagnosis of acute myocarditis in the Extracorporeal Life Support Organization database from 1995 through 2011. Survival to hospital discharge was 61%. Nine patients underwent heart transplantation, and transplant-free survival to discharge was 56%. Extracorporeal membrane oxygenation was deployed during extracorporeal cardiopulmonary resuscitation in 31 patients (21% of the cohort). In a multivariate model evaluating pre-extracorporeal membrane oxygenation and extracorporeal membrane oxygenation support factors, pre-extracorporeal membrane oxygenation arrest (adjusted odds ratio, 2.4; 95% CI, 1.1-5.0) and need for higher extracorporeal membrane oxygenation flows at 4 hours post-extracorporeal membrane oxygenation cannulation (odds ratio, 2.8; 95% CI, 1.1-7.3) were associated with increased odds of in-hospital mortality. In a second multivariate model evaluating adverse events while on extracorporeal membrane oxygenation, central nervous system injury (odds ratio, 26.5; 95% CI, 7.3-96.6), renal failure (odds ratio, 3.6; 95% CI, 1.4-9.3), arrhythmia (odds ratio, 5.8; 95% CI, 2.2 15.1), and hyperbilirubinemia (odds ratio, 9.1; 95% CI, 2.6-31.8) were associated with increased odds of in-hospital mortality. CONCLUSIONS: Extracorporeal membrane oxygenation can be used effectively in adults with myocarditis to support the circulation while awaiting myocardial recovery. Early extracorporeal membrane oxygenation deployment prior to cardiac arrest may be associated with better outcomes. PMID- 25738857 TI - Estimating dead-space fraction for secondary analyses of acute respiratory distress syndrome clinical trials. AB - OBJECTIVES: Pulmonary dead-space fraction is one of few lung-specific independent predictors of mortality from acute respiratory distress syndrome. However, it is not measured routinely in clinical trials and thus altogether ignored in secondary analyses that shape future research directions and clinical practice. This study sought to validate an estimate of dead-space fraction for use in secondary analyses of clinical trials. DESIGN: Analysis of patient-level data pooled from acute respiratory distress syndrome clinical trials. Four approaches to estimate dead-space fraction were evaluated: three required estimating metabolic rate; one estimated dead-space fraction directly. SETTING: U.S. academic teaching hospitals. PATIENTS: Data from 210 patients across three clinical trials were used to compare performance of estimating equations with measured dead-space fraction. A second cohort of 3,135 patients from six clinical trials without measured dead-space fraction was used to confirm whether estimates independently predicted mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Dead-space fraction estimated using the unadjusted Harris-Benedict equation for energy expenditure was unbiased (mean +/- SD Harris-Benedict, 0.59 +/- 0.13; measured, 0.60 +/- 0.12). This estimate predicted measured dead-space fraction to within +/-0.10 in 70% of patients and +/-0.20 in 95% of patients. Measured dead-space fraction independently predicted mortality (odds ratio, 1.36 per 0.05 increase in dead-space fraction; 95% CI, 1.10-1.68; p < 0.01). The Harris-Benedict estimate closely approximated this association with mortality in the same cohort (odds ratio, 1.55; 95% CI, 1.21-1.98; p < 0.01) and remained independently predictive of death in the larger Acute Respiratory Distress Syndrome Network cohort. Other estimates predicted measured dead-space fraction or its association with mortality less well. CONCLUSIONS: Dead-space fraction should be measured in future acute respiratory distress syndrome clinical trials to facilitate incorporation into secondary analyses. For analyses where dead space fraction was not measured, the Harris-Benedict estimate can be used to estimate dead-space fraction and adjust for its association with mortality. PMID- 25738859 TI - Fibrillar structures formed by covalently bound, short, beta-stranded peptides on self-assembled monolayers. AB - The ability to maintain or reproduce biomolecular structures on inorganic substrates has the potential to impact diverse fields such as sensing and molecular electronics, as well as the study of biological self-assembly and structure-function relationships. Because the structure and self-assembly of biomolecules are exquisitely sensitive to their local chemical and electrostatic environment, the goal of reproducing or mimicking biological function in an abiological environment, including at a surface, is challenging. However, simple and well-characterized chemical modifications of prepared surfaces can be used to tune surface chemistry, structure, electrostatics, and reactivity of inorganic materials to facilitate biofunctionalization and function. Here, we describe the covalent attachment of 13-residue beta-stranded peptides containing alkyne groups to a flat gold surface functionalized with an azide-terminated self-assembled monolayer through a Huisgen cycloaddition, or "click", reaction. The chemical composition and structural morphology of these surfaces were characterized using X-ray photoelectron spectroscopy, grazing incidence angle reflection-absorption infrared spectroscopy, surface circular dichroism, and atomic force microscopy. The surface-bound beta-strands self-assemble into antiparallel beta-sheets to form fibrillar structures 24.9 +/- 1.6 nm in diameter and 2.83 +/- 0.74 nm in height on the reactive surface. The results herein provide a platform for studying and controlling the self-assembly process of biomolecules into larger supermolecular structures while allowing tunable control through chemical functionalization of the surface. Interest in the mechanisms of formation of fibrillar structures has most commonly been associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's, but fibrils may actually represent the thermodynamic low-energy conformation of a much larger class of peptides and proteins. The protocol developed here is an important step toward uncovering not only the factors that dictate self-assembly but also the mechanisms by which this fibrillar class of superstructures forms. PMID- 25738860 TI - Synthesis of multifunctional cellulose nanocrystals for lectin recognition and bacterial imaging. AB - Multifunctional cellulose nanocrystals have been synthesized and applied as a new type of glyconanomaterial in lectin binding and bacterial imaging. The cellulose nanocrystals were prepared by TEMPO-mediated oxidation and acidic hydrolysis, followed by functionalization with a quinolone fluorophore and carbohydrate ligands. The cellulose nanocrystals were subsequently applied in interaction studies with carbohydrate-binding proteins and in bacterial imaging. The results show that the functional cellulose nanocrystals could selectively recognize the corresponding cognate lectins. In addition, mannosylated nanocrystals were shown to selectively interact with FimH-presenting E. coli, as detected by TEM and confocal fluorescence microscopy. These glyconanomaterials provide a new application of cellulose nanocrystals in biorecognition and imaging. PMID- 25738861 TI - A regression-based differential expression detection algorithm for microarray studies with ultra-low sample size. AB - Global gene expression analysis using microarrays and, more recently, RNA-seq, has allowed investigators to understand biological processes at a system level. However, the identification of differentially expressed genes in experiments with small sample size, high dimensionality, and high variance remains challenging, limiting the usability of these tens of thousands of publicly available, and possibly many more unpublished, gene expression datasets. We propose a novel variable selection algorithm for ultra-low-n microarray studies using generalized linear model-based variable selection with a penalized binomial regression algorithm called penalized Euclidean distance (PED). Our method uses PED to build a classifier on the experimental data to rank genes by importance. In place of cross-validation, which is required by most similar methods but not reliable for experiments with small sample size, we use a simulation-based approach to additively build a list of differentially expressed genes from the rank-ordered list. Our simulation-based approach maintains a low false discovery rate while maximizing the number of differentially expressed genes identified, a feature critical for downstream pathway analysis. We apply our method to microarray data from an experiment perturbing the Notch signaling pathway in Xenopus laevis embryos. This dataset was chosen because it showed very little differential expression according to limma, a powerful and widely-used method for microarray analysis. Our method was able to detect a significant number of differentially expressed genes in this dataset and suggest future directions for investigation. Our method is easily adaptable for analysis of data from RNA-seq and other global expression experiments with low sample size and high dimensionality. PMID- 25738862 TI - A protocol to assess insect resistance to heat waves, applied to bumblebees (Bombus Latreille, 1802). AB - Insect decline results from numerous interacting factors including climate change. One of the major phenomena related to climate change is the increase of the frequency of extreme events such as heat waves. Since heat waves are suspected to dramatically increase insect mortality, there is an urgent need to assess their potential impact. Here, we determined and compared the resistance to heat waves of insects under hyperthermic stress through their time before heat stupor (THS) when they are exposed to an extreme temperature (40 degrees C). For this, we used a new experimental standardised device available in the field or in locations close to the field collecting sites. We applied this approach on different Arctic, Boreo-Alpine and Widespread bumblebee species in order to predict consequences of heat waves. Our results show a heat resistance gradient: the heat stress resistance of species with a centred arctic distribution is weaker than the heat resistance of the Boreo-Alpine species with a larger distribution which is itself lower than the heat stress resistance of the ubiquitous species. PMID- 25738863 TI - Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E cadherin by miR-200 and ZEB1. AB - Downregulation of E-cadherin (gene: CDH1) plays an important role in epithelial mesenchymal transition (EMT), which is critical for normal development and disease states. As a result of long-term treatment of endometrial carcinoma Ishikawa cells with epoxomicin (EXM), the cells exhibited the phenotype for EXM resistance (Ish/EXM cells). Moreover, CDH1 mRNA and its protein were suppressed and EMT was induced in Ish/EXM cells. Ish/EXM cells exhibited drug-resistance to other proteasome inhibitors, MG-132, PSI and PS-341 (Bortezomib). The proteasome inhibitor-resistant cells acquired invasiveness as a result of the chemotherapy. In Ish/EXM cells, E-cadherin was suppressed by upregulation of its transcriptional repressor ZEB1. Furthermore, expression of the miR-200 family (miR-200a, miR-200b, miR-200c and miR-141) found in Ishikawa cells was suppressed in Ish/EXM cells. Overexpression of the miR-200 family in Ish/EXM cells caused by transfection with the pre-miR-200 family induced downregulation of ZEB1 and enhanced expression of E-cadherin. Conversely, suppression of miR-200 expression in the Ishikawa cells by transfection with anti-miR-200 elevated the expression of ZEB1 and suppressed the expression of E-cadherin. These results suggest that acquirement of EXM-resistance in Ish/EXM cells induces up regulation of ZEB1 via suppression of the miR-200 family following suppression of E-cadherin. Since suppression of ZEB1 in Ish/EXM cells by treatment with its siRNA did not restore the miR-200 family expression, miR-200 family was placed upstream of ZEB1 to regulate the expression. PMID- 25738864 TI - Modeling and analysis of unsteady axisymmetric squeezing fluid flow through porous medium channel with slip boundary. AB - The aim of this article is to model and analyze an unsteady axisymmetric flow of non-conducting, Newtonian fluid squeezed between two circular plates passing through porous medium channel with slip boundary condition. A single fourth order nonlinear ordinary differential equation is obtained using similarity transformation. The resulting boundary value problem is solved using Homotopy Perturbation Method (HPM) and fourth order Explicit Runge Kutta Method (RK4). Convergence of HPM solution is verified by obtaining various order approximate solutions along with absolute residuals. Validity of HPM solution is confirmed by comparing analytical and numerical solutions. Furthermore, the effects of various dimensionless parameters on the longitudinal and normal velocity profiles are studied graphically. PMID- 25738865 TI - Migration and common mental disorder: an improvement in mental health over time? AB - Global migration is reaching record high levels and UK migrant groups comprise an increasing proportion of the total population. The migratory process causes stress that can affect mental health. There is limited consistent empirical evidence of a longitudinal nature to explain the association between migration and mental health. This review aims to examine the evidence of a relationship between migration and common mental disorder (CMD) amongst migrants over time. A comprehensive search of medical and psychiatric databases for global quantitative empirical studies investigating incidence of CMD amongst adult migrants from 1975 to July 2012 was conducted. Declines in rates of CMD amongst migrants over time were reported by two thirds of the 18 studies reviewed, less than one third of which were statistically significant. On the contrary, three studies showed an increased rate of CMD, one statistically significant. Individual psychological resources, social support, the acculturation process, cultural variations and time since relocation are identified as statistically significant protective factors against the development of CMD amongst migrants. New enlightening points include the significant impact of varying patterns of psychological distress, of which negative is the most adverse for CMD. Migration is an extremely complex process. Further clarification is needed to gain deeper understanding of the relationship between migration and CMD to address contradictions in the literature and health inequalities amongst migrants. PMID- 25738866 TI - Development of an Australian practice-based research network as a community of practice. AB - There are many aspects of the communities of practice (CoP) framework that are applicable to the development of a practice-based research network (PBRN), where the focus is upon building primary health-care workers' research capacity and research questions. However, there is limited literature focussed on the application of CoP principles applied to research capacity building in Australia. The purpose of this paper is to demonstrate, through a case study, how a developing PBRN, the Illawarra and Southern Practice Research Network, successfully applied the theoretical foundation of CoP to develop a PBRN in a time- and resource-limited context. PMID- 25738867 TI - Immunohistochemical profile of cytokines and growth factors expressed in vestibular schwannoma and in normal vestibular nerve tissue. AB - Vestibular schwannomas, also known as acoustic neuromas, are benign tumors, which originate from myelin-forming Schwann cells. They develop in the vestibular branch of the eighth cranial nerve in the internal auditory canal or cerebellopontine angle. The clinical progression of the condition involves slow and progressive growth, eventually resulting in brainstem compression. The objective of the present study was to investigate the expression level and the localization of the pro-inflammatory cytokines, transforming growth factor-beta1 (TGF-beta1) interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF alpha), as well as the adhesion molecules, intracellular adhesion molecule-1 and vascular endothelial growth factor (VEGF), in order to determine whether these factors are involved in the transformation and development of human vestibular schwannoma. The present study investigated whether changes in inflammation are involved in tumor growth and if so, the mechanisms underlying this process. The results of the current study demonstrated that pro-inflammatory cytokines, including TGF-beta1, IL-1beta and IL-6 exhibited increased expression in human vestibular schwannoma tissue compared with normal vestibular nerve samples. TNF alpha was weakly expressed in Schwann cells, confirming that a lower level of this cytokine is involved in the proliferation of Schwann cells. Neoplastic Schwann cells produce pro-inflammatory cytokines that may act in an autocrine manner, stimulating cellular proliferation. In addition, the increased expression of VEGF in vestibular schwannoma compared with that in normal vestibular nerve tissue, suggests that this factor may induce neoplastic growth via the promotion of angiogenesis. The present findings suggest that inflammation may promote angiogenesis and consequently contribute to tumor progression. In conclusion, the results of the present study indicated that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in vestibular schwannoma. Further studies are necessary to confirm the involvement of these factors in the growth of neoplasms and to develop inhibitors of pro-inflammatory cytokines as a potential treatment option in the future. PMID- 25738868 TI - Assessing relations between PTSD's dysphoria and reexperiencing factors and dimensions of rumination. AB - The purpose of the present study was to investigate the relations between posttraumatic stress disorder's (PTSD) dysphoria and reexperiencing factors and underlying dimensions of rumination. 304 trauma-exposed primary care patients were administered the Stressful Life Events Screening Questionnaire, PTSD Symptom Scale based on their worst traumatic event, and Ruminative Thought Style Questionnaire (RTSQ). Confirmatory factor analyses (CFAs) were conducted to determine the dysphoria and reexperiencing factors' relationships with the four factors of rumination. Results revealed that both the dysphoria and reexperiencing factors related more to problem-focused thinking and anticipatory thoughts than counterfactual thinking. Additionally, the reexperiencing factor related more to anticipatory thinking than repetitive thinking. Clinical and theoretical implications are discussed. PMID- 25738869 TI - Phytochemical investigation of Gynura bicolor leaves and cytotoxicity evaluation of the chemical constituents against HCT 116 cells. AB - Gynura bicolor (Compositae) is a popular vegetable in Asia and believed to confer a wide range of benefits including anti-cancer. Our previous findings showed that the ethyl acetate extract of G. bicolor possessed cytotoxicity and induced apoptotic and necrotic cell death in human colon carcinoma cells (HCT 116). A combination of column chromatography had been used to purify chemical constituents from the ethyl acetate and water extract of G. bicolor leaves. Eight chemical constituents 5-p-trans-coumaroylquinic acid (I), 4-hydroxybenzoic acid (II), rutin (III), kampferol-3-O-rutinoside (IV), 3,5-dicaffeoylquinic acid (V), kampferol-3-O-glucoside (VI), guanosine (VII) and chlorogenic acid (VIII) were isolated from G. bicolor grown in Malaysia. To our best knowledge, all chemical constituents were isolated for the first time from G. bicolor leaves except rutin (III). 3,5-dicaffeoylquinic acid (V), guanosine (VII) and chlorogenic acid (VIII) demonstrated selective cytotoxicity (selective index>3) against HCT 116 cancer cells compared to CCD-18Co human normal colon cells. PMID- 25738870 TI - The role of maternal, health system, and psychosocial factors in prevention of mother-to-child transmission failure in the era of programmatic scale up in western Kenya: a case control study. AB - The aim of this study was to identify factors associated with prevention of mother-to-child transmission (PMTCT) in an area of Kenya with widely accessible free PMTCT services. A matched case-control study was conducted at 31 public facilities in western Kenya. HIV-infected mothers with infants aged 6 weeks to 6 months were interviewed and medical charts were reviewed. Cases were mothers of infants with a definitive diagnosis of HIV. Controls were mothers of infants testing HIV negative. Cases and controls were matched in a 1:3 ratio on socio demographic factors. Fifty cases and 135 controls were enrolled. Conditional (matched) logistic regression analysis was conducted. Odds of being a case were higher for women who first learned their HIV status during pregnancy [OR:2.85, 95%CI:1.41-5.78], did not adhere to antiretroviral therapy (ART) [OR:3.35, 95%CI:1.48-7.58], or had a home delivery [OR:2.42, 95%CI:1.01-5.80]. Based on medical record review, cases had higher odds of their provider not following guidelines for prescription of ART for mothers [OR:8.61, 95%CI:2.83-26.15] and infants [OR:9.72, 95%CI:2.75-34.37]. Stigma from the community [OR:0.37, 95% CI:0.14-1.02] or facility [OR:0.38, 95%CI:0.04-3.41], did not increase the odds of MTCT. Poor adherence to PMTCT guidelines and recommendations by both infected women and health care providers hamper efforts to attain elimination of MTCT. PMID- 25738871 TI - Apigenin and Breast Cancers: From Chemistry to Medicine. AB - Breast cancer is one of the most common causes of the death among women worldwide. Metabolic disorders, alcohol consumption, hormone replacement therapy, genetic susceptibility and not having children are well known risk factors for breast cancer. Surgical resection, radiation therapy, and chemotherapy are among the limited treatment options for breast cancer. Thus, there is growing need to find new chemopreventive agents that may be effective in prevention and/or management of breast cancer. Natural products such as flavonoids provide a variety of anticancer compounds which can be useful for prevention or treatment of breast cancer. The usefulness of dietary phytochemicals in the prevention of this disease is supported by a plethora of experimental and epidemiological studies. Apigenin, a well-known flavone, is found in several dietary plant foods such as parsley, celery, thyme, celeriac, chamomile, onions, lemon balm, and oranges. Extensive studies have shown that apigenin have potent antioxidant, anti inflammatory, and anticarcinogenic properties. The aim of the present communication is to establish the therapeutic potential of apigenin against breast cancer through critical analysis of data from 5 in vitro and in vivo studies. We also review the molecular mechanisms underlying the anticancer effects, natural sources, bioavailability, as well as the chemistry of apigenin. PMID- 25738872 TI - RUNX2 and Osteosarcoma. AB - Osteosarcoma (OS) is the most common pediatric bone cancer in children and young adults. Previous studies have suggested the importance of osteoblast activity in OS tumorigenesis and metastasis, as OS is characterized by abnormal bone formation, while osteoblast is the predominant cell type both in OS and in metastatic tumor tissues. RUNX2 is a known essential transcription factor for osteoblast differentiation. RUNX2 has also been linked to many human cancers, including bone cancers and cancer metastasis in bone. However, the view of RUNX2 during OS tumorigenesis has not been unanimous. In this manuscript, we reviewed the osteoblastic origin in OS etiology. The oncogenic property of RUNX2 in human OS studies was briefly summarized. RUNX2 may be involved in OS pathogenesis by regulating cell cycle controlling of (pre)-osteoblasts, which subsequently convert to OS cells. The roles and mechanisms of RUNX2 during OS metastasis and bone metastasis in target cancers (herein prostate and breast cancers), were as described. The potential involvement of Runx2 in multiple mouse OS models that use human OS cell lines (Xenografts), tumor suppressor genes p53 and Rb1 were also discussed. Finally, we updated some microRNAs studies and their relation with RUNX2 in OS pathogenesis. This review provides a comprehensive understanding of RUNX2's function during OS pathogenesis and will help with the research designing and strategy in controlling OS. PMID- 25738873 TI - The Bicoid class homeodomain factors ceh-36/OTX and unc-30/PITX cooperate in C. elegans embryonic progenitor cells to regulate robust development. AB - While many transcriptional regulators of pluripotent and terminally differentiated states have been identified, regulation of intermediate progenitor states is less well understood. Previous high throughput cellular resolution expression studies identified dozens of transcription factors with lineage specific expression patterns in C. elegans embryos that could regulate progenitor identity. In this study we identified a broad embryonic role for the C. elegans OTX transcription factor ceh-36, which was previously shown to be required for the terminal specification of four neurons. ceh-36 is expressed in progenitors of over 30% of embryonic cells, yet is not required for embryonic viability. Quantitative phenotyping by computational analysis of time-lapse movies of ceh-36 mutant embryos identified cell cycle or cell migration defects in over 100 of these cells, but most defects were low-penetrance, suggesting redundancy. Expression of ceh-36 partially overlaps with that of the PITX transcription factor unc-30. unc-30 single mutants are viable but loss of both ceh-36 and unc 30 causes 100% lethality, and double mutants have significantly higher frequencies of cellular developmental defects in the cells where their expression normally overlaps. These factors are also required for robust expression of the downstream developmental regulator mls-2/HMX. This work provides the first example of genetic redundancy between the related yet evolutionarily distant OTX and PITX families of bicoid class homeodomain factors and demonstrates the power of quantitative developmental phenotyping in C. elegans to identify developmental regulators acting in progenitor cells. PMID- 25738874 TI - Visualizing peripheral nerve regeneration by whole mount staining. AB - Peripheral nerve trauma triggers a well characterised sequence of events both proximal and distal to the site of injury. Axons distal to the injury degenerate, Schwann cells convert to a repair supportive phenotype and macrophages enter the nerve to clear myelin and axonal debris. Following these events, axons must regrow through the distal part of the nerve, re-innervate and finally are re myelinated by Schwann cells. For nerve crush injuries (axonotmesis), in which the integrity of the nerve is maintained, repair may be relatively effective whereas for nerve transection (neurotmesis) repair will likely be very poor as few axons may be able to cross between the two parts of the severed nerve, across the newly generated nerve bridge, to enter the distal stump and regenerate. Analysing axon growth and the cell-cell interactions that occur following both nerve crush and cut injuries has largely been carried out by staining sections of nerve tissue, but this has the obvious disadvantage that it is not possible to follow the paths of regenerating axons in three dimensions within the nerve trunk or nerve bridge. To try and solve this problem, we describe the development and use of a novel whole mount staining protocol that allows the analysis of axonal regeneration, Schwann cell-axon interaction and re-vascularisation of the repairing nerve following nerve cut and crush injuries. PMID- 25738875 TI - PARVA promotes metastasis by modulating ILK signalling pathway in lung adenocarcinoma. AB - alpha-parvin (PARVA) is known to be involved in the linkage of integrins, regulation of actin cytoskeleton dynamics and cell survival. However, the role that PARVA plays in cancer progression remains unclear. Here, using a lung cancer invasion cell line model and expression microarrays, we identify PARVA as a potential oncogene. The overexpression of PARVA increased cell invasion, colony forming ability and endothelial cell tube formation. By contrast, knockdown of PARVA inhibited invasion and tube formation in vitro. Overexpression of PARVA also promoted tumorigenicity, angiogenesis and metastasis in in vivo mouse models. To explore the underlying mechanism, we compared the expression microarray profiles of PARVA-overexpressing cells with those of control cells to identify the PARVA-regulated signalling pathways. Pathway analysis showed that eight of the top 10 pathways are involved in invasion, angiogenesis and cell death. Next, to identify the direct downstream signalling pathway of PARVA, 371 significantly PARVA-altered genes were analysed further using a transcription factor target model. Seven of the top 10 PARVA-altered transcription factors shared a common upstream mediator, ILK. Lastly, we found that PARVA forms a complex with SGK1 and ILK to enhance the phosphorylation of ILK, which led to the phosphorylation of Akt and GSK3beta. Notably, the inactivation of ILK reversed PARVA-induced invasion. Taken together, our findings imply that PARVA acts as an oncogene by activating ILK, and that this activation is followed by the activation of Akt and inhibition of GSK3beta. To our knowledge, this is the first study to characterize the role of PARVA in lung cancer progression. PMID- 25738876 TI - Virulence regulation with Venus flytrap domains: structure and function of the periplasmic moiety of the sensor-kinase BvgS. AB - Two-component systems (TCS) represent major signal-transduction pathways for adaptation to environmental conditions, and regulate many aspects of bacterial physiology. In the whooping cough agent Bordetella pertussis, the TCS BvgAS controls the virulence regulon, and is therefore critical for pathogenicity. BvgS is a prototypical TCS sensor-kinase with tandem periplasmic Venus flytrap (VFT) domains. VFT are bi-lobed domains that typically close around specific ligands using clamshell motions. We report the X-ray structure of the periplasmic moiety of BvgS, an intricate homodimer with a novel architecture. By combining site directed mutagenesis, functional analyses and molecular modeling, we show that the conformation of the periplasmic moiety determines the state of BvgS activity. The intertwined structure of the periplasmic portion and the different conformation and dynamics of its mobile, membrane-distal VFT1 domains, and closed, membrane-proximal VFT2 domains, exert a conformational strain onto the transmembrane helices, which sets the cytoplasmic moiety in a kinase-on state by default corresponding to the virulent phase of the bacterium. Signaling the presence of negative signals perceived by the periplasmic domains implies a shift of BvgS to a distinct state of conformation and activity, corresponding to the avirulent phase. The response to negative modulation depends on the integrity of the periplasmic dimer, indicating that the shift to the kinase-off state implies a concerted conformational transition. This work lays the bases to understand virulence regulation in Bordetella. As homologous sensor-kinases control virulence features of diverse bacterial pathogens, the BvgS structure and mechanism may pave the way for new modes of targeted therapeutic interventions. PMID- 25738877 TI - Selective ion-permeable membranes by insertion of biopores into polymersomes. AB - In nature there are various specific reactions for which highly selective detection or support is required to preserve their bio-specificity or/and functionality. In this respect, mimics of cell membranes and bio-compartments are essential for developing tailored applications in therapeutic diagnostics. Being inspired by nature, we present here biomimetic nanocompartments with ion selective membrane permeability engineered by insertion of ionomycin into polymersomes with sizes less than 250 nm. As a marker to assess the proper insertion and functionality of ionomycin inside the synthetic membrane, we used a Ca(2+)-sensitive dye encapsulated inside the polymersome cavity prior to inserting the biopore. The calcium sensitive dye, ionomycin, and Ca(2+) did not influence the architecture and the size of polymersomes. Successful ionomycin functionality inside the synthetic membrane with a thickness of 10.7 nm was established by a combination of fluorescence spectroscopy and stopped-flow spectroscopy. Polymersomes equipped with ion selective membranes are ideal candidates for the development of medical applications, such as cellular ion nanosensors or nanoreactors in which ion exchange is required to support in situ reactions. PMID- 25738878 TI - Patient-provider interaction, patient satisfaction, and health outcomes: testing explanatory models for people living with HIV/AIDS. AB - In the era of highly active antiretroviral therapy era, medication adherence and health-related quality of life (HRQOL) have become critical issues for people living with HIV/AIDS (PLWH). The purpose of this study was to test explanatory models of how patient-provider interaction and patient satisfaction are related to medication adherence and HRQOL for PLWH. A total of 344 PLWH receiving health care services from a federally funded clinic in the southwest USA completed a survey questionnaire about their perception of interactions with providers, their satisfaction with services, their medication adherence, and their HRQOL. Comparing four latent variable structural equation models of direct and mediated effects of patient-provider interaction and patient satisfaction, the findings illustrate that the best model is one in which patient-provider interaction has a direct and positive effect on patient satisfaction, medication adherence, and HRQOL. These findings suggest that quality patient-provider interaction is a critical element of health-care services for PLWH, while patient satisfaction is an outcome measure and not a mediating factor for medication adherence and HRQOL. PMID- 25738879 TI - Recombinant receptor activator of nuclear factor kappaB exhibits more marked inhibitory effects on osteoclasts compared with recombinant osteoprotegerin in vitro and in vivo. AB - The aim of the present study was to compare the osteoclast-inhibiting ability of recombinant osteoprotegerin (OPG) protein (rhOPG-Fc) and recombinant receptor activator of nuclear factor kappaB (rhRANK) in vitro and in vivo. Osteoclasts were cultured with either rhOPG-Fc or rhRANK for 9 days. The number of tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells and resorption pits in bone slices were then counted. In the in vivo investigation, female mice were bilaterally ovariectomized (OVX) and intraperitoneally injected with 3 mg/kg rhOPG-Fc or rhRANK for 12 weeks, respectively. Bone metabolism, bone mineral density and microstructure changes were then evaluated. The number of TRAP positive cells and bone resorption pits decreased significantly following culture with either rhOPG-Fc or rhRANK, and this was more marked following culture with rhRANK compared with rhOPG-Fc. The levels of calcium and alkaline phosphatase in the serum were similar pre-OVX and after 12 weeks of treatment, while the levels of phosphorus in the serum were higher following treatment with rhRANK compared with rhOPG. The bone mineral density (BMD) of the whole body, femoral neck and L4 lumbar vertebral body in the mice treated with either rhOPG-Fc or rhRANK increased markedly. In addition, the mice treated with rhRANK exhibited significantly higher BMD in the femoral neck and lumbar vertebral body compared with those treated with rhOPG-Fc. Microcomputed tomography analysis demonstrated that the mice treated with rhRANK exhibited an increased bone volume and structure model index, and decreased trabecular spacing compared with those treated with rhOPG-Fc. rhRANK increased the inhibition of osteoclast differentiation and bone resorption, and rescued OVX-induced osteoporosis more effectively compared with rhOPG-Fc. PMID- 25738880 TI - Molecular dynamics explorations of active site structure in designed and evolved enzymes. AB - This Account describes the use of molecular dynamics (MD) simulations to reveal how mutations alter the structure and organization of enzyme active sites. As proposed by Pauling about 70 years ago and elaborated by many others since then, biocatalysis is efficient when functional groups in the active site of an enzyme are in optimal positions for transition state stabilization. Changes in mechanism and covalent interactions are often critical parts of enzyme catalysis. We describe our explorations of the dynamical preorganization of active sites using MD, studying the fluctuations between active and inactive conformations normally concealed to static crystallography. MD shows how the various arrangements of active site residues influence the free energy of the transition state and relates the populations of the catalytic conformational ensemble to the enzyme activity. This Account is organized around three case studies from our laboratory. We first describe the importance of dynamics in evaluating a series of computationally designed and experimentally evolved enzymes for the Kemp elimination, a popular subject in the enzyme design field. We find that the dynamics of the active site is influenced not only by the original sequence design and subsequent mutations but also by the nature of the ligand present in the active site. In the second example, we show how microsecond MD has been used to uncover the role of remote mutations in the active site dynamics and catalysis of a transesterase, LovD. This enzyme was evolved by Tang at UCLA and Codexis, Inc., and is a useful commercial catalyst for the production of the drug simvastatin. X-ray analysis of inactive and active mutants did not reveal differences in the active sites, but relatively long time scale MD in solution showed that the active site of the wild-type enzyme preorganizes only upon binding of the acyl carrier protein (ACP) that delivers the natural acyl group to the active site. In the absence of bound ACP, a noncatalytic arrangement of the catalytic triad is dominant. Unnatural truncated substrates are inactive because of the lack of protein-protein interactions provided by the ACP. Directed evolution is able to gradually restore the catalytic organization of the active site by motion of the protein backbone that alters the active site geometry. In the third case, we demonstrate the key role of MD in combination with crystallography to identify the origins of substrate-dependent stereoselectivities in a number of Codexis-engineered ketoreductases, one of which is used commercially for the production of the antibiotic sulopenem. Here, mutations alter the shape of the active site as well as the accessibility of water to different regions of it. Each of these examples reveals something different about how mutations can influence enzyme activity and shows that directed evolution, like natural evolution, can increase catalytic activity in a variety of remarkable and often subtle ways. PMID- 25738881 TI - Revelation of varying bonding motif of alloxazine, a flavin analogue, in selected ruthenium(II/III) frameworks. AB - The reaction of alloxazine (L) and Ru(II)(acac)2(CH3CN)2 (acac(-) = acetylacetonate) in refluxing methanol leads to the simultaneous formation of Ru(II)(acac)2(L) (1 = bluish-green) and Ru(III)(acac)2(L(-)) (2 = red) encompassing a usual neutral alpha-iminoketo chelating form of L and an unprecedented monodeprotonated alpha-iminoenolato chelating form of L(-), respectively. The crystal structure of 2 establishes that N5,O4(-) donors of L(-) result in a nearly planar five-membered chelate with the {Ru(III)(acac)2(+)} metal fragment. The packing diagram of 2 further reveals its hydrogen-bonded dimeric form as well as pi-pi interactions between the nearly planar tricyclic rings of coordinated alloxazine ligands in nearby molecules. The paramagnetic 2 and one-electron-oxidized 1(+) display ruthenium(III)-based anisotropic axial EPR in CH3CN at 77 K with ?g?/Deltag of 2.136/0.488 and 2.084/0.364, respectively (?g? = {1/3(g1(2) + g2(2) + g3(2))}(1/2) and Deltag = g1 - g3). The multiple electron-transfer processes of 1 and 2 in CH3CN have been analyzed by DFT calculated MO compositions and Mulliken spin density distributions at the paramagnetic states, which suggest successive two-electron uptake by the pi system of the heterocyclic ring of L (L -> L(*-) -> L(2-)) or L(-) (L(-) -> L(*2 ) -> L(3-)) besides metal-based (Ru(II)/Ru(III)) redox process. The origin of the ligand as well as mixed metal-ligand-based multiple electronic transitions of 1(n) (n = +1, 0, -1, -2) and 2(n) (n = 0, -1, -2) in the UV and visible regions, respectively, has been assessed by TD-DFT calculations in each redox state. The pKa values of 1 and 2 incorporating two and one NH protons of 6.5 (N3H, pKa1)/8.16 (N1H, pKa2) and 8.43 (N1H, pKa1), respectively, are estimated by monitoring their spectral changes as a function of pH in CH3CN-H2O (1:1). 1 and 2 in CH3CN also participate in proton-driven internal reorganizations involving the coordinated alloxazine moiety, i.e., transformation of an alpha-iminoketo chelating form to an alpha-iminoenolato chelating form and the reverse process without any electron-transfer step: Ru(II)(acac)2(L) (1) -> Ru(II)(acac)2(L(-)) (2(-)) and Ru(III)(acac)2(L(-)) (2) -> Ru(III)(acac)2(L) (1(+)). PMID- 25738882 TI - Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part I). AB - Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models. PMID- 25738883 TI - N-acetylcysteine treatment following spinal cord trauma reduces neural tissue damage and improves locomotor function in mice. AB - Following spinal cord trauma, mitochondrial dysfunction associated with increased oxidative stress is a critical event leading to leukocyte inflammatory responses, neuronal cell death and demyelination, contributing to permanent locomotor and neurological disability. The present study demonstrated that the mitochondrial enhancer N-acetylcysteine (NAC) may restore redox balance via enhancement of mitochondrial respiratory activity following traumatic spinal cord injury (SCI). In addition, NAC ameliorates oxidative stress-induced neuronal loss, demyelination, leukocyte infiltration and inflammatory mediator expression and improves long-term locomotor function. Furthermore, neuronal survival and neurological recovery are significantly correlated with increased mitochondrial bioenergetics in SCI following treatment with NAC. Therefore, NAC may represent a potential therapeutic agent for preserving mitochondrial dynamics and integrity following traumatic SCI. PMID- 25738884 TI - Re-validation of the Van Rie HIV/AIDS-related stigma scale for use with people living with HIV in the United States. AB - There is little consensus about which of the many validated human immunodeficiency virus (HIV) stigma scales should be regularly used, with few being re-validated in different contexts or evaluated for how they compare to other, existing HIV stigma scales. The purpose of this exploratory study was to re-validate the Van Rie HIV/AIDS-Related Stigma Scale, originally validated in Thailand and using a third-person wording structure, for use with people living with HIV in the United States. Adult HIV clinic patients completed a survey including the Berger and Van Rie scales, and measures of social support and depression. Eighty-five of 211 (40%) eligible participants provided data for both stigma scales. Exploratory factor analyses identified three factors to the Van Rie scale: Loss of Social Relationships (new subscale), Managing HIV Concealment (new subscale), and Perceived Community Stigma (original subscale). These subscales were moderately inter-related (r = 0.51 to 0.58) with acceptable to excellent reliability (Cronbach's alpha = 0.69 to 0.90). The Van Rie subscales were also moderately inter-correlated with the Berger subscales (r = 0.44 to 0.76), had similar construct validity, and tended to have higher mean stigma scores when compared with Berger subscales that were conceptually most similar. The revised Van Rie HIV-related Stigma Scale demonstrates good validity and internal consistency, offering a valid measure of HIV stigma with a three-factor structure. The third-person wording may be particularly suitable for measuring stigmatizing attitudes during an individual's transition from at-risk and undergoing HIV testing to newly diagnosed, a time when experiences of discrimination and processing issues of disclosure have not yet occurred. The stigma mechanisms for individuals making this transition have not been well explored. These scenarios, combined with the observed non-response to the Berger Enacted Stigma subscale items (a surprise finding), highlight gaps in our understanding of HIV stigma and how best to measure it. PMID- 25738885 TI - Use of the disulfiram/copper complex for breast cancer chemoprevention in MMTV erbB2 transgenic mice. AB - The disulfiram/copper complex (DS/Cu) has been demonstrated to exert potent anti tumor effects in various types of cancer. At present, whether DS/Cu has chemopreventive effects on breast cancer development remains to be fully elucidated. In the present study, using MMTV-erbB2 transgenic mice, it was identified for the first time that DS/Cu treatment was able to inhibit cell growth in breast cancer cells while sparing normal cells in vitro, in addition to delaying the development of mammary tumor development in MMTV-erbB2 transgenic mice in vivo. Morphological examination demonstrated that DS/Cu treatment resulted in cell proliferation inhibition and apoptosis activation in vitro and in vivo. Furthermore, the present study observed that DS/Cu may inhibit proliferation via inhibition of AKT and cyclin D1 signaling and promote apoptosis via c-Jun N-terminal kinase activation and suppression of nuclear factor kappaB signaling. These results suggested that DS/Cu treatment may be a promising therapy for the prevention of erbB2-positive breast cancer. PMID- 25738886 TI - Linearly bridging CO2 in a metal-organic framework. AB - A very rare structurally characterized CO2-coordinated metal-organic framework was synthesized by a solvothermal reaction. The CO2 ligand links two open Zn metal centers in a linear and symmetrical MU(O,O') coordination mode with a C[double bond, length as m-dash]O distance of 1.107(4) A. The new complex reported here is stable under ambient conditions and may provide a new strategy for CO2 fixation. PMID- 25738887 TI - Differential role of MACC1 expression and its regulation of the HGF/c-Met pathway between breast and colorectal cancer. AB - The newly identified gene, metastasis-associated in colon cancer 1 (MACC1), is suggested to be a transcriptional regulator of c-Met, leading to cancer progression in colorectal cancer. To date however, little is known of the role of MACC1 in breast cancer. In a series of 300 breast cancer patients, we analyzed the association of MACC1 mRNA and protein expression with breast cancer survival using Cox proportional hazard models. In an in vitro study, we evaluated activities of c-Met protein after transfection with a MACC1-harboring plasmid as well as the binding ability of MACC1 to the c-Met promoter using a chromatin immunoprecipitation (ChIP) assay. In survival analyses, reduced MACC1 expression was associated with patient mortality. MACC1 expression was an independent prognostic factor in multivariate analysis. In the cell lines tested, MACC1 expression was much higher in colorectal than in breast cancer cells. After cells were transfected with MACC1, c-Met expression was not induced in MCF7 cells, whereas corresponding c-Met expression was upregulated in SW480 cells. Further, SW480 cells transfected with MACC1 showed enhanced migratory ability, whereas in MDA-MB-231 cells, transfection of MACC1 had no impact on this ability. In ChIP assay, the binding of MACC1 to the c-Met promoter was suggested in SW480 cells, but not in MCF7 cells. In conclusion, our findings provide some novel insights into the role of MACC1 in breast cancer, indicating that it plays different roles in breast and several other cancers. There is a possibility that MACC1 does not modulate the transcriptional role of c-Met signaling in breast cancer. PMID- 25738888 TI - Stealth surface modification of surface-enhanced Raman scattering substrates for sensitive and accurate detection in protein solutions. AB - Reliable surface-enhanced Raman scattering (SERS) based biosensing in complex media is impeded by nonspecific protein adsorptions. Because of the near-field effect of SERS, it is challenging to modify SERS-active substrates using conventional nonfouling materials without introducing interference from their SERS signals. Herein, we report a stealth surface modification strategy for sensitive, specific and accurate detection of fructose in protein solutions using SERS by forming a mixed self-assembled monolayer (SAM). The SAM consists of a short zwitterionic thiol, N,N-dimethyl-cysteamine-carboxybetaine (CBT), and a fructose probe 4-mercaptophenylboronic acid (4-MPBA). The specifically designed and synthesized CBT not only resists protein fouling effectively, but also has very weak Raman activity compared to 4-MPBA. Thus, the CBT SAM provides a stealth surface modification to SERS-active substrates. The surface compositions of mixed SAMs were investigated using X-ray photoelectron spectroscopy (XPS) and SERS, and their nonfouling properties were studied with a surface plasmon resonance (SPR) biosensor. The mixed SAM with a surface composition of 94% CBT demonstrated a very low bovine serum albumin (BSA) adsorption (~3 ng/cm(2)), and moreover, only the 4-MPBA signal appeared in the SERS spectrum. With the use of this surface modified SERS-active substrate, quantification of fructose over clinically relevant concentrations (0.01-1 mM) was achieved. Partial least-squares regression (PLS) analysis showed that the detection sensitivity and accuracy were maintained for the measurements in 1 mg/mL BSA solutions. This stealth surface modification strategy provides a novel route to introduce nonfouling property to SERS-active substrates for SERS biosensing in complex media. PMID- 25738889 TI - Coronary computed tomography angiography of spontaneous coronary artery dissection: a case report and review of the literature. AB - BACKGROUND: Multidetector computed tomography (MDCT) has gained wide acceptance in the evaluation of the cardiovascular system. Of particular clinical interest is its ability to non-invasively evaluate coronary arteries in patients presenting to the emergency room. In acute coronary syndromes, myocardial ischemia is most often caused by atherosclerosis. We present a case of a rare cause of acute coronary syndrome, spontaneous coronary artery dissection (SCAD), which was initially evaluated with MDCT and followed by intravascular ultrasound (IVUS) and invasive coronary angiography (ICA). We discuss the findings and role of each modality with particular attention to coronary computed tomographic angiography (CCTA) in the diagnosis and management of SCAD. As the use of CCTA in the emergency department continues to rise, radiologists must become familiar with CT appearance of SCAD. CASE REPORT: We report the multidetector computed tomography (MDCT), intravascular ultrasound (IVUS), and invasive coronary angiography (ICA) findings in a case of spontaneous coronary artery dissection of the left anterior descending artery in a previously healthy 23-year-old man. The role of coronary computed tomographic angiography (CCTA) in diagnosis and management of this potentially life-threatening condition is discussed. CONCLUSIONS: In the clinical setting of acute coronary syndrome, SCAD must be a consideration, particularly in young patients without clear risk factors for coronary artery disease and in women in the peripartum period. CCTA is a very helpful diagnostic tool to diagnose the condition in a non-invasive manner and to follow up after treatment. PMID- 25738890 TI - Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1alpha signaling pathways in human retinal pigment epithelial cells under hypoxic conditions. AB - Choroidal neovascularization (CNV) can lead to progressive and severe visual loss. Vascular endothelial growth factor (VEGF) promotes the development of CNV. Caffeic acid phenethyl ester (CAPE), a biologically active component of the honeybee (Apis mellifera) propolis, has been demonstrated to have several interesting biological regulatory properties. The objective of this study was to determine whether treatment with CAPE results in the inhibition of the production of vascular endothelial growth factor (VEGF) in retinal pigment epithelial cells (RPE cells) under hypoxic conditions and to explore the possible underlying mechanisms. An in vitro experimental model of hypoxia was used to mimic an ischemic microenvironment for the RPE cells. Human RPE cells (ARPE-19) were exposed to hypoxia with or without CAPE pre-treatment. ARPE-19 cells were used to investigate the pathway involved in the regulation of VEGF production under hypoxic conditions, based on western blot analysis, enzyme-linked immunosorbent assay (ELISA) and electrophoretic mobility shift assay (EMSA). The amount of VEGF released from the hypoxia-exposed cells was significantly higher than that of the normoxic controls. Pre-treatment with CAPE suppressed the hypoxia-induced production of VEGF in the ARPE-19 cells, and this effect was inhibited through the attenuation of reactive oxygen species (ROS) production, and the inhibition of phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor-1alpha (HIF 1alpha) expression. These in vitro findings suggest that CAPE may prove to be a novel anti-angiogenic agent for the treatment of diseases associated with CNV. PMID- 25738891 TI - Long-Term Behavioral Outcomes after a Randomized, Clinical Trial of Counselor Assisted Problem Solving for Adolescents with Complicated Mild-to-Severe Traumatic Brain Injury. AB - Family problem-solving therapy (FPST) has been shown to reduce behavior problems after pediatric traumatic brain injury (TBI). It is unclear whether treatment gains are maintained. We sought to evaluate the maintenance of improvements in behavior problems after a Web-based counselor-assisted FPST (CAPS) intervention compared to an Internet resource comparison (IRC) intervention provided to adolescents within the initial year post-TBI. We hypothesized that family socioeconomic status, child educational status, and baseline levels of symptoms would moderate the efficacy of the treatment over time. Participants included 132 adolescents ages 12-17 years who sustained a complicated mild-to-severe TBI 1-6 months before study enrollment. Primary outcomes were the Child Behavior Checklist Internalizing and Externalizing Totals. Mixed-models analyses, using random intercepts and slopes, were conducted to examine group differences over time. There was a significant group*time*grade interaction (F(1,304)=4.42; p=0.03) for internalizing problems, with high school-age participants in CAPS reporting significantly lower symptoms at 18 months postbaseline than those in the IRC. Post-hoc analyses to elucidate the nature of effects on internalizing problems revealed significant group*time*grade interactions for the anxious/depressed (p=0.03) and somatic complaints subscales (p=0.04). Results also indicated significant improvement over time for CAPS participants who reported elevated externalizing behavior problems at baseline (F(1, 310)=7.17; p=0.008). Findings suggest that CAPS may lead to long-term improvements in behavior problems among older adolescents and those with pretreatment symptoms. PMID- 25738892 TI - Prion-like nanofibrils of small molecules (PriSM): A new frontier at the intersection of supramolecular chemistry and cell biology. AB - Formed by non-covalent interactions and not defined at genetic level, the assemblies of small molecules in biology are complicated and less explored. A common morphology of the supramolecular assemblies of small molecules is nanofibrils, which coincidentally resembles the nanofibrils formed by proteins such as prions. So these supramolecular assemblies are termed as prion-like nanofibrils of small molecules (PriSM). Emerging evidence from several unrelated fields over the past decade implies the significance of PriSM in biology and medicine. This perspective aims to highlight some recent advances of the research on PriSM. This paper starts with description of the intriguing similarities between PriSM and prions, discusses the paradoxical features of PriSM, introduces the methods for elucidating the biological functions of PriSM, illustrates several examples of beneficial aspects of PriSM, and finishes with the promises and current challenges in the research of PriSM. We anticipate that the research of PriSM will contribute to the fundamental understanding at the intersection of supramolecular chemistry and cell biology and ultimately lead to a new paradigm of molecular (or supramolecular) therapeutics for biomedicine. PMID- 25738893 TI - Time, dose and ataxia telangiectasia mutated (ATM) status dependency of coding and noncoding RNA expression after ionizing radiation exposure. AB - Studies of gene expression have proved important in defining the molecular mechanisms of radiation action and identifying biomarkers of ionizing radiation exposure and susceptibility. The full transcriptional response to radiation is very complex since it also involves epigenetic mechanisms triggered by radiation exposure such as modifications of expression of noncoding RNA such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that have not been fully characterized. To improve our understanding of the transcriptional response to radiation, we simultaneously monitored the expression of ten protein-coding genes, as well as 19 miRNAs and 3 lncRNAs in a time- and dose-dependent manner in stimulated human T lymphocytes obtained from two healthy donors (C1 and C2) and one patient with ataxia telangiectasia (AT), which is a well characterized radiosensitivity disorder. After 2 Gy X irradiation, expression levels were monitored at time points ranging from 15 min up to 24 h postirradiation. The majority of genes investigated responded rapidly to radiation exposure, with the peak up-regulation (CDKN1A, SESN1, ATF3, MDM2, PUMA and GADD45A) or down regulation (CCNB1) occurring 2-3 h postirradiation, while DDB2, FDXR and CCNG1 responded with slower kinetics reaching a peak of expression between 5 and 24 h. A significant modification of expression after radiation exposure was observed for miR-34a-5p and miR-182-5p, with an up-regulation occurring at late time points reaching two to threefold at 24 h. Differences between two donors in miR 182-5p response to radiation were detected: for C2, up-regulation reached a plateau-phase around 5 Gy, while for C1, up-regulation was at its maximum around 3 Gy and then decreased at higher doses. Among the three lncRNAs studied, TP53TG1 demonstrated a weak up-regulation, reaching a maximum of 1.5-fold at 24 h after radiation exposure. Conversely, FAS-AS1 was up-regulated up to fivefold by 5 Gy irradiation. Our results indicate that expression of the majority of protein coding genes allows discrimination of the AT from healthy donors when analyzed at 2 h. However, differences in expression between AT and healthy donors are no longer detectable 24 h postirradiation although, interestingly, linear dose responses for some of the genes studied are obtained at this time point. Furthermore, our study shows that miRNAs miR-34a-5p and miR-182-5p are responsive to radiation exposure in a dose- and time-dependent manner. Additionally, to the best of our knowledge, this is the first study to report that FAS-AS1 lncRNA is up-regulated by radiation exposure in an ATM-dependent fashion in human T lymphocytes. PMID- 25738894 TI - The major DNA repair pathway after both proton and carbon-ion radiation is NHEJ, but the HR pathway is more relevant in carbon ions. AB - The purpose of this study was to identify the roles of non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways in repairing DNA double-strand breaks (DSBs) induced by exposure to high-energy protons and carbon ions (C ions) versus gamma rays in Chinese hamster cells. Two Chinese hamster cell lines, ovary AA8 and lung fibroblast V79, as well as various mutant sublines lacking DNA-PKcs (V3), X-ray repair cross-complementing protein-4 [XRCC4 (XR1), XRCC3 (irs1SF) and XRCC2 (irs1)] were exposed to gamma rays ((137)Cs), protons (200 MeV; 2.2 keV/MUm) and C ions (290 MeV; 50 keV/MUm). V3 and XR1 cells lack the NHEJ pathway, whereas irs1 and irs1SF cells lack the HR pathway. After each exposure, survival was measured using a clonogenic survival assay, in situ DSB induction was evaluated by immunocytochemical analysis of histone H2AX phosphorylation at serine 139 (gamma-H2AX foci) and chromosome aberrations were examined using solid staining. The findings from this study showed that clonogenic survival clearly depended on the NHEJ and HR pathway statuses, and that the DNA-PKcs(-/-) cells (V3) were the most sensitive to all radiation types. While protons and gamma rays yielded almost the same biological effects, C-ion exposure greatly enhanced the sensitivity of wild-type and HR-deficient cells. However, no significant enhancement of sensitivity in cell killing was seen after C-ion irradiation of NHEJ deficient cells. Decreases in the number of gamma-H2AX foci after irradiation occurred more slowly in the NHEJ deficient cells. In particular, V3 cells had the highest number of residual gamma-H2AX foci at 24 h after C-ion irradiation. Chromosomal aberrations were significantly higher in both the NHEJ- and HR-deficient cell lines than in wild-type cell lines in response to all radiation types. Protons and gamma rays induced the same aberration levels in each cell line, whereas C ions introduced higher but not significantly different aberration levels. Our results suggest that the NHEJ pathway plays an important role in repairing DSBs induced by both clinical proton and C-ion beams. Furthermore, in C ions the HR pathway appears to be involved in the repair of DSBs to a greater extent compared to gamma rays and protons. PMID- 25738895 TI - Energy metabolism in a matched model of radiation resistance for head and neck squamous cell cancer. AB - While radiation therapy is commonly used for treating cancer, radiation resistance can limit long-term control of the disease. In this study, we investigated the reprogramming of the energy metabolism in radiosensitive and radioresistant head and neck squamous cell carcinomas (HNSCC) using a preclinical matched model of radiation resistance. Our investigation found that radioresistant rSCC-61 cells: 1. They display increased glucose uptake and decreased fatty acid uptake; 2. They deviate from the classical Warburg effect by diverting the glycolytic flux into the pentose phosphate pathway; 3. They are more dependent on glucose than glutamine metabolism to support growth; 4. They have decreased mitochondrial oxidative phosphorylation; 5. They have enhanced fatty acid biosynthesis by increasing the expression of fatty acid synthase; and 6. They utilize endogenous fatty acids to meet the energy demands for proliferation. Inhibition of fatty acid synthase with orlistat or FASN siRNA resulted in increased cytotoxicity and sensitivity to radiation in rSCC-61 cells. These results demonstrate the potential of combination therapy using radiation and orlistat or other inhibitors of lipid and energy metabolism for treating radiation resistance in HNSCC. PMID- 25738896 TI - The triterpenoid RTA 408 is a robust mitigator of hematopoietic acute radiation syndrome in mice. AB - Bone marrow suppression due to exposure to ionizing radiation is a significant clinical problem associated with radiation therapy as well as with nonmedical radiation exposure. Currently, there are no small molecule agents available that can enhance hematopoietic regeneration after radiation exposure. Here, we report on the effective mitigation of acute hematopoietic radiation syndrome in mice by the synthetic triterpenoid, RTA 408. The administration of a brief course of RTA 408 treatment, beginning 24 h after lethal doses of radiation to bone marrow, significantly increased overall survival. Importantly, treatment with RTA 408 led to the full recovery of steady state hematopoiesis with normalization of the frequency of hematopoietic stem and progenitor cells. Moreover, hematopoietic stem cells from RTA 408-mitigated mice showed lineage-balanced, long-term, multilineage potential in serial transplantation assays, indicative of their normal self-renewal activity. The potency of RTA 408 in mitigating radiation induced bone marrow suppression makes it an attractive candidate for potential clinical use in treating both therapy-related and unanticipated radiation exposure. PMID- 25738897 TI - Effect of dose rate on residual gamma-H2AX levels and frequency of micronuclei in X-irradiated mouse lymphocytes. AB - The biological risks associated with low-dose-rate (LDR) radiation exposures are not yet well defined. To assess the risk related to DNA damage, we compared the yields of two established biodosimetry end points, gamma-H2AX and micronuclei (MNi), in peripheral mouse blood lymphocytes after prolonged in vivo exposure to LDR X rays (0.31 cGy/min) vs. acute high-dose-rate (HDR) exposure (1.03 Gy/min). C57BL/6 mice were total-body irradiated with 320 kVP X rays with doses of 0, 1.1, 2.2 and 4.45 Gy. Residual levels of total gamma-H2AX fluorescence in lymphocytes isolated 24 h after the start of irradiation were assessed using indirect immunofluorescence methods. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to determine apoptotic cell frequency in lymphocytes sampled at 24 h. Curve fitting analysis suggested that the dose response for gamma-H2AX yields after acute exposures could be described by a linear dependence. In contrast, a linear-quadratic dose-response shape was more appropriate for LDR exposure (perhaps reflecting differences in repair time after different LDR doses). Dose-rate sparing effects (P < 0.05) were observed at doses <=2.2 Gy, such that the acute dose gamma-H2AX and TUNEL-positive cell yields were significantly larger than the equivalent LDR yields. At the 4.45 Gy dose there was no difference in gamma-H2AX expression between the two dose rates, whereas there was a two- to threefold increase in apoptosis in the LDR samples compared to the equivalent 4.45 Gy acute dose. Micronuclei yields were measured at 24 h and 7 days using the in vitro cytokinesis-blocked micronucleus (CBMN) assay. The results showed that MNi yields increased up to 2.2 Gy with no further increase at 4.45 Gy and with no detectable dose-rate effect across the dose range 24 h or 7 days post exposure. In conclusion, the gamma-H2AX biomarker showed higher sensitivity to measure dose-rate effects after low-dose LDR X rays compared to MNi formation; however, confounding factors such as variable repair times post exposure, increased cell killing and cell cycle block likely contributed to the yields of MNi with accumulating doses of ionizing radiation. PMID- 25738898 TI - Effect of a preoperative decontamination protocol on surgical site infections in patients undergoing elective orthopedic surgery with hardware implantation. AB - IMPORTANCE: Surgical site infections (SSIs), commonly caused by methicillin resistant Staphylococcus aureus (MRSA), are associated with significant morbidity and mortality, specifically when hardware is implanted in the patient. Previously, we have demonstrated that a preoperative decontamination protocol using chlorhexidine gluconate washcloths and intranasal antiseptic ointment is effective in eradicating MRSA in the nose and on the skin of patients. OBJECTIVE: To examine the effect of a decontamination protocol on SSIs in patients undergoing elective orthopedic surgery with hardware implantation. DESIGN, SETTING, AND PARTICIPANTS: A prospective database of patients undergoing elective orthopedic surgery with hardware implantation at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, was analyzed from October 1, 2012, to December 31, 2013. Cohort groups before and after the intervention were compared. INTERVENTIONS: Starting in May 2013, during their preoperative visit, all of the patients watched an educational video about MRSA decontamination and were given chlorhexidine washcloths and oral rinse and nasal povidone-iodine solution to be used the night before and the morning of scheduled surgery. MAIN OUTCOMES AND MEASURES: Thirty-day SSI rates were collected according to the definitions of the Centers for Disease Control and Prevention National Nosocomial Infections Surveillance. Data on demographics, comorbidities such as chronic obstructive pulmonary disease and coronary artery disease, tobacco use, alcohol use, and body mass index were also collected. Univariate analysis was performed between the 2 groups of patients. Multivariate analysis was used to identify independent predictors of SSI. RESULTS: A total of 709 patients were analyzed (344 controls and 365 patients who were decolonized). Both groups were well matched with no significant differences in age, body mass index, sex, or comorbidities. All of the patients (100%) completed the MRSA decontamination protocol. The SSI rate in the intervention group was significantly lower (1.1%; 4 of 365 patients developed an SSI) than the SSI rate in the control group (3.8%; 13 of 344 patients developed an SSI) (P = .02). Multivariate logistic regression identified MRSA decontamination as an independent predictor of not developing an SSI (adjusted odds ratio, 0.24 [95% CI, 0.08-0.77]; P = .02). CONCLUSIONS AND RELEVANCE: Our study demonstrates that preoperative MRSA decontamination with chlorhexidine washcloths and oral rinse and intranasal povidone-iodine decreased the SSI rate by more than 50% among patients undergoing elective orthopedic surgery with hardware implantation. Universal decontamination using this low-cost protocol may be considered as an additional prevention strategy for SSIs in patients undergoing orthopedic surgery with hardware implantation and warrants further study. PMID- 25738900 TI - A novel video tracking method to evaluate the effect of influenza infection and antiviral treatment on ferret activity. AB - Ferrets are the preferred animal model to assess influenza virus infection, virulence and transmission as they display similar clinical symptoms and pathogenesis to those of humans. Measures of disease severity in the ferret include weight loss, temperature rise, sneezing, viral shedding and reduced activity. To date, the only available method for activity measurement has been the assignment of an arbitrary score by a 'blind' observer based on pre-defined responsiveness scale. This manual scoring method is subjective and can be prone to bias. In this study, we described a novel video-tracking methodology for determining activity changes in a ferret model of influenza infection. This method eliminates the various limitations of manual scoring, which include the need for a sole 'blind' observer and the requirement to recognise the 'normal' activity of ferrets in order to assign relative activity scores. In ferrets infected with an A(H1N1)pdm09 virus, video-tracking was more sensitive than manual scoring in detecting ferret activity changes. Using this video-tracking method, oseltamivir treatment was found to ameliorate the effect of influenza infection on activity in ferret. Oseltamivir treatment of animals was associated with an improvement in clinical symptoms, including reduced inflammatory responses in the upper respiratory tract, lower body weight loss and a smaller rise in body temperature, despite there being no significant reduction in viral shedding. In summary, this novel video-tracking is an easy-to-use, objective and sensitive methodology for measuring ferret activity. PMID- 25738901 TI - MicroRNA-21, induced by high glucose, modulates macrophage apoptosis via programmed cell death 4. AB - MicroRNA-21 (miR-21) has been found to promote cell proliferation and survival. It has also been shown to exhibit an increased expression in a number of forms of cardiovascular disease. However, the mechanisms underlying the involvement of miR 21 in atherosclerosis remain to be elucidated. In the present study, it was demonstrated that miR-21 was upregulated in a time-dependent manner in response to high-concentration glucose stimulation in Raw 264.7 macrophages. High concentrations of glucose induce macrophage apoptosis. miR-21-inhibited macrophages treated with a normal concentration of glucose exhibited increased levels of cell apoptosis and augmented levels of activated caspase-3, while cells treated with an miR-21 inhibitor and a high concentration of glucose, revealed significantly increased levels of apoptosis. In addition, inhibition of miR-21 increased mRNA and protein levels of programmed cell death 4 (PDCD4), which, by contrast, were reduced in miR-21-inhibited cells that had been treated with a high concentration of glucose. In conclusion, miR-21 is sensitive to high concentration glucose treatment in macrophages, and appears to have a protective effect in macrophage apoptosis induced by high concentrations of glucose via PDCD4. PMID- 25738902 TI - Size-fractionated particulate air pollution and circulating biomarkers of inflammation, coagulation, and vasoconstriction in a panel of young adults. AB - BACKGROUND: Short-term associations between size-fractionated particulate air pollution and circulating biomarkers are not well established, especially in developing countries with high levels of particulate matter (PM). METHODS: We designed a panel study involving 34 healthy young adults to evaluate acute effects of size-fractionated PM on 13 circulating biomarkers of inflammation, coagulation, and vasoconstriction. We measured real-time, size-fractionated number concentrations of PM (aerodynamic diameters from 0.25 to 10 MUm, mass concentrations of PM < 10 MUm) over four follow-up measurements. The short-term associations between size-fractionated PM and biomarkers were assessed using linear mixed effect models. RESULTS: We found positive associations between short term exposure to PM and 10 biomarkers. PM with smaller size had stronger associations. The size fractions with the strongest associations were 0.25-0.40 MUm for number concentrations and <1 MUm for mass concentrations. For example, an interquartile range increase in 24-hour-average number concentrations of PM0.25 0.40 was associated with a 7%-32% increase in biomarkers of inflammation, 34%-68% of blood coagulation, and 45% of vasoconstriction. Similar estimates were found for mass concentrations of PM1. Furthermore, our results demonstrated an apparent acute effect on circulating biomarkers, even 2 hours after exposure. The effects were strongest within the first 12-24 hours, and effects on inflammation occurred more quickly than on coagulation and vasoconstriction. CONCLUSIONS: Our results provided potentially vital insights into the size and temporal characteristics of PM that could modify subclinical cardiovascular effects. These findings may have implications on disease prevention and environmental regulation in China. PMID- 25738903 TI - PM2.5 and survival among older adults: effect modification by particulate composition. AB - BACKGROUND: Fine particulate (PM2.5) air pollution has been consistently linked to survival, but reported effect estimates are geographically heterogeneous. Exposure to different types of particle mixtures may explain some of this variation. METHODS: We used k-means cluster analyses to identify cities with similar pollution profiles, (ie, PM2.5 composition) across the United States. We examined the impact of PM2.5 on survival, and its variation across clusters of cities with similar PM2.5 composition, among Medicare enrollees in 81 US cities (2000-2010). We used time-varying annual PM2.5 averages, measured at ambient central monitoring sites, as the exposure of interest. We ran by-city Cox models, adjusting for individual data on previous cardiopulmonary-related hospitalizations and stratifying by follow-up time, age, gender, and race. This eliminates confounding by factors varying across cities and long-term trends, focusing on year-to-year variations of air pollution around its city-specific mean and trend. We then pooled the city-specific effects using a random effects meta-regression. In this second stage, we also assessed effect modification by cluster membership and estimated cluster-specific PM2.5 effects. RESULTS: We followed more than 19 million subjects and observed more than 6 million deaths. We found a harmful impact of annual PM2.5 concentrations on survival (hazard ratio = 1.11 [95% confidence interval = 1.01, 1.23] per 10 MUg/m). This effect was modified by particulate composition, with higher effects observed in clusters containing high concentrations of nickel, vanadium, and sulfate. For instance, our highest effect estimate was observed in cities with harbors in the Northwest, characterized by high nickel, vanadium, and elemental carbon concentrations (1.9 [1.1, 3.3]). We observed null or negative associations in clusters with high oceanic and crustal particles. CONCLUSIONS: To the best of our knowledge, this is the first study to examine the association between PM2.5 composition and survival. Our findings indicate that long-term exposure to fuel oil combustion and power plant emissions have the highest impact on survival. PMID- 25738904 TI - Hydrolates from lavender (Lavandula angustifolia)--their chemical composition as well as aromatic, antimicrobial and antioxidant properties. AB - It was shown that the method for obtaining hydrolates from lavender (Lavandula angustifolia) influences the content of active compounds and the aromatic, antimicrobial and antioxidant properties of the hydrolates. The content of volatile organic compounds ranged from 9.12 to 97.23 mg/100 mL of hydrolate. Lavender hydrolate variants showed low antimicrobial activity (from 0% to 0.05%). The radical scavenging activity of DPPH was from 3.6 +/- 0.5% to 3.8 +/- 0.6% and oxygen radical absorbance capacity (ORAC(FL)) results were from 0 to 266 MUM Trolox equivalent, depending on the hydrolate variant. PMID- 25738905 TI - Evaluation of the implementation of the protocol of an early vocational rehabilitation intervention for people with acquired brain injury. AB - PURPOSE: The purpose of this study was to evaluate (1) the feasibility of an early vocational rehabilitation (EVR) protocol in the standard rehabilitation process, (2) promoting factors and barriers encountered with the EVR protocol, and (3) perceived effectiveness of the protocol in facilitating return to work (RTW) following acquired brain injury (ABI). METHOD: A pre- and post-process evaluation was performed in a Dutch rehabilitation center. Dependent variables were feasibility (defined by the usability on process level and fulfillment of usability expectations), promoting factors and barriers, and perceived effectiveness of the protocol. Usability (defined by 13 performance and timing goals) was evaluated with existing forms and registrations. Fulfillment of usability expectations, perceived promoting factors and barriers, and perceived effectiveness were investigated with questionnaires. Data of 23 patients were available for process evaluation. Nine rehabilitation professionals, 10 patients with ABI, nine employers, and six occupational physicians completed the questionnaires. RESULTS: Two-thirds of the performance goals and one-fourth of the timing goals were reached. All respondents cited the structured protocol as a promoting factor. Thirty-two of the thirty-four participants perceived the protocol as being suitable facilitating RTW after ABI. CONCLUSIONS: The EVR protocol provides a structured strategy to focus on RTW during standard rehabilitation. It is now possible to implement and test the protocol in other rehabilitation settings. IMPLICATIONS FOR REHABILITATION: The early vocational rehabilitation (EVR) facilitates an interdisciplinary and systematic focus on return to work during rehabilitation of people with acquired brain injury. The feasibility of the EVR protocol has been tested. The EVR protocol is ready for implementation and wider testing in other rehabilitation settings. PMID- 25738907 TI - Impact of the role of senior dual disability coordinator on the perceived self efficacy and job satisfaction of mental health clinicians. AB - PURPOSE: This study aimed to evaluate a new service role in mental health services, namely, the senior dual disability coordinator role (SDDC) for its impact on the perceived self-efficacy of mental health clinicians in managing clients with dual disability (mental illness and acquired brain injury and/or intellectual disability) and their job satisfaction. METHOD: Mental health clinicians from a health service district in Queensland, Australia who contacted the SDDC for clinical consultation and liaison between July 2011 and July 2013 were asked to complete a questionnaire assessing perceived self-efficacy in working with clients with dual disability as well as their job satisfaction, prior to (T1) and following (T2) their contact with the SDDC. RESULTS: Twenty five clinicians completed and returned pre- and post-measure questionnaires. Self reported knowledge of dual disability, clinical skills in dual disability, service knowledge in dual disability as well as perceived self-efficacy, and job satisfaction increased significantly from T1 to T2. There were no significant differences across professional discipline or years of service. CONCLUSIONS: The delivery of a clinical consultation liaison service as part of the role of SDDC may assist mental health clinicians with self-efficacy and job satisfaction, regardless of the number of years they have worked in the service or their professional discipline. Mental health clinicians with improved self-efficacy for working with clients with dual disability may be more likely to consider the client suitable for services through mental health and follow-up with treatment and linking the client with other identified suitable services. Implications for Rehabilitation Dual disability (mental illness and acquired brain injury and/or intellectual disability) presents specific challenges for mental health services Specific strategies are needed to build capacity among mental health practitioners in order to meet the needs of people with dual disability and provide appropriate services. Introducing dual disability coordinators as a specific position within a health service district may assist to improve self efficacy and job satisfaction of mental health practitioners assisting people with dual disability. PMID- 25738906 TI - Supporting children with disabilities at school: implications for the advocate role in professional practice and education. AB - PURPOSE: School settings are a common practice context for rehabilitation professionals; health advocacy is a common and challenging practice role for professionals in this context. This study explored how pediatric practitioners advocate for children with disabilities at school. Specifically, we examined everyday advocacy in the context of school-based support for children with disabilities. METHOD: Our theoretical framework and methodological approach were informed by institutional ethnography, which maps and makes visible hidden social coordinators of work processes with a view to improving processes and outcomes. We included families, educators, and health/rehabilitation practitioners from Ontario. Of the 37 consented informants, 27 were interviewed and 15 observed. Documents and texts were collected from the micro-level (e.g. clinician reports) and the macro-level (e.g. policies). RESULTS: Pediatric practitioners' advocacy work included two main work processes: spotlighting invisible disabilities and orienteering the special education terrain. Practitioners advocated indirectly, by proxy, with common proxies being documents and parents. Unintended consequences of advocacy by proxy included conflict and inefficiency, which were often unknown to the practitioner. CONCLUSIONS: The findings of this study provide practice-based knowledge about advocacy for children with disabilities, which may be used to inform further development of competency frameworks and continuing education for pediatric practitioners. The findings also show how everyday practices are influenced by policies and social discourses and how rehabilitation professionals may enact change. Implications for Rehabilitation Rehabilitation professionals frequently perform advocacy work. They may find it beneficial to perform advocacy work that is informed by overarching professional and ethical guidelines, and a nuanced understanding of local processes and structures. Competency frameworks and education for pediatric rehabilitation professionals may be improved by: encouraging professionals to consider how their practices, including their written documents, may affect parental burden, (mis)interpretation by document recipients, and potential unintended consequences. Policies and texts, e.g. privacy legislation and the Diagnostic and Statistical Manual (DSM), influence rehabilitation professionals' actions and interactions when supporting children with disabilities at school. An awareness of the influence of policies and texts may enable practitioners to work more effectively within current systems when supporting individuals with disabilities. PMID- 25738908 TI - Physical functioning of low back pain patients: perceived physical functioning and functional capacity, but not physical activity is affected. AB - PURPOSE: Physical functioning is a multidimensional construct covering perceived functioning, functional capacity and actual physical activity. Currently, the assessment of physical functioning in low back pain (LBP) patients has been limited to only one or two of these aspects. This study evaluates physical functioning of LBP patients by assessing the three individual aspects using questionnaires and ambulant sensor-based measurements. METHODS: Actual physical activity, functional capacity and perceived functioning were measured in 26 patients undergoing patient specific treatment before, direct and 3-4 weeks after the first treatment using, respectively, sensor-based activity monitoring, sensor based motion analysis test and the Oswestry questionnaire. Patients were compared to a healthy control group. RESULTS: Perceived functioning and functional capacity, but not actual physical activity is impaired in pre-treatment LBP patients. After treatment, patients improved in perceived physical functioning and functional capacity approaching healthy levels, however only slight (p > 0.05) improvements in actual physical activity were found. Moreover, only few and weak correlations were found between the different aspects of physical functioning. CONCLUSION: Perceived functioning, actual physical activity and functional capacity are three independent outcome dimensions, being complementary but not redundant. Especially, perceived functioning and physical capacity need attention when evaluating LBP patients during rehabilitation. Implications for Rehabilitation Perceived physical functioning and physical capacity are negatively affected by low back pain and improve after treatment. Low back pain patients perform their daily activity independent of pain and complaints. Inertia sensor-based motion analysis can objectify treatment effects showing low back pain patients their progress in rehabilitation. New interventions can be justified with inertia sensor technology in low back pain patients. PMID- 25738909 TI - An exploration of knowledge and practice of patient handling among undergraduate occupational therapy students. AB - PURPOSE: To explore knowledge and practice relating to patient handling among final year occupational therapy students in the Republic of Ireland. METHOD: We conducted a survey of final year students in three out of four occupational therapy programs in the Republic of Ireland (n = 81). The survey measured students' knowledge of manual handling principles and techniques and explored their experiences and ability to apply this knowledge to clinical situations. RESULTS: All students (n = 81) had undertaken training in patient handling. Just under half of students (n = 35, 43.2%) had received additional training outside of the university setting. Overall knowledge of safe patient handling principles techniques and risk assessment was low (Mean Score = 15.71/28; SD = 3.81). Participants who received additional training achieved a lower mean total score (M = 13.89, SD = 3.54) than those who only undertook university-based training (M = 18.11; SD = 2.66; t(79) = -5.87; p < 0.05). The majority of participants reported intermittent use of taught principles while on clinical practice placements (n = 50, 61.8%) Reasons for not using taught principles included; selection of alternative technique by supervisor (n = 30, 56.6%); lack of available equipment (n = 13, 24.5%) and lack of time (n = 13, 24.5%). CONCLUSIONS: While occupational therapy students in Ireland receive training in safe patient handling they appear to have limited knowledge of best practice and experience difficulties in applying their learning to clinical situations. There is an urgent need to consider the effectiveness of current educational strategies in this area. Implications for Rehabilitation Safe patient handling is a key component in preventing musculoskeletal injury among rehabilitation professionals The extent to which pre-professional training prepares rehabilitation professionals to practice safe patient handling is unclear Occupational therapy students in this study had limited knowledge of safe patient handling and had difficulty applying their learning to clinical practice Alternative education models are required to support development of safe patient handling skills. Educators may wish to consider how safe patient handling can be embedded across curricula to avoid the challenges of once off instruction and massed practice. PMID- 25738910 TI - Service use and family-centred care in young people with severe cerebral palsy: a population-based, cross-sectional clinical survey. AB - PURPOSE: To assess healthcare use and family perception of family-centred care in children and young adults with severe cerebral palsy (CP) within a geographical region of the UK. METHOD: Young people (4-27years) with severe forms of CP; Gross Motor Function Classification System levels IV and V, were recruited via an established case register. Data were collected in the participant's home using a standardised background proforma and validated questionnaires. The Measure of Processes of Care was used to assess the family's perception of family-centred care. RESULTS: One-hundred and twenty-three children, young people and their families/guardians participated. Results showed high accessing of specialist services in childhood with a considerable decrease in young adults. Use of generalist services remained relatively constant. The reported use of formal respite services and support groups/youth clubs was relatively poor. Family centred care was poor in the area of "providing general information" (2.8 +/- 1.73) but more moderate in the areas of "providing specific information about the young person" (4.2 +/- 1.94), "enabling and partnership" (4.2 +/- 1.9), "co ordinated and comprehensive care" (4.3 +/- 1.95) and "respectful and supportive care" (4.7 +/- 1.75). CONCLUSIONS: The accessing of specialist services and respite care notably decreases amongst adolescents with severe forms of CP and the perception of family-centred care amongst families was fair at best. In particular, the results highlight the need for families to be provided with more general information and advice. Implications for Rehabilitation In a quest to enhance the rehabilitation process in young people with severe forms of cerebral palsy: Commissioners and service providers need to a adopt a more rationalised, needs led approach to service provision across the lifespan of people with severe forms of cerebral palsy, to include an effective and efficient transitional period. Habilitation specialists working with young adults need to continue to recognise the importance of family-centred care in managing this complex and chronic condition. Professionals working within the healthcare system must provide better communication and improve their dissemination of information to the families of children and young people with complex needs. PMID- 25738911 TI - Effects of balance-specific exercises on balance, physical activity and quality of life in adults with multiple sclerosis: a pilot investigation. AB - OBJECTIVE: To evaluate the efficacy of functional balance exercises on balance impairment, physical activity and quality of life (QOL) in adults with multiple sclerosis (MS). DESIGN: A multiple-baseline time-series design with an uncontrolled intervention. METHOD: Ten subjects with MS completed assessments twice before and once after a 10-week balance intervention. ANOVA were used to evaluate the effects of testing session on the Brief-BESTest, instrumented stance and gait recordings by inertial motion sensors, lower-limb strength recorded by force transducers, accelerometry-based activity, the 12-item MS Walking Scale (MSWS-12), the Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaire, the Modified Fatigue Impact scale (MFIS) and the Activity-specific Balance Confidence (ABC) scale. RESULTS: The intervention associated with significantly improved scores on the MSQOL-54 mental component, MFIS, MSWS-12 and Brief BESTest. Sway amplitude significantly decreased and jerk significantly increased during instrumented standing on foam with eyes closed. Instrumented gait recordings of sagittal trunk range of motion also significantly decreased. ABC scores, strength measures and activity measures were not significantly changed. CONCLUSIONS: Ten weeks of functional balance exercises provided a feasible intervention for individuals with MS that improved components of balance, mental well-being and perceived fatigue impact and ambulation disability. A future randomized, controlled clinical trial should confirm these preliminary findings. Implications for Rehabilitation A balance-specific exercise program is both safe and feasible for individuals with mild-to-moderate MS. Comprehensive exercise interventions that are conceptually driven and employ well-designed progressive exercise across multiple contexts of balance control can facilitate improvements in balance impairments associated with MS. Functional balance exercises can positively impact clinical and objective measures of balance control and favorably influence perceptions of ambulation disability and fatigue as well as perceived quality of life in people with MS. PMID- 25738912 TI - A pilot study - the potential value of an activity-based feedback system for treatment of individuals with chronic lower back pain. AB - PURPOSE: The aim of this pilot study was to evaluate the potential value of a new personalized activity-based feedback treatment. METHOD: A prognostic cohort study was carried out in the daily environment of the patients. Seventeen individuals with chronic lower back pain (CLBP) symptoms for >3 months were included. Patients were from the Netherlands, aged 18-65 years. Patients wore an accelerometer and a Personal Digital Assistant (PDA) for 15 d. Patients received continuous and time-related personalized feedback and were instructed to follow the activity pattern as displayed on the PDA. Technical performance and compliance with the system were rated. Objective and subjective activity scores were compared for exploring awareness. The absolute difference between the activity pattern of the patient and the norm value used was calculated and expressed as mean difference. Pain intensity was measured using the VAS. RESULTS: The technical performance and compliance with the system were rated moderate. More than half of the patients were aware of their activity level during the feedback days (67%). A positive effect of the feedback was seen in a trend which showed a decrease in the absolute difference between the activity pattern of the patient and the norm value (p = 0.149) and a significant decrease in pain intensity levels (p = 0.005). CONCLUSIONS: This pilot study suggested that an individual-tailored feedback system that focuses on the activity behavior of the patient has potential as the treatment of individuals with CLBP. Implications for Rehabilitation Activity-based feedback for individuals with chronic low back pain: Many patients are not aware of their activity patterns. The activity patterns of patients differ from those of healthy controls. It is important to make patients aware of their activity patterns in order to change activity behavior. An individual-tailored feedback system seems promising in decreasing pain intensity levels for a subgroup of patients. PMID- 25738913 TI - A review of culturally adapted versions of the Oswestry Disability Index: the adaptation process, construct validity, test-retest reliability and internal consistency. AB - The Oswestry Disability Index (ODI) is a self-report-based outcome measure used to quantify the extent of disability related to low back pain (LBP), a substantial contributor to workplace absenteeism. The ODI tool has been adapted for use by patients in several non-English speaking nations. It is unclear, however, if these adapted versions of the ODI are as credible as the original ODI developed for English-speaking nations. The objective of this study was to conduct a review of the literature to identify culturally adapted versions of the ODI and to report on the adaptation process, construct validity, test-retest reliability and internal consistency of these ODIs. Following a pragmatic review process, data were extracted from each study with regard to these four outcomes. While most studies applied adaptation processes in accordance with best-practice guidelines, there were some deviations. However, all studies reported high quality psychometric properties: group mean construct validity was 0.734 +/- 0.094 (indicated via a correlation coefficient), test-retest reliability was 0.937 +/- 0.032 (indicated via an intraclass correlation coefficient) and internal consistency was 0.876 +/- 0.047 (indicated via Cronbach's alpha). Researchers can be confident when using any of these culturally adapted ODIs, or when comparing and contrasting results between cultures where these versions were employed. Implications for Rehabilitation Low back pain is the second leading cause of disability in the world, behind only cancer. The Oswestry Disability Index (ODI) has been developed as a self-report outcome measure of low back pain for administration to patients. An understanding of the various cross-cultural adaptations of the ODI is important for more concerted multi-national research efforts. This review examines 16 cross-cultural adaptations of the ODI and should inform the work of health care and rehabilitation professionals. PMID- 25738914 TI - "Our child's significant disability shapes our lives": experiences of family social participation. AB - PURPOSE: This study explored the stories of parents of youth with severe physical disabilities to understand how they viewed the quality of their family social participation; the barriers to social participation faced as families and the strategies and supports that might be used to reduce these barriers. METHOD: Ten parents of youth (10-18 years) with severe physical disabilities, recruited through specialist schools, health and disability services, were interviewed using a narratively-oriented interview tool: the Occupational Performance History Interview-II. Interviews were audio-recorded and transcribed verbatim. Narrative and thematic analytic approaches were used to construct each parent's story of family social participation issues, and to identify themes across stories. RESULTS: Parents used highly structured routines and required substantial resources, particularly adult assistance and financial means, to facilitate family social participation. Needs were greater when the youth was more severely impaired, heavier, incontinent or had fragile health. Parents' choice of family activities and belief that they could influence the quality, enjoyment and satisfaction derived from family social participation were shaped by past experiences and the perceived benefits of participation. CONCLUSIONS: Family social participation relied on flexible supports tailored to families' needs and preferences. Greater choice and control of resources are central to enabling valued participation. Implications for Rehabilitation Government resources need to be directed towards improving community based wheelchair accessibility and public toilet facilities for youth with Level V GMFCS-E&R impairments and their families. Disability service delivery models need to enable families to choose the types of high quality care and support that will facilitate valued family social participation. Clinicians need to be aware that families of the most severely impaired children, who are heavier, incontinent or in fragile health, will require substantially more resources than other families to facilitate their social participation. PMID- 25738915 TI - [Required Effekt Sizes of Preventive Measures for Overweight in Children and Adolescents]. AB - BACKGROUND AND AIM OF THE STUDY: Successful preventive measures can stop a further increase in the prevalence of overweight in children and adolescents. However, up to now, the required effect sizes of interventions for reducing childhood overweight remain unclear. The calculation of the energy gap (excess calories consumed over calories expended) offers the possibility to estimate the required effect sizes. In this work 2 approaches to calculate the energy gap will be compared. METHODS: Longitudinal data of 1690 children and adolescents of the Kiel Obesity Prevention Study (KOPS) on measured height, weight, fat mass and fat free mass (using bioelectrical impedance analysis) at age 6 and 10 years will be used to calculate energy gap with 2 different approaches: (i) using age independent changes in fat mass and fat-free mass (old approach) and (ii) using a mathematic model of weight dynamic (new approach). RESULTS: Energy gap according to the old approach was 140 kcal/day; by contrast, new modeling resulted in an energy gap between 270 and 370 kcal/day. Both, BMI and fat mass were suitable to calculate energy gap and led to nearly same results. Exceeding the 90(th) percentile of BMI or fat mass (incidence approach) as well as large changes within the normal range (i.e. between the 10(th) and the 90(th) percentile) led to large energy gaps. Thus, all children with large energy gaps have to be characterized as at risk for overweight. CONCLUSION: The new approach seems to be convincing because it considered the additional energy expenditure for building fat-free mass due to increasing age and weight.Calculating energy gap offers a new approach for prevention of overweight. It shows that the required effect sizes of prevention measures have to be in a region of 140 to 400 kcal/day. This differs clearly from energy reduction of diets in the therapy of obesity. PMID- 25738916 TI - [The Danish Debate on Priority Setting in Medicine--An Update]. AB - In the last years, the Danish debate about priority setting in medicine has gained new strength. This paper shows the main focuses of the current discussion based on a research of Danish primary literature. For the first time since the 1990s the Danish Council of Ethics has been involved with priority setting in medicine in a project running from 2011 to 2013. The Council emphasises the importance of legitimate processes and calls for visible values and criteria. A focus of the debate is how to deal with new expensive drugs. Politicians, physicians, health economists and the Council of Ethics have called for a national institution for priority setting in medicine. They have mainly looked to the Norwegian National Council for Priority Setting in Health Care and the British National Institute for Health and Care Excellence for inspiration. The Danish Government considered establishing a national institute for priority setting, but the plans were not put into practice. In the year 2012 a new national project was launched to create clinical guidelines. Danish doctors welcome the guidelines as a good basis for priority setting. Just like in earlier Danish priority setting debates, a coordinating institution is lacking to bundle the discussion and keep it going. The debate seems to have come to an end once again. The fact that it was seriously considered to establish an institute for priority setting is a new development. It can be expected that the discussion will be resumed in the near future, possibly the idea of an institute for priority setting will be readopted. The general conditions for priority setting in health care have improved. PMID- 25738917 TI - RNA-binding motif protein 5 negatively regulates the activity of Wnt/beta-catenin signaling in cigarette smoke-induced alveolar epithelial injury. AB - Cigarette smoking is closely associated with various respiratory diseases. Oxidants and carcinogens in cigarettes are reported to induce various airway epithelial injuries. However, the underlying mechanisms remain unclear. The aims of the present study were to determine the involvement of RNA-binding motif protein 5 (RBM5) and Wnt/beta-catenin signaling in cigarette smoke-induced alveolar epithelial injury, as well as the interaction between both. A549 cells were treated with cigarette smoke extract (CSE). The MTT assay was used to assess the effects of CSE on cell viability. The levels of RBM5 and Wnt/beta catenin/GSK3beta were detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. A luciferase assay was used to assess the activity of beta-catenin/T-cell factor (TCF) signaling. The results revealed that CSE inhibited A549 cell viability in both a dose- and time-dependent manner. Cytosolic and nuclear beta-catenin levels were significantly increased following CSE treatment, compared with those in the control cells (P<0.05). The luciferase activity in CSE-exposed cells transfected with the TCF luciferase reporter wild-type plasmid (pGL3-OT) was significantly greater than that in cells without CSE exposure (33,167+/-3,085 vs. 19,978+/ 1,916, respectively, P<0.05). Both the mRNA and protein levels of RBM5 in the CSE treated cells were significantly reduced compared to the levels in the controls (all P<0.05). The overexpression of RBM5 inhibited Wnt/beta-catenin signaling in the A549 cells, while silencing of RBM5 enhanced Wnt/beta-catenin signaling. The beta-catenin/TCF signaling inhibitor ICG-001 had no apparent effect on the RBM5 levels. Downregulation of RBM5 and activation of Wnt/beta-catenin signaling are involved in CSE-induced alveolar epithelial injury. RBM5 acts as an upstream molecule that negatively regulates the activity of Wnt/beta-catenin signaling. PMID- 25738918 TI - Palladium/copper-catalyzed aerobic oxidative C-H carbonylation for the synthesis of o-aminobenzoates. AB - The palladium/copper-catalyzed aerobic oxidative C-H carbonylation for the synthesis of o-aminobenzoates is described. Molecular oxygen is used as the terminal oxidant. This methodology proceeds with a wide range of N-substituted anilines and alcohols and gives straightforward access to valuable o aminobenzoates. PMID- 25738920 TI - Relationship between measured average glucose by continuous glucose monitor and HbA1c measured by three different routine laboratory methods. AB - OBJECTIVES: The relationship between glycated hemoglobin A1c (HbA1c) and average glucose has been described by the empirically derived estimated average glucose (eAG) equation in the A1c-Derived Average Glucose (ADAG) study, with extensive calibration efforts in four secondary reference HbA1c methods. It is not known if this relationship is preserved when HbA1c is measured by routine laboratory methods under routine conditions. DESIGN AND METHODS: We measured average glucose (mAG) by six days of continuous glucose monitoring in 45 adults with stable HbA1c (<1% HbA1c change in the preceding two months). Subjects with medical conditions that may confound HbA1c measurement, including anemia and hemoglobinopathy, were excluded. HbA1c was measured using Bio-Rad Variant II (cation-exchange HPLC), Bio Rad in2it (boronate affinity HPLC) and Roche Tina-quant (immunoassay) methods. RESULTS: The average differences between eAG derived from the routine HbA1c methods and mAG were 10.4% (Variant II), 6.0% (Tina-quant) and 1.0% (in2it). The regression coefficients between the mAG and HbA1c are different between in2it (mAG, mmol/L=0.58 * %HbA1c + 2.3), Tina-quant and Variant II (both mAG, mmol/L=0.66 * %HbA1c + 1.9). However, the 95% confidence intervals of the slope and bias of these methods overlap. The correlation between mAG and HbA1c was greatest when measured using the Variant II (r(2)=0.84), followed by Tina-quant (r(2)=0.82) and in2it (r(2)=0.71). CONCLUSIONS: The relationship between HbA1c and measured average glucose is method-dependent despite improved HbA1c standardization. The differences in relationship may reflect as discrepant eAG and home glucose monitoring results. PMID- 25738919 TI - Autophagy is involved in high glucose-induced heart tube malformation. AB - Both pre-gestational and gestational diabetes have an adverse impact on heart development, but little is known about the influence on the early stage of heart tube formation. Using early gastrulating chick embryos, we investigated the influence of high glucose on the process of heart tube formation, specifically during the primary heart field phase. We demonstrated that high-glucose exposure resulted in 3 types of heart tube malformation: 1) ventricular hypertrophy, 2) ventricular hypertrophy with dextrocardia and 3) ventricular hypertrophy and dextrocardia with the fusion anomaly of a bilateral primary heart tube. Next, we found that these malformation phenotypes of heart tubes might mainly originate from the migratory anomaly of gastrulating precardiac mesoderm cells rather than cell proliferation in the developmental process of bilateral primary heart field primordia. The treatment of rapamycin (RAPA), an autophagy inducer, led to a similar heart tube malformation phenotype as high glucose. Additionally, high glucose exposure promoted the expression of the key autophagy protein LC3B in early chick tissue. Atg7 is strongly expressed in the fusion site of bilateral primary heart tubes. All of these data imply that autophagy could be involved in the process of high-glucose-induced malformation of the heart tube. PMID- 25738921 TI - A Chinese Herb, Indigo Naturalis, Extracted in Oil (Lindioil) Used Topically to Treat Psoriatic Nails: A Randomized Clinical Trial. PMID- 25738922 TI - Martensitic transformation between competing phases in Ti-Ta alloys: a solid state nudged elastic band study. AB - A combined density functional theory and solid-state nudged elastic band study is presented to investigate the martensitic transformation between beta -> (alpha", omega) phases in the Ti-Ta system. The minimum energy paths along the transformation are calculated and the transformation mechanisms as well as relative stabilities of the different phases are discussed for various compositions. The analysis of the transformation paths is complemented by calculations of phonon spectra to determine the dynamical stability of the beta, alpha", and omega phase. Our theoretical results confirm the experimental findings that with increasing Ta concentration there is a competition between the destabilisation of the alpha" and omega phase and the stabilisation of the high temperature beta phase. PMID- 25738923 TI - Differential proteomic profiling of primary and recurrent chordomas. AB - Chordomas are locally destructive tumors with high rates of recurrence and a poor prognosis. The mechanisms involved in chordoma recurrence remain largely unknown. In the present study, we examined the proteomic profile of a chordoma primary tumor (CSO) and a recurrent tumor (CSR) through mass spectrum in a chordoma patient who underwent surgery. Bioinformatic analysis of the profile showed that 359 proteins had a significant expression difference and 21 pathways had a striking alteration between the CSO and the CSR. The CSR showed a significant increase in carbohydrate metabolism. Immunohistochemistry (IHC) confirmed that the cancer stem cell marker activated leukocyte cell adhesion molecule (ALCAM or CD166) expression level was higher in the recurrent than that in the primary tumor. The present study analyzed the proteomic profile change between CSO and CSR and identified a new biomarker ALCAM in recurrent chordomas. This finding sheds light on unraveling the pathophysiology of chordoma recurrence and on exploring more effective prognostic biomarkers and targeted therapies against this devastating disease. PMID- 25738924 TI - Normal Distribution of CD8+ T-Cell-Derived ELISPOT Counts within Replicates Justifies the Reliance on Parametric Statistics for Identifying Positive Responses. AB - Accurate assessment of positive ELISPOT responses for low frequencies of antigen specific T-cells is controversial. In particular, it is still unknown whether ELISPOT counts within replicate wells follow a theoretical distribution function, and thus whether high power parametric statistics can be used to discriminate between positive and negative wells. We studied experimental distributions of spot counts for up to 120 replicate wells of IFN-gamma production by CD8+ T-cell responding to EBV LMP2A (426 - 434) peptide in human PBMC. The cells were tested in serial dilutions covering a wide range of average spot counts per condition, from just a few to hundreds of spots per well. Statistical analysis of the data using diagnostic Q-Q plots and the Shapiro-Wilk normality test showed that in the entire dynamic range of ELISPOT spot counts within replicate wells followed a normal distribution. This result implies that the Student t-Test and ANOVA are suited to identify positive responses. We also show experimentally that borderline responses can be reliably detected by involving more replicate wells, plating higher numbers of PBMC, addition of IL-7, or a combination of these. Furthermore, we have experimentally verified that the number of replicates needed for detection of weak responses can be calculated using parametric statistics. PMID- 25738925 TI - Bromination of olefins with HBr and DMSO. AB - A simple and inexpensive methodology is reported for the conversion of alkenes to 1,2-dibromo alkanes via oxidative bromination using HBr paired with dimethyl sulfoxide, which serves as the oxidant as well as cosolvent. The substrate scope includes 21 olefins brominated in good to excellent yields. Three of six styrene derivatives yielded bromohydrins under the reaction conditions. PMID- 25738926 TI - Fluid: a new "drug" in the PICU. PMID- 25738927 TI - Pharmacologic recipes for tracheal intubation in the PICU: what's on the menu? PMID- 25738928 TI - Pediatric critical care ultrasound education: the importance of a common denominator. PMID- 25738929 TI - Cell-based therapy for pediatric traumatic brain injury: not (yet) an update to the traumatic brain injury guidelines. PMID- 25738930 TI - Is glucose metabolism important for patients on extracorporeal membrane oxygenation? PMID- 25738931 TI - Critical care for rare diseases (and procedures): redux. PMID- 25738932 TI - Outcomes and risk factors in pediatric ventilator-associated pneumonia: guilt by association. PMID- 25738933 TI - Bringing back the (weighing) balance in the PICU--for good measure. PMID- 25738934 TI - H/D exchange in reactions of OH(-) with D2 and of OD(-) with H2 at low temperatures. AB - Using a cryogenic linear 22-pole rf ion trap, rate coefficients for H/D exchange reactions of OH(-) with D2 (1) and OD(-) with H2 (2) have been measured at temperatures between 11 K and 300 K with normal hydrogen. Below 60 K, we obtained k1 = 5.5 * 10(-10) cm(3) s(-1) for the exoergic . Upon increasing the temperature above 60 K, the data decrease with a power law, k1(T) ~T(-2.7), reaching ~1 * 10( 10) cm(3) s(-1) at 200 K. This observation is tentatively explained with a decrease of the lifetime of the intermediate complex as well as with the assumption that scrambling of the three hydrogen atoms is restricted by the topology of the potential energy surface. The rate coefficient for the endoergic increases with temperature from 12 K up to 300 K, following the Arrhenius equation, k2 = 7.5 * 10(-11) exp(-92 K/T) cm(3) s(-1) over two orders of magnitude. The fitted activation energy, EA-Exp = 7.9 meV, is in perfect accordance with the endothermicity of 24.0 meV, if one accounts for the thermal population of the rotational states of both reactants. The low mean activation energy in comparison with the enthalpy change in the reaction is mainly due to the rotational energy of 14.7 meV contributed by ortho-H2 (J = 1). Nonetheless, one should not ignore the reactivity of pure para-H2 because, according to our model, it already reaches 43% of that of ortho-H2 at 100 K. PMID- 25738936 TI - N-bromo-dimethylhydantoin polystyrene resin for water microbial decontamination. AB - N-bromo-dimethylhydantoin polystyrene beads were synthesized and tested as antimicrobial agents for water microbial decontamination. Optimization of synthetic process was thoroughly investigated, including solvents used, ratio of reactants and reaction conditions, kilogram scale production, and detailed spectral analysis. The microbial inactivation efficiency was studied according to the NSF-231 Guide Standard and Protocol for Testing Microbiological Water Purifiers against Escherichia coli and MS2 phage. The tested resins maintained their activity for 550 L. Thus, N-bromo-dimethylhydantoin-polystyrene beads synthesized under optimized conditions at kilogram quantities have a potential use in water purification filters. PMID- 25738935 TI - Gastrointestinal infections and diarrheal disease in Ghanaian infants and children: an outpatient case-control study. AB - INTRODUCTION: Diarrheal diseases are among the most frequent causes of morbidity and mortality in children worldwide, especially in resource-poor areas. This case control study assessed the associations between gastrointestinal infections and diarrhea in children from rural Ghana. METHODS: Stool samples were collected from 548 children with diarrhea and from 686 without gastrointestinal symptoms visiting a hospital from 2007-2008. Samples were analyzed by microscopy and molecular methods. RESULTS: The organisms most frequently detected in symptomatic cases were Giardia lamblia, Shigella spp./ enteroinvasive Escherichia coli (EIEC), and Campylobacter jejuni. Infections with rotavirus (adjusted odds ratio [aOR] = 8.4; 95% confidence interval [CI]: 4.3-16.6), C. parvum/hominis (aOR = 2.7; 95% CI: 1.4-5.2) and norovirus (aOR = 2.0; 95%CI: 1.3-3.0) showed the strongest association with diarrhea. The highest attributable fractions (AF) for diarrhea were estimated for rotavirus (AF = 14.3%; 95% CI: 10.9-17.5%), Shigella spp./EIEC (AF = 10.5%; 95% CI: 3.5-17.1%), and norovirus (AF = 8.2%; 95% CI 3.2 12.9%). Co-infections occurred frequently and most infections presented themselves independently of other infections. However, infections with E. dispar, C. jejuni, and norovirus were observed more often in the presence of G. lamblia. CONCLUSIONS: Diarrheal diseases in children from a rural area in sub-Saharan Africa are mainly due to infections with rotavirus, Shigella spp./EIEC, and norovirus. These associations are strongly age-dependent, which should be considered when diagnosing causes of diarrhea. The presented results are informative for both clinicians treating gastrointestinal infections as well as public health experts designing control programs against diarrheal diseases. PMID- 25738938 TI - Ear wax. AB - INTRODUCTION: Ear wax only becomes a problem if it causes a hearing impairment or other ear-related symptoms. Ear wax is more likely to accumulate and cause a hearing impairment when normal extrusion is prevented; for example, by the use of hearing aids, or by the use of cotton buds to clean the ears. Ear wax can visually obscure the ear drum, and may need to be removed for diagnostic purposes. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of methods to remove ear wax? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: ear irrigation (syringing); manual removal (other than ear irrigation); wax softeners prior to irrigation; and wax softeners alone. PMID- 25738937 TI - Innovative delivery of siRNA to solid tumors by super carbonate apatite. AB - RNA interference (RNAi) technology is currently being tested in clinical trials for a limited number of diseases. However, systemic delivery of small interfering RNA (siRNA) to solid tumors has not yet been achieved in clinics. Here, we introduce an in vivo pH-sensitive delivery system for siRNA using super carbonate apatite (sCA) nanoparticles, which is the smallest class of nanocarrier. These carriers consist simply of inorganic ions and accumulate specifically in tumors, yet they cause no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA abundantly accumulated in the cytoplasm of tumor cells at 4 h, indicating quick achievement of endosomal escape. sCA-survivin-siRNA induced apoptosis in HT29 tumors and significantly inhibited in vivo tumor growth of HCT116, to a greater extent than two other in vivo delivery reagents. With innovative in vivo delivery efficiency, sCA could be a useful nanoparticle for the therapy of solid tumors. PMID- 25738939 TI - Involvement of CitCHX and CitDIC in developmental-related and postharvest-hot-air driven citrate degradation in citrus fruits. AB - Citrate is the predominant organic acid associated with taste in citrus fruit. Although citrate metabolism has been widely studied in recent years, the potential contributions of transport proteins to citrate content remain unclear. In the present study, high-acid citrus fruit Gaocheng ('GC', Citrus sp.) and low acid citrus fruit Satsuma mandarin ('SM', Citrus unshiu Marc.) were selected for study, and the degradation of citrate was deduced to be the main cause of the difference in acidity in fully mature fruits. RNA-seq analysis was carried out on 'GC' and 'SM' fruit samples over the same time course, and the results indicated that citrate degradation occurred mainly through the glutamine pathway, catalyzed by CitAco3-CitGS2-CitGDU1, and also two transport-related genes, CitCHX and CitDIC, were shown to be associated with citrate degradation. These results were confirmed by real-time PCR. In postharvest 'GC' fruit, the expressions of these two transport-related genes were induced by 2-fold under hot air treatment, accompanied by a reduction of 7%-9% in total acid degradation. Transient expression of CitCHX and CitDIC in tobacco leaves was performed, and the citrate content was reduced by 62%, 75% and 78% following CitCHX, CitDIC and CitCHX plus CitDIC treatments, respectively, as compared with expression of an empty vector. Overall, these data indicated that two transport proteins, CitCHX and CitDIC, are not only involved in citrate degradation during fruit development, but also involved in postharvest hot air triggered citrate reduction. PMID- 25738940 TI - Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies. AB - Inflammatory abnormalities have been implicated in the pathogenesis of various human diseases, including cancer. Interleukin-1 receptor antagonist (IL1RN) is a potent anti-inflammatory molecule that modulates the biological activity of the proinflammatory cytokine, interleukin-1. The aim of this study was to examine the expression of IL1RN in oral squamous cell carcinomas (OSCCs), and to determine its clinical significance. Expression levels of IL1RN in matched normal and tumor specimens from 39 OSCCs were evaluated using real-time quantitative polymerase chain reaction methods, and immunohistochemical analysis. Protein expression of IL1RN was also examined in 18 oral premalignant lesions (OPLs). Expression of IL1RN mRNA was significantly downregulated in OSCCs compared with normal tissues. Decreased expression of IL1RN protein was also observed in OPLs and OSCCs. The IL1RN expression level was lower in the OPL cases with severe dysplasia compared to those with mild/moderate dysplasia. Significantly downregulated IL1RN expression was observed in all OSCC lesion sites examined when compared with the matched normal tissues. However, the decreased level of IL1RN expression did not correspond with tumor progression. Noteworthy, IL1RN expression was higher in the advanced OSCC cases (T3/T4) compared to early cases (T1/T2). Among OSCC samples, relatively higher IL1RN expression was associated with active tumor development in the OSCCs occurring in the buccal mucosa, oral floor, fauces and gingiva, but not the tongue. These data suggest that IL1RN may exhibit opposing characteristics in oral malignancies depending on the stage of cancer development, suppressing early carcinogenic events, yet promoting tumor development in some lesion sites. Thus, IL1RN could represent a reliable biomarker for the early diagnosis of OSCCs. Furthermore, IL1RN may possess unknown and complex functions in the developed OSCC. PMID- 25738941 TI - Perspectives of family members participating in cultural assessment of psychiatric disorders: findings from the DSM-5 International Field Trial. AB - Despite the important roles families play in the lives of many individuals with mental illness across cultures, there is a dearth of data worldwide on how family members perceive the process of cultural assessment as well as to how to best include them. This study addresses this gap in our knowledge through analysis of data collected across six countries as part of a DSM-5 Field Trial of the Cultural Formulation Interview (CFI). At clinician discretion, individuals who accompanied patients to the clinic visit (i.e. patient companions) at the time the CFI was conducted were invited to participate in the cultural assessment and answer questions about their experience. The specific aims of this paper are (1) to describe patterns of participation of patient companions in the CFI across the six countries, and (2) to examine the comparative feasibility, acceptability, and clinical utility of the CFI from companion perspectives through analysis of both quantitative and qualitative data. Among the 321 patient interviews, only 86 (at four of 12 sites) included companions, all of whom were family members or other relatives. The utility, feasibility and acceptability of the CFI were rated favourably by relatives, supported by qualitative analyses of debriefing interviews. Cross-site differences in frequency of accompaniment merit further study. PMID- 25738942 TI - Indirect short- and long-term effects of aboveground invertebrate and vertebrate herbivores on soil microarthropod communities. AB - Recognition is growing that besides ungulates, small vertebrate and invertebrate herbivores are important drivers of grassland functioning. Even though soil microarthropods play key roles in several soil processes, effects of herbivores especially those of smaller body size-on their communities are not well understood. Therefore, we progressively excluded large, medium and small vertebrate and invertebrate herbivores for three growing seasons using size selective fences in two vegetation types in subalpine grasslands; short-grass and tall-grass vegetation generated by high and low historical levels of ungulate grazing. Herbivore exclusions generally had few effects on microarthropod communities, but exclusion of all herbivore groups resulted in decreased total springtail and Poduromorpha richness compared with exclusion of only ungulates and medium-sized mammals, regardless of vegetation type. The tall-grass vegetation had a higher total springtail richness and mesostigmatid mite abundance than the short-grass vegetation and a different oribatid mite community composition. Although several biotic and abiotic variables differed between the exclusion treatments and vegetation types, effects on soil microarthropods were best explained by differences in nutrient and fibre content of the previous year's vegetation, a proxy for litter quality, and to a lesser extent soil temperature. After three growing seasons, smaller herbivores had a stronger impact on these functionally important soil microarthropod communities than large herbivores. Over longer time-scales, however, large grazers created two different vegetation types and thereby influenced microarthropod communities bottom-up, e.g. by altering resource quality. Hence, both short- and long-term consequences of herbivory affected the structure of the soil microarthropod community. PMID- 25738943 TI - Absence of sex differential plasticity to light availability during seed maturation in Geranium sylvaticum. AB - Sex-differential plasticity (SDP) hypothesis suggests that since hermaphrodites gain fitness through both pollen and seed production they may have evolved a higher degree of plasticity in their reproductive strategy compared to females which achieve fitness only through seed production. SDP may explain the difference in seed production observed between sexes in gynodioecious species in response to resource (nutrients or water) availability. In harsh environments, hermaphrodites decrease seed production whereas females keep it relatively similar regardless of the environmental conditions. Light availability can be also a limiting resource and thus could theoretically affect differently female and hermaphrodite seed output even though this ecological factor has been largely overlooked. We tested whether the two sexes in the gynodioecious species Geranium sylvaticum differ in their tolerance to light limitation during seed maturation in the field. We used a fully factorial block experiment exposing female and hermaphrodite plants to two different light environments (control and shade) after their peak flowering period. Specifically, we measured fruit and seed production in response to decreased light availability and compared it between the sexes. Shading reduced the number of fruits and seeds produced, but the decrease was similar between the sexes. Furthermore, shading delayed seed production by three days in both sexes, but did not affect seed mass, seed P content, or the probability of re-flowering the following year. Our results give no evidence for reproductive SDP in response to light during seed maturation. PMID- 25738944 TI - Metastasis-associated in colon cancer-1 is associated with poor prognosis in hepatocellular carcinoma, partly by promoting proliferation through enhanced glucose metabolism. AB - Metastasis-associated in colon cancer-1 (MACC1) is a newly identified gene that is involved in the development and progression of hepatocellular carcinoma (HCC), however its investigation has not been comprehensive. In the present study, in vitro techniques, including immunohistochemistry, western blotting, reverse transcription quantitative polymerase chain reaction, metabolic assay, MTT assay, colony formation assay and prognostic analysis were used to confirm the involvement of MACC1 in HCC. Histological examination confirmed that the protein expression of MACC1 was upregulated in HCC and was associated with the hexokinase 2 (HK2) protein, which also indicates a poor prognosis. Knockdown of MACC1 induced the reduction of glycogen consumption and lactate production, which then lead to a marked reduction of proliferation in the MHCC-97H cells. However, the overexpression of MACC1 produced the opposite results in the HepG2 cells. These results suggested that MACC1 leads to a poor prognosis in HCC, partly by promoting proliferation via enhancement in glucose metabolism by HK2. Therefore, this pathway has the potential to become an important therapeutic target in HCC. PMID- 25738945 TI - Two industrial cohorts: baseline characteristics and factors associated with obesity. AB - OBJECTIVE: To describe demographic and health characteristics, and factors associated with obesity among production workers. METHODS: This cross-sectional study analyzed baseline data from two occupational cohorts. Regression modeling was used to assess associations between worker characteristics and obesity. RESULTS: A total of 1974 subjects were included in these analyses. The mean body mass index was 29.5 kg/m (SD = 6.5). Having smoked in the past and currently smoking decreased the odds of being obese in the WISTAH Distal Upper Extremity cohort, whereas those feeling depressed had increased odds of being obese. Being a Pacific Islander/Native Hawaiian and married increased the odds of obesity in the BackWorks Low Back Pain cohort. CONCLUSIONS: Factors associated with obesity differed substantially between the two cohorts. Recognizing factors associated with obesity in specific work settings may provide opportunities for optimizing preventive workplace interventions. PMID- 25738946 TI - Health risk change as a predictor of productivity change. AB - OBJECTIVE: To assess how health risk change influences concurrent and subsequent change in absenteeism and presenteeism. METHODS: A retrospective, longitudinal study design analyzed repeated health assessment survey data using maximum likelihood structural equation modeling. RESULTS: A statistically significant relationship was detected between self-reported health risks at one point in time and lower productivity (absenteeism and presenteeism) at the same point in time as well as a longitudinal effect of increasing risks at one point in time associated with decreased productivity at subsequent measurement periods. CONCLUSIONS: Health is a predictor of productivity, and the benefits of improved health on improved productivity are cumulative over time. PMID- 25738947 TI - Development and validity of a scale to measure workplace culture of health. AB - OBJECTIVE: To describe the development of and test the validity and reliability of the Workplace Culture of Health (COH) scale. METHODS: Exploratory factor analysis and confirmatory factor analysis were performed on data from a health care organization (N = 627). To verify the factor structure, confirmatory factor analysis was performed on a second data set from a medical equipment manufacturer (N = 226). RESULTS: The COH scale included a structure of five orthogonal factors: senior leadership and polices, programs and rewards, quality assurance, supervisor support, and coworker support. With regard to construct validity (convergent and discriminant) and reliability, two different US companies showed the same factorial structure, satisfactory fit statistics, and suitable internal and external consistency. CONCLUSIONS: The COH scale represents a reliable and valid scale to assess the workplace environment and culture for supporting health. PMID- 25738948 TI - The relationship between occupational metal exposure and arterial compliance. AB - BACKGROUND: The objective of this study was to evaluate the relationship between cumulative occupational exposure to various metals and arterial compliance in welders. METHODS: The observational follow-up study consisted of 25 subjects. Levels of nickel (Ni), lead, cadmium, manganese, and arsenic from toenails were assessed using mass spectrometry. Arterial compliance as reflected by augmentation index (AIx) was measured using SphygmoCor Px Pulse Wave Analysis System. Linear regression models were used to assess the associations. RESULTS: For every 1 unit increase in log-transformed toenail Ni, there was a statistically significant 5.68 (95% confidence interval, 1.38 to 9.98; P = 0.01) unit increase in AIx. No significant associations were found between AIx and lead, cadmium, manganese, and arsenic. CONCLUSIONS: Cumulative Ni exposure is associated with increased arterial stiffness in welders and may increase risk of adverse cardiovascular outcomes. PMID- 25738950 TI - Australian academic primary health-care careers: a scoping survey. AB - This study was undertaken to provide a snapshot of the academic primary health care workforce in Australia and to provide some insight into research capacity in academic primary health care following changes to funding for this sector. A convenience sample of individuals self-identifying as working within academic primary health care (n=405) completed an anonymous online survey. Respondents were identified from several academic primary health-care mailing lists. The survey explored workforce demographics, clarity of career pathways, career trajectories and enablers/barriers to 'getting in' and 'getting on'. A mix of early career (41%), mid-career (25%) and senior academics (35%) responded. Early career academics tended to be female and younger than mid-career and senior academics, who tended to be male and working in 'balanced' (teaching and research) roles and listing medicine as their disciplinary background. Almost three-quarters (74%) indicated career pathways were either 'completely' or 'somewhat unclear', irrespective of gender and disciplinary backgrounds. Just over half (51%) had a permanent position. Males were more likely to have permanent positions, as were those with a medical background. Less than half (43%) reported having a mentor, and of the 57% without a mentor, more than two thirds (69%) would like one. These results suggest a lack of clarity in career paths, uncertainty in employment and a large number of temporary (contract) or casual positions represent barriers to sustainable careers in academic primary health care, especially for women who are from non-medicine backgrounds. Professional development or a mentoring program for primary health-care academics was desired and may address some of the issues identified by survey respondents. PMID- 25738949 TI - Learning Ability as a Function of Practice: Does It Apply to Farmworkers? AB - OBJECTIVE: Farmworkers experience significant work-related health risks including pesticide-associated cognitive impairment. Practice effect is a surrogate for learning ability. This study examined differences in cognitive function and learning capacity in Latino farmworkers and nonfarmworkers. METHODS: Tasks of learning and short-term memory, executive function and working memory, perceptual coding, and psychomotor function were assessed at baseline and 3-month follow-up in 136 farmworkers and 116 nonfarmworkers. RESULTS: Farmworkers had better performance on visuospatial learning and short-term memory at baseline (P < 0.05). Nevertheless, nonfarmworkers showed more practice effects, or improvement on cognitive performance, at 3-month follow-up relative to farmworkers. Furthermore, the amount of improvement on visuospatial learning ability, short term visuospatial memory, and perceptual coding ability was significantly higher in nonfarmworkers than in farmworkers. CONCLUSIONS: Practice effects may serve as an additional cognitive readout to differentiate healthy individuals from those with cognitive impairment. PMID- 25738951 TI - Inhibitory effect of mammea E/BB from Mammea siamensis seed extract on Wilms' tumour 1 protein expression in a K562 leukaemic cell line. AB - Mammea siamensis is used in traditional Thai medicine. This study was designed to extract and isolate an active compound from the M. siamensis seeds and to investigate its activity on Wilms' tumour 1 (WT1) protein expression in K562 cells. WT1 is a transcription factor that stimulates cell proliferation. The ethanol saraphi seed (ESS) extract was fractionated using n-hexane, ethyl acetate, n-butanol and water to obtain n-hexane saraphi seed (HSS), ethyl acetate saraphi seed (EASS), n-butanol saraphi seed (BSS), and water saraphi seed (WSS) extracts, respectively. The ESS, HSS and EASS extracts had strong cytotoxic effects on K562 cells in the MTT assay. All three fractions decreased WT1 protein levels and decreased total cell numbers. The HSS extract decreased the WT1 protein levels in a time- and dose-dependent manner. HPLC and NMR analyses indicated that the active compound of HSS was mammea E/BB. M. siamensis seeds are thus identified as a promising source of bioactive compounds for potential inhibition of WT1 protein expression. PMID- 25738953 TI - Commentary on "Disability Trajectories at the End of Life: A Countdown Model" The Problems With Time-to-Death as a Predictor of Disability. PMID- 25738952 TI - The effects of a mass media HIV-risk reduction strategy on HIV-related stigma and knowledge among African American adolescents. AB - HIV-related stigma undermines HIV prevention, testing, and treatment. Multipronged risk-reduction strategies may reduce stigma among African American adolescents. To test the effectiveness of a risk-reduction strategy in addressing stigma, 1613 African American adolescents from four mid-sized cities participated in a randomized control trial. Participants received a sexual-risk reduction [Focus on Youth (FOY)] or general health curriculum [Promoting Health Among Teens (PHAT)]. Two cities received a culturally-tailored media intervention. Participants completed baseline, 3-, 6-, and 12-month surveys to measure HIV related stigma and knowledge. Analysis of covariance tested for stigma and knowledge differences by media city status and curriculum/media city status (PHAT media vs. PHAT non-media, FOY media vs. FOY non-media; FOY media vs. PHAT media; FOY non-media vs. PHAT non-media) at each measurement. Hierarchical linear modeling (HLM) determined stigma and knowledge differences over time. Media participants demonstrated greater HIV-related knowledge (p<0.10) at 6 months and lower stigma at 3 months (p<0.10). FOY media participants had lower 3-month (p<0.05) and 12-month (p<0.10) stigma scores than non-media FOY participants. FOY media and non-media participants had greater knowledge than PHAT for all intervals after baseline. FOY media had lower stigma than PHAT media after baseline for all intervals after baseline. HLM indicated greater knowledge slopes for the media group (p<0.05). FOY media participants had greater knowledge slopes (p<0.05) relative to non-media FOY participants and media PHAT participants (p<0.01). A combination of a HIV risk-reduction curriculum and culturally tailored media demonstrated some effectiveness in reducing stigma. Future use of media in HIV-prevention should include and evaluate effects on stigma. PMID- 25738954 TI - Correction: Mice lacking GD3 synthase display morphological abnormalities in the sciatic nerve and neuronal disturbances during peripheral nerve regeneration. PMID- 25738955 TI - An industry-scale mass marking technique for tracing farmed fish escapees. AB - Farmed fish escape and enter the environment with subsequent effects on wild populations. Reducing escapes requires the ability to trace individuals back to the point of escape, so that escape causes can be identified and technical standards improved. Here, we tested if stable isotope otolith fingerprint marks delivered during routine vaccination could be an accurate, feasible and cost effective marking method, suitable for industrial-scale application. We tested seven stable isotopes, (134)Ba, (135)Ba, (136)Ba, (137)Ba, (86)Sr, (87)Sr and (26)Mg, on farmed Atlantic salmon reared in freshwater, in experimental conditions designed to reflect commercial practice. Marking was 100% successful with individual Ba isotopes at concentrations as low as 0.001 ug. g-1 fish and for Sr isotopes at 1 ug. g-1 fish. Our results suggest that 63 unique fingerprint marks can be made at low cost using Ba (0.0002 - 0.02 $US per mark) and Sr (0.46 0.82 $US per mark) isotopes. Stable isotope fingerprinting during vaccination is feasible for commercial application if applied at a company level within the world's largest salmon producing nations. Introducing a mass marking scheme would enable tracing of escapees back to point of origin, which could drive greater compliance, better farm design and improved management practices to reduce escapes. PMID- 25738956 TI - High rates of ofloxacin resistance in Mycobacterium tuberculosis among both new and previously treated patients in Tamil Nadu, South India. AB - Periodic drug resistance surveillance provides useful information on trends of drug resistance and effectiveness of tuberculosis (TB) control measures. The present study determines the prevalence of drug resistance among new sputum smear positive (NSP) and previously treated (PT) pulmonary TB patients, diagnosed at public sector designated microscopy centers (DMCs) in the state of Tamil Nadu, India. In this single-stage cluster-sampling prevalence survey, 70 of 700 DMCs were randomly selected using a probability-proportional to size method. A cluster size of 24 for NSP and a varying size of 0 to 99 for PT cases were fixed for each selected DMC. Culture and drug susceptibility testing was done on Lowenstein Jensen medium using the economic variant of proportion sensitivity test for isoniazid (INH), rifampicin (RMP), ofloxacin (OFX) and kanamycin (KAN). Human Immunodeficiency Virus (HIV) status was collected from patient records. From June 2011 to August 2012, 1524 NSP and 901 PT patients were enrolled. Any RMP resistance and any INH resistance were observed in 2.6% and 15.1%, and in 10.4% and 30% respectively in NSP and PT cases. Among PT patients, multi drug resistant TB (MDR-TB) was highest in the treatment failure (35%) group, followed by relapse (13%) and treatment after default (10%) groups. Extensively drug resistant TB (XDRTB) was seen in 4.3% of MDR-TB cases. Any OFX resistance was seen in 10.4% of NSP, 13.9% of PT and 29% of PT MDR-TB patients. The HIV status of the patient had no impact on drug resistance levels. RMP resistance was present in 2.6% of new and 15.1% of previously treated patients in Tamil Nadu. Rates of OFX resistance were high among NSP and PT patients, especially among those with MDR-TB, a matter of concern for development of new treatment regimens for TB. PMID- 25738957 TI - Mapping isoflavone QTL with main, epistatic and QTL * environment effects in recombinant inbred lines of soybean. AB - Soybean (Glycine max (L.) Merr.) isoflavone is important for human health and plant defense system. To identify novel quantitative trait loci (QTL) and epistatic QTL underlying isoflavone content in soybean, F5:6, F5:7 and F5:8 populations of 130 recombinant inbred (RI) lines, derived from the cross of soybean cultivar 'Zhong Dou 27' (high isoflavone) and 'Jiu Nong 20' (low isoflavone), were analyzed with 95 new SSR markers. A new linkage map including 194 SSR markers and covering 2,312 cM with mean distance of about 12 cM between markers was constructed. Thirty four QTL for both individual and total seed isoflavone contents of soybean were identified. Six, seven, ten and eleven QTL were associated with daidzein (DZ), glycitein (GC), genistein (GT) and total isoflavone (TI), respectively. Of them 23 QTL were newly identified. The qTIF_1 between Satt423 and Satt569 shared the same marker Satt569 with qDZF_2, qGTF_1 and qTIF_2. The qGTD2_1 between Satt186 and Satt226 was detected in four environments and explained 3.41%-10.98% of the phenotypic variation. The qGTA2_1, overlapped with qGCA2_1 and detected in four environments, was close to the previously identified major QTL for GT, which were responsible for large a effects. QTL (qDZF_2, qGTF_1 and qTIF_2) between Satt144-Satt569 were either clustered or pleiotropic. The qGCM_1, qGTM_1 and qTIM_1 between Satt540-Sat_244 explained 2.02%-9.12% of the phenotypic variation over six environments. Moreover, the qGCE_1 overlapped with qGTE_1 and qTIE_1, the qTIH_2 overlapped with qGTH_1, qGCI_1 overlapped with qDZI_1, qTIL_1 overlapped with qGTL_1, and qTIO_1 overlapped with qGTO_1. In this study, some of unstable QTL were detected in different environments, which were due to weak expression of QTL, QTL by environment interaction in the opposite direction to a effects, and/or epistasis. The markers identified in multi-environments in this study could be applied in the selection of soybean cultivars for higher isoflavone content and in the map based gene cloning. PMID- 25738958 TI - Expression of hypoxic marker carbonic anhydrase IX predicts poor prognosis in resectable hepatocellular carcinoma. AB - Carbonic anhydrase IX (CA-IX), a hypoxia marker, correlates with tumor progression in a variety of human cancers. However, the role of CA-IX in hepatocellular carcinomas (HCCs) remains largely unknown. We examined the expression of 277 unifocal, resectable, primary HCC tumors using immunohistochemistry. The CA-IX protein was expressed in 110 of the 227 (48.5%) HCC tumors. The expression of CA-IX correlated with younger age (P = 0.0446), female sex (P = 0.0049), high serum alpha-fetoprotein levels (P<1x10-6), larger tumor size (P = 0.0031), high tumor grade P<1x10-6) and high tumor stage (P = 1.5x10-6). Patients with HCC tumors that expressed CA-IX were more likely to have lower 5-year disease-free survival (DFS; P = 0.0001) and 5-year overall survival (OS; P<1x10-6). The multivariate analysis indicated that CA-IX expression was an independent predictor for high tumor stage (P = 0.0047) and DFS (P = 0.0456), and a borderline predictor for OS (P = 0.0762). Furthermore, CA-IX expression predicted poor DFS and OS in patients with high tumor stage (P = 0.0004 and P<1x10-6, respectively). Interestingly, CA-IX expression might contribute to the worse prognosis of female patients with advanced HCCs. Our study indicates the expression of the CA-IX protein is a crucial predictor of poor prognosis in resectable HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage. PMID- 25738959 TI - Rapid evolution of recombinant Saccharomyces cerevisiae for Xylose fermentation through formation of extra-chromosomal circular DNA. AB - Circular DNA elements are involved in genome plasticity, particularly of tandem repeats. However, amplifications of DNA segments in Saccharomyces cerevisiae reported so far involve pre-existing repetitive sequences such as ribosomal DNA, Ty elements and Long Terminal Repeats (LTRs). Here, we report the generation of an eccDNA, (extrachromosomal circular DNA element) in a region without any repetitive sequences during an adaptive evolution experiment. We performed whole genome sequence comparison between an efficient D-xylose fermenting yeast strain developed by metabolic and evolutionary engineering, and its parent industrial strain. We found that the heterologous gene XylA that had been inserted close to an ARS sequence in the parent strain has been amplified about 9 fold in both alleles of the chromosomal locus of the evolved strain compared to its parent. Analysis of the amplification process during the adaptive evolution revealed formation of a XylA-carrying eccDNA, pXI2-6, followed by chromosomal integration in tandem arrays over the course of the evolutionary adaptation. Formation of the eccDNA occurred in the absence of any repetitive DNA elements, probably using a micro-homology sequence of 8 nucleotides flanking the amplified sequence. We isolated the pXI2-6 eccDNA from an intermediate strain of the evolutionary adaptation process, sequenced it completely and showed that it confers high xylose fermentation capacity when it is transferred to a new strain. In this way, we have provided clear evidence that gene amplification can occur through generation of eccDNA without the presence of flanking repetitive sequences and can serve as a rapid means of adaptation to selection pressure. PMID- 25738960 TI - Pregnant women's experiences of male partner involvement in the context of prevention of mother-to-child transmission in Khayelitsha, South Africa. AB - Male partner involvement (MPI) has been identified as a priority intervention in programmes for the prevention of mother-to-child transmission (PMTCT) of HIV, but rates of MPI remain low worldwide. This study used a quantitative survey (n=170) and two focus group discussions (FGDs) with 16 HIV-positive pregnant women attending a public sector antenatal care service in Khayelitsha, South Africa, to examine the determinants of high levels of involvement and generate a broader understanding of women's experiences of MPI during pregnancy. Among survey participants, 74% had disclosed their status to their partner, and most reported high levels of communication around HIV testing and preventing partner transmission, as well as high levels of MPI. High MPI was significantly more likely among women who were cohabiting with their partner; who had reportedly disclosed their HIV status to their partner; and who reported higher levels of HIV-related communication with their partner. FGD participants discussed a range of ways in which partners can be supportive during pregnancy, not limited to male attendance of antenatal care. MPI appears to be a feasible intervention in this context, and MPI interventions should aim to encourage male partner attendance of antenatal care as well as greater involvement in pregnancy more generally. Interventions that target communication are needed to facilitate HIV-related communication and disclosure within couples. MPI should remain a priority intervention in PMTCT programmes, and increased efforts should be made to promote MPI in PMTCT. PMID- 25738961 TI - Looking Maori predicts decreased rates of home ownership: institutional racism in housing based on perceived appearance. AB - This study examined differences in rates of home ownership among Maori (the indigenous peoples of New Zealand). We identified systematic factors that predicted why some Maori were more likely to own their own home (partially or fully) relative to other Maori. Data were drawn from a large national postal sample of 561 self-identified Maori collected as part of the New Zealand Attitudes and Values Study. As predicted, our analyses indicated that self reported appearance as Maori, or the extent to which people thought they personally displayed features which visibly identified them as Maori to others, significantly predicted decreased rates of home ownership. This association held when adjusting for numerous demographic covariates, such as education, level of deprivation of the immediate area, household income, age, relationship status, region of residence, and so forth. Our analyses suggest there is, or at least has been in the recent past, institutional racism against Maori in New Zealand's home lending industry based on merely appearing more Maori. PMID- 25738962 TI - Sensing cytosolic RpsL by macrophages induces lysosomal cell death and termination of bacterial infection. AB - The intracellular bacterial pathogen Legionella pneumophila provokes strong host responses and has proven to be a valuable model for the discovery of novel immunosurveillance pathways. Our previous work revealed that an environmental isolate of L. pneumophila induces a noncanonical form of cell death, leading to restriction of bacterial replication in primary mouse macrophages. Here we show that such restriction also occurs in infections with wild type clinical isolates. Importantly, we found that a lysine to arginine mutation at residue 88 (K88R) in the ribosome protein RpsL that not only confers bacterial resistance to streptomycin, but more importantly, severely attenuated the induction of host cell death and enabled L. pneumophila to replicate in primary mouse macrophages. Although conferring similar resistance to streptomycin, a K43N mutation in RpsL does not allow productive intracellular bacterial replication. Further analysis indicated that RpsL is capable of effectively inducing macrophage death via a pathway involved in lysosomal membrane permeabilization; the K88R mutant elicits similar responses but is less potent. Moreover, cathepsin B, a lysosomal protease that causes cell death after being released into the cytosol upon the loss of membrane integrity, is required for efficient RpsL-induced macrophage death. Furthermore, despite the critical role of cathepsin B in delaying RpsL-induced cell death, macrophages lacking cathepsin B do not support productive intracellular replication of L. pneumophila harboring wild type RpsL. This suggests the involvement of other yet unidentified components in the restriction of bacterial replication. Our results identified RpsL as a regulator in the interactions between bacteria such as L. pneumophila and primary mouse macrophages by triggering unique cellular pathways that restrict intracellular bacterial replication. PMID- 25738963 TI - Optical reading aids for children and young people with low vision. AB - BACKGROUND: Low vision in childhood is a significant barrier to learning and development, particularly for reading and education. Optical low vision aids may be used to maximise the child's functional vision. The World Health Organization (WHO) has previously highlighted the importance of the use of low vision aids in managing children with visual impairment across the world. OBJECTIVES: To assess the effect of optical low vision aids on reading in children and young people with low vision. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015), the Health Technology Assessment Programme (HTA) (www.hta.ac.uk/), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 8 January 2015.We also used manual searching to check the references listed in retrieved articles. Manufacturers of low vision aids were contacted to request any information about studies or research regarding their products. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs where any optical low vision aid was compared to standard refractive correction in children and young people aged between 5 and 16 years of age with low vision as defined by the WHO. We planned to include within-person design studies where the order of presentation of devices was randomised. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the search results for eligibility . MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: There is a lack of good quality evidence regarding the use of optical low vision aids in children and young people. As such, no implications for practice can be drawn. We believe future research should include functional outcome measures such as reading speed, accuracy and comprehension, as well as the effect of low vision aids on quality of life, in order to truly assess and compare the effect of these devices on a child's life and development. PMID- 25738964 TI - Protective role of isoflurane pretreatment in rats with focal cerebral ischemia and the underlying molecular mechanism. AB - Inflammation and immunity are important in the pathogenesis of cerebral ischemia. Toll-like receptor 4 (TLR4) is involved in the inflammatory responses of injured brain tissues. Emerging studies have focused on the effect of isoflurane (ISO) pretreatment on cerebral ischemia, however, the association between ISO pretreatment and TLR4 during cerebral ischemia remains to be elucidated. In the present study, the protective role of ISO pretreatment in rats with focal cerebral ischemia reperfusion was investigated and the molecular mechanism was discussed. Using a middle cerebral artery occlusion (MCAO) model, triphenyltetrazolium chloride staining was utilized to measure the infarct volume and brain edema and immunofluorescence staining was used to detect the MCAO induced TLR4 expression and localization. Western blot analyses were conducted to quantify the protein expression levels of TLR4, myeloid differentiation primary response 88 (MyD88) and nuclear factor (NF)-kappaB in ischemic brain tissue at different time points. The results demonstrated that, following ISO pretreatment, the neurological deficits, brain edema and cerebral infarct size caused by ischemia/reperfusion were attenuated. The astrocyte and microglial activation in the brain tissue was decreased. In addition, the expression levels of TLR4, MyD88 and NF-kappaB were decreased. The present study indicated that ISO pretreatment may protect the brain from ischemic damage by downregulating the expression levels of TLR4, MyD88 and NF-kappaB. PMID- 25738965 TI - Pandemic influenza virus: tracking a three-headed monster. PMID- 25738966 TI - Sophorolipid biosurfactants: Possible uses as antibacterial and antibiofilm agent. AB - Biosurfactants are amphipathic, surface-active molecules of microbial origin which accumulate at interfaces reducing interfacial tension and leading to the formation of aggregated micellular structures in solution. Some biosurfactants have been reported to have antimicrobial properties, the ability to prevent adhesion and to disrupt biofilm formation. We investigated antimicrobial properties and biofilm disruption using sophorolipids at different concentrations. Growth of Gram negative Cupriavidus necator ATCC 17699 and Gram positive Bacillus subtilis BBK006 were inhibited by sophorolipids at concentrations of 5% v/v with a bactericidal effect. Sophorolipids (5% v/v) were also able to disrupt biofilms formed by single and mixed cultures of B. subtilis BBK006 and Staphylococcus aureus ATCC 9144 under static and flow conditions, as was observed by scanning electron microscopy. The results indicated that sophorolipids may be promising compounds for use in biomedical application as adjuvants to other antimicrobial against some pathogens through inhibition of growth and/or biofilm disruption. PMID- 25738967 TI - Origins of the Quinolone Class of Antibacterials: An Expanded "Discovery Story". AB - Published descriptions of the specific lines of research leading to the discovery of therapeutically important medicines, especially major new class medicines, have long provided value to the biopharmaceutical community as models of success, often influencing the strategies and methods of subsequent drug research. Quinolone antibacterials represent one of medicine's most important classes of anti-infective agents; yet in contrast to many other classes of anti-infectives, astonishingly few details concerning the origin of the class or the rationale leading to the selection of the first clinical agent, nalidixic acid, were ever published by the discoverers. Moreover, earlier disclosures of an independent discovery of the quinolone class of antibacterials have been almost entirely overlooked by the scientific literature. This review brings together all the available information from primary literature sources relating to both discoveries and provides for the first time a much fuller, if still partially speculative, story of the earliest years of this important class of drugs. PMID- 25738968 TI - What controls the hybridization thermodynamics of spherical nucleic acids? AB - The hybridization of free oligonucleotides to densely packed, oriented arrays of DNA modifying the surfaces of spherical nucleic acid (SNA)-gold nanoparticle conjugates occurs with negative cooperativity; i.e., each binding event destabilizes subsequent binding events. DNA hybridization is thus an ever changing function of the number of strands already hybridized to the particle. Thermodynamic quantification of this behavior reveals a 3 orders of magnitude decrease in the binding constant for the capture of a free oligonucleotide by an SNA conjugate as the fraction of pre-hybridized strands increases from 0 to ~30%. Increasing the number of pre-hybridized strands imparts an increasing enthalpic penalty to hybridization that makes binding more difficult, while simultaneously decreasing the entropic penalty to hybridization, which makes binding more favorable. Hybridization of free DNA to an SNA is thus governed by both an electrostatic barrier as the SNA accumulates charge with additional binding events and an effect consistent with allostery, where hybridization at certain sites on an SNA modify the binding affinity at a distal site through conformational changes to the remaining single strands. Leveraging these insights allows for the design of conjugates that hybridize free strands with significantly higher efficiencies, some of which approach 100%. PMID- 25738969 TI - Afzelin attenuates asthma phenotypes by downregulation of GATA3 in a murine model of asthma. AB - Asthma is a serious health problem causing significant mortality and morbidity globally. Persistent airway inflammation, airway hyperresponsiveness, increased immunoglobulin E (IgE) levels and mucus hypersecretion are key characteristics of the condition. Asthma is mediated via a dominant T-helper 2 (Th2) immune response, causing enhanced expression of Th2 cytokines. These cytokines are responsible for the various pathological changes associated with allergic asthma. To investigate the anti-asthmatic potential of afzelin, as well as the underlying mechanisms involved, its anti-asthmatic potential were investigated in a murine model of asthma. In the present study, BALB/c mice were systemically sensitized using ovalbumin (OVA) followed by aerosol allergen challenges. The effect of afzelin on airway hyperresponsiveness, eosinophilic infiltration, Th2 cytokine and OVA-specific IgE production in a mouse model of asthma were investigated. It was found that afzelin-treated groups suppressed eosinophil infiltration, allergic airway inflammation, airway hyperresponsiveness, OVA-specific IgE and Th2 cytokine secretion. The results of the present study suggested that the therapeutic mechanism by which afzelin effectively treats asthma is based on reduction of Th2 cytokine via inhibition of GATA-binding protein 3 transcription factor, which is the master regulator of Th2 cytokine differentiation and production. PMID- 25738971 TI - Antiproliferative effects of anastrozole on MCF-7 human breast cancer cells in vitro are significantly enhanced by combined treatment with testosterone undecanoate. AB - The present study aimed to assess the effects of aromatase inhibitor anastrozole and testosterone undecanoate, separately and in combination, on proliferation and apoptosis in MCF-7 human breast cancer cells cultured in vitro. The effects of various concentrations of these drugs on the proliferation of MCF-7 cells were evaluated by CCK8 assay, the levels of cell apoptosis were evaluated by flow cytometry with Annexin-V/propidium iodide staining and androgen receptor (AR) protein expression was determined by western blot analysis. The results of the CCK8 assay indicated that greater antiproliferative activity was detected in the MCF-7 cells in the combined treatment groups, compared with those treated with anastrozole or testosterone undecanoate alone. Flow cytometric analysis of apoptosis revealed that treatment with a combination of the two drugs generated a higher percentage of apoptotic cells, particularly when the two drugs were applied for 48 h, compared with single drug treatment. Western blot analysis revealed a significant decrease in AR protein expression in the combined treatment groups compared with MCF7 cells treated with single drugs. The results of the present study provided evidence supporting the potential of a combination of anastrozole and testosterone undecanoate as a novel therapeutic strategy for the treatment of breast cancer. Furthermore, it was demonstrated that the antiproliferative effects of anastrozole were significantly enhanced by combined treatment with testosterone undecanoate via the AR signaling pathway. PMID- 25738970 TI - The value of signs, symptoms and plasma heart-type fatty acid-binding protein (H FABP) in evaluating patients presenting with symptoms possibly matching acute coronary syndrome: background and methods of a diagnostic study in primary care. AB - BACKGROUND: Chest complaints presented to a general practitioner (GP) are frequently caused by diseases which have advantageous outcomes. However, in some cases, acute coronary syndrome (ACS) is present (1.5-22% of cases). The patient's signs, symptoms and electrocardiography results are insufficient diagnostic tools to distinguish mild disease from ACS. Therefore, most patients presenting chest complaints are referred to secondary care facilities where ACS is then ruled out in a majority of patients (78%). Recently, a point of care test for heart-type fatty acid-binding protein (H-FABP) using a low cut-off value between positive and negative of 4 ng/ml has become available. We aim to study the role of this point of care device in triage of patients presenting chest complaints possibly due to ACS, in primary care. Our research protocol is presented in this article. Results are expected in 2015. METHODS/DESIGN: Participating GPs will register signs and symptoms in all patients presenting chest complaints possibly due to ACS. Point of care H-FABP testing will also be performed. Our study will be a derivation study to identify signs and symptoms that, combined with point of care H-FABP testing, can be part of an algorithm to either confirm or rule out ACS. The diagnostic value for ACS of this algorithm in general practice will be determined. DISCUSSION: A safe diagnostic elimination of ACS by application of the algorithm can be of significant clinical relevance. Improved triage and thus reduction of the number of patients with chest complaints without underlying ACS, that are referred to secondary care facilities, could lead to a substantial cost reduction. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01826994, accepted April 8th 2013. PMID- 25738972 TI - Mobile phone radiation causes brain tumors and should be classified as a probable human carcinogen (2A) (review). AB - Quickly changing technologies and intensive uses of radiofrequency electromagnetic field (RF-EMF)-emitting phones pose a challenge to public health. Mobile phone users and uses and exposures to other wireless transmitting devices (WTDs) have increased in the past few years. We consider that CERENAT, a French national study, provides an important addition to the literature evaluating the use of mobile phones and risk of brain tumors. The CERENAT finding of increased risk of glioma is consistent with studies that evaluated use of mobile phones for a decade or longer and corroborate those that have shown a risk of meningioma from mobile phone use. In CERENAT, exposure to RF-EMF from digitally enhanced cordless telephones (DECTs), used by over half the population of France during the period of this study, was not evaluated. If exposures to DECT phones could have been taken into account, the risks of glioma from mobile phone use in CERENAT are likely to be higher than published. We conclude that radiofrequency fields should be classified as a Group 2A probable human carcinogen under the criteria used by the International Agency for Research on Cancer (Lyon, France). Additional data should be gathered on exposures to mobile and cordless phones, other WTDs, mobile phone base stations and Wi-Fi routers to evaluate their impact on public health. We advise that the as low as reasonable achievable (ALARA) principle be adopted for uses of this technology, while a major cross disciplinary effort is generated to train researchers in bioelectromagnetics and provide monitoring of potential health impacts of RF-EMF. PMID- 25738973 TI - Macroscopic, freestanding, and tubular graphene architectures fabricated via thermal annealing. AB - Manipulation of individual graphene sheets/films into specific architectures at macroscopic scales is crucially important for practical uses of graphene. We present herein a versatile and robust method based on annealing of solid carbon precursors on nickel templates and thermo-assisted removal of poly(methyl methacrylate) under low vacuum of ~0.6 Pa for fabrication of macroscopic, freestanding, and tubular graphene (TG) architectures. Specifically, the TG architectures can be obtained as individual and woven tubes with a diameter of ~50 MUm, a wall thickness in the range of 2.1-2.9 nm, a density of ~1.53 mg.cm( 3), a thermal stability up to 600 degrees C in air, an electrical conductivity of ~1.48 * 10(6) S.m(-1), and field emission current densities on the order of 10(4) A.cm(-2) at low applied electrical fields of 0.6-0.7 V.MUm(-1). These properties show great promise for applications in flexible and lightweight electronics, electron guns, or X-ray tube sources. PMID- 25738974 TI - Comparison of hIGF-1 gene transfection to the hBMSCs and human meniscal fibrochondrocytes. AB - BACKGROUND: Treatment strategies for meniscal injury are shifting from meniscectomy to repair, especially cell-based therapy. Delivering selected genes to donor cells can modify differentiation and proliferation. Efficiency of gene transfection and expression may relate to cell type. MATERIAL AND METHODS: Full length hIGF-1 cDNA was cloned into eukaryotic expression vector by PCR. Human BMSCs and meniscal fibrochondrocytes were isolated and cultured in vitro and hIGF 1 gene was transfected by FuGene 6. Expression of EGFP and hIGF-1 were determined. Biological activity of the hIGF-1 in medium was assessed by MTT chromatometry. Real-time quantitative PCR and Western blot were used to assess the expression of exogenous genes. Efficacy of gene transfection was detected by immunohistochemistry staining and flow cytometry. RESULTS: Sequences of hIGF-1 were verified by sequence analysis. Expression of EGFP increased gradually and reached peak intensity 48 h after transfection. Transfection efficiency of BMSCs was higher than meniscal fibrochondrocytes. The population doubling time was decreased in both cell types. Peak concentration of hIGF-1 in the medium of BMSCs and meniscal cells was 32.5+/-4.8 ng/ml and 24.5+/-4.6 ng/ml, respectively. Secreted hIGF-1 possessed the ability to enhance proliferation of the cell line. Results of qPCR and Western blot confirmed the expression of hIGF-1. Type II collagen appeared within the cells, and percentage of cells in S stage was increased in both cell types after transfection. CONCLUSIONS: hIGF-1 cDNA can be transfected into BMSCs and meniscal fibrochondrocytes, resulting in gene expression. Expression efficiency in BMSCs was higher than that in fibrochondrocytes. PMID- 25738975 TI - Associations between Muscle Strength Asymmetry and Impairments in Gait and Posture in Young Brain-Injured Patients. AB - Traumatic brain injury (TBI) can lead to deficits in gait and posture, which are often asymmetric. A possible factor mediating these deficits may be asymmetry in strength of the leg muscles. However, muscle strength in the lower extremities has rarely been investigated in (young) TBI patients. Here, we investigated associations between lower-extremity muscle weakness, strength asymmetry, and impairments in gait and posture in young TBI patients. A group of young patients with moderate-to-severe TBI (n=19; age, 14 years 11 months +/-2 years) and a group of typically developing subjects (n=31; age, 14 years 1 month+/-3 years) participated in this study. A force platform was used to measure postural sway to quantify balance control during normal standing and during conditions of compromised visual and/or somatosensory feedback. Spatiotemporal gait parameters were assessed during comfortable and fast-speed walking, using an electronic walkway. Muscle strength in four lower-extremity muscle groups was measured bilaterally using a handheld dynamometer. Findings revealed that TBI patients had poorer postural balance scores across all sensory conditions, as compared to typically developing subjects. During comfortable and fast gait, TBI patients demonstrated a lower gait velocity, longer double-support phase, and increased step-length asymmetry. Further, TBI patients had a reduced strength of leg muscles and an increased strength asymmetry. Correlation analyses revealed that asymmetry in muscle strength was predictive of a poorer balance control and a more variable and asymmetric gait. To the best of our knowledge, this is the first study to measure strength asymmetry in leg muscles of a sample of TBI patients and illustrate the importance of muscular asymmetry as a potential marker and possible risk factor of impairments in control of posture and gait. PMID- 25738976 TI - Anti-inflammatory effects of methanol extract of Canarium lyi C.D. Dai & Yakovlev in RAW 264.7 macrophages and a murine model of lipopolysaccharide-induced lung injury. AB - Canarium lyi C.D. Dai & Yakovlev (CL) is a member of the Anacardiaceae family. To the best of our knowledge, no studies on its anti-inflammatory effects have yet been reported. In the present study, we investigated the protective effects of CL on inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and LPS induced acute lung injury (ALI) mice. CL attenuated the production of LPS stimulated inflammatory mediators such as tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-1beta, and interleukin-6 (IL-6). Furthermore, CL suppressed phosphorylation of the inhibitor kappaB-alpha (IkappaB-alpha), p38, c Jun terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), as well as the translocation of the nuclear factor-kappaB (NF-kappaB) p65 subunit into the nucleus. For the in vivo efficacy, the effect of CL on a mouse model of LPS-induced acute lung injury was assessed. CL treatment of the mice significantly inhibited the inflammatory cell recruitment and pro-inflammatory cytokine production in bronchoalveolar lavage fluids (BALF). CL-treated mice also showed a marked inhibition of cyclooxygenase-2 (COX-2) and phosphorylation of IkappaB and p65. In addition, CL attenuated lung histopathological changes in LPS induced ALI mice. In conclusion, our results suggest that CL is a potential therapeutic candidate for the treatment of inflammatory diseases, including pneumonia. PMID- 25738977 TI - Buffer-induced swelling and vesicle budding in binary lipid mixtures of dioleoylphosphatidylcholine:dioleoylphosphatidylethanolamine and dioleoylphosphatidylcholine:lysophosphatidylcholine using small-angle X-ray scattering and 31P static NMR. AB - A large variety of data exists on lipid phase behavior; however, it is mostly in nonbuffered systems over nonbiological temperature ranges. We present biophysical data on lipid mixtures of dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), and lysophosphatidylcholine (LysoPC) examining their behaviors in excess water and buffer systems over the temperature range 4-34 degrees C. These mixtures are commonly used to investigate the effects of spontaneous curvature on integral membrane proteins. Using small-angle X-ray scattering (SAXS) and (31)P NMR, we observed lamellar and vesicle phases, with the buffer causing an increase in the layer spacing. Increasing amounts of DOPE in a DOPC bilayer decreased the layer spacing of the mesophase, while the opposite trend was observed for increasing amounts of LysoPC. (31)P static NMR was used to analyze the DOPC:LysoPC samples to investigate the vesicle sizes present, with evidence of vesicle budding observed at LysoPC concentrations above 30 mol %. NMR line shapes were fitted using an adapted program accounting for the distortion of the lipids within the magnetic field. The distortion of the vesicle, because of magnetic susceptibility, varied with LysoPC content, and a discontinuity was found in both the water and buffer samples. Generally, the distortion increased with LysoPC content; however, at a ratio of DOPC:LysoPC 60:40, the sample showed a level of distortion of the vesicle similar to that of pure DOPC. This implies an increased flexibility in the membrane at this point. Commonly, the assumption is that for increasing LysoPC concentration there is a reduction in membrane tension, implying that estimations of membrane tension based on spontaneous curvature assumptions may not be accurate. PMID- 25738978 TI - Sensory integration and response to balance perturbation in overweight physically active individuals. AB - The purpose of this study was to compare sensory integration and response to balance perturbation between physically active normal weight and overweight adults. Physically active young adults were grouped into normal weight (n = 45) or overweight (n = 17) according to the World Health Organization body mass index classification for Asian adults. Participants underwent two balance tests: sensory organization and motor control. Overweight participants presented marginally lower somatosensory score compared to normal weight participants. However, they scored significantly higher in response to balance perturbation. There was no difference in the onset of participants' active response to balance perturbation. Physical activity might have contributed to improved muscle strength and improved the ability of overweight individuals to maintain balance. PMID- 25738980 TI - Are the Multidimensional Body Self-Relations Questionnaire Scales stable or transient? AB - Body image is an important concept when assessing mental health and, thus, a target for intervention work. The common approach to assess body image is via self-report and, consequently, it is important to assess stability and susceptibility of items to random change. Participants (N = 99, aged: 18-30 years) completed the 34-item Multidimensional Body Self-Relations Questionnaire Appearance Scales (MBSRQ-AS) twice, separated by two weeks. Stability was quantified by calculating the test-retest differences for each item, with a stable item showing 90% of respondents' differences within a criterion of <=+/-1. This method was used in preference to correlation, which is a test of association rather than agreement. Analyses identified 29 stable items. Five items were found to be unstable including the entire "Appearance Evaluation" scale. One particular unstable question, Q9 = "Most people would consider me good-looking", revealed strong associations with both gender and weight status. Forty-four per cent of "overweight" respondents changed their minds by more than +/-1 compared with only 10% of "normal-weight" participants, suggesting that being overweight is associated with uncertainty and instability. We suggest that future research is needed to investigate why such factors as being overweight appear to be linked to instability in self-report measures of body image. PMID- 25738979 TI - Engineering enhanced protein disaggregases for neurodegenerative disease. AB - Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious alpha-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones. PMID- 25738981 TI - Trends in incident hemodialysis access and mortality. AB - IMPORTANCE: Based on evidence of survival benefit when initiating hemodialysis (HD) via arteriovenous fistula (AVF) or arteriovenous graft (AVG) vs hemodialysis catheter (HC), the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative published practice guidelines in 1997 recommending 50% or greater AVF rates in incident HD patients. A decade after, lapses exist and the impact on HD outcomes is uncertain. OBJECTIVE: To assess the achievement of the practice goals for incident vascular access and the effects on HD outcomes. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted using the US Renal Data System. All patients with end-stage renal disease in the United States without prior renal replacement therapy who had incident vascular access for HD created between January 1, 2006, and December 31, 2010 (N = 510 000) were included. MAIN OUTCOMES AND MEASURES: Incident vascular access use rates and mortality. Relative mortality was quantified using multivariable Cox proportional hazard models. Coarsened exact matching and propensity score-matching techniques were used to better account for confounding by indication. RESULTS: Of 510 000 patients included in this study, 82.6% initiated HD via HC, 14.0% via AVF, and 3.4% via AVG. Arteriovenous fistula use increased only minimally, from 12.2% in 2006 to 15.0% in 2010. Patients initiating HD with AVF had 35% lower mortality than those with HC (adjusted hazard ratio, 0.65; 95% CI, 0.64-0.66; P < .001). Those initiating HD with AVF had 23% lower mortality than those initiating with an HC while awaiting maturation of an AVF (adjusted hazard ratio, 0.77; 95% CI, 0.76-0.79; P < .001). CONCLUSIONS AND RELEVANCE: Current incident AVF practice falls exceedingly short years after recommendations were made in 1997. The impact of this shortcoming on mortality for patients with end-stage renal disease is enormous. Functioning permanent access at initiation of HD confers lower mortality even compared with patients temporized with an HC while awaiting maturation of permanent access. A change of current policies and structured multidisciplinary efforts are required to establish matured fistulae prior to HD to ameliorate this deficit in delivering care. PMID- 25738982 TI - Investigation into the mechanism and microstructure of reaction intermediates in the two-phase synthesis of alkanethiol-capped silver nanoparticles. AB - To gain better control over the characteristics of the alkanethiol-capped silver nanoparticles (SNP) prepared by the two-phase method, the intermediate stage of this reaction and the structure of the precursor compound were investigated. Samples taken from the intermediate stage of the reaction were analyzed by NMR and vibrational spectroscopy both in solution and after solvent removal. The (1)H NMR chemical shifts of the complexes formed during the phase-transfer step were used to detect any structural changes that occur upon introduction of nonanethiol. Moreover, the presence of silver thiolate was monitored by comparing the FTIR and Raman spectra of silver nonanethiolate with the dried samples. Further insights into the microstructure of the intermediate compounds were sought by characterizing samples differing in molar ratios of tetraoctylammonium bromide (TOAB) to silver nitrate (AgNO3). (13)C solid-state NMR chemical shifts, (13)C relaxation times, and the DSC transitions of these samples revealed a dependence of their phase structure on the initial concentration of the reagents. At least two phases with distinct mobility and conformational ordering of their octyl chains were identified in the samples prepared with excess TOAB, which was associated with the presence of multiple anionic species. The observations regarding the composition of the phase-transfer product were further related to the quality of the resulting nanoparticles. It was demonstrated that a large excess of TOAB, which is commonly used in two-phase methods, can be avoided without compromising the size and dispersity of the silver nanoparticles produced. This modification to the synthetic procedure simplifies the purification of the product, mitigates the propensity of the nanoparticles for aggregation, and facilitates their redispersion. PMID- 25738983 TI - Recurrent invasive pneumococcal disease in children: underlying clinical conditions, and immunological and microbiological characteristics. AB - PURPOSE: Clinical, immunological and microbiological characteristics of recurrent invasive pneumococcal disease (IPD) in children were evaluated, differentiating relapse from reinfection, in order to identify specific risk factors for both conditions. METHODS: All patients <18 years-old with recurrent IPD admitted to a tertiary-care pediatric center from January 2004 to December 2011 were evaluated. An episode of IPD was defined as the presence of clinical findings of infection together with isolation and/or pneumococcal DNA detection by Real-Time PCR in any sterile body fluid. Recurrent IPD was defined as 2 or more episodes in the same individual at least 1 month apart. Among recurrent IPD, we differentiated relapse (same pneumococcal isolate) from reinfection. RESULTS: 593 patients were diagnosed with IPD and 10 patients died. Among survivors, 23 episodes of recurrent IPD were identified in 10 patients (1.7%). Meningitis was the most frequent form of recurrent IPD (10 episodes/4 children) followed by recurrent empyema (8 episodes/4 children). Three patients with recurrent empyema caused by the same pneumococcal clone ST306 were considered relapses and showed high bacterial load in their first episode. In contrast, all other episodes of recurrent IPD were considered reinfections. Overall, the rate of relapse of IPD was 0.5% and the rate of reinfection 1.2%. Five out of 7 patients with reinfection had an underlying risk factor: cerebrospinal fluid leak (n = 3), chemotherapy treatment (n = 1) and a homozygous mutation in MyD88 gene (n = 1). No predisposing risk factors were found in the remainder. CONCLUSIONS: recurrent IPD in children is a rare condition associated with an identifiable risk factor in case of reinfection in almost 80% of cases. In contrast, recurrent IPD with pleuropneumonia is usually a relapse of infection. PMID- 25738985 TI - Tetrahedral DNA nanostructure-based microRNA biosensor coupled with catalytic recycling of the analyte. AB - MicroRNAs are not only important regulators of a wide range of cellular processes but are also identified as promising disease biomarkers. Due to the low contents in serum, microRNAs are always difficult to detect accurately . In this study, an electrochemical biosensor for ultrasensitive detection of microRNA based on tetrahedral DNA nanostructure is developed. Four DNA single strands are engineered to form a tetrahedral nanostructure with a pendant stem-loop and modified on a gold electrode surface, which largely enhances the molecular recognition efficiency. Moreover, taking advantage of strand displacement polymerization, catalytic recycling of microRNA, and silver nanoparticle-based solid-state Ag/AgCl reaction, the proposed biosensor exhibits high sensitivity with the limit of detection down to 0.4 fM. This biosensor shows great clinical value and may have practical utility in early diagnosis and prognosis of certain diseases. PMID- 25738986 TI - Basic fibroblast growth factor lentiviral vector-transfected sheep bone marrow mesenchymal stem cells and non-specific osteogenic gene expression. AB - In the present study, sheep bone marrow stem cells (BMSCs) were transfected with basic fibroblast growth factor (bFGF)-lentivirus in order to investigate the influence of bFGF on osteogenic gene expression. bFGF-transfected BMSCs (experimental group) and non-transfected BMSCs (control group) were also transfected with a green fluorescent protein gene in order to measure the transfection efficiency of the (bFGF)-lentivirus using flow cytometry. Using quantitative polymerase chain reaction assays, the changes in expression from three genes (osteopontin, OPN; osteocalcin, OC; and collagen-I) in BMSCs from the experimental and control groups were measured. Transfection efficiency was 87.3% in the experimental group and 1.1% in the control group. OPN gene expression was high in BMSCs from the experimental group. However, there was no significant difference in OPN expression between BMSCs from the control and experimental group (P>0.05). Collagen-I expression was significantly lower in the experimental group compared with that in the control groups (P<0.05). By contrast, OC expression was significantly higher in BMSCs from the experimental group compared with that in the control group (P<0.05). Changes in osteogenic gene expression indicated that the BMSCs from the experimental group had better osteogenic ability, as compared with the control cells. Therefore, bFGF-transfected cells may be useful seed cells for bone tissue engineering. PMID- 25738987 TI - Migration of Cosmetic Products into the Tear Film. AB - PURPOSE: To examine, record, and quantify the migration of a conventional eye cosmetic pencil when applied to periocular skin in two different locations: behind the lash line (ELI) and along the periocular skin (ELO). METHODS: This was a pilot study (prospective, randomized crossover design) involving two visits on separate days. Three female subjects were randomly assigned one of two eyeliner application conditions: ELI (inside the lash line) or ELO (anterior to the lash line). Pencil eyeliner ("Glimmerstick" in Graphite; Avon, Northampton, United Kingdom) was applied to the subject's upper and lower right eyelid by the examiner. Slitlamp video recording of glitter particles suspended within the tear film was conducted for 30 sec on 10 occasions up to 2 hr post-eyeliner application. The number of glitter particles suspended in the tear film, analyzed using ImageJ software, is reported. RESULTS: The migration of the glitter particles occurred more readily in ELI application, with maximum contamination of the tear film achieved 5 to 10 min post-application. The migration of eyeliner following ELO application was comparatively slower and reduced compared with ELI application. The quantity of glitter particles suspended in the tear film varied between subjects; however, 2 hr post-application, contamination of the tear film from pencil eyeliner was negligible. CONCLUSIONS: Pencil eyeliner migrates most readily and maximally contaminates the tear film when applied posterior to the lash line. This has implications for contact lens wearers and patients with dry eye syndrome or sensitive eyes. Eye cosmetic usage for participants involved in anterior eye and contact lens research should be carefully considered in the design of studies. PMID- 25738988 TI - Strategies to Regulate Myopia Progression With Contact Lenses: A Review. AB - PURPOSE: Higher myopic refractive errors are associated with serious ocular complications that can put visual function at risk. There is respective interest in slowing and if possible stopping myopia progression before it reaches a level associated with increased risk of secondary pathology. The purpose of this report was to review our understanding of the rationale(s) and success of contact lenses (CLs) used to reduce myopia progression. METHODS: A review commenced by searching the PubMed database. The inclusion criteria stipulated publications of clinical trials evaluating the efficacy of CLs in regulating myopia progression based on the primary endpoint of changes in axial length measurements and published in peer-reviewed journals. Other publications from conference proceedings or patents were exceptionally considered when no peer-review articles were available. RESULTS: The mechanisms that presently support myopia regulation with CLs are based on the change of relative peripheral defocus and changing the foveal image quality signal to potentially interfere with the accommodative system. Ten clinical trials addressing myopia regulation with CLs were reviewed, including corneal refractive therapy (orthokeratology), peripheral gradient lenses, and bifocal (dual-focus) and multifocal lenses. CONCLUSIONS: CLs were reported to be well accepted, consistent, and safe methods to address myopia regulation in children. Corneal refractive therapy (orthokeratology) is so far the method with the largest demonstrated efficacy in myopia regulation across different ethnic groups. However, factors such as patient convenience, the degree of initial myopia, and non-CL treatments may also be considered. The combination of different strategies (i.e., central defocus, peripheral defocus, spectral filters, pharmaceutical delivery, and active lens-borne illumination) in a single device will present further testable hypotheses exploring how different mechanisms can reinforce or compete with each other to improve or reduce myopia regulation with CLs. PMID- 25738989 TI - A predictive in vitro model of the impact of drugs with anticholinergic properties on human neuronal and astrocytic systems. AB - The link between off-target anticholinergic effects of medications and acute cognitive impairment in older adults requires urgent investigation. We aimed to determine whether a relevant in vitro model may aid the identification of anticholinergic responses to drugs and the prediction of anticholinergic risk during polypharmacy. In this preliminary study we employed a co-culture of human derived neurons and astrocytes (NT2.N/A) derived from the NT2 cell line. NT2.N/A cells possess much of the functionality of mature neurons and astrocytes, key cholinergic phenotypic markers and muscarinic acetylcholine receptors (mAChRs). The cholinergic response of NT2 astrocytes to the mAChR agonist oxotremorine was examined using the fluorescent dye fluo-4 to quantitate increases in intracellular calcium [Ca2+]i. Inhibition of this response by drugs classified as severe (dicycloverine, amitriptyline), moderate (cyclobenzaprine) and possible (cimetidine) on the Anticholinergic Cognitive Burden (ACB) scale, was examined after exposure to individual and pairs of compounds. Individually, dicycloverine had the most significant effect regarding inhibition of the astrocytic cholinergic response to oxotremorine, followed by amitriptyline then cyclobenzaprine and cimetidine, in agreement with the ACB scale. In combination, dicycloverine with cyclobenzaprine had the most significant effect, followed by dicycloverine with amitriptyline. The order of potency of the drugs in combination frequently disagreed with predicted ACB scores derived from summation of the individual drug scores, suggesting current scales may underestimate the effect of polypharmacy. Overall, this NT2.N/A model may be appropriate for further investigation of adverse anticholinergic effects of multiple medications, in order to inform clinical choices of suitable drug use in the elderly. PMID- 25738990 TI - Effective photothermal chemotherapy with docetaxel-loaded gold nanospheres in advanced prostate cancer. AB - BACKGROUND: Multifunctional gold nanospheres (MGNs)-loaded with docetaxel (MGN@DTX) were prepared and evaluated for therapeutic efficacy in nude mice bearing human prostate cancer xenografts. METHODS: MGNs were prepared from PEGylated hollow gold nanospheres (HGNs) coated with folic acid and DTPTT chelate. Then, the effect of radiolabelled MGNs ((99m)Tc-MGNs) on PC-3 cell apoptosis was assessed by flow cytometry, while their binding affinity to these cells was evaluated by cell binding assays. Next, biodistribution of (99m)Tc-MGNs in xenograft bearing mice was measured by SPECT imaging. Also, DTX loading and release rates were estimated in MGN@DTX. Finally, in vitro stability in human serum and cytotoxicity of MGN@DTX were assessed, as well as their antitumor effect in xenograft bearing mice. RESULTS: (99m)Tc-MGNs (97.69% purity) showed good binding affinity to PC-3 cells, a specific recognition blocked by excess folic acid. Interestingly, MGN@DTX remained stable in human serum for 24 h, and exhibited higher mean cytotoxicity after NIR laser irradiation than free DTX. By day 28, tumor inhibition rates were higher in the MGN@DTX + NIR laser irradiation group compared with the DTX and MGNs + NIR laser irradiation groups. CONCLUSIONS: Loading chemotherapeutic drugs into MGNs can increase antitumor potency, reduce normal cell damage and decrease drug resistance, thus representing a promising approach for advanced prostate cancer treatment. PMID- 25738991 TI - Polybutylcyanoacrylate nanocarriers as promising targeted drug delivery systems. AB - Among the materials for preparing the polymeric nanocarriers, poly(n butylcyanoacrylate) (PBCA), a polymer with medium length alkyl side chain, is of lower toxicity and proper degradation time. Therefore, PBCA has recently been regarded as a kind of widely used, biocompatible, biodegradable, low-toxic drug carrier. This review highlights the use of PBCA-based nanocarriers (PBCA-NCs) as targeting drug delivery systems and presents the methods of preparation, the surface modification and the advantages and limitations of PBCA-NCs. The drugs loaded in PBCA-NCs are summarized according to the treatment of diseases, and the different therapeutic applications and the most recent developments of PBCA-NCs are also discussed, which provides useful guidance on the targeting research of PBCA-NCs. PMID- 25738992 TI - Aprotinin revisited: formulation, characterization, biodistribution and therapeutic potential of new aprotinin microemulsion in acute pancreatitis. AB - The aim of this study was to develop aprotinin-loaded microemulsion (MA) for intravenous administration and evaluate the biodistribution and therapeutic potential of developed formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify microemulsion region and the optimal microemulsion was evaluated for physicochemical properties and treatment effect in rats, and comparisons made with the solution of aprotinin (SA). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was radiolabeled with (99m)Tc radionuclide. Mild and severe acute pancreatitis was induced in rats by subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue myeloperoxidase activities were measured to evaluate the pancreatic damage. According to gamma scintigraphy and biodistribution studies, accumulation times and distribution of (99m)Tc-MA and SA were different. While MA was highly uptake by reticuloendothelial system, SA was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis group, treatment with MA significantly decreased the serum amylase activity and pancreas myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has therapeutic potential in acute pancreatitis. Finally, MA may be suggested as a promising alternative for treatment of acute pancreatitis. PMID- 25738993 TI - Antibacterial alkaloids from Artabotrys crassifolius Hook.f. & Thomson. AB - Chloroform extract of bark of Artabotrys crassifolius Hook.f. & Thomson exhibited antibacterial activities against both American Type Culture Collection and clinical bacterial strains in vitro with zones of inhibition ranging from 7 to 14 mm. Further analysis of this extract yielded artabotrine, liridine, lysicamine and atherospermidine. Artabotrine displayed a broad array of antibacterial activity mostly against Gram-positive bacteria with minimum inhibitory concentration (MIC) values ranging from 1.25 MUg/mL to 5 MUg/mL. Of note, artabotrine, liridine and lysicamine are bactericidal against Gram-negative extended-spectrum beta-lactamase-producing Klebsiella with MIC values equal 2.5, 2.5 and 10 MUg/mL, respectively, and minimum bactericidal concentrations values equal to 2.5, 5 and 20 MUg/mL. PMID- 25738994 TI - Two Novel Mutations in the Thyroid Hormone Receptor beta in Patients with Resistance to Thyroid Hormone (RTH beta): Clinical, Biochemical, and Molecular Data. AB - The syndrome of resistance to thyroid hormone (RTH beta) is an inherited disorder characterized by variable tissue hyposensitivity to 3,5,30-L-triiodothyronine (T(3)), with persistent elevation of free-circulating T(3) (FT(3)) and free thyroxine (FT(4)) levels in association with nonsuppressed serum thyrotropin (TSH). Clinical presentation is variable and the molecular analysis of THRB gene provides a short cut diagnosis. Here, we describe 2 cases in which RTH beta was suspected on the basis of laboratory findings. The diagnosis was confirmed by direct THRB sequencing that revealed 2 novel mutations: the heterozygous p.Ala317Ser in subject 1 and the heterozygous p.Arg438Pro in subject 2. Both mutations were shown to be deleterious by SIFT, PolyPhen, and Align GV-GD predictive methods. PMID- 25738995 TI - Adrenal Insufficiency in Australia: Is it Possible that the Use of Lower Dose, Short-Acting Glucocorticoids has Increased the Risk of Adrenal Crises? AB - Morbidity from adrenal insufficiency (AI) in Australia is poorly described. The objective of this study was to evaluate AI morbidity patterns in adults between 1999/2000 and 2011/2012 using national databases. A descriptive study of hospitalisations for AI and adrenal crises (AC) in adults and trends in prescriptions for 2 short-acting glucocorticoids (GC) was designed. The setting was the Australian healthcare system. Main outcome measures are the trends in hospitalisation and prescription rates. There were 7,378 hospital admissions for treatment of AI in adults between 1999/00 and 2011/12. Of these, 29.5% were for an AC. Admission rates for AC increased from 9.5 to 12.4 admissions/10(6)/year (p < 0.05). There was a 5.8% decrease in admission rates for AI (excluding AC), from 27.0 to 25.5/10(6)/year (p = ns). Short-acting GC [hydrocortisone (HCT) and cortisone acetate (CA)] prescription rates increased significantly (p < 0.001) from 3,176.1/10(6) to 3,463.8/10(6). Prescription rates for CA decreased by 22.4% (p < 0.001) but HCT prescription rates increased to 77.1% (p < 0.001). The increase in AC admission rates was positively correlated with the rise in both the total GC prescription rate (r = 0.63, p < 0.05) and the HCT prescription rate (r = 0.74, p< 0.01). Over the 13-year study period, there was a 30.8% increase in hospitalisation rates for ACs and a concomitant 77.1% increase in prescribing of HCT. The association between AC events and HCT use and/or reduced effective GC dose is plausibly causal, but confirmatory studies are required before suggesting any change to GC replacement in AI. PMID- 25738996 TI - Expression Profile of Human Fc Receptor-Like 1, 2, and 4 Molecules in Peripheral Blood Mononuclear Cells of Patients with Hashimoto's Thyroiditis and Graves' Disease. AB - Recently identified Fc receptor-like (FCRL) molecules are new members of the immunoglobulin superfamily dominantly expressed by B cells. Although FCRL expression patterns have been studied in normal and malignant cells, their biological functions and roles remain to be clearly identified in humans. Research has particularly focused on FCRL gene polymorphisms in autoimmune diseases, however, their involvement in the pathogenesis of autoimmune diseases is an interesting field for investigation. In the present study, we have investigated the gene expression profiles of FCRL1, 2, and 4 in 2 common thyroid diseases, Hashimoto's thyroiditis (HT) and Graves' disease (GD). FCRL1, 2, and 4 expressions were determined in peripheral blood samples of 55 HT patients, 40 GD patients and equal numbers of normal subjects by quantitative real-time PCR. Our results showed downregulation of FCRL1 and upregulation of FCRL2 transcripts in both HT and GD groups compared to healthy counterparts. Overexpression of FCRL4 was observed only in GD patients compared to controls. A significant correlation was observed between all FCRL gene expression levels in HT patients. Only FCRL2 and 4 had a correlation in GD patients. In addition, FCRL1, 2, and 4 gene expressions showed no correlations with the level of anti-thyroid peroxidase antibody (anti-TPO) or anti-thyroglobulin (anti-Tg) antibody from patients' sera. In conclusion, expressions of activating or inhibitory FCRL1, 2, and 4 showed significant alterations in HT and GD patients compared to healthy subjects. PMID- 25738997 TI - Psychosocial Factors in Disorders of Sex Development in a Long-Term Perspective: What Clinical Opportunities are there to Intervene? AB - Disorders or differences in sex development (DSD) comprise a wide spectrum of severity. The overall goal for the treatment and care is good quality of life but current knowledge concerning the psychosocial situation and health related quality of life for patients with different forms of DSD is limited. Follow-up studies have often focused on surgical results, sexual function, and psychosexual outcome and indicated unsatisfactory results in many cases. Epidemiological studies show less than optimal psychosocial situation for some of the diagnostic groups. Studies indicate that access to psychological support and understandable information is important for the outcome. Hormonal and surgical treatments are improving and new and better ways to strengthen the patient's ability to cope with the situation are needed. In a well-functioning multidisciplinary team, the patient's and family's needs should be identified. Tools to accomplish this can be developed. The care and our knowledge about disorders of sex development have developed considerably during the last decade. These are small patient groups with rare conditions that require specialized, highly qualified care in all aspects: medical, surgical, and psychological. It is important that changes in treatment practice are continuously evaluated. PMID- 25738998 TI - High level of CFTR expression is associated with tumor aggression and knockdown of CFTR suppresses proliferation of ovarian cancer in vitro and in vivo. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter family, members of which are involved in various types of cancer. The relationship between CFTR and ovarian cancer remains to be elucidated. The aim of the present study was to investigate the expression of CFTR in human ovarian cancer tissues and its clinical significance in the progression of ovarian cancer. The role of CFTR in the malignant invasion, migration and proliferation of ovarian cancer in vitro and in vivo was also investigated. Immunohistochemical staining analysis was performed to detect the expression of CFTR in 83 cases of human epithelial ovarian cancer specimens. Moreover, SKOV3 and A2780 stable cell lines containing shRNA gene specific for CFTR were established. Cell proliferation and motility were observed and compared with CFTR-RNAi cells. Tumorigenicity of CFTR-RNAi cells was investigated by tumor xenograft experiments conducted subcutaneously in nude mice. The expresssion of CFTR in ovarian cancer was significantly higher than that in benign ovarian tumor and normal ovaries (P<0.05). In ovarian cancer, CFTR expression was significantly associated with advanced FIGO stage, poor histopathological grade and serum Ca 125 (P<0.05). Furthermore, we observed that CFTR staining was stronger in the serous type as compared to the other types (P<0.05). Compared with the negative control, decreased cell invasion, migration, proliferation, adhesion and colony formation were observed in CFTR-RNAi cells in vitro. In vivo, tumorigenic abilities of CFTR-RNAi cells were significantly repressed compared with that of the control groups. CFTR overexpression may play an important role in the development and progression of ovarian cancer. Additionally, the downregulation of CFTR suppresses aggressive malignant biological behaviors of ovarian cancer cells in vitro and in vivo. PMID- 25739000 TI - Overexpression of ANO1/TMEM16A, an arterial Ca2+-activated Cl- channel, contributes to spontaneous hypertension. AB - Calcium-activated chloride channels (CaCCs) have been implicated in hypertension; however, the mechanism underlying their involvement is unknown. The aim of this study was to determine whether the CaCC ANO1 is involved in the pathogenesis of spontaneous hypertension. Arterial ANO1 expression and the effects on blood pressure (BP) of inhibiting ANO1 with an ANO1 inhibitor, T16(Ainh)-A01, and in vivo RNAi, were examined in spontaneously hypertensive rats (SHRs). Knockdown of ANO1 by siRNA prevented hypertensive development, and attenuation of ANO1 channel activity reduced BP in SHRs. Angiotensin II upregulated ANO1 expression in primary cultures of vascular smooth muscle cells (VSMCs). The protein level and activity of cellular ANO1 positively correlated with VSMC proliferation. Our data indicate an important role of increased ANO1 expression and activity in inducing hypertension in SHRs. It may mediate angiotensin II-dependent vascular remodeling. Our results increase the mechanistic understanding of hypertension and suggest ANO1 as a possible therapeutic target for hypertension. PMID- 25739001 TI - The reactivity of 4-hydroxy- and 4-silyloxy-1,5-allenynes with homogeneous gold(I) catalysts. AB - Two new gold(I)-catalyzed cascade reactions of 4-hydroxy- and 4-silyloxy-1,5 allenynes are disclosed, offering access to a variety of mono- and bicyclic, polyunsaturated carbonyl compounds. The diverse reactivity observed for the investigated allenyne system is controlled by the nature of the unsaturated substrate: Allenynes bearing a free hydroxyl group engage in what is likely an oxycyclization/allene-ene carbocyclization cascade, while their silylated analogues are converted through a carbocyclization/pinacol-type rearrangement process. PMID- 25739002 TI - Bullous Lichen Planus of the Nails. PMID- 25738999 TI - Metabolic control of cancer cell stemness: Lessons from iPS cells. AB - The Nobel prized discovery of nuclear reprogramming is swiftly providing mechanistic evidence of a role for metabolism in the generation of cancer stem cells (CSC). Traditionally, the metabolic demands of tumors have been viewed as drivers of the genetic programming detected in cancer tissues. Beyond the energetic requirements of specific cancer cell states, it is increasingly recognized that metabolism per se controls epi-transcriptional networks to dictate cancer cell fate, i.e., metabolism can define CSC. Here I review the CSC related metabolic features found in induced pluripotent stem (iPS) cells to provide an easily understandable framework in which the infrastructure and functioning of cellular metabolism might control the efficiency and kinetics of reprogramming in the re-routing of non-CSC to CSC-like cellular states. I suggest exploring how metabolism-dependent regulation of epigenetics can play a role in directing CSC states beyond conventional energetic demands of stage-specific cancer cell states, opening a new dimension of cancer in which the "physiological state" of CSC might be governed not only by cell-autonomous cues but also by local micro-environmental and systemic metabolo-epigenetic interactions. Forthcoming studies should decipher how specific metabolites integrate and mediate the overlap between the CSC-intrinsic "micro-epigenetics" and the "upstream" local and systemic "macro-epigenetics," thus paving the way for targeted epigenetic regulation of CSCs through metabolic modulation including "smart foods" or systemic "metabolic nichotherapies." PMID- 25739003 TI - Cross-national user priorities for housing provision and accessibility--findings from the European innovAge Project. AB - To develop an innovative information and communication technology (ICT) tool intended to help older people in their search for optimal housing solutions, a first step in the development process is to gain knowledge from the intended users. Thus the aim of this study was to deepen the knowledge about needs and expectations about housing options as expressed and prioritized by older people, people ageing with disabilities and professionals. A participatory design focus was adopted; 26 people with a range of functional limitations representing the user perspective and 15 professionals with a variety of backgrounds, participated in research circles that were conducted in four European countries. An additional 20 experts were invited as guests to the different research circle meetings. Three themes illustrating cross-national user priorities for housing provision and accessibility were identified: "Information barrier: accessible housing", "Information barrier: housing adaptation benefits", and "Cost barrier: housing adaptations". In conclusion, early user involvement and identification of cross national differences in priorities and housing options will strengthen the development of a user-friendly ICT tool that can empower older people and people with disabilities to be more active consumers regarding housing provision. PMID- 25739004 TI - Effect of forest walking on autonomic nervous system activity in middle-aged hypertensive individuals: a pilot study. AB - There has been increasing attention on the therapeutic effects of the forest environment. However, evidence-based research that clarifies the physiological effects of the forest environment on hypertensive individuals is lacking. This study provides scientific evidence suggesting that a brief forest walk affects autonomic nervous system activity in middle-aged hypertensive individuals. Twenty participants (58.0+/-10.6 years) were instructed to walk predetermined courses in forest and urban environments (as control). Course length (17-min walk), walking speed, and energy expenditure were equal between the forest and urban environments to clarify the effects of each environment. Heart rate variability (HRV) and heart rate were used to quantify physiological responses. The modified semantic differential method and Profile of Mood States were used to determine psychological responses. The natural logarithm of the high-frequency component of HRV was significantly higher and heart rate was significantly lower when participants walked in the forest than when they walked in the urban environment. The questionnaire results indicated that, compared with the urban environment, walking in the forest increased "comfortable", "relaxed", "natural" and "vigorous" feelings and decreased "tension-anxiety," "depression," "anxiety hostility," "fatigue" and "confusion". A brief walk in the forest elicited physiological and psychological relaxation effects on middle-aged hypertensive individuals. PMID- 25739005 TI - Validation analysis of a geriatric dehydration screening tool in community dwelling and institutionalized elderly people. AB - Dehydration is common among elderly people. The aim of this study was to perform validation analysis of a geriatric dehydration-screening tool (DST) in the assessment of hydration status in elderly people. This tool was based on the DST proposed by Vivanti et al., which is composed by 11 items (four physical signs of dehydration and seven questions about thirst sensation, pain and mobility), with four questions extra about drinking habits. The resulting questionnaire was evaluated in a convenience sample comprising institutionalized (n=29) and community-dwelling (n=74) elderly people. Urinary parameters were assessed (24-h urine osmolality and volume) and free water reserve (FWR) was calculated. Exploratory factor analysis was used to evaluate the scale's dimensionality and Cronbach's alpha was used to measure the reliability of each subscale. Construct's validity was tested using linear regression to estimate the association between scores in each dimension and urinary parameters. Two factors emerged from factor analysis, which were named "Hydration Score" and "Pain Score", and both subscales showed acceptable reliabilities. The "Hydration Score" was negatively associated with 24-h urine osmolality in community-dwelling; and the "Pain Score" was negatively associated with 24-h urine osmolality, and positively associated with 24-h urine volume and FWR in institutionalized elderly people. PMID- 25739006 TI - Understanding socio-cultural influences on smoking among older Greek-Australian smokers aged 50 and over: facilitators or barriers? A qualitative study. AB - Smokers of all ages can benefit by quitting, but many smokers continue to smoke. Older Greek-Australian smokers, one of the largest ethnic groups in Australia, have higher rates of smoking than other groups of older Australians. This qualitative study aimed to explore older Greek-Australians' views about socio cultural influences on their smoking. A snowball sampling technique was used to identify twenty Greek-Australian smokers (12 males and eight females), aged >=50 years. They were recruited through the Greek Orthodox Community Center of South Australia (GOCSA). Qualitative data were collected using semi-structured face-to face interviews. The audio-taped interviews were translated and transcribed, and then analysed using content analysis. Results suggested that smoking was considered as the "norm" by older Greek-Australian smokers. There were four groups embedded in the participants' social networks that were reported to be important in relation to either encouraging smoking or, smoking abstinence. These support groups included: family members, friends, the Greek community, and physicians. Smokers' family members (brothers) and friends were identified as facilitators of smoking whereas non-smoker family members (children and spouses) were reported as providing barriers to smoking. Different approaches were used by supporter groups to assist smokers to quit smoking-both planned and unplanned. Knowledge, planning of social and cultural supports, and addressing barriers to smoking cessation are a important part of health planning for older Greek Australians. Social norms, including those arising from social interactions, and predisposing traits can influence smoking behaviour. Addressing the specific barriers to smoking cessation of older Greek-Australians is critical to addressing the risk for chronic disease in this group. PMID- 25739007 TI - Temperature variation and heat wave and cold spell impacts on years of life lost among the urban poor population of Nairobi, Kenya. AB - Weather extremes are associated with adverse health outcomes, including mortality. Studies have investigated the mortality risk of temperature in terms of excess mortality, however, this risk estimate may not be appealing to policy makers assessing the benefits expected for any interventions to be adopted. To provide further evidence of the burden of extreme temperatures, we analyzed the effect of temperature on years of life lost (YLL) due to all-cause mortality among the population in two urban informal settlements. YLL was generated based on the life expectancy of the population during the study period by applying a survival analysis approach. Association between daily maximum temperature and YLL was assessed using a distributed lag nonlinear model. In addition, cold spell and heat wave effects, as defined according to different percentiles, were investigated. The exposure-response curve between temperature and YLL was J shaped, with the minimum mortality temperature (MMT) of 26 degrees C. An average temperature of 21 degrees C compared to the MMT was associated with an increase of 27.4 YLL per day (95% CI, 2.7-52.0 years). However, there was no additional effect for extended periods of cold spells, nor did we find significant associations between YLL to heat or heat waves. Overall, increased YLL from all causes were associated with cold spells indicating the need for initiating measure for reducing health burdens. PMID- 25739009 TI - In situ synthesis and high adsorption performance of MoO2/Mo4O11 and MoO2/MoS2 composite nanorods by reduction of MoO3. AB - MoO2/Mo4O11 and MoO2/MoS2 composite nanorods were successfully synthesized by reducing MoO3 nanorods. The adsorption performance of samples was evaluated by using Rhodamine B (RhB) and metal ions in aqueous solutions as the targets. The results indicated that the obtained MoO2/Mo4O11 and MoO2/MoS2 composite nanorods can present excellent adsorption performance. The BET surface areas of samples increased with increasing the MoO3 : S mass ratio. The adsorption kinetics for the RhB and Cu(2+) ions on the composite nanorods were well fitted to a pseudo second order model. PMID- 25739008 TI - Method comparison for enhanced recovery, isolation and qualitative detection of C. jejuni and C. coli from wastewater effluent samples. AB - Seeking a sensitive protocol, culture-dependent methods were compared to detect thermophilic Campylobacter species in untreated urban effluents. We evaluated various combinations of selective media, with and without an enrichment steps, as well as an extra filtration step. Culture-independent real-time quantitative PCR was also included and all detected isolates underwent antimicrobial susceptibility testing. All tested water samples contained Campylobacter DNA, but only 64% were positive after culture. Although enrichment using Preston broth resulted in better recovery of potentially stressed Campylobacter than Bolton or Campyfood broth (CFB), there was no significant increase in efficiency compared to direct plating. The type of selective agar media used, on the other hand, had a significant effect, with CASA plates performing better than mCCDA or CFA ones. Inclusion of an enrichment step increased the ratio of C. coli vs. C. jejuni being isolated. Resistances against all antimicrobials tested were observed in C. coli, but fewer instances of resistance were found in C. jejuni isolates. Whether this difference was the result of selection during the enrichment step could not be determined. The presence of Campylobacter in urban effluents can be considered as a valuable proxy for Campylobacter populations present in urban environments. PMID- 25739010 TI - Optimized effective potential method and application to static RPA correlation. AB - The optimized effective potential (OEP) method is a promising technique for calculating the ground state properties of a system within the density functional theory. However, it is not widely used as its computational cost is rather high and, also, some ambiguity remains in the theoretical framework. In order to overcome these problems, we first introduced a method that accelerates the OEP scheme in a static RPA-level correlation functional. Second, the Krieger-Li Iafrate (KLI) approximation is exploited to solve the OEP equation. Although seemingly too crude, this approximation did not reduce the accuracy of the description of the magnetic transition metals (Fe, Co, and Ni) examined here, the magnetic properties of which are rather sensitive to correlation effects. Finally, we reformulated the OEP method to render it applicable to the direct RPA correlation functional and other, more precise, functionals. Emphasis is placed on the following three points of the discussion: (i) level-crossing at the Fermi surface is taken into account; (ii) eigenvalue variations in a Kohn-Sham functional are correctly treated; and (iii) the resultant OEP equation is different from those reported to date. PMID- 25739011 TI - Total synthesis of (+)-isatisine a: application of a silicon-directed mukaiyama type [3 + 2]-annulation. AB - Complete details of an asymmetric synthesis of (+)-isatisine A (1) are described. The synthesis highlights the use of a highly diastereoselective Mukaiyama-type [3 + 2]-annulation of allylsilane 5 with the unsaturated aldehyde 9a to assemble the functionalized tetrahydrofuran core of isatisine A. A convergent route to the framework of the natural product was established that employed a substrate controlled indole coupling that was followed by a late-stage intramolecular copper(I)-mediated amidation to complete the assembly of the tetracyclic framework of (+)-isatisine A. In addition, the scope of the [3 + 2]-annulation was evaluated and enhanced utilizing diastereomeric allylsilanes anti-5 and syn-5 to establish an efficient route to stereochemically well-defined tetrahydrofurans. PMID- 25739012 TI - DHFR-mediated effects of methotrexate in medulloblastoma and osteosarcoma cells: the same outcome of treatment with different doses in sensitive cell lines. AB - Although methotrexate (MTX) is the most well-known antifolate included in many standard therapeutic regimens, substantial toxicity limits its wider use, particularly in pediatric oncology. Our study focused on a detailed analysis of MTX effects in cell lines derived from two types of pediatric solid tumors: medulloblastoma and osteosarcoma. The main aim of this study was to analyze the effects of treatment with MTX at concentrations comparable to MTX plasma levels in patients treated with high-dose or low-dose MTX. The results showed that treatment with MTX significantly decreased proliferation activity, inhibited the cell cycle at S-phase and induced apoptosis in Daoy and Saos-2 reference cell lines, which were found to be MTX-sensitive. Furthermore, no difference in these effects was observed following treatment with various doses of MTX ranging from 1 to 40 uM. These findings suggest the possibility of achieving the same outcome with the application of low-dose MTX, an extremely important result, particularly for clinical practice. Another important aspect of treatment with high-dose MTX in clinical practice is the administration of leucovorin (LV) as an antidote to reduce MTX toxicity in normal cells. For this reason, the combined application of MTX and LV was also included in our experiments; however, this application of MTX together with LV did not elicit any detectable effect. The expression analysis of genes involved in the mechanisms of resistance to MTX was a final component of our study, and the results helped us to elucidate the mechanisms of the various responses to MTX among the cell lines included in our study. PMID- 25739013 TI - Timing of death in children referred for intensive care with severe sepsis: implications for interventional studies. AB - OBJECTIVE: Early deaths in pediatric sepsis may limit the impact of therapies that can only be provided on PICUs. By introducing selection and survivorship biases, these very early deaths may also undermine the results of trials that employ standard consent procedures. We hypothesized that: 1) the majority of deaths in children with severe sepsis occur very early, within 24 hours of referral to PICU; and 2) a significant proportion of deaths occur before PICU admission. DESIGN, SETTING, AND PATIENTS: We studied consecutive referrals of newborns through to 16 years of age, between 2005 and 2011 to the Children's Acute Transport Service, the North Thames regional pediatric intensive care transport service, with a working diagnosis of "sepsis," "severe sepsis," "meningococcal sepsis," or "septic shock." INTERVENTIONS: The primary outcome measure was the proportion of deaths within 24 hours of referral. Survival distributions of previously healthy children were compared with those with significant comorbidities. MEASUREMENTS AND MAIN RESULTS: Thirteen thousand four hundred and nine referrals were made to Children's Acute Transport Service, of whom 703 (5%) met inclusion criteria. Data on survival to 1 year were available in 627 of 703 patients (89%). One hundred thirty children (130/627; 21%; 95% CI, 18-24%) died in the first year. A higher proportion of children with comorbidity cases (46/85, 54%, 44-64) died compared with previously healthy cases (84/542; 16%; 13-19; p < 0.0005, Fisher exact test). Seventy-one deaths occurred within 24 hours of PICU referral (71/130, 55%, 46-63). The timing of death differed with comorbidity. Similar proportions of children survived to 24 hours (previously healthy children 90% vs children with comorbidity 83%, p = 0.06). However, deaths after 24 hours were infrequent among previously healthy cases (28/84 deaths, 33%, 24-44%) compared with children with comorbidity cases (31/46 deaths, 66%, 53-79%) (p < 0.001, Fisher exact test). CONCLUSIONS: This majority of deaths among children referred for pediatric intensive care with for severe sepsis occur within 24 hours. This has important implications for future clinical trials and quality improvement initiatives aimed at improving sepsis outcomes. PMID- 25739014 TI - A pleiotropic effect of the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p on insulin-like growth factor II, insulin-like growth factor-1 receptor and insulin-like growth factor-binding protein-3 in hepatocellular carcinoma. AB - MicroRNAs (miRs) have a major role in the pathogenesis of hepatocellular carcinoma (HCC). As the insulin-like growth factor (IGF) axis is a highly tumorigenic pathway in HCC, the present study attempted to target it with miRs. Potential targeting of crucial members of the IGF axis by miRNAs at the 3' untranslated region (3'-UTR) was predicted using bioinformatic tools, such as microrna.org, Diana lab and Targetscan, while 5'-UTR targeting was predicted using bibiserv software. Expression profiling of obtained miRNAs was performed using quantitative polymerase chain reaction (qPCR) in 22 non-metastatic HCC biopsy samples and 10 healthy tissues. To investigate the impact of miRNAs on their potential downstream targets, transfection of miRNAs was performed in HuH-7 cells and the targets' expression was quantified using qPCR. Transcripts of insulin-like growth factor-1 receptor (IGF-1R), insulin-like growth factor binding protein-3 (IGFBP-3) and IGF-II were found to be potentially targeted at the 5'-UTR and 3'-UTR regions by the single clustered hepatic metastamiRs miR-96 5p and miR-182-5p. The two miRNAs showed a similar expression pattern in HCC tissues compared to those in healthy tissues. Forced expression of miR-96-5p and miR-182-5p in the HCC cell line HuH-7 had inducing effects on IGFBP-3 and IGF-II transcripts. Of note, the two miRs had differential effects on IGF-1R, where miR 96-5p induced IGF-1R mRNA expression and miR-182-5p inhibited its expression. The present study revealed the pleiotropic impact of the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p on IGF-1R, and an inducing effect on IGF-II and IGFBP-3 in hepatocellular carcinoma. PMID- 25739015 TI - Live tweeting in medicine: 'Tweeting the meeting'. AB - Medical conferences create an opportunity for lifelong learning for healthcare practitioners. The use of Twitter at such conferences continues to expand. This article focuses on how Twitter can be used by physicians and other healthcare providers at regional, national and international conferences, and also at local conferences, such as grand rounds. It also addresses the potential utility of Twitter chats and journal clubs in the promotion of lifelong learning. The impact of Twitter use in healthcare in general, and specifically at conferences, and how it can be measured, is discussed. PMID- 25739016 TI - Site-specific, intramolecular cross-linking of Pin1 active site residues by the lipid electrophile 4-oxo-2-nonenal. AB - Products of oxidative damage to lipids include 4-hydroxy-2-nonenal (HNE) and 4 oxo-2-nonenal (ONE), both of which are cytotoxic electrophiles. ONE reacts more rapidly with nucleophilic amino acid side chains, resulting in covalent protein adducts, including residue-residue cross-links. Previously, we demonstrated that peptidylprolyl cis/trans isomerase A1 (Pin1) was highly susceptible to adduction by HNE and that the catalytic cysteine (Cys113) was the preferential site of modification. Here, we show that ONE also preferentially adducts Pin1 at the catalytic Cys but results in a profoundly different modification. Results from experiments using purified Pin1 incubated with ONE revealed the principal product to be a Cys-Lys pyrrole-containing cross-link between the side chains of Cys113 and Lys117. In vitro competition assays between HNE and ONE demonstrate that ONE reacts more rapidly than HNE with Cys113. Exposure of RKO cells to alkynyl-ONE (aONE) followed by copper-mediated click chemistry and streptavidin purification revealed that Pin1 is also modified by ONE in cells. Analysis of the Pin1 crystal structure reveals that Cys113 and Lys117 are oriented toward each other in the active site, facilitating formation of an ONE cross-link. PMID- 25739017 TI - Why latrines are not used: communities' perceptions and practices regarding latrines in a Taenia solium endemic rural area in Eastern Zambia. AB - Taenia solium cysticercosis is a neglected parasitic zoonosis occurring in many developing countries. Socio-cultural determinants related to its control remain unclear. Studies in Africa have shown that the underuse of sanitary facilities and the widespread occurrence of free-roaming pigs are the major risk factors for porcine cysticercosis. The study objective was to assess the communities' perceptions, practices and knowledge regarding latrines in a T. solium endemic rural area in Eastern Zambia inhabited by the Nsenga ethno-linguistic group, and to identify possible barriers to their construction and use. A total of 21 focus group discussions on latrine use were organized separately with men, women and children, in seven villages of the Petauke district. The themes covered were related to perceived latrine availability (absence-presence, building obstacles) and perceived latrine use (defecation practices, latrine management, socio cultural constraints).The findings reveal that latrines were not constructed in every household because of the convenient use of existing latrines in the neighborhood. Latrines were perceived to contribute to good hygiene mainly because they prevent pigs from eating human feces. Men expressed reluctance to abandon the open-air defecation practice mainly because of toilet-associated taboos with in-laws and grown-up children of the opposite gender. When reviewing conceptual frameworks of people's approach to sanitation, we found that seeking privacy and taboos hindering latrine use and construction were mainly explained in our study area by the fact that the Nsenga observe a traditionally matrilineal descent. These findings indicate that in this local context latrine promotion messages should not only focus on health benefits in general. Since only men were responsible for building latrines and mostly men preferred open defecation, sanitation programs should also be directed to men and address related sanitary taboos in order to be effective. PMID- 25739018 TI - Contraceptive use and pregnancy outcomes among opioid drug-using women: a retrospective cohort study. AB - OBJECTIVE: The contraceptive needs of illicit opioid users differ from non-drug users but are poorly understood. The aim of this study was to describe contraceptive use and pregnancy outcomes in opioid-using women, and to examine their association with a range of risk factors. METHOD: This retrospective cohort study used UK general practice records, Treatment Outcomes Profile and National Drug Treatment Monitoring System data, and a nested data validation exercise. A cohort of 376 women aged 20-61 years were in active treatment for opioid addiction in October 2010 at two specialised primary care practices in North-East England. Outcomes were age-adjusted prevalence estimates for contraceptive use and pregnancy outcomes in users of illicit opioids. The association between lifestyle-related risk factors and contraception was explored. RESULTS: Drug using women made lower use of planned (non-condom) contraception (24% vs 50%, p<0.001), had more frequent pregnancy terminations (0.46 vs. 0.025, p = 0.004) and higher annual incidence of chlamydia (1.1% vs. 0.33%, p<0.001), when compared with age-matched population data. Specifically, there was low use of oral contraceptives (4% vs. 25%, p<0.001), IUCD (1% vs. 6%, p<0.001), and sterilisation (7% vs. 6%, p = 0.053), but higher rates of injectable contraceptives (6% vs. 3%, p = 0.003). A total of 64% of children aged <16 years born to this group did not live with their mother. No individual risk factor (such as sex-working) significantly explained the lower use or type of non-condom contraception. CONCLUSIONS: This is the first study to describe planned contraceptive use among drug-users, as well as the association with a range of risk factors and pregnancy outcomes. The low uptake of planned contraception, set against high rates of terminations and sexually transmitted disease demonstrates the urgent clinical need to improve contraceptive services, informed by qualitative work to explore the values and beliefs influencing low contraceptive uptake. PMID- 25739019 TI - Exome sequencing identifies a novel gene, WNK1, for susceptibility to pelvic organ prolapse (POP). AB - Pelvic organ prolapse (POP) is a common gynecological disorder; however, the genetic components remain largely unidentified. Exome sequencing has been widely used to identify pathogenic gene mutations of several diseases because of its high chromosomal coverage and accuracy. In this study, we performed whole exome sequencing (WES), for the first time, on 8 peripheral blood DNA samples from representative POP cases. After filtering the sequencing data from the dbSNP database (build 138) and the 1000 Genomes Project, 2 missense variants in WNK1, c.2668G > A (p.G890R) and c.6761C> T (p.P2254L), were identified and further validated via Sanger sequencing. In validation stage, the c.2668G > A (p.G890R) variant and 8 additional variants were detected in 11 out of 161 POP patients. All these variants were absent in 231 healthy controls. Functional experiments showed that fibroblasts from the utero-sacral ligaments of POP with WNK1 mutations exhibited loose and irregular alignment compared with fibroblasts from healthy controls. In sum, our study identified a novel gene, WNK1, for POP susceptibility, expanded the causal mutation spectrums of POP, and provided evidence for the genetic diagnosis and medical management of POP in the future. PMID- 25739020 TI - Diastolic dysfunction is an independent predictor of cardiovascular events in incident dialysis patients with preserved systolic function. AB - BACKGROUND: Diastolic heart failure (HF), the prevalence of which is gradually increasing, is associated with cardiovascular (CV) morbidity and mortality in the general population and, more specifically, in patients with end-stage renal disease (ESRD). However, the impact of diastolic dysfunction on CV outcomes has not been studied in incident dialysis patients with preserved systolic function. METHODS: This prospective observational cohort study investigates the clinical consequence of diastolic dysfunction and the predictive power of diastolic echocardiographic parameters for CV events in 194 incident ESRD patients with normal or near normal systolic function, who started dialysis between July 2008 and August 2012. RESULTS: During a mean follow-up duration of 27.2 months, 57 patients (29.4%) experienced CV events. Compared to the CV event-free group, patients with CV events had a significantly higher left ventricular (LV) mass index, ratio of early mitral flow velocity (E) to early mitral annulus velocity (E') (E/E'), LA volume index (LAVI), deceleration time, and right ventricular systolic pressure, and a significantly lower LV ejection fraction and E'. In multivariate Cox proportional hazard analysis, E/E'>15 and LAVI>32 mL/m2 significantly predicted CV events (E/E'>15: hazard ratio [HR] = 5.40, 95% confidence interval [CI] = 2.73-10.70, P< .001; LAVI>32 mL/m2: HR = 5.56, 95% CI = 2.28-13.59, P< .001]. Kaplan-Meier analysis revealed that patients with both E/E'>15 and LAVI>32 mL/m2 had the worst CV outcomes. CONCLUSION: An increase in E/E' or LAVI is a significant risk factor for CV events in incident dialysis patients with preserved LV systolic function. PMID- 25739021 TI - Activation of the unfolded protein response in aged human lenses. AB - Cataract formation is a multifactorial disease, induced by a variety of stressors. The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is known to produce reactive oxygen species (ROS) leading to apoptosis. The present study aimed to investigate whether activation of the UPR occurs in human lenses, using human lens epithelial cell (HLEC) lines and lenses obtained from an eye bank, from individuals aged between 50 and 90 years. In vitro analysis was performed using calcimycin (10 uM) as an ER stressor. The level of ER stress was measured by the production of ROS, staining for cell death, detection of binding immunoglobulin proteins (BIP) and levels of other UPR proteins, including inositol-requiring enzyme-1 (IRE), activating transcription factor (ATF) 6 and PKR-like eukaryotic initiation factor 2a kinase (PERK). These parameters were examined in HLECs exposed to calcimycin for 12, 24, 48 and 72 h. Fluorescent activated cell sorting analysis of the levels of ROS and apoptosis revealed an increase following 24 h calcimycin exposure. The reverse transcription quantitative polymerase chain reaction results demonstrated a gradual increase in the mRNA levels of BIP, IRE1, ATF6 and PERK between 12 and 72 h. A similar effect was observed in the protein levels, which also demonstrated a gradual increase in the levels of endoplasmic oxidoreductin-1-like (Ero1-L)-beta and protein disulfide isomerase, but a lower level of Ero1-Lalpha. Activation of the UPR involved the apoptotic pathway, revealed by increased levels of C/EBP homologous protein, ATF4 and caspase-4. Additionally, the antioxidant protein levels were also suppressed. The investigation of aged human lenses revealed a similar increase in the protein expression of UPR. These results indicated that activation of the UPR-induced ROS production suppressed the antioxidant status and triggered the apoptotic pathway, ultimately leading to the formation of age related cataracts. PMID- 25739022 TI - Co-prescription trends in a large cohort of subjects predict substantial drug drug interactions. AB - Pharmaceutical prescribing and drug-drug interaction data underlie recommendations on drug combinations that should be avoided or closely monitored by prescribers. Because the number of patients taking multiple medications is increasing, a comprehensive view of prescribing patterns in patients is important to better assess real world pharmaceutical response and evaluate the potential for multi-drug interactions. We obtained self-reported prescription data from NHANES surveys between 1999 and 2010, and confirm the previously reported finding of increasing drug use in the elderly. We studied co-prescription drug trends by focusing on the 2009-2010 survey, which contains prescription data on 690 drugs used by 10,537 subjects. We found that medication profiles were unique for individuals aged 65 years or more, with >=98 unique drug regimens encountered per 100 subjects taking 3 or more medications. When drugs were viewed by therapeutic class, it was found that the most commonly prescribed drugs were not the most commonly co-prescribed drugs for any of the 16 drug classes investigated. We cross-referenced these medication lists with drug interaction data from Drugs.com to evaluate the potential for drug interactions. The number of drug alerts rose proportionally with the number of co-prescribed medications, rising from 3.3 alerts for individuals prescribed 5 medications to 11.7 alerts for individuals prescribed 10 medications. We found 22% of elderly subjects taking both a substrate and inhibitor of a given cytochrome P450 enzyme, and 4% taking multiple inhibitors of the same enzyme simultaneously. By examining drug pairs prescribed in 0.1% of the population or more, we found low agreement between co-prescription rate and co-discussion in the literature. These data show that prescribing trends in treatment could drive a large extent of individual variability in drug response, and that current pairwise approaches to assessing drug-drug interactions may be inadequate for predicting real world outcomes. PMID- 25739023 TI - Discovery of putative small non-coding RNAs from the obligate intracellular bacterium Wolbachia pipientis. AB - Wolbachia pipientis is an endosymbiotic bacterium that induces a wide range of effects in its insect hosts, including manipulation of reproduction and protection against pathogens. Little is known of the molecular mechanisms underlying the insect-Wolbachia interaction, though it is likely to be mediated via the secretion of proteins or other factors. There is an increasing amount of evidence that bacteria regulate many cellular processes, including secretion of virulence factors, using small non-coding RNAs (sRNAs), but sRNAs have not previously been described from Wolbachia. We have used two independent approaches, one based on comparative genomics and the other using RNA-Seq data generated for gene expression studies, to identify candidate sRNAs in Wolbachia. We experimentally characterized the expression of one of these candidates in four Wolbachia strains, and showed that it is differentially regulated in different host tissues and sexes. Given the roles played by sRNAs in other host-associated bacteria, the conservation of the candidate sRNAs between different Wolbachia strains, and the sex- and tissue-specific differential regulation we have identified, we hypothesise that sRNAs may play a significant role in the biology of Wolbachia, and in particular in its interactions with its host. PMID- 25739024 TI - Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats. AB - Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively. PMID- 25739026 TI - Subcutaneous panniculitis-like T-cell lymphoma presenting with diffuse cutaneous edema in a 2-year-old child. PMID- 25739025 TI - Coronary endothelial dysfunction induced by nucleotide oligomerization domain like receptor protein with pyrin domain containing 3 inflammasome activation during hypercholesterolemia: beyond inflammation. AB - AIMS: This study hypothesized that activation of endothelial nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasomes directly produces endothelial dysfunction during hypercholesterolemia, which is distinct from its canonical roles in inflammation. RESULTS: Acute hypercholesterolemia in mice was induced by intraperitoneal administration of poloxamer 407 (0.5 g/kg) for 24 h. Endothelial dysfunction was assessed by evaluating endothelium-dependent vasodilation in isolated, perfused, and pressurized coronary arteries in response to bradykinin (10(-10)-10(-6) M) and acetylcholine (10(-9)-10(-5) M). Impaired endothelium-dependent vasodilation was observed in Nlrp3(+/+) mice with acute hypercholesterolemia, which was markedly ameliorated in Nlrp3(-/-) mice. Treatment of mice with inhibitors for caspase-1 or high mobility group box 1 (HMGB1) significantly restored endothelium dependent vasodilation in Nlrp3(+/+) mice with acute hypercholesterolemia. Confocal microscopic analysis demonstrated that hypercholesterolemia markedly increased caspase-1 activity and HMGB1 expression in coronary arterial endothelium of Nlrp3(+/+) mice, which was absent in Nlrp3-deficient mice. Further, recombinant HMGB1 directly induced endothelial dysfunction in normal Nlrp3(+/+) coronary arteries. In vitro, Nlrp3 inflammasome formation and its activity were instigated in cultured endothelial cells by cholesterol crystal, a danger factor associated with hypercholesterolemia. Moreover, cholesterol crystals directly induced endothelial dysfunction in coronary arteries from Nlrp3(+/+) mice, which was attenuated in Nlrp3(-/-) arteries. Such cholesterol crystal-induced impairment was associated with enhanced superoxide production, downregulation of endothelial nitric oxide synthase activity, and pyroptosis. INNOVATION AND CONCLUSION: Our data provide the first evidence that activation of endothelial Nlrp3 inflammasome directly impairs endothelial function beyond its canonical inflammatory actions. This novel non-canonical action of Nlrp3 inflammasomes may initiate or exacerbate vascular injury during hypercholesterolemia. PMID- 25739027 TI - Isolated midbrain ischemic infarct in association with hyperlipoproteinemia (a): a report of 2 adolescent patients. AB - Arterial ischemic strokes (AIS) localized solely to the midbrain are extremely uncommon in the pediatric population. Elevated lipoprotein (a), which promotes atherosclerosis and a prothrombotic state, has been associated with increased risk of AIS in children and adults. Here we describe a 17-year-old boy and a 15 year-old girl who presented with internuclear ophthalmoplegia secondary to an isolated midbrain AIS. Evaluation for risk factors for AIS in these otherwise healthy adolescents identified hyperlipoproteinemia (a) in combination with other potential prothrombotic conditions suggesting that hypercoagulable states such as hyperlipoproteinemia (a) may have contributed to development of small-vessel arteriopathy and localized AIS. PMID- 25739028 TI - Successful Pregnancy and Delivery After Radiation With Ovarian Shielding for Acute Lymphocytic Leukemia Before Menarche. AB - Total body irradiation is performed as a preconditioning regimen to inhibit graft versus-host disease after bone marrow transplantation and to eradicate remaining tumor cells. However, these regimens result in delayed secondary sex characteristics and failure of ovarian function recovery, leading to amenorrhea and infertility. Herein, we report a case of an 11-year-old girl diagnosed with acute lymphocytic leukemia who received induction chemotherapy and prophylactic cranial irradiation. For bone marrow transplantation, she received total body irradiation of 12 Gy with uterine and ovarian shielding at 13 years of age. The patient remained in remission and menarche began at 14 years of age. At 23, she became pregnant and delivered a baby naturally with no abnormalities. PMID- 25739030 TI - Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma. AB - Two CT features were developed to quantitatively describe lung adenocarcinomas by scoring tumor shape complexity (feature 1: convexity) and intratumor density variation (feature 2: entropy ratio) in routinely obtained diagnostic CT scans. The developed quantitative features were analyzed in two independent cohorts (cohort 1: n = 61; cohort 2: n = 47) of patients diagnosed with primary lung adenocarcinoma, retrospectively curated to include imaging and clinical data. Preoperative chest CTs were segmented semi-automatically. Segmented tumor regions were further subdivided into core and boundary sub-regions, to quantify intensity variations across the tumor. Reproducibility of the features was evaluated in an independent test-retest dataset of 32 patients. The proposed metrics showed high degree of reproducibility in a repeated experiment (concordance, CCC>=0.897; dynamic range, DR>=0.92). Association with overall survival was evaluated by Cox proportional hazard regression, Kaplan-Meier survival curves, and the log-rank test. Both features were associated with overall survival (convexity: p = 0.008; entropy ratio: p = 0.04) in Cohort 1 but not in Cohort 2 (convexity: p = 0.7; entropy ratio: p = 0.8). In both cohorts, these features were found to be descriptive and demonstrated the link between imaging characteristics and patient survival in lung adenocarcinoma. PMID- 25739031 TI - Comparison of the effects of chlormadinone acetate versus drospirenone containing oral contraceptives on metabolic and hormonal parameters in women with PCOS for a period of two-year follow-up. AB - OBJECTIVE: A randomized trial to compare the effects of two oral contraceptive pills containing either chlormadinone acetate or drospirenone as the progestogen, in women with PCOS for a period of two-year follow-up. METHODS: Group A received ethinyl-estradiol 0.03 mg + drospirenone 3 mg (EE + DRSP; n = 56) and Group B received ethinyl-estradiol 0.03 mg + chlormadinone acetate 2 mg (EE + CMA; n = 50). Clinical, hormonal and biochemical parameters were compared at baseline, 6 months, 12 months and 24 months. RESULTS: The increase in total cholesterol and hsCRP levels was statistically significantly higher at 6, 12 and 24 months in Group B when compared with Group A. The change in the high-density lipoprotein cholesterol level at the 24 months of treatment was statistically significantly higher in Group A. Group A has a significantly higher reduction in FAI at 6 and 24 months, in FGS at 6, 12 and 24 months and in HOMA-IR index at 12 and 24 months when compared with Group B. CONCLUSIONS: Drospirenone containing combined oral contraceptive (COC) is found to have more favorable effects on lipid profiles, hsCRP levels, insulin resistance and hyperandrogenism when compared with the CMA containing COC and appears to be more beneficial for the long-term cardiovascular and metabolic aspects of PCOS. PMID- 25739033 TI - Publication outputs from a Primary and Community Health Research Unit, 2011-14. AB - Publication of research is a goal of research capacity building initiatives. We reviewed the publications generated by practitioner researchers involved with the Primary and Community Health Research Unit (PCHRU), within the Division of Community Health in South Western Sydney Local Health District (SWSLHD), between 2011 and 2014. Publications were categorised using the Higher Education Research Data Collection Specifications. Published outputs included five refereed articles, one refereed full conference paper and 25 non-published conference presentations. A further 11 refereed articles in draft form were located. The majority of publications were considered 'not published' and not widely discoverable. Evidence for expected timeframes for project completion, including support for publication of research, is needed. PMID- 25739032 TI - Des-gamma-carboxyprothrombin (DCP) and NX-DCP expressions and their relationship with clinicopathological features in hepatocellular carcinoma. AB - AIM: Des-gamma-carboxyprothrombin (DCP) has been used as a tumor marker for hepatocellular carcinoma (HCC). Recently the DCP/NX-DCP ratio, calculated by dividing DCP by NX-DCP, has been reported useful in detecting HCC. The purpose of this study is to clarify the significance of DCP and NX-DCP expression in HCC tissues. METHODS: HCC and non-HCC tissue samples were obtained from 157 patients and were immunohistochemically examined for DCP and NX-DCP expression using anti DCP antibody and anti-NX-DCP antibody. DCP and NX-DCP expression scores were calculated by multiplying staining intensity grade by percentage of stained area. Serum DCP and NX-DCP levels were determined in 89 patients. We evaluated the relationship between tumor expression, serum level, and pathomorphological findings. RESULTS: Intrahepatic metastasis (im) was significantly more frequent in cases with high DCP expression than in cases with low DCP expression. High NX DCP expression was associated with significantly lower histological grade, and less frequent im or portal vein invasion (vp) than low NX-DCP expression. Serum DCP was correlated with DCP expression, but serum NX-DCP was not correlated with NX-DCP expression. DCP-positive (>=40 mAU/L), NX-DCP-positive (>=90 mAU/L), and DCP/NX-DCP ratio-positive (>=1.5) cases were associated with significantly larger tumor size and more frequent vp than negative cases. DCP was rarely expressed, but NX-DCP was frequently expressed in non-cancerous liver tissues. Patients with NX-DCP expression-negative tumors showed a lower survival rate than those with NX DCP expression-positive tumors (p = 0.04), whereas the survival in serum NX-DCP positive cases was lower than that of serum negative cases (p = 0.02). CONCLUSIONS: DCP and NX-DCP were produced in HCC tissues, but differed in expression level and biological properties. DCP expression, serum DCP or NX-DCP level, and DCP/NX-DCP ratio were closely related to malignant properties of HCC. PMID- 25739034 TI - Comparing the health state preferences of older persons, informal caregivers and healthcare professionals: a vignette study. AB - BACKGROUND: The Older Persons and Informal Caregivers Survey-Minimum Dataset (TOPICS-MDS) collects uniform information from research projects funded under the Dutch National Care for the Elderly Programme. To compare the effectiveness of these projects a preference-weighted outcome measure that combined multidimensional TOPICS-MDS outcomes into a composite endpoint (TOPICS-CEP) was developed based on the health state preferences of older persons and informal caregivers. OBJECTIVES: To derive preference weights for TOPICS-CEP's components based on health state preferences of healthcare professionals and to investigate whether these weights differ between disciplines and differ from those of older persons and informal caregivers. MATERIALS AND METHODS: Vignette studies were conducted. Participants assessed the general wellbeing of older persons described in vignettes on a scale (0-10). Mixed linear analyses were used to obtain and compare the preference weights of the eight TOPICS-CEP components: morbidities, functional limitations, emotional wellbeing, pain experience, cognitive problems, social functioning, self-perceived health, and self-perceived quality of life (QOL). RESULTS: Overall, 330 healthcare professionals, 124 older persons and 76 informal caregivers participated. The preference weights were not significantly different between disciplines. However, the professionals' preference weights differed significantly from those of older persons and informal caregivers. Morbidities and functional limitations were given more weight by older persons and informal caregivers than by healthcare professionals [difference between preference weights: 0.12 and 0.07] while the opposite was true for pain experience, social functioning, and self-perceived QOL [difference between preference weights: 0.13, 0.15 and 0.26]. CONCLUSION: It is important to recognize the discrepancies between the health state preferences of various stakeholders to (1) correctly interpret results when studying the effectiveness of interventions in elderly care and (2) establish appropriate healthcare policies. Furthermore, we should strive to include older persons in our decision making process through a shared decision making approach. PMID- 25739035 TI - In Vitro Skin Permeation Enhancement of Sumatriptan by Microneedle Application. AB - Different dimensions of commercially available microneedle devices, namely, Admin Patch((r)) microneedle arrays (MN) (0.6, 0.9, 1.2 and 1.5 mm lengths) and Dermaroller((r)) microneedle rollers (DR) (0.5 and 1mm lengths) were evaluated for their relative efficiency in enhancement of transdermal permeation of Sumatriptan (SMT). Solubility assessment of SMT was carried out using propylene glycol (PG), polyethylene glycol (PEG) in combination with saline (S) at different ratios and the order of solubility was found to be 70:30 > 80:20 > 90:10 %v/v in both PG:S and PEG:S. In vitro skin permeation studies were performed using PG:S (70:30 %v/v) as donor vehicle. A significant increase in cumulative amount of SMT permeated, steady state flux, permeability coefficient and diffusion coefficient values were observed after microneedle treatment, and the values were in the order of 1.5mm MN >1.2mm MN >0.9mm MN >1mm DR >0.6mm MN >0.5mm DR > passive permeation. Lag times were significantly shorter after longer microneedle application (0.24h for 1.5mm MN). Arrays were found to be superior to rollers with similar microneedle lengths in enhancing SMT permeation and may be attributed to higher density of microneedles and force of application onto skin. The in vitro flux values revealed that 2.5cm(2) area patch is sufficient for effective therapy after treatment of skin with 1.5mm MN. It may be inferred that microneedle application significantly enhances the transdermal penetration of SMT and that it may be feasible to deliver clinically relevant therapeutic levels of SMT using microneedle assisted transdermal delivery systems. PMID- 25739036 TI - Correction: Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria. PMID- 25739037 TI - Licensing of primordial germ cells for gametogenesis depends on genital ridge signaling. AB - In mouse embryos at mid-gestation, primordial germ cells (PGCs) undergo licensing to become gametogenesis-competent cells (GCCs), gaining the capacity for meiotic initiation and sexual differentiation. GCCs then initiate either oogenesis or spermatogenesis in response to gonadal cues. Germ cell licensing has been considered to be a cell-autonomous and gonad-independent event, based on observations that some PGCs, having migrated not to the gonad but to the adrenal gland, nonetheless enter meiosis in a time frame parallel to ovarian germ cells - and do so regardless of the sex of the embryo. Here we test the hypothesis that germ cell licensing is cell-autonomous by examining the fate of PGCs in Gata4 conditional mutant (Gata4 cKO) mouse embryos. Gata4, which is expressed only in somatic cells, is known to be required for genital ridge initiation. PGCs in Gata4 cKO mutants migrated to the area where the genital ridge, the precursor of the gonad, would ordinarily be formed. However, these germ cells did not undergo licensing and instead retained characteristics of PGCs. Our results indicate that licensing is not purely cell-autonomous but is induced by the somatic genital ridge. PMID- 25739038 TI - The aerodynamic cost of head morphology in bats: maybe not as bad as it seems. AB - At first sight, echolocating bats face a difficult trade-off. As flying animals, they would benefit from a streamlined geometric shape to reduce aerodynamic drag and increase flight efficiency. However, as echolocating animals, their pinnae generate the acoustic cues necessary for navigation and foraging. Moreover, species emitting sound through their nostrils often feature elaborate noseleaves that help in focussing the emitted echolocation pulses. Both pinnae and noseleaves reduce the streamlined character of a bat's morphology. It is generally assumed that by compromising the streamlined charactered of the geometry, the head morphology generates substantial drag, thereby reducing flight efficiency. In contrast, it has also been suggested that the pinnae of bats generate lift forces counteracting the detrimental effect of the increased drag. However, very little data exist on the aerodynamic properties of bat pinnae and noseleaves. In this work, the aerodynamic forces generated by the heads of seven species of bats, including noseleaved bats, are measured by testing detailed 3D models in a wind tunnel. Models of Myotis daubentonii, Macrophyllum macrophyllum, Micronycteris microtis, Eptesicus fuscus, Rhinolophus formosae, Rhinolophus rouxi and Phyllostomus discolor are tested. The results confirm that non-streamlined facial morphologies yield considerable drag forces but also generate substantial lift. The net effect is a slight increase in the lift-to-drag ratio. Therefore, there is no evidence of high aerodynamic costs associated with the morphology of bat heads. PMID- 25739039 TI - Conditioned medium from umbilical cord mesenchymal stem cells induces migration and angiogenesis. AB - Umbilical cord mesenchymal stem cells (UC-MSCs) have been suggested as a candidate for various clinical applications, however, major limitations include the lack of organ-specific accumulation and low survival rates of transplanted cells. In the present study, it was hypothesized that the paracrine effects of UC MSCs may enhance stem cell-based tissue repair and regeneration by promoting the specific homing of stem/progenitor cells and the overall ability to drive them to the damaged area. UC-MSCs-derived conditioned medium (UC-CM) was analyzed using liquid chip and ELISA techniques. In vitro tube formation assays of human umbilical vein endothelial cells (HUVECs) and UC-MSCs were then performed to assess the angiogenic properties of UC-CM. Subsequently, UC-MSCs, HUVECs and fibroblasts were labeled with PKH26 for an in vivo cell migration assay. The expression levels of C-X-C chemokine receptor 4 (CXCR4), C-C chemokine receptor 2 (CCR2) and c-met were determined in the UC-MSCs, HUVECs and fibroblasts using reverse transcription-quantitative polymerase chain reaction and flow cytometry. UC-CM was incubated with or without antibodies, and the contribution of stromal cell-derived factor 1 (SDF-1), monocyte chemotactic protein 1 (MCP-1) and hepatocyte growth factor (HGF) on the migration of cells was investigated in vitro. The results demonstrated that UC-MSCs secreted different cytokines and chemokines, including increased quantities of SDF-1, MCP-1 and HGF, in addition to the angiogenic factors, vascular cell adhesion protein-1, interleukin-8, insulin-like growth factor-1 and vascular endothelial growth factor. The total lengths of the tubes were significantly increased in the UC-MSCs and HUVECs incubated in UC-CM compared with those incubated in Dulbecco's modified Eagle's medium. In vivo cell migration assays demonstrated that UC-CM was a chemotactic stimulus for the UC-MSCs and HUVECs. In vitro Matrigel migration and scratch healing assays demonstrated that UC-CM increased the migration of CXCR4-positive or/and CCR2-positive cells in a dose-dependent manner. In addition, different molecules were screened under antibody-based blocking migration conditions. The data revealed that the SDF-1/CXCR4 and MCP-1/CCR2 axes were involved in the chemoattractive activity of UC-CM and suggested that the effective paracrine factor of UC-CM is a large complex rather than a single factor. The results of the present study supported the hypothesis that UC-MSCs release soluble factors, which may extend the therapeutic applicability of stem cells. PMID- 25739040 TI - Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy. AB - BACKGROUND: Multifocal motor neuropathy (MMN) is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin (IVIg) is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005, 2008 and 2011. OBJECTIVES: To assess the effects of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH METHODS: On 22 September 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE and LILACS for trials of MMN. We also searched two trials registers for ongoing studies. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs. We considered prospective and retrospective case series and case reports in the Discussion. DATA COLLECTION AND ANALYSIS: Two review authors searched the titles and abstracts of the articles identified and extracted the data independently. MAIN RESULTS: Only one RCT of an immunosuppressive or immunomodulatory agent has been performed in MMN. This study randomised 28 participants and showed that mycophenolate mofetil, when used with IVIg, did not significantly improve strength, function or reduce the need for IVIg. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion. AUTHORS' CONCLUSIONS: According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for IVIg or improving muscle strength in MMN. Trials of other immunosuppressants should be undertaken. PMID- 25739042 TI - Looking back, looking forward. PMID- 25739041 TI - Enhanced killing of SCC17B human head and neck squamous cell carcinoma cells after photodynamic therapy plus fenretinide via the de novo sphingolipid biosynthesis pathway and apoptosis. AB - Because photodynamic therapy (PDT) alone is not always effective as an anticancer treatment, PDT is combined with other anticancer agents for improved efficacy. The clinically-relevant fenretinide [N-(4-hydroxyphenyl) retinamide; 4HPR], was combined with the silicon phthalocyanine photosensitizer Pc4-mediated PDT to test for their potential to enhance killing of SCC17B cells, a clinically-relevant model of human head and neck squamous cell carcinoma. Because each of these treatments induces apoptosis and regulates the de novo sphingolipid (SL) biosynthesis pathway, the role of ceramide synthase, the pathway-associated enzyme, in PDT+4HPR-induced apoptotic cell death was determined using the ceramide synthase inhibitor fumonisin B1 (FB). PDT+4HPR enhanced loss of clonogenicity. zVAD-fmk, a pan-caspase inhibitor, and FB, protected cells from death post-PDT+4HPR. In contrast, the anti-apoptotic protein Bcl2 inhibitor ABT199 enhanced cell killing after PDT+4HPR. Combining PDT with 4HPR led to FB sensitive, enhanced Bax associated with mitochondria and cytochrome c redistribution. Mass spectrometry data showed that the accumulation of C16 dihydroceramide, a precursor of ceramide in the de novo SL biosynthesis pathway, was enhanced after PDT+4HPR. Using quantitative confocal microscopy, we found that PDT+4HPR enhanced dihydroceramide/ceramide accumulation in the ER, which was inhibited by FB. The results suggest that SCC17B cells are sensitized to PDT by 4HPR via the de novo SL biosynthesis pathway and apoptosis, and imply potential clinical relevance of the combination for cancer treatment. PMID- 25739043 TI - Evaluation of an unplanned school closure in a Colorado school district: implications for pandemic influenza preparedness. AB - OBJECTIVE: From January 29 through February 5, 2013, a school district outside metropolitan Denver, Colorado, was closed because of absenteeism related to influenza-like illness (ILI) among students and staff. We evaluated the consequences and acceptability of the closure among affected households. METHODS: We conducted a household survey regarding parent or guardian employment and income interruptions, alternative child care arrangements, interruption of noneducational school services, ILI symptoms, student re-congregation, and communication preferences during the closure. RESULTS: Of the 35 (31%) of 113 households surveyed, the majority (28 [80%]) reported that the closure was not challenging. Seven (20%) households reported challenges: 5 (14%) reported that 1 or more adults missed work, 3 (9%) reported lost pay, and 1 (3%) reported challenges because of missed subsidized school meals. The majority (22 [63%]) of households reported that a hypothetical 1-month closure would not represent a problem; 6 of 8 households that did anticipate challenges reported that all adults worked outside the home. The majority (58%) of students visited at least 1 outside venue during the closure. CONCLUSIONS: A brief school closure did not pose a major problem for the majority of the affected households surveyed. School and public health officials should consider the needs of families in which all adults work outside the home when creating school closure contingency plans. PMID- 25739044 TI - Identification of disaster-vulnerable communities by use of census data prior to the Great East Japan Earthquake. AB - OBJECTIVES: The role of the community is becoming increasingly recognized as a crucial determinant of human health, particularly during a disaster and during disaster recovery. To identify disaster-vulnerable communities, we sought factors related to communities in need of support by using census information from before the Great East Japan Earthquake. METHODS: We identified vulnerable communities by using a needs-assessment survey conducted 6 to 12 months after the Great East Japan Earthquake in Ishinomaki City, Miyagi Prefecture, as indicated by higher proportions of households with at least 1 of 3 major support needs (medical, elderly, psychological, and dwelling environment). The associations between the need for support and 9 demographic characteristics of the community from census data prior to the Great East Japan Earthquake were examined for 71 communities by use of logistic regression analysis. RESULTS: The need for elderly support was positively associated with the proportions of aged people (odds ratio [OR]=1.5; 95% confidence interval [CI]: 1.2-1.8) and one-person households (OR=1.3; 95% CI: 1.0-1.7), whereas the need for psychological support was associated with the proportion of people engaged in agriculture (OR=4.6; 95% CI: 1.0-20.7). The proportion of fisheries was negatively associated with the need for dwelling environment support (OR=0.5; 95% CI: 0.3-0.9). CONCLUSIONS: The consideration of simple demographic characteristics from the census may be useful for identifying vulnerable communities and preparing for future disasters. PMID- 25739045 TI - Operationalizing public health skills to resource poor settings. PMID- 25739046 TI - Reply to Tin and Wiwanitkit. PMID- 25739047 TI - Ebola and the limited effectiveness of travel restrictions. PMID- 25739048 TI - Dimeric Abietane Diterpenoids and Sesquiterpenoid Lactones from Teucrium viscidum. AB - A new abietane diterpenoid, teuvisone (2), a pair of new dimeric abietane diterpenoid stereoisomers, biteuvisones A (3) and B (4), and three new sesquiterpenoid lactones, teuvislactones A-C (6, 7, and 10), were isolated from the whole plants of Teucrium viscidum, along with four known terpenoids (1, 5, 8, and 9). The structures of the new compounds were elucidated by spectroscopic analysis, and the absolute configurations of 5-10 were determined by electronic circular dichroism analysis. The isolated compounds were evaluated for their cytotoxic effects against five human cancer cell lines and for their alpha glucosidase inhibitory effects. PMID- 25739049 TI - Controlling the Balance of Fibroblast Proliferation and Differentiation: Impact of Thy-1. AB - Fibroblasts provide matrix and regulatory mediators to the microenvironment and thereby contribute to maintenance of tissue homeostasis, wound healing, and tumor progression. In the present study, we addressed the functional relevance of Thy-1 for fibroblast functions in vitro and in vivo. Using fibroblasts from Thy-1(-/-) and wild-type mice, recombinant expression of Thy-1, and analysis of the interaction of fibroblasts with immobilized Thy-1, we showed that Thy-1 has a crucial role in the control of cell growth by suppressing proliferation and promoting apoptosis and differentiation of dermal fibroblasts. Function-blocking studies revealed that Thy-1 mediates the control of apoptosis and proliferation via modulation of beta3 integrin function. Interestingly, Thy-1-mediated growth control appears to be a more general mechanism because it also regulates growth of tumor cells of different origin dependent on their beta3 integrin expression. In summary, our findings point to an important role of Thy-1 in controlling the balance between proliferation and differentiation in dermal fibroblasts. PMID- 25739050 TI - Elastin Modification by 4-Hydroxynonenal in Hairless Mice Exposed to UV-A. Role in Photoaging and Actinic Elastosis. AB - Chronic exposure to ultraviolet (UV) radiation causes oxidative stress, which is involved in photoaging and actinic elastosis. UV and reactive oxygen species generate lipid peroxidation products, including the alpha, beta-unsaturated carbonyl compounds such as acrolein or 4-hydroxynonenal (4-HNE). These aldehydes can modify proteins of the extracellular matrix, but their role in the pathogenesis of photoaging is not clarified. The aim of this study was to investigate whether these aldehydes contribute to alter elastin metabolism and whether topical carbonyl scavengers delay UV-induced skin photoaging. Hairless mice (4-6-week old) daily exposed to UV-A (20 J cm(-2) per day, up to 600 J cm( 2)) exhibited the typical features of photoaging, associated with a significant increase in 4-HNE- and acrolein-adduct content, and elastotic material deposition. Immunofluorescence studies showed the accumulation of 4-HNE adducts on elastin in the dermis of UV-A-exposed mice. This was mimicked in vitro by incubating orcein-elastin with 4-HNE or acrolein, which altered its digestion by leukocyte-elastase, a feature possibly involved in the accumulation of elastotic material. A daily topical application of carnosine completely reversed the development of photoaging alterations and 4-HNE-adduct formation on elastin. These data emphasize the role of 4-HNE and acrolein in the mechanism of photoaging, and the preventive effect of carbonyl scavengers. PMID- 25739051 TI - Epidermal Expression and Regulation of Interleukin-33 during Homeostasis and Inflammation: Strong Species Differences. AB - IL-33 is a novel IL-1 family member with a putative role in inflammatory skin disorders and a complex biology. Therefore, recent conflicting data regarding its function in experimental models justify a close assessment of its tissue expression and regulation. Indeed, we report here that there are strong species differences in the expression and regulation of epidermal IL-33. In murine epidermis, IL-33 behaved similar to an alarmin, being constitutively expressed in keratinocyte nuclei and rapidly lost during acute inflammation. By contrast, human and porcine IL-33 were weakly expressed or absent in keratinocytes of noninflamed skin but induced during acute inflammation. To this end, we observed that expression of IL-33 in human keratinocytes but not murine keratinocytes was strongly induced by IFN-gamma, and this upregulation completely depended on the presence of EGFR ligands. Accordingly, IFN-gamma increased the expression of IL 33 in the basal layers of the epidermis in human ex vivo skin cultures only, despite good evidence of IFN-gamma activity in cultures from both species. Together these findings demonstrate that a full understanding of IL-33 function in clinical settings must take species-specific differences into account. PMID- 25739052 TI - Ethanol sclerotherapy of ovarian endometrioma: a safe and effective minimal invasive procedure. Preliminary results. AB - OBJECTIVE: To study if ultrasound-guided aspiration with ethanol sclerosis is a safe and effective treatment for endometriomas. STUDY DESIGN: We conducted a prospective study of 25 women with 27 endometriomas (two bilateral) measuring 4 10cm in diameter with no suspected malignancy, who underwent ultrasound-guided aspiration and ethanol sclerosis between August 2010 and July 2014. Patients were followed up by ultrasound at 6, 12, 24, and 36 months to identify rates of complication and recurrence. Clinical characteristics of the patients (age, history of infertility, previous surgery, and abdominal pain), the cysts (location, diameter, and volume) and the procedure (duration and complications) were recorded. Kaplan-Meier survival curves were used to analyze the recurrence rates by SPSS statistical software. RESULTS: The recurrence rate after sclerosis was 12%. The mean length of follow-up was 17 (SD 9.9) months. Although no major procedure-related complications were recorded, minor complications included three cases of low abdominal pain during the procedure (10.7%) and two cases of abdominal ethanol extravasation (7.1%). CONCLUSION: Ultrasound-guided aspiration and ethanol sclerotherapy are a safe and effective treatment for endometriomas measuring 4-10cm in diameter with no evidence of malignancy. This conservative treatment could possibly achieve a symptomatic cure while preserving healthy ovarian tissue, thereby improving fertility outcomes and avoiding early menopause. PMID- 25739053 TI - The association between follicular fluid levels of cathepsin B, relaxin or AMH with clinical pregnancy rates in infertile patients. AB - OBJECTIVE: The aim of this study was to investigate the relationship of cathepsin B, relaxin and anti-Mullerian hormone (AMH) in follicular fluid (FF) with pregnancy rates in infertility patients. STUDY DESIGN: Seventy-nine infertile couples who underwent ICSI were included in the study. The FF levels of cathepsin B, relaxin and AMH were measured using ELISA kits. RESULTS: The FF cathepsin B levels were statistically higher in pregnant patients compared with non-pregnant patients (0.20+/-0.13 versus 0.13+/-0.03; P<0.001). There were statistically significant differences in the total number of oocytes (10.00+/-6.85 versus 5.96+/-3.94); the mean number of M2 oocytes (8.65+/-5.63 versus 4.58+/-3.36) between the pregnant and non-pregnant patients (P<0.05). There were no significant correlations between pregnancy rates and relaxin and AMH (P>0.05). The area under the curve of cathepsin B for prediction of pregnancy was 0.662 (p=0.024, 95% Confidence Interval 0.528-0.797). CONCLUSIONS: This study demonstrated that increased level of cathepsin B in FF significantly correlates with a better chance of clinical pregnancy. Further studies are needed to clarify the role of cathepsin B in the reproductive process of humans. PMID- 25739054 TI - Correlation between three-dimensional rectosonography and magnetic resonance imaging in the diagnosis of rectosigmoid endometriosis: a preliminary study on the first fifty cases. AB - OBJECTIVES: Deep infiltrating endometriosis (DIE) raises a number of diagnostic and therapeutic problems. Magnetic resonance imaging (MRI), the reference technique in endometriosis, is questioned for posterior pelvic lesions, especially in rectosigmoid locations. In this study, we describe a new technique called three-dimensional rectosonography (3D-RSG), which combines standard transvaginal ultrasonography (TVUS), 3-dimensional (3D) ultrasonography and the use of water for rectal contrast. We also assess the correlation between 3D-RSG and MRI in the diagnosis of rectosigmoid endometriosis. STUDY DESIGN: This study included 50 consecutive women with symptoms suggestive of DIE. After colorectal enema, they underwent a gynecological examination and a 3D TVUS during which 120ml of water was injected in the rectosigmoid to improve the performance of the examination. All patients also underwent an MRI and surgery was offered to the patient if there was discordance between the two procedures. RESULTS: Fifty women underwent 3D-RSG between May and November 2012. All procedures were well tolerated by patients. Two examinations (4%) were stopped for technical reasons. Nineteen rectosigmoid nodules were diagnosed in 18 women (36%). Eighteen of these nodules were also identified on MRI, and one (2%) nodule seen on MRI was not diagnosed by 3D-RSG. In 31 examinations (62%), neither technique identified an intestinal lesion. There was a concordance rate of 96% between the two techniques. Using MRI as the reference technique, 3D-RSG had a sensitivity of 0.95, a specificity of 0.97, a positive predictive values of 0.95, and a negative predictive value of 0.97. There was a 30.3 positive likelihood ratio and a 0.05 negative likelihood ratio. CONCLUSIONS: 3D-RSG seems an interesting new method for diagnosis of rectosigmoid endometriosis and is both feasible and well tolerated. 3D-RSG is highly concordant with MRI in this indication, although further studies are needed to confirm these primary results. PMID- 25739056 TI - Clinical documentation improvement and the agency for healthcare research and quality accidental puncture or laceration patient safety indicator. PMID- 25739055 TI - Thymosin beta 4 is associated with RUNX2 expression through the Smad and Akt signaling pathways in mouse dental epithelial cells. AB - In previous studies by our group, we reported that thymosin beta 4 (Tb4) is closely associated with the initiation and development of the tooth germ, and can induce the expression of runt-related transcription factor 2 (RUNX2) during the development of the tooth germ. RUNX2 regulates the expression of odontogenesis related genes, such as amelogenin, X-linked (Amelx), ameloblastin (Ambn) and enamelin (Enam), as well as the differentiation of osteoblasts during bone formation. However, the mechanisms through which Tb4 induces the expression of RUNX2 remain unknown. In the present study, we employed a mouse dental epithelial cell line, mDE6, with the aim to elucidate these mechanisms. The mDE6 cells expressed odontogenesis-related genes, such as Runx2, Amelx, Ambn and Enam, and formed calcified matrices upon the induction of calcification, thus showing characteristics of odontogenic epithelial cells. The expression of odontogenesis related genes, and the calcification of the mDE6 cells were reduced by the inhibition of phosphorylated Smad1/5 (p-Smad1/5) and phosphorylated Akt (p-Akt) proteins. Furthermore, we used siRNA against Tb4 to determine whether RUNX2 expression and calcification are associated with Tb4 expression in the mDE6 cells. The protein expression of p-Smad1/5 and p-Akt in the mDE6 cells was reduced by treatment with Tb4-siRNA. These results suggest that Tb4 is associated with RUNX2 expression through the Smad and PI3K-Akt signaling pathways, and with calcification through RUNX2 expression in the mDE6 cells. This study provides putative information concerning the signaling pathway through which Tb4 induces RUNX2 expression, which may help to understand the regulation of tooth development and tooth regeneration. PMID- 25739057 TI - Nasal mucosa derived-mesenchymal stem cells from mice reduce inflammation via modulating immune responses. AB - Mesenchymal stem cells (MSCs) have arisen the attention to be a new attractive therapeutic tool treating autoimmune diseases such as allergic rhinitis (AR). AR is a chronic reversible allergic inflammation caused by the excessive activation of T-helper 2 (Th2) cells. Recently, MSCs have been proposed as a new therapy of AR as it can suppress some cytokines to control allogeneic Th2 response and functions. However, how MSCs function to reduce inflammation remains unclear. In this study, we aimed to investigate the role of ectomesenchymal stem cells (ECTO MSCs) derived from nasal mucosa in eosinophilic inflammation and how it affects some immunoglobulins and cytokines. We used ovalbumin (OVA) as a sensitizer to induce nasal inflammation in mice by both injection and inhalation. In order to obtain deeper insights into the influences of ECTO-MSCs on nasal inflammation, the migration of ECTO-MSCs was assessed, the numbers of eosinophils and sneezing were counted, and several immunoglobulins and cytokines were measured. Here we show the ECTO-MSCs are able to migrate to inflammation site via tail vein injection. Eosinophils and sneezing were suppressed by ECTO-MSCs. Interestingly, IgE, interleukin (IL)-4, IL-5 and IL-10 secreted by Th-2 cells were down regulated by ECTO-MSCs whereas IgG2 and IFN-gamma were up-regulated. In conclusion, we have observed that ECTO-MSCs are associated with enhanced Th-1 immune response to nasal inflammation and reduced Th-2 immune response. Given the contributions of Th-2 cells to AR, the injection of ECTO-MSCs can be a promising therapy of AR through balancing immune response. PMID- 25739058 TI - The ribosome-associated complex antagonizes prion formation in yeast. AB - The number of known fungal proteins capable of switching between alternative stable conformations is steadily increasing, suggesting that a prion-like mechanism may be broadly utilized as a means to propagate altered cellular states. To gain insight into the mechanisms by which cells regulate prion formation and toxicity we examined the role of the yeast ribosome-associated complex (RAC) in modulating both the formation of the [PSI(+)] prion - an alternative conformer of Sup35 protein - and the toxicity of aggregation-prone polypeptides. The Hsp40 RAC chaperone Zuo1 anchors the RAC to ribosomes and stimulates the ATPase activity of the Hsp70 chaperone Ssb. We found that cells lacking Zuo1 are sensitive to over-expression of some aggregation-prone proteins, including the Sup35 prion domain, suggesting that co-translational protein misfolding increases in Deltazuo1 strains. Consistent with this finding, Deltazuo1 cells exhibit higher frequencies of spontaneous and induced prion formation. Cells expressing mutant forms of Zuo1 lacking either a C-terminal charged region required for ribosome association, or the J-domain responsible for Ssb ATPase stimulation, exhibit similarly high frequencies of prion formation. Our findings are consistent with a role for the RAC in chaperoning nascent Sup35 to regulate folding of the N-terminal prion domain as it emerges from the ribosome. PMID- 25739060 TI - Corrigendum. PMID- 25739059 TI - Experimental Traumatic Brain Injury Results in Long-Term Recovery of Functional Responsiveness in Sensory Cortex but Persisting Structural Changes and Sensorimotor, Cognitive, and Emotional Deficits. AB - Traumatic brain injury (TBI) is a leading cause of death worldwide. In recent studies, we have shown that experimental TBI caused an immediate (24-h post) suppression of neuronal processing, especially in supragranular cortical layers. We now examine the long-term effects of experimental TBI on the sensory cortex and how these changes may contribute to a range of TBI morbidities. Adult male Sprague-Dawley rats received either a moderate lateral fluid percussion injury (n=14) or a sham surgery (n=12) and 12 weeks of recovery before behavioral assessment, magnetic resonance imaging, and electrophysiological recordings from the barrel cortex. TBI rats demonstrated sensorimotor deficits, cognitive impairments, and anxiety-like behavior, and this was associated with significant atrophy of the barrel cortex and other brain structures. Extracellular recordings from ipsilateral barrel cortex revealed normal neuronal responsiveness and diffusion tensor MRI showed increased fractional anisotropy, axial diffusivity, and tract density within this region. These findings suggest that long-term recovery of neuronal responsiveness is owing to structural reorganization within this region. Therefore, it is likely that long-term structural and functional changes within sensory cortex post-TBI may allow for recovery of neuronal responsiveness, but that this recovery does not remediate all behavioral deficits. PMID- 25739061 TI - Resident health advocates in public housing family developments. AB - Translation of research to practice often needs intermediaries to help the process occur. Our Prevention Research Center has identified a total of 89 residents of public housing in the last 11 years who have been working in the Resident Health Advocate (RHA) program to engage residents in improving their own and other residents' health status by becoming trained in skills needed by community health workers. Future directions include training for teens to become Teen RHAs and further integration of our RHA program with changes in the health care system and in the roles of community health workers in general. PMID- 25739062 TI - Understanding low-income African American women's expectations, preferences, and priorities in prenatal care. AB - We aimed to explore factors affecting prenatal care attendance and preferences for prenatal care experiences among low-income black women by conducting a focus group study using a community-based participatory research framework and nominal group technique. Discussions were audiorecorded, transcribed, and coded by trained reviewers. Friends/family and baby's health were the top attendance motivators. Greatest barriers were insurance, transportation, and ambivalence. Facilitators included transportation services, social support, and resource education. In a "perfect system," women wanted continuity of care, personal connection, and caring/respect from providers. Relationship-centered maternity care models may mitigate disparities. Group prenatal care may provide the continuity and support system desired. PMID- 25739063 TI - The experience of primary care providers with an integrated mental health care program in safety-net clinics. AB - Primary care providers participating in a statewide implementation of an integrated mental health care program for "safety-net" patients in primary care clinics were surveyed to elicit their experiences and level of satisfaction. Quantitative analyses were performed to identify respondent characteristics and satisfaction with the program. Qualitative analyses were done to identify common themes in response to the question "How could psychiatric consultation [in the program] be improved?" Primary care providers were generally satisfied with the integrated mental health care program and raised several concerns that suggest important principles for successful future implementations of these types of programs. PMID- 25739064 TI - Neighborhood social environment and patterns of adherence to oral hypoglycemic agents among patients with type 2 diabetes mellitus. AB - This study examined whether neighborhood social environment was related to patterns of adherence to oral hypoglycemic agents among primary care patients with type 2 diabetes mellitus. Residents in neighborhoods with high social affluence, high residential stability, and high neighborhood advantage, compared to residents in neighborhoods with one or no high features present, were significantly more likely to have an adherent pattern compared to a nonadherent pattern. Neighborhood social environment may influence patterns of adherence. Reliance on a multilevel contextual framework, extending beyond the individual, to promote diabetic self-management activities may be essential for notable public health improvements. PMID- 25739065 TI - Playgroups offering health and well-being support for families: a systematic review. AB - This systematic review explores the health and well-being outcomes that families experience as a result of their participation in playgroups that provide health and well-being services. A systematic review of peer-reviewed literature resulted in 12 articles for inclusion. A meta-synthesis method, using reciprocal translation, was implemented to synthesize findings. Findings suggest that programs support children's social development, transition to school, and overall health. For parents, programs provide targeted social and health support, and knowledge sharing and learning opportunities. Future research in this area will benefit from participatory research approaches and exploring how universal approaches to program provision benefit families. PMID- 25739066 TI - An academic-practice model to improve the health of underserved neighborhoods. AB - The Interprofessional Care Access Network is an innovative model for academic practice partnership providing care coordination for vulnerable and underserved clients and populations in identified neighborhoods. Interprofessional student teams, including health professions students from nursing, medicine, pharmacy, and dentistry, collaborate with community service organizations and primary care clinics to address social determinants of health identified as barriers to achieving health care outcomes and Triple Aim goals. Teams are supervised by a nursing faculty in residence and address issues such as housing, health insurance, food security, and lack of primary care. Two case studies demonstrate the potential impact of the project. PMID- 25739067 TI - Effect of astragaloside IV against rat myocardial cell apoptosis induced by oxidative stress via mitochondrial ATP-sensitive potassium channels. AB - Astragaloside is one of the most common traditional Chinese medicines and is derived from Astragalus membranaceus. Astragaloside IV (AsIV) is a monomer located in an extract of astragaloside. The current study investigated the protective effects of AsIV against hydrogen peroxide (H2O2)-induced injury in cardiocytes and elucidated the mechanisms responsible for this protective effect. Cultured neonatal rat cardiocytes were divided into five experimental groups as follows: i) Dimethyl sulfoxide; ii) H2O2; iii) AsIV+H2O2; iv) AsIV+H2O2+5 hydroxydecanoate (5-HD); and v) nicorandil+H2O2. Cardiocyte survival was analyzed using an MTT assay. Lactate dehydrogenase (LDH) release was also assessed to evaluate the viability of the cells. Intracellular reactive oxygen species (ROS) were measured by 2,7-dichlorodihydrofluorescein diacetate staining. The apoptotic rate was measured by flow cytometry. Mitochondrial membrane potential (DeltaPsim) and intracellular calcium were observed using a laser confocal microscopy system. The results indicated that AsIV promoted the survival of cardiocytes (P<0.05), attenuated LDH release (P<0.05), ROS production (P<0.01) and apoptosis (P<0.01), stabilized the DeltaPsim and reduced intracellular calcium overload (P<0.01) compared with the H2O2 group. The mitochondrial adenosine triphosphate-sensitive potassium channel (mitoKATP) inhibitor 5-HD was observed to partially reverse the protective effect of AsIV. Following treatment with 5-HD, the survival of cardiocytes was reduced (P<0.05), LDH release (P<0.01) and ROS production (P<0.05) were stimulated, DeltaPsim and intracellular calcium change were increased (P<0.01) and apoptosis was increased (P<0.01) compared with the AsIV+H2O2 group. Thus, AsIV has potential for use in the suppression of apoptosis resulting from H2O2 exposure, and mitoKATP activation may underlie this protective mechanism. PMID- 25739068 TI - Influence of intraaortic balloon pump counterpulsation on transesophageal echocardiography derived determinants of diastolic function. AB - INTRODUCTION: Intraaortic balloon pump counterpulsation (IABP) is often used in patients with acute coronary syndrome for its favourable effects on left ventricular (LV) systolic function and coronary perfusion. However, the effects of IABP on LV diastolic function have not been comprehensively investigated. Acute diastolic dysfunction has been linked to increased morbidity and mortality. The aim of this study was to examine the influence of IABP on LV diastolic dysfunction using standard TEE derived parameters. METHODS: Intraoperative TEE was performed in 10 patients (mean age 65 +/- 11 yrs) undergoing urgent coronary artery bypass graft surgery (CABG), who had received an IABP preoperatively. TEE derived measures of diastolic dysfunction included early to late transmitral Doppler inflow velocity ratio (E/A), deceleration time (Dt), pulmonary venous systolic to diastolic Doppler velocity ratio (S/D), transmitral propagation velocity (Vp), and the ratio of early to late mitral annular tissue Doppler velocities (e'/a'). Statistical analyses included the Wilcoxon Sign-Rank test, and a p<0.05 was considered significant. RESULTS: Transmitral inflow E/A ratios increased significantly from 0.86 to 1.07 (p < 0.05), while Dt decreased significantly from 218 to 180 ms (p < 0.05) with the use of IABP. Significant increases in Vp (34 cm/s to 43 cm/s; p < 0.05), and e'/a' (0.58 to 0.71; p < 0.05) suggested a favourable influence of intraaortic counterpulsation on diastolic function. CONCLUSION: The use of perioperative IABP significantly improves TEE derived parameters of diastolic function consistent with a favourable impact on LV relaxation in cardiac surgery patients undergoing CABG. PMID- 25739069 TI - [The wrong suspected diagnosis of a glomus jugulare tumor]. PMID- 25739070 TI - [A Rare Tumor of the Tongue]. PMID- 25739071 TI - [Surgical Simulation Models for Sialendoscopy]. AB - OBJECTIVE: Different simulation models are in use to teach the technique of sialendoscopy. Only a few reports in literature deal with this topic with no comparison having been published, yet. We therefore asked sialendoscopy training course participants about our applied models by using a questionnaire. Material und Methods: A tube-, a pepper-, a porcine kidney-, and a pig head-model were developed as training models and used during 6 consecutive practical sialendoscopy courses from 2012 to 2014. Participants were asked to answer a questionnaire specifically designed to assess the value of the different training models. RESULTS: All respondents (n=61) rated all training models positively. However, porcine kidney- and pig head-models were described to be superior, especially with respect to realistic simulation. Intubation of the papilla can be practised sufficiently only in the pig head-model. The tube- and peppers-models have the advantage of being less expensive, easier to handle and cleaner. CONCLUSIONS: The models described are all useful in learning the sialendoscopy technique. However, they have distinct advantages and disadvantages making a combination of different models useful. PMID- 25739072 TI - [Normative Data of Pharyngeal and Upper Esophageal Sphincter High Resolution Manometry]. AB - BACKGROUND: High resolution manometry (HRM) can provide information about the muscular contraction of the pharynx and the upper esophageal sphincter (UES) and represents an important tool in the diagnostics of dysphagia. To compare the results of swallowing studies interindividually and to identify pathological swallows, normative data are necessary. Normative data for the use of an HRM probe with a large diameter has already been published. As previously has been shown these probes can influence the normal contraction of the pharynx and the UES. In this study comprehensive normal values are presented for small HRM-probes in diameter (2 mm), that only minimally affect pharyngeal and UES contractions. METHOD: 29 healthy volunteers underwent pharyngeal and upper esophageal HRM. All subjects performed 10 water swallows of 2 ml in an upright position. Pressure and time dependent parameters of the velopharyngeal region, the tongue base and the UES have been evaluated. Mean and median values and different percentile ranges were calculated. RESULTS: The normative values for the key parameters were (mean+/-SD): maximum velopharyngeal pressure 269.9+/-113.1 mmHg, maximum tongue base pressure 278+/-93.6 mmHg, maximum UES pressure 205.8+/-64.0 mmHg, UES resting pressure 42.5+/-18.7 mmHg and relaxation time of the UES 681.6+/-86.8 ms. Further parameters have been measured. CONCLUSION: Time dependent values are comparable to those already published. Especially in the UES lower pressures can be measured when a small HRM-probe is used. The normative data established in this study might help to distinguish pathological from physiological swallows using HRM. PMID- 25739073 TI - [The Electronic Patient Record of the University Hospital Ulm in the Clinical Routine]. PMID- 25739074 TI - A simple method to adjust the morphology of gradient three-dimensional PTB7 Th:PC71BM polymer solar cells. AB - Multiple interfaces are necessary for exciton separation in bulk heterojunction (BHJ) solar cells and continuous pathways for carrier transportation in donor : acceptor blend films, especially along the vertical direction, for efficient charge collection. Therefore film morphology is critically important to satisfy both in the construction of high performance organic solar cells (OSCs). In this work, the cooperative effect of solvent additives and solvent flux treatment on film morphology was confirmed. Furthermore, the correlation between a single processing parameter and the resulting morphology has been investigated. Our results show that film morphology can be tuned by changing the volume fraction of the solvent additive. Beyond that, after methanol fluxing, the OSC performance improves significantly, as short circuit current density (JSC) increases from 13.85 mA cm(-2) to 15.17 mA cm(-2) and fill factor (FF) from 62.9% to 65.7%, simultaneously. As a result, power conversion efficiency (PCE) increases from 6.79% to 7.67%. The favorable morphology was further investigated using time-of flight secondary-ion mass spectroscopy (TOF-SIMS), and atomic force microscopy (AFM). PMID- 25739075 TI - Immune regulatory cells and IL17-producing lymphocytes in patients with benign and malignant salivary gland tumors. AB - The relationship between salivary gland tumors and immune system has not been well inspected. We aimed to investigate the distribution of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells, CTLA4(+)CD4(+) lymphocytes, as well asIL-17 producing CD4(+) and CD8(+) (Th17 and Tc17) lymphocytes in peripheral blood of patients with benign and malignant salivary gland tumors and a group of healthy controls. Peripheral blood samples were obtained from 27 patients with salivary gland tumors (19 benign and 8 malignant; mean age of 49.2+/-18.3), as well as19 age/sex matched healthy donors. Fluorochrome-conjugated antibodies were used to stain the cell surface markers, as well as intracellular molecules following cell-membrane fixation and permeabilization. The stained cells were acquired on a FACSCalibur four-color flowcytometer and analyzed by CellQuest Pro software package. The data were presented as mean percentages+/-SEM. Results indicated that the patients with malignant salivary gland tumors have increased percentage of Treg cells (7.74+/-1.1) and intracellular CTLA4 (inCTLA4)-positive CD4(+) lymphocytes (8.18+/-1.77) in comparison to the patients with benign tumors (4.38+/-0.56 for Treg cells and 3.83+/-0.56 for CTLA4(+)CD4(+) cells), as well as control subjects (2.34+/-0.28 for Treg cells and 2.22+/-0.25 for CTLA4(+)CD4(+) cells) (p<=0.001). Conversely these patients had reduced percentage of Th17 cells (0.84+/-0.14) comparing to the patients with benign tumors (2.09+/-0.31) as well as control subjects (2.31+/-0.23) (p<=0.001). In addition, the ratio of Th17/Treg lymphocytes was significantly lower in both malignant (0.12+/-0.03) and benign (0.48+/-0.09) tumors in comparison to control subjects (1.26+/-0.23) (p<0.001). The mean percentage of Tc17 cells in patients with benign (1.14+/-0.15) and malignant (0.60+/-0.13) tumors was nearly similar to those in control subjects (0.83+/-0.14) but the mean expression intensityofIL-17 by these cells was significantly higher in patients with malignant tumors (11.06+/-1.26) than controls (7.61+/-0.69) (p=0.01). Increase in the prevalence of regulatory lymphocytes, Treg cells and CTLA4(+)CD4(+) lymphocytes, as well as the imbalance of Th17/Treg ratio may suggest the contribution of these immune effector cells in the progression of salivary gland tumors. From immune-regulatory point of view, these data also suggest that benign salivary gland tumors might fall between healthy and malignant conditions. The immunity to salivary gland tumors, as well as the findings presented here merits more in-depth investigation. PMID- 25739076 TI - Anti-metastatic effects of DNA vaccine encoding single-chain trimer composed of MHC I and vascular endothelial growth factor receptor 2 peptide. AB - Vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling is the key rate-limiting step in angiogenesis. VEGFR2 serves as the most important target of anti-angiogenic therapy for cancers. Single-chain trimer (SCT) comprising antigen peptide, beta2-microglobulin (beta2m), and major histocompatibility complex (MHC) class I heavy chain was a particularly powerful strategy involved in the increase of the potency of DNA vaccine against tumors and infections. In the present study, we constructed an SCT-encoding VEGFR2 antigen peptide [aa400-408, also known as kinase insert domain-containing receptor (KDR2)], beta2m, and mouse MHC class I heavy chain H-2Db [pcDNA3.1(+) KDR2-beta2m-H-2Db, or SCT-KDR2]. The constructed SCT-KDR2 DNA was efficiently expressed in the human A293 embryonic kidney cell line. Intradermal immunization of C57BL/6 mice with SCT-KDR2 DNA was able to successfully break self immunological tolerance and induce robust cytotoxic T-lymphocyte (CTL) response to VEGFR2, leading to marked suppression of tumor cell-induced angiogenesis and metastasis in murine models of B16 melanoma and 3LL Lewis lung carcinoma. Taken together, the results showed that VEGFR2-targeted SCT vaccination is an effective modality that can be utilized in anti-angiogenic active immunotherapy for various types of cancer. PMID- 25739077 TI - Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. AB - Preeclampsia (PE) is characterized by disturbed extravillous trophoblast migration toward uterine spiral arteries leading to increased uteroplacental vascular resistance and by vascular dysfunction resulting in reduced systemic vasodilatory properties. Its pathogenesis is mediated by an altered bioavailability of nitric oxide (NO) and tissue damage caused by increased levels of reactive oxygen species (ROS). Furthermore, superoxide (O2-) rapidly inactivates NO and forms peroxynitrite (ONOO-). It is known that ONOO- accumulates in the placental tissues and injures the placental function in PE. In addition, ROS could stimulate platelet adhesion and aggregation leading to intravascular coagulopathy. ROS-induced coagulopathy causes placental infarction and impairs the uteroplacental blood flow in PE. The disorders could lead to the reduction of oxygen and nutrients required for normal fetal development resulting in fetal growth restriction. On the other hand, several antioxidants scavenge ROS and protect tissues against oxidative damage. Placental antioxidants including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) protect the vasculature from ROS and maintain the vascular function. However, placental ischemia in PE decreases the antioxidant activity resulting in further elevated oxidative stress, which leads to the appearance of the pathological conditions of PE including hypertension and proteinuria. Oxidative stress is defined as an imbalance between ROS and antioxidant activity. This review provides new insights about roles of oxidative stress in the pathophysiology of PE. PMID- 25739078 TI - Methods for biomimetic remineralization of human dentine: a systematic review. AB - This study aimed to review the laboratory methods on biomimetic remineralization of demineralized human dentine. A systematic search of the publications in the PubMed, TRIP, and Web of Science databases was performed. Titles and abstracts of initially identified publications were screened. Clinical trials, reviews, non English articles, resin-dentine interface studies, hybrid layer studies, hybrid scaffolds studies, and irrelevant studies were excluded. The remaining papers were retrieved with full texts. Manual screening was conducted on the bibliographies of remaining papers to identify relevant articles. A total of 716 studies were found, and 690 were excluded after initial screening. Two articles were identified from the bibliographies of the remaining papers. After retrieving the full text, 23 were included in this systematic review. Sixteen studies used analogues to mimic the functions of non-collagenous proteins in biomineralization of dentine, and four studies used bioactive materials to induce apatite formation on demineralized dentine surface. One study used zinc as a bioactive element, one study used polydopamine, and another study constructed an agarose hydrogel system for biomimetic mineralization of dentine. Many studies reported success in biomimetic mineralization of dentine, including the use of non-collagenous protein analogues, bioactive materials, or elements and agarose hydrogel system. PMID- 25739079 TI - Chloroplast-expressed MSI-99 in tobacco improves disease resistance and displays inhibitory effect against rice blast fungus. AB - Rice blast is a major destructive fungal disease that poses a serious threat to rice production and the improvement of blast resistance is critical to rice breeding. The antimicrobial peptide MSI-99 has been suggested as an antimicrobial peptide conferring resistance to bacterial and fungal diseases. Here, a vector harboring the MSI-99 gene was constructed and introduced into the tobacco chloroplast genome via particle bombardment. Transformed plants were obtained and verified to be homoplastomic by PCR and Southern hybridization. In planta assays demonstrated that the transgenic tobacco plants displayed an enhanced resistance to the fungal disease. The evaluation of the antimicrobial activity revealed that the crude protein extracts from the transgenic plants manifested an antimicrobial activity against E. coli, even after incubation at 120 degrees C for 20 min, indicating significant heat stability of MSI-99. More importantly, the MSI-99 containing protein extracts were firstly proved in vitro and in vivo to display significant suppressive effects on two rice blast isolates. These findings provide a strong basis for the development of new biopesticides to combat rice blast. PMID- 25739080 TI - Nerve demyelination increases metabotropic glutamate receptor subtype 5 expression in peripheral painful mononeuropathy. AB - Wallerian degeneration or nerve demyelination, arising from spinal nerve compression, is thought to bring on chronic neuropathic pain. The widely distributed metabotropic glutamate receptor subtype 5 (mGluR5) is involved in modulating nociceptive transmission. The purpose of this study was to investigate the potential effects of mGluR5 on peripheral hypersensitivities after chronic constriction injury (CCI). Sprague-Dawley rats were operated on with four loose ligatures around the sciatic nerve to induce thermal hyperalgesia and mechanical allodynia. Primary afferents in dermis after CCI exhibited progressive decreases, defined as partial cutaneous denervation; importantly, mGluR5 expressions in primary afferents were statistically increased. CCI-induced neuropathic pain behaviors through the intraplantar injections of 2-methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, were dose-dependently attenuated. Furthermore, the most increased mGluR5 expressions in primary afferents surrounded by reactive Schwann cells were observed at the distal CCI stumps of sciatic nerves. In conclusion, these results suggest that nerve demyelination results in the increases of mGluR5 expression in injured primary afferents after CCI; and further suggest that mGluR5 represents a main therapeutic target in developing pharmacological strategies to prevent peripheral hypersensitivities. PMID- 25739081 TI - A hyaluronan-based scaffold for the in vitro construction of dental pulp-like tissue. AB - Dental pulp tissue supports the vitality of the tooth, but it is particularly vulnerable to external insults, such as mechanical trauma, chemical irritation or microbial invasion, which can lead to tissue necrosis. In the present work, we present an endodontic regeneration method based on the use of a tridimensional (3D) hyaluronan scaffold and human dental pulp stem cells (DPSCs) to produce a functional dental pulp-like tissue in vitro. An enriched population of DPSCs was seeded onto hyaluronan-based non-woven meshes in the presence of differentiation factors to induce the commitment of stem cells to neuronal, glial, endothelial and osteogenic phenotypes. In vitro experiments, among which were gene expression profiling and immunofluorescence (IF) staining, proved the commitment of DPSCs to the main components of dental pulp tissue. In particular, the hyaluronan-DPSCs construct showed a dental pulp-like morphology consisting of several specialized cells growing inside the hyaluronan fibers. Furthermore, these constructs were implanted into rat calvarial critical-size defects. Histological analyses and gene expression profiling performed on hyaluronan-DPSCs grafts showed the regeneration of osteodentin-like tissue. Altogether, these data suggest the regenerative potential of the hyaluronan-DPSC engineered tissue. PMID- 25739082 TI - The anti-TNF-alpha antibody infliximab inhibits the expression of fat-transporter protein FAT/CD36 in a selective hepatic-radiation mouse model. AB - Previously, we reported a radiation-induced inflammation triggering fat accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36) in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36 expression by anti-tumor necrosis factor-alpha (anti-TNF-alpha) (infliximab) was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray) and the effect of anti-TNF-alpha therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1-3 h) induction of TNF-alpha-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6-12 h), compared to sham irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6-12 h) increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-alpha. TNF-alpha-blockage by anti-TNF-alpha showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with alpha-smooth muscle actin (alpha-SMA+) cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-alpha-therapy prevented early radiation-induced expression of FAT/CD36 in vivo. PMID- 25739083 TI - Knockdown of UbcH10 enhances the chemosensitivity of dual drug resistant breast cancer cells to epirubicin and docetaxel. AB - Breast cancer is one of the most common and lethal cancers in women. As a hub gene involved in a diversity of tumors, the ubiquitin-conjugating enzyme H10 (UbcH10), may also play some roles in the genesis and development of breast cancer. In the current study, we found that the expression of UbcH10 was up regulated in some breast cancer tissues and five cell lines. We established a dual drug resistant cell line MCF-7/EPB (epirubicin)/TXT (docetaxel) and a lentiviral system expressing UbcH10 shRNA to investigate the effects of UbcH10 knockdown on the chemosensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel. The knockdown of UbcH10 inhibited the proliferation of both MCF-7 and MCF-7/EPB/TXT cells, due to the G1 phase arrest in cell cycle. Furthermore, UbcH10 knockdown increased the sensitivity of MCF-7/EPB/TXT cells to epirubicin and docetaxel and promoted the apoptosis induced by these two drugs. Protein detection showed that, in addition to inhibiting the expression of Ki67 and cyclin D1, UbcH10 RNAi also impaired the increased BCL-2 and MDR-1 expression levels in MCF-7/EPB/TXT cells, which may contribute to abating the drug resistance in the breast cancer cells. Our research in the current study demonstrated that up-regulation of UbcH10 was involved in breast cancer and its knockdown can inhibit the growth of cancer cells and increase the chemosensitivity of the dual drug resistant breast cancer cells to epirubicin and docetaxel, suggesting that UbcH10 may be a promising target for the therapy of breast cancer. PMID- 25739084 TI - Proteome analysis of dormancy-released seeds of Fraxinus mandshurica Rupr. in response to re-dehydration under different conditions. AB - Desiccation tolerance is the ability of orthodox seeds to achieve equilibrium with atmospheric relative humidity and to survive in this state. Understanding how orthodox seeds respond to dehydration is important for improving quality and long-term storage of seeds under low temperature and drought stress conditions. Long-term storage of seeds is an artificial situation, because in most natural situations a seed that has been shed may not remain in a desiccated state for very long, and if dormant it may undergo repeated cycles of hydration. Different types of seeds are differentially sensitive to desiccation and this directly affects long-term storage. For these reasons, many researchers are investigating loss of desiccation tolerance during orthodox seed development to understand how it is acquired. In this study, the orthodox seed proteome response of Fraxinus mandshurica Rupr. to dehydration (to a relative water content of 10%, which mimics seed dehydration) was investigated under four different conditions viz. 20 degrees C; 20 degrees C with silica gel; 1 degrees C; and 1 degrees C after pretreatment with Ca2+. Proteins from seeds dehydrated under different conditions were extracted and separated by two-dimensional difference gel electrophoresis (2D-DIGE). A total of 2919 protein spots were detected, and high-resolution 2D DIGE indicated there were 27 differentially expressed. Seven of these were identified using MALDI TOF/TOF mass spectrometry. Inferences from bioinformatics annotations of these proteins established the possible involvement of detoxifying enzymes, transport proteins, and nucleotide metabolism enzymes in response to dehydration. Of the seven differentially abundant proteins, the amounts of six were down-regulated and one was up-regulated. Also, a putative acyl-coenzyme A oxidase of the glyoxylate cycle increased in abundance. In particular, the presence of kinesin-1, a protein important for regulation and cargo interaction, was up-regulated in seeds exposed to low temperature dehydration. Kinesin-1 is present in all major lineages, but it is rarely detected in seed desiccation tolerance of woody species. These observations provide new insight into the proteome of seeds in deep dormancy under different desiccation conditions. PMID- 25739085 TI - Discovery of a potent anti-yeast triterpenoid saponin, clematoside-S from Urena lobata L. AB - Urena lobata has been used as a traditional medicinal plant in India and China. In this study, we investigated the antimicrobial activity and isolated the active compound from the leaves of U. lobata. The 80% ethanol extract from U. lobata leaves showed an effective anti-yeast activity against Saccharomyces cerevisiae (S. cerevisiae) strains. Using a combination of chromatographic methods, (-) trachelogenin (1) and clematoside-S (2) were isolated from this plant for the first time, and their chemical structure was identified by mass spectrometry (MS) and extensive nuclear magnetic resonance (NMR) data analysis. In addition, 1 was found to be inactive against all of the test microorganisms in the antimicrobial assay, whereas 2 exhibits a specific anti-yeast activity against S. cerevisiae strains with diameter of inhibition zones in the range from 11 to 20 mm. Furthermore, the MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) values of 2 against S. cerevisiae strains were detected to be in the ranges of 0.61 to 9.8 MUg/mL and 2.42 to 9.8 MUg/mL, respectively. This is the first report of 2 with a specific anti-yeast activity. The above result suggests the potential application of U. lobata to be used as a natural anti-yeast agent in food preservation. PMID- 25739086 TI - Transcriptome analysis in rat kidneys: importance of genes involved in programmed hypertension. AB - Suboptimal conditions in pregnancy can elicit long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether there are common genes and pathways in the kidney are responsible for generating programmed hypertension among three different models using next generation RNA sequencing (RNA-Seq) technology. Pregnant Sprague-Dawley rats received dexamethasone (DEX, 0.1 mg/kg) from gestational day 16 to 22, 60% high fructose (HF) diet, or NG-nitro-l-arginine-methyester (l-NAME, 60 mg/kg/day) to conduct DEX, HF, or l-NAME model respectively. All three models elicited programmed hypertension in adult male offspring. We observed five shared genes (Bcl6, Dmrtc1c, Egr1, Inmt, and Olr1668) among three different models. The identified differential genes (DEGs) that are related to regulation of blood pressure included Aqp2, Ptgs1, Eph2x, Hba-a2, Apln, Guca2b, Hmox1, and Npy. RNA Seq identified genes in arachidonic acid metabolism are potentially gatekeeper genes contributing to programmed hypertension. In addition, HF and DEX increased expression and activity of soluble epoxide hydrolase (Ephx2 gene encoding protein). Conclusively, the DEGs in arachidonic acid metabolism are potentially gatekeeper genes in programmed hypertension. The roles of DEGs identified by the RNA-Seq in this study deserve further clarification, to develop the potential interventions in the prevention of programmed hypertension. PMID- 25739087 TI - Molecular characterization of vitellogenin and its receptor genes from citrus red mite, Panonychus citri (McGregor). AB - The production and uptake of yolk protein play an important role in the reproduction of all oviparous organisms. Vitellogenin (Vg) is the precursor of vitellin (Vn), which is the major egg storage protein, and vitellogenin receptor (VgR) is a necessary protein for the uptake of Vg into developing oocytes. In this paper, we characterize the full-length Vg and VgR, PcVg1 and PcVgR, respectively, of the citrus red mite Panonychus citri (McGregor). The PcVg1 cDNA is 5748 nucleotides (nt) with a 5553-nt open reading frame (ORF) coding for 1851 amino acids (aa), and the PcVgR is 6090 nt, containing an intact ORF of 5673 nt coding an expected protein of 1891 aa. The PcVg1 aa sequence shows a typical GLCG domain and several K/RXXR cleavage sites, and PcVgR comprises two ligand-binding domains, two epidermal growth factor (EGF)-like regions containing YWTD motifs, a transmembrane domain, and a cytoplasmic domain. An analysis of the aa sequences and phylogenetics implied that both genes were genetically distinct from those of ticks and insects. The transcriptional profiles determined by real-time quantitative PCR in different developmental stages showed that both genes present the same expressional tendencies in eggs, larvae, nymphs, and adults. This suggested that the biosynthesis and uptake of PcVg occurs coordinately. The strong reproductive capacity of P. citri has been hypothesized as an important factor in its resistance; consequently, understanding the molecular mechanisms regulating Vg and VgR are fundamental for mite control. PMID- 25739088 TI - Filter-Dense Multicolor Microscopy. AB - Immunofluorescence microscopy is a unique method to reveal the spatial location of proteins in tissues and cells. By combining antibodies that are labeled with different fluorochromes, the location of several proteins can simultaneously be visualized in one sample. However, because of the risk of bleed-through signals between fluorochromes, standard multicolor microscopy is restricted to a maximum of four fluorescence channels, including one for nuclei staining. This is not always enough to address common scientific questions. In particular, the use of a rapidly increasing number of marker proteins to classify functionally distinct cell populations and diseased tissues emphasizes the need for more complex multistainings. Hence, multicolor microscopy should ideally offer more channels to meet the current needs in biomedical science. Here we present an enhanced multi-fluorescence setup, which we call Filter-Dense Multicolor Microscopy (FDMM). FDMM is based on condensed filter sets that are more specific for each fluorochrome and allow a more economic use of the light spectrum. FDMM allows at least six independent fluorescence channels and can be applied to any standard fluorescence microscope without changing any operative procedures for the user. In the present study, we demonstrate an FDMM setup of six channels that includes the most commonly used fluorochromes for histology. We show that the FDMM setup is specific and robust, and we apply the technique on typical biological questions that require more than four fluorescence microscope channels. PMID- 25739089 TI - Transcriptomic analysis reveals differential gene expressions for cell growth and functional secondary metabolites in induced autotetraploid of Chinese woad (Isatis indigotica Fort.). AB - The giant organs and enhanced concentrations of secondary metabolites realized by autopolyploidy are attractive for breeding the respective medicinal and agricultural plants and studying the genetic mechanisms. The traditional medicinal plant Chinese woad (Isatis indigotica Fort., 2n = 2x = 14) is now still largely used for the diseases caused by bacteria and viruses in China. In this study, its autopolyploids (3x, 4x) were produced and characterized together with the 2x donor for their phenotype and transcriptomic alterations by using high throughput RNA sequencing. With the increase of genome dosage, the giantism in cells and organs was obvious and the photosynthetic rate was higher. The 4x plants showed predominantly the normal meiotic chromosome pairing (bivalents and quadrivalents) and equal segregation and then produced the majority of 4x progeny. The total 70136 All-unigenes were de novo assembled, and 56,482 (80.53%) unigenes were annotated based on BLASTx searches of the public databases. From pair-wise comparisons between transcriptomic data of 2x, 3x, 4x plants, 1856 (2.65%)(2x vs 4x), 693(0.98%)(2x vs 3x), 1045(1.48%)(3x vs 4x) unigenes were detected to differentially expressed genes (DEGs), including both up- and down regulated ones. These DEGs were mainly involved in cell growth (synthesis of expansin and pectin), cell wall organization, secondary metabolite biosynthesis, response to stress and photosynthetic pathways. The up-regulation of some DEGs for metabolic pathways of functional compounds in the induced autotetraploids substantiates the promising new type of this medicinal plant with the increased biomass and targeted metabolites. PMID- 25739090 TI - George Washington and Smallpox: A Revolutionary Hero and Public Health Activist. PMID- 25739091 TI - Relationship between antibody susceptibility and lipopolysaccharide O-antigen characteristics of invasive and gastrointestinal nontyphoidal Salmonellae isolates from Kenya. AB - BACKGROUND: Nontyphoidal Salmonellae (NTS) cause a large burden of invasive and gastrointestinal disease among young children in sub-Saharan Africa. No vaccine is currently available. Previous reports indicate the importance of the O-antigen of Salmonella lipopolysaccharide for virulence and resistance to antibody mediated killing. We hypothesised that isolates with more O-antigen have increased resistance to antibody-mediated killing and are more likely to be invasive than gastrointestinal. METHODOLOGY/PRINCIPAL FINDINGS: We studied 192 NTS isolates (114 Typhimurium, 78 Enteritidis) from blood and stools, mostly from paediatric admissions in Kenya 2000-2011. Isolates were tested for susceptibility to antibody-mediated killing, using whole adult serum. O-antigen structural characteristics, including O-acetylation and glucosylation, were investigated. Overall, isolates were susceptible to antibody-mediated killing, but S. Enteritidis were less susceptible and expressed more O-antigen than Typhimurium (p<0.0001 for both comparisons). For S. Typhimurium, but not Enteritidis, O antigen expression correlated with reduced sensitivity to killing (r = 0.29, 95% CI = 0.10-0.45, p = 0.002). Both serovars expressed O-antigen populations ranging 21-33 kDa average molecular weight. O-antigen from most Typhimurium were O acetylated on rhamnose and abequose residues, while Enteritidis O-antigen had low or no O-acetylation. Both Typhimurium and Enteritidis O-antigen were approximately 20%-50% glucosylated. Amount of S. Typhimurium O-antigen and O antigen glucosylation level were inversely related. There was no clear association between clinical presentation and antibody susceptibility, O-antigen level or other O-antigen features. CONCLUSION/SIGNIFICANCE: Kenyan S. Typhimurium and Enteritidis clinical isolates are susceptible to antibody-mediated killing, with degree of susceptibility varying with level of O-antigen for S. Typhimurium. This supports the development of an antibody-inducing vaccine against NTS for Africa. No clear differences were found in the phenotype of isolates from blood and stool, suggesting that the same isolates can cause invasive disease and gastroenteritis. Genome studies are required to understand whether invasive and gastrointestinal isolates differ at the genotypic level. PMID- 25739094 TI - The crystal structure and upconversion properties of Yb3+, Er3+/Ho3+ codoped BaLiF3 microcrystals with different morphologies. AB - A series of x mol% Yb(3+), 1 mol% Ho(3+)/1 mol% Er(3+) (0 <= x <= 25) codoped BaLiF3 microcrystals with different cubic morphologies and sizes (1.52 MUm-3.83 MUm) were synthesized by a facile surfactant-assisted hydrothermal-microemulsion approach for the first time. The crystalline structure of BaLiF3 was established via the Rietveld refinement result of the powder X-ray diffraction (XRD) data. In addition, the growth process of cubic BaLiF3 crystals and the influence of different synthesis conditions on the morphology were studied by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Moreover, in this paper we first investigated the upconversion luminescence (UCL) properties of new Er(3+)/Ho(3+), Yb(3+)-codoped BaLiF3 microcrystals under 980 nm excitation. The characteristic emission of Er(3+) and Ho(3+) was obtained, respectively. The blue emission in BaLiF3:Yb(3+), Ho(3+) which was comparatively more difficult to discover was also observed and explained by the energy level diagram. It is worthwhile to point out that BaLiF3:Yb(3+), Er(3+) practically showed pure red upconversion (UC) emission under excitation at 980 nm and the reasons behind this behavior are presented and discussed. PMID- 25739093 TI - The relationship between body mass index and hospitalisation rates, days in hospital and costs: findings from a large prospective linked data study. AB - BACKGROUND: Internationally there is limited empirical evidence on the impact of overweight and obesity on health service use and costs. We estimate the burden of hospitalisation-admissions, days and costs-associated with above-normal BMI. METHODS: Population-based prospective cohort study involving 224,254 adults aged >=45y in Australia (45 and Up Study). Baseline questionnaire data (2006-2009) were linked to hospitalisation and death records (median follow-up 3.42y) and hospital cost data. The relationships between BMI and hospital admissions and days were modelled using zero-inflated negative binomial regression; generalised gamma models were used to model costs. Analyses were stratified by sex and age (45-64, 65-79, >=80y), and adjusted for age, area of residence, education, income, smoking, alcohol-intake and private health insurance status. Population attributable fractions were also calculated. RESULTS: There were 459,346 admissions (0.55/person-year) and 1,483,523 hospital days (1.76/person-year) during follow-up. For ages 45-64y and 65-79y, rates of admissions, days and costs increased progressively with increments of above-normal BMI. Compared to BMI 22.5 <25kg/m2, rates of admissions and days were 1.64-2.54 times higher for BMI 40 50kg/m2; costs were 1.14-1.24 times higher for BMI 27.5-<30kg/m2, rising to 1.77 2.15 times for BMI 40-50kg/m2. The BMI-hospitalisation relationship was less clear for >=80y. We estimated that among Australians 45-79y, around 1 in every 8 admissions are attributable to overweight and obesity (2% to overweight, 11% to obesity), as are 1 in every 6 days in hospital (2%, 16%) and 1 in every 6 dollars spent on hospitalisation (3%, 14%). CONCLUSIONS: The dose-response relationship between BMI and hospital use and costs in mid-age and older Australians in the above-normal BMI range suggests even small downward shifts in BMI among these people could result in considerable reductions in their annual health care costs; whether this would result in long-term savings to the health care system is not known from this study. PMID- 25739095 TI - Prevalence of learned grapheme-color pairings in a large online sample of synesthetes. AB - In this paper we estimate the minimum prevalence of grapheme-color synesthetes with letter-color matches learned from an external stimulus, by analyzing a large sample of English-speaking grapheme-color synesthetes. We find that at least 6% (400/6588 participants) of the total sample learned many of their matches from a widely available colored letter toy. Among those born in the decade after the toy began to be manufactured, the proportion of synesthetes with learned letter-color pairings approaches 15% for some 5-year periods. Among those born 5 years or more before it was manufactured, none have colors learned from the toy. Analysis of the letter-color matching data suggests the only difference between synesthetes with matches to the toy and those without is exposure to the stimulus. These data indicate learning of letter-color pairings from external contingencies can occur in a substantial fraction of synesthetes, and are consistent with the hypothesis that grapheme-color synesthesia is a kind of conditioned mental imagery. PMID- 25739096 TI - Rapid screening for the adulterants of Berberis aristata using direct analysis in real-time mass spectrometry and principal component analysis for discrimination. AB - Adulteration or substitution of commercial Berberis aristata and its herbal products with inferior-quality substituents is very common. Metabolic profiling of B. aristata, along with its common adulterants/contaminants/substituents such as B. asiatica, Mahonia borealis and Coscinium fenestratum, was rapidly carried out using direct analysis in real-time mass spectrometry (DART MS) to generate the chemical fingerprints for the differentiation of these species. Phytochemical analysis showed the presence of mainly alkaloids. The identified alkaloids were berberrubine, berberine, jatrorrhizine, ketoberberine, palmatine, dihydropalmatine or 7,8-dihydro-8-hydroxyberberine, berbamine and pakistanamine. Berberine, which was mainly reported from the root and stem bark of B. aristata, was also identified in the leaf along with chlorogenic acid. The DART MS data have been subjected to principal component analysis (PCA). The resulting score plots showed clustering and clear differentiation of the species and plant parts. It is thus apparent that the technique of DART MS followed by PCA is a quick and reliable method for the direct profiling of B. aristata and its adulterant plants and plant parts. The study reports the rapid analytical method to identify the possibility of illegal adulteration/contamination/substitution in potential plant materials and herbal extracts. PMID- 25739097 TI - Preconception and prenatal environmental factors associated with communication impairments in 9 year old children using an exposome-wide approach. AB - Although speech and language deficits are common in children and strongly associated with poor educational and social outcomes, little attention has been paid to the antecedents. In this study we used the information from the Avon Longitudinal Study of Parents and Children to examine preconception and prenatal environmental risk factors that were related to communication difficulties in children using the Children's Communication Checklist (CCC). We used an exposome wide approach to identify environmental factors univariably associated with the CCC. Taking account of the False Discovery rate, we used a P value of 0.000157 to identify 621 of 3855 items tested. These were then subjected to a series of stepwise linear regression analyses, firstly within 10 domains: personal characteristics, health, development, education, socio-economic variables, lifestyle, home and social environments, life events and chemical and other exposures; and then with the predictive variables from each domain. The final model consisted of 19 variables independently associated with the communication scale. These variables suggested 6 possible mechanisms: stressors primarily associated with socio-economic disadvantage although other lifestyle choices such as a social network of family or friends can ameliorate these effects; indicators of future parenting skills primarily associated with aspects of parental personality; aspects of the home environment; poor maternal health with a novel finding concerning maternal hearing loss; and maternal education which was partially mediated by the child's IQ. Finally, there may be a mechanism via the maternal diet in pregnancy in particular the consumption of fatty or processed foods. This is the subject of ongoing investigation. PMID- 25739098 TI - Attenuation of enoyl coenzyme A hydratase 1 expression in colorectal cancer cells using small interfering RNA inhibits cell proliferation and migration. AB - Colorectal cancer is one of the most commonly diagnosed types of cancer and is a leading cause of cancer-associated mortality worldwide. Short chain enoyl coenzyme A hydratase 1 (ECHS1) is an important gene involved in the mitochondrial fatty acid beta-oxidation pathway. In addition, ECHS1 has been implicated in a variety of cancers, including breast, prostate, colon and liver cancer. The aim of the present study was to examine the expression of ECHS1 in the human HCT-8 colorectal cancer cell line. The results showed that ECHS1 expression was significantly increased in poorly-differentiated cells compared with that in well differentiated cells. In order to further investigate the functions of ECHS1 in colorectal cancer cells, a stably transfected HCT-8 cell line expressing small interfering (si)RNA targeting the ECHS1 gene was established. The expression of the ECHS1 siRNA was found to reduce ECHS1 protein levels in ECHS1-silenced cells by >40%. Cell proliferation and cell migration of the siECHS1 cells were characterized using Cell Counting Kit-8 and Transwell assays, respectively, the results of which showed that the constitutive knockdown of the ECSH1 gene in HCT 8 cells significantly inhibited cell proliferation and migration. Furthermore, decreased levels of Akt and glycogen synthase kinase (GSK)3beta phosphorylation were observed in ECHS1-silenced HCT-8 cells compared with that of parental or pU6 empty vector-transfected cells. In conclusion, the results of the present study suggested that ECHS1 may have an important role in colorectal cancer cell proliferation and migration via activation of Akt- and GSK3beta-associated signaling pathways. PMID- 25739099 TI - A rapid molecular approach for chromosomal phasing. AB - Determining the chromosomal phase of pairs of sequence variants - the arrangement of specific alleles as haplotypes - is a routine challenge in molecular genetics. Here we describe Drop-Phase, a molecular method for quickly ascertaining the phase of pairs of DNA sequence variants (separated by 1-200 kb) without cloning or manual single-molecule dilution. In each Drop-Phase reaction, genomic DNA segments are isolated in tens of thousands of nanoliter-sized droplets together with allele-specific fluorescence probes, in a single reaction well. Physically linked alleles partition into the same droplets, revealing their chromosomal phase in the co-distribution of fluorophores across droplets. We demonstrated the accuracy of this method by phasing members of trios (revealing 100% concordance with inheritance information), and demonstrate a common clinical application by phasing CFTR alleles at genomic distances of 11-116 kb in the genomes of cystic fibrosis patients. Drop-Phase is rapid (requiring less than 4 hours), scalable (to hundreds of samples), and effective at long genomic distances (200 kb). PMID- 25739100 TI - Polymorphisms in microRNA target sites of forkhead box O genes are associated with hepatocellular carcinoma. AB - The forkhead box O (FOXO) transcription factors play important roles in various cancer development including Hepatocellular Carcinoma (HCC). In this study we conducted a hospital-based case control study including 1049 cases (HCC patients) and 1052 controls (non-tumor patients) to examine whether single nucleotide polymorphisms (SNPs) within microRNA (miRNA) target sites of FOXO genes confer HCC susceptibility. A total of three miRNA target site SNPs in the 3' untranslated regions (UTR) of FOXO1 (rs17592236), FOXO3 (rs4946936) and FOXO4 (rs4503258) were analyzed. No statistically significant differences were found in genotype distribution for rs17592236, rs4946936, and rs4503258 between the HCC patient group and the tumor-free control group using single factor chi-square analysis (P>0.05). However, multivariate logistic regression analysis showed that the CT/TT genotype in rs17592236 was significantly associated with decreased risk of HCC development (P = 0.010, OR = 0.699, 95% CI: 0.526-0.927) as compared to the CC genotype in rs17592236. Additionally, a genetic interaction was found between rs17592236 and rs4503258 (P = 0.003, OR = 0.755, 95% CI: 0.628-0.908). Functional dual luciferase reporter assays verified that the rs17592236 SNP was a target site of human miRNA miR-137. Together, these results indicate that the rs17592236 polymorphism is associated with decreasing of HCC hereditary susceptibility likely through modulating the binding affinity of miR-137 to the 3'UTR in FOXO1 messenger RNA (mRNA). Further knowledge obtained from this study may provide important evidence for the prevention and targeted therapy of HCC. PMID- 25739101 TI - MicroRNA-377 suppresses cell proliferation and invasion by inhibiting TIAM1 expression in hepatocellular carcinoma. AB - Increasing evidence has suggested that microRNAs (miRNAs) play an important role in the initiation and progression of hepatocellular carcinoma (HCC). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role in HCC. The expression of miR-377 in HCC tissues and cell lines was detected by real time reverse-transcription PCR. The effects of miR-377 on HCC cell proliferation and invasion were also investigated. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. The expression of miR-377 was markedly downregulated in human HCC tissues and cell lines. MiR 377 can dramatically inhibit cell growth and invasion in HCC cells. Subsequent investigation revealed that T lymphoma invasion and metastasis 1 (TIAM1) was a direct and functional target of miR-377 in HCC cells. Overexpression of miR-377 impaired TIAM1-induced promotion of proliferation and invasion in HCC cells. Finally, miR-377 is inversely correlated with TIAM1 expression in human HCC tissues. These findings reveal that miR-377 functions as a tumor suppressor and inhibits the proliferation and invasion of HCC cells by targeting TIAM1, which may consequently serve as a therapeutic target for HCC patients. PMID- 25739103 TI - Understand, elucidate and rationalize the coordination mode of pyrimidylmethylamines: an intertwined study combining NMR and DFT methods. AB - Conception of new pyrimidylmethylamine (pyrma) ligands and their corresponding Pd(II) complexes has been described. Both symmetrical and non-symmetrical ligands were prepared and subjected to complexation. Two different coordination modes, Pd(N,N)- or Pd(C,N,N)-pyrma, have been evidenced depending on the substitution of the pyrimidine ring and the nature or the shape of the additional pendant arm. In a non-symmetrical pyrimidine series, the substituent-induced discrimination of each heterocyclic nitrogen atom provoked regio-controlled coordination to the metal center. The molecular structure of pyrma-Pd(II) complexes in the solution state has been elucidated thanks to combined NMR experiments and DFT calculations. This study highlights the potency of (15)N and (13)C NMR spectroscopy for the elucidation of the regio-selective coordination to the Pd(II) in the pyrma-based complex series. DFT calculations were highly relevant to the identification of crucial factors that govern the regio-selectivity and the complexation modes. Close predicted and experimental chemical shift values put into relief the reliability of coordination modes for the most stable complexes in solution, depicted by DFT approaches. PMID- 25739102 TI - The role of mAKAPbeta in the process of cardiomyocyte hypertrophy induced by angiotensin II. AB - Angiotensin II (AngII) is the central product of the renin-angiotensin system (RAS) and this octapeptide contributes to the pathophysiology of cardiac hypertrophy and remodeling. mAKAPbeta is an A-kinase anchoring protein (AKAP) that has the function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. In this study, we aimed to investigate the role of mAKAPbeta in AngII-induced cardiomyocyte hypertrophy and the possible mechanisms involved. Cultured cardiomyocytes from neonatal rats were treated with AngII. Subsequently, the morphology of the cardiomyocytes was observed and the expression of mAKAPbeta and cardiomyocyte hypertrophic markers was measured. mAKAPbeta-shRNA was constructed for RNA interference; the expression of mAKAPbeta and hypertrophic markers, the cell surface area and the [3H]Leucine incorporation rate in the AngII-treated rat cardiomyocytes were detected following RNA interference. Simultaneously, changes in the expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK)2 in the cardiomyocytes were assessed. The cell size of the AngII-treated cardiaomyocytes was significantly larger than that of the untreated cardiomyocytes. The expression of hypertrophic markers and p-ERK2, the cell surface area and the [3H]Leucine incorporation rate were all significantly increased in the AngII-treated cells. However, the expression of mAKAPbeta remained unaltered in this process. RNA interference simultaneously inhibited the protein expression of mAKAPbeta and p-ERK2, and the hypertrophy of the cardiomyocytes induced by AngII was attenuated. These results demonstrate that AngII induces hypertrophy in cardiomyocytes, and mAKAPbeta is possibly involved in this process. The effects of mAKAPbeta on AngII-induced cardiomyocyte hypertrophy may be associated with p-ERK2 expression. PMID- 25739105 TI - Case report: median arcuate ligament syndrome diagnosed with computed tomography and Doppler ultrasonography. AB - BACKGROUND: Median arcuate ligament syndrome is a condition in which the median arcuate ligament crosses the aorta in a lower than normal position and compresses the celiac artery during respiration. The effects of compression are most notable during suspended expiration and when the patient is supine. Patients with median arcuate ligament syndrome present with postprandial abdominal pain, nausea, vomiting, weight loss, and abdominal bruit. The compression leads to a narrowing of the artery, which could cause bowel ischemia, although this theory is controversial. Alternately, the median arcuate ligament could compress the celiac plexus, causing an inflammatory reaction from the nerves and producing a pain pattern that is similar to ischemia. DISCUSSION: Computed tomography and Doppler ultrasonography have high sensitivity and specificity to detect and monitor median arcuate ligament syndrome. Neither imaging modality shows superiority to the other, and the selection of either to image median arcuate ligament syndrome should be based on the patient's needs. CONCLUSION: Treatment for median arcuate ligament syndrome ranges from stenting to open celiac artery decompression with revascularization and results in only a fair degree of long-term symptom relief. PMID- 25739104 TI - Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. AB - IMPORTANCE: The identification of genomic signatures that aid early identification of individuals at risk for autism spectrum disorder (ASD) in the toddler period remains a major challenge because of the genetic and phenotypic heterogeneity of the disorder. Generally, ASD is not diagnosed before the fourth to fifth birthday. OBJECTIVE: To apply a functional genomic approach to identify a biologically relevant signature with promising performance in the diagnostic classification of infants and toddlers with ASD. DESIGN, SETTING, AND PARTICIPANTS: Proof-of-principle study of leukocyte RNA expression levels from 2 independent cohorts of children aged 1 to 4 years (142 discovery participants and 73 replication participants) using Illumina microarrays. Coexpression analysis of differentially expressed genes between Discovery ASD and control toddlers were used to define gene modules and eigengenes used in a diagnostic classification analysis. Independent validation of the classifier performance was tested on the replication cohort. Pathway enrichment and protein-protein interaction analyses were used to confirm biological relevance of the functional networks in the classifier. Participant recruitment occurred in general pediatric clinics and community settings. Male infants and toddlers (age range, 1-4 years) were enrolled in the study. Recruitment criteria followed the 1-Year Well-Baby Check Up Approach. Diagnostic judgment followed DSM-IV-TR and Autism Diagnostic Observation Schedule criteria for autism. Participants with ASD were compared with control groups composed of typically developing toddlers as well as toddlers with global developmental or language delay. MAIN OUTCOMES AND MEASURES: Logistic regression and receiver operating characteristic curve analysis were used in a classification test to establish the accuracy, specificity, and sensitivity of the module-based classifier. RESULTS: Our signature of differentially coexpressed genes was enriched in translation and immune/inflammation functions and produced 83% accuracy. In an independent test with approximately half of the sample and a different microarray, the diagnostic classification of ASD vs control samples was 75% accurate. Consistent with its ASD specificity, our signature did not distinguish toddlers with global developmental or language delay from typically developing toddlers (62% accuracy). CONCLUSIONS AND RELEVANCE: This proof-of principle study demonstrated that genomic biomarkers with very good sensitivity and specificity for boys with ASD in general pediatric settings can be identified. It also showed that a blood-based clinical test for at-risk male infants and toddlers could be refined and routinely implemented in pediatric diagnostic settings. PMID- 25739106 TI - Increasing source-to-image distance to reduce radiation dose from digital radiography pelvic examinations. AB - PURPOSE: To investigate the effects of increasing source-to-image distance (SID) on radiation dose and image quality for digital radiography examinations of the pelvis. METHODS: Using a Carestream DirectView DR 7500 unit, anteroposterior pelvic images were obtained on 97 consecutive patients at a standard 115-cm SID (group 1). Ninety-nine patients were examined using the same equipment and acquisition parameters but with the maximum achievable SID (group 2). For each examination, tube potential, milliampere seconds, SID, and source-to-skin distances were recorded. This facilitated the calculation of entrance surface dose, including backscatter, and effective dose using Quality Assurance Dose Data System software. The resultant images were independently assessed for image quality by 3 blinded observers-2 reporting radiographers and 1 consultant radiologist. Image quality was graded using an established scoring system, which assessed image quality at multiple anatomical locations. RESULTS: For group 1, median (interquartile range [IQR]; the median value is presented with the corresponding interquartile range in parentheses) entrance surface dose with backscatter was 1.95 mGy (1.23 mGy-3.10 mGy), which was lower by 1.15 mGy (0.78 mGy-2.22 mGy) for the increased SID group (22 patients at 135 cm, 77 patients at 144 cm) (Mann-Whitney U test, P < .001). Effective dose calculations generated a median (IQR) of 0.32 mSv (0.13 mSv-0.52 mSv) for group 1 and a lower median of 0.19 mSv (0.13 mSv-0.37 mSv) for group 2 (P < .001). No observers (intraclass correlation coefficient = 0.675) found a significant change in image quality by increasing SID (group 1, 2.0 +/- 1.8; group 2, 1.6 +/- 1.4; P > .05) when comparing the difference in image quality scores with the maximum score available. DISCUSSION: Our results demonstrate a reduction in entrance surface dose, including backscatter and effective dose, of 39% and 41%, respectively, when operating at extended SIDs. Results were generated from a clinically based study and included a wide spectrum of patients. Multiple regression confirmed that increasing the SID contributes to a dose reduction. Increasing SID is a simple and cost-effective method for reducing radiation dose and can be applied to all patients by all radiographers and with all commercially available digital radiography units. CONCLUSION: For digital pelvic radiography, increasing SID is a potential method for reducing entrance surface and effective radiation doses without compromising image quality. PMID- 25739107 TI - Managing clinical education through understanding key principles. AB - BACKGROUND: Traditionally, a practicum facilitated the integration of on-campus learning and practical workplace training. Over the past 3 decades, an educative practicum has evolved that promotes clinical reasoning, including analytical and evaluative abilities, through reflective practice. Anecdotal evidence indicates that the delivery of clinical education within medical radiation science entry level programs continues to vacillate between traditional practicums and the new reflective practicums. PURPOSE: To review the literature about clinical education within the medical radiation sciences and identify key principles for practitioners seeking to reflect upon and improve their approach to teaching and supporting students in the clinical environment. METHODS: A search of 3 major journal databases, Internet searches, and hand searches of reference lists were conducted to identify literature about clinical education in the medical radiation sciences from January 1, 2000, to December 31, 2012. Twenty-two studies were included in this review. RESULTS: The 5 key elements associated with clinical education include the clinical support model and quality, overcoming the theory-practice gap, learning outcomes and reliable and valid assessment, preparing and supporting students, and accommodating differing teaching and learning needs. DISCUSSION: Many factors influence the quality of clinical education, including the culture of the clinical environment and clinical leadership roles. Several approaches can help students bridge the theory-practice gap, including simulators, role-playing activities, and reflective journals. In addition, clinical educators should use assessment strategies that objectively measure student progress, and they should be positive role models for their students. CONCLUSION: The successful clinical education of students in the medical radiation sciences depends upon the systems, structures, and people in the clinical environment. Clinical education is accomplished through the collaborative efforts of the clinical practitioner, the academic, and the student. Universities should include introductory material on clinical learning and teaching in their radiologic science curriculum. PMID- 25739108 TI - Examining suicide: imaging's contributions. AB - For many people, the death of hope leads inexorably to the conclusion that the only viable solution, the only way to put an end to unendurable pain, is suicide. What leads a person to commit this final, desperate act, and how might we predict, intervene, and prevent suicide? Health care workers, including radiologic technologists, can play an important role in detecting warning signs in patients and in better understanding what factors may lead to suicide. Although certain forms of suicide such as suicide bombings and assisted suicide are beyond its scope, this article explores medical imaging's contributions to the study of this phenomenon. PMID- 25739109 TI - Diagnosis and treatment of vertebral compression fractures. AB - A healthy spine is an integral part of an individual's overall well-being. The spinal column's essential role in physiological and neurological function can be compromised when disease or trauma causes a vertebra to compress under the body's weight, producing a vertebral compression fracture. This is a common ailment among adults older than 65 years of age, especially for those with low bone mass or osteoporosis. This article describes vertebral compression fractures, with a special emphasis on medical imaging. PMID- 25739111 TI - Digital detectors and electromagnetic interference. PMID- 25739112 TI - The philosophy of the editorial review board. PMID- 25739113 TI - Spontaneous popliteal artery entrapment. PMID- 25739115 TI - Dual-energy computed tomography. AB - Dual-energy computed tomography (DECT) yields precise anatomic and functional images by exploiting differences in the interactions of high- and low-energy photon spectra with different tissues' and materials' atomic components to more precisely differentiate the chemistry of tissues and disease processes than is possible with traditional single-energy CT scan acquisitions. This article introduces the history of DECT, its physical basis, scanner designs, radiation dose considerations, and postprocessing techniques. DECT's clinical applications also are described, and this relatively new imaging modality's clinical limitations and future prospects are discussed. PMID- 25739116 TI - Breast disease in children and adolescents. AB - Breast abnormalities and disease are rare in the young developing breast. Malignancy is even more uncommon. Yet evaluation and management of breast disease in infants, children, and adolescents requires a conservative approach to preserve developing structures and cosmetic appearance. Diagnosing breast disease in young patients can be made more difficult by developing breast anatomy, which is denser than adult breasts. In addition, ordering physicians, radiologists, and radiologic technologists must carefully consider the use of ionizing radiation in the diagnosis and management of pediatric breast disease. PMID- 25739117 TI - Antibiotics for cancer therapy. PMID- 25739118 TI - Identification of a new class of natural product MDM2 inhibitor: In vitro and in vivo anti-breast cancer activities and target validation. AB - The MDM2 oncogene has been suggested as a molecular target for treating human cancers, including breast cancer. Most MDM2 inhibitors under development are targeting the MDM2-p53 binding, and have little or no effects on cancers without functional p53, such as advanced breast cancer. The present study was designed to develop a new class of MDM2 inhibitors that exhibit anticancer activity in MDM2 dependent and p53-independent manners. The selective MDM2 inhibitors were discovered by a computational structure-based screening, yielding a lead compound, termed JapA. We further found that JapA inhibited cell growth, decreased cell proliferation, and induced G2/M phase arrest and apoptosis in breast cancer cells through an MDM2-dependent mechanism, regardless of p53 status. It also inhibited the tumor growth and lung metastasis in breast cancer xenograft models without causing any host toxicity. Furthermore, JapA directly bound to MDM2 protein and reduced MDM2 levels in cancer cells in vitro and in vivo by promoting MDM2 protein degradation and inhibiting MDM2 transcription, which is distinct from the existing MDM2 inhibitors. In conclusion, JapA represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and might be developed as a novel cancer therapeutic agent. PMID- 25739119 TI - Novel antigens in non-small cell lung cancer: SP17, AKAP4, and PTTG1 are potential immunotherapeutic targets. AB - Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the CTAs, Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in cancer samples, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes from patients' peripheral blood mononuclear cells. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in lung cancer patients. PMID- 25739120 TI - Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma. AB - Medulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYC- overexpressing medulloblastoma cells with AZD1152 HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma. PMID- 25739123 TI - Using productivity to improve claims throughput. PMID- 25739122 TI - Osmium iodide positive granules in spinous and granular layers of guinea pig epidermis. AB - The structure and distribution of osmium-iodide positive granules in cells of the spinous and granular layers of the epidermis is described. They are similar in every respect to granules described by previous authors in material not stained by the osmium-iodide technic, and the assumption that these latter granules are phospholipid in nature is augmented by the present observations. PMID- 25739121 TI - Potential impact of human papilloma virus on survival of basaloid squamous carcinoma of the head and neck. AB - OBJECTIVES: Basaloid-squamous-carcinomas (BSCC) have been considered as aggressive variants of common squamous-cell-carcinomas (HNSCC). Recent studies demonstrated a different clinical course depending on the tumour site. The aim of the study is to analyze the histopathologic/clinical features of BSCC/HNSCC resolved by the HPV-status. METHODS: We analysed the histopathologic/clinical features of BSCC (n=59) and HNSCC (n=981), subdivided due to the HPV status. Differences were analysed using Chi square, Fisher exact, and student's t-test. Survival rates were calculated by Kaplan-Meier and log-rank test. Prognostic variables were subsequently evaluated by Cox regression. RESULTS: Our cohort was congruent with the literature regarding sex, age, metastases, and a predilection in the oropharynx. HNSCC/BSCC did not show a different disease-specific-survival. After UICC matching, univariate analysis revealed a better survival of UICC stage IVa BSCC compared to HNSCC (69% vs. 42%, p=0.022) that was associated with a better response to radio-chemotherapy (p = 0.009). These results referred to the high prevalence of HPV+ (86%) oropharyngeal BSCC. Subgroup analysis demonstrated a better survival of HPV+ oropharyngeal BSCC than HPV- BSCC (p=0.017). CONCLUSION: The clinical outcome in BSCC depends on the tumour site and HPV status. Prospective studies have to evaluate the beneficial application of postoperative radio-chemotherapy in HPV+ BSCC. PMID- 25739124 TI - Dangerous cases. Laws designed to compel those with serious mental illness into treatment are gaining traction. PMID- 25739125 TI - [Modern polymers in matrix tablets technology]. AB - Matrix tablets are the most popular method of oral drug administration, and polymeric materials have been used broadly in matrix formulations to modify and modulate drug release rate. The main goal of the system is to extend drug release profiles to maintain a constant in vivo plasma drug concentration and a consistent pharmacological effect. Polymeric matrix tablets offer a great potential as oral controlled drug delivery systems. Cellulose derivatives, like hydroxypropyl methylcellulose (HPMC) are often used as matrix formers. However, also other types of polymers can be used for this purpose including: Kollidon SR, acrylic acid polymers such as Eudragits and Carbopols. Nevertheless, polymers of natural origin like: carragens, chitosan and alginates widely used in the food and cosmetics industry are now coming to the fore of pharmaceutical research and are used in matrix tablets technology. Modern polymers allow to obtain matrix tablets by 3D printing, which enables to develop new formulation types. In this paper, the polymers used in matrix tablets technology and examples of their applications were described. PMID- 25739126 TI - Dr Lew and colleagues respond. PMID- 25739128 TI - [Somatic symptom and related disorders]. PMID- 25739127 TI - Diagnosing FASD in adults: the development and operation of an adult FASD clinic in Ontario, Canada. AB - This paper describes the development and operation of an interdisciplinary Fetal Alcohol Spectrum Disorders (FASD) diagnostic clinic focussing specifically on adults. The clinic is embedded within a community-based interdisciplinary health agency specializing in intellectual and developmental disabilities. A review of the clinic's assessment process is presented describing the steps from intake to feedback and intervention. To date, the clinic has received 93 referrals and given 41 alcohol-related diagnoses including 10 completed using videoconferencing technology. Issues unique to adult diagnosis are discussed as well as some of the challenges, including high rates of cancellations/no-shows for appointments, obtaining background and historical information, establishing maternal alcohol history, working collaboratively with other support sectors such as children's protective services and the justice system, and finding appropriate follow-up and intervention services in the community. Recommendations for future work to support adults with FASD and their families are presented. PMID- 25739129 TI - In vitro hemocompatibility studies of (poly(L-lactide) and poly(L-lactide-co glycolide) as materials for bioresorbable stents manufacture. AB - Vascular stents are one of the most popular modern methods of dealing with advanced coronary artery disease. At the same time stents are foreign objects to the body, they can stimulate proliferation of vascular endothelium and finally lead to restenosis. Biomaterials designed for temporary and permanent contact with an organism should be biologically inert especially in the case of contact with liquid tissue such as blood. The study aims to assess the impact of resorbable polymers: poly(L-lactide) (PLLA) and poly(L-lactide-co-glycolide) (PLGA), intended for the construction of bioresorbable stents, on activation of coagulation, haemolysis, and morphology of blood cells. The test results showed that in terms of haemolytic activity the samples selected from PLLA and PLGA, shaped by compression pressure followed by laser cutting, do not cause changes in the structural elements of blood and meet the biocompatibility requirements for materials intended for use in the circulatory system. PMID- 25739130 TI - Celiac disease and iron deficiency anemia: author's reply. PMID- 25739131 TI - The impact of prior antibiotic use on blood culture and antibiotic susceptibility results in patients with biliary obstruction: author's reply. PMID- 25739132 TI - Comment on long-term results of nonoperative treatment for uncomplicated acute appendicitis: author's response. PMID- 25739133 TI - NJDA membership and value. PMID- 25739134 TI - The dilemma of effectively communicating with members. PMID- 25739135 TI - Moorestown dentists unite to Give Kids a Smile. PMID- 25739136 TI - Five considerations in cosmetic and esthetic dentistry. PMID- 25739137 TI - Botoxonomics. The economics of adding Botox and dermal fillers to your practice. PMID- 25739138 TI - Oral pathology quiz #85. Case number 1. Squamous cell carcinoma. PMID- 25739139 TI - Oral pathology quiz #85. Case number 2. Squamous cell papilloma. PMID- 25739140 TI - Oral pathology quiz #85. Case number 3. Irritation fibroma. PMID- 25739141 TI - Oral pathology quiz #85. Case number 4. Traumatic ulcer. PMID- 25739142 TI - Medical risk assessment algorithm for invasive dental care in patients with HIV disease. PMID- 25739143 TI - Manage patients in peri-implant health. PMID- 25739144 TI - Image Gently. Responsible use of X-rays in dentistry for children is aim of new education and awareness initiative. PMID- 25739145 TI - The new patient paradox. PMID- 25739146 TI - Vesalius in Vesalius. PMID- 25739147 TI - Looking backwards and forwards. PMID- 25739148 TI - Guglielmo Riva (1627-1677) and the end of hepatocentrism: a 17th-century painting. AB - During the seventeenth century, the description of the lymphatic system provided a decisive contribution to resolving the misconceptions of Galenic physiology concerning the production of blood in the liver. The transition from a liver centered (hepatocentrism) to a heart-centered model (cardiocentrism) was fundamental in the history of medicine, since it allowed the role of the liver and of the heart in the bodily processes to be more correctly identified. The modification of the medical knowledge on the liver and its functions during that period is well represented in a 17th-century painting,"ll Fegato" ("The Liver"), probably belonging to the "anatomical museum" of the Roman surgeon Giovanni Guglielmo Riva (1627-1677). In particular, this Italian physician significantly contributed to the discovery of the lymphatic system and to the study of the hematopoiesis. Thus, this painting as well as the figure of Guglielmo Riva would deserve a major consideration in the history of medicine and of hepatology in particular. PMID- 25739149 TI - Kleoniki Klonari (c 1872 - 1951): the turbulent life of the first licensed nurse in Greece. AB - Miss Kleoniki Klonari, a Greek woman from Mantamado of Lesbos, then occupied by the Turks, decided to go to America, in the 1890s, to study Pediatric Nursing and specialize in Hospitals Administration. Now a qualified nurse she was hired by Princess Sophia, in around 1902, as Medical Director of the Children's Hospital "Aghia Sofia". She had a turbulent life, as her professional route was full of dismissals and returns to the hospital she loved. She died after a long adventure in Africa's jungle, leaving all her money to the hospital. PMID- 25739150 TI - Yaroslav Okunevsky: Ukrainian doctor and rear-admiral of the military fleet of the Austria-Hungarian Empire. AB - Yaroslav Okunevsky (1860 - 1929) was born in Halychyna, Ukraine and graduated from the University of Vienna (1884). He served as a ship's doctor in the military fleet of the Austria-Hungarian Empire. Later, he attained the rank of Rear-admiral of the Military Fleet. He promoted access to healthcare for sailors and instigated the first statute of navy medical service. Many nations awarded him the highest honors. He is also the author of scientific and medical publications as well as interesting memoirs from the trips to many countries of the world. In 1919-1921, he participated in the process of establishing Ukraine as an independent state. PMID- 25739151 TI - Henri Rouviere (1876-1952) French anatomist. AB - Henri Rouviere (1876-1952): medical doctor and professor of human anatomy at Paris University and Honorary Member of the French Academy of Medicine. He wrote important essays on human anatomy and related topics, including a Compendium of Anatomy and Dissection (1911), A Treatise on Descriptive, Topographical and Functional Anatomy (1921), an anatomy of the human lymphatic system (1932), General Anatomy, Original Forms and Anatomical Structures (1939). PMID- 25739152 TI - Pheidias the physician from Rhodes, son of Apollonius (late 4th c B.C.). PMID- 25739153 TI - Sano, kuracado, higieno (health, medicine, hygiene): ophthalmologists and Esperanto. AB - Historically, some ophthalmologists were closely associated with the constructed language Esperanto. These include the founder of the language Ludwig Lazar Zamenhof (1859-1917), his son Leon, Max Talmud (1869-1941), Kazimierz Bein (1872 1959), and Louis Emile Javal (1839-1907).This paper considers the role of these ophtalmologists who attempted to create international languages, whether oral, written or musical. PMID- 25739154 TI - Did Jews avoid using products made of pigs as medical materials? "And the swine ... it is unclean unto you" (Deut. 14 : 8). AB - Medical and halakhic literature in medieval and modern times teach us that healing by porcine produce was used quite extensively. Medical materials made of pig were mentioned in Jewish manuscripts in Christian and Islamic territories. We assume that, in fact, they were in wider usage in Europe, where the pig was common. Much of the permitted uses seem to involve external application and there was little ingestion orally unless there were compelling reasons. The Jewish medical literature mentions many treatments using pig products, such as: the fat for skin diseases, diaphoresis; bile for gynecologic problems; dung to stop bleeding in circumcision and drinking urine for kidney stones. PMID- 25739155 TI - Treatment of gout in a recently published 9th century manuscript of Rhazes. AB - Gout is a common lifestyle disease and was identified by Hippocrates in the fifth century BC although the condition was known ancient Egypt some two millennia earlier. The pharmaceutical suggestions described in a recently edited manuscript, the oldest known medical manuscript of the Arab world, is presented, here for the first time. It is entitled Treatise on Gout by Rhazes, the greatest of Arab clinicians, and was written in the late 9th or early 10th century. Rhazes' pharmaceutics are presented in descriptive tables and their components are also compared with other recipes from manuscripts of the Galen and a recently edited medieval Syrian manuscript of Le Livre des simples (Tables 1-2). It is noteworthy that Rhazes insists that the drugs should be taken before sunrise and at down, showing ignorance of current knowledge of circadian rhythms. This is of interest as arthritis chronotherapy is widely discussed in recent literature. PMID- 25739156 TI - The Torrance Collection at the Archive, Records Management and Museum Services of the University of Dundee, Scotland. PMID- 25739157 TI - A doctor's line: poetry and prescriptions in health and healing. PMID- 25739158 TI - Paucity of laboratory-confirmed failures of high-dose influenza vaccine in an elderly population, 2012-2013. . PMID- 25739159 TI - A method of treating common colds. 1915. PMID- 25739160 TI - Views of nonmedical, health system professionals regarding the return of whole genome sequencing incidental findings. AB - BACKGROUND: Use of genome sequencing in the clinic continues to increase. In addition to its potential to provide findings of clinical benefit, it also has the potential to identify findings unrelated to the indication for testing (incidental findings). Incidental findings are the subject of considerable debate, particularly following the publication of recommendations by the American College of Medical Genetics and Genomics. This debate involves how and which results should be returned as well as stakeholders' desires for such results. Part of the difficulty in determining best practice in relation to returning incidental findings is the dearth of empirical data available regarding laypersons' attitudes and desire for the sometimes controversial information. METHODS: In an effort to contribute data on views regarding the return of incidental findings following genome sequencing in a clinical setting, a survey specifically designed around the various types of incidental findings that occur, ranging from clinically actionable to nonactionable, was administered to a nonmedical population of medical coders working at a medical school (N = 97). Almost all (98%) of the respondents were women, 80% had 6 or more years of experience as a medical coder, and about three-fourths (74%) of participants reported that they had children. RESULTS: The group surveyed was considerably more interested in receiving all types of results for both themselves and their children than previously surveyed genetics professionals. CONCLUSION: Results from this study offer a snapshot of opinions beyond those of the professional genetic community and demonstrate a striking difference between genetic professionals and a more lay population in terms of their attitudes and desires regarding the return of incidental findings. Additional research is needed to explain the nuances in the perspectives motivating these variations. PMID- 25739161 TI - A one-to-one mentoring support service for breast cancer survivors. AB - PURPOSE: ABCD: After Breast Cancer Diagnosis (ABCD) is a Wisconsin-based mentoring service that pairs breast cancer survivors with women recently diagnosed with breast cancer. Since 1999, ABCD has trained volunteers to provide personalized information and emotional support. This review describes participants' perceptions of this survivorship program and its utility for breast cancer patients. METHODS: ABCD conducted 3 "program effectiveness" surveys between 2002 and 2006. Surveys were conducted over the telephone and used a 5 point Likert scale to elicit evaluations of the organization, mentors, resources, and other program dimensions. RESULTS: Survey results indicate that this model is a successful resource that could be replicated for breast cancer survivors nationally. Respondents were especially satisfied with the helpfulness of the program for them and their families, mentor confidentiality, and emotional support. Areas for improvement focused on mentee familiarity with the ABCD website and helpline and improvement in mentor knowledge. Approximately 60% of respondents would consider becoming mentors. CONCLUSION: ABCD is a positive and successful program with consistent participant satisfaction. The program has expanded nationally to address the needs of survivors. This model could be further replicated to provide support to survivors, family, and friends at no cost. PMID- 25739162 TI - Identifying opportunities to improve aspirin utilization for the primary prevention of cardiovascular disease in a regional health care system. AB - OBJECTIVE: Aspirin is an important part of primary cardiovascular disease prevention, but little is known about aspirin use patterns in regional health care systems. This study used electronic health records from Marshfield Clinic to identify demographic, geographic, and clinical predictors of aspirin utilization in central Wisconsin adults without cardiovascular disease. METHODS: A cross sectional design was employed using 2010-2012 data from patients in the Marshfield Epidemiologic Study Area. Individuals who took aspirin-containing medication daily or every other day were considered regular aspirin users. There were a total of 6678 adults in the target region who were clinically indicated for aspirin therapy for primary cardiovascular disease prevention, per national guidelines. RESULTS: Aspirin was generally underutilized in this population, with 35% of all clinically indicated adults taking it regularly. Adjusted models found that individuals who were younger, female, not covered by health insurance, did not visit a medical provider regularly, smokers, were not obese, or did not have diabetes were least likely to take aspirin. In addition, there was some local variation in that aspirin use was less common in northeastern communities within the regional service area. CONCLUSION: Several aspirin use disparities were identified in central Wisconsin adults without cardiovascular disease, with particularly low utilization observed in those without diabetes and/or without regular physician contact. Methods of using electronic health records to conduct primary care surveillance as outlined here can be adopted by other large health care systems in the state to optimize future cardiovascular disease prevention initiatives. PMID- 25739163 TI - Osmotic demyelination syndrome. AB - Formerly known as central pontine myelinolysis, osmotic demyelination syndrome (ODS) is defined by a symmetrical destruction of myelin sheaths involving mainly the central portion of the basis pontis without evidence of vascular involvement. We report the case of a 60-year-old man who presented to the emergency department with a 2-week history of progressive confusion, memory loss, and lower extremity weakness with limited ambulation. A computed tomography scan of the head revealed areas of low attenuation within the pons, and brain magnetic resonance imaging (MRI) confirmed the changes as compatible with ODS. PMID- 25739164 TI - Daptomycin-induced acute eosinophilic pneumonia. AB - INTRODUCTION: Daptomycin is a cyclic lipopeptide antibiotic with activity against gram-positive organisms. With increasing use, acute eosinophilic pneumonia is a rare, but potentially fatal adverse drug reaction that requires prompt recognition. The authors present a definite case of daptomycin-induced acute eosinophilic pneumonia. CASE SUMMARY: A 61-year-old woman with poorly controlled type 2 diabetes who presented with bilateral foot pain was found to have bilateral calcaneal osteomyelitis. She was started on an antibiotic regimen that included daptomycin. Within 1 week, she developed fever, a dry cough, and shortness of breath and was treated for hospital-acquired pneumonia (HAP). Daptomycin was discontinued. Upon completion of therapy for HAP, the patient was subsequently restarted on daptomycin for continued therapy of bilateral calcaneal osteomyelitis. Within 48 hours of restarting daptomycin, the patient developed hypoxemic respiratory failure, bilateral pulmonary infiltrates, and peripheral eosinophilia. Bronchoscopic lavage revealed 30% eosinophils. Daptomycin-induced acute eosinophilic pneumonia was diagnosed. Daptomycin was discontinued, and the patient had complete resolution of symptoms, peripheral eosinophilia, and radiographic findings. DISCUSSION: Daptomycin initially was approved for skin and soft tissue infections, but its utility has expanded to bacteremia and endocarditis. Daptomycin-induced acute eosinophilic pneumonia is rare. A recent Federal Drug Administration review identified a total of 58 cases of daptomycin induced acute eosinophilic pneumonia. Of these, 38 were possible, 13 were probable, and 7 were definite. We believe this is the 8th definite case of daptomycin-induced acute eosinophilic pneumonia to be reported in the literature. PMID- 25739165 TI - Streptococcus infection in a newborn. AB - Streptococcus salivarius is an uncommon cause of infection in neonates. Normally present in the oral flora of humans, S salivarius is the least pathogenic member of the viridans group streptococci and is often considered a contaminant when detected on blood culture. While rare, it has been shown in the literature to cause clinically relevant bacteremia and other invasive infections typically in the immunocompromised. We report the case of a well-appearing 1-day-old female with sequential positive blood cultures for S salivarius. This case has important implications as it demonstrates that S salivarius should not be automatically ruled out as a contaminant when isolated on blood culture. PMID- 25739166 TI - MetaStar shows marked improvements for Medicare patients, looks to future. PMID- 25739167 TI - Ask this one question. PMID- 25739168 TI - Expression of NLRP3 inflammasome, cytokines and vascular mediators in the skin of systemic sclerosis patients. AB - BACKGROUND: The activated NLRP3 inflammasome is associated with the etiology of fibrotic diseases. The role of inflammasomes in SSc is still poorly understood. OBJECTIVES: To determine the expression of NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) in the skin of patients with systemic sclerosis (SSc) and its relationship with pro-inflammatory cytokines and vascular mediators expression. METHODS: Skin biopsies were taken from 42 patients with either limited or diffuse SSc (21 lcSSc and 21 dcSSc), and from 13 healthy individuals. Using real-time polymerase chain reaction (PCR), the relative expression of caspase-1, IL-1beta, IL-18, IL-33, TGF-beta, ET-1, iNOS and eNOS genes, were measured. The location of NLRP3 and IL-1beta were also determined by immunohistochemistry. Clinical characteristics were evaluated. RESULTS: The mean age of the patients was 49.3 +/- 12.9 (lcSSc), 44.6 +/- 1 3.8 (dcSSc), and 45 +/- 14.1 (healthy individuals). Compared to healthy individuals, the skin of both subtypes of SSc showed a significant increase (P < 0.05) in NLRP3, caspase-1, IL-1beta, IL-18 and ET-1. Samples of lcSSc also showed a significant increase of eNOS (P < 0.029), iNOS (P < 0.04) and TGF-beta (P < 0.05). Dermal fibrosis evaluated by modified Rodnan skin score (MRSS) had significant correlation with NLRP3, IL-1beta, IL-18, and ET-1. Immunohistochemical analysis showed stronger staining of NLRP3 and IL-1beta cytoplasmic expression in the keratinizing squamous epithelium of skin from SSc patients compared to controls. CONCLUSIONS: This study identified NLRP3 over expression in skin of patients with SSc. Skin thickness correlates positively with the NLRP3 inflammasome gene expression and with the vascular mediator and pro-fibrotic ET-1, suggesting that NLRP3 inflammasome plays a role in the pathophysiology of skin fibrosis in human SSc. PMID- 25739169 TI - The yield of tuberculosis screening of undocumented migrants from the Horn of Africa based on chest radiography. AB - BACKGROUND: Since 2006 more than 60,000 migrants arrived in Israel from the Horn of Africa (HoA: Sudan, Eritrea, Ethiopia). They were detained in prison and screened for tuberculosis (TB) by means of an interview and chest X-ray (CXR). OBJECTIVES: To evaluate the yield of this screening process. METHODS: This cross sectional study evaluated the validity of CXR in a random sample of 1087 of the 5335 HoA migrants (20.4%) who arrived in 2009, and assessed its related costs. RESULTS: Sixty-two migrants (5.7%) had CXRs with TB-suspicious findings, and 11 of them were finally diagnosed with TB (17.7% of all TB-suspicious CXRs). TB point-prevalence was 1000 cases per 100,000 migrants (1.0%). As no additional TB cases were diagnosed on arrival, CXR sensitivity, specificity and positive predictive value were 100%, 96.1% and 17.7%, respectively. The interview did not contribute to the detection of migrants with TB. Direct costs related to the detection of single TB cases in prison was 17,970 shekels (US$ 4585), lower than the treating cost of 28,745 shekels ($7335). During 2008-2010, 88 HoA migrants who had been screened at the prison after crossing the border were later diagnosed with TB in the community. The average annual TB incidence was 132 cases/100,000 migrants. We traced 56 (63.6%) of the CXRs that were performed during detention. Of those, 41 (73.2%) were unremarkable, 8 (14.2%) were TB suspicious and 7 (12.5%) had non-TB-related abnormalities. CONCLUSIONS: CXR-based screening is a valid and cost-saving tool for screening HoA migrants for TB; the interview has significant limitations. PMID- 25739170 TI - Etanercept increases tumor necrosis factor-alpha level but not sFas level in patients with rheumatoid arthritis. AB - BACKGROUND: Targeted anti-tumor necrosis factor-alpha (TNFalpha) therapy in patients with rheumatoid arthritis (RA) has resulted in dramatic improvement in the disease course and prognosis. One of the features of RA is hyperplasia of synovial cells, particularly RA synovial fibroblasts (RA-SF), caused partially by impaired apoptosis of RA-SF cells. It has been shown that TNFalpha may inhibit apoptosis in RA-SF cells and this process may be reversed by the use of TNFalpha antagonists. OBJECTIVES: To determine the influence of etanercept, an anti TNFalpha agent, on sFas (CD 95) receptor. METHODS: We analyzed serum levels of sFaS and TNFalpha in a group of 26 patients with high RA disease activity who were selected to start treatment with etanercept. Assessment of sFas receptor and TNFalpha levels was performed before and 6 months after treatment with etanercept. RESULTS: Treatment with etanercept resulted in increased TNFalpha levels (log TNFalpha 0.602 vs. 1.17, P < 0.05) but no change in sFas levels (log sFas 3.17 vs. 3.11, P = 0.37). As expected, treatment resulted in significant reduction in both disease activity and levels of inflammatory markers. CONCLUSIONS: Etanercept may increase TNFalpha levels in patients with RA. We also speculate that the Fas pathway is not the main apoptotic pathway in patients with RA treated with etenercept, since sFas, a marker of apoptotic activity, remained unchanged and was not influenced by disease activity and concomitant treatment. PMID- 25739171 TI - A novel porcine model for chemically inducible Crohn's-like reaction. AB - BACKGROUND: New animal models provide insights into the pathogenesis of different types of inflammatory bowel disease as well as novel pathways for new therapeutic options. However, the scarcity of large animal models hinders the research and development of new surgical procedures and technological devices in inflammatory bowel disease surgery. Common small animal inducible models involve chemical agents that result in the development of acute intestinal inflammation. OBJECTIVES: To assess a novel method for the induction of Crohn's-like colitis using intramural injection of sclerosants in a porcine model. METHODS: Seven domestic pigs underwent several experimental protocols to assess the efficacy of intramural colonic injections of two different compounds (lauromacrogol, and phenol in almond oil).Twenty-five different large bowel segments were treated with intramural injections of the compounds. The animals were followed for 6 weeks, and treated colonic segments were resected for histopathological examination. RESULTS: Intramural injection of lauromacrogol resulted in non specific, mild reactive foreign body changes only. Injection of various dosages of 5% phenol in almond oil caused a range of histopathological changes varying from focal fibrosis to Crohn's-like reactions com rising acute and chronic infiltrates, mucosal ulceration and focal necrosis with enteric and lymphoid non caseating granulomas. CONCLUSIONS: Intramural colonic phenol in almond oil injection in pigs induces inflammatory reactions that histologically resemble Crohn's disease in humans. PMID- 25739172 TI - First experience in ambulatory ultrafiltration therapy for congested heart failure patients in Israel: a feasibility study. AB - BACKGROUND: The prevalence of heart failure (HF) is increasing rapidly with high readmission rates, mainly due to fluid retention. Ultrafiltration (UF) is a mechanical method for removing fluids. Since UF was introduced only recently in Israel, the skill and experience required for outpatient congested HF patients is scarce. OBJECTIVEs: To evaluate the feasibility and safety of UF therapy in congested HF patients in outpatient clinics under a strict protocol of monitoring and therapy that we developed. METHODS: Between April and September 2013 we applied UF in our outpatient clinic to seven chronically congested HF patients with NYHA III-IV who did not respond adequately to diuretics. We administered a total of 38 courses. RESULTS: On average, 1982 ml fluid per course was removed without significant adverse events and with patients' subjective feeling of improvement. Only two courses were interrupted prematurely due to mechanical problems but were completed without harm to the patients. CONCLUSIONS: Under appropriate professional medical supervision, UF therapy in an outpatient setting is a safe and effective procedure and serves as an additional tool for managing congested HF patients who do not respond adequately to diuretics. PMID- 25739173 TI - Chloramphenicol use and susceptibility patterns in Israel: a national survey. AB - BACKGROUND: Due to increasing antimicrobial resistance, there has been renewed interest in old drugs that have fallen into disuse because of toxic side effects. One such drug is chloramphenicol. Data on the use and susceptibility patterns to chloramphenicol in developed countries in recent years are limited. OBJECTIVES: To assess the susceptibility of bacteria to chloramphenicol, and evaluate the use of chloramphenicol in Israeli hospitals as influenced by infectious disease specialists' attitudes with regard to its potential harms. METHODS: A national survey was conducted in all Israeli hospitals. Questionnaires were sent to the directors of infectious disease units and included items on chloramphenicol susceptibility in clinical isolates, use of chloramphenicol for the treatment of inpatients, local recommendations for use of chloramphenicol, and concerns regarding side effects. RESULTS: Chloramphenicol is used in 83.3% of hospitals, mostly for the treatment of aspiration pneumonia. While 22.2% of infectious disease unit directors believe that chloramphenicol should be avoided because of dangerous side effects, 88.9% believe there is a place for chloramphenicol in the treatment of patients in this era of increasing antibiotic resistance. Chloramphenicol susceptibility is routinely assessed in 44.4% of hospitals, with high susceptibility rates found among gram-positive, gram-negative and anaerobic bacteria. CONCLUSIONS: In an era of increasing antibiotic resistance, many Israeli infectious disease unit directors believe that chloramphenicol has a role in the treatment of respiratory tract and other infections in hospitalized patients. PMID- 25739174 TI - A case series of congenital hepatic hilar cyst: recommendations for diagnosis and management. AB - BACKGROUND: Congenital hepatic hilar cysts are rare. Some are simple and do not require intervention, but some biliary cystic malformations impose the risk of morbidity and mortality. OBJECTIVES: To assess a series of five patients presenting with congenital hepatic hilar cysts. METHODS: We retrospectively reviewed all cases presenting to our pediatric surgical service between January 2010 and December 2012 and found to have a congenital hepatic hilar cyst. Data regarding clinical, radiological, operative and pathological features were analyzed. RESULTS: Five children with congenital cyst of the hepatic hilum were identified; four of them were diagnosed prenatally. Four children had undergone surgical intervention: one with intrahepatic choledochal cyst, one with epidermoid cyst, and two with biliary atresia and an associated cyst of the common bile duct. In another case of choledochal cyst the treatment was conservative. All children except one had a good prognosis; one child with biliary atresia required liver transplantation. CONCLUSIONS: The differential diagnosis of congenital hepatic hilar cyst includes a broad spectrum of pathologies. It is essential to diagnose biliary atresia as early as possible. Signs such as smaller cysts in association with a hypoplastic gallbladder and direct hyperbilirubinemia may be suggestive of biliary atresia. PMID- 25739175 TI - Total en bloc spondylectomy for vertebral tumors. AB - BACKGROUND: Most spine tumors are resistant to radiation and chemotherapy. Complete surgical removal provides the best chance for long-term control of the tumor. Total en bloc spondylectomy (TES) is a radical new technique that entails total removal of the tumor and affected vertebras with clean margins. OBJECTIVES: To review our initial experience with TES, focusing on feasibility, surgical challenges and the short-term outcome. METHODS: We retrospectively reviewed the hospitalization charts and follow-up data of all patients treated with TES for spine tumors in the spine unit at Tel Aviv Medical Center. RESULTS: TES was performed in 12 patients aged 13-78 years. Nine patients had primary spinal tumors and three had metastasis. Total en bloc removal was achieved in all cases with spondylectomy of one to three affected vertebras. There was no perioperative mortality and only one major intraoperative complication of injury to a major blood vessel. Late complications were mainly related to hardware failure. CONCLUSIONS: Total en bloc spondylectomy is feasible and effective for the management of selected patients with extradural spinal tumors. Since the surgical procedure is demanding and carries significant risk, careful preoperative evaluation and collaboration with colleagues from other specialties are crucial. PMID- 25739176 TI - Use of low dose computed tomography with 3D reconstructions for the prenatal evaluation of suspected skeletal dysplasia. AB - BACKGROUND: Sonographic evaluation of congenital skeletal dysplasias is often challenging. Ultrasound may be limited in demonstrating the skeleton and may overlook specific signs of skeletal abnormality. Computed tomography (CT) with 3D reconstruction was proposed as an aid in the diagnosis of skeletal dysplasias. OBJECTIVES: To describe our experience with 3D-CT imaging for the evaluation of suspected skeletal dysplasias. METHODS: The study group comprised 20 pregnant women carrying 22 fetuses, referred for further evaluation by CT following sonographic suspicion of fetal skeletal dysplasia at 17-39 weeks of gestation. Examinations were performed using various CT protocols. Radiation exposure was decreased during the study period, with eventual lowering of the dose to 1-3 mSv. Meticulous review of the skeleton and long bone measurements were performed on 3D reconstructions. For cases of pregnancy termination, the postmortem diagnosis was compared retrospectively with the CT findings. RESULTS: Very low dose CT protocols provided excellent diagnostic images. Of 22 fetuses suspected of having skeletal dysplasia on ultrasound, 8 were found by CT to be dysplastic and in 7 the pregnancy was terminated. Postmortem findings, when available, concurred with the CT diagnosis. The remaining 14 fetuses within this cohort were found to be normal according to CT and were carried to term. CONCLUSIONS: 3D-CT may be a valuable complimentary imaging tool to ultrasound for the diagnosis of skeletal dysplasias. With low dose protocols, this examination is relatively safe, and in the appropriate clinical context may assist in making difficult decisions prenatally. PMID- 25739177 TI - The autoinflammatory side of systemic sclerosis. PMID- 25739178 TI - Chest radiography for tuberculosis screening: a valuable tool. PMID- 25739179 TI - HIV-associated neurocognitive disorders: still a hot topic? PMID- 25739180 TI - HIV-associated neurocognitive disorders (HAND). AB - Neurocognitive impairment still occurs in the era of HAART, though its onset appears to be delayed and its severity reduced, while HIV-infected individuals live longer with the infection. HAND defines three categories of disorders according to standardized measures of dysfunction: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). The pathogenic mechanisms underlying HAND involve host and virus characterizations and interactions and seem to depend heavily on the overall condition of the immune system. Since there are insufficient data at this point to determine the best therapeutic approach, and since HAART apparently is not sufficient to prevent or reverse HAND, therapy with a combination of drugs with high CPE should be considered while adjunctive and alternative therapies are being explored. PMID- 25739181 TI - CA 19-9 in the presence of obstructive jaundice due to Mirizzi syndrome. PMID- 25739182 TI - A novel STAT3 mutation in a patient with hyper-immunoglobulin E syndrome. PMID- 25739183 TI - Paget's disease of the male breast with underlying ductal carcinoma in situ. PMID- 25739184 TI - Ankyloblepharon filiforme adnatum. PMID- 25739185 TI - [The dynamics of behavioral and neuroreceptor effects after acute and long-term noopept administration in C57BL/6 and BALB/c mice]. AB - The effect of acute, 7-fold and 14-fold noopept (1 mg/kg/day) administration on the dynamics of anxiolitic and nootropic behavioral effects in cross-maze, as well as their correlations with NMDA- and BDZ-receptor density was studied in inbred mice strains, differing in exploratory and emotional status--C57BL/6 and BALB/c. The dipeptide failed to affect the anxiety and exploration activity in C57BL/6 mice at each of 3 steps of experimental session. In this strain the B(max) values of [3H]-MK-801 and [3H]-Flunitrazepam binding changed only after single administration. In respect to BALB/c mice noopept induced both the anxiolitic and nootropic effects reaching their maximum on 7th day. In BALB/c strain the dynamics of hippocampal NMDA-receptor binding corresponds to the dynamics of exploratory efficacy whereas the dynamics of BDZ-receptors in prefrontal cortex was reciprocally to dynamics of anxiety level. PMID- 25739186 TI - [Morphological changes in brain tissues of rat with local permanent ischemia model under the action of 2-methyl-6-ethyl-3-hydroxypyridine hemisuccinate]. AB - The influence of 2-methyl-6-ethyl-3-hydroxypiridine hemisuccinate on the morphological state of rat brain tissue after the occlusion of left middle cerebral artery has been studied. It was found that 6- and 12-day treatment with 2-methyl-6-ethyl-3-hydroxypyridine hemisuccinate at a dose of 100 mg/kg (intraperitoneal) led to regenerative processes in ischemic brain tissue. The latter treatment duration was most effective. PMID- 25739187 TI - [Determining the relative content of cisplatin in cells by acridine orange fluorescence intensity]. AB - The fluorescence intensity of acridine orange (AO) dye bound to living human leukocytes, rat leukocytes, and Pliss lymphosarcoma cells of rat has been studied by fluorescence microscopy. The cell suspension of each test was divided into two parts, to one of which the drug cisplatin was added to a final concentration of 0.1 MUg/mL and the mixture was incubated for 20 - 60 min. Acridine orange was then added and the average intensity of red and green fluorescence of cells was determined. The brightness of AO in the green region of the spectrum was reduced approximately 3-fold (p = 0.001) in cells with cisplatin. In the red region of the fluorescence, differences in the brightness of cells with and without cisplatin were not observed. These data indicate that a decrease in the brightness of green fluorescence of AO can be a test for the presence of cisplatin in cells. PMID- 25739188 TI - [Comparative effectiveness hepatotropic activity remaxol and Essentiale N in chronic viral hepatitis]. AB - Studied hepatotropic activity remaxol and Essentiale N with chronic viral hepatitis (hug) and: 45 patients received the drug remaxol (intravenous drip, 400 ml per day, 10 days), 45 patients Essentiale N (intravenous bolus, 5 ml per day, 10 days). The efficacy was assessed by clinical symptoms, activity ofAlt, AST, bilirubin, alkaline phosphatase, molecules of average weight (MSM), and total effective concentration of albumin (ECA). Remaxol when hug had a hepatotropic effect comparable with Essentiale N, but more effectively cut short asteno vegetative, dyspeptic, cholestatic and intoxication syndrome, which was confirmed by the significantly low values of MSM and high rates of ECA. The inclusion remaxol in the treatment of patients hug should be considered pathogenetically justified, clinically justified and promising. PMID- 25739189 TI - [Using deltalicin for the treatment of patients with diabetic retinopathy]. AB - The characteristics of visual evoked potential (VEP) have been investigated in a group of 15 healthy volunteers (aged 31.7 +/- 3.6 years) and 30 insulin-dependent patients (aged 32.1 +/- 4.0 years) with diabetes mellitus, among which 15 patients suffered from diabetic retinopathy and 15 patients had no retinopathy. An increase in the latent period along with reduction of the VEP amplitude after photostress action upon the macular part of retina have been observed in patients with diabetes, these effects were more pronounced in the subgroup with retinopathy. The restoration of VEP characteristics in 73.5 +/- 3.3 s from the moment of photostress was observed in the control group, while this index in both subgroups of diabetic patients without and with retinopathy was 88.7 +/- 5.9 and 137.2 +/- 11.3 s, respectively. Treatment with deltalicin (daily dose of 0.0003 g of delta sleep-inducing peptide intranasally for two months) decreased the latent period and led to less pronounced depression of VEP amplitude in patients with diabetic retinopathy, and reduced the period of restoration of VEP characteristics to 95.1 +/- 6.8 s. PMID- 25739190 TI - [Relative bioavailability of glucosamine after oral, intramuscular and transdermal administration of hondroxid maximum preparation in experiment]. AB - A comparison of the relative bioavailability and intensity of penetration of glucosamine sulfate in oral, injection and topical administration of the dosage form Hondroxid Maximum as a cream containing micellar system for transdermal delivery of glucosamine in the experiment by Sprague-Dawley rats was carried out. On the base on the pharmacokinetic profiles data of glucosamine in rat blood plasma with daily administration in 3 times a day for 1 week by cream Hondroxid Maximum 400 mg/kg and the single injection solution of 4% Glucosamine sulfate 400 mg/kg was found that the relative bioavailability was 61.6%. Calculated penetration rate of glucosamine in the plasma through the rats skin in 4 hours, equal to 26.9 MUg/cm2 x h, and the penetration of glucosamine through the skin into the plasma after a single dose of cream in 4 hours was 4.12%. Comparative analysis of literature and experimental data and calculations based on them suggest that medicine Hondroxid Maximum, cream with transdermal glucosamine complex in the treatment in accordance with the instructions can provide an average concentration of glucosamine in the synovial fluid of an inflamed joint in the range (0.7 - 1.5) MUg/ml, much higher than the concentration of endogenous glucosamine human synovial joint fluid (0.02 - 0.07 MUg/ml). By theoretical calculations taking into account experimental data it is shown that the medicine Hondroxid Maximum can reach the bioavailability level of the modern injection forms and exceed the bioavailability level of modern oral forms of glucosamine up to 2 times. PMID- 25739192 TI - Congratulate Academician Wanzhen LU 90th birthday. PMID- 25739191 TI - [Preclinical study of safety of the new pharmacological substance AV0012 to treat hepatitis C]. AB - Pharmacological safety of a new type of HCV inhibitor, AV0012, was studied including acute, subchronic and chronic toxicity in mice, rats and monkeys. Genotoxicity was assessed using the Ames test and the chromosomal aberrations assay in the bone marrow cells of mice. It is established that AV0012 has low toxicity in SHK line mice, Wistar line rats, and monkey of Rhesus macaques species. Results obtained in the study of genetic toxicity showed that AV0012 exhibits no mutagenic activity. Data on general toxicity and mutagenicity discussed in this paper, together with data on 1 the pharmacological activity, pharmacokinetics, and metabolism published previously, allow us to consider AV0012 as a candidate drug for clinical research phase I. PMID- 25739193 TI - [Research and application progress of near infrared spectroscopy analytical technology in China in the past five years]. AB - In the past decade, near infrared spectroscopy (NIR) has expanded rapidly and been applied widely in many fields in China. The recent progress of the research and application of NIR analytical technology in China especially in the past five years has been reviewed. It includes hardware and software R&D, Chemometric algorithms and experimental methods research, and quantitative and qualitative applications in the typical fields such as food, agriculture, pharmaceuticals, petrochemicals, forestry, and medical diagnosis. 209 references are cited, which are mainly published in national journals, professional magazines, and book chapters. The developing trend of near infrared spectroscopy and the strategies to further promote its innovation and development in China in the near future are put forward and discussed. PMID- 25739194 TI - [A correction method of baseline drift of discrete spectrum of NIR]. AB - In the present paper, a new correction method of baseline drift of discrete spectrum is proposed by combination of cubic spline interpolation and first order derivative. A fitting spectrum is constructed by cubic spline interpolation, using the datum in discrete spectrum as interpolation nodes. The fitting spectrum is differentiable. First order derivative is applied to the fitting spectrum to calculate derivative spectrum. The spectral wavelengths which are the same as the original discrete spectrum were taken out from the derivative spectrum to constitute the first derivative spectra of the discrete spectra, thereby to correct the baseline drift of the discrete spectra. The effects of the new method were demonstrated by comparison of the performances of multivariate models built using original spectra, direct differential spectra and the spectra pretreated by the new method. The results show that negative effects on the performance of multivariate model caused by baseline drift of discrete spectra can be effectively eliminated by the new method. PMID- 25739195 TI - [Prediction of the side-cut product yield of atmospheric/vacuum distillation unit by NIR crude oil rapid assay]. AB - In the present paper, based on the fast evaluation technique of near infrared, a method to predict the yield of atmos- pheric and vacuum line was developed, combined with H/CAMS software. Firstly, the near-infrared (NIR) spectroscopy method for rapidly determining the true boiling point of crude oil was developed. With commercially available crude oil spectroscopy da- tabase and experiments test from Guangxi Petrochemical Company, calibration model was established and a topological method was used as the calibration. The model can be employed to predict the true boiling point of crude oil. Secondly, the true boiling point based on NIR rapid assay was converted to the side-cut product yield of atmospheric/vacuum distillation unit by H/CAMS software. The predicted yield and the actual yield of distillation product for naphtha, diesel, wax and residual oil were compared in a 7-month period. The result showed that the NIR rapid crude assay can predict the side-cut product yield accurately. The near infrared analytic method for predicting yield has the advantages of fast analysis, reliable results, and being easy to online operate, and it can provide elementary data for refinery planning optimization and crude oil blending. PMID- 25739196 TI - [Update of near-infrared models for testing ceftazidime, water and arginine in ceftazidime for injection]. AB - To find a more reasonable index to decide whether the universal quantitative NIR model needs to be updated and to develop a general method to update universal quantitative NIR models, the quantitative models for testing ceftazidime, water and arginine contents in ceftazidime for injection were taken as example. The study was performed by analyzing the similarity between new sample spectra and the training set spectra of the original models. At first, new samples of ceftazidime for injection were divided into five groups by cluster analysis. Then representative samples of each group were selected by sample selection strategy. Spectra of those samples were used to update the original quantitative models. The prediction deviation of the new ceftazidime powder injection samples by the models before and after updating was calculated. Decreasing the prediction deviation was regarded as the standard to decide if the updating was effective. At the same time, the correlation coefficient of new sample spectra and reference sample spectra was defined as the index to study the general method for model updating. (Reference sample refers to training set sample) Finally, the proposed method was validated by updating universal models for testing ceftazidime, water and arginine contents in ceftazidime powder injections. Results show that the correlation coefficient of new sample spectra and training set sample spectra of the original model was calculated within modeling wavelength range. It was proved that when correlation coefficient rT < 96.5%, the model needs to be updated. Accordingly, rT = 96.5% was set as the threshold. The quantitative models were updated by the method mentioned above. As a result, when testing ceftazidime for injection containing sodium carbonate using newly updated models, the average predicting deviation of ceftazidime contents decreased from 8.1% to 2.3%. And the average predicting deviation of water contents decreased from 2.2% to 0.3%. Meanwhile, with regard to samples containing arginine using the updated models, the average predicting deviation of ceftazidime contents decreased from 7.0% to 1.9%. The average predicting deviation of water contents decreased from 0.6% to 0.3%. And that of arginine contents de- creased from 2.3% to 0.4%. CONCLUSION: The newly updated models can be used for testing ceftazidime, water and arginine contens in ceftazidime for injection samples of domestic market. It is reasonable to set rT as the index to decide whether the model needs updating. Moreover, it is necessary to take PCA scores graph of new sample spectra and training set spectra of the original model into account. The proposed method for updating models can be used as a usual approach. And rT = 96.5% can be set as the threshold to determine whether the model needs to be updated. PMID- 25739197 TI - [Using 2-DCOS to identify the molecular spectrum peaks for the isomer in the multi-component mixture gases Fourier transform infrared analysis]. AB - The generalized two-dimensional correlation spectroscopy and Fourier transform infrared were used to identify hydrocarbon isomers in the mixed gases for absorption spectra resolution enhancement. The Fourier transform infrared spectrum of n-butane and iso-butane and the two-dimensional correlation infrared spectrum of concentration perturbation were used for analysis as an example. The all band and the main absorption peak wavelengths of Fourier transform infrared spectrum for single component gas showed that the spectra are similar, and if they were mixed together, absorption peaks overlap and peak is difficult to identify. The synchronous and asynchronous spectrum of two-dimensional correlation spectrum can clearly identify the iso-butane and normal butane and their respective characteristic absorption peak intensity. Iso-butane has strong absorption characteristics spectrum lines at 2,893, 2,954 and 2,893 cm(-1), and n butane at 2,895 and 2,965 cm(-1). The analysis result in this paper preliminary verified that the two-dimensional infrared correlation spectroscopy can be used for resolution enhancement in Fourier transform infrared spectrum quantitative analysis. PMID- 25739198 TI - [Recent progress in diagnosis of malignant tumors by Fourier transform infrared spectroscopy]. AB - Malignant tumors pose a serious threat to mankind health and life. As a result, early diagnosis is very important. In recent years, Fourier transform infrared spectroscopy has shown enormous development potential of cancer diagnosis. Compared with traditional methods, this technology has apparent advantages in the aspects of accuracy, rapidity, noninvasion, in situ, cheapness, automation, replication, without pretreatment and early diagnosis at the molecular level. This paper summarized study progress that FTIR technology applied in diagnosis of respiratory system tumor, digestive system tumor, urinary genital system tumor, brain tumor, skin tumor and blood system tumor, and combined with the international present state of clinical medicine, spectroscopy and chemometrics, five prospects were put forward: expand the sample size and undertake multi center study; combined with endoscopy and puncture biopsy to guide real-time in situ diagnosis and biopsy during surgery; further automated; find more efficient chemometric methods; the identification of individual parameters has yet to be confirmed by further studies. With the further development and improvement of FTIR technology, it will become an important method for the diagnosis of malignant tumors, and may even as a routine screening tool applied to stage and grade the tumors. PMID- 25739199 TI - [Applications and prospects of on-line near infrared spectroscopy technology in manufacturing of Chinese materia medica]. AB - The quality of Chinese materia medica (CMM) is affected by every process in CMM manufacturing. According to multi-unit complex features in the production of CMM, on-line near infrared spectroscopy (NIR) is used as an evaluating technology with its rapid, non-destructive and non-pollution etc. advantages. With the research in institutions, the on-line NIR applied in process analysis and control of CMM was described systematically, and the on-line NIR platform building was used as an example to clarify the feasibility of on-line NIR technology in CMM manufacturing process. Then, from the point of application by pharmaceutical companies, the current on-line NIR research on CMM and its production in pharmaceutical companies was relatively comprehensively summarized. Meanwhile, the types of CMM productions were classified in accordance with two formulations (liquid and solid dosage formulations). The different production processes (extraction, concentration and alcohol precipitation, etc. ) were used as liquid formulation diacritical points; the different types (tablets, capsules and plasters, etc.) were used as solid dosage formulation diacritical points, and the reliability of on-line NIR used in the whole process in CMM production was proved in according to the summary of literatures in recent 10 years, which could support the modernization of CMM production. PMID- 25739200 TI - [Applications of near infrared reflectance spectroscopy technique (NIRS) to soil attributes research]. AB - Soil is a much complicated substance, because animals, plants and microbes live together, organic and inorganic exist together. So soil contains a large amount of information. The traditional method in laboratory is a time-consuming effort. But the technology of near infrared reflectance spectroscopy (NIRS) has been widely used in many areas, owing to its rapidness, high efficiency, no pollution and low cost, NIRS has become the most important method to detect the composition of soil. This paper mainly introduce some traditional methods in laboratory, the basic processes of soil detection by NIRS, some algorithms for data preprocessing and modeling. Besides, the present paper illustrates the latest research progress and the development of portable near infrared instruments of the soil. According to this paper, the authors also hope to promote the application conditions of NIRS in the grassland ecology research in China, and accelerate the modernization of research measures in this area. PMID- 25739201 TI - [Study on the detection of active ingredient contents of Paecilomyces hepiali mycelium via near infrared spectroscopy]. AB - Partial least squares (PLS) and radial basis function neural network (RBFNN) combined with near infrared spectros- copy (NIR) were applied to develop models for cordycepic acid, polysaccharide and adenosine analysis in Paecilomyces hepialid fermentation mycelium. The developed models possess well generalization and predictive ability which can be applied for crude drugs and related productions determination. During the experiment, 214 Paecilomyces hepialid mycelium samples were obtained via chemical mutagenesis combined with submerged fermentation. The contents of cordycepic acid, polysaccharide and adenosine were determined via traditional methods and the near infrared spectroscopy data were collected. The outliers were removed and the numbers of calibration set were confirmed via Monte Carlo partial least square (MCPLS) method. Based on the values of degree of approach (Da), both moving window partial least squares (MWPLS) and moving window radial basis function neural network (MWRBFNN) were applied to optimize characteristic wavelength variables, optimum preprocessing methods and other important variables in the models. After comparison, the RBFNN, RBFNN and PLS models were developed successfully for cordycepic acid, polysaccharide and adenosine detection, and the correlation between reference values and predictive values in both calibration set (R2c) and validation set (R2p) of optimum models was 0.9417 and 0.9663, 0.9803 and 0.9850, and 0.9761 and 0.9728, respectively. All the data suggest that these models possess well fitness and predictive ability. PMID- 25739202 TI - [Rapid determination of the multi-marker ingredients in Heterosmilacis Japonicae Rhizoma and Sophorae Flavescentis Radix with near-infrared diffused reflection spectroscopy]. AB - A rapid NIRS method for determination of macrozamin in Heterosmilacis japonicae rhizoma (HJR), and the total content of oxymatrine and matrine (OMT + MT) as well as the total content of oxysophocarpine and sophocarpine (OSC + SC) in sophorae flavescens radix (SFR) was developed to explore the application feasibility of NIRS for the quality assurance system of Chinese patent drugs. The contents of macrozamin in HJR samples, and OMT + MT and OSC + SC in SFR samples were determined by HPLC as reference values. The NIR spectra of the samples were measured in a diffused reflection mode. The different characteristic wavebands and pretreatment methods were optimized. The quantitative calibration models between the NIR spectra and the content reference values of marker components in HJR and SFR samples, were established with partial least square method, and further optimized through the cross validation and external validation. The contents of macrozamin in 88 batches of HJR samples were over the range of 0.36 12.88 mg . g(-1). The total contents of OMT + MT and OSC + SC in 75 batches of SFR samples were over the range of 8.87-66.31 and 2.30-15.11 mg . g(-1), respectively. The performance of the final models for macrozamin, OMT + MT and OSC + SC was evaluated well according to correlation coefficients (r), root mean square error of cross-validation (RMSECV) and root mean square error of prediction (RMSEP). The R2 values of the cross-validation for macrozamin, OMT + MT and OSC + SC were 0.9025, 0.9491 and 0.9137, and those of RMSECV were 0.961, 2.45 and 0.724 mg . g(-1) respectively. The R2 values of external validation for the three models were 0.9817, 0.9826 and 0.9609, and those of RMSEP were 0.693, 2.27 and 0.658 mg . g(-1), respectively. This is the first report on rapid determination of macrozamin in Heterosmilacis japonicae rhizoma, and oxymatrine, matrine, oxysophocarpine and sophocarpine in sophorae flavescens radix by NIRS method. The presented method can fulfill the requirement of rapid acquirement of chemical information of raw medicinal materials prior the manufacturing of compound Kushen injection. PMID- 25739203 TI - [Application of uncertainty assessment in NIR quantitative analysis of traditional Chinese medicine]. AB - The near infrared (NIR) spectra of Liuyi San samples were collected during the mixing process and the quantitative models by PLS (partial least squares) method were generated for the quantification of the concentration of glycyrrhizin. The PLS quantitative model had good calibration and prediction performances (r(cal) 0.998 5, RMSEC = 0.044 mg . g(-1); r(val) = 0.947 4, RMSEP = 0.124 mg . g(-1)), indicating that NIR spectroscopy can be used as a rapid determination method of the concentration of glycyrrhizin in Liuyi San powder. After the validation tests were designed, the Liao-Lin-Iyer approach based on Monte Carlo simulation was used to estimate beta-content-gamma-confidence tolerance intervals. Then the uncertainty was calculated, and the uncer- tainty profile was drawn. The NIR analytical method was considered valid when the concentration of glycyrrhizin is above 1.56 mg . g(-1) since the uncertainty fell within the acceptable limits (lambda = +/- 20%). The results showed that uncertainty assessment can be used in NIR quantitative models of glycyrrhizin for different concentrations and provided references for other traditional Chinese medicine to finish the uncertainty assessment using NIR quantitative analysis. PMID- 25739204 TI - [Determination of wine original regions using information fusion of NIR and MIR spectroscopy]. AB - Geographical origins of wine grapes are significant factors affecting wine quality and wine prices. Tasters' evaluation is a good method but has some limitations. It is important to discriminate different wine original regions quickly and accurately. The present paper proposed a method to determine wine original regions based on Bayesian information fusion that fused near-infrared (NIR) transmission spectra information and mid-infrared (MIR) ATR spectra information of wines. This method improved the determination results by expanding the sources of analysis information. NIR spectra and MIR spectra of 153 wine samples from four different regions of grape growing were collected by near infrared and mid-infrared Fourier transform spe trometer separately. These four different regions are Huailai, Yantai, Gansu and Changli, which areall typical geographical originals for Chinese wines. NIR and MIR discriminant models for wine regions were established using partial least squares discriminant analysis (PLS-DA) based on NIR spectra and MIR spectra separately. In PLS-DA, the regions of wine samples are presented in group of binary code. There are four wine regions in this paper, thereby using four nodes standing for categorical variables. The output nodes values for each sample in NIR and MIR models were normalized first. These values stand for the probabilities of each sample belonging to each category. They seemed as the input to the Bayesian discriminant formula as a priori probability value. The probabilities were substituteed into the Bayesian formula to get posterior probabilities, by which we can judge the new class characteristics of these samples. Considering the stability of PLS-DA models, all the wine samples were divided into calibration sets and validation sets randomly for ten times. The results of NIR and MIR discriminant models of four wine regions were as follows: the average accuracy rates of calibration sets were 78.21% (NIR) and 82.57% (MIR), and the average accuracy rates of validation sets were 82.50% (NIR) and 81.98% (MIR). After using the method proposed in this paper, the accuracy rates of calibration and validation changed to 87.11% and 90.87% separately, which all achieved better results of determination than individual spectroscopy. These results suggest that Bayesian information fusion of NIR and MIR spectra is feasible for fast identification of wine original regions. PMID- 25739205 TI - [Application of Fourier transform infrared spectroscopy in identification of wine spoilage]. AB - In the present work, fresh and spoiled wine samples from three wines produced by different companies were studied u- sing Fourier transform infrared (FTIR) spectroscopy. We analyzed the physicochemical property change in the process of spoil- age, and then, gave out the attribution of some main FTIR absorption peaks. A novel determination method was explored based on the comparisons of some absorbance ratios at different wavebands although the absorbance ratios in this method were relative. Through the compare of the wine spectra before and after spoiled, the authors found that they were informative at the bands of 3,020~2,790, 1,760~1,620 and 1,550~800 cm(-1). In order to find the relation between these informative spectral bands and the wine deterioration and achieve the discriminant analysis, chemometrics methods were introduced. Principal compounds analysis (PCA) and soft independent modeling of class analogy (SIMCA) were used for classifying different-quality wines. And partial least squares discriminant analysis (PLS-DA) was applied to identify spoiled wines and good wines. Results showed that FTIR technique combined with chemometrics methods could effectively distinguish spoiled wines from fresh samples. The effect of classification at the wave band of 1 550-800 cm(-1) was the best. The recognition rate of SIMCA and PLSDA were respectively 94% and 100%. This study demonstrates that Fourier transform infrared spectroscopy is an effective tool for monitoring red wine's spoilage and provides theoretical support for developing early-warning equipments. PMID- 25739206 TI - [Identification of adulterants in adulterated milks by near infrared spectroscopy combined with non-linear pattern recognition methods]. AB - In the present work, two hundred and eighty seven raw milks collected from pastures in Shanghai and surrounding areas of Shanghai were used as true milk samples and divided into three true milk sets. Five hundred and twenty six adulterated milk samples, which contained dextrin (or starch) mixed with melamine (or urea, or ammonium nitrate), were prepared as six different adulterated milk sets. The concentrations of these adulterants in the adulterated milks were designed to be 0.15%~ 0.45% (starch or dextrin), 700-2,100 mg . kg(-1) (ammonium nitrate), 524-1,572 mg . kg(-1) (urea), and 365.5-1,096.5 mg . kg(-1) (melamine) to guarantee the protein content of adulterated milks detected by Kjeldahl method not lower than 3%. All the near infrared spectra (NIR) of the samples should have a pretreatment of normal variable transformation (SNV) before they were used to build discriminating models. The three true milk sets and six adulterated milk sets were combined in different ways in order to build NIR models for discriminating different kinds of adulterants (i. e. , dextrin, starch, melamine, urea and ammonium nitrate) based on simplified K-nearest neighbor classification algorithm (IS-KNN) and an improved and simplified of support vector machine (nu SVM) method. The relationship between mass concentration of the adulterants and the rate of correct discrimination was also investigated. The results show that the average discrimination accuracy of IS-KNN and nu-SVM for identifying melamine, urea and ammonium nitrate were in the region of 49.55% to 51.01%, 61.78% to 68.79% and 68.25% to 73.51%, respectively. Therefore within the concentration regions designed in this study, it is difficult to distinguish different kinds of pseudo proteins by NIR spectroscopy. However, the average accuracy of IS-KNN and nu-SVM for identifying starch and dextrin are 92.33% and 93.66%, 77.29% and 85.08%, respectively. Most discrimination results of nu-SVM are better than those of IS-KNN. The correlative analysis between the discrimination accuracy rate and the content levels of the adulterants indicated that near infrared spectroscopy combined with non-linear pattern recognition methods can distinguish dextrin and starch in milks with higher concentration levels (> 0.15%), but do not work well on identifying the adulterants with lower concentrations such as melamine (365.5 to 1,096.5 mg kg(-1)), urea (524 to 1,572 mg . kg(-1)), ammonium nitrate (700 to 2,100 mg . kg(-1)). Therefore near Infrared Spectroscopy is not suitable for identifying the adulterants with concentrations are below 0.1%. PMID- 25739207 TI - [On-site evaluation of raw milk qualities by portable Vis/NIR transmittance technique]. AB - To ensure the material safety of dairy products, visible (Vis)/near infrared (NIR) spectroscopy combined with che- mometrics methods was used to develop models for fat, protein, dry matter (DM) and lactose on-site evaluation. A total of 88 raw milk samples were collected from individual livestocks in different years. The spectral of raw milk were measured by a porta- ble Vis/NIR spectrometer with diffused transmittance accessory. To remove the scatter effect and baseline drift, the diffused transmittance spectra were preprocessed by 2nd order derivative with Savitsky-Golay (polynomial order 2, data point 25). Changeable size moving window partial least squares (CSMWPLS) and genetic algorithms partial least squares (GAPLS) meth- ods were suggested to select informative regions for PLS calibration. The PLS and multiple linear regression (MLR) methods were used to develop models for predicting quality index of raw milk. The prediction performance of CSMWPLS models were similar to GAPLS models for fat, protein, DM and lactose evaluation, the root mean standard errors of prediction (RMSEP) were 0.115 6/0.103 3, 0.096 2/0.113 7, 0.201 3/0.123 7 and 0.077 4/0.066 8, and the relative standard deviations of prediction (RPD) were 8.99/10.06, 3.53/2.99, 5.76/9.38 and 1.81/2.10, respectively. Meanwhile, the MLR models were also cal- ibrated with 8, 10, 9 and 7 variables for fat, protein, DM and lactose, respectively. The prediction performance of MLR models was better than or close to PLS models. The MLR models to predict fat, protein, DM and lactose yielded the RMSEP of 0.107 0, 0.093 0, 0.136 0 and 0.065 8, and the RPD of 9.72, 3.66, 8.53 and 2.13, respectively. The results demonstrated the usefulness of Vis/NIR spectra combined with multivariate calibration methods as an objective and rapid method for the quality evaluation of complicated raw milks. And the results obtained also highlight the potential of portable Vis/NIR instruments for on-site assessing quality indexes of raw milk. PMID- 25739208 TI - [Potentiality of synchronous fluorescence technology for determination of reconstituted milk adulteration in fresh milk]. AB - In the present research, synchronous fluorescence technique was used for qualitative and quantitative detection of re- constituted milk mixed into two kinds of milk samples, raw milk and pasteurized milk, respectively. The total accuracy of sample was used to evaluate the performance of the qualitative discrimination models. The correlation coefficient (r), the root mean square error of correction (RMSEC) and the root mean square error of prediction (RMSEC) were used to evaluate the perform- ance of the quantitative analysis models. The constant wavelength difference (Deltalambda) between the excitation and emission scanning was determined to be 80 nm from three-dimensional fluorescence spectrum of milk. The total discrimination accuracy was 100% by partial least squares discrimination analysis (PLS-DA) for raw milk, pasteurized milk and reconstituted milk samples. When checking whether the raw milk and pasteurized milk were mixed with reconstituted milk, the total accuracy of calibration samples was 100% and the accuracy of prediction samples was 75% and 81.25%, respectively. The effects of qualitative discrimination models were satisfactory. The PLS regression was used for quantitative analysis of the reconstituted milk content mixed in raw milk and pasteurized milk. The correlation coefficients of actual values versus predicted values were 0.911 2 and 0.911 2, re-spectively. The RMSEC was 0.042 2 and 0.0384, respectively. The RMSEP was 0.054 8 and 0.057 5, respectively. The cor- relation coefficients of quantitative analysis models could reach up to 0.9. The results showed that synchronous fluorescence technology could be applied for rapid detection of reconstituted milk mixed in fresh milk PMID- 25739209 TI - [Authentication and adulteration analysis of sesame oil by FTIR spectroscopy]. AB - It's common in edible oil market that adulterating low price oils in high price oils. Sesame oil was often adulterated because of its high quality and price, so the authentication and adulteration of sesame oil were qualitatively and quantitatively analyzed by Fourier transform infrared (FTIR) spectroscopy combined with chemometrics. Firstly, FTIR spectra of sesame oil, soybean oil, and sunflower seed oil in 4,000-650 cm(-1) were analyzed. It was very difficult to detect the difference among the spectra of above edible oils, because they are all mixtures of triglyceride fatty acids and have similar spectra. However, the FTIR data of edible oils in the fingerprint region of 1,800-650 cm(-1) differed slightly because their fatty acid compositions are different, so the data could be classified and recognized by chemometric methods. The authenticity model of sesame oil was built by principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA). The recognition rate was 100%, and the built model was satisfactory. The classification limits of both soybean oil and sunflower seed oil adulterated in sesame oil were 10%, with the chemometric treatments of standard normal variation (SNV), partial least square (PLS) and PCA. In addition, the FTIR data processed by PCA and PLS were used to establish an analysis model of binary system of sesame oil mixed with soybean oil or sunflower oil, the prediction values had good corresponding relationship with true values, and the relative errors of prediction were between -6.87% and 8.07%, which means the quantitative model was practical. This method is very convenient and rapid after the models have been built, and can be used for rapid detection of authenticity and adulteration of sesame oil. The method is also practical and suitable for the daily analysis of large amount of samples. PMID- 25739210 TI - [Raman spectroscopy combined with pattern recognition methods for rapid identification of crude soybean oil adulteration]. AB - In the present paper, a non-destructive, simple and rapid analytical method was proposed based on Raman spectroscopy (Raman) combined with principal component analysis (PCA) and support vector machine (SVM) as pattern recognition methods for adulteration of crude soybean oil (CSO). Based on fingerprint characteristics of Raman, the spectra of 28 CSOs, 46 refined edible oils (REOs) and 110 adulterated oil samples were analyzed and used for discrimination model establishment. The preprocessing methods include choosing spectral band of 780 1,800 cm(-1), Y-axis intensity correction, baseline correction and normalization in succession. After those series of spectral pretreatment, PCA was usually employed for extracting characteristic variables of all Raman spectral data and 7 principal components which were the highest contributions of all data were used as var- iables for SVM model. The SVM discrimination model was established by randomly picking 20 CSOs and 95 adulterated oils as calibration set, and 8 CSOs and 35 adulterated oils as validation set. There were 4 kinds of kernel function algorithm (linear, polynomial, RBF, sigmoid) respectively used for establishing SVM models and grid-search for optimization of parameters of all the SVM models. The classification results of 4 models were compared by their discrimination performances and the optimal SVM model was based on linear kernel classification algorithm with 100% accuracy rate of calibration set recognition, a zero misjudgment rate and the lowest detection limit of 2.5%. The above results showed that Raman combined PCA-SVM could discriminate CSO adulteration with refined edible oils. Since Raman spectroscopy is simple, rapid, non-destructive, environment friendly, and suitable for field testing, it will provide an alternative method for edible oil adulteration analysis. PMID- 25739211 TI - [Vis-NIR spectroscopic pattern recognition combined with SG smoothing applied to breed screening of transgenic sugarcane]. AB - Based on Savitzky-Golay (SG) smoothing screening, principal component analysis (PCA) combined with separately supervised linear discriminant analysis (LDA) and unsupervised hierarchical clustering analysis (HCA) were used for non-destructive visible and near-infrared (Vis-NIR) detection for breed screening of transgenic sugarcane. A random and stability-dependent framework of calibration, prediction, and validation was proposed. A total of 456 samples of sugarcane leaves planting in the elongating stage were collected from the field, which was composed of 306 transgenic (positive) samples containing Bt and Bar gene and 150 non-transgenic (negative) samples. A total of 156 samples (negative 50 and positive 106) were randomly selected as the validation set; the remaining samples (negative 100 and positive 200, a total of 300 samples) were used as the modeling set, and then the modeling set was subdivided into calibration (negative 50 and positive 100, a total of 150 samples) and prediction sets (negative 50 and positive 100, a total of 150 samples) for 50 times. The number of SG smoothing points was ex- panded, while some modes of higher derivative were removed because of small absolute value, and a total of 264 smoothing modes were used for screening. The pairwise combinations of first three principal components were used, and then the optimal combination of principal components was selected according to the model effect. Based on all divisions of calibration and prediction sets and all SG smoothing modes, the SG-PCA-LDA and SG-PCA-HCA models were established, the model parameters were optimized based on the average prediction effect for all divisions to produce modeling stability. Finally, the model validation was performed by validation set. With SG smoothing, the modeling accuracy and stability of PCA-LDA, PCA-HCA were signif- icantly improved. For the optimal SG PCA-LDA model, the recognition rate of positive and negative validation samples were 94.3%, 96.0%; and were 92.5%, 98.0% for the optimal SG-PCA-LDA model, respectively. CONCLUSION: Vis-NIR spectro- scopic pattern recognition combined with SG smoothing could be used for accurate recognition of transgenic sugarcane leaves, and provided a convenient screening method for transgenic sugarcane breeding. PMID- 25739212 TI - [Application of characteristic NIR variables selection in portable detection of soluble solids content of apple by near infrared spectroscopy]. AB - In order to detect the soluble solids content(SSC)of apple conveniently and rapidly, a ring fiber probe and a portable spectrometer were applied to obtain the spectroscopy of apple. Different wavelength variable selection methods, including unin- formative variable elimination (UVE), competitive adaptive reweighted sampling (CARS) and genetic algorithm (GA) were pro- posed to select effective wavelength variables of the NIR spectroscopy of the SSC in apple based on PLS. The back interval LS- SVM (BiLS-SVM) and GA were used to select effective wavelength variables based on LS-SVM. Selected wavelength variables and full wavelength range were set as input variables of PLS model and LS-SVM model, respectively. The results indicated that PLS model built using GA-CARS on 50 characteristic variables selected from full-spectrum which had 1512 wavelengths achieved the optimal performance. The correlation coefficient (Rp) and root mean square error of prediction (RMSEP) for prediction sets were 0.962, 0.403 degrees Brix respectively for SSC. The proposed method of GA-CARS could effectively simplify the portable detection model of SSC in apple based on near infrared spectroscopy and enhance the predictive precision. The study can provide a reference for the development of portable apple soluble solids content spectrometer. PMID- 25739213 TI - [Detection of citrus greening based on Vis-NIR spectroscopy and spectral feature analysis]. AB - In the present paper we discussed the methods of classification of citrus greening and extraction of spectral features based on the spectral reflectance of four different statuses of citrus leaves (healthy, HLB, iron deficiency and nitrogen deficiency). Between two classes of classification, the values of discriminability of different spectra were calculated to extract spectral features. The greater value of discriminability showed a bigger difference of the two spectra, which means it would be easier to distinguish the two classes. By the Fisher linear discriminant analysis, three classification models (HLB & healthy, HLB & iron deficiency and HLB & nitrogen deficiency) based on the spectral features yielded more than 90% accuracies, which were better than expected. And at last, we discussed the application of the classification tree in multi-class discriminant analysis and spectral features extraction. The models trained based on the original reflectance spectra, first derivative and selected spectral features yielded more than 88% average accuracy, and especially the model based on the spectral features yielded more than 94% average accuracies, which verified the feasibility of detection of citrus greening in multi-class discriminant analysis and the importance of the spectral feature extraction. The results were compared based on classification tree, k-NN and Bayesian classifiers. Adoption of spectral features as input variables was significantly superior to using the original spectrum, which confirmed the validity of spectral feature selection. Spectral features could be used well for developing a multi spectral imaging system to detect the citrus greening. PMID- 25739214 TI - [Determination of steviol in Stevia Rebaudiana leaves by near infrared spectroscopy]. AB - The objective of the present study is to develop a method for rapid determination of the content of stevioside (ST) and rebaudioside A (RA) in Stevia Rebaudiana leaves. One hundred and five samples of stevia from different areas containing ST of 0.27%-1.40% and RA of 0.61%-3.98% were used. The 105 groups' NIRS diagram was processed by different methods including subtracting a straight line (SLS), multiplicative scatter correction (MSC), first derivative (FD), second derivative (SD) and so on, and then all data were analyzed by partial least square (PLS). The study showed that SLS can be used to extracted spectra information thoroughly to analyze the contents of ST, the correlation coefficients of calibration (Re), the root-mean-square errors of calibration (RMSEC) and prediction (RMSEP), and the residual predictive deviation (RPD) were 0.986, 0.341, 1.00 and 2.8, respectively. The correlation coefficients of RA was 0.967, RMSEC was 1.50, RMSEP was 1.98 and RPD was 4.17. The results indicated that near infrared spectroscopy (NIRS) technique offers effective quantitative capability for ST and RA in Stevia Rebaudiana leaves. Then the model of stevia dried leaves was used to compare with the stevia powder near infrared model whose correlation coefficients of ST was 0.986, RMSEC was 0.32, RMSEP was 0.601 and RPD was 2.86 and the correlation coefficients of RA was 0.968, RMSEC was 1.50, RMSEP was 1.48 and RPD was 4.2. The result showed that there was no significant difference between the model of dried leaves and that of the powders. However, the dried leaves NIR model reduces the unnecessary the steps of drying and grinding in the actual detection process, saving the time and reducing the workload. PMID- 25739215 TI - [Rapid discriminating hogwash oil and edible vegetable oil using near infrared optical fiber spectrometer technique]. AB - In the present study, a new method using near infrared spectroscopy combined with optical fiber sensing technology was applied to the analysis of hogwash oil in blended oil. The 50 samples were a blend of frying oil and "nine three" soybean oil according to a certain volume ratio. The near infrared transmission spectroscopies were collected and the quantitative analysis model of frying oil was established by partial least squares (PLS) and BP artificial neural network The coefficients of determina- tion of calibration sets were 0.908 and 0.934 respectively. The coefficients of determination of validation sets were 0.961 and 0.952, the root mean square error of calibrations (RMSEC) was 0.184 and 0.136, and the root mean square error of predictions (RMSEP) was all 0.111 6. They conform to the model application requirement. At the same time, frying oil and qualified edible oil were identified with the principal component analysis (PCA), and the accurate rate was 100%. The experiment proved that near infrared spectral technology not only can quickly and accurately identify hogwash oil, but also can quantitatively detect hog- wash oil. This method has a wide application prospect in the detection of oil. PMID- 25739216 TI - [Rapid determination of beet sugar content using near infrared spectroscopy]. AB - In order to classify and set different prices on basis of difference of beet sugar content in the acquisition process and promote the development of beet sugar industry healthily, a fast, nondestructive, accurate method to detect sugar content of beet was determined by applying near infrared spectroscopy technology. Eight hundred twenty samples from 28 representative varieties of beet were collected as calibration set and 70 samples were chosen as prediction set. Then near infrared spectra of calibration set samples were collected by scanning, effective information was extracted from NIR spectroscopy, and the original spectroscopy data was optimized by data preprocessing methods appropriately. Then partial least square(PLS)regression was used to establish beet sugar quantitative prediction mathematical model. The performances of the models were evaluated by the root mean square of cross-validation (RMSECV), the coefficient of determination (R2) of the calibration model and the standard error of prediction (SEP), and the predicted results of these models were compared. Results show that the established mathematical model by using first derivative (FD) and standard normal variate transformation (SNV) coupled with partial least squares has good predictive ability. The R2 of calibration models of sugar content of beet is 0.908 3, and the RMSECV is 0.376 7. Using this model to forecast the prediction set including 70 samples, the correlation coefficient is 0.921 4 between predicted values and measured values, and the standard error of prediction (SEP) is 0.439, without significant difference (p > 0.05) between predicted values and measured values. These results demonstrated that NIRS can take advantage of simple, rapid, nondestructive and environmental detection method and could be applied to predict beet sugar content. This model owned high accuracy and can meet the precision need of determination of beet sugar content. This detection method could be used to classify and set different prices on basis of difference of beet sugar content in the acquisition process. PMID- 25739217 TI - [Freshwater fish freshness on-line detection method based on near-infrared spectroscopy]. AB - In the present study, the near infrared spectrum of freshwater fish was used to detect the freshness on line, and the near infrared spectra on-line acquisition device was built to get the fish spectrum. In the process of spectrum acquisition, experiment samples move at a speed of 0.5 m . s(-1), the near infrared diffuse reflection spectrum (900-2,500 nm) could be got for the next analyzing, and SVM was used to build on-line detection model. Sample set partitioning based on joint X-Y distances algo- rithm (SPXY) was used to divide sample set, there were 111 samples in calibration set (57 fresh samples and 54 bad samples), and 37 samples in test set (19 fresh samples and 18 bad samples). Seven spectral preprocessing methods were utilized to prepro- cess the spectrum, and the influences of different methods were compared. Model results indicated that first derivative (FD) with autoscale was the best preprocessing method, the model recognition rate of calibration set was 97.96%, and the recognition rate of test set was 95.92%. In order to improve the modeling speed, it is necessary to optimize the spectra variables. Therefore genetic algorithm (GA), successive projection algorithm (SPA) and competitive adaptive reweighed sampling (CARS) were adopted to select characteristic variables respectively. Finally CARS was proved to be the optimal variable selection method, 10 characteristic wavelengths were selected to develop SVM model, recognition rate of calibration set reached 100%, and recognition rate of test set was 93.88%. The research provided technical reference for freshwater fish freshness online detection. PMID- 25739218 TI - [Discrimination of donkey meat by NIR and chemometrics]. AB - Donkey meat samples (n = 167) from different parts of donkey body (neck, costalia, rump, and tendon), beef (n = 47), pork (n = 51) and mutton (n = 32) samples were used to establish near-infrared reflectance spectroscopy (NIR) classification models in the spectra range of 4,000~12,500 cm(-1). The accuracies of classification models constructed by Mahalanobis distances analysis, soft independent modeling of class analogy (SIMCA) and least squares-support vector machine (LS-SVM), respectively combined with pretreatment of Savitzky-Golay smooth (5, 15 and 25 points) and derivative (first and second), multiplicative scatter correction and standard normal variate, were compared. The optimal models for intact samples were obtained by Mahalanobis distances analysis with the first 11 principal components (PCs) from original spectra as inputs and by LS-SVM with the first 6 PCs as inputs, and correctly classified 100% of calibration set and 98. 96% of prediction set. For minced samples of 7 mm diameter the optimal result was attained by LS-SVM with the first 5 PCs from original spectra as inputs, which gained an accuracy of 100% for calibration and 97.53% for prediction. For minced diameter of 5 mm SIMCA model with the first 8 PCs from original spectra as inputs correctly classified 100% of calibration and prediction. And for minced diameter of 3 mm Mahalanobis distances analysis and SIMCA models both achieved 100% accuracy for calibration and prediction respectively with the first 7 and 9 PCs from original spectra as inputs. And in these models, donkey meat samples were all correctly classified with 100% either in calibration or prediction. The results show that it is feasible that NIR with chemometrics methods is used to discriminate donkey meat from the else meat. PMID- 25739219 TI - [Principles and applications of hyperspectral imaging technique in quality and safety inspection of fruits and vegetables]. AB - The quality and safety of fruits and vegetables are the most concerns of consumers. Chemical analytical methods are traditional inspection methods which are time-consuming and labor intensive destructive inspection techniques. With the rapid development of imaging technique and spectral technique, hyperspectral imaging technique has been widely used in the nondestructive inspection of quality and safety of fruits and vegetables. Hyperspectral imaging integrates the advantages of traditional imaging and spectroscopy. It can obtain both spatial and spectral information of inspected objects. Therefore, it can be used in either external quality inspection as traditional imaging system, or internal quality or safety inspection as spectroscopy. In recent years, many research papers about the nondestructive inspection of quality and safety of fruits and vegetables by using hyperspectral imaging have been published, and in order to introduce the principles of nondestructive inspection and track the latest research development of hyperspectral imaging in the nondestructive inspection of quality and safety of fruits and vegetables, this paper reviews the principles, developments and applications of hyperspectral imaging in the external quality, internal quality and safety inspection of fruits and vegetables. Additionally, the basic components, analytical methods, future trends and challenges are also reported or discussed in this paper. PMID- 25739220 TI - [Hyperspectral technology combined with CARS algorithm to quantitatively determine the SSC in Korla fragrant pear]. AB - Hyperspectral imaging has large data volume and high dimensionality, and original spectra data includes a lot of noises and severe scattering. And, quality of acquired hyperspectral data can be influenced by non-monochromatic light, external stray light and temperature, which resulted in having some non-linear relationship between the acquired hyperspectral data and the predicted quality index. Therefore, the present study proposed that competitive adaptive reweighted sampling (CARS) algorithm is used to select the key variables from visible and near infrared hyperspectral data. The performance of CARS was compared with full spectra, successive projections algorithm (SPA), Monte Carlo-uninformative variable elimination (MC-UVE), genetic algorithm (GA) and GA-SPA (genetic algorithm-successive projections algorithm). Two hundred Korla fragrant pears were used as research object. SPXY algorithm was used to divided sample set to correction set with 150 samples and prediction set with 50 samples, respectively. Based on variables selected by different methods, linear PLS and nonlinear LS-SVM models were developed, respectively, and the performance of models was assessed using parameters r2, RMSEP and RPD. A comprehensive comparison found that GA, GA SPA and CARS can effectively select the variables with strong and useful information. These methods can be used for selection of Vis-NIR hyperspectral data variables, particularly for CARS. LS-SVM model can obtain the best results for SSC prediction of Korla fragrant pear based on variables obtained from CARS method. r2, RMSEP and RPD were 0.851 2, 0.291 3 and 2.592 4, respectively. The study showed that CARS is an effectively hyperspectral variable selection method, and nonlinear LS-SVM model is more suitable than linear PLS model for quantitatively determining the quality of fra- grant pear based on hyperspectral information. PMID- 25739221 TI - Analysis of tobacco color and location features using visible-near infrared hyperspectral data. AB - In the present paper, six categories of standard industrial grading tobacco provided by Hongta Group are taken as experimental samples, including three different tobacco locations-upper (B), middle(C) and lower(X) parts, with each part containing two kinds of tobacco colors-orange (O) and lemon yellow (L). Two methods including projection model method based on principal component and Fisher criterion (PPF) and support vector machine (SVM) method are used to analyze color and location features of tobacco based on visible-near infrared hyperspectral data. The results of projection model method indicate that in the projection and similarity analysis of tobacco color, location and six tobacco groups classified by color and location, two kinds of color can be fully differentiated, of which the similarity value is -1.000 8. Tobacco from upper and lower parts can also be fully differentiated with similarity value 0.405 3, but they both have intersections with tobac- co from middle part. Six tobacco groups classified by color and location can be fully differentiated as well and their projection positions meet the actual external features of tobacco. The results of support vector machine method indicate that in the discriminant analysis of tobacco color, location and six tobacco groups classified by color and location, the average recognition rate of tobacco colors reaches 98%. The average recognition rate of tobacco location is 96%. The average recognition rate of six tobacco groups is 94%. Therefore, it's feasible to analyze color and location features of tobacco using visible-near infrared hyperspectral data, which can provide reference for tobacco quality evaluation, computer-aided grading and tobacco intelligent acquisition, and also offers a new approach to the analysis of exterior features of other agricultural products. PMID- 25739222 TI - [Analysis of tobacco style features using near-infrared spectroscopy and projection model]. AB - In the present paper, a total of 4,733 flue-cured tobacco samples collected from 2003 to 2012 in 17 provincial origins and 5 ecological areas were tested by near infrared spectroscopy, including the NONG(Luzhou) flavor 1,580 cartons, QING (Fen) flavor 2004 cartons and Intermediate flavor 1 149 cartons. Using projection model based on principal component and Fisher criterion (PPF), Projection analysis models of tobacco ecological regions and style characteristics were established. Reasonableness of style flavor division is illustrated by the model results of tobacco ecological areas. With the Euclidean distance between the predicted sample projection values and the mean projection values of each class in style characteristics model, a description is given for the prediction samples to quantify the extent of the style features, and their first and second close categories. Using the dispersion of projected values in model and the given threshold value, prediction results can be refined into typical NONG, NONG to Intermediate, Intermediate to NONG, typical Intermediate, Intermediate to QING, QING to Intermediate, typical QING, QING to NONG, NONG to QING, or super-model range. The model was validated by 35 tobacco samples obtained from the re dryingprocess in 2012 with different origins and parts. This kind of analysis methods not only can achieve discriminant analysis, but also can get richer feature attribute information and provide guidance to raw tobacco processing and formulations. PMID- 25739223 TI - [Fourier transform infrared spectroscopy combined with attenuated total reflection applied to reagent-free quantitative analysis of thalassemia screening indicators]. AB - A simultaneous quantitative analysis method for the thalassemia screening indicators mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), and hemoglobin (Hb) was developed with Fourier transform infrared (FTIR) spectrometers and attenuated total reflection (ATR) combined with partial least squares (PLS). A total of 380 human peripheral blood samples were collected, which were composed of 180 positive samples and 200 negative samples according to the criteria of hematological indicator screening for thalassemia. One hundred fifty samples (64 negative, 86 positive) were randomly selected from all samples as the validation set, the remaining 230 samples (136 negative, 94 positive) were used as modeling samples; and then the modeling set was further subdivided into calibration set (68 negative, 47 positive, and 115 in total) and prediction set (68 negative, 47 positive, and 115 in total) for 200 times. Comparison of experimental results show that the prediction effect of PLS models in mid infrared (MIR) fingerprint region (1,600-900 cm(-1)) was significantly better those of PLS models in the full scanning region (4,000-600 cm(-1)), and model complexity is significantly reduced. Based on PLS model in MIR fingerprint region, the optimal numbers of PLS factors for MCH, MCV and Hb were 10, 10 and 6, respectively, and the root mean square error (M_SEP(Ave)) and the correlation coefficient (M_Rp, Ave) of prediction in the modeling set were 2.19 pg, 0.902 for MCH, 5.13 fL, 0.898 for MCV and 8.0 g . L(-1), 0.922 for Hb, respectively. The root mean square error (V_SEP) and the correlation coefficient (V_Rp) of prediction in the validation set were 2.22 pg, 0.900 for MCH, 5.38 fL, 0.895 for MCV and 7.7 g . L(-1), 0.929 for Hb, respectively. The sensitivity and specificity for thalassemia screening achieved 100.0% and 95.3%, respectively. CONCLUSION: FTIR/ATR spectroscopy combined with PLS method could provide a new reagent-free and rapid technique for thalassemia screening for large populations. PMID- 25739224 TI - [Study on detection methods of interstitial fluid glucose concentration based on infrared attenuated total reflection]. AB - Measuring the glucose concentrations in the interstitial fluid is currently the main method to achieve the continuous blood glucose monitoring. The MIR-ATR(Mid infrared, Attenuated Total Reflection)Spectroscopy has prominent advantage on the analysis of small biological molecule for composition information like the glucose, but it is still an unresolved problem that how to detect the subcutaneous glucose concentration by using the MIR-ATR Spectroscopy. In the present paper, we carry out the experiment based on MIR-ATR for the detection of subcutaneous glucose information on both the natural state and the penetration state based on the theoryanalysis of MIR penetration depth. Firstly, collect spectral data of the subcutaneous glucose concentration of human finger on the natural state were collected as the light shined the skin directly, and it was discussed whether the MIR can penetrate the skin to get the information of subcutaneous glucose. On this basis, collect spectral data of the subcutaneous glucose concentration of human finger at the penetration state were collected when the Interstitial fluid is permeated to the surface layer by using low frequency ultrasound and vacuum, then it analyzed that whether it can detect the glucose-specific information or not. As the two-dimensional correlation spectroscopy has high resolution and good versatility, it is widely used to analyze the inter-molecular reaction and judge the absorption peaks information in many fields including the MIR spectroscopy field, so we choose the Two dimensional correlation spectroscopy to analyze the information of subcutaneous glucose concentration at the natural state and the penetration state. The experiment result shows that the MIR-ATR spectroscopy can't be applied in the detection of subcutaneous glucose concentrationdirectly, and it is a promising direction to make the Interstitial fluid permeated to the surface layer by the physical methods or chemical methods. PMID- 25739225 TI - [Analyzing and modeling methods of near infrared spectroscopy for in-situ prediction of oil yield from oil shale]. AB - In order to in-situ detect the oil yield of oil shale, based on portable near infrared spectroscopy analytical technology, with 66 rock core samples from No. 2 well drilling of Fuyu oil shale base in Jilin, the modeling and analyzing methods for in-situ detection were researched. By the developed portable spectrometer, 3 data formats (reflectance, absorbance and K-M function) spectra were acquired. With 4 different modeling data optimization methods: principal component mahalanobis distance (PCA-MD) for eliminating abnormal samples, uninformative variables elimination (UVE) for wavelength selection and their combina- tions: PCA-MD + UVE and UVE + PCA-MD, 2 modeling methods: partial least square (PLS) and back propagation artificial neural network (BPANN), and the same data pre processing, the modeling and analyzing experiment were performed to determine the optimum analysis model and method. The results show that the data format, modeling data optimization method and modeling method all affect the analysis precision of model. Results show that whether or not using the optimization method, reflectance or K-M function is the proper spectrum format of the modeling database for two modeling methods. Using two different modeling methods and four different data optimization methods, the model precisions of the same modeling database are different. For PLS modeling method, the PCA-MD and UVE + PCA-MD data optimization methods can improve the modeling precision of database using K-M function spectrum data format. For BPANN modeling method, UVE, UVE + PCA-MD and PCA- MD + UVE data optimization methods can improve the modeling precision of database using any of the 3 spectrum data formats. In addition to using the reflectance spectra and PCA-MD data optimization method, modeling precision by BPANN method is better than that by PLS method. And modeling with reflectance spectra, UVE optimization method and BPANN modeling method, the model gets the highest analysis precision, its correlation coefficient (Rp) is 0.92, and its standard error of prediction (SEP) is 0.69%. PMID- 25739226 TI - The establishment and external validation of NIR qualitative analysis model for waste polyester-cotton blend fabrics. AB - A series of 354 polyester-cotton blend fabrics were studied by the near-infrared spectra (NIRS) technology, and a NIR qualitative analysis model for different spectral characteristics was established by partial least squares (PLS) method combined with qualitative identification coefficient. There were two types of spectrum for dying polyester-cotton blend fabrics: normal spectrum and slash spectrum. The slash spectrum loses its spectral characteristics, which are effected by the samples' dyes, pigments, matting agents and other chemical additives. It was in low recognition rate when the model was established by the total sample set, so the samples were divided into two types of sets: normal spectrum sample set and slash spectrum sample set, and two NIR qualitative analysis models were established respectively. After the of models were established the model's spectral region, pretreatment methods and factors were optimized based on the validation results, and the robustness and reliability of the model can be improved lately. The results showed that the model recognition rate was improved greatly when they were established respectively, the recognition rate reached up to 99% when the two models were verified by the internal validation. RC (relation coefficient of calibration) values of the normal spectrum model and slash spectrum model were 0.991 and 0.991 respectively, RP (relation coefficient of prediction) values of them were 0.983 and 0.984 respectively, SEC (standard error of calibration) values of them were 0.887 and 0.453 respectively, SEP (standard error of prediction) values of them were 1.131 and 0.573 respectively. A series of 150 bounds samples reached used to verify the normal spectrum model and slash spectrum model and the recognition rate reached up to 91.33% and 88.00% respectively. It showed that the NIR qualitative analysis model can be used for identification in the recycle site for the polyester-cotton blend fabrics. PMID- 25739227 TI - Model research of electric coal calorific value based on near infrared frequency domain self-adaption analysis method. AB - At present, because the blending coal was taken in some power stations as the major fuel which has too complex physical and chemical characters to build accurate normal near infrared quantitative models in some cases, which brought difficulties for on-line electric coal calorific value detection. For this reason, it was carefully studied that the time domain and frequency domain properties of the power generation coal near infrared spectra, and was proposed that a new quantitative near infrared method named frequency domain self-adaption analysis. The first step, time domain near infrared spectra are converted into frequency domain near infrared signal by Fast Fourier Transform; The second step, the suitable frequency information range by means of valid spectra energy parameter etaE was obtained by this method; The third step, it was constructed that an information volume parameter which is formed by correlation coefficient, standard deviation spectra and coordinate of harmonic in frequency domain to initialize the regression model input parameters' position; Finally, the optimal model is established by way of discrete frequency domain scooping and synthesized performance function. At the same time, compared with the principle component regression, partial least squares regression, back propagation artificial network, support vector regression and partial least squares regression optimized by genetic algorithm models, it is acquired that a more accurate method which can effectively avoid over fitting and virtual effective models and has a very useful application prospect by verifying the electric coal calorific value. Additionally, this method can be used in other quantitative spectra analysis. PMID- 25739228 TI - [Near infrared spectroscopy quantitative analysis model based on incremental neural network with partial least squares]. AB - This paper proposes an near infrared spectroscopy quantitative analysis model based on incremental neural network with partial least squares. The proposed model adopts the typical three-layer back-propagation neural network (BPNN), and the absorbance of different wavelengths and the component concentration are the inputs and the outputs, respectively. Partial least square (PLS) regression is performed on the history training samples firstly, and the obtained history loading matrices of the in- dependent variables and the dependent variables are used for determining the initial weights of the input layer and the output lay- er, respectively. The number of the hidden layer nodes is set as the number of the principal components of the independent varia- bles. After a set of new training samples is collected, PLS regression is performed on the combination dataset consisting of the new samples and the history loading matrices to calculate the new loading matrices. The history loading matrices and the new loading matrices are fused to obtain the new initial weights of the input layer and the output layer of the proposed model. Then the new samples are used for training the proposed mode to realize the incremental update. The proposed model is compared with PLS, BPNN, the BPNN based on PLS (PLS-BPNN) and the recursive PLS (RPLS) by using the spectra data of flue gas of nat- ural gas combustion. For the concentration prediction of the carbon dioxide in the flue gas, the root mean square error of predic- tion (RMSEP) of the proposed model are reduced by 27.27%, 58.12%, 19.24% and 14.26% than those of PLS, BPNN, PLS- BPNN and RPLS, respectively. For the concentration prediction of the carbon monoxide in the flue gas, the RMSEP of the pro- posed model are reduced by 20.65%, 24.69%, 18.54% and 19.42% than those of PLS, BPNN, PLS-BPNN and RPLS, re- spectively. For the concentration prediction of the methane in the flue gas, the RMSEP of the proposed model are reduced by 27.56%, 37.76%, 8.63% and 3.20% than those of PLS, BPNN, PLS-BPNN and RPLS, respectively. Experiments results show that the proposed model could optimize the construction and the initial weights of BPNN by PLS and has higher prediction effectiveness. Moreover, based on the information of the built model, the proposed model uses the new samples for incremental update without accessing the history samples. Hence, the proposed model has better robustness and generalization. PMID- 25739229 TI - [Rapid determination of COD in aquaculture water based on LS-SVM with ultraviolet/visible spectroscopy]. AB - Ultraviolet/visible (UV/Vis) spectroscopy was studied for the rapid determination of chemical oxygen demand (COD), which was an indicator to measure the concentration of organic matter in aquaculture water. In order to reduce the influence of the absolute noises of the spectra, the extracted 135 absorbance spectra were preprocessed by Savitzky-Golay smoothing (SG), EMD, and wavelet transform (WT) methods. The preprocessed spectra were then used to select latent variables (LVs) by partial least squares (PLS) methods. Partial least squares (PLS) was used to build models with the full spectra, and back- propagation neural network (BPNN) and least square support vector machine (LS-SVM) were applied to build models with the selected LVs. The overall results showed that BPNN and LS-SVM models performed better than PLS models, and the LS-SVM models with LVs based on WT preprocessed spectra obtained the best results with the determination coefficient (r2) and RMSE being 0. 83 and 14. 78 mg . L(-1) for calibration set, and 0.82 and 14.82 mg . L(-1) for the prediction set respectively. The method showed the best performance in LS-SVM model. The results indicated that it was feasible to use UV/Vis with LVs which were obtained by PLS method, combined with LS-SVM calibration could be applied to the rapid and accurate determination of COD in aquaculture water. Moreover, this study laid the foundation for further implementation of online analysis of aquaculture water and rapid determination of other water quality parameters. PMID- 25739230 TI - Absolutely nondestructive discrimination of Huoshan Dendrobium nobile species with miniature near-infrared (NIR) spectrometer engine. AB - As one very precious traditional Chinese medicine (TCM), Huoshan Dendrobium has not only high price, but also significant pharmaceutical efficacy. However, different species of Huoshan Dendrobium exhibit considerable difference in pharmaceutical efficacy, so rapid and absolutely non-destructive discrimination of Huoshan Dendrobium nobile according to different species is crucial to quality control and pharmaceutical effect. In this study, as one type of miniature near infrared (NIR) spectrometer, MicroNIR 1700 was used for absolutely nondestructive determination of NIR spectra of 90 batches of Dendrobium from five species of differ- ent commodity grades. The samples were intact and not smashed. Soft independent modeling of class analogy (SIMCA) pattern recognition based on principal component analysis (PCA) was used to classify and recognize different species of Dendrobium samples. The results indicated that the SIMCA qualitative models established with pretreatment method of standard normal variate transformation (SNV) in the spectra range selected by Qs method had 100% recognition rates and 100% rejection rates. This study demonstrated that a rapid and absolutely non-destructive analytical technique based on MicroNIR 1700 spectrometer was developed for successful discrimination of five different species of Huoshan Dendrobium with acceptable accuracy. PMID- 25739231 TI - [Drug discrimination by near infrared spectroscopy based on summation wavelet extreme learning machine]. AB - As an effective technique to identify counterfeit drugs, Near Infrared Spectroscopy has been successfully used in the drug management of grass-roots units, with classifier modeling of Pattern Recognition. Due to a major disadvantage of the characteristic overlap and complexity, the wide bandwidth and the weak absorption of the Spectroscopy signals, it seems difficult to give a satisfactory solutions for the modeling problem. To address those problems, in the present paper, a summation wavelet extreme learning machine algorithm (SWELM(CS)) combined with Cuckoo research was adopted for drug discrimination by NIRS. Specifically, Extreme Learning Machine (ELM) was selected as the classifier model because of its properties of fast learning and insensitivity, to improve the accuracy and generalization performances of the classifier model; An inverse hyperbolic sine and a Morlet-wavelet are used as dual activation functions to improve convergence speed, and a combination of activation functions makes the network more adequate to deal with dynamic systems; Due to ELM' s weights and hidden layer threshold generated randomly, it leads to network instability, so Cuckoo Search was adapted to optimize model parameters; SWELM(CS) improves stability of the classifier model. Besides, SWELM(CS) is based on the ELM algorithm for fast learning and insensitivity; the dual activation functions and proper choice of activation functions enhances the capability of the network to face low and high frequency signals simultaneously; it has high stability of classification by Cuckoo Research. This compact structure of the dual activation functions constitutes a kernel framework by extracting signal features and signal simultaneously, which can be generalized to other machine learning fields to obtain a good accuracy and generalization performances. Drug samples of near in- frared spectroscopy produced by Xian-Janssen Pharmaceutical Ltd were adopted as the main objects in this paper. Experiments for binary classification and multi label classification were conducted, and the conclusion proved that the proposed method has more stable performance, higher classification accuracy and lower sensitivity to training samples than the existing ones, such as the BP neural network, ELM and-ELM by particle swarm optimization. PMID- 25739232 TI - [Research on NIR-CI parameters optimization of chlorpheniramine maleate tablets based on binary image and statistical measurement]. AB - The optimization method was established to investigate the effect of near infrared chemical imaging (NIR-CI) detection parameters on hyperspectral data quality. In order to optimize the detection parameters, chlorpheniramine maleate (CPM) tablets were chosen as examples and the L9(3(4)) orthogonal-test design was adopted to research the effects of spectral resolution, spatial resolution, scan times and scan height. Binary image coupled with statistical measurement was proposed to quantitatively analyze hyperspectral data and determine the content of CPM on the tablet surface. High-performance liquid chromatography (HPLC) was used as reference method for accurate CPM determination. The absolute value of the difference between CPM con- tents obtained from NIR-CI and HPLC was chosen as index. The result demonstrated that the optimum parameters for acquiring hyperspectral data were: 25 MUm x 25 MUm (spatial resolution), 5340 (scan height, the value of Z, precise focus), 16 cm(-1) (spectral resolution) and 16 (scan times). The influence of scan height on hyperspectral data was firstly investigated. The optimized parameters could be applied to CPM tablets and other drugs for NIR-CI data acquisition and methodology establishment. PMID- 25739233 TI - [NIR spectroscopy combined with stability and equivalence MW-PLS method applied to analysis of hyperlipidemia indexes]. AB - Moving window partial least square (MW-PLS) method was improved by considering the stability and equivalence, and was used for the wavelength optimization of reagent-free near-infrared (NIR) spectroscopic analysis of total cholesterol (TC) and triglycerides (TG) for hyperlipidemia. A random and stability-dependent framework of calibration, prediction, and validation was proposed. From all human serum samples (negative 145 and positive 158, a total of 303 sample), 103 samples (negative 44 and positive 59) were randomly selected for the validation set, the remaining samples (negative 101 and positive 99, a total of 200 sample) were used as modeling set; then the modeling set was randomly divided into calibration set (negative 51 and positive 49, a total of 100 sample) and prediction set (negative 50 and positive 50, a total of 100 sample) by 50 times. To produce modeling stability, the model parameters were optimized based on the average prediction effect for all divisions; the optimized models were validated by using the validation samples. The obtained optimal MW-PLS wavebands were 1,556~1,852 nm for TC and 1,542-1,866 nm for TG. In order to solve the problem that instrument design typically involves some limitations of position and number of wavelengths because of cost and material properties, the equivalent model sets were proposed, and a unique public waveband 1,542-1,852 nm of the equivalent model sets for TC, TG was found. The validation results show that: using the optimal MW-PLS wavebands, validation samples' root mean square error of prediction (V SEP) for TC, TG were 0.177, 0.100 mmol . L(-1), the correlation coefficient of prediction (V_Rp) for TC, TG were 0.988, 0.996, and the sensitivity and specificity for hyperlipidemia achieved 95.0%, 90.5%, respectively; using the public equivalent wavebands, the V_SEP for TC, TG were 0.177, 0.101 mmol . L(-1)), the V_Rp for TC, TG were 0.988, 0.996, and the sensitivity and specificity achieved 92.7%, 90.3%, respectively. CONCLUSION: NIR spectroscopy combined with the stability and equivalenceimprovement MW-PLS method can provide a potential tool for detecting hyperlipidemia for large population. PMID- 25739234 TI - [Tracking analysis of three extraction processes of Arenaria Polytrichoides by Fourier transform infrared spectrocopy]. AB - In order to develop a process analysis method to guide extraction process of Arenaria polytrichoides (AP) based on tracking analysis by Fourier transform infrared (FTIR), IR spectra of petroleum ether extracts (PE-E), ethyl acetate extracts (EtOAc-E), n-butanol extracts (n-BuOH-E) and water extracts (H2O-E) of AP from three extraction methods were recorded. The FTIR and corresponding second derivative infrared (SDIR) spectra were analyzed comparatively from two aspects, namely, different extracts from a same extraction process and the same extracts from different methods. The spectral analysis results show that different extracts obtained from a same extraction process have distinctly different spectral absorbance character. Although the IR spectral absorption characteristics of the same extracts from different methods are rather similar in holistic, some explicit spectral differences still could be found among each other. In extraction process one (M1), main flavonoids and their glycosides of AP migrated to EtOAc-E and the rest part of them shift to n-BuOH-E according to FTIR peaks such as 1,603 and 1,123 cm(-1). However, the circumstances in method two (M2) and method three (M3) were just the reverse. Moreover, a few flavonoid glycosides got into H2O-E. The relative content of all kinds of aglycones and higher saturated alkyl are much higher in EtOAc-E of M2 than that of M1 and M3 according to the relative absorption intensive of peak at 2,850 cm(-1). Similarly, n-BuOH-E of M3 has relative rich contents of glycosides: and polysaccharides than those of M1 and M2 by peaks, such as 1,066 and 2,927 cm(-1). These results demonstrate that the migration rules of AP components are not always same in different extrac- tion process. The substance migration information during the extraction process could be recorded and disclosed in an intuitive way by FTIR tracking analysis of corresponding extracts. Consequently, FTIR tracking analysis is a fast, efficient, low-carbon and environment-friendly process analysis method. The method has important macro guiding significance for quality control and process optimization of extraction and isolation process of medicinal plant including AP. PMID- 25739235 TI - [Carbon monoxide gas detection system based on mid-infrared spectral absorption technique]. AB - Based on infrared spectral absorption technique, a carbon monoxide (CO) detection system was developed using the fundamental absorption band at the wavelength of 4.6 MUm of CO molecule and adopting pulse-modulated wideband incandescence and dual-channel detector. The detection system consists of pulse-modulated wideband incandescence, open ellipsoid light-collec- tor gas-cell, dual-channel detector, main-control and signal-processing module. By optimizing open ellipsoid light collector gas- cell, the optical path of the gas absorption reaches 40 cm, and the amplitude of the electrical signal from the detector is 2 to 3 times larger than the original signal. Therefore, by using the ellipsoidal condenser, the signal-to-noise ratio of the system will be to some extent increased to improve performance of the system. With the prepared standard CO gas sample, sensing characteris- tics on CO gas were investigated. Experimental results reveal that, the limit of detection (LOD) is about 10 ppm; the relative er- ror at the LOD point is less than 14%, and that is less than 7. 8% within the low concentration range of 20~180 ppm; the maxi- mum absolute error of 50 min long-term measurement concentration on the 0 ppm gas sample is about 3 ppm, and the standard deviation is as small as 0. 18 ppm. Compared with the CO detection systems utilizing quantum cascaded lasers (QCLs) and dis- tributed feedback lasers (DFBLs), the proposed sensor shows potential applications in CO detection under the circumstances of coal-mine and environmental protection, by virtue of high performance-cost ratio, simple optical-path structure, etc. PMID- 25739236 TI - [Fast and accurate extraction of ring-down time in cavity ring-down spectroscopy]. AB - Research is conducted to accurate and efficient algorithms for extracting ring down time (r) in cavity ring-down spectroscopy (CRDS) which is used to measure NO3 radical in the atmosphere. Fast and accurate extraction of ring-down time guarantees more precise and higher speed of measurement. In this research, five kinds of commonly used algorithms are selected to extract ring-down time which respectively are fast Fourier transform (FFT) algorithm, discrete Fourier transform (DFT) algorithm, linear regression of the sum (LRS) algorithm, Levenberg-Marquardt (LM) algorithm and least squares (LS) algorithm. Simulated ring-down signals with various amplitude levels of white noises are fitted by using five kinds of the above-mentioned algorithms, and comparison and analysis is conducted to the fitting results of five kinds of algorithms from four respects: the vulnerability to noises, the accuracy and precision of the fitting, the speed of the fitting and preferable fitting ring-down signal waveform length The research results show that Levenberg-Marquardt algorithm and linear regression of the sum algorithm are able to provide more precise results and prove to have higher noises immunity, and by comparison, the fitting speed of Leven- berg-Marquardt algorithm turns out to be slower. In addition, by analysis of simulated ring-down signals, five to ten times of ring-down time is selected to be the best fitting waveform length because in this case, standard deviation of fitting results of five kinds of algorithms proves to be the minimum. External modulation diode laser and cavity which consists of two high reflectivity mirrors are used to construct a cavity ring-down spectroscopy detection system. According to our experimental conditions, in which the noise level is 0.2%, linear regression of the sum algorithm and Levenberg-Marquardt algorithm are selected to process experimental data. The experimental results show that the accuracy and precision of linear regression of the sum algorithm is considerably close to those of Levenberg-Marquardt algorithm, and on the other hand, the fitting speed of linear regression of the sum algorithm is faster than that of Levenberg Marquardt algorithm about five times. The experimental results are consistent with the simulation analysis, and it indicates that linear regression of the sum algorithm is the desirable fitting method, as far as our experimental conditions are concerned. PMID- 25739237 TI - [A review of mixed gas detection system based on infrared spectroscopic technique]. AB - In order to provide the experiences and references to the researchers who are working on infrared (IR) mixed gas detection field. The proposed manuscript reviews two sections of the aforementioned field, including optical multiplexing structure and detection method. At present, the coherent light sources whose representative are quantum cascade laser (QCL) and inter-band cascade laser(ICL) become the mainstream light source in IR mixed gas detection, which replace the traditional non-coherent light source, such as IR radiation source and IR light emitting diode. In addition, the photon detector which has a super high detectivity and very short response time is gradually beyond thermal infrared detector, dominant in the field of infrared detector. The optical multiplexing structure is the key factor of IR mixed gas detection system, which consists of single light source multi-plexing detection structure and multi light source multiplexing detection structure. Particularly, single light source multiplexing detection structure is advantages of small volume and high integration, which make it a plausible candidate for the portable mixed gas detection system; Meanwhile, multi light source multiplexing detection structure is embodiment of time division multiplex, frequency division multiplexing and wavelength division multiplexing, and become the leading structure of the mixed gas detection system because of its wider spectral range, higher spectral resolution, etc. The detection method applied to IR mixed gas detection includes non-dispersive infrared (NDIR) spectroscopy, wavelength and frequency-modulation spectroscopy, cavity-enhanced spectroscopy and photoacoustic spectroscopy, etc. The IR mixed gas detection system designed by researchers after recognizing the whole sections of the proposed system, which play a significant role in industrial and agricultural production, environmental monitoring, and life science, etc. PMID- 25739238 TI - [Design and implementation of a long wavelength near infrared spectrometer based on MEMS scanning mirror]. AB - Long Wavelength Near InfraRed (LW-NIR) spectrometer has wide applications. Miniaturization and low-cost are two major goals of the development of LW-NIR spectrometer in the industrial or research community. Under the background that having a trend of spectrometer miniaturization and integration, method and main problems involved in miniaturization of LW-NIR spectrometer through MEMS scanning mirror, such as the design strategy of the light-splitting optical system, selection considerations of the MEMS scanning mirror, design method of the preamplifier circuit, etc, have been presented in detail. A prototype of miniaturized LW-NIR spectrometer, with the spectrum range of detection of 900 2,055 nm, is designed and implemented using MEMS scanning mirror, InGaAs single detector unit with high sensitivity. Littrow optical layout is used for its light splitting optical system, and the spectral resolution is between 9.4-16 nm at 1,000-1,965 nm detection wavelength range. The prototype is successfully applied in LW-NIR spectrum measurement on pure water and ethanol aqueous solution, and a forecast analysis on ethanol aqueous solution concentration is also demonstrated. Through adopting MEMS scanning mirror into the spectrometer system, the complexity of the mechanical scanning fixtures and its controlling mechanism is greatly reduced therefore the size of the spectrometer is reduced. Furthermore, due to MEMS scanning mirror technology, LW-NIR spectrometer with single InGaAs detector is achieved, thus the cost reduction of the NIR spectrometer system is also realized because the expensive InGaAs arrays are avoided. PMID- 25739239 TI - [Research on error reduction of path change of liquid samples based on near infrared trans-reflective spectra measurement]. AB - Based on sucrose solution as the research object, this paper measured the trans reflective spectrum of sucrose solution of different concentration by the technique of near infrared spectrum in three optical path (4, 5, 6 mm). Five kinds of pretreatment method (vector normalization, baseline offset correction, multiplicative scatter correction, standard normal variate transformation, a derivative) were used to eliminate the influence of the optical path difference, and to establish model of the calibration set in combination with the PLS (Partial Least Squares)method. Five kinds of pretreatment method could restrain the inter ference of light path in varying degrees. Compared with the PLS model of original spectra, the model of multiple scattering correction combined with PLS method is the optimal model. The results of quantitative analysis of original spectra: the number of principal component PC= 6, the determination coefficient R2 = 0.891 278, the determination coefficient of cross validation R2CV = 0.888 374, root mean square error of calibration RMSEC = 1.704%, root mean square error of cross validation RMSECV = 1.827%; The results of quantitative analysis of spectra after MSC pretreatment: the number of principal component PC = 3, the determination coefficient R2 = 0.987 535, the determination coefficient of cross validation R2CV = 0.983 343, root mean square er- ror of calibration RMSEC = 0.89%, root mean square error of cross validation RMSECV = 1.05%. The correlation coefficient of the prediction set is as much as 0.976 22. root mean square error of prediction is 0.01, lesser than 0.014 36. The results show that the MSC can eliminate the influence of optical path difference, improve the prediction precision and improve the stability. PMID- 25739240 TI - [A novel metabolomic data scaling method based on K-L divergence]. AB - A new scaling method in the current study based on Kullback-Leibler (K-L) divergence is proposed for NMR metabolomic data. The proposed method (called K-L scaling) is a supervised scaling method as group information is incorporated in the scaling procedure. Notably, K-L divergence measures the difference between two different datasets by their probability distributions, it can be used for the analysis of data that either follows Gaussian or non-Gaussian distributions. In K L scaling, all variables were first standardized to unit variance, then their variance was adjusted using Kullback-Leibler divergence to highlight the significant variables. K-L scaling can tell effectively the difference in spectral data points between two experimental groups, and then enhances the weights of biological-relevant variables, and at the same time reduces the weight of noise and uninformative variables. The developed method was applied to a H-NMR metabolomic dataset acquired from human urine. Analysis results of the dataset showed that this new scaling method is efficient in suppressing the contribution of noise in the resulting multivariate model In addition, it can increase the weights of important variables, and improve the interpretability and predictability of subsequent principal component regression (PCR) and partial least squares discriminant analysis (PLS-DA). Furthermore, the scaling method facilitated the identification of metabolic signatures. The current result suggested that the developed K-L scaling method may become a useful alternative for the preprocessing of NMR-based metabolomic data. PMID- 25739242 TI - [Treatment of distal femur fractures]. PMID- 25739241 TI - [The research of the relationship between snow properties and the bidirectional polarized reflectance from snow surface]. AB - In the context of remote sensing, the reflectance of snow is a key factor for accurate inversion for snow properties, such as snow grain size, albedo, because of it is influenced by the change of snow properties. The polarized reflectance is a general phenomenon during the reflected progress in natural incident light In this paper, based on the correct measurements for the multiple-angle reflected property of snow field in visible and near infrared wavelength (from 350 to 2,500 nm), the influence of snow grain size and wet snow on the bidirectional polarized property of snow was measured and analyzed. Combining the results measured in the field and previous conclusions confirms that the relation between polarization and snow grain size is obvious in infrared wavelength (at about 1,500 nm), which means the degree of polarization increasing with an increase of snow grain size in the forward scattering direction, it is because the strong absorption of ice near 1,500 nm leads to the single scattering light contributes to the reflection information obtained by the sensor; in other word, the larger grain size, the more absorption accompanying the larger polarization in forward scattering direction; we can illustrate that the change from dry snow to wet snow also influences the polarization property of snow, because of the water on the surface of snow particle adheres the adjacent particles, that means the wet snow grain size is larger than the dry snow grain size. Therefore, combining the multiple angle polarization with reflectance will provide solid method and theoretical basis for inversion of snow properties. PMID- 25739243 TI - [Effect of preoperative skeletal traction and skin traction on operative indicators and functional outcome of patients with femur fractures]. AB - OBJECTIVE: To compare the effect on surgical indicators and functional outcome between preoperative skeletal traction and skin traction for adult femoral fracture and guide the choice of preoperative traction method of adult femoral fractures. METHODS: From February 2008 to September 2012, 68 patients aged greater than 18-year-old with femoral fractures were treated and randomly divided into two groups according hospitalization order,the odd with skeletal traction of tibial tubercle (group A) and the even with skin traction (group B). In group A, there were 25 males and 9 females with an average age of (36.3+/-9.9) years old,including 11 cases with transverse fracture, 15 cases with oblique fracture, 8 cases with spiral fracture. In group B, there 26 males and 8 females with an average age of (37.1+/-11.0) years old,including 10 cases with transverse fracture, 13 cases with oblique fracture,11 cases with spiral fracture. The operative time,blood loss,the number and amount of blood transfusion ,fracture healing time, hemoglobin, pain scores and functional scores between two groups were analyzed and compared. Results:All patients were followed up, the follow-up time was (33.5+/-6.5) months in group A, (31.3+/-7.5) months in groupB. In group A,the operation time was (108.8+/-14.2) min and the intraoperative blood loss was (383.1+/-117.1) ml and the postoperative blood transfusion was 14 cases and the blood transfusion was (350.0+/-122.5) ml and the average bone healing time was(15.0+/-3.3) weeks. In group B, the operation time was (111.6+/-12.7) min and the intraoperative blood loss was (392.0+/- 116.7) ml and the blood transfusion was 11 cases and the blood transfusion was(327.3+/-129.1) ml and the average healing time was (15.5+/-3.4) weeks. These obseration indicators had no significant difference between two groups. There was no significant difference between two groups in terms of Hemoglobin, the pain scores before and after traction, the femoral fractures efficacy score,knee function score and knee range. CONCLUSION: Preoperative skeletal traction does not reduce surgery time, blood loss and pain and so on. The bone healing time and limb functional outcomes were also not significantly improved. PMID- 25739244 TI - [Application of bridge wire splint fixation on ankle dorsiflexion in femoral shaft fractures in young children]. AB - OBJECTIVE: To explore the technique and therapeutic effect of bridge wire splint fixation with ankle dorsiflexion for the treatment of femoral shaft fractures in young children. Methods:From June 2006 to June 2012,45 young children with femoral shaft fractures were treated by bridge wire splint fixation with ankle dorsiflexion,which was designed according to arch bridge mechanical principle and structure. There were 31 males and 14 females with an average age of 3.2 years old ranging from 8 months to 5.5 years old; 14 cases were upper 1/3 femoral fractures,26 cases were middle 1/3 femoral fractures,5 cases were lower 1/3 femoral fractures; 20 cases were transverse fractures, 14 cases were oblique fractures,6 cases were spiral frac- tures, and 5 cases were comminuted fractures. X-ray, follow-up imaging changes,clinical curative effect and complications were assessed. RESULTS: Forty-five patients were followed up for 6 to 21 months (averaged 12 months). All fractures were reached clinical bone healing after 5 to 7 weeks (averaged 6 weeks) fixation. Seven cases appearred limb soft tissue complications, including buttocks bedsore,dorsal foot and Achilles tendon epidermal necrosis, and healed after dressing and removal of external fixation. During follow-up,the original overlap angle and lateral displacement were remodeled, and limbs were restored to the normal line of force and bone structure. According to Flynn standard, 35 cases got excellent results, 8 cases good, 2 cases fair. CONCLUSION: The bridge wire splint fixation with ankle dorsiflexion for the treatment of femoral. shaft fractures in young children (less than 6 years old) is safe,feasible, simple,and has raliable effect, which can be applied in primary hospitals. PMID- 25739245 TI - [Titanium elastic nail versus plate-screw fixation for the treatment of upper segment fractures of femoral shaft in children]. AB - ABSTRA CT OBJECTIVE To compare the complications and clinical outcome of titanium elastic nail (TEN) versus plate-screw fixation (PF) for the treatment of upper segment fractures of femoral shaft in children. METHODS: From May 2006 and August 2012,32 consecutive children with upper segment fractures of femoral shaft were studied prospectively. They were randomly divided into TEN group and PF group. Ninteen patients were treated with titanic elastic nail (TEN) fixation including 11 males and 8 females with an average age of (6.9?2.2) years old ranging from 3 to 11,11 cases of them were type A, 6 cases were type B,2 cases were type C according to AO classification. The other 13 patients were treated with plate screw fixation (PF) including 9 males and 4 females with an average age of (7.5+/ 2.1) years old ranging from 5 to 12 years, and 3 cases of them were type A,6 cases were type B,2 cases were type C. Operative time, blood loss,incision length,the time of hospitalization,fracture healing time, postoperative complications and function recovery between two groups were compared and evaluated. RESULTS: The average follow-up period of the patients was 25.3 months (ranging from 15 to 48 months) in TEN group, and 36.2 months (ranging from 13 to 36 months) in the PF group. The operation time, time of hospitalization, the time of implants removed after the initial surgery, fracture healing time in TEN group were respectively (56.7+/-11.2) min, (6.6+/-3.9) d, (8.1+/-2.3) months, (12.6+3.8) weeks; and in PF group were respectively (51.5+/-8.3) min, (7.8+/-4.8) d, (7.8+/-1.6) months, (11.8+/-2.8) weeks, there was no significant difference between two groups (P>0.05). However, the length of incisions was (4.3+/-1.7) cm and the intraoperative blood loss was (12.7+3.2) ml in TEN group,which were significantly less than that in PF group respectively (89.2+/-21.1) ml and (11.6?2.3) cm (P<0.05). There was no statistically difference in postoperative in complication between two groups, but the patients in TEN group had a higher incidence of soft tissue irritation and misalignment. Outcome scores according to Sanders had no significant difference between two groups (P>0.05). In TEN group,the result was excellent in 13 cases, good in 3,fair in 2, and poor in 1, while in PF group excellent in 10, good in 2, fair in 1. CONCLUSION: There is no significant difference in therapeutic effects between TEN and PF for children with upper segment fractures of femoral shaft. The internal fixation should be selected according to the associated fracture type, weight, the expected value of the parents, scars, and so on. PMID- 25739246 TI - [Augmentative locking compression plate (LCP) combined with bone graft for the treatment of aseptic femoral shaft nonunion after intramedullary nailing]. AB - OBJECTIVE: To investigate the effect of augmentative locking compression plate combined with bone graft in treating aseptic femoral shaft nonunion after intramedullary nailing. METHODS: Twenty-one cases with aseptic femoral shaft nonunion after intramedullary nailing from January 2007 to January 2013 were treated,including 18 males and 3 females with a mean age of 37.7 years (ranged from 23 to 64 years). The mean period of nonunion after surgery was 23.9 months (ranged from 9 to 62 months). According to Weber-Cech classification,10 of those 21 cases were hypertrophic nonunion,7 were atrophic, and 4 had oligotrophic fracture nonunion. All patients retained the original intramedullary nail, and applied with augmentation plating of 6 to 8 holes locking compression plate, unicortical fixation with 2 to 3 locking screws in the proximal or distal end, with simultaneous autologous iliac bone grafting. After treatment,all patients were allowed to partial weight-bearing until full weight-bearing according to the radiological results. All patients were followed up and were evaluated with clinical and imaging results. RESULTS: All patients were followed up from 8 to 24 months, averaged (13.5+/-3.5) months,which showed clinical union at 4 to 8 months, averaged (6.0+/-1.0) months and radiological solid union at 7 to 12 months, averaged (9.1+/-1.5) months. No such complications as infection,hardware loosening or breaking were found. CONCLUSION: Augmentative locking compression plate(LCP) combined with bone graft for aseptic femoral shaft nonunion after intramedullary nail has a satisfied clinical efficacy. It's an useful and simple method. PMID- 25739247 TI - [Treatment of femoral shaft fractures by closed reduction and interlocking intramedullary nailing]. AB - OBJECTIVE: To discuss the clinical effect of closed reduction and interlocking intramedullary nailing in the treatment of femoral shaft fracture. METHODS: From March 2006 to December 2011,103 patients with femoral shaft fracture were treated by closed reduction and interlocking intramedullary nailing including 76 males and 27 females with an average age of 36 years old ranging from 19 to 55 years old. According to AO classification,there were 64 cases with type A,27 with type B, 12 with type C. Thirteen cases were open fractures including 5 cases with Gustilo type I , 8 with Gustilo type II . The time of bone healing were observed after operation, the knee function recovery was evaluated by HSS scoring standard at 1 year after operation. RESULTS: The intraoperative complications included femoral neck fracture in 1 case and proximal femoral fracture in 1 case,both of the patients were treated with reconstructive intramedullary interlocking nail and the fractures healed postoperatively. One patient was suffered from common peroneal nerve injury,which were fully recovered at 4 months later after medical treatment. All the patients were followed up from 12 to 28 months (averaged 22 months). All of the fractures were healed well and the average healing time was 3 to 9 months (averaged 5 months). All the hip joints were recovered to normal function. The average HSS was 90.89+/-5.06 at 1 year after operation. CONCLUSION: Interlocking intramedullary nailing is the preferred treatment for patients with femoral shaft fracture. Carefully operating and closed reduction can reduce the complications. PMID- 25739248 TI - [Case-control study on the treatmentof the fifth metatarsal base fractures by cardboard compression pad versus short leg plaster]. AB - OBJECTIVE: To compare the effect,safety,and advantage of flexible fixation with paperboard and pad versus short leg plaster in treating the fifth metatarsal base fracture,and establish the standard of diagnosis and treatment of the fifth metatarsal base fractures in flexible fixation with paperboard and pad. METHODS: From June 2010 to March 2013,59 patients with the fifth metatarsal base fracture were treated with paperboard and pad fixation or short leg plaster. Patients were enrolled and divided into paperboard and pad treatment group (paperboard group) and short leg plaster treatment group (plaster group) randomly according to the random number table. In paperboard group,there were 29 cases including 9 males and 20 females with an average age of (51.79+/-11.40) years old; the average course of injury was (11.59+/-6.58) hours. In plaster group, there were 30 cases including 9 males and 21 females with an average age of (52.13+17.34) years old ;the average course of injury was (11.03+/-7.06) hours. According to whether the fracture line across the articular surface, in paperboard group there were 14 cases of type A,15 of type B; in plaster group,16 of type A, 14 of type B. According to the degree of dislocation,in paperboard group there were 16 cases of degree I ,13 of degree II ; in plaster group,20 were degree I ,10 were degree II. Fracture was restored according to the type in manual. Patients in paperboard group were treated with paperboard and pad, and patients in plaster group were treated with short leg plaster. Fracture was fixed for 4 to 6 weeks according to fracture healing. On the 2nd, 4th,6th, 8th week and 3rd, 6th month after fixation, patients were followed up, and the foot function score was used to evaluate the function of injured foot. X-ray of injured foot was taken on the 2nd, 4th, 6th and 8th week were used to assess fracture healing. RESULTS: All patients got complete follow-up. The X-ray result showed that all fracture reached at clinical healing on the 8th week after fixation without skin ulcer,nonunion and displacement of fracture. From the 4th to 8th week after fixation, paperboard group had a higher X-ray score than plaster group, but the difference between two groups had no statistically significance. Repeated analysis result showed that there was interact at different time point and between groups,the difference had statistically significance (P<0.01). The foot function score showed that at all time point, paperboard group had a higher score than plaster group, and on the 2nd, 4th, and 6th week, it had statistically significant difference(P<0.01) between two groups. On the 6th months after fixation,the excellent and good rate of paperboard group was 93.10%, higher than that of plaster group, which was 86.67%. But it had no statistically difference(P=0.483) between two groups. CONCLUSION: Using paperboard and pad fixation to treat the fifth metatarsal base fracture has the advantage of simplicity operating,reliable fixation, satisfactory effects, easily obtainable material. PMID- 25739249 TI - [Surgical treatment of lumbosacral tuberculosis by anterior debridement,bone graft,and posterior pedicle screw-rod internal fixation]. AB - OBJECTIVE: To investigate the effectiveness of anterior debridement,bone graft, and posterior pedicle screw-rod internal fixation in the treatment of lumbosacral tuberculosis. METHODS: From January 2005 to June 2012,18 patients with lumbosacral tuberculosis undergoing the surgical treatment by anterior debridement, bone graft, and posterior pedicle screw-rod internal fixation were reviewed retrospectively. There were 12 males and 6 females with an average age of 44 years old ranging from 35 to 67. Among them, 2 cases were simple low back pain,3 cases were low back pain combined with radiating pain of lower extremity and 13 cases were muscle strength hypesthesia. According to Fankle grading,the nerve function was grade C in 3 cases,grade D in 10 cases,grade E in 5 cases. Of these cases,L4.5 was involved in 8 cases,L5 in 4 cases and L5S1 in 6 cases. The lumbosacral angle was 150 to 270 and the erythrocyte sedimentation rate (ESR) was 45 to 93 mm/h before treatment. The clinical indexes including the lumbosacral incidence, Frankel grade and ESR were reviewed at follow-up. RESULTS: All 18 cases were followed up for 14 to 22 months. The mean operation time was 180 min. The amount of bleeding was 400 to 800 ml. Except 1 case with iliac vein injuried and 4 cases with abdominal distension,no spinal injuries and severe relative complication occurred, and neurologic function improved in various degrees. Pain in lumbosacral area and radicular pain in lower extremities disappeared. The X ray and CT films demonstrated that bony fusion was obtained in all patients during 9 to 13 months postoperatively. The lumbosacral angle and ESR were improved significantly. CONCLUSION: Anterior debridement, bone graft, and posterior pedicle screw-rod internal fixation is an effective method in dealing with lumbosacral spine tuberculosis. PMID- 25739250 TI - [Panlongqi tablet (Chinese characters) combined with lumbar facet joint release for the treatment of lumbar spinal stenosis of Fengshi Bizu (Chinese characters)]. AB - OBJECTIVE: To investigate the clinical efficacy of Panlongqi tablet (Chinese characters?) combined with lumbar facet joint release for lumbar spinal stenosis of type Fengshi Bizu (Chinese characters). METHODS: Since February 2012 to February 2013, 120 patients with lumbar spinal stenosis of Fengshi Bizu (Chinese characters) syndrome were retrospectively studied. According to different treatment methods, 120 patients with lumbar spinal stenosis were divided into Panlongqi tablet (Chinese characters)group and control groups, respectively. In Panlongqi tablet (Chinese characters)group, 60 patients were treated by Panlongqi tablet (Chinese characters) combined with lumbar facet joints release solution including 26 males and 34 females with an average age of (60.40+/-3.36) years old ranging from 46 to 65 ; the course of the disease was 2 to 15 years (averaged 7.6 years). In control group the other 60 patients were treated with lumbar facet joint release including 24 males and 36 females with an average age of (61.20+/ 2.47) years old ranging from 48 to 63; the course was 3 to 14 years (averaged 6.9 years). The clinical effect of patients were evaluated by JOA and ODI score before treatment, at 4 weeks and 3 months after treatment. RESULTS: All patients were followed up for 4 to 7 months (means 5.6 months). After 3 months,7 cases in control group recurrenced symptoms,only 1 case in Panlongqi tablet (Chinese characters) group recurrenced. At 4 weeks and 3 months of follow-up, ODI score and JOA score of Panlongqi tablet group were much better than those of the control group. CONCLUSION: For lumbar spinal stenosis of type Fengshi Bizu (Chinese characters),which were treated with lumbar facet joint release with Panlongqi tablet(Chinese characters), supplemented by back muscle exercise, in relieving waist and low back pain symptoms and improving functional status of lower lumbar spine, can obtain satisfactory clinical outcome, is a good method of conservative treatment for such diseases. PMID- 25739251 TI - [Effect of tensile stress on human heel skin fibroblast proliferation in vitro]. AB - OBJECTIVE: To observe the effect of tensile stress on human heel skin fibroblast proliferation in vitro, providing a theoretical basis for preventing the wound edge skin necrosis and nonunion after calcaneal fracture surgery. METHODS: Fibroblast cells were taken from lateral heel skin of a 40 year-old-man, then cultured and subcultured in vitro. After that, they were divided into three groups: 0 hours group, 6 hours group and 24 hours group and were tested by tensile stress testing. The levels of TGF-beta1 and IL-6 in nutrient fluid were measured. Transmission electron microscope and light microscope was applied for observe mitochondria and nucleus. RESULTS: Under 10% of the tensile stress, mitochondria decreased, the levels of TGF-beta1 and IL-6 in nutrient fluid were decreased and cell proliferation was inhibited gradually with time increasing. CONCLUSION: The human lateral heel skin in a long-time tensile stress state is an important cause of wound edge skin necrosis and nonunion after calcaneus fracture surgery. PMID- 25739252 TI - [A method for isolated culture of bone microvascular endothelial cells of human femoral head]. AB - OBJCETIVE: To investigate the method of separation of culture of bone microvascular endothelial cells (BMECs) of human femoral head in vitro. METHODS: From October 2013 to January 2014,15 femoral heads without pathologic change from patients resected during hip replacement were selected involving 2 males and 13 females with a mean age of 71.2 years old ranging from 38 to 92. Cancellous bone in femoral head was bited into broken bone grain and transfered into medium in aseptic contidion. Cells were isolated by the methods of enzymic digestion and density gradient centrifugation,purified by differiential attachment. The characteristics of cells was observed by inverted microscope. vWF and CD31 immunofluorescence analysis was applied for identification of cells. RESULTS: The number of cells was positively correlated with patients' age after 24 hours in primary culture. The older patients had the less cells numbered. After 4 to 5 days' culture, primary cells appeared short spindle,polygon shaped and cobblestone-like morphology. After 7 to 10 days' culture, primary cells proliferated densely, became fusion, arranged in swirl, and contact inhibition appeared significantly. Immunofluorescence staining revealed the cells were 100% positive for vWF and CD31, and it showed that the cultured cells were BMECs. CONCLUSION: It was a simple, steady, effective method with good reproducibility, by which highly purified human BMECs can be obtained. PMID- 25739253 TI - [Application of vacuum sealing drainage and cryopreservation technology in hand and foot skin replantation]. AB - OBJECTIVE: To summarize the clinical effect of avulsed skin replantation of hand and foot via vacuum sealing drainage (VSD) combing low temperature technique. METHODS: From March 2012 to October 2013,13 cases with avulsed skin replantation of hand foot using combined technique included 8 males and 5 females with an average age of 32 years old ranging from 18 to 62 years. The time from injury to hospital was 1 to 4 hours (2.4 hour in average). The reasons of injury included machine injury in 7 cases and rolling over by cars in 6 cases. The parts of injuried involved finger in 2 cases,back of the hand in 5 cases and dorsum of foot in 6 cases. The area of avulsed skin was 5 cm x 6 cm to 12 cm x 16 cm,tendon and bone exposure was found in 4 cases. VSD was operated in all patients and the avulsed skin was refrigerated in the temperature of -4 degrees C or -80 degrees C. After 4 days, the skin stored in the -4 degrees C was replanted to the wounded place in 5 cases and in 3 cases the skin was planted to the donor site of flap. The skin stored in the -80 degrees C was replanted in 4 cases after 7 or 8 days, 1 case after 45 days. RESULTS: Of the 13 cases, 1 case of degloved injury from lower leg to dorsal foot,the replanted skin was necrosis completely; 1 case of degloving injury with fourth finger,the skin which replanted after 45 days survived approximately 30%,cured after skin-graft many times. In the other cases, the survival area of replanted skin was more than 85%, all cured after dressing. According to the standard of skin survival area evaluation by Jia et al, 11 cases showed excellent, 1 showed medium and 1 showed inferior. There were no complication about grafted skin rupture after the skin survived in 11 patients,after 4 to 22 months follow-up, the resiliency of grafted skin showed good. Sensation recovery was measured by BMRC standard: 3 cases of S3, 5 cases of S3, 3 cases of S2. CONCLUSION: VSD combining lower temperature technique in skin replantation provides time and space for wound preparation and treatment plan for the patients who need second surgery, especially for the large area skin degloving,this method could utilize the degloved skin efficiently, decrease the donor site area, alleviate the pain and financial burden,reduce the scar formation of donor site and impediment. PMID- 25739254 TI - [One-stage compound grafting of antibiotic-impregnated calcium sulfate and autogenous cancellous bone for the treatment of chronic calcaneal osteomyelitis]. AB - OBJECTIVE: To explore the treatment of chronic calcaneal osteomyelitis with bone defect after debridement and evaluate its clinical outcomes. METHODS: From June 2009 to June 2011, 52 patients with chronic calcaneal osteomyelitis were treated with stage-one compound grafting of antibiotic-impregnated calcium sulfate and autogenous cancellous bone,including 12 females and 40 males with an average age of 43 years old ranging from 18 to 67. According to Cierny-Mader classification, there were 34 cases with stage III and 18 with stage IV. There were 32 cases on right side and 20 on left,with a course of 6 months to 3 years. The area of soft tissue wound ranged from 3.0 cm x l.5 cm to 23.0 cm x l2.0 cm. The clinical effects were evaluated according to infection controlling, calcium sulfate absorption,bone defect repair and heel functional recovery. RESULTS: All patients were followed up for 2 to 3.8 years (averaged 2.8 years). Primary healing was achieved in 52 patients. Two cases of recurrence were found post-operatively, 1 case in 3 months and another in 5 months,which were cured after a second operation. Bone repair healing was gained in 1.5 to 3.5 months (averaged 2.5 months). Complete radiological absorption of calcium sulfate was found in 1.2 to 3 months(averaged 2.2 months). Local exudation after removal of drainage tube had been persisting in 10 patients for 2 to 3 months, which was consistent with the time when cacium sulfate were totally absorbed. Flap had partial necrosis in 4 cases,and the wounds were closed after appropriate treatment finally. The mean Maryland score was 88.15+/-7.70. There were excellent results in 32 cases, good in 14, fair in 6. CONCLUSION: A satisfactory short-term clinical results can be gained by one-stage compound grafting of antibiotic-impregnated calcium sulfate and autogenous cancellous bone in chronic calcaneal osteomyelitis, but the long term results need further follow-up. And much more study is also demanded to reduce the exudation of calcium sulfate. PMID- 25739255 TI - [Clinical observation of microsurgial repairing for the treatment of soft tissue defection of heel]. AB - OBJECTIVE: T o summarize the clinical effects of the repairing methods for skin and soft tissue defection of heel. METHODS: From June 1998 to June 2009,42 patients with skin and soft tissue defection of heel underwent the repairing treatment,including 23 males and 19 females, with an average age of 37 years old ranging from 18 to 65. The causes of injuries included mangled injury in 22 cases, high fall injury in 10 cases, cut injury in 5 cases,melanoma in 3 cases, decubital ulcer in 2 cases. Of the 42 cases, 27 were on left side and 15 on right side. The defect area of skin ranged from 3 cm x 2 cm to 18 cm x 16 cm. The time between the injury and surgery ranged from 8 hours to 10 years. The wounds were repaired separately by medial plantar flap in 13 cases, lesser saphenous sural nerve vascular island flap in 18 cases, saphenous neurocutaneous vascular flap in 11 cases. The patients' outcome were evaluated with appearance,blood supply, texture, resilience and two points discrimination of the flaps. RESULTS: All of the 42 flaps were survived. The distal skin necrosis occurred in 2 flaps, but healing occurred after debridement and intermediate thickness skin grafting. Three patients with sinus formation healed after 5 to 12 months of dressing change. All patients were follow-up for 8 months to 6 years. The flaps of all patients gained a satisfied shape after operation. The patients had a normal gait, the flaps had a good sense and a resistance to wearing,and no ulcer occurred. The two point discrimination of the flap was 4 to 12 mm. CONCLUSION: It is convenient and effective to repair the heel skin and soft tissue defects using medial plantar island skin flap when the defects is less then 8 cmx6 cm. As reliable blood supply,major artery preservation and high survival, the lesser saphenous sural nerve vascular island flap and saphenous neurocutaneous vascular flap can be transferred to repair the large soft tissue defect of heel. PMID- 25739256 TI - [Manual reduction of children's Monteggia fractures associated with anterior interosseous nerve injury]. AB - OBJECTIVE: To study clinical results of the manual reduction in treatment. METHODS: From October 2010 to April 2013,39 children with Monteggia fracture associated with anterior interosseous nerve injury were treated by manual reduction and fixation on buckling rotation backward,including 17 females and 22 males with an average age of 6.3 years old ranging from 3.2 to 11 years old. Among them, 15 cases were on the right side and 24 cases on the left. The course of disease was 40 minutes to 8 days (averaged 1.5 days). There were 7 cases with skateboard injured, 13 cases with stumble injured, 11 cases with falling injured,8 cases with air bed injured. According to Bado classification, 13 cases were type II, 22 cases were type III, 4 cases were type IV. RESULTS: The distal forefinger showed exercise normally in 34 cases at 3 weeks after treatment, and the patients restored normal activities at 6 weeks after treatment. All patients were follow-up from 54 days to 6 months (averaged 67 days. According to Mayo elbow functional evaluation standard,the scoring result was 19.62+/-1.35 in activity, 45.00 +/- 0.00 in pain, 9.87 +/- 0.80 in stability, 25.00+/-0.00 in strength, 99.49 +/-1.92 in total. The outcome of all patients was excellent and good evaluation results. CONCLUSION: If the anterior interosseous nerve injury could be identified early and treated timely, patients could gradually restore reasonable function and recover with satisfactory results. Raising understanding of anterior interosseous nerve injury can effectively reduce misdiagnosis. PMID- 25739257 TI - [Classification of upper sacral segment based on continuous axial pelvic computed tomography scan]. AB - OBJECTIVES: To introduce a classification system of upper sacral segment and its significance based on the continuous pelvic axial computed tomography scan. METHODS: The whole pelvis 2.0 mm thick axial scan images of 127 cases were observed, the sacroiliac screw channel of S1 were measured, according to the size of the transverse screw channel the upper sacral segment were classified. Such as transverse screw channel existed and in at least 4 layer scan images its width was > 7.3 mm, it was defined as sacral segment of the normal type. Such as transverse screw channel existed and its maximum width was 7.3 mm or less on scanning level, it was defined as a transitional. Such as transverse channel did not exist, or its width on all scanning level was 0 mm or less, it was defined as dysplastic. Various cases,percentage, and the average of the transverse screw channel were calculated. RESULTS: There were 58 normal (45.7%),42 transitional (33.1%), and 27 dysplastic (21.2%) upper sacral segments with an averaged width of the tansverse screw channel of 13.9 mm, 5.2 mm, and 0.9 mm, respectively. Each specimen could be defined as one of the three types of upper sacral segment without exceptions. CONCLUSION: It is possible to insert a transverse iliosacral screw into a normal upper sacral segment when indicated because of the capacious transverse screw channel. The transverse iliosacral screw placement into the transitional and dysplastic upper sacral segments was contraindicated because of the limited or none transverse screw channel. The transitional upper sacral segment was superior to the dysplastic segment due to its starting point location restriction on the true lateral sacral view. PMID- 25739258 TI - [Outcome of accessory navicular fusion for the treatment of the painful accessory navicular bone of type II in adults]. AB - OBJECTIVE: To evaluate the clinical outcome of accessory navicular fusion for treatment of the painful accessory navicular bone of type II in adults. METHODS: From June 2006 to June 2012, a total of 38 feet (in 35 adult patients) with painful accessory navicular with type I underwent an fusion operation of the primary and accessory navicular bones,including 26 males and 9 females with a mean age of (32.4+/-7.3) years old ranging from 18 to 44 years old. The course of disease ranged from 3 to 10 months. The perioperative complications and radiological outcomes were observed and recorded. The foot function before and after operation were assessed by the American Orthopedic Foot and Ankle Society (AOFAS) midfoot score, and the easement of the pain was evaluated by visual analog score (VAS). RESULTS: Two patients had transient superficial inflammation of the incision, no obvious perioperative complications occurred. All patients were follow-up for (53.5+/-14.7) months (12 to 84 months). Bone union was confirmed on plain radiography in 32 cases (35 feet). The mean time from the operation to union was (13.7+/-2.3) weeks (9 to 18 weeks). Postoperative pain VAS score was improved obviosly than preoperative (V=12.14,P< 0.01). The talar-to first metatarsal angle [(9.4+/-3.5) degrees vs (8.3+/-2.7) degrees , t=0.736, P>0.05)], calcaneal tilt angle [(17.7+/-2.2) degrees vs (18.9+/-3.4) degrees , t=0.794, P>0.05],talonavicular uncoverage angle [(14.3+/-3.4) degrees vs(12.5?4.6) degrees ,t=0.947, P>0.05) ],and height of the first tarsometatarsal joint [(14.8+/-3.1) mm vs (15.9+/-2.8) mm,t=0.814,P>0.05)] before and after operations had no statistic difference. The AOFAS midfoot score was improced from preoperative 45.6+/-5.3 to postoperative 82.5+/-7.4 (t=3.214,P< 0.01). CONCLUSION: For the painful accessory navicular bone of type II in adults, if the patient has a large navicular bone and not complicated with rigid flatfoot, once the conservative treatment fails, fusion of the primary and accessory naviculars may be a successful intervention. Overall, the procedure provides reliable pain relief, definite foot function improvement, and good patient satisfaction. PMID- 25739259 TI - [Comparison of three fixation methods for the treatment of tibial fractures in adolescents]. AB - OBJECTIVE: To explore the fixation methods in treatment of tibial fracture in adolescents by comparing the results and complications of three fixation methods and to determine the factors related to those complications. METHODS: From January 2007 to January 2012, 83 diaphyseal tibial fractures in 79 adolescents were treated with elastic stable intramedullary nail fixation, plate fixation, or external fixation respectively. There were 55 males and 24 females with an average age of 13.9 years (ranging from 11 to 17.6 years). Outcomes were compared in terms of the hospital stay,time to union, complications, and reoperation rates. RESULTS: All patients were followed up for 15.8 months in average. The time to union was significant associated with the pattern of fixation, energy of the injury, multiple and open fracture. The time of bone union of external fixation group was longer than that of elastic stable intramedullary nail fixation and plate fixation groups. But complication rates of external fixation group were higher than that of elastic stable intramedullary nail fixation and plate fixation groups. Four patients were treated with elastic nail fixation underwent a reoperation (loss of reduction in 2 cases, delayed union and nonunion in each 1 case). Six patients were treated with external fixation required a reoperation (loss of reduction in 3 cases, malunion in 2 cases, and replacement of a pin canal infection in 1 case). Two fractures were treated with plate fixation required refixation following nonunion and malunion. A multivariate analysis with adjustment for baseline differences showed external fixation to be associated with a 7.56 times (95% confidence interval=3.74 to 29.87) greater risk of loss of reduction and (or) malunion than elastic stable intramedullary nail fixation. At the final follow-up,there were agreeable results among three groups and no significant differences among them in final therapeutic effect (P>0.05). CONCLUSION: External fixation for treatment of tibial fracture in adolescents has the highest rate of complications than the other two fixation methods. Elastic stable intramedullary nail fixation can achieve the same effect of other fixed system and avoid most of the complications. Operation method choice depends on the experience of doctors and patients' basic situation and the fracture types. PMID- 25739260 TI - [MRI-based follow-up study of spinal tuberculosis in children]. AB - OBJECTIVE: To investigate the value of MRI follow-up in pediatric patients with spinal tuberculosis. METHODS: From February 2004 to April 2013, MRI imaging data in 21 children with spinal tuberculosis by pathologically and clinically proven were retrospectively analysed. There were 11 males and 10 males, with an average age of 9.4 years old ranging from 2 to 14 years old. Eighteen patients were received conservative treatment, 3 patients were treated by surgical operation. The course of disease ranged from 2 months to 3 years. All cases underwent two or more MRI examinations for follow-up. MRI findings of the first and second examination were comparatively analyzed,including signal changes of vertebral body and intervertebral, paraspinal abscess and the change of kyphosis angle. RESULTS: In the 21 cases with tuberculosis, 85 vertebral bodies were affected in total, including 10.6%(9/85), 49.4%(42/85) and 40%(34/85) vertebral bodies separately in the cervical,thoracic, lumbosacral spine. Follow-up MRI showed vertebral body shape and signal had no obvious change during or after treatment, 15 cases with vertebral bodies changed flat or cuneate, 10 cases with disc involvement,and intervertebral space became narrowing at different level. Among 13 patients with kyphosis angle greater than 0 degrees , 7 were located on thoracic, 2, 3, 1 were on thoracolumbar, lumbar and cervical spine, respectively. Among 18 cases with conservative treatment,kyphosis angle were 0 degrees on the first and the follow up MRI of 8 patients. One case of mild (<10 degrees ) kyphosis,follow-up MRI during therapy showed the angle slightly increased; 5 cases with moderate (10 degrees to 30 degrees ), follow-up MRI during therapy showed no obvious change; 4 cases with severe (>30 degrees ), follow-up MRI during and after therapy showed kyphosis increased in varying degrees. CONCLUSION: Follow-up MRI can make a big difference in the spinal tuberculosis of children; it can clearly show the change of the vertebral body and intervertebral space, paraspinal abscess and the kyphosis angle after the treatment,which can provide reference for clinical treatment and estimating prognosis. PMID- 25739261 TI - [Progress on peri-operative hidden blood loss after hip fracture]. AB - Hip fracture patients preoperative and postoperative exist hidden blood loss which often affect patients' wound healing, increase the probability of infection, prolong rehabilitation exercise, influence postoperative effect. At the same time, the body's blood loss increase the activation of the blood clotting mechanism, promote the incidence of deep vein thrombosis, bleeding and deep vein thrombosis has become the main causes of high risk in hip operation. It is very important to stop bleeding, anticoagulation should not be ignored, so how to effectively deal with the prominent contradiction between the postoperative anticoagulation and bleeding or looking for a best balance has become a intractable problems in hip fracture treatment. PMID- 25739262 TI - [Preparation of epitope imprinted particles for transferrin recognition by reversible addition fragmentation chain transfer strategy]. AB - A kind of novel epitope surface imprinted particles was prepared by the reversible addition fragmentation chain transfer (RAFT) strategy. The epitope of transferrin, N-terminal peptide of the protein with nine amino acid residues, was chosen as the template and immobi- lized with covalent interaction on the surface of silica particles through the truss arm glutaraldehyde. The living/controlled polymerization was initialed by 2,2'-azobisisobutyronitrile (AIBN) at 70 degrees C in the solution of N,N-dimethylformamide, with the regulation by triothioester agent 2-(dodecylthiocarbonothioylthio)-2-methylpropanoic acid. Methacrylic acid and 2-hydroxyethyl methacrylate were chosen as the functional monomers and N, N methylenebisacrylamide was chosen as the cross-linker in this polymerization. For this material, the binding capacity of the nine residue peptide could reach 2.36 mg/g with the imprinting factor (IF) of 1.89, while that for transferrin could reach 4.98 mg/g with IF of 1.61. The equilibrium could be achieved in 120 min for the transferrin recognition. In multi-protein competitive recognition, the imprinted factor of transferrin was the highest in the mixture of transferrin and other competitive proteins, such as cytochrome C and beta-lactoglobulin. The results indicated that these epitope surface imprinted particles with RAFT strategy could recognize not only the nine residue peptide but also the transferrin with good selectivity, high binding capacity and fast mass transfer. PMID- 25739263 TI - [Progresses on the applications of microporous organic polymers in sample preparation techniques]. AB - Microporous organic polymers (MOPs) are a class of novel porous materials consisting of the lighter elements, which possess low framework density, large surface area, tunable pore size and structure, excellent chemical and physical stability. In recent years, MOPs have shown great potential in the field of sample preparation techniques. In this paper, the classification and synthetic methods of MOPs are summarized, and the applications of MOPs in sample preparation techniques such as solid phase extraction, batch adsorption experiments, monolith and sensing film are reviewed. PMID- 25739264 TI - [Magnetic micro-/nano-materials: functionalization and their applications in pretreatment for food samples]. AB - Magnetic solid phase extraction technique, based on functional magnetic materials, is currently a hot topic in the separation and analysis of complex samples. This paper reviews the reported methods for the functionalization of magnetic micro-/nano-materials, such as sur- face grafting organic groups, coating carbon or inorganic oxide, grafting or coating polymer, being loaded to the surface or pores of supports, being introduced into the skeleton of sup- ports, and physically co-mixing methods. Moreover, we briefly introduce the applications of the functional magnetic micro-/nano-materials in pretreatment for food samples. PMID- 25739265 TI - [Advances of metabolite identification in liquid chromatography-mass spectrometry based metabolomics]. AB - Liquid chromatography-mass spectrometry (LC-MS) based metabolomics has become an important approach in life science research due to its powerful separation and high sensitivity detection. However, because of the lack of an effective mass spectra library for metabolite identification, a vast amount of detected metabolites are unable to be identified. The improvement of the metabolite coverage and the discovery of biomarkers are harmed, leading to the severe loss of chemical and biological information. The metabolite identification has become a major bottleneck in metabolomics studies. This review describes recent advances of metabolite identification based on atmospheric pressure ionization (API)-MS data. In particular, it focuses on the advances in mass spectrometer instruments, assignment of elemental compositions, database and spectral search, computer aided spectral interpretation, etc. PMID- 25739266 TI - [Recent advances in analysis of petroleum geological samples by comprehensive two dimensional gas chromatography]. AB - Abundant geochemical information can be acquired by analyzing the chemical compositions of petroleum geological samples. The information obtained from the analysis provides scientifical evidences for petroleum exploration. However, these samples are complicated and can be easily influenced by physical (e. g. evaporation, emulsification, natural dispersion, dissolution and sorption), chemical (photodegradation) and biological (mainly microbial degradation) weathering processes. Therefore, it is very difficult to analyze the petroleum geological samples and they cannot be effectively separated by traditional gas chromatography/mass spectrometry. A newly developed separation technique, comprehensive two-dimensional gas chromatography (GC x GC), has unique advantages in complex sample analysis, and recently it has been applied to petroleum geological samples. This article mainly reviews the research progres- ses in the last five years, the main problems and the future research about GC x GC applied in the area of petroleum geology. PMID- 25739267 TI - [Concentration techniques in capillary electrophoresis analysis and their applications]. AB - Capillary electrophoresis (CE), as a modern analytical technique, has been successfully applied in the analysis of metal ions, organics, proteins, nucleic acids and cells, due to its short analysis time, high separation efficiency, low sample consumption and low cost. Since most commercial CE instruments are equipped with ultraviolet detectors (UV) , the application of CE-UV with low sensitivity owing to limited optical pathway of on-capillary photometry and the small sample injection volume, is strictly limited in real sample analysis. On column preconcentration technique is an efficient approach to greatly improve the sensitivity of CE-UV, which can be achieved by merely adjusting the parameters, without any modification of the instrument. At present, stacking, dynamic pH junction, sweeping and transient isotachophoresis are the commonly used on-column preconcentration techniques in CE analysis, and have been extensively utilized in food science, environmental science and biomedicine fields. On the other hand, for real sample analysis, proper sample pretreatment is often necessary prior to instrumental analysis, aiming to remove sample matrix and enrich target analytes simultaneously. With the development tendency of economy, miniaturization and automation in modern analytical methods, green and miniaturized sample pretreatment techniques such as solid phase microextraction (SPME) and liquid phase microextraction (LPME) have been developed rapidly in recent decades. The combination of miniaturized sample pretreatment techniques and CE on-column preconcentration techniques can provide a promising method for the determination of trace analytes in complicated real samples. PMID- 25739268 TI - [Novel imidazolium-embedded amine stationary phase: preparation and its performance for hydrophilic interaction chromatography]. AB - The development of the novel and highly efficient hydrophilic interaction chromatography stationary phase is important for the separation of polar compounds. In the present work, a novel imidazolium-embedded amine stationary phase (Sil-IEASP) was designed and prepared for hydrophilic interaction chromatographic separation. The prepared material was respectively characterized by Fourier transform infrared spectrometer, thermogravimetric analyzer and organic element analyzer. The results indicated that the novel stationary phase was successfully prepared with the present used method. The effects of the contents of water, salt concentration and pH on the retention of nucleosides and nucleic acid bases were respectively investigated, and the results indicated that Sil-IEASP is of hydrophilic interaction chromatographic nature. Furthermore, no obvious effect of buffer pH and salt concentration on the retention of these compounds were found. The developed material was further used for the separation of uracil, adenine, cytosine, uridine and positional isomers (o-terphenyl, m terphenyl and triphenylene). Compared with the commonly used amino stationary phase, improved separation efficiency was achieved with the developed material, indicating the potential merit of the developed stationary phase for highly efficient hydrophilic interaction chromatographic separation. We anticipate that the novel stationary phase is promising for the hydrophilic interaction chromatography of polar compounds in the future research. PMID- 25739269 TI - [Hydrophilic interaction liquid chromatography coupled with mass spectrometry for metabolomic analysis of Escherichia coli]. AB - The zwitterionic hydrophilic interaction liquid chromatography coupled with mass spectrometry (ZIC-HILIC/MS) method was developed and applied for studying the metabolome of Escherichia coli. In this method, the linear ranges of the 52 representative compounds were between 2-6 orders of magnitude. Moreover the lowest limits of detection of most compounds were at ng/mL levels. The analysis for six samples prepared in parallel showed that the method had good reproducibility with more than 85% metabolites with the RSDs of peak area less than 30%. The precision of the method was tested by evaluating the relative recoveries of six internal standards at the low, middle and high concentrations. The results exhibited that the intraday precisions (RSDs) of the six compounds in the same concentrations were less than 20%. The recoveries of most compounds were accepted in the range of 70%-130%. The results of metabolomic analysis of three Escherichia coli strains with genetic modified yfcC gene showed that some small peptides, amino acids, nucleosides, organic acids and phospholipids changed differentially after the yfcC gene modification. These results indicated that the ZIC-HILIC/MS method could detect diverse metabolites and be used for metabolomic analysis purpose with good reproducibility and stability. PMID- 25739270 TI - [An automatic and sensitive method for the determination of endogenous brassinosteroids in plant tissues by an online trapping-in situ derivatization ultra performance liquid chromatography-tandem mass spectrometry system]. AB - Brassinosteroids (BRs) are a class of naturally occurring phytohormones with poly hydroxy steroid structure, which regulate general plant growth and many physiological processes. The reported methods for BR analysis were complicated, and the detection sensitivity was relatively low. To realize the automatic analysis of trace BRs in limited plant tissues, an in-tube solid phase microextraction-ultra performance liquid chromatography-tandem mass spectrometry (SPME-UPLC-MS/MS) system was constructed based on two valves-two pumps. Using C18 PEEK column as the trapping column and 4-(dimethylamino) phenylboronic acid (4 DMAPBA) as the derivatization reagent, an on line trapping and in situ derivatization assay method of BRs was developed. BRs could be programmed to fulfill the procedures of injection, extraction, derivatization, LC separation and MS detection in the system. The detection limits of BRs were improved more than one order of magnitude by the online trapping and in situ derivatization techniques, thus endogenous BRs could be quantified in only 300 mg plant tissues. PMID- 25739276 TI - [Determination of ultraviolet filters in environmental aqueous samples by dispersive liquid-liquid microextraction with online derivatization-gas chromatography-mass spectrometry]. AB - A method of dispersive liquid-liquid microextraction (DLLME) combined with online derivatization-gas chromatography-mass spectrometry (GC-MS) was developed for the determination of benzophenone-type ultraviolet (UV) filers (BPs) in environmental aqueous samples. It is found that the online derivatization was superior to the off-line derivatization with its simplicity, high reaction efficiency and less consumption of potential poisonous reagents. The influential factors for online derivatization, including the temperature of the injection port, the splitless time, the proportion of derivatization reagent and sample solution, were initially optimized. In addition, the influential factors for DLLME, including the type of the extractant and dispersing solvent, the proportion of the extractant and the dispersing solvent, the volume of sample solution, the pH and the salt concentration of the sample solution were individually optimized in detail. Under the optimized derivatization and DLLME conditions, the limits of detection for the six BPs, benzophenone, 2,4-dihydroxybenzophenone, oxybenzone, 4 hydroxybenzophenone, octabenzone and 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, ranged from 0.011 to 0.15 MUg/L. The intra-day and inter-day relative standard deviations varied from 0.7% to 16.6%. The method was applied to the analysis of lake and river water with good recoveries. It is cost effective, reliable, easy to operate, environment-friendly and promising in the real applications. PMID- 25739272 TI - [Determination of erythromycin residue in pork samples using molecularly imprinted solid phase extraction coupled with high performance liquid chromatography]. AB - Molecularly imprinted polymers (MIPs) for erythromycin (ERY) were prepared by precipitation polymerization, using ERY as template molecule, methacrylic acid (MAA) as functional monomer, ethylene glycol dimethacrylate (EGDMA) as cross linker and methanol/acetonitrile (1:4, v/v) as porogens. The characterization of the prepared MIPs and non-imprinted polymers (NIPs) were evaluated by scanning electron microscope (SEM) and equilibrium adsorption experiment. The results showed that the MIPs possessed the specific adsorptivity toward ERY. Scatchard analysis revealed that the apparent maximum binding capacity (Qmax) and the dissociation content (Kd) to ERY were as follows: Qmax1 = 45.24 mg/g, Kd1 = 0.028 g/L; Qmax2 = 87.53 mg/g, Kd2 = 0.20 g/L. Using the prepared MIPs as selective adsorbent, the proposed molecularly imprinted solid phase extraction (MISPE) coupled with high performance liquid chromatography (HPLC) was successfully applied to determine ERY residue in pork samples. A linear correlation was obtained over a range of 0.5-50 mg/L (r2 = 0.999 4), and the limit of detection was 0.2 mg/kg (S/N = 3). The spiked recoveries of ERY were 95.2%-104.2% with the relative standard deviations (RSDs) of less than 5%. The proposed method is selective, sensitive and reliable for the analysis of ERY residue in pork samples. PMID- 25739275 TI - [Magnetic solid phase extraction combined with gas chromatography-flame photometric detection for the determination of organophosphorus pesticides in juice samples]. AB - A novel method for the determination of organophosphorous pesticides (OPPs) in fresh juice samples was developed. Fe3O4 @ P (St-co-MAA) magnetic microparticles were synthesized and modified with styrene (St) and methacrylic acid (MAA) by coating St and MAA on magnetic particles and characterized by a series of techniques. The results indicated that Fe3 O4 magnetic nanoparticles (MNPs) have been successfully modified with St and MAA. Based on the prepared FeO4 @ P (St-co MAA) magnetic microparticles, a novel method of magnetic solid phase extraction (MSPE)-gas chromatography (GC)-flame photometric detection (FPD) was developed for the determination of OPPs. The extraction/desorption conditions of MSPE were optimized, and the analytical performance was evaluated under the optimal conditions. The limits of detection (LODs, S/N = 3) for target OPPs were in the range of 0.013-0.305 MUg/L with the RSDs (n = 7) ranging from 3.1% to 8.8%. The enrichment factors varied from 406 to 951. The linear ranges were over three orders of magnitudes (R2 > 0.99) and the reproducibilities were 7.4%-14.5% (n = 5). Finally, the proposed MSPE-GC-FPD method was successfully applied to the analysis of the five OPPs in fresh tomato and strawberry juice samples, with the recoveries of target OPPs in the range of 85.4%-118.9% for the spiked samples. The proposed MSPE-GC-FPD method is featured with low cost, fast separation and high enrichment factor. PMID- 25739273 TI - [Preparation of mixed stationary phase of cellulose and polysiloxane ionic liquid for gas chromatography]. AB - Cellulose has been widely used to synthesize chiral stationary phases for liquid chro- matography, but it is still absent in the family of stationary phases of gas chromatography due to its poor film-forming property. Based on the unique dissolution characteristic, ionic liquids provide a great chance to solve this problem. In this paper, cellulose triacetate (CTA) was syn- thesized, and then mixed with the home-made polysiloxane ionic liquid (PIL-C12-NTf2) to pro- duce a novel mixed stationary phase (CTA@ PIL-C12-NTf2). After that, it was used to prepare a capillary column for gas chromatography. The column efficiency was measured to be 3,165 plates/m (110 degrees C, naphthalene, k = 4.95), demonstrating the excellent film-forming capability of this stationary phase, and then the solvation parameter model was employed to find out the interaction parameters of CTA@ PIL-C12-NTf2. In the aspect of selectivity, CTA was firstly demonstrated to be able to improve the resolutions of tri-substituted aromatic positional isomers and the six isomers of nonane (C9). Moreover, some mixtures of representative chemicals like di-substituted aromatic positional isomers, n alkanes, alcohols, aliphatic esters and phthalates can also be separated well on CTA@ PIL-C12-NTf2. This work proposed a novel way for the application of cellulose modified stationary phase of gas chromatography, and revealed some features of this stationary phase in selectivity resulting from cellulose. PMID- 25739277 TI - [Characterization of compounds in crude oils by gas purge micro-syringe extraction coupled to comprehensive two-dimensional gas chromatography]. AB - A novel sample pretreatment method, gas purge micro-syringe extraction (GP- MSE), coupled to comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC x GC/TOFMS) has been developed for the characterization of volatile and semi-volatile compounds in crude oils. In the sample pretreatment process, the analytes were carried to the microsyringe barrel by inert gas, and at the same time, trapped by an organic solvent. The whole process of extraction takes less than 10 min, and only 20 MUL of organic solvent was needed. Using two custom standard solutions containing alkanes and polycyclic aromatic hydrocarbons (PAHs), the influences of the extraction conditions were investigated. The optimized conditions were as follows: 5 mg crude oil, 20 MUL hexane (extraction solvent), extraction for 3 min at 300 degrees C, condensation temperature set at -2 degrees C, gas flow rate set at 2 mL/min. Under the optimized conditions, a real crude oil sample was extracted and then analyzed in detail. It showed that the proposed method was very effective in simultaneously analyzing the normal and branched alkanes, cycloalkanes, aromatic hydrocarbons, and biomarkers of crude oil such as steranes and terpanes. The recoveries obtained ranged from 82.0% to 107.3% and the detection limits ranged from 34 to 93 MUg/L. The correlation coefficients (R2) were more than 0.99. The relative standard deviations (RSDs, n = 5) for all the analytes were below 10%. The results indicate that the proposed method is suitable for the characterization of volatile and semi-volatile compounds in crude oils with easy operation, high sensitivity and efficiency. PMID- 25739271 TI - [International comparison APMP. QM-S6: determination of clenbuterol in porcine meat by isotopic dilution mass spectrometry]. AB - A method was developed for the determination of clenbuterol in porcine meat by iso- topic dilution mass spectrometry (IDMS). National Institute of Metrology of China (NIM) par- ticipated in the international comparison activity organized by Asia Pacific Metrology (APMP) and got an international mutual recognition result using this method. The important factors of the method, such as the spray voltage, mobile phase, chromatographic column, extraction, purification and filtration conditions were investigated to acquire optimum conditions. The opti- mization results showed that the composition and pH value of the mobile phase had effects on the response of the mass spectrum of clenbuterol and the optimal value of the spray voltage. The solvent of sample had influences on the chromatographic retention behavior of clenbuterol. It was found that methanol caused a serious solvent effect, even made chromatographic peak split. Since clenbuterol was easily adsorbed on hydrophilic filter membranes and solid phase extraction columns, there were interference suppressions for the quantification of clenbuterol because of the eluate of the solid phase extraction columns. The homogenate method with extraction solvent of 0.1% (v/v) formic acid in acetonitrile had the highest extraction efficiency. The limit of the detection (LOD, S/N > 3) of the method was 0.2 MUg/kg. The determination results of clenbuterol in the porcine meat by this method were 5.18 MUg/kg +/- 0.50 MUg/kg (k = 2). This method is accurate, reliable, reproducible, and suitable for the determination of clenbuterol with trace quantity in porcine meat. PMID- 25739274 TI - [Rapid determination of pesticide multiresidues in porphyra by dispersive solid phase extraction coupled with online gel permeation chromatography-gas chromatography-mass spectrometry]. AB - A rapid method for the simultaneous identification and quantification of pesticide multiresidues in porphyra was developed using gel permeation chromatography (GPC) coupled to gas chromatography-mass spectrometry (GPC-GC/MS). Nineteen pesticides (organochlorines, organophosphoruses, triazines and pyrethroids) were selected as the target analytes. The pretreatment method was applied consisting of organic solvent extraction followed by dispersive solid phase extraction with graphitized carbon black (GCB) and primary secondary amine (PSA) adsorbents. GPC was also employed online to remove the large molecules such as pigments and lipids. The quantitative analysis was carried out by external standard method using gas chromatography coupled with mass spectrometry in selective ion monitoring (SIM) mode. Moreover, a large volume of sample was allowed to be injected using the program of GPC programmed-temperature vaporizer of gas chromatography to improve the sensitivity of measurements. The results showed that the calibration curves were linear (r > 0.995) in the range of 10 1,000 MUg/L for all the pesticides. The limits of detection (LODs) for the pesticides in porphyra were from 0.005 to 0.03 mg/kg, and the average recoveries were between 70% and 120%. The advantages of the method are simple, sensitive and shorter operation time for analysis of pesticide residues in porphyra samples. PMID- 25739278 TI - [Determination of short chain chlorinated paraffins in leather products by solid phase extraction coupled with gas chromatography-mass spectrometry]. AB - The short chain chlorinated paraffins (SCCPs) are the additives frequently used in the leather production in China, but they have been put into the list of forbidden chemicals issued by European Union recently. In fact, there is not a commonly recognized method for the determination of the SCCPs in the leather products due to the serious matrix interferences from the leather products and the complex chemical structures of the SCCPs. A method of solid phase extraction coupled with gas chromatography-mass spectrometry (SPE-GC-MS) was established for the determination of the SCCPs in the leather products after the optimization of the SPE conditions. It was found that the interferences from the leather products were thor- oughly separated from the analyte of the SCCPs on a home-made solid phase extraction (SPE) column filled with silica packing while eluted with a mixed solvent of n-hexane-methylene chloride (2:1, v/v). With this method, the recoveries for the SCCPs spiked in the real leather samples varied from 90.47% to 99.00% with the relative standard deviations (RSDs) less than 6.7%, and the limits of detection (LODs) were between 0.069 and 0.110 mg/kg. This method is suitable for qualitative and quantitative analysis of SCCPs in the leather products. PMID- 25739279 TI - [Determination of tris (2-chloroethyl) phosphate in leather by gas chromatography mass spectrometry coupled with mixed-mode sorbent solid phase extraction]. AB - Leather is one of the important exporting products to European Union (EU), and tris(2-chloroethyl) phosphate (TCEP) is a commonly used flame retardant in leather and leather products. Recently, TCEP has been classified as a kind of substance of very high concern (SVHC) by EU for its carcinogenicity and reproductive toxicity. But to date, there is not a recognized method for the determination of TCEP in leather and leather products due to the serious matrix interferences and relatively low recovery of TCEP. In this work, a home-made mixed-mode sorbent (Silica-WCX) with carboxyl and alkyl groups was tested as the sorbent of solid phase extraction (SPE) to extract TECP from leather. The results demonstrated that, making the carboxyl groups protonized under acidic condition, Silica-WCX exhibited better extraction performance towards TCEP over some frequently used commercial sorbents tested. After the optimization of the SPE conditions based on Silica-WCX, a method of gas chromatography/mass spectrometry (GC-MS) was established for the determination of TCEP in leather samples. The linear range for TCEP ranged from 0.10 to 100.0 MUg/L and the limit of quantification (LOQ, S/N = 10) was 44.46 ng/kg. The recoveries of TCEP spiked in samples at varied levels were in the range of 91.45%-99.98% with the relative standard deviations (RSDs) of 4.33%-5.97%. The method is simple, sensitive and reliable for the analysis of TCEP in leather and leather products. PMID- 25739280 TI - [Construction of high-effective symbiotic bacteria: evolutionary models and genetic approaches]. AB - Using the example of N2-fixing legume-rhizobial symbiosis, we demonstrated that the origin and evolution of bacteria symbiotic for plants involve the following: 1) the formation of novel sym gene systems based on reorganizations of the bacterial genomes and on the gene transfer from the distant organisms; 2) the loss of genes encoding for functions that are required for autonomous performance but interfere with symbiotic functions (negative regulators of symbiosis). Therefore, the construction of effective rhizobia strains should involve improvement of sym genes activities (for instance, nif, fix, and dct genes, encoding for nitrogenase synthesis or for the energy supply of N2 fixation), as well as the inactivation of negative regulators of symbiosis identified in our lab (eff genes encoding for the transport of sugars, and the production of polysaccharides, and storage compounds, as well as for oxidative-reductive processes). PMID- 25739281 TI - [High-priority research directions in genetics, and the breeding of the sugar beet (Beta vulgaris L.) in the 21st century]. AB - High-priority research directions for the genetics and breeding of the sugar beet in the 21st century were developed with consideration of the available scientific achievements of domestic and foreign scholars. These directions unite the classical and molecular approaches to solving the problems of increasing the effectiveness of sugar beet breeding carried out on a genetic basis, and they correspond to the contemporary level of scientific research. Seven such directions are proposed. PMID- 25739282 TI - [Species-specific localization of DNA from pericentromeric heterochromatin on polytene chromosomes in the salivary gland cells and 3D-nuclear organization nurse cells in Drosophila virilis, and Drosophila kanekoi (Diptera: Drosophilidae)]. AB - Microdissection of the chromocenter of D. virilis salivary gland polytene chromosomes has been carried out and the region-specific. DNA library (DvirIII) has been obtained. FISH was used for DvirIII hybridization with salivary gland polytene chromosomes and ovarian nurse cells of D. virilis and D. kanekoi. Localization of DvirIII in the pericentromeric regions of chromosomes and in the telomeric region of chromosome 5 was observed in both species. Moreover, species specificity in the localization of DNA sequences of DvirIII in some chromosomal regions was detected. In order to study the three-dimensional organization of pericentromeric heterochromatin region of polytene chromosomes of ovarian nurse cells of D. virilis and D. kanekoi, 3D FISH DvirIII was performed with nurse cells of these species. As a result, species specificity in the distribution of DvirIII signals in the nuclear space was revealed. Namely, the signal was detected in the local chromocenter at one pole of the nucleus in D. virilis, while the signal from the telomeric region of chromosome 5 was detected on another pole. At the same time, DvirIII signals in D. kanekoi are localized in two separate areas in the nucleus: the first belongs to the pericentromeric region of chromosome 2 and another to pericentromeric regions of the remaining chromosomes. PMID- 25739283 TI - [Use of the common winter wheat homozygous population for genetic analysis of beta-amylase and evaluation of its aggregation ability]. AB - We investigated a self-pollinated homozygous population of common winter wheat, F(-> infinity) 24/04 x Odesskaya krasnokolosaya, for variants of beta-amylase and the aggregation ability of the protein complex of weevil via disulfide bonds. It was found that variation in the electrophoretic types of this enzyme was due to four isoenzymes. Two of them (a and b) are doubled and controlled by separate loci with independent inheritance. Isoenzyme c was due to three dominant factors, and four loci were responsible for d. Analysis of the number of -S-S-bonds of five genotypes, which were harvested in 2013 and differed in the types of beta amylase, showed that some of them were significantly different from others in this indicator. In general, the samples were grouped by the type of this enzyme, forming the following continuous series with respect to aggregation ability: I >= B >= F >= D >= G or 59.13 +/- 3.18 >= 56.65 +/- 2.46 >= 52.54 +/- 2.24 >= 50.16 +/- 1.67 >= 48.63 +/- 6.25 of cond. units. Significant differences were observed for this property between groups B > D and I > D. Therefore, genotypes having types I and B have a positive influence on the rheological properties of dough. PMID- 25739285 TI - [Chromosome composition of wheat-rye lines and the influence of rye chromosomes on disease resistance and agronomic traits]. AB - Identification of the chromosomal composition of common wheat lines with rye chromosomes was carried out using genomic in situ hybridization and 1RS- and 5P specific PCR markers. It was demonstrated that wheat chromosomes 5A or 5D were substituted by rye chromosome 5R in the wheat-rye lines. It was established that one of the lines with complex disease resistance contained rye chromosome 5R and T1RS.1BL, while another line was found to contain, in addition to T1RS.1BL, a new Robertsonian translocation, T5AS.5RL. Substitution of the wheat chromosome 5A with the dominant Vrn-A1 gene for the Onokhoiskaya rye chromosome 5R led to lengthening of the germination-heading period or to a change in the type of development. A negative influence of T1RS.1BL on SDS sedimentation volume and grain hardness was demonstrated, along with a positive effect of the combination of T1RS. BL and 5R(5D) substitution on grain protein content. Quantitative traits of the 5R(5A) and 5R(5D) substitution lines were at the level of recipient cultivars. A line with two translocations, T1RS.1BL + T5AS.5R1, appeared to be more productive as compared to the line carrying T1RS.1BL in combination with the 5R(5D) substitution. PMID- 25739284 TI - [Inheritance and phenotype expression of functional and null alleles of aromatic alcohol dehydrogenase (CAD) in diploid wheats]. AB - Functional F and null 0 alleles of the CAD1 (Aadh1) gene, which controls the biosynthesis of aromatic alcohol dehydrogenase, were studied in hybrids of the diploid wheat T. monococcum L. and Triticum sinskajae A.Filat. et Kurk. The gene CAD1 is located in chromosome 5A and is linked with the awnless gene awnS (La) with a recombination frequency of about 32%. Plants with genotypes FF, F0, and 00 were significantly different in the height and mechanical strength of the stalk (culm). The elastic limit of the culm tissues of plants FF was considerably higher than in 00 plants. F0 heterozygotes had intermediate values. The thickness of the wall of the sclerenchyma was thinner in plants with genotype 00. The chemical structure of lignin of plants with the functional CAD allele contained units of a phloroglucinol series missing in the mutant plants. The CAD genotypes had no effect on the relative content of cellulose and lignin in stalks ofdiploid wheat and insignificantly influenced the ratio of H :G : S units in the lignin structure, as well as some components of extractives. PMID- 25739286 TI - Genetic diversity in wild populations of Paulownia fortune. AB - The genetic diversities of 16 Paulownia fortunei populations involving 143 individuals collected from 6 provinces in China were analyzed using amplified fragment length polymorphism (AFLP). A total of 9 primer pairs with 1169 polymorphic loci were screened out, and each pair possessed 132 bands on average. The percentage of polymorphic bands (98.57%), the effective number of alleles (1.2138-1.2726), Nei's genetic diversity (0.1566-0.1887), and Shannon's information index (0.2692-0.3117) indicated a plentiful genetic diversity and different among Paulownia fortunei populations. The genetic differentiation coefficient between populations was 0.2386, while the gene flow was 1.0954, and the low gene exchange promoted genetic differentiation. Analysis of variance indicated that genetic variation mainly occurred within populations (81.62% of total variation) rather than among populations (18.38%). The 16 populations were divided by unweighted pair-group method with arithmetic means (UPGMA) into 4 groups with obvious regionalism, in which the populations with close geographical locations (latitude) were clustered together. PMID- 25739287 TI - Assessment of DNA methylation changes in tissue culture of Brassica napus. AB - Plant tissue culture, as a fundamental technique for genetic engineering, has great potential of epigenetic variation, of which DNA methylation is well known of importance to genome activity. We assessed DNA methylation level of explants during tissue culture of Brassica napus (cv. Yangyou 9), using high-performance liquid chromatography (HPLC) assisted quantification. By detecting methylation levels in hypocotyls cultured in mediums with different concentrations of hormones, we found dissected tissue:cultured with 0.1 mg/L 2,4-D and 1.0 mg/L 6 BA, presented the lowest methylation level and highest induction rate of callus (91.0%). Different time point of cultured explants also showed obvious methylation variations, explants cultured after 6 and 21 days exhibited methylation ratios of 4.33 and 8.07%, respectively. Whereas, the methylation ratio raised to 38.7% after 30 days cultivation, indicating that methylation level of hypocotyls ranged during tissue culture. Moreover, we observed that the methylation level in callus is the highest during regeneration of rape-seed, following the regenerated plantlets and hypocotyls. This paper indicated the function of hormones and differentiation of callus is relevant to the methylation levels during tissue culture. PMID- 25739288 TI - [Genetic diversity and relatedness in different generations of the Siberian crane (Grus leucogeranus Pallas) captive population]. AB - Eight variable microsatellite loci were analyzed in terms of studying the genetic structure of different generations of a captive population of a rare endemic Russian species, the Siberian crane (Grus leucogeranus Pallas). It was shown that the founding population of natural origin (15 birds) is characterized by high genetic diversity (N(A) = 6.625, H(O) = 0.767, H(E) = 0.731) and a lack of relatedness (R = -0.079). In the total sample of descendents of the founders (122 individuals from generations F1, F1/F2, F,/F3, F2, F2/F3), this characteristic level of genetic variation was retained; however, we observed a decrease in allelic richness in some generations (F1/F2, F1/F3, F2). We found a low level of relatedness inthe sample of descendents of the founders (F1, F1/F2, F1/F3), while the relatedness was maximal (R = 0.302) in the first-generation descendents of the breeders. A small sample of breeders related to each other of generations F1 and F2 (eight birds) does not represent the entire gene pool of the founders of the Siberian Crane captive population. In view of this, we discuss the need to form a new genetically heterogeneous generation of breeders that would also include Siberian Cranes from the virtually extinct Western Siberian population. PMID- 25739289 TI - [Analysis of genome instability in offspring of "Mayak" workers families: minisatellite CEB1]. AB - Genome instability transmission in offspring was analyzed in order to evaluate the risk of delayed genetic effects of exposure in 95 family triplets in which only fathers experienced prolonged occupational radiation exposure. The mean total preconceptive absorbed dose (TPAD) of external gamma radiation in the paternal gonads was 1.65 +/- 0.08 Gy (dose range of 0.57-5.70 Gy), and the mean TPAD of internal alpha radiation from incorporated plutonium-239 in.the gonads was 0.0015 +/- 0.0003 Gy (dose range 0.000-0.015 Gy). The control group consisted of 50 family triplets in which parents were not occupationally exposed. The mutation process was studied using PCR based on hypervariable minisatellite marker CEB 1 (chromosome 2, 2q37.3). The paternal type of inheritance of mutations for minisatellite CEB 1 was found in 80% of cases. The analysis revealed a statistically significant increase in minisatellite CEB1 mutations in the common group of families in which fathers experienced prolonged occupational radiation exposure and in the group of families in which fathers were exposed to radiation in a dosage range of 0.5-1.0 Gy as compared to the control, reaching a significance level of p = 0.109 and p = 0.058, respectively. The dose threshold of mutation detection in the off-spring of Mayak PA workers was estimated. PMID- 25739290 TI - [Analysis of polymorphisms of genes associated with immune response and tissue remodeling in occupational chronic bronchitis]. AB - The involvement of polymorphisms of genes encoding immune response-associated molecules (LTA, TNFA, ILB, ILRN, IL8, IL10, VDBP), matrix metalloproteinases (MMP1, MMP2, MMP3, MMP9, MMP12, ADAM33), and tissue and serum inhibitors of proteases (TIMP2, TIMP3, SERPINA1, SERPINA3) in the predisposition to occupational chronic bronchitis was assessed by PCR-RFLP analysis in groups of patients (n = 122) and healthy employees (n = 166). It was found that occupational chronic bronchitis was associated with polymorphisms of VDBP (P(adj) = 0.00005, OR(adj) = 2.06), MMP1 (P(adj) = 0.00002, OR(adj) = 2.57), ADAM33 (P(adj) = 0.0004, OR(adj) = 2.52), and IL8 (P(adj) = 0.0058, OR(adj) = 2.87). The most significant association was observed for the VDBP polymorphism 1296T>G. The VDBP haplotype GC*1S by the loci 1296T>G and 1307C>A was an informative susceptibility marker (P(adj) = 0.0001, OR(adj) = 2.60, 95% CI (1.62-4.19)). There was also a significant interaction between the VDBP polymorphism 1307C>A and the duration of occupational exposure to hazardous factors (P(interaction) = 0.02). Apparently, the investigated polymorphisms of VDBP, MMP1, ADAM33, and IL8 contribute to the genetic susceptibility to chronic bronchitis induced by dust and toxic agents. PMID- 25739291 TI - Maternal and paternal diversity in Xinjiang Kazakh population from China. AB - The ancient silk road of China passed through Xinjiang and facilitated gene exchanges from the East and the West which impacted on the genetic variation and structure of the nomadic Kazakh population residing there. In order to understand the nature of this genetic variation; 151 Xinjiang Kazakh samples were obtained from four main Kazakh groups and were analyzed using mtDNA and Y-chromosome markers. The Xinjiang Kazakh population is heterogeneous, showing the coexistence of matrilineal lineages with different origins. No genetic differentiation of mtDNA is observed among the four different regional Xinjiang Kazakh populations in Xinjiang by AMOVA and Networks. The genetic diversity of Y-STR loci is higher in Xinjiang Kazakhs (0.968 +/- 0.014) than the Kazakhs from Kazakhstan (0.629 +/- 0.071) and Russia (0.835 +/- 0.020). East Eurasians make a more than 50% contribution to the maternal and paternal lineages of Xinjiang Kazakhs. There is more gene flow from West Eurasian into the maternal lineages of Xinjiang Kazakh than to the Kazakhs from Russia and Kazakhstan. Moreover, mtDNA and Y-STR displayed high polymorphism in Xinjiang Kazakhs (the haplotype diversity and power of discrimination were 0.990 +/- 0.003, 0.9137 for mtDNA HVS and 0.968 +/- 0.014, 0.9489 for Y-STR system, respectively), suggesting they would be very useful and important markers for forensic analysis and population genetic studies. PMID- 25739292 TI - [The rate of transposition and the specificity of transposable element insertions are not sufficient to cause gonadal dysgenesis in Drosophila melanogaster]. AB - Data disputing the unique role of transposable elements (TEs) in the induction of intraspecific gonadal dysgenesis (GD) in Drosophila are discussed. Transposable elements (TEs) occupy the fifth part of the genome of Drosophila melanogaster. PMID- 25739293 TI - [Coevolution of symbiotic bacteria Wolbachia and host mtDNA in Russian populations of the Culex pipiens mosquito complex]. AB - The mitochondrial DNA phylogenies of closely related forms of mosquitoes from the Culex pipiens complex and of strains of the endosymbiotic bacteria Wolbachia pipientis were compared. Based on the cytochrome oxidase subunit I gene polymorphism, six mitochondrial haplotypes and four W. pipientis groups were discovered in mosquitoes from geographically remote populations. A strict correlation between the COI type and the type of W. pipientis proves the stable coinheritance and distribution of both cytoplasmic components in the examined mosquito populations and suggests either the absence or rarity of horizontal transfer of the symbionts in the Culex pipiens complex. PMID- 25739294 TI - Characterization of new microsatellites selected from EST resources of Chinese mitten crab, Eriocheir sinensis. AB - Sixteen new microsatellites were, identified by screening 7533 expressed sequence tags of Chinese mitten crab, Eriocheir sinensis from GenBank data we published. They were polymorphic with the PIC value ranged from 0.349 to 0.957, the number of alleles ranged from 22 to 48, and the observed and expected heterozygosities ranged from 0.375 to 1.000 and 0.366 to 0.983, respectively. Five loci could be applicable to genetic diversity and population structure of E. sinensis. PMID- 25739295 TI - [Cajal bodies and histone locus bodies: molecular structure and function]. AB - The review provides modern classification of evolutionarily conserved coilin containing nuclear bodies of somatic and germ cells that is based on the characteristic features of their molecular composition and the nature of their functions. The main differences between Cajal bodies and histone locus bodies, which are involved in the biogenesis of small nuclear spliceosomal and nucleolar RNAs and in the 3'-end processing of histone precursor messenger RNA, respectively, are considered. It is shown that a significant contribution to the investigation of the diversity of coilin-containing bodies was made by the studies on the architecture of the RNA processing machinery in oocyte nuclei in a number of model organisms. The characteristics features of the molecular composition of coilin-containing bodies in the nuclei of growing oocytes (the so called germinal vesicles) of vertebrates, including amphibians and birds, are described. PMID- 25739296 TI - [Effects of thyroid hormone level alterations on the Weberian apparatus ontogeny of cyprinids (Cyprinidae; Teleostei)]. AB - Effects of thyroid hormone (TH) level alterations on the development and definitive morphology of the Weberian apparatus (WA, morphofunctional complex, providing transmission of sound signals from the gas bladder to the labyrinth of inner ear) were experimentally assessed in cyprinid fishes (Labeobarbus intermedius and Danio rerio). Alterations of TH-level were shown to lead to heterochronies, changes of timing and rates of ontogenetic events resulting in changes of definitive morphology of some structures as well as of the WA as a whole. Differences, in reaction of WA structures to the TH-level alterations, and inter- and intraspecific variability of TH-responsiveness were revealed. PMID- 25739297 TI - [Key morphofunctional transformations in the evolution of chiropterans (Bats, Chiroptera)]. AB - Study on the morphology and morphogenesis of wing membranes in Bats has revealed some peculiarities in their structure and development. Understanding the embryogenesis of these animals, as well as attraction of data obtained on their molecular genetics and paleontology, allows one to single out some factors that could have initiated evolutionary modifications in development programs. A scenario of the key morphofunctional transformations in the forelimbs during the evolution of chiropterans is given. PMID- 25739298 TI - [Features of development and reproduction of transgenic flax]. AB - Primary transformants carrying a genetic construct with the chimeric gfp-tua6 gene were obtained using biolistic transformation of hypocotyl explants of flax variety Vasilek. Viable modified plants were used as a basis for the production of inbred lines with confirmed inheritance of introduced genetic construct in three generations. The characteristics of phenological growth stages, plant height, number of bolls and meiosis were studied for transgenic plants. A comparison of transformed lines based on reproduction years revealed a significant decrease of seed production in one line. Meiotic analysis of this line at metaphase I and anaphase I stages was conducted. The percentage of cells with impaired meiosis was highest in transgenic plants of the line with the lowest seed production. Thus, the nonspecific incorporation of genetic construct into the flax genome using biolistic transformation impairs meiosis to a different extent and it is the main reason for unequal reproducibility of transgenic flax. The production of stably reproducing transgenic lines requires systematic analysis of meiosis. PMID- 25739300 TI - [Morphometric parameters of nutria kidney structures in postnatal ontogeny]. AB - Data on the morphometric parameters of the renal corpuscle, renal tubules, and collecting ducts of male and female nutrias in postnatal ontogenesis were obtained. It was found that the area of the renal corpuscle, glomerulus, the cavity and lumen of the capsule, and the proximal tubule diameter in the right and left kidney of female and male nutrias in the first year of life increase. The distal tubule diameter also increases; however, the dynamics of its changes becomes sinuous after 4.5 months. The collecting duct diameter varies depending on gender, age, and renal topography. The nuclear-cytoplasmic ratio in the cells of proximal and distal tubules and collecting ducts changes in a sinuous manner and depends on the gender and age of nutrias. The minimum mean value of the nuclear-cytoplasmic ratio was found in the proximal tubule cells in the left kidney of 12-month-old female nutrias (0.162 +/- 0.002), and the maximum value was found in the distal tubule cells in the left kidney of newborn male nutrias (0.435 +/- 0.007). PMID- 25739299 TI - [Cellular dynamics of the outer layers of the hair follicle of fine-wool sheep during the phase of stable hair growth]. AB - The structure, origin, and migration of outer sheath cells of the hair follicles of domestic sheep were studied by electron microscopic, autoradiographic, and histochemical (glycogen) in order to understand the role of this layer in hair morphogenesis. We demonstrated that the cells of the outer layers of the outer sheath interpose into the inner "companion" layer of the outer sheath. Although this process takes place all along the hair follicle from the lower bulb up to the sebaceous glands orifices, it mainly takes place over the bulb. Labeled cells interposed into the companion layer move towards sebaceous glands orifices more than 24 hours faster than labeled cells of the inner sheath and hair, because these cells included the label not in the bulb cambium (as hair and inner sheath) but over the bulb, and from this point they start movement. Interposition of cells into the companion layer must cause increase of its volume and additional volume supposed to be led away into the pillar canal around the hair near the sebaceous glands orifices. This can provide the mechanism for the propagation of the hair and inner sheath promotion to sebaceous gland orifices. PMID- 25739301 TI - [Investigation of morphogenesis of inflorescence and determination of the nature of inheritance of "supernumerary spikelets" trait of bread wheat (Triticum aestivum L.) mutant line]. AB - Using C-banding and FISH methods, the karyotype of MC1611 induced mutant of bread wheat, which develop additional spikelets at a rachis node (trait "supernumerary spikelets") was characterized. It was determined that the mutant phenotype is not associated with aneuploidy and major chromosomal rearrangements. The results of genetic analysis showed that supernumerary spikelets of the line are caused by a mutation of the single bh-D. 1 gene, influenced by the genetic background. The mutation causes abnormalities of inflorescence morphogenesis associated with the development of ectopic spikelet meristems in place of floral meristems in the basal part of the spikelets, causing the appearance of additional spikes at a rachis node. The mutant phenotype suggests that the Bh-D gene determines the fate of the lateral meristem in ear, which develops as floral meristem and gives rise to floral organs in wild-type inflorescences. In the Bh-D. 1 mutant, the establishing identity is impaired. The characterized mutant can be used in further studies on molecular genetic basis of development of wheat inflorescence. PMID- 25739302 TI - [Method of fixing the heterotic effect--implementation on plants (on the hundredth anniversary of the birth of V.A. Strunnikov)]. AB - The article is devoted to the 100th anniversary of the outstanding world-renown Russian scientist Vladimir Alexandrovich Strunnikov, Academician, Professor, Head of Group of Developmental Cytology and Sex Regulation at Koltzov Institute of Developmental Biology and Head of genetic studies on silkworms in a number ofsericulture institutes in CIS. Laureate of the State Prize of the USSR (1981), Hero of Socialist Labor (1990), awarded the I.I. Mechnikov Gold Medal, Academy of Sciences of the USSR (1981), founder of the theory explaining the origin of heterosis. One of his most significant achievements is the "Methods of Fixing the Heterosis Effect," which makes it possible to abandon the production of hybrid seed and increase the yield of many crops by 20-50%. Fixing the gene complexes that determine the heterosis effect will become the "springboard" that will allow obtaining even more productive heterotic hybrids on the basis of new-generation varieties. The efficiency of this method in plant objects at the organismal and molecular levels was shown in the All-Russia Research Institute of Rice. A modification of this method reducing its laboriousness and increasing its efficiency was developed. PMID- 25739303 TI - [Effect of embryonic anlage allografts of the rat spinal cord on growth of regenerating fibers of the recipient nerve]. AB - A comparative study of the effect of tissue and suspension allografts of an embryonic spinal cord on regeneration of nerve fibers of impaired (by application of a ligature) sciatic nerve in rats was conducted. It was demonstrated that unlike tissue grafts that reach a large volume 21 and 60 days after transplantation, suspension grafts do not inhibit the growth of axons of the recipient to the periphery. It was established that introduction of a suspension of dissociated cells of the spinal cord embryonic anlages (but not fragments of these anlages) into the impaired sciatic nerve in rats results in an increase in the amount of myelinated regenerating nerve fibers of the recipient 60 days after the operation. PMID- 25739304 TI - [Physicochemical, catalytic, and regulatory properties of malate dehydrogenase from Rhodovulum steppense bacteria, strain A-20s]. AB - The physicochemical, regulatory, and kinetic properties of malate dehydrogenase (EC 1.1.1.37) from haloalkaliphilic purple nonsulfur Rhodovulum steppense bacteria, strain A-20s, were studied. The malate dehydrogenase (MDH) preparation with a specific activity of 0.775 +/- 0.113 U/mg protein was obtained in an electrophoretically homogeneous state using multistep purification. Using homogenous preparations, the molecular weight and the Michaelis constant of the enzyme were determined; the effects of metal ions, the temperature effect, and the thermal stability of the MDH were studied. The dimer structure of the enzyme was demonstrated by DS-Na-electrophoresis. PMID- 25739305 TI - [The level of genetic variability of cells in prolonged suspension culture of Arabidopsis thaliana]. AB - The level of heterogeneity and genetic variability of cells in a suspension of Arabidopsis thaliana cultured in vitro for more than seven years was studied. The considerable heterogeneity of the suspension in cell size was shown. As revealed by nuclear DNA cytophotometry, the suspension culture was mixoploid and the amount of DNA in the cells varied from 4 to 16 C. However, PCR with 6 RAPD- and 4 ISSR-primers and their intra-group combinations showed the lowest degree of variability of DNA markers. The genetic distances of clones obtained from a suspension culture of the parent plant were only 1.5%. Differences between the clones were identified with only one pair of 31 primer combinations tested, indicating low level of genetic heterogeneity of the suspension. The results showed that variations in the amount of DNA in the suspension culture cells are not accompanied by significant changes in the DNA sequence. PMID- 25739306 TI - [Microbial communities of frozen soils of the Tuimaada Valley in Central Sakha]. AB - This study determined the characteristic features of microbial communities inhabiting frozen soils of Central Sakha. All groups of microorganisms were present in high numbers comparable with the microbial densities in steppe soils of Transbaikalia; their distribution along soil profiles followed a specific pattern with no decrease in abundance with depth. In summer, the dominant groups of the microbial pool were actinomycetes and oligonitrophilic bacteria, while in autumn it was heterotrophic bacteria. A typical feature of the frozen soils of Central Sakha was the gradual penetration of microorganisms into deeper soil horizons during the vegetation season and their accumulation in the suprapermafrost horizon by autumn. PMID- 25739307 TI - [Influence of genotype, explant type and component of culture medium on in vitro callus induction and shoot organogenesis of tomato (Solanum lycopersicum L.)]. AB - The influence of explant type as well as of the type of growth regulators and concentration on callus induction processes and somatic organogenesis of shoots was studied in vitro on four tomato genotypes of Russian breeding. Cytological study of callus tissue was conducted. It was established that tomato varieties possess a substantially greater ability to indirect shoot organogenesis compared with the F1 hybrid. The highest frequency of somatic organogenesis of shoots, as well as their number per explant, was observed for most of the genotypes studied during the cultivation of cotyledons on Murashige-Skoog culture medium containing 2 mg/l of zeatin in combination with 0.1 mg/l of 3-indoleacetic acid. An effective protocol of indirect somatic organogenesis of shoots from different explants of tomato varieties with a frequency of more than 80% was developed. PMID- 25739308 TI - [The role of the Urals in the genetic diversity of the European moose subspecies (Alces alces alces)]. AB - The genetic diversity of the Uralian moose population and the role of the Ural region in the phylogeographic structure of the European moose were evaluated based on sequence polymorphisms of the mtDNA control region. The nucleotide diversity of the Ural moose was low, whereas haplotype diversity was rather high. It was found that the haplotype pool of the Ural moose reflects both the unique features of their mitochondrial lineages and their connection with Alces alces alces populations of Europe and West Siberia. The structure of median networks and the territorial haplotype distribution support the hypothesis that the mitochondrial lineages typical for this part of the European moose area originate from a late Pleistocene refugium that was located in the Urals. PMID- 25739309 TI - [Adaptive features of the ecology and annual cycle of the willow warbler (Phylloscopus trochilus L.) at the northern boundary of the Siberian part of the range]. AB - The ecology of the willow warbler in the north of Western Siberia is considered, and the adaptations that enable the spread of this species to the Subarctic are analyzed. It is established that one of the key factors that caused the change in the range of this species is the northward distribution of shrubs and, hence, the biomass of insects (available food items of these birds). PMID- 25739310 TI - [The effects of dexamethasone and hypoxia on the content of active caspase-3 in the cerebellum and the behavior of neonatal rats]. AB - Synthetic glucocorticoid dexamethasone decreased locomotor activity of neonatal rats 120 h after administration. Behavioral changes were associated with an increase in the content of active caspase-3 in the cerebellum. We found that expression of this apoptotic protease was similar to the control value when dexamethasone action was combined to hypoxic treatment to rats; however, the locomotor activity decreased to the hormone action did not recovered. We found that proapoptotic action of dexamethasone was blocked by hypoxic treatment; however, it was not sufficient for prevention of the effect of hormone on behavior. PMID- 25739311 TI - [Determinacy and synchronicity of fallow succession in the Tuva steppes]. AB - Succession on five fallows of Tuva has been studied. It has been shown that the fallow succession proceeds regularly and synchronously. Under the arid conditions of Tuva, weeds are developed at the initial stage of the succession (0-4 years). The first intermediate stage (4-7 years) on all fallows is characterized by the absolute predominance of weeds and the appearance of dominants typical for specific steppes. At the second intermediate stage (7-11 years), the species of aboriginal steppes dominate on all fallows. At the late stage (11-17 years), terminal communities with the combinations of species typical for each steppe, including predominant species, are developed. PMID- 25739312 TI - [Analysis of the sequences of internal transcribed spacers ITS1, ITS2 and the 5.8S ribosomal gene of species of the Amaranthus genus]. AB - Analysis of the sequence ITS1-5.8S-ITS2 in 11 samples of the amaranth species (Amaranthus caudatus, A. cruentus, A. hybridus, A. tricolor, A. paniculatus, A. hypohondriacus) was performed. It has been shown that the variability of the sequences of the intergenic spacers ITS1, ITS2 and 5.8S rRNA gene of the amaranth species analyzed is extremely low. A possible secondary structure of the 5.8S rRNA molecule was determined for the first time; three conservative motifs were identified. A single nucleotide substitution found in A. hybridus did not change the loop topology. In the sample of Celosia cristata taken as an external group, a four-nucleotide insertion in the 5'-end of the gene and a one-nucleotide deletion in the fourth hairpin not affecting the general topology of the 5.8S rRNA molecule were found. PMID- 25739313 TI - [Experimental hybridization of voies of the genus Microtus s.l. M. socialis with species of the group arvalis (Mammalia, Rodentia)]. AB - The results of interspecific crosses of the social vole Microtus socialis with the Altai vole M. obscurus, the East European vole M. rossiaemeridionalis, and the Transcaspian vole M. transcaspicus are presented. The role of the sperm head structure in the reproductive isolation of this species was studied. Hybrids were obtained in five of the six crossing combinations. It is established that significant differences in the sperm head shape in the social vole and in arvalis group species do not prevent fertilization. The sterility of hybrids indicates the existence of postcopulative mechanisms of reproductive isolation. PMID- 25739314 TI - The role for microRNAs in drug toxicity and in safety assessment. AB - INTRODUCTION: Adverse drug reactions present significant challenges that impact pharmaceutical development and are major burdens to public health services worldwide. In response to this need, the field of toxicology is rapidly expanding to identify key pathways involved in drug toxicity. AREAS COVERED: MicroRNAs (miRNAs) are a class of small evolutionary conserved endogenous non-coding RNAs that regulate the translation of protein-coding genes. A wide range of toxicants alter miRNA levels in target organs and these altered miRNAs can also be detected in easily accessible biological fluids. This, combined with an early miRNA response to toxic insults and miRNA stability, substantiates the potential for these small molecules to be useful biomarkers for drug safety assessment. EXPERT OPINION: miRNAs are early indicators and useful tools to detect drug-induced toxicity. Incorporation of miRNA profiling into the drug safety testing process will complement currently used techniques and may substantially enhance drug safety. With the increasing interests in translational research, the field of miRNA biomarker research will continue to expand and become an important part of the investigation of human drug toxicity. PMID- 25739315 TI - The financial crisis and the expected effects on vaccinations in Europe: a literature review. AB - Starting in 2008 several European countries experienced a financial crisis. Historically, diseases whose prevention and treatment depend highly on the continuity of healthcare re-emerge during political and financial crises. Evidence suggests that the current financial crisis has had an impact on the health and welfare of Europeans and that population health status and morbidity as well as mortality patterns may change in the coming years. At the same time decisions about expenditure for health services may impact the ability of public health providers to respond. It is expected that the current crisis will further exacerbate socioeconomic and health inequalities and novel vulnerable groups will emerge in addition to existing ones. We review the available evidence and discuss how the current crisis may have an impact on vaccine-preventable diseases and influence vaccination coverage rates in Europe. PMID- 25739316 TI - Production of transgenic cloned pigs expressing the far-red fluorescent protein monomeric Plum. AB - Monomeric Plum (Plum), a far-red fluorescent protein with photostability and photopermeability, is potentially suitable for in vivo imaging and detection of fluorescence in body tissues. The aim of this study was to generate transgenic cloned pigs exhibiting systemic expression of Plum using somatic cell nuclear transfer (SCNT) technology. Nuclear donor cells for SCNT were obtained by introducing a Plum-expression vector driven by a combination of the cytomegalovirus early enhancer and chicken beta-actin promoter into porcine fetal fibroblasts (PFFs). The cleavage and blastocyst formation rates of reconstructed SCNT embryos were 81.0% (34/42) and 78.6% (33/42), respectively. At 36-37 days of gestation, three fetuses systemically expressing Plum were obtained from one recipient to which 103 SCNT embryos were transferred (3/103, 2.9%). For generation of offspring expressing Plum, rejuvenated PFFs were established from one cloned fetus and used as nuclear donor cells. Four cloned offspring and one stillborn cloned offspring were produced from one recipient to which 117 SCNT embryos were transferred (5/117, 4.3%). All offspring exhibited high levels of Plum fluorescence in blood cells, such as lymphocytes, monocytes and granulocytes. In addition, the skin, heart, kidney, pancreas, liver and spleen also exhibited Plum expression. These observations demonstrated that transfer of the Plum gene did not interfere with the development of porcine SCNT embryos and resulted in the successful generation of transgenic cloned pigs that systemically expressed Plum. This is the first report of the generation and characterization of transgenic cloned pigs expressing the far-red fluorescent protein Plum. PMID- 25739317 TI - The UK HeartSpare Study (Stage IB): randomised comparison of a voluntary breath hold technique and prone radiotherapy after breast conserving surgery. AB - PURPOSE: To compare mean heart and left anterior descending coronary artery (LAD) doses (NTDmean) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold (VBH) and free-breathing prone techniques. MATERIALS AND METHODS: Following surgery for early breast cancer, patients with estimated breast volumes >750 cm(3) underwent planning-CT scans in supine VBH and free-breathing prone positions. Radiotherapy treatment plans were prepared, and mean heart and LAD doses were calculated. Patients were randomised to receive one technique for fractions 1-7, before switching techniques for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging and alternate-day cone-beam CT (CBCT) imaging were performed. The primary endpoint was the difference in mean LAD NTDmean between techniques. Population systematic (Sigma) and random errors (sigma) were estimated. Within-patient comparisons between techniques used Wilcoxon signed-rank tests. RESULTS: 34 patients were recruited, with complete dosimetric data available for 28. Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 (p<0.001) and 2.9 and 7.8 (p<0.001). Clip-based CBCT errors for VBH and prone respectively were ?3.0 mm and ?6.5 mm (Sigma) and ?3.5 mm and ?5.4 mm (sigma). CONCLUSIONS: In larger-breasted women, supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position. PMID- 25739318 TI - The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer. AB - Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E-cadherin and decreased levels of mesenchymal markers such as N-cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target. PMID- 25739319 TI - A comparative study of the local cytokine response in the lungs of pigs experimentally infected with different PRRSV-1 strains: upregulation of IL-1alpha in highly pathogenic strain induced lesions. AB - Porcine reproductive and respiratory syndrome viruses (PRRSV) show high genetic differences both among and within genotypes. Recently, several highly pathogenic PRRSV (HP-PRRSV) strains have been described. This study compares and characterizes the production of cytokines by pulmonary macrophages in pigs experimentally infected with four different PRRSV-1 strains: two low-virulent strains, Lelystad (LV) and a British field strain (215-06); a HP strain (SU1-bel) from Belarus and the attenuated vaccine strain DV (Porcilis((r)) PRRS). Animals were clinically monitored and post-mortem examinations were performed at 3, 7 and 35 days post-infection (dpi). Lung samples were processed for histopathological and immunohistochemical studies by using specific antibodies against PRRSV, IL1 alpha, IL-6, TNF-alpha, IL-10 and IFN-gamma. SU1-bel infected animals presented the highest mean scores for clinical observations, gross and microscopic lesions as well as for PRRSV expression compared with the other infected groups (p<=0.027). These animals displayed the highest expression of IL1-alpha at 7dpi, together with the highest score for lung pathology, whereas LV, 215-06 and DV inoculated animals only showed a transient enhancement in some of these cytokines. SU1-bel-infected pigs showed a positive correlation between the amount of PRRSV antigen and IL-1alpha expression (r=0.645, p<0.001). The highest expression of IL-10 was detected in 215-06-infected animals (p<=0.004), with a positive correlation with the numbers of virus-infected cells (r=0.375, p<=0.013). In conclusion, the HP-PRRSV SU1-bel strain replicated more efficiently in the lung of infected animals and induced a higher expression of IL-1alpha than the other PRRSV-1-infected groups, which may have played a key role in the onset of the clinical signs and interstitial pneumonia. PMID- 25739320 TI - Impact of total solid content and extraction pH on enzyme-aided recovery of protein from defatted rapeseed (Brassica rapa L.) press cake and physicochemical properties of the protein fractions. AB - Pectinase treatment was used to facilitate protein recovery from defatted rapeseed (Brassica rapa) cold-pressing residue in water-lean conditions and without pH adjustment. Effect of extraction pH on protein yield and physiochemical properties of the protein concentrates was assessed. Enzymatic hydrolysis of carbohydrates was feasible at high (40%) solid content and improved protein recovery at pH 6. Comparable protein yields (40-41% of total protein) from enzyme-aided water extraction (pH 6) and nonenzymatic alkaline extraction (pH10) at 10% solid content suggested that after enzymatic treatment, rapeseed protein could be extracted without exposure to alkali. However, water extraction required dilute conditions, whereas alkaline extraction was feasible also at 20% solid content. The water extracts possessed better protein solubility, higher zeta-potential, and smaller particle size than isoelectric precipitates from alkaline extraction, indicating higher dispersion stability. This is suggested to be mediated by electrostatic interactions between proteins and pectic carbohydrates in the water extracts. PMID- 25739321 TI - A review of color blindness for microscopists: guidelines and tools for accommodating and coping with color vision deficiency. AB - "Color blindness" is a variable trait, including individuals with just slight color vision deficiency to those rare individuals with a complete lack of color perception. Approximately 75% of those with color impairment are green diminished; most of those remaining are red diminished. Red-Green color impairment is sex linked with the vast majority being male. The deficiency results in reds and greens being perceived as shades of yellow; therefore red green images presented to the public will not illustrate regions of distinction to these individuals. Tools are available to authors wishing to accommodate those with color vision deficiency; most notable are components in FIJI (an extension of ImageJ) and Adobe Photoshop. Using these tools, hues of magenta may be substituted for red in red-green images resulting in striking definition for both the color sighted and color impaired. Web-based tools may be used (importantly) by color challenged individuals to convert red-green images archived in web accessible journal articles into two-color images, which they may then discern. PMID- 25739323 TI - Influence of NRGN rs12807809 polymorphism on symptom severity in individuals with schizophrenia in the Han population but not the Zhuang population of south China. AB - BACKGROUND: NRGN is one of the most promising candidate genes for schizophrenia based on function and position. Therefore, this study aimed to examine the genetic association of this polymorphism with schizophrenia in the Zhuang and Han populations of south China. Subjects and methods A total of 282 patients (188 Han and 94 Zhuang) and 282 healthy subjects (188 Han and 94 Zhuang) were recruited. Of these, 246 schizophrenia patients underwent an assessment of psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS). A TaqMan genotyping assay method was used to determine the genotypes. RESULTS: We did not find a significant association of rs12807809 polymorphism with schizophrenia in the total pooled samples, or in the separate ethnic groups. However, in Han schizophrenia patients, quantitative data analyses showed that the CC genotype of the rs12807809 polymorphism was associated with PANSS aggression subscale score and activation subscale score. Furthermore, carriers of the C allele of rs12807809 polymorphism among Han schizophrenia patients had higher scores of general, activation, depression, aggression, and global symptoms than the T allele carriers. CONCLUSION: In conclusion rs12807809 polymorphism may not contribute to the risk of schizophrenia but influence the clinical symptoms of schizophrenia in the Han population. PMID- 25739322 TI - Emergency physicians' views of direct notification of laboratory and radiology results to patients using the Internet: a multisite survey. AB - BACKGROUND: Patients are increasingly using the Internet to communicate with health care providers and access general and personal health information. Missed test results have been identified as a critical safety issue with studies showing up to 75% of tests for emergency department (ED) patients not being followed-up. One strategy that could reduce the likelihood of important results being missed is for ED patients to have direct access to their test results. This could be achieved electronically using a patient portal tied to the hospital's electronic medical record or accessed from the relevant laboratory information system. Patients have expressed interest in accessing test results directly, but there have been no reported studies on emergency physicians' opinions. OBJECTIVE: The aim was to explore emergency physicians' current practices of test result notification and attitudes to direct patient notification of clinically significant abnormal and normal test results. METHODS: A cross-sectional survey was self-administered by senior emergency physicians (site A: n=50; site B: n=39) at 2 large public metropolitan teaching hospitals in Australia. Outcome measures included current practices for notification of results (timing, methods, and responsibilities) and concerns with direct notification. RESULTS: The response rate was 69% (61/89). More than half of the emergency physicians (54%, 33/61) were uncomfortable with patients receiving direct notification of abnormal test results. A similar proportion (57%, 35/61) was comfortable with direct notification of normal test results. Physicians were more likely to agree with direct notification of normal test results if they believed it would reduce their workload (OR 5.72, 95% CI 1.14-39.76). Main concerns were that patients could be anxious (85%, 52/61), confused (92%, 56/61), and lacking in the necessary expertise to interpret their results (90%, 55/61). CONCLUSIONS: Although patients' direct access to test results could serve as a safety net reducing the likelihood of abnormal results being missed, emergency physicians' concerns need further exploration: which results are suitable and the timing and method of direct release to patients. Methods of access, including secure Web-based patient portals with drill-down facilities providing test descriptions and result interpretations, or laboratories sending results directly to patients, need evaluation to ensure patient safety is not compromised and the processes fit with ED clinician and laboratory work practices and patient needs. PMID- 25739325 TI - Anti-inflammatory potential of carotenoid meso-zeaxanthin and its mode of action. AB - CONTEXT: meso-Zeaxanthin (MZ) is a xanthophyll carotenoid with profound antioxidant activity. OBJECTIVE: Oxidative stress plays a decisive role in numerous degenerative diseases including cancer. The present study evaluates anti inflammatory effect of MZ. MATERIALS AND METHODS: Balb/c mice were treated with different doses of MZ (50 and 250 mg/kg b.wt, orally) 5 d before subcutaneous injection of carrageenan (1%), dextran (1%), and formalin (2%). Paw edema formation in MZ-treated and -untreated animals was measured using vernier calipers. Anti-inflammatory activity of MZ against lipopolysaccharide (LPS) induced inflammatory model was studied by culturing macrophages in the presence and absence of LPS (5 MUg/ml) and different concentrations of MZ (5, 10, and 25 MUg/ml). After 24 h, the effect of MZ on pro-inflammatory cytokine levels in macrophages was analyzed by ELISA and its effect on various inflammatory genes was studied by RT-PCR. RESULTS: MZ administration at different doses significantly (p < 0.001) inhibited paw edema induced by carrageenan, dextran, and formalin in mice. MZ also exhibited profound anti-inflammatory effect against LPS-induced inflammation in macrophages. Increased production of nitric oxide, C reactive proteins, and various pro-inflammatory cytokines (TNF-alpha, interleukin 1beta, and interleukin-6) in LPS-stimulated macrophages was significantly reduced by MZ treatment. Moreover, LPS-stimulated up-regulated mRNA expression of various inflammatory mediator genes like COX-2, TNF-alpha, and iNOS was down-regulated by MZ administration. DISCUSSION AND CONCLUSION: MZ has potent anti-inflammatory effect which can be due to its down-regulated expression of various inflammatory mediator genes. Since cancer is considered as an inflammatory disease, the present study points towards the importance of MZ in chemo-preventive strategy. PMID- 25739324 TI - Switching from visibility to invisibility via Fano resonances: theory and experiment. AB - Subwavelength structures demonstrate many unusual optical properties which can be employed for engineering of a new generation of functional metadevices, as well as controlled scattering of light and invisibility cloaking. Here we demonstrate that the suppression of light scattering for any direction of observation can be achieved for a uniform dielectric object with high refractive index, in a sharp contrast to the cloaking with multilayered plasmonic structures suggested previously. Our finding is based on the novel physics of cascades of Fano resonances observed in the Mie scattering from a homogeneous dielectric rod. We observe this effect experimentally at microwaves by employing high temperature dependent dielectric permittivity of a glass cylinder with heated water. Our results open a new avenue in analyzing the optical response of high-index dielectric nanoparticles and the physics of cloaking. PMID- 25739326 TI - Practices and challenges in community aphasia groups in Australia: Results of a national survey. AB - PURPOSE: This study reports on practices and challenges in developing community aphasia groups in Australia. METHOD: A 24-item web-based survey addressed the structure of existing community aphasia groups, funding models, group activities, facilitator satisfaction, challenges to group development and maintenance and suggestions for improvement. A total of 156 surveys were completed, mostly by speech-language pathologists (SLPs), with 66% urban and 34% regional/rural/remote participants representing all Australian states/territories consistent with their populations. RESULT: Seventy respondents indicated running a total of 86 groups, reflecting a substantial under-representation of service in proportion to the population of people with aphasia. Further, 23.6% of respondents reported dissatisfaction with aspects of their groups. The primary barriers to achieving satisfaction relate to limited resources and staffing, inability to run sufficient numbers of groups and to tailor them effectively, dispersed populations beyond major cities, group dynamics and a lack of group promotion and referral to groups. Respondents suggested means for improvement including changes to group structure, improved SLP training, dedicated funding and staffing, development of specific resources and better liaison and promotion. CONCLUSION: The major features differentiating the community aphasia groups run in Australia from those running overseas are discussed and practical ways to achieve service improvement are suggested. PMID- 25739327 TI - [Fertility preservation in breast cancer patients: the state of art in 2014?]. AB - Fertility preservation has become the second major objective in association with the remission, in young patients suffering from breast cancer. Patients should be referred for oncofertility counseling, as soon as possible after the diagnosis. A multidisciplinary approach, involving oncologists, reproductive endocrinologists and embryologists will allow an optimal strategy according to patients' age, the ovarian reserve and the cancer treatments. The field of fertility preservation is improving and offers more and more flexible techniques. Oocyte vitrification is no more considered experimental. Ovarian stimulation combining exogenous FSH and aromatase inhibitors may be the optimal strategy of fertility preservation, while maintaining physiologic serum estradiol levels. In vitro maturation of oocyte may offer an interesting option, possibly in combination with ovarian tissue cryopreservation, in case of neo-adjuvant chemotherapy. All these techniques should not be considered only as a frozen hope but should be part of the treatment of young patients. PMID- 25739328 TI - Hypoxia-Inducible Factor-1alpha and CD271 inversely correlate with melanoma invasiveness. AB - Melanoma is characterized, among other features, by microenvironmental factors and by an altered apoptotic machinery. Melanoma cell response to a hypoxic environment is transcriptionally regulated by the Hypoxia-Inducible Factor (HIF) 1alpha. p75 neurotrophin receptor (p75(NTR) ), also called CD271, mediates apoptosis in several cell systems. The purpose of this study was to analyze the expression of HIF-1alpha and CD271 in melanomas at different phases of progression, as evaluated by histology and reflectance confocal microscopy (RCM). By RCM, 41.67% tumors were characterized by the presence of a population of dendritic and pleomorphic cells (D+P), corresponding to in situ melanoma; 25% exhibited a predominantly round-cell (RN) proliferation with histologic features of superficial melanoma, and 33.33% showed the presence of cells aggregated in nests (DN), typical of invasive melanoma. HIF-1alpha was scarcely detected in D+P and in RN melanomas, while it was highly expressed in DN tumors. By contrast, CD271 positive cells were mostly detected in D+P population, and barely observed in the other subtypes. This work demonstrates that CD271 expression inversely correlates with hypoxia in melanoma, and that the two markers may be used in the future as diagnostic/prognostic tools for this neoplasm. PMID- 25739329 TI - Predicting mortality in older adults with kidney disease: a pragmatic prediction model. AB - OBJECTIVES: To develop mortality risk prediction models for older adults with chronic kidney disease (CKD) that include comorbidities and measures of health status and use not associated with particular comorbid conditions (nondisease specific measures). DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Northwest (KPNW) Health Maintenance Organization. PARTICIPANTS: Individuals with severe CKD (estimated glomerular filtration rate<30 mL/min per 1.73 m2; N=4,054; n=1,915 aged 65-79, n=2,139 aged >=80) who received care at KPNW between 2000 and 2008. MEASUREMENTS: Cox proportional hazards analysis was used to examine the association between selected participant characteristics and all-cause mortality and to generate age group-specific risk prediction models. Predicted and observed risks were evaluated according to quintile. Predictors from the Cox models were translated into a points-based system. Internal validation was used to provide best estimates of how these models might perform in an external population. RESULTS: The risk prediction models used 16 characteristics to identify participants with the highest risk of mortality at 2 years for adults aged 65 to 79 and 80 and older. Predicted and observed risks agreed within 5% for each quintile; a 4 to 5 times difference in 2-year predicted mortality risk was observed between the highest and lowest quintiles. The c statistics for each model (0.68-0.69) indicated effective discrimination without evidence of significant overfit (slope shrinkage 0.06-0.09). Models for each age group performed similarly for mortality prediction at 6 months and 2 years in terms of discrimination and calibration. CONCLUSION: When validated, these risk prediction models may be helpful in supporting discussions about prognosis and treatment decisions sensitive to prognosis in older adults with CKD in real-world clinical settings. PMID- 25739331 TI - Dual soft-template system based on colloidal chemistry for the synthesis of hollow mesoporous silica nanoparticles. AB - A new dual soft-template system comprising the asymmetric triblock copolymer poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-b-P2VP-b-PEO) and the cationic surfactant cetyltrimethylammonium bromide (CTAB) is used to synthesize hollow mesoporous silica (HMS) nanoparticles with a center void of around 17 nm. The stable PS-b-P2VP-b-PEO polymeric micelle serves as a template to form the hollow interior, while the CTAB surfactant serves as a template to form mesopores in the shells. The P2VP blocks on the polymeric micelles can interact with positively charged CTA(+) ions via negatively charged hydrolyzed silica species. Thus, dual soft-templates clearly have different roles for the preparation of the HMS nanoparticles. Interestingly, the thicknesses of the mesoporous shell are tunable by varying the amounts of TEOS and CTAB. This study provides new insight on the preparation of mesoporous materials based on colloidal chemistry. PMID- 25739330 TI - Loss-of-function mutation of rice SLAC7 decreases chloroplast stability and induces a photoprotection mechanism in rice. AB - Plants absorb sunlight to power the photochemical reactions of photosynthesis, which can potentially damage the photosynthetic machinery. However, the mechanism that protects chloroplasts from the damage remains unclear. In this work, we demonstrated that rice (Oryza sativa L.) SLAC7 is a generally expressed membrane protein. Loss-of-function of SLAC7 caused continuous damage to the chloroplasts of mutant leaves under normal light conditions. Ion leakage indicators related to leaf damage such as H2 O2 and abscisic acid levels were significantly higher in slac7-1 than in the wild type. Consistently, the photosynthesis efficiency and Fv/Fm ratio of slac7-1 were significantly decreased (similar to photoinhibition). In response to chloroplast damage, slac7-1 altered its leaf morphology (curled or fused leaf) by the synergy between plant hormones and transcriptional factors to decrease the absorption of light, suggesting that a photoprotection mechanism for chloroplast damage was activated in slac7-1. When grown in dark conditions, slac7 1 displayed a normal phenotype. SLAC7 under the control of the AtSLAC1 promoter could partially complement the phenotypes of Arabidopsis slac1 mutants, indicating a partial conservation of SLAC protein functions. These results suggest that SLAC7 is essential for maintaining the chloroplast stability in rice. PMID- 25739332 TI - Effect of acute high-intensity resistance exercise on optic nerve sheath diameter and ophthalmic artery blood flow pulsatility. AB - Exertional hypertension associated with acute high-intensity resistance exercise (RE) increases both intravascular and intracranial pressure (ICP), maintaining cerebrovascular transmural pressure. Carotid intravascular pressure pulsatility remains elevated after RE. Whether ICP also remains elevated after acute RE in an attempt to maintain the vessel wall transmural pressure is unknown. Optic nerve sheath diameter (ONSD), a valid proxy of ICP, was measured in 20 participants (6 female; 24 +/- 4 yr, 24.2 +/- 3.9 kg m(-)(2)) at rest (baseline), following a time-control condition, and following RE (5 sets, 5 repetition maximum bench press, 5 sets 10 repetition maximum biceps curls) using ultrasound. Additionally, intracranial hemodynamic pulsatility index (PI) was assessed in the ophthalmic artery (OA) by using Doppler. Aortic pulse wave velocity (PWV) was obtained from synthesized aortic pressure waveforms obtained via a brachial oscillometric cuff and carotid pulse pressure was measured by using applanation tonometry. Aortic PWV (5.2 +/- 0.5-6.0 +/- 0.7 m s(-1), P < 0.05) and carotid pulse pressure (45 +/ 17-59 +/- 19 mm Hg, P < 0.05) were significantly elevated post RE compared with baseline. There were no significant changes in ONSD (5.09 +/- 0.7-5.09 +/- 0.7 mm, P > 0.05) or OA flow PI (1.35 +/- 0.2-1.38 +/- 0.3, P > 0.05) following acute RE. In conclusion, during recovery from acute high-intensity RE, there are increases in aortic stiffness and extracranial pressure pulsatility in the absence of changes in ICP and flow pulsatility. These findings may have implications for alterations in cerebral transmural pressure and cerebral aneurysmal wall stress following RE. PMID- 25739333 TI - Improving the detection of preclinical organ damage in newly diagnosed hypertension: nocturnal hypertension versus non-dipping pattern. AB - The clinical relevance of nocturnal hypertension (NH) in comparison with non dipping status has not been clarified yet, as regards subclinical target organ damage. We aimed to elucidate whether NH or dipping status reflects better organ damage. The study population included 319 newly diagnosed hypertensive patients. Subclinical organ damage was evaluated to all participants. On the basis of nocturnal blood pressure (BP) levels the population was divided into two groups: NH and nocturnal normotension. Also, individuals were defined as dippers and non dippers according to systolic BP fall. Patients with NH were characterized by increased arterial pulse wave velocity (PWV; 9.1+/-1.7 vs 8.4+/-1.5 m s(-1), P=0.0001) and carotid intima-media thickness (0.77+/-0.18 vs 0.69+/-0.15 mm, P=0.016) compared with normotensive subjects. Notably, they also exhibited higher values of left ventricular mass index (88.1+/-22.9 vs 82.8+/-16.6 g m(-)(2) P=0.043). On the contrary, non-dipping status was associated only with differences in PWV (9.26+/-0.2 vs 8.64+/-0.2 m s(-1), P=0.031, 8) and in creatinine clearance (95+/-3 vs 106+/-4, P=0.025) in the group of NH. The presence of NH is accompanied by subclinical atherosclerosis, as well as structural abnormalities of the left ventricle. Therefore, NH rather than non dipping status could be preferably integrated with the risk of organ damage. PMID- 25739335 TI - Why are there so few freshwater fish species in most estuaries? AB - The freshwater fish assemblage in most estuaries is not as species rich as the marine assemblage in the same systems. Coupled with this differential richness is an apparent inability by most freshwater fish species to penetrate estuarine zones that are mesohaline (salinity: 5.0-17.9), polyhaline (salinity: 18.0-29.9) or euhaline (salinity: 30.0-39.9). The reason why mesohaline waters are avoided by most freshwater fishes is difficult to explain from a physiological perspective as many of these species would be isosmotic within this salinity range. Perhaps, a key to the poor penetration of estuarine waters by freshwater taxa is an inability to develop chloride cells in gill filament epithelia, as well as a lack of other osmoregulatory adaptations present in euryhaline fishes. Only a few freshwater fish species, especially some of those belonging to the family Cichlidae, have become fully euryhaline and have successfully occupied a wide range of estuaries, sometimes even dominating in hyperhaline systems (salinity 40+). Indeed, this review found that there are few fish species that can be termed holohaline (i.e. capable of occupying waters with a salinity range of 0-100+) and, of these taxa, there is a disproportionally high number of freshwater species (e.g. Cyprinodon variegatus, Oreochromis mossambicus and Sarotherodon melanotheron). Factors such as increased competition for food and higher predation rates by piscivorous fishes and birds may also play an important role in the low species richness and abundance of freshwater taxa in estuaries. Added to this is the relatively low species richness of freshwater fishes in river catchments when compared with the normally higher diversity of marine fish species for potential estuarine colonization from the adjacent coastal waters. The almost complete absence of freshwater fish larvae from the estuarine ichthyoplankton further reinforces the poor representation of this guild within these systems. An explanation as to why more freshwater fish species have not become euryhaline and occupied a wide range of estuaries similar to their marine counterparts is probably due to a combination of the above described factors, with physiological restrictions pertaining to limited salinity tolerances probably playing the most important role. PMID- 25739334 TI - Excess of rare variants in genes that are key epigenetic regulators of spermatogenesis in the patients with non-obstructive azoospermia. AB - Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. To explore the genetic basis of this condition, we successfully sequenced ~650 infertility related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole. We found a significant excess of rare, non-silent variants in genes that are key epigenetic regulators of spermatogenesis, such as BRWD1, DNMT1, DNMT3B, RNF17, UBR2, USP1 and USP26, in NOA patients (P = 5.5 * 10( 7)), corresponding to a carrier frequency of 22.5% of patients and 13.7% of controls (P = 1.4 * 10(-5)). An accumulation of low-frequency variants was also identified in additional epigenetic genes (BRDT and MTHFR). Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human. PMID- 25739336 TI - Risk of bile duct cancer among printing workers exposed to 1,2-dichloropropane and/or dichloromethane. AB - OBJECTIVES: We conducted a retrospective cohort study to examine the risk of bile duct cancer among current and former workers in the offset color proof printing department at a printing company in Osaka, Japan. METHODS: Standardized incidence ratios (SIRs) between January 1, 1985, and December 31, 2012, were estimated for the cumulative years of exposure to two chemicals, dichloromethane (DCM) and 1,2 dichloropropane (1,2-DCP), using the national incidence level as a reference. In addition, we examined risk patterns by the calendar year in which observation started. RESULTS: Among 106 workers with a total of 1,452.4 person-years of exposure, 17 bile duct cancer cases were observed, resulting in an estimated overall SIR of 1,132.5 (95% confidence interval (CI): 659.7-1,813.2). The SIR was 1,319.9 (95% CI: 658.9-2,361.7) for those who were exposed to both DCM and 1,2 DCP, and it was 1,002.8 (95% CI: 368.0-2,182.8) for those exposed to 1,2-DCP only. SIRs tended to increase according to years of exposure to 1,2-DCP but not DCM when a 5-year lag time was assumed. The SIRs were higher for the cohorts in which observation started in 1993-2000, particularly in cohorts in which it started in 1996-1999, compared with those in which it started before or after 1993-2000. CONCLUSIONS: We observed an extraordinarily high risk of bile duct cancer among the offset color proof printing workers. Elevated risk may be related to cumulative exposure to 1,2-DCP, but there remains some possibility that a portion of the risk is due to other unidentified substances. PMID- 25739337 TI - Sense of coherence modifies the effect of overtime work on mental health. AB - OBJECTIVES: In the occupational health field, it is important to know how workload influences mental health. Overtime work and job strain appear to affect the mental health status of workers. Sense of coherence (SOC) may mediate the relationship between work stress and mental health. Since SOC represents a personal ability to manage psychological stressors, we hypothesized that a strong SOC would modify the adverse effect of an objective measure of overtime work on mental health. METHODS: A total of 1,558 Japanese workers employed in an information technology company were asked to complete a 3-item SOC Questionnaire and 28-item General Health Questionnaire (GHQ) to assess mental health status. Workload was assessed by the actual amount of overtime work hours recorded by the company. RESULTS: Multiple regression analysis revealed a main effect of overtime work (beta=0.08, p=0.0003) and SOC scores (beta=0.41, p <0.0001) on GHQ scores. There was a tendency toward interaction between overtime work and SOC scores (beta=0.05, p=0.051). Simple slope analysis supported this association (-1 SD below the mean, simple slope=0.04, SE=0.01, p < 0.0001; +1 SD above the mean, simple slope=0.01, SE=0.01, p=0.188). CONCLUSIONS: These results suggest that SOC buffers the mental health impacts of workload as measured by an objective index of overtime work, and should be considered when assessing the effects of workload on mental health. PMID- 25739338 TI - Myo-inositol: with or without. PMID- 25739339 TI - Novel scoring system using cardiopulmonary exercise testing predicts prognosis in heart failure patients receiving guideline-directed medical therapy. AB - BACKGROUND: Among variables obtained from cardiopulmonary exercise testing (CPXT), peak oxygen consumption (PVO2) and the minute ventilation vs. carbon dioxide output (VE vs. VCO2) slope were established as predictors of death of patients with heart failure (HF) at the cutoff points of 14 ml.min(-1).kg(-1)and 34, respectively. However, a recent update of guideline-directed medical treatment (GDMT) might alter the implication of these variables. METHODS AND RESULTS: We enrolled 77 HF patients receiving GDMT who had undergone symptom limited CPXT between 2006 and 2014. Among them, 29 patients were re-hospitalized for HF and there were 13 cardiac deaths during the 4-year study period. Cox regression analyses demonstrated that the VE vs. VCO2slope, peak heart rate, peak systolic blood pressure, and PVO2were significant predictors of both re-admission and cardiac death at each cutoff point calculated by receiver-operating characteristic analyses. A new scoring system was constructed using the following criteria: 1 point was assigned to a variable meeting the cutoff point for re admission; 2 points were assigned to that for cardiac death. The total scores calculated as the summation of each point (range, 0-8 points) had significantly highest area under the curves compared with each CPXT variable (P<0.05), and significantly stratified both event-free rate into 3 groups (P<0.05). CONCLUSIONS: A novel scoring system using 4 CPXT variables simultaneously predicted re-admission and cardiac death even in patients with HF receiving GDMT. PMID- 25739340 TI - Clinical and electrophysiological characteristics of typical atrioventricular nodal reentrant tachycardia in the elderly - changing of slow pathway location with aging. AB - BACKGROUND: The aim of this study was to retrospectively evaluate the clinical and electrophysiological characteristics of elderly patients with typical atrioventricular nodal reentrant tachycardia (AVNRT), and to assess the acute safety and efficacy of slow-pathway radiofrequency (RF) ablation in this specific group of patients. METHODS AND RESULTS: The present study retrospectively included a total of 1,290 patients receiving successful slow-pathway RF ablation for typical slow-fast AVNRT. Patients were divided into 2 groups: group I included 1,148 patients aged <65 years and group II included 142 patients aged >65 years. The required total procedure duration and total fluoroscopy exposure time were significantly higher in group II vs. group I (P=0.005 and P=0.0001, respectively). The number of RF pulses needed for a successful procedural end point was significantly higher in group II than in group I (4.4 vs. 7.2, P=0.005). While the ratio of the anterior location near to the His-bundle region was significantly higher in group II, the ratio of posterior and midseptal locations were significantly higher in group I (P=0.0001). The overall procedure success rates were similar. There was no significant difference between the 2 groups in respect of the complications rates. CONCLUSIONS: This experience demonstrates that RF catheter ablation, targeting the slow pathway, could be considered as first-line therapy for typical AVNRT patients older than 65 years as well as younger patients, as it is very safe and effective in the acute period of treatment. PMID- 25739341 TI - Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease. AB - BACKGROUND: Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. METHODS: We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. RESULTS: We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein-protein interactions to intracellular myosin 1E. CONCLUSIONS: COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non-COL4 'podocyte gene' mutations in XLAS when clinical nephropathy is more severe than expected for an individual's age and sex. PMID- 25739342 TI - Does Disability Correlate With Impairment After Hand Injury? AB - BACKGROUND: Any loss or deviation in body function and structure is considered impairment, whereas limitations on activities are fundamental to the definition of disability. Although it seems intuitive that the two should be closely related, this might not be the case; there is some evidence that psychosocial factors are more important determinants of disability than are objective impairments. However, the degree to which this is the case has been incompletely explored. QUESTIONS/PURPOSES: The purpose of this study was to determine if disability (as measured by the Disabilities of the Arm, Shoulder and Hand [DASH] and the Michigan Hand Questionnaire [MHQ]) and pain intensity correlate with impairment (as measured by the American Medical Association [AMA] impairment guide). Secondary study questions addressed the effect of pain intensity and symptom of depression on predicting disability. METHODS: Impairment and disability were evaluated in a sample of 107 hand-injured patients a mean of 11 months after injury. Impairment rating was performed prospectively. From the patients who came for therapy, they were invited to fill out the questionnaire and evaluated for impairment rating. Response variables of DASH, MHQ, and visual analog scale pain intensity values were collected at the same setting. Other explanatory variables included demographic, injury-related, and psychological factors (symptoms of depression measured with the Beck Depression Inventory). Initial bivariate and multivariate analyses were performed to determine correlations of disability and pain to impairment rating and other exploratory variables. RESULTS: Disability as measured by the DASH showed intermediate correlation with AMA impairment (r = 0 .38, beta = 0.36, p = 0.000). Together with gender, it accounted for only 22% of the variability in DASH scores. Similarly, MHQ score correlated with impairment rating (r = -0.24, beta = -0.23, p < 0.05). However, together with age, injured hand accounted for only 19% of the variability in MHQ scores. However, pain intensity did not correlate with impairment (r = -0.46, p > 0.05). Interestingly, pain intensity did correlate with the time passed from surgery but it was correlated with symptom of depression (r(2) = 0.10, beta = 0.33, p = 0.001). CONCLUSIONS: The limited correlation between impairment and disability emphasizes the importance of factors other than pathophysiology in human illness behavior. These may include physical (pain, dominant injured hand) and conditional factors (time since surgery) or psychological factors such as depression and adapting; all mentioned can be considered as personal factors that may be different in each patient. So considering personal difference and any other condition except the impairment alone can help to better plan interventions and also diminish disability level. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25739343 TI - How Does Bone Strength Compare Across Sex, Site, and Ethnicity? AB - BACKGROUND: The risk of fragility fractures in the United States is approximately 2.5 times greater among black and white women compared with their male counterparts. On average, men of both ethnicities have wider bones of greater cortical mass compared with the narrower bones of lower cortical mass among women. However, it remains uncertain whether the low cortical area observed in the long bones of women is consistent with their narrower bone diameter or if their cortical area is reduced beyond that which is expected for the sex differences in body size and external bone size. QUESTIONS/PURPOSES: We asked (1) do black and white women consistently have narrower bones of less strength across long bones compared with black and white men; and (2) do all long bones of black and white women have reduced cortical area compared with black and white men? METHODS: Peripheral quantitative CT was used to quantify bone strength and cross sectional morphology from the major long bones of 125 white and 115 black adult men and women (20-35 years of age). Regression analyses were used to test for differences in bone strength and cortical area after for adjusting for either body size, bone size, or both. RESULTS: After adjusting bone strength for body size, regression analyses showed that black women had lower bone strength compared with black men (women: mean=298.7-25,522 mg HA mm4, 95% confidence interval [CI], 270-27,692 mg HA mm4; men: mean = 381.6-30,945 mg HA mm4, 95% CI, 358.2-32,853 mg HA mm4; percent difference=12%-38%, p=0.06-0.0001). Similarly, white women also had lower bone strength compared with white men (women: mean=229.5-22,892 mg HA mm4, 95% CI, 209.3-24,539 mg HA mm4; men: mean=314.3 29,986 mg HA mm4, 95% CI, 297.3-31,331 mg HA mm4; percent difference=27%-49%, p=0.0001). All long bones of women for both ethnicities showed lower cortical area compared with men. After accounting for both body size and external bone size, black women (women: mean=43.25-357.70 mm2, 95% CI, 41.45-367.52 mm2; men: mean=48.06-400.10 mm2, 95% CI, 46.67-408.72; percent difference=6%-25%, p=0.02 0.0001) and white women (women: mean=38.53-350.10 mm2, 95% CI, 36.99-359.80 mm2; men: mean=42.06-394.30 mm2, 95% CI, 40.95-402.10 mm2; percent difference=6%-22%, p=0.02-0.0001) were shown to have lower cortical area than their male counterparts. Therefore, the long bones of women are not only more slender than those of men, but also show a reduced cortical area that is 6% to 25% greater than expected for their external size, depending on the bone being considered. CONCLUSIONS: The long bones of females are not just a more slender version of male long bones. Women have less cortical area than expected for their body size and bone size, which in part explains their reduced bone strength when compared with the more robust bones of men. CLINICAL RELEVANCE: The outcome of this assessment may be clinically important for the development of diagnostics and treatment regimens used to combat fractures. Future work should look at how the relationship among parameters reported here translates to the more fracture-prone metaphyseal regions. PMID- 25739344 TI - Relationship between health literacy, health information access, health behavior, and health status in Japanese people. AB - OBJECTIVE: To examine the relationship between health literacy (HL), health information access, health behavior, and health status in Japanese people. METHODS: A questionnaire survey was conducted at six healthcare facilities in Japan. Eligible respondents aged 20-64 years (n=1218) were included. Path analysis with structural equation modeling was performed to test the hypothesis model linking HL to health information access, health behavior, and health status. RESULTS: The acceptable fitting model indicated that the pathways linking HL to health status consisted of two indirect paths; one intermediated by health information access and another intermediated by health behavior. Those with higher HL as measured by the 14-item Health Literacy Scale (HLS-14) were significantly more likely to get sufficient health information from multiple sources, less likely to have risky habits of smoking, regular drinking, and lack of exercise, and in turn, more likely to report good self-rated health. CONCLUSION: HL was significantly associated with health information access and health behavior in Japanese people. HL may play a key role in health promotion, even in highly educated countries like Japan. PRACTICE IMPLICATIONS: In order to enhance the effects of health promotion interventions, health professionals should aim at raising HL levels of their target population groups. PMID- 25739345 TI - A Query Tool for Investigator Access to the Data and Images of the National Lung Screening Trial. AB - The National Cancer Institute (NCI), in conjunction with blinded university, provides a mechanism to enable public access to the study data, CT radiology images, and pathology images from the National Lung Screening Trial (NLST). Access to the data and images is through the NCI-sponsored, blinded university hosted The Cancer Imaging Archive (TCIA), a repository of more than 40 study collections of cancer images. Once access to the NLST data has been granted by NCI, a Query Tool within TCIA is used to access the NLST data and images. The Query Tool is a simple-to-use menu-driven database application designed to quickly pose queries and retrieve/save results (from 53,452 NLST participants), download CT images (~20 million available), and view pathology images (~1200 available). NLST study data are contained in 17 Query Tool tables with ~370 variables to query. This paper describes Query Tool design, functionality, and usefulness for researchers, clinicians, and software developers to query data, save query results, and download/view images. PMID- 25739346 TI - Assessment of DICOM Viewers Capable of Loading Patient-specific 3D Models Obtained by Different Segmentation Platforms in the Operating Room. AB - Patient-specific 3D models obtained by the segmentation of volumetric diagnostic images play an increasingly important role in surgical planning. Surgeons use the virtual models reconstructed through segmentation to plan challenging surgeries. Many solutions exist for the different anatomical districts and surgical interventions. The possibility to bring the 3D virtual reconstructions with native radiological images in the operating room is essential for fostering the use of intraoperative planning. To the best of our knowledge, current DICOM viewers are not able to simultaneously connect to the picture archiving and communication system (PACS) and import 3D models generated by external platforms to allow a straight integration in the operating room. A total of 26 DICOM viewers were evaluated: 22 open source and four commercial. Two DICOM viewers can connect to PACS and import segmentations achieved by other applications: Synapse 3D(r) by Fujifilm and OsiriX by University of Geneva. We developed a software network that converts diffuse visual tool kit (VTK) format 3D model segmentations, obtained by any software platform, to a DICOM format that can be displayed using OsiriX or Synapse 3D. Both OsiriX and Synapse 3D were suitable for our purposes and had comparable performance. Although Synapse 3D loads native images and segmentations faster, the main benefits of OsiriX are its user friendly loading of elaborated images and it being both free of charge and open source. PMID- 25739347 TI - Candidate comprehension of key concepts in kidney transplantation. AB - BACKGROUND: Although kidney transplant candidates receive education regarding transplantation and donation, little is known about the extent of their comprehension. We aimed to identify factors that affect patient comprehension of important concepts regarding kidney transplantation. MATERIAL AND METHODS: We performed a cross-sectional survey of consecutive adult kidney transplant candidates seen at our center between July 2013 and October 2013 for initial evaluation (n=100) or for reevaluation (n=117). The main outcome measure was a Knowledge Assessment Questionnaire completed by patients. We assessed factors affecting patient understanding of key kidney transplant concepts as measured by mean knowledge score. RESULTS: Mean knowledge scores of those at evaluation (72+/ 21) and those at reevaluation (70+/-20; p=0.4769) were similar; therefore the entire cohort was analyzed as a single group. Compared to the high-scoring group, low-scorers (<75%; median value) were significantly more likely to be older, Hispanic, with lower education attainment, and have end-stage renal disease due to hypertension or diabetes rather than other etiologies. On multivariate analysis, independent risk factors for low-scores were increasing age (aOR 1.03 (95% CI 1.01-1.06) and educational level (less than high school; aOR 4.23, 95%CI 1.82-9.80; high school or GED aOR2.85, 95% CI 1.43-5.70 compared to some college or technical school). Of 139 candidates that consented to receive ECD and 152 consenting to CDCHR kidneys, 52% and 27%, respectively, answered the high-risk specific question incorrectly. CONCLUSIONS: Educational level and older age are independent risk factors for poor comprehension. Kidney candidate knowledge of organs with increased risks is suboptimal despite previous consent to receive such organs. PMID- 25739349 TI - Molecular weight characterization of single globular proteins using optical nanotweezers. AB - We trap a set of molecular weight standard globular proteins using a double nanohole optical trap. The root mean squared variation of the trapping laser transmission intensity gives a linear dependence with the molecular weight, showing the potential for analysis of globular proteins. The characteristic time of the autocorrelation of the trapping laser intensity variations scales with a 2/3 power dependence with the volume of the particle. A hydrodynamic laser tweezer model is used to explain these dependencies. Since this is a single particle technique that operates in solution and can be used to isolate an individual particle, we believe that it provides an interesting alternative to existing analysis methods and shows promise to expand the capabilities of protein related studies to the single particle level. PMID- 25739348 TI - Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: A SEER database analysis. AB - BACKGROUND: Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged <= 65 years. A recent report suggested a substantial decline in the early, or 1-month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population. METHODS: The authors examined the 1-month mortality rate in a large population-based series of 9380 patients with AML who were aged <= 65 years and were diagnosed and treated with chemotherapy between 1973 and 2010. RESULTS: A significant decline was observed in the 1-month mortality rate from 18.7% among patients diagnosed from 1973 through 1977 (95% confidence interval [95% CI], 16.4%-21.2%) to 5.8% for those diagnosed between 2008 and 2010 (95% CI, 4.5% 7.6%) (P <.001). The median overall survival improved significantly from 6 months (95% CI, 5 months-7 months) in 1973 to 1977 to 23 months (95% CI, 16 months-20 months) in 2008 to 2010 (P <.001). Although age and geographic variation were found to significantly influence the 1-month mortality for the period between 1973 and 1977, these differences in 1-month mortality were no longer significant among patients with AML who were treated more recently (2008-2010). CONCLUSIONS: Over the past 4 decades, early mortality has become uncommon in younger patients (aged <= 65 years) with newly diagnosed AML undergoing induction chemotherapy. It is encouraging that the improvements noted in 1-month mortality rate among a selective cohort of patients in clinical trials have also been observed in a population-based analysis. PMID- 25739350 TI - Moderate and late preterm infants exhibit widespread brain white matter microstructure alterations at term-equivalent age relative to term-born controls. AB - Despite the many studies documenting cerebral white matter microstructural alterations associated with very preterm birth (<32 weeks' gestation), there is a dearth of similar research in moderate and late preterm infants (born 32-36 weeks' gestation), who experience higher rates of neurodevelopmental delays than infants born at term (>= 37 weeks' gestation). We therefore aimed to determine whether whole brain white matter microstructure differs between moderate and late preterm infants and term-born controls at term-equivalent age, as well as to identify potential perinatal risk factors for white matter microstructural alterations in moderate and late preterm infants. Whole brain white matter microstructure was studied in 193 moderate and late preterm infants and 83 controls at term-equivalent age by performing Tract-Based Spatial Statistics analysis of diffusion tensor imaging data. Moderate and late preterm infants had lower fractional anisotropy and higher mean, axial and radial diffusivities compared with controls in nearly 70% of the brain's major white matter fiber tracts. In the moderate and late preterm group, being born small for gestational age and male sex were associated with lower fractional anisotropy, largely within the optic radiation, corpus callosum and corona radiata. In conclusion, moderate and late preterm infants exhibit widespread brain white matter microstructural alterations compared with controls at term-equivalent age, in patterns consistent with delayed or disrupted white matter microstructural development. These findings may underpin some of the neurodevelopmental delays observed in moderate and late preterm children. PMID- 25739351 TI - Spatial learning associated with stimulus response in goldfish Carassius auratus: relationship to activation of CREB signalling. AB - Earlier, we reported spatial learning ability in goldfish (Carassius auratus) by using spatial paradigm with food reward. Therefore, we hypothesized that goldfish may use associated cue to integrate "where" and "what" for spatial memory. To test our hypothesis, we first trained goldfish to learn to cross the gate1, which is associated with spatial task. Subsequently, they were trained to learn to enter the task chamber and to identify the food reward chamber associated with visual cue (red/green light). Red and green lights were positioned randomly for each trial but always the food reward was kept in green chamber. In addition, to elucidate the role of the signalling cascade in spatial memory associated with visual cue, nicotinamide (NAM, 1000 mg/kg, i.p), a NAD(+) precursor, was used to inhibit the Sirtuin 1 (SIRT1) cyclic AMP response element binding protein (CREB) pathway. Fishes were trained for 5 days in a maze after treating with either vehicle (VEH, DD H2O) or NAM, and then, they were individually tested for memory. We found that VEH-treated fish learned and recalled the task successfully by showing less latency and making more correct choices than NAM-treated group. Subsequent analysis showed that NAM treatment significantly down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK1/2), CREB, expression of SirT1 and brain-derived neurotrophic factor (Bdnf) in telencephalon. Taken together, our results provide behavioural evidence of spatial memory associated with visual cue in C. auratus, which could be regulated by ERK1/2-CREB-SirT1-Bdnf pathway. PMID- 25739355 TI - Understanding and communicating risk. PMID- 25739352 TI - On the lack of polymorphism in Abeta-peptide aggregates derived from patient brains. AB - The amyloid beta (Abeta) oligomers and fibrils that are found in neural tissues of patients suffering from Alzheimer's disease may either cause or contribute to the pathology of the disease. In vitro, these Abeta-aggregates are characterized by structural polymorphism. However, recent solid state NMR data of fibrils acquired post mortem from the brains of two Alzheimer's patients indicate presence of only a single, patient-specific structure. Using enhanced molecular dynamic simulations we investigate the factors that modulate the stability of Abeta-fibrils. We find characteristic differences in molecular flexibility, dynamics of interactions, and structural behavior between the brain-derived Abeta fibril structure and in vitro models. These differences may help to explain the lack of polymorphism in fibrils collected from patient brains, and have to be taken into account when designing aggregation inhibitors and imaging agents for Alzheimer's disease. PMID- 25739356 TI - Extracellular galectin-3 induces MMP9 expression by activating p38 MAPK pathway via lysosome-associated membrane protein-1 (LAMP1). AB - Matrix metalloproteinases (MMPs) play a key role in matrix remodelling and thus invasion and metastasis. Extracellular galectin-3 has been shown to induce MMP9 secretion. Here, we demonstrate that galectin-3 induces MMP9 at transcript level and it is dependent on the surface levels of poly-N-acetyllactosamine (polyLacNAc). By employing signalling pathway inhibitors, MMP9 expression was shown to be induced via p38 MAP-kinase pathway. Using clones of melanoma cells expressing shRNAs to lysosome-associated membrane protein-1 (LAMP1), a major carrier of polyLacNAc, surface LAMP1 was demonstrated to serve as one of the key mediators of galectin-3-induced MMP9 expression via p38 MAPK pathway. PMID- 25739357 TI - High salt diet modulates vascular response in A2AAR (+/+) and A 2AAR (-/-) mice: role of sEH, PPARgamma, and K ATP channels. AB - This study aims to investigate the signaling mechanism involved in HS-induced modulation of adenosine-mediated vascular tone in the presence or absence of adenosine A2A receptor (A2AAR). We hypothesized that HS-induced enhanced vascular relaxation through A2AAR and epoxyeicosatrienoic acid (EETs) is dependent on peroxisome proliferator-activated receptor gamma (PPARgamma) and ATP-sensitive potassium channels (KATP channels) in A2AAR(+/+) mice, while HS-induced vascular contraction to adenosine is dependent on soluble epoxide hydrolase (sEH) that degrades EETs in A2AAR(-/-) mice. Organ bath and Western blot techniques were conducted in HS (4 % NaCl) and normal salt (NS, 0.45 % NaCl)-fed A2AAR(+/+) and A2AAR(-/-) mouse aorta. We found that enhanced vasodilation to A2AAR agonist, CGS 21680, in HS-fed A2AAR(+/+) mice was blocked by PPARgamma antagonist (T0070907) and KATP channel blocker (Glibenclamide). Also, sEH inhibitor (AUDA)-dependent vascular relaxation was mitigated by PPARgamma antagonist. PPARgamma agonist (Rosiglitazone)-induced relaxation in HS-A2AAR(+/+) mice was attenuated by KATP channel blocker. Conversely, HS-induced contraction in A2AAR(-/-) mice was attenuated by sEH inhibitor. Overall, findings from this study that implicates the contribution of EETs, PPARgamma and KATP channels downstream of A2AAR to mediate enhanced vascular relaxation in response to HS diet while, role of sEH in mediating vascular contraction in HS-fed A2AAR(-/-) mice. PMID- 25739358 TI - Functional and structural changes of human erythrocyte catalase induced by cimetidine: proposed model of binding. AB - In erythrocyte, catalase plays an important role to protect cells from hydrogen peroxide toxicity. Hydrogen peroxide is a byproduct compound which is produced during metabolic pathway of cells. Cimetidine, a histamine H2 receptor antagonist, is used for gastrointestinal tract diseases and prevents the extra release of gastric acid. In this study, the effect of cimetidine on the activity of human erythrocyte catalase was investigated. Erythrocytes were broken by hypotonic solution. The supernatant was used for catalase assay and kinetics study. Lineweaver-Burk plot was performed to determine the type of inhibition. The kinetics data revealed that cimetidine inhibited the catalase activity by mixed inhibition. The IC50 (1.54 MUM) and Ki (0.45 MUM) values of cimetidine determined that the drug was bound to the enzyme with high affinity. Circular dichroism and fluorescence measurement showed that the binding of cimetidine to the enzyme affected the content of secondary structure of the enzyme as well as its conformational changes. Docking studies were carried out to detect the site in which the drug was bound to the enzyme. Molecular modeling and energy calculation of the binding showed that the cyanoguanidine group of the drug connected to Asp59 via two hydrogen bonds, while the imidazole group of the drug interacted with Phe64 in the enzyme by a hydrophobic interaction. In conclusion, cimetidine could bind to human erythrocyte catalase, and its interaction caused functional and conformational changes in the enzyme. PMID- 25739359 TI - Conditioned medium from gerbil--mouse T cell heterohybridomas improved antibody secretion. AB - Mongolian gerbils (Meriones unguiculatus) are widely used as animal models for a variety of infectious diseases. However, immunological reagents such as cytokines have not been characterized. Two heterohybridomas, D9(E6)C2B3 and D9(E4), obtained by fusion of gerbil splenocytes with mouse myeloma cells (P3-X63 Ag8.653), expressed gerbil CD3G mRNA. These cells were suggested to be T cell heterohybridomas. They also expressed gerbil IL6 [D9(E6)C2B3] and TGFB [D9(E4) and D9(E6)C2B3] mRNAs. The addition of conditioned medium (CM) obtained from the culture of D9(E6)C2B3 significantly enhanced antibody secretion and expression of gerbil Cgamma1 and Cepsilon IGHC mRNAs in the B11D2(C2) heterohybridoma, which secretes gerbil IgG1. However, the addition of CM from both heterohybridomas did not improve in proliferation of B11D2(C2) cells. These results indicate that CM from D9(E6)C2B3 improved the culture of gerbil-mouse heterohybridomas, possibly by secreting gerbil IL6. PMID- 25739360 TI - Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging. AB - Oca2(p-cas) (oculocutaneous albinism II; pink-eyed dilution castaneus) is a coat color mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus musculus castaneus mice. Mice homozygous for Oca2(p-cas) usually exhibit pink eyes and gray coat hair on the non-agouti genetic background, and this ordinary phenotype remains unchanged throughout life. During breeding of a mixed strain carrying this gene on the C57BL/6J background, we discovered a novel spontaneous mutation that causes darkening of the eyes and coat hair with aging. In this study, we developed a novel mouse model showing this unique phenotype. Gross observations revealed that the pink eyes and gray coat hair of the novel mutant young mice became progressively darker in color by approximately 3 months after birth. Light and transmission-electron microscopic observations revealed a marked increase in melanin pigmentation of coat hair shafts and choroid of the eye in the novel mice compared to that in the ordinary mice. Sequence analysis of Oca2(p cas) revealed a 4.1-kb deletion involving exons 15 and 16 of its wild-type gene. However, there was no sequence difference between the two types of mutant mice. Mating experiments suggested that the novel mutant phenotype was not inherited in a simple fashion, due to incomplete penetrance. The novel spontaneous mutant mouse is the first example of progressive hair darkening animals and is an essential animal model for understanding of the regulation mechanisms of melanin biosynthesis with aging. PMID- 25739361 TI - A rare self-injurious case of multiple penetrating brain injury by nails in a young patient with depressive disorder. PMID- 25739362 TI - A patient with agrammatic primary progressive aphasia developing frontotemporal dementia. PMID- 25739363 TI - Ultimate limit of field confinement by surface plasmon polaritons. AB - We show that electric field confinement in surface plasmon polaritons propagating at metal/dielectric interfaces enhances the loss due to Landau damping, which effectively limits the degree of confinement itself. We prove that Landau damping, and associated with it surface collision damping, follow directly from the Lindhard formula for the dielectric constant of a free electron gas. Furthermore, we demonstrate that even if all of the conventional loss mechanisms, caused by phonons, electron-electron interactions, and interface roughness scattering, were eliminated, the maximum attainable degree of confinement and the loss accompanying it would not change significantly compared to the best existing plasmonic materials, such as silver. PMID- 25739365 TI - The Plasmodium vivax in China: decreased in local cases but increased imported cases from Southeast Asia and Africa. AB - Currently the local P. vivax was sharply decreased while the imported vivax malaria increased in China. Despite Southeast Asia was still the main import source of vivax malaria, the trend of Africa become serious, especially for west and central Africa. Herein we have clarified the trend of P. vivax in China from 2004-2012, and made some analysis for the differences of imported vivax back from different regions. There are significantly different of P. vivax between Southeast Asia and Africa, also the difference was observed for different regions in Africa. Additionally, we have explored the possibility for the difference of the P. vivax between migrant workers back from west and central Africa and the prevalence of local population. This reminds us that surveillance and training should be strengthened by medical staffs on the imported P. vivax cases reported especially from west and central Africa, in order to reduce the risk of malaria reintroduction and, specific tools should be developed, as well as the epidemiological study to avoid the misdiagnosis such as P. ovale and P. vivax. PMID- 25739364 TI - The ribosome challenge to the RNA world. AB - An RNA World that predated the modern world of polypeptide and polynucleotide is one of the most widely accepted models in origin of life research. In this model, the translation system shepherded the RNA World into the extant biology of DNA, RNA, and protein. Here, we examine the RNA World Hypothesis in the context of increasingly detailed information available about the origins, evolution, functions, and mechanisms of the translation system. We conclude that the translation system presents critical challenges to RNA World Hypotheses. Firstly, a timeline of the RNA World is problematic when the ribosome is incorporated. The mechanism of peptidyl transfer of the ribosome appears distinct from evolved enzymes, signaling origins in a chemical rather than biological milieu. Secondly, we have no evidence that the basic biochemical toolset of life is subject to substantive change by Darwinian evolution, as required for the transition from the RNA world to extant biology. Thirdly, we do not see specific evidence for biological takeover of ribozyme function by protein enzymes. Finally, we can find no basis for preservation of the ribosome as ribozyme or the universality of translation, if it were the case that other information transducing ribozymes, such as ribozyme polymerases, were replaced by protein analogs and erased from the phylogenetic record. We suggest that an updated model of the RNA World should address the current state of knowledge of the translation system. PMID- 25739366 TI - On the relationship between NMR-derived amide order parameters and protein backbone entropy changes. AB - Molecular dynamics simulations are used to analyze the relationship between NMR derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O(2) NH ) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O(2) NH < 0.8) shows that these report both on the local flexibility of the protein and on a different component of the conformational entropy than that reported by the side chain methyl axis order parameters, O(2) axis . A calibration curve for backbone entropy vs. O(2) NH is developed, which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O(2) NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, for example, upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O(2) axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements. PMID- 25739367 TI - Mitsunobu mischief: neighbor-directed histidine N(tau)-alkylation provides access to peptides containing selectively functionalized imidazolium heterocycles. AB - There are few methodologies that yield peptides containing His residues with selective N(tau), N(pi)-bis-alkylated imidazole rings. We have found that, under certain conditions, on-resin Mitsunobu coupling of alcohols with peptides having a N(pi)-alkylated His residue results in selective and high-yield alkylation of the imidazole N(tau) nitrogen. The reaction requires the presence of a proximal phosphoric, carboxylic or sulfonic acid, and proceeds through an apparent intramolecular mechanism involving Mitsunobu intermediates. These transformations have particular application to phosphopeptides, where "charge masking" of one phosphoryl anionic charge by the cationic histidine imidazolium ion is now possible. This chemistry opens selective access to peptides containing differentially functionalized imidazolium heterocycles, which provide access to new classes of peptides and peptide mimetics. PMID- 25739368 TI - HIV-infected mothers' experiences during their infants' HIV testing. AB - Both survival with HIV and rates of perinatal HIV infection have significantly declined during the past decade, due to antiretroviral therapies that interrupt HIV transmission to the fetus and newborn. Although HIV is no longer routinely fatal to mothers or transmitted to fetuses, and the testing of newborns for HIV has been improved, evidence about HIV-infected mothers' experiences during the months of their infants' HIV testing predates these improvements. This qualitative study on 16 mothers was an analysis of interviews conducted several weeks after testing was completed and all infants had been determined to be uninfected. Mothers reported that their experiences evolved during the months of testing. Initial reactions included maternal trauma and guilt associated with infant testing. They then reported learning to cope with the roller coaster ride of repeated testing with the help of information from clinicians. By the end of the testing period, ambiguity began to resolve as they engaged in tentative maternal-infant attachment and expressed desire for a sense of normalcy. Need for support and fear of stigma persisted throughout. These findings expand current knowledge about this experience and suggest clinical strategies to guide HIV infected women during this stressful period. PMID- 25739369 TI - C-H bond functionalization based on metal carbene migratory insertion. AB - Cross-coupling reactions involving metal carbene migratory insertion have been established as a new type of coupling reaction with diazo compounds as the reaction partners. Since 2011, an interesting development has been made in which the carbene migratory insertion process is successfully merged into C-H bond activations. Along this line, a series of investigations have been documented in the past few years. This feature article summarizes the developments in this area. PMID- 25739370 TI - Bifunctional metal-free catalysis of mesoporous noble carbons for oxygen reduction and evolution reactions. AB - Electrochemical oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are key reactions in lithium-oxygen batteries (LOBs) being a promising candidate to store renewable energies due to their high specific energy. However current development on LOBs is suffering from unsuitable catalysts. In particular, carbon-based catalysts were found to perform poorly in this system. Here, we show that metal-free mesoporous nitrogen-doped carbons (meso-NdCs) offer highly promising performances in both ORR and OER; they act as bifunctional catalysts, and can be synthesized by a very simple method. The efficient electrocatalytic activity of ORR and OER was used in a LOB cell during discharge and charge, respectively, and the present system showed a lower overpotential comparable to metal-based catalysts in LOB system. Thus, we demonstrate that meso NdCs act as a new and affordable candidate for the efficient bifunctional oxygen catalysis, therefore can be applied to many energy-related applications. PMID- 25739371 TI - Efficient uptake of dimethyl sulfoxide by the desoxomolybdenum(IV) dithiolate complex containing bulky hydrophobic groups. AB - A desoxomolybdenum(IV) complex containing bulky hydrophobic groups and NH...S hydrogen bonds, (Et4N)[Mo(IV)(OSi(t)BuPh2)(1,2-S2-3,6-{(4 (t)BuC6H4)3CCONH}2C6H2)2], was synthesized. This complex promotes the oxygen-atom transfer (OAT) reaction of DMSO by efficient uptake of the substrate into the active center. The clean OAT reaction of Me3NO is also achieved. PMID- 25739372 TI - Highly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour. AB - Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments' inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours' acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy. PMID- 25739373 TI - [Anti-VEGF therapy for neovascular age-related macular degeneration -therapeutic strategies: statement of the German Ophthalmological Society, the German Retina Society and the Professional Association of Ophthalmologists in Germany - November 2014]. PMID- 25739374 TI - Modulation of Interparticle Distance in Discrete Gold Nanoparticle Dimers and Trimers by DNA Single-Base Pairing. AB - Self-assembled structures of metallic nanoparticles with dynamically changeable interparticle distance hold promise for the regulation of collective physical properties. This paper describes gold nanoparticle dimers and trimers that exhibit spontaneous and reversible changes in interparticle distance. To exploit this property, a gold nanoparticle is modified with precisely one long DNA strand and approximately five short DNA strands. The long DNA serves to align the nanoparticles on a template DNA via hybridization, while the short DNAs function to induce the interparticle distance changes. The obtained dimer and trimer are characterized with gel electrophoresis, dynamic light scattering measurements, and transmission electron microscopy (TEM). When the complementary short DNA is added to form the fully matched duplexes on the particle surface in the presence of MgCl2 , spontaneous reduction of the interparticle distance is observed with TEM and cryo-electron microscopy. By contrast, when the terminal-mismatched DNA is added, no structural change occurs under the same conditions. Therefore, the single base pairing/unpairing at the outermost surface of the nanoparticle impacts the interparticle distance. This unique feature could be applied to the regulation of structures and properties of various DNA-functionalized nanoparticle assemblies. PMID- 25739375 TI - Plasma fibrin clot phenotype independently affects intracoronary thrombus ultrastructure in patients with acute myocardial infarction. AB - Determinants of intracoronary thrombus (ICT) composition in patients with ST elevation myocardial infarction (STEMI) are largely unknown. We sought to investigate whether plasma fibrin phenotype and platelet reactivity affect ICT ultrastructure. We assessed the content of fibrin, platelets and erythrocytes including polyhedrocytes by scanning electron microscopy on the surface and inside ICT aspirated from 80 STEMI patients within 12 hours since chest pain onset. Plasma fibrin clot permeability (Ks), which indicates the average pore size, lysis time (t50 %), platelet reactivity index (PRI) and ADP-induced platelet aggregation (ADP5, 20uM) were evaluated on admission. All patients received aspirin and 45 (56.3 %) 600 mg of clopidogrel, 80 (60-120) min prior to aspiration. Higher content of fibrin (61.6 vs 34.3 %, P< 0.0001) and platelets (8.2 vs 4.8 %, P=0.018) and lower erythrocyte content (15.8 vs 42.9 %, P< 0.0001) were found on ICT surface compared with its inner part. After adjustment for fibrinogen, in both ICT parts fibrin content was correlated with Ks (r<=-0.55, P< 0.0001) and t50 % (r>= 0.29, P<= 0.02) but not with PRI and ADP5,20uM. Polyhedrocytes were observed in 16 (20 %) patients and their large amount expressed as >= 50 % fields of view covered by polyhedrocytes was associated with the lower PRI values (40 vs 69 %, P=0.015), but not Ks or t50 %. By multivariate regression, Ks (beta=-0.62, P< 0.0001), clopidogrel pretreatment (beta=-0.36, P< 0.001), ischemia time (beta=0.19, P=0.044) and family history (beta=0.18, P=0.049) independently predicted fibrin content in the whole ICT (R2=0.65, P< 0.0001). Formation of denser plasma fibrin clots is independently associated with high fibrin content within the ICT in STEMI. PMID- 25739376 TI - Dietary legume consumption reduces risk of colorectal cancer: evidence from a meta-analysis of cohort studies. AB - Previous epidemiological studies on the relation between dietary legume consumption and risk of colorectal cancer (CRC) remain controversial. We conducted a meta-analysis based on prospective cohort studies to investigate the association between dietary legume consumption and risk of CRC. Fourteen cohort studies were finally included, containing a total of 1,903,459 participants and 12,261 cases who contributed 11,628,960 person-years. We found that higher legume consumption was associated with a decreased risk of CRC (RR, relative risk = 0.91; 95% CI, confidence interval = 0.84-0.98). Subgroup analyses suggested that higher legume consumption was inversely associated with CRC risk in Asian (RR = 0.82; 95% CI = 0.74-0.91) and soybean intake was associated with a decreased risk of CRC (RR = 0.85; 95% CI = 0.73-0.99). Findings from our meta-analysis supported an association between higher intake of legume and a reduced risk of CRC. Further studies controlled for appropriate confounders are warranted to validate the associations. PMID- 25739377 TI - Effects of sulfur dioxide on the respiratory system of Miyakejima child residents 6 years after returning to the island. AB - OBJECTIVES: This study investigated the health effects of volcanic gas, mainly sulfur dioxide (SO2), exposure on the children of Miyakejima Island. METHODS: Health checkups were conducted in November from 2006 to 2011. Health effects were evaluated through a self-administered questionnaire on respiratory and irritative symptoms, and spirometry. SO2 was measured continuously from February 2005 onward at six fixed monitoring stations in inhabitable areas. Based on mean SO2 concentration during 3 months before each health checkup, inhabitable areas were classified into three categories: (1) lower (area L); (2) higher (area H-1); and (3) highest (area H-2). RESULTS: Average concentrations (ppb) of SO2 decreased year-by-year and ranged from 11.3 to 2.47 in area L, from 32.2 to 12.2 in area H 1, and from 75.1 to 12.1 in area H-2, respectively. In general, prevalence of respiratory and irritative symptoms was higher in area H-2, and the prevalence decreased year-by-year in all three areas by Cochran-Armitage test for trend. We defined a study population in area L in 2008 as a reference population because we had no unexposed population. Applying a logistic regression model, age-, sex-, and hypersusceptibility-adjusted prevalence odds ratios to the reference population showed clear exposure-dependent increases in some irritative symptoms such as "Irritation and/or pain in throat" and "in eyes," and approximately 30 ppb seemed to be the threshold concentration. Spirometry did not show any significant differences. CONCLUSIONS: Though no pulmonary functions were affected, some subjective symptoms were detected dose-dependently by SO2 exposure concentration in child residents during the 6 years after the eruption. PMID- 25739378 TI - Pre-employment examination for low back risk in workers exposed to manual handling of loads: French guidelines. AB - BACKGROUND: Low back pain (LBP) is a major cause of sickness absence and disability in the working population, and the pre-employment examination should insure that worker's state of health is compatible with the requirements of proposed job. This paper summarizes the main recommendations of the good practice guidelines of the French Society of Occupational Medicine for pre-employment examination in workers exposed to manual handling of loads apart from pre employment test. METHODS: The recommendations were developed according to the Clinical Practice Guidelines proposed by the French National Health Authority and based on a systematic search of the literature 1990-2012 in several databases. The guidelines were written and reviewed by two multidisciplinary committees. On the basis of the level of evidence in the literature, the proposed guidelines are classified as grade A, B, C or expert consensus. RESULTS: The main recommendations of these guidelines are as follows: (1) medical contraindications alone should not exclude employment in a job associated with a low back risk on the basis of a history of "simple" nonspecific LBP; (2) the relevance of examining a previous history of LBP, which is the best predictor of future LBP due to the recurrent nature of LBP. CONCLUSIONS: These guidelines correspond to a constant concern with prevention of occupational risk. Primarily intended for occupational physicians, they are also intended for general practitioners who carry out pre-employment examinations in many countries and are likely to be increasingly faced with this type of situation because of the combination of increasing work constraints with ageing of the workforce. PMID- 25739380 TI - Catalysing mirror life. AB - Origin of life: Although current life is homochiral (with D nucleic acids), little is known about how homochirality emerged or even if it was a necessary step. The isolation of cross-chiral nucleic acid ligases demonstrate that an early heterochiral life could have been possible. PMID- 25739379 TI - Bacterial community analysis of drinking water biofilms in southern Sweden. AB - Next-generation sequencing of the V1-V2 and V3 variable regions of the 16S rRNA gene generated a total of 674,116 reads that described six distinct bacterial biofilm communities from both water meters and pipes. A high degree of reproducibility was demonstrated for the experimental and analytical work-flow by analyzing the communities present in parallel water meters, the rare occurrence of biological replicates within a working drinking water distribution system. The communities observed in water meters from households that did not complain about their drinking water were defined by sequences representing Proteobacteria (82 87%), with 22-40% of all sequences being classified as Sphingomonadaceae. However, a water meter biofilm community from a household with consumer reports of red water and flowing water containing elevated levels of iron and manganese had fewer sequences representing Proteobacteria (44%); only 0.6% of all sequences were classified as Sphingomonadaceae; and, in contrast to the other water meter communities, markedly more sequences represented Nitrospira and Pedomicrobium. The biofilm communities in pipes were distinct from those in water meters, and contained sequences that were identified as Mycobacterium, Nocardia, Desulfovibrio, and Sulfuricurvum. The approach employed in the present study resolved the bacterial diversity present in these biofilm communities as well as the differences that occurred in biofilms within a single distribution system, and suggests that next-generation sequencing of 16S rRNA amplicons can show changes in bacterial biofilm communities associated with different water qualities. PMID- 25739381 TI - Chlorhexidine skin or cord care for prevention of mortality and infections in neonates. AB - BACKGROUND: Affordable, feasible and efficacious interventions to reduce neonatal infections and improve neonatal survival are needed. Chlorhexidine, a broad spectrum topical antiseptic agent, is active against aerobic and anaerobic organisms and reduces neonatal bacterial colonisation and may reduce infection. OBJECTIVES: To evaluate the efficacy of neonatal skin or cord care with chlorhexidine versus routine care or no treatment for prevention of infections in late preterm or term newborn infants in hospital and community settings. SEARCH METHODS: We searched CENTRAL, latest issue of The Cochrane Library, MEDLINE (1966 to November 2013), EMBASE (1980 to November 2013), and CINAHL (1982 to November 2013). Ongoing trials were detected by searching the following databases: www.clinicaltrials.gov and www.controlled-trials.com. SELECTION CRITERIA: Cluster and individual patient randomised controlled trials of chlorhexidine use (for skin care, or cord care, or both) in term or late preterm neonates in hospital and community settings were eligible for inclusion. Three authors independently screened and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, and assessed study risk of bias. The quality of evidence for each outcome was assessed using GRADE. We calculated pooled risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals (CIs), and presented results using GRADE 'Summary of findings' tables. MAIN RESULTS: We included 12 trials in this review. There were seven hospital-based and five community-based studies. In four studies maternal vaginal wash with chlorhexidine was done in addition to neonatal skin and cord care. Newborn skin or cord cleansing with chlorhexidine compared to usual care in hospitalsLow quality evidence from one trial showed that chlorhexidine cord cleansing compared to dry cord care may lead to no difference in neonatal mortality (RR 0.11, 95% CI 0.01 to 2.04). Moderate-quality evidence from two trials showed that chlorhexidine cord cleansing compared to dry cord care probably reduces the risk of omphalitis/infections (RR 0.48, 95% CI 0.28 to 0.84).Low-quality evidence from two trials showed that chlorhexidine skin cleansing compared to dry cord care may lead to no difference in omphalitis/infections (RR 0.88, 95% CI 0.56 to 1.39). None of the studies in this comparison reported effects of the treatments on neonatal mortality. Newborn skin or cord cleansing with chlorhexidine compared to usual care in the communityHigh-quality evidence from three trials showed that chlorhexidine cord cleansing compared to dry cord care reduces neonatal mortality (RR 0.81, 95% CI 0.71 to 0.92) and omphalitis/infections (RR 0.48, 95% CI 0.40 to 0.57).High-quality evidence from one trial showed no difference between chlorhexidine skin cleansing and usual skin care on neonatal mortality (RR 1.03, 95% CI 0.87 to 1.23). None of the studies in this comparison reported effects of the treatments on omphalitis/infections. Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in hospitalsModerate-quality evidence from one trial showed no difference between maternal vaginal chlorhexidine in addition to total body cleansing and no intervention on neonatal mortality (RR 0.98, 95% CI 0.67 to 1.42). High-quality evidence from two trials showed no difference between maternal vaginal chlorhexidine in addition to total body cleansing and no intervention on the risk of infections (RR 0.93, 95% CI 0.82 to 1.16).Findings from one trial showed that maternal vaginal cleansing in addition to total body cleansing results in increased risk of hypothermia (RR 1.33, 95% CI 1.19 to 1.49). Maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention (sterile saline solution) in the communityLow-quality evidence from one trial showed no difference between maternal vaginal chlorhexidine in addition to total body cleansing and no intervention on neonatal mortality (RR 0.20, 95% CI 0.01 to 4.03). Moderate-quality evidence from one trial showed that maternal vaginal chlorhexidine in addition to total body cleansing compared to no intervention probably reduces the risk of neonatal infections (RR 0.69, 95% CI 0.49 to 0.95). These studies did not report effect on omphalitis. AUTHORS' CONCLUSIONS: There is some uncertainty as to the effect of chlorhexidine applied to the umbilical cords of newborns in hospital settings on neonatal mortality. The quality of evidence for the effects on infection are moderate for cord application and low for application to skin. There is high quality evidence that chlorhexidine skin or cord care in the community setting results in a 50% reduction in the incidence of omphalitis and a 12% reduction in neonatal mortality. Maternal vaginal chlorhexidine compared to usual care probably leads to no difference in neonatal mortality in hospital settings. Maternal vaginal chlorhexidine compared to usual care results in no difference in the risk of infections in hospital settings. The uncertainty over the effect of maternal vaginal chlorhexidine on mortality outcomes reflects small sample sizes and low event rates in the community settings. PMID- 25739382 TI - Analysis of clinical characteristics and prognostic factors for angioimmunoblastic T-cell lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma entity exhibiting peculiar clinical features and poor prognosis. Its clinical characteristics and prognostic factors are not well established. To clarify the clinical characteristics and prognostic features of AITL, we conducted a multicenter, retrospective study. Fifty-six patients were enrolled. The median patient age was 68 years. Immunohistochemical examinations of tumor cells showed positivity for CD10 and T-cell markers, and chromosomal examination detected several types of abnormalities. More than 80 % of patients show advanced disease at diagnosis and poor prognostic scores. A high proportion of patients showed accompanying B symptoms, splenomegaly, and hepatomegaly at diagnosis. The 5-year overall survival (OS) rate was 48 % and progression-free survival was 25 %. Univariate analysis revealed higher age, fever, poor performance status, anemia, and low albumin level to be poor prognostic factors for OS. In addition to these factors, both IPI and PIT were also predictive of OS. Multivariate analysis indicated only a low level of serum albumin to be a significant prognostic factor for OS. Serum albumin may be one of the important prognostic factors for AITL. Further investigation is needed to confirm these results. PMID- 25739383 TI - SVA retrotransposition in exon 6 of the coagulation factor IX gene causing severe hemophilia B. AB - Hemophilia B is an X-linked recessive bleeding disorder caused by abnormalities of the coagulation factor IX gene (F9). Insertion mutations in F9 ranging from a few to more than 100 base pairs account for only a few percent of all hemophilia B cases. We investigated F9 to elucidate genetic abnormalities causing severe hemophilia B in a Japanese subject. We performed PCR-mediated analysis of F9 and identified a large insertion in exon 6. Next, we carried out direct sequencing of a PCR clone of the whole insert using nested deletion by exonuclease III and S1 nuclease. We identified an approximately 2.5-kb SINE-VNTR-Alu (SVA)-F element flanked by 15-bp duplications in the antisense orientation in exon 6. Additionally, we carried out exontrap analysis to assess the effect of this retrotransposition on mRNA splicing. We observed that regular splicing at exons 5 and 6 of F9 was disturbed by the SVA retrotransposition, suggesting that abnormal FIX mRNA may be reduced by nonsense-mediated mRNA decay. In conclusion, this is the first report of SVA retrotransposition causing severe hemophilia B; only five cases of LINE-1 or Alu retrotranspositions in F9 have been reported previously. PMID- 25739384 TI - Widely metastatic squamous cell carcinoma originating from malignant transformation of hypertrophic lichen planus in a 24-year-old woman: case report and review of the literature. AB - Hypertrophic lichen planus (HLP) is a T-cell-mediated process typically presenting with hypertrophic or verrucous plaques on the lower limbs. We report the case of a 24-year-old woman with a history of HLP since age 3 years presenting with rapid malignant transformation of one lesion into a large squamous cell carcinoma (SCC). Subsequent examination revealed progressive, widespread metastatic involvement, and the patient ultimately died from her disease. SCC associated with HLP is rare, with a review of the literature revealing fewer than 50 cases. This case highlights the need to be aware of suspicious changes in HLP and to educate patients as to when to be reevaluated. PMID- 25739385 TI - Optimized couplers for interfacial thermal transport. AB - To find optimized interfacial thermal couplers we study thermal transport though a one dimensional atomic chain which includes three parts--two semi-infinite leads and a center region acting as a thermal coupler. It is found that the spring constant and atomic mass of an interfacial coupler can be selected to maximize interfacial thermal conductance. For the case of two lead materials with equal cutoff phonon frequencies, the interfacial system will reach a maximum thermal conductance if the coupler has the same cutoff frequency as those of the leads and its spring constant is equal to the geometric mean of those of leads. If two leads have equal acoustic impedances, one can find optimized interfacial coupler around the point where its acoustic impedance is the same as those of the leads and its spring constant is equal to the harmonic mean of those of leads. For general lead materials the interfacial thermal conductance can be optimized near the cross point of the geometric mean of impedances and harmonic mean of cutoff frequencies of the leads. Our findings can have potential applications in high performance interfacial thermal transport. PMID- 25739386 TI - Double Stranded RNA-Dependent Protein Kinase is Necessary for TNF-alpha-Induced Osteoclast Formation In Vitro and In Vivo. AB - Double-stranded RNA-dependent protein kinase (PKR) is involved in cell cycle progression, cell proliferation, cell differentiation, tumorgenesis, and apoptosis. We previously reported that PKR is required for differentiation and calcification in osteoblasts. TNF-alpha plays a key role in osteoclast differentiation. However, it is unknown about the roles of PKR in the TNF-alpha induced osteoclast differentiation. The expression of PKR in osteoclast precursor RAW264.7 cells increased during TNF-alpha-induced osteoclastogenesis. The TNF alpha-induced osteoclast differentiation in bone marrow-derived macrophages and RAW264.7 cells was markedly suppressed by the pretreatment of PKR inhibitor, 2 aminopurine (2AP), as well as gene silencing of PKR. The expression of gene markers in the differentiated osteoclasts including TRAP, Calcitonin receptor, cathepsin K, and ATP6V0d2 was also suppressed by the 2AP treatment. Bone resorption activity of TNF-alpha-induced osteoclasts was also supressed by 2AP treatment. Inhibition of PKR supressed the TNF-alpha-induced activation of NF kappaB and MAPK in RAW264.7 cells. 2AP inhibited both the nuclear translocation of NF-kappaB and its transcriptional activity in RAW264.7 cells. 2AP inhibited the TNF-alpha-induced expression of NFATc1 and c-fos, master transcription factors in osteoclastogenesis. TNF-alpha-induced nuclear translocation of NFATc1 in mature osteoclasts was clearly inhibited by the 2AP treatment. The PKR inhibitor C16 decreased the TNF-alpha-induced osteoclast formation and bone resorption in mouse calvaria. The present study indicates that PKR is necessary for the TNF-alpha-induced osteoclast differentiation in vitro and in vivo. PMID- 25739388 TI - In reply: unrecognized arterial cannulation due to the backflow feature of the BD InsyteTM AutoguardTM BC cannula. PMID- 25739389 TI - An Integrative Breakage Model of genome architecture, reshuffling and evolution: The Integrative Breakage Model of genome evolution, a novel multidisciplinary hypothesis for the study of genome plasticity. AB - Our understanding of genomic reorganization, the mechanics of genomic transmission to offspring during germ line formation, and how these structural changes contribute to the speciation process, and genetic disease is far from complete. Earlier attempts to understand the mechanism(s) and constraints that govern genome remodeling suffered from being too narrowly focused, and failed to provide a unified and encompassing view of how genomes are organized and regulated inside cells. Here, we propose a new multidisciplinary Integrative Breakage Model for the study of genome evolution. The analysis of the high-level structural organization of genomes (nucleome), together with the functional constrains that accompany genome reshuffling, provide insights into the origin and plasticity of genome organization that may assist with the detection and isolation of therapeutic targets for the treatment of complex human disorders. PMID- 25739390 TI - Transcriptional regulation of Niemann-Pick C1-like 1 gene by liver receptor homolog-1. AB - Factors that modulate cholesterol levels have major impacts on cardiovascular disease. Niemann-Pick C1-like 1 (NPC1L1) functions as a sterol transporter mediating intestinal cholesterol absorption and counter-balancing hepatobiliary cholesterol excretion. The liver receptor homolog 1 (LRH-1) had been shown to regulate genes involved in hepatic lipid metabolism and reverse cholesterol transport. To study whether human NPC1L1 gene is regulated transcriptionally by LRH-1, we have analyzed evolutionary conserved regions (ECRs) in HepG2 cells. One ECR was found to be responsive to the LRH-1. Through deletion studies, LRH-1 response element was identified and the binding of LRH-1 was demonstrated by EMSA and ChIP assays. When SREBP2, one of several transcription factors which had been shown to regulate NPC1L1 gene, was co-expressed with LRH-1, synergistic transcriptional activation resulted. In conclusion, we have identified LRH-1 response elements in NPC1L1 gene and propose that LRH-1 and SREBP may play important roles in regulating NPC1L1 gene. PMID- 25739391 TI - Effect of respiratory syncytial virus on the growth of hepatocellular carcinoma cell-lines. AB - In several reports, the respiratory syncytial virus (RSV) was identified as an oncolytic virus in cancer cells (e.g., lung and prostate cancer). However, the effects of RSV in hepatocellular carcinoma (HCC) cells have not yet been investigated. Here, we observed the inhibitory effects of RSV infection in HCC cell-lines. Cell growth was significantly decreased by RSV infection in BNL-HCC, Hep3B, Huh-7 and SNU-739 cells. After RSV infection, plaque formation and syncytial formation were observed in affected Hep3B and Huh-7 cells. RSV protein expression was also detected in Hep3B and Huh-7 cells; however, only Huh-7 cells showed apoptosis after RSV infection. Furthermore, inhibition of cell migration by RSV infection was observed in BNL-HCC, Hep3B, Huh-7 and SNU-739 cells. Therefore, further investigation is required to clarify the molecular mechanism of RSV-mediated inhibition of HCC cell growth, and to develop potential RSV oncolytic viro-therapeutics. PMID- 25739392 TI - Mangiferin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase 9 expression and cellular invasion by suppressing nuclear factor-kappaB activity. AB - We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-alpha stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-alpha-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-alpha significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-alpha-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-alpha-induced invasion of LNCaP cells. Compared to untreated controls, TNF-alpha-stimulated LNCaP cells showed a significant increase in nuclear factor-kappaB (NF-kappaB) luciferase activity. However, mangiferin treatment markedly decreased TNF-alpha-induced NF-kappaB luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-kappaB subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-kappaB mediated MMP-9 expression. PMID- 25739394 TI - The BMJ illustrates hazardous co-sleeping. PMID- 25739393 TI - Baicalin, baicalein and wogonin inhibits high glucose-induced vascular inflammation in vitro and in vivo. AB - Vascular inflammatory process has been suggested to play a key role in initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, in this study, we attempted to determine whether three structurally related polyphenols found in the Chinese herb Huang Qui, namely baicalin, baicalein, and wogonin, can suppress vascular inflammatory processes induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. Data showed that HG induced markedly increased vascular permeability, monocyte adhesion, expressions of cell adhesion molecules (CAMs), formation of reactive oxygen species (ROS) and activation of nuclear factor (NF)-kappaB. Remarkably, all of the above mentioned vascular inflammatory effects of HG were attenuated by pretreatment with baicalin, baicalein, and wogonin. Vascular inflammatory responses induced by HG are critical events underlying development of various diabetic complications, therefore, our results suggest that baicalin, baicalein, and wogonin may have significant therapeutic benefits against diabetic complications and atherosclerosis. PMID- 25739395 TI - Biosorption of heavy metals by Pseudomonas species isolated from sugar industry. AB - Heavy metal-resistant bacteria can be efficient bioremediators of metals and may provide an alternative or additional method to conventional methods of metal removal. In this study, 10 bacterial isolates were isolated from soil samples of a sugar industry, located at Peshawar, Pakistan. Morphological, physiological, and biochemical characteristics of these isolates were observed. Sequence analysis (16S ribosomal RNA) revealed that isolated strains were closely related to the species belonging to the genera Pseudomonas, Arthrobacter, Exiguobacterium, Citrobacter, and Enterobacter Bacterial isolates were resistant with a minimum inhibitory concentration (500-900 ppm) to lead ion (Pb(2+)), (500 600 ppm) nickel ion (Ni(2+)), (500-800 ppm) copper ion (Cu(2+)), and (600-800 ppm) chromium ion (Cr(3+)) in solid media. Furthermore, biosorption of metals proved considerable removal of heavy metals by isolated metal-resistant strains. Pseudomonas sp. reduced 37% (Pb(2+)), 32% (Ni(2+)), 29% (Cu(2+)), and 32% (Cr(3+)) and was thus found to be most effective, whereas Enterobacter sp. reduced 19% (Pb(2+)), 7% (Ni(2+)), 14% (Cu(2+)), and 21% (Cr(3+)) and was found to be least effective. While average reduction of Pb(2+), Ni(2+), Cu(2+), and Cr(3+) by Citrobacter sp. was found to be 24%, 18%, 23%, and 27%, respectively, among recognized species. This study revealed that Pseudomonas sp. may provide a new microbial community that can be used for enhanced remediation of contaminated environment. PMID- 25739396 TI - Particle loading time and humidity effects on the efficiency of an N95 filtering facepiece respirator model under constant and inhalation cyclic flows. AB - It is necessary to investigate the efficiencies of filtering facepiece respirators (FFRs) exposed to ultrafine particles (UFPs) for long periods of time, since the particle loading time may potentially affect the efficiency of FFRs. This article aims to investigate the filtration efficiency for a model of electrostatic N95 FFRs with constant and 'inhalation-only' cyclic flows, in terms of particle loading time effect, using different humidity conditions. Filters were exposed to generated polydisperse NaCl particles. Experiments were performed mimicking an 'inhalation-only' scenario with a cyclic flow of 85 l min(-1) as the minute volume [or 170 l min(-1) as mean inhalation flow (MIF)] and for two constant flows of 85 and 170 l min(-1), under three relative humidity (RH) levels of 10, 50, and 80%. Each test was performed for loading time periods of 6h and the particle penetration (10-205.4nm in electrical mobility diameter) was measured once every 2h. For a 10% RH, the penetration of smaller size particles (<80nm), including the most penetrating particle size (MPPS), decreased over time for both constant and cyclic flows. For 50 and 80% RH levels, the changes in penetration were typically observed in an opposite direction with less magnitude. The penetrations at MPPS increased with respect to loading time under constant flow conditions (85 and 170 l min(-1)): it did not substantially increase under cyclic flows. The comparison of the cyclic flow (85 l min(-1) as minute volume) and constant flow equal to the cyclic flow minute volume indicated that, for all conditions the penetration was significantly less for the constant flow than that of cyclic flow. The comparison between the cyclic (170 l min(-1) as MIF) and constant flow equal to cyclic flow MIF indicated that, for the initial stage of loading, the penetrations were almost equal, but they were different for the final stages of the loading time. For a 10% RH, the penetration of a wide range of sizes was observed to be higher with the cyclic flow (170 as MIF) than with the equivalent constant flow (170 l min(-1)). For 50 and 80% RH levels, the penetrations were usually greater with a constant flow (170 l min(-1)) than with a cyclic flow (170 l min(-1) as MIF). It is concluded that, for the tested electrostatic N95 filters, the change in penetration as a function of the loading time does not necessarily take place with the same rate under constant (MIF) and cyclic flow. Moreover, for all tested flow rates, the penetration is not only affected by the loading time but also by the RH level. Lower RH levels (10%) have decreasing penetration rates in terms of loading time, while higher RH levels (50 and 80%) have increasing penetration rates. Also, the loading of the filter is normally accompanied with a shift of MPPS towards larger sizes. PMID- 25739397 TI - A pre-synchronization program at early postpartum might increase the chances of Bos indicus cows cycling prior to 50 days regardless of the length of calf separation. AB - The aim of this study was to establish if pre-synchronization would enhance the number of animals cycling prior to conventional breeding at 45 days irrespective of the length of calf separation. Multiparous Bos indicus cows were allotted in four groups (n = 10). Control group (C) dams remained with their calves; groups G24, G48 and G72, which were partially weaned for 24, 48 and 72 h, respectively, were estrus synchronized using a controlled internal drug. These procedures were performed at 25 days and again at 45 days postpartum. The number of follicles, presence of a corpus luteum and back fat thickness (BFT) were determined by ultrasound. The proportion of cows with estrus and ovulation at day 25 postpartum was statistically different between the control and treated groups, with the values being 20, 60, 50 and 70 for the control, G24, G48 and G72 groups respectively (P < 0.05). At days 45 postpartum, the proportion of cows with estrus and ovulation was different in group G48 compared with the other groups (P <0.05). The average BFT and body condition score for the four experimental groups in the two periods were similar (P >0.05). Animals with a higher proportion of follicles from 17 to 21 mm, BFT values above 3.5 mm and a regular body condition were significantly different regardless of whether the dams remained with their calves or were separated, regardless of the length of this event. It can be concluded that (1) a pre-synchronization program at day 25 could trigger the onset of ovarian activity and facilitate a breeding program at day 50 and (2) temporary weaning enhances the effect of a pre-synchronization program. PMID- 25739398 TI - High potency cannabis: a risk factor for dependence, poor psychosocial outcomes, and psychosis. PMID- 25739399 TI - Wikipedia and medicine: quantifying readership, editors, and the significance of natural language. AB - BACKGROUND: Wikipedia is a collaboratively edited encyclopedia. One of the most popular websites on the Internet, it is known to be a frequently used source of health care information by both professionals and the lay public. OBJECTIVE: This paper quantifies the production and consumption of Wikipedia's medical content along 4 dimensions. First, we measured the amount of medical content in both articles and bytes and, second, the citations that supported that content. Third, we analyzed the medical readership against that of other health care websites between Wikipedia's natural language editions and its relationship with disease prevalence. Fourth, we surveyed the quantity/characteristics of Wikipedia's medical contributors, including year-over-year participation trends and editor demographics. METHODS: Using a well-defined categorization infrastructure, we identified medically pertinent English-language Wikipedia articles and links to their foreign language equivalents. With these, Wikipedia can be queried to produce metadata and full texts for entire article histories. Wikipedia also makes available hourly reports that aggregate reader traffic at per-article granularity. An online survey was used to determine the background of contributors. Standard mining and visualization techniques (eg, aggregation queries, cumulative distribution functions, and/or correlation metrics) were applied to each of these datasets. Analysis focused on year-end 2013, but historical data permitted some longitudinal analysis. RESULTS: Wikipedia's medical content (at the end of 2013) was made up of more than 155,000 articles and 1 billion bytes of text across more than 255 languages. This content was supported by more than 950,000 references. Content was viewed more than 4.88 billion times in 2013. This makes it one of if not the most viewed medical resource(s) globally. The core editor community numbered less than 300 and declined over the past 5 years. The members of this community were half health care providers and 85.5% (100/117) had a university education. CONCLUSIONS: Although Wikipedia has a considerable volume of multilingual medical content that is extensively read and well-referenced, the core group of editors that contribute and maintain that content is small and shrinking in size. PMID- 25739400 TI - Long noncoding RNAs as inducers and terminators of vascular development. PMID- 25739402 TI - Microstructure and Mechanical Properties of Ti Cold-Spray Splats Determined by Electron Channeling Contrast Imaging and Nanoindentation Mapping. AB - Cold spray is a thermo-mechanical process where the velocity of the sprayed particles affects the deformation, bonding, and mechanical properties of the deposited material, in the form of splats or coatings. At high strain rates, the impact stresses are converted into heat, a phenomenon known as adiabatic shear, which leads to grain re-crystallization. Grain re-crystallization and growth are shown to have a direct impact on the mechanical properties of the cold-sprayed material. The present study ties the microstructural features within the cold sprayed Ti splats and the substrate to the bonding mechanism and mechanical properties. High-resolution electron channeling contrast imaging, electron backscatter diffraction mapping, and nanoindentation were used to correlate the microstructure to the mechanical properties distribution within the titanium cold spray splats. The formation of nanograins was observed at the titanium splat/substrate interface and contributed to metallurgical bonding. An increase in grain re-crystallization within the splat and substrate materials was observed with pre-heating of the substrate. In the substrate material, the predominant mechanism of deformation was twinning. A good relationship was found between the hardness and distribution of the twins within the substrate and the size distribution of the re-crystallized grains within the splats. PMID- 25739401 TI - Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators with important functions in development and disease. Here, we sought to identify and functionally characterize novel lncRNAs critical for vertebrate development. METHODS AND RESULTS: By relying on human pluripotent stem cell differentiation models, we investigated lncRNAs differentially regulated at key steps during human cardiovascular development with a special focus on vascular endothelial cells. RNA sequencing led to the generation of large data sets that serve as a gene expression roadmap highlighting gene expression changes during human pluripotent cell differentiation. Stage-specific analyses led to the identification of 3 previously uncharacterized lncRNAs, TERMINATOR, ALIEN, and PUNISHER, specifically expressed in undifferentiated pluripotent stem cells, cardiovascular progenitors, and differentiated endothelial cells, respectively. Functional characterization, including localization studies, dynamic expression analyses, epigenetic modification monitoring, and knockdown experiments in lower vertebrates, as well as murine embryos and human cells, confirmed a critical role for each lncRNA specific for each analyzed developmental stage. CONCLUSIONS: We have identified and functionally characterized 3 novel lncRNAs involved in vertebrate and human cardiovascular development, and we provide a comprehensive transcriptomic roadmap that sheds new light on the molecular mechanisms underlying human embryonic development, mesodermal commitment, and cardiovascular specification. PMID- 25739403 TI - Delusion-like experiences in older people with anxiety disorders. AB - BACKGROUND: Little is known about the occurrence of psychotic or quasi-psychotic experiences in older people with anxiety disorders. METHODS: We used a cross sectional national probability sample of community-residing individuals to investigate the prevalence and correlates of delusion-like experiences in older people with DSM-IV anxiety disorders. The 2007 Australian National Survey of Mental Health and Well-being (NSMHWB) included 1,905 persons between the ages of 65 and 85 years. Anxiety disorder diagnoses were established using the Composite International Diagnostic Interview (CIDI v3). Participants were asked about three types of delusion-like experiences: thought control or interference, special meaning, and special powers. We used multivariate logistic regression to examine the relationship between a 12-month history of any anxiety disorder and the presence of these delusion-like experiences, adjusting for several potential confounders. RESULTS: Eighty-two of 1,905 (4.3%) older people met criteria for an anxiety disorder over the previous 12 months. Of these, six reported delusion like experiences, whereas the prevalence of these experiences among older people without anxiety disorder was 26/1,822 (7.3% vs. 1.4%; chi(2) = 16.5; p = 0.000). In a logistic regression model, male gender (OR 0.38; p = 0.019), separated marital status (OR 4.86; p = 0.017), and the presence of anxiety disorder (OR 5.33; p = 0.001) were independently associated with delusion-like experiences, whereas MMSE (Mini-Mental State Examination) score, general medical conditions and affective disorder were not. CONCLUSIONS: In this cross-sectional study, self reported delusion-like experiences occurred at increased prevalence among community-residing older persons with anxiety disorder. More work is needed to clarify the nature and significance of these findings. PMID- 25739404 TI - WS6 induces both alpha and beta cell proliferation without affecting differentiation or viability. AB - Agents that stimulate human pancreatic beta cell proliferation are needed to improve diabetes mellitus treatment. Recently, a small molecule, WS6, was observed to stimulate human beta cell proliferation. However, little is known about its other effects on human islets. To better understand the role of WS6 as a possible beta cell regenerative therapy, we carried out in-depth phenotypic analysis of WS6-treated human islets, exploring its effects on non-beta cell proliferation, beta cell differentiation, and islet cell viability. WS6 not only stimulated beta cell proliferation in cultured human islets (in agreement with previous reports), but also human alpha cell proliferation, indicating that WS6 is not a beta cell-specific mitogen. WS6 did not change the proportion of insulin positive beta cells or the expression of beta cell-specific transcription factors, suggesting that WS6 does not alter beta cell differentiation, and WS6 had no effect on human islet cell apoptosis or viability. In conclusion, WS6 stimulates proliferation of both human beta and alpha cells while maintaining cellular viability and the beta cell differentiated phenotype. These findings expand the literature on WS6 and support the suggestion that WS6 may help increase human islet mass needed for successful treatment of diabetes. PMID- 25739405 TI - Chemical exposure levels in printing workers with cholangiocarcinoma (second report). AB - OBJECTIVE: In several Japanese printing plants, printing workers have suffered from cholangiocarcinoma. 1,2-dichloropropane (1,2-DCP) is considered to be a causative agent, and whether or not other chemicals also contribute to the development of this disease has not been conclusively determined. This study aimed to identify the chemicals used by seven printing workers who developed cholangiocarcinoma, as well as to estimate the levels of chemical exposure among them. METHODS: Information was obtained from the Ministry of Health, Labour and Welfare, Japan, to identify chemicals used by printing workers who developed cholangiocarcinoma and to estimate chemical exposure concentrations. Working environment concentrations of the chemicals in the printing rooms were estimated using a well-mixed model, and exposure concentrations during the ink removal operation were estimated using a near-field and far-field model. Shift time weighted averages of exposure concentrations were also calculated. RESULTS: Four of the seven printing workers were exposed to both 1,2-DCP and dichloromethane (DCM). The estimated maximum exposure concentrations for each of the four workers were 230 to 420 ppm for 1,2-DCP and 58 to 720 ppm for DCM, and the estimated shift average exposure concentrations were 0 to 210 ppm for 1,2-DCP and 15 to 270 ppm for DCM. The remaining three workers were exposed to DCM but not 1,2-DCP. The estimated maximum exposure concentrations of DCM for each of the three workers were 600 to 1,300 ppm, and the estimated shift average exposure concentrations were 84 to 440 ppm. CONCLUSIONS: Our findings suggest that DCM may contribute to the development of cholangiocarcinoma in humans. PMID- 25739406 TI - Comparison of the exposure-excretion relationship between men and women exposed to organic solvents. AB - OBJECTIVES: The present study was initiated to examine if application of the same biological occupational exposure limits (BOELs) for organic solvents is applicable across the sexes. METHODS: A survey was conducted in 69 micro-scale enterprises in a furniture-producing industrial park. In practice, 211 men and 52 women participated in the survey. They worked in a series of production process, and were exposed to solvent vapor mixtures. The exposure intensities were monitored with two types of diffusive samplers, one with carbon cloth (for solvents in general) and the other with water (for methyl alcohol) as adsorbents. Solvents in the adsorbents and head-space air from urine samples were analyzed with capillary FID-GC. The measured values were subjected to linear regression analysis followed by statistical evaluation for possible sex-related differences in slopes. RESULTS: Essentially no significant difference was detected between men and women in regression line parameters including slopes. Possible differences in the cases of acetone and toluene were discussed and excluded. CONCLUSIONS: With the exceptions for acetone and toluene, the present study did not detect any clear differences between men and women. In examinations of past reports, no support for the observed differences was found. The present findings deserve further study so that a solid conclusion can be formed. PMID- 25739407 TI - Combined Non-Invasive Doppler Echocardiography and Coronary Computed Tomography Lead to Diagnosis of Anomalous Left Coronary Artery From the Pulmonary Artery (ALCAPA) Syndrome. PMID- 25739408 TI - Valsalva sinus perforation into the right atrium due to infective endocarditis of transcatheter heart valve. PMID- 25739409 TI - Paleoanthropology. Late Pliocene fossiliferous sedimentary record and the environmental context of early Homo from Afar, Ethiopia. AB - Sedimentary basins in eastern Africa preserve a record of continental rifting and contain important fossil assemblages for interpreting hominin evolution. However, the record of hominin evolution between 3 and 2.5 million years ago (Ma) is poorly documented in surface outcrops, particularly in Afar, Ethiopia. Here we present the discovery of a 2.84- to 2.58-million-year-old fossil and hominin bearing sediments in the Ledi-Geraru research area of Afar, Ethiopia, that have produced the earliest record of the genus Homo. Vertebrate fossils record a faunal turnover indicative of more open and probably arid habitats than those reconstructed earlier in this region, which is in broad agreement with hypotheses addressing the role of environmental forcing in hominin evolution at this time. Geological analyses constrain depositional and structural models of Afar and date the LD 350-1 Homo mandible to 2.80 to 2.75 Ma. PMID- 25739410 TI - Paleoanthropology. Early Homo at 2.8 Ma from Ledi-Geraru, Afar, Ethiopia. AB - Our understanding of the origin of the genus Homo has been hampered by a limited fossil record in eastern Africa between 2.0 and 3.0 million years ago (Ma). Here we report the discovery of a partial hominin mandible with teeth from the Ledi Geraru research area, Afar Regional State, Ethiopia, that establishes the presence of Homo at 2.80 to 2.75 Ma. This specimen combines primitive traits seen in early Australopithecus with derived morphology observed in later Homo, confirming that dentognathic departures from the australopith pattern occurred early in the Homo lineage. The Ledi-Geraru discovery has implications for hypotheses about the timing and place of origin of the genus Homo. PMID- 25739411 TI - Interferon-gamma +874A/T polymorphism and hepatocellular carcinoma risk: a meta analysis. AB - BACKGROUND: Studies have evaluated the association between interferon-gamma (IFN gamma) +874A/T polymorphism and hepatocellular carcinoma (HCC) risk, but the results are controversial. We performed this meta-analysis to further investigate this association. MATERIAL AND METHODS: Relevant studies were searched by using the PubMed, Web of Science, and Embase databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Subgroup analysis and sensitivity analysis were conducted. RESULTS: Seven case control studies (859 HCC patients and 1482 healthy controls) were identified to assess the association between IFN-gamma +874A/T polymorphism and risk of HCC. IFN-gamma +874A/T polymorphism was significantly associated with an increased risk of HCC (OR=1.38; 95% CI 1.12-1.70; P=0.002). In the subgroup analysis by ethnicity, IFN-gamma +874A/T polymorphism was significantly associated with HCC risk in Asians (OR=1.42; 95% CI 1.08-1.87; P=0.01), but no significant association was found in Caucasians (OR=1.21; 95% CI 0.86-1.70; P=0.28). IFN gamma +874A/T polymorphism also increased HBV-induced HCC risk (OR=1.42; 95% CI 1.08-1.87; P=0.01). In the subgroup analysis by control source, IFN-gamma +874A/T polymorphism was associated with HCC risk in hospital-based studies (OR=1.45; 95% CI 1.09-1.53; P=0.01). A marginal association was found in population-based studies (OR=1.33; 95% CI 0.97-1.83; P=0.08). CONCLUSIONS: This meta-analysis indicates that the IFN-gamma +874A/T polymorphism might contribute to HCC risk. PMID- 25739412 TI - Cognitive training on stroke patients via virtual reality-based serious games. AB - PURPOSE: Use of virtual reality environments in cognitive rehabilitation offers cost benefits and other advantages. In order to test the effectiveness of a virtual reality application for neuropsychological rehabilitation, a cognitive training program using virtual reality was applied to stroke patients. METHODS: A virtual reality-based serious games application for cognitive training was developed, with attention and memory tasks consisting of daily life activities. Twenty stroke patients were randomly assigned to two conditions: exposure to the intervention, and waiting list control. RESULTS: The results showed significant improvements in attention and memory functions in the intervention group, but not in the controls. CONCLUSIONS: Overall findings provide further support for the use of VR cognitive training applications in neuropsychological rehabilitation. Implications for Rehabilitation Improvements in memory and attention functions following a virtual reality-based serious games intervention. Training of daily life activities using a virtual reality application. Accessibility to training contents. PMID- 25739413 TI - Is the left hemisphere androcentric? Evidence of the learned categorical perception of gender. AB - Effects of language learning on categorical perception have been detected in multiple domains. We extended the methods of these studies to gender and pitted the predictions of androcentrism theory and the spatial agency bias against each other. Androcentrism is the tendency to take men as the default gender and is socialized through language learning. The spatial agency bias is a tendency to imagine men before women in the left-right axis in the direction of one's written language. We examined how gender-ambiguous faces were categorized as female or male when presented in the left visual fields (LVFs) and right visual fields (RVFs) to 42 native speakers of English. When stimuli were presented in the RVF rather than the LVF, participants (1) applied a lower threshold to categorize stimuli as male and (2) categorized clearly male faces as male more quickly. Both findings support androcentrism theory suggesting that the left hemisphere, which is specialized for language, processes face stimuli as male-by-default more readily than the right hemisphere. Neither finding evidences an effect of writing direction predicted by the spatial agency bias on the categorization of gender ambiguous faces. PMID- 25739414 TI - Prevalence of stuttering in primary school children in Cairo-Egypt. AB - PURPOSE: To determine the prevalence of stuttering among primary school children in Cairo. METHOD: A cross-sectional design was employed. Using a multi-stage random sample from 10 schools in Cairo, a total of 8765 primary school students were enrolled in the study. The teacher referring method was initially used to detect stuttering students, which was then confirmed by a Speech Language Pathologist (SLP) using Diagnostic and Statistical Manual for Mental Disorders Fourth Edition (DSM-IV) criteria. Personal data were collected for all students and separate questionnaires were administered to the parents of each stuttering child, inquiring about consanguinity, family history, presence of other disorders and family attitudes towards the child. RESULT: Prevalence of stuttering among primary school children in Cairo was 1.03%. The prevalence of stuttering showed a declining trend in the older age group. Stuttering was 7-fold more prevalent among left-handed students. Males had a higher prevalence of stuttering, but didn't reach statistical significance. Anxiety was expressed in 25% of the families of affected children. Positive family history was found in 28% of cases, mainly among first-degree relatives. CONCLUSION: The current study showed a prevalence of stuttering comparable to other areas of the world with some evidence of hereditary background, although lower than that reported by other studies. PMID- 25739415 TI - Developments in intracerebral stem cell grafts. AB - The field of stem cell therapy has emerged as a promising research area for brain repair. Optimizing the safety and efficacy of the therapy for clinical trials will require revisiting transplantation protocols. The cell delivery route stands as a key translational item that warrants careful consideration in facilitating the success of stem cell therapy in the clinic. Intracerebral administration, compared to peripheral route, requires an invasive procedure to directly implant stem cells into injured brain. Although invasive, intracerebral transplantation circumvents the prohibitive blood brain barrier in allowing grafted cells when delivered peripherally to penetrate the brain and reach the discreet damaged brain tissues. This review will highlight milestone discoveries in cell therapy for neurological disorders, with emphasis on intracerebral transplantation in relevant animal models and provide insights necessary to optimize the safety and efficacy of cell therapy for the treatment of Parkinson's disease, Huntington's disease, stroke and traumatic brain injury. PMID- 25739416 TI - Three-point fix tympanoplasty. AB - CONCLUSION: The three-point fix tympanoplasty procedure is a stable and effective technique - with a high degree of graft take and satisfactory hearing results - for reconstruction of most tympanic membrane (TM) perforations. OBJECTIVE: It is difficult to repair a TM perforation, including subtotal perforation, involving the anterior part of the annulus. Reperforation can occur when an underlay graft technique is used. An overlay graft technique may result in anterior blunting/lateralization. We introduce a three-point fix tympanoplasty procedure, which can provide additional support to yield a stable graft. METHODS: The study enrolled a total of 234 patients who underwent a three-point fix tympanoplasty procedure from November 2005 to June 2011. Anatomic success was defined as an intact, repaired TM, while functional success was defined as a significant decrease in the air-bone gap at the end of follow-up compared with preoperative hearing (air-bone gap). The complication rate was also analyzed. RESULTS: The anatomic success rate was 93.2% (218/234 patients). The functional success rate after an average of 1 year was 73.5%. The postoperative average pure-tone air bone gap (15.4 +/- 11.4 dB) decreased successfully in comparison with the preoperative average air-bone gap (20.6 +/- 12.1 dB). There were few postoperative complications (7.7%). PMID- 25739417 TI - RE: Comparative effectiveness of neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis. PMID- 25739418 TI - Response. PMID- 25739419 TI - Doll and Peto's quantitative estimates of cancer risks: holding generally true for 35 years. PMID- 25739420 TI - Aerosol-phase activity of iodine captured from a triiodide resin filter on fine particles containing an infectious virus. AB - AIMS: To avoid interference by water-iodine disinfection chemistry and measure directly the effect of iodine, captured from a triiodide complex bound to a filter medium, on viability of penetrating viral particles. METHODS AND RESULTS: Aerosols of MS2 coli phage were passed through control P100 or iodinated High Efficiency Particulate Air media, collected in plastic bags, incubated for 0-10 min, collected in an impinger containing thiosulphate to consume all unreacted iodine, plated and enumerated. Comparison of viable counts demonstrated antimicrobial activity with an apparent half-life for devitalization in tens of seconds; rate of kill decreased at low humidity and free iodine was captured by the bags. CONCLUSIONS: The results support the mechanism of near-contact capture earlier proposed; however, the disinfection chemistry in the aerosol phase is very slow on the time scale of inhalation. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that disinfection by filter-bound iodine in the aerosol phase is too slow to be clinically significant in individual respiratory protection, but that it might be of benefit to limit airborne transmission of infections in enclosed areas. PMID- 25739421 TI - Characteristics of Metroxylon sagu resistant starch type III as prebiotic substance. AB - Resistant starch type III (RS3 ) was produced from sago (Metroxylon sagu) and evaluated for its characteristics as a prebiotic. Two RS3 samples designated sago RS and HCl-sago RS contained 35.71% and 68.30% RS, respectively, were subjected to hydrolyses by gastric juice and digestive enzymes and to absorption. Both sago RS and HCl-sago RS were resistant to 180 min hydrolysis by gastric acidity at pH 1 to 4 with less than 0.85% hydrolyzed. Both samples were also resistant toward hydrolysis by gastrointestinal tract enzymes and intestinal absorption with 96.75% and 98.69% of RS3 were recovered respectively after 3.5 h digestion and overnight dialysis at 37 degrees C. Sago RS3 supported the growth of both beneficial (lactobacilli and Bifidobacteria) and pathogenic microbes (Escherichia coli, Campylobacter coli, and Clostridium perfringens) in the range of 2.60 to 3.91 log10 CFU/mL. Hence, prebiotic activity score was applied to describe the extent to which sago RS3 supports selective growth of the lactobacilli and bifidobacteria strains over pathogenic bacteria. The highest scores were obtained from Bifidobacterium sp. FTDC8943 grown on sago RS (+0.26) and HCl-sago RS (+0.24) followed by L. bulgaricus FTDC1511 grown on sago RS (+0.21). The findings had suggested that sago RS3 has the prebiotic partial characteristics and it is suggested to further assess the suitability of sago RS3 as a prebiotic material. PMID- 25739422 TI - Total and differential white blood cell counts in late life predict 8-year incident stroke: the Honolulu Heart Program. AB - OBJECTIVES: To study the association between total and differential white blood cell (WBC) count and incident stroke in an older Asian population. DESIGN: Prospective population-based study with 8 years of follow-up. SETTING: The Honolulu Heart Program, Oahu, Hawaii. PARTICIPANTS: Japanese-American men aged 71 to 93 who were free of stroke and had baseline WBC counts measured in 1991-93 (N=3,342). MEASUREMENTS: Participants were divided into quartiles of total and differential WBC count for analysis and were followed for incident stroke (thromboembolic and hemorrhagic (hemorrhagic)) for 8 years using data from a comprehensive hospital surveillance system. RESULTS: Age-adjusted incident stroke rates increased significantly with increasing WBC quartile (Q1, 7.68; Q2, 9.04; Q3, 9.26; Q4, 14.10 per 1,000 person-years of follow-up, P=.001). Hazard ratios (HRs) for stroke for each quartile of total and differential WBC count were obtained using Cox regression analysis, with the lowest quartile as the reference group. After full adjustment, including age; cardiovascular risk factors; fibrinogen; prevalent coronary heart disease, cancer, or chronic obstructive pulmonary disease, and nonsteroidal anti-inflammatory drug use, HRs were 1.62 (95% confidence interval (CI)=1.04-2.52, P=.03) in the highest quartile of total WBC and 2.19 (95% CI=1.41-3.39, P<.001) in the highest quartile of neutrophil counts. Significant associations were also seen for thromboembolic but not for hemorrhagic strokes. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes. CONCLUSION: In elderly Japanese American men, higher total WBC and neutrophil counts were independent predictors of overall stroke, as well as thromboembolic stroke. PMID- 25739423 TI - Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: role of opioid receptors. AB - Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to acute ischaemia/reperfusion injury. The objective of this study was to find out whether the cardioprotective effect of CNH mediated by opioid receptors is associated with preservation of mitochondrial function. Rats were adapted to CNH (12% oxygen) for 3 weeks. Isolated perfused hearts were subjected to 45 min of global ischaemia and 30 min of reperfusion; subgroups were pretreated with non-selective opioid receptor antagonist naloxone (300 nmol/L) for 10 min. Cardiac contractile function, creatine kinase activity in coronary effluent, mitochondrial respiration rate, and calcium retention capacity were assessed. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the post-ischaemic recovery of contractile function, mitochondrial state 3 and uncoupled respiration rates, and calcium retention capacity compared to the normoxic group. These protective effects were completely abolished by naloxone. The contractile recovery positively correlated with state 3 respiration and calcium retention capacity. The results suggest that the preserved mitochondrial function contributes to the protected cardiac phenotype afforded by adaptation to CNH and point to an important role of opioid receptor activation. PMID- 25739424 TI - Barriers and facilitators in the implementation of recommendations for hand eczema prevention among healthcare workers. AB - BACKGROUND: Evidence-based recommendations are available for the prevention of hand eczema among healthcare workers. However, the implementation of these recommendations is not always successful. OBJECTIVES: To identify barriers and facilitators in the implementation of recommendations for the prevention of hand eczema among healthcare workers alongside a randomized controlled trial. METHODS: A qualitative study was performed in which 19 healthcare workers were interviewed. The interview transcripts were open coded and also coded by means of a template by two researchers to identify relevant barriers and facilitators. RESULTS: Most barriers and facilitators reported for the recommendations were found at the level of the innovation (e.g. the recommendations), whereas for the guideline as a whole, multiple levels (socio-political, organization, user, and facilities) were identified. CONCLUSIONS: To enhance the implementation of recommendations for the prevention of hand eczema in a healthcare setting, having knowledge about these recommendations seems to be an important first step. In addition, maintaining the attention of the subject, testing the products beforehand and close collaboration with the infection control department might enhance implementation. Furthermore, it is important that the recommendations fit in with the work of the healthcare workers. When the implementation of the recommendations is prepared, these points should be taken into account. PMID- 25739425 TI - A MULTI-DIMENSIONAL SUPPORT PROGRAMME FOR PATIENTS WITH DIABETIC KIDNEY DISEASE. AB - BACKGROUND: Diabetes is currently the most common cause of kidney disease among patients receiving renal replacement therapy. Pedagogical interventions to promote self-management and secondary prevention have been shown to be effective in delaying disease progression. OBJECTIVES AND DESIGN: A non-randomised, quasi experimental design ('uncontrolled before and after') to evaluate the effects of a group-based, multidisciplinary and multidimensional support programme in patients with diabetic kidney disease. The programme comprised 1) Disease-related knowledge, 2) Skills training and increased self-care agency 3) A motivational approach, with group discussions, participant questions and narratives, setting and follow-up of individual health goals. PARTICIPANTS: Fifty-eight patients with diabetic kidney disease. OUTCOME MEASURES: Glycated haemoglobin (HbA1c), urine albumin/creatinine ratio, blood pressure, body mass index, waist, physical activity and participant experiences from the programme. RESULTS: The evaluation indicated positive effects on HbA1c, albuminuria and physical activity at follow up after four months. The proportion of patients achieving blood pressure targets increased. The participants reported improved understanding of their health condition and treatment regime. CONCLUSION: The multidimensional support programme, addressing health-promoting factors and self-management in small patient groups, has a potential to effectively reduce HbA1c and may have some beneficial effects which contribute to health promotion in patients with diabetic kidney disease. This mode of a multidimensional support programme should continue to develop, with longer term follow-up and further evaluations with appropriate research designs. PMID- 25739426 TI - Heat shock protein 90 is required for ex vivo neutrophil-driven autoantibody induced tissue damage in experimental epidermolysis bullosa acquisita. AB - A broad range of immunosuppressive and immunomodulatory effects of heat shock protein 90 (Hsp90) blockade has been described in models of autoimmune bullous diseases, but the direct contribution of this chaperone to neutrophil effector pathways in the context of autoantibody-driven blistering is generally unknown. Therefore, this has been addressed in the current study on the basis of the subepidermal blistering disease epidermolysis bullosa acquisita (EBA) characterized by autoantibodies against type VII collagen, in which a crucial role of neutrophils and both their reactive oxygen species and matrix metalloproteinases in mediating tissue injury has been established. First, the Hsp90 antagonist 17-DMAG dose-dependently inhibited dermal-epidermal separation ex vivo in cryosections of human skin induced by co-incubation of EBA patient autoantibodies with neutrophils from healthy blood donors. Next, 17-DMAG dose dependently suppressed production and release of reactive oxygen species by human neutrophils induced by both fMLP +/- LPS and EBA-specific immune complexes. In addition, co-immunoprecipitation studies revealed that extracellular Hsp90 interacted with secreted matrix metalloproteinases 2 and 12 in sera of EBA patients, suggesting that these basement membrane-degrading proteolytic enzymes are client proteins of Hsp90 and dependent on its chaperone function. Our findings add to the knowledge of the multimodal anti-inflammatory effects of Hsp90 blockade and implicate that Hsp90 is closely involved in the effector mechanisms of neutrophil-driven autoantibody-induced tissue damage, thus being a relevant therapeutic target in patients with neutrophil-mediated autoimmune diseases such as inflammatory types of EBA. PMID- 25739427 TI - Cartography of 5-HT1A and 5-HT2A Receptor Subtypes in Prefrontal Cortex and Its Projections. AB - Since the development of chemical neuroanatomical tools in the 1960s, a tremendous wealth of information has been generated on the anatomical components of the serotonergic system, at the microscopic level in the brain including the prefrontal cortex (PFC). The PFC receives a widespread distribution of serotonin (5-hydroxytryptamine, 5-HT) terminals from the median and dorsal raphe nuclei. 5 HT receptors were first visualized using radioligand autoradiography in the late 1980s and early 1990s and showed, in contrast to 5-HT innervation, a differential distribution of binding sites associated with different 5-HT receptor subtypes. Due to the cloning of the different 5-HT receptor subtype genes in the late 1980s and early 1990s, it was possible, using in situ hybridization histochemistry, to localize cells expressing mRNA for these receptors. Double in situ hybridization histochemistry and immunohistochemistry allowed for the chemical characterization of the phenotype of cells expressing 5-HT receptors. Tract tracing technology allowed a detailed cartography of the neuronal connections of PFC and other brain areas. Based on these data, maps have been constructed that reflect our current understanding of the different circuits where 5-HT receptors can modulate the electrophysiological, pharmacological, and behavioral functions of the PFC. We will review current knowledge regarding the cellular localization of 5-HT1A and 5 HT2A receptors in mammalian PFC and their possible functions in the neuronal circuits of the PFC. We will discuss data generated in our laboratory as well as in others, focusing on localization in the pyramidal and GABAergic neuronal cell populations in different mammalian species using molecular neuroanatomy and on the connections with other brain regions. PMID- 25739428 TI - Diagnosis of moyamoya disease: international standard and regional differences. AB - Moyamoya disease is a chronic, occlusive cerebrovascular disease with unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. These diagnostic criteria of the moyamoya disease, stated by the Research Committee on Spontaneous Occlusion of the Circle of Willis (moyamoya disease) in Japan, are well established and generally accepted as the definition of this rare entity. On the contrary to the diagnosis of definitive moyamoya disease, there is some confusion in the terminology and understanding of quasi moyamoya disease; moyamoya disease in association with various disease entities, such as atherosclerosis, autoimmune diseases, Down syndrome, etc. Although the clinical management is not affected by these semantic distinctions, terminological confusion may interfere with the international collaboration of the clinical investigation of these rare conditions. In this article, we sought to review the international standard and regional differences in the diagnosis of moyamoya disease and quasi-moyamoya disease. PMID- 25739429 TI - Visualization of periventricular collaterals in moyamoya disease with flow sensitive black-blood magnetic resonance angiography: preliminary experience. AB - Fragile abnormal collaterals in moyamoya disease, known as "moyamoya vessels," have rarely been defined. While flow-sensitive black-blood magnetic resonance angiography (FSBB-MRA) is a promising technique for visualizing perforating arteries, as of this writing no other reports exist regarding its application to moyamoya disease. Six adults with moyamoya disease underwent FSBB-MRA. It depicted abnormal collaterals as extended lenticulostriate, thalamic perforating, or choroidal arteries, which were all connected to the medullary or insular artery in the periventricular area and supplied the cortex. This preliminary case series illustrates the potential for FSBB-MRA to reveal abnormal moyamoya vessels, which could be reasonably defined as periventricular collaterals. PMID- 25739430 TI - Preliminary experience with air transfer of patients for rescue endovascular therapy after failure of intravenous tissue plasminogen activator. AB - The present report describes our experience with air transfer of patients with acute ischemic stroke in whom intravenous tissue plasminogen activator (IV t-PA) failed for rescue endovascular therapy (EVT). Twenty-three consecutive patients in whom IV t-PA failed were transferred to our hospital for rescue EVT between February 2011 and April 2013. The amount of time required for transfer, distance, clinical outcomes, and complications were compared between patients transferred by ground (TG group; n = 17) and by air (TA group; n = 6). Computed tomography imaging on arrival revealed hemorrhagic transformation in 1 (5.9%) patient in the TG group, whereas none of the patients in the TA group developed any type of complication. The remaining 22 patients received rescue EVT. The elapsed time from the request call to arrival at our hospital did not significantly differ between the TG and TA groups (45.8 +/- 4.9 min vs. 41.6 +/- 2.3 min). However, the distance from the primary hospital to our institution was significantly longer for the TA group than for the TG group (38.8 +/- 10.4 km vs. 13.5 +/- 1.2 km, p = 0.001). The frequency of favorable outcomes (modified Rankin Scale 0-1 at 90 days after onset) in the TG and TA groups were 25.0% and 50.0%, respectively (p = 0.267). Air transfer for patients after IV t-PA failure allowed for more rapid delivery of patients over longer distances than ground transfer. PMID- 25739431 TI - Risk factors and prevention of guiding catheter-induced vasospasm in neuroendovascular treatment. AB - Mechanically-induced vasospasm often occurs during guiding catheter insertion, occasionally preventing catheter advancement to the desired location. Delicate manipulation would be impossible without the proper positioning of guiding catheters, and vasospasm-induced cerebral hypoperfusion may cause thrombotic complications. From June 2012 to December 2013, we prospectively analyzed 150 endovascular treatment cases, excluding acute cases, for the frequency of vasospasm, risk factors, and countermeasures. The associated risk factors such as the Japanese-style State-Trait Anxiety Inventory (STAI) score; anatomy and devices; and the efficacies of warm compresses, intra-arterial lidocaine/nicardipine, and tranquilizers were analyzed. Groups 1, 2, and 3 comprised 50 patients each with controls, tranquilizer administration, and prophylactic warm compresses/intra-arterial drug injection, respectively. Moderate or severe vasospasm was seen in approximately 40% patients in each group; however, severe vasospasm was absent in Group 3. Mild vasospasm-induced cerebral infarction occurred in one patient each in Groups 1 and 2. Vasospasm during diagnostic angiography [odds ratio (OR) = 10.63; P = 0.01], many >= 30 degrees vessel curves [OR = 4.21; P = 0.01], and the high STAI score [OR = 1.84; P = 0.01] were risk factors for severe vasospasm. Although the relationship between anxiety and sympathetic tone remained unclear, tranquilizer administration relieved vasospasm. Warm compresses and the intra-arterial drug infusion were also useful for relieving vasospasm. Prophylactic measures such as a tranquilizer and warm compresses are expected to alleviate vasospasm; in addition, countermeasures such as the intra-arterial injection of lidocaine/nicardipine are effective. PMID- 25739432 TI - Endovascular embolization of brain arteriovenous malformations with Eudragit-E. AB - Eudragit-E was originally developed as a non-adhesive liquid embolic material in the late 1990s and is a copolymer of methyl and butyl methacrylate and dimethylaminoethyl methacrylate that is dissolved in ethanol and iopamidol. This material has been used for endovascular embolization of brain arteriovenous malformations (AVMs) for some time but is currently not widely used. Because safety and feasibility of Eudragit-E has not been well documented, we here report our experience using this material for treating 22 human brain AVMs. From June 1998 to February 2014, 30 endovascular procedures using Eudragit-E were performed to treat 22 patients, including 14 men and 8 women with a mean age of 41.1 years (15-70 years). The mean follow-up period was 56 months (12-129 months), and the Spetzler-Martin grades were I (4 patients), II (9 patients), III (5 patients), and IV (4 patients). Residual AVMs were treated with stereotactic radiosurgery or surgery. The rate of complete obliteration with embolization alone was 27.3%. The overall obliteration rate after endovascular embolization with/without subsequent stereotactic radiosurgery or surgery was 72.7%. Eudragit-E caused two cases of cerebral infarction. One case of intracerebral hemorrhage due to postoperative hemodynamic changes also occurred. The rate of complications directly related to embolization was 10.0%. The safety and effectiveness of Eudragit-E embolization were satisfactory. PMID- 25739433 TI - Effect of edaravone on favorable outcome in patients with acute cerebral large vessel occlusion: subanalysis of RESCUE-Japan Registry. AB - The data of the nationwide prospective registry of acute cerebral large vessel occlusion (LVO; RESCUE-Japan Registry) were analyzed to know the effect of edaravone, a free radical scavenger, on clinical outcome at 90 days after onset. In this registry, patients with acute cerebral LVO admitted within 24 h after onset were prospectively registered. The effect of various factors including endovascular treatment (EVT), intravenous recombinant tissue plasminogen activator (IV rt-PA), and other medication including edaravone on favorable outcome (modified Rankin scale 0-1) was analyzed. Of the 1,454 registered patients, 1,442 patients (99.2%) had the information of edaravone were analyzed. In total, edaravone group had more patients with favorable outcome compared to non-edaravone group (22.9% vs. 13.8%, p = 0.0006). Edaravone increased favorable outcome in patients treated with IV rt-PA (29.4% vs. 11.1%, p = 0.0107), but not with EVT (21.2% vs. 13.9%, p = 0.309). Logistic regression analysis revealed that higher National Institutes of Health Stroke Scale (NIHSS) score on admission [odds ratio (OR) 0.875, 95% confidence interval (CI) 0.858-0.894] and advanced age (OR 0.963, 95%CI 0.952-0.975) were significantly related to unfavorable outcome. In contrast, IV rt-PA (OR 2.489, 95%CI 1.867-3.319), EVT (OR 1.375, 95%CI 1.013-1.865), and edaravone (OR 1.483, 95%CI 1.027-2.143) were significantly associated with favorable outcome. This analysis indicated that IV rt-PA, EVT, and edaravone were effective to obtain favorable outcome in patients with acute LVO. Combination IV rt-PA with edaravone was more effective. PMID- 25739434 TI - Asymptomatic moyamoya disease: literature review and ongoing AMORE study. AB - Recent development of a non-invasive magnetic resonance examination has increased the opportunity to identify asymptomatic patients with moyamoya disease who have experienced no cerebrovascular events. However, their clinical features, prognosis, and treatment strategy are still unclear because of small number of subjects and short follow-up periods. Therefore, we have designed Asymptomatic Moyamoya Registry (AMORE) study in Japan. The objectives of this nation-wide, multi-center prospective study are to clarify long-term prognosis of asymptomatic patients with moyamoya disease and to determine the risk factors that cause ischemic and hemorrhagic stroke in them. In this article, we review the published data on asymptomatic moyamoya disease and report the on-going multi-center prospective cohort study, AMORE study. We would like to emphasize the importance to determine the clinical features, prognosis, and treatment strategies of asymptomatic moyamoya disease in very near future. PMID- 25739435 TI - Cognitive Dysfunction Survey of the Japanese Patients with Moyamoya Disease (COSMO-JAPAN Study): study protocol. AB - Moyamoya disease is a cerebrovascular occlusive disease characterized by progressive stenosis or by occlusion at the terminal portion of the bilateral internal carotid arteries. The unusual vascular network (moyamoya vessels) at the base of the brain with this disease as collateral channels is developed in this disease. Social independence because of cognitive impairment has recently been recognized as an important unsolved social issue with adult moyamoya disease. The patients with cognitive impairment have difficulty in proving their status because the standard neuroradiological and neuropsychological methods to define cognitive impairment with moyamoya disease are not determined. These patients with cognitive impairment should be supported by social welfare as psychologically handicapped persons. Thus Cognitive Dysfunction Survey of the Japanese Patients with Moyamoya Disease (COSMO-JAPAN study) is planned. In this study, we want to establish a standard finding of the cognitive impairment in patients with moyamoya disease. PMID- 25739436 TI - Zigzag skin incision effectively camouflages the scar and alopecia for moyamoya disease: technical note. AB - Moyamoya disease is commonly diagnosed in children, and requires various vascular reconstruction to improve symptoms. Therefore, scar widening and hair loss after craniotomy, which sometimes occurs in this disease, are serious problems for patients. A variety of plastic surgical techniques in scalp have been reported to minimize the scar widening and hair loss. However, any neurosurgical reports describing this purpose have never been published for moyamoya disease. The objective of this study was to investigate whether these plastic surgical techniques could be applied to bypass surgery without any compromise of vascular reconstruction for moyamoya disease. We performed direct and indirect vascular reconstruction in six hemispheres of moyamoya disease patients not only in the middle cerebral artery territory but also in the anterior cerebral artery territory. The scalp incision was designed not parallel to the hair stream, and the bevelled incision was conducted not to jeopardize the hair follicles. The scar and hair loss were effectively camouflaged throughout the postoperative period in all cases. This study demonstrates that our design of scalp incision achieve effective vascular reconstruction and obscure the scar and hair loss. PMID- 25739437 TI - Evidence for management of carotid artery stenosis. AB - In this review, we presented the evidence concerning carotid artery stenosis treatment in symptomatic stenosis and asymptomatic stenosis separately, and discussed the future challenges. The validity of carotid endarterectomy (CEA) to treat moderate or greater degree of symptomatic carotid artery stenosis appears to be established. Due to the additional option of carotid artery stenting (CAS), it is necessary to comprehensively determine whether CEA or CAS is more appropriate for each individual patient. Moreover, since there are rapid advancements in devices for CAS and improvements in treatment outcomes, continual learning of the latest treatment method is essential. For asymptomatic stenosis, due to improvements in the outcomes with best medical treatment (BMT), it is essential to re-evaluate the use of invasive CEA/CAS. Continual verification of the latest randomized clinical trial that compares CEA, CAS, and BMT, and establishment of a diagnostic method that can accurately extract the group of patients who have the highest future risk of developing ischemia, are desired. PMID- 25739438 TI - Metabotropic glutamate receptor 3 is downregulated and its expression is shifted from neurons to astrocytes in the mouse lateral septum during the postpartum period. AB - The inhibitory metabotropic glutamate receptor 3 (mGluR3) plays diverse and complex roles in brain function, including synaptic plasticity and neurotransmission. We recently found that mGluR3 is downregulated in the lateral septum (LS) of postpartum females using microarray and qPCR analysis. In this study, we used double fluorescence immunohistochemical approaches to characterize mGluR3 changes in LS of the postpartum brain. The number of mGluR3-immunoractive cells was significantly reduced in the dorsal (LSD) and intermediate (LSI) but not ventral (LSV) parts of the LS in postpartum versus virgin females. mGluR3 immunoreactivity in the LS was found predominantly in neurons (~70%), with a smaller portion (~20%-30%) in astrocytes. Colocalization analysis revealed a reduced mGluR3 expression in neurons but an increased astrocytic localization in postpartum LSI. This change in the pattern of expression suggests that mGluR3 expression is shifted from neurons to astrocytes in postpartum LS, and the decrease in mGluR3 is neuron-specific. Because mGluR3 is inhibitory and negatively regulates glutamate and GABA release, decreases in neuronal expression would increase glutamate and GABA signaling. Given our recent finding that ~90% of LS neurons are GABAergic, the present data suggest that decreases in mGluR3 are a mechanism for elevated GABA in LS in the postpartum state. PMID- 25739439 TI - Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration. AB - Complement 5a (C5a), a potent immune mediator generated by complement activation, promotes tumor growth; however, its role in tumor metastasis remains unclear. We demonstrate that C5a contributes to tumor metastases by modulating tumor inflammation in hepatic metastases of colon cancer. Colon cancer cell lines generate C5a under serum-free conditions, and C5a levels increase over time in a murine syngeneic colon cancer hepatic metastasis model. Furthermore, in the absence of C5a receptor or upon pharmacological inhibition of C5a production with an anti-C5 monoclonal antibody, tumor metastasis is severely impaired. A lack of C5a receptor in colon cancer metastatic foci reduces the infiltration of macrophages, neutrophils, and dendritic cells, and the role for C5a receptor on these cells were further verified by bone marrow transplantation experiments. Moreover, C5a signaling increases the expression of the chemokine monocyte chemoattractant protein-1 and the anti-inflammatory molecules arginase-1, interleukin 10, and transforming growth factor beta, but is inversely correlated with the expression of pro-inflammatory molecules, which suggests a mechanism for the role of C5a in the inflammatory microenvironment required for tumor metastasis. Our results indicate a new and potentially promising therapeutic application of complement C5a inhibitor for the treatment of malignant tumors. PMID- 25739441 TI - Endoplasmic reticulum (ER) localization is critical for DsbA-L protein to suppress ER stress and adiponectin down-regulation in adipocytes. AB - Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions. We previously reported that adiponectin multimerization and stability are promoted by the disulfide bond A oxidoreductase-like protein (DsbA-L) in cells and in vivo. However, the precise mechanism by which DsbA-L regulates adiponectin biosynthesis remains elusive. Here we show that DsbA-L is co localized with the endoplasmic reticulum (ER) marker protein disulfide isomerase and the mitochondrial marker MitoTracker. In addition, DsbA-L interacts with the ER chaperone protein Ero1-Lalpha in 3T3-L1 adipocytes. In silico analysis and truncation mapping studies revealed that DsbA-L contains an ER targeting signal at its N terminus. Deletion of the first 6 residues at the N terminus greatly impaired DsbA-L localization in the ER. Overexpression of the wild type but not the ER localization-defective mutant of DsbA-L protects against thapsigargin induced ER stress and adiponectin down-regulation in 3T3-L1 adipocytes. In addition, overexpression of the wild type but not the ER localization-defective mutant of DsbA-L promotes adiponectin multimerization. Together, our results reveal that DsbA-L is localized in both the mitochondria and the ER in adipocytes and that its ER localization plays a critical role in suppressing ER stress and promoting adiponectin biosynthesis and secretion. PMID- 25739440 TI - Targeted ablation of the Pde6h gene in mice reveals cross-species differences in cone and rod phototransduction protein isoform inventory. AB - Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3',5' monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h(-/ )) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h(-/-) retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h(-/-) mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. PMID- 25739442 TI - A conserved glutamate residue in the C-terminal deaminase domain of pentatricopeptide repeat proteins is required for RNA editing activity. AB - Many transcripts expressed from plant organelle genomes are modified by C-to-U RNA editing. Nuclear encoded pentatricopeptide repeat (PPR) proteins include an RNA binding domain that provides site specificity. In addition, many PPR proteins include a C-terminal DYW deaminase domain with characteristic zinc binding motifs (CXXC, HXE) and has recently been shown to bind zinc ions. The glutamate residue of the HXE motif is catalytically required in the reaction catalyzed by cytidine deaminase. In this work, we examine the activity of the DYW deaminase domain through truncation or mutagenesis of the HXE motif. OTP84 is required for editing three chloroplast sites, and transgenes expressing OTP84 with C-terminal truncations were capable of editing only one of the three cognate sites at high efficiency. These results suggest that the deaminase domain of OTP84 is required for editing two of the sites, but another deaminase is able to supply the deamination activity for the third site. OTP84 and CREF7 transgenes were mutagenized to replace the glutamate residue of the HXE motif, and transgenic plants expressing OTP84-E824A and CREF7-E554A were unable to efficiently edit the cognate editing sites for these genes. In addition, plants expressing CREF7-E554A exhibited substantially reduced capacity to edit a non-cognate site, rpoA C200. These results indicate that the DYW deaminase domains of PPR proteins are involved in editing their cognate editing sites, and in some cases may participate in editing additional sites in the chloroplast. PMID- 25739444 TI - The outcome of pulmonary vein thrombosis in non-surgical patients. A systematic review and case report. PMID- 25739443 TI - Population structure of Endomicrobia in single host cells of termite gut flagellates (Trichonympha spp.). AB - The gut microbiota of many phylogenetically lower termites is dominated by the cellulolytic flagellates of the genus Trichonympha, which are consistently associated with bacterial symbionts. In the case of Endomicrobia, an unusual lineage of endosymbionts of the Elusimicrobia phylum that is also present in other gut flagellates, previous studies have documented strict host specificity, leading to the cospeciation of "Candidatus Endomicrobium trichonymphae" with their respective flagellate hosts. However, it currently remains unclear whether one Trichonympha species is capable of harboring more than one Endomicrobia phylotype. In the present study, we selected single Trichonympha cells from the guts of Zootermopsis nevadensis and Reticulitermes santonensis and characterized their Endomicrobia populations based on internal transcribed spacer (ITS) region sequences. We found that each host cell harbored a homogeneous population of symbionts that were specific to their respective host species, but phylogenetically distinct between each host lineage, corroborating cospeciation being caused by vertical inheritance. The experimental design of the present study also allowed for the identification of an unexpectedly large amount of tag switching between samples, which indicated that any high-resolution analysis of microbial community structures using the pyrosequencing technique has to be interpreted with great caution. PMID- 25739446 TI - A DFT+nonhomogeneous DMFT approach for finite systems. AB - For reliable and efficient inclusion of electron-electron correlation effects in nanosystems we formulate a combined density functional theory/nonhomogeneous dynamical mean-field theory (DFT+DMFT) approach which employs an approximate iterated perturbation theory impurity solver. We further apply the method to examine the size-dependent magnetic properties of iron nanoparticles containing 11-100 atoms. We show that for the majority of clusters the DFT+DMFT solution is in very good agreement with experimental data, much better compared to the DFT and DFT+U results. In particular, it reproduces the oscillations in magnetic moment with size as observed experimentally. We thus demonstrate that the DFT+DMFT approach can be used for accurate and realistic description of nanosystems containing about hundred atoms. PMID- 25739445 TI - Functionalized triazolopeptoids--a novel class for mitochondrial targeted delivery. AB - Here we introduce linear 1,4-triazolopeptoids as a novel class of cell penetrating peptidomimetics suitable as organ targeting molecular transporters of bioactive cargo. Repetitive triazole moieties with up to three residues were assembled on solid supports using copper-catalyzed alkyne-azide cycloadditions (CuAAC) in a submonomer approach. Depending on the lipophilicity of their side chain appendages the 1,4-triazolopeptoids showed either endosomal localization or a strong colocalization with the mitochondria of HeLa cells with moderate toxicity. While the basic triazolopeptoids mainly target the neuromast cells in zebrafish embryos, the lipophilic ones colocalize with either cartilage in the jaws and the blood vessel system. PMID- 25739447 TI - The titanium tris-anilide cation [Ti(N[(t)Bu]Ar)3](+) stabilized as its perfluoro tetra-phenylborate salt: structural characterization and synthesis in connection with redox activity of 4,4'-bipyridine dititanium complexes. AB - This work explores the reduction of 4,4'-bipyridine using two equivalents of the titanium(iii) complex Ti(N[(t)Bu]Ar)3 resulting in formation of a black, crystalline complex, (4,4'-bipy){Ti(N[(t)Bu]Ar)3}2, for which an X-ray structure determination is reported. The neutral, black, 4,4'-bipyridine-bridged bimetallic was found to be redox active, with mono- and di-anions being accessible electrochemically, and with the mono- and di-cations also being accessible chemically, and isolable, at least when using the weakly coordinating anion [B(C6F5)4](-) as the counter-ion. It proved possible to crystallize the salt [(4,4'-bipy){Ti(N[(t)Bu]Ar)3}2][B(C6F5)4]2 for a single-crystal X-ray structure investigation; in this instance it was revealed that the aromaticity of the 4,4' bipyridine ligand, that had been disrupted upon reduction, had been regained. A rare cationic d(0) metal tris-amide complex, shown by X-ray crystallography to contain an intriguing pyramidal TiN3 core geometry, namely {Ti(N[(t)Bu]Ar)3}(+), could also be isolated when using [B(C6F5)4] as the essentially non-interacting counter-ion. This highly reactive cation should be considered as a potential intermediate in the plethora of reactions wherein Ti(N[(t)Bu]Ar)3 has been shown to effect the reduction of substrates including halogenated organic molecules, carbonyl compounds, organic nitriles, and metal complexes. PMID- 25739448 TI - Close-packed two-dimensional silver nanoparticle arrays: quadrupolar and dipolar surface plasmon resonance coupling. AB - Silver nanoparticles (NPs) ranging in size from 40 to 100 nm were prepared in high yield by using an improved seed-mediated method. The homogeneous Ag NPs were used as building blocks for 2D assembled Ag NP arrays by using an oil/water interface. A close-packed 2D array of Ag NPs was fabricated by using packing molecules (3-mercaptopropyltrimethoxysilane) to control the interparticle spacing. The homogeneous 2D Ag NP array exhibited a strong quadrupolar cooperative plasmon mode resonance and a dipolar red-shift relative to individual Ag NPs suspended in solution. A well-arranged 2D Ag NP array was embedded in polydimethylsiloxane film and, with biaxial stretching to control the interparticle distance, concomitant variations of the quadrupolar and dipolar couplings were observed. As the interparticle distance increased, the intensity of the quadrupolar cooperative plasmon mode resonance decreased and dipolar coupling completely disappeared. The local electric field of the 2D Ag NP array was calculated by using finite difference time domain simulation and qualitatively showed agreement with the experimental measurements. PMID- 25739449 TI - Leaders needed! Message from the president. PMID- 25739450 TI - Synthesis and luminescence of Eu(3+)-doped in triple phosphate Ca8MgBi(PO4)7 with whitlockite structure. AB - Triple whitlockite-type structure-based red phosphors Ca8 MgBi1-x(PO4)7:xEu(3+) (x = 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80 and 1.00) were synthesized by a conventional solid-state reaction route and characterized by their X-ray crystal structures. The X-ray diffraction (XRD) patterns, Fourier transform infrared spectra, morphologies, photoluminescence spectra, UV/Vis reflectance spectra, decay times and the International Commission on Illumination (CIE) chromaticity coordinates of Ca8MgBi1-x(PO4)7:xEu(3+) were analyzed. Eu-doped Ca8MgBi(PO4)7 phosphors exhibited strong red luminescence with peaks at 616 nm due to the (5)D0 -> (7)F2 electric dipole transition of Eu(3+) ions after excitation at 396 nm. The UV/Vis spectra indicated that the band gap of Ca8MgBi0.30(PO4)7:0.70Eu(3+) is larger than that of Ca8MgBi(PO4)7. The phosphor developed in this study has great potential as a red-light-emitting phosphor for UV light-emitting diodes. PMID- 25739451 TI - Left Ventricular Twist Mechanics Are Impaired in Patients with Coronary Slow Flow. AB - PURPOSE: Coronary slow flow (CSF) is a rare condition described as the delayed angiographic passage of a contrast agent in the absence of stenosis in epicardial coronary arteries. Left ventricular (LV) systolic and diastolic dysfunctions have been described in the presence of CSF. However, the effect of CSF on LV twist functions has not been assessed. We aimed to evaluate the effects of CSF on LV twist mechanics using speckle tracking echocardiography (STE). METHODS: Twenty CSF patients (24-60 years) were enrolled according to the exclusion criteria. Twenty subjects with similar demographic characteristics and normal coronary arteries were the controls. Participants were evaluated with conventional echocardiography and STE. RESULTS: The general characteristics of the two groups were similar. LV twist, LV torsion, and apical rotation were impaired in the CSF group (P = 0.015, P = 0.012, and P < 0.001, respectively). Time to peak twist (TPT) and time to peak untwisting (TPU) were prolonged in CSF patients (P < 0.001 and P < 0.001, respectively). In the CSF group, rotation-deformation delay was shortened (P < 0.001) and global longitudinal strain (GLS) was lower (P < 0.001). The thrombolysis in myocardial infarction (TIMI) frame count was negatively correlated with LV twist, LV torsion and apical rotation (P = 0.002, r = -0.624; P = 0.002, r = -0.624; and P = 0.002, r = -0.632, respectively). CONCLUSIONS: We demonstrated that LV twist mechanics are impaired in CSF patients. Worse LV twist parameters were associated with greater TIMI frame count. PMID- 25739452 TI - Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis. AB - Polarized membrane morphogenesis is a fundamental activity of eukaryotic cells. This process is essential for the biology of cells and tissues, and its execution demands exquisite temporal coordination of functionally diverse membrane signaling reactions with high spatial resolution. Moreover, mechanisms must exist to establish and preserve such organization in the face of randomizing forces that would diffuse it. Here we identify the conserved AtSfh1 Sec14-nodulin protein as a novel effector of phosphoinositide signaling in the extreme polarized membrane growth program exhibited by growing Arabidopsis root hairs. The data are consistent with Sec14-nodulin proteins controlling the lateral organization of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) landmarks for polarized membrane morphogenesis in plants. This patterning activity requires both the PtdIns(4,5)P2 binding and homo-oligomerization activities of the AtSfh1 nodulin domain and is an essential aspect of the polarity signaling program in root hairs. Finally, the data suggest a general principle for how the phosphoinositide signaling landscape is physically bit mapped so that eukaryotic cells are able to convert a membrane surface into a high-definition lipid signaling screen. PMID- 25739453 TI - Homer3 regulates the establishment of neutrophil polarity. AB - Most chemoattractants rely on activation of the heterotrimeric G-protein Galphai to regulate directional cell migration, but few links from Galphai to chemotactic effectors are known. Through affinity chromatography using primary neutrophil lysate, we identify Homer3 as a novel Galphai2-binding protein. RNA interference mediated knockdown of Homer3 in neutrophil-like HL-60 cells impairs chemotaxis and the establishment of polarity of phosphatidylinositol 3,4,5-triphosphate (PIP3) and the actin cytoskeleton, as well as the persistence of the WAVE2 complex. Most previously characterized proteins that are required for cell polarity are needed for actin assembly or activation of core chemotactic effectors such as the Rac GTPase. In contrast, Homer3-knockdown cells show normal magnitude and kinetics of chemoattractant-induced activation of phosphoinositide 3-kinase and Rac effectors. Chemoattractant-stimulated Homer3-knockdown cells also exhibit a normal initial magnitude of actin polymerization but fail to polarize actin assembly and intracellular PIP3 and are defective in the initiation of cell polarity and motility. Our data suggest that Homer3 acts as a scaffold that spatially organizes actin assembly to support neutrophil polarity and motility downstream of GPCR activation. PMID- 25739454 TI - Hsp70 clears misfolded kinases that partitioned into distinct quality-control compartments. AB - Hsp70 aids in protein folding and directs misfolded proteins to the cellular degradation machinery. We describe discrete roles of Hsp70,SSA1 as an important quality-control machinery that switches functions to ameliorate the cellular environment. SSA1 facilitates folding/maturation of newly synthesized protein kinases by aiding their phosphorylation process and also stimulates ubiquitylation and degradation of kinases in regular protein turnover or during stress when kinases are denatured or improperly folded. Significantly, while kinases accumulate as insoluble inclusions upon SSA1 inhibition, they form soluble inclusions upon Hsp90 inhibition or stress foci during heat stress. This suggests formation of inclusion-specific quality-control compartments under various stress conditions. Up-regulation of SSA1 results in complete removal of these inclusions by the proteasome. Elevation of the cellular SSA1 level accelerates kinase turnover and protects cells from proteotoxic stress. Upon overexpression, SSA1 targets heat-denatured kinases toward degradation, which could enable them to recover their functional state under physiological conditions. Thus active participation of SSA1 in the degradation of misfolded proteins establishes an essential role of Hsp70 in deciding client fate during stress. PMID- 25739455 TI - A novel function for the Caenorhabditis elegans torsin OOC-5 in nucleoporin localization and nuclear import. AB - Torsin proteins are AAA+ ATPases that localize to the endoplasmic reticular/nuclear envelope (ER/NE) lumen. A mutation that markedly impairs torsinA function causes the CNS disorder DYT1 dystonia. Abnormalities of NE membranes have been linked to torsinA loss of function and the pathogenesis of DYT1 dystonia, leading us to investigate the role of the Caenorhabditis elegans torsinA homologue OOC-5 at the NE. We report a novel role for torsin in nuclear pore biology. In ooc-5-mutant germ cell nuclei, nucleoporins (Nups) were mislocalized in large plaques beginning at meiotic entry and persisted throughout meiosis. Moreover, the KASH protein ZYG-12 was mislocalized in ooc-5 gonads. Nups were mislocalized in adult intestinal nuclei and in embryos from mutant mothers. EM analysis revealed vesicle-like structures in the perinuclear space of intestinal and germ cell nuclei, similar to defects reported in torsin-mutant flies and mice. Consistent with a functional disruption of Nups, ooc-5-mutant embryos displayed impaired nuclear import kinetics, although the nuclear pore size exclusion barrier was maintained. Our data are the first to demonstrate a requirement for a torsin for normal Nup localization and function and suggest that these functions are likely conserved. PMID- 25739456 TI - The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin. AB - Kv1.3 channels play a pivotal role in the activation and migration of T lymphocytes. These functions are accompanied by the channels' polarization, which is essential for associated downstream events. However, the mechanisms that govern the membrane movement of Kv1.3 channels remain unclear. F-actin polymerization occurs concomitantly to channel polarization, implicating the actin cytoskeleton in this process. Here we show that cortactin, a factor initiating the actin network, controls the membrane mobilization of Kv1.3 channels. FRAP with EGFP-tagged Kv1.3 channels demonstrates that knocking down cortactin decreases the actin-based immobilization of the channels. Using various deletion and mutation constructs, we show that the SH3 motif of Kv1.3 mediates the channel immobilization. Proximity ligation assays indicate that deletion or mutation of the SH3 motif also disrupts interaction of the channel with cortactin. In T-lymphocytes, the interaction between HS1 (the cortactin homologue) and Kv1.3 occurs at the immune synapse and requires the channel's C terminal domain. These results show that actin dynamics regulates the membrane motility of Kv1.3 channels. They also provide evidence that the SH3 motif of the channel and cortactin plays key roles in this process. PMID- 25739459 TI - Barriers to treatment for older adults seeking psychological therapy. AB - BACKGROUND: Older adults with mental health disorders underutilize mental health services more than other adults. While there are well known general barriers to help seeking across the population, specific barriers for older adults include difficulties with transportation, beliefs that it is normal to be anxious and depressed in old age, and beliefs by referrers that psychological therapy is less likely to be effective. This study examined barriers related to identifying the need for help, seeking help and participating in therapy in a clinical population of older adults. METHOD: Sixty older adults (aged 60-79 years) with comorbid anxiety and unipolar mood disorders completed barriers to treatment questionnaires before and after psychological group treatment, as well as measures of cognitive ability, anxiety, depression, and quality of life at baseline. RESULTS: The greatest barriers to help seeking related to difficulties identifying the need for help, with 50% of the sample reporting their belief that their symptoms were normal as a major barrier. Other major barriers identified were related to: self-reliance, cost of treatment, and fear of medication replicating previous findings. The main barriers reported for difficulties in continuing therapy included not finding therapy helpful, cost of treatment, and thinking that the therapist did not understand their issues. CONCLUSIONS: The main barriers identified related to issues with identifying the need to seek help. More attention is needed to educate older adults and professionals about the need for, and effectiveness of, psychological therapies for older adults with anxiety and depression to reduce this barrier to help seeking. PMID- 25739458 TI - Wash functions downstream of Rho1 GTPase in a subset of Drosophila immune cell developmental migrations. AB - Drosophila immune cells, the hemocytes, undergo four stereotypical developmental migrations to populate the embryo, where they provide immune reconnoitering, as well as a number of non-immune-related functions necessary for proper embryogenesis. Here, we describe a role for Rho1 in one of these developmental migrations in which posteriorly located hemocytes migrate toward the head. This migration requires the interaction of Rho1 with its downstream effector Wash, a Wiskott-Aldrich syndrome family protein. Both Wash knockdown and a Rho1 transgene harboring a mutation that prevents Wash binding exhibit the same developmental migratory defect as Rho1 knockdown. Wash activates the Arp2/3 complex, whose activity is needed for this migration, whereas members of the WASH regulatory complex (SWIP, Strumpellin, and CCDC53) are not. Our results suggest a WASH complex-independent signaling pathway to regulate the cytoskeleton during a subset of hemocyte developmental migrations. PMID- 25739457 TI - Basolateral sorting of chloride channel 2 is mediated by interactions between a dileucine motif and the clathrin adaptor AP-1. AB - In spite of the many key cellular functions of chloride channels, the mechanisms that mediate their subcellular localization are largely unknown. ClC-2 is a ubiquitous chloride channel usually localized to the basolateral domain of epithelia that regulates cell volume, ion transport, and acid-base balance; mice knocked out for ClC-2 are blind and sterile. Previous work suggested that CLC-2 is sorted basolaterally by TIFS(812)LL, a dileucine motif in CLC-2's C-terminal domain. However, our in silico modeling of ClC-2 suggested that this motif was buried within the channel's dimerization interface and identified two cytoplasmically exposed dileucine motifs, ESMI(623)LL and QVVA(635)LL, as candidate sorting signals. Alanine mutagenesis and trafficking assays support a scenario in which ESMI(623)LL acts as the authentic basolateral signal of ClC-2. Silencing experiments and yeast three-hybrid assays demonstrated that both ubiquitous (AP-1A) and epithelium-specific (AP-1B) forms of the tetrameric clathrin adaptor AP-1 are capable of carrying out basolateral sorting of ClC-2 through interactions of ESMI(623)LL with a highly conserved pocket in their gamma1-sigma1A hemicomplex. PMID- 25739460 TI - Food supplementation for improving the physical and psychosocial health of socio economically disadvantaged children aged three months to five years. AB - BACKGROUND: Undernutrition contributes to five million deaths of children under five each year. Furthermore, throughout the life cycle, undernutrition contributes to increased risk of infection, poor cognitive functioning, chronic disease, and mortality. It is thus important for decision-makers to have evidence about the effectiveness of nutrition interventions for young children. OBJECTIVES: Primary objective1. To assess the effectiveness of supplementary feeding interventions, alone or with co-intervention, for improving the physical and psychosocial health of disadvantaged children aged three months to five years.Secondary objectives1. To assess the potential of such programmes to reduce socio-economic inequalities in undernutrition.2. To evaluate implementation and to understand how this may impact on outcomes.3. To determine whether there are any adverse effects of supplementary feeding. SEARCH METHODS: We searched CENTRAL, Ovid MEDLINE, PsycINFO, and seven other databases for all available years up to January 2014. We also searched ClinicalTrials.gov and several sources of grey literature. In addition, we searched the reference lists of relevant articles and reviews, and asked experts in the area about ongoing and unpublished trials. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster-RCTs, controlled clinical trials (CCTs), controlled before-and-after studies (CBAs), and interrupted time series (ITS) that provided supplementary food (with or without co-intervention) to children aged three months to five years, from all countries. Adjunctive treatments, such as nutrition education, were allowed. Controls had to be untreated. DATA COLLECTION AND ANALYSIS: Two or more review authors independently reviewed searches, selected studies for inclusion or exclusion, extracted data, and assessed risk of bias. We conducted meta-analyses for continuous data using the mean difference (MD) or the standardised mean difference (SMD) with a 95% confidence interval (CI), correcting for clustering if necessary. We analysed studies from low- and middle-income countries and from high-income countries separately, and RCTs separately from CBAs. We conducted a process evaluation to understand which factors impact on effectiveness. MAIN RESULTS: We included 32 studies (21 RCTs and 11 CBAs); 26 of these (16 RCTs and 10 CBAs) were in meta-analyses. More than 50% of the RCTs were judged to have low risk of bias for random selection and incomplete outcome assessment. We judged most RCTS to be unclear for allocation concealment, blinding of outcome assessment, and selective outcome reporting. Because children and parents knew that they were given food, we judged blinding of participants and personnel to be at high risk for all studies.Growth. Supplementary feeding had positive effects on growth in low- and middle-income countries. Meta-analysis of the RCTs showed that supplemented children gained an average of 0.12 kg more than controls over six months (95% confidence interval (CI) 0.05 to 0.18, 9 trials, 1057 participants, moderate quality evidence). In the CBAs, the effect was similar; 0.24 kg over a year (95% CI 0.09 to 0.39, 1784 participants, very low quality evidence). In high-income countries, one RCT found no difference in weight, but in a CBA with 116 Aboriginal children in Australia, the effect on weight was 0.95 kg (95% CI 0.58 to 1.33). For height, meta-analysis of nine RCTs revealed that supplemented children grew an average of 0.27 cm more over six months than those who were not supplemented (95% CI 0.07 to 0.48, 1463 participants, moderate quality evidence). Meta-analysis of seven CBAs showed no evidence of an effect (mean difference (MD) 0.52 cm, 95% CI -0.07 to 1.10, 7 trials, 1782 participants, very low quality evidence). Meta-analyses of the RCTs demonstrated benefits for weight-for-age z-scores (WAZ) (MD 0.15, 95% CI 0.05 to 0.24, 8 trials, 1565 participants, moderate quality evidence), and height-for-age z-scores (HAZ) (MD 0.15, 95% CI 0.06 to 0.24, 9 trials, 4638 participants, moderate quality evidence), but not for weight-for-height z-scores MD 0.10 (95% CI -0.02 to 0.22, 7 trials, 4176 participants, moderate quality evidence). Meta-analyses of the CBAs showed no effects on WAZ, HAZ, or WHZ (very low quality evidence). We found moderate positive effects for haemoglobin (SMD 0.49, 95% CI 0.07 to 0.91, 5 trials, 300 participants) in a meta-analysis of the RCTs.Psychosocial outcomes. Eight RCTs in low- and middle-income countries assessed psychosocial outcomes. Our meta-analysis of two studies showed moderate positive effects of feeding on psychomotor development (SMD 0.41, 95% CI 0.10 to 0.72, 178 participants). The evidence of effects on cognitive development was sparse and mixed.We found evidence of substantial leakage. When feeding was given at home, children benefited from only 36% of the energy in the supplement. However, when the supplementary food was given in day cares or feeding centres, there was less leakage; children took in 85% of the energy provided in the supplement. Supplementary food was generally more effective for younger children (less than two years of age) and for those who were poorer/ less well-nourished. Results for sex were equivocal. Our results also suggested that feeding programmes which were given in day-care/feeding centres and those which provided a moderate-to-high proportion of the recommended daily intake (% RDI) for energy were more effective. AUTHORS' CONCLUSIONS: Feeding programmes for young children in low- and middle-income countries can work, but good implementation is key. PMID- 25739461 TI - The minimum peptides of IGF-1 and substance P protect vestibular hair cells against neomycin ototoxicity. AB - CONCLUSIONS: Our data indicate that SSSR and SSSR + FGLM-NH2 protect sensory hair cells against neomycin-induced death in the vestibular epithelium. In addition, the results show that SSSR and FGLM-NH2 can be used as protective molecules against aminoglycoside ototoxicity. OBJECTIVES: This study investigated the role of the peptides SSSR and SSSR + FGLM-NH2 in mammalian vestibular hair cell death induced by aminoglycoside. METHODS: Cultured utricles from mature CBA/N mice were used in this study. The cultured utricles were assigned to five groups (control group, neomycin group, neomycin + SSSR group, neomycin + FGLM-NH2 group, and neomycin + SSSR + FGLM-NH2 group). Aat 24 h after exposure to neomycin, the hair cells were labeled immunohistochemically, and the rate of survival of vestibular hair cells was evaluated using a fluorescence microscope. RESULTS: The rate of survival of vestibular hair cells was significantly higher in the neomycin + SSSR and neomycin + SSSR + FGLM-NH2 groups than in the neomycin group. The results suggest that SSSR could protect hair cells against aminoglycoside ototoxicity. PMID- 25739462 TI - One-step high-efficiency CRISPR/Cas9-mediated genome editing in Streptomyces. AB - The RNA-guided DNA editing technology CRISPRs (clustered regularly interspaced short palindromic repeats)/Cas9 had been used to introduce double-stranded breaks into genomes and to direct subsequent site-specific insertions/deletions or the replacement of genetic material in bacteria, such as Escherichia coli, Streptococcus pneumonia, and Lactobacillus reuteri. In this study, we established a high-efficiency CRISPR/Cas9 genome editing plasmid pKCcas9dO for use in Streptomyces genetic manipulation, which comprises a target-specific guide RNA, a codon-optimized cas9, and two homology-directed repair templates. By delivering pKCcas9dO series editing plasmids into the model strain Streptomyces coelicolor M145, through one-step intergeneric transfer, we achieved the genome editing at different levels with high efficiencies of 60%-100%, including single gene deletion, such as actII-orf4, redD, and glnR, and single large-size gene cluster deletion, such as the antibiotic biosynthetic clusters of actinorhodin (ACT) (21.3 kb), undecylprodigiosin (RED) (31.6 kb), and Ca(2+)-dependent antibiotic (82.8 kb). Furthermore, we also realized simultaneous deletions of actII-orf4 and redD, and of the ACT and RED biosynthetic gene clusters with high efficiencies of 54% and 45%, respectively. Finally, we applied this system to introduce nucleotide point mutations into the rpsL gene, which conferred the mutants with resistance to streptomycin. Notably, using this system, the time required for one round of genome modification is reduced by one-third or one-half of those for conventional methods. These results clearly indicate that the established CRISPR/Cas9 genome editing system substantially improves the genome editing efficiency compared with the currently existing methods in Streptomyces, and it has promise for application to genome modification in other Actinomyces species. PMID- 25739463 TI - Uterine artery impedance during the first eight postpartum weeks. AB - The aim of this study was to construct reference ranges for the uterine artery (UtA) mean pulsatility (PI) and resistance (RI) indices from 1-8 weeks postpartum. A prospective, cross-sectional, and observational study was performed with 320 healthy women from week 1 through week 8 postpartum. UtAs were examined transvaginally using colour and pulsed Doppler imaging, and the means of the right and left values of the PI and RI, as well as the presence or absence of a bilateral protodiastolic notch, were recorded. The 5(th), 50(th) and 95(th) reference percentile curves for the UtA-PI and UtA-RI were derived using regression models. The adjusted reference intervals uncovered a convergence trend at the week 8 time-point, although impedance was lower at the week 1 time-point in multiparous women compared with primiparous women. The notching prevalence was 22.5% (9/40) at week 1 and 95.0% (38/40) at week 8. The study revealed consistent evidence of a progressive increase of postpartum uterine impedance and provided new average UtA-PI and UtA-RI reference charts for weeks 1 through 8. Multiparity does not change the trend but does impart a lower rate of increase, likely as a consequence of previous vascular structural and functional differences. PMID- 25739464 TI - Deep vein puncture under ultrasonographic guidance-an alternative approach for vascular access of apheresis therapies. PMID- 25739465 TI - A classical treatment of optical tunneling in plasmonic gaps: extending the quantum corrected model to practical situations. AB - The optical response of plasmonic nanogaps is challenging to address when the separation between the two nanoparticles forming the gap is reduced to a few nanometers or even subnanometer distances. We have compared results of the plasmon response within different levels of approximation, and identified a classical local regime, a nonlocal regime and a quantum regime of interaction. For separations of a few Angstroms, in the quantum regime, optical tunneling can occur, strongly modifying the optics of the nanogap. We have considered a classical effective model, so called Quantum Corrected Model (QCM), that has been introduced to correctly describe the main features of optical transport in plasmonic nanogaps. The basics of this model are explained in detail, and its implementation is extended to include nonlocal effects and address practical situations involving different materials and temperatures of operation. PMID- 25739466 TI - Systematic review and economic modelling of the clinical effectiveness and cost effectiveness of art therapy among people with non-psychotic mental health disorders. AB - BACKGROUND: Mental health problems account for almost half of all ill health in people under 65 years. The majority are non-psychotic (e.g. depression, anxiety and phobias). For some people, art therapy may provide more profound and long lasting healing than more standard forms of treatment, perhaps because it can provide an alternative means of expression and release from trauma. As yet, no formal evaluation of art therapy for non-psychotic mental health disorders has been conducted. AIM: This review aimed to evaluate evidence for the clinical effectiveness and cost-effectiveness of art therapy for non-psychotic mental health disorders. METHODS: Comprehensive literature searches for studies examining art therapy in populations with non-psychotic mental health disorders were performed in major health-related and social science bibliographic databases including MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Allied and Complementary Medicine Database (AMED) and Applied Social Sciences Index and Abstracts (ASSIA) from inception up to May 2013. A quantitative systematic review of clinical effectiveness, a qualitative review to explore the acceptability, relative benefits and potential harms, and a cost-utility analysis of studies evaluating cost-effectiveness of art therapy were conducted. RESULTS: In the quantitative review, 15 randomised controlled trials (RCTs) were included (n = 777). Meta analysis was not possible because of clinical heterogeneity and insufficient comparable data on outcome measures across studies. A narrative synthesis reports that art therapy was associated with significant positive changes relative to the control group in mental health symptoms in 10 out of the 15 studies. The control groups varied between studies but included wait-list/no treatment, attention placebo controls and psychological therapy comparators. Four studies reported improvement from baseline but no significant difference between groups. One study reported that outcomes were more favourable in the control group. The quality of included RCTs was generally low. In the qualitative review, 12 cohort studies were included (n = 188 service users; n = 16 service providers). Themes relating to benefits of art therapy for service users included the relationship with the therapist, personal achievement and distraction. Areas of potential harms were related to the activation of emotions that were then unresolved, lack of skill of the art therapist and sudden termination of art therapy. The quality of included qualitative studies was generally low to moderate. In the cost-effectiveness review, a de novo model was constructed and populated with data identified from the clinical review. Scenario analyses were conducted allowing comparisons of group art therapy with wait-list control, group art therapy with group verbal therapy, and individual art therapy versus control. Art therapy appeared cost effective compared with wait-list control with high certainty, although generalisability to the target population was unclear. Verbal therapy appeared more cost-effective than art therapy but there was considerable uncertainty and a sizeable probability that art therapy was more clinically effective. The cost effectiveness of individual art therapy was uncertain and dependent on assumptions regarding clinical benefit and duration of benefit. CONCLUSIONS: From the limited available evidence, art therapy was associated with positive effects when compared with a control in a number of studies in patients with different clinical profiles, and it was reported to be an acceptable treatment and was associated with a number of benefits. Art therapy appeared to be cost-effective compared with wait-list but further studies are needed to confirm this finding as well as evidence to inform future cost-effective analyses of art therapy versus other treatments. STUDY REGISTRATION: The study is registered as PROSPERO CRD42013003957. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25739467 TI - Genome-wide computational determination of the human metalloproteome. AB - Accurate prediction of protein function in humans is important for understanding biological processes at the molecular level in biomedicine and drug design. Over a third of proteins are commonly held to bind metal, and ~10% of human proteins, to bind zinc. Therefore, an initial step in protein function prediction frequently involves predicting metal ion binding. In recent years, methods have been developed to predict a set of residues in 3D space forming the metal-ion binding site, often with a high degree of accuracy. Here, using extensions of these methods, we provide an extensive list of human proteins and their putative metal ion binding site residues, using translated gene sequences derived from the complete, resolved human genome. Under conditions of ~90% selectivity, over 900 new human putative metal ion binding proteins are identified. A statistical analysis of resolved metal ion binding sites in the human metalloproteome is furnished and the importance of remote homology analysis is demonstrated. As an example, a novel metal-ion binding site involving a complex of a botulinum substrate with its inhibitor is presented. On the basis of the location of the predicted site and the interactions of the contacting residues at the complex interface, we postulate that metal ion binding in this region could influence complex formation and, consequently, the functioning of the protein. Thus, this work provides testable hypotheses about novel functions of known proteins. PMID- 25739469 TI - Correction to: Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls. PMID- 25739468 TI - Biophysical characterization of naturally occurring titin M10 mutations. AB - The giant proteins titin and obscurin are important for sarcomeric organization, stretch response, and sarcomerogenesis in myofibrils. The extreme C-terminus of titin (the M10 domain) binds to the N-terminus of obscurin (the Ig1 domain) in the M-band. The high-resolution structure of human M10 has been solved, along with M10 bound to one of its two known molecular targets, the Ig1 domain of obscurin-like. Multiple M10 mutations are linked to limb-girdle muscular dystrophy type 2J (LGMD2J) and tibial muscular dystrophy (TMD). The effect of the M10 mutations on protein structure and function has not been thoroughly characterized. We have engineered all four of the naturally occurring human M10 missense mutants and biophysically characterized them in vitro. Two of the four mutated constructs are severely misfolded, and cannot bind to the obscurin Ig1 domain. One mutation, H66P, is folded at room temperature but unfolds at 37 degrees C, rendering it binding incompetent. The I57N mutation shows no significant structural, dynamic, or binding differences from the wild-type domain. We suggest that this mutation is not directly responsible for muscle wasting disease, but is instead merely a silent mutation found in symptomatic patients. Understanding the biophysical basis of muscle wasting disease can help streamline potential future treatments. PMID- 25739470 TI - Intracranial Hemorrhage Caused by Non-Vitamin K Antagonist Oral Anticoagulants (NOACs)- Multicenter Retrospective Cohort Study in Japan. AB - BACKGROUND: We conducted a multicenter retrospective cohort study to elucidate the characteristics of intracranial hemorrhage (ICH) in patients with atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants (NOACs). METHOD AND RESULTS: We sent a questionnaire to the directors of 241 stroke centers in Japan to establish the clinical characteristics of NOAC-associated cerebral hemorrhage (CH), including hematoma size, hematoma enlargement (HE) and in-hospital mortality of patients treated in their institutions. We undertook a literature review to establish the clinical characteristics of warfarin associated CH and compared these with our data. We received 174 responses (72.2%), of which 67 (38.5%) gave anonymous details of 130 eligible patients (male, 67.7%; mean age, 77.3+/-8.3 years, in-hospital mortality rate, 11.5%). We judged that 87 of the 130 patients had presented with CH: one-fifth had taken antiplatelet drugs. We found that the incidences of HE and mortality in the 87 patients presenting with NOAC-associated CH were lower than would have been expected in those with warfarin-associated CH (17% vs. 26%, and 16% vs. 35%, respectively). CONCLUSIONS: More than half the stroke center directors who responded to our questionnaire had not experienced cases of NOAC-associated ICH. Compared with warfarin, NOACs appear to present a lower risk of HE and death in patients with atrial fibrillation who develop CH. PMID- 25739471 TI - Water intake disorder in a DEND syndrome afflicted patient with R50P mutation. AB - In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K(+) (KATP) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 MUL aliquot of 340 MUM KATP channel opener diazoxide or 100 MUM KATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the KATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered KATP channel activity. PMID- 25739472 TI - Putative neuropathological interactions in MSA: focus in the rostral ventrolateral medulla. AB - We used double immunocytochemistry for alpha-synuclein and markers of sympathoexcitatory neurons, oligodendrocytes, iron metabolism, and autophagy to study putative neuropathological interactions in multiple system atrophy. We focused in the rostral ventrolateral medulla as a prototype vulnerable region. We found that loss of C1 neurons and oligodendrocytes related to glial cytoplasmic inclusion accumulation, downregulation of iron transport, and upregulation of autophagy and ferritin expression in these area. PMID- 25739473 TI - The effect of statins on sympathetic activity: a meta-analysis. AB - OBJECTIVE: Beyond lipid-lowering properties, statins decrease sympathetic nervous activity. Due to the limited number of studies and included participants, a meta analysis of randomized, placebo-controlled studies using microneurography (MSNA) was performed to assess sympatholytic effect of statins. METHODS: We conducted a comprehensive search of online databases (Cochrane, Embase, and EBSCO) for published human studies up to April 2014. Randomized controlled trials (parallel and crossover design) were eligible for inclusion if results of statins versus placebo treatments on sympathetic activity were measured with MSNA. RESULTS: Data from five studies with a total number of subjects n = 82 were included into the meta-analysis. MSNA expressed as bursts/min and as bursts/100 heartbeats was lower in the statin group than in the placebo group with a mean difference of 4.37 95% CI (-7.03; -1.70), p < 0.0013 and -5.85 95% CI (-7.56; -4.13), p < 0.0001, respectively. No significant publication bias was observed. Meta regression revealed no significant effect of baseline total cholesterol or dose of statin. No change in blood pressure and heart rate was observed. CONCLUSIONS: Published data show that regardless of type and dose, statins reduce sympathetic activity measured by microneurography. The role of decreased sympathetic outflow during statin therapy on clinical end points needs to be clarified. PMID- 25739474 TI - Prevalence of REM sleep behavior disorder in multiple system atrophy: a multicenter study and meta-analysis. AB - OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia frequently affecting patients with synucleinopathies, but its exact prevalence in multiple system atrophy (MSA) is unclear. Whether questionnaires alone are sufficient to diagnose RBD is also unknown. METHODS: We performed a cross sectional study of patients with probable MSA from six academic centers in the US and Europe. RBD was ascertained clinically and with polysomnography; we also performed a meta-analysis according to PRISMA guidelines for studies published before September 2014 that reported the prevalence of RBD in MSA. A random effects model was constructed using weighted prevalence proportions. Only articles in English were included. Studies were classified into those that ascertained the presence of RBD in MSA clinically and with polysomnography. Case reports or case series (<= 5 patients) were not included. RESULTS: Forty-two patients completed questionnaires and underwent polysomnography. Of those, 32 (76.1%) had clinically suspected RBD and 34 (81%) had polysomnography-confirmed RBD. Two patients reported no symptoms of RBD but had polysomnography-confirmed RBD. The primary search strategy yielded 374 articles of which 12 met the inclusion criteria. The summary prevalence of clinically suspected RBD was 73% (95 % CI, 62-84%) in a combined sample of 324 MSA patients. The summary prevalence of polysomnography-confirmed RBD was 88 % (95% CI, 79-94%) in a combined sample of 217 MSA patients. INTERPRETATION: Polysomnography-confirmed RBD is present in up to 88% of patients with MSA. RBD was present in some patients that reported no symptoms. More than half of MSA patients report symptoms of RBD before the onset of motor deficits. PMID- 25739475 TI - Repurpose terbutaline sulfate for amyotrophic lateral sclerosis using electronic medical records. AB - Prediction of new disease indications for approved drugs by computational methods has been based largely on the genomics signatures of drugs and diseases. We propose a method for drug repositioning that uses the clinical signatures extracted from over 13 years of electronic medical records from a tertiary hospital, including >9.4 M laboratory tests from >530,000 patients, in addition to diverse genomics signatures. Cross-validation using over 17,000 known drug disease associations shows this approach outperforms various predictive models based on genomics signatures and a well-known "guilt-by-association" method. Interestingly, the prediction suggests that terbutaline sulfate, which is widely used for asthma, is a promising candidate for amyotrophic lateral sclerosis for which there are few therapeutic options. In vivo tests using zebrafish models found that terbutaline sulfate prevents defects in axons and neuromuscular junction degeneration in a dose-dependent manner. A therapeutic potential of terbutaline sulfate was also observed when axonal and neuromuscular junction degeneration have already occurred in zebrafish model. Cotreatment with a beta2 adrenergic receptor antagonist, butoxamine, suggests that the effect of terbutaline is mediated by activation of beta2-adrenergic receptors. PMID- 25739477 TI - [Carl Djerassi (1923-2015)]. PMID- 25739476 TI - DEGRO/DGK guideline for radiotherapy in patients with cardiac implantable electronic devices. AB - An increasing number of patients undergoing radiotherapy (RT) have cardiac implantable electronic devices [CIEDs, cardiac pacemakers (PMs) and implanted cardioverters/defibrillators (ICDs)]. Ionizing radiation can cause latent and permanent damage to CIEDs, which may result in loss of function in patients with asystole or ventricular fibrillation. Reviewing the current literature, the interdisciplinary German guideline (DEGRO/DGK) was developed reflecting patient risk according to type of CIED, cardiac condition, and estimated radiation dose to the CIED. Planning for RT should consider the CIED specifications as well as patient-related characteristics (pacing-dependent, previous ventricular tachycardia/fibrillation). Antitachyarrhythmia therapy should be suspended in patients with ICDs, who should be under electrocardiographic monitoring with an external defibrillator on stand-by. The beam energy should be limited to 6 (to 10) MV CIEDs should never be located in the beam, and the cumulative scatter radiation dose should be limited to 2 Gy. Personnel must be able to respond adequately in the case of a cardiac emergency and initiate basic life support, while an emergency team capable of advanced life support should be available within 5 min. CIEDs need to be interrogated 1, 3, and 6 months after the last RT due to the risk of latent damage. PMID- 25739478 TI - [Identification of immunodominant components of an isolate of Trypanosoma cruzi by immunoblot and its standardization for diagnostic purposes]. AB - INTRODUCTION: Conventional serology was used for the detection of Trypanosoma cruzi infection, with diverse sensitivity and specificity results. Due to the number of samples with doubtful results, it is necessary to develop additional confirmation tests such as the immunoblot. OBJECTIVE: The aim of this study was identify major immunogenic proteins of T. cruzi isolate and establish criteria for immunoblot positivity with diagnostic purposes. METHODS: Immunoblot initial standardization was performed, determining optimal concentrations of antigen, serum, and second antibody. Thirty-five positive and thirty negative sera were assayed to evaluate different criteria of positivity and determine which provides greater sensitivity and specificity. RESULTS: Immunoblot of T. cruzi positive sera shared a rich pattern of components with molecular weights between 10-250 kDa. Twelve components had a recognition rate higher than 50%, of which the polypeptides of 27, 32, 34, and 38 kDa were close to 100%. Of the positivity criteria evaluated, the recognition of the components of 27 and 32 kDa provided sensitivity and specificity of 100%. DISCUSSION: The Immunoblot is suitable for confirmation of infection by T. cruzi, so it is strongly recommended for confirmation and discrimination of discordant cases. PMID- 25739479 TI - [Application of cantharidin, podophyllotoxin, and salicylic acid in recalcitrant plantar warts. A preliminary study]. AB - INTRODUCTION: Plantar warts often are refractory to any treatment and can last for decades in adults. Recalcitrant warts are defined as those that have persisted for more than two years, or after at least two treatment modalities. METHODS: A total of 15 consecutive patients with recalcitrant plantar warts were included in this preliminary study. The treatment consisted of applying one to two sessions that comprised compounding 1% cantharidin, 5% of podophyllotoxin, and 30% salicylic acid (CPS), with an interval between applications of four weeks. RESULTS: With treatment and subsequent follow-up for six months, there was complete eradication of lesions in 15 patients, eight (53.3%) required a single application of the solution, and seven (46.7%) two applications, with no side effects. Patient satisfaction related to treatment was measured by a visual analog scale (VAS) of 10 cm in length, with an average score 9.73 +/- 0.46, and all said they would proceed with the treatment again if necessary. CONCLUSIONS: Topical treatment by compounding is safe, effective, and a promising therapeutic modality when applied in recalcitrant plantar warts. PMID- 25739480 TI - [Patients with solid organ transplantation and skin cancer: determination of risk factors with emphasis in photoexposure and immunosuppressive regimen. Experience in a third level hospital]. AB - BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common malignancy in transplant patients. The incidence of basal cell carcinoma (BCC) is 10 times greater than in the general population, while squamous cell carcinoma (SCC) is 100 times greater. The relationship between the BCC and SCC reverses and increases according to the degree of immunosuppression and sun exposure. One way to predict the risk of NMSC should be based on factors such as: total sun burden factor (TSB). OBJECTIVE: To determine the influence of various risk factors in the development of NMSC and its relation to the type and duration of immunosuppressive treatment, type of transplant, and TSB. METHODS: We worked with a fledgling historical cohort in which patients with kidney or liver transplant were identified and recorded if they developed some form of skin cancer. To study the factors associated with NMSC, we resorted to the strategy of a case-control study. Dermatological examination was performed and a questionnaire of risk factors made in both groups. RESULTS: Of the 140 patients enrolled, 51 were women and 89 men, 120 were renal transplant recipients and 20 liver transplants. Of patients who developed NMSC, 100% were renal transplant recipients. The median age was 48.5 years. Most cancer patients worked outdoors. A total of 78 lesions were found in 40 NMSC patients, 59 (76%) of them were SCC, and 19 (24%) BCC; 45% of all skin cancer patients had more than one injury. The worst affected areas were those photoexposed: 60% head and neck, trunk and upper extremities 18% 50%. In 30% of patients (12/40) 22 new tumors were identified (SCC 18 and BCC 4). No lesions were identified for melanoma. In multivariate logistic regression analysis, statistically significant features were: type-based immunosuppressive regimen of cyclosporine A, azathioprine and prednisone (OR: 59.7; 95% CI: 10.2 348), TSB > 10 (OR: 19; 95% CI: 3-120) and duration of use of immunosuppressive therapy (OR: 1.06; 95% CI: 0.9-1.1). The mean time from transplantation to first dermatological assessment was six years (+5.4). Of the patients, 93% had not regularly used sunscreen before and after transplantation. CONCLUSIONS: The dermatological assessment is convenient and easy to perform. Primary prevention, close monitoring, diagnosis, and treatment of skin lesions are essential components of a comprehensive program for the evaluation of transplant recipients, the purpose of which is to reduce the incidence and morbidity associated with cancer. PMID- 25739481 TI - [Socioeconomic inequalities in oral health service utilization any time in their lives for Mexican schoolchildren from 6 to 12 years old]. AB - OBJECTIVE: To determine the prevalence and the existence of socioeconomic inequalities in dental health service utilization (DHSU) any time in the life of Mexican schoolchildren aged 6-12 years of Pachuca Hidalgo, Mexico. MATERIAL AND METHODS: We performed a cross-sectional study in 1,404 school children 6-12 years of age from 14 public schools in the city of Pachuca, Hidalgo, Mexico. Questionnaires were distributed to determine socioeconomic position variables (SEP). The dependent variable was DHSU once in life (0 = No, 1 = Yes). The analysis was performed in Stata 9 using chi-square tests. RESULTS: The mean age was 8.97 +/- 1.99 years, 50.1% were boys. The prevalence of DHSU any time in life was 71.4%. The DHSU percentage increased according increasing age (p < 0.05). Significant differences (p < 0.05) in percentages of USSB through SEP variables: health insurance, car ownership in the home, dwelling and household characteristics, a better level of SEP increased prevalence of DHSU. Although in the mother's schooling no differences were observed (p > 0.05), father's schooling was associated (p < 0.05) inversely to expectations. CONCLUSIONS: The findings of this study demonstrate that the prevalence of DHSU was not 100%; 28.6% of children have never had contact with a dentist. We identified certain indicator variables of SEP associated with DHSU, indicating the existence of inequalities in this oral health indicator. PMID- 25739482 TI - [Molecular identification of glucose-6-phosphate dehydrogenase (G6PD) detected in neonatal screening]. AB - AIMS: To present the strategy of identifying the molecular variants of G6PD detected in neonatal screening (NS). MATERIAL AND METHODS: We present a series of incident cases of newborns positive for G6PD deficiency detected in NS. From nuclear DNA with the methodology of real-time PCR we sought molecular G6PD variants: G202A, A376G, T968C and C563T. RESULTS: Of a total of 21,619 neonates, 41 cases were reactive in NS for G6PD (189.6/100,000 RN screened rate), 34 cases confirmed the molecular variant of G6PD (157.3/100,000 RN screened rate). The most frequent allele combination G202A/A376G (G6PD ratio and median activity, 0.460 and 1.72 +/- 0.35 U/g Hb, respectively), followed by G202A (0.170 and 1.74 +/- 0.27 U/g Hb) and A376G/T968C (ratio 0.150 and 1.10 +/- 0.44 U/g Hb). The T968C allelic variant showed lower enzyme activity than the rest (1.1 +/- 0.4; p = 0.02). Two women were detected with G6PD deficiency with G202A/A376G and G202A variant. CONCLUSIONS: African alleles were prevalently detected in neonatal screening. This strategy allows the identification of molecular variants involved in 80% of cases. PMID- 25739483 TI - [Seroprevalence of risk factors associated with rickettsiosis (Rickettsia rickettsii) in humans in Baja California, Mexico]. AB - INTRODUCTION: Rickettsiosis caused by Rickettsia rickettsii is capable of infecting vertebrates, including humans. The symptoms are high fever, headache, myalgia, nausea, vomiting, abdominal pain, and cough. Mortality can be up to 30% in untreated patients. AIMS: To prove the existence of rickettsiosis in Ensenada, Baja California, Mexico, because no human cases have been reported. MATERIAL AND METHODS: This observational, cross-sectional, descriptive study included 384 samples of humans in Ensenada, Baja California. Antibodies against R. rickettsii were measured with the kit R. rickettsii ELISA((r)) Helica Biosystems, Inc., adapted for use in humans using human IgG conjugate antibodies. To determine the sensitivity and specificity, 32 human samples were submitted to IFA. Specific primers were used for the molecular diagnosis of R. rickettsii in dogs and ticks. RESULTS: The seroprevalence adjusted rickettsiosis in humans was 2.9% (95% CI: 0.8-5.3), seropositivity was not associated with sex, age, occupation, household, dogs, pet deworming program against ticks, the type of yard, and mobility of the dog between home and the street. CONCLUSIONS: With substantial agreement of k between ELISA and IFA, it follows that the results of seroprevalence of this work are reliable. PMID- 25739484 TI - [Myasthenia gravis in adults of institutions pertaining to the Mexican public health system: an analysis of hospital discharges during 2010]. AB - INTRODUCTION: Epidemiological studies on myasthenia gravis (MG) in Mexico is mainly derived from experiences in referral centers. OBJECTIVE: To describe the epidemiological characteristics of hospital discharges during 2010 with the diagnosis of MG in adults hospitalized in the Mexican public health system. METHODS: We consulted the database of hospital discharges during 2010 of the National Health Information System (Ministry of Health, IMSS, IMSS oportunidades, ISSSTE, PEMEX, and the Ministry of Defense). The MG records were identified by the code G70.0 of the International Classification of Diseases 10th revision. RESULTS: During 2010 there were 5,314,132 hospital discharges (4,254,312 adults). Among them, 587 (0.01%) were adults with MG (median age: 47 years, 60% women). Women with MG were significantly younger than men (median age: 37 vs. 54 years, respectively; p < 0.001). The median hospital stay was six days. The case fatality rate was 3.4%, without gender differences. Age was associated with the probability of death. CONCLUSIONS: We confirmed the bimodal age-gender distribution in MG. The in-hospital case fatality rate in Mexico is consistent with recent reports around the world. PMID- 25739485 TI - [The use of seatbelts and child seats in drivers and passengers of motor vehicles in four metropolitan areas in Mexico]. AB - OBJECTIVES: To estimate the rate of seatbelt and child seat use in drivers and passengers of motor vehicles in four metropolitan areas in Mexico (Guadalajara, Leon, Monterrey and Mexico City). To evaluate the impact of the Mexican Initiative for Road Safety (IMESEVI) in this respect. MATERIAL AND METHODS: Data were collected at the start of IMESEVI (June 2008) and one year after the program's implementation (October 2009) in the four participating metropolitan areas. In particular, the use of seatbelts and child seats was observed in occupants of automobiles, station wagons, and light trucks. The sample included 28,412 (pre) and 52,274 (post) individuals, of which 1,454 (pre) and 1,679 (post) were younger than five years old. The data analysis was based on a hierarchical logistic model. RESULTS: Globally, the probability of using either safety device is 46% (95% CI: 43-49%) at baseline and 52% (95% CI: 48-55%) at the post measurement, with large differences, though, among the four participating metropolitan areas. Factors that significantly affect their use include the individual's position in the vehicle, the type and age of the vehicle, and the individual's sex. Child seat use is very limited. At baseline, about 17% (95% CI: 11-25%) of children below five years old travelled in a special seat, with this number increasing to 26% (95% CI: 19-34%) after the implementation of IMESEVI. Child seat use for children above four years is virtually nonexistent. CONCLUSIONS: Continued efforts are required to raise the public awareness of the importance of using safety devices, especially for passengers in the back of the car as well as with respect to the use of adapted seats for small children. PMID- 25739486 TI - [Human amniotic epithelium (HAE) as a possible source of stem cells (SC)]. AB - There have been major recent advances in the field of developmental biology due to the investigation on stem cells (SC). Stem cells are characterized by their capacity of auto-renewal and differentiation to different cellular phenotypes. Based on the developmental stage, they can be classified into two different types: embryonic SCs and adult SCs. It has been widely reported that several problems need to be resolved before their possible clinical applications. As a result, fetal membranes have been suggested as an alternative source of SCs. In the human amniotic epithelium, the presence of markers of pluripotent SC's has been reported, and its capacity as a feeder layer for expansion of different SC types. Also, fetal membranes are a discarded product after delivery, and thus there are not any ethical issues related to its use. In conclusion, the human amniotic epithelium can be a strong candidate for regenerative medicine. PMID- 25739487 TI - [Ventilation strategies in the child with severe hypoxemic respiratory failure]. AB - In this review, we assemble the fundamental concepts of the use of mechanical ventilation (MV) in children with acute respiratory failure (ARDS) and refractory hypoxemia. We also discusses topics of protective ventilation and recruitment potential, and specifically examine the options of ventilation and/or maneuvers designed to optimize the non-aerated lung tissue: alveolar recruitment maneuvers, positive end-expiratory pressure (PEEP) titulation, high frequency oscillatory ventilation (HFOV), airway pressure release ventilation (APRV), aimed at correcting the mismatch ventilation/perfusion (V/Q): use of prone position. The only pharmacological intervention analyzed is the use of neuromuscular blockers. In clinical practice, the protective MV concept involves using an individual adjustment of the PEEP and volume tidal (V(T)). Use of recruitment maneuvers and PEEP downward titration can improve lung function in patients with ARDS and severe hypoxemia. We must keep in mind HFOV instauration as early as possible in response to failure of MV. The use of early and prolonged prone can improve gas exchange in hopes of a better control of what caused the use of MV. PMID- 25739488 TI - [Use of nanoparticles (NP) in photodynamic therapy (PDT) against cancer]. AB - Nanotechnology is a promising interdisciplinary field for developing improved methods of diagnosis and treatment of different diseases, including cancer. Give their optical, magnetic, and structural property, the nanoparticles have been proposed to be use in the development of unconventional treatments for cancer such as photodynamic therapy (PDT). In PDT, a photosensitizing agent is used that accumulates in tumor cells, generating reactive oxygen species that causes the death of malignant cells after irradiation with light at a particular wavelength. However, the use of PDT presents different problems in its application due to the characteristics of hydrophobicity of the photosensitizers, which hinder the efficiency of administration and treatment. It is here where the use of nanoparticles is proposed as a delivery vehicle to optimize treatment application. In this review we describe the use of nanoparticles coupled to PDT in the treatment of cancer and its molecular mechanism of action. PMID- 25739489 TI - [Effects of sleep deprivation in hippocampal neurogenesis]. AB - Adult neurogenesis in the dentate gyrus (DG) in the hippocampus is a process that involves proliferation, differentiation, maturation, migration, and integration of young neurons in the granular layer of DG. These newborn neurons mature in three to four weeks and incorporate into neural circuits in the hippocampus. There, these new neurons play a role in cognitive functions, such as acquisition and retention of memory, which are consolidated during sleep period. In this review, we describe recent findings that associate sleep deprivation with changes in hippocampal neurogenesis and cognitive processes. In addition, we describe possible mechanisms implicated in this deterioration such as circadian rhythm, melatonin receptors, and growth factors. PMID- 25739490 TI - [Subtotal-supracrioid laryngectomy (SCSL): the importance of the histopathological analysis]. AB - The purpose of conservative surgical treatment of laryngeal cancer is to obtain cancer control with preservation of laryngeal function, and in turn, the preservation of laryngeal function should be understood as the preservation of the patient's ability to ventilate in the normal way without tracheostomy and without aspiration and maintaining intelligible speech. This objective is achieved by maintaining a balance between two fundamental aspects: proper patient selection (based on tumor extension and preoperative laryngeal function) and an adequate histopathological analysis of the surgical specimen. Supracricoid subtotal laryngectomy (SCSL) is the voice conservative surgical technique which offers the best possibility of control in patients with locally advanced laryngeal cancer, and the proper histopathological analysis allows staging and selecting patients eligible for adjuvant therapy, avoiding unnecessary therapies, and allows design of a monitoring and surveillance program based on risk factors. The aim of this manuscript is to highlight key points in the histopathological evaluation of the surgical specimen of SCSL. The proper communication between the surgeon and pathologist, offering complete information on preoperative clinical evaluation and the knowledge of the key points in the evaluation of the surgical specimen (sites of tumor leakage and surgical resection margins) are fundamental parameters to achieve a proper histopathologic evaluation of the surgical specimen. PMID- 25739491 TI - [Genetic factors associated with dementia in Parkinson's disease (PD)]. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dementia is a frequent complication of idiopathic Parkinsonism or PD, usually occurring later in the protracted course of the illness. Some risk factors to develop dementia in PD are aging, severe Parkinson's symptoms, rigid-akinetic form, hallucinations, and mild cognitive impairment documented at the first examinations. It is not yet clear if some genetic factors are either risk or protector for progression to dementia. In a review of the literature, we found that mutations in the alpha-synuclein gene are the most responsible for developing dementia, either from PARK1 or 4 mutations. GBA (glucocerebrosidase) is another accountable factor. However, the vast majority of patients suffer from non-Mendelian or complex forms of PD, which are likely caused by the combined effects of genetic and environmental factors. There is not until now a clear relation between some polymorphisms in candidate genes and cognitive deterioration, as many studies have not clearly identified this phenotype. PMID- 25739493 TI - [Civil hospital of Zamora de Hidalgo]. AB - The city of Zamora de Hidalgo is home to one of the most important hospitals in the region, built in 1841 and named the Civil Hospital of Zamora. Built following demand for municipal health needs and with the support of the City Council of Zamora and private donations, it functioned as a hostel for pilgrims, the destitute and the sick. It was administered and maintained by residents, subsequently by the mothers of the Sacred Heart of Jesus, and finally by the federal Government. It currently gives the Zamorano community services, and admits sick people from other locations such as Jacona, Jiquilpan, Patamban Ocumicho, Chavinda, Tangancicuaro, Chilchota, and Tangamandapio, among others. It was called the Civil hospital because as the only hospital that operated in Zamora, it ceased to be administered by the Ecclesiastic Chapter, and passed into the hands of the State. PMID- 25739492 TI - [Palliative care regulation and assisted death]. AB - This article analyzes the Mexican regulation on palliative care and its relationship with the public debate on assisted death or suicide. This paper focuses on the rights that people with incurable diseases have, given the current contents of the General Health Statute and other applicable rules. Its main purpose is to activate the public debate on these matters. PMID- 25739494 TI - [Medical Narrative at the 150 aniversary of the National Academy of Medicine. A book presentation]. PMID- 25739495 TI - Pediatric bariatric surgery: the clinical pathway. AB - PURPOSE: Despite the rising interest in bariatric surgery (BS) for children and adolescents, algorithms that incorporate BS in weight management (WM) programs are lacking. This study presents the results of the pediatric bariatric surgery clinical pathway employed in our institution. MATERIALS AND METHODS: Starting March 2008, we enrolled obese children and adolescents in a standardized multidisciplinary obesity management program. Weight loss, complications, comorbidities, and growth results of those who eventually underwent BS were compared with a matched (age, gender, and height z-score) group of patients on non-surgical WM only. RESULTS: Up to July 2014, a total of 659 patients received care through the pathway, of whom 291 patients underwent laparoscopic sleeve gastrectomy (LSG). Mean age and pre-LSG body mass index (BMI) were 14.4 +/- 4.0 years (range; 5 to 21 years) and 48.3 +/- 10.0 (range; 31.8-109.6). Mean BMI change (% excess weight loss) at 1, 2, 3, and 4 postoperative years was -16.9 +/- 4.9 (56.6 +/- 22.6), -17.5 +/- 5.2 (69.8 +/- 22.5), -18.9 +/- 4.3 (75.1 +/- 26.8), and -19.6 +/- 6.4 (73.6 +/- 24.3), respectively. Postoperatively, complications occurred in 12 patients (4.1%), with no leaks or mortality, and more than 90% of comorbidities were resolved or improved without recurrence. Additionally, LSG patients exhibited significantly higher postoperative growth velocity compared to WM patients. CONCLUSIONS: Applying this standardized clinical pathway with its BS component results in safe and successful weight loss for pediatric patients, with low complication rates, maximum comorbidity resolution, and minimum morbidity. PMID- 25739497 TI - Raising public awareness of aphasia in southern Ontario, Canada: A survey. AB - PURPOSE: Despite the relatively high prevalence of aphasia, research indicates that, world-wide, public awareness of aphasia is lacking. Of the surveys that have been conducted internationally, none has studied the Canadian public's awareness of aphasia. The purpose of the present survey was to assess public awareness and basic knowledge of aphasia of individuals in southern Ontario, Canada. METHOD: Using the same questionnaire that has been used in other countries, face-to-face surveys were conducted in public places (e.g. parks) at various locations in southern Ontario. Respondents were asked questions pertaining to their awareness and knowledge of aphasia. The number of surveys retained for analysis was 831. In addition to an evaluation of public awareness and knowledge of aphasia, the potential influences of age, gender, and occupation were analysed. For those who had heard of aphasia, questions were asked to determine how or where they had heard of aphasia. RESULT: Consistent with the literature, overall public awareness and basic knowledge of aphasia in southern Ontario was found to be limited. The factors of age, gender and occupation were found to influence the results. CONCLUSION: This investigation supports the need for better promotion of aphasia awareness to the public in southern Ontario and, by extension, in Canada. PMID- 25739496 TI - Cancer stage at diagnosis in patients infected with the human immunodeficiency virus and transplant recipients. AB - BACKGROUND: It is unknown whether immunosuppression results in more aggressive, advanced stage cancers. Because cancer stage is influenced both by tumor biology and medical surveillance, the authors assessed cancer stage in individuals infected with the human immunodeficiency virus (HIV) and solid organ transplant recipients, 2 immunosuppressed groups with differences in their health care use. METHODS: The authors used data on all cases of 15 cancer types diagnosed during 1996 through 2010 in 2 studies that linked US cancer registries with HIV and transplant registries. Odds ratios (ORs) for advanced (vs local) disease were estimated comparing HIV and transplant populations with immunocompetent individuals in polytomous logistic regression models adjusted for age, sex, race, registry, and year. RESULTS: A total of 8411 of 4.5 million cancer cases occurred in HIV-infected individuals and 7322 of 6.4 million cancer cases occurred in transplant recipients. Compared with immunocompetent patients with cancer, those infected with HIV were more likely to be diagnosed with distant stage lung (OR, 1.13), female breast (OR, 1.99), and prostate (OR, 1.57) cancers, whereas transplant recipients had fewer distant stage lung (OR, 0.54), female breast (OR, 0.75), and prostate (OR, 0.72) cancers. Both immunosuppressed populations had a shift toward advanced stage melanoma (ORs of 1.97 for HIV-infected individuals and 1.82 for transplant recipients) and bladder cancer (ORs of 1.42 for HIV infected individuals and 1.54 for transplant recipients). CONCLUSIONS: Bladder cancer and melanoma were more likely to be diagnosed at a nonlocal stage in both HIV-infected individuals and transplant recipients, suggesting a role for immunosuppression in their progression. In addition, we observed a shift for some common cancers toward later stages in HIV-infected individuals and toward earlier stages in transplant recipients, which is consistent with differential access to medical care or surveillance. PMID- 25739498 TI - Neuroscience: hot on the trail of temperature processing. PMID- 25739500 TI - Corrigendum: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. PMID- 25739499 TI - Multi-omics of permafrost, active layer and thermokarst bog soil microbiomes. AB - Over 20% of Earth's terrestrial surface is underlain by permafrost with vast stores of carbon that, once thawed, may represent the largest future transfer of carbon from the biosphere to the atmosphere. This process is largely dependent on microbial responses, but we know little about microbial activity in intact, let alone in thawing, permafrost. Molecular approaches have recently revealed the identities and functional gene composition of microorganisms in some permafrost soils and a rapid shift in functional gene composition during short-term thaw experiments. However, the fate of permafrost carbon depends on climatic, hydrological and microbial responses to thaw at decadal scales. Here we use the combination of several molecular 'omics' approaches to determine the phylogenetic composition of the microbial communities, including several draft genomes of novel species, their functional potential and activity in soils representing different states of thaw: intact permafrost, seasonally thawed active layer and thermokarst bog. The multi-omics strategy reveals a good correlation of process rates to omics data for dominant processes, such as methanogenesis in the bog, as well as novel survival strategies for potentially active microbes in permafrost. PMID- 25739501 TI - Regulation of star formation in giant galaxies by precipitation, feedback and conduction. AB - The Universe's largest galaxies reside at the centres of galaxy clusters and are embedded in hot gas that, if left undisturbed, would cool quickly and create many more new stars than are actually observed. Cooling can be regulated by feedback from accretion of cooling gas onto the central black hole, but requires an accretion rate finely tuned to the thermodynamic state of the hot gas. Theoretical models in which cold clouds precipitate out of the hot gas via thermal instability and accrete onto the black hole exhibit the necessary tuning. Recent observational evidence shows that the abundance of cold gas in the centres of clusters increases rapidly near the predicted threshold for instability. Here we report observations showing that this precipitation threshold extends over a large range in cluster radius, cluster mass and cosmic time. We incorporate the precipitation threshold into a framework of theoretical models for the thermodynamic state of hot gas in galaxy clusters. According to that framework, precipitation regulates star formation in some giant galaxies, while thermal conduction prevents star formation in others if it can compensate for radiative cooling and shut off precipitation. PMID- 25739502 TI - Thermosensory processing in the Drosophila brain. AB - In Drosophila, just as in vertebrates, changes in external temperature are encoded by bidirectional opponent thermoreceptor cells: some cells are excited by warming and inhibited by cooling, whereas others are excited by cooling and inhibited by warming. The central circuits that process these signals are not understood. In Drosophila, a specific brain region receives input from thermoreceptor cells. Here we show that distinct genetically identified projection neurons (PNs) in this brain region are excited by cooling, warming, or both. The PNs excited by cooling receive mainly feed-forward excitation from cool thermoreceptors. In contrast, the PNs excited by warming ('warm-PNs') receive both excitation from warm thermoreceptors and crossover inhibition from cool thermoreceptors through inhibitory interneurons. Notably, this crossover inhibition elicits warming-evoked excitation, because warming suppresses tonic activity in cool thermoreceptors. This in turn disinhibits warm-PNs and sums with feed-forward excitation evoked by warming. Crossover inhibition could cancel non thermal activity (noise) that is positively correlated among warm and cool thermoreceptor cells, while reinforcing thermal activity which is anti correlated. Our results show how central circuits can combine signals from bidirectional opponent neurons to construct sensitive and robust neural codes. PMID- 25739503 TI - Regulated eukaryotic DNA replication origin firing with purified proteins. AB - Eukaryotic cells initiate DNA replication from multiple origins, which must be tightly regulated to promote precise genome duplication in every cell cycle. To accomplish this, initiation is partitioned into two temporally discrete steps: a double hexameric minichromosome maintenance (MCM) complex is first loaded at replication origins during G1 phase, and then converted to the active CMG (Cdc45 MCM-GINS) helicase during S phase. Here we describe the reconstitution of budding yeast DNA replication initiation with 16 purified replication factors, made from 42 polypeptides. Origin-dependent initiation recapitulates regulation seen in vivo. Cyclin-dependent kinase (CDK) inhibits MCM loading by phosphorylating the origin recognition complex (ORC) and promotes CMG formation by phosphorylating Sld2 and Sld3. Dbf4-dependent kinase (DDK) promotes replication by phosphorylating MCM, and can act either before or after CDK. These experiments define the minimum complement of proteins, protein kinase substrates and co factors required for regulated eukaryotic DNA replication. PMID- 25739504 TI - Corrigendum: Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism. PMID- 25739506 TI - Temperature representation in the Drosophila brain. AB - In Drosophila, rapid temperature changes are detected at the periphery by dedicated receptors forming a simple sensory map for hot and cold in the brain. However, flies show a host of complex innate and learned responses to temperature, indicating that they are able to extract a range of information from this simple input. Here we define the anatomical and physiological repertoire for temperature representation in the Drosophila brain. First, we use a photolabelling strategy to trace the connections that relay peripheral thermosensory information to higher brain centres, and show that they largely converge onto three target regions: the mushroom body, the lateral horn (both of which are well known centres for sensory processing) and the posterior lateral protocerebrum, a region we now define as a major site of thermosensory representation. Next, using in vivo calcium imaging, we describe the thermosensory projection neurons selectively activated by hot or cold stimuli. Fast-adapting neurons display transient ON and OFF responses and track rapid temperature shifts remarkably well, while slow-adapting cell responses better reflect the magnitude of simple thermal changes. Unexpectedly, we also find a population of broadly tuned cells that respond to both heating and cooling, and show that they are required for normal behavioural avoidance of both hot and cold in a simple two-choice temperature preference assay. Taken together, our results uncover a coordinated ensemble of neural responses to temperature in the Drosophila brain, demonstrate that a broadly tuned thermal line contributes to rapid avoidance behaviour, and illustrate how stimulus quality, temporal structure, and intensity can be extracted from a simple glomerular map at a single synaptic station. PMID- 25739507 TI - The clinical practice project: planning to publish. AB - PURPOSE: An increasing number of journals focused on clinical practice publish high-quality projects. However, research reports typically follow a distinct design, which is not always appropriate for reporting clinical practice projects. The purpose of this article is to provide a succinct guide for planning and reporting clinical projects, specifically, the Doctor of Nursing Practice applied clinical project. DATA SOURCES: Literature concerning clinical practice project planning and preparation for publication was reviewed for this article. CONCLUSIONS: This article provides a section-by-section summary of elements frequently included when preparing a manuscript for publication. The elements addressed in this article are suggestions and their inclusion and sequencing may vary depending on specific journal requirements. IMPLICATIONS FOR PRACTICE: If information from clinical research projects is to contribute to nursing knowledge in the form of lessons learned and information about translation of research into clinical practice, the design and conduct of the project must be rigorous and information about implementation and findings must be accurate and clearly communicated. PMID- 25739508 TI - Pain in stroke patients: characteristics and impact on the rehabilitation treatment. A multicenter cross-sectional study. AB - BACKGROUND: Post-stroke pain (PSP) is a common and disabling complication, difficult to treat, that often decreases patients' quality of life (QoL). The hypothesis is that PSP may negatively affect rehabilitation treatment. AIM: The aim of this paper was to quantify and characterize pain in a sample of post stroke patients undergoing rehabilitation and to investigate the impact of pain in slowing down or discontinuing the rehabilitation program. DESIGN: Multicenter cross-sectional study. SETTING: Inpatients and outpatients of rehabilitation department. POPULATION: One hundred and six subacute and chronic stroke patients. METHODS: Pain intensity was measured with the NRS or the PAINAD (if cognitive/language impairment was present); pain characteristics were assessed with the DN4, and NPSI questionnaire. Qol was measured with the SF-36. A clinical assessment and a semi-structured questionnaire on pain occurrence, impact, and management was administered by the physiotherapist in charge of the patients and by the physician. RESULTS: Nearly 1/3 of the patients (32.9%) with normal cognitive functions and language reported pain occurrence after stroke; 81.8% of them had NRS>=3 and 31.8% DN4>=4 (meaning neuropathic origin of pain). In about 20% of the patients the PAINAD was used to measure pain; 17.4% of them presented a score >=3. In 24.5% of our sample, pain influenced rehabilitation treatment. In 16% of the whole sample, pain influenced patients' attention during rehabilitation session. Patients with hypoesthesia presented significantly higher neuropathic pain scores than patients with normal sensory function. Regarding QoL, we found that patients with higher neuropathic pain showed more severe deterioration of mental aspects of QoL, where patients with higher nociceptive pain presented more severe deterioration of physical aspects of QoL. CONCLUSION: The results from this multicenter study showed that in about 1/4 of the patients, pain negatively influenced the rehabilitation program delaying the recovery and likely increasing the cost of rehabilitation. CLINICAL REHABILITATION IMPACT: Clinicians should pay more attention to pain, especially neuropathic pain, in post-stroke patients. Tailored pharmacological therapy, to treat and prevent pain, might improve patients' compliance during the rehabilitation process. PMID- 25739505 TI - A direct GABAergic output from the basal ganglia to frontal cortex. AB - The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning. Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems. Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT(+) cells, which have been historically identified as an extension of the nucleus basalis, as well as ChAT( ) cells, release the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices. PMID- 25739509 TI - Does outcome of neuropsychological treatment in patients with unilateral spatial neglect after stroke affect functional outcome? AB - BACKGROUND: Unilateral spatial neglect (USN) after stroke is associated to severe disability and to a poor rehabilitation outcome. However it is still unclear if a reduction of USN after a specific neurophsycological treatment could also favor the functional recovery. AIM: The first aim of this study was to determine if low responders to neuropsychological treatment of unilateral spatial neglect may have a worse functional prognosis for activities of daily living. The second aim was to investigate which variables can predict a low response to neuropsychological treatment. DESIGN: Observational study. SETTING: Neurorehabilitation hospital in Italy. POPULATION: Two hundred inpatients with the diagnosis of ischemic stroke were screened in this observational study. Inclusion criteria were: patients in subacute phase of first ischemic stroke in right hemisphere. Exclusion criteria were: presence of previous and/or other disabling pathologies, medical conditions contraindicating physical therapy. Data of 73 patients who performed neurorehabilitation and visual scanning training for reducing USN were analysed, while the remaining others were excluded for at least one of the following reasons: hemorrhagic lesions, presence of other chronic disabling pathologies, contraindications for therapy. METHODS: USN was evaluated using: Letter Cancellation Test, Barrage Test, Sentence Reading Test and Wundt-Jastrow Area Illusion Test. Barthel Index (BI), Beck Depression Inventory, and Canadian Neurological Scale were also administered. According to the aim of the study, forward binary logistic regressions were performed to evaluate the effects of different factors on functional recovery. RESULTS: Three factors were identified as predictors of low effectiveness in terms of BI-score: older age (odds ratio OR=9.882, P=0.002), severity of disease at admission (OR=12.594, P=0.002) and being low responders to neuropsychological treatment (OR=3.847, P=0.027). Further, the initial barrage score (OR=3.313, P=0.027) and the initial BI-score (OR=3.252, P=0.039) effectively predict the response to neuropsychological treatment. CONCLUSION: The outcome of the whole rehabilitation resulted affected by the outcome of neuropsychological treatment in patients with USN, being a low score at Barrage test at the beginning of therapy a negative predictor of USN recovery. CLINICAL REHABILITATION IMPACT: Patients with USN after stroke can benefit of a specific training for reducing USN also in terms of functional outcome. Further, the simple use of Barrage test could provide important prognostic information about recovery. PMID- 25739510 TI - Quantitative Microanalysis of (1-x)Pb(Mg(1/3)Nb(2/3))O3*xPbTiO3 (PMNT) Ferroelectric Ceramics. AB - Optimized quantitative electron-probe microanalysis was applied for compositional characterization of a ferroelectric ceramic single crystal that was made from the complex perovskite-type solid-solution (1-x)Pb(Mg(1/3)Nb(2/3))O3*xPbTiO3 (PMNT). Cation concentrations were determined with high accuracy and ultimate relative experimental uncertainty of <=+/-1%, showing that the average chemical composition of the crystal corresponds to Pb(Mg(1/3)Nb(2/3))(0.67)Ti(0.33)O3 (i.e., x=0.33), which is close to the morphotropic phase boundary composition. Over the PMNT single crystal slight compositional heterogeneity was measured for concentrations of the perovskite B-site cations Ti4+, Mg2+, and Nb5+, with variations up to +/-2.3%, whereas the Pb concentration remained uniform within a variation below +/-0.5%. PMID- 25739511 TI - [Distinctive features of orofacial pain perception]. AB - BACKGROUND: In the widely used German pain questionnaire, qualitative pain characteristics are assessed by the Schmerzbeschreibungsliste (SBL). In clinical practice these adjectives insufficiently cover the spectrum of orofacial pain perceptions (OFP) and have not been proven by data. The aim of this study was the analysis of a questionnaire focussing on OFP (ZZM-FB) in which nine additional pain descriptors were amended to the SBL (SBL-OF). OBJECTIVES: The objectives of this work were to (1) compare selection frequencies between the items of the SBL and the SBL-OF and (2) test the null hypothesis that the SBL and SBL-OF item selection is not influenced by gender, age, pain features (intensity, duration, time pattern, distribution), hospital anxiety and depression scale (HADS) and diagnosis. MATERIAL AND METHODS: A total of 224 patients consecutively referred to the interdisciplinary OFP unit between 2010 and 2012 completed a ZZM-FB. The corresponding diagnosis was obtained from the clinical reports. In all, 209 OFP-Q were anonymized and data retrospectively analysed at a significance level of p <= 0.01. RESULTS: The descending rank order of the 12 most frequently selected items was as follow: pressing (SBL), dull (SBL), pulling (SBL), stinging (SBL), dreadful (SBL), miserable (SBL), exhausting (SBL-OF), grueling (SBL-OF), agonizing (SBL-OF), atrocious (SBL), horrible (SBL), pulsating (SBL). The null hypothesis was rejected for all parameters except for age. The selection frequency was significantly influenced by gender, pain intensity, duration and distribution, time pattern, HADS values and diagnosis. CONCLUSIONS: In this cohort, some ADD descriptors were selected more frequently than some SBL items, indicating that the SBL does not adequately capture the characteristics of OFP. These results will be considered in the construction of a revised ZZM-FB, which is currently in development. PMID- 25739512 TI - The long-term effects of FSH and triiodothyronine administration during the pubertal period on Connexin 43 expression and spermatogenesis efficiency in adult rats. AB - Follicle-stimulating hormone (FSH) and triiodothyronine (T3) are known regulatory factors of spermatogenesis initiation. Hyperstimulation of both hormones evokes regressional changes in connexin 43 expression and the seminiferous epithelium in young rats during testicular maturation. However, separate treatments with T3 reduce Sertoli cell number, which seems to be closely connected with the maturation of connexin 43 gap junctions. FSH elevates Sertoli cell number and function, but this effect may take place regardless of the presence of connexin 43-dependent intercellular communication. The aim of the study was to evaluate the later effects of such treatments. Newborn, male Wistar rats were divided randomly into experimental groups receiving daily subcutaneous injections of either 7.5 IU/animal FSH, or 100 mg/kg b.w. T3, or both substances or the same volume of vehicle (control group) until day 15 of life. The animals were sacrificed on day 50. Morphometric analysis and immunohistochemical reactions were performed using antibodies against Vimentin, Proliferating Cell Nuclear Antigen and Connexin 43 in the testis. Sertoli cell count, efficiency of spermatogenesis, and hormonal pattern were examined. Disturbances in the connexin 43 expression reduced the number of Sertoli cells, the efficiency of spermatogenesis and impaired endocrine function of testes in adult rats treated with FSH and T3 during puberty. Stimulation with FSH alone increased Sertoli cell number, but was associated with a negative effect on cell-to-cell connexin 43 dependent communication, with a consequential reduction of spermatogenesis efficiency. J. Exp. Zool. 323A: 256-265, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25739513 TI - Direct mechanochemical cleavage of functional groups from graphene. AB - Mechanical stress can drive chemical reactions and is unique in that the reaction product can depend on both the magnitude and the direction of the applied force. Indeed, this directionality can drive chemical reactions impossible through conventional means. However, unlike heat- or pressure-driven reactions, mechanical stress is rarely applied isometrically, obscuring how mechanical inputs relate to the force applied to the bond. Here we report an atomic force microscope technique that can measure mechanically induced bond scission on graphene in real time with sensitivity to atomic-scale interactions. Quantitative measurements of the stress-driven reaction dynamics show that the reaction rate depends both on the bond being broken and on the tip material. Oxygen cleaves from graphene more readily than fluorine, which in turn cleaves more readily than hydrogen. The technique may be extended to study the mechanochemistry of any arbitrary combination of tip material, chemical group and substrate. PMID- 25739514 TI - Comparative genomics reveals conservation of filaggrin and loss of caspase-14 in dolphins. AB - The expression of filaggrin and its stepwise proteolytic degradation are critical events in the terminal differentiation of epidermal keratinocytes and in the formation of the skin barrier to the environment. Here, we investigated whether the evolutionary transition from a terrestrial to a fully aquatic lifestyle of cetaceans, that is dolphins and whales, has been associated with changes in genes encoding filaggrin and proteins involved in the processing of filaggrin. We used comparative genomics, PCRs and re-sequencing of gene segments to screen for the presence and integrity of genes coding for filaggrin and proteases implicated in the maturation of (pro)filaggrin. Filaggrin has been conserved in dolphins (bottlenose dolphin, orca and baiji) but has been lost in whales (sperm whale and minke whale). All other S100 fused-type genes have been lost in cetaceans. Among filaggrin-processing proteases, aspartic peptidase retroviral-like 1 (ASPRV1), also known as saspase, has been conserved, whereas caspase-14 has been lost in all cetaceans investigated. In conclusion, our results suggest that filaggrin is dispensable for the acquisition of fully aquatic lifestyles of whales, whereas it appears to confer an evolutionary advantage to dolphins. The discordant evolution of filaggrin, saspase and caspase-14 in cetaceans indicates that the biological roles of these proteins are not strictly interdependent. PMID- 25739515 TI - Evaluating simulant materials for understanding cranial backspatter from a ballistic projectile. AB - In cranial wounds resulting from a gunshot, the study of backspatter patterns can provide information about the actual incidents by linking material to surrounding objects. This study investigates the physics of backspatter from a high-speed projectile impact and evaluates a range of simulant materials using impact tests. Next, we evaluate a mesh-free method called smoothed particle hydrodynamics (SPH) to model the splashing mechanism during backspatter. The study has shown that a projectile impact causes fragmentation at the impact site, while transferring momentum to fragmented particles. The particles travel along the path of least resistance, leading to partial material movement in the reverse direction of the projectile motion causing backspatter. Medium-density fiberboard is a better simulant for a human skull than polycarbonate, and lorica leather is a better simulant for a human skin than natural rubber. SPH is an effective numerical method for modeling the high-speed impact fracture and fragmentations. PMID- 25739516 TI - Effects of in-feed copper and tylosin supplementations on copper and antimicrobial resistance in faecal enterococci of feedlot cattle. AB - AIMS: The objective was to investigate whether in-feed supplementation of copper, at elevated level, co-selects for macrolide resistance in faecal enterococci. METHODS AND RESULTS: The study was conducted in cattle (n = 80) with a 2 * 2 factorial design of copper (10 or 100 mg kg(-1) of feed) and tylosin (0 or 10 mg kg(-1) of feed). Thirty-seven isolates (4.6%; 37/800) of faecal enterococci were positive for the tcrB and all were Enterococcus faecium. The prevalence was higher among cattle fed diets with copper and tylosin (8.5%) compared to control (2.0%), copper (4.5%) and tylosin (3.5%) alone. All tcrB-positive isolates were positive for erm(B) and tet(M) genes. Median copper minimum inhibitory concentrations (MICs) for tcrB-positive and tcrB-negative enterococci were 20 and 4 mmol l(-1) , respectively. CONCLUSIONS: Feeding of elevated dietary copper and tylosin alone or in combination resulted in an increased prevalence of tcrB and erm(B)-mediated copper and tylosin-resistant faecal enterococci in feedlot cattle. SIGNIFICANCE AND IMPACT OF THE STUDY: In-feed supplementation of elevated dietary copper has the potential to co-select for macrolide resistance. Further studies are warranted to investigate the factors involved in maintenance and dissemination of the resistance determinants and their co-selection mechanism in relation to feed-grade antimicrobials' usage in feedlot cattle. PMID- 25739518 TI - How to count chromosomes in a cell: An overview of current and novel technologies. AB - Aneuploidy, an aberrant number of chromosomes in a cell, is a feature of several syndromes associated with cognitive and developmental defects. In addition, aneuploidy is considered a hallmark of cancer cells and has been suggested to play a role in neurodegenerative disease. To better understand the relationship between aneuploidy and disease, various methods to measure the chromosome numbers in cells have been developed, each with their own advantages and limitations. While some methods rely on dividing cells and thus bias aneuploidy rates to that population, other, more unbiased methods can only detect the average aneuploidy rates in a cell population, cloaking cell-to-cell heterogeneity. Furthermore, some techniques are more prone to technical artefacts, which can result in over- or underestimation of aneuploidy rates. In this review, we provide an overview of several "traditional" karyotyping methods as well as the latest high throughput next generation sequencing karyotyping protocols with their respective advantages and disadvantages. PMID- 25739517 TI - Motion cues improve the performance of harnessed bees in a colour learning task. AB - The proboscis extension conditioning (PER) is a successful behavioural paradigm for studying sensory and learning mechanisms in bees. Whilst mainly used with olfactory and tactile stimuli, more recently reliable PER conditioning has been achieved with visual stimuli such as colours and looming stripes. However, the results reported in different studies vary quite strongly, and it remains controversially discussed how to best condition visual PER. It is particularly striking that visual PER leads to more limited performance as compared to visual conditioning of free-flying bees. It could be that visual PER learning is affected by the lack of movement and that the presence of visual motion cues could compensate for it. We tested whether bees would show differences in learning performances when conditioned either with a colour and motion stimulus in combination or with colour alone. Colour acquisition was improved in the presence of the motion stimulus. The result is consistent with the idea that visual learning might be tightly linked to movement in bees, given that they use vision predominantly during flight. Our results further confirm recent findings that successful visual PER conditioning in bees is achievable without obligatorily removing the antennae. PMID- 25739519 TI - Involvement of the left insula in the ecological validity of the human voice. AB - A subtle difference between a real human and an artificial object that resembles a human evokes an impression of a large qualitative difference between them. This suggests the existence of a neural mechanism that processes the sense of humanness. To examine the presence of such a mechanism, we compared the behavioral and brain responses of participants who listened to human and artificial singing voices created from vocal fragments of a real human voice. The behavioral experiment showed that the song sung by human voices more often elicited positive feelings and feelings of humanness than the same song sung by artificial voices, although the lyrics, melody, and rhythm were identical. Functional magnetic resonance imaging revealed significantly higher activation in the left posterior insula in response to human voices than in response to artificial voices. Insular activation was not merely evoked by differences in acoustic features between the voices. Therefore, these results suggest that the left insula participates in the neural processing of the ecological quality of the human voice. PMID- 25739521 TI - Optical magnetoplasmons in rhombohedral graphite with a three-dimensional Dirac cone structure. AB - Rhombohedral graphite has a three-dimensional Dirac cone structure, differing only perturbatively from the bulk stack of independent graphene layers, so that the three-dimensional integer quantum Hall effect can be well exhibited in this system. In this paper, optical magnetoplasmons are obtained by using the random phase approximation. Such collective excitations do not exist in monolayer graphene but are shown to originate from Landau level mixing due to interlayer Coulomb interaction in the quantum Hall effect regime. The three-dimensional character of rhombohedral graphite is thus demonstrated. The results should be realized in response to a longitudinal external electric field or an incident infrared electromagnetic wave. PMID- 25739520 TI - Efficacy of It's Your Game-Tech: A Computer-Based Sexual Health Education Program for Middle School Youth. AB - PURPOSE: Few computer-based HIV, sexually transmitted infection (STI), and pregnancy prevention programs are available, and even fewer target early adolescents. In this study, we tested the efficacy of It's Your Game (IYG)-Tech, a completely computer-based, middle school sexual health education program. The primary hypothesis was that students who received IYG-Tech would significantly delay sexual initiation by ninth grade. METHODS: We evaluated IYG-Tech using a randomized, two-arm nested design among 19 schools in a large, urban school district in southeast Texas (20 schools were originally randomized). The target population was English-speaking eighth-grade students who were followed into the ninth grade. The final analytic sample included 1,374 students. Multilevel logistic regression models were used to test for differences in sexual initiation between intervention and control students, while adjusting for age, gender, ethnicity, time between measures, and family structure. RESULTS: There was no significant difference in the delay of sexual activity or in any other sexual behavior between intervention and control students. However, there were significant positive between-group differences for psychosocial variables related to STI and condom knowledge, attitudes about abstinence, condom use self efficacy, and perceived norms about sex. Post hoc analyses conducted among intervention students revealed some significant associations: "full exposure" (completion of all 13 lessons) and "mid-exposure" (5-8 lessons) students were less likely than "low exposure" (1-4 lessons) students to initiate sex. CONCLUSIONS: Collectively, our findings indicate that IYG-Tech impacts some determinants of sexual behavior, and that additional efficacy evaluation with full intervention exposure may be warranted. PMID- 25739522 TI - Intercalation and retention of carbon dioxide in a smectite clay promoted by interlayer cations. AB - A good material for CO2 capture should possess some specific properties: (i) a large effective surface area with good adsorption capacity, (ii) selectivity for CO2, (iii) regeneration capacity with minimum energy input, allowing reutilization of the material for CO2 adsorption, and (iv) low cost and high environmental friendliness. Smectite clays are layered nanoporous materials that may be good candidates in this context. Here we report experiments which show that gaseous CO2 intercalates into the interlayer nano-space of smectite clay (synthetic fluorohectorite) at conditions close to ambient. The rate of intercalation, as well as the retention ability of CO2 was found to be strongly dependent on the type of the interlayer cation, which in the present case is Li(+), Na(+) or Ni(2+). Interestingly, we observe that the smectite Li fluorohectorite is able to retain CO2 up to a temperature of 35 degrees C at ambient pressure, and that the captured CO2 can be released by heating above this temperature. Our estimates indicate that smectite clays, even with the standard cations analyzed here, can capture an amount of CO2 comparable to other materials studied in this context. PMID- 25739523 TI - Antiasthmatic effects of resveratrol in ovalbumin-induced asthma model mice involved in the upregulation of PTEN. AB - Resveratrol, a natural polyphenolic compound known for its antioxidative and antiinflammatory effects, exerts antiasthmatic effects, although the mechanism underlying these effects remains elusive. The phosphatase and tensin homology deleted on chromosome ten gene (PTEN) is involved in the pathogenesis of asthma, and PTEN overexpression in asthmatic mice improved asthma symptoms. To investigate whether the antiasthmatic mechanisms of resveratrol correlated with the upregulation of PTEN expression, an ovalbumin (OVA)-induced murine asthma model was used to determine the effectiveness of resveratrol treatment. PTEN mRNA and protein expression was assessed with real-time polymerase chain reaction (PCR) and immunochemistry. To determine whether airway remodeling occurred, the inner airway wall, mucous layer, and smooth muscle areas were each determined using an image analysis system. The lung epithelial cell line 16HBE was used to study the regulation of PTEN expression levels by resveratrol in vitro. Our data demonstrated that resveratrol inhibited OVA-induced airway inflammation and airway remodeling in asthmatic mice. PTEN expression was decreased in the murine asthma model, although the expression of PTEN was restored following treatment with resveratrol. Correlation efficiency analysis showed that PTEN expression was associated with the degree of airway remodeling. Further in vitro studies demonstrated that the inhibition of Sirtuin 1 (SIRT1) activity by a SIRT1 inhibitor and RNA interference decreased PTEN protein expression, while resveratrol attenuated the decreases in PTEN expression induced by the SIRT1 inhibitor. These data suggest the mechanism of the antiasthmatic effects of resveratrol in an OVA-induced murine asthma model, which resulted in the upregulation of PTEN via SIRT1 activation. PMID- 25739524 TI - Cobalt-catalyzed ammonia borane dehydrocoupling and transfer hydrogenation under aerobic conditions. AB - Two cobalt compounds, Cp*Co(CO)I2 (1) and CpCo(CO)I2 (2) (Cp* = eta(5)-C5Me5, Cp = eta(5)-C5H5), catalyze the dehydrogenation of ammonia borane under either anaerobic or aerobic conditions and are also effective hydrogenation catalysts for alkenes and alkynes using ammonia borane as a hydrogen source, also in the presence of air. PMID- 25739525 TI - Studies on uniformity of the active ingredients in acetaminophen suppositories re solidified after melting under high temperature conditions. AB - The target of the present pharmaceutical study was the antipyretic analgesic, acetaminophen; its suppository form is usually split when used in pediatric patients. We focused on the active ingredient uniformity in these products, which were re-solidified after melting under high temperature condition. When sections of the cut surfaces of the seven acetaminophen suppository products (SUP-A-G) commercially available in Japan were visualized by polarized microscopy, acetaminophen crystals that were dispersed in the base were identified. The results of the quantitative determination of agent concentration for each cut portion (mg/g) suggested uniform dispersion of these crystals in the base of each product. The agent concentration in each portion of the suppositories that was re solidified after melting at high temperatures was measured. Segregation of the active ingredient was observed in four products at a temperature of 40 degrees C for 1 h, while active ingredient uniformity was maintained in the other three products (SUP-C, SUP-F and SUP-G). The latter three products also showed high viscosity at 40 degrees C. At 50 degrees C for 4 h, only the uniformity of the active ingredient in SUP-C was maintained. These results suggest that the uniformity of the active ingredient is lost in some acetaminophen suppositories that were re-solidified after melting under high temperature conditions. The degree of loss varies depending on the product. PMID- 25739526 TI - SERT and NET polymorphisms, temperament and antidepressant response. AB - BACKGROUND: The genetic variations in norepinephrine transporter (NET) and serotonin transporter (SERT) genes have been associated with personality traits, several psychiatric disorders and the efficacy of antidepressant treatment. AIMS: We investigated the separate effects and possible interactions between NET T-182C (rs2242446) and SERT 5-HTTLPR (rs4795541) polymorphisms on selective serotonin reuptake inhibitors (SSRI) treatment response and temperamental traits assessed by the Temperament and Character Inventory (TCI) in a clinical sample of subjects with major depressive disorder (MDD). METHODS: Our sample of 97 patients with major depression completed the 107-item TCI temperament questionnaire (version IX) at the initial assessment of the study and after 6 weeks of follow-up. All subjects received selective SSRI medications. Temperament dimension scores at baseline ( 1 ) and endpoint ( 2 ) during antidepressant treatment were analyzed between NET and SERT genotypes. RESULTS: SS-genotype of 5-HTTLPR was associated with higher baseline Persistence scores than SL- or LL-genotype. A corresponding but weaker association was found at endpoint. No differences were found between 5 HTTLPR genotypes and other temperament dimensions and 5-HTTLPR genotypes had no effect on treatment response. CONCLUSIONS: Our results suggest that the SS genotype of 5-HTTLPR is associated with Persistence scores in patients with MDD. Higher Persistence could be viewed as a negative trait when recovering from stress and its association with short and "weaker" S-allele may be related to less efficient serotonin neurotransmission, possibly resulting in less effective coping strategies on a behavioral level. PMID- 25739527 TI - Enhancing sense of coherence via early intervention among depressed occupational health care clients. AB - BACKGROUND: Research on interventions improving psychological adjustment has suggested that sense of coherence (SOC) could be improved. AIMS: In the present study, we measured the impact of an intervention on the SOC among adults with first-episode depression. We also examined whether rehabilitation, depression, occupational stressors, life situation stressors and socio-demographic characteristics are associated with a change in the SOC. METHODS: Occupational health care clients were screened for depression using the Beck Depression Inventory (BDI) and a structured clinical interview (the The Structured Clinical Interview for DSM-IV: SCID-I). The participating subjects were randomized into a rehabilitation group (n = 134) and control group (n = 100) receiving treatment as usual. The Sense of Coherence Scale (SOC-13) was used at the baseline and in a 1 year follow-up to compare the change of the SOC between the groups. RESULTS: The increase in the mean SOC score was statistically significant both in the rehabilitation group (54.91 compared with 62.85, P < 0.001) and in the control group (55.29 compared with 61.64, P < 0.001). There was no significant difference in the mean SOC scores between the groups at the follow-up. The improved SOC was associated with less severe depression (P = 0.003) and greater decreasing in BDI (P = 0.041) in the rehabilitation group. CONCLUSIONS: The results suggest that both rehabilitation and conventional depression treatment in a first episode of depression may enhance the SOC and that rehabilitation itself enhances the SOC more effectively among those with less severe depression or those whose BDI scores had further decreased at the 1-year follow-up. PMID- 25739528 TI - The effect of the temperature changes of EDTA and MTAD on the removal of the smear layer: a scanning electron microscopy study. AB - The purpose of this study was to determine the effectiveness of EDTA and MTAD at different temperatures as a final irrigant to remove the smear layer after the use of 5.25% NaOCl. Seventy-eight human mandibular premolars with single straight canal were prepared by a crown-down technique using rotary 0.06 taper nickel titanium files. Final irrigation was performed with EDTA and MTAD at different temperatures. The removal of the smear layer in the coronal, middle and apical level of each canal was examined under scanning electron microscope. No difference was found between the EDTA and MTAD at 4 degrees C, 25 degrees C, and 37 degrees C temperatures regardless of the canal level (coronal, middle and apical) (P = 0.286). In EDTA-25, EDTA-37, MTAD-25, and MTAD-37 groups, the difference among the coronal, middle, and apical levels were statistically no significant (P > 0.05). Our findings showed that EDTA and MTAD at 25 degrees C and 37 degrees C are more effective than EDTA and MTAD at 4 degrees C even in the apical level. PMID- 25739529 TI - Parenting a child with autism in India: narratives before and after a parent child intervention program. AB - In many low and middle income countries where autism-related resources are scarce, interventions must rely on family and parents. A 3-month Parent-Child Training Program (PCTP) at Action For Autism, New Delhi, India is aimed at empowering and educating parents, encouraging acceptance of their child, and decreasing parent stress. Forty couples were asked to describe their child with autism using the Five Minute Speech Sample (FMSS), an open-ended narrative method, before and after the program. Parents described a wide range of child behaviors, primarily social and cognitive skills. While all families were of a relatively affluent strata compared to the general Indian population, there were nonetheless significant differences in parents' narratives based on their income levels. Coming into the program, parents with relatively less income focused on their child's immediate and material needs, while higher income parents discussed their parental roles and vision for society. After the PCTP, parents were more likely to reflect on their child beyond comparisons to 'normality,' and beyond the here-and-now. Mothers were more likely than fathers to reflect on themselves and their relationships with their child. Understanding parents' experiences and narratives is essential for the evaluation of interventions such as the PCTP, as Indian parents are incorporated into a growing global network of 'parents of children with autism.' PMID- 25739530 TI - "Maybe at birth there was an injury": drivers and implications of caretaker explanatory models of autistic characteristics in Kerala, India. AB - Explanatory models (EMs) are the way people explain the presence and meaning of an illness or disability and are reliant on and reflective of culturally specific values of normalcy, disability, health, and illness. EMs about autism spectrum disorder (ASD) are particularly revealing because there is no known cause, and so people can explain this disability in ways more appropriate for and useful to them. This article presents caretaker EMs about children with autistic characteristics in Kerala, India. I argue that the reliance on biological, but not genetic, causal models is reflective of the state's high access to biomedical heath care. These EMs are used to deflect the stigma of 'bad blood' and reflect a nuanced relationship between stigma and biological EMs. Understanding how caretakers talk about ASD and related conditions is critical for anyone interested in engaging in crosscultural or international autism-related work. PMID- 25739531 TI - A new water-soluble phosphorus-dipyrromethene and phosphorus-azadipyrromethene dye: PODIPY/aza-PODIPY. AB - PODIPY and aza-PODIPY have been successfully prepared by the treatment of dipyrromethene and azadipyrromethene with POCl3 in the presence of Et3 N. The new PODIPY and aza-PODIPY dyes are found to have photophysical properties. PODIPY and aza-PODIPY are water-soluble, and aza-PODIPY is suited for labeling living Hep-2 cells for imaging assays in the near-infrared region. Molecular orbital calculations show that the increase in the HOMO-LUMO band gap for the lowest energy absorption bands is observed in the new phosphorus-containing aza-PODIPY, and the HOMO and LUMO energies of aza-PODIPY are found to be higher than those of aza-BODIPY. PMID- 25739532 TI - Contact sensitization to Geranium robertianum L. in an amateur gardener. PMID- 25739533 TI - Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. AB - The effectiveness and safety of dabigatran for stroke prevention in atrial fibrillation (SPAF) demonstrated in RE-LY needs to be confirmed in daily care. To evaluate treatment persistence, effectiveness and safety of dabigatran therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non interventional registry of more than 2,500 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 341 SPAF patients receiving dabigatran were enrolled. The combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.93/100 patient-years in the intention-to-treat analysis (95%-CI 1.6-4.9) and at 1.9/100 patient-years in the on treatment analysis (events within three days after last intake). On-treatment rates were higher in patients selected for 110 mg dabigatran (n=183) BID compared to the 158 patients selected for 150 mg BID (2.88 [95% CI 1.16- 5.93] vs 0.86/100 patient-years [95% CI 0.10, 3.12]). On treatment, major bleeding occurred at a rate of 2.3/100 patient-years and numerically more often in patients receiving the 110 mg BID dose compared to the 150 mg BID dose (2.9 vs 1.7/100 patient-years). Dabigatran treatment discontinuation occurred in a total of 124 patients during follow-up (25.8 per 100 patient-years in Kaplan Meier analysis). Main reasons for treatment discontinuation were non-bleeding side effects. Our data contribute to the confirmation of effectiveness and relative safety of dabigatran in unselected patients in daily care. However, discontinuation rates are not lower than those reported for patients treated with vitamin K antagonists. PMID- 25739534 TI - Significant Association between Serum Monokine Induced by Gamma Interferon and Carotid Intima Media Thickness. AB - AIM: The immune system may play an important role in the pathogenesis of cardiovascular disease. T cell-driven inflammation in human hypertension and atherosclerosis has recently been revealed. In the present study, we evaluated the association between serum levels of the C-X-C chemokine receptor type 3 chemokines and the carotid intima media thickness (IMT) in humans. METHODS: One hundred sixty-four consecutive patients undergoing baseline and 2-year follow-up carotid IMT (110 men, 62.4+/-10.0 years) were enrolled. The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at baseline and after 24 months. Clinical and laboratory variables, including serum levels of the monokine induced by gamma interferon (MIG) and interferon gamma-induced protein 10 (IP-10), were analyzed at the time of initial enrollment. RESULTS: The baseline max- and mean-IMT were 0.992+/-0.235 and 0.793+/-0.191 mm, respectively. The serum levels of MIG and IP-10 significantly correlated with the carotid IMT. However, there was no significant correlation between the serum levels of MIG or IP-10 and IMT changes. A multivariate regression analysis revealed the serum MIG to be independently associated with the carotid IMT (max-IMT: beta=0.194, p=0.010; mean-IMT: beta=0.184, p=0.016) when controlled for age, sex, diabetes mellitus history, smoking history, body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and aspirin and statin medication. CONCLUSIONS: Circulating MIG levels are independently associated with the carotid IMT, after adjusting for confounding factors and medications. These findings indicate the potential clinical implication of MIG with respect to early atherosclerosis in humans. PMID- 25739535 TI - A triphenylphosphine mediated photo-rearrangement and methanol addition of aryl chalcones to 1-propanones. AB - Aryl chalcones rearrange and add methanol to give substituted propane-1-ones upon UV-A irradiation in the presence of PPh3. We propose two possible mechanisms for this photo-rearrangement. The reaction involves either the formation of a phosphine-carbonyl intermediate, nucleophilic addition of MeOH and 1,2-aryl migration or the formation of ylide and carbene intermediates. The intermediates trapped from the reaction mixture support the first mechanistic hypothesis. PMID- 25739537 TI - Spatial distribution and temporal trends of VOCs in a highly industrialized town in Turkey. AB - An extensive monitoring study of volatile organic compounds (VOCs) was conducted at sites across the highly industrialized town of Dilovasi, northern Turkey to determine temporal and spatial trends in pollutant concentrations and relate to the effects of source locations, meteorology, and topography. Two-week passive samplers (Tenax tubes) were deployed at twelve sites from February to December 2012 and analysed using thermal desorption and gas chromatography with mass spectrometric detection (TD-GC-MS). Sampled total VOC (TVOC) levels were highest in the July through October period and were highest at low-altitude sites near industry facilities and vehicle traffic sources (148.3 ug/m(3) at site 11, 154.1 ug/m(3) at site 10) and lowest at high-altitude sites located furthest upwind from industry and traffic sources (78.4 ug/m(3) at site 5 and 78.5 ug/m(3) at site 6). Analysis of "T/B" ratios suggested that contributions to ambient VOC in Dilovasi are dominated by the town's industrial sources. Meteorological conditions and the town's basin topography were also found to significantly influence the city's air quality, with strong winds from the NE observed to correlate with periods of higher sampled TVOC. Compared with other industrialized urban centers, the study revealed that there is significant toluene pollution in Dilovasi and recommended enhanced continuous monitoring at the city's industrial and residential zones. PMID- 25739536 TI - Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain. AB - Major depressive disorder and alcoholism are significant health burdens that can affect executive functioning, cognitive ability, job responsibilities, and personal relationships. Studies in animal models related to depression or alcoholism reveal that the expression of Kruppel-like factor 11 (KLF11, also called TIEG2) is elevated in frontal cortex, which suggests that KLF11 may play a role in stress- or ethanol-induced psychiatric conditions. KLF11 is a transcriptional activator of monoamine oxidase A and B, but also serves other functions in cell cycle regulation and apoptotic cell death. In the present study, immunohistochemistry was used to quantify intensity of nuclear KLF11, combined with an unbiased stereological approach to assess nuclei in fronto limbic, limbic, and other brain regions of rats exposed chronically to social defeat or ethanol. KLF11 immunoreactivity was increased significantly in the medial prefrontal cortex, frontal cortex, and hippocampus of both stressed rats and rats fed ethanol. However, expression of KLF11 protein was not significantly affected in the thalamus, hypothalamus, or amygdala in either treatment group compared to respective control rats. Triple-label immunofluorescence revealed that KLF11 protein was localized in nuclei of neurons and astrocytes. KLF11 was also co-localized with the immunoreactivity of cleaved caspase-3. In addition, Western blot analysis revealed a significant reduction in anti-apoptotic protein, Bcl-xL, but an increase of caspase-3 expression in the frontal cortex of ethanol treated rats compared to ethanol-preferring controls. Thus, KLF11 protein is up regulated following chronic exposure to stress or ethanol in a region-specific manner and may contribute to pro-apoptotic signaling in ethanol-treated rats. Further investigation into the KLF11 signaling cascade as a mechanism for neurotoxicity and cell death in depression and alcoholism may provide novel pharmacological targets to lessen brain damage and maximize neuroprotection in these disorders. PMID- 25739538 TI - Arsenite Interacts with Dibenzo[def,p]chrysene (DBC) at Low Levels to Suppress Bone Marrow Lymphoid Progenitors in Mice. AB - Arsenite (As(+3)) and dibenzo[def,p]chrysene (DBC), a polycyclic aromatic hyrdrocarbon (PAH), are found in nature as environmental contaminants. Both are known to individually suppress the immune system of humans and mice. In order to determine their potential interactive and combined immunosuppressive effects, we examined murine bone marrow (BM) immune progenitor cells' responses following combined oral exposures at very low levels of exposure to As(+3) and DBC. Oral 5 day exposure to DBC at 1 mg/kg (cumulative dose) was found to suppress mouse BM lymphoid progenitor cells, but not the myeloid progenitors. Previously established no-effect doses of As(+3) in drinking water (19 and 75 ppb for 30 days) produced more lymphoid suppression in the bone marrow when mice were concomitantly fed a low dose of DBC during the last 5 days. The lower dose (19 ppb) As(+3) had a stronger suppressive effect with DBC than the higher dose (75 ppb). Thus, the interactive toxicity of As(+3) and DBC in vivo could be As(+3) dose dependent. In vitro, the suppressive interaction of As(+3) and DBC was also evident at low concentrations (0.5 nM), but not at higher concentrations (5 nM) of As(+3). These studies show potentially important interactions between As(+3) and DBC on mouse BM at extremely low levels of exposure in vivo and in vitro. PMID- 25739539 TI - Bioaccessibility of Copper in Turkish Hazelnuts (Corylus avellana L.) by Chemical Fractionation and In Vitro Methods. AB - Copper is known as either an essential or toxic trace element in foods to living organisms at sufficient or excess intake levels, respectively. In this study, in vitro simulated gastric and intestinal digestion methods combined with n-octanol extraction and activated carbon adsorption were applied to Turkish hazelnuts (Corylus avellana L.) to evaluate the bioaccessibility of copper. Additionally, analytical fractionation procedures based on water, diethyl ether, n-hexane, and methanol extractions were applied to identify copper-related matrix structures. The macrochemical compositions of the samples were determined to be associated with the fractionation results. The total contents of copper in the samples, digests, and fractions were determined by inductively coupled plasma mass spectrometry after microwave-assisted digestion, and additional validation was performed using atomic absorption spectroscopy. The limits of detection and quantification were 0.016 and 0.053 mg kg(-1), respectively. The bioaccessibility of copper was found to be in the range from 16 to 31 % for hazelnut samples. The recommended dietary allowance of copper for adults is 0.9 mg daily, and considering this value, 100 g of hazelnuts supplies 33-44 % of daily copper intake. PMID- 25739540 TI - Selenium Deficiency Downregulates Selenoproteins and Suppresses Immune Function in Chicken Thymus. AB - Selenoproteins and selenium (Se) play important roles in the immune system. Selenoprotein expression in the immune system of mammals is sensitive to dietary Se levels; however, little is known about the expression of selenoproteins and their immune functions in the chicken thymus. We assessed selenoprotein gene expression and cytokine content in the chicken thymus in this study. The animals were randomly assigned to two groups as follows: the Se-deficient group (L group) was fed a diet containing 0.033 mg Se/Kg, and the control group was fed the same basal diet supplemented with Se at 0.15 mg/kg (sodium selenite). Real-time qPCR was used to investigate the expression level of selenoproteins on days 15, 25, 35, 45, and 55, and ELISA was used to evaluate the cytokine content on days 15, 35, and 55. The messenger RNA (mRNA) levels of Txnrd1, Txnrd2, Txnrd3, Dio1, Dio2, Dio3, GPx1, GPx2, GPx3, Gpx4, Sepp1, Selo, Sep15, Sepx1, Sels, Seli, Selu, Selh, and SPS2 were all significantly decreased (P < 0.05) in the L group compared to the control group. A significant decrease in IL-2, IL-10, IL-17, IL 1beta, IFN-alpha, and IFN-beta was observed in the L group, and there was also a significant increase in IL-6, IL-8, IFN-gamma, and TNF-alpha in the L group. In summary, Se deficiency results in significant changes in the expression of selenoproteins, which may cause oxidative stress in the chicken thymus tissue. Moreover, immunological changes and immune stress may occur because of Se deficiency in the chicken thymus. PMID- 25739547 TI - EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide. AB - BACKGROUND: Lack of robust predictive biomarkers, other than MGMT promoter methylation, makes temozolomide responsiveness in newly diagnosed glioblastoma (GBM) patients difficult to predict. However, we identified patients with long term survival (>=35 months) within a group of newly diagnosed GBM patients treated with standard or metronomic adjuvant temozolomide schedules. We thus investigated possible molecular profiles associated with longer survival following temozolomide treatment. METHODS: We investigated the association of molecular features with progression-free (PFS) and overall survival (OS). Human derived GBM cancer stem cells (CSCs) were used to investigate in vitro molecular mechanisms associated with temozolomide responsiveness. Surgically removed recurrences allowed investigation of molecular changes occurring during therapy in vivo. Statistical analyses included one- and two-way analysis of variance, Student's t test, Cox proportional hazards, and the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: No association was found between survival and gene classifiers associated with different molecular GBM subtypes in the standard-treated group, while in metronomic-treated patients robust association was found between EGFR amplification/overexpression and PFS and OS (OS, EGFR-high vs low: hazard ratiodeath = 0.22, 95% confidence interval = 0.09 to 0.55, P = .001). The result for OS remained statistically significant after Bonferroni correction (P interaction < .0005). Long-term survival following metronomic temozolomide was independent from MGMT and EGFRvIII status and was more pronounced in EGFR-overexpressing GBM patients with PTEN loss. In vitro findings confirmed a selective dose- and time-dependent decrease in survival of temozolomide-treated EGFR+ human-derived glioblastoma CSCs, which occurred through inhibition of NF-kappaB transcriptional activity. In addition, reduction in EGFR-amplified cells, along with a statistically significant decrease in NF kappaB/p65 expression, were observed in specimens from recurrent metronomic treated EGFR-overexpressing GBM patients. CONCLUSIONS: EGFR amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies. PMID- 25739548 TI - Analysis of serum heat shock protein 70 (HSPA1A) concentrations for diagnosis and disease activity monitoring in patients with rheumatoid arthritis. AB - Heat shock proteins (HSPs) have been repeatedly implicated in the pathogenesis of rheumatoid arthritis (RA). The authors aimed to study applicability of heat shock protein 70 (HSPA1A) serum levels as a diagnostic factor and a severity indicator in patients with RA and to quantify cut-off point that predicts status of RA with highest specificity. A total of 76 patients with RA and 36 healthy adults were studied in this case-control analysis. Patients had a higher HSPA1A level than the control group (0.78 +/- 0.13 vs. 0.12 +/- 0.02 ng/mL, p = 0.006), irrespective of presence of absence of rheumatoid factor or anti-citrullinated cyclic peptide. Next, diagnostic accuracy of the HSPA1A in diagnosis of RA was evaluated (area under curve 0.71; p < 0.05). HSPA1A predicted status of having RA in levels above 0.42 ng/mL with more than 90 % specificity. In addition to diagnostic value, HSPA1A can distinguish between high disease activity (1.66 +/- 0.75 ng/mL) and low (0.49 +/- 0.1 ng/mL), moderate (0.52 +/- 0.12 ng/mL), or remission phase (0.48 +/- 0.11 ng/mL). Moreover, patients in remission still had a higher HSPA1A level compared to normal subject (0.48 +/- 0.11 vs. 0.12 +/- 0.02 ng/mL, p < 0.05). Our results showed that serum HSPA1A could be implemented as a specific tool to facilitate diagnosis and monitoring disease activity in patients with rheumatoid arthritis. PMID- 25739549 TI - Cross-sectional study of social support and psychological distress among displaced earthquake survivors in Japan. AB - AIM: This cross-sectional study aims to explore the relationship between different types and sources of social support and psychological distress by age and sex among survivors living in temporary housing 10 months after the Great East Japan Earthquake. METHODS: Self-reported questionnaires/structured interviews administered from January to March 2012 recorded demographic characteristics, damage involving participants' families, social support, and psychological distress. RESULTS: Data on 296 participants aged 20 years or more from nine temporary housing complexes in Otsuchi were analyzed; K6 scores indicating psychological distress averaged 5.1 (standard deviation, 5.9; range, 0 24). Multiple logistic regression analyses indicated differences among types and sources of social support with regard to psychological distress by age and sex among disaster survivors. For men aged less than 65 years, social support by family was related to lower psychological distress. For women aged 65 years or more, emotional support from family, informational and instrumental support, and social companionship from friends in their own temporary housing complexes were related to less psychological distress. CONCLUSION: Differences in age and sex were related to different sources of social support in relation to psychological distress. It is necessary to pay more attention to those who lost family members in the disaster, especially men aged less than 65 years. It may also be necessary to support survivors in making friends when they relocate to temporary housing, especially women aged 65 years or more. PMID- 25739550 TI - "Waiting for Better Times": Experiences in the First Postpartum Year by Swedish Fathers With Depressive Symptoms. AB - Swedish fathers are largely involved in their infant's care, and Sweden has a generous parental leave, with 2 months especially assigned for fathers. The prevalence of depressive symptoms postpartum for fathers appears to be similar as for mothers in Sweden. This study aimed to describe fathers' experiences of the first year postpartum, when they showed depressive symptoms 3 to 6 months postpartum. Semistructured interviews with 19 fathers were conducted and analyzed with content analysis. The fathers experienced loss of control and powerlessness due to discrepancies between their expectations and the reality they met after birth. They found the everyday-life turbulent, with much stress and worries for the infant, conflicts between family and work, and lack of support in everyday life. In addition, the fathers struggled with impaired partner-relationship, losses, and contradictory messages from both the society and their partners. These findings indicate that the fathers had difficulties to balance the competing demands of family, work, and their own needs. Thus, it is important to identify fathers with depressive symptoms at the Child Health Care Centers and attend to fathers' needs of support and acknowledge them as parents equal to mothers. PMID- 25739551 TI - HER3 protein expression in relation to HER2 positivity in patients with primary colorectal cancer: clinical relevance and prognostic value. AB - The clinical and prognostic significance of HER3 expression and its relation to HER2 status in primary colorectal cancer (pCRC) were investigated. We retrospectively analysed 365 consecutive cases of pCRC that had been previously evaluated for HER2 status and included their 143 matched lymph node metastases. Immunohistochemistry (IHC) was performed to assess HER3 expression using tissue array methods. Of 364 eligible patients, HER3 overexpression was detected in 251 cases (69 %) (IHC 2+, n = 186 and IHC 3+, n = 65). HER3 overexpression was inversely correlated with histologic grade (p = 0.006), tumour size (p < 0.001), tumour depth (p < 0.001), TNM stage (p = 0.002), lymphatic invasion (p = 0.004), lymph node metastasis (p = 0.013) and distant metastasis (p = 0.039). Moreover, it positively correlated with both HER2 overexpression (p = 0.007) and HER2 gene amplification (p = 0.006). Although HER3 overexpression was associated with longer survival in univariate analysis (p = 0.026), it was not an independent prognostic factor in multivariate analysis (p = 0.359). Moreover, co-alteration of HER3 and HER2 was associated with neither survival nor any clinicopathologic parameter except tumour location in the rectum. Although not an independent prognostic factor for overall survival, HER3 overexpression was associated with several favourable prognostic clinicopathologic parameters. Additionally, HER3 overexpression strongly correlated with HER2 positivity in this cohort of patients. PMID- 25739552 TI - An approach to fertility preservation in prepubertal and postpubertal females: a critical review of current literature. AB - Advancements in childhood cancer treatment have led to increasing survivorship, creating a greater emphasis on long-term management of patients, including quality of life and side effects from therapy; foremost of which is preserving fertility. The American Society of Clinical Oncology (ASCO) recently revised their guidelines and recommend fertility preservation options be discussed at the earliest possible opportunity for newly diagnosed patients, including methods available for children that remain investigational. Herein, we discuss the current barriers to and the impact of these guidelines for pediatric oncologists caring for young female patients, and provide some suggestions on how to approach this complicated topic. PMID- 25739553 TI - Long-term modeling on HPV vaccination: do we really need any more? AB - The human papillomavirus (HPV) is closely related to cervical cancer. In 2007, the EMA approved two vaccines, a bivalent and a quadrivalent one, launched at three-dose schedules and very high prices worldwide. We describe what happened in the EU and what might change in the near future from an economic perspective. HPV vaccination is now established in most EU countries. The main target group of the programs is girls aged 10-14 years. Many western countries used competitive tendering to purchase the two vaccines, achieving considerable savings. The extension to males has been a hotly debated issue. The sex limitation implies that this vaccination cannot by definition achieve a 'herd immunity' effect. EMA recently approved a two-dose schedule for both vaccines that should lead to savings, although it is hard to predict how the forthcoming nonavalent vaccine will affect the market situation. Several economic evaluations based on long-term models have been published on the HPV vaccination in the recent years, using official list prices as a baseline. Most of these models can be considered mere exercises in long-term forecasting. Recently, further long-term models have been published with two- and three-dose schedules as alternatives, and the nonavalent vaccine. We wonder what added value they give for public policy purposes. PMID- 25739554 TI - Nanospheres of doxorubicin as cross-linkers for a supramolecular hydrogelation. AB - In this study, we synthesized a peptide of Nap-GFFYGRGD, which could self assemble into supramolecular nanofibers. The peptide itself could only form nanofibers but not hydrogels due to the relative weak inter-fiber interactions. The resulting nanofibers were then utilized as the vehicles for anticancer drug doxorubicin. It was found that the nanofibers of Nap-GFFYGRGD could not encapsulate doxorubicin, whereas the drug formed nanospheres, which were located at the surface of the nanofibers. Due to the electrostatic interactions between the negatively charged nanofibers and the positively charged doxorubicin nanospheres, the doxorubicin nanospheres were able to serve as a cross-linker to increase the inter-fiber interactions, leading to the formation of stable three dimentional fiber networks and hydrogels. The resulting doxorubicin-peptide hydrogels were capable of releasing the drug in a sustained manner, which also showed comparable cytotoxicity as compared to free doxorubicin against a variety of cancer cell lines including HeLa and MCF-7 cancer cells. Therefore, this successful example using drug as the peptide nanofiber cross-linkers provided a new strategy for fabricating supramolecular hydrogelation for controlled delivery of anticancer drugs. PMID- 25739555 TI - Aerobic capacity in persons with multiple sclerosis: a systematic review and meta analysis. AB - BACKGROUND: Aerobic capacity (VO2max) is a strong health and performance predictor and is regarded as a key physiological measure in the healthy population and in persons with multiple sclerosis (PwMS). However, no studies have tried to synthesize the existing knowledge regarding VO2max in PwMS. OBJECTIVES: The objectives of this study were to (1) systematically review the psychometric properties of the VO2max test; (2) systematically review the literature on VO2max compared with healthy populations; (3) summarize correlates of VO2max; and (4) to review and conduct a meta-analysis of longitudinal exercise studies evaluating training-induced effects on VO2max in PwMS. DATA SOURCES AND STUDY SELECTION: A systematic literature search of six databases (PubMed, EMBASE, Cochrane Library, PEDro, CINAHL and SPORTDiscus) was performed. To be included, the study had to (1) enrol participants with definite MS according to defined criteria; (2) assess aerobic capacity (VO2max) by means of a graded exercise test to voluntary exhaustion; (3) had undergone peer review; and (4) be available in English, Danish or Dutch. STUDY APPRAISAL AND SYNTHESIS METHODS: The psychometric properties of the VO2max test in PwMS were reviewed with respect to reliability, validity and responsiveness. Simple Pearson correlation analysis was used to assess the relation between key study characteristics and the reported mean VO2max. The methodological quality of the intervention studies was evaluated using the original 11-item Physiotherapy Evidence Database (PEDro) scale. A random coefficient model was used to summarize individual, weighted, standardized effects of studies that assessed the effects of exercise on aerobic capacity in PwMS. RESULTS: A total of 40 studies, covering 165 healthy controls and 1,137 PwMS, fulfilled the inclusion criteria. VO2max testing in PwMS can be considered a valid measure of aerobic capacity, at least in PwMS having low-to-mild disability, and an ~10% change between two tests performed on separate days can be considered the smallest reliable change (with 95% certainty) in VO2max in PwMS. The average body-weight-adjusted VO2max was significantly lower in PwMS (25.5 +/- 5.2 mL.kg(-1).min(-1)) compared with healthy controls (30.9 +/- 5.4 mL.kg(-1).min(-1)). The analysis of VO2max correlates revealed associations with a variety of outcomes covering all levels of the International Classification of Functioning, Disability and Health (ICF) model. The meta-analysis showed that aerobic training in PwMS may improve VO2max by as much as 3.5 mL.kg(-1).min(-1). CONCLUSIONS: A valid and reliable test can be performed, in at least ambulant PwMS, by the gold standard whole-body maximal exercise test. Aerobic capacity in PwMS is impaired compared with healthy people, and is significantly associated with factors on all levels of the ICF model, including disease severity. Aerobic training can improve aerobic capacity in PwMS to a degree that is associated with secondary health benefits. PMID- 25739556 TI - Authors' Reply to Li et al.: "Alternative Statistical Analysis Shows Exercise Training-Induced Improvements in Peak VO2 are Clinically Significant". PMID- 25739557 TI - Alternative Statistical Analysis Shows Exercise Training-Induced Improvements in Peak VO2 are Clinically Significant. PMID- 25739558 TI - Black and White race differences in aerobic capacity, muscle fiber type, and their influence on metabolic processes. AB - Obesity is a known risk factor for cardiometabolic disease. Increasing aerobic capacity (VO2max) reduces adiposity, maintains weight, and reduces the risk of developing obesity and cardiometabolic disease. Two major determinants of aerobic capacity are the metabolic properties specific to a particular muscle fiber type and the capacity of the cardiorespiratory system to deliver nutrient-rich content to the muscle. Recent research suggests that some race/ethnic groups, particularly non-Hispanic Black subjects, are predisposed to a reduced VO2max by way of muscle fiber type. Combined with insufficient physical activity, these characteristics place non-Hispanic Black subjects at an increased risk for obesity and other adverse health outcomes when compared with other race/ethnic groups. The purpose of this review was to suggest a model for explaining how skeletal muscle fiber type may contribute to reduced aerobic capacity and obesity among non-Hispanic Black subjects. Our review indicates that metabolic properties of type II skeletal muscle (e.g. reduced oxidative capacity, capillary density) are related to various cardiometabolic diseases. Based on the review, non Hispanic Black subjects appear to have a lower maximal aerobic capacity and a greater percentage of type II skeletal muscle fibers. Combined with reduced energy expenditure and reduced hemoglobin concentration, non-Hispanic Black subjects may be inherently predisposed to a reduced maximal aerobic capacity compared with non-Hispanic White subjects, thereby increasing the risk for obesity and related metabolic diseases. PMID- 25739559 TI - A review of resistance training-induced changes in skeletal muscle protein synthesis and their contribution to hypertrophy. AB - Muscle protein synthesis (MPS) is stimulated by resistance exercise (RE) and is further stimulated by protein ingestion. The summation of periods of RE-induced increases in MPS can induce hypertrophy chronically. As such, studying the response of MPS with resistance training (RT) is informative, as adaptations in this process can modulate muscle mass gain. Previous studies have shown that the amplitude and duration of increases in MPS after an acute bout of RE are modulated by an individual's training status. Nevertheless, it has been shown that the initial responses of MPS to RE and nutrition are not correlated with subsequent hypertrophy. Thus, early acute responses of MPS in the hours after RE, in an untrained state, do not capture how MPS can affect RE-induced muscle hypertrophy. The purpose of this review is provide an in-depth understanding of the dynamic process of muscle hypertrophy throughout RT by examining all of the available data on MPS after RE and in different phases of an RT programme. Analysis of the time course and the overall response of MPS is critical to determine the potential protein accretion after an RE bout. Exercise-induced increases in MPS are shorter lived and peak earlier in the trained state than in the untrained state, resulting in a smaller overall muscle protein synthetic response in the trained state. Thus, RT induces a dampening of the MPS response, potentially limiting protein accretion, but when this occurs remains unknown. PMID- 25739560 TI - Combined biological removal of methylene blue from aqueous solutions using rice straw and Phanerochaete chrysosporium. AB - The aim of this study was to develop a low-cost and environmental friendly treatment method for the removal of cationic dye from wastewater. Rice straw powder combined with the white rot fungus Phanerochaete chrysosporium (P. chrysosporium) were used to remove methylene blue (MB) from wastewater at varied operational conditions. Results demonstrated that this combined biodegradation and adsorption method was effective for the removal of MB from aqueous solutions; a maximum removal efficiency of 88 % was achieved for an initial dye concentration of 400 mg/L. Of the total removed MB, 28.4 % was biodegraded by P. chrysosporium, and the rest was adsorbed on the biodegraded rice straw and the fungal cells. The amount of total adsorbed MB in the treatment group (400 mg/L) is almost three times of that in the control without P. chrysosporium group. This significant improvement in the adsorption capacity is mainly because P. chrysosporium increased the specific surface area of the straw and produced more functional groups on it. Besides, P. chrysosporium also affect the pH in a positive way for the adsorption. PMID- 25739561 TI - Curcumin ameliorates asthmatic airway inflammation by activating nuclear factor E2-related factor 2/haem oxygenase (HO)-1 signalling pathway. AB - Previous studies have shown that curcumin alleviates asthma in vivo. However, the relationship between curcumin and the nuclear factor-E2-related factor 2 (Nrf2)/haem oxygenase (HO)-1 pathway in asthma treatment remains unknown. The aim of the present study was to investigate the mechanisms of curcumin involved in the amelioration of airway inflammation in a mouse asthma model. Curcumin was administrated to asthmatic mice, and bronchoalveolar lavage fluid was collected. Inflammatory cell infiltration was measured by Giemsa staining. Immunoglobulin E production in bronchoalveolar lavage fluid was measured by enzyme-linked immunosorbent assay. Histological analyses were evaluated with haematoxylin-eosin and periodic acid-Schiff staining. Airway hyperresponsiveness was examined by whole-body plethysmography. Nuclear factor-E2-related factor 2, HO-1, nuclear factor-kappaB and inhibitory kappaB/p-inhibitory kappaB levels in lung tissues were detected by western blot, and Nrf2 activity was measured by electrophoretic mobility shift assay. Tumour necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 levels in the small interfering RNA-transfected cells were detected by enzyme-linked immunosorbent assay. Curcumin treatment significantly reduced immunoglobulin E production, attenuated inflammatory cell accumulation and goblet cell hyperplasia, and ameliorated mucus secretion and airway hyperresponsiveness. Nuclear factor-E2-related factor 2 and HO-1 levels in lung tissues were significantly increased. Meanwhile, Nrf2 activity was enhanced. Nuclear factor kappaB and p-inhibitory kappaB levels were elevated in the lung tissue of ovalbumin-challenged mice. Both were restored to normal levels after curcumin treatment. Haem oxygenase-1 and nuclear Nrf2 levels were enhanced in dose- and time-dependent manners in curcumin-treated RAW264.7 cells. Curcumin blocked lipopolysaccharide-upregulated expression of tumour necrosis factor-alpha, IL 1beta, and IL-6. After the cells were transfected with HO-1 or Nrf2 small interfering RNA, lipopolysaccharide-induced pro-inflammation cytokine expression was significantly restored. In summary, curcumin might alleviate airway inflammation in asthma through the Nrf2/HO-1 pathway, potentially making it an effective drug in asthma treatment. PMID- 25739562 TI - Phenotype switching through epigenetic conversion. AB - Different cell types have been suggested as candidates for use in regenerative medicine. Embryonic pluripotent stem cells can give rise to all cells of the body and possess unlimited self-renewal potential. However, they are unstable, difficult to control and have a risk of neoplastic transformation. Adult stem cells are safe but have limited proliferation and differentiation abilities and are usually not within easy access. In recent years, induced pluripotent stem (iPS) cells have become a new promising tool in regenerative medicine. However, the use of transgene vectors, commonly required for the induction of iPS cells, seriously limits their use in therapy. The same problem arising from the use of retroviruses is associated with the use of cells obtained through transdifferentiation. Developing knowledge of the mechanisms controlling epigenetic regulation of cell fate has boosted the use of epigenetic modifiers that drive cells into a 'highly permissive' state. We recently set up a new strategy for the conversion of an adult mature cell into another cell type. We increased cell plasticity using 5-aza-cytidine and took advantage of a brief window of epigenetic instability to redirect cells to a different lineage. This approach is termed 'epigenetic conversion'. It is a simple, direct and safe way to obtain both cells for therapy avoiding gene transfection and a stable pluripotent state. PMID- 25739563 TI - [Healthcare-associated infections and antimicrobial use in long term care facilities (HALT-2): German results of the second European prevalence survey]. AB - Prevention of infections and strategies for the prudent use of antimicrobials in long-term care facilities have gained importance in view of the demographic changes, not only in Germany. To generate appropriate data and to identify relevant aspects of infection prevention in this field, the European Centre for Disease Prevention and Control (ECDC) launched the second point prevalence survey of healthcare-associated infections and antimicrobial use in European long-term care facilities in 2013 (HALT-2). Despite methodical adjustments in the collection of data on healthcare-associated infections, in this second survey healthcare workers in the participating facilities were intensively trained in methodology and data collection. Overall, 221 German facilities participated and collected data from 17,208 residents. Well-established structures of regional networks facilitated the recruitment of participants as well as the preparations for training and survey. The median prevalence of residents receiving at least one antimicrobial agent was 1.1% (95 %-CI 0,7-1,6)), which is remarkably low. However, the most frequently used antimicrobials in German facilities beside beta lactams (penicillins 18.2%, other beta-lactams 17.2%) were quinolones (28.2%). Data collection of infections was performed based on signs and symptoms in detailed decision algorithms according to the recently updated McGeer surveillance criteria and yielded a median prevalence of 1.7% (95 %-CI 1,1-2,2). Symptomatic urinary tract infections (28.4%), skin and soft tissue infection (27.9%), and respiratory tract infections (24.7%) were identified both as the most common types of infections and the most common indications for the use of systemic antimicrobials. Clinical implications evolve mainly from the high use of quinolones. In terms of infection prevention measures, compliance of health care workers with a hand hygiene regimen revealed further potential for improvement. PMID- 25739564 TI - High molecular weight bioemulsifiers, main properties and potential environmental and biomedical applications. AB - High molecular weight bioemulsifiers are amphipathic polysaccharides, proteins, lipopolysaccharides, lipoproteins, or complex mixtures of these biopolymers, produced by a wide variety of microorganisms. They are characterized by highly structural diversity and have the ability to decrease the surface and interfacial tension at the surface and interface respectively and/or emulsify hydrophobic compounds. Emulsan, fatty acids, phospholipids, neutral lipids, exopolysaccharides, vesicles and fimbriae are among the most popular high molecular weight bioemulsifiers. They have great physic-chemical properties like tolerance to extreme conditions of pH, temperature and salinity, low toxicity and biodegradability. Owing their emulsion forming and breaking capacities, solubilization, mobilization and dispersion activities and their viscosity reduction activity; they possess great environmental application as enhancer of hydrocarbon biodegradation and for microbial enhanced oil recovery. Besides, they are applied in biomedical fields for their antimicrobial and anti-adhesive activities and involvement in immune responses. PMID- 25739565 TI - Co-occurence of Crenarchaeota, Thermoplasmata and methanogens in anaerobic sludge digesters. AB - 16S rRNA Crenarchaeota and Thermoplasmata sequences retrieved from 22 anaerobic digesters were analysed. 4.8 and 0.53 % of archaeal sequences were simultaneously affiliated to these lineages. A core of 2 operational taxonomic units (OTUs) representing 0.6 to -33.6 % of all archaeal sequences were defined for the Crenarchaeotes and identified to already known but not yet cultivable organisms in almost half of the digesters sampled. For the Thermoplasmata, apparently less abundant with 0.7 to -4.7 % of the archaeal sequences, 3 OTUs were identified. We showed here that Crenarchaeotes coexist with methanogens and are particularly abundant when Arch I lineage (also called WSA2 by Hugenholtz) is dominant in digesters. Moreover, Thermoplasmata were detected when Crenarchaeota were present. Interactions between methanogens, Crenarchaeotea and Thermoplamata were thus discussed. PMID- 25739567 TI - Water-assisted isomerization of the [H, C, N, O] system. AB - Ten minima of [H, C, N, O] isomers were investigated in gas phase and water solution using the polarizable continuum model at the CCSD(T)//M06-2X/6-311 + G(3df,2p) level of theory. The results show that the stability order of all isomers in water solution is HNCO > HOCN > HCNO > HONC > Y-OC(H)N > cycl-OCN(H)-a ~ cycl-OCN(H)-b > cycl-NCO(H) > HNOC > HCON, i.e., the same as that in the gas phase. Potential energy surfaces of [H, C, N, O] system isomerization were constructed in gas phase and in water solution, showing that the isomerization of [H, C, N, O] isomers in gas phase is unfavorable because of the high barrier height. Interestingly, although the water solvent has a little impact on the isomeric mechanism, water molecules (H2O)n(n = 1-3) acting as catalyst dramatically lower the barrier height in the hydrogen transfer processes (HCNO -> HONC, HNCO -> HOCN, and HCON -> HNOC). Water is the most abundant compound in the interstellar area. These results give new insight into the mechanism of [H, C, N, O] system isomerization in interstellar gas. Enthalpies of formation of the isomers were predicted at the CBS-QB3, G4MP2 and W1U levels. PMID- 25739566 TI - Archaeal communities associated with roots of the common reed (Phragmites australis) in Beijing Cuihu Wetland. AB - The richness, phylogeny and composition of archaeal community associated with the roots of common reed (Phragmites australis) growing in the Beijing Cuihu Wetland, China was investigated using a 16S rDNA library. In total, 235 individual sequences were collected, and a phylogenetic analysis revealed that 69.4 and 11.5 % of clones were affiliated with the Euryarchaeota and the Crenarchaeota, respectively. In Euryarchaeota, the archaeal community was dominated by species in following genera: Methanobacterium in the order Methanobacteriales (60.7 %); Methanoregula and Methanospirillum in the order Methanomicrobiales (20.2 %), and Methanomethylovorans, Methanosarcina and Methanosaeta in the order Methanosarcinales (17.2 %). Of 27 sequences assigned to uncultured Crenarchaeota, 22 were grouped into Group 1.3, and five grouped into Group 1.1b. Hence, the archaeal communities associated with reed roots are largely involved in methane production, and, to a lesser extent, in ammonia oxidization. Quantification of the archaeal amoA gene indicated that ammonia oxidizing archaea were more numerous in the rhizosphere soil than in the root tissue or surrounding water. A total of 19.1 % of the sequences were unclassified, suggesting that many unidentified archaea are probably involved in the reed wetland ecosystem. PMID- 25739568 TI - Fetal bradyarrhythmia associated with congenital heart defects - nationwide survey in Japan. AB - BACKGROUND: Because there is limited information on fetal bradyarrhythmia associated with congenital heart defects (CHD), we investigated its prognosis and risk factors. METHODS AND RESULTS: In our previous nationwide survey of fetal bradyarrhythmia from 2002 to 2008, 38 fetuses had associated CHD. Detailed clinical data were collected from secondary questionnaires on 29 fetuses from 18 institutions, and were analyzed. The 29 fetuses included 22 with isomerism, 4 with corrected transposition of the great arteries (TGA) and 3 with critical pulmonary stenosis; 14 had complete atrioventricular block (AVB), 8 had second degree AVB, and 16 had sick sinus syndrome; 5 died before birth, and 10 died after birth (5 in the neonatal period). Neonatal and overall survival rates for fetal bradyarrhythmia with CHD were 66% and 48%, respectively. Pacemaker implantation was needed in 17 cases (89%). Beta-sympathomimetics were administered in utero in 13 cases and were effective in 6, but were not associated with prognosis. All cases of corrected TGA or ventricular rate >=70 beats/min survived. A ventricular rate <55 beats/min had significant effects on fetal myocardial dysfunction (P=0.02) and fetal hydrops (P=0.04), resulting in high mortality. CONCLUSIONS: The prognosis of fetal bradyarrhythmia with CHD is still poor. The type of CHD, fetal myocardial dysfunction, and fetal hydrops were associated with a poor prognosis, depending on the ventricular rate. PMID- 25739569 TI - Attenuation in peripheral endothelial function after continuous flow left ventricular assist device therapy is associated with cardiovascular adverse events. AB - BACKGROUND: Patients with heart failure (HF) have abnormal endothelial function. Although use of a continuous flow left ventricular assist device (CF-LVAD) results in significant hemodynamic improvement, the effects on systemic endothelial function are unclear. METHODS AND RESULTS: Eighteen HF patients with CF-LVAD implantation were included in this prospective observational study. We measured reactive hyperemia index (RHI) before and after CF-LVAD implantation to evaluate sequential changes in endothelial function. Patients were followed clinically for the occurrence of adverse cardiovascular events, a composite of death, thrombosis, bleeding, HF, renal failure, and arrhythmia. Preoperative RHI was 1.77+/-0.39. Early in the postoperative period (7-14 days after operation) RHI significantly decreased to 1.19+/-0.31 (P<0.001, compared with preoperative RHI). At first and second follow-up (4-6 weeks and 3-7 months after operation) RHI remained lower at 1.48+/-0.50 (P=0.030) and 1.26+/-0.37 (P=0.002), respectively, compared with preoperative RHI. The decrease in early postoperative RHI relative to preoperative RHI was significantly associated with adverse cardiovascular events after CF-LVAD (age-adjusted risk ratio for 0.25 decrease in RHI, 1.35; 95% confidence interval: 1.13-1.62, P=0.001). CONCLUSIONS: Peripheral endothelial function had a significant and persistent decline up to 5 months following implantation of CF-LVAD, and this decline was associated with adverse cardiovascular events. These findings may provide insight into some of the vascular complications following CF-LVAD in HF patients. PMID- 25739570 TI - Notched QRS for the assessment of myocardial fibrosis in hypertrophic cardiomyopathy. AB - BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) sometimes develop myocardial fibrosis in association with adverse cardiovascular events. Electrocardiography (ECG) could provide helpful information on myocardial fibrosis in HCM, as in coronary artery disease. METHODS AND RESULTS: A total of 60 patients with HCM without bundle branch block underwent cardiac magnetic resonance imaging (CMR). The extent or location of late gadolinium enhancement (LGE) was examined in relation to 12-lead ECG. A notch on QRS was defined as at least 2 consecutive spikes in the same polarity with a reversal of direction >=90 degrees and the initial negative deflection >=0.05 mV. LGE was associated with notched QRS, leftward QRS axis, and prolonged QRS duration, but not with any other findings such as abnormal Q waves, R-wave amplitude, or ST-T changes. Notched QRS was most useful in determining the presence or absence of myocardial fibrosis, with a sensitivity of 70% and a specificity of 81% using a cut-off of the number of leads with notched QRS >=2. The number of notched QRS leads was positively correlated with LGE volume (P<0.01) and the lead distribution of notched QRS was informative about the location of LGE. CONCLUSIONS: A notch on QRS was useful in estimating myocardial fibrosis as assessed on CMR LGE in HCM patients without bundle branch block. PMID- 25739571 TI - Major non-cardiac surgery is a risk factor for rapid hemodynamic progression of non-rheumatic aortic stenosis. AB - BACKGROUND: Inflammatory processes are suggested to play a pathogenic role in the development and progression of non-rheumatic aortic stenosis (AS). Major surgery causes an inflammatory reaction. With the increasing prevalence of non-rheumatic AS, the number of affected patients undergoing major surgery increases. We hypothesized that major non-cardiac surgery (MNCS) could accelerate the progression of non-rheumatic AS. METHODS AND RESULTS: We enrolled 218 consecutive patients with non-rheumatic AS who underwent transthoracic echocardiography (TTE) at least twice more than 6 months apart. Study patients were divided into the MNCS group and the non-MNCS group. The MNCS group consisted of patients who underwent MNCS during the TTE follow-up interval. At baseline, peak pressure gradient across the aortic valve (AVG) was similar between the groups. Also baseline clinical characteristics and TTE follow-up interval were similar. The annual rate of peak AVG increase was much higher in the MNCS group than in the non-MNCS group. The proportion of patients with rapid hemodynamic progression was much higher in the MNCS group than in the non-MNCS group. Multiple logistic regression analysis showed that MNCS was an independent predictor of rapid hemodynamic progression of non-rheumatic AS. CONCLUSIONS: The present study indicates for the first time that MNCS is associated with the rapid progression of non-rheumatic AS. PMID- 25739572 TI - Clinical impact of left ventricular outflow tract obstruction in takotsubo cardiomyopathy. AB - BACKGROUND: A hyperdynamic state of the basal left ventricle sometimes results in obstruction of the left ventricular outflow tract (LVOT). However, the prevalence, clinical presentation, and prognostic effect of LVOT obstruction in takotsubo cardiomyopathy (TC) have not been fully evaluated. METHODS AND RESULTS: Among 933 consecutive patients who underwent emergency coronary angiography for suspected acute coronary syndrome, 35 patients (3.8%) were diagnosed as TC. The cumulative 3-year incidence of all-cause death, cardiac death, hospitalization for congestive heart failure (CHF), and recurrent TC was 24.2%, 0.0%, 6.5%, and 12.2%, respectively. Among 27 patients with information of a LVOT pressure gradient, LVOT obstruction was present in 9 (33%). The prevalence of moderate to severe mitral regurgitation (67% vs. 11%, P=0.003), CHF (78% vs. 28%, P=0.02), and hypotension (56% vs. 5.6%, P=0.008) was significantly higher in patients with LVOT obstruction than in those without. Nevertheless, the cumulative 3-year incidence of all-cause death was not significantly different between the 2 groups (49.2% vs. 23.0%, P=0.22) with no cardiac deaths in either group. Hospitalization for CHF and recurrent TC were significantly more frequent in patients with LVOT obstruction (25.0% vs. 0.0%, P=0.04, and 25.0% vs. 6.7%, P=0.02). CONCLUSIONS: In 35 consecutive patients with TC, those with significant LVOT obstruction (33%) had a more serious clinical presentation such as CHF and hypotension, but had similar 3-year mortality rate as compared with those without. PMID- 25739573 TI - Impact of peripheral artery disease on prognosis in hospitalized heart failure patients. AB - BACKGROUND: The impact of peripheral artery disease (PAD) on heart failure (HF) prognosis remains unclear. METHODS AND RESULTS: A total of 388 consecutive decompensated HF patients were divided into 2 groups based on the presence of PAD: HF with PAD (PAD group, n=101, 26.0%) and HF without PAD (non-PAD group, n=287, 74.0%). We compared clinical features, echocardiographic parameters, cardiopulmonary exercise testing results, laboratory findings, as well as cardiac, non-cardiac, and all-cause mortality between the 2 groups. The PAD group, as compared with the non-PAD group, had (1) higher prevalence of coronary artery disease (40.6 vs. 27.5%, P=0.011) and cerebrovascular disease (34.7 vs. 18.2%, P=0.001); (2) higher tumor necrosis factor-alpha (1.82 vs. 1.49 pg/ml, P=0.023), C-reactive protein (0.32 vs. 0.19 mg/dl, P=0.045), and troponin T (0.039 vs. 0.021 ng/ml, P=0.019); (3) lower LVEF (42.4 vs. 48.5%, P<0.001); (4) lower peak VO2(13.4 vs. 15.9 ml.kg(-1).min(-1), P=0.001); and (5) higher VE/VCO2slope (38.8 vs. 33.7, P<0.001). On Kaplan-Meier analysis, cardiac, non cardiac, and all-cause mortality were significantly higher in the PAD group than in the non-PAD group (P<0.05, respectively). On Cox proportional hazard analysis after adjusting for confounding factors, PAD was an independent predictor of cardiac and all-cause mortality (P<0.05, respectively) in HF patients. CONCLUSIONS: PAD was common and an independent predictor of cardiac and all-cause mortality in HF patients. PMID- 25739574 TI - Combining a sensor and a pH-gated nanopore based on an avidin-biotin system. AB - Here we propose a new approach to tailor nanopores, which combines both pH gating and sensing properties. This strategy is based on PEG like-avidin grafting in nanopores designed by atomic layer deposition (ALD). Below pH 5 the nanopore is blocked. We show that the PEG chains are at the origin of these properties. PMID- 25739575 TI - NCI launches exceptional responders initiative: researchers will attempt to identify why some patients respond to treatment so much better than others. PMID- 25739576 TI - Inaugural palliative care symposium focuses on improving field. PMID- 25739578 TI - Noncardiac comorbidities in heart failure with preserved ejection fraction - commonly ignored fact. AB - It has been well described that many patients with heart failure (HF) have a normal left ventricular ejection fraction. This entity has been termed "heart failure with preserved ejection fraction (HFPEF)". Significant advances have been made in understanding the clinical characteristics of HFPEF over the past 2 decades on the basis of large HF registries and randomized clinical trials. However, most multicenter clinical trials that investigated medical therapies in HFPEF have yielded disappointing results. HFPEF being a clinical syndrome involving multiple organ systems may be a potential explanation for treatment failure. In this review we discuss the prevalence of noncardiac comorbidities in HFPEF patients as well as their effect on the prognosis of HFPEF. PMID- 25739579 TI - Evaluation of the genetic risk of hypertension-related diseases. PMID- 25739581 TI - X-ray crystallographic validation of structure predictions used in computational design for protein stabilization. AB - Protein engineering aimed at enhancing enzyme stability is increasingly supported by computational methods for calculation of mutant folding energies and for the design of disulfide bonds. To examine the accuracy of mutant structure predictions underlying these computational methods, crystal structures of thermostable limonene epoxide hydrolase variants obtained by computational library design were determined. Four different predicted effects indeed contributed to the obtained stabilization: (i) enhanced interactions between a flexible loop close to the N-terminus and the rest of the protein; (ii) improved interactions at the dimer interface; (iii) removal of unsatisfied hydrogen bonding groups; and (iv) introduction of additional positively charged groups at the surface. The structures of an eightfold and an elevenfold mutant showed that most mutations introduced the intended stabilizing interactions, and side-chain conformations were correctly predicted for 72-88% of the point mutations. However, mutations that introduced a disulfide bond in a flexible region had a larger influence on the backbone conformation than predicted. The enzyme active sites were unaltered, in agreement with the observed preservation of catalytic activities. The structures also revealed how a c-Myc tag, which was introduced for facile detection and purification, can reduce access to the active site and thereby lower the catalytic activity. Finally, sequence analysis showed that comprehensive mutant energy calculations discovered stabilizing mutations that are not proposed by the consensus or B-FIT methods. PMID- 25739580 TI - ABO-incompatible living donor kidney transplantation without post-transplant therapeutic plasma exchange. AB - Blood group incompatibility remains a significant barrier to kidney transplantation. Approximately, one-third of donors are blood group incompatible with their intended recipient. Options for these donor-recipient pairs include blood group incompatible transplantation or kidney paired donation. However, the optimal protocol for blood group incompatible transplantation is unknown. Protocols differ in techniques to remove ABO antibodies, titer targets, and immunosuppression regimens. In addition, the mechanisms of graft accommodation to blood group antigens remain poorly understood. We describe a blood group incompatible protocol using pretransplant therapeutic plasma exchange (TPE), high dose intravenous immunoglobulin, and rituximab in addition to prednisone, mycophenolate mofetil, and tacrolimus. In this protocol, we do not exclude patients based on a high initial titer and do not implement post-transplant TPE. All 16 patients who underwent this protocol received a living donor transplant with 100% patient and graft survival, and no reported episodes of antibody mediated rejection to date with a median follow-up of 2.6 years (range 0.75-4.7 years). We conclude that blood group incompatible transplantation can be achieved without post-transplant TPE. PMID- 25739582 TI - Orangutans (Pongo spp.) do not spontaneously share benefits with familiar conspecifics in a choice paradigm. AB - Humans are thought to be unique in their ability to help others voluntarily even though it may sometimes incur substantial costs. However, there are a growing number of studies showing that prosocial behaviors can be observed, not only in humans, but also among nonhuman primates that live in complex social groups. Prosociality has often been described as a major factor that facilitates group living. Nonetheless, it has seldom been explored whether solitary living primates, such as orangutans, share this propensity. In the present study, we tested four captive orangutans (Pongo abelii * pigmaeus, Pongo pigmaeus) in a simple food-delivering task. They had a choice, incurring the same cost, between getting a food reward for themselves and providing an additional food reward to a conspecific recipient passively sitting in an adjacent booth. Two orangutans played the actor's role, and two orangutans participated as recipients. The results showed that the actors did not choose to deliver food to the recipients more often than expected by chance (51.3 % on average). The control condition demonstrated that this tendency was independent of the actor's understanding of the task. These findings suggest that orangutans do not spontaneously share benefits with other conspecifics, even when the prosocial choice does not disadvantage them. This study gives the first experimental evidence that socially housed captive orangutans do not behave prosocially in a choice paradigm experiment. Further studies using a different experimental paradigm should be conducted to examine whether this tendency is consistent with previous findings hypothesizing that the enhanced prosocial propensity shown in humans and other group living primates is an evolutionary outcome of living in complex social environments. PMID- 25739583 TI - Parturition and potential infanticide in free-ranging Alouatta guariba clamitans. AB - Parturition is a key process of mammalian reproduction that is rarely documented in New World monkeys because it often occurs at night. However, diurnal births have been recorded in several species. In howler monkeys (Alouatta spp.) they have often been observed during prolonged resting periods. Similarly, infanticide is a behavior observed quite infrequently. Infanticide in howler monkeys is often inferred from infant deaths or disappearances after group takeovers by nonresident male(s). Here we report the first observation of parturition and birth-related behaviors in the brown howler monkey (Alouatta guariba clamitans) and the likely attack on the infant that caused its death. The mother was a multiparous female that lived in a ca. 3-ha Atlantic forest fragment in southern Brazil with nine group mates. The behavior ("all occurrences") sampling method was used to record birth-related behaviors and social interactions. The parturition occurred during the day of 27 October 2013 during a feeding session. The female showed no sign of contraction or birth delivery posture. Parturition began apparently after matrix rupture and release of the amniotic fluid. Expulsion of the newborn occurred between 1 and 3 min later (the exact moment of delivery was not observed). Then, the female held and licked the newborn and began to ingest the placenta and the umbilical cord. The other group members continued feeding and had no interaction with the parturient during the preparturition and parturition events. The infant died ca. 35 days later as a consequence of injuries to his forehead and face, potentially caused by a conspecific bite. Because the adult and subadult males chased the female in the day that the infant's wounds were detected, we believe that one of them might have been the aggressor. We discuss this putative case of infanticide in light of the potential motivation of each male. PMID- 25739584 TI - Antioxidant activity of bovine alpha lactalbumin Maillard products and evaluation of their in vitro gastro-duodenal digestive proteolysis. AB - Food processing offers various pathways to tailor food functionality and digestibility. This work sought to study the impact of thermally-induced Maillard reaction between bovine alpha-lactalbumin (alpha-la) and fructose or fructo oligosacchrides on physicochemical properties, antioxidant capacity and in vitro digestive fate under simulated adult and infant conditions. Colloidal stability (measured by DLS) was decreased as a result of the Maillard glycation, while antioxidant capacity (determined by FRAP) and surface hydrophobicity (H0 measurements) were elevated. Semi-dynamic in vitro digestion of Maillard conjugates revealed a mixed trend as a result of postulated competing effects of glycation on alpha-la's susceptibility to proteolysis; steric hindrance accompanied by protein unfolding could hinder or promote the availability of enzymatic cleavage sites. Results also showed thermal processing altered the digestive breakdown profile of alpha-la under infant conditions contrary to negligible effects observed under adult conditions. Evaluation of the antioxidant capacity during digestion (via DPPH assay) revealed that adult digesta possessed increased antioxidant activity throughout the gastric phase compared to infant digesta, whereas infant digesta of conjugates exhibited an increase in antioxidant capacity in the duodenum compared to adult. Moreover, during infant digestion of conjugates, an increase in antioxidant capacity was observed in the later stages of the digestion. Overall, this work demonstrates that controlled thermal processing of bovine alpha-la could potentially modulate its functionality and digestibility, particularly as it pertains to its ability to interfere with oxidative reactions in the lumen, possibly through the generation of bioactive peptides. PMID- 25739585 TI - Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats. AB - The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet beta cells and concentration of vWF in islets in ASC group increased, while activity of caspase 3 in islets was reduced. Moreover, concentrations of TNF-alpha, IL-6 and IL-1beta in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet beta cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM. PMID- 25739586 TI - Effects of rapid-acting insulin analogues insulin glulisine and insulin aspart on postprandial glycemic excursion with single bout of exercise in patients with type 2 diabetes. AB - The analogue insulin glulisine (Glu) shows both more rapid onset and shorter duration of action compared with the other rapid-acting insulin analogues. The current study investigates these properties in regard to the occurrence of hypoglycemia related to exercise. A randomized, single-center, open-label, crossover study was conducted in 12 hospitalized type 2 diabetes patients (all male, mean +/- SD age of 51.9 +/- 11.3 years; BMI: 25.5 +/- 3.9 kg/m2; HbA1c: 11.2 +/- 2.4 %). Glu or insulin aspart (Asp) was subcutaneously administered just before breakfast. Insulin dosage was determined as the usual dose of pre-prandial rapid-acting insulin for patients treated with insulin therapy or as 0.1 unit/kg for patients treated with oral anti-hyperglycemic agents. Sixty min after the start of eating, the patients began aerobic exercise on a bicycle ergometer for 30 min at 50% of maximum heart rate. Hypoglycemic episodes (plasma glucose level < 70 mg/dL with or without symptoms) were observed more frequently in Asp group (p < 0.05). Post-exercise plasma glucose levels at 90, 120, and 150 min were significantly lower in Asp group (p < 0.05). In patients with BMI < 25 kg/m2 (n = 6), post-exercise blood glucose levels were significantly lower in Asp group (p < 0.05), while in patients with BMI >= 25 kg/m2 (n = 6) the difference was not significant. Glu may therefore be a suitable choice of rapid-acting insulin for patients with type 2 diabetes who are at high risk of post-exercise hypoglycemia. PMID- 25739587 TI - Vaginal Cytology of the Laboratory Rat and Mouse: Review and Criteria for the Staging of the Estrous Cycle Using Stained Vaginal Smears. AB - Microscopic evaluation of the types of cells present in vaginal smears has long been used to document the stages of the estrous cycle in laboratory rats and mice and as an index of the functional status of the hypothalamic-pituitary-ovarian axis. The estrous cycle is generally divided into the four stages of proestrus, estrus, metestrus, and diestrus. On cytological evaluation, these stages are defined by the absence, presence, or proportion of 4 basic cell types as well as by the cell density and arrangement of the cells on the slide. Multiple references regarding the cytology of the rat and mouse estrous cycle are available. Many contemporary references and studies, however, have relatively abbreviated definitions of the stages, are in reference to direct wet mount preparations, or lack comprehensive illustrations. This has led to ambiguity and, in some cases, a loss of appreciation for the encountered nuances of dividing a steadily moving cycle into 4 stages. The aim of this review is to provide a detailed description, discussion, and illustration of vaginal cytology of the rat and mouse estrous cycle as it appears on smears stained with metachromatic stains. PMID- 25739588 TI - Adjunctive treatment with quetiapine for major depressive disorder: are the benefits of treatment worth the risks? PMID- 25739589 TI - Attacking scientists who lead work on reducing sugar intake damages the cause. PMID- 25739591 TI - Gone fishing. PMID- 25739590 TI - Changing prevalence of Helicobacter pylori infection and peptic ulcer among dyspeptic Sardinian patients. AB - Over the past 50 years, the prevalence of Helicobacter pylori infection has fallen as standards of living improved. The changes in the prevalence of infection and its manifestations (peptic ulcer disease and gastric mucosal lesions) were investigated in a large cohort of Sardinians undergoing upper endoscopy for dyspepsia. A retrospective observational study was conducted involving patients undergoing endoscopy for dyspepsia from 1995 to 2013. H. pylori status was assessed by histology plus the rapid urease test or 13C-UBT. Gastric mucosal lesions were evaluated histologically. Data including non steroidal anti-inflammatory drugs (NSAIDs) use and the presence of peptic ulcers were collected. The prevalence of H. pylori was calculated for each quartile and for each birth cohort from 1910 to 2000. 11,202 records were retrieved for the analysis (62.9% women). The overall prevalence of H. pylori infection was 43.8% (M: 46.6% vs. F: 42.0%; P = 0.0001). A dramatic decrease in the prevalence of infection occurred over the 19-year observation period. The birth cohort effect was evident in each category (quartile) reflecting the continuous decline in H. pylori acquisition. Over time, the prevalence of peptic ulcers also declined, resulting in an increase in the proportion of H. pylori negative/NSAID positive and H. pylori negative/NSAID negative peptic ulcers. The prevalence of gastric mucosal changes also declined despite aging. The decline in H. pylori prevalence over time likely reflects the improvement in socioeconomic conditions in Sardinia such that H. pylori infection and its clinical outcomes including peptic ulcer are becoming less frequent even among dyspeptic patients. PMID- 25739592 TI - Fatal fallout. PMID- 25739593 TI - Hues and cry. PMID- 25739594 TI - China's scientists must engage the public on GM. PMID- 25739606 TI - Ebola's mental-health wounds linger in Africa. PMID- 25739607 TI - Robo-rescuers battle it out in disaster challenge. PMID- 25739608 TI - UN climate panel charts next steps. PMID- 25739609 TI - World's deadliest volcanoes identified. PMID- 25739610 TI - Therapeutic cancer vaccine survives biotech bust. PMID- 25739611 TI - Slick idea proposed to stretch water supplies. PMID- 25739613 TI - Developing world: the minority minority. PMID- 25739615 TI - Economics: support low-carbon investment. PMID- 25739614 TI - Maternal health: Ebola's lasting legacy. PMID- 25739619 TI - Athlete testing: sports doping vastly underestimated. PMID- 25739620 TI - Neutrinos: glass-blowing's Nobel moment. PMID- 25739621 TI - Laboratory animals: German initiative opens up animal data. PMID- 25739622 TI - Finland: target for ecosystem repair is impractical. PMID- 25739623 TI - In retrospect: a marine biologist's remarkable legacy. PMID- 25739624 TI - Carl Djerassi (1923-2015). PMID- 25739625 TI - Materials science: nanoscale locomotion without fuel. PMID- 25739626 TI - Materials science: gating mechanism under pressure. PMID- 25739627 TI - Catalysis: dual catalysis at the flick of a switch. PMID- 25739628 TI - State preservation by repetitive error detection in a superconducting quantum circuit. AB - Quantum computing becomes viable when a quantum state can be protected from environment-induced error. If quantum bits (qubits) are sufficiently reliable, errors are sparse and quantum error correction (QEC) is capable of identifying and correcting them. Adding more qubits improves the preservation of states by guaranteeing that increasingly larger clusters of errors will not cause logical failure-a key requirement for large-scale systems. Using QEC to extend the qubit lifetime remains one of the outstanding experimental challenges in quantum computing. Here we report the protection of classical states from environmental bit-flip errors and demonstrate the suppression of these errors with increasing system size. We use a linear array of nine qubits, which is a natural step towards the two-dimensional surface code QEC scheme, and track errors as they occur by repeatedly performing projective quantum non-demolition parity measurements. Relative to a single physical qubit, we reduce the failure rate in retrieving an input state by a factor of 2.7 when using five of our nine qubits and by a factor of 8.5 when using all nine qubits after eight cycles. Additionally, we tomographically verify preservation of the non-classical Greenberger-Horne-Zeilinger state. The successful suppression of environment induced errors will motivate further research into the many challenges associated with building a large-scale superconducting quantum computer. PMID- 25739629 TI - Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour. AB - Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. The ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems. But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries, a single system capable of controlling complex, selective multiphase transport has remained a distant prospect, and fouling is nearly inevitable. Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid lined pore in the open state. Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold-the pressure needed to open the pores-can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping. These capabilities allow us to dynamically modulate gas-liquid sorting in a microfluidic flow and to separate a three-phase air-water-oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications. PMID- 25739630 TI - The direct arylation of allylic sp(3) C-H bonds via organic and photoredox catalysis. AB - The direct functionalization of unactivated sp(3) C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp(3) C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C H bonds (that is, C-H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds. PMID- 25739631 TI - Drought impact on forest carbon dynamics and fluxes in Amazonia. AB - In 2005 and 2010 the Amazon basin experienced two strong droughts, driven by shifts in the tropical hydrological regime possibly associated with global climate change, as predicted by some global models. Tree mortality increased after the 2005 drought, and regional atmospheric inversion modelling showed basin wide decreases in CO2 uptake in 2010 compared with 2011 (ref. 5). But the response of tropical forest carbon cycling to these droughts is not fully understood and there has been no detailed multi-site investigation in situ. Here we use several years of data from a network of thirteen 1-ha forest plots spread throughout South America, where each component of net primary production (NPP), autotrophic respiration and heterotrophic respiration is measured separately, to develop a better mechanistic understanding of the impact of the 2010 drought on the Amazon forest. We find that total NPP remained constant throughout the drought. However, towards the end of the drought, autotrophic respiration, especially in roots and stems, declined significantly compared with measurements in 2009 made in the absence of drought, with extended decreases in autotrophic respiration in the three driest plots. In the year after the drought, total NPP remained constant but the allocation of carbon shifted towards canopy NPP and away from fine-root NPP. Both leaf-level and plot-level measurements indicate that severe drought suppresses photosynthesis. Scaling these measurements to the entire Amazon basin with rainfall data, we estimate that drought suppressed Amazon-wide photosynthesis in 2010 by 0.38 petagrams of carbon (0.23-0.53 petagrams of carbon). Overall, we find that during this drought, instead of reducing total NPP, trees prioritized growth by reducing autotrophic respiration that was unrelated to growth. This suggests that trees decrease investment in tissue maintenance and defence, in line with eco-evolutionary theories that trees are competitively disadvantaged in the absence of growth. We propose that weakened maintenance and defence investment may, in turn, cause the increase in post-drought tree mortality observed at our plots. PMID- 25739633 TI - Data visualization: science on the map. PMID- 25739632 TI - Reconstructed Homo habilis type OH 7 suggests deep-rooted species diversity in early Homo. AB - Besides Homo erectus (sensu lato), the eastern African fossil record of early Homo has been interpreted as representing either a single variable species, Homo habilis, or two species. In the latter case, however, there is no consensus over the respective groupings, and which of the two includes OH 7, the 1.8-million year-old H. habilis holotype. This partial skull and hand from Olduvai Gorge remains pivotal to evaluating the early evolution of the Homo lineage, and by priority names one or other of the two taxa. However, the distorted preservation of the diagnostically important OH 7 mandible has hindered attempts to compare this specimen with other fossils. Here we present a virtual reconstruction of the OH 7 mandible, and compare it to other early Homo fossils. The reconstructed mandible is remarkably primitive, with a long and narrow dental arcade more similar to Australopithecus afarensis than to the derived parabolic arcades of Homo sapiens or H. erectus. We find that this shape variability is not consistent with a single species of early Homo. Importantly, the jaw morphology of OH 7 is incompatible with fossils assigned to Homo rudolfensis and with the A.L. 666-1 Homo maxilla. The latter is morphologically more derived than OH 7 but 500,000 years older, suggesting that the H. habilis lineage originated before 2.3 million years ago, thus marking deep-rooted species diversity in the genus Homo. We also reconstructed the parietal bones of OH 7 and estimated its endocranial volume. At between 729 and 824 ml it is larger than any previously published value, and emphasizes the near-complete overlap in brain size among species of early Homo. Our results clarify the H. habilis hypodigm, but raise questions about its phylogenetic relationships. Differences between species of early Homo appear to be characterized more by gnathic diversity than by differences in brain size, which was highly variable within all taxa. PMID- 25739636 TI - Electroacupuncture therapy for abducent palsy after acoustic neuroma surgery. PMID- 25739637 TI - In depressed older persons higher blood pressure is associated with symptoms of apathy. The NESDO study. AB - BACKGROUND: In older persons, a relationship between both higher and lower blood pressure and depression has inconsistently been reported. Blood pressure may be differentially associated with distinct symptom domains of depression. We examined the cross-sectional relation of current systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) with different depressive symptom domains among depressed older persons. METHODS: In the Netherlands Study of Depression in Older Persons (NESDO), 270 participants aged 60 years and above were diagnosed with depression in the past month. Using the three corresponding subscales of the Inventory of Depressive Symptoms-Self Report (IDS-SR), motivational, mood and somatic symptom domains were assessed. Additionally, symptoms of apathy were determined with the Apathy Scale. Multiple linear regression was used to examine the cross-sectional relationship between current SBP, DBP and MAP with both IDS-SR subscale and Apathy Scale scores. Unstandardized betas were calculated per 10 mmHg increase in blood pressure measures. RESULTS: Mean age of participants was 70.4 years (standard deviation 7.3). Higher SBP (Beta 0.33, t (254) = 2.01, p = 0.045), higher DBP (Beta 0.68, t (254) = 2.15, p = 0.03) and higher MAP (Beta 0.63, t (254) = 2.33, p = 0.02) were associated with higher Apathy Scale scores in the fully adjusted model. Furthermore, a higher SBP was associated with higher IDS-SR mood subscale scores (Beta 0.25, t (254) = 2.13, p = 0.03). CONCLUSIONS: Depressed older people with higher blood pressure measures had particularly more symptoms of apathy. To disentangle the relationship of blood pressure with late-life depression, it is important to pay attention to the role of apathy symptoms. PMID- 25739638 TI - Structure of amylase-binding protein A of Streptococcus gordonii: a potential receptor for human salivary alpha-amylase enzyme. AB - Amylase-binding protein A (AbpA) of a number of oral streptococci is essential for the colonization of the dental pellicle. We have determined the solution structure of residues 24-195 of AbpA of Streptococcus gordonii and show a well defined core of five helices in the region of 45-115 and 135-145. (13) Calpha/beta chemical shift and heteronuclear (15) N-{(1) H} NOE data are consistent with this fold and that the remainder of the protein is unstructured. The structure will inform future molecular experiments in defining the mechanism of human salivary alpha-amylase binding and biofilm formation by streptococci. PMID- 25739639 TI - (18)F-FDG uptake on PET correlates with biological potential in early oral squamous cell carcinoma. AB - CONCLUSION: The maximum standardized uptake value (SUVmax) of early oral squamous cell carcinoma (OSCC) may have a role as an imaging biomarker for assessment of malignant potential, including cell metabolism and angiogenesis. OBJECTIVE: The usefulness of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been proven in various cancers, including OSCC. Moreover, in several carcinomas, the SUVmax of the tumor has been shown to correlate with the histological type, tumor stage, differentiation, and prognosis. Here, we investigated whether the SUVmax of early OSCC was associated with the biological features. METHODS: Twenty seven patients with newly diagnosed early OSCC who underwent preoperative FDG-PET and curative surgical resection were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), L-type amino acid transporter 1 (LAT1), CD98, microvessels (CD34), cell proliferation marker (Ki-67), and cell cycle regulator (p53). The correlation between SUVmax and clinicopathological findings or the expression level of these molecules was analyzed. RESULTS: SUVmax of primary OSCC was significantly higher in patients with T2 stage. Moreover, patients whose tumors showed vascular invasion had a tendency to show higher SUVmax. A significant correlation was observed between SUVmax and the expression of LAT1 or microvessel density. PMID- 25739640 TI - Structure formation in diindenoperylene thin films on copper(111). AB - First-principles calculations were combined with scanning tunneling microscopy (STM) measurements to analyze the adsorption of diindenoperylene (DIP) molecules on Cu(111) surfaces. The influence of the substrate on the geometry of single adsorbed molecules, their diffusion barriers, as well as the role of step-edges and intermolecular interactions for molecular self-assembly and structure growth are studied. Long-range ordered arrangements of DIP molecules are found to be most favorable irrespective of the terrace width. Energetically less favored short-range order structures, however, are observed as well. PMID- 25739641 TI - Modulation of the chaperone DnaK allosterism by the nucleotide exchange factor GrpE. AB - Hsp70 chaperones comprise two domains, the nucleotide-binding domain (Hsp70NBD), responsible for structural and functional changes in the chaperone, and the substrate-binding domain (Hsp70SBD), involved in substrate interaction. Substrate binding and release in Hsp70 is controlled by the nucleotide state of DnaKNBD, with ATP inducing the open, substrate-receptive DnaKSBD conformation, whereas ADP forces its closure. DnaK cycles between the two conformations through interaction with two cofactors, the Hsp40 co-chaperones (DnaJ in Escherichia coli) induce the ADP state, and the nucleotide exchange factors (GrpE in E. coli) induce the ATP state. X-ray crystallography showed that the GrpE dimer is a nucleotide exchange factor that works by interaction of one of its monomers with DnaKNBD. DnaKSBD location in this complex is debated; there is evidence that it interacts with the GrpE N-terminal disordered region, far from DnaKNBD. Although we confirmed this interaction using biochemical and biophysical techniques, our EM-based three dimensional reconstruction of the DnaK-GrpE complex located DnaKSBD near DnaKNBD. This apparent discrepancy between the functional and structural results is explained by our finding that the tail region of the GrpE dimer in the DnaK-GrpE complex bends and its tip contacts DnaKSBD, whereas the DnaKNBD-DnaKSBD linker contacts the GrpE helical region. We suggest that these interactions define a more complex role for GrpE in the control of DnaK function. PMID- 25739642 TI - Yoga and meditation for menopausal symptoms in breast cancer survivors-A randomized controlled trial. AB - BACKGROUND: Breast cancer survivors have only very limited treatment options for menopausal symptoms. The objective of this trial was to evaluate the effects of a 12-week traditional Hatha yoga and meditation intervention on menopausal symptoms in breast cancer survivors. METHODS: Patients were randomly assigned either to a 12-week yoga and meditation intervention or to usual care. The primary outcome measure was total menopausal symptoms (Menopause Rating Scale [MRS] total score). Secondary outcome measures included MRS subscales, quality of life (Functional Assessment of Cancer Therapy-Breast), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), depression, and anxiety (Hospital Anxiety and Depression Scale). Outcomes were assessed at week 12 and week 24 after randomization. RESULTS: In total, 40 women (mean age +/- standard deviation, 49.2 +/- 5.9 years) were randomized to yoga (n = 19) or to usual care (n = 21). Women in the yoga group reported significantly lower total menopausal symptoms compared with the usual care group at week 12 (mean difference, -5.6; 95% confidence interval, -9.2 to -1.9; P = .004) and at week 24 (mean difference, -4.5; 95% confidence interval, -8.3 to -0.7; P = .023). At week 12, the yoga group reported less somatovegetative, psychological, and urogenital menopausal symptoms; less fatigue; and improved quality of life (all P < .05). At week 24, all effects persisted except for psychological menopausal symptoms. Short-term effects on menopausal symptoms remained significant when only women who were receiving antiestrogen medication (n = 36) were analyzed. Six minor adverse events occurred in each group. CONCLUSIONS: Yoga combined with meditation can be considered a safe and effective complementary intervention for menopausal symptoms in breast cancer survivors. The effects seem to persist for at least 3 months. PMID- 25739644 TI - Preface: 25th Austin Symposium on Molecular Structure and Dynamics. PMID- 25739645 TI - Nanoscopic Localization of Surface-Exposed Antigens of Borrelia burgdorferi. AB - Borrelia burgdorferi sensu lato, the causative agent of Lyme disease, is transmitted to humans through the bite of infected Ixodes spp. ticks. Successful infection of vertebrate hosts necessitates sophisticated means of the pathogen to escape the vertebrates' immune system. One strategy employed by Lyme disease spirochetes to evade adaptive immunity involves a highly coordinated regulation of the expression of outer surface proteins that is vital for infection, dissemination, and persistence. Here we characterized the expression pattern of bacterial surface antigens using different microscopy techniques, from fluorescent wide field to super-resolution and immunogold-scanning electron microscopy. A fluorescent strain of B. burgdorferi spirochetes was labeled with monoclonal antibodies directed against various bacterial surface antigens. Our results indicate that OspA is more evenly distributed over the surface than OspB and OspC that were present as punctate areas. PMID- 25739643 TI - Manipulating topological states by imprinting non-collinear spin textures. AB - Topological magnetic states, such as chiral skyrmions, are of great scientific interest and show huge potential for novel spintronics applications, provided their topological charges can be fully controlled. So far skyrmionic textures have been observed in noncentrosymmetric crystalline materials with low symmetry and at low temperatures. We propose theoretically and demonstrate experimentally the design of spin textures with topological charge densities that can be tailored at ambient temperatures. Tuning the interlayer coupling in vertically stacked nanopatterned magnetic heterostructures, such as a model system of a Co/Pd multilayer coupled to Permalloy, the in-plane non-collinear spin texture of one layer can be imprinted into the out-of-plane magnetised material. We observe distinct spin textures, e.g. vortices, magnetic swirls with tunable opening angle, donut states and skyrmion core configurations. We show that applying a small magnetic field, a reliable switching between topologically distinct textures can be achieved at remanence. PMID- 25739646 TI - Correlation between average tissue depth data and quantitative accuracy of forensic craniofacial reconstructions measured by geometric surface comparison method. AB - Accuracy is the most important factor supporting the reliability of forensic facial reconstruction (FFR) comparing to the corresponding actual face. A number of methods have been employed to evaluate objective accuracy of FFR. Recently, it has been attempted that the degree of resemblance between computer-generated FFR and actual face is measured by geometric surface comparison method. In this study, three FFRs were produced employing live adult Korean subjects and three dimensional computerized modeling software. The deviations of the facial surfaces between the FFR and the head scan CT of the corresponding subject were analyzed in reverse modeling software. The results were compared with those from a previous study which applied the same methodology as this study except average facial soft tissue depth dataset. Three FFRs of this study that applied updated dataset demonstrated lesser deviation errors between the facial surfaces of the FFR and corresponding subject than those from the previous study. The results proposed that appropriate average tissue depth data are important to increase quantitative accuracy of FFR. PMID- 25739647 TI - PrEP: A case study. AB - PURPOSE: The purpose of this case study is to present information and raise awareness about the provision of pre-exposure prophylaxis (PrEP) to those individuals who are at risk for HIV infection. DATA SOURCES: PubMed, CINAHL, government websites, press releases, and the author's clinical experiences. CONCLUSIONS: PrEP is the latest tool available for HIV prevention that has been approved by the FDA. It involves taking the HIV medication TDF/FTC on a daily basis. Documented side effects are minimal but renal monitoring is recommended because of possible kidney damage. PrEP may provide as much as 90% protection against HIV infection, but this is dependent upon patient compliance. IMPLICATIONS FOR PRACTICE: Nurse practitioners are in an ideal position to be the gatekeepers for information and access to PrEP. However, this requires that they engage in thorough risk assessments with their patients. This includes both a comprehensive sexual history and drug use history. The case study demonstrates the importance of intervention in and recognition of high-risk stigmatized populations such as transgender individuals and that prompt action may prevent future HIV infections. PMID- 25739649 TI - Efficacy, safety, and tolerability of antihypertensive therapy with aliskiren/amlodipine in clinical practice in Austria. The RALLY (Rasilamlo long lasting efficacy) study. AB - AIM: This observational study evaluated the efficacy and tolerability of 3-month aliskiren/amlodipine therapy under outpatient conditions. METHODS: This Austria wide observational study included 579 hypertensive patients (566 [98 %] who could be analyzed biometrically) under the care of 140 physicians. The average age of the patient collective was 64 +/- 11 years and the mean duration of hypertension was 10 +/- 7 years. Regarding 92 % of the study participants, an antihypertensive therapy already existed. Efficacy was assessed in accordance with the Austrian hypertension guidelines while tolerability was evaluated on the basis of adverse events. A descriptive physician judgment based on efficacy, tolerability, and compliance was available for 539 patients (95 %). Office blood pressure values were used for the evaluation. RESULTS: On average, the systolic and diastolic blood pressures were reduced from 161 +/- 14 to 135 +/- 10 mmHg and 93 +/- 9 to 81 +/- 6 mmHg, respectively. Blood pressure values of < 140/90 mmHg and < 130/80 mmHg were achieved in 56 and 7 % patients, respectively. A subgroup analysis of 242 patients (43 %) with diabetes mellitus and/or renal disease, as well as those with a high cardiovascular risk, demonstrated nearly identical results compared to the total population. Overall, 44 adverse events were documented in 41 patients, and physicians reported that 94 % of patients were compliant in a final survey on evaluation of therapy. CONCLUSION: The fixed-dose combination of aliskiren/amlodipine provided clinically relevant blood pressure reductions along with good tolerance and compliance. During the 3-month duration of observation under outpatient conditions, it was seen that aliskiren and amlodipine reduced the systolic and diastolic blood pressures on average by 26 and 13 mmHg, respectively. PMID- 25739648 TI - Thyroid screening in HIV-infected patients with antiretroviral therapy. AB - BACKGROUND: The literature reports an increased incidence of thyroid disorders in human immunodeficiency virus (HIV)-positive persons. We therefore retrospectively analyzed the strategy of collecting thyroid parameters on a routine basis. METHODS: Overall 410 patients (147 women, 263 men; age, 10-74 years; median age, 45 years) were included. For screening purposes, three parameters were determined; basal thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3). Descriptive and statistical analyses were performed in the patient groups with increased bTSH (> 4.0 uU/ml) and with decreased fT4 (< 8.9 pg/ml) to evaluate possible correlation with age, gender, duration of antiretroviral therapy (ART), substance classes of ART (nucleosidal reverse transcriptase inhibitors (NRTIs), nonnucleosidal reverse transcriptase inhibitors, and protease inhibitors (PIs)), Centers for Disease Control and Prevention (CDC) disease stage, lowest number of CD4 cells during course of disease, and coexistent hepatitis C. RESULTS: Elevated bTSH was found in 27 patients (median, 5.26 uU/ml), who also showed a correlation with ART duration and NRTI use. Decreased fT4 was seen in 53 persons, and a correlation with PI intake was observed. Of these patients, 31 exhibited normalization in follow-up. Decreased fT3 was observed in eight cases related to nonthyroid illness, and fT3 was elevated in ten patients. No overt hyperthyroidism was noticed; three cases of subclinical hyperthyroidism were transient. CONCLUSIONS: In the examined group of patients, the prevalence of abnormal thyroidal parameters was 23 %. Decreased fT4, which does not require therapy, was observed most frequently (12 %) and correlated with PI use. On the other hand, elevated bTSH (6 %) correlated with ART duration and NRTI use. In mild subclinical hypothyroidism as observed in this patient population, thyroxine medication is not indicated in principle. Annual TSH screening is probably sufficient in HIV-infected patients with no clinical symptoms suggestive for thyroid disease. PMID- 25739651 TI - Remodelling of a homeobox gene cluster by multiple independent gene reunions in Drosophila. AB - Genome clustering of homeobox genes is often thought to reflect arrangements of tandem gene duplicates maintained by advantageous coordinated gene regulation. Here we analyse the chromosomal organization of the NK homeobox genes, presumed to be part of a single cluster in the Bilaterian ancestor, across 20 arthropods. We find that the ProtoNK cluster was extensively fragmented in some lineages, showing that NK clustering in Drosophila species does not reflect selectively maintained gene arrangements. More importantly, the arrangement of NK and neighbouring genes across the phylogeny supports that, in two instances within the Drosophila genus, some cluster remnants became reunited via large-scale chromosomal rearrangements. Simulated scenarios of chromosome evolution indicate that these reunion events are unlikely unless the genome neighbourhoods harbouring the participating genes tend to colocalize in the nucleus. Our results underscore how mechanisms other than tandem gene duplication can result in paralogous gene clustering during genome evolution. PMID- 25739650 TI - Migration characteristics and early clinical results of the NANOS(r) short-stem hip arthroplasty. AB - BACKGROUND: Femoral short stems promise essential advantages in total hip arthroplasty. Up to now, only short- and midterm clinical studies exist. Data on early stem migration that could predict later aseptic loosening at an early stage are rare. The purpose of this study was to assess migration patterns and clinical outcome 2 years after hip replacement by a metaphyseal anchored cementless short stem. METHODS: Migration data and clinical results were prospectively assessed in 49 patients. Clinical outcome was measured using the Harris Hip Score (HHS). Migration analyses were performed using the computer-assisted Einzel-Bild Roentgen-Analyse (EBRA) system. RESULTS: At 2 years after surgery, none of the implants needed revision, and HHS increased from 47.9 up to 98.1. Of 49 patients, 5 (10%) showed increased vertical stem migration (1.5 mm/2a) that might predict late aseptic loosening. Of 49 stems, 44 (90%) showed stable migration patterns indicating a beneficial long-term outcome. CONCLUSIONS: Results of this study confirm the excellent clinical data of previous works. Migration patterns strongly suggest that short-stem arthroplasty is not only an innovative but also a reliable strategy in total hip replacement. PMID- 25739652 TI - HNF1beta and S100A1 are useful biomarkers for distinguishing renal oncocytoma and chromophobe renal cell carcinoma in FNA and core needle biopsies. AB - BACKGROUND: Morphologic overlap between renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC) can pose diagnostic challenges, especially in biopsy samples in which tumor quantity may be limited, architectural features are not well represented, and gross examination is not possible. It has been demonstrated that immunohistochemistry (IHC) for HNF1alpha, HNF1beta, and S100A1 are differentially expressed in RO and ChRCC in resection specimens. We evaluated the utility of these markers in FNA and core biopsies of RO and ChRCC. METHODS: IHC for HNF1alpha, HNF1beta, and S100A1 were performed on 61 RO specimens (36 FNA biopsies and 25 core biopsies) and on 14 ChRCC specimens (10 FNA biopsies and 4 core biopsies), and results were scored semiquantitatively for staining intensity (0-3: negative, weak, moderate, strong) and staining extent (0-4: 0%, 1-25%, 26 50%, 51-75%, 76-100%). RESULTS: Forty-four (44) of 60 (73%) RO displayed moderate to-strong nuclear reactivity for HNF1beta compared to 3 of 14 (21%) ChRCC (P < .001). Staining was present in >50% of tumor cells in 34 of 60 (57%) RO and in 2 of 14 (14%) ChRCC (P = .004). S100A1 was moderately-to-strongly positive in 45 of 56 (80%) RO and in 1 of 13 (8%) ChRCC (P < .001), with 39 of 56 (70%) and 2 of 13 (15%) cases, respectively showing positivity in >50% of tumor cells (P< .001). No ChRCCs were positive for both markers. There was no statistically significant difference in intensity or extent of HNF1alpha staining between RO and ChRCC. CONCLUSIONS: HNF1beta and S100A1 positivity was observed in a significantly greater proportion of RO than ChRCC. IHC for both markers can thus aid in the differential diagnosis. Accurate distinction is of increasing importance as tumor ablative procedures and active surveillance become more widely adopted. PMID- 25739653 TI - Uncovering motivators and stumbling blocks: Exploring the clinical research experiences of speech-language pathologists. AB - PURPOSE: Healthcare providers increasingly expect that allied health staff will not only translate research evidence into their clinical practice, but also generate research. Little is known about how well prepared clinicians are to meet these expectations. Research suggests that allied health professionals, including speech-language pathologists, have moderate levels of interest in research, but only little-to-moderate experience participating in research activities. The present study aimed to explore the experiences and attitudes of speech-language pathologists in regards to undertaking research in their clinical settings. METHOD: Focus groups were conducted with 21 practising speech-language pathologists (13 research engaged, eight not research engaged). The focus groups were transcribed and the data analysed qualitatively using content analysis. RESULT: Two overarching themes mediated research engagement. Engagement in research was shaped by whether participants overcame any "fear" of research and the unique characteristics of their clinical context. Contextualizing and further shaping participants' experiences of these themes were personal factors, such as initiative and proactivity. CONCLUSION: The success of increasing the research engagement of the speech-language pathology workforce may be contingent on providing clinicians with more exposure to research opportunities and mentors as well as ensuring organizational structures are in place to encourage, support and facilitate research. PMID- 25739654 TI - UVB induces epidermal 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo. AB - Detrimental consequences of ultraviolet radiation (UVR) in skin include photoageing, immunosuppression and photocarcinogenesis, processes also significantly regulated by local glucocorticoid (GC) availability. In man, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) generates the active GC cortisol from cortisone (or corticosterone from 11 dehydrocorticosterone in rodents). 11beta-HSD1 oxo-reductase activity requires the cofactor NADPH, generated by hexose-6-phosphate dehydrogenase. We previously demonstrated increased 11beta-HSD1 levels in skin obtained from photoexposed versus photoprotected anatomical regions. However, the direct effect of UVR on 11beta-HSD1 expression remains to be elucidated. To investigate the cutaneous regulation of 11beta-HSD1 following UVR in vivo, the dorsal skin of female SKH1 mice was irradiated with 50, 100, 200 and 400 mJ/cm(2) UVB. Measurement of transepidermal water loss, 11beta-HSD1 activity, mRNA/protein expression and histological studies was taken at 1, 3 and 7 days postexposure. 11beta-HSD1 and hexose-6-phosphate dehydrogenase mRNA expression peaked 1 day postexposure to 400 mJ/cm(2) UVB before subsequently declining (days 3 and 7). Corresponding increases in 11beta-HSD1 protein and enzyme activity were observed 3 days postexposure coinciding with reduced GC receptor mRNA expression. Immunofluorescence studies revealed 11beta-HSD1 localization to hyperproliferative epidermal keratinocytes in UVB-exposed skin. 11beta-HSD1 expression and activity were also induced by 200 and 100 (but not 50) mJ/cm(2) UVB and correlated with increased transepidermal water loss (indicative of barrier disruption). UVB-induced 11beta-HSD1 activation represents a novel mechanism that may contribute to the regulation of cutaneous responses to UVR exposure. PMID- 25739656 TI - Evolutionarily conserved phenylpropanoid pattern on angiosperm pollen. AB - The male gametophyte of higher plants appears as a solid box containing the essentials to transmit genetic material to the next generation. These consist of haploid generative cells that are required for reproduction, and an invasive vegetative cell producing the pollen tube, both mechanically protected by a rigid polymer, the pollen wall, and surrounded by a hydrophobic pollen coat. This coat mediates the direct contact to the biotic and abiotic environments. It contains a mixture of compounds required not only for fertilization but also for protection against biotic and abiotic stressors. Among its metabolites, the structural characteristics of two types of phenylpropanoids, hydroxycinnamic acid amides and flavonol glycosides, are highly conserved in Angiosperm pollen. Structural and functional aspects of these compounds will be discussed. PMID- 25739655 TI - Ultrasonographic evaluation of geniohyoid muscle and hyoid bone during swallowing in young adults. AB - OBJECTIVES/HYPOTHESIS: The geniohyoid muscle plays an important role in hyoid bone movement. Adequate hyoid bone movement during swallowing is important for effective bolus flow and pharyngeal clearing. The aim of this study was to estimate the relationship between the geniohyoid muscle size and function and hyoid bone movement during swallowing in healthy young adults, as measured via ultrasound, in different body positions. STUDY DESIGN: Cross-sectional study. METHODS: Forty young (20-40 years old) adults (20 male and 20 female) participated. The cross-sectional area of the geniohyoid muscle at rest (seated position), the geniohyoid muscle contraction velocity, and the hyoid bone displacement during swallowing 10 mL of mineral water were measured by ultrasound in seated, supine, and right lateral decubitus positions. RESULTS: The size of the geniohyoid muscle correlated with body height. Males had larger geniohyoid cross-sectional area than females and greater maximal and anterior hyoid displacement during swallowing than females, and maximal and anterior hyoid bone displacement during swallowing correlated with the size of geniohyoid muscle only when the body was in the supine position; these two movements were positively correlated to each other. CONCLUSIONS: Genders vary in hyoid bone movement during swallowing, and the correlation between geniohyoid muscle size and hyoid bone displacement varies among different body positions during swallowing. This investigation also illuminates the use of ultrasound in providing quantitative measures of geniohyoid muscle and hyoid bone displacement during swallowing. LEVEL OF EVIDENCE: 2c. PMID- 25739657 TI - Effects of alcohol septal ablation on left ventricular diastolic filling patterns in obstructive hypertrophic cardiomyopathy. AB - Alcohol septal ablation (ASA) has been shown to improve left ventricular (LV) diastolic function in patients with obstructive hypertrophic cardiomyopathy (HCM). However, its beneficial effect on diastolic function assessed by cardiac magnetic resonance (CMR) has not been reported. We investigated the mid-term changes of diastolic function by CMR combined with echocardiography in HCM patients after ASA at a median of 14-month follow-up. CMR parameters of diastolic function including peak filling rate (PFR), and time to peak filling rate (TPFR) were evaluated in 43 patients (aged 48 +/- 9 years). LV diastolic function improved significantly measured by echocardiography with the decrease in ratio of transmitral early LV filling velocity (E) to early diastolic mitral lateral annular velocity (E') (14.20 +/- 1.17 to 11.58 +/- 1.16, p < 0.001) and E-wave deceleration time (194.04 +/- 19.30 to 168.45 +/- 12.58 ms, p < 0.001). PFR increased significantly with associated decrease in TPFR after ASA (both p < 0.001) at follow-up. Furthermore, patients with larger decrease in LVOT gradients had a greater improvement of LV diastolic function, as measured by the reduction of E/E' (p < 0.001) and increase of PFR (p < 0.001). In conclusion, this study demonstrated that successful ASA results in both echocardiographic and CMR indices of diastolic function improvement after ASA at 14-month follow-up. ASA therapy can significantly reduce LVOT gradient and mitral regurgitation, both of which may contribute to the improvement of diastolic function. PMID- 25739658 TI - Practical issues in multi-lingual research. AB - BACKGROUND: With an increasing number of ethnic minority populations, the use of multiple languages in one research study has increased in recent years. The use of multiple languages helps increase comprehensiveness of educational materials and/or survey questionnaires, and promote ethnic minorities' participation in research. However, little has been clearly known about practical issues in using multiple languages in one research study. OBJECTIVES: The purpose of this paper is to explore practical issues in using multiple languages in a study among diverse sub-ethnic groups of Asian American breast cancer survivors in order to propose future directions for the use of multiple languages in research projects. METHODS: Throughout the research process, research team made written records of practical issues and possible reasons for the issues as they arose. Weekly group discussions among research team members were administered, and the written records of these discussions were reviewed and analyzed using the content analysis. The unit of analysis was individual words. The words in the data (memos and written records) were classified into idea categories that emerged from the coding process. RESULTS: The idea categories included issues in: (a) collaborators from various sub-ethnic groups; (b) IRB protocol submissions; (c) consistencies in translation process, (d) conceptual equivalence; (e) cultural differences; (f) existing translated versions; and (g) authorship issues. Based on the issues, we made the following suggestions for multi-lingual research: (a) networking and setting multiple communication channels with potential collaborators; (b) checking the institution's IRB policies related to the use of multiple languages; (c) setting the rules and procedures for translation process; (d) checking existing different language versions of instruments; and (e) setting the rules for authorship in advance. CONCLUSIONS: The suggestions made in this study would help the researchers be prepared in advance to deal with the challenges. PMID- 25739659 TI - The effects of delayed auditory feedback revealed by bone conduction microphone in adult zebra finches. AB - Vocal control and learning are critically dependent on auditory feedback in songbirds and humans. Continuous delayed auditory feedback (cDAF) robustly disrupts speech fluency in normal humans and has ameliorative effects in some stutterers; however, evaluations of the effects of cDAF on songbirds are rare. We exposed singing young (141-151 days old) adult zebra finch males to high amplitude cDAF. cDAF exposure was achieved by the recording of bone-conducted sounds using a piezoelectric accelerometer, which resulted in high-quality song recordings that were relatively uncontaminated by airborne sounds. Under this condition of cDAF, birds rapidly (2-6 days) changed their song syllable timing. The one bird for which we were able to maintain the accelerometer recordings over a long period of time recovered slowly over more than a month after cDAF was discontinued. These results demonstrate that cDAF can cause substantial changes in the motor program for syllable timing generation over short intervals of time in adult zebra finches. PMID- 25739660 TI - Mass spectrometry-based metabolomics: applications to biomarker and metabolic pathway research. AB - Mass spectrometry-based metabolomics has become increasingly popular in molecular medicine. High-definition mass spectrometry (MS), coupled with pattern recognition methods, have been carried out to obtain comprehensive metabolite profiling and metabolic pathway of large biological datasets. This sets the scene for a new and powerful diagnostic approach. Analysis of the key metabolites in body fluids has become an important part of improving disease diagnosis. With technological advances in analytical techniques, the ability to measure low molecular-weight metabolites in bio-samples provides a powerful platform for identifying metabolites that are uniquely correlated with a specific human disease. MS-based metabolomics can lead to enhanced understanding of disease mechanisms and to new diagnostic markers and has a strong potential to contribute to improving early diagnosis of diseases. This review will highlight the importance and benefit with certain characteristic examples of MS-metabolomics for identifying metabolic pathways and metabolites that accurately screen for potential diagnostic biomarkers of diseases. PMID- 25739661 TI - Time estimation with multichannel digital silicon photomultipliers. AB - Accuracy in timemark estimation is crucial for time-of-flight positron emission tomography, in order to ensure high quality images after reconstruction. Since the introduction of multichannel digital silicon photomultipliers, it is possible to acquire several photoelectron timestamps for each individual gamma event. We study several timemark estimators based on multiple photoelectron timestamps by means of a comprehensive statistical model. In addition, we calculate the MSE of the estimators in comparison to the Cramer-Rao lower bound as a function of the system design parameters. We investigate the effect of skipping some of the photoelectron timestamps, which is a direct consequence of the limited number of time-to-digital converters and we propose a technique to compensate for this effect. In addition, we carry out an extensive analysis to evaluate the influence of dark counts on the detector timing performance. Moreover, we investigate the improvement of the timing performance that can be obtained with dark count filtering and we propose an appropriate filtering method based on measuring the time difference between sorted timestamps. Finally, we perform a full Monte Carlo simulation to compare different timemark estimators by exploring several system design parameters. It is demonstrated that a simple weighted-average estimator can achieve a comparable performance as the more complex maximum likelihood estimator. PMID- 25739662 TI - Super low threshold plasmonic WGM lasing from an individual ZnO hexagonal microrod on an Au substrate for plasmon lasers. AB - We demonstrate an individual ZnO hexagonal microrod on the surface of an Au substrate which can become new sources for manufacturing miniature ZnO plasmon lasers by surface plasmon polariton coupling to whispering-gallery modes (WGMs). We also demonstrate that the rough surface of Au substrates can acquire a more satisfied enhancement of ZnO emission if the surface geometry of Au substrates is appropriate. Furthermore, we achieve high Q factor and super low threshold plasmonic WGM lasing from an individual ZnO hexagonal microrod on the surface of the Au substrate, in which Q factor can reach 5790 and threshold is 0.45 KW/cm(2) which is the lowest value reported to date for ZnO nanostructures lasing, at least 10 times smaller than that of ZnO at the nanometer. Electron transfer mechanisms are proposed to understand the physical origin of quenching and enhancement of ZnO emission on the surface of Au substrates. These investigations show that this novel coupling mode holds a great potential of ZnO hexagonal micro and nanorods for data storage, bio-sensing, optical communications as well as all-optic integrated circuits. PMID- 25739663 TI - Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial mesenchymal transition and fibrosis during peritoneal dialysis. PMID- 25739664 TI - The effect of cilia and the mucociliary clearance on successful drug delivery. AB - Nasal mucociliary clearance is one of the most important factors affecting nasal delivery of drugs and vaccines. This is also the most important physiological defense mechanism inside the nasal cavity. It removes inhaled (and delivered) particles, microbes and substances trapped in the mucus. Almost all inhaled particles are trapped in the mucus carpet and transported with a rate of 8-10 mm/h toward the pharynx. This transport is conducted by the ciliated cells, which contain about 100-250 motile cellular appendages called cilia, 0.3 um wide and 5 um in length that beat about 1000 times every minute or 12-15 Hz. For efficient mucociliary clearance, the interaction between the cilia and the nasal mucus needs to be well structured, where the mucus layer is a tri-layer: an upper gel layer that floats on the lower, more aqueous solution, called the periciliary liquid layer and a third layer of surfactants between these two main layers. Pharmacokinetic calculations of the mucociliary clearance show that this mechanism may account for a substantial difference in bioavailability following nasal delivery. If the formulation irritates the nasal mucosa, this mechanism will cause the irritant to be rapidly diluted, followed by increased clearance, and swallowed. The result is a much shorter duration inside the nasal cavity and therefore less nasal bioavailability. PMID- 25739665 TI - Comparison of the effect of the rotation palatoplasty and V-Y pushback palatoplasty techniques on palate elongation with magnetic resonance imaging. AB - Most surgical techniques used in cleft palate repair require the extension of the palate to the pharynx. However, no adequate information exists regarding the extent to which this elongation obtained during operation continues in late postoperative period. In this study, we compared and measured palate elongation in patients with a cleft palate who underwent a V-Y pushback or rotation palatoplasty, by means of magnetic resonance images obtained before and 1 year after surgery. The hard palate, soft palate, and total palate lengths were measured for all of the patients, and the velopharyngeal opening area width was calculated. In patients who underwent the V-Y pushback technique (n=13), the total palate and soft palate lengths were shortened by an average of 0.10 and 0.14cm after surgery, respectively. However, the hard palate length was elongated by an average of 0.13cm. In the rotation palatoplasty group (n=13), the total palate, hard palate, and soft palate lengths were elongated by 0.57, 0.10, and 0.49cm, respectively. The velopharyngeal opening was narrowed by 0.06cm(2) using the V-Y pushback technique and by 0.29cm(2) using the rotational palatoplasty. This study demonstrated that the palate does not elongate during the V-Y pushback technique, as expected. However, rotational palatoplasty elongates the soft palate. PMID- 25739666 TI - Ethyl cinnamate derivatives as promising high-efficient acaricides against Psoroptes cuniculi: synthesis, bioactivity and structure-activity relationship. AB - This paper reported the synthesis, structure-activity relationship (SAR) and acaricidal activity in vitro against Psoroptes cuniculi, a mange mite, of 25 ethyl cinnamate derivatives. All target compounds were synthesized and elucidated by means of MS, (1)H- and (13)C-NMR analysis. The results showed that 24 out of 25 tested compounds at 1.0 mg/mL demonstrated acaricidal activity in varying degrees. Among them, 6, 15, 26, 27 and 30 showed significant activity with median lethal concentration values (LC50) of 89.3, 119.0, 39.2, 29.8 and 41.2 ug/mL, respectively, which were 2.1- to 8.3-fold the activity of ivermectin (LC50=247.4 ug/mL), a standard drug in the treatment of Psoroptes cuniculi. Compared with ivermectin, with a median lethal time value (LT50) of 8.9 h, 27 and 30 showed smaller LT50 values of 7.9 and 1.3 h, respectively, whereas 6, 15 and 26 showed slightly larger LT50 values of 10.6, 11.0 and 10.4 h at 4.5 umol/mL. SARs showed that the presence of o-NO2 or m-NO2 on the benzene ring significantly improved the activity, whereas the introduction of a hydroxy, methoxy, acetoxy, methylenedioxy, bromo or chloro group reduced the activity. (E)-Cinnamates were more effective than their (Z)-isomer. Nevertheless, the carbon-carbon double bond in the acrylic ester moiety was proven not to be essential to improve the activity of cinnamic acid esters. Thus, the results strongly indicate that cinnamate derivatives, especially their dihydro derivatives, should be promising candidates or lead compounds for the development of novel acaricides for the effective control of animal or human acariasis. PMID- 25739667 TI - Correlation between gloss reflectance and surface texture in photographic paper. AB - Surface textures of a large collection of photographic papers dating from 1896 to the present were measured using a laser scanning confocal microscope (LSCM) with four different objective lenses. Roughness characterization parameters were calculated from the texture measurements and were compared with gloss measurements. Characterization by the area-scale fractal dimension (Das) and the area-scale fractal complexity (Asfc) provided the strongest correlations between gloss reflectance and surface texture. The measurements with the 5* and 10* objectives, which contained many large-scale, spiky measurement artifacts that distorted the measurement, resulted in the strongest correlations (R(2) > 0.8) compared to the 20* and 50* (R(2) < 0.5). The presence of spiky artifacts in the measurements, which increases when the magnification of the objective lens is decreased, appears to amplify surface features in such a way to improve the correlations. PMID- 25739668 TI - Mobile phone SMS messages can enhance healthy behaviour: a meta-analysis of randomised controlled trials. AB - Healthy behaviour, such as smoking cessation and adherence to prescribed medications, mitigates illness risk factors but health behaviour change can be challenging. Mobile phone short-message service (SMS) messages are increasingly used to deliver interventions designed to enhance healthy behaviour. This meta analysis used a random-effects model to synthesise 38 randomised controlled trials that investigated the efficacy of SMS messages to enhance healthy behaviour. Participants (N = 19,641) lived in developed and developing countries and were diverse with respect to age, ethnicity, socioeconomic background and health behaviours targeted for change. SMS messages had a small, positive, significant effect (g = 0.291) on a broad range of healthy behaviour. This effect was maximised when multiple SMS messages per day were used (g = 0.395) compared to using lower frequencies (daily, multiple per week and once-off) (g = 0.244). The low heterogeneity in this meta-analysis (I (2) = 38.619) supports reporting a summary effect size and implies that the effect of SMS messaging is robust, regardless of population characteristics or healthy behaviour targeted. SMS messaging is a simple, cost-effective intervention that can be automated and can reach any mobile phone owner. While the effect size is small, potential health benefits are well worth achieving. PMID- 25739669 TI - Invasive Fungal Infections in Renal Transplant Recipients: Epidemiology and Risk Factors. AB - BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among renal transplant recipients. OBJECTIVES: The aim of this study was to investigate the frequency and risk factors for fungal infections in renal transplant recipients. METHODS: We retrospectively evaluated all kidney transplant recipients at our center from December 1988 to June 2010 for the epidemiology, spectrum, risk factors, and mortality of invasive fungal infections. RESULTS: In 32 patients (10.30 %), at least one fungal infection developed after the transplantation. The most common pathogens causing fungal infections in our patients were Candida spp. and Aspergillus spp. The independent risk factors associated with invasive fungal infection episodes were antibiotic treatment within the last 3 months (OR 15.88, 95 % CI 3.90-64.73, p < 0.001), cytomegalovirus infection (OR 18.54, 95 % CI 9.01-38.17, p < 0.001), and the presence of diabetes mellitus (OR 6.01, 95 % CI 2.95-12.25, p < 0.001). Mortality was significantly higher among patients with fungal infections than among other patients (53.10 and 17.80 %, respectively; p < 0.001). CONCLUSIONS: It is difficult to diagnose and treat fungal infections early, and it can be useful to determine independent risk factors in order to identify and treat high-risk patients. PMID- 25739670 TI - Meningitis Caused by Rhodotorula mucilaginosa in HIV-Infected Patient: A Case Report and Review of the Literature. AB - Rhodotorula species are increasingly being identified as a cause of fungal infection in the central nervous system, especially in patients with compromised immunity. The diagnosis could easily be missed due to low index of suspicion, as cryptococcus meningitis and cerebral toxoplasmosis are more common amongst immunocompromised hosts. To date, there are six cases of Rhodotorula-related meningitis reported, and three are associated with human immunodeficiency virus infection. In this report, a case of a Malaysian male with underlying human immunodeficiency virus infection who developed Rhodotorula mucilaginosa meningitis is presented. High-grade fever and severe headaches were the complaints presented in three previous case reports. India ink and nigrosin stainings were performed in the two previous reports and both revealed positive results. R. mucilaginosa were isolated from the culture of the patient's cerebrospinal fluid in all three previous reports. Predominant lymphocyte infiltration in the cerebrospinal fluid examination was documented in two reports. CD4 counts were above 100/ul in two previously published reports, while another report documented CD4 count as 56/ul. Amphotericin B and itraconazole are identified to be the first line of antifungal used and as the maintenance therapy, respectively. The possibility of relapse cannot be excluded as it was reported in the first report. It was also revealed that the current case has almost similar clinical presentation and therapeutic outcome as compared to the published reports, but some differences in diagnostic details were to be highlighted. PMID- 25739671 TI - Postoperative irinotecan in resected stage II-III rectal cancer: final analysis of the French R98 Intergroup trial?. AB - BACKGROUD: The R98 trial explores the addition of irinotecan to a 5-fluorouracil (5-FU) plus leucovorin (5-FU/LV) adjuvant regimen in optimally resected stages II III rectal cancers. We report the updated long-term results. Disease-free survival (DFS) was the primary end point. PATIENST AND METHODS: Between March 1999 and December 2005, 357 patients were randomized: 178 in 5-FU/LV and 179 in LV5-FU2 + irinotecan arm. The trial was stratified by control arm: Mayo Clinic regimen or LV5-FU2 regimen. RESULTS: Three hundred and fifty-seven randomized patients were evaluable for efficacy. With a follow-up of 156 months, the DFS was in favour of experimental arm but did not reach statistical significance [hazard ratio (HR) = 0.80, P = 0.154]. The same was observed for overall survival (OS) (HR = 0.87, P = 0.433). The 5-year DFS was 58% in the control arm and 63% in the experimental arm. The 5-year OS was 74% in the control arm and 75% in the experimental arm. Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5-FU2 arm (33% versus 6%, P = 0.03), but not when compared with the Mayo Clinic arm (33% versus 36%, P = 0.84). Grade 3-4 diarrhoea tended to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction P = 0.44). CONCLUSION: Even though a benefit of irinotecan in subgroups of patients cannot be excluded, due to early termination and lack of power, the study does not support the addition of irinotecan to 5 FU/LV in routine in patients with resected stage II-III rectal cancer. PMID- 25739672 TI - Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. AB - PURPOSE: This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m(2) and up to 10 doses of docetaxel (75 mg/m(2)) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study. RESULTS: Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease. CONCLUSIONS: ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m(2). PMID- 25739673 TI - NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma. AB - PURPOSE: Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of these findings and assessed whether NRF2 activation predicts benefit from adjuvant chemotherapy in SCC. EXPERIMENTAL DESIGN: Logistic regression (LR) and significance analysis of microarrays (SAM) were applied to all 104 TCGA (The Cancer Genome Atlas) SCC cases that had microarray gene expression and mutation data to identify genes associated with somatic NRF2 pathway alterations. The resulting signature (NRF2(ACT)) was tested in 3 independent SCC datasets to evaluate its prognostic and predictive effects. IHC and sequencing for NRF2 and KEAP1 were evaluated in one cohort (n = 43) to assess the relationship between gene expression, mutational status, and protein expression. RESULTS: Twenty-eight genes were identified by overlap between LR (291 genes) and SAM (30 genes), and these consistently separated SCC into 2 groups in all datasets, corresponding to putatively NRF pathway-activated and wild-type (WT) tumors. NRF2(ACT) was not prognostic. However, improved survival with adjuvant chemotherapy in the JBR.10 randomized trial appears limited to patients with the WT signature (HR 0.32, P = 0.16; NRF2(ACT) HR 2.28, P = 0.48; interaction P = 0.15). NRF2(ACT) was highly correlated with mutations in NRF2 and KEAP1, and with high NRF2 protein expression. CONCLUSIONS: A gene expression signature of NRF2 pathway activation is associated with benefit from adjuvant cisplatin/vinorelbine in SCC. Patients with NRF2 pathway-activating somatic alterations may have reduced benefit from this therapy. PMID- 25739675 TI - New Phenomena in Organometallic-Mediated Radical Polymerization (OMRP) and Perspectives for Control of Less Active Monomers. AB - The impact of reversible bond formation between a growing radical chain and a metal complex (organometallic-mediated radical polymerization (OMRP) equilibrium) to generate an organometallic intermediate/dormant species is analyzed with emphasis on the interplay between this and other one-electron processes involving the metal complex, which include halogen transfer in atom transfer radical polymerization (ATRP), hydrogen-atom transfer in catalytic chain transfer (CCT), and catalytic radical termination (CRT). The challenges facing the controlled polymerization of "less active monomers" (LAMs) are outlined and, after reviewing the recent achievements of OMRP in this area, the perspectives of this technique are analyzed. PMID- 25739674 TI - The Hippo Coactivator YAP1 Mediates EGFR Overexpression and Confers Chemoresistance in Esophageal Cancer. AB - PURPOSE: Esophageal cancer is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of patients with esophageal cancer. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. EXPERIMENTAL DESIGN: In this study, expression of YAP1 and EGFR were examined in EAC-resistant tumor tissues versus sensitive tissues by IHC. Western blot analysis, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis, and in vitro and in vivo functional assays were performed to elucidate the YAP1 mediated EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. RESULTS: We demonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer tissues compared with sensitive esophageal cancer tissues. Furthermore, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEAD-binding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. CONCLUSIONS: Our data provide evidence that YAP1 upregulation of EGFR plays an important role in conferring therapy resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in esophageal cancer. PMID- 25739676 TI - Photophysical properties of electron-deficient free-base corroles bearing meso fluorophenyl substituents. AB - The ultrafast photophysical behaviors of a series of meso-fluorophenyl substituted electron-deficient free base corroles F0C, F5C, F10C and F15C in toluene have been investigated using femtosecond time resolved absorption spectroscopy and steady-state spectroscopy. The S2->S1* transformation was found to be accelerated with the enhancement of electron-deficiency (from 550 fs for F0C to 140 fs for F15C), while S1*->S1 prolonged from ~9 ps for F0C to ~24 ps for F15C, which was assigned to an intermolecular vibrational cooling process. The intersystem crossing process was directly observed. The intersystem crossing rate constant (kISC) from S1 to T1 was found to increase significantly with the fluorophenyl substituents (from F0C to F10C), while it does not totally follow the trend of the increase of the atomic number of the peripheral fluorine atoms. The order of ISC time constants from larger to smaller is F0C < F5C < F10C > F15C. It indicates that the electron-withdrawing effect of fluorophenyl substitutions, together with the heavy atom effect, influences the photophysical properties of excited states of corroles. PMID- 25739677 TI - Kallmann syndrome patient with gender dysphoria, multiple sclerosis, and thrombophilia. AB - One of the challenging issues in patients with complex problems is that the various diseases and their treatment can influence each other and present unusual hurdles in management. We investigated one such complex case. A 34-year-old XY male presented with azoospermia, detected on semen analysis for pre-orchidectomy sperm banking. He had a 20-year history of gender dysphoria and bilateral breast swelling. The patient suffered a deep vein thrombosis at the age of 19 years. Examination confirmed clinical features of Kallmann syndrome including unilateral cryptorchidism, micropenis, congenital anosmia, and bimanual synkinesis (mirror movements), with reduced serum testosterone and normal gonadotropin levels demonstrating hypogonadotropic hypogonadism. MRI showed missing olfactory bulbs. Osteopenia and reduced vitamin D levels of 21 nmol/L were identified. He was found to harbor a heterozygous factor-V-Leiden mutation. The genetic basis of Kallmann syndrome remains unknown: his screening tests were negative for mutations in CHD7, FGF8, FGFR1, GNRH1, GNRHR, HS6ST1, KAL1, KISS1R, KISS1, NELF, PROK2, PROKR2, TAC3, and TACR3. The patient initially declined testosterone therapy with a view to undergo gender reassignment. Over the next 2 years, the patient experienced recurrent episodes of weakness and paresthesia, associated with classical MRI appearances of multiple sclerosis-related demyelination in the spinal cord and brain. Although it was difficult to elucidate an association between the patient's gender dysphoria and untreated congenital hypogonadism, his desire to become female together with his co-existing thrombophilia, presented challenges to the administration of hormone treatment. Furthermore, we have considered an association between multiple sclerosis and hypogonadotropic hypogonadism. PMID- 25739678 TI - Contrasts in Practices and Perceived Barriers to Colorectal Cancer Screening by Nurses and Physicians Working in Primary Care Settings in Oman. AB - Colorectal cancer (CRC) is the fourth most common type of cancer worldwide and it is responsible for 610,000 deaths annually, despite availability of screening tests that ensure early detection. Predictions specific to the Middle East show that this region will experience a significant increase in cancer mortality over the next 15 years. This study explored the practices and perceived barriers to CRC screening from the perspective of health care providers (HCPs) working in primary care settings in Muscat, Oman. A cross-sectional design and self administered questionnaires were used to collect data from 142 HCPs. The HCPs were nurses (57.7 %) and physicians (42.3 %) with average age and clinical experience of 32.5 and 9.5 years, respectively. The majority of the HCPs (64.8 %) rarely ordered, referred, health educated, or recommended CRC screening to eligible patients. The only major patient-related barrier to CRC screening reported by HCPs was lack of awareness about CRC tests (63.7 %). There were significant differences between nurses' and physicians' rating of patient-related barriers such as fear of cancer diagnosis (p = 0.037), belief that screening is not effective (p = 0.036), embarrassment or anxiety about screening tests (p = 0.022), and culture (p = 0.001). The major system barriers to CRC screening were lack of hospital policy or protocols, lack of trained HCPs, lack of CRC screening services, and timely appointments to get CRC screening. The findings indicate a need for interventions to enhance patient awareness, HCPs CRC screening practices, and strategies to ameliorate patient and system barriers to CRC screening. PMID- 25739680 TI - Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. AB - The efficacy and safety of dabigatran for treatment of venous thromboembolism (VTE) were demonstrated in two trials. It is unclear if the results pertain to patients with cancer and VTE. Data from two randomised trials comparing dabigatran and warfarin for acute VTE were pooled. Primary efficacy outcome was symptomatic recurrent VTE and related death from randomisation to the end of the treatment period. Safety outcomes were major, major and clinically relevant non major, and any bleeding during the oral-only treatment period. Patients with active cancer (=within 5 years) at baseline or diagnosed during the study were analysed. Compared with 4,772 patients without cancer, recurrent VTE occurred more frequently in 335 patients with cancer at any time (hazard ratio [HR] 3.3; 95 % confidence interval [CI], 2.1-5.3) and more often in 114 with cancer diagnosed during the study compared to 221 with cancer at baseline (HR 2.6; 95 % CI, 1.1-6.2). There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95 % CI, 0.20-2.8) or diagnosed during the study (HR 0.63; 95 % CI, 0.20-2.0). Major bleeding (HR 4.1; 95 % CI, 2.2-7.5) and any bleeding (HR 1.5; 95 % CI, 1.2-2.0) were more frequent in patients with cancer than without, but with similar incidence in cancer with dabigatran or warfarin. In conclusion, in cancer patients, dabigatran provided similar clinical benefit as warfarin. VTE recurrence or bleeding were similar in patients on dabigatran or warfarin. The efficacy of dabigatran has not been assessed in comparison with low-molecular-weight heparin. PMID- 25739681 TI - Academically buoyant students are less anxious about and perform better in high stakes examinations. AB - BACKGROUND: Prior research has shown that test anxiety is negatively related to academic buoyancy, but it is not known whether test anxiety is an antecedent or outcome of academic buoyancy. Furthermore, it is not known whether academic buoyancy is related to performance on high-stakes examinations. AIMS: To test a model specifying reciprocal relations between test anxiety and academic buoyancy and to establish whether academic buoyancy is related to examination performance. SAMPLE: A total of 705 students in their final year of secondary education (Year 11). METHODS: Self-report data for test anxiety and academic buoyancy were measured in two waves in Year 11. Examination performance was taken from the mean English, mathematics, and science scores from the high-stakes General Certificate of Secondary Education (GCSE) examinations taken at the end of Year 11. RESULTS: Measurement invariance was demonstrated for test anxiety and academic buoyancy across both waves of measurement. The worry component of test anxiety, but not the tension component, showed reciprocal relations with academic buoyancy. Worry predicted lower mean GCSE score and academic buoyancy predicted a higher mean GCSE score. Tension did not predict mean GCSE score. CONCLUSION: Academic buoyancy protects against the appraisal of examinations as threatening by influencing self-regulative processes and enables better examination performance. Worry, but not tension, shows a negative feedback loop to academic buoyancy. PMID- 25739682 TI - Appreciation of diversity and nomenclature within clinical practice. PMID- 25739683 TI - Sexual health care for people with physical disabilities. AB - BACKGROUND: People with physical disabilities make up a large and heterogeneous population, many with specific sexual health needs that differ from the general population. METHODS: To conduct a review of current definitions and statuses relating to the sexual well-being of people with physical disabilities. Medical, social, and behavioral literature was searched and included to address the specific sexual health needs and disparities in this population. RESULTS: People with physical disabilities encompass a broad population, including those with concomitant mental and cognitive impairments. People with physical disabilities have significant sexual and reproductive health disparities when compared with the general population and higher rates of sexual distress. There are specific sexual health concerns for men and women with physical disabilities and approach to their care needs to be interdisciplinary. CONCLUSIONS: Sexual health needs for people with physical disabilities should be a priority for healthcare providers. Continued education is essential to ensure disparities and health needs are addressed and treated. PMID- 25739691 TI - Epicardial Fat Thickness is Increased in Vitamin D Deficient Premenopausal Women and does not Decrease after Short-term Replacement. AB - AIM: Vitamin D deficiency, which is prevalent among young women in Middle Eastern populations, has been linked to cardiovascular disease. Epicardial adipose tissue (EAT) has also been found to be associated with coronary artery disease. However, data on the relationship between vitamin D status and epicardial adiposity is limited. This study aims to investigate the effect of vitamin D deficiency and replacement therapy on EAT thickness in healthy, young premenopausal women. METHODS: Thirty-one premenopausal women with vitamin D deficiency and 31 age matched women with normal vitamin D levels were enrolled in this study. EAT thickness was measured echocardiographically. Measurements were performed at baseline in both groups and were repeated at the 6-month follow-up in vitamin D deficient subjects after vitamin D replacement therapy. RESULTS: The baseline plasma 25-hydroxyvitamin D levels were lower in the vitamin D deficient group compared to the control group and were significantly improved following replacement therapy. EAT thickness was significantly higher in the vitamin D deficient group, and no significant change occurred following replacement therapy. In the linear regression analysis, waist circumference (beta=0.031 [0.005-0.057], p=0.020) and 25(OH)D level (beta=-0.020 [(-0.028)-(-0.013)], p<0.001) independently correlated with EAT thickness. CONCLUSION: Vitamin D deficiency is associated with a significant increase in EAT thickness in premenopausal women; however, a net beneficial response to adequate replacement therapy was not observed during the short period of therapy during our study. Longer periods of replacement therapy and follow-up may be useful to demonstrate the potential beneficial effects of vitamin D replacement on epicardial adiposity. PMID- 25739692 TI - Navigating toward a novel environment from a route or survey perspective: neural correlates and context-dependent connectivity. AB - When we move toward a novel environment we may learn it in different ways, i.e., by walking around or studying a map. Both types of learning seem to be very effective in daily life navigation and correspond to two different types of mental representation of space: route and survey representation. In the present study, we investigated the neural basis of route and survey perspectives during learning and retrieval of novel environments. The study was carried out over 5 days, during which participants learned two paths from a different perspective (i.e., route learning and survey learning). Then participants had to retrieve these paths using a survey or route perspective during fMRI scans, on the first and fifth day. We found that the left inferior temporal lobe and right angular gyrus (AG) were activated more during recall of paths learned in a survey perspective than in a route perspective. We also found a session by perspective interaction effect on neural activity in brain areas classically involved in navigation such as the parahippocampal place area (PPA) and the retrosplenial cortex (RSC). A set of frontal, parietal and temporal areas showed different patterns of activity according to the type of retrieval perspective. We tested the context-dependent connectivity of right PPA, RSC and AG, finding that these areas showed different patterns of connectivity in relation to the learning and recalling perspective. Our results shed more light on the segregation of neural circuits involved in the acquisition of a novel environment and navigational strategies. PMID- 25739693 TI - Comparison of Perinatal Risk Factors Associated with Autism Spectrum Disorder (ASD), Intellectual Disability (ID), and Co-occurring ASD and ID. AB - While studies report associations between perinatal outcomes and both autism spectrum disorder (ASD) and intellectual disability (ID), there has been little study of ASD with versus without co-occurring ID. We compared perinatal risk factors among 7547 children in the 2006-2010 Autism and Developmental Disability Monitoring Network classified as having ASD + ID, ASD only, and ID only. Children in all three groups had higher rates of preterm birth (PTB), low birth weight, small-for-gestational-age, and low Apgar score than expected based on the US birth cohort adjusted for key socio-demographic factors. Associations with most factors, especially PTB, were stronger for children with ID only than children with ASD + ID or ASD only. Associations were similar for children with ASD + ID and ASD only. PMID- 25739695 TI - [Erratum to: Sporting loads to Spondylodesis of lumbar spine: The return-to-play process]. PMID- 25739694 TI - Age Differences in Emergency Department Visits and Inpatient Hospitalizations in Preadolescent and Adolescent Youth with Autism Spectrum Disorders. AB - This paper evaluated age differences in emergency department care and inpatient hospitalizations in 252 preadolescent and adolescent youth with autism spectrum disorders (ASDs; ages 9-18). Records from youth with ASDs were linked to acute care utilization records and were compared to a demographically similar comparison group of youth without ASDs (N = 1260). A particular focus was placed on utilization for psychiatric concerns and injuries or accidents. Results suggested that psychiatric care was more likely for youth with ASDs in both the preadolescent and adolescent cohorts versus comparison youth, with no significant differences between age cohorts. In contrast, results for the accident and injury categories suggested age-specific findings. Results suggest opportunities for prevention efforts for youth with ASDs. PMID- 25739696 TI - [Endoprosthetic replacement of the elbow joint in rheumatoid arthritis : Video article]. AB - Endoprosthetic replacement of the elbow joint is comparatively rare with less than 100 cases per year in Germany. Patients with forms of rheumatism constitute the major proportion and they also show the significantly best results. The indications are assessed in a stage-adapted manner and depend mostly on the stability and the grade of bony destruction. An acceptable function of this joint, which transmits high strength but is not load bearing, is the main target. The accompanying video demonstrates the implantation of a total elbow endoprosthesis. PMID- 25739697 TI - CD1 Antigen Presentation and Autoreactivity in the Pregnant Human Uterus. AB - PROBLEM: CD11c(HI) human decidual macrophages express several isoforms of CD1 molecules. Their expression pattern and function required investigation. METHOD OF STUDY: CD11c(HI) macrophages were isolated from decidua. Expression of CD1 isoforms and their ability to present lipid antigens to T cells was studied. RESULTS: CD1a, CD1c, and CD1d were all expressed on CD11c(HI) dMphi, a pattern differing from those previously observed. Exposure of peripheral monocytes and dendritic cells to lipid isolates from decidua led to increased surface CD1a levels only. The CD1a and CD1c on dMphi were able to present the appropriate lipid antigens to lipid antigen-specific T cells. Finally, autoreactivity of decidual T cells to CD1a was observed. CONCLUSION: The unique pattern of expression of CD1 isoforms on CD11c(HI) dMphi is consistent with organ-specific roles of CD1 in human T-cell responses. dMphi are able to present lipid antigens to both peripheral and decidual T cells and are major antigen-presenting cells in human decidua. PMID- 25739698 TI - The Xanthomonas campestris type III effector XopJ proteolytically degrades proteasome subunit RPT6. AB - Many animal and plant pathogenic bacteria inject type III effector (T3E) proteins into their eukaryotic host cells to suppress immunity. The Yersinia outer protein J (YopJ) family of T3Es is a widely distributed family of effector proteins found in both animal and plant pathogens, and its members are highly diversified in virulence functions. Some members have been shown to possess acetyltransferase activity; however, whether this is a general feature of YopJ family T3Es is currently unknown. The T3E Xanthomonas outer protein J (XopJ), a YopJ family effector from the plant pathogen Xanthomonas campestris pv vesicatoria, interacts with the proteasomal subunit Regulatory Particle AAA-ATPase6 (RPT6) in planta to suppress proteasome activity, resulting in the inhibition of salicylic acid related immune responses. Here, we show that XopJ has protease activity to specifically degrade RPT6, leading to reduced proteasome activity in the cytoplasm as well as in the nucleus. Proteolytic degradation of RPT6 was dependent on the localization of XopJ to the plasma membrane as well as on its catalytic triad. Mutation of the Walker B motif of RPT6 prevented XopJ-mediated degradation of the protein but not XopJ interaction. This indicates that the interaction of RPT6 with XopJ is dependent on the ATP-binding activity of RPT6, but proteolytic cleavage additionally requires its ATPase activity. Inhibition of the proteasome impairs the proteasomal turnover of Nonexpressor of Pathogenesis Related1 (NPR1), the master regulator of salicylic acid responses, leading to the accumulation of ubiquitinated NPR1, which likely interferes with the full induction of NPR1 target genes. Our results show that YopJ family T3Es are not only highly diversified in virulence function but also appear to possess different biochemical activities. PMID- 25739699 TI - Three R2R3-MYB transcription factors regulate distinct floral pigmentation patterning in Phalaenopsis spp. AB - Orchidaceae are well known for their fascinating floral morphologic features, specialized pollination, and distinctive ecological strategies. With their long lasting flowers of various colors and pigmentation patterning, Phalaenopsis spp. have become important ornamental plants worldwide. In this study, we identified three R2R3-MYB transcription factors PeMYB2, PeMYB11, and PeMYB12. Their expression profiles were concomitant with red color formation in Phalaenopsis spp. flowers. Transient assay of overexpression of three PeMYBs verified that PeMYB2 resulted in anthocyanin accumulation, and these PeMYBs could activate the expression of three downstream structural genes Phalaenopsis spp. Flavanone 3 hydroxylase5, Phalaenopsis spp. Dihydroflavonol 4-reductase1, and Phalaenopsis spp. Anthocyanidin synthase3. In addition, these three PeMYBs participated in the distinct pigmentation patterning in a single flower, which was revealed by virus induced gene silencing. In the sepals/petals, silencing of PeMYB2, PeMYB11, and PeMYB12 resulted in the loss of the full-red pigmentation, red spots, and venation patterns, respectively. Moreover, different pigmentation patterning was regulated by PeMYBs in the sepals/petals and lip. PeMYB11 was responsive to the red spots in the callus of the lip, and PeMYB12 participated in the full pigmentation in the central lobe of the lip. The differential pigmentation patterning was validated by RNA in situ hybridization. Additional assessment was performed in six Phalaenopsis spp. cultivars with different color patterns. The combined expression of these three PeMYBs in different ratios leads to a wealth of complicated floral pigmentation patterning in Phalaenopsis spp. PMID- 25739702 TI - Derogatory nomenclature is still being used: the example of split hand/foot. PMID- 25739701 TI - Reducing isozyme competition increases target fatty acid accumulation in seed triacylglycerols of transgenic Arabidopsis. AB - One goal of green chemistry is the production of industrially useful fatty acids (FAs) in crop plants. We focus on hydroxy fatty acids (HFAs) and conjugated polyenoic FAs (alpha-eleostearic acids [ESAs]) using Arabidopsis (Arabidopsis thaliana) as a model. These FAs are found naturally in seed oils of castor (Ricinus communis) and tung tree (Vernicia fordii), respectively, and used for the production of lubricants, nylon, and paints. Transgenic oils typically contain less target FA than that produced in the source species. We hypothesized that competition between endogenous and transgenic isozymes for substrates limits accumulation of unique FAs in Arabidopsis seeds. This hypothesis was tested by introducing a mutation in Arabidopsis diacylglycerol acyltransferase1 (AtDGAT1) in a line expressing castor FA hydroxylase and acyl-Coenzyme A:RcDGAT2 in its seeds. This led to a 17% increase in the proportion of HFA in seed oil. Expression of castor phospholipid:diacylglycerol acyltransferase 1A in this line increased the proportion of HFA by an additional 12%. To determine if our observations are more widely applicable, we investigated if isozyme competition influenced production of ESA. Expression of tung tree FA conjugase/desaturase in Arabidopsis produced approximately 7.5% ESA in seed lipids. Coexpression of VfDGAT2 increased ESA levels to approximately 11%. Overexpression of VfDGAT2 combined with suppression of AtDGAT1 increased ESA accumulation to 14% to 15%. Our results indicate that isozyme competition is a limiting factor in the engineering of unusual FAs in heterologous plant systems and that reduction of competition through mutation and RNA suppression may be a useful component of seed metabolic engineering strategies. PMID- 25739700 TI - The micro-RNA72c-APETALA2-1 node as a key regulator of the common bean-Rhizobium etli nitrogen fixation symbiosis. AB - Micro-RNAs are recognized as important posttranscriptional regulators in plants. The relevance of micro-RNAs as regulators of the legume-rhizobia nitrogen-fixing symbiosis is emerging. The objective of this work was to functionally characterize the role of micro-RNA172 (miR172) and its conserved target APETALA2 (AP2) transcription factor in the common bean (Phaseolus vulgaris)-Rhizobium etli symbiosis. Our expression analysis revealed that mature miR172c increased upon rhizobial infection and continued increasing during nodule development, reaching its maximum in mature nodules and decaying in senescent nodules. The expression of AP2-1 target showed a negative correlation with miR172c expression. A drastic decrease in miR172c and high AP2-1 mRNA levels were observed in ineffective nodules. Phenotypic analysis of composite bean plants with transgenic roots overexpressing miR172c or a mutated AP2-1 insensitive to miR172c cleavage demonstrated the pivotal regulatory role of the miR172 node in the common bean rhizobia symbiosis. Increased miR172 resulted in improved root growth, increased rhizobial infection, increased expression of early nodulation and autoregulation of nodulation genes, and improved nodulation and nitrogen fixation. In addition, these plants showed decreased sensitivity to nitrate inhibition of nodulation. Through transcriptome analysis, we identified 114 common bean genes that coexpressed with AP2-1 and proposed these as being targets for transcriptional activation by AP2-1. Several of these genes are related to nodule senescence, and we propose that they have to be silenced, through miR172c-induced AP2-1 cleavage, in active mature nodules. Our work sets the basis for exploring the miR172 mediated improvement of symbiotic nitrogen fixation in common bean, the most important grain legume for human consumption. PMID- 25739703 TI - Optimizing quality of life in multiple myeloma patients: current options, challenges and recommendations. AB - Multiple myeloma (MM) is a plasma cell neoplasm with a chronic disease course that primarily affects elderly individuals. The introduction of novel agents such as thalidomide, lenalidomide and bortezomib has significantly improved the outcome for MM patients, including the elderly. Quality of life in MM is influenced by disease-related symptoms, treatment-related toxicity and treatment response. In addition to conventional endpoints as response, quality of life should be carefully evaluated during each therapeutic phase. Caring for older adults with MM is particularly challenging because of the heterogeneity of aging and the presence of comorbidities and frailty, with a potential risk of over- or under-treatment. Moreover, elderly patients may sometimes prioritize maintaining quality of life above prolonging survival. A careful evaluation of comorbidities and a geriatric assessment can facilitate risk-stratification of elderly patients to identify the older population fit enough to tolerate standard drug dosing, and to detect the frail patients who need age-adapted treatment. PMID- 25739704 TI - Estimated glomerular filtration rates cannot replace measured GFR in type 1 diabetes patients with hyperfiltration. AB - AIM: This study of children and young adults with type 1 diabetes with normal to high glomerular filtration rates (GFR) compared estimated GFR (eGFR) with measured GFR (mGFR). METHODS: GFR was measured by inulin clearance, and we carried out simultaneous analyses of standardised creatinine and cystatin C. eGFR was calculated using different formulas. RESULTS: We enrolled 106 patients, including 56 males, aged 21.9 (standard deviation 9.2) years with 13.7 (9.1) years' duration of diabetes and a mean haemoglobin A1c (HbA1c ) of 7.7% (61 mmol/mol). The median mGFR was 128 (111-143) mL/min/1.73 m(2) . Most of the eGFR estimations failed to detect a significant proportion of hyperfiltration based on inulin clearance. The best accuracy (P30) between eGFR and mGFR was seen with eGFRCKD - EPI (92%), eGFRcys C Berg (86%), eGFRcys C CAPA (78%) and eGFRcys C Inker (84%) where eGFRCKD - EPI and eGFR cys C Berg showed the lowest bias. Most eGFRcys C measurements showed greater accuracy when combined with eGFRcr (P30 92 94%). CONCLUSION: The best accuracy (P30) and lowest bias were found with eGFRCKD - EPI and eGFR Berg. in this cohort. However, eGFR cannot accurately replace mGFR to detect hyperfiltration and follow GFR over time in young patients with type 1 diabetes. PMID- 25739705 TI - Prognostic impact of HOTAIR expression is restricted to ER-negative breast cancers. AB - Expression of HOX transcript antisense intergenic RNA (HOTAIR), a large intergenic noncoding RNA (lincRNA), has been described as a metastases-associated lincRNA in various cancers including breast, liver and colon cancer cancers. We sought to determine if expression of HOTAIR could be used as a surrogate for assessing nodal metastases and evaluated RNA in situ hybridization (RNA-ISH) assay in a tissue microarray constructed from 133 breast cancer patients. The prognostic value of HOTAIR was further validated in large cohorts using The Cancer Genome Atlas (TCGA) breast cancer subjects. RNA-ISH analysis was successful in 94 cases (17% cases scored 0, 32.9% scored 1, 30.8% scored 2, and 19.1% scored 3). The expression of HOTAIR did not correlate with nodal metastasis regardless of the scoring intensity or with other study parameters (age, tumor size and grade, expression status). Further analysis of TCGA dataset showed that HOTAIR expression was lower in ductal carcinomas but higher in ER-negative tumors. Overexpression of HOTAIR was not associated with nodal metastases or prognosis in ER-positive patients. Its function as a poor prognostic indicator in ER-negative patients was restricted to node-positive patients. HOTAIR appears to be a marker for lymphatic metastases rather than hematogenous metastases in ER negative patients. PMID- 25739706 TI - Deep gluteal syndrome: anatomy, imaging, and management of sciatic nerve entrapments in the subgluteal space. AB - Deep gluteal syndrome (DGS) is an underdiagnosed entity characterized by pain and/or dysesthesias in the buttock area, hip or posterior thigh and/or radicular pain due to a non-discogenic sciatic nerve entrapment in the subgluteal space. Multiple pathologies have been incorporated in this all-included "piriformis syndrome," a term that has nothing to do with the presence of fibrous bands, obturator internus/gemellus syndrome, quadratus femoris/ischiofemoral pathology, hamstring conditions, gluteal disorders and orthopedic causes. The concept of fibrous bands playing a role in causing symptoms related to sciatic nerve mobility and entrapment represents a radical change in the current diagnosis of and therapeutic approach to DGS. The development of periarticular hip endoscopy has led to an understanding of the pathophysiological mechanisms underlying piriformis syndrome, which has supported its further classification. A broad spectrum of known pathologies may be located nonspecifically in the subgluteal space and can therefore also trigger DGS. These can be classified as traumatic, iatrogenic, inflammatory/infectious, vascular, gynecologic and tumors/pseudo tumors. Because of the ever-increasing use of advanced magnetic resonance neurography (MRN) techniques and the excellent outcomes of the new endoscopic treatment, radiologists must be aware of the anatomy and pathologic conditions of this space. MR imaging is the diagnostic procedure of choice for assessing DGS and may substantially influence the management of these patients. The infiltration test not only has a high diagnostic but also a therapeutic value. This article describes the subgluteal space anatomy, reviews known and new etiologies of DGS, and assesses the role of the radiologist in the diagnosis, treatment and postoperative evaluation of sciatic nerve entrapments, with emphasis on MR imaging and endoscopic correlation. PMID- 25739707 TI - Targeting Na+/K+ -translocating adenosine triphosphatase in cancer treatment. AB - The Na(+) /K(+) -translocating adenosine triphosphatase (ATPase) transports sodium and potassium across the plasma membrane and represents a potential target in cancer chemotherapy. Na(+) /K(+) -ATPase belongs to the P-type ATPase family (also known as E1-E2 ATPase), which is involved in transporting certain ions, metals, and lipids across the plasma membrane of mammalian cells. In humans, the Na(+) /K(+) -ATPase is a binary complex of an alpha-subunit that has four isoforms (alpha1 -alpha4 ) and a beta-subunit that has three isoforms (beta1 beta3 ). This review aims to update our knowledge on the role of Na(+) /K(+) ATPase in cancer development and metastasis, as well as on how Na(+) /K(+) ATPase inhibitors kill tumour cells. The Na(+) /K(+) -ATPase has been found to be associated with cancer initiation, growth, development, and metastasis. Cardiac glycosides have exhibited anticancer effects in cell-based and mouse studies via inhibition of the Na(+) /K(+) -ATPase and other mechanisms. Na(+) /K(+) -ATPase inhibitors may kill cancer cells via induction of apoptosis and autophagy, radical oxygen species production, and cell cycle arrest. They also modulate multiple signalling pathways that regulate cancer cell survival and death, which contributes to their antiproliferative activities in cancer cells. The clinical evidence supporting the use of Na(+) /K(+) -ATPase inhibitors as anticancer drugs is weak. Several phase I and phase II clinical trials with digoxin, Anvirzel, and huachansu (an intravenous formulated extract of the venom of the wild toad), either alone or more often in combination with other anticancer agents, have shown acceptable safety profiles but limited efficacy in cancer patients. Well designed randomized clinical trials with reasonable sample sizes are certainly warranted to confirm the efficacy and safety of cardiac glycosides for the treatment of cancer. PMID- 25739708 TI - Nutrition-focused physical examination in pediatric patients. AB - A complete nutrition assessment includes several components: medical record review, anthropometric measurements, diet/nutrition intake, interview, and physical examination. The nutrition-focused physical examination (NFPE) can identify or confirm muscle wasting, subcutaneous fat loss, and edema and clarify information gathered during the medical record review. The physical examination component of the nutrition assessment is more critical in pediatric patients because pediatric patients can become malnourished more quickly than adults and because prolonged malnutrition can negatively affect growth and development. In addition, case studies of micronutrient deficiencies, essential fatty acid deficiency, and protein-calorie malnutrition with skin manifestations have been reported in developed countries. The etiologies of the deficiencies are chronic disease, long-term tube feedings, or long-term parenteral nutrition. An NFPE involves an in-depth examination of the patient from head to toe by a trained nutrition professional. Nutrition professionals recognize the importance and value of an NFPE, yet it is seldom completed, particularly in pediatrics, most likely due to lack of training and lack of pediatric-specific information or training opportunities. Although there are similarities between NFPE in pediatric and adult patients such as the techniques used (inspection, palpation, percussion, and auscultation), there are important differences related to growth and development. This review provides an overview of nutrition assessment with focus on the NFPE and aspects unique to the pediatric patient. PMID- 25739709 TI - [Prefabrication of bone transplants]. AB - Prefabrication of bone transplants is a promising option for large defects of the long bones, especially if there is compromised vascularization of the defect. This is especially true for postinfection bone defects and other types of atrophic nonunion. The generation of a foreign body membrane (Masquelet's technique) has been investigated in order to ameliorate the response of the host tissue surrounding the defect. In an experimental animal study, a blood vessel within a bone construct could be used to generate customized, vascularized osteogenic constructs that can be used to treat large bone defects in the future. PMID- 25739710 TI - [Oncological result of T1N0M0 rectal adenocarcinoma : comparison of local and radical procedures]. PMID- 25739711 TI - The impact of storage temperature and sperm number on the fertility of liquid stored bull semen. AB - In Ireland, liquid bull semen is stored at unregulated ambient temperatures, typically at 5*106 spermatozoa per dose, and inseminated within 2.5 days of collection. In Experiment 1, the effect of storage temperature (5, 15, 22, 32 degrees C and fluctuations (Flux) between these temperatures) on progressive motility, viability, acrosomal status, DNA fragmentation and osmotic resistance was assessed. In Experiment 2, the field fertility of liquid semen at 5, 4 and 3*106 spermatozoa per dose, up to Day 2 after collection, was assessed in comparison to frozen-thawed semen at 20*106 spermatozoa per dose (n=35328 inseminations). In Experiment 1, storage at 15 degrees C resulted in the highest progressive motility (PP6 spermatozoa per dose on Day 2 of storage was reduced in comparison to frozen-thawed semen (P<0.01). In conclusion, liquid semen is versatile between storage temperatures of 5 and 22 degrees C, but demonstrates reduced fertility on Day 2 of storage at lower sperm numbers in comparison to frozen-thawed semen. PMID- 25739712 TI - Real time monitoring of layer-by-layer polyelectrolyte deposition and bacterial enzyme detection in nanoporous anodized aluminum oxide. AB - Porous anodized aluminum oxide (pAAO) is a nanostructured material, which due to its optical properties lends itself to the design of optical biosensors where interactions in the pores of this material are transduced into interferometric reflectance shifts. In this study, a pAAO-based biosensor was developed as a biosensing platform to detect proteinase K, an enzyme which is a readily available model system for the proteinase produced by Pseudomonas aeruginosa. The pAAO pore walls are decorated by means of the layer-by-layer (LbL) deposition technique using poly(sodium-4-styrenesulfonate) and poly-l-lysine as negatively and positively charged polyelectrolytes, respectively. Interferometric reflectance spectroscopy utilized to observe the optical properties of pAAO during LbL deposition shows that the deposition of the polyelectrolyte onto the pore walls increases the net refractive index, thus red-shifting the effective optical thickness (EOT). Upon incubation with proteinase K, a conspicuous blue shift of the EOT is observed, which is attributed to the destabilization of the LbL film upon enzymatic degradation of the poly-l-lysine components. This result is confirmed by scanning electron microscopy results. Finally, as a proof-of principle, we demonstrate the ability of the label-free pAAO-based biosensing platform to detect the presence of the proteinase K in human wound fluid, highlighting the potential for detection of bacterial infections in chronic wounds. PMID- 25739713 TI - Improving detection of obstructive sleep apnoea by overnight oximetry in children using pulse rate parameters. AB - PURPOSE: Overnight oximetry is a simple tool for investigation of obstructive sleep apnoea (OSA) in children, but only severe cases will be detected, and children with obstructive events resulting in arousal, but not desaturation, will have a normal (inconclusive) result. We hypothesised that pulse rate rises using pulse rate indices per hour (PRI) and pulse rate standard deviation (PR-SD) automatically calculated from commercially available software would improve oximetry as a diagnostic tool. METHODS: Children having home overnight oximetry for suspected OSA were identified over 12 months, and those with a normal result who went on to have polysomnography (PSG) were included. Oximetry, including PR SD and PRI (rises of 8, 10 and 15 beats/min per hour), was analyzed using commercially available software. PR parameters were compared between those with OSA (obstructive apnoea-hypopnoea index (OAHI) >1 event/h) and those without OSA. RESULTS: One hundred sixteen children had normal oximetry, of whom 93 (median age 4.5 years; 55 % M) had PSG. Fifty-seven of 93 (61 %) children had OSA (median OAHI 4.5 events/h, range 1.1-24). PR-SD was not different between the OSA and non OSA groups (p = 0.87). PRI tended to be higher in those with OSA, but there was considerable overlap between the groups: PRI-8 (mean +/- SD 58.5 +/- 29.0/h in OSA group vs 48.6 +/- 20.2/h in non-OSA group, p = 0.07), PRI-10 (45.1 +/- 25.0 vs 36.2 +/- 16.7, p = 0.06) and PRI-15 (24.4 +/- 14.5 vs 18.9 +/- 9.0, p = 0.04). A PRI-15 threshold of >35/h had specificity of 97 % for OSA. CONCLUSION: The PRI 15 shows promise as an indicator of OSA in children with normal oximetry. PMID- 25739714 TI - A nation-wide population-based study of inguinal hernia repair incidence and age stratified recurrence in an Asian population. AB - PURPOSE: It has been estimated in the UK that 27 % of men and 3 % of women will undergo an inguinal hernia repair (IHR) during their lifetimes. However, no epidemiologic study investigating IHR has been performed to date in an Asian population. The present study explored the incidence and recurrence of IHR in an Asian population using a nation-wide population-based dataset in Taiwan. METHODS: Based on the National Health Insurance Database, we identified 5806 patients who underwent an IHR between 2000 and 2010 and followed them until they had a recurrence, died during hospitalization, left the program, or the study ended. We calculated the age-stratified recurrence rates and used Cox proportional hazards to explore the influence of demographic and clinical factors on recurrence. We also plotted IHR occurrence over the study period. RESULTS: Among the 5806 sampled subjects who had an IHR, 565 (9.73 %) had an IHR recurrence yielding an overall incidence of 18.23 per 1000 person-years. The hazard ratios for recurrence increased with age, and were greater among men and blue collar workers. The incidence of IHR decreased from 168.21 to 92.10 per 100,000 person years over the study period. Surgical complication rates ranged between 0.16 and 2.57 %. CONCLUSIONS: On account of the increased risk of recurrence with age, young hernia patients may not want to delay surgery. This study detected a decreasing trend in initial IHR rates, confirming similar trends reported in Western countries. However, the incidence of initial IHR is lower in Taiwan than it is in the West. PMID- 25739715 TI - Abdominal compartment syndrome as a rare complication following component separation repair: case report and review of the literature. AB - One of the most feared complications following a massive ventral hernia repair is abdominal compartment syndrome (ACS). ACS is caused by an acute increase in intra abdominal pressure (IAP), which can lead to multi-organ dysfunction and ultimately result in death. Component separation repair (CST) has been successful for most large hernia repairs in reducing the risk of ACS by increasing abdominal volume and reducing abdominal wall tension during a tight closure. However, reduction of a large hernia can lead to elevated IAP and possible progression to ACS. Here, we describe the detailed intra-operative and post-operative course of a patient who developed abdominal compartment syndrome following CST repair. PMID- 25739716 TI - Diaphragmatic hernia post-minimally invasive esophagectomy: a discussion and review of literature. AB - BACKGROUND: Diaphragmatic hernia (DH) after esophagectomy is a known complication which can occur and the incidence may be higher after minimally invasive esophagectomy (MIE). A review of our cases involving post-MIE diaphragmatic hernias and the published literature is presented. METHODS: A retrospective review of patients who underwent MIE from November 2006 to January 2013 was performed. An Embase and Pub Med literature search on diaphragmatic hernia post esophagectomy was conducted from 1990 to 2013 and reviewed. RESULTS: In total, 120 consecutive patients underwent MIE at our institution. Neoadjuvant chemoradiotherapy had been performed in 71.4 % of patients. The mean age was 65 +/- 22 years and 85 % were male. Seven patients (5.8 %) were diagnosed with DH by radiographic imaging with 5 (71.4 %) requiring surgical intervention. Diagnosis was made at a median time of 3.4 months (range 1-45 months) after MIE. One patient recurred after repair and underwent a second repair. There were no related mortalities. In literature review, 11 publications reporting DH were reviewed documenting a total of 4669 esophagectomies, with 756 MIE. The incidence of DH observed was 121 (2.6 %) in all patients and 34 (4.5 %) in MIE. Two studies comparing open versus MIE also reported a higher incidence of DH in MIE. CONCLUSIONS: Post-esophagectomy diaphragmatic hernia can occur and may be underreported. Minimally invasive esophagectomy appears to have a higher incidence of postoperative herniation when compared to traditional, open esophagectomy. PMID- 25739717 TI - Tricuspid annular dynamics before and after tricuspid annuloplasty- three dimensional transesophageal echocardiography. AB - BACKGROUND: Little is known about the impact of tricuspid annuloplasty (TAP) on annular dynamics. We assessed tricuspid annular dynamics using 3-D transesophageal echocardiography (3D-TEE) before and after TAP with different types of prosthetic ring. METHODS AND RESULTS: 3D-TEE of the tricuspid valve was acquired in 30 patients (TAP with rigid ring [RR], n=8; TAP with flexible ring [FR], n=10; control, n=12). Tricuspid annular dimensions (circumference, area, annular height, anteroposterior [AP], septolateral [SL] diameter) were measured throughout the cardiac cycle. All postoperative tricuspid annular dimension parameters were significantly reduced by TAP, while the AP/SL ratio was significantly increased (before, 0.96+/-0.16; after, 1.03+/-0.06; P<0.05). The difference in annular area between diastole and systole was significantly smaller in the TAP groups (11.6%) than in the control (27.9%, P<0.05). Annular height in the FR patients was significantly lower than in the RR group, while the postoperative AP/SL ratio was lower in the RR than the FR and control groups. Change in annular area was not seen in RR patients, while it was seen in the FR and control groups. CONCLUSIONS: Annulus motion and shape differ according to the type of prosthetic ring used, although tricuspid regurgitation was well controlled by all types of ring utilized. The present results provide important information for selection of an appropriate prosthetic ring for TAP. PMID- 25739718 TI - Coronary angiographic characteristics that influence fractional flow reserve. AB - BACKGROUND: Percutaneous coronary intervention (PCI) guided with fractional flow reserve (FFR) has been shown to improve clinical outcome. Although coronary angiography is the standard method for PCI guidance, the visual severity of stenosis is not always correlated with functional severity, suggesting that there are additional angiographic factors that affect functional ischemia. METHODS AND RESULTS: To evaluate angiographic predictors of positive FFR in stenotic lesions, angiographic characteristics of 260 consecutive patients (362 lesions) who underwent FFR testing from April 2009 to September 2012 were analyzed. A scoring system (STABLED score) using these predictors was developed and compared with quantitative coronary angiography (QCA). %Diameter stenosis >50% (OR, 8.43; P<0.0001), tandem lesion (OR, 4.00; P<0.0001), true bifurcation (OR, 2.42; P=0.028), lesion length >20 mm (OR, 5.40; P=0.0002), and distance from ostium <20 mm (OR, 1.94; P=0.028) were determined as independent predictors of positive FFR. Area under the ROC curve for probability of positive FFR using the STABLED score (Stenosis 2 points, TAndem lesion 1 point, Bifurcation 1 point, LEsion length 1 point, Distance from ostium 1 point) was 0.85, higher than that for QCA stenosis alone (0.76). STABLED score >=3 had 72.3% sensitivity and 83.6% specificity for predicting positive FFR, and PPV was 76.7%. CONCLUSIONS: Specific angiographic features are applicable for predicting functional ischemia. STABLED score correlates well with FFR. PMID- 25739720 TI - Pulmonary embolism severity index and simplified pulmonary embolism severity index risk scores are useful to predict mortality in Japanese patients with pulmonary embolism. AB - BACKGROUND: The Pulmonary Embolism Severity Index (PESI) and simplified PESI (sPESI) have not been fully evaluated in Japan, so the present study aimed to evaluate these risk stratification models in the prediction of mortality of affected patients in Japan. METHODS AND RESULTS: We retrospectively analysed 302 PE patients (63.9+/-17.2 years of age; 42.4% male) from January 2011 to December 2012 using data from the Tokyo CCU Network. The areas under the receiver operating characteristic curves were 0.92 (95% confidence interval (CI): 0.88 0.97) for the PESI and 0.88 (95% CI: 0.77-0.98) for the sPESI. CONCLUSIONS: Both scores can be used to predict PE mortality in Japan. PMID- 25739719 TI - Very low utility of surveillance imaging in early-stage classic Hodgkin lymphoma treated with a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine and radiation therapy. AB - BACKGROUND: This study evaluated the need for surveillance imaging in early-stage classic Hodgkin lymphoma (cHL) after planned combined-modality therapy (CMT). METHODS: Primary early-stage cHL patients who underwent CMT were included. Positron emission tomography (PET)/computed tomography (CT), CT, or both were performed at the initial staging, during or after chemotherapy, and for at least 2 years during follow-up. Imaging studies and medical records were reviewed to determine if and when relapse had occurred. Radiation doses and costs were also calculated from follow-up imaging. RESULTS: The study included 78 patients with a median follow-up of 46 months; 85% of the patients had stage II disease (32% with bulky disease). Four of 77 interim PET scans were positive; none of these patients relapsed during follow-up, which ranged from 24 to 80 months. After a total of 466 follow-up imaging studies (91% with CT and 9% with PET/CT), no cHL relapse was detected. Eleven abnormal findings were noted on surveillance imaging: 9 were false-positives, and 2 were second primary malignancies. The average cumulative dose per patient from follow-up imaging was 107 mSv, which translated into an estimated lifetime excess cancer risk of 0.5%; the estimated total costs were $296,817 according to Medicare reimbursements. CONCLUSIONS: Surveillance imaging with either CT or PET/CT can be omitted safely for early stage cHL treated with a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine and radiation therapy because the risk of relapse is extremely low. This observation also applies to patients with bulky disease. The elimination of surveillance imaging will also reduce healthcare expenses and cumulative radiation doses in these predominantly young patients. PMID- 25739721 TI - Pioglitazone revisited to illuminate contemporary vascular reparative therapy in the era of drug-eluting stents. PMID- 25739723 TI - Public healthcare interests require strict competition enforcement. AB - CONTEXT: Several countries have introduced competition in their health systems in order to maintain the supply of high quality health care in a cost-effective manner. The introduction of competition triggers competition enforcement. Since healthcare is characterized by specific market failures, many favor healthcare specific competition enforcement in order not only to account for the competition interest, but also for the healthcare interests. The question is whether healthcare systems based on competition can succeed when competition enforcement deviates from standard practice. METHODS: This paper analyzes whether healthcare specific competition enforcement is theoretically sound and practically effective. This is exemplified by the Dutch system that is based on regulated competition and thus crucially depends on getting competition enforcement right. FINDINGS: Governments are responsible for correcting market failures. Markets are responsible for maximizing the public healthcare interests. By securing sufficient competitive pressure, competition enforcement makes sure they do. When interpreted according to welfare-economics, competition law takes into account both costs and benefits specific market behavior may have for healthcare. Competition agencies and judiciary are not legitimized to deviate from standard evidentiary requirements. Dutch case law shows that healthcare-specific enforcement favors the healthcare undertakings concerned, but to the detriment of public health care. CONCLUSION: Healthcare-specific competition enforcement is conceptually flawed and counterproductive. In order for healthcare systems based on competition to succeed, competition enforcement should be strict. PMID- 25739722 TI - Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP2 -containing membranes. AB - The dopamine transporter (DAT) is a transmembrane protein belonging to the family of neurotransmitter:sodium symporters (NSS). Members of the NSS are responsible for the clearance of neurotransmitters from the synaptic cleft, and for their translocation back into the presynaptic nerve terminal. The DAT contains long intracellular N- and C-terminal domains that are strongly implicated in the transporter function. The N-terminus (N-term), in particular, regulates the reverse transport (efflux) of the substrate through DAT. Currently, the molecular mechanisms of the efflux remain elusive in large part due to lack of structural information on the N-terminal segment. Here we report a computational model of the N-term of the human DAT (hDAT), obtained through an ab initio structure prediction, in combination with extensive atomistic molecular dynamics (MD) simulations in the context of a lipid membrane. Our analysis reveals that whereas the N-term is a highly dynamic domain, it contains secondary structure elements that remain stable in the long MD trajectories of interactions with the bilayer (totaling >2.2 MUs). Combining MD simulations with continuum mean-field modeling we found that the N-term engages with lipid membranes through electrostatic interactions with the charged lipids PIP2 (phosphatidylinositol 4,5-Biphosphate) or PS (phosphatidylserine) that are present in these bilayers. We identify specific motifs along the N-term implicated in such interactions and show that differential modes of N-term/membrane association result in differential positioning of the structured segments on the membrane surface. These results will inform future structure-based studies that will elucidate the mechanistic role of the N-term in DAT function. PMID- 25739724 TI - Relationship between spatial ability, visuospatial working memory and self assessed spatial orientation ability: a study in older adults. AB - This paper describes some novel spatial tasks and questionnaires designed to assess spatial and orientation abilities. The new tasks and questionnaires were administered to a sample of 90 older adults (41 males, age range 57-90), along with some other tests of spatial ability (Minnesota Paper Form Board, Mental Rotations Test, and Embedded Figures Test) and tests of visuospatial working memory (Corsi's Block Test and Visual Pattern Test). The internal reliability of the new tasks and questionnaires was analyzed, as well as their relationship with the spatial and working memory tests. The results showed that the new spatial tasks are reliable, correlate with working memory and spatial ability tests and, compared with the latters, show stronger correlations with the self-report questionnaires referring to orientation abilities. A model was also tested (with reference to Allen et al. in Intelligence 22:327-355, 1996) in which the new tasks were assumed to relate to spatial ability and predict orientation abilities as assessed by the self-report measures. PMID- 25739725 TI - Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. AB - Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model aided drug development. While the need for a functional design considering organ organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into the current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in the different stages of PBPK modeling and drug development; these are MUOrgans-on-a-chip and MUHuman-on-a-chip. Then we establish the design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations for estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on the design of microphysiological platforms for PBPK/PD based drug discovery. PMID- 25739726 TI - Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes. AB - There is little information on direct comparison between metformin and glucagon like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 +/- 0.80% vs. -0.80 +/- 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM. PMID- 25739727 TI - Glucocorticoid replacement therapy in adrenal insufficiency--a challenge to physicians? AB - Adrenal insufficiency (AI) is a rare disease caused by destruction of the adrenal glands or dysfunction of the pituitary gland or the hypothalamus. Treatment usually requires lifelong replacement therapy with glucocorticoids. Correct use of glucocorticoids and early dose adjustments are essential to cover the increased glucocorticoid demand in stress. Repeated education of patients and their partners is the best strategy to avoid life-threatening emergencies. However, there is a debate whether physicians' knowledge regarding AI is sufficient, in part due to the rareness of this endocrine disorder. To determine the present specific knowledge of physicians in a large University Department of Internal Medicine with a clinically and scientifically active Division of Endocrinology, all interns, residents / fellows, specialists or senior physicians / consultants were asked to complete a questionnaire with various possible answers on the subject of AI (n=69, median age 30 years, range 23-49 years). The present data suggest that in the investigated University Hospital setting current physicians' knowledge of medical replacement strategies in AI may be insufficient depending on the level of education and experience. Even physicians with training in endocrinology in part demonstrated extensive knowledge gaps. There might be a need for additional structured information and training on AI, even in specialized hospitals. PMID- 25739728 TI - Advancements in the delivery of epigenetic drugs. AB - INTRODUCTION: Advancements in epigenetic treatments are not only coming from new drugs, but also from modifications or encapsulation of the existing drugs into different formulations leading to greater stability and enhanced delivery to the target site. The epigenome is highly regulated and complex; therefore, it is important that off-target effects of epigenetic drugs be minimized. The step from in vitro to in vivo treatment of these drugs often requires development of a method of effective delivery for clinical translation. AREAS COVERED: This review covers epigenetic mechanisms such as DNA methylation, chromatin remodeling and small-RNA-mediated gene regulation. There is a section in the review with examples of diseases where epigenetic alterations lead to impaired pathways, with an emphasis on cancer. Epigenetic drugs, their targets and clinical status are presented. Advantages of using a delivery method for epigenetic drugs as well as examples of current advancements and challenges are also discussed. EXPERT OPINION: Epigenetic drugs have the potential to be very effective therapy against a number of diseases, especially cancers and neurological disorders. As with many chemotherapeutics, undesired side effects need to be minimized. Finding a suitable delivery method means reducing side effects and achieving a higher therapeutic index. Each drug may require a unique delivery method exploiting the drug's chemistry or other physical characteristic requiring interdisciplinary participation and would benefit from a better understanding of the mechanisms of action. PMID- 25739730 TI - Cyclic fatty acids found in frying oils are detoxified via classical drug metabolic pathway but also by beta-oxidation and eliminated as conjugates in rats. AB - Cyclic fatty acid monomers (CFAM) are mainly formed during heat treatments, such as frying, of edible oils. These fatty acids are mixtures of disubstituted five- or six-carbon-membered ring structures. Some earlier studies have suggested that some of these molecules could be metabolized and detoxified, but so far, neither the detoxification mechanisms nor the metabolite identifications have been elucidated. The objective of the present study was to identify the metabolites resulting from the metabolism and detoxification of CFAM. A deuterium-labeled CFAM, [9-(2)H]-10-(6-propyl-2-cyclohexenyl)-dodecenoic acid, was synthesized and fed to rats for 3 days, along with a standard chow diet while the control group was fed the same chow diet which did not contain any CFAM. Biological fluids (urine, blood) were collected for both groups of rats and analyzed using an untargeted metabolomic approach by ultra-performance liquid chromatography coupled with mass spectrometry. Two discriminant metabolites and 18 molecules derived from CFAM were identified or tentatively identified in plasma and urine samples, respectively. The structures of the metabolites suggest that CFAM having a six-carbon-membered ring could be detoxified by the classical drug metabolic pathway (phase I and phase II reactions), but our study also indicates that these are substrates for the beta-oxidation pathway and eliminated as glucuronide, sulphate, and/or nitrate conjugates. Urine metabolomics investigations without diet effects have indicated a higher excretion of medium-chain acylcarnitines in the D-CFAM diet group, which may indicate an incomplete beta-oxidation. PMID- 25739731 TI - Double bond stereochemistry influences the susceptibility of short-chain isoprenoids and polyprenols to decomposition by thermo-oxidation. AB - Isoprenoid alcohols are common constituents of living cells. They are usually assigned a role in the adaptation of the cell to environmental stimuli, and this process might give rise to their oxidation by reactive oxygen species. Moreover, cellular isoprenoids may also undergo various chemical modifications resulting from the physico-chemical treatment of the tissues, e.g., heating during food processing. Susceptibility of isoprenoid alcohols to heat treatment has not been studied in detail so far. In this study, isoprenoid alcohols differing in the number of isoprene units and geometry of the double bonds, beta-citronellol, geraniol, nerol, farnesol, solanesol and Pren-9, were subjected to thermo oxidation at 80 degrees C. Thermo-oxidation resulted in the decomposition of the tested short-chain isoprenoids as well as medium-chain polyprenols with simultaneous formation of oxidized derivatives, such as hydroperoxides, monoepoxides, diepoxides and aldehydes, and possible formation of oligomeric derivatives. Oxidation products were monitored by GC-FID, GC-MS, ESI-MS and spectrophotometric methods. Interestingly, nerol, a short-chain isoprenoid with a double bond in the cis (Z) configuration, was more oxidatively stable than its trans (E) isomer, geraniol. However, the opposite effect was observed for medium chain polyprenols, since Pren-9 (di-trans-poly-cis-prenol) was more susceptible to thermo-oxidation than its all-trans isomer, solanesol. Taken together, these results experimentally confirm that both short- and long-chain polyisoprenoid alcohols are prone to thermo-oxidation. PMID- 25739732 TI - Fabrication of three-dimensionally interconnected nanoparticle superlattices and their lithium-ion storage properties. AB - Three-dimensional superlattices consisting of nanoparticles represent a new class of condensed materials with collective properties arising from coupling interactions between close-packed nanoparticles. Despite recent advances in self assembly of nanoparticle superlattices, the constituent materials have been limited to those that are attainable as monodisperse nanoparticles. In addition, self-assembled nanoparticle superlattices are generally weakly coupled due to the surface-coating ligands. Here we report the fabrication of three-dimensionally interconnected nanoparticle superlattices with face-centered cubic symmetry without the presynthesis of the constituent nanoparticles. We show that mesoporous carbon frameworks derived from self-assembled supercrystals can be used as a robust matrix for the growth of nanoparticle superlattices with diverse compositions. The resulting interconnected nanoparticle superlattices embedded in a carbon matrix are particularly suitable for energy storage applications. We demonstrate this by incorporating tin oxide nanoparticle superlattices as anode materials for lithium-ion batteries, and the resulting electrochemical performance is attributable to their unique architectures. PMID- 25739733 TI - Tree of life reveals clock-like speciation and diversification. AB - Genomic data are rapidly resolving the tree of living species calibrated to time, the timetree of life, which will provide a framework for research in diverse fields of science. Previous analyses of taxonomically restricted timetrees have found a decline in the rate of diversification in many groups of organisms, often attributed to ecological interactions among species. Here, we have synthesized a global timetree of life from 2,274 studies representing 50,632 species and examined the pattern and rate of diversification as well as the timing of speciation. We found that species diversity has been mostly expanding overall and in many smaller groups of species, and that the rate of diversification in eukaryotes has been mostly constant. We also identified, and avoided, potential biases that may have influenced previous analyses of diversification including low levels of taxon sampling, small clade size, and the inclusion of stem branches in clade analyses. We found consistency in time-to-speciation among plants and animals, ~2 My, as measured by intervals of crown and stem species times. Together, this clock-like change at different levels suggests that speciation and diversification are processes dominated by random events and that adaptive change is largely a separate process. PMID- 25739734 TI - Initial Molecular-Level Response to Artificial Selection for Increased Aerobic Metabolism Occurs Primarily through Changes in Gene Expression. AB - Experimental evolution combined with genome or transcriptome resequencing (Evolve and Resequence) represents a promising approach for advancing our understanding of the genetic basis of adaptation. Here, we applied this strategy to investigate the effect of selection on a complex trait in lines derived from a natural population of a small mammal. We analyzed the liver and heart transcriptomes of bank voles (Myodes [=Clethrionomys] glareolus) that had been selected for increased aerobic metabolism. The organs were sampled from 13th generation voles; at that point, the voles from four replicate selected lines had 48% higher maximum rates of oxygen consumption than those from four control lines. At the molecular level, the response to selection was primarily observed in gene expression: Over 300 genes were found to be differentially expressed between the selected and control lines and the transcriptome-wide pattern of expression distinguished selected lines from controls. No evidence for selection-driven changes of allele frequencies at coding sites was found: No single nucleotide polymorphism (SNP) changed frequency more than expected under drift alone and frequency changes aggregated over all SNPs did not separate selected and control lines. Nevertheless, among genes which showed highest differentiation in allele frequencies between selected and control lines we identified, using information about gene functions and the biology of the selected phenotype, plausible targets of selection; these genes, together with those identified in expression analysis, have been prioritized for further studies. Because our selection lines were derived from a natural population, the amount and the spectrum of variation available for selection probably closely approximated that typically found in populations of small mammals. Therefore, our results are relevant to the understanding of the molecular basis of complex adaptations occurring in natural vertebrate populations. PMID- 25739735 TI - Genetic adaptation to levels of dietary selenium in recent human history. AB - As humans migrated around the world, they came to inhabit environments that differ widely in the soil levels of certain micronutrients, including selenium (Se). Coupled with cultural variation in dietary practices, these migrations have led to a wide range of Se intake levels in populations around the world. Both excess and deficiency of Se in the diet can have adverse health consequences in humans, with severe Se deficiency resulting in diseases of the bone and heart. Se is required by humans mainly due to its function in selenoproteins, which contain the amino acid selenocysteine as one of their constituent residues. To understand the evolution of the use of this micronutrient in humans, we surveyed the patterns of polymorphism in all selenoprotein genes and genes involved in their regulation in 50 human populations. We find that single nucleotide polymorphisms from populations in Asia, particularly in populations living in the extreme Se deficient regions of China, have experienced concerted shifts in their allele frequencies. Such differentiation in allele frequencies across genes is not observed in other regions of the world and is not expected under neutral evolution, being better explained by the action of recent positive selection. Thus, recent changes in the use and regulation of Se may harbor the genetic adaptations that helped humans inhabit environments that do not provide adequate levels of Se in the diet. PMID- 25739736 TI - Human adaptation to arsenic-rich environments. AB - Adaptation drives genomic changes; however, evidence of specific adaptations in humans remains limited. We found that inhabitants of the northern Argentinean Andes, an arid region where elevated arsenic concentrations in available drinking water is common, have unique arsenic metabolism, with efficient methylation and excretion of the major metabolite dimethylated arsenic and a less excretion of the highly toxic monomethylated metabolite. We genotyped women from this population for 4,301,332 single nucleotide polymorphisms (SNPs) and found a strong association between the AS3MT (arsenic [+3 oxidation state] methyltransferase) gene and mono- and dimethylated arsenic in urine, suggesting that AS3MT functions as the major gene for arsenic metabolism in humans. We found strong genetic differentiation around AS3MT in the Argentinean Andes population, compared with a highly related Peruvian population (FST = 0.014) from a region with much less environmental arsenic. Also, 13 of the 100 SNPs with the highest genome-wide Locus-Specific Branch Length occurred near AS3MT. In addition, our examination of extended haplotype homozygosity indicated a selective sweep of the Argentinean Andes population, in contrast to Peruvian and Colombian populations. Our data show that adaptation to tolerate the environmental stressor arsenic has likely driven an increase in the frequencies of protective variants of AS3MT, providing the first evidence of human adaptation to a toxic chemical. PMID- 25739737 TI - The path to high drug resistance for staph infections. PMID- 25739738 TI - Effect of anti-heart failure therapy on diastolic function in children with single-ventricle circulations. AB - BACKGROUND: Children with functionally univentricular circulations have chronic volume loading of the systemic ventricle, potentially affecting ventricular function. Medications including angiotensin-converting enzyme inhibitors and beta blockers are used to treat ventricular dysfunction, despite limited evidence of their efficacy in this population. OBJECTIVE: To determine the effects of angiotensin-converting enzyme inhibitors on elevated filling pressures in children with single ventricle physiology. METHODS: We performed a single-centre, retrospective review of patients with single ventricle physiology who underwent multiple cardiac catheterisations between 1991 and 2013. Study population comprised of patients who commenced or had optimised dosing of angiotensin converting enzyme inhibitors between assessments in response to high ventricular filling pressures. Patients undergoing interventions influencing loading conditions between assessments were excluded. RESULTS: A total of 17 patients were identified, with dominant morphologic right ventricle in eight patients (47.1%). Among them, 11 (64.7%) were pre-Fontan and six (35.3%) were post-Fontan completion. Median inter-assessment interval was 9.4 months (range 7.3-19.1). There was a reduction in end-diastolic pressure from 13 to 10 mmHg (p=0.002), mean pulmonary artery pressure from 16 to 13 mmHg (p=0.049), and mean atrial pressure from 12 to 9 mmHg (p=0.001). There was one cardiac transplant, and there were no patient deaths at median follow-up after 31 months. CONCLUSIONS: We observed a reduction in ventricular end-diastolic pressure, pulmonary artery pressure, and mean atrial pressure following treatment with angiotensin converting enzyme inhibitors in patients with single ventricle physiology. Our study provides insights into the potential impact of anti-heart failure therapy in single ventricle circulations and calls for larger, controlled studies to assess for a therapeutic response. PMID- 25739739 TI - First water-soluble backbone Ru-Ru-Ni heterometallic organometallic polymer. AB - The water-soluble backbone heterometallic polymer {[(PTA)2 CpRu-MU-CN-RuCp(PTA)2 MU-NiCl3 ]}n (2) is synthesized using a reproducible and robust method and fully characterized by X-ray single crystal diffraction. The Ru-Ru-Ni polymer is found to be stable in the solid state and soluble in water. Nuclear magnetic resonance (NMR) and light scattering studies show that the polymer is stable in water for several days in air. PMID- 25739740 TI - Differences in taste detection thresholds between normal-weight and obese young adults. AB - CONCLUSION: Compared with normal-weight individuals, obese young adults exhibited a significantly higher taste threshold for salty taste. Smoking also affected taste functions in this population. OBJECTIVE: The aim of this study was to investigate the differences in taste detection thresholds between normal-weight and obese young adults. METHODS: Taste threshold was measured using electrogustometry (EGM) and chemically with sucrose, NaCl, citric acid, and quinine hydrochloride in 41 volunteers in their twenties, 23 with body mass index (BMI) <23 kg/m(2) (normal-weight group) and 18 with BMI >25 kg/m(2) (obese group). RESULTS: BMI was significantly higher in the obese than in the normal weight group (p < 0.05). The obese group exhibited significantly higher EGM thresholds than the normal-weight group on the right (p < 0.05) and left (p < 0.05) posterior tongue. In chemical taste tests, the obese group had higher thresholds for sweet, salty, sour, and bitter tastes than the normal-weight group, although the difference in threshold was significant only for salty taste (p < 0.05). Smoking had an impact on taste threshold, with smokers having higher thresholds than non-smokers, with significantly higher EGM thresholds on the right anterior and posterior and the left anterior tongue (p < 0.05 each). PMID- 25739741 TI - Local structure and dynamics of lithium garnet ionic conductors: tetragonal and cubic Li7La3Zr2O7. AB - To better understand the ionic conduction in lithium garnet oxides, we employed molecular dynamics simulation to investigate the local structure and dynamics of a model material Li7La3Zr2O12 and origin of its tetragonal to cubic phase transition. Our simulations were able to produce lattice parameter, neutron scattering, and conductivity data close to those gathered using experimental techniques, which allows us to study atomic-scale details of this complex material. First, it was found that lithium atoms primarily perform oscillation and "structured diffusion" dynamics in the tetragonal and cubic phase, respectively. Second, we believe that the tetragonal to cubic phase transition is an entropy-driven one that involves redistribution of lithium atoms among all tetrahedral sites. The transition is likely to initiate on the tetrahedral 8a site but needs the cooperation of neighboring octahedral 32g Li as relay atoms. Finally, it was found that a few types of lithium clusters dominate in both phases of Li7La3Zr2O12, which leads to highly correlated motion of lithium atoms. The local symmetry of these clusters dictates a "center-pass" mechanism as lithium goes through the bottleneck. PMID- 25739742 TI - Developmental plasticity of coordinated action patterns in the perinatal rat. AB - Some of the most simple, stereotyped, reflexive, and spinal-mediated motor behaviors expressed by animals display a level of flexibility and plasticity that is not always recognized. We discuss several examples of how coordinated action patterns have been shown to be flexible and adaptive in response to sensory feedback. We focus on interlimb and intralimb coordination during the expression of two action patterns (stepping and the leg extension response) in newborn rats, as well as interlimb motor learning. We also discuss the idea that the spinal cord is a major site for supporting plasticity in the developing motor system. An implication of this research is that normally occurring sensory stimulation during the perinatal period influences the typical development and expression of action patterns, and that exploiting the developmental plasticity of the motor system may lead to improved strategies for promoting recovery of function in human infants with motor disorders. PMID- 25739743 TI - Revealing bending and force in a soft body through a plant root inspired approach. AB - An emerging challenge in soft robotics research is to reveal mechanical solicitations in a soft body. Nature provides amazing clues to develop unconventional components that are capable of compliant interactions with the environment and living beings, avoiding mechanical and algorithmic complexity of robotic design. We inspire from plant-root mechanoperception and develop a strategy able to reveal bending and applied force in a soft body with only two sensing elements of the same kind, and a null computational effort. The stretching processes that lead to opposite tissue deformations on the two sides of the root wall are emulated with two tactile sensing elements, made of soft and stretchable materials, which conform to reversible changes in the shape of the body they are built in and follow its deformations. Comparing the two sensory responses, we can discriminate the concave and the convex side of the bent body. Hence, we propose a new strategy to reveal in a soft body the maximum bending angle (or the maximum deflection) and the externally applied force according to the body's mechanical configuration. PMID- 25739744 TI - Surgeon's case shows misunderstanding of female genital mutilation. PMID- 25739745 TI - Posttraumatic growth and demoralization after cancer: The effects of patients' meaning-making. AB - OBJECTIVE: It is common for patients to experience positive and negative psychological changes (e.g., posttraumatic growth or demoralization) after being diagnosed with cancer. Although demoralization and posttraumatic growth are both related to meaning-making, little attention has been paid to the associations among these concepts. The current study investigated the relationship between demoralization, posttraumatic growth, and meaning-making (focusing on sense making and benefit-finding during the experience of illness) in cancer patients. METHOD: Some 200 cancer patients (with lung cancer, lymphoma, or leukemia) at the MacKay Memorial Hospital in New Taipei completed the Demoralization Scale Mandarin Version (DS-MV), the Chinese Posttraumatic Growth Inventory (CPTGI), and a self-designed questionnaire for assessing sense-making and benefit-finding. RESULTS: Demoralization was negatively correlated with posttraumatic growth, sense-making, benefit-finding, and time-since-diagnosis. Multiple regression analysis showed that meaning-making had different effects on demoralization and posttraumatic growth. The interactions of sense-making with either benefit finding or time-since-diagnosis significantly predicted demoralization. Individuals with relatively higher sense-making and benefit-finding or shorter time-since-diagnosis experienced less demoralization. SIGNIFICANCE OF RESULTS: The suffering of cancer may turn on the psychological process of demoralization, posttraumatic growth, and meaning-making in patients. Cancer patients who evidenced higher posttraumatic growth experienced less demoralization. Trying to identify positive changes in the experience of cancer may be a powerful way to increase posttraumatic growth. As time goes by, patients experienced less demoralization. Facilitating sense-making can have similar effects. Cancer patients with less benefit-finding experience higher demoralization, but sense making buffers this effect. PMID- 25739747 TI - Fear of falling is common in patients with type 2 diabetes and is associated with increased risk of falls. AB - AIMS: fear of falling is an important falls-related symptom that has received little attention in studies of falls risk in older adults with type 2 diabetes. METHODS: matched pairs of participants with diabetes or with normoglycaemia (n = 186 per group) recruited from a community-based survey underwent an assessment of fear of falling and associated falls risk factors. Multivariate methods examined associations between fear of falling and risk factors for history of recent falls. RESULTS: compared with the normoglycaemic participants, those with diabetes had worse mobility (slow timed Up and Go test times: 16.2 versus 4.9%, P < 0.01), more fear of falling (24.2 versus 15.1%, P < 0.05) and more activity restriction from fear of falling (indoors: 14.0 versus 4.8%, P = 0.006), but there was no increase in reported recent falls. In the combined sample, a history of recent falls was negatively associated with fear-related limitation of outdoor activities (odds ratio (95% confidence interval): 0.30 (0.15-0.58), P < 0.001) and positively associated with age (1.65 (1.20-2.28) per 10-year increase, P = 0.002) and use of antidepressants (2.14 (1.02-4.50, P = 0.044). The frequency of falls in those with recurrent falls was negatively associated with measures of balance. CONCLUSIONS: type 2 diabetes is associated with increased fear of falling and fear-associated activity restriction, and this modifies the risk of falls even in the face of increased falls risk factors including worse mobility. Future studies of falls in diabetes need to consider that fear of falling is an important modifier of the relationship between risk factors and falls. PMID- 25739746 TI - Applicability of the ParaDNA((r)) Screening System to Seminal Samples. AB - Seminal fluid represents a common biological material recovered from sexual assault crime scenes. Such samples can be prescreened using different techniques to determine cell type and relative amount before submitting for full STR profiling. The ParaDNA((r)) Screening System is a novel forensic test which identifies the presence of DNA through amplification and detection of two common STR loci (D16S539 and TH01) and the Amelogenin marker. The detection of the Y allele in samples could provide a useful tool in the triage and submission of sexual assault samples by enforcement authorities. Male template material was detected on a range of common sexual assault evidence items including cotton pillow cases, condoms, swab heads and glass surfaces and shows a detection limit of 1 in 1000 dilution of neat semen. These data indicate this technology has the potential to be a useful tool for the detection of male donor DNA in sexual assault casework. PMID- 25739748 TI - Heterogeneity of lower airway inflammation in children with severe-persistent asthma. AB - RATIONALE: The treatment of children with severe-persistent asthma remains problematic. Recent studies suggest that stratification of this cohort by inflammatory type may be useful in designing effective treatment strategies. In this study, we examined the inflammatory profile in bronchoalveolar lavage fluid from children with severe-persistent asthma and compared this profile with serum IgE levels. METHODS: The inflammatory profile in the bronchoalveolar fluid from 32 children who met criteria for severe-persistent asthma as defined by the Severe Asthma Research Program (SARP) were analyzed retrospectively. Inflammatory patterns were classified as neutrophilic, eosinophilic, mixed, or pauci granulocytic. Serum total IgE was measured prior to bronchoscopy and determined by ELISA at each hospital's lab by standard procedures. RESULTS: The most common pattern of inflammation in this cohort was neutrophilic (37.5%) followed by eosinophilic (28.1%), mixed (21.9%), and pauci-granulocytic (11.1%). The odds ratio of an eosinophilic BAL pattern for patients with an elevated serum IgE was 4.67 (CI 0.78-28, P = 0.12). A correlation between serum IgE levels and BAL eosinophil percentages was present (P = 0.04). CONCLUSIONS: To our knowledge, ours is one of few studies to systematically investigate the pattern of lower airway inflammation in children with severe-persistent asthma. Our results differ from a recent investigation in children, showing more heterogeneity and a greater proportion of neutrophilic inflammation. Further investigation is required to determine whether specific inflammatory patterns are associated with specific etiologies, and whether individualized therapy is warranted. PMID- 25739749 TI - Accelerated exploration of multi-principal element alloys with solid solution phases. AB - Recent multi-principal element, high entropy alloy (HEA) development strategies vastly expand the number of candidate alloy systems, but also pose a new challenge--how to rapidly screen thousands of candidate alloy systems for targeted properties. Here we develop a new approach to rapidly assess structural metals by combining calculated phase diagrams with simple rules based on the phases present, their transformation temperatures and useful microstructures. We evaluate over 130,000 alloy systems, identifying promising compositions for more time-intensive experimental studies. We find the surprising result that solid solution alloys become less likely as the number of alloy elements increases. This contradicts the major premise of HEAs--that increased configurational entropy increases the stability of disordered solid solution phases. As the number of elements increases, the configurational entropy rises slowly while the probability of at least one pair of elements favouring formation of intermetallic compounds increases more rapidly, explaining this apparent contradiction. PMID- 25739750 TI - MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. AB - AIMS: Differentiation of heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction independent of echocardiography is challenging in the community. Diagnostic strategies based on monitoring circulating microRNA (miRNA) levels may prove to be of clinical value in the near future. The aim of this study was to identify a novel miRNA signature that could be a useful HF diagnostic tool and provide valuable clinical information on whether a patient has HFrEF or HFpEF. METHODS AND RESULTS: MiRNA biomarker discovery was carried out on three patient cohorts, no heart failure (no-HF), HFrEF, and HFpEF, using Taqman miRNA arrays. The top five miRNA candidates were selected based on differential expression in HFpEF and HFrEF (miR-30c, -146a, -221, -328, and 375), and their expression levels were also different between HF and no-HF. These selected miRNAs were further verified and validated in an independent cohort consisting of 225 patients. The discriminative value of BNP as a HF diagnostic could be improved by use in combination with any of the miRNA candidates alone or in a panel. Combinations of two or more miRNA candidates with BNP had the ability to improve significantly predictive models to distinguish HFpEF from HFrEF compared with using BNP alone (area under the receiver operating characteristic curve >0.82). CONCLUSION: This study has shown for the first time that various miRNA combinations are useful biomarkers for HF, and also in the differentiation of HFpEF from HFrEF. The utility of these biomarker combinations can be altered by inclusion of natriuretic peptide. MiRNA biomarkers may support diagnostic strategies in subpopulations of patients with HF. PMID- 25739751 TI - Perceived timeliness of referral to hospice palliative care among bereaved family members in Korea. AB - PURPOSE: We aimed to explore the perceived timeliness of referral to hospice palliative care unit (HPCU) among bereaved family members in Korea and factors associated therewith. METHODS: Cross-sectional questionnaire survey was performed for bereaved family members of patients who utilized 40 designated HPCUs across Korea. The questionnaire assessed whether admission to the HPCU was "too late" or "appropriate" and the Good Death Inventory (GDI). RESULTS: A total of 383 questionnaires were analyzed. Of participants, 25.8 % replied that admission to HPCU was too late. Patients with hepatobiliary cancer, poor performance status, abnormal consciousness level, and unawareness of terminal status were significantly related with the too late perception. Family members with younger age and being a child of the patient were more frequently noted in the too late group. Ten out of 18 GDI scores were significantly lower in the too late group. Multiple logistic regression analysis revealed patients' unawareness of terminal status, shorter stay in the HPCU, younger age of bereaved family, and lower scores for two GDI items (staying in a favored place, living without concerning death or disease) were significantly associated with the too late group. CONCLUSIONS: To promote timely HPCU utilization and better quality of end of life care, patients need to be informed of the terminal status and their preference should be respected. PMID- 25739752 TI - Comparing men's and women's experiences of work after cancer: a photovoice study. AB - PURPOSE: Work is an important quality of life indicator for many cancer survivors. There is, however, a lack of appropriate support to help survivors with work integration. As a result, many survivors are forced to independently navigate their return to work, experiencing unnecessary pitfalls in the process. As a preliminary step toward addressing this current gap in survivorship support, we explored the work integration experiences of 20 cancer survivors, 10 women and 10 men. METHODS: Photovoice methods were combined with two individual interviews per participant. Participant-produced photographs and interview transcripts were analyzed to identify key themes. RESULTS: Both commonalities and gender differentiated motivations underlying work integration emerged. Female and male participants both demonstrated and discussed differentiated manners of coping. Men expressed a propensity for productivity and active engagements over talking used predominantly by women. CONCLUSION: Appreciation of men's proclivity for productivity and activity suggests that a gender-tailored approach to rehabilitation may enhance male survivors' participation and the utility of rehabilitation efforts. PMID- 25739753 TI - Cancer rehabilitation: a barometer for survival? AB - PURPOSE: This pilot study was conducted to describe the clinical features and functional outcomes of patients attending inpatient rehabilitation for cancer related deconditioning and neurological deficits and to explore factors associated with improved survival. METHODS: Using a retrospective audit, demographic characteristics, discharge outcomes, survival time, and functional status as measured by Functional Independence Measure (FIM) were recorded for 73 patients. Clinical status was estimated by Karnofsky Performance Status Scale (KPS). Cox regression was used to assess factors associated with improved survival following discharge from rehabilitation. RESULTS: Significant functional gains following rehabilitation were observed in total FIM (p = 0.02), motor FIM (p = 0.001), and KPS (p = 0.003). Length of survival ranged from 9.0 to 25.0 months, with 26 cases surviving to the end of study (censored). Patients scoring a total FIM of >=80 survived significantly longer than patients scoring <80 (p = 0.002). At discharge, motor FIM scores (p = 0.004), FIM Efficiency (p = 0.001), KPS scores (p = 0.022), ambulation ability (p = 0.026), return to home (p = 0.009), and receipt of in-home services (p = 0.045) were significantly associated with improved survival. CONCLUSIONS: Functional improvement achieved through inpatient rehabilitation was associated with prolonged survival among cancer patients. Rehabilitation leading to improved independence among cancer patients may act as a marker of those with greater likelihood of better prognosis. PMID- 25739754 TI - Hyposmia: an underestimated and frequent adverse effect of chemotherapy. AB - OBJECTIVES: Optimal function of both the olfactory sensory neurons and the olfactory mucosa is a prerequisite for normal olfactory perception. Both the olfactory neurons and mucosa might be subjects to the neurotoxic and mucotoxic effects of chemotherapy. Despite the recognized importance of olfaction in nutrition and quality of life, the potential olfactory toxicity of chemotherapy regimens has not been adequately assessed. The aim of this study is to investigate whether mucotoxic and/or neurotoxic drugs compromise olfactory performance. PATIENTS AND METHODS: Forty-four consecutive patients completed the "Sniffin' Sticks" test, an objective quantitative/qualitative method to assess olfactory function, at diagnosis and immediately before the infusion of the last session of three to four chemotherapy cycles, according to the therapeutic protocol. The patients underwent therapy containing oxaliplatin and antimetabolites (5-FU or capecitabine; O+A group), taxanes and platinum analogues (cisplatin and carboplatin; T+P group), or taxanes and anthracyclines (doxorubicin or liposomal doxorubicin; T+A group). RESULTS: A significant decrease was noted for olfactory threshold (OT), olfactory discrimination (OD), olfactory identification (OI), and the composite threshold-discrimination identification (TDI) score. A significant deterioration of all olfactory indices was found for each chemotherapy group. Pairwise comparisons revealed significant differences between the O+A and the T+P group regarding OT and TDI. TDI scores were significantly lower after chemotherapy in all age groups. Patients older than 50 years were found to be more susceptible to olfactory toxicity than younger patients. CONCLUSIONS: Patients who undergo chemotherapy experience significant compromise in their olfactory function. A grading system for olfactory toxicity is proposed. PMID- 25739755 TI - Hyponatremia is a predictor of hospital length and cost of stay and outcome in cancer patients. AB - PURPOSE: Hyponatremia is the most common electrolyte disorder in hospitalized patients, and it might be an indicator of poor prognosis and might have negative effects on hospitalization length and quality of life in non-malignant as well as in malignant diseases. The aim of this study is to determine the impact of hyponatremia on the length and on the cost of hospitalization as well as on outcome in cancer patients. METHODS: The present study includes 105 consecutive cancer patients hospitalized at our institution from June 2013 to December 2013. Data regarding age, sex, staging, histology, chemotherapy, and serum sodium levels at admission, during hospitalization, and at discharge were recorded and statistically analyzed. Impact of hyponatremia on length and cost of hospitalization and on outcome was evaluated. RESULTS: A significant difference in overall survival since the date of admission was observed between eunatremic and hyponatremic patients (p = 0.0255). A statistically significant correlation was also found between the length of stay and the detection of hyponatremia. At multivariate analysis, hyponatremia at admission, severity of hyponatremia, and stage of disease resulted independent prognostic factors. Furthermore, a patient with moderate or severe hyponatremia cost, in rate terms, 128 and 299 % more than a normonatremic patient, respectively. CONCLUSIONS: The occurrence of hyponatremia at the admission or during the hospitalization may represent a significant factor influencing the outcome and the length of hospitalization. Acting effective and timely on the normalization of sodium levels might have a positive effect on prognosis in this setting of patients, as well as on the length of stay in hospital, thus potentially resulting in savings. PMID- 25739756 TI - Pseudomonas aeruginosa arylsulfatase: a purified enzyme for the mild hydrolysis of steroid sulfates. AB - The hydrolysis of sulfate ester conjugates is frequently required prior to analysis for a range of analytical techniques including gas chromatography-mass spectrometry (GC-MS). Sulfate hydrolysis may be achieved with commercial crude arylsulfatase enzyme preparations such as that derived from Helix pomatia but these contain additional enzyme activities such as glucuronidase, oxidase, and reductase that make them unsuitable for many analytical applications. Strong acid can also be used to hydrolyze sulfate esters but this can lead to analyte degradation or increased matrix interference. In this work, the heterologously expressed and purified arylsulfatase from Pseudomonas aeruginosa is shown to promote the mild enzyme-catalyzed hydrolysis of a range of steroid sulfates. The substrate scope of this P. aeruginosa arylsulfatase hydrolysis is compared with commercial crude enzyme preparations such as that derived from H. pomatia. A detailed kinetic comparison is reported for selected examples. Hydrolysis in a urine matrix is demonstrated for dehydroepiandrosterone 3-sulfate and epiandrosterone 3-sulfate. The purified P. aeruginosa arylsulfatase contains only sulfatase activity allowing for the selective hydrolysis of sulfate esters in the presence of glucuronide conjugates as demonstrated in the short three-step chemoenzymatic synthesis of 5alpha-androstane-3beta,17beta-diol 17-glucuronide (ADG, 1) from epiandrosterone 3-sulfate. The P. aeruginosa arylsulfatase is readily expressed and purified (0.9 g per L of culture) and thus provides a new and selective method for the hydrolysis of steroid sulfate esters in analytical sample preparation. PMID- 25739757 TI - Quantitative evaluation of diffusion-weighted imaging techniques for the purposes of radiotherapy planning in the prostate. AB - OBJECTIVE: Diffusion-weighted imaging (DWI) is an important technique for the localization of prostate cancer, and its response assessment during treatment with radiotherapy (RT). However, it has known limitations in terms of distortions and artefacts using standard acquisition techniques. This study evaluates two alternative methods that offer the promise of improved image quality and the potential for more reliable and consistent diffusion data. METHODS: Three DWI techniques were investigated; single-shot echoplanar imaging (EPI), EPI combined with reduced volume excitation (ZOOMit; Siemens Healthcare, Erlangen, Germany) and read-out segmentation with navigator-echo correction (RESOLVE; Siemens Healthcare). Daily measurements of apparent diffusion coefficient (ADC) value were made in a quality assurance phantom to assess the repeatability of each sequence. In order to evaluate the geometric integrity of these sequences, ten normal volunteers were scanned, and the prostate was contoured to compare its similarity with T2 weighted images. RESULTS: Phantom ADC values were significantly higher using the standard EPI sequence than those of the other two sequences. Differences were also observed between sequences in terms of repeatability, with RESOLVE and EPI performing better than ZOOMit. Overall, the RESOLVE sequence provided the best agreement for the in vivo data with smaller differences in volume and higher contour similarity than T2 weighted imaging. CONCLUSION: Important differences have been observed between each of the three techniques investigated with RESOLVE performing the best overall. We have adopted this sequence for routine RT simulation of prostate patients at Liverpool Cancer Therapy Centre. ADVANCES IN KNOWLEDGE: This work will be of interest to the increasing number of centres wanting to incorporate quantitative DWI in a clinical setting. PMID- 25739758 TI - A new live-cell biobank workflow efficiently recovers heterogeneous melanoma cells from native biopsies. AB - Fibroblast contamination can make establishing primary melanoma cell cultures from native biopsies a major challenge, due to fibroblasts overgrowing the melanoma cells. Standard protocols therefore enrich for highly proliferative melanoma cells that grow well in vitro but may not represent the full range of in vivo tumor heterogeneity. Here we apply conditional methods that more effectively retrieve melanoma cells by differential trypsinization or by inducing fibroblast senescence through contact inhibition, serum starvation or deprivation of adhesion. Simple mixing experiments of melanoma and fibroblast cells demonstrated the efficacy of the new protocols in retrieving slow-growing melanoma cells. Applying our protocols to 20 cultures that had failed to grow by conventional methods, we could retrieve 12 (60%) validated melanoma cell cultures. Further application of the protocols in the live-cell biobank of 124 early passage cultures significantly improved recovery rates from 13% using standard protocols to 70% overall for the new workflow. PMID- 25739759 TI - Moving medicine forward faster. PMID- 25739760 TI - Erratum for the Research Article: "Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice" by G. Fredman, N. Kamaly, S. Spolitu, J. Milton, D. Ghorpade, R. Chiasson, G. Kuriakose, M. Perretti, O. Farokzhad, I. Tabas. PMID- 25739761 TI - Make the bleeding stop. PMID- 25739762 TI - Liver-directed lentiviral gene therapy in a dog model of hemophilia B. AB - We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia. PMID- 25739763 TI - A synthetic fibrin cross-linking polymer for modulating clot properties and inducing hemostasis. AB - Clotting factor replacement is the standard management of acute bleeding in congenital and acquired bleeding disorders. We present a synthetic approach to hemostasis using an engineered hemostatic polymer (PolySTAT) that circulates innocuously in the blood, identifies sites of vascular injury, and promotes clot formation to stop bleeding. PolySTAT induces hemostasis by cross-linking the fibrin matrix within clots, mimicking the function of the transglutaminase factor XIII. Furthermore, synthetic PolySTAT binds specifically to fibrin monomers and is uniformly integrated into fibrin fibers during fibrin polymerization, resulting in a fortified, hybrid polymer network with enhanced resistance to enzymatic degradation. In vivo hemostatic activity was confirmed in a rat model of trauma and fluid resuscitation in which intravenous administration of PolySTAT improved survival by reducing blood loss and resuscitation fluid requirements. PolySTAT-induced fibrin cross-linking is a novel approach to hemostasis using synthetic polymers for noninvasive modulation of clot architecture with potentially wide-ranging therapeutic applications. PMID- 25739766 TI - Molecular biology, epidemiology, and the elusive nature of pancreatitis. AB - The myriad of presentations of pancreatitis can cause confusion and controversy among clinicians affecting the diagnosis, treatment, and research of patients with these disorders. Although the disease is best thought of as a spectrum with classic presentations, the underlying pathophysiologic reasons for the differences in manifestations remains unknown. In this issue of the Journal, LaRusch and colleagues provide an elegant study combining epidemiology and molecular biology to explain why some patients with pancreatitis develop fibrosis chronic pancreatitis. The implications of the findings add to the growing request to support large multidisciplinary, combined genetic, and epidemiologic studies in pancreatic disease. PMID- 25739767 TI - Suitability of biochar as a matrix for improving the performance of composting toilets. AB - To evaluate the suitability of biochar (rice husk charcoal) as a matrix in composting toilets that can decompose human faeces and recover fertiliser components, the composting process during toilet operation and the agricultural value of the resulting compost were characterised by performing a comparison with sawdust, rice husks, and corn stalks. The faecal decomposition ratio in biochar was 42%, similar to the values for rice husks (46%) and corn stalks (41%), but higher than the value for sawdust (25%). Heterotroph micro-organism acidity is qualitatively higher in biochar than in sawdust. However, nitrogen loss in biochar was 19%, lower than that in rice husks (36%) and corn stalks (25%), but similar to that in sawdust (16%). Although the biochar compost had no significant impact on the cation exchange capacity and water retention of sandy soil, the ratio of nitrogen transportation into plants was 12.8%, higher than that for the other materials. These results suggest that biochar is effective for achieving high faecal decomposition, low nitrogen loss, and high nutrient supply. PMID- 25739764 TI - Immunological mechanisms of the antitumor effects of supplemental oxygenation. AB - Antitumor T cells either avoid or are inhibited in hypoxic and extracellular adenosine-rich tumor microenvironments (TMEs) by A2A adenosine receptors. This may limit further advances in cancer immunotherapy. There is a need for readily available and safe treatments that weaken the hypoxia-A2-adenosinergic immunosuppression in the TME. Recently, we reported that respiratory hyperoxia decreases intratumoral hypoxia and concentrations of extracellular adenosine. We show that it also reverses the hypoxia-adenosinergic immunosuppression in the TME. This, in turn, stimulates (i) enhanced intratumoral infiltration and reduced inhibition of endogenously developed or adoptively transfered tumor-reactive CD8 T cells, (ii) increased proinflammatory cytokines and decreased immunosuppressive molecules, such as transforming growth factor-beta (TGF-beta), (iii) weakened immunosuppression by regulatory T cells, and (iv) improved lung tumor regression and long-term survival in mice. Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors. These effects are entirely T cell- and natural killer cell-dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer. PMID- 25739765 TI - Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. AB - Heart failure (HF) is a disease of epidemic proportion and is associated with exceedingly high health care costs. G protein (heterotrimeric guanine nucleotide binding protein)-coupled receptor (GPCR) kinase 2 (GRK2), which is up-regulated in the failing human heart, appears to play a critical role in HF progression in part because enhanced GRK2 activity promotes dysfunctional adrenergic signaling and myocyte death. Recently, we found that the selective serotonin reuptake inhibitor (SSRI) paroxetine could inhibit GRK2 with selectivity over other GRKs. Wild-type mice were treated for 4 weeks with paroxetine starting at 2 weeks after myocardial infarction (MI). These mice were compared with mice treated with fluoxetine, which does not inhibit GRK2, to control for the SSRI effects of paroxetine. All mice exhibited similar left ventricular (LV) dysfunction before treatment; however, although the control and fluoxetine groups had continued degradation of function, the paroxetine group had considerably improved LV function and structure, and several hallmarks of HF were either inhibited or reversed. Use of genetically engineered mice indicated that paroxetine was working through GRK2 inhibition. The beneficial effects of paroxetine were markedly greater than those of beta-blocker therapy, a current standard of care in human HF. These data demonstrate that paroxetine-mediated inhibition of GRK2 improves cardiac function after MI and represents a potential repurposing of this drug, as well as a starting point for innovative small-molecule GRK2 inhibitor development. PMID- 25739768 TI - Modelling and evaluating municipal solid waste management strategies in a mega city: the case of Ho Chi Minh City. AB - Ho Chi Minh City is a large city that will become a mega-city in the near future. The city struggles with a rapidly increasing flow of municipal solid waste and a foreseeable scarcity of land to continue landfilling, the main treatment of municipal solid waste up to now. Therefore, additional municipal solid waste treatment technologies are needed. The objective of this article is to support decision-making towards more sustainable and cost-effective municipal solid waste strategies in developing countries, in particular Vietnam. A quantitative decision support model is developed to optimise the distribution of municipal solid waste from population areas to treatment plants, the treatment technologies and their capacities for the near future given available infrastructure and cost factors. PMID- 25739770 TI - Too much medicine: the challenge of finding common ground. PMID- 25739769 TI - The impact of providing rapid diagnostic malaria tests on fever management in the private retail sector in Ghana: a cluster randomized trial. AB - OBJECTIVE: To examine the impact of providing rapid diagnostic tests for malaria on fever management in private drug retail shops where most poor rural people with fever present, with the aim of reducing current massive overdiagnosis and overtreatment of malaria. DESIGN: Cluster randomized trial of 24 clusters of shops. SETTING: Dangme West, a poor rural district of Ghana. PARTICIPANTS: Shops and their clients, both adults and children. INTERVENTIONS: Providing rapid diagnostic tests with realistic training. MAIN OUTCOME MEASURES: The primary outcome was the proportion of clients testing negative for malaria by a double read research blood slide who received an artemisinin combination therapy or other antimalarial. Secondary outcomes were use of antibiotics and antipyretics, and safety. RESULTS: Of 4603 clients, 3424 (74.4%) tested negative by double-read research slides. The proportion of slide-negative clients who received any antimalarial was 590/1854 (32%) in the intervention arm and 1378/1570 (88%) in the control arm (adjusted risk ratio 0.41 (95% CI 0.29 to 0.58), P<0.0001). Treatment was in high agreement with rapid diagnostic test result. Of those who were slide-positive, 690/787 (87.8%) in the intervention arm and 347/392 (88.5%) in the control arm received an artemisinin combination therapy (adjusted risk ratio 0.96 (0.84 to 1.09)). There was no evidence of antibiotics being substituted for antimalarials. Overall, 1954/2641 (74%) clients in the intervention arm and 539/1962 (27%) in the control arm received appropriate treatment (adjusted risk ratio 2.39 (1.69 to 3.39), P<0.0001). No safety concerns were identified. CONCLUSIONS: Most patients with fever in Africa present to the private sector. In this trial, providing rapid diagnostic tests for malaria in the private drug retail sector significantly reduced dispensing of antimalarials to patients without malaria, did not reduce prescribing of antimalarials to true malaria cases, and appeared safe. Rapid diagnostic tests should be considered for the informal private drug retail sector.Registration Clinicaltrials.gov NCT01907672. PMID- 25739771 TI - Looking at it wrong. PMID- 25739772 TI - What counts? Justifications, not labels. PMID- 25739773 TI - The buried curriculum. PMID- 25739774 TI - World Health Organization reform: lessons learned from the Ebola epidemic. PMID- 25739775 TI - Case study. Temporizing after spinal cord injury. Commentary. PMID- 25739776 TI - Embodied storytellers: disability studies and medical humanities. PMID- 25739777 TI - Why It's Not Time for Health Care Rationing. PMID- 25739778 TI - Teaching nonauthoritarian clinical ethics: using an inventory of bioethical positions. PMID- 25739781 TI - How much for that stress test? PMID- 25739779 TI - Translational research may be most successful when it fails. PMID- 25739782 TI - Field notes. Compassionate imagining. PMID- 25739783 TI - Choose wisely: Network, ontology and annotation resources for the analysis of Staphylococcus aureus omics data. AB - Staphylococcus aureus (S. aureus) is a prominent human and livestock pathogen investigated widely using omic technologies. Critically, due to availability, low visibility or scattered resources, robust network and statistical contextualisation of the resulting data is generally under-represented. Here, we present novel meta-analyses of freely-accessible molecular network and gene ontology annotation information resources for S. aureus omics data interpretation. Furthermore, through the application of the gene ontology annotation resources we demonstrate their value and ability (or lack-there-of) to summarise and statistically interpret the emergent properties of gene expression and protein abundance changes using publically available data. This analysis provides simple metrics for network selection and demonstrates the availability and impact that gene ontology annotation selection can have on the contextualisation of bacterial omics data. PMID- 25739784 TI - Sanat Bhagwati (1928-2013): a tribute. PMID- 25739785 TI - Unfolding and aggregation of monoclonal antibodies on cation exchange columns: effects of resin type, load buffer, and protein stability. AB - The chromatographic behavior of a monoclonal antibody (mAb) that exhibits a pronounced two-peak elution behavior is studied for a range of strong cation exchange resins and with varying load buffer pH and composition. Six stationary phases are considered, including two tentacle-type resins (Fractogel EMD SO3-(M) and Eshmuno S), a resin with grafted polymeric surface extenders (Nuvia S), a resin with a bimodal pore size distribution (POROS HS 50), and two macroporous resins without polymer grafts (Source 30S and UNOsphere Rapid S). The two-peak elution behavior is very pronounced for the tentacle and polymer-grafted resins and for POROS HS 50, but is essentially absent for the two macroporous resins. The extent of this behavior decreases as the buffer pH and concentration increase and, consequently, mAb binding becomes weaker. Replacing sodium with arginine as the buffer counterion, which is expected to decrease the mAb binding strength, nearly completely eliminates the two-peak behavior, while replacing sodium with tetra-n-butylammonium hydroxide, which is expected to increase the mAb binding strength, dramatically exacerbate the effect. As shown by hydrogen-deuterium exchange mass spectrometry (HX-MS), the two-peak elution behavior is related to conformational changes that occur when the mAb binds. These changes result in increased solvent exposure of specific peptides in the Fc-region for either the Fractogel or the Nuvia resin. No significant conformational changes were seen by HX-MS when the mAb was bound to the UNOsphere resin or on the Fractogel resin when arginine was used in lieu of sodium as the load buffer counterion. Experiments with two additional mAbs on the Fractogel resin show that the two peak elution behavior is dependent on the particular antibody. Circular dichroism suggests that the propensity of different mAbs to either precipitate directly or to form stabilizing intermolecular structures upon exposure to thermal stress can be related to their chromatographic behaviors. PMID- 25739787 TI - Musculoskeletal concerns do not justify failure to use safer sequential trigger to prevent acute nail gun injuries. AB - BACKGROUND: Acute nail gun injuries can be controlled significantly by using tools with sequential triggers and training. Concern has been raised that sequential triggers, which require that the nose piece of the gun be depressed prior to pulling the trigger, could increase risk of musculoskeletal problems. METHODS: We conducted active injury surveillance among union carpenter apprentices to monitor acute injuries and musculoskeletal disorders between 2010 and 2013. RESULTS: Acute injury risk was 70% higher with contact trip rather than sequential triggers. Musculoskeletal risk was comparable (contact trip 0.09/10,000 hr (95% CI, 0.02-0.26); sequential 0.08/ 10,000 hr (95% CI 0.02 0.23)). CONCLUSIONS: Concern about excess risk of musculoskeletal problems from nail guns with sequential triggers is unwarranted. Both actuation systems carry comparable musculoskeletal risk which is far less than the risk of acute injury; there is clearly no justification for failure to prevent acute injuries through use of the safer sequential trigger. PMID- 25739786 TI - MiR-181a regulates lipid metabolism via IDH1. AB - Lipid metabolism is important for cellular energy homeostasis. Excessive cellular lipid accumulation is associated with various human diseases such as obesity, cardiovascular disease or even cancer. It has been recognized that miR-181a is an important modulator in regulating T lymphocyte differentiation, vascular development and cerebellar neurodegeneration. Here we reports a novel function of miR-181a in the regulation of lipid metabolism. MiR-181a is able to target isocitrate dehydrogenase 1 (IDH1), a metabolic enzyme in TCA cycle. Via targeting IDH1, miR-181a decreases expression of genes involved in lipid synthesis and increases expression of genes involved in beta-oxidation, thereafter inhibiting lipid accumulation. MiR-181a transgenic mice show a lower body weight as compared with their wild-type littermates, and moreover, miR-181a transgenic mice exhibit less lipid accumulation. Collectively, these findings uncover a novel miR-181a IDH1 axis that has an important role in regulating lipid metabolism, and implicate miR-181a as a potential therapeutic target for lipid metabolism disorders. PMID- 25739788 TI - Soft tissue imaging with photon counting spectroscopic CT. AB - The purpose of this work was experimental investigation of photon counting spectroscopic CT (PCS-CT) imaging of anatomical soft tissue with clinically relevant size. The imaging experiments were performed using a spectroscopic CT system based on CdZnTe photon counting detector with two rows of pixels, 256 pixels in each row, 1 * 1 mm(2) pixel size, and 25.6 cm detector length. The detector could split the x-ray energy spectrum to 5 regions (energy bins), and acquire 5 multi-energy (spectroscopic) CT images in a single CT scan. A sample of round shaped anatomical soft tissue of 14 cm diameter including lean and fat was used for imaging. To avoid the negative effect of anatomical noise on quantitative analysis, a spectroscopic CT phantom with tissue equivalent solid materials was used. The images were acquired at 60, 90, and 120 kVp tube voltages, and spectroscopic image series were acquired with 3 and 5 energy bins. Spectroscopic CT numbers were introduced and used to evaluate an energy selective image series. The anatomical soft tissue with 14 cm diameter was visualized with good quality and without substantial artifacts by the photon counting spectroscopic CT system. The effects of the energy bin crosstalk on spectroscopic CT numbers were quantified and analyzed. The single and double slice PCS-CT images were acquired and compared. Several new findings were observed, including the effect of soft tissue non-uniformity on image artifacts, unique status of highest energy bin, and material dependent visualization in spectroscopic image series. Fat-lean decomposition was performed using dual energy subtraction and threshold segmentation methods, and compared. Using K-edge filtered x-rays improved fat-lean decomposition as compared to conventional x-rays. Several new and important aspects of the PCS-CT were investigated. These include imaging soft tissue with clinically relevant size, single- and double-slice PCS-CT imaging, using spectroscopic CT numbers to quantify multi-energy PCS-CT images, application of K-edge filtered x-rays for improved soft tissue decomposition, and several others. The study suggests that the presented PCS-CT technology meets the requirements of a particular clinical application, i.e. dedicated breast CT. PMID- 25739790 TI - Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. AB - Regorafenib is a small molecule inhibitor of tyrosine kinases, and has been shown to improve the outcomes of patients with advanced colorectal cancer and advanced gastrointestinal stromal tumors. The transport profiles of regorafenib by various transporters were evaluated. HEK293/organic anion transporting polypeptide 1B1 (OATP1B1) cells exhibited increased drug sensitivity to regorafenib. Regorafenib inhibited the uptake of 3H-estrone sulfate by HEK293/OATP1B1 cells in a dose dependent manner, but did not affect its elimination by P-glycoproteins. The concentration of regorafenib was significantly lower in LLC-PK1/multidrug resistance protein 2 (MRP2) cells than in LLC-PK1 cells treated with the MRP2 inhibitor, MK571. MK571 abolished the inhibitory effects of regorafenib on intracellular accumulation in LLC-PK1/MRP2 cells. The uptake of regorafenib was significantly higher in HEK293/OATP1B1 cells than in OATP1B1-mock cells. Transport kinetics values were estimated to be Km=15.9 uM and Vmax=1.24 nmol/mg/min. No significant difference was observed in regorafenib concentrations between HEK293/OATP1B3 and OATP1B3-mock cells. These results indicated that regorafenib is a substrate for MRP2 and OATP1B1, and also suggest that the substrate preference of regorafenib may implicate the pharmacokinetic profiles of regorafenib. PMID- 25739789 TI - Lessons from hepatocyte-specific Cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury. AB - We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. We prepared a mouse hepatocyte-specific knockout (LKO) of lanosterol 14alpha-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. LKO mice developed hepatomegaly with oval cell proliferation, fibrosis and inflammation, but without steatosis. The key trigger was reduced cholesterol esters that provoked cell cycle arrest, senescence-associated secretory phenotype and ultimately the oval cell response, while elevated CYP51 substrates promoted the integrated stress response. In spite of the oval cell-driven fibrosis being histologically similar in both sexes, data indicates a female-biased down regulation of primary metabolism pathways and a stronger immune response in males. Liver injury was ameliorated by dietary fats predominantly in females, whereas dietary cholesterol rectified fibrosis in both sexes. Our data place defective cholesterol synthesis as a focus of sex-dependent liver pathologies. PMID- 25739791 TI - Outcome quality assessment by surgical process compliance measures in laparoscopic surgery. AB - OBJECTIVE: The effective and efficient assessment, management, and evolution of surgical processes are intrinsic to excellent patient care. Hence, in addition to economic interests, the quality of the outcome is of great importance. Process benchmarking examines the compliance of an intraoperative surgical process to another process that is considered as best practice. The objective of this work is to assess the relationship between the course and the outcome of surgical processes of the study. MATERIALS AND METHODS: By assessing 450 skill practices on rapid prototyping models in minimally invasive surgery training, we extracted descriptions of surgical processes and examined the hypothesis that a significant relationship exists between the course of a surgical process and the quality of its outcome. RESULTS: The results showed a significant correlation with Person correlation coefficients >0.05 between the quality of process outcome and process compliance for simple and complex suturing tasks in the study. CONCLUSIONS: We conclude that high process compliance supports good quality outcomes and, therefore, excellent patient care. We also showed that a deviation from best training processes led to a decreased outcome quality. This is relevant for identifying requirements for surgical processes, for generating feedback for the surgeon with regard to human factors and for inducing changes in the workflow in order to improve the outcome quality. PMID- 25739792 TI - Pedunculated haemangioma of the palate. AB - Haemangiomas are the most common tumours of vascular origin of the head and neck region and can appear anywhere in the oral cavity. They are benign, appear in early childhood and usually involute as the child grows older. The dental surgeon should manage them appropriately if they are symptomatic. This report presents a rare case of a pedunculated haemangioma in a 4-year-old child. PMID- 25739793 TI - Neurosyphilis presenting with a stroke-like syndrome. AB - Neurosyphilis results from infection of the central nervous system (CNS) by Treponema pallidum. Neurosyphilis can occur at any time after initial infection, particularly in immunocompromised patients. We describe a case of a 47-year-old man who presented with mixed dysphasia, right upper motor neuron facial palsy and right hemiparesis. Collateral history from the family revealed slowly progressive cognitive impairment and behavioural changes. Neuroimaging was unremarkable, suggesting a non-vascular aetiology. As there was no clear cause for the presentation, a lumbar puncture was performed and serum samples were sent for syphilis serology. The diagnosis of neurosyphilis was made on the basis of a positive RPR test in cerebrospinal fluid. The patient was treated with benzylpenicillin and made a full recovery, with restoration of cognitive function to baseline. PMID- 25739794 TI - Adalimumab-induced lupus serositis. AB - A 61-year-old man presented with a 1-month history of breathlessness, chest pain and lethargy. He had been taking adalimumab for ankylosing spondylitis for 2 years. Pleural and pericardial effusions were both found. A video-assisted thorascopic (VATS) pleural and lung biopsy were performed. The pleural pathology showed eosinophils, acute inflammatory cells and lymphoid aggregates. The patient was positive for antinuclear, antidouble-stranded and antihistone antibodies consistent with drug-induced lupus due to adalimumab. His serositis resolved on withdrawal of the drug. Drug-induced lupus can occur as a consequence of anti-TNF alpha agents from induction of autoimmunity in a predisposed host. PMID- 25739795 TI - Neuralgic amyotrophy complicating acute hepatitis E infection: a rare association. AB - Hepatitis E virus infection (HEV) is an emerging pathogen that is under recognised in developed countries. Preceding infection manifested by acute transaminitis has been associated with neurological manifestations, predominately involving the peripheral nervous system, even in immunocompetent patients. We present a case of a 65-year-old previously fit and well Caucasian man with bilateral neuralgic amyotrophy (NA) and acute transaminitis. Serology testing for immunoglobulin (Ig) M and G established the diagnosis of acute HEV infection. The patient received immunomodulatory treatment with an excellent long-term outcome. The temporal association of the clinical presentation of bilateral NA and acute transaminitis from HEV infection suggested the causal association of HEV to NA. We propose screening for HEV in patients presenting with NA and acute hepatitis. PMID- 25739796 TI - Gastric perforation due to foreign body ingestion mimicking acute cholecystitis. AB - An 82-year-old man presented with signs and symptoms that were suggestive of acute cholecystitis. He underwent a laparoscopic cholecystectomy. During the intervention, a wooden foreign body was removed from the infiltrated omentum, probably after it had perforated the gastric antrum. The gastric perforation had led to a secondary infection of the gallbladder. The presumed gastric perforation was treated conservatively, and the patient recovered well and was discharged after 7 days. Secondary inflamed gallbladders are rare; the current case is, to the best of our knowledge, the first case reporting a secondary infection of the gallbladder due to a gastric perforation. Clinicians should be aware of possible ingestion of foreign bodies in elderly patients wearing dental prosthetic devices. PMID- 25739797 TI - Idiopathic granulomatous mastitis: an inflammatory breast condition with review of the literature. AB - A 29-year-old woman noticed a tender mass in her right breast. The patient was seen by her gynaecologist and was prescribed antibiotics for 10 days for mastitis. Subsequently, she underwent a core biopsy of this mass and the pathology showed granulomatous mastitis. Cultures from the biopsy sample were negative for fungus and tuberculosis. The patient's clinical symptoms initially appeared to improve with antibiotic treatment, but were complicated by the formation of an abscess, which was drained in clinic. The patient was referred to rheumatology in anticipation of steroid or methotrexate therapy, and was placed again on antibiotic treatment to which she responded adequately. PMID- 25739799 TI - Correction. PMID- 25739798 TI - Major haemorrhage in pubic rami fractures. AB - A 62-year-old man presented to the emergency department, having fallen 6 ft from a ladder, with pain over his left hip and shoulder. He was managed according to the Advanced Trauma Life Support (ATLS) protocol, and his primary survey showed no haemodynamic compromise. Initial radiographs showed a unilateral left superior and inferior pubic rami fracture, which was treated conservatively. Forty-eight hours post-admission, the patient became tachycardic and hypotensive and was found to have dropped his haemoglobin from 125 to 89 g/L. After resuscitation, a repeat contrast CT scan revealed an enlarging haematoma in his pelvis. This was treated with urgent angioembolisation and the patient was further stabilised in the intensive care unit. This report shows the need for a low threshold in suspecting intrapelvic bleeds in patients with pubic rami fractures, and the need for prompt treatment of such patients, either surgically or radiologically. PMID- 25739800 TI - Shared pleasure in early mother-infant interaction: predicting lower levels of emotional and behavioral problems in the child and protecting against the influence of parental psychopathology. AB - Shared pleasure (SP) was analyzed in fifty-eight 2-month-old infants and their mothers in face-to-face interaction (T1, at 2 months). The association of SP with child's emotional and behavioral outcome at 2 years (T2) was examined. SP as a possible protecting factor in the presence of parental psychopathology also was studied. Mean duration of SP moments (SP-MD) was related to subsequent socioemotional outcome of the child: Infants of dyads with longer SP-MD showed fewer internalizing and externalizing problems 2 years later. In hierarchical linear regressions, SP-MD uniquely and significantly contributed to internalizing problems after adjusting for infant and maternal factors and mother's interactive behavior. SP protected the child against the influence of parental psychopathology. Father's mental health problems during the follow-up increased the child's risk for higher externalizing and internalizing problems, but only among children with short SP-MD at T1. Internalizing symptoms at T2 increased when moving from the category "no mental health problems" to "mental health problems in one parent" and further to "mental health problems in both parents," but this increase was found only among those with short SP-MD at T1. SP in parent child interaction is an important feature that fosters positive psychological development and moderates the health effects of other risks such as parental psychopathology. PMID- 25739801 TI - Determinants of the accuracy of occupational hygiene expert judgment. AB - An experimental study was performed to determine the applicability and accuracy of occupational hygienist's expert judgment in occupational exposure assessment. The effect of tier 1 model application on improvement of expert judgments were also realized. Hygienists were asked to evaluate inhalation exposure intensity in seven operating units in a tile factory before and after an exposure training session. Participants' judgments were compared to air sampling data in the units; then after relative errors for judgments were calculated. Stepwise regressions were performed to investigate the defining variables. In all situations there were almost a perfect agreement (ICC >0.80) among raters. Correlations between estimated mean exposure and relative percentage error of participants before and after training were significant at 0.01 (correlation coefficients were -0.462 and -0.443, respectively). Results showed that actual concentration and experience resulted in 22.4% prediction variance for expert error as an independent variable. Exposure rating by hygienists was susceptible to error from several sources. Experienced subjects had a better ability to predict the exposures intensity. In lower concentrations, the rating error increased significantly. Leading causes of judgment error should be taken into account in epidemiological studies. PMID- 25739803 TI - On the development, evaluation and evolution of health behaviour theory. PMID- 25739802 TI - 2,5-hexanedione induced apoptosis in mesenchymal stem cells from rat bone marrow via mitochondria-dependent caspase-3 pathway. AB - 2,5-hexanedione (HD) induces apoptosis of nerve cells. However,the mechanism of HD-induced apoptosis remains unknown. Mesenchymal stem cells (MSCs) are multipotential stem cells with the ability to differentiate into various cell types. This study is designed to investigate the apoptosis induced by HD in rat bone marrow MSCs (BMSCs) and the related underlying mechanisms. The fifth generation of MSCs was treated with 0, 10, 20 and 40 mM HD respectively. The viability of BMSCs was observed by MTT. Apoptosis were estimated by Hoechst 33342 staining and TUNEL assay. The disruption of mitochondrial transmembrane potential (MMP) was examined by JC-1 staining. Moreover, the expression of Bax and Bcl-2, cytochrome c release, and caspase-3 activity were determined by real-time RT-PCR, Western blot and Spectrophotometry. Our results showed that HD induced apoptosis in MSCs in a dose dependent manner. Moreover, HD downregulated the Bcl-2 expression,upregulated the Bax expression and the Bax/Bcl-2 ratio, promoted the disruption of MMP, induced the release of cytochrome c from mitochondria to cytosol, and increased the activity of caspase-3 in MSCs. These results indicate that HD induces apoptosis in MSCs and the activated mitochondria-dependent caspase-3 pathway may be involved in the HD-induced apoptosis. PMID- 25739804 TI - Rapid degradation of cyclic peroxides by titanium and antimony chlorides. AB - First responders face extraordinary risks when dealing with organic peroxides such as TATP due to the extreme sensitivity of this class of explosives, and to a lack of a robust chemical means of safe and rapid neutralisation. The Lewis acids TiCl4 and SbCl3 have been found to demonstrate a novel degradation mechanism, with TiCl4 degrading a model cyclic peroxide in minutes when used in a two-fold excess, or ~3 hours at half equivalence. The products cannot re-form peroxide compounds as is the case with acid degradation, suggesting the two mechanisms are fundamentally different. The Lewis acids mediate a rearrangement reaction in the cyclic peroxide backbone leading to relatively innocuous products through deactivation of oxidising O. Sub-stoichiometric TiCl4 reactions highlight a secondary reaction pathway that also leads to some oxidative chlorination products, possibly mediated by an unconfirmed titanium-oxychloride species. SbCl3 was found to exhibit similar reactivity to TiCl4, although at a slower rate. A mechanism is proposed, consistent with the observations for both stoichiometric and sub-stoichiometric quantities of TiCl4. PMID- 25739805 TI - Diffusive transport of molecular cargo tethered to a DNA origami platform. AB - Fast and efficient transport of molecular cargoes along tracks or on supramolecular platforms is an important prerequisite for the development of future nanorobotic systems and assembly lines. Here, we study the diffusive transport of DNA cargo strands bound to a supramolecular DNA origami structure via an extended tether arm. For short distances (on the order of a few nanometers), transport from a start to a target site is found to be less efficient than for direct transfer without tether. For distances on the scale of the origami platform itself, however, cargo transfer mediated by a rigid tether arm occurs very fast and robust, whereas a more flexible, hinged tether is found to be considerably less efficient. Our results suggest diffusive motion on a molecular tether as a highly efficient mechanism for fast transfer of cargoes over long distances. PMID- 25739806 TI - Three-dimensional simulation of mass transfer in artificial kidneys. AB - In this work, the three-dimensional velocity and concentration fields on both the blood and dialysate sides in an artificial kidney were simulated, taking into account the effects of the flow profiles induced by the inlet and outlet geometrical structures and the interaction between the flows of blood and dialysate. First, magnetic resonance imaging experiments were performed to validate the mathematical model. Second, the effects of the flow profiles induced by the blood and dialysate inlet and outlet geometrical structures on mass transfer were theoretically investigated. Third, the clearance of toxins was compared with the clearance value calculated by a simple model that is based on the ideal flow profiles on both the blood and dialysate sides. Our results show that as the blood flow rate increases, the flow field on the blood side becomes less uniform; however, as the dialysate flow rate increases, the flow field on the dialysate side becomes more uniform. The effect of the inlet and outlet geometrical structures of the dialysate side on the velocity and concentration fields is more significant than that of the blood side. Due to the effects of the flow profiles induced by the inlet and outlet geometrical structures, the true clearance of toxins is lower than the ideal clearance, especially when the dialysate flow rate is low or the blood flow rate is high. The results from this work are significant for the structural optimization of artificial kidneys and the accurate prediction of toxin clearance. PMID- 25739807 TI - Calcium-catalyzed carboarylation of alkynes. AB - Invited for the cover of this issue is the group of Meike Niggemann at the RWTH Aachen University. The image depicts a calcium catalyst brewing a magic potion-a carefully balanced choice of ingredients results in a new one-pot procedure for the carboarylation of internal alkynes. Read the full text of the article at 10.1002/chem.201406503. PMID- 25739808 TI - Polymer fullerene solution phase behaviour and film formation pathways. AB - We report the phase behaviour of polymer/fullerene/solvent ternary mixtures and its consequence for the morphology of the resulting composite thin films. We focus particularly on solutions of polystyrene (PS), C60 fullerene and toluene, which are examined by static and dynamic light scattering, and films obtained from various solution ages and thermal annealing conditions, using atomic force and light microscopy. Unexpectedly, the solution phase behaviour below the polymer overlap concentration, c*, is found to be described by a simple excluded volume argument (occupied by the polymer chains) and the neat C60/solvent miscibility. Scaling consistent with full exclusion is found when the miscibility of the fullerene in the solvent is much lower than that of the polymer, giving way to partial exclusion with more soluble fullerenes (phenyl-C61-butyric acid methyl ester, PCBM) and a less asymmetric solvent (chlorobenzene), employed in photovoltaic devices. Spun cast and drop cast films were prepared from PS/C60/toluene solutions across the phase diagram to yield an identical PS/C60 composition and film thickness, resulting in qualitatively different morphologies in agreement with our measured solution phase boundaries. Our findings are relevant to the solution processing of polymer/fullerene composites (including organic photovoltaic devices), which generally require effective solubilisation of fullerene derivatives and polymer pairs in this concentration range, and the design of well-defined thin film morphologies. PMID- 25739809 TI - Giovanni Battista Morgagni: facial reconstruction by virtual anthropology. AB - Multidisciplinary research was carried out on human skeletal remains to identify if they belonged to the famous pathologist Giovanni Battista Morgagni, who died at a very old age and was buried in a church in Padua. The purpose of this study was to analyze the skull, creating a virtual model necessary for facial reconstruction, so as to contribute to the identification of the skull. The skeletal remains were found buried in the Morgagni family grave. Based on preliminary anthropological evidence, that the skull might be ascribable to Giovanni Battista Morgagni, a digitized model of the skull was created and restored. From this, a virtual facial reconstruction was developed using an assumed relationship between the soft-tissues and the underlying skeletal structure. Finally, the anthropological profile and the face reconstruction were compared with historical documentation and the portrait of Morgagni by Pietro Danieletti, showing clear similarities. Virtual anthropological techniques create new perspectives for anthropological and medical studies and can be used successfully in the forensic sciences to make a positive identification, such as in this case, which has been examined by different experts with similar results. PMID- 25739810 TI - Segmental neurofibromatosis type 2: discriminating two hit from four hit in a patient presenting multiple schwannomas confined to one limb. AB - BACKGROUND: A clinical overlap exists between mosaic Neurofibromatosis Type 2 and sporadic Schwannomatosis conditions. In these cases a molecular analysis of tumors is recommended for a proper genetic diagnostics. This analysis is challenged by the fact that schwannomas in both conditions bear a somatic double inactivation of the NF2 gene. However, SMARCB1-associated schwannomas follow a four-hit, three-step model, in which both alleles of SMARCB1 and NF2 genes are inactivated in the tumor, with one of the steps being always the loss of a big part of chromosome 22 involving both loci. CASE PRESENTATION: Here we report a 36 year-old woman who only presented multiple subcutaneous schwannomas on her right leg. To help discriminate between both possible diagnoses, an exhaustive molecular genetic and genomic analysis was performed on two schwannomas of the patient, consisting in cDNA and DNA sequencing, MLPA, microsatellite multiplex PCR and SNP-array analyses. The loss of a big part of chromosome 22 (22q12.1q13.33) was identified in both tumors. However, this loss involved the NF2 but not the SMARCB1 locus. SNP-array analysis revealed the presence of the same deletion breakpoint in both schwannomas, indicating that this alteration was actually the first NF2 inactivating hit. In addition, a distinct NF2 point mutation in each tumor was identified, representing independent second hits. In accordance with these results, no deletions or point mutations in the SMARCB1 gene were identified. None of the mutations were present in the blood. Two of the patient's children inherited chromosome 22 deleted in schwannomas of the mother, but in its wild type form. CONCLUSIONS: These results conclusively confirm the segmental mosaic NF2 nature of the clinical phenotype presented. PMID- 25739811 TI - USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death. AB - Mitochondria play a pivotal role in the orchestration of cell death pathways. Here, we show that the control of ubiquitin dynamics at mitochondria contributes to the regulation of apoptotic cell death. The unique mitochondrial deubiquitylase, USP30, opposes Parkin-dependent ubiquitylation of TOM20, and its depletion enhances depolarization-induced cell death in Parkin-overexpressing cells. Importantly, USP30 also regulates BAX/BAK-dependent apoptosis, and its depletion sensitizes cancer cells to BH3-mimetics. These results provide the first evidence for a fundamental role of USP30 in determining the threshold for mitochondrial cell death and suggest USP30 as a potential target for combinatorial anti-cancer therapy. PMID- 25739814 TI - Rebuttal to Partsch et al. "Pain relief by compression in acute DVT. A critique of Kahn et al." Thromb Haemost 2015; 113: 906. PMID- 25739813 TI - T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in Nairobi, Kenya. AB - HIV-infected children are less capable of mounting and maintaining protective humoral responses to vaccination against measles compared to HIV-uninfected children. This poses a public health challenge in countries with high HIV burdens. Administration of anti-retroviral therapy (ART) and revaccinating children against measles is one approach to increase measles immunity in HIV infected children, yet it is not effective in all cases. Immune anergy and activation during HIV infection are factors that could influence responses to measles revaccination. We utilized a flow cytometry-based approach to examine whether T cell anergy and activation were associated with the maintenance of measles-specific immunoglobulin (Ig)G antibodies generated in response to measles revaccination in a cohort of HIV-infected children on ART in Nairobi, Kenya. Children who sustained measles-specific IgG for at least 1 year after revaccination displayed significantly lower programmed cell death 1 (PD-1) surface expression on CD8(+) T cells on a per-cell basis and exhibited less activated CD4(+) T cells compared to those unable to maintain detectable measles specific antibodies. Children in both groups were similar in age and sex, CD4(+) T cell frequency, duration of ART treatment and HIV viral load at enrolment. These data suggest that aberrant T cell anergy and activation are associated with the impaired ability to sustain an antibody response to measles revaccination in HIV-infected children on ART. PMID- 25739812 TI - Effects of inflammation on stem cells: together they strive? AB - Inflammation entails a complex set of defense mechanisms acting in concert to restore the homeostatic balance in organisms after damage or pathogen invasion. This immune response consists of the activity of various immune cells in a highly complex manner. Inflammation is a double-edged sword as it is reported to have both detrimental and beneficial consequences. In this review, we discuss the effects of inflammation on stem cell activity, focusing primarily on neural stem/progenitor cells in mammals and zebrafish. We also give a brief overview of the effects of inflammation on other stem cell compartments, exemplifying the positive and negative role of inflammation on stemness. The majority of the chronic diseases involve an unremitting phase of inflammation due to improper resolution of the initial pro-inflammatory response that impinges on the stem cell behavior. Thus, understanding the mechanisms of crosstalk between the inflammatory milieu and tissue-resident stem cells is an important basis for clinical efforts. Not only is it important to understand the effect of inflammation on stem cell activity for further defining the etiology of the diseases, but also better mechanistic understanding is essential to design regenerative therapies that aim at micromanipulating the inflammatory milieu to offset the negative effects and maximize the beneficial outcomes. PMID- 25739815 TI - Controlled and Targeted Drug Delivery by a UV-responsive Liposome for Overcoming Chemo-resistance in Non-Hodgkin Lymphoma. AB - Although chemotherapy plays a vital role in treating non-Hodgkin lymphomas, the clinical applications are limited because of intolerable side-effects and multidrug resistance at the beginning or during the course of therapy. In this study, we successfully fabricated a CD20-targeting immuno-liposome based on 1,2 bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC-8,9PC), which can form intermolecular cross-linking through the diacetylenic group by ultraviolet irradiation. This immuno-liposome showed appropriate size distribution, well defined regular spherical structure, favorable biocompatibility, high serum stability, and prolonged circulation time in blood vessels. The in and ex vivo experiments demonstrate enhanced tumor suppression abilities against both wild type and resistant non-Hodgkin lymphomas for liposomal doxorubicin when compared with free drugs. The outstanding antitumor activities are attributed to the accumulation and retention of liposomal drugs in malignant tissues and cells, which are realized by the co-operation of active targeting via antibody-antigen reaction and passive targeting via enhanced permeability and retention effect. PMID- 25739816 TI - Human Health Relevance of Pharmaceutically Active Compounds in Drinking Water. AB - In Canada, as many as 20 pharmaceutically active compounds (PhACs) have been detected in samples of treated drinking water. The presence of these PhACs in drinking water raises important questions as to the human health risk posed by their potential appearance in drinking water supplies and the extent to which they indicate that other PhACs are present but have not been detected using current analytical methods. Therefore, the goal of the current investigation was to conduct a screening-level assessment of the human health risks posed by the aquatic release of an evaluation set of 335 selected PhACs. Predicted and measured concentrations were used to estimate the exposure of Canadians to each PhAC in the evaluation set. Risk evaluations based on measurements could only be performed for 17 PhACs and, of these, all were found to pose a negligible risk to human health when considered individually. The same approach to risk evaluation, but based on predicted rather than measured environmental concentrations, suggested that 322 PhACs of the evaluation set, when considered individually, are expected to pose a negligible risk to human health due to their potential presence in drinking waters. However, the following 14 PhACs should be prioritized for further study: triiodothyronine, thyroxine, ramipril and its metabolite ramiprilat, candesartan, lisinopril, atorvastatin, lorazepam, fentanyl, atenolol, metformin, enalaprilat, morphine, and irbesartan. Finally, the currently available monitoring data for PhACs in Canadian surface and drinking waters was found to be lacking, irrespective of whether their suitability was assessed based on risk posed, predicted exposure concentrations, or potency. PMID- 25739817 TI - In Silico Evaluation of the Potential Impact of Bioanalytical Bias Difference between Two Therapeutic Protein Formulations for Pharmacokinetic Assessment in a Biocomparability Study. AB - Formulation changes at later stages of biotherapeutics development require biocomparability (BC) assessment. Using simulation, this study aims to determine the potential effect of bias difference observed between the two formulations after spiking into serum in passing or failing of a critical BC study. An ELISA method with 20% total error was used to assess any bias differences between a reference (RF) and test formulations (TF) in serum. During bioanalytical comparison of these formulations, a 9% difference in bias was observed between the two formulations in sera. To determine acceptable level of bias difference between the RF and TF bioanalytically, two in silico simulations were performed. The in silico analysis showed that the likelihood of the study meeting the BC criteria was >90% when the bias difference between RF and TF in serum was 9% and the number of subjects was >=20 per treatment arm. An additional simulation showed that when the bias difference was increased to 13% and the number of subjects was <40, the likelihood of meeting the BC criteria decreased to 80%. The result from in silico analysis allowed the bioanalytical laboratory to proceed with sample analysis using a single calibrator and quality controls made from the reference formulation. This modeling approach can be applied to other BC studies with similar situations. PMID- 25739818 TI - Nonlinear Mixed-effect Models for Prostate-specific Antigen Kinetics and Link with Survival in the Context of Metastatic Prostate Cancer: A Comparison by Simulation of Two-stage and Joint Approaches. AB - In metastatic castration-resistant prostate cancer (mCRPC) clinical trials, the assessment of treatment efficacy essentially relies on the time to death and the kinetics of prostate-specific antigen (PSA). Joint modeling has been increasingly used to characterize the relationship between a time to event and a biomarker kinetics, but numerical difficulties often limit this approach to linear models. Here, we evaluated by simulation the capability of a new feature of the Stochastic Approximation Expectation-Maximization algorithm in Monolix to estimate the parameters of a joint model where PSA kinetics was defined by a mechanistic nonlinear mixed-effect model. The design of the study and the parameter values were inspired from one arm of a clinical trial. Increasingly high levels of association between PSA and survival were considered, and results were compared with those found using two simplified alternatives to joint model, a two-stage and a joint sequential model. We found that joint model allowed for a precise estimation of all longitudinal and survival parameters. In particular, the effect of PSA kinetics on survival could be precisely estimated, regardless of the strength of the association. In contrast, both simplified approaches led to bias on longitudinal parameters, and two-stage model systematically underestimated the effect of PSA kinetics on survival. In summary, we showed that joint model can be used to characterize the relationship between a nonlinear kinetics and survival. This opens the way for the use of more complex and physiological models to improve treatment evaluation and prediction in oncology. PMID- 25739820 TI - Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. AB - The conventional paradigm of nonalcoholic fatty liver disease representing the "hepatic manifestation of the metabolic syndrome" is outdated. We identified and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions. Online Medical databases were searched, relevant articles were identified, their references were further assessed and tabulated data were checked. Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes. Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk factor for the future development of the metabolic syndrome. Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not associated with insulin resistance and metabolic syndrome. Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome. PMID- 25739819 TI - Cold Exposure Improves the Anti-diabetic Effect of T0901317 in Streptozotocin Induced Diabetic Mice. AB - Activation of liver X receptors (LXRs) can improve glucose tolerance in insulin independent diabetes, however, whether similar effects can be achieved in insulin dependent diabetes remains unclear. Here, we evaluated the anti-diabetic activity of T0901317, a potent agonist of LXRs, in diabetic mice induced by streptozotocin, and our data demonstrate that T0901317 is most effective when combined with cold treatment of animals. Treatment with T0901317 improved glucose tolerance of diabetic mice, which was associated with repressed expression of key genes involved in hepatic gluconeogenesis such as Pepck and G6p. Combined treatment by T0901317 and cold exposure reduced transcription of gluconeogenic genes to similar levels. Intriguingly, combined treatment greatly increased expression of Ucp1, Cidea, Dio2, and Elvol3 predominantly in the inguinal white adipose tissue, consequently leading to browning of this fat pad, and resulting in further improvement of glucose tolerance which was associated with increased protein levels of UCP1 and GLUT4. Collectively, these results suggest that browning of white adipose tissue via cold exposure in combination with activation of liver X receptors is an alternative and effective strategy to manage insulin dependent diabetes. PMID- 25739821 TI - Arginase activity and CD3zeta expression after major surgery. PMID- 25739822 TI - Impact of Remnant Lipoprotein on Coronary Plaque Components. AB - AIM: Intravascular ultrasound (IVUS) is a useful modality for visualizing atherosclerotic lesions in coronary arteries, not only for the degree of arterial luminal stenosis but also for the plaque composition within the vessel walls. We aimed to determine the relationship between the clinical parameters and coronary plaque characteristics evaluated by IVUS in patients with stable angina under medical treatment. METHODS: Plaque measurements within the coronary arteries were collected by coronary angiography and iMAP-IVUS in 40 men with stable angina. The serum remnant-like cholesterol (RemL-C) was measured using homogeneous assays and serum adiponectin and omentin-1 levels were measured by enzyme-linked immunosorbent assays. RESULTS: The iMAP-IVUS analysis of the coronary arteries demonstrated that the plaque cross-sectional area (CSA) was 11.0+/-3.5 mm(2). Plaque CSA positively correlated with body mass index and negatively correlated with the serum adiponectin levels. Both areal and volumetric analyses of the plaque characteristics demonstrated that the serum RemL-C level was a positive determinant for %Necrosis and the negative determinant for %Fibrosis of the plaques. Neither serum high-density lipoprotein cholesterol nor low-density lipoprotein cholesterol levels correlated with the proportion of any plaque components. Additionally, the RemL-C/triglyceride ratio positively correlated with %Lipid significantly in the areal analysis. CONCLUSION: Elevation of the serum RemL-C levels in the patients with stable angina may link to coronary plaque vulnerability, which is characterized by high necrotic and low fibrotic components. PMID- 25739823 TI - Prevalence of High Arterial Stiffness and Gender-specific Differences in the Relationships with Classical Cardiovascular Risk Factors. AB - AIM: To investigate the relationships between arterial stiffness and classic cardiovascular risk factors with respect to gender differences in addition to the prevalence of high arterial stiffness in Chongqing, China based on an examination of 18,336 subjects. METHODS: The cardio-ankle vascular index was used as a marker of arterial stiffness. The relationships between arterial stiffness and body mass index (BMI) as well as metabolic syndrome (MetS) were estimated using logistic regression models. RESULTS: The prevalence of high arterial stiffness was 12.74% in men and 9.91% in women. For age and BMI, compared with the reference group, men had higher adjusted odds ratios (ORs) in each group versus their female counterparts. For each individual index of MetS, the effects of waist circumference and systolic blood pressure (SBP) on high arterial stiffness exhibited remarkable gender differences, with women having higher ORs and adjusted ORs than men. As the sum of MetS traits increased, the ORs and adjusted ORs in the subjects also increased, with women having higher values than men in each group. CONCLUSIONS: Gender-specific differences exist in the prevalence of high arterial stiffness among subjects compared by age, BMI and MetS, with varying effects of influence for these factors between genders. PMID- 25739824 TI - Serum 25-Hydroxyvitamin D and the Incidence of Peripheral Artery Disease in the Elderly: The Pro.V.A Study. AB - AIM: This study was conducted to examine whether low serum levels of 25 hydroxyvitamin D (25OHD)are associated with a higher risk of incident peripheral artery disease (PAD) in a representative group of elderly people. METHODS: We followed 1568 community-dwelling elderly participants without PAD at the baseline (among a sample of 2097 initially eligible) over a mean of 4.4 years as part of the Progetto Veneto Anziani (Pro.V.A.) study. The baseline serum 25OHD levels were categorized as <24, 25-49, 50-74, >75 nmol/L, and incident PAD was defined as an ankle-brachial index below 0.9. RESULTS: At the baseline, there were no differences in known risk factors for PAD (BMI, waist circumference, diabetes, cardiovascular diseases, smoking habits, total cholesterol) or in the ankle brachial index (ABI) between the groups with different serum 25OHD levels (<24, 25-49, 50-74, >75 nmol/L). During a 4.4-year follow-up, 371 subjects developed PAD. The group with serum 25OHD levels >75 nmol/L was set as the reference group, and an adjusted Cox's regression analysis showed no association between low vitamin D levels and incident PAD during the follow-up: the hazard ratio ranged from 0.76 (95%CI: 0.41-1.42) for participants with serum 25OHD levels below 25 nmol/L to 1.32 (95%CI: 0.72-2.39) for those with serum 25OHD levels between 50-74 nmol/L (p for trend=0.08). These results did not change when participants were stratified by several risk factors for PAD. CONCLUSIONS: Baseline hypovitaminosis D did not predict the onset of PAD over a 4.4-year follow-up in elderly people. PMID- 25739825 TI - Novel Link between Inhibition of Angiogenesis and Tolerance to Vascular Stress. AB - The functional integrity of the vascular endothelium is an essential component required for the maintenance of vascular health, thus counteracting the onset of vascular diseases, including atherosclerosis and vascular complications of diabetes. In light of this important role, the vascular endothelium is expected to have a self-defense system. One candidate factor of such a system is vasohibin 1 (VASH1), a protein that is preferentially expressed in vascular endothelial cells (ECs). The unique features of VASH1 are its anti-angiogenic activity and ability to promote the stress tolerance and survival of ECs. This review summarizes current knowledge regarding VASH1 in terms of its roles in maintaining vascular integrity and protecting the vasculature against various forms of stress. PMID- 25739826 TI - Inflammatory markers and mortality among US adults with obstructive lung function. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease is characterized by an inflammatory state of uncertain significance. The objective of this study was to examine the association between elevated inflammatory marker count (white blood cell count, C-reactive protein and fibrinogen) on all-cause mortality in a national sample of US adults with obstructive lung function (OLF). METHODS: Data for 1144 adults aged 40-79 years in the National Health and Nutrition Examination Survey III Linked Mortality Study were analysed. Participants entered the study from 1988 to 1994, and mortality surveillance was conducted through 2006. White blood cell count and fibrinogen were dichotomized at their medians, and C reactive protein was divided into >3 and <=3 g/L. The number of elevated inflammatory markers was summed to create a score of 0-3. RESULTS: The age adjusted distribution of the number of elevated inflammatory markers differed significantly among participants with normal lung function, mild OLF, and moderate or worse OLF. Of the three dichotomized markers, only fibrinogen was significantly associated with mortality among adults with any OLF (maximally adjusted hazard ratio 1.49; 95% confidence interval (CI): 1.17-1.91). The maximally adjusted hazard ratios for having 1, 2 or 3 elevated markers were 1.17 (95% CI: 0.71-1.94), 1.44 (95% CI: 0.89-2.32) and 2.08 (95% CI: 1.29-3.37), respectively (P=0.003). CONCLUSIONS: An index of elevated inflammatory markers predicted all-cause mortality among adults with OLF. PMID- 25739827 TI - The prognostic relevance of node metastases in optimally cytoreduced advanced ovarian cancer. AB - PURPOSE: To delineate the relevance of pelvic and para-aortic node involvement in optimally cytoreduced (residual tumour <1 cm) stage IIIC ovarian cancer patients. METHODS: Ninety-five consecutive optimally cytoreduced (R <= 1 cm) patients with primary stage IIIc ovarian cancer underwent stage-related surgery and got adjuvant platinum-based chemotherapy. Median follow-up: 53.5 months. All patients got systematic lymphadenectomy. On average, 24.7 pelvic and para-aortic lymph nodes were removed per patient (range 1-60 nodes). Patients were stratified into three groups to evaluate node involvement (ratio: affected to resected nodes): (1) (=0); (2) (>0-<= 0.5) >0 and <= 50 % of affected nodes; (3) (>0.5-<= 1) >50 % of affected nodes. Clinical parameters were retrospectively evaluated. Kaplan Meier survival curve was used to evaluate the prognostic value. RESULTS: Most often serous histology, histologic grade 3 and a node ratio >0-<= 0.5 (61.1 %) were detected. Complete cytoreduction (R = 0 mm) has significant best prognostic impact compared to R > 0 mm-1 cm (OS: p = 0.047, PFS: p = 0.00). Node involvement was associated with serous histology and grade 3. Increasing node ratio leads to significant decreased OS (p = 0.019) and significant best OS was associated with node ratio >0-<=0.5. CONCLUSIONS: The goal is optimal cytoreduction in advanced ovarian cancer. More extensive lymphadenectomy seems to play an important role in providing an accurate staging, and the node ratio might give prognostic information. Current prospective studies like the LION study (AGO-Ovar) had to investigate if these data have therapeutic implications and may be considered in future staging. PMID- 25739828 TI - Cadherin-13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder. AB - Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P >= 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P-value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P-value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD. PMID- 25739829 TI - Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial. AB - OBJECTIVES: The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS: Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week*4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS: The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS: At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER: ISRCTN28528813. PMID- 25739831 TI - Gender differences in sleep disordered breathing: implications for therapy. AB - There are gender differences in the upper airway function and respiratory stability in obstructive sleep apnea (OSA). Hormones are implicated in some gender-related differences, and these differences between men and women appear to mitigate as age increases. In addition, changes in the airway and lung function during pregnancy can contribute to snoring and OSA that might have an adverse effect on the mother and fetus. The limited data available suggest that although the prevalence and severity of OSA may be lower in women, the consequences of the disease are similar, if not worse. Women with OSA may have greater risk for hypertension and endothelial dysfunction, be more likely to develop comorbid conditions such as anxiety and depression and have increased mortality. Therefore, treatment options specifically targeting female presentations and pathophysiology of sleep-disordered breathing (SDB) are expected to result in improved outcomes in women. PMID- 25739830 TI - Gout and the risk of Alzheimer's disease: a population-based, BMI-matched cohort study. AB - OBJECTIVE: While gout is associated with cardiovascular (CV)-metabolic comorbidities and their sequelae, the antioxidant effects of uric acid may have neuroprotective benefits. We evaluated the potential impact of incident gout on the risk of developing Alzheimer's disease (AD) in a general population context. METHODS: We conducted an age-matched, sex-matched, entry-time-matched and body mass index (BMI)-matched cohort study using data from The Health Improvement Network, an electronic medical record database representative of the UK general population, from 1 January 1995 to 31 December 2013. Up to five non-gout individuals were matched to each case of incident gout by age, sex, year of enrolment and BMI. We compared incidence rates of AD between the gout and comparison cohorts, excluding individuals with prevalent gout or dementia at baseline. Multivariate hazard ratios (HRs) were calculated, while adjusting for smoking, alcohol use, physician visits, social deprivation index, comorbidities and medication use. We repeated the same analysis among patients with incident osteoarthritis (OA) as a negative control exposure. RESULTS: We identified 309 new cases of AD among 59 224 patients with gout (29% female, mean age 65 years) and 1942 cases among 238 805 in the comparison cohort over a 5-year median follow up (1.0 vs 1.5 per 1000 person-years, respectively). Univariate (age-matched, sex matched, entry-time-matched and BMI-matched) and multivariate HRs for AD among patients with gout were 0.71 (95% CI 0.62 to 0.80) and 0.76 (95% CI 0.66 to 0.87), respectively. The inverse association persisted among subgroups stratified by sex, age group (<75 and >=75 years), social deprivation index and history of CV disease. The association between incident OA and the risk of incident AD was null. CONCLUSIONS: These findings provide the first general population-based evidence that gout is inversely associated with the risk of developing AD, supporting the purported potential neuroprotective role of uric acid. PMID- 25739832 TI - Double-scattering/reflection in a single nanoparticle for intensified ultrasound imaging. AB - Ultrasound contrast agents (UCAs) designed by the conventional composition-based strategy, often suffer from relatively low ultrasound utilization efficiency. In this report, a structure-based design concept of double-scattering/reflection in a single nanoparticle for enhancing ultrasound imaging has been proposed. To exemplify this concept, a rattle-type mesoporous silica nanostructure (MSN) with two contributing interfaces has been employed as the ideal model. Contributed by double-scattering/reflection interfaces, the rattle-type MSN, as expected, performs much better in in vitro and in vivo ultrasound imaging than the other two nanostructures (solid and hollow) containing only one scattering/reflection interface. More convincingly, related acoustic measurements and simulation calculations also confirm this design concept. Noticeably, the rattle-type MSN has also been demonstrated capable of improving intracellular ultrasound molecular imaging. As a universal method, the structure-design concept can extend to guide the design of new generation UCAs with many other compositions and similar structures (e.g., heterogeneous rattle-type, double-shelled). PMID- 25739833 TI - Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study. AB - Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events. PMID- 25739834 TI - Hide and seek: a comparative autoradiographic in vitro investigation of the adenosine A3 receptor. AB - PURPOSE: Since the adenosine A3 receptor (A3R) is considered to be of high clinical importance in the diagnosis and treatment of ischaemic conditions (heart and brain), glaucoma, asthma, arthritis, cancer and inflammation, a suitable and selective A3R PET tracer such as [(18)F]FE@SUPPY would be of high clinical value for clinicians as well as patients. A3R was discovered in the late 1990s, but there is still little known regarding its distribution in the CNS and periphery. Hence, in autoradiographic experiments the distribution of A3R in human brain and rat tissues was investigated and the specific binding of the A3R antagonist FE@SUPPY and MRS1523 compared. Immunohistochemical staining (IHC) experiments were also performed to validate the autoradiographic findings. METHODS: For autoradiographic competition experiments human post-mortem brain and rat tissues were incubated with [(125)I]AB-MECA and highly selective compounds to block the other adenosine receptor subtypes. Additionally, IHC was performed with an A3 antibody. RESULTS: Specific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0% and 46.4%), lung (44.5% and 45.0%), heart (39.9% and 42.9%) and testes (27.4% and 29.5%, respectively). Low amounts of A3R were found in rat brain tissues (5.9% and 5.6%, respectively) and human brain tissues (thalamus 8.0% and 9.1%, putamen 7.8% and 8.2%, cerebellum 6.0% and 7.8%, hippocampus 5.7% and 5.6%, caudate nucleus 4.9% and 6.4%, cortex 4.9% and 6.3%, respectively). The outcome of the A3 antibody staining experiments complemented the results of the autoradiographic experiments. CONCLUSION: The presence of A3R protein was verified in central and peripheral tissues by autoradiography and IHC. The specificity and selectivity of FE@SUPPY was confirmed by direct comparison with MRS1523, providing further evidence that [(18)F]FE@SUPPY may be a suitable A3 PET tracer for use in humans. PMID- 25739835 TI - The influence of aortic valve calcification on the risk of periprocedural myocardial injury after elective coronary intervention. AB - BACKGROUND: Aortic valve calcification (AVC) is a common progressive condition that involves several inflammatory and atherosclerotic mediators. However, it is unclear whether the occurrence of periprocedural myocardial injury (PMI) after elective coronary intervention is associated with AVC in stable coronary artery disease (CAD) patients. METHODS: A total of 530 stable CAD patients who underwent elective coronary intervention were enrolled in this clinical study. High sensitive cardiac troponin T (hs-cTnT) was detected before and after the procedure. PMI was defined as hs-cTnT after coronary intervention higher than 99th percentile upper reference limit (URL). All patients underwent echocardiography to detect the occurrence of AVC. Univariate and multivariate analyses were applied to analyze risk factors of PMI. RESULTS: A total of 210 patients (39.6 %) were diagnosed with PMI after elective coronary intervention. Compared with non-AVC patients (n = 386), AVC patients (n = 144) had higher rate of PMI (64.6 vs. 30.3 %, P < 0.01). CAD patients with AVC had higher Gensini score (39.9 +/- 26.6 vs. 34.2 +/- 22.1, P < 0.05) and more number of implanted stents (1.7 +/- 0.8 vs. 1.5 +/- 0.7, P < 0.05). After stratification by classic risk factors of CAD (such as age, male gender and diabetes) in subgroup analyses, we found that AVC patients had increased risk of PMI compared with non-AVC patients. Importantly, even after being adjusted by multivariate analysis, AVC still independently increased the risk of PMI (OR = 3.329, 95 % CI = 2.087-5.308, P < 0.01). CONCLUSION: AVC significantly increased the risk of PMI after elective coronary intervention. It could be one of the independent predictors for PMI in stable CAD patients. PMID- 25739836 TI - Comparative and quantitative proteomic analysis of normal and degenerated human annulus fibrosus cells. AB - Degeneration of the intervertebral disc (IVD) is a major chronic medical condition associated with back pain. To better understand the pathogenesis of IVD degeneration, we performed comparative and quantitative proteomic analyses of normal and degenerated human annulus fibrosus (AF) cells and identified proteins that are differentially expressed between them. Annulus fibrosus cells were isolated and cultured from patients with lumbar disc herniation (the experimental group, degenerated AF cells) and scoliosis patients who underwent orthopaedic surgery (the control group, normal AF cells). Comparative proteomic analyses of normal and degenerated cultured AF cells were carried out using 2-D electrophoresis, mass spectrometric analyses, and database searching. Quantitative analyses of silver-stained 2-D electrophoresis gels of normal and degenerated cultured AF cells identified 10 protein spots that showed the most altered differential expression levels between the two groups. Among these, three proteins were decreased, including heat shock cognate 71-kDa protein, glucose-6 phosphate 1-dehydrogenase, and protocadherin-23, whereas seven proteins were increased, including guanine nucleotide-binding protein G(i) subunit alpha-2, superoxide dismutase, transmembrane protein 51, adenosine receptor A3, 26S protease regulatory subunit 8, lipid phosphate phosphatase-related protein, and fatty acyl-crotonic acid reductase 1. These differentially expressed proteins might be involved in the pathophysiological process of IVD degeneration and have potential values as biomarkers of the degeneration of IVD. PMID- 25739837 TI - Antioxidant supplementation during in vitro culture improves mitochondrial function and development of embryos from aged female mice. AB - Maternal aging results in reduced oocyte and blastocyst quality, thought to be due, in part, to mitochondrial dysfunction and accumulation of reactive oxygen species. To reduce oxidative stress, the antioxidants alpha-lipoic acid (ALA; 10uM), alpha-tocopherol (250uM), hypotaurine (1mM) and N-acetylcysteine (NAC; 1mM), and sirtuin (100ngmL(-1)) were added to embryo culture medium (AntiOX) and compared with a control (CON) without antioxidants to assess blastocyst development after in vitro maturation and fertilisation of oocytes from aged B6D2F1 female mice (13.5 months). Development to the blastocyst stage increased in the AntiOX compared with CON group (87.6% vs 72.7%, respectively; P<0.01), in addition to higher mitochondrial membrane potential and ATP levels in the AntiOX group. Expression of genes associated with oxidative stress (PI3K, FOXO3A and GLRX2) was upregulated in the CON compared with AntiOX group. In addition to AntiOX, a medium containing only NAC and ALA (rAntiOX) was used to culture embryos from young CF1 females (6-8 weeks). More blastocysts developed in the rAntiOX compared with CON group (64.1% vs 43.3%, respectively; P<0.01), although AntiOX (48.0% blastocysts) did not result in improved development in young mice. Antioxidants improved mitochondrial activity, gene expression and development in embryos of older female mice, whereas a reduced level of antioxidants during culture was beneficial to embryos from young mice. PMID- 25739838 TI - Folate receptor-targeted and cathepsin B-activatable nanoprobe for in situ therapeutic monitoring of photosensitive cell death. AB - The integration of diagnostic and therapeutic functions in a single system holds great promise to enhance the theranostic efficacy and prevent the under- or overtreatment. Herein, a folate receptor-targeted and cathepsin B-activatable nanoprobe is designed for background-free cancer imaging and selective therapy. The nanoprobe is prepared by noncovalently assembling phospholipid-poly(ethylene oxide) modified folate and photosensitizer-labeled peptide on the surface of graphene oxide. After selective uptake of the nanoprobe into lysosome of cancer cells via folate receptor-mediated endocytosis, the peptide can be cleaved to release the photosensitizer in the presence of cancer-associated cathepsin B, which leads to 18-fold fluorescence enhancement for cancer discrimination and specific detection of intracellular cathepsin B. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen for triggering photosensitive lysosomal cell death. After lysosomal destruction, the lighted photosensitizer diffuses from lysosome into cytoplasm, which provides a visible method for in situ monitoring of therapeutic efficacy. The nanoprobe exhibits negligible dark toxicity and high phototoxicity with the cell mortality rate of 0.06% and 72.1%, respectively, and the latter is specific to folate receptor positive cancer cells. Therefore, this work provides a simple but powerful protocol with great potential in precise cancer imaging, therapy, and therapeutic monitoring. PMID- 25739839 TI - Source, profile, and carcinogenic risk assessment for cohorts occupationally exposed to dust-bound PAHs in Lahore and Rawalpindi cities (Punjab province, Pakistan). AB - In this study, the occurrence and concentrations of PAHs in dust samples, which were collected from the traffic police cabins/working spots, located on the main busy roads of Lahore (TP-L) and Rawalpindi (TP-R) cities (Punjab province, Pakistan) and from the public transport vehicles in the same cities (named as AM L and AM-R, respectively) were determined. The mean and median concentrations of ?PAHs were observed in the following descending order: AM-L (1340 and 774 ng g( 1) d.w., respectively), TP-L (866 and 854 ng g(-1) d.w.), TP-R (504 and 379 ng g( 1) d.w.), and AM-R (393 and 290 ng g(-1) d.w. Source apportionment of the soil/dust-bound PAHs was also performed. In all the sampling areas, the diagnostic ratios, principal component analysis (PCA) followed by multiple linear regression (MLR) analysis indicated signatures of mixed sources of PAHs (including vehicular exhaust emission, gasoline/diesel, and coal/wood combustion). Estimated results of incremental lifetime cancer risk (ILCR) indicated that the traffic policemen and drivers, especially those in the urban area of Lahore, were at high risk of cancer via routes of dust ingestion and dermal contact. The results of this research could be very useful for the local Government in order to control the exposure and promote actions to alleviate PAH contamination and to manage health both at work places in the big cities of Pakistan. PMID- 25739840 TI - Immobilization of fungal laccase onto a nonionic surfactant-modified clay material: application to PAH degradation. AB - Nonionic surfactant-modified clay is a useful absorbent material that effectively removes hydrophobic organic compounds from soil/groundwater. We developed a novel material by applying an immobilized fungal laccase onto nonionic surfactant modified clay. Low-water-solubility polycyclic aromatic hydrocarbons (PAHs) (naphthalene/phenanthrene) were degraded in the presence of this bioactive material. PAH degradation by free laccase was higher than degradation by immobilized laccase when the surfactant concentration was allowed to form micelles. PAH degradation by immobilized laccase on TX-100-modified clay was higher than on Brij35-modified clay. Strong laccase degradation of PAH can be maintained by adding surfactant monomers or micelles. The physical adsorption of nonionic surfactants onto clay plays an important role in PAH degradation by laccase, which can be explained by the structure and molecular interactions of the surfactant with the clay and enzyme. A system where laccase is immobilized onto TX-100-monomer-modified clay is a good candidate bioactive material for in situ PAHs bioremediation. PMID- 25739841 TI - Evaluation of the potential for trophic transfer of roxithromycin along an experimental food chain. AB - Pharmaceuticals have been recognized as a new class of environmental pollutants in recent years. But data about their potential for transfer and biomagnification in aquatic food chains are still lacking. In this study, bioaccumulation of the macrolide antibiotic roxithromycin (ROX) was determined in an experimental aquatic food chain involving the green algae Scenedesmus obliquus, the water flea Daphnia magna and the crucian carp Carassius auratus. After 48 h of exposure, S. obliquus accumulated ROX from media, with bioconcentration factors (BCFs) of 74.6, 46.3, and 24.5 l kg(-1) at nominal exposure concentrations of 4, 20, and 100 MUg l(-1), respectively. After 48 h of feeding ROX-contaminated algae, D. magna was able to accumulate ROX in all three concentration treatments, but biomagnification did not occur at this trophic level, as biomagnification factors (BMFs) varied from 0.21 to 0.29 in different concentration treatments were well below one. In tissues (muscle, gill, liver, and bile) of C. auratus fed with contaminated daphnia for 8 days, no biomagnification was observed. However, this species did accumulate a certain degree of ROX through food chain transfer, and the tissue burden was greatest in the liver > muscle > gill and lowest in the bile. This work suggests that the trophic transfer should be a matter of concern for ecological risk assessments of pharmaceutical substances in aquatic food webs. PMID- 25739842 TI - The comparative effects of spinal and peripheral thrust manipulation and exercise on pain sensitivity and the relation to clinical outcome: a mechanistic trial using a shoulder pain model. AB - STUDY DESIGN: Single-blind randomized trial. OBJECTIVES: To compare the effects of cervical and shoulder thrust manipulation (TM) and exercise on pain sensitivity, and to explore associations with clinical outcomes in patients with shoulder pain. BACKGROUND: Experimental studies indicate that spinal TM has an influence on central pain processes, supporting its application for treatment of extremity conditions. Direct comparison of spinal and peripheral TM on pain sensitivity has not been widely examined. METHODS: Seventy-eight participants with shoulder pain (36 female; mean +/- SD age, 39.0 +/- 14.5 years) were randomized to receive 3 treatments of cervical TM (n = 26), shoulder TM (n = 27), or shoulder exercise (n = 25) over 2 weeks. Twenty-five healthy participants (13 female; mean +/- SD age, 35.2 +/- 11.1 years) were assessed to compare pain sensitivity with that in clinical participants at baseline. Primary outcomes were changes in local (eg, shoulder) and remote (eg, tibialis anterior) pressure pain threshold and heat pain threshold occurring over 2 weeks. Secondary outcomes were shoulder pain intensity and patient-rated function at 4, 8, and 12 weeks. Analysis-of-variance models and partial-correlation analyses were conducted to examine comparative effects and the relationship between measures. RESULTS: At baseline, clinical participants demonstrated lower local (mean difference, - 1.63 kg; 95% confidence interval [CI]: -2.40, -0.86) and remote pressure pain threshold (mean difference, -1.96 kg; 95% CI: -3.09, -0.82) and heat pain threshold (mean difference, -1.15 degrees C; 95% CI: -2.06, -0.24) compared to controls, suggesting enhanced pain sensitivity. Following intervention, there were no between-group differences in pain sensitivity or clinical outcome (P>.05). However, improvements were noted, regardless of intervention, for pressure pain threshold (range of mean differences, 0.22-0.32 kg; 95% CI: 0.03, 0.43), heat pain threshold (range of mean differences, 0.30-0.58; 95% CI: 0.06, 0.96), pain intensity (range of mean differences, -1.79 to -1.45; 95% CI: -2.34, 0.94), and function (range of mean differences, 3.15-3.82; 95% CI: 0.69, 6.20) at all time points. We did not find an association between pain sensitivity changes and clinical outcome (P>.05). Conclusion Clinical participants showed enhanced pain sensitivity, but did not respond differently to cervical or peripheral TM. In fact, in this sample, cervical TM, shoulder TM, and shoulder exercise had similar pain sensitivity and clinical effects. The lack of association between pain sensitivity and clinical pain and function outcomes suggests different (eg, nonspecific) pain pathways for clinical benefit following TM or exercise. LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 25739843 TI - The geography of fatty infiltrates within the cervical multifidus and semispinalis cervicis in individuals with chronic whiplash-associated disorders. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: To quantify the magnitude and distribution of muscle fat infiltration (MFI) within the cervical multifidus and semispinalis cervicis muscles in participants with chronic whiplash-associated disorders (WADs) compared to those who have fully recovered from a whiplash injury and healthy controls. BACKGROUND: Previous research has established the presence of increased MFI throughout the cervical extensor muscles of individuals with WAD when compared to healthy controls. These changes appear to be greater in the deepest muscles (eg, multifidus and semispinalis cervicis) than in the more superficial muscles. A detailed analysis of the distribution of MFI within these deep extensor muscles in chronic WAD, recovered, and control groups would provide a foundation for further investigation of specific mechanisms, etiologies, and targets for treatments. METHODS: Fifteen participants (WAD, n = 5; recovered, n = 5; and control, n = 5) were studied using a 3-D fat-water separation magnetic resonance imaging sequence. Bilateral measures of cervical multifidus and semispinalis cervicis MFI in 4 quartiles (1 [medial] to 4 [lateral]) at cervical levels C3 through C7 were included in the analysis. Intrarater and interrater reliability were established. A mixed-model analysis was performed to control for covariates, identify interaction effects, and compare MFI distribution between groups. RESULTS: The limits of agreement confirmed strong intrarater and interrater agreement at all levels (C3-C7). Sex, age, and body mass index were identified as significant covariates for MFI. Significant interactions were found between group and muscle quartile (P<.001) and between muscle quartile and cervical level (P<.001). Pairwise comparisons for intraquartile MFI between groups revealed significantly greater MFI in the WAD group when compared to the recovered group in the first quartile (P<.001), second quartile (P<.001), and third quartile (P = .03). When compared to the control group, the WAD group had significantly greater MFI in the first quartile (P = .002) and the second quartile (P = .045). The control group had significantly higher MFI in comparison to the recovered group in the first quartile (P = .048). CONCLUSION: This study provides preliminary data mapping the spatial distribution of MFI in the cervical multifidus and semispinalis cervicis muscles in individuals with chronic WAD, those who have recovered from a whiplash injury, and healthy controls. Muscle fat infiltration is more concentrated in the medial portion of the muscles in all participants. However, the magnitude of MFI in the medial quartiles (1 and 2) is greatest in the chronic WAD group. PMID- 25739844 TI - The effect of additional ankle and midfoot mobilizations on plantar fasciitis: a randomized controlled trial. AB - STUDY DESIGN: A single-blind randomized controlled trial. OBJECTIVE: To evaluate the efficacy of ankle and midfoot mobilization on pain and function of patients with plantar fasciitis (PF). BACKGROUND: Plantar fasciitis is a degenerative process of the plantar fascia, with a lifetime prevalence of approximately 10%. Limited ankle dorsiflexion is a common finding and apparently acts as a contributing factor to the development of PF. METHODS: Fifty patients with PF, aged 23 to 73 years, were randomly assigned to either the intervention or control group. Both groups received 8 treatments, twice a week, consisting of stretching exercises and ultrasound. In addition, the intervention group received mobilization of the ankle and midfoot joints. Dorsiflexion range of motion was measured at the beginning and at the end of treatment. The results were evaluated by 3 outcomes: the numeric pain-rating scale, Lower Extremity Functional Scale, and algometry. RESULTS: No significant difference was found between groups in any of the outcomes. Both groups showed a significant difference in the numeric pain rating scale and Lower Extremity Functional Scale. Both groups significantly improved in dorsiflexion range of motion, with no difference between groups. CONCLUSION: The addition of ankle and foot joint mobilization aimed at improving dorsiflexion range of motion is not more effective than stretching and ultrasound alone in treating PF. The association between limited ankle dorsiflexion and PF is most probably due to soft tissue limitations, not the joints. Trial registered at ClinicalTrials.gov (registration number NCT01439932). LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 25739845 TI - Rheumatologic manifestations of the "MonoMAC" syndrome. a systematic review. AB - MonoMAC syndrome is characterized by monocytopenia with susceptibility to nontuberculous mycobacterial infections. First recognized in 2011, it is caused by GATA2 mutations and can manifest as disseminated mycobacterial, fungal, and viral infections. While mortality rates for this disorder have been high, it has recently been successfully treated with haploidentical allogeneic stem cell transplant. Since approximately one third of patients may have rheumatologic symptoms, such as erythema nodosum, panniculitis, or arthralgias, rheumatologists may expect to encounter this newly described entity with increasing frequency. PMID- 25739846 TI - Teriparatide: an unexpected adjunct for the treatment of a long-standing infected elbow prosthesis prevented arm amputation. AB - A 76-year-old woman with rheumatoid arthritis, osteoporosis and multiple comorbidities presented with septic left elbow prosthesis. Treatment included combination antibiotic therapy and removal of the prosthesis. Weeks later she was started on teriparatide. Her elbow symptoms resolved. In our experience, this is the first case in the literature reporting teriparatide efficacy in the treatment of septic arthritis. PMID- 25739847 TI - A qualitative analysis of methotrexate self-injection education videos on YouTube. AB - The aim of this study is to identify and evaluate the quality of videos for patients available on YouTube for learning to self-administer subcutaneous methotrexate. Using the search term "Methotrexate injection," two clinical reviewers analyzed the first 60 videos on YouTube. Source and search rank of video, audience interaction, video duration, and time since video was uploaded on YouTube were recorded. Videos were classified as useful, misleading, or a personal patient view. Videos were rated for reliability, comprehensiveness, and global quality scale (GQS). Reasons for misleading videos were documented, and patient videos were documented as being either positive or negative towards methotrexate (MTX) injection. Fifty-one English videos overlapped between the two geographic locations; 10 videos were classified as useful (19.6 %), 14 misleading (27.5 %), and 27 personal patient view (52.9 %). Total views of videos were 161,028: 19.2 % useful, 72.8 % patient, and 8.0 % misleading. Mean GQS: 4.2 (+/ 1.0) useful, 1.6 (+/-1.1) misleading, and 2.0 (+/-0.9) for patient videos (p < 0.0001). Mean reliability: 3.3 (+/-0.6) useful, 0.9 (+/-1.2) misleading, and 1.0 (+/-0.7) for patient videos (p < 0.0001). Comprehensiveness: 2.2 (+/-1.9) useful, 0.1 (+/-0.3) misleading, and 1.5 (+/-1.5) for patient view videos (p = 0.0027). This study demonstrates a minority of videos are useful for teaching MTX injection. Further, video quality does not correlate with video views. While web video may be an additional educational tool available, clinicians need to be familiar with specific resources to help guide and educate their patients to ensure best outcomes. PMID- 25739848 TI - Modelling of reversible single chain polymer self-assembly: from the polymer towards the protein limit. AB - The thermodynamic properties of reversible single chain polymer self-assembly are characterized by all-atom simulations. The ensemble of closed chains collapses from multiple conformations for long chains to nearly unique conformations for shorter chains, suggesting that the engineered polymers can fold into stable unique conformations at moderate temperatures. PMID- 25739849 TI - Cross-Disciplinary Biomarkers Research: Lessons Learned by the CKD Biomarkers Consortium. AB - Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays. PMID- 25739850 TI - How the ESRD quality incentive program could potentially improve quality of life for patients on dialysis. AB - For over 20 years, the quality of medical care of the Medicare ESRD Program has been a concern. The Centers for Medicare and Medicaid Services have implemented the ESRD Quality Incentive Program, which uses the principles of value-based purchasing; dialysis providers are paid for performance on predefined quality measures, with a goal of improving patient outcomes and the quality of patient care. The ESRD Quality Incentive Program measures have been criticized, because they are largely disease oriented and use easy-to-obtain laboratory-based indicators, such as Kt/V and hemoglobin, that do not reflect outcomes that are most important to patients and have had a minimal effect on survival or quality of life. A key goal of improving quality of care is to enhance quality of life, a patient-important quality measure that matters more to many patients than even survival. None of the ESRD Quality Incentive Program measures assess patient reported quality of life. As outlined in the National Quality Strategy, the Centers for Medicare and Medicaid Services are holding providers accountable in six priority domains, in which quality measures have been and are being developed for value-based purchasing. Three measures-patient experience and engagement, clinical care, and care coordination-are particularly relevant to quality care in the ESRD Program; the 2014 ESRD Quality Incentive Program includes six measures, none of which provide data from a patient-centered perspective. Value-based purchasing is a well intentioned step to improve care of patients on dialysis. However, the Centers for Medicare and Medicaid Services need to implement significant change in what is measured for the ESRD Quality Incentive Program to be patient centered and aligned with patients' values, preferences, and needs. This paper provides examples of potential quality measures for patient experience and engagement, clinical care, and care coordination, which if implemented, would be much more likely to enhance quality of life for patients with ESRD than present ESRD Quality Incentive Program measures. PMID- 25739851 TI - Frailty and mortality in dialysis: evaluation of a clinical frailty scale. AB - BACKGROUND AND OBJECTIVES: Frailty is associated with poor outcomes for patients on dialysis; however, previous studies have not taken into account the severity of frailty as a predictor of outcomes. The purpose of this study was to assess if there was an association between the degree of frailty and mortality among patients on incident dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort study of incident chronic dialysis patients was conducted between January of 2009 and June of 2013 (last follow-up in December of 2013). On the basis of overall clinical impression, the Clinical Frailty Scale (CFS) score was determined for patients at the start of dialysis by their primary nephrologist. This simple scale allocates a single point to different states of frailty (1, very fit; 2, well; 3, managing well; 4, vulnerable; 5, mildly frail; 6, moderately frail; 7, severely frail or terminally ill) with an emphasis on function of the assessed individual. The primary outcome was time to death. Patients were censored at the time of transplantation. RESULTS: The cohort consisted of 390 patients with completed CFS scores (mean age of 63+/-15 years old). Most were Caucasian (89%) and men (67%), and 30% of patients had ESRD caused by diabetic nephropathy. The median Charlson Comorbidity Index score was 4 (interquartile range =3-6), and the median CFS score was 4 (interquartile range =2-5). There were 96 deaths over 750 patient-years at risk. In an adjusted Cox survival analysis, the hazard ratio associated with each 1-point increase in the CFS was 1.22 (95% confidence interval, 1.04 to 1.43; P=0.02). CONCLUSIONS: A higher severity of frailty (as defined by the CFS) at dialysis initiation is associated with higher mortality. PMID- 25739852 TI - Echocardiographic epicardial fat thickness is associated with coronary artery calcification - results from the CAESAR study. AB - BACKGROUND: Few studies have addressed the relationship between echocardiographic epicardial fat thickness (EFT) and coronary artery calcification in an apparently healthy Asian population, and those that have, are inconsistent. METHODS AND RESULTS: A total of 2,299 individuals (1,871 men; mean age, 45+/-8.9 years) were enrolled in the CArdiometabolic risk, Epicardial fat, and Subclinical Atherosclerosis Registry (CAESAR) study and underwent CT for measurement of coronary artery calcium score (CACS) and echocardiography for EFT. According to EFT quartiles, the prevalence of CAC >0 was 8.3%, 16.8%, 24.6%, and 28.3% in the lowest, second, third, and highest EFT quartiles, respectively (P<0.001). On multivariate logistic regression after adjusting for variables with a univariate relationship (P<0.05), the second, third, and highest quartile groups of EFT had higher odds ratios (OR) for the presence of CAC compared with those of the lowest quartile (OR, 1.634; 95% confidence interval (CI): 0.940-2.839; 1.762, 1.019 3.048; and 1.924, 1.107-3.342, respectively), and the increase in absolute EFT was also independently associated with higher OR for the presence of CAC (1.842; 95% CI: 1.057-3.208, P=0.031). Moreover, increasing absolute EFT was associated with increasing CACS on multivariate linear regression (standardized beta=0.081, P=0.005). CONCLUSIONS: There was an independent relationship between EFT and coronary artery calcification in Korean adults, suggesting that echocardiographic EFT might be an easily accessible tool for early detection of subclinical coronary atherosclerosis. PMID- 25739853 TI - The anatomic distribution of malignant and premalignant glottic lesions and its relations to smoking. AB - OBJECTIVE: To describe the anatomic location and distribution of glottic dysplasia and early glottic cancer. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care referral center. SUBJECTS AND METHODS: Review of 167 glottic dysplasia or carcinoma patients between 2008 and 2013. Lesions were described in terms of location and size, and a novel grid system was used to map out anatomic distribution. RESULTS: Seventy-eight patients with dysplasia and 89 with early glottic carcinoma were included. One hundred twenty-eight were smokers and 39 nonsmokers. The medial aspect of the vocal fold was more involved than the superior aspect, 95% versus 71%, respectively (P < .001). The superior aspect was more involved in smokers, 77% versus 51% in nonsmokers (P = .0016). Using a grid system, the most involved area was the midpoint of the membranous vocal fold at the transition between the superior and medial aspects. Ninety-seven percent of the lesions occupied this specific area, with no difference between smokers and nonsmokers. The vocal process mucosa was involved in 48 patients. Exclusive vocal process involvement was limited to 2 cases. All other 46 patients demonstrated extensive disease, encompassing more than half of the vocal fold's length. Carcinomatous lesions tended to be larger relative to dysplastic lesions. Otherwise, all lesion types showed a similar pattern of distribution. CONCLUSIONS: Premalignant and malignant glottic lesions tend to involve the medial aspect of the vocal fold and the midpoint of the membranous part in particular. In smokers, lesions tend to be larger on presentation and are more likely to involve the superior aspect. PMID- 25739854 TI - Management patterns and predictors of mortality among US patients with cancer hospitalized for malignant bowel obstruction. AB - BACKGROUND: Malignant bowel obstruction affects an estimated 3% to 15% of patients with cancer, with a mean survival of <4 weeks reported in patients with inoperable malignant bowel obstruction. In the current study, the authors assessed predictors of survival and the influence of treatment modality in US patients with cancer who were hospitalized for malignant bowel obstruction. METHODS: All the US cancer patients hospitalized with malignant bowel obstruction in 2006 and 2010 were included. Data were obtained from the Nationwide Inpatient Sample provided by the Agency for Healthcare Research and Quality. Malignant bowel obstruction diagnoses and treatment variables were identified using Clinical Classifications Software codes based on International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. Univariate and multivariate analyses were performed with a logistic model, weighted chi-square test, and a generalized linear model. RESULTS: The authors identified 942,014 and 1,103,528 hospitalizations for malignant bowel obstruction in 2006 and 2010, respectively. Medical management, upper gastrointestinal obstruction, health insurance coverage, and obesity were found to be significantly associated with better hospital survival. Multivariate analysis also demonstrated significantly increased odds of death with male sex, advanced age, AJCC stage IV disease, multiple comorbid conditions (except acquired immunodeficiency syndrome), and weight loss. There were no significant differences with stratification based on the location and etiology of the obstruction (primary tumor vs metastatic). CONCLUSIONS: Malignant bowel obstruction is a common cause of death in hospitalized patients with advanced cancer in the United States. The odds of death are especially high in older patients and those with concurrent medical illnesses. Lack of insurance coverage, significant weight loss, and surgical management also appear to be associated with higher mortality in this population. PMID- 25739855 TI - Microtubules dual chemo and thermo-responsive depolymerization. AB - The effects of chemotherapeutic agent vinblastine versus low temperature of 277 K were investigated on the structure of alphabeta-tubulin heterodimer by means of molecular dynamics simulations. Individual experiments have shown that the vinblastine-bound heterodimer, and its apo structure under low temperature of 277 K, both undergo conformational changes toward destabilization of the dimer as compared to the apo tubulin at 300 K. Both factors exhibited weakening of the longitudinal interactions of tubulin heterodimer through displacing dimer interfacial segments, resulting in dominant electrostatic repulsion at the interface of the subunits. The two independent factors of temperature and anti mitotic agent facilitate alteration of secondary structure in functional segments such as H1-S2 loop, H3, H10 helices, and T7 loop, which are known to be important in either longitudinal or lateral contacts among alphabeta-heterodimers in MTs protofilaments and their depolymerization mechanism. PMID- 25739856 TI - Nationwide distribution of cardiovascular practice in Japan - results of Japanese circulation society 2010 annual survey. AB - BACKGROUND: The geographic distribution of cardiovascular (CV) health-care services has not been assessed systematically. METHODS AND RESULTS: Data of the Japanese Circulation Society (JCS) annual survey were provided to the JCS working group with the permission of the JCS Scientific Committee. The status of CV practice in 2010 was then assessed in 47 prefectures retrospectively, along with national census and gross domestic product (GDP) data. The surveyed indices included resources (hospitals, beds and cardiologists), burden (number of inpatients), and outcome (CV mortality and autopsy) in each prefecture, which correlated well with respective populations or GDP. Inequality of geographic distribution was evident for pediatrics among the 47 prefectures, according to Lorenz curve, Gini coefficient or the maximum/minimum ratio for each index. According to the Gini coefficients, only the number of inpatients (medical or acute myocardial infarction) and beds for the total number of general hospitals or the hospitals surveyed in the present JCS study were lower than expected with regard to GDP. CONCLUSIONS: Geographic disparity of CV resources or burden was larger in pediatrics than in CV medicine or surgery. Improvement of equality in CV practice with regard to appropriateness and quality are the coming challenges for the JCS. PMID- 25739857 TI - Glycemic Variability Determined by Continuous Glucose Monitoring System Predicts Left Ventricular Remodeling in Patients With a First ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Impaired glucose metabolism plays an important role in patients with acute myocardial infarction, but the clinical significance of glycemic variability (GV) early after the onset of ST-segment elevation myocardial infarction (STEMI) remains to be fully elucidated. METHODS AND RESULTS: We prospectively investigated the clinical impact of GV, as determined by a continuous glucose monitoring system (CGMS), on left ventricular remodeling (LVR) assessed by cardiac magnetic resonance imaging (CMR) in 69 patients (63+/-13 years, 59 men) with a first reperfused STEMI within 12 h of onset. All patients were equipped with a CGMS when in a stable phase after admission and underwent repeat CMR at baseline and 7 months follow-up. Patients were divided into 2 groups according to the mean amplitude of glycemic excursions (MAGE). Patients in the upper tertile of MAGE were categorized as group High (H) and the other two thirds as group Low (L). LVR was defined as an absolute increase in left ventricular end-diastolic volume index of >=20%. LVR more frequently occurred in group H than in group L (56% vs. 11%, P<0.001). Multivariate analysis showed the higher MAGE group was an independent predictor of LVR in the chronic phase (odds ratio, 13.999; 95% confidence interval, 3.059 to 64.056; P=0.001). CONCLUSIONS: MAGE early after the onset of STEMI identified patients with LVR in the chronic phase. PMID- 25739858 TI - Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia. AB - BACKGROUND: Uric acid (UA) serves as an antioxidant in vascular endothelial cells. UA transporter 1 (URAT1) encoded by SLC22A12 is expressed in the kidney and vessels and its loss of function causes hypouricemia. The purpose of this study was to examine whether there is any endothelial dysfunction in patients with hypouricemia. METHODS AND RESULTS: Twenty-six patients with hypouricemia (<2.5 mg/dl) and 13 healthy control subjects were enrolled. Endothelial function was evaluated using flow-mediated dilation (FMD). mRNA of UA transporters expressed in cultured human umbilical endothelial cells (HUVEC) was detected on RT-PCR. There was a positive correlation between FMD and serum UA in the hypouricemia group. URAT1 loss-of-function mutations were found in the genome of 21 of 26 patients with hypouricemia, and not in the other 5. In the hypouricemia groups, serum UA in homozygous and compound heterozygous patients was significantly lower than in other groups, suggesting that severity of URAT1 dysfunction may influence the severity of hypouricemia. Thirteen of 16 hypouricemia subjects with homozygous and compound heterozygote mutations had SUA <0.8 mg/dl and their FMD was lower than in other groups. HUVEC do not express mRNA of URAT1, suggesting the null role of URAT1 in endothelial function. CONCLUSIONS: Depletion of UA due to SLC22A12/URAT1 loss-of-function mutations causes endothelial dysfunction in hypouricemia patients. PMID- 25739859 TI - QTc Interval Prolongation Predicts Arrhythmia Recurrence After Catheter Ablation of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy. AB - BACKGROUND: In hypertrophic cardiomyopathy (HCM) patients complicated with atrial fibrillation (AF), catheter ablation has been recommended as a treatment option. Meanwhile, prolongation of QTc interval has been linked to an increased AF incidence in the general population and to poor outcomes in HCM patients. However, whether QTc prolongation predicts arrhythmia recurrence after AF ablation in the HCM population remains unknown. METHODS AND RESULTS: Thirty-nine HCM patients undergoing primary AF ablation were enrolled. The ablation strategy included bilateral pulmonary vein isolation (PVI) for paroxysmal AF (n=27) and PVI plus left atrial roof, mitral isthmus and tricuspid isthmus linear ablations for persistent AF (n=12). Pre-procedural QTc was corrected by using the Bazett's formula. At a 14.8-month follow up, 23 patients experienced atrial tachyarrhythmia recurrence. Recurrent patients had longer QTc than non-recurrent patients (461.0+/-28.8 ms vs. 434.3+/-18.2 ms, P=0.002). QTc and left atrial diameter (LAD) were independent predictors of recurrence. The cut-off value of QTc 448 ms predicted arrhythmia recurrence with a sensitivity of 73.9% and a specificity of 81.2%. A combination of LAD and QTc (global chi-squared=13.209) was better than LAD alone (global chi-squared=6.888) or QTc alone (global chi squared=8.977) in predicting arrhythmia recurrence after AF ablation in HCM patients. CONCLUSIONS: QTc prolongation is an independent predictor of arrhythmia recurrence in HCM patients undergoing AF ablation, and might be useful for identifying those patients likely to have a better outcome following the procedure. PMID- 25739860 TI - Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering. AB - INTRODUCTION: Bisphosphonates (BPs) were introduced 45 years ago as anti osteoporotic drugs and during the last decade have been utilized as bone targeting groups in systemic treatment of bone diseases. Very recently, strategies of chemical immobilization of BPs in hydrogels and nanocomposites for bone tissue engineering emerged. These strategies opened new applications of BPs in bone tissue engineering. AREAS COVERED: Conjugates of BPs to different drug molecules, imaging agents, proteins and polymers are discussed in terms of specific targeting to bone and therapeutic affect induced by the resulting prodrugs in comparison with the parent drugs. Conversion of these conjugates into hydrogel scaffolds is also presented along with the application of the resulting materials for bone tissue engineering. EXPERT OPINION: Calcium-binding properties of BPs can be successfully extended via different conjugation strategies not only for purposes of bone targeting, but also in supramolecular assembly affording either new nanocarriers or bulk nanocomposite scaffolds. Interaction between carrier-linked BPs and drug molecules should also be considered for the control of release of these molecules and their optimized delivery. Bone-targeting properties of BP-functionalized nanomaterials should correspond to bone adhesive properties of their bulk analogs. PMID- 25739861 TI - Let-7-mediated suppression of mucin 1 expression in the mouse uterus during embryo implantation. AB - Mucin 1 (Muc1) is an integral transmembrane mucin glycoprotein expressed on the apical surface of most epithelia. It is considered to be a barrier to the regulation of embryo implantation by inhibiting attachment of the embryo to the endometrium. Therefore, loss of Muc1 on the surface of uterine epithelial cells is necessary for embryo implantation. Studies have demonstrated that microRNAs (miRNAs) play a key role in enhancing embryo implantation in mammals. In this study, we investigated the regulatory role of two miRNAs (let-7a and let-7b) on the expression of Muc1 in mouse uteri during implantation. Western blotting indicated that Muc1 expression was highest on day1 of pregnancy and constantly decreased thereafter until day 4. In contrast to Muc1 expression, increased expression of let-7a and let-7b was evident on day 4 of pregnancy as measured by real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). We demonstrated direct binding of let-7a and let-7b to the 3'untranslated region of muc1. Furthermore, Muc1 expression was suppressed after transfection of mouse uterine epithelial cells isolated from day 1 of pregnancy with let-7a and let-7b. In summary, the present study provides evidence that Muc1 is a direct target of let-7a and let-7b. Additionally, the current study suggests that miRNAs are novel targets which can be used to facilitate a successful pregnancy and repair implantation failure. PMID- 25739864 TI - Optically switchable transistors by simple incorporation of photochromic systems into small-molecule semiconducting matrices. AB - The fabrication of multifunctional high-performance organic thin-film transistors as key elements in future logic circuits is a major research challenge. Here we demonstrate that a photoresponsive bi-functional field-effect transistor with carrier mobilities exceeding 0.2 cm(2) V(-1) s(-1) can be developed by incorporating photochromic molecules into an organic semiconductor matrix via a single-step solution processing deposition of a two components blend. Tuning the interactions between the photochromic diarylethene system and the organic semiconductor is achieved via ad-hoc side functionalization of the diarylethene. Thereby, a large-scale phase-segregation can be avoided and superior miscibility is provided, while retaining optimal pi-pi stacking to warrant efficient charge transport and to attenuate the effect of photoinduced switching on the extent of current modulation. This leads to enhanced electrical performance of transistors incorporating small conjugated molecules as compared with polymeric semiconductors. These findings are of interest for the development of high performing optically gated electronic devices. PMID- 25739866 TI - Planar tetracoordinate carbons with a double bond in CAl3E clusters. AB - The potential energy surfaces of a series of clusters with the formula CAl3E (E = P, As, Sb, Bi) are systematically explored using density functional theory and high level ab initio calculations. The global minimum structure of these clusters contains a planar tetracoordinate carbon atom. The presence of a C=E double bond is supported by the Wiberg bond indices, the adaptive natural density partitioning analysis, and the magnetic response. Our results show that these planar tetracoordinate carbon clusters are both thermodynamically and kinetically viable species in the gas phase. PMID- 25739862 TI - Physical activity and survival among Hispanic and non-Hispanic white long-term breast cancer survivors and population-based controls. AB - PURPOSE: We investigated the association of physical activity with survival for 601 Hispanic women and 682 non-Hispanic white women who participated in the population-based breast cancer case-control New Mexico Women's Health Study. METHODS: We identified 240 deaths among cases diagnosed with a first primary invasive breast cancer between 1992 and 1994, and 88 deaths among controls. Follow-up extended through 2012 for cases and 2008 for controls. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. RESULTS: Higher levels of total physical activity were inversely associated with all-cause mortality among Hispanic cases (Quartile (Q)4: HR = 0.55, 95% CI 0.31-0.99). A non-significant trend was observed for recreational activity in Hispanic cases also (Q4: HR = 0.50, 95% CI 0.23-1.09, p for trend = 0.08). No significant associations were noted for non Hispanic white cases or for controls. CONCLUSIONS: The results suggest that increasing physical activity may be protective against mortality in Hispanic women with breast cancer, despite reporting lower levels of recreational activity than non-Hispanic white women or Hispanic controls. IMPLICATIONS FOR CANCER SURVIVORS: Public health programs in Hispanic communities should promote physical activity in women as a means of decreasing breast cancer risk and improving survival. PMID- 25739865 TI - Indications for cardiovascular magnetic resonance in children with congenital and acquired heart disease: an expert consensus paper of the Imaging Working Group of the AEPC and the Cardiovascular Magnetic Resonance Section of the EACVI. AB - This article provides expert opinion on the use of cardiovascular magnetic resonance (CMR) in young patients with congenital heart disease (CHD) and in specific clinical situations. As peculiar challenges apply to imaging children, paediatric aspects are repeatedly discussed. The first section of the paper addresses settings and techniques, including the basic sequences used in paediatric CMR, safety, and sedation. In the second section, the indication, application, and clinical relevance of CMR in the most frequent CHD are discussed in detail. In the current era of multimodality imaging, the strengths of CMR are compared with other imaging modalities. At the end of each chapter, a brief summary with expert consensus key points is provided. The recommendations provided are strongly clinically oriented. The paper addresses not only imagers performing CMR, but also clinical cardiologists who want to know which information can be obtained by CMR and how to integrate it in clinical decision making. PMID- 25739867 TI - Clinical observation on hearing conditions of centenarians in northern district of China. AB - CONCLUSION: The hearing conditions of the centenarians were quite poor as regards hearing thresholds and speech detection ability. OBJECTIVE: To investigate hearing conditions of centenarians. METHODS: A total of 54 centenarians in Rizhao and Linyi Districts in Shandong Province were investigated to assess hearing conditions of centenerians comprehensively by questionnaire investigation, pure tone audiometry, acoustic immitance, intelligence evaluation, and speech detection scores. Also, 135 individuals were recruited as controls and divided into four groups according to their age: 45-59 years, 60-69 years, 70-79 years, and 80-89 years. RESULTS: The hearing thresholds of the centenarians were dramatically higher than those of the control group (p < 0.05) and all centenarians suffered moderate to profound hearing loss according to the World Health Organization (WHO) criteria. Few centenarians had normal level of speech detection scores. All centenarians showed descending hearing curve, and the hearing threshold of the male centenarians at 8000 Hz was higher than that of the females (p = 0.047). There was a significant air-bone conduction gap in the centenarians (p < 0.05). PMID- 25739868 TI - Merits of collaboration between industry and academia. PMID- 25739869 TI - EGF Suppresses the Initiation and Drives the Reversion of TGF-beta1-induced Transition in Hepatic Oval Cells Showing the Plasticity of Progenitor Cells. AB - Transforming growth factor-beta1 (TGF-beta1) induces hepatic progenitors to tumor initiating cells through epithelial-mesenchymal transition (EMT), thus raising an important drawback for stem cell-based therapy. How to block and reverse TGF beta1-induced transition is crucial for progenitors' clinical application and carcinogenic prevention. Rat adult hepatic progenitors, hepatic oval cells, experienced E-cadherin to N-cadherin switch and changed to alpha-smooth muscle actin (alpha-SMA) positive cells after TGF-beta1 incubation, indicating EMT. When TGF-beta1 plus EGF were co-administrated to these cells, EGF dose-dependently suppressed the cadherin switch and alpha-SMA expression. Interestingly, if EGF was applied to TGF-beta1-pretreated cells, the cells that have experienced EMT could return to their epithelial phenotype. Abruption of EGF receptor revealed that EGF exerted its blockage and reversal effects through phosphorylation of ERK1/2 and Akt. These findings suggest an important attribute of EGF on opposing and reversing TGF-beta1 effects, indicating the plasticity of hepatic progenitors. PMID- 25739870 TI - Substitution of tryptophan 89 with tyrosine switches the DNA binding mode of PC4. AB - PC4, a well-known general transcription cofactor, has multiple functions in transcription and DNA repair. Residue W89, is engaged in stacking interactions with DNA in PC4, but substituted by tyrosine in some PC4 orthologous proteins. In order to understand the consequences and reveal the molecular details of this substitution we have determined the crystal structures of the PC4 orthologue MoSub1 and a PC4 W89Y mutant in complex with DNA. In the structure of MoSub1-DNA complex, Y74 interacts directly with a single nucleotide of oligo DNA. By comparison, the equivalent residue, W89 in wild type PC4 interacts with two nucleotides and the base of the second nucleotide has distinct orientation relative to that of the first one. A hydrophobic patch around W89 that favours interaction with two nucleotides is not formed in the PC4 W89Y mutant. Therefore, the change of the surface hydrophobicity around residue 89 results in a difference between the modes of DNA interaction. These results indicate that the conserved Y74 in MoSub1 or W89 in PC4, are not only key residues in making specific interactions with DNA but also required to determine the DNA binding mode of PC4 proteins. PMID- 25739871 TI - The association between religiosity and resuscitation status preference among patients with advanced cancer. AB - OBJECTIVE: The potential influence of patient religious and spiritual beliefs on the approach to end-of-life care and resuscitation status preferences is not well understood. The aim of this study was to assess the association between religiosity and resuscitation preferences in advanced-cancer patients. METHOD: We performed a secondary analysis of a randomized controlled trial that evaluated the influence of physician communication style on patient resuscitation preferences. All patients completed the Santa Clara Strength of Religious Faith Questionnaire-Short Form (SCSRFQ-SF) and expressed their resuscitation preferences. We determined the frequency of resuscitation preferences and its association with intensity of religiosity. RESULTS: A total of 78 patients completed the study. The median age was 54 years, with a range of 18-78. Some 46 (59%) were women; 57 patients (73%) were Caucasian, 15 (19%) African American, and 5 (7%) Hispanic. A total of 46 patients (56%) were Protestant and 13 (17%) Catholic. Some 53 of 60 patients who chose Do Not Resuscitate status (DNR) (88%) and 16 of 18 patients who refused DNR (89%) for a video-simulated patient were highly religious (p = 0.64). When asked about a DNR for themselves after watching the videos, 43 of 48 who refused DNR (90%) and 26 of 30 patients who chose DNR (87%) were highly religious (p = 0.08). The Spearman correlation coefficient for patients choosing DNR for themselves and intensity of religiosity was r = -0.16 (p = 0.16). Some 30 patients (38%) who chose DNR for the video patient refused DNR for themselves, and 42 who chose DNR for both the video patient and themselves (54%) were highly religious (p = NS). SIGNIFICANCE OF RESULTS: There was no significant association between intensity of patient religiosity and DNR preference for either the video patient or the patients themselves. Other beliefs and demographic factors likely impact end-of-life discussions and resuscitation status preferences. PMID- 25739872 TI - Childhood interstitial lung disease: Family experiences. AB - AIMS: To present experiences of UK families of children diagnosed with ILD, to inform clinical practice and service development. METHODS: Thirty seven such families completed an anonymous web-based survey between February and March 2014. RESULTS: Median time from first symptoms to diagnosis was 25 weeks. Most reported that they were happy with the overall management of their child. Areas highlighted for development included improved communication especially the need for written information; psychological support (91% reported anxiety). Feeding issues (not described in current literature) were reported by 77% and persisted in 35%. Other requests included better written communication between hospitals with training for smaller hospitals, and improved specialist nurse support for children with ILD. CONCLUSIONS: These family perspectives need to be addressed by professionals looking after these children as well as when planning of future services. PMID- 25739873 TI - Characterization of the major bacterial-fungal populations colonizing dandruff scalps in Shanghai, China, shows microbial disequilibrium. AB - Dandruff is a scalp disorder characterized by the formation of flaky white yellowish scales due to an altered proliferation and differentiation status; a disrupted barrier function; a decrease in the level of hydration and of natural moisturizing factors (NMF) in the scalp, with a persistent and relapsing inflammatory condition. It was recently reported that an imbalance between bacterial and fungal species colonizing the scalp of French volunteers was associated with dandruff condition. The purpose of the present study was to analyze the major bacterial and fungal species present on the scalp surface of Chinese volunteers and to investigate possible region-related variation in the microbiota linked to dandruff condition. The data obtained from the Chinese populations were highly similar to those obtained in France, confirming that dandruff scalps are associated with a higher incidence of Malassezia restricta and Staphylococcal sp. The ratios of Malassezia to Propionibacterium and Propionibacterium to Staphylococcus were also significantly higher in the dandruff volunteers as compared to normal volunteers, suggesting that equilibrium between the major bacterial and fungal taxa found on the normal scalps is perturbed in the dandruff scalps. The main difference between the French and Shanghai subjects was in their Staphylococcal biota. The results obtained in China and in France suggest that targeting one particular Malassezia sp. by antifungals instead of using large spectrum antifungals and rebalancing the dandruff scalp microbiota could be common approach to improve dandruff condition in the two countries. PMID- 25739874 TI - Erratum: Flow damping due to stochastization of the magnetic field. PMID- 25739875 TI - Reconstruction of random heterogeneous media. AB - Stochastic reconstruction is a technique to generate samples of random structures with prescribed distributional properties in the sense that certain of their statistical summary characteristics match target values or forms. This technique can be used to produce structures of any wanted size for further statistical analysis starting from small samples, which may be even only lower dimensional, for instance, when three-dimensional imaging techniques are not available. In this review we explain the main ideas of stochastic reconstruction, concentrating on the most important case of digitized binary media and with a particular emphasis on stereological reconstruction. PMID- 25739876 TI - Post-dural puncture headaches following spinal drain placement during thoracoabdominal aortic aneurysm repair: incidence, associated risk factors, and treatment. AB - PURPOSE: Spinal drains are used as a neuroprotective measure during thoracoabdominal aortic aneurysm (TAA) repair. Unfortunately, these drains can cause post-dural puncture headaches (PDPH). While PDPH following spinal anesthesia have been thoroughly evaluated, limited data exists about the incidence and risk factors for PDPH following spinal drains. Additionally, the efficacy of treatment with conservative therapies and epidural blood patches (EBP) for PDPH secondary to spinal drains has not been well documented. METHODS: Data on 235 patients receiving spinal drains for scheduled TAA repair and surviving to discharge between January, 2005 and July, 2012 at the University of Wisconsin Hospitals and Clinics were retrospectively reviewed. The following data were extracted from the patient medical record: patient demographics, pre existing medical conditions, spinal drain details, PDPH presentation, PDPH treatment methods, and success of treatments used. This data was then analyzed for statistical significance. RESULTS: Of 235 patients, 43 (18.3 %) developed PDPH. Younger age (p < 0.001) and history of preoperative headache (p <= 0.001) were found to increase the risk of PDPH. Use of EBP, either as the primary treatment, or following failed conservative therapy, was found to be a more effective treatment for PDPH than conservative therapies alone (p = 0.017). CONCLUSIONS: Spinal drain placement carries a risk of PDPH, as supported by an 18.3 % PDPH incidence in this study. Younger patients and/or patients with a history of chronic headache are at elevated risk for PDPH. Treatment using EBP, either as primary therapy or following unsuccessful conservative therapies, is a significantly more effective treatment than conservative therapies alone. PMID- 25739877 TI - Fighting back against chikungunya. PMID- 25739878 TI - Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active comparator, first-in-man trial. AB - BACKGROUND: Chikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus based chikungunya vaccine. METHODS: We did a randomised, double-blind, placebo controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18-45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1.5 * 10(4) median tissue culture infection doses (TCID50) per 0.05 mL], medium dose [7.5 * 10(4) TCID50 per 0.25 mL], or high dose [3.0 * 10(5) TCID50 per 1.0 mL]), or the active comparator-Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23. FINDINGS: Between Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded. INTERPRETATION: The live recombinant measles-virus based chikungunya vaccine had good immunogenicity, even in the presence of anti vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings. FUNDING: Themis Bioscience GmBH. PMID- 25739879 TI - HIV testing in re-education through labour camps in Guangxi Autonomous Region, China (a cross-sectional survey). AB - OBJECTIVE: HIV testing is mandatory in re-education-through-labour camps (laojiaosuo) in China yet no studies have reported on the process. METHODS: The survey response rate was 100% although 29 detainees were excluded because they were under 18 years of age. A cross-sectional face-to-face survey was conducted in three labour camps in Guangxi, located in the south-western region of China. RESULTS: Of the 755 detainees surveyed, 725 (96%) reported having a blood test in the labour camps of whom 493 (68%) thought this included an HIV test. 61 detainees self-reported they were HIV infected, their status confirmed by medical records, if available. Of these, 53 (87%) recalled receiving post-test HIV education, and 15 (25%) were currently receiving HIV antiretroviral therapy. Pretest education on HIV was provided to 233/725 (32%) detainees. The study further reports on detainees' reactions and feelings towards non-disclosure and disclosure of their HIV test results in the labour camps. CONCLUSIONS: Mandatory testing is almost universal in the labour camps although a proportion of detainees were unaware that this included an HIV test. HIV test results should be disclosed to all labour camp detainees to reduce their distress of not knowing and prevent misconceptions about their HIV status. Labour camps provide another opportunity to implement universal treatment ('Test and Treat') to prevent the spread of HIV. PMID- 25739880 TI - Diagnosis and management of depression in children and young people: summary of updated NICE guidance. PMID- 25739881 TI - Activation of the JAK/STAT pathway in Behcet's disease. PMID- 25739882 TI - Clinical characteristics, management, and outcomes of acute heart failure patients: observations from the Gulf acute heart failure registry (Gulf CARE). AB - AIMS: The purpose of this study was to describe the clinical characteristics, management, and outcomes of acute heart failure (HF) patients from the Gulf acute heart failure registry (Gulf CARE). METHODS AND RESULTS: Data from 5005 HF patients admitted to 47 hospitals in seven Gulf countries during February to November 2012 were analysed. Fifty-five per cent of patients presented with acute decompensated chronic HF, while 45% had new-onset HF. Mean age was 59 +/- 15 years, 63% were males, and 83% were Gulf citizens. Co-morbid conditions were hypertension (61%), diabetes mellitus (50%), CAD (47%), and atrial fibrillation or flutter (14%). The median LVEF was 35% (25-45%) with 69% presenting as HF with reduced EF (HFrEF). CAD was the most prevalent aetiology (53%) followed by idiopathic cardiomyopathy (18%), hypertensive heart disease (16%), and valvular heart disease (9%). At discharge, 71% and 78% of patients received beta-blockers and ACE inhibitors/ARBs, respectively. Use of coronary intervention and device therapy was <10%. In-hospital mortality was 6.3%. Re-hospitalization and cumulative mortality at 3 and 12 months were 18%/13% and 40%/20%, respectively. CONCLUSIONS: Gulf CARE results show that patients from this region are a decade younger than their Western counterparts, with a high prevalence of diabetes and HFrEF, and a lower prevalence of AF. Use of coronary intervention and device therapy was low, with high re-hospitalization rates. Short- and long-term mortality rates were similar to those of Western registries, but should be interpreted in the light of the younger age of Gulf CARE patients. PMID- 25739884 TI - Assessment of a fully 3D Monte Carlo reconstruction method for preclinical PET with iodine-124. AB - Iodine-124 is a radionuclide well suited to the labeling of intact monoclonal antibodies. Yet, accurate quantification in preclinical imaging with I-124 is challenging due to the large positron range and a complex decay scheme including high-energy gammas. The aim of this work was to assess the quantitative performance of a fully 3D Monte Carlo (MC) reconstruction for preclinical I-124 PET. The high-resolution small animal PET Inveon (Siemens) was simulated using GATE 6.1. Three system matrices (SM) of different complexity were calculated in addition to a Siddon-based ray tracing approach for comparison purpose. Each system matrix accounted for a more or less complete description of the physics processes both in the scanned object and in the PET scanner. One homogeneous water phantom and three heterogeneous phantoms including water, lungs and bones were simulated, where hot and cold regions were used to assess activity recovery as well as the trade-off between contrast recovery and noise in different regions. The benefit of accounting for scatter, attenuation, positron range and spurious coincidences occurring in the object when calculating the system matrix used to reconstruct I-124 PET images was highlighted. We found that the use of an MC SM including a thorough modelling of the detector response and physical effects in a uniform water-equivalent phantom was efficient to get reasonable quantitative accuracy in homogeneous and heterogeneous phantoms. Modelling the phantom heterogeneities in the SM did not necessarily yield the most accurate estimate of the activity distribution, due to the high variance affecting many SM elements in the most sophisticated SM. PMID- 25739883 TI - Disparities in occupational injury hospitalization rates in five states (2003 2009). AB - BACKGROUND: Achievement of health equity and elimination of disparities are overarching goals of Healthy People 2020, yet there is a paucity of population based data regarding race/ethnicity-based disparities in occupational injuries. METHODS: Hospital discharge data for five states (Arizona, California, Florida, New Jersey, and New York) were obtained from the Healthcare Cost & Utilization Project (HCUP) for 2003-2009. Age-adjusted rates and trends for work-related injury hospitalizations were calculated using negative binomial regression (reference category: non-Latino white). RESULTS: Latinos were significantly more likely to have a work-related traumatic injury hospitalization. The disparity for Latinos was greatest for machinery-related hospitalizations. Latinos were also more likely to have a fall-related hospitalization. African-Americans were more likely to have an occupational assault-related hospitalization, but less likely to have a fall-related hospitalization. CONCLUSIONS: We found evidence of substantial multistate disparities in occupational injury-related hospitalizations. Enhanced surveillance and further research are needed to identify and address underlying causes. PMID- 25739885 TI - Consumer participation in nurse education: a national survey of Australian universities. AB - Consumers of mental health services have an important role to play in the higher education of nursing students, by facilitating understanding of the experience of mental illness and instilling a culture of consumer participation. Yet the level of consumer participation in mental health nursing programmes in Australia is not known. The aim of the present study was to scope the level and nature of involvement of consumers in mental health nursing higher education in Australia. A cross-sectional study was undertaken involving an internet survey of nurse academics who coordinate mental health nursing programmes in universities across Australia, representing 32 universities. Seventy-eight percent of preregistration and 75% of post-registration programmes report involving consumers. Programmes most commonly had one consumer (25%) and up to five. Face-to-face teaching, curriculum development, and membership-to-programme committees were the most regular types of involvement. The content was generally codeveloped by consumers and nurse academics (67.5%). The frequency of consumer involvement in the education of nursing students in Australia is surprisingly high. However, involvement is noticeably variable across types of activity (e.g. curriculum development, assessment), and tends to be minimal and ad hoc. Future research is required into the drivers of increased consumer involvement. PMID- 25739886 TI - Can indeterminate colitis cause colonic cancer in non-colitic colon? A case report. PMID- 25739887 TI - The relation between quality of life and histopathology in diverticulitis; can we predict specimen-related outcome? AB - PURPOSE: An important factor in the decision to perform laparoscopic sigmoid resection for patient suffering from recurrent and ongoing diverticulitis is quality of life (QoL). It is unknown whether quality of life relates to the severity of diverticulitis as seen in the resected colonic segment. The aim of this study is to analyze histopathological findings of patients suffering from recurrent or ongoing diverticulitis and their QoL before and after surgery in order to improve patient outcome prediction. METHODS: A cohort of consecutive patients with diverticulitis between January 2010 and April 2014 was analyzed. All patients were scheduled for surgery and had at least three episodes of diverticulitis or more within the last 2 years or experienced ongoing complaints for at least 3 months or more and confirmation by a radiologist. We compared QoL questionnaires, to known histopathological entities. RESULTS: For this study, 54 consecutive patients were included, 15 (27.8%) men and 39 (72.2%) women. A marked difference in quality of life before and after surgery for patients having a more severe histopathological entity was not found (p = 0.83). However, a clinically relevant higher VAS score 6 months after surgery was shown in patients with peritonitis. Furthermore, these patients had more fibrosis in the histopathological samples. CONCLUSION: In conclusion, even though a relation between the different pathological entities and QoL could not be determined, patients with diverticulitis and concomitant microscopic peritonitis had significantly more fibrosis and suffered from a higher VAS scores 6 months after surgery. PMID- 25739888 TI - Amelioration of titanium dioxide nanoparticles-induced liver injury in mice: possible role of some antioxidants. AB - This study investigates the efficacy of idebenone, carnosine and vitamin E in ameliorating some of the biochemical indices induced in the liver of titanium dioxide nanoparticles (TiO2 NPs) intoxicated mice. Nano-anatase TiO2 (21 nm) was administered (150 mg/kg/day) for 2 weeks followed by the aforementioned antioxidants either alone or in combination for 1 month. TiO2 NPs significantly increased serum liver function enzyme activities, liver coefficient and malondialdehyde levels in hepatic tissue. They also suppressed hepatic glutathione level and triggered an inflammatory response via the activation of macrophages and the enhancement of tumor necrosis factor-alpha and interleukin-6 levels. Moreover, the mRNA expression of nuclear factor-erythroid-2-related factor 2, nuclear factor kappa B and Bax was up-regulated whereas that of Bcl-2 was down-regulated following TiO2 NPs. Additionally, these NPs effectively activated caspase-3 and caused liver DNA damage. Oral administration of idebenone (200mg/kg), carnosine (200mg/kg) and vitamin E (100mg/kg) alleviated the hazards of TiO2 NPs with the combination regimen showing a relatively higher effect. The histopathological examination reinforced these findings. In conclusion, oxidative stress could be regarded as a key player in TiO2 NPs-induced liver injury. The study also highlights the anti-inflammatory and the anti-apoptotic potentials of these antioxidants against the detrimental effects of TiO2 NPs. PMID- 25739889 TI - Photoinduced modulation and relaxation characteristics in LaAlO3/SrTiO3 heterointerface. AB - We report the modulation and relaxation characteristics in the two-dimensional electron gas system at LaAlO3/SrTiO3 heterointerface induced by the ultraviolet light illumination (365 nm). The suppression of Kondo effect at the interface illuminated by the light originates from the light irradiation-induced decoherence effect of localized states. It is interesting to note that the persistent and transient photoinduced effects are simultaneously observed and the photoinduced maximum change values in resistance are 80.8% and 51.4% at T = 20 K, respectively. Moreover, the photoinduced relaxation processes after the irradiation are systematically analyzed using the double exponential model. These results provide the deeper understanding of the photoinduced effect and the experimental evidence of tunable Kondo effect in oxides-based two-dimensional electron gas systems. PMID- 25739890 TI - Electronic reorganization triggered by electron transfer: the intervalence charge transfer of a Fe3+/Fe2+ bimetallic complex. AB - The key role of the molecular orbitals in describing electron transfer processes is put in evidence for the intervalence charge transfer (IVCT) of a synthetic nonheme binuclear mixed-valence Fe(3+)/Fe(2+) compound. The electronic reorganization induced by the IVCT can be quantified by controlling the adaptation of the molecular orbitals to the charge transfer process. We evaluate the transition energy and its polarization effects on the molecular orbitals by means of ab initio calculations. The resulting energetic profile of the IVCT shows strong similarities to the Marcus' model, suggesting a response behaviour of the ensemble of electrons analogue to that of the solvent. We quantify the extent of the electronic reorganization induced by the IVCT process to be 11.74 eV, a very large effect that induces the crossing of states reducing the total energy of the transfer to 0.89 eV. PMID- 25739891 TI - Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice. AB - Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-kappaB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes. PMID- 25739892 TI - Synthesis and (spectro)electrochemistry of mixed-valent diferrocenyl dihydrothiopyran derivatives. AB - Three novel diferrocenyl complexes were prepared and characterised. 2,2 Diferrocenyl-4,5-dimethyl-3,6-dihydro-2H-thiopyran (1, sulphide) was accessible by the hetero-Diels-Alder reaction of diferrocenyl thioketone with 2,3-dimethyl 1,3-butadiene. Stepwise oxidation of 1 gave the respective oxides 2,2 diferrocenyl-4,5-dimethyl-3,6-dihydro-2H-thiopyran-1-oxide (2, sulfoxide) and 2,2 diferrocenyl-4,5-dimethyl-3,6-dihydro-2H-thiopyran-1,1-dioxide (3, sulfone), respectively. The molecular structures of 1 and 3 in the solid state were determined by single crystal X-ray crystallography. The oxidation of sulphide 1 to sulfone 3, plays only a minor role on the overall structure of the two compounds. Electrochemical (cyclic voltammetry (= CV), square wave voltammetry (= SWV)) and spectroelectrochemical (in situ UV-Vis/NIR spectroscopy) studies were carried out. The CV and SWV measurements showed that an increase of the sulphur atom oxidation from -2 in 1 to +2 in 3 causes an anodic shift of the ferrocenyl based oxidation potentials of about 100 mV. The electrochemical oxidation of 1-3 generates mixed-valent cations 1(+)-3(+). These monooxidised species display low energy electronic absorption bands between 1000 and 3000 nm assigned to IVCT (= Inter-Valence Charge Transfer) electronic transitions. Accordingly, the mixed valent cations 1(+)-3(+) are classified as weakly coupled class II systems according to Robin and Day. PMID- 25739893 TI - A meta-meta-analysis of the effect of physical activity on depression and anxiety in non-clinical adult populations. AB - Amidst strong efforts to promote the therapeutic benefits of physical activity for reducing depression and anxiety in clinical populations, little focus has been directed towards the mental health benefits of activity for non-clinical populations. The objective of this meta-meta-analysis was to systematically aggregate and quantify high-quality meta-analytic findings of the effects of physical activity on depression and anxiety for non-clinical populations. A systematic search identified eight meta-analytic outcomes of randomised trials that investigated the effects of physical activity on depression or anxiety. The subsequent meta-meta-analyses were based on a total of 92 studies with 4310 participants for the effect of physical activity on depression and 306 study effects with 10,755 participants for the effect of physical activity on anxiety. Physical activity reduced depression by a medium effect [standardised mean difference (SMD) = -0.50; 95% CI: -0.93 to -0.06] and anxiety by a small effect (SMD = -0.38; 95% CI: -0.66 to -0.11). Neither effect showed significant heterogeneity across meta-analyses. These findings represent a comprehensive body of high-quality evidence that physical activity reduces depression and anxiety in non-clinical populations. PMID- 25739895 TI - Catalytic, asymmetric, aldol/O-conjugate addition sequence for the construction of highly substituted furanoids. AB - A new method for the enantioselective synthesis of highly functionalized dihydrofurans has been developed. This process, related to the interrupted Feist Benary reaction, involves the reaction of 2-ene 1,4-diketones with dimedone in the presence of bis(cinchona alkaloid)pyrimidine catalysts to afford dihydrofuran products in excellent yields and high diastereo- and enantioselectivities. PMID- 25739894 TI - An efficient strategy for producing a stable, replaceable, highly efficient transgene expression system in silkworm, Bombyx mori. AB - We developed an efficient strategy that combines a method for the post integration elimination of all transposon sequences, a site-specific recombination system, and an optimized fibroin H-chain expression system to produce a stable, replaceable, highly efficient transgene expression system in the silkworm (Bombyx mori) that overcomes the disadvantages of random insertion and post-integration instability of transposons. Here, we generated four different transgenic silkworm strains, and of one the transgenic strains, designated TS1-RgG2, with up to 16% (w/w) of the target protein in the cocoons, was selected. The subsequent elimination of all the transposon sequences from TS1 RgG2 was completed by the heat-shock-induced expression of the transposase in vivo. The resulting transgenic silkworm strain was designated TS3-g2 and contained only the attP-flanked optimized fibroin H-chain expression cassette in its genome. A phiC31/att-system-based recombinase-mediated cassette exchange (RMCE) method could be used to integrate other genes of interest into the same genome locus between the attP sites in TS3-g2. Controlling for position effects with phiC31-mediated RMCE will also allow the optimization of exogenous protein expression and fine gene function analyses in the silkworm. The strategy developed here is also applicable to other lepidopteran insects, to improve the ecological safety of transgenic strains in biocontrol programs. PMID- 25739896 TI - Ergonomic task reduction prevents bone osteopenia in a rat model of upper extremity overuse. AB - We evaluated the effectiveness of ergonomic workload reduction of switching rats from a high repetition high force (HRHF) lever pulling task to a reduced force and reach rate task for preventing task-induced osteopenic changes in distal forelimb bones. Distal radius and ulna trabecular structure was examined in young adult rats performing one of three handle-pulling tasks for 12 wk: (1) HRHF, (2) low repetition low force (LRLF); or (3) HRHF for 4 wk and than LRLF thereafter (HRHF-to-LRLF). Results were compared to age-matched controls rats. Distal forelimb bones of 12-wk HRHF rats showed increased trabecular resorption and decreased volume, as control rats. HRHF-to-LRLF rats had similar trabecular bone quality as control rats; and decreased bone resorption (decreased trabecular bone volume and serum CTX1), increased bone formation (increased mineral apposition, bone formation rate, and serum osteocalcin), and decreased osteoclasts and inflammatory cytokines, than HRHF rats. Thus, an ergonomic intervention of HRHF to-LRLF prevented loss of trabecular bone volume occurring with prolonged performance of a repetitive upper extremity task. These findings support the idea of reduced workload as an effective approach to management of work-related musculoskeletal disorders, and begin to define reach rate and load level boundaries for such interventions. PMID- 25739898 TI - A consideration of the operation of automatic production machines. AB - At worksites, various automatic production machines are in use to release workers from muscular labor or labor in the detrimental environment. On the other hand, a large number of industrial accidents have been caused by automatic production machines. In view of this, this paper considers the operation of automatic production machines from the viewpoint of accident prevention, and points out two types of machine operation - operation for which quick performance is required (operation that is not permitted to be delayed) - and operation for which composed performance is required (operation that is not permitted to be performed in haste). These operations are distinguished by operation buttons of suitable colors and shapes. This paper shows that these characteristics are evaluated as "asymmetric on the time-axis". Here, in order for workers to accept the risk of automatic production machines, it is preconditioned in general that harm should be sufficiently small or avoidance of harm is easy. In this connection, this paper shows the possibility of facilitating the acceptance of the risk of automatic production machines by enhancing the asymmetric on the time-axis. PMID- 25739897 TI - Effects of vehicle-ride exposure on cervical pathology: a meta-analysis. AB - Research to date on the effect vehicle-ride exposure has on the development of cervical pathologies in mounted Warfighters is conflicting. The purpose of this study was to determine if the literature suggests a definite effect of vehicle ride exposure on cervical pathology. Databases were searched using multiple combinations of select terms. Twelve studies meeting the inclusion criteria were included in the meta-analysis. The results of the meta-analysis revealed that overall vehicle-ride exposure was likely to increase cervical pathology (p=0.01, odds ratio=1.59, 95% CI=1.16-2.17). Using vehicle type as a moderator it was found that vehicle-ride exposure in ground-based vehicles (p=0.01, odds ratio=2.33, 95% CI=1.41-3.85) and fixed-wing aircraft (p=0.01, odds ratio =1.59, 95% CI=1.13-2.23) were likely to increase cervical pathology. Using operator/other personnel moderator it was found that in the populations tested, fighter pilots or fighter jet weapons systems operators were more likely to develop a cervical pathology (p<0.001, odds ratio=1.78, 95% CI=1.26-2.50). The available studies indicate an increase in cervical pathology for personnel exposed to ground-based vehicles and fixed-wing aircraft. PMID- 25739899 TI - Brighter than the sun: Rajni Govindjee at 80 and her fifty years in photobiology. AB - We celebrate distinguished photobiologist Rajni Govindjee for her pioneering research in photosynthesis and retinal proteins on the occasion of her 80th birthday. PMID- 25739900 TI - High prevalence of diffusive uptake of CO2 by macroalgae in a temperate subtidal ecosystem. AB - Productivity of most macroalgae is not currently considered limited by dissolved inorganic carbon (DIC), as the majority of species have CO2-concentrating mechanisms (CCM) allowing the active uptake of DIC. The alternative, diffusive uptake of CO2 (non-CCM), is considered rare (0-9% of all macroalgal cover in a given ecosystem), and identifying species without CCMs is important in understanding factors controlling inorganic carbon use by eukaryotic algae. CCM activity has higher energetic requirements than diffusive CO2 uptake, therefore when light is low, CCM activity is reduced in favour of diffusive CO2 uptake. We hypothesized that the proportional cover of macroalgae without CCMs (red and green macroalgae) would be low (<10%) across four sites in Tasmania, southern Australia at two depths (4-5 and 12-14 m); the proportion of species lacking CCMs would increase with decreasing depth; the delta(13)C values of macroalgae with CCMs would be more depleted with depth. We found the proportion of non-CCM species ranged from 0 to 90% and included species from all three macroalgal phyla: 81% of red (59 species), 14% of brown (three species) and 29% of green macroalgae (two species). The proportion of non-CCM species increased with depth at three of four sites. 35% of species tested had significantly depleted delta(13)C values at deeper depths. Non-CCM macroalgae are more abundant in some temperate reefs than previously thought. If ocean acidification benefits non-CCM species, the ramifications for subtidal macroalgal assemblages could be larger than previously considered. PMID- 25739901 TI - A simple routine for quantitative analysis of light and dark kinetics of photochemical and non-photochemical quenching of chlorophyll fluorescence in intact leaves. AB - Paper describes principles and application of a novel routine that enables the quantitative analysis of the photochemical O-J phase of the variable fluorescence F v associated with the reversible photo-reduction of the secondary electron acceptor QA of photosystem II (PSII) in algae and intact leaves. The kinetic parameters that determine the variable fluorescence F (PP)(t) associated with the release of photochemical quenching are estimated from 10 us time-resolved light on and light-off responses of F v induced by two subsequent light pulses of 0.25 (default) and 1000 ms duration, respectively. Application of these pulses allows estimations of (i) the actual value of the rate constants k L and k AB of the light excitation (photoreduction of QA) and of the dark re-oxidation of photoreduced QA ([Formula: see text]), respectively, (ii) the actual maximal normalized variable fluorescence [nF v] associated with 100 % photoreduction of QA of open RCs, and (iii) the actual size beta of RCs in which the re-oxidation of [Formula: see text] is largely suppressed (QB-nonreducing RC with k AB ~ 0). The rate constants of the dark reversion of Fv associated with the release of photo-electrochemical quenching F (PE) and photo-electric stimulation F (CET) in the successive J-I and I-P parts of the thermal phase are in the range of (100 ms)(-1) and (1 s)(-1), respectively. The kinetics of fluorescence changes during and after the I-P phase are given special attention in relation to the hypothesis on the involvement of a Deltau H+-dependent effect during this phase and thereafter. Paper closes with author's personal view on the demands that should be fulfilled for chlorophyll fluorescence methods being a correct and unchallenged signature of photosynthesis in algae and plants. PMID- 25739902 TI - Diagnosis of bovine tuberculosis using a metal oxide-based electronic nose. AB - Electronic noses (e-noses) have been used for environmental monitoring, standardization of medicinal flavourings, food safety tests and diagnosis of infectious diseases based on the statistical analysis of volatile organic compounds (VOCs). Bovine tuberculosis (bTB) is officially diagnosed using the intradermal skin test (IST), which is time-consuming and labour-intensive. Therefore, a more convenient and rapid test with greater sensitivity would be advantageous as prescreening test. In this study, we used a metal oxide sensor (MOS) type e-nose to analyse VOCs in a bTB-infected (n = 11) and bTB-free (n = 10) sera, from cattle whose health status was confirmed using the IST, and pathological and bacteriological examinations. The differences in VOCs from bTB infected and bTB-free sera detected by the e-nose were statistically analysed using principal components and discriminant factor analyses. bTB-infected and bTB free sera could be discriminated by MOS type e-nose, and analysing time per sample was only 20 min. VOC analysis using a MOS e-nose was a rapid and automated prescreening method to diagnose bTB, and can be used to select bTB-suspect cattle for IST confirmation. Further studies are required to estimate test sensitivity and specificity. Significance and impact of the study: Bovine tuberculosis (bTB) in cattle is diagnosed using the intradermal skin test (IST); however, this method is very time-consuming and labour-intensive. We analysed volatile organic compounds that are obtained from serum using a metal oxide sensor type of electronic nose to discriminate between TB-infected and TB-free sera. This simple and automated technique will be useful to prescreen bTB-suspects and reduce the time and labour required to perform the IST. PMID- 25739904 TI - Pharmacokinetics and Pharmacodynamics of Tissue Plasminogen Activator Administered Through an External Ventricular Drain. AB - BACKGROUND: Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity. METHODS: Twelve patients with aneurysmal SAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2 mg intraventricular TPA or placebo every 12 h (five doses). CT scans were performed 12, 48, and 72 h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12 h after the first dose using ELISA assays. RESULTS: Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12 h after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had slightly elevated levels (283-285 ng/ml) when the second dose was due after 12 h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6 h, had declined by 12 h, and correlated strongly with radiographic IVH clearance (r = 0.82, p = 0.02). CONCLUSIONS: The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2 mg. The optimal administration interval is every 8-12 h. PMID- 25739905 TI - Bio-inspired surfactants capable of generating plant volatiles. AB - Plants are able to synthesize, store and release lipophilic organic molecules known as plant volatiles (PVs) utilizing specific biological pathways and different enzymes which play vital roles in the plant's defence and in dealing with biotic and abiotic stress situations. The process of generation, storage and release of PVs by plants acquired during the course of evolution is a very complex phenomenon. Bio-inspired molecular design of farnesol-based surfactants facilitates similar production, storage and release of PVs. The designed molecules adsorb at air-water interface and self-aggregate into micelles in aqueous system. The structural design of the molecules allows them to self activate in water via intramolecular cation-pi interactions. The activated molecules undergo molecular rearrangements generating volatile organic molecules both at interface and inside the micelle core. The molecules adsorbed at the interface initially release the formed volatile molecules creating vacant space at interface, thus thermodynamically directing the micelle to release the manufactured volatile products. PMID- 25739906 TI - TRPV4 activates autonomic and behavioural warmth-defence responses in Wistar rats. AB - AIM: In this study, we aimed at investigating the involvement of the warmth sensitive channel - TRPV4 (in vitro sensitive to temperatures in the range of approx. 24-34 degrees C) - on the thermoregulatory mechanisms in rats. METHODS: We treated rats with a chemical selective agonist (RN-1747) and two antagonists (RN-1734 and HC-067047) of the TRPV4 channel and measured core body temperature, metabolism, heat loss index and preferred ambient temperature. RESULTS: Our data revealed that chemical activation of TRPV4 channels by topical application of RN 1747 on the skin leads to hypothermia and this effect was blocked by the pre treatment with the selective antagonist of this channel. Intracerebroventricular treatment with RN-1747 did not cause hypothermia, indicating that the observed response was indeed due to activation of TRPV4 channels in the periphery. Intravenous blockade of this channel with HC-067047 caused an increase in core body temperature at ambient temperature of 26 and 30 degrees C, but not at 22 and 32 degrees C. At 26 degrees C, HC-067047-induced hyperthermia was accompanied by increase in oxygen consumption (an index of thermogenesis), while chemical stimulation of TRPV4 increased tail heat loss, indicating that these two autonomic thermoeffectors in the rat are modulated through TRPV4 channels. Furthermore, rats chemically stimulated with TRPV4 agonist choose colder ambient temperatures and cold-seeking behaviour after thermal stimulation (28-31 degrees C) was inhibited by TRPV4 antagonist. CONCLUSION: Our results suggest, for the first time, that TRPV4 channel is involved in the recruitment of behavioural and autonomic warmth-defence responses to regulate core body temperature. PMID- 25739907 TI - Dietary high-polyphenols extra-virgin olive oil is effective in reducing cholesterol content in eggs. AB - BACKGROUND: Extra-virgin olive oil (EVOO) represents an important food in Mediterranean diet due to its favorable effects on human and animal health derived from the consumption of polyphenols. We studied the effects of dietary EVOO differing in polyphenols levels on egg quality. METHODS: A total of 150 laying hens were allotted into three groups over 10 weeks of the experimental period. The three diets were based on wheat-soybean meal with added oils at 2.5%. Hens were fed the following diets: (1) commercial diet containing sunflower oil (Control), (2) diet EVOO from Cima di Bitonto variety (low-polyphenols content; Low-P), and (3) diet EVOO from Coratina variety (high-polyphenols content; High P). The performance of the hen, the qualitative traits of eggs, and the fatty acid composition and cholesterol content of egg-yolk were measured. RESULTS: None of the egg productive parameters studied were influenced by dietary treatment, except for yolk color score that was enhanced in hens fed the both EVOO diets (P<0.05). Feeding high-polyphenols EVOO reduced serum cholesterol level in hens (P<0.01) and egg-yolk cholesterol levels (as per egg; P<0.05). The dietary supplementation of high-polyphenols EVOO raised the polyunsaturated fatty acids (PUFAs) composition and increased the content of oleic and linolenic acids in egg yolk. Moreover, the atherogenic index in egg-yolk decreased linearly in accordance with increasing levels of dietary polyphenols (P<0.01). CONCLUSION: In conclusion, a diet for hens consisting of high-polyphenols level from extra virgin olive oil can improve the fatty acid quality of egg-yolk while lowering the egg-yolk cholesterol level, which could be a beneficial functional food for human health. PMID- 25739908 TI - Ultra-pure soft water ameliorates atopic skin disease by preventing metallic soap deposition in NC/Tnd mice and reduces skin dryness in humans. AB - Mineral ions in tap water react with fatty acids in soap, leading to the formation of insoluble precipitate (metallic soap) on skin during washing. We hypothesised that metallic soap might negatively alter skin conditions. Application of metallic soap onto the skin of NC/Tnd mice with allergic dermatitis further induced inflammation with elevation of plasma immunoglobulin E and proinflammatory cytokine expression. Pruritus and dryness were ameliorated when the back of mice was washed with soap in Ca2+- and Mg2+-free ultra-pure soft water (UPSW). Washing in UPSW, but not tap water, also protected the skin of healthy volunteers from the soap deposition. Furthermore, 4 weeks of showering with UPSW reduced dryness and pruritus of human subjects with dry skin. Washing with UPSW may be therapeutically beneficial in patients with skin troubles. PMID- 25739909 TI - In ovo gene manipulation of melanocytes and their adjacent keratinocytes during skin pigmentation of chicken embryos. AB - During skin pigmentation in avians and mammalians, melanin is synthesized in the melanocytes, and subsequently transferred to adjacently located keratinocytes, leading to a wide coverage of the body surface by melanin-containing cells. The behavior of melanocytes is influenced by keratinocytes shown mostly by in vitro studies. However, it has poorly been investigated how such intercellular cross talk is regulated in vivo because of a lack of suitable experimental models. Using chicken embryos, we developed a method that enables in vivo gene manipulations of melanocytes and keratinocytes, where these cells are separately labeled by different genes. Two types of gene transfer techniques were combined: one was a retrovirus-mediated gene infection into the skin/keratinocytes, and the other was the in ovo DNA electroporation into neural crest cells, the origin of melanocytes. Since the Replication-Competent Avian sarcoma-leukosis virus long terminal repeat with Splice acceptor (RCAS) infection was available only for the White leghorn strain showing little pigmentation, melanocytes prepared from the Hypeco nera (pigmented) were back-transplanted into embryos of White leghorn. Prior to the transplantation, enhanced green fluorescent protein (EGFP)(+) Neo(r+) -electroporated melanocytes from Hypeco nera were selectively grown in G418-supplemented medium. In the skin of recipient White leghorn embryos infected with RCAS-mOrange, mOrange(+) keratinocytes and transplanted EGFP(+) melanocytes were frequently juxtaposed each other. High-resolution confocal microscopy also revealed that transplanted melanocytes exhibited normal behaviors regarding distribution patterns of melanocytes, dendrite morphology, and melanosome transfer. The method described in this study will serve as a useful tool to understand the mechanisms underlying intercellular regulations during skin pigmentation in vivo. PMID- 25739910 TI - Accelerated ageing of the lung in COPD: new concepts. AB - The rise in life expectancy worldwide has been accompanied by an increased incidence of age-related diseases, representing an enormous burden on healthcare services and society. All vital organs lose function with age, and this is well described in the lung, with a progressive decline in pulmonary function after the age of about 25 years. The lung ages, like any other organ, with progressive functional impairment and reduced capacity to respond to environmental stresses and injury. Normal physiological ageing results in enlarged alveolar spaces and loss of lung elasticity in the elderly known as 'senile emphysema', whereas in COPD there is destruction of the alveolar walls and fibrosis of peripheral airways. However, COPD shows striking age-associated features, such as an increase in cellular senescence, stem cell exhaustion, increased oxidative stress, alteration in the extracellular matrix and a reduction in endogenous antiageing molecules and protective pathways such as autophagy. In this review we discuss the evidence showing how oxidative stress induces accelerated ageing by upregulating the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT/mechanistic target of rapamycin signalling pathway resulting in depletion of stem cells, defective autophagy, reduced antioxidant responses and defective mitochondrial function thus generating further oxidative stress. Understanding the mechanisms of accelerated ageing in COPD may identify novel therapeutic approaches. PMID- 25739911 TI - Targeted lung denervation for moderate to severe COPD: a pilot study. AB - BACKGROUND: Parasympathetic pulmonary nerves release acetylcholine that induces smooth muscle constriction. Disruption of parasympathetic pulmonary nerves improves lung function and COPD symptoms. AIMS: To evaluate 'targeted lung denervation' (TLD), a novel bronchoscopic therapy based on ablation of parasympathetic pulmonary nerves surrounding the main bronchi, as a potential therapy for COPD. METHODS: This 1-year, prospective, multicentre study evaluated TLD in patients with COPD forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (FEV1/FVC <0.70; FEV1 30%-60% predicted). Patients underwent staged TLD at 20 watts (W) or 15 W following baseline assessment off bronchodilators. Assessments were repeated on tiotropium before treatment and off bronchodilators at 30, 90, 180, 270 and 365 days after TLD. The primary endpoint was freedom from documented and sustained worsening of COPD directly attributable to TLD to 1 year. Secondary endpoints included technical feasibility, change in pulmonary function, exercise capacity, and quality of life. RESULTS: Twenty-two patients were included (n=12 at 20 W, n=10 at 15 W). The procedures were technically feasible 93% of the time. Primary safety endpoint was achieved in 95%. Asymptomatic bronchial wall effects were observed in 3 patients at 20 W. The clinical safety profiles were similar between the two energy doses. At 1 year, changes from baseline in the 20 W dose compared to the 15 W dose were: FEV1 (+11.6%+/-32.3 vs +0.02%+/-15.1, p=0.324), submaximal cycle endurance (+6.8 min+/ 12.8 vs 2.6 min+/-8.7, p=0.277), and St George's Respiratory Questionnaire (-11.1 points +/-9.1 vs -0.9 points +/-8.6, p=0.044). CONCLUSIONS: Bronchoscopic TLD, based on the concept of ablating parasympathetic pulmonary nerves, was feasible, safe, and well tolerated. Further investigation of this novel therapy is warranted. TRIAL REGISTRATION NUMBER: NCT01483534. PMID- 25739912 TI - Quantitative MRI characterization of arthroscopically verified supraspinatus pathology: comparison of tendon tears, tendinosis and asymptomatic supraspinatus tendons with T2 mapping. AB - PURPOSE: Quantitative MRI T2 mapping is a non-invasive imaging technique sensitive to biochemical changes, but no studies have evaluated T2 mapping in pathologic rotator cuff tendons. It was sought to evaluate the efficacy of T2 mapping in detecting differences in the supraspinatus tendon (SST) among patients with tendinosis, partial tears and minimally retracted full-thickness tears, relative to asymptomatic volunteers. METHODS: The pathologic cohort consisted of two arthroscopically verified groups: tendinosis and a tear group of partial tears or minimally retracted full-thickness tears, and was compared to an asymptomatic cohort with no prior history of shoulder pathology. The SST was manually segmented from the footprint to the medial humeral head in the coronal and sagittal planes and divided into six clinically relevant subregions. Mean T2 values and inter- and intra-rater reliability were assessed. RESULTS: In the anterolateral subregion, the tear group exhibited significantly higher mean T2 values (43.9 +/- 12.7 ms) than the tendinosis (34.9 +/- 3.9 ms; p = 0.006) and asymptomatic (33.6 +/- 5.3 ms; p = 0.015) groups. In the posterolateral subregion, the tear group had higher mean T2 values (45.2 +/- 13.7) than the asymptomatic group (34.7 +/- 6.7; p = 0.012). Inter- and intra-rater reliability was mostly excellent (ICC > 0.75). CONCLUSION: T2 mapping is an accurate non invasive method to identify quantitatively early rotator cuff pathology. The lateral region in the coronal plane in particular may differentiate partial and small minimally retracted full-thickness tears from tendinosis and asymptomatic tendons. Understanding and being able to measure quantitatively the process of tendon degeneration and subsequent tearing may help clinicians to better predict at-risk groups and to stratify treatment options. LEVEL OF EVIDENCE: III. PMID- 25739913 TI - Orally disintegrating films and mini-tablets-innovative dosage forms of choice for pediatric use. AB - Oral drug delivery is a non-invasive and therefore a very convenient route of administration. Orally disintegrating dosage forms, like soluble films and (mini )tablets, appear promising for use in the pediatric population. New guidance for the development of pediatric medicines has been published, which provides considerations on how pediatric products should be designed. However, most of the considerations leave a lot of room for interpretations. Bearing in mind the different aspects discussed in the latest guideline, the use of orally disintegrating films and tablets, in particular, small-sized tablets, is discussed and reflected upon by providing evidence from the scientific literature. The available dosage forms for children are various and examples of currently licensed products for use in the pediatric population were compiled. Aspects such as the appropriateness for pediatrics, the choice of excipients, the opportunities for modified drug release preparations or fixed-dose combinations, the acceptability and palatability, and also limitations were discussed with respect to the new dosage forms of orally disintegrating films and mini-tablets. This paper points out that innovation in pediatric medicines are planned and should be encouraged; however, supported by the regulatory guidance, only general considerations are provided. Nevertheless, the guideline summarizes multiple points to consider during the development of medicines for pediatric use. Considering the scientific evidence and the regulatory guidance, orally disintegrating dosage forms, like soluble films and (mini-)tablets, offer an innovative solution for pediatric drug delivery. PMID- 25739914 TI - RAG1 deficiency may present clinically as selective IgA deficiency. AB - BACKGROUND: Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype. OBJECTIVE: We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies. METHODS: We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow. RESULTS: Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function. CONCLUSIONS: The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases. PMID- 25739915 TI - A mutation in the human tetraspanin CD81 gene is expressed as a truncated protein but does not enable CD19 maturation and cell surface expression. AB - A homozygous mutation in a splice site of the CD81 gene was identified previously in a patient, as the cause in a case of common variable immune deficiency (CVID). CD19 expression is reduced in mice that lack CD81; however, B cells in this patient lacked completely CD19 surface expression. The mutation led to an absence of the CD81 protein on the cell surface and it was assumed that the CD81 protein was not produced. Here we demonstrate that a truncated human CD81 mutant (CD81mut) was actually produced, but retained intracellularly. We also demonstrate that the truncated CD81mut protein is in close proximity to the intracellularly sequestered CD19. However, this interaction does not enable normal CD19 maturation and surface expression. In addition, we show that specific domains of CD81 enable retrieval and trafficking of human CD19 to the cell surface. Finally, we demonstrate that surface expression of CD19 requires CD81, even in non-B cells. PMID- 25739917 TI - Seroprevalence of Antibody-Mediated, Complement-Dependent Opsonophagocytic Activity against Neisseria meningitidis Serogroup B in England. AB - The correlate of protection for the licensure of meningococcal vaccines is serum bactericidal activity. However, evidence indicates that a complex situation and other mechanisms, such as antibody-mediated, complement-dependent opsonophagocytosis (OP), may play a role in protection and should be investigated in order to understand immunity to this disease. In this study, a high-throughput flow cytometric opsonophagocytic assay (OPA) was optimized. The assay measures the presence of killed fluorescently labeled Neisseria meningitidis within human granulocytes (differentiated HL60 cells) by flow cytometry, using IgG-depleted pooled human plasma as an exogenous source of complement. This method was found to be reliable and correlated with the results of an opsonophagocytic killing assay. The OPA was used to measure OP activity in 1,878 serum samples from individuals ranging from 0 to 99 years of age against N. meningitidis strain NZ98/254 (B:4:P1.7-2,4). The levels of OP activity in individual serum samples varied greatly. OP activity showed an initial peak in the 6- to 12-month age group corresponding to a peak in disease incidence. The OP activity dropped in childhood until the late teenage years, although there was still a higher percentage of individuals with OP activity than with protective bactericidal antibody titers. OP activity reached a peak in the 30- to 39-year age group and then declined. This later peak in OP activity did not coincide with the young adults in whom peak serum bactericidal activity and disease incidence occurred. The demonstration of OP activity when disease incidence is low and when protective bactericidal antibody titers are not detected may indicate a role for OP in protection from meningococcal disease in these age groups. PMID- 25739918 TI - Evaluation of the characteristics of the enzyme-linked immunospot assay for diagnosis of active tuberculosis in China. AB - The purpose of this study was to evaluate the characteristics of the T-SPOT.TB test for the diagnosis of active tuberculosis (ATB) and to distinguish ATB from other diseases using a receiver operating characteristic (ROC) curve. A total of 535 patients with suspected active tuberculosis were enrolled in the study and divided into ATB and nonactive tuberculosis (NATB) groups, as well as pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) subgroups. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of the T-SPOT.TB test for the diagnosis of ATB were 84.95%, 85.12%, 82.94%, 86.93%, 5.71, and 0.18, respectively. The median number of spot-forming cells (SFCs) in the ATB group was higher than that in the NATB group (71 versus 1; P < 0.0001). The sensitivities in the PTB and EPTB subgroups were 92.31% and 81.77%. The areas under the curve (AUC) for the diagnosis of ATB using the T-SPOT.TB, early secreted antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP-10) were 0.906, 0.884, and 0.877, respectively. A cutoff of 42.5 SFCs for ATB yielded a positive predictive value of 100%. Our study shows that the T-SPOT.TB test is useful for the diagnosis of ATB. Utilizing an ROC curve to select an appropriate cutoff made it possible to discriminate ATB from NATB. PMID- 25739920 TI - The neurocognitive impact of Fabry disease on pediatric patients. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder that results in progressive multisystemic organ complications. Several studies have examined neurocognitive impairments in adults; however, there is a paucity of research examining neurocognitive functioning in children with FD. This is the first exploratory study to examine the neurocognitive functioning of pediatric patients with FD and to evaluate the effects of enzyme replacement therapy (ERT) on neurocognitive functioning within this population. Families attending a national conference with at least one child with FD and one parent affected by FD comprised the sample (n = 48; 24 pediatric patients, 24 parents). Pediatric participants (10 males, 14 females) between the ages of 6 and 18 years and their parent(s) were involved in the study. Data from a demographic questionnaire and two neurocognitive self-report and parent-report measures were analyzed. Parent reports of neurocognitive functioning were also compared to a sample of children with and without head injury and to a sample of children who had undergone liver transplant (LT). Children with FD had poorer cognitive and executive functioning than healthy peers, and were comparable to children with head injury and LT. In addition, children using ERT had higher scores on measures of overall cognitive functioning, as well as fewer problems with attention/working memory and executive functioning. Results of this study suggest that children with FD may exhibit poorer cognitive and executive functioning relative to healthy peers. The use of ERT may mitigate the negative impact of FD on neurocognitive functioning in pediatric patients. PMID- 25739919 TI - Assessment of the safety and efficacy of an attenuated live vaccine based on highly pathogenic porcine reproductive and respiratory syndrome virus. AB - The safety and efficacy of the JXA1-R vaccine, an attenuated strain of highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV), were examined using an intramuscular challenge model in piglets. The JXA1-R vaccine was obtained by passing HP-PRRSV JXA1 through Marc-145 cells (82nd passage). Genomic sequence comparisons showed that strain JXA1-R and its parental strain, JXA1, differ by 47 amino acids, and most of these differences are scattered throughout the PRRSV genome. Four-week-old PRRSV-free piglets were inoculated intramuscularly with JXA1-R vaccine (10(3.0), 10(4.0), 10(5.0), 10(6.0), and 10(7.0) 50% tissue culture infective doses [TCID50]/ml for groups 1 to 5, respectively) and then challenged intramuscularly with the 5th passage virus of JXA1 virus (JXA1-F5, 3 ml * 10(4.5) TCID50/ml) 28 days after inoculation. The humoral immune response, swine growth, clinical signs, and differential organ lesions were monitored. The results showed that all vaccinated piglets had a perceptible humoral immune response to vaccination after day 7, which then promptly increased, almost reaching the maximum sample/positive (S/P) ratio value at 28 days postimmunization. Viremia detection indicated that the viral replication levels of the challenge virus in the immunized groups (immunization doses >=10(4.0)/ml) were significantly lower than that of the virus-challenged unvaccinated control group. Piglets in groups 2 to 5 were effectively protected against lethal HP-PRRSV infection and did not show any obvious changes in body temperature or clinical signs of disease at any point during the experiment. However, two of five piglets in group 1 showed mild pathological lesions and transitory high fever. These results suggest that JXA1-R (TCID50/ml >=10(4.0)) is sufficiently attenuated and can provide effective protection against the lethal wild-type HP-PRRSV. PMID- 25739921 TI - Efficacy of fipronil combined with permethrin commercial spot on (Effitix) preventing Culex pipiens from feeding on dogs. AB - A controlled clinical trial was carried out to assess the adulticidal and anti feeding effectiveness of a spot-on combining fipronil and permethrin (Effitix, Virbac, Carros, France) in preventing Culex pipiens from feeding on dogs. Twelve dogs with equal sensitivity to mosquitoes were included in the study and divided into two groups of six dogs: an untreated control group and a group treated with Effitix. All dogs were challenged with 80 females C. pipiens for 90 +/- 5 min on days -7, 1, 7, 14, 21, and 28 (day 0 being treatment day). The number of engorged, dead, and live mosquitoes was determined after each exposure to treated and untreated dogs. Dead mosquitoes were also counted 24 h after exposure. The anti-feeding effect of the spot-on formulation was 100, 99.5, 97.7, 98.3, and 96.7% on days 1, 7, 14, 21, and 28, respectively. The mortality effect was 66.6, 55.9, 38, 17.2, and 12.3% on days 1, 7, 14, 21, and 28, respectively. At each challenge point, the mortality and anti-feeding effects on mosquitoes were significantly different between the control and treated group (p < 0.05). The results indicate that a combination of permethrin and fipronil could be used as an effective mosquito control strategy in dogs and is therefore recommended for use in a dirofilariasis prevention program. PMID- 25739922 TI - Reference Ranges for the Non-High-Density Lipoprotein Cholesterol Levels in Japanese Children and Adolescents. AB - AIM: The aim of this study was to identify the age and sex-specific reference ranges for the non-high-density lipoprotein cholesterol (non-HDLC) levels in Japanese children. METHODS: The subjects included 441,431 schoolchildren (207,015 boys, 234,416 girls) 9-16 years of age who participated in a screening and care program for lifestyle-related diseases from 2006 to 2011. The serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels were measured, and the non-HDL-C levels were calculated. The serum lipid levels were analyzed according to age and sex. RESULTS: The overall mean non-HDL-C level was 105.7+/-24.0 mg/dL, with a sex difference: boys= 103.0+/-24.0 mg/dL and girls=108.2+/-23.8 mg/dL. In boys, the median non-HDL-C level decreased gradually from 104 mg/dL in the 9-year-old age group to 96 mg/dL in the 15-year old age group. The 75th percentile level was approximately 120 mg/dL in the 9- to 11-year-old groups and decreased at approximately 113 mg/dL in the 12- to 15-year old groups, whereas the 95th percentile level was approximately 150 mg/dL in the 9- to 11-year-old groups and decreased at approximately 140 mg/dL in the 13- to 15-year-old groups. In girls, the median non-HDL-C level remained unchanged at approximately 105 mg/dL, with 75th and 95th percentile levels of approximately 122 and 150 mg/dL, respectively. CONCLUSIONS: The non-HDL-C levels vary by age and sex. The age- and sex-specific reference ranges for the non-HDL-C levels may be a valuable tool for management with respect to preventing the development of atherosclerosis in childhood. PMID- 25739923 TI - Absence of Preceding Intermittent Claudication and its Associated Clinical Freatures in Patients with Critical Limb Ischemia. AB - AIM: The current study investigated how prevalent the absence of a prior history of intermittent claudication would be in patients with critical limb ischemia (CLI) and examined the associated clinical features. METHODS: We used a database of 559 Japanese CLI patients participating in a multicenter prospective study. A history of intermittent claudication prior to CLI onset was surveyed at registration. The 95% confidence interval (CI) of its prevalence was calculated using the Clopper-Pearson method. Logistic regression analysis was performed to assess the association between the clinical features and the absence of preceding intermittent claudication. RESULTS: The study subjects were 73+/-10 years old and 67% were male. Tissue loss occurred in 82% of this population. The prevalence of the absence of prior intermittent claudication was 50% [95% CI: 46-55%]. In multivariate logistic regression analysis, a non-ambulatory status, diabetes mellitus, and regular dialysis were significantly and independently associated with the lack of a prior history of intermittent claudication (all p<0.05). Indeed, the presence of these features was associated with a higher prevalence of the lack of the history. Regular dialysis, but not non-ambulatory status or diabetes mellitus, lost its statistical significance after further adjustment for the presence of isolated infrapopliteal lesions, whereas the presence of isolated infrapopliteal lesions itself was significantly associated with a lack of prior intermittent claudication. CONCLUSIONS: The absence of a prior history of intermittent claudication was prevalent in CLI patients. Patients with a non ambulatory status, diabetes mellitus, and regular dialysis were more likely to lack a prior history of intermittent claudication. PMID- 25739924 TI - Probing the molecular architecture of Arabidopsis thaliana secondary cell walls using two- and three-dimensional (13)C solid state nuclear magnetic resonance spectroscopy. AB - The plant secondary cell wall is a thickened polysaccharide and phenolic structure, providing mechanical strength to cells, particularly in woody tissues. It is the main feedstock for the developing bioenergy and green chemistry industries. Despite the role that molecular architecture (the arrangement of biopolymers relative to each other, and their conformations) plays in dictating biomass properties, such as recalcitrance to breakdown, it is poorly understood. Here, unprocessed dry (13)C-labeled stems from the model plant Arabidopsis thaliana were analyzed by a variety of (13)C solid state magic angle spinning nuclear magnetic resonance methods, such as one-dimensional cross-polarization and direct polarization, two-dimensional refocused INADEQUATE, RFDR, PDSD, and three-dimensional DARR, demonstrating their viability for the study of native polymer arrangements in intact secondary cell walls. All carbon sites of the two main glucose environments in cellulose (previously assigned to microfibril surface and interior residues) are clearly resolved, as are carbon sites of the other major components of the secondary cell wall: xylan and lignin. The xylan carbon 4 chemical shift is markedly different from that reported previously for solution or primary cell wall xylan, indicating significant changes in the helical conformation in these dried stems. Furthermore, the shift span indicates that xylan adopts a wide range of conformations in this material, with very little in the 31 conformation typical of xylan in solution. Additionally, spatial connections of noncarbohydrate species were observed with both cellulose peaks conventionally assigned as "surface" and as "interior" cellulose environments, raising questions about the origin of these two cellulose signals. PMID- 25739926 TI - Nutritional assessment: comparison of clinical assessment and objective variables for the prediction of length of hospital stay and readmission. AB - BACKGROUND: Nutritional assessment commonly includes multiple nutrition indicators (NIs). To promote efficiency, a minimum set is needed for the diagnosis of malnutrition in the acute care setting. OBJECTIVE: The objective was to compare the ability of different NIs to predict outcomes of length of hospital stay and readmission to refine the detection of malnutrition in acute care. DESIGN: This was a prospective cohort study of 1022 patients recruited from 18 acute care hospitals (academic and community), from 8 provinces across Canada, between 1 July 2010 and 28 February 2013. Participants were patients aged >=18 y admitted to medical and surgical wards. NIs measured at admission were subjective global assessment (SGA; SGA A = well nourished, SGA B = mild or moderate malnutrition, and SGA C = severe malnutrition), Nutrition Risk Screening (2002), body weight, midarm and calf circumference, serum albumin, handgrip strength (HGS), and patient-self assessment of food intake. Logistic regression determined the independent effect of NIs on the outcomes of length of hospital stay (<7 d and >=7 d) and readmission within 30 d after discharge. RESULTS: In total, 733 patients had complete NI data and were available for analysis. After we controlled for age, sex, and diagnosis, only SGA C (OR: 2.19; 95% CI: 1.28, 3.75), HGS (OR: 0.98; 95% CI: 0.96, 0.99 per kg of increase), and reduced food intake during the first week of hospitalization (OR: 1.51; 95% CI: 1.08, 2.11) were independent predictors of length of stay. SGA C (OR: 2.12; 95% CI: 1.24, 3.93) and HGS (OR: 0.96; 95% CI: 0.94, 0.98) but not food intake were independent predictors of 30-d readmission. CONCLUSIONS: SGA, HGS, and food intake were independent predictors of outcomes for malnutrition. Because food intake in this study was judged days after admission and HGS has a wide range of normal values, SGA is the single best predictor and should be advocated as the primary measure for diagnosis of malnutrition. This study was registered at clinicaltrials.gov as NCT02351661. PMID- 25739925 TI - Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans. AB - Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes meningoencephalitis. Due to the increasing global risk of cryptococcosis and the emergence of drug-resistant strains, the development of predictive genetics platforms for the rapid identification of novel genes governing pathogenicity and drug resistance of C. neoformans is imperative. The analysis of functional genomics data and genome-scale mutant libraries may facilitate the genetic dissection of such complex phenotypes but with limited efficiency. Here, we present a genome-scale co-functional network for C. neoformans, CryptoNet, which covers ~81% of the coding genome and provides an efficient intermediary between functional genomics data and reverse-genetics resources for the genetic dissection of C. neoformans phenotypes. CryptoNet is the first genome-scale co functional network for any fungal pathogen. CryptoNet effectively identified novel genes for pathogenicity and drug resistance using guilt-by-association and context-associated hub algorithms. CryptoNet is also the first genome-scale co functional network for fungi in the basidiomycota phylum, as Saccharomyces cerevisiae belongs to the ascomycota phylum. CryptoNet may therefore provide insights into pathway evolution between two distinct phyla of the fungal kingdom. The CryptoNet web server (www.inetbio.org/cryptonet) is a public resource that provides an interactive environment of network-assisted predictive genetics for C. neoformans. PMID- 25739927 TI - Dairy products: good or bad for cardiometabolic disease? PMID- 25739928 TI - It's the context! PMID- 25739929 TI - alpha-Tocopherol disappearance rates from plasma depend on lipid concentrations: studies using deuterium-labeled collard greens in younger and older adults. AB - BACKGROUND: Little is known about alpha-tocopherol's bioavailability as a constituent of food or its dependence on a subject's age. OBJECTIVE: To evaluate the alpha-tocopherol bioavailability from food, we used collard greens grown in deuterated water ((2)H collard greens) as a source of deuterium-labeled ((2)H) alpha-tocopherol consumed by younger and older adults in a post hoc analysis of a vitamin K study. DESIGN: Younger (mean +/- SD age: 32 +/- 7 y; n = 12 women and 9 men) and older (aged 67 +/- 8 y; n = 8 women and 12 men) adults consumed a test breakfast that included 120 g (2)H collard greens (1.2 +/- 0.1 mg (2)H-alpha tocopherol). Plasma unlabeled alpha-tocopherol and (2)H-alpha-tocopherol were measured by using liquid chromatography-mass spectrometry from fasting (>12 h) blood samples drawn before breakfast (0 h) and at 24, 48, and 72 h and from postprandial samples collected at 4, 5, 6, 7, 9, 12, and 16 h. RESULTS: Times (12.6 +/- 2.5 h) of maximum plasma (2)H-alpha-tocopherol concentrations (0.82% +/ 0.59% total alpha-tocopherol), fractional disappearance rates (0.63 +/- 0.26 pools/d), half-lives (30 +/- 11 h), and the minimum estimated (2)H-alpha tocopherol absorbed (24% +/- 16%) did not vary between age groups or sexes (n = 41). Unlabeled alpha-tocopherol concentrations were higher in older adults (26.4 +/- 8.6 MUmol/L) than in younger adults (19.3 +/- 4.2 MUmol/L; P = 0.0019) and correlated with serum lipids (r = 0.4938, P = 0.0012). In addition, (2)H-alpha tocopherol half-lives were correlated with lipids (r = 0.4361, P = 0.0044). CONCLUSIONS: Paradoxically, alpha-tocopherol remained in circulation longer in participants with higher serum lipids, but the (2)H-alpha-tocopherol absorbed was not dependent on the plasma lipid status. Neither variable was dependent on age. These data suggest that plasma alpha-tocopherol concentrations are more dependent on mechanisms that control circulating lipids rather than those related to its absorption and initial incorporation into plasma. This trial was registered at clinicaltrials.gov as NCT0036232. PMID- 25739931 TI - Modelling Dominance Hierarchies Under Winner and Loser Effects. AB - Animals that live in groups commonly form themselves into dominance hierarchies which are used to allocate important resources such as access to mating opportunities and food. In this paper, we develop a model of dominance hierarchy formation based upon the concept of winner and loser effects using a simulation based model and consider the linearity of our hierarchy using existing and new statistical measures. Two models are analysed: when each individual in a group does not know the real ability of their opponents to win a fight and when they can estimate their opponents' ability every time they fight. This estimation may be accurate or fall within an error bound. For both models, we investigate if we can achieve hierarchy linearity, and if so, when it is established. We are particularly interested in the question of how many fights are necessary to establish a dominance hierarchy. PMID- 25739932 TI - Erratum to: Individual-based model for quorum sensing with background flow. PMID- 25739930 TI - Long-chain omega-3 fatty acid intake and endometrial cancer risk in the Women's Health Initiative. AB - BACKGROUND: Inflammation may be important in endometrial cancer development. Long chain omega-3 (n-3) polyunsaturated fatty acids (LComega-3PUFAs) may reduce inflammation and, therefore, reduce cancer risk. Because body mass is associated with both inflammation and endometrial cancer risk, it may modify the association of fat intake on risk. OBJECTIVE: We examined whether intakes of LComega-3PUFAs were associated with endometrial cancer risk overall and stratified by body size and histologic subtype. DESIGN: Women were n = 87,360 participants of the Women's Health Initiative Observational Study and Clinical Trials who were aged 50-79 y, had an intact uterus, and completed a baseline food-frequency questionnaire. After 13 y of follow-up, n = 1253 incident invasive endometrial cancers were identified. Cox regression models were used to estimate HRs and 95% CIs for the association of intakes of individual omega-3 fatty acids and fish with endometrial cancer risk. RESULTS: Intakes of individual LComega-3PUFAs were associated with 15-23% linear reductions in endometrial cancer risk. In women with body mass index (BMI; in kg/m(2)) <25, those in the upper compared with lowest quintiles of total LComega-3PUFA intake (sum of eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids) had significantly reduced endometrial cancer risk (HR: 0.59; 95% CI: 0.40, 0.82; P-trend = 0.001), whereas there was little evidence of an association in overweight or obese women. The reduction in risk observed in normal-weight women was further specific to type I cancers. CONCLUSIONS: Long-chain omega-3 intake was associated with reduced endometrial cancer risk only in normal-weight women. Additional studies that use biomarkers of omega-3 intake are needed to more accurately estimate their effects on endometrial cancer risk. This trial was registered at clinicaltrials.gov as NCT00000611. PMID- 25739933 TI - Getting it right for children: improving tuberculosis treatment access and new treatment options. AB - Children were often the forgotten victims of the global tuberculosis (TB) epidemic, neglected by traditional TB services as well as maternal and child health initiatives. Luckily this is changing with a greater focus on children and the issues regarding their optimal management. A common misconception is that children with TB are always difficult to diagnose and treat. New diagnostic tools are urgently needed, but most children with TB in high-burden settings can be diagnosed with available approaches and treatment outcomes are generally excellent. Increased TB awareness, appropriate training of health care workers and inclusion in integrated management of childhood illness strategies will improve the access and quality of care that children receive. This review highlights what needs to be done to ensure that no child unnecessarily dies from TB and provides a brief overview of new advances in the field. PMID- 25739934 TI - Impact of an Enduring War on Two Military Psychiatry Residency Programs. AB - Four active duty military psychiatrists at different points in their careers were asked to reflect on the impact that the wars in Iraq and Afghanistan had on their respective training in military psychiatry residency programs. The result is an inside look from four unique perspectives on how military psychiatry residency training adapted over time to prepare their graduates to practice psychiatry in a wartime setting as many graduates went to the front lines of war shortly after graduation. This article will provide an understanding of the challenges faced by these residency programs striving to meet the behavioral health needs created by war while balancing this with ongoing ACGME requirements, how those challenges were met, and the impact it had on residents. PMID- 25739935 TI - Reading the Mind: A Social Media-Facilitated Collaboration of US and UK Graduate Psychiatry Trainees. PMID- 25739936 TI - Knowledge transfer and exchange frameworks in health and their applicability to palliative care: scoping review protocol. AB - AIM: To review knowledge transfer and exchange frameworks used in health, to analyse the core concepts of these frameworks and appraise their potential applicability to palliative care. BACKGROUND: Although there are over 60 different models of knowledge transfer and exchange designed for various areas of the fields of health care, many remain largely unrefined and untested. There is a lack of studies that create guidelines for scaling-up successful implementation of research findings and of proven models ensuring that patients have access to optimal health care, guided by current research. DESIGN: The protocol for this scoping review was devised according to the guidelines proposed by Arksey and O'Malley (2005) and Levac et al. (2010). METHODS: The protocol includes decisions about the review objectives, inclusion criteria, search strategy, study selection, data extraction, quality assessment, data synthesis and plans for dissemination. DISCUSSION: The review will allow us to identify the currently used models of knowledge transfer and exchange in healthcare setting and analyse their applicability to the complex demands of palliative care. Results from this review will identify effective way of translating different types of knowledge to different PC providers and could be used in hospital, community and home based PC and future research. PMID- 25739937 TI - Takotsubo cardiomyopathy and left ventricular outflow tract obstruction. PMID- 25739938 TI - A subset of CD45+/CD19 - cells in bone marrow may be associated with clinical outcomes of patients with mantle cell lymphoma. AB - Mantle cell lymphoma has features of both indolent and aggressive non-Hodgkin lymphomas. Repeated relapses leading to treatment failure in patients with mantle cell lymphoma might suggest the presence of cancer stem cells. A small cell population with CD45+/CD19 - was previously reported to represent cancer stem cells. We evaluated the clinical relevance of CD45+/CD19 - cells in bone marrow of patients with mantle cell lymphoma (n = 20). A CD45+/CD19 - cell population was observed in newly diagnosed mantle cell lymphoma, and its percentage correlated with tumor cells in bone marrow (r = 0.832, p = 0.001) and score on the simplified mantle cell lymphoma prognostic index (r = 0.675, p = 0.016). After treatment, CD45+/CD19 - cells decreased (mean: 0.012%), and CD45+/CD19 - cells (0.276%) were higher at relapse or progression than at diagnosis. In conclusion, a CD45+/CD19 - cell population in bone marrow aspirates correlated with the clinical outcome of patients with mantle cell lymphoma. PMID- 25739939 TI - Impact of body mass index on pulmonary complications in patients with non-Hodgkin lymphoma treated with hematopoietic stem cell transplant. AB - The objective of this study was to examine the association between body mass index (BMI) and the incidence of pulmonary complications (PCs) after hematopoietic stem cell transplant (HCT). We reviewed 398 adult patients with non Hodgkin lymphoma (NHL) who received autologous or allogeneic HCT between 1993 and 1997. BMI was classified as normal (18.5 < BMI <= 24.9), overweight (24.9 < BMI <= 30) and obese (BMI > 30). Multivariate logistic regression was used to analyze the relationship between BMI and presence of PCs within 100 days post-HCT while adjusting for patient-, disease- and transplant-related variables. The incidence of PCs within 100 days post-HCT was 32% (n = 129). Median BMI was 25.4 (range: 18.6-52.2). Median age was 48.8 years (range: 19.5-73.6 years). Multivariate analysis failed to show significant association between BMI and PCs. However, a total body irradiation (TBI)-based conditioning regimen was associated with lower rate of PCs. PMID- 25739940 TI - Sarcopenia is associated with autologous transplant-related outcomes in patients with lymphoma. AB - Sarcopenia is associated with treatment-related complications and shorter overall survival in patients with cancer. Psoas area indices were calculated for 121 patients with lymphoma who underwent autologous transplant. Controlling for age, body mass index, comorbidities and performance status for the 73 men included, the hazard ratio (95% confidence interval, CI) for non-relapse mortality was 2.37 (1.01, 5.58), p = 0.048 for every 100 unit decrease in total psoas index and 2.67 (1.04, 6.86), p = 0.041 for every 100 unit decrease in lean psoas index. Men with a lower total psoas index experienced more complications (p = 0.001) and spent more days in hospital (p = 0.03) during the transplant admission. A strong association existed between sarcopenia and number of hospital days in the 100 days following transplant among both men (p < 0.0001) and women (p < 0.0001). Sarcopenia may impact negative outcomes after autologous transplant thereby serving as a potentially modifiable predictor of outcomes and aiding in treatment selection. PMID- 25739941 TI - Low-dose arsenic trioxide combined with aclacinomycin A synergistically enhances the cytotoxic effect on human acute myelogenous leukemia cell lines by induction of apoptosis. AB - Acute myeloid leukemia (AML) is a common disorder in the elderly. Although remarkable progress has been made over recent decades, the outcome remains poor. Thus, the development of a more effective method to overcome this problem is necessary. In this study, we aimed to investigate the synergistic cytotoxic effect of low-dose arsenic trioxide (As2O3) combined with aclacinomycin A (ACM) on the human AML cell lines KG-1a and HL-60, and to clarify the underlying mechanism. Results showed that As2O3 combined with ACM exerted a synergistic cytotoxic effect by activation of the apoptosis pathway. Additionally, we found that the combination treatment decreased Bcl-2, c-IAP and XIAP expression but increased SMAC and caspase-3 expression more significantly than the single drug treatments. Furthermore, combination index (CI) values were < 1 in all matched combination groups. Additional evaluation of As2O3 combined with ACM as a potential therapeutic benefit for AML seems warranted. PMID- 25739942 TI - Why do we treat the children of Jehovah's Witnesses differently from their adult parents? PMID- 25739943 TI - Disability and economic disadvantage: facing the facts. PMID- 25739944 TI - Subacute multicranial neuropathy revealing an early case of meningeal syphilis. AB - We report a case of neurosyphilis presenting with meningitis and subacute multicranial neuropathy in a young immune-competent man. Signs of primary and secondary stages of syphilitic infection occurred almost contemporarily in our patient. MRI revealed the involvement of several cranial nerves. CSF examination proved to be diagnostic. Syphilitic meningitis should be considered among the differential diagnoses of subacute, multicranial neuropathy, or skull base meningitis. The clinical course of this patient shows that early diagnosis and treatment warrant a good neurological outcome. PMID- 25739945 TI - Association of ubiquitin carboxy-terminal hydrolase-L1 in cerebrospinal fluid with clinical severity in a cohort of patients with Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an acute immune-mediated polyneuropathy. Although its pathogenic mechanism has been revealed and various therapeutic trials have been performed, a proportion of patients experience the severe sequelae associated with GBS. In this paper, we investigated whether the amount of the neuron-specific protein, ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), in the cerebrospinal fluid of patients with GBS was correlated with the clinical course of the disease. UCH-L1 protein levels were greater in patients with GBS than in controls. The patients with GBS whose UCH-L1 protein levels were higher than those of the controls presented with more severe symptoms at peak. UCH-L1 protein levels tended to become elevated as the total protein levels were increased; however, elevated UCH-L1 without an increase in total protein might be correlated with severe disease course (bedridden or ventilator supported). These results suggest that UCH-L1 could be a biomarker associated with the severity of the disease at the acute phase of GBS. PMID- 25739946 TI - A case of Trousseau's syndrome and pulmonary arteriovenous fistula: a malignant combination for ischemic stroke. PMID- 25739947 TI - Erratum to: Italian neuropsychology in the second half of the twentieth century. PMID- 25739948 TI - Neuronal activity and AMPA-type glutamate receptor activation regulates the morphological development of oligodendrocyte precursor cells. AB - Myelination is initiated when oligodendrocyte precursor cells (OPC) contact target axons. Neuronal activity promotes myelination through actions that may involve OPC AMPA and NMDA glutamate receptors (AMPAR, NMDAR). Therefore, activity and AMPAR/NMDAR activation are predicted to promote the morphological development of OPC. AMPAR can regulate OPC development, but this analysis was not performed in situ and the role of action potentials was not examined. Hence, the influence of activity and AMPAR on OPC morphology and development remain untested in the CNS where axon-glial interactions are preserved. Data on NMDAR are mixed with conflicting results from in vitro and in vivo work. To gain a fuller understanding of activity-dependent OPC development in situ, we explored the role of AMPAR and NMDAR in cerebellar slice cultures that permit the study of endogenous OPC development and myelination. The structure of individual OPC was resolved from cells labeled with membrane targeted GFP. Morphological data were then validated against assays of OPC development. Blocking either activity or AMPAR impaired the morphological development of OPC and promoted proliferation and differentiation. Increasing the pool of oligodendrocytes by blocking activity or AMPAR failed to promote myelination. Instead both myelination and the expression of myelin basic protein were reduced by these treatments suggesting that full differentiation to a myelinating phenotype did not occur. Blocking NMDAR left OPC proliferation, differentiation and morphology unchanged. These data indicate an important role for AMPAR but not NMDAR in mediating the activity dependent signals that regulate OPC morphology, development and myelination. PMID- 25739949 TI - Causal path analyses of the association of protein intake with risk of mortality and graft failure in renal transplant recipients. AB - The effect of a low protein intake on survival in renal transplant recipients (RTR) is unknown. A low protein intake may increase risks of malnutrition, low muscle mass, and death. We aimed to study associations of protein intake with mortality and graft failure and to identify potential intermediate factors. Protein intake was estimated from 24-h urinary urea excretion (24-h UUE). Graft failure was defined as return to dialysis or retransplantation. We used Cox regression analyses to analyze associations with outcome and potential intermediate factors in the causal path. In 604 RTR, mean +/- SD 24-h UUE was 380 +/- 114 mmol/24-h. During median follow-up for 7.0 yr (interquartile range: 6.2 7.5 yr), 133 RTR died and 53 developed graft failure. In univariate analyses, 24 h UUE was associated with lower risk of mortality (HR [95% CI] = 0.80 [0.69 0.94]) and graft failure (HR [95% CI] = 0.72 [0.56-0.92]). These associations were independent of potential confounders. In causal path analyses, the association of 24-h UUE with mortality disappeared after adjustment for muscle mass. Low protein intake is associated with increased risk of mortality and graft failure in RTR. Causal path analyses reveal that the association with mortality is explained by low muscle mass. These findings suggest that protein intake restriction should not be advised to RTR. PMID- 25739950 TI - Quantitative Validation of a Human Body Finite Element Model Using Rigid Body Impacts. AB - Validation is a critical step in finite element model (FEM) development. This study focuses on the validation of the Global Human Body Models Consortium full body average male occupant FEM in five localized loading regimes-a chest impact, a shoulder impact, a thoracoabdominal impact, an abdominal impact, and a pelvic impact. Force and deflection outputs from the model were compared to experimental traces and corridors scaled to the 50th percentile male. Predicted fractures and injury severity measures were compared to evaluate the model's injury prediction capabilities. The methods of ISO/TS 18571 were used to quantitatively assess the fit of model outputs to experimental force and deflection traces. The model produced peak chest, shoulder, thoracoabdominal, abdominal, and pelvis forces of 4.8, 3.3, 4.5, 5.1, and 13.0 kN compared to 4.3, 3.2, 4.0, 4.0, and 10.3 kN in the experiments, respectively. The model predicted rib and pelvic fractures related to Abbreviated Injury Scale scores within the ranges found experimentally all cases except the abdominal impact. ISO/TS 18571 scores for the impacts studied had a mean score of 0.73 with a range of 0.57-0.83. Well-validated FEMs are important tools used by engineers in advancing occupant safety. PMID- 25739951 TI - Sleep Stage Detection Using Tracheal Breathing Sounds: A Pilot Study. AB - Sleep stage detection is needed in many sleep studies and clinical assessments. Generally, sleep stages are identified using spectral analysis of electrocephologram (EEG) and electrooculogram (EOG) signals. This study, for the first time, has investigated the feasibility of detecting sleep stages using tracheal breathing sounds, and whether the change of breathing sounds due to sleeping stage differs at different periods of sleeping time; the motivation was seeking an alternative technique for sleep stage identification. The tracheal breathing sounds of 12 individuals, who were referred for full overnight polysomnography (PSG) assessment, were recorded using a microphone placed over the suprasternal notch, and analyzed using higher order statistical analysis. Five noise-and-snore-free breathing cycles from wakefulness, REM and Stage II of sleep were selected from each subject for analysis. Data of the REM and Stage II were selected from beginning, middle and close to end of sleeping time. Hurst exponent was calculated from the bispectra of the inspiratory sounds of each subject at each sleeping stage in different periods of sleeping time. The participants' sleep stage were determined by sleep lab technologists during the PSG study using EEG and EOG signals. The results show separate and non overlapping clusters for wakefulness, REM and Stage II for each subject. Thus, using a simple linear classifier, we were able to classify REM and Stage II of each subject with 100% accuracy. In addition, the results show that the same pattern existed as long as the REM and Stage II segments were close (less than 3 h) to each other in terms of time. PMID- 25739952 TI - Blinatumomab for the treatment of B-cell lymphoma. AB - INTRODUCTION: Blinatumomab is a bispecific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens. Among the various formats of bispecific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or costimulation. Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL). AREAS COVERED: This article reviews the current literature on blinatumomab including its pharmacology, preclinical findings, clinical trials in B-cell NHL and, to a lesser extent, Phase II studies in B-ALL. The authors discuss the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market. EXPERT OPINION: The recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers. Although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches. Larger trials are needed to demonstrate blinatumomab's curative potential in aggressive histologies. PMID- 25739953 TI - Early estimates of SEER cancer incidence for 2012: Approaches, opportunities, and cautions for obtaining preliminary estimates of cancer incidence. AB - BACKGROUND: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program collects and publishes population-based cancer incidence data from registries covering approximately 28% (seer.cancer.gov/registries/data.html) of the US population. SEER incidence rates are released annually in April from data submitted the prior November. The time needed to identify, consolidate, clean, and submit data requires the latest diagnosis year included to be 3 years before release. Approaches, opportunities, and cautions for an earlier release of data based on a February submission are described. METHODS: First, cases submitted in February for the latest diagnosis year represented 92% to 98% of those in the following November submission. A reporting delay model was used to statistically adjust counts in recent diagnosis years for cases projected in the future. February submissions required larger adjustment factors than November submissions. Second, trends were checked to assess the validity. RESULTS: Most cancer sites had similar annual percent change (APC) trends for February and November 2013. Male colon and rectum cancer and female lung and bronchus cancer showed an acceleration in declining APC trends only in February. Average annual percent change (AAPC) trends for the 2 submissions were similar for all sites. CONCLUSIONS: For the first time, preliminary 2012 incidence rates, based on February submissions, are provided. An accelerated decline starting in 2008 for male colon and rectum cancer rates and male lung cancer rates did not persist when 2012 data were added. An earlier release of SEER data is possible. Caution must be exercised when one is interpreting changing trends. Use of the more conservative AAPC is advised. PMID- 25739954 TI - Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation - The Kumamoto Intervention Conference Study (KICS) Registry. AB - BACKGROUND: The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS: This study included 5,801 consecutive patients (males, 4,160; age, 69.7+/-11.1 years, mean+/-SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to moderate CKD (30<=eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS: In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events. PMID- 25739955 TI - Association of epicardial and abdominal visceral adipose tissue with coronary atherosclerosis in patients with a coronary artery calcium score of zero. AB - BACKGROUND: We sought to examine whether epicardial and abdominal visceral adipose tissue distribution is associated with coronary atherosclerosis in patients with a coronary artery calcium (CAC) score of zero, assessed by coronary computed tomography angiography (CCTA). METHODS AND RESULTS: We studied 352 patients with suspected coronary artery disease (mean age 61+/-11 years, 57% male) with a CAC score of zero who had undergone CCTA. Non-calcified coronary plaques (NCPs) were detected in 102 patients (29%); those causing >=50% stenosis were found in 15 patients (4%). Patients were divided into 4 groups on the basis of CT-based epicardial adipose tissue (EAT) volume and abdominal visceral adipose tissue (VAT) area using the sex-specific median value. Multivariate analysis showed that the adjusted odds ratios for the presence of NCPs in the high VAT area/low EAT volume group, and the high VAT area/high EAT volume group were 2.80 (95% confidence interval [95% CI]: 1.25-6.35, P=0.01) and 2.68 (95% CI: 1.36 5.45, P=0.004), respectively. Interestingly, the low VAT area/high EAT volume group showed an equivalent adjusted odds ratio of 3.02 (95% CI: 1.33-6.90, P=0.008). CONCLUSIONS: EAT volume is eligible as a marker to be evaluated in addition to VAT area in patients with a CAC score of zero. PMID- 25739956 TI - Comparative proteomic analyses of urine from rat urothelial carcinoma chemically induced by exposure to N-butyl-N-(4-hydroxybutyl)-nitrosamine. AB - Bladder cancer is estimated to be the ninth most common malignancy with a high rate of recurrence and progression despite therapy, early diagnosis being crucial for timely intervention. Using a well-established animal model of urothelial carcinoma, we performed a comprehensive analysis of urine proteome profile from healthy animals and animals with urothelial carcinoma at two time-points of disease pathogenesis. GeLC-MS/MS, followed by bioinformatics analysis of unique proteins and the ones present in significantly distinct levels among groups, highlighted the biological processes involved in disease pathogenesis such as, for instance, response to selenium and to drugs, neutral lipid metabolism at earlier stages of disease, and inflammation, immune response and wound healing at advanced stages. Proteins from up-regulated biological processes might be seen as putative disease biomarkers. These include, for example, cadherins, lipoproteins, and glysosyltransferases, which may be included in multimarker strategies. Taken together, the data support the application of urine proteomics for the identification of the biological processes modulated by bladder cancer in an integrative perspective. The present exploratory urinary proteomic analysis might be seen as an important starting point for studies targeting urinary proteins in human, aiming at the implementation of novel laboratory approaches for the detection and successful management of urothelial carcinoma. PMID- 25739957 TI - Evaluation of sperm DNA damage in bulls by TUNEL assay as a parameter of semen quality. AB - Sperm DNA damage affects the conception rate resulting from human assisted reproduction technology. The objective of this study was to adapt the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay to provide a quality parameter for bull semen based on the detection of sperm DNA damage. Fresh semen was collected from two Japanese Black bulls (A, B) several times over the course of a year, and the percentage of TUNEL-positive spermatozoa (sperm TUNEL index) was determined. Individual differences in semen were detected using the sperm TUNEL index in these bulls (P < 0.01). The sperm TUNEL index of cryopreserved semen obtained from test-mated Japanese Black (n = 30, including two bulls with a conception rate lower than 10%) and Holstein (n = 34) bulls were analyzed. The average sperm TUNEL index and conception rate resulting from artificial insemination (AI) were 4.7% and 55.7% for Japanese Black, and 4.9% and 39.5% for Holstein, respectively. A weak negative correlation between sperm TUNEL index and conception rate was observed in Holstein bulls (P < 0.05). Semen samples from six bulls with more than 10% sperm TUNEL index were studied, and these samples showed low sperm viability. However, semen resulting in a very low conception rate did not have a high sperm TUNEL index. Although it would be difficult to predict a low conception rate resulting from AI using the sperm TUNEL index alone, the index can be used as an additional parameter to provide a more comprehensive description of semen quality. PMID- 25739959 TI - p63 Sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. AB - The predominant p63 isoform, DeltaNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of DeltaNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway. PMID- 25739960 TI - Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. AB - DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system. PMID- 25739961 TI - NFkappaB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses. AB - Neutrophils are antigen-transporting cells that generate vaccinia virus (VACV) specific T-cell responses, yet how VACV modulates neutrophil recruitment and its significance in the immune response are unknown. We generated an attenuated VACV strain that expresses HIV-1 clade C antigens but lacks three specific viral genes (A52R, K7R, and B15R). We found that these genes act together to inhibit the NFkappaB signaling pathway. Triple ablation in modified virus restored NFkappaB function in macrophages. After virus infection of mice, NFkappaB pathway activation led to expression of several cytokines/chemokines that increased the migration of neutrophil populations (Nalpha and Nbeta) to the infection site. Nbeta cells displayed features of antigen-presenting cells and activated virus specific CD8 T cells. Enhanced neutrophil trafficking to the infection site correlated with an increased T-cell response to HIV vector-delivered antigens. These results identify a mechanism for poxvirus-induced immune response and alternatives for vaccine vector design. PMID- 25739962 TI - Stochastic transitions into silence cause noise correlations in cortical circuits. AB - The spiking activity of cortical neurons is highly variable. This variability is generally correlated among nearby neurons, an effect commonly interpreted to reflect the coactivation of neurons due to anatomically shared inputs. Recent findings, however, indicate that correlations can be dynamically modulated, suggesting that the underlying mechanisms are not well understood. Here, we investigate the hypothesis that correlations are dominated by neuronal coinactivation: the occurrence of brief silent periods during which all neurons in the local network stop firing. We recorded spiking activity from large populations of neurons in the auditory cortex of anesthetized rats across different brain states. During spontaneous activity, the reduction of correlation accompanying brain state desynchronization was largely explained by a decrease in the density of the silent periods. The presentation of a stimulus caused an initial drop of correlations followed by a rebound, a time course that was mimicked by the instantaneous silence density. We built a rate network model with fluctuation-driven transitions between a silent and an active attractor and assumed that neurons fired Poisson spike trains with a rate following the model dynamics. Variations of the network external input altered the transition rate into the silent attractor and reproduced the relation between correlation and silence density found in the data, both in spontaneous and evoked conditions. This suggests that the observed changes in correlation, occurring gradually with brain state variations or abruptly with sensory stimulation, are due to changes in the likeliness of the microcircuit to transiently cease firing. PMID- 25739963 TI - Nucleation of metastable aragonite CaCO3 in seawater. AB - Predicting the conditions in which a compound adopts a metastable structure when it crystallizes out of solution is an unsolved and fundamental problem in materials synthesis, and one which, if understood and harnessed, could enable the rational design of synthesis pathways toward or away from metastable structures. Crystallization of metastable phases is particularly accessible via low temperature solution-based routes, such as chimie douce and hydrothermal synthesis, but although the chemistry of the solution plays a crucial role in governing which polymorph forms, how it does so is poorly understood. Here, we demonstrate an ab initio technique to quantify thermodynamic parameters of surfaces and bulks in equilibrium with an aqueous environment, enabling the calculation of nucleation barriers of competing polymorphs as a function of solution chemistry, thereby predicting the solution conditions governing polymorph selection. We apply this approach to resolve the long-standing "calcite aragonite problem"--the observation that calcium carbonate precipitates as the metastable aragonite polymorph in marine environments, rather than the stable phase calcite--which is of tremendous relevance to biomineralization, carbon sequestration, paleogeochemistry, and the vulnerability of marine life to ocean acidification. We identify a direct relationship between the calcite surface energy and solution Mg:Ca [corrected] ion concentrations, showing that the calcite nucleation barrier surpasses that of metastable aragonite in solutions with Mg:Ca ratios consistent with modern seawater, allowing aragonite to dominate the kinetics of nucleation. Our ability to quantify how solution parameters distinguish between polymorphs marks an important step toward the ab initio prediction of materials synthesis pathways in solution. PMID- 25739964 TI - Profile of Susan Fiske. PMID- 25739965 TI - Correction for Torella et al., Efficient solar-to-fuels production from a hybrid microbial-water-splitting catalyst system. PMID- 25739966 TI - Interest of repetitive transcranial magnetic stimulation of the motor cortex in the management of refractory cancer pain in palliative care: Two case reports. AB - BACKGROUND: Non-drug treatments should be systematically associated to the medical analgesic treatment during the terminal phase of cancer. CASES PRESENTATION: Patient 1, a 23-year-old woman, presented an adenocarcinoma of the rectum, with liver and lung metastases. Pain was initially treated by oral morphine and a combination of pregabalin and amitriptyline. Ketamine and intrathecal administration of morphine were both ineffective. Patient 2, a 69 year-old woman, presented a cutaneous T-cell lymphoma. She was admitted to the palliative care unit with mixed pain related to cutaneous lymphomatous infiltration. World Health Organization (WHO) step 3 analgesics had not been tolerated. CASES MANAGEMENT: Both patients received five consecutive 20-min sessions of repetitive transcranial magnetic stimulation to the right motor cortex. CASES OUTCOME: Patient 1 experienced a marked improvement of her pain over the days following the first repetitive transcranial magnetic stimulation session. Medical treatment was able to be rapidly decreased by about 50%, which restored an almost normal level of consciousness and lucidity. Patient 2's pain was also markedly decreased over the days following these five consecutive sessions, and repetitive transcranial magnetic stimulation also appeared to have had a beneficial effect on the patient's anxiety and mood. CONCLUSION: In the context of palliative care of cancer patients experiencing refractory pain that is difficult to control by the usual treatments, motor cortex repetitive transcranial magnetic stimulation, due to its noninvasive nature, can be used as an adjuvant therapy to improve various components of pain, including the emotional components. By reducing the doses of analgesics, repetitive transcranial magnetic stimulation decreases the severity of their adverse effects and improves the patient's quality of life. PMID- 25739968 TI - Spanning the scales of granular materials through microscopic force imaging. AB - If you walk on sand, it supports your weight. How do the disordered forces between particles in sand organize, to keep you from sinking? This simple question is surprisingly difficult to answer experimentally: measuring forces in three dimensions, between deeply buried grains, is challenging. Here we describe experiments in which we have succeeded in measuring forces inside a granular packing subject to controlled deformations. We connect the measured micro-scale forces to the macro-scale packing force response with an averaging, mean field calculation. This calculation explains how the combination of packing structure and contact deformations produce the observed nontrivial mechanical response of the packing, revealing a surprising microscopic particle deformation enhancement mechanism. PMID- 25739967 TI - How decentralisation influences the retention of primary health care workers in rural Nigeria. AB - BACKGROUND: In Nigeria, the shortage of health workers is worst at the primary health care (PHC) level, especially in rural communities. And the responsibility for PHC - usually the only form of formal health service available in rural communities - is shared among the three tiers of government (federal, state, and local governments). In addition, the responsibility for community engagement in PHC is delegated to community health committees. OBJECTIVE: This study examines how the decentralisation of health system governance influences retention of health workers in rural communities in Nigeria from the perspective of health managers, health workers, and people living in rural communities. DESIGN: The study adopted a qualitative approach, and data were collected using semi structured in-depth interviews and focus group discussions. The multi-stakeholder data were analysed for themes related to health system decentralisation. RESULTS: The results showed that decentralisation influences the retention of rural health workers in two ways: 1) The salary of PHC workers is often delayed and irregular as a result of delays in transfer of funds from the national to sub-national governments and because one tier of government can blame failure on another tier of government. Further, the primary responsibility for PHC is often left to the weakest tier of government (local governments). And the result is that rural PHC workers are attracted to working at levels of care where salaries are higher and more regular - in secondary care (run by state governments) and tertiary care (run by the federal government), which are also usually in urban areas. 2) Through community health committees, rural communities influence the retention of health workers by working to increase the uptake of PHC services. Community efforts to retain health workers also include providing social, financial, and accommodation support to health workers. To encourage health workers to stay, communities also take the initiative to co-finance and co-manage PHC services in order to ensure that PHC facilities are functional. CONCLUSIONS: In Nigeria and other low- and middle-income countries with decentralised health systems, intervention to increase the retention of health workers in rural communities should seek to reform and strengthen governance mechanisms, using both top-down and bottom-up strategies to improve the remuneration and support for health workers in rural communities. PMID- 25739969 TI - RGB measurements as a novel objective diagnostic test for otitis media with effusion. AB - CONCLUSIONS: This study revealed a significant correlation between red-green-blue (RGB) values of tympanic membrane (TM) images and the presence of effusion in the middle ear. These results confirm that endoscopic RGB evaluation is a rapid and non-invasive procedure yielding objective results. OBJECTIVE: To investigate, in cases of otitis media with effusion (OME), the correlation of the TM color changes with the presence and viscosity of the effusion in the middle ear. METHODS: Endoscopic images of the TMs of 52 patients (group 1) and 52 healthy controls (group 2) were taken during their otologic examinations. RGB values of particular points were measured on the TM images of both groups. Additionally, in group 1 the viscosity of each effusion taken by paracentesis during surgery was also measured intraoperatively with a viscometer. Patients with viscosity values lower and higher than 450 cP (centipoise) were subdivided into groups 1a and 1b, respectively. RESULTS: Study and control groups were comparable regarding the number of patients and their mean ages (p > 0.05). Statistically significant differences were found in RGB values of the TM between groups 1 and 2, but not between groups 1a and 1b. PMID- 25739970 TI - Duplicated left pulmonary artery: an unknown disease? Three case reports and review of the literature. AB - We report three cases of an abnormal finding of duplicated left pulmonary artery: two of these occurring in children with Kabuki syndrome and configuring the setting of a pseudo-pulmonary sling without any clinical or cardiac cross sectional evidence of tracheal compression. The other case instead represents duplicated left pulmonary artery with pulmonary sling caused by the retro tracheal course of the lower left pulmonary artery associated with "Christmas Tree" arrangement of the tracheo-bronchial system. In both patients with pseudo pulmonary sling and Kabuki syndrome, the abnormal finding was incidental during echocardiographic examination and neither of the patients required surgical repair for the condition. To the best of our knowledge, they represent the third and fourth cases in which such an anomaly of the pulmonary artery branches not forming a sling is seen in association with Kabuki syndrome. Another case represents our second experience and the second case reported in literature with duplicated left pulmonary artery in the setting of a complex tracheal anatomy. In this symptomatic patient, surgical repair of atrial septal defect and relief of the vascular ring were indicated, and the surgical repair was performed successfully at the age of 3 years. PMID- 25739971 TI - Cancer biomarker detection: recent achievements and challenges. AB - The early detection of cancer can significantly reduce cancer mortality and saves lives. Thus, a great deal of effort has been devoted to the exploration of new technologies to detect early signs of the disease. Cancer biomarkers cover a broad range of biochemical entities, such as nucleic acids, proteins, sugars, small metabolites, and cytogenetic and cytokinetic parameters, as well as entire tumour cells found in the body fluid. They can be used for risk assessment, diagnosis, prognosis, and for the prediction of treatment efficacy and toxicity and recurrence. In this review, we provide an overview of recent advances in cancer biomarker detection. Several representative examples using different approaches for each biomarker have been reviewed, and all these cases demonstrate that the multidisciplinary technology-based cancer diagnostics are becoming an increasingly relevant alternative to traditional techniques. In addition, we also discuss the unsolved problems and future challenges in the evaluation of cancer biomarkers. Clearly, solving these hurdles requires great effort and collaboration from different communities of chemists, physicists, biologists, clinicians, material-scientists, and engineering and technical researchers. A successful outcome will result in the realization of point-of-care diagnosis and individualized treatment of cancers by non-invasive and convenient tests in the future. PMID- 25739973 TI - Subcutaneous immunotherapy in hemophilic patients. PMID- 25739974 TI - Pharmacokinetics and immunogenicity investigation of a human anti-interleukin-17 monoclonal antibody in non-naive cynomolgus monkeys. AB - The pharmacokinetics (PK) of biologic therapeutics, especially monoclonal antibodies (mAbs), in monkeys generally presents the most relevant predictive PK information for humans. However, human mAbs, xenogeneic proteins to monkeys, are likely to be immunogenic. Monkeys previously treated with a human mAb (non-naive) may have developed antidrug antibodies (ADAs) that cross-react with another test mAb in subsequent studies. Unlike PK studies for small-molecule therapeutics, in which animals may be reused, naive monkeys have been used almost exclusively for preclinical PK studies of biologic therapeutics to avoid potential pre-existing immunologic cross-reactivity issues. The propensity and extent of pre-existing ADAs have not been systematically investigated to date. In this study, the PK and immunogenicity of mAb A, a human anti-human interkeukin-17 mAb, were investigated in a colony of 31 cynomolgus monkeys previously exposed to other human mAbs against different targets. We screened the monkeys for pre-existing antibodies to mAb A prior to the PK study and showed that 44% of the monkeys had pre-existing cross-reactive antibodies to mAb A, which could affect the PK characterization of the antibody. In the subcolony of monkeys without measurable pre-existing ADAs, PK and immunogenicity of mAb A were successfully characterized. The impact of ADAs on mAb A PK was also demonstrated in the monkeys with pre-existing ADAs. Here we report the results and propose a pragmatic approach for the use of non naive monkeys when conducting PK studies of biologic therapeutics. PMID- 25739975 TI - Establishment of a hepatocyte-kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters. AB - Elevated levels of proinflammatory cytokines associated with infection and inflammation can modulate cytochrome P450 enzymes, leading to potential disease drug interactions and altered small-molecule drug disposition. We established a human-derived hepatocyte-Kupffer cell (Hep:KC) coculture model to assess the indirect cytokine impact on hepatocytes through stimulation of KC-mediated cytokine release and compared this model with hepatocytes alone. Characterization of Hep:KC cocultures showed an inflammation response after treatment with lipopolysaccharide and interleukin (IL)-6 (indicated by secretion of various cytokines). Additionally, IL-6 exposure upregulated acute-phase proteins (C reactive protein, alpha-1-acid glycoprotein, and serum amyloid A2) and downregulated CYP3A4. Compared with hepatocytes alone, Hep:KC cocultures showed enhanced IL-1beta-mediated effects but less impact from both IL-2 and IL-23. Hep:KC cocultures treated with IL-1beta exhibited a higher release of proinflammatory cytokines, an increased upregulation of acute-phase proteins, and a larger extent of metabolic enzyme and transporter suppression. IC50 values for IL-1beta-mediated CYP3A4 suppression were lower in Hep:KC cocultures (98.0-144 pg/ml) compared with hepatocytes alone (IC50 > 5000 pg/ml). Cytochrome suppression was preventable by blocking IL-1beta interaction with IL-1R1 using an antagonist cytokine or an anti-IL-1beta antibody. Unlike IL-1beta, IL-6-mediated effects were comparable between hepatocyte monocultures and Hep:KC cocultures. IL 2 and IL-23 caused a negligible inflammation response and a minimal inhibition of CYP3A4. In both hepatocyte monocultures and Hep:KC cocultures, IL-2RB and IL-23R were undetectable, whereas IL-6R and IL-1R1 levels were higher in Hep:KC cocultures. In summary, compared with hepatocyte monocultures, the Hep:KC coculture system is a more robust in vitro model for studying the impact of proinflammatory cytokines on metabolic enzymes. PMID- 25739976 TI - Antidepressant Effects of Exercise: A Role for the Adiponectin-PGC-1alpha kynurenine Triad? PMID- 25739978 TI - Dharmasena case illustrates what is wrong with complaints procedures. PMID- 25739979 TI - Predicting reattendance at a high-risk breast cancer clinic. AB - OBJECTIVE: The research about follow-up patterns of women attending high-risk breast-cancer clinics is sparse. This study sought to profile daughters of breast cancer patients who are likely to return versus those unlikely to return for follow-up care in a high-risk clinic. METHOD: Our investigation included 131 patients attending the UCLA Revlon Breast Center High Risk Clinic. Predictor variables included age, computed breast-cancer risk, participants' perceived personal risk, clinically significant depressive symptomatology (CES-D score >= 16), current level of anxiety (State-Trait Anxiety Inventory), and survival status of participants' mothers (survived or passed away from breast cancer). RESULTS: A greater likelihood of reattendance was associated with older age (adjusted odds ratio [AOR] = 1.07, p = 0.004), computed breast-cancer risk (AOR = 1.10, p = 0.017), absence of depressive symptomatology (AOR = 0.25, p = 0.009), past psychiatric diagnosis (AOR = 3.14, p = 0.029), and maternal loss to breast cancer (AOR = 2.59, p = 0.034). Also, an interaction was found between mother's survival and perceived risk (p = 0.019), such that reattendance was associated with higher perceived risk among participants whose mothers survived (AOR = 1.04, p = 0.002), but not those whose mothers died (AOR = 0.99, p = 0.685). Furthermore, a nonlinear inverted "U" relationship was observed between state anxiety and reattendance (p = 0.037); participants with moderate anxiety were more likely to reattend than those with low or high anxiety levels. SIGNIFICANCE OF RESULTS: Demographic, medical, and psychosocial factors were found to be independently associated with reattendance to a high-risk breast-cancer clinic. Explication of the profiles of women who may or may not reattend may serve to inform the development and implementation of interventions to increase the likelihood of follow-up care. PMID- 25739977 TI - Genome-wide DNA methylome analysis reveals epigenetically dysregulated non-coding RNAs in human breast cancer. AB - Despite growing appreciation of the importance of epigenetics in breast cancer, our understanding of epigenetic alterations of non-coding RNAs (ncRNAs) in breast cancer remains limited. Here, we explored the epigenetic patterns of ncRNAs in breast cancers using published sequencing-based methylome data, primarily focusing on the two most commonly studied ncRNA biotypes, long ncRNAs and miRNAs. We observed widely aberrant methylation in the promoters of ncRNAs, and this abnormal methylation was more frequent than that in protein-coding genes. Specifically, intergenic ncRNAs were observed to comprise a majority (51.45% of the lncRNAs and 51.57% of the miRNAs) of the aberrantly methylated ncRNA promoters. Moreover, we summarized five patterns of aberrant ncRNA promoter methylation in the context of genomic CpG islands (CGIs), in which aberrant methylation occurred not only on CGIs, but also in regions flanking CGI and in CGI-lacking promoters. Integration with transcriptional datasets enabled us to determine that the ncRNA promoter methylation events were associated with transcriptional changes. Furthermore, a panel of ncRNAs were identified as biomarkers that discriminated between disease phenotypes. Finally, the potential functions of aberrantly methylated ncRNAs were predicted, suggestiong that ncRNAs and coding genes cooperatively mediate pathway dysregulation during the development and progression of breast cancer. PMID- 25739980 TI - Modulation of HMGB1 translocation and RAGE/NFkappaB cascade by quercetin treatment mitigates atopic dermatitis in NC/Nga transgenic mice. AB - Quercetin, glycosylated form of flavonoid compound, has potent antioxidant and anti-inflammatory properties. In this study, we have investigated the effects of quercetin on skin lesion, high-mobility group box (HMGB)1 cascade signalling and inflammation in atopic dermatitis (AD) mouse model. AD-like lesion was induced by the application of house dust mite extract to the dorsal skin of NC/Nga transgenic mouse. After AD induction, quercetin (50 mg/kg, p.o) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for HMGB1, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)4, nuclear factor (NF)kappaB, nuclear factor erythroid-2-related factor (Nrf)2, kelch-like ECH associated protein (Keap)1, extracellular signal-regulated kinase (ERK)1/2, cyclooxygenase (COX)2, tumor necrosis factor (TNF)alpha, interleukin (IL)-1beta, IL-2Ralpha and other inflammatory markers in the skin of AD mice. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)gamma, IL-4) were measured by enzyme-linked immunosorbent assay. Quercetin treatment attenuated the development of AD-like skin lesions. Histological analysis showed that quercetin inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells. Furthermore, quercetin treatment downregulated cytoplasmic HMGB1, RAGE, nuclear p-NFkappaB, p-ERK1/2, COX2, TNFalpha, IL-1beta, IL-2Ralpha, IFNgamma and IL-4 and upregulated nuclear Nrf2. Our data demonstrated that the HMGB1/RAGE/NFkappaB signalling might play an important role in skin inflammation, and quercetin treatment could be a promising agent for AD by modulating the HMGB1/RAGE/NFkappaB signalling and induction of Nrf2 protein. PMID- 25739982 TI - mTOR is involved in 17beta-estradiol-induced, cultured immature boar Sertoli cell proliferation via regulating the expression of SKP2, CCND1, and CCNE1. AB - Mammalian target of rapamycin (mTOR) is known to be involved in mammalian cell proliferation, while S-phase kinase-associated protein 2 (SKP2) plays a vital role in the cell cycle. Within the testis, estrogen also plays an important role in Sertoli cell proliferation, although it is not clear how. The present study asked if mTOR is involved in 17beta-estradiol-dependent Sertoli cell proliferation. We specifically assessed if extracellular signal-regulated kinase 1/2 (ERK1/2) and/or phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) exert convergent effects toward the activation of mTOR signaling, and if this signaling regulates the expression of SKP2 through retinoblastoma (RB) and early mitotic inhibitor 1 (EMI1) protein and on CCNE1 and CCND1 mRNA levels. Treatment with 17beta-estradiol for 15-90 min activated mTOR, with mTOR phosphorylation peaking after 30 min. U0126 (5 MUM), a specific inhibitor of (MEK1/2), and 10-DEBC (2 MUM), a selective inhibitor of AKT, both significantly reduced 17beta-estradiol induced phosphorylation of mTOR. Rapamycin suppressed 17beta-estradiol-induced Sertoli cell proliferation, appearing to act by reducing the abundance of SKP2, CCND1, and CCNE1 mRNA as well as RB and EMI1 protein. These data indicated that 17beta-estradiol enhances Sertoli cell proliferation via mTOR activation, which involves both ERK1/2 and PI3K/AKT signaling. Activated mTOR subsequently increases SKP2 mRNA and protein expression by enhancing the expression of CCND1 and CCNE1, and inhibits SKP2 protein degradation by increasing EMI1 abundance. PMID- 25739981 TI - Host-pathogen interaction profiling using self-assembling human protein arrays. AB - Host-pathogen protein interactions are fundamental to every microbial infection, yet their identification has remained challenging due to the lack of simple detection tools that avoid abundance biases while providing an open format for experimental modifications. Here, we applied the Nucleic Acid-Programmable Protein Array and a HaloTag-Halo ligand detection system to determine the interaction network of Legionella pneumophila effectors (SidM and LidA) with 10 000 unique human proteins. We identified known targets of these L. pneumophila proteins and potentially novel interaction candidates. In addition, we applied our Click chemistry-based NAPPA platform to identify the substrates for SidM, an effector with an adenylyl transferase domain that catalyzes AMPylation (adenylylation), the covalent addition of adenosine monophosphate (AMP). We confirmed a subset of the novel SidM and LidA targets in independent in vitro pull-down and in vivo cell-based assays, and provided further insight into how these effectors may discriminate between different host Rab GTPases. Our method circumvents the purification of thousands of human and pathogen proteins, and does not require antibodies against or prelabeling of query proteins. This system is amenable to high-throughput analysis of effectors from a wide variety of human pathogens that may bind to and/or post-translationally modify targets within the human proteome. PMID- 25739983 TI - Effect of alpha-synuclein on membrane permeability and synaptic transmission: a clue to neurodegeneration? AB - This is an Editorial highlighting the article "Extracellular alpha-synuclein alters synaptic transmission in rain neurons by perforating the neuronal plasma membrane" by Pacheco and coauthors, in this issue of Journal of Neurochemistry. The authors demonstrate, using a variety of techniques, that alpha-synuclein possesses neurotoxicity toward brain neuronal plasma membranes exposed directly to extracellular alpha-synuclein oligomers. Extracellular oligomeric alpha synuclein rapidly associates to hippocampal membranes and induces pore formation in the hippocampal cells. This increases membrane conductance and calcium influx. Oligomeric alpha-synuclein also induces changes in synaptic current activity in hippocampal neurons. The authors' findings support the pathogenic role of extracellular alpha-synuclein in the brain, and should provide a new strategy for the treatment of Parkinson's disease and other synucleinopathies, neurodegenerative diseases with aberrant accumulation of aggregated alpha synuclein in neurons, nerve fibers or glial cells. Read the full article 'Extracellular alpha-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane' on page 731. PMID- 25739984 TI - Corrigendum: Dark-field X-ray microscopy for multiscale structural characterization. PMID- 25739987 TI - Hearts beating through decellularized scaffolds: whole-organ engineering for cardiac regeneration and transplantation. AB - Whole-organ decellularization and tissue engineering approaches have made significant inroads during recent years. If proven to be successful and clinically viable, it is highly likely that this field would be poised to revolutionize organ transplantation surgery. In particular, whole-heart decellularization has captured the attention and imagination of the scientific community. This technique allows for the generation of a complex three dimensional (3D) extracellular matrix scaffold, with the preservation of the intrinsic 3D basket-weave macroarchitecture of the heart itself. The decellularized scaffold can then be recellularized by seeding it with cells and incubating it in perfusion bioreactors in order to create functional organ constructs for transplantation. Indeed, research into this strategy of whole heart tissue engineering has consequently emerged from the pages of science fiction into a proof-of-concept laboratory undertaking. This review presents current trends and advances, and critically appraises the concepts involved in various approaches to whole-heart decellularization and tissue engineering. PMID- 25739988 TI - Impaired bone mineral density as a predictor of graft subsidence following minimally invasive transpsoas lateral lumbar interbody fusion. AB - PURPOSE: The LLIF procedure is a useful stand-alone and adjunct surgical approach for many spinal conditions. One complication of LLIF is subsidence of the interbody graft into the vertebral bodies, resulting in severe pain, impaired arthrodesis and potentially fracture of the body. Low bone density, as measured by T score on DEXA scanning, has also been postulated to increase the risk of subsidence. METHODS: A retrospective review of prospectively collected data was performed on all patients who underwent LLIF at this institution consisting of 712 levels in 335 patients. Patients with subsidence following LLIF were recorded. We utilized the T score obtained from the femoral neck DEXA scans, which is used to determine overall fracture risk. The T score of patients with subsidence was compared to those without subsidence. RESULTS: 20 of 57 (35 %) patients without subsidence had a DEXA T score between -1.0 and -2.4 consistent osteopenia, one patient (1.8 %) exhibited a T score less than -2.5, consistent with osteoporosis. 13 patients of 23 (57 %) with subsidence exhibited a T score between -1.0 and -2.4, consistent with osteopenia, five (22 %) exhibited a T score of -2.5 or less, consistent with osteoporosis. The mean DEXA T score in patients with subsidence was -1.65 (SD 1.04) compared to -0.45 (SD 0.97) in patients without subsidence (p < 0.01). The area under the receiver operating characteristic curve for patients with a T score of -1.0 or less was 80.1 %. CONCLUSIONS: Patients with DEXA T scores less than -1.0 who undergo stand-alone LLIF are at a much higher risk of developing graft subsidence. Further, they are at an increased risk of requiring additional surgery. In patients with poor bone quality, consideration could be made to supplement the LLIF cage with posterior instrumentation. PMID- 25739990 TI - Mortality after acute primary mesenteric infarction: a systematic review and meta analysis of observational studies. AB - AIM: The primary aim of this study was to determine whether the in-hospital mortality for acute mesenteric infarction has reduced in the last decade. The secondary aim was to determine if there was a statistical difference in mortality between patients having acute primary mesenteric infarction due to different causes. METHOD: A literature search was performed of PubMed, Ovid (Embase) and Google Scholar databases. Studies on acute mesenteric infarction of primary vascular pathology were included for pooled analyses while studies that had reported comparative mortality between arterial, venous and non-occlusive mesenteric infarction (NOMI) were included in meta-analyses. Their quality was assessed using the National Institute for Health and Care Excellence assessment scale. Odds ratios (ORs) of mortality were calculated using a Mantel-Haenszel random effect model. RESULTS: The total number of patients was 4527 and the male/female ratio was 1912/2247. The pooled in-hospital mortality was 63%. There was no significant reduction of in-hospital mortality rate in the last decade (P = 0.78). There was a significant difference in in-hospital mortality between acute arterial mesenteric infarction (73.9%) compared with acute venous mesenteric infarction (41.7%) [OR 3.47, confidence interval (CI) 2.43-4.96, P < 0.001] and NOMI (68.5%) compared with acute venous mesenteric infarction (44.2%) (OR 3.2, CI 1.83-5.6, P < 0.001). There was no difference in mortality between acute arterial mesenteric infarction and NOMI (OR 1.08, CI 0.57-2.03, P = 0.82). CONCLUSION: In-hospital mortality rate has not changed in the last decade. Patients with arterial mesenteric infarction or with NOMI are over three times more likely to die during the first hospital admission compared with those with venous mesenteric infarction. PMID- 25739989 TI - Tolerance of activated pathogenic CD4+ T cells by transcriptional targeting of dendritic cells. AB - We have recently shown that targeted expression of myelin oligodendrocyte glycoprotein (MOG) to dendritic cells with self-inactivating-lentivirus vectors induces antigen-specific tolerance in naive antigen-specific CD4+ T cells and protects mice from experimental autoimmune encephalomyelitis (EAE). In the present study, we demonstrate that this approach also induces tolerance of activated antigen-specific CD4+ T cells and completely protects mice from passive EAE induction. Tolerance induction did not correlate with the depletion of the preactivated antigen-specific CD4+ T cells. However, upon isolation and in vitro re-stimulation at day 6 after adoptive transfer the MOG-specific CD4+ T cells from the non-tolerized mice produced large amounts of inflammatory cytokines, whereas those from tolerized mice did not. This unresponsiveness correlated with the upregulation of regulatory molecules associated with anergy and regulatory T cells (Tregs). The in vivo depletion of Tregs resulted in EAE susceptibility of the tolerized animals, suggesting that these cells have indeed a role in tolerance induction/maintenance. PMID- 25739991 TI - The Singh Index does not correlate with bone mineral density (BMD) measured with dual energy X-ray absorptiometry (DXA) or peripheral quantitative computed tomography (pQCT). AB - The Singh Index (SI), a classification system by which the severity of osteoporosis is assessed based on plain radiographs, is a renowned, simple and inexpensive form of evaluating osteoporosis. The aim of this study was to evaluate the correlation between the SI and bone mineral density (BMD) as measured by dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). The SI was evaluated in 128 cadaveric femora (64 patients, mean age 66.7 years, range 24-89 years) by three independent observers, all blinded to plain radiographs. BMD was also analysed by means of DXA and pQCT in the cadaveric femora. The mean interrater correlation was found to be 0.629. The correlation of the mean BMD measured by DXA (DXA-BMD) and SI was found to be poor, with r = 0.49. The corresponding sensitivity of 45.2 % and specificity of 92.3 % were even poor. The BMD measured by pQCT (pQCT-BMD) also revealed a poor correlation with SI, such that r = 0.337 and r = 0.428 for the trochanteric and neck regions, respectively. Due to the poor correlation of the SI with BMD and the poorer interrater correlation, the SI should be rejected as a tool for evaluating osteoporosis. The SI was found to be too imprecise and is therefore unsuitable for diagnosing osteoporosis and osteopenia. PMID- 25739992 TI - One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. AB - BACKGROUND: Tranexamic acid (TXA) in orthopedics has recently been gaining favor due to its efficacy and ease of use, both in intravenous (IV) and intraarticular (IA) usage. However, because of safety concerns with IV administration, there has been a growing interest in the IA use of TXA to prevent bleeding. MATERIALS AND METHODS: This study conducted a systematic review and meta-analysis that included 31 randomized, controlled trials in which the effect of systemic and topical TXA on total blood loss (TBL), rates of transfusion, and thromboembolic events was investigated. RESULTS: Compared to the control, the IA administration of TXA led to the significant reduction of mean TBL (p < 0.001), rate of transfusion (p < 0.001), and reduction of rate of thromboembolic events (p = 0.29). Compared to the control group, the IV administration of TXA resulted in significant reduction of mean TBL (p < 0.001), rate of transfusion (p < 0.001), and rate of thromboembolic events (p = 0.66). Although no significant differences in efficacy and safety between the IA and IV administration of TXA were found, the IA method was safer than the IV method in that it reduced rate of transfusion and thromboembolic events. CONCLUSION: This study showed that TXA leads to significant reductions in TBL and the rate of allogeneic transfusions. Generally, no significant difference was detected between IA and IV administration of TXA; however, more studies with focus on safety and efficacy are warranted. PMID- 25739993 TI - Surface or full cementation of the tibial component in total knee arthroplasty: a matched-pair analysis of mid- to long-term results. AB - INTRODUCTION: Despite the clinical success of cemented TKA, aseptic loosening of the tibial component remains a potential long-term complication. Considering the constantly growing revision burden, there is a need for clarification regarding controversial views on primary fixation techniques. In this retrospective analysis, surface (SC) or full cementation (FC) of tibial components was compared in a matched-pair and long-term setting. METHODS: Matching pairs were identified in a patient series from 1989 to 1994. Hence, 25 primary TKA (SC) were compared to 42 TKA (FC). The study population included 34 patients with rheumatoid arthritis. Patients were matched in a 1:1.7 fashion according to age, gender and initial diagnosis. Outcome was assessed by multiple clinical parameters, detailed radiographic evaluation and survivorship analysis. RESULTS: Clinical follow-up (FU) was at 10.3 years (range 1.5-15.6) for the SC and 12 years (range 0.2-16.2) for the FC group. Survivorship at 10 years was 100 % for the surface cemented trays and 93.3 % (95 % CI 80.5-100) for the fully cemented implants considering aseptic loosening as endpoint (p = 0.3918). Improvement of the AKS Score was greater in the SC group (p = 0.044) and patients in this group were more satisfied (p = 0.013). For any other clinical parameter, no difference could be observed (p > 0.05). CONCLUSION: Results of this study showed no statistically significant difference regarding long-term survivorship for the two cementing techniques. This finding questions the claimed advantage of full cementation for tibial components. The presented data do not support the concern that surface cementation results in insufficient fixation in patients with rheumatoid arthritis. PMID- 25739994 TI - State selection in Markov models for panel data with application to psoriatic arthritis. AB - Markov multistate models in continuous-time are commonly used to understand the progression over time of disease or the effect of treatments and covariates on patient outcomes. The states in multistate models are related to categorisations of the disease status, but there is often uncertainty about the number of categories to use and how to define them. Many categorisations, and therefore multistate models with different states, may be possible. Different multistate models can show differences in the effects of covariates or in the time to events, such as death, hospitalisation, or disease progression. Furthermore, different categorisations contain different quantities of information, so that the corresponding likelihoods are on different scales, and standard, likelihood based model comparison is not applicable. We adapt a recently developed modification of Akaike's criterion, and a cross-validatory criterion, to compare the predictive ability of multistate models on the information which they share. All the models we consider are fitted to data consisting of observations of the process at arbitrary times, often called 'panel' data. We develop an implementation of these criteria through Hidden Markov models and apply them to the comparison of multistate models for the Health Assessment Questionnaire score in psoriatic arthritis. This procedure is straightforward to implement in the R package 'msm'. PMID- 25739995 TI - Natural high pCO2 increases autotrophy in Anemonia viridis (Anthozoa) as revealed from stable isotope (C, N) analysis. AB - Contemporary cnidarian-algae symbioses are challenged by increasing CO2 concentrations (ocean warming and acidification) affecting organisms' biological performance. We examined the natural variability of carbon and nitrogen isotopes in the symbiotic sea anemone Anemonia viridis to investigate dietary shifts (autotrophy/heterotrophy) along a natural pCO2 gradient at the island of Vulcano, Italy. delta(13)C values for both algal symbionts (Symbiodinium) and host tissue of A. viridis became significantly lighter with increasing seawater pCO2. Together with a decrease in the difference between delta(13)C values of both fractions at the higher pCO2 sites, these results indicate there is a greater net autotrophic input to the A. viridis carbon budget under high pCO2 conditions. delta(15)N values and C/N ratios did not change in Symbiodinium and host tissue along the pCO2 gradient. Additional physiological parameters revealed anemone protein and Symbiodinium chlorophyll a remained unaltered among sites. Symbiodinium density was similar among sites yet their mitotic index increased in anemones under elevated pCO2. Overall, our findings show that A. viridis is characterized by a higher autotrophic/heterotrophic ratio as pCO2 increases. The unique trophic flexibility of this species may give it a competitive advantage and enable its potential acclimation and ecological success in the future under increased ocean acidification. PMID- 25739996 TI - Optimization of high cell density fermentation process for recombinant nitrilase production in E. coli. AB - Nitrilases constitute an important class of biocatalysts for chiral synthesis. This work was undertaken with the aim to optimize nitrilase production in a host that is well-studied for protein production. Process parameters were optimized for high cell density fermentation, in batch and fed-batch modes, of Escherichia coli BL21 (DE3) expressing Pseudomonas fluorescens nitrilase with a T7 promoter based expression system. Effects of different substrates, temperature and isopropyl beta-D-1-thiogalactopyranoside (IPTG) induction on nitrilase production were studied. Super optimal broth containing glycerol but without an inducer gave best results in batch mode with 32 degrees C as the optimal temperature. Use of IPTG led to insoluble protein and lower enzyme activity. Optimized fed-batch strategy resulted in significant improvement in specific activity as well as volumetric productivity of the enzyme. On a volumetric basis, the activity improved 40-fold compared to the unoptimized batch process. PMID- 25739997 TI - Evidence of syntrophic acetate oxidation by Spirochaetes during anaerobic methane production. AB - To search for evidence of syntrophic acetate oxidation by cluster II Spirochaetes with hydrogenotrophic methanogens, batch reactors seeded with five different anaerobic sludge samples supplemented with acetate as the sole carbon source were operated anaerobically. The changes in abundance of the cluster II Spirochaetes, two groups of acetoclastic methanogens (Methanosaetaceae and Methanosarcinaceae), and two groups of hydrogenotrophic methanogens (Methanomicrobiales and Methanobacteriales) in the reactors were assessed using qPCR targeting the 16S rRNA genes of each group. Increase in the cluster II Spirochaetes (9.0+/-0.4 fold) was positively correlated with increase in hydrogenotrophic methanogens, especially Methanomicrobiales (5.6+/-1.0-fold), but not with acetoclastic methanogens. In addition, the activity of the cluster II Spirochaetes decreased (4.6+/-0.1-fold) in response to high hydrogen partial pressure, but their activity was restored after consumption of hydrogen by the hydrogenotrophic methanogens. These results strongly suggest that the cluster II Spirochaetes are involved in syntrophic acetate oxidation in anaerobic digesters. PMID- 25739998 TI - Phosphate enhancing fermentative hydrogen production from substrate with municipal solid waste composting leachate as a nutrient. AB - To overcome phosphorus deficiency in municipal solid waste composting leachate, orthophosphate (OP) and pyrophosphate (PP) were separately added into leachate to evaluate the possibility of fermentative H2 production with leachate and phosphorus-rich streams as a full nutrient source. Results indicate H2 production is significantly promoted by OP addition but slightly facilitated by PP in some cases, depending on initial pH and P dosage. The highest hydrogen yield (1.95+/ 0.07mol H2/mol glucose) was achieved at a COD/P ratio of 27.64 (mg/mg) with OP as phosphorus source at initial pH 5. For PP, a maximum yield of 1.58+/-0.09mol H2/mol glucose can be attained at the optimal COD/P ratio of 221.12 (mg/mg) and initial pH 5. OP promotes H2 production via dual approaches: supplying nutrient and relieving inhibition from excessive Ca(2+) on granule sludge. However, both the roles in nutrient supply and Ca(2+) removal by PP addition are limited. PMID- 25739999 TI - Prediction of sugar yields during hydrolysis of lignocellulosic biomass using artificial neural network modeling. AB - The present investigation was carried out to study application of ANN as a tool for predicting sugar yields of pretreated biomass during hydrolysis process at various time intervals. Since it is known that biomass loading and particle size influences the rheology and mass transfer during hydrolysis process, these two parameters were chosen for investigating the efficiency of hydrolysis. Alkali pretreated rice straw was used as the model feedstock in this study and biomass loadings were varied from 10% to 18%. Substrate particle sizes used were <0.5mm, 0.5-1mm, >1mm and mixed size. Effectiveness of hydrolysis was strongly influenced by biomass loadings, whereas particle size did not have any significant impact on sugar yield. Higher biomass loadings resulted in higher sugar concentration in the hydrolysates. Optimum hydrolysis conditions predicted were 10 FPU/g cellulase, 5 IU/g BGL, 7500 U/g xylanase, 18% biomass loading and mixed particle size with reaction time between 12-28 h. PMID- 25740000 TI - Improved production of reducing sugars from rice straw using crude cellulase activated with Fe3O4/alginate nanocomposite. AB - Effect of Fe3O4 nanoparticles (NPs) and Fe3O4/Alginate nanocomposites (NCs) have been investigated on production and thermostability of crude cellulase enzyme system obtained by newly isolated thermotolerant Aspergillus fumigatus AA001. Fe3O4 NPs and Fe3O4/Alginate NCs have been synthesized by co-precipitation method and characterized through various techniques. In presence of Fe3O4 NPs and Fe3O4/Alginate NCs, filter paper activity of crude cellulase was increased about 35% and 40%, respectively in 72 h as compared to control. Fe3O4/Alginate NCs treated crude enzyme was thermally stable up to 8h at 70 degrees C and retained 56% of its relative activity whereas; control samples could retain only 19%. Further, the hydrolysis of 1.0% alkali treated rice straw using Fe3O4/Alginate NCs treated cellulase gave much higher sugar productivity than control at optimal condition. These findings may be utilized in the area of biofuels and biowaste management. PMID- 25740001 TI - CaFeAl mixed oxide derived heterogeneous catalysts for transesterification of soybean oil to biodiesel. AB - CaAl layered double oxides (LDO) were prepared by co-precipitation and calcined at 750 degrees C, and then applied to biodiesel production by transesterification reaction between methanol and soybean oil. Compared with characteristics of CaFe/LDO and CaAl/LDO, CaFeAl/LDO had the best performance based on prominent catalytic activity and stability, and achieved over 90% biodiesel yield, which stayed stable (over 85%) even after 8 cycles of reaction. The optimal catalytic reaction condition was 12:1M-ratio of methanol/oil, reaction temperatures of 60 degrees C, 270rpm stirring rate, 60min reaction time, and 6% weight-ratio of catalyst/oil. In addition, the CaFeAl/LDO catalyst is insoluble in both methanol and methyl esters and can be easily separated for further reaction, turning it into an excellent alternative for biodiesel synthesis. PMID- 25740002 TI - Poly(ornithine-co-arginine-co-glycine-co-aspartic Acid): Preparation via NCA Polymerization and its Potential as a Polymeric Tumor-Penetrating Agent. AB - A novel random copolypeptide of ornithine, arginine, glycine, and aspartic acid [Poly(ornithine-co-arginine-co-glycine-co-aspartic acid), Poly(O,R,G,D)] has been prepared through ring-opening polymerization of N-delta-carbobenzoxy-l-ornithine N-carboxyanhydride [Orn(Cbz)-NCA)], l-glycine N-carboxyanhydride (Gly-NCA) and beta-benzyl l-aspartate N-carboxyanhydride [Asp(Bn)-NCA], following by subsequent deprotection and guanidization. The structure of Poly(O,R,G,D) was confirmed by nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC). Low cytotoxicity of Poly(O,R,G,D) was confirmed from MTT assay. The Poly(O,R,G,D) contain some internal sequences of RXXR (X = O, R, G, or D) that could be proteolytically cleaved to expose the cryptic CendR element and bind to Neuropilin-1. This would lead to vascular and tissue permeabilization. Therefore trypsin-cleaved Poly(O,R,G,D) increase the vascular leakage of Evans blue from dermal microvessels at the injection site in vivo skin permeability assay. The intratumoral injection of the Poly(O,R,G,D) significantly enhanced the concentration of cisplatin-loaded nanoparticles in MCF-7 solid tumors. These results show that Poly(O,R,G,D) could increase the vascular leakage and tissue penetration of nanoparticles in a solid tumor and can be used as a potential polymeric tumor-penetrating agent. PMID- 25740003 TI - Comparison between Long- and Short-Acting Erythropoiesis-Stimulating Agents in the Period Required for Haemoglobin Stabilisation in Treatment of Anaemia in Patients with Chronic Kidney Disease. AB - Comparative studies of the potency of long- and short-acting erythropoiesis stimulating agents (L-ESAs and S-ESAs) on erythropoietic activity in patients with chronic kidney disease without dialysis have not been performed, although L ESAs are used in many countries. We performed a retrospective analysis of non dialysis (ND) patients who had received L-ESA or S-ESA. More days were needed for the S-ESA-treated group (368 d) to reach the haemoglobin (Hb) reference range than for the L-ESA-treated group (126 d). Therefore, we investigated risk factors that influence the period until the Hb level reaches the reference range. Patients were classified into two groups by the period until the Hb level was stabilised within the reference range: the short- and long-term group. Two risk factors for delayed Hb stabilisation were identified: age >=60 years; and administration of an S-ESA for initial treatment. These findings suggest that the Hb level should be carefully monitored during ESA therapy in elderly ND patients, and that the ESA dose should be increased or L-ESA therapy should be utilised to treat renal anaemia. PMID- 25740004 TI - State-specific multireference perturbation theory with improved virtual orbitals: taming the ground state of F2 , Be2, and N2. AB - Adaptation of improved virtual orbitals (IVOs) in state-specific multireference perturbation theory using Moller-Plesset multipartitioning of the Hamiltonian (IVO-SSMRPT) is examined in which the IVO-complete active space configuration interaction (CASCI) is used as an inexpensive alternative to the more involved CAS-self-consistent field (CASSCF) orbitals. Unlike the CASSCF approach, IVO CASCI does not bear tedious and costly iterations beyond those in the initial SCF calculation. The IVO-SSMRPT is intruder-free, and explicitly size-extensive. In the present preliminary study, the IVO-SSMRPT method which relies on a small reference space is applied to study potential energy surfaces (PES) of the ground state of challenging, multiconfigurational F2 , Be2 , and N2 molecules. These systems provide a serious challenge to any ab initio methodology due to the presence of an intricate interplay of nondynamical and dynamical correlations to the entire PES. The quality of the computed PES has been judged by extracting spectroscopic parameters and vibrational levels. The reported results illustrate that the IVO-SSMRPT method has a potential to yield accuracies as good as the CASSCF-SSMRPT one with reduced computational labor. Even with small reference spaces, our estimates demonstrate a good agreement with the available experimental values, and some benchmark computations. The blend of accuracy and low computational cost of IVO-SSMRPT should deserve future attention for the accurate treatment of electronic states of small to large molecular systems for which the wavefunction is characterized by various configurations. PMID- 25740006 TI - Core-level photoemission spectra of Mo0.3Cu0.7Sr2ErCu2Oy, a superconducting perovskite derivative. Unconventional structure-property relationships. AB - Detailed studies of the electronic states for Mo(0.3)Cu(0.7)Sr(2)ErCu(2)Oy samples with different oxygen contents are presented here. The influence of oxygenation on the electronic states for the Mo(0.3)Cu(0.7)Sr(2)ErCu(2)Oy system from the semiconducting to the superconducting state has been investigated by means of X-ray photoelectron spectroscopy (XPS). The XPS studies show that Mo is in a mixed Mo(V) and Mo(VI) oxidation state and Mo(V) is predominant over the Mo(VI) in the as-prepared (AP) sample. Yet annealing under an oxygen atmosphere enhances the Mo(VI) state. At the same time, a reduction in the copper species is observed. In the Cu 2p spectra, a larger energy separation between the satellite and main peaks (E(S)-E(M)) and a lower intensity ratio (I(S)/I(M)) are found to correlate with higher values of the superconducting transition temperature (T(C)). Analysis of these spectra within the Configuration Interaction (CI) model suggests that higher values of TC are related to lower values of the O 2p-Cu 3d charge transfer energy. The change in the Sr 3d and O 1s core level spectra correlates with the oxygen insertion in the (Mo/Cu)O(1+delta) chain site, after oxygenation. The hole concentration (Ph) in the copper plane has been obtained using the room temperature thermoelectric power (TEP) value; this shows an increasing tendency with increasing T(C), after oxygenation. From these experimental results, one observes that T(C)increases with decreasing charge transfer energy. This is, indeed, opposite to the accepted views and occurs in parallel with the shortening of the apical copper-oxygen distance (Cu(2)-O(2)) and the increasing of the CuO(2) plane buckling angle. PMID- 25740007 TI - Shift schedules, work factors, and mental health among onshore and offshore workers in the Norwegian petroleum industry. AB - The purpose of the present study was to answer the following research questions: (1) Do workers in different shift schedules differ in mental distress? (2) Do workers in different shift schedules differ in neuroticism? (3) Do shift schedules differ in psychosocial work exposures? (4) Do psychosocial work exposures contribute to mental distress among onshore- and offshore workers? (5) Does neuroticism confound the association between work exposures and mental distress? Workers on six shift-schedules answered a questionnaire (1,471 of 2,628 employees). Psychological and social work factors were measured by QPSNordic, mental distress was measured by HADS and neuroticism was measured by EPQ. The results showed 1) No differences in mental distress between workers in different shift schedules, 2) Revolving-shift workers reported higher neuroticism compared to day workers, 3) Swing-shift workers and revolving-shift workers reported lower job control compared to permanent-night and -day workers, 4) Job demands and role conflict were associated with more mental distress. Job control, role clarity, support, and leadership were associated with lower mental distress, 5) Neuroticism influenced the relationship between psychosocial work factors and mental distress. The present study did not find differences in mental distress between shift schedules. Job characteristics may be contributing factors when determining health effects of shift work. PMID- 25740008 TI - Rearrangement of dypnones to 1,3,5-triarylbenzenes. AB - Rearrangement of dypnones to 1,3,5-triarylbenzenes is described. The reaction is proposed to involve an aldol-type self-condensation of dypnones, followed by an intramolecular [2 + 2] cycloaddition and a retro-[2 + 2] cycloaddition. The reaction goes smoothly under obviously milder conditions in comparison to the cyclotrimerization of acetophenones to 1,3,5-triarylbenzenes (10 mol % of TsOH, 80 degrees C versus 130-148 degrees C). This unexpected rearrangement would provide new possible considerations in dypnone-involved organic synthesis. PMID- 25740010 TI - Erratum to: The acceptability of parenting strategies for grandparents providing care to their grandchildren. PMID- 25740009 TI - Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis. AB - The diagnostic performance of M-type phospholipase A2 receptor (PLA2R) autoantibodies and PLA2R glomerular staining in discriminating between idiopathic membranous nephropathy (iMN) and secondary membranous nephropathy (sMN) has not been fully evaluated. We conducted an updated meta-analysis to investigate the accuracy and clinical value of serological anti-PLA2R test and histological PLA2R staining for differentiation iMN from sMN. A total of 19 studies involving 1160 patients were included in this meta-analysis. The overall sensitivity, specificity, diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC) of serum anti-PLA2R were 0.68 (95% CI, 0.61-074), 0.97 (95% CI, 0.85-1.00), 73.75 (95% CI, 12.56-432.96) and 0.82 (95% CI, 0.78 0.85), respectively, with substantial heterogeneity (I(2) = 86.42%). Subgroup analyses revealed the study design, publication type, study origin, assay method might account for the heterogeneity. Additionally, the overall sensitivity, specificity, DOR and AUROC of glomerular PLA2R staining were 0.78 (95% CI, 0.72 0.83), 0.91 (95% CI, 0.75-0.97), 34.70 (95% CI, 9.93-121.30) and 0.84 (95% CI, 0.81-0.87), respectively, without heterogeneity (I(2) = 0%). Serological anti PLA2R testing has diagnostic value, but it must be interpreted in context with patient clinical characteristics and histological PLA2R staining in seronegative patients is recommended. PMID- 25740011 TI - Erratum to: The family check-up and service use in high-risk families of young children: a prevention strategy with a bridge to community-based treatment. PMID- 25740012 TI - Erratum to: Preventing weight gain and obesity: indirect effects of the family check-up in early childhood. PMID- 25740013 TI - Insulin-like Growth Factor 1 Differentially Affects Lithium Sensitivity of Lymphoblastoid Cell Lines from Lithium Responder and Non-responder Bipolar Disorder Patients. AB - Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50-60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 (IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder. PMID- 25740014 TI - Wogonin Induced Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Human Malignant Neuroblastoma Cells Via IRE1alpha-Dependent Pathway. AB - Wogonin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been reported to exhibit a variety of biological effects including anti-cancer effects. It has a pro-apoptotic role in many cancer types. However, the molecular mechanisms of wogonin in treating neuroblastoma remain elusive. In the present study, two malignant neuroblastoma cell lines (SK-N-BE2 and IMR-32 cells) were treated with different doses of wogonin (0-150 MUM). Wogonin showed significant cytotoxic effects in SK-N-BE2 and IMR-32 cells in a dose- and time-dependent manner. Treatment of SK-N-BE2 and IMR-32 cells with 75 MUMU wogonin for 48 h significantly promoted apoptosis, the release of cytochrome c, altered the expression of certain members of Bcl-2 family (Bcl-2, Bax and Bid), and increased the activation of caspase-3, caspase-8, caspase-9, and PARP-1, which demonstrated that the cytotoxic effect of wogonin in SK-N-BE2 and IMR-32 cells is mediated by mitochondrial dysfunction. Moreover, wogonin induced the expression of endoplasmic reticulum (ER) stress-related proteins (GRP78/Bip and GRP94/gp96) and activation of caspase-12 and caspase-4 in SK-N-BE2 and IMR-32 cells. In addition, wogonin increase the expression of IRE1alpha and TRAF2, and phosphorylation of ASK1 and JNK in SK-N-BE2 and IMR-32 cells. Knockdown of IRE1alpha by siRNA not only markedly inhibited wogonin-induced up-regulation of IRE1alpha and TRAF2, and phosphorylation of ASK1 and JNK but also reduced wogonin-induced cytotoxic effects and mitochondrial dysfunction in SK-N-BE2 and IMR-32 cells. These results indicated that wogonin could induce apoptosis, mitochondrial dysfunction, and ER stress in SK-N-BE2 and IMR-32 cells by modulating IRE1alpha-dependent pathway. PMID- 25740016 TI - Reactivity and operational stability of N-Tailed TAMLs through kinetic studies of the catalyzed oxidation of orange II by H2 O2 : synthesis and X-ray structure of an N-phenyl TAML. AB - Invited for the cover of this issue are Terrence J. Collins and co-workers at Carnegie Mellon University (USA) and the National Chemical Laboratory (India). The image depicts five generations of tetraamido macrocyclic ligand (TAML) activators, which are small molecule, full-functional mimics of oxidizing enzymes that arguably outperform the peroxidase enzymes they mimic. Read the full text of the article at 10.1002/chem.201406061. PMID- 25740015 TI - Microtubule Dynamicity Is More Important than Stability in Memory Formation: an In Vivo Study. AB - It has been shown that microtubule (MT) activity and dynamics can have huge impacts on synaptic plasticity and memory formation. This is mainly due to various functions of MTs in neurons; MTs are involved in dendritic spine formation, axonal transportation, neuronal polarity, and receptor trafficking. Recent studies from our group and other labs have suggested the possible role of brain MT dynamicity and activity in memory; however, there is a need for more detailed studies regarding this aspect. In this study, we have tried to evaluate the importance of microtubule dynamicity rather than stability in memory formation in vivo. In order to investigate the role of MT stability in memory formation, we treated mice with paclitaxel-a classic microtubule-stabilizing agent. We then studied the behavior of treated animals using Morris water maze (MWM) test. To measure the effect of injected paclitaxel on MT polymerization kinetics, we conducted polymerization assays on brain extracts of the same paclitaxel-treated animals. Our results show that paclitaxel treatment affects animals' memory in a negative way and treated animals behave poorly in MWM compared to control group. In addition, our kinetics studies show that MT stability is significantly increased in brain extracts from paclitaxel-treated mice, but MT dynamics is reduced. Thus, we suggest that dynamicity is a very important feature of MT protein structures, and regarding memory formation, dynamicity is more important than stability and high activity. PMID- 25740017 TI - Cortical motor output decreases after neuromuscular fatigue induced by electrical stimulation of the plantar flexor muscles. AB - AIM: Neuromuscular electrical stimulation (NMES) causes early onset of neuromuscular fatigue. Peripheral electrophysiological explorations suggest that supra-spinal alterations are involved through sensitive afferent pathways. As sensory input is projected over the primary somatosensory cortex (S1), S1 area involvement in inhibiting the central motor drive can be hypothesized. This study assessed cortical activity under a fatiguing NMES protocol at low frequency. METHODS: Twenty healthy males performed five NMES sequences of 17 trains over the plantar flexors (30 Hz, 4 s on/6 s off). Before and after each sequence, neuromuscular tests composed of maximal voluntary contractions (MVCs) were carried out. Cortical activity was assessed during MVCs with functional near infrared spectroscopy over S1 and primary motor (M1) areas, through oxy- [HbO] and deoxy-haemoglobin [HbR] variation. Electrophysiological data (H-reflex during MVC, EMG activity and level of voluntary activation) were also recorded. RESULTS: MVC torque significantly decreased after the first 17 NMES trains (P < 0.001). The electrophysiological data were consistent with supra-spinal alterations. In addition, [HbO] declined significantly during the protocol over the S1 and M1 areas from the first 17 NMES trains (P < 0.01 and P < 0.001 respectively), while [HbR] increased (P < 0.05 and P < 0.01 respectively), indicating early decline in cortical activity over both primary cortical areas. CONCLUSIONS: The declining cortical activity over the M1 area is highly consistent with the electrophysiological findings and supports motor cortex involvement in the loss of force after a fatiguing NMES protocol. In addition, the declining cortical activity over the S1 area indicates that the decreased motor output from M1 is not due to increased S1 inhibitory activity. PMID- 25740018 TI - Glassy dynamics of poly(2-vinyl-pyridine) brushes with varying grafting density. AB - The molecular dynamics of poly(2-vinyl-pyridine) (P2VP) brushes is measured by Broadband Dielectric Spectroscopy (BDS) in a wide temperature (250 K to 440 K) and broad spectral (0.1 Hz to 1 MHz) range. This is realized using nanostructured, highly conductive silicon electrodes being separated by silica spacers as small as 35 nm. A "grafting-to"-method is applied to prepare the P2VP brushes with five different grafting densities (0.030 nm(-2) to 0.117 nm(-2)), covering the "true-brush" regime with highly stretched coils and the "mushroom-to brush" transition regime. The film thickness ranges between 1.8 to 7.1 (+/-0.2) nm. Two relaxations are observed, an Arrhenius-like process being attributed to fluctuations in the poly(glycidyl-methacrylate) (PGMA) linker used for the grafting reaction and the segmental dynamics (dynamic glass transition) of the P2VP brushes. The latter is characterized by a Vogel-Fulcher-Tammann dependence similar to bulk P2VP. The results can be comprehended considering the length scale on which the dynamic glass transition (<=1 nm) takes place. PMID- 25740020 TI - Primary cardiac leiomyosarcoma: an analysis of clinical characteristics and outcome patterns. AB - BACKGROUND: Primary cardiac leiomyosarcoma is an extremely rare entity. There is no accumulated knowledge about the clinical characteristics and therapeutic strategies for this tumor. This study aimed to systematically review the available literature to investigate the clinicoradiologic and clinicopathologic characteristics, treatment, and outcomes in patients with primary cardiac leiomyosarcoma. METHODS: We identified 79 instances derived from 72 unique reports and carefully analyzed all clinical presentations, imaging, pathology, treatments, and outcomes. RESULTS: The mean age at onset was 48 years. A symptom of obstruction was the most frequent complaint at diagnosis. Routine imaging methods such as echocardiography, computed tomography, and magnetic resonance imaging had high sensitivity in diagnosis. The tumor has a poorer life expectancy than its counterparts in other sites. The 5-year overall survival and recurrence free survival rates were 25.4% and 14.7%, respectively. Overall survival was affected by age, surgery, and adjunctive chemotherapy or radiotherapy. CONCLUSIONS: Our findings suggest that primary cardiac leiomyosarcomas tend to be biologically more aggressive compared to their counterparts in other sites. However, complete resection and adjunctive chemotherapy or radiotherapy may help to increase the life expectancy. PMID- 25740019 TI - Hypoxia-induced overexpression of stanniocalcin-1 is associated with the metastasis of early stage clear cell renal cell carcinoma. AB - BACKGROUND: Although metastasis of clear cell renal cell carcinoma (ccRCC) is predominantly observed in late stage tumors, early stage metastasis of ccRCC can also be found with indefinite molecular mechanism, leading to inappropriate clinical decisions and poor prognosis. Stanniocalcin-1 (STC1) is a glycoprotein hormone involved in calcium/phosphate homeostasis, which regulates various cellular processes in normal development and tumorigenesis. This study aimed to investigate the role and mechanism of regulation of STC1 in the metastasis of early stage ccRCC. METHODS: STC1 mRNA and protein expression was determined in ccRCC surgical specimens, RCC cell lines, and human kidney tubule epithelial cell line HKC by real-time polymerase chain reaction (RT-PCR) and western blotting. Immunohistochemistry staining (IHC) and immunofluorescence were also used to examine the expression and localization of STC1 in ccRCC tissues and cancer cells. Knockdown and overexpression studies were conducted in vitro in RCC cell lines using small interfering RNAs (siRNA) and lentiviral-mediated gene delivery to evaluate the role of STC1 in cell proliferation, anchorage-dependent and independent growth, cell cycle control, and migration and invasion. RESULTS: STC1 mRNA and protein expression were significantly up-regulated in tumors when compared with non-tumor tissues, with the greatest increase in expression observed in metastatic tissues. Clinicopathological analysis revealed that STC1 mRNA expression was associated with Fuhrman tumor grade (P = 0.008) and overall Tumor Node Metastasis (TNM) staging (P = 0.018). STC1 expression was elevated in T1 stage metastatic tumors when compared with localized tumors, and was positively correlated with average tumor diameter. Silencing of STC1 expression by Caki-1 and A498 resulted in the inhibition of cell proliferation, migration, and invasion, meanwhile down-regulation of STC1 impaired epithelial-mesenchymal transition (EMT) of ccRCC cell lines. Overexpression of STC1 in Caki-2 enhanced cell growth and proliferation but not migration and invasion. Further investigation identified hypoxia and HIF-1alpha as candidate regulators of STC1 expression. CONCLUSIONS: Our findings demonstrate a role for STC1 in metastasis of early stage ccRCC and suggest that STC1 may be a biomarker of potential value both for the prognosis of this disease and for guiding clinical decisions regarding surgical strategies and adjuvant treatment. PMID- 25740021 TI - Surgical treatment of a mitral-aortic intervalvular fibrosa pseudoaneurysm. PMID- 25740022 TI - Work and non-work stressors, psychological distress and obesity: evidence from a 14-year study on Canadian workers. AB - OBJECTIVE: This study aimed to evaluate the contribution of work, non-work and individual factors to obesity with regard to gender-related differences, and to clarify the mediating role that psychological distress plays in these dynamics in Canada from 1994 to 2008 using the Canadian National Population Health Survey (NPHS). DESIGN: Longitudinal. SETTINGS: The NPHS is a randomised longitudinal cohort study with biennial interviews of the Canadian adult population from 18 to 64. PARTICIPANTS: 5925 non-obese workers in cycle 1 (49% were women). MEASUREMENTS: Obesity was measured using the body mass index (BMI), with a threshold of BMI >30 kg/m(2). BMI was corrected in accordance with the recommendations of Connor Gorber et al to adjust for gender bias in responses. RESULTS: Of the work characteristics evaluated, only decision authority was associated with obesity for women but not for men. Living as a couple, child related strains, psychotropic drug use, hypertension, being physically inactive and low psychological distress were obesity risk factors but were not moderated by gender. Overall, psychological distress did not mediate the associations that work factors have on obesity. CONCLUSIONS: Our study suggests that men and women differ little in the extent to which work, non-work and individual factors predict obesity. However, for women, the level of decision authority is associated with a lower obesity risk. In addition, psychological distress did not mediate the contribution of work factors and actually seems, contrary to expectations, to decrease the obesity risk when work, non-work and individual factors are taken into account. PMID- 25740023 TI - A population-based observational study on the factors associated with the completion of palliative chemotherapy among patients with oesophagogastric cancer. AB - OBJECTIVES: Palliative chemotherapy is routinely given to patients diagnosed with locally advanced or metastatic oesophagogastric (O-G) cancer. We examine which patients with O-G cancer in England receive palliative chemotherapy, and identify factors associated with treatment completion. DESIGN: A prospective population based observational study. SETTING: All English National Health Service (NHS) trusts diagnosing patients with O-G cancer. PARTICIPANTS: Data were prospectively collected on patients diagnosed with invasive epithelial cancer of the oesophagus or stomach between 1 October 2007 and 30 June 2009 in English NHS hospitals, and those who had palliative treatment intent. OUTCOME MEASURE: We calculated the proportion of patients with different characteristics (eg, age, sex, stage at diagnosis, performance status) starting palliative chemotherapy. Multiple logistic regression was used to identify characteristics associated with non completion of chemotherapy. RESULTS: There were 9768 patients in the study whose treatment intent was palliative. Among these, 2313 (24%) received palliative chemotherapy. It was received by 51% of patients aged under 55 years but only 9% of patients aged 75 years or over. Overall, 917 patients (53%) completed their treatment among the 1741 patients for whom information on treatment completion was recorded. Treatment completion ranged from 50-60% for patients with good performance status but was under 35% for patients aged 55 years or older with poor performance status. Treatment completion was not associated with site of cancer, pretreatment stage, sex, comorbidities or histology. CONCLUSIONS: Completion rates of palliative chemotherapy in patients with O-G cancer are low and elderly patients with poor performance status are very unlikely to complete a palliative chemotherapy treatment. Clinicians and patients should consider this information when balancing potential (survival) benefits, toxicity of treatment and its effect on quality of life. PMID- 25740024 TI - Changes in endothelial microparticles and endothelial progenitor cells in obese patients in response to surgical stress. AB - BACKGROUND: Obese patients undergoing surgery are at increased risk of intraoperative and postoperative cardiovascular complications. The present study was designed to study the changes in endothelial microparticles, endothelial progenitor cells, and adipokines in obese patients in response to limb ischemia during knee surgery. METHODS: This prospective study included seventy-four patients who underwent total knee arthroplasty. Patients were stratified in tertiles according to their body mass index. Flow cytometry was used for quantification and characterization of endothelial microparticles, endothelial progenitor cells, and adipokines. ELISA (enzyme-linked immunosorbent assay) was used to measure the adiponectin level. RESULTS: The number of endothelial microparticles was greater in obese compared with nonobese patients. The number of endothelial microparticles increased further immediately after surgery in all tertiles. Three days after surgery, endothelial microparticles returned to the basal preoperative level except in the most obese patients. The percentage of endothelial progenitor cells was lower in obese patients. Concentrations of adipokines increased after surgery, but the increase was more accentuated in obese patients. CONCLUSIONS: Obese patients present with a high number of endothelial microparticles, a low number of endothelial progenitor cells, and high levels of adipokines, with further increases in adipokines after surgery, suggesting an inflammatory condition that worsens after surgery and may affect endothelial repair. PMID- 25740025 TI - Revision total hip arthoplasty: factors associated with re-revision surgery. AB - BACKGROUND: The survivorship of implants after revision total hip arthroplasty and risk factors associated with re-revision are not well defined. We evaluated the re-revision rate with use of the institutional total joint replacement registry. The purpose of this study was to determine patient, implant, and surgeon factors associated with re-revision total hip arthroplasty. METHODS: A retrospective cohort study was conducted. The total joint replacement registry was used to identify patients who had undergone revision total hip arthroplasty for aseptic reasons from April 1, 2001, to December 31, 2010. The end point of interest was re-revision total hip arthroplasty. Risk factors evaluated for re revision total hip arthroplasty included: patient risk factors (age, sex, body mass index, race, and general health status), implant risk factors (fixation type, bearing surface, femoral head size, and component replacement), and surgeon risk factors (volume and experience). A multivariable Cox proportional hazards model was used. RESULTS: Six hundred and twenty-nine revision total hip arthroplasties with sixty-three (10%) re-revisions were evaluated. The mean cohort age (and standard deviation) was 57.0 +/- 12.4 years, the mean body mass index (and standard deviation) was 29.5 +/- 6.1 kg/m(2), and most of the patients were women (64.5%) and white (81.9%) and had an American Society of Anesthesiologists score of <3 (52.9%). The five-year implant survival after revision total hip arthroplasty was 86.8% (95% confidence interval, 83.57% to 90.25%). In adjusted models, age, total number of revision surgical procedures performed by the surgeon, fixation, and bearing surface were associated with the risk of re-revision. For every ten-year increase in patient age, the hazard ratio for re-revision decreases by a factor of 0.72 (95% confidence interval, 0.58 to 0.90). For every five revision surgical procedures performed by a surgeon, the risk of revision decreases by a factor of 0.93 (95% confidence interval, 0.86 to 0.99). At the time of revision, a new or retained cemented femoral implant or all cemented hip implant increases the risk of revision by a factor of 3.19 (95% confidence interval, 1.22 to 8.38) relative to a retained or new uncemented hip implant. A ceramic on a highly cross-linked polyethylene bearing articulation decreases the hazard relative to metal on highly cross-linked polyethylene by a factor of 0.32 (95% confidence interval, 0.11 to 0.95). Metal on constrained bearing increases the hazard relative to metal on highly cross-linked polyethylene by a factor of 3.32 (95% confidence interval, 1.16 to 9.48). CONCLUSIONS: When evaluating patient, implant, and surgical factors at the time of revision total hip arthroplasty, age, surgeon experience, implant fixation, and bearing surfaces had significant impacts on the risk of re-revision. PMID- 25740026 TI - Pain control after simultaneous bilateral total knee arthroplasty: a randomized controlled trial comparing periarticular injection and epidural analgesia. AB - BACKGROUND: Periarticular injection is becoming more commonly utilized for pain relief following total knee arthroplasty. However, we are aware of no randomized controlled trial that has investigated the efficacy of periarticular injection for pain relief after simultaneous bilateral total knee arthroplasty. METHODS: We performed a randomized controlled trial of patients scheduled for simultaneous bilateral total knee arthroplasty. Seventy-one patients with 142 involved knees were randomly assigned to receive periarticular injection or epidural analgesia. Other perioperative interventions, including spinal anesthesia, surgical techniques, and postoperative medication protocols, were identical for all patients. The primary outcome was postoperative pain at rest, measured with the use of a 100-mm visual analog scale (VAS) during the initial twenty-four-hour postoperative period. The cumulative VAS score was calculated with use of the area under the curve and compared between the groups. RESULTS: Postoperative pain at rest, quantified as the area under the curve of serial assessments during the initial twenty-four-hour postoperative period, was significantly less in the periarticular injection group than in the epidural analgesia group (174.9 +/- 181.5 mm * day compared with 360.4 +/- 360.6 mm * day; p = 0.0073). The prevalences of nausea on the night of surgery and postoperative day 1 and of pruritus were significantly lower in the periarticular injection group than in the epidural analgesia group (14% and 45%, p = 0.0031; 14% and 55%, p = 0.0003; and 0% and 15%, p = 0.014, respectively). CONCLUSIONS: Periarticular injection was associated with better pain relief during the first twenty-four hours following simultaneous bilateral total knee arthroplasty and decreased opioid related side effects compared with epidural analgesia. Periarticular injection may be preferable to epidural analgesia for pain relief after simultaneous bilateral total knee arthroplasty. PMID- 25740027 TI - The effectiveness of bivalving, cast spreading, and webril cutting to reduce cast pressure in a fiberglass short arm cast. AB - BACKGROUND: A fiberglass short arm cast can be used to treat a distal radial fracture, but posttraumatic edema may lead to excessive cast tightness and resultant soft-tissue injury. We sought to quantify a simulated edema-induced pressure within a fiberglass short arm cast and to determine the effectiveness of different cast-cutting methods for pressure reduction. We hypothesized that cast cutting could eliminate all clinically relevant pressure and Ace wrap would insignificantly increase pressure. METHODS: Skin surface pressure under fiberglass short arm casts was measured on ninety wrists from forty-five volunteers randomly assigned to one cast-cutting method: single-cut (cast bivalve and Ace wrap), double-cut (cast bivalve, spread, and Ace wrap), or triple-cut (cast bivalve, spread, Webril cut, and Ace wrap). Each wrist was immobilized in a cast in the neutral position with one roll of 2-inch (5.1-cm) cotton Webril and one roll of 2-inch (5.1-cm) fiberglass. Each fiberglass short arm cast contained an empty intravenous fluid bag in which we infused air. This simulated edema, which generated a skin surface pressure, which was measured by a pressure transducer. RESULTS: Each cast-cutting method significantly reduced (p < 0.0001) the skin surface pressure from the average maximum of 92.5 mm Hg in a non fracture setting. Prior to Ace wrapping, there was a reduction in skin surface pressure of 70.8% for the single-cut method, 85.1% for the double-cut method, and 99.9% for the triple-cut method. Ace wrap significantly increased skin surface pressure (p < 0.0001), lessening the effectiveness of cast cutting. There was an overall reduction in skin surface pressure of 55.9% for the single-cut method, 64.3% for the double-cut method, and 77.2% for the triple-cut method. Throughout our study, women had significantly higher skin surface pressure than men (p < 0.0001); the average maximum was 104.4 mm Hg for women and 81.1 mm Hg for men. CONCLUSIONS: The single-cut method provides the greatest pressure reduction, but only the triple-cut method eliminated all relevant skin surface pressure. Ace wrapping a cut cast noticeably increased skin surface pressure. CLINICAL RELEVANCE: In volunteers without a fracture, only the triple-cut method is effective enough to eliminate clinically relevant skin surface pressure. Ace wrap should be applied with caution after the cast is cut. The specific effect on pressure reduction in a patient who requires some soft-tissue pressure to maintain fracture reduction was not studied. PMID- 25740028 TI - A cohort study of patients undergoing distal tibial osteotomy without fibular osteotomy for medial ankle arthritis with mortise widening. AB - BACKGROUND: Although the supramalleolar osteotomy can shift the weight-bearing axis laterally, it cannot reconstruct a widened ankle mortise caused by progression of medial ankle osteoarthritis. The aim of this study was to evaluate radiographic and clinical outcomes of distal tibial osteotomy without fibular osteotomy in patients with medial ankle osteoarthritis and mortise widening. METHODS: Distal tibial osteotomy without fibular osteotomy was performed in eighteen patients to treat medial ankle osteoarthritis with mortise widening. Fifteen women and three men with a mean age of fifty-seven years (range, forty nine to sixty-four years) were followed for a mean of thirty-four months (range, twenty-four to sixty-six months). Mortise widening was diagnosed using valgus stress radiographs and intraoperative examination. The clinical outcome was assessed with the American Orthopaedic Foot & Ankle Society (AOFAS) score, visual analog scale (VAS) score for pain, and the ankle osteoarthritis scale (AOS) score. The translation of the talus within the ankle mortise, talar tilt, medial distal tibial angle, and anterior distal tibial angle were evaluated on weight bearing radiographs made preoperatively and postoperatively. RESULTS: The AOFAS score improved significantly from 78.4 points (95% confidence interval [CI], 74.6 to 80.5 points) to 89 points (95% CI, 86.5 to 90.5 points) (p < 0.001). The VAS score for pain also decreased significantly from 6.7 points (95% CI, 6 to 7.5 points) to 2.7 points (95% CI, 2.3 to 3.3 points) (p < 0.001). The mean AOS score was 29.8 points (95% CI, 22 to 38.2 points) at the latest follow-up. The center of the talus moved laterally within the ankle mortise after the distal tibial osteotomy. The mean medial distal tibial angle changed from 86.6 degrees (95% CI, 85.7 degrees to 87.6 degrees ) to 92.9 degrees (95% CI, 91.6 degrees to 94.3 degrees ) (p < 0.001), and the mean anterior distal tibial angle changed from 81.1 degrees (95% CI, 78.6 degrees to 83.6 degrees ) to 84.3 degrees (95% CI, 81.9 degrees to 86.4 degrees ) (p < 0.001). However, talar tilt was not corrected significantly (p = 0.916). CONCLUSIONS: Distal tibial osteotomy without fibular osteotomy reduces pain in the short term in patients with ankle arthritis, a widened mortise, and minimal talar tilt. PMID- 25740029 TI - Management of pediatric patients with synovial fluid white blood-cell counts of 25,000 to 75,000 cells/mm3 after aspiration of the hip. AB - BACKGROUND: In this study, we sought to elucidate the presentation, clinical course, treatments pursued, final diagnosis, and risk factors for septic arthritis in a series of children with hip pain and intermediate synovial fluid values (white blood-cell [WBC] counts of 25,000 to 75,000 cells/mm(3) [25 to 75 * 10(9) cells/L]). METHODS: We reviewed the records of pediatric patients who underwent hip aspiration between 2005 and 2012 at a tertiary-care pediatric hospital. Demographic data, laboratory values, final diagnosis, and treatment details were recorded for the subpopulation of patients with an aspirate WBC count of 25,000 to 75,000 cells/mm(3) (25 to 75 * 10(9) cells/L). Univariate and multivariable logistic regression analysis was used to assess risk factors for septic arthritis of the hip across final diagnostic groups and subgroups with WBC values of <50,000 and >=50,000 cells/mm(3) (<50 and >=50 * 10(9) cells/L). RESULTS: Forty-six children (twenty-seven males and nineteen females) with a mean age of 7.6 years met the inclusion criteria. The final diagnoses were septic arthritis of the hip (n = 15; 33%), Lyme arthritis (n = 13; 28%), transient synovitis (n = 8; 17%), and other findings (n = 10; 22%). Subjects with a synovial fluid WBC count of >=50,000 cells/mm(3) (>=50 * 10(9) cells/L) were more likely to be diagnosed with septic arthritis of the hip (odds ratio, 4.4; 95% confidence interval, 1.1 to 16.9; p = 0.03). While septic arthritis of the hip was the most common diagnosis (48%) in patients with WBC values of >=50,000 cells/mm(3) (>=50 * 10(9) cells/L), it also represented 17% of cases with WBC values of <50,000 cells/mm(3) (<50 * 10(9) cells/L). CONCLUSIONS: Septic arthritis of the hip is the most common ultimate diagnosis in children with synovial fluid WBC values of 25,000 to 75,000 cells/mm(3) (25 to 75 * 10(9) cells/L) following hip aspiration, and it should be high on the differential diagnosis, even in cases with synovial fluid WBC values of <50,000 cells/mm(3) (<50 * 10(9) cells/L). PMID- 25740030 TI - Effect of age on cost-effectiveness of unicompartmental knee arthroplasty compared with total knee arthroplasty in the U.S. AB - BACKGROUND: Trade-offs between upfront benefits and later risk of revision of unicompartmental knee arthroplasty compared with those of total knee arthroplasty are poorly understood. The purpose of our study was to compare the cost effectiveness of unicompartmental knee arthroplasty with that of total knee arthroplasty across the age spectrum of patients undergoing knee replacement. METHODS: Using a Markov decision analytic model, we compared unicompartmental knee arthroplasty with total knee arthroplasty with regard to lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) from a societal perspective for patients undergoing surgery at forty five, fifty-five, sixty-five, seventy-five, or eighty-five years of age. Transition probabilities were estimated from the literature; survival, from the Swedish Knee Arthroplasty Register; and costs, from the literature and the Healthcare Cost and Utilization Project (HCUP) database. Costs and QALYs were discounted at 3.0% annually. We conducted sensitivity analyses to test the robustness of model estimates and threshold analyses. RESULTS: For patients sixty five years of age and older, unicompartmental knee arthroplasty dominated total knee arthroplasty, with lower lifetime costs and higher QALYs. Unicompartmental knee arthroplasty was no longer cost-effective at a $100,000/QALY threshold when total knee arthroplasty rehabilitation costs were reduced by two-thirds or more for these older patients. Lifetime societal savings from utilizing unicompartmental knee arthroplasty in all older patients (sixty-five or older) in 2015 and 2020 were $56 to $336 million and $84 to $544 million, respectively. In the forty-five and fifty-five-year-old age cohorts, total knee arthroplasty had an ICER of $30,300/QALY and $63,000/QALY, respectively. Unicompartmental knee arthroplasty became cost-effective when its twenty-year revision rate dropped from 27.8% to 25.7% for the forty-five-year age group and from 27.9% to 26.7% for the fifty-five-year age group. CONCLUSIONS: Unicompartmental knee arthroplasty is an economically attractive alternative in patients sixty-five years of age or older, and modest improvements in implant survivorship could make it a cost effective alternative in younger patients. PMID- 25740031 TI - The incidence of upper and lower extremity surgery for rheumatoid arthritis among Medicare beneficiaries. AB - BACKGROUND: For elderly patients with rheumatoid arthritis, aggressive immunosuppression can be difficult to tolerate, and surgery remains an important treatment option for joint pain and deformity. We sought to examine the epidemiology of surgical reconstruction for rheumatoid arthritis among older individuals who were newly diagnosed with the disorder. METHODS: We identified a 5% random sample of Medicare beneficiaries (sixty-six years of age and older) newly diagnosed with rheumatoid arthritis from 2000 to 2005, and followed these patients longitudinally for a mean of 4.6 years. We used univariate analysis to compare the time from the diagnosis of rheumatoid arthritis to the first operation among the 360 patients who underwent surgery during the study period. RESULTS: In our study cohort, 589 procedures were performed among 360 patients, and 132 patients (37%) underwent multiple procedures. The rate of upper extremity reconstruction was 0.9%, the rate of lower extremity reconstruction was 1.2%, and knee arthroplasty was the most common procedure performed initially (31%) and overall (29%). Upper extremity procedures were performed sooner than lower extremity procedures (fourteen versus twenty-five months; p = 0.02). In multivariable analysis, surgery rates declined with age for upper and lower extremity procedures (p < 0.001). CONCLUSIONS: Knee replacement remains the most common initial procedure among patients with rheumatoid arthritis. However, upper extremity procedures are performed earlier than lower extremity procedures. Understanding the patient and provider factors that underlie variation in procedure rates can inform future strategies to improve the delivery of care to patients with rheumatoid arthritis. PMID- 25740032 TI - High prevalence of cervical deformity and instability requires surveillance in Loeys-Dietz syndrome. AB - BACKGROUND: Loeys-Dietz syndrome is a connective tissue disorder characterized by vascular, craniofacial, and musculoskeletal malformation. Our goal was to report the manifestations, surgical treatment, and complications in the cervical spine in patients with Loeys-Dietz syndrome. METHODS: We reviewed the clinical and cervical spine imaging data of eighty patients with Loeys-Dietz syndrome who were seen at our institution from January 2005 through January 2014. Their mean age at presentation was 17.3 years (range, three months to seventy-five years). We tested associations with use of the Fisher exact test (type of TGF-betaR [transforming growth factor-beta receptor] mutation and cervical abnormalities) and the Student t test (age at presentation and type of TGF-betaR mutation) (significance, p = 0.05). RESULTS: Vertebral anomalies and cervical instability were common; we found no significant association of TGF-betaR-type with cervical abnormalities or age at presentation. Twenty-eight patients had atlas defects (anterior and/or posterior arch defects or hypoplasia), fifty-three had axis malformations (elongation, apex-anterior dens angulation, or spondylolysis), and twelve had focal kyphosis. Ten patients had hypoplastic subaxial vertebrae, leading to focal kyphosis (eight) and subaxial instability (nine). Eight patients had atlantoaxial instability. Of the thirteen patients with cervical instability, nine were treated surgically: fusion (eight patients) and halo application (one) (mean age, four years; range, three months to twelve years). Postoperative complications (seven patients) were pseudarthrosis, failure of fixation, junctional kyphosis or instability, and development of occipital-cervical instability. CONCLUSIONS: Cervical midline defects (most often C1-C3) are common in Loeys-Dietz syndrome. Patients have a high prevalence of cervical instability, particularly a pattern of instability at C2-C3 associated with C3 vertebral body hypoplasia and C2-C3 focal kyphosis. Patients requiring surgery typically present in early childhood. PMID- 25740033 TI - Risk factors for pulmonary metastases from giant cell tumor of bone. AB - BACKGROUND: Giant cell tumor (GCT) of bone is a rare, benign, aggressive bone tumor with an unusual capacity to metastasize to the lung. It was the goal of this study to identify patient and treatment-specific variables associated with the development of pulmonary metastases of GCT of bone. METHODS: From 1980 to 2009, 291 patients with benign GCT of bone were treated at our institution, and 167 were followed for at least two years. Eleven (6.6%) of these 167 patients developed biopsy-confirmed pulmonary metastasis. All patients were evaluated relative to nine patient, disease, and treatment-specific variables. RESULTS: We identified four properties of benign GCT of bone associated with an increased risk of metastasis on univariate analysis: age at diagnosis, axial location of the primary GCT, primary Enneking stage-3 disease, and local recurrence. Multivariate analysis showed local recurrence to be an independent risk factor for pulmonary metastasis (adjusted odds ratio, 7.42). CONCLUSIONS: There is an increased risk of pulmonary metastasis of GCT of bone in patients who are younger, present with Enneking stage-3 disease, develop local recurrence, and/or present with axial disease. The mode of treatment was not found to be associated with the development of pulmonary metastasis. PMID- 25740034 TI - Sarcopenia and fragility fractures: molecular and clinical evidence of the bone muscle interaction. AB - ? Bone and muscle tissues are in close relationship, and the aging process is a factor involved in the loss of the functionality of both bones and muscles.? Sarcopenia and osteoporosis are linked from a biological and functional perspective and are related to an increased fracture risk in the elderly.? The increased fracture risk in sarcopenic and osteoporotic subjects is due to the decline of muscle mass and strength, the decrease in bone mineral density, and limited mobility. PMID- 25740035 TI - Characteristics of clinical shoulder research over the last decade: a review of shoulder articles in The Journal of Bone & Joint Surgery from 2004 to 2014. AB - BACKGROUND: The purpose of this study was to determine characteristics and trends in published shoulder research over the last decade in a leading orthopaedic journal. METHODS: We examined all clinical shoulder articles published in The Journal of Bone & Joint Surgery from 2004 to 2014. The number of citations, authorship, academic degrees of the authors, country and institution of origin, topic, level of evidence, positive or nonpositive outcome, and inclusion of validated patient-reported outcome measures were assessed for each article. RESULTS: Shoulder articles that included an author with an advanced research degree (MD [Doctor of Medicine] with a PhD [Doctor of Philosophy] or other advanced degree) increased during the study period (p = 0.047). Level-I, II, and III studies were more likely to have an author with an advanced research degree, and Level-IV studies were more likely to have MDs only (p = 0.03). Overall, there was great variability of outcome measures, with at least thirty-nine different validated or nonvalidated outcome measures reported. CONCLUSIONS: Over the last decade, there was an improvement in the level of evidence of shoulder articles published in The Journal of Bone & Joint Surgery that corresponds with recent emphasis on evidence-based medicine. A consensus is needed in shoulder research for more consistent application of validated patient-reported outcome measurement tools. PMID- 25740036 TI - Impact of fellowship training on clinical practice of orthopaedic sports medicine. AB - BACKGROUND: Approximately 90% of current orthopaedic graduates are engaging in fellowship training, with sports medicine being the most commonly chosen specialty. The purpose of this study was to evaluate the impact of fellowship training on clinical decision-making by fellowship-trained sports medicine surgeons. METHODS: A survey was designed to assess the importance of fellowship on common clinical decisions made in the nonoperative and surgical treatment of knee, shoulder, and elbow disorders. The survey also included questions for the respondents on their comfort level with a variety of routine and complex surgical procedures. The survey was sent to alumni of 113 orthopaedic sports medicine programs across the United States. RESULTS: Completed surveys were returned by 310 surgeons who had been in practice for an average of 9.0 years. They represented alumni of twenty-nine orthopaedic sports medicine fellowship programs across sixteen states. Fellowship was considered very important for surgical decision-making in the knee and shoulder. For nonoperative treatment, fellowship had a greater impact on shoulder disorders than on knee or elbow disorders. Fellowship was significantly more important than residency (p < 0.001) for determining preferred surgical equipment, implants, and braces. Among the surgical procedures assessed, respondents were least comfortable with the treatment of multi-ligamentous knee injuries, posterior cruciate ligament injuries, and shoulder instability with bone loss. CONCLUSIONS: Fellowship has a significantly higher impact than residency on industry-related decision-making. Fellowship-trained sports surgeons should consider seeking additional training in the treatment of multi-ligamentous knee injuries, posterior cruciate ligament injuries, shoulder instability with bone loss, and elbow disorders. The current findings were limited by the relatively small respondent pool, which represented only 26% of sports medicine fellowship programs in the United States. PMID- 25740037 TI - Obesity and the balancing act of endothelial damage and repair: Commentary on an article by Maria-Victoria Noci, MD, et al.: "Changes in endothelial microparticles and endothelial progenitor cells in obese patients in response to surgical stress". PMID- 25740038 TI - Are cast application and maintenance of complications a lost art? Commentary on an article by Christian J. Zaino, MD, et al.: "The effectiveness of bivalving, cast spreading, and webril cutting to reduce cast pressure in a fiberglass short arm cast". PMID- 25740045 TI - Successful treatment of refractory neuropathic pruritus with capsaicin 8% patch: a bicentric retrospective study with long-term follow-up. PMID- 25740046 TI - Commentary: Should consciousness be used to describe seizures and what terms should be applied: Epilepsia's survey results. PMID- 25740047 TI - Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report. AB - Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P = 1.27 * 10(-9) ). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude. PMID- 25740048 TI - Natural product-based therapeutics for the treatment of cancer stem cells: a patent review (2010 - 2013). AB - INTRODUCTION: Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess numerous intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs and radiation therapy, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. This review presents the up-to-date natural product-based therapeutics for the treatment of CSCs. AREAS COVERED: This review gives an account of the recent therapeutic patent literature (2010 - 2013) describing the applications of natural products on CSCs. In this review, many of the therapeutic applications of natural products reported in international patents have been discussed. In addition to selected biological data, some of pharmaceutical applications are also summarized. Because of the large number of patents registered in this period relative to natural products the attention was focused, in this first part of the review, on inhibitors of six cancers. EXPERT OPINION: This patent review aims to highlight the use of natural products to treat cancer by targeting CSCs. Most of the described products are shown to have beneficial therapeutic effects and their uses for developing new formulations. PMID- 25740050 TI - Osteoprotegerin: osteo-vascular connection. PMID- 25740049 TI - Multiple origins of the phenol reaction negative phenotype in foxtail millet, Setaria italica (L.) P. Beauv., were caused by independent loss-of-function mutations of the polyphenol oxidase (Si7PPO) gene during domestication. AB - Foxtail millet shows variation in positive phenol color reaction (Phr) and negative Phr in grains, but predominant accessions of this crop are negative reaction type, and the molecular genetic basis of the Phr reaction remains unresolved. In this article, we isolated polyphenol oxidase (PPO) gene responsible for Phr using genome sequence information and investigated molecular genetic basis of negative Phr and crop evolution of foxtail millet. First of all, we searched for PPO gene homologs in a foxtail millet genome database using a rice PPO gene as a query and successfully found three copies of the PPO gene. One of the PPO gene homologs on chromosome 7 showed the highest similarity with PPO genes expressed in hulls (grains) of other cereal species including rice, wheat, and barley and was designated as Si7PPO. Phr phenotypes and Si7PPO genotypes completely co-segregated in a segregating population. We also analyzed the genetic variation conferring negative Phr reaction. Of 480 accessions of the landraces investigated, 87 (18.1 %) showed positive Phr and 393 (81.9 %) showed negative Phr. In the 393 Phr negative accessions, three types of loss-of-function Si7PPO gene were predominant and independently found in various locations. One of them has an SNP in exon 1 resulting in a premature stop codon and was designated as stop codon type, another has an insertion of a transposon (Si7PPO-TE1) in intron 2 and was designated as TE1-insertion type, and the other has a 6-bp duplication in exon 3 resulting in the duplication of 2 amino acids and was designated as 6-bp duplication type. As a rare variant of the stop codon type, one accession additionally has an insertion of a transposon, Si7PPO-TE2, in intron 2 and was designated as "stop codon +TE2 insertion type". The geographical distribution of accessions with positive Phr and those with three major types of negative Phr was also investigated. Accessions with positive Phr were found in subtropical and tropical regions at frequencies of ca. 25-67 % and those with negative Phr were broadly found in Europe and Asia. The stop codon type was found in 285 accessions and was broadly distributed in Europe and Asia, whereas the TE 1 insertion type was found in 99 accessions from Europe and Asia but was not found in India. The 6-bp duplication type was found in only 8 accessions from Nansei Islands (Okinawa Prefecture) of Japan. We also analyzed Phr in the wild ancestor and concluded that the negative Phr type was likely to have originated after domestication of foxtail millet. It was also implied that negative Phr of foxtail millet arose by multiple independent loss of function of PPO gene through dispersal because of some advantages under some environmental conditions and human selection as in rice and barley. PMID- 25740051 TI - Year in review in journal of clinical monitoring and computing 2014: cardiovascular and hemodynamic monitoring. PMID- 25740052 TI - The impact of three nursing staffing models on nursing outcomes. AB - AIM: To examine the impact of application of different nursing staffing models on patient safety, quality of care and nursing costs. BACKGROUND: One proposed means of addressing the staff shortage while decreasing nursing costs is the application of nursing staffing models. However, the optimal proportion of registered nurses to nurse aides remains unclear. DESIGN: A retrospective cohort study. METHODS: To examine a total of 667 inpatients of a 20-bed respiratory care centre at a medical centre located in southern Taiwan. Three mixed models of nursing staffing, where the portion of nurses compared with nurse aides was 76% (n = 213), 100% (n = 209) and 92% (n = 245), were applied during three different periods between 2006 - 2010. RESULTS: The 76% RNs group made fewer medication errors than the 100% RNs group; the 76% and 92% RNs groups had a higher rate of urinary tract infections; the 92% RNs group had a lower rate of bloodstream infections; the 76% RNs group had a lower rate of ventilator weaning; and the 76% and 92% RNs groups incurred higher nursing costs. CONCLUSIONS: Use of different nursing staffing models that substitute nurse aides for RNs may negatively affect patient safety and quality of care and increase nursing costs. To avoid this risk, hospitals should employ and train their own nurse aides and develop a training system and education materials for RN and nurse aides. PMID- 25740053 TI - Is de novo stress incontinence after sacrocolpopexy related to anatomical changes and surgical approach? Response to comments by van der Weiden and Withagen. PMID- 25740054 TI - Comments on LeClaire et al.: is de novo stress incontinence after sacrocolpopexy related to anatomical changes and surgical approach? PMID- 25740055 TI - Heterogeneous effects of association between blood pressure loci and coronary artery disease in east Asian individuals. AB - BACKGROUND: A coronary artery disease (CAD) association study of genetic loci previously identified as being associated with blood pressure (BP) was performed in east Asian populations. METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) from 9 candidate loci robustly confirmed to be associated with BP in east Asian people, were genotyped. Genotyping was done in up to 17,785 CAD case-control samples (6,522 cases and 11,263 controls). We then tested the associations with other metabolic traits (n<=17,900) and with type 2 diabetes (931 cases and 1,404 controls), and looked up the datasets in silico in other populations. Significant (adjusted P<0.05) CAD associations were found for 5 BP loci: 3 new CAD associations at FIGN,FGF5 and NPR3, and 2 previously reported ones at ATP2B1 and CNNM2. The strongest CAD association was detected at ATP2B1rs2681472 (P=1.7*10(-8)), in the direction inverted to what is generally recognized for BP in the epidemiological studies.CNNM2rs12413409 showed significant association with CAD (P=8.7*10(-7)) and BMI (P=3.5*10(-8), when meta analyzed with 75,807 east Asian people). The genetic risk score combining BP raising alleles at each of the SNPs was positively associated with CAD (P=0.011). CONCLUSIONS: A substantial proportion of genetic variants associated with BP were also associated with the risk of CAD in east Asian people, and there was some counter-evidence for causal inference. PMID- 25740056 TI - Comparable accuracy of micro-electromechanical blood flowmetry-based analysis vs. electrocardiography-based analysis in evaluating heart rate variability. AB - BACKGROUND: Because the conventional evaluation of autonomic nervous system (ANS) function inevitably uses long-lasting uncomfortable electrocardiogram (ECG) recording, a more simplified and comfortable analysis system has been sought for this purpose. The feasibility of using a portable micro-electromechanical system (MEMS) blood flowmeter to analyze heart rate variability (HRV) for evaluating ANS function was thus examined. METHODS AND RESULTS: Measurements of the R-R interval (TRR) derived from an ECG, simultaneously with the pulse wave interval (TPP) derived from a MEMS blood flowmeter, in 8 healthy subjects was performed and resultant HRV variables in time and frequency domains were compared. The TRR- and TPP-derived variables were strongly correlated (coefficients of regression for low frequency (LF), high frequency (HF), and LF/HF of 1.1, 0.66, and 0.35, respectively; corresponding coefficients of determination of 0.92, 0.63, and 0.91, respectively (P<0.01)). In addition, the values of LF, HF, and LF/HF, as analyzed using TPP, changed significantly from the supine to the standing position in another 6 subjects. CONCLUSIONS: Miniaturized-MEMS blood flowmetry can be used to perform HRV analysis for the evaluation of ANS function, which is as accurate as analysis based on ECG within comparable tolerances. As MEMS blood flowmetry can more easily and comfortably record physiological variables for longer durations than ECG recording, and can further capture skin blood flow information, this device has great potential to be used in a wider area of physiological analyses. PMID- 25740057 TI - Fabrication of three dimensional (3D) hierarchical Ag/WO3 flower-like catalyst materials for the selective oxidation of m-xylene to isophthalic acid. AB - A three dimensional (3D) hierarchical silver supported tungsten oxide flower-like microsphere catalyst has been fabricated using a cationic surfactant CTAB. It was found that the crystal-splitting mechanism plays a key role in the formation of this flower-like structure. This catalyst was proved to be highly effective in the liquid phase selective oxidation of m-xylene to isophthalic acid. PMID- 25740058 TI - The circadian gene CRY2 is associated with breast cancer aggressiveness possibly via epigenomic modifications. AB - Although the role of core circadian gene cryptochrome 2 (CRY2) in breast tumorigenesis has been demonstrated, the correlations of CRY2 with clinical parameters in breast cancer patients and its involvement in epigenetic processes such as DNA methylation remain relatively unexplored. In the current study, we first queried the Oncomine database and the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) database to identify associations between CRY2 expression levels and clinical parameters in breast cancer patients. We then silenced CRY2 in vitro and performed a genome-wide methylation array to determine the epigenetic impact of CRY2 silencing. The Ingenuity Pathway Analysis software was used to further explore the genes exhibiting altered methylation identified using the array. We found that CRY2 was frequently down-regulated in breast cancer tissue compared to adjacent normal tissue or breast tissue from healthy controls. Lower CRY2 expression was associated with estrogen receptor (ER) negativity (P < 0.0001), higher tumor grade (P < 0.0001), and shorter overall survival time in breast cancer patients (HR = 1.44, 95 % confidence interval (CI) 1.09-1.91). Genome-wide methylation analysis showed that a total of 515 CpG sites were hypermethylated following CRY2 knockdown, while 730 sites were hypomethylated. The pathway analysis revealed several cancer-relevant networks with genes exhibiting significantly altered methylation following CRY2 silencing. These findings suggest that the core circadian gene CRY2 is associated with breast cancer progression and prognosis, and that knockdown of CRY2 causes the epigenetic dysregulation of genes involved in cancer-relevant pathways, which provide further evidence supporting a role of the circadian system in breast tumorigenesis. PMID- 25740059 TI - Potential role of miR-100 in cancer diagnosis, prognosis, and therapy. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function by base pairing with messenger RNAs, thereby regulating protein expression. Functional studies indicate that miRNAs are involved in the regulation of almost every biological pathway. Moreover, changes in miRNA expression are associated with several human pathologies, including cancer. Dysregulation and aberrant expression of microRNA 100 (miR-100) have been reported to be involved in tumorigenesis and tumor progression of several cancer types, suggesting that miR-100 might serve as a diagnostic and/or prognostic marker for human malignancy. In this review, we summarize the potential application of miR-100 in cancer treatment and as a new molecular marker for cancer prognosis and diagnosis. We will provide a brief introduction to miR-100 and discuss its role as a non-invasive biomarker and a potential therapeutic target in human cancers. PMID- 25740060 TI - Combined effects of anticancer drugs and new synthetic alpha-methylene-delta lactones on MCF-7 cells. AB - The search for novel drug candidates is a priority goal for cancer therapy. Natural products isolated from plants are often used as valuable leads for the synthesis of analogs with simpler structure. Two synthetic alpha-methylene-delta lactones with chroman-2-one skeleton, designated DL-3 and DL-5, exhibiting strong cytotoxic activity against several cancer cell lines, have been tested alone and in combination with well-known anticancer drugs, 5-fluorouracil, oxaliplatin, and taxol, in breast cancer MCF-7 cells. Parthenolide, a plant-derived alpha methylene-gamma-lactone, was used as a positive control. The effects on cell proliferation, DNA damage, and apoptosis induction were evaluated. Neither of the tested compounds significantly enhanced the effects produced by taxol, but a strong synergistic effect was observed with 5-fluorouracil and oxaliplatin. Only small differences between the actions of both alpha-methylene-delta-lactones were found. The synergistic effects produced by these compounds in MCF-7 cells were stronger as compared with parthenolide. Our findings show that simple and easy-to obtain synthetic compounds with alpha-methylene-delta-lactone motif can potentiate the efficiency of anticancer drugs. PMID- 25740061 TI - Targeting delivery of lipocalin 2-engineered mesenchymal stem cells to colon cancer in order to inhibit liver metastasis in nude mice. AB - One of the major obstacles in cancer therapy is the lack of anticancer agent specificity to tumor tissues. The strategy of cell-based therapy is a promising therapeutic option for cancer treatment. The specific tumor-oriented migration of mesenchymal stem cells (MSCs) makes them a useful vehicle to deliver anticancer agents. In this study, we genetically manipulated bone marrow-derived mesenchymal stem cells with their lipocalin 2 (Lcn2) in order to inhibit liver metastasis of colon cancer in nude mice. Lcn2 was successfully overexpressed in transfected MSCs. The PCR results of SRY gene confirmed the presence of MSCs in cancer liver tissue. This study showed that Lcn2-engineered MSCs (MSC-Lcn2) not only inhibited liver metastasis of colon cancer but also downregulated the expression of vascular endothelial growth factor (VEGF) in the liver. Overall, MSCs by innate tropism toward cancer cells can deliver the therapeutic agent, Lcn2, and inhibit cancer metastasis. Hence, it could be a new modality for efficient targeted delivery of anticancer agent to liver metastasis. PMID- 25740062 TI - Centrosome maturation requires YB-1 to regulate dynamic instability of microtubules for nucleus reassembly. AB - Microtubule formation from the centrosome increases dramatically at the onset of mitosis. This process is termed centrosome maturation. However, regulatory mechanisms of microtubule assembly from the centrosome in response to the centrosome maturation are largely unknown. Here we found that YB-1, a cellular cancer susceptibility protein, is required for the centrosome maturation. Phosphorylated YB-1 accumulated in the centrosome at mitotic phase. By YB-1 knockdown, microtubules were found detached from the centrosome at telophase and an abnormal nuclear shape called nuclear lobulation was found due to defective reassembly of nuclear envelope by mis-localization of non-centrosomal microtubules. In conclusion, we propose that YB-1 is important for the assembly of centrosomal microtubule array for temporal and spatial regulation of microtubules. PMID- 25740063 TI - Detection of global hypermethylation in well-differentiated thyroid neoplasms by immunohistochemical (5-methylcytidine) analysis. AB - PURPOSE: While global hypomethylation of DNA has been found in several malignancies, studies on thyroid tumours have shown controversial results using different techniques. To help resolve this issue, we assessed methylation status using two different techniques in papillary thyroid carcinomas (PTC) and follicular adenomas (FA) and carcinomas (FTC), comparing adjacent non-neoplastic thyroid tissue. METHODS: A series of 15 FA, 18 FTC and 17 PTC were assessed by: (1) measurement of methylation levels of long interspersed nuclear elements (LINE 1) using a combined bisulfite restriction analysis polymerase chain reaction protocol and (2) immunostaining with an anti-5-methylcytidine antibody that detects methylated DNA regardless of the DNA sequence. Immunostaining was scored by image analysis. RESULTS: Methylation levels of LINE-1 in FA, FTC and PTC were not significantly different from adjacent normal tissue. There was no significant difference in methylation levels of LINE-1 between FA, FTC and PTC (p = 0.44). By immunohistochemical staining for methylation, the 5-methylcytidine score was significantly higher in tumours than in normal tissue counterparts, for FA (p < 0.001), FTC (p = 0.04) and PTC (p = 0.02). PTC showed the highest 5 methylcytidine expression amongst all tumours which was significantly different from FTC (p = 0.015), but not FA (p = 0.09). There was no correlation in methylation level between LINE-1 and 5-methylcytidine scores for each group and overall. CONCLUSIONS: Well-differentiated thyroid neoplasms (FA, FTC and PTC) were not found by two independent methods to undergo global hypomethylation as part of an oncogenic sequence from normal tissue to carcinoma. Instead, hypermethylation was detected in all types of tumours, implying that this epigenetic event may contribute to oncogenic development of thyroid neoplasms (both benign and malignant). PMID- 25740064 TI - Mechanistic approach to the pathophysiology of target organ damage in hypertension from studies in a human model with characteristics opposite to hypertension: Bartter's and Gitelman's syndromes. AB - INTRODUCTION: Extensive studies using Bartter's/Gitelman's syndrome patients have provided insights into the angiotensin II (Ang II) signaling pathways involved in the regulation of vascular tone and cardiovascular-renal remodeling. The renin angiotensin-aldosterone system is activated in these syndromes, however, patients do not develop hypertension and cardiovascular remodeling and clinically manifest conditions opposite to hypertension. The short- and the long-term signaling of Ang II remains an important matter of investigation to shed light on mechanisms responsible for the pathophysiology of hypertension and its long-term complications. The long-term signaling of Ang II is involved in the pathophysiology of cardiovascular-renal remodeling and inflammatory responses in which the balance between RhoA/Rho kinase pathway and NO system plays a crucial role. METHODS AND RESULTS: In this brief review, the results of our studies in Bartter's and Gitelman's syndromes are reported on these processes. CONCLUSIONS: The information obtained from these studies can clarify, confirm or be used to extend the biochemical mechanisms responsible for the pathophysiology of hypertension and its long-term complications and could offer further chances to identify additional potential significant targets of therapy. PMID- 25740065 TI - Total thyroid ablation in Graves' orbitopathy. AB - Graves' orbitopathy (GO) is an autoimmune condition almost always associated with autoimmune thyroid disease, especially Graves' disease (GD). According to the most widely accepted model, the autoantigens responsible for GO would include molecules expressed by thyroid epithelial cells that are present also in orbital tissues. The high likelihood that the etiologies of GO and of the underlying autoimmune thyroid diseases are somehow linked is confirmed by the very close relationship between GO, the onset and the course of Graves' diseases, the size of the thyroid gland, and most importantly, thyroid function and thyroid treatment. Based on these considerations, it has been proposed that complete removal of thyroid antigens and of thyroid infiltrating lymphocytes, the so called total thyroid ablation (TTA), may be followed by an attenuation of the immune reaction against orbital antigens, and ultimately by an amelioration of GO. The possibility that TTA, achieved by near total thyroidectomy followed by radioiodine, may be beneficial for GO was initially suggested by two retrospective studies and more recently by two prospective, randomized clinical trials conducted in patients with moderate GO treated with intravenous glucocorticoids. Although there seemed to be no difference in the long term, compared with near total thyroidectomy alone TTA was associated with a shorter time required for GO to improve, or anyway to reach its best possible outcome, and with a lesser requirement for additional treatments for GO to improve. Whether this is sufficient to offer ablation to patients remains a matter of discussion. At present, this procedure could be offered only to patients scheduled to thyroidectomy and glucocorticoid treatment. PMID- 25740066 TI - Embolization of left spermatic vein in non-obstructive azoospermic men with varicocele: role of FSH to predict the appearance of ejaculated spermatozoa after treatment. AB - PURPOSE: Varicocele repair in non-obstructive azoospermia (NOA) was occasionally associated to ejaculated spermatozoa independently from clinical and laboratory measures. We performed a prospective study in infertile men affected by NOA and left side varicocele to find whether or not the appearance of ejaculated spermatozoa after varicocele repair is predicted by baseline measures. METHODS: Patients with NOA and grade II, or grade III left side varicocele were submitted to hormone analysis and to scrotal color Doppler ultrasound (CDU). Azoospermia was confirmed in 23 patients aged 25-47 years who were than submitted to varicocele repair through a retrograde internal spermatic vein embolization. Patients were re-evaluated after 6 months. RESULTS: Six months after varicocele repair 12 patients (52.2 %) were still azoospermic (Group 1) while 11 patients (47.8 %) reported ejaculated spermatozoa (Group 2) [sperm count: 1.3 * 10(6)/mL; 0.5 * 10(6)/mL-1.6 * 10(6)/mL (median 25th-75th centiles)]. Serum baseline FSH was lower in Group 2 compared to Group 1 (p = 0.012), while no differences between groups were revealed for all other clinical and laboratory parameters. ROC analysis indicated that baseline FSH level predicted the appearance of ejaculated spermatozoa after treatment [AUC = 0.811; 95 % Confidence Interval (CI) 0.6-0.9; p = 0.0029]. A cut-off level of FSH <10.06 mIU/mL identified 82.0 % of cases with ejaculated spermatozoa with a specificity of 81.8 % and a sensitivity of 83.3 %. CONCLUSION: Selected patients with NOA may show ejaculated spermatozoa after a non-invasive repair of a left side varicocele, therefore avoiding testicular sperm extraction. Baseline serum FSH was a valuable predictor for ejaculated spermatozoa after treatment. PMID- 25740067 TI - Study on the zona pellucida 4 (ZP4) gene sequence and its expression in the ovaries of patients with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown pathology, involving reproductive and metabolic abnormalities. Oocyte specific genes are a group of genes expressed exclusively in ovarian tissue; therefore, they can play an important role in ovarian pathologies such as PCOS. The zona pellucida 4 (ZP4) gene encodes glycoprotein which is a part of the extracellular matrix of oocyte. MATERIALS AND METHODS: We analyzed 87 patients with PCOS, which were divided into four groups depending on their phenotype. In each patient, we performed profound clinical and biochemical analysis, including the measurement of serum androgens. The ovarian tissue samples were used to perform a real-time polymerase chain reaction and immunohistochemical staining using anti-ZP4 monoclonal antibodies. The ZP4 gene was sequenced from peripheral lymphocytes. RESULTS: The expression of ZP4 was present in early antral follicles and was stronger in mature follicles. The subgroup of patients with eumenorrhea and without hyperandrogenism presented the highest expression of ZP4 in ovarian tissue. In one case, we found a mutation of the ZP4 gene. No correlations were found between the ZP4 expression level and biochemical or clinical indices. CONCLUSIONS: Data from this and animal studies suggest a possible relationship between androgens and ZP4 expression. ZP4 expression is highest among patients with PCOS and a regular cycle, and this is a consequence of the presence of mature follicles in this group. In some patients with PCOS and infertility, ZP4 mutation can be found. PMID- 25740068 TI - The impact of thyroid hormone replacement therapy on left ventricular diastolic function in patients with subclinical hypothyroidism. AB - OBJECTIVE: Subclinical hypothyroidism (SH) is associated with a moderately elevated risk of heart failure events among older adults. The objective of our prospective study was to assess the impact of thyroid hormone replacement therapy (HRT) with low doses of L-thyroxine (6.25-25 ug/day) on left ventricular diastolic function in patients with SH. MATERIALS AND METHODS: 33 patients with SH and 25 healthy controls were involved. All participants underwent standard echocardiography and Doppler imaging at baseline and, the patient group, also after a course of HRT. RESULTS: At baseline, patients with SH showed significantly lower E (0.79 +/- 0.22 vs. 0.93 +/- 0.19, p < 0.001), E/A ratio (1.19 +/- 0.29 vs. 1.31 +/- 0.25, p < 0.003), and higher intraventricular septum thickness (IVST) (0.99 +/- 0.14 vs. 0.89 +/- 0.18, p < 0.001) in comparison with healthy controls. After 6 months of therapy, the E/A ratio underwent significant increase (1.28 +/- 0.21 vs. 1.19 +/- 0.29, p < 0.001), while the IVS displayed a robust reduction (0.92 +/- 0.16 vs. 0.99 +/- 0.14, p < 0.001). CONCLUSIONS: HRT with low-dosed L-thyroxine may improve left ventricular diastolic function in patients with SH. PMID- 25740069 TI - Women self-perception of excess hair growth, as a predictor of clinical hirsutism: a population-based study. AB - PURPOSE: Hirsutism is the most common indicator of hyperandrogenism. Both, the sensitivity of the patients to the serum androgen levels and the responsiveness of women to the perceived excess hair growth vary among different populations. This report elaborates the relationship between the woman's discerned abnormal hair growths with the clinical diagnosis of hirsutism. METHODS: The survey was conducted among 1160 women aged 18-45 and randomly selected from Tehran Lipid and Glucose Study for further detailed assessment of Hirsutism; using the m-FG scoring method. Data gathering was performed by interviews and physical examinations. The receiver operating characteristic curve was drawn and the new cutoff value, sensitivity, specificity and concordance percentage were calculated. RESULTS: The results demonstrated that among 12 androgen-dependent body areas, the chin skin had the highest area under curve of 0.81 (CI; 0.78 0.84). According to the patient's evaluation, a threshold point of 4 had the optimum concordance percentage of 0.77 with the modified Ferriman-Gallwey scoring system. CONCLUSIONS: Patient's self-identification of excess terminal hair based on the chin area has great sensitivity and reliability in predicting the clinical hirsutism. PMID- 25740070 TI - Reference ranges for an automated chemiluminescent assay for serum insulin-like growth factor I (IGF-I) in a large population of healthy adults from Buenos Aires. AB - PURPOSE: Insulin-like growth factor I (IGF-I) represents an essential tool in the diagnostic work-up and in the monitoring of treatment efficacy for somatotrophic axis disorders both in children and adults. A large number of factors including, but not limited to, age, sex and weight as well as analytical variables influence IGF-I serum levels; therefore, reliable normative data are essential for a correct interpretation of results. The aim of the present study was to establish reference range values for serum IGF-I, in a large population of healthy adults from Buenos Aires city. METHODS: The study included serum samples from 1044 healthy subjects aged 21-87 years (423 females and 621 males) divided into groups by sex at 5-year intervals from 21 to >75 years. Serum IGF-I concentrations were determined by a fully automated two-site, solid-phase, enzyme-labeled chemiluminescent immunometric assay (Immulite 2000, Siemens Healthcare Diagnostics). IGF-BP interferences are circumvented by blocking IGF-BP binding sites with excess IGF-II in the on-board predilution step. RESULTS: Results show the age dependence of circulating IGF-I levels, with a smooth and steady decrease in levels with age. No sex differences were found in subjects >26 years; however, in the group aged 21-25 years, IGF-I levels were significantly higher in females. In conclusion, this study provides age- and gender-adjusted normal reference ranges for IGF-I levels obtained with an automated immunometric chemiluminescent assay Immulite 2000 in healthy adult subjects. PMID- 25740071 TI - A relation between cell cycle and intestinal metaplasia in oesophageal biopsies using optical and digital microscopy. AB - Protein expression changes in relation to cell cycles provide important information, and it may represent a new method for an early diagnosis of metaplasia - dysplasia - adenocarcinoma sequence. We investigated potential changes in cell cycle genes such as protooncogenes (PCNA, EGFR), tumour suppressor gene (p53), apoptotic TUNNEL (Tdt mediated dUTP nick and labelling) gene, as well as small intestinal mucus antigen (SIMA) and large intestinal mucus antigen (LIMA), which accumulates in metaplastic epithelium due to the inflammatory process in routine oesophageal biopsies using immunohistochemistry. Oesophageal biopsies were taken from patients with Barrett's oesophagus (n = 30), reflux oesophagitis (n = 30), healthy oesophagus (n = 30) and healthy cardia (n = 10). Immunohistochemical signalling was carried out by Streptavidin-Biotin-AEC (aminoetil-carbazol). Expression of PCNA was statistically significantly lower in healthy oesophagus (p < 0.05) versus reflux oesophagitis and Barrett's oesophagus. However, no significant change was detected in the expression of SIMA and LIMA in intestinal metaplasia. Further, EGFR, p53 and TUNNEL levels were significantly different in healthy versus Barrett's oesophagus. Manual counting using virtual microscopy was comparable with the result using conventional light microscopy, but the former is significantly quicker. There was no difference between manual and automated cell counting (p > 0.05). PMID- 25740072 TI - Studies on Deimmunization of Antileukaemic L-Asparaginase to have Reduced Clinical Immunogenicity--An in silico Approach. AB - Protein therapeutics, particularly of heterologous origin are shown to elicit immunogenic responses which result in adverse allergic reactions in spite of their promising clinical benefit. L-Asparaginase is one such well known chemotherapeutic agent that has enhanced the survival rates to 90 % in the treatment of acute lymphoblastic leukaemia for past 30 years. But the use of this enzyme is accompanied by hypersensitive reactions ranging from allergy to anaphylactic shock which have a drastic influence in treatment outcomes. Numerous attempts have been made to minimize the problems of immunogenicity, which remained as a major bottleneck in the treatment protocols. Conjugating the enzyme L- Asparaginase with PEG was successful as it has reduced the complications in therapy and frequency of injections (dosages), and thus became prominent in reducing the immunogenicity up to a certain extent. Keeping the bottlenecks in consideration during the development of therapeutics, the present study concentrates on engineering of protein as an alternative to the PEGylated enzyme, having reduced immunogenicity as an inbuilt character of protein by using in silico approaches. L-Asparaginase from Escherichia coli and Pectobacterium carotovorum were selected for the present study. The methodology consists of (i) locating the B and CD4+ T cell epitopes of enzyme by in silico tools (ii) generating point mutations of these epitopes to alter or reduce the immunogenicity of protein (iii) generating enzyme models by molecular modelling (iv) assessing the binding affinity of the substrate with L-Asparaginase variants by in silico docking methods using Autodock 4.2 and (v) validating the mutated model for stability by molecular dynamics simulation studies using Gromacs. PMID- 25740073 TI - The role of the mediators of inflammation in cancer development. AB - Epigenetic disorders such as point mutations in cellular tumor suppressor genes, DNA methylation and post-translational modifications are needed to transformation of normal cells into cancer cells. These events result in alterations in critical pathways responsible for maintaining the normal cellular homeostasis, triggering to an inflammatory response which can lead the development of cancer. The inflammatory response is a universal defense mechanism activated in response to an injury tissue, of any nature, that involves both innate and adaptive immune responses, through the collective action of a variety of soluble mediators. Many inflammatory signaling pathways are activated in several types of cancer, linking chronic inflammation to tumorigenesis process. Thus, Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, growth, invasion, and metastasis, affecting also the immune surveillance. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. A range of inflammation mediators, including cytokines, chemokines, free radicals, prostaglandins, growth and transcription factors, microRNAs, and enzymes as, cyclooxygenase and matrix metalloproteinase, collectively acts to create a favorable microenvironment for the development of tumors. In this review are presented the main mediators of the inflammatory response and discussed the likely mechanisms through which, they interact with each other to create a condition favorable to development of cancer. PMID- 25740074 TI - Differential Expression of Sonic Hedgehog Protein in Human Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. AB - Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) are the two most common primary liver malignancies in adult patients. The molecular mechanisms underlying the pathogenesis of HCC and CCA are still poorly understood. Sonic hedgehog (SHH) signaling plays an essential role during mammalian development, i.e., promoting organ growth, tissue differentiation, and cell polarity. The upregulation of SHH has been observed during carcinogenesis, including colorectal carcinoma. Our aim was to investigate the expression pattern of SHH in HCC and CCA. We investigated 40 malignant tumors of the liver, including 21 HCC and 19 of intrahepatic CCA cases by immunohistochemistry (IHC) using a polyclonal antibody against SHH and Avidin-Biotin Complex method. We also investigated the co-localization of SHH and Bone morphogenetic protein 4 (BMP4) in CCA using indirect double IHC. Moreover, we examined whether SHH is expressed in two HCC cell lines HepG2 and HuH-7 and three CCA cell lines OZ, HuCCT1 and HuH28. We found that SHH was expressed in 15 out of 21 cases (71.4 %) of HCC and 100 % of CCA cases by immunohistochemistry. SHH expression showed a positive trend in liver tumors (HCC, CCA) with high grade (G2-G3). SHH localized to the epithelial cells, while BMP4 was expressed in the stromal cells in CCA by double IHC. However, both HCC and CCA cell lines showed SHH expression by Western blot analysis. In conclusion, SHH seems to be an interesting marker of de differentiation in liver tumors and the simultaneous epithelial-mesenchymal expression may be an intriguing prompt to investigate cross-talks between SHH and BMP4. PMID- 25740075 TI - GNAS mutation affecting codon 201 is rare in most human tumors. PMID- 25740076 TI - Pectoralis major fascia in rhinoplasty. AB - Fascia is frequently used in rhinoplasty, for several different purposes. The deep temporalis fascia is most often chosen, though harvesting this fascia requires a separate surgical field that adds surgical time to the procedure and morbidity to the patient. In augmentation rhinoplasty cases as well as in many revision rhinoplasty cases, costal cartilage may be required. In these cases, when costal cartilage is harvested from the 5(th) to 7(th) ribs, pectoralis major fascia is in the surgical field and must be incised to provide access to the costal cartilage. Pectoralis major fascia is similar to the deep temporalis fascia, sharing many physical and histological characteristics with it. Pectoralis major fascia can be harvested from the same surgical field as costal cartilage and used in the nose whenever autologous costal cartilage is harvested, thus precluding the need for a separate surgical field for fascia harvest. The surgical technique for harvesting pectoralis major fascia is demonstrated, and two clinical cases of patients in whom this fascia was harvested and used in the nose are presented. Pectoralis major fascia may be considered an alternative option for use in rhinoplasty cases whenever autologous costal cartilage is used. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25740077 TI - "Pickaxe" double flap: a useful "tool" for reconstruction of deep large medial canthal defects-5-year experience and brief literature review. AB - OBJECTIVE: Reconstruction of large, deep medial canthal defects presents a challenge to reconstructive surgeons, since both safe oncologic excision and aesthetically pleasant results should be met. We report our 5-year experience with the use of a double flap technique, which looks like a "pickaxe", in reconstruction of the aforementioned kind of defects. METHODS: The technique is based on the simultaneous use a glabellar and a nasolabial flap designed and raised on either side of the medial canthal defect. The complex of the defect with the flaps looks like a pickaxe. The technique was applied in 17 patients during the last 5 years. RESULTS: No tumour relapses were recorded in our series (mean follow-up period of 24.8 months). Also neither disfiguring scar contractures nor trapdoor deformities were noticed because of the ample tissue provided and the w-plasty outline of the resulting surgical scar. All patients were satisfied with the aesthetic outcome. CONCLUSION: The suggested technique is simple, reliable and provides very good aesthetic results without disfiguring deformities. Most importantly, consistent long-term results with high patient satisfaction and no tumour relapses were achieved. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25740078 TI - Breast implant-associated anaplastic large cell lymphoma: a case report and literature review. AB - Breast implant-associated anaplastic large cell lymphoma (ALCL) is a rare new clinical entity. The incidence is 0.3 % per 100,000 women per year. Patients present with non-specific implant-related complications resulting in delayed diagnosis. We present such a case to raise awareness and discuss management. A 48 year-old female presented with a 3-month history of left breast pain and swelling. She had undergone multiple bilateral augmentations 8 years previously. Triple assessment revealed a seroma, and a magnetic resonance imaging scan excluded implant rupture. Cytology showed a typical cells with mitotic activity which lead to removal of implants and a left capsulectomy. Final histology revealed an anaplastic lymphoma kinase (ALK) negative ALCL confined to the capsule. A computerised tomography scan and bone marrow biopsy excluded systemic disease, but due to later identified B symptoms, she received CHOP chemotherapy under the care of the haematologists. ALK-negative ALCL is associated with breast implants, and any persistent late onset seroma or breast symptoms should raise the suspicion of ALK-negative ALCL as a differential diagnosis. The recommended treatment is surgical removal of the implant including a full capsulectomy, highlighting the suspicion of ALCL to the pathologist. Exclusion of systematic disease is also recommended in all patients, and the need for adjuvant therapy should be addressed on an individual case basis. For disease confined to the capsule, adjuvant chemoradiotherapy is not needed. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 . PMID- 25740079 TI - Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions. AB - Elevated plasma homocysteine levels are considered an independent risk factor for cardiovascular diseases. Experimental evidence has shown that hydrogen sulfide anion (HS(-)) protects the myocardium from ischemia/reperfusion (IR) injury. Both homocysteine levels and endogenous HS(-) production are mainly regulated by two transsulfuration enzymes, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CTH). We hypothesized that the transsulfuration pathway plays essential roles in the development of cardiac adaptive responses against ischemia, and investigated the roles of homocysteine, HS(-), and transsulfuration enzymes in fasting-induced cardioprotection against IR injury utilizing hyperhomocysteinemic Cbs (-/-) and Cth (-/-) mice. Langendorff-perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. Two-day fasting ameliorated left ventricular dysfunction after reperfusion via propargylglycine- and glibenclamide-sensitive pathways in wild-type mice but not in Cbs (-/-) or Cth (-/-) mice, although fasting induced cardiac expression of several Nrf2 target antioxidant genes in both wild-type and Cth (-/-) mice. Intraperitoneal administration of sodium hydrosulfide (a HS(-) donor) at 24 h prior to IR improved myocardial recovery in wild-type mice but not in Cth (-/-) or high-methionine-diet-fed (thus intermediately hyperhomocysteinemic) wild-type mice. Quantitative analysis of reactive sulfur species using monobromobimane derivatization methods revealed that homocysteine efficiently captures HS(-) to form homocysteine persulfide in the hearts as well as in the in vitro reactions. Here we propose a novel molecular and pathophysiological basis for hyperhomocysteinemia; excessive circulatory homocysteine interferes with HS(-) related cardioprotection against IR injury by capturing endogenous HS(-) to form homocysteine persulfide. KEY MESSAGE: Two-day fasting of mice ameliorates ischemia/reperfusion injury in Langendorff hearts. H2S-producing enzymes, CBS and CTH, are essential in fasting-induced cardioprotection. Administration of a H2S donor (NaHS) confers cardioprotection against IR injury. NaHS effects are absent in Cth (-/-), Cbs (-/-), and dietary hyperhomocysteinemic mice. Homocysteine captures cardioprotective HS(-) to form homocysteine persulfide. PMID- 25740081 TI - Analytic morphomics identifies predictors of new-onset diabetes after liver transplantation. AB - Among liver transplant recipients, development of post-transplant complications such as new-onset diabetes after transplantation (NODAT) is common and highly morbid. Current methods of predicting patient risk are inaccurate in the pre transplant period, making implementation of targeted therapies difficult. We sought to determine whether analytic morphomics (using computed tomography scans) could be used to predict the incidence of NODAT. We analyzed peri-transplant scans from 216 patients with varying indications for liver transplantation, among whom 61 (28%) developed NODAT. Combinations of visceral fat, subcutaneous fat, and psoas area were considered in addition to traditional risk factors. On multivariate analysis adjusting for usual risk factors such as type of immunosuppression, subcutaneous fat thickness remained significantly associated with NODAT (OR = 1.43, 95% CI 1.00-1.88, p = 0.047). Subgroup analysis showed that patients with later-onset of NODAT had higher visceral fat, whereas subcutaneous fat thickness was more correlated with earlier-onset of NODAT (using 10 months post-transplant as the cut-off). CONCLUSION: Analytic morphomics may be used to help assess NODAT risk in patients undergoing liver transplantation. PMID- 25740080 TI - A novel role of microglial NADPH oxidase in mediating extra-synaptic function of norepinephrine in regulating brain immune homeostasis. AB - Although the peripheral anti-inflammatory effect of norepinephrine (NE) is well documented, the mechanism by which this neurotransmitter functions as an anti inflammatory/neuroprotective agent in the central nervous system (CNS) is unclear. This article aimed to determine the anti-inflammatory/neuroprotective effects and underlying mechanisms of NE in inflammation-based dopaminergic neurotoxicity models. In mice, NE-depleting toxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) was injected at 6 months of lipopolysaccharide (LPS) induced neuroinflammation. It was found that NE depletion enhanced LPS-induced dopaminergic neuron loss in the substantia nigra. This piece of in vivo data prompted us to conduct a series of studies in an effort to elucidate the mechanism as to how NE affects dopamine neuron survival by using primary midbrain neuron/glia cultures. Results showed that submicromolar concentrations of NE dose dependently protected dopaminergic neurons from LPS-induced neurotoxicity by inhibiting microglia activation and subsequent release of pro-inflammatory factors. However, NE-elicited neuroprotection was not totally abolished in cultures from beta2-adrenergic receptor (beta2-AR)-deficient mice, suggesting that novel pathways other than beta2-AR are involved. To this end, It was found that submicromolar NE dose-dependently inhibited NADPH oxidase (NOX2)-generated superoxide, which contributes to the anti-inflammatory and neuroprotective effects of NE. This novel mechanism was indeed adrenergic receptors independent since both (+) and (-) optic isomers of NE displayed the same potency. We further demonstrated that NE inhibited LPS-induced NOX2 activation by blocking the translocation of its cytosolic subunit to plasma membranes. In summary, we revealed a potential physiological role of NE in maintaining brain immune homeostasis and protecting neurons via a novel mechanism. PMID- 25740082 TI - Orofacial plasmacytosis: a management conundrum. AB - Plasmacytosis of the mucous membrane is a rare, benign, inflammatory condition of poorly understood aetiology that affects the mucous membranes. Most reported cases involve the gingival tissues, larynx, and occasionally the lips. We describe an interesting case of orofacial plasmacytosis that affected the lower lip, mandibular gingiva, and buccal mucosa. It mimicked an oral squamous cell carcinoma and presented a management dilemma. PMID- 25740083 TI - Current indications for low level laser treatment in maxillofacial surgery: a review. AB - Low level laser treatment (LLLT) is currently being used for various disorders, but with no convincing scientific evidence. Most recently we have noticed an increase in published randomised controlled trials (RCTs) that have focused on its applications in wound healing, scarring, disorders of the temporomandibular joint (TMJ), oral mucositis, and dental pain. Our aim therefore was to assess the scientific evidence about its current efficacy in maxillofacial surgery. We reviewed PubMed from January 2003 to January 2013 using the key phrase "low level laser treatment". Our inclusion criterion was intervention studies in humans of more than 10 patients. We excluded animal studies and papers in languages other than English, French, and German. We found 45 papers that we screened independently. The resulting full texts were scrutinised by two authors who awarded a maximum of 5 points using the Jadad scale for assessing the quality of RCT, and extracted the data according to sample size, variables of LLLT, the authors' conclusions, and the significance of the result. LLLT seems to be effective for the treatment of oral mucositis after treatment for head and neck cancer. However, it cannot yet be considered a valid treatment for disorders of the TMJ. It seems to improve gingival healing, and myofacial and dental pain. PMID- 25740084 TI - The use of legal, illegal and roll-your-own cigarettes to increasing tobacco excise taxes and comprehensive tobacco control policies: findings from the ITC Uruguay Survey. AB - BACKGROUND: Little research has been done to examine whether smokers switch to illegal or roll-your-own (RYO) cigarettes in response to a change in their relative price. OBJECTIVE: This paper explores how relative prices between three cigarette forms (manufactured legal, manufactured illegal and RYO cigarettes) are associated with the choice of one form over another after controlling for covariates, including sociodemographic characteristics, smokers' exposure to antismoking messaging, health warning labels and tobacco marketing. METHODS: Generalised estimating equations were employed to analyse the association between the price ratio of two different cigarette forms and the usage of one form over the other. FINDINGS: A 10% increase in the relative price ratio of legal to RYO cigarettes is associated with a 4.6% increase in the probability of consuming RYO cigarettes over manufactured legal cigarettes (p<=0.05). In addition, more exposure to antismoking messaging is associated with a lower odds of choosing RYO cigarettes over manufactured legal cigarettes (p<=0.05). Non-significant associations exist between the manufactured illegal to legal cigarette price ratios and choosing manufactured illegal cigarettes, suggesting that smokers do not switch to manufactured illegal cigarettes as prices of legal ones increase. However, these non-significant findings may be due to lack of variation in the price ratio measures. To improve the effectiveness of increased taxes and prices in reducing smoking, policymakers need to narrow price variability in the tobacco market. Moreover, increasing antismoking messaging reduces tax avoidance in the form of switching to cheaper RYO cigarettes in Uruguay. PMID- 25740085 TI - Effects of neurofeedback on adult patients with psychiatric disorders in a naturalistic setting. AB - Few well-controlled studies have considered neurofeedback treatment in adult psychiatric patients. In this regard, the present study investigates the characteristics and effects of neurofeedback on adult psychiatric patients in a naturalistic setting. A total of 77 adult patients with psychiatric disorders participated in this study. Demographic data and neurofeedback states were retrospectively analyzed, and the effects of neurofeedback were evaluated using clinical global impression (CGI) and subjective self-rating scales. Depressive disorders were the most common psychiatric disorders (19; 24.7 %), followed by anxiety disorders (18; 23.4 %). A total of 69 patients (89.6 %) took medicine, and the average frequency of neurofeedback was 17.39 +/- 16.64. Neurofeedback was applied to a total of 39 patients (50.6 %) more than 10 times, and 48 patients (62.3 %) received both beta/SMR and alpha/theta training. The discontinuation rate was 33.8 % (26 patients). There was significant difference between pretreatment and posttreatment CGI scores (<.001), and the self-rating scale also showed significant differences in depressive symptoms, anxiety, and inattention (<.001). This is a naturalistic study in a clinical setting, and has several limitations, including the absence of a control group and a heterogenous sample. Despite these limitations, the study demonstrates the potential of neurofeedback as an effective complimentary treatment for adult patients with psychiatric disorders. PMID- 25740086 TI - Reply to discrepant results for smoking and cessation among electronic cigarette users. PMID- 25740087 TI - Emerging drugs for the treatment of erectile dysfunction. AB - INTRODUCTION: Erectile dysfunction adversely affects the lives of millions of men, and is the most commonly treated sexual disorder today. The erectile process has been extensively investigated, with major advances made in elucidating many of the complex molecular pathways involved. These advances have allowed researchers to design and study drug formulations that target various aspects of this complex process. The initial culmination of this research was the introduction of phosphodiesterase 5-inhibitors. While effective in many patients, they are not satisfactory for all afflicted men. As a result, researchers are developing novel drugs that target different molecular pathways. AREAS COVERED: The paper will review these pathways, and the potential agents that target them. More specifically, first dopaminergic and melanocortin receptor agonists that act centrally will be covered. Then, the paper will examine the "second-generation" phosphodiesterase 5-inhibitors, soluble guanylate cyclases, rho-kinase inhibitors, and maxi-k channel activators that act peripherally. EXPERT OPINION: Most of these novel drugs have yet to reach Phase III studies. However, it is likely that in years to come, patients will be selectively treated with these novel agents as a monotherapy or in combination with others acting in a synergistic manner. PMID- 25740088 TI - Secondary prevention strategy of cardiovascular disease using endothelial function testing. AB - Over the past decades, secondary prevention of cardiovascular (CV) disease has improved and considerably reduced mortality rates. However, there remains a high rate of new or recurrent CV events in those with established atherosclerotic vascular diseases. Although most of the prevailing therapies target the conventional risk factors, there is notable interindividual heterogeneity in adaptation to risk factors and response to therapies, which affects efficacy. It is desirable to have a methodology for directly assessing the functional significance of atherogenesis, and for managing individual patients based on their comprehensive vascular health. Endothelial function plays a pivotal role in all stages of atherosclerosis, from initiation to atherothrombotic complication. Endothelial function reflects the integrated effect of all the atherogenic and atheroprotective factors present in an individual, and is therefore regarded as an index of active disease process and a significant risk factor for future CV events. Moreover, improvement in endothelial function is associated with decreased risk of CV events, even in the secondary prevention setting. The introduction of endothelial function assessment into clinical practice may trigger the development of a more tailored and personalized medicine and improve patient outcomes. In this review, we summarize current knowledge on the contribution of endothelial dysfunction to atherosclerotic CV disease in the secondary prevention setting. Finally, we focus on the potential of an endothelial function-guided management strategy in secondary prevention. PMID- 25740089 TI - Fetal bradycardia associated with congenital heart defects - is there a clinicohistological correlation? PMID- 25740090 TI - Decorating graphene nanosheets with electron accepting pyridyl-phthalocyanines. AB - We describe herein the preparation of novel exfoliated graphene-phthalocyanine nanohybrids, and the investigation of their photophysical properties. Pyridyl phthalocyanines (Pcs) are presented as novel electron accepting building blocks of variable strengths with great potential for the exfoliation of graphite via their immobilization onto the basal plane of graphene in dimethylformamide (DMF) affording single layered and turbostratic graphene based . were fully characterized (AFM, TEM, Raman, steady-state and pump probe transient absorption spectroscopy) and were studied in terms of electron donor-acceptor interactions in the ground and excited states. In this context, electron transfer upon photoexcitation from graphene to the electron accepting Pcs with dynamics, for example, in of <1 and 330 +/- 50 ps for charge separation and charge recombination, respectively, was corroborated in a series of steady-state and time-resolved spectroscopy experiments. PMID- 25740092 TI - Prostate cancer: active surveillance may prove organisationally impossible. PMID- 25740093 TI - Predicting difficult airways: 3-3-2 rule or 3-3 rule? AB - BACKGROUND: The goal of this study was to assess the value of the 3-3 rule and the 3-3-1 rule in predicting difficult airways. METHODS: The authors conducted an observational study over a 6-month period. For each consenting adult patient undergoing general anesthesia, preoperative patient characteristics and data regarding difficult airway assessments and airway outcomes were collected. The 3 3-2 rule, 3-3-1 rule and 3-3 rule were included in preoperative difficult airway assessments. The 3-3-1 rule is defined as an interincisor distance (IID) less than three fingers, a hyoid-mental distance (HMD) less than three fingers, and a hyoid-thyroid cartilage distance (HTD) less than one finger. RESULTS: Among the 732 patients who were successfully recruited in this study, 67 patients had difficult laryngoscopy (DL) (9.2 %), and 25 patients had difficult intubation (DI) (3.4 % of the total). All of the DI patients were also DL patients (25/67, 37.3 %). The AUC of the 3-3-2, 3-3, and 3-3-1 rules for predicting difficult laryngoscopy were 0.702, 0.709, and 0.631, respectively. Significant differences between the 3-3-2 and 3-3-1 rules as well as between the 3-3 and 3-3-1 rules were evident. The AUC values for the 3-3-2, 3-3, and 3-3-1 rules for predicting DI were 0.830, 0.822, and 0.725, respectively. CONCLUSIONS: The 3-3 rule and the 3-3 2 rule are similar regarding their ability to predict difficult airways. A HTD less than two fingers or one finger is not predictive of DV or DI. PMID- 25740094 TI - Twitter expands the reach and engagement of a national scientific meeting: the Irish Society of Urology. AB - BACKGROUND: Social media is the interaction among people in which they create, share or exchange information and ideas in virtual communities and web-based networks. This year, the Irish Society of Urology (ISU) expanded its involvement in social media with a preregistered Twitter hashtag (#ISU14) for the annual meeting. AIM: The aim of this study was to highlight the use of Twitter at an annual national meeting held in 2014. METHODS: The Symplur healthcare analytics website was used to prospectively examine traffic related to the 2014 ISU Annual Meeting. This feature was used to generate statistics for the number of impressions, unique tweets (excluding retweets) and distinct contributors who used the indexing hashtag #ISU14. Individual tweets were assessed using the conference hashtag on the Twitter website. RESULTS: The total number of attendees at the conference was 119, and 99 individuals participated in Twitter using the conference hashtag (#ISU14). 31 % of attendees participated in tweeting at the conference. Over the course of the conference, a total of 798 unique tweets were generated, creating over 665,000 impressions in cyberspace. 590 (73.9 %) tweets were generated from attendees at the conference, while 26.1 % of tweets were from virtual followers. 702 (87.9 %) tweets were from urologists and 439 (55 %) tweets were of scientific nature. Tweet activity peaked during the guest lectures on both days. CONCLUSION: Twitter use at the ISU has been shown to facilitate interaction between delegates and allows users to follow as well as participate from afar. PMID- 25740095 TI - Kinase-mediated orchestration of NADPH oxidase in plant immunity. AB - Reactive oxygen species (ROS) are important signalling molecules, which participate in multiple physiological processes including immune response, development, cell elongation and hormonal signalling in plants. Plant NADPH oxidase, termed respiratory burst oxidase homologue (RBOH), is frequently studied as a main player for pathogen-responsive ROS burst. Our understanding of the activation mechanism of RBOH after pathogen recognition has increased in recent years. In this review, we focus on kinase-mediated regulatory mechanisms of RBOHs. Calcium-dependent protein kinases (CDPKs) are well known to activate RBOHs by direct phosphorylation. In addition to functions of CDPKs in plants, we also describe the involvement of receptor-like cytoplasmic kinases (RLCKs) and mitogen activated protein kinases (MAPKs) in fine-tuning RBOH activity at the post translational and transcriptional levels, respectively. PMID- 25740096 TI - Collagen complexes increase the efficiency of iPS cells generated using fibroblasts from adult mice. AB - Different interventions are being tested for restoration of the youthfulness of adult mouse-derived fibroblasts. However, fundamental issues, such as the decline of adult mouse-derived fibroblast activity with age, remain unresolved. Therefore, in this study, we examined whether treatment with collagen complexes has beneficial effects on the rejuvenation or reprogramming of adult mouse derived fibroblasts. Further, we investigated the mechanisms of rejuvenation of adult mouse-derived fibroblasts during treatment with total collagen complexes. We isolated total collagen complexes from the tails of young mice and cultured adult mouse-derived fibroblasts with or without the collagen complexes. When compared with fibroblasts cultured without collagen complexes, adult-derived fibroblasts cultured with collagen complexes over five consecutive passages showed a more youthful state, expanded at a higher rate, and exhibited reduced spontaneous cell death. The fibroblasts cultured in the presence of collagen complexes also showed extensive demethylation in the promoter regions of cell cycle-related genes such as PCNA, increased proliferation, and decreased senescence. In addition, the efficiency of reprogramming of fibroblasts to become induced pluripotent stem (iPS) cells was significantly higher in young- and adult derived fibroblasts cultured with collagen complexes than in adult-derived fibroblasts cultured alone. Furthermore, mechanistic evidence shows that genes involved in anti-proliferative pathways, including Ink4a/Arf locus genes and p53, were downregulated in fibroblasts exposed to collagen complexes. Interestingly, our results suggest that the rejuvenation process was mediated via the alpha2beta1 integrin-dependent Bmi-1 pathway. Thus, collagen complexes both stimulate proliferation and inhibit cell death and growth arrest in fibroblasts, which appears to be a promising approach for improving the efficiency of reprogramming. PMID- 25740097 TI - The gene expression pattern induced by high plating density in cultured bovine and buffalo granulosa cells might be regulated by specific miRNA species. AB - Precise regulation of cell type-specific gene expression profiles precedes the profound morphological reorganization of somatic cell layers during folliculogenesis, ovulation and luteinization. Cell culture models are essential to the study of corresponding molecular mechanisms of gene regulation. In a recent study, it was shown that an increased cell plating density can largely change gene expression profiles of cultured bovine granulosa cells. In our present study, we comparatively analyzed cell plating density effects on cultured bovine and buffalo granulosa cells. Cells were isolated from small- to medium sized follicles (2-6 mm) and cultured under serum-free conditions at different plating densities. The abundance of selected marker transcripts and associated miRNA candidates was determined by quantitative real-time RT-PCR. We found in both species that the abundance of CYP19A1, CCNE1 and PCNA transcripts was remarkably lower at a high plating density, whereas VNN2 and RGS2 transcripts significantly increased. In contrast, putative regulators of CYP19A1, miR-378, miR-106a and let-7f were significantly higher in both species or only in buffalo, respectively. Also miR-15a, a regulator of CCNE1, was upregulated in both species. Thus, increased plating density induced similar changes of mRNA and miRNA expression in granulosa cells from buffalo and cattle. From these data, we conclude that specific miRNA species might be involved in the observed density induced gene regulation. PMID- 25740098 TI - Physical growth in the neonatal intensive-care unit and neuropsychological performance at preschool age in very preterm-born singletons. AB - We studied the associations between early postnatal growth gains and neuropsychological outcome in very preterm-born children. Specifically, we wished to establish whether relationships exist between gains in head circumference (relative to gains in body-weight or length), from birth to hospital discharge, and intellectual, language, or motor, performance at preschool age. We used data from 127 preschoolers, born <33 weeks, all graduates of the William Beaumont Hospital Neonatal Intensive-Care Unit (NICU) in Royal Oak, MI. Cognitive, motor, and language outcomes were evaluated using the Wechsler Preschool and Primary Scales of Intelligence-Revised, Peabody Developmental Scales - 2(nd) Edition, and the Preschool Language Scale - 3(rd) Edition, respectively. Differences between Z scores at birth and hospital discharge, calculated for three anthropometric measures (head circumference, weight, length), were variables of interest in separate simultaneous multiple regression procedures. We statistically adjusted for sex, socioeconomic status, birth weight, length of hospitalization, perinatal complications, and intrauterine growth. Examination of the relationships between anthropometric indices and outcome measures revealed a significant association between NICU head growth and global intelligence, with the Z-difference score for head circumference accounting for a unique portion of the variance in global intelligence (etap(2) =.04). Early postnatal head growth is significantly associated with neuropsychological outcome in very preterm-born preschoolers. To conclude, despite its relative brevity, NICU stay, often overlapping with the end of 2(nd) and with the 3(rd) trimester of pregnancy, appears to be a sensitive developmental period for brain substrates underlying neuropsychological functions. PMID- 25740099 TI - The use of in vitro model systems to study dental biofilms associated with caries: a short review. AB - A dental biofilm forms a distinct environment where microorganisms live in a matrix of extracellular polysaccharides. The biofilm favors certain bacteria and creates a habitat that functions differently compared to planktonic bacteria. Reproducible model systems which help to address various questions related to biofilm formation, the process of caries development, and its prevention are needed and are continuously developed. Recent research using both batch culture, continuous culture and flow cells in caries biofilm formation is presented. The development of new techniques and equipment has led to a deeper understanding of how caries biofilms function. Biofilm models have also been used in the development of materials inhibiting secondary caries. This short review summarizes available models to study these questions. PMID- 25740100 TI - Mesoporous monoliths of inverse bicontinuous cubic phases of block copolymer bilayers. AB - Solution self-assembly of block copolymers into inverse bicontinuous cubic mesophases is a promising new approach for creating porous polymer films and monoliths with highly organized bicontinuous mesoporous networks. Here we report the direct self-assembly of block copolymers with branched hydrophilic blocks into large monoliths consisting of the inverse bicontinuous cubic structures of the block copolymer bilayer. We suggest a facile and scalable method of solution self-assembly by diffusion of water to the block copolymer solution, which results in the unperturbed formation of mesoporous monoliths with large-pore (>25 nm diameter) networks weaved in crystalline lattices. The surface functional groups of the internal large-pore networks are freely accessible for large guest molecules such as protein complexes of which the molecular weight exceeded 100 kDa. The internal double-diamond (Pn3m) networks of large pores within the mesoporous monoliths could be replicated to self-supporting three-dimensional skeletal structures of crystalline titania and mesoporous silica. PMID- 25740101 TI - Chemistry at the interior atoms of polycyclic aromatic hydrocarbons. AB - For more than 150 years, chemical reactions that make new covalent bonds to polycyclic aromatic hydrocarbons (PAHs) have been confined almost exclusively to substitution and addition reactions on the perimeters of the compounds ("edge chemistry"). The "interior" atoms of PAHs, those belonging to three rings, almost never engage in new sigma-bond-forming reactions. A compound with no edges, C60, was the first polycyclic carbon pi-system observed to exhibit such reactivity. More recently, smaller subunits of C60, which we call geodesic polyarenes, have also been found to exhibit "fullerene-type chemistry" at their interior carbon atoms. These reactions are all reviewed together here for the first time. The review ends with speculation that sigma-bond-forming reactions may also be observed someday even in certain planar, benzenoid PAHs, although no examples have yet been reported. PMID- 25740102 TI - Utricular paresis and semicircular canal hyperactivity: a distinct otolith syndrome. AB - CONCLUSIONS: Although combined utricular and canal paresis has been described previously, this is the first report of canal hyperactivity associated with utricular hypofunction. Unsteadiness and swaying were the most common symptoms, and patients with shorter duration of symptoms also had positional vertigo. We propose that this syndrome is a variant of utricular dysfunction and should be considered in the differential diagnosis of peripheral vestibular disorders. OBJECTIVE: To describe a syndrome of instability associated with utricular dysfunction and hyperactive caloric responses. METHODS: The study comprised 11 consecutive patients exhibiting abnormalities of the eccentric subjective visual vertical test (e-SVV) and high responses during the caloric test of the videonystagmography (VNG). We carried out a review of symptoms, physical examination, and vestibular tests. RESULTS: There was no gender predilection or obvious etiology. The patients' main complaint included instability with linear symptoms (i.e., tilting, rocking, and swaying), with positional vertigo as a secondary symptom. Oculomotor testing, visual fixation index, and brain MRI were normal, excluding a central nervous system disorder. VNG was essentially normal except for hyperactive responses during the caloric testing in all patients. Abnormal e-SVV was found in 10 patients unilaterally and bilaterally in 1 patient. Abnormal oVEMP was found in seven of seven patients, further supporting a utricular site of lesion. PMID- 25740103 TI - Characterization of transsphenoidal complications in patients with acromegaly: an analysis of inpatient data in the United States from 2002 to 2010. AB - BACKGROUND: Transsphenoidal surgery (TSS) is a common procedure for a variety of pituitary lesions. This procedure can be associated with complications related to the surgery or specific pathology. In this study, we evaluate inpatient postoperative complications among patients who underwent TSS for growth hormone adenomas using a nationally representative database, and compare patient characteristics and complications to patients who underwent TSS for other benign pituitary neoplasms. METHODS: Analysis of the Nationwide Inpatient Sample revealed 13,070 TSS patients (including 892 with acromegaly) between 2002 and 2010. Complication rates, outcomes, patient demographics, hospital stay, and total charges were evaluated among TSS patients with and without acromegaly. RESULTS: There was an increase in TSS performed in both cohorts from 2002 to 2010. Acromegaly patients were younger, had shorter hospital stays, and incurred fewer charges. Acromegaly patients had a lower occurrence of postoperative urinary/renal complications (0.2% vs 1.1%), thromboembolic events (0% vs 0.4%), fluid/electrolyte abnormalities (5.7% vs 9.1%), and iatrogenic hypopituitarism (0.3% vs 1.1%) compared to other TSS patients (all p < 0.05). After adjusting for age, acromegalic patients maintained a statistically lower occurrence of fluid/electrolyte abnormalities (p = 0.007). Cerebrospinal fluid leak occurrence in acromegaly patients was 2.6% vs 1.7% in non-acromegaly patients, a result that did not reach significance (p = 0.054). CONCLUSION: Upon comparison of inpatient hospitalizations for patients undergoing TSS for growth hormone adenomas and other benign pituitary neoplasms, acromegaly patients had a significantly lower occurrence of postoperative fluid/electrolyte abnormalities. Acromegaly patients had shorter hospitalizations and subsequently fewer total charges. PMID- 25740104 TI - T-ALL: ALL a matter of Translation? PMID- 25740105 TI - Tyrosine kinase inhibitors in BCR-ABL positive acute lymphoblastic leukemia. PMID- 25740106 TI - The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 rearrangements share singular biological features. PMID- 25740107 TI - The subtype-specific features of EVI1 and PRDM16 in acute myeloid leukemia. PMID- 25740108 TI - Comment on "the negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.". PMID- 25740109 TI - Comment on "efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors". PMID- 25740110 TI - I think I am doing great but I feel pretty bad about it: affective versus cognitive verbs and self-reports. AB - Four experiments were conducted to examine the effect of responding to self report items framed with either a cognitive verb (think) or an affective verb (feel). Participants' open-ended self-descriptions were significantly more negative when they responded to a feel prompt than when they responded to a think prompt (Experiments 1 and 2). This effect persisted and influenced scores on a subsequent measure of self-esteem (Experiment 2). Substituting the verb think for feel in the Rosenberg self-esteem scale resulted in significantly higher reported self-esteem for female participants but not for male participants (Experiments 3 and 4). The research contributes to the literature demonstrating the subtle effects of word choice on responses to self-report items. PMID- 25740112 TI - Phosphorylation of Runx2, induced by cyclic mechanical tension via ERK1/2 pathway, contributes to osteodifferentiation of human periodontal ligament fibroblasts. AB - Occlusal force is an important stimulus for maintaining periodontal homeostasis. This is attributed to the quality of human periodontal ligament fibroblasts (hPDLFs) that could transfer occlusal force into biological signals modulating osteoblst differentiation. However, few studies investigated the mechanism of occlusal force-induced osteodifferentiation of hPDLFs. In our study, we used the cyclic mechanical tension (CMT) at 10% elongation with 0.5 Hz to mimic occlusal force, and explored its effects on osteogenesis of hPDLFs. Firstly, elevated expressions of several osteoblast marker genes (Runx2, ATF4, SP7, OCN, and BSP), as well as activated ERK1/2 pathway were detected during CMT loading for 1, 3, 6, 12, 18, and 24 h. To gain further insight into how CMT contributed to those effects, we focused on the classic ERK1/2-Runx2 pathway by inhibiting ERK1/2 and overexpressing Runx2. Our results reflected that Runx2 overexpression alone could induce osteodifferentiation of hPDLFs. Meanwhile, CMT loading could intensify while combined ERK1/2 blockage could weaken this process. Furthermore, we found that CMT promoted Runx2 transcription and phosphorylation via ERK1/2; protein level of phospho-Runx2 (p-Runx2), rather than Runx2, was in parallel with mRNA expressions of SP7, OCN, and BSP. Taken together, our study proved that p-Runx2, elevated by CMT via ERK1/2 pathway, is the predominate factor in promoting osteoblast differentiation of hPDLFs. PMID- 25740111 TI - New Cyt-like delta-endotoxins from Dickeya dadantii: structure and aphicidal activity. AB - In the track of new biopesticides, four genes namely cytA, cytB, cytC and cytD encoding proteins homologous to Bacillus thuringiensis (Bt) Cyt toxins have been identified in the plant pathogenic bacteria Dickeya dadantii genome. Here we show that three Cyt-like delta-endotoxins from D. dadantii (CytA, CytB and CytC) are toxic to the pathogen of the pea aphid Acyrthosiphon pisum in terms of both mortality and growth rate. The phylogenetic analysis of the comprehensive set of Cyt toxins available in genomic databases shows that the whole family is of limited taxonomic occurrence, though in quite diverse microbial taxa. From a structure-function perspective the 3D structure of CytC and its backbone dynamics in solution have been determined by NMR. CytC adopts a cytolysin fold, structurally classified as a Cyt2-like protein. Moreover, the identification of a putative lipid binding pocket in CytC structure, which has been probably maintained in most members of the Cyt-toxin family, could support the importance of this lipid binding cavity for the mechanism of action of the whole family. This integrative approach provided significant insights into the evolutionary and functional history of D. dadantii Cyt toxins, which appears to be interesting leads for biopesticides. PMID- 25740113 TI - Processing silk hydrogel and its applications in biomedical materials. AB - This review mainly introduces the types of silk hydrogels, their processing methods, and applications. There are various methods for hydrogel preparation, and many new processes are being developed for various applications. Silk hydrogels can be used in cartilage tissue engineering, drug release materials, 3D scaffolds for cells, and artificial skin, among other applications because of their porous structure and high porosity and the large surface area for growth, migration, adhesion and proliferation of cells that the hydrogels provide. All of these advantages have made silk hydrogels increasingly attractive. In addition, silk hydrogels have wide prospects for application in the field of biomedical materials. PMID- 25740114 TI - Insights From Twin Research: Conference at Royal Childrens Hospital, Melbourne, Australia / Twin Studies: Timing of Monozygotic Splitting and Commentary; Gestational Diabetes; ICOMBO'S Post-Partum Depression Study; Photographs of Conjoined Twins / Human Interest: Rare Quadruplets; Mistaken Identity on the Soccer Field; Prenatal Laser Surgery on Triplets; Twins Born to Prince and Princess of Monaco. AB - Highlights from a conference, 'Healthier Kids: Insights From Twin Research', held in Melbourne, Australia on December 5, 2014, are summarized. In addition to informative and exciting presentations and discussions of recent findings, three key themes emerged: (1) results from twin research have important implications for non-twins, (2) researchers from diverse disciplines should be encouraged to participate actively in twin research, and (3) investigators, twins and families need to work more collaboratively. Next, papers and studies concerning the biological bases of monozygotic (MZ) twinning, gestational diabetes and post partum depression are reviewed. Finally, general interest reports of rare quadruplets, mistaken identity, prenatal laser surgery and a royal twin birth are provided. PMID- 25740115 TI - Hd3a promotes lateral branching in rice. AB - Accumulating evidence indicates that the FLOWERING LOCUS T (FT) protein is the mobile floral signal known as florigen. A rice FT homolog, Heading date 3a (Hd3a), is transported from the phloem to shoot apical cells, where it interacts with 14-3-3 proteins and transcription factor OsFD1 to form a florigen activation complex (FAC) that activates a rice homolog of the floral identity gene APETALA1. Recent studies showed that florigen has roles in plant development beyond flowering; however, the exact nature of these roles is not well understood. It is not clear whether FT is transported to organs outside the shoot apex, and whether FAC formation is required for processes other than flowering. We show here that the Hd3a protein accumulates in axillary meristems to promote branching, and that FAC formation is required. Analysis of transgenic plants revealed that Hd3a promotes branching through lateral bud outgrowth. Hd3a protein produced in the phloem reached the axillary meristem in the lateral bud, and its transport was required for promotion of branching. Moreover, mutant Hd3a proteins defective in FAC formation but competent with respect to transport did not promote branching. Finally, we show that Hd3a promotes branching independently from strigolactone and FC1, a transcription factor that inhibits branching in rice. Together, these results suggest that Hd3a functions as a mobile signal for branching in rice. PMID- 25740116 TI - Amplification of chirality through self-replication of micellar aggregates in water. AB - We describe a system in which the self-replication of micellar aggregates results in a spontaneous amplification of chirality in the reaction products. In this system, amphiphiles are synthesized from two "clickable" fragments: a water soluble "head" and a hydrophobic "tail". Under biphasic conditions, the reaction is autocatalytic, as aggregates facilitate the transfer of hydrophobic molecules to the aqueous phase. When chiral, partially enantioenriched surfactant heads are used, a strong nonlinear induction of chirality in the reaction products is observed. Preseeding the reaction mixture with an amphiphile of one chirality results in the amplification of this product and therefore information transfer between generations of self-replicating aggregates. Because our amphiphiles are capable of catalysis, information transfer, and self-assembly into bounded structures, they present a plausible model for prenucleic acid "lipid world" entities. PMID- 25740117 TI - Depression of neuronal excitability and epileptic activities by group II metabotropic glutamate receptors in the medial entorhinal cortex. AB - Whereas the ionotropic glutamate receptors are the major mediator in glutamatergic transmission, the metabotropic glutamate receptors (mGluRs) usually play a modulatory role. Whereas the entorhinal cortex (EC) is an essential structure involved in the generation and propagation of epilepsy, the roles and mechanisms of mGluRs in epilepsy in the EC have not been determined. Here, we studied the effects of activation of group II metabotropic glutamate receptors (mGluRs II) on epileptiform activity induced by picrotoxin or deprivation of extracellular Mg2+ and neuronal excitability in the medial EC. We found that activation of mGluRs II by application of the selective agonist, LY354740, exerted robust inhibition on epileptiform activity. LY354740 hyperpolarized entorhinal neurons via activation of a K+ conductance and inhibition of a Na+ permeable channel. LY354740-induced hyperpolarization was G protein-dependent, but independent of adenylyl cyclase and protein kinase A. However, the function of Gbetagamma was involved in mGluRs II-mediated depression of both neuronal excitability and epileptiform activity. Our results provide a novel cellular mechanism to explain the antiepileptic effects of mGluRs II in the treatment of epilepsy. PMID- 25740119 TI - Safety considerations for IMRT: Executive summary. PMID- 25740118 TI - Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline. AB - PURPOSE: To provide guidance to physicians and patients with regard to the use of external beam radiotherapy, endobronchial brachytherapy, and concurrent chemotherapy in the setting of palliative thoracic treatment for lung cancer, based on available evidence complemented by expert opinion. METHODS AND MATERIALS: A Task Force authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors synthesized and assessed evidence from 3 systematic reviews on the following topics: (1) dose fractionation in thoracic external beam radiotherapy (EBRT); (2) clinical utility of initial and salvage endobronchial brachytherapy (EBB); and (3) use of concurrent chemotherapy (CC) with palliative thoracic radiotherapy. Practice guideline recommendations were produced and are contained herein. RESULTS: Studies suggest that higher dose/fractionation palliative EBRT regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status. No defined role for EBB in the routine initial palliative treatment of chest disease has been demonstrated; however, EBB can be a reasonable option for the palliation of endobronchial lesions causing obstructive symptomatology including lung collapse, or for hemoptysis after EBRT failure. The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature. CONCLUSION: This Guideline is intended to serve as a guide for the use of EBRT, EBB, and CC in thoracic palliation of lung cancer outside the clinical trial setting. Further prospective clinical investigations with relevant palliative endpoints into the respective roles of EBB and CC/targeted therapy in the thoracic palliation of lung cancer are warranted, given the current state of the medical literature in these areas. PMID- 25740120 TI - Quality and safety considerations in stereotactic radiosurgery and stereotactic body radiation therapy: Executive summary. PMID- 25740122 TI - Scientist-industry partnerships do not constitute a "tangled web". PMID- 25740125 TI - Memory with a spin. PMID- 25740123 TI - Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. AB - The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC. PMID- 25740126 TI - A new spin on magnetic memories. PMID- 25740124 TI - Thio-urethane oligomers improve the properties of light-cured resin cements. AB - Thio-urethanes were synthesized by combining 1,6-hexanediol-diissocyante (aliphatic) with pentaerythritol tetra-3-mercaptopropionate (PETMP) or 1,3-bis(1 isocyanato-1-methylethyl)benzene (aromatic) with trimethylol-tris-3 mercaptopropionate (TMP), at 1:2 isocyanate:thiol, leaving pendant thiols. Oligomers were added at 10-30 phr to BisGMA-UDMA-TEGDMA (5:3:2, BUT). 25 wt% silanated inorganic fillers were added. Commercial cement (Relyx Veneer, 3M-ESPE) was also evaluated with 10-20 phr of aromatic oligomer. Near-IR was used to follow methacrylate conversion (DC) and rate of polymerization (Rpmax). Mechanical properties were evaluated in three-point bending (ISO 4049) for flexural strength/modulus (FS/FM, and toughness), and notched specimens (ASTM Standard E399-90) for fracture toughness (KIC). Polymerization stress (PS) was measured on the Bioman. Volumetric shrinkage (VS, %) was measured with the bonded disk technique. Results were analyzed with ANOVA/Tukey's test (alpha=5%). In general terms, for BUT cements, conversion and mechanical properties in flexure increased for selected groups with the addition of thio-urethane oligomers. The aromatic versions resulted in greater FS/FM than aliphatic. Fracture toughness increased by two-fold in the experimental groups (from 1.17 +/- 0.36 MPam(1/2) to around 3.23 +/- 0.22 MPam(1/2)). Rpmax decreased with the addition of thio urethanes, though the vitrification point was not statistically different from the control. VS and PS decreased with both oligomers. For the commercial cement, 20 phr of oligomer increased DC, vitrification, reduced Rpmax and also significantly increased KIC, and reduced PS and FM. Thio-urethane oligomers were shown to favorably modify conventional dimethacrylate networks. Significant reductions in polymerization stress were achieved at the same time conversion and fracture toughness increased. PMID- 25740128 TI - Memory on the racetrack. PMID- 25740127 TI - Memory leads the way to better computing. PMID- 25740129 TI - The (nano) entrepreneur's dilemma. PMID- 25740131 TI - Upconversion nanocrystals: Bright colours ahead. PMID- 25740132 TI - Control of magnetism by electric fields. AB - The electrical manipulation of magnetism and magnetic properties has been achieved across a number of different material systems. For example, applying an electric field to a ferromagnetic material through an insulator alters its charge carrier population. In the case of thin films of ferromagnetic semiconductors, this change in carrier density in turn affects the magnetic exchange interaction and magnetic anisotropy; in ferromagnetic metals, it instead changes the Fermi level position at the interface that governs the magnetic anisotropy of the metal. In multiferroics, an applied electric field couples with the magnetization through electrical polarization. This Review summarizes the experimental progress made in the electrical manipulation of magnetization in such materials, discusses our current understanding of the mechanisms, and finally presents the future prospects of the field. PMID- 25740133 TI - Expect the unexpected. PMID- 25740134 TI - Novel permissive murine immunocompetent orthotopic colon carcinoma model for comparison of the antitumoral and safety profiles of three Adv-TKs. PMID- 25740135 TI - Via media. PMID- 25740136 TI - What history tells us XXXVI. Reverse transcriptase and Lamarckian scenarios of evolution. PMID- 25740137 TI - Lack of IL-6 increases blood-brain barrier permeability in fungal meningitis. AB - The pathogenesis of increased blood-brain barrier permeability during Cryptococcus meningitis is still largely unknown. Interleukin (IL-6) is a multifunctional cytokine, and numerous studies have shown that IL-6 influences the integrity of the blood-brain barrier. In this study we investigated the role of IL-6 in Cryptococcus meningitis. First, wild-type or IL-6(-/-) mice were injected with Cryptococcus neoformans (C. neoformans) and the survival time in both groups was recorded. Second, the number of fungi was measured in the brains of IL-6(-/-) wild-type mice. Finally, the blood-brain barrier permeability index was detected in infected IL-6(-/-) mice treated with recombinant human IL-6. The blood-brain barrier permeability index was measured in infected wild-type mice treated with anti-IL-6 antibodies as well. The survival of IL-6(-/-) mice injected with C. neoformans was significantly lower than that of identically challenged wild-type mice. The infected IL-6(-/-) mice had significantly larger brain fungal burdens than wild-type mice. Furthermore, increased blood-brain barrier index was found in infected IL-6(-/-) mice when compared with that in infected control mice. Similar results were obtained when mice challenged with C. neoformans were treated systemically with neutralizing anti-IL-6 antibodies, resulting in an elevation of vascular permeability. Our data revealed that IL-6 reduced the blood-brain barrier permeability during Cryptococcus meningitis, and it might provide an explanation for the significantly lower survival of infected IL-6(-/-) mice. PMID- 25740138 TI - Structural studies on Mycobacterium tuberculosis RecA: molecular plasticity and interspecies variability. AB - Structures of crystals of Mycobacterium tuberculosis RecA, grown and analysed under different conditions, provide insights into hitherto underappreciated details of molecular structure and plasticity. In particular, they yield information on the invariant and variable features of the geometry of the P-loop, whose binding to ATP is central for all the biochemical activities of RecA. The strengths of interaction of the ligands with the P-loop reveal significant differences. This in turn affects the magnitude of the motion of the 'switch' residue, Gln195 in M. tuberculosis RecA, which triggers the transmission of ATP mediated allosteric information to the DNA binding region. M. tuberculosis RecA is substantially rigid compared with its counterparts from M. smegmatis and E. coli, which exhibit concerted internal molecular mobility. The interspecies variability in the plasticity of the two mycobacterial proteins is particularly surprising as they have similar sequence and 3D structure. Details of the interactions of ligands with the protein, characterized in the structures reported here, could be useful for design of inhibitors against M. tuberculosis RecA. PMID- 25740139 TI - Biochemical characterization of blood plasma of coronary artery disease patients by in vitro high-resolution proton NMR spectroscopy. AB - This study aimed to investigate the biochemical profile of blood plasma of patients with coronary artery disease (CAD) and angiographically normal subjects (controls) to determine biomarkers for their differentiation. In this double blind study, 5 mL venous blood was drawn before angiography from CAD patients (n=60) and controls (n=13) comprising angiography normal individuals. In vitro high-resolution NMR spectroscopy of these blood plasma samples was carried out at 400 MHz, and intensity data were analysed with partial least square discriminant analysis. Categorization of subjects as controls or CAD patients and the patients further as single vessel disease (SVD), double vessel disease (DVD) and triple vessel disease (TVD) was done at the end of the study based on their angiography reports. Raised levels of lipids, alanine (Ala) and isoleucine/leucine/valine (Ile/Leu/Val) were observed in CAD patients compared with controls. Partial least square discriminant analysis showed separation between controls vs CAD patients. TVD patients showed increased levels of Ile/Leu/Val and Ala compared with controls and SVD. Alanine, Ile/Leu/Val, and LDL/VLDL appear as possible biomarkers for distinguishing between controls and patients with SVD and TVD. A metabolic adaptation of myocardium may play a role in raising the Ala level. PMID- 25740141 TI - Effects of Sunphenon and Polyphenon 60 on proteolytic pathways, inflammatory cytokines and myogenic markers in H2O2-treated C2C12 cells. AB - The effect of Sunphenon and Polyphenon 60 in oxidative stress response, myogenic regulatory factors, inflammatory cytokines, apoptotic and proteolytic pathways on H2O2-induced myotube atrophy was addressed. Cellular responses of H2O2-induced C2C12 cells were examined, including mRNA expression of myogenic regulatory factors, such as MyoD and myogenin, inflammatory pathways, such as TNF-alpha and NF-kB, as well as proteolytic enzymes, such as MU-calpain and m-calpain. The pre treatment of Sunphenon (50 MUg/mL)/Polyphenon 60 (50 MUg/mL) on H2O2-treated C2C12 cells significantly down-regulated the mRNA expression of myogenin and MyoD when compared to those treated with H2O2-induced alone. Additionally, the mRNA expression of MU-calpain and m-calpain were significantly(p<0.05) increased in H2O2-treated C2C12 cells, whereas pre-treatment with Sunphenon/Polyphenon significantly down-regulated the above genes, namely MU-calpain and m-calpain. Furthermore, the mRNA expression of TNF-alpha and NF-kB were significantly increased in H2O2-treated C2C12 cells, while pre-treatment with Sunphenon (50 MUg/mL)/Polyphenon 60 (50 MUg/mL) significantly (p<0.05) down-regulated it when compared to the untreated control group.Subsequent analysis of DNA degeneration and caspase activation revealed that Sunphenon (50 MUg/mL)/Polyphenon 60 (50 MUg/mL) inhibited activation of caspase-3 and showed an inhibitory effect on DNA degradation. From this result, we know that, in stress conditions, MU-calpain may be involved in the muscle atrophy through the suppression of myogenin and MyoD. Moreover, Sunphenon may regulate the skeletal muscle genes/promote skeletal muscle recovery by the up-regulation of myogenin and MyoD and suppression of MU calpain and inflammatory pathways and may regulate the apoptosis pathways. Our findings suggest that dietary supplementation of Sunphenon might reduce inflammatory events in muscle-associated diseases, such as myotube atrophy. PMID- 25740140 TI - BARF1 gene silencing triggers caspase-dependent mitochondrial apoptosis in Epstein-Barr virus-positive malignant cells. AB - Epstein-Barr virus (EBV)-encoded BARF1 (BamH1-A Rightward Frame-1) is expressed in EBV-positive malignancies such as nasopharyngeal carcinoma, EBV-associated gastric cancer, B-cell lymphoma and nasal NK/T-cell lymphoma, and has been shown to have an important role in oncogenesis. However, the mechanism by which BARF1 elicits its biological effects is unclear. We investigated the effects of BARF1 silencing on cell proliferation and apoptosis in EBV-positive malignant cells. We observed that BARF1 silencing significantly inhibits cell proliferation and induces apoptosis-mediated cell death by collapsing the mitochondrial membrane potential in AG876 and Hone-Akata cells. BARF1 knockdown up-regulates the expression of pro-apoptotic proteins and downregulates the expression of anti apoptotic proteins. In BARF1-down-regulated cells, the Bcl-2/BAX ratio is decreased. The caspase inhibitor z-VAD-fmk was found to rescue siBARF1-induced apoptosis in these cells. Immunoblot analysis showed significant increased levels of cleaved caspase 3 and caspase 9. We observed a significant increase in cytochrome c level as well as the formation of apoptosome complex in BARF1 silenced cells. In conclusion, siRNA-mediated BARF1 down-regulation induces caspase-dependent apoptosis via the mitochondrial pathway through modulation of Bcl-2/BAX ratio in AG876 and Hone-Akata cells. Targeting BARF1 using siRNA has the potential to be developed as a novel therapeutic strategy in the treatment of EBV-associated malignancies. PMID- 25740142 TI - Human platelet releasates combined with polyglycolic acid scaffold promote chondrocyte differentiation and phenotypic maintenance. AB - In the present study, we aimed to demonstrate the differentiating properties of platelet-rich plasma releasates (PRPr) on human chondrocytes seeded on a polygtlycolic acid (PGA) 3D scaffold. Gene expression and biochemical analysis were carried out to assess the improved quality of our PGA-based cartilage constructs supplemented with PRPr. We observed that the use of PRPr as cell cultures supplementation to PGA-chondrocyte constructs may promote chondrocyte differentiation, and thus may contribute to maintaining the chondrogenic phenotype longer than conventional supplementation by increasing high levels of important chondrogenic markers (e.g. sox9, aggrecan and type II collagen), without induction of type I collagen. Moreover, our constructs were analysed for the secretion and deposition of important ECM molecules (sGAG, type II collagen, etc.). Our results indicate that PRPr supplementation may synergize with PGA based scaffolds to stimulate human articular chondrocyte differentiation, maturation and phenotypic maintenance. PMID- 25740143 TI - Collagen I-induced dendritic cells activation is regulated by TNF-alpha production through down-regulation of IRF4. AB - Previously we have shown that collagen I enhances the maturation and function of dendritic cells (DCs). Inflammatory mediators such as tumour necrosis factor (TNF)- alpha, interleukin (IL)-1 beta and lipopolysaccharide (LPS) are also known to activate DCs. Here we investigated the involvement of TNF-alpha on the collagen I-induced DCs activation. TNF-a neutralization inhibited collagen I induced IL-12 secretions by DCs. Additionally, we observed suppression of collagen I-induced costimulatory molecules expression along with down-regulation of genes involved in DCs activation pathway. Furthermore, TNF- alpha inhibition upon collagen Istimulation up-regulated the expression of interferon regulatory transcription factor IRF4, when compared to collagen I only treated cells. Collectively, our data demonstrate that collagen I induce TNF- alpha production, which is crucial for the activation and function of DCs, through down-regulation of IRF4, and implicates the importance in development of anti- TNF-alpha therapeutics for several inflammatory diseases. PMID- 25740144 TI - Co-expression of the C-terminal domain of Yersinia enterocolitica invasin enhances the efficacy of classical swine-fever-vectored vaccine based on human adenovirus. AB - The use of adenovirus vector-based vaccines is a promising approach for generating antigen-specific immune responses. Improving vaccine potency is necessary in other approaches to address their inadequate protection for the majority of infectious diseases. This study is the first to reconstruct a recombinant replication-defective human adenovirus co-expressing E2 and invasin C terminal (InvC) glycoproteins (rAd-E2-InvC). rAd-E2-InvC with 2 x 10(6) TCID50 was intramuscularly administered two times to CSFV-free pigs at 14 day intervals. No adverse clinical reactions were observed in any of the pigs after the vaccination. The CSFV E2-specific antibody titer was significantly higher in the rAd-E2-InvC group than that in the rAdV-E2 group as measured by NPLA and blocking ELISA. Pigs immunized with rAd-E2-InvC were completely protected against lethal challenge. Neither CSFV RNA nor pathological changes were detected in the tissues after CSFV challenge. These results demonstrate that rAd-E2-InvC could be an alternative to the existing CSF vaccine. Moreover, InvC that acts as an adjuvant could enhance the immunogenicity of rAdV-E2 and induce high CSFV E2-specific antibody titer and protection level. PMID- 25740145 TI - Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes. AB - Whether nucleic acids that circulate in blood have any patho-physiological functions in the host have not been explored.We report here that far from being inert molecules, circulating nucleic acids have significant biological activities of their own that are deleterious to healthy cells of the body. Fragmented DNA and chromatin (DNAfs and Cfs) isolated from blood of cancer patients and healthy volunteers are readily taken up by a variety of cells in culture to be localized in their nuclei within a few minutes. The intra-nuclear DNAfs and Cfs associate themselves with host cell chromosomes to evoke a cellular DNA-damage-repair response (DDR) followed by their incorporation into the host cell genomes. Whole genome sequencing detected the presence of tens of thousands of human sequence reads in the recipient mouse cells. Genomic incorporation of DNAfs and Cfs leads to dsDNA breaks and activation of apoptotic pathways in the treated cells. When injected intravenously into Balb/C mice, DNAfs and Cfs undergo genomic integration into cells of their vital organs resulting in activation of DDR and apoptotic proteins in the recipient cells. Cfs have significantly greater activity than DNAfs with respect to all parameters examined, while both DNAfs and Cfs isolated from cancer patients are more active than those from normal volunteers. All the above pathological actions of DNAfs and Cfs described above can be abrogated by concurrent treatment with DNase I and/or anti-histone antibody complexed nanoparticles both in vitro and in vivo. Taken together, our results suggest that circulating DNAfs and Cfs are physiological, continuously arising, endogenous DNA damaging agents with implications to ageing and a multitude of human pathologies including initiation of cancer. PMID- 25740146 TI - Whole genome analysis of a Vietnamese trio. AB - We here present the first whole genome analysis of an anonymous Kinh Vietnamese (KHV) trio whose genomes were deeply sequenced to 30-fold average coverage. The resulting short reads covered 99.91 percent of the human reference genome (GRCh37d5). We identified 4,719,412 SNPs and 827,385 short indels that satisfied the Mendelian inheritance law. Among them, 109,914 (2.3 percent) SNPs and 59,119 (7.1 percent) short indels were novel. We also detected 30,171 structural variants of which 27,604 (91.5 percent) were large indels. There were 6,681 large indels in the range 0.1-100 kbp occurring in the child genome that were also confirmed in either the father or mother genome. We compared these large indels against the DGV database and found that 1,499 (22.44 percent) were KHV specific. De novo assembly of high-quality unmapped reads yielded 789 contigs with the length greater than or equal to 300 bp. There were 235 contigs from the child genome of which 199 (84.7 percent) were significantly matched with at least one contig from the father or mother genome. Blasting these 199 contigs against other alternative human genomes revealed 4 novel contigs. The novel variants identified from our study demonstrated the necessity of conducting more genome-wide studies not only for Kinh but also for other ethnic groups in Vietnam. PMID- 25740147 TI - BDP-30, a systemic resistance inducer from Boerhaavia diffusa L., suppresses TMV infection, and displays homology with ribosome-inactivating proteins. AB - Root extract of Boerhaavia diffusa L. induced systemic resistance in tobacco against Tobacco mosaic virus. A 30 kDa protein was isolated as the active component, called BDP-30 on the basis of the molecular weight and source plant. BDP-30, a glycoprotein, was found to be temperature and protease resistant. It was basic, possessing a pI greater than 9.0. In-gel proteolytic digestion of BDP 30 generated two peptides that possessed the amino acid sequence KLYDIPPLR and KVTLPYSGNYER by LC/MS/MS. Both peptides shared absolute sequence identity with trichosanthin, a ribosome-inactivating protein from Trichosanthes kirilowii, and a 78 percent and 100 percent homology respectively with an RIP from Bryonia dioica, bryodin. Further, effort was made to look at the fate of TMV in induced resistant Nicotiana tabacum cv. Xanthi, a systemic host of the virus, at specified days after inoculation in control and treated plants. TMV coat protein (CP) was detected by immunoblot 7 days post inoculation up to 21 days in the control set, but not in treated resistant plants. TMV RNA was detected by RT-PCR using TMV-CP specific primers. Resistant tobacco did not show presence of TMV RNA up to 21 days of inoculation. This suggests that BDP-30 may be suppressing TMV replication. PMID- 25740148 TI - Identification of plant defence regulators through transcriptional profiling of Arabidopsis thaliana cdd1 mutant. AB - A sustainable balance between defence and growth is essential for optimal fitness under pathogen stress. Plants activate immune response at the cost of normal metabolic requirements. Thus, plants that constitutively activate defence are deprived of growth. Arabidopsis thaliana mutant constitutive defence without defect in growth and development1 (cdd1) is an exception. The cdd1 mutant is constitutive for salicylic acid accumulation, signalling, and defence against biotrophic and hemibiotrophic pathogens, without having much impact on growth. Thus, cdd1 offers an ideal genetic background to identify novel regulators of plant defence. Here we report the differential gene expression profile between cdd1 and wild-type plants as obtained by microarray hybridization. Expression of several defence-related genes also supports constitutive activation of defence in cdd1. We screened T-DNA insertion mutant lines of selected genes, for resistance against virulent bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). Through bacterial resistance, callose deposition and pathogenesis associated expression analyses, we identified four novel regulators of plant defence. Resistance levels in the mutants suggest that At2g19810 and [rom] At5g05790 are positive regulators, whereas At1g61370 and At3g42790 are negative regulators of plant defence against bacterial pathogens. PMID- 25740149 TI - Frost hardiness of tree species is independent of phenology and macroclimatic niche. AB - The differences in timing in bud burst between species have been interpreted as an adaptation to late frost events in spring. Thus, it has been suggested that the degree of frost susceptibility of leaves is species-specific and depends on the species' phenology and geographic distribution range. To test for relationships between frost tolerance and phenology as well as between frost tolerance and distribution range across Central European tree species, we studied the frost hardiness of closed buds before bud burst and of freshly opened buds at the time of bud burst. We hypothesized that species with early bud burst and species distributed in eastern and northern areas were more frost tolerant than species with late bud burst and species distributed in western and southern areas. Frost hardiness was estimated by exposing twigs to 11 frost temperatures between -4 degrees C and -80 degrees C and by assessing tissue damage by the electrolyte leakage method. In contrast to our hypotheses, neither frost hardiness of closed buds nor frost hardiness of freshly opened buds were related to any variable describing species' macroclimatic niche. Furthermore, frost hardiness of freshly opened buds did not differ among species. Thus, the investigated species with early bud burst take higher risks of frost damage than the species with late bud bursts. These findings indicate that frost hardiness might not play the key role in limiting the geographic distribution ranges previously anticipated. PMID- 25740152 TI - Analysis of gene expression dynamics revealed delayed and abnormal epidermal repair process in aged compared to young skin. AB - With aging, epidermal homeostasis and barrier function are disrupted. In a previous study, we analyzed the transcriptomic response of young skin epidermis after stratum corneum removal, and obtained a global kinetic view of the molecular processes involved in barrier function recovery. In the present study, the same analysis was performed in aged skin in order to better understand the defects which occur with aging. Thirty healthy male volunteers (67 +/- 4 years old) were involved. Tape-strippings were carried out on the inner face of one forearm, the other unstripped forearm serving as control. At 2, 6, 18, 30 and 72 h after stripping, TEWL measurements were taken, and epidermis samples were collected. Total RNA was extracted and analyzed using DermArray((r)) cDNA microarrays. The results highlighted that barrier function recovery and overall kinetics of gene expression were delayed following stripping in aged skin. Indeed, the TEWL measurements showed that barrier recovery in the young group appeared to be dramatically significant during the overall kinetics, while there were no significant evolution in the aged group until 30 h. Moreover, gene expression analysis revealed that the number of modulated genes following tape stripping increased as a function of time and reached a peak at 6 h after tape stripping in young skin, while it was at 30 h in aged skin, showing that cellular activity linked to the repair process may be engaged earlier in young epidermis than in aged epidermis. A total of 370 genes were modulated in the young group. In the aged group, 382 genes were modulated, whose 184 were also modulated in the young group. Only eight genes that were modulated in both groups were significantly differently modulated. The characterization of these genes into 15 functional families helped to draw a scenario for the aging process affecting epidermal repair capacity. PMID- 25740153 TI - Spatio-temporal behaviour of atomic-scale tribo-ceramic films in adaptive surface engineered nano-materials. AB - Atomic-scale, tribo-ceramic films associated with dissipative structures formation are discovered under extreme frictional conditions which trigger self organization. For the first time, we present an actual image of meta-stable protective tribo-ceramics within thicknesses of a few atomic layers. A mullite and sapphire structure predominates in these phases. They act as thermal barriers with an amazing energy soaking/dissipating capacity. Less protective tribo-films cannot sustain in these severe conditions and rapidly wear out. Therefore, a functional hierarchy is established. The created tribo-films act in synergy, striving to better adapt themselves to external stimuli. Under a highly complex structure and non-equilibrium state, the upcoming generation of adaptive surface engineered nano-multilayer materials behaves like intelligent systems - capable of generating, with unprecedented efficiency, the necessary tribo-films to endure an increasingly severe environment. PMID- 25740154 TI - Can't live with or without it: calcium and its role in Duchenne muscular dystrophy-induced muscle weakness. Focus on "SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models". PMID- 25740151 TI - De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. AB - Hepatic de novo lipogenesis (DNL) is the biochemical process of synthesising fatty acids from acetyl-CoA subunits that are produced from a number of different pathways within the cell, most commonly carbohydrate catabolism. In addition to glucose which most commonly supplies carbon units for DNL, fructose is also a profoundly lipogenic substrate that can drive DNL, important when considering the increasing use of fructose in corn syrup as a sweetener. In the context of disease, DNL is thought to contribute to the pathogenesis of non-alcoholic fatty liver disease, a common condition often associated with the metabolic syndrome and consequent insulin resistance. Whether DNL plays a significant role in the pathogenesis of insulin resistance is yet to be fully elucidated, but it may be that the prevalent products of this synthetic process induce some aspect of hepatic insulin resistance. PMID- 25740150 TI - Stochastic developmental variation, an epigenetic source of phenotypic diversity with far-reaching biological consequences. AB - This article reviews the production of different phenotypes from the same genotype in the same environment by stochastic cellular events, nonlinear mechanisms during patterning and morphogenesis, and probabilistic self reinforcing circuitries in the adult life. These aspects of phenotypic variation are summarized under the term 'stochastic developmental variation' (SDV) in the following. In the past, SDV has been viewed primarily as a nuisance, impairing laboratory experiments, pharmaceutical testing, and true-to-type breeding. This article also emphasizes the positive biological effects of SDV and discusses implications for genotype-to-phenotype mapping, biological individuation, ecology, evolution, and applied biology. There is strong evidence from experiments with genetically identical organisms performed in narrowly standardized laboratory set-ups that SDV is a source of phenotypic variation in its own right aside from genetic variation and environmental variation. It is obviously mediated by molecular and higher-order epigenetic mechanisms. Comparison of SDV in animals, plants, fungi, protists, bacteria, archaeans, and viruses suggests that it is a ubiquitous and phylogenetically old phenomenon. In animals, it is usually smallest for morphometric traits and highest for life history traits and behaviour. SDV is thought to contribute to phenotypic diversity in all populations but is particularly relevant for asexually reproducing and genetically impoverished populations, where it generates individuality despite genetic uniformity. In each generation, SDV produces a range of phenotypes around a well-adapted target phenotype, which is interpreted as a bet-hedging strategy to cope with the unpredictability of dynamic environments. At least some manifestations of SDV are heritable, adaptable, selectable, and evolvable, and therefore, SDV may be seen as a hitherto overlooked evolution factor. SDV is also relevant for husbandry, agriculture, and medicine because most pathogens are asexuals that exploit this third source of phenotypic variation to modify infectivity and resistance to antibiotics. Since SDV affects all types of organisms and almost all aspects of life, it urgently requires more intense research and a better integration into biological thinking. PMID- 25740155 TI - Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells. AB - The renin angiotensin system (RAS) plays a vital role in the regulation of the cardiovascular and renal functions. COS7 is a robust and easily transfectable cell line derived from the kidney of the African green monkey, Cercopithecus aethiops. The aims of this study were to 1) demonstrate the presence of an endogenous and functional RAS in COS7, and 2) investigate the role of a disintegrin and metalloproteinase-17 (ADAM17) in the ectodomain shedding of angiotensin converting enzyme-2 (ACE2). Reverse transcription coupled to gene specific polymerase chain reaction demonstrated expression of ACE, ACE2, angiotensin II type 1 receptor (AT1R), and renin at the transcript levels in total RNA cell extracts. Western blot and immunohistochemistry identified ACE (60 kDa), ACE2 (75 kDa), AT1R (43 kDa), renin (41 kDa), and ADAM17 (130 kDa) in COS7. At the functional level, a sensitive and selective mass spectrometric approach detected endogenous renin, ACE, and ACE2 activities. ANG-(1-7) formation (m/z 899) from the natural substrate ANG II (m/z 1,046) was detected in lysates and media. COS7 cells stably expressing shRNA constructs directed against endogenous ADAM17 showed reduced ACE2 shedding into the media. This is the first study demonstrating endogenous expression of the RAS and ADAM17 in the widely used COS7 cell line and its utility to study ectodomain shedding of ACE2 mediated by ADAM17 in vitro. The transfectable nature of this cell line makes it an attractive cell model for studying the molecular, functional, and pharmacological properties of the renal RAS. PMID- 25740158 TI - Molecular recognition of pyrimidine nucleobases by triplex DNA receptors. AB - Triplex DNA receptors are known for their strong and specific binding of a variety of purine ligands. However, not many studies have been reported on their binding of pyrimidine ligands. Here we used fluorophore-labeled DNA receptors to study these binding interactions. The results suggest that in general, cytosine binds more strongly than thymine and uracil, although the selectivity between two pyrimidine ligands can be tuned by changing the surrounding nucleobases of the DNA receptor. In contrast, binding of pyrimidine nucleosides is much weaker, possibly due to lack of the N1 hydrogen bonding donor. PMID- 25740157 TI - Lens ion homeostasis relies on the assembly and/or stability of large connexin 46 gap junction plaques on the broad sides of differentiating fiber cells. AB - The eye lens consists of layers of tightly packed fiber cells, forming a transparent and avascular organ that is important for focusing light onto the retina. A microcirculation system, facilitated by a network of gap junction channels composed of connexins 46 and 50 (Cx46 and Cx50), is hypothesized to maintain and nourish lens fiber cells. We measured lens impedance in mice lacking tropomodulin 1 (Tmod1, an actin pointed-end capping protein), CP49 (a lens specific intermediate filament protein), or both Tmod1 and CP49. We were surprised to find that simultaneous loss of Tmod1 and CP49, which disrupts cytoskeletal networks in lens fiber cells, results in increased gap junction coupling resistance, hydrostatic pressure, and sodium concentration. Protein levels of Cx46 and Cx50 in Tmod1(-/-);CP49(-/-) double-knockout (DKO) lenses were unchanged, and electron microscopy revealed normal gap junctions. However, immunostaining and quantitative analysis of three-dimensional confocal images showed that Cx46 gap junction plaques are smaller and more dispersed in DKO differentiating fiber cells. The localization and sizes of Cx50 gap junction plaques in DKO fibers were unaffected, suggesting that Cx46 and Cx50 form homomeric channels. We also demonstrate that gap junction plaques rest in lacunae of the membrane-associated actin-spectrin network, suggesting that disruption of the actin-spectrin network in DKO fibers may interfere with gap junction plaque accretion into micrometer-sized domains or alter the stability of large plaques. This is the first work to reveal that normal gap junction plaque localization and size are associated with normal lens coupling conductance. PMID- 25740156 TI - Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels. AB - Abnormally elevated bone morphogenetic protein 4 (BMP4) expression and mediated signaling play a critical role in the pathogenesis of chronic hypoxia-induced pulmonary hypertension (CHPH). In this study, we investigated the expression level and functional significance of four reported naturally occurring BMP4 antagonists, noggin, follistatin, gremlin1, and matrix gla protein (MGP), in the lung and distal pulmonary arterial smooth muscle cell (PASMC). A 21-day chronic hypoxic (10% O2) exposure rat model was utilized, which has been previously shown to successfully establish experimental CHPH. Among the four antagonists, noggin, but not the other three, was selectively downregulated by hypoxic exposure in both the lung tissue and PASMC, in correlation with markedly elevated BMP4 expression, suggesting that the loss of noggin might account for the hypoxia triggered BMP4 signaling transduction. Then, by using treatment of extrogenous recombinant noggin protein, we further found that noggin significantly normalized 1) BMP4-induced phosphorylation of cellular p38 and ERK1/2; 2) BMP4-induced phosphorylation of cellular JAK2 and STAT3; 3) hypoxia-induced PASMC proliferation; 4) hypoxia-induced store-operated calcium entry (SOCE), and 5) hypoxia-increased expression of transient receptor potential cation channels (TRPC1 and TRPC6) in PASMC. In combination, these data strongly indicated that the hypoxia-suppressed noggin accounts, at least partially, for hypoxia-induced excessive PASMC proliferation, while restoration of noggin may be an effective way to inhibit cell proliferation by suppressing SOCE and TRPC expression. PMID- 25740159 TI - Thermodynamic equilibrium solubility measurements in simulated fluids by 96-well plate method in early drug discovery. AB - An early prediction of solubility in physiological media (PBS, SGF and SIF) is useful to predict qualitatively bioavailability and absorption of lead candidates. Despite of the availability of multiple solubility estimation methods, none of the reported method involves simplified fixed protocol for diverse set of compounds. Therefore, a simple and medium-throughput solubility estimation protocol is highly desirable during lead optimization stage. The present work introduces a rapid method for assessment of thermodynamic equilibrium solubility of compounds in aqueous media using 96-well microplate. The developed protocol is straightforward to set up and takes advantage of the sensitivity of UV spectroscopy. The compound, in stock solution in methanol, is introduced in microgram quantities into microplate wells followed by drying at an ambient temperature. Microplates were shaken upon addition of test media and the supernatant was analyzed by UV method. A plot of absorbance versus concentration of a sample provides saturation point, which is thermodynamic equilibrium solubility of a sample. The established protocol was validated using a large panel of commercially available drugs and with conventional miniaturized shake flask method (r(2)>0.84). Additionally, the statistically significant QSPR models were established using experimental solubility values of 52 compounds. PMID- 25740160 TI - Oxidative calcium release from catechol. AB - Oxidation of 4-methylcatechol previously exposed to aqueous calcium chloride was shown by ion chromatography to be associated with release of calcium ions. The catechol was oxidised to the corresponding orthoquinone by the use of tyrosinase from Agaricus bisporus. The oxidative release of calcium from the catechol is ascribed to the diminution of the available hydroxyl functions able to act as chelating groups. Our results suggest that the redox status of melanin may regulate calcium binding and influence calcium levels in pigmented cells. PMID- 25740161 TI - Effects of porous-hydroxyapatite incorporated into glass-ionomer sealants. AB - The purpose of the present study was to evaluate the mechanical and chemical properties of a novel glass ionomer cement for use as a pit and fissure sealant containing a porous hydroxyapatite, namely, apatite ionomer cement (AIC). Control sealant samples were used Fuji III (GIC-S). The experiment sealant samples (AIC S) consisted of porous spherical hydroxyapatite (HApS) particles added at 28 wt% to GIC-S powder. The GIC-S and AIC-S samples were evaluated through mechanical strength measurements, scanning electron microscopy observations, energy dispersive X-ray spectroscopy analysis, fluoride ion release tests, and antibacterial tests. The flexural strength of the AIC-S was significantly higher than that of GIC-S for each period, 1 h, 24 h and 1 year. The fluoride release dose for AIC-S was consistently higher than that for GIC-S. In addition, the antibacterial properties of AIC-S were superior to those of GIC-S. The novel AIC S may be a more suitable sealant material for pits and fissures with intact and/or infected enamel. PMID- 25740162 TI - Fracture resistance of endodontically treated teeth restored with ceramic inlays and different base materials. AB - This study evaluated the fracture resistance of endodontically treated teeth restored with different base materials and mesioocclusal-distal (MOD) ceramic inlays. Fifty mandibular molars were assigned into five groups (n=10 per group). Group1 (control) comprised intact molar teeth without any treatment. Teeth in other groups were subjected to root canal treatment and restored with MOD ceramic inlays on different base materials. In Group 2, base material was zinc phosphate cement; Group 3's was glass ionomer cement; Group 4's was composite resin, and Group 5's was composite resin reinforced with fiber. Finally, a continuous occlusal load was applied until fracture occurred. Mean fracture resistance of Group 1 (3,027 N) was significantly higher than the other groups (890, 1,070, 1,670, 1,226 N respectively). Fracture resistance of Group 4 was statistically comparable with Group 5 and significantly higher than Groups 2 and 3 (p<0.05; Tukey's HSD). Use of different base materials under ceramic inlay restorations could affect the fracture resistance of endodontically treated teeth. PMID- 25740163 TI - Effect of flowability on the flow rate, polymerization shrinkage, and mass change of flowable composites. AB - As a lining or restoration material, flowable composites are popular due to their ease in use and agreeable marginal adaptation of tooth cavity. The purpose of the present study was to evaluate various properties of flowable composites which were claimed to be of high or low flowability by the manufacturers. For the study, twelve flowable composites from six different manufacturers were used. Based on the manufacturers' claim, they were divided into two groups: high or low flowability. The products grouped in high flowability showed significantly higher (p<0.05) flow rate (flow distance), polymerization shrinkage, and microhardness (on the top surface), regardless of light-curing unit, than those grouped in low flowability. On the other hand, water sorption and solubility showed nonsignificantly different values regardless of flowability. Through the study, flow rate had low correlation with microhardness (R<0.23), polymerization shrinkage (R<0.60), and water sorption and solubility (R<0.36) regardless of light-curing unit. PMID- 25740164 TI - Evaluation of glass transition temperature and dynamic mechanical properties of autopolymerized hard direct denture reline resins. AB - This study assessed methods for evaluation of glass transition temperature (Tg) of autopolymerized hard direct denture reline resins using dynamic mechanical analysis and differential scanning calorimetry in addition to the dynamic mechanical properties. The Tg values of 3 different reline resins were determined using a dynamic viscoelastometer and differential scanning calorimeter, and rheological parameters were also determined. Although all materials exhibited higher storage modulus and loss modulus values, and a lower loss tangent at 37C with a higher frequency, the frequency dependence was not large. Tg values obtained by dynamic mechanical analysis were higher than those by differential scanning calorimetry and higher frequency led to higher Tg, while more stable Tg values were also obtained by that method. These results suggest that dynamic mechanical analysis is more advantageous for characterization of autopolymerized hard direct denture reline resins than differential scanning calorimetry. PMID- 25740165 TI - High-cycle fatigue behavior of beta-titanium orthodontic wires. AB - This study investigated high-cycle fatigue behavior in three beta-Ti wires (TMA, Resolve, Gummetal). Fatigue was evaluated using a static three-point bending test and a high-cycle fatigue test with a three-point bending mode. The surfaces of fractured wires were observed with scanning electron microscopy, and the post fatigue crystal structures were determined by micro-X-ray diffraction. The Gummetal wire exhibited the lowest elastic modulus, bending strength and fatigue limit, and exhibited the highest resilience of the three types of wire studied. However, no difference in the number of cycles to failure was observed among the three types of wire. The fatigue crack propagation and rapid propagation regions of all wires contained single-phase beta-Ti. The elastic modulus and bending strength influenced the fatigue limit, although these properties did not affect the number of cycles to fracture. The three types of beta-Ti wires exhibited similar risks of wire fracture. PMID- 25740166 TI - Effect of remaining dentin thickness on microtensile bond strength of current adhesive systems. AB - The purpose of this study was to evaluate the effect of remaining dentin thickness (RDT) on the bond strength of current adhesive systems. Third molars were randomly allocated among four groups depending on the adhesive system used: Clearfil SE Bond ONE (SE1), G-Bond PLUS (GB), BeautiBond (BB), and Clearfil Mega Bond (MB). Bonded specimens were stored in water at 37 degrees C for 24 h. Teeth were then sectioned perpendicular to the adhesive interface to produce beams. After measuring RDT of each beam, microtensile bond strength test was carried out using a universal testing machine at a crosshead speed of 1 mm/min. All data were analyzed by linear regression analysis. Bond strengths of one-step self-etch materials used in this study increased with an increase in RDT. In contrast, that of two-step self-etch adhesive system was not affected by RDT. PMID- 25740167 TI - The role of MDP in a bonding resin of a two-step self-etching adhesive system. AB - The purpose of this study was to evaluate the role of 10-methacryloyloxydecyl dihydrogen phosphate (MDP) contained in the bonding resin of a two-step self-etch adhesive system. An experimental adhesive (M0) containing MDP only in the primer, but not in the bonding resin was prepared. Clearfil SE Bond (MM) and M0 were compared in terms of microtensile bond strength to dentin, ultimate tensile strength of the bonding resin, and dentin-resin bonding interface morphology under SEM and TEM. The immediate uTBS values of MM significantly decreased after thermal cycles while M0 were stable even after 10,000 cycles. In the SEM observations, formation of erosion was observed beneath the acid-base resistant zone only in M0. The results suggested that MDP in the bonding resin of the two step self-etching system; 1) improved the immediate bond strength, but caused reduction in long-term bond durability; 2) offered the advantages of acid-base resistance at the ABRZ forefront area. PMID- 25740168 TI - Effect of a self-etching primer and phosphoric acid etching on the bond strength of 4-META/MMA-TBB resin to human enamel. AB - The purpose of this study was to evaluate the shear bond strength and durability of 4-META/MMA-TBB resin to human enamel. A self-etching primer that contained 4 META (Teeth Primer, TP) and 35-45% or 60-65% concentrations of phosphoric acid (K Etchant Gel, KE, and Super Bond C&B Red Activator, RA) were used as the surface treatment agents. A methyl methacrylate (MMA)-based self-polymerizing resin (Super-Bond C&B) was used as a luting agent. The shear bond strength was determined both pre and post thermocycling. The results were statistically analyzed with a non-parametric procedure. The post-thermocycling shear bond strength of the TP group was significantly higher than that of other groups, and that of the KE group was significantly higher compared with the RA group. These results demonstrated that 4-META was effective. Furthermore, when the degree of tooth demineralization was compared, surface treatment with less demineralization using TP was the most effective treatment. PMID- 25740169 TI - Effect of low-concentration bleaching products on enamel bond strength at different elapsed times after bleaching treatment. AB - This study evaluated the effects of several low-concentration bleaching products on microtensile bond strength (uTBS) to enamel at different elapsed times after the bleaching treatment. One hundred and fifty bovine incisors were divided into five groups: No treatment, 10% carbamide peroxide (Opalescence), 10% hydrogen peroxide (Opalescence Treswhite Supreme), 3% carbamide peroxide plus lactoperoxidase (WhiteKin), or 3% carbamide peroxide plus 2.7% carbamide peroxide (Clysiden Kit Express). All treatments lasted 4 weeks. After bleaching treatment or non-treatment, teeth were restored immediately, at 1, 3, 7, or 14 days after bleaching and submitted to uTBS test. Data were analyzed by ANOVA and Tukey's test (p<0.05). For WhiteKin and Clysiden, uTBS to enamel was significantly reduced immediately, at 1, 3 and 7 days after bleaching. At 14 days after bleaching, similar uTBS values were obtained regardless of bleaching product. Therefore, while over-the-counter (OTC) products might affect bond strength to enamel, this effect was no longer observed after 14 days. PMID- 25740170 TI - QuickFF: A program for a quick and easy derivation of force fields for metal organic frameworks from ab initio input. AB - QuickFF is a software package to derive accurate force fields for isolated and complex molecular systems in a quick and easy manner. Apart from its general applicability, the program has been designed to generate force fields for metal organic frameworks in an automated fashion. The force field parameters for the covalent interaction are derived from ab initio data. The mathematical expression of the covalent energy is kept simple to ensure robustness and to avoid fitting deficiencies as much as possible. The user needs to produce an equilibrium structure and a Hessian matrix for one or more building units. Afterward, a force field is generated for the system using a three-step method implemented in QuickFF. The first two steps of the methodology are designed to minimize correlations among the force field parameters. In the last step, the parameters are refined by imposing the force field parameters to reproduce the ab initio Hessian matrix in Cartesian coordinate space as accurate as possible. The method is applied on a set of 1000 organic molecules to show the easiness of the software protocol. To illustrate its application to metal-organic frameworks (MOFs), QuickFF is used to determine force fields for MIL-53(Al) and MOF-5. For both materials, accurate force fields were already generated in literature but they requested a lot of manual interventions. QuickFF is a tool that can easily be used by anyone with a basic knowledge of performing ab initio calculations. As a result, accurate force fields are generated with minimal effort. (c) 2015 Wiley Periodicals, Inc. PMID- 25740171 TI - Development and validation of an improved method for the determination of chloropropanols in paperboard food packaging by GC-MS. AB - The objective of this study was to develop an improved analytical method for the determination of 3-chloro-1,2-propanediol (3-MCPD) and 1,3-dichloropropanol (1,3 DCP) in paper-type food packaging. The established method includes aqueous extraction, matrix spiking of a deuterated surrogate internal standard (3-MCPD d5), clean-up using Extrelut solid-phase extraction, derivatisation using a silylation reagent, and GC-MS analysis of the chloropropanols as their corresponding trimethyl silyl ethers. The new method is applicable to food-grade packaging samples using European Commission standard aqueous extraction and aqueous food stimulant migration tests. In this improved method, the derivatisation procedure was optimised; the cost and time of the analysis were reduced by using 10 times less sample, solvents and reagents than in previously described methods. Overall the validation data demonstrate that the method is precise and reliable. The limit of detection (LOD) of the aqueous extract was 0.010 mg kg(-1) (w/w) for both 3-MCPD and 1,3-DCP. Analytical precision had a relative standard deviation (RSD) of 3.36% for 3-MCPD and an RSD of 7.65% for 1,3 DCP. The new method was satisfactorily applied to the analysis of over 100 commercial paperboard packaging samples. The data are being used to guide the product development of a next generation of wet-strength resins with reduced chloropropanol content, and also for risk assessments to calculate the virtual safe dose (VSD). PMID- 25740172 TI - Modular microfluidics for point-of-care protein purifications. AB - Biochemical separations are the heart of diagnostic assays and purification methods for biologics. On-chip miniaturization and modularization of separation procedures will enable the development of customized, portable devices for personalized health-care diagnostics and point-of-use production of treatments. In this report, we describe the design and fabrication of miniature ion exchange, size exclusion and affinity chromatography modules for on-chip clean-up of recombinantly-produced proteins. Our results demonstrate that these common separations techniques can be implemented in microfluidic modules with performance comparable to conventional approaches. We introduce embedded 3-D microfluidic interconnects for integrating micro-scale separation modules that can be arranged and reconfigured to suit a variety of fluidic operations or biochemical processes. We demonstrate the utility of the modular approach with a platform for the enrichment of enhanced green fluorescent protein (eGFP) from Escherichia coli lysate through integrated affinity and size-exclusion chromatography modules. PMID- 25740173 TI - Effects of the application of digestates from wet and dry anaerobic fermentation to Japanese paddy and upland soils on short-term nitrification. AB - Wet and dry anaerobic fermentation processes are operated for biogas production from organic matter, resulting in wet and dry digestates as by-products, respectively. The application of these digestates to soil as fertilizer has increased in recent years. Therefore, we herein compared the effects of applying wet digestates (pH 8.2, C/N ratio 4.5), dry digestates (pH 8.8, C/N ratio 23.4), and a chemical fertilizer to Japanese paddy and upland soils on short-term nitrification under laboratory aerobic conditions. Chloroform-labile C, an indicator of microbial biomass, was only minimally affected by these applications, indicating that a small amount of labile N was immobilized by microbes. All applications led to rapid increases in NO3 -N contents in both soils, and ammonia-oxidizing bacteria, but not archaea may play a critical role in net nitrification in the amended soils. The net nitrification rates for both soils were the highest after the application of dry digestates, followed by wet digestates and then the chemical fertilizer in order of decreasing soil pH. These results suggest that the immediate effects of applying digestates, especially dry digestates with the highest pH, on nitrate leaching need to be considered when digestates are used as alternative fertilizers. PMID- 25740175 TI - Analysis of sclerotia-associated fungal communities in cool-temperate forest soils in north Japan. AB - We herein investigated sclerotia that were obtained from cool-temperate forests in Mt. Chokai and Mt. Iwaki in north Japan and tentatively identified as the resting bodies of Cenococcum geophilum. The profiles of sclerotia-associated fungal communities were obtained through T-RFLP combined with clone library techniques. Our results showed that sclerotia in Mt. Chokai and Mt. Iwaki were predominated by Arthrinium arundinis and Inonotus sp., respectively. The results of the present study suggested that these sclerotia-associated species were responsible for the formation of sclerotia or sclerotia were originally formed by C. geophilum, but were subsequently occupied by these species after C. geophilum germinated or failed to survive due to competition. PMID- 25740174 TI - Characterization of leaf blade- and leaf sheath-associated bacterial communities and assessment of their responses to environmental changes in CO2, temperature, and nitrogen levels under field conditions. AB - Rice shoot-associated bacterial communities at the panicle initiation stage were characterized and their responses to elevated surface water-soil temperature (ET), low nitrogen (LN), and free-air CO2 enrichment (FACE) were assessed by clone library analyses of the 16S rRNA gene. Principal coordinate analyses combining all sequence data for leaf blade- and leaf sheath-associated bacteria revealed that each bacterial community had a distinct structure, as supported by PC1 (61.5%), that was mainly attributed to the high abundance of Planctomycetes in leaf sheaths. Our results also indicated that the community structures of leaf blade-associated bacteria were more sensitive than those of leaf sheath associated bacteria to the environmental factors examined. Among these environmental factors, LN strongly affected the community structures of leaf blade-associated bacteria by increasing the relative abundance of Bacilli. The most significant effect of FACE was also observed on leaf blade-associated bacteria under the LN condition, which was explained by decreases and increases in Agrobacterium and Pantoea, respectively. The community structures of leaf blade-associated bacteria under the combination of FACE and ET were more similar to those of the control than to those under ET or FACE. Thus, the combined effects of environmental factors need to be considered in order to realistically assess the effects of environmental changes on microbial community structures. PMID- 25740176 TI - Evidences of adaptive traits to rocky substrates undermine paradigm of habitat preference of the Mediterranean seagrass Posidonia oceanica. AB - Posidonia oceanica meadows are acknowledged as one of the most valuable ecosystems of the Mediterranean Sea. P. oceanica has been historically described as a species typically growing on mobile substrates whose development requires precursor communities. Here we document for the first time the extensive presence of sticky hairs covering P. oceanica seedling roots. Adhesive root hairs allow the seedlings to firmly anchor to rocky substrates with anchorage strength values up to 5.23 N, regardless of the presence of algal cover and to colonise bare rock without the need for precursor assemblages to facilitate settlement. Adhesive root hairs are a morphological trait common on plants living on rocks in high energy habitats, such as the riverweed Podostemaceae and the seagrass Phyllospadix scouleri. The presence of adhesive root hairs in P. oceanica juveniles suggests a preference of this species for hard substrates. Such an adaptation leads to hypothesize a new microsite driven bottleneck in P. oceanica seedling survival linked to substrate features. The mechanism described can favour plant establishment on rocky substrates, in contrast with traditional paradigms. This feature may have strongly influenced P. oceanica pattern of colonisation through sexual propagules in both the past and present. PMID- 25740177 TI - 2-Nitro-thioglycosides: alpha- and beta-selective generation and their potential as beta-selective glycosyl donors. AB - Michael-type addition of thiolates to 2-nitro-D-glucal or to 2-nitro-D-galactal derivatives readily provides 2-deoxy-2-nitro-1-thioglycosides. Kinetic and thermodynamic reaction control permitted formation of either the alpha- or preferentially the beta-anomers, respectively. Addition of achiral and chiral thiourea derivatives to the reaction mixture increased the reaction rate; the outcome is substrate-controlled. The 2-deoxy-2-nitro-1-thioglycosides are excellent glycosyl donors under arylsulfenyl chloride/silver triflate (ArSCl/AgOTf) activation, and they provide, anchimerically assisted by the nitro group, mostly beta-glycosides. PMID- 25740178 TI - Down-regulation of Frizzled-7 expression inhibits migration, invasion, and epithelial-mesenchymal transition of cervical cancer cell lines. AB - Frizzled-7 (FZD7) has been demonstrated as a critical receptor of the Wnt signaling and involves in tumorigenesis and metastasis in many cancer types. However, limited information was found in cervical cancer. The aim of this study was to investigate the functional role of FZD7 in migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. HeLa and SiHa cervical carcinoma cell lines with FZD7 expression were chosen in this study. A short hairpin RNA (shRNA) construct targeting FZD7 mRNA was transfected into HeLa and SiHa cells, and the stably transfected cell lines were obtained through G418 screening. Functional experiments were further performed to assess whether FZD7 down-regulation affects the migration, invasion, and EMT of HeLa and SiHa cells. Our results revealed that down-regulation of FZD7 expression significantly inhibited cell invasion and migration, as well as decreased the expression and activities of MMP2 and MMP9 in both cell types. Additionally, FZD7 silencing resulted in down-regulation of mesenchymal markers including Vimentin and Snail while increased the levels of epithelial marker E-cadherin. We further found that decreased FZD7 expression inhibited the phosphorylation levels of JNK and c-jun in both HeLa and SiHa cells, as determined by Western blot analysis and immunofluorescence. Overall, our results indicate that shRNA-mediated knockdown of FZD7 inhibits invasion, metastasis, and EMT of cervical cancer cells. FZD7 may provide a promising therapeutic target in cervical cancer. PMID- 25740179 TI - A Comparison of the Nutritional Contribution of Thirty-nine Aromatic Plants used as Condiments and/or Herbal Infusions. AB - Aromatic plants have been used worldwide in human diet to improve the flavor and taste of meals or as herbal infusions. Beyond the culinary purposes, these plants are also used for their medicinal purposes, as antimicrobial, anti-inflammatory, antimutagenic and anti-carcinogenic, among others. In the present study, 39 species of condiments and/or herbal infusions were assessed in order to provide scientific information concerning their nutritional value and energetic contribution; furthermore, the fatty acids composition was also evaluated. Carbohydrates were the most abundant compounds in the condiments that also revealed a varied range of sugars with fructose, glucose, sucrose and trehalose detected in all the condiments. In respect to fatty acids, PUFA were prevalent with the great contribution of linoleic and alpha-linolenic acids among the different 32 detected fatty acids. The herbal infusions revealed low quantities of sugars with most of the plants revealing fructose, glucose and sucrose. In a general way, the energetic value of the condiments and herbal infusions was very low and these plants revealed good nutritional properties that make them suitable for a balanced and diversified low caloric diet. The results obtained in the present systematization study will allow the readers to perform easy and quick comparisons among these different aromatic plants regarding nutritional purposes. PMID- 25740180 TI - Knee MRI under varying flexion angles utilizing a flexible flat cable antenna. AB - The aim of this study is to fabricate and test a novel flexible flat cable antenna (FFCA) for MRI of the knee at different flexion angles. The FFCA was made of a flat cable, a tuning/matching circuit and a signal transmission line. To test its feasibility and validity, in vitro and in vivo experiments were carried out on a 3.0 T MR scanner. The in vitro experiment suggested that the proposed FFCA could achieve a high signal-to-noise ratio (SNR) of 336, while the SNR of an eight-channel knee coil was 291, and phantom images from the FFCA are homogeneously distributed. In the in vivo experiment, the FFCA had a higher SNR of 169 in the region of interest and more than 48.5 cm of longitudinal coverage, while the corresponding values for the commercial coil were 153 and 22.5 cm. Finally, five sagittal knee images at different flexion angles were acquired. The FFCA could acquire satisfactory knee images at different flexion angles, with the advantages of simplicity, low cost, large field of view and high SNR. It may therefore be further used to improve MR image quality of the knee joint. PMID- 25740181 TI - A Metric-Based System for Evaluating the Productivity of Preclinical Faculty at an Academic Medical Center in the Era of Clinical and Translational Science. AB - Academic medical centers are faced with increasing budgetary constraints due to a flat National Institutes of Health budget, lower reimbursements for clinical services, higher costs of technology including informatics and a changing competitive landscape. As such, institutional stakeholders are increasingly asking whether resources are allocated appropriately and whether there are objective methods for measuring faculty contributions and engagement. The complexities of translational research can be particularly challenging when trying to assess faculty contributions because of team science. For over a decade, we have used an objective scoring system called the Matrix to assess faculty productivity and engagement in four areas: research, education, scholarship, and administration or services. The Matrix was developed to be dynamic, quantitative, and able to insure that a fully engaged educator would have a Matrix score that was comparable to a fully engaged investigator. In this report, we present the Matrix in its current form in order to provide a well tested objective system of performance evaluation for nonclinical faculty to help academic leaders in decision making. PMID- 25740182 TI - VTE risk assessment in cancer. Who needs prophylaxis and who does not? AB - Venous thromboembolism (VTE) in patients with cancer is associated with an increased morbidity and mortality, and its prevention is of major clinical importance. However, the VTE rates in the cancer population vary between 0.5% - 20%, depending on cancer-, treatment- and patient-related factors. The most important contributors to VTE risk are the tumor entity, stage and certain anti cancer treatments. Cancer surgery represents a strong risk factor for VTE, and medical oncology patients are at increased risk of developing VTE, especially when receiving chemotherapy or immunomodulatory drugs. Also biomarkers have been investigated for their usefulness to predict risk of VTE (e.g. elevated leukocyte and platelet counts, soluble P-selectin, D-dimer, etc.). In order to identify cancer patients at high risk of VTE and to improve risk stratification, risk assessment models have been developed, which contain both clinical parameters and biomarkers. While primary thromboprophylaxis with low-molecular-weight-heparin (LMWH) is recommended postoperatively for a period of up to 4 weeks after major cancer surgery, the evidence is less clear for medical oncology patients. Thromboprophylaxis in hospitalized medical oncology patients is advocated, and is based on results of randomized controlled trials which evaluated the efficacy and safety of LMWH for prevention of VTE in hospitalized medically ill patients. In recent trials the benefit of primary thromboprophylaxis in cancer patients receiving chemotherapy in the ambulatory setting has been investigated. However, at the present stage primary thromboprophylaxis for prevention of VTE in these patients is still a matter of debate and cannot be recommended for all cancer outpatients. PMID- 25740183 TI - [Leptospirosis]. AB - Leptospirosis is a zoonosis caused by pathogenic Leptospira species. Leptospira infection can range from subclinical to life-threatening disease. Renal failure and severe respiratory symptoms may occur and are associated with a high mortality rate. It is important to realise that renal failure and other symptoms can occur in the absence of icterus. Leptospiraemia occurs mostly during the first week of acute illness, so blood cultures should be taken as soon as possible. Most cases of leptospirosis are diagnosed by serology. Antibodies are detectable in the blood approximately 5 to 7 days after onset of symptoms. Early recognition and treatment with either cephalosporins or penicillin may shorten the duration and severity of multi-organ failure and is therefore mandatory. PMID- 25740184 TI - [Treatment of spasticity in nursing homes: botulinum toxin type A as part of therapy]. AB - Complications of spasticity can severely limit daily activities and care-giving. For those who treat or provide care to patients with spasticity in nursing homes, it is important to recognise complaints in order to prevent serious complications such as care-related pain, contractures and pressure sores. The involvement of a rehabilitation physician is essential to provide a high standard of care. We present two nursing home patients, a 95-year-old woman and a 63-year-old man, with severe upper limb complications following spasticity. Both patients received botulinum toxin injections in the affected muscles, combined with an appropriate splint. A treatment team consisting of a specialist in geriatric medicine, a rehabilitation physician, a physical and an occupational therapist provided consistent daily care in the institution. These efforts substantially reduced care-related pain and improved social behaviour and care options. If spasticity prohibits treatment or care, consultation of a rehabilitation physician at an early stage is indicated. PMID- 25740185 TI - [Slipped capital femoral epiphysis in children]. AB - BACKGROUND: Slipped capital femoral epiphysis (SCFE) is among the most common causes of hip problems in childhood and adolescence. Its incidence is increasing due to rising childhood obesity. There are three different types of SCFE, the rarest of which is the acute traumatic slip. Early identification and urgent surgical treatment are necessary to minimise the risk of complications such as avascular necrosis. CASE DESCRIPTION: An overweight 12-year-old boy visited the emergency department complaining of pain in the left hip after falling from his scooter. The patient was unable to bear weight on his left leg and kept the hip in slight exorotation. An X-ray showed a slip of the femoral epiphysis, which was treated by emergency surgery. During short term follow-up there were no signs of complications such as avascular necrosis of the femoral head. CONCLUSION: Acute traumatic slip of the femoral epiphysis is rare. Patients with this condition require urgent surgical treatment to minimise the risk of complications. PMID- 25740186 TI - [Measuring pain is useful and every doctor can do it: 7 tips]. AB - Pain is one of the main factors influencing quality of life; its incidence is higher than is generally assumed. Pain is not spontaneously reported in all cases; it should be asked about more often. Not measuring pain is one of the main reasons for inadequate pain treatment. Pain should be assessed and recorded more routinely in both primary and secondary healthcare. This can be done in simple and quick ways. Self-reporting using a visual-analogue scale or numeric rating scale is the preferred method. This can be done even by patients with a mild cognitive disorder. Several simple and reliable observational scales exist for patients who cannot report well, e.g. elderly patients with a cognitive disorder or young children. For chronic pain, the low-threshold use of a multi-dimensional scale will increase the likelihood of successful treatment. PMID- 25740187 TI - [Neurosarcoidosis and paraneurosarcoidosis: new online registration of patients]. AB - The clinical spectrum of neurosarcoidosis is highly diverse; virtually any neurological syndrome can present, depending upon granuloma localization. There are indications that neurosarcoidosis is insufficiently recognized as a separate clinical entity. In the absence of major prospective clinical trials, we launched a large national online registry of neurosarcoidosis patients in the Netherlands in June 2014 at www.neurosarcoidose.nl. When a patient with sarcoidosis presents with neurological symptoms that may compatible with sarcoidosis, it is important to locate sites of disease activity accessible for biopsy outside the nervous system. Small nerve fibre neuropathy is a common neurological complication of sarcoidosis. It is considered an epiphenomenon, and therefore classified as 'para neurosarcoidosis'. Neurological symptoms causing disability are an indication for immunosuppressive therapy. There is increasing evidence for the effective treatment of refractory neurosarcoidosis using biologicals. Whether the intravenous administration of immunoglobulins or ARA290, an erythropoietin derivative with TNF-alpha-antagonistic and tissue-protective characteristics, is effective for small nerve fibre neuropathy in sarcoidosis is subject for study. PMID- 25740188 TI - [A neonate with anaemia of prematurity: zinc protoporphyrin identifies iron deficiency anaemia without iron deficiency]. AB - Anaemia is a common problem in premature infants and is generally easy to treat with iron supplementation. If the anaemia persists despite appropriate correction of deficiencies, more extensive evaluation is required. We describe a case of a premature male infant with a production-deficient anaemia without metabolic deficiencies, eventually identified as anaemia of prematurity. This type of anaemia is commonly diagnosed but its highly variable and complex aetiology and phenotype are often poorly understood. A probable explanation for the anaemia of prematurity in this case was a transient iron incorporation defect, identifiable by high levels of zinc protoporphyrin. PMID- 25740189 TI - [Bronchoscopic interventions in severe COPD: improvement of pulmonary function, exercise capacity and quality of life]. AB - The current drug treatment of patients with severe and very severe COPD is often insufficient to achieve an acceptable quality of life. Surgical treatment of patients with COPD, by means of lung volume reduction surgery or lung transplantation is invasive and only available to a limited number of patients. Bronchoscopic lung volume reduction is a novel, minimally invasive, experimental treatment option for patients with severe COPD. Two different treatment options are currently available, depending on the type of pulmonary emphysema: bronchoscopic intervention with one-way endobronchial valves or with lung volume reduction coils. In selected patients with severe emphysema, bronchoscopic lung volume reduction brings about a clinically relevant improvement in pulmonary function, exercise capacity and quality of life. In view of the innovative and specialist nature of bronchoscopic lung volume reduction, it is prudent to perform this treatment in a centre of expertise for COPD. PMID- 25740190 TI - [A woman with floating spheres in her abdomen]. AB - A 55-year-old postmenopausal woman presented with acute abdominal pain. Ultrasound and MRI revealed a large, unilocular, cystic abdominal mass, with remarkable floating spheres. Histopathology showed a dermoid cyst. This is a benign ovarian neoplasm, which can contain elements of all three germ layers: primarily hair, teeth, skin or sebaceous tissue. PMID- 25740191 TI - [Unannounced simulation of obstetric emergencies: safe for medical staff?]. AB - Management of obstetric emergencies is difficult to learn in real life due to the rarity of emergency events. Simulation-based medical education (SBME) has been shown to be a useful training method. A safe learning environment is a crucial condition for successful, applicable SBME. It is therefore essential to understand how SBME is perceived by healthcare professionals. A study by Sorensen et al. published recently in Postgraduate Medical Journal found that the number of staff members with positive perceptions increased after unannounced in situ simulation of obstetric emergencies. However, the number of staff who viewed the simulation as stressful also increased, especially among midwives. Although this study had some limitations, these results should be taken seriously. Randomised trials are warranted to explore the perceptions of healthcare professionals with regard to SBME. PMID- 25740192 TI - [More than 200 reporting guidelines--and counting]. AB - Reporting guidelines have been developed for randomized clinical trials, systematic reviews, and many other types of studies. Most of these have a checklist of essential items that have to be included in every study report. Describing these essential items enables readers to better judge the validity, relevance and applicability of study findings. The website of the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network now lists more than 200 such reporting guidelines. While they have been endorsed by many journals and other organizations, uptake has been incomplete. The implicit assumption in many guidelines was that editors of scientific journals would police authors, thereby enforcing the use of the checklists. We argue that the groups responsible for reporting guidelines could put more effort into the development of tools for authors, reviewers and editors to facilitate the implementation of these guidelines. This would contribute to completeness and transparency in reporting clinical and biomedical research. PMID- 25740193 TI - Changes in body-site distribution of common melanocytic naevi among 7-year-old Swedish children between 2002 and 2007. AB - An observational population-based study conducted among 2 sets of 7-year-old children in Sweden in 2002 and 2007 revealed evidence of improved sun protection, also reflected in a significant reduction in the total number of melanocytic naevi. Based on these data-sets, the aim of the current study was to determine whether the overall reduction in naevi had impacted differently on body sites based on their main pattern of sun exposure. In 2002, median naevi counts/m2 were highest on intermittently sun-exposed sites: 13.8 (95% CI 8.0-22.7) compared with chronically sun-exposed sites: 11.0 (95% CI 0.0-20.5). In 2007, median naevi counts/m2 on intermittently sun-exposed body sites were significantly lower: 8.7 (95% CI 4.7-15.2), p < 0.0001, while on chronically exposed sites median naevi counts/m2 were unaltered: 10.3 (95% CI 0.0-14.4), p = 0.9313. Changes were most evident among boys. Future research can evaluate whether this shift in naevi distribution in Swedish children translates into a reduction in cutaneous melanomas on intermittently sun-exposed body sites. PMID- 25740194 TI - Young Aboriginal women's voices on pregnancy care: factors encouraging antenatal engagement. AB - BACKGROUND: Rates of adolescent pregnancy in Australia have decreased over time for all population groups but for Aboriginal adolescents remain higher than their non-Aboriginal counterparts. There is limited literature identifying the motivations of young Aboriginal women to present for pregnancy care. AIM: Understanding young Aboriginal women's views on pregnancy care is important knowledge to assist maternity services develop localised pathways that encourage engagement with pregnancy care. METHODS: A descriptive qualitative study with data collected using a bi-cultural research approach and an interview method known as yarning, with data interpretation informed by first hand cultural knowledge and current evidence. FINDINGS: The sample included 28 young women and 56 senior women and service providers. Typical actions indicative of antenatal engagement included: female relatives directing young woman to pregnancy care; availability at Aboriginal Health Services or in public hospitals and community based settings of multidisciplinary teams (midwife/Aboriginal Health Worker and/or Grandmother Liaison Officer); and, a continuous relationship with known and trusted care providers. Factors such as relocation for childbirth may interrupt pregnancy care. Active measures such as providing appointment reminders and transport to and from appointments assists young women to maintain antenatal contact. CONCLUSION: The role of female relatives in directing young women's engagement with pregnancy care is crucial combined with availability of known and trusted care providers. Relocation from a home community to the nearest birth facility, and associated accommodation and transport options, are causes of concern requiring health system changes which more fully support culturally safe maternity options regardless of location. PMID- 25740195 TI - Metal-mediated and metal-catalyzed reactions of isocyanides. PMID- 25740196 TI - Commentary: The return of consciousness to epilepsy seizure classification. PMID- 25740197 TI - RGS2 ggenetic variation: association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety. AB - Accumulating evidence from mouse models points to the G protein-coupled receptor RGS2 (regulator of G-protein signaling 2) as a promising candidate gene for anxiety in humans. Recently, RGS2 polymorphisms were found to be associated with various anxiety disorders, e.g., rs4606 with panic disorder (PD), but other findings have been negative or inconsistent concerning the respective risk allele. To further examine the role of RGS2 polymorphisms in the pathogenesis of PD, we genotyped rs4606 and five additional RGS2 tag single nucleotide polymorphisms (SNPs; rs16834831, rs10801153, rs16829458, rs1342809, rs1890397) in two independent PD samples, comprising 531 matched case/control pairs. The functional SNP rs4606 was nominally associated with PD when both samples were combined. The upstream SNP rs10801153 displayed a Bonferroni-resistant significant association with PD in the second and the combined sample (P = 0.006 and P = 0.017). We furthermore investigated the effect of rs10801153 on dimensional anxiety traits, a behavioral avoidance test (BAT), and an index for emotional processing in the respective subsets of the total sample. In line with categorical results, homozygous risk (G) allele carriers displayed higher scores on the Agoraphobic Cognitions Questionnaire (ACQ; P = 0.015) and showed significantly more defensive behavior during fear provoking situations (P = 0.001). Furthermore, significant effects on brain activation in response to angry (P = 0.013), happy (P = 0.042) and neutral faces (P = 0.032) were detected. Taken together, these findings provide further evidence for the potential role of RGS2 as a candidate gene for PD. PMID- 25740198 TI - LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease. AB - Exposure to rotenone in vivo results in selective degeneration of dopaminergic neurons and development of neuropathologic features of Parkinson's disease (PD). As rotenone acts as an inhibitor of mitochondrial respiratory complex I, we employed oxidative lipidomics to assess oxidative metabolism of a mitochondria specific phospholipid, cardiolipin (CL), in substantia nigra (SN) of exposed animals. We found a significant reduction in oxidizable polyunsaturated fatty acid (PUFA)-containing CL molecular species. We further revealed increased contents of mono-oxygenated CL species at late stages of the exposure. Notably, linoleic acid in sn-1 position was the major oxidation substrate yielding its mono-hydroxy- and epoxy-derivatives whereas more readily "oxidizable" fatty acid residues (arachidonic and docosahexaenoic acids) remained non-oxidized. Elevated levels of PUFA CLs were detected in plasma of rats exposed to rotenone. Characterization of oxidatively modified CL molecular species in SN and detection of PUFA-containing CL species in plasma may contribute to better understanding of the PD pathogenesis and lead to the development of new biomarkers of mitochondrial dysfunction associated with this disease. PMID- 25740199 TI - Dopamine D1 and D5 receptors differentially regulate oxidative stress through paraoxonase 2 in kidney cells. AB - BACKGROUND: The renal dopaminergic system plays an important role in the pathogenesis of hypertension. Dopamine D1-like receptors (D1R and D5R) decrease reactive oxygen species (ROS) production via inhibition of pro-oxidant enzymes such as NADPH oxidase. Paraoxonase 2 (PON2) is also involved in the inhibition of NADPH oxidase activity. Therefore, we tested the hypothesis that D1R and D5R inhibit ROS production by increasing the expression of PON2, including those in membrane microdomains. METHODS AND RESULTS: PON2 colocalized with D1R and D5R in mouse renal proximal tubules (RPTs), human RPT (hRPT) cells, and HEK293 cells heterologously expressing human D1R (HEK-hD1R) or D5R (HEK-hD5R). Fenoldopam, an agonist for both D1R and D5R, increased PON2 co-immunoprecipitation with D1R and D5R in HEK-hD1R and HEK-hD5R cells, respectively. Silencing PON2 increased ROS production and NADPH oxidase activity, and impaired the inhibitory effect of fenoldopam. Fenoldopam increased PON2 protein in both lipid rafts (LRs) and non LRs in HEK-hD1R cells, but only in non-LRs in HEK-hD5R and hRPT cells. Long-term (hrs) fenoldopam stimulation increased PON2 protein in a time-dependent manner in HEK-hD5R, but not in HEK-hD1R cells. Because the effects of fenoldopam on non-LR and total PON2 expressions were similar in HEK-hD5R and hRPT cells, additional studies were performed to determine the relationship between D5R and PON2. Renal PON2 protein was decreased in D5(-/-) mice. In hRPT cells, silencing D5R decreased PON2 expression and increased ROS production. CONCLUSIONS: We conclude that D1-like receptors inhibit ROS production by altering PON2 distribution in membrane microdomains in the short-term, and by increasing PON2 expression in the long-term. PMID- 25740200 TI - How to count cells: the advantages and disadvantages of the isotropic fractionator compared with stereology. AB - The number of cells comprising biological structures represents fundamental information in basic anatomy, development, aging, drug tests, pathology and genetic manipulations. Obtaining unbiased estimates of cell numbers, however, was until recently possible only through stereological techniques, which require specific training, equipment, histological processing and appropriate sampling strategies applied to structures with a homogeneous distribution of cell bodies. An alternative, the isotropic fractionator (IF), became available in 2005 as a fast and inexpensive method that requires little training, no specific software and only a few materials before it can be used to quantify total numbers of neuronal and non-neuronal cells in a whole organ such as the brain or any dissectible regions thereof. This method entails transforming a highly anisotropic tissue into a homogeneous suspension of free-floating nuclei that can then be counted under the microscope or by flow cytometry and identified morphologically and immunocytochemically as neuronal or non-neuronal. We compare the advantages and disadvantages of each method and provide researchers with guidelines for choosing the best method for their particular needs. IF is as accurate as unbiased stereology and faster than stereological techniques, as it requires no elaborate histological processing or sampling paradigms, providing reliable estimates in a few days rather than many weeks. Tissue shrinkage is also not an issue, since the estimates provided are independent of tissue volume. The main disadvantage of IF, however, is that it necessarily destroys the tissue analyzed and thus provides no spatial information on the cellular composition of biological regions of interest. PMID- 25740202 TI - Impact of the Serum Uric Acid Level on Subclinical Atherosclerosis in Middle-aged and Elderly Chinese. AB - AIM: The carotid intima-media thickness (CIMT) is now validated as a sensitive marker of atherosclerosis and is directly associated with an increased risk of cardiovascular disease. Considering that the independent association between the serum uric acid level and CIMT remains controversial due to the complex interrelationship with other known cardiovascular risk factors, further studies are needed. The aim of the present study is to explore the association between the serum uric acid level and CIMT in a general Chinese population and determine whether the association differs according to varied metabolic status. METHODS: The present study was cross-sectional in design. A total of 10,281 community based participants 40 years of age or older from Shanghai, China were included in the current analysis. All participants underwent a detailed questionnaire interview, anthropometric measurements and ultrasonography to assess the CIMT. Blood and urine samples were collected for the biochemical measurements. RESULTS: The serum uric acid levels were positively associated with obesity- and diabetes related parameters and the CIMT. In a logistic regression model controlling for potential confounders, compared with the participants in the first quartile of the uric acid level, those in the fourth quartile had a higher odds of an elevated CIMT in both men (odds ratio [OR]=1.37; 95% confidence interval [CI]=1.07-1.75) and women (OR=1.48; 95% CI=1.12-1.94). The subgroup analyses revealed that an association between an elevated CIMT and the serum uric acid level persisted regardless of diuretic use and the hypertension, diabetes mellitus and chronic kidney disease status. However, the association disappeared in the patients who consumed alcohol and in premenopausal women. CONCLUSIONS: The serum uric acid level is positively associated with an elevated CIMT in middle aged and elderly Chinese subjects, independent of known risk determinants of cardiovascular disease. PMID- 25740201 TI - Structural changes in thestrial blood-labyrinth barrier of aged C57BL/6 mice. AB - Tight control over cochlear blood flow (CoBF) and the blood-labyrinth barrier (BLB) in the striavascularis is critical for maintaining the ionic, fluid and energy balance necessary for hearing function. Inefficient CoBF and disruption of BLB integrity have long been considered major etiologic factors in a variety of hearing disorders. In this study, we investigate structural changes in the BLB of the striavascularis in age-graded C57BL/6 mice (1 to 21 months) with a focus on changes in two blood barrier accessory cells, namely pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms). Decreased capillary density was detectable at 6 months, with significant capillary degeneration seen in 9- to 21-month-old mice. Reduced capillary density was highly correlated with lower numbers of PCs and PVM/Ms. "Drop-out" of PCs and "activation" of PVM/Ms were seen at 6 months, with drastic changes being observed by 21 months. With newly established in vitro three-dimensional cell-based co-culture models, we demonstrate that PCs and PVM/Ms are essential for maintaining cochlear vascular architecture and stability. PMID- 25740203 TI - Quantification of fibrous cap thickness in intracoronary optical coherence tomography with a contour segmentation method based on dynamic programming. AB - OBJECTIVES: Fibrous cap thickness is the most critical component of plaque stability. Therefore, in vivo quantification of cap thickness could yield valuable information for estimating the risk of plaque rupture. In the context of preoperative planning and perioperative decision making, intracoronary optical coherence tomography imaging can provide a very detailed characterization of the arterial wall structure. However, visual interpretation of the images is laborious, subject to variability, and therefore not always sufficiently reliable for immediate decision of treatment. METHODS: A novel semiautomatic segmentation method to quantify coronary fibrous cap thickness in optical coherence tomography is introduced. To cope with the most challenging issue when estimating cap thickness (namely the diffuse appearance of the anatomical abluminal interface to be detected), the proposed method is based on a robust dynamic programming framework using a geometrical a priori. To determine the optimal parameter settings, a training phase was conducted on 10 patients. RESULTS: Validated on a dataset of 179 images from 21 patients, the present framework could successfully extract the fibrous cap contours. When assessing minimal cap thickness, segmentation results from the proposed method were in good agreement with the reference tracings performed by a medical expert (mean absolute error and standard deviation of 22 +/- 18 MUm) and were similar to inter-observer reproducibility (21 +/- 19 MUm, R = .74), while being significantly faster and fully reproducible. CONCLUSION: The proposed framework demonstrated promising performances and could potentially be used for online identification of high-risk plaques. PMID- 25740204 TI - A semiautomatic method for in vivo three-dimensional quantitative analysis of fascial layers mobility based on 3D ultrasound scans. AB - PURPOSE: Recently, there has been an increasing interest in the role of deep fascia mobility in musculoskeletal dynamics and chronic pain mechanisms; however, no strategies have been presented so far to study in vivo fascial motion in 3D. This paper presents a semiautomatic method, based on ultrasound (US) imaging, enabling a 3D evaluation of fascia mobility. METHODS: The proposed approach relies on the acquisition of 3D US datasets at rest and during a voluntary muscular contraction and consists of two phases: 3D US dataset analysis and generation of a displacement vector field using a block matching technique (Phase 1) and validation and filtering of the resulting displacement vector field for outliers removal (Phase 2). The accuracy and effectiveness of the proposed method were preliminarily tested on different 3D US datasets, undergoing either simulated (procedural) or real (muscular contraction) deformations. RESULTS: As for the simulated deformation, estimated displacement vectors resulting from Phase 1 presented a mean magnitude percentage error of 8.05 % and a mean angular error of 4.78 degrees which, after Phase 2, were reduced by 69.44 and by 83.05 %, respectively. Tests on real deformations further validated the effectiveness of Phase 2 in the removal of outliers from the displacement vector field. CONCLUSIONS: Obtained results preliminarily demonstrate the viability of the proposed algorithm for the analysis of fascia mobility. Such analysis can enable clinicians to better understand the fascia role in musculoskeletal dynamics and disorder. Further experiments are needed to optimize the method in consideration of the anatomical region to be studied. PMID- 25740205 TI - Strong Induction of Minor Terpenes in Italian Cypress, Cupressus sempervirens, in Response to Infection by the Fungus Seiridium cardinale. AB - Seiridium cardinale, the main fungal pathogen responsible for cypress bark canker, is the largest threat to cypresses worldwide. The terpene response of canker-resistant clones of Italian cypress, Cupressus sempervirens, to two differently aggressive isolates of S. cardinale was studied. Phloem terpene concentrations, foliar terpene concentrations, as well as foliar terpene emission rates were analyzed 1, 10, 30, and 90 days after artificial inoculation with fungal isolates. The phloem surrounding the inoculation point exhibited de novo production of four oxygenated monoterpenes and two unidentified terpenes. The concentrations of several constitutive mono- and diterpenes increased strongly (especially alpha-thujene, sabinene, terpinolene, terpinen-4-ol, oxygenated monoterpenes, manool, and two unidentified diterpenes) as the infection progressed. The proportion of minor terpenes in the infected cypresses increased markedly from the first day after inoculation (from 10% in the control to 30-50% in the infected treatments). Foliar concentrations showed no clear trend, but emission rates peaked at day 10 in infected trees, with higher delta-3-carene (15 fold) and total monoterpene (10-fold) emissions than the control. No substantial differences were found among cypresses infected by the two fungal isolates. These results suggest that cypresses activate several direct and indirect chemical defense mechanisms after infection by S. cardinale. PMID- 25740206 TI - Revising the American dream: how Asian immigrants adjust after an HIV diagnosis. AB - AIM: We explored how acculturation and self-actualization affect depression in the HIV-positive Asians and Pacific Islanders immigrant population. BACKGROUND: Asians and Pacific Islanders are among the fastest growing minority groups in the USA. Asians and Pacific Islanders are the only racial/ethnic group to show a significant increase in HIV diagnosis rate. DESIGN: A mixed-methods study was conducted. METHODS: Thirty in-depth interviews were conducted with HIV-positive Asians and Pacific Islanders in San Francisco and New York. Additionally, cross sectional audio computer-assisted self-interviews were conducted with a sample of 50 HIV-positive Asians and Pacific Islanders. Content analysis was used to analyse the in-depth interviews. Also, descriptive, bivariate statistics and multivariable regression analysis was used to estimate the associations among depression, acculturation and self-actualization. The study took place from January-June 2013. DISCUSSION: Major themes were extracted from the interview data, including self-actualization, acculturation and depression. The participants were then divided into three acculturation levels correlating to their varying levels of self-actualization. For those with low acculturation, there was a large discrepancy in the Center for Epidemiologic Studies Depression Scale scores between those who had totally lost their self-actualization and those who believed they could still achieve their 'American dreams'. Among those who were less acculturated, there was a significant difference in depression scores between those who felt they had totally lost their ability to self actualize and those who still believed they could 'make their dreams come true.' CONCLUSION: Acculturation levels influence depression and self-actualization in the HIV-positive Asians and Pacific Islanders population. Lower acculturated Asian Americans achieved a lower degree of self-actualization and suffered from depression. Future interventions should focus on enhancing acculturation and reducing depression to achieve self-actualization. PMID- 25740207 TI - A longitudinal study of bone area, content, density, and strength development at the radius and tibia in children 4-12 years of age exposed to recreational gymnastics. AB - This study investigated the long-term relationship between the exposure to childhood recreational gymnastics and bone measures and bone strength parameters at the radius and tibia. It was observed that individuals exposed to recreational gymnastics had significantly greater total bone content and area at the distal radius. No differences were observed at the tibia. INTRODUCTION: This study investigated the relationship between exposure to early childhood recreational gymnastics with bone measures and bone strength development at the radius and tibia. METHODS: One hundred twenty seven children (59 male, 68 female) involved in either recreational gymnastics (gymnasts) or other recreational sports (non gymnasts) between 4 and 6 years of age were recruited. Peripheral quantitative computed tomography (pQCT) scans of their distal and shaft sites of the forearm and leg were obtained over 3 years, covering the ages of 4-12 years at study completion. Multilevel random effects models were constructed to assess differences in the development of bone measures and bone strength measures between those exposed and not exposed to gymnastics while controlling for age, limb length, weight, physical activity, muscle area, sex, and hours of training. RESULTS: Once age, limb length, weight, muscle area, physical activity, sex, and hours of training effects were controlled, it was observed that individuals exposed to recreational gymnastics had significantly greater total bone area (18.0 +/- 7.5 mm(2)) and total bone content (6.0 +/- 3.0 mg/mm) at the distal radius (p < 0.05). This represents an 8-21 % benefit in ToA and 8-15 % benefit to ToC from 4 to 12 years of age. Exposure to recreational gymnastics had no significant effect on bone measures at the radius shaft or at the tibia (p > 0.05). CONCLUSIONS: Exposure to early life recreational gymnastics provides skeletal benefits to distal radius bone content and area. Thus, childhood recreational gymnastics exposure may be advantageous to bone development at the wrist. PMID- 25740208 TI - Cost-effective osteoporosis treatment thresholds in Greece. AB - A Greek-specific cost-effectiveness analysis determined the FRAX-based intervention thresholds. Assuming a willingness to pay of 30,000 , osteoporosis treatment is cost-effective in subjects under the age of 75 with 10 year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, respectively, while for older patients, the same thresholds are raised to 5 and 15 %. INTRODUCTION: The purpose of this study was to determine the FRAX calculated fracture probabilities at which therapeutic intervention can be considered as cost-effective in the Greek setting. METHODS: A Markov cohort model was populated with Greek data, and quality-adjusted life years (QALYs) were used to calculate the cost-effective thresholds for an annual medication cost of 733.7 by gender and age. Average FRAX-based 10-year probabilities for both major osteoporotic and hip fractures were multiplied by the model-derived relative risk at which a cost of 30,000 for each QALY gained was observed for treatment versus to no intervention. RESULTS: A biphasic intervention threshold model is supported by our findings. Osteoporosis treatment becomes cost-effective when absolute 10-year probabilities for hip and major osteoporotic fractures reach 2.5 and 10 %, respectively, among both men and women under the age of 75. For older subjects, the proposed intervention thresholds are raised to 5 and 15 % 10-year probability for hip and major osteoporotic fractures, respectively. CONCLUSIONS: Cost-effective osteoporosis treatment may be facilitated in Greece if FRAX algorithm is used to identify subjects with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, under the age of 75, while for older patients, the relevant thresholds are 5 and 15 %, respectively. PMID- 25740209 TI - Coronary microvascular dysfunction in asymptomatic patients affected by systemic sclerosis - limited vs. diffuse form. AB - BACKGROUND: This observational study was designed to evaluate the prevalence of coronary microvascular dysfunction (CMD) in asymptomatic patients affected by systemic sclerosis (SSc), stratifying the results according to the limited (lcSSc) and the diffuse (dcSSc) forms of the disease. METHODS AND RESULTS: We enrolled 19 consecutive asymptomatic patients with dcSSc (n=7) or lcSSc (n=12). In all subjects, coronary flow reserve (CFR) was assessed by measuring diastolic coronary flow velocities in the left anterior descending artery by pulsed wave Doppler at baseline and after dipyridamole infusion (0.84 mg.kg(-1).6 min(-1)). Wall motion score index was evaluated at baseline and during stress. We enrolled 20 healthy subjects as controls. Mean CFR was 1.96+/-0.62 in patients and 2.69+/ 0.47 in controls (P<0.001). Abnormal values of CFR (<=2) were significantly more prevalent in patients than in controls (10/19 vs. 0/20; P<0.001) and in the dcSSc subgroup than in the lcSSc subgroup (6/7 vs. 4/12; P=0.05). An inverse relationship between disease duration (from time of onset of Raynaud's phenomenon) and CFR value was observed in the lcSSc group (correlation coefficient -0.583; P=0.046). Neither patients nor controls had wall motion abnormalities during dipyridamole administration. CONCLUSIONS: A blunted CFR, most likely because of CMD, is more frequent in patients affected by the dcSSc form in the early stages of the disease, whereas it seems to appear later in lcSSc. PMID- 25740210 TI - Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center. PMID- 25740211 TI - Erratum to: Genome-wide association study of antibody level response to NDV and IBV in Jinghai yellow chicken based on SLAF-seq technology. PMID- 25740212 TI - Structure of human dipeptidyl peptidase 10 (DPPY): a modulator of neuronal Kv4 channels. AB - The voltage-gated potassium channel family (Kv) constitutes the most diverse class of ion channels in the nervous system. Dipeptidyl peptidase 10 (DPP10) is an inactive peptidase that modulates the electrophysiological properties, cell surface expression and subcellular localization of voltage-gated potassium channels. As a consequence, DPP10 malfunctioning is associated with neurodegenerative conditions like Alzheimer and fronto-temporal dementia, making this protein an attractive drug target. In this work, we report the crystal structure of DPP10 and compare it to that of DPP6 and DPP4. DPP10 belongs to the S9B serine protease subfamily and contains two domains with two distinct folds: a beta-propeller and a classical alpha/beta-hydrolase fold. The catalytic serine, however, is replaced by a glycine, rendering the protein enzymatically inactive. Difference in the entrance channels to the active sites between DPP10 and DPP4 provide an additional rationale for the lack of activity. We also characterize the DPP10 dimer interface focusing on the alternative approach for designing drugs able to target protein-protein interactions. PMID- 25740213 TI - Mitochondrial genome of Caenorhabditis nigoni (Rhabditida: Rhabditidae). AB - To facilitate comparative genomic study in the Caenorhabditis species, the mitochondrial genome (mitogenome) of a nematode species Caenorhabditis nigoni (previous name: Caenorhabditis sp. 9) was generated using next-generation sequencing. The mitogenome length is 13,413 bp, containing 12 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs) and 2 non-coding regions (NCR). The genome organization and nucleotide composition is very similar to that of the mitogenome of C. elegans and C. briggsae. Mitogenome of C. nigoni shows higher sequence similarity to C. briggsae than to C. elegans, which is consistent with the fact that C. nigoni is a sister species of C. briggsae. However, as in C. elegans, two NCRs present in the mitogenome of C. briggsae are missing in C. nigoni. The mitogenome sequence of C. nigoni plays an important role in further studies of phylogenetics, population genetics and evolutionary genetics in nematode species. PMID- 25740214 TI - The complete chloroplast genome sequence of Safflower (Carthamus tinctorius L.). AB - Safflower (Carthamus tinctorius L.) is a traditional medical plants of Asia. In this study, the complete chloroplast genome of safflower was presented. The total genome size was 153,675 bp in length, containing a pair of inverted repeats (IRs) of 25,407 bp, separated by large single copy (LSC) and small single copy (SSC) of 83,606 bp and 19,156 bp, respectively. Overall GC content of the genome was 37.4%. The chloroplast genome harbored 127 annotated genes, including 89 protein coding genes, 30 tRNA genes and 8 rRNA genes. A total of 7 of these genes were duplicated in the inverted repeat regions. Twelve genes contained one intron. PMID- 25740215 TI - Complete mitochondrial genome of Chuanzhong black goat in southwest of China (Capra hircus). AB - The Chuanzhong black goat (Capra hircus) is a breed native to southwest of China. Its complete mitochondrial genome is 16,641 nt in length, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, and a non-coding control region. As in other mammals, most mitochondrial genes are encoded on the heavy strand, except for ND6 and eight tRNA genes, which are encoded on the light strand. Its overall base composition is A: 33.5%, T: 27.3%, C: 26.1%, and G: 13.1%. The complete mitogenome of the Chinese indigenous breed of goat could provide a basic data for further phylogenetics analysis. PMID- 25740216 TI - The complete mitochondrial genome of a Chinese rufous horseshoe bat subspecies, Rhinolophus sinicus sinicus (Chiroptera: Rhinolophidae). AB - There are two subspecies of Rhinolophus sinicus currently recognized in China. In this study, using next generation sequencing approaches, the complete mitochondrial genome of one subspecies R. s. sinicus was obtained. The total length of the genome sequence is 16,898 bp. The arrangement and contents of R. s. sinicus mitochondrial genes exhibit high similarity with other bats of family Rhinolophida. Phylogenetic reconstructions support the sister relationship of the two subspecies and confirm the subspecies status of our specimen. PMID- 25740217 TI - Anti-inflammatory, antioxidant and anti-acetylcholinesterase activities of Bouvardia ternifolia: potential implications in Alzheimer's disease. AB - Bouvardia ternifolia has been used medicinally to treat inflammation. In the present study, we investigate the anti-Alzheimer's potential effect of the hydroalcoholic extract of B. ternifolia through evaluation of anti-inflammatory and antioxidant activities, quantification of the percentage inhibition of acetylcholinesterase activity, protection effect against beta-amyloid fibrillar induce neurotoxicity, and the identification of the main constituents. Our results show that B. ternifolia extract and ethyl acetate fraction induced anti inflammatory effects by reducing inflammation by >70 %, while antioxidant test revealed significant IC50 values for flavonoid content fraction (30.67 +/- 2.09 MUg/ml) and ethyl acetate fraction (42.66 +/- 0.93 MUg/ml). The maximum inhibition of acetylcholinesterase was exhibited by scopoletin content fraction (38.43 +/- 3.94 %), while ethyl acetate fraction exerted neuroprotective effect against beta-amyloid peptide (83.97 +/- 5.03 %). Phytochemical analysis, showed the presence of 3-O-quercetin glucopyranoside (415 mg/g), rutin (229.9 mg/g), ursolic and oleanolic acid (54 and 20.8 mg/g respectively), 3-O-quercetin rhamnopyranoside (12.8 mg/g), chlorogenic acid (9.5 mg/g), and scopoletin (1.38 mg/g). Our findings support the use of B. ternifolia since the extract induced significant neuroprotection against beta-amyloid peptide, anti-inflammatory, antioxidant and anti-acetylcholinesterase effects that could be attributed to its contents of polyphenols, coumarins, and triterpenes, and encourage further studies for development of this extract as therapeutic agent in treatment of Alzheimer's disease. PMID- 25740218 TI - Diagnostic power of the non-ischaemic forearm exercise test in detecting glycogenosis type V. AB - BACKGROUND AND PURPOSE: This was a retrospective study to assess the diagnostic value of the non-ischaemic forearm exercise test in detecting McArdle's disease. METHODS: The study is a retrospective diagnostic study over 15 years (1999-2013) on a referred sample of patients suffering from exercise intolerance and various muscle complaints, generally with elevated creatine kinase (CK). In all, 1226 patients underwent the non-ischaemic forearm exercise test. Blood lactate, ammonia and CK levels were analyzed. DNA analyses and/or muscle biopsies were assessed to confirm the diagnosis of McArdle's disease. The results of 60 volunteers were used to compare with the results of study subjects. RESULTS: In this cohort, 40 patients were finally diagnosed with McArdle's disease. Absolute values of lactate and ammonia rise were used to discriminate all McArdle patients from healthy patients. A sensitivity and specificity of respectively 100% and 99.7% were calculated. The 24-h CK level showed no significant difference from the CK level at the day of the test and confirms the safety of the test. CONCLUSIONS: This study has formally assessed the diagnostic value of the non ischaemic forearm exercise test in the detection of McArdle's disease. Very high sensitivity and specificity were observed. Furthermore, the test is easy to set up and to perform, it is non-traumatic and cost effective. It may circumvent a muscle biopsy in McArdle patients presenting the most common mutations. Hence, it is a perfect and safe screening instrument to detect patients with McArdle's disease. Glycogen storage disease type III patients, however, may show similar patterns to McArdle patients. PMID- 25740219 TI - Acute post-traumatic stress symptoms and age predict outcome in military blast concussion. AB - High rates of adverse outcomes have been reported following blast-related concussive traumatic brain injury in US military personnel, but the extent to which such adverse outcomes can be predicted acutely after injury is unknown. We performed a prospective, observational study of US military personnel with blast related concussive traumatic brain injury (n = 38) and controls (n = 34) enrolled between March and September 2012. Importantly all subjects returned to duty and did not require evacuation. Subjects were evaluated acutely 0-7 days after injury at two sites in Afghanistan and again 6-12 months later in the United States. Acute assessments revealed heightened post-concussive, post-traumatic stress, and depressive symptoms along with worse cognitive performance in subjects with traumatic brain injury. At 6-12 months follow-up, 63% of subjects with traumatic brain injury and 20% of controls had moderate overall disability. Subjects with traumatic brain injury showed more severe neurobehavioural, post-traumatic stress and depression symptoms along with more frequent cognitive performance deficits and more substantial headache impairment than control subjects. Logistic regression modelling using only acute measures identified that a diagnosis of traumatic brain injury, older age, and more severe post-traumatic stress symptoms provided a good prediction of later adverse global outcomes (area under the receiver-operating characteristic curve = 0.84). Thus, US military personnel with concussive blast-related traumatic brain injury in Afghanistan who returned to duty still fared quite poorly on many clinical outcome measures 6-12 months after injury. Poor global outcome seems to be largely driven by psychological health measures, age, and traumatic brain injury status. The effects of early interventions and longer term implications of these findings are unknown. PMID- 25740220 TI - Neural detection of complex sound sequences in the absence of consciousness. AB - The neural response to a violation of sequences of identical sounds is a typical example of the brain's sensitivity to auditory regularities. Previous literature interprets this effect as a pre-attentive and unconscious processing of sensory stimuli. By contrast, a violation to auditory global regularities, i.e. based on repeating groups of sounds, is typically detectable when subjects can consciously perceive them. Here, we challenge the notion that global detection implies consciousness by testing the neural response to global violations in a group of 24 patients with post-anoxic coma (three females, age range 45-87 years), treated with mild therapeutic hypothermia and sedation. By applying a decoding analysis to electroencephalographic responses to standard versus deviant sound sequences, we found above-chance decoding performance in 10 of 24 patients (Wilcoxon signed rank test, P < 0.001), despite five of them being mildly hypothermic, sedated and unarousable. Furthermore, consistently with previous findings based on the mismatch negativity the progression of this decoding performance was informative of patients' chances of awakening (78% predictive of awakening). Our results show for the first time that detection of global regularities at neural level exists despite a deeply unconscious state. PMID- 25740222 TI - Estimating glomerular filtration rate in acute coronary syndromes: Different equations, different mortality risk prediction. AB - AIMS: Renal dysfunction is a powerful predictor of adverse outcomes in patients hospitalized for acute coronary syndrome. Three new glomerular filtration rate (GFR) estimating equations recently emerged, based on serum creatinine (CKD EPIcreat), serum cystatin C (CKD-EPIcyst) or a combination of both (CKD EPIcreat/cyst), and they are currently recommended to confirm the presence of renal dysfunction. Our aim was to analyse the predictive value of these new estimated GFR (eGFR) equations regarding mid-term mortality in patients with acute coronary syndrome, and compare them with the traditional Modification of Diet in Renal Disease (MDRD-4) formula. METHODS AND RESULTS: 801 patients admitted for acute coronary syndrome (age 67.3+/-13.3 years, 68.5% male) and followed for 23.6+/-9.8 months were included. For each equation, patient risk stratification was performed based on eGFR values: high-risk group (eGFR<60ml/min per 1.73m(2)) and low-risk group (eGFR?60ml/min per 1.73m(2)). The predictive performances of these equations were compared using area under each receiver operating characteristic curves (AUCs). Overall risk stratification improvement was assessed by the net reclassification improvement index. The incidence of the primary endpoint was 18.1%. The CKD-EPIcyst equation had the highest overall discriminate performance regarding mid-term mortality (AUC 0.782+/-0.20) and outperformed all other equations (rho<0.001 in all comparisons). When compared with the MDRD-4 formula, the CKD-EPIcyst equation accurately reclassified a significant percentage of patients into more appropriate risk categories (net reclassification improvement index of 11.9% (p=0.003)). The CKD-EPIcyst equation added prognostic power to the Global Registry of Acute Coronary Events (GRACE) score in the prediction of mid-term mortality. CONCLUSION: The CKD-EPIcyst equation provides a novel and improved method for assessing the mid-term mortality risk in patients admitted for acute coronary syndrome, outperforming the most widely used formula (MDRD-4), and improving the predictive value of the GRACE score. These results reinforce the added value of cystatin C as a risk marker in these patients. PMID- 25740221 TI - Methods for association analysis and meta-analysis of rare variants in families. AB - Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code. PMID- 25740223 TI - Advanced cardiovascular life support algorithm for the management of the hospitalized unresponsive patient on continuous flow left ventricular assist device support outside the intensive care unit. AB - Over the past decade, continuous flow left ventricular assist devices (CF-LVADs) have become the mainstay of therapy for end stage heart failure. While the number of patients on support is exponentially growing, at present there are no American Heart Association or European Society of Cardiology Advanced Cardiovascular Life Support guidelines for the management of this unique patient population. We propose an algorithm for the hospitalized unresponsive CF-LVAD patient outside of the intensive care unit setting. Key elements of this algorithm are: creation of a dedicated LVAD code pager and LVAD code team; early assessment and correction of LVAD malfunction; early determination of blood flow using Doppler technique in carotid and femoral arteries; prompt administration of external chest compressions in the absence of Doppler flow; bedside veno-arterial extracorporeal membranous oxygenation support if no response to resuscitation measures; and early consideration for stroke. PMID- 25740224 TI - Policies, land use, and water resource management in an arid oasis ecosystem. AB - This paper addresses two questions concerning the relationship between state policies and environmental transformation in China in the past four decades. The first one deals with the promotion of agricultural productivity since the 1980s; the second, the water conservation measures as a response to the water crisis that peaked in the early 2000s. We had chosen Minqin County in northwestern China, one of the most fragile arid oasis systems in the world, as the study area. We found that the irrigated farmland in up and midstream areas had greatly expanded between the 1980s and the 2000s under the government policy of promoting commodity grain production. As a result, the runoff flowing into Minqin Oasis had reduced 80 % from the 1950s to early 2000s. Irrigated farmland in Minqin Oasis expanded 15.76 % from 1995 to 2000. In the 2000s, because of the changing policy discourse that has shifted from productivity to conservation, a new set of environmentally framed policies has restructured agricultural production in Minqin by 2005. These new policies included establishing a watershed-level water management system, promoting drought resistant crops, introducing water-saving irrigation measures, and forced reduction of irrigated farming acreage. These policies have produced positive results in terms of greater coverage of vegetation, rising ground water table, and reduction of evaporation. Nevertheless, new policies have also brought new challenges to both farmers and policy makers to keep the balance between poverty reduction and environmental sustainability in Minqin Oasis in the historically poor region in China's Northwest. PMID- 25740225 TI - Allelopathic effect of a native species on a major plant invader in Europe. AB - Biological invasions have become a major global issue in ecosystem conservation. As formalized in the "novel weapon hypothesis", the allelopathic abilities of species are actively involved in invasion success. Here, we assume that allelopathy can also increase the biotic resistance of native species against invasion. We tested this hypothesis by studying the impact of the native species Sambucus ebulus on the colonization of propagules of the invasive species Fallopiaxbohemica and the subsequent development of plants from these. Achenes and rhizome fragments from two natural populations were grown in a greenhouse experiment for 50 days. We used an experimental design that involved "donor" and "target" pots in order to separate resource competition from allelopathy. An allelopathic treatment effect was observed for plant growth but not for propagule establishment. Treatment affected, in particular, the growth of Fallopia plants originating from achenes, but there was less influence on plants originating from rhizomes. By day 50, shoot height had decreased by 27% for plants originating from rhizomes and by 38% for plants originating from achenes. The number of leaves for plants originating from achenes had only decreased by 20%. Leaf and above- and below-ground dry masses decreased with treatment by 40, 41 and 25% for plants originating from rhizomes and 70, 61 and 55% for plants originating from achenes, respectively. S. ebulus extracts were analysed using high-performance chromatography, and the choice of test molecules was narrowed down. Our results suggest native species use allelopathy as a biotic containment mechanism against the naturalization of invasive species. PMID- 25740227 TI - Long-term follow-up of biliary complications after adult right-lobe living donor liver transplantation. AB - INTRODUCTION: Long-term biliary complications after living donor liver transplantation (LDLT) are not well described in the literature. This study was undertaken to determine the long-term impact of biliary complications after adult right-lobe LDLT. METHODS: This retrospective review analyzed an 11-yr experience of 344 consecutive right-lobe LDLTs with at least two yr of follow-up. RESULTS: Biliary leaks occurred in 50 patients (14.5%), and strictures occurred in 67 patients (19.5%). Cumulative biliary complication rates at 1, 2, 5, and 10 yr were 29%, 32%, 36%, and 37%, respectively. Most early biliary leaks were treated with surgical drainage (N = 29, 62%). Most biliary strictures were treated first with endoscopic retrograde cholangiography (42%). There was no association between biliary strictures and the number of ducts (hazard ratio [HR] 1.017 [0.65 1.592], p = 0.94), but freedom from biliary stricture was associated with a more recent era (2006-2010) (HR 0.457 [0.247-0.845], p = 0.01). Long-term graft survival did not differ between those who had or did not have biliary complications (66% vs. 67% at 10 yr). CONCLUSIONS: Biliary strictures are common after LDLT but may decline with a center's experience. With careful follow-up, they can be successfully treated, with excellent long-term graft survival rates. PMID- 25740226 TI - Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPbeta-associated mechanism. AB - BACKGROUND: Polymorphisms in inflammation-related genes have been associated with a risk of gastric carcinoma (GC). However, the biological mechanisms underlying these associations are still elusive. Our objective was to determine whether chronic inflammation-associated IL1Beta signalling, as seen in the context of Helicobacter pylori infection, could be linked to gastric carcinogenesis by modulating the behaviour of gastric epithelial cells. METHODS: The effect of IL1B was assessed by studying the expression and activation status of the IL1Beta activated transcription factors C/EBPbeta and CREB in GC cell lines. Interaction between CREB and C/EBPbeta was explored through interference RNA, chromatin immunoprecipitation and chemical inhibition. CREB and C/EBPbeta expression was analysed in 66 samples of primary GC and in normal gastric mucosa. GC cell growth was analysed in vitro by BrdU incorporation and in vivo employing a chicken embryo chorioallantoic membrane model. RESULTS: We found that IL1B regulates the expression/activation status of both C/EBPbeta and CREB in GC cells through an ERK1/2-dependent mechanism. Our results show that CREB is a direct transactivator of CEBPB, acting as an upstream effector in this regulatory mechanism. Furthermore, we found CREB to be overexpressed in 94 % of GC samples and significantly associated with C/EBPbeta expression (P < 0.05). Finally, we demonstrated both in vitro and in vivo that CREB can mediate IL1B-induced GC cell proliferation. CONCLUSIONS: Our results support the hypothesis that the effect of chronic inflammation on gastric carcinogenesis, as seen in the context of genetically susceptible individuals infected with Helicobacter pylori, includes the modulation of signalling pathways that regulate survival mechanisms in epithelial cells. IL1B is able to increase the expression/activation status of CREB and its target gene C/EBPbeta, which are mandatory for GC cell survival. Our results may help inform new strategies for the prevention and treatment of GC, including the control of chronic inflammation. PMID- 25740229 TI - Shoulder arthroplasty and its effect on strain in the subscapularis muscle. AB - BACKGROUND: Increasing the thickness of the prosthetic humeral head on subscapularis strain in patients undergoing total shoulder arthroplasty has not been elucidated. The optimal postoperative rehabilitation for total shoulder arthroplasty that does not place excessive strain on the subscapularis is not known. We hypothesize that the use of expanded non-anatomic humeral heads during shoulder replacement will cause increased tension in the repaired subscapularis. We identified a recommended passive range of motion program without invoking an increase in tension in the repaired subscapularis, and determined the impact of the thickness of the humeral head on subscapularis strain. METHODS: Eight fresh frozen, forequarter cadaver specimens were obtained. An extended deltopectoral incision was performed and passive range-of-motion exercises with the following motions were evaluated: external rotation, abduction, flexion, and scaption. An optical motion analysis system measured strain in the subscapularis. The same protocol was repeated after performing a subscapularis osteotomy and after placement of an anatomic hemiarthroplasty of three different thicknesses. FINDINGS: For abduction and forward flexion, we observed a trend of decreasing strain of the subscapularis, as the laxity is removed with increasing humeral head component thickness. With the short humeral head, strain was similar to native joint with passive scaption and flexion but not with external rotation or abduction. INTERPRETATION: The passive range of motion that minimizes tension on the subscapularis is forward flexion and scaption. Therefore, passive forward flexion or scaption does not need to be limited, but external rotation should have passive limits and abduction should be avoided. PMID- 25740231 TI - Discrepant results for smoking and cessation among electronic cigarette users. PMID- 25740230 TI - APLP1 promotes dFoxO-dependent cell death in Drosophila. AB - The amyloid precursor like protein-1 (APLP1) belongs to the amyloid precursor protein family that also includes the amyloid precursor protein (APP) and the amyloid precursor like protein-2 (APLP2). Though the three proteins share similar structures and undergo the same cleavage processing by alpha-, beta- and gamma secretases, APLP1 shows divergent subcellular localization from that of APP and APLP2, and thus, may perform distinct roles in vivo. While extensive studies have been focused on APP, which is implicated in the pathogenesis of Alzheimer's disease, the functions of APLP1 remain largely elusive. Here we report that the expression of APLP1 in Drosophila induces cell death and produces developmental defects in wing and thorax. This function of APLP1 depends on the transcription factor dFoxO, as the depletion of dFoxO abrogates APLP1-induced cell death and adult defects. Consistently, APLP1 up-regulates the transcription of dFoxO target hid and reaper-two well known pro-apoptotic genes. Thus, the present study provides the first in vivo evidence that APLP1 is able to induce cell death, and that FoxO is a crucial downstream mediator of APLP1's activity. PMID- 25740232 TI - Metabolism and pharmacokinetics of radium-223 in prostate cancer. AB - INTRODUCTION: Prostate cancer metastatic to bone is a cause of significant morbidity and mortality. Bone pain and other skeletal events negatively impact the quality of life in patients who might otherwise be functioning well. As such, there has been intense interest in the development of strategies and pharmaceuticals to address this problem. AREAS COVERED: The authors reviewed the current literature for articles relevant to metastatic prostate cancer, clinical radiopharmaceuticals, castrate-resistant prostate cancer and development of Radium-223 . The authors have referenced primary literature, clinical trials and relevant review articles that summarize the history, development and current utilization of radiopharmaceuticals for management of bone metastases from prostate cancer. EXPERT OPINION: Radium-223 is the first radiopharmaceutical with an overall survival benefit approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastasis and no known visceral metastatic disease. The additional benefit of clinically significant improved overall survival should lead to exploration of whether this agent can be used earlier in the treatment algorithm or combined with chemotherapy or androgen deprivation therapy. An individualized approach needs to be tailored to each patient based on their overall symptoms, disease burden, hematologic profile and goals of care. PMID- 25740233 TI - MRI-based evidence for myocardial involvement in women with hypereosinophilic syndrome. AB - PURPOSE: The aim of the study was to assess the presence and spectrum of cardiac abnormalities identified by cardiac magnetic resonance (CMR) in women with hypereosinophilic syndrome (HES) of undefined etiology, who present with normal electrocardiography (ECG) and transthoracic echocardiography (TTE) and no history of heart disease. METHODS: Ten women (mean age, 48 +/- 14 years) with HES of undefined etiology, normal ECG and TTE, and no history of heart disease underwent CMR. RESULTS: CMR showed cardiac abnormalities in 6 subjects. Five patients had nonischemic late gadolinium enhancement (LGE) lesions within the left ventricular (LV) myocardium, and 3 patients demonstrated CMR evidence of myocardial inflammation. The LV ejection fraction was 68.5 +/- 5.7%, and the end-diastolic volume index was 62.7 +/- 14.7 mL/m(2). The maximum measured blood eosinophil count correlated with LVLGE volume (r = 0.80, P = 0.006) and was 11374 +/- 6242 cells/MUL and 4114 +/- 2972 cells/MUL (P = 0.047) in patients with and without LGE lesions, respectively. The actual blood eosinophil count in subjects with and without CMR evidence of myocarditis was 1058 +/- 520 cells/MUL and 354 +/- 377 cells/MUL (P = 0.04), respectively. CONCLUSIONS: Despite normal ECG, TTE, and absence of history of heart disease, women with HES of unknown etiology frequently demonstrate cardiac abnormalities on CMR, the presence and extent of which are related to blood eosinophil count. PMID- 25740234 TI - MR-based computational fluid dynamics with patient-specific boundary conditions for the initiation of a sidewall aneurysm of a basilar artery. AB - We performed 3-dimensional cine phase-contrast magnetic resonance-based computational fluid dynamics for a basilar artery that developed a sidewall aneurysm over a 25-month period. There was an area with high gradient oscillatory number in the location of the future aneurysm ostium and an area with high wall shear stress (WSS) and high spatial WSS gradient at the distal edge of the future aneurysm. These could be biomarkers for development of intracranial aneurysms. PMID- 25740235 TI - Optimization and Clinical Feasibility of Free-breathing Diffusion-weighted Imaging of the Liver: Comparison with Respiratory-Triggered Diffusion-weighted Imaging. AB - PURPOSE: We compared the image quality of free-breathing diffusion-weighted imaging (FB-DWI) to that of respiratory-triggered DWI (RT-DWI) after proper optimization. MATERIALS AND METHODS: Three healthy subjects were scanned to optimize magnetic resonance (MR) parameters of FB-DWI to improve image quality, including spatial resolution, image noise, and chemical shift artifacts. After this optimization, we scanned 32 patients with liver disease to assess the clinical feasibility of the optimized FB-DWI. Of the 32 patients, 14 had a total of 28 hepatocellular carcinomas (HCCs), four had a total of 15 metastatic liver tumors, and the other 14 had no tumor. Qualitatively, we compared the image quality scores of FB-DWI with those of RT-DWI with the Wilcoxon signed-rank test. Quantitatively, we compared the signal-to-noise ratios (SNRs) of the liver parenchyma, lesion-to-nonlesion contrast-to-noise ratios (CNRs) and apparent diffusion coefficient (ADC) values of the liver parenchyma and liver tumor by the paired t-test. RESULTS: The average scores of image quality for sharpness of liver contour, image noise, and chemical shift artifacts were significantly higher for FB-DWI than RT-DWI (P < 0.05). SNRs, CNRs, and ADC values of the liver parenchyma and tumors did not differ significantly between the 2 DWI methods. CONCLUSION: Compared with RT-DWI, the optimized FB-DWI provided better spatial resolution, fewer artifacts, and comparable SNRs, lesion-to-nonlesion CNRs, and ADC values. PMID- 25740236 TI - Magnetic resonance microscopy of chemically fixed human embryos at high spatial resolution. AB - We acquired magnetic resonance (MR) microscopic images of chemically fixed human embryos of Carnegie stages 16 to 22 with a large image matrix (256 * 256 * 512) using an MR microscope that we developed with a 9.4-tesla vertical wide-bore superconducting magnet and a dual-channel receiver system to extend the dynamic range of the MR signal. The images showed clear anatomical structures at spatial resolutions of (40 um)(3) to (60 um)(3). We concluded that the experimental technique we developed will aid construction of the next anatomical database of the collection of chemically fixed human embryos. PMID- 25740237 TI - Pseudonormal Corticomedullary Differentiation of the Kidney Assessed on T1 weighted Imaging for Chronic Kidney Disease Patients with Cirrhosis. AB - PURPOSE: We investigated whether corticomedullary differentiation (CMD) increased to a pseudonormal appearance on T1-weighted magnetic resonance (MR) images in patients with chronic kidney disease (CKD) with cirrhosis compared with patients with CKD without chronic liver disease. METHODS: We assessed CMD on T1-weighted MR images of 32 patients with CKD with liver cirrhosis and 32 age-matched patients with CKD without liver cirrhosis, grading CMD visualization as good, moderate, or poor. We calculated quantitative CMD by the ratio of the signal intensity of the cortex to that of the medulla. RESULTS: The proportions of patients in each of the good, moderate, and poor groups differed significantly between those with and without liver cirrhosis (P = 0.048). In patients with CKD with liver cirrhosis, the estimated glomerular filtration rate (eGFR) differed between those with poor CMD and those with good or moderate CMD (P < 0.01) but not between those with good and those with moderate CMD. In patients with CKD without cirrhosis, the eGFR differed significantly among the good, moderate, and poor CMD groups (P < 0.05). We observed no significant correlation between CMD and eGFR in patients with and without cirrhosis (P < 0.05, r = 0.62). CONCLUSION: CMD of the kidney had a pseudonormal appearance on T1-weighted MR imaging in patients with CKD with cirrhosis. PMID- 25740239 TI - Susceptibility-weighted Imaging of Ovarian Torsion: A Case Report. AB - We report findings of magnetic resonance imaging including susceptibility weighted imaging (SWI) of the subacute torsion of an ovarian fibrothecoma in a patient with renal dysfunction. Although venous thrombosis within the vascular pedicle mimicked a malignant tumor, showing high signal intensity on T2-weighted images and diffusion-weighted imaging, we diagnosed ovarian torsion on SWI without the administration of contrast medium, aided by the prominent susceptibility-induced signal void caused by the thrombosis. PMID- 25740238 TI - Inflammatory Pseudotumor-like Follicular Dendritic Cell Tumor of the Spleen: Case Report and Review of the Literature. AB - A 74-year-old woman underwent contrast-enhanced (CE) computed tomography (CT) that revealed an enlarging splenic lesion. This splenic tumor was suspected as metastasis because the patient had been diagnosed with right breast cancer with lung and right axillary lymph node metastases 4 years earlier and had undergone surgery and hormone therapy at another hospital. T2-weighted imaging of magnetic resonance (MR) imaging demonstrated the tumor with slightly high intensity with a rim of low intensity at the margin. On dynamic contrast-enhanced (DCE)-MR imaging after intravenous administration of gadolinium diethylenetriamine pentaacetic acid, delayed enhancement was observed in the center and margin of the tumor. On positron emission tomography with 2-deoxy-2-[18F] fluoro-D-glucose (FDG) integrated with CT, the tumor showed high FDG uptake. Splenic metastasis was considered based on the imaging findings, lack of inflammation on laboratory data, and clinical course, so she underwent splenectomy. Histopathologically, the tumor was encapsulated by a fibrous structure, which was depicted as the rim at the tumor margin on T2-weighted imaging and DCE-MR imaging. Immunohistochemical study allowed the diagnosis of inflammatory pseudotumor (IPT)-like follicular dendritic cell tumor (FDCT). FDCT is a primary neoplasm of lymph nodes that shows features of follicular dendritic cell differentiation, and it is rare at the spleen. Differential diagnosis is difficult between IPT-like FDCT and similar splenic tumors, such as IPT, splenic metastases, hamartoma and hemangioma. However, in addition to the enhancement pattern within a tumor on DCE-MR imaging, detection of the capsular-like rim on MR imaging might aid the diagnosis of splenic IPT-like FDCT. PMID- 25740240 TI - Noninvasive Evaluation of Trunk Muscle Recruitment after Trunk Exercises using Diffusion-weighted MR Imaging. AB - PURPOSE: We evaluated trunk muscle recruitment in abdominal and back exercises with magnetic resonance (MR) diffusion-weighted imaging. METHODS: Twelve men performed bent-knee sit-up, crunch, trunk lateral flexion, and trunk extension exercises. We obtained axial diffusion-weighted images of the trunk before and after each exercise using a 1.5-tesla MR system, calculated apparent diffusion coefficient (ADC) values from the right and left rectus abdominis, lateral abdominal, psoas major, quadratus lumborum, and intrinsic back muscles to evaluate the activity of these muscles during each exercise, and compared ADC values before and after exercise using a paired t-test. RESULTS: The ADCs of the rectus abdominis (right, +19.1%; left, +11.7%), lateral abdominal (right, +15.5%; left, +14.1%), and psoas major (right, +14.8%; left, +15.9%) muscles on both sides increased after the bent-knee sit-up (P < 0.01). The ADCs of the rectus abdominis (right, +16.8%; left, +10.2%) and lateral abdominal (right, +8.4%; left, +7.0%) muscles on both sides increased after the crunch exercise (P < 0.01). Trunk lateral flexion resulted in increased ADC on only the right side of all of the muscles (rectus abdominis, +12.3%; lateral abdominal muscles, +20.3%; quadratus lumborum, +17.1%; intrinsic back muscles, +12.0%; psoas major, +15.4%) (P < 0.01). The ADCs of the lateral abdominal (right, +5.2%; left, +5.6%), quadratus lumborum (right, +6.0%; left, +3.0%), and intrinsic back (right, +13.2%; left, +14.6%) muscles on both sides were elevated after trunk extension (right lateral abdominal muscles and left quadratus lumborum, P < 0.05; other muscles, P < 0.01). CONCLUSION: Diffusion-weighted imaging reveals the recruitment patterns of superficial and deep trunk muscles in abdominal and back exercises through exercise-induced activation in intramuscular water movement. PMID- 25740241 TI - Intersite Reliability of Diffusion Tensor Imaging on Two 3T Scanners. AB - We report the intersite scan reliability of diffusion tensor imaging (DTI) parameters using identical 3T scanners and acquisition protocols at 2 sites. Voxel-based analysis revealed several regions with significant intersite differences. The intersite reliability of DTI measures showed coefficients of variation below 4% in tract-specific analysis (TSA) and below 6% in atlas-based analysis. Given the excellent reliability of TSA, our results suggest it as a promising and useful tool for multicenter DTI studies. PMID- 25740242 TI - Evaluation of Regional White Matter Volume Reduction after Diffuse Axonal Injury using Voxel-based Morphometry. AB - PURPOSE: We developed a new and convenient method that employs voxel-based morphometry (VBM) to evaluate regional reduction in the volume of white matter after diffuse axonal injury (DAI). METHODS: We studied 29 patients with moderate cognitive disability after DAI. Each subject underwent 3-dimensional volumetric magnetic resonance (MR) imaging. Images were preprocessed automatically using stand-alone software running on a Windows PC for VBM of volumetric MR imaging utilizing a statistical parametric mapping (SPM) version 8 software engine and an algorithm for diffeomorphic anatomic registration through exponentiated lie algebra (DARTEL). We then computed a Z-score for all coordinates on the white matter, which represented the relative reduction in white matter volume. Finally, we used voxel-based stereotactic extraction estimation (vbSEE) to compute the extent of regional reduction in the volume of white matter (rWMVR) for each region of interest (ROI), defined as the rate of coordinates with Z-scores exceeding 2.0 in the ROI. For each ROI, we used Pearson's correlation analysis to examine the correlation between the extent of regional volume reduction and patient scores on the Wechsler Adult Intelligence Scale III (WAIS-III). RESULTS: We detected marked rWMVR in several ROIs, including the corpus callosum, and rWMVR correlated significantly with performance IQ and processing speed index in the splenium of the corpus callosum. CONCLUSIONS: The results indicate the utility of our applications for the daily clinical evaluation of DAI. That they can be used on a PC and allow acquisition of volumetric data from standard MR images are their advantages. PMID- 25740243 TI - Gadoxetic acid-induced acute transient dyspnea: the perspective of Japanese radiologists. PMID- 25740244 TI - Naphthol AS-E Phosphate Inhibits the Activity of the Transcription Factor Myb by Blocking the Interaction with the KIX Domain of the Coactivator p300. AB - The transcription factor c-Myb is highly expressed in hematopoietic progenitor cells and controls the transcription of genes important for lineage determination, cell proliferation, and differentiation. Deregulation of c-Myb has been implicated in the development of leukemia and certain other types of human cancer. c-Myb activity is highly dependent on the interaction of the c-Myb with the KIX domain of the coactivator p300, making the disruption of this interaction a reasonable strategy for the development of Myb inhibitors. Here, we have used bacterial Autodisplay to develop an in vitro binding assay that mimics the interaction of Myb and the KIX domain of p300. We have used this binding assay to investigate the potential of Naphthol AS-E phosphate, a compound known to bind to the KIX domain, to disrupt the interaction between Myb and p300. Our data show that Naphthol AS-E phosphate interferes with the Myb-KIX interaction in vitro and inhibits Myb activity in vivo. By using several human leukemia cell lines, we demonstrate that Naphthol AS-E phosphate suppresses the expression of Myb target genes and induces myeloid differentiation and apoptosis. Our work identifies Naphthol AS-E phosphate as the first low molecular weight compound that inhibits Myb activity by disrupting its interaction with p300, and suggests that inhibition of the Myb-KIX interaction might be a useful strategy for the treatment of leukemia and other tumors caused by deregulated c-Myb. PMID- 25740245 TI - Hsp27 Inhibition with OGX-427 Sensitizes Non-Small Cell Lung Cancer Cells to Erlotinib and Chemotherapy. AB - Non-small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and EGFR tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. Although Hsp27 is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant-derived cell line (HCC 827Resistant), and sensitivity to erlotinib was examined in Hsp27-overexpressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC-827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427. The effect of OGX-427 in combination with erlotinib was also assessed in mice bearing A549 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, whereas OGX-427 sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 erlotinib-resistant or overexpressing A549 cells. Combining OGX-427 with erlotinib significantly enhanced antitumor effects in vitro and delayed A549 xenograft growth in vivo. OGX-427 also significantly enhanced the activity of cytotoxic drugs used for NSCLC. These data indicate that treatment-induced Hsp27 contributes to the development of resistance, and provides preclinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib and chemotherapeutics. PMID- 25740247 TI - Quality measures for colonoscopy: where should we be in 2015? AB - Colonoscopy is an effective colorectal cancer (CRC) screening and prevention modality as evidenced by a 30-year decline in both incident colon cancers and CRC mortality in the USA. The USA is unique among the developed countries in its use of colonoscopy as the most common method to screen for CRC. Individual patients gain maximum value from their colonoscopy experience when they undergo a comfortable exam that is of highest quality, during which all polyps are found and removed safely and completely, where their physicians adhere to all appropriate guidelines and when they (or their insurance) pay a reasonable amount for their care. Colonoscopy "quality" publications to date have been focused on how to improve the individual physician's procedural results and this narrow focus has birthed an entire industry (usually based on entering data into a national registry) that is focused on demonstrating a physician's success in achieving a certain threshold performance metric that is usually (a) marginally related to true health outcomes, (b) can be captured from the myriad electronic medical records (EMR) in existence today, and (c) is attainable by most practicing gastroenterologists. Medical societies have worked diligently to link these registries and recognition programs to commercial or federal payer-based incentive funds. As health care reform drives massive consolidation of delivery systems and reimbursement moves toward population-level two-sided financial risk models, our current measurement infrastructure will become irrelevant. The focus on "value" and the Triple Aim will drive development of a radically different approach. The process by which individual gastroenterologists (or practices) demonstrate the value of colonoscopy as a colorectal cancer (CRC) prevention tool will change dramatically. Essentially, six measures will be reported by a health system: (1) percent of eligible population screened, (2) access to colonoscopy services, (3) complication rates, (4) patient experience scores, (5) episode (bundle) cost, and (6) frequency with which interval cancers occur after a colonoscopy exam (likely using a 3-year interval). Each gastroenterologist within a health system will be evaluated using familiar metrics (cecal intubation, withdrawal time, adenoma detection rate) but these results will likely be used internally to determine whether they are included in a provider network. If they continue to be used in commercial or government incentive programs, then the enterprise electronic medical record will be constructed to populate external programs directly. Population-level metrics (listed above) will determine whether higher cost provider networks (including academic health centers) who might deliver better health outcomes can compete successfully for regional market share with lower cost providers. This article will outline a plan for a health system initiative focused on provision of colonoscopy for CRC prevention; a plan that will help a group of gastroenterologists (whether employed within a health system or independent) demonstrate why they should be a preferred provider and whether they will survive and thrive in the coming world of accountable care. PMID- 25740248 TI - Radiofrequency ablation for Barrett's dysplasia: past, present and the future? AB - Barrett's oesophagus is the only know pre-cursor to oesophageal adenocarcinoma. The incidence of OAC is growing rapidly in the western world with a poor prognosis for most with a 5-year survival of only 15%. The approach to treating patients with neoplasia arising within BE has dramatically changed in the past 5 years. Resection of visible lesions with endoscopic mucosal resection followed by field ablation with radio-frequency ablation is now the accepted standard of care in these patients worldwide. This combined approach has shown high rates of disease reversal in several high quality clinical trials but also large volume registry studies. As well as being a minimally invasive and oesophageal sparing interventions compared to surgery with oesophagectomy, endoscopic therapy has proved to be safe and emerging long-term data show sustained benefit in the majority of patients and low rates of cancer progression. However, in a sub-group of patients, recurrences have been reported after successful endoscopic therapy making it mandatory to follow these patients post therapy. Improvements in endoscopic imaging continue to aid early diagnosis, and in turn, this will allow clinicians the ability to offer patient's treatment at an early stage. PMID- 25740249 TI - Management of hepatic adenomatosis. AB - Hepatic adenomatosis (HeAs) is a rare clinical entity defined by the presence of 10 or more hepatic adenomas (HA) within the background of an otherwise normal liver parenchyma, in the absence of glycogen storage disease or anabolic steroid use. HA is a benign tumor associated with oral contraceptive use. Recent advances in pathogenesis and classification of HA have questioned the distinction between these two diseases. HA are currently classified into four different subtypes with genotypic and phenotypic correlation: HNF-1a inactivated HA, B-catenin activated HA, inflammatory HA, and undetermined subtype. The clinical presentation of HA depends on the lesion size and the subtype. MRI using hepatospecific contrast agents is helpful in diagnosing the most common subtypes. When diagnosis is uncertain, biopsy with immunohistochemistry is used to diagnose and classify the lesions. Management is governed by the molecular subtype and tumor size. Pregnancy is not routinely discouraged but management is individualized. PMID- 25740250 TI - Liver transplantation for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is an increasing problem in the USA and worldwide. Current treatments for HCC include chemoembolization, radioembolization, liver resection, and liver transplantation in the setting of selected cirrhotic patients. Liver transplantation for HCC was controversial initially, but is now widely accepted as a curative approach. Cirrhotic patients who meet standards for transplantation and have a tumor burden within Milan criteria are eligible for transplantation and receive Model for End-Stage Liver Disease (MELD) exception points once listed. Given the decline in availability of donor organs, rewarding MELD exception points and performing liver transplants in these patients remain controversial. Despite this, various guidelines propose expanding eligibility criteria for cirrhotics with HCC, due to post-transplant outcomes comparable to patients transplanted without HCC. Following the transplant, issues include optimizing the type and amount of immunosuppression and screening for and treating recurrence of HCC. PMID- 25740251 TI - Strategically designed biomodel: engineering C3-C4 cleavage of D-fructose. AB - Amongst a library of aldolase inspired, rationally designed compounds, the acridine derivative carrying a (S)-Tyr-Gly-(S)-Lys tripeptide selectively effected C3-C4 scissoring of D-fructose and produced D-glyceraldehyde and dihydroxyacetone. PMID- 25740253 TI - Involvement of histone H2B monoubiquitination in the regulation of mouse preimplantation development. AB - Histone H2B monoubiquitination (H2Bub1) plays an important role in developmental regulation in various vertebrate species. However, the role of H2Bub1 in mammalian preimplantation development remains unclear. In the present study, we examined the role of H2Bub1 in the regulation of mouse preimplantation development. Based on immunocytochemical analysis using an anti-H2Bub1 antibody, no H2Bub1 signal was detected in the metaphase chromosomes of unfertilized oocytes or the pronuclei of early 1-cell stage embryos, but a weak signal was observed in late 1-cell stage embryos. The signal increased after cleavage into the 2-cell stage, and thereafter a strong signal was observed until the blastocyst stage. To assess the significance of H2Bub1 in the regulation of preimplantation development, RNF20 (an H2B-specific ubiquitin E3 ligase) was knocked down using small interfering RNA (siRNAs). In embryos treated with siRNA, the levels of Rnf20 mRNA and H2Bub1 decreased at the 4-cell and morula stages. Although these embryos developed normally until the morula stage, only one-third developed into the blastocyst stage. These results suggested that H2Bub1 is involved in the regulation of preimplantation development. PMID- 25740252 TI - Regulation of secondary follicle growth by theca cells and insulin-like growth factor 1. AB - Ovaries contain follicles at various stages of development, including primordial, primary, secondary, antral and Graafian follicles. Although the growth of these follicles is controlled to maintain regular ovulation, the mechanism through which this occurs remains unclear. In our study, we found that the growth rate of cultured secondary follicles separated from mice ovaries differed between follicles. After 4 days of culture, the size of some secondary follicles was markedly increased, while that of others had either slightly increased, remained unchanged or shrunk. We compared the expression levels of growth factors between these secondary follicles and found that the growth rate of cultured secondary follicles correlated with the expression level of insulin-like growth factor 1 (Igf1) mRNA. Igf1 mRNA expression level in secondary follicles containing theca cells was higher than that in secondary follicles without theca cells, and the granulosa cell proliferation around follicles containing theca cells was increased. Furthermore, an IGF1 inhibitor also inhibited the granulosa cell proliferation, and administration of IGF1 to secondary follicles without growth promoted granulosa cell proliferation. These results indicated that the theca cells of secondary follicles induced the expression of IGF1 and promoted the follicle growth. PMID- 25740254 TI - 'Life does not make it easy to breast-feed': using the socio-ecological framework to determine social breast-feeding obstacles in a low-income population in Tijuana, Mexico. AB - OBJECTIVE: Breast-feeding rates reflect sociodemographic discrepancies. In Mexico, exclusive breast-feeding under 6 months of age has deteriorated among the poor, rural and indigenous populations from 1999 to 2012. Our objective of the present study was to identify the main social obstacles to breast-feeding in a low-income population in Tijuana, Mexico. DESIGN: Qualitative study using a socio ecological framework for data collection. SETTING: Low-income communities in Tijuana, Mexico. SUBJECTS: Mothers (n 66), fathers (n 11), grandparents (n 27) and key informants (n 25). RESULTS: One hundred and twenty-nine individuals participated in the study: six focus groups (n 53) and fifty-one interviews among mothers, fathers and grandparents; and twenty-five interviews among key informants. Seven social themes were identified: (i) embarrassment to breast-feed in public; (ii) migrant experience; (iii) women's role in society; (iv) association of formula with higher social status; (v) marketing by the infant food industry; (vi) perception of a non-breast-feeding culture; and (vii) lack of breast-feeding social programmes. CONCLUSIONS: Socio-structural factors influence infant feeding practices in low-income communities in Tijuana. We hypothesize that messages emphasizing Mexican traditions along with modern healthy practices could help to re-establish and normalize a breast-feeding culture in this population. The target audience for these messages should not be limited to mothers but also include family, health-care providers, the work environment and society as a whole. PMID- 25740256 TI - Photo-control of the magnetic properties of Dy(III) and Ho(III) homometal coordination polymers bridged by a diarylethene ligand. AB - Two-dimensional Dy(III) and Ho(III) homometal coordination polymers containing the photochromic ligand 1,2-bis(5-carboxyl-2-methyl-3 thienyl)perfluorocyclopentene (DTE) with the general formula [Ln2(DTE)3(bipyridine)2(H2O)2]n (Ln = Dy and Ho) were obtained, and the magnetic properties of their open (Dy-o and Ho-o) and closed forms (Dy-c and Ho-c) were investigated. The Dy complexes exhibited slow magnetic relaxation without an external dc field. The magnetic properties of the Dy complexes were irreversibly affected by the conformation of the ligand. PMID- 25740257 TI - Adaptive responses of Bacillus cereus ATCC14579 cells upon exposure to acid conditions involve ATPase activity to maintain their internal pH. AB - This study examined the involvement of ATPase activity in the acid tolerance response (ATR) of Bacillus cereus ATCC14579 strain. In the current work, B. cereus cells were grown in anaerobic chemostat culture at external pH (pHe ) 7.0 or 5.5 and at a growth rate of 0.2 h-1 . Population reduction and internal pH (pHi ) after acid shock at pH 4.0 was examined either with or without ATPase inhibitor N,N'-dicyclohexylcarbodiimide (DCCD) and ionophores valinomycin and nigericin. Population reduction after acid shock at pH 4.0 was strongly limited in cells grown at pH 5.5 (acid-adapted cells) compared with cells grown at pH 7.0 (unadapted cells), indicating that B. cereus cells grown at low pHe were able to induce a significant ATR and Exercise-induced increase in ATPase activity. However, DCCD and ionophores had a negative effect on the ability of B. cereus cells to survive and maintain their pHi during acid shock. When acid shock was achieved after DCCD treatment, pHi was markedly dropped in unadapted and acid adapted cells. The ATPase activity was also significantly inhibited by DCCD and ionophores in acid-adapted cells. Furthermore, transcriptional analysis revealed that atpB (ATP beta chain) transcripts was increased in acid-adapted cells compared to unadapted cells before and after acid shock. Our data demonstrate that B. cereus is able to induce an ATR during growth at low pH. These adaptations depend on the ATPase activity induction and pHi homeostasis. Our data demonstrate that the ATPase enzyme can be implicated in the cytoplasmic pH regulation and in acid tolerance of B. cereus acid-adapted cells. PMID- 25740255 TI - Interferon-lambda rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. AB - Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single nucleotide polymorphism (rs12979860) in the intronic region of interferon-lambda4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology independent predictor of tissue inflammation and fibrosis. PMID- 25740258 TI - Cochlear implant candidates with psychogenic hearing loss. AB - CONCLUSIONS: Specific requests for cochlear implantations by persons with psychogenic hearing loss are a relatively new phenomenon. A number of features seems to be over-represented in this group of patients. The existence of these requests stresses the importance of auditory brainstem response (ABR) measurements before cochlear implantation. OBJECTIVE: To describe the phenomenon of patients with psychogenic hearing losses specifically requesting cochlear implantation, and to gain first insights into the characteristics of this group. METHODS: Analysis of all cases seen between 2004 and 2013 at the University Hospital of Bern, Switzerland. RESULTS: Four cochlear implant candidates with psychogenic hearing loss were identified. All were female, aged 23-51 years. Hearing thresholds ranged from 86 dB to 112 dB HL (pure-tone average 500-4000 Hz). ABRs and otoacoustic emissions (OAEs) showed bilaterally normal hearing in two subjects, and hearing thresholds between 30 and 50 dB in the other two subjects. Three subjects suffered from depression and one from a pathologic fear of cancer. Three had a history of five or more previous surgeries. Three were smokers and three reported other close family members with hearing losses. All four were hearing aid users at the time of presentation. PMID- 25740259 TI - Autoimmunity conferred by chs3-2D relies on CSA1, its adjacent TNL-encoding neighbour. AB - Plant innate immunity depends on the function of a large number of intracellular immune receptor proteins, the majority of which are structurally similar to mammalian nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) proteins. CHILLING SENSITIVE 3 (CHS3) encodes an atypical Toll/Interleukin 1 Receptor (TIR)-type NLR protein with an additional Lin-11, Isl-1 and Mec-3 (LIM) domain at its C-terminus. The gain-of-function mutant allele chs3-2D exhibits severe dwarfism and constitutively activated defense responses, including enhanced resistance to virulent pathogens, high defence marker gene expression, and salicylic acid accumulation. To search for novel regulators involved in CHS3 mediated immune signaling, we conducted suppressor screens in the chs3-2D and chs3-2D pad4-1 genetic backgrounds. Alleles of sag101 and eds1-90 were isolated as complete suppressors of chs3-2D, and alleles of sgt1b were isolated as partial suppressors of chs3-2D pad4-1. These mutants suggest that SAG101, EDS1-90, and SGT1b are all positive regulators of CHS3-mediated defense signaling. Additionally, the TIR-type NLR-encoding CSA1 locus located genomically adjacent to CHS3 was found to be fully required for chs3-2D-mediated autoimmunity. CSA1 is located 3.9 kb upstream of CHS3 and is transcribed in the opposite direction. Altogether, these data illustrate the distinct genetic requirements for CHS3 mediated defense signaling. PMID- 25740260 TI - Genetic Architecture of Sexual Dimorphism in Humans. AB - Males and females differ across a broad spectrum of morphological, physiological, and behavioral characters. In fact, sexually dimorphic traits typically contribute the largest component of phenotypic variance in most taxa that use sex to reproduce. However, we know very little about the mechanisms that maintain these dimorphic states and how these sexually dimorphic traits evolve. Here, we review our current knowledge of the underlying genetic basis of sexual dimorphism in humans. First, we briefly review the etiology of sex differences starting from sex determination's initial switch early in embryogenesis. We then survey recent sex-biased transcriptomic expression literature in order to provide additional insight into the landscape of sex-biased gene expression in both gonadal and non gonadal tissues: from overall prevalence to tissue specificity to conservation across species. Finally, we discuss implications of sex-biased genetic architecture to human health and disease in light of the National Institute of Health's recently proposed initiative to promote study samples from both sexes. PMID- 25740261 TI - CGRP mediate the isosorbide-5-mononitrate cardiovascular response in healthy Chinese male volunteers through a XOR-independent pathway. AB - OBJECTIVES: This study was designed to determine whether xanthine oxidoreductase (XOR) is involved in Isosorbide- 5-mononitrate (IS-5-MN) metabolism, and to elucidate the role of the neuropeptide calcitonin gene-related peptide (CGRP) in the IS-5-MN response. METHODS: In 15 Chinese volunteers, we observed the relationship between baseline XOR-mRNA expression in peripheral blood mononuclear cells (PBMCs) and the response to 20 mg IS-5-MN. IS-5-MN pharmacokinetics profiles, changes in plasma concentrations of CGRP, and CGRPmRNA expression in PBMCs were assessed in vivo and in vitro. RESULTS: Individuals with a lower baseline XOR-mRNA expression showed lower plasma XOR activity and significantly greater changes in SBP (DeltaSBP) after IS-5-MN administration. Individuals with a lower baseline XOR-mRNA expression also showed significantly greater increases in plasma concentrations of CGRP. There were no differences in IS-5-MN AUC between the two groups. IS-5-MN significantly up-regulated the expression of CGRP alpha- and CGRP beta-mRNA in PBMCs, which were not affected by the XOR inhibitor allopurinol. CONCLUSIONS: Our study suggests that CGRP may contribute to the response to IS-5 MN in a XOR-independent pathway. PMID- 25740262 TI - Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects. AB - OBJECTIVES: Assess the safety, tolerability, and pharmacokinetic (PK) profiles of daclatasvir (DCV) and asunaprevir (ASV) in healthy male Japanese subjects. METHODS: AI444-007 and AI447-005 were phase I, double-blind, placebo-controlled, sequential, single-ascending dose (SAD), and multiple-ascending dose (MAD) studies assessing DCV or ASV, respectively. Eight subjects per panel were randomized to study drug or placebo (3 : 1). In the SAD part of each study, subjects received single oral dose DCV 1/10/50/100/200 mg or ASV 200/400/600/900/1,200 mg. In MAD, subjects received 14-day oral multiple dose DCV 1/10/100 mg once-daily or ASV 200/400/600 mg every 12 hours. Serial PK blood sampling occurred from predose to 72-hours postdose or post-last-dose. Safety and tolerability was assessed throughout. RESULTS: 64 (SAD, n = 40; MAD, n = 24) and 65 (SAD, n = 40; MAD, n = 25) subjects were enrolled in AI444-007 and AI447-005, respectively. DCV and ASV were generally well tolerated, with no serious adverse events or clinicallyrelevant changes in vital signs or ECG parameters. Baseline demographic characteristics were comparable across treatment groups in both studies. DCV was readily absorbed, with median tmax of ~ 1 - 2 hours postdose and concentrations declining in a multi-phasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state was achieved between days 4 and 5 of multiple dosing. ASV was readily absorbed, with median tmax of ~ 2 - 4 hours postdose and concentrations declining in a biphasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state appeared to be achieved between days 3 - 5 of multiple dosing. CONCLUSIONS: Results suggest no clinically significant short-term safety signals with DCV and ASV at single or multiple doses in this population. PMID- 25740263 TI - Tacrolimus therapy causes hepatotoxicity in patients with a history of liver disease. AB - OBJECTIVE: Tacrolimus is known to have little hepatotoxicity. Nevertheless, a few case studies have shown liver toxicities of tacrolimus, particularly in patients on multiple medications. This study is a retrospective data analysis on the potential of tacrolimus hepatotoxicity. METHODS: A data analysis was conducted on the electronic medical records (EMRs) of 2,462 Korean patients taking tacrolimus or cyclosporine from 2002 through to 2008. Alanine aminotransferase (ALT) and total bilirubin level (TBL) were also monitored. The maximum ALT, time to reach ALTmax (TALTmax), and TBL(ALTmax) were compared between the tacrolimus and cyclosporine groups. Other possible factors that may aggravate liver function were also investigated. RESULTS: ALTmax and TBL(ALTmax) were higher in the tacrolimus group compared to the cyclosporine group (i.e., 50 IU/L vs. 41 IU/L and 1 mg/dL vs. 0.9 mg/dL, respectively), and TALTmax was shorter (i.e., 101 days vs. 142 days) in the tacrolimus group. In addition, the frequency of ALTmax > 3x upper limit of normal (ULN) (i.e., ALTmax > 120) was significantly increased in the tacrolimus group compared to the cyclosporine group (30% vs. 21%). The severity of tacrolimusinduced liver damage was greater in patients with history of liver disease, as indicated by > two-fold greater ALTmax than that of cyclosporine (i.e., 153 IU/L vs. 65 IU/L). Moreover, the ALTmax was significantly lowered by switching from tacrolimus to cyclosporine in patients with a history of liver disease. In patients with preexisting renal disease, neither tacrolimus nor cyclosporine showed any effect on ALTmax. CONCLUSION: Results indicate that tacrolimus may have a higher risk of inducing liver injury in Korean patients with a history of liver disease and may require close monitoring. PMID- 25740264 TI - Glutamine supplementation and immune function during heavy load training. AB - Athletes with heavy training loads are prone to infectious illnesses, suggesting that their training may suppress immune function. This study sought to determine whether supplementation with the amino acid glutamine, which supports immune health, alters immune function in athletes during heavy load training. 24 athletes were randomly assigned to either an experimental group (n = 12) or a control group (n = 12). Athletes exercised using heavy training loads for 6 weeks. Athletes in the experimental group took 10 g glutamine orally once a day beginning 3 weeks after initial testing, while athletes in the control group were given a placebo. Immune function was assessed by measuring the following immunity markers: CD4+ and CD8+ T cell counts, serum IgA, IgG, and IgM levels, and natural killer (NK) cell activity both before and after the completion of training. The percentages of circulating CD8+ T cells were significantly different before (39.13 +/- 5.87%) and after (26.63 +/- 3.95%) training in the experimental group (p < 0.05). Although CD8+ T cell percentages in the control group were similar before (38.57 +/- 5.79%) and after (37.21 +/- 5.58%) training, the post-training CD8+ T cell percentages were significantly different between the two groups (p < 0.05). The ratios of CD4+/CD8+ cells in the experimental group were significantly different before (0.91 +/- 0.14) and after (1.39 +/- 0.19) training (p < 0.05). The CD4+/CD8+ ratios in the control group were similar before (0.93 A +/- 0.15) and after (0.83 +/- 0.11) training, but the post-training CD4+T/CD8+ T cell ratio was higher in the experimental group than in the control group (p < 0.05). NK cell activity was also significantly different between the two groups after training (experimental, 25.21 +/- 3.12 vs. control, 20.21 +/- 2.59; p < 0.05). However, no differences were observed in serum IgA, IgG, or IgM levels. Thus, glutamine supplementation may be able to restore immune function and reduce the immunosuppressive effects of heavy-load training. PMID- 25740265 TI - Pharmacokinetics of QMF149 in Japanese versus Caucasian subjects: an open-label, randomized phase I study. AB - OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting beta2-agonist, indacaterol (Onbrez(r) Breezhaler(r) for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex(r) Twisthaler(r) for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 MUg and 150/320 MUg via the Breezhaler(r) device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 MUg or 150/320 MUg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations. PMID- 25740266 TI - Impact of pharmacist intervention on preventing nephrotoxicity from vancomycin. AB - OBJECTIVES: To evaluate the impact of pharmacist interventions on preventing nephrotoxicity from vancomycin. METHODS: A pre- to postpharmacist intervention study was performed in the Tsuyama Central Hospital. 508 Patients admitted from May 2007 to May 2012 served as the non-pharmacist intervention group, while 102 patients admitted from June 2012 to November 2013 formed the pharmacist intervention group. Pharmacist interventions were mainly performed for the initial dosage planning, controlling vancomycin prescriptions, and real-time monitoring of medical records before routine therapeutic drug monitoring. The non and pharmacist intervention groups were compared to evaluate the outcomes of pharmacist interventions. RESULTS: By pharmacist interventions, initial trough concentration of vancomycin promptly tightened within the 10 - 20 MUg/mL therapeutic trough concentration range (p < 0.001), and reaching an ineffective or risky trough concentration was avoided. Also, the mean vancomycin trough concentrations of patients with and without nephrotoxicity were 23.9 and 13.9 MUg/mL, respectively. Furthermore, by multivariate logistic regression analysis, significant increased risks of nephrotoxicity in baseline creatinine clearance, and 15 - 20 and over 20 MUg/mL of initial vancomycin trough concentration were observed. Significant decreased risk of nephrotoxicity was gender (male). Although pharmacist intervention showed a trend of 45% decrease in the incidence of nephrotoxicity, there was no significant difference between the pharmacist intervention and non-intervention groups. CONCLUSION: Pharmacist intervention may have an impact on vancomycin therapy from the standpoint of balancing a higher vancomycin trough concentration with risk of nephrotoxicity. PMID- 25740267 TI - Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor. AB - OBJECTIVE: An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. METHODS: The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. RESULTS: Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 MUM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17beta glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 +/- 0.95 MUM, 3.34 +/- 0.64 MUM, and 0.973 +/- 0.11 MUM, respectively. In the presence of steady state pradigastat concentrations, AUC(tau, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(tau, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. CONCLUSION: These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin. PMID- 25740268 TI - Effect of pradigastat, a diacylglycerol acyltransferase 1 inhibitor, on the pharmacokinetics of a combination oral contraceptive in healthy female subjects. AB - OBJECTIVE: We evaluated the potential pharmacokinetic interaction between pradigastat, a potent and selective diacylglycerol acyltransferase 1 inhibitor, and Levora-28(r), a combination oral contraceptive (COC) containing 30 MUg ethinylestradiol (EE) and 150 MUg levonorgestrel (LVG). METHODS: An open-label, single-sequence three-period (period 1, single dose of COC; period 2, pradigastat 100 mg x 3 days followed by 40 mg x 7 days; and period 3, both pradigastat 40 mg and a single dose of COC) study involving 24 healthy female subjects of childbearing potential was conducted. RESULTS: The pharmacokinetic parameters of EE were similar when administered alone or in combination with pradigastat, as the 90% confidence interval (CI) of geometric mean ratios for EE exposure (AUC and C(max)) were all within the range of 0.80 - 1.25. The AUC(infinity), AUC(last), and C(max) of LVG were slightly increased in the presence of pradigastat, the geometric mean ratios (90% CI) were 1.25 (1.16, 1.35), 1.24 (1.15, 1.34), and 1.16 (1.06, 1.27), respectively. CONCLUSIONS: Pradigastat did not elicit clinically relevant changes in the magnitude of Levora-28(r) exposure. Therefore, dose adjustment is not required for Levora-28(r) when co-administered with pradigastat. PMID- 25740269 TI - Osmotic demyelination syndrome after correction of severe hyponatremia associated with pituitrin. AB - Osmotic demyelination syndrome (ODS) may be precipitated by aggressive correction of a hypoosmolar state. We report the case of a 24-year-old woman who developed ODS during rapid correction of asymptomatic hyponatremia caused by pituitrin prescribed for hemoptysis. After hyponatremia correction by NaCl supplementation, the patient developed limb weakness, blurred vision, hand and perioral numbness, and lisp. Magnetic resonance imaging (MRI) revealed bilateral signal hyperintensity of the globus pallidus and caudate nucleus, compatible with extra pontine ODS. These symptoms improved gradually with treatment, and brain MRI ~ 3 months later indicated substantial resolution of ODS. This case serves as a warning to physicians that hypoosmotic correction must be achieved at a controlled rate. PMID- 25740270 TI - Decoding the 'embryonic' nature of embryonal rhabdomyosarcoma. AB - Embryonal rhabdomyosarcoma is one of the major defined histologic variants of rhabdomyosarcoma that is mainly reported in children. The histologic appearance of this neoplastic entity recapitulates normal myogenesis. The tumor cells variably exhibit the different cellular phases of myogenesis ranging from undifferentiated mesenchymal cells to elongated myoblasts, multinucleated myotubes and differentiated muscle fibers. The carefully orchestrated embryonic signaling pathways that are involved in myogenesis, conceivably also result in the genesis of rhabdomyosarcoma; albeit as a corollary to an imbalance. We have attempted to review the pathogenesis of embryonal rhabdomyosarcoma in an endeavor to understand better, how closely it is linked to normal myogenesis in terms of its molecular dynamics and histologic presentation. PMID- 25740271 TI - A straightforward and reliable method for bacterial in planta transcriptomics: application to the Dickeya dadantii/Arabidopsis thaliana pathosystem. AB - Transcriptome analysis of bacterial pathogens is a powerful approach to identify and study the expression patterns of genes during host infection. However, analysis of the early stages of bacterial virulence at the genome scale is lacking with respect to understanding of plant-pathogen interactions and diseases, especially during foliar infection. This is mainly due to both the low ratio of bacterial cells to plant material at the beginning of infection, and the high contamination by chloroplastic material. Here we describe a reliable and straightforward method for bacterial cell purification from infected leaf tissues, effective even if only a small amount of bacteria is present relative to plant material. The efficiency of this method for transcriptomic analysis was validated by analysing the expression profiles of the phytopathogenic enterobacterium Dickeya dadantii, a soft rot disease-causing agent, during the first hours of infection of the model host plant Arabidopsis thaliana. Transcriptome profiles of epiphytic bacteria and bacteria colonizing host tissues were compared, allowing identification of approximately 100 differentially expressed genes. Requiring no specific equipment, cost-friendly and easily transferable to other pathosystems, this method should be of great interest for many other plant-bacteria interaction studies. PMID- 25740272 TI - Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice. AB - New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult-born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here, we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP expressing retrovirus. Animals were exposed to a reference memory protocol for 10 14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype, and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM. PMID- 25740273 TI - A population-based cost description study of oral treatment of hospitalized Western Australian children aged younger than 15 years. AB - OBJECTIVES: We sought to analyze the economic cost of a decade of dental hospital admissions in Western Australian children under the age of 15 years and to identify socio-demographic characteristics associated with these costs. METHODS: This study analyzed the cost of 43,937 child patients under the age of 15 years hospitalized for an oral health-related condition, as determined by principal diagnosis International Classification of Diseases (ICD-10AM). The Australian Refine Diagnosis Related Group version 5.1 was used to calculate the direct cost. An analysis of costs was broken down by socioeconomic status, primary place of residency, age, gender, insurance status, and Indigenous status. RESULTS: The total DRG cost of these admissions was approximately AUS$92 million million over 10 years. Most of these funds went toward treating "Dental caries" and "Embedded and impaction" conditions of children under the age of 15 years. Approximately 95 percent of the total cost of hospitalization for oral conditions, over the last decade, accounted for non-Indigenous children. Since 2000, the direct cost of child hospitalization for oral-related conditions has increased to reach $13 million AUD in 2009. CONCLUSIONS: This study identified the substantial economic burden of child oral-related hospitalizations that emphasizes the importance of preventing costly inpatient treatments. PMID- 25740274 TI - [Effect of intraoperative intravenous lidocaine on pain and plasma interleukin-6 in patients undergoing hysterectomy]. AB - BACKGROUND AND OBJECTIVES: Interleukin-6 (IL-6) is a predictor of trauma severity. The purpose of this study was to evaluate the effect of intravenous lidocaine on pain severity and plasma IL-6 after hysterectomy. METHOD: A prospective, randomized, comparative, double-blind study with 40 patients, aged 18-60 years. G1 received lidocaine (2mg.kg(-1).h(-1)) or G2 received 0.9% saline solution during the operation. Anesthesia was induced with O2/isoflurane. Pain severity (T0: awake and 6, 12, 18 and 24hours), first analgesic request, and dose of morphine in 24hours were evaluated. IL-6 was measured before starting surgery (T0), five hours after the start (T5), and 24hours after the end of surgery (T24). RESULTS: There was no difference in pain severity between groups. There was a decrease in pain severity between T0 and other measurement times in G1. Time to first supplementation was greater in G2 (76.0+/-104.4min) than in G1 (26.7+/-23.3min). There was no difference in supplemental dose of morphine between G1 (23.5+/-12.6mg) and G2 (18.7+/-11.3mg). There were increased concentrations of IL-6 in both groups from T0 to T5 and T24. There was no difference in IL-6 dosage between groups. Lidocaine concentration was 856.5+/ 364.1 ng.mL(-1) in T5 and 30.1+/-14.2 ng.mL(-1) in T24. CONCLUSION: Intravenous lidocaine (2mg.kg(-1).h(-1)) did not reduce pain severity and plasma levels of IL 6 in patients undergoing abdominal hysterectomy. PMID- 25740275 TI - [Comparative study between fast and slow induction of propofol given by target controlled infusion: expected propofol concentration at the effect site. Randomized controlled trial]. AB - BACKGROUND AND OBJECTIVE: studies have shown that rate of propofol infusion may influence the predicted propofol concentration at the effect site (Es). The aim of this study was to evaluate the Es predicted by the Marsh pharmacokinetic model (ke0 0.26min(-1)) in loss of consciousness during fast or slow induction. METHOD: the study included 28 patients randomly divided into two equal groups. In slow induction group (S), target-controlled infusion (TCI) of propofol with plasma, Marsh pharmacokinetic model (ke0 0.26min(-1)) with target concentration (Tc) at 2.0-MUg.mL(-1) were administered. When the predicted propofol concentration at the effect site (Es) reached half of Es value, Es was increased to previous Es + 1MUg.mL(-1), successively, until loss of consciousness. In rapid induction group (R), patients were induced with TCI of propofol with plasma (6.0MUg.ml(-1)) at Es, and waited until loss of consciousness. RESULTS: in rapid induction group, Tc for loss of consciousness was significantly lower compared to slow induction group (1.67+/-0.76 and 2.50+/-0.56MUg.mL(-1), respectively, p=0.004). CONCLUSION: the predicted propofol concentration at the effect site for loss of consciousness is different for rapid induction and slow induction, even with the same pharmacokinetic model of propofol and the same balance constant between plasma and effect site. PMID- 25740276 TI - [Prevalence of burnout syndrome among anesthesiologists in the Federal District]. AB - BACKGROUND: burnout syndrome is a result of chronic stress, characterized by emotional exhaustion, depersonalization, and sense of low professional accomplishment. It affects workers under extreme responsibility or those who care for individuals at risk, including anesthesiologists who distanced themselves from the work, patients and colleagues because they feel safer in maintaining indifference. OBJECTIVE: evaluate the prevalence of burnout syndrome and the intensity of its components and identify the characteristics of those with the syndrome among anesthesiologists in the Federal District. METHOD: cross-sectional study with 241 anesthesiologists enrolled in the Society of Anesthesiology of the Federal District. A self-administered questionnaire was used, which included the Maslach Burnout Inventory, demographic, professional, and leisure data. RESULTS: of the 134 completed questionnaires (55.8%), there was a predominance of male (65.6%), aged 30-50 years (67.9%). Significant lower levels of job satisfaction (47.7%), depersonalization (28.3%), and emotional exhaustion (23.1%) were found. Burnout syndrome showed a prevalence of 10.4%, occurring mainly in men (64.2%), aged 30-50 years (64.2%), with over ten years of experience (64.2%), working in night shifts (71.4%), sedentary (57.1%), and not taking courses unrelated to medicine (78.5%). Of the participants, 50.7% had at least one of three criteria to develop the syndrome and only 8.2% have a low risk to manifest it. CONCLUSION: the prevalence of burnout is relevant among anesthesiologists in the Federal District. It is advisable to seek strategies for labor restructuring to reduce stress factors and loss of motivation and increase job satisfaction. PMID- 25740277 TI - [Hyperalgesic effect of subarachnoid administration of phentolamine in mice]. AB - BACKGROUND AND OBJECTIVES: Painful phenomenon is one of the most important and complex experiences. Phentolamine is a non-selective alpha-adrenergic antagonist. The objective of this study was to compare the effect of increasing doses of phentolamine into subarachnoid space in rats in the modulation of painful phenomenon. METHODS: 84 male Wistar rats were divided into formalin and plantar incision groups, subdivided into six subgroups (n=7). Control group (CG) received only saline (10MUL); active subgroups received phentolamine 10MUmg (GF10), 20mg (GF20), 30mg (GF30), 40mg (GF40), and 50g (GF50). In formalin group, pain was induced by injection of 50MUL of 2% formalin in dorsal region of right posterior paw. In plantar incision group, pain was induced by plantar incision and evaluated using Von Frey filaments. Induction and maintenance of anesthesia were performed with 3% halothane for catheter placement into subarachnoid space and plantar incision. Statistical analysis was performed using the JMP program from SAS with 5% significance level. RESULTS: Phentolamine at doses of 20 and 30g increased the algesic response in the intermediate phase of the formalin test. In plantar incision test, it had hyperalgic effect on first, third, fifth, and seventh days at a dose of 10g and on first, third, and fifth days at a dose of 20g and on fifth day at a dose of 30g. CONCLUSION: Subarachnoid administration of phentolamine showed hyperalgesic effect, possibly due to the involvement of different subclasses of alpha-adrenergic receptors in modulating pain pathways. PMID- 25740278 TI - [Reduced fasting time improves comfort and satisfaction of elderly patients undergoing anesthesia for hip fracture]. AB - BACKGROUND AND OBJECTIVES: Patient's satisfaction is a standard indicator of care quality. The aim of this study was to evaluate whether a preoperative oral ingestion of 200mL of a carbohydrate drink can improve comfort and satisfaction with anesthesia in elderly patients with hip fracture. METHOD: Prospective randomized clinical trial conducted in a Brazilian public hospital, with patients ASA I-III undergoing surgery for hip fracture. The control group (NPO) received nothing by mouth after 9:00 p.m. the night before, while patients in the experimental group (CHO) received 200mL of a carbohydrate drink 2-4hours before the operation. Patients' characteristics, subjective perceptions, thirst and hunger and satisfaction were determined in four steps. Mann-Whitney U-test and Fisher exact test were used for comparison of control and experimental groups. A p-value <0.05 was considered significant. RESULTS: A total of 100 patients were included in one of two regimens of preoperative fasting. Fasting time decreased significantly in the study group. Patients drank 200mL 2:59h before surgery and showed no hunger (p <0.00) and thirsty on arrival to OR (p <0.00), resulting in increased satisfaction with the perioperative anesthesia care (p <0.00). CONCLUSIONS: The satisfaction questionnaire for surgical patient could become a useful tool in assessing the quality of care. In conclusion, CHO significantly reduces preoperative discomfort and increases satisfaction with anesthesia care. PMID- 25740279 TI - [Subarachnoid meloxicam does not inhibit the mechanical hypernociception on carrageenan test in rats]. AB - BACKGROUND AND OBJECTIVE: Evaluate the antinociceptive effects of subarachnoid meloxicam on the mechanical hypernociception induced by carrageenan in rats. METHODS: Randomized controlled trial. Eighteen adult male Wistar rats underwent a cannula implantation into the subarachnoid space and were randomly divided into two groups: Group I (GI) received saline solution 5MUL, while Group II (GII) received meloxicam 30mg. The mechanical hypernociception was induced by intraplantar injection of carrageenan and evaluated using a digital analgesymeter every 30minutes during a 4 hour period. The results were recorded as the Delta withdrawal threshold (in g), calculated by subtracting the measurement value after RESULTS: The Delta withdrawal threshold mean values were lower in the group of patients treated with meloxicam over all time points between 45 and 165minutes, however, there was no statistical significance, (p=0.835) for this difference. CONCLUSION: Subarachnoid meloxicam at a dose of 30MUg.animal(-1) did not suppress the mechanical hypernociception in a model of inflammatory pain induced by intraplantar administration of carrageenan in rats. The data suggest that other dosages should be investigated the drug effect is discarded. PMID- 25740280 TI - [Use of positive pressure in pre and intraoperative of bariatric surgery and its effect on the time of extubation]. AB - BACKGROUND AND OBJECTIVE: to investigate the influence of intraoperative and preoperative airway positive pressure in the time of extubation in patients undergoing bariatric surgery. METHOD: Randomized clinical trial, in which 40 individuals with a body mass index between 40 and 55kg/m(2), age between 25 and 55 years, nonsmokers, underwent bariatric surgery type Roux-en-Y gastric bypass by laparotomy and with normal preoperative pulmonary function were randomized into the following groups: G-pre (n = 10): individuals who received treatment with noninvasive positive pressure before surgery for one hour, G-intra (n = 10): individuals who received positive end-expiratory pressure of 10cm H2O throughout the surgical procedure and G-control (n = 20): not received any pre or intraoperative intervention. Following were recorded: time between induction of anesthesia and extubation, between the end of anesthesia and extubation, duration of mechanical ventilation, and time between extubation and discharge from the Post-Anesthetic Recovery. RESULTS: there was no statistical difference between groups. However, when applied to the Cohen coefficient, the use of positive end expiratory pressure of 10cm H2O during surgery showed a large effect on the time between the end of anesthesia and extubation. About this same time, the treatment performed preoperatively showed moderate effect. CONCLUSION: The use of positive end-expiratory pressure of 10cm H2O in the intraoperative and positive pressure preoperatively, influenced the time of extubation of patients undergoing bariatric surgery. PMID- 25740281 TI - [Clinical application of thoracic paravertebral anesthetic block in breast surgeries]. AB - INTRODUCTION: optimum treatment for postoperative pain has been of fundamental importance in surgical patient care. Among the analgesic techniques aimed at this group of patients, thoracic paravertebral block combined with general anesthesia stands out for the good results and favorable risk-benefit ratio. Many local anesthetics and other adjuvant drugs are being investigated for use in this technique, in order to improve the quality of analgesia and reduce adverse effects. OBJECTIVE: evaluate the effectiveness and safety of paravertebral block compared to other analgesic and anesthetic regimens in women undergoing breast cancer surgeries. METHODS: integrative literature review from 1966 to 2012, using specific terms in computerized databases of articles investigating the clinical characteristics, adverse effects, and beneficial effects of thoracic paravertebral block. RESULTS: on the selected date, 16 randomized studies that met the selection criteria established for this literature review were identified. Thoracic paravertebral block showed a significant reduction of post operative pain, as well as decreased pain during arm movement after surgery. CONCLUSION: thoracic paravertebral block reduced postoperative analgesic requirement compared to placebo group, markedly within the first 24hours. The use of this technique could ensure postoperative analgesia of clinical relevance. Further studies with larger populations are necessary, as paravertebral block seems to be promising for preemptive analgesia in breast cancer surgery. PMID- 25740282 TI - [Implementation of a residency program in anesthesiology in the Northeast of Brazil: impact on work processes and professional motivation]. AB - BACKGROUND AND OBJECTIVES: Understand, through the theory of social representations, the influence exerted by the establishment a residency program in anesthesiology on anesthetic care and professional motivation in a tertiary teaching hospital in the Northeast of Brazil. METHOD: Qualitative methodology. The theoretical framework comprised the phenomenology and the Social Representation Theory. Five multidisciplinary focus groups were formed with 17 health professionals (five surgeons, five anesthesiologists, two nurses, and five nursing technicians), who work in operating rooms and post-anesthesia care units, all with prior and posterior experience to the establishment of residency. RESULTS: From the response content analysis, the following empirical categories emerged: motivation to upgrade, recycling of anesthesiologists and improving anesthetic practice, resident as an interdisciplinary link in perioperative care, improvements in the quality of perioperative care, recognition of weaknesses in the perioperative process. It was evident upper gastrointestinal bleeding secondary to prolonged intubation that the creation of a residency in anesthesiology brings advancements that are reflected in the motivation of anesthesiologists; the resident worked as an interdisciplinary link between the multidisciplinary team; there was recognition of weaknesses in the system, which were identified and actions to overcome it were proposed. CONCLUSION: The implementation of a residency program in anesthesiology at a tertiary education hospital in the Northeast of Brazil promoted scientific updates, improved the quality of care and processes of interdisciplinary care, recognized the weaknesses of the service, developed action plans and suggested that this type of initiative may be useful in remote areas of developing countries. PMID- 25740283 TI - Futurescapes: expectations in Europe for relative effectiveness evidence for drugs in 2020. AB - AIM: Explore key factors influencing future expectations for the production of evidence of relative effectiveness (RE) for drugs in Europe in 2020; construct three plausible future scenarios for RE evidence generation. MATERIALS & METHODS: Semi-structured key informant interviews and three rounds of modified Delphi to gather expert perspectives and develop future scenarios. RESULTS & CONCLUSION: Most influential factors were degree of regulator use of postmarketing authorization (postlaunch) efficacy studies and adaptive licensing; degree of pan European health technology assessment body coordination in reviewing prelaunch evidence and demanding postlaunch studies; the nature of regulator - health technology assessment body interaction. The most likely scenario entailed some change with postlaunch regulatory studies driving the likely nature of RE evidence generated. PMID- 25740284 TI - A lack of experience-dependent plasticity after more than a decade of recovered sight. AB - In 2000, monocular vision was restored to M. M., who had been blind between the ages of 3 and 46 years. Tests carried out over 2 years following the surgery revealed impairments of 3-D form, object, and face processing and an absence of object- and face-selective blood-oxygen-level-dependent responses in ventral visual cortex. In the present research, we reexamined M. M. to test for experience-dependent recovery of visual function. Behaviorally, M. M. remains impaired in 3-D form, object, and face processing. Accordingly, we found little to no evidence of the category-selective organization within ventral visual cortex typically associated with face, body, scene, or object processing. We did observe remarkably normal object selectivity within lateral occipital cortex, consistent with M. M.'s previously reported shape-discrimination performance. Together, these findings provide little evidence for recovery of high-level visual function after more than a decade of visual experience in adulthood. PMID- 25740285 TI - First genome sequence of St. Louis encephalitis virus (SLEV) isolated from a human in Brazil. AB - St. Louis encephalitis virus (SLEV), a member of the family Flaviviridae, genus Flavivirus, is a causative agent of encephalitis in the Americas. In Brazil, sporadic cases of SLEV infection have been reported since 1953, but the first outbreak of SLEV in Brazil was identified only in 2007, concomitant with an outbreak of dengue virus (DENV) serotype 3. This finding, along with other reports, indicates that SLEV circulation in Brazil is largely unknown, and there may be epidemiological implications of the co-circulation of SLEV, DENV and other flaviviruses in Brazil. Here, we describe the first complete genome sequence of an SLEV strain isolated from a human patient in Brazil, strain BeH 355964. Phylogenetic analysis was performed to determine the genotype of BeH 355964 using the full-length genome and envelope (E) gene sequences separately. Both analyses showed that BeH 355964 could be classified as genotype V. Although the number of single gene sequences available is greater (such as for the E gene), the phylogenetic tree based on the complete genome sequence was better supported and provided further information about the virus. PMID- 25740287 TI - Evolution of adjuvant chemotherapy for breast cancer. PMID- 25740288 TI - Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy. AB - The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats' choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate-reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine. PMID- 25740286 TI - Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 * 2 factorial, randomised phase 3 trial. AB - BACKGROUND: Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. METHODS: In this 2 * 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. FINDINGS: Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7.0 years (interquartile range [IQR] 4.5-6.3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0.77, 95% CI 0.65-0.92; p=0.004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0.65, 0.51-0.84; p=0.001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC P groups (HR 1.06, 0.89-1.25; p=0.561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1.16, 0.91-1.46; p=0.234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3 4 of anaemia (14 [1.4%] of 988 patients vs two [0.2%] of 984 patients; p=0.002); transaminitis (19 [1.9%] vs four [0.4%]; p=0.001), and myalgias (31 [3.1%] vs 16 [1.6%]; p=0.019), and decreased rates of grade 3-4 neutropenia (147 [14.9%] vs 433 [44.0%]; p<0.0001). Addition of fluorouracil led to increased rates of grade 3-4 neutropenia (354 [34.5%] of 1025 patients on FEC-P vs 250 [24.2%] of 1032 patients on EC-P; p<0.0001), fever (nine [0.9%] vs two [0.2%]), nausea (47 [4.6%] vs 28 [2.7%]), and vomiting (32 [3.1%] vs 15 [1.4%]). INTERPRETATION: In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome. FUNDING: Bristol-Myers Squibb, Pharmacia, and Dompe Biotec. PMID- 25740289 TI - Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits. AB - Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use. PMID- 25740290 TI - Soluble urokinase plasminogen activator receptor and hypertension among black South Africans after 5 years. AB - Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker that links inflammation with cardiovascular risk. However, studies linking suPAR and hypertension are scant. First, we determined whether baseline suPAR is elevated in normotensive black South Africans who developed hypertension over 5 years, compared with those who remained normotensive; and second, whether hypertension is associated with suPAR. This substudy is embedded in the South African leg of the Prospective Urban and Rural Epidemiology study, performed in the North West Province. We investigated 429 normotensive individuals, of which 191 developed hypertension and 238 remained normotensive over 5 years. We determined suPAR from plasma (ethylenediaminetetraacetic acid) samples with the suPARnostic ELISA Kit and blood pressure with an OMRON HEM-757 device. Despite similar mean baseline suPAR levels (P=0.43), suPAR increased more in the group that developed hypertension compared with those who remained normotensive (14.2% vs. 6.94%; P=0.007). Five-year percentage change in systolic blood pressure correlated positively (r=0.23; P=0.002) and associated independently with baseline suPAR (beta=0.14; P=0.043), only in participants who developed hypertension. Participants were 1.41 times more likely (P=0.015) to develop hypertension with 1 s.d. increase in percentage change in suPAR levels over 5 years. Change in systolic blood pressure was associated with baseline suPAR in hypertensive participants and change in suPAR with hypertensive status. This study highlights the need for more research on the role of suPAR in hypertension and cardiovascular disease development in black South Africans. PMID- 25740291 TI - Combined Aliskiren and L-arginine treatment reverses renovascular hypertension in an animal model. AB - Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following five groups were divided: SHAM operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4+/-5.2 to 204+/-12.7 mm Hg (P<0.05) and was only reduced by ALSK+L-ARG treatment (138.4+/-4.37 mm Hg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4+/-6.39 vs. 2K1C: 97.4+/-8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7+/-2.39; 2K1C ALSK+L-ARG: 69.3+/-4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2+/-2.5%). Urinary water, Na(+), Cl(-) and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats. PMID- 25740292 TI - Exogenous nitric oxide inhibits Rho-associated kinase activity in patients with angina pectoris: a randomized controlled trial. AB - The RhoA/Rho-associated kinase (ROCK) pathway has a key physiological role in the pathogenesis of atherosclerosis. Increased ROCK activity is associated with cardiovascular diseases. Endogenous nitric oxide (NO) has an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in patients with angina pectoris. This is a prospective, open label, randomized, controlled study. A total of 30 patients with angina pectoris were randomly assigned to receive 40 mg day(-1) of isosorbide mononitrate (n=15, 12 men and 3 women, mean age of 63+/-12 years, isosorbide mononitrate group) or conventional treatment (n=15, 13 men and 2 women, mean age of 64+/-13 years, control group) for 12 weeks. ROCK activity in peripheral leukocytes was measured by western blot analysis. ROCK activities at 4 and 12 weeks after treatment were decreased in the isosorbide mononitrate group (0.82+/-0.33 at 0 week, 0.62+/-0.20 at 4 weeks, 0.61+/-0.19 at 12 weeks, n=15 in each group, P<0.05, respectively) but not altered in the control group. ROCK1 and ROCK2 expression levels were similar in all treatment periods in the two groups. These findings suggest that the administration of exogenous NO can inhibit ROCK activity, indicating that the usage of exogenous NO could have a protective effect in patients with angina pectoris. PMID- 25740293 TI - Brachial and central blood pressure in HIV-infected subjects. AB - HIV infected subjects present an unfavorable cardiovascular (CV) risk profile that is determined by the infection itself, highly active anti-retroviral therapy (HAART) and other factors, such as chronic kidney disease (CKD). Information is scant and contradictory on whether these factors are associated with arterial stiffness and blood pressure (BP) alteration. Our study aimed to evaluate those parameters in HIV-positive subjects both with and without HAART and with and without CKD, which was defined as the presence of microalbuminuria with a normal glomerular filtration rate. We enrolled 94 HIV-infected subjects without known CV risk factors and compared them with 37 control subjects. We recorded brachial and central BP (pulse wave analysis) and pulse wave velocity ( SphygmoCor). HIV positive subjects of similar ages and with similar BP values showed central pulse pressure values that were significantly greater than those of controls; this was also the case for the Aix value. Central systolic and pulse pressure values and Aix were significantly greater in HIV-positive subjects with HAART and CKD than in the other HIV-positive subgroups and control subjects. PWV was also superimposable between groups when the data were analyzed relative to the presence of HAART and CKD. Our study shows that the unfavorable CV risk profile associated with HIV infection includes an increase in both central BP and Aix. The central BP increase seems to be favored by renal damage, which apparently has a role in the early stages of the disease. PMID- 25740294 TI - Leptin links with plasminogen activator inhibitor-1 in human obesity: the SABPA study. AB - The relationship between obesity and the development of cardiovascular disease is well established. However, the underlying mechanisms contributing to vascular disease and increased cardiovascular risk in the obese remain largely unexplored. Since leptin exerts direct vascular effects, we investigated leptin and the relationship thereof with circulating markers of vascular damage, namely plasminogen activator inhibitor-1 antigen (PAI-1(ag)), von Willebrand factor antigen (vWF(ag)) and urinary albumin-to-creatinine ratio (ACR). The study included a bi-ethnic population of 409 African and Caucasian teachers who were stratified into lean (<0.5) and obese (?0.5) groups according to waist-to-height ratio. We obtained ambulatory blood pressure measurements and determined serum leptin levels, PAI-1(ag), vWF(ag) and ACR, as markers of vascular damage. The obese group had higher leptin (P<0.001) and PAI-1(ag) (P<0.001) levels and a tendency existed for higher vWF(ag) (P=0.068). ACR did not differ between the two groups (P=0.21). In single regression analyses positive associations existed between leptin and all markers of vascular damage (all P<0.001) only in the obese group. After adjusting for covariates and confounders in multiple regression analyses, only the association between leptin and PAI-1(ag) remained (R(2)=0.440; beta=0.293; P=0.0021). After adjusting for gender, ethnicity and age, additional analyses indicated that leptin also associated with fibrinogen and clot lysis time in both lean and obese groups, which in turn is associated with 24- h blood pressure and pulse pressure. This result provides evidence that elevated circulating leptin may directly contribute to vascular damage, possibly through mechanism related to thrombotic vascular disease. PMID- 25740295 TI - [Workplace patrol reported in the disaster waste treatment plants at the Great East Japan Earthquake disaster area]. PMID- 25740296 TI - Can three-dimensional ultrasound measurement of fetal adrenal gland enlargement predict preterm birth? AB - PURPOSE: To assess the diagnostic accuracy of three-dimensional (3D) ultrasound measurements of fetal adrenal gland volume (AGV) and fetal zone enlargement (FZE) as predictors of PTB compared to measurements of cervical length (CL) and cervicovaginal fetal fibronectin (CVFF). METHOD: This prospective study included women presenting at 28-36 weeks of gestation with threatened preterm labor (TPL). Fetal AGV and FZE were measured using 3D ultrasound. Two-dimensional (2D) ultrasound was used to measure the CL. The AGV was corrected for the ultrasound estimated fetal weight (cAGV). Qualitative CVFF detection was also performed. The diagnostic accuracy of cAGV, FZE, CL, and CVFF was compared considering preterm birth (PTB) within 7 days of recruitment as the main outcome measure. RESULTS: Seventy-five pregnant women were included in the final statistical analysis. Twenty-seven women (36 %) delivered within 7 days. cAGV and FZE had the highest sensitivities and specificities to predict PTB within 7 days when compared with CL and CVFF. Multivariate analysis, including cAGV, FZE, CL, and CVFF, revealed that cAGV and FZE were independent predictors of PTB within 7 days in the study participants. CONCLUSION: In women who presented at 28-36 weeks of gestation with TPL, cAGV and FZE can be used as independent predictors of PTB. PMID- 25740297 TI - Effects of serum from patients with early-onset pre-eclampsia, HELLP syndrome, and antiphospholipid syndrome on fatty acid oxidation in trophoblast cells. AB - BACKGROUND AND AIMS: The role of metabolic disorders of long-chain fatty acid oxidation in the development of pre-eclampsia (PE), hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and antiphospholipid syndrome (APS) is unclear. The aim of this study was to research the effects of three serum on fatty acid oxidation in trophoblast cells. METHODS: Primary human trophoblast cells and HTR8/SVneo cells were treated with serum from patients with early-onset severe PE (E-PE), E-PE with HELLP (PE-HELLP), APS, and normal pregnant women as controls (NC). Cells treated with free fatty acids (FFAs) of various lengths were used as controls. RESULTS: Triglyceride (TG) and FFA levels of the E-PE and APS groups were significantly higher than the PE-HELLP and NC groups (P < 0.05). Trophoblast cells treated with serum from the E-PE and APS groups showed obvious morphological changes and a large amount of lipid droplet deposition. Cells in the E-PE group had more severe damage of mitochondria ultrastructure, presenting with cell morphological changes, lipid droplet deposition, and mitochondria damage similar to the long-chain FFA group. FFA levels in the PE-HELLP group increased significantly compared with the NC group (P < 0.05), while TG levels did not change significantly (P > 0.05). Trophoblast cells treated with serum from the PE-HELLP group showed cellular morphology and mitochondria changes similar to the E-PE group, but had relatively less lipid droplet deposition. CONCLUSION: Serum from patients with E-PE, PE-HELLP, and APS with elevated levels of FFA had different effects on trophoblast cells, including cell morphology, lipid droplets deposition, and mitochondrial ultrastructure, suggesting disorders of lipid metabolism and fatty acid oxidation of various degrees and types. Serum from patients with E-PE led to damage similar to that of long-chain FFA in cell morphology, lipid droplet deposition and mitochondrial ultrastructure, indicating the correlation between disorders of long-chain fatty acid oxidation and the development of the disease. PMID- 25740298 TI - Monodisperse porous silicon spheres as anode materials for lithium ion batteries. AB - Highly monodisperse porous silicon nanospheres (MPSSs) are synthesized via a simple and scalable hydrolysis process with subsequent surface-protected magnesiothermic reduction. The spherical nature of the MPSSs allows for a homogenous stress-strain distribution within the structure during lithiation and delithiation, which dramatically improves the electrochemical stability. To fully extract the real performance of the MPSSs, carbon nanotubes (CNTs) were added to enhance the electronic conductivity within the composite electrode structure, which has been verified to be an effective way to improve the rate and cycling performance of anodes based on nano-Si. The Li-ion battery (LIB) anodes based on MPSSs demonstrate a high reversible capacity of 3105 mAh g(-1). In particular, reversible Li storage capacities above 1500 mAh g(-1) were maintained after 500 cycles at a high rate of C/2. We believe this innovative approach for synthesizing porous Si-based LIB anode materials by using surface-protected magnesiothermic reduction can be readily applied to other types of SiOx nano/microstructures. PMID- 25740299 TI - Surgeon in female genital mutilation case should not have been prosecuted. PMID- 25740300 TI - Marr's Attacks: On Reductionism and Vagueness. AB - It has been suggested that Marr took the three levels he famously identifies to be independent. In this paper, we argue that Marr's view is more nuanced. Specifically, we show that the view explicitly articulated in his work attempts to integrate the levels, and in doing so results in Marr attacking both reductionism and vagueness. The result is a perspective in which both high-level information-processing constraints and low-level implementational constraints play mutually reinforcing and constraining roles. We discuss our recent work on Spaun-currently the world's largest functional brain model-that demonstrates the positive impact of this kind of unifying integration of Marr's levels. We argue that this kind of integration avoids his concerns with both reductionism and vagueness. In short, we suggest that the methods behind Spaun can be used to satisfy Marr's explicit interest in combining high-level functional and detailed mechanistic explanations. PMID- 25740301 TI - Two novel nebulin variants in an adult patient with congenital nemaline myopathy. AB - Congenital myopathies are clinically and genetically heterogeneous disorders, which often remain genetically undiagnosed for many years. Here we present a 40 year old patient with an almost lifelong history of a congenital myopathy of unknown cause. Muscle biopsy in childhood revealed mild myopathic features and rods. Clinical examination on presentation at the age of 40 revealed a facial weakness, atrophy and weakness of the arm muscles and distal leg muscles with mild contractures of the foot flexors and the right elbow. Subsequently, the nebulin gene was identified as a putative candidate gene by linkage analyses, but sequence analysis only revealed one heterozygous splice site mutation in intron 73 (c.10872+1G>T). Therefore, "Next Generation Sequencing" was performed, which revealed a second pathogenic variant in exon 145 (c.21622A>C). Compound heterozygous carrier status was confirmed via sequence analysis of the index patient's parents. Whole body muscle MRI showed a muscle involvement as previously described in nebulin-associated myopathies. Based on biopsy material, genetic analyses and muscle MRI, we identified two novel, compound-heterozygous variants in the nebulin gene after a 30 year clinical history, which cause a classical childhood type of nemaline myopathy. PMID- 25740302 TI - Taste responsiveness to sweeteners is resistant to elevations in plasma leptin. AB - There is uncertainty about the relationship between plasma leptin and sweet taste in mice. Whereas 2 studies have reported that elevations in plasma leptin diminish responsiveness to sweeteners, another found that they enhanced responsiveness to sucrose. We evaluated the impact of plasma leptin on sweet taste in C57BL/6J (B6) and leptin-deficient ob/ob mice. Although mice expressed the long-form leptin receptor (LepRb) selectively in Type 2 taste cells, leptin failed to activate a critical leptin-signaling protein, STAT3, in taste cells. Similarly, we did not observe any impact of intraperitoneal (i.p.) leptin treatment on chorda tympani nerve responses to sweeteners in B6 or ob/ob mice. Finally, there was no effect of leptin treatment on initial licking responses to several sucrose concentrations in B6 mice. We confirmed that basal plasma leptin levels did not exceed 10ng/mL, regardless of time of day, physiological state, or body weight, suggesting that taste cell LepRb were not desensitized to leptin in our studies. Furthermore, i.p. leptin injections produced plasma leptin levels that exceeded those previously reported to exert taste effects. We conclude that any effect of plasma leptin on taste responsiveness to sweeteners is subtle and manifests itself only under specific experimental conditions. PMID- 25740303 TI - Taste bud leptin: sweet dampened at initiation site. AB - The intriguing observation that leptin decreases sweet-evoked peripheral gustatory responses has aroused much interest (Kawai K, Sugimoto K, Nakashima K, Miura H, Ninomiya Y. 2000. Leptin as a modulator of sweet taste sensitivities in mice. Proc Natl Acad Sci U S A. 97(20):11044-11049.) due to its implied importance in controlling appetite. The effects of this anorexic hormone, however, appear more conditional than originally believed. In this issue of Chemical Senses, a careful study by Glendinning and colleagues, find no effects of leptin on sweet-evoked chorda tympani responses, whereas an equally careful study by Meredith and colleagues, find decreased release of ATP and increased release of 5-HT from taste buds in response to sweet stimuli. PMID- 25740305 TI - Fitting accuracy and fracture resistance of crowns using a hybrid zirconia frame made of both porous and dense zirconia. AB - The purpose of this study is to evaluate the fitting accuracy and fracture resistance of crowns using a hybrid zirconia frame made of both porous and dense zirconia. Commercial semi-sintered zirconia, sintered dense zirconia and sintered hybrid zirconia were used. Sintered zirconia was milled using the CAD/CAM system, and semi-sintered zirconia was milled and sintered to fabricate molar crown frames. Completed frames were veneered with tooth-colored porcelain. The marginal and internal gaps between frames/crowns and abutments were measured. Each crown specimen was subjected to a fracture test. There were no significant differences in marginal and internal gap among all the frames and crowns. The crown with the hybrid zirconia frame had a 31-35% greater fracture load than that with the commercial or dense zirconia frame (p<0.01). This suggests that the all-ceramic crowns with a hybrid zirconia frame have a high fracture resistance. PMID- 25740306 TI - Effects of various denture cleansers on surface roughness of hard permanent reline resins. AB - The aim of this study was to investigate the influence of denture cleansers on surface roughness (Ra, um) of two hard permanent reline resins and a conventional acrylic denture base resin. Fifty specimens of each material, measuring 10 mm*2 mm were randomly divided into 1 control and 4 experimental subgroups (n=10). Surface roughness values were measured using profilometer before and after immersion in distilled water and in 4 different denture cleansers for 8 h for 140 days. The Kruskal Wallis and Wilcoxon Signed Ranks tests were used for comparison among groups with a significance level of alpha=0.05. Immersion in denture cleansers significantly increased the surface roughness of reline resins and the difference among the cleansers was statistically significant (p=0.059). Denture cleansers can cause significant surface roughness alterations on hard permanent reline resins and denture base resin where their effect may differ according to the selected resin material. PMID- 25740304 TI - Long-term memory for odors: influences of familiarity and identification across 64 days. AB - Few studies have investigated long-term odor recognition memory, although some early observations suggested that the forgetting rate of olfactory representations is slower than for other sensory modalities. This study investigated recognition memory across 64 days for high and low familiar odors and faces. Memory was assessed in 83 young participants at 4 occasions; immediate, 4, 16, and 64 days after encoding. The results indicated significant forgetting for odors and faces across the 64 days. The forgetting functions for the 2 modalities were not fundamentally different. Moreover, high familiar odors and faces were better remembered than low familiar ones, indicating an important role of semantic knowledge on recognition proficiency for both modalities. Although odor recognition was significantly better than chance at the 64 days testing, memory for the low familiar odors was relatively poor. Also, the results indicated that odor identification consistency across sessions, irrespective of accuracy, was positively related to successful recognition. PMID- 25740307 TI - Deterioration of polymethyl methacrylate dentures in the oral cavity. AB - Polymethyl methacrylate (PMMA)-made prostheses used in the oral cavity were evaluated by multimodal assessment in order to elucidate the biodeterioration of PMMA. In used dentures (UD), the micro-Vickers hardness of the polished denture surface and denture basal surface was lower than that of the torn surface (p<0.05), whereas the shaved surface approximately 100 um from the polished surface showed a similar value to the torn surface. By contrast, there were no differences among these surfaces in new resin (NR). The volatile content of UD was higher than that of NR (p<0.05). Component analysis by ATR-FTIR showed specific spectra (1,700-1,400 cm(-1)) only in UD. This study revealed that PMMA deteriorated during long-term use in the oral cavity in terms of hardness and volatile content with component alteration, and suggests the involvement of biodeterioration, possibly due to saliva and oral microbiota. PMID- 25740308 TI - A new technique for analyzing trace element uptake by human enamel. AB - Fluorine (F) and strontium (Sr) are key elements in the de- and remineralization of teeth. To quantitatively analyze the distribution of F and Sr, micro-particle induced gamma/X-ray emission (PIGE/PIXE) technique was used. The cavities were prepared and filled with the fluoride- and Sr-containing restorative materials (FSCMs) in extracted human molars. The single-section enamel specimens were prepared by slicing from the buccal to lingual surface including the FSCMs. After 5 weeks of automatic pH cycling, the demineralization was calculated by integrated mineral loss (DeltaIML) from transverse-microradiography. The distributions of F and Sr were analyzed by the PIGE/PIXE technique. The micro PIGE/PIXE technique indicated a fluorine uptake difference between the enamel surface and enamel cavity wall. DeltaIML of FSCMs were significantly lower than intact enamel. The micro-PIGE/PIXE technique enables measurement of F and Sr uptake from FSCMs into enamel, which would be beneficial for research on caries development and prevention. PMID- 25740309 TI - Development of a novel fluorapatite-forming calcium phosphate cement with calcium silicate: in vitro and in vivo characteristics. AB - Aim of this study was to develop a novel fluorapatite-forming calcium phosphate cement (FA-CPC) with tricalcium silicate (TCS) for endodontic applications and to examine its in vitro and in vivo characteristics. The FA-CPC powder consisted of 62.8% CaHPO4, 30.8% CaCO3, and 6.4% NaF. One part of TCS was combined with 9 parts of FA-CPC powder (FA-CPC with TCS). A 1.5 M phosphate solution was used as cement liquid. Setting time (ST), diametral tensile strength (DTS), phase composition by X-ray diffraction (XRD), and cement alkalinity were analyzed. Cement biocompatibility was assessed using rat subcutaneous model. Cement ST was 10.3+/-0.6 min and DTS was 3.89+/-0.76 MPa. XRD patterns showed that highly crystalline apatitic material was the only significant phase present and pH value was approximate 11.0. FA-CPC with TCS demonstrated similar biocompatibility as that of mineral trioxide aggregate control. These results suggest that FA-CPC with TCS may be useful for endodontic applications. PMID- 25740310 TI - Measurement of surface hardness of primary carious lesions in extracted human enamel -measurement of Knoop hardness using Cariotester. AB - The clinical feasibility of a novel device called a Cariotester was investigated by measuring the Knoop hardness (KHN) of white spot lesions diagnosed as ICDAS code 1, 2 or 3. To obtain an equation for converting the Cariotester indentation depth into the KHN, a regression analysis was performed between the depth and measured KHN for human enamel. The Cariotester was then used to measure the indentation depth for white spots (ICDAS code 1, 2 or 3) in extracted teeth, and the KHN values were determined using the above equation. The KHN was 219.9+/ 19.7, 162.4+/-24.0 and 31.7+/-17.5 for code 1, 2 and 3 lesions, respectively, which was 30, 49 and 90% lower than that for healthy enamel. Using the formula reported in the literature, the mineral density was calculated to be 87.7 vol.% for healthy enamel, and 75.1, 66.1 and 35.5 vol.% for code 1, 2 and 3 lesions, respectively. PMID- 25740311 TI - Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. AB - Proteins of the echinoderm microtubule (MT)-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase MT network. EML1-4 consist of Trp-Asp 40 (WD40) repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4-ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding; however, this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4-ALK and EML1-ABL1 (Abelson 1) fusions in which variable portions of the EML component are present. Uniquely, EML4-ALK variant 3, which includes the TD and basic region of EML4 but none of the WD40 repeats, was localized to MTs, both when expressed recombinantly and when expressed in a patient-derived NSCLC cell line (H2228). This raises the question of whether the mislocalization of ALK activity to MTs might influence downstream signalling and malignant properties of cells. Furthermore, the structure of EML4 TD may enable the development of protein protein interaction inhibitors targeting the trimerization interface, providing a possible avenue towards therapeutic intervention in EML4-ALK NSCLC. PMID- 25740312 TI - Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis. AB - Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance. PMID- 25740313 TI - High resolution imaging of acne lesion development and scarring in human facial skin using OCT-based microangiography. AB - BACKGROUND AND OBJECTIVE: Acne is a common skin disease that often leads to scarring. Collagen and other tissue damage from the inflammation of acne give rise to permanent skin texture and microvascular changes. In this study, we demonstrate the capabilities of optical coherence tomography-based microangiography in detecting high-resolution, three-dimensional structural, and microvascular features of in vivo human facial skin during acne lesion initiation and scar development. MATERIALS AND METHODS: A real time swept source optical coherence tomography system is used in this study to acquire volumetric images of human skin. The system operates on a central wavelength of 1,310 nm with an A line rate of 100 kHz, and with an extended imaging range (~12 mm in air). The system uses a handheld imaging probe to image acne lesion on a facial skin of a volunteer. We utilize optical microangiography (OMAG) technique to evaluate the changes in microvasculature and tissue structure. RESULTS: Thanks to the high sensitivity of OMAG, we are able to image microvasculature up to capillary level and visualize the remodeled vessels around the acne lesion. Moreover, vascular density change derived from OMAG measurement is provided as an alternative biomarker for the assessment of human skin diseases. In contrast to other techniques like histology or microscopy, our technique made it possible to image 3D tissue structure and microvasculature up to 1.5 mm depth in vivo without the need of exogenous contrast agents. CONCLUSIONS: The presented results are promising to facilitate clinical trials aiming to treat acne lesion scarring, as well as other prevalent skin diseases, by detecting cutaneous blood flow and structural changes within human skin in vivo. PMID- 25740314 TI - Most hydrocarbonoclastic bacteria in the total environment are diazotrophic, which highlights their value in the bioremediation of hydrocarbon contaminants. AB - Eighty-two out of the 100 hydrocarbonoclastic bacterial species that have been already isolated from oil-contaminated Kuwaiti sites, characterized by 16S rRNA nucleotide sequencing, and preserved in our private culture collection, grew successfully in a mineral medium free of any nitrogenous compounds with oil vapor as the sole carbon source. Fifteen out of these 82 species were selected for further study based on the predominance of most of the isolates in their specific sites. All of these species tested positive for nitrogenase using the acetylene reduction reaction. They belonged to the genera Agrobacterium, Sphingomonas, and Pseudomonas from oily desert soil and Nesiotobacter, Nitratireductor, Acinetobacter, Alcanivorax, Arthrobacter, Marinobacter, Pseudoalteromonas, Vibrio, Diatzia, Mycobacterium, and Microbacterium from the Arabian/Persian Gulf water body. A PCR-DGGE-based sequencing analysis of nifH genes revealed the common occurrence of the corresponding genes among all the strains tested. The tested species also grew well and consumed crude oil effectively in NaNO3 containing medium with and without nitrogen gas in the top space. On the other hand, these bacteria only grew and consumed crude oil in the NaNO3 -free medium when the top space gas contained nitrogen. We concluded that most hydrocarbonoclastic bacteria are diazotrophic, which allows for their wide distribution in the total environment. Therefore, these bacteria are useful for the cost-effective, environmentally friendly bioremediation of hydrocarbon contaminants. PMID- 25740315 TI - Acute ER stress regulates amyloid precursor protein processing through ubiquitin dependent degradation. AB - Beta-amyloid (Abeta), a major pathological hallmark of Alzheimer's disease (AD), is derived from amyloid precursor protein (APP) through sequential cleavage by beta-secretase and gamma-secretase enzymes. APP is an integral membrane protein, and plays a key role in the pathogenesis of AD; however, the biological function of APP is still unclear. The present study shows that APP is rapidly degraded by the ubiquitin-proteasome system (UPS) in the CHO cell line in response to endoplasmic reticulum (ER) stress, such as calcium ionophore, A23187, induced calcium influx. Increased levels of intracellular calcium by A23187 induces polyubiquitination of APP, causing its degradation. A23187-induced reduction of APP is prevented by the proteasome inhibitor MG132. Furthermore, an increase in levels of the endoplasmic reticulum-associated degradation (ERAD) marker, E3 ubiquitin ligase HRD1, proteasome activity, and decreased levels of the deubiquitinating enzyme USP25 were observed during ER stress. In addition, we found that APP interacts with USP25. These findings suggest that acute ER stress induces degradation of full-length APP via the ubiquitin-proteasome proteolytic pathway. PMID- 25740316 TI - Microvascular disturbance with decreased pericyte coverage is prominent in the ventral horn of patients with amyotrophic lateral sclerosis. AB - In amyotrophic lateral sclerosis (ALS) there is emerging evidence for vasculature disturbance. The aim of this study was to investigate the area of predominant vasculature disturbance in ALS. We used immunohistochemistry to quantitatively evaluate the microvascular density (MVD) and pericyte coverage (PC) in the lumbar spinal cord of 25 ALS patients and six controls. In controls, MVD was almost equal in the ventral horn (VH) and dorsal horn (DH). In the VH of ALS, MVD was significantly increased, and PC was significantly decreased compared with the DH in ALS and the VH in controls (p < 0.001), possibly reflecting that PC is an essential requirement for the vasculature in the VH. We then found a significant relationship between the severity of aberrant angiogenesis and the use of artificial respiratory support (ARS). In conclusion, vasculature disturbance is observed in all ALS patients including patients with ARS. Therefore, breakdown of the blood-spinal cord barrier due to aberrant angiogenesis with decreased PC may be responsible for the predominant neuronal death in the VH in ALS. PMID- 25740317 TI - Republished: gastric neuroendocrine neoplasms and related precursor lesions. AB - Gastric neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours showing different clinicopathological features and behaviour, implying a wide spectrum of therapeutic options. They are currently classified using the 2010 WHO classification of digestive neuroendocrine neoplasms into G1-neuroendocrine tumours (NETs), G2-NETs, neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs). However, most gastric NENs are composed of ECL-cells (ECL-cell NETs) that can be preceded by ECL-cell hyperplastic and dysplastic lesions, whose oncologic potential has not yet been completely elucidated. ECL-cell NETs differ considerably in terms of prognosis depending on the proliferative status and clinicopathological background. The integration of both aspects in the diagnostic pathway may help to better classify tumours in different prognostic categories, especially when diagnosing them in small bioptic specimens. NECs are all poorly differentiated, highly aggressive carcinomas, while MANECs can show different morphological features that are directly associated with different prognoses. Precursor lesions of such carcinomas are not entirely understood. In this review, the clinicopathological features of gastric NENs and related precursor lesions will be described to give the reader a comprehensive overview on this topic. PMID- 25740318 TI - Intracranial plasmacytoma with hypoglossal nerve palsy in multiple myeloma. PMID- 25740319 TI - Concentric conversations. PMID- 25740320 TI - Republished: value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age. AB - OBJECTIVE: The leukocyte count is frequently used to evaluate suspected bacterial infections but estimates of its test performance vary considerably. We evaluated its accuracy for the detection of serious bacterial infections in febrile children. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department. PATIENTS: Febrile 0-5-year-olds who had a leukocyte count on presentation. OUTCOME MEASURES: Accuracy of total white blood cell and absolute neutrophil counts for the detection of urinary tract infection, bacteraemia, pneumonia and a combined ('any serious bacterial infection') category. Logistic regression models were fitted for each outcome. Reference standards were microbiological/radiological tests and clinical follow-up. RESULTS: Serious bacterial infections were present in 714 (18.3%) of 3893 illness episodes. The area under the receiver operating characteristic curve for 'any serious bacterial infection' was 0.653 (95% CI 0.630 to 0.676) for the total white blood cell count and 0.638 (95% CI 0.615 to 0.662) for absolute neutrophil count. A white blood cell count threshold >15*10(9)/L had a sensitivity of 47% (95% CI 43% to 50%), specificity 76% (95% CI 74% to 77%), positive likelihood ratio 1.93 (95% CI 1.75 to 2.13) and negative likelihood ratio 0.70 (95% CI 0.65 to 0.75). An absolute neutrophil count threshold >10*10(9)/L had a sensitivity of 41% (95% CI 38% to 45%), specificity 78% (95% CI 76% to 79%), positive likelihood ratio 1.87 (95% CI 1.68 to 2.09) and negative likelihood ratio 0.75 (95% CI 0.71 to 0.80). CONCLUSIONS: The total white blood cell count and absolute neutrophil count are not sufficiently accurate triage tests for febrile children with suspected serious bacterial infection. PMID- 25740321 TI - High-Yield Expression of M2e Peptide of Avian Influenza Virus H5N1 in Transgenic Duckweed Plants. AB - Avian influenza is a major viral disease in poultry. Antigenic variation of this virus hinders vaccine development. However, the extracellular domain of the virus encoded M2 protein (peptide M2e) is nearly invariant in all influenza A strains, enabling the development of a broad-range vaccine against them. Antigen expression in transgenic plants is becoming a popular alternative to classical expression methods. Here we expressed M2e from avian influenza virus A/chicken/Kurgan/5/2005(H5N1) in nuclear-transformed duckweed plants for further development of avian influenza vaccine. The N-terminal fragment of M2, including M2e, was selected for expression. The M2e DNA sequence fused in-frame to the 5' end of beta-glucuronidase was cloned into pBI121 under the control of CaMV 35S promoter. The resulting plasmid was successfully used for duckweed transformation, and western analysis with anti-beta-glucuronidase and anti-M2e antibodies confirmed accumulation of the target protein (M130) in 17 independent transgenic lines. Quantitative ELISA of crude protein extracts from these lines showed M130-beta-glucuronidase accumulation ranging from 0.09-0.97 mg/g FW (0.12 1.96 % of total soluble protein), equivalent to yields of up to 40 MUg M2e/g plant FW. This relatively high yield holds promise for the development of a duckweed-based expression system to produce an edible vaccine against avian influenza. PMID- 25740322 TI - Clinical Endocrinology Education Project: a tribute to Professor Steve Judd. PMID- 25740323 TI - Interactions of a few azole derivatives with a transport protein: role of heteroatoms. AB - The interaction of a few azole derivatives, 2-(4'-N,N dimethylaminophenyl)benzimidazole, 2-(4'-N,N-dimethylaminophenyl)benzoxazole, 2 (4'-N,N-dimethylaminophenyl)oxazolo[4,5-b]pyridine with bovine serum albumin (BSA) were examined by absorption and fluorescence spectroscopy. The results were compared with the previously studied imidazopyridine derivative 2-(4'-N,N dimethylaminophenyl)imidazo[4,5-b]pyridine. Displacement studies were carried out with site selective probes to locate the binding site of these ligands. The spectral shifts and the binding constant vary depending on the nature of the ligand. The fluorescence intensity of both oxazole derivatives 2-(4'-N,N dimethylaminophenyl)benzoxazole and 2-(4'-N,N-dimethylaminophenyl) oxazolo[4,5 b]pyridine increases substantially in the presence of BSA, whereas the intensity of 2-(4'-N,N-dimethylaminophenyl)benzimidazole decreases. However, hypsochromic shift is observed in presence of BSA. The results obtained from the docking studies are also in good agreement with the experimental results. The location and orientation of binding depend upon the nature of the ligand. The studies revealed that apart from hydrophobic interaction, hydrogen bonding also plays a vital role in the molecular binding. Oxazoles have higher binding affinity than imidazoles and substitution of extra nitrogen further increases the binding affinity. PMID- 25740324 TI - Dengue virus and antiplatelet autoantibodies synergistically induce haemorrhage through Nlrp3-inflammasome and FcgammaRIII. AB - Dengue haemorrhagic fever (DHF) typically occurs during secondary infections with dengue viruses (DENVs). Although it is generally accepted that antibody-dependent enhancement is the primary reason why patients with secondary infection are at an increased risk of developing DHF, a growing body of evidence shows that other mechanisms, such as the elicitation of antiplatelet autoantibodies by DENV nonstructural protein NS1, also play crucial roles in the pathogenesis of DHF. In this study, we developed a "two-hit" model of secondary DENV infection to examine the respective roles of DENV (first hit) and antiplatelet Igs (second hit) on the induction of haemorrhage. Mice were first exposed to DENV and then exposed to antiplatelet or anti-NS1 Igs 24 hours later. The two-hit treatment induced substantial haemorrhage, coagulopathy, and cytokine surge, and additional treatment with antagonists of TNF-alpha, IL-1, caspase-1, and FcgammaRIII ameliorated such effects. In addition, knockout mice lacking the Fcgamma receptor III, Toll-like receptor 3, and inflammasome components Nlrp3 and caspase-1 exhibited considerably fewer pathological alterations than did wild type controls. These findings may provide new perspectives for developing feasible approaches to treat patients with DHF. PMID- 25740325 TI - Prevalence of chronic itch and associated factors in haemodialysis patients: a representative cross-sectional study. AB - Chronic itch is a common symptom in haemodialysis (HD) patients, which is often underestimated. The aim of this cross-sectional study was to investigate the prevalence and factors associated with chronic itch in HD patients. A total of 860 HD patients from a randomly selected cluster-sample of patients attending dialysis units in Germany were included. The patients' mean?+/-?SD age was 67.2?+/-?13.5 years, 57.2% were male. The point prevalence of chronic itch was 25.2% (95% CI 22.4-28.1), 12-month prevalence was 27.2% (95% CI 24.1-30.3) and lifetime prevalence was 35.2% (95% CI 31.9-38.3). Chronic itch was significantly less prevalent in patients with secondary glomerulonephritis as primary renal disease. A history of dry skin, eczema, and age = 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = 0.0023). Furthermore, the incidence of hypernatremia, defined as >= 150 mEq/L in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = 0.3657). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients. PMID- 25740390 TI - Platelet-derived growth factor receptor-tyrosine kinase inhibitor, imatinib, is effective for treating pulmonary hypertension induced by pulmonary tumor thrombotic microangiopathy. AB - Pulmonary hypertension (PH) induced by pulmonary tumor thrombotic microangiopathy (PTTM) can be fatal because its rapid progression confounds diagnosis, and it is difficult to control with therapy. Here we describe a woman with symptomatic PTTM PH accompanying gastric cancer that was suspected from perfusion scintigraphy. PTTM-PH was diagnosed by gastroesophageal endoscopy and lung biopsy after partial control of PH using the platelet-derived growth factor (PDGF) receptor (PDGFR) tyrosine kinase inhibitor, imatinib. Treatment with sildenafil and ambrisentan further decreased PH, and she underwent total gastrectomy followed by adjuvant TS 1 chemotherapy. PH did not recur before her death from metastasis. Postmortem histopathology showed recanalized pulmonary arteries where the embolized cancer masses disappeared. PDGF-A, -B, and PDGFR-alpha, beta expression was detected in cancer cells and proliferating pulmonary vascular endothelial cells. Thus, PTTM PH was successfully controlled using a combination of imatinib, drugs to treat pulmonary arterial hypertension, and cancer management. PMID- 25740391 TI - Enhanced expression of hemoglobin scavenger receptor CD163 in accumulated macrophages within filtered debris between acute coronary syndromes and stable angina pectoris. AB - Coronary intraplaque hemorrhage up-regulates hemoglobin scavenger receptor CD163 expression on macrophages, and has an association with vulnerable plaque development. During percutaneous coronary intervention, mechanical plaque disruption exposes potentially embolic atheromatous contents from culprit plaque.In 37 patients with stable angina pectoris (SAP, n = 20) or acute coronary syndrome (ACS, n = 17), atherothrombotic debris was collected using a filter based distal embolic protection device. We immunohistochemically determined CD14 positive macrophages and CD163-positive macrophages in filtered debris. We also examined the relation of CD14- and CD163-positive macrophages with culprit plaque volume and components evaluated with ultrasonic tissue characterization (VH IVUS).The only significant difference in clinical characteristics between the two groups was in hs-CRP. In ACS, the percentage of CD14- and CD163-positive macrophages to the whole cells (%CD14 and %CD163, respectively) was significantly higher than that in SAP (20.1 +/- 8.2 versus 8.8 +/- 6.8%, P < 0.001 and 32.6 +/- 18.9 versus 9.0 +/- 3.8%, P < 0.001, respectively). In IVUS indices of culprit plaque, the remodeling index was significantly higher in ACS than in SAP. However, necrotic core component (%NC) in ACS was significantly higher than that in SAP. Furthermore, fibrotic component (%Fibrous) in ACS was significantly lower than that in SAP (56.1 +/- 4.7 versus 60.1 +/- 3.3%, P = 0.03). %CD14 and %CD163 had a significant positive correlation with %NC (%CD14: r = 0.40, P = 0.01 and %CD163: r = 0.45, P = 0.01), but only %CD163 was negatively correlated with %Fibrous (%CD163: r = -0.48, P = 0.01).These findings suggest that the presence of CD14- and CD163-positive macrophages may reflect plaque inflammation, NC expansion, and plaque vulnerability in patients with coronary heart disease. PMID- 25740392 TI - Effect of periodontitis on cardiovascular manifestations in Marfan syndrome. Critical common role of TGF-beta. AB - Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations in the extracellular matrix protein fibrillin-1. While MFS patients are considered to be at high risk of dental disorders and cardiovascular complications, little causal relationship has been provided to date. It is well known that an elevated level of active TGF-beta in the plasma is a major manifestation of MFS. TGF-beta is known to play a critical role in the development of cardiovascular diseases and its levels were also elevated in the serum and saliva of periodontitis patients. These findings may suggest an association between periodontitis and the cardiovascular complications of MFS. In this article, we review the influence of periodontitis in MFS patients with cardiovascular complications in order to identify critical therapeutic targets of TGF-beta. PMID- 25740393 TI - Late rejection occurred in recipients who experienced acute cellular rejection within the first year after heart transplantation. AB - Serial endomyocardial biopsies (EMBs) are scheduled even several years after heart transplantation (HTx) to monitor for late rejection (LR). However, repeated EMBs are associated with an increased risk for fatal complications and decrease the quality of life of the recipient. We retrospectively analyzed clinical data from 42 adult recipients who had received HTx and were followed > 1 year at the University of Tokyo Hospital. Five recipients experienced LR at 1130 +/- 157 days after HTx, and all 5 had experienced acute cellular rejection (ACR) with ISHLT grade >= 2R within the first year, which was treated with methylprednisolone pulse therapy (sensitivity, 1.000; specificity, 0.7027). Logistic regression analyses demonstrated that positive panel reactive antibody (PRA) was the only significant predictor for LR among all parameters at 1 year after HTx (P = 0.020, odds ratio 24.00). Among the 5 recipients with LR, LR occurred earlier in the two PRA positive recipients than in those with a negative PRA (981 +/- 12 versus 1230 +/- 110 days, P = 0.042). Among the perioperative parameters, gender mismatch [n = 13 (31%)] was the only significant predictor for ACR within the first year in logistic regression analyses (P = 0.042, odds ratio 4.200). In conclusion, the current schedule of serial EMBs should perhaps be reconsidered for recipients without any history of ACR within the first year due to their lower risk of LR. PMID- 25740394 TI - Liberal versus restricted fluid administration in heart failure patients. A systematic review and meta-analysis of randomized trials. AB - Restrictive fluid intake is recommended, in addition to standard pharmacologic treatment, in the treatment of patients with chronic heart failure (CHF). However, this recommendation lacks firm scientific evidence. We conducted a systematic review and meta-analysis of published randomized controlled trials to estimate the effect of fluid restriction in patients with heart failure.Randomized controlled trials were identified in the MEDLINE, EMBASE, and Cochrane databases using the search-keywords "fluid" and "heart failure". Outcomes were compared in heart failure patients with liberal and restricted fluid intake. Pooled risk ratios (RR) and weighted mean differences (WMD) were calculated using random effects models. Studies focusing on decompensated heart failure were analyzed separately.Six small randomized trials comparing liberal and restricted fluid intake met the inclusion criteria. Significant heterogeneity was noted in the reported studies for several outcomes. There were no differences in readmission rate (5 studies, pooled RR = 1.32; 95% CI: 0.86 to 2.01; P = 0.2), mortality rate (5 studies, pooled RR = 1.50; 95% CI: 0.87 to 2.57; P = 0.14), perceived thirst (4 studies, WMD = -0.7; 95% CI: -2.58 to 1.17; P = 0.46), duration of intravenous diuretics (2 studies, WMD = 0.17; 95% CI: -1.26 to 1.6; P = 0.81) or serum sodium levels (WMD = -1.61; 95% CI: -3.28 to 0.07; P = 0.06) between the liberal fluid intake group and the restrictive fluid intake group. Mean serum creatinine and BNP levels were significantly higher in the liberal fluid group: WMD 0.20 (95% CI: 0.15 to 0.25; P < 0.00001) and 172.59 (95% CI: 67.38 to 277.8; P = 0.001), respectively. There was no difference in any of the outcomes after correcting for heterogeneity.While studies to date are limited by heterogeneity and small sample sizes, the combined data suggest similar clinical outcomes in patients with CHF managed with liberal and restrictive fluid intake. Larger studies are needed to confirm our findings. PMID- 25740395 TI - Association between virtual histology intravascular ultrasound findings and subsequent coronary events in patients with acute coronary syndrome. AB - Virtual histology intravascular ultrasound (VH-IVUS) was employed to compare coronary plaque characteristics between acute coronary syndrome (ACS) patients with and without subsequent coronary events.It is critical to predict subsequent coronary events in patients treated for ACS. Coronary artery events sometimes occur in lesions that do not receive intervention.VH-IVUS was performed in 57 patients with ACS to analyze 83 non-culprit lesions. Characteristics of plaques in the non-culprit lesions were determined. Patients were followed-up for 4.8 +/- 1.8 years.During the follow-up period, ACS and stable angina pectoris occurred in 7 patients in whom 13 non-culprit lesions had been analyzed. Seventy non-culprit lesions in 50 patients who did not experience subsequent coronary events were also analyzed. Plaque area was greater in 7 patients who had subsequent coronary events than in those who did not (11.5 +/- 3.1 versus 9.1 +/- 3.6 mm(3)/mm, P = 0.03). However, there was no significant difference in plaque burden between the two groups (57.1 +/- 8.9 versus 55.6 +/- 8.7%, P = 0.18). Areas of dense calcium (DC) and necrotic core (NC) were greater in patients who had subsequent coronary events than in those who did not (0.6 +/- 0.5 versus 0.2 +/- 0.3 mm(3)/mm, P < 0.001, and 1.8 +/- 1.0 versus 1.0 +/- 0.8 mm(3)/mm, P < 0.01, respectively). When DC area was larger (>= 3.4% of the plaque area), the cumulative coronary event rate increased significantly (28.6 versus 6.5%, P < 0.01). This was also true for NC area (>= 20.9%, 31.4 versus 5.1%, P < 0.01).Area size of DC or NC in non culprit plaques may be associated with subsequent coronary events in patients with ACS. PMID- 25740396 TI - Predictors of low cardiac output syndrome after isolated coronary artery bypass grafting. AB - Low cardiac output syndrome (LCOS) is one of the most important complications following coronary artery bypass grafting (CABG) and results in higher morbidity and mortality. However, few reports have focused on the predictors of LCOS following CABG. This study aimed to evaluate the predictors of LCOS following isolated CABG through the review of 1524 consecutive well-documented patients in a single center, retrospective trial.The relevant preoperative and intraoperative data of patients with complete information from medical records undergoing isolated CABG from January 2010 to December 2013 in our center were investigated and retrospectively analyzed. LCOS was considered when the following criteria were met: signs of impairment of body perfusion and need for inotropic support with vasoactive drugs or mechanical circulatory support with an intra-aortic balloon pump to maintain systolic blood pressure greater than 90 mmHg.LCOS developed in 205 patients following CABG, accounting for 13.5% of the total population. The in-hospital mortality in the LCOS group was significantly higher than that in the non-LCOS group (25.4% versus 1.8%, P < 0.0001). In addition to the length of ICU stay and postoperative hospital stay, LCOS was correlated with negative cerebral, respiratory and renal outcomes. Through univariate analysis and then logistic regression analysis, the predictors of LCOS following CABG included older age (age > 65 years) (OR = 1.85, 95%CI 1.27-3.76), impaired left ventricular function (OR = 2.05, 95%CI 1.53-4.54), on-pump CABG (OR = 2.16, 95%CI 1.53-4.86), emergent CPB (OR = 9.15, 95%CI 3.84-16.49), and incomplete revascularization (OR = 2.62, 95%CI 1.79-5.15).LCOS following isolated CABG caused higher mortality, higher rates of morbidity, and longer ICU and postoperative hospital stays. Older age, impaired left ventricular function, on pump CABG, emergent CPB, and incomplete revascularization were identified as 5 predictors of LCOS following isolated CABG surgery. PMID- 25740397 TI - Antiarrhythmic peptide AAP10 prevents arrhythmias induced by protein kinase C activation in rabbit left ventricular wedges. AB - As the mechanisms underlying PKC activation induced arrhythmias are not yet fully verified, we investigated the role of gap junctions in arrhythmias induced by PKC activation.Arterially-perfused rabbit left ventricular preparations were randomly assigned to perfusion with phorbol ester (PMA) or in combination with AAP10. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded throughout all experiments. Changes in connexin43 (Cx43) and nonphosphorylated Cx43 on S368 were measured by Western blot analysis.In the PMA group, the QT interval was shortened, the interval from the peak to the end of the electrocardiographic T wave (Tp-e) and induced nonsustained ventricular tachycardia (VT) were increased, and the expressions of Cx43 and nonphosphorylated Cx43 on S368 were decreased compared with the control group. Compared with the PMA group, without significant changes in the QT interval and the expression of nonphosphorylated connexin43 on S368, Tp-e and induced VT decreased and the expression of Cx43 increased in the AAP10 group.AAP10 can prevent PMA-induced rabbit ventricular arrhythmias by attenuating the increase of Tp-e and the decrease of expression of Cx43. These data suggest that increasing gap junction coupling prevents arrhythmias induced by protein kinase C activation. PMID- 25740398 TI - Predictors of left ventricular hypertrophy and their cutoffs in peritoneal dialysis patients. AB - Cardiovascular complications are the main cause of morbidity and mortality in peritoneal dialysis (PD) patients. Left ventricular hypertrophy (LVH) is a major predictor of the development of cardiovascular events. This study aimed to identify risk factors that contribute to the development of LVH and to determine their cutoffs in patients on maintenance peritoneal dialysis.In this cross sectional study we evaluated the association of 23 variables including age, PD vintage, ultrafiltration, urine volume, residual renal function, mean daily SBP, mean daily DBP, fasting glucose, HbA1c, peritoneal glucose load index (PGLI), fluid overload (FO), plasma brain natriuretic peptide (BNP), plasma hsCRP and IL 6, serum albumin, white blood cell (WBC) count, hemoglobin, hematocrit, triglycerides, LDL-C (low density lipoprotein cholesterol), HDL-C (high density lipoprotein cholesterol), and PTH with LVH in 38 stable patients on maintenance PD >= 24 months.LVH was detected in 57.9% of patients. Logistic regression and receiver operating characteristics (ROC) analysis revealed that HbA1c, PGLI, FO, plasma BNP, hsCRP and IL-6 seem to be possible predictors of LVH. The cutoffs associated with the presence of LVH were: 7.5%, 3.2 g/kg/day, 1.7 L, 330 pg/mL, 7.5 mg/dL and 3.3 pg/mL for HbA1c, PGLI, FO, plasma BNP, hsCRP and IL-6, respectively (sensitivity 72.8 to 81.8% and specificity 75.0 to 93.8%).The results suggest that efforts should be made to reduce the peritoneal glucose load (PGL), to improve the hydration status, and to attenuate the inflammatory process in order to reduce the risk of the development of LVH among PD patients. PMID- 25740399 TI - Vasopressin V2 receptor antagonist tolvaptan is effective in heart failure patients with reduced left ventricular systolic function and low blood pressure. AB - Diuresis is a major therapy for the reduction of congestive symptoms in acute decompensated heart failure (ADHF) patients. Carperitide has natriuretic and vasodilatory effects, and tolvaptan produces water excretion without electrolyte excretion. We previously reported the usefulness of tolvaptan compared to carperitide in ADHF patients with fluid volume retention. The purpose of this study was to examine whether the efficacy of tolvaptan was altered in ADHF patients with reduced left ventricular systolic function and in those with hypotension. A total of 109 hospitalized ADHF patients were randomly assigned to either a tolvaptan or a carperitide treatment group. Baseline clinical characteristics were not different between the two groups. We divided these patients based on the left ventricular ejection fraction (EF) by echocardiography, and blood pressure (BP) at the time of admission. Daily urine volume between the tolvaptan and carperitide groups in patients with preserved EF (>= 50%) was not different, however, in those with reduced EF (< 50%), the urine volume was significantly higher in the tolvaptan group than in the carperitide group (day 2, 3, 4, P < 0.05 for all). Daily urine volume did not differ between these two groups in the high blood pressure group (BP >= 140 mmHg), but was significantly higher in the tolvaptan group than in the carperitide group (day 1, P = 0.021; day 3, P = 0.017) in the low blood pressure group (BP < 140 mmHg). The present study reveals that tolvaptan is more effective than carperitide, especially in ADHF patients with reduced left ventricular systolic function and without hypertension. PMID- 25740400 TI - High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery. AB - BACKGROUND: Postoperative non-cardiac complication rates are as high as 11-28% after high-risk abdominal procedures. Emerging evidence indicates that postoperative cardiac troponin T elevations are associated with adverse outcome in non-cardiac surgery. The aim of this study was to determine the relationship between postoperative high-sensitive cardiac troponin T elevations and non cardiac complications in patients after major abdominal surgery. METHODS: This prospective observational single-centre cohort study included patients at risk for coronary artery disease undergoing elective major abdominal surgery. Cardiac troponin was measured before surgery and at day 1, 3, and 7. Multivariable logistic regression analysis was performed to examine the adjusted association for different cut-off concentrations of postoperative myocardial injury and non cardiac outcome. RESULTS: In 203 patients, 690 high-sensitive cardiac troponin T measurements were performed. Fifty-three patients (26%) had a non-cardiac complication within 30 days after surgery. Hospital mortality was 4% (8/203). An increase in cardiac troponin T concentration >=100% compared with baseline was a superior independent predictor of non-cardiac postoperative clinical complications (adjusted odds ratio 4.3, 95% confidence interval 1.8-10.1, P<0.001) and was associated with increased length of stay (9 days, 95% confidence interval 7-11 vs 7 days, 95% confidence interval 6-8, P=0.004) and increased hospital mortality (12 vs 2%, P=0.028). CONCLUSIONS: A postoperative high sensitive cardiac troponin T increase >=100% is a strong predictor of non-cardiac 30 day complications, increased hospital stay and hospital mortality in patients undergoing major abdominal surgery. CLINICALTRIALSGOV IDENTIFIER: NCT02150486. PMID- 25740401 TI - A hyperactive piggyBac transposon system is an easy-to-implement method for introducing foreign genes into mouse preimplantation embryos. AB - Transgenic mice are important tools for genetic analysis. A current prominent method for producing transgenic mice involves pronuclear microinjection into 1 cell embryos. However, the total transgenic efficiency obtained using this method is less than 10%. Here, we demonstrate that highly efficient transgenesis in mice can be achieved by cytoplasmic microinjection using a hyperactive piggyBac system. In embryos in which hyPBase mRNA and pPB-CAG-TagRFP DNA were co-injected into the cytoplasm, TagRFP fluorescence was observed after the 2-cell stage; when 30 ng/ul pPB-CAG-TagRFP DNA and 30 ng/ul hyPBase mRNA were co-injected, 94.4% of blastocysts were TagRFP positive. Furthermore, a high concentration of hyPBase mRNA resulted in creation of mosaic embryos in which the TagRFP signals partially disappeared. However, suitable concentrations of injected DNA and hyPBase mRNA produced embryos in which almost all blastomeres were TagRFP positive. Thus, the hyperactive piggyBac transposon system is an easy-to-implement and highly effective method that can contribute to production of transgenic mice. PMID- 25740402 TI - Spectral and temporal analysis of simulated dead regions in cochlear implants. AB - A cochlear implant (CI) electrode in a "cochlear dead region" will excite neighboring neural populations. In previous research that simulated such dead regions, stimulus information in the simulated dead region was either added to the immediately adjacent frequency regions or dropped entirely. There was little difference in speech perception ability between the two conditions. This may imply that there may be little benefit of ensuring that stimulus information on an electrode in a suspected cochlear dead region is transmitted. Alternatively, performance may be enhanced by a broader frequency redistribution, rather than adding stimuli from the dead region to the edges. In the current experiments, cochlear dead regions were introduced by excluding selected CI electrodes or vocoder noise-bands. Participants were assessed for speech understanding as well as spectral and temporal sensitivities as a function of the size of simulated dead regions. In one set of tests, the normal input frequency range of the sound processor was distributed among the active electrodes in bands with approximately logarithmic spacing ("redistributed" maps); in the remaining tests, information in simulated dead regions was dropped ("dropped" maps). Word recognition and Schroeder-phase discrimination performance, which require both spectral and temporal sensitivities, decreased as the size of simulated dead regions increased, but the redistributed and dropped remappings showed similar performance in these two tasks. Psychoacoustic experiments showed that the near match in word scores may reflect a tradeoff between spectral and temporal sensitivity: spectral-ripple discrimination was substantially degraded in the redistributed condition relative to the dropped condition while performance in a temporal modulation detection task degraded in the dropped condition but remained constant in the redistributed condition. PMID- 25740403 TI - Harmony of CdI2 with CuBr for the one-pot synthesis of optically active alpha allenols. AB - A highly efficient one-pot synthesis of chiral alpha-allenols from propargylic alcohols, aldehydes and pyrrolidine induced by CuBr and (R,Ra)-N-PINAP or (R,Sa) N-PINAP and CdI2 has been developed. Both the yields and enantioselectivities of the allenols of this one-pot procedure are practical. Comparison with ZnI2 control experiments revealed that CdI2 can convert propargylic amine to allene in the presence of CuBr efficiently. PMID- 25740405 TI - Control of coherent information via on-chip photonic-phononic emitter-receivers. AB - Rapid progress in integrated photonics has fostered numerous chip-scale sensing, computing and signal processing technologies. However, many crucial filtering and signal delay operations are difficult to perform with all-optical devices. Unlike photons propagating at luminal speeds, GHz-acoustic phonons moving at slower velocities allow information to be stored, filtered and delayed over comparatively smaller length-scales with remarkable fidelity. Hence, controllable and efficient coupling between coherent photons and phonons enables new signal processing technologies that greatly enhance the performance and potential impact of integrated photonics. Here we demonstrate a mechanism for coherent information processing based on travelling-wave photon-phonon transduction, which achieves a phonon emit-and-receive process between distinct nanophotonic waveguides. Using this device, physics--which supports GHz frequencies--we create wavelength insensitive radiofrequency photonic filters with frequency selectivity, narrow linewidth and high power-handling in silicon. More generally, this emit-receive concept is the impetus for enabling new signal processing schemes. PMID- 25740404 TI - Venous congestion, endothelial and neurohormonal activation in acute decompensated heart failure: cause or effect? AB - Venous congestion and endothelial and neurohormonal activation are known to occur in acute decompensated heart failure (ADHF), yet the temporal role of these processes in the pathophysiology of decompensation is not fully understood. Conventional wisdom presumes congestion to be a consequence of worsening cardiovascular function; however, the biomechanically driven effects of venous congestion are biologically plausible contributors to ADHF that remain largely unexplored in vivo. Recent experimental evidence from human models suggests that fluid accumulation and venous congestion are not simply consequences of poor cardiovascular function, but rather are fundamental pro-oxidant, pro inflammatory, and hemodynamic stimuli that contribute to acute decompensation. The latest advances in the monitoring of volume status using implantable devices allow for the detection of venous congestion before symptoms arise. This may ultimately lead to improved treatment strategies including not only diuretics, but also specific, adjuvant interventions to counteract endothelial and neurohormonal activation during early preclinical decompensation. PMID- 25740406 TI - In situ heater design for nanoscale synchrotron-based full-field transmission X ray microscopy. AB - The oxidation of nickel powder under a controlled gas and temperature environment was studied using synchrotron-based full-field transmission X-ray microscopy. The use of this technique allowed for the reaction to be imaged in situ at 55 nm resolution. The setup was designed to fit in the limited working distance of the microscope and to provide the gas and temperature environments analogous to solid oxide fuel cell operating conditions. Chemical conversion from nickel to nickel oxide was confirmed using X-ray absorption near-edge structure. Using an unreacted core model, the reaction rate as a function of temperature and activation energy were calculated. This method can be applied to study many other chemical reactions requiring similar environmental conditions. PMID- 25740407 TI - Office-Based Balloon Sinus Dilation: 1-Year Follow-up of a Prospective, Multicenter Study. AB - OBJECTIVE: Balloon sinus dilation (BSD) instruments afford the opportunity for office-based sinus procedures in properly selected patients with chronic rhinosinusitis (CRS). This study evaluated patient-reported outcomes 1 year after office-based BSD. METHODS: Adult patients with medically refractory CRS were prospectively enrolled into a multicenter, single-arm study and treated with office-based BSD under local anesthesia. Follow-up on 203 patients was conducted at 2, 8, and 24 weeks postsurgery using validated outcome measures for quality of life (SNOT-20) and computed tomography imaging (Lund-Mackay score). After 24 weeks, patients were re-enrolled for 1-year follow-up to evaluate changes in SNOT 20 scores and revisions. RESULTS: All patients who re-enrolled (n = 122) completed the study, with an average follow-up of 1.4 years. Neither preoperative SNOT-20 nor Lund-Mackay CT scores were predictive of re-enrollment and return for follow-up. Compared to baseline, improvements in SNOT-20 scores remained statistically significant (P < .001) and clinically meaningful (mean decrease >= 0.8). In patients followed to 1.4 years, 9 of 122 (7.4%) had revision surgery. CONCLUSION: Following office-based BSD, significant improvements in quality of life observed at 24 weeks were maintained 1 year postsurgery. These extended results provide further evidence of office-based BSD as an effective, minimally invasive procedure for appropriately selected patients with CRS. PMID- 25740408 TI - Bright luminescence in lanthanide coordination polymers with tetrafluoroterephthalate as a bridging ligand. AB - Ten new coordination polymers of the general compositions infinity2[Ln(III)(tfBDC)(NO3)(DMF)2].DMF with Ln(III) = Eu(3+) (1), Gd(3+) (2), Tb(3+) (3), Ho(3+) (4), Tm(3+) (5), infinity2[Ln(III)(tfBDC)(CH3COO)(FA)3].3FA with Ln(III) = Sm(3+) (6), Eu(3+) (7) and infinity2[Ln(III)(tfBDC)(NO3)(DMSO)2] with Ln(III) = Ho(3+) (8), Er(3+) (9) and Tm(3+) (10) were synthesized and structurally characterized by X-ray single crystal diffraction (tfBDC(2-) = 2,3,5,6-tetrafluoroterephthalate, DMF = N,N'-dimethylformamide, FA = formamide, DMSO = dimethyl sulfoxide). 1-5 crystallize in the monoclinic space group C2/c with Z = 8, 6 and 7 in P1 with Z = 2 and 8-10 in Pbca with Z = 8. All crystal structures contain binuclear lanthanide nodes that are connected by 2,3,5,6 tetrafluoroterephthalates (tfBDC(2-)) to form two-dimensional polymeric structural units. Despite this common structural feature the coordination within these binuclear units is quite different in detail, e.g. CN = 9 for 1-7 and CN = 8 for 8-10. The emission spectra of the europium (1, 7) and terbium (3) compounds reveal bright red and green emission in the visible region. The resulting high quantum yields of 53% (1) and 67% (3) at room temperature show that the replacement of organic ligands with C-H groups by perfluorinated ligands leads to compounds with intense emission, as vibrational quenching is reduced. On the other hand, the influence of the coordinating solvent and additional ligands cannot be neglected, as the replacement of DMF by FA and NO3(-) by CH3COO(-) in 7 leads to a reduced quantum yield of only 10%. Thermoanalytical investigations show that all compounds are stable up to 100-150 degrees C, before a stepwise release of solvent molecules starts followed by a decomposition of the coordination polymer. PMID- 25740409 TI - Dynamics of marine bacterial community diversity of the coastal waters of the reefs, inlets, and wastewater outfalls of southeast Florida. AB - Coastal waters adjacent to populated southeast Florida possess different habitats (reefs, oceanic inlets, sewage outfalls) that may affect the composition of their inherent microbiomes. To determine variation according to site, season, and depth, over the course of 1 year, we characterized the bacterioplankton communities within 38 nearshore seawater samples derived from the Florida Area Coastal Environment (FACE) water quality survey. Six distinct coastal locales were profiled - the Port Everglades and Hillsboro Inlets, Hollywood and Broward wastewater outfalls, and associated reef sites using culture-independent, high throughput pyrosequencing of the 16S rRNA V4 region. More than 227,000 sequences helped describe longitudinal taxonomic profiles of marine bacteria and archaea. There were 4447 unique operational taxonomic units (OTUs) identified with a mean OTU count of 5986 OTUs across all sites. Bacterial taxa varied significantly by season and by site using weighted and unweighted Unifrac, but depth was only supported by weighted Unifrac, suggesting a change due to presence/absence of certain OTUs. Abundant microbial taxa across all samples included Synechococcus, Pelagibacteraceae, Bacteroidetes, and various Proteobacteria. Unifrac analysis confirmed significant differences at inlet sites relative to reef and outfalls. Inlet-based bacterioplankton significantly differed in greater abundances of Rhodobacteraceae and Cryomorphaceae, and depletion of SAR406 sequences. This study also found higher counts of Firmicutes, Chloroflexi, and wastewater associated SBR1093 bacteria at the outfall and reef sites compared to inlet sites. This study profiles local bacterioplankton populations in a much broader context, beyond culturing and quantitative PCR, and expands upon the work completed by the National Oceanic and Atmospheric Administration FACE program. PMID- 25740410 TI - Reconstruction of the segmental mandibular defect using a retroauricular or modified face-lift incision with an intraoral approach in head and neck cancer. AB - CONCLUSIONS: This is the first report of mandibular reconstruction using the retroauricular (RA) or the modified face-lift (MFL) approach in head and neck cancer. This approach may have advantages over the conventional approach, especially in its superior aesthetic results. OBJECTIVE: The fibular osseous or osteocutaneous free flap is a widely accepted option for the reconstruction of mandibular defects. Recently, we devised an RA or an MFL approach for neck dissection (ND) using an endoscopic or robotic surgical system. Here, we performed the reconstruction of a segmental mandibular defect with a fibular free flap using the RA or the MFL approach. METHODS: A total of five patients underwent mandibular reconstruction with the RA or MFL approach for mandibular discontinuity, which developed after the surgical extirpation of head and neck cancer. We performed ND, segmental mandibulectomy, and the reconstruction of the mandibular defect via RA or MFL incisions. RESULTS: An osseous free flap was used for the reconstruction in two patients and the osteocutaneous free flap was used in three patients. The mean operation times for mandibulectomy and ND were 82 (range 45-120) min and 156 (range 140-180) min, respectively. No significant complications were noted. All flaps survived successfully. PMID- 25740411 TI - Effect of solute atoms on dislocation motion in Mg: an electronic structure perspective. AB - Solution strengthening is a well-known approach to tailoring the mechanical properties of structural alloys. Ultimately, the properties of the dislocation/solute interaction are rooted in the electronic structure of the alloy. Accordingly, we compute the electronic structure associated with, and the energy barriers to dislocation cross-slip. The energy barriers so obtained can be used in the development of multiscale models for dislocation mediated plasticity. The computed electronic structure can be used to identify substitutional solutes likely to interact strongly with the dislocation. Using the example of a-type screw dislocations in Mg, we compute accurately the Peierls barrier to prismatic plane slip and argue that Y, Ca, Ti, and Zr should interact strongly with the studied dislocation, and thereby decrease the dislocation slip anisotropy in the alloy. PMID- 25740412 TI - Effect of the siliconization method on particle generation in a monoclonal antibody formulation in pre-filled syringes. AB - Silicone oil is used as a lubricant in glass pre-filled syringes (PFS) but can contribute to the generation of particles within protein formulations in PFS. To mitigate the production of such particles, various silicone oil coating processes have been proposed. In this study, three siliconization methods (the "covalent" method, the "baked silicone oil" method, and the "liquid silicone oil" method) were used to coat glass syringes with silicone oil. Glide forces were determined for syringes coated by each method. Then, a monoclonal antibody formulation or a buffer solution were incubated in the coated syringes in either the presence or absence of an air bubble, and the syringes were rotated end-over-end to induce air bubble movement within the syringe. The particle concentrations were measured throughout the incubation period using flow microscopy. The coating method did not affect particle concentrations measured in buffer alone, nor did the coating method affect particle concentrations measured in antibody formulations in the absence of an air bubble. Particle concentrations were influenced by the syringe coating method in protein formulations agitated in the presence of an air bubble, with the most particles formed in syringes lubricated with liquid silicone oil. Fewer particles were produced in syringes lubricated with baked silicone oil, and the fewest particles were produced in syringes with covalently-attached silicone oil. However, the glide forces measured in syringes coated with silicone oil by each method are inversely correlated with the measured particle concentrations. PMID- 25740414 TI - Genetic rescue of small inbred populations: meta-analysis reveals large and consistent benefits of gene flow. AB - Many species have fragmented distribution with small isolated populations suffering inbreeding depression and/or reduced ability to evolve. Without gene flow from another population within the species (genetic rescue), these populations are likely to be extirpated. However, there have been only ~ 20 published cases of such outcrossing for conservation purposes, probably a very low proportion of populations that would potentially benefit. As one impediment to genetic rescues is the lack of an overview of the magnitude and consistency of genetic rescue effects in wild species, I carried out a meta-analysis. Outcrossing of inbred populations resulted in beneficial effects in 92.9% of 156 cases screened as having a low risk of outbreeding depression. The median increase in composite fitness (combined fecundity and survival) following outcrossing was 148% in stressful environments and 45% in benign ones. Fitness benefits also increased significantly with maternal DeltaF (reduction in inbreeding coefficient due to gene flow) and for naturally outbreeding versus inbreeding species. However, benefits did not differ significantly among invertebrates, vertebrates and plants. Evolutionary potential for fitness characters in inbred populations also benefited from gene flow. There are no scientific impediments to the widespread use of outcrossing to genetically rescue inbred populations of naturally outbreeding species, provided potential crosses have a low risk of outbreeding depression. I provide revised guidelines for the management of genetic rescue attempts. PMID- 25740415 TI - Editorial statement on negative findings. PMID- 25740413 TI - Molecular interaction of alpha-conotoxin RgIA with the rat alpha9alpha10 nicotinic acetylcholine receptor. AB - The alpha9alpha10 nicotinic acetylcholine receptor (nAChR) was first identified in the auditory system, where it mediates synaptic transmission between efferent olivocochlear cholinergic fibers and cochlea hair cells. This receptor gained further attention due to its potential role in chronic pain and breast and lung cancers. We previously showed that alpha-conotoxin (alpha-CTx) RgIA, one of the few alpha9alpha10 selective ligands identified to date, is 300-fold less potent on human versus rat alpha9alpha10 nAChR. This species difference was conferred by only one residue in the (-), rather than (+), binding region of the alpha9 subunit. In light of this unexpected discovery, we sought to determine other interacting residues with alpha-CTx RgIA. A previous molecular modeling study, based on the structure of the homologous molluscan acetylcholine-binding protein, predicted that RgIA interacts with three residues on the alpha9(+) face and two residues on the alpha10(-) face of the alpha9alpha10 nAChR. However, mutations of these residues had little or no effect on toxin block of the alpha9alpha10 nAChR. In contrast, mutations of homologous residues in the opposing nAChR subunits (alpha10 Epsilon197, P200 and alpha9 T61, D121) resulted in 19- to 1700-fold loss of toxin activity. Based on the crystal structure of the extracellular domain (ECD) of human alpha9 nAChR, we modeled the rat alpha9alpha10 ECD and its complexes with alpha-CTx RgIA and acetylcholine. Our data support the interaction of alpha-CTx RgIA at the alpha10/alpha9 rather than the alpha9/alpha10 nAChR subunit interface, and may facilitate the development of selective ligands with therapeutic potential. PMID- 25740416 TI - The tomato I-3 gene: a novel gene for resistance to Fusarium wilt disease. AB - Plant resistance proteins provide race-specific immunity through the recognition of pathogen effectors. The resistance genes I, I-2 and I-3 have been incorporated into cultivated tomato (Solanum lycopersicum) from wild tomato species to confer resistance against Fusarium oxysporum f. sp. lycopersici (Fol) races 1, 2 and 3, respectively. Although the Fol effectors corresponding to these resistance genes have all been identified, only the I-2 resistance gene has been isolated from tomato. To isolate the I-3 resistance gene, we employed a map-based cloning approach and used transgenic complementation to test candidate genes for resistance to Fol race 3. Here, we describe the fine mapping and sequencing of genes at the I-3 locus, which revealed a family of S-receptor-like kinase (SRLK) genes. Transgenic tomato lines were generated with three of these SRLK genes and one was found to confer Avr3-dependent resistance to Fol race 3, confirming it to be I-3. The finding that I-3 encodes an SRLK reveals a new pathway for Fol resistance and a new class of resistance genes, of which Pi-d2 from rice is also a member. The identification of I-3 also allows the investigation of the complex effector-resistance protein interaction involving Avr1-mediated suppression of I 2- and I-3-dependent resistance in tomato. PMID- 25740417 TI - Multimodality imaging of multivalvular endocarditis after transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to surgery for severe aortic stenosis in non-operable and high surgical risk patients. While endocarditis following TAVR is rare, the significant co morbidities commonly found in this patient population can complicate evaluation and management. A case of TAVR endocarditis initially diagnosed by cardiac computed tomography angiography and confirmed with transesophageal echocardiogram is presented. In addition to demonstrating the appearance of vegetations and perivalvular involvement in endocarditis complicating TAVR, this case illustrates the utility of cardiac CT techniques in imaging suspected TAVR endocarditis. PMID- 25740418 TI - Assessment of physiological factors for the establishment of serum insulin reference intervals in healthy Chinese Han adults: A community-based large cross sectional study. AB - The aim of this study was to investigate physiological factors that affect serum insulin levels and to establish insulin reference intervals for healthy Chinese Han adults. A total of 4401 subjects with normal glucose tolerance (NGT) were screened from 10,027 individuals in an epidemiological study. Based on the exclusion criteria, 2414 apparently healthy adults (healthy) were selected as reference individuals. Serum insulin levels of the reference individuals were measured at fasting, 30 min and 120 min after oral glucose tolerance test (OGTT). Significant correlations were found between serum insulin levels and physiological factors in healthy subjects, including body mass index (BMI), weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), etc. (p < 0.05). No increase or decrease was found in age-dependent insulin levels by ANOVA (p > 0.05). There was also no substantial difference in fasting serum insulin levels between males and females (p > 0.05). However, we detected notable differences in serum insulin levels between males and females at 30 min (p < 0.01), which became more pronounced at 120 min (p < 0.001). According to our data, BMI/gender-related insulin reference intervals were defined by calculating 2.5th and 97.5th percentiles. The insulin reference intervals, determined after assessing the relationship between physiological factors and serum insulin levels in Chinese adults, will provide valuable information for physicians in their interpretation of insulin levels. PMID- 25740419 TI - Immunolocalization of sulfhydryl oxidase in reptilian epidermis indicates that the enzyme participates mainly to the hardening process of the beta-corneous layer. AB - Reptilian skin is tough and scaled representing an evolutionary adaptation to the terrestrial environment. The presence of sulfhydryl oxidase during the process of hardening of the corneous layer in reptilian epidermis has been analyzed by immunocytochemistry and immunoblotting. Sulfhydryl oxidase-like immunoreactivity of proteins in the 50-65 kDa range of molecular weight is mainly observed in the transitional and pre-corneous layers of crocodilians, chelonian, and in the forming beta-layer of lepidosaurians. The ultrastructural localization of the enzyme by immunogold in lizard epidermis during renewal and resting stages shows that the labeling is mainly distributed in the cytoplasm and along the accumulating beta-packets of differentiating beta-cells while it appears very low to undetectable in differentiating alpha-cells of the lacunar, clear, mesos, and alpha-layers. The labeling however becomes absent or undetectable also in the fully mature beta-layer. The study shows that an oxidative enzyme is likely responsible of the cross-linking of the numerous cysteines present in the main proteins accumulated in corneocytes of reptilian epidermis, known as corneous beta-proteins (beta-keratins). This process of disulphide bond formation is probably largely responsible for the formation of hard beta-corneous layers in reptilian scales, a difference with alpha-corneous layers where substrate proteins of transglutaminase appear predominant. PMID- 25740420 TI - Endoplasmic reticulum Ca(2+) content decrease by PKA-dependent hyperphosphorylation of type 1 IP3 receptor contributes to prostate cancer cell resistance to androgen deprivation. AB - Reference treatment of advanced prostate cancer (PCa) relies on pharmacological or surgical androgen deprivation therapy. However, it is only temporarily efficient as tumor cells inevitably adapt to the low testosterone environment and become hormone-refractory (HRPCa). We observed that androgen removal in HRPCa derived LNCaP cells causes different alterations in their Ca(2+) homeostasis among which a reduction of ER Ca(2+) content. We show that the decrease in [Ca(2+)]ER is due to a modest overexpression of type 1 IP3R and a threefold increased phosphorylation of IP3R1 on Ser-1716, a protein kinase A (PKA) consensus site, both implicated in ER Ca(2+) leak. Accordingly, ER Ca(2+) content was restored by siRNA-mediated down-regulation of IP3R1 or by inhibition of its phosphorylation by competition with a permeant TAT-peptide containing the Ser 1716 consensus phosphorylation sequence or by treatment with the PKA inhibitor H89. Moreover, inhibition of the IP3R1 phosphorylation by both methods sensitized the LNCaP cells to androgen deprivation-induced apoptosis. In addition, SERCA2b overexpression precluded the effect of androgen deprivation on ER Ca(2+) store content and reduced resistance to androgen deprivation. Taken together, these results indicate that lowering the ER Ca(2+)-store content by increasing IP3R1 levels and IP3R1 phosphorylation by PKA is a protective mechanism by which HRPCa derived cells escape cell death in the absence of androgenic stimulation. PMID- 25740421 TI - Tumorigenesis: Order matters. PMID- 25740422 TI - Inflammation: An innate response. PMID- 25740423 TI - [Epidemiological characteristic of occupational pneumatosis cystoides intestinalis]. PMID- 25740424 TI - Dharmasena case: responsibility takes precedence over accountability. PMID- 25740425 TI - Retrospective cohort study comparing activated partial thromboplastin time versus anti-factor Xa activity nomograms for therapeutic unfractionated heparin monitoring in pediatrics. AB - BACKGROUND: Unfractionated heparin (UFH) is widely used to treat thromboembolic disease, but monitoring in children is challenging. Both activated partial thromboplastin time (aPTT) and anti-factor Xa activity (anti-Xa) are utilized, but a comparison of dosing nomograms has not been reported in pediatrics. OBJECTIVE: To compare the performance of aPTT and anti-Xa for UFH monitoring in pediatric patients. DESIGN/METHODS: A retrospective cohort study was conducted in patients <= 21 years old treated with UFH at Johns Hopkins Hospital from January 2009 to May 2011. For monitoring, an aPTT nomogram was used for the initial 15 months, and an anti-Xa nomogram was used for the subsequent 12 months. Clinical characteristics, laboratory data and outcomes were analyzed. RESULTS: Thirty-four patients were monitored with aPTT and 26 patients with anti-Xa. There was no significant difference in median time to therapeutic range (11.6 h aPTT, 95%CI = 6.0-17.0; 9.9 h anti-Xa, 95%CI = 7.3-20.7) or per cent of patients achieving therapeutic measurements at 24 (79% aPTT, 95%CI = 62-91; 73% anti-Xa, 95%CI = 52 88) and 48 h (88% aPTT, 95%CI = 73-97; 96% anti-Xa, 95%CI = 80-100). However, anti-Xa measurements were more frequently therapeutic than aPTT (74% [95%CI = 69 78] vs. 54% [95%CI = 50-59]). Variance between anti-Xa and aPTT measurements was high (R(2) = 0.236). No significant difference was seen in bleeding incidence (9% aPTT, 95%CI = 2-24; 15% anti-Xa, 95%CI = 4-35). CONCLUSION: The time to achieve therapeutic measures and bleeding outcomes were not significantly different between anti-Xa and aPTT nomograms. However, a small study size limits the power to detect clinically relevant differences. The results warrant larger prospective studies of UFH monitoring in children with thromboembolic disease. PMID- 25740426 TI - N-(1-Oxy-2-picolyl)oxalamic acids as a new type of O,O-ligands for the Cu catalyzed N-arylation of azoles with aryl halides in water or organic solvent. AB - N-(1-Oxy-pyridin-2-ylmethyl)oxalamic acids (L3-L5) were identified as novel efficient ligands for copper-catalyzed C-N cross-coupling of azoles and aryl halides in water. The N-arylation of imidazoles, indoles and pyrazoles proceeded with moderate to excellent yields and complete selectivity over aromatic amines and phenols. Moreover, L5, which is also efficient in organic solvent with low catalyst loading, can be used to promote the N-arylation reactions with water sensitive materials. The catalytic mechanism was proposed based on the results of several verification experiments which indicated that the ligands as new-type chelators may coordinate to Cu(I) with two oxygen atoms of N-oxide and amide in the coupling process. PMID- 25740427 TI - HPTLC Method for Quantitative Determination of Zopiclone and Its Impurity. AB - This study was designed to establish, optimize and validate a sensitive, selective and accurate high-performance thin layer chromatographic (HPTLC) method for determination of zopiclone (ZPC) and its main impurity, 2-amino-5 chloropyridine, one of its degradation products, in raw material and pharmaceutical formulation. The proposed method was applied for analysis of ZPC and its impurity over the concentration range of 0.3-1.4 and 0.05-0.8 ug/band with accuracy of mean percentage recovery 99.92% +/- 1.521 and 99.28% +/- 2.296, respectively. The method is based on the separation of two components followed by densitometric measurement of the separated peaks at 305 nm. The separation was carried out on silica gel HPTLC F254 plates, using chloroform-methanol-glacial acetic acid (9:1:0.1, by volume) as a developing system. The suggested method was validated according to International Conference on Harmonization guidelines and can be applied for routine analysis in quality control laboratories. The results obtained by the proposed method were statistically compared with the reported method revealing high accuracy and good precision. PMID- 25740428 TI - Biomass yield efficiency of the marine anammox bacterium, "Candidatus Scalindua sp.," is affected by salinity. AB - The growth rate and biomass yield efficiency of anaerobic ammonium oxidation (anammox) bacteria are markedly lower than those of most other autotrophic bacteria. Among the anammox bacterial genera, the growth rate and biomass yield of the marine anammox bacterium "Candidatus Scalindua sp." is still lower than those of other anammox bacteria enriched from freshwater environments. The activity and growth of marine anammox bacteria are generally considered to be affected by the presence of salinity and organic compounds. Therefore, in the present study, the effects of salinity and volatile fatty acids (VFAs) on the anammox activity, inorganic carbon uptake, and biomass yield efficiency of "Ca. Scalindua sp." enriched from the marine sediments of Hiroshima Bay, Japan, were investigated in batch experiments. Differences in VFA concentrations (0-10 mM) were observed under varying salinities (0.5%-4%). Anammox activity was high at 0.5%-3.5% salinity, but was 30% lower at 4% salinity. In addition, carbon uptake was higher at 1.5%-3.5% salinity. The results of the present study clearly demonstrated that the biomass yield efficiency of the marine anammox bacterium "Ca. Scalindua sp." was significantly affected by salinity. On the other hand, the presence of VFAs up to 10 mM did not affect anammox activity, carbon uptake, or biomass yield efficiency. PMID- 25740429 TI - Increasing the stability of the bacteriophage endolysin PlyC using rationale based FoldX computational modeling. AB - Endolysins are bacteriophage-derived peptidoglycan hydrolases that represent an emerging class of proteinaceous therapeutics. While the streptococcal endolysin PlyC has been validated in vitro and in vivo for its therapeutic efficacy, the inherent thermosusceptible structure of the enzyme correlates to transient long term stability, thereby hindering the feasibility of developing the enzyme as an antimicrobial. Here, we thermostabilized the cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) domain of the PlyCA catalytic subunit of PlyC using a FoldX-driven computational protein engineering approach. Using a combination of FoldX and Rosetta algorithms, as well as visual inspection, a final list of PlyC point mutant candidates with predicted stabilizing DeltaDeltaG values was assembled and thermally characterized. Five of the eight point mutations were found experimentally to be destabilizing, a result most likely attributable to computationally modeling a complex and dynamic nine-subunit holoenzyme with a corresponding 3.3-A X-ray crystal structure. However, one of the mutants, PlyC (PlyCA) T406R, was shown experimentally to increase the thermal denaturation temperature by ~2.2 degrees C and kinetic stability 16-fold over wild type. This mutation is expected to introduce a thermally advantageous hydrogen bond between the Q106 side chain of the N-terminal glycosyl hydrolase domain and the R406 side chain of the C-terminal CHAP domain. PMID- 25740430 TI - Motor functions and adaptive behaviour in children with childhood apraxia of speech. AB - PURPOSE: Undiagnosed motor and behavioural problems have been reported for children with childhood apraxia of speech (CAS). This study aims to understand the extent of these problems by determining the profile of and relationships between speech/non-speech oral, manual and overall body motor functions and adaptive behaviours in CAS. METHOD: Eighteen children (five girls and 13 boys) with CAS, 4 years 4 months to 10 years 6 months old, participated in this study. The assessments used were the Verbal Motor Production Assessment for Children (VMPAC), Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) and Adaptive Behaviour Assessment System (ABAS-II). RESULT: Median result of speech/non-speech oral motor function was between -1 and -2 SD of the mean VMPAC norms. For BOT-2 and ABAS-II, the median result was between the mean and -1 SD of test norms. However, on an individual level, many children had co-occurring difficulties (below -1 SD of the mean) in overall and manual motor functions and in adaptive behaviour, despite few correlations between sub-tests. CONCLUSION: In addition to the impaired speech motor output, children displayed heterogeneous motor problems suggesting the presence of a global motor deficit. The complex relationship between motor functions and behaviour may partly explain the undiagnosed developmental difficulties in CAS. PMID- 25740431 TI - Wheat enolase demonstrates potential as a non-toxic cryopreservation agent for liver and pancreatic cells. AB - Cryopreservation is essential for long-term storage of cells and tissues, which can be used for clinical applications such as drug toxicity testing, human transplantation, reproductive, regenerative and transfusion medicine. It requires use of cryoprotectants (e.g. dimethyl disulfoxide (DMSO), glycerol) that protect cells and tissues from dehydration and damage caused by formation of intracellular ice during freezing. As an alternative to these cytotoxic cryoprotectants, we are developing new technology using natural substances produced by plants that survive freezing conditions. We previously showed that soluble protein extracts such as wheat protein extract (WPE) prepared from winter wheat plants can substitute for DMSO as a cryoprotectant for certain mammalian cell types. To identify novel cryoactive proteins, WPE was separated using different chromatographic procedures and cryoactive fractions were analyzed by mass spectrometry. The analysis revealed enolase as a potential wheat protein candidate. A recombinant enolase protein was prepared and was able to successfully cryopreserve rat hepatocytes and insulin-secreting INS832/13 pancreatic cells. Post-thaw cells had high viability and levels of metabolic activities. Cryopreserved cells were plateable and had good adherence and morphological properties. These results indicate that individual plant proteins such as enolase have promising potential as new, non-toxic technology for cryopreservation protocols used for clinical applications. PMID- 25740432 TI - AKT and 14-3-3 regulate Notch4 nuclear localization. AB - Members of the Notch family of transmembrane receptors, Notch1-4 in mammals, are involved in the regulation of cell fate decisions and cell proliferation in various organisms. The Notch4 isoform, which is specific to mammals, was originally identified as a viral oncogene in mice, Int3, able to initiate mammary tumors. In humans, Notch4 expression appears to be associated with breast cancer stem cells and endocrine resistance. Following ligand binding, the Notch4 receptor undergoes cleavage at the membrane and the Notch4-intracellular domain (ICD), translocates to the nucleus and regulates gene transcription. Little is known on the mechanisms regulating Notch4-ICD and its nuclear localization. Here, we describe the identification of four distinct AKT phosphorylation sites in human Notch4-ICD and demonstrate that AKT binds Notch4-ICD and phosphorylates all four sites in vitro and in vivo. The phosphorylation in cells is regulated by growth factors and is sensitive to phosphatidyl inositol-3 kinase (PI3K) inhibitors. This phosphorylation generates binding sites to the 14-3-3 regulatory proteins, which are involved in the regulation of nucleocytoplasmic shuttling of target proteins, restricting phosphorylated Notch4-ICD to the cytoplasm. Our findings provide a novel mechanism for Notch4-ICD regulation, suggesting a negative regulatory role for the PI3K-AKT pathway in Notch4 nuclear signaling. PMID- 25740433 TI - Precise in-frame integration of exogenous DNA mediated by CRISPR/Cas9 system in zebrafish. AB - The CRISPR/Cas9 system provides a powerful tool for genome editing in various model organisms, including zebrafish. The establishment of targeted gene disrupted zebrafish (knockouts) is readily achieved by CRISPR/Cas9-mediated genome modification. Recently, exogenous DNA integration into the zebrafish genome via homology-independent DNA repair was reported, but this integration contained various mutations at the junctions of genomic and integrated DNA. Thus, precise genome modification into targeted genomic loci remains to be achieved. Here, we describe efficient, precise CRISPR/Cas9-mediated integration using a donor vector harbouring short homologous sequences (10-40 bp) flanking the genomic target locus. We succeeded in integrating with high efficiency an exogenous mCherry or eGFP gene into targeted genes (tyrosinase and krtt1c19e) in frame. We found the precise in-frame integration of exogenous DNA without backbone vector sequences when Cas9 cleavage sites were introduced at both sides of the left homology arm, the eGFP sequence and the right homology arm. Furthermore, we confirmed that this precise genome modification was heritable. This simple method enables precise targeted gene knock-in in zebrafish. PMID- 25740434 TI - Stability of CART peptide expression in the nucleus accumbens in aging. AB - Aging is accompanied by changes of several anorexigenic and orexigenic neuropeptides expressed in various brain areas that control food intake and these changes correlate with senescent anorexia. During aging expression of cocaine- and amphetamine-regulated transcript (CART) peptide was reported to be reduced in the hypothalamic nuclei related to food intake. Although CART peptide is abundant in the nucleus accumbens that also plays a crucial role in the food intake regulation, no data is available about the CART peptide expression in this region through aging. In the present study, CART peptide immunoreactivity was compared in the nucleus accumbens of young adult (4- and 7-month-old) middle-aged (15 month-old) and aging (25-32-month-old) Long-Evans rats. The density of CART immunoreactive cells and axon terminals in the nucleus accumbens was measured with computer-aided densitometry. CART-immunodensity was similar in the old rats and in the younger animals without significant difference between age groups. In addition, no gender-difference was observed when CART-immunoreactivities in the nucleus accumbens of male and female animals were compared. Our results indicate that CART peptide expression in the nucleus accumbens is stable in adults and does not change with age. PMID- 25740435 TI - Rutin, a flavonoid phytochemical, ameliorates certain behavioral and electrophysiological alterations and general toxicity of oral arsenic in rats. AB - Arsenic affects large populations and attacks, among others, the nervous system. Waterborne or occupational exposure causes electrophysiological alterations and motor disturbances in humans, and analogous effects were found in animals. Certain phytochemicals may be protective against As-caused damages. In the present study it was investigated whether the flavonoid rutin, applied via the drinking water (2 g/L), ameliorates the effects of arsenic given by gavage (10 mg/kg b.w., in form of NaAsO2) on open field motility, evoked cortical and peripheral electrophysiological activity, and body weight gain in adult male Wistar rats. Body weight gain was significantly reduced from the 4th week of the 6 weeks arsenic treatment and this effect was largely abolished by rutin in the combination treatment group. Rats treated by arsenic alone showed decreased open field motility; latency of the cortical evoked potentials increased and peripheral nerve conduction velocity decreased. These functional alterations were also counteracted by co-administration of rutin, and both the antioxidant and the chelating activity of rutin might have contributed to the ameliorative effect. These results are apparently novel and support the potential role of natural agents in preserving human health in a contaminated environment. PMID- 25740436 TI - A comparison of rating and coding behavioural traits in dogs. AB - The aim of the present study was to examine the links between independent rating and coding approaches to assessing activity-impulsivity and inattention in dogs. Fifty-six adult Belgian shepherd dogs were videotaped performing in behavioural tests. Seventeen behavioural variables were measured by coders (video coding). Raters watched the same videotapes and then rated the activity-impulsivity and inattention of each dog (video rating). Owners filled out the Dog ADHS-RS questionnaire measuring activity-impulsivity and inattention. Video rating of activity-impulsivity correlated with the scale scores of the owner, but video codings did not. The results suggest that the owner ratings and video ratings are tapping the same constructs, but behavioural variables assessed in the present study were not appropriate for mirroring the owners' assessments. The findings suggest that if consistent individual differences in broad behavioural traits are the primary focus of analyses, then ratings seem to capture information not easily captured in coding approaches designed to assess the same constructs. PMID- 25740437 TI - Determination of 17alpha-hydroxylase-C17,20-lyase (P45017alpha) enzyme activities and their inhibition by selected steroidal picolyl and picolinylidene compounds. AB - 17alpha-hydroxylase-C17,20-lyase (P45017alpha) is a key regulator enzyme of the steroid hormone biosynthesis in both the adrenals and the testes. Inhibition of this enzyme can block androgen synthesis in an early step, and may thereby be useful in the treatment of several androgen-dependent diseases. We developed radio-substrate in vitro incubation methods for the determination of the distinct 17alpha-hydroxylase and C17,20-lyase activities of the enzyme using rat testicular homogenate as enzyme source. With this method we have studied the inhibiting activity of selected steroidal picolyl and picolinylidene compounds. Tests revealed a substantial inhibitory action of the 17-picolinyliden-androst-4 en-3-one compound. PMID- 25740439 TI - Localization of BEN1-LIKE protein and nuclear degradation during development of metaphloem sieve elements in Triticum aestivum L. AB - Metaphloem sieve elements (MSEs) in the developing caryopsis of Triticum aestivum L. undergo a unique type of programmed cell death (PCD); cell organelles gradually degrade with the MSE differentiation while mature sieve elements keep active. This study focuses on locating BEN1-LIKE protein and nuclear degradation in differentiating MSEs of wheat. Transmission electron microscopy (TEM) showed that nuclei degraded in MSE development. First, the degradation started at 2-3 days after flowering (DAF). The degraded fragments were then swallowed by phagocytic vacuoles at 4 DAF. Finally, nuclei almost completely degraded at 5 DAF. We measured the BEN1-LIKE protein expression in differentiating MSEs. In situ hybridization showed that BEN1-LIKE mRNA was a more obvious hybridization signal at 3-4 DAF at the microscopic level. Immuno-electron microscopy further revealed that BEN1-LIKE protein was mainly localized in MSE nuclei. Furthermore, MSE differentiation was tested using a TSQ Zn2+ fluorescence probe which showed that the dynamic change of Zn2+ accumulation was similar to BEN1-LIKE protein expression. These results suggest that nucleus degradation in wheat MSEs is associated with BEN1-LIKE protein and that the expression of this protein may be regulated by Zn2+ accumulation variation. PMID- 25740438 TI - Pretreatment with polyamines alleviate the deleterious effects of diuron in maize leaves. AB - The effects of diuron, a photosystem II inhibiting herbicide, on lipid peroxidation, photosynthetic pigments, soluble protein, proline contents and some antioxidant enzymes in maize leaves were studied and protective effects of polyamines against diuron toxicity were investigated. Diuron significantly increased lipid peroxidation, suggesting oxidative damage in the plants and proline content, while it decreased total chlorophyll, carotenoid and soluble protein levels in the leaves during the experiments. Pretreatment with polyamines statistically decreased lipid peroxidation induced by diuron and spermine (SPM) proved to be the most effective polyamine. Also, pretreatment with polyamines significantly prevented the losses of total chlorophyll, carotenoid and soluble protein induced by diuron. On the other hand, pretreatment with polyamines significantly increased proline contents of the leaves in comparison with the leaves treated with diuron. Superoxide dismutase (SOD), guaiacol peroxidase (GPX) and glutathione reductase (GR) activities increased in the leaves treated with diuron while catalase (CAT ) activity decreased. Pretreatment with spermidine (SPD) did not change significantly SOD activity at 24 and 72 hrs of diuron treatment but prevented the increase in SOD activity induced by diuron at 48 h. However, pretreatment with SPD increased GPX activity at 24 h and GR activity at 48 and 72 hrs. CAT activity in the leaves pretreated with SPD was similar to that of the leaves treated with diuron. Pretreatment with SPM prevented the increase in SOD activity induced by diuron at 48 h but significantly increased it at 72 h of diuron treatment. However, pretreatment with SPM did not significantly change GPX and GR activities during the experiments but reversed the decrease in CAT activity induced by diuron at 72 h. Pretreatment with putrescine (PUT) prevented the increase in SOD activity induced by diuron at 48 and 72 hrs while it increased GPX and GR activities at 48 h of diuron treatment. Also, the decrease in CAT activity induced by diuron at 72 h was completely prevented by PUT. It can be concluded that pretreatment of maize leaves with polyamines reduced the damage produced by diuron and the protective effects of polyamines against diuron toxicity were closely associated with antioxidant system. PMID- 25740440 TI - Chromium translocation, concentration and its phytotoxic impacts in in vivo grown seedlings of Sesbania sesban L. Merrill. AB - The present in vivo pot culture study showed hexavalent chromium (Cr+6) induced phytotoxic impacts and its translocation potential in 21 days old sesban (Sesbania sesban L. Merrill.) seedlings. Cr+6 showed significant growth retardation in 21 days old sesban (Sesbania sesban L. Merrill.) seedlings. Germination of seeds at 10,000 mg L-1 of Cr+6 exhibit 80% inhibition in germination. Seedling survival was 67% after 7 days of seedling exposure to 300 mg kg-1 of Cr+6. Shoot phytotoxicity was enhanced from 6% to 31% with elevated supply of Cr+6 from 10 mg kg-1 to 300 mg kg-1. Elevated supply of Cr+6 exhibited increasing and decreasing trends in % phytotoxicity and seedling tolerance index, respectively. Elevated supply of chromium showed decreased chlorophyll and catalase activities. Peroxidase activities in roots and leaves were significantly higher at increased supply of Cr+6. Cr bioconcentration in roots was nearly 10 times more than stems whereas leaves showed nearly double accumulation than stems. Tissue specific chromium bioaccumulation showed 53 and 12 times more in roots and shoots respectively at 300 mg kg-1 Cr+6 than control. The present study reveals potential of sesban for effective Cr translocation from roots to shoots as evident from their translocation factor and Total Accumulation Rate values. PMID- 25740441 TI - Identification of new SSR markers linked to leaf chlorophyll content, flag leaf senescence and cell membrane stability traits in wheat under water stressed condition. AB - Segregating F4 families from the cross between drought sensitive (Yecora Rojo) and drought tolerant (Pavon 76) genotypes were made to identify SSR markers linked to leaf chlorophyll content, flag leaf senescence and cell membrane stability traits in wheat (Triticum aestivum L.) under water-stressed condition and to map quantitative trait locus (QTL) for the three physiological traits. The parents and 150 F4 families were evaluated phenotypically for drought tolerance using two irrigation treatments (2500 and 7500 m3/ha). Using 400 SSR primers tested for polymorphism in testing parental and F4 families genotypes, the results revealed that QTL for leaf chlorophyll content, flag leaf senescence and cell membrane stability traits were associated with 12, 5 and 12 SSR markers, respectively and explained phenotypic variation ranged from 6 to 42%. The SSR markers for physiological traits had genetic distances ranged from 12.5 to 25.5 cM. These SSR markers can be further used in breeding programs for drought tolerance in wheat. PMID- 25740442 TI - Diversity of active constituents in Cichorium endivia and Cynara cornigera extracts. AB - The present study attempts to explore the phytochemical constituents of different extracts from Cynara cornigera and Cichorium endivia plant materials. The two species studied are native in Egypt. Five different solvents, viz., aqueous, methylene chloride, petroleum ether, ethyl acetate, and n-butanol were used. Phytochemical analysis revealed the presence of phenols, flavonoids, sterols (stigmasterol and beta-sitosterol), terpenes (alpha-amyrin, ursolic and oleanolic acid), and hydrocarbons (n-alkane), the latter found in low amount. The ethyl acetate and water extracts of C. cornigera root showed lower mass fractions of phenolic compounds ranged from 20 to 81 g/100 g, and higher amounts in ethyl acetate extract of the inflorescences and butanol extract of the root where values ranged from 195 to 399 g/100 g. The beta-sitosterol and stigmasterol were present in all plant extracts. Oleanolic and ursolic acids were detected in roots, leaves and inflorescences of C. cornigera and in C. endivia shoot. The ethyl acetate extracts from C. cornigera leaf and inflorescence attained higher chemical diversity than the other extracts. Alternatively, sterols and triterpenes were the major constituents. The high chemical diversity of active constituents justifies the future potential use of the two species at commercial level. PMID- 25740443 TI - Screening, morphological and molecular characterization of fungi producing cystathionine gamma-lyase. AB - The potency for production of cystathionine gamma-lyase (CGL) by the fungal isolates was screened. Among the tested twenty-two isolates, Aspergillus carneus was the potent CGL producer (6.29 U/mg), followed by A. ochraceous (6.03 U/mg), A. versicolor (2.51 U/mg), A. candidus (2.12 U/mg), A. niveus and Penicillium notatum (2.0 U/mg). The potent six isolates producing CGL was characterized morphologically, A. carneus KF723837 was further molecularly characterized based on the sequence of 18S-28S rDNA. Upon sulfur starvation, the yield of A. carneus extracellular CGL was increased by about 1.7- and 4.1-fold comparing to non sulfur starved and L-methionine free medium, respectively. Also, the uptake of L methionine was duplicated upon sulfur starvation, assuming the activation of specific transporters for L-methionine and efflux of CGL. Also, the intracellular thiols and GDH activity of A. carneus was strongly increased by S starvation, revealing the activation of in vivo metabolic antioxidant systems. Upon irradiation of A. carneus by 2.0 kGy of gamma-rays, the activity of CGL was increased by two-fold, regarding to control, with an obvious decreases on its yield upon further doses. Practically, CGL activity from the solid A. carneus cultures, using rice bran as substrate, was increased by 1.2-fold, comparing to submerged cultures, under optimum conditions. PMID- 25740444 TI - A Case of Benign Esophageal Schwannoma Causing Life-threatening Tracheal Obstruction. AB - A 59-year-old woman presented with a 1-year history of dysphagia. She suffered from a large mediastinal mass obstructing trachea and bilateral main bronchus, which led to dyspnea and disturbed consciousness. Immediate intubation and surgery was required. A solid tumor that included esophagus and right vagal nerve, and adhered to the membranous part of the bronchus was found. However, the tumor could be resected en bloc and the patient has been free from recurrence. Pathologically, the tumor exhibited proliferative spindle cells and was diffusely positive for S-100 protein. It was therefore diagnosed as a benign esophageal schwannoma. To our knowledge, this is the first report of tracheal obstruction from a benign esophageal schwannoma, which we successfully treated with emergency subtotal esophagectomy. PMID- 25740445 TI - Ectopic Cervical Thymoma Excised through a Transcervical Approach Combined with Video-assisted Thoracoscopic Surgery: A Case Report. AB - Ectopic cervical thymoma (ECT) is a rare tumor. We present a case of 56-year-old woman with an ECT in the anterior neck that was correctly diagnosed preoperatively. The patient had no symptoms of myasthenia gravis or other immune disorders, and the tumor was not invading any adjacent structures. We performed tumor resection and thymectomy through a transcervical approach using video assisted thoracoscopic surgery with a multi-access single port. To our knowledge, this is a novel combined technique for the resection of an ECT. PMID- 25740446 TI - Predictive Power and Implication of EuroSCORE, EuroSCORE II and STS Score for Isolated Repeated Aortic Valve Replacement. AB - OBJECTIVE: We evaluated the predictive power of the EuroSCORE, EuroSCORE II and Society of Thoracic Surgeons (STS) score for isolated redo aortic valve replacement. MATERIALS AND METHODS: 78 consecutive patients underwent the aforementioned procedure mainly with a stentless valve prosthesis at our institution. Observed mortality was compared to the predicted mortality, Receiver Operating Characteristics (ROC) curves were calculated and the area under the curve (AUC) analyzed. RESULT: Observed mortality was 11.5%. EuroSCORE and EuroScore II predicted a mortality of 28.2 +/- 21.6% (p <0.001) and 10.2 +/- 11.8% (p = 0.75), respectively. AUC of the EuroSCORE was 0.74 (95% CI: 0.62 0.83), p = 0.009 and of the EuroSCORE II 0.86 (95% CI: 0.76-0.93), p <0.0001. Optimal Youden index of the EuroSCORE II was 0.59 referring to a predicted mortality of 9.9% (sensitivity: 77.8% and specificity: 81.2%). Predicted mortality of STS score was 17.8 +/- 10.6% (p = 0.08) and AUC was 0.64 (95% CI: 0.53-0.75), p = 0.06. CONCLUSION: EuroSCORE II calculation was not only superior to EuroSCORE and STS score but led to a very realistic mortality prediction for this special procedure at our institution. A EuroSCORE II greater 10 should encourage to consider an alternative treatment. PMID- 25740447 TI - Results of Lung Cancer Surgery for Octogenarians. AB - PURPOSE: Growing number of elderly lung cancer patients reflecting a lengthening life span has become a serious problem. Purpose of this study was to elucidate the short and long-term outcome of the surgery for octogenarians, and to evaluate the role of lung cancer surgery for this high age group. METHODS: The patients with lung cancer aged 80 years or more who underwent the surgery at our institute from January 1998 through December 2012 were retrospectively analyzed by chart review, and the operative mortality, morbidity and the long-term survival were assessed. RESULTS: Out of a total of 1107 patients with primary lung cancer who received surgery during the study period, 94 were octogenarians (8.5%). Sixty nine patients (73.4%) had preoperative co-morbidity including hypertension in 50 (53.2%), coincidence of other malignancy in 35 (37.2%), anti-coagulant therapy in 29 (30.9%). Twenty-six patients (27.7%) had major or minor postoperative morbidity, and one (1.1%) died due to bronchopleural fistula. Overall-5-year survival rate was 57.5%. Univariative and multivariative analysis using Cox proportional hazard model revealed that male gender and non-adenocarcinoma histology were significant risk factors for poor prognosis. CONCLUSION: Gender and histology should be taken into account in preoperative evaluation of indication for lung cancer in octogenarians. PMID- 25740448 TI - Combined resection of great vessels or the heart for non-small lung cancer. AB - OBJECTIVES: The surgical indications for non-small cell lung cancer (NSCLC) infiltrating a great vessel or the heart are controversial. We assessed clinical features and surgical outcomes of patients with non-small cell lung cancer who underwent combined resection of a lung and great vessel. METHODS: Fourteen patients underwent great vessel resection under a lobectomy (n = 9), sleeve lobectomy (n = 2), or pneumonectomy (n = 3) between 2000 and 2011, in whom the aorta was resected in 6, superior vena cava in 5, right atrium in 1, and left atrium in 2. The histological types were adenocarcinoma (n = 8) and squamous cell carcinoma (n = 6). RESULTS: Complete resection was performed in 12 patients. Of all patients, 7 had pN0 disease, 2 had pN1, and 4 had pN2. The postoperative morbidity rate was 28.6% and mortality rate was 7.1%. The 5-year survival rate was 26.8% for all patients, 46.9% for those with an adenocarcinoma, 0% for those with a squamous cell carcinoma, 53.6% for those with pN0, and 0% for those with pN1-2. CONCLUSION: Resection of the great vessels and heart involved by NSCLC can be performed with acceptable morbidity and mortality, and results in prolonged survival in patients, with an adenocarcinoma or N0 status. PMID- 25740449 TI - Surgical strategy for ischemic mitral regurgitation adopting subvalvular and ventricular procedures. AB - PURPOSE: The progression of left ventricular (LV) remodeling and subsequent mitral valve tethering impair the results of reduction annuloplasty for ischemic mitral regurgitation (MR). METHODS: We studied 90 patients who underwent surgical repair of ischemic MR between 1999 and 2013 according to our surgical strategy adding submitral and ventricular procedures to annuloplasty as follows: annuloplasty alone (stage 1, n = 30), additional papillary muscle approximation (PMA) for progression of tethering (stage 2, n = 26), and additional left ventriculoplasty with PMA for progression of LV remodeling and tethering (stage 3, n = 34). RESULTS: The preoperative New York Heart Association (NYHA) functional classes (2.5 +/- 0.7, 3.1 +/- 0.7 and 3.3 +/- 0.7 for stages 1, 2 and 3, respectively, P <0.001), LV end-diastolic diameters (56 +/- 7 mm, 66 +/- 5 mm and 70 +/- 7 mm, P <0.001), and LV ejection fractions (45 +/- 12%, 32 +/- 9% and 27 +/- 9%, P <0.001) significantly differed among the stages. In contrast, the MR grades did not significantly differ (2.9 +/- 0.8, 3.0 +/- 1.0, and 2.9 +/- 1.1, respectively; P = 0.93). Both the rates of cardiac-related survival and freedom from reoperation were comparable among the 3 groups (log-rank P = 0.92 and 0.58, respectively). CONCLUSION: Additional submitral and ventricular procedures can compensate for the possible impairment of the outcomes after annuloplasty alone for ischemic MR in patients with severe LV remodeling and tethering. PMID- 25740450 TI - Noninvasive Differential Diagnosis of Pulmonary Nodules Using the Standardized Uptake Value Index. AB - OBJECTIVES: We previously showed that the standardized uptake value (SUV) index, which was defined as the ratio of the maximum SUV of the tumor to mean SUV of the liver, was a surrogate marker of lung cancer aggressiveness. In this study of patients with pulmonary nodules (PNs), we explored whether the SUV index could be used to differentiate small malignant from small benign PNs. METHODS: A total of 284 patients with solitary PNs <=2 cm in size underwent positron emission tomography/computed tomography and surgery. The associations between pathological findings and clinical factors were evaluated. RESULTS: The median SUV indices of lung cancer, metastatic PNs and benign nodules were 1.2, 1.5, and 0.6, respectively (P <0.01). A SUV index cut-off value of 1.2 was used to differentiate benign from malignant nodules. When patients were grouped according to SUV index cut-off values of <1.2 or >=1.2, the following cases were false negative: lung adenocarcinoma (P <0.01), kidney as primary site (P <0.01), and metastatic PNs with long disease-free survival (P = 0.02). CONCLUSIONS: As a noninvasive diagnostic marker, the SUV index was found to be useful for differentiating benign from malignant small PNs. PMID- 25740451 TI - Prognostic significance of clinical/pathological stage IA non-small-cell lung cancer showing partially solid or solid tumours on radiological exam. AB - PURPOSE: Although curative resection is expected to be effective in patients with clinical (c-) stage IA/pathological (p-) stage IA non-small-cell lung cancers, recurrence is often observed. Hence, the aim of this study was to identify predictors of recurrence. METHODS: Between 2005 and 2009, 138 patients with c stage IA/p-stage IA non-small-cell lung cancers underwent resection. Recurrence and recurrence-free survival (RFS) were compared with clinical, radiographic and pathological findings. RESULTS: The 5-year cancer-specific survival rate was 97% and the RFS rate was 89% at a median follow-up time of 91 months. Recurrence was observed in 10 patients (7.2%). Significant differences were observed in RFS according to tumour dimensions on the mediastinal window image (>1.5 cm), serum carcinoembryonic antigen levels (>5.0 ng/mL), maximum standardised uptake values (SUVmax >2.5) and angiolymphatic invasion. Patients were grouped according to the number of risk factors for poor RFS. Patients with 0-1 of the identified risk factors had an RFS of 97%, where those with 2-4 factors had an RFS of 68% (p <0.001). CONCLUSION: Prognosis of patients exhibiting more than two of these risk factors is considerably poor. Thus, close observation and individualised adjuvant therapy may be beneficial to these patients. PMID- 25740452 TI - Impact of transapical aortic cannulation for acute type A aortic dissection. AB - OBJECTIVE: Early and mid-term result of transapical aortic (TAA) cannulation technique was evaluated compared with femoral artery (FA) cannulation in Acute Type A Aortic Dissection(AAAD). METHODS: From January 2000 to October 2013, 80 consecutive patients with AAAD were underwent the ascending aortic replacement at Nagasaki Kouseikai Hospital. These patients were divided into two groups according to the cannulation site, FA cannulation (n = 34) and TAA cannulation (n = 46). Early and mid-term outcomes were compared between two groups. RESULT: Preoperative patient characteristics were almost comparable between groups. The time from skin incision to starting cardiopulmonary bypass (CPB) was significantly shorter in the TAA group (45 +/- 16 vs 23 +/- 5.1 min; P <0.001). There were no significant differences in post-operative cerebral infarction in two groups (17% versus 11%; P = NS). The operative mortality rate was 8.8% in FA group and 4.3% in TAA group (P = NS). During follow up (mean, 6.8 years), survival at 3 years and 5 years was 77.4% and 71.9% in TAA group and 76.3% and 73.8% in FA group, respectively. CONCLUSION: The postoperative morbidity and mortality between the two groups were almost the same. TAA cannulation for acute Type A aortic dissection is faster, easy and safe with acceptable early and mid term outcome. PMID- 25740453 TI - Effects of continuous infusion of low-dose human atrial natriuretic peptide (hANP) on the lungs during cardiac surgery. AB - OBJECTIVE: The objective of this study was to determine the effects of a continuous infusion of low-dose hANP on the lungs during cardiac surgery in patients under cardiopulmonary bypass (CPB). METHODS: We analyzed 30 consecutive cases of cardiac surgery performed at our hospital from 2007-2008. The patients were divided into a group that received hANP (hANP group) or a group that received saline and no hANP (N-hANP group). We measured various parameters before and after surgery using a PiCCO monitor. RESULT: There were no differences in the preoperative characteristics between the groups, although urine volume during the operation was significantly greater in the hANP group. After surgery, there were no significant differences between the groups in cardiac output index (CI), global enddiastolic volume index (GEDVI), intrathoracic blood volume index (ITBI), pulmonary blood volume index (PBI), extravascular lung water index (ELWI) and pulmonary vascular permeability index (PVPI), total protein, and creatine. In contrast, interleukin-6 (IL-6) and renin were significantly lower, and albumin was significantly higher in the hANP group. CONCLUSION: We found that low-dose hANP during open cardiac surgery inhibited the secretion and plasma activity of IL-6 and renin. Although there were no differences in lung circulatory parameters such as the amount of fluid in the pulmonary blood vessels between the two groups, we believe that the strong diuretic effect of hANP reduced third-space fluid retention caused by CPB. PMID- 25740454 TI - Significant prognostic factors for completely resected pN2 non-small cell lung cancer without neoadjuvant therapy. AB - PURPOSE: To identify prognostic factors for pathologic N2 (pN2) non-small cell lung cancer (NSCLC) treated by surgical resection. METHODS: Between 1990 and 2009, 287 patients with pN2 NSCLC underwent curative resection at the Cancer Institute Hospital without preoperative treatment. RESULTS: The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) rates were 46%, 55% and 24%, respectively. The median follow-up time was 80 months. Multivariate analysis identified four independent predictors for poor OS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.616; p = 0.003); ipsilateral intrapulmonary metastasis (HR, 1.042; p = 0.002); tumor size >30 mm (HR, 1.013; p = 0.002); and clinical stage N1 or N2 (HR, 1.051; p = 0.030). Multivariate analysis identified three independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (HR, 1.457; p = 0.011); ipsilateral intrapulmonary metastasis (HR, 1.040; p = 0.002); and tumor size >30 mm (HR, 1.008; p = 0.032). CONCLUSION: Multiple-zone mediastinal lymph node metastasis, ipsilateral intrapulmonary metastasis, and tumor size >30 mm were common independent prognostic factors of OS, CSS, and RFS in pN2 NSCLC. PMID- 25740456 TI - Synthesis of nanostructured carbon through ionothermal carbonization of common organic solvents and solutions. AB - A combination of ionothermal synthesis and hot-injection techniques leads to novel nanocarbons made from organic solvents. Controlled addition of commonly used organic solvents into a hot ZnCl2 melt gives rise to spherical, sheetlike, and branched nanofibrous carbon nanoparticles with surprisingly high carbon efficiency. When heteroatom-containing solvents were used, the doping levels reach up to 14 wt. % nitrogen and 13 wt. % sulfur. Materials with high surface areas and large pore volumes of solvent carbons as high as 1666 m(2) g(-1) and 2.80 cm(3) g(-1) in addition to CO2 adsorption capacities of 4.13 mmol g(-1) at 273 K and 1 bar can be obtained. The new method works not only for pure carbon materials, but was also extended for the synthesis of carbon/inorganic nanocomposites. ZnS@C, Ni@C, and Co@C were successfully prepared with this straightforward procedure. The obtained Ni@C nanocomposites perform well in the electrocatalytic water oxidation, comparable with commercial noble-metal catalysts. PMID- 25740455 TI - Long term results and predictors of left ventricular function recovery after aortic valve replacement for chronic aortic regurgitation. AB - OBJECTIVES: In most patients with aortic regurgitation (AR), aortic valve replacement (AVR) improves left ventricular (LV) function, but some patients will not have favorable remodeling. Our objectives were to review long term clinical results of AVR for AR and to examine what factors affect the normalization of LV function after AVR for chronic AR. METHODS: Between 1989 and 2010, 177 patients underwent isolated AVR for chronic pure AR. The patients were divided into 2 groups based on indexed end-systolic LV diameter (iESD): Group L (iESD) >=25 mm/m(2)) (130 patients) and Group S (iESD <25 mm/m(2)) (47 patients). RESULTS: There was no significant difference between groups in late mortality, freedom from cardiac-related death and rehospitalization for heart failure at late follow up after operation. At postoperative follow-up, 16% of patients had not recovered normal LV systolic function. By means of multivariate analysis, iESD and cardiac index (CI) were independent predictors of recovery of LV function and iESD >26.7 mm/m(2) and CI <2.71 l/min/m(2) were the best cut-off values. CONCLUSIONS: Early and late surgical results of AVR for chronic AR were good, but for the preservation of postoperative normal LV function, AVR for AR patients should be performed before iESD reaches 26.7 mm/m(2). PMID- 25740457 TI - Macroscopic Carbon Nanotube-based 3D Monoliths. AB - Carbon nanotubes (CNTs) are one of the most promising carbon allotropes with incredible diverse physicochemical properties, thereby enjoying continuous worldwide attention since their discovery about two decades ago. From the point of view of practical applications, assembling individual CNTs into macroscopic functional and high-performance materials is of paramount importance. For example, multiscaled CNT-based assemblies including 1D fibers, 2D films, and 3D monoliths have been developed. Among all of these, monolithic 3D CNT architectures with porous structures have attracted increasing interest in the last few years. In this form, theoretically all individual CNTs are well connected and fully expose their surfaces. These 3D architectures have huge specific surface areas, hierarchical pores, and interconnected conductive networks, resulting in enhanced mass/electron transport and countless accessible active sites for diverse applications (e.g. catalysis, capacitors, and sorption). More importantly, the monolithic form of 3D CNT assemblies can impart additional application potentials to materials, such as free-standing electrodes, sensors, and recyclable sorbents. However, scaling the properties of individual CNTs to 3D assemblies, improving use of the diverse, structure-dependent properties of CNTs, and increasing the performance-to-cost ratio are great unsolved challenges for their real commercialization. This review aims to provide a comprehensive introduction of this young and energetic field, i.e., CNT-based 3D monoliths, with a focus on the preparation principles, current synthetic methods, and typical applications. Opportunities and challenges in this field are also presented. PMID- 25740458 TI - Enhanced biodiesel production in Neochloris oleoabundans by a semi-continuous process in two stage photobioreactors. AB - Under autotrophic conditions, highly productive biodiesel production was achieved using a semi-continuous culture system in Neochloris oleoabundans. In particular, the flue gas generated by combustion of liquefied natural gas and natural solar radiation were used for cost-effective microalgal culture system. In semi continuous culture, the greater part (~80%) of the culture volume containing vegetative cells grown under nitrogen-replete conditions in a first photobioreactor (PBR) was directly transferred to a second PBR and cultured sequentially under nitrogen-deplete conditions for accelerating oil accumulation. As a result, in semi-continuous culture, the productivities of biomass and biodiesel in the cells were increased by 58% (growth phase) and 51% (induction phase) compared to the cells in batch culture, respectively. The semi-continuous culture system using two stage photobioreactors is a very efficient strategy to further improve biodiesel production from microalgae under photoautotrophic conditions. PMID- 25740459 TI - DNA damage in blood cells exposed to low-level lasers. AB - BACKGROUND AND OBJECTIVE: In regenerative medicine, there are increasing applications of low-level lasers in therapeutic protocols for treatment of diseases in soft and in bone tissues. However, there are doubts about effects on DNA, and an adequate dosimetry could improve the safety of clinical applications of these lasers. This work aimed to evaluate DNA damage in peripheral blood cells of Wistar rats induced by low-level red and infrared lasers at different fluences, powers, and emission modes according to therapeutic protocols. MATERIAL AND METHODS: Peripheral blood samples were exposed to lasers and DNA damage was accessed by comet assay. In other experiments, DNA damage was accessed in blood cells by modified comet assay using formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III enzymes. RESULTS: Data show that exposure to low-level red and infrared lasers induce DNA damage depending on fluence, power and emission mode, which are targeted by Fpg and endonuclease III. CONCLUSION: Oxidative DNA damage should be considered for therapeutic efficacy and patient safety in clinical applications based on low-level red and infrared lasers. PMID- 25740460 TI - PhytoREF: a reference database of the plastidial 16S rRNA gene of photosynthetic eukaryotes with curated taxonomy. AB - Photosynthetic eukaryotes have a critical role as the main producers in most ecosystems of the biosphere. The ongoing environmental metabarcoding revolution opens the perspective for holistic ecosystems biological studies of these organisms, in particular the unicellular microalgae that often lack distinctive morphological characters and have complex life cycles. To interpret environmental sequences, metabarcoding necessarily relies on taxonomically curated databases containing reference sequences of the targeted gene (or barcode) from identified organisms. To date, no such reference framework exists for photosynthetic eukaryotes. In this study, we built the PhytoREF database that contains 6490 plastidial 16S rDNA reference sequences that originate from a large diversity of eukaryotes representing all known major photosynthetic lineages. We compiled 3333 amplicon sequences available from public databases and 879 sequences extracted from plastidial genomes, and generated 411 novel sequences from cultured marine microalgal strains belonging to different eukaryotic lineages. A total of 1867 environmental Sanger 16S rDNA sequences were also included in the database. Stringent quality filtering and a phylogeny-based taxonomic classification were applied for each 16S rDNA sequence. The database mainly focuses on marine microalgae, but sequences from land plants (representing half of the PhytoREF sequences) and freshwater taxa were also included to broaden the applicability of PhytoREF to different aquatic and terrestrial habitats. PhytoREF, accessible via a web interface (http://phytoref.fr), is a new resource in molecular ecology to foster the discovery, assessment and monitoring of the diversity of photosynthetic eukaryotes using high-throughput sequencing. PMID- 25740461 TI - Scalloping of the Liver. PMID- 25740462 TI - Reducing PSA-Based Prostate Cancer Screening in Men Aged 75 Years and Older with the Use of Highly Specific Computerized Clinical Decision Support. AB - INTRODUCTION: In 2012, the Veterans Health Administration (VHA) implemented guidelines seeking to reduce PSA-based screening for prostate cancer in men aged 75 years and older. OBJECTIVES: To reduce the use of inappropriate PSA-based prostate cancer screening among men aged 75 and over. SETTING: The Veterans Affairs Greater Los Angeles Healthcare System (VA GLA) PROGRAM DESCRIPTION: We developed a highly specific computerized clinical decision support (CCDS) alert to remind providers, at the moment of PSA screening order entry, of the current guidelines and institutional policy. We implemented the tool in a prospective interrupted time series study design over 15 months, and compared the trends in monthly PSA screening rate at baseline to the CCDS on and off periods of the intervention. RESULTS: A total of 30,150 men were at risk, or eligible, for screening, and 2,001 men were screened. The mean monthly screening rate during the 15-month baseline period was 8.3%, and during the 15-month intervention period, was 4.6%. The screening rate declined by 38% during the baseline period and by 40% and 30%, respectively, during the two periods when the CCDS tool was turned on. The screening rate ratios for the baseline and two periods when the CCDS tool was on were 0.97, 0.78, and 0.90, respectively, with a significant difference between baseline and the first CCDS-on period (p < 0.0001), and a trend toward a difference between baseline and the second CCDS-on period (p = 0.056). CONCLUSION: Implementation of a highly specific CCDS tool alone significantly reduced inappropriate PSA screening in men aged 75 years and older in a reproducible fashion. With this simple intervention, evidence-based guidelines were brought to bear at the point of care, precisely for the patients and providers for whom they were most helpful, resulting in more appropriate use of medical resources. PMID- 25740463 TI - MRSA-Associated Lemierre's Syndrome in an Intravenous Drug User. PMID- 25740464 TI - Aspirin in secondary prevention of recurrent venous thromboembolism. PMID- 25740465 TI - Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation. AB - Ischaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vasculature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation. PMID- 25740466 TI - The TNM system (version 7) is the most accurate staging system for the prediction of loss of life expectancy in differentiated thyroid cancer. AB - OBJECTIVE: Many prognostic systems have been developed for differentiated thyroid cancer. It is unclear which one of these performs 'best'. Our aim was to compare staging systems applicable to our patient database to identify which best predicts DTC-related loss of life expectancy and DTC-specific mortality. DESIGN: Database study of patients with DTC treated in our centre between 1978 (earliest available data) up to and including 1 July 2014. All were staged in accordance with the AMES, Clinical Class, Memorial Sloan Kettering, Ohio State University, TNM versions 5 and 6/7, University of Alabama, University of Munster and qTNM systems. PATIENTS: A total of 2257 patients with differentiated thyroid cancer. MEASUREMENTS: Loss of life expectancy expressed as relative survival and thyroid cancer-specific mortality. Comparison was based on P values of univariate Cox regression analyses as well as analysis of the proportion of variance explained (PVE). RESULTS: Median available follow-up time was 7.2 years (range: 0-35.1 years). Three hundred and twenty-seven patients died, 149 of whom died of DTC. Version 7 of the TNM system was best for predicting DTC-related mortality (P = 7.1 * 10-52 ; PVE = 0.296), followed by TNM version 5 (P = 6.7 * 10-44 ; PVE = 0.255). For prediction of loss of life expectancy, version 7 of the TNM system was also best, closely followed by the Clinical Class system (P both < 2 * 10-16 ). CONCLUSIONS: The UICC/AJCC TNM system version 7 outperforms other prognostic classification systems based on extent of disease at the start of treatment both for prediction of differentiated thyroid cancer-related death and for prediction of loss life expectancy. PMID- 25740467 TI - Cancer resistance, high molecular weight hyaluronic acid, and longevity. AB - Longevity varies greatly among mammals. The naked mole rat is among the longest lived rodents, having an average lifespan of 32 years, compared to the similarly sized house mouse with lifespan of 4 years. The rate of cancer also varies widely among mammals and interestingly, the naked mole rat is essentially cancer-free (Gorbunova et al., Nat Rev Genet 15(531):540, 2014). A series of elegant studies (Tian et al. Nature 499:346-349, 2013) has revealed that this cancer resistance derives from the abundant production of high molecular weight hyaluronic acid. Remarkably, high molecular weight hyaluronic acid, which accumulates within the extracellular matrix, stimulates an intracellular pathway that induces expression of p16(ink4a) and suppresses oncogenic transformation. PMID- 25740468 TI - Lovastatin rescues human and mice cartilage disorders. AB - Statin, a well-known inhibitor of cholesterol synthesis, combats excessive FGF signaling and may rescue the affected. Relevance to CCN family function may be suspected therein. PMID- 25740469 TI - The father of Osseointegration and the godfather of the BAHA: Professor Per Ingvar Branemark, Goteborg Sweden has passed away in his 86th year. PMID- 25740470 TI - A branchial cyst of the pyriform fossa transoral laser resection: a case report. AB - Pyriform sinus malformations represent rare third and fourth branchial anomalies. Fistulae at the latter site were initially described and make up less than 1 % of all brachial anomalies. They may be discovered incidentally, or may present as a neck mass with recurrent infection, dysphagia, or airway compromise, and can be an unusual cause of dysphonia in infant and children. Here, we present a case of third branchial cyst located in pharyngeal wall of the left pyriform sinus which presented with dysphonia since birth in a 6-year-old girl. Transoral CO2 laser excision was carried out successfully with no communicating tract. The patient's dysphonia showed progressive regression at 1-year follow-up. Third branchial cyst in the left pyriform sinus (Bailey's type IV) is an unusual cause of dysphonia in pediatric. Our present case report is the first brachial cyst to be reported in the pyriform fossa and the second branchial anomalies to be excised transorally with CO2 laser. PMID- 25740471 TI - A Targeted Multiple Antigenic Peptide Vaccine Augments the Immune Response to Self TGF-beta1 and Suppresses Ongoing Hepatic Fibrosis. AB - Transforming growth factor (TGF)-beta1 expression is induced upon liver injury, and plays a critical role in hepatic fibrosis. Antibodies against TGF-beta1 represent a novel approach in the treatment of hepatic fibrosis. However, TGF beta1 is not a suitable antigen due to immunological tolerance. In the current study, we synthesized a multiple antigenic peptide (MAP) vaccine against the dominant B-cell epitope of TGF-beta1. The immunogenicity and potential therapeutic effects of this vaccine were examined using a rat model of hepatic fibrosis. Dominant B-cell epitopes of TGF-beta1 were identified using bioinformatic program. An MAP vaccine corresponding to the 90-98 amino acid domain of TGF-beta1 and containing four dendritic arms was synthesized using a 9 fluorenylmethoxycarbonyl solid phase method. Hepatic fibrosis which was induced in male Sprague-Dawley rats received a high-fat diet and ethanol (1.8 g/kg). Starting from the third week, rats were exposed to 40 % carbon tetrachloride (CCl4; 150 MUl/100 g body weight twice weekly, initially 200 MUl/100 g) treatment for a duration of 8 weeks. Rats received the MAP vaccine (100 MUg) or Freund's adjuvant at weeks 1, 3, 5. A group of rats receiving the fibrosis-inducing regimen alone and a group of healthy rats (receiving an olive oil vehicle alone) were included as controls. At the conclusion of the experiment, serum titre of TGF-beta1 antibody was measured using ELISA and a standard liver functional test panel was examined. The extent of hepatic fibrosis was determined by measuring hydroxyproline content in the liver as well as hematoxylin-eosin (HE) and van Gieson (VG) staining. The expression of TGF-beta1 and alpha-smooth muscle actin (alpha-SMA) was examined using immunohistochemistry, and presented as positive staining cells. The MAP purity was >90 % upon reverse phase high-performance liquid chromatography, with apparent molecular weight at 4.77 kDa. Serum TGF beta1 antibody titre was 1:256. The fibrosis-inducing treatment produced significant liver damage, as reflected by increases in liver functional test, HE and VG staining. The MAP vaccine attenuated such damage, as reflected by decreased alanine aminotransferase, aspartate aminotransferase, total bilirubin, and hepatic hydroxyproline (116.78 +/- 23.76 vs. 282.71 +/- 136.94 IU/L; 319.78 +/- 82.48 vs. 495.29 +/- 137.13 IU/L; 2.02 +/- 0.27 vs. 4.01 +/- 0.52 MUmol/L; 263.67 +/- 41.18 vs. 439.14 +/- 43.29 MUg/g vs. in model rats, respectively; p < 0.01), as well as fibrosis extent by HE and VG staining. The MAP vaccine reduced TGF-beta1 and alpha-SMA expression in rats (0.325 +/- 0.059 vs. 0.507 +/- 0.044 IOD/area; 0.318 +/- 0.058 vs. 0.489 +/- 0.029 IOD/area vs. model rats, respectively; p < 0.05). The TGF-beta1 MAP vaccine could generate sufficient antibody that suppresses the development of hepatic fibrosis. PMID- 25740472 TI - Paediatric end-of-life care needs in Switzerland: current practices, and perspectives from parents and professionals. A study protocol. AB - AIM: To present a protocol for a multi-phase study about the current practice of end-of-life care in paediatric settings in Switzerland. BACKGROUND: In Switzerland, paediatric palliative care is usually provided by teams, who may not necessarily have specific training. There is a lack of systematic data about specific aspects of care at the end of a child's life, such as symptom management, involvement of parents in decision-making and family-centred care and experiences and needs of parents, and perspectives of healthcare professionals. DESIGN: This retrospective nationwide multicentre study, Paediatric End-of-LIfe CAre Needs in Switzerland (PELICAN), combines quantitative and qualitative methods of enquiry. METHODS: The PELICAN study consists of three observational parts, PELICAN I describes practices of end-of-life care (defined as the last 4 weeks of life) in the hospital and home care setting of children (0-18 years) who died in the years 2011-2012 due to a cardiac, neurological or oncological disease, or who died in the neonatal period. PELICAN II assesses the experiences and needs of parents during the end-of-life phase of their child. PELICAN III focuses on healthcare professionals and explores their perspectives concerning the provision of end-of-life care. CONCLUSION: This first study across Switzerland will provide comprehensive insight into the current end-of-life care in children with distinct diagnoses and the perspectives of affected parents and health professionals. The results may facilitate the development and implementation of programmes for end-of-life care in children across Switzerland, building on real experiences and needs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01983852. PMID- 25740473 TI - Variation in salamanders: an essay on genomes, development, and evolution. AB - Regeneration is studied in a few model species of salamanders, but the ten families of salamanders show considerable variation, and this has implications for our understanding of salamander biology. The most recent classification of the families identifies the cryptobranchoidea as the basal group which diverged in the early Jurassic. Variation in the sizes of genomes is particularly obvious, and reflects a major contribution from transposable elements which is already present in the basal group.Limb development has been a focus for evodevo studies, in part because of the variable property of pre-axial dominance which distinguishes salamanders from other tetrapods. This is thought to reflect the selective pressures that operate on a free-living aquatic larva, and might also be relevant for the evolution of limb regeneration. Recent fossil evidence suggests that both pre-axial dominance and limb regeneration were present 300 million years ago in larval temnospondyl amphibians that lived in mountain lakes. A satisfying account of regeneration in salamanders may need to address all these different aspects in the future. PMID- 25740474 TI - Maintaining Eastern newts (Notophthalmus viridescens) for regeneration research. AB - The adult Eastern newt, Notophthalmus viridescens, has long served as a model for appendage as well as heart muscle regeneration studies. Newt tissues include all major cell types known in other vertebrates and mammals, including bone, cartilage, tendon, muscle, nerves, dermis, and epidermis. Therefore, these aquatic salamanders make an excellent model for studying the regeneration of complex tissues. Regeneration of adult tissues requires the integration of new tissues with preexisting tissues to form a functioning unit through a process that is not yet well understood. Scale is also an issue, because the regenerating tissues or structures are magnitudes larger than their embryonic counterparts during development, and therefore, it is likely that different physics and mechanics apply. Regardless, regeneration recapitulates to some degree developmental processes. In this chapter, we will describe basic methods for maintaining adult Eastern newts in the laboratory for the study of regeneration. To determine similarities and differences between development and regeneration at the cellular and molecular level, there is also a need for embryonic newt tissue. We therefore also outline a relatively simple way to produce and raise newt embryos in the laboratory. PMID- 25740475 TI - Housing and maintenance of Ambystoma mexicanum, the Mexican axolotl. AB - The aim of this paper is to assemble a significant amount of information on Ambystoma mexicanum, the axolotl salamander, to assist in the basic knowledge needed to raise, breed, and study most aspects of axolotl biology. It is important to understand the basic biology of the axolotl in order to make informed decisions on their proper care and use in experiments. Therefore, we will provide necessary information to the non-herpetologist that will assist in their study of this unique and fascinating animal. We also aim to provide a resource on the general anatomy, behavior, and experimental tips specific to the Mexican axolotl that will be of use to most axolotl laboratories. Axolotls have been actively researched since the 1860s, giving testament to their relatively straightforward maintenance and their versatility as an animal model for development and regeneration. Interest in using the axolotl in laboratory research has grown tremendously over the past decade, so dedicated resources to support the study of this species are needed and encouraged. PMID- 25740476 TI - Husbandry of Spanish ribbed newts (Pleurodeles waltl). AB - Research on urodele amphibians, such as newts, is constantly contributing to our understanding of fundamental biological processes. In the present chapter, we present detailed husbandry protocols for the Spanish ribbed newt (Pleurodeles waltl ). We describe the main phases of their life cycle, with emphasis on the progressive development of sensory, motor, and integration systems, which lead to the acquisition of specific stereotyped (and conditioned) behaviors. The methods are outlined to manage housing, feeding, handling, captive breeding, health monitoring, and euthanasia in this species under laboratory conditions. With minor changes, these protocols can also be applied to other species of urodele amphibians commonly used in laboratory research. PMID- 25740477 TI - Maintaining plethodontid salamanders in the laboratory for regeneration studies. AB - Limb regeneration studies have been extensively carried out in species of Ambystomatidae and Salamandridae families. So far limited research has been conducted in species belonging to the Plethodontidae family, where some of the species differs from other salamander families due to their direct development, thus absence of a larval life. Here, we describe a protocol to maintain the plethodontid salamanders of genus Bolitoglossa species under laboratory conditions to perform regeneration studies. PMID- 25740478 TI - Newt lens transdifferentiation: from lentectomy to immuno-FISH. AB - Newt lens regeneration is achieved by a unique cellular regulation of transdifferentiation where the dorsal iris pigmented epithelial cells (PECs) dedifferentiate and redifferentiate into lens cells. Recent studies have shown that nuclear architecture of PECs is dynamically changed and unique epigenetic regulation in somatic nucleus is crucial in the lens transdifferentiation. Immuno FISH, detection of protein and gene loci in nucleus, is one of the effective tools to analyze nuclear architecture of PECs. In this chapter a whole process from lentectomy to immuno-FISH is described. PMID- 25740479 TI - Studying newt brain regeneration following subtype specific neuronal ablation. AB - The realization that neuronal injury does not result in permanent functional or cellular loss in all vertebrates has fascinated regenerative biologists. Neuronal regeneration occurs in a subset of species, including lizards, teleost fish, axolotls, and newts. One tool for studying neuronal regeneration in the adult brain is intraventricular injection of selective neuronal toxins, which leads to loss of subpopulations of neurons. To trace cells involved in the regeneration process, plasmids encoding reporter proteins can be electroporated in vivo into the cells of interest. This protocol describes methods to label the ependymoglial cells of the brain of the red spotted newt Notophthalmus viridescens and follow their response after ablation of dopaminergic neurons. PMID- 25740480 TI - The accessory limb model: an alternative experimental system of limb regeneration. AB - Accessory limb model (ALM) was developed as an experimental model and functional assay for limb regeneration. The ALM provides several ways to identify pathways and test for signaling molecules that regulate limb regeneration. Here, we summarize the history of the ALM and describe the specific details involved in inducing ectopic blastemas and limbs from a skin wound on the side of the arm. PMID- 25740481 TI - High-efficiency electroporation of the spinal cord in larval axolotl. AB - Axolotls are well known for their remarkable ability to regenerate complex body parts and structures throughout life, including the entire limb and tail. Particularly fascinating is their ability to regenerate a fully functional spinal cord after losing the tail. Electroporation of DNA plasmids or morpholinos is a valuable tool to gain mechanistic insight into the cellular and molecular basis of regeneration. It provides among other advantages a simple and fast method to test gene function in a temporally and spatially controlled manner. Some classic drawbacks of the method, such as low transfection efficiency and damage to the tissue, had hindered our understanding of the contribution of different signaling pathways to regeneration. Here, we describe a comprehensive protocol for electroporation of the axolotl spinal cord that overcomes this limitations using a combination of high-voltage and short-length pulses followed by lower-voltage and longer-length pulses. Our approach yields highly efficient transfection of spinal cord cells with minimal tissue damage, which now allows the molecular dissection of spinal cord regeneration. PMID- 25740482 TI - Pseudotyped retroviruses for infecting axolotl. AB - The ability to introduce DNA elements into host cells and analyze the effects has revolutionized modern biology. Here we describe a protocol to generate Moloney murine leukemia virus (MMLV)-based, replication-incompetent pseudotyped retrovirus capable of infecting axolotls and incorporating genetic information into their genome. When pseudotyped with vesicular stomatitis virus (VSV)-G glycoprotein, the retroviruses can infect a broad range of proliferative axolotl cell types. However, if the retrovirus is pseudotyped with an avian sarcoma leukosis virus (ASLV)-A envelope protein, only axolotl cells experimentally manipulated to express the cognate tumor virus A (TVA) receptor can be targeted by infections. These strategies enable robust transgene expression over many cell divisions, cell lineage tracing, and cell subtype targeting for gene expression. PMID- 25740483 TI - Thyroxine-induced metamorphosis in the axolotl (Ambystoma mexicanum). AB - The axolotl (Ambystoma mexicanum) has remained an important model for regeneration and developmental biology for over a century. Although axolotls in captive-bred colonies usually exist in an aquatic form, they retain the ability to undergo metamorphosis following exposure to thyroid hormone. Here we present a robust method for inducing metamorphosis in adult axolotls that results in high survivability and produces terrestrial animals that can be maintained in long term captivity. PMID- 25740484 TI - Generation of aneurogenic larvae by parabiosis of salamander embryos. AB - Limb regeneration of salamanders is nerve dependent, and the removal of the nerves in early stages of limb regeneration severely curtails the proliferation of the blastemal cells and growth of the regenerate. The removal of the neural tube from a developing salamander embryo results in an aneurogenic larva and the aneurogenic limb (ANL) develops independently without innervation. Paradoxically, the limb in an ANL is capable of regeneration in a nerve-independent manner. Here, we describe a detailed method for the generation of ANL in the spotted salamander, Ambystoma maculatum, for regeneration studies. PMID- 25740486 TI - Derivation and long-term culture of cells from newt adult limbs and limb blastemas. AB - Notwithstanding the key importance of in vivo models for understanding patterning and cellular interactions in the regenerating tailed amphibian (salamander) limb, dissection of molecular mechanisms, as in other species, can be greatly aided by robust in vitro models. This chapter focuses on derivation and maintenance of cell lines from adult post-metamorphic salamanders and in particular cells derived from normal and regenerating limbs. We also describe a protocol for nucleofecting newt cells that can be used both to investigate the gene function in short-term studies and to establish stable cell lines. PMID- 25740487 TI - Culture and transfection of axolotl cells. AB - The use of cells grown in vitro has been instrumental for multiple aspects of biomedical research and especially molecular and cellular biology. The ability to grow cells from multicellular organisms like humans, squids, or salamanders is important to simplify the analyses and experimental designs to help understand the biology of these organisms. The advent of the first cell culture has allowed scientists to tease apart the cellular functions, and in many situations these experiments help understand what is happening in the whole organism. In this chapter, we describe techniques for the culture and genetic manipulation of an established cell line from axolotl, a species widely used for studying epimorphic regeneration. PMID- 25740485 TI - In vivo modulation and quantification of microRNAs during axolotl tail regeneration. AB - The ability to regenerate diseased, injured, or missing complex tissue is widespread throughout lower vertebrates and invertebrates; however, our knowledge of the molecular mechanisms that regulate this amazing ability is still in its infancy. Many recent papers have shown important roles for microRNAs in regulating regeneration in a number of species. The ability to detect and quantify miRNA expression fluctuations at a single cell level in vivo in different cell types during processes like regeneration is very informative. In this chapter, we describe how to use a dual-fluorescent green fluorescent protein (GFP)-reporter/monomeric red fluorescent protein (mRFP)-sensor (DFRS) plasmid to quantitate the dynamics of specific miRNAs over time following miRNA mimic injection as well as during regeneration. In this bicistronic vector, the mRFP allows for verification of miRNA expression, while the GFP functions as an internal control to normalize miRNA expression and thus obtain quantitative results. In addition, we demonstrate how this technique revealed dynamic miR-23a expression and function during tail regeneration. PMID- 25740488 TI - Isolation and culture of neurospheres from the adult newt brain. AB - Neural stem cells (NSCs) give rise to neurons in the adult brain and are possible targets in regenerative therapies. In vitro cultures of NSCs as neurospheres have been established from cells isolated from diverse species. Newts are exceptional regenerators among vertebrates. These animals are able to efficiently replace neurons following ablation of those by activation and subsequent differentiation of NSCs. Here we describe the method for isolating and culturing of NSCs from the newt brain both during self-renewing and differentiating conditions. Newt NSC culture provides a useful tool for functional studies of NSC fate with the potential of resulting in novel regenerative strategies. PMID- 25740489 TI - Methods for axolotl blood collection, intravenous injection, and efficient leukocyte isolation from peripheral blood and the regenerating limb. AB - The vertebrate immune system comprises both adaptive and innate immune cells with distinct functions during the resolution of inflammation and wound healing after tissue injury. Recent evidence implicates a requirement for innate immune cells from the myeloid lineage during the early stages of limb regeneration in the Mexican axolotl. Understanding the functions of innate and adaptive immune cells in the axolotl has been hampered by a lack of approaches to isolate and analyze these cells. Here we describe a protocol to isolate myeloid cells from the regenerating axolotl limb that incorporates intravenous delivery of physiological labels. In addition we provide a protocol to enrich for leukocytes in the peripheral blood. These protocols produce single-cell suspensions that can be analyzed using flow cytometry or sorted into specific subsets using fluorescent activated cell sorting (FACS). FACS is a routine approach to sort cells based on their physical characteristics as well as their cell surface antigen repertoire. Isolated cell populations can then be analyzed in a wide range of downstream assays to facilitate a greater understanding of leukocyte biology in the axolotl. PMID- 25740490 TI - Assessing cardiomyocyte proliferative capacity in the newt heart and primary culture. AB - Unlike humans, adult newts possess extraordinary abilities to functionally regenerate lost and injured organs, including cardiac muscle. The most remarkable feature of mature newt cardiomyocytes is their ability to reenter the cell cycle, undergo cell division, and serve as a reservoir for progenitor cells. There are, however, a number of unsolved questions concerning the cellular and molecular mechanisms that underlie this plasticity; for example, we still lack a deeper understanding of the cell-inherent properties of newt cardiomyocytes and to what degree they differ from their mammalian counterparts. Along with considerable morphological changes at the wound site, a striking feature shared by different regenerating tissues in the newt is an extensive and dynamic remodeling of the extracellular environment. The dynamic signaling between cardiomyocytes and extracellular environment is of eminent importance in the control of the differentiated state of the cell, but the molecular details remain elusive. In this chapter, we describe methods to assess cardiomyocyte proliferation in vivo and enrich primary cardiomyocytes from newt hearts to study their behavior, taking extracellular matrix components into consideration. PMID- 25740491 TI - Long-term organ cultures of newt hearts. AB - Adult newts regenerate their hearts after injury by initiating proliferation of cardiac muscle and non-muscle cells. Mechanistic studies in vivo to analyze heart regeneration are challenging due to the long reproduction cycle of newts and the complexity of the genome. Culture of primary newt cells might offer alternative experimental approaches, but monolayers of newt cardiomyocytes and slice cultures of newt hearts show extensive morphological changes during cultivation. Hence, we developed a protocol to culture intact newt hearts in vitro, avoiding major morphological changes of explanted organs during a 5-week cultivation. The model provides improved accessibility and allows manipulation of cultured organs by small molecules and viral vectors. We found that dedifferentiation and S-phase entry of cardiomyocytes, which are hallmarks of cardiac regeneration in vivo, can be recapitulated in cultured hearts in vitro. We reason that long-term organ cultures of newts are a versatile tool for mechanistic studies on organ regeneration. PMID- 25740492 TI - In vitro preparation of newt inner ear sensory epithelia as a model for repair and regeneration. AB - The sensory "hair" cells of the inner ear transform sound energy into electrical signals, but are readily lost through aging, excessive noise, and ototoxic agents. The newt provides an excellent model in which to explore regeneration and whilst loss of hair cells from inner ear epithelia does not require whole organ regeneration, new hair cells are generated from differentiated supporting cells that transdifferentiate without an intervening mitotic event. Here we describe the methods for maintaining the sensory epithelia in long term culture; for the use of the aminoglycoside, gentamicin, to kill the hair cells; and for the examination of the tissue by electron microscopy or fluorescence microscopy. Demembranation of the epithelium reveals the underlying ultrastructure of the tissue for examination by scanning electron microscopy (SEM) and is a technique that can be utilized with immunogold labelling. PMID- 25740493 TI - Transgenesis in axolotl (Ambystoma mexicanum). AB - Transgenic animals have been indispensable in elucidating and deciphering mechanisms underlying various biological phenomena. In regeneration, transgenic animals expressing fluorescent protein genes have been crucial for identifying the source cells for regeneration and the mechanism of blastema formation. Animals are usually generated by manipulating their genome using various techniques at/in one cell embryo/fertilized egg stage. Here, we describe the generation of germline transgenic axolotls (Ambystoma mexicanum) using the I-SceI meganuclease and Tol2 transposase. PMID- 25740494 TI - Generating and identifying axolotls with targeted mutations using Cas9 RNA-guided nuclease. AB - The CRISPR/Cas9 RNA-guided nuclease now enables a reverse genetics approach to investigate the function of genes of interest during regeneration in the axolotl. The process of generating the constructs necessary for targeting a gene of interest is considerably less labor intensive than for other methods of targeted mutagenesis such as Zinc finger nucleases or Transcription activator-like effector nucleases. Here, we describe the identification of targetable sequences in the gene of interest, the construction of unique guide RNAs, the microinjection of these RNAs with Cas9-encoding mRNA, the selection of well injected animals, and an inexpensive, PCR-based method for identifying highly mutagenized animals. PMID- 25740495 TI - Gene manipulation for regenerative studies using the Iberian ribbed newt, Pleurodeles waltl. AB - Newts provide a unique model animal for regenerative studies. An experimental model system for molecular genetics in newts is needed in order to clarify the mechanisms of regeneration from the perspective of gene functions. We have identified that Iberian ribbed newt (Pleurodeles waltl) is a suitable model animal for such studies. Here we describe protocols for gene manipulation using Pleurodeles waltl. PMID- 25740496 TI - Transcriptomics using axolotls. AB - Microarray and RNA-sequencing technology now exists for the characterization of the Ambystoma mexicanum transcriptome. With sufficient replication, these tools give the opportunity to truly investigate gene expression in a variety of experimental paradigms. Analysis of data from the Amby002 array and RNA sequencing technology can identify genes that change expression levels in concert with each other, which in turn may reveal mechanisms associated with biological processes and molecular functions. PMID- 25740497 TI - Sal-Site: research resources for the Mexican axolotl. AB - Sal-Site serves axolotl research efforts by providing Web access to genomic data and information, and living stocks that are reared and made available by the Ambystoma Genetic Stock Center (AGSC). In this chapter, we detail how investigators can search for genes of interest among Sal-Site resources to identify orthologous nucleotide and protein-coding sequences, determine genome positions within the Ambystoma meiotic map, and obtain estimates of gene expression. In the near future, additional genomic resources will be made available for the axolotl, including a listing of genes that are partially or wholly contained within Bacterial Artificial Chromosome (BAC) vectors, a prioritized collection of deeply sequenced BAC clones, chromosome-specific assemblies of genomic DNA, and transgenic axolotls that are engineered using TALENs and CRISPRs. Also, services provided by the AGSC will be expanded to include microinjection of user constructs into single cell embryos and distribution of axolotl tissues, DNA, and RNA. In conclusion, Sal-Site is a useful resource that generates, shares, and evolves Ambystoma associated information and databases to serve research and education. PMID- 25740498 TI - Data mining in newt-omics, the repository for omics data from the newt. AB - Salamanders are an excellent model organism to study regenerative processes due to their unique ability to regenerate lost appendages or organs. Straightforward bioinformatics tools to analyze and take advantage of the growing number of "omics" studies performed in salamanders were lacking so far. To overcome this limitation, we have generated a comprehensive data repository for the red-spotted newt Notophthalmus viridescens, named newt-omics, merging omics style datasets on the transcriptome and proteome level including expression values and annotations. The resource is freely available via a user-friendly Web-based graphical user interface ( http://newt-omics.mpi-bn.mpg.de) that allows access and queries to the database without prior bioinformatical expertise. The repository is updated regularly, incorporating new published datasets from omics technologies. PMID- 25740499 TI - An online learning module improves specialist palliative care nurses' pain assessments and patient-reported pain. PMID- 25740500 TI - Hemodynamic Performance and Durability of Mosaic Bioprostheses for Aortic Valve Replacement, up to 13 Years. AB - BACKGROUND: This study evaluated the mid to long-term durability and hemodynamics of the small-size Mosaic bioprosthesis, a third-generation stented porcine bioprosthesis, for aortic valve replacement (AVR). METHODS AND RESULTS: From 2000 to 2012, 207 patients (117 women; age, 74+/-8 years; body surface area, 1.48+/ 0.25 m(2)) underwent AVR with a Mosaic bioprosthesis. The mean follow-up period was 3.5+/-2.7 years (maximum, 12.4 years) and the follow-up rate was 93.7%. A 19 , 21-, 23-, 25-, and 27-mm prosthesis was used in 103, 53, 35, 13, and 3 patients, respectively. The measured effective orifice area was 1.17+/-0.25, 1.29+/-0.19, 1.39+/-0.24, and 1.69 cm(2)for the 19-25 mm prostheses, and the mean transvalvular pressure gradient was 19.4+/-6.0, 18.5+/-5.8, 16.5+/-7.3, and 13.2+/-2.9 mmHg, respectively. The left ventricular mass regression was significant (P<0.05) with rates of 74.6+/-18.8%, 75.5+/-30.2%, 68.1+/-30.5%, 55.9+/-12.9%, and 49.2%, respectively. The 30-day mortality rate was 1.9% and the 5- and 10-year actuarial survival rates were 86.0% and 73.7%, respectively. Valve related comorbidities occurred in 3 patients (structural valve deterioration [SVD] in 1 after 7.2 years, and prosthetic valve endocarditis in 2). Freedom from SVD at 10-year was 96.7%. CONCLUSIONS: The mid to long-term performance of the small Mosaic bioprosthesis was satisfactory, with excellent hemodynamics and few valve-related adverse events. PMID- 25740501 TI - New Self-Expanding Transcatheter Aortic Valve Device for Transfemoral Implantation- Early Results of the First-in-Asia Implantation of the ACURATE Neo/TF(TM) System. AB - BACKGROUND: Feasibility and early results of transfemoral aortic valve implantation using the ACURATE neo/TF(TM)self-expanding stent are reported. METHODS AND RESULTS: The study group of 15 patients (mean age 83.3+/-6.0) was enrolled with a mean EuroSCORE and STS score of 21.9+/-11.6% and 7.5+/-3.1%, respectively. Clinical and echocardiographic evaluations were performed at baseline, discharge, 30 days and 6 months. The primary endpoint was all-cause mortality at 30 days. Transcatheter aortic valve implantation (TAVI) using the ACURATE neo/TF device was successful in 14 patients; 1 patient underwent valve-in valve implantation because the prosthetic valve embolized during withdrawal of the delivery system. Conversion to surgery, coronary obstruction, peri-operative stroke, and pacemaker implantation did not occur at 30 days. Mean transvalvular gradients at discharge significantly decreased from 44.2+/-10.5 mmHg (preprocedural) to 7.7+/-3.1 mmHg (P<0.0001) and effective orifice area significantly increased from 0.77+/-0.12 to 1.69+/-0.25 cm(2)(P<0.0001). None or trace paravalvular leak was revealed in 50.0%, and no patient exhibited moderate or higher paravalvular leak. The overall mortality at 30 days and 6 months was 0% and 6.7%, respectively. CONCLUSIONS: A new self-expanding TF TAVI device, ACURATE neo/TF, is safe and effective in the treatment of severe aortic stenosis in elderly patients at high risk for surgery. PMID- 25740502 TI - Relationships among red cell distribution width, anemia, and interleukin-6 in adult congenital heart disease. AB - BACKGROUND: Red cell distribution width (RDW) is known to be associated with anemia and mortality in cardiovascular diseases, while anemia itself is related to increased mortality. RDW may also be related to cytokine activation. We investigated the potential of RDW to predict anemia-adjusted mortality in patients with adult congenital heart disease (ACHD) and we evaluated the relationships among RDW, anemia, and interleukin-6 (IL-6). METHODS AND RESULTS: This was a single-center, retrospective cohort study. Blood RDW and IL-6 levels were measured in 144 patients with ACHD (median age [interquartile range (IQR)], 28 [22-36] years), 84% in New York Heart Association class I/II. During a mean 4.8-year follow-up, 21 (15%) patients died of cardiovascular causes. Elevated RDW (>15.0%) correlated significantly with mortality risk in a univariate analysis (RDW hazard ratio [HR]: 1.570; 95% confidence interval [CI]: 1.208-2.040 per 1 standard deviation increase; P=0.001). Elevated RDW levels correlated significantly with increased anemia-adjusted mortality (adjusted RDW HR: 1.912; 95% CI: 1.369-2.670; P<0.001). The high RDW group had significantly elevated serum IL-6 levels (RDW >15%, median [IQR], 3.7 [0.9-13.9] pg/ml vs. RDW <=15%, 1.4 [0.8-2.5 pg/ml]; P=0.001), as did patients with anemia (anemia, 1.9 [0.9-5.2] pg/ml vs. no anemia, 1.4 [0.8-2.5 pg/ml]; P=0.021). CONCLUSIONS: Elevation of RDW may be related with increased IL-6 and anemia-adjusted cardiovascular mortality in patients with ACHD. PMID- 25740503 TI - beta1-Integrin alters ependymal stem cell BMP receptor localization and attenuates astrogliosis after spinal cord injury. AB - Astrogliosis after spinal cord injury (SCI) is a major impediment to functional recovery. More than half of new astrocytes generated after SCI are derived from ependymal zone stem cells (EZCs). We demonstrate that expression of beta1 integrin increases in EZCs following SCI in mice. Conditional knock-out of beta1 integrin increases GFAP expression and astrocytic differentiation by cultured EZCs without altering oligodendroglial or neuronal differentiation. Ablation of beta1-integrin from EZCs in vivo reduced the number of EZC progeny that continued to express stem cell markers after SCI, increased the proportion of EZC progeny that differentiated into GFAP+ astrocytes, and diminished functional recovery. Loss of beta1-integrin increased SMAD1/5/8 and p38 signaling, suggesting activation of BMP signaling. Coimmunoprecipitation studies demonstrated that beta1-integrin directly interacts with the bone morphogenetic protein receptor subunits BMPR1a and BMPR1b. Ablation of beta1-integrin reduced overall levels of BMP receptors but significantly increased partitioning of BMPR1b into lipid rafts with increased SMAD1/5/8 and p38 signaling. Thus beta1-integrin expression by EZCs reduces movement of BMPR1b into lipid rafts, thereby limiting the known deleterious effects of BMPR1b signaling on glial scar formation after SCI. PMID- 25740504 TI - Nicotinic receptor subtype-selective circuit patterns in the subthalamic nucleus. AB - The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either alpha4beta2 or alpha7 nAChRs. STN neurons containing alpha4beta2 nAChRs (alpha4beta2 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing alpha7 nAChRs (alpha7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of alpha4beta2 neurons but exerted strong inhibition in 58% of alpha7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects alpha4beta2 nAChRs in STN: this treatment increased the number of alpha4beta2 neurons, upregulated alpha4-containing nAChR number and sensitivity, and enhanced the basal firing rate of alpha4beta2 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving alpha4beta2 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons. PMID- 25740506 TI - The subventricular zone continues to generate corpus callosum and rostral migratory stream astroglia in normal adult mice. AB - Astrocytes are the most abundant cells in the CNS, and have many essential functions, including maintenance of blood-brain barrier integrity, and CNS water, ion, and glutamate homeostasis. Mammalian astrogliogenesis has generally been considered to be completed soon after birth, and to be reactivated in later life only under pathological circumstances. Here, by using genetic fate-mapping, we demonstrate that new corpus callosum astrocytes are continuously generated from nestin(+) subventricular zone (SVZ) neural progenitor cells (NPCs) in normal adult mice. These nestin fate-mapped corpus callosum astrocytes are uniformly postmitotic, express glutamate receptors, and form aquaporin-4(+) perivascular endfeet. The entry of new astrocytes from the SVZ into the corpus callosum appears to be balanced by astroglial apoptosis, because overall numbers of corpus callosum astrocytes remain constant during normal adulthood. Nestin fate-mapped astrocytes also flow anteriorly from the SVZ in association with the rostral migratory stream, but do not penetrate into the deeper layers of the olfactory bulb. Production of new astrocytes from nestin(+) NPCs is absent in the normal adult cortex, striatum, and spinal cord. Our study is the first to demonstrate ongoing SVZ astrogliogenesis in the normal adult mammalian forebrain. PMID- 25740505 TI - Dissociable rate-dependent effects of oral methylphenidate on impulsivity and D2/3 receptor availability in the striatum. AB - We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [(18)F]fallypride PET scan. Before MPH treatment, we found that D2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms. PMID- 25740507 TI - Characterizing the associative content of brain structures involved in habitual and goal-directed actions in humans: a multivariate FMRI study. AB - While there is accumulating evidence for the existence of distinct neural systems supporting goal-directed and habitual action selection in the mammalian brain, much less is known about the nature of the information being processed in these different brain regions. Associative learning theory predicts that brain systems involved in habitual control, such as the dorsolateral striatum, should contain stimulus and response information only, but not outcome information, while regions involved in goal-directed action, such as ventromedial and dorsolateral prefrontal cortex and dorsomedial striatum, should be involved in processing information about outcomes as well as stimuli and responses. To test this prediction, human participants underwent fMRI while engaging in a binary choice task designed to enable the separate identification of these different representations with a multivariate classification analysis approach. Consistent with our predictions, the dorsolateral striatum contained information about responses but not outcomes at the time of an initial stimulus, while the regions implicated in goal-directed action selection contained information about both responses and outcomes. These findings suggest that differential contributions of these regions to habitual and goal-directed behavioral control may depend in part on basic differences in the type of information that these regions have access to at the time of decision making. PMID- 25740508 TI - Spine loss in primary somatosensory cortex during trace eyeblink conditioning. AB - Classical conditioning that involves mnemonic processing, that is, a "trace" period between conditioned and unconditioned stimulus, requires awareness of the association to be formed and is considered a simple model paradigm for declarative learning. Barrel cortex, the whisker representation of primary somatosensory cortex, is required for the learning of a tactile variant of trace eyeblink conditioning (TTEBC) and undergoes distinct map plasticity during learning. To investigate the cellular mechanism underpinning TTEBC and concurrent map plasticity, we used two-photon imaging of dendritic spines in barrel cortex of awake mice while being conditioned. Monitoring layer 5 neurons' apical dendrites in layer 1, we show that one cellular expression of barrel cortex plasticity is a substantial spine count reduction of ~15% of the dendritic spines present before learning. The number of eliminated spines and their time of elimination are tightly related to the learning success. Moreover, spine plasticity is highly specific for the principal barrel column receiving the main signals from the stimulated vibrissa. Spines located in other columns, even those directly adjacent to the principal column, are unaffected. Because layer 1 spines integrate signals from associative thalamocortical circuits, their column specific elimination suggests that this spine plasticity may be the result of an association of top-down signals relevant for declarative learning and spatially precise ascending tactile signals. PMID- 25740509 TI - Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. AB - Mutations in Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3) genes, encoding for voltage-gated K(+) channel subunits underlying the neuronal M-current, have been associated with a wide spectrum of early-onset epileptic disorders ranging from benign familial neonatal seizures to severe epileptic encephalopathies. The aim of the present work has been to investigate the molecular mechanisms of channel dysfunction caused by voltage-sensing domain mutations in Kv7.2 (R144Q, R201C, and R201H) or Kv7.3 (R230C) recently found in patients with epileptic encephalopathies and/or intellectual disability. Electrophysiological studies in mammalian cells transfected with human Kv7.2 and/or Kv7.3 cDNAs revealed that each of these four mutations stabilized the activated state of the channel, thereby producing gain-of-function effects, which are opposite to the loss-of function effects produced by previously found mutations. Multistate structural modeling revealed that the R201 residue in Kv7.2, corresponding to R230 in Kv7.3, stabilized the resting and nearby voltage-sensing domain states by forming an intricate network of electrostatic interactions with neighboring negatively charged residues, a result also confirmed by disulfide trapping experiments. Using a realistic model of a feedforward inhibitory microcircuit in the hippocampal CA1 region, an increased excitability of pyramidal neurons was found upon incorporation of the experimentally defined parameters for mutant M-current, suggesting that changes in network interactions rather than in intrinsic cell properties may be responsible for the neuronal hyperexcitability by these gain-of function mutations. Together, the present results suggest that gain-of-function mutations in Kv7.2/3 currents may cause human epilepsy with a severe clinical course, thus revealing a previously unexplored level of complexity in disease pathogenetic mechanisms. PMID- 25740510 TI - Astrocyte-mediated ischemic tolerance. AB - Preconditioning (PC) using a preceding sublethal ischemic insult is an attractive strategy for protecting neurons by inducing ischemic tolerance in the brain. Although the underlying molecular mechanisms have been extensively studied, almost all studies have focused on neurons. Here, using a middle cerebral artery occlusion model in mice, we show that astrocytes play an essential role in the induction of brain ischemic tolerance. PC caused activation of glial cells without producing any noticeable brain damage. The spatiotemporal pattern of astrocytic, but not microglial, activation correlated well with that of ischemic tolerance. Interestingly, such activation in astrocytes lasted at least 8 weeks. Importantly, inhibiting astrocytes with fluorocitrate abolished the induction of ischemic tolerance. To investigate the underlying mechanisms, we focused on the P2X7 receptor as a key molecule in astrocyte-mediated ischemic tolerance. P2X7 receptors were dramatically upregulated in activated astrocytes. PC-induced ischemic tolerance was abolished in P2X7 receptor knock-out mice. Moreover, our results suggest that hypoxia-inducible factor-1alpha, a well known mediator of ischemic tolerance, is involved in P2X7 receptor-mediated ischemic tolerance. Unlike previous reports focusing on neuron-based mechanisms, our results show that astrocytes play indispensable roles in inducing ischemic tolerance, and that upregulation of P2X7 receptors in astrocytes is essential. PMID- 25740512 TI - Attending to pitch information inhibits processing of pitch information: the curious case of amusia. AB - In normal listeners, the tonal rules of music guide musical expectancy. In a minority of individuals, known as amusics, the processing of tonality is disordered, which results in severe musical deficits. It has been shown that the tonal rules of music are neurally encoded, but not consciously available in amusics. Previous neurophysiological studies have not explicitly controlled the level of attention in tasks where participants ignored the tonal structure of the stimuli. Here, we test whether access to tonal knowledge can be demonstrated in congenital amusia when attention is controlled. Electric brain responses were recorded while asking participants to detect an individually adjusted near threshold click in a melody. In half the melodies, a note was inserted that violated the tonal rules of music. In a second task, participants were presented with the same melodies but were required to detect the tonal deviation. Both tasks required sustained attention, thus conscious access to the rules of tonality was manipulated. In the click-detection task, the pitch deviants evoked an early right anterior negativity (ERAN) in both groups. In the pitch-detection task, the pitch deviants evoked an ERAN and P600 in controls but not in amusics. These results indicate that pitch regularities are represented in the cortex of amusics, but are not consciously available. Moreover, performing a pitch-judgment task eliminated the ERAN in amusics, suggesting that attending to pitch information interferes with perception of pitch. We propose that an impaired top down frontotemporal projection is responsible for this disorder. PMID- 25740511 TI - Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves. AB - Inhibition of beta-site APP cleaving enzyme 1 (BACE1) is being pursued as a therapeutic target for treating patients with Alzheimer's disease because BACE1 is the sole beta-secretase for generating beta-amyloid peptide. Knowledge regarding the other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination in injured sciatic nerves. Since BACE1 is expected to be ubiquitously expressed, we asked whether axonal or Schwann cell BACE1 is required for optimal remyelination. By swapping sciatic nerve segments from BACE1-null mice with the corresponding wild-type nerve segments or vice versa, we tested how a deficiency of BACE1 in Schwann cells or axons affects remyelination. Our results show that BACE1 in axons and Schwann cells is similarly important for remyelination of regenerated axons. Nerve injury induces BACE1 transcription and protein levels are elevated in Schwann cells. Expression of type I neuregulin 1 (Nrg1), rather than type III Nrg1, was induced by Schwann cells, and the abolished Nrg1 cleavage in BACE1-null Schwann cells contributed to decreased remyelination of regenerated axons. Hence, this study is the first to demonstrate the equal importance of axonal and Schwann cell BACE1 for remyelination of injured nerves. PMID- 25740513 TI - Neural population coding of multiple stimuli. AB - In natural scenes, objects generally appear together with other objects. Yet, theoretical studies of neural population coding typically focus on the encoding of single objects in isolation. Experimental studies suggest that neural responses to multiple objects are well described by linear or nonlinear combinations of the responses to constituent objects, a phenomenon we call stimulus mixing. Here, we present a theoretical analysis of the consequences of common forms of stimulus mixing observed in cortical responses. We show that some of these mixing rules can severely compromise the brain's ability to decode the individual objects. This cost is usually greater than the cost incurred by even large reductions in the gain or large increases in neural variability, explaining why the benefits of attention can be understood primarily in terms of a stimulus selection, or demixing, mechanism rather than purely as a gain increase or noise reduction mechanism. The cost of stimulus mixing becomes even higher when the number of encoded objects increases, suggesting a novel mechanism that might contribute to set size effects observed in myriad psychophysical tasks. We further show that a specific form of neural correlation and heterogeneity in stimulus mixing among the neurons can partially alleviate the harmful effects of stimulus mixing. Finally, we derive simple conditions that must be satisfied for unharmful mixing of stimuli. PMID- 25740514 TI - Cannabinoid CB1 receptor calibrates excitatory synaptic balance in the mouse hippocampus. AB - The endocannabinoid system negatively regulates the release of various neurotransmitters in an activity-dependent manner, thereby influencing the excitability of neuronal circuits. In the hippocampus, cannabinoid type 1 (CB1) receptor is present on both GABAergic and glutamatergic axon terminals. CB1 receptor-deficient mice were previously shown to have increased hippocampal long term potentiation (LTP). In this study, we have investigated the consequences of cell-type-specific deletion of the CB1 receptor on the induction of hippocampal LTP and on CA1 pyramidal cell morphology. Deletion of CB1 receptor in GABAergic neurons in GABA-CB1-KO mice leads to a significantly decreased hippocampal LTP compared with WT controls. Concomitantly, CA1 pyramidal neurons have a significantly reduced dendritic branching both on the apical and on the basal dendrites. Moreover, the average spine density on the apical dendrites of CA1 pyramidal neurons is significantly diminished. In contrast, in mice lacking CB1 receptor in glutamatergic cells (Glu-CB1-KO), hippocampal LTP is significantly enhanced and CA1 pyramidal neurons show an increased branching and an increased spine density in the apical dendritic region. Together, these results indicate that the CB1 receptor signaling system both on inhibitory and excitatory neurons controls functional and structural synaptic plasticity of pyramidal neurons in the hippocampal CA1 region to maintain an appropriate homeostatic state upon neuronal activation. Consequently, if the CB1 receptor is lost in either neuronal population, an allostatic shift will occur leading to a long-term dysregulation of neuronal functions. PMID- 25740515 TI - Impaired leptomeningeal collateral flow contributes to the poor outcome following experimental stroke in the Type 2 diabetic mice. AB - Collateral status is an independent predictor of stroke outcome. However, the spatiotemporal manner in which collateral flow maintains cerebral perfusion during cerebral ischemia is poorly understood. Diabetes exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, and it continued to grow over the course of 1 week. In contrast, an impairment of collateral recruitment was evident in the Type 2 diabetic db/db mice, which coincided with a worse stroke outcome compared with their normoglycemic counterpart db/+, despite their equally well collateralized leptomeningeal anastomoses. Similar to the wild-type mice, both db/+ and db/db mice underwent collateral growth 7 d after MCA stroke, although db/db mice still exhibited significantly reduced retrograde flow into the MCA territory chronically. Acutely induced hyperglycemia in the db/+ mice did not impair collateral flow after stroke, suggesting that the state of hyperglycemia alone was not sufficient to impact collateral flow. Human albumin was efficacious in improving collateral flow and outcome after stroke in the db/db mice, enabling perfusion to proximal MCA territory that was usually not reached by retrograde flow from anterior cerebral artery without treatment. Our results suggest that the impaired collateral status contributes to the exacerbated ischemic injury in mice with Type 2 diabetes, and modulation of collateral flow has beneficial effects on stroke outcome among these subjects. PMID- 25740516 TI - Converging structural and functional connectivity of orbitofrontal, dorsolateral prefrontal, and posterior parietal cortex in the human striatum. AB - Modification of spatial attention via reinforcement learning (Lee and Shomstein, 2013) requires the integration of reward, attention, and executive processes. Corticostriatal pathways are an ideal neural substrate for this integration because these projections exhibit a globally parallel (Alexander et al., 1986), but locally overlapping (Haber, 2003), topographical organization. Here we explore whether there are unique striatal regions that exhibit convergent anatomical connections from orbitofrontal cortex, dorsolateral prefrontal cortex, and posterior parietal cortex. Deterministic fiber tractography on diffusion spectrum imaging data from neurologically healthy adults (N = 60) was used to map frontostriatal and parietostriatal projections. In general, projections from cortex were organized according to both a medial-lateral and a rostral-caudal gradient along the striatal nuclei. Within rostral aspects of the striatum, we identified two bilateral convergence zones (one in the caudate nucleus and another in the putamen) that consisted of voxels with unique projections from orbitofrontal cortex, dorsolateral prefrontal cortex, and parietal regions. The distributed cortical connectivity of these striatal convergence zones was confirmed with follow-up functional connectivity analysis from resting state fMRI data, in which a high percentage of structurally connected voxels also showed significant functional connectivity. The specificity of this convergent architecture to these regions of the rostral striatum was validated against control analysis of connectivity within the motor putamen. These results delineate a neurologically plausible network of converging corticostriatal projections that may support the integration of reward, executive control, and spatial attention that occurs during spatial reinforcement learning. PMID- 25740517 TI - Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. AB - Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety. PMID- 25740518 TI - Coronin-1 and calcium signaling governs sympathetic final target innervation. AB - Development of a functional peripheral nervous system requires axons to rapidly innervate and arborize into final target organs and then slow but not halt their growth to establish stable connections while keeping pace with organ growth. Here we examine the role of the NGF-TrkA effector protein, Coronin-1, on postganglionic sympathetic neuron final target innervation. In the absence of Coronin-1 we find that NGF-TrkA-PI3K signaling drives robust axon growth and branching in part by suppressing GSK3beta. In contrast, the presence of Coronin-1 (wild-type neurons) suppresses but does not halt NGF-TrkA-dependent growth and branching. This relative suppression in axon growth behaviors is due to Coronin-1 dependent calcium release via PLC-gamma1 signaling, which releases PI3K-dependent suppression of GSK3beta. Finally, we demonstrate that Coro1a(-/-) mice display sympathetic axon overgrowth and overbranching phenotypes in the developing heart. Together with previous work demonstrating the Coronin-1 expression is NGF dependent, this work suggests that periods before and after NGF-TrkA-induced Coronin-1 expression (and likely other factors) defines two distinct axon growth states, which are critical for proper circuit formation in the sympathetic nervous system. PMID- 25740519 TI - Executive control signals in orbitofrontal cortex during response inhibition. AB - Orbitofrontal cortex (OFC) lesions produce deficits in response inhibition and imaging studies suggest that activity in OFC is stronger on trials that require suppression of behavior, yet few studies have examined neural correlates at the single-unit level in a behavioral task that probes response inhibition without varying other factors, such as anticipated outcomes. Here we recorded from single neurons in lateral OFC in a task that required animals in the minority of trials to STOP or inhibit an ongoing movement and respond in the opposite direction. We found that population and single-unit firing was modulated primarily by response direction and movement speed, and that very few OFC neurons exhibited a response independent inhibition signal. Remarkably, the strength of the directional signal was not diminished on STOP trials and was actually stronger on STOP trials during conflict adaptation. Finally, directional signals were stronger during sessions in which rats had the most difficulty inhibiting behavior. These results suggest that "inhibition" deficits observed with OFC interference studies reflect deficits unrelated to signaling the need to inhibit behavior, but instead support a role for OFC in executive functions related to dissociating between two perceptually similar actions during response conflict. PMID- 25740520 TI - A novel mouse model of subcortical infarcts with dementia. AB - Subcortical white matter (WM) is a frequent target of ischemic injury and extensive WM lesions are important substrates of vascular cognitive impairment (VCI) in humans. However, ischemic stroke rodent models have been shown to mainly induce cerebral infarcts in the gray matter, while cerebral hypoperfusion models show only WM rarefaction without infarcts. The lack of animal models consistently replicating WM infarct damage may partially explain why many neuroprotective drugs for ischemic stroke or VCI have failed clinically, despite earlier success in preclinical experiments. Here, we report a novel animal model of WM infarct damage with cognitive impairment can be generated by surgical implantation of different devices to the right and left common carotid artery (CCA) in C57BL/6J mice. Implantation of an ameroid constrictor to the right CCA resulted in gradual occlusion of the vessel over 28 d, whereas placement of a microcoil to the left CCA induced ~50% arterial stenosis. Arterial spin labeling showed a gradual reduction of cerebral blood flow over 28 d post operation. Such reductions were more marked in the right, compared with the left, hemisphere and in subcortical, rather than the cortical, areas. Histopathological analysis showed multiple infarct damage in right subcortical regions, including the corpus callosum, internal capsule, hippocampal fimbria, and caudoputamen, in 81% of mice. Mice displaying such damage performed significantly poorer in locomotor and cognitive tests. The current mouse model replicates the phenotypes of human subcortical VCI, including multiple WM infarcts with motor and cognitive impairment. PMID- 25740521 TI - Cortical activity predicts which older adults recognize speech in noise and when. AB - Speech recognition in noise can be challenging for older adults and elicits elevated activity throughout a cingulo-opercular network that is hypothesized to monitor and modify behaviors to optimize performance. A word recognition in noise experiment was used to test the hypothesis that cingulo-opercular engagement provides performance benefit for older adults. Healthy older adults (N = 31; 50 81 years of age; mean pure tone thresholds <32 dB HL from 0.25 to 8 kHz, best ear; species: human) performed word recognition in multitalker babble at 2 signal to-noise ratios (SNR = +3 or +10 dB) during a sparse sampling fMRI experiment. Elevated cingulo-opercular activity was associated with an increased likelihood of correct recognition on the following trial independently of SNR and performance on the preceding trial. The cingulo-opercular effect increased for participants with the best overall performance. These effects were lower for older adults compared with a younger, normal-hearing adult sample (N = 18). Visual cortex activity also predicted trial-level recognition for the older adults, which resulted from discrete decreases in activity before errors and occurred for the oldest adults with the poorest recognition. Participants demonstrating larger visual cortex effects also had reduced fractional anisotropy in an anterior portion of the left inferior frontal-occipital fasciculus, which projects between frontal and occipital regions where activity predicted word recognition. Together, the results indicate that older adults experience performance benefit from elevated cingulo-opercular activity, but not to the same extent as younger adults, and that declines in attentional control can limit word recognition. PMID- 25740522 TI - Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome. AB - The Fmr1 knock-out mouse model of fragile X syndrome (Fmr1(-/y)) has an epileptogenic phenotype that is triggered by group I metabotropic glutamate receptor (mGluR) activation. We found that a membrane-permeable peptide that disrupts mGluR5 interactions with long-form Homers enhanced mGluR-induced epileptiform burst firing in wild-type (WT) animals, replicating the early stages of hyperexcitability in Fmr1(-/y). The peptide enhanced mGluR-evoked endocannabinoid (eCB)-mediated suppression of inhibitory synapses, decreased it at excitatory synapses in WTs, but had no effect on eCB actions in Fmr1(-/y). At a low concentration, the mGluR agonist did not generate eCBs at excitatory synapses but nevertheless induced burst firing in both Fmr1(-/y) and peptide treated WT slices. This burst firing was suppressed by a cannabinoid receptor antagonist. We suggest that integrity of Homer scaffolds is essential for normal mGluR-eCB functioning and that aberrant eCB signaling resulting from disturbances of this molecular structure contributes to the epileptic phenotype of Fmr1(-/y). PMID- 25740523 TI - Structure of a single whisker representation in layer 2 of mouse somatosensory cortex. AB - Layer (L)2 is a major output of primary sensory cortex that exhibits very sparse spiking, but the structure of sensory representation in L2 is not well understood. We combined two-photon calcium imaging with deflection of many whiskers to map whisker receptive fields, characterize sparse coding, and quantitatively define the point representation in L2 of mouse somatosensory cortex. Neurons within a column-sized imaging field showed surprisingly heterogeneous, salt-and-pepper tuning to many different whiskers. Single whisker deflection elicited low-probability spikes in highly distributed, shifting neural ensembles spanning multiple cortical columns. Whisker-evoked response probability correlated strongly with spontaneous firing rate, but weakly with tuning properties, indicating a spectrum of inherent responsiveness across pyramidal cells. L2 neurons projecting to motor and secondary somatosensory cortex differed in whisker tuning and responsiveness, and carried different amounts of information about columnar whisker deflection. From these data, we derive a quantitative, fine-scale picture of the distributed point representation in L2. PMID- 25740524 TI - Obesity is associated with decreased MU-opioid but unaltered dopamine D2 receptor availability in the brain. AB - Neurochemical pathways involved in pathological overeating and obesity are poorly understood. Although previous studies have shown increased MU-opioid receptor (MOR) and decreased dopamine D2 receptor (D2R) availability in addictive disorders, the role that these systems play in human obesity still remains unclear. We studied 13 morbidly obese women [mean body mass index (BMI), 42 kg/m(2)] and 14 nonobese age-matched women, and measured brain MOR and D2R availability using PET with selective radioligands [(11)C]carfentanil and [(11)C]raclopride, respectively. We also used quantitative meta-analytic techniques to pool previous evidence on the effects of obesity on altered D2R availability. Morbidly obese subjects had significantly lower MOR availability than control subjects in brain regions relevant for reward processing, including ventral striatum, insula, and thalamus. Moreover, in these areas, BMI correlated negatively with MOR availability. Striatal MOR availability was also negatively associated with self-reported food addiction and restrained eating patterns. There were no significant differences in D2R availability between obese and nonobese subjects in any brain region. Meta-analysis confirmed that current evidence for altered D2R availability in obesity is only modest. Obesity appears to have unique neurobiological underpinnings in the reward circuit, whereby it is more similar to opioid addiction than to other addictive disorders. The opioid system modulates motivation and reward processing, and low MU-opioid availability may promote overeating to compensate decreased hedonic responses in this system. Behavioral and pharmacological strategies for recovering opioidergic function might thus be critical to curb the obesity epidemic. PMID- 25740525 TI - Impaired attention and synaptic senescence of the prefrontal cortex involves redox regulation of NMDA receptors. AB - Young (3-6 months) and middle-age (10-14 months) rats were trained on the five choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline. PMID- 25740526 TI - Movement-related discharge in the macaque globus pallidus during high-frequency stimulation of the subthalamic nucleus. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an "informational lesion," whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism. PMID- 25740527 TI - Dual mechanism for bitter avoidance in Drosophila. AB - In flies and humans, bitter chemicals are known to inhibit sugar detection, but the adaptive role of this inhibition is often overlooked. At best, this inhibition is described as contributing to the rejection of potentially toxic food, but no studies have addressed the relative importance of the direct pathway that involves activating bitter-sensitive cells versus the indirect pathway represented by the inhibition of sugar detection. Using toxins to selectively ablate or inactivate populations of bitter-sensitive cells, we assessed the behavioral responses of flies to sucrose mixed with strychnine (which activates bitter-sensitive cells and inhibits sugar detection) or with L-canavanine (which only activates bitter-sensitive cells). As expected, flies with ablated bitter sensitive cells failed to detect L-canavanine mixed with sucrose in three different feeding assays (proboscis extension responses, capillary feeding, and two-choice assays). However, such flies were still able to avoid strychnine mixed with sucrose. By means of electrophysiological recordings, we established that bitter molecules differ in their potency to inhibit sucrose detection and that sugar-sensing inhibition affects taste cells on the proboscis and the legs. The optogenetic response of sugar-sensitive cells was not reduced by strychnine, thus suggesting that this inhibition is linked directly to sugar transduction. We postulate that sugar-sensing inhibition represents a mechanism in insects to prevent ingesting harmful substances occurring within mixtures. PMID- 25740528 TI - Sensitivity of locus ceruleus neurons to reward value for goal-directed actions. AB - The noradrenergic nucleus locus ceruleus (LC) is associated classically with arousal and attention. Recent data suggest that it might also play a role in motivation. To study how LC neuronal responses are related to motivational intensity, we recorded 121 single neurons from two monkeys while reward size (one, two, or four drops) and the manner of obtaining reward (passive vs active) were both manipulated. The monkeys received reward under three conditions: (1) releasing a bar when a visual target changed color; (2) passively holding a bar; or (3) touching and releasing a bar. In the first two conditions, a visual cue indicated the size of the upcoming reward, and, in the third, the reward was constant through each block of 25 trials. Performance levels and lipping intensity (an appetitive behavior) both showed that the monkeys' motivation in the task was related to the predicted reward size. In conditions 1 and 2, LC neurons were activated phasically in relation to cue onset, and this activation strengthened with increasing expected reward size. In conditions 1 and 3, LC neurons were activated before the bar-release action, and the activation weakened with increasing expected reward size but only in task 1. These effects evolved as monkeys progressed through behavioral sessions, because increasing fatigue and satiety presumably progressively decreased the value of the upcoming reward. These data indicate that LC neurons integrate motivationally relevant information: both external cues and internal drives. The LC might provide the impetus to act when the predicted outcome value is low. PMID- 25740529 TI - Reward-dependent modulation of movement variability. AB - Movement variability is often considered an unwanted byproduct of a noisy nervous system. However, variability can signal a form of implicit exploration, indicating that the nervous system is intentionally varying the motor commands in search of actions that yield the greatest success. Here, we investigated the role of the human basal ganglia in controlling reward-dependent motor variability as measured by trial-to-trial changes in performance during a reaching task. We designed an experiment in which the only performance feedback was success or failure and quantified how reach variability was modulated as a function of the probability of reward. In healthy controls, reach variability increased as the probability of reward decreased. Control of variability depended on the history of past rewards, with the largest trial-to-trial changes occurring immediately after an unrewarded trial. In contrast, in participants with Parkinson's disease, a known example of basal ganglia dysfunction, reward was a poor modulator of variability; that is, the patients showed an impaired ability to increase variability in response to decreases in the probability of reward. This was despite the fact that, after rewarded trials, reach variability in the patients was comparable to healthy controls. In summary, we found that movement variability is partially a form of exploration driven by the recent history of rewards. When the function of the human basal ganglia is compromised, the reward dependent control of movement variability is impaired, particularly affecting the ability to increase variability after unsuccessful outcomes. PMID- 25740530 TI - Extracellular pH regulates excitability of vomeronasal sensory neurons. AB - The mouse vomeronasal organ (VNO) plays a critical role in semiochemical detection and social communication. Vomeronasal stimuli are typically secreted in various body fluids. Following direct contact with urine deposits or other secretions, a peristaltic vascular pump mediates fluid entry into the recipient's VNO. Therefore, while vomeronasal sensory neurons (VSNs) sample various stimulatory semiochemicals dissolved in the intraluminal mucus, they might also be affected by the general physicochemical properties of the "solvent." Here, we report cycle stage-correlated variations in urinary pH among female mice. Estrus specific pH decline is observed exclusively in urine samples from sexually experienced females. Moreover, patch-clamp recordings in acute VNO slices reveal that mouse VSNs reliably detect extracellular acidosis. Acid-evoked responses share the biophysical and pharmacological hallmarks of the hyperpolarization activated current Ih. Mechanistically, VSN acid sensitivity depends on a pH induced shift in the voltage-dependence of Ih activation that causes the opening of HCN channels at rest, thereby increasing VSN excitability. Together, our results identify extracellular acidification as a potent activator of vomeronasal Ih and suggest HCN channel-dependent vomeronasal gain control of social chemosignaling. Our data thus reveal a potential mechanistic basis for stimulus pH detection in rodent chemosensory communication. PMID- 25740531 TI - Spatiotemporal memory is an intrinsic property of networks of dissociated cortical neurons. AB - The ability to process complex spatiotemporal information is a fundamental process underlying the behavior of all higher organisms. However, how the brain processes information in the temporal domain remains incompletely understood. We have explored the spatiotemporal information-processing capability of networks formed from dissociated rat E18 cortical neurons growing in culture. By combining optogenetics with microelectrode array recording, we show that these randomly organized cortical microcircuits are able to process complex spatiotemporal information, allowing the identification of a large number of temporal sequences and classification of musical styles. These experiments uncovered spatiotemporal memory processes lasting several seconds. Neural network simulations indicated that both short-term synaptic plasticity and recurrent connections are required for the emergence of this capability. Interestingly, NMDA receptor function is not a requisite for these short-term spatiotemporal memory processes. Indeed, blocking the NMDA receptor with the antagonist APV significantly improved the temporal processing ability of the networks, by reducing spontaneously occurring network bursts. These highly synchronized events have disastrous effects on spatiotemporal information processing, by transiently erasing short-term memory. These results show that the ability to process and integrate complex spatiotemporal information is an intrinsic property of generic cortical networks that does not require specifically designed circuits. PMID- 25740533 TI - Functional roles of complexin in neurotransmitter release at ribbon synapses of mouse retinal bipolar neurons. AB - Ribbon synapses of photoreceptor cells and bipolar neurons in the retina signal graded changes in light intensity via sustained release of neurotransmitter. One molecular specialization of retinal ribbon synapses is the expression of complexin protein subtypes Cplx3 and Cplx4, whereas conventional synapses express Cplx1 and Cplx2. Because complexins bind to the molecular machinery for synaptic vesicle fusion (the SNARE complex) and modulate transmitter release at conventional synapses, we examined the roles of ribbon-specific complexin in regulating release at ribbon synapses of ON bipolar neurons from mouse retina. To interfere acutely with the interaction of native complexins with the SNARE complex, a peptide consisting of the highly conserved SNARE-binding domain of Cplx3 was introduced via a whole-cell patch pipette placed directly on the synaptic terminal, and vesicle fusion was monitored using capacitance measurements and FM-dye destaining. The inhibitory peptide, but not control peptides, increased spontaneous synaptic vesicle fusion, partially depleted reserve synaptic vesicles, and reduced fusion triggered by opening voltage-gated calcium channels under voltage clamp, without affecting the number of synaptic vesicles associated with ribbons, as revealed by electron microscopy of recorded terminals. The results are consistent with a dual role for ribbon-specific complexin, acting as a brake on the SNARE complex to prevent spontaneous fusion in the absence of calcium influx, while at the same time facilitating release evoked by depolarization. PMID- 25740532 TI - Role of the indirect pathway of the basal ganglia in perceptual decision making. AB - The basal ganglia (BG) play an important role in motor control, reinforcement learning, and perceptual decision making. Modeling and experimental evidence suggest that, in a speed-accuracy tradeoff, the corticostriatal pathway can adaptively adjust a decision threshold (the amount of information needed to make a choice). In this study, we go beyond the focus of previous works on the direct and hyperdirect pathways to examine the contribution of the indirect pathway of the BG system to decision making in a biophysically based spiking network model. We find that the mechanism of adjusting the decision threshold by plasticity of the corticostriatal connections is effective, provided that the indirect pathway counterbalances the direct pathway in their projections to the output nucleus. Furthermore, in our model, changes within basal ganglia connections similar to those that arise in parkinsonism give rise to strong beta oscillations. Specifically, beta oscillations are produced by an abnormal enhancement of the interactions between the subthalamic nucleus (STN) and the external segment of globus pallidus (GPe) in the indirect pathway, with an oscillation frequency that depends on the excitatory cortical input to the STN and the inhibitory input to the GPe from the striatum. In a parkinsonian state characterized by pronounced beta oscillations, the mean reaction time and range of threshold variation (a measure of behavioral flexibility) are significantly reduced compared with the normal state. Our work thus reveals a specific circuit mechanism for impairments of perceptual decision making associated with Parkinson's disease. PMID- 25740534 TI - Losing the music: aging affects the perception and subcortical neural representation of musical harmony. AB - When two musical notes with simple frequency ratios are played simultaneously, the resulting musical chord is pleasing and evokes a sense of resolution or "consonance". Complex frequency ratios, on the other hand, evoke feelings of tension or "dissonance". Consonance and dissonance form the basis of harmony, a central component of Western music. In earlier work, we provided evidence that consonance perception is based on neural temporal coding in the brainstem (Bones et al., 2014). Here, we show that for listeners with clinically normal hearing, aging is associated with a decline in both the perceptual distinction and the distinctiveness of the neural representations of different categories of two-note chords. Compared with younger listeners, older listeners rated consonant chords as less pleasant and dissonant chords as more pleasant. Older listeners also had less distinct neural representations of consonant and dissonant chords as measured using a Neural Consonance Index derived from the electrophysiological "frequency-following response." The results withstood a control for the effect of age on general affect, suggesting that different mechanisms are responsible for the perceived pleasantness of musical chords and affective voices and that, for listeners with clinically normal hearing, age-related differences in consonance perception are likely to be related to differences in neural temporal coding. PMID- 25740535 TI - A direct descending pathway informing locomotor networks about tactile sensor movement. AB - Much like visually impaired humans use a white-cane, nocturnal insects and mammals use antennae or whiskers for near-range orientation. Stick insects, for example, rely heavily on antennal tactile cues to find footholds and detect obstacles. Antennal contacts can even induce aimed reaching movements. Because tactile sensors are essentially one-dimensional, they must be moved to probe the surrounding space. Sensor movement is thus an essential cue for tactile sensing, which needs to be integrated by thoracic networks for generating appropriate adaptive leg movements. Based on single and double recordings, we describe a descending neural pathway comprising three identified ON- and OFF-type neurons that convey complementary, unambiguous, and short-latency information about antennal movement to thoracic networks in the stick insect. The neurons are sensitive to the velocity of antennal movements across the entire range covered by natural movements, regardless of movement direction and joint angle. Intriguingly, none of them originates from the brain. Instead, they descend from the gnathal ganglion and receive input from antennal mechanoreceptors in this lower region of the CNS. From there, they convey information about antennal movement to the thorax. One of the descending neurons, which is additionally sensitive to substrate vibration, feeds this information back to the brain via an ascending branch. We conclude that descending interneurons with complementary tuning characteristics, gains, input and output regions convey detailed information about antennal movement to thoracic networks. This pathway bypasses higher processing centers in the brain and thus constitutes a shortcut between tactile sensors on the head and the thorax. PMID- 25740536 TI - Juvenile obesity enhances emotional memory and amygdala plasticity through glucocorticoids. AB - In addition to metabolic and cardiovascular disorders, obesity is associated with adverse cognitive and emotional outcomes. Its growing prevalence during adolescence is particularly alarming since recent evidence indicates that obesity can affect hippocampal function during this developmental period. Adolescence is a decisive period for maturation of the amygdala and the hypothalamic-pituitary adrenal (HPA) stress axis, both required for lifelong cognitive and emotional processing. However, little data are available on the impact of obesity during adolescence on amygdala function. Herein, we therefore evaluate in rats whether juvenile high-fat diet (HFD)-induced obesity alters amygdala-dependent emotional memory and whether it depends on HPA axis deregulation. Exposure to HFD from weaning to adulthood, i.e., covering adolescence, enhances long-term emotional memories as assessed by odor-malaise and tone-shock associations. Juvenile HFD also enhances emotion-induced neuronal activation of the basolateral complex of the amygdala (BLA), which correlates with protracted plasma corticosterone release. HFD exposure restricted to adulthood does not modify all these parameters, indicating adolescence is a vulnerable period to the effects of HFD induced obesity. Finally, exaggerated emotional memory and BLA synaptic plasticity after juvenile HFD are alleviated by a glucocorticoid receptor antagonist. Altogether, our results demonstrate that juvenile HFD alters HPA axis reactivity leading to an enhancement of amygdala-dependent synaptic and memory processes. Adolescence represents a period of increased susceptibility to the effects of diet-induced obesity on amygdala function. PMID- 25740537 TI - Dopamine D2-receptor blockade enhances decoding of prefrontal signals in humans. AB - The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2 receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs. PMID- 25740538 TI - Immunology of progressive multifocal leukoencephalopathy. AB - The high prevalence of asymptomatic JC polyomavirus (JCV) infection in the general population indicates coexistence with the human host and efficient immune control in healthy individuals. For unknown reasons, kidney-resident archetypic JCV strains can turn into neurotropic JCV strains which in hereditary or acquired states of immunodeficiency cause opportunistic infection and cytolytic destruction of glial cells or granule cell neurons resulting in progressive multifocal demyelination in the central nervous system (CNS) or cerebellar atrophy, respectively. Immunomodulatory or immunosuppressive therapies with specific monoclonal antibodies including natalizumab, efalizumab, and rituximab have increased the risk of progressive multifocal leukoencephalopathy (PML) among treated patients, highlighting that symptomatic JCV infection of the CNS is associated with disturbances of adaptive immunity affecting B cells, antibodies, and CD4(+) and/or CD8(+) T cells. To date, no specific therapy to overcome PML is available and the only way to eliminate the virus from the CNS is to reconstitute global immune function. However, since the identification of JCV as the causative agent of PML 40 years ago, it is still not fully understood which components of the immune system prevent the development of PML and which immune mechanisms are involved in eliminating the virus from the CNS. This review gives an update about adaptive JCV-specific immune responses. PMID- 25740539 TI - Human immunodeficiency virus (HIV) modulates the associations between insulin resistance and cognition in the current combination antiretroviral therapy (cART) era: a study of the Women's Interagency HIV Study (WIHS). AB - Cognitive impairment (CI) remains common despite access to combination antiretroviral therapy (cART); it has been linked to HIV-specific, HIV-related, and HIV-unrelated factors. Insulin resistance (IR) was associated with CI in the early cART era, when antiretroviral medications had greater mitochondrial and metabolic toxicity. We sought to examine these relationships in the current cART era of reduced antiretroviral toxicities. This study examined IR among non diabetics in relation to a 1-h neuropsychological test battery among 994 women (659 HIV-infected and 335 HIV-uninfected controls) assessed between 2009 and 2011. The mean (standard deviation (SD)) age of the sample was 45.1 (9.3) years. The HIV-infected sample had a median interquartile range (IQR) cluster of differentiation 4 (CD4) T-lymphocyte count of 502 (310-727) cells/MUL, and 54 % had undetectable plasma HIV RNA levels. Among all, the homeostasis model assessment (HOMA) of IR ranged from 0.25 to 37.14. In adjusted models, increasing HOMA was significantly associated with reduced performance on Letter-Number Sequencing (LNS) attention task (beta = -0.10, p < 0.01) and on Hopkins Verbal Learning Test (HVLT) recognition (beta = -0.10, p < 0.01) with weaker but statistically significant associations on phonemic fluency (beta = -0.09, p = 0.01). An HIV*HOMA interaction effect was identified on the LNS attention task and Stroop trials 1 and 2, with worse performance in HIV-infected vs. HIV uninfected women. In separate analyses, cohort members who had diabetes mellitus (DM) performed worse on the grooved pegboard test of psychomotor speed and manual dexterity. These findings confirm associations between both IR and DM on some neuropsychological tests and identify an interaction between HIV status and IR. PMID- 25740541 TI - Polarized Epithelial Cells Secrete Interleukin 6 Apically in the Bovine Endometrium. AB - Endometrial epithelial cells are the first line of defense against pathogenic bacteria infecting the uterus. Innate immune responses by these polarized epithelial cells to bacteria and tissue damage are characterized by release of the chemokine (C-X-C motif) ligand 8 (CXCL8) to attract immune cells from the circulation to the site of infection, where they are regulated by the cytokine interleukin (IL) 6. The present study tested the hypothesis that IL6 is predominantly secreted apically from polarized bovine endometrial epithelial cells in response to stimuli associated with bacterial infection and tissue damage. In postpartum animals, concentrations of IL6, but not of CXCL8, were higher in uterine mucus than in peripheral blood. In vitro, polarized endometrial epithelial cells only secreted IL6 apically when treated with bacteria, the pathogen-associated molecule lipopolysaccharide, or the damage-associated molecule IL1alpha, whereas CXCL8 accumulated apically and basolaterally. Furthermore, IL6 accumulated apically irrespective of whether lipopolysaccharide was applied to the apical or basolateral surface of epithelial cells. Secretion of IL6 from epithelial cells was dependent on the trans-Golgi network but was not affected by exogenous ovarian steroids or by coculture with stromal cells. However, a confluent epithelium was essential to protect underlying stromal cells against noxious challenges, including bacteria, lipopolysaccharide, IL1alpha, and a cytolysin. In summary, when a confluent endometrial epithelial cell barrier is faced with infection and damage, chemokines attract immune cells to the uterine lumen, but IL6 is solely secreted apically to ensure immune cells are only exposed to IL6 once they reach the lumen. PMID- 25740540 TI - Development of hematopoietic stem and progenitor cells from human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a new cell source for regenerative medicine, disease modeling, drug discovery, and preclinical toxicity screening. Understanding of the onset and the sequential process of hematopoietic cells from differentiated hPSCs will enable the achievement of personalized medicine and provide an in vitro platform for studying of human hematopoietic development and disease. During embryogenesis, hemogenic endothelial cells, a specified subset of endothelial cells in embryonic endothelium, are the primary source of multipotent hematopoietic stem cells. In this review, we discuss current status in the generation of multipotent hematopoietic stem and progenitor cells from hPSCs via hemogenic endothelial cells. We also review the achievements in direct reprogramming from non hematopoietic cells to hematopoietic stem and progenitor cells. Further characterization of hematopoietic differentiation in hPSCs will improve our understanding of blood development and expedite the development of hPSC-derived blood products for therapeutic purpose. PMID- 25740542 TI - PLK4 is essential for meiotic resumption in mouse oocytes. AB - Polo-like kinase (PLK) 4 is a unique member of the PLK family that plays vital roles in centriole biogenesis during mitosis. The localization of PLK4 on centrioles must be precisely regulated during mitosis to ensure correct centriole duplication. However, little is known about the function of PLK4 in mammalian oocyte meiosis. We addressed this question by examining the expression and localization of PLK4 in mouse oocytes and using RNA interference and protein overexpression to investigate its function in meiosis. PLK4 expression peaked at the germinal vesicle breakdown (GVBD) stage, and the protein was localized in the cytoplasm throughout meiotic maturation. Depletion of PLK4 caused meiotic arrest at the GV stage and suppressed CYCLINB1 and CDC2 activities. Moreover, PLK4 depletion prevented the de-phosphorylation of CDC2-Tyr15 in nucleus and induced a decrease in the level of the CDC25C protein. PLK1 overexpression failed to rescue GV-stage arrest in PLK4-depleted oocytes, whereas overexpressing PLK4 resulted in normal GVBD in oocytes in which PLK1 activity was inhibited. In addition, PLK4 overexpression did not cause abnormal spindle formation or affect extrusion of the first polar body. These results illustrate the fact that PLK4 is essential for meiotic resumption but may not influence spindle formation in mouse oocytes during meiotic maturation. PMID- 25740543 TI - Retractions. PMID- 25740544 TI - Characterization of an L-amino acid oxidase in equine spermatozoa. AB - This study demonstrates for the first time the presence of an L-amino acid oxidase (LAAO) enzyme in equine spermatozoa that is able to generate significant amounts of reactive oxygen species (ROS) and create a state of oxidative stress. RT-PCR analysis revealed that the mRNA for this enzyme was present in the equine testis and spermatozoa, while immunocytochemical studies demonstrated that the mature LAAO protein was located in the sperm head, particularly in the acrosomal and postacrosomal domains. Experimental studies demonstrated that the aromatic amino acids (L-phenylalanine > L-tryptophan > L-tyrosine) were substrates for this enzyme, eliciting the dose- and time-dependent generation of ROS via mechanisms that were enhanced by cell death. This unexpected result was confirmed by analyses of ROS generation in subcellular sperm fractions, which again located a majority of LAAO activity to the sperm head. Equine cryopreservation medium was shown to contain sufficient quantities of aromatic amino acids to activate the LAAO system and generate ROS. The biological significance of this activity was established in an experiment in which physiological concentrations of aromatic amino acids were found to suppress sperm motility but only if dead spermatozoa were present in the same suspension. The combination of aromatic amino acids and nonviable cells was also found to enhance the levels of lipid peroxidation in live spermatozoa. These results suggest the potential significance of LAAO activity in generating the oxidative stress associated with the cryopreservation of equine spermatozoa. It is possible that inhibitors of this enzyme system may facilitate the development of modified cryostorage regimes for clinical validation in vivo. PMID- 25740546 TI - European analytical column no. 43. PMID- 25740545 TI - Combining liquid chromatography with ozone-induced dissociation for the separation and identification of phosphatidylcholine double bond isomers. AB - Revealing the inherent molecular diversity of lipid biology requires advanced analytical technologies. Distinguishing phospholipids that differ in the position(s) of carbon-carbon double bonds within their acyl chains presents a particular challenge because of their similar chromatographic and mass spectral behaviours. Here-for the first time-we combine reversed-phase liquid chromatography for separation of isomeric phospholipids with on-line mass spectral analysis by ozone-induced dissociation (OzID) for unambiguous double bond position assignment. The customised tandem linear ion-trap mass spectrometer used in our study is capable of acquiring OzID scans on a chromatographic timescale. Resolving the contributions of isomeric lipids that are indistinguishable based on conventional mass spectral analysis is achieved using the combination of liquid chromatography and OzID. Application of this method to the analysis of simple (egg yolk) and more complex (sheep brain) extracts reveals significant populations of the phosphatidylcholine PC 16:0_18:1(n-7) alongside the expected PC 16:0_18:1(n-9) isomer. PMID- 25740548 TI - New Insights of the Tissue Factor Pathway Inhibitor in Patients with Hypercholesterolemia Treated with Statins. PMID- 25740547 TI - New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource. AB - Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host-pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions. PMID- 25740549 TI - Reduction of NO-mediated Relaxing Effects in the Thoracic Aorta in an Experimental Chronic Kidney Disease Mouse Model. AB - AIM: Chronic kidney disease (CKD) is known to frequently cause cardiovascular events. However, it is unclear how renal dysfunction affects the vascular response. We herein studied the effects of renal dysfunction on the aortic behavior in adenine-fed mice, investigating mechanisms underlying the occurrence of cardiovascular events in CKD patients. METHODS: Biochemical analyses of the plasma creatinine, blood urea nitrogen (BUN) and glucose levels and measurements of the blood pressure were performed using C57BL/6 mice fed with and without an adenine-containing diet. The relaxing effects of acetylcholine (ACh) or sodium nitropurusside (SNP) and effects of NO synthase (NOS) inhibitors on the contractions induced by phenylephrine (PE) were measured in endothelium-intact aortas obtained from both mice. RESULTS: The mice fed 0.25% adenine for four weeks showed greater plasma creatinine and BUN concentrations than the control mice, suggesting that adenine-fed mice are a useful CKD model. Furthermore, ACh relaxed the PE-stimulated, endothelium-intact aortas, the effect of which was less potent in the adenine-fed mice than in the control mice. In contrast, the degree of SNP-induced relaxation of the aortas was the same in the adenine-fed mice and control mice. The alpha1-adrenergic agonist, PE, induced more potent absolute tension of the endothelium-intact aortas in the CKD model mice than in the control mice, while the NOS inhibitors, N-nitro-L-arginine (LNA) and asymmetric dimethylarginine (ADMA) enhanced the contraction effects of PE in both mice. CONCLUSIONS: The findings of this study indicate that spontaneous and stimulated NO release from the endothelium is decreased in the CKD model mouse aorta. The NO-mediated correlation between renal and elastic arterial endothelial dysfunction is suggested to be a cause of cardiovascular events in patients with CKD. PMID- 25740550 TI - Cost-effectiveness of the 21-gene breast cancer assay in Mexico. AB - INTRODUCTION: The 21-gene breast cancer assay (Oncotype DX((r)); Genomic Health, Inc.) is a validated diagnostic test that predicts the likelihood of adjuvant chemotherapy benefit and 10-year risk of distant recurrence in patients with hormone-receptor-positive, human epidermal growth receptor 2-negative, early stage breast cancer. The aim of this analysis was to evaluate the cost effectiveness of using the assay to inform adjuvant chemotherapy decisions in Mexico. METHODS: A Markov model was developed to make long-term projections of distant recurrence, survival, and direct costs in scenarios using conventional diagnostic procedures or the 21-gene assay to inform adjuvant chemotherapy recommendations. Transition probabilities and risk adjustment were taken from published landmark trials. Costs [2011 Mexican Pesos (MXN)] were estimated from an Instituto Mexicano del Seguro Social perspective. Costs and clinical benefits were discounted at 5% annually. RESULTS: Following assay testing, approximately 66% of patients previously receiving chemotherapy were recommended to receive hormone therapy only after consideration of assay results. Furthermore, approximately 10% of those previously allocated hormone therapy alone had their recommendation changed to add chemotherapy. This optimized therapy allocation led to improved mean life expectancy by 0.068 years per patient and increased direct costs by MXN 1707 [2011 United States Dollars (USD) 129] per patient versus usual care. This is equated to an incremental cost-effectiveness ratio (ICER) of MXN 25,244 (USD 1914) per life-year gained. CONCLUSION: In early-stage breast cancer patients in Mexico, guiding decision making on adjuvant therapy using the 21-gene assay was projected to improve life expectancy in comparison with the current standard of care, with an ICER of MXN 25,244 (USD 1914) per life-year gained, which is within the range generally considered cost-effective. PMID- 25740552 TI - History of Persecution and Health Outcomes Among U.S. Refugees. AB - Our goal was to describe the forms of persecution reported by adult refugees in the U.S. and the relationships between persecution and health status among this population. Data were derived from the 2003 New Immigrant Survey, a representative sample of new U.S. lawful permanent residents. Major depression, impairment in daily activities due to pain, poor self-reported health, and declining health were described for refugees who had and had not reported persecution prior to arrival in the U.S. Health status was also examined for refugees who reported different forms of persecution. Half of refugees (46.7 %) in this sample reported that they or an immediate family member had been persecuted. One in three persecuted refugees (31.8 %) reported both incarceration and physical punishment. Major depression, pain-related impairment, poor health, and declining health were twice as common among persecuted refugees than among non persecuted refugees. Notably, despite these adverse experiences, the majority of persecuted refugees did not report poor health outcomes. PMID- 25740551 TI - Contributors to Patients' Ratings of Quality of Care Among Ethnically Diverse Patients with Type 2 Diabetes. AB - We examined racial/ethnic differences in patients' ratings of components of interpersonal quality [participatory decision making (PDM) style, being treated as an equal partner, and feelings of trust], and evaluated the association between each of these components and patients' ratings of overall healthcare quality among non-Hispanic white (NHW), Vietnamese American, and Mexican American patients with type 2 diabetes. The findings indicated that although all three components were significantly associated with ratings of overall healthcare quality, the significant interactions between race/ethnicity and both PDM style (beta = -0.09, p < 0.01) and equal partner (beta = -0.06, p < 0.05) for the Vietnamese American patients suggested that the relationship between these components and patients' ratings of healthcare quality were less strong among Vietnamese American patients than among the NHW patients. Understanding racial/ethnic differences in the components of interpersonal quality that are associated with patients' ratings of overall healthcare quality is an important step for improving patients' experiences of their own care. PMID- 25740553 TI - Incorporating Cultural Perspectives into Diabetes Self-Management Programs for East Asian Immigrants: A Mixed-Study Review. AB - It is important to understand East Asian immigrants (EAIs)' unique perspectives in managing diabetes in order to provide culturally-competent care. However, it is not known whether EAIs' perspectives are addressed in diabetes self-management interventions developed for EAIs. Therefore, a mixed-study review was conducted to identify EAIs' perspective from qualitative research (n = 9 studies) and to evaluate the components of EAI diabetes self-management interventions (n = 7). Themes from the qualitative synthesis demonstrated that EAIs have unique cultural values and traditional health beliefs while struggling with multi-contextual barriers due to immigration. The evaluation of EAI diabetes self-management interventions revealed that there was a lack of consensus on cultural strategies for EAIs' across the interventions. Addressing language barriers was the only factor consistently integrated in the cultural components of intervention by employing bilingual interventionists. EAIs' perspectives and experiences need to be incorporated in the future diabetes self-management interventions to better provide culturally-competent care. PMID- 25740554 TI - Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis. AB - We have used probe-based molecular dynamics (pMD) simulations to search for interaction hotspots on the surface of the therapeutically highly relevant oncogenic K-Ras G12D. Combining the probe-based query with an ensemble-based pocket identification scheme and an analysis of existing Ras-ligand complexes, we show that (i) pMD is a robust and cost-effective strategy for binding site identification, (ii) all four of the previously reported ligand binding sites are suitable for structure-based ligand design, and (iii) in some cases probe binding and expanded sampling of configurational space enable pocket expansion and increase the likelihood of site identification. Furthermore, by comparing the distribution of hotspots in nonpocket-like regions with known protein- and membrane-interacting interfaces, we propose that pMD has the potential to predict surface patches responsible for protein-biomolecule interactions. These observations have important implications for future drug design efforts and will facilitate the search for potential interfaces responsible for the proposed transient oligomerization or interaction of Ras with other biomolecules in the cellular milieu. PMID- 25740555 TI - Melanocytes from dark and light skin respond differently after ultraviolet B irradiation: effect of keratinocyte-conditioned medium. AB - BACKGROUND/PURPOSE: The response to the damage provoked by exposure to UV radiation is mediated by melanocytes and a network of paracrine factors produced by keratinocytes, and it varies among individuals of different geographical origin and skin colour. The mechanisms underlying this differential response, however, have not been completely elucidated. METHODS: We characterized the differential behaviour of melanocytes (proliferation and differentiation/melanogenesis) from both dark- and light-skinned individuals in response to ultraviolet B (UVB) irradiation, cultured with and without keratinocyte-conditioned medium (KCM). ELISA assays and real-time quantitative PCR were used to assess the production of keratinocyte-derived factors. RESULTS: After UVB irradiation, dark melanocytes showed a decreased proliferation consistent with the highly differentiated state inferred by the increased dendricity of the cells and higher levels of melanogenic genes expression, whereas light melanocytes showed an increase in proliferation in accord with a less differentiated state and decreased melanogenesis levels. KCM induced melanogenesis in dark melanocytes after UVB irradiation, but not in light pigmented melanocytes. CONCLUSION: Proliferation and differentiation are coordinated in response to UVB. A lower proliferative rate and a higher differentiation state in dark melanocytes could account for more effective photoprotective mechanisms that would prevent from cell damage against UVB irradiation. PMID- 25740557 TI - Flexible sigmoidoscopy: more than a unilateral breast exam? PMID- 25740556 TI - The impact of screening on colorectal cancer mortality and incidence: has it really made a difference? AB - About sixty percent of the US population of those age fifty and older are currently up to date with colorectal cancer screening recommendations. Has this level of screening made a difference for reducing colorectal cancer (CRC) incidence and/or mortality? Randomized controlled trials of guaiac-based fecal occult blood tests, which have relatively low sensitivity but high specificity for CRC, have shown a modest effect but with a long-term reduction in CRC mortality. Newer fecal immunochemical tests are expected to have a greater effect. Randomized controlled trials of flexible sigmoidoscopy have also demonstrated a reduction in CRC mortality. Observational studies of screening colonoscopy suggest an effect of greater than fifty percent reduction in CRC mortality. We have assessed past trends of colorectal cancer screening in the US population which suggest that more than fifty percent of the decline in colorectal cancer mortality can be attributed to the increased acceptance and uptake in colorectal cancer screening. Current and future levels of increased screening could provide for even larger reductions for the USA. Colorectal cancer screening has and will continue to make a significant impact on reducing colorectal cancer mortality. PMID- 25740558 TI - YKL-40 level in gingival crevicular fluid from patients with periodontitis and type 2 diabetes. AB - OBJECTIVE: YKL-40 is a chitin-binding glycoprotein, the level of which increases in inflammatory diseases, diabetes mellitus (DM), cardiovascular diseases, and tumors. Gingival crevicular fluid (GCF) contains many proteins and markers of periodontitis. The purpose of this study was to investigate YKL-40 level in GCF from patients with periodontitis and DM and the association between YKL-40 level and chronic periodontitis (CP) or DM. SUBJECTS AND METHODS: The subjects were 121 patients with DM, CP, DM and periodontitis (DM-P), and healthy subjects (H). GCF was collected using paper strips after the sites for GCF collection were clinically evaluated for probing depth (PD), gingival index (GI), and bleeding on probing (BOP). YKL-40 in GCF was identified by Western blotting, and its level was determined by ELISA. RESULTS: YKL-40 was contained in GCF samples from H, DM, CP, and DM-P sites, and its levels (amount and concentration) in CP and DM-P were significantly higher than those in H and DM. GCF YKL-40 level significantly correlated with PD and GI, and its level in BOP-positive sites was significantly higher than that in BOP-negative ones. CONCLUSIONS: GCF YKL-40 level was elevated in periodontitis, but not DM. YKL-40 in GCF may be an inflammatory marker for periodontitis. PMID- 25740559 TI - Conformational composition, molecular structure and decomposition of difluorophosphoryl azide in the gas phase. AB - The conformational composition, molecular structure and decomposition of difluorophosphoryl azide F2P(O)N3 in the gas phase were studied using gas electron diffraction (GED), matrix isolation IR spectroscopy, and quantum chemical calculations, respectively. While computational methods predict only minor differences in the total energy between the two possible conformers (syn and anti), the analysis of electron diffraction data reveals the dominating abundance of the syn conformer in the gas phase at room temperature. Ab initio frequency analyses suggest that a low-frequency large-amplitude motion of the N3 group with respect to the P-N-N-N torsion is to be expected for the syn conformer. The large amplitude motion was included explicitly into the GED structure refinement procedure. It presumably contributes to a thermodynamic stabilization of the syn-conformer with respect to the anti-conformer in the gas phase at ambient temperature. Upon flash vacuum pyrolysis, this syn conformer undergoes a stepwise decomposition via the difluorophosphoryl nitrene, F2P(O)N, which features as the first experimentally observed phosphoryl nitrene that can be thermally produced in the gas phase. To reveal the reaction mechanism, quantum chemical calculations on the potential energy surface (PES) of F2P(O)N3 were performed. Both B3LYP/6-311+G(3df) and CBS-QB3 calculation results strongly support a stepwise decomposition into the singlet F2P(O)N, which prefers intersystem crossing to the thermally persistent triplet ground state instead of a Curtius rearrangement into FP(O)NF. PMID- 25740561 TI - Pharmacokinetic/pharmacodynamic evaluation of eslicarbazepine for the treatment of epilepsy. AB - INTRODUCTION: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug registered as the adjunctive treatment of partial-onset seizures in adults. As a third-generation medication, ESL is believed to have favorable efficacy/safety profile and pharmacokinetic properties in comparison with related drugs (carbamazepine and oxcarbazepine). AREAS COVERED: The aim of the paper was to evaluate pharmacodynamic and pharmacokinetic properties of ESL with aspect to epilepsy treatment. The review of the scientific literature was based on the PubMed database, Clinical Trials, FDA and European Medicines Agency websites to elicit current information on drug metabolism, mechanism of action and efficacy/safety profile. EXPERT OPINION: Results of clinical trials indicate that ESL possessed a favorable profile of anticonvulsant efficacy and tolerability as an add-on therapy in adult patients at daily doses of 800 and 1200 mg. Pediatric trials are in progress and their results will allow to characterize a role of ESL in the treatment of epilepsy in children. PMID- 25740560 TI - Long-term outcomes of an antimicrobial stewardship program implemented in a hospital with low baseline antibiotic use. AB - OBJECTIVE: To evaluate the long-term outcomes of an antimicrobial stewardship program (ASP) implemented in a hospital with low baseline antibiotic use. DESIGN: Quasi-experimental, interrupted time-series study. SETTING: Public safety net hospital with 525 beds. INTERVENTION: Implementation of a formal ASP in July 2008. METHODS: We conducted a time-series analysis to evaluate the impact of the ASP over a 6.25-year period (July 1, 2008-September 30, 2014) while controlling for trends during a 3-year preintervention period (July 1, 2005-June 30, 2008). The primary outcome measures were total antibacterial and antipseudomonal use in days of therapy (DOT) per 1,000 patient-days (PD). Secondary outcomes included antimicrobial costs and resistance, hospital-onset Clostridium difficile infection, and other patient-centered measures. RESULTS: During the preintervention period, total antibacterial and antipseudomonal use were declining (-9.2 and -5.5 DOT/1,000 PD per quarter, respectively). During the stewardship period, both continued to decline, although at lower rates (-3.7 and 2.2 DOT/1,000 PD, respectively), resulting in a slope change of 5.5 DOT/1,000 PD per quarter for total antibacterial use (P=.10) and 3.3 DOT/1,000 PD per quarter for antipseudomonal use (P=.01). Antibiotic expenditures declined markedly during the stewardship period (-$295.42/1,000 PD per quarter, P=.002). There were variable changes in antimicrobial resistance and few apparent changes in C. difficile infection and other patient-centered outcomes. CONCLUSION: In a hospital with low baseline antibiotic use, implementation of an ASP was associated with sustained reductions in total antibacterial and antipseudomonal use and declining antibiotic expenditures. Common ASP outcome measures have limitations. PMID- 25740562 TI - Fine-mapping of a major QTL controlling angular leaf spot resistance in common bean (Phaseolus vulgaris L.). AB - KEY MESSAGE: A major QTL for angular leaf spot resistance in the common bean accession G5686 was fine-mapped to a region containing 36 candidate genes. Markers have been developed for marker-assisted selection. Common bean (Phaseolus vulgaris L.) is an important grain legume and an essential protein source for human nutrition in developing countries. Angular leaf spot (ALS) caused by the pathogen Pseudocercospora griseola (Sacc.) Crous and U. Braun is responsible for severe yield losses of up to 80%. Breeding for resistant cultivars is the most ecological and economical means to control ALS and is particularly important for yield stability in low-input agriculture. Here, we report on a fine-mapping approach of a major quantitative trait locus (QTL) ALS4.1(GS, UC) for ALS resistance in a mapping population derived from the resistant genotype G5686 and the susceptible cultivar Sprite. 180 F3 individuals of the mapping population were evaluated for ALS resistance and genotyped with 22 markers distributed over 11 genome regions colocating with previously reported QTL for ALS resistance. Multiple QTL analysis identified three QTL regions, including one major QTL on chromosome Pv04 at 43.7 Mbp explaining over 75% of the observed variation for ALS resistance. Additional evaluation of 153 F4, 89 BC1F2 and 139 F4/F5/BC1F3 descendants with markers in the region of the major QTL delimited the region to 418 kbp harboring 36 candidate genes. Among these, 11 serine/threonine protein kinases arranged in a repetitive array constitute promising candidate genes for controlling ALS resistance. Single nucleotide polymorphism markers cosegregating with the major QTL for ALS resistance have been developed and constitute the basis for marker-assisted introgression of ALS resistance into advanced breeding germplasm of common bean. PMID- 25740563 TI - New QTL alleles for quality-related traits in spring wheat revealed by RIL population derived from supernumerary * non-supernumerary spikelet genotypes. AB - KEY MESSAGE: A population developed from an exotic line with supernumerary spikelets was genetically dissected for eight quality traits, discovering new genes/alleles with potential use in wheat breeding programs. Identifying new QTLs and alleles in exotic germplasm is paramount for further improvement of quality traits in wheat. In the present study, an RIL population developed from a cross of an elite wheat line (WCB414) and an exotic genotype with supernumerary spikelets (SS) was used to identify QTLs and new alleles for eight quality traits. Composite interval mapping for 1,000 kernels weight (TKW), kernel volume weight (KVW), grain protein content (GPC), percent of flour extraction (FE) and four mixograph-related traits identified a total of 69 QTLs including 19 stable QTLs. These QTLs were located on 18 different chromosomes (except 4D, 5D, and 6D). Thirteen of these QTLs explained more than 15% of phenotypic variation (PV) and were considered as major QTLs. In this study, we identified 11 QTLs for TKW (R (2) = 7.2-17.1 %), 10 for KVW (R (2) = 6.7-22.5%), 11 for GPC (R (2) = 4.7 16.9%), 6 for FE (R (2) = 4.8-19%) and 31 for mixograph-related traits (R (2) = 3.2-41.2%). In this population, several previously identified QTLs for SS, nine spike-related and ten agronomic traits were co-located with the quality QTLs, suggesting pleiotropic effects or close linkage among loci. The traits GPC and mixogram-related traits were positively correlated with SS. Indeed, several loci for quality traits were co-located with QTL for SS. The exotic parent contributed positive alleles that increased PV of the traits at 56% of loci demonstrating the suitability of germplasm with SS to improve quality traits in wheat. PMID- 25740564 TI - Treatment decisional regret among men with prostate cancer: Racial differences and influential factors in the North Carolina Health Access and Prostate Cancer Treatment Project (HCaP-NC). AB - BACKGROUND: It has been demonstrated that treatment decisional regret affects quality of life in patients with prostate cancer (CaP); however, there are limited studies that identify factors associated with treatment decisional regret, particularly within a racially diverse patient population that has extended follow-up. METHODS: Logistic regression analysis was used to determine associations between decisional regret and potential predictors in a population based cohort of 348 African American men and 446 Caucasian American men approximately 3 years after CaP diagnosis. RESULTS: Of 794 research participants, 12% experienced treatment decisional regret. Decisional regret was associated with androgen-deprivation therapy (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.1-4.0), recent urinary bother (OR, 3.4; 95% CI, 1.6-7.3), satisfaction with understanding potential treatment side effects (very unsatisfied: OR, 13.3; 95% CI, 5.5-32.2; somewhat unsatisfied: OR, 5.0; 95% CI, 2.3-11.2; neutral: OR, 3.8; 95% CI, 1.9-7.6), and CaP treatment effect on the spousal relationship (very affected: OR, 3.9; 95% CI, 2.0-7.6; somewhat affected: OR, 3.1; 95% CI, 1.4-7.3; neutral: OR, 2.4; 95% CI, 1.9-7.6). Younger African Americans were more likely to experience regret than older African Americans (OR, 3.0; 95% CI, 1.1-8.1), and older African Americans were less likely to experience regret than older Caucasian Americans (OR, 0.2; 95% CI, 0.1-0.7). CONCLUSIONS: Treatment decisional regret remains an important issue in CaP survivors beyond initial treatment. Potential interventions should involve younger African Americans and patient spouses. Increased regret may reflect the unexpected influence of treatment side effects on the patient's everyday life; helping the patient relate potential side effects to his individual situation could improve patient satisfaction. PMID- 25740566 TI - TCGA Releases Head and Neck Cancer Data. AB - The largest molecular and genomic study of head and neck cancers to date reveals genomic alterations that may help these cancers start and grow. The results also identify a patient subgroup likely to respond to less-aggressive therapy and suggest new treatment targets. PMID- 25740565 TI - Biomechanical analysis of acromioclavicular joint dislocation repair using coracoclavicular suspension devices in two different configurations. AB - BACKGROUND: The best treatment option for some acromioclavicular (AC) joint dislocations is controversial. For this reason, the aim of this study was to evaluate the vertical biomechanical behavior of two techniques for the anatomic repair of coracoclavicular (CC) ligaments after an AC injury. MATERIALS AND METHODS: Eighteen human cadaveric shoulders in which repair using a coracoclavicular suspension device was initiated after injury to the acromioclavicular joint were included in the study. Three groups were formed; group I (n = 6): control; group II (n = 6): repair with a double tunnel in the clavicle and in the coracoid (with two CC suspension devices); group III (n = 6): repair in a "V" configuration with two tunnels in the clavicle and one in the coracoid (with one CC suspension device). The biomechanical study was performed with a universal testing machine (Electro Puls 3000, Instron, Boulder, MA, USA), with the clamping jaws set in a vertical position. The force required for acromioclavicular reconstruction system failure was analyzed for each cadaveric piece. RESULTS: Group I reached a maximum force to failure of 635.59 N (mean 444.0 N). The corresponding force was 939.37 N (mean 495.6 N) for group II and 533.11 N (mean 343.9 N) for group III. A comparison of the three groups did not find any significant difference despite the loss of resistance presented by group III. CONCLUSION: Anatomic repair of coracoclavicular ligaments with a double system (double tunnel in the clavicle and in the coracoid) permits vertical translation that is more like that of the acromioclavicular joint. Acromioclavicular repair in a "V" configuration does not seem to be biomechanically sufficient. PMID- 25740567 TI - Influence of Polymer Molecular Weight on Drug-Polymer Solubility: A Comparison between Experimentally Determined Solubility in PVP and Prediction Derived from Solubility in Monomer. AB - In this study, the influence of polymer molecular weight on drug-polymer solubility was investigated using binary systems containing indomethacin (IMC) and polyvinylpyrrolidone (PVP) of different molecular weights. The experimental solubility in PVP, measured using a differential scanning calorimetry annealing method, was compared with the solubility calculated from the solubility of the drug in the liquid analogue N-vinylpyrrolidone (NVP). The experimental solubility of IMC in the low-molecular-weight PVP K12 was not significantly different from that in the higher molecular weight PVPs (K25, K30, and K90). The calculated solubilities derived from the solubility in NVP (0.31-0.32 g/g) were found to be lower than those experimentally determined in PVP (0.38-0.40 g/g). Nevertheless, the similarity between the values indicates that the analogue solubility can provide valuable indications on the solubility in the polymer. Hence, if a drug is soluble in an analogue of the polymer, it is most likely also soluble in the polymer. In conclusion, the solubility of a given drug-polymer system is determined by the strength of the drug-polymer interactions rather than the molecular weight of the polymer. Therefore, during the first screenings for drug solubility in polymers, only one representative molecular weight per polymer is needed. PMID- 25740568 TI - Questionnaire study on parasite control practices on Thoroughbred and Standardbred breeding farms in New Zealand. AB - Against a global background of increasing anthelmintic resistance in parasites, little is known about the current parasite control strategies adopted within the equine industry in New Zealand. The aim of the study was to describe and compare the current parasite management and control practices used on Thoroughbred and Standardbred stud farms in New Zealand. An online questionnaire was used to collect data on the demographics of respondents, parasite control methods, grazing management, and use of faecal egg counts. Questions regarding parasite control strategy, how often horses were dewormed, number of treatments per year and stocking density were stratified by horse type: young stock (foals/weanlings/yearlings), wet mares (nursing a foal) or dry mares, and industry (Thoroughbred and Standardbred). Questions on grazing management were stratified by horse type and the breeding and non-breeding season. In total, 136 respondents completed the survey, of which most (66%; 90/136) were involved in the Thoroughbred breeding industry. Most (98%; 134/136) respondents used anthelmintic products to treat the horses on their property, and regardless of industry type most respondents were using interval drenching for young stock (86/129; 53%), dry mares (51/124; 41%) or wet mares (50/126; 40%). Of those respondents treating on regular interval, 55% (68/123), 42% (50/119) and 38% (46/122) were treating young stock, wet mares and dry mares every 6-8 weeks. The median number of treatments per year for young stock, dry mares and wet mares was 6 (IQR 4-8), 4 (IQR 3-6) and 4 (IQR 3-6), respectively; there was no difference in frequency of treatments by industry type. In the last 12 months respondents used a median of 2 (IQR 2-4) and 3 (IQR 2-4) different anthelmintic products to treat horses on Thoroughbred and Standardbred breeding farms, respectively. Of the respondents reporting the anthelmintic products used in the last 12 months, 95% used at least one product containing macrocyclic lactones. Overall, faecal egg counts were done by 20% (25/124) of respondents and over half of respondents in both industries were consulting their veterinarian for advice on worming products. This study identified a high reliance on anthelmintic products and limited on-farm control practices that would delay the development of anthelmintic resistance in equine parasites. Further research is now required to identify the level of resistance in the New Zealand equine parasite population. PMID- 25740569 TI - Adherence to the Food and Agricultural Organization guidelines on trypanocide usage among cattle farmers in Itezhi tezhi, Central Zambia. AB - Trypanocides will continue to play an important role in the control of tsetse fly transmitted trypanosomosis now and in the near future. The drugs are mostly administered by farmers without any veterinary supervision leading to misuse and under dosing of medication, and these could be factors that promote trypanocidal drug resistance (TDR) development. In order to delay or prevent TDR, the Food and Agriculture Organization (FAO) recommended guidelines on trypanocide use. It is not known if these recommended guidelines are adhered to in Itezhi tezhi district of Zambia. A survey was undertaken to examine how socio-economic and environmental factors were associated with adherence to the recommended guidelines on trypanocide use in Itezhi tezhi, Central Zambia. Ninety farmers who use trypanocides were interviewed using a questionnaire to collect their socio economic characteristics (age, education in years, cattle herd size, competence on trypanocide use and their access to extension on trypanocide use) and trypanocide usage practices while crush pens which they use were stratified according to location, whether in the Game Management Area (GMA) (Mutenda, Itumbi, Kapulwe and Banachoongo) or non-GMA (Iyanda, New Ngoma and Shinampamba) as an environmental factor. Associations and measures of associations to adherence of FAO guidelines were determined. The results showed that 25.6% of the farmers adhered to guidelines by FAO on trypanocide use and that none of the socio-economic factors under investigation were significantly associated with it. Further the farmers that used crush pens that were in the GMA had an 80% reduction in the likelihood of adhering to the FAO guidelines on trypanocide use than those that used crush pens in the non-GMA (AOR 0.20, 95% CI: 0.05-0.81, P=0.02). There was low adherence to the recommended FAO guidelines on trypanocide use and it was associated with the location of the crush pen whether in the GMA or not, as an environmental factor. With farmers in the GMA less likely to adhere to FAO guidelines than those in the non-GMA, we recommend an integrated approach of measures to control trypanosomosis in the GMA of Itezhi tezhi to lessen overuse of trypanocides by the farmers. PMID- 25740570 TI - Bone cells and bone turnover in diabetes mellitus. AB - Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due, at least in part, to altered bone remodeling and bone cell function in diabetes. Circulating biochemical markers of bone formation, including P1NP, osteocalcin and bone-specific alkaline phosphatase have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). These findings have been corroborated by preliminary histomorphometric data. Reductions in the bone resorption marker serum CTx in T2D have also been reported. Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Other factors such as bone marrow fat saturation, advanced glycation endproduct (AGE) accumulation, and microarchitectural changes might also relate to bone cell function and fracture risk in diabetes. PMID- 25740571 TI - Collagen structure deterioration in the skin of patients with pelvic organ prolapse determined by atomic force microscopy. AB - We used atomic force microscopy (AFM) to diagnose pathological changes in the extracellular matrix (ECM) of skin connective tissue in patients with pelvic organ prolapse (POP). POP is a common condition affecting women that considerably decreases the patients' quality of life. Deviations from normal morphology of the skin ECM from patients with POP occur including packing and arrangement of individual collagen fibers and arrangement of collagen fibrils. The nanoindentation study revealed significant deterioration of the mechanical properties of collagen fibril bundles in the skin of POP patients as compared with the skin of healthy subjects. Changes in the skin ECM appeared to correlate well with changes in the ECM of the pelvic ligament tissue associated with POP. AFM data on the ECM structure of normal and pathologically altered connective tissue were in agreement with results of the standard histological study on the same clinical specimens. Thus, AFM and related techniques may serve as independent or complementary diagnostic tools for tracking POP-related pathological changes of connective tissue. PMID- 25740573 TI - Debunking myths about "allergy" to radiocontrast media in an academic institution. AB - PURPOSE: Patients with "allergy" to iodine and shellfish often do not obtain necessary radiologic procedures due to anxiety about potential radiocontrast media reactions. This study assesses the impact of an educational intervention to dispel these myths. METHODS: The authors surveyed 252 internal medicine, emergency medicine, pediatrics, radiology, obstetrics/gynecology, and surgery health professionals before and after an educational intervention. Pre- and posttest responses were analyzed to assess the impact of the intervention on beliefs about radiocontrast media reactions and their perceived relationship to shellfish allergy and iodine "allergy." RESULTS: The mean pre- and posttest correct response scores were 41% and 91%, respectively. The intervention had a greater impact on respondents' knowledge about iodine allergy than shellfish allergy, most likely due to the difference in baseline knowledge (P < 0.005). Emergency medicine garnered the highest pretest correct response score (54%). Internal medicine earned the lowest pretest score (30%). There was a significant difference between the highest and lowest scoring specialties on the pretest (P = 0.037). There was no statistically significant correlation with training levels. There was a considerable decrease in the percentage of respondents who would withhold radiologic studies from patients suspected of shellfish or iodine allergy. The percentage of respondents who would premedicate patients with antihistamines or steroids also decreased significantly. CONCLUSION: An educational intervention helps rectify misconceptions among health care professionals about radiocontrast media reactions and their perceived relationship to shellfish or iodine allergy. PMID- 25740574 TI - Photoassisted formation of Cu(x)S-based cathodes for CdS-sensitized solar cells with S(2-)/S(x)(2-) electrolyte. AB - The sulfidation of copper nanoparticles deposited onto ZnO surface by the photocatalytic reduction of Cu(II) results in the formation of ZnO/CuxS films that can be used as efficient counter electrodes in solar cells based on sulfide/polysulfide electrolytes. The films are formed by the spherical copper sulfide nano/micro-aggregates of tabulate CuxS nanoparticles with x = 1.3-1.4. A model cell with a FTO/ZnO/CdS photoanode produced by SILAR and FTO/ZnO/CuxS films as counter-electrode showed a light conversion efficiency, eta = 1.73%, which is 25% higher than a similar cell where copper sulfide was deposited onto ZnO in "dark" conditions. Varying the conditions of the photocatalytic deposition of the starting copper nanoparticles slightly affects the electrocatalytic properties of the final FTO/ZnO/CuxS heterostructures. PMID- 25740572 TI - Combination of angiotensin-(1-7) with perindopril is better than single therapy in ameliorating diabetic cardiomyopathy. AB - We recently found that overexpression of angiotensin (Ang)-converting enzyme 2, which metabolizes Ang-II to Ang-(1-7) and Ang-I to Ang-(1-9), may improve left ventricular remodeling in diabetic cardiomyopathy. Here we aimed to test whether chronic infusion of Ang-(1-7) can dose-dependently ameliorate left ventricular remodeling and function in a rat model of diabetic cardiomyopathy and whether the combination of Ang-(1-7) and Ang-converting enzyme inhibition may be superior to single therapy. Our results showed that Ang-(1-7) treatment dose-dependently ameliorated left ventricular remodeling and dysfunction in diabetic rats by attenuating myocardial fibrosis, myocardial hypertrophy and myocyte apoptosis via both the Mas receptor and angiotensin II type 2 receptor. Furthermore, combining Ang-(1-7) with perindopril provided additional cardioprotection relative to single therapy. Ang-(1-7) administration provides a novel and promising approach for treatment of diabetic cardiomyopathy. PMID- 25740575 TI - Dementia beyond 2025: Knowledge and uncertainties. AB - Given that there may well be no significant advances in drug development before 2025, prevention of dementia-Alzheimer's disease through the management of vascular and lifestyle-related risk factors may be a more realistic goal than treatment. Level of education and cognitive reserve assessment in neuropsychological testing deserve attention, as well as cultural, social, and economic aspects of caregiving. Assistive technologies for dementia care remain complex. Serious games are emerging as virtual educational and pleasurable tools, designed for individual and cooperative skill building. Public policies are likely to pursue improving awareness and understanding of dementia; providing good quality early diagnosis and intervention for all; improving quality of care from diagnosis to the end of life, using clinical and economic end points; delivering dementia strategies quicker, with an impact on more people. Dementia should remain presented as a stand-alone concept, distinct from frailty or loss of autonomy. The basic science of sensory impairment and social engagement in people with dementia needs to be developed. E-learning and serious games programs may enhance public and professional education. Faced with funding shortage, new professional dynamics and economic models may emerge through coordinated, flexible research networks. Psychosocial research could be viewed as an investment in quality of care, rather than an academic achievement in a few centers of excellence. This would help provide a competitive advantage to the best operators. Stemming from care needs, a logical, systems approach to dementia care environment through organizational, architectural, and psychosocial interventions may be developed, to help reduce symptoms in people with dementia and enhance quality of life. Dementia-friendly environments, culture, and domesticity are key factors for such interventions. PMID- 25740576 TI - Anatomy of the clitoris and its impact on neophalloplasty (metoidioplasty) in female transgenders. AB - The current management of female to male transgender surgery is based on the advances in neophalloplasty, perioperative care and the knowledge of the female genital anatomy, as well as the changes that occur to this anatomy with preoperative hormonal changes in transgender population. Since the clitoris plays the main role in female sexual satisfaction, its impact on the outcome in female to male transgender surgery is predictable. Although female genital anatomy was poorly described in majority of anatomical textbooks, recent studies have provided a better insight in important details such as neurovascular supply, ligaments, body configuration, and relationship with urethral/vaginal complex. This article aims to review current state of knowledge of the clitoral anatomy as well its impact on clitoral reconstruction in female to male sex reassignment surgery. PMID- 25740577 TI - Impact of Doctor Car with Mobile Cloud ECG in reducing door-to- balloon time of Japanese ST-elevation myocardial infarction patients. AB - Early reperfusion by percutaneous coronary intervention (PCI) is the current standard therapy for ST-elevation myocardial infarction (STEMI). To achieve better prognoses for these patients, reducing the door-to-balloon time is essential. As we reported previously, the Kitasato University Hospital Doctor Car (DC), an ambulance with a physician on board, is equipped with a novel mobile cloud 12-lead ECG system. Between September 2011 and August 2013, there were 260 emergency dispatches of our Doctor Car, of which 55 were for suspected acute myocardial infarction with chest pain and cold sweat. Among these 55 calls, 32 patients received emergent PCI due to STEMI (DC Group). We compared their data with those of 76 STEMI patients who were transported directly to our hospital by ambulance around the same period (Non-DC Group). There were no differences in patient age, gender, underlying diseases, or Killip classification between the two groups. The door-to-balloon time in the DC group was 56.1 +/- 13.7 minutes and 74.0 +/- 14.1 minutes in the Non-DC Group (P < 0.0001). Maximum levels of CPK were 2899 +/- 308 and 2876 +/- 269 IU/L (P = 0.703), and those of CK-MB were 292 +/- 360 and 295 +/- 284 ng/mL (P = 0.423), respectively, in the 2 groups. The Doctor Car system with the Mobile Cloud ECG was useful for reducing the door-to balloon time. PMID- 25740578 TI - Changes of naturally occurring CD4(+)CD25(+) FOXP3(+) regulatory T cells in patients with acute coronary syndrome and the beneficial effects of atorvastatin treatment. AB - To determine the number and function of naturally occurring CD4(+)CD25(+)FOXP3(+) regulatory T cells (nTregs) in patients with acute coronary syndrome (ACS) and to determine the effects of a low dose of atorvastatin treatment (20 mg/day) on nTregs.Patients with ACS were randomly divided into a group receiving conventional therapy (n = 60) or conventional therapy supplemented with atorvastatin (20 mg/day) (n = 60). A group of healthy volunteers that did not suffer from ACS was used as controls (n = 60). T lymphocytes were isolated from ACS patients, both before and 4 weeks after treatment, or control patients and the percentage of nTregs was determined by flow cytometry. Serum levels of cytokines were determined by enzyme-linked immunosorbent assays. A mixed lymphocyte reaction was used to determine the ability of nTregs to inhibit proliferation of effector T cells. Quantitative PCR and Western blot were used to analyze (forkhead box P3) FOXP3 mRNA transcript levels and the expression of FOXP3 protein.In ACS patients, the percentage and inhibitory properties of nTregs were reduced, IFN-gamma and hsCRP levels were increased, and IL-10 and TGF-beta1 levels were lowered. Atorvastatin treatment increased the percentage and inhibitory ability of nTregs, decreased serum IFN-gamma and hsCRP levels, and decreased IL-10 and TGF-beta1 levels, as compared with the non-atorvastatin group.Our findings suggest that nTregs play an atheroprotective role in atherosclerosis. The inhibitory effects of atorvastatin on inflammation in ACS may be due to its beneficial effects on nTregs and restoration of immune homeostasis. PMID- 25740579 TI - Fulminant type 1 diabetes mellitus and fulminant viral myocarditis. A case report and literature review. AB - A 35-year-old Japanese woman was admitted with coma following flu-like symptoms. She was diagnosed with diabetic ketoacidosis and fulminant type 1 diabetes (FT1D) and received intravenous infusion of insulin and saline. The next day, the ketoacidosis disappeared, and she recovered consciousness. However, extensive ST segment elevations in the electrocardiogram appeared with a positive troponin test, and the patient developed pulmonary edema on day 3. An echocardiogram showed globally reduced wall motion of the left ventricle and mild pericardial effusion. Despite medical therapy with intravenous furosemide, carperitide, and catecholamines, her cardiac function deteriorated rapidly, with the left ventricular ejection fraction decreasing to 26% within 7 hours, and progressed to cardiogenic shock that afternoon. The patient received mechanical circulatory support for 4 days with intra-aortic balloon pumping and percutaneous cardiopulmonary support, and recovered fully from circulatory failure. A paired serum antibody test showed a significantly elevated titer against parainfluenza-3 virus, indicating a diagnosis of fulminant viral myocarditis. She was discharged on multiple daily insulin injection therapy, and her subsequent clinical course has been uneventful. In summary, we present a case of concurrent FT1D and fulminant viral myocarditis. Parainfluenza-3 viral infection was confirmed serologically and was considered to be a cause of both the FT1D and fulminant myocarditis. PMID- 25740580 TI - Assessment of transthyretin combined with mini nutritional assessment on admission provides useful prognostic information in patients with acute decompensated heart failure. AB - Decreased Transthyretin (TTR) can be observed in heart failure patients with malnutrition evaluated by the Mini Nutritional Assessment (MNA). This study investigated whether a combination of different nutritional assessment methods would be useful for assessing prognosis in patients with acute decompensated heart failure (ADHF).This prospective study included 52 patients with ADHF (mean age, 71.1 +/- 14.7 years; men 55.8%) who were admitted to our hospital between June 2012 and August 2013. On admission, nutritional status was evaluated according to levels of TTR and the MNA. Of 52 patients, 28 (53.8%) had TTR < 15 mg/dL, 39 (75.0%) had malnutrition or were at risk of malnutrition (MNA score <= 23.5), and 21 (40.4%) were categorized into group L (MNA score <= 23.5 and TTR < 15 mg/dL). Readmission due to worsening heart failure occurred in 12 patients (23.1%), and there were 4 (7.7%) allcause deaths. The 1-year event-free survival rates in group L and the remaining patients (group O) were 27.7% and 85.6%, respectively (P = 0.001). Using Cox multivariate analysis, group L also had a poorer prognosis (hazard ratio 4.35, 95% confidence interval 1.26-17.74, P = 0.020).MNA revealed that 75% of patients with ADHF had malnutrition or were at risk of malnutrition. The combination of low MNA and low TTR on admission can predict the prognosis of patients with ADHF. PMID- 25740581 TI - Successful weight reduction improves left ventricular diastolic function and physical performance in severe obesity. AB - Obesity and the metabolic syndrome (MetS) are risk factors for left ventricular diastolic dysfunction (LVDD). However, little is known about the impact of successful weight reduction (WR) on diastolic function and physical performance.Obese subjects (oBMI 40.2 +/- 8.6 kg/m(2)) underwent a 1-year WR program comprising diet and lifestyle components. Echocardiography and exercise capacity (6-minute walk) were performed at baseline and after 1 year. The distribution of weight reduction was split at the sample median and subjects were dichotomized in "successful WR" (% WR >= median, corresponding to a weight loss of 8%) and "failed-WR" (% WR < median).From a total of 188 obese subjects, 71 had LVDD at baseline. Obese patients with successful WR improved their MetS alterations, including fasting glucose, insulin, lipids, adipokines, blood pressure levels, and epicardial fat thickness. The same was not true for obesity with failed WR. Subjects with successful WR demonstrated significant improvement in echocardiographic LVDD parameters (median [interquartile range]): Deltae' (2,5 [-1.0, 4.7], P < 0.01), Deltae'/a' (0.34 [0.07, 079], P < 0.01), DeltaE/e' (-1.14 [-2.72, -0.54], P < 0.05), DeltaE/A (0.08 [-0.04, 0.26], P < 0.05), DeltaArd-Ad ( 28 [-54, -4], P < 0.01), and 6-minute walk distance (65 [19, 135], P < 0.01). Improvement of >= 2 LVDD criteria was accomplished in 30% of subjects with WR versus 10% without (P = 0.009). Using multivariable regression analysis, reduction of epicardial fat thickness was particularly predictive for the improvement of diastolic function.In summary, in severe obesity, successful long term WR was associated with improved LV diastolic function and exercise capacity. PMID- 25740582 TI - Waon therapy improves quality of life as well as cardiac function and exercise capacity in patients with chronic heart failure. AB - Waon therapy (WT), which in Japanese means soothing warmth, is a repeated sauna therapy that improves cardiac and vascular endothelial function in patients with chronic heart failure (CHF). We investigated whether WT could improve the quality of life (QOL) of CHF patients in addition to improving cardiac function and exercise capacity.A total of 49 CHF patients (69 +/- 14 years old) were treated with a 60 degrees C far infrared-ray dry sauna bath for 15 minutes and then kept in a bed covered with blankets for 30 minutes once a day for 3 weeks. At baseline and 3 weeks after starting WT, cardiac function, 6-minute walk distance (6MWD), flow mediated dilation (FMD) of the brachial artery, and SF36-QOL scores were determined.WT significantly improved left ventricular ejection fraction (LVEF), B type natriuretic peptide (BNP), 6MWD, and FMD (3.6 +/- 2.3 to 5.1 +/- 2.8%, P < 0.01). Moreover, WT significantly improved not only the physical (PC) but also mental component (MC) of the QOL scores. WT-induced improvement of PC was negatively correlated with changes in BNP (r = -0.327, P < 0.05), but MC improvement was not related directly to changes in BNP, LVEF, or 6MWD. WT-induced changes in MC were not parallel to PC improvement.WT improved QOL as well as cardiac function and exercise capacity in patients with CHF. Mental QOL improved independently of WT-induced improvement of cardiac function and exercise capacity. PMID- 25740583 TI - Prediction of coronary artery disease in patients with lower extremity peripheral artery disease. AB - Coronary artery disease (CAD) is a major determinant of long-term prognosis in patients with peripheral artery disease (PAD). We investigated the predictors of CAD in patients with lower extremity PAD.A total of 107 patients with PAD who underwent peripheral and simultaneous coronary angiography were reviewed. PAD was defined as (>= 50%) stenosis associated with claudication or critical limb ischemia. PAD was divided into proximal and distal lesions. CAD was defined as angiographically significant (>= 50%) stenosis of coronary arteries.The prevalence of CAD in patients with PAD was 62% (67/107), and of this 62%, only 13% (9/67) had angina and 72% (48/67) had multi-vessel disease. Diabetes significantly increased the risk of CAD in patients with PAD and the odds ratio of having multi-vessel CAD was 2.5 (1.1-5.9, P = 0.037) in multivariate regression analysis. The patients with multi-vessel CAD had more cardiovascular risk factors than those with normal, minimal and single CAD (P = 0.032). Interestingly, the prevalence of proximal PAD was higher in the normal or single CAD group than the multi-vessel CAD group, whereas both proximal and distal involvement of PAD was higher in the multi-vessel CAD group.Diabetes, multi cardiovascular risk factors, and involvement of both proximal and distal lesions significantly increased the risk of multi-vessel CAD. Therefore, simultaneous CAD evaluation should be considered in patients with lower extremity PAD having diabetes, multi-cardiovascular risk factors, or multi-level disease. PMID- 25740584 TI - Incidence and predictors of rehospitalization of acute heart failure patients. AB - Repeated hospitalization due to acute decompensated heart failure (HF) is a pandemic health problem in Japan. However, it is difficult to predict rehospitalization after discharge for acute decompensated HF. We used a single hospital-based cohort from the Shinken Database 2004-2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 282 patients discharged after their first acute HF admission were included in the analysis. The median follow-up period was 908 +/- 865 days. Of these patients, rehospitalization due to worsening HF occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. Patients with rehospitalization were older than those without rehospitalization. Prevalence of diabetes mellitus (DM) was more common in patients with rehospitalization. Average heart rate (HR) tended to be higher in patients with rehospitalization. Loop diuretics were more commonly used at hospital discharge in patients with rehospitalization. Multivariate Cox regression analysis revealed that age >= 75 years, DM, HR >= 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for rehospitalization. The number of these independent risk factors could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk patients. HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HR, and loop diuretics use at discharge were independently associated with HF rehospitalization. By simply counting these risk factors, we might be able to predict the risk of HF rehospitalization after discharge. PMID- 25740585 TI - Parasympathetic reinnervation accompanied by improved post-exercise heart rate recovery and quality of life in heart transplant recipients. AB - Although sympathetic reinnervation is accompanied by the improvement of exercise tolerability during the first years after heart transplantation (HTx), little is known about parasympathetic reinnervation and its clinical impact. We enrolled 21 recipients (40 +/- 16 years, 71% male) who had received successive cardiopulmonary exercise testing at 6 months, and 1 and 2 years after HTx. Exercise parameters such as peak oxygen consumption or achieved maximum load remained unchanged, whereas recovery parameters including heart rate (HR) recovery during 2 minutes and the delay of peak HR, which are influenced by parasympathetic activity, improved significantly during post-HTx 2 years (P < 0.05 for both). HR variability was analysed at post-HTx 6 months in 18 recipients, and high frequency power, representing parasympathetic activity, was significantly associated with the 2 recovery parameters (P < 0.05 for all). We also assessed quality of life using the Minnesota Living with Heart Failure (HF) Questionnaire at post-HTx 6 months and 2 years in the same 18 recipients, and those with improved recovery parameters enjoyed a better HF-specific quality of life (P < 0.05 for both). In conclusion, parasympathetic reinnervation emerges along with improved post-exercise recovery ability of HR and quality of life during post-HTx 2 years. PMID- 25740586 TI - Assessment of endothelial function. History, methodological aspects, and clinical perspectives. AB - In 1986, endothelial function was measured for the first time in patients with atherosclerotic coronary arteries. Since then, several methods for assessment of endothelial function, such as endothelium-dependent vasodilation induced by intra arterial infusion of vasoactive agents using coronary angiography, Doppler flow guide wire, mercury-filled Silastic strain-gauge plethysmography, flow-mediated vasodilation, reactive hyperemia-peripheral arterial tonometry, and vascular response using an oscillometric method have been performed in humans. This review focuses on the assessment of endothelial function, including measurement history, methodological issues, and clinical perspectives. PMID- 25740587 TI - Octogenarian patients with heart failure. Commonly encountered in clinical practice but only a minority in clinical trials. PMID- 25740588 TI - Effects of reaggregated granulosa cells and oocytes derived from early antral follicles on the properties of oocytes grown in vitro. AB - In this study, we examined the effects of reconstructed oocyte-granulosa cell complexes (OGCs) on the development of porcine oocytes derived from early antral follicles (EAFs; 0.5-0.7 mm in diameter). When denuded oocytes were cocultured with granulosa cells derived from other EAFs, the oocytes and granulosa cells aggregated to form OGCs after 2 days of culture. After 14 days of culture, we compared cell number, oocyte diameter, and oocyte chromatin configuration in unmanipulated (natural) OGCs, reconstructed OGCs, and OGCs collected from antral follicles (AFs, 3.0-6.0 mm in diameter). The diameters of oocytes from reconstructed OGCs grown in vitro were not different from those of oocytes from natural OGCs, although they were significantly smaller than those of oocytes from antral follicle (AF) OGCs. Oocyte chromatin configuration did not differ among the 3 OGC groups, but the oocyte nuclear maturation rate was lower in the reconstructed OGCs and higher in the AF OGCs. However, when the in vitro culture period for the reconstructed OGCs was extended by 2 days, the nuclear maturation rate of oocytes from reconstructed OGCs was similar to that of oocytes from natural OGCs. In addition, blastocysts were successfully obtained from oocytes from reconstructed OGCs. In conclusion, we established an innovative culture method that allows oocytes and granulosa cells from EAFs to reaggregate as reconstructed OGCs, which yield oocytes with the ability to develop to the blastocyst stage. PMID- 25740589 TI - Reconciling spatial and temporal soil moisture effects on afternoon rainfall. AB - Soil moisture impacts on precipitation have been strongly debated. Recent observational evidence of afternoon rain falling preferentially over land parcels that are drier than the surrounding areas (negative spatial effect), contrasts with previous reports of a predominant positive temporal effect. However, whether spatial effects relating to soil moisture heterogeneity translate into similar temporal effects remains unknown. Here we show that afternoon precipitation events tend to occur during wet and heterogeneous soil moisture conditions, while being located over comparatively drier patches. Using remote-sensing data and a common analysis framework, spatial and temporal correlations with opposite signs are shown to coexist within the same region and data set. Positive temporal coupling might enhance precipitation persistence, while negative spatial coupling tends to regionally homogenize land surface conditions. Although the apparent positive temporal coupling does not necessarily imply a causal relationship, these results reconcile the notions of moisture recycling with local, spatially negative feedbacks. PMID- 25740590 TI - Reply: To PMID 25370843. PMID- 25740591 TI - Oocyte donor information - how much is enough? PMID- 25740592 TI - Addressing Missing Data in Patient-Reported Outcome Measures (PROMS): Implications for the Use of PROMS for Comparing Provider Performance. AB - Patient-reported outcome measures (PROMs) are now routinely collected in the English National Health Service and used to compare and reward hospital performance within a high-powered pay-for-performance scheme. However, PROMs are prone to missing data. For example, hospitals often fail to administer the pre operative questionnaire at hospital admission, or patients may refuse to participate or fail to return their post-operative questionnaire. A key concern with missing PROMs is that the individuals with complete information tend to be an unrepresentative sample of patients within each provider and inferences based on the complete cases will be misleading. This study proposes a strategy for addressing missing data in the English PROM survey using multiple imputation techniques and investigates its impact on assessing provider performance. We find that inferences about relative provider performance are sensitive to the assumptions made about the reasons for the missing data. PMID- 25740594 TI - Synthesis, structure, and magnetic properties of novel B-site ordered double perovskites, SrLaMReO6 (M = Mg, Mn, Co and Ni). AB - Four new double perovskites, SrLaMReO(6) (M = Mg, Mn, Co, Ni) in which Re(5+) (5d(2)) is present, were prepared via conventional solid state reactions and characterized by X-ray and neutron powder diffraction, XANES, SQUID magnetometry, and muon spin relaxation (MUSR). Synchrotron X-ray and neutron diffraction experiments confirmed that all compounds crystallize in the monoclinic P2(1)/n structure type, which consists of alternately corner-shared octahedra of MO(6) and ReO(6). Rietveld refinement results indicated anti-site mixing of less than 7% on the M/Re sites. Bond valence sum calculations (BVS) suggest all M and Re ions are 2+ and 5+, respectively, and for the Mn-containing phase this is also supported by XANES measurements. All of the materials are paramagnetic at room temperature and their Curie-Weiss temperatures are positive (except for Mg) indicating net ferromagnetic interactions. No evidence for long-range magnetic order is evident in the dc magnetic susceptibility and MUSR measurements for SrLaMgReO(6) to 2 K. The Mn-phase shows long-range order at T(C) = 190 K and neutron diffraction revealed a ferromagnetic structure with a refined net moment of ~3.7MU(B). Both Co- and Ni-containing phases exhibit spin glass behavior at T(G) = 23 and 30 K, respectively, which is supported by neutron diffraction and a.c. susceptibility data. The structure and physical properties of these four new rhenium based ordered double perovskites are compared to the closely related "pillared perovskites", La(5)Re(3)MO(16), the isoelectronic Os(6+) (5d(2)) double perovskite Sr(2)CoOsO(6), and the Re(6+) (5d(1)) double perovskites, Sr(2)MReO(6), (M = Mg, Ca, Mn, Co, Ni). PMID- 25740593 TI - Inhibition of cellulose enzymatic hydrolysis by laccase-derived compounds from phenols. AB - The presence of inhibitors compounds after pretreatment of lignocellulosic materials affects the saccharification and fermentation steps in bioethanol production processes. Even though, external addition of laccases selectively removes the phenolic compounds from lignocellulosic prehydrolysates, when it is coupled to saccharification step, lower hydrolysis yields are attained. Vanillin, syringaldehyde and ferulic acid are phenolic compounds commonly found in wheat straw prehydrolysate after steam-explosion pretreatment. These three phenolic compounds were used in this study to elucidate the inhibitory mechanisms of laccase-derived compounds after laccase treatment. Reaction products derived from laccase oxidation of vanillin and syringaldehyde showed to be the strongest inhibitors. The presence of these products causes a decrement on enzymatic hydrolysis yield of a model cellulosic substrate (Sigmacell) of 46.6 and 32.6%, respectively at 24 h. Moreover, a decrease in more than 50% of cellulase and beta glucosidase activities was observed in presence of laccase and vanillin. This effect was attributed to coupling reactions between phenoxyl radicals and enzymes. On the other hand, when the hydrolysis of Sigmacell was performed in presence of prehydrolysate from steam-exploded wheat straw a significant inhibition on enzymatic hydrolysis was observed independently of laccase treatment. This result pointed out that the other components of wheat-straw prehydrolysate are affecting the enzymatic hydrolysis to a higher extent than the possible laccase-derived products. PMID- 25740595 TI - Interleukin-22 in kidney injury and regeneration. AB - Interleukins have become well-known regulators of innate and adaptive immunity related tissue inflammation. Recently, IL-22 has gained a lot of interest for its unique functions in maintaining and regaining epithelial integrity. IL-22 is exclusively secreted by different immune cell subsets, while IL-22 receptors are mainly expressed by epithelial cells. As the kidney is largely an epithelial organ, the functional role of IL-22 in the kidney deserves to be explored in detail. Here, we briefly summarize the key features of IL-22 biology and review the available data on its expression and functional roles in kidney injury and kidney regeneration. Furthermore, we provide suggestions on how to explore this evolving field in the future. PMID- 25740597 TI - mTOR inhibition with temsirolimus causes acute increases in glomerular permeability, but inhibits the dynamic permeability actions of puromycin aminonucleoside. AB - Inhibitors of the mammalian target of rapamycin (mTORi) can produce de novo proteinuria in kidney transplant patients. On the other hand, mTORi has been shown to suppress disease progression in several animal models of kidney disease. In the present study, we investigated whether glomerular permeability can be acutely altered by the mTORi temsirolimus and whether mTORi can affect acute puromycin aminonucleoside (PAN) or angiotensin II (ANG II)-induced glomerular hyperpermeability. In anesthetized Wistar rats, the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Temsirolimus was administered as a single intravenous dose 30 min before the start of the experiments in animals infused with PAN or ANG II or in nonexposed animals. Polydispersed FITC-Ficoll-70/400 (molecular radius 10-80 A) and (51)Cr EDTA infusion was given during the whole experiment. Measurements of Ficoll in plasma and urine were performed sequentially before the temsirolimus injection (baseline) and at 5, 15, 30, 60, and 120 min after the start of the experiments. Urine and plasma samples were analyzed by high-performance size-exclusion chromatography (HPSEC) to assess glomerular sieving coefficients (theta) for Ficoll10-80A. Temsirolimus per se increased baseline glomerular permeability to Ficoll50-80A 45 min after its administration, a reactive oxygen species (ROS) dependent phenomenon. PAN caused a rapid and reversible increase in glomerular permeability, peaking at 5 min, and again at 60-120 min, which could be blocked by the ROS scavenger tempol. mTORi abrogated the second permeability peak induced by PAN. However, it had no effect on the immediate ANG II- or PAN-induced increases in glomerular permeability. PMID- 25740596 TI - N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus. AB - Systemic lupus erythematosus is an autoimmune disease characterized by the development of auto antibodies against a variety of self-antigens and deposition of immune complexes that lead to inflammation, fibrosis, and end-organ damage. Up to 60% of lupus patients develop nephritis and renal dysfunction leading to kidney failure. N-acetyl-seryl-aspartyl-lysyl-proline, i.e., Ac-SDKP, is a natural tetrapeptide that in hypertension prevents inflammation and fibrosis in heart, kidney, and vasculature. In experimental autoimmune myocarditis, Ac-SDKP prevents cardiac dysfunction by decreasing innate and adaptive immunity. It has also been reported that Ac-SDKP ameliorates lupus nephritis in mice. We hypothesize that Ac-SDKP prevents lupus nephritis in mice by decreasing complement C5-9, proinflammatory cytokines, and immune cell infiltration. Lupus mice treated with Ac-SDKP for 20 wk had significantly lower renal levels of macrophage and T cell infiltration and proinflammatory chemokine/cytokines. In addition, our data demonstrate for the first time that in lupus mouse Ac-SDKP prevented the increase in complement C5-9, RANTES, MCP-5, and ICAM-1 kidney expression and it prevented the decline of glomerular filtration rate. Ac-SDKP treated lupus mice had a significant improvement in renal function and lower levels of glomerular damage. Ac-SDKP had no effect on the production of autoantibodies. The protective Ac-SDKP effect is most likely achieved by targeting the expression of proinflammatory chemokines/cytokines, ICAM-1, and immune cell infiltration in the kidney, either directly or via C5-9 proinflammatory arm of complement system. PMID- 25740598 TI - Gene conversion events between GYPB and GYPE abolish expression of the S and s blood group antigens. AB - BACKGROUND AND OBJECTIVE: The locus specifying the MNS blood group system is composed of three highly homologous genes, glycophorin A (GYPA), B (GYPB) and E (GYPE). While more than 20 hybrid genes between GYPA and GYPB have been identified, no hybrid genes between GYPB and GYPE have been reported so far. We serendipitously identified GYPB-E-B hybrid genes by studying three individuals whose rare S-s- blood phenotype failed to be predicted by our genotyping platform. MATERIALS AND METHODS: Long-range PCR amplification and extended Sanger sequencing were required to identify and characterize these GYPB-E-B hybrid genes. A PCR assay was developed to detect them in individual or pooled gDNA samples. RESULTS: The first S-s- proband appeared to have two silenced GYPB alleles, one harbouring the so-called P2 mutation and one harbouring GYPE Pseudoexon E4 in place of GYPB Exon B4 (GYPB-E-B hybrid). The two other S-s- probands were homozygous or hemizygous for other GYPB-E-B hybrid alleles, which also lack GYPB Exon B4 and thus do not carry the S/s polymorphism. CONCLUSION: The three GYPB-E-B hybrid genes reported here constitute the first evidence of recombination events between GYPB and GYPE. As these GYPB-E-B hybrid genes drive the S-s- blood phenotype, it is important to know they are a limitation for the current blood group genotyping methods, including those performed by commercial platforms. PMID- 25740599 TI - Do the mechanical and chemical properties of InvisalignTM appliances change after use? A retrieval analysis. AB - AIM: To investigate the mechanical and chemical alterations of Invisalign appliances after intraoral aging. MATERIALS AND METHODS: Samples of Invisalign appliances (Align Technology, San Jose, California, USA) were collected following routine treatment for a mean period of 44+/-15 days (group INV), whereas unused aligners of the same brand were used as reference (group REF). A small sample from the central incisors region was cut from each appliance and the buccal surface was analysed by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy (n = 5). Then the appliances were cut (n = 25) and embedded in acrylic resin, ground/polished in a grinding polishing machine, and the prepared surfaces were subjected to Instrumented Indentation Testing under 4.9 N load. Force-indentation depth curves were recorded for each group and the following parameters were calculated according to ISO 14577-1; 2002 specification: indentation modulus (E IT), elastic to total work ratio also known as elastic index (etaIT), Martens Hardness (HM), and indentation creep (C IT) The mean values of the mechanical properties were statistically analysed by unpaired t-test (a = 0.05). RESULTS: ATR-FTIR analysis confirmed the urethane based structure of the appliances, without important chemical differences attributed to the aging process. INV group showed significantly lower E IT (REF: 2466+/-20, INV: 2216+/-168MPa), HM (REF: 119+/-1, INV: 110+/-6 N mm-2) and higher etaIT (REF: 40.0+/-0.3, INV: 41.5+/-1.2%), and C IT (REF: 3.7+/-0.2 INV: 4.0+/-0.1%). The increase in etaIT indicates that INV is a more brittle than REF, whereas the increase in C IT, a decrease in creep resistance. CONCLUSION: Despite the lack of detectable chemical changes, intraoral aging adversely affected the mechanical properties of the Invisalign appliance. PMID- 25740600 TI - Statistical analysis in orthodontic journals: are we ignoring confounding? AB - AIM: To assess the prevalence of adjustment for confounding within statistical analysis and matching at the design stage in leading orthodontic journals and to explore potential associations between accounting for confounding and publication characteristics. MATERIALS AND METHODS: Twenty-four issues of four leading orthodontic journals with the highest impact factor were searched from July 2014 backwards. Confounding adjustment through statistical analysis and study characteristics including journal, study design, region of origin, number of authors, number of centres, involvement of a statistician, significance of results, and type of analysis were recorded. Reporting of matching at the design stage was also recorded. RESULTS: Of 426 studies identified, only 71 (17 per cent) accounted for confounding in the statistical analysis. There was evidence that journal, country of authorship, and involvement of a statistician (odds ratio = 3.91, 95 per cent confidence interval: 2.16-7.10; P < 0.001) were significant predictors of accounting for confounding at the analysis level. Reporting of matching at the design stage was identified in 111 of 426 (26 per cent) studies in which 9 studies adjusted for confounding at the analysis level. CONCLUSIONS: Appropriate adjustment for confounding in orthodontic literature either at the design or at the analysis stage was identified in less than half of studies overall (41 per cent), suggesting lack of expertise and awareness in design, conduct, analysis, and reporting of non-randomized studies in this field. This is a critical limitation that can potentially result in biased estimates and associations between examined exposures and outcomes. PMID- 25740601 TI - Force decay of latex and non-latex intermaxillary elastics: a clinical study. AB - OBJECTIVE: To evaluate force decay between intermaxillary orthodontic elastics with and without latex in the oral medium at different time intervals. MATERIALS AND METHODS: Intermaxillary orthodontic elastics with and without latex [1/8" (3.2mm), 1/4" (6.35mm), and 5/16" (7.94mm) in diameter] were evaluated 'clinically'. For this purpose, 26 patients served as hosts for the elastics during the evaluation period. Initially, 52 thermoplasticized plates 1mm thick were made according to the patients' mould. Then, the orthodontic accessories were bonded to the plates, which kept the elastics distended throughout the experimental period. The force released by the elastics at this distance was evaluated at 0, 12, and 24 hours. Statistical analyses were performed using the Friedman, Wilcoxon, and Mann-Whitney tests (significance set at 5 per cent). RESULTS: Elastics with and without latex presented with permanent deformation and increasing internal diameter throughout the entire period. Elastics with latex, 1/8" (3.2mm) in diameter, sustained higher levels of force than those without latex. Elastics measuring 1/4" (6.35mm) and 5/16" (7.94mm) in diameter without latex sustained higher levels of force at 0 and 12 hours compared to those with latex. At the end of the experiment (24 hours), no significant difference was observed between the elastics (P > 0.05). LIMITATIONS: This study only evaluated three time intervals: 0, 12, and 24 hours. If the behaviour was evaluated at different time intervals, different behaviours of these materials might be revealed. CONCLUSION: Elastics with latex 1/8" in diameter sustained a higher level of final force than the corresponding type without latex. The 1/4 and 5/16 elastics with and without latex were not different at the end of the evaluation period. PMID- 25740602 TI - microRNA-181a enhances cell proliferation in acute lymphoblastic leukemia by targeting EGR1. AB - Acute lymphoblastic leukemia (ALL) is an aggressive cancer that occurs in both children and adults. Starting from an integrated analysis of miRNA/mRNA expression profiles in 20 ALL patients, we identify a negative correlation between miR-181a and EGR1. Coherently, miR-181a over-expression in Jurkat T-ALL cells decreases EGR1 expression, increasing cell proliferation and enhancing the cell-cycle progression from G1 to S phase. We show that EGR1 is a new direct target of miR-181a. Our findings suggest that miR-181a behaves as an onco-miRNA in ALL by down-regulating EGR1. PMID- 25740603 TI - Incidental power morcellation of malignancy: a retrospective cohort study. AB - OBJECTIVE: Uterine fibroids often require hysterectomy via a laparotomy or utilizing minimally invasive surgical (MIS) approach. Morcellation is a fragmentation of the uterus into smaller pieces. The objective of this study is to determine the incidence of malignancies found in morcellated specimens at our institution. METHODS: Women who had a minimally invasive hysterectomy, for presumptive benign uterine conditions were identified, included and reviewed. Patients were divided into two groups being either benign disease or malignancies. The continuous variables uterine weight and patient age were tested for normalcy with the Shapiro-Wilk test. The exposure of subspecialist vs general gynecology was interrogated via a Chi-Squared analysis. RESULTS: 10 cases of malignancies were identified including endometrioid endometrial carcinomas (3), uterine serous carcinoma (1), endometrial stromal sarcomas (ESS) (3), and leiomyosarcomas (LMS) (3). An overall risk of occult cancer on a morcellated specimen was .73%; leiomyosarcoma was 0.22%, endometrial stromal sarcoma 0.22%, and endometrial cancer 0.29%. The median uterine weight for the 10 morcellated malignancies was 293.5g whereas the median weight for the benign uteri was only 117.5g giving a theta of -106 (95% CI -261,20). There was no difference in patient age or surgeon type between the groups (See Table 1). CONCLUSIONS: Morcellation was associated with substantially higher risk of abdominopelvic recurrence and lower disease-free survival. Morcellated uterine malignancies were significantly heavier than benign uteri. Further research on uterine morcellation should focus on decision and cost-benefit analyses to determine the ideal candidate in whom uterine morcellation during minimally invasive hysterectomy would facilitate more good than harm. PMID- 25740604 TI - Secretory overexpression and isotopic labeling of the chimeric relaxin family peptide R3/I5 in Pichia pastoris. AB - Relaxin family peptides are a group of peptide hormones with divergent biological functions. Mature relaxin family peptides are typically composed of two polypeptide chains with three disulfide linkages, rendering their preparation a challenging task. In the present study, we established an efficient approach for preparation of the chimeric relaxin family peptide R3/I5 through secretory overexpression in Pichia pastoris and in vitro enzymatic maturation. A designed single-chain R3/I5 precursor containing the B-chain of human relaxin-3 and the A chain of human INSL5 was overexpressed in PichiaPink strain 1 by high-density fermentation in a two-liter fermenter, and approximately 200 mg of purified precursor was obtained from one liter of the fermentation supernatant. We also developed an economical approach for preparation of the uniformly (15)N-labeled R3/I5 precursor by culturing in shaking flasks, and approximately 15 mg of purified (15)N-labeled precursor was obtained from one liter of the culture supernatant. After purification by cation ion-exchange chromatography and reverse phase high performance liquid chromatography, the R3/I5 precursor was converted to the mature two-chain form by sequential treatment with endoproteinase Lys-C and carboxypeptidase B. The mature R3/I5 peptide had an alpha-helix-dominated conformation and retained full receptor-binding and receptor activation activities. Thus, Pichia overexpression was an efficient approach for sample preparation and isotopic labeling of the chimeric R3/I5 peptide. This approach could also be extended to the preparation of other relaxin family peptides in future studies. PMID- 25740605 TI - A cluster of protein kinases and phosphatases modulated in fetal Down syndrome (trisomy 21) brain. AB - Down syndrome (DS; trisomy 21) is the most frequent cause of mental retardation with major cognitive and behavioral deficits. Although a series of aberrant biochemical pathways has been reported, work on signaling proteins is limited. It was, therefore, the aim of the study to test a selection of protein kinases and phosphatases known to be essential for memory and learning mechanisms in fetal DS brain. 12 frontal cortices from DS brain were compared to 12 frontal cortices from controls obtained at legal abortions. Proteins were extracted from brains and western blotting with specific antibodies was carried out. Primary results were used for networking (IntAct Molecular Interaction Database) and individual predicted pathway components were subsequently quantified by western blotting. Levels of calcium-calmodulin kinase II alpha, transforming growth factor beta activated kinase 1 as well as phosphatase and tensin homolog (PTEN) were reduced in cortex of DS subjects and network generation pointed to interaction between PTEN and the dendritic spine protein drebrin that was subsequently determined and reduced levels were observed. The findings of reduced levels of cognitive function-related protein kinases and the phosphatase may be relevant for interpretation of previous work and may be useful for the design of future studies on signaling in DS brain. Moreover, decreased drebrin levels may point to dendritic spine abnormalities. PMID- 25740606 TI - Maternal L-glutamine supplementation prevents prenatal alcohol exposure-induced fetal growth restriction in an ovine model. AB - Prenatal alcohol exposure is known to cause fetal growth restriction and disturbances in amino acid bioavailability. Alterations in these parameters can persist into adulthood and low birth weight can lead to altered fetal programming. Glutamine has been associated with the synthesis of other amino acids, an increase in protein synthesis and it is used clinically as a nutrient supplement for low birth weight infants. The aim of this study was to explore the effect of repeated maternal alcohol exposure and L-glutamine supplementation on fetal growth and amino acid bioavailability during the third trimester-equivalent period in an ovine model. Pregnant sheep were randomly assigned to four groups, saline control, alcohol (1.75-2.5 g/kg), glutamine (100 mg/kg, three times daily) or alcohol + glutamine. In this study, a weekend binge drinking model was followed where treatment was done 3 days per week in succession from gestational day (GD) 109-132 (normal term ~147). Maternal alcohol exposure significantly reduced fetal body weight, height, length, thoracic girth and brain weight, and resulted in decreased amino acid bioavailability in fetal plasma and placental fluids. Maternal glutamine supplementation successfully mitigated alcohol-induced fetal growth restriction and improved the bioavailability of glutamine and glutamine-related amino acids such as glycine, arginine, and asparagine in the fetal compartment. All together, these findings show that L-glutamine supplementation enhances amino acid availability in the fetus and prevents alcohol-induced fetal growth restriction. PMID- 25740607 TI - Co-ingestion of carbohydrate with branched-chain amino acids or L-leucine does not preferentially increase serum IGF-1 and expression of myogenic-related genes in response to a single bout of resistance exercise. AB - The purpose of this study was to determine if the co-ingestion of carbohydrate (CHO) with branched-chain amino acids (BCAA) or L-leucine (LEU) preferentially affected serum IGF-1 and the expression of myogenic-related genes in response to resistance exercise (RE). Forty-one college-age males were randomly assigned to 1 of 4 groups: CHO, CHO-BCAA, CHO-LEU, or placebo (PLC). Resistance exercise consisted of 4 sets of 10 repetitions of leg press and leg extension at 80 % 1RM. Supplements were ingested peri-exercise, and venous blood and muscle biopsies were obtained pre-exercise (PRE), and at 30, 120, and 360 min post-exercise. Serum IGF-1 was determined with ELISA, and skeletal muscle mRNA expression of myostatin, ACTRIIB, p21kip, p27kip, CDK2, cyclin B1, cyclin D1, Myo-D, myogenin, MRF-4, and myf5 was determined using real-time PCR. Results were analyzed by two way ANOVA for serum IGF-1 and two-way MANOVA for mRNA expression. Serum IGF-1 in CHO + BCAA was greater than PLC (p < 0.05) but was not affected by RE (p > 0.05). A significant group * time interaction was located for cylin D1 (p < 0.05), but not for any other genes. However, significant time effects were noted for cyclin B1 and p21cip (p < 0.05). At 30, 120 and 360 min post-exercise, p21cip was significantly less than PRE. Cyclin D1 was greater than PRE and 30 min post exercise at 120 and 360 min post-exercise, whereas cyclin B1 was significantly greater than PRE at 120 min post-exercise (p < 0.05). Unlike the co-ingestion of CHO with either BCAA or L-leucine in conjunction with RE, the expression of various myogenically related genes were up-regulated with RE. PMID- 25740608 TI - Antiresorptives and anabolic therapy in sequence or combination for postmenopausal osteoporosis. AB - Osteoporosis is a chronic disease which may require treatment for many years and requires not only individual management but often sequential or combination treatments. Monotherapy with antiresorptives is usually the first choice. Sometimes, it is necessary to modify this option for therapeutic failure or for the time of use and risk of side-effects. Due to their different mode of action, therapy with anabolic drugs has increased our options in the treatment of osteoporosis. Postmenopausal women and men with severe and progressive osteoporosis despite antiresorptive treatment ('therapeutic failure') should be evaluated for treatment with an anabolic option. Moreover, anabolic agents are indicated for 18-24 months in patients at high risk. Then, sequential antiresorptive therapy is recommended to maintain drug increases in bone mass and support secondary mineralization of the newly formed bone. Combination therapies of antiresorptives and anabolic agents have shown a significant increase in bone mineral density compared to monotherapies. However, none of the combinations have been studied for the prevention of fractures. Combination therapy may not be recommended because of the possible increase in cost. PMID- 25740609 TI - PR55alpha-containing protein phosphatase 2A complexes promote cancer cell migration and invasion through regulation of AP-1 transcriptional activity. PMID- 25740610 TI - No support for replication of the genetic variants identified by a recent mega analysis of the treatment response to antidepressants. PMID- 25740611 TI - Incidence and clinical importance of BCR-ABL1 mutations in Iranian patients with chronic myeloid leukemia on imatinib. AB - Mutations of the BCR-ABL1 kinase domain seem to be the most common cause of imatinib mesylate resistance in chronic myeloid leukemia (CML). We screened BCR ABL1 kinase domain mutations using nested reverse transcriptase polymerase chain reaction and direct sequencing in 30 CML patients including 22 resistant patients and 8 patients with optimal response to imatinib. Three mutations of two different types were identified in 3 of 22 (13.6%) resistant patients. Two patients had p.E355G mutation in the catalytic domain, and the third patient had p.G398R in the activation loop that is reported here for the first time. No mutation was found in patients with optimal response to imatinib. The frequency of mutations was similar in patients with primary resistance compared with patients with secondary resistance (25 vs 11%; P=1). Mutation status had no impact on the overall survival and progression-free survival. p.E355G mutation was correlated with shorter survival (P=0.047) in resistant patients. We conclude that BCR- ABL1 mutations are associated with the clinical resistance, but may not be considered the only cause of resistance to imatinib. Mutational analysis may identify resistant patients at risk of disease progression. PMID- 25740612 TI - New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing. AB - Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis. PMID- 25740613 TI - Increment of serum C-peptide measured by glucagon test closely correlates with human relative beta-cell area. AB - Pancreatic beta-cell mass contributes to glucose tolerance. The aim of this study was to evaluate the relationships between human beta-cell mass and various clinical parameters, including insulin secretory capacity. The study included 32 Japanese patients who underwent pancreatectomy and were naive to oral hypoglycemic agents and insulin. They were classified into those with normal glucose tolerance (n=13), impaired glucose tolerance (n=9) and diabetes (n=10), and their insulin secretory capacity and insulin resistance were evaluated. Immunohistochemistry was used to determine relative beta-cell area (%) which represented the proportion of insulin-positive cell area to whole pancreatic section. Increment of C-peptide immunoreactivity level by glucagon test (DeltaC peptide, increment of serum C-peptide [nmol/L] at 6 min after intravenous injection of 1-mg glucagon; r=0.64, p=0.002), homeostasis model assessment of beta-cell function (HOMA-beta, fasting immunoreactive insulin [MUIU/mL] x 20 / (fasting plasma glucose [mmol/L] - 3.5); r=0.50, p=0.003), C-peptide index (CPI, fasting C-peptide [nmol/L] / fasting plasma glucose [mmol/L]; r=0.36, p=0.042), and fasting immunoreactive insulin (F-IRI [pmol/L]; r=0.36, p=0.044) correlated significantly and positively with the relative beta-cell area. The area under the curve of plasma glucose level from 0 to 120 min by 75 g-OGTT (AUC0-120) also correlated significantly and inversely with the relative beta-cell area (r=-0.36, p=0.045). Stepwise multiple regression analysis identified DeltaC-peptide as the only independent and significant determinant of the relative beta-cell area. We conclude that DeltaC-peptide, HOMA-beta, CPI, F-IRI and AUC0-120 correlated closely with the relative beta-cell area, and DeltaC-peptide was the most valuable index for the prediction of the area. PMID- 25740614 TI - Influence of multiple UV exposures on serum cobalamin and vitamin D levels in healthy females. AB - AIMS: Ultraviolet (UV) radiation is a major source for vitamin D production. Furthermore, UV destroys cobalamins (also called vitamin B12) in solution. However, data from humans are scarce. The aim of the present study was to clarify if UV exposure has any effect on serum cobalamins, as compared to vitamin D levels, in healthy volunteers. METHODS: This single-center, open observational study was conducted in a research institute: 23 non-pregnant, non-lactating, healthy, fair-skinned female subjects had their serum cobalamin and 25 hydroxyvitamin D (25(OH)D, the marker for vitamin D status) levels measured before and after exposure to UV. RESULTS: UV exposure increased serum 25(OH)D levels from 61.6 nmol/L to 88.5 nmol/L (44%; p < 0.001). A statistically insignificant decay in serum cobalamin levels from 300 pmol/L to 260 pmol/L (13%; p = 0.142) was observed in the volunteers after the first UV exposure; however, no additional decline of statistical significance was seen after subsequent exposures. CONCLUSIONS: Multiple exposure to UV radiation give a significant increase in 25(OH)D levels, but has no detrimental effect on cobalamin concentrations. PMID- 25740615 TI - Longitudinal analysis of lifestyle habits in relation to body mass index, onset of overweight and obesity: results from a large population-based cohort in Sweden. AB - AIMS: It is currently unknown whether the prevalence of obesity is increasing or has levelled off in Sweden and other Westernised countries. Given the major importance of lifestyle habits on weight status, we aimed to explore associations of longitudinal changes in lifestyle habits with changes in body mass index (BMI), and the onset of overweight and obesity. METHODS: Participants (aged 18-84 years at baseline) were included from the Stockholm Public Health Cohort 2002 2010 (n=23,108). Weight status was from self-reported height and weight. Investigated lifestyle habits were leisure-time physical activity, and fruit, alcohol and smoking habits. We estimated associations of stable, improving or worsening lifestyle habits with longitudinal changes in BMI and onset of overweight or obesity between 2002 and 2010. RESULTS: Both men and women increased in weight during the eight years of follow-up. Incidence of obesity was lower in men who increased their leisure-time physical activity (Relative Risk [RR]=0.58, 95% confidence interval 0.42-0.81) than in inactive individuals; the same applied to women (RR=0.37, 0.25-0.54), and similar patterns were identified for overweight and BMI in both genders. Smoking cessation was associated with onset of obesity for men (RR=1.69, 1.15-2.50) and women (RR=1.99, 1.39-2.85). Stable low alcohol intake or decreasing alcohol intake and daily fruit intake was associated with less weight gain, but only in men. CONCLUSIONS: Improving physical activity in both men and women, and alcohol habits and fruit intake in men, prevents excess weight gain among adult people in Sweden. Such an improvement might diminish weight gain after smoking cessation. PMID- 25740616 TI - Gambling frequency, gambling problems and concerned significant others of problem gamblers in Finland: cross-sectional population studies in 2007 and 2011. AB - AIMS: This study compares past-year gambling frequency, gambling problems and concerned significant others (CSOs) of problem gamblers in Finland by age, from 2007 and 2011. METHODS: We used random sample data collected in 2007 (n = 4722) and 2011 (n = 4484). The data were weighted, based on gender, age and region of residence. We measured the past-year gambling frequency using a categorical variable, while gambling severity was measured with the South Oaks Gambling Screen. We identified CSOs by a single question including seven response options. Chi-Squared and Fisher's exact tests were used. RESULTS: Overall, the past-year gambling frequency change was statistically significant between 2007 and 2011. Among 18-64-year-old Finnish people, the proportion of non-gamblers decreased. Yet, among 15-17-year-old respondents, non-gambling increased and gambling problems decreased. Among 18-24 year olds, the proportion of close ones with gambling problems also decreased. On the other hand, the proportion of family members with gambling problems increased among the 50-64 year olds. CONCLUSIONS: The increase in adult gambling participation was mainly explained by infrequent gambling. The proportion of gambling problems from the gamblers' and CSOs' perspective remained unchanged, yet significant changes were observed within age groups. The short-term changes in under-age gambling problems were desirable. Future studies should explore the adaptation and access hypotheses alongside gambling problems. PMID- 25740617 TI - Vigorous physical activity rather than sedentary behaviour predicts overweight and obesity in pubertal boys: a 2-year follow-up study. AB - AIM: Current physical activity (PA) recommendations indicate that children should get involved in 60 minutes of moderate-to-vigorous PA (MVPA), and should include vigorous-intensity PA at least three days a week. However, it is not known how many minutes of vigorous PA they should do. Using objective methods and a longitudinal design, this study aimed to examine how different PA intensities and sedentary behaviour relate with the risk of being overweight and obese during puberty over a two-year period. METHODS: A sample of 136 10-12-year-old (at baseline) boys participated. PA was measured by seven-day accelerometry. RESULTS: From MVPA thresholds, only 90 minutes per day of MVPA had important odds ratios (OR) for being overweight at baseline (OR=8.14, 95% confidence interval [CI] 1.03 64.04). A significant cut-off point for being overweight was indicated by 59 minutes per day of MVPA with at least 14 minutes per day of vigorous PA, and 55 minutes per day MVPA with at least 10 minutes per day of vigorous PA for those who were obese. Sedentary behaviour did not have any significant ORs for being overweight or obese. Subjects who did not meet the thresholds of 5 and 20 minutes per day of vigorous PA at baseline had an increased risk of being overweight (OR=4.05, 95% CI 1.41-11.59, and OR=4.14, 95% CI 1.35-12.73, respectively) and obese (OR=6.54, 95% CI 1.97-21.69, and OR=8.75, 95% CI 1.12-68.51, respectively) two years later. CONCLUSIONS: The results indicate that vigorous PA in particular predicts overweight and obesity in boys. They should aim to do at least 60 minutes per day of MVPA. These results contribute to the recommendations suggesting that a minimum of 15 minutes per day of vigorous PA is desired to reduce the risk of developing overweight/obesity in later puberty. PMID- 25740618 TI - Identification and risk assessment of Swedish youth at risk of chlamydia. AB - AIMS: The aim of the study was to identify youth at high risk of chlamydia including variables related to sexual health and negative experiences of sexuality. METHODS: In late 2009, a questionnaire on sexuality was answered by Swedish youth. The study sample was self-selected from different Internet communities. Data from 6544 sexually active participants, aged 15-24 years, were analyzed in a multivariable logistic regression model. Discriminative power was measured by the area under the receiver operating characteristic curve. RESULTS: In the univariate analysis, self-reported chlamydia was associated with most risk behavior variables, experience of coerced sex, and reimbursement for sex, with slight gender variation. The factors that best predicted self-reported chlamydia among females were number of partners, age, and having been reimbursed for sex. Among males, the number of partners and alcohol consumption were the strongest predictors. Increasing number of partners up to 10 during the past 12 months was the most important predictor for both genders. A skewed distribution of chlamydia was demonstrated, in that 37.6% of cases in females and 38.6% in males were estimated to occur among a tenth of the population. CONCLUSIONS: Testing, prevention, and care for chlamydia should be directed toward those most at risk, as they account for a large proportion of the total number of chlamydia cases. The special needs of the high-risk group need to be acknowledged and chlamydia regarded as a possible marker for risk behavior and negative sexuality experiences. PMID- 25740620 TI - Erratum corrige. PMID- 25740619 TI - Cellulose structure and lignin distribution in normal and compression wood of the Maidenhair tree (Ginkgo biloba L.). AB - We studied in detail the mean microfibril angle and the width of cellulose crystals from the pith to the bark of a 15-year-old Maidenhair tree (Ginkgo biloba L.). The orientation of cellulose microfibrils with respect to the cell axis and the width and length of cellulose crystallites were determined using X ray diffraction. Raman microscopy was used to compare the lignin distribution in the cell wall of normal/opposite and compression wood, which was found near the pith. Ginkgo biloba showed a relatively large mean microfibril angle, varying between 19 degrees and 39 degrees in the S2 layer, and the average width of cellulose crystallites was 3.1-3.2 nm. Mild compression wood without any intercellular spaces or helical cavities was observed near the pith. Slit-like bordered pit openings and a heavily lignified S2L layer confirmed the presence of compression wood. Ginkgo biloba showed typical features present in the juvenile wood of conifers. The microfibril angle remained large over the 14 annual rings. The entire stem disc, with a diameter of 18 cm, was considered to consist of juvenile wood. The properties of juvenile and compression wood as well as the cellulose orientation and crystalline width indicate that the wood formation of G. biloba is similar to that of modern conifers. PMID- 25740621 TI - Metagenomic analysis of the bacterial community associated with the taproot of sugar beet. AB - We analyzed a metagenome of the bacterial community associated with the taproot of sugar beet (Beta vulgaris L.) in order to investigate the genes involved in plant growth-promoting traits (PGPTs), namely 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, indole acetic acid (IAA), N2 fixation, phosphate solubilization, pyrroloquinoline quinone, siderophores, and plant disease suppression as well as methanol, sucrose, and betaine utilization. The most frequently detected gene among the PGPT categories encoded beta-1,3-glucanase (18 per 10(5) reads), which plays a role in the suppression of plant diseases. Genes involved in phosphate solubilization (e.g., for quinoprotein glucose dehydrogenase), methanol utilization (e.g., for methanol dehydrogenase), siderophore production (e.g. isochorismate pyruvate lyase), and ACC deaminase were also abundant. These results suggested that such PGPTs are crucially involved in supporting the growth of sugar beet. In contrast, genes for IAA production (iaaM and ipdC) were less abundant (~1 per 10(5) reads). N2 fixation genes (nifHDK) were not detected; bacterial N2 -fixing activity was not observed in the (15)N2 -feeding experiment. An analysis of nitrogen metabolism suggested that the sugar beet microbiome mainly utilized ammonium and nitroalkane as nitrogen sources. Thus, N2 fixation and IAA production did not appear to contribute to sugar beet growth. Taxonomic assignment of this metagenome revealed the high abundance of Mesorhizobium, Bradyrhizobium, and Streptomyces, suggesting that these genera have ecologically important roles in the taproot of sugar beet. Bradyrhizobium-assigned reads in particular were found in almost all categories of dominant PGPTs with high abundance. The present study revealed the characteristic functional genes in the taproot-associated microbiome of sugar beet, and suggest the opportunity to select sugar beet growth-promoting bacteria. PMID- 25740622 TI - Bioconversion of styrene to poly(hydroxyalkanoate) (PHA) by the new bacterial strain Pseudomonas putida NBUS12. AB - Styrene is a toxic pollutant commonly found in waste effluents from plastic processing industries. We herein identified and characterized microorganisms for bioconversion of the organic eco-pollutant styrene into a valuable biopolymer medium-chain-length poly(hydroxyalkanoate) (mcl-PHA). Twelve newly-isolated styrene-degrading Pseudomonads were obtained and partial phaC genes were detected by PCR in these isolates. These isolates assimilated styrene to produce mcl-PHA, forming PHA contents between 0.05+/-0.00 and 23.10+/-3.25% cell dry mass (% CDM). The best-performing isolate was identified as Pseudomonas putida NBUS12. A genetic analysis of 16S rDNA and phaZ genes revealed P. putida NBUS12 as a genetically-distinct strain from existing phenotypically-similar bacterial strains. This bacterium achieved a final biomass of 1.28+/-0.10 g L(-1) and PHA content of 32.49+/-2.40% CDM. The extracted polymer was mainly comprised of 3 hydroxyhexanoate (C6 ), 3-hydroxyoctanoate (C8 ), 3-hydroxydecanoate (C10 ), 3 hydroxydodecanoate (C12 ), and 3-hydroxytetradecanoate (C14 ) monomers at a ratio of 2:42:1257:17:1. These results collectively suggested that P. putida NBUS12 is a promising candidate for the biotechnological conversion of styrene into mcl PHA. PMID- 25740623 TI - Tetraphenylethene modified [n]rotaxanes: synthesis, characterization and aggregation-induced emission behavior. AB - A series of novel [n]rotaxanes based on a tetraphenylethene (TPE) backbone were constructed by a template-directed clipping approach and their structures were well-characterized. Investigation of their optical properties showed that these rotaxanes and their corresponding ammonium salts showed aggregation-induced emission (AIE) behavior. However, there were obvious differences as follows: (1) rotaxanes reached the aggregation state in the presence of less water compared with the corresponding ammonium salt; (2) the rotaxanes with a long alkoxyl chain on the pyridine unit of the crown ether formed the aggregation state in the presence of less water than for those without an alkoxyl substituent and (3) a smaller distance between the TPE unit and N-hetero crown ether component resulted in the aggregation state being reached more easily than when there is a longer distance. The results suggest that the mechanically interlocked structures can adjust the aggregation state of AIE molecules. PMID- 25740624 TI - Selective chemical binding enhances cesium tolerance in plants through inhibition of cesium uptake. AB - High concentrations of cesium (Cs(+)) inhibit plant growth but the detailed mechanisms of Cs(+) uptake, transport and response in plants are not well known. In order to identify small molecules with a capacity to enhance plant tolerance to Cs(+), chemical library screening was performed using Arabidopsis. Of 10,000 chemicals tested, five compounds were confirmed as Cs(+) tolerance enhancers. Further investigation and quantum mechanical modelling revealed that one of these compounds reduced Cs(+) concentrations in plants and that the imidazole moiety of this compound bound specifically to Cs(+). Analysis of the analogous compounds indicated that the structure of the identified compound is important for the effect to be conferred. Taken together, Cs(+) tolerance enhancer isolated here renders plants tolerant to Cs(+) by inhibiting Cs(+) entry into roots via specific binding to the ion thus, for instance, providing a basis for phytostabilisation of radiocesium-contaminated farmland. PMID- 25740625 TI - The challenge of overdiagnosis begins with its definition. PMID- 25740626 TI - Heat shock protein 27 overexpression in CHO cells modulates apoptosis pathways and delays activation of caspases to improve recombinant monoclonal antibody titre in fed-batch bioreactors. AB - CHO cells are major production hosts for recombinant biologics including the rapidly expanding recombinant monoclonal antibodies (mAbs). Heat shock protein 27 (HSP27) expression was observed to be down-regulated towards the late-exponential and stationary phase of CHO fed-batch bioreactor cultures, whereas HSP27 was found to be highly expressed in human pathological cells and reported to have anti-apoptotic functions. These phenotypes suggest that overexpression of HSP27 is a potential cell line engineering strategy for improving robustness of CHO cells. In this work, HSP27 was stably overexpressed in CHO cells producing recombinant mAb and the effects of HSP27 on cell growth, volumetric production titer and product quality were assessed. Concomitantly, HSP27 anti-apoptosis functions in CHO cells were investigated. Stably transfected clones cultured in fed-batch bioreactors displayed 2.2-fold higher peak viable cell density, delayed loss of culture viability by two days and 2.3-fold increase in mAb titer without affecting the N-glycosylation profile, as compared to clones stably transfected with the vector backbone. Co-immunoprecipitation studies revealed HSP27 interactions with Akt, pro-caspase 3 and Daxx and caspase activity profiling showed delayed increase in caspase 2, 3, 8 and 9 activities. These results suggest that HSP27 modulates apoptosis signaling pathways and delays caspase activities to improve performance of CHO fed-batch bioreactor cultures. PMID- 25740627 TI - Observer perspective imagery with stuttering. AB - PURPOSE: Adults who stutter are at risk of developing a range of psychological conditions. Social anxiety disorder is the most common anxiety disorder associated with stuttering. Observer perspective imagery is one cognitive process involved in the maintenance of some anxiety disorders. This involves viewing images as if looking at the self from the perspective of another. In contrast, the field perspective involves looking out from the self at the surrounding environment. The purpose of this study was to assess the presence of observer perspective imagery with stuttering. METHOD: The authors administered the Hackmann, Surawy and Clark (1998) semi-structured interview to 30 adults who stutter and 30 controls. Group images and impressions were compared for frequency, perspective recalled and emotional valence. RESULT: The stuttering group was significantly more likely than controls to recall images and impressions from an observer rather than a field perspective for anxious situations. CONCLUSION: It is possible the present results could reflect the same attentional processing bias that occurs with anxiety disorders in the non stuttering population. These preliminary results provide an explanation for the persistence of conditions such as social anxiety disorder with stuttering. Clinical implications are discussed. PMID- 25740628 TI - Development of a reporter peptide that catalytically produces a fluorescent signal through alpha-complementation. AB - In alpha-complementation, inactive N-terminal (alpha-domain) and C-terminal (omega-domain) fragments of beta-galactosidase associate to reconstitute the active protein. To date, the effect of alpha-domain size on alpha-complementation activity has not been systematically investigated. In this study, we compared the complementation activities of alpha-domains of various sizes using an in vitro system. We found that the complementation activities are similar for alpha domains comprising between 45 and 229 N-terminal residues but are significantly decreased for those containing less than 37 residues. However, these smaller alpha-domains (15 and 25 residues) exhibited sufficient alpha-complementation activity for application as reporters. PMID- 25740629 TI - The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice. AB - Patient-derived xenografts (PDXs) of tumors are increasingly becoming important tools for translational research in oncology. The NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic (NOG) mouse is an efficient host for PDXs. Thus as a basis for future development of methods to obtain PDXs from various disease types, we have studied the factors that affect the outcome of transplantation of human colorectal cancer in NOG mice. Of the original donor cases examined, 73% had successful engraftment. The outcome of donor-matched tissues was consistent in most cases, and was thought to show that the condition of the host did not affect engraftment. Next we analyzed the tumor aggressiveness in terms of histology grade of the original tumor and found that they were related to engraftment. Detailed histopathological examination of the transplanted tissues strongly indicated that lymphocytes engrafted with the tumor cells affect engraftment. As a factor related to transplantation of lymphocytes, we studied the human IgG concentration in the serum of tumor-bearing mice, but there was no tendency for higher concentrations to result in unsuccessful engraftment. Finally, we studied the type, density and location of T cells in the original donor tissue to determine the immune contexture and found that the unsuccessful engraftment cases tended to have an adequate or coordinated immune contexture compared to successful engraftment cases. From these results, we concluded that the aggressiveness and the T cell infiltration of the original tumor affect the outcome of transplantation in the NOG mouse. PMID- 25740630 TI - One-step synthesis of a [20]silafullerane with an endohedral chloride ion. AB - Silicon analogues of the most prominent carbon nanostructures, namely, hollow spheroidals such as C60 and the fullerene family, have been unknown to date. Herein we show that discrete Si20 dodecahedra, stabilized by an endohedral guest and valence saturation, are accessible in preparative yields through a chloride induced disproportionation reaction of hexachlorodisilane in the presence of tri(n-butyl)amine. X-ray crystallography revealed that each silicon dodecahedron contains an endohedral chloride ion that imparts a net negative charge. Eight chloro substituents and twelve trichlorosilyl groups are attached to the surface of each cluster in a strictly regioregular arrangement, a thermodynamically preferred substitution pattern according to quantum-chemical assessment. Our results demonstrate that the wet-chemical self-assembly of a complex, monodisperse Si nanostructure is possible under mild conditions starting from simple Si2 building blocks. PMID- 25740632 TI - Systematic ligand modulation enhances the moisture stability and gas sorption characteristics of quaternary metal-organic frameworks. AB - Complex metal-organic frameworks (MOFs) that maintain high structural order promise sophisticated and tunable properties. Here, we build on our strategy of using combinations of structurally distinct ligands to generate a new isoreticular series of ordered quaternary Zn4O-carboxylate MOFs. Rational design of the framework components steers the system toward multicomponent MOFs and away from competing phases during synthesis. Systematic ligand modulation led to the identification of a set of frameworks with unusually high stability toward water vapor. These frameworks lose no porosity after 100 days' exposure to ambient air or 20 adsorption-desorption cycles up to 70% relative humidity. Across this series of frameworks, a counterintuitive relationship between the length of pendant alkyl groups and framework stability toward water vapor emerges. This phenomenon was probed via a series of gas and vapor adsorption experiments together with Grand Canonical Monte Carlo (GCMC) simulations, and could be rationalized on the basis of the propensity of the frameworks to adsorb water vapor and the proximity of the adsorbed water molecules to the water-sensitive metal clusters. Systematic variation of the pore volume and topography also tunes the CO2 and CH4 gas adsorption behavior. Certain of these materials display increases in their adsorption capacities of 237% (CO2) and 172% (CH4) compared to the parent framework. PMID- 25740631 TI - Mechanism of action of thalassospiramides, a new class of calpain inhibitors. AB - Thalassospiramides comprise a large family of lipopeptide natural products produced by Thalassospira and Tistrella marine bacteria. Here we provide further evidence of their nanomolar inhibitory activity against the human calpain 1 protease. Analysis of structure-activity relationship data supported our hypothesis that the rigid 12-membered ring containing an alpha,beta-unsaturated carbonyl moiety is the pharmacologically active functional group, in contrast to classic electrophilic "warheads" in known calpain inhibitors. Using a combination of chemical modifications, mass spectrometric techniques, site-directed mutagenesis, and molecular modeling, we show the covalent binding of thalassospiramide's alpha,beta-unsaturated carbonyl moiety to the thiol group of calpain's catalytic Cys115 residue by a Michael 1,4-addition reaction. As nanomolar calpain inhibitors with promising selectivity and low toxicity from natural sources are rare, we consider thalassospiramides as promising drug leads. PMID- 25740633 TI - Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries. AB - The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production. PMID- 25740634 TI - Discovery of anthranilamides as a novel class of inhibitors of neurotropic alphavirus replication. AB - Neurotropic alphaviruses are debilitating pathogens that infect the central nervous system (CNS) and are transmitted to humans via mosquitoes. There exist no effective human vaccines against these viruses, underlining the need for effective antivirals, but no antiviral drugs are available for treating infection once the viruses have invaded the CNS. Previously, we reported the development of novel indole-2-carboxamide-based inhibitors of alphavirus replication that demonstrate significant reduction of viral titer and achieve measurable brain permeation in a pharmacokinetic mouse model. Herein we report our continued efforts to improve physicochemical properties predictive of in vivo blood-brain barrier (BBB) permeability through reduction of overall molecular weight, replacing the indole core with a variety of aromatic and non-aromatic monocyclics. These studies culminated in the identification of simple anthranilamides that retain excellent potency with improved metabolic stability and significantly greater aqueous solubility. Furthermore, in a live virus study, we showed that two new compounds were capable of reducing viral titer by two orders of magnitude and that these compounds likely exert their effects through a mechanism similar to that of our indole-2-carboxamide inhibitors. PMID- 25740635 TI - Anti-trypanosomal cadinanes synthesized by transannular cyclization of the natural sesquiterpene lactone nobilin. AB - Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19+/-1.69MUM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46+/-0.01MUM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity. PMID- 25740636 TI - Synthesis and biological evaluation of fluconazole analogs with triazole-modified scaffold as potent antifungal agents. AB - In order to find new azole antifungals, we have recently designed a series of triazole alcohols in which one of the 1,2,4-triazol-1-yl group in fluconazole structure has been replaced with 4-amino-5-aryl-3-mercapto-1,2,4-triazole motif. In this paper, we focused on the structural refinement of the primary lead, by removing the amino group from the structure to achieve 5-aryl-3-mercapto-1,2,4 triazole derivatives 10a-i and 11a-i. The in vitro antifungal susceptibility testing of title compounds demonstrated that most compounds had potent inhibitory activity against Candida species. Among them, 5-(2,4-dichlorophenyl)triazole analogs 10h and 11h with MIC values of <0.01 to 0.5MUg/mL were 4-256 times more potent than fluconazole against Candida species. PMID- 25740637 TI - Intraoperative core needle biopsy under complete video-assisted thoracic surgery for indeterminate tumor of lung. AB - BACKGROUND: The accuracy, feasibility, and safety of intraoperative core needle biopsy under complete video-assisted thoracic surgery (VATS) (V-CNB) for indeterminate tumors are examined retrospectively, as well as the possibility of pleural dissemination. METHODS: The diagnostic yield and complications of V-CNB were evaluated for a total of 95 patients who underwent V-CNB for indeterminate tumor during the period of April 2002 through March 2012. Moreover, operation time, number of auto-suture instruments used for resection of the lung, and pleural dissemination were compared between the patients who underwent V-CNB (n = 44) and those who did not (n = 87, non-V-CNB) among stage I primary lung cancer patients, for whom lobectomy was performed under complete VATS during the same period. RESULTS: Of the 95 patients, eighty three had primary lung cancer, four had metastatic lung cancer, and eight had benign tumor. Sensitivity, specificity, and accuracy were 94.3, 87.5, and 93.7%, respectively. There were no complications associated with V-CNB. Among stage I primary lung cancer, for which lobectomy and lymph node dissection were performed, there was no significant difference between the V-CNB group and the non-V-CNB group for tumor size (23.5 and 24.7 mm, p = 0.482), distance between pleura and tumor (3.4 and 5.0 mm, p = 0.202), operation time (228 and 217 min, p = 0.186), and number of auto-suture instruments used for resection of the lung (4.77 and 4.61, p = 0.533). There was no pleural dissemination in the V-CNB group, although there were two cases (2.3%) in the non-V-CNB group. CONCLUSION: V-CNB diagnosed small-sized indeterminate lung tumors accurately during complete VATS operation, without any complications. V-CNB can reduce the use of auto-suture instruments necessary for performing wedge resection on frozen section diagnosis prior to lobectomy without increasing operation time and the risk of pleural dissemination. PMID- 25740638 TI - Novel strategy for laparoscopic treatment of pT2 gallbladder carcinoma. AB - BACKGROUND: This study evaluated our new strategy for treating suspected T2 gallbladder carcinoma (GBC) using a laparoscopic approach. METHODS: We examined 19 patients with suspected T2 GBC who were treated laparoscopically (LS group) between December 2007 and December 2013; these patients were compared with 14 patients who underwent open surgery (OS group). Laparoscopic staging was initially performed to exclude factors making the patients ineligible for curative resection. Intraoperative pathological examination of the surgical margin of the cystic duct was performed prior to laparoscopic gallbladder bed resection, and pathological examination was again performed to confirm the presence of carcinoma and the depth of tumor invasion. Surgery was completed when the pathological findings indicated that the patient was cancer free. Lymph node dissection was performed according to the depth of tumor invasion. RESULTS: None of the patients required conversion to laparotomy. For three patients with benign lesions, only gallbladder bed resection was required. Additional regional lymph node dissection was performed in 16 patients in the LS group. The mean operative time (309 vs. 324 min, p = 0.755) and mean number of dissected lymph nodes (12.6 vs. 10.2, p = 0.361) were not significantly different between the LS and OS groups. The intraoperative blood loss was significantly lower (104 vs. 584 mL, p = 0.002) and the postoperative hospital stay was significantly shorter (9.1 vs. 21.6 days, p = 0.002) for LS patients than for those in the OS group. In the LS group, one patient developed postoperative pneumonia, but all patients survived without recurrence after a mean follow-up of 37 months. CONCLUSION: Our strategy for suspected T2 gallbladder GBC is safe and useful, avoids unnecessary procedures, and is associated with similar oncologic outcomes as the open method. PMID- 25740639 TI - Partial splenectomy in the era of minimally invasive surgery: the current laparoscopic and robotic experiences. AB - BACKGROUND: Partial splenectomy (PS) is a spleen-preserving technique that is applied as a result of trauma, focal lesions or hematological conditions. Despite the improvement of laparoscopic techniques within the past several decades, minimally invasive PS has remained a marginal technique that has not been well evaluated. Our objective was to provide an update on the indications and the feasibility of this procedure. METHODS: The MEDLINE database (PubMed) was searched, and all relevant articles that involved a true minimally invasive PS (i.e., segmental or lobar devascularization of the spleen with parenchymal transection) were included. The search was conducted until the 31st of March 2014. Demographic data, operative indications, estimated blood losses, operative times, conversion rates and complications were extracted from the included articles and were summarized for discussion. RESULTS: Out of the 195 publications that were retrieved, 33 were included, which were mainly case reports and case series that represented a total of 187 patients. There were 37 men, 33 women and 117 patients of unknown gender. The mean age of the patients was ranged from 6 to 58 years. The mean total operative time was between 70 and 216 min for conventional laparoscopy and between 108 and 120 min for the robotic approach. For most studies, the mean estimated blood loss was minimal. The complication rate was 5.36% for conventional laparoscopy and 5.56% for the robotic approach. CONCLUSION: The outcomes of minimally invasive PS were favorable and comparable to those of the open technique according to the literature. This procedure may constitute an attractive alternative to the open technique for selected cases. Moreover, a robotic approach might be an interesting technical option, but additional research is needed before any definitive conclusions can be drawn. PMID- 25740640 TI - Clinical impact of submucosal tunneling endoscopic resection for the treatment of gastric submucosal tumors originating from the muscularis propria layer (with video). AB - BACKGROUND: Submucosal tunneling endoscopic resection (STER) can be adequately adopted as an effective treatment for submucosal tumors (SMTs) originating from the muscularis propria (MP) layer at the esophagus and cardia. However, it has been seldom used for gastric SMTs. Our purpose was to evaluate the clinical impact of STER for gastric SMTs arising from the MP layer. METHODS: Thirty-two patients with gastric SMTs from the MP layer were retrospectively included. The main outcome measurements were complete resection rate, adverse events, local recurrence, and distant metastases during follow-up. RESULTS: Of the 32 lesions, 12 were located in the gastric corpus close to the cardia, 3 in the gastric fundus close to the cardia, 6 in the lesser curvature of the gastric corpus, and 11 in the greater curvature of the gastric antrum. STER was successfully performed in all patients with en bloc resection of tumors. The mean tumor size was 2.3 cm (range 1.0-5.0 cm). The complete resection rate was 100%. The operation time ranged from 25 to 125 min (mean 51.8 min). All complications related to STER were successfully managed with conservative treatments. Local recurrence or distant metastasis did not occur during a follow-up period of 6-32 months. CONCLUSION: STER is a safe and effective therapeutic strategy for eligible gastric SMTs originating from the MP layer. Submucosal tunneling in the stomach may be more challenging than that in the esophagus, but does not increase procedure-related adverse events or prevent successful STER for eligible gastric SMTs. PMID- 25740641 TI - Randomized control trial for evaluation of a hands-free pointer for surgical instruction during laparoscopic cholecystectomy. AB - INTRODUCTION: Training surgeons in minimally invasive surgery (MIS) requires surgical residents to operate under the direction of a consultant. The inability of the instructing surgeon to point at the laparoscopic monitor without releasing the instruments remains a barrier to effective instruction. The wireless hands free surgical pointer (WHaSP) has been developed to aid instruction during MIS. METHODS: The objective of this study was to evaluate the effectiveness and likeability of the WHaSP as an instructional tool compared with the conventional methods. Data were successfully collected during 103 laparoscopic cholecystectomy procedures, which had been randomized to use or not use the WHaSP as a teaching tool. Audio and video from the surgeries were recorded and analyzed. Instructing surgeons, operating surgeons, and camera assistants provided feedback through a post-operative questionnaire that used a five-level Likert scale. The questionnaire results were analyzed using a Mann-Whitney U test. RESULTS: There were no negative effects on surgery completion time or instruction practice due to the use of the WHaSP. The number of times an instructor surgeon pointed to the laparoscopic screen with their hand was significantly reduced when the WHaSP was utilized (p < 0.001). The questionnaires showed that WHaSP users found it to be comfortable, easy to use, and easy to control. Compared to when the WHaSP was not used, users found that communication was more effective (p = 0.002), locations were easier to communicate (p < 0.001), and instructions were easier to follow (p = 0.005). CONCLUSIONS: The WHaSP system was successfully used in surgery. It integrated seamlessly into existing equipment within the operating room and did not affect flow. The positive outcomes of utilizing the WHaSP were improved communication in the OR, improved efficiency and safety of the surgery, easy to use, and comfortable to wear. The surgeons showed a preference for utilizing the WHaSP if given a choice. PMID- 25740642 TI - Risk factors of delayed ulcer healing after gastric endoscopic submucosal dissection. AB - BACKGROUND: Although post-endoscopic submucosal dissection (ESD) iatrogenic ulcer is known to heal faster than peptic ulcer, some iatrogenic ulcers show delayed healing. The aim of this study was to clarify risk factors of delayed ulcer healing after gastric ESD. METHODS: We retrospectively reviewed medical records of all patients who had ESD for gastric neoplasms (866 adenomas and 814 early gastric cancers) between January 2005 and February 2011. RESULTS: Of 1680 subjects, 95 had delayed ulcer healing in 3-month follow-up. Multivariate analysis showed that diabetes (OR 1.743; 95% CI 1.017-2.989, p = 0.043), coagulation abnormality (OR 3.195; 95% CI 1.535-6.650, p = 0.002), specimen size greater than 4 cm (OR 2.999; 95% CI 1.603-5.611, p = 0.001), and electrocoagulation (OR 7.149; 95% CI 1.738-29.411, p = 0.006) were revealed to be independent risk factors of delayed ulcer healing. Meanwhile, persistent Helicobacter pylori infection was not related to the delayed ulcer healing. CONCLUSIONS: Large iatrogenic ulcer by ESD with massive hemostasis, especially in patients with diabetes mellitus or coagulation abnormalities, tends to take more than 3 months to heal. For such cases, initial dosage increment of PPI or addition of other anti-ulcer agents after ESD may be beneficial. PMID- 25740643 TI - Stochastic resonance enhanced tactile feedback in laparoscopic surgery. AB - BACKGROUND: One of the disadvantages of laparoscopic surgery is its decreased tactile feedback. Surgical experience compensates for the decline in the sense of touch due to an improved ability to process visual information. Stochastic resonance (SR) is known to improve tactile sensation. In this study, we sought to improve the tactile feedback in laparoscopic surgery using SR to safely perform laparoscopic surgery. METHODS: Ten surgeons (nine males and one female, age: 30 44 years, median age: 34) with the experiences of >50 laparoscopic surgeries volunteered to participate in this study. We tested the hypothesis that low-level noise applied to the hand can enhance the tactile sensation during surgery. We performed this experiment under three hand conditions (bare-handed conditions, gloved conditions and using the laparoscopic instrument with gloved hands). A piezoelectric actuator that generates vibrations was attached on the radial side of the participant's index finger or to the grip of the laparoscopic instrument. Fine-touch tests were performed using the Semmes-Weinstein test kit. Moreover, we planned laparoscopic suturing and knot-tying tasks in the dry box and using an animal model under controlled vibrations. RESULTS: In the touch tests using bare hands, gloved hands and the laparoscopic instrument, the mean correct ratio was significantly lower than that observed in the test with no vibrations. Moreover, the OSATS scores for the laparoscopic suturing and knot-tying tasks showed significantly better scores with vibrations. CONCLUSIONS: This technique has a potential to be a great help in establishing safer and high-quality laparoscopic procedures. PMID- 25740644 TI - Safety and long-term outcomes of percutaneous endoscopic gastrostomy in patients with head and neck cancer. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is used for nutritional support during treatment in patients with head and neck cancer, but long-term nutritional outcomes have not been reported in detail. The purpose of this study was to determine short- and long-term outcomes and success in meeting nutritional goals in patients with head and neck cancer who had PEGs placed over an 18-year period. METHODS: Medical records of all patients who had PEG procedures performed by one of the authors (REB) from 1997 through 2010 were reviewed. Demographic data, patient weights, timing of procedure in relation to cancer treatment, complications, and long-term outcomes were recorded. RESULTS: Five hundred and sixty-five patients with head and neck cancer underwent PEG. Mean age was 59.6 +/ 13.6 years; 71% were men. Mean follow-up was 33 +/- 38 months. 99% of PEGs were used for nutritional support. Average weight loss prior to PEG was 23 +/- 17 lbs (range 0-133 lbs). Average weight loss between PEG and completion of treatment was 2.3 lbs; 44% of patients gained weight or remained stable after PEG. There were no PEG-related deaths. Complications included cellulitis in 27 (4%), pain in 14 (2.5%); leakage in 11 (2%), self-limited gastric bleeding in one patient. PEGs were used an average of 8.1 months. No PEG site tumor implants were observed. Among 366 patients treated with intention to cure, 45% were alive an average of 68 months later. CONCLUSIONS: PEG is both safe and efficacious in arresting weight loss and maintaining nutrition in patients undergoing surgery and/or chemoradiotherapy for head and neck cancer. PEG can be recommended for patients in whom dysphagia and weight loss is anticipated or in whom weight loss occurs as a result of their treatment; 20% of patients will need the PEG for a year or more. PMID- 25740646 TI - 2015 Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Nashville, Tennessee, USA, 15-18 April 2015 : Exhibit Hall Videos. PMID- 25740645 TI - 2015 Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Nashville, Tennessee, USA, 15-18 April 2015 : Resident Fellow. PMID- 25740647 TI - 2015 Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Nashville, Tennessee, USA, 15-18 April 2015 : Posters of Distinction. PMID- 25740648 TI - Crystal structure of Hop2-Mnd1 and mechanistic insights into its role in meiotic recombination. AB - In meiotic DNA recombination, the Hop2-Mnd1 complex promotes Dmc1-mediated single stranded DNA (ssDNA) invasion into homologous chromosomes to form a synaptic complex by a yet-unclear mechanism. Here, the crystal structure of Hop2-Mnd1 reveals that it forms a curved rod-like structure consisting of three leucine zippers and two kinked junctions. One end of the rod is linked to two juxtaposed winged-helix domains, and the other end is capped by extra alpha-helices to form a helical bundle-like structure. Deletion analysis shows that the helical bundle like structure is sufficient for interacting with the Dmc1-ssDNA nucleofilament, and molecular modeling suggests that the curved rod could be accommodated into the helical groove of the nucleofilament. Remarkably, the winged-helix domains are juxtaposed at fixed relative orientation, and their binding to DNA is likely to perturb the base pairing according to molecular simulations. These findings allow us to propose a model explaining how Hop2-Mnd1 juxtaposes Dmc1-bound ssDNA with distorted recipient double-stranded DNA and thus facilitates strand invasion. PMID- 25740649 TI - Cwc21p promotes the second step conformation of the spliceosome and modulates 3' splice site selection. AB - Pre-mRNA splicing involves two transesterification steps catalyzed by the spliceosome. How RNA substrates are positioned in each step and the molecular rearrangements involved, remain obscure. Here, we show that mutations in PRP16, PRP8, SNU114 and the U5 snRNA that affect this process interact genetically with CWC21, that encodes the yeast orthologue of the human SR protein, SRm300/SRRM2. Our microarray analysis shows changes in 3' splice site selection at elevated temperature in a subset of introns in cwc21Delta cells. Considering all the available data, we propose a role for Cwc21p positioning the 3' splice site at the transition to the second step conformation of the spliceosome, mediated through its interactions with the U5 snRNP. This suggests a mechanism whereby SRm300/SRRM2, might influence splice site selection in human cells. PMID- 25740650 TI - How 'arm-twisting' by the inducer triggers activation of the MalT transcription factor, a typical signal transduction ATPase with numerous domains (STAND). AB - Signal transduction ATPases with numerous domains (STAND) get activated through inducer-dependent assembly into multimeric platforms. This switch relies on the conversion of their nucleotide-binding oligomerization domain (NOD) from a closed, ADP-bound form to an open, ATP-bound form. The NOD closed form is stabilized by contacts with the arm, a domain that connects the NOD to the inducer-binding domain called the sensor. How the inducer triggers NOD opening remains unclear. Here, I pinpointed the NOD-arm interface of the MalT STAND transcription factor, and I generated a MalT variant in which this interface can be covalently locked on demand, thereby trapping the NOD in the closed state. By characterizing this locked variant, I found that the inducer is recognized in two steps: it first binds to the sole sensor with low affinity, which then triggers the recruitment of the arm to form a high-affinity arm-sensor inducer-binding site. Strikingly, this high-affinity binding step was incompatible with arm-NOD contacts maintaining the NOD closed. Through this toggling between two mutually exclusive states reminiscent of a single-pole double-throw switch, the arm couples inducer binding to NOD opening, shown here to precede nucleotide exchange. This scenario likely holds for other STANDs like mammalian NLR innate immunity receptors. PMID- 25740651 TI - Detection of sarcocystosis in goats in Malaysia by light microscopy, histology, and PCR. AB - A number of methods have been used for the detection of the presence of microsarcocysts in animals, but little information exists on the value between the various methods. This study therefore examined for Sarcocystis spp. using three different methods in 105 samples of skeletal muscle collected from goats slaughtered in an abattoir in Selangor, Malaysia from January to February 2014. Three methods were used, direct light microscopy of squashed fresh muscle tissues; histological examination of fixed, sectioned, and hematoxylin and eosin (H&E)-stained samples of muscle; and molecular identification by polymerase chain reaction (PCR). Of the 105 tissue samples, 55 (52.38 %) were positive by light microscopy (LM), 46 (43.8 %) by histology, and 95 (90.48 %) by PCR. Only 29 (27.6 %) and 5 (4.76 %) samples were positive and negative, respectively, by all three methods. The cysts were elongated to a spindle shape with a mean size of 393.30 * 81.6 MUm and containing banana-shaped bradyzoites of size 12.32 * 2.08 MUm. The wall of the cyst was radially striated with a thickness of 2.83 MUm. Samples were tested for the presence of Sarcocystis-specific 18S rRNA and were identified as Sarcocystis capracanis. Of the three methods used, the PCR test appears to be the most useful method for the diagnosis of sarcocystosis especially for species identification. PMID- 25740652 TI - Tag jumps illuminated--reducing sequence-to-sample misidentifications in metabarcoding studies. AB - Metabarcoding of environmental samples on second-generation sequencing platforms has rapidly become a valuable tool for ecological studies. A fundamental assumption of this approach is the reliance on being able to track tagged amplicons back to the samples from which they originated. In this study, we address the problem of sequences in metabarcoding sequencing outputs with false combinations of used tags (tag jumps). Unless these sequences can be identified and excluded from downstream analyses, tag jumps creating sequences with false, but already used tag combinations, can cause incorrect assignment of sequences to samples and artificially inflate diversity. In this study, we document and investigate tag jumping in metabarcoding studies on Illumina sequencing platforms by amplifying mixed-template extracts obtained from bat droppings and leech gut contents with tagged generic arthropod and mammal primers, respectively. We found that an average of 2.6% and 2.1% of sequences had tag combinations, which could be explained by tag jumping in the leech and bat diet study, respectively. We suggest that tag jumping can happen during blunt-ending of pools of tagged amplicons during library build and as a consequence of chimera formation during bulk amplification of tagged amplicons during library index PCR. We argue that tag jumping and contamination between libraries represents a considerable challenge for Illumina-based metabarcoding studies, and suggest measures to avoid false assignment of tag jumping-derived sequences to samples. PMID- 25740653 TI - Femtosecond Laser Fabrication of Cavity Microball Lens (CMBL) inside a PMMA Substrate for Super-Wide Angle Imaging. AB - Since microlenses have to date been fabricated primarily by surface manufacturing, they are highly susceptible to surface damage, and their microscale size makes it cumbersome to handle. Thus, cavity lenses are preferred, as they alleviate these difficulties associated with the surface-manufactured microlenses. Here, it is shown that a high repetition femtosecond laser can effectively fabricate cavity microball lenses (CMBLs) inside a polymethyl methacrylate slice. Optimal CMBL fabrication conditions are determined by examining the pertinent parameters, including the laser processing time, the average irradiation power, and the pulse repetition rates. In addition, a heat diffusion modeling is developed to better understand the formation of the spherical cavity and the slightly compressed affected zone surrounding the cavity. A micro-telescope consisting of a microscope objective and a CMBL demonstrates a super-wide field-of-view imaging capability. Finally, detailed optical characterizations of CMBLs are elaborated to account for the refractive index variations of the affected zone. The results presented in the current study demonstrate that a femtosecond laser-fabricated CMBL can be used for robust and super-wide viewing micro imaging applications. PMID- 25740654 TI - Redox sensing and signaling by malaria parasite in vertebrate host. AB - Plasmodium parasites, which is responsible to cause malaria, are also exceedingly receptive to oxidative stress during their intraerythrocytic life stage as they devour haemoglobin inside their food vacuoles and engender toxic haem moieties and reactive oxygen species (ROS). Other than, several studies suggest that the generation of reactive oxygen and nitrogen species (ROS and RNS) associated with oxidative stress, plays a decisive role in the ripeness of systemic complications caused by malaria. Malaria infection provokes the generation of hydroxyl radicals (OH(*)), which most probably is the main reason for the induction of oxidative stress and apoptosis. In this study, it has been described to understand how redox molecules and NO carry out their diverse functions in both parasites and host. It is very important to understand the chemical reactions that produce those outcomes and how its regulation carried out by parasite during erythrocytic phase. PMID- 25740655 TI - Promotion of cardiorespiratory fitness in schizophrenia: a clinical overview and meta-analysis. AB - OBJECTIVE: Cardiorespiratory fitness (CRF) is a major modifiable risk factor for cardiovascular disease (CVD). We conducted a clinical overview to highlight the reduced CRF expressed as maximal oxygen uptake (VO2max) (or predicted) or peak oxygen uptake (VO2 peak) in people with schizophrenia compared to the general population. We also aimed to identify correlates of and clinical strategies to improve CRF. METHOD: We systematically searched major electronic databases from inception until November 2014. A meta-analysis calculating the standardised mean difference (SMD) was employed. RESULTS: CRF was significantly reduced in people with schizophrenia (n = 154) with a SMD of -0.96 (95% CI -1.29 to -0.64) (N = 5) compared to controls (n = 182). Negative symptoms, increased body mass index and female gender were negatively associated with CRF. Promoting physical activity may improve CRF in people with schizophrenia by up to 4-4.5 ml/kg/min following a 6-8 weeks programme (N = 4, n = 98). CONCLUSION: People with schizophrenia have a large and significantly reduced CRF. Given the overwhelming evidence for physical activity as the cornerstone of preventing and managing CVD in the general population, incorporating such interventions in the treatment of people with schizophrenia is justified and urgently required. We present clear practical strategies of how this can be achieved within clinical settings. PMID- 25740656 TI - Simulated microgravity promotes monocyte adhesion to rat aortic endothelium via nuclear factor-kappaB activation. AB - Microgravity-induced vascular remodelling may play an important role in post spaceflight orthostatic intolerance. In this study, we aimed to investigate the effects of simulated microgravity on monocyte adhesion to aortic endothelium in hindlimb unweighted rats and to elucidate the underlying mechanisms associated with this event. Sprague-Dawley rats were subjected to 4-week hindlimb unweighting to simulate microgravity. The recruitment of monocytes to the abdominal aorta was investigated by en face immunofluorescence staining and monocyte binding assays. The expression of the adhesion molecules E-selectin and vascular cell adhesion molecule-1 as well as the cytokine monocyte chemoattractant protein (MCP)-1 was evaluated by immunohistochemical staining, western blot, and quantitative reverse transcription polymerase chain reaction analyses. Additionally, nuclear factor-kappaB (NF-kappaB) activation and the messenger RNA expression levels of E-selectin, vascular cell adhesion molecule-1, and MCP-1 were assessed with the administration of an NF-kappaB inhibitor, pyrrolidine dithiocarbamate. Results showed that simulated microgravity significantly increased monocyte recruitment to the aortic endothelium, protein expression of E-selectin and MCP-1, and NF-kappaB activation in the abdominal aorta of rats. Pyrrolidine dithiocarbamate treatment not only significantly inhibited NF-kappaB activity but also reduced the messenger RNA levels of E selectin, vascular cell adhesion molecule-1, and MCP-1 as well as monocyte recruitment in the abdominal aorta of hindlimb unweighted rats. These results suggest that simulated microgravity increases monocyte adhesion to rat aortic endothelium via the NF-kappaB-mediated expression of the adhesion molecule E selectin and the cytokine MCP-1. Therefore, an NF-kappaB-mediated inflammatory response may be one of the cellular mechanisms responsible for arterial remodelling during exposure to microgravity. PMID- 25740657 TI - The molecular signature and spermatogenesis potential of newborn chicken spermatogonial stem cells in vitro. AB - Although chicken spermatogonial stem cells (SSCs) have received considerable attention in recent years, only a few studies so far have focused on their derivation and characterization in vitro. Identification of specific molecular biomarkers and differentiation capacity of chicken SSCs would not only help us to understand cell and molecular biology of these cells, but also can contribute to their applications in biotechnology. In this regard, we found that colony-forming cells (SSCs) in newborn chicken testicular cell cultures were positive for alkaline phosphatase activity and also expressed specific markers including DAZL, STRA-8, CVH, PLZF, SPRY-1, GFRalpha1, GDNF, POU5F1, NANOG, GPR125, THY-1, c-KIT, and BCL6B, at mRNA level. Moreover, these cells expressed POU5F1 and GPR125 proteins as reliable intracellular and cell surface markers, respectively; whereas they were negative for SSEA-1. Furthermore, we showed that newborn chicken colony-forming cells had spermatogenesis potential and thus could be produced sperm-like cells in a three-dimensional matrix in vitro. In conclusion, this study reports novel insights into the molecular signature of newborn chicken SSCs in comparison with mammalian SSCs and for the first time we report a successful protocol for in vitro spermatogenesis and thus production of sperm like cells from newborn chicken testicular cell cultures. PMID- 25740658 TI - Rapid immunochromatographic test for detection of anti-factor XIII A subunit antibodies can diagnose 90 % of cases with autoimmune haemorrhaphilia XIII/13. AB - Autoimmune haemorrhaphilia XIII/13 (AH13) is an acquired life-threatening bleeding disorder due to anti-factor XIII (FXIII) autoantibodies (auto-Abs). AH13 patients may die of haemorrhage without correct diagnosis and proper treatment because of lack of awareness and the absence of rapid easy-to-use tests specific for this disease. Currently, the definitive diagnosis is established by cumbersome and time-consuming laboratory tests such as dot-blot assays and enzyme linked immunosorbent assays (ELISA), and therefore these tests are generally not carried out. To save AH13 patients' lives, there is an urgent necessity for developing a rapid test for FXIII auto-Abs. We first generated and characterised mouse monoclonal antibodies (mAb) against human FXIII A subunit (FXIII-A), and then developed a rapid immunochromatographic test (ICT) for detection of anti FXIII-A auto-Abs using one mAb with a dissociation constant of 9.3 * 10-11 M. The auto-Ab-FXIII-A complex was captured by the mAb on a nitrocellulose membrane and visualised by Au-conjugated anti-human IgG Ab. Mixing with healthy control plasma improved the detection of auto-Abs in patients having extremely low levels of FXIII-A. The specificity and sensitivity of the ICT were 87 % and 94 %, respectively. We also detected auto-Abs against activated FXIII (FXIIIa) in three patients by pre-converting FXIII to FXIIIa by thrombin treatment. ICT values were significantly inversely correlated with FXIII activity levels, indicating an association between the quantity of anti-FXIII autoantibodies and AH13. This reliable rapid ICT assay can be applied to a point-of-care test to detect anti FXIII-A auto-Abs, and will contribute to early diagnosis and treatment of AH13. PMID- 25740659 TI - Factors influencing publication of scientific articles derived from masters theses in public health. AB - OBJECTIVES: To evaluate theses of a Masters program in Public Health (MPH), in terms of the students' and theses' characteristics that influence publication of the thesis as a scientific article. METHODS: Longitudinal study of students who successfully completed the MPH at Universitat Pompeu Fabra and Universitat Autonoma de Barcelona (Spain) from 2006 to 2010. Participants completed an electronic survey and additional data were gathered from university files. RESULTS: 162 students participated in the study (83 % response rate). 60.5 % had already published an article derived from their thesis at the time of the study or were in process of publishing it. The likelihood of publishing in a peer reviewed journal was greater among women (aRR = 1.41), among those who had a bachelor's degree in sciences other than health (aRR = 1.40), had completed the MPH on time (aRR = 2.10), had enrolled in a doctoral program after the MPH (aRR = 1.44) or had a masters thesis score of >=7 (aRR = 1.61). CONCLUSIONS: The majority of MPH students published their thesis in a peer-reviewed journal. The strongest predictors of successful publication were related to academic performance. PMID- 25740660 TI - The challenge of compiling data profiles to stimulate local preventive health action: a European case study from child safety. AB - OBJECTIVES: Positive recent experience of presenting comparative child safety data at national level has instigated policy action in Europe. It was hoped a Child Safety Index could quantify how safe a community, region or locality is for its children in comparison with similar areas within Europe, as a focus for local targeted action. METHODS: Validated indicators proposed by previous European projects identified from areas of child injury prevention, such as road safety, burns or poisoning, were selected to give a balanced profile, and populated from available published data. An index using a sub-score for each specific injury topic was proposed. The indicators' presentation, sensitivity and appropriateness were considered, as well as data availability. RESULTS: Satisfactory indicators were not identified for all areas and very few local area data were available. This forced the researchers to conclude that at present, constructing a reliable Child Safety Index for use at the local level is not feasible. CONCLUSIONS: There is a worrying lack of data available at the sub-national level to support injury prevention, evaluate interventions, and enable informed local decision making. PMID- 25740661 TI - Maternal diet and larval diet influence survival skills of larval red drum Sciaenops ocellatus. AB - Larval red drum Sciaenops ocellatus survival, turning rate, routine swimming speed, escape response latency and escape response distance were significantly correlated with essential fatty-acid (EFA) concentrations in eggs. Of the five traits that varied with egg EFA content, two (escape response latency and routine swimming speed) were significantly different when larvae were fed enriched diets compared with the low fatty-acid diet, indicating that the larval diet can compensate for some imbalances in egg composition. Turning rate during routine swimming and escape response distance, however, did not change when larvae predicted to have low performance (based on egg composition) were fed an enriched diet, indicating that these effects of egg composition may be irreversible. Escape response distances and survival rates of larvae predicted to perform well (based on egg composition) and fed highly enriched diets were lower than expected, suggesting that high levels of EFA intake can be detrimental. Altogether, these results suggest that both maternal diet, which is responsible for egg EFA composition, and larval diet may play a role in larval survivorship and recruitment. PMID- 25740662 TI - Deep brain stimulation for Alzheimer disease: a decision and cost-effectiveness analysis. AB - Alzheimer disease (AD) is characterized by impairments in memory function. Standard AD treatment provides marginal improvements in this domain. Recent reports, however, suggested that deep brain stimulation (DBS) may result in improved memory. Given significant equipment costs and health expenses required for DBS surgery, we determine clinical and economic thresholds required for it to be as effective as standard AD treatment. Literature review yielded annual AD progression probabilities, health-related quality of life (QoL), and costs by AD stage. Our 5-year decision analysis model compared cumulative QoL in quality adjusted life years (QALYs) and costs of standard therapy to theoretical DBS treatment of various success rates, using known complication rates and QoL data. The base case was a patient with mild-stage AD. DBS success was defined as regression to and maintenance of minimal stage AD, which was defined as midway between mild and no dementia, for the first year, and continuation of the natural course of AD for the remaining 4 years. Compared to standard treatment alone, DBS for mild-stage AD requires a success rate of 3% to overcome effects of possible surgical complications on QoL. If DBS can be delivered with success rates above 20% ($200 K/QALY) or 74% ($50 K/QALY) for mild AD, it can be considered cost effective. Above a success rate of 80%, DBS treatment is both clinically more effective and more cost-effective than standard treatment. Our findings demonstrate that clinical and economic thresholds required for DBS to be cost effective for AD are relatively low. PMID- 25740663 TI - Role of handedness-related vestibular cortical dominance upon the vestibular ocular reflex. PMID- 25740664 TI - Validation of the multimodal assessment of capacities in severe dementia: a novel cognitive and functional scale for use in severe dementia. AB - The multimodal assessment of capacities in severe dementia (MAC-SD), a novel cognitive and functional assessment, was developed for use with patients with severe dementia. Its psychometric attributes were examined in a unicenter, open, observational study. The MAC-SD along with the Spanish language Severe Mini Mental Exam were administered to 103 patients with a diagnosis of severe dementia. Psychometric analyses were performed to determine acceptability, reliability, validity, and responsiveness. As a whole, the MAC-SD sections showed no floor effects, satisfactory internal consistency, reproducibility, construct validity, precision, and sensitivity to change. The MAC-SD performed as a useful, valid, and potentially responsive tool to measure cognition and functioning in the most advanced stages of dementia. PMID- 25740665 TI - Influence of neurologists' experience on the outcome of patients treated by intravenous thrombolysis for cerebral ischaemia. AB - Intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) should be available on a 24/7 basis in hospitals admitting patients with stroke. We aimed at evaluating the influence of the number of patients previously treated with i.v. rt-PA by neurologists on patients' outcome. For each patient consecutively treated with i.v. rt-PA for cerebral ischaemia at the Lille University Hospital, we determined the number of previous treatments with rt-PA administered by the neurologist. We performed logistic regression analyses to determine the influence of the experience on the outcome evaluated by the modified Rankin scale (mRS) after 3 months, 0-1 meaning independence, and 0-2 meaning absence of handicap. We compared outcomes of patients treated by the 25% less experienced neurologists with those of trials. Forty-four neurologists treated 800 patients. The experience of the treating neurologist was independently associated with independence (adjusted odds ratio [(adj)OR] 1.062 for 10 patients more; 95% confidence interval [CI] 1.008-1.120), and absence of handicap ((adj)OR 1.076 for 10 patients more; 95%CI 1.016-1.140) at 3 months, but not with symptomatic intracerebral haemorrhage and death. The proportions of patients from the 1st quartile who were independent and without handicap at 3 months were 37.9 and 51.1%. Patients treated by less experienced neurologists, have similar outcomes than expected from trials, suggesting they benefit from thrombolysis. However, the outcome of patients treated by more experienced neurologists was slightly better. Less experienced neurologists should not be excluded from rt-PA programmes, but their practices should be evaluated and educational programmes organised. PMID- 25740666 TI - Expression of IMP3 and IGF2 in giant cell tumor of spine is associated with tumor recurrence and angiogenesis. AB - PURPOSE: Giant cell tumor (GCT) of bone is a vessel-rich and infiltrative tumor, but the fundamental knowledge of its biological behavior remains unknown now. METHODS: In this study, we evaluated the expression levels of Insulin-like growth factor 2 mRNA-binding protein 3 (IMP3), Insulin-like growth factor 2 (IGF2) and CD105 in 38 patients with GCT of spine by Immunohistochemical staining. Additionally, we also analyzed their correlations with clinicopathological factors of giant cell tumor of spine. RESULTS: The results showed that positive expression of IMP3 and IGF2 was tightly related to the tumor extension and local recurrence of GCT (P < 0.05), but it did not indicate any association with patients' age, gender, tumor location and size. The mean microvessel densities (MVDs) of IMP3 and IGF2 were significantly higher in positive group than negative group (P < 0.05). Moreover, a significant correlation was found between IMP3 and IGF2 expression (r = 0.355, P = 0.029). The log-rank test revealed that local recurrence-free survival time was significantly shorter in the IMP3 positive group (P = 0.004), and the difference in the IGF2 positive group and negative group was also statistically significant (P = 0.008). CONCLUSION: IMP3 and IGF2 might be potential biomarkers for GCT of spine in regulating the angiogenesis of giant cell tumor of bone and predicting the patients' prognosis. PMID- 25740667 TI - Does vitamin D mediate inhibition of epithelial ovarian cancer by modulating cytokines? AB - OBJECTIVE: Vitamin D deficiency is reported to be involved in pathogenesis of ovarian cancer. But the mechanism is yet to be explored. An imbalance between Th1 and Th2 activity play a crucial role in pathogenesis of many cancers. The purpose of the study is to find out the Th1/Th2 status by estimating TNF-alpha (Th1 marker) and IL-4 (Th2 marker) in ovarian cancer cases and controls and to correlate these with serum vitamin D levels. MATERIALS AND METHODS: A case control study with 50 ovarian cancer cases and 50 healthy controls was conducted. The cytokines TNF-alpha and IL-4 were estimated by ELISA. Serum vitamin D was measured by electro-chemiluminescence immunoassay method. RESULTS: Median TNF alpha levels (12.2 vs 6.2 pg/ml; p value <0.001) were significantly higher in ovarian cancer patients and mean IL-4 levels (2.22 +/- 0.51 vs 2.99 +/- 0.68 pg/ml; p value <0.05) were significantly lower as compared to those of controls. Levels of TNF-alpha and IL-4 did not vary significantly with clinical staging, and histological grading. Vitamin D levels were negatively correlated with TNF alpha and positively correlated with IL-4. CONCLUSIONS: Low vitamin D levels promotes Th1 activity increasing TNF-alpha levels and inhibits Th2 activity decreasing IL-4 levels in ovarian cancer. These low levels of vitamin D may induce pro-inflammatory micro ambience which might contribute to pathogenesis of ovarian cancer. PMID- 25740668 TI - Thin cap fibroatheroma defined as lipid core abutting lumen (LCAL) on integrated backscatter intravascular ultrasound - comparison with optical coherence tomography and correlation with peri-procedural myocardial infarction. AB - BACKGROUND: This study evaluated the ability of a newly developed integrated backscatter intravascular ultrasound (IB-IVUS) system (VISIWAVE, Terumo, Tokyo, Japan) to detect optical coherence tomography (OCT)-verified thin cap fibroatheroma (TCFA) and assessed the correlation with peri-procedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI). METHODS AND RESULTS: One hundred culprit lesions in 100 consecutive patients with ischemic heart disease who consented to repeated IVUS and OCT prior to PCI were studied. Of 100 lesions, 48 had OCT-verified TCFA with a cap thickness <65 um. Such lesions had larger percentage lipid area and lipid angle >2 quadrants on IB-IVUS. A lipid core abutting lumen (LCAL) was defined as a lipid core pool in the plaque area, directly contacting with the lumen regardless of its circumferential extension. IB-IVUS-identified TCFA defined as a combination of percentage lipid area >=53.6%, remodeling index >=1.03, and the presence of LCAL was the best predictor of OCT-verified TCFA with sensitivity, specificity, positive and negative predictive values, and accuracy of 72.9%, 90.4%, 87.5%, 78.3%, and 82.0%, respectively. IB-IVUS-identified TCFA as well as OCT-verified TCFA were significant independent predictors of PMI, after adjusting for other predictors on multivariate analysis. CONCLUSIONS: IB-IVUS can be used to identify plaques with a high prevalence of TCFA. Such techniques can therefore potentially be used to identify lesions with an elevated risk of PMI after PCI. PMID- 25740669 TI - Low Body Weight Is Associated With the Incidence of Stroke in Atrial Fibrillation Patients - Insight From the Fushimi AF Registry. AB - BACKGROUND: Japanese patients with atrial fibrillation (AF) are generally small and lean, but knowledge of the clinical characteristics of those with low body weight (LBW: <=50 kg) is limited. METHODS AND RESULTS: The Fushimi AF Registry is a community-based prospective survey of AF patients who visited the participating medical institutions in Fushmi-ku, Japan. The BW and follow-up data were available for 2,945 patients. We compared the background and the incidence of clinical events during a median follow-up of 746 days between a LBW and non-LBW group. Patients in the LBW group accounted for 26.8% (788 patients) of the total. The LBW group was more often female, older, and had higher CHADS2score. The incidence of stroke/systemic embolism (SE) during follow-up was higher in the LBW group (hazard ratio (HR): 2.19, 95% confidence interval (CI): 1.57-3.04; P<0.01), whereas that of major bleeding was comparable (HR: 1.05, 95% CI: 0.64-1.68; P=0.84). This trend was consistently observed in the subgroups stratified by age, sex, and oral anticoagulant prescription at baseline. Multivariate analysis as well as propensity-score matching analysis further supported the significance of LBW as a risk of stroke/SE. CONCLUSIONS: Patients in the LBW group had high risk profiles and showed a higher incidence of stroke/SE, but the incidence of major bleeding was not particularly high. PMID- 25740670 TI - Faster is briefer: The symbolic meaning of speed influences time perception. AB - The present study investigates how the symbolic meaning of the stimuli presented for marking time intervals affects perceived duration. Participants were engaged in a time bisection task in which they were first trained with two standard durations, 400 ms and 1600 ms, and then asked to judge if the following temporal intervals were closer to the short or to the long standard. Stimuli were images of vehicles representing speed, with a motorbike representing fastness and a bicycle representing slowness. Results showed that presenting images with different speed meanings affects time perception: an image representing a fast object, the motorbike, leads to shorter perceived time than presenting an image representing a slower object, the bicycle. This finding is attributed to an impact on the memory mechanism involved in the processing of temporal information. PMID- 25740671 TI - Biomechanical rationale of coronary artery bypass grafting of multivessel disease. AB - The biomechanical model of human coronary arteries was modified for improving the quality of diagnosis and surgical treatment for coronary heart disease. The problem of hemodynamics in the left coronary artery with multivessel bed disease 45% stenosis of the anterior descending branch and 75% stenosis of the circumflex branch - was particularly considered. Numerical simulation of the coronary arterial bypass of the main trunk was carried out to estimate the functional condition of the coronary arteries after restoring myocardial blood supply by surgery. PMID- 25740672 TI - Topical timolol solution versus laser in treatment of infantile hemangioma: a comparative study. AB - Lasers, 595-nm pulsed dye and 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG), have been used successfully for the treatment of infantile hemangiomas (IHs). Recently the use of a topical beta-blocker, specifically timolol maleate, has been promising in the treatment of IHs. The objective of this study was to compare the effectiveness of topical timolol 5 mg/mL solution with that of combined sequential dual-wavelength laser in the treatment of IHs. Sixty children with IHs were divided randomly into two equal groups. Group 1 was treated with applications of timolol drops (5 mg/mL) twice daily. Group 2 was treated with sequential pulsed dye and Nd:Yag laser. Treatments were performed every month for a maximum of six sessions. Efficacy was evaluated clinically and by measuring the average hemoglobin level. A significant decrease in the average hemoglobin level was determined in both groups and a dramatic response was observed in superficial hemangiomas in the timolol group. The timolol group received treatment for an average of 4.0 +/- 1.1 months and the laser group for 5.5 +/- 0.9 months. The degree of improvement of mixed hemangiomas to laser treatment was greater than that of the timolol group. During 3 months of follow-up, no further improvement or relapse was reported in either group. Timolol solution is a safe and effective alternative to laser treatment in superficial hemangiomas. In mixed hemangiomas, the combined sequential 595-nm and 1,064-nm dual-wavelength laser provided better results than timolol solution because it penetrated deeply so that deep dermal blood vessels were reached. PMID- 25740673 TI - Bicarbonate- versus lactate-buffered solutions for acute continuous haemodiafiltration or haemofiltration. AB - BACKGROUND: Acute kidney injury (AKI) is a severe loss of kidney function that results in patients' inability to appropriately excrete nitrogenous wastes and creatinine. Continuous haemodiafiltration (HDF) or haemofiltration (HF) are commonly used renal replacement therapies for people with AKI. Buffered dialysates and solutions used in HDF or HF have varying effects on acid-base physiology and several electrolytes. The benefits and harms of bicarbonate- versus lactate-buffered HDF or HF solutions for treating patients with AKI remain unclear. OBJECTIVES: To assess the benefits and harms of bicarbonate- versus lactate-buffered solutions for HDF or HF for treating people with AKI. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 6 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched the Chinese Biomedical Literature Database. SELECTION CRITERIA: All randomised controlled trials (RCT) and quasi RCTs that reported comparisons of bicarbonate-buffered solutions with lactate buffered solutions for AKI were selected for inclusion irrespective of publication status or language. DATA COLLECTION AND ANALYSIS: Two authors independently assessed titles and abstracts, and where necessary the full text of studies, to determine which satisfied our inclusion criteria. Data were extracted by two authors who independently assessed studies for eligibility and quality using a standardised data extraction form. Methodological quality was assessed using the Cochrane risk of bias tool. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified four studies (171 patients) that met our inclusion criteria. Overall, study quality was suboptimal. There were significant reporting omissions related to methodological issues and potential harms. Outcome measures were not defined or reported adequately. The studies were small and lacked follow-up phases.Serum lactate levels were significantly lower in patients treated with bicarbonate buffered solutions (4 studies, 171 participants: MD -1.09 mmol/L, 95% CI -1.30 to -0.87; I(2) = 0%). There were no differences in mortality (3 studies, 163 participants: RR 0.76, 95% CI 0.50 to 1.15; I(2) = 0%); serum bicarbonate levels (3 studies, 163 participants: MD 0.27 mmol/L, 95% CI -1.45 to 1.99; I(2) = 78%), serum creatinine (2 studies, 137 participants: MD -22.81 umol/L, 95% CI -129.61 to 83.99; I(2) = 73%), serum base excess (3 studies, 145 participants: MD 0.80, 95% CI -0.91 to 2.50; I(2) = 38%), serum pH (4 studies, 171 participants: MD 0.01, 95% CI -0.02 to 0.03; I(2) = 70%) or carbon dioxide partial pressure (3 studies, 151 participants: MD -1.04, 95% CI -3.84 to 1.76; I(2) = 83%). A single study reported fewer cardiovascular events (RR 0.39, 95% CI 0.20 to 0.79), higher mean arterial pressure (10.25 mm Hg, 95% CI 6.68 to 13.82) and less hypotensive events (RR 0.44, 95% CI 0.26 to 0.75) in patients receiving bicarbonate-buffered solutions. One study reported no significant difference in central venous pressure (MD 2.00 cm H2O, 95% CI -0.7 to, 4.77). Total length of hospital and ICU stay and relapse were not reported by any of the included studies. AUTHORS' CONCLUSIONS: There were no significant different between bicarbonate- and lactate buffered solutions for mortality, serum bicarbonate levels, serum creatinine, serum base excess, serum pH, carbon dioxide partial pressure, central venous pressure and serum electrolytes. Patients treated with bicarbonate-buffered solutions may experience fewer cardiovascular events, lower serum lactate levels, higher mean arterial pressure and less hypotensive events. With the exception of mortality, we were not able to assess the main primary outcomes of this review - length of time in ICU, total length of hospital stay and relapse. PMID- 25740674 TI - Research and development-where people are exposed to nanomaterials. AB - OBJECTIVES: Many nanomaterials (materials with structures smaller than 100 nm) have chemical, physical and bioactive characteristics of interest for novel applications. Considerable research efforts have been launched in this field. This study aimed to study exposure scenarios commonly encountered in research settings. METHODS: We studied one of the leading Swiss universities and first identified all research units dealing with nanomaterials. After a preliminary evaluation of quantities and process types used, a detailed analysis was conducted in units where more than a few micrograms were used per week. RESULTS: In the investigated laboratories, background levels were usually low and in the range of a few thousand particles per cubic centimeter. Powder applications resulted in concentrations of 10,000 to 100,000 particles/cm(3) when measured inside fume hoods, but there were no or mostly minimal increases in the breathing zone of researchers. Mostly low exposures were observed for activities involving liquid applications. However, centrifugation and lyophilization of nanoparticle containing solutions resulted in high particle number levels (up to 300,000 particles/cm(3)) in work spaces where researchers did not always wear respiratory protection. No significant increases were found for processes involving nanoparticles bound to surfaces, nor were they found in laboratories that were visualizing properties and structure of small amounts of nanomaterials. CONCLUSIONS: Research activities in modern laboratories equipped with control techniques were associated with minimal releases of nanomaterials into the working space. However, the focus should not only be on processes involving nanopowders but should also be on processes involving nanoparticle-containing liquids, especially if the work involves physical agitation, aerosolization or drying of the liquids. PMID- 25740675 TI - Effect of a brief training program based on cognitive behavioral therapy in improving work performance: A randomized controlled trial. AB - OBJECTIVES: Efforts to improve performance in the workplace with respect to positive mental health have increased, and cognitive behavioral therapy (CBT) has recently attracted attention as an intervention measure to this end. Here, we conducted a randomized controlled trial to evaluate the effectiveness of a brief training program on CBT for improving work performance of employees. METHODS: The participants were employees of an electric company in Japan. The intervention consisted of 1 group session of CBT (120 min) and web-based CBT homework for 1 month. We evaluated employees in both the intervention and control groups at baseline and follow-up after three months. The main outcome was work performance, which was evaluated by a subjective score from 1 to 10. The secondary outcome was self-evaluation of cognitive flexibility. Analyses were conducted based on ITT. RESULTS: In the intervention group, 84 participants attended the group session, with 79 subsequently completing at least 1 instance of online homework. ITT analysis showed that the subjective performance of the intervention group was significantly improved compared with that of the control group (1.47 vs. 0.69, mean difference 0.78 [95% confidence interval {CI}, 0.05 to 1.51], Cohen's d=0.31). The ability to recognize dysfunctional thinking patterns and change them to positive ones significantly improved in the intervention group compared to the control group (0.71 vs. 0.26, mean difference 0.45 [95% CI 0.06 to 0.83], d=0.33). However, after adjustment for baseline scores, no significant difference was observed. The ability to view a situation from multiple perspectives and expand one's repertoire of thought patterns in the intervention group also significantly improved (0.83 vs. 0.35, mean difference 0.48 [95% CI 0.35 to 0.95], d=0.29), but here again, significance was lost after adjusting for baseline scores. DISCUSSION: Our results suggest that a brief training program that combines a group CBT session with web-based CBT homework improved subjective work performance. In addition, this program might help improve employees' cognitive flexibility. PMID- 25740676 TI - Mitochondrial and Oxidative Stress Response in HepG2 Cells Following Acute and Prolonged Exposure to Antiretroviral Drugs. AB - Chronic HIV treatment with antiretroviral drugs has been associated with adverse health outcomes. Mitochondrial toxicity exhibited by nucleoside reverse transcriptase inhibitors (NRTIs) is pinpointed as a molecular mechanism of toxicity. This study evaluated the effect of NRTIs: Zidovudine (AZT, 7.1 MUM), Stavudine (d4T, 4 MUM) and Tenofovir (TFV, 1.2 MUM), on mitochondrial (mt) stress response, mtDNA integrity and oxidative stress response in human hepatoma cells at 24 and 120 h. Markers for mt function, mt biogenesis, oxidative stress parameters, and antioxidant response were evaluated by spectrophotometry, luminometry, flow cytometry, qPCR and western blots. We found that AZT and d4T reduced mtDNA integrity (120 h, AZT: 76.1%; d4T:36.1%, P < 0.05) and remained unchanged with TFV. All three NRTIs, however, reduced ATP levels (AZT: 38%; d4T: 56.4%; TFV: 27.4%, P = 0.01) and mt membrane potential at 120 h (P < 0.005). Oxidative damage and reactive oxygen species (ROS) were increased by TFV and AZT at 24 h, and by d4T at 120 h (P < 0.05). Antioxidant response molecules and mt biogenesis markers were elevated by all NRTIs, with TFV causing the most significant increase (P < 0.05). Data from this study suggest that AZT, d4T and TFV alter mt function. TFV, however, achieves this independently of mtDNA depletion. Furthermore, AZT exerts toxicity soon after exposure as noted from changes at 24 h and d4T exerts greater toxicity over prolonged exposure (120 h). PMID- 25740677 TI - Pharmacokinetics of linezolid treatment using intravenous and oral administrations in extremely premature infants. AB - INTRODUCTION: Vancomycin is the usual antibiotic treatment in coagulase-negative staphylococcus sepsis in premature infants but causes renal toxicity. As linezolid is effective in Gram-positive cocci infection, and devoid of renal side effects, it has been used in Nantes neonatal intensive care units and linezolid plasma concentrations were monitored. AIM: The aims of this study are to report data on linezolid concentrations in premature infants, describe clinical and bacteriological evolution during treatment, and determine potential side effects. METHODS: A retrospective observational study of premature infants treated with linezolid in Nantes Hospital from January 2008 through November 2011 was conducted. Linezolid plasma concentrations, possible side effects due to linezolid, and clinical response to linezolid treatment were collected from folder review. RESULTS: Twenty-four linezolid plasma concentrations were monitored in 16 premature patients, at steady state for continuous intravenous administration or 7 +/- 1.5 h after last oral administration. Except for one case, linezolid plasma concentrations were >=minimal inhibition concentration (MIC) for linezolid for both parenteral and oral administrations. We observed three cases of thrombocytopenia, two of leukopenia, three of neutropenia, and one of severe hyperlactacidemia, resolving after discontinuation of treatment. Clinical signs of infection resolved in 13/16 cases. Bacteria were coagulase negative Staphylococci in 12/16 cases and were eradicated in 9/12 evaluable cases. CONCLUSIONS: This study reports an adequate linezolid plasma concentration with regard to the linezolid MIC in extremely premature infants. However, considering adverse events reported, its use should be cautious and may concern only oral administration during the late phase of infection, to limit paradoxical catheter use to treat nosocomial infections. Moreover, safe and efficient anti Staphylococcus therapies should be identified to treat this vulnerable population. PMID- 25740678 TI - Germ line polymorphisms as predictive markers for pre-surgical radiochemotherapy in locally advanced rectal cancer: a 5-year literature update and critical review. AB - PURPOSE: Locally advanced rectal cancer is currently treated with pre-surgical radiotherapy and chemotherapy. Approximately one-half of patients obtain a relevant shrinkage/disappearance of tumour, with major clinical advantages. The remaining patients, in contrast, show no benefit and possibly need alternative treatment. To provide the best therapeutic option for each individual patient, predictive markers have been widely researched. This review was undertaken to evaluate recent progress made in this field. METHODS: A systematic literature search was performed using PubMed and Scopus database, focused on germ line gene polymorphisms as biomarkers and response and toxicity as outcomes. Because an exhaustive previous review was available describing findings up to 2008, we restricted our analysis to the last 5 years. RESULTS: Ten original research articles were found, reporting promising results for some candidate genes in drug metabolism (TYMS, MTHFR), DNA repair (XRCC1, OGG1, CCND1) and inflammation (SOD2, TGFB1)/immunity (IL13) pathways, but with no firm conclusion. All the studies had small sample size and were defined as exploratory. This review highlights pivotal molecular, clinical, genetic and statistical issues in the investigation of genetic polymorphisms as outcome predictors for rectal cancer and offers suggestions for future development. CONCLUSIONS: What emerges is a clear need for new proposals, especially in view of the increasing evidence for tumour-host and gene-gene interactions during anticancer treatment, together with stronger adherence to proper methodological requirements. PMID- 25740679 TI - Enhancing spoof surface-plasmons with gradient metasurfaces. AB - The coupling between surface plasmons and free electrons may be used to amplify waves or accelerate particles. Nonetheless, such an interaction is usually weak due to the small interaction length or velocity mismatching. Here a mechanism for enhancing the coupling between plasmonic fields and relativistic electrons is proposed. By using a weakly gradient meta-surface that supports the spoof surface plasmons (SSP), the phase velocity of SSP mode can be manipulated and quasi velocity-matching between SSP and electrons may be achieved. The dynamic coupling equations suggest that, due to the strong coupling, the energy can be extracted continuously from the relativistic electrons. The sustained increase of SSP in a narrow frequency band has been demonstrated by the particle-in-cell simulations, where the output power of SSP attains 65 W at 1 THz (with 28 mm interaction length) and the coupling efficiency is enhanced by two orders of magnitude. The results may find potential applications for designing new compact and efficient THz wave sources. PMID- 25740681 TI - The Medical Jungle. PMID- 25740680 TI - Interolog interfaces in protein-protein docking. AB - Proteins are essential elements of biological systems, and their function typically relies on their ability to successfully bind to specific partners. Recently, an emphasis of study into protein interactions has been on hot spots, or residues in the binding interface that make a significant contribution to the binding energetics. In this study, we investigate how conservation of hot spots can be used to guide docking prediction. We show that the use of evolutionary data combined with hot spot prediction highlights near-native structures across a range of benchmark examples. Our approach explores various strategies for using hot spots and evolutionary data to score protein complexes, using both absolute and chemical definitions of conservation along with refinements to these strategies that look at windowed conservation and filtering to ensure a minimum number of hot spots in each binding partner. Finally, structure-based models of orthologs were generated for comparison with sequence-based scoring. Using two data sets of 22 and 85 examples, a high rate of top 10 and top 1 predictions are observed, with up to 82% of examples returning a top 10 hit and 35% returning top 1 hit depending on the data set and strategy applied; upon inclusion of the native structure among the decoys, up to 55% of examples yielded a top 1 hit. The 20 common examples between data sets show that more carefully curated interolog data yields better predictions, particularly in achieving top 1 hits. Proteins 2015; 83:1940-1946. (c) 2015 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc. PMID- 25740682 TI - Understanding and controlling airborne organic compounds in the indoor environment: mass transfer analysis and applications. AB - Mass transfer is key to understanding and controlling indoor airborne organic chemical contaminants (e.g., VVOCs, VOCs, and SVOCs). In this study, we first introduce the fundamentals of mass transfer and then present a series of representative works from the past two decades, focusing on the most recent years. These works cover: (i) predicting and controlling emissions from indoor sources, (ii) determining concentrations of indoor air pollutants, (iii) estimating dermal exposure for some indoor gas-phase SVOCs, and (iv) optimizing air-purifying approaches. The mass transfer analysis spans the micro-, meso-, and macroscales and includes normal mass transfer modeling, inverse problem solving, and dimensionless analysis. These representative works have reported some novel approaches to mass transfer. Additionally, new dimensionless parameters such as the Little number and the normalized volume of clean air being completely cleaned in a given time period were proposed to better describe the general process characteristics in emissions and control of airborne organic compounds in the indoor environment. Finally, important problems that need further study are presented, reflecting the authors' perspective on the research opportunities in this area. PMID- 25740683 TI - River water quality management considering agricultural return flows: application of a nonlinear two-stage stochastic fuzzy programming. AB - In this paper, a new fuzzy methodology is developed to optimize water and waste load allocation (WWLA) in rivers under uncertainty. An interactive two-stage stochastic fuzzy programming (ITSFP) method is utilized to handle parameter uncertainties, which are expressed as fuzzy boundary intervals. An iterative linear programming (ILP) is also used for solving the nonlinear optimization model. To accurately consider the impacts of the water and waste load allocation strategies on the river water quality, a calibrated QUAL2Kw model is linked with the WWLA optimization model. The soil, water, atmosphere, and plant (SWAP) simulation model is utilized to determine the quantity and quality of each agricultural return flow. To control pollution loads of agricultural networks, it is assumed that a part of each agricultural return flow can be diverted to an evaporation pond and also another part of it can be stored in a detention pond. In detention ponds, contaminated water is exposed to solar radiation for disinfecting pathogens. Results of applying the proposed methodology to the Dez River system in the southwestern region of Iran illustrate its effectiveness and applicability for water and waste load allocation in rivers. In the planning phase, this methodology can be used for estimating the capacities of return flow diversion system and evaporation and detention ponds. PMID- 25740684 TI - Erratum to: The effect of functional forms of nitrogen on fuel-NOx emissions. PMID- 25740685 TI - Study on heavy metal levels and its health risk assessment in some edible fishes from Nansi Lake, China. AB - Eight heavy metals, namely Cu, Zn, Fe, Mn, Cd, Ni, Pb, and As in the muscles of nine fish species collected from Nansi Lake, China. were determined, and the potential health risks to local residents via consumption of the fishes were estimated. The results of two-way ANOVA that showed the concentrations of heavy metals in the investigated fish samples were influenced significantly by fish species and sampling sites. Correlation analysis indicated that sampling sites had significant effects on the levels of correlation coefficients among different heavy metal concentrations. Interestingly, although none of the hazard quotient (HQ) values of any individual element was greater than 1 for the investigated exposure population through fish consumption, the hazard index (HI) values were more than 1 for local fishermen, suggesting that local fishermen may be experiencing some adverse health effects. Among the investigated nine fish species, Cyprinus carpio had the highest HQ and HI. As, Pb, and Cd were the most concerning heavy metals in the investigated fish samples due to their higher relative contributions to the HI values. PMID- 25740686 TI - Tropical soils cultivated with tomato: fractionation and speciation of Al. AB - Soil acidity and the associated problems of aluminum (Al) toxicity and scarce exchangeable bases are typically the most important limiting factors of agricultural yield in wet tropical regions. The goals of this study were to test how soil lime rates affect the forms and distribution of Al in the soil fractions and how different levels of bioavailable Al affect two tomato genotypes grown in wet tropical soils. The tomato genotypes CNPH 0082 and Calabash Rouge were grown in two wet tropical soils in a greenhouse. Soil lime rates of 0, 560, and 2240 mg kg(-1) soil (clay soil) and 0, 280, and 1120 mg kg(-1) soil (sandy soil) were applied to modify Al concentrations. Dry mass production and Al concentrations were determined in shoots and roots. Al was fractionated in the soil, and the soil solution was speciated after cultivation. The Calabash Rouge genotype possesses mechanisms to tolerate Al3+, absorbed less Al, exhibited smaller reduction in growth, and lower Al concentrations in plant parts than the CNPH 0082. Increased soil pH reduced the exchangeable Al fraction and increased the fraction mainly linked to organic matter. Al in the soil in the form of complexes with organic compounds and Al(SO4)+ (at the highest lime rate) did not affect plant development. Soil acidity can be easily neutralized by liming the soil, which transforms toxic Al3+ in the soil into forms that do not harm tomato plants, thereby avoiding oxidative stress in the plants. Al-induced stress in tomatoes varies with genotypes and soil type. PMID- 25740687 TI - Effects of the algicide, thiazolidinedione derivative TD49, on microbial communities in a mesocosm experiment. AB - We investigated the effects of the algicide thiazolidinedione derivative TD49 on microbial community in mesocosm experiments. The TD49 concentration exponentially decreased over time, with half-life of 3.5 h, following addition in the seawater (R2=0.98, P<0.001). Among microbial communities, heterotrophic bacteria and heterotrophic nanoflagellates (HNFs) grew well in all treatments following the addition of TD49. The abundance of HNFs lagged behind the increase in heterotrophic bacteria by 24 h in the 0.2 and 0.4 MUM TD49 concentrations (R2=0.28, P<0.05), and by 48 h in the 0.6 and 1.0 MUM TD49 concentrations (R2=0.30, P<0.05). This implies a strong concentration-dependent top-down effect of TD49 on microbial communities, with indications that the degradation of planktonic organisms, including the target alga, led to high heterotrophic bacteria concentrations, which in turn stimulated the population growth of predatory HNF. However, total ciliate numbers remained relatively low in the TD49 treatments relative to the control and blank groups, suggesting limited carbon flow from bacteria to these grazers even though the abundance of aloricate ciliates gradually increased toward the end of the experimental period, particularly at the high TD49 concentrations. TD49 appears to provide an environmentally safe approach to the control of harmful algal blooms (HABs) in aquatic ecosystems. PMID- 25740688 TI - Relation between magnetic parameters and nematode abundance in agricultural soils of Portugal--a multidisciplinary study in the scope of environmental magnetism. AB - Soil is composed of different types of particles which are either natural or of anthropogenic origin. Anthropogenic particles are often related to the presence of heavy metals and thus provide information on soil quality. Magnetic parameters can detect the presence of such particles and may be used as a proxy for environmental pollution. This study explores the relationships between magnetic particles and the nematofauna of agricultural soils. Magnetic, pedological, microscopy and nematological analyses were conducted in soils collected from major regions of potato production in Portugal. The magnetic characterisation of soils identified regions with magnetic particles with possible anthropogenic origin. Microscopy analysis revealed the presence of spherical particles dominantly composed of Fe, O and C. A positive and significant relationship was found between saturation isothermal remanent magnetisation (SIRM) and mass specific susceptibility (chi), confirming the importance the ferrimagnetic fraction to magnetic properties. The nematode communities were composed of nematodes belonging to four trophic groups (bacterial feeding, plant feeders, fungal feeders and omnivores/predators). The relationships between magnetic parameters and the nematodes showed that (1) S-25 has a linear correlation with number of nematodes per kilogram of soil and with plant feeders' trophic group and (2) SIRM correlates with the bacterial feeders trophic group. This study reveals that magnetic proxies may provide means for detecting regions with higher levels of pollution, possibly related to heavy metals. Due to the large background variability found in magnetic parameters, the sampling spacial mesh should to be further refined and the input of magnetic minerals needs to be locally calibrated. PMID- 25740689 TI - Mapping of groundwater potential zones in Salem Chalk Hills, Tamil Nadu, India, using remote sensing and GIS techniques. AB - This study proposes to introduce the remote sensing and geographic information system (GIS) techniques in mapping the groundwater potential zones. Remote sensing and GIS techniques have been used to map the groundwater potential zones in Salem Chalk Hills, Tamil Nadu, India. Charnockites and fissile hornblende biotite gneiss are the major rock types in this region. Dunites and peridodites are the ultramafic rocks which cut across the foliation planes of the gneisses and are highly weathered. It comprises magnesite and chromite deposits which are excavated by five mining companies by adopting bench mining. The thickness of weathered and fracture zone varies from 2.2 to 50 m in gneissic formation and 5.8 to 55 m in charnockite. At the contacts of gneiss and charnockite, the thickness ranges from 9.0 to 90.8 m favoring good groundwater potential. The mine lease area is underlined by fractured and sheared hornblende biotite gneiss where groundwater potential is good. Water catchment tanks in this area of 5 km radius are small to moderate in size and are only seasonal. They remain dry during summer seasons. As perennial water resources are remote, the domestic and agricultural activities in this region depend mainly upon the groundwater resources. The mines are located in gently slope area, and accumulation of water is not observed except in mine pits even during the monsoon period. Therefore, it is essential to map the groundwater potential zones for proper management of the aquifer system. Satellite imageries were also used to extract lineaments, hydrogeomorphic landforms, drainage patterns, and land use, which are the major controlling factors for the occurrence of groundwater. Various thematic layers pertaining to groundwater existence such as geology, geomorphology, land use/land cover, lineament, lineament density, drainage, drainage density, slope, and soil were generated using GIS tools. By integrating all the above thematic layers based on the ranks and weightages, eventually groundwater potential zones were demarcated. The study indicates that groundwater potential is good to high in 22 villages and moderate in 13 villages. The good to high potential zone occupies an area of 128 km2 and moderate potential zone occupies an area of 77 km2. Groundwater occurrence is poor in five villages which need artificial recharge to augment groundwater. PMID- 25740690 TI - Abnormal white matter structural networks characterize heroin-dependent individuals: a network analysis. AB - Neuroimaging studies suggested that drug addiction is linked to abnormal brain functional connectivity. However, little is known about the alteration of brain white matter (WM) connectivity in addictive drug users and nearly no study has been performed to examine the alterations of brain WM connectivity in heroin dependent individuals (HDIs). Diffusion tensor imaging (DTI) offers a comprehensive technique to map the whole brain WM connectivity in vivo. In this study, we acquired DTI datasets from 20 HDIs and 18 healthy controls and constructed their brain WM structural networks using a deterministic fibre tracking approach. Using graph theoretical analysis, we explored the global and nodal topological parameters of brain network for both groups and adopted a network-based statistic (NBS) approach to assess between-group differences in inter-regional WM connections. Statistical analysis indicated the global efficiency and network strength were significantly increased, but the characteristic path length was significantly decreased in the HDIs compared with the controls. We also found that in the HDIs, the nodal efficiency was significantly increased in the left prefrontal cortex, bilateral orbital frontal cortices and left anterior cingulate gyrus. Moreover, the NBS analysis revealed that in the HDIs, the significant increased connections were located in the paralimbic, orbitofrontal, prefrontal and temporal regions. Our results may reflect the disruption of whole brain WM structural networks in the HDIs. Our findings suggest that mapping brain WM structural network may be helpful for better understanding the neuromechanism of heroin addiction. PMID- 25740691 TI - First-in-human, phase I/IIa dose-escalation and safety study of balugrastim in breast cancer patients receiving myelosuppressive chemotherapy. AB - PURPOSE: To evaluate safety of balugrastim, a recombinant human serum albumin and granulocyte colony-stimulating factor (G-CSF), administered over a range of therapeutic doses in women with breast cancer receiving doxorubicin plus docetaxel chemotherapy. METHODS: The phase I, sequential dose-escalation first segment compared subcutaneous balugrastim 50, 150, 300, and 450 ug/kg during chemotherapy cycles 0-2. The randomized (2:2:1), open-label, phase IIa second segment compared balugrastim 300 or 450 ug/kg with pegfilgrastim 6 mg during chemotherapy cycles 1 and 2. RESULTS: In the phase I segment, balugrastim was escalated to 450 ug/kg in 13 patients without dose-limiting toxicity. Three (9.7 %) of the 31 adverse events (AEs) reported in nine patients were grade 3 (agranulocytosis, vomiting, hypertension); none was grade 4. In the open-label phase IIa segment (N = 51), the majority of the 64 AEs reported in 31 (75.6 %) balugrastim-treated patients were grade 1 (59.4 %), with 39.1 % grade 2, 1.6 % grade 3 (one AE of vomiting), and none grade 4. Of the 16 AEs reported in seven (70.0 %) pegfilgrastim-treated patients, 87.5 % were grade 1, 6.3 % were grade 2, 6.3 % were grade 3 (one AE of thrombocytopenia), and none were grade 4. Overall, there were six bone pain AEs reported, one in the balugrastim 300 ug/kg group and five in the balugrastim 450 ug/kg group. No AEs in either study necessitated treatment interruption/discontinuation. The incidence and duration of grade 3-4 neutropenia were similar between balugrastim- and pegfilgrastim-treated patients. CONCLUSIONS: Balugrastim was well tolerated in this small population of breast cancer patients. PMID- 25740692 TI - Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model. AB - PURPOSE: Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration. METHODS: Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration-time curves. RESULTS: Peak plasma concentrations (C max) ranged from 11.7-19.3 uM, and remained >1 uM for >28 days. Time to C max (T max) was 19 h. The median (range) AUCPl was 3148 (2502-4705) uM/h, with a median (range) terminal half-life (t 1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (T max 64-235 h). CSF AUCs and t 1/2 were 6358 (2266-7568) nM/h and 277 (146-350) h, respectively. Perifosine concentrations in the CSF remained over nM for >35 days. The mean CSF penetration was 0.16 %. CONCLUSION: CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2 months) after a single oral dose. PMID- 25740693 TI - Synthesis of new zeolite structures. AB - The search for new zeolites is of continuous interest in the field of zeolite science because of their widespread application in catalysis and adsorption separation. To this end, considerable efforts have been devoted to the preparation of new zeolites with novel porous architectures and compositions. Taking account of the key factors governing the formation of zeolites (e.g., guest species, framework elements, construction processes, etc.), several synthetic strategies have been developed recently. These allow the discovery of many new zeolites with unprecedented structural features, such as hierarchical pores, odd-ring numbers (11-, 15-rings), extra-large pores (16-, 18-, 20-, 28-, and 30-rings), chiral pores, and extremely complex framework topologies, etc. In this review, we will present the advances in the synthesis of new zeolite structures in the last decade, which are achieved by utilization of the synthetic strategies based on pre-designed structure-directing agents, heteroatom substitution, and topotactic transformations. PMID- 25740694 TI - The role of mouse Akt2 in insulin-dependent suppression of adipocyte lipolysis in vivo. AB - AIM/HYPOTHESIS: The release of fatty acids from adipocytes, i.e. lipolysis, is maintained under tight control, primarily by the opposing actions of catecholamines and insulin. A widely accepted model is that insulin antagonises catecholamine-dependent lipolysis through phosphorylation and activation of cAMP phosphodiesterase 3B (PDE3B) by the serine-threonine protein kinase Akt (protein kinase B). Recently, this hypothesis has been challenged, as in cultured adipocytes insulin appears, under some conditions, to suppress lipolysis independently of Akt. METHODS: To address the requirement for Akt2, the predominant isoform expressed in classic insulin target tissues, in the suppression of fatty acid release in vivo, we assessed lipolysis in mice lacking Akt2. RESULTS: In the fed state and following an oral glucose challenge, Akt2 null mice were glucose intolerant and hyperinsulinaemic, but nonetheless exhibited normal serum NEFA and glycerol levels, suggestive of normal suppression of lipolysis. Furthermore, insulin partially inhibited lipolysis in Akt2 null mice during an insulin tolerance test (ITT) and hyperinsulinaemic-euglycaemic clamp, respectively. In support of these in vivo observations, insulin antagonised catecholamine-induced lipolysis in primary brown fat adipocytes from Akt2-deficient mice. CONCLUSIONS/INTERPRETATION: These data suggest that suppression of lipolysis by insulin in hyperinsulinaemic states can take place in the absence of Akt2. PMID- 25740695 TI - Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes. AB - AIMS/HYPOTHESIS: We selected the most informative protein biomarkers for the prediction of incident cardiovascular disease (CVD) in people with type 2 diabetes. METHODS: In this nested case-control study we measured 42 candidate CVD biomarkers in 1,123 incident CVD cases and 1,187 controls with type 2 diabetes selected from five European centres. Combinations of biomarkers were selected using cross-validated logistic regression models. Model prediction was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Sixteen biomarkers showed univariate associations with incident CVD. The most predictive subset selected by forward selection methods contained six biomarkers: N-terminal pro-B-type natriuretic peptide (OR 1.69 per 1 SD, 95% CI 1.47, 1.95), high-sensitivity troponin T (OR 1.29, 95% CI 1.11, 1.51), IL-6 (OR 1.13, 95% CI 1.02, 1.25), IL-15 (OR 1.15, 95% CI 1.01, 1.31), apolipoprotein C III (OR 0.79, 95% CI 0.70, 0.88) and soluble receptor for AGE (OR 0.84, 95% CI 0.76, 0.94). The prediction of CVD beyond clinical covariates improved from an AUROC of 0.66 to 0.72 (AUROC for Framingham Risk Score covariates 0.59). In addition to the biomarkers, the most important clinical covariates for improving prediction beyond the Framingham covariates were estimated GFR, insulin therapy and HbA1c. CONCLUSIONS/INTERPRETATION: We identified six protein biomarkers that in combination with clinical covariates improved the prediction of our model beyond the Framingham Score covariates. Biomarkers can contribute to improved prediction of CVD in diabetes but clinical data including measures of renal function and diabetes-specific factors not included in the Framingham Risk Score are also needed. PMID- 25740696 TI - Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans. AB - AIMS/HYPOTHESIS: This study aimed to perform a comprehensive analysis of interlobular, intralobular and parenchymal pancreatic fat in order to assess their respective effects on beta cell function. METHODS: Fifty-six participants (normal glucose tolerance [NGT] (n = 28), impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (n = 14) and patients with type 2 diabetes (n = 14)) underwent a frequent-sampling OGTT and non-invasive magnetic resonance imaging (MRI; whole-body and pancreatic) and proton magnetic resonance spectroscopy ((1)H-MRS; liver and pancreatic fat). Total pancreatic fat was assessed by a standard 2 cm(3) (1)H-MRS method, intralobular fat by 1 cm(3) (1)H MRS that avoided interlobular fat within modified DIXON (mDIXON) water images, and parenchymal fat by a validated mDIXON-MRI fat-fraction method. RESULTS: Comparison of (1)H-MRS techniques revealed an inhomogeneous distribution of interlobular and intralobular adipose tissue, which increased with decreasing glucose tolerance. mDIXON-MRI measurements provided evidence against uniform steatosis, revealing regions of parenchymal tissue void of lipid accumulation in all participants. Total (r = 0.385, p < 0.01) and intralobular pancreas adipose tissue infiltration (r = 0.310, p < 0.05) positively associated with age, but not with fasting or 2 h glucose levels, BMI or visceral fat content (all p > 0.5). Furthermore, no associations were found between total and intralobular pancreatic adipose tissue infiltration and insulin secretion or beta cell function within NGT, IFG/IGT or patients with type 2 diabetes (all p > 0.2). CONCLUSIONS/INTERPRETATION: The pancreas does not appear to be another target organ for abnormal endocrine function because of ectopic parenchymal fat storage. No relationship was found between pancreatic adipose tissue infiltration and beta cell function, regardless of glucose tolerance status. PMID- 25740697 TI - Genetic variants in noncoding PIWI-interacting RNA and colorectal cancer risk. AB - BACKGROUND: PIWI-interacting RNAs (piRNAs), which are a novel type of identified small noncoding RNA (ncRNA), play a crucial role in germline development and carcinogenesis. METHODS: By systematically screening all known piRNAs, the authors identified 7 common single nucleotide polymorphisms (SNPs) in 9 piRNAs. Associations between these selected SNPs and the risk of colorectal cancer (CRC) were detected in a case-control study. A quantitative real-time polymerase chain reaction assay was used to evaluate messenger RNA (mRNA) expression levels of piR 015551 and of the long ncRNA (lncRNA) LNC00964-3 in 88 pairs of tissue samples. RESULTS: The assay revealed that reference SNP rs11776042 in piR-015551 was significantly associated with a decreased risk of CRC in an additive model (P = .020). However, this protective effect was not significant after correction for multiple comparisons (test for the false discovery rate; P = .140). Furthermore, the authors observed that mRNA expression levels of LNC00964-3 (an lncRNA that included the piR-015551 sequence but not piR-015551) were significantly lower in CRC tissues than in corresponding normal tissues (P = 1.5 * 10(-5) for LNC00964 3; P = .899 for piR-015551). Correlation analysis revealed that piR-015551 expression was positively correlated with expression levels of LNC00964-3 (CRC tissues: r = 0.574, P = 5.13 * 10(-9) ; normal tissues: r = 0.601, P = 5.76 * 10( 10)). Moreover, rs11776042 was not significantly correlated with mRNA expression levels of piR-015551 or LNC00964-3 (all P > .05). CONCLUSIONS: The current findings reveal the possibility that piR-015551 may be generated from LNC00964-3, which may be involved in the development of CRC. PMID- 25740698 TI - Making animals alcoholic: shifting laboratory models of addiction. AB - The use of animals as experimental organisms has been critical to the development of addiction research from the nineteenth century. They have been used as a means of generating reliable data regarding the processes of addiction that was not available from the study of human subjects. Their use, however, has been far from straightforward. Through focusing on the study of alcoholism, where the nonhuman animal proved a most reluctant collaborator, this paper will analyze the ways in which scientists attempted to deal with its determined sobriety and account for their consistent failure to replicate the volitional consumption of ethanol to the point of physical dependency. In doing so, we will see how the animal model not only served as a means of interrogating a complex pathology, but also came to embody competing definitions of alcoholism as a disease process, and alternative visions for the very structure and purpose of a research field. PMID- 25740699 TI - MR neurography in traumatic brachial plexopathy. AB - OBJECTIVES: Imaging of the brachial plexus has come a long way and has progressed from plain radiography to CT and CT myelography to MRI. Evolution of MR imaging sequences has enabled good visualization of the small components of the plexus. The purpose of our study was to correlate the results of MR neurography (MRN) in patients with traumatic brachial plexopathy with their operative findings. We wanted to determine the usefulness of MRN and how it influenced surgical planning and outcome. METHODS: Twenty patients with features of traumatic brachial plexopathy who were referred to the MRI section of the Department of Radiology between September 2012 and January 2014 and subsequently underwent exploration were included in the study. MR neurography and operative findings were recorded at three levels of the brachial plexus-roots, trunks and cords. RESULTS: Findings at the level of roots and trunks were noted in 14 patients each and at the level of the cords in 16 patients. 10 patients had involvement at all levels. Axillary nerve involvement as a solitary finding was noted in two patients. These patients were subsequently operated and their studies were assigned a score based on the feedback from the operating surgeons. The MRN study was scored as three (good), two (average) or one (poor) depending on whether the MR findings correlated with operative findings at all three levels, any two levels or at any one level, respectively. CONCLUSIONS: MR neurography is an extremely useful modality to image the traumatized brachial plexus. It influences both surgical planning and outcome/prognosis. PMID- 25740700 TI - Whole-body CT with high heat-capacity X-ray tube and automated tube current modulation--effect of tube current limitation on contrast enhancement, image quality and radiation dose. AB - PURPOSE: To evaluate the effect of tube current limitation on contrast enhancement, image quality, and radiation dose in whole-body 64-detector CT with a high heat-capacity X-ray tube and automated tube current modulation. MATERIALS AND METHODS: One hundred eighteen patients were randomized into three whole-body CT protocols: tube current limitation at 210 mA, 450 mA, and no limitation. Signal-to-noise ratio (SNR), dose-length product (DLP), estimated effective dose (ED), and image quality were assessed. RESULTS: Mean SNR of aorta was comparable among protocols, but that of liver was somewhat lower in 210-mA than in 450-mA and no-limitation protocols (p<0.05). Mean DLP with 210-mA (533.8 mGy cm) was reduced by 31% from that with 450-mA (768.4 mGy cm) and by 38% from that with no limitation protocol (861.3 mGy cm), respectively. Image quality was slightly degraded (p<0.017) with 210 mA relative to the others in thorax and pelvis, but no difference was found in diagnostic acceptability. CONCLUSION: For whole-body CT using multidetector CT mounted with a high heat-capacity X-ray tube, an appropriate tube current limitation setting may help reduce excessive radiation dose without significant compromise in diagnostic acceptability. PMID- 25740701 TI - Computer-aided detection of artificial pulmonary nodules using an ex vivo lung phantom: influence of exposure parameters and iterative reconstruction. AB - OBJECTIVES: To evaluate the influence of exposure parameters and raw-data based iterative reconstruction (IR) on the performance of computer-aided detection (CAD) of pulmonary nodules on chest multidetector computed tomography (MDCT). MATERIAL AND METHODS: Seven porcine lung explants were inflated in a dedicated ex vivo phantom shell and prepared with n=162 artificial nodules of a clinically relevant volume and maximum diameter (46-1063 MUl, and 6.2-21.5 mm). n=118 nodules were solid and n=44 part-solid. MDCT was performed with different combinations of 120 and 80 kV with 120, 60, 30 and 12 mA*s, and reconstructed with both filtered back projection (FBP) and IR. Subsequently, 16 datasets per lung were subjected to dedicated CAD software. The rate of true positive, false negative and false positive CAD marks was measured for each reconstruction. RESULTS: The rate of true positive findings ranged between 88.9-91.4% for FBP and 88.3-90.1% for IR (n.s.) with most exposure settings, but was significantly lower with the combination of 80 kV and 12 mA*s (80.9% and 81.5%, respectively, p<0.05). False positive findings ranged between 2.3-8.1 annotations per lung. For nodule volumes <200 MUl the rate of true positives was significantly lower than for >300 MUl (p<0.05). Similarly, it was significantly lower for diameters <12 mm compared to >=12 mm (p<0.05). The rate of true positives for solid and part-solid nodules was similar. CONCLUSIONS: Nodule CAD on chest MDCT is robust over a wide range of exposure settings. Noise reduction by IR is not detrimental for CAD, and may be used to improve image quality in the setting of low-dose MDCT for lung cancer screening. PMID- 25740702 TI - Perioperative management of patients with pulmonary hypertension for non-cardiac surgery. AB - Pulmonary hypertension (PH) is associated with significant morbidity and mortality. While the advent of disease-modifying therapies in the treatment of PH has dramatically increased the life expectancy of these patients, they remain at high risk for perioperative complications. Outcome studies suggest that patients with PH undergoing non-cardiac surgery have higher morbidity and mortality than those without, independent of severity. Despite these risks, more and more of these patients are presenting for non-cardiac surgery. Patients with rheumatologic disorders in particular often have pulmonary arterial hypertension (PAH), a group that is associated with a poorer prognosis. Yet, these patients invariably develop debilitating joint diseases and not uncommonly present for elective surgery. Preoperatively, patients with PH should be appropriately risk stratified based on functional class, etiology, exercise capacity, pulmonary hemodynamics, and the risk of surgery. If the risks and benefits assessment proves favorable, they should undergo optimization prior to surgery, with any chronic therapy continuing without cessation through the perioperative period. A multidisciplinary approach involving all intraoperative physicians is imperative to forming a safe intraoperative plan based on the inherent physiology underlying the patient's disease. Finally, because complications in this patient population often occur postoperatively, patients should be monitored in an appropriate setting with a goal of preventing right ventricular dysfunction. In this review article, we focus on the evaluation, risk stratification, and optimization of patients with PH undergoing non-cardiac surgery. PMID- 25740704 TI - Hyperuricemia, gout, and cardiovascular disease: an update. AB - Across the globe, both gout and hyperuricemia have become increasingly common over the last few decades. The burden of gouty disease is made heavier by its association with several comorbid conditions, including hypertension, cardiovascular disease, and chronic kidney disease. Accruing evidence from prospective studies suggests that gout is an independent risk factor for developing cardiovascular disease and for higher cardiovascular mortality. While asymptomatic hyperuricemia does not seem to be an independent risk factor for cardiovascular disease, increasing data implicates hyperuricemia as a risk factor for developing incidental hypertension. Important questions that remain unanswered include whether addressing asymptomatic hyperuricemia forestalls the onset of hypertension, and whether treating gout with urate-lowering agents improves cardiovascular outcomes. This article reviews the most recent data regarding the relationship between hyperuricemia, gout, hypertension, and cardiovascular disease, as well as emerging evidence as to whether treatment of hyperuricemia and gout improves cardiovascular outcomes. PMID- 25740703 TI - The significance and management of thrombocytopenia in antiphospholipid syndrome. AB - The association between antiphospholipid antibodies (aPL) and clinical problems goes beyond what is stated in the antiphospholipid syndrome (APS) classification criteria, namely thrombosis and pregnancy morbidity, and thrombocytopenia is the most common non-criteria hematologic manifestation of aPL with a frequency ranging from 20 to 50 %. Thrombocytopenia is rarely severe, and hemorrhage is far less common than thrombosis. However, when anticoagulation is considered, it may constitute a clinical problem with increased bleeding risk. Furthermore, thrombocytopenia represents a risk factor for thrombosis in aPL-positive patients. Therefore, it is important to understand the pathogenesis and the clinical associations of thrombocytopenia to build the right medical approach in aPL-positive patients. In this paper, we review the literature on aPL/APS associated thrombocytopenia and briefly discuss the other conditions that can result in thrombocytopenia as they have commonalities with APS and their recognition is important to establish the most appropriate treatment strategy. PMID- 25740705 TI - New insights on biomarkers in systemic vasculitis. AB - The systemic vasculitis is a heterogeneous group of diseases characterized by the inflammation of blood vessels. The development of advanced diagnostic tests and genetic studies have resulted in greater improvement in our understanding of vasculitis pathogenesis and thus in the development of newer therapies. However, there is still an unmet need in the management of systemic vasculitis, focused on developing of new biomarkers that would enable distinction between active disease from damage or infection and predict treatment response and prognosis. PMID- 25740707 TI - Isolation and characterization of PDT-resistant cancer cells. AB - Even though the efficacy of photodynamic therapy (PDT) for treating premalignant and malignant lesions has been demonstrated, resistant tumor cells to this therapy occasionally appear. Here, we describe the published methods to isolate resistant cancer cells to PDT and propose new procedures that may be used, as laboratory models allow a better understanding of resistance mechanisms. For this purpose, the treatment conditions, the photosensitizer (PS) or pro-drug, the cell line and the final selection - clonal of total population - must be taken into account. In general, high and repeated treatment doses are used. The resistant cell population characterization may include cell morphology, response to PDT, expression of death proteins or survival related genes and cell proliferation analysis. In addition, in vivo models such as the resistant cell transplantation to mice, allow evaluating tumorigenicity and aggressiveness, leading to the determination of the in vivo resistance. Summarizing, in order to improve clinical results, cellular models can help understand PDT-resistance mechanisms in vivo and in vitro. PMID- 25740706 TI - FOXK2 transcription factor suppresses ERalpha-positive breast cancer cell growth through down-regulating the stability of ERalpha via mechanism involving BRCA1/BARD1. AB - Estrogen receptors (ERs) are critical regulators of breast cancer development. Identification of molecules that regulate the function of ERs may facilitate the development of more effective breast cancer treatment strategies. In this study, we showed that the forkhead transcription factor FOXK2 interacted with ERalpha, and inhibited ERalpha-regulated transcriptional activities by enhancing the ubiquitin-mediated degradation of ERalpha. This process involved the interaction between FOXK2 and BRCA1/BARD1, the E3 ubiquitin ligase of ERalpha. FOXK2 interacted with BARD1 and acted as a scaffold protein for BRCA1/BARD1 and ERalpha, leading to enhanced degradation of ERalpha, which eventually accounted for its decreased transcriptional activity. Consistent with these observations, overexpression of FOXK2 inhibited the transcriptional activity of ERalpha, decreased the transcription of ERalpha target genes, and suppressed the proliferation of ERalpha-positive breast cancer cells. In contract, knockdown of FOXK2 in MCF-7 cells promoted cell proliferation. However, when ERalpha was also knocked down, knockdown of FOXK2 had no effect on cell proliferation. These findings suggested that FOXK2 might act as a negative regulator of ERalpha, and its association with both ERalpha and BRCA1/BARD1 could lead to the down regulation of ERalpha transcriptional activity, effectively regulating the function of ERalpha. PMID- 25740708 TI - Partial oxidation as a rational approach to kinetic control in bioinspired magnetite synthesis. AB - Biological systems show impressive control over the shape, size and organization of mineral structures, which often leads to advanced physical properties that are tuned to the function of these materials. Such control is also found in magnetotactic bacteria, which produce-in aqueous medium and at room temperature magnetite nanoparticles with precisely controlled morphologies and sizes that are generally only accessible in synthetic systems with the use of organic solvents and/or the use of high-temperature methods. The synthesis of magnetite under biomimetic conditions, that is, in water and at room temperature and using polymeric additives as control agents, is of interest as a green production method for magnetic nanoparticles. Inspired by the process of magnetite biomineralization, a rational approach is taken by the use of a solid precursor for the synthesis of magnetite nanoparticles. The conversion of a ferrous hydroxide precursor, which we demonstrate with cryo-TEM and low-dose electron diffraction, is used to achieve control over the solution supersaturation such that crystal growth can be regulated through the interaction with poly (alpha,beta)-dl-aspartic acid, a soluble, negatively charged polymer. In this way, stable suspensions of nanocrystals are achieved that show remanence and coercivity at the size limit of superparamagnetism, and which are able to align their magnetic moments forming strings in solution as is demonstrated by cryo electron tomography. PMID- 25740709 TI - Metal organic framework-mediated synthesis of highly active and stable Fischer Tropsch catalysts. AB - Depletion of crude oil resources and environmental concerns have driven a worldwide research on alternative processes for the production of commodity chemicals. Fischer-Tropsch synthesis is a process for flexible production of key chemicals from synthesis gas originating from non-petroleum-based sources. Although the use of iron-based catalysts would be preferred over the widely used cobalt, manufacturing methods that prevent their fast deactivation because of sintering, carbon deposition and phase changes have proven challenging. Here we present a strategy to produce highly dispersed iron carbides embedded in a matrix of porous carbon. Very high iron loadings (>40 wt %) are achieved while maintaining an optimal dispersion of the active iron carbide phase when a metal organic framework is used as catalyst precursor. The unique iron spatial confinement and the absence of large iron particles in the obtained solids minimize catalyst deactivation, resulting in high active and stable operation. PMID- 25740710 TI - A chromogenic molecular capsule attributable to dipolar amide resonance structure. AB - A new chromogenic, self-assembled molecular capsule G@22 is developed by introducing four (N,N-dimethyl-4-aminophenyl) azobenzyl moieties on the upper rim of a resorcin[4]arene-based amidoimino-cavitand. The tuning of conjugation between amido and (N,N-dimethyl-4-aminophenyl)azobenzyl groups by acid-base titration allows naked-eye detection of molecular capsule formation. PMID- 25740711 TI - ERAP1 Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis. AB - OBJECTIVE: Several polymorphisms in ERAP1 are strongly associated with susceptibility to spondyloarthritis (SpA). The combination of rs17482078, rs10050860, and rs30187 results in the construction of 3 major haplotypes that are associated with SpA (the "protective" haplotype T/T/C, the "neutral" haplotype C/C/C, and the "susceptibility" haplotype C/C/T). The aim of the present study was to determine whether such haplotypes might affect endoplasmic reticulum aminopeptidase 1 (ERAP-1) messenger RNA (mRNA) expression, protein level, and/or enzymatic activity in antigen-presenting cells, a type of cell that is potentially relevant to disease pathogenesis. METHODS: Monocyte-derived dendritic cells (DCs) were generated in 2 cohorts (a discovery cohort and a replication cohort) comprising a total of 23 SpA patients and 44 healthy controls. Lymphoblastoid B cell lines were established from individuals who were homozygous for the risk, the neutral, or the protective ERAP1 haplotype, respectively. In those samples, we investigated the relationship between ERAP1 haplotypes and mRNA expression level. We also used Western blot analysis to measure the relative protein expression of ERAP-1 and a fluorogenic assay to measure its enzymatic activity. RESULTS: In monocyte-derived DCs, there was a strong association between ERAP1 haplotypes and the ERAP-1 mRNA expression level, with higher levels in subjects harboring the susceptibility haplotype (P = 0.001 and P = 5.6 * 10(-7) in the discovery and replication cohorts, respectively). In lymphoblastoid B cell lines, we observed a significant correlation between haplotype risk score and ERAP1 transcript or protein level (P = 0.003, rho = 0.92 for both). Enzymatic activity followed a similar trend both in monocyte-derived DCs and in lymphoblastoid B cell lines. CONCLUSION: These data provide strong evidence that SpA-associated ERAP1 polymorphisms affect the level of gene expression in antigen-presenting cells. How increased production/activity of ERAP 1 may influence susceptibility to SpA remains to be determined. PMID- 25740712 TI - 2H -> 1T phase transition and hydrogen evolution activity of MoS2, MoSe2, WS2 and WSe2 strongly depends on the MX2 composition. AB - We investigate herein the four most widely considered TMD materials: MoS2, MoSe2, WS2 and WSe2. A 2H -> 1T phase transition occurs during the chemical exfoliation with different efficiencies among the four materials. PMID- 25740713 TI - Regulatory Networks Acted Upon by the GID1-DELLA System After Perceiving Gibberellin. AB - Recent studies have revealed that DELLA proteins (DELLAs) interact with various kinds of transcription factors (TFs) and other kinds of proteins to regulate GA signaling. Here, we enumerate some of these DELLA interactors to show the multiple functions of DELLAs in the GA signaling pathway. Through interaction with TFs, DELLAs regulate the expression of many genes in an inhibitory or enhancing manner under various biological events including the crosstalk between GA and other phytohormones, and the development of organs and tissues. DELLA interacting TFs can be categorized into two types in terms of the effect of DELLA on their transacting activity. The first group includes those that are inhibited by DELLAs in terms of their DNA-binding activity, which includes the phytochrome interacting factor family of proteins involved in hypocotyl elongation, chlorophyll biosynthesis, fruit patterning, and cotyledon expansion; squamosa promoter binding-like proteins involved in floral transition; ethylene insensitive 3 and EIN3-like 1 proteins involved in GA-ethylene crosstalk; brassinazole-resistant 1 involved in GA-brassinosteroid crosstalk; and jasmonate ZIM domain and MYC2 proteins involved in GA-jasmonate crosstalk. The second group includes those TFs that affected in terms of their transcriptional activity but not DNA-binding activity upon interaction with DELLA, which includes the ABA insensitive 3 and ABI5 involved in GA-abscisic acid crosstalk, indeterminate domain involved in feedback regulation of GA signaling, and Botrytis-susceptible interactor proteins involved in DELLAs transrepression activity. We also mentioned that interaction of DELLAs with proteins besides TFs regulates the crosstalk between GA and strigolactone, and tubulin folding. The interaction of all of these various TFs and proteins with DELLAs strongly demonstrates that DELLA functions as a hub protein linking GA signaling to a myriad of biological events. PMID- 25740714 TI - Phosphorylation networks in the abscisic Acid signaling pathway. AB - Abscisic acid (ABA) is one of the major phytohormones and regulates various processes in the plant life cycle, for example, seed development and abiotic/biotic stress responses. Recent studies have made significant progress in elucidating ABA signaling and established a simple ABA signaling model consisting of three core components: PYR/PYL/RCAR receptors, 2C-type protein phosphatases, and SnRK2 protein kinases. This model highlights the importance of protein phosphorylation mediated by SnRK2, but the downstream substrates of SnRK2 remain to be determined to complete the model. Previous studies have identified several SnRK2 substrates involving transcription factors and ion channels. Recently, SnRK2 substrates have been further surveyed by a phosphoproteomic approach, giving new insights on the SnRK2 downstream pathway. Other protein kinases, e.g., Ca(2+)-dependent protein kinase (CDPK) and mitogen-activated protein kinase (MAPK), have been identified as ABA signaling factors. Some evidence suggests that the SnRK2 pathway partially interacts with CDPK or MAPK pathways. In this chapter, recent advances in ABA signaling study are summarized, primarily focusing on two major protein kinases, SnRK2 and MAPK. Challenges for further study of the ABA-dependent protein phosphorylation network are also discussed. PMID- 25740715 TI - Action of strigolactones in plants. AB - Strigolactones (SLs) have diverse roles that afford plants robust adaptive capacities to interact with diverse growth environments. Based on recent progress in the characterization of a class of SLs-insensitive shoot branching mutants, key components of the SL signal transduction pathway have been identified, and a framework of SL actions in plant development is emerging. The ubiquitin proteasome system-mediated target protein turnover is an integral component in SL signaling, as is the case with other plant hormone signaling pathways. Although the detailed ligand perception mechanism and the downstream events of SL signaling still remain illusive, it has been shown that SLs can act as communication molecules to coordinate internal developmental programs and regulate diverse plant responses to the external environments. Here, we review our current understanding of the molecular mechanism that underlies SL signaling, mainly focusing on the role of SLs in shoot branching and the comparison with other plant hormones in an effort to highlight the unique characteristics of SL signaling and action in plant growth and development. PMID- 25740716 TI - Peptide ligands in plants. AB - Plants have evolved small peptide ligands as intercellular signaling molecules. Previous studies have uncovered pairs of ligands and receptors in cell-cell communications. This review focuses on signaling and function of key plant peptide ligands. PMID- 25740717 TI - Florigen signaling. AB - Florigen is a systemic signal that promotes flowering. Its molecular nature is a conserved FLOWERING LOCUS T (FT) protein that belongs to the PEBP family. FT is expressed in the leaf phloem and transported to the shoot apical meristem where it initiates floral transition. In the cells of the meristem, FT binds 14-3-3 proteins and bZIP transcription factor FD to form the florigen activation complex, FAC, which activates floral meristem identity genes such as AP1. The FAC model provides molecular basis for multiple functions of FT beyond flowering through changes of its partners and transcriptional targets. The surface of FT protein includes several regions essential for transport and functions, suggesting the binding of additional components that support its function. FT expression is under photoperiodic control, involving a conserved GIGANTEA CONSTANS-FT regulatory module with species-specific modifications that contribute variations of flowering time in natural populations. PMID- 25740718 TI - Signaling Pathway that Controls Plant Cytokinesis. AB - Cytokinesis is the final process of cell division cycle that properly separates cytoplasmic components and duplicated nuclei into two daughter cells. Plant cytokinesis occurs in phragmoplast, the cytokinetic machinery composed mainly of microtubule (MT) arrays. Recent studies have revealed that a plant-specific mitogen-activated protein kinase (MAPK) cascade is involved in cytokinesis. The activity of this cascade is controlled by cytokinesis-specific kinesin called NACK in tobacco and Arabidopsis, which is required for the cell plate formation in the phragmoplast. Functions of NACK are strictly controlled by cyclin dependent kinase/cyclin B complexes so as to be activated at the correct timing for cytokinesis. Thus, this pathway constitutes a part of the regulatory system controlling the cell cycle progression. Here, we review recent advancements for understanding how the activation of this pathway can be specified in the late stage of the M phase and how this MAPK cascade can control cytokinesis through MT turnover. PMID- 25740720 TI - Multiple Roles of the Plasma Membrane H(+)-ATPase and Its Regulation. AB - The plasma membrane H(+)-ATPase is the pump that provides the driving force for transport of numerous solutes in plant cells, and plays an essential role for the growth and maintenance of cell homeostasis. Recent investigations using guard cells with respect to blue-light-induced stomatal opening uncovered the regulatory mechanisms of the H(+)-ATPase, and revealed that the phosphorylation status of penultimate threonine in the C-terminus of H(+)-ATPase is key step for the activity regulation. The same regulatory mechanisms for the H(+)-ATPase were evidenced in hypocotyl elongation in response to ABA and auxin, suggesting that the phosphorylation of the penultimate threonine is a common regulatory mechanism for the H(+)-ATPase. We also present the data that the activity of the H(+) ATPase limits the plant growth. Typical structure of the H(+)-ATPase in the C terminus was acquired in the transition of plants from water to the terrestrial land. PMID- 25740719 TI - Cryptochrome-mediated light responses in plants. AB - Cryptochromes (CRYs) are photolyase-like flavoproteins that have been found in all evolutionary lineages. Plant and animal CRYs are no longer DNA-repairing enzymes but they apparently gained other biochemical functions in evolution. Plant CRYs are UV-A/blue-light photoreceptors and play a pivotal role in plant growth and development, whereas animal CRYs act as either photoreceptors or transcription regulators. The first CRY gene was isolated from Arabidopsis thaliana, which regulates stem growth, flowering time, stomatal opening, circadian clock, and other light responses. CRYs are also found in all major crops investigated, with additional functions discovered, such as seed germination, leaf senescence, and stress responses. In this chapter, we will review some aspects of CRY-mediated light responses in plants. Readers are referred to other review articles for photochemistry and signal transduction mechanism of plant CRYs (Liu et al., 2010, 2011; Fankhauser and Ulm, 2011) [1-3]. PMID- 25740721 TI - Structure and Function of the ZTL/FKF1/LKP2 Group Proteins in Arabidopsis. AB - The ZTL/FKF1/LKP2 group proteins are LOV-domain-based blue-light photoreceptors that control protein degradation by ubiquitination. These proteins were identified relatively recently and are known to be involved in the regulation of the circadian clock and photoperiodic flowering in Arabidopsis. In this review, we focus on two topics. First, we summarize the molecular mechanisms by which ZTL and FKF1 regulate these biological phenomena based on genetic and biochemical analyses. Next, we discuss the chemical properties of the ZTL family LOV domains obtained from structural, biophysical, and photochemical characterizations of the LOV domains. These two different levels of approach unveiled the molecular mechanisms by which plants utilize ZTL and FKF1 proteins to monitor light for daily and seasonal adaptation. PMID- 25740722 TI - Preface. PMID- 25740723 TI - Soft Budget Constraints in Public Hospitals. AB - A soft budget constraint arises when a government is unable to commit to not 'bailout' a public hospital if the public hospital exhausts its budget before the end of the budget period. It is shown that if the political costs of a 'bailout' are relatively small, then the public hospital exhausts the welfare-maximising budget before the end of the budget period and a 'bailout' occurs. In anticipation, the government offers a budget to the public hospital that may be greater than or less than the welfare-maximising budget. In either case, the public hospital treats 'too many' elective patients before the 'bailout' and 'too few' after. The introduction of a private hospital reduces the size of any 'bailout' and increases welfare. PMID- 25740724 TI - Effect of dilution rate and methanol-glycerol mixed feeding on heterologous Rhizopus oryzae lipase production with Pichia pastoris Mut(+) phenotype in continuous culture. AB - The induction using substrate mixtures is an operational strategy for improving the productivity of heterologous protein production with Pichia pastoris. Glycerol as a cosubstrate allows for growth at a higher specific growth rate, but also has been reported to be repressor of the expression from the AOX1 promoter. Thus, further insights about the effects of glycerol are required for designing the induction stage with mixed substrates. The production of Rhizopus oryzae lipase (ROL) was used as a model system to investigate the application of methanol-glycerol feeding mixtures in fast metabolizing methanol phenotype. Cultures were performed in a simple chemostat system and the response surface methodology was used for the evaluation of both dilution rate and methanol glycerol feeding composition as experimental factors. Our results indicate that productivity and yield of ROL are strongly affected by dilution rate, with no interaction effect between the involved factors. Productivity showed the highest value around 0.04-0.06 h(-1) , while ROL yield decreased along the whole dilution rate range evaluated (0.03-0.1 h(-1) ). Compared to production level achieved with methanol-only feeding, the highest specific productivity was similar in mixed feeding (0.9 UA g-biomass(-1) h(-1) ), but volumetric productivity was 70% higher. Kinetic analysis showed that these results are explained by the effects of dilution rate on specific methanol uptake rate, instead of a repressor effect caused by glycerol feeding. It is concluded that despite the effect of dilution rate on ROL yield, mixed feeding strategy is a proper process option to be applied to P. pastoris Mut(+) phenotype for heterologous protein production. PMID- 25740725 TI - A surface plasmon enabled liquid-junction photovoltaic cell. AB - Plasmonic nanosystems have recently been shown to be capable of functioning as photovoltaics and of carrying out redox photochemistry, purportedly using the energetic electrons and holes created following plasmonic decay as charge carriers. Although such devices currently have low efficiency, they already manifest a number of favorable characteristics, such as their tunability over the entire solar spectrum and a remarkable resistance to photocorrosion. Here, we report a plasmonic photovoltaic using a 25 MUm thick electrolytic liquid junction which supports the iodide/triiodide (I-/I3-) redox couple. The device produces photocurrent densities in excess of 40 MUA cm(-2), an open circuit voltage (Voc) of ~0.24 V and a fill factor of ~0.5 using AM 1.5 G solar radiation at 100 mW cm( 2). The photocurrent and the power conversion efficiency are primarily limited by the low light absorption in the 2-D gold nanoparticle arrays. The use of a liquid junction greatly reduces dielectric breakdown in the oxide layers utilized, which must be very thin for optimal performance, leading to a great improvement in the long-term stability of the cell's performance. PMID- 25740726 TI - Treatment with granulocyte colony-stimulating factor in patients with repetitive implantation failures and/or recurrent spontaneous abortions. AB - Granulocyte colony-stimulating factor (G-CSF) belongs to the family of colony stimulating factors (CSF). As the name suggests, it was initially identified as being able to target and influence granulopoiesis, but was soon shown to be a ubiquitous growth factor, with synthesis and receptors, such as the related granulocyte macrophage colony-stimulating factor (GM-CSF), which is found in a wide variety of tissue types, including the organs and cell populations involved in reproduction. It must now be assumed that both G-CSF and GM-CSF control, or play a role in controlling, key processes in oocyte and sperm maturation, endometrial receptivity, implantation, and embryo and fetal development, possibly extending to birth. The following article offers an overview of the current findings with regard to animal experimental studies, initial clinical applications in reproductive medicine, and potential risks. PMID- 25740727 TI - Current dynamics of scholarly publishing. AB - BACKGROUND: Scholarly publishing is an essential vehicle for actively participating in the scientific debate and for sustaining the invisible colleges of the modern research environment, which extend far beyond the borders of individual research institutions. However, its current dynamics have deeply transformed the scientific life and conditioned in new ways the economics of academic knowledge production. They have also challenged the perceived common sense view of scientific research. METHOD: Analytical approach to set out a comprehensive framework on the current debate on scholarly publishing and to shed light on the peculiar organization and the working of this peculiar productive sector. RESULT: The way in which scientific knowledge is produced and transmitted has been dramatically affected by the series of recent major technosocietal transformations. Although the effects are many, in particular the current overlap and interplay between two distinct and somewhat opposite stances-scientific and economic-tend to blur the overall understanding of what scholarly publishing is and produces distortion on its working which in turn affect the scientific activities. The outcome is thus a series of intended and unintended effects on the production and dissemination of scientific knowledge. CONCLUSION: The article suggests that a substantial transformation characterizes science today that seems more like a thrusting, entrepreneurial business than a contemplative, disinterested endeavor. In this essay, we provide a general overview of the pivotal role of the scholarly publishing in fostering this change and its pros and cons connected to the idiosyncratic interplay between social norms and market stances. PMID- 25740728 TI - Clinical outcome of low-grade central osteosarcoma and role of CDK4 and MDM2 immunohistochemistry as a diagnostic adjunct. AB - INTRODUCTION: Low-grade osteosarcoma encompasses parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LCOS), with LCOS more rare than POS. LCOS is also more likely to be misdiagnosed and inappropriately treated with an intralesional procedure, due to its misleading radiological features and the overlap of its pathological characteristics with those of benign bone tumors. Therefore, as a diagnostic adjunct for LCOS, immunohistochemical assay with murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) have been tried with controversial results. We investigated (1) the clinical course and surgical outcome of LCOS, and (2) the diagnostic role of immune-histochemical markers (CDK4, MDM2) and their correlation with clinico-radiologic findings. MATERIALS AND METHODS: We retrospectively reviewed 16 LCOS patients with regard to age, gender, tumor location, plain radiographic pattern, tumor volume, extraosseous extension, initial diagnosis, initial treatment, definitive diagnosis, definitive treatment, surgical margins, histochemical markers, and oncological outcome. RESULTS: Final survival status was continuous disease-free in 14, alive with disease in 1, and remaining 1 patient died of other cancer. Except for 1 patient who had not undergone excision of their primary lesion, no patients developed a local recurrence. Eight tumors (50%) showed diffuse immunostaining for CDK4. Three of 8 tumors labeled for CDK4 were also positive for MDM2. Six (75%) of 8 CDK4-positive tumors displayed lytic lesions on a plain radiograph; in contrast, 2 (33%) of 6 tumors showing a sclerotic pattern on a plain radiograph were positive for CDK4. CONCLUSIONS: The diagnosis of LCOS is challenging; however, if it is properly diagnosed, there is a high chance of a cure with wide excision alone. Positive immunostaining for CDK4 or MDM2 may be used as a diagnostic adjunct, although negative immunostaining cannot rule out this tumor. The clinical, radiological, and typical pathological findings are vital in raising the suspicion of this rare tumor. PMID- 25740729 TI - Is the canal flare index a reliable means of estimation of canal shape? Measurement of proximal femoral geometry by use of 3D models of the femur. AB - BACKGROUND: The canal flare index (CFI; the ratio of the diameter of the femoral canal at the isthmus in the anteroposterior (A-P) view to the diameter of the medullary canal 20 mm above the lesser trochanter) is often used as a canal characteristic. Clinically, however, CFI measurements are sometimes untrustworthy because of femoral rotation and, especially, greater anteversion among Japanese patients. Our objectives were to analyze femoral geometry, by use of 3D CAD models, to evaluate the effects of rotational error, and to seek an index less affected by rotation. METHODS: Computed axial tomography (CAT) scan data from 60 femurs were used. By use of CAD software, 3D femoral models were created. The outside of the femur and the inside canal width 20 mm (P20) and 10 mm proximal (P10), and 10 mm (D10), 20 mm (D20), 30 mm (D30), and 40 mm (D40) distal from the center of the lesser trochanter, and at the isthmus were measured for different angles of femoral rotation. CFI, FFI (femoral flare index; the ratio of the extra cortical diameters at the same levels as for the CFI), and other canal ratios (P20/D10, P20/D20, P20/D30, and P20/D40) were then calculated and the effect of rotational errors was investigated. RESULTS: Mean CFI, FFI, P20/D10, P20/D20, P20/D30, and P20/D40 were 4.29, 2.08, 2.05, 2.49, 2.85, and 3.09 in the position without rotational error. CFI was not related to anteversion but had a negative correlation with isthmus canal width (only). In contrast FFI was almost constant at approximately 2.1 for different anteversion and age. With regard to the effect of rotational error, CFI changed by 1.31, FFI by 0.40, P20/D10 by 0.41, P20/D20 by 0.40, P20/D30 by 0.59, and P20/D40 by 0.80 for a variety of rotational angles. CONCLUSIONS: Outside femoral shape was little different for any person; as a result, FFI was almost constant. In contrast, CFI was revealed to be affected by canal width at the isthmus only. With regard to the effect of rotation, P20/D20 was much less affected by rotation than CFI; it could, therefore, be an appropriate index for expressing proximal canal shape. PMID- 25740731 TI - Electrocatalysis of lithium polysulfides: current collectors as electrodes in Li/S battery configuration. AB - Lithium Sulfur (Li/S) chemistries are amongst the most promising next-generation battery technologies due to their high theoretical energy density. However, the detrimental effects of their intermediate byproducts, polysulfides (PS), have to be resolved to realize these theoretical performance limits. Confined approaches on using porous carbons to entrap PS have yielded limited success. In this study, we deviate from the prevalent approach by introducing catalysis concept in Li/S battery configuration. Engineered current collectors were found to be catalytically active towards PS, thereby eliminating the need for carbon matrix and their processing obligatory binders, additives and solvents. We reveal substantial enhancement in electrochemical performance and corroborate our findings using a detailed experimental parametric study involving variation of several kinetic parameters such as surface area, temperature, current rate and concentration of PS. The resultant novel battery configuration delivered a discharge capacity of 700 mAh g(-1) with the two dimensional (2D) planar Ni current collectors and an enhancement in the capacity up to 900 mAh g(-1) has been realized using the engineered three dimensional (3D) current collectors. The battery capacity has been tested for stability over 100 cycles of charge discharge. PMID- 25740732 TI - The relationship between response inhibition and posttraumatic stress symptom clusters in adolescent earthquake survivors: an event-related potential study. AB - Posttraumatic stress disorder (PTSD) patients experience impaired response inhibition. Little is known about the relationship between response inhibition abnormalities and distinct PTSD symptom clusters. This study investigated the relationship between response inhibition processing and a five-factor model of posttraumatic stress symptomatology in adolescents. The event-related potentials of 54 unmedicated adolescent earthquake survivors (age 15-18 years) were recorded as they completed a Go/NoGo task. The PTSD Checklist-Specific Stressor Version (PCL-S) was used to assess PTSD symptoms. Regression analyses were conducted to examine the associations between the five symptom-cluster model and response inhibition processing. The results revealed that the avoidance symptom cluster score, but not the numbing or other clusters' scores, was positively associated with NoGo-P3 latency. These results suggest that a specific PTSD symptom cluster- avoidance--has a distinct association with the slowed speed of the late step of response inhibition processing, i.e., decision or success of response inhibition in adolescent earthquake survivors. PMID- 25740735 TI - Environment-sensitive fluorescent probe: a benzophosphole oxide with an electron donating substituent. AB - Electron-donating aryl groups were attached to electron-accepting benzophosphole skeletons. Among several derivatives thus prepared, one benzophosphole oxide was particularly interesting, as it retained high fluorescence quantum yields even in polar and protic solvents. This phosphole-based compound exhibited a drastic color change of its fluorescence spectrum as a function of the solvent polarity, while the absorption spectra remained virtually unchanged. Capitalizing on these features, this phosphole-based compound was used to stain adipocytes, in which the polarity of subcellular compartments could then be discriminated on the basis of the color change of the fluorescence emission. PMID- 25740736 TI - Public Health & Nutrition in the Asia-Pacific: reflections on a quarter century. AB - Some reflections from work in the Asia Pacific Region, mostly with WHO, in the past 25 years, and the changes in nutrition seen in this time are shared. In 1988 89 I helped to start a Centre for Child Nutrition in Chengdu, Sichuan, through the Italian Development Cooperation. The nutritional problems in urban and rural China, 25 years ago, were similar to those elsewhere in the Region. Like China, these countries underwent rapid economic development and changes in health patterns, within two decades. The main problems for child nutrition had to do with infant feeding practices and less breastfeeding: anaemia, protein energy malnutrition and rickets were frequent. How did China and other countries tackle these and other nutrition problems? In the 1990s the global nutrition community started working on a problem-solving framework. In 1992, at the 1st FAO/WHO International Conference on Nutrition, 159 countries agreed to develop national nutrition plans. In 2014, 22 years later, FAO and WHO invited countries to review their national nutrition situation and plans. The epidemiological picture today is profoundly different. Many Asia-Pacific countries have achieved remarkable progress in socio-economic development, including malnutrition reduction. To reach the MDGs and the post-MDG goals being formulated, the remaining under nutrition problems need to be alleviated, inequalities between sectors of society reduced, and also the growing threat of overweight/obesity and NCDs prevented and controlled. Assessing, monitoring and evaluating programmes to improve progress, now requires focusing not only on biological outcomes, but also on food security, programme process, and the policy environment. PMID- 25740737 TI - Omega-3 polyunsaturated fatty acids and non-communicable diseases: meta-analysis based systematic review. AB - The aim of this updated systematic review is to summarize the evidence of the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on non-communicable diseases (NCDs). Publications of meta-analysis up to August 2014 were systematically searched from PubMed, the Cochrane and EMBASE databases. N-3 PUFAs have the following beneficial effects; cardio-protective effects, reduce ischemic stroke risk in both men and women and total stroke risk in women, increase insulin sensitivity in Asians, decrease risk of breast cancer and colorectal cancer in men. However, n-3 PUFAs may have unfavourable effects on type 2 diabetes in Caucasians. In conclusion, n-3 PUFA plays a crucial role in the prevention of NCDs, however, unfavourable effects should be considered in subjects with certain clinical conditions. Cross-cultural studies on the effect of n-3 PUFA on type 2 diabetes are needed to verify why diabetic patients with different ancestries have a different response to n-3 PUFA. PMID- 25740738 TI - Feeding practices among Indonesian children above six months of age: a literature review on their magnitude and quality (part 1). AB - BACKGROUND: In Indonesia, 37% of children under-five are stunted, 12% wasted and 12% overweight. Adequate feeding practices among children above 6 months of age are critical to tackle malnutrition. National surveys have been conducted to assess feeding practices but these aggregates hide geographic disparities. While several studies have been conducted in specific country locations to address this gap, no attempt has been made to reconcile available information. This paper aims to provide a comprehensive review of the literature on feeding practices among Indonesian children above six months of age. METHODS: A literature search was conducted in several databases using combinations of different search terms: feeding, child, Indonesia, MPASI/complementary feeding, gizi/nutrition, factor, determinant, praktek/practices. All documents were reviewed using a three-step procedure to assess content appropriateness and research quality. Available information was analyzed using current recommendations on feeding practices. RESULTS: Dietary diversity, consumption of iron-rich foods, active feeding and hygiene practices were among the non-optimal feeding practices. Consequently dietary intakes are not fulfilled for several micronutrients. Some feeding practices are worst in younger children. Differences between data from national and site-specific surveys are noted. Overall quality of the surveys needs to be strengthened. CONCLUSIONS: Generally, child feeding practices are not optimal. Indicators used to assess components of child feeding vary and make inter-survey comparisons challenging. The results also stress the need to investigate the underlying factors to optimal child feeding practices. The results may be used for advocacy of additional resource allocation for effective child feeding promotion programs. PMID- 25740739 TI - Feeding practices among Indonesian children above six months of age: a literature review on their potential determinants (part 2). AB - BACKGROUND: Feeding practices among young children are not optimal in Indonesia. Improving these practices is crucial to prevent and reduce malnutrition among young children. A better understanding of the underlying factors to appropriate practices is essential to address barriers and identify opportunities to optimal practices. This paper aims to shed light on potential determinants of feeding practices among children above 6 months of age. METHODS: A systematic research of several databases using combinations of different search terms: feeding, child, Indonesia, MPASI/complementary food, gizi/nutrition, factor, determinant, praktek/practices was conducted. All documents were reviewed using a three-step procedure to assess content appropriateness and research quality. Data were analyzed using the Hector's framework on behaviour change. RESULTS: Available data on individual factors influencing feeding practices related mainly to mother's attributes, namely knowledge, perceptions, attitudes, beliefs and skills. Some of them are positively linked to good practices. Some environmental related factors such as health services, home and peer environment were conducive to improved practices. Studies on societal factors were mostly restricted to food systems which do not favour optimal feeding practices. CONCLUSIONS: The review provides insights on underlying factors conducive to optimal feeding practices. Yet, relevant and quality research is required to get a better understanding on factors related to the environment and society as well as on how they are related with each other and operate in different contexts. Indonesia has already experimented successful programs which can be used as a reference to strengthen young child feeding practices. PMID- 25740740 TI - Early enteral nutrition for upper digestive tract malformation in neonate. AB - BACKGROUND: Early enteral nutrition (EEN) is better than total parenteral nutrition (TPN) for many reasons. Our aim was to determine the safety and feasibility of EEN using a jejunum feeding tube in the duodenum or jejunum for congenital obstruction in neonates post-operatively. METHODS: This was a retrospective review of 120 patients who had duodenal and jejunal congenital obstructions in our hospital. The patients were categorized into two groups (EEN group [n=70 patients] and control group [n=50 patients]). Differences in operative time, postoperative time to tolerate oral feeding (40 mL/3 h), post operative hospital stay, and complications, such as catheter obstruction, diarrhea, and nutrition index, were reviewed. RESULTS: The operative time and time to first defecation post-operatively was not significantly different between the two groups. The time to tolerate oral feeding (40 mL/3 h) and the hospital length of stay post-operatively for the EEN group were significantly shorter than the control group. Total protein, pre-albumin, and retinol binding protein were significantly higher in the EEN group than the control group 14 days post operatively. The incidence of cholestasis and obstruction in the EEN group was significantly lower than the control group, and the incidence of diarrhea was lower than the control group, but not significantly lower. CONCLUSION: EEN using a jejunal feeding tube in an upper digestive tract malformation in newborns post operatively is safe, easy, and has fewer complications. PMID- 25740741 TI - Comparison of a three-in-one total nutrient mixture with conventional peripheral parenteral nutrition in children. AB - BACKGROUND: The aim of this study was to compare clinical aspects of the application of three-in-one total nutrient mixture (TNA) for peripheral parenteral nutrition (PPN) with those of the conventional PPN (cPPN) method of providing short-term parenteral nutrition for pediatric inpatients. METHODS: We conducted a retrospective study in children from 2 to 18 years old who were hospitalized and underwent PPN administration. We compared clinical aspects of two methods of PPN, cPPN (n=39) and TNA (n=57). RESULTS: The mean age was 6.5+/ 3.1 years in the cPPN group and 8.2+/-3.4years in the TNA group (p=0.015). In the TNA group, there was a significantly shorter period between the day of admission and the first day of PPN or oral feeding (p<0.0001 & p<0.0001, respectively).The TNA group also fasted for a shorter period before PN after admission, and the total duration of fasting was also shorter (p<0.0001 & p<0.0001, respectively). The TNA group showed a lower glucose infusion rate and fewer daily administered total calories per weight (p<0.0001 & p=0.001, respectively). However, there was no significant difference in the amount of administered amino acids and lipids (p=0.584 & p=0.650, respectively) and PPN-related complications. CONCLUSIONS: When providing nutrients to hospitalized children who cannot take in enough nutrients via the enteral route, TNA formula may be an easier and faster method than cPPN. PMID- 25740742 TI - Early jejunal feeding by bedside placement of a nasointestinal tube significantly improves nutritional status and reduces complications in critically ill patients versus enteral nutrition by a nasogastric tube. AB - BACKGROUND AND OBJECTIVE: Unguided nasojejunal feeding tube insertion success rates are low. Controversy persists about how to safely and efficiently perform enteral nutrition (EN) in critically ill patients. This study explores an innovative blind nasointestinal tube (NIT) insertion method and compares nasogastric and nasointestinal feeding. METHODS: Seventy critically ill patients admitted to the intensive care unit (ICU) were divided randomly into a nasogastric tube group (NGT; n=35) and an NIT group (NIT; n=35). After bedside NGT and blind-type NIT insertion, tube position was assessed and EN was started on day 1. Patients' nutritional status parameters, mechanical ventilation duration, average ICU stay, nutritional support costs, and feeding complications were compared. RESULTS: Pre-albumin and transferrin levels on days 7 and 14 were significantly higher in the NIT group than in the NGT group (p<0.01, p<0.05). Bloating, diarrhea, upper gastrointestinal bleeding, and liver damage did not differ significantly between groups (p>0.05). Interleukin-6 and tumor necrosis factor-alpha levels and APACHE II score were significantly lower in the NIT group than in the NGT group (p<0.01, p<0.05). Reflux and pneumonia incidences, mechanical ventilation duration, average ICU stay length, and nutritional support costs were significantly lower in the NIT group than in the NGT group (p<0.01). CONCLUSION: Blind bedside NIT insertion is convenient and its use can effectively improve nutritional status, reduce feeding complications, and decrease nutritional support costs of critically ill patients. PMID- 25740743 TI - Impacts of dietary fat changes on pregnant women with gestational diabetes mellitus: a randomized controlled study. AB - OBJECTIVE: This study aims to determine the impact of increasing polyunsaturated fatty acid intake on blood glucose, lipid metabolism, and pregnancy outcomes of pregnant women with gestational diabetes mellitus. METHODS: Under constant total energy and protein intake, 84 pregnant women with gestational diabetes mellitus were randomly divided into the experimental and control groups, which were given oil-rich and conventional low-oil meals, respectively. RESULTS: After the dietary intervention, the intake and energy supply of fat and the three fatty acids were significantly higher in the experimental group than the control group (p<0.001). The intake and energy supply of polyunsaturated fatty acids increased significantly post-intervention in the experimental group but did not change in the control group. In both the intervention and the control group, fasting blood glucose, 2 h postprandial plasma glucose, and the insulin resistance index decreased significantly post-intervention (p<0.05); the lipid changes were consistent between groups. Pregnancy outcomes did not differ significantly between the two groups (p>0.05). CONCLUSIONS: An appropriate increase in polyunsaturated fatty acid intake benefits pregnant women with gestational diabetes mellitus as well as fetuses, as long as the diet therapy follows basic recommendations and total energy intake is strictly controlled. PMID- 25740744 TI - BMI status influences the response of insulin sensitivity to diacylglycerol oil in Chinese type 2 diabetic patients. AB - Present study was a post-hoc analysis and aimed to examine the influence of adiposity status on the response of insulin sensitivity to diacylglycerol (DAG) oil in type 2 diabetic patients. A total of 127 type 2 diabetic patients were recruited into a randomized double-blind controlled parallel trial in Hangzhou, China. Subjects were allocated to consume the same amount (25 mL/d) of DAG (n=66) or triacylglycerol (TAG) oil (n=61) with similar fatty acid compositions for 120 days. Marginally significant interaction was observed between BMI status (overweight versus normal weight) and test oils for fasting insulin (p interaction=0.046) and Homeostasis Model Assessment of Insulin Resistance (HOMA IR) (p-interaction=0.059). For normal weight subjects (BMI<=25), DAG group showed significant decrease of fasting insulin (-2.0, 95% CI: -3.90, -0.10; p=0.036) and HOMA-IR (-0.69, 95% CI: -1.36, -0.03; p=0.015), but not in the TAG group. No significant change of either trait in DAG or TAG group was observed for overweight subjects (BMI>25). In summary, the effect of DAG oil on insulin sensitivity in type 2 diabetic patients is influenced by the baseline BMI status. Type 2 diabetic patients may benefit from DAG oil in terms of insulin sensitivity improvement, however only when they are in normal body weight range. PMID- 25740745 TI - Dietary modifications to improve micronutrient status of Indian children and adolescents with type 1 diabetes. AB - INTRODUCTION: Diet plays a crucial role for maintaining normal growth and development while optimizing glycemic control in children with diabetes. Dietary restrictions, in a diabetic child's diet may lead to micronutrient deficiencies. OBJECTIVES: To examine dietary nutritional deficiencies of Asian Indian children with Type 1 diabetes mellitus and develop micronutrient-rich recipes suitable for them. METHODS: Anthropometry, diet (3-day recall) of 70 children with diabetes (24 boys) was recorded. Daily nutrient intakes and nutrient content of recipes were estimated using CDIET version 2.0. RESULTS: Mean intake amongst children for energy was 79% of Indian Recommended Dietary Allowance (RDA), protein was 105% RDA, but fat intakes were high (143% RDA). Mean intakes of riboflavin, beta carotene, zinc, iron were less than 50%, and thiamin and calcium were around 60% RDA suggesting a possible multiple micronutrient deficiency. Based on popularly consumed snacks, 20 healthy recipes were devised that can be incorporated in children's diet. Mean energy content of new recipes was similar to routine snacks (281+/-28 kcal/100 g vs 306+/-27 kcal/100 g cooked weight). However, the mean vitamin and mineral content of new recipes was significantly higher (p<0.01). There was a five-fold increase in total mineral content (zinc, calcium and iron) and twofold increase in total vitamin content (beta carotene, vitamin C, vitamin B-1, B-2, and B-3) in new recipes compared with the routine snacks. CONCLUSION: Multiple dietary micronutrient deficiencies are observed in diabetic children. Addition of newly developed recipes in their everyday diet may help to enhance micronutrient intakes without increasing their energy load. PMID- 25740746 TI - Associations of decreased serum transthyretin with elevated high-sensitivity CRP, serum copper and decreased hemoglobin in ambulatory elderly women. AB - BACKGROUND: Transthyretin (TTR), a sensitive indicator of malnutrition and inflammation, has been shown to be associated with mortality in elderly population. METHODS: We examined relationships between serum TTR and a range of risk factors for mortality in 185 free-living elderly women. Blood was drawn between breakfast and lunch. RESULTS: TTR was correlated negatively with age (r= 0.30, p<0.001). After controlling for age, TTR was negatively associated with log high-sensitivity CRP (hsCRP) and serum copper. It was positively associated with albumin, serum iron and hemoglobin. In addition, TTR was positively correlated with systolic and diastolic blood pressure and postprandial triglyceride (TG). In multiple regression analysis for TTR as a dependent variable, hemoglobin (standardized beta, 0.244), serum copper (standardized beta, -0.134), postprandial TG (standardized beta, 0.223) and log hsCRP (standardized beta, 0.190) emerged as determinants of TTR independently of age, albumin, serum iron, systolic and diastolic blood pressure, and explained 22.8% of TTR variability. CONCLUSIONS: Subclinical low-grade inflammation, elevated serum copper and decreased hemoglobin were associated with decreased serum TTR in community-living elderly Japanese women and may represent important confounders of the relationship between low TTR and mortality in the elderly. The positive association of TTR with postprandial TG warrants further investigation. PMID- 25740748 TI - Intake of cruciferous vegetables is associated with reduced risk of ovarian cancer: a meta-analysis. AB - BACKGROUND: Epidemiological studies on the association between cruciferous vegetable (CV) consumption and the risk of ovarian cancer have demonstrated inconsistent results. We conducted a meta-analysis on CV consumption and ovarian cancer risk. METHODS: The relevant studies were identified by searching the Medline (Pubmed), Embase and Web of Science databases. The references of related articles and reviews up to October 2013 were also screened. The pooled relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest CV consumption levels were calculated using a random-effects model. The heterogeneity and publication bias were also evaluated. RESULTS: Eight studies (4 case-control studies and 4 cohort studies) were identified and included in this meta-analysis. When all studies were pooled together, there was a significantly inverse association between CV consumption and the risk of ovarian cancer (RR: 0.89; 95% CI: 0.81-0.99). No significant heterogeneity or publication bias was found. CONCLUSIONS: The findings from this study suggest that the consumption of CVs may reduce the risk of ovarian cancer. Further investigations are needed to confirm the clinical effect of CVs on ovarian cancer. PMID- 25740747 TI - Dairy consumption and risk of cardiovascular disease: an updated meta-analysis of prospective cohort studies. AB - BACKGROUND: Epidemiological studies to-date provided inconsistent findings on the effects of dairy consumption on the risk of cardiovascular disease (CVD). We aimed to examine the association of dairy consumption and its specific subtypes with CVD risk, including the risk of stroke and coronary heart disease (CHD) by a metaanalysis. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for articles published up to February 2014 to identify prospective cohort studies. Random-effects model or fix-effects model was used to compute the summary risk estimates. RESULTS: A total of 22 studies were eligible for analysis. An inverse association was found between dairy consumption and overall risk of CVD [9 studies; relative risk (RR)=0.88, 95% confidence interval (CI): 0.81, 0.96] and stroke (12 studies; RR=0.87, 95% CI: 0.77, 0.99). However, no association was established between dairy consumption and CHD risk (12 studies; RR=0.94, 95% CI: 0.82, 1.07). Stroke risk was significantly reduced by consumption of low-fat dairy (6 studies; RR=0.93, 95% CI: 0.88, 0.99) and cheese (4 studies; RR=0.91, 95% CI: 0.84, 0.98), and CHD risk was significantly lowered by cheese consumption (7 studies; RR=0.84, 95% CI: 0.71, 1.00). Restricting studies according to various inclusion criteria yielded similar results for CVD and CHD analyses, but showed attenuated results for stroke analysis. Heterogeneity across studies was found for stroke and CHD analyses, and publication bias was found for stroke analysis. CONCLUSION: This meta-analysis provided further evidence supporting the beneficial effect of dairy consumption on CVD. Low-fat dairy products and cheese may protect against stroke or CHD incidence. PMID- 25740749 TI - Change in weight status and academic performance among senior high school students in Taiwan. AB - INTRODUCTION: This study examines how the changes in weight status across the spectrum of a senior high school study are associated with academic performance measured by the university entrance exam scores. MATERIALS AND METHODS: A unique dataset which compiles a national health examination profile and the General Scholastic Ability Test data bank in Taiwan was constructed. The final sample comprised 149,240 senior high school students of which 70,662 were males and 78,578 were female students. The school-level fixed effect models were estimated. RESULTS: Students who were either (a) not overweight in the first year but overweight in the third year of senior high school, (b) overweight in both the first and third year, or (c) overweight in the first year but not overweight in the third year, were more likely to score lower on the university entrance exam, compared with their never-overweight counterparts. The findings differ by gender and test subjects. DISCUSSIONS: The change in weight status during senior high school period is associated with subsequent university entrance exam outcome. Students who start senior high school being overweight should be paid attention. School-based programs and practices need to be implemented to reduce the prevalence of overweight among students. PMID- 25740750 TI - Weight-related stigmatization and binge eating among overweight adults in Southern Taiwan. AB - OBJECTIVE: The purpose of this study was to investigate the association between the level of weight-related stigmatizing experiences and binge eating in overweight adults in southern Taiwan. METHODS: This study design was a cross sectional questionnaire survey with convenience sample. A total of 141 questionnaires were analyzed. RESULTS: The study showed that 97.9% participants had at least one weight-related stigmatizing experience in their lifetime. The main sources of weight-related stigmatizing experiences were from either parents, relatives or doctors. BMI and age were significantly correlated with weight related stigmatizing experiences. Furthermore, about 19.9% of participants experienced binge eating. The scores of the weight-related stigmatizing experiences and binge eating were positively correlated (r=0.33, p<0.01). The scores of the weight-related stigmatizing experiences and monthly income significantly explained factors of binge eating. CONCLUSIONS: The findings showed that there is a need to develop interventions to assist overweight people cope with weight-related stigmatization and prevent binge eating in the future. PMID- 25740751 TI - Circulating IGF-1 may mediate improvements in haemoglobin associated with vitamin A status during pregnancy in rural Nepalese women. AB - Pregnancy exacerbates vitamin A (VA) deficiency and anaemia among women in developing countries. Improving circulating haemoglobin (Hb) requires erythrocyte production and availability of iron. Insulin-like growth factor- 1 (IGF-1) functions in erythropoiesis, but its association with VA status and pregnancy associated anaemia has not been studied. The aim of this study was to examine the relationship between serum retinol, IGF-1, and Hb among pregnant women in extant samples collected during a placebo-controlled trial of VA and beta-carotene (BC) supplementation in rural Nepal conducted from 1994 to 1997. Mid-pregnancy serum IGF-1 was measured in serum from n=589 randomly selected women of n=1186 in whom anthropometric, VA (retinol) and iron (Hb, erythrocyte zinc protoporphyrin (ZP), and ferritin) status data were available. Associations of IGF-1 with retinol, Hb or anaemia, and iron status were determined using multiple linear and logistic regression. Path analysis was used to explore the role of IGF-1 as a mediator between retinol and Hb, accounting for iron status. A 2.6 g/L increase in IGF-1 was observed per 0.1 mol/L increment in retinol (p<0.0001). Hb increased with each quartile of IGF-1, and odds of anaemia declined 68.8% from the 1st to 4th quartile. Improved iron status indicators explained only 29.1% of the association between IGF-1 and Hb, while IGF-1 explained 25.6% of the association between retinol and Hb. Increasing IGF-1 was likely one mechanism by which retinol improved circulating Hb in pregnant women of rural Nepal, although IGF-1 worked primarily through pathways independent of improved iron status indicators, perhaps by stimulating erythrocyte production. PMID- 25740752 TI - Maternal serum lipid levels during late pregnancy and neonatal body size. AB - OBJECTIVE: The aim of this study was to determine the predictive value of maternal serum lipid levels during late pregnancy for neonatal body size. METHODS: This study was conducted from January 1, 2011 to July 31, 2012 at a Maternal and Child Health Hospital. Fasting blood glucose, serum triglyceride, total cholesterol, HDL and LDL were estimated in maternal collected before delivery. Detailed anthropometry of the neonates was performed. RESULTS: Women who delivered a large for gestational age baby were older, taller, had a higher pre-pregnancy weight, higher pre-pregnancy BMI, and higher weight gain during pregnancy than women who delivered an appropriate for gestational age infant. After adjusting for maternal age, pre-pregnancy BMI, weight gain during pregnancy, parity, neonatal sex and gestational age at delivery, we found that only maternal HDL level was inverse associated with birth weight, length and head circumference (p<0.05). On logistic regression analysis, the significant metabolic predictors of large for gestational age was HDL (OR 0.57, 95%CI: 0.38 0.84, per 1 mmol/L increase) after adjusting for the confounders. CONCLUSIONS: Maternal serum HDL level determined in maternal blood taken close to delivery was independently associated with neonatal size and was the independent predictor for large for gestational age. PMID- 25740753 TI - Micronutrient status and its relationship with nutritional status in preschool children in urban Sri Lanka. AB - OBJECTIVE: To assess the micronutrient status and its relationship with nutritional status in preschool children. METHODS: In a cross sectional study, anthropometric data and fasting blood samples were obtained from 340 children attending preschool in urban Sri Lanka. Serum concentrations of vitamin D, parathyroid hormone, vitamin A, zinc and haemoglobin were measured. Z-scores of anthropometric indices of height-for-age, weight-for-age and weight-for-height were computed to evaluate the nutritional status. RESULTS: Prevalence of stunting, underweight, wasting and anaemia among children were 7.1%, 16.9%, 21.2% and 7.4%, respectively. Deficiencies of zinc and vitamin A occurred among 67% and 38% of children, respectively. Vitamin D deficiency (<10 ng/mL) and insufficiency (10-20 ng/mL) occurred in 5.0% and 29.1% of children, respectively, and12% had parathyroid hormone levels indicative of hypocalcaemia. Nutritional status was significantly correlated (p<0.05) with vitamin D status [height-for-age (r=0.10), weight-for-age (r=-0.18), weight-for-height (r=-0.12)], and with haemoglobin status [weight-for-age (r=0.11)]. Zinc and vitamin A levels were lower in severe stunting compared with normal height (p<0.05). Significant correlations (p<0.05) were observed between vitamin D and parathyroid hormone (r=-0.12) and between haemoglobin and vitamin A (r=0.01), zinc (r=0.02) and vitamin D (r=0.02) levels. CONCLUSIONS: In the surveyed population, zinc deficiency was high and to a lesser degree vitamin A deficiency and vitamin D insufficiency prevailed. The nutritional status of the children was related to vitamin D status and with haemoglobin status. Zinc and vitamin A levels were low in children with severe stunting. Vitamins A, D and zinc levels were associated with haemoglobin status. PMID- 25740754 TI - Locally produced cereal/nut/legume-based biscuits versus peanut/milk-based spread for treatment of moderately to mildly wasted children in daily programmes on Nias Island, Indonesia: an issue of acceptance and compliance? AB - BACKGROUND: Treatment effects of fortified ready-to-use foods for moderately to mildly wasted children are largely unknown. METHODS: Two nutritionally comparable forms of locally produced ready-to-use foods for daily feeding programmes of moderately to mildly wasted children (weight-for-height Z-score/WHZ>=-3 to < 1.5SD) were assessed on Nias, Indonesia. The frequencies of reaching target WHZ>= 1.5SD, compliance to the ready-touse food programme, and weight gain until recovery or programme closure among children treated with peanut/ milk-based spreads (n=29) were compared among children receiving cereal/nut/legume-based biscuits (n=44) and a second group treated with cereal/nut/legume-based biscuits whose mothers received intensive nutrition education (n=38). RESULTS: Children in the cereal/nut/legume-based biscuits groups were younger (31 and 33 vs 39 months, p=0.004) and more likely to be moderately wasted (45 and 39 vs 21% with WHZ<-2, p=0.114) at admission, but had a higher rate in recovery (84 and 79 vs 62%, p=0.086) and showed more frequently a high compliance (>80%) to the ready-to-use (86 and 84 vs 45%, p<0.001) than those children in the peanut/milk-based spreads programme. Multivariable logistic regression revealed high compliance followed by weight gain and a lower degree of wasting at admission as independent and significant predictors of reaching target WHZ>=-1.5SD (all p<0.01). Weight gain was positively associated with the consumption of the biscuits (vs peanut//milk based spreads: r=0.188, p=0.051) and was highest in the cereal/nut/legume-based biscuits plus intensive education compared with the cereal/nut/legume-based biscuits and peanut/milk-based spreads groups. CONCLUSIONS: Locally produced ready-to-use foods as biscuits or spreads were similarly effective for rehabilitation of moderately to mildly wasted children. PMID- 25740755 TI - Factors associated with not using antenatal iron/folic acid supplements in Indonesia: the 2002/2003 and 2007 Indonesia Demographic and Health Survey. AB - BACKGROUND: This analysis examined factors associated with non-use of antenatal iron/folic acid supplements in Indonesia. METHODS: Data from the 2002/2003 and 2007 Indonesia Demographic and Health Surveys (IDHS) were used, providing survival information for 26,591 most recent deliveries over the five-year period prior to each survey. The main outcome variable was non-use of iron/folic acid supplements. Using logistic regression, we examined the role of external environment, predisposing, enabling, need factors, and previous utilization of other maternal care services in non-use of antenatal iron/folic acid supplements. RESULTS: Mothers from outer Java- Bali Region and rural areas (OR=1.73, 95% CI: 1.48-2.03) had increased odds for not using antenatal iron/folic acid supplements. The likelihood for not using the supplements increased with the reduction of household wealth index and parental education. The odds increased amongst mothers with low autonomy on her own health care (OR=1.24, 95% CI: 1.04 1.49), high birth-rank infants, mothers with low knowledge of obstetric complications and low exposure to mass media. Enabling factors associated with increased odds for non-use of iron/folic acid supplements included mothers reporting money to pay health services (OR=1.28, 95% CI: 1.13- 1.44) and distance to health services (OR=1.20, 95% CI: 1.02-1.40) were major problems. Our study demonstrated the importance of antenatal care as a distribution channel of the supplements. CONCLUSIONS: Increasing community awareness, coverage and access to health services along with strengthening counselling sessions during antenatal care and community participation in health programs are necessary to improve the uptake of iron/folic acid supplements, to increase infant survival in Indonesia. PMID- 25740756 TI - Trying to lose weight among non-overweight university students from 22 low, middle and emerging economy countries. AB - The aim of this study was to assess the prevalence of trying to lose weight among non-overweight in university students and its sociodemographic and behavioural factors from 22 low and middle income and emerging economy countries. In a cross sectional survey we took anthropometric measurements and used a self-administered questionnaire among 15997 undergraduate university students (mean age 20.8, Standard deviation=2.8, age range of 16-30 years) from 22 universities in 22 countries. Body mass index (BMI) was used for weight status. Results indicate that 27.1% non-overweight students were trying to lose weight, 34.6% among women and 16.5% among men. Among underweight or normal weight students, 19.0% perceived themselves to be overweight, 11.3% were dieting to lose weight, and 53.5% considered to lose weight of high importance. Multivariate logistic regression found that being female, coming from a low income country, the perception of being overweight, high importance of losing weight, dieting to lose weight, trying to eat fibre, and avoiding foods with fat and cholesterol were associated with trying to lose weight in non-overweight university students. The study found a high prevalence of weight control practices and several specific risk factors were identified that can be utilized in interventions to target unhealthy weight control measures. PMID- 25740757 TI - Effects of different parenteral nutrition infusions in a patient with short bowel syndrome. AB - In this case study, we demonstrate the effects of different lipid emulsions on liver function in a 52-year-old woman with short bowel syndrome who was totally dependent on parenteral nutrition. Over a 13-month period after small bowel resection and jejunostomy, we followed the patient's plasma triglycerides and liver enzyme levels as well as body weight and discomfort levels. During the first 3 months when parenteral nutrition including a lipid emulsion containing 50% soybean oil/50% medium-chain triglyerides was administered daily, the patient reported feeling unwell (experiencing dizziness and palpitations) and her triglycerides and liver enzyme levels rose to 366 mg/dL and 145 U/L (alanine aminotransferase [ALT]), respectively; these levels recovered when this emulsion was discontinued. For the following 9 months, an emulsion containing 80% olive oil and 20% soybean oil was administered, and the patient's triglycerides (182 mg/dL) did not increase to abnormal levels and liver enzyme levels were only mildly elevated (109 U/L). The patient felt well and her body weight increased from 51 kg to 55 kg during this period. These results suggest that parenteral nutrition with a reduced soybean oil content may better preserve liver function in patients with short bowel syndrome. PMID- 25740758 TI - Pathway and kinetics of cyhalothrin biodegradation by Bacillus thuringiensis strain ZS-19. AB - Cyhalothrin is a common environmental pollutant which poses increased risks to non-target organisms including human beings. This study reported for the first time a newly isolated strain, Bacillus thuringiensis ZS-19 completely degraded cyhalothrin in minimal medium within 72 h. The bacterium transformed cyhalothrin by cleavage of both the ester linkage and diaryl bond to yield six intermediate products. Moreover, a novel degradation pathway of cyhalothrin in strain ZS-19 was proposed on the basis of the identified metabolites. In addition to degradation of cyhalothrin, this strain was found to be capable of degrading 3 phenoxybenzoic acid, a common metabolite of pyrethroids. Furthermore, strain ZS 19 participated in efficient degradation of a wide range of pyrethroids including cyhalothrin, fenpropathrinn, deltamethrin, beta-cypermethrin, cyfluthrin and bifenthrin. Taken together, our results provide insights into the mechanism of cyhalothrin degradation and also highlight the promising potentials of B.thuringiensis ZS-19 in bioremediation of pyrethroid-contaminated environment. This is the first report of (i) degradation of cyhalothrin and other pyrethroids by B.thuringiensis, (ii) identification of 3-phenoxyphenyl acetonitrile and N-(2 isoproxy-phenyl)-4-phenoxy-benzamide as the metabolites in the degradation pathway of pyrethroids, and (iii) a pathway of degradation of cyhalothrin by cleavage of both the ester linkage and diaryl bond in a microorganism. PMID- 25740759 TI - Clinical outcomes of first-line antiretroviral therapy in Latin America: analysis from the LATINA retrospective cohort study. AB - Nearly 2 million people are infected with human immunodeficiency virus (HIV) in Latin America. However, information regarding population-scale outcomes from a regional perspective is scarce. We aimed to describe the baseline characteristics and therapeutic outcomes of newly-treated individuals with HIV infection in Latin America. A Retrospective cohort study was undertaken. The primary explanatory variable was combination antiretroviral therapy based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The main outcome was defined as the composite of all-cause mortality and the occurrence of an AIDS-defining clinical event or a serious non-AIDS-defining event during the first year of therapy. The secondary outcomes included the time to a change in treatment strategy. All analyses were performed according to the intention to treat principle. A total of 937 treatment-naive patients from four participating countries were included (228 patients with PI therapy and 709 with NNRTI-based treatment). At the time of treatment initiation, the patients had a mean age of 37 (SD: 10) years and a median CD4 + T-cell count of 133 cells/mm(3) (interquartile range: 47.5-216.0). Patients receiving PI-based regimens had a significantly lower CD4 + count, a higher AIDS prevalence at baseline and a shorter time from HIV diagnosis until the initiation of treatment. There was no difference in the hazard ratio for the primary outcome between groups. The only covariates associated with the latter were CD4 + cell count at baseline, study site and age. The estimated hazard ratio for the time to a change in treatment (NNRTI vs PI) was 0.61 (95% CI 0.47-0.80, p < 0.01). This study concluded that patients living with HIV in Latin America present with similar clinical outcomes regardless of the choice of initial therapy. Patients treated with PIs are more likely to require a treatment change during the first year of follow up. PMID- 25740760 TI - Facebook study: a little bit unethical but worth it? AB - Human research involving the use social media raises many of the same issues as medical research. The publication of a paper in June 2014 investigating "emotional contagion" received extensive publicity recently because of the methods used. The approach involved manipulating the "News Feeds" of Facebook users, but the participants were not informed of their involvement in the research and had no opportunity to consent or opt out. Some commentators have argued that although it would have been preferable to obtain informed consent, it was not strictly required because the research was unlikely to cause significant harm and was important. This paper argues that the research was unethical because (i) it should have been overseen by an independent ethics committee or review board and (ii) informed consent could and should have been obtained. Regardless of the importance of any research and irrespective of its likelihood to cause harm, the ethical principles that have evolved since the 1940s should be followed in all instances when experimental research is being carried out on human participants. PMID- 25740761 TI - Affective norms of 875 Spanish words for five discrete emotional categories and two emotional dimensions. AB - In the present study, we introduce affective norms for a new set of Spanish words, the Madrid Affective Database for Spanish (MADS), that were scored on two emotional dimensions (valence and arousal) and on five discrete emotional categories (happiness, anger, sadness, fear, and disgust), as well as on concreteness, by 660 Spanish native speakers. Measures of several objective psycholinguistic variables--grammatical class, word frequency, number of letters, and number of syllables--for the words are also included. We observed high split half reliabilities for every emotional variable and a strong quadratic relationship between valence and arousal. Additional analyses revealed several associations between the affective dimensions and discrete emotions, as well as with some psycholinguistic variables. This new corpus complements and extends prior databases in Spanish and allows for designing new experiments investigating the influence of affective content in language processing under both dimensional and discrete theoretical conceptions of emotion. These norms can be downloaded as supplemental materials for this article from www.dropbox.com/s/o6dpw3irk6utfhy/Hinojosa%20et%20al_Supplementary%20materials.xl x?dl=0 . PMID- 25740762 TI - Is the cognitive reflection test a measure of both reflection and intuition? AB - The Cognitive Reflection Test (CRT) is one of the most widely used tools to assess individual differences in intuitive-analytic cognitive styles. The CRT is of broad interest because each of its items reliably cues a highly available and superficially appropriate but incorrect response, conventionally deemed the "intuitive" response. To do well on the CRT, participants must reflect on and question the intuitive responses. The CRT score typically employed is the sum of correct responses, assumed to indicate greater "reflectiveness" (i.e., CRT Reflective scoring). Some recent researchers have, however, inverted the rationale of the CRT by summing the number of intuitive incorrect responses, creating a putative measure of intuitiveness (i.e., CRT-Intuitive). We address the feasibility and validity of this strategy by considering the problem of the structural dependency of these measures derived from the CRT and by assessing their respective associations with self-report measures of intuitive-analytic cognitive styles: the Faith in Intuition and Need for Cognition scales. Our results indicated that, to the extent that the dependency problem can be addressed, the CRT-Reflective but not the CRT-Intuitive measure predicts intuitive-analytic cognitive styles. These results provide evidence that the CRT is a valid measure of reflective but not of intuitive thinking. PMID- 25740763 TI - Infection with Bartonella henselae in a Danish family. AB - Bartonella species constitute emerging, vector-borne, intravascular pathogens that produce long-lasting bacteremia in reservoir-adapted (natural host or passive carrier of a microorganism) and opportunistic hosts. With the advent of more sensitive and specific diagnostic tests, there is evolving microbiological evidence supporting concurrent infection with one or more Bartonella spp. in more than one family member; however, the mode(s) of transmission to or among family members remains unclear. In this study, we provide molecular microbiological evidence of Bartonella henselae genotype San Antonio 2 (SA2) infection in four of six Danish family members, including a child who died of unknown causes at 14 months of age. PMID- 25740764 TI - Assessing the public health risk of Shiga toxin-producing Escherichia coli by use of a rapid diagnostic screening algorithm. AB - Shiga toxin-producing Escherichia coli (STEC) is an enteropathogen of public health concern because of its ability to cause serious illness and outbreaks. In this prospective study, a diagnostic screening algorithm to categorize STEC infections into risk groups was evaluated. The algorithm consists of prescreening stool specimens with real-time PCR (qPCR) for the presence of stx genes. The qPCR positive stool samples were cultured in enrichment broth and again screened for stx genes and additional virulence factors (escV, aggR, aat, bfpA) and O serogroups (O26, O103, O104, O111, O121, O145, O157). Also, PCR-guided culture was performed with sorbitol MacConkey agar (SMAC) and CHROMagar STEC medium. The presence of virulence factors and O serogroups was used for presumptive pathotype (PT) categorization in four PT groups. The potential risk for severe disease was categorized from high risk for PT group I to low risk for PT group III, whereas PT group IV consists of unconfirmed stx qPCR-positive samples. In total, 5,022 stool samples of patients with gastrointestinal symptoms were included. The qPCR detected stx genes in 1.8% of samples. Extensive screening for virulence factors and O serogroups was performed on 73 samples. After enrichment, the presence of stx genes was confirmed in 65 samples (89%). By culture on selective media, STEC was isolated in 36% (26/73 samples). Threshold cycle (CT) values for stx genes were significantly lower after enrichment compared to direct qPCR (P < 0.001). In total, 11 (15%), 19 (26%), 35 (48%), and 8 (11%) samples were categorized into PT groups I, II, III, and IV, respectively. Several virulence factors (stx2, stx2a, stx2f, toxB, eae, efa1, cif, espA, tccP, espP, nleA and/or nleB, tir cluster) were associated with PT groups I and II, while others (stx1, eaaA, mch cluster, ireA) were associated with PT group III. Furthermore, the number of virulence factors differed between PT groups (analysis of variance, P < 0.0001). In conclusion, a diagnostic algorithm enables fast discrimination of STEC infections associated with a high to moderate risk for severe disease (PT groups I and II) from less-virulent STEC (PT group III). PMID- 25740765 TI - Detection of enterovirus D68 in Canadian laboratories. AB - The recent emergence of a severe respiratory disease caused by enterovirus D68 prompted investigation into whether Canadian hospital and provincial laboratories can detect this virus using commercial and laboratory-developed assays. This study demonstrated analytical sensitivity differences between commercial and laboratory-developed assays for the detection of enterovirus D68. PMID- 25740766 TI - Impact of introduction of the BD Kiestra InoqulA on urine culture results in a hospital clinical microbiology laboratory. AB - This study compared results from plating urine specimens with the BD InoqulA instrument using a 10-MUl inoculum with results from cultures plated manually with a 1-MUl loop for comparable 2-month periods. The positivity rates, turnaround times for positive cultures, and BD Phoenix identification and antimicrobial susceptibility test results were comparable for both time periods. We experienced no problems with culture interpretation as the result of moving to the 10-MUl inoculum. PMID- 25740767 TI - Serologic cross-reactions between nucleocapsid proteins of human respiratory syncytial virus and human metapneumovirus. AB - Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) share virologic and epidemiologic features and cause clinically similar respiratory illness predominantly in young children. In a previous study of acute febrile respiratory illness in Bangladesh, we tested paired serum specimens from 852 children presenting fever and cough for diagnostic increases in titers of antibody to hRSV and hMPV by enzyme immunoassay (EIA). Unexpectedly, of 93 serum pairs that showed a >= 4-fold increase in titers of antibody to hRSV, 24 (25.8%) showed a concurrent increase in titers of antibody to hMPV; of 91 pairs showing an increase to hMPV, 13 (14.3%) showed a concurrent increase to hRSV. We speculated that common antigens shared by these viruses explain this finding. Since the nucleocapsid (N) proteins of these viruses show the greatest sequence homology, we tested hyperimmune antisera prepared for each virus against baculovirus-expressed recombinant N (recN) proteins for potential cross reactivity. The antisera were reciprocally reactive with both proteins. To localize common antigenic regions, we first expressed the carboxy domain of the hMPV N protein that was the most highly conserved region within the hRSV N protein. Although reciprocally reactive with antisera by Western blotting, this truncated protein did not react with hMPV IgG-positive human sera by EIA. Using 5 synthetic peptides that spanned the amino-terminal portion of the hMPV N protein, we identified a single peptide that was cross-reactive with human sera positive for either virus. Antiserum prepared for this peptide was reactive with recN proteins of both viruses, indicating that a common immunoreactive site exists in this region. PMID- 25740768 TI - Culture-independent genome sequencing of clinical samples reveals an unexpected heterogeneity of infections by Chlamydia pecorum. AB - Chlamydia pecorum is an important global pathogen of livestock, and it is also a significant threat to the long-term survival of Australia's koala populations. This study employed a culture-independent DNA capture approach to sequence C. pecorum genomes directly from clinical swab samples collected from koalas with chlamydial disease as well as from sheep with arthritis and conjunctivitis. Investigations into single-nucleotide polymorphisms within each of the swab samples revealed that a portion of the reads in each sample belonged to separate C. pecorum strains, suggesting that all of the clinical samples analyzed contained mixed populations of genetically distinct C. pecorum isolates. This observation was independent of the anatomical site sampled and the host species. Using the genomes of strains identified in each of these samples, whole-genome phylogenetic analysis revealed that a clade containing a bovine and a koala isolate is distinct from other clades comprised of livestock or koala C. pecorum strains. Providing additional evidence to support exposure of koalas to Australian livestock strains, two minor strains assembled from the koala swab samples clustered with livestock strains rather than koala strains. Culture independent probe-based genome capture and sequencing of clinical samples provides the strongest evidence yet to suggest that naturally occurring chlamydial infections are comprised of multiple genetically distinct strains. PMID- 25740769 TI - Isolation and characterization of porcine deltacoronavirus from pigs with diarrhea in the United States. AB - Porcine deltacoronavirus (PDCoV) is a novel coronavirus that causes diarrhea in nursing piglets. Following its first detection in the United States in February 2014, additional PDCoV strains have been identified in the United States and Canada. Currently, no treatments or vaccines for PDCoV are available. In this study, U.S. PDCoV strain OH-FD22 from intestinal contents of a diarrheic pig from Ohio was isolated in swine testicular (ST) and LLC porcine kidney (LLC-PK) cell cultures by using various medium additives. We also isolated PDCoV [OH-FD22(DC44) strain] in LLC-PK cells from intestinal contents of PDCoV OH-FD22 strain inoculated gnotobiotic (Gn) pigs. Cell culture isolation and propagation were optimized, and the isolates were serially propagated in cell culture for >20 passages. The full-length S and N genes were sequenced to study PDCoV genetic changes after passage in Gn pigs and cell culture (passage 11 [P11] and P20). Genetically, the S and N genes of the PDCoV isolates were relatively stable during the first 20 passages in cell culture, with only 5 nucleotide changes, each corresponding to an amino acid change. The S and N genes of our sequenced strains were genetically closely related to each other and to other U.S. PDCoV strains, with the highest sequence similarity to South Korean strain KNU14-04. This is the first report describing cell culture isolation, serial propagation, and biological and genetic characterization of cell-adapted PDCoV strains. The information presented in this study is important for the development of diagnostic reagents, assays, and potential vaccines against emergent PDCoV strains. PMID- 25740770 TI - Molecular identification of Mycobacterium avium subsp. silvaticum by duplex high resolution melt analysis and subspecies-specific real-time PCR. AB - Accurate identification of mycobacterial species and subspecies is essential to evaluate their significance and to perform epidemiological studies. The subspecies of Mycobacterium avium have different attributes but coincide in their zoonotic potential. Our knowledge about M. avium subsp. silvaticum is limited, since its identification is uncertain. Mycobacterium avium subsp. avium and M. avium subsp. silvaticum can be discriminated from each other based only on phenotypic characteristics, as they have almost identical genome sequences. Here we describe the development of a diagnostic method which enables the molecular identification of M. avium subsp. silvaticum and discrimination from M. avium subsp. avium based on genomic differences in a duplex high-resolution melt and M. avium subsp. silvaticum-specific mismatch real-time PCR. The developed assay was tested on reference strains and 199 field isolates, which were analyzed by phenotypic methods previously. This assay not only identified all 63 M. avium subsp. silvaticum and 138 M. avium subsp. avium strains correctly but also enabled the detection of mixed M. avium subsp. avium-M. avium subsp. silvaticum cultures. This is the first time that such a large panel of strains has been analyzed, and we also report the first isolation of M. avium subsp. silvaticum from red fox, red deer, wild boar, cattle, and badger. This assay is reliable, rapid, simple, inexpensive, and robust. It eliminates the long-existing problem of ambiguous phenotypic identification and opens up the possibility for detailed and comprehensive strain studies. PMID- 25740771 TI - Antimicrobial resistance and virulence characterization among Escherichia coli clinical isolates causing severe obstetric infections in pregnant women. AB - The virulence markers and the antimicrobial resistance profiles of 78 Escherichia coli isolates causing obstetric infections accompanied by sepsis or not were studied. Adhesion-related virulence factors were the most prevalent markers. Low rates of resistance to the antimicrobial agents used as first-line therapy suggest their correct implementation in stewardship guidelines. PMID- 25740772 TI - Matrix-assisted laser desorption ionization-time of flight and comparative genomic analysis of M-18 group a Streptococcus strains associated with an acute rheumatic fever outbreak in northeast Italy in 2012 and 2013. AB - Acute rheumatic fever (ARF) is a postsuppurative sequela caused by Streptococcus pyogenes infections affecting school-age children. We describe here the occurrence of an ARF outbreak that occurred in Bologna province, northeastern Italy, between November 2012 and May 2013. Molecular analysis revealed that ARF related group A Streptococcus (GAS) strains belonged to the M-18 serotype, including subtypes emm18.29 and emm18.32. All M-18 GAS strains shared the same antigenic profile, including SpeA, SpeB, SpeC, SpeL, SpeM, and SmeZ. Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) analysis revealed that M-18 GAS strains grouped separately from other serotypes, suggesting a different S. pyogenes lineage. Single nucleotide polymorphisms and phylogenetic analysis based on whole-genome sequencing showed that emm18.29 and emm18.32 GAS strains clustered in two distinct groups, highlighting genetic variations between these subtypes. Comparative analysis revealed a similar genome architecture between emm18.29 and emm18.32 strains that differed from noninvasive emm18.0 strains. The major sources of differences between M-18 genomes were attributable to the prophage elements. Prophage regions contained several virulence factors that could have contributed to the pathogenic potential of emm18.29 and emm18.32 strains. Notably, phage PhiSPBO.1 carried erythrogenic toxin A gene (speA1) in six ARF-related M-18 GAS strains but not in emm18.0 strains. In addition, a phage encoded hyaluronidase gene (hylP.2) presented different variants among M-18 GAS strains by showing internal deletions located in the alpha-helical and TSbetaH regions. In conclusion, our study yielded insights into the genome structure of M 18 GAS strains responsible for the ARF outbreak in Italy, thus expanding our knowledge of this serotype. PMID- 25740773 TI - Evaluation of the Bruker Biotyper matrix-assisted laser desorption ionization time of flight mass spectrometry system for identification of blood isolates of Vibrio species. AB - Among 56 blood isolates of Vibrio species identified by sequencing analysis of 16S rRNA and rpoB genes, the Bruker Biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system correctly identified all isolates of Vibrio vulnificus (n = 20), V. parahaemolyticus (n = 2), and V. fluvialis (n = 1) but none of the isolates of serogroup non-O1/O139 (non-serogroup O1, non-O139) V. cholerae (n = 33) to the species level. All of these serogroup non-O1/O139 V. cholerae isolates were correctly identified using the newly created MALDI-TOF MS database. PMID- 25740774 TI - Descending mediastinitis in Epstein-Barr virus infection. AB - Our case report describes a previously healthy 34-year-old male who develops a descending mediastinitis as a complication of an Epstein-Barr virus (EBV) infection. The mediastinitis was suspected to have developed by a breakthrough of a peritonsillar abscess through the space between the alar and prevertebral space. PMID- 25740775 TI - Improved diagnosis of orthopedic implant-associated infection by inoculation of sonication fluid into blood culture bottles. AB - Sonication improved the diagnosis of orthopedic implant-associated infections (OIAI). We investigated the diagnostic performance of sonication fluid inoculated into blood culture bottles in comparison with that of intraoperative tissue and sonication fluid cultures. Consecutive patients with removed orthopedic hardware were prospectively included and classified as having OIAI or aseptic failure (AF) according to standardized criteria. The diagnostic procedure included the collection of five intraoperative tissue cultures and sonication of the removed device, followed by conventional culture of the sonication fluid. Cultures were incubated for 7 days (aerobic) or 14 days (anaerobic). In addition, 10 ml of sonication fluid was inoculated into each aerobic and anaerobic BacT/Alert FAN blood culture bottle and incubated in the automated blood culture system for 5 days. Of 75 included patients, 39 had OIAI and 36 AF. The sensitivity of sonication fluid inoculated into blood culture bottles (100%) was higher than that of conventional sonication fluid (87%; P = 0.05) or intraoperative tissue cultures (59%; P < 0.01). Previous antibiotic therapy reduced the culture sensitivity of conventional sonication fluid to 77% and that of intraoperative tissue to 55%, while it remained 100% for blood culture-inoculated sonication fluid. The time to positivity was shorter in blood culture-inoculated sonication fluid, with detection of 72% of microorganisms after 1 day of incubation, than for intraoperative tissue and conventional sonication fluid cultures, with detection of 18% and 28% of microorganisms, respectively. In conclusion, compared to conventional sonication fluid and intraoperative tissue cultures, sonication fluid inoculated into blood culture bottles improved the diagnosis of OIAI and considerably reduced the time to culture positivity. PMID- 25740776 TI - Molecular and clinical characteristics of hospital and community onset methicillin-resistant Staphylococcus aureus strains associated with bloodstream infections. AB - Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are classified epidemiologically as health care-associated hospital onset (HAHO) , health care-associated community onset (HACO)-, or community-associated (CA) MRSA. Clinical and molecular differences between HAHO- and HACO-MRSA BSI are not well known. Thus, we evaluated clinical and molecular characteristics of MRSA BSI to determine if distinct features are associated with HAHO- or HACO-MRSA strains. Molecular genotyping and medical record reviews were conducted on 282 MRSA BSI isolates from January 2007 to December 2009. MRSA classifications were 38% HAHO-, 54% HACO-, and 8% CA-MRSA. Comparing patients with HAHO-MRSA to those with HACO MRSA, HAHO-MRSA patients had significantly higher rates of malignancy, surgery, recent invasive devices, and mortality and longer hospital stays. Patients with HACO-MRSA were more likely to have a history of renal failure, hemodialysis, residence in a long-term-care facility, long-term invasive devices, and higher rate of MRSA relapse. Distinct MRSA molecular strain differences also were seen between HAHO-MRSA (60% staphylococcal cassette chromosome mec type II [SCCmec II], 30% SCCmec III, and 9% SCCmec IV) and HACO-MRSA (47% SCCmec II, 35% SCCmec III, and 16% SCCmec IV) (P < 0.001). In summary, our study reveals significant clinical and molecular differences between patients with HAHO- and HACO-MRSA BSI. In order to decrease rates of MRSA infection, preventive efforts need to be directed toward patients in the community with health care-associated risk factors in addition to inpatient infection control. PMID- 25740777 TI - Laboratory evaluation of the Liat HIV Quant (IQuum) whole-blood and plasma HIV-1 viral load assays for point-of-care testing in South Africa. AB - Point-of-care (POC) HIV viral load (VL) testing offers the potential to reduce turnaround times for antiretroviral therapy monitoring, offer near-patient acute HIV diagnosis in adults, extend existing centralized VL services, screen women in labor, and prompt pediatrics to early treatment. The Liat HIV Quant plasma and whole-blood assays, prerelease version, were evaluated in South Africa. The precision, accuracy, linearity, and agreement of the Liat HIV Quant whole-blood and plasma assays were compared to those of reference technologies (Roche CAP CTMv2.0 and Abbott RealTime HIV-1) on an HIV verification plasma panel (n = 42) and HIV clinical specimens (n = 163). HIV Quant plasma assay showed good performance, with a 2.7% similarity coefficient of variation (CV) compared to the Abbott assay and a 1.8% similarity CV compared to the Roche test on the verification panel, and 100% specificity. HIV Quant plasma had substantial agreement (pc [concordance correlation] = 0.96) with Roche on clinical specimens and increased variability (pc = 0.73) in the range of <3.0 log copies/ml range with the HIV Quant whole-blood assay. HIV Quant plasma assay had good linearity (2.0 to 5.0 log copies/ml; R(2) = 0.99). Clinical sensitivity at a viral load of 1,000 copies/ml of the HIV Quant plasma and whole-blood assays compared to that of the Roche assay (n = 94) was 100% (confidence interval [CI], 95.3% to 100%). The specificity of HIV Quant plasma was 88.2% (CI, 63.6% to 98.5%), and that for whole blood was 41.2% (CI, 18.4% to 67.1%). No virological failure (downward misclassification) was missed. Liat HIV Quant plasma assay can be interchanged with existing VL technology in South Africa. Liat HIV Quant whole-blood assay would be advantageous for POC early infant diagnosis at birth and adult adherence monitoring and needs to be evaluated further in this clinical context. LIAT cartridges currently require cold storage, but the technology is user-friendly and robust. Clinical cost and implementation modeling is required. PMID- 25740780 TI - Comparison of Abbott RealTime HCV Genotype II with Versant line probe assay 2.0 for hepatitis C virus genotyping. AB - Genotyping and subtyping of 225 samples with hepatitis C virus (HCV) genotype 1, 2, 3, or 6 infection were done with Versant LiPA 2.0 and Abbott RealTime HCV Genotype (GT) II by using direct sequencing of the NS5B and 5' untranslated regions as the reference standards. The concordance rates were >99.2% for genotypes and 96.1% for subtypes 1a and 1b. Both the Abbott RealTime and Versant LiPA assays can accurately determine hepatitis C virus genotypes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00979979.). PMID- 25740778 TI - High-level association of bovine digital dermatitis Treponema spp. with contagious ovine digital dermatitis lesions and presence of Fusobacterium necrophorum and Dichelobacter nodosus. AB - Contagious ovine digital dermatitis (CODD) is an important foot disease in sheep, with significant animal welfare and economic implications. It is thought that CODD emerged from bovine digital dermatitis (BDD) via treponemal bacteria. With wildlife species such as elk now suffering a CODD-like disease, it is imperative to clarify these disease etiologies. A large investigation into treponemal association with CODD is warranted. CODD lesions (n = 58) and healthy sheep foot tissues (n = 56) were analyzed by PCR for the three BDD-associated Treponema phylogroups and two other lameness-associated bacteria, Dichelobacter nodosus and Fusobacterium necrophorum. Spirochete culture was also attempted on CODD lesions. "Treponema medium/Treponema vincentii-like," "Treponema phagedenis-like," and Treponema pedis spirochetes were identified in 39/58 (67%), 49/58 (85%), and 41/58 (71%) of CODD lesions, respectively. One or more BDD-associated Treponema phylogroups were detected in 100% of CODD lesions. Healthy foot tissues did not amplify BDD-associated Treponema phylogroup DNA. D. nodosus and F. necrophorum were present in 34/58 (59%) and 41/58 (71%) of CODD lesions and 22/56 (39%) and 5/56 (9%) of healthy foot tissues, respectively. Thirty-two spirochetes were isolated from CODD lesions, with representatives clustering with, and indistinguishable from, each of the three BDD-associated Treponema phylogroups based on 16S rRNA gene comparisons. This study for the first time demonstrates a high-level association for BDD treponeme phylogroups in CODD and their absence from healthy tissues, supporting the hypothesis that BDD treponemes play a primary causative role in CODD and confirming that the specific PCR assays are an effective differential diagnostic tool for CODD. PMID- 25740781 TI - Isolation of Bordetella bronchiseptica from blood and a pancreatic abscess. AB - Bordetella bronchiseptica is a respiratory pathogen rarely encountered in human hosts. We describe a case of bacteremia and pancreatic abscess caused by this organism. To our knowledge, this is the first reported case of B. bronchiseptica causing intra-abdominal infection in the form of an abscess. PMID- 25740779 TI - Multicenter evaluation of the BD max enteric bacterial panel PCR assay for rapid detection of Salmonella spp., Shigella spp., Campylobacter spp. (C. jejuni and C. coli), and Shiga toxin 1 and 2 genes. AB - Diarrhea due to enteric bacterial pathogens causes significant morbidity and mortality in the United States and worldwide. However, bacterial pathogens may be infrequently identified. Currently, culture and enzyme immunoassays (EIAs) are the primary methods used by clinical laboratories to detect enteric bacterial pathogens. We conducted a multicenter evaluation of the BD Max enteric bacterial panel (EBP) PCR assay in comparison to culture for the detection of Salmonella spp., Shigella spp., Campylobacter jejuni, and Campylobacter coli and an EIA for Shiga toxins 1 and 2. A total of 4,242 preserved or unpreserved stool specimens, including 3,457 specimens collected prospectively and 785 frozen, retrospective samples, were evaluated. Compared to culture or EIA, the positive percent agreement (PPA) and negative percent agreement (NPA) values for the BD Max EBP assay for all specimens combined were as follows: 97.1% and 99.2% for Salmonella spp., 99.1% and 99.7% for Shigella spp., 97.2% and 98.4% for C. jejuni and C. coli, and 97.4% and 99.3% for Shiga toxins, respectively. Discrepant results for prospective samples were resolved with alternate PCR assays and bidirectional sequencing of amplicons. Following discrepant analysis, PPA and NPA values were as follows: 97.3% and 99.8% for Salmonella spp., 99.2% and 100% for Shigella spp., 97.5% and 99.0% for C. jejuni and C. coli, and 100% and 99.7% for Shiga toxins, respectively. No differences in detection were observed for samples preserved in Cary-Blair medium and unpreserved samples. In this large, multicenter study, the BD Max EBP assay showed superior sensitivity compared to conventional methods and excellent specificity for the detection of enteric bacterial pathogens in stool specimens. PMID- 25740782 TI - DNA sequencing for confirmation of rifampin resistance detected by Cepheid Xpert MTB/RIF assay. AB - DNA sequencing of rpoB and culture-based drug susceptibility results were evaluated for samples referred for confirmation of rifampin resistance detected by the Cepheid Xpert MTB/RIF assay. Silent mutations and mutations associated with low-level resistance were found in the study population. These data support CDC recommendations to confirm Xpert rifampin resistance results. PMID- 25740783 TI - Paradoxical Enlargement of Giant Intracranial Tuberculoma Mimicking Glioma. PMID- 25740785 TI - Mini-Mental State Examination (MMSE) for the detection of Alzheimer's disease and other dementias in people with mild cognitive impairment (MCI). AB - BACKGROUND: Dementia is a progressive global cognitive impairment syndrome. In 2010, more than 35 million people worldwide were estimated to be living with dementia. Some people with mild cognitive impairment (MCI) will progress to dementia but others remain stable or recover full function. There is great interest in finding good predictors of dementia in people with MCI. The Mini Mental State Examination (MMSE) is the best-known and the most often used short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings. OBJECTIVES: To determine the diagnostic accuracy of the MMSE at various thresholds for detecting individuals with baseline MCI who would clinically convert to dementia in general, Alzheimer's disease dementia or other forms of dementia at follow-up. SEARCH METHODS: We searched ALOIS (Cochrane Dementia and Cognitive Improvement Specialized Register of diagnostic and intervention studies (inception to May 2014); MEDLINE (OvidSP) (1946 to May 2014); EMBASE (OvidSP) (1980 to May 2014); BIOSIS (Web of Science) (inception to May 2014); Web of Science Core Collection, including the Conference Proceedings Citation Index (ISI Web of Science) (inception to May 2014); PsycINFO (OvidSP) (inception to May 2014), and LILACS (BIREME) (1982 to May 2014). We also searched specialized sources of diagnostic test accuracy studies and reviews, most recently in May 2014: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). No language or date restrictions were applied to the electronic searches and methodological filters were not used as a method to restrict the search overall so as to maximize sensitivity. We also checked reference lists of relevant studies and reviews, tracked citations in Scopus and Science Citation Index, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on MMSE for dementia diagnosis to try to locate possibly relevant but unpublished data. SELECTION CRITERIA: We considered longitudinal studies in which results of the MMSE administered to MCI participants at baseline were obtained and the reference standard was obtained by follow-up over time. We included participants recruited and clinically classified as individuals with MCI under Petersen and revised Petersen criteria, Matthews criteria, or a Clinical Dementia Rating = 0.5. We used acceptable and commonly used reference standards for dementia in general, Alzheimer's dementia, Lewy body dementia, vascular dementia and frontotemporal dementia. DATA COLLECTION AND ANALYSIS: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create two by two tables for dementia in general and other dementias. Two authors independently performed quality assessment using the QUADAS-2 tool. Due to high heterogeneity and scarcity of data, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic curve. MAIN RESULTS: In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer's disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer's disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis. AUTHORS' CONCLUSIONS: Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia. PMID- 25740784 TI - Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. AB - BACKGROUND: Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. METHODS: We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. RESULTS: We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. CONCLUSIONS: We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments. PMID- 25740786 TI - Growth Hormone Induces Transforming Growth Factor-Beta-Induced Protein in Podocytes: Implications for Podocyte Depletion and Proteinuria. AB - The glomerular podocytes form a major size selective barrier for the filtration of serum proteins and reduced podocyte number is a critical event in the pathogenesis of proteinuria during diabetic nephropathy (DN). An elevated level of growth hormone (GH) is implicated as a causative factor in the development of nephropathy in patients with type 1 diabetes mellitus. We have previously shown that podocytes express GH receptor and are a target for GH action. To elucidate the molecular basis for the effects of GH on podocyte depletion, we conducted PCR array analyses for extracellular matrix and adhesion molecules in podocytes. Our studies reveal that GH increases expression of a gene that encodes transforming growth factor-beta-induced protein (TGFBIp) expression. Similarly, microarray data retrieved from the Nephromine database revealed elevation of TGFBIp in patients with DN. Treatment with GH results in increased secretion of extracellular TGFBIp by podocytes. Both GH and TGFBIp induced apoptosis and epithelial mesenchymal transition (EMT) of podocytes. Exposure of podocytes to GH and TGFBIp resulted in increased migration of cells and altered podocyte permeability to albumin across podocyte monolayer. Administration of GH to rats induced EMT and apoptosis in the glomerular fraction of the kidney. Therefore, we conclude that the GH-dependent increase in TGFBIp in the podocyte is one of the mechanisms responsible for podocyte depletion in DN. PMID- 25740788 TI - A population-level and longitudinal study of adolescent mothers and intergenerational maltreatment. AB - For teenage mothers in California, we generated population-level estimates of the relationship between maternal history of maltreatment and next-generation abuse and neglect. California birth records for all infants born to primiparous teen mothers in 2006 or 2007 were linked to statewide child protective services (CPS) records. For each birth, we used CPS records to document 1) whether the teen mother had a history of reported or substantiated maternal maltreatment at or after age 10 years and before the estimated date of conception and 2) whether the teen's child was reported or substantiated for maltreatment before age 5 years. We fitted multivariable survival models to examine the association between a teenage mother's CPS involvement and child maltreatment, after adjusting for a range of sociodemographic variables. Our final data set included 85,084 births to first-time mothers aged 15-19 years. Significantly heightened rates of abuse and neglect were observed for children of mothers who had been reported to CPS as possible victims of maltreatment (P < 0.001). After adjustment for other risk factors, a maternal history of either unsubstantiated (hazard ratio = 2.19, 95% confidence interval: 2.06, 2.33) or substantiated (hazard ratio = 3.19, 95% confidence interval: 3.00, 3.39) maltreatment emerged as a strong predictor of maltreatment and CPS involvement in the next generation. PMID- 25740789 TI - Duration of nicotine replacement therapy use and smoking cessation: a population based longitudinal study. AB - In the present study, we examined the association between duration of nicotine replacement therapy (NRT) use and smoking cessation using data from the Ontario Tobacco Survey longitudinal study (3 waves of data collected between July 2005 and December 2009). We used logistic regression with generalized estimating equations to examine the association between NRT use (any use and <4 weeks, 4.0 7.9 weeks, 8.0-11.9 weeks, and >= 12 weeks of use compared with nonuse) and quitting smoking (>= 1 month). Using NRT was not associated with quitting when use duration was not taken into account (adjusted odds ratio (OR) = 1.08, 95% confidence interval (CI): 0.86, 1.35). Compared with abstaining from NRT when attempting to quit smoking, using NRT for less than 4 weeks was associated with a lower likelihood of quitting (adjusted OR = 0.51, 95% CI: 0.38, 0.67); however, using NRT for 4 weeks or longer was associated with a higher likelihood of cessation (for 4.0-7.9 weeks of NRT use, adjusted OR = 2.26, 95% CI: 1.58, 3.22; for 8.0-11.9 weeks of NRT use, adjusted OR = 3.84, 95% CI: 2.24, 6.58; and for >= 12 weeks of NRT use, adjusted OR = 2.80, 95% CI: 1.70, 4.61). Thus, use of NRT for less than 4 weeks was associated with reduced likelihood of cessation, whereas NRT use for longer periods of time was associated with a higher likelihood of cessation. PMID- 25740790 TI - Patients with subarachnoid haemorrhage from vertebrobasilar dissection: treatment with stent-in-stent technique. AB - INTRODUCTION: Vertebrobasilar dissection is an uncommon cause of subarachnoid haemorrhage (SAH) that carries a high risk for early repeat haemorrhage. The need for rapid treatment of this disease entity is without question; however, the best method for treatment is still undetermined. Here, we present our results using the stent-in-stent technique, without coiling, for these patients and propose that it is a viable treatment strategy. METHODS: We identified in our local database for neurointerventional therapy, between 1st October 2000 and 1st January 2014, 93 patients with potential subarachnoid haemorrhage secondary to vertebrobasilar pathology. After review of the clinical notes and imaging, 15 were found to have presented with subarachnoid haemorrhage and treated with stents alone. All dissections were spontaneous with no history of preceding trauma. The ages ranged between 46 and 71 years (mean 61 years). RESULTS: All patients presented with Fischer grade 4 SAH and had a visible pseudoaneurysm. The pre-operative GCS varied with two patients scoring 3, one patient scoring 6 and the remaining 12 patients scoring 8 or above. All cases were subjected to stent in-stent treatment alone. We did not experience any intra-procedural complications. In our series, eight patients had full recovery with a Glasgow Outcome Scale (GOS) of 5, three had moderate disability (GOS 4), one had severe disability (GOS 3), and three patents died, one patient from stent thrombosis or re-bleeding and two from their initial SAH. CONCLUSION: The stent-in-stent technique represents a viable reconstructive endovascular surgical technique with a low risk of intra-procedural complication and post-operative repeat haemorrhage. PMID- 25740791 TI - Protein adduct formation initiates acrolein-induced endothelial cell toxicity. PMID- 25740793 TI - Rolfes MA et al (Clin Infect Dis 2014; 59:1607-14). PMID- 25740792 TI - The role of astrocyte mitochondria in differential regional susceptibility to environmental neurotoxicants: tools for understanding neurodegeneration. AB - In recent decades, there has been a significant expansion in our understanding of the role of astrocytes in neuroprotection, including spatial buffering of extracellular ions, secretion of metabolic coenzymes, and synaptic regulation. Astrocytic neuroprotective functions require energy, and therefore require a network of functional mitochondria. Disturbances to astrocytic mitochondrial homeostasis and their ability to produce ATP can negatively impact neural function. Perturbations in astrocyte mitochondrial function may accrue as the result of physiological aging processes or as a consequence of neurotoxicant exposure. Hydrophobic environmental neurotoxicants, such as 1,3-dinitrobenzene and alpha-chlorohydrin, cause regionally specific spongiform lesions mimicking energy deprivation syndromes. Astrocyte involvement includes mitochondrial damage that either precedes or is accompanied by neuronal damage. Similarly, environmental neurotoxicants that are implicated in the etiology of age-related neurodegenerative conditions cause regionally specific damage in the brain. Based on the regioselective nature of age-related neurodegenerative lesions, chemically induced models of regioselective lesions targeting astrocyte mitochondria can provide insight into age-related susceptibilities in astrocyte mitochondria. Most of the available research to date focuses on neuronal damage in cases of age related neurodegeneration; however, there is a body of evidence that supports a central mechanistic role for astrocyte mitochondria in the expression of neural injury. Regional susceptibility to neuronal damage induced by aging by exposure to neurotoxicants may be a reflection of highly variable regional energy requirements. This review identifies region-specific vulnerabilities in astrocyte mitochondria in examples of exposure to neurotoxicants and in age-related neurodegeneration. PMID- 25740794 TI - Valacyclovir Decreases Plasma HIV-1 RNA in HSV-2 Seronegative Individuals: A Randomized Placebo-Controlled Crossover Trial. AB - BACKGROUND: Acyclovir (ACV), a highly specific anti-herpetic drug, acts as a DNA chain terminator for several human herpesviruses (HHVs), including HHV-2 (HSV-2), a common human immunodeficiency virus (HIV)-1 co-pathogen. Several trials demonstrated that HSV-2 suppressive therapy using ACV or its prodrug valacyclovir (valACV) reduced plasma HIV-1 viral load (VL) in HIV-1/HSV-2 coinfected persons, and this was proposed to be due to a decrease in generalized immune activation. Recently, however, we found that ACV directly suppresses HIV-1 ex vivo in tissues free of HSV-2 but endogenously coinfected with other HHVs. Here, we asked whether valACV suppresses VL in HIV-1 infected HSV-2-seronegative persons. METHODS: Eighteen HIV-1 infected HSV-2-seronegative individuals were randomly assigned in a double blind placebo-controlled, crossover trial. Eligible participants had CD4 cell counts of >=500 cells/uL and were not taking antiretroviral therapy. Subjects in group A received 12 weeks of valACV 500 mg given twice daily by mouth followed by 2 weeks of a no treatment washout and then 12 weeks of placebo; subjects in group B received 12 weeks of placebo followed by 2 weeks of no treatment washout and then 12 weeks of valACV 500 mg twice daily. RESULTS: HIV-1 VL in plasma of patients treated with valACV 500 mg twice daily for 12 weeks was reduced on average by 0.37 log10 copies/mL. CONCLUSIONS: These data indicate that the effects of valACV on HIV-1 replication are not related to the suppression of HSV-2-mediated inflammation and are consistent with a direct effect of ACV on HIV 1 replication. PMID- 25740795 TI - Time to antibiotics in solid organ transplant recipients with gram-negative rod bloodstream infections. PMID- 25740796 TI - Rapid access to comprehensive care may explain better outcomes in persons with sepsis with solid organ transplant versus those without solid organ transplant. PMID- 25740797 TI - Reply to Thomason et al and Bahr et al. PMID- 25740798 TI - Natriuretic peptide tests in suspected acute heart failure. PMID- 25740799 TI - The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting. AB - OBJECTIVES: To determine and compare the diagnostic accuracy of serum natriuretic peptide levels (B type natriuretic peptide, N terminal probrain natriuretic peptide (NTproBNP), and mid-regional proatrial natriuretic peptide (MRproANP)) in people presenting with acute heart failure to acute care settings using thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure. DESIGN: Systematic review and diagnostic meta-analysis. DATA SOURCES: Medline, Embase, Cochrane central register of controlled trials, Cochrane database of systematic reviews, database of abstracts of reviews of effects, NHS economic evaluation database, and Health Technology Assessment up to 28 January 2014, using combinations of subject headings and terms relating to heart failure and natriuretic peptides. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible studies evaluated one or more natriuretic peptides (B type natriuretic peptide, NTproBNP, or MRproANP) in the diagnosis of acute heart failure against an acceptable reference standard in consecutive or randomly selected adults in an acute care setting. Studies were excluded if they did not present sufficient data to extract or calculate true positives, false positives, false negatives, and true negatives, or report age independent natriuretic peptide thresholds. Studies not available in English were also excluded. RESULTS: 37 unique study cohorts described in 42 study reports were included, with a total of 48 test evaluations reporting 15 263 test results. At the lower recommended thresholds of 100 ng/L for B type natriuretic peptide and 300 ng/L for NTproBNP, the natriuretic peptides have sensitivities of 0.95 (95% confidence interval 0.93 to 0.96) and 0.99 (0.97 to 1.00) and negative predictive values of 0.94 (0.90 to 0.96) and 0.98 (0.89 to 1.0), respectively, for a diagnosis of acute heart failure. At the lower recommended threshold of 120 pmol/L, MRproANP has a sensitivity ranging from 0.95 (range 0.90-0.98) to 0.97 (0.95-0.98) and a negative predictive value ranging from 0.90 (0.80-0.96) to 0.97 (0.96-0.98). At higher thresholds the sensitivity declined progressively and specificity remained variable across the range of values. There was no statistically significant difference in diagnostic accuracy between plasma B type natriuretic peptide and NTproBNP. CONCLUSIONS: At the rule-out thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure, plasma B type natriuretic peptide, NTproBNP, and MRproANP have excellent ability to exclude acute heart failure. Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required. There is no statistical difference between the diagnostic accuracy of plasma B type natriuretic peptide and NTproBNP. Introduction of natriuretic peptide measurement in the investigation of patients with suspected acute heart failure has the potential to allow rapid and accurate exclusion of the diagnosis. PMID- 25740800 TI - Distinct muscle apoptotic pathways are activated in muscles with different fiber types in a rat model of critical illness myopathy. AB - Critical illness myopathy (CIM) is associated with severe muscle atrophy and fatigue in affected patients. Apoptotic signaling is involved in atrophy and is elevated in muscles from patients with CIM. In this study we investigated underlying mechanisms of apoptosis-related pathways in muscles with different fiber type composition in a rat model of CIM using denervation and glucocorticoid administration (denervation and steroid-induced myopathy, DSIM). Soleus and tibialis anterior (TA) muscles showed severe muscle atrophy (40-60% of control muscle weight) and significant apoptosis in interstitial as well as myofiber nuclei that was similar between the two muscles with DSIM. Caspase-3 and -8 activities, but not caspase-9 and -12, were elevated in TA and not in soleus muscle, while the caspase-independent proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) were not changed in abundance nor differentially localized in either muscle. Anti-apoptotic proteins HSP70, -27, and apoptosis repressor with a caspase recruitment domain (ARC) were elevated in soleus compared to TA muscle and ARC was significantly decreased with induction of DSIM in soleus. Results indicate that apoptosis is a significant process associated with DSIM in both soleus and TA muscles, and that apoptosis-associated processes are differentially regulated in muscles of different function and fiber type undergoing atrophy due to DSIM. We conclude that interventions combating apoptosis with CIM may need to be directed towards inhibiting caspase-dependent as well as -independent mechanisms to be able to affect muscles of all fiber types. PMID- 25740801 TI - Characterization of Deep Sea Fish Gut Bacteria with Antagonistic Potential, from Centroscyllium fabricii (Deep Sea Shark). AB - The bacterial isolates from Centroscyllium fabricii (deep sea shark) gut were screened for antagonistic activity by cross-streak method and disc diffusion assay. This study focuses on strain BTSS-3, which showed antimicrobial activity against pathogenic bacteria including Salmonella Typhimurium, Proteus vulgaris, Clostridium perfringens, Staphylococcus aureus, Bacillus cereus, Bacillus circulans, Bacillus macerans and Bacillus pumilus. BTSS3 was subjected to phenotypic characterization using biochemical tests, SEM imaging, exoenzyme profiling and antibiotic susceptibility tests. Comparative 16S rDNA gene sequence analysis indicated that this strain belonged to the genus Bacillus, with high (98%) similarity to 16S rDNA sequences of Bacillus amyloliquefaciens. The chemical nature of the antibacterial substance was identified by treatment with proteolytic enzymes. The antibacterial activity was reduced by the action of these enzymes pointing out its peptide nature. It was observed from the growth and production kinetics that the bacteriocin was produced in the eighth hour of incubation, i.e., during the mid-log growth phase of the bacteria. PMID- 25740802 TI - Malignancy risk and characteristics of thyroid nodules with two consecutive results of atypia of undetermined significance or follicular lesion of undetermined significance on cytology. AB - PURPOSE: To evaluate the malignancy risk and characteristics of thyroid nodules with two "Atypia of Undetermined Significance" or "Follicular Lesion of Undetermined Significance" (AUS/FLUS) results, and compare characteristics of malignancies with two AUS/FLUS results to those with one AUS/FLUS result. METHODS: Of 441 thyroid nodules with initial AUS/FLUS results, 236 underwent repeat fine-needle-aspiration (FNA), with 58 obtaining repeated AUS/FLUS results. Thyroid Imaging Reporting and Data System (TIRADS) categories were assigned, and clinico-pathological characteristics were compared between benign and malignant nodules and between malignancies with two consecutive AUS/FLUS results and those with one AUS/FLUS result. RESULTS: Thirty-one percent (18/58) of nodules with two AUS/FLUS results and 58.1% (18/31) of confirmed nodules were malignant. Age, gender, nodule size, ultrasound features and TIRADS categories did not differ between benign and malignant nodules or between malignancies with one and two AUS/FLUS results. Malignancies with two AUS/FLUS results had a higher proportion of a follicular variant of papillary thyroid carcinoma (PTC) (46.7% vs. 13.6%, P = 0.009). CONCLUSIONS: Thyroid nodules with two AUS/FLUS results had a high malignancy risk of at least 31.0% and a higher proportion of a follicular variant of PTC. Surgery should be considered regardless of ultrasound features. KEY POINTS: * Thyroid nodules with two consecutive AUS/FLUS results had a high malignancy risk. * Ultrasound features are less useful in nodules with two AUS/FLUS results. * The follicular variant of PTC is more frequent in malignancies with two AUS/FLUS results. PMID- 25740803 TI - The Z0011 Trial: Is this the end of axillary ultrasound in the pre-operative assessment of breast cancer patients? AB - OBJECTIVES: The Z0011 trial questioned the role of axillary ultrasound (AxUS) in preoperative staging of breast cancer in patients with <=2 positive sentinel lymph nodes (SLN). The purpose of this study was to correlate the number of abnormal nodes on AxUS with final nodal burden and determine the utility of AxUS with sampling (AxUS + S) in preoperative staging. METHODS: Six hundred and seventy-nine patients underwent pre-operative AxUS. Suspicious nodes were sampled. Negative axillae proceeded to SLN biopsy. The number of abnormal nodes identified on ultrasound and final histology as well as sensitivity and specificity for AxUS + S were calculated. Subgroup analysis was performed on Z0011 eligible patients. RESULTS: Two hundred and ninety-six patients had positive axillary nodes on final histology with 169 detected by AxUS + S (sensitivity 86.2%, specificity 100%, PPV 100 %, NPV 71.9%). Patients with nodal metastases identified by AxUS had a mean burden of 7.3 nodes on histology (1 node on AxUS = 5.2 nodes on histology, 2 nodes on AxUS = 7.5 nodes, >2 nodes = 10.1 nodes). Patients diagnosed on SLNB had a mean burden of 2.2 nodes. CONCLUSION: A single nodal metastasis detected on AxUS + S correlated with a mean of 5.2 nodes on final histology highlighting that AxUS remains essential in guiding appropriate management of the axilla in breast cancer. KEY POINTS: * Axillary ultrasound +/- sampling is an essential technique in preoperative axillary staging. * Axillary ultrasound findings correlate with final histological axillary node disease burden. * Axillary ultrasound can help triage patients who require axillary lymph node dissection. * The role of axillary ultrasound in breast cancer staging continues to evolve. PMID- 25740804 TI - Ranibizumab for subfoveal choroidal neovascularisation associated with Stargardt disease. AB - INTRODUCTION: To describe the clinical outcomes of intravitreal ranibizumab treatment for subfoveal choroidal neovascularisation (CNV) associated with Stargardt disease. METHODS: Prospective, interventional, case series. All patients underwent intravitreal ranibizumab injections following a pro re nata regimen with monthly examination, over a 24-month follow-up. RESULTS: Three eyes were included in the study. Best corrected visual acuity changed from 0.47+/-0.06 (mean+/-SD) at baseline to 0.90+/-0.17 LogMAR at the end of the 24-month follow up. Overall, a mean number of 11 ranibizumab injections were administered in 24 months. Significant atrophic growth was detected in all cases, with the mean atrophy area increasing from 2.34+/-2.60 mm(2) (mean+/-SD) at baseline to 4.23+/ 3.31 mm(2) at the end of the follow-up. CONCLUSIONS: Ranibizumab treatment can stop the CNV progression, but cannot ensure a significant visual improvement. Macular atrophy tends to significantly enlarge under ranibizumab treatment over the follow-up. PMID- 25740805 TI - Re-appraisal of topical 1% voriconazole and 5% natamycin in the treatment of fungal keratitis in a randomised trial. AB - PURPOSE: To compare the efficacy of topical 1% voriconazole vs 5% natamycin for the treatment of fungal keratitis. METHODS: In a prospective, double-masked, randomised, controlled, registered clinical trial, 118 patients with fungal keratitis were treated using identical dosage schedule with either voriconazole (58) or natamycin (60) as inpatients for 7 days and followed up weekly. The outcome measures were percentage of patients with healed or resolving ulcer and final visual acuity at last follow-up (primary) and on day 7 (secondary) in each group. RESULTS: More patients (p=0.005) on natamycin (50/56, 89.2%) had healed or resolving ulcer compared with voriconazole (34/51, 66.6%) at last follow-up. The improvement in vision was marginally greater in patients in the natamycin group compared with the voriconazole group at day 7 (p=0.04) and significantly greater at final visit (p=0.01). In univariate analysis, drug, age and mean size of corneal infiltrate and epithelial defect had a significant effect on the final visual outcome. In multivariate analysis, the effect of drug (voriconazole vs natamycin, adjusted coefficient 0.27 (-0.04 to 0.57), p=0.09) was marginal while the effect of age and epithelial defect was significant (p<0.001 for both). In the group treated with natamycin, the final visual acuity was significantly better (p=0.005, Wilcoxon signed-rank test) in patients with Fusarium keratitis but not with Aspergillus keratitis (p=0.714, paired t test). CONCLUSIONS: When compared with voriconazole, natamycin was more effective in the treatment of fungal keratitis, especially Fusarium keratitis. TRIAL REGISTRATION NUMBER: Clinical Trial Registry India (2010/091/003041). PMID- 25740806 TI - Compatibility of recombinant tissue plasminogen activator (rtPA) and aflibercept or ranibizumab coapplied for neovascular age-related macular degeneration with submacular haemorrhage. AB - BACKGROUND/AIMS: Subretinal coapplication of recombinant tissue plasminogen activator (rtPA) and vascular endothelial growth factor (VEGF)-antagonists is a new treatment option for age-related macular degeneration complicated by submacular haemorrhage. Here, we investigate the compatibility of rtPA and aflibercept or ranibizumab in vitro because intraoperatively, rtPA or rtPA induced plasmin may cleave aflibercept or ranibizumab. METHODS: Aflibercept and ranibizumab, respectively, were incubated with rtPA or plasmin, separated in gel electrophoresis and stained with Coomassie or silver. The antiangiogenic activity of the VEGF-antagonists was quantified by VEGF-ELISA after incubation with the supernatant of primary porcine retinal pigment epithelium cell cultures. RESULTS: In electrophoresis, ranibizumab displayed no additional fragments when it was coapplied with rtPA or plasmin. Its VEGF-inhibiting efficacy remained unchanged in coapplication with rtPA with or without blood, or plasmin. rtPA did not cleave or functionally compromise aflibercept. When aflibercept was coapplied with plasmin, electrophoresis displayed additional bands in Coomassie (30 kDa, 27 kDa, 19 kDa, 15 kDa) and silver staining (31 kDa, 26 kDa, 21 kDa, 19 kDa, 15 kDa). While at a clinical dosage (800 ug/mL) VEGF was inhibited by aflibercept when coapplied with plasmin, at borderline concentrations (400 ng/mL) VEGF-binding ability of aflibercept was abolished. CONCLUSIONS: Ranibizumab is not cleaved or functionally compromised by rtPA or plasmin. Aflibercept is cleaved and its VEGF binding ability is reduced when coapplied with plasmin. In clinical practice, rtPA and ranibizumab can be coapplied as a treatment for neovascular age-related macular degeneration with submacular haemorrhage while the antiangiogenic activity of aflibercept may be compromised when coapplied with rtPA in the presence of plasmin. PMID- 25740807 TI - Large-diameter deep anterior lamellar keratoplasty for keratoconus: visual and refractive outcomes. AB - BACKGROUND: To investigate the difference in clinical outcomes between large diameter deep anterior lamellar keratoplasty (L-DALK) and standard DALK (S-DALK) for the treatment of keratoconus. METHODS: 132 patients (132 eyes) from the Zhongshan Ophthalmic Center with a clinical diagnosis of keratoconus were enrolled. The participants were featured by the intolerance to rigid gas permeable contact lenses or unsuccessful fitting of contact lenses. Using stratified blocked randomisation, eligible eyes were allocated into the L-DALK group or the S-DALK group (66 eyes, respectively). Postoperative uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), refractive sphere, manifest cylinder and spherical equivalent refractive error were tested at 6, 12, 18 and 24 months after surgery. RESULTS: After surgery, the L-DALK group had better UCVA and BSCVA than the S-DALK group (p=0.000 and 0.021, respectively). At 24 months, mean BSCVA was 0.17+/-0.10 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent, 20/25) in the L-DALK group vs 0.22+/-0.10 logMAR (Snellen equivalent, 20/32) in the S-DALK group. Differences were observed between the L-DALK group and the S-DALK group in terms of refractive sphere (p=0.015), manifest cylinder (p=0.014) and spherical equivalent refractive error (p=0.034) at any time interval postoperatively. At 24 months, the mean spherical equivalent refractive error was -3.5+/-3.2 D and -5.2+/-2.6 D in the L-DALK and S-DALK groups, respectively. CONCLUSIONS: L-DALK can reduce the degree of postoperative myopia and manifest astigmatism and improve visual acuity outcomes in keratoconus compared with S-DALK. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (TRC-13003122). PMID- 25740808 TI - Endothelial cell loss following tissue harvesting by pneumodissection for endothelial keratoplasty: an ex vivo study. AB - AIMS: To study ex vivo the difference in endothelial cell density (ECD) in tissue harvested by pneumodissection for pre-Descemet's endothelial keratoplasty (PDEK) and Descemet's membrane endothelial keratoplasty (DMEK). METHODS: Tissue for PDEK and DMEK were obtained from 10 eye bank sclerocorneal discs by trephination after air injection into corneal stroma and big bubble (BB) formation. PDEK tissue was prepared in five corneas after achieving a type 1 BB and DMEK after a type 2 BB in five corneas. Five sclerocorneal discs for each group were used as controls. Endothelial cell counts were obtained from all samples before and after injection using phase-contrast microscopy with an eyepiece reticle. We used paired t test to analyse the results using the GraphPad Prism V.6 software. RESULTS: The range of change of ECD before and after injection in the PDEK sample group varied from 9% to +0.2% with an average of -5.36% +/-3.8%. The difference was not statistically significant (p=0.0512). On the other hand, the range of change of ECD of the DMEK groups before and after injection varied from -0.4 to -20.6, with an average of -12.44% +/-8.11%. This difference was statistically significant (p=0.0456). Also, there was a significant difference between DMEK test samples (postinjection) and their controls (p=0.028). CONCLUSIONS: Corneal endothelial cell loss in PDEK tissue preparation is no worse, if not slightly better than, in DMEK tissue prepared by pneumodissection. PDEK preparation by pneumodissection represents a viable graft preparation technique. PMID- 25740809 TI - Cell dedifferentiation and organogenesis in vitro require more snRNA than does seedling development in Arabidopsis thaliana. AB - Small nuclear RNA (snRNA) is a class of non-coding RNAs that processes pre-mRNA and rRNA. Transcription of abundant snRNA species is regulated by the snRNA activating protein complex (SNAPc), which is conserved among multicellular organisms including plants. SRD2, a putative subunit of SNAPc in Arabidopsis thaliana, is essential for development, and the point mutation srd2-1 causes severe defects in hypocotyl dedifferentiation and de novo meristem formation. Based on phenotypic analysis of srd2-1 mutant plants, we previously proposed that snRNA content is a limiting factor in dedifferentiation in plant cells. Here, we performed functional complementation analysis of srd2-1 using transgenic srd2-1 Arabidopsis plants harboring SRD2 homologs from Populus trichocarpa (poplar), Nicotiana tabacum (tobacco), Oryza sativa (rice), the moss Physcomitrella patens, and Homo sapiens (human) under the control of the Arabidopsis SRD2 promoter. Only rice SRD2 suppressed the faulty tissue culture responses of srd2-1, and restore the snRNA levels; however, interestingly, all SRD2 homologs except poplar SRD2 rescued the srd2-1 defects in seedling development. These findings demonstrated that cell dedifferentiation and organogenesis induced during tissue culture require higher snRNA levels than does seedling development. PMID- 25740810 TI - D-Serine in the aging hippocampus. AB - Experimental evidences now indicate that memory formation relies on the capacity of neuronal networks to manage long-term changes in synaptic communication. This property is driven by N-methyl-D-aspartate receptors (NMDAR), which requires the binding of glutamate but also the presence of the co-agonist D-serine at the glycine site. Defective memory function and impaired brain synaptic plasticity observed in aging are rescued by partial agonist acting at this site suggesting that this gating process is targeted to induce age-related cognitive defects. This review aims at compelling recent studies characterizing the role of D-serine in changes in functional plasticity that occur in the aging hippocampus since deficits are rescued by D-serine supplementation. The impaired efficacy of endogenous D-serine is not due to changes in the affinity to glycine-binding site but to a decrease in tissue levels of the amino acid resulting from a weaker expression of the producing enzyme serine racemase (SR). Interestingly, neither SR expression, D-serine levels, nor NMDAR activation is affected in aged LOU/C rats, a model of healthy aging in which memory deficits do not occur. These old animals do not develop oxidative stress suggesting that the D-serine-related pathway could be targeted by the age-related accumulation of reactive oxygen species. Accordingly, senescent rats chronically treated with the reducing agent N-acetyl-cysteine to prevent oxidative damage, show intact NMDAR activation linked to preserved D-serine levels and SR expression. These results point to a significant role of D-serine in age-related functional alterations underlying hippocampus-dependent memory deficits, at least within the CA1 area since the amino acid does not appear as critical in changes affecting the dentate gyrus. PMID- 25740811 TI - Epstein-Barr virus in inflammatory bowel disease: the spectrum of intestinal lymphoproliferative disorders. AB - BACKGROUND: Inflammatory bowel disease (IBD) patients on thiopurine therapy are at increased risk of Epstein-Barr virus (EBV)-associated lymphomas. This virus is frequently detected in the intestinal mucosa of IBD patients and may cause a wide spectrum of lymphoproliferations similar to post-transplantation lymphoproliferative disorders (PTLDs). We aimed to assess whether histological aberrations aid in predicting EBV presence and to correlate histological assessment and EBV load with disease outcome in IBD. METHODS: We included all IBD patients from our centre who underwent EBV testing of intestinal biopsies between January 2004 and October 2013. All biopsies were classified according to the WHO PTLD classification and the EBV load was scored per high-power field (HPF). Clinical data were collected from patient charts. Reported clinical outcomes included colectomy, need for chemotherapy and mortality. RESULTS: Our cohort included 58 patients: 28 were EBV-positive and 30 EBV-negative. An atypical infiltrate was seen more frequently in EBV-positive than in EBV-negative patients (57.1 versus 3.3%; p < 0.001). A high EBV load occurred more frequently in EBV positive patients undergoing colectomy than in EBV-positive patients without colectomy (50.0 versus 10.0%; p = 0.048). Monomorphic lymphoproliferative disorders, including two overt lymphomas, were present in 10 patients. Reduction of immunosuppression resulted in histological normalization and loss of EBV expression in seven of eight non-lymphoma patients. CONCLUSION: The presence of atypical infiltrate in the intestinal mucosa of IBD patients warrants EBV testing. Reduction of immunosuppression is an effective strategy to achieve morphological normalization and loss of EBV. Lymphoproliferation related to IBD appears to have less aggressive clinical behaviour than PTLDs. PMID- 25740812 TI - Patient-relevant endpoints in inflammatory bowel diseases--have changes occurred in Germany over the past twelve years? AB - BACKGROUND AND AIMS: Inflammatory bowel diseases (IBDs) are gaining increasing medical as well as economic significance. Improving medical treatment options can have a positive effect on number of hospitalized patients, necessary operations and the inability to work. METHODS: To understand patient-relevant endpoints in IBDs, the data for 2000-12 published by the Federal Statistical Office and the data for 2012 according to Article 21 of the Hospital Reimbursement Act in Germany were assessed. In addition, data records held by a public health insurance company on the medication of IBD patients were evaluated. RESULTS: During 2000-12, the number of hospitalized IBD patients (ICD 10 K50, K51) rose from 38533 to 43452 (+12.7%). The necessity of surgical intervention increased during the period under review. The number of people unable to work increased differently for Crohn's disease (CD) and ulcerative colitis (UC), by 2.1 and 9.5%, respectively. Entry of persons into the statutory pension insurance system did not decline from 2000 to 2012. The number of potential years of life lost (PYLL) in patients with IBD also remained constant during the period under review (2017 in 2000-02 versus 2011 in 2010-012). From 2009 to 2013 the percentage of patients treated with an anti-TNF-antibodies rose (2009, 4.3% for CD and 1.4% for UC; 2013, 8.4% for CD and 3.2% for UC). CONCLUSIONS: An improvement in patient relevant endpoints was not observed between 2000 and 2012 in IBD patients in Germany. Improvements can only be achieved through structured and interdisciplinary treatment concepts involving all healthcare providers. PMID- 25740813 TI - Cerebrovascular events in inflammatory bowel disease patients treated with anti tumour necrosis factor alpha agents. AB - BACKGROUND AND AIMS: Cerebrovascular accidents [CVA] have rarely been reported in inflammatory bowel disease [IBD] patients treated with anti-tumour necrosis alpha [anti-TNF alpha] agents. Our aim here was to describe the clinical course of CVA in these patients. METHODS: This was a European Crohn's and Colitis Organisation [ECCO] retrospective observational study, performed as part of the CONFER [COllaborative Network For Exceptionally Rare case reports] project. A call to all ECCO members was made to report on IBD patients afflicted with CVA during treatment with anti-TNF alpha agents. Clinical data were recorded in a standardised case report form and analysed for event association with anti-TNF alpha treatment. RESULTS: A total of 19 patients were identified from 16 centres: 14 had Crohn's disease, four ulcerative colitis and one IBD colitis unclassified [median age at diagnosis: 38.0 years, range: 18.6-62.5]. Patients received anti TNF alpha for a median duration of 11.8 months [range: 0-62] at CVA onset; seven had previously been treated with at least one other anti-TNF alpha agent. Complete neurological recovery was observed in 16 patients. Anti-TNF alpha was discontinued in 16/19 patients. However, recurrent CVA or neurological deterioration was not observed in any of the 11 patients who received anti-TNF alpha after CVA [eight resumed after temporary cessation, three continued without interruption] for a median follow-up of 39.8 months [range: 5.6-98.2]. CONCLUSION: These preliminary findings do not unequivocally indicate a causal role of anti-TNF alpha in CVA complicating IBD. Resuming or continuing anti-TNF alpha in IBD patients with CVA may be feasible and safe in selected cases, but careful weighing of IBD activity versus neurological status is prudent. PMID- 25740814 TI - Histological remission in inflammatory bowel disease: where are we, and where are we going? PMID- 25740815 TI - Administration of two anti-TNFalpha agents in an ulcerative colitis patient with HBV-related cirrhosis. PMID- 25740816 TI - Hallus rigidus and the challenge of motion for the first metatarsophalangeal. PMID- 25740817 TI - Pilot study evaluating the feasibility and initial outcomes of a primary care weight loss intervention with peer coaches. AB - PURPOSE: The purpose of this single-group pilot study was to evaluate the feasibility, acceptability, and initial outcomes of a novel approach to delivering weight loss treatment in primary care using peer coaches and targeting predominantly African American patients with diabetes or prediabetes. METHODS: Participants (N = 33) were recruited from a family medicine practice for a 6 month lifestyle intervention. Eligible patients were obese adults (body mass index [BMI] >=30 kg/m(2)) with >=1 additional cardiometabolic risk factor(s), including (1) elevated hemoglobin A1C or diagnosed diabetes, (2) elevated blood pressure, (3) elevated triglycerides, and/or (4) low high-density lipoprotein. The intervention included a combination of 12 group-based office visits with health professionals plus 12 individual phone contacts with peer coaches. Outcomes included weight loss, program adherence, and program satisfaction. RESULTS: Participants (mean age = 56 +/- 10 years; BMI = 42.9 +/- 11.0 kg/m(2)) were predominantly female (88%) and African American (85%). Treatment resulted in a significant mean weight loss of -4.5 +/- 7.2 kg, and approximately 27% of participants lost >=5% of their initial body weight. Participants completed approximately 50% of the group visits and 40% of the telephone calls with peer coaches. Participants rated both components of the intervention favorably. CONCLUSIONS: Results of this pilot study indicated that a primary care weight management program including group-based visits and peer-delivered telephone contacts achieved significant weight loss among predominantly African American patients with weight-related comorbidities, including diabetes and prediabetes. Additional research is needed to examine the long-term outcomes of this novel approach and to identify program components supporting patients' success. PMID- 25740819 TI - India's health ministry bans pioglitazone, metamizole, and flupentixol melitracen. PMID- 25740818 TI - Stress resilience and physical fitness in adolescence and risk of coronary heart disease in middle age. AB - OBJECTIVE: Psychosocial stress is a suggested risk for coronary heart disease (CHD). The relationship of stress resilience in adolescence with subsequent CHD risk is underinvestigated, so our objective was to assess this and investigate the possible mediating role of physical fitness. METHODS: In this register-based study, 237,980 men born between 1952 and 1956 were followed from 1987 to 2010 using information from Swedish registers. Stress resilience was measured at a compulsory military conscription examination using a semistructured interview with a psychologist. Some 10,581 diagnoses of CHD were identified. Cox regression estimated the association of stress resilience with CHD, with adjustment for established cardiovascular risk factors. RESULTS: Low-stress resilience was associated with increased CHD risk. The association remained after adjustment for physical fitness and other potential confounding and mediating factors, with adjusted HRs (and 95% CIs) of 1.17 (1.10 to 1.25), with some evidence of mediation by physical fitness. CHD incidence rates per 1000 person-years (and 95% CIs) for low-stress, medium-stress and high-stress resilience were 2.61 (2.52 to 2.70), 1.97 (1.92 to 2.03) and 1.59 (1.53 to 1.67) respectively. Higher physical fitness was inversely associated with CHD risk; however, this was attenuated by low-stress resilience, shown by interaction testing (p < 0.001). CONCLUSIONS: Low stress resilience in adolescence was associated with increased risk of CHD in middle age and may diminish the benefit of physical fitness. This represents new evidence of the role of stress resilience in determining risk of CHD and its interrelationship with physical fitness. PMID- 25740820 TI - Moderate hypothermia during ex vivo machine perfusion promotes recovery of hearts donated after cardiocirculatory death?. AB - OBJECTIVES: To establish the optimal machine perfusion temperature for recovery of hearts in a rodent model of donation after declaration of cardiocirculatory death (DCD). METHODS: Hearts from male Lewis rats (n = 14/group) were subjected to 25 min of in situ warm (37 degrees C) ischaemia to simulate DCD. They were then explanted and reperfused with diluted autologous blood for 60 min at 20, 25, 30, 33 or 37 degrees C, after which they were stored at 0-4 degrees C in Custodiol preservation solution for 240 min. Fresh-excised and cold-stored ischaemic hearts were used as controls. The viability of the different groups was assessed by comparing heart rate and left ventricular contractility in a Langendorff circuit, as well as perfusate levels of troponin-t and creatine kinase (CK), and myocardial levels of adenosine triphosphate (ATP) and reduced glutathione. RESULTS: During ex vivo reperfusion, hearts in all groups resumed beating within minutes. The mean heart rate was highest in the 37 degrees C group at 154.72 +/- 33.01 beats * min(-1) (bpm), and declined in proportion to temperature to 39.72 +/- 5.53 bpm at 20 degrees C. Troponin-t levels were highest in the 37 degrees C group (79.49 +/- 20.79 ug/l), the values were significantly lower in all other reconditioned groups with a minimum of 12.472 +/- 7.08 ug/l in the 20 degrees C group (P < 0.0001). Tissue ATP levels ranged from 4.32 +/- 1.71 umol/g at 33 degrees C to 4.59 +/- 1.41 umol/g at 30 degrees C, all significantly higher than the mean ATP level of 1.41 +/- 0.93 umol/g in untreated ischaemic hearts (P < 0.0001). During Langendorff assessment, the mean heart rate and contractility of all groups were higher than those of cold-stored ischaemic hearts (P < 0.0001), yet not significantly different from those of fresh controls. The perfusate levels of troponin-t and CK, and myocardial levels of reduced-glutathione and ATP were not significantly different between groups. CONCLUSION: Our results suggest that mild hypothermia during ex vivo reperfusion improves recovery of ischaemic hearts in a rodent DCD model. PMID- 25740821 TI - Evolution of the metazoan mitochondrial replicase. AB - The large number of complete mitochondrial DNA (mtDNA) sequences available for metazoan species makes it a good system for studying genome diversity, although little is known about the mechanisms that promote and/or are correlated with the evolution of this organellar genome. By investigating the molecular evolutionary history of the catalytic and accessory subunits of the mtDNA polymerase, pol gamma, we sought to develop mechanistic insight into its function that might impact genome structure by exploring the relationships between DNA replication and animal mitochondrial genome diversity. We identified three evolutionary patterns among metazoan pol gammas. First, a trend toward stabilization of both sequence and structure occurred in vertebrates, with both subunits evolving distinctly from those of other animal groups, and acquiring at least four novel structural elements, the most important of which is the HLH-3beta (helix-loop helix, 3 beta-sheets) domain that allows the accessory subunit to homodimerize. Second, both subunits of arthropods and tunicates have become shorter and evolved approximately twice as rapidly as their vertebrate homologs. And third, nematodes have lost the gene for the accessory subunit, which was accompanied by the loss of its interacting domain in the catalytic subunit of pol gamma, and they show the highest rate of molecular evolution among all animal taxa. These findings correlate well with the mtDNA genomic features of each group described above, and with their modes of DNA replication, although a substantive amount of biochemical work is needed to draw conclusive links regarding the latter. Describing the parallels between evolution of pol gamma and metazoan mtDNA architecture may also help in understanding the processes that lead to mitochondrial dysfunction and to human disease-related phenotypes. PMID- 25740822 TI - Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice. AB - A major etiological risk factor for hepatocellular carcinoma (HCC) is infection by Hepatitis viruses, especially hepatitis B virus and hepatitis C virus. Hepatitis B virus and hepatitis C virus do not cause aggressive activation of an oncogenic pathway, but they transactivate a broad array of genes, cause chronic inflammation, and, through interference with mitotic processes, lead to mitotic error-induced chromosome instability (ME-CIN). However, how ME-CIN is involved in the development of HCC remains unclear. Delineating the effect of ME-CIN on HCC development should help in identifying measures to combat HCC. In this study, we used ME-CIN model mice haploinsufficient in Shugoshin 1 (Sgo1(-/+)) to assess the role of ME-CIN in HCC development. Treatment with the carcinogen azoxymethane caused Sgo1(-/+) ME-CIN model mice to develop HCCs within 6 months, whereas control mice developed no HCC (P < 0.003). The HCC development was associated with expression of early HCC markers (glutamine synthetase, glypican 3, heat shock protein 70, and the serum marker alpha fetoprotein), although without fibrosis. ME-CIN preceded the expression of HCC markers, suggesting that ME-CIN is an important early event in HCC development. In 12-month-old untreated Sgo1 mice, persistent DNA damage, altered gene expression, and spontaneous HCCs were observed. Sgo1 protein accumulated in response to DNA damage in vitro. Overall, Sgo1(-/+)-mediated ME-CIN strongly promoted/progressed development of HCC in the presence of an initiator carcinogen, and it had a mild initiator effect by itself. Use of the ME-CIN model mice should help in identifying drugs to counteract the effects of ME-CIN and should accelerate anti-HCC drug development. PMID- 25740823 TI - Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors. AB - Activation of signaling dependent on the mammalian target of rapamycin (mTOR) has been demonstrated in a variety of human malignancies, and our previous work suggests that mTOR complex (mTORC) 1 and mTORC2 may play unique roles in skin tumorigenesis. The purpose of these studies was to investigate the function of mTORC2-dependent pathways in skin tumor development and the maintenance of established tumors. Using mice that allow spatial and temporal control of mTORC2 in epidermis by conditional knockout of its essential component Rictor, we studied the effect of mTORC2 loss on both epidermal proliferation and chemical carcinogenesis. The results demonstrate that mTORC2 is dispensable for both normal epidermal proliferation and the hyperproliferative response to treatment with tetradecanoyl phorbol acetate (TPA). In contrast, deletion of epidermal Rictor prior to initiation in DMBA/TPA chemical carcinogenesis was sufficient to dramatically delay tumor development and resulted in reduced tumor number and size compared with control groups. Silencing of Rictor expression in tumor bearing animals triggered regression of established tumors and increased caspase 3 cleavage without changes in proliferation. In vitro experiments demonstrate an increased sensitivity to caspase-dependent apoptosis in the absence of rictor, which is dependent on mTORC2 signaling. These studies demonstrate that mTORC2 activation is essential for keratinocyte survival, and suggest that inhibition of mTORC2 has value in chemoprevention by eliminating carcinogen-damaged cells during the early stages of tumorigenesis, and in therapy of existing tumors by restricting critical pro-survival pathways. PMID- 25740824 TI - Epigenetic clustering of gastric carcinomas based on DNA methylation profiles at the precancerous stage: its correlation with tumor aggressiveness and patient outcome. AB - The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (betaN) using the 3861 probes. This divided the 109 patients into three clusters: A (n = 20), B1 (n = 20), and B2 (n = 69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which betaN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (betaT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, betaT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that betaT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome. PMID- 25740825 TI - Tracking rotors with minimal electrodes: modulation index-based strategy. AB - BACKGROUND: High-frequency periodic sources during cardiac fibrillation can be detected by phase mapping techniques. To enable practical therapeutic options for modulating periodic sources (existing techniques require high density multielectrode arrays and real time simultaneous mapping capability), a method to identify electrogram morphologies colocalizing to rotors that can be implemented on few electrograms needs to be devised. METHOD AND RESULTS: Multichannel ventricular fibrillation electrogram data from 7 isolated human hearts using Langendorff setup and intraoperative clinical data from 2 human hearts were included in the analysis. The spatial locations of rotors were identified using phase maps constructed from 112 electrograms. Electrograms were analyzed for repeating patterns and discriminating signal morphologies around the locations of rotors and nonrotors were identified and quantified. Features were extracted from the unipolar electrogram patterns, which corroborated well with the spatial location of rotors. The results suggest that using the proposed modulation index feature, and as low as 1 sample point in the vicinity of the rotors, an accuracy as high as 86% (P<0.001) was obtained in separating rotor locations versus nonrotor locations. The analysis of bipolar electrogram signatures in the vicinity of the rotor locations suggest that 62.5% of the rotors occur at locations where the bipolar electrogram demonstrates continuous activities during ventricular fibrillation. CONCLUSIONS: Unipolar electrogram extracted modulation index-based detection of rotors is feasible with few electrodes and has greater detection rate than bipolar approach. This strategy may be suitable for nonarray based single mapping catheter enabled detection of rotors. PMID- 25740826 TI - Electromyographic monitoring for prevention of phrenic nerve palsy in second generation cryoballoon procedures. AB - BACKGROUND: Electromyography-guided phrenic nerve (PN) monitoring using a catheter positioned in a hepatic vein can aid in preventing phrenic nerve palsy (PNP) during cryoballoon ablation for atrial fibrillation. We wanted to evaluate the feasibility and efficacy of PN monitoring during procedures using second generation cryoballoons. METHODS AND RESULTS: This study included 140 patients (43 women) in whom pulmonary vein isolation was performed using a second generation cryoballoon. Electromyography-guided PN monitoring was performed by pacing the right PN at 60 per minute and recording diaphragmatic compound motor action potential (CMAP) via a quadripolar catheter positioned in a hepatic vein. If a 30% decrease in CMAP amplitude was observed, cryoapplication was discontinued with forced deflation to avoid a PNP. Monitoring was unfeasible in 8 of 140 patients (5.7%), PNP occurred in 1. Stable CMAP amplitudes were achieved before ablation in 132 of 140 patients (94.3%). In 18 of 132 patients (13.6%), a 30% decrease in CMAP amplitude occurred and cryoablation was discontinued. Each time, recovery of CMAP amplitude took <60 s. In 9 of 18 cases, a second cryoapplication in the same pulmonary vein was safely performed. We observed no PNP or complication related to electromyography-guided PN monitoring. CONCLUSIONS: Electromyography-guided PN monitoring using a catheter positioned in a hepatic vein seems feasible and effective to prevent PNP during cryoballoon ablation using second-generation cryoballoon. PMID- 25740827 TI - alpha-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of alpha-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT. PMID- 25740828 TI - MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia. AB - Leukemias with MLL translocations are often found in infants and are associated with poor outcomes. The pathogenesis of MLL-fusion leukemias has been linked to upregulation of HOX/MEIS1 genes. The functions of the Hox/Meis1 complex in leukemia, however, remain elusive. Here, we used inducible Meis1-knockout mice coupled with MLL-AF9 knockin mice to decipher the mechanistic role of Meis1 in established MLL leukemia. We demonstrate that Meis1 is essential for maintenance of established leukemia. In addition, in both the murine model and human leukemia cells, we found that Meis1 loss led to increased oxidative stress, oxygen flux, and apoptosis. Gene expression and chromatin immunoprecipitation studies revealed hepatic leukemia factor (HLF) as a target gene of Meis1. Hypoxia or HLF expression reversed the oxidative stress, rescuing leukemia development in Meis1 deficient cells. Thus, the leukemia-promoting properties of Meis1 are at least partly mediated by a low-oxidative state, aided by HLF. These results suggest that stimulants of oxidative metabolism could have therapeutic potential in leukemia treatment. PMID- 25740829 TI - Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjogren's syndrome. AB - OBJECTIVE: The aim of this study was to investigate the biological effects of belimumab on B cells in the first phase II open-label trial with belimumab in patients with primary SS (pSS) (BELISS). METHODS: Peripheral blood B cell subsets and their B cell activating factor-receptor (BAFF-R) expression were analysed by multicolour flow cytometry in 10 pSS patients either before or after 24 and 52 weeks of therapy with belimumab. Serum BAFF levels were analysed by ELISA. RESULTS: At baseline, pSS patients showed a significant increase in circulating B cells compared with healthy donors matched for age and sex, with a predominant expansion of transitional and naive B cell subsets. pSS patients also showed higher serum BAFF levels and lower B cell BAFF-R expression. Therapy with belimumab in pSS patients induced a significant reduction in transitional and naive B cell subsets to levels similar to those observed in healthy donors. Furthermore, belimumab normalized BAFF-R expression in all B subsets comprised within the memory compartment. The restoration of B cell frequency and subset composition in response to belimumab was also associated with a decrease in serum levels of Ig, RF, ANAs, and with an increase in the C4 complement fraction. All of these belimumab-mediated effects were observed after 24 weeks of therapy and maintained until the end of the therapeutic protocol. CONCLUSION: Taken together, our findings show that targeting BAFF with belimumab is successful in normalizing B cell frequency, phenotype and functions in pSS. TRIAL REGISTRATION: clinicaltrials.gov; https://clinicaltrials.gov/; NCT01008982. PMID- 25740830 TI - Long-term experience with rituximab in anti-synthetase syndrome-related interstitial lung disease. AB - OBJECTIVE: To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD). METHODS: Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8). RESULTS: Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%). CONCLUSION: This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention. PMID- 25740831 TI - Vulvar myiasis following suction and evacuation for incomplete abortion. AB - Myiasis is caused by fly larva capable of penetrating healthy or necrotic tissue, usually in tropical and subtropical countries. The involvement of an exposed area is common; however it may very rarely involve the genital region. We present a rare case of vulvar myiasis which occurred after suction and evacuation performed for incomplete abortion. PMID- 25740832 TI - Local production of skeletal traction pins to improve access to skeletal traction. AB - Femoral fractures represent a substantial orthopaedic injury. In the developed world, closed reduction and locked intramedullary nailing is recognized as the optimal treatment. In the less developed world, the use of skeletal traction remains limited by cost and availability of traction pins, which are obtained from orthopaedic companies in the UK or Indian subcontinent. This study aimed to establish whether traction pins may be manufactured locally in resource-limited countries from cut down stainless steel rods. The overall costs for traction pins were obtained from five UK, Indian subcontinent-based companies and metal fabrication shops in Africa. Strict design specifications were provided. The mean price for 100 Steinmann pins was$428 in the Indian subcontinent,$96 in Malawi,$105 in Kenya and$244 in Tanzania. Our results indicate that Steinmann pins may be manufactured locally in resource-limited countries at a significantly cheaper price, which may increase the access to skeletal traction. PMID- 25740833 TI - The effect of trochlear dysplasia on patellofemoral biomechanics: a cadaveric study with simulated trochlear deformities. AB - BACKGROUND: Trochlear dysplasia appears in different geometrical variations. The Dejour classification is widely used to grade the severity of trochlear dysplasia and to decide on treatment. PURPOSE: To investigate the effect of trochlear dysplasia on patellofemoral biomechanics and to determine if different types of trochlear dysplasia have different effects on patellofemoral biomechanics. STUDY DESIGN: Controlled laboratory study. METHODS: Trochlear dysplasia was simulated in 4 cadaveric knees by replacing the native cadaveric trochlea with different types of custom-made trochlear implants, manufactured with 3-dimensional printing. For each knee, 5 trochlear implants were designed: 1 implant simulated the native trochlea (control condition), and 4 implants simulated 4 types of trochlear dysplasia. The knees were subjected to 3 biomechanical tests: a squat simulation, an open chain extension simulation, and a patellar stability test. The patellofemoral kinematics, contact area, contact pressure, and stability were compared between the control condition (replica implants) and the trochlear dysplastic condition and among the subgroups of trochlear dysplasia. RESULTS: The patellofemoral joint in the trochlear dysplastic group showed increased internal rotation, lateral tilt, and lateral translation; increased contact pressures; decreased contact areas; and decreased stability when compared with the control group. Within the trochlear dysplastic group, the implants graded as Dejour type D showed the largest deviations for the kinematical parameters, and the implants graded as Dejour types B and D showed the largest deviations for the patellofemoral contact areas and pressures. CONCLUSION: Patellofemoral kinematics, contact area, contact pressure, and stability are significantly affected by trochlear dysplasia. Of all types of trochlear dysplasia, the models characterized with a pronounced trochlear bump showed the largest deviations in patellofemoral biomechanics. CLINICAL RELEVANCE: Investigating the relationship between the shape of the trochlea and patellofemoral biomechanics can provide insight into the short-term effects (maltracking, increased pressures, and instability) and long-term effects (osteoarthritis) of different types of trochlear dysplasia. Furthermore, this investigation provides an empirical explanation for better treatment outcomes of trochleoplasty for Dejour types B and D dysplasia. PMID- 25740834 TI - Status of the contralateral rotator cuff in patients undergoing rotator cuff repair. AB - BACKGROUND: Although the prevalence of rotator cuff tear (RCT) in the general population has been analyzed, little information is available on the status of the opposite-side rotator cuff in patients who have undergone arthroscopic rotator cuff repair. PURPOSE/HYPOTHESIS: To identify the characteristics of the contralateral shoulder and to identify factors associated with RCT of the contralateral shoulder in patients who underwent surgery for symptomatic RCT. The hypothesis was that the prevalence of RCT in the contralateral shoulder would be higher in patients with increasingly larger cuff tears requiring surgical intervention. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The study cohort consisted of 140 patients with RCT who underwent arthroscopic rotator cuff repair. Opposite-shoulder rotator cuff tendons of all patients were evaluated by ultrasonography. Demographic information and factors related to contralateral RCT were investigated, and risk factors associated with contralateral RCT were assessed. RESULTS: Of the 140 patients who underwent arthroscopic rotator cuff repair, 54 (38.6%) had an RCT of the contralateral shoulder. Of 51 patients with partial-thickness and small-sized full-thickness tears of the operated shoulder, 35 (68.6%) had no tears; 14 (27.5%) had partial-thickness tears; and 2 (3.9%) had small-sized full-thickness tears of the contralateral shoulder. Of 75 patients with medium-sized full-thickness tears, 43 (57.3%) had no tears; 12 (16%) had partial-thickness tears; and 20 (26.7%) had full-thickness tears of the contralateral shoulder. Of 14 patients with large to massive full-thickness tears, 8 (57.1%) had no tears; 1 (7.1%) had a partial-thickness tear; and 5 (35.7%) had full-thickness tears of the contralateral shoulder. The prevalence of RCT of the contralateral shoulder differed significantly among groups classified by tear size (P=.007). The mean American Shoulder and Elbow Surgeons score was significantly lower in the RCT than in the nontear group (55.8+/-16.9 vs 61.6+/ 13.3; P=.03). Of 29 subjects with symptomatic tears involving the nondominant arm, 17 (58.6%) had contralateral asymptomatic RCT, compared with 37 of 111 (33.3%) subjects with symptomatic tears involving the dominant arm (P=.007). CONCLUSION: The prevalence of RCT of the contralateral asymptomatic shoulder tends to be higher in patients with more symptomatic RCT on one side, in patients with medium-sized or larger RCT in the operated shoulder, and in patients with symptomatic RCT in the nondominant arm. PMID- 25740835 TI - Outcome of a Combined Anterior Cruciate Ligament and Anterolateral Ligament Reconstruction Technique With a Minimum 2-Year Follow-up. AB - BACKGROUND: The anterolateral ligament has recently been identified as an important structure involved in rotational laxity after anterior cruciate ligament (ACL) rupture. Results of a combined ACL and anterolateral ligament (ALL) reconstruction technique have never been reported. PURPOSE: To report subjective and objective outcomes after combined ACL and minimally invasive ALL reconstruction with a minimum 2-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 92 patients underwent a combined ACL and ALL reconstruction. Indications for a combined procedure were associated Segond fracture, chronic ACL lesion, grade 3 pivot shift, high level of sporting activity, pivoting sports, and radiographic lateral femoral notch sign. Patients were assessed pre- and postoperatively with objective and subjective International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner activity scale. Instrumented knee testing was performed with the Rolimeter arthrometer. The Knee injury and Osteoarthritis Outcome Score (KOOS) was obtained at the last follow-up. Complications including graft failure or contralateral ACL rupture were also recorded. RESULTS: The mean follow-up time was 32.4 +/- 3.9 months. One patient (1.1%) was lost to follow-up, 1 patient (1.1%) suffered an ACL graft rupture, and 7 patients (7.6%) had a contralateral ACL rupture, leaving 83 patients for final evaluation. At the last follow-up, all patients had full range of motion. The Lysholm, subjective IKDC, and objective IKDC scores were significantly improved (all P < .0001). The Tegner activity scale at the last follow-up (7.1 +/- 1.8) was slightly lower than before surgery (7.3 +/- 1.7) (P < .01). The mean differential anterior laxity was 8 +/- 1.9 mm before surgery and significantly decreased to 0.7 +/- 0.8 mm at the last follow-up (P < .0001). Preoperatively, 41 patients had a grade 1 pivot shift, 23 had a grade 2, and 19 had a grade 3 according to the IKDC criteria. Postoperatively, 76 patients had a negative pivot shift (grade 0), and 7 patients were grade 1 (P < .0001). CONCLUSION: This study demonstrates that a combined reconstruction can be an effective procedure without specific complications at a minimum follow-up of 2 years. Longer term and comparative follow-up studies are necessary to determine whether these combined reconstructions improve the results of ACL treatment. PMID- 25740836 TI - Relationship between sinus rhythm late activation zones and critical sites for scar-related ventricular tachycardia: systematic analysis of isochronal late activation mapping. AB - BACKGROUND: It is not known whether the most delayed late potentials are functionally most specific for scar-related ventricular tachycardia (VT) circuits. METHODS AND RESULTS: Isochronal late activation maps were constructed to display ventricular activation during sinus rhythm over 8 isochrones. Analysis was performed at successful VT termination sites and prospectively tested. Thirty three patients with 47 scar-related VTs where a critical site was demonstrated by termination of VT during ablation were retrospectively analyzed. In those who underwent mapping of multiple surfaces, 90% of critical sites were on the surface that contained the latest late potential. However, only 11% of critical sites were localized to the latest isochrone (87.5%-100%) of ventricular activation. The median percentage of latest activation at critical sites was 78% at a distance from the latest isochrone of 18 mm. Sites critical to reentry were harbored in regions with slow conduction velocity, where 3 isochrones were present within a 1-cm radius. Ten consecutive patients underwent ablation prospectively guided by isochronal late activation maps, targeting concentric isochrones outside of the latest isochrone. Elimination of the targeted VT was achieved in 90%. Termination of VT was achieved in 6 patients at a mean ventricular activation percentage of 78%, with only 1 requiring ablation in the latest isochrone. CONCLUSIONS: Late potentials identified in the latest isochrone of activation during sinus rhythm are infrequently correlated with successful ablation sites for VT. The targeting of slow conduction regions propagating into the latest zone of activation may be a novel and promising strategy for substrate modification. PMID- 25740837 TI - Characterization of a novel eukaryal nick-sealing RNA ligase from Naegleria gruberi. AB - The proteome of the amoebo-flagellate protozoan Naegleria gruberi is rich in candidate RNA repair enzymes, including 15 putative RNA ligases, one of which, NgrRnl, is a eukaryal homolog of Deinococcus radiodurans RNA ligase, DraRnl. Here we report that purified recombinant NgrRnl seals nicked 3'-OH/5'-PO4 duplexes in which the 3'-OH strand is RNA. It does so via the "classic" ligase pathway, entailing reaction with ATP to form a covalent NgrRnl-AMP intermediate, transfer of AMP to the nick 5'-PO4, and attack of the RNA 3'-OH on the adenylylated nick to form a 3'-5' phosphodiester. Unlike members of the four known families of ATP dependent RNA ligases, NgrRnl lacks a carboxy-terminal appendage to its nucleotidyltransferase domain. Instead, it contains a defining amino-terminal domain that we show is important for 3'-OH/5'-PO4 nick-sealing and ligase adenylylation, but dispensable for phosphodiester synthesis at a preadenylylated nick. We propose that NgrRnl, DraRnl, and their homologs from diverse bacteria, viruses, and unicellular eukarya comprise a new "Rnl5 family" of nick-sealing ligases with a signature domain organization. PMID- 25740838 TI - Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or beta1-Adrenergic Stimulation. AB - BACKGROUND: Mammalian hearts exhibit positive inotropic responses to beta adrenergic stimulation as a consequence of protein kinase A-mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin-binding protein-C (cMyBP-C) by protein kinase A accelerates the kinetics of force development in permeabilized heart muscle, but its role in vivo is unknown. Such understanding is important because adrenergic responsiveness of the heart and the Bowditch effect are both depressed in heart failure. METHODS AND RESULTS: The roles of cMyBP-C phosphorylation were studied using mice in which either WT or nonphosphorylatable forms of cMyBP-C [ser273ala, ser282ala, ser302ala: cMyBP-C(t3SA)] were expressed at similar levels on a cMyBP-C null background. Force and [Ca(2+)]in measurements in isolated papillary muscles showed that the increased force and twitch kinetics because increased pacing or beta1-adrenergic stimulation were nearly absent in cMyBP-C(t3SA) myocardium, even though [Ca(2+)]in transients under each condition were similar to WT. Biochemical measurements confirmed that protein kinase A phosphorylated ser273, ser282, and ser302 in WT cMyBP-C. In contrast, CaMKIIdelta, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all. CONCLUSIONS: Phosphorylation of cMyBP-C increases the force and kinetics of twitches in living cardiac muscle. Further, cMyBP-C is a principal mediator of increased contractility observed with beta-adrenergic stimulation or increased pacing because of protein kinase A and CaMKIIdelta phosphorylations of cMyB-C. PMID- 25740840 TI - Routine use of sedatives before surgery has little benefit, study shows. PMID- 25740839 TI - Phosphorylation of cardiac Myosin-binding protein-C is a critical mediator of diastolic function. AB - BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for ~50% of all cases of HF and currently has no effective treatment. Diastolic dysfunction underlies HFpEF; therefore, elucidation of the mechanisms that mediate relaxation can provide new potential targets for treatment. Cardiac myosin-binding protein-C (cMyBP-C) is a thick filament protein that modulates cross-bridge cycling rates via alterations in its phosphorylation status. Thus, we hypothesize that phosphorylated cMyBP-C accelerates the rate of cross-bridge detachment, thereby enhancing relaxation to mediate diastolic function. METHODS AND RESULTS: We compared mouse models expressing phosphorylation-deficient cMyBP C(S273A/S282A/S302A)-cMyBP-C(t3SA), phosphomimetic cMyBP-C(S273D/S282D/S302D) cMyBP-C(t3SD), and wild-type-control cMyBP-C(tWT) to elucidate the functional effects of cMyBP-C phosphorylation. Decreased voluntary running distances, increased lung/body weight ratios, and increased brain natriuretic peptide levels in cMyBP-C(t3SA) mice demonstrate that phosphorylation deficiency is associated with signs of HF. Echocardiography (ejection fraction and myocardial relaxation velocity) and pressure/volume measurements (-dP/dtmin, pressure decay time constant tau-Glantz, and passive filling stiffness) show that cMyBP-C phosphorylation enhances myocardial relaxation in cMyBP-C(t3SD) mice, whereas deficient cMyBP-C phosphorylation causes diastolic dysfunction with HFpEF in cMyBP-C(t3SA) mice. Simultaneous force and [Ca(2+)]i measurements on intact papillary muscles show that enhancement of relaxation in cMyBP-C(t3SD) mice and impairment of relaxation in cMyBP-C(t3SA) mice are not because of altered [Ca(2+)]i handling, implicating that altered cross-bridge detachment rates mediate these changes in relaxation rates. CONCLUSIONS: cMyBP-C phosphorylation enhances relaxation, whereas deficient phosphorylation causes diastolic dysfunction and phenotypes resembling HFpEF. Thus, cMyBP-C is a potential target for treatment of HFpEF. PMID- 25740841 TI - Body mass estimates of an exceptionally complete Stegosaurus (Ornithischia: Thyreophora): comparing volumetric and linear bivariate mass estimation methods. AB - Body mass is a key biological variable, but difficult to assess from fossils. Various techniques exist for estimating body mass from skeletal parameters, but few studies have compared outputs from different methods. Here, we apply several mass estimation methods to an exceptionally complete skeleton of the dinosaur Stegosaurus. Applying a volumetric convex-hulling technique to a digital model of Stegosaurus, we estimate a mass of 1560 kg (95% prediction interval 1082-2256 kg) for this individual. By contrast, bivariate equations based on limb dimensions predict values between 2355 and 3751 kg and require implausible amounts of soft tissue and/or high body densities. When corrected for ontogenetic scaling, however, volumetric and linear equations are brought into close agreement. Our results raise concerns regarding the application of predictive equations to extinct taxa with no living analogues in terms of overall morphology and highlight the sensitivity of bivariate predictive equations to the ontogenetic status of the specimen. We emphasize the significance of rare, complete fossil skeletons in validating widely applied mass estimation equations based on incomplete skeletal material and stress the importance of accurately determining specimen age prior to further analyses. PMID- 25740842 TI - Reported maternal tendencies predict the reward value of infant facial cuteness, but not cuteness detection. AB - The factors that contribute to individual differences in the reward value of cute infant facial characteristics are poorly understood. Here we show that the effect of cuteness on a behavioural measure of the reward value of infant faces is greater among women reporting strong maternal tendencies. By contrast, maternal tendencies did not predict women's subjective ratings of the cuteness of these infant faces. These results show, for the first time, that the reward value of infant facial cuteness is greater among women who report being more interested in interacting with infants, implicating maternal tendencies in individual differences in the reward value of infant cuteness. Moreover, our results indicate that the relationship between maternal tendencies and the reward value of infant facial cuteness is not due to individual differences in women's ability to detect infant cuteness. This latter result suggests that individual differences in the reward value of infant cuteness are not simply a by-product of low-cost, functionless biases in the visual system. PMID- 25740843 TI - Deficiency in lymphotoxin beta receptor protects from atherosclerosis in apoE deficient mice. AB - RATIONALE: Lymphotoxin beta receptor (LTbR) regulates immune cell trafficking and communication in inflammatory diseases. However, the role of LTbR in atherosclerosis is still unclear. OBJECTIVE: The aim of this study was to elucidate the role of LTbR in atherosclerosis. METHODS AND RESULTS: After 15 weeks of feeding a Western-type diet, mice double-deficient in apolipoprotein E and LTbR (apoE(-/-)/LTbR(-/-)) exhibited lower aortic plaque burden than did apoE(-/-) littermates. Macrophage content at the aortic root and in the aorta was reduced, as determined by immunohistochemistry and flow cytometry. In line with a decrease in plaque inflammation, chemokine (C-C motif) ligand 5 (Ccl5) and other chemokines were transcriptionally downregulated in aortic tissue from apoE(-/ )/LTbR(-/-) mice. Moreover, bone marrow chimeras demonstrated that LTbR deficiency in hematopoietic cells mediated the atheroprotection. Furthermore, during atheroprogression, apoE(-/-) mice exhibited increased concentrations of cytokines, for example, Ccl5, whereas apoE(-/-)/LTbR(-/-) mice did not. Despite this decreased plaque macrophage content, flow cytometric analysis showed that the numbers of circulating lymphocyte antigen 6C (Ly6C)(low) monocytes were markedly elevated in apoE(-/-)/LTbR(-/-) mice. The influx of these cells into atherosclerotic lesions was significantly reduced, whereas apoptosis and macrophage proliferation in atherosclerotic lesions were unaffected. Gene array analysis pointed to chemokine (C-C motif) receptor 5 as the most regulated pathway in isolated CD115(+) cells in apoE(-/-)/LTbR(-/-) mice. Furthermore, stimulating monocytes from apoE(-/-) mice with agonistic anti-LTbR antibody or the natural ligand lymphotoxin-alpha1beta2, increased Ccl5 mRNA expression. CONCLUSIONS: These findings suggest that LTbR plays a role in macrophage-driven inflammation in atherosclerotic lesions, probably by augmenting the Ccl5-mediated recruitment of monocytes. PMID- 25740844 TI - Trusts have used part of L700m winter pressures fund to pay off debts, doctors claim. PMID- 25740845 TI - HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity. AB - Huntington's disease (HD) is a fatal neurodegenerative disease, caused by expansion of polyglutamine repeats in the Huntingtin gene, with longer expansions leading to earlier ages of onset. The HD iPSC Consortium has recently reported a new in vitro model of HD based on the generation of induced pluripotent stem cells (iPSCs) from HD patients and controls. The current study has furthered the disease in a dish model of HD by generating new non-integrating HD and control iPSC lines. Both HD and control iPSC lines can be efficiently differentiated into neurons/glia; however, the HD-derived cells maintained a significantly greater number of nestin-expressing neural progenitor cells compared with control cells. This cell population showed enhanced vulnerability to brain-derived neurotrophic factor (BDNF) withdrawal in the juvenile-onset HD (JHD) lines, which appeared to be CAG repeat-dependent and mediated by the loss of signaling from the TrkB receptor. It was postulated that this increased death following BDNF withdrawal may be due to glutamate toxicity, as the N-methyl-d-aspartate (NMDA) receptor subunit NR2B was up-regulated in the cultures. Indeed, blocking glutamate signaling, not just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death phenotype. This study suggests that the pathogenesis of JHD may involve in part a population of 'persistent' neural progenitors that are selectively vulnerable to BDNF withdrawal. Similar results were seen in adult hippocampal-derived neural progenitors isolated from the BACHD model mouse. Together, these results provide important insight into HD mechanisms at early developmental time points, which may suggest novel approaches to HD therapeutics. PMID- 25740846 TI - The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle. AB - Distal arthrogryposis is the most common known heritable cause of congenital contractures (e.g. clubfoot) and results from mutations in genes that encode proteins of the contractile complex of skeletal muscle cells. Mutations are most frequently found in MYH3 and are predicted to impair the function of embryonic myosin. We measured the contractile properties of individual skeletal muscle cells and the activation and relaxation kinetics of isolated myofibrils from two adult individuals with an R672C substitution in embryonic myosin and distal arthrogryposis syndrome 2A (DA2A) or Freeman-Sheldon syndrome. In R672C containing muscle cells, we observed reduced specific force, a prolonged time to relaxation and incomplete relaxation (elevated residual force). In R672C containing muscle myofibrils, the initial, slower phase of relaxation had a longer duration and slower rate, and time to complete relaxation was greatly prolonged. These observations can be collectively explained by a small subpopulation of myosin cross-bridges with greatly reduced detachment kinetics, resulting in a slower and less complete deactivation of thin filaments at the end of contractions. These findings have important implications for selecting and testing directed therapeutic options for persons with DA2A and perhaps congenital contractures in general. PMID- 25740847 TI - Mutated myocilin and heterozygous Sod2 deficiency act synergistically in a mouse model of open-angle glaucoma. AB - Glaucoma is a multifactorial optic neuropathy characterized by retinal ganglion cell (RGC) death and axonal degeneration leading to irreversible blindness. Mutations in the myocilin (MYOC) gene are the most common genetic factors of primary open-angle glaucoma. To develop a genetic mouse model induced by the synergistic interaction of mutated myocilin and another significant risk factor, oxidative stress, we produced double-mutant mice (Tg-MYOC(Y437H/+)/Sod2(+/-)) bearing human MYOC with a Y437H point mutation and a heterozygous deletion of the gene for the primary antioxidant enzyme, superoxide dismutase 2 (SOD2). Sod2 is broadly expressed in most tissues including the trabecular meshwork (TM) and heterozygous Sod2 knockout mice exhibit the reduced SOD2 activity and oxidative stress in all studied tissues. Accumulation of Y437H myocilin in the TM induced endoplasmic reticulum stress and led to a 45% loss of smooth muscle alpha-actin positive cells in the eye drainage structure of 10- to 12-month-old Tg MYOC(Y437H/+)/Sod2(+/-) mice as compared with wild-type littermates. Tg MYOC(Y437H/+)/Sod2(+/-) mice had higher intraocular pressure, lost about 37% of RGCs in the peripheral retina, and exhibited axonal degeneration in the retina and optic nerve as compared with their wild-type littermates. Single-mutant littermates containing MYOC(Y437H/+) or Sod2(+/-) exhibited no significant pathological changes until 12 months of age. Additionally, we observed elevated expression of endothelial leukocyte adhesion molecule-1, a human glaucoma marker, in the TM of Tg-MYOC(Y437H/+)/Sod2(+/-) mice. This is the first reported animal glaucoma model that combines expression of a glaucoma-causing mutant gene and an additional mutation mimicking a deleterious environment factor that acts synergistically. PMID- 25740848 TI - HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain. AB - Both gain- and loss-of-function mutations have recently implicated HCFC1 in neurodevelopmental disorders. Here, we extend our previous HCFC1 over-expression studies by employing short hairpin RNA to reduce the expression of Hcfc1 in embryonic neural cells. We show that in contrast to over-expression, loss of Hcfc1 favoured proliferation of neural progenitor cells at the expense of differentiation and promoted axonal growth of post-mitotic neurons. To further support the involvement of HCFC1 in neurological disorders, we report two novel HCFC1 missense variants found in individuals with intellectual disability (ID). One of these variants, together with three previously reported HCFC1 missense variants of unknown pathogenicity, were functionally assessed using multiple cell based assays. We show that three out of the four variants tested result in a partial loss of HCFC1 function. While over-expression of the wild-type HCFC1 caused reduction in HEK293T cell proliferation and axonal growth of neurons, these effects were alleviated upon over-expression of three of the four HCFC1 variants tested. One of these partial loss-of-function variants disrupted a nuclear localization sequence and the resulting protein displayed reduced ability to localize to the cell nucleus. The other two variants displayed negative effects on the expression of the HCFC1 target gene MMACHC, which is responsible for the metabolism of cobalamin, suggesting that these individuals may also be susceptible to cobalamin deficiency. Together, our work identifies plausible cellular consequences of missense HCFC1 variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain development. PMID- 25740849 TI - Ethnic differences in BMI, subcutaneous fat, and serum leptin levels during and after pregnancy and risk of gestational diabetes. AB - OBJECTIVE: To explore the differences between Europeans and South Asians in BMI, subcutaneous fat, and serum leptin (s-leptin) levels during and after pregnancy and their relationship with gestational diabetes (GDM). DESIGN: Multi-ethnic population-based cohort study, whereof 353 Europeans (93.1% of the included) and 190 South Asians (95.0% of the included). METHODS: S-leptin, BMI, and subcutaneous fat (sum of triceps, subscapular, and suprailiac skinfolds) were measured at 14 and 28 weeks of gestation, and 14 weeks after delivery. GDM was diagnosed with the WHO criteria 2013. RESULTS: South Asians had similar thickness of the triceps and suprailiac skinfolds, thicker subscapular skinfold, and higher s-leptin than Europeans in early pregnancy, despite lower BMI. South Asians retained more subcutaneous fat (mean (95% CI) 10.0 (7.4-12.7) mm vs 3.8 (1.9-5.8) mm) and BMI (1.5 (1.2-1.8) kg/m(2) vs 0.1 (-0.1 to 0.3) kg/m(2)) than Europeans 14 weeks after delivery and s-leptin decreased less in South Asians than Europeans (-0.13 (-0.27 to -0.00) MUg/l vs -0.47 (-0.57 to -0.37) MUg/l, P<0.001 for all). The prevalence of GDM was 23.8% (n=84) in Europeans and 42.6% (n=81) in South Asians. BMI, subcutaneous fat, and s-leptin were all positively associated with GDM, also after adjustment for covariates. CONCLUSIONS: The relatively high amounts of subcutaneous fat and s-leptin in South Asians in early pregnancy contributed to their increased risk of GDM. South Asians retained more weight and subcutaneous fat after delivery, potentially increasing their risk of adiposity and GDM in future pregnancies. PMID- 25740850 TI - Screening for mutations in 17beta-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development. AB - CONTEXT AND OBJECTIVE: The precise diagnosis of partially virilised women with 46,XY disorders of sex development (DSD) is often obscure. In practice, this group often comes under the poorly defined, clinically based label of partial androgen insensitivity syndrome (PAIS). In a previous study, we found that 5alpha reductase 2 (SRD5A2) mutations occurred in 43% of women in this subgroup. We expand this work to include biochemical and genetic screening for 17beta hydroxysteroid dehydrogenase (HSD17B3) and androgen receptor (AR) mutations. METHODS: Analysis of serum androgens (androstenedione and testosterone) and genetic analyses for HSD17B3 and AR were performed in 42 women from 36 pedigrees with partially virilised 46,XY DSD in whom SRD5A2 deficiency had been excluded by urine steroid profiling. RESULTS: Out of 36 unrelated women, 14 (38%) were found to have HSD17B3 mutations and one (2.7%) to have an AR defect. Six novel pathogenic HSD17B3 mutations were identified: three splice site mutations and three missense changes. Seven patients with HSD17B3 deficiency tested before gonadectomy had basal testosterone/androstenedione (T/A) ratio <0.8 (sensitivity 100% and specificity 91%). CONCLUSIONS: HSD17B3 deficiency is prevalent in the adolescent and adult 46,XY female DSD population and is often associated with lesser degrees of virilisation compared with those with 5alpha-reductase deficiency. This diagnosis should be considered for individuals labelled as PAIS, particularly, but not exclusively, those who present with virilisation at puberty or primary amenorrhoea. Before gondadectomy, T/A ratio is useful to aid diagnosis, but after gonadectomy sequencing of HSD17B3 must be performed to confirm the diagnosis. PMID- 25740851 TI - Does selenium supplementation affect thyroid function? Results from a randomized, controlled, double-blinded trial in a Danish population. AB - OBJECTIVE: Selenium is present in the active site of proteins important for thyroid hormone synthesis and metabolism. The objective of this study is to investigate the effect of selenium supplementation in different doses on thyroid function, under conditions of suboptimal dietary selenium intake. DESIGN: The Danish PREvention of Cancer by Intervention with SElenium pilot study (DK PRECISE) is a randomized, double-blinded, placebo-controlled trial. A total of 491 males and females aged 60-74 years were randomized to 100 MUg (n=124), 200 MUg (n=122), or 300 MUg (n=119) selenium-enriched yeast or matching yeast-based placebo tablets (n=126). A total of 361 participants, equally distributed across treatment groups, completed the 5-year intervention period. METHODS: Plasma samples were analyzed for selenium and serum samples for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) at baseline, and after 6 months, and 5 years of supplementation. RESULTS: Plasma selenium concentrations increased significantly and dose-dependently in treatment groups receiving selenium (P<0.001). Serum TSH and FT4 concentrations decreased significantly and dose dependently by 0.066 mIU/l (P=0.010) and 0.11 pmol/l (P=0.015), respectively, per 100 MUg/day increase, with insignificant differences between 6 months and 5 years. No significant effects were found for FT3 and FT3:FT4 ratio. CONCLUSIONS: In euthyroid subjects, selenium supplementation minutely and dose-dependently affects thyroid function, when compared with placebo, by decreasing serum TSH and FT4 concentrations. Based on these findings, selenium supplementation is not warranted under conditions of marginal selenium deficiency. However, a role for selenium supplementation in the treatment of autoimmune thyroid diseases is still unresolved. PMID- 25740852 TI - The serum inhibin B concentration and reference ranges in normozoospermia. AB - OBJECTIVE: Although an inhibin B assay may be useful in the assessment of testicular function in a number of genital conditions, reliable reference ranges are still lacking. The present study sought to establish the reference range for serum inhibin B by applying the updated Gen II assay. DESIGN: This prospective study included 818 men referred for semen analysis: 377 were normozoospermic (reference group) and 441 presented at least one abnormal semen parameter (case group). METHODS: Semen parameters were interpreted according to the 2010 World Health Organization manual and David's modified classification for normal morphology. The inhibin B concentration was determined with the current ELISA. RESULTS: In the reference group, the 2.5th percentile for inhibin B was 92 pg/ml and the 97.5th percentile for FSH was 7.8 IU/l. In the overall population, an inhibin B level <92 pg/ml was associated with increased odds ratio (OR; 95% CI) for oligozoospermia (16.93 (9.82-29.18), P<0.0001), asthenozoospermia (4.87 (2.88 8.10), P<0.0001), and teratozoospermia (2.20 (1.31-3.68), P=0.0026). The combination of a FSH >7.8 IU/l and an inhibin B <92 pg/ml was associated with greater OR for oligozoospermia (98.74 (23.99-406.35), P<0.0001) than for each hormone considered separately. CONCLUSIONS: A new reference range for serum inhibin B was established by the use of updated immunoassay. The correlations between hormone levels and semen parameters highlighted the importance of establishing these values with respect to the spermogram. When combined with FSH assay, the inhibin B range may be of value in the evaluation of spermatogenesis in a number of male genital conditions. PMID- 25740853 TI - Residual deformations in ocular tissues. AB - Residual deformations strongly influence the local biomechanical environment in a number of connective tissues. The sclera is known to be biomechanically important in healthy and diseased eyes, such as in glaucoma. Here, we study the residual deformations of the sclera, as well as the adjacent choroid and retina. Using freshly harvested porcine eyes, we developed two approaches of quantifying residual deformations in the spherically shaped tissues of interest. The first consisted of punching discs from the posterior wall of the eye and quantifying the changes in the area and eccentricity of these samples. The second consisted of cutting a ring from the equatorial sclera and making stress-relieving cuts in it. Measurements of curvature were made before and after the stress-relieving cuts. Using the first approach, we observed a 42% areal contraction of the choroid, but only modest contractions of the sclera and retina. The observed contractions were asymmetric. In the second approach, we observed an opening of the scleral rings (approx. 10% decrease in curvature). We conclude that residual bending deformations are present in the sclera, which we speculate may be due to radially heterogeneous growth and remodelling of the tissue during normal development. Further, residual areal deformations present in the choroid may be due to the network of elastic fibres in this tissue and residual deformations in the constituent vascular bed. Future studies of ocular biomechanics should attempt to include effects of these residual deformations into mechanical models in order to gain a better understanding of the biomechanics of the ocular wall. PMID- 25740854 TI - Modelling the heart as a communication system. AB - Electrical communication between cardiomyocytes can be perturbed during arrhythmia, but these perturbations are not captured by conventional electrocardiographic metrics. We developed a theoretical framework to quantify electrical communication using information theory metrics in two-dimensional cell lattice models of cardiac excitation propagation. The time series generated by each cell was coarse-grained to 1 when excited or 0 when resting. The Shannon entropy for each cell was calculated from the time series during four clinically important heart rhythms: normal heartbeat, anatomical reentry, spiral reentry and multiple reentry. We also used mutual information to perform spatial profiling of communication during these cardiac arrhythmias. We found that information sharing between cells was spatially heterogeneous. In addition, cardiac arrhythmia significantly impacted information sharing within the heart. Entropy localized the path of the drifting core of spiral reentry, which could be an optimal target of therapeutic ablation. We conclude that information theory metrics can quantitatively assess electrical communication among cardiomyocytes. The traditional concept of the heart as a functional syncytium sharing electrical information cannot predict altered entropy and information sharing during complex arrhythmia. Information theory metrics may find clinical application in the identification of rhythm-specific treatments which are currently unmet by traditional electrocardiographic techniques. PMID- 25740855 TI - Locomotion control of hybrid cockroach robots. AB - Natural systems retain significant advantages over engineered systems in many aspects, including size and versatility. In this research, we develop a hybrid robotic system using American (Periplaneta americana) and discoid (Blaberus discoidalis) cockroaches that uses the natural locomotion and robustness of the insect. A tethered control system was firstly characterized using American cockroaches, wherein implanted electrodes were used to apply an electrical stimulus to the prothoracic ganglia. Using this approach, larger discoid cockroaches were engineered into a remotely controlled hybrid robotic system. Locomotion control was achieved through electrical stimulation of the prothoracic ganglia, via a remotely operated backpack system and implanted electrodes. The backpack consisted of a microcontroller with integrated transceiver protocol, and a rechargeable battery. The hybrid discoid roach was able to walk, and turn in response to an electrical stimulus to its nervous system with high repeatability of 60%. PMID- 25740856 TI - Global burden of untreated caries: a systematic review and metaregression. AB - We aimed to consolidate all epidemiologic data about untreated caries and subsequently generate internally consistent prevalence and incidence estimates for all countries, 20 age groups, and both sexes for 1990 and 2010. The systematic search of the literature yielded 18,311 unique citations. After screening titles and abstracts, we excluded 10,461 citations as clearly irrelevant to this systematic review, leaving 1,682 for full-text review. Furthermore, 1,373 publications were excluded following the validity assessment. Overall, 192 studies of 1,502,260 children aged 1 to 14 y in 74 countries and 186 studies of 3,265,546 individuals aged 5 y or older in 67 countries were included in separate metaregressions for untreated caries in deciduous and permanent teeth, respectively, using modeling resources from the Global Burden of Disease 2010 study. In 2010, untreated caries in permanent teeth was the most prevalent condition worldwide, affecting 2.4 billion people, and untreated caries in deciduous teeth was the 10th-most prevalent condition, affecting 621 million children worldwide. The global age-standardized prevalence and incidence of untreated caries remained static between 1990 and 2010. There is evidence that the burden of untreated caries is shifting from children to adults, with 3 peaks in prevalence at ages 6, 25, and 70 y. Also, there were considerable variations in prevalence and incidence between regions and countries. Policy makers need to be aware of a predictable increasing burden of untreated caries due to population growth and longevity and a significant decrease in the prevalence of total tooth loss throughout the world from 1990 to 2010. PMID- 25740857 TI - Oral disease profiles in chronic graft versus host disease. AB - At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow <= 1 mL/5 min, mouth-opening <= 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will improve clinical diagnosis, observational research data collection, and the definitions of outcome measures in clinical trials. PMID- 25740858 TI - Optimization modeling to maximize population access to comprehensive stroke centers. AB - OBJECTIVE: The location of comprehensive stroke centers (CSCs) is critical to ensuring rapid access to acute stroke therapies; we conducted a population-level virtual trial simulating change in access to CSCs using optimization modeling to selectively convert primary stroke centers (PSCs) to CSCs. METHODS: Up to 20 certified PSCs per state were selected for conversion to maximize the population with 60-minute CSC access by ground and air. Access was compared across states based on region and the presence of state-level emergency medical service policies preferentially routing patients to stroke centers. RESULTS: In 2010, there were 811 Joint Commission PSCs and 0 CSCs in the United States. Of the US population, 65.8% had 60-minute ground access to PSCs. After adding up to 20 optimally located CSCs per state, 63.1% of the US population had 60-minute ground access and 86.0% had 60-minute ground/air access to a CSC. Across states, median CSC access was 55.7% by ground (interquartile range 35.7%-71.5%) and 85.3% by ground/air (interquartile range 59.8%-92.1%). Ground access was lower in Stroke Belt states compared with non-Stroke Belt states (32.0% vs 58.6%, p = 0.02) and lower in states without emergency medical service routing policies (52.7% vs 68.3%, p = 0.04). CONCLUSION: Optimal system simulation can be used to develop efficient care systems that maximize accessibility. Under optimal conditions, a large proportion of the US population will be unable to access a CSC within 60 minutes. PMID- 25740859 TI - Motor evoked potential polyphasia: a novel endophenotype of idiopathic generalized epilepsy. AB - OBJECTIVE: We compared the motor evoked potential (MEP) phases using transcranial magnetic stimulation in patients with idiopathic generalized epilepsy (IGE), their relatives, and healthy controls, hypothesizing that patients and their unaffected relatives may share a subtle pathophysiologic abnormality. METHODS: In a cross-sectional study, we investigated 23 patients with IGE, 34 first-degree relatives, and 30 matched healthy controls. Transcranial magnetic stimulation was performed to produce a series of suprathreshold single-pulse MEPs. A semiautomated method was used to count phases. We compared between groups the mean number of MEP phases, the stimulus-to-stimulus variability in MEP phases, and the proportion of polyphasic MEPs within subjects. RESULTS: Patients with IGE and their relatives had a significantly increased number of MEP phases (median for patients 2.24, relatives 2.17, controls 2.01) and a significantly higher proportion of MEPs with more than 2 phases than controls (median for patients 0.118, relatives 0.088, controls 0.013). Patients had a greater stimulus-to stimulus variability in number of MEP phases than controls. There were no differences between patients and relatives. CONCLUSION: Increased MEP polyphasia in patients with IGE and their first-degree relatives may reflect transient abnormal evoked oscillations. The presence of polyphasic MEPs in relatives as well as patients suggests that MEP polyphasia is not related to treatment, and is in isolation insufficient to predispose to epilepsy. Polyphasic MEP may be a novel endophenotype in IGE. PMID- 25740860 TI - Cortical microarchitecture changes in genetic epilepsy. AB - OBJECTIVE: The human GABAAgamma2(R43Q) mutation is associated with genetic epilepsy. Because of the role of gamma-aminobutyric acid (GABA) in brain development, we asked whether this epilepsy mutation might affect excitability by changing cortical cytoarchitecture. METHODS: We used a mouse model harboring a heterozygous R43Q missense mutation in the GABAA receptor subunit gamma2, as identified in a family with absence epilepsy and febrile seizures. Three dimensional quantification of immunostained neurons (NeuN), inhibitory neurons (GABA), and inhibitory neuron subpopulations (calretinin, parvalbumin, and calbindin) was performed in fiducial somatosensory cortical columns of seizure naive GABAAgamma2(R43Q) and control mice. RESULTS: Of note, the densities of GABA , calretinin-, parvalbumin-, and calbindin-containing neurons were increased, and somewhat perplexing, the ratio between putative excitatory and inhibitory neurons was decreased in GABAAgamma2(R43Q) mice. Differences were detected in a layer specific manner with greater overall effects in layers 2/3, 5, and 6, as compared with layers 1 and 4. CONCLUSIONS: Our results suggest that the gamma2(R43Q) mutation significantly affects cortical microcircuitry in the cortex of this model of human genetic epilepsy. PMID- 25740861 TI - Acute EEG findings in HIV-infected Zambian adults with new-onset seizure. AB - OBJECTIVE: To describe acute EEG findings in HIV-infected adults with new-onset seizure, assess baseline clinical characteristics associated with EEG abnormalities, and evaluate the relationship between EEG abnormalities and recurrent seizure. METHODS: Eighty-one HIV-infected adults with new-onset seizure had EEG recordings during their index admission. Baseline characteristics assessed included HIV stage, seizure semiology, serum and CSF studies, neuroimaging, cognitive function based on the Zambian Mini-Mental State Examination and International HIV Dementia Scale, and psychiatric symptoms using the Shona Symptom Questionnaire. We evaluated the relationship between baseline characteristics and EEG abnormalities. Patients were followed for seizure recurrence, and the association between acute EEG abnormalities and seizure recurrence was assessed. Death was a secondary outcome. RESULTS: Fifty-five patients had abnormal EEGs (68%): 18 (22%) had interictal spikes (12) or a recorded seizure (6). Among baseline clinical characteristics, more advanced HIV disease (p = 0.039) and any imaging abnormality (p = 0.027) were associated with abnormal EEGs. Cortical (p = 0.008) and white matter (p = 0.004) abnormalities were associated with slow posterior dominant rhythm. Patients were followed for a median of 303 days (interquartile range 103-560). Twenty-four (30%) died and 23 (28%) had recurrent seizures. EEG abnormalities were not associated with recurrent seizure. There was a nonsignificant association between seizures recorded during EEG and death (67% vs 26%, p = 0.051). CONCLUSIONS: EEG abnormalities are common in this population, particularly in patients with imaging abnormalities and advanced HIV. Acute EEG abnormalities were not associated with recurrent seizure, but high mortality rates during follow-up limited this analysis. PMID- 25740862 TI - Long-term impact of stroke on family caregiver well-being: a population-based case-control study. AB - OBJECTIVE: Three-year changes in well-being were studied among family caregivers of an epidemiologically derived sample of stroke survivors from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and compared to matched noncaregivers. METHODS: Family caregivers of REGARDS participants who experienced a stroke event completed telephone interviews assessing depressive symptoms, mental and physical health quality of life (QOL), life satisfaction, and leisure satisfaction at approximately 9, 18, 27, and 36 months after the stroke (n = 235). For each stroke caregiver, a family member of a stroke-free REGARDS participant was enrolled as a matched noncaregiving control (n = 235) and completed similar interviews. RESULTS: Multilevel longitudinal models found that caregivers showed poorer well-being at 9 months poststroke than controls on all measures except physical health QOL. Significant differences were sustained for 22 months after the stroke event for depressive symptoms, 31 months for mental health QOL, and 15 months for life satisfaction. For leisure satisfaction, differences were still significant at 36 months poststroke. Caregiving effects were similar across race and sex. CONCLUSIONS: Stroke caregiving is associated with persistent psychological distress, but life satisfaction, depression, and mental health QOL became comparable to noncaregivers by 3 years after stroke. Caregiver leisure satisfaction was chronically lower than in noncaregivers. Intervention for stroke caregivers should recognize both the strains faced by caregivers and their capacity for successful coping over time. PMID- 25740863 TI - Glycated albumin predicts the effect of dual and single antiplatelet therapy on recurrent stroke. AB - OBJECTIVE: To determine the relationship of glycated albumin (GA) and the recurrence of stroke in patients on either dual or single antiplatelet therapy. METHODS: The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial randomized minor ischemic stroke or TIA patients to antiplatelet therapy of clopidogrel plus aspirin or aspirin alone. A subgroup of 3,044 consecutive patients with baseline GA levels from 73 (64%) prespecified clinical sites was analyzed. Patients were categorized into 2 groups based on GA level of 15.5%, the cut point for development of diabetes. The primary outcome was stroke recurrence during 90-day follow-up. Cox proportional hazards models were used to assess the interaction of GA with randomized antiplatelet therapy on their risk of recurrent stroke. RESULTS: Significant interaction of GA levels with the 2 antiplatelet therapy groups was found after adjustment for age, sex, and other conventional confounding factors (p = 0.009). The interaction remained consistent after further adjustment for history of diabetes (p = 0.010). In patients with lower GA level, stroke occurred in 5.5% of patients in the clopidogrel-aspirin group, and 12.7% in the aspirin group (adjusted hazard ratio [HR] 0.40; 95% confidence interval [CI] 0.26-0.61; p < 0.001). Furthermore, in patients with elevated GA level, stroke occurred in 9.2% of patients in the clopidogrel-aspirin group, and 11.4% in the aspirin group (adjusted HR 0.79; 95% CI 0.60-1.05; p = 0.103). CONCLUSIONS: GA could be a potential biomarker to predict the effects of dual and single antiplatelet therapy in patients with minor stroke or TIA. PMID- 25740864 TI - Epstein-Barr virus genetic variants are associated with multiple sclerosis. AB - OBJECTIVE: We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in persons with multiple sclerosis (MS) and control subjects to verify whether virus genetic variants are involved in disease development. METHODS: A seminested PCR approach and Sanger sequencing were used to analyze EBNA2 in 53 patients and 38 matched healthy donors (HDs). High-throughput sequencing by Illumina MiSeq was also applied in a subgroup of donors (17 patients and 17 HDs). Patients underwent gadolinium enhanced MRI and human leucocyte antigen typing. RESULTS: MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84-14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08-0.51; p = 0.0006). We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19-78.72; p = 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and patients with MS (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features. CONCLUSIONS: Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development. PMID- 25740865 TI - Balancing access and quality in comprehensive stroke care. PMID- 25740866 TI - Comment: TIA response to antiplatelets stratified by glycated albumin. PMID- 25740867 TI - Studying long-term caregiver health outcomes with methodologic rigor. PMID- 25740868 TI - Microscopic brain structure revisited in genetic epilepsy. PMID- 25740869 TI - Nuclear Medicine Technology Certification Board. PMID- 25740870 TI - Best practices: "Expert opinion" versus "evidence-based medicine" in the new SNMMI-TS Quality Initiative. PMID- 25740871 TI - Quality in nuclear medicine technology. PMID- 25740873 TI - National Council of Representatives. PMID- 25740874 TI - Early-onset central diabetes insipidus is associated with de novo arginine vasopressin-neurophysin II or Wolfram syndrome 1 gene mutations. AB - OBJECTIVE: Idiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin-neurophysin II (AVP-NPII (AVP)) or wolframin (WFS1) genes. DESIGN AND METHODS: Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia. RESULTS: Two patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome. CONCLUSIONS: Early-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling. PMID- 25740875 TI - The cost of misremembering: Inferring the loss function in visual working memory. AB - Visual working memory (VWM) is a highly limited storage system. A basic consequence of this fact is that visual memories cannot perfectly encode or represent the veridical structure of the world. However, in natural tasks, some memory errors might be more costly than others. This raises the intriguing possibility that the nature of memory error reflects the costs of committing different kinds of errors. Many existing theories assume that visual memories are noise-corrupted versions of afferent perceptual signals. However, this additive noise assumption oversimplifies the problem. Implicit in the behavioral phenomena of visual working memory is the concept of a loss function: a mathematical entity that describes the relative cost to the organism of making different types of memory errors. An optimally efficient memory system is one that minimizes the expected loss according to a particular loss function, while subject to a constraint on memory capacity. This paper describes a novel theoretical framework for characterizing visual working memory in terms of its implicit loss function. Using inverse decision theory, the empirical loss function is estimated from the results of a standard delayed recall visual memory experiment. These results are compared to the predicted behavior of a visual working memory system that is optimally efficient for a previously identified natural task, gaze correction following saccadic error. Finally, the approach is compared to alternative models of visual working memory, and shown to offer a superior account of the empirical data across a range of experimental datasets. PMID- 25740876 TI - Modulation of microsaccade rate by task difficulty revealed through between- and within-trial comparisons. AB - Microsaccades (MSs) are small eye movements that occur during attempted visual fixation. While most studies concerning MSs focus on their roles in visual processing, some also suggest that the MS rate can be modulated by the amount of mental exertion involved in nonvisual processing. The current study focused on the effects of task difficulty on MS rate in a nonvisual mental arithmetic task. Experiment 1 revealed a general inverse relationship between MS rate and subjective task difficulty. During Experiment 2, three task phases with different requirements were identified: during calculation (between stimulus presentation and response), postcalculation (after reporting an answer), and a control condition (undergoing a matching sequence of events without the need to make a calculation). MS rate was observed to approximately double from the during calculation phase to the postcalculation phase, and was significantly higher in the control condition compared to postcalculation. Only during calculation was the MS rate generally decreased with greater task difficulty. Our results suggest that the nonvisual cognitive processing can suppress MS rate, and that the extent of such suppression is related to the task difficulty. PMID- 25740877 TI - Live birth rates after MESA or TESE in men with obstructive azoospermia: is there a difference? AB - STUDY QUESTION: How do live birth rates compare after intracytoplasmic sperm injection (ICSI) for men with obstructive azoospermia when using sperm derived from testicular sperm extraction (TESE) versus microsurgical epididymal sperm aspiration (MESA)? SUMMARY ANSWER: Our study suggests that proximal epididymal sperm (from MESA) result in higher live birth rates as compared with testicular sperm (from TESE) in couples where the man has obstructive azoospermia due to congenital bilateral absence of the vas deferens (CBAVD) or vasectomy. WHAT IS KNOWN ALREADY: For couples with obstructive azoospermia, MESA (epididymal sperm) and TESE (testicular sperm) have generally been assumed to be equivalent for use in ICSI. But this assumption has never been confirmed, and this view has important clinical and basic scientific consequences. STUDY DESIGN, SIZE, DURATION: This was a retrospective study of a consecutive cohort of 374 men with obstructive azoospermia and normal spermatogenesis, who underwent IVF and ICSI using either epididymal sperm or testicular sperm in the period 2000-2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included men undergoing MESA or TESE at St. Luke's Hospital for obstructive azoospermia due to CBAVD or vasectomy. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 280 couples underwent MESA and 94 underwent TESE with ICSI. The live birth rate was 39% after MESA-ICSI and 24% after TESE-ICSI. The MESA-ICSI cycles also resulted in a significantly higher implantation rate and significantly higher clinical and ongoing pregnancy rates than the TESE-ICSI cycles. There was no significant difference in results between fresh or frozen sperm for both MESA and TESE. When adjusted for the available confounders, the odds ratio for live birth was significantly in favour of MESA-ICSI versus TESE-ICSI (OR 1.82; 95% CI 1.05-3.67). The only significant confounders were female age and ovarian reserve. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective cohort study and not a randomized clinical trial. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that some aspect of sperm maturation after the sperm leaves the testicle to enter the epididymis is required for the most optimal results, even when ICSI is used for fertilization. STUDY FUNDING/COMPETING INTERESTS: No funding was used and there are no competing interests. PMID- 25740878 TI - Trophoblast subtype-specific EGFR/ERBB4 expression correlates with cell cycle progression and hyperplasia in complete hydatidiform moles. AB - STUDY QUESTION: Do trophoblast subtypes differ in their expression of erythroblastic leukaemia viral oncogene homologue (ERBB) receptor family members and responsiveness towards specific growth factor ligands? SUMMARY ANSWER: Our data reveal a reciprocal expression pattern of epidermal growth factor receptor (EGFR)/ERBB4 in proliferative and ERBB2/ERBB3 in invasive trophoblast subtypes, as well as a restricted responsiveness to epidermal growth factor (EGF) and heparin-binding (HB)-EGF. WHAT IS KNOWN ALREADY: EGFR is expressed by villous cytotrophoblasts (vCTBs), but absent from extravillous trophoblasts (EVTs), which specifically up-regulate ERBB2. STUDY DESIGN, SIZE, DURATION: Tissue samples of human first trimester placentae (n = 50) and deciduae (n = 5) obtained from elective pregnancy terminations were used to study trophoblast subtype-specific ERBB receptor expression and responsiveness to recombinant human EGF and HB-EGF. Age-matched complete hydatidiform mole (CHM) placentae (n = 12) were assessed for EGFR and ERBB4 expression in proliferation-competent regions. PARTICIPANTS/MATERIALS, SETTING, METHODS: ERBB receptor expression was analysed in primary trophoblast cell isolates by means of microarray, quantitative real time PCR and western blotting, as well as immunofluorescence stainings of placental and decidual tissue sections. EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR(+) and HLA-G(+) trophoblasts. 5-Ethynyl-2'-deoxyuridine incorporation assays were performed to study the effect of both ligands on the proliferative capacity of primary trophoblasts as well as of vCTBs and proximal cell column trophoblasts (pCCTs) in placental floating explants. Finally, the average number of EGFR(+) vCTB and pCCT layers was determined in CHM placentae and compared with healthy age-matched controls. MAIN RESULTS AND THE ROLE OF CHANCE: Proliferative vCTBs and pCCTs co express EGFR and ERBB4, but are devoid of ERBB2 and ERBB3. In contrast, HLA-G(+) trophoblast subtypes exhibit an EGFR/ERBB4(-) and ERBB2/ERBB3(+) phenotype. EGF and HB-EGF activate EGFR, ERBB4, AKT and extracellular signal-regulated kinase 1/2 in EGFR(+) primary trophoblasts; however, they do not show an effect on HLA G(+) EVTs. Both ligands strongly induce cell cycle progression in primary trophoblasts (P < 0.05) and placental explant-associated vCTBs (P < 0.05) and pCCTs (P < 0.05). Notably, EGFR(+) vCTB (P < 0.0001) and pCCT (P < 0.0001) layers are significantly expanded in CHM placentae when compared with healthy controls. LIMITATIONS, REASONS FOR CAUTION: Cells were removed from their physiological context and may therefore respond differently to various stimuli. WIDER IMPLICATIONS OF THE FINDINGS: In this study we define EGFR as a marker for proliferative trophoblast subtypes within the human placenta. Manipulation of EGFR signalling might thus offer a promising therapeutic avenue for the treatment of molar pregnancies associated with trophoblast hyperplasia. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P.). There are no competing interests to declare. PMID- 25740879 TI - Impaired active DNA demethylation in zygotes generated by round spermatid injection. AB - STUDY QUESTION: Is the poor development of embryos generated from round spermatid injection (ROSI) in humans and animals associated with abnormal active DNA demethylation? SUMMARY ANSWER: A significant proportion of ROSI-derived embryos failed to undergo active DNA demethylation. WHAT IS KNOWN ALREADY: Active DNA demethylation is initiated by the conversion of 5-methylcytosine (5mC) to 5 hydroxycytosine (5hmC) by the Tet3 enzyme. Active demethylation proceeds in a more pronounced manner in the male pronucleus than in the female one. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mouse zygotes generated by ICSI or ROSI were analyzed for active DNA methylation by quantification of 5mC and 5hmC using specific antibodies. Some ROSI-derived embryos were subjected to time-lapse imaging for DNA methylation levels and were transferred into recipient pseudo pregnant female mice. MAIN RESULTS AND THE ROLE OF CHANCE: In ICSI-derived embryos, the male:female pronucleus (M/F) ratio of 5mC immunostaining intensity was decreased while that of 5hmC was increased. However, a significant proportion of ROSI-derived embryos showed unchanged M/F ratios for 5mC and 5hmC even at the late zygotic period, indicating that they failed to undergo asymmetric active DNA demethylation. Consistent with this, some ROSI-derived embryos did not show preferential localization of Tet3 to the male pronucleus. ROSI-derived embryos were classified into 'demethylated' or 'non-demethylated' groups by time-lapse imaging and transferred into recipient female mice separately. More normal-sized fetuses were retrieved from the 'demethylated' group than 'non-demethylated' group at Day 11.5 of pregnancy. LIMITATIONS, REASONS FOR CAUTION: A causal relationship between impaired active DNA demethylation and the poor developmental ability of ROSI-derived embryos remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: We identified two types of ROSI-derived embryos in terms of the degree of active DNA demethylation. Induction of normal DNA demethylation at the zygotic stage might help in the technical improvement of ROSI. STUDY FUNDING/COMPETING INTERESTS: The work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by the RIKEN Epigenetics Program. The authors have no competing interests to declare. PMID- 25740880 TI - Serum miR-155 as a potential biomarker of male fertility. AB - STUDY QUESTION: Are serum levels of micro-RNAs miR-155 and miR-146a associated with male fertility, low-grade systemic inflammation (LGSI) and androgens? SUMMARY ANSWER: miR-155 was associated with male subfertility independent of LGSI or androgens while miR-146a was only weakly associated with subfertility and LGSI. WHAT IS KNOWN ALREADY: Male subfertility has been associated with LGSI as well as with androgen deficiency. miR-155 and miR-146a are central regulators of inflammation and their level in cells and in the serum has been associated with several inflammatory conditions. STUDY DESIGN, SIZE, DURATION: In this case control study, two independent groups of 60 subjects each (exploratory and confirmatory cohort) were randomly selected from an ongoing study on subfertile men (in total: hypogonadal; n = 40, eugonadal; n = 40 and control group n = 39) at a University Hospital Reproductive Medicine Centre. Individuals were matched for age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total RNA was isolated from cell-free serum. As internal control a synthetic miRNA, UniSp6, was added to each sample prior to extraction. miRNA expression levels were measured by real-time RT PCR and presented as fold difference (arbitrary units, U) from control. Sera from these individuals had been previously analyzed for hormone and cytokine levels. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of miR-155 were associated with levels of miR-146a (P < 0.0001), but only miR-146a was associated with inflammatory markers. miR-155 was strongly associated with subfertility (for subfertile group 1.88 U, 95% confidence interval (CI) 1.6-2.1 U versus 1.15, 95% CI 1.0-1.2 U in controls; P = 0.001). Receiver operating characteristic curve analysis indicated that miR-155 but not miR-146a can be used as a marker of subfertility. MiR-155 with a cutoff value of 1.77 had 47% sensitivity and 95% specificity for identifying subfertility and a positive predictive value (PPV) and negative predictive value (NPV) of 95 and 47%, respectively. When used in combination with FSH, sensitivity and specificity were 80 and 100%, respectively, while PPV and NPV were 100 and 71%, respectively, those values being higher than for the FSH alone. Repeating the results obtained in the exploratory cohort in an independent confirmatory cohort reduced the risk of a chance finding. LIMITATIONS, REASONS FOR CAUTION: Although the results from the exploratory cohort were confirmed in the confirmatory cohort, studies from other centers are needed to establish the role of miR-155 as a new biomarker of male fertility. Furthermore, the role of this marker in distinguishing between different groups of male subfertility is to be elucidated. WIDER IMPLICATIONS OF THE FINDINGS: Association of the inflammatory miRNA miR-155 with male fertility contributes to our understanding of the pathophysiology of subfertility and suggests a novel biomarker. Serum miR-155 in combination with FSH has higher diagnostic specificity and sensitivity compared with FSH alone. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from Swedish Governmental Grant (ALF), Skane county council research and development foundation, Skane University Hospital Fonds and by the EU and Greek funds under the action 'Education and lifelong learning' program THALIS-FAT-VESSEL (No 379527). The authors have no competing interests to disclose. PMID- 25740881 TI - Platelets are an unindicted culprit in the development of endometriosis: clinical and experimental evidence. AB - STUDY QUESTION: Do platelets play any role in the development of endometriosis? SUMMARY ANSWER: Activated platelets aggregate in endometriotic lesions and play important roles in the development of endometriosis. WHAT IS KNOWN ALREADY: Platelets play important roles in cancer development and metastasis but there is no published study on their role in the development of endometriosis, even though endometriotic lesions undergo repeated cycles of tissue injury and repair, which characteristically involve platelets. STUDY DESIGN, SIZE, DURATION: Cross sectional clinical studies of women with and without endometriosis, in vitro experimentation, and animal studies using platelet and/or macrophage depletion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemistry analysis of ectopic/eutopic endometrial tissues from 58 women with and 47 without endometriosis. Proliferation assay, cell cycle analysis by flow cytometry, gene expression and protein analysis for COX-2, VEGF, MMP-9, and Bcl-2 using primary cell culture, and evaluation of the rate of platelet activation induced by peritoneal fluid from women with and without endometriosis. Two mouse experiments, one that evaluated the effect of platelet depletion on lesion development and its associated phenotypic changes, and the other, the effect of platelet and/or macrophage depletion. MAIN RESULTS AND THE ROLE OF CHANCE: We found that platelets aggregated in endometriotic lesions, concomitant with elevated VEGF expression and microvessel density. Co-culture of endometriotic stromal cells with platelets enhanced cellular proliferation, and increased the expression of COX-2, MMP-9, VEGF, and Bcl-2. IL-1beta-induced COX-2 up-regulation and increased production of the coagulant TXA(2) in endometriotic stromal cells. Tissue factor (TF) expression was elevated in endometriosis and TF concentrations were significantly elevated both in the supernatant of cultured primary endometriotic stromal cells and in peritoneal fluid from women with endometriosis. Platelet depletion resulted in significantly reduced lesion size and improved hyperalgesia in mice with induced endometriosis. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its cross-sectional design and by its focus on ovarian endometriomas. WIDER IMPLICATIONS OF THE FINDINGS: The demonstration that platelets are involved in the development of endometriosis provides a rationale for the use of anti-coagulants to treat endometriosis, and opens prospects for developing novel biomarkers for diagnostic or prognostic purposes. STUDY FUNDING/COMPETING INTERESTS: Financial support for this study was provided by grants from the National Science Foundation of China, a grant from the Shanghai Science and Technology Commission, support from the Key Specialty Project of the Ministry of Health, People's Republic of China. None of the authors has any conflict of interest to disclose. PMID- 25740882 TI - Recombinant follicle-stimulating hormone and recombinant luteinizing hormone versus recombinant follicle-stimulating hormone alone during GnRH antagonist ovarian stimulation in patients aged >=35 years: a randomized controlled trial. AB - STUDY QUESTION: Does luteinizing hormone (LH) supplementation improve live birth rate after in vitro fertilization (IVF) in patients aged >=35 years receiving a gonadotrophin-releasing hormone (GnRH) antagonist protocol? SUMMARY ANSWER: There was no difference in live birth rate with use of LH during IVF in patients aged >=35 years undergoing IVF treatment using a GnRH antagonist protocol. WHAT IS KNOWN ALREADY: Use of GnRH analogues as part of a controlled ovarian hyperstimulation protocol during IVF treatment cycles decreases the amount of LH available to developing follicles. The role of LH supplementation for improving outcomes in patients undergoing controlled ovarian hyperstimulation as part of assisted reproduction treatments, particularly those involving a GnRH antagonist protocol, is unclear. It has been suggested that higher risk patients (e.g. age >=35 years, poor ovarian reserve) may benefit from LH supplementation. STUDY DESIGN, SIZE, DURATION: This single-centre, randomized controlled trial was conducted from 1 October 2012 to 30 June 2014. A total of 240 women aged >=35 years undergoing IVF received ovarian stimulation using a GnRH antagonist protocol, with recombinant follicle-stimulating hormone (r-FSH; Gonal-F((r))) starting from cycle day 2 or 3. GnRH antagonist (Cetrotide((r))) was administered on Day 5 of r-FSH administration. On Day 6, patients in the LH supplementation group were switched to r-FSH/r-LH (Pergoveris((r))) 150/75 IU/day. Randomization to study treatments was performed in blocks of 4 via a computer-generated random number list. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 240 patients randomized to treatment, 120 received r-FSH/r-LH and 120 received r-FSH. Patients were recruited from the IVFAS, An Sinh Hospital, Ho Chi Minh City, Vietnam. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rate did not differ significantly (P > 0.05) between r-FSH/r-LH and r-FSH recipients (16.7 versus 17.5%; between-group difference 0.8, 95% confidence interval [CI] -9.5, 11.2). In addition, there were no significant differences between the r-FSH/r-LH and r-FSH groups with respect to the number of oocytes retrieved, implantation rate, miscarriage rate and clinical pregnancy rate. LIMITATIONS, REASONS FOR CAUTION: The open-label design could have introduced bias, and the relatively small sample size may have allowed detection of only the most common adverse events. In addition, the study was likely to be underpowered based on differences between the response rate assumptions used in the sample size calculation and the actual response rate during the study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study found no additional benefit from adding LH supplementation to ovarian stimulation with a GnRH antagonist protocol in women aged >=35 years, and add to the body of evidence in this area. However, findings across studies are still inconsistent and additional research is needed before any clear recommendations for clinical practice can be made. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University HCMC. The authors state that they have no financial or commercial conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered with clinicaltrials.gov (NCT02244866). PMID- 25740883 TI - Surgical diminished ovarian reserve after endometrioma cystectomy versus idiopathic DOR: comparison of in vitro fertilization outcome. AB - STUDY QUESTION: Does the live birth rate after IVF depend on the etiology of diminished ovarian reserve (DOR)? SUMMARY ANSWER: IVF outcome and live birth rate are significantly impaired in women with DOR caused by a previous cystectomy for endometrioma compared with women with idiopathic DOR. WHAT IS KNOWN ALREADY: The safety of the surgical treatment of endometriomas is being discussed in terms of damage to ovarian reserve. Several studies have reported a poor response to controlled ovarian stimulation and a significantly impaired IVF outcome in women with DOR consecutive to an endometrioma cystectomy compared with women with tubal factor infertility. STUDY DESIGN, SIZE, DURATION: Retrospective case-control study conducted in women aged under 40 treated in our Reproductive Medicine Center between January 2010 and January 2014 for a DOR defined by anti-Mullerian hormone level <2 ng/ml. Two groups of patients were selected: group A included patients with a DOR diagnosed after cystectomy(s) for endometrioma(s), group B included patients with an idiopathic DOR. In each group, subgroups of patients 'poor ovarian responders', based on the ESHRE criteria ('Bologna criteria'), have been established. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 51 patients in group A were matched to 116 patients in group B, representing respectively 125 and 243 IVF cycles. Among them, 39 patients in group A and 78 patients in group B validated strictly by the Bologna criteria, representing 99 and 189 IVF cycles, respectively. Each patient underwent a controlled ovarian hyperstimulation and IVF with fresh embryo transfer. Primary end-point was the live birth rate. Secondary end-points were the number of retrieved oocytes, fertilization rate, implantation rate, clinical pregnancy rate, spontaneous abortion rate and cycle cancelation rate. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly lower pregnancy (11.2% in group A versus 20.6% in group B, P = 0.02) and live birth (7.2 versus 16.9% respectively, P = 0.01) rates per cycle were assessed in women in group A compared with women in group B. The same results were obtained in the Bologna criteria subgroup analysis with a significantly lower pregnancy (9.1 versus 20.1%, P = 0.016) and live birth (5.1 versus 15.3%, P = 0.001) rates per cycle in women in subgroup A compared with women in subgroup B. Patients in group A required significantly higher gonadotrophins doses (2881 IU +/- 1111 versus 2526 IU +/- 795, P = 0.005), longer ovarian stimulation (10.6 Days +/- 2.8 versus 9.9 Days +/- 2.4, P = 0.019) and higher cancelation rate for poor response (12 versus 6.2%, P = 0.05). Despite a mean number of retrieved oocytes similar with the group B (5.4 +/- 3.1 and 5.1 +/ 3.2, NS), and a significantly higher fertilization rate (65.7 versus 47.2%, P < 0.001), women in group A showed a significantly lower implantation rate (7.2 versus 13.5%, P = 0.03). Abortion rate, ectopic pregnancy rate and multiple pregnancy rate were similar in both groups. LIMITATIONS, REASONS FOR CAUTION: Data were collected retrospectively using the database of our Department. Sample size is relatively small but our study provides statistically significant evidence that the chances of IVF success are decreased in women with DOR after cystectomy for endometrioma. Further larger series are needed to confirm these findings. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study evaluating IVF outcome in patients with DOR after cystectomy(s) for endometrioma(s) versus in patients with an idiopathic DOR. In addition to the risk of damaging ovarian reserve, we hypothesize that endometrioma surgery would not have qualitative benefits on results in IVF in patients with DOR. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interests to declare. PMID- 25740884 TI - Medroxyprogesterone acetate impairs human dendritic cell activation and function. AB - STUDY QUESTION: Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function? SUMMARY ANSWER: In vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function). WHAT IS KNOWN ALREADY: MPA is the active molecule in Depo-Provera((r)) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes. STUDY DESIGN, SIZE, DURATION: This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naive allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation. MAIN RESULTS AND THE ROLE OF CHANCE: Several pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls. LIMITATIONS, REASON FOR CAUTION: While our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract. WIDER IMPLICATIONS OF THE FINDINGS: Identification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection. STUDY FUNDING/COMPETING INTERESTS: Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no conflicts of interest to declare. PMID- 25740885 TI - Prenatal smoking and age at menarche: influence of the prenatal environment on the timing of puberty. AB - STUDY QUESTION: Do prenatal exposure to cigarette smoking and birthweight influence age at menarche (AAM) in a cohort of Australian girls? SUMMARY ANSWER: We find that prenatal smoke exposure and lower birthweight increase the chance of earlier menarche in accordance with theoretical predictions as do confounding factors of maternal AAM and higher BMI of the girls. WHAT IS KNOWN ALREADY: Much prior research focuses on the role of the early childhood environment in determining AAM but fewer studies consider the role of the prenatal environment. Those studies that examine the prenatal period find an acceleration of maturation associated with maternal smoking and low birthweight. Life history theory predicts that early life exposure to stressful environments should promote more rapid maturation and that this timing can be established before birth, making the prenatal environment particularly important. STUDY DESIGN, SIZE, DURATION: Statistical analysis of longitudinal survey data collected from a large cohort (n = 2446) of Australian children using data from birth to 12-13 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Owing to missing data, 1493 girls were included in the final analysis. Using cox regression, we examine how (i) maternal cigarette smoking during gestation and (ii) birthweight influence girls' AAM. Cox regression was used because not all girls had reached menarche. MAIN RESULTS AND THE ROLE OF CHANCE: We find that older maternal AAM (hazards ratio (HR): 0.75, confidence interval (CI) (95%): 0.71-0.79) and higher birthweight (HR: 0.86, CI (95%): 0.75-0.97) lower the chance of earlier menarche; while higher girls' BMI at 8-9 years (HR: 1.12, CI (95%): 1.10-1.15), and maternal cigarette smoking on 'most days' during gestation (HR: 1.40, CI (95%): 1.10-1.79 with 'no smoking' as the reference level) increased the chance of earlier menarche. All factors were statistically significant at P = 0.05. LIMITATIONS, REASONS FOR CAUTION: Not all girls had reached menarche, necessitating the use of cox regression. As with other longitudinal studies, there was study sample attrition and some missing data, particularly in reports of maternal smoking. In addition, as the degree of bias in the missing data is unknown, possible inaccurate reporting of maternal smoking may influence the results of birthweight on AAM. WIDER IMPLICATIONS OF THE FINDINGS: Because of the association between younger AAM and higher risk of uterine, endometrial and breast cancer development, our finding adds to the need to consider the stress caused by prenatal smoke exposure as an important health risk. In addition, this study needs to be extended, when the same girls are 14-15 years of age, and on a larger dataset from a younger cohort within the same Australian Government project. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study and there are no competing interests to declare. PMID- 25740886 TI - Effects of ulipristal acetate on human embryo attachment and endometrial cell gene expression in an in vitro co-culture system. AB - STUDY QUESTION: Does ulipristal acetate (UPA) used for emergency contraception (EC) interfere with the human embryo implantation process? SUMMARY ANSWER: UPA, at the dosage used for EC, does not affect human embryo implantation process, in vitro. WHAT IS KNOWN ALREADY: A single pre-ovulatory dose of UPA (30 mg) acts by delaying or inhibiting ovulation and is recommended as first choice among emergency contraceptive pills due to its efficacy. The compound has also been demonstrated to have a dose-dependent effect on the endometrium, which theoretically could impair endometrial receptivity but its direct action on human embryo implantation has not yet been studied. STUDY DESIGN, SIZE, DURATION: Effect of UPA on embryo implantation process was studied in an in vitro endometrial construct. Human embryos were randomly added to the cultures and cultured for 5 more days with UPA (n = 10) or with vehicle alone (n = 10) to record the attachment of embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies were obtained from healthy, fertile women on cycle day LH+4 and stromal and epithelial cells were isolated. A three-dimensional in vitro endometrial co-culture system was constructed by mixing stromal cells with collagen covered with a layer of epithelial cells and cultured in progesterone containing medium until confluence. The treatment group received 200 ng/ml of UPA. Healthy, viable human embryos were placed on both control and treatment cultures. Five days later the cultures were tested for the attachment of embryos and the 3D endometrial constructs were analysed for endometrial receptivity markers by real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the embryo attachment rate between the UPA treated group and the control group as 5 out of 10 human embryos exposed to UPA and 7 out of 10 embryos in the control group attached to the endometrial cell surface (P = 0.650). Out of 17 known receptivity genes studied here, only 2 genes, HBEGF (P = 0.009) and IL6 (P = 0.025) had a significant up-regulation and 4 genes, namely HAND2 (P = 0.003), OPN (P = 0.003), CALCR (P = 0.016) and FGF2 (P = 0.023) were down-regulated with the exposure of UPA, compared with control group. LIMITATIONS, REASONS FOR CAUTION: This proof of concept study was conducted with a few human embryos, as their availability was limited. Although the 3D model used for this study is well established and the artificial endometrial luminal epithelium shown to express progesterone regulated markers of endometrial receptivity it is still an in vitro model, lacking all cell types that constitute the receptive endometrium in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insights on the mechanism of action of UPA on human embryo implantation, demonstrating that UPA in a dosage used for EC does not affect embryo viability and the implantation process of embryo. Progesterone receptor modulators (PRMs) hold the potential to be attractive estrogen- and gestagen-free contraceptives and thus may be made available to a larger proportion of women globally due to these findings. STUDY FUNDING/COMPETING INTERESTS: Swedish Research Council (K2010-54X-14212-09-3) and support provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska University Hospital. PMID- 25740887 TI - Reproductive interference explains persistence of aggression between species. AB - Interspecific territoriality occurs when individuals of different species fight over space, and may arise spontaneously when populations of closely related territorial species first come into contact. But defence of space is costly, and unless the benefits of excluding heterospecifics exceed the costs, natural selection should favour divergence in competitor recognition until the species no longer interact aggressively. Ordinarily males of different species do not compete for mates, but when males cannot distinguish females of sympatric species, females may effectively become a shared resource. We model how reproductive interference caused by undiscriminating males can prevent interspecific divergence, or even cause convergence, in traits used to recognize competitors. We then test the model in a genus of visually orienting insects and show that, as predicted by the model, differences between species pairs in the level of reproductive interference, which is causally related to species differences in female coloration, are strongly predictive of the current level of interspecific aggression. Interspecific reproductive interference is very common and we discuss how it may account for the persistence of interspecific aggression in many taxonomic groups. PMID- 25740888 TI - Broad supernatural punishment but not moralizing high gods precede the evolution of political complexity in Austronesia. AB - Supernatural belief presents an explanatory challenge to evolutionary theorists it is both costly and prevalent. One influential functional explanation claims that the imagined threat of supernatural punishment can suppress selfishness and enhance cooperation. Specifically, morally concerned supreme deities or 'moralizing high gods' have been argued to reduce free-riding in large social groups, enabling believers to build the kind of complex societies that define modern humanity. Previous cross-cultural studies claiming to support the MHG hypothesis rely on correlational analyses only and do not correct for the statistical non-independence of sampled cultures. Here we use a Bayesian phylogenetic approach with a sample of 96 Austronesian cultures to test the MHG hypothesis as well as an alternative supernatural punishment hypothesis that allows punishment by a broad range of moralizing agents. We find evidence that broad supernatural punishment drives political complexity, whereas MHGs follow political complexity. We suggest that the concept of MHGs diffused as part of a suite of traits arising from cultural exchange between complex societies. Our results show the power of phylogenetic methods to address long-standing debates about the origins and functions of religion in human society. PMID- 25740889 TI - Selection on male sex pheromone composition contributes to butterfly reproductive isolation. AB - Selection can facilitate diversification by inducing character displacement in mate choice traits that reduce the probability of maladaptive mating between lineages. Although reproductive character displacement (RCD) has been demonstrated in two-taxa case studies, the frequency of this process in nature is still debated. Moreover, studies have focused primarily on visual and acoustic traits, despite the fact that chemical communication is probably the most common means of species recognition. Here, we showed in a large, mostly sympatric, butterfly genus, a strong pattern of recurrent RCD for predicted male sex pheromone composition, but not for visual mate choice traits. Our results suggest that RCD is not anecdotal, and that selection for divergence in male sex pheromone composition contributed to reproductive isolation within the Bicyclus genus. We propose that selection may target olfactory mate choice traits as a more common sensory modality to ensure reproductive isolation among diverging lineages than previously envisaged. PMID- 25740890 TI - Subtropical mouse-tailed bats use geothermally heated caves for winter hibernation. AB - We report that two species of mouse-tailed bats (Rhinopoma microphyllum and R. cystops) hibernate for five months during winter in geothermally heated caves with stable high temperature (20 degrees C). While hibernating, these bats do not feed or drink, even on warm nights when other bat species are active. We used thermo-sensitive transmitters to measure the bats' skin temperature in the natural hibernacula and open flow respirometry to measure torpid metabolic rate at different ambient temperatures (Ta, 16-35 degrees C) and evaporative water loss (EWL) in the laboratory. Bats average skin temperature at the natural hibernacula was 21.7 +/- 0.8 degrees C, and no arousals were recorded. Both species reached the lowest metabolic rates around natural hibernacula temperatures (20 degrees C, average of 0.14 +/- 0.01 and 0.16 +/- 0.04 ml O2 g( 1) h(-1) for R. microphyllum and R. cystops, respectively) and aroused from torpor when Ta fell below 16 degrees C. During torpor the bats performed long apnoeas (14 +/- 1.6 and 16 +/- 1.5 min, respectively) and had a very low EWL. We hypothesize that the particular diet of these bats is an adaptation to hibernation at high temperatures and that caves featuring high temperature and humidity during winter enable these species to survive this season on the northern edge of their world distribution. PMID- 25740891 TI - The search for human pheromones: the lost decades and the necessity of returning to first principles. AB - As humans are mammals, it is possible, perhaps even probable, that we have pheromones. However, there is no robust bioassay-led evidence for the widely published claims that four steroid molecules are human pheromones: androstenone, androstenol, androstadienone and estratetraenol. In the absence of sound reasons to test the molecules, positive results in studies need to be treated with scepticism as these are highly likely to be false positives. Common problems include small sample sizes, an overestimate of effect size (as no effect can be expected), positive publication bias and lack of replication. Instead, if we are to find human pheromones, we need to treat ourselves as if we were a newly discovered mammal, and use the rigorous methods already proven successful in pheromone research on other species. Establishing a pheromone relies on demonstration of an odour-mediated behavioural or physiological response, identification and synthesis of the bioactive molecule(s), followed by bioassay confirmation of activity. Likely sources include our sebaceous glands. Comparison of secretions from adult and pre-pubertal humans may highlight potential molecules involved in sexual behaviour. One of the most promising human pheromone leads is a nipple secretion from the areola glands produced by all lactating mothers, which stimulates suckling by any baby not just their own. PMID- 25740892 TI - An out-of-body experience: the extracellular dimension for the transmission of mutualistic bacteria in insects. AB - Across animals and plants, numerous metabolic and defensive adaptations are a direct consequence of symbiotic associations with beneficial microbes. Explaining how these partnerships are maintained through evolutionary time remains one of the central challenges within the field of symbiosis research. While genome erosion and co-cladogenesis with the host are well-established features of symbionts exhibiting intracellular localization and transmission, the ecological and evolutionary consequences of an extracellular lifestyle have received little attention, despite a demonstrated prevalence and functional importance across many host taxa. Using insect-bacteria symbioses as a model, we highlight the diverse routes of extracellular symbiont transfer. Extracellular transmission routes are unified by the common ability of the bacterial partners to survive outside their hosts, thereby imposing different genomic, metabolic and morphological constraints than would be expected from a strictly intracellular lifestyle. We emphasize that the evolutionary implications of symbiont transmission routes (intracellular versus extracellular) do not necessarily correspond to those of the transmission mode (vertical versus horizontal), a distinction of vital significance when addressing the genomic and physiological consequences for both host and symbiont. PMID- 25740893 TI - Early-life reproduction is associated with increased mortality risk but enhanced lifetime fitness in pre-industrial humans. AB - The physiology of reproductive senescence in women is well understood, but the drivers of variation in senescence rates are less so. Evolutionary theory predicts that early-life investment in reproduction should be favoured by selection at the cost of reduced survival and faster reproductive senescence. We tested this hypothesis using data collected from preindustrial Finnish church records. Reproductive success increased up to age 25 and was relatively stable until a decline from age 41. Women with higher early-life fecundity (ELF; producing more children before age 25) subsequently had higher mortality risk, but high ELF was not associated with accelerated senescence in annual breeding success. However, women with higher ELF experienced faster senescence in offspring survival. Despite these apparent costs, ELF was under positive selection: individuals with higher ELF had higher lifetime reproductive success. These results are consistent with previous observations in both humans and wild vertebrates that more births and earlier onset of reproduction are associated with reduced survival, and with evolutionary theory predicting trade-offs between early reproduction and later-life survival. The results are particularly significant given recent increases in maternal ages in many societies and the potential consequences for offspring health and fitness. PMID- 25740894 TI - Artificial selection for food colour preferences. AB - Colour is an important factor in food detection and acquisition by animals using visually based foraging. Colour can be used to identify the suitability of a food source or improve the efficiency of food detection, and can even be linked to mate choice. Food colour preferences are known to exist, but whether these preferences are heritable and how these preferences evolve is unknown. Using the freshwater fish Poecilia reticulata, we artificially selected for chase behaviour towards two different-coloured moving stimuli: red and blue spots. A response to selection was only seen for chase behaviours towards the red, with realized heritabilities ranging from 0.25 to 0.30. Despite intense selection, no significant chase response was recorded for the blue-selected lines. This lack of response may be due to the motion-detection mechanism in the guppy visual system and may have novel implications for the evolvability of responses to colour related signals. The behavioural response to several colours after five generations of selection suggests that the colour opponency system of the fish may regulate the response to selection. PMID- 25740895 TI - Evolution of hosts paying manifold costs of defence. AB - Hosts are expected to incur several physiological costs in defending against parasites. These include constitutive energetic (or other resource) costs of a defence system, facultative resource costs of deploying defences when parasites strike, and immunopathological costs of collateral damage. Here, we investigate the evolution of host recovery rates, varying the source and magnitude of immune costs. In line with previous work, we find that hosts paying facultative resource costs evolve faster recovery rates than hosts paying constitutive costs. However, recovery rate is more sensitive to changes in facultative costs, potentially explaining why constitutive costs are hard to detect empirically. Moreover, we find that immunopathology costs which increase with recovery rate can erode the benefits of defence, promoting chronicity of infection. Immunopathology can also lead to hosts evolving low recovery rate in response to virulent parasites. Furthermore, when immunopathology reduces fecundity as recovery rate increases (e.g. as for T-cell responses to urogenital chlamydiosis), then recovery and reproductive rates do not covary as predicted in eco-immunology. These results suggest that immunopathological and resource costs have qualitatively different effects on host evolution and that embracing the complexity of immune costs may be essential for explaining variability in immune defence in nature. PMID- 25740896 TI - Evaluation of rosuvastatin as an organic anion transporting polypeptide (OATP) probe substrate: in vitro transport and in vivo disposition in cynomolgus monkeys. AB - Organic anion transporting polypeptides (OATPs) mediate hepatic drug uptake and serve as the loci of drug-drug interactions (DDIs). Consequently, there is a major need to develop animal models and refine in vitro-in vivo extrapolations. Therefore, the in vivo disposition of a model OATP substrate, [(3)H]rosuvastatin (RSV), was studied in the cynomolgus monkey and reported for the first time. After monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (mean total recovery of radioactivity of 103.6%). Forty-two percent of the RSV dose was recovered in urine and bile, and the elimination pathways were similar to those reported for human subjects; 61.7%, 39.0%, and 2.9% of the dose was recovered in the feces, bile, and urine, respectively. The high levels of unchanged RSV recovered in urine and bile (26% of the dose) and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion. Also, for the first time, the in vitro inhibitory potential of cyclosporin A (CsA) toward cynomolgus monkey OATPs and sodium-taurocholate cotransporting polypeptide was studied in vitro (primary hepatocytes and transporter-transfected cells). It is concluded that one can study the CsA-RSV DDI in the cynomolgus monkey. For example, the in vitro IC50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC0-inf (6.3-fold) and Cmax (10.2-fold) with CsA (100 mg/kg) was similar to that reported for humans. The results further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition. PMID- 25740897 TI - Beneficial effect of the soluble guanylyl cyclase stimulator BAY 41-2272 on impaired penile erection in db/db-/- type II diabetic and obese mice. AB - Type 2 diabetes mellitus (DM2) and obesity are major risk factors for erectile dysfunction (ED). In diabetes, increased oxidative stress leads to decreased nitric oxide (NO) bioavailability, and diabetic patients appear to be less responsive to conventional therapy with phosphodiesterase type 5 inhibitors. We investigated whether the soluble guanylyl cyclase stimulator BAY 41-2272 (5 cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin 4ylamine) is effective in improving impaired corpus cavernosum (CC) relaxation in obese DM2 mice by reducing oxidative stress. Adult db/db(-/-) mice or their lean db(/+) littermates were used to assess vascular function, cGMP levels, antioxidant status, NADPH oxidase expression, and superoxide formation in the absence or presence of BAY 41-2272. Results showed that BAY 41-2272 (10(-8) to 10(-5) M) potently relaxed CC from db(/+) or db/db(-/-) mice in a similar manner. BAY 41-2272 significantly enhanced both endothelium-dependent and nitrergic relaxation induced by electrical field stimulation (EFS), and improved the impaired relaxation to acetylcholine and EFS in the diabetic animals in a concentration-dependent manner (10(-8) to 10(-7) M). BAY 41-2272 increased cGMP levels and potentiated relaxation responses to exogenous NO in CC. Total antioxidant status was reduced in plasma and urine whereas expression of vascular NADPH oxidase subunits (gp91phox, p22phox, and p47phox) was increased in the CC of db/db(-/-) mice, suggesting a state of oxidative stress. These effects were prevented by BAY 41-2272 in a concentration-dependent manner. These results suggest that BAY 41-2272 improves CC relaxation in db/db(-/-) mice by increasing cGMP and augmenting antioxidant status, making this drug is a potential novel candidate to treat ED. PMID- 25740898 TI - The novel prostaglandin I2 mimetic ONO-1301 escapes desensitization in an antiplatelet effect due to its inhibitory action on thromboxane A2 synthesis in mice. AB - ONO-1301 [(E)-[5-[2-[1-phenyl-1-(3-pyridyl)methylidene-aminooxy]ethyl]-7,8 dihydronaphthalene-1-yloxy]acetic acid] is a novel prostaglandin (PG) I2 mimetic with inhibitory activity on the thromboxane (TX) A2 synthase. Interestingly, ONO 1301 retains its inhibitory effect on platelet aggregation after repeated administration, while beraprost, a representative agonist for the PGI2 receptor (IP), loses its inhibitory effect after repeated administration. In the present study, we intended to clarify the mechanism by which ONO-1301 escapes desensitization of an antiplatelet effect. In platelets prepared from wild-type mice, ONO-1301 inhibited collagen-induced aggregation and stimulated cAMP production in an IP-dependent manner. In addition, ONO-1301 inhibited arachidonic acid-induced TXA2 production in platelets lacking IP. Despite the decrease in stimulatory action on cAMP production, the antiplatelet effect of ONO-1301 hardly changed after repeated administration for 10 days in wild-type mice. Noteworthy, beraprost could retain its antiplatelet effect after repeated administration in combination with a low dose of ozagrel, a TXA2 synthase inhibitor. Therefore, we hypothesized that chronic IP stimulation by beraprost induces an increase in TXA2 production, leading to reduction in the antiplatelet effect. As expected, repeated administration of beraprost increased the plasma and urinary levels of a TXA2 metabolite, while ONO-1301 did not increase them significantly. In addition, beraprost could retain the ability to inhibit platelet aggregation after repeated administration in mice lacking the TXA2 receptor (TP). These results indicate that TP-mediated signaling participates in platelet desensitization against IP agonists and that simultaneous inhibition of TXA2 production confers resistance against desensitization on IP agonists. PMID- 25740899 TI - Bat flight: aerodynamics, kinematics and flight morphology. AB - Bats evolved the ability of powered flight more than 50 million years ago. The modern bat is an efficient flyer and recent research on bat flight has revealed many intriguing facts. By using particle image velocimetry to visualize wake vortices, both the magnitude and time-history of aerodynamic forces can be estimated. At most speeds the downstroke generates both lift and thrust, whereas the function of the upstroke changes with forward flight speed. At hovering and slow speed bats use a leading edge vortex to enhance the lift beyond that allowed by steady aerodynamics and an inverted wing during the upstroke to further aid weight support. The bat wing and its skeleton exhibit many features and control mechanisms that are presumed to improve flight performance. Whereas bats appear aerodynamically less efficient than birds when it comes to cruising flight, they have the edge over birds when it comes to manoeuvring. There is a direct relationship between kinematics and the aerodynamic performance, but there is still a lack of knowledge about how (and if) the bat controls the movements and shape (planform and camber) of the wing. Considering the relatively few bat species whose aerodynamic tracks have been characterized, there is scope for new discoveries and a need to study species representing more extreme positions in the bat morphospace. PMID- 25740901 TI - Coordination between catch connective tissue and muscles through nerves in the spine joint of the sea urchin Diadema setosum. AB - Echinoderms have catch connective tissues that change their stiffness as a result of nervous control. The coordination between catch connective tissue and muscles was studied in the spine joint of the sea urchin Diadema setosum. Spine joints are equipped with two kinds of effector: spine muscles and a kind of catch connective tissue, which is called the catch apparatus (CA). The former is responsible for spine movements and the latter for maintenance of spine posture. Diadema show a shadow reaction in which they wave spines when a shadow falls on them, which is a reflex involving the radial nerves. Dynamic mechanical tests were performed on the CA in a joint at which the muscles were severed so as not to interfere with the mechanical measurements. The joint was on a piece of the test that contained other spines and a radial nerve. Darkening of the preparation invoked softening of the CA and spine waving (the shadow reaction). Electrical stimulation of the radial nerve invoked a similar response. These responses were abolished after the nerve pathways from the radial nerve to spines had been cut. A touch applied to the CA stiffened it and the adjacent spines inclined toward the touched CA. A touch to the base of the adjacent spine softened the CA and the spines around the touched spine inclined towards it. The softening of the CA can be interpreted as a response that reduces the resistance of the ligaments to spine movements. Our results clearly show coordination between catch connective tissue and muscles through nerves. PMID- 25740900 TI - Ammonia excretion in Caenorhabditis elegans: mechanism and evidence of ammonia transport of the Rhesus protein CeRhr-1. AB - The soil-dwelling nematode Caenorhabditis elegans is a bacteriovorous animal, excreting the vast majority of its nitrogenous waste as ammonia (25.3+/-1.2 umol gFW(-1) day(-1)) and very little urea (0.21+/-0.004 umol gFW(-1) day(-1)). Although these roundworms have been used for decades as genetic model systems, very little is known about their strategy to eliminate the toxic waste product ammonia from their bodies into the environment. The current study provides evidence that ammonia is at least partially excreted via the hypodermis. Starvation reduced the ammonia excretion rates by more than half, whereas mRNA expression levels of the Rhesus protein CeRhr-2, V-type H(+)-ATPase (subunit A) and Na(+)/K(+)-ATPase (alpha-subunit) decreased correspondingly. Moreover, ammonia excretion rates were enhanced in media buffered to pH 5 and decreased at pH 9.5. Inhibitor experiments, combined with enzyme activity measurements and mRNA expression analyses, further suggested that the excretion mechanism involves the participation of the V-type H(+)-ATPase, carbonic anhydrase, Na(+)/K(+) ATPase, and a functional microtubule network. These findings indicate that ammonia is excreted, not only by apical ammonia trapping, but also via vesicular transport and exocytosis. Exposure to 1 mmol l(-1) NH4Cl caused a 10-fold increase in body ammonia and a tripling of ammonia excretion rates. Gene expression levels of CeRhr-1 and CeRhr-2, V-ATPase and Na(+)/K(+)-ATPase also increased significantly in response to 1 mmol l(-1) NH4Cl. Importantly, a functional expression analysis showed, for the first time, ammonia transport capabilities for CeRhr-1 in a phylogenetically ancient invertebrate system, identifying these proteins as potential functional precursors to the vertebrate ammonia-transporting Rh-glycoproteins. PMID- 25740902 TI - Penguin lungs and air sacs: implications for baroprotection, oxygen stores and buoyancy. AB - The anatomy and volume of the penguin respiratory system contribute significantly to pulmonary baroprotection, the body O2 store, buoyancy and hence the overall diving physiology of penguins. Therefore, three-dimensional reconstructions from computerized tomographic (CT) scans of live penguins were utilized to measure lung volumes, air sac volumes, tracheobronchial volumes and total body volumes at different inflation pressures in three species with different dive capacities [Adelie (Pygoscelis adeliae), king (Aptenodytes patagonicus) and emperor (A. forsteri) penguins]. Lung volumes scaled to body mass according to published avian allometrics. Air sac volumes at 30 cm H2O (2.94 kPa) inflation pressure, the assumed maximum volume possible prior to deep dives, were two to three times allometric air sac predictions and also two to three times previously determined end-of-dive total air volumes. Although it is unknown whether penguins inhale to such high volumes prior to dives, these values were supported by (a) body density/buoyancy calculations, (b) prior air volume measurements in free-diving ducks and (c) previous suggestions that penguins may exhale air prior to the final portions of deep dives. Based upon air capillary volumes, parabronchial volumes and tracheobronchial volumes estimated from the measured lung/airway volumes and the only available morphometry study of a penguin lung, the presumed maximum air sac volumes resulted in air sac volume to air capillary/parabronchial/tracheobronchial volume ratios that were not large enough to prevent barotrauma to the non-collapsing, rigid air capillaries during the deepest dives of all three species, and during many routine dives of king and emperor penguins. We conclude that volume reduction of airways and lung air spaces, via compression, constriction or blood engorgement, must occur to provide pulmonary baroprotection at depth. It is also possible that relative air capillary and parabronchial volumes are smaller in these deeper-diving species than in the spheniscid penguin of the morphometry study. If penguins do inhale to this maximum air sac volume prior to their deepest dives, the magnitude and distribution of the body O2 store would change considerably. In emperor penguins, total body O2 would increase by 75%, and the respiratory fraction would increase from 33% to 61%. We emphasize that the maximum pre-dive respiratory air volume is still unknown in penguins. However, even lesser increases in air sac volume prior to a dive would still significantly increase the O2 store. More refined evaluations of the respiratory O2 store and baroprotective mechanisms in penguins await further investigation of species-specific lung morphometry, start-of-dive air volumes and body buoyancy, and the possibility of air exhalation during dives. PMID- 25740903 TI - The biological significance of acoustic stimuli determines ear preference in the music frog. AB - Behavioral and neurophysiological studies support the idea that right ear advantage (REA) exists for perception of conspecific vocal signals in birds and mammals. Nevertheless, few studies have focused on anuran species that typically communicate through vocalization. The present study examined the direction and latencies of orientation behaviors in Emei music frogs (Babina daunchina) produced in response to six auditory stimuli emitted by a speaker placed directly behind the subjects. The stimuli included male advertisement calls produced from within burrow nests, which have been shown to be highly sexually attractive (HSA), calls produced from outside burrows, which are of low sexual attractiveness (LSA), screech calls produced when frogs are attacked by snakes, white noise, thunder and silence. For all sound stimuli except the screech, the frogs preferentially turned to the right. Right ear preference was strongest for HSA calls. For the screech and thunder stimuli, there was an increased tendency for subjects to move further from the speaker rather than turning. These results support the idea that in anurans, right ear preference is associated with perception of positive or neutral signals such as the conspecific advertisement call and white noise, while a left ear preference is associated with perception of negative signals such as predatory attack. PMID- 25740904 TI - Differences in survival and cause-specific mortality in a culturally diverse Greek population, 1999-2008. AB - BACKGROUND: Modern urban populations exhibit considerable internal heterogeneity. Several social groups, such as ethnic minorities or immigrants, constitute individual clusters with different demographic and epidemiological characteristics. METHODS: Death records were collected from the Municipality Registry between 1999 and 2008. Kaplan-Meier survival analysis was conducted for (i) natively born Greeks, (ii) former USSR-repatriated Greeks and (iii) Roma. Further evaluation was conducted by log-rank (Mantel-Cox) test. Relative mortality rates were assessed by means of cross-tabulation (Pearson's chi(2)). RESULTS: Statistically significant differences in median survival were observed among the three social groups (P < 0.001). The relative mortality from infectious diseases was higher in the Roma population compared with natively born Greeks, odds ratio (OR) = 8.31 [confidence interval (CI) 95% 3.19-21.61]. More than 70% of these deaths were attributed to respiratory tract infections and were associated with children under the age of 5. Excess mortality due to external causes, injuries and substance abuse was observed in repatriated males compared with their natively born counterparts, OR = 2.27 (CI 95% 1.35-3.81). CONCLUSIONS: Specific public health interventions are required, to improve the survival of different cultural groups. For example, improvement of immunization status and increase in overall hygiene awareness can ameliorate high infant/childhood mortality in Roma population, while social integration can help reduce acculturation-related mortality among repatriated Greeks. PMID- 25740905 TI - A case of popliteal artery stenosis: masquerading as an infective foot ulcer in a young male traveller. AB - Here, we present a case report of a young male who had been travelling in Thailand. The patient sustained a relatively minor trauma to the soft tissue under his left third metatarsal head on a piece of coral reef. He subsequently developed an infected ulcer, which did not heal despite appropriate antibiotic therapy and surgical debridement. Unfortunately, the patient required amputation of the left third toe and metatarsal head due to osteomyelitic destruction. It later transpired that the ulcer was initially ischaemic in nature due to previously undiagnosed and asymptomatic popliteal artery stenosis. PMID- 25740906 TI - Long-term green tea extract supplementation does not affect fat absorption, resting energy expenditure, and body composition in adults. AB - BACKGROUND: Green tea (GT) extract may play a role in body weight regulation. Suggested mechanisms are decreased fat absorption and increased energy expenditure. OBJECTIVE: We examined whether GT supplementation for 12 wk has beneficial effects on weight control via a reduction in dietary lipid absorption as well as an increase in resting energy expenditure (REE). METHODS: Sixty Caucasian men and women [BMI (in kg/m2): 18-25 or >25; age: 18-50 y] were included in a randomized placebo-controlled study in which fecal energy content (FEC), fecal fat content (FFC), resting energy expenditure, respiratory quotient (RQ), body composition, and physical activity were measured twice (baseline vs. week 12). For 12 wk, subjects consumed either GT (>0.56 g/d epigallocatechin gallate + 0.28-0.45 g/d caffeine) or placebo capsules. Before the measurements, subjects recorded energy intake for 4 consecutive days and collected feces for 3 consecutive days. RESULTS: No significant differences between groups and no significant changes over time were observed for the measured variables. Overall means +/- SDs were 7.2 +/- 3.8 g/d, 6.1 +/- 1.2 MJ/d, 67.3 +/- 14.3 kg, and 29.8 +/- 8.6% for FFC, REE, body weight, and body fat percentage, respectively. CONCLUSION: GT supplementation for 12 wk in 60 men and women did not have a significant effect on FEC, FFC, REE, RQ, and body composition. PMID- 25740907 TI - Low circulating 25-hydroxyvitamin D concentrations are associated with defects in insulin action and insulin secretion in persons with prediabetes. AB - BACKGROUND: Individuals with prediabetes mellitus (PreDM) and low circulating 25 hydroxyvitamin D [25(OH)D] are at increased risk of type 2 diabetes mellitus (T2DM). OBJECTIVE: We aimed to determine whether low 25(OH)D concentrations are associated with defects in insulin action and insulin secretion in persons with PreDM. METHODS: In this cross-sectional study, we stratified 488 nondiabetic subjects as having PreDM or normal fasting glucose (NFG) and a 25(OH)D concentration <=20 ng/mL (deficient) or >20 ng/mL (sufficient). We determined insulin resistance by steady state plasma glucose (SSPG) concentration and homeostasis model assessment of insulin resistance (HOMA-IR) and insulin secretion by homeostasis model assessment of beta-cell function (HOMA-beta). We compared insulin resistance and secretion measures in PreDM and NFG groups; 25(OH)D-deficient and 25(OH)D-sufficient groups; and PreDM-deficient, PreDM sufficient, NFG-deficient, and NFG-sufficient subgroups, adjusting for age, sex, race, body mass index, multivitamin use, and season. RESULTS: In the PreDM group, mean SSPG concentration and HOMA-IR were higher and mean HOMA-beta was lower than in the NFG group (P < 0.001 for all comparisons). In the 25(OH)D-deficient group, mean SSPG concentration was higher (P < 0.001), but neither mean HOMA-IR nor HOMA beta was significantly different from that in the 25(OH)D-sufficient group. In the PreDM-deficient subgroup, mean (95% CI) SSPG concentration was higher (P < 0.01) than in the PreDM-sufficient, NFG-deficient, and NFG-sufficient subgroups [192 (177-207) mg/dL vs. 166 (155-177) mg/dL, 148 (138-159) mg/dL, and 136 (127 144) mg/dL, respectively]. Despite greater insulin resistance, mean HOMA-beta was not significantly higher in the PreDM-deficient subgroup than in the PreDM sufficient, NFG-deficient, and NFG-sufficient subgroups [98 (85-112) vs. 91 (82 101), 123 (112-136), and 115 (106-124), respectively]. CONCLUSION: Subjects with PreDM and low circulating 25(OH)D concentrations are the subgroup of nondiabetic individuals who are the most insulin resistant and have impaired beta-cell function, attributes that put them at enhanced risk of T2DM. PMID- 25740908 TI - The Global Nutrition Report 2014: actions and accountability to accelerate the world's progress on nutrition. AB - In 2013, the Nutrition for Growth Summit called for a Global Nutrition Report (GNR) to strengthen accountability in nutrition so that progress in reducing malnutrition could be accelerated. This article summarizes the results of the first GNR. By focusing on undernutrition and overweight, the GNR puts malnutrition in a new light. Nearly every country in the world is affected by malnutrition, and multiple malnutrition burdens are the "new normal." Unfortunately, the world is off track to meet the 2025 World Health Assembly (WHA) targets for nutrition. Many countries are, however, making good progress on WHA indicators, providing inspiration and guidance for others. Beyond the WHA goals, nutrition needs to be more strongly represented in the Sustainable Development Goal (SDG) framework. At present, it is only explicitly mentioned in 1 of 169 SDG targets despite the many contributions improved nutritional status will make to their attainment. To achieve improvements in nutrition status, it is vital to scale up nutrition programs. We identify bottlenecks in the scale-up of nutrition-specific and nutrition-sensitive approaches and highlight actions to accelerate coverage and reach. Holding stakeholders to account for delivery on nutrition actions requires a well-functioning accountability infrastructure, which is lacking in nutrition. New accountability mechanisms need piloting and evaluation, financial resource flows to nutrition need to be made explicit, nutrition spending targets should be established, and some key data gaps need to be filled. For example, many UN member states cannot report on their WHA progress and those that can often rely on data >5 y old. The world can accelerate malnutrition reduction substantially, but this will require stronger accountability mechanisms to hold all stakeholders to account. PMID- 25740909 TI - Flaxseed consumption may reduce blood pressure: a systematic review and meta analysis of controlled trials. AB - BACKGROUND: High blood pressure is a major health burden positively associated with the risk of cardiovascular disease and other chronic diseases. Flaxseed is a rich dietary source of alpha-linolenic acid, lignans, and fiber, with a number of positive health benefits on blood pressure. OBJECTIVE: The purpose of this study was to clarify the effect of flaxseed consumption on blood pressure. Further, the influence of baseline blood pressure, type of flaxseed supplementation, and duration of flaxseed supplementation on blood pressure was explored. METHOD: PubMed (MEDLINE), Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library (Central) were searched through July 2014 for studies in which humans supplemented their habitual diet with flaxseed or its extracts (i.e., oil, lignans, fiber) for >=2 wk. RESULTS: A total of 11 studies (14 trials) were included in the analysis. Random-effects meta-analyses were conducted for the mean difference in blood pressure. Results indicated that flaxseed supplementation reduced systolic blood pressure (-1.77 mm Hg; 95% CI: -3.45, 0.09 mm Hg; P = 0.04) and diastolic blood pressure (-1.58 mm Hg; 95% CI: -2.64, 0.52 mm Hg; P = 0.003). These results were not influenced by categorization of participants into higher baseline blood pressure (>=130 mm Hg). An improvement in diastolic blood pressure was observed in subgroup analysis for consuming whole flaxseed (-1.93 mm Hg; 95% CI: -3.65, -0.21 mm Hg; P < 0.05) and duration of consumption >=12 wk (-2.17 mm Hg; 95% CI: -3.44, -0.89 mm Hg; P < 0.05). CONCLUSION: The present meta-analysis suggests that consumption of flaxseed may lower blood pressure slightly. The beneficial potential of flaxseed to reduce blood pressure (especially diastolic blood pressure) may be greater when it is consumed as a whole seed and for a duration of >12 wk. PMID- 25740910 TI - Citrulline does not prevent skeletal muscle wasting or weakness in limb-casted mice. AB - BACKGROUND: Increasing arginine (Arg) availability reduces atrophy in cultured skeletal muscle cells. Supplementation with its metabolic precursor citrulline (Cit) is more effective at improving skeletal muscle Arg concentrations. OBJECTIVE: We tested the hypothesis that Cit supplementation would attenuate skeletal muscle atrophy and loss of function during hindlimb immobilization in mice. METHODS: Male C57BL/6JArc mice underwent 14 d of unilateral hindlimb immobilization/plaster casting and were supplemented with ~0.81 g Cit . kg-1 . d 1 (CIT group) or Ala (ALA group) mixed into their food. The uncasted contralateral limb (internal control) and an uncasted group (CON) served as controls. Muscle atrophy was evaluated with mass, fiber area, and in situ muscle function. RESULTS: Tibialis anterior (TA) muscle mass [ALA: 37.6 +/- 0.92 mg; CIT: 38.3 +/- 1.25 mg] and peak tetanic force (ALA: 1150 +/- 38.5 mN; CIT: 1150 +/- 52.0 mN) were lower (P < 0.001) in the ALA (53.9 +/- 0.42 mg) and CIT (1760 +/- 28.5 mN) groups than in the CON group. No difference was found between ALA and CIT groups for TA mass, fiber area, or peak force. The mRNA expression of the nitric oxide synthase 2, inducible (Nos2; ~15-fold) and B-cell chronic lymphoid leukemia/lymphoma 2/adenovirus E1B 19 kDa interacting protein 3 (Bnip3; ~17-fold) genes and the ratio of microtubule-associated protein light chain 3BII to 3BI (LC3BII:LC3BI) (50.5% +/- 17.7%) were higher (P < 0.05) in the ALA group than in the CON group, suggesting increased autophagy. In the CIT group, Bnip3 mRNA was lower (-70%; P < 0.05) and Nos2 mRNA tended to be lower (-45%; P = 0.05) than in the ALA group, whereas LC3BII:LC3BI was not different from the CON group. CONCLUSIONS: Cit treatment of male mice did not affect therapeutically relevant outcome measures such as skeletal muscle mass and peak muscle force after 14 d of hindlimb immobilization. PMID- 25740911 TI - A glaring paradox. PMID- 25740913 TI - Corrigendum. PMID- 25740915 TI - Has the fit note reduced general practice sickness certification rates? AB - BACKGROUND: In 2010, the fit note replaced the sick note to help focus on what people are capable of doing, rather than signing patients 'off sick'. AIMS: To compare proportions of work-related ill-health issued with sickness certification pre- and post-fit note introduction and assess sickness absence trends. METHODS: General practitioners (GPs) report data on work-related ill-health and sickness absence via The Health and Occupation Research network in General Practice. The proportion of cases issued with sickness certification 4 years before and 3 years after the fit note introduction were compared. Changes in certification incidence rate ratios were measured over time. RESULTS: Participating GPs reported 5517 cases of work-related ill-health. Pre-fit note introduction 50% of cases were certified sick. There was no change in the proportion of cases certified sick in the first year post-fit note, despite 13% of cases classified as 'maybe fit'. However, in the second year, the proportion of cases certified sick had reduced significantly (41%) and a larger proportion (19%) was advised on workplace adjustments. In the third year post-introduction, there was a slight rise in the proportion of cases certified sick; therefore, although there was a fall of 2% per annum in certification rates, this was not significant. CONCLUSIONS: In the first year post-fit note introduction, modifications to work were recommended for people who would previously have been declared fit. Trends analyses showed a slight decrease in the certification rate, possibly indicating GPs will become more practised in advising on workplace adjustments. PMID- 25740916 TI - Dopamine Receptor D2 and Associated microRNAs Are Involved in Stress Susceptibility and Resistance to Escitalopram Treatment. AB - BACKGROUND: Early life stress has been demonstrated to increase the risk of developing depression in adulthood. However, the roles and associated molecular mechanisms of stresses in the onset and relapse of depression have yet to be fully elucidated. METHODS: Depression-like behaviors were induced in rats by maternal deprivation and chronic unpredictable stress. Depression- and anxiety like behaviors of rats, dopamine receptor D2 level, and microRNAs expression in rats' brain tissues were measured. RESULTS: Chronic unpredictable stress alone induced depression-like behaviors in rats, but maternal deprivation enhanced the effect of chronic unpredictable stress. Escitalopram significantly decreased depression-like behaviors in chronic unpredictable stress rats but was less effective in maternal deprivation with chronic unpredictable stress rats. Maternal deprivation increased dopamine receptor D2 messenger RNA expression and decreased microRNA-9 expression in the striatum. Chronic unpredictable stress increased dopamine receptor D2 mRNA and protein levels and decreased microRNA-9 expression in the nucleus accumbens. Furthermore, maternal deprivation enhanced the effect of chronic unpredictable stress on dopamine receptor D2 gene and microRNA-9 expression. Chronic unpredictable stress increased the expression of microRNA-326 in the nucleus accumbens but decreased it in the striatum, whereas maternal deprivation elevated microRNA-326 expression in the striatum. Escitalopram normalized microRNA-326 expression but had no effect on the expression of microRNA-9, dopamine receptor D2 mRNA, and dopamine receptor D2 protein in both the nucleus accumbens and striatum. The in vitro study showed that only microRNA-9 directly targeted the 3' untranslated region of dopamine receptor D2 mRNA and inhibited dopamine receptor D2 protein expression. CONCLUSION: Early life stress enhanced the susceptibility to late life stress and resistance to escitalopram treatment through decreasing microRNA-9 expression and subsequently upregulating dopamine receptor D2 expression in the nucleus accumbens. microRNA-326 may be a novel target of escitalopram. PMID- 25740912 TI - Genetic and genomic toolbox of Zea mays. AB - Maize has a long history of genetic and genomic tool development and is considered one of the most accessible higher plant systems. With a fully sequenced genome, a suite of cytogenetic tools, methods for both forward and reverse genetics, and characterized phenotype markers, maize is amenable to studying questions beyond plant biology. Major discoveries in the areas of transposons, imprinting, and chromosome biology came from work in maize. Moving forward in the post-genomic era, this classic model system will continue to be at the forefront of basic biological study. In this review, we outline the basics of working with maize and describe its rich genetic toolbox. PMID- 25740917 TI - Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid. AB - BACKGROUND: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. METHODS: A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC). RESULTS: After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained >=7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and alpha catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121). CONCLUSIONS: LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain. PMID- 25740918 TI - Disability Trajectories at the End of Life: A "Countdown" Model. AB - OBJECTIVES: Studies of late-life disablement typically address the role of advancing age as a factor in developing disability, and in some cases have pointed out the importance of time to death (TTD) in understanding changes in functioning. However, few studies have addressed both factors simultaneously, and none have dealt satisfactorily with the problem of missing data on TTD in panel studies. METHODS: We fit latent-class trajectory models of disablement using data from the Health and Retirement Study. Among survivors (~20% of the sample), TTD is unknown, producing a missing-data problem. We use an auxiliary regression equation to impute TTD and employ multiple imputation techniques to obtain final parameter estimates and standard errors. RESULTS: Our best-fitting model has 3 latent classes. In all 3 classes, the probability of having a disability increases with nearness to death; however, in only 2 of the 3 classes is age associated with disability. We find gender, race, and educational differences in class-membership probabilities. DISCUSSION: The model reveals a complex pattern of age- and time-dependent heterogeneity in late-life disablement. The techniques developed here could be applied to other phenomena known to depend on TTD, such as cognitive change, weight loss, and health care spending. PMID- 25740919 TI - The plant nuclear envelope as a multifunctional platform LINCed by SUN and KASH. AB - The nuclear envelope (NE) is a double membrane system enclosing the genome of eukaryotes. Besides nuclear pore proteins, which form channels at the NE, nuclear membranes are populated by a collection of NE proteins that perform various cellular functions. However, in contrast to well-conserved nuclear pore proteins, known NE proteins share little homology between opisthokonts and plants. Recent studies on NE protein complexes formed by Sad1/UNC-84 (SUN) and Klarsicht/ANC 1/Syne-1 Homology (KASH) proteins have advanced our understanding of plant NE proteins and revealed their function in anchoring other proteins at the NE, nuclear shape determination, nuclear positioning, anti-pathogen defence, root development, and meiotic chromosome organization. In this review, we discuss the current understanding of plant SUN, KASH, and other related NE proteins, and compare their function with the opisthokont counterparts. PMID- 25740920 TI - Abundance and distribution of RNA polymerase II in Arabidopsis interphase nuclei. AB - RNA polymerase II (RNAPII) is responsible for the transcription of most eukaryotic protein-coding genes. Analysing the topological distribution and quantification of RNAPII can contribute to understanding its function in interphase nuclei. Previously it was shown that RNAPII molecules in plant nuclei form reticulate structures within euchromatin of differentiated Arabidopsis thaliana nuclei rather than being organized in distinct 'transcription factories' as observed in mammalian nuclei. Immunosignal intensity measurements based on specific antibody labelling in maximum intensity projections of image stacks acquired by structured illumination microscopy (SIM) suggested a relative proportional increase of RNAPII in endopolyploid plant nuclei. Here, photoactivated localization microscopy (PALM) was applied to determine the absolute number and distribution of active and inactive RNAPII molecules in differentiated A. thaliana nuclei. The proportional increase of RNAPII during endopolyploidization is confirmed, but it is also shown that PALM measurements are more reliable than those based on SIM in terms of quantification. The single molecule localization results show that, although RNAPII molecules are globally dispersed within plant euchromatin, they also aggregate within smaller distances as described for mammalian transcription factories. PMID- 25740921 TI - Phenotyping pipeline reveals major seedling root growth QTL in hexaploid wheat. AB - Seedling root traits of wheat (Triticum aestivum L.) have been shown to be important for efficient establishment and linked to mature plant traits such as height and yield. A root phenotyping pipeline, consisting of a germination paper based screen combined with image segmentation and analysis software, was developed and used to characterize seedling traits in 94 doubled haploid progeny derived from a cross between the winter wheat cultivars Rialto and Savannah. Field experiments were conducted to measure mature plant height, grain yield, and nitrogen (N) uptake in three sites over 2 years. In total, 29 quantitative trait loci (QTLs) for seedling root traits were identified. Two QTLs for grain yield and N uptake co-localize with root QTLs on chromosomes 2B and 7D, respectively. Of the 29 root QTLs identified, 11 were found to co-localize on 6D, with four of these achieving highly significant logarithm of odds scores (>20). These results suggest the presence of a major-effect gene regulating seedling root vigour/growth on chromosome 6D. PMID- 25740922 TI - Assessing the influence of the rhizosphere on soil hydraulic properties using X ray computed tomography and numerical modelling. AB - Understanding the dynamics of water distribution in soil is crucial for enhancing our knowledge of managing soil and water resources. The application of X-ray computed tomography (CT) to the plant and soil sciences is now well established. However, few studies have utilized the technique for visualizing water in soil pore spaces. Here this method is utilized to visualize the water in soil in situ and in three-dimensions at successive reductive matric potentials in bulk and rhizosphere soil. The measurements are combined with numerical modelling to determine the unsaturated hydraulic conductivity, providing a complete picture of the hydraulic properties of the soil. The technique was performed on soil cores that were sampled adjacent to established roots (rhizosphere soil) and from soil that had not been influenced by roots (bulk soil). A water release curve was obtained for the different soil types using measurements of their pore geometries derived from CT imaging and verified using conventional methods, such as pressure plates. The water, soil, and air phases from the images were segmented and quantified using image analysis. The water release characteristics obtained for the contrasting soils showed clear differences in hydraulic properties between rhizosphere and bulk soil, especially in clay soil. The data suggest that soils influenced by roots (rhizosphere soil) are less porous due to increased aggregation when compared with bulk soil. The information and insights obtained on the hydraulic properties of rhizosphere and bulk soil will enhance our understanding of rhizosphere biophysics and improve current water uptake models. PMID- 25740923 TI - An Arabidopsis soluble chloroplast proteomic analysis reveals the participation of the Executer pathway in response to increased light conditions. AB - The Executer1 and Executer2 proteins have a fundamental role in the signalling pathway mediated by singlet oxygen in chloroplast; nonetheless, not much is known yet about their specific activity and features. Herein, we have followed a differential-expression proteomics approach to analyse the impact of Executer on the soluble chloroplast protein abundance in Arabidopsis. Because singlet oxygen plays a significant role in signalling the oxidative response of plants to light, our analysis also included the soluble chloroplast proteome of plants exposed to a moderate light intensity in the time frame of hours. A number of light- and genotype-responsive proteins were detected, and mass-spectrometry identification showed changes in abundance of several photosynthesis- and carbon metabolism related proteins as well as proteins involved in plastid mRNA processing. Our results support the participation of the Executer proteins in signalling and control of chloroplast metabolism, and in the regulation of plant response to environmental changes. PMID- 25740924 TI - Sap fluxes from different parts of the rootzone modulate xylem ABA concentration during partial rootzone drying and re-wetting. AB - Previous studies with partial rootzone drying (PRD) irrigation demonstrated that alternating the wet and dry parts of the rootzone (PRD-Alternated) increased leaf xylem ABA concentration ([X-ABA]leaf) compared with maintaining the same wet and dry parts of the rootzone (PRD-Fixed). To determine the relative contributions of different parts of the rootzone to this ABA signal, [X-ABA]leaf of potted, split root tomato (Solanum lycopersicum) plants was modelled by quantifying the proportional water uptake from different soil compartments, and [X-ABA]leaf responses to the entire pot soil-water content (thetapot). Continuously measuring soil-moisture depletion by, or sap fluxes from, different parts of the root system revealed that water uptake rapidly declined (within hours) after withholding water from part of the rootzone, but was rapidly restored (within minutes) upon re-watering. Two hours after re-watering part of the rootzone, [X ABA]leaf was equally well predicted according to thetapot alone and by accounting for the proportional water uptake from different parts of the rootzone. Six hours after re-watering part of the rootzone, water uptake by roots in drying soil was minimal and, instead, occurred mainly from the newly irrigated part of the rootzone, thus [X-ABA]leaf was best predicted by accounting for the proportional water uptake from different parts of the rootzone. Contrary to previous results, alternating the wet and dry parts of the rootzone did not enhance [X-ABA]leaf compared with PRD-Fixed irrigation. Further work is required to establish whether altered root-to-shoot ABA signalling contributes to the improved yields of crops grown with alternate, rather than fixed, PRD. PMID- 25740925 TI - Liming can decrease legume crop yield and leaf gas exchange by enhancing root to shoot ABA signalling. AB - To meet future requirements for food production, sustainable intensive agricultural systems need to optimize nutrient availability to maximize yield, traditionally achieved by maintaining soil pH within an optimal range (6-6.5) by applying lime (calcium carbonate). However, a field trial that applied recommended liming rates to a sandy loam soil (increasing soil pH from 5.5 to 6.2) decreased pod yield of field bean (Vicia faba L. cv. Fuego) by ~30%. Subsequent pot trials, with liming that raised soil pH to 6.3-6.7, reduced stomatal conductance (g(s)) by 63, 26, and 59% in V. faba, bean (Phaseolus vulgaris), and pea (Pisum sativum), respectively. Furthermore, liming reduced shoot dry biomass by 16-24% in these species. Ionomic analysis of root xylem sap and leaf tissue revealed a decrease in phosphorus concentration that was correlated with decreased g(s): both reductions were partially reversed by adding superphosphate fertilizer. Further analysis of pea suggests that leaf gas exchange was reduced by a systemic increase (roots, xylem sap, and leaves) in the phytohormone abscisic acid (ABA) in response to lime-induced suboptimal plant phosphorus concentrations. Supplying synthetic ABA via the transpiration stream to detached pea leaves, at the same xylem sap concentrations induced by liming, decreased transpiration. Furthermore, the g(s) of the ABA-deficient mutant pea wilty was unresponsive to liming, apparently confirming that ABA mediates some responses to low phosphorus availability caused by liming. This research provides a detailed mechanistic understanding of the physiological processes by which lime application can limit crop yields, and questions the suitability of current liming recommendations. PMID- 25740926 TI - The identification of Cucumis sativus Glabrous 1 (CsGL1) required for the formation of trichomes uncovers a novel function for the homeodomain-leucine zipper I gene. AB - The spines and bloom of cucumber (Cucumis sativus L.) fruit are two important quality traits related to fruit market value. However, until now, none of the genes involved in the formation of cucumber fruit spines and bloom trichomes has been identified. Here, the characterization of trichome development in wild-type (WT) cucumber and a spontaneous mutant, glabrous 1 (csgl1) controlled by a single recessive nuclear gene, with glabrous aerial organs, is reported. Via map-based cloning, CsGL1 was isolated and it was found that it encoded a member of the homeodomain-leucine zipper I (HD-Zip I) proteins previously identified to function mainly in the abiotic stress responses of plants. Tissue-specific expression analysis indicated that CsGL1 was strongly expressed in trichomes and fruit spines. In addition, CsGL1 was a nuclear protein with weak transcriptional activation activity in yeast. A comparative analysis of the digital gene expression (DGE) profile between csgl1 and WT leaves revealed that CsGL1 had a significant influence on the gene expression profile in cucumber, especially on genes related to cellular process, which is consistent with the phenotypic difference between csgl1 and the WT. Moreover, two genes, CsMYB6 and CsGA20ox1, possibly involved in the formation of cucumber trichomes and fruit spines, were characterized. Overall, the findings reveal a new function for the HD-Zip I gene subfamily, and provide some candidate genes for genetic engineering approaches to improve cucumber fruit external quality. PMID- 25740927 TI - Interaction between carbon metabolism and phosphate accumulation is revealed by a mutation of a cellulose synthase-like protein, CSLF6. AB - Phosphorus is an essential macronutrient for plant growth and development. However, the network that affects phosphate (Pi) accumulation in crops is not well established. It is reported here that OsCSLF6, a member of the cellulose synthase-like family (CSLF), which is found only in grasses, is involved in Pi accumulation. The oscslf6 mutants (oscslf6-1 and oscslf6-2) display Pi toxic symptoms and increased Pi accumulation in both roots and shoots under the Pi sufficient condition, which correlate with the induced expression of Pi transporters in the knockout mutants. Consistent with the over-accumulation of Pi, a significant decrease in primary root length, adventitious root length, and adventitious root number were observed in the oscslf6 mutants when compared with the wild type (WT) under Pi-sufficient conditions. In addition, the sucrose (Suc) level was increased in the oscslf6 mutants and the expression of sucrose synthases (OsSUS4/5) and sucrose transporters (OsSUT1/2/4/OsSweet14) genes were also induced in the shoots of oscslf6 mutants, suggesting that OsCSLF6 may play a role in affecting Pi accumulation by affecting the level of carbon metabolism. PMID- 25740928 TI - Linking phosphorus availability with photo-oxidative stress in plants. AB - Plants have evolved a plethora of mechanisms to circumvent the potential damaging effects of living under low phosphorus availability in the soil. These mechanisms include different levels of organization, from root-shoot signalling at the whole plant level to specific biochemical responses at the subcellular level, such as reductions in photosynthesis and the consequent activation of photo- and antioxidant mechanisms in chloroplasts. Some recent studies clearly indicate that severe phosphorus deficiency can lead to alterations in the photosynthetic apparatus, including reductions in CO2 assimilation rates, a down-regulation of photosynthesis-related genes and photoinhibition at the photosystem II level, thus causing potential photo-oxidative stress. Photo-oxidative stress is characterized by an increased production of reactive oxygen species in chloroplasts, which at low concentrations can serve a signalling, protective role, but when present at high concentrations can cause damage to lipids, proteins and nucleic acids, thus leading to irreversible injuries. We discuss here the mechanisms that phosphate-starved plants have evolved to withstand photo oxidative stress, including changes at the subcellular level (e.g. activation of photo- and antioxidant protection mechanisms in chloroplasts), cellular and tissular levels (e.g. activation of photorespiration and anthocyanin accumulation) and whole-plant level (alterations in source-sink relationships modulated by hormones). Of particular importance is the current evidence demonstrating that phosphate-starved plants activate simultaneous responses at multiple levels, from transcriptional changes to root-shoot signalling, to prevent oxidative damage. In this review, we summarize current knowledge about the occurrence of photo-oxidative stress in phosphate-starved plants and highlight the mechanisms these plants have evolved to prevent oxidative damage under phosphorus limitation at the subcellular, cellular and whole-plant levels. PMID- 25740929 TI - Function of glutathione peroxidases in legume root nodules. AB - Glutathione peroxidases (Gpxs) are antioxidant enzymes not studied so far in legume nodules, despite the fact that reactive oxygen species are produced at different steps of the symbiosis. The function of two Gpxs that are highly expressed in nodules of the model legume Lotus japonicus was examined. Gene expression analysis, enzymatic and nitrosylation assays, yeast cell complementation, in situ mRNA hybridization, immunoelectron microscopy, and LjGpx green fluorescent protein (GFP) fusions were used to characterize the enzymes and to localize each transcript and isoform in nodules. The LjGpx1 and LjGpx3 genes encode thioredoxin-dependent phospholipid hydroperoxidases and are differentially regulated in response to nitric oxide (NO) and hormones. LjGpx1 and LjGpx3 are nitrosylated in vitro or in plants treated with S-nitrosoglutathione (GSNO). Consistent with the modification of the peroxidatic cysteine of LjGpx3, in vitro assays demonstrated that this modification results in enzyme inhibition. The enzymes are highly expressed in the infected zone, but the LjGpx3 mRNA is also detected in the cortex and vascular bundles. LjGpx1 is localized to the plastids and nuclei, and LjGpx3 to the cytosol and endoplasmic reticulum. Based on yeast complementation experiments, both enzymes protect against oxidative stress, salt stress, and membrane damage. It is concluded that both LjGpxs perform major antioxidative functions in nodules, preventing lipid peroxidation and other oxidative processes at different subcellular sites of vascular and infected cells. The enzymes are probably involved in hormone and NO signalling, and may be regulated through nitrosylation of the peroxidatic cysteine essential for catalytic function. PMID- 25740930 TI - Candida funiuensi sp. nov., a cellobiose-fermenting yeast species isolated from rotten wood. AB - Two strains of an asexual cellobiose-fermenting yeast species were isolated from rotten wood samples collected in Funiu Mountain Nature Reserve in Henan Province, central China. Molecular phylogenetic analysis that included the nearly complete small subunit (SSU), the internal transcribed spacer (ITS) region and the D1/D2 domains of the large subunit (LSU) rDNA showed that these strains belonged to the Candida kruisii clade, with Candida kruisii and Candida cretensis as their closest phylogenetic neighbours. The nucleotide differences between the novel strains and the type strains of C. kruisii and C. cretensis were 30 and 36 substitutions, respectively, in the D1/D2 LSU rDNA, 40 and 44 substitutions, respectively, in the ITS region and 19 and 23 substitutions, respectively, in the SSU rDNA. The novel strains can also be distinguished from their closest described species, C. kruisii and C. cretensis, by a number of physiological characteristics, and represent a novel species of the genus Candida, for which the name Candida funiuensis sp. nov. is proposed. The type strain is NYNU 14625T ( = CICC 33050T = CBS 13911T). The Mycobank number is MB 811503. PMID- 25740931 TI - Algibacter psychrophilus sp. nov., a psychrophilic bacterium isolated from marine sediment. AB - A Gram-stain-negative, aerobic, yellow-pigmented, flexirubin-negative, rod shaped, non-motile and psychrophilic bacterial strain, PAMC 27237T, was isolated from marine sediment of the Ross Sea, Antarctica. Strain PAMC 27237T grew at 0-20 degrees C (optimally at 17 degrees C), at pH 5.0-9.5 (optimally at pH 7.0) and in the presence of 0-3.5 % (w/v) NaCl (optimally at 1.5-2.5 %). The major fatty acids (>=5 %) were iso-C17 : 0 3-OH, C17 : 0 2-OH, anteiso-C15 : 0, summed feature 3 (C16 : 1omega6c/C16 : 1omega7c), iso-C15 : 0 3-OH, anteiso-C17 : 1omega9c, anteiso-C15 : 1 A, iso-C16 : 0 3-OH and iso-C15 : 1 G. The major polar lipids were phosphatidylethanolamine, two unidentified aminolipids, four unidentified lipids and a glycolipid. The major respiratory quinone was MK-6. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain PAMC 27237T belongs to the genus Algibacter, showing high similarities with the type strains of Algibacter agarivorans (97.2 %), Algibacter agarilyticus (97.0 %) and Algibacter mikhailovii (96.4 %). Average nucleotide identity values between strain PAMC 27237T and the type strains of A. agarivorans and A. agarilyticuswere 83.1 and 84.2 %, respectively, and mean genome-to-genome distances were 22.4-24.2 %, indicating that strain PAMC 27237T is clearly distinguished from the most closely related species of the genus Algibacter. The genomic DNA G+C content calculated from genome sequences was 33.5 mol%. Based on the phenotypic, chemotaxonomic and phylogenetic data presented, strain PAMC 27237T is considered to represent a novel species of the genus Algibacter, for which the name Algibacter psychrophilus sp. nov. is proposed. The type strain is PAMC 27237T ( = KCTC 42130T = JCM 30370T). PMID- 25740932 TI - Lysinibacillus acetophenoni sp. nov., a solvent-tolerant bacterium isolated from acetophenone. AB - A Gram-stain-positive, solvent-tolerating, aerobic, rod-shaped bacterium that formed terminal endospores was isolated from the organic solvent acetophenone. The strain, designated JC23T, was oxidase- and catalase-positive. The strain grew in the presence of a wide range of organic solvents with partition coefficients (log p values) between 1 and 4, which are exceptionally toxic to micro-organisms. Based on 16S rRNA gene sequence analysis, strain JC23T was identified as belonging to the genus Lysinibacillus and was most closely related to Lysinibacillus manganicus Mn1-7T (98.5 % similarity), L. massiliensis 440831T (97.2 %) and L. chungkukjangi 2RL3-2T (96.8 %). DNA-DNA relatedness of strain JC23T with the type strains of the closest species was <39 %. Strain JC23T grew chemo-organoheterotrophically with optimal growth at pH 7 (range pH 6-9) and at 35 degrees C (range 25-40 degrees C). The DNA G+C content was 41 mol%. Major cellular fatty acids of strain JC23T were iso-C15 : 0, iso-C16 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The cell-wall peptidoglycan type was determined to be A4alpha (l-Lys-d-Asp), which is in agreement with the cell-wall characteristics of the genus Lysinibacillus. The predominant quinone system was MK-7. Polar lipids of strain JC23T included diphosphatidylglycerol, phosphatidylglycerol, two unidentified glycolipids, beta-gentiobiosyldiacylglycerol, two unidentified phospholipids and two unidentified lipids. On the basis of our morphological, physiological, genetic, phylogenetic and chemotaxonomic analyses, we conclude that strain JC23T should be assigned to a novel species of the genus Lysinibacillus, for which the name Lysinibacillus acetophenoni sp. nov. is proposed. The type strain is strain JC23T ( = CCUG 57911T = KCTC 13605T = NBRC 105754T = DSM 23394T). PMID- 25740933 TI - Tepidicaulis marinus gen. nov., sp. nov., a marine bacterium that reduces nitrate to nitrous oxide under strictly microaerobic conditions. AB - A moderately thermophilic, aerobic, stalked bacterium (strain MA2T) was isolated from marine sediments in Kagoshima Bay, Japan. Phylogenetic analysis of 16S rRNA gene sequences indicated that strain MA2T was most closely related to the genera Rhodobium,Parvibaculum, and Rhodoligotrophos (92-93 % similarity) within the class Alphaproteobacteria. Strain MA2T was a Gram-stain-negative and stalked dimorphic bacteria. The temperature range for growth was 16-48 degrees C (optimum growth at 42 degrees C). This strain required yeast extract and NaCl (>1 %, w/v) for growth, tolerated up to 11 % (w/v) NaCl, and was capable of utilizing various carbon sources. The major cellular fatty acid and major respiratory quinone were C18 : 1omega7c and ubiquinone-10, respectively. The DNA G+C content was 60.7 mol%. Strain MA2T performed denitrification and produced N2O from nitrate under strictly microaerobic conditions. Strain MA2T possessed periplasmic nitrate reductase (Nap) genes but not membrane-bound nitrate reductase (Nar) genes. On the basis of this morphological, physiological, biochemical and genetic information a novel genus and species, Tepidicaulis marinus gen. nov., sp. nov., are proposed, with MA2T ( = NBRC 109643T = DSM 27167T) as the type strain of the species. PMID- 25740934 TI - Genetic Analysis of Substrain Divergence in Non-Obese Diabetic (NOD) Mice. AB - The non-obese diabetic (NOD) mouse is a polygenic model for type 1 diabetes that is characterized by insulitis, a leukocytic infiltration of the pancreatic islets. During ~35 years since the original inbred strain was developed in Japan, NOD substrains have been established at different laboratories around the world. Although environmental differences among NOD colonies capable of impacting diabetes incidence have been recognized, differences arising from genetic divergence have not been analyzed previously. We use both mouse diversity array and whole-exome capture sequencing platforms to identify genetic differences distinguishing five NOD substrains. We describe 64 single-nucleotide polymorphisms, and two short indels that differ in coding regions of the five NOD substrains. A 100-kb deletion on Chromosome 3 distinguishes NOD/ShiLtJ and NOD/ShiLtDvs from three other substrains, whereas a 111-kb deletion in the Icam2 gene on Chromosome 11 is unique to the NOD/ShiLtDvs genome. The extent of genetic divergence for NOD substrains is compared with similar studies for C57BL6 and BALB/c substrains. As mutations are fixed to homozygosity by continued inbreeding, significant differences in substrain phenotypes are to be expected. These results emphasize the importance of using embryo freezing methods to minimize genetic drift within substrains and of applying appropriate genetic nomenclature to permit substrain recognition when one is used. PMID- 25740936 TI - Modeling X-linked ancestral origins in multiparental populations. AB - The models for the mosaic structure of an individual's genome from multiparental populations have been developed primarily for autosomes, whereas X chromosomes receive very little attention. In this paper, we extend our previous approach to model ancestral origin processes along two X chromosomes in a mapping population, which is necessary for developing hidden Markov models in the reconstruction of ancestry blocks for X-linked quantitative trait locus mapping. The model accounts for the joint recombination pattern, the asymmetry between maternally and paternally derived X chromosomes, and the finiteness of population size. The model can be applied to various mapping populations such as the advanced intercross lines (AIL), the Collaborative Cross (CC), the heterogeneous stock (HS), the Diversity Outcross (DO), and the Drosophila synthetic population resource (DSPR). We further derive the map expansion, density (per Morgan) of recombination breakpoints, in advanced intercross populations with L inbred founders under the limit of an infinitely large population size. The analytic results show that for X chromosomes the genetic map expands linearly at a rate (per generation) of two-thirds times 1 - 10/(9L) for the AIL, and at a rate of two-thirds times 1 - 1/L for the DO and the HS, whereas for autosomes the map expands at a rate of 1 - 1/L for the AIL, the DO, and the HS. PMID- 25740938 TI - Language and unintentional injury mortality in Quebec, Canada. AB - Language-based differences in unintentional injury are poorly understood, despite the importance of language as a determinant of health. This study assessed inequalities in unintentional injury mortality between Francophones and Anglophones of Quebec, Canada. We calculated age-standardised rates of death by period, region, residential deprivation and cause of injury, and estimated rate ratios for Francophones relative to Anglophones. Francophones had higher unintentional injury mortality rates than Anglophones. Inequalities decreased over time for men, but rates remained 50% higher for Francophones at the end of the study period. Rates were stable for women, but were 30% higher for Francophones compared with Anglophones. Inequalities were larger at age 15-44 years, in urban areas, and for MVCs. Better understanding of risk factors for MVCs may benefit injury prevention in Quebec. Language-based differences in injury mortality warrant attention in other multilingual populations, especially across different demographic, temporal, regional and cause-of-injury groups. PMID- 25740937 TI - Rapid and Efficient Identification of Caenorhabditis elegans Legacy Mutations Using Hawaiian SNP-Based Mapping and Whole-Genome Sequencing. AB - The production of viable embryos requires the coordination of many cellular processes, including protein synthesis, cytoskeletal reorganization, establishment of polarity, cell migration, cell division, and in Caenorhabditis elegans, eggshell formation. Defects in any of these processes can lead to embryonic lethality. We examined six temperature-sensitive mutants as well as one nonconditional mutant that were previously identified in genetic screens as either embryonic lethal (maternal-effect or zygotic lethal) or eggshell defective. The responsible molecular lesion for each had never been determined. After confirmation of temperature sensitivity and lethality, we performed whole genome sequencing using a single-nucleotide polymorphism mapping strategy to pinpoint the molecular lesions. Gene candidates were confirmed by RNA interference phenocopy and/or complementation tests and one mutant was further validated by CRISPR (Clustered Regularly Interspaced Short Palidromic Repeats)/Cas9 gene editing. This approach identified new alleles of several genes that had only been previously studied by RNA interference depletion. Our identification of temperature-sensitive alleles for all of these essential genes provides an extremely useful tool for further investigation for the C. elegans community, such as the ability to address mutant phenotypes at various developmental stages and the ability to carry out suppressor/enhancer screens to identify other genes that function in a specific cellular process. PMID- 25740939 TI - Simulated Driving Assessment (SDA) for teen drivers: results from a validation study. AB - BACKGROUND: Driver error and inadequate skill are common critical reasons for novice teen driver crashes, yet few validated, standardised assessments of teen driving skills exist. The purpose of this study is to evaluate the construct and criterion validity of a newly developed Simulated Driving Assessment (SDA) for novice teen drivers. METHODS: The SDA's 35 min simulated drive incorporates 22 variations of the most common teen driver crash configurations. Driving performance was compared for 21 inexperienced teens (age 16-17 years, provisional license <=90 days) and 17 experienced adults (age 25-50 years, license >=5 years, drove >=100 miles per week, no collisions or moving violations <=3 years). SDA driving performance (Error Score) was based on driving safety measures derived from simulator and eye-tracking data. Negative driving outcomes included simulated collisions or run-off-the-road incidents. A professional driving evaluator/instructor (DEI Score) reviewed videos of SDA performance. RESULTS: The SDA demonstrated construct validity: (1) teens had a higher Error Score than adults (30 vs. 13, p=0.02); (2) For each additional error committed, the RR of a participant's propensity for a simulated negative driving outcome increased by 8% (95% CI 1.05 to 1.10, p<0.01). The SDA-demonstrated criterion validity: Error Score was correlated with DEI Score (r=-0.66, p<0.001). CONCLUSIONS: This study supports the concept of validated simulated driving tests like the SDA to assess novice driver skill in complex and hazardous driving scenarios. The SDA, as a standard protocol to evaluate teen driver performance, has the potential to facilitate screening and assessment of teen driving readiness and could be used to guide targeted skill training. PMID- 25740940 TI - Two types of galactosylated fucose motifs are present on N-glycans of Haemonchus contortus. AB - N-Glycans from the nematode Haemonchus contortus (barber pole worm), a parasite of sheep and cattle, were the first to be described to possess up to three fucose residues associated with the N,N'-diacetylchitobiosyl core, two being on the reducing-terminal proximal GlcNAc and one on the distal core GlcNAc residue. The assumption was that truncated glycans from this organism with three hexose residues have the composition Man3GlcNAc2Fuc1-3. In this study, we have performed HPLC and MALDI-TOF MS/MS in combination with selected digestions of N-glycans from Haemonchus. A dominant trifucosylated Hex3HexNAc2Fuc3 glycan was modified not only with alpha1,6-fucose but also with a proximal core alpha1,3-fucose and a galactosylated distal alpha1,3-fucose; thereby, only two of the hexose residues were mannose. Other N-glycans displayed galactosylation of the core alpha1,6 fucose, antennal fucosylation or modification with phosphorylcholine. Thus, the N glycans of Haemonchus contain a number of potentially immunogenic glycan epitopes also found in other parasites and our proposed structures are in line with the previously defined specificity of nematode glycosyltransferases as we show that distal fucosylation and the presence of an alpha1,6-mannose are apparently mutually exclusive. These data are thereby of importance for engineering cell lines capable of mimicking Haemonchus-type N-glycans in the preparation of recombinant proteins as vaccine candidates. PMID- 25740941 TI - Screening for psychological difficulties in young children in crisis: complementary cross-cultural validation. AB - BACKGROUND: Detection of children's psychological difficulties in crises and low resource settings is challenged by the lack of a validated, rapid and simple tool. We present the results of two confirmatory validations of the Psychological Screening for Young Children aged 3 to 6 years (PSYCa 3-6) scale. METHODS: We performed cross-cultural validations, assessing the performance of the scale in different contexts. These were conducted in Mathare, Nairobi, Kenya and Buenaventura, Colombia between December 2009 and February 2012. External validity was assessed comparing the PSYCa 3-6 against a clinical interview and the Clinical Global Impression Severity scale (CGI). RESULTS: A total of 160 mothers or caregivers of children 3 to 6 years old in Mathare and 148 in Buenaventura were included in the study. Both demonstrated good concurrent validity (Buenaventura rho=0.49, p<0.0001; Mathare rho=0.41, p<0.0001). Inter-rater reliability was found to be acceptable in Buenaventura (intraclass correlation [ICC]=0.69 [0.4-0.84]) and high in Mathare (0.87 [0.75-0.94]). CONCLUSIONS: As shown by its validation in diverse contexts, use in other populations may help improve the delivery of mental health care to children in crises and low-resource settings. Additional research on the design and delivery of intervention models for crises remains essential. PMID- 25740942 TI - DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. AB - NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell-resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti-PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3zeta signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-gamma release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation defective ITAM were not activated. Notably, infused YTS cells armed with anti PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12 based CARs are a promising tool for adoptive tumor immunotherapy. PMID- 25740943 TI - Cellular mechanisms of CCL22-mediated attenuation of autoimmune diabetes. AB - Autoimmune destruction of insulin-producing beta cells in type 1 diabetes and islet transplantation involves a variety of immune pathways but is primarily mediated by self-reactive T cells. Chemokines can modulate local immune responses in inflammation and tumors by recruiting immune cells. We have reported that expression of the chemokine CCL22 in pancreatic beta cells in the NOD mouse prevents autoimmune attack by recruiting T regulatory cells (Tregs), protecting mice from diabetes. In this study we show that invariant NKT cells are also recruited to CCL22-expressing islet transplants and are required for CCL22 mediated protection from autoimmunity. Moreover, CCL22 induces an influx of plasmacytoid dendritic cells, which correlates with higher levels of IDO in CCL22 expressing islet grafts. In addition to its chemotactic properties, we found that CCL22 activates Tregs and promotes their ability to induce expression of IDO by dendritic cells. Islet CCL22 expression thus produces a tolerogenic milieu through the interplay of Tregs, invariant NKT cells, and plasmacytoid dendritic cells, which results in suppression of effector T cell responses and protection of beta cells. The immunomodulatory properties of CCL22 could be harnessed for prevention of graft rejection and type 1 diabetes as well as other autoimmune disorders. PMID- 25740944 TI - Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments. AB - Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8(+) T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-beta transcription factor isoforms correlated with the suppressive activity of IND treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity. PMID- 25740945 TI - TLR7- and TLR9-responsive human B cells share phenotypic and genetic characteristics. AB - B cells activated by nucleic acid-sensing TLR7 and TLR9 proliferate and secrete immune globulins. Memory B cells are presumably more responsive due to higher TLR expression levels, but selectivity and differential outcomes remain largely unknown. In this study, peripheral blood human B cells were stimulated by TLR7 or TLR9 ligands, with or without IFN-alpha, and compared with activators CD40L plus IL-21, to identify differentially responsive cell populations, defined phenotypically and by BCR characteristics. Whereas all activators induced differentiation and Ab secretion, TLR stimulation expanded IgM(+) memory and plasma cell lineage committed populations, and favored secretion of IgM, unlike CD40L/IL-21, which drove IgM and IgG more evenly. Patterns of proliferation similarly differed, with CD40L/IL-21 inducing proliferation of most memory and naive B cells, in contrast with TLRs that induced robust proliferation in a subset of these cells. On deep sequencing of the IgH locus, TLR-responsive B cells shared patterns of IgHV and IgHJ usage, clustering apart from CD40L/IL-21 and control conditions. TLR activators, but not CD40L/IL-21, similarly promoted increased sharing of CDR3 sequences. TLR-responsive B cells were characterized by more somatic hypermutation, shorter CDR3 segments, and less negative charges. TLR activation also induced long positively charged CDR3 segments, suggestive of autoreactive Abs. Testing this, we found culture supernatants from TLR-stimulated B cells to bind HEp-2 cells, whereas those from CD40L/IL-21-stimulated cells did not. Human B cells possess selective sensitivity to TLR stimulation, with distinctive phenotypic and genetic signatures. PMID- 25740946 TI - Demethylation of the RORC2 and IL17A in human CD4+ T lymphocytes defines Th17 origin of nonclassic Th1 cells. AB - Th17-derived Th1 lymphocytes, termed nonclassic, differ from classic Th1 cells because of the presence of retinoic acid orphan receptor (ROR)C2 and the surface expression of CD161 and CCR6. We demonstrate in this article that nonclassic Th1 cells, like Th17 cells, have a marked RORC2 and IL17A demethylation, whereas classic Th1 cells exhibit a complete methylation of these genes. The analysis of RORC2 DNA methylation in the CD4(+)CD161(+) and CD4(+)CD161(-) naive Th subsets from umbilical cord blood surprisingly revealed comparable hypermethylation levels. PCR analysis at the single-cell level revealed that RORC2 mRNA was expressed by none of the CD4(+)CD161(-) and present only in a minority of CD4(+)CD161(+) naive Th cells. These findings provide two important novel observations on the physiology of human Th17 cells: 1) they confirm at the epigenetic level the origin of nonclassic Th1 cells from Th17 cells, also identifying in the RORC2 and IL17A methylation status a novel tool for their distinction from classic Th1 cells, and 2) they demonstrate that RORC2-expressing cells are only a minority in the subset of CD4(+)CD161(+) naive Th cells, which are known to contain all Th17 cell precursors. PMID- 25740947 TI - B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses. AB - Class switch DNA recombination (CSR) is central to the maturation of the Ab response because it diversifies Ab effector functions. Like somatic hypermutation, CSR requires activation-induced cytidine deaminase (AID), whose expression is restricted to B cells, as induced by CD40 engagement or dual TLR BCR engagement (primary CSR-inducing stimuli). By constructing conditional knockout Igh(+/C)gamma(1-cre)Rab7(fl/fl) mice, we identified a B cell-intrinsic role for Rab7, a small GTPase involved in intracellular membrane functions, in mediating AID induction and CSR. Igh(+/C)gamma(1-cre)Rab7(fl/fl) mice displayed normal B and T cell development and were deficient in Rab7 only in B cells undergoing Igh(C)gamma(1-cre) Igamma1-Sgamma1-Cgamma1-cre transcription, as induced--like Igh germline Igamma1-Sgamma1-Cgamma1 and Iepsilon-Sepsilon-Cepsilon transcription--by IL-4 in conjunction with a primary CSR-inducing stimulus. These mice could not mount T-independent or T-dependent class-switched IgG1 or IgE responses while maintaining normal IgM levels. Igh(+/C)gamma(1-cre)Rab7(fl/fl) B cells showed, in vivo and in vitro, normal proliferation and survival, normal Blimp-1 expression and plasma cell differentiation, as well as intact activation of the noncanonical NF-kappaB, p38 kinase, and ERK1/2 kinase pathways. They, however, were defective in AID expression and CSR in vivo and in vitro, as induced by CD40 engagement or dual TLR1/2-, TLR4-, TLR7-, or TLR9-BCR engagement. In Igh(+/C)gamma(1-cre)Rab7(fl/fl) B cells, CSR was rescued by enforced AID expression. These findings, together with our demonstration that Rab7-mediated canonical NF-kappaB activation, as critical to AID induction, outline a novel role of Rab7 in signaling pathways that lead to AID expression and CSR, likely by promoting assembly of signaling complexes along intracellular membranes. PMID- 25740948 TI - Noncanonical STAT3 activation regulates excess TGF-beta1 and collagen I expression in muscle of stricturing Crohn's disease. AB - Increased TGF-beta1 and TGF-beta1-dependent Collagen I production in intestinal mesenchymal cells result in fibrosis in patients with Montreal B2 fibrostenotic Crohn's disease. Numerous cytokines, including IL-6, are produced by activated mesenchymal cells themselves and activate STAT3. The aim of the current study was to determine the mechanisms by which STAT-3 activation might result in intestinal fibrosis. Cytokine levels were measured by ELISA. STAT3 and suppressor of cytokine signaling 3 protein levels were measured by immunoblot, STAT3-TGFB1 DNA binding activity by chromatin immunoprecipitation, and TGFB1 transcriptional activity by luciferase reporter assay. TGF-beta1 (TGFB1), Collagen1alpha1, and connective tissue growth factor (CTGF) gene expression was measured by quantitative RT-PCR. The role of STAT3 activation was determined using STAT3 inhibitor, Stattic, and by transfection of STAT3 mutants. Autocrine production of cytokines was increased in muscle cells of B2 phenotype patients from strictures and normal intestine in the same patient and compared with other Crohn's phenotypes, ulcerative colitis, and non-Crohn's patients. A unique pattern of STAT3 phosphorylation emerged: high STAT3(S727) and low STAT3(Y705) in strictures and the opposite in unaffected intestine. TGFB1 transcriptional activity was regulated by phospho-STAT3(S727) and was decreased by Stattic or dominant negative STAT3(S727A). TGF-beta1, COL1A1, and CTGF expression was inhibited by Stattic or dominant-negative STAT3(S727A). Treatment of normal muscle cells with IL-6 or expression of constitutively active STAT3(S727E) phenocopied muscle cells from strictured intestine. Neutralization of autocrine IL-6 reversed STAT3 phosphorylation and normalized expression of TGF-beta1 in strictured intestinal muscle. The ability of Stattic to improve development of fibrosis was confirmed in mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis. We observed a unique phospho-STAT3(S727) response in patients with Montreal B2 Crohn's disease, particularly in response to IL-6 leading to increased TGF-beta1, collagen, and CTGF production in ileal strictures. PMID- 25740949 TI - Linezolid resistance in clinical isolates of Staphylococcus epidermidis from German hospitals and characterization of two cfr-carrying plasmids. AB - OBJECTIVES: This study was a detailed investigation of Staphylococcus epidermidis clinical isolates exhibiting linezolid resistance. METHODS: Thirty-six linezolid resistant S. epidermidis from eight German hospitals, including isolates from suspected hospital-associated outbreaks between January 2012 and April 2013, were analysed with respect to their antimicrobial susceptibility and the presence of cfr and/or mutations in the 23S rRNA, rplC, rplD and rplV genes. Relatedness of isolates was estimated by MLST and SmaI macrorestriction analysis. Characterization of cfr plasmids was carried out by means of Illumina sequencing. RESULTS: The MICs of linezolid varied substantially between the isolates. No apparent correlation was detected between the level of resistance, the presence of cfr and ribosomal target site mutations. S. epidermidis isolates from two hospitals were confirmed as clonally related, indicating the spread of the respective clone over a period of 1 year. Next-generation sequencing revealed two different categories of cfr-expressing plasmids, both of them varying in genetic arrangement and composition from previously published cfr plasmids: p12-00322 like plasmids showed incorporation of cfr into a pGO1-like backbone and displayed capabilities for intra- and inter-species conjugational transfer. CONCLUSIONS: To date, linezolid-resistant S. epidermidis have rarely been isolated from human clinical sources in Germany. Here, we describe the emergence and outbreaks of these strains. We detected previously described and novel point mutations in the 23S ribosomal genes. The cfr gene was only present in six isolates. However, this is the first known description of cfr incorporation into conjugative vectors; under selective pressure, these vectors could give reasonable cause for concern. PMID- 25740950 TI - Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe. AB - BACKGROUND: The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice. METHODS: A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm. RESULTS: Efficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count <200 cells/mm3 (P < 0.001), GSS <3 (P = 0.002) and use of lamivudine (P < 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT). CONCLUSIONS: In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3. PMID- 25740951 TI - Louis Sambon and the Clash of Pellagra Etiologies in Italy and the United States, 1905-14. AB - This article explores the extent to which the bacterial concept of disease acted as an obstacle to the understanding of deficiency diseases, by focusing on explorations into the cause of pellagra in the early twentieth century. In 1900, pellagra had been epidemic in Italy for 150 years and was soon to become so in the United States, yet the responses of medical investigators differed substantially. To account for these, the article reconstructs the sharply contrasting reactions to a provocative theory proposed by Louis Sambon. Applying a tropical diseases approach to pellagra, Sambon argued that pellagra had nothing at all to do with maize consumption, as the Italians had long thought, but was caused by the bite of a parasite-carrying insect. Italian pellagrologists, involved in a dogmatic quest for a toxin in maize, and with pellagra rates there on the decline, marginalized the Sambon hypothesis. By contrast, in the United States, with pellagra on the rise, the dominant infectious paradigm put Sambon center stage, his proposed etiology shaping the earliest American investigations. When the deficiency disease concept gained currency in 1913, the relatively closed world of Italian pellagrology was wrong-footed, while the more open-ended U.S. community was better able to follow up the new lead. The article discusses what these shifts and the resulting controversies reveal about the medical contexts. The actor-centered approach, with reaction to Sambon's intervention as a kind of test-case, is the key to understanding these controversies and why they mattered. PMID- 25740952 TI - About to burst. Lung and liver hydatid cysts. PMID- 25740953 TI - Erythema ab igne. PMID- 25740954 TI - Erratum. PMID- 25740955 TI - Evolution of insecticide resistance diagnostics in malaria vectors. AB - Malaria control is reliant upon effective, programmatic-scale, anti-vector interventions. The widespread distribution of pyrethroid-treated bednets in sub Saharan Africa has been a driver of morbidity and mortality reductions over the last decade. Unfortunately resistance to insecticides, and to pyrethroids in particular, is increasingly common in Anopheles malaria vectors, and is a major threat to continued control and future elimination. Here we argue that current methods to diagnose resistance often have limited utility and should be augmented or even partially replaced by wider application of DNA markers. PMID- 25740958 TI - Isolation and genomic characterization of a novel orthoreovirus from a brown eared bulbul (Hypsipetes amaurotis) in Japan. AB - Five species, Mammalian orthoreovirus, Avian orthoreovirus (ARV), Nelson Bay orthoreovirus (NBV), Baboon orthoreovirus and Reptilian orthoreovirus, have been identified in the genus Orthoreovirus. Their genomes each consist of 10 dsRNA segments. A novel orthoreovirus was isolated from the haemorrhagic intestine of a dead brown-eared bulbul (Hypsipetes amaurotis) in Japan. The virus formed syncytia in Caco-2 and Vero cells. Electron microscopy revealed non-enveloped capsids of ~70 nm diameter, which were characteristic of reoviruses. Complete genomic sequences were determined. The S1 segment was tricistronic and encoded three proteins, p10, p17 and sigmaC, as in the two species ARV and NBV. Sequence and phylogenetic analyses showed that the virus was similar to ARV and NBV, but was located on a phylogenetic branch different from that of ARV and NBV. The virus had the closest phylogenetic relationship to two reovirus strains: SSRV from a Steller sea lion in Canada and PsRV Ge01 from a psittaciform bird in Europe. The 10 RNA segments had a 3' pentanucleotide sequence (UCAUC-3') conserved amongst all members of the genus Orthoreovirus, and a unique 5' terminal heptasequence (5'-GCUUUUC) that was the same as those of SSRV and PsRV Ge01. These results suggested that the novel virus might form a new species with the two strains in the genus Orthoreovirus. PMID- 25740956 TI - HLA Class I Supertype Associations With Clinical Outcome of Secondary Dengue Virus Infections in Ethnic Thais. AB - BACKGROUND: Human leukocyte antigen (HLA) supertypes are groups of functionally related alleles that present structurally similar antigens to the immune system. OBJECTIVES: To analyze HLA class I supertype associations with clinical outcome in hospitalized Thai children with acute dengue illness. METHODS: Seven hundred sixty-two patients and population-matched controls recruited predominantly in Bangkok were HLA-A and -B typed. HLA supertype frequencies were compared and tested for significant dengue disease associations using logistic regression analyses. Multivariable models were built by conducting forward stepwise selection procedures. RESULTS: In the final logistic regression model, the HLA B44 supertype was protective against dengue hemorrhagic fever (DHF) in secondary infections (odds ratio [OR] = 0.46, 95% confidence interval [CI], .30-.72), while the HLA-A02 supertype (OR = 1.92, 95% CI, 1.30-2.83) and the HLA-A01/03 supertype (OR = 3.01, 95% CI, 1.01-8.92) were associated with susceptibility to secondary dengue fever. The B07 supertype was associated with susceptibility to secondary DHF in the univariate analysis (OR = 1.60, 95% CI, 1.05-2.46), whereas that was not retained in the final model. CONCLUSIONS: As the HLA-B44 supertype is predicted to target conserved epitopes in dengue, our results suggest that B44 supertype-restricted immune responses to highly conserved regions of the dengue proteome may protect against secondary DHF. PMID- 25740957 TI - Pregnancy Does Not Attenuate the Antibody or Plasmablast Response to Inactivated Influenza Vaccine. AB - BACKGROUND: Inactivated influenza vaccine (IIV) is recommended during pregnancy to prevent influenza infection and its complications in pregnant women and their infants. However, the extent to which pregnancy modifies the antibody response to vaccination remains unclear, and prior studies have focused primarily on hemagglutinin inhibition (HI) titers. A more comprehensive understanding of how pregnancy modifies the humoral immune response to influenza vaccination will aid in maximizing vaccine efficacy. METHODS: Healthy pregnant women and control women were studied prior to, 7 days after, and 28 days after vaccination with IIV. HI titers, microneutralization (MN) titers, and the frequency of circulating plasmablasts were evaluated in pregnant versus control women. RESULTS: Pregnant women and control women mount similarly robust serologic immune responses to IIV, with no significant differences for any influenza strain in postvaccination geometric mean HI or MN titers. HI and MN titers correlate, though MN titers demonstrate more robust changes pre- versus postvaccination. The induction of circulating plasmablasts is increased in pregnant women versus controls (median fold-change 2.60 vs 1.49 [interquartile range, 0.94-7.53 vs 0.63-2.67]; P = .03). CONCLUSIONS: Pregnant women do not have impaired humoral immune responses to IIV and may have increased circulating plasmablast production compared to control women. PMID- 25740959 TI - The predominant species of nonstructural protein 4B in hepatitis C virus replicating cells is not palmitoylated. AB - Hepatitis C virus (HCV) represents a significant global health burden. Viral replication is thought to occur in close association with remodelled host cell membranes, with non-structural protein 4B (NS4B) being a key player in this process. NS4B is a poorly characterized integral membrane protein, which has been reported to be palmitoylated at its carboxy-terminal end. In order to extend this observation and to establish a functional role for NS4B palmitoylation, we sought to determine the status of this post-translational modification when the protein was expressed as part of a functional viral replicase. We performed direct metabolic labelling and polyethylene glycol-maleimide palmitoylation reporter assays on NS4B expressed in cells containing subgenomic replicons and infectious viral RNA. In a vaccinia virus-based expression system NS4B palmitoylation was detected in a genotype-dependent manner. However, in spite of the high sensitivity of the methods used, no NS4B palmitoylation was found in physiologically more relevant systems. Thus, NS4B palmitoylation is most likely dispensable for HCV RNA replication. PMID- 25740961 TI - A negative-feedback function of PKCbeta in the formation and accumulation of signaling-active B cell receptor microclusters within B cell immunological synapse. AB - Advanced live cell imaging studies suggested that B cell activation is initiated by the formation of BCR microclusters and subsequent B cell IS upon BCR and antigen recognition. PKC family member PKCbeta is highly expressed in B cells and plays an important role in the initiation of B cell activation. Here, we reported an inhibitory function of PKCbeta through a negative-feedback manner in B cell activation. Compared with WT (PKCbeta-WT) or the constitutively active (PKCbeta DeltaNPS) form of PKCbeta, DN PKCbeta (PKCbeta-DN) unexpectedly enhanced the accumulation of BCR microclusters into the B cell IS, leading to the recruitment of an excessive amount of pSyk, pPLC-gamma2, and pBLNK signaling molecules into the membrane-proximal BCR signalosome. Enhanced calcium mobilization responses in the decay phase were also observed in B cells expressing PKCbeta-DN. Mechanistic studies showed that this negative-feedback function of PKCbeta works through the induction of an inhibitory form of pBtk at S180 (pBtk-S180). Indeed, the capability of inducing the formation of an inhibitory pBtk-S180 is in the order of PKCbeta-DeltaNPS > PKCbeta-WT > PKCbeta-DN. Thus, these results improve our comprehensive understanding on the positive and negative function of PKCbeta in the fine tune of B cell activation. PMID- 25740962 TI - Kruppel-like factor 4 is a transcriptional regulator of M1/M2 macrophage polarization in alcoholic liver disease. AB - Macrophages play an important role in inflammation and liver injury. In ALD, activated macrophages, including M1 (proinflammatory) and M2 (anti-inflammatory) macrophages, are present in the liver. As KLF4 has been described as a regulator of macrophage polarization, we investigated its role in ALD. Chronic alcohol feeding in C57Bl/6 mice led to increased expression of M1 (TNF-alpha, MCP1, and IL-1beta) and M2 (Arg1, Mrc1, and IL-10) genes and the frequency of CD206+CD163+ M2 macrophages in the liver. KLF4 mRNA and protein levels were increased in the livers of EtFed compared with PF mice. In macrophages, in vivo and in vitro, EtOH increased KLF4 levels, transcriptional activity, and expression of M1 and M2 genes. KLF4 knockdown and overexpression experiments demonstrated alcohol dependent and -independent functions of KLF4 in regulating M1 and M2 markers. KLF4 siRNA treatment, alone and in synergy with alcohol, increased the levels of M1 markers. In contrast, KLF4 overexpression increased the levels of M2 and decreased M1 markers, and this was enhanced further by alcohol. KLF4 was regulated by alcohol and its metabolites. KLF4 mRNA and activity were increased in the presence of 4-MP, an inhibitor of ADH, and CYP2E1. However, inhibition of acetaldehyde breakdown attenuated KLF4 induction and promoted M1 polarization. We conclude that KLF4 regulates M1 and M2 markers in ALD. EtOH promotes KLF4 and M2 phenotype, whereas acetaldehyde attenuates KLF4 and promotes M1 macrophage, which may explain the increased presence of M1 and M2 macrophage populations in ALD. PMID- 25740960 TI - Physico-chemical requirements and kinetics of membrane fusion of flavivirus-like particles. AB - Flaviviruses deliver their RNA genome into the host-cell cytoplasm by fusing their lipid envelope with a cellular membrane. Expression of the flavivirus pre membrane and envelope glycoprotein genes in the absence of other viral genes results in the spontaneous assembly and secretion of virus-like particles (VLPs) with membrane fusion activity. Here, we examined the physico-chemical requirements for membrane fusion of VLPs from West Nile and Japanese encephalitis viruses. In a bulk fusion assay, optimal hemifusion (or lipid mixing) efficiencies were observed at 37 degrees C. Fusion efficiency increased with decreasing pH; half-maximal hemifusion was attained at pH 5.6. The anionic lipids bis(monoacylglycero)phosphate and phosphatidylinositol-3-phosphate, when present in the target membrane, significantly enhanced fusion efficiency, consistent with the emerging model that flaviviruses fuse with intermediate-to-late endosomal compartments, where these lipids are most abundant. In a single-particle fusion assay, VLPs catalysed membrane hemifusion, tracked as lipid mixing with the cellular membrane, on a timescale of 7-20 s after acidification. Lipid mixing kinetics suggest that hemifusion is a kinetically complex, multistep process. PMID- 25740963 TI - A prospective, randomized, pivotal trial of a novel extravascular collagen-based closure device compared to manual compression in diagnostic and interventional patients. AB - OBJECTIVES: The RESPECT trial was aimed at evaluating safety/efficacy of a new extravascular closure system in diagnostic (Dx) and interventional (Ix) procedures performed through 6 or 7 Fr introducer sheaths. BACKGROUND: Although vascular closure devices (VCDs) have been available for two decades, manual compression (MC) remains the standard of care in many institutions. VCDs have not been shown to have greater safety than MC. METHODS: The RESPECT trial was a multicenter, randomized comparison of the Vascade VCD (Cardiva Medical, Inc) versus MC in Dx and Ix patients undergoing femoral access. Endpoints included time to hemostasis (TTH), time to ambulation (TTA), time to discharge eligibility (TTDe), device and procedure success, major and minor complications. Subjects were randomized 2:1 (Vascade vs MC). RESULTS: A total of 420 patients were enrolled (211 Dx, 209 Ix). Mean age was 62 +/- 11 years and 29% were female. For Ix Vascade/MC patients, 77%/69% received bivalirudin, 27%/26% received heparin, and 8%/3% received glycoprotein IIb/IIIa inhibitors, respectively. Patients were followed for 30 +/- 7 days. A total of 415 subjects (98.8%) completed follow-up. TTH was 3.0 minutes (range, 0.6-31.6 minutes) for Vascade vs 20.0 minutes (range, 0.0-97.0 minutes) for MC; TTA was 3.2 hours (range, 1.0-78.0 hours) for Vascade vs. 5.2 hours (range, 1.7-22.8 hours) for MC; and TTDe was 3.6 hours (range, 1.4 78.4 hours) for Vascade vs. 5.7 hours (range, 2.2-23.2 hours) for MC. Device and procedure success rates were 98% for Vascade and 100% for MC. Minor events were 1.1% for Vascade and 7% for MC. No major access-site related complications were reported in either arm. CONCLUSION: Despite high percentage of bivalirudin use, there were no major access-site related complications in either arm. Vascade use reduced rates of minor access-site related complications, and significantly shortened TTH, TTA, and TTDe compared to MC. PMID- 25740964 TI - Where are we with vascular closure devices after percutaneous arteriotomy? PMID- 25740965 TI - Adoption of the hybrid CTO approach by a single non-CTO operator: procedural and clinical outcomes. AB - BACKGROUND: The feasibility of adopting the "hybrid" approach by a single operator without prior experience in percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) has not been described. METHODS: Consecutive patients who underwent CTO-PCI by a single operator using the "hybrid" approach between 2012 and 2013 formed the analytic cohort. No patient was declined on the basis of angiographic findings. Clinical and angiographic characteristics together with procedural and hospital outcomes are described. RESULTS: During the study period, a total of 48 consecutive patients underwent PCI of 50 CTOs. Mean age was 63.4 +/- 9.4 years and most patients (83%) were men. The right coronary artery (RCA) was the most commonly treated CTO vessel (54%) and mean J-CTO score was 2.3 +/- 1.1. A primary retrograde approach was chosen for 33% of lesions and 40% required use of an epicardial collateral vessel. The primary strategy was effective in 65% of successful cases, 35% required one change in strategy, and 15% requiring two strategy changes. Procedural success rate was 92%. The median number of stents used was 3 (interquartile range [IQR], 2-4] and the total stent length was 73 mm [IQR, 38-96 mm). Mean contrast volume was 356.4 +/- 148.3 mL and the mean air kerma radiation exposure was 3.5 +/- 2.0 Gy. No patient experienced a major periprocedural complication. CONCLUSION: The "hybrid" approach to CTO-PCI can be successfully adopted by a single operator with excellent early procedural success and low complication rates, despite a lack of prior CTO-PCI experience. PMID- 25740966 TI - CTO-PCI: an emerging new subspecialty in interventional cardiology. PMID- 25740967 TI - Clinical and economic effectiveness of percutaneous ventricular assist devices for high-risk patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Comparative effectiveness research (CER) is taking a more prominent role in formalizing hospital treatment protocols and health-care coverage policies by having health-care providers consider the impact of new devices on costs and outcomes. CER balances the need for innovation with fiscal responsibility and evidence-based care. This study compared the clinical and economic impact of percutaneous ventricular assist devices (pVAD) with intraaortic balloon pumps for high-risk patients undergoing percutaneous coronary intervention (PCI). METHODS: This study conducted a review of all comparative randomized control trials of the pVADS (Impella and TandemHeart) vs IABP for patients undergoing high-risk percutaneous coronary intervention (PCI). A retrospective analysis of the 2010 and 2011 Medicare MEDPAR data files was also performed to compare procedural costs and hospital length of stay (LOS). Readmission rates between the devices were also studied. RESULTS: Based on available trials, there is no significant clinical benefit with pVAD compared to IABP. Use of pVADs is associated with increased length of Intensive Care Unit stay and a total longer LOS. The incremental budget impact for pVADs was $33,957,839 for the United States hospital system (2010-2011). CONCLUSIONS: pVADs are not associated with improved clinical outcomes, reduced hospital length of stay, or reduced readmission rates. Management of high-risk PCI and cardiogenic shock patients with IABP is more cost effective than a routine use of pVADS. Use of IABP as initial therapy in high-risk PCI and cardiogenic shock patients may result in savings of up to $2.5 billion annually of incremental costs to the hospital system. PMID- 25740968 TI - Intraaortic balloon pump versus percutaneous ventricular assist for the high-risk patient: keep it simple except when you can't. PMID- 25740935 TI - Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution. AB - The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25 50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu. PMID- 25740969 TI - Safety, feasibility, and long-term results of percutaneous closure of atrial septal defects using the Amplatzer septal occluder without periprocedural echocardiography. AB - OBJECTIVES: We sought to assess the safety and efficacy of percutaneous closure of atrial septal defects (ASDs) under fluoroscopic guidance only, without periprocedural echocardiographic guidance. BACKGROUND: Percutaneous closure of ASDs is usually performed using simultaneous fluoroscopic and transthoracic, transesophageal (TEE), or intracardiac echocardiographic (ICE) guidance. However, TEE requires deep sedation or general anesthesia, which considerably lengthens the procedure. TEE and ICE increase costs. METHODS: Between 1997 and 2008, a total of 217 consecutive patients (age, 38 +/- 22 years; 155 females and 62 males), of whom 44 were children <=16 years, underwent percutaneous ASD closure with an Amplatzer ASD occluder (AASDO). TEE guidance and general anesthesia were restricted to the children, while devices were implanted under fluoroscopic guidance only in the adults. For comparison of technical safety and feasibility of the procedure without echocardiographic guidance, the children served as a control group. RESULTS: The implantation procedure was successful in all but 3 patients (1 child and 2 adults; 1.4%). Mean device size was 23 +/- 8 mm (range, 4 40 mm). There was 1 postprocedural complication (0.5%; transient perimyocarditis in an adult patient). At last echocardiographic follow-up, 13 +/- 23 months after the procedure, 90% of patients had no residual shunt, whereas a minimal, moderate, or large shunt persisted in 7%, 1%, and 2%, respectively. Four adult patients (2%) underwent implantation of a second device for a residual shunt. During a mean follow-up period of 3 +/- 2 years, 2 deaths and 1 ischemic stroke occurred. CONCLUSION: According to these results, percutaneous ASD closure using the AASDO without periprocedural echocardiographic guidance seems safe and feasible. PMID- 25740970 TI - Ultrasound guidance for vascular access in patients undergoing coronary angiography via the transradial approach. AB - BACKGROUND: We assessed the value of routine real-time ultrasound (RTUS) guidance to improve transradial access (TRA) for cardiac catheterization. METHODS: A prospective, single-center descriptive observational study of patients presenting for cardiac catheterization via the transradial approach. The first phase of the study enrolled 100 consecutive patients who underwent TRA without the assistance of RTUS followed by 100 consecutive patients who underwent TRA using RTUS guidance. The primary outcome measure was time between needle attempts for arterial access and sheath insertion. RESULTS: There were no statistically significant differences in any outcome measures. Median time between commencing needle attempts for arterial access to sheath insertion was 82.5 seconds (interquartile range [IQR], 64-161.5 seconds) with no RTUS guidance vs 84 seconds (IQR, 52.75-122.5 seconds) with RTUS; P=.19. Median number of needle passes through the skin required was 1 (IQR, 1-3) with no RTUS guidance vs 2 (IQR, 1-3) with RTUS; P=.25. Median number of arterial punctures was 1 (IQR, 1-1) with no RTUS guidance vs 1 (IQR, 1-1) with RTUS; P=.21. CONCLUSION: Routine RTUS guidance to assist in TRA does not significantly improve parameters of successful vascular access among high-volume radial operators. However, RTUS guidance should still be considered in selected cases and among less experienced radial practitioners. PMID- 25740972 TI - The extent of aortic annulus calcification is a predictor of postprocedural eccentricity and paravalvular regurgitation: a pre- and postinterventional cardiac computed tomography angiography study. AB - PURPOSE: To investigate if the extent of aortic valve calcification is associated with postprocedural prosthesis eccentricity and paravalvular regurgitation (PAR) in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: Cardiac computed tomography angiography (CCTA) was performed before and 3 months after TAVI in 46 patients who received the self-expanding CoreValve and in 22 patients who underwent balloon-expandable Edwards Sapien XT implantation. Aortic annulus calcification was measured with CCTA prior to TAVI and prosthesis eccentricity was assessed with post-TAVI CCTA. Standard echocardiography was also performed in all patients at 3-month follow-up exam. RESULTS: Annulus eccentricity was reduced during TAVI using both implantation systems (from 0.23 +/- 0.06 to 0.18 +/- 0.07 using CoreValve and from 0.20 +/- 0.07 to 0.05 +/- 0.03 using Edwards Sapien XT; P<.001 for both). With Edwards Sapien XT, eccentricity reduction at the level of the aortic annulus was significantly higher compared with CoreValve (P<.001). Annulus eccentricity after CoreValve use was significantly related to absolute valve calcification and to valve calcification indexed to body surface area (BSA) (r = 0.48 and 0.50, respectively; P<.001 for both). Furthermore, a significant association was observed between aortic valve calcification and PAR (P<.01 by ANOVA) in patients who received CoreValve. Using ROC analysis, a cut-off value over 913 mm2 aortic valve calcification predicted the occurrence of moderate or severe PAR with a sensitivity of 92% and a specificity of 63% (area under the curve = 0.75). Furthermore, multivariable analysis showed that aortic valve calcification was a robust predictor of postprocedural eccentricity and PAR, independent of the aortic annulus size and native valve eccentricity and of CoreValve prosthesis size (adjusted r = 0.46 and 0.50, respectively; P<.01 for both). Such associations were not present with the Edwards Sapien XT system. CONCLUSION: The extent of native aortic annulus calcification is predictive for postprocedural prosthesis eccentricity and PAR, which is an important marker for long-term mortality in patients undergoing TAVI. This observation applies for the CoreValve, but not for the Edwards Sapien XT valve. PMID- 25740971 TI - Comparison of diabetic and non-diabetic patients undergoing endovascular revascularization for peripheral arterial disease. AB - OBJECTIVE: Peripheral arterial disease (PAD) is associated with poor outcomes. We assessed the clinical outcomes of diabetic versus non-diabetic patients with PAD who underwent peripheral transluminal angioplasty (PTA). METHODS: The outcomes of 239 consecutive patients with symptomatic PAD who underwent PTA were analyzed. Restenosis and clinical outcomes were assessed at a follow-up of 2 years. RESULTS: Diabetic patients had a higher percentage of wound as the initial diagnosis for PTA (72.7% vs. 14.2%; P<.001), chronic kidney disease (26.7% vs. 6.3%; P<.01), need for dialysis (19.3% vs. 3.1%; P<.01), and coronary artery disease (67.6% vs. 50.7%; P=.02). Infrapopliteal PTA was more commonly performed in the diabetic group (70.4% vs. 25.3%; P<.001). Diabetic patients had lower rates of angiographic follow-up at 8 months (38.6% vs. 60.3%; P<.01). Diabetic patients had higher binary restenosis (54.4% vs. 31.5%; P=.02) and had a trend toward a higher incidence of total occlusion (34.0% vs. 19.5%; P=.08). At 2-year follow-up, the amputation rate was higher in the diabetic group (24.4% vs. 1.5%; P<.001) despite PTA. CONCLUSION: Diabetic patients more frequently presented with critical limb ischemia compared with non-diabetic patients and had higher rates of restenosis and amputation at 2 years following standard PTA. Improved therapies are needed for this high-risk group of patients. PMID- 25740973 TI - Intravascular-ultrasound assisted localization and revascularization of an ostial chronic total occlusion: utility of near-field and far-field imaging. AB - Percutaneous coronary interventions (PCI) of chronic total occlusions (CTOs) can be technically challenging, but are valuable in patients with severe angina. Recently, algorithms for CTO-PCI have been proposed to facilitate the selection of the PCI approach that can best achieve procedural success. When the ostium of the occluded vessel is ambiguous or not well visualized, the success rate of antegrade approaches is significantly diminished. In our case, we demonstrate the utility of intravascular ultrasound imaging in the localization of an ambiguous or "stump-less" ostial CTO in addition to providing real-time far-field imaging, which is helpful in tracking wire progress through the occluded segment. Adjunctive imaging was instrumental in achieving procedural success using the antegrade approach. PMID- 25740974 TI - Percutaneous transcatheter balloon valvuloplasty for bioprosthetic tricuspid valve stenosis in a patient with orthotopic heart transplant. AB - A 47-year-old man with history of familial cardiomyopathy and orthotopic heart transplant at the age of 34 years presented severe tricuspid stenosis (TS) with a mean transvalvular gradient of 10 mm Hg. The patient opted against tricuspid valve replacement and was offered percutaneous transcatheter tricuspid balloon valvuloplasty (PTTBV). To the best of our knowledge, this is the first report of a PTTBV in an orthotopic allograft, and demonstrates excellent clinical outcome at 1 year. PMID- 25740975 TI - Interventional cardiology: reflections on my career choice at 10 years. PMID- 25740976 TI - Is the evaluation sufficient? Interpretation on the cardiac inhomogeneity without considering the transmural dispersion. PMID- 25740977 TI - A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life. AB - BACKGROUND: Mutations in the cardiac myosin binding protein C (MYBPC3) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis. METHODS AND RESULTS: Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 45 mutation carriers were identified during the evaluation of 14 families. Eleven (38%) mutation carriers were diagnosed between ages 30 years and 40 years. Disease penetrance was incomplete (64.4%), age related and was greater in men than women (85% vs 48%, p=0.009). Probands carrying the founder mutation exhibited highest prevalence of non-sustained ventricular tachycardia (63% vs 22%, p=0.003; 63% vs 23%, p=0.01) and implantable cardioverter-defibrillator (58% vs 17%, p=0.001; 58% vs 18%, p=0.005) when compared with probands without MYBPC3 mutations or carrying other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD occurred more frequently after the fourth decade of life in probands carrying p.F305Pfs*27 mutation than those without MYBPC3 mutations (32% vs 15%, p=0.01). CONCLUSIONS: p.F305Pfs*27 mutation carriers have a high probability to develop the disease between ages 30 years and 40 years with a significant major risk if they are men. This founder mutation is associated with an increase of SCD/aborted SCD events after the fourth decade of life.These findings are of relevant importance for management and clinical decision-making in patients with HCM. PMID- 25740978 TI - Plasmonic graded-chains as deep-subwavelength light concentrators. AB - We have studied the plasmonic properties of aperiodic arrays of identical nanoparticles (NPs) formed by two opposite and equal graded-chains (a chain where interactions change gradually). We found that these arrays concentrate the external electromagnetic fields even in the long wavelength limit. The phenomenon was understood by identifying the system with an effective cavity where plasmonics excitations are trapped between effective band edges, resulting from the change of passband with the NP's position. Dependence of excitation concentration on several system parameters was also assessed. This includes different gradings as well as NP couplings, damping, and resonant frequencies. In the spirit of the scaling laws in condensed matter physics, we developed a theory that allows us to rationalize all these system parameters into universal curves. The theory is quite general and can also be used in many other situations (different arrays for example). Additionally, we also provided an analytical solution, in the tight-binding limit, for the plasmonic response of homogeneous linear chains of NPs illuminated by a plane wave. Our results can find applications in sensing, near field imaging, plasmon-enhanced photodetectors, as well as to increase solar cell efficiency. PMID- 25740979 TI - Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. AB - BACKGROUND: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. METHODS: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80 degrees C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. RESULTS: Mean age was 52.1+/-9.5 years in the metformin group and 52.6 +/- 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. CONCLUSIONS: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin. PMID- 25740980 TI - Exosomal communication goes viral. AB - Exosomes are small vesicles secreted from cells that participate in intercellular communication events. Accumulating evidence demonstrates that host exosome pathways are hijacked by viruses and that virally modified exosomes contribute to virus spread and immune evasion. In the case of tumor viruses, recent findings suggest that alterations in normal exosome biology may promote the development and progression of cancer. These studies will be discussed in the context of our current knowledge of Epstein-Barr virus (EBV)-modified exosomes. PMID- 25740981 TI - Dynamic Interaction of Stress Granules, DDX3X, and IKK-alpha Mediates Multiple Functions in Hepatitis C Virus Infection. AB - The ubiquitous ATP-dependent RNA helicase DDX3X is involved in many cellular functions, including innate immunity, and is a pivotal host factor for hepatitis C virus (HCV) infection. Recently, we showed that DDX3X specifically recognizes the HCV 3' untranslated region (UTR), leading to the activation of IKK-alpha and a cascade of lipogenic signaling to facilitate lipid droplet biogenesis and viral assembly (Q. Li, V. Pene, S. Krishnamurthy, H. Cha, and T. J. Liang, Nat Med 19:722-729, 2013, http://dx.doi.org/10.1038/nm.3190). The interaction of DDX3X with HCV core protein seems to be dispensable for its proviral role. In this study, through systematic imaging and biochemical and virologic approaches, we identified a dynamic association between DDX3X and various cellular compartments and viral elements mediating multiple functions of DDX3X in productive HCV infection. Upon HCV infection, the HCV 3'UTR interacts with DDX3X and IKK-alpha, which redistribute to speckle-like cytoplasmic structures shown to be stress granules (SGs). As viral proteins accumulate in infected cells, DDX3X granules together with SG-associated proteins redistribute and colocalize with HCV core protein around lipid droplets (LDs). IKK-alpha, however, does not relocate to the LD but translocates to the nucleus. In HCV-infected cells, various HCV nonstructural proteins also interact or colocalize with DDX3X in close proximity to SGs and LDs, consistent with the tight juxtaposition of the replication complex and the assembly site at the surface of LDs. Short interfering RNA (siRNA)-mediated silencing of DDX3X and multiple SG components markedly inhibits HCV infection. Our data suggest that DDX3X initiates a multifaceted cellular program involving dynamic associations with HCV RNA and proteins, IKK-alpha, SG, and LD surfaces for its crucial role in the HCV life cycle. IMPORTANCE DDX3X is a proviral host factor for HCV infection. Recently, we showed that DDX3X binds to the HCV 3'UTR, activating IKK-alpha and cellular lipogenesis to facilitate viral assembly (Q. Li et al., Nat Med 19:722-729, 2013, http://dx.doi.org/10.1038/nm.3190). Here, we report associations of DDX3X with various cellular compartments and viral elements that mediate its multiple functions in the HCV life cycle. Upon infection, the HCV 3'UTR redistributes DDX3X and IKK-alpha to speckle-like cytoplasmic structures shown to be SGs. Subsequently, interactions between DDX3X, SG, and HCV proteins facilitate the translocation of DDX3X-SG complexes to the LD surface. HCV nonstructural proteins are shown to colocalize with DDX3X in close proximity to SGs and LDs, consistent with the tight juxtaposition of the HCV replication complex and assembly site at the LD surface. Our data demonstrate that DDX3X initiates a multifaceted cellular program involving dynamic associations with HCV elements, IKK-alpha, SGs, and LDs for its critical role in HCV infection. PMID- 25740982 TI - Transmitted/Founder Viruses Rapidly Escape from CD8+ T Cell Responses in Acute Hepatitis C Virus Infection. AB - The interaction between hepatitis C virus (HCV) and cellular immune responses during very early infection is critical for disease outcome. To date, the impact of antigen-specific cellular immune responses on the evolution of the viral population establishing infection and on potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine. Three subjects who were followed longitudinally from the detection of viremia preseroconversion until disease outcome were analyzed. The evolution of transmitted/founder (T/F) viruses was undertaken using deep sequencing. CD8(+) T cell responses were measured via enzyme-linked immunosorbent spot (ELISpot) assay using HLA class I-restricted T/F epitopes. T/F viruses were rapidly extinguished in all subjects associated with either viral clearance (n = 1) or replacement with viral variants leading to establishment of chronic infection (n = 2). CD8(+) T cell responses against 11 T/F epitopes were detectable by 33 to 44 days postinfection, and 5 of these epitopes had not previously been reported. These responses declined rapidly in those who became chronically infected and were maintained in the subject who cleared infection. Higher-magnitude CD8(+) T cell responses were associated with rapid development of immune escape variants at a rate of up to 0.1 per day. Rapid escape from CD8(+) T cell responses has been quantified for the first time in the early phase of primary HCV infection. These rapid escape dynamics were associated with higher magnitude CD8(+) T cell responses. These findings raise questions regarding optimal selection of immunogens for HCV vaccine development and suggest that detailed analysis of individual epitopes may be required. IMPORTANCE: A major limitation in our detailed understanding of the role of immune response in HCV clearance has been the lack of data on very early primary infection when the transmitted viral variants successfully establish the acute infection. This study was made possible through the availability of specimens from a unique cohort of asymptomatic primary infection cases in whom the first available viremic samples were collected approximately 3 weeks postinfection and at regular intervals thereafter. The study included detailed examination of both the evolution of the viral population and the host cellular immune responses against the T/F viruses. The findings here provide the first evidence of host cellular responses targeting T/F variants and imposing a strong selective force toward viral escape. The results of this study provide useful insight on how virus escapes the host response and consequently on future analysis of vaccine-induced immunity. PMID- 25740983 TI - Profiling of Virus-Encoded MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma and Their Roles in Gastric Carcinogenesis. AB - Epstein-Barr virus (EBV) is one of the major oncogenic viruses and is found in nearly 10% of gastric carcinomas. EBV is known to encode its own microRNAs (miRNAs); however, their roles have not been fully investigated. The present report is the largest series to comprehensively profile the expression of 44 known EBV miRNAs in tissue samples from patients with EBV-associated gastric carcinoma. Several miRNAs were highly expressed in EBV-associated gastric carcinoma, and in silico analysis revealed that the target genes of these EBV miRNAs had functions associated with cancer-related pathways, especially the regulation of apoptosis. Apoptosis was reduced in EBV-associated gastric carcinoma tissue samples, and gastric carcinoma cell lines infected with EBV exhibited downregulation of the proapoptotic protein Bid (the BH3-interacting domain death agonist), a member of the Bcl-2 family. The luciferase activity of the reporter vector containing the 3' untranslated region of BID was inhibited by an ebv-miR-BART4-5p mimic in gastric cancer cell lines. Transfection of an ebv miR-BART4-5p mimic reduced Bid expression in EBV-negative cell lines, leading to reduced apoptosis under serum deprivation. The inhibition of ebv-miR-BART4-5p expression was associated with partial recovery of Bid levels in EBV-positive cell lines. The results demonstrated the antiapoptotic role of EBV miRNA via regulation of Bid expression in EBV-associated gastric carcinoma. These findings provide novel insights in the roles of EBV miRNAs in gastric carcinogenesis, which would be a potential therapeutic target. IMPORTANCE: This report is the largest series to comprehensively profile the expression of 44 known EBV miRNAs in clinical samples from EBV-associated gastric carcinoma patients. Of the EBV miRNAs, ebv-miR-BART4-5p plays an important role in gastric carcinogenesis via regulation of apoptosis. PMID- 25740984 TI - Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues. AB - The majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur in women when semen harboring infectious virus is deposited onto the mucosal barriers of the vaginal, ectocervical, and endocervical epithelia. Seminal factors such as semen-derived enhancer of virus infection (SEVI) fibrils were previously shown to greatly enhance the infectivity of HIV-1 in cell culture systems. However, when SEVI is intravaginally applied to living animals, there is no effect on vaginal transmission. To define how SEVI might function in the context of sexual transmission, we applied HIV-1 and SEVI to intact human and rhesus macaque reproductive tract tissues to determine how it influences virus interactions with these barriers. We show that SEVI binds HIV-1 and sequesters most virions to the luminal surface of the stratified squamous epithelium, significantly reducing the number of virions that penetrated the tissue. In the simple columnar epithelium, SEVI was no longer fibrillar in structure and was detached from virions but allowed significantly deeper epithelial virus penetration. These observations reveal that the action of SEVI in intact tissues is very different in the anatomical context of sexual transmission and begin to explain the lack of stimulation of infection observed in the highly relevant mucosal transmission model. IMPORTANCE: The most common mode of HIV-1 transmission in women occurs via genital exposure to the semen of HIV-infected men. A productive infection requires the virus to penetrate female reproductive tract epithelial barriers to infect underlying target cells. Certain factors identified within semen, termed semen-derived enhancers of virus infection (SEVI), have been shown to significantly enhance HIV-1 infectivity in cell culture. However, when applied to the genital tracts of living female macaques, SEVI did not enhance virus transmission. Here we show that SEVI functions very differently in the context of intact mucosal tissues. SEVI decreases HIV-1 penetration of squamous epithelial barriers in humans and macaques. At the mucus coated columnar epithelial barrier, the HIV-1/SEVI interaction is disrupted. These observations suggest that SEVI may not play a significant stimulatory role in the efficiency of male-to-female sexual transmission of HIV. PMID- 25740985 TI - Flexibility of bunyavirus genomes: creation of an orthobunyavirus with an ambisense S segment. AB - The Bunyamwera (BUNV) orthobunyavirus NSs protein has proven a challenge to study in the context of viral infection. NSs is encoded in a reading frame that overlaps that of the viral nucleocapsid (N) protein thus limiting options for mutagenesis. In addition, NSs is poorly immunogenic, and antibodies only work in certain techniques while the protein itself is subject to proteasomal degradation. In order to generate a virus that expresses NSs independently of N, an ambisense S RNA segment was designed by mutating the 5'- and 3'-terminal nucleotide sequences. These mutations were previously shown to alter promoter activity so that both replication and transcription were promoted from both the genome and the antigenome RNAs (J. N. Barr et al., J. Virol. 79: 12602-12607, 2005). As proof of principle, a recombinant BUNV was created that expressed green fluorescent protein (GFP) in the ambisense orientation. GFP expression was detected throughout at least 10 passages. Recombinant BUNV encoding epitope tagged versions of NSs in the ambisense orientation expressed NSs via a subgenomic mRNA, and two viruses grew to titers only modestly lower than parental rBUNdelNSs2 virus. The ambisense viruses were temperature sensitive, and NSs was shown to localize to both the nucleus and the cytoplasm during infection. These viruses will be useful in further studies on structure-function relationships of the orthobunyavirus NSs protein. IMPORTANCE: Bunyamwera virus (BUNV) is the type species and model system for both the family Bunyaviridae and the genus Orthobunyavirus, a group that includes many significant human and animal pathogens. Studying the basic molecular biology of these viruses is of great importance to underpin research into vaccines and antivirals. We demonstrate here the plasticity of the BUNV genome by generating recombinant viruses where the normal negative-sense S segment has been converted into an ambisense segment, allowing independent expression of either a foreign gene (green fluorescent protein) or the viral nonstructural NSs protein. These new reagents will allow detailed investigation of NSs, the orthobunyavirus interferon antagonist. PMID- 25740986 TI - B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells. AB - Glycoprotein D (gD) plays an essential role in cell entry of many simplexviruses. B virus (Macacine herpesvirus 1) is closely related to herpes simplex virus 1 (HSV-1) and encodes gD, which shares more than 70% amino acid similarity with HSV 1 gD. Previously, we have demonstrated that B virus gD polyclonal antibodies were unable to neutralize B virus infectivity on epithelial cell lines, suggesting gD is not required for B virus entry into these cells. In the present study, we confirmed this finding by producing a B virus mutant, BV-DeltagDZ, in which the gD gene was replaced with a lacZ expression cassette. Recombinant plaques were selected on complementing VD60 cells expressing HSV-1 gD. Virions lacking gD were produced in Vero cells infected with BV-DeltagDZ. In contrast to HSV-1, B virus lacking gD was able to infect and form plaques on noncomplementing cell lines, including Vero, HEp-2, LLC-MK2, primary human and macaque dermal fibroblasts, and U373 human glioblastoma cells. The gD-negative BV-DeltagDZ also failed to enter entry-resistant murine B78H1 cells bearing a single gD receptor, human nectin-1, but gained the ability to enter when phenotypically supplemented with HSV-1 gD. Cell attachment and penetration rates, as well as the replication characteristics of BV-DeltagDZ in Vero cells, were almost identical to those of wild-type (wt) B virus. These observations indicate that B virus can utilize gD-independent cell entry and transmission mechanisms, in addition to generally used gD-dependent mechanisms. IMPORTANCE: B virus is the only known simplexvirus that causes zoonotic infection, resulting in approximately 80% mortality in untreated humans or in lifelong persistence with the constant threat of reactivation in survivors. Here, we report that B virus lacking the gD envelope glycoprotein infects both human and monkey cells as efficiently as wild-type B virus. These data provide evidence for a novel mechanism(s) utilized by B virus to gain access to target cells. This mechanism is different from those used by its close relatives, HSV-1 and -2, where gD is a pivotal protein in the virus entry process. The possibility remains that unidentified receptors, specific for B virus, permit virus entry into target cells through gD-independent pathways. Understanding the molecular mechanisms of B virus entry may help in developing rational therapeutic strategies for the prevention and treatment of B virus infection in both macaques and humans. PMID- 25740987 TI - Mutational analysis of vaccinia virus E3 protein: the biological functions do not correlate with its biochemical capacity to bind double-stranded RNA. AB - Vaccinia E3 protein has the biochemical capacity of binding to double-stranded RNA (dsRNA). The best characterized biological functions of the E3 protein include its host range function, suppression of cytokine expression, and inhibition of interferon (IFN)-induced antiviral activity. Currently, the role of the dsRNA binding capacity in the biological functions of the E3 protein is not clear. To further understand the mechanism of the E3 protein biological functions, we performed alanine scanning of the entire dsRNA binding domain of the E3 protein to examine the link between its biochemical capacity of dsRNA binding and biological functions. Of the 115 mutants examined, 20 were defective in dsRNA binding. Although the majority of the mutants defective in dsRNA binding also showed defective replication in HeLa cells, nine mutants (I105A, Y125A, E138A, F148A, F159A, K171A, L182A, L183A, and I187/188A) retained the host range function to various degrees. Further examination of a set of representative E3L mutants showed that residues essential for dsRNA binding are not essential for the biological functions of E3 protein, such as inhibition of protein kinase R (PKR) activation, suppression of cytokine expression, and apoptosis. Thus, data described in this communication strongly indicate the E3 protein performs its biological functions via a novel mechanism which does not correlate with its dsRNA binding activity. IMPORTANCE: dsRNAs produced during virus replication are important pathogen-associated molecular patterns (PAMPs) for inducing antiviral immune responses. One of the strategies used by many viruses to counteract such antiviral immune responses is achieved by producing dsRNA binding proteins, such as poxvirus E3 family proteins, influenza virus NS1, and Ebola virus V35 proteins. The most widely accepted model for the biological functions of this class of viral dsRNA binding proteins is that they bind to and sequester viral dsRNA PAMPs; thus, they suppress the related antiviral immune responses. However, no direct experimental data confirm such a model. In this study of vaccinia E3 protein, we found that the biological functions of the E3 protein are not necessarily linked to its biochemical capacity of dsRNA binding. Thus, our data strongly point to a new concept of virus modulation of cellular antiviral responses triggered by dsRNA PAMPs. PMID- 25740988 TI - Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env. AB - Similar to other type I fusion machines, the HIV-1 envelope glycoprotein (Env) requires proteolytic activation; specifically, cleavage of a gp160 precursor into gp120 and gp41 subunits creates an N-terminal gp41 fusion peptide and permits folding from an immature uncleaved state to a mature closed state. While the atomic-level consequences of cleavage for HIV-1 Env are still being determined, the uncleaved state is antigenically distinct from the mature closed state, and cleavage has been reported to be essential for mimicry of the mature viral spike by soluble versions of Env. Here we report the redesign of a current state-of-the art soluble Env mimic, BG505.SOSIP, to make it cleavage independent. Specifically, we replaced the furin cleavage site between gp120 and gp41 with Gly Ser linkers of various lengths. The resultant linked gp120-gp41 constructs, termed single-chain gp140 (sc-gp140), exhibited different levels of structural and antigenic mimicry of the parent cleaved BG505.SOSIP. When constructs were subjected to negative selection to remove subspecies recognized by poorly neutralizing antibodies, trimers of high antigenic mimicry of BG505.SOSIP could be obtained; negative-stain electron microscopy indicated these to resemble the mature closed state. Higher proportions of BG505.SOSIP-trimer mimicry were observed in sc-gp140s with linkers of 6 or more residues, with a linker length of 15 residues exhibiting especially promising traits. Overall, flexible linkages between gp120 and gp41 in BG505.SOSIP can thus substitute for cleavage, and sc gp140s that closely mimicked the vaccine-preferred mature closed state of Env could be obtained. IMPORTANCE: The trimeric HIV-1 envelope glycoprotein (Env) is the sole target of virus-directed neutralizing antibody responses and a primary focus of vaccine design. Soluble mimics of Env have proven challenging to obtain and have been thought to require proteolytic cleavage into two-component subunits, gp120 and gp41, to achieve structural and antigenic mimicry of mature Env spikes on virions. Here we show that replacement of the cleavage site between gp120 and gp41 in a lead soluble gp140 construct, BG505.SOSIP, with flexible linkers can result in molecules that do not require cleavage to fold efficiently into the mature closed state. Our results provide insights into the impact of cleavage on HIV-1 Env folding. In some contexts such as genetic immunization, optimized cleavage-independent soluble gp140 constructs may have utility over the parental BG505.SOSIP, as they would not require furin cleavage to achieve mimicry of mature Env spikes on virions. PMID- 25740989 TI - Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5 Tropic HIV-1 in a Subset of Elite Controllers. AB - Elite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4(+) T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4(+) T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1alpha (MIP-1alpha), CCL3 and CCL3L1, were found to be upregulated. The MIP-1alpha, MIP-1beta, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP 1alpha and/or MIP-1beta at the protein level. The supernatant from resistant EC cells contained MIP-1alpha and MIP-1beta and was sufficient to confer R5-tropic resistance to susceptible CD4(+) T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry. IMPORTANCE: HIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4(+) T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV seropositive individuals. PMID- 25740990 TI - Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Inhibits Major Histocompatibility Complex Class II Expression by Disrupting Enhanceosome Assembly through Binding with the Regulatory Factor X Complex. AB - Major histocompatibility complex class II (MHC-II) molecules play a central role in adaptive antiviral immunity by presenting viral peptides to CD4(+) T cells. Due to their key role in adaptive immunity, many viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), have evolved multiple strategies to inhibit the MHC-II antigen presentation pathway. The expression of MHC-II, which is controlled mainly at the level of transcription, is strictly dependent upon the binding of the class II transactivator (CIITA) to the highly conserved promoters of all MHC-II genes. The recruitment of CIITA to MHC-II promoters requires its direct interactions with a preassembled MHC-II enhanceosome consisting of cyclic AMP response element-binding protein (CREB) and nuclear factor Y (NF-Y) complex and regulatory factor X (RFX) complex proteins. Here, we show that KSHV-encoded latency-associated nuclear antigen (LANA) disrupts the association of CIITA with the MHC-II enhanceosome by binding to the components of the RFX complex. Our data show that LANA is capable of binding to all three components of the RFX complex, RFX-associated protein (RFXAP), RFX5, and RFX associated ankyrin-containing protein (RFXANK), in vivo but binds more strongly with the RFXAP component in in vitro binding assays. Levels of MHC-II proteins were significantly reduced in KSHV-infected as well as LANA-expressing B cells. Additionally, the expression of LANA in a luciferase promoter reporter assay showed reduced HLA-DRA promoter activity in a dose-dependent manner. Chromatin immunoprecipitation assays showed that LANA binds to the MHC-II promoter along with RFX proteins and that the overexpression of LANA disrupts the association of CIITA with the MHC-II promoter. These assays led to the conclusion that the interaction of LANA with RFX proteins interferes with the recruitment of CIITA to MHC-II promoters, resulting in an inhibition of MHC-II gene expression. Thus, the data presented here identify a novel mechanism used by KSHV to downregulate the expressions of MHC-II genes. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus is the causative agent of multiple human malignancies. It establishes a lifelong latent infection and persists in infected cells without being detected by the host's immune surveillance system. Only a limited number of viral proteins are expressed during latency, and these proteins play a significant role in suppressing both the innate and adaptive immunities of the host. Latency associated nuclear antigen (LANA) is one of the major proteins expressed during latent infection. Here, we show that LANA blocks MHC-II gene expression to subvert the host immune system by disrupting the MHC-II enhanceosome through binding with RFX transcription factors. Therefore, this study identifies a novel mechanism utilized by KSHV LANA to deregulate MHC-II gene expression, which is critical for CD4(+) T cell responses in order to escape host immune surveillance. PMID- 25740991 TI - Role of hydrogen sulfide in paramyxovirus infections. AB - Hydrogen sulfide (H2S) is an endogenous gaseous mediator that has gained increasing recognition as an important player in modulating acute and chronic inflammatory diseases. However, its role in virus-induced lung inflammation is currently unknown. Respiratory syncytial virus (RSV) is a major cause of upper and lower respiratory tract infections in children for which no vaccine or effective treatment is available. Using the slow-releasing H2S donor GYY4137 and propargylglycin (PAG), an inhibitor of cystathionine-gamma-lyase (CSE), a key enzyme that produces intracellular H2S, we found that RSV infection led to a reduced ability to generate and maintain intracellular H2S levels in airway epithelial cells (AECs). Inhibition of CSE with PAG resulted in increased viral replication and chemokine secretion. On the other hand, treatment of AECs with the H2S donor GYY4137 reduced proinflammatory mediator production and significantly reduced viral replication, even when administered several hours after viral absorption. GYY4137 also significantly reduced replication and inflammatory chemokine production induced by human metapneumovirus (hMPV) and Nipah virus (NiV), suggesting a broad inhibitory effect of H2S on paramyxovirus infections. GYY4137 treatment had no effect on RSV genome replication or viral mRNA and protein synthesis, but it inhibited syncytium formation and virus assembly/release. GYY4137 inhibition of proinflammatory gene expression occurred by modulation of the activation of the key transcription factors nuclear factor kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF-3) at a step subsequent to their nuclear translocation. H2S antiviral and immunoregulatory properties could represent a novel treatment strategy for paramyxovirus infections. IMPORTANCE: RSV is a global health concern, causing significant morbidity and economic losses as well as mortality in developing countries. After decades of intensive research, no vaccine or effective treatment, with the exception of immunoprophylaxis, is available for this infection as well as for other important respiratory mucosal viruses. This study identifies hydrogen sulfide as a novel cellular mediator that can modulate viral replication and proinflammatory gene expression, both important determinants of lung injury in respiratory viral infections, with potential for rapid translation of such findings into novel therapeutic approaches for viral bronchiolitis and pneumonia. PMID- 25740992 TI - Viral Bcl-2 Encoded by the Kaposi's Sarcoma-Associated Herpesvirus Is Vital for Virus Reactivation. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 16 (orf16) encodes a viral Bcl-2 (vBcl-2) protein which shares sequence and functional homology with the Bcl-2 family. Like its cellular homologs, vBcl-2 protects various cell types from apoptosis and can also negatively regulate autophagy. vBcl-2 is transcribed during lytic infection; however, its exact function has not been determined to date. By using bacterial artificial chromosome 16 (BAC16) clone carrying the full-length KSHV genome, we have generated recombinant KSHV mutants that fail to express vBcl-2 or express mCherry-tagged vBcl-2. We show that the vBcl-2 protein is expressed at relatively low levels during lytic induction and that a lack of vBcl-2 largely reduces the efficiency of KSHV reactivation in terms of lytic gene expression, viral DNA replication, and production of infectious particles. In contrast, the establishment of latency was not affected by the absence of vBcl-2. Our findings suggest an important role for vBcl-2 during initial phases of lytic reactivation and/or during subsequent viral propagation. Given the known functions of vBcl-2 in regulating apoptosis and autophagy, which involve its direct interaction with cellular proteins and thus require high levels of protein expression, it appears that vBcl-2 may have additional regulatory functions that do not depend on high levels of protein expression. IMPORTANCE: The present study shows for the first time the expression of endogenous vBcl-2 protein in KSHV-infected cell lines and demonstrates the importance of vBcl-2 during the initial phases of lytic reactivation and/or during its subsequent propagation. It is suggested that vBcl-2 has additional regulatory functions beyond apoptosis and autophagy repression that do not depend on high levels of protein expression. PMID- 25740993 TI - BH3 Profiling Reveals Selectivity by Herpesviruses for Specific Bcl-2 Proteins To Mediate Survival of Latently Infected Cells. AB - Herpesviruses, including human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus, establish latency by modulating or mimicking antiapoptotic Bcl-2 proteins to promote survival of carrier cells. BH3 profiling, which assesses the contribution of Bcl-2 proteins towards cellular survival, was able to globally determine the level of dependence on individual cellular and viral Bcl-2 proteins within latently infected cells. Moreover, BH3 profiling predicted the sensitivity of infected cells to small-molecule inhibitors of Bcl-2 proteins. PMID- 25740994 TI - Identification of the Essential Role of Viral Bcl-2 for Kaposi's Sarcoma Associated Herpesvirus Lytic Replication. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) evades host defenses through tight suppression of autophagy by targeting each step of its signal transduction: by viral Bcl-2 (vBcl-2) in vesicle nucleation, by viral FLIP (vFLIP) in vesicle elongation, and by K7 in vesicle maturation. By exploring the roles of KSHV autophagy-modulating genes, we found, surprisingly, that vBcl-2 is essential for KSHV lytic replication, whereas vFLIP and K7 are dispensable. Knocking out vBcl-2 from the KSHV genome resulted in decreased lytic gene expression at the mRNA and protein levels, a lower viral DNA copy number, and, consequently, a dramatic reduction in the amount of progeny infectious viruses, as also described in the accompanying article (A. Gelgor, I. Kalt, S. Bergson, K. F. Brulois, J. U. Jung, and R. Sarid, J Virol 89:5298-5307, 2015). More importantly, the antiapoptotic and antiautophagic functions of vBcl-2 were not required for KSHV lytic replication. Using a comprehensive mutagenesis analysis, we identified that glutamic acid 14 (E14) of vBcl-2 is critical for KSHV lytic replication. Mutating E14 to alanine totally blocked KSHV lytic replication but showed little or no effect on the antiapoptotic and antiautophagic functions of vBcl-2. Our study indicates that vBcl-2 harbors at least three important and genetically separable functions to modulate both cellular signaling and the virus life cycle. IMPORTANCE: The present study shows for the first time that vBcl-2 is essential for KSHV lytic replication. Removal of the vBcl-2 gene results in a lower level of KSHV lytic gene expression, impaired viral DNA replication, and consequently, a dramatic reduction in the level of progeny production. More importantly, the role of vBcl-2 in KSHV lytic replication is genetically separated from its antiapoptotic and antiautophagic functions, suggesting that the KSHV Bcl-2 carries a novel function in viral lytic replication. PMID- 25740995 TI - Protease Inhibitors Block Multiple Functions of the NS3/4A Protease-Helicase during the Hepatitis C Virus Life Cycle. AB - Hepatitis C virus (HCV) NS3 is a multifunctional protein composed of a protease domain and a helicase domain linked by a flexible linker. Protease activity is required to generate viral nonstructural (NS) proteins involved in RNA replication. Helicase activity is required for RNA replication, and genetic evidence implicates the helicase domain in virus assembly. Binding of protease inhibitors (PIs) to the protease active site blocks NS3-dependent polyprotein processing but might impact other steps of the virus life cycle. Kinetic analyses of antiviral suppression of cell culture-infectious genotype 1a strain H77S.3 were performed using assays that measure different readouts of the viral life cycle. In addition to the active-site PI telaprevir, we examined an allosteric protease-helicase inhibitor (APHI) that binds a site in the interdomain interface. By measuring nucleotide incorporation into HCV genomes, we found that telaprevir inhibits RNA synthesis as early as 12 h at high but clinically relevant concentrations. Immunoblot analyses showed that NS5B abundance was not reduced until after 12 h, suggesting that telaprevir exerts a direct effect on RNA synthesis. In contrast, the APHI could partially inhibit RNA synthesis, suggesting that the allosteric site is not always available during RNA synthesis. The APHI and active-site PI were both able to block virus assembly soon (<12 h) after drug treatment, suggesting that they rapidly engage with and block a pool of NS3 involved in assembly. In conclusion, PIs and APHIs can block NS3 functions in RNA synthesis and virus assembly, in addition to inhibiting polyprotein processing. IMPORTANCE: The NS3/4A protease of hepatitis C virus (HCV) is an important antiviral target. Currently, three PIs have been approved for therapy of chronic hepatitis C, and several others are in development. NS3-dependent cleavage of the HCV polyprotein is required to generate the mature nonstructural proteins that form the viral replicase. Inhibition of protease activity can block RNA replication by preventing expression of mature replicase components. Like many viral proteins, NS3 is multifunctional, but how PIs affect stages of the HCV life cycle beyond polyprotein processing has not been well studied. Using cell based assays, we show here that PIs can directly inhibit viral RNA synthesis and also block a late stage in virus assembly/maturation at clinically relevant concentrations. PMID- 25740996 TI - Origins and Evolutionary Dynamics of H3N2 Canine Influenza Virus. AB - Influenza A viruses (IAVs) are maintained mainly in wild birds, and despite frequent spillover infections of avian IAVs into mammals, only a small number of viruses have become established in mammalian hosts. A new H3N2 canine influenza virus (CIV) of avian origin emerged in Asia in the mid-2000s and is now circulating in dog populations of China and South Korea, and possibly in Thailand. The emergence of CIV provides new opportunities for zoonotic infections and interspecies transmission. We examined 14,764 complete IAV genomes together with all CIV genomes publicly available since its first isolation until 2013. We show that CIV may have originated as early as 1999 as a result of segment reassortment among Eurasian and North American avian IAV lineages. We also identified amino acid changes that might have played a role in CIV emergence, some of which have not been previously identified in other cross-species jumps. CIV evolves at a lower rate than H3N2 human influenza viruses do, and viral phylogenies exhibit geographical structure compatible with high levels of local transmission. We detected multiple intrasubtypic and heterosubtypic reassortment events, including the acquisition of the NS segment of an H5N1 avian influenza virus that had previously been overlooked. In sum, our results provide insight into the adaptive changes required by avian viruses to establish themselves in mammals and also highlight the potential role of dogs to act as intermediate hosts in which viruses with zoonotic and/or pandemic potential could originate, particularly with an estimated dog population of ~ 700 million. IMPORTANCE: Influenza A viruses circulate in humans and animals. This multihost ecology has important implications, as past pandemics were caused by IAVs carrying gene segments of both human and animal origin. Adaptive evolution is central to cross species jumps, and this is why understanding the evolutionary processes that shape influenza A virus genomes is key to elucidating the mechanisms underpinning viral emergence. An avian-origin canine influenza virus (CIV) has recently emerged in dogs and is spreading in Asia. We reconstructed the evolutionary history of CIV and show that it originated from both Eurasian and North American avian lineages. We also identified the mutations that might have been responsible for the cross-species jump. Finally, we provide evidence of multiple reassortment events between CIV and other influenza viruses (including an H5N1 avian virus). This is a cause for concern, as there is a large global dog population to which humans are highly exposed. PMID- 25740997 TI - Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses. AB - Human infections by avian influenza A(H7N9) virus entail substantial morbidity and mortality. Treatment of infected patients with the neuraminidase (NA) inhibitor oseltamivir was associated with emergence of viruses carrying NA substitutions. In the NA inhibition (NI) assay, R292K conferred highly reduced inhibition by oseltamivir, while E119V and I222K each caused reduced inhibition. To facilitate establishment of laboratory correlates of clinically relevant resistance, experiments were conducted in ferrets infected with virus carrying wild-type or variant NA genes recovered from the A/Taiwan/1/2013 isolate. Oseltamivir treatment (5 or 25 mg/kg of body weight/dose) was given 4 h postinfection, followed by twice-daily treatment for 5 days. Treatment of ferrets infected with wild-type virus resulted in a modest dose-dependent reduction (0.7 to 1.5 log10 50% tissue culture infectious dose [TCID50]) in nasal wash viral titers and inflammation response. Conversely, treatment failed to significantly inhibit the replication of R292K or E119V virus. A small reduction of viral titers was detected on day 5 in ferrets infected with the I222K virus. The propensity for oseltamivir resistance emergence was assessed in oseltamivir treated animals infected with wild-type virus; emergence of R292K virus was detected in 3 of 6 ferrets within 5 to 7 days postinfection. Collectively, we demonstrate that R292K, E119V, and I222K reduced the inhibitory activity of oseltamivir, not only in the NI assay, but also in infected ferrets, judged particularly by viral loads in nasal washes, and may signal the need for alternative therapeutics. Thus, these clinical outcomes measured in the ferret model may correlate with clinically relevant oseltamivir resistance in humans. IMPORTANCE: This report provides more evidence for using the ferret model to assess the susceptibility of influenza A(H7N9) viruses to oseltamivir, the most prescribed anti-influenza virus drug. The information gained can be used to assist in the establishment of laboratory correlates of human disease and drug therapy. The rapid emergence of viruses with R292K in treated ferrets correlates well with the multiple reports on this NA variant in treated human patients. Our findings highlight the importance of the discovery and characterization of new antiviral drugs with different mechanisms of action and the use of combination treatment strategies against emerging viruses with pandemic potential, such as avian H7N9 virus, particularly against those carrying drug resistance markers. PMID- 25740998 TI - A metagenomics and case-control study to identify viruses associated with bovine respiratory disease. AB - Bovine respiratory disease (BRD) is a common health problem for both dairy and beef cattle, resulting in significant economic loses. In order to identify viruses associated with BRD, we used a metagenomics approach to enrich and sequence viral nucleic acids in the nasal swabs of 50 young dairy cattle with symptoms of BRD. Following deep sequencing, de novo assembly, and translated protein sequence similarity searches, numerous known and previously uncharacterized viruses were identified. Bovine adenovirus 3, bovine adeno associated virus, bovine influenza D virus, bovine parvovirus 2, bovine herpesvirus 6, bovine rhinitis A virus, and multiple genotypes of bovine rhinitis B virus were identified. The genomes of a previously uncharacterized astrovirus and picobirnaviruses were also partially or fully sequenced. Using real-time PCR, the rates of detection of the eight viruses that generated the most reads were compared for the nasal secretions of 50 animals with BRD versus 50 location matched healthy control animals. Viruses were detected in 68% of BRD-affected animals versus 16% of healthy control animals. Thirty-eight percent of sick animals versus 8% of controls were infected with multiple respiratory viruses. Significantly associated with BRD were bovine adenovirus 3 (P < 0.0001), bovine rhinitis A virus (P = 0.005), and the recently described bovine influenza D virus (P = 0.006), which were detected either alone or in combination in 62% of animals with BRD. A metagenomics and real-time PCR detection approach in carefully matched cases and controls can provide a rapid means to identify viruses associated with a complex disease, paving the way for further confirmatory tests and ultimately to effective intervention strategies. IMPORTANCE: Bovine respiratory disease is the most economically important disease affecting the cattle industry, whose complex root causes include environmental, genetics, and infectious factors. Using an unbiased metagenomics approach, we characterized the viruses in respiratory secretions from BRD cases and identified known and previously uncharacterized viruses belonging to seven viral families. Using a case-control format with location-matched animals, we compared the rates of viral detection and identified 3 viruses associated with severe BRD signs. Combining a metagenomics and case-control format can provide candidate pathogens associated with complex infectious diseases and inform further studies aimed at reducing their impact. PMID- 25740999 TI - Peptide-Dependent Recognition of HLA-B*57:01 by KIR3DS1. AB - Killer cell immunoglobulin-like receptors (KIRs) play an important role in the activation of natural killer (NK) cells, which in turn contribute to the effective immune control of many viral infections. In the context of HIV infection, the closely related KIR3DL1 and KIR3DS1 molecules, in particular, have been associated with disease outcome. Inhibitory signals via KIR3DL1 are disrupted by downregulation of HLA class I ligands on the infected cell surface and can also be impacted by changes in the presented peptide repertoire. In contrast, the activatory ligands for KIR3DS1 remain obscure. We used a structure driven approach to define the characteristics of HLA class I-restricted peptides that interact with KIR3DL1 and KIR3DS1. In the case of HLA-B*57:01, we used this knowledge to identify bona fide HIV-derived peptide epitopes with similar properties. Two such peptides facilitated productive interactions between HLA B*57:01 and KIR3DS1. These data reveal the presence of KIR3DS1 ligands within the HIV-specific peptide repertoire presented by a protective HLA class I allotype, thereby enhancing our mechanistic understanding of the processes that enable NK cells to impact disease outcome. IMPORTANCE: Natural killer (NK) cells are implicated as determinants of immune control in many viral infections, but the precise molecular mechanisms that initiate and control these responses are unclear. The activating receptor KIR3DS1 in combination with HLA-Bw4 has been associated with better outcomes in HIV infection. However, evidence of a direct interaction between these molecules is lacking. In this study, we demonstrate that KIR3DS1 recognition of HLA-Bw4 is peptide dependent. We also identify HIV derived peptide epitopes presented by the protective HLA-B*57:01 allotype that facilitate productive interactions with KIR3DS1. Collectively, these findings suggest a mechanism whereby changes in the peptide repertoire associated with viral infection provide a trigger for KIR3DS1 engagement and NK cell activation. PMID- 25741000 TI - Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes. AB - Identification and characterization of CD8(+) T cells effectively controlling HIV 1 variants are necessary for the development of AIDS vaccines and for studies of AIDS pathogenesis, although such CD8(+) T cells have been only partially identified. In this study, we sought to identify CD8(+) T cells controlling HIV-1 variants in 401 Japanese individuals chronically infected with HIV-1 subtype B, in which protective alleles HLA-B*57 and HLA-B*27 are very rare, by using comprehensive and exhaustive methods. We identified 13 epitope-specific CD8(+) T cells controlling HIV-1 in Japanese individuals, though 9 of these epitopes were not previously reported. The breadths of the T cell responses to the 13 epitopes were inversely associated with plasma viral load (P = 2.2 * 10(-11)) and positively associated with CD4 count (P = 1.2 * 10(-11)), indicating strong synergistic effects of these T cells on HIV-1 control in vivo. Nine of these epitopes were conserved among HIV-1 subtype B-infected individuals, whereas three out of four nonconserved epitopes were cross-recognized by the specific T cells. These findings indicate that these 12 epitopes are strong candidates for antigens for an AIDS vaccine. The present study highlighted a strategy to identify CD8(+) T cells controlling HIV-1 and demonstrated effective control of HIV-1 by those specific for 12 conserved or cross-reactive epitopes. IMPORTANCE: HLA-B*27 restricted and HLA-B*57-restricted cytotoxic T lymphocytes (CTLs) play a key role in controlling HIV-1 in Caucasians and Africans, whereas it is unclear which CTLs control HIV-1 in Asian countries, where HLA-B*57 and HLA-B*27 are very rare. A recent study showed that HLA-B*67:01 and HLA-B*52:01-C*12:02 haplotypes were protective alleles in Japanese individuals, but it is unknown whether CTLs restricted by these alleles control HIV-1. In this study, we identified 13 CTLs controlling HIV-1 in Japan by using comprehensive and exhaustive methods. They included 5 HLA-B*52:01-restricted and 3 HLA-B*67:01-restricted CTLs, suggesting that these CTLs play a predominant role in HIV-1 control. The 13 CTLs showed synergistic effects on HIV-1 control. Twelve out of these 13 epitopes were recognized as conserved or cross-recognized ones. These findings strongly suggest that these 12 epitopes are candidates for antigens for AIDS vaccines. PMID- 25741002 TI - Complementary Assays Reveal a Low Level of CA Associated with Viral Complexes in the Nuclei of HIV-1-Infected Cells. AB - During uncoating, the conical capsid of HIV disassembles by dissociation of the p24 capsid protein (CA). Uncoating is known to be required for HIV replication, but the mechanism is poorly defined. Here, we examined the timing and effect of two capsid binding drugs (PF74 and BI2) on infectivity and capsid integrity in HIV-1-infected cells. The virus remained susceptible to the action of PF74 and BI2 for hours after uncoating as defined in parallel drug addition and cyclosporine (CsA) washout assays to detect the kinetics of drug susceptibility and uncoating, respectively. Resistance mutations in CA decreased the potency of these compounds, demonstrating that CA is the target of drug action. However, neither drug altered capsid integrity in a fluorescence microscopy-based assay. These data suggest that PF74 and BI2 do not alter HIV-1 uncoating but rather affect a later step in viral replication. Because both drugs bind CA, we hypothesized that a residual amount of CA associates with the viral complex after the loss of the conical capsid to serve as a target for these drugs. Superresolution structured illumination microscopy (SIM) revealed that CA localized to viral complexes in the nuclei of infected cells. Using image quantification, we determined that viral complexes localized in the nucleus displayed a smaller amount of CA than complexes at the nuclear membrane, in the cytoplasm, or in controls. Collectively, these data suggest that a subset of CA remains associated with the viral complex after uncoating and that this residual CA is the target of PF74 and BI2. IMPORTANCE: The HIV-1 capsid is a target of interest for new antiviral therapies. This conical capsid is composed of monomers of the viral CA protein. During HIV-1 replication, the capsid must disassemble by a poorly defined process called uncoating. CA has also been implicated in later steps of replication, including nuclear import and integration. In this study, we used cell-based assays to examine the effect of two CA binding drugs (PF74 and BI2) on viral replication in infected cells. HIV-1 was susceptible to both drugs for hours after uncoating, suggesting that these drugs affect later steps of viral replication. High-resolution structured illumination microscopy (SIM) revealed that a subset of CA localized to viral complexes in the nuclei of cells. Collectively, these data suggest that a subset of CA remains associated with the viral complex after uncoating, which may facilitate later steps of viral replication and serve as a drug target. PMID- 25741001 TI - Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta. AB - Human cytomegalovirus (HCMV) is a major cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, and hypoxia associated with symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed that HCMV infection impedes terminal stages of differentiation and invasion by various molecular mechanisms. We recently discovered that HCMV arrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to the mature cell types of chorionic villi-syncytiotrophoblasts on the surfaces of floating villi and invasive CTBs that remodel the uterine vasculature. Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection. In vitro studies revealed that HCMV replicates in continuously self renewing TBPC lines derived from the chorion and alters expression and subcellular localization of proteins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatment with a human monoclonal antibody to HCMV glycoprotein B rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development. Our results suggest that HCMV replicates in TBPCs in the chorion in vivo, interfering with the earliest steps in the growth of new villi, contributing to virus transmission and impairing compensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of substances from maternal blood and contributes to fetal growth restriction. IMPORTANCE: Human cytomegalovirus (HCMV) is a leading cause of birth defects in the United States. Congenital infection can result in permanent neurological defects, mental retardation, hearing loss, visual impairment, and pregnancy complications, including intrauterine growth restriction, preterm delivery, and stillbirth. Currently, there is neither a vaccine nor any approved treatment for congenital HCMV infection during gestation. The molecular mechanisms underlying structural deficiencies in the placenta that undermine fetal development are poorly understood. Here we report that HCMV replicates in trophoblast progenitor cells (TBPCs)-precursors of the mature placental cells, syncytiotrophoblasts and cytotrophoblasts, in chorionic villi-in clinical cases of congenital infection. Virus replication in TBPCs in vitro dysregulates key proteins required for self renewal and differentiation and inhibits normal division and development into mature placental cells. Our findings provide insights into the underlying molecular mechanisms by which HCMV replication interferes with placental maturation and transport functions. PMID- 25741003 TI - Spread and persistence of influenza A viruses in waterfowl hosts in the North American Mississippi migratory flyway. AB - While geographic distance often restricts the spread of pathogens via hosts, this barrier may be compromised when host species are mobile. Migratory waterfowl in the order Anseriformes are important reservoir hosts for diverse populations of avian-origin influenza A viruses (AIVs) and are assumed to spread AIVs during their annual continental-scale migrations. However, support for this hypothesis is limited, and it is rarely tested using data from comprehensive surveillance efforts incorporating both the temporal and spatial aspects of host migratory patterns. We conducted intensive AIV surveillance of waterfowl using the North American Mississippi Migratory Flyway (MMF) over three autumn migratory seasons. Viral isolates (n = 297) from multiple host species were sequenced and analyzed for patterns of gene dispersal between northern staging and southern wintering locations. Using a phylogenetic and nucleotide identity framework, we observed a larger amount of gene dispersal within this flyway rather than between the other three longitudinally identified North American flyways. Across seasons, we observed patterns of regional persistence of diversity for each genomic segment, along with limited survival of dispersed AIV gene lineages. Reassortment increased with both time and distance, resulting in transient AIV constellations. This study shows that within the MMF, AIV gene flow favors spread along the migratory corridor within a season, and also that intensive surveillance during bird migration is important for identifying virus dispersal on time scales relevant to pandemic responsiveness. In addition, this study indicates that comprehensive monitoring programs to capture AIV diversity are critical for providing insight into AIV evolution and ecology in a major natural reservoir. IMPORTANCE: Migratory birds are a reservoir for antigenic and genetic diversity of influenza A viruses (AIVs) and are implicated in the spread of virus diversity that has contributed to previous pandemic events. Evidence for dispersal of avian origin AIVs by migratory birds is rarely examined on temporal scales relevant to pandemic or panzootic threats. Therefore, characterizing AIV movement by hosts within a migratory season is important for implementing effective surveillance strategies. We conducted surveillance following birds along a major North American migratory route and observed that within a migratory season, AIVs rapidly reassorted and gene lineages were dispersed primarily within the migratory corridor. Patterns of regional persistence were observed across seasons for each gene segment. We show that dispersal of AIV gene lineages by migratory birds occurs quickly along migratory routes and that surveillance for AIVs threatening human and animal health should focus attention on these routes. PMID- 25741004 TI - Changes in Susceptibility to Oncolytic Vesicular Stomatitis Virus during Progression of Prostate Cancer. AB - A major challenge to oncolytic virus therapy is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. Variability in response may arise due to differences in the initial genetic lesions leading to cancer development. Alternatively, susceptibility to viral oncolysis may change during cancer progression. These hypotheses were tested using cells from a transgenic mouse model of prostate cancer infected with vesicular stomatitis virus (VSV). Primary cultures from murine cancers derived from prostate-specific Pten deletion contained a mixture of cells that were susceptible and resistant to VSV. Castration-resistant cancers contained a higher percentage of susceptible cells than cancers from noncastrated mice. These results indicate both susceptible and resistant cells can evolve within the same tumor. The role of Pten deletion was further investigated using clonal populations of murine prostate epithelial (MPE) progenitor cells and tumor derived Pten(-/-) cells. Deletion of Pten in MPE progenitor cells using a lentivirus vector resulted in cells that responded poorly to interferon and were susceptible to VSV infection. In contrast, tumor-derived Pten(-/-) cells expressed higher levels of the antiviral transcription factor STAT1, activated STAT1 in response to VSV, and were resistant to VSV infection. These results suggest that early in tumor development following Pten deletion, cells are primarily sensitive to VSV, but subsequent evolution in tumors leads to development of cells that are resistant to VSV infection. Further evolution in castration-resistant tumors leads to tumors in which cells are primarily sensitive to VSV. IMPORTANCE: There has been a great deal of progress in the development of replication-competent viruses that kill cancer cells (oncolytic viruses). However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. The experiments presented here were to determine whether both sensitive and resistant cells are present in prostate cancers originating from a single genetic lesion in transgenic mice, prostate-specific deletion of the gene for the tumor suppressor Pten. The results indicate that murine prostate cancers are composed of both cells that are sensitive and cells that are resistant to oncolytic vesicular stomatitis virus (VSV). Furthermore, androgen deprivation led to castration-resistant prostate cancers that were composed primarily of cells that were sensitive to VSV. These results are encouraging for the use of VSV for the treatment of prostate cancers that are resistant to androgen deprivation therapy. PMID- 25741005 TI - Efficiently editing the vaccinia virus genome by using the CRISPR-Cas9 system. AB - Vaccinia virus (VACV) continues to be used in immunotherapy for the prevention of infectious diseases and treatment of cancer since its use for the eradication of smallpox. However, the current method of editing the VACV genome is not efficient. Here, we demonstrate that the CRISPR-Cas9 system can be used to edit the VACV genome rapidly and efficiently. Additionally, a set of 8,964 computationally designed unique guide RNAs (gRNAs) targeting all VACV genes will be valuable for the study of VACV gene functions. PMID- 25741006 TI - Alterations in hemagglutinin receptor-binding specificity accompany the emergence of highly pathogenic avian influenza viruses. AB - Highly pathogenic avian influenza viruses (HPAIVs) of hemagglutinin H5 and H7 subtypes emerge after introduction of low-pathogenic avian influenza viruses (LPAIVs) from wild birds into poultry flocks, followed by subsequent circulation and evolution. The acquisition of multiple basic amino acids at the endoproteolytical cleavage site of the hemagglutinin (HA) is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry. Apart from the well-studied significance of the multibasic HA cleavage site, there is only limited knowledge on other alterations in the HA and neuraminidase (NA) molecules associated with changes in tropism during the emergence of HPAIVs from LPAIVs. We hypothesized that changes in tropism may require alterations of the sialyloligosaccharide specificities of HA and NA. To test this hypothesis, we compared a number of LPAIVs and HPAIVs for their HA mediated binding and NA-mediated desialylation of a set of synthetic receptor analogs, namely, alpha2-3-sialylated oligosaccharides. NA substrate specificity correlated with structural groups of NAs and did not correlate with pathogenic potential of the virus. In contrast, all HPAIVs differed from LPAIVs by a higher HA receptor-binding affinity toward the trisaccharides Neu5Acalpha2-3Galbeta1 4GlcNAcbeta (3'SLN) and Neu5Acalpha2-3Galbeta1-3GlcNAcbeta (SiaLe(c)) and by the ability to discriminate between the nonfucosylated and fucosylated sialyloligosaccharides 3'SLN and Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAcbeta (SiaLe(x)), respectively. These results suggest that alteration of the receptor binding specificity accompanies emergence of the HPAIVs from their low-pathogenic precursors. IMPORTANCE: Here, we have found for the first time correlations of receptor-binding properties of the HA with a highly pathogenic phenotype of poultry viruses. Our study suggests that enhanced receptor-binding affinity of HPAIVs for a typical "poultry-like" receptor, 3'SLN, is provided by substitutions in the receptor-binding site of HA which appeared in HA of LPAIVs in the course of transmission of LPAIVs from wild waterfowl into poultry flocks, with subsequent adaptation in poultry. The identification of LPAIVs with receptor characteristics of HPAIVs argues that the sialic acid-binding specificity of the HA may be used as a novel phenotypic marker of HPAIVs. PMID- 25741007 TI - Characterization of Two Novel Linear B-Cell Epitopes in the Capsid Protein of Avian Hepatitis E Virus (HEV) That Are Common to Avian, Swine, and Human HEVs. AB - Antisera raised against the avian hepatitis E virus (HEV) capsid protein are cross-reactive with human and swine HEV capsid proteins. In this study, two monoclonal antibodies (MAbs) against the avian HEV capsid protein, namely, 3E8 and 1B5, were shown to cross-react with the swine HEV capsid protein. The motifs involved in binding both MAbs were identified and characterized using phage display biopanning, peptide synthesis, and truncated or mutated protein expression, along with indirect enzyme-linked immunosorbent assay (ELISA) and Western blotting. The results showed that the I/VPHD motif is a necessary core sequence and that P and H are two key amino acids for recognition by MAb 3E8. The VKLYM/TS motif is the minimal amino acid sequence necessary for recognition by MAb 1B5. Cross-reactivity between the two epitopes and antibodies against avian, swine, and human HEVs in sera showed that both epitopes are common to avian, swine, and human HEVs. In addition, amino acid sequence alignment of the capsid proteins revealed that the key motifs of both novel epitopes are the same in HEVs from different animal species, predicting that they may be common to HEV isolates from boars, rabbits, rats, ferrets, mongooses, deer, and camels as well. Protein modeling analysis showed that both epitopes are at least partially exposed on the surface of the HEV capsid protein. Protective capacity analysis demonstrated that the two epitopes are nonprotective against avian HEV infection in chickens. Collectively, these studies characterize two novel linear B-cell epitopes common to avian, swine, and human HEVs, which furthers the understanding of HEV capsid protein antigenic structure. IMPORTANCE: More and more evidence indicates that the host range diversity of hepatitis E virus (HEV) is a global public health concern. A better understanding of the antigenic structure of the HEV capsid protein may improve disease diagnosis and prevention. In this study, binding site mapping and localization as well as the antigenic biology of two novel linear B cell epitopes common to several different species of HEV were characterized. These findings partially reveal the antigenic structure of the HEV capsid protein and provide potential applications for the development of diagnostics and interventions for HEV infection. PMID- 25741009 TI - Viral sensing of the subcellular environment regulates the assembly of new viral replicase complexes during the course of infection. AB - Replication of plus-stranded RNA [(+)RNA] viruses depends on the availability of coopted host proteins and lipids. But, how could viruses sense the accessibility of cellular resources? An emerging concept based on tombusviruses, small plant viruses, is that viruses might regulate viral replication at several steps depending on what cellular factors are available at a given time point. I discuss the role of phospholipids, sterols, and cellular WW domain proteins and eukaryotic elongation factor 1A (eEF1A) in control of activation of the viral RNA dependent RNA polymerase (RdRp) and regulation of the assembly of viral replicase complexes (VRCs). These regulatory mechanisms might explain how tombusviruses could adjust the efficiency of RNA replication and new VRC assembly to the limiting resources of the host cells during infections. PMID- 25741008 TI - Role of EXT1 and Glycosaminoglycans in the Early Stage of Filovirus Entry. AB - Filoviruses, including both Ebola virus (EBOV) and Marburg virus (MARV), can infect humans and other animals, causing hemorrhagic fever with a high mortality rate. Entry of these viruses into the host is mediated by a single filoviral glycoprotein (GP). GP is composed of two subunits: GP1, which is responsible for attachment and binding to receptor(s) on susceptible cells, and GP2, which mediates viral and cell membrane fusion. Although numerous host factors have been implicated in the entry process, the initial attachment receptor(s) has not been well defined. In this report, we demonstrate that exostosin 1 (EXT1), which is involved in biosynthesis of heparan sulfate (HS), plays a role in filovirus entry. Expression knockdown of EXT1 by small interfering RNAs (siRNAs) impairs GP mediated pseudoviral entry and that of infectious EBOV and MARV in tissue cultured cells. Furthermore, HS, heparin, and other related glycosaminoglycans (GAGs), to different extents, can bind to and block GP-mediated viral entry and that of infectious filoviruses. These results strongly suggest that HS and other related GAGs are attachment receptors that are utilized by filoviruses for entry and infection. These GAGs may have therapeutic potential in treating EBOV- and MARV-infected patients. IMPORTANCE: Infection by Ebola virus and Marburg virus can cause severe illness in humans, with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The ongoing 2014 outbreak in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we provide several pieces of evidence that demonstrate that heparan sulfate and other closely related glycosaminoglycans are the molecules that are used by filoviruses for initial attachment. Furthermore, we demonstrate that these glycosaminoglycans can block entry of and infection by filoviruses. Thus, this work provides mechanistic insights on the early step of filoviral infection and suggests a possible therapeutic option for diseases caused by filovirus infection. PMID- 25741010 TI - Functional properties and genetic relatedness of the fusion and hemagglutinin neuraminidase proteins of a mumps virus-like bat virus. AB - A bat virus with high phylogenetic relatedness to human mumps virus (MuV) was identified recently at the nucleic acid level. We analyzed the functional activities of the hemagglutinin-neuraminidase (HN) and the fusion (F) proteins of the bat virus (batMuV) and compared them to the respective proteins of a human isolate. Transfected cells expressing the F and HN proteins of batMuV were recognized by antibodies directed against these proteins of human MuV, indicating that both viruses are serologically related. Fusion, hemadsorption, and neuraminidase activities were demonstrated for batMuV, and either bat-derived protein could substitute for its human MuV counterpart in inducing syncytium formation when coexpressed in different mammalian cell lines, including chiropteran cells. Cells expressing batMuV glycoproteins were shown to have lower neuraminidase activity. The syncytia were smaller, and they were present in lower numbers than those observed after coexpression of the corresponding glycoproteins of a clinical isolate of MuV (hMuV). The phenotypic differences in the neuraminidase and fusion activity between the glycoproteins of batMuV and hMuV are explained by differences in the expression level of the HN and F proteins of the two viruses. In the case of the F protein, analysis of chimeric proteins revealed that the signal peptide of the bat MuV fusion protein is responsible for the lower surface expression. These results indicate that the surface glycoproteins of batMuV are serologically and functionally related to those of hMuV, raising the possibility of bats as a reservoir for interspecies transmission. IMPORTANCE: The recently described MuV-like bat virus is unique among other recently identified human-like bat-associated viruses because of its high sequence homology (approximately 90% in most genes) to its human counterpart. Although it is not known if humans can be infected by batMuV, the antigenic relatedness between the bat and human forms of the virus suggests that humans carrying neutralizing antibodies against MuV are protected from infection by batMuV. The close functional relationship between MuV and batMuV is demonstrated by cooperation of the respective HN and F proteins to induce syncytium formation in heterologous expression studies. An interesting feature of the glycoproteins of batMuV is the downregulation of the fusion activity by the signal peptide of F, which has not been reported for other paramyxoviruses. These results are important contributions for risk assessment and for a better understanding of the replication strategy of batMuV. PMID- 25741011 TI - Diversifying Selection Analysis Predicts Antigenic Evolution of 2009 Pandemic H1N1 Influenza A Virus in Humans. AB - Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified 16 amino acid sites experiencing diversifying selection during the evolution of prepandemic seasonal H1N1 strains and found that 11 sites were located in experimentally determined B cell/antibody (Ab) epitopes, including three distinct neutralizing Caton epitopes: Sa, Sb, and Ca2 [A. J. Caton, G. G. Brownlee, J. W. Yewdell, and W. Gerhard, Cell 31:417-427, 1982, http://dx.doi.org/10.1016/0092-8674(82)90135-0]. We predicted that these diversified epitope regions would be the targets of mutation as the 2009 H1N1 pandemic (pH1N1) lineage evolves in response to the development of population-level protective immunity in humans. Using a chi squared goodness-of-fit test, we identified 10 amino acid sites that significantly differed between the pH1N1 isolates and isolates from the recent 2012-2013 and 2013-2014 influenza seasons. Three of these sites were located in the same diversified B-cell/Ab epitope regions as identified in the analysis of prepandemic sequences, including Sa and Sb. As predicted, hemagglutination inhibition (HI) assays using human sera from subjects vaccinated with the initial pH1N1 isolate demonstrated reduced reactivity against 2013-2014 isolates. Taken together, these results suggest that diversifying selection analysis can identify key immune epitopes responsible for protective immunity to influenza virus in humans and thereby predict virus evolution. IMPORTANCE: The WHO estimates that approximately 5 to 10% of adults and 20 to 30% of children in the world are infected by influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza virus infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza virus strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted. PMID- 25741014 TI - Thrombocytosis in a patient with alpha thalassemia trait. PMID- 25741012 TI - Retroviral cyclin controls cyclin-dependent kinase 8-mediated transcription elongation and reinitiation. AB - Walleye dermal sarcoma virus (WDSV) infection is associated with the seasonal development and regression of walleye dermal sarcoma. Previous work showed that the retroviral cyclin (RV-cyclin), encoded by WDSV, has separable cyclin box and transcription activation domains. It binds to cyclin-dependent kinase 8 (CDK8) and enhances its kinase activity. CDK8 is evolutionarily conserved and is frequently overexpressed in human cancers. It is normally activated by cyclin C and is required for transcription elongation of the serum response genes (immediate early genes [IEGs]) FOS, EGR1, and cJUN. The IEGs drive cell proliferation, and their expression is brief and highly regulated. Here we show that constitutive expression of RV-cyclin in the HCT116 colon cancer cell line significantly increases the level of IEG expression in response to serum stimulation. Quantitative reverse transcription-PCR (RT-PCR) and nuclear run-on assays provide evidence that RV-cyclin does not alter the initiation of IEG transcription but does enhance the overall rate of transcription elongation and maintains transcription reinitiation. RV-cyclin does not increase activating phosphorylation events in the mitogen-activated protein kinase pathway and does not inhibit decay of IEG mRNAs. At the EGR1 gene locus, RV-cyclin increases and maintains RNA polymerase II (Pol II) occupancy after serum stimulation, in conjunction with increased and extended EGR1 gene expression. The RV-cyclin increases CDK8 occupancy at the EGR1 gene locus before and after serum stimulation. Both of RV-cyclin's functional domains, i.e., the cyclin box and the activation domain, are necessary for the overall enhancement of IEG expression. RV-cyclin presents a novel and ancient mechanism of retrovirus-induced oncogenesis. IMPORTANCE: The data reported here are important to both virology and cancer biology. The novel mechanism pinpoints CDK8 in the development of walleye dermal sarcoma and sheds light on CDK8's role in many human cancers. CDK8 controls expression from highly regulated genes, including the interferon stimulated genes. Its function is likely the target of many viral interferon resistance mechanisms. CDK8 also controls cellular responses to metabolic stimuli, stress, and hypoxia, in addition to the serum response. The retroviral cyclin (RV-cyclin) represents a highly selected probe of CDK8 function. RV-cyclin does not control CDK8 specificity but instead enhances CDK8's effects on regulated genes, an important distinction for its use to delineate natural CDK8 targets. The outcomes of this research are applicable to investigations of normal and abnormal CDK8 functions. The mechanisms defined here will contribute directly to the dermal sarcoma model in fish and clarify an important path for oncogenesis and innate resistance to viruses. PMID- 25741013 TI - Ebola virus VP35 interaction with dynein LC8 regulates viral RNA synthesis. AB - Ebola virus VP35 inhibits alpha/beta interferon production and functions as a viral polymerase cofactor. Previously, the 8-kDa cytoplasmic dynein light chain (LC8) was demonstrated to interact with VP35, but the functional consequences were unclear. Here we demonstrate that the interaction is direct and of high affinity and that binding stabilizes the VP35 N-terminal oligomerization domain and enhances viral RNA synthesis. Mutational analysis demonstrates that VP35 interaction is required for the functional effects of LC8. PMID- 25741015 TI - Reduction of aflatoxin production by Aspergillus flavus and Aspergillus parasiticus in interaction with Streptomyces. AB - The aim of this study is to investigate aflatoxin gene expression during Streptomyces-Aspergillus interaction. Aflatoxins are carcinogenic compounds produced mainly by Aspergillus flavus and Aspergillus parasiticus. A previous study has shown that Streptomyces-A. flavus interaction can reduce aflatoxin content in vitro. Here, we first validated this same effect in the interaction with A. parasiticus. Moreover, we showed that growth reduction and aflatoxin content were correlated in A. parasiticus but not in A. flavus. Secondly, we investigated the mechanisms of action by reverse-transcriptase quantitative PCR. As microbial interaction can lead to variations in expression of household genes, the most stable [act1, betatub (and cox5 for A. parasiticus)] were chosen using geNorm software. To shed light on the mechanisms involved, we studied during the interaction the expression of five genes (aflD, aflM, aflP, aflR and aflS). Overall, the results of aflatoxin gene expression showed that Streptomyces repressed gene expression to a greater level in A. parasiticus than in A. flavus. Expression of aflR and aflS was generally repressed in both Aspergillus species. Expression of aflM was repressed and was correlated with aflatoxin B1 content. The results suggest that aflM expression could be a potential aflatoxin indicator in Streptomyces species interactions. Therefore, we demonstrate that Streptomyces can reduce aflatoxin production by both Aspergillus species and that this effect can be correlated with the repression of aflM expression. PMID- 25741017 TI - A coming disruption in pharmacy? PMID- 25741018 TI - Time for consensus on a new approach for assessments. PMID- 25741016 TI - The membrane protein PrsS mimics sigmaS in protecting Staphylococcus aureus against cell wall-targeting antibiotics and DNA-damaging agents. AB - Staphylococcus aureus possesses a lone extracytoplasmic function (ECF) sigma factor, sigma(S). In Bacillus subtilis, the ECF sigma factor, sigma(W), is activated through a proteolytic cascade that begins with cleavage of the RsiW anti-sigma factor by a site-1 protease (S1P), PrsW. We have identified a PrsW homologue in S. aureus (termed PrsS) and explored its role in sigma(S) regulation. Herein, we demonstrate that although a cognate sigma(S) anti-sigma factor currently remains elusive, prsS phenocopies sigS in a wealth of regards. Specifically, prsS expression mimics the upregulation observed for sigS in response to DNA-damaging agents, cell wall-targeting antibiotics and during ex vivo growth in human serum and murine macrophages. prsS mutants also display the same sensitivities of sigS mutants to the DNA-damaging agents methyl methane sulfonate (MMS) and hydrogen peroxide, and the cell wall-targeting antibiotics ampicillin, bacitracin and penicillin-G. These phenotypes appear to be explained by alterations in abundance of proteins involved in drug resistance (Pbp2a, FemB, HmrA) and the response to DNA damage (BmrA, Hpt, Tag). Our findings seem to be mediated by putative proteolytic activity of PrsS, as site-directed mutagenesis of predicted catalytic residues fails to rescue the sensitivity of the mutant to H2O2 and MMS. Finally, a role for PrsS in S. aureus virulence was identified using human and murine models of infection. Collectively, our data indicate that PrsS and sigma(S) function in a similar manner, and perhaps mediate virulence and resistance to DNA damage and cell wall-targeting antibiotics, via a common pathway. PMID- 25741019 TI - Pharmacy education in the Palestinian territories. PMID- 25741020 TI - Recommendations for the successful pursuit of scholarship by pharmacy practice faculty members. AB - Scholarship has long been a basic expectation of faculty members at institutions of higher learning in the United States and elsewhere. This expectation is no less assumed in academic pharmacy. A number of organizations have verbalized and enforced this precept over the years.(1-3) For example, this expectation is spoken to directly in the American Council for Pharmacy Education's Accreditation Standards and Guidelines.(4) This expectation is further emphasized in the draft document of the accreditation standards to be implemented in 2016, in Standard 20. Specifically, Element 20.2 states: "The college or school must create an environment that both requires and promotes scholarship, and must also develop mechanisms to assess both the quantity and quality of faculty scholarly productivity."(5) The successful pursuit of scholarship by clinical faculty members (those engaged in both clinical practice and teaching, without regard to tenure or clinical track status) is challenging. (6-10) Thus, faculty member job descriptions or models should be designed so clinical faculty members can successfully meet all academic job expectations, including productive and meaningful scholarship. In 2012, an AACP Section of Teachers of Pharmacy Practice task force was charged with examining this issue and providing recommendations for models for clinical faculty members that would allow the successful pursuit of scholarship. The task force gathered information relating to the current state of affairs at a number of colleges and reviewed relevant literature. This information, along with personal experiences and much discussion and contemplation, led to some general observations as well as specific recommendations. This paper reiterates the task force's observations and recommendations and provides further detail regarding our interpretation of the findings and basis for the eventual recommendations to the section. PMID- 25741021 TI - Effect of an experiential exercise in diabetes management on pharmacy students' fear and perceived pain of injection and fingertip lancing. AB - OBJECTIVE: To determine if a diabetes management exercise would change pharmacy students' fear and perceived pain associated with injection and fingertip lancing. METHODS: Before and after a 1-week experiential exercise of living with diabetes, students completed questionnaires measuring fear of injection and self testing and recorded the level of perceived pain associated with injection and fingertip lancing. Anticipated (baseline) and experienced (follow-up) scores were compared. RESULTS: Forty students returned both baseline and follow-up survey instruments. Reported levels of fear decreased significantly for self-injection (p<0.0001) and self-testing (p=0.0089) after the exercise. Experienced pain was also significantly lower than anticipated pain for both injection (p<0.0001) and fingertip lancing (p=0.013). Experienced pain of injection was significantly lower than fingertip lancing (p=0.017). CONCLUSION: Participation in the exercise significantly reduced pharmacy students' fear and perceived pain associated with injection and fingertip lancing. Students can use information gained from their experiences when helping patients manage diabetes. PMID- 25741022 TI - A qualitative analysis of common concerns about challenges facing pharmacy experiential education programs. AB - OBJECTIVE: To qualitatively analyze free-text responses gathered as part of a previously published survey in order to systematically identify common concerns facing pharmacy experiential education (EE) programs. METHODS: In 2011, EE directors at all 118 accredited pharmacy schools in the US were asked in a survey to describe the most pressing issues facing their programs. Investigators performed qualitative, thematic analysis of responses and compared results against demographic data (institution type, class size, number of practice sites, number and type of EE faculty member/staff). Expert and novice investigators identified common themes via an iterative process. To check validity, additional expert and novice reviewers independently coded responses. The Cohen kappa coefficient was calculated and showed good agreement between investigators and reviewers. RESULTS: Seventy-eight responses were received (66% response rate) representing 75% of publicly funded institutions and 71% of schools with class sizes 51-150. Themes identified as common concerns were site capacity, workload/financial support, quality assurance, preceptor development, preceptor stipends, assessment, onboarding, and support/recognition from administration. Good agreement (mean percent agreement 93%, k range=0.59-0.92) was found between investigators and reviewers. CONCLUSION: Site capacity for student placements continues to be the foremost concern for many experiential education programs. New concerns about preceptor development and procedures for placing and orienting students at individual practice sites (ie, "onboarding") have emerged and must be addressed as new accreditation standards are implemented. PMID- 25741023 TI - What secondary school career advisors in New Zealand Know about pharmacy and how that knowledge affects student career choices. AB - OBJECTIVE: To explore what career advisors at secondary schools (high schools) in New Zealand know about the pharmacy profession, how they obtain that knowledge, and what their potential influence is on students' decisions to study pharmacy. METHODS: This study employed a cross sectional questionnaire design. A postal questionnaire was sent to 250 randomly selected secondary schools in New Zealand. RESULTS: The response rate was 112/248 (45%). Responding career advisors were familiar with many of the roles of pharmacists (mean knowledge score 11.5 out of 16). Over 90% of career advisors were familiar with the roles of pharmacists in the community setting; however, many had a poorer understanding of other pharmacist roles. One suggestion for improving the promotion of pharmacy within secondary schools was a greater involvement of pharmacists and pharmacy students in the promotion of pharmacy as a profession. CONCLUSION: Career advisors need a broader understanding of the potential roles of pharmacists. Increasing contact from practicing pharmacists and undergraduate pharmacy students are potential ways of increasing student interest in pharmacy. PMID- 25741024 TI - An analysis of motivation factors for students' pursuit of leadership positions. AB - OBJECTIVE: To identify factors that influence student involvement and leadership within organizations and to assess the impact of involvement in organizations on professional skill development. METHODS: A printed survey was administered to fourth-year pharmacy students at one college of pharmacy (N=202). RESULTS: Most students (82%) indicated they were involved in at least one organization during pharmacy school and 58% reported holding a leadership position at some point. Factors with the largest impact on involvement in organizations were desire to present a well-rounded image to employers, ability to network, and interest in the activities sponsored by the organization. Involvement in professional organizations had a strong influence on their leadership, teamwork, confidence, and time-management skills. CONCLUSION: That presenting a well-rounded image to employers and having the ability to network with mentors and peers drove student involvement in professional organizations may be reflective of increasing competition for residencies and jobs. PMID- 25741025 TI - Sleep quality among pharmacy students. AB - OBJECTIVE: To determine the quality of sleep among pharmacy students in the didactic portion of the curriculum at one school of pharmacy. METHODS: The study consisted of an anonymous, voluntary survey that included the Pittsburgh Sleep Quality Index (PSQI), a self-rated instrument that measures sleep habits for a month. RESULTS: The survey was completed by 253 students. Students in the lower grade point average (GPA) category had higher scores on 2 of 7 components of the PSQI and on the global score. Poor sleep quality, indicated by a global PSQI score of greater than 5, was reported by 140 students. The rate of poor sleeping was higher among students in the lower GPA category. CONCLUSION: Poor sleep quality was pervasive among surveyed pharmacy students in the didactic portion of the pharmacy school curriculum, especially among those with lower GPAs. PMID- 25741026 TI - Alignment of learning objectives and assessments in therapeutics courses to foster higher-order thinking. AB - OBJECTIVE: To determine whether national educational outcomes, course objectives, and classroom assessments for 2 therapeutics courses were aligned for curricular content and cognitive processes, and if they included higher-order thinking. METHOD: Document analysis and student focus groups were used. Outcomes, objectives, and assessment tasks were matched for specific therapeutics content and cognitive processes. Anderson and Krathwohl's Taxonomy was used to define higher-order thinking. Students discussed whether assessments tested objectives and described their thinking when responding to assessments. RESULTS: There were 7 outcomes, 31 objectives, and 412 assessment tasks. The alignment for content and cognitive processes was not satisfactory. Twelve students participated in the focus groups. Students thought more short-answer questions than multiple choice questions matched the objectives for content and required higher-order thinking. CONCLUSION: The alignment analysis provided data that could be used to reveal and strengthen the enacted curriculum and improve student learning. PMID- 25741027 TI - Process-oriented guided inquiry learning strategy enhances students' higher level thinking skills in a pharmaceutical sciences course. AB - OBJECTIVE: To determine if the process-oriented guided inquiry learning (POGIL) teaching strategy improves student performance and engages higher-level thinking skills of first-year pharmacy students in an Introduction to Pharmaceutical Sciences course. DESIGN: Overall examination scores and scores on questions categorized as requiring either higher-level or lower-level thinking skills were compared in the same course taught over 3 years using traditional lecture methods vs the POGIL strategy. Student perceptions of the latter teaching strategy were also evaluated. ASSESSMENT: Overall mean examination scores increased significantly when POGIL was implemented. Performance on questions requiring higher-level thinking skills was significantly higher, whereas performance on questions requiring lower-level thinking skills was unchanged when the POGIL strategy was used. Student feedback on use of this teaching strategy was positive. CONCLUSION: The use of the POGIL strategy increased student overall performance on examinations, improved higher-level thinking skills, and provided an interactive class setting. PMID- 25741028 TI - Retention of advanced cardiac life support knowledge and skills following high fidelity mannequin simulation training. AB - OBJECTIVE: To assess pharmacy students' ability to retain advanced cardiac life support (ACLS) knowledge and skills within 120 days of previous high-fidelity mannequin simulation training. DESIGN: Students were randomly assigned to rapid response teams of 5-6. Skills in ACLS and mannequin survival were compared between teams some members of which had simulation training 120 days earlier and teams who had not had previous training. ASSESSMENT: A checklist was used to record and assess performance in the simulations. Teams with previous simulation training (n=10) demonstrated numerical superiority to teams without previous training (n=12) for 6 out of 8 (75%) ACLS skills observed, including time calculating accurate vasopressor infusion rate (83 sec vs 113 sec; p=0.01). Mannequin survival was 37% higher for teams who had previous simulation training, but this result was not significant (70% vs 33%; p=0.20). CONCLUSION: Teams with students who had previous simulation training demonstrated numerical superiority in ACLS knowledge and skill retention within 120 days of previous training compared to those who had no previous training. Future studies are needed to add to the current evidence of pharmacy students' and practicing pharmacists' ACLS knowledge and skill retention. PMID- 25741029 TI - Integrating a new medicinal chemistry and pharmacology course sequence into the PharmD curriculum. AB - OBJECTIVE: To evaluate the implementation of an integrated medicinal chemistry/pharmacology course sequence and its alignment with a therapeutics series. DESIGN: Each topic was divided into modules consisting of 2-hour blocks, and the content was integrated and aligned with the therapeutics series. Recitation sessions emphasizing application skills in an interactive environment followed each of three 2-hour blocks. To ensure that students achieved competency in each unit, students failing any unit examination were encouraged to undergo remediation. ASSESSMENT: Student feedback was collected by an independent researcher through social media and focus groups and relayed anonymously to course directors for midcourse improvements. Responses from surveys, interviews, and student ratings of faculty members and of courses were used to implement changes for future editions of the courses. CONCLUSION: The majority of students and faculty members felt the integration and alignment processes were beneficial changes to the curriculum. Elements of the new sequence, including remediation, were viewed positively by students and faculty members as well. PMID- 25741030 TI - Staging a reflective capstone course to transition PharmD graduates to professional life. AB - OBJECTIVE: To develop and implement a capstone course that would allow students to reflect on their development as a professional, assess and share their achievement of the college's outcomes, complete a professional portfolio, establish a continuing professional development plan, and prepare to enter the pharmacy profession. DESIGN: Students were required to complete a hybrid course built around 4 online and inclass projects during the final semester of the curriculum. ASSESSMENT: Faculty used direct measures of learning, such as reading student portfolios and program outcome reflections, evaluating professional development plans, and directly observing each student in a video presentation. All projects were evaluated using standardized rubrics. Since 2012, all graduating students met the course's minimum performance requirements. CONCLUSION: The course provided an opportunity for student-based summative evaluation, direct observation of student skills, and documentation of outcome completion as a means of evaluating readiness to enter the profession. PMID- 25741031 TI - Effectiveness of educational technology to improve patient care in pharmacy curricula. AB - A review of the literature on the effectiveness of educational technologies to teach patient care skills to pharmacy students was conducted. Nineteen articles met inclusion criteria for the review. Seven of the articles included computer aided instruction, 4 utilized human-patient simulation, 1 used both computer aided instruction and human-patient simulation, and 7 utilized virtual patients. Educational technology was employed with more than 2700 students at 12 colleges and schools of pharmacy in courses including pharmacotherapeutics, skills and patient care laboratories, drug diversion, and advanced pharmacy practice experience (APPE) orientation. Students who learned by means of human-patient simulation and virtual patients reported enjoying the learning activity, whereas the results with computer-aided instruction were mixed. Moreover, the effect on learning was significant in the human-patient simulation and virtual patient studies, while conflicting data emerged on the effectiveness of computer-aided instruction. PMID- 25741032 TI - Sexual Partners of Street-Based Female Sex Workers in St. Petersburg, Russia: A Model of Partnership Characteristics as a Basis for Further Research. AB - Street-based sex work in Russia, as in many countries, carries with it a high risk for violence and the transmission of infectious diseases. The male partners of female sex workers are both cause and recipient of such risks. Because little is known about the men, we undertook a preliminary study to determine the feasibility of recruiting and interviewing them, develop typologies that describe partners, and derive hypotheses for further study and risk reduction intervention projects. We were able to conduct open-ended, qualitative interviews with street based sex workers and, largely through these contacts, their male partners. To these data, we added interviews with social work and medical experts who engage with the sex workers. The text of interviews from 37 respondents were analyzed to identify commonly mentioned partner characteristics in five distinct domains: sociodemographics, behavioral patterns of the partners, motivations in seeking sex services, levels of partner engagement with the sex workers, and the social circumstances that moderate the engagement. Four of the five domains (all but sociodemographics) proved useful in identifying typologies that were best described as populated points in a matrix generated from the intersection of the four domains. The data were too limited to specify which of the points in the matrix are most common, but the points populated are useful in generating hypotheses for further study and in identifying potential avenues for risk reduction interventions. PMID- 25741033 TI - METABOLISM OF IRON STORES. AB - Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis. Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953. However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia). We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order (1) labile iron, (2) ferritin and (3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes. We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal. In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects. PMID- 25741034 TI - Hypertension-related knowledge, practice and drug adherence among inpatients of a hospital in samarkand, uzbekistan. AB - Hypertension is one of the most important preventable causes of premature morbidity and mortality in the world. Many people with hypertension both in developing and developed countries have no adequate control of their blood pressure (BP). Hypertension-related knowledge and practice of patients play an important role in controlling hypertension and in preventing its long-term complications. The objective here was to study hypertension-related knowledge, practice and drug adherence of inpatients, and to examine an association between the knowledge regarding hypertension with BP control status and drug adherence. We studied hypertension-related knowledge, practice and drug adherence of patients in a hospital setting. A cross-sectional study was conducted among 209 patients with the diagnosis of primary hypertension at the Samarkand State Medical Institute. The study was conducted from June to September 2012. Drug adherence was studied using the Morisky 4-item self-report measure of medication taking behavior. The reasons for drug non-adherence were assessed using a self administered questionnaire. Odds ratio (OR) and 95% confidence interval (CI) were estimated by a logistic model. The BP control rate and drug adherence of the patients were suboptimal (24.4% and 36.8%, respectively). Overall, 64.6% of patients had good or adequate and 35.5% had inadequate knowledge about hypertension. Good knowledge of patients was significantly associated with controlled BP (OR=5.4, 95% CI, 1.7-16.2) and drug adherence (OR=3.8, 95% CI, 1.4 10.8). In conclusion, the inpatients of the secondary hospital had sufficient general knowledge about hypertension, but they had inadequate knowledge about specific issues such as treatment for and symptoms of hypertension. Both drug adherence and BP control rate were suboptimal and significantly associated with hypertension knowledge. This study specifies potential areas of hypertension education that could be improved by patients' knowledge of hypertension. PMID- 25741035 TI - Cardiac counterclockwise rotation is a risk factor for high-dose irradiation to the left anterior descending coronary artery in patients with left-sided breast cancer who receiving adjuvant radiotherapy after breast-conserving surgery. AB - Patients irradiated for left-sided breast cancer have higher incidence of cardiovascular disease than those receiving irradiation for right-sided breast cancer. Most abnormalities were in the left anterior descending (LAD) coronary artery territory. We analyzed the relationships between preoperative examination results and irradiation dose to the LAD artery in patients with left-sided breast cancer. Seventy-one patients receiving breast radiotherapy were analyzed. The heart may rotate around longitudinal axis, showing either clockwise or counterclockwise rotation (CCWR). On electrocardiography, the transition zone (TZ) was judged in precordial leads. CCWR was considered to be present if TZ was at or to the right of V3. The prescribed dose was 50 Gy in 25 fractions. The maximum (Dmax) and mean (Dmean) doses to the LAD artery and the volumes of the LAD artery receiving at least 20 Gy, 30 Gy and 40 Gy (V20Gy, V30Gy and V40Gy, respectively) were significantly higher in CCWR than in the non-CCWR patients. On multivariate analysis, TZ was significantly associated with Dmax, Dmean, V20Gy, V30Gy, and V40Gy. CCWR is a risk factor for high-dose irradiation to the LAD artery. Electrocardiography is useful for evaluating the cardiovascular risk of high-dose irradiation to the LAD artery. PMID- 25741036 TI - Undergraduate nursing education to address patients' concerns about sexual health: the perceived learning needs of senior traditional four-year and two-year recurrent education (rn-bsn) undergraduate nursing students in taiwan. AB - The aims of this study were to identify learning needs among traditional four year and two-year recurrent education (RN-BSN) undergraduate nursing students in Taiwan with regard to patients' concerns about sexual health. A 24-item instrument (Learning Needs for Addressing Patients' Sexual Health Concerns) was used to collect data. Compared to RN-BSN undergraduate nursing students, traditional four-year undergraduate nursing students had more learning needs in the aspects of sexuality in health and illness (2.19 +/- 0.66 vs. 1.80 +/- 0.89, P = 0.005) and approaches to sexual health care (2.03 +/- 0.72 vs. 1.76 +/- 0.86, P = 0.033). After adjustment for other variables by the backward selection approach, those with experience in assessing patient's sexual functioning had fewer learning needs in sexuality in health and illness (beta = -0.375, P = 0.001), communication about patient's intimate relationships (beta = -0.242, P = 0.031), and approaches to sexual health care (beta = -0.288, P = 0.013); those who agreed that sexual health care was a nursing role also expressed greater needs to learn about these 3 aspects (all P < 0.01). Content related to sexuality in health and illness and approaches to sexual health care should be strengthened in the traditional undergraduate nursing curriculum in order to support sexual health related competence, build a positive attitude regarding sexual health care as a nursing role, and strengthen the experience of assessing patient's sexual functioning. A different, simplified program may be more suitable for those with clinical experience. PMID- 25741037 TI - Visualization of brain white matter tracts using heavily t2-weighted three dimensional fluid-attenuated inversion-recovery magnetic resonance imaging. AB - The purpose of this study was to elucidate which white matter (WM)-tracts are visualized on heavily T2-weighted three-dimensional fluid-attenuated inversion recovery (hT2w-3D-FLAIR) images. Records of seven patients who underwent hT2w-3D FLAIR and diffusion tensor imaging (DTI) of the head at 3 Tesla were analyzed. Two neuroradiologists determined WM-tracts visualized on hT2w-3D-FLAIR and identified anatomical points through which they ran. A third neuroradiologist determined the WM-tracts running through those points on DTI. Correspondence between hT2w-3D-FLAIR and DTI WM-tracts was used to confirm technique validity. As a result, the corticospinal tract (CST), medial lemniscus (ML), and superior cerebellar peduncle (SCP) were visualized as high intensity on hT2w-3D-FLAIR and ran through the following points: CST, 20 mm lateral from the lateral margin of the third ventricle at the thalamic level; ML, 6 mm anterior to the anterior margin of the fourth ventricle at the trigeminal nerve level; and SCP, just lateral to the fourth ventricle at the trigeminal nerve level. The third neuroradiologist determined that the WM-tracts ran through those points on DTI in all patients. Consequently, WM-tracts determined on hT2w-3D-FLAIR and DTI completely corresponded. In conclusion, the CST, ML, and SCP were visualized as high intensity on hT2w-3D-FLAIR. This technique is a potentially supplemental DTI neurographic modality. PMID- 25741038 TI - Rhof promotes murine marginal zone B cell development. AB - RhoF is a member of the Rho GTPase family that has been implicated in various cell functions including long filopodia formation, adhesion, and migration of cells. Although RhoF is expressed in lymphoid tissues, the roles of RhoF in B cell development remain largely unclear. On the other hand, other members of the Rho GTPase family, such as Cdc42, RhoA, and Rac, have been intensively studied and are known to be required for B cell development in the bone marrow and spleen. We hypothesized that RhoF is also involved in B cell development. To examine our hypothesis, we analyzed B cell development in RhoF knockout (KO) mice and found a significant reduction in marginal zone (MZ) B cells in the spleen, although T cell development in the thymus and spleen was not affected. Consistent with these results, the width of the MZ B cell region in the spleen was significantly reduced in the RhoF KO mice. However, the antigen-specific antibody titer of IgM and IgG3 after MZ B cell-specific antigen (T cell-independent antigen, type I) stimulation was not affected by RhoF deletion. Furthermore, we demonstrated that RhoF was dispensable for stromal cell-derived factor-1alpha- and B lymphocyte chemoattractant-induced B cell migration. These results suggest that RhoF promotes MZ B cell development in the spleen. PMID- 25741039 TI - Combined posterior-anterior surgery for osteoporotic delayed vertebral fracture with neurologic deficit. AB - With the aging of society, osteoporotic thoracolumbar compression fracture is a concern. This fracture occurs occasionally; however, some cases progress to neural compromise due to delayed vertebral body collapse requiring surgery. Surgical treatment and postoperative care are difficult because of patients' serious comorbidities and poor bone quality, and hence, optimum treatment is not clear, even though some surgical approaches have been reported. There were 35 consecutive patients (5 males and 30 females) with osteoporotic delayed vertebral fractures and associated neurological deficit. Mean age at surgery was 70.7 years (range 60-84 years). Average postoperative follow-up was 3.8 years (range 0.6 11.3 years). All patients experienced a single vertebra collapse, except for 1 with a 2-level collapse of lumbar vertebrae. One thoracic (Th7), 19 thoracolumbar (Th12-L1), and 16 lumbar (L2-5) fractures were treated with combined posterior anterior surgery. The American Spinal Injury Association (ASIA) impairment scale, activities of daily living (ADL) status, and local sagittal angle were evaluated both before and after surgery. Forty-six percent of all patients showed an improvement of more than 1 grade postoperatively on the ASIA impairment scale, and 74% demonstrated an improvement in ADL status. No deterioration was observed in neurological or ADL status after surgery. With regard to sagittal alignment, preoperative kyphosis of 18.4 degrees was corrected to 2.4 degrees of kyphosis postoperatively. However, 11.5 degrees loss of correction was observed at final follow-up observation. Combined posterior-anterior surgery could provide reliable improvement in both neurological and ADL status, although maintenance of postoperative alignment was difficult to achieve in some cases. PMID- 25741040 TI - An awareness survey of surgeons involved in breast cancer treatment regarding their patients returning to work. AB - Surgeons focus on the period of absence from work during the initial treatment of breast cancer. The aim of this study was to determine surgeons' perceptions and awareness regarding the necessary period of absence from work during breast cancer treatment. We created a questionnaire for all surgeons involved in breast cancer treatment who are affiliated with the Department of Surgery at the Nagoya University Graduate School of Medicine and its associated facilities. The necessary leave of absence period for each treatment was considered, and the decision regarding whether patients should return to work was examined. The surgeons were instructed to assume that a 'heavy load worker' was a nurse or caregiver and that a 'light load worker' was a medical office worker. This study included 184 surgeons (response rate: 96.8%). More than half of the surgeons considered that light load workers could return to work within 2 weeks; 89.8% after conservative resection, 71.6% after total mastectomy, 50.3% after axillary dissection. In contrast, more than half of the surgeons considered that heavy load worker should wait returning to work more than 3 weeks; 49.4% after conservative resection, 73.3% after total mastectomy, 85.7% after axillary dissection. For patients treated with chemotherapy, three-quarters of the surgeons indicated that it would be difficult to work while receiving anthracycline regimens. The results suggest that surgeons can predict the approximate period of absence from work for patients who receive an initial treatment of breast cancer. PMID- 25741041 TI - Involvement of glial activation in trigeminal ganglion in a rat model of lower gingival cancer pain. AB - Glial cells were investigated to elucidate their involvement in mechanisms underlying oral cancer pain. Squamous cell carcinoma (SCC-158) was inoculated into the lower gingiva of male Fisher rats. Pharmacological and immunohistochemical studies were performed to examine the roles played by TRPV1 and TRPV2 expressed in neurons and satellite glia in trigeminal ganglia (TG), and microglia and astrocytes in trigeminal spinal nucleus caudalis. Inoculation of SCC-158 into the lower gingiva induced marked mechanical allodynia in the whisker pad skin area on days 16 through 28, and in the submandibular skin area on days 10 through 20. Cutaneous allodynia was diminished by systemic morphine administration. The number of TRPV1 and TRPV2-positive neurons in trigeminal ganglia increased in the medium and large cell groups on day 14 after tumor inoculation. The number of satellite glial cells encircling the medium and large trigeminal ganglion neurons increased on day 28 after tumor inoculation. In this gingival cancer pain model, microglia and astrocytes in trigeminal spinal nucleus caudalis were not activated, although they were reported to be activated in neuropathic and inflammatory pain models. These results suggest that TRPV1 and TRPV2 upregulation in trigeminal ganglion neurons may play an important role in inducing the mechanical allodynia observed in experimental models of oral squamous cell carcinoma. In addition, activation of satellite cells seems to be involved in the maintenance of mechanical allodynia, which could be the potential therapeutic target for oral cancer pain. PMID- 25741042 TI - ASSOCIATIONS BETWEEN BODY MASS INDEX AND SERUM URIC ACID LEVELS IN A JAPANESE POPULATION WERE SIGNIFICANTLY MODIFIED BY LRP2 rs2544390. AB - The genome-wide association study identified associations between the LRP2 polymorphism rs2544390 and serum uric acid (SUA) levels in a Japanese population. Our previous study on the LRP2 rs2544390 polymorphism identified an interaction between SUA and alcohol consumption. Here, we investigated an interaction with body mass index (BMI) using the same dataset. Subjects were 3,742 health checkup examinees (2,544 males and 1,198 females) aged 35-69 years. Those with the SLC22A12 258WW genotype, SLC2A9 rs11722228 C allele, and ABCG2 126QQ genotype and 141Q allele were selected for analysis to remove the strong influences of these genetic traits. In males, the odds ratio of BMI >=25.0 relative to BMI <18.5 for hyperuricemia (SUA >=7 mg/dL and/or under medication for hyperuricemia) was 6.58 (95% confidence interval [CI], 0.84-51.32) for CC, 10.08 (2.38-42.83) for CT, and 2.53 (0.54-11.78) for TT. The interaction was 0.59 (p=0.029) from the model including BMI (<25.0 and >=25.0), genotype (CC/CT and TT), and the multiplicative interaction term between BMI >=25.0 and the TT genotype. In females, the odds ratio of BMI >=25.0 relative to BMI <18.5 for high SUA (>=5 mg/dL and/or under medication for hyperuricemia) was 6.35 (95%CI, 1.68-24.08) for CC, 4.55 (1.85 11.18) for CT, and 5.93 (1.97-17.90) for TT. The interaction term was significant in the opposite direction for females (OR=2.75, p=0.011). The association between BMI and SUA was therefore modified by the LRP2 polymorphism in this Japanese population. PMID- 25741043 TI - The surgical treatment method for an adult posttraumatic thoracolumbar kyphosis patient with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is an inheritable bone disorder characterized by osseous fragility and ligamentous laxity. It is sometimes difficult to obtain bone union in patients with OI. The purpose of this report is to present a rare case of posttraumatic kyphosis due to a L1 burst fracture in a patient with OI, and to discuss how to treat it to achieve an adequate correction and circumferential fusion. The patient was a 29-year-old man with OI (Sillence type IA) who had sustained an L1 fracture when he dived head first into a river. After 3 months of conservative therapy with a body cast, he showed disability at work because of his persistent low back pain and fatigue in his whole back. He showed no neurological disorder. Diagnostic imaging revealed localized kyphotic deformity at L1. Therefore, lumbar lordosis and thoracic kyphosis worsened. Anterior release and fusion, and posterior fusion were conducted. Three months after surgical treatment, circumferential fusion was obtained. His low back pain and fatigue in the whole back disappeared, and he could resume work without any difficulty. From the bone union standpoint, the surgical strategy for spinal correction in OI patients is still controversial because of the intractableness of bone union and fragility of the bone itself. The authors achieved circumferential union using anterior fusion and posterior fusion, in which wide bone bed is available owing to spared posterior elements of the spinal column. PMID- 25741044 TI - Primary cauda equina lymphoma: case report and literature review. AB - The central nervous system, in particular the spinal cord, is a rare site for primary lymphoma occurrence, with very few published cases. We report an extremely rare primary lymphoma in the cauda equina in a single case with literature review. An immunocompetent 59-year-old male, who complained of progressive low back and bilateral leg pain for 7 months, was studied. Magnetic resonance imaging (MRI) revealed an intradural space-occupying lesion from T12 to S1, poorly demarcated to the normal cauda equina. The intradural lesion showed T1 low intensity, T2 low isointensity, and marked homogeneous enhancement with gadolinium-diethylenetriaminepentaacetic acid on MRI. We performed spinal tap to obtain additional information about the intradural lesion. Large-sized atypical lymphoid cells were found during pathological examination. Fluorodeoxyglucose accumulation was found only in the lumbar area, which corresponded with the MRI findings, and the primary lymphoma site was defined as the cauda equina area. For further detailed pathological diagnosis, we performed surgical biopsy of the cauda equina. Morphological and immunohistochemical assessment made a diagnosis of diffuse large B-cell lymphoma of the cauda equina. The patient received radiotherapy to the lumbosacral area (50 Gy) and methotrexate (MTX) therapy after surgery. The patient was able to walk without help after the therapies. Follow-up MRI performed 1 year after biopsy showed remission of the lesion. MRI and spinal tap were effective tools for the early definitive diagnosis of cauda equina lymphoma. Combined treatment with radiotherapy and MTX should be performed as early as possible. PMID- 25741045 TI - A rare case of middle ear adenoma. AB - Middle ear adenoma is a rare disease that is thought to originate in the middle ear mucosa. It occurs over a wide age range, has no gender predilection, and is not characterized by specific symptoms or findings. The most frequent complaints are unilateral hearing loss and ear fullness. We report a 48-year-old woman with middle ear adenoma who had a history of unilateral ear fullness and hearing loss on the left side. Middle ear adenoma was suspected following a biopsy performed under local anesthesia. To remove the tumor, the patient underwent a left postauricular canal wall-up tympanoplasty type IIIc. Microscopic examination and immunohistochemistry confirmed a middle ear adenoma. In this case, we diagnosed the lesion as middle ear adenoma with neuroendocrine differentiation on the basis of the pathological findings. The patient has shown no recurrence for almost 5 years, but since this adenoma showed neuroendocrine differentiation, long-term observation is required. PMID- 25741046 TI - Limbic encephalitis associated with relapsing polychondritis responded to infliximab and maintained its condition without recurrence after discontinuation: a case report and review of the literature. AB - Central nervous system (CNS) manifestations are rare complications of relapsing polychondritis (RP). The majority of patients respond well to glucocorticoid therapy, but need to maintain it. Some patients are refractory to initial glucocorticoid therapy and to additional immunosuppressants, and end up with an outcome worse than at therapy initiation. The standardized therapeutic protocol for this condition has not been established. The effects of anti-tumor necrosis factor (TNF) -alpha agents have been reported recently. We experienced a patient with RP and limbic encephalitis who was refractory to initial high-dose glucocorticoid, but subsequently responded to infliximab and did not show deterioration of signs and symptoms after stopping therapy. We report this case together with a systematic literature review. This is the first case report of RP with CNS manifestations successfully treated by an anti-TNF-alpha agent without recurrence after discontinuation. PMID- 25741047 TI - Three cases with active bleeding from radiation enteritis that were diagnosed with video capsule endoscopy without retention. AB - Endoscopic exploration of the small bowel after pelvic radiation has limitations related to strong abdominal adhesion. It is often difficult to demonstrate the findings of radiation enteritis endoscopically, even with video capsule endoscopy (VCE) or double-balloon enteroscopy (DBE). We present our experience with three cases of radiation enteritis that were diagnosed using VCE and DBE, including their effective aspects. Radiation enteritis has not been diagnosed using conventional methods, and DBE may not accomplish deeper insertion into the ileum, although it is capable of both diagnosis and hemostasis. Therefore, VCE is thought to be the initial tool for the diagnosis of radiation enteritis when small bowel stenosis has not been previously detected and the risk of retention has been discussed. PMID- 25741048 TI - Full-thickness small intestine necrosis with midgut volvulus, distributed in a patchy fashion, is reversible with moderate blood flow: resumption of normal function to non-viable intestine. AB - Midgut volvulus is a highly life-threatening condition that carries a high risk of short gut syndrome. We report a case of catastrophic neonatal midgut volvulus in which second-look laparotomy revealed apparently non-viable remnant small intestine but with a moderate blood supply. Full-thickness small intestine necrosis was distributed in a patchy fashion, with non-viable and necrotic areas distributed so widely that no portion of the intestine could be resected. A section of full-thickness necrotic intestine preserved at surgery was able to regenerate, and normal function was restored over a period of 1 month. This case indicated that intestinal resumption may be dependent on blood flow. Even when intestinal viability is questionable, preservation enables the chance of regeneration if moderate blood flow is present. PMID- 25741049 TI - Impact of Alkyl Polyglucosides Surfactant Lutensol GD 70 on Modification of Bacterial Cell Surface Properties. AB - Alkyl polyglucosides, due to their low toxicity and environmental compatibility, could be used in biodegradation of hydrophobic compounds. In this study, the influence of Lutensol GD 70 on the cell hydrophobicity and zeta potential was measured. The particle size distribution and surfactant biodegradation were also investigated. Microbacterium sp. strain E19, Pseudomonas stutzeri strain 9, and the same strain cultivated in stress conditions were used in studies. Adding surfactant to the diesel oil system resulted in an increase of the cell surface hydrophobicity and the formation of cell aggregates (a high polydispersity index). The correlation between cell hydrophobicity and zeta potential in examined samples was not found. The results showed a significant influence of Lutensol GD 70 on the changes in cell surface properties. Moreover, a high biodegradation of a surfactant (over 50 %) by tested strains was observed. The biodegradation of Lutensol GD 70 depends on the length of both polar and nonpolar chains. A long-term contact with diesel oil of stressed strain modifies not only cell surface properties but also its ability to a surfactant biodegradation. PMID- 25741050 TI - Marine Tar Residues: a Review. AB - Marine tar residues originate from natural and anthropogenic oil releases into the ocean environment and are formed after liquid petroleum is transformed by weathering, sedimentation, and other processes. Tar balls, tar mats, and tar patties are common examples of marine tar residues and can range in size from millimeters in diameter (tar balls) to several meters in length and width (tar mats). These residues can remain in the ocean environment indefinitely, decomposing or becoming buried in the sea floor. However, in many cases, they are transported ashore via currents and waves where they pose a concern to coastal recreation activities, the seafood industry and may have negative effects on wildlife. This review summarizes the current state of knowledge on marine tar residue formation, transport, degradation, and distribution. Methods of detection and removal of marine tar residues and their possible ecological effects are discussed, in addition to topics of marine tar research that warrant further investigation. Emphasis is placed on benthic tar residues, with a focus on the remnants of the Deepwater Horizon oil spill in particular, which are still affecting the northern Gulf of Mexico shores years after the leaking submarine well was capped. PMID- 25741051 TI - Correlation between PET/CT results and histological and immunohistochemical findings in breast carcinomas. AB - OBJECTIVE: To correlate the results of (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) performed with a specific protocol for assessment of breasts with histological/immunohistochemical findings in breast carcinoma patients. MATERIALS AND METHODS: Cross-sectional study with prospective data collection, where patients with biopsy-confirmed breast carcinomas were studied. The patients underwent PET/CT examination in prone position, with a specific protocol for assessment of breasts. PET/CT findings were compared with histological and immunohistochemical data. RESULTS: The authors identified 59 malignant breast lesions in 50 patients. The maximum diameter of the lesions ranged from 6 to 80 mm (mean: 32.2 mm). Invasive ductal carcinoma was the most common histological type (n = 47; 79.7%). At PET/CT, 53 (89.8%) of the lesions demonstrated anomalous concentrations of (18)F-FDG, with maximum SUV ranging from 0.8 to 23.1 (mean: 5.5). A statistically significant association was observed between higher values of maximum SUV and histological type, histological grade, molecular subtype, tumor diameter, mitotic index and Ki 67 expression. CONCLUSION: PET/CT performed with specific protocol for assessment of breasts has demonstrated good sensitivity and was associated with relevant histological/immunohistochemical factors related to aggressiveness and prognosis of breast carcinomas. PMID- 25741052 TI - Complete internal audit of a mammography service in a reference institution for breast imaging. AB - OBJECTIVE: Undertaking of a complete audit of the service of mammography, as recommended by BI-RADS((r)), in a private reference institution for breast cancer diagnosis in the city of Sao Paulo, SP, Brazil, and comparison of results with those recommended by the literature. MATERIALS AND METHODS: Retrospective, analytical and cross-sectional study including 8,000 patients submitted to mammography in the period between April 2010 and March 2011, whose results were subjected to an internal audit. The patients were followed-up until December 2012. RESULTS: The radiological classification of 7,249 screening mammograms, according to BI-RADS, was the following: category 0 (1.43%), 1 (7.82%), 2 (80.76%), 3 (8.35%), 4 (1.46%), 5 (0.15%) and 6 (0.03%). The breast cancer detection ratio was 4.8 cases per 1,000 mammograms. Ductal carcinoma in situ was found in 22.8% of cases. Positive predictive values for categories 3, 4 and 5 were 1.3%, 41.3% and 100%, respectively. In the present study, the sensitivity of the method was 97.1% and specificity, 97.4%. CONCLUSION: The complete internal audit of a service of mammography is essential to evaluate the quality of such service, which reflects on an early breast cancer detection and reduction of mortality rates. PMID- 25741053 TI - Radiographic adenoid evaluation: proposal of an objective parameter. AB - OBJECTIVE: The objective of the present study was to evaluate current radiographic parameters designed to investigate adenoid hypertrophy and nasopharyngeal obstruction, and to present an alternative radiographic assessment method. MATERIALS AND METHODS: In order to do so, children (4 to14 years old) who presented with nasal obstruction or oral breathing complaints were submitted to cavum radiographic examination. One hundred and twenty records were evaluated according to quantitative radiographic parameters, and data were correlated with a gold-standard videonasopharyngoscopic study, in relation to the percentage of choanal obstruction. Subsequently, a regression analysis was performed in order to create an original model so the percentage of the choanal obstruction could be predicted. RESULTS: The quantitative parameters demonstrated moderate, if not weak correlation with the real percentage of choanal obstruction. The regression model (110.119*A/N) demonstrated a satisfactory ability to "predict" the actual percentage of choanal obstruction. CONCLUSION: Since current adenoid quantitative radiographic parameters present limitations, the model presented by the present study might be considered as an alternative assessment method in cases where videonasopharyngoscopic evaluation is unavailable. PMID- 25741054 TI - Clinical and videofluoroscopic diagnosis of dysphagia in chronic encephalopathy of childhood. AB - OBJECTIVE: To evaluate the contribution of deglutition videofluoroscopy in the clinical diagnosis of dysphagia in chronic encephalopathy of childhood. MATERIALS AND METHODS: The study sample consisted of 93 children diagnosed with chronic encephalopathy, in the age range between two and five years, selected by convenience among patients referred to the authors' institution by speech therapists, neurologists and gastroenterologists in the period from March 2010 to September 2011. The data collection was made at two different moments, by different investigators who were blind to each other. RESULTS: The method presented low sensitivity for detecting aspiration with puree consistency (p = 0.04). Specificity and negative predictive value were high for clinical diagnosis of dysphagia with puree consistency. CONCLUSION: In the present study, the value for sensitivity in the clinical diagnosis of dysphagia demonstrates that this diagnostic procedure may not detect any change in the swallowing process regardless of the food consistency used during the investigation. Thus, the addition of the videofluoroscopic method can significantly contribute to the diagnosis of dysphagia. PMID- 25741055 TI - Relationship between two year PSA nadir and biochemical recurrence in prostate cancer patients treated with iodine-125 brachytherap. AB - OBJECTIVE: To evaluate the relationship between two year PSA nadir (PSAn) after brachytherapy and biochemical recurrence rates in prostate cancer patients. MATERIALS AND METHODS: In the period from January 1998 to August 2007, 120 patients were treated with iodine-125 brachytherapy alone. The results analysis was based on the definition of biochemical recurrence according to the Phoenix Consensus. RESULTS: Biochemical control was observed in 86 patients (71.7%), and biochemical recurrence, in 34 (28.3%). Mean PSAn was 0.53 ng/ml. The mean follow up was 98 months. The patients were divided into two groups: group 1, with two year PSAn < 0.5 ng/ml after brachytherapy (74 patients; 61.7%), and group 2, with two year PSAn >= 0.5 ng/ml after brachytherapy (46 patients; 38.3%). Group 1 presented biochemical recurrence in 15 patients (20.3%), and group 2, in 19 patients (43.2%) (p < 0.02). The analysis of biochemical disease-free survival at seven years, stratified by the two groups, showed values of 80% and 64% (p < 0.02), respectively. CONCLUSION: Levels of two year PSAn >= 0.5 ng/ml after brachytherapy are strongly correlated with a poor prognosis. This fact may help to identify patients at risk for disease recurrence. PMID- 25741056 TI - Learning on human resources management in the radiology residency program. AB - OBJECTIVE: To investigate the process of learning on human resource management in the radiology residency program at Escola Paulista de Medicina - Universidade Federal de Sao Paulo, aiming at improving radiologists' education. MATERIALS AND METHODS: Exploratory study with a quantitative and qualitative approach developed with the faculty staff, preceptors and residents of the program, utilizing a Likert questionnaire (46), taped interviews (18), and categorization based on thematic analysis. RESULTS: According to 71% of the participants, residents have clarity about their role in the development of their activities, and 48% said that residents have no opportunity to learn how to manage their work in a multidisciplinary team. CONCLUSION: Isolation at medical records room, little interactivity between sectors with diversified and fixed activities, absence of a previous culture and lack of a training program on human resources management may interfere in the development of skills for the residents' practice. There is a need to review objectives of the medical residency in the field of radiology, incorporating, whenever possible, the commitment to the training of skills related to human resources management thus widening the scope of abilities of the future radiologists. PMID- 25741057 TI - Raspberry Pi: a 35-dollar device for viewing DICOM images. AB - Raspberry Pi is a low-cost computer created with educational purposes. It uses Linux and, most of times, freeware applications, particularly a software for viewing DICOM images. With an external monitor, the supported resolution (1920 * 1200 pixels) allows for the set up of simple viewing workstations at a reduced cost. PMID- 25741058 TI - Functional magnetic resonance imaging in oncology: state of the art. AB - In the investigation of tumors with conventional magnetic resonance imaging, both quantitative characteristics, such as size, edema, necrosis, and presence of metastases, and qualitative characteristics, such as contrast enhancement degree, are taken into consideration. However, changes in cell metabolism and tissue physiology which precede morphological changes cannot be detected by the conventional technique. The development of new magnetic resonance imaging techniques has enabled the functional assessment of the structures in order to obtain information on the different physiological processes of the tumor microenvironment, such as oxygenation levels, cellularity and vascularity. The detailed morphological study in association with the new functional imaging techniques allows for an appropriate approach to cancer patients, including the phases of diagnosis, staging, response evaluation and follow-up, with a positive impact on their quality of life and survival rate. PMID- 25741059 TI - The carpal boss: a review of different sonographic findings. AB - Carpal boss is an uncommon condition whose incidence is underestimated and that is frequently confused with other causes of development of tumor-like lesions on the dorsum of the wrist. From the clinical point of view, the main obstacle to its recognition is the nonspecificity of symptoms, frequently attributed to dorsal ganglion cysts, since both conditions share a similar location on the dorsum of the wrist. The assessment by ultrasonography allows for a correct diagnosis and appropriate management, with better chances of resolution of the clinical complaint and lower probability of iatrogenic worsening of the lesion. The present review is aimed at describing the different sonographic findings of carpal boss. PMID- 25741060 TI - Bosniak classification of renal cystic lesions according to multidetector computed tomography findings. AB - Renal cystic lesions are usually diagnosed in the radiologists' practice and therefore their characterization is crucial to determine the clinical approach to be adopted and prognosis. The Bosniak classification based on computed tomography findings has allowed for standardization and categorization of lesions in increasing order of malignancy (I, II, IIF, III and IV) in a simple and accurate way. The present iconographic essay developed with multidetector computed tomography images of selected cases from the archives of the authors' institution, is aimed at describing imaging findings that can help in the diagnosis of renal cysts. PMID- 25741061 TI - Radiological findings of uterine arteriovenous malformation: a case report of an unusual and life-threatening cause of abnormal vaginal bleeding. AB - Uterine arteriovenous malformations may cause life-threatening abnormal genital bleeding in women at childbearing age. Transvaginal Doppler ultrasonography is a widely available, noninvasive and excellent diagnostic method. The authors report the case of a patient with history of gestational trophoblastic disease and multiple curettage procedures who developed uterine arteriovenous malformations, with remission of the lesions after treatment with methotrexate. PMID- 25741062 TI - Primary neuroendocrine breast carcinoma: a case report and literature review. AB - The authors present a case of a neuroendocrine carcinoma in an asymptomatic 75 year-old woman, detected in routine breast screening. The lesion was visible at mammography as a well circumscribed, medium density nodule, with no associated microcalcifications, and at ultrasonography as a hypoechoic nodule, with irregular shape and ill-defined margins. Magnetic resonance imaging revealed findings consistent with malignancy. PMID- 25741063 TI - Bullet embolism of pulmonary artery: a case report. AB - The authors report the case of a patient victim of gunshots, with a very rare complication: venous bullet embolism from the left external iliac vein to the lingular segment of the left pulmonary artery. Diagnosis is made with whole-body radiography or computed tomography. Digital angiography is reserved for supplementary diagnosis or to be used as a therapeutic procedure. PMID- 25741064 TI - Mobile health. PMID- 25741065 TI - Audit in a diagnostic breast imaging service. PMID- 25741066 TI - Carpal boss: a sonographic view. PMID- 25741067 TI - Medical knowledge on ionizing radiations. PMID- 25741068 TI - Which is your diagnosis? PMID- 25741069 TI - CT colonography: the value of this method in the view of specialists. AB - OBJECTIVE: To map the view of surgeons on the role played by computed tomography colonography (CTC). MATERIALS AND METHODS: An electronic questionnaire was sent to members of the Brazilian College of Surgeons. The questionnaire consisted of 16 multiple-choice questions about demographics and general knowledge about CTC. RESULTS: The authors obtained 144 responses; 90.3% of the specialists were men, 60% with less than 30 years from graduation, 77.1% were gastrointestinal surgeons, 22.9% were general surgeons, 53.5% were involved in academic activity, and 59.7% had their professional activity in cities with more than 500,000 inhabitants. As regards the knowledge about CTC, 84.7% of the respondents knew the method, 70.8% knew how it is performed, 56.9% reported knowing the bowel preparation used for the procedure, 31.3% used the method, and 53.5% knew some CTC service in their city. About half of the respondents did not know the precise indication of the method. The method is most frequently known and used by professionals working in cities with more than 500,000 inhabitants (p < 0.005). There was a tendency of a more frequent use of the method by the professionals pursuing an academic career. CONCLUSION: Despite its infrequent use in Brazil, CTC is a well known method, particularly in large urban centers and in the academic environment. PMID- 25741070 TI - SUS in nuclear medicine in Brazil: analysis and comparison of data provided by Datasus and CNEN. AB - OBJECTIVE: To investigate the outpatient access to nuclear medicine procedures by means of the Brazilian Unified Health System (SUS), analyzing the correspondence between data provided by this system and those from Comissao Nacional de Energia Nuclear (CNEN) (National Commission of Nuclear Energy). MATERIALS AND METHODS: Data provided by Datasus regarding number of scintillation chambers, outpatient procedures performed from 2008 to 2012, administrative responsibility for such procedures, type of service providers and outsourced services were retrieved and evaluated. Also, such data were compared with those from institutions certified by CNEN. RESULTS: The present study demonstrated that the system still lacks maturity in terms of correct data input, particularly regarding equipment available. It was possible to list the most common procedures and check the growth of the specialty along the study period. Private centers are responsible for most of the procedures covered and reimbursed by SUS. However, many healthcare facilities are not certified by CNEN. CONCLUSION: Datasus provides relevant data for analysis as done in the present study, although some issues still require attention. The present study has quantitatively depicted the Brazilian reality regarding access to nuclear medicine procedures offered by/for SUS. PMID- 25741071 TI - Sonographic evaluation of visceral and subcutaneous fat in obese children. AB - OBJECTIVE: To evaluate sonographic measurements of visceral and subcutaneous fat in children, and to investigate the usefulness of preperitoneal fat (PF) and the abdominal wall fat index (AFI) as parameters to determine visceral fat and presence of nonalcoholic fatty liver disease (NAFLD) in obese children. MATERIALS AND METHODS: A case-control study of a sample including 44 children (22 cases and 22 controls) matched by sex and age. The Student t test and the Fisher exact test were utilized in the descriptive and bivariate analysis. RESULTS: The sonographic parameters evaluated - subcutaneous cell tissue, PF and intraperitoneal fat, and NAFLD - presented high statistical association with body mass index. NAFLD was observed in eight obese patients (36.36%), and PF and AFI were the variables with highest statistical significance, with p < 0.0001. CONCLUSION: Ultrasonography is useful tool in the differentiation and quantification of visceral and subcutaneous fat in children. The measures of PF and AFI are useful in the assessment of visceral fat and NAFLD in obese children. PMID- 25741072 TI - The learning of resources of the unified health system in the radiology residency program. AB - OBJECTIVE: To investigate the learning on the management of resources of the Unified Health System (Sistema Unico de Saude - SUS) and its interfaces with private institutions in the radiology residency program of Escola Paulista de Medicina - Universidade Federal de Sao Paulo, in order to improve radiologists' training. MATERIALS AND METHODS: Exploratory research with quantitative and qualitative approach to residents, faculty staff and preceptors of the program, utilizing Likert questionnaires (46), deepening interviews (18) and categorization based upon meaning units (thematic analysis). RESULTS: Sixty-three per cent of the respondents claim the non-existence of an opportunity for the residents to be acquainted with the management of SUS resources, and were even more categorical (76%) regarding the knowledge about resources from private institutions in the intersection with SUS. CONCLUSION: The learning on the management of SUS resources represents a relevant challenge to be overcome by residency programs, considering the extensiveness and complexity of the Brazilian health system, that is not sufficiently approached during the program, even in its most basic aspects, with daily experiences involving an excessive number of patients and a busy agenda, besides the inadequate public health infrastructure. The present study indicates the need for a greater emphasis on the development of the learning on aspects related to the management of resources from the SUS, assimilating particularities and overcoming the frequent difficulties, thus improving the training of radiologists. PMID- 25741073 TI - Current situation of high-dose-rate brachytherapy for cervical cancer in Brazil. AB - OBJECTIVE: To assess the current situation of high-dose-rate (HDR) brachytherapy for cancer of the cervix in Brazil, regarding apparatuses, planning methods, prescription, fractionation schedule and evaluation of dose in organs at risk. MATERIALS AND METHODS: In the period between March/2012 and May/2013, a multiple choice questionnaire was developed and sent to 89 Brazilian hospitals which perform HDR brachytherapy. RESULTS: Sixty-one services answered the questionnaire. All regions of the country experienced a sharp increase in the number of HDR brachytherapy services in the period from 2001 to 2013. As regards planning, although a three-dimensional planning software was available in 91% of the centers, conventional radiography was mentioned by 92% of the respondents as their routine imaging method for such a purpose. Approximately 35% of respondents said that brachytherapy sessions are performed after teletherapy. The scheme of four 7 Gy intracavitary insertions was mentioned as the most frequently practiced. CONCLUSION: The authors observed that professionals have difficulty accessing adjuvant three-dimensional planning tools such as computed tomography and magnetic resonance imaging. PMID- 25741075 TI - Intraventricular mass lesions at magnetic resonance imaging: iconographic essay - part 1. AB - The present essay is illustrated with magnetic resonance images obtained at the authors' institution over the past 15 years and discusses the main imaging findings of intraventricular tumor-like lesions (ependymoma, pilocytic astrocytoma, central neurocytoma, ganglioglioma, choroid plexus papilloma, primitive neuroectodermal tumors, meningioma, epidermoid tumor). Such lesions represent a subgroup of intracranial lesions with unique characteristics and some image patterns that may facilitate the differential diagnosis. PMID- 25741074 TI - Walled-off pancreatic necrosis and other current concepts in the radiological assessment of acute pancreatitis. AB - Acute pancreatitis is an inflammatory condition caused by intracellular activation and extravasation of inappropriate proteolytic enzymes determining destruction of pancreatic parenchyma and peripancreatic tissues. This is a fairly common clinical condition with two main presentations, namely, endematous pancreatitis - a less severe presentation -, and necrotizing pancreatitis - the most severe presentation that affects a significant part of patients. The radiological evaluation, particularly by computed tomography, plays a fundamental role in the definition of the management of severe cases, especially regarding the characterization of local complications with implications in the prognosis and in the definition of the therapeutic approach. New concepts include the subdivision of necrotizing pancreatitis into the following presentations: pancreatic parenchymal necrosis with concomitant peripancreatic tissue necrosis, and necrosis restricted to peripancreatic tissues. Moreover, there was a systematization of the terms acute peripancreatic fluid collection, pseudocyst, post-necrotic pancreatic/peripancreatic fluid collections and walled-off pancreatic necrosis. The knowledge about such terms is extremely relevant to standardize the terminology utilized by specialists involved in the diagnosis and treatment of these patients. PMID- 25741076 TI - Liliequist membrane: radiological evaluation, clinical and therapeutic implications. AB - In a simplistic and succinct way, Liliequist membrane may be understood as a projection formed by an arachnoid membrane extending from the dorsum sellae to the mammillary bodies. In spite of being well known to neurosurgeons, many radiologists neither know this anatomical structure nor give importance to its study. The imaging evaluation of this membrane is feasible and may be interesting for a better preoperative planning; postoperative evaluation of third ventriculostomies; and understanding of suprasellar arachnoid cysts and perimesencephalic hemorrhage. The present article illustrates the anatomy of the membrane, with emphasis on imaging findings, besides describing its possible clinical and surgical implications. PMID- 25741077 TI - Parry-Romberg syndrome: findings in advanced magnetic resonance imaging sequences - case report. AB - Parry-Romberg syndrome is a rare disease characterized by progressive hemifacial atrophy associated with other systemic changes, including neurological symptoms. Currently, there are few studies exploring the utilization of advanced magnetic resonance sequences in the investigation of this disease. The authors report the case of a 45-year-old patient and describe the findings at structural magnetic resonance imaging and at advanced sequences, correlating them with pathophysiological data. PMID- 25741078 TI - Cloverleaf skull syndrome: case report. AB - The present report is aimed at describing a rare case of cranial malformation - cloverleaf skull syndrome -, whose presence was noticed after the birth of a child with signs of abnormality. Imaging diagnosis methods such as computed tomography and conventional radiography were used to characterize the syndrome. PMID- 25741079 TI - Laryngeal schwannoma: a case report with emphasis on sonographic findings. AB - Schwannomas are benign nerve sheath tumors composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral, cranial and autonomic nerves. Twenty-five to forty-five percent of all schwannomas occur in the head and neck region, but location of such tumors in the larynx is rarely observed. The present report is aimed at describing a clinical case of laryngeal schwannoma, with emphasis on sonographic findings. PMID- 25741080 TI - Multifocal and metastatic hepatic hemangioendothelioma: case report and literature review. AB - Epithelioid hemangioendothelioma is a rare neoplasm of vascular origin whose involvement of organs such as lung, spleen, bone, breast and liver has already been reported. The clinical signs and the prognosis of this tumor are quite variable. From the present case report, the authors have sought to contribute with literature data, by reviewing clinical and radiological features which may be useful to include such a condition in the differential diagnosis of liver lesions. PMID- 25741081 TI - Visceral and subcutaneous fat. PMID- 25741082 TI - Computed tomography colonography: a well-known but poorly utilized screening method. PMID- 25741083 TI - Nuclear medicine in the Brazilian Unified Health System. PMID- 25741084 TI - Which is your diagnosis? PMID- 25741085 TI - Reference intervals of fetal cisterna magna volume by two-dimensional method using the multiplanar mode of three-dimensional ultrasonography. AB - OBJECTIVE: To establish reference intervals for the fetal cisterna magna volume by means of two-dimensional (2D) method using the multiplanar mode of three dimensional ultrasonography. MATERIALS AND METHODS: Cross-sectional study with 224 healthy pregnant women between the 17th and 29th gestational weeks. The volume was automatically obtained by multiplying the three major axes in axial and sagittal planes by the constant 0.52. Polynomial regression was utilized to establish the correlation between fetal cisterna magna volume and gestational age, with adjustments by coefficient of determination (R(2)). Reliability and agreement were obtained by intraclass correlation coefficient (ICC) and limits of agreement, respectively. RESULTS: Mean fetal cisterna volume with the 2D method ranged from 0.71 +/- 0.19 cm(3) to 4.18 +/- 0.75 cm(3) at the 17th and 29th weeks, respectively. The authors observed a good correlation between fetal cisterna magna volume and gestational age (R(2) = 0.67), excellent intraobserver reliability and agreement with ICC = 0.89 and limits of agreement 95% (-52.0; 51.8), respectively, and low interobserver reliability and agreement with ICC = 0.64 and limits of agreement 95% (-110.1; 84.6), respectively. CONCLUSION: Reference intervals for fetal cisterna magna volume by means of 2D method using the multiplanar mode of three-dimensional ultrasonography were established and presented excellent intraobserver reliability and agreement. PMID- 25741086 TI - Prediction of early and late preeclampsia by flow-mediated dilation of the brachial artery. AB - OBJECTIVE: To assess the accuracy in the prediction of both early and late preeclampsia by flow-mediated dilation of the brachial artery (FMD), a biophysical marker for endothelial dysfunction. MATERIALS AND METHODS: A total of 91 patients, considered at high risk for development of preeclampsia were submitted to brachial artery FMD between 24 and 28 weeks of gestation. RESULTS: Nineteen out of the selected patients developed preeclampsia, 8 in its early form and 11 in the late form. With a cut-off value of 6.5%, the FMD sensitivity for early preeclampsia prediction was 75.0%, with specificity of 73.3%, positive predictive value (PPV) of 32.4% and negative predictive value (NPV) of 91.9%. For the prediction of late preeclampsia, sensitivity = 83.3%, specificity = 73.2%, PPV = 34.4% and NPV = 96.2% were observed. And for the prediction of all associated forms of preeclampsia, sensitivity = 84.2%, specificity = 73.6%, PPV = 45.7% and NPV = 94.6% were observed. CONCLUSION: FMD of the brachial artery is a test with good accuracy in the prediction of both early and late preeclampsia, which may represent a positive impact on the follow-up of pregnant women at high risk for developing this syndrome. PMID- 25741087 TI - Evaluation of non-radiologist physicians' knowledge on aspects related to ionizing radiation in imaging. AB - OBJECTIVE: To assess the non-radiologist physicians' knowledge on the use of ionizing radiation in imaging. MATERIALS AND METHODS: Cross-sectional study utilizing an anonymous questionnaire responded by physicians in clinical and surgical specialties, divided into two parts as follows: one including questions about the physicians' characteristics, frequency of imaging studies requests and participation in professional updating events, and another part including multiple choice questions approaching general knowledge about radiation, optimization principles and radioprotection. RESULTS: From a total of 309 questionnaires, 120 (38.8%) were responded, 50% by physicians in surgical specialties and 50% in clinical specialties; respectively 45% and 2.5% of physicians responded that magnetic resonance imaging and ultrasonography use ionizing radiation. Overall, the average grade was higher for surgical specialists with no significant difference, except for the question about exposure in pregnant women (p = 0.047). Physicians who are professionally updated, particularly those attending clinical meetings (p = 0.050) and participating in teaching activities (p = 0.047), showed statistically superior knowledge about ionizing radiation as compared with others. CONCLUSION: The non radiologist physicians' knowledge is heterogeneous and in some points needs to be improved. Multidisciplinary clinical meetings and teaching activities are important ways to disseminate information on the subject. PMID- 25741088 TI - Optimization of a protocol for myocardial perfusion scintigraphy by using an anthropomorphic phantom. AB - OBJECTIVE: To develop a study aiming at optimizing myocardial perfusion imaging. MATERIALS AND METHODS: Imaging of an anthropomorphic thorax phantom with a GE SPECT Ventri gamma camera, with varied activities and acquisition times, in order to evaluate the influence of these parameters on the quality of the reconstructed medical images. The (99m)Tc-sestamibi radiotracer was utilized, and then the images were clinically evaluated on the basis of data such as summed stress score, and on the technical image quality and perfusion. The software ImageJ was utilized in the data quantification. RESULTS: The results demonstrated that for the standard acquisition time utilized in the procedure (15 seconds per angle), the injected activity could be reduced by 33.34%. Additionally, even if the standard scan time is reduced by 53.34% (7 seconds per angle), the standard injected activity could still be reduced by 16.67%, without impairing the image quality and the diagnostic reliability. CONCLUSION: The described method and respective results provide a basis for the development of a clinical trial of patients in an optimized protocol. PMID- 25741089 TI - Characterization of a lead breast shielding for dose reduction in computed tomography. AB - OBJECTIVE: Several studies have been published regarding the use of bismuth shielding to protect the breast in computed tomography (CT) scans and, up to the writing of this article, only one publication about barium shielding was found. The present study was aimed at characterizing, for the first time, a lead breast shielding. MATERIALS AND METHODS: The percentage dose reduction and the influence of the shielding on quantitative imaging parameters were evaluated. Dose measurements were made on a CT equipment with the aid of specific phantoms and radiation detectors. A processing software assisted in the qualitative analysis evaluating variations in average CT number and noise on images. RESULTS: The authors observed a reduction in entrance dose by 30% and in CTDIvol by 17%. In all measurements, in agreement with studies in the literature, the utilization of cotton fiber as spacer object reduced significantly the presence of artifacts on the images. All the measurements demonstrated increase in the average CT number and noise on the images with the presence of the shielding. CONCLUSION: As expected, the data observed with the use of lead shielding were of the same order as those found in the literature about bismuth shielding. PMID- 25741090 TI - Imaging of the adrenal gland lesions. AB - With the steep increase in the use of cross-sectional imaging in recent years, the incidentally detected adrenal lesion, or "incidentaloma", has become an increasingly common diagnostic problem for the radiologist, and a need for an approach to classifying these lesions as benign, malignant or indeterminate with imaging has spurred an explosion of research. While most incidentalomas represent benign disease, typically an adenoma, the possibility of malignant involvement of the adrenal gland necessitates a reliance on imaging to inform management decisions. In this article, we review the literature on adrenal gland imaging, with particular emphasis on computed tomography, magnetic resonance imaging, and photon-emission tomography, and discuss how these findings relate to clinical practice. Emerging technologies, such as contrast-enhanced ultrasonography, dual energy computed tomography, and magnetic resonance spectroscopic imaging will also be briefly addressed. PMID- 25741091 TI - Axillary lymph nodes in breast cancer patients: sonographic evaluation. AB - Axillary staging of patients with early-stage breast cancer is essential in the treatment planning. Currently such staging is intraoperatively performed, but there is a tendency to seek a preoperative and less invasive technique to detect lymph node metastasis. Ultrasonography is widely utilized for this purpose, many times in association with fine-needle aspiration biopsy or core needle biopsy. However, the sonographic criteria for determining malignancy in axillary lymph nodes do not present significant predictive values, producing discrepant results in studies evaluating the sensitivity and specificity of this method. The present study was aimed at reviewing the literature approaching the utilization of ultrasonography in the axillary staging as well as the main morphological features of metastatic lymph nodes. PMID- 25741092 TI - Intraventricular mass lesions at magnetic resonance imaging: iconographic essay - part 2. AB - The present essay is illustrated with magnetic resonance images obtained at the authors' institution over the past 15 years and discusses the main imaging findings of intraventricular tumor-like lesions (colloid cyst, oligodendroglioma, astroblastoma, lipoma, cavernoma) and of inflammatory/infectious lesions (neurocysticercosis and an atypical presentation of neurohistoplasmosis). Such lesions represent a subgroup of intracranial lesions with unique characteristics and some imaging patterns that may facilitate the differential diagnosis. PMID- 25741093 TI - Imaging diagnosis of dural and direct cavernous carotid fistulae. AB - Arteriovenous fistulae of the cavernous sinus are rare and difficult to diagnose. They are classified into dural cavernous sinus fistulae or direct carotid cavernous fistulae. Despite the similarity of symptoms between both types, a precise diagnosis is essential since the treatment is specific for each type of fistula. Imaging findings are remarkably similar in both dural cavernous sinus fistulae and carotid-cavernous fistulae, but it is possible to differentiate one type from the other. Amongst the available imaging methods (Doppler ultrasonography, computed tomography, magnetic resonance imaging and digital subtraction angiography), angiography is considered the gold standard for the diagnosis and classification of cavernous sinus arteriovenous fistulae. The present essay is aimed at didactically presenting the classification and imaging findings of cavernous sinus arteriovenous fistulae. PMID- 25741094 TI - Lymphocytic mastopathy mimicking breast malignancy: a case report. AB - Lymphocytic mastopathy affects both young and middle-aged women and is frequently associated with autoimmune diseases. Diagnosis is done by associating clinical (breast tissue thickening or hardened breast lump), radiological (increased breast density, presence of mass and calcifications), sonographic (nodule with posterior acoustic shadowing), histopathological (fibrosis and lymphocytic infiltrate) and immunohistochemical findings. Lymphocytic mastopathy is a benign entity that may mimic carcinoma. The authors report the case of a patient with lymphocytic mastopathy. PMID- 25741095 TI - Churg-Strauss syndrome: a case report. AB - Churg-Strauss syndrome is a rare systemic disease primarily characterized by hypereosinophilia, asthma and vasculitis. The lung is the organ most frequently involved. In the present report, the authors describe a relatively rare finding in this disease - the presence of a pulmonary nodule -, while recalling the main radiological findings and the most relevant differential diagnoses. PMID- 25741096 TI - Encapsulating peritonitis: computed tomography and surgical correlation. AB - Sclerosing encapsulating peritonitis is a rare and frequently severe entity characterized by total or partial involvement of small bowel loops by a membrane of fibrous tissue. The disease presents with nonspecific clinical features of intestinal obstruction, requiring precise imaging diagnosis to guide the treatment. The present report emphasizes the importance of computed tomography in the diagnosis of this condition and its confirmation by surgical correlation. PMID- 25741097 TI - Imaging evaluation of the fetal posterior fossa. PMID- 25741098 TI - Mammography: a history of success and scientific enthusiasm. PMID- 25741099 TI - Which is your diagnosis? PMID- 25741100 TI - Computed tomography-guided percutaneous biopsy of bone lesions: rate of diagnostic success and complications. AB - OBJECTIVE: To determine the rates of diagnostic success and complications of computed tomography (CT)-guided percutaneous biopsy of bone lesions suspected for malignancy. MATERIALS AND METHODS: Retrospective study including 186 cases of CT guided percutaneous biopsies of bone lesions in the period from January, 2010 to December, 2012. All the specimens were obtained with 8-10 gauge needles. The following data were collected: demographics, previous history of malignancy, data related to the lesion, to the procedure, and to histological results. RESULTS: Most patients were women (57%), and the mean age was 53.0 +/- 16.4 years. In 139 cases (74.6%), there was diagnostic suspicion of metastasis and the most common primary tumors were breast (32.1%) and prostate (11.8%). The bones most commonly involved were spine (36.0%), hip (32.8%) and long bones (18.3%). Complications occurred in only three cases (1.6%) including bone fracture, paresthesia with functional impairment, and needle breakage requiring surgical removal. The specimens collected from 183 lesions (98.4%) were considered appropriate for diagnosis. Malignant results were more frequently found in patients who had a suspected secondary lesion and history of known malignancy (p < 0.001), and in patients who underwent PET/CT-guided procedures (p = 0.011). CONCLUSION: CT guided percutaneous biopsy is a safe and effective procedure for the diagnosis of suspicious bone lesions. PMID- 25741101 TI - Application for internal dosimetry using biokinetic distribution of photons based on nuclear medicine images. AB - OBJECTIVE: This article presents a way to obtain estimates of dose in patients submitted to radiotherapy with basis on the analysis of regions of interest on nuclear medicine images. MATERIALS AND METHODS: A software called DoRadIo (Dosimetria das Radiacoes Ionizantes [Ionizing Radiation Dosimetry]) was developed to receive information about source organs and target organs, generating graphical and numerical results. The nuclear medicine images utilized in the present study were obtained from catalogs provided by medical physicists. The simulations were performed with computational exposure models consisting of voxel phantoms coupled with the Monte Carlo EGSnrc code. The software was developed with the Microsoft Visual Studio 2010 Service Pack and the project template Windows Presentation Foundation for C# programming language. RESULTS: With the mentioned tools, the authors obtained the file for optimization of Monte Carlo simulations using the EGSnrc; organization and compaction of dosimetry results with all radioactive sources; selection of regions of interest; evaluation of grayscale intensity in regions of interest; the file of weighted sources; and, finally, all the charts and numerical results. CONCLUSION: The user interface may be adapted for use in clinical nuclear medicine as a computer-aided tool to estimate the administered activity. PMID- 25741102 TI - Celiac plexus block: an anatomical study and simulation using computed tomography. AB - OBJECTIVE: To analyze anatomical variations associated with celiac plexus complex by means of computed tomography simulation, assessing the risk for organ injury as the transcrural technique is utilized. MATERIALS AND METHODS: One hundred eight transaxial computed tomography images of abdomen were analyzed. The aortic vertebral, celiac trunk (CeT)-vertebral, CeT-aortic and celiac-aortic-vertebral topographical relationships were recorded. Two needle insertion pathways were drawn on each of the images, at right and left, 9 cm and 4.5 cm away from the midline. Transfixed vital organs and gender-related associations were recorded. RESULTS: Aortic-vertebral - 45.37% at left and 54.62% in the middle; CeT vertebral - T12, 36.11%; T12-L1, 32.4%; L1, 27.77%; T11-T12, 2.77%; CeT-aortic - 53.7% at left and 46.3% in the middle; celiac-aortic-vertebral - L-l, 22.22%; M m, 23.15%; L-m, 31.48%; M-l, 23.15%. Neither correspondence on the right side nor significant gender-related associations were observed. CONCLUSION: Considering the wide range of abdominal anatomical variations and the characteristics of needle insertion pathways, celiac plexus block should not be standardized. Imaging should be performed prior to the procedure in order to reduce the risks for injuries or for negative outcomes to patients. Gender-related anatomical variations involved in celiac plexus block should be more deeply investigated, since few studies have addressed the subject. PMID- 25741103 TI - Determination of dosimetric quantities in pediatric abdominal computed tomography scans. AB - OBJECTIVE: Aiming at contributing to the knowledge on doses in computed tomography (CT), this study has the objective of determining dosimetric quantities associated with pediatric abdominal CT scans, comparing the data with diagnostic reference levels (DRL). MATERIALS AND METHODS: The study was developed with a Toshiba Asteion single-slice CT scanner and a GE BrightSpeed multi-slice CT unit in two hospitals. Measurements were performed with a pencil-type ionization chamber and a 16 cm-diameter polymethylmethacrylate trunk phantom. RESULTS: No significant difference was observed in the values for weighted air kerma index (CW), but the differences were relevant in values for volumetric air kerma index (CVOL), air kerma-length product (PKL,CT) and effective dose. CONCLUSION: Only the CW values were lower than the DRL, suggesting that dose optimization might not be necessary. However, PKL,CT and effective dose values stressed that there still is room for reducing pediatric radiation doses. The present study emphasizes the importance of determining all dosimetric quantities associated with CT scans. PMID- 25741104 TI - Multiparametric magnetic resonance imaging of the prostate: current concepts. AB - Multiparametric MR (mpMR) imaging is rapidly evolving into the mainstay in prostate cancer (PCa) imaging. Generally, the examination consists of T2-weighted sequences, diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) evaluation, and less often proton MR spectroscopy imaging (MRSI). Those functional techniques are related to biological properties of the tumor, so that DWI correlates to cellularity and Gleason scores, DCE correlates to angiogenesis, and MRSI correlates to cell membrane turnover. The combined use of those techniques enhances the diagnostic confidence and allows for better characterization of PCa. The present article reviews and illustrates the technical aspects and clinical applications of each component of mpMR imaging, in a practical approach from the urological standpoint. PMID- 25741105 TI - Hepatobiliary contrast agents: differential diagnosis of focal hepatic lesions, pitfalls and other indications. AB - The characterization of focal liver lesions is very important. Magnetic resonance imaging is considered the best imaging method for evaluating such lesions, but does not allow for the diagnosis in all cases. The use of hepatobiliary contrast agents increases the diagnostic accuracy of magnetic resonance imaging and reduces the number of non-specific liver lesions. The main indications for the method include: differentiation between focal nodular hyperplasia and adenoma; characterization of hepatocellular carcinomas in cirrhotic patients; detection of small liver metastases; evaluation of biliary anatomy; and characterization of postoperative biliary fistulas. The use of hepatobiliary contrast agents may reduce the need for invasive diagnostic procedures and further investigations with other imaging methods, besides the need for imaging follow-up. PMID- 25741106 TI - Uncommon hepatic tumors: iconographic essay - Part 1. AB - Most malignant liver tumors are represented by hepatocellular carcinoma and cholangiocarcinoma; however a variety of other uncommon hepatic lesions might also be found. Common lesions such as hemangioma, focal nodular hyperplasia and metastases are well known and have already been extensively documented in the literature. The diagnosis of typical hepatic lesions may be done with some reliability by means of several imaging methods; on the other hand, uncommon lesions normally represent a diagnostic challenge for the radiologist. In this first part of the study, the authors will approach five uncommon liver tumors - angiosarcoma, angiomyolipoma, cystadenoma/biliary carcinoma, epithelioid hemangioendothelioma, and fibrolamellar hepatocellular carcinoma -, describing their main characteristics and image findings with focus on computed tomography and magnetic resonance imaging. PMID- 25741107 TI - Acute tracheobronchitis caused by Aspergillus: case report and imaging findings. AB - Acute tracheobronchitis is a rare manifestation of invasive aspergillosis, generally occurring in severely immunocompromised patients. The authors report the case of a patient presenting with this condition after bone-marrow transplantation, with emphasis on tomographic findings. PMID- 25741108 TI - Aortic lesion simulating pulmonary disease: a case report. AB - The authors report the case of an elderly woman assessed for dyspnea and right costal margin pain, whose chest radiography demonstrated opacity simulating pulmonary lesion, and computed tomography revealed the vascular origin of the condition. Acute aortic syndrome due to ruptured atheromatous plaque penetrating through the elastic lamina in association with aortic hematoma and aneurysm is a relevant differential diagnosis to be considered in these cases. PMID- 25741109 TI - Atypical retroperitoneal endometriosis and use of tamoxifen. AB - The involvement of the retroperitoneum by endometriosis occurs only sporadically. In the present report, emphasis will be given to the magnetic resonance imaging findings which raised the diagnostic suspicion of periureteral lesion in a patient undergoing tamoxifen therapy, presenting with left upper quadrant pain and hydronephrosis. Histopathological findings obtained by means of computed tomography-guided percutaneous biopsy revealed the diagnosis of periureteral endometriosis. PMID- 25741110 TI - Clinical and radiological repercussions of plexiform neurofibroma in the pelvic region. AB - The authors report the case of a plexiform neurofibroma located in the pelvis, affecting the bladder, prostate and spine (lumbar/sacral), followed-up for three years and six months. Surgical removal was contraindicated and the patient underwent biannual clinical and radiological follow-up that did not demonstrate any tumor increase. The clinical manifestations of neurofibromatosis type 1 are variable, and the medical team should be attentive to further investigations, considering possible unexpected rare findings. Large pelvic masses may correspond to plexiform neurofibromas, so the diagnostic hypothesis of neurofibromatosis should be taken into consideration. PMID- 25741111 TI - Imaging findings of unusual hepatic tumors: expanding the differential diagnosis. PMID- 25741112 TI - Multiparametric magnetic resonance imaging of prostate: the evolution of a technique. PMID- 25741113 TI - The role of MRI using liver-specific contrast agent in the assessment of focal liver lesion. PMID- 25741114 TI - Which is your diagnosis? PMID- 25741115 TI - Application of a protocol for magnetic resonance spectroscopy of adrenal glands: an experiment with over 100 cases. AB - OBJECTIVE: To evaluate a protocol for two-dimensional (2D) hydrogen proton (1H) magnetic resonance spectroscopy (MRS) (Siemens Medical Systems; Erlangen, Germany) in the detection of adrenal nodules and differentiation between benign and malignant masses (adenomas, pheochromocytomas, carcinomas and metastases). MATERIALS AND METHODS: A total of 118 patients (36 men; 82 women) (mean age: 57.3 +/- 13.3 years) presenting with 138 adrenal nodules/masses were prospectively assessed. A multivoxel system was utilized with a 2D point-resolved spectroscopy/chemical shift imaging sequence. The following ratios were calculated: choline (Cho)/creatine (Cr), 4.0-4.3/Cr, lipid (Lip)/Cr, Cho/Lip and lactate (Lac)/Cr. RESULTS: 2D-1H-MRS was successful in 123 (89.13%) lesions. Sensitivity and specificity values observed for the ratios and cutoff points were the following: Cho/Cr >= 1.2, 100% sensitivity, 98.2% specificity (differences between adenomas/pheochromocytomas and carcinomas/ metastases); 4.0-4.3 ppm/Cr >= 1.5, 92.3% sensitivity, 96.9% specificity (differences between carcinomas/pheochromocytomas and adenomas/metastases); Lac/Cr <= -7.449, 90.9% sensitivity and 77.8% specificity (differences between pheochromocytomas and carcinomas/adenomas). CONCLUSION: Information provided by 2D-1H-MRS were effective and allowed for the differentiation between adrenal masses and nodules in most cases of lesions with > 1.0 cm in diameter. PMID- 25741116 TI - X-linked adrenoleukodystrophy: correlation between Loes score and diffusion tensor imaging parameters. AB - OBJECTIVE: The present study was aimed at evaluating the correlation between diffusion tensor imaging parameters and Loes score as well as whether those parameters could indicate early structural alterations. MATERIALS AND METHODS: Diffusion tensor imaging measurements were obtained in 30 studies of 14 patients with X-linked adrenoleukodystrophy and were correlated with Loes scores. A control group including 28 male patients was created to establish agematched diffusion tensor imaging measurements. Inter- and intraobserver statistical analyses were undertaken. RESULTS: Diffusion tensor imaging measurements presented strong Pearson correlation coefficients (r) of -0.86, 0.89, 0.89 and 0.84 for fractional anisotropy and mean, radial and axial diffusivities (p < 0.01). Analysis of changes in diffusion tensor measurements at early stage of the disease indicates that mean and radial diffusivities might be useful to predict the disease progression. CONCLUSION: Measurements of diffusion tensor parameters can be used as an adjunct to the Loes score, aiding in the monitoring of the disease and alerting for possible Loes score progression in the range of interest for therapeutic decisions. PMID- 25741117 TI - Dosimetry of patients submitted to cerebral PET/CT for the diagnosis of mild cognitive impairment. AB - OBJECTIVE: The present study was aimed at evaluating the effective radiation dose in patients submitted to PET/CT for the diagnosis of mild cognitive impairment. MATERIALS AND METHODS: TLD-100 detectors inserted into an Alderson Rando(r) anthropomorphic phantom were utilized to measure the absorbed dose coming from the CT imaging modality. The anthropomorphic phantoms (male and female adult versions) were submitted to the same technical protocols for patients' images acquisition. The absorbed dose resulting from the radiopharmaceutical injection was estimated by means of the model proposed by the ICRP publication 106. RESULTS: The effective dose in patients submitted to this diagnostic technique was approximately (5.34 +/- 1.99) mSv. CONCLUSION: Optimized protocols for calculation of radioactive activity injected into patients submitted to this diagnostic technique might contribute to reduce the effective radiation dose resulting from PET/CT in the diagnosis of mild cognitive impairment. PMID- 25741118 TI - Intensity modulated radiotherapy (IMRT) for patients of the Brazilian unified health system (SUS): an analysis of 508 treatments two years after the technique implementation. AB - The Bosniak classification for renal cysts was developed in the late 1980s in an attempt to standardize the description and management of complex cystic renal lesions. Alterations were made to such a classification in the 1990s and, the last one, in 2005. Currently, five categories of cystic renal lesions are defined - namely, I, II, II-F, III and IV -, according to their degree of complexity and likelihood of malignancy. Despite being initially described for computed tomography, this classification has been also utilized with some advantages also for magnetic resonance imaging. The present article reviews the different phases of this classification, its diagnostic efficacy and the most controversial features of its use. PMID- 25741119 TI - Dosimetry and image quality assessment in a direct radiography system. AB - OBJECTIVE: To evaluate the mean glandular dose with a solid state detector and the image quality in a direct radiography system, utilizing phantoms. MATERIALS AND METHODS: Irradiations were performed with automatic exposure control and polymethyl methacrylate slabs with different thicknesses to calculate glandular dose values. The image quality was evaluated by means of the structures visualized on the images of the phantoms. RESULTS: Considering the uncertainty of the measurements, the mean glandular dose results are in agreement with the values provided by the equipment and with internationally adopted reference levels. Results obtained from images of the phantoms were in agreement with the reference values. CONCLUSION: The present study contributes to verify the equipment conformity as regards dose values and image quality. PMID- 25741120 TI - Bosniak classification for complex renal cysts: history and critical analysis. AB - The Bosniak classification for renal cysts was developed in the late 1980s in an attempt to standardize the description and management of complex cystic renal lesions. Alterations were made to such a classification in the 1990s and, the last one, in 2005. Currently, five categories of cystic renal lesions are defined - namely, I, II, II-F, III and IV -, according to their degree of complexity and likelihood of malignancy. Despite being initially described for computed tomography, this classification has been also utilized with some advantages also for magnetic resonance imaging. The present article reviews the different phases of this classification, its diagnostic efficacy and the most controversial features of its use. PMID- 25741121 TI - Uncommon hepatic tumors: iconographic essay - Part 2. AB - In cases where typical aspects are shown, the diagnosis of most frequent hepatic lesions can be made with some safety by means of several imaging methods; on the other hand, uncommon lesions generally represent a diagnostic challenge for the radiologist. In the present second part of the study, the authors describe four rare hepatic lesions, as follows: primary hepatic lymphoma, myofibroblastic tumor, primary hepatic neuroendocrine tumor and desmoplastic small round cell tumor, approaching their main characteristics and imaging findings with emphasis on computed tomography and magnetic resonance imaging. PMID- 25741122 TI - Uncommon primary tumors of the orbit diagnosed by computed tomography-guided core needle biopsy: report of two cases. AB - Computed tomography-guided percutaneous biopsy is a safe and effective alternative method for evaluating selected intra-orbital lesions where the preoperative diagnosis is important for the therapeutic planning. The authors describe two cases of patients with uncommon primary orbital tumors whose diagnosis was obtained by means of computed tomography-guided core needle biopsy, with emphasis on the technical aspects of the procedure. PMID- 25741123 TI - Leiomyosarcoma of the inferior vena cava: a case report. AB - The authors report a case of a 48 year-old female patient with moderate abdominal pain and bulging in the abdomen. Physical examination demonstrated the presence of a palpable abdominal mass. Computed tomography showed a heterogeneously enhancing retroperitoneal mass in close contact with the inferior vena cava. En bloc resection of the mass and of the attached vena cava segment was performed. Histological analysis revealed leiomyosarcoma. PMID- 25741124 TI - Urachal neoplasia: a case report. AB - Diseases of urachal remnants are uncommon and generally located on the junction of the urachal remnant with the bladder dome. In most cases such diseases correspond to mucinous adenocarcinomas and present hematuria as their most common clinical finding. The authors report the case of a 62-year-old female patient undergoing follow-up due to macroscopic hematuria for three years. Ultrasonography and computed tomography findings are described. PMID- 25741125 TI - History and importance of the Bosniak classification for complex renal cysts. PMID- 25741126 TI - Imaging techniques in the characterization of adrenal lesions. PMID- 25741127 TI - X-linked adrenoleucodystrophy: diagnosis and progression quantification. PMID- 25741128 TI - Which is your diagnosis? PMID- 25741129 TI - Method of calculating tsunami travel times in the Andaman Sea region. AB - A new model to calculate tsunami travel times in the Andaman Sea region has been developed. The model specifically provides more accurate travel time estimates for tsunamis propagating to Patong Beach on the west coast of Phuket, Thailand. More generally, the model provides better understanding of the influence of the accuracy and resolution of bathymetry data on the accuracy of travel time calculations. The dynamic model is based on solitary wave theory, and a lookup function is used to perform bilinear interpolation of bathymetry along the ray trajectory. The model was calibrated and verified using data from an echosounder record, tsunami photographs, satellite altimetry records, and eyewitness accounts of the tsunami on 26 December 2004. Time differences for 12 representative targets in the Andaman Sea and the Indian Ocean regions were calculated. The model demonstrated satisfactory time differences (<2 min/h), despite the use of low resolution bathymetry (ETOPO2v2). To improve accuracy, the dynamics of wave elevation and a velocity correction term must be considered, particularly for calculations in the nearshore region. PMID- 25741130 TI - Lipid peroxidation-mediated inflammation promotes cell apoptosis through activation of NF-kappaB pathway in rheumatoid arthritis synovial cells. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints. The central pathogenesis of RA is the proliferation of synovial fibroblasts in response to inflammatory cytokines. However, some of the targeted therapies for inflammation reactions do not display significant clinical improvement after initiation of therapy. Thus, the relationship between inflammatory responses and RA therapy is still incompletely understood. In the present study, we proposed to determine whether enhanced inflammations may lead to cell apoptosis in rheumatoid arthritis synoviocytes. Our results indicated that products of lipid peroxidations, 4-HNE, may induce synovial intrinsic inflammations by activating NF-kappaB pathways and it may lead to cell apoptosis. Pharmacological inhibition of NF-kappaB activation may reduce the 4-HNE mediated inflammation responses and subsequent cell apoptosis. Our results may help to clarify the role of inflammations on RA development and imply that blocking NF-kappaB activation may be partly beneficial for human RA therapy. These findings might provide a mechanism-based rationale for developing new strategy to RA clinical therapy. PMID- 25741131 TI - The prevalence of autoantibodies in complex regional pain syndrome type I. AB - Autoimmunity has been suggested as one of the pathophysiologic mechanisms that may underlie complex regional pain syndrome (CRPS). Screening for antinuclear antibodies (ANA) is one of the diagnostic tests, which is usually performed if a person is suspected to have a systemic autoimmune disease. Antineuronal antibodies are autoantibodies directed against antigens in the central and/or peripheral nervous system. The aim of this study was to compare the prevalence of these antibodies in CRPS patients with the normal values of those antibodies in the healthy population. Twenty seven (33%) of the 82 CRPS patients of whom serum was available showed a positive ANA test. This prevalence is significantly higher than in the general population. Six patients (7.3%) showed a positive result for typical antineuronal antibodies. This proportion, however, does not deviate from that in the general population. Our findings suggest that autoantibodies may be associated with the pathophysiology of CRPS, at least in a subset of patients. Further research is needed into defining this subset and into the role of autoantibodies in the pathogenesis of CRPS. PMID- 25741132 TI - Use of non-selective beta blockers in cirrhosis: the evidence we need before closing (or not) the window. AB - Non selective beta blockers (NSBBs) are used in primary and secondary prophylaxis of portal hypertension-related bleeding in patients with cirrhosis. The efficacy of NSBBs treatment is predicted by hemodynamic response in term of reduction of the hepatic venous pressure gradient (HVPG) below 12 mmHg or at least 20% of the basal value. Nevertheless a relevant number of patients who do not achieve this HVPG reduction during NSBBs therapy do not bleed during follow up; this evidence suggests an additional non-hemodynamic advantage of NSBBs treatment to modify the natural history of cirrhosis. Recent studies have questioned the efficacy and safety of NSBBs in patients with advanced stage of liver disease characterized by refractory ascites and/or spontaneous bacterial peritonitis. These studies have suggested the existence of a defined and limited period to modify the natural history of cirrhosis by NSBBs: the "window hypothesis". According with this hypothesis, patients with cirrhosis benefit from the use of NSBBs from the appearance of varices up to the development of an advanced stage of cirrhosis. Indeed, in patients with refractory ascites and/or spontaneous bacterial peritonitis the hemodynamic effects of NSBBs may expose to a high risk of further complications such as renal insufficiency and/or death. Methodological concerns and contrasting results counterbalance the evidence produced up to now on this issue and are the main topic of this editorial. PMID- 25741133 TI - Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview. AB - Hepatitis C virus (HCV) infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease. Among the extrahepatic manifestations, neuropsychiatric disorders have been reported in up to 50% of chronic HCV infected patients. Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations. Main HCV-associated neurological conditions include cerebrovascular events, encephalopathy, myelitis, encephalomyelitis, and cognitive impairment, whereas "brain fog", depression, anxiety, and fatigue are at the top of the list of psychiatric disorders. Moreover, HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia, and has also been recently recognized as an independent risk factor for stroke. These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy. The brain is a suitable site for HCV replication, where the virus may directly exert neurotoxicity; other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells, alterations in neurotransmitter circuits, autoimmune disorders, and cerebral or systemic inflammation. A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment; however, further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders. PMID- 25741134 TI - New challenges in perioperative management of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the industrialized world. Despite progress in the understanding of the molecular and genetic basis of this disease, the 5-year survival rate has remained low and usually does not exceed 5%. Only 20%-25% of patients present with potentially resectable disease and surgery represents the only chance for a cure. After decades of gemcitabine hegemony and limited therapeutic options, more active chemotherapies are emerging in advanced PDAC, like 5-Fluorouracil, folinic acid, irinotecan and oxaliplatin and nab-paclitaxel plus gemcitabine, that have profoundly impacted therapeutic possibilities. PDAC is considered a systemic disease because of the high rate of relapse after curative surgery in patients with resectable disease at diagnosis. Neoadjuvant strategies in resectable, borderline resectable, or locally advanced pancreatic cancer may improve outcomes. Incorporation of tissue biomarker testing and imaging techniques into preoperative strategies should allow clinicians to identify patients who may ultimately achieve curative benefit from surgery. This review summarizes current knowledge of adjuvant and neoadjuvant treatment for PDAC and discusses the rationale for moving from adjuvant to preoperative and perioperative therapeutic strategies in the current era of more active chemotherapies and personalized medicine. We also discuss the integration of good specimen collection, tissue biomarkers, and imaging tools into newly designed preoperative and perioperative strategies. PMID- 25741135 TI - Anal cancer treatment: current status and future perspectives. AB - Anal cancers (AC) are relatively rare tumors. Their incidence is increasing, particularly among men who have sex with other men due to widespread infection by human papilloma virus. The majority of anal cancers are squamous cell carcinomas, and they are treated according to stage. In local and locally advanced AC, concomitant chemoradiation therapy based on mitomycin C and 5-Fluorouracil (5-FU) is the current best treatment, while metastatic AC, chemotherapy with 5-FU and cisplatin remains the gold standard. There are no indications for induction or maintenance therapies in locally advanced tumors. Many novel strategies, such as targeted therapies, vaccination, immunotherapy and photodynamic therapy are in clinical trials for the treatment of AC, with promising results in some indications. PMID- 25741137 TI - Treatment of irritable bowel syndrome in China: a review. AB - Irritable bowel syndrome (IBS) is a common, chronic, functional gastrointestinal disorder with a high incidence rate in the general population, and it is common among the Chinese population. The pathophysiology, etiology and pathogenesis of IBS are poorly understood, with no evidence of inflammatory, anatomic, metabolic, or neoplastic factors to explain the symptoms. Treatment approaches are mainly focused on symptom management to maintain everyday functioning and to improve quality of life for patients with IBS. However, prescribed medications often result in significant side effects, and many IBS sufferers (particularly Chinese) do not improve. Instead of taking a variety of conventional medications, many have turned to taking traditional Chinese medicine or integrated Chinese and Western medicine for remedy. A number of clinical trials have shown that Chinese herbal, acupuncture or integrative therapies presented improved treatment outcomes and reduced side effects in IBS patients. The purpose of this review article is to examine the treatment approaches of IBS that have been published in recent years, especially in China, to assess the possible differences in treating IBS between China and other countries. This would provide some useful information of unique treatment approach in clinical practice for physicians in the management of IBS in China, thus offering more treatment options for IBS patients with potentially better treatment outcomes while reducing the medical cost burden. PMID- 25741136 TI - Succinate dehydrogenase-deficient gastrointestinal stromal tumors. AB - Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1alpha may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH deficient GISTs. PMID- 25741138 TI - Silencing profilin-1 inhibits gastric cancer progression via integrin beta1/focal adhesion kinase pathway modulation. AB - AIM: To investigate the role of profilin-1 (PFN1) in gastric cancer and the underlying mechanisms. METHODS: Immunohistochemical analysis, quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were performed to detect PFN1 expression in clinical gastric carcinoma and adjacent tissues, and the association of PFN1 expression with patient clinicopathological characteristics was analyzed. PFN1 was knocked down to investigate the role of this protein in cell proliferation and metastasis in the SGC-7901 cell line. To explore the underlying mechanisms, the expression of integrin beta1 and the activity of focal adhesion kinase (FAK) and the downstream proteins extracellular regulated kinase (ERK)1/2, P38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) were measured through Western blot or qRT-PCR analysis. Fibronectin (FN), a ligand of integrin beta1, was used to verify the correlation between alterations in the integrin beta1/FAK pathway and changes in tumor cell aggressiveness upon PFN1 perturbation. RESULTS: Immunohistochemical, Western blot and qRT-PCR analyses revealed that PFN1 expression was higher at both the protein and mRNA levels in gastric carcinoma tissues compared with the adjacent tissues. In addition, high PFN1 expression (53/75, 70.4%) was correlated with tumor infiltration, lymph node metastasis and TNM stage in gastric cancer, but not with gender, age, location, tumor size, or histological differentiation. In vitro experiments showed that PFN1 knockdown inhibited the proliferation of SGC-7901 cells through the induction G0/G1 arrest. Silencing PFN1 inhibited cell migration and invasion and down-regulated the expression of matrix metalloproteinase (MMP) 2 and MMP9. Moreover, silencing PFN1 reduced the expression of integrin beta1 at the protein level and inhibited the activity of FAK, and the downstream effectors ERK1/2, P38MAPK, PI3K, AKT and mTOR. FN-promoted cell proliferation and metastasis via the integrin beta1/FAK pathway was ameliorated by PFN1 silencing. CONCLUSION: These findings suggest that PFN1 plays a critical role in gastric carcinoma progression, and these effects are likely mediated through the integrin beta1/FAK pathway. PMID- 25741140 TI - Screening analysis of candidate gene mutations in a kindred with polycystic liver disease. AB - AIM: To find potential mutable sites by detecting mutations of the candidate gene in a kindred with polycystic liver disease (PCLD). METHODS: First, we chose a kindred with PCLD and obtained five venous blood samples of this kindred after the family members signed the informed consent form. In the kindred two cases were diagnosed with PCLD, and the left three cases were normal individuals. All the blood samples were preserved at -85 degrees C. Second, we extracted the genomic DNA from the venous blood samples of the kindred using a QIAamp DNA Mini Kit and then performed long-range polymerase chain reaction (PCR) with different primers. The exons of PKD1 were all sequenced with the forward and reverse primers to ensure the accuracy of the results. Next, we purified the PCR products and directly sequenced them using Big Dye Terminator Chemistry version 3.1. The sequencing reaction was conducted with BiomekFX (Beckman). Finally, we analyzed the results. RESULTS: A total of 42 normal exons were identified in detecting mutations of the PKD1 gene. A synonymous mutation occurred in exon 5. The mutation was a homozygous T in the proband and was C in the reference sequence. This mutation was located in the third codon and did not change the amino acid encoded by the codon. Missense mutations occurred in exons 11 and 35. These mutations were located in the second codon; they changed the amino acid sequence and existed in the dbSNP library. A nonsense mutation occurred in exon 15. The mutation was a heterozygous CT in the proband and was C in the reference sequence. This mutation was located in the first codon and resulted in a termination codon. This mutation had an obvious influence on the encoded protein and changed the length of the protein from 4303 to 2246 amino acids. This was a new mutation that was not present in the dbSNP library. CONCLUSION: The nonsense mutation of exon 15 existed in the proband and in the third individual. Additionally, the proband was heterozygous for this mutation, so the mutable site was a pathogenic mutation. PMID- 25741139 TI - Biological effects of low-dose-rate irradiation of pancreatic carcinoma cells in vitro using 125I seeds. AB - AIM: To determine the mechanism of the radiation-induced biological effects of 125I seeds on pancreatic carcinoma cells in vitro. METHODS: SW1990 and PANC-1 pancreatic cancer cell lines were cultured in DMEM in a suitable environment. Gray's model of iodine-125 (125I) seed irradiation was used. In vitro, exponential phase SW1990, and PANC-1 cells were exposed to 0, 2, 4, 6, and 8 Gy using 125I radioactive seeds, with an initial dose rate of 12.13 cGy/h. A clonogenic survival experiment was performed to observe the ability of the cells to maintain their clonogenic capacity and to form colonies. Cell-cycle and apoptosis analyses were conducted to detect the apoptosis percentage in the SW1990 and PANC-1 cells. DNA synthesis was measured via a tritiated thymidine (3H TdR) incorporation experiment. After continuous low-dose-rate irradiation with 125I radioactive seeds, the survival fractions at 2 Gy (SF2), percentage apoptosis, and cell cycle phases of the SW1990 and PANC-1 pancreatic cancer cell lines were calculated and compared. RESULTS: The survival fractions of the PANC-1 and SW1990 cells irradiated with 125I seeds decreased exponentially as the dose increased. No significant difference in SF2 was observed between SW1990 and PANC 1 cells (0.766+/-0.063 vs 0.729+/-0.045, P<0.05). The 125I seeds induced a higher percentage of apoptosis than that observed in the control in both the SW1990 and PANC-1 cells. The rate of apoptosis increased with increasing radiation dosage. The percentage of apoptosis was slightly higher in the SW1990 cells than in the PANC-1 cells. Dose-dependent G2/M cell-cycle arrest was observed after 125I seed irradiation, with a peak value at 6 Gy. As the dose increased, the percentage of G2/M cell cycle arrest increased in both cell lines, whereas the rate of DNA incorporation decreased. In the 3H-TdR incorporation experiment, the dosimetry results of both the SW1990 and PANC-1 cells decreased as the radiation dose increased, with a minimum at 6 Gy. There were no significant differences in the dosimetry results of the two cell lines when they were exposed to the same dose of radiation. CONCLUSION: The pancreatic cancer cell-killing effects induced by 125I radioactive seeds mainly occurred via apoptosis and G2/M cell cycle arrest. PMID- 25741141 TI - Detection of human papillomavirus DNA in esophageal carcinoma in Greece. AB - AIM: To detect human papillomavirus (HPV) in the esophageal mucosa and the possible relationship with esophageal cancer in Greece. METHODS: Forty-nine patients underwent esophagogastroduodenoscopy (EGD) and esophageal biopsy at a university hospital that acts as a referral center for Northern Greece. Nineteen of these patients (14 male and 5 female) had esophageal squamous cell carcinoma (ESCC) and 30 (15 male and 15 female) did not have any reported esophageal malignancy. Histopathological assessment was followed by polymerase chain reaction analysis of all the samples. Patient demographic data (age, sex, and place of birth) and information regarding smoking habits, alcohol consumption or sexual habits were collected. A method of statistical interference, verification of hypotheses based on homogeneity and independent chi(2) test, was used. RESULTS: From the 49 patients that underwent EGD and biopsy, 19 had ESCC and 30 had normal esophageal mucosa, with a mean age of 65.2 years. Regarding the prevalence of oncogenic risk factors for esophageal carcinoma, an interesting conclusion was that 78% of the patients used tobacco and almost one-third had multiple sexual partners, whereas only 20% of the patients consumed alcohol, which was not statistically significant, when compared to the control group. In the ESCC group, the only two positive samples were among the male patients (2/14 male patients with ESCC, 14.5%). No HPV was identified in the control group. The predominant HPV types identified were 11 and 31, which have a low malignancy potential. The presence of HPV DNA in the ESCC group was not statistically significant, 95% confidence interval (chi2=3.292, P=0.07). CONCLUSION: This is the first relevant study in Greece, and despite the lack of statistical significance, the issue of HPV infection and ESCC does merit further investigation. PMID- 25741142 TI - Synchronous splenectomy and hepatectomy for patients with hepatocellular carcinoma and hypersplenism: A case-control study. AB - AIM: To investigate whether the use of synchronous hepatectomy and splenectomy (HS) is more effective than hepatectomy alone (HA) for patients with hepatocellular carcinoma (HCC) and hypersplenism. METHODS: From January 2007 to March 2013, 84 consecutive patients with HCC and hypersplenism who underwent synchronous hepatectomy and splenectomy in our center were compared with 84 well matched patients from a pool of 268 patients who underwent hepatectomy alone. The short-term and long-term outcomes of the two groups were analyzed and compared. RESULTS: The mean time to recurrence was 21.11+/-12.04 mo in the HS group and 11.23+/-8.73 mo in the HA group, and these values were significantly different (P=0.001). The 1-, 3-, 5-, and 7-year disease-free survival rates for the patients in the HS group and the HA group were 86.7%, 70.9%, 52.7%, and 45.9% and 88.1%, 59.4%, 43.3%, and 39.5%, respectively (P=0.008). Platelet and white blood cell counts in the HS group were significantly increased compared with the HA group one day, one week, one month and one year postoperatively (P<0.001). Splenectomy and micro-vascular invasion were significant independent prognostic factors for disease-free survival. Gender, tumor number, and recurrence were independent prognostic factors for overall survival. CONCLUSION: Synchronous hepatectomy and hepatectomy potentially improves disease-free survival rates and alleviates hypersplenism without increasing the surgical risks for patients with HCC and hypersplenism. PMID- 25741143 TI - Diagnosis of ectopic pancreas by endoscopic ultrasound with fine-needle aspiration. AB - AIM: To study the clinical, endoscopic, sonographic, and cytologic features of ectopic pancreas (EP). METHODS: This was a retrospective study performed at an academic referral center including two hospitals. Institutional review board approval was obtained. Patients referred to the University Hospital or Denver Health Medical Center Gastrointestinal Endoscopy Lab for gastroduodenal subepithelial lesions (SEL) with a final diagnosis of EP between January 2009 and December 2013 were identified. Patients in this group were selected for the study if they underwent endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) or deep biopsy. A review of the medical record was performed specifically to review the following information: presenting symptoms, endoscopic and EUS findings, computed tomography or magnetic resonance imaging findings, pathology results, procedure-related adverse events, and subsequent treatments after EUS FNA. EUS with FNA or deep submucosal biopsy was performed in all patients on an outpatient basais by one of two physicians (Attwell A, Fukami N). Review of all subsequent clinic notes and operative reports was performed in order to determine follow-up and final diagnoses. RESULTS: Between July 2009 and December 2013, 10 patients [3 males, 7 females, median age 52 (26-64) years] underwent EUS for a gastroduodenal SEL and were diagnosed with EP. One patient was symptomatic. Six (60%) lesions were in the antrum, 3 (30%) in the body, and 1 (10%) in the duodenum. A mucosal dimple was noted in 6 (60%). Mean lesion size was 17 (8-25) mm. Gastrointestinal wall involvement: muscularis mucosae, 10%; submucosa, 70%; muscularis propria, 60%; and serosa, 10%. Nine (90%) lesions were hypoechoic and 5 (50%) were homogenous. A duct was seen in 5 (50%). FNA was attempted in 9 (90%) and successful in 8 (80%) patients after 4 (2-6) passes. Cytology showed acini or ducts in 7 of 8 (88%). Superficial biopsies in 7 patients (70%) showed normal gastric mucosa. Deep endoscopic biopsies were taken in 2 patients and diagnostic in one. One patient (10%) developed pancreatitis after EUS-FNA. Two patients (20%) underwent surgery to relieve symptoms or confirm the diagnosis. The main limitation of the study was the fact that it was retrospective and performed at a single medical center. CONCLUSION: EUS features of EP include antral location, mucosal dimple, location in layers 3-4, and lesional duct, and FNA or biopsy is accurate and effective. PMID- 25741144 TI - Retrospective study of colorectal cancer in Zimbabwe: colonoscopic and clinical correlates. AB - AIM: To compare differences in the frequency of colorectal cancer at colonoscopy in Zimbabwe according to ethnicity. METHODS: All lower gastrointestinal endoscopic procedures performed between January 2006 and December 2011 at a gastroenterology clinic in Harare, Zimbabwe were reviewed. The demographic characteristics, clinical indications, differences in bowel preparation and the endoscopic and histological diagnoses were compared between different ethnic groups with emphasis on colorectal cancer. The clinical and demographic characteristics and the endoscopic findings were compared using the student t test and the chi2 test, while the clinical indications associated with a diagnosis of colorectal cancer were determined by logistic regression. RESULTS: All colonoscopies and sigmoidoscopies performed in 1236 Caucasians, 460 black Africans and 109 Asians were analysed. Colorectal cancer was diagnosed more frequently in the black African patients compared to Caucasians or Asians (10% vs 3%, 10% vs 2%, P<0.001). However, polyps were less common among black Africans (5%) compared to both Caucasians (8%) and Asians (9%) (P=0.03). Among patients with colorectal cancer, black Africans tended to be younger than Caucasians, who were over-represented in the oldest age category; 32 % vs 2% were less than 50 years and 41% vs 78% were older than 60 years (P<0.001). Anaemia and weight loss were associated with colorectal cancer in both black African [odds ratio (OR): 2.73 (95%CI: 1.33-5.61) and 3.09 (1.35-7.07)] and Caucasian patients [OR: 6.65 (95%CI: 2.93-15.09) and 3.47 (1.52-7.94)]. CONCLUSION: The likelihood of diagnosing colorectal cancer in patients referred for colonoscopy in Zimbabwe is at least as likely among black Africans as it is among Caucasians. PMID- 25741145 TI - Single-port laparoscopic surgery for sigmoid volvulus. AB - AIM: To report our experience with single-port laparoscopic surgery (SPLS) for sigmoid volvulus (SV). METHODS: Between October 2009 and April 2013, 10 patients underwent SPLS for SV. SPLS was performed transumbilically or through a predetermined stoma site. Conventional straight and rigid-type laparoscopic instruments were used. After intracorporeal, segmental resection of the affected sigmoid colon, the specimen was extracted through the single-incision site. Patient demographics and perioperative data were analyzed. RESULTS: SPLS for SV was successful in all 10 patients (4, resection and primary anastomosis; 6, Hartmann's procedure). The median operative time and postoperative hospitalization period were 168 (range, 85-315) min and 6.5 (range, 4-29) d, respectively. No intraoperative complications were noted; there were 2 postoperative complications, including 1 anastomotic leak. CONCLUSION: SPLS was a safe and feasible therapeutic approach for SV, when performed by a surgeon experienced in conventional laparoscopic surgery. PMID- 25741146 TI - Comparison of scoring systems in predicting the severity of acute pancreatitis. AB - AIM: To investigate the prognostic usefulness of several existing scoring systems in predicting the severity of acute pancreatitis (AP). METHODS: We retrospectively analyzed the prospectively collected clinical database from consecutive patients with AP in our institution between January 2011 and December 2012. Ranson, Acute Physiology and Chronic Health Evaluation (APACHE)-II, and bedside index for severity in acute pancreatitis (BISAP) scores, and computed tomography severity index (CTSI) of all patients were calculated. Serum C reactive protein (CRP) levels were measured at admission (CRPi) and after 24 h (CRP24). Severe AP was defined as persistent organ failure for more than 48 h. The predictive accuracy of each scoring system was measured by the area under the receiver-operating curve (AUC). RESULTS: Of 161 patients, 21 (13%) were classified as severe AP, and 3 (1.9%) died. Statistically significant cutoff values for prediction of severe AP were Ranson>=3, BISAP>=2, APACHE-II>=8, CTSI>=3, and CRP24>=21.4. AUCs for Ranson, BISAP, APACHE-II, CTSI, and CRP24 in predicting severe AP were 0.69 (95%CI: 0.62-0.76), 0.74 (95%CI: 0.66-0.80), 0.78 (95%CI: 0.70-0.84), 0.69 (95%CI: 0.61-0.76), and 0.68 (95%CI: 0.57-0.78), respectively. APACHE-II demonstrated the highest accuracy for prediction of severe AP, however, no statistically significant pairwise differences were observed between APACHE-II and the other scoring systems, including CRP24. CONCLUSION: Various scoring systems showed similar predictive accuracy for severity of AP. Unique models are needed in order to achieve further improvement of prognostic accuracy. PMID- 25741147 TI - Outcome of transarterial chemoembolization-based multi-modal treatment in patients with unresectable hepatocellular carcinoma. AB - AIM: To investigate the efficacy and safety of transarterial chemoembolization (TACE)-based multimodal treatment in patients with large hepatocellular carcinoma (HCC). METHODS: A total of 146 consecutive patients were included in the analysis, and their medical records and radiological data were reviewed retrospectively. RESULTS: In total, 119 patients received TACE-based multi-modal treatments, and the remaining 27 received conservative management. Overall survival (P<0.001) and objective tumor response (P=0.003) were significantly better in the treatment group than in the conservative group. After subgroup analysis, survival benefits were observed not only in the multi-modal treatment group compared with the TACE-only group (P=0.002) but also in the surgical treatment group compared with the loco-regional treatment-only group (P<0.001). Multivariate analysis identified tumor stage (P<0.001) and tumor type (P=0.009) as two independent pre-treatment factors for survival. After adjusting for significant pre-treatment prognostic factors, objective response (P<0.001), surgical treatment (P=0.009), and multi-modal treatment (P=0.002) were identified as independent post-treatment prognostic factors. CONCLUSION: TACE-based multi modal treatments were safe and more beneficial than conservative management. Salvage surgery after successful downstaging resulted in long-term survival in patients with large, unresectable HCC. PMID- 25741148 TI - Expression profile of polyunsaturated fatty acids in colorectal cancer. AB - AIM: To investigate the relationship between the metabolism of polyunsaturated fatty acids (PUFAs) and tumor-associated factors for predicting the outcome of colorectal carcinoma (CRC) in Chinese patients. METHODS: Fresh-frozen malignant and normal tissues from 82 Chinese patients with CRC were analyzed for PUFA composition using gas-liquid chromatography. The levels of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), prostaglandin E2 and platelet derived growth factor (PDGF) were measured by enzyme-linked immunosorbent assay, and the levels of VEGF, p53 and Ki-67 were measured by immunohistochemistry. RESULTS: In malignant tissue, compared with normal tissue, the levels of total omega-6 PUFAs (24.64%+/-3.41% vs 26.77%+/-3.37%, P=0.00) and linoleic acid (LA) (15.46%+/-3.51% vs 18.30%+/-2.83%, P<0.01) were lower, whereas the levels of total omega-3 PUFAs (1.58%+/-0.74% vs 1.35%+/-0.60%, P<0.01) and dihomo-gamma linolenic acid (DGLA) (1.32%+/-0.69% vs 0.85%+/-0.29%, P<0.01) were significantly higher. The ratios of arachidonic acid (AA)/LA (0.53+/-0.22 vs 0.42+/-0.19, P<0.01) and AA/total omega-6 PUFAs (0.31+/-0.09 vs 0.27+/-0.10, P<0.01) were also significantly higher in malignant tissue. The levels of PDGF (353.10+/-148.85 pg/mL vs 286.09+/-104.91 pg/mL, P<0.01), COX-2 (125.21+/-70.29 ng/mL vs 67.06+/ 42.22 ng/mL, P<0.01) and VEGF (357.11+/-128.76 pg/mL vs 211.38+/-99.47 pg/mL, P<0.01) were also higher in malignant tissue compared to normal tissue. COX-2 was inversely correlated with LA (R=-0.3244, P<0.05) and positively correlated with AA/total omega-6 PUFAs (R=0.3083, P<0.05) and AA/LA (R=0.3001, P<0.05). The tissue level of LA was highest in poorly differentiated tumors (19.9%+/-6.3%, P<0.05), while the ratio of AA/omega-3 PUFAs was lowest in these tumors (10.8+/ 2.6, P<0.05). In VEGF-positive tumors, the level of LA was higher (16.2%+/-3.7% vs 13.9%+/-2.7%, P<0.01), while the AA/omega-3PUFA, AA/omega-6 PUFA, and AA/LA ratios were lower than in VEGF-negative tumors (5.0+/-1.8 vs 6.7+/-3.3, 0.30+/ 0.09 vs 0.34+/-0.09, 0.50+/-0.21 vs 0.61+/-0.21, P<0.01). CONCLUSION: The metabolism of PUFAs may play an important role in the evolution of inflammation driven tumorigenesis in CRC and may be considered a potential marker for prognosis. PMID- 25741149 TI - Transjugular intrahepatic portosystemic shunt for severe jaundice in patients with acute Budd-Chiari syndrome. AB - AIM: To evaluate the feasibility of transjugular intrahepatic portosystemic shunt (TIPS) for severe jaundice secondary to acute Budd-Chiari syndrome (BCS). METHODS: From February 2009 to March 2013, 37 patients with severe jaundice secondary to acute BCS were treated. Sixteen patients without hepatic venule, hepatic veins (HV) obstruction underwent percutaneous angioplasty of the inferior vena cava (IVC) and/or HVs. Twenty-one patients with HV occlusion underwent TIPS. Serum bilirubin, liver function, demographic data and operative data of the two groups of patients were analyzed. RESULTS: Twenty-one patients underwent TIPS and the technical success rate was 100%, with no technical complications. Sixteen patients underwent recanalization of the IVC and/or HVs and the technical success rate was 100%. The mean procedure time for TIPS was 84.0+/-12.11 min and angioplasty was 44.11+/-5.12 min (P<0.01). The mean portosystemic pressure in the TIPS group decreased significantly from 40.50+/-4.32 to 16.05+/-3.50 mmHg (P<0.01). The mean portosystemic pressure gradient decreased significantly from 33.60+/-2.62 to 7.30+/-2.21 mmHg (P<0.01). At 8 wk after the procedures, in the TIPS group, total bilirubin (TBIL) decreased significantly from 266.24+/-122.03 before surgery to 40.11+/-3.52 MUmol/L (P<0.01) and direct bilirubin (DBIL) decreased significantly from 194.22+/-69.82 MUmol/L to 29.82+/-3.10 MUmol/L (P<0.01). In the angioplasty group, bilirubin returned to the normal range, with TBIL decreased significantly from 258.22+/-72.71 MUmol/L to 13.33+/-3.54 MUmol/L (P<0.01) and DBIL from 175.08+/-39.27 to 4.03+/-1.74 MUmol/L (P<0.01). Liver function improved faster than TBIL. After 2 wk, in the TIPS group, alanine aminotransferase (ALT) decreased significantly from 50.33+/-40.61 U/L to 28.67+/ 7.02 U/L (P<0.01) and aspartate aminotransferase (AST) from 49.46+/-34.33 U/L to 26.89+/-8.68 U/L (P<0.01). In the angioplasty group, ALT decreased significantly from 51.56+/-27.90 to 14.22+/-2.59 MUmol/L (P<0.01) and AST from 60.66+/-39.89 MUmol/L to 8.18+/-1.89 MUmol/L (P<0.01). After mean follow-up of 12.6 mo, there was no recurrence of jaundice in either group. CONCLUSION: Severe jaundice is not a contraindication for TIPS in patients with acute BCS and TIPS is appropriate for severe jaundice due to BCS. PMID- 25741150 TI - Determination of the upper cut-off values of serum alanine aminotransferase and aspartate aminotransferase in Chinese. AB - AIM: To determine the upper cut-off values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a Northern Chinese population. METHODS: A total of 3769 subjects in Jilin Province Northeast China were stratified to determine the potential factors affecting serum ALT and AST levels. The upper cut-off values of serum ALT and AST in these subjects were determined using receiver operating characteristic analysis and their sensitivity and specificity were evaluated. RESULTS: Stratification analysis revealed that serum ALT and AST levels were associated with gender, alcohol consumption, serum cholesterol and triglyceride levels, and body mass index. The upper cut-off values of serum ALT and AST were 22.15 U/L and 25.35 U/L for healthy men and 22.40 U/L and 24.25 U/L for healthy women, respectively. The new cut-off values had a higher sensitivity, but a slightly lower specificity than the current standards. CONCLUSION: Our results indicate that the new upper cut-off values of serum ALT and AST are markedly lower than current standards and may be valuable for the evaluation of liver function. PMID- 25741151 TI - Small-volume chylous ascites after laparoscopic radical gastrectomy for gastric cancer: results from a large population-based sample. AB - AIM: To report the incidence and potential risk factors of small-volume chylous ascites (SVCA) following laparoscopic radical gastrectomy (LAG). METHODS: A total of 1366 consecutive gastric cancer patients who underwent LAG from January 2008 to June 2011 were enrolled in this study. We analyzed the patients based on the presence or absence of SVCA. RESULTS: SVCA was detected in 57 (4.17%) patients, as determined by the small-volume drainage (range, 30-100 mL/24 h) of triglyceride-rich fluid. Both univariate and multivariate analyses revealed that the total number of resected lymph nodes (LNs), No. 8 or No. 9 LN metastasis and N stage were independent risk factors for SVCA following LAG (P<0.05). Regarding hospital stay, there was a significant difference between the groups with and without SVCA (P<0.001). The 3-year disease-free and overall survival rates of the patients with SVCA were 47.4% and 56.1%, respectively, which were similar to those of the patients without SVCA (P>0.05). CONCLUSION: SVCA following LAG developed significantly more frequently in the patients with >=32 harvested LNs, >=3 metastatic LNs, or No. 8 or No. 9 LN metastasis. SVCA, which was successfully treated with conservative management, was associated with a prolonged hospital stay but was not associated with the prognosis. PMID- 25741152 TI - Coexpression of MYC and BCL-2 predicts prognosis in primary gastrointestinal diffuse large B-cell lymphoma. AB - AIM: To investigate whether MYC and BCL-2 coexpression has prognostic significance in primary gastrointestinal diffuse large B-cell lymphoma (PGI DLBCL) patients, and explore its associations with patients' clinical parameters. METHODS: Fresh and paraffin-embedded tumor tissue samples from 60 PGI-DLBCL patients who had undergone surgery at the Tianjin Medical University Cancer Institute and Hospital from January 2005 to May 2010 were obtained, and 30 lymphoid tissue samples from reactive lymph nodes of age- and sex-matched patients represented control samples. Staging and diagnostic procedures were conducted according to the Lugano staging system. All patients had been treated with three therapeutic modalities: surgery, chemotherapy, or radiotherapy. Expression of MYC and BCL-2 were detected at both protein and mRNA levels by immunohistochemistry and real-time RT-PCR. RESULTS: Positive expression levels of MYC and BCL-2 proteins were detected in 35% and 45% of patients, respectively. MYC+/BCL-2+ protein was present in 30% of patients. MYC and BCL-2 protein levels were correlated with high MYC and BCL-2 mRNA expression, respectively (both P<0.05). We found that advanced-stage disease (at IIE-IV) was associated with MYC and BCL-2 coexpression levels (P<0.05). In addition, MYC+/BCL-2+ patients had more difficulty in achieving complete remission than others (P<0.05). Presence of MYC protein expression only affected overall survival and progression-free survival (PFS) when BCL-2 protein was coexpressed. The adverse prognostic impact of MYC+/BCL-2+ protein on PFS remained significant (P<0.05) even after adjusting for age, Lugano stage, international prognostic index, and BCL-2 protein expression in a multivariable model. CONCLUSION: MYC+/BCL-2+ patients have worse chemotherapy response and poorer prognosis than patients who only express one of the two proteins, suggesting that assessment of MYC and BCL-2 expression by immunohistochemistry has clinical significance in predicting clinical outcomes of PGI-DLBCL patients. PMID- 25741153 TI - Nasobiliary drainage after endoscopic papillary balloon dilatation may prevent postoperative pancreatitis. AB - AIM: To evaluate the necessity of endoscopic nasobiliary drainage (ENBD) catheter placement after clearance of common bile duct (CBD) stones. METHODS: Patients enrolled in this study were randomly divided into two groups, according to whether or not they received ENBD after the removal of CBD stones. Group 1 (ENBD group) was then subdivided into three groups: G1a patients received an endoscopic papillary balloon dilatation (EPBD), G1b patients received an endoscopic sphincterotomy (EST), and G1c patients received neither. Group 2 (non-ENBD group) patients were also subdivided into three groups (G2a, G2b, and G2c), similar to Group 1. The maximum CBD diameter, the time for C-reactive protein (CRP) to normalize, levels of serum amylase, total serum bilirubin (TB) and alanine aminotransferase (ALT), and postoperative hospitalization duration (PHD) were measured. RESULTS: A total of 218 patients (139 males, 79 females), with an average age of 60.1+/-10.8 years, were enrolled in this study. One hundred and thirteen patients who received ENBD were included in Group 1, and 105 patients who did not receive ENBD were included in Group 2. The baseline clinical characteristics were similar in both groups. There were no significant differences in post-endoscopic retrograde cholangiopancreatography (ERCP)-related complications when Groups 1 and 2 were compared. Seventy-seven patients underwent EPBD, and 41 received an ENBD tube (G1a) and 36 did not (G2a). Seventy-three patients underwent EST, and 34 patients received an ENBD tube (G1b) and 39 did not (G2b). The remaining 68 patients underwent neither EPBD nor EST; of these patients, 38 received an ENBD tube (G1c) and 30 did not (G2c). For each of the three pairs of subgroups (G1a vs G2a, G1b vs G2b, G1c vs G2c), there were no significant differences detected in the PHD or the time to normalization of CRP, TB and ALT. In the EPBD group, the incidence of post-ERCP pancreatitis, hyperamylasemia and overall patient complications was significantly higher for G2a (post-ERCP pancreatitis: 6/36 vs 0/41, P=0.0217; hyperamylasemia: 11/36 vs 4/41, P=0.0215; overall patient complications: 18/36 vs 7/41, P=0.0029). CONCLUSION: After successful CBD stone clearance, ENBD is only beneficial when an EPBD procedure has been performed. PMID- 25741154 TI - Appropriateness of systemic treatments in unresectable metastatic well differentiated pancreatic neuroendocrine tumors. AB - AIM: To evaluate systemic treatment choices in unresectable metastatic well differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled secretory symptoms, octreotide LAR doses can be titrated up to 60 mg every 4 wk or up to 40 mg every 3 or 4 wk. CONCLUSION: Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs. PMID- 25741155 TI - Impact of endoscopic screening on mortality reduction from gastric cancer. AB - AIM: To investigate mortality reduction from gastric cancer based on the results of endoscopic screening. METHODS: The study population consisted of participants of gastric cancer screening by endoscopy, regular radiography, and photofluorography at Niigata city in 2005. The observed numbers of cumulative deaths from gastric cancers and other cancers were accumulated by linkage with the Niigata Prefectural Cancer Registry. The standardized mortality ratio (SMR) of gastric cancer and other cancer deaths in each screening group was calculated by applying the mortality rate of the reference population. RESULTS: Based on the results calculated from the mortality rate of the population of Niigata city, the SMRs of gastric cancer death were 0.43 (95%CI: 0.30-0.57) for the endoscopic screening group, 0.68 (95%CI: 0.55-0.79) for the regular radiographic screening group, and 0.85 (95%CI: 0.71-0.94) for the photofluorography screening group. The mortality reduction from gastric cancer was higher in the endoscopic screening group than in the regular radiographic screening group despite the nearly equal mortality rates of all cancers except gastric cancer. CONCLUSION: The 57% mortality reduction from gastric cancer might indicate the effectiveness of endoscopic screening for gastric cancer. Further studies and prudent interpretation of results are needed. PMID- 25741156 TI - Percutaneous needle decompression in treatment of malignant small bowel obstruction. AB - AIM: To investigate the efficacy and safety of percutaneous needle decompression in the treatment of malignant small bowel obstruction (MSBO). METHODS: A prospective analysis of the clinical data of 52 MSBO patients undergoing percutaneous needle decompression was performed. RESULTS: Percutaneous needle decompression was successful in all 52 patients. Statistically significant differences were observed in symptoms such as vomiting, abdominal distension and abdominal pain before and after treatment (81.6% vs 26.5%, 100% vs 8.2%, and 85.7% vs 46.9%, respectively; all P < 0.05). The overall significantly improved rate was 19.2% (11/52) and the response rate was 94.2% (49/52) using decompression combined with nasal tube placement, local arterial infusion of chemotherapy and nutritional support. During the one-month follow-up period, puncture-related complications were acceptable. CONCLUSION: Percutaneous needle intestinal decompression is a safe and effective palliative treatment for MSBO. PMID- 25741157 TI - Long-term outcome of infliximab combined with surgery for perianal fistulizing Crohn's disease. AB - AIM: To evaluate the efficacy and long-term outcome of infliximab combined with surgery to treat perianal fistulizing Crohn's disease (CD). METHODS: The work was performed as a prospective study. All patients received infliximab combined with surgery to treat perianal fistulizing CD, which was followed by an immunosuppressive agent as maintenance therapy. RESULTS: A total of 28 patients with perianal fistulizing CD were included. At week 30, 89.3% (25/28) of the patients were clinically cured with an average healing time of 31.4 d. The CD activity index decreased to 70.07+/-77.54 from 205.47+/-111.13 (P<0.01) after infliximab treatment. The perianal CD activity index was decreased to 0.93+/-2.08 from 8.54+/-4.89 (P<0.01). C-reactive protein, erythrocyte sedimentation rate, platelets, and neutrophils all decreased significantly compared with the pretreatment levels (P<0.01). Magnetic resonance imaging results for 16 patients after therapy showed that one patient had a persistent presacral-rectal fistula and another still had a cavity without clinical symptoms at follow-up. After a median follow-up of 26.4 mo (range: 14-41 mo), 96.4% (27/28) of the patients had a clinical cure. CONCLUSION: Infliximab combined with surgery is effective and safe in the treatment of perianal fistulizing CD, and this treatment was associated with better long-term outcomes. PMID- 25741158 TI - Effect of pronase as mucolytic agent on imaging quality of magnifying endoscopy. AB - AIM: To investigate the efficacy of premedication with pronase, a proteolytic enzyme, in improving image quality during magnifying endoscopy. METHODS: The study was of a blinded, randomized, prospective design. Patients were assigned to groups administered oral premedication of either pronase and simethicone (Group A) or simethicone alone (Group B). First, the gastric mucosal visibility grade (1 4) was determined during conventional endoscopy, and then a magnifying endoscopic examination was conducted. The quality of images obtained by magnifying endoscopy at the stomach and the esophagus was scored from 1 to 3, with a lower score indicating better visibility. The endoscopist used water flushes as needed to obtain satisfactory magnifying endoscopic views. The main study outcomes were the visibility scores during magnifying endoscopy and the number of water flushes. RESULTS: A total of 144 patients were enrolled, and data from 143 patients (M:F=90:53, mean age 57.5 years) were analyzed. The visibility score was significantly higher in the stomach following premedication with pronase (73% with a score of 1 in Group A vs 49% in Group B, P<0.05), but there was no difference in the esophagus visibility scores (67% with a score of 1 in Group A vs 58% in Group B). Fewer water flushes [mean 0.7+/-0.9 times (range: 0-3 times) in Group A vs 1.9+/-1.5 times (range: 0-6 times) in Group B, P<0.05] in the pronase premedication group did not affect the endoscopic procedure times [mean 766 s (range: 647-866 s) for Group A vs 760 s (range: 678-854 s) for Group B, P=0.88]. The total gastric mucosal visibility score was also lower in Group A (4.9+/-1.5 vs 8.3+/-1.8 in Group B, P<0.01). CONCLUSION: The addition of pronase to simethicone premedication resulted in clearer images during magnifying endoscopy and reduced the need for water flushes. PMID- 25741159 TI - Clinical observations on the treatment of prolapsing hemorrhoids with tissue selecting therapy. AB - AIM: To compare the effects and postoperative complications between tissue selecting therapy stapler (TST) and Milligan-Morgan hemorrhoidectomy (M-M). METHODS: Four hundred and eighty patients with severe prolapsing hemorrhoids, who were admitted to the Shenyang Coloproctology Hospital between 2009 and 2012, were randomly divided into observation (n=240) and control (n=240) groups. Hemorrhoidectomies were performed with TST in the observation group and with the M-M technique in the control group. The therapeutic effects, operation security, and postoperative complications in the two groups were compared. The immediate and long-term complications were assessed according to corresponding criteria. Pain was assessed on a visual analogue scale. The efficacy was assessed by specialized criteria. The follow-up was conducted one year after the operation. RESULTS: The total effective rates of the observation and control groups were 99.5% (217/218) and 98.6% (218/221) respectively; the difference was not statistically significant (P=0.322). Their were significant differences between observation and control groups in intraoperative blood loss (5.07+/-1.14 vs 2.45+/-0.57, P=0.000), pain (12 h after the surgery: 5.08+/-1.62 vs 7.19+/-2.01, P=0.000; at first dressing change: 2.64+/-0.87 vs 4.34+/-1.15, P=0.000; first defecation: 3.91+/-1.47 vs 5.63+/-1.98, P=0.001), urine retention (n=22 vs n=47, P=0.001), anal pendant expansion after the surgery (2.35+/-0.56 vs 5.16+/-1.42, P=0.000), operation time (18.3+/-5.6 min vs 29.5+/-8.2 min, P=0.000), and the length of hospital stay (5.3+/-0.6 d vs 11.4+/-1.8 d, P=0.000). Moreover TST showed significant reductions compared to M-M in the rates of long-term complications such as fecal incontinence (n=3 vs n=16, P=0.003), difficult bowel movement (n=1 vs n=9, P=0.011), intractable pain (n=2 vs n=12, P=0.007), and anal discharge (n=3 vs n=23, P=0.000). CONCLUSION: TST for severe prolapsing hemorrhoids is a satisfactory technique for more rapid recovery, lower complication rates, and higher operation security. PMID- 25741160 TI - Optimal initiation of Helicobacter pylori eradication in patients with peptic ulcer bleeding. AB - AIM: To evaluate when Helicobacter pylori (H. pylori) eradication therapy (ET) should be started in patients with peptic ulcer bleeding (PUB). METHODS: Clinical data concerning adults hospitalized with PUB were retrospectively collected and analyzed. Age, sex, type and stage of peptic ulcer, whether endoscopic therapy was performed or not, methods of H. pylori detection, duration of hospitalization, and specialty of the attending physician were investigated. Factors influencing the confirmation of H. pylori infection prior to discharge were determined using multiple logistic regression analysis. The H. pylori eradication rates of patients who received ET during hospitalization and those who commenced ET as outpatients were compared. RESULTS: A total of 232 patients with PUB were evaluated for H. pylori infection by histology and/or rapid urease testing. Of these patients, 53.7% (127/232) had confirmed results of H. pylori infection prior to discharge. In multivariate analysis, duration of hospitalization and ulcer stage were factors independently influencing whether H. pylori infection was confirmed before or after discharge. Among the patients discharged before confirmation of H. pylori infection, 13.3% (14/105) were lost to follow-up. Among the patients found to be H. pylori-positive after discharge, 41.4% (12/29) did not receive ET. There was no significant difference in the H. pylori eradication rate between patients who received ET during hospitalization and those who commenced ET as outpatients [intention-to-treat: 68.8% (53/77) vs 60% (12/20), P=0.594; per-protocol: 82.8% (53/64) vs 80% (12/15), P=0.723]. CONCLUSION: Because many patients with PUB who were discharged before H. pylori infection status was confirmed lost an opportunity to receive ET, we should confirm H. pylori infection and start ET prior to discharge. PMID- 25741161 TI - Tenofovir rescue therapy in pregnant females with chronic hepatitis B. AB - AIM: To evaluate the safety and efficacy of tenofovir monotherapy in pregnant females resistant to lamivudine or telbivudine. The effect of tenofovir on the fetus was also assessed. METHODS: The clinical data of 17 females were reviewed in this study. Adverse events and pregnancy outcomes from January 1, 2011 to June 30, 2013 were evaluated in the Department of Gynecology and Obstetrics of Beijing Ditan Hospital, Capital Medical University, Beijing, China. These pregnant females developed lamivudine (LAM)- or telbivudine (LdT)-resistant chronic hepatitis B and received tenofovir (TDF) therapy (300 mg/d), and its curative effect, maternal and perinatal adverse events, fetal growth and development, and neonatal prognosis were evaluated. RESULTS: The median hepatitis B virus (HBV) DNA level in the pregnant females with LAM or LdT resistance was 5.9 (range, 4.2 7.2) log10 copies/mL before the initiation of TDF. Ten of these females had abnormal alanine aminotransferase (ALT) levels. The patients were treated with TDF for a median of 24 wk (range, 12-40 wk). Fourteen females (82.4%) had an HBV DNA level of <500 copies/mL at the time of delivery. This decrease was statistically significant (P<0.0001). Serum ALT levels were normalized in all subjects with an elevated serum ALT level at baseline (P=0.0003). There were no significant changes in serum creatinine and phosphorus levels during TDF treatment. In addition, no adverse events related to TDF treatment were observed. Seventeen females delivered 17 live infants, and all infants had good Apgar scores. The mean birth weight was 3226.5+/-331.7 g, and the mean length at birth was 50.4+/-1.1 cm. The growth and development of the infants was normal at birth, and no infants had birth defects related to TDF treatment. Eleven infants completed HBV vaccination and had no evidence of vertical transmission. CONCLUSION: The use of TDF in pregnant females with chronic HBV and LAM or LdT resistance was safe and effective. PMID- 25741162 TI - Prophylactic intra-peritoneal drain placement following pancreaticoduodenectomy: a systematic review and meta-analysis. AB - AIM: To conduct a meta-analysis comparing outcomes after pancreaticoduodenectomy (PD) with or without prophylactic drainage. METHODS: Relevant comparative randomized and non-randomized studies were systemically searched based on specific inclusion and exclusion criteria. Postoperative outcomes were compared between patients with and those without routine drainage. Pooled odds ratios (OR) with 95%CI were calculated using either fixed effects or random effects models. RESULTS: One randomized controlled trial and four non-randomized comparative studies recruiting 1728 patients were analyzed. Patients without prophylactic drainage after PD had significantly higher mortality (OR=2.32, 95%CI: 1.11-4.85; P=0.02), despite the fact that they were associated with fewer overall complications (OR=0.62, 95%CI: 0.48-0.82; P=0.00), major complications (OR=0.75, 95%CI: 0.60-0.93; P=0.01) and readmissions (OR=0.77, 95%CI: 0.60-0.98; P=0.04). There were no significant differences in the rates of pancreatic fistula, intra abdominal abscesses, postpancreatectomy hemorrhage, biliary fistula, delayed gastric emptying, reoperation or radiologic-guided drains between the two groups. CONCLUSION: Indiscriminate abandonment of intra-abdominal drainage following PD is associated with greater mortality, but lower complication rates. Future randomized trials should compare routine vs selective drainage. PMID- 25741163 TI - Meta-analysis: is combination of tetracycline and amoxicillin suitable for Helicobacter pylori infection? AB - AIM: To access the efficacy of combination with amoxicillin and tetracycline for eradication of Helicobacter pylori (H. pylori), thus providing clinical practice guidelines. METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, China National Knowledge Infrastructure, Wanfang, and Chinese Biomedical Literature databases and abstract books of major European, American, and Asian gastroenterological meetings were searched. All clinical trials that examined the efficacy of H. pylori eradication therapies and included both tetracycline and amoxicillin in one study arm were selected for this systematic review and meta-analysis. Statistical analysis was performed with Comprehensive Meta-Analysis Software (Version 2). Subgroup, meta-regression, and sensitivity analyses were also carried out. RESULTS: Thirty-three studies met the inclusion criteria. The pooled odds ratio (OR) was 0.90 (95%CI: 0.42-1.78) for quadruple therapy with amoxicillin and tetracycline vs other quadruple regimens, and total eradication rates were 78.1% by intention-to-treat (ITT) and 84.5% by per-protocol (PP) analyses in the experimental groups. The pooled eradication rates of 14-d quadruple regimens with a combination of amoxicillin and tetracycline were 82.3% by ITT and 89.0% by PP, and those of 10-d regimens were 84.6% by ITT and 93.7% by PP. The OR by ITT were 1.21 (95%CI: 0.64-2.28) for triple regimens with amoxicillin and tetracycline vs other regimens and 1.81 (95%CI: 1.37-2.41) for sequential treatment with amoxicillin and tetracycline vs other regimens, respectively. CONCLUSION: The effectiveness of regimens employing amoxicillin and tetracycline for H. pylori eradication may be not inferior to other regimens, but further study should be necessary. PMID- 25741164 TI - Endoscopic variceal ligation compared with endoscopic injection sclerotherapy for treatment of esophageal variceal hemorrhage: a meta-analysis. AB - AIM: To compare the effect of endoscopic variceal ligation (EVL) with that of endoscopic injection sclerotherapy (EIS) in the treatment of patients with esophageal variceal bleeding. METHODS: We performed a systematic literature search of multiple online electronic databases. Meta-analysis was conducted to evaluate risk ratio (RR) and 95% confidence interval (CI) of combined studies for the treatment of patients with esophageal variceal bleeding between EVL and EIS. RESULTS: Fourteen studies comprising 1236 patients were included in the meta analysis. The rebleeding rate in actively bleeding varices patients in the EVL group was significantly lower than that in the EIS group (RR=0.68, 95%CI: 0.57 0.81). The variceal eradication rate in actively bleeding varices patients in the EVL group was significantly higher than that in the EIS group (RR=1.06, 95%CI: 1.01-1.12). There was no significant difference about mortality rate between the EVL group and EIS group (RR=0.95, 95%CI: 0.77-1.17). The rate of complications in actively bleeding varices patients in the EVL group was significantly lower than that in the EIS group (RR=0.28, 95%CI: 0.13-0.58). CONCLUSION: Our meta-analysis has found that EVL is better than EIS in terms of the lower rates of rebleeding, complications, and the higher rate of variceal eradication. Therefore, EVL is the first choice for esophageal variceal bleeding. PMID- 25741165 TI - Catastrophic gastrointestinal complication of systemic immunosuppression. AB - We present a case of acute upper gastrointestinal haemorrhage in a patient with systemic vasculitis immunosuppressed on cyclophosphamide and prednisolone. The patient presented with a diffuse haemorrhagic oesophagitis and a non-specific duodenitis. Biopsies taken from the oesophagus and duodenum demonstrated infection with herpes simplex virus (HSV) and cytomegalovirus (CMV) respectively. Viral infection of the upper gastrointestinal tract is a recognised complication of immunosuppression and HSV is one of the most common pathogens. CMV on the other hand most commonly causes a colitis or less commonly oesophagitis. CMV enteritis is rare as is the synchronous infection with two viral agents in an immunocompromised patient having being described in a few case series only. Viral infection of the gastrointestinal tract in immunocompromised patients should be treated with systemic anti-viral medication and consideration to withdrawal of the immunosuppressive therapy if possible and appropriate. The authors highlight the need for a high suspicion of viral infection in immunosuppressed patients presenting with upper gastrointestinal bleeding. PMID- 25741166 TI - Portomesenteric venous thrombosis: an early postoperative complication after laparoscopic biliopancreatic diversion. AB - The number of bariatric operations, as well as the incidence of perioperative complications, has risen sharply in the past ten years. Perioperative acute portal vein thrombosis is an infrequent and potentially severe postoperative complication that has not yet been reported after biliopancreatic diversion (BPD). Three cases are presented of portal vein thrombosis that occurred following BPD treatment for morbid obesity and type 2 diabetes. The thromboses were detected by abdominal ultrasound and computed tomography with intravenous contrast. The portomesenteric venous thromboses in all three cases presented as unexpected abdominal pain several days after discharge from the hospital. The complications occurred despite adequate perioperative prophylaxis and progressed to bowel gangrene in the diabetic patients only. These cases demonstrate the occurrence of this rare type of complication, which may be observed by physicians that do not routinely treat bariatric patients. Awareness of this surgical complication will allow for early diagnosis and prompt initiation of adequate therapy. PMID- 25741167 TI - Hepatic phenotypes of HNF1B gene mutations: a case of neonatal cholestasis requiring portoenterostomy and literature review. AB - Hepatocyte nuclear factor 1-beta (HNF1B) defects cause renal cysts and diabetes syndrome (RCAD), or HNF1B-maturity-onset diabetes of the young. However, the hepatic phenotype of HNF1B variants is not well studied. We present a female neonate born small for her gestational age [birth weight 2360 g; -2.02 standard deviations (SD) and birth length 45 cm; -2.40 SD at the 38(th) gestational week]. She developed neonatal cholestasis due to biliary atresia and required surgical intervention (portoenterostomy) when 32-d old. Following the operation, icterus resolved, but laboratory signs of liver dysfunction persisted. She had hyperechogenic kidneys prenatally with bilateral renal cysts and pancreatic hypoplasia postnatally that led to the diagnosis of an HNF1B deletion. This represents the most severe hepatic phenotype of an HNF1B variant recognized thus far. A review of 12 published cases with hepatic phenotypes of HNF1B defects allowed us to distinguish three severity levels, ranging from neonatal cholestasis through adult-onset cholestasis to non-cholestatic liver impairment, all of these are associated with congenital renal cysts and mostly with diabetes later in life. We conclude that to detect HNF1B variants, neonates with cholestasis should be checked for the presence of renal cysts, with special focus on those who are born small for their gestational age. Additionally, patients with diabetes and renal cysts at any age who develop cholestasis and/or exocrine pancreatic insufficiency should be tested for HNF1B variants as the true etiological factor of all disease components. Further observations are needed to confirm the potential reversibility of cholestasis in infancy in HNF1B mutation/deletion carriers. PMID- 25741168 TI - Successful hemostasis of intractable rectal variceal bleeding using variceal embolization. AB - Portal hypertension causes portosystemic shunting along the gastrointestinal tract, resulting in gastrointestinal varices. Rectal varices and their bleeding is a rare complication, but it can be fatal without appropriate treatment. However, because of its rarity, no established treatment strategy is yet available. In the setting of intractable rectal variceal bleeding, a transjugular intravenous portosystemic shunt can be a treatment of choice to enable portal decompression and thus achieve hemostasis. However, in the case of recurrent rectal variceal bleeding despite successful transjugular intravenous portosystemic shunt, alternative measures to control bleeding are required. Here, we report on a patient with liver cirrhosis who experienced recurrent rectal variceal bleeding even after successful transjugular intravenous portosystemic shunt and was successfully treated with variceal embolization. PMID- 25741169 TI - Rectal tonsil: a case report and literature review. AB - The rectal tonsil, a reactive proliferation of lymphoid tissue located in the rectum, is rare. Histologically, benign lymphoid hyperplasia of the rectum is usually characterized by large lymphoid follicles with active germinal centers and a narrow surrounding mantle zone and marginal zone. This lesion is benign, but must be differentiated from the polypoid type of mucosa-associated lymphoid tissue lymphomas. In the current paper, we present a case of rectal tonsil in a 59-year-old woman. We describe the endoscopic ultrasound imaging findings with literature review. PMID- 25741170 TI - Complete remission of advanced hepatocellular carcinoma by radiofrequency ablation after sorafenib therapy. AB - Sorafenib, a potent multikinase inhibitor, lead to a significant improvement in progression free survival and overall survival in patients with advanced hepatocellular carcinoma (HCC). Though sorafenib has proven its efficacy in advanced stage HCC, there are limited reports on the role of sorafenib allowing for curative treatment by down-staging. We herein report a case of advanced HCC with vascular invasion, which showed treatment response by sorafenib therapy as to allow for radiofrequency ablation as curative treatment. The patient was followed-up for 6 mo without recurrence with continued sorafenib therapy. PMID- 25741172 TI - Social Understanding in Israeli-Jewish, Israeli-Palestinian, Palestinian, and Jordanian 5-year-old Children: Moral Judgments and Stereotypes. AB - An empirical investigation was conducted of young Palestinian, Jordanian, Israeli Palestinian, and Israeli-Jewish children's (N = 433; M = 5.7 years of age) cultural stereotypes and their evaluations of peer intergroup exclusion based upon a number of different factors, including being from a different country and speaking a different language. Children in this study live in a geographical region that has a history of cultural and religious tension, violence, and extreme intergroup conflict. Our findings revealed that the negative consequences of living with intergroup tension are related to the use of stereotypes. At the same time, the results for moral judgments and evaluations about excluding peers provided positive results about the young children's inclusive views regarding peer interactions. PMID- 25741171 TI - Primary gastrointestinal stromal tumor of the liver treated with sequential therapy. AB - A 67-year-old female presented with a primary hepatic gastrointestinal stromal tumor that was detected by computed tomography and diagnosed based on histopathological and genetic analyses. The tumor was microscopically composed of spindle cells and epithelioid cells, and immunohistochemistry results showed positive staining for CD117 and CD34 expression. A genetic analysis revealed a heterozygous point mutation and deletion in exon 11 of c-KIT. After an R0 resection, imatinib mesylate was administered for 1 year until its use was discontinued due to severe side effects. Two years after the original operation, the tumor recurred in the residual liver and was completely resected again. Imatinib mesylate was administered for 2 years until it was replaced by sunitinib malate because of disease progression. The patient has survived for 53 mo after undergoing a sequential therapy consisting of surgical excision, imatinib and sunitinib. PMID- 25741173 TI - Cluster-based Epidemic Control Through Smartphone-based Body Area Networks. AB - Increasing population density, closer social contact and interactions make epidemic control difficult. Traditional offline epidemic control methods (e.g., using medical survey or medical records) or model-based approach are not effective due to its inability to gather health data and social contact information simultaneously or impractical statistical assumption about the dynamics of social contact networks, respectively. In addition, it is challenging to find optimal sets of people to be quarantined to contain the spread of epidemics for large populations due to high computational complexity. Unlike these approaches, in this paper, a novel cluster-based epidemic control scheme is proposed based on Smartphone-based body area networks. The proposed scheme divides the populations into multiple clusters based on their physical location and social contact information. The proposed control schemes are applied within the cluster or between clusters. Further, we develop a computational efficient approach called UGP to enable an effective cluster-based quarantine strategy using graph theory for large scale networks (i.e., populations). The effectiveness of the proposed methods is demonstrated through both simulations and experiments on real social contact networks. PMID- 25741174 TI - The Domestic Violence Fatality Review: Can It Mobilize Community-Level Change? AB - Domestic Violence Fatality Review (DVFR) teams are a means of identifying systems' gaps in the coordinated response to domestic violence. While the number of homicide reviews has grown, little is known about whether DVFRs facilitate change in the community-level response to domestic violence. This research evaluated whether the recommendations made by one state-level DVFR had an effect on community and organizational priorities and practices. The results indicate that the recommendations influence countywide priorities, but less was done to implement the recommendations. DVFRs have the capacity to influence community level change agendas; however, organizations need support moving from issue prioritization to implementation. PMID- 25741175 TI - Adsorption of Sb(III) and Sb(V) on Freshly Prepared Ferric Hydroxide (FeOxHy). AB - This study prepared fresh ferric hydroxide (in-situ FeOxHy) by the enhanced hydrolysis of Fe3+ ions, and investigates its adsorptive behaviors toward Sb(III) and Sb(V) through laboratory and pilot-scale studies. A contact time of 120-min was enough to achieve adsorption equilibrium for Sb(III) and Sb(V) on the in-situ FeOxHy, and the Elovich model was best to describe the adsorption kinetics of Sb(III) and Sb(V). The Freundlich model was better than Langmuir model to describe the adsorption of Sb(III) and Sb(V) on the in-situ FeOxHy, and the maximum adsorption capacity of Sb(III) and Sb(V) was determined to be 12.77 and 10.21 mmol/g the in-situ FeOxHy as Fe, respectively. Adsorption of Sb(V) decreased whereas that of Sb(III) increased with elevated pH over pH 3-10, owing to the different electrical properties of Sb(III) and Sb(V). Adsorption of Sb(III) and Sb(V) was slightly affected by ionic strength, and thus indicated the formation of inner sphere complexes between Sb and the adsorbent. Sulfate and carbonate showed little effect on the adsorption of Sb(III) and Sb(V). Phosphate significantly inhibited the adsorption of Sb(V), whereas slightly effected that of Sb(III) due to its similar chemical structure to Sb(V). Pilot-scale continuous experiment indicated the feasibility of using in-situ FeOxHy to remove Sb(V), and equilibrium adsorption capacity at the equilibrium Sb(V) concentration of 10 MUg/L was determined to be 0.11, 0.07, 0.07, 0.11, and 0.12 mg/g the in-situ FeOxHy as Fe at equilibrium pH of 7.5-7.7, 6.9-7.0, 6.3-6.6, 5.9-6.4, and 5.2 5.9, respectively. PMID- 25741176 TI - Fate and Transport of Molybdenum Disulfide Nanomaterials in Sand Columns. AB - Research and development of two-dimensional transition metal dichalcogenides (TMDC) (e.g., molybdenum disulfide [MoS2]) in electronic, optical, and catalytic applications has been growing rapidly. However, there is little known regarding the behavior of these particles once released into aquatic environments. Therefore, an in-depth study regarding the fate and transport of two popular types of MoS2 nanomaterials, lithiated (MoS2-Li) and Pluronic PF-87 dispersed (MoS2-PL), was conducted in saturated porous media (quartz sand) to identify which form would be least mobile in aquatic environments. The electrokinetic properties and hydrodynamic diameters of MoS2 as a function of ionic strength and pH were determined using a zeta potential analyzer and dynamic light scattering techniques. Results suggest that the stability is significantly decreased beginning at 10 and 31.6 mM KCl, for MoS2-PL and MoS2-Li, respectively. Transport study results from breakthrough curves, column dissections, and release experiments suggest that MoS2-PL exhibits a greater affinity to be irreversibly bound to quartz surfaces as compared with the MoS2-Li at a similar ionic strength. Derjaguin-Landau-Verwey-Overbeek theory was used to help explain the unique interactions between the MoS2-PL and MoS2-Li surfaces between particles and with the quartz collectors. Overall, the results suggest that the fate and transport of MoS2 is dependent on the type of MoS2 that enters the environment, where MoS2-PL will be least mobile and more likely be deposited in porous media from pluronic-quartz interactions, whereas MoS2-Li will travel greater distances and have a greater tendency to be remobilized in sand columns. PMID- 25741178 TI - Do Molecular Structures of Migraine Drugs Point to a Common Cause of this Elusive Disease and Suggest Future Drug Designs? PMID- 25741177 TI - Network analysis of circular permutations in multidomain proteins reveals functional linkages for uncharacterized proteins. AB - Various studies have implicated different multidomain proteins in cancer. However, there has been little or no detailed study on the role of circular multidomain proteins in the general problem of cancer or on specific cancer types. This work represents an initial attempt at investigating the potential for predicting linkages between known cancer-associated proteins with uncharacterized or hypothetical multidomain proteins, based primarily on circular permutation (CP) relationships. First, we propose an efficient algorithm for rapid identification of both exact and approximate CPs in multidomain proteins. Using the circular relations identified, we construct networks between multidomain proteins, based on which we perform functional annotation of multidomain proteins. We then extend the method to construct subnetworks for selected cancer subtypes, and performed prediction of potential link-ages between uncharacterized multidomain proteins and the selected cancer types. We include practical results showing the performance of the proposed methods. PMID- 25741179 TI - An exploration of smoking behavior of african male immigrants living in glasgow. AB - INTRODUCTION: The aim of this research study was to explore the smoking behavior of adult African male immigrant smokers living in Glasgow to inform and contribute to primary health promotion frameworks. METHODS: 25 adult African male immigrant smokers living in Glasgow were recruited via consecutive sampling by soliciting for participation through the use of flyers, posters and word of mouth. Data collection occurred via semi-structured face-to-face interviews. The interviews were audio taped, after which verbatim transcription was carried out and the data analyzed thematically. RESULTS: The participants' smoking habits were influenced by cold weather environment as well as societal norms that appear to make the smoking habit more acceptable in Glasgow than Africa. It appears the more educated the participants were, the fewer cigarettes they smoked. However, there was only a slight difference in the number of cigarettes smoked between participants with a degree and those with a postgraduate degree. CONCLUSION: The participants' smoking habits in Glasgow appear to have increased because of environmental variables associated with living in Glasgow, specifically the cold weather environment and high acceptability of smoking habits in Glasgow. PMID- 25741180 TI - The prevalence of smoking among karbala/iraq university students in iraq in 2005. AB - BACKGROUND: Tobacco use is considered one of the largest public health threats facing the world. The estimated number of current smokers in the world exceeds 1.3 billion, which means that one third of the world's population above 15 years are smokers. Smoking prevalence is increasing in the developing world but monitoring of this trend is poor in these countries. Studies on smoking in Iraq are scarce, with the current smoking prevalence rate reported to be 15-25% for males and 1-10% for females in surveys conducted in the past ten years. OBJECTIVES: This study aimed to find the prevalence of smoking among Karbala University students in Iraq and determine its associations with participants' demographic and other related predictors, including other substance use behaviors, to help inform and develop future prevention and control programs. MATERIAL AND METHODS: A categorical random sample included 2298 students at Karbala University in Iraq who answered a self-completed questionnaire. The questionnaire was based on the Drug Abuse Program questionnaire and was piloted before implementation. Descriptive and analytic statistical tools (SPSS-20) were used to assess significant associations at P < 0.001 to compensate for multiple comparisons. RESULTS: The prevalence of current smoking among Karbala University students was 10.5%, shisha smoking 4.4% and previous smoking (having ceased smoking for more than 30 days) 1.0%. Approximately half of the smokers surveyed (45.7%) started smoking before the age of 18. Smoking was positively related to male gender, increasing age, being unmarried, college, drinking alcohol, having a positive attitude toward smoking and higher fathers' educational level. CONCLUSION: Lifetime smoking prevalence was found to be approximately two out of ten students. Significant positive association was found between smoking and other substance use behaviours. Additionally it was associated with positive attitudes toward substance use. Significant predictors were determined. Further studies are needed to explore the prevalence of smoking among Iraqi youths to find trends and help to guide the implementation scientifically based control and prevention programs. PMID- 25741181 TI - Psychosocial and behavioral characteristics among subgroups of nondaily college student smokers. AB - Nondaily smoking is becoming common in young adults and there appear to be different characteristics associated with past month smoking frequency among nondaily smokers. The present study examines behavioral and psychosocial correlates of smoking among subgroups of nondaily college student smokers (N = 80; 18-25 years of age) attending a large, public university. Nondaily smokers were categorized based on the frequency of days smoked in the past month and were divided into two subgroups: 1-5 days and 6-29 days. A quarter of nondaily smokers considered themselves as a smoker and significantly more 6-29 nondaily smokers were identified as a smoker and smoked more cigarettes per day (CPD). Almost half (45%) of nondaily smokers have attempted to quit smoking completely and 71% of the 6-29 nondaily smokers reported significantly higher quit attempts. The 6-29 nondaily smokers had significantly higher perceived risk related to smoking. Self efficacy to abstain from smoking was significantly higher for 1-5 nondaily smokers. These results suggest heterogeneity among subgroups of nondaily college student smokers exists in a number of behavioral and psychosocial factors. Prevention and cessation strategies may be improved by considering frequency of nondaily smoking and targeting subgroups differently. PMID- 25741182 TI - Prevalence and Pattern of Smoking among Bus Drivers of Dhaka, Bangladesh. AB - BACKGROUND: Smoking is an increasingly prevalent habit in Bangladesh, particularly among men with low socioeconomic status. AIM: The aim of this study was determining the prevalence and pattern of smoking among bus drivers of Dhaka city, Bangladesh. METHODS: A cross-sectional study was carried out from 15 to 26 March 2013 among four hundred bus drivers of Dhaka city, Bangladesh aged between 18 and 50 determining the prevalence, pattern, and socioeconomic determinants of smoking. Data were input into a pre-designed access database with data management and analysis using standard statistical tools (SPSS-15) to assess significance through cross-tabulation. RESULTS: The overall prevalence of smoking among bus drivers was 93%, and 20% of their daily income was spent on smoking. Though most (32.3%) of the drivers started smoking before involving in driving profession, but excessive smoking had been promoted by occupational and environmental stress experiencing hectic work schedule. Individuals with no education were three times (odds ratio (OR) 2.8; 95% CI 1.2-6.13) more likely to be smoker. Smoking was detected among 53.2% of smokers aged 26 or above (chi (2) = 8.30, P < 0.05), and they showed significantly high prevalence. The reasons behind smoking were almost exclusively habit (38.1%), peer influence (26.8%), and thinking of stress relief (25.3%). Smoking can also worsen poverty among users and their families because most of the drivers reported chest pain (34.4%), heart disease (25.8%), and other health complications caused by smoking depriving families of much-needed income and imposing additional costs of health care. CONCLUSION: Interventions and preventions by policy makers, public health experts, and other stakeholders should be introduced considering high prevalence of smoking among Bangladeshi bus drivers with detrimental health sequel. PMID- 25741183 TI - Does increased knowledge of risk and complication of smoking on diabetes affect quit rate? Findings from a randomized controlled trial in kerala, India. AB - BACKGROUND: Data on quit rates among diabetes patients are limited. PURPOSE: To find whether positive change in knowledge on smoking-related complications is associated with increased quit rates among diabetes patients. METHODS: We randomized 224 male diabetes patients into intervention groups 1 and 2. Both groups received a standard diabetic-specific smoking cessation message from a doctor. Intervention group 2 additionally received counseling. We compared the positive change in knowledge and the quit rates between the two groups at 6 months. RESULTS: Positive change in knowledge in group 2 was two times higher than that in group 1. The odds of quitting among patients who reported a positive change in knowledge was 2.65 times higher compared to those who reported no positive change in knowledge. CONCLUSIONS: Increasing the knowledge of persons with diabetes about the risks of developing severe complications if they continue smoking leads to significantly higher quit rates. PMID- 25741184 TI - Joint instability and osteoarthritis. AB - Joint instability creates a clinical and economic burden in the health care system. Injuries and disorders that directly damage the joint structure or lead to joint instability are highly associated with osteoarthritis (OA). Thus, understanding the physiology of joint stability and the mechanisms of joint instability-induced OA is of clinical significance. The first section of this review discusses the structure and function of major joint tissues, including periarticular muscles, which play a significant role in joint stability. Because the knee, ankle, and shoulder joints demonstrate a high incidence of ligament injury and joint instability, the second section summarizes the mechanisms of ligament injury-associated joint instability of these joints. The final section highlights the recent advances in the understanding of the mechanical and biological mechanisms of joint instability-induced OA. These advances may lead to new opportunities for clinical intervention in the prevention and early treatment of OA. PMID- 25741185 TI - Predictive factors related to the efficacy of golimumab in patients with rheumatoid arthritis. AB - In order to investigate the predictive factors related to clinical efficacy and radiographic progression at 24 weeks by looking at the serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 including baseline characteristics in patients with rheumatoid arthritis (RA) treated with golimumab, serum concentrations of TNF-alpha and IL-6 were analyzed every 4 weeks up to 24 weeks in 47 patients treated with golimumab. Baseline levels of the Disease Activity Score 28 C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI) scores were also assessed. Radiographic progression using the van der Heijde-modified Sharp (vdH-S) score was assessed in 29 patients. Multiple regression analyses related to the DAS28-CRP score and delta total sharp score at 24 weeks was undertaken using the baseline characteristics of patients and serum concentrations of matrix metallo-proteinase (MMP)-3, TNF-alpha, and IL 6. The DAS28-CRP score and SDAI decreased significantly at 4 weeks up to 24 weeks compared with baseline. Serum levels of TNF-alpha were not changed significantly up to 24 weeks compared with baseline, but those of IL-6 decreased significantly at 4 weeks up to 8 weeks. Multiple regression analyses showed that disease duration and serum levels of MMP-3 were related significantly to the DAS28-CRP score at 24 weeks. Radiographic progression was related significantly to disease duration with regard to joint space narrowing and bone erosion. However, serum levels of TNF-alpha and IL-6 were not correlated significantly with the DAS28-CRP score and radiographic progression. These data suggest that decreasing serum levels of IL-6 significantly, MMP-3, and disease duration are predictive factors for RA activity in patients taking golimumab. PMID- 25741186 TI - Imaging surveillance of patients with breast cancer after primary treatment: current recommendations. AB - Women who have been treated for breast cancer are at risk for second breast cancers, such as ipsilateral recurrence or contralateral metachronous breast cancer. As the number of breast cancer survivors increases, interest in patient management and surveillance after treatment has also increased. However, post treatment surveillance programs for patients with breast cancer have not been firmly established. In this review, we focus on the imaging modalities that have been used in post-treatment surveillance for patients with breast cancer, such as mammography, ultrasonography, magnetic resonance imaging, and positron emission tomography, the effectiveness of each modality for detecting recurrence, and how they can be applied to manage patients. PMID- 25741187 TI - Characterization of breast lesions: comparison of digital breast tomosynthesis and ultrasonography. AB - OBJECTIVE: To compare the diagnostic performance of digital breast tomosynthesis (DBT) and conventional breast ultrasound (US) to characterize breast lesions as benign or malignant. MATERIALS AND METHODS: A total of 332 women, presenting for screening examinations or for breast biopsy between March and June 2012 were recruited to undergo digital mammography (DM), DBT, and breast US examination. Among them, 113 patients with 119 breast lesions depicted on DM were finally included. Three blinded radiologists performed an enriched reader study and reviewed the DBT and US images. Each reader analyzed the lesions in random order, assigned Breast Imaging Reporting and Data System (BI-RADS) descriptors, rated the images for the likelihood of malignancy (%) and made a BI-RADS final assessment. Diagnostic accuracy, as assessed by the area under the receiver operating characteristic curve, sensitivity, and specificity of DBT and US were compared. RESULTS: Among the 119 breast lesions depicted on DM, 75 were malignant and the remaining 44 were benign. The average diagnostic performance for characterizing breast lesions as benign or malignant in terms of area under the curve was 0.899 for DBT and 0.914 for US (p = 0.394). Mean sensitivity (97.3% vs. 98.7%, p = 0.508) and specificity (44.7% vs. 39.4%, p = 0.360) were also not significantly different. CONCLUSION: Digital breast tomosynthesis may provide similar reader lesion characterization performance to that of US for breast lesions depicted on DM. PMID- 25741188 TI - Coronary artery imaging in children. AB - Coronary artery problems in children usually have a significant impact on both short-term and long-term outcomes. Early and accurate diagnosis, therefore, is crucial but technically challenging due to the small size of the coronary artery, high heart rates, and limited cooperation of children. Coronary artery visibility on CT and MRI in children is considerably improved with recent technical advancements. Consequently, CT and MRI are increasingly used for evaluating various congenital and acquired coronary artery abnormalities in children, such as coronary artery anomalies, aberrant coronary artery anatomy specific to congenital heart disease, Kawasaki disease, Williams syndrome, and cardiac allograft vasculopathy. PMID- 25741190 TI - Propensity score matching: a conceptual review for radiology researchers. AB - The propensity score is defined as the probability of each individual study subject being assigned to a group of interest for comparison purposes. Propensity score adjustment is a method of ensuring an even distribution of confounders between groups, thereby increasing between group comparability. Propensity score analysis is therefore an increasingly applied statistical method in observational studies. The purpose of this article was to provide a step-by-step nonmathematical conceptual guide to propensity score analysis with particular emphasis on propensity score matching. A software program code used for propensity score matching was also presented. PMID- 25741191 TI - Effects of MR parameter changes on the quantification of diffusion anisotropy and apparent diffusion coefficient in diffusion tensor imaging: evaluation using a diffusional anisotropic phantom. AB - OBJECTIVE: To validate the usefulness of a diffusional anisotropic capillary array phantom and to investigate the effects of diffusion tensor imaging (DTI) parameter changes on diffusion fractional anisotropy (FA) and apparent diffusion coefficient (ADC) using the phantom. MATERIALS AND METHODS: Diffusion tensor imaging of a capillary array phantom was performed with imaging parameter changes, including voxel size, number of sensitivity encoding (SENSE) factor, echo time (TE), number of signal acquisitions, b-value, and number of diffusion gradient directions (NDGD), one-at-a-time in a stepwise-incremental fashion. We repeated the entire series of DTI scans thrice. The coefficients of variation (CoV) were evaluated for FA and ADC, and the correlation between each MR imaging parameter and the corresponding FA and ADC was evaluated using Spearman's correlation analysis. RESULTS: The capillary array phantom CoVs of FA and ADC were 7.1% and 2.4%, respectively. There were significant correlations between FA and SENSE factor, TE, b-value, and NDGD, as well as significant correlations between ADC and SENSE factor, TE, and b-value. CONCLUSION: A capillary array phantom enables repeated measurements of FA and ADC. Both FA and ADC can vary when certain parameters are changed during diffusion experiments. We suggest that the capillary array phantom can be used for quality control in longitudinal or multicenter clinical studies. PMID- 25741192 TI - Fluid retention associated with imatinib treatment in patients with gastrointestinal stromal tumor: quantitative radiologic assessment and implications for management. AB - OBJECTIVE: We aimed to describe radiologic signs and time-course of imatinib associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. MATERIALS AND METHODS: In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. RESULTS: The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. CONCLUSION: Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management. PMID- 25741189 TI - Korean guidelines for the appropriate use of cardiac CT. AB - The development of cardiac CT has provided a non-invasive alternative to echocardiography, exercise electrocardiogram, and invasive angiography and cardiac CT continues to develop at an exponential speed even now. The appropriate use of cardiac CT may lead to improvements in the medical performances of physicians and can reduce medical costs which eventually contribute to better public health. However, until now, there has been no guideline regarding the appropriate use of cardiac CT in Korea. We intend to provide guidelines for the appropriate use of cardiac CT in heart diseases based on scientific data. The purpose of this guideline is to assist clinicians and other health professionals in the use of cardiac CT for diagnosis and treatment of heart diseases, especially in patients at high risk or suspected of heart disease. PMID- 25741193 TI - The accuracy of ultrasonography for the evaluation of portal hypertension in patients with cirrhosis: a systematic review. AB - OBJECTIVE: Studies have presented conflicting results regarding the accuracy of ultrasonography (US) for diagnosing portal hypertension (PH). We sought to identify evidence in the literature regarding the accuracy of US for assessing PH in patients with liver cirrhosis. MATERIALS AND METHODS: We conducted a systematic review by searching databases, including MEDLINE, EMBASE, and the Cochrane Library, for relevant studies. RESULTS: A total of 14 studies met our inclusion criteria. The US indices were obtained in the portal vein (n = 9), hepatic artery (n = 6), hepatic vein (HV) (n = 4) and other vessels. Using hepatic venous pressure gradient (HVPG) as the reference, the sensitivity (Se) and specificity (Sp) of the portal venous indices were 69-88% and 67-75%, respectively. The correlation coefficients between HVPG and the portal venous indices were approximately 0.296-0.8. No studies assess the Se and Sp of the hepatic arterial indices. The correlation between HVPG and the hepatic arterial indices ranged from 0.01 to 0.83. The Se and Sp of the hepatic venous indices were 75.9-77.8% and 81.8-100%, respectively. In particular, the Se and Sp of HV arrival time for clinically significant PH were 92.7% and 86.7%, respectively. A statistically significant correlation between HVPG and the hepatic venous indices was observed (0.545-0.649). CONCLUSION: Some US indices, such as HV, exhibited an increased accuracy for diagnosing PH. These indices may be useful in clinical practice for the detection of significant PH. PMID- 25741194 TI - Mini-gastric bypass to control morbid obesity and diabetes mellitus: what radiologists need to know. AB - Laparoscopic mini-gastric bypass surgery is a safe and simple surgical intervention for treating morbid obesity and diabetes mellitus and is now being performed more frequently. Radiologists must be critical in their postoperative evaluation of these patients. In this pictorial review, we explain and illustrate the surgical technique, normal postoperative anatomy, and associated complications as seen on imaging examinations, including fluoroscopy and computed tomography. PMID- 25741195 TI - Qualitative and quantitative analysis with contrast-enhanced ultrasonography: diagnosis value in hypoechoic renal angiomyolipoma. AB - OBJECTIVE: To evaluate the value of enhancement features and quantitative parameters of contrast-enhanced ultrasonography (CEUS) in differentiating solid hypoechoic renal angiomyolipomas (AMLs) from clear cell renal cell carcinomas (ccRCCs). MATERIALS AND METHODS: We analyzed the enhancement features and quantitative parameters of CEUS in 174 hypoechoic renal masses (32 AMLs and 142 ccRCCs) included in the study. RESULTS: Centripetal enhancement pattern was more common in AMLs than in ccRCCs on CEUS (71.9% vs. 23.2%, p < 0.001). At peak enhancement, all AMLs showed homogeneous enhancement (100% in AML, 27.5% in ccRCCs; p < 0.001). Quantitative analysis showed no significant difference between rise time and time to peak. Tumor-to-cortex (TOC) enhancement ratio in AMLs was significantly lower than that in ccRCCs (p < 0.001). The criteria of centripetal enhancement and homogeneous peak enhancement together with TOC ratio < 91.0% used to differentiate hypoechoic AMLs from ccRCCs resulted in a sensitivity and specificity of 68.9% and 95.8%, respectively. CONCLUSION: Both qualitative and quantitative analysis with CEUS are valuable in the differential diagnosis of hypoechoic renal AMLs from ccRCCs. PMID- 25741196 TI - Multiphase contrast-enhanced magnetic resonance imaging features of Bacillus Calmette-Guerin-induced granulomatous prostatitis in five patients. AB - OBJECTIVE: To evaluate the multiphase contrast-enhanced magnetic resonance (MR) imaging features of Bacillus Calmette-Guerin (BCG)-induced granulomatous prostatitis (GP). MATERIALS AND METHODS: Magnetic resonance images obtained from five patients with histopathologically proven BCG-induced GP were retrospectively analyzed for tumor location, size, signal intensity on T2-weighted images (T2WI) and diffusion-weighted images (DWI), apparent diffusion coefficient (ADC) value, and appearance on gadolinium-enhanced multiphase images. MR imaging findings were compared with histopathological findings. RESULTS: Bacillus Calmette-Guerin induced GP (size range, 9-40 mm; mean, 21.2 mm) were identified in the peripheral zone in all patients. The T2WI showed lower signal intensity compared with the normal peripheral zone. The DWIs demonstrated high signal intensity and low ADC values (range, 0.44-0.68 * 10(-3) mm(2)/sec; mean, 0.56 * 10(-3) mm(2)/sec), which corresponded to GP. Gadolinium-enhanced multiphase MR imaging performed in five patients showed early and prolonged ring enhancement in all cases of GP. Granulomatous tissues with central caseation necrosis were identified histologically, which corresponded to ring enhancement and a central low intensity area on gadolinium-enhanced MR imaging. The findings on T2WI, DWI, and gadolinium-enhanced images became gradually obscured with time. CONCLUSION: Bacillus Calmette-Guerin-induced GP demonstrates early and prolonged ring enhancement on gadolinium-enhanced MR imaging which might be a key finding to differentiate it from prostate cancer. PMID- 25741198 TI - Comparison of radiation exposure during fluoroscopy-guided transforaminal epidural steroid injections at different vertebral levels. AB - OBJECTIVE: To estimate and compare radiation exposure during transforaminal fluoroscopy-guided epidural steroid injection (TFESI) at different vertebral levels. MATERIALS AND METHODS: Fluoroscopy-guided TFESI was performed in 181 patients. The patients were categorized into three groups according to the injected lumbosacral nerve level of L2-4, L5, or S1. Fluoroscopy time (FT) and dose area product (DAP) were recorded for all patients; correlations between FT and DAP were determined at each level, and both FT and DAP were compared between the different vertebral levels. RESULTS: The numbers of patients who received ESI at L2-4, L5, and S1 were 29, 123, and 29. Mean FT was 44 seconds at L2-4, 33.5 seconds at L5, and 37.7 seconds at S1. Mean DAP was 138.6 uGy.m(2) at L2-4, 100.6 uGy.m(2) at L5, and 72.1 uGy.m(2) at S1. FT and DAP were positively correlated in each group (p values < 0.001). FT was significantly shorter at L5 than that at L2 4 (p = 0.004) but was not significantly different between S1 and L2-4 or L5 (p values = 0.286 and 0.532, respectively). DAP was significantly smaller at L5 and S1 than that at L2-4, but L5 and S1 were not significantly different. After correcting for FT, DAP was significantly smaller at S1 than that at either L2-4 or L5 (p values = 0.001 and 0.010). CONCLUSION: The radiation dose was small during a single procedure of ESI and showed differences between different lumbosacral spine levels. PMID- 25741197 TI - Endovascular recanalization of a thrombosed native arteriovenous fistula complicated with an aneurysm: technical aspects and outcomes. AB - OBJECTIVE: To evaluate the technical aspects and outcomes of endovascular recanalization of a thrombosed native arteriovenous fistula (AVF) complicated with an aneurysm. MATERIALS AND METHODS: Sixteen patients who had a thrombosed AVF complicated with an aneurysm (two radiocephalic and 14 brachiocephalic) were included in this study. Recanalization procedures were performed by mechanical thrombectomy using the Arrow-Trerotola percutaneous thrombectomy device and adjunctive treatments. We evaluated dose of thrombolytic agent, underlying stenosis, procedure time, technical and clinical success, and complications. The primary and secondary patency rates were calculated using the Kaplan-Meier analysis. RESULTS: The thrombolytic agents used were 100000 U urokinase mixed with 500 IU heparin (n = 10) or a double dose of the mixture (n = 6). The thrombi in aneurysms were removed in all but two patients with non-flow limiting residual thrombi. One recanalization failure occurred due to a device failure. Aspiration thrombectomy was performed in 87.5% of cases (n = 14). Underlying stenoses were found in the outflow draining vein (n = 16), arteriovenous anastomosis or juxtaanastomosis area (n = 5), and the central vein (n = 3). Balloon angioplasty was performed for all stenoses in 15 patients. Two patients with a symptomatic central vein stenosis underwent insertion of a stent after balloon angioplasty. Mean procedure time was 116.3 minutes. Minor extravasation (n = 1) was resolved by manual compression. Both technical and clinical success rates were 93.8% (n = 15). The primary patency rates at 3, 6, and 12 months were 70.5%, 54.8%, and 31.3%, respectively. The secondary patency rates at 3, 6, and 12 months were 70.5%, 70.5%, and 47.0%, respectively. CONCLUSION: Thrombosed AVF complicated with an aneurysm can be successfully recanalized, and secondary patency can be prolonged with endovascular treatment. PMID- 25741199 TI - Repaired supraspinatus tendons in clinically improving patients: early postoperative findings and interval changes on MRI. AB - OBJECTIVE: To demonstrate and further determine the incidences of repaired supraspinatus tendons on early postoperative magnetic resonance imaging (MRI) findings in clinically improving patients and to evaluate interval changes on follow-up MRIs. MATERIALS AND METHODS: Fifty patients, who showed symptomatic and functional improvements after supraspinatus tendon repair surgery and who underwent postoperative MRI twice with a time interval, were included. The first and the second postoperative MRIs were obtained a mean of 4.4 and 11.5 months after surgery, respectively. The signal intensity (SI) patterns of the repaired tendon on T2-weighted images from the first MRI were classified into three types of heterogeneous high SI with fluid-like bright high foci (type I), heterogeneous high SI without fluid-like bright high foci (type II), and heterogeneous or homogeneous low SI (type III). Interval changes in the SI pattern, tendon thickness, and rotator cuff interval thickness between the two postoperative MRIs were evaluated. RESULTS: The SI patterns on the first MRI were type I or II in 45 tendons (90%) and type III in five (10%). SI decreased significantly on the second MRI (p < 0.050). The mean thickness of repaired tendons and rotator cuff intervals also decreased significantly (p < 0.050). CONCLUSION: Repaired supraspinatus tendons exhibited high SI in 90% of clinically improving patients on MRI performed during the early postsurgical period. The increased SI and thickness of the repaired tendon decreased on the later MRI, suggesting a gradual healing process rather than a retear. PMID- 25741201 TI - Ultrasound-guided fine needle aspiration of thyroid nodules: a consensus statement by the korean society of thyroid radiology. AB - Ultrasound (US)-guided fine needle aspiration (US-FNA) has played a crucial role in managing patients with thyroid nodules, owing to its safety and accuracy. However, even with US guidance, nondiagnostic sampling and infrequent complications still occur after FNA. Accordingly, the Task Force on US-FNA of the Korean Society of Thyroid Radiology has provided consensus recommendations for the US-FNA technique and related issues to improve diagnostic yield. These detailed procedures are based on a comprehensive analysis of the current literature and from the consensus of experts. PMID- 25741200 TI - Imaging-based management of acute ischemic stroke patients: current neuroradiological perspectives. AB - Advances in imaging-based management of acute ischemic stroke now provide crucial information such as infarct core, ischemic penumbra/degree of collaterals, vessel occlusion, and thrombus that helps in the selection of the best candidates for reperfusion therapy. It also predicts thrombolytic efficacy and benefit or potential hazards from therapy. Thus, radiologists should be familiar with various imaging studies for patients with acute ischemic stroke and the applicability to clinical trials. This helps radiologists to obtain optimal rapid imaging as well as its accurate interpretation. This review is focused on imaging studies for acute ischemic stroke, including their roles in recent clinical trials and some guidelines to optimal interpretation. PMID- 25741202 TI - Comparison between ultrasonography and computed tomography for detecting the pyramidal lobe of the thyroid gland: a prospective multicenter study. AB - OBJECTIVE: To compare the detection rates of the pyramidal lobe of the thyroid gland (TPL) using ultrasonography (US) and computed tomography (CT) in a prospective multi-center study. MATERIALS AND METHODS: We enrolled 582 patients who underwent neck CT at six institutions. Each radiologist prospectively evaluated the presence and features of TPLs on thyroid US. Radiologists were divided into two groups according to their previous experience in detecting TPL on US or CT. The same radiologist also retrospectively assessed CT findings, blinded to the corresponding US findings. RESULTS: The pyramidal lobe of the thyroid glands were detected in 230 cases (39.5%) on US and in 276 cases (47.6%) on CT. The TPL detection rate at the six institutions ranged from 22.0% to 59% for US and from 34.1% to 59% using CT. There were significant differences between US and CT in the detection rate, length, anteroposterior diameter, volume, and superior extent of TPL (p <= 0.027). The TPL detection rates on both US and CT (p < 0.001) differed significantly according to the experience level of the radiologists. When the CT result was used as a reference standard, the sensitivity, specificity, positive and negative predictive values, as well as the accuracy of US for TPL detection were 72.6%, 91.5%, 89.3%, 77.3%, and 82.1%, respectively. CONCLUSION: Our prospective multicenter study revealed that US could detect TPL with relatively high diagnostic accuracy compared to CT. Because the detection rate of TPL varied significantly according to the radiologists' level of experience, careful inspection is necessary to avoid imaging pitfalls and ensure appropriate evaluation of TPL on both US and CT. PMID- 25741203 TI - Effect of increasing diffusion gradient direction number on diffusion tensor imaging fiber tracking in the human brain. AB - OBJECTIVE: To assess the effects of varying the number of diffusion gradient directions (NDGDs) on diffusion tensor fiber tracking (FT) in human brain white matter using tract characteristics. MATERIALS AND METHODS: Twelve normal volunteers underwent diffusion tensor imaging (DTI) scanning with NDGDs of 6, 11, 15, 21, and 31 orientations. Three fiber tract groups, including the splenium of the corpus callosum (CC), the entire CC, and the full brain tract, were reconstructed by deterministic DTI-FT. Tract architecture was first qualitatively evaluated by visual observation. Six quantitative tract characteristics, including the number of fibers (NF), average length (AL), fractional anisotropy (FA), relative anisotropy (RA), mean diffusivity (MD), and volume ratio (VR) were measured for the splenium of the CC at the tract branch level, for the entire CC at tract level, and for the full brain tract at the whole brain level. Visual results and those of NF, AL, FA, RA, MD, and VR were compared among the five different NDGDs. RESULTS: The DTI-FT with NDGD of 11, 15, 21, and 31 orientations gave better tracking results compared with NDGD of 6 after the visual evaluation. NF, FA, RA, MD, and VR values with NDGD of six were significantly greater (smallest p = 0.001 to largest p = 0.042) than those with four other NDGDs (11, 15, 21, or 31 orientations), whereas AL measured with NDGD of six was significantly smaller (smallest p = 0.001 to largest p = 0.041) than with four other NDGDs (11, 15, 21, or 31 orientations). No significant differences were observed in the results among the four NDGD groups of 11, 15, 21, and 31 directions (smallest p = 0.059 to largest p = 1.000). CONCLUSION: The main fiber tracts were detected with NDGD of six orientations; however, the use of larger NDGD (>= 11 orientations) could provide improved tract characteristics at the expense of longer scanning time. PMID- 25741204 TI - Ultrasonography of various thyroid diseases in children and adolescents: a pictorial essay. AB - Thyroid imaging is indicated to evaluate congenital hypothyroidism during newborn screening or in cases of a palpable thyroid mass in children and adolescents. This pictorial essay reviews the ultrasonography (US) of thyroid diseases in children and adolescents, including normal thyroid gland development, imaging features of congenital thyroid disorders (dysgenesis, [aplasia, ectopy, hypoplasia], dyshormonogenesis, transient hypothyroidism, thyroglossal duct cyst), diffuse thyroid disease (Grave's disease, Hashimoto's thyroiditis, and suppurative thyroiditis), and thyroid nodules. The primary imaging modalities for evaluating thyroid diseases are US and radionuclide scintigraphy. Additionally, US can be used to guide aspiration of detected nodules. PMID- 25741205 TI - Digital tomosynthesis for evaluating metastatic lung nodules: nodule visibility, learning curves, and reading times. AB - OBJECTIVE: To evaluate nodule visibility, learning curves, and reading times for digital tomosynthesis (DT). MATERIALS AND METHODS: We included 80 patients who underwent computed tomography (CT) and DT before pulmonary metastasectomy. One experienced chest radiologist annotated all visible nodules on thin-section CT scans using computer-aided detection software. Two radiologists used CT as the reference standard and retrospectively graded the visibility of nodules on DT. Nodule detection performance was evaluated in four sessions of 20 cases each by six readers. After each session, readers were unblinded to the DT images by revealing the true-positive markings and were instructed to self-analyze their own misreads. Receiver-operating-characteristic curves were determined. RESULTS: Among 414 nodules on CT, 53.3% (221/414) were visible on DT. The main reason for not seeing a nodule on DT was small size (93.3%, <= 5 mm). DT revealed a substantial number of malignant nodules (84.1%, 143/170). The proportion of malignant nodules among visible nodules on DT was significantly higher (64.7%, 143/221) than that on CT (41.1%, 170/414) (p < 0.001). Area under the curve (AUC) values at the initial session were > 0.8, and the average detection rate for malignant nodules was 85% (210/246). The inter-session analysis of the AUC showed no significant differences among the readers, and the detection rate for malignant nodules did not differ across sessions. A slight improvement in reading times was observed. CONCLUSION: Most malignant nodules > 5 mm were visible on DT. As nodule detection performance was high from the initial session, DT may be readily applicable for radiology residents and board-certified radiologists. PMID- 25741206 TI - Single nodular opacity of granulomatous pneumocystis jirovecii pneumonia in an asymptomatic lymphoma patient. AB - The radiologic findings of a single nodule from Pneumocystis jirovecii pneumonia (PJP) have been rarely reported. We described a case of granulomatous PJP manifesting as a solitary pulmonary nodule with a halo sign in a 69-year-old woman with diffuse large B cell lymphoma during chemotherapy. The radiologic appearance of the patient suggested an infectious lesion such as angioinvasive pulmonary aspergillosis or lymphoma involvement of the lung; however, clinical manifestations were not compatible with the diseases. The nodule was confirmed as granulomatous PJP by video-assisted thoracoscopic surgery biopsy. PMID- 25741207 TI - Colonic perforations caused by migrated plastic biliary stents. PMID- 25741208 TI - Pancreatico-colonic fistula-demonstrated by multidetector-row CT. PMID- 25741209 TI - Aspects of ancient mitochondrial DNA analysis in different populations for understanding human evolution. AB - The evolution of modern humans is a long and difficult process which started from their first appearance and continues to the present day. The study of the genetic origin of populations can help to determine population kinship and to better understand the gradual changes of the gene pool in space and time. Mitochondrial DNA (mtDNA) is a proper tool for the determination of the origin of populations due to its high evolutionary importance. Ancient mitochondrial DNA retrieved from museum specimens, archaeological finds and fossil remains can provide direct evidence for population origins and migration processes. Despite the problems with contaminations and authenticity of ancient mitochondrial DNA, there is a developed set of criteria and platforms for obtaining authentic ancient DNA. During the last two decades, the application of different methods and techniques for analysis of ancient mitochondrial DNA gave promising results. Still, the literature is relatively poor with information for the origin of human populations. Using comprehensive phylogeographic and population analyses we can observe the development and formation of the contemporary populations. The aim of this study was to shed light on human migratory processes and the formation of populations based on available ancient mtDNA data. PMID- 25741210 TI - Family physicians' management of genetic aspects of a cardiac disease: a scenario based study from slovenia. AB - The aim of this study was to find out how Slovenian family physicians (FPs) would manage a hypothetical clinical case, to explore their views about possible ethical dilemmas associated with this clinical case and to determine possible associations with demographic and other characteristics of FPs. This was an observational cross-sectional postal study in the Slovenian FPs' surgeries. The study population consisted of the whole population of Slovenian FPs (n = 950). The main outcome measures were the percentages of the answers of FPs on different questions about the clinical case on the management of patient and his relative with hereditary cardiomyopathy. There were 271 FPs who answered the questionnaire (response rate was 27.1%). A sample included 66 (24.4%) men and the mean age of all respondents was 45.5 +/- 10.6 years. When dealing with the clinical case, most FPs expressed willingness to take the patient's family history. Only 34.2% FPs did not believe that ordering genetic tests was part of their job. Additionally, only 50.0% of them felt competent to interpret the genetic risk, 25.0% of them would give information about genetic testing and only 6.0% would interpret the results of the genetic testing. Family physicians in Slovenia were willing to include genetic tasks into routine management of their patients, but they do not feel competent enough to interpret the genetic risks and the results of genetic testing. However, an important part of FPs would not refer patients at risk to genetic counseling. The inclusion of genetic topics to family medicine specialization curriculum is needed. PMID- 25741211 TI - Phenotypic variations in wolf-hirschhorn syndrome. AB - Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by terminal deletion of the short arm of chromosome 4. The clinical picture includes growth retardation, severe mental retardation, characteristic "Greek helmet" like face, seizures and midline defects in the brain, heart, palate and genitalia. Recently used molecular techniques increase the number of diagnosed cases due to the detection of smaller deletions. The severity of the clinical presentation is variable depending on the haploinsufficiency of genes in a deleted region. We present six children with WHS with variable clinical appearance. The assessment of several elements (facial dysmorphism, mental retardation, additional congenital anomalies) provided classification into minor, mild or severe forms. Three of the children had a visible cytogenetic deletion on chromosome 4p, two had microdeletions detected with fluorescent in situ hybridization (FISH), and one child with a less characteristic clinical picture had a mosaic type of the deletion. Correlation between the clinical presentation and the length of the deleted region was confirmed. PMID- 25741212 TI - High incidence of congenital hypothyroidism in one region of the republic of macedonia. AB - Congenital hypothyroidism (CH) is the most common preventable cause of mental retardation in children. Diagnosis is difficult at birth without neonatal screening. Neonatal thyroid screening was established in Prilep, Republic of Macedonia as an integral part of the nationwide screening program. To estimate the prevalence of CH in this region, neonatal thyroid screening was performed on 9757 newborns, during the period 2002-2011. The DELFIA method was applied to measure the thyroid-stimulating hormone (TSH) concentration in dried blood spot samples on standard filter paper taken 48 hours after birth by heel-stick. The TSH cut-off level was 10 mU/L. The neonatal thyroid screening coverage was 93.4%. Eight newborns with CH were detected, with an incidence of 1:1220 live births, significantly higher compared to the nationwide results 1:2602. The TSH level was not significantly dependent on the gender of the newborn. There was a statistically significant difference between the TSH level and the timing of newborn screening sampling (p <0.05) and between the TSH level and the newborn birth weight (p = 0.01). One point ninety-two percent of newborns with TSH levels above 5 mU/L indicated an iodine sufficiency in Prilep. The incidence of CH in Prilep, which is higher when compared with that reported in surrounding countries, might be a consequence of the higher percentage of the Romany population in this region. Further analysis of this population in other regions is warranted. PMID- 25741213 TI - Analysis of human bradykinin receptor gene and endothelial nitric oxide synthase gene polymorphisms in end-stage renal disease among malaysians. AB - The aim of this study was to determine the association of the c.894G>T; p.Glu298Asp polymorphism and the variable number tandem repeat (VNTR) polymorphism of the endothelial nitric oxide synthase (eNOS) gene and c.181C>T polymorphism of the bradykinin type 2 receptor gene (B2R) in Malaysian end-stage renal disease (ESRD) subjects. A total of 150 ESRD patients were recruited from the National Kidney Foundation's (NKF)dialysis centers in Malaysia and compared with 150 normal healthy individuals. Genomic DNA was extracted from buccal cells of all the subjects. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was carried out to amplify the products and the restricted fragments were separated by agarose gel electrophoresis. Statistical analyses were carried out using software where a level of p <0.05 was considered to be statistically significant. The genotypic and allelic frequencies of the B2R gene (c.181C>T, 4b/a) and eNOS gene (c.894G>T) polymorphisms were not statistically significant (p >0.05) when compared to the control subjects. The B2R and eNOS gene polymorphisms may not be considered as genetic susceptibility markers for Malaysian ESRD subjects. PMID- 25741214 TI - Does the A9285G Polymorphism in Collagen Type XII alpha1 Gene Associate with the Risk of Anterior Cruciate Ligament Ruptures? AB - One of the most severe injuries sustained by athletes is rupture of the anterior cruciate ligament (ACL). Recent investigations suggest that a predisposition for ACL rupture may be the result of specific genetic sequence variants. In light of this, we decided to investigate whether the COL12A1 A9285G polymorphism was associated with ACL ruptures in Polish football players. We compared genotypic and allelic frequencies of the COL12A1 A9285G polymorphism in two groups of athletes: 91 male football players (23 +/- 3 years) with surgically diagnosed primary ACL ruptures who qualified for ligament reconstruction (cases) and 143 apparently healthy, male football players of the same ethnicity, a similar age category, and a comparable level of exposure to ACL injury, who were without any self-reported history of ligament or tendon injury (controls). DNA samples extracted from the oral epithelial cells were genotyped by using a real-time polymerase chain reaction (Ri-Ti-PCR) method. The genotype distribution in the cases were not different from those in controls (p = 0.70). The frequency of the G allele was lower in the cases (18.1%) but not statistically significant (p = 0.40) when compared with controls (21.3%). Our results are in contradiction to the hypothesis that the COL12A1 A9285G polymorphism is associated with a predisposition for ACL injury. However, these conclusions should be supported with more experimental studies on COL12A1 polymorphisms. PMID- 25741215 TI - Association of Glutathione-S-Transferase (GSTM1 and GSTT1) and FTO Gene Polymorphisms with Type 2 Diabetes Mellitus Cases in Northern India. AB - Type 2 diabetes mellitus (T2DM) is growing in an epidemic manner across the world and India has the world's largest number of diabetic subjects. The present study was carried out to investigate the association of glutathione-S-transferase (GSTM1, GSTT1) and fat mass and obesity associated (FTO) gene polymorphisms with T2DM patients and controls, and its role in increasing the susceptibility to T2DM. A total of 198 subjects (101 T2DM patients and 97 controls) participated in this study. GSTM1, GSTT1 and FTO gene polymorphisms in the patients and controls were evaluated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). We observed significant association of GSTM1 positive (p = 0.046) and GSTM1 null (p = 0.046) genotypes with T2DM, while no significant association was found with the FTO gene polymorphism in our study. It seems that the GSTM1 gene polymorphism can be a predictive marker for early identification of a population at risk of T2DM. The potential role of GST and FTO gene polymorphisms as a marker of susceptibility to T2DM needs further studies in a larger number of patients. PMID- 25741216 TI - The Largest Paracentric Inversion, the Highest Rate of Recombinant Spermatozoa. Case Report: 46,XY, inv(2)(q21.2q37.3) and Literature Review. AB - Carriers of inversions involving euchromatic regions are at risk of having unbalanced offspring due to meiotic crossover. In carriers, recombination can occur during gametogenesis and cause genetically unbalanced sperm and subsequently unbalanced embryos. Here we present segregation analysis results of an infertile male with 46,XY,inv(2) (q21.2q37.3) using fluorescent in situ hybridization (FISH) on sperm cells. This is the largest paracentric inversion (PAI) reported so far in a meiotic segregation analysis study. Sperm FISH revealed 28.0% recombinant spermatozoa rate for chromo-some 2, which was the highest rate in PAI carriers in the literature. Our results indicate a clear correlation between the size of the inverted segment and the frequency of the recombinant spermatozoa. The results of the FISH analysis with the information of unbalanced spermatozoa rate can provide accurate counseling on the genetic risk of infertility. PMID- 25741217 TI - Translocation t(3;12)(q26;q21) in JAK2(V617F) Point Mutation Negative Chronic Idiopathic Myelofibrosis: A Case Report. AB - The myeloproliferative diseases (MPDs) or myelo-proliferative neoplasms (MPNs) are a group of diseases of the bone marrow in which excess cells are produced. Chronic idiopathic myelofibrosis (CIMF) is a stem cell defect characterized by splenomegaly with multiorgan extramedullary hematopoiesis, immature peripheral blood granulocytes and erythrocytes and progressive bone marrow fibrosis. The most common chromosomal abnormalities seen in CIMF patients include numerical changes of chromosomes 7, 8 and 9, and structural changes of 1q, 5q, 13q and 20q. At least 75.0% of patients with bone marrow abnormalities have one or more of these chromosomal anomalies. Detection of the Janus kinase 2 (JAK2) mutation may be a potential major breakthrough for understanding the pathobiology of MPNs, and is an essential part of the diagnostic algorithm. In this study, we describe a JAK2(V617F) mutation negative CIMF patient who has the chromosomal translocation t(3;12)(q26;q21) in her karyotype. PMID- 25741218 TI - Adult B Lymphoblastic Leukemia with a Novel De Novo Chromosomal Translocation [der(9)t(9;12)(p24;q12),-12]: A Case Report. AB - Patients suffering from adult acute lymphoblastic leukemia (ALL) are very ill and present most commonly with shortness of breath during physical activity, a pale complexion from anemia, a very low platelet count, the appearance of pinhead sized red spots under the skin called petechiae, or prolonged bleeding from minor cuts and discomfort in the bones and joints. Fever in the absence of an obvious cause is common. Leukemic lymphoblasts may accumulate in the lymphatic system, and lymph nodes can be enlarged. We report a young adult male with a novel translocation in ALL, who had vague (uncertain) minimal symptoms and splenomegaly. The patient had a unique cytogenetic abnormality: 45,XY,der(9)t(9;12)(p24;q12),-12, which has not been previously described in ALL. This is categorized as a poor risk due to his failure to achieve complete remission after induction chemotherapy. PMID- 25741219 TI - Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway. AB - BACKGROUND: Duguelin is a rotenoid extracted from plants and has potent antitumor effects in vitro and in vivo. However, the mechanism underlying the antitumor effect remains unclear. Our preliminary study showed that Deguelin is effective to stimulate the generation of Reactive Oxygen Species (ROS). In the current study, we evaluated the in vitro cytotoxicity of Deguelin against lung cancer cells and studied whether a ROS scavenger, N-acetyl-cysteine (NAC), can reverse the inhibitory effect of Deguelin. RESULTS: We showed that the dose-dependent apoptotic inducing effect of Deguelin could be partially reversed by the co administration of NAC. Moreover, Deguelin reduced the phosphorylation of Akt protein and induced the apoptotic protein Caspase-3 in a dose-dependent manner. Co-treatment with NAC partially attenuated this effect and rescued some cells from apoptosis. CONCLUSION: Deguelin induces the apoptosis of cancer cells through a ROS driven Akt pathway, which could translate into a promising therapeutic for lung cancer. PMID- 25741220 TI - Proteome changes in the small intestinal mucosa of broilers (Gallus gallus) induced by high concentrations of atmospheric ammonia. AB - BACKGROUND: Ammonia is a well-known toxicant both existing in atmospheric and aquatic system. So far, most studies of ammonia toxicity focused on mammals or aquatic animals. With the development of poultry industry, ammonia as a main source of contaminant in the air is causing more and more problems on broiler production, especially lower growth rate. The molecular mechanisms that underlie the negative effects of ammonia on the growth and intestine of broilers are yet unclear. We investigated the growth, gut morphology, and mucosal proteome of Arbor Acres broilers (Gallus gallus) exposed to high concentrations of atmospheric ammonia by performing a proteomics approach integrated with traditional methods. RESULTS: Exposure to ammonia interfered with the development of immune organ and gut villi. Meanwhile, it greatly reduced daily weight gain and feed intake, and enhanced feed conversion ratio. A total of 43 intestinal mucosal proteins were found to be differentially abundant. Up-regulated proteins are related to oxidative phosphorylation and apoptosis. Down-regulated proteins are related to cell structure and growth, transcriptional and translational regulation, immune response, oxidative stress and nutrient metabolism. These results indicated that exposure to ammonia triggered oxidative stress, and interfered with nutrient absorption and immune function in the small intestinal mucosa of broilers. CONCLUSIONS: These findings have important implications for understanding the toxic mechanisms of ammonia on intestine of broilers, which provides new information that can be used for intervention using nutritional strategies in the future. PMID- 25741222 TI - What are the support needs of men with multiple sclerosis, and are they being met? AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, degenerative condition of the central nervous system that can lead to high levels of disability and a range of psychological and social problems. Although considerable research has been conducted on the experience of living with MS and the disease's psychosocial consequences, much of this has focused on women, with the male perspective seldom considered. It is possible, therefore, that men differ from women in how they experience MS and the type of support or interventions that meet their needs. METHODS: A literature review was undertaken to identify the specific support needs of men with MS, describe current support available to men with MS, and evaluate the extent to which these needs are met by current service provision. RESULTS: The literature reviewed suggests that the needs of men with MS are different from those of women in terms of psychological factors such as well being and mental health and support. CONCLUSIONS: If interventions are to be evidence based, health-care professionals need to take into account the needs, desires, and capabilities of men with MS in the development of services. Further qualitative and quantitative research is required to address the gaps in the evidence base of support needs for men with MS. PMID- 25741221 TI - Development and effectiveness of a psychoeducational wellness program for people with multiple sclerosis: description and outcomes. AB - BACKGROUND: Multiple sclerosis (MS) mostly affects young and middle-aged adults and is known to be associated with a host of factors involved in overall quality of life and well-being. The biopsychosocial model of disease takes into account the multifaceted nature of chronic illness and is commonly applied to MS. The present investigation examined the effectiveness of a 10-week psychoeducational MS wellness program that was developed on the basis of the biopsychosocial model and a wellness approach to treatment. METHODS: The program consisted of 90 minute, weekly psychoeducational wellness group sessions aimed at improving quality of life by increasing awareness of the various social, intellectual, emotional, and spiritual factors that can affect the overall well-being of people living with MS. Fifty-four individuals with MS participated in the study (43 individuals who completed the wellness intervention and 11 individuals with MS who did not participate; "controls"). All participants completed a series of self report questionnaires at baseline and at the 10-week follow-up, assessing depression, anxiety, perceived stress, cognitive complaints, pain, social support, and fatigue. RESULTS: Repeated-measures analysis revealed improvements in depression, anxiety, overall mental health, perceived stress, and pain in the treatment group compared with the control group. No significant differences were observed between the groups on measures assessing social support, cognitive complaints, and fatigue. CONCLUSIONS: The findings suggest that a psychoeducational wellness program is effective in improving the overall quality of life and well-being of individuals with MS. PMID- 25741223 TI - Lower urinary tract symptom prevalence and management among patients with multiple sclerosis. AB - BACKGROUND: This study was conducted to assess self-reported prevalence and management of lower urinary tract symptoms (LUTS), along with drivers of treatment seeking, among patients with multiple sclerosis (MS). METHODS: An online, cross-sectional survey was administered to US-residing participants with self-reported MS to assess presence of LUTS, including urinary incontinence (UI). Participants experiencing LUTS were asked additional questions related to management and current therapies. Multivariate logistic regression identified drivers of treatment-seeking behavior. RESULTS: A total of 1052 participants completed the survey; 1047 were included in the analysis. Nine hundred sixty-six participants (92%) reported at least one LUTS, the most common being post micturition dribble (64.9%), urinary urgency (61.7%), and a feeling of incomplete emptying (60.7%). Eight hundred twenty-six (79%) reported having some type of UI. Of those with any type of LUTS, 70% (n = 680) had previously discussed urinary symptoms with a health-care provider (HCP), while only 32% (n = 311) had seen an HCP in the past year. Logistic regression found urgency (odds ratio [OR] 1.20 [95% confidence interval (CI), 1.00-1.44]), intermittent urine stream (OR 1.40 [95% CI, 1.15-1.69]), and urgency UI (OR 1.78 [95% CI, 1.22-2.60]) to be significant predictors of seeking treatment. Of those who had discussed LUTS with an HCP, 480 (70.6%) were currently receiving at least one LUTS treatment; the most common treatments were reducing fluid intake, pelvic exercises, oral anticholinergic medications, and avoiding certain foods/alcohol. CONCLUSIONS: LUTS are commonly experienced among people with MS but are largely untreated. Proper LUTS assessment and work-up is warranted in MS patients. PMID- 25741224 TI - Disease-related determinants of quality of life 10 years after clinically isolated syndrome. AB - BACKGROUND: The main clinical determinants of quality of life (QOL) 5 years after clinically isolated syndrome (CIS) are Expanded Disability Status Scale (EDSS) score and conversion to clinically definite multiple sclerosis (CDMS). The aim of this study was to determine the demographic, clinical, and magnetic resonance imaging (MRI) factors associated with QOL 10 years after CIS. METHODS: Controlled High Risk Avonex(r) Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS) 10-year patients were assessed for CDMS, EDSS score, MRI T2 activity, brain parenchymal fraction, and patient-reported QOL. Associations were evaluated using analysis of variance models. RESULTS: A second clinical event consistent with CDMS and higher EDSS scores at years 5 and 10 were associated with lower 36-item Short Form Health Status Survey (SF-36) Physical Component Summary scores at year 10 (P < .01). Patients with earlier onset of CDMS had worse patient-reported Physical Component Summary, SF-36 Mental Component Summary, fatigue, and pain scores at year 10 than patients with later or no onset of CDMS. Neither initial randomization group nor any MRI metrics assessed at baseline or during follow-up were associated with QOL at 10 years. CONCLUSIONS: These results support the development of therapies for patients with CIS that significantly reduce the risk of conversion to CDMS and the progression of physical disability to milestones as low as EDSS scores of 2.0. PMID- 25741225 TI - Effects of functional electrical stimulation on gait function and quality of life for people with multiple sclerosis taking dalfampridine. AB - BACKGROUND: Multiple sclerosis (MS) can adversely affect gait, causing gait slowing, loss of balance, decreased functional mobility, and gait deficits, such as footdrop. Current treatments for gait dysfunction due to MS are pharmacologic, using dalfampridine, or orthotic, using an ankle-foot orthosis. Functional electrical stimulation (FES) to the fibular nerve stimulates active dorsiflexion and provides an alternative treatment for gait dysfunction caused by footdrop. The objective of this study was to determine the effect of FES on gait function and the impact of MS on walking and quality of life for people with MS taking a stable dalfampridine dose. METHODS: Participants demonstrating gait slowing and footdrop completed the Timed 25-Foot Walk (T25FW) test, 6-Minute Walk (6MW) test, GaitRite Functional Ambulation Profile, 12-item Multiple Sclerosis Walking Scale (MSWS-12), and 36-item Short Form Health Status Survey (SF-36) at screening without FES; the measures were repeated with FES at baseline, 1 month, and 3 months. RESULTS: Twenty participants (8 men and 12 women) completed this unblinded case series study. The mean age, duration of MS, and time taking dalfampridine were 51.7, 15.8, and 1.4 years, respectively. Changes from screening to baseline and screening to 3 months were analyzed. Significant improvement was noted from screening to baseline for the MSWS-12 (P = .024) and SF-36 Physical Function domain (P = .028) and from screening to 3 months for the T25FW (P = .015), MSWS-12 (P = .003), and SF-36 Physical Function (P = .032) and Role Limitation-Physical Health (P = .012) domains. CONCLUSIONS: Improvements above those induced pharmacologically suggest that FES can augment pharmacologic intervention and significantly improve gait function, decrease the impact of MS on walking, and improve quality of life for people with MS. PMID- 25741226 TI - Informing the children when a parent is diagnosed as having multiple sclerosis. AB - BACKGROUND: The aim of this study was to gain an understanding of how health-care services can support the empowerment of children when a parent is diagnosed as having multiple sclerosis (MS). The study focuses on what information parents with MS, their partners, and their children desire from health-care professionals. METHODS: Focus group interviews were conducted with nine adolescents, nine parents with diagnosed MS, and five partners representing members of ten families. RESULTS: The main finding was that parents with MS, their partners, and the adolescents stressed their need to be well informed about the disease. Information should be provided at the time of diagnosis and then offered regularly throughout the disease course. The information should be suited to the recipient's level of maturity and individualized to reflect the parent's clinical picture. CONCLUSIONS: It is usually beneficial for children if their parents feel informed about the illness and encourage their children to ask questions and discuss the situation. This knowledge, gained from several sources, is likely to be of value for health-care professionals and their ongoing efforts to improve services for parents with MS, their partners, and their children. PMID- 25741227 TI - Editorial. PMID- 25741228 TI - Obesity and Physical Function in Rural Women who enroll in a Lifestyle Modification Intervention for Reducing Blood Pressure. AB - PURPOSE: Rural women have high prevalence of obesity and prehypertension. Obesity, if associated with poor physical function, may have implications for applying activity guidelines for women volunteering for lifestyle modification. This study examined associations of body mass index (BMI) and percent body fat with measures of 1-mile walk time, post-walk perceived exertion, and 10 repetition chair stands in rural women ages 40-69. METHODS: Cross-sectional baseline data were collected using standardized methods from 289 rural women with prehypertension who volunteered for a lifestyle clinical trial for reducing blood pressure. ANOVAs and linear regression were used for analysis. RESULTS: With exception of the chair stands measure across categories of BMI, group differences were noted in all measures across categories of BMI and percent body fat, with women in the two highest categories demonstrating the poorest performance. These two body composition measures were significant predictors for 1-mile walk-time and 10-repetition chair stands, after controlling for confounding variables. CONCLUSIONS: Poorer scores were observed in performance-based measures in women with higher BMI and percent body fat, though mean scores were above thresholds for functional limitation. Physical performance needs to be assessed and addressed by physical therapists when providing lifestyle interventions for overweight and obese women. PMID- 25741230 TI - A unique array of neuroprotective effects of pyruvate in neuropathology. PMID- 25741229 TI - On the effects of testosterone on brain behavioral functions. AB - Testosterone influences the brain via organizational and activational effects. Numerous relevant studies on rodents and a few on humans focusing on specific behavioral and cognitive parameters have been published. The results are, unfortunately, controversial and puzzling. Dosing, timing, even the application route seem to considerably affect the outcomes. In addition, the methods used for the assessment of psychometric parameters are a bit less than ideal regarding their validity and reproducibility. Metabolism of testosterone contributes to the complexity of its actions. Reduction to dihydrotestosterone by 5-alpha reductase increases the androgen activity; conversion to estradiol by aromatase converts the androgen to estrogen activity. Recently, the non-genomic effects of testosterone on behavior bypassing the nuclear receptors have attracted the interest of researchers. This review tries to summarize the current understanding of the complexity of the effects of testosterone on brain with special focus on their role in the known sex differences. PMID- 25741231 TI - Condition interference in rats performing a choice task with switched variable- and fixed-reward conditions. AB - Because humans and animals encounter various situations, the ability to adaptively decide upon responses to any situation is essential. To date, however, decision processes and the underlying neural substrates have been investigated under specific conditions; thus, little is known about how various conditions influence one another in these processes. In this study, we designed a binary choice task with variable- and fixed-reward conditions and investigated neural activities of the prelimbic cortex and dorsomedial striatum in rats. Variable- and fixed-reward conditions induced flexible and inflexible behaviors, respectively; one of the two conditions was randomly assigned in each trial for testing the possibility of condition interference. Rats were successfully conditioned such that they could find the better reward holes of variable-reward condition and fixed-reward-condition trials. A learning interference model, which updated expected rewards (i.e., values) used in variable-reward-condition trials on the basis of combined experiences of both conditions, better fit choice behaviors than conventional models which updated values in each condition independently. Thus, although rats distinguished the trial condition, they updated values in a condition-interference manner. Our electrophysiological study suggests that this interfering value-updating is mediated by the prelimbic cortex and dorsomedial striatum. First, some prelimbic cortical and striatal neurons represented the action-reward associations irrespective of trial conditions. Second, the striatal neurons kept tracking the values of variable-reward condition even in fixed-reward-condition trials, such that values were possibly interferingly updated even in the fixed-reward condition. PMID- 25741232 TI - A hypothesis on the biological origins and social evolution of music and dance. AB - The origins of music and musical emotions is still an enigma, here I propose a comprehensive hypothesis on the origins and evolution of music, dance, and speech from a biological and sociological perspective. I suggest that every pitch interval between neighboring notes in music represents corresponding movement pattern through interpreting the Doppler effect of sound, which not only provides a possible explanation for the transposition invariance of music, but also integrates music and dance into a common form-rhythmic movements. Accordingly, investigating the origins of music poses the question: why do humans appreciate rhythmic movements? I suggest that human appreciation of rhythmic movements and rhythmic events developed from the natural selection of organisms adapting to the internal and external rhythmic environments. The perception and production of, as well as synchronization with external and internal rhythms are so vital for an organism's survival and reproduction, that animals have a rhythm-related reward and emotion (RRRE) system. The RRRE system enables the appreciation of rhythmic movements and events, and is integral to the origination of music, dance and speech. The first type of rewards and emotions (rhythm-related rewards and emotions, RRREs) are evoked by music and dance, and have biological and social functions, which in turn, promote the evolution of music, dance and speech. These functions also evoke a second type of rewards and emotions, which I name society related rewards and emotions (SRREs). The neural circuits of RRREs and SRREs develop in species formation and personal growth, with congenital and acquired characteristics, respectively, namely music is the combination of nature and culture. This hypothesis provides probable selection pressures and outlines the evolution of music, dance, and speech. The links between the Doppler effect and the RRREs and SRREs can be empirically tested, making the current hypothesis scientifically concrete. PMID- 25741234 TI - Early life stress and hippocampal neurogenesis in the neonate: sexual dimorphism, long term consequences and possible mediators. AB - Adverse early life experience decreases adult hippocampal neurogenesis and results in increased vulnerability to neuropsychiatric disorders. Despite that the effects of postnatal stress on neurogenesis have been widely studied in adult individuals, few efforts have been done to evaluate its immediate effects on the developing hippocampus. Moreover, it is not clear whether postnatal stress causes a differential impact in hippocampus development in male and female neonates that could be related to emotional deficits in adulthood. It has been proposed that the long term effects of early stress exposure rise from a persistent HPA axis activation during sensitive time windows; nevertheless the exact mechanisms and mediators remain unknown. Here, we summarize the immediate and late effects of early life stress on hippocampal neurogenesis in male and female rat pups, compare its later consequences in emotionality, and highlight some relevant mediator peptides that could be potentially involved in programming. PMID- 25741233 TI - Blood-brain barrier dysfunction in disorders of the developing brain. AB - Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data. PMID- 25741235 TI - Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans. AB - Familial hemiplegic migraine type 1 (FHM1) is caused by gain-of-function mutations in CaV2.1 (P/Q-type) Ca(2+) channels. Knockin (KI) mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD) in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca(2+) dependence of the excitatory postsynaptic current were similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca(2+) influx at voltages sub-threshold for action potential generation. PMID- 25741236 TI - Hydrogels as scaffolds and delivery systems to enhance axonal regeneration after injuries. AB - Damage caused to neural tissue by disease or injury frequently produces a discontinuity in the nervous system (NS). Such damage generates diverse alterations that are commonly permanent, due to the limited regeneration capacity of the adult NS, particularly the Central Nervous System (CNS). The cellular reaction to noxious stimulus leads to several events such as the formation of glial and fibrous scars, which inhibit axonal regeneration in both the CNS and the Peripheral Nervous System (PNS). Although in the PNS there is some degree of nerve regeneration, it is common that the growing axons reinnervate incorrect areas, causing mismatches. Providing a permissive substrate for axonal regeneration in combination with delivery systems for the release of molecules, which enhances axonal growth, could increase regeneration and the recovery of functions in the CNS or the PNS. Currently, there are no effective vehicles to supply growth factors or cells to the damaged/diseased NS. Hydrogels are polymers that are biodegradable, biocompatible and have the capacity to deliver a large range of molecules in situ. The inclusion of cultured neural cells into hydrogels forming three-dimensional structures allows the formation of synapses and neuronal survival. There is also evidence showing that hydrogels constitute an amenable substrate for axonal growth of endogenous or grafted cells, overcoming the presence of axonal regeneration inhibitory molecules, in both the CNS and PNS. Recent experiments suggest that hydrogels can carry and deliver several proteins relevant for improving neuronal survival and axonal growth. Although the use of hydrogels is appealing, its effectiveness is still a matter of discussion, and more results are needed to achieve consistent recovery using different parameters. This review also discusses areas of opportunity where hydrogels can be applied, in order to promote axonal regeneration of the NS. PMID- 25741237 TI - Ontogeny of CX3CR1-EGFP expressing cells unveil microglia as an integral component of the postnatal subventricular zone. AB - The full spectrum of cellular interactions within CNS neurogenic niches is still poorly understood. Only recently has the monocyte counterpart of the nervous system, the microglial cells, been described as an integral cellular component of neurogenic niches. The present study sought to characterize the microglia population in the early postnatal subventricular zone (SVZ), the major site of postnatal neurogenesis, as well as in its anterior extension, the rostral migratory stream (RMS), a pathway for neuroblasts during their transit toward the olfactory bulb (OB) layers. Here we show that microglia within the SVZ/RMS pathway are not revealed by phenotypic markers that characterize microglia in other regions. Analysis of the transgenic mice strain that has one locus of the constitutively expressed fractalkine CX3CR1 receptor replaced by the gene encoding the enhanced green fluorescent protein (EGFP) circumvented the antigenic plasticity of the microglia, thus allowing us to depict microglia within the SVZ/RMS pathway during early development. Notably, microglia within the early SVZ/RMS are not proliferative and display a protracted development, retaining a more immature morphology than their counterparts outside germinal layers. Furthermore, microglia contact and phagocyte radial glia cells (RG) processes, thereby playing a role on the astroglial transformation that putative stem cells within the SVZ niche undergo during the first postnatal days. PMID- 25741238 TI - Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS. AB - It is well known that mitochondrial damage (MD) is both the major contributor to oxidative stress (OS) (the condition arising from unbalance between production and removal of reactive oxygen species) and one of the major consequences of OS, because of the high dependance of mitochondrial function on redox-sensitive targets such as intact membranes. Conditions in which neuronal cells are not able to cope with MD and OS seem to lead or contribute to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), at least in the most studied superoxide dismutase 1 (SOD1)-linked genetic variant. As summarized in this review, new evidence indicates that MD and OS play a role also in non-SOD1 ALS and thus they may represent a target for therapy despite previous failures in clinical trials. PMID- 25741239 TI - A pre-docking source for the power-law behavior of spontaneous quantal release: application to the analysis of LTP. AB - In neurons, power-law behavior with different scaling exponents has been reported at many different levels, including fluctuations in membrane potentials, synaptic transmission up to neuronal network dynamics. Unfortunately in most cases the source of this non-linear feature remains controversial. Here we have analyzed the dynamics of spontaneous quantal release at hippocampal synapses and characterized their power-law behavior. While in control conditions a fractal exponent greater than zero was rarely observed, its value was greatly increased by alpha-latrotoxin (alpha-LTX), a potent stimulator of spontaneous release, known to act at the very last step of vesicle fusion. Based on computer modeling, we confirmed that at an increase in fusion probability would unmask a pre-docking phenomenon with 1/f structure, where alpha estimated from the release series appears to sense the increase in release probability independently from the number of active sites. In the simplest scenario the pre-docking 1/f process could coincide with the Brownian diffusion of synaptic vesicles. Interestingly, when the effect of long-term potentiation (LTP) was tested, a ~200% long-lasting increase in quantal frequency was accompanied by a significant increase in the scaling exponent. The similarity between the action of LTP and of alpha-LTX suggests an increased contribution of high release probability sites following the induction of LTP. In conclusion, our results indicate that the source of the synaptic power-law behavior arises before synaptic vesicles dock to the active zone and that the fractal exponent alpha is capable of sensing a change in release probability independently from the number of active sites or synapses. PMID- 25741240 TI - Legal but lethal: functional protein aggregation at the verge of toxicity. AB - Many neurodegenerative disorders are linked to irreversible protein aggregation, a process that usually comes along with toxicity and serious cellular damage. However, it is emerging that protein aggregation can also serve for physiological purposes, as impressively shown for prions. While the aggregation of this protein family was initially considered exclusively toxic in mammalians organisms, it is now almost clear that many other proteins adopt prion-like attributes to rationally polymerize into higher order complexes with organized physiologic roles. This implies that cells can tolerate at least in some measure the accumulation of inherently dangerous protein aggregates for functional profit. This review summarizes currently known strategies that living organisms adopt to preserve beneficial aggregation, and to prevent the catastrophic accumulation of toxic aggregates that frequently accompany neurodegeneration. PMID- 25741241 TI - Using the zebrafish lateral line to uncover novel mechanisms of action and prevention in drug-induced hair cell death. AB - The majority of hearing loss and balance disorders are caused by the permanent loss of mechanosensory hair cells of the inner ear. Identification of genes and compounds that modulate susceptibility to hair cell death is frequently confounded by the difficulties of assaying for such complex phenomena in mammalian models. The zebrafish has emerged as a powerful animal model for genetic and chemical screening in many contexts. Several characteristics of the zebrafish, such as its small size and external location of mechanosensory hair cells within the lateral line sensory organ, uniquely position it as an ideal model organism for the study of hair cell toxicity. We have used this model to screen for genes and compounds that affect hair cell survival during ototoxin exposure and have identified agents that would not be expected to play a role in this process based on a priori knowledge of their function. The identification of such agents yields better understanding of hair cell death and holds promise to stem hearing loss and balance disorders in the human population. PMID- 25741242 TI - Origin and early development of the chicken adenohypophysis. AB - The adenohypophysis (ADH) is an important endocrine organ involved in the regulation of many physiological processes. The late morphogenesis of this organ at neural tube stages is well known: the epithelial ADH primordium is recognized as an invagination of the stomodeal roof (Rathke's pouch), whose walls later thicken and differentiate as the primordium becomes pediculated, and then fully separated from the stomodeum. The primordium attaches to the pial surface of the basal hypothalamus, next to the neurohypophyseal field (NH; future posterior pituitary), from which it was previously separated by migrating prechordal plate (pp) cells. Once the NH evaginates, the ADH surrounds it and jointly forms with it the pituitary gland. In contrast, little is known about the precise origin of the ADH precursors at neural plate stages and how the primordium reaches the stomodeum. For that reason, we produced in the chicken a specific ADH fate map at early neural plate stages, which was amplified with gene markers. By means of experiments labeling the mapped presumptive ADH, we were able to follow the initial anlage into its transformation into Rathke's pouch. The ADH origin was corroborated to be strictly extraneural, i.e., to lie at stage HH4/5 outside of the anterior neural plate (anp) within the pre-placodal field. The ADH primordium is fully segregated from the anterior neural border cells and the neighboring olfactory placodes both in terms of precursor cells and molecular profile from head fold stages onwards. The placode becomes visible as a molecularly characteristic ectodermal thickening from stage HH10 onwards. The onset of ADH genoarchitectonic regionalization into intermediate and anterior lobes occurs at closed neural tube stages. PMID- 25741243 TI - Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats. AB - Thyroid hormones are fundamental for the expression of genes involved in the development of the CNS and their deficiency is associated with a wide spectrum of neurological diseases including mental retardation, attention deficit hyperactivity disorder and autism spectrum disorders. We examined in rat whether developmental and early postnatal hypothyroidism affects the distribution of vesicular glutamate transporter-1 (VGluT1; glutamatergic) and vesicular inhibitory amino acid transporter (VGAT; GABAergic) immunoreactive (ir) boutons in the hippocampus and somatosensory cortex, and the behavior of the pups. Hypothyroidism was induced by adding 0.02% methimazole (MMI) and 1% KClO4 to the drinking water starting at embryonic day 10 (E10; developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at postnatal day 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. The distribution, density and size of VGluT1-ir and VGAT-ir boutons in the hippocampus and somatosensory cortex was abnormal in MMI pups and these changes correlate with behavioral changes, as prepulse inhibition of the startle response amplitude was reduced, and the percentage of time spent in open arms increased. In conclusion, both developmental and early postnatal hypothyroidism significantly decreases the ratio of GABAergic to glutamatergic boutons in dentate gyrus leading to an abnormal flow of information to the hippocampus and infragranular layers of the somatosensory cortex, and alter behavior in rats. Our data show cytoarchitectonic alterations in the basic excitatory hippocampal loop, and in local inhibitory circuits of the somatosensory cortex and hippocampus that might contribute to the delayed neurocognitive outcome observed in thyroid hormone deficient children born in iodine deficient areas, or suffering from congenital hypothyroidism. PMID- 25741244 TI - Mesencephalic basolateral domain specification is dependent on Sonic Hedgehog. AB - In the study of central nervous system morphogenesis, the identification of new molecular markers allows us to identify domains along the antero-posterior and dorso-ventral (DV) axes. In the past years, the alar and basal plates of the midbrain have been divided into different domains. The precise location of the alar-basal boundary is still under discussion. We have identified Barhl1, Nhlh1 and Six3 as appropriate molecular markers to the adjacent domains of this transition. The description of their expression patterns and the contribution to the different mesencephalic populations corroborated their role in the specification of these domains. We studied the influence of Sonic Hedgehog on these markers and therefore on the specification of these territories. The lack of this morphogen produced severe alterations in the expression pattern of Barhl1 and Nhlh1 with consequent misspecification of the basolateral (BL) domain. Six3 expression was apparently unaffected, however its distribution changed leading to altered basal domains. In this study we confirmed the localization of the alar basal boundary dorsal to the BL domain and demonstrated that the development of the BL domain highly depends on Shh. PMID- 25741245 TI - Hemodynamic responses on prefrontal cortex related to meditation and attentional task. AB - Recent neuroimaging studies state that meditation increases regional cerebral blood flow (rCBF) in the prefrontal cortex (PFC). The present study employed functional near infrared spectroscopy (fNIRS) to evaluate the relative hemodynamic changes in PFC during a cognitive task. Twenty-two healthy male volunteers with ages between 18 and 30 years (group mean age +/- SD; 22.9 +/- 4.6 years) performed a color-word stroop task before and after 20 min of meditation and random thinking. Repeated measures ANOVA was performed followed by a post hoc analysis with Bonferroni adjustment for multiple comparisons between the mean values of "During" and "Post" with "Pre" state. During meditation there was an increased in oxy-hemoglobin (DeltaHbO) and total hemoglobin (DeltaTHC) concentration with reduced deoxy-hemoglobin (DeltaHbR) concentration over the right prefrontal cortex (rPFC), whereas in random thinking there was increased DeltaHbR with reduced total hemoglobin concentration on the rPFC. The mean reaction time (RT) was shorter during stroop color word task with concomitant reduction in DeltaTHC after meditation, suggestive of improved performance and efficiency in task related to attention. Our findings demonstrated that meditation increased cerebral oxygenation and enhanced performance, which was associated with activation of the PFC. PMID- 25741248 TI - A survey of substance use for cognitive enhancement by university students in the Netherlands. AB - BACKGROUND: Pharmacological cognitive enhancement, using chemicals to change cellular processes in the brain in order to enhance one's cognitive capacities, is an often discussed phenomenon. The prevalence among Dutch university students is unknown. METHODS: The study set out to achieve the following goals: (1) give an overview of different methods in order to assess the prevalence of use of prescription, illicit and lifestyle drugs for cognitive enhancement (2) investigate whether polydrug use and stress have a relationship with cognitive enhancement substance use (3) assessing opinions about cognitive enhancement prescription drug use. A nationwide survey was conducted among 1572 student respondents of all government supported Dutch universities. RESULTS: The most detailed level of analysis-use of specific substances without a prescription and with the intention of cognitive enhancement-shows that prescription drugs, illicit drugs and lifestyle drugs are respectively used by 1.7, 1.3, and 45.6% of the sample. The use of prescription drugs and illicit drugs is low compared to other countries. We have found evidence of polydrug use in relation to cognitive enhancement. A relation between stress and the use of lifestyle drugs for cognitive enhancement was observed. We report the findings of several operationalizations of cognitive enhancement drug use to enable comparison with a wider variety of previous and upcoming research. CONCLUSIONS: RESULTS of this first study among university students in the Netherlands revealed a low prevalence of cognitive enhancement drug use compared to other countries. Multiple explanations, such as a difference in awareness of pharmacological cognitive enhancement among students, accessibility of drugs in the student population and inclusion criteria of enhancement substances are discussed. We urge enhancement researchers to take the different operationalizations and their effects on the prevalence numbers into account. PMID- 25741246 TI - Direct hypothalamic and indirect trans-pallidal, trans-thalamic, or trans-septal control of accumbens signaling and their roles in food intake. AB - Due in part to the increasing incidence of obesity in developed nations, recent research aims to elucidate neural circuits that motivate humans to overeat. Earlier research has described how the nucleus accumbens shell (AcbSh) motivates organisms to feed by activating neuronal populations in the lateral hypothalamus (LH). However, more recent research suggests that the LH may in turn communicate with the AcbSh, both directly and indirectly, to re-tune the motivation to consume foods with homeostatic and food-related sensory signals. Here, we discuss the functional and anatomical evidence for an LH to AcbSh connection and its role in eating behaviors. The LH appears to modulate Acb activity directly, using neurotransmitters such as hypocretin/orexin or melanin concentrating hormone (MCH). The LH also indirectly regulates AcbSh activity through certain subcortical "relay" regions, such as the lateral septum (LS), ventral pallidum (VP), and paraventricular thalamus, using a variety of neurotransmitters. This review aims to summarize studies on these topics and outline a model by which LH circuits processing energy balance can modulate AcbSh neural activity to regulate feeding behavior. PMID- 25741249 TI - Classification of single-trial auditory events using dry-wireless EEG during real and motion simulated flight. AB - Application of neuro-augmentation technology based on dry-wireless EEG may be considerably beneficial for aviation and space operations because of the inherent dangers involved. In this study we evaluate classification performance of perceptual events using a dry-wireless EEG system during motion platform based flight simulation and actual flight in an open cockpit biplane to determine if the system can be used in the presence of considerable environmental and physiological artifacts. A passive task involving 200 random auditory presentations of a chirp sound was used for evaluation. The advantage of this auditory task is that it does not interfere with the perceptual motor processes involved with piloting the plane. Classification was based on identifying the presentation of a chirp sound vs. silent periods. Evaluation of Independent component analysis (ICA) and Kalman filtering to enhance classification performance by extracting brain activity related to the auditory event from other non-task related brain activity and artifacts was assessed. The results of permutation testing revealed that single trial classification of presence or absence of an auditory event was significantly above chance for all conditions on a novel test set. The best performance could be achieved with both ICA and Kalman filtering relative to no processing: Platform Off (83.4% vs. 78.3%), Platform On (73.1% vs. 71.6%), Biplane Engine Off (81.1% vs. 77.4%), and Biplane Engine On (79.2% vs. 66.1%). This experiment demonstrates that dry-wireless EEG can be used in environments with considerable vibration, wind, acoustic noise, and physiological artifacts and achieve good single trial classification performance that is necessary for future successful application of neuro-augmentation technology based on brain-machine interfaces. PMID- 25741250 TI - Tapping into rhythm generation circuitry in humans during simulated weightlessness conditions. AB - An ability to produce rhythmic activity is ubiquitous for locomotor pattern generation and modulation. The role that the rhythmogenesis capacity of the spinal cord plays in injured populations has become an area of interest and systematic investigation among researchers in recent years, despite its importance being long recognized by neurophysiologists and clinicians. Given that each individual interneuron, as a rule, receives a broad convergence of various supraspinal and sensory inputs and may contribute to a vast repertoire of motor actions, the importance of assessing the functional state of the spinal locomotor circuits becomes increasingly evident. Air-stepping can be used as a unique and important model for investigating human rhythmogenesis since its manifestation is largely facilitated by a reduction of external resistance. This article aims to provide a review on current issues related to the "locomotor" state and interactions between spinal and supraspinal influences on the central pattern generator (CPG) circuitry in humans, which may be important for developing gait rehabilitation strategies in individuals with spinal cord and brain injuries. PMID- 25741251 TI - The contribution of LM to the neuroscience of movement vision. AB - The significance of early and sporadic reports in the 19th century of impairments of motion vision following brain damage was largely unrecognized. In the absence of satisfactory post-mortem evidence, impairments were interpreted as the consequence of a more general disturbance resulting from brain damage, the location and extent of which was unknown. Moreover, evidence that movement constituted a special visual perception and may be selectively spared was similarly dismissed. Such skepticism derived from a reluctance to acknowledge that the neural substrates of visual perception may not be confined to primary visual cortex. This view did not persist. First, it was realized that visual movement perception does not depend simply on the analysis of spatial displacements and temporal intervals, but represents a specific visual movement sensation. Second persuasive evidence for functional specialization in extrastriate cortex, and notably the discovery of cortical area V5/MT, suggested a separate region specialized for motion processing. Shortly thereafter the remarkable case of patient LM was published, providing compelling evidence for a selective and specific loss of movement vision. The case is reviewed here, along with an assessment of its contribution to visual neuroscience. PMID- 25741252 TI - Neuronal correlates of attention and its disengagement in the superior colliculus of rat. AB - Orienting attention to a new target requires prior disengagement of attention from the current focus. Previous studies indicate that the superior colliculus (SC) plays an important role in attention. However, recordings of responses of SC neurons during attentional disengagement have not yet been reported. Here, we analyzed rat SC neuronal activity during performance of an attention-shift task with and without disengagement. In this task, conditioned stimuli (CSs; right and/or left light-flash or sound) were sequentially presented. To obtain an intracranial self-stimulation reward, rats were required to lick a spout when an infrequent conditioned stimulus appeared (reward trials). In the disengagement reward trials, configural stimuli consisting of an infrequent stimulus and frequent stimulus in the former trials were presented; in the non-disengagement reward trials, only an infrequent stimulus was presented. Of the 186 SC neurons responding to the CSs, 41 showed stronger responses to the CSs in the disengagement reward trials than in the non-disengagement reward trials (disengagement-related neurons). Furthermore, lick latencies in the disengagement reward trials were negatively correlated with response magnitudes to the CSs in half of the disengagement-related neurons. These disengagement-related neurons were located mainly in the deep layers of the SC. Another 70 SC neurons responded to the CSs in both disengagement and non-disengagement reward trials, suggesting that these neurons were involved in attention engagement. Our results suggest complementary mechanisms of attentional shift based on two subpopulations of neurons in the SC. PMID- 25741253 TI - Modeling circadian and sleep-homeostatic effects on short-term interval timing. AB - Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior. PMID- 25741247 TI - To ingest or rest? Specialized roles of lateral hypothalamic area neurons in coordinating energy balance. AB - Survival depends on an organism's ability to sense nutrient status and accordingly regulate intake and energy expenditure behaviors. Uncoupling of energy sensing and behavior, however, underlies energy balance disorders such as anorexia or obesity. The hypothalamus regulates energy balance, and in particular the lateral hypothalamic area (LHA) is poised to coordinate peripheral cues of energy status and behaviors that impact weight, such as drinking, locomotor behavior, arousal/sleep and autonomic output. There are several populations of LHA neurons that are defined by their neuropeptide content and contribute to energy balance. LHA neurons that express the neuropeptides melanin-concentrating hormone (MCH) or orexins/hypocretins (OX) are best characterized and these neurons play important roles in regulating ingestion, arousal, locomotor behavior and autonomic function via distinct neuronal circuits. Recently, another population of LHA neurons containing the neuropeptide Neurotensin (Nts) has been implicated in coordinating anorectic stimuli and behavior to regulate hydration and energy balance. Understanding the specific roles of MCH, OX and Nts neurons in harmonizing energy sensing and behavior thus has the potential to inform pharmacological strategies to modify behaviors and treat energy balance disorders. PMID- 25741254 TI - Helping or punishing strangers: neural correlates of altruistic decisions as third-party and of its relation to empathic concern. AB - Social norms are a cornerstone of human society. When social norms are violated (e.g., fairness) people can either help the victim or punish the violator in order to restore justice. Recent research has shown that empathic concern influences this decision to help or punish. Using functional magnetic resonance imaging (fMRI) we investigated the neural underpinnings of third-party help and punishment and the involvement of empathic concern. Participants saw a person violating a social norm, i.e., proposing unfair offers in a dictator game, at the expense of another person. The participants could then decide to either punish the violator or help the victim. Our results revealed that both third-party helping as well as third-party punishing activated the bilateral striatum, a region strongly related with reward processing, indicating that both altruistic decisions share a common neuronal basis. In addition, also different networks were involved in the two processes compared with control conditions; bilateral striatum and the right lateral prefrontal cortex (lPFC) during helping and bilateral striatum as well as left lPFC and ventral medial prefrontal cortex (vmPFC) during punishment. Further we found that individual differences in empathic concern influenced whether people prefer to help or to punish. People with high empathic concern helped more frequently, were faster in their decision and showed higher activation in frontoparietal regions during helping compared with punishing. Our findings provide insights into the neuronal basis of human altruistic behavior and social norm enforcement mechanism. PMID- 25741255 TI - Motion and emotion: depression reduces psychomotor performance and alters affective movements in caregiving interactions. AB - BACKGROUND: Impaired social functioning is a well-established feature of depression. Evidence to date suggests that disrupted processing of emotional cues may constitute part of this impairment. Beyond processing of emotional cues, fluent social interactions require that people physically move in synchronized, contingent ways. Disruptions to physical movements are a diagnostic feature of depression (psychomotor disturbance) but have not previously been assessed in the context of social functioning. Here we investigated the impact of psychomotor disturbance in depression on physical responsive behavior in both an experimental and observational setting. METHODS: In Experiment 1, we examined motor disturbance in depression in response to salient emotional sounds, using a laboratory-based effortful motor task. In Experiment 2, we explored whether psychomotor disturbance was apparent in real-life social interactions. Using mother-infant interactions as a model affective social situation, we compared physical behaviors of mothers with and without postnatal depression (PND). RESULTS: We found impairments in precise, controlled psychomotor performance in adults with depression relative to healthy adults (Experiment 1). Despite this disruption, all adults showed enhanced performance following exposure to highly salient emotional cues (infant cries). Examining real-life interactions, we found differences in physical movements, namely reduced affective touching, in mothers with PND responding to their infants, compared to healthy mothers (Experiment 2). CONCLUSIONS: Together, these findings suggest that psychomotor disturbance may be an important feature of depression that can impair social functioning. Future work investigating whether improvements in physical movement in depression could have a positive impact on social interactions would be of much interest. PMID- 25741256 TI - Behavioral changes in response to sound exposure and no spatial avoidance of noisy conditions in captive zebrafish. AB - Auditory sensitivity in fish serves various important functions, but also makes fish susceptible to noise pollution. Human-generated sounds may affect behavioral patterns of fish, both in natural conditions and in captivity. Fish are often kept for consumption in aquaculture, on display in zoos and hobby aquaria, and for medical sciences in research facilities, but little is known about the impact of ambient sounds in fish tanks. In this study, we conducted two indoor exposure experiments with zebrafish (Danio rerio). The first experiment demonstrated that exposure to moderate sound levels (112 dB re 1 MUPa) can affect the swimming behavior of fish by changing group cohesion, swimming speed and swimming height. Effects were brief for both continuous and intermittent noise treatments. In the second experiment, fish could influence exposure to higher sound levels by swimming freely between an artificially noisy fish tank (120-140 dB re 1 MUPa) and another with ambient noise levels (89 dB re 1 MUPa). Despite initial startle responses, and a brief period in which many individuals in the noisy tank dived down to the bottom, there was no spatial avoidance or noise-dependent tank preference at all. The frequent exchange rate of about 60 fish passages per hour between tanks was not affected by continuous or intermittent exposures. In conclusion, small groups of captive zebrafish were able to detect sounds already at relatively low sound levels and adjust their behavior to it. Relatively high sound levels were at least at the on-set disturbing, but did not lead to spatial avoidance. Further research is needed to show whether zebrafish are not able to avoid noisy areas or just not bothered. Quantitatively, these data are not directly applicable to other fish species or other fish tanks, but they do indicate that sound exposure may affect fish behavior in any captive condition. PMID- 25741258 TI - Between-group competition, intra-group cooperation and relative performance. AB - We report the results of a new public goods experiment with an intra-group cooperation dilemma and inter-group competition. In our design subjects receive information about their relative individual and group performance after each round with non-incentivized and then incentivized group competition. We found that, on average, individuals with low relative performance reduce their contributions to the public good, but groups with low performance increase theirs. With incentivized competition, where the relative ranking of the group increases individual payoffs, the reaction to relative performance is larger with individuals contributing more to the group; further, we observe that the variance of strategies decreases as individual and group rankings increase. These results offer new insights on how social comparison shapes similar reactions in games with different incentives for group performance and how competition and cooperation can influence each other. PMID- 25741257 TI - Behavior in the elevated plus maze is differentially affected by testing conditions in rats under and over three weeks of age. AB - The late postnatal period in rats is marked by numerous changes in perceptual and cognitive abilities. As such, age-related variation in cognitive test performance might result in part from disparate sensitivities to environmental factors. To better understand how testing conditions might interact with age, we assessed anxiety behavior on an elevated plus maze (EPM) in juvenile rats around 3 weeks of age under diverse testing conditions. Plasma corticosterone and neuronal activation patterns in the forebrain were examined after maze exposure. We found that anxiety was differentially expressed during different stages of late postnatal development. Bright illumination and morning testing encouraged greatest open arm exploration on the EPM in younger animals, while older rats explored open areas more under dim illumination in the morning compared to bright illumination in the afternoon/evening. Older rats exhibited higher plasma corticosterone levels at baseline compared to younger rats; however, this trend was reversed for post-testing corticosterone. Additionally, post-testing corticosterone levels were inversely related to time of testing. Compared to testing in the morning, EPM exposure in the afternoon/evening elicited greater neuronal Arc expression in the amygdala. Arc expression in the amygdala after morning testing was greater at P22-24 than P17-19. In layer 2/3 of primary visual cortex, Arc expression was elevated in younger animals and age interacted with time of testing to produce opposing effects at P17-19 and P22-24. These data suggest that age-related differences in anxiety-associated behavior during the late postnatal period are due in part to changes in light sensitivity and emergence of a circadian cycle for corticosterone. The findings illustrate that late postnatal behavioral development in rodents is a complex orchestration of changes in neural systems involved in perception, cognition, affect and homeostatic regulation. PMID- 25741259 TI - Olfactory memory networks: from emotional learning to social behaviors. PMID- 25741260 TI - A FreeSurfer-compliant consistent manual segmentation of infant brains spanning the 0-2 year age range. AB - We present a detailed description of a set of FreeSurfer compatible segmentation guidelines tailored to infant MRI scans, and a unique data set of manually segmented acquisitions, with subjects nearly evenly distributed between 0 and 2 years of age. We believe that these segmentation guidelines and this dataset will have a wide range of potential uses in medicine and neuroscience. PMID- 25741261 TI - Figurative language processing in atypical populations: the ASD perspective. AB - This paper is intended to provide a critical overview of experimental and clinical research documenting problems in figurative language processing in atypical populations with a focus on the Autistic Spectrum. Research in the comprehension and processing of figurative language in autism invariably documents problems in this area. The greater paradox is that even at the higher end of the spectrum or in the cases of linguistically talented individuals with Asperger syndrome, where structural language competence is intact, problems with extended language persist. If we assume that figurative and extended uses of language essentially depend on the perception and processing of more concrete core concepts and phenomena, the commonly observed failure in atypical populations to understand figurative language remains a puzzle. Various accounts have been offered to explain this issue, ranging from linking potential failure directly to overall structural language competence (Norbury, 2005; Brock et al., 2008) to right-hemispheric involvement (Gold and Faust, 2010). We argue that the dissociation between structural language and figurative language competence in autism should be sought in more general cognitive mechanisms and traits in the autistic phenotype (e.g., in terms of weak central coherence, Vulchanova et al., 2012b), as well as failure at on-line semantic integration with increased complexity and diversity of the stimuli (Coulson and Van Petten, 2002). This perspective is even more compelling in light of similar problems in a number of conditions, including both acquired (e.g., Aphasia) and developmental disorders (Williams Syndrome). This dissociation argues against a simple continuity view of language interpretation. PMID- 25741262 TI - Changes in functional connectivity within the fronto-temporal brain network induced by regular and irregular Russian verb production. AB - Functional connectivity between brain areas involved in the processing of complex language forms remains largely unexplored. Contributing to the debate about neural mechanisms underlying regular and irregular inflectional morphology processing in the mental lexicon, we conducted an fMRI experiment in which participants generated forms from different types of Russian verbs and nouns as well as from nonce stimuli. The data were subjected to a whole brain voxel-wise analysis of context dependent changes in functional connectivity [the so-called psychophysiological interaction (PPI) analysis]. Unlike previously reported subtractive results that reveal functional segregation between brain areas, PPI provides complementary information showing how these areas are functionally integrated in a particular task. To date, PPI evidence on inflectional morphology has been scarce and only available for inflectionally impoverished English verbs in a same-different judgment task. Using PPI here in conjunction with a production task in an inflectionally rich language, we found that functional connectivity between the left inferior frontal gyrus (LIFG) and bilateral superior temporal gyri (STG) was significantly greater for regular real verbs than for irregular ones. Furthermore, we observed a significant positive covariance between the number of mistakes in irregular real verb trials and the increase in functional connectivity between the LIFG and the right anterior cingulate cortex in these trails, as compared to regular ones. Our results therefore allow for dissociation between regularity and processing difficulty effects. These results, on the one hand, shed new light on the functional interplay within the LIFG-bilateral STG language-related network and, on the other hand, call for partial reconsideration of some of the previous findings while stressing the role of functional temporo-frontal connectivity in complex morphological processes. PMID- 25741263 TI - The intrahemispheric functional properties of the developing sensorimotor cortex are influenced by maturation. AB - The investigation of the functional changes in the sensorimotor cortex has important clinical implications as deviations from normal development can anticipate developmental disorders. The functional properties of the sensorimotor cortex can be characterized through the rolandic mu rhythm, already present during infancy. However, how the sensorimotor network develops from early infancy to adulthood, and how sensorimotor processing contributes to the generation of perceptual-motor coupling remains largely unknown. Here, we analyzed magnetoencephalographic (MEG) data recorded in two groups of infants (11-24 and 26-47 weeks), two groups of children (24-34 and 36-60 months), and a control group of adults (20-39 years), during intermixed conditions of rest and prehension. The MEG sensor array was positioned over the sensorimotor cortex of the contralateral hemisphere. We characterized functional connectivity and topological properties of the sensorimotor network across ages and conditions through synchronization likelihood and segregation/integration measures in an individual mu rhythm frequency range. All functional measures remained almost unchanged during the first year of life, whereas they varied afterwards through childhood to reach adult values, demonstrating an increase of both segregation and integration properties. With age, the sensorimotor network evolved from a more random (infants) to a "small-world" organization (children and adults), more efficient both locally and globally. These findings are in line with prior studies on structural and functional brain development in infants, children and adults. We could not demonstrate any significant change in the functional properties of the sensorimotor cortex in the prehension condition with respect to rest. Our results support the view that, since early infancy, the functional properties of the developing sensorimotor cortex are modulated by maturation. PMID- 25741264 TI - A comparison of two sleep spindle detection methods based on all night averages: individually adjusted vs. fixed frequencies. AB - Sleep spindles are frequently studied for their relationship with state and trait cognitive variables, and they are thought to play an important role in sleep related memory consolidation. Due to their frequent occurrence in NREM sleep, the detection of sleep spindles is only feasible using automatic algorithms, of which a large number is available. We compared subject averages of the spindle parameters computed by a fixed frequency (FixF) (11-13 Hz for slow spindles, 13 15 Hz for fast spindles) automatic detection algorithm and the individual adjustment method (IAM), which uses individual frequency bands for sleep spindle detection. Fast spindle duration and amplitude are strongly correlated in the two algorithms, but there is little overlap in fast spindle density and slow spindle parameters in general. The agreement between fixed and manually determined sleep spindle frequencies is limited, especially in case of slow spindles. This is the most likely reason for the poor agreement between the two detection methods in case of slow spindle parameters. Our results suggest that while various algorithms may reliably detect fast spindles, a more sophisticated algorithm primed to individual spindle frequencies is necessary for the detection of slow spindles as well as individual variations in the number of spindles in general. PMID- 25741265 TI - Test-retest reliability of white matter structural brain networks: a multiband diffusion MRI study. AB - The multiband EPI sequence has been developed for the human connectome project to accelerate MRI data acquisition. However, no study has yet investigated the test retest (TRT) reliability of the graph metrics of white matter (WM) structural brain networks constructed from this new sequence. Here, we employed a multiband diffusion MRI (dMRI) dataset with repeated scanning sessions and constructed both low- and high-resolution WM networks by volume- and surface-based parcellation methods. The reproducibility of network metrics and its dependence on type of construction procedures was assessed by the intra-class correlation coefficient (ICC). We observed conserved topological architecture of WM structural networks constructed from the multiband dMRI data as previous findings from conventional dMRI. For the global network properties, the first order metrics were more reliable than second order metrics. Between two parcellation methods, networks with volume-based parcellation showed better reliability than surface-based parcellation, especially for the global metrics. Between different resolutions, the high-resolution network exhibited higher TRT performance than the low resolution in terms of the global metrics with a large effect size, whereas the low-resolution performs better in terms of local (region and connection) properties with a relatively low effect size. Moreover, we identified that the association and primary cortices showed higher reproducibility than the paralimbic/limbic regions. The important hub regions and rich-club connections are more reliable than the non-hub regions and connections. Finally, we found WM networks from the multiband dMRI showed higher reproducibility compared with those from the conventional dMRI. Together, our results demonstrated the fair to good reliability of the WM structural brain networks from the multiband EPI sequence, suggesting its potential utility for exploring individual differences and for clinical applications. PMID- 25741266 TI - Perceptual salience affects the contents of working memory during free recollection of objects from natural scenes. AB - One of the most important issues in the study of cognition is to understand which are the factors determining internal representation of the external world. Previous literature has started to highlight the impact of low-level sensory features (indexed by saliency-maps) in driving attention selection, hence increasing the probability for objects presented in complex and natural scenes to be successfully encoded into working memory (WM) and then correctly remembered. Here we asked whether the probability of retrieving high-saliency objects modulates the overall contents of WM, by decreasing the probability of retrieving other, lower-saliency objects. We presented pictures of natural scenes for 4 s. After a retention period of 8 s, we asked participants to verbally report as many objects/details as possible of the previous scenes. We then computed how many times the objects located at either the peak of maximal or minimal saliency in the scene (as indexed by a saliency-map; Itti et al., 1998) were recollected by participants. Results showed that maximal-saliency objects were recollected more often and earlier in the stream of successfully reported items than minimal saliency objects. This indicates that bottom-up sensory salience increases the recollection probability and facilitates the access to memory representation at retrieval, respectively. Moreover, recollection of the maximal- (but not the minimal-) saliency objects predicted the overall amount of successfully recollected objects: The higher the probability of having successfully reported the most-salient object in the scene, the lower the amount of recollected objects. These findings highlight that bottom-up sensory saliency modulates the current contents of WM during recollection of objects from natural scenes, most likely by reducing available resources to encode and then retrieve other (lower saliency) objects. PMID- 25741267 TI - Higher levels of cardiovascular fitness are associated with better executive function and prefrontal oxygenation in younger and older women. AB - AIM: Many studies have suggested that physical exercise training improves cognition and more selectively executive functions. There is a growing interest to clarify the neurophysiological mechanisms that underlie this effect. The aim of the current study was to evaluate the neurophysiological changes in cerebral oxygenation associated with physical fitness level and executive functions. METHOD: In this study, 22 younger and 36 older women underwent a maximal graded continuous test (i.e., [Formula: see text]O2max ) in order to classify them into a fitness group (higher vs. lower fit). All participants completed neuropsychological paper and pencil testing and a computerized Stroop task (which contained executive and non-executive conditions) in which the change in prefrontal cortex oxygenation was evaluated with near infrared spectroscopy (NIRS). RESULTS: Our findings revealed a Fitness * Condition interaction (p < 0.05) such that higher fit women scored better on measures of executive functions than lower fit women. In comparison to lower fit women, higher fit women had faster reaction times in the Executive condition of the computerized Stroop task. No significant effect was observed in the non-executive condition of the test and no interactions were found with age. In measures of cerebral oxygenation (DeltaHbT and DeltaHbO2), we found a main effect of fitness on cerebral oxygenation during the Stroop task such that only high fit women demonstrated a significant increase in the right inferior frontal gyrus. DISCUSSION/CONCLUSION: Higher fit individuals who demonstrate better cardiorespiratory functions (as measured by [Formula: see text]O2max ) show faster reaction times and greater cerebral oxygenation in the right inferior frontal gyrus than women with lower fitness levels. The lack of interaction with age, suggests that good cardiorespiratory functions can have a positive impact on cognition, regardless of age. PMID- 25741268 TI - Proprioceptive bimanual test in intrinsic and extrinsic coordinates. AB - Is there any difference between matching the position of the hands by asking the subjects to move them to the same spatial location or to mirror-symmetric locations with respect to the body midline? If the motion of the hands were planned in the extrinsic space, the mirror-symmetric task would imply an additional challenge, because we would need to flip the coordinates of the target on the other side of the workspace. Conversely, if the planning were done in intrinsic coordinates, in order to move both hands to the same spot in the workspace, we should compute different joint angles for each arm. Even if both representations were available to the subjects, the two tasks might lead to different results, providing some cue on the organization of the "body schema". In order to answer such questions, the middle fingertip of the non-dominant hand of a population of healthy subjects was passively moved by a manipulandum to 20 different target locations. Subjects matched these positions with the middle fingertip of their dominant hand. For most subjects, the matching accuracy was higher in the extrinsic modality both in terms of systematic error and variability, even for the target locations in which the configuration of the arms was the same for both modalities. This suggests that the matching performance of the subjects could be determined not only by proprioceptive information but also by the cognitive representation of the task: expressing the goal as reaching for the physical location of the hand in space is apparently more effective than requiring to match the proprioceptive representation of joint angles. PMID- 25741269 TI - Differential cerebral response to somatosensory stimulation of an acupuncture point vs. two non-acupuncture points measured with EEG and fMRI. AB - Acupuncture can be regarded as a complex somatosensory stimulation. Here, we evaluate whether the point locations chosen for a somatosensory stimulation with acupuncture needles differently change the brain activity in healthy volunteers. We used EEG, event-related fMRI, and resting-state functional connectivity fMRI to assess neural responses to standardized needle stimulation of the acupuncture point ST36 (lower leg) and two control point locations (CP1 same dermatome, CP2 different dermatome). Cerebral responses were expected to differ for stimulation in two different dermatomes (CP2 different from ST36 and CP1), or stimulation at the acupuncture point vs. the control points. For EEG, mu rhythm power increased for ST36 compared to CP1 or CP2, but not when comparing the two control points. The fMRI analysis found more pronounced insula and S2 (secondary somatosensory cortex) activation, as well as precuneus deactivation during ST36 stimulation. The S2 seed-based functional connectivity analysis revealed increased connectivity to right precuneus for both comparisons, ST36 vs. CP1 and ST36 vs. CP2, however in different regions. Our results suggest that stimulation at acupuncture points may modulate somatosensory and saliency processing regions more readily than stimulation at non-acupuncture point locations. Also, our findings suggest potential modulation of pain perception due to acupuncture stimulation. PMID- 25741270 TI - Memory integration in the autobiographical narratives of individuals with autism. PMID- 25741271 TI - The Dynamic Ebbinghaus: motion dynamics greatly enhance the classic contextual size illusion. AB - The Ebbinghaus illusion is a classic example of the influence of a contextual surround on the perceived size of an object. Here, we introduce a novel variant of this illusion called the Dynamic Ebbinghaus illusion in which the size and eccentricity of the surrounding inducers modulates dynamically over time. Under these conditions, the size of the central circle is perceived to change in opposition with the size of the inducers. Interestingly, this illusory effect is relatively weak when participants are fixating a stationary central target, less than half the magnitude of the classic static illusion. However, when the entire stimulus translates in space requiring a smooth pursuit eye movement to track the target, the illusory effect is greatly enhanced, almost twice the magnitude of the classic static illusion. A variety of manipulations including target motion, peripheral viewing, and smooth pursuit eye movements all lead to dramatic illusory effects, with the largest effect nearly four times the strength of the classic static illusion. We interpret these results in light of the fact that motion-related manipulations lead to uncertainty in the image size representation of the target, specifically due to added noise at the level of the retinal input. We propose that the neural circuits integrating visual cues for size perception, such as retinal image size, perceived distance, and various contextual factors, weight each cue according to the level of noise or uncertainty in their neural representation. Thus, more weight is given to the influence of contextual information in deriving perceived size in the presence of stimulus and eye motion. Biologically plausible models of size perception should be able to account for the reweighting of different visual cues under varying levels of certainty. PMID- 25741272 TI - Neuroimaging for detecting covert awareness in patients with disorders of consciousness: reinforce the place of clinical feeling! PMID- 25741273 TI - Neuroesthetics is Not Just about Art. PMID- 25741274 TI - Revisiting the body-schema concept in the context of whole-body postural-focal dynamics. AB - The body-schema concept is revisited in the context of embodied cognition, further developing the theory formulated by Marc Jeannerod that the motor system is part of a simulation network related to action, whose function is not only to shape the motor system for preparing an action (either overt or covert) but also to provide the self with information on the feasibility and the meaning of potential actions. The proposed computational formulation is based on a dynamical system approach, which is linked to an extension of the equilibrium-point hypothesis, called Passive Motor Paradigm: this dynamical system generates goal oriented, spatio-temporal, sensorimotor patterns, integrating a direct and inverse internal model in a multi-referential framework. The purpose of such computational model is to operate at the same time as a general synergy formation machinery for planning whole-body actions in humanoid robots and/or for predicting coordinated sensory-motor patterns in human movements. In order to illustrate the computational approach, the integration of simultaneous, even partially conflicting tasks will be analyzed in some detail with regard to postural-focal dynamics, which can be defined as the fusion of a focal task, namely reaching a target with the whole-body, and a postural task, namely maintaining overall stability. PMID- 25741275 TI - Walking Speed and Brain Glucose Uptake are Uncoupled in Patients with Multiple Sclerosis. AB - Motor impairments of the upper and lower extremities are common symptoms of multiple sclerosis (MS). While some peripheral effects like muscle weakness and loss of balance have been shown to influence these symptoms, central nervous system activity has not been fully elucidated. The purpose of this study was to determine if alterations in glucose uptake were associated with motor impairments in patients with multiple sclerosis. Eight patients with multiple sclerosis (four men) and eight sex matched healthy controls performed 15 min of treadmill walking at a self-selected pace, during which ~322 MBq of the positron emission tomography (PET) glucose analog [(18)F]-fluorodeoxyglucose (FDG) was injected. Immediately after the cessation of walking, participants underwent PET imaging. Patients with MS had lower FDG uptake in ~40% of the brain compared to the healthy controls (p FWE-corr < 0.001, q FDR-corr < 0.001, k e = 93851) and walked at a slower speed [MS, 1.1 (0.2), controls 1.4 (0.1), m/s, P = 0.014]. Within the area of lower FDG uptake 15 regions were identified. Of these 15 regions, 13 were found to have strong to moderate correlations to walking speed within the healthy controls (r > -0.75, P < 0.032). Within patients with MS only 3 of the 15 regions showed significant correlations: insula (r = -0.74, P = 0.036), hippocampus (r = 0.72, P = 0.045), and calcarine sulcus (r = -0.77, P = 0.026). This data suggest that walking impairments in patients with MS may be due to network wide alterations in glucose metabolism. Understanding how brain activity and metabolism are altered in patients with MS may allow for better measures of disability and disease status within this clinical population. PMID- 25741276 TI - Neuronal networks with NMDARs and lateral inhibition implement winner-takes-all. AB - A neural circuit that relies on the electrical properties of NMDA synaptic receptors is shown by numerical and theoretical analysis to be capable of realizing the winner-takes-all function, a powerful computational primitive that is often attributed to biological nervous systems. This biophysically-plausible model employs global lateral inhibition in a simple feedback arrangement. As its inputs increase, high-gain and then bi- or multi-stable equilibrium states may be assumed in which there is significant depolarization of a single neuron and hyperpolarization or very weak depolarization of other neurons in the network. The state of the winning neuron conveys analog information about its input. The winner-takes-all characteristic depends on the nonmonotonic current-voltage relation of NMDA receptor ion channels, as well as neural thresholding, and the gain and nature of the inhibitory feedback. Dynamical regimes vary with input strength. Fixed points may become unstable as the network enters a winner-takes all regime, which can lead to entrained oscillations. Under some conditions, oscillatory behavior can be interpreted as winner-takes-all in nature. Stable winner-takes-all behavior is typically recovered as inputs increase further, but with still larger inputs, the winner-takes-all characteristic is ultimately lost. Network stability may be enhanced by biologically plausible mechanisms. PMID- 25741277 TI - EEG entropy measures in anesthesia. AB - HIGHLIGHTS: ? Twelve entropy indices were systematically compared in monitoring depth of anesthesia and detecting burst suppression.? Renyi permutation entropy performed best in tracking EEG changes associated with different anesthesia states.? Approximate Entropy and Sample Entropy performed best in detecting burst suppression. OBJECTIVE: Entropy algorithms have been widely used in analyzing EEG signals during anesthesia. However, a systematic comparison of these entropy algorithms in assessing anesthesia drugs' effect is lacking. In this study, we compare the capability of 12 entropy indices for monitoring depth of anesthesia (DoA) and detecting the burst suppression pattern (BSP), in anesthesia induced by GABAergic agents. METHODS: Twelve indices were investigated, namely Response Entropy (RE) and State entropy (SE), three wavelet entropy (WE) measures [Shannon WE (SWE), Tsallis WE (TWE), and Renyi WE (RWE)], Hilbert-Huang spectral entropy (HHSE), approximate entropy (ApEn), sample entropy (SampEn), Fuzzy entropy, and three permutation entropy (PE) measures [Shannon PE (SPE), Tsallis PE (TPE) and Renyi PE (RPE)]. Two EEG data sets from sevoflurane-induced and isoflurane induced anesthesia respectively were selected to assess the capability of each entropy index in DoA monitoring and BSP detection. To validate the effectiveness of these entropy algorithms, pharmacokinetic/pharmacodynamic (PK/PD) modeling and prediction probability (Pk) analysis were applied. The multifractal detrended fluctuation analysis (MDFA) as a non-entropy measure was compared. RESULTS: All the entropy and MDFA indices could track the changes in EEG pattern during different anesthesia states. Three PE measures outperformed the other entropy indices, with less baseline variability, higher coefficient of determination (R (2)) and prediction probability, and RPE performed best; ApEn and SampEn discriminated BSP best. Additionally, these entropy measures showed an advantage in computation efficiency compared with MDFA. CONCLUSION: Each entropy index has its advantages and disadvantages in estimating DoA. Overall, it is suggested that the RPE index was a superior measure. Investigating the advantages and disadvantages of these entropy indices could help improve current clinical indices for monitoring DoA. PMID- 25741278 TI - Expressive suppression and enhancement during music-elicited emotions in younger and older adults. AB - When presented with emotional visual scenes, older adults have been found to be equally capable to regulate emotion expression as younger adults, corroborating the view that emotion regulation skills are maintained or even improved in later adulthood. However, the possibility that gaze direction might help achieve an emotion control goal has not been taken into account, raising the question whether the effortful processing of expressive regulation is really spared from the general age-related decline. Since it does not allow perceptual attention to be redirected away from the emotional source, music provides a useful way to address this question. In the present study, affective, behavioral, and physiological consequences of free expression of emotion, expressive suppression and expressive enhancement were measured in 31 younger and 30 older adults while they listened to positive and negative musical excerpts. The main results indicated that compared to younger adults, older adults reported experiencing less emotional intensity in response to negative music during the free expression of emotion condition. No age difference was found in the ability to amplify or reduce emotional expressions. However, an age-related decline in the ability to reduce the intensity of emotional state and an age-related increase in physiological reactivity were found when participants were instructed to suppress negative expression. Taken together, the current data support previous findings suggesting an age-related change in response to music. They also corroborate the observation that older adults are as efficient as younger adults at controlling behavioral expression. But most importantly, they suggest that when faced with auditory sources of negative emotion, older age does not always confer a better ability to regulate emotions. PMID- 25741279 TI - Bone mineral density, adiposity, and cognitive functions. AB - Cognitive decline and dementia due to Alzheimer's disease (AD) have been associated with genetic, lifestyle, and environmental factors. A number of potentially modifiable risk factors should be taken into account when preventive or ameliorative interventions targeting dementia and its preclinical stages are investigated. Bone mineral density (BMD) and body composition are two such potentially modifiable risk factors, and their association with cognitive decline was investigated in this study. 164 participants, aged 34-87 years old (62.78 +/- 9.27), were recruited for this longitudinal study and underwent cognitive and clinical examinations at baseline and after 3 years. Blood samples were collected for apolipoprotein E (APOE) genotyping and dual energy x-ray absorptiometry (DXA) was conducted at the same day as cognitive assessment. Using hierarchical regression analysis, we found that BMD and lean body mass, as measured using DXA were significant predictors of episodic memory. Age, gender, APOE status, and premorbid IQ were controlled for. Specifically, the List A learning from California Verbal Learning Test was significantly associated with BMD and lean mass both at baseline and at follow up assessment. Our findings indicate that there is a significant association between BMD and lean body mass and episodic verbal learning. While the involvement of modifiable lifestyle factors in human cognitive function has been examined in different studies, there is a need for further research to understand the potential underlying mechanisms. PMID- 25741280 TI - Protein kinases as switches for the function of upstream stimulatory factors: implications for tissue injury and cancer. AB - The upstream stimulatory factors (USFs) are regulators of important cellular processes. Both USF1 and USF2 are supposed to have major roles in metabolism, tissue protection and tumor development. However, the knowledge about the mechanisms that control the function of USFs, in particular in tissue protection and cancer, is limited. Phosphorylation is a versatile tool to regulate protein functions. Thereby, phosphorylation can positively or negatively affect different aspects of transcription factor function including protein stability, protein protein interaction, cellular localization, or DNA binding. The present review aims to summarize the current knowledge about the regulation of USFs by direct phosphorylation and the consequences for USF functions in tissue protection and cancer. PMID- 25741282 TI - Distinguishing between overdrive excited and suppressed ventricular beats in guinea pig ventricular myocardium. AB - Rapid ventricular pacing rates induces two types of beats following pacing cessation: recovery cycle length (RCL) prolongation (overdrive suppression) and RCL shortening (overdrive excitation). The goals of this study were to compare common experimental protocols for studying triggered activity in whole-heart preparations and differentiate between recovery beats using a new methodology. Post-pacing recovery beat cycle length (RCL) and QRS were normalized to pre-paced R-R and QRS intervals and analyzed using a K-means clustering algorithm. Control hearts only produced suppressed beats: RCL ratio increased with rapid pacing (25 +/- 4.0%, n = 10) without changing QRS duration. Rapid pacing during hypercalcemia + hypothermia (5.5 mM and 34 degrees C) produced significantly earlier excited beats (53 +/- 14%, n = 5) with wider QRS durations (58 +/- 6.3%, n = 5) than suppressed beats. Digoxin + hypothermia (0.75 MUM) produced the most excited beats with significantly earlier RCL (44 +/- 3.2%, n = 6) and wider QRS (60 +/- 3.1%, n = 6) ratios relative to suppressed beats. Increasing pacing further shortened RCL (30 +/- 7.8%, n = 6). In a prospective study, TTX (100 nM) increased RCL ratio (15 +/- 6.0%, n = 10) without changing the QRS duration of excited beats. The algorithm was compared to a cross-correlation analysis with 93% sensitivity and 94% specificity. This ECG based algorithm distinguishes between triggered and automatic activity. PMID- 25741281 TI - G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer? AB - G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1-7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtypes of GPCRs, namely AT1, AT2, and Mas receptors, to regulate cardiovascular functions. Over the past decade, the contribution of several RAS components in tumorigenesis has emerged as a novel important concept, AngII being considered as harmful and Ang1-7 as protective against cancer. Development of selective ligands targeting each RAS receptor may provide novel and efficient targeted therapeutic strategies against cancer. In this review, we focus on breast cancer to summarize current knowledge on angiotensin receptors (AT1, AT2, and Mas), and discuss the potential use of angiotensin receptor agonists and antagonists in clinics. PMID- 25741283 TI - Nitric oxide and mitochondria in metabolic syndrome. AB - Metabolic syndrome (MS) is a cluster of metabolic disorders that collectively increase the risk of cardiovascular disease. Nitric oxide (NO) plays a crucial role in the pathogeneses of MS components and is involved in different mitochondrial signaling pathways that control respiration and apoptosis. The present review summarizes the recent information regarding the interrelations of mitochondria and NO in MS. Changes in the activities of different NO synthase isoforms lead to the formation of metabolic disorders and therefore are highlighted here. Reduced endothelial NOS activity and NO bioavailability, as the main factors underlying the endothelial dysfunction that occurs in MS, are discussed in this review in relation to mitochondrial dysfunction. We also focus on potential therapeutic strategies involving NO signaling pathways that can be used to treat patients with metabolic disorders associated with mitochondrial dysfunction. The article may help researchers develop new approaches for the diagnosis, prevention and treatment of MS. PMID- 25741284 TI - From two competing oscillators to one coupled-clock pacemaker cell system. AB - At the beginning of this century, debates regarding "what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells" dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., "M-clock") is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a "Ca(2+)-clock" rhythmically discharges diastolic local Ca(2+) releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na(+)/Ca(2+) exchanger) that prompts the surface membrane "M-clock" to ignite an AP. Theoretical and experimental evidence has mounted to indicate that this clock "crosstalk" operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept. PMID- 25741285 TI - Intraspecific variation in aerobic and anaerobic locomotion: gilthead sea bream (Sparus aurata) and Trinidadian guppy (Poecilia reticulata) do not exhibit a trade-off between maximum sustained swimming speed and minimum cost of transport. AB - Intraspecific variation and trade-off in aerobic and anaerobic traits remain poorly understood in aquatic locomotion. Using gilthead sea bream (Sparus aurata) and Trinidadian guppy (Poecilia reticulata), both axial swimmers, this study tested four hypotheses: (1) gait transition from steady to unsteady (i.e., burst assisted) swimming is associated with anaerobic metabolism evidenced as excess post exercise oxygen consumption (EPOC); (2) variation in swimming performance (critical swimming speed; U crit) correlates with metabolic scope (MS) or anaerobic capacity (i.e., maximum EPOC); (3) there is a trade-off between maximum sustained swimming speed (U sus) and minimum cost of transport (COTmin); and (4) variation in U sus correlates positively with optimum swimming speed (U opt; i.e., the speed that minimizes energy expenditure per unit of distance traveled). Data collection involved swimming respirometry and video analysis. Results showed that anaerobic swimming costs (i.e., EPOC) increase linearly with the number of bursts in S. aurata, with each burst corresponding to 0.53 mg O2 kg(-1). Data are consistent with a previous study on striped surfperch (Embiotoca lateralis), a labriform swimmer, suggesting that the metabolic cost of burst swimming is similar across various types of locomotion. There was no correlation between U crit and MS or anaerobic capacity in S. aurata indicating that other factors, including morphological or biomechanical traits, influenced U crit. We found no evidence of a trade-off between U sus and COTmin. In fact, data revealed significant negative correlations between U sus and COTmin, suggesting that individuals with high U sus also exhibit low COTmin. Finally, there were positive correlations between U sus and U opt. Our study demonstrates the energetic importance of anaerobic metabolism during unsteady swimming, and provides intraspecific evidence that superior maximum sustained swimming speed is associated with superior swimming economy and optimum speed. PMID- 25741286 TI - Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels. AB - Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials. PMID- 25741287 TI - TNF-alpha and TNFR1 responses to recovery therapies following acute resistance exercise. AB - The purpose of this investigation was to compare the effect of two commonly used therapeutic modalities (a) neuromuscular electrical stimulation (NMES) and (b) cold water immersion (CWI) on circulating tumor necrosis factor alpha (TNF-alpha) and monocyte TNF-alpha receptor (TNFR1) expression following intense acute resistance exercise and subsequent recovery. Thirty (n = 30) resistance trained men (22.5 +/- 2.7 y) performed an acute heavy resistance exercise protocol on three consecutive days followed by one of three recovery methods (CON, NMES, and CWI). Circulating TNF-alpha levels were assayed and TNFR1 expression on CD14+ monocytes was measured by flow cytometry measured PRE, immediately post (IP), 30 min post (30M), 24 h post (24H), and 48 h post (48H) exercise. Circulating TNF alpha was elevated at IP (p = 0.001) and 30M (p = 0.005) and decreased at 24H and 48H recovery from IP in CON (p = 0.015) and CWI (p = 0.011). TNF-alpha did not significantly decrease from IP during recovery in NMES. TNFR1 expression was elevated (p < 0.001) at 30M compared to PRE and all other time points. No significant differences between groups were observed in TNFR1 expression. During recovery (24H, 48H) from muscle damaging exercise, NMES treatment appears to prevent the decline in circulating TNF-alpha observed during recovery in those receiving no treatment or CWI. PMID- 25741288 TI - Alternative models of addiction. PMID- 25741289 TI - Radio electric asymmetric conveyer: a novel neuromodulation technology in Alzheimer's and other neurodegenerative diseases. AB - Global research in the field of pharmacology has not yet found effective drugs to treat Alzheimer's disease (AD). Thus, alternative therapeutic strategies are under investigation, such as neurostimulation by physical means. Radio electric asymmetric conveyer (REAC) is one of these technologies and has, until now, been used in clinical studies on several psychiatric and neurological disorders with encouraging results in the absence of side effects. Moreover, studies at the cellular level have shown that REAC technology, with the appropriate protocols, is able to induce neuronal differentiation both in murine embryonic cells and in human adult differentiated cells. Other studies have shown that REAC technology is able to positively influence senescence processes. Studies conducted on AD patients and in transgenic mouse models have shown promising results, suggesting REAC could be a useful therapy for certain components of AD. PMID- 25741290 TI - Visual anticipation biases conscious decision making but not bottom-up visual processing. AB - Prediction plays a key role in control of attention but it is not clear which aspects of prediction are most prominent in conscious experience. An evolving view on the brain is that it can be seen as a prediction machine that optimizes its ability to predict states of the world and the self through the top-down propagation of predictions and the bottom-up presentation of prediction errors. There are competing views though on whether prediction or prediction errors dominate the formation of conscious experience. Yet, the dynamic effects of prediction on perception, decision making and consciousness have been difficult to assess and to model. We propose a novel mathematical framework and a psychophysical paradigm that allows us to assess both the hierarchical structuring of perceptual consciousness, its content and the impact of predictions and/or errors on conscious experience, attention and decision-making. Using a displacement detection task combined with reverse correlation, we reveal signatures of the usage of prediction at three different levels of perceptual processing: bottom-up fast saccades, top-down driven slow saccades and consciousnes decisions. Our results suggest that the brain employs multiple parallel mechanism at different levels of perceptual processing in order to shape effective sensory consciousness within a predicted perceptual scene. We further observe that bottom-up sensory and top-down predictive processes can be dissociated through cognitive load. We propose a probabilistic data association model from dynamical systems theory to model the predictive multi-scale bias in perceptual processing that we observe and its role in the formation of conscious experience. We propose that these results support the hypothesis that consciousness provides a time-delayed description of a task that is used to prospectively optimize real time control structures, rather than being engaged in the real-time control of behavior itself. PMID- 25741291 TI - A cognitive account of belief: a tentative road map. AB - Over the past decades, delusions have become the subject of growing and productive research spanning clinical and cognitive neurosciences. Despite this, the nature of belief, which underpins the construct of delusions, has received little formal investigation. No account of delusions, however, would be complete without a cognitive level analysis of belief per se. One reason for this neglect is the assumption that, unlike more established and accessible modular psychological process (e.g., vision, audition, face-recognition, language processing, and motor-control systems), beliefs comprise more distributed and therefore less accessible central cognitive processes. In this paper, we suggest some defining characteristics and functions of beliefs. Working back from cognitive accounts of delusions, we consider potential candidate cognitive processes that may be involved in normal belief formation. Finally, we advance a multistage account of the belief process that could provide the basis for a more comprehensive model of belief. PMID- 25741292 TI - Math achievement is important, but task values are critical, too: examining the intellectual and motivational factors leading to gender disparities in STEM careers. AB - Although young women now obtain higher course grades in math than boys and are just as likely to be enrolled in advanced math courses in high school, females continue to be underrepresented in some Science, Technology, Engineering, and Mathematics (STEM) occupations. This study drew on expectancy-value theory to assess (1) which intellectual and motivational factors in high school predict gender differences in career choices and (2) whether students' motivational beliefs mediated the pathway of gender on STEM career via math achievement by using a national longitudinal sample in the United States. We found that math achievement in 12th grade mediated the association between gender and attainment of a STEM career by the early to mid-thirties. However, math achievement was not the only factor distinguishing gender differences in STEM occupations. Even though math achievement explained career differences between men and women, math task value partially explained the gender differences in STEM career attainment that were attributed to math achievement. The identification of potential factors of women's underrepresentation in STEM will enhance our ability to design intervention programs that are optimally tailored to female needs to impact STEM achievement and occupational choices. PMID- 25741293 TI - The bachelor's to Ph.D. STEM pipeline no longer leaks more women than men: a 30 year analysis. AB - For decades, research and public discourse about gender and science have often assumed that women are more likely than men to "leak" from the science pipeline at multiple points after entering college. We used retrospective longitudinal methods to investigate how accurately this "leaky pipeline" metaphor has described the bachelor's to Ph.D. transition in science, technology, engineering, and mathematics (STEM) fields in the U.S. since the 1970s. Among STEM bachelor's degree earners in the 1970s and 1980s, women were less likely than men to later earn a STEM Ph.D. However, this gender difference closed in the 1990s. Qualitatively similar trends were found across STEM disciplines. The leaky pipeline metaphor therefore partially explains historical gender differences in the U.S., but no longer describes current gender differences in the bachelor's to Ph.D. transition in STEM. The results help constrain theories about women's underrepresentation in STEM. Overall, these results point to the need to understand gender differences at the bachelor's level and below to understand women's representation in STEM at the Ph.D. level and above. Consistent with trends at the bachelor's level, women's representation at the Ph.D. level has been recently declining for the first time in over 40 years. PMID- 25741294 TI - Dreams of the Rarebit Fiend: food and diet as instigators of bizarre and disturbing dreams. AB - In the early 1900s, the Dream of the Rarebit Fiend comic strip conveyed how the spicy cheese dish Welsh rarebit leads to bizarre and disturbing dreams. Today, the perception that foods disturb dreaming persists. But apart from case studies, some exploratory surveys, and a few lab studies on how hunger affects dreaming, there is little empirical evidence addressing this topic. The present study examines three aspects of the food/dreaming relationship; it attempts to: (1) assess the prevalence of the perception of food-dependent dreaming and the types of foods most commonly blamed; (2) determine if perceived food-dependent dreaming is associated with dietary, sleep or motivational factors; and (3) explore whether these factors, independent of food/dreaming perceptions, are associated with reports of vivid and disturbing dreams. Three hundred and ninety six students completed questionnaires evaluating sleep, dreams, and dietary habits and motivations. Items queried whether they had noticed if foods produced bizarre or disturbing dreams and if eating late at night influenced their dreams. The perception of food-dependent dreaming had a prevalence of 17.8%; with dairy products being the most frequently blamed food category (39-44%). Those who perceived food-dependent dreaming differed from others by reporting more frequent and disturbing dreams, poorer sleep, higher coffee intake, and lower Intuitive Eating Scale scores. Reports of disturbing dreams were associated with a pathological constellation of measures that includes poorer sleep, binge-eating, and eating for emotional reasons. Reports of vivid dreams were associated with measures indicative of wellness: better sleep, a healthier diet, and longer times between meals (fasting). Results clarify the relationship between food and dreaming and suggest four explanations for the perception of food-dependent dreaming: (1) food specific effects; (2) food-induced distress; (3) folklore influences, and (4) causal misattributions. Research and clinical implications are discussed. PMID- 25741295 TI - Beethoven recordings reviewed: a systematic method for mapping the content of music performance criticism. AB - Critical reviews offer rich data that can be used to investigate how musical experiences are conceptualized by expert listeners. However, these data also present significant challenges in terms of organization, analysis, and interpretation. This study presents a new systematic method for examining written responses to music, tested on a substantial corpus of music criticism. One hundred critical reviews of Beethoven's piano sonata recordings, published in the Gramophone between August 1934 and July 2010, were selected using in-depth data reduction (qualitative/quantitative approach). The texts were then examined using thematic analysis in order to generate a visual descriptive model of expert critical review. This model reveals how the concept of evaluation permeates critical review. It also distinguishes between two types of descriptors. The first characterizes the performance in terms of specific actions or features of the musical sound (musical parameters, technique, and energy); the second appeals to higher-order properties (artistic style, character and emotion, musical structure, communicativeness) or assumed performer qualities (understanding, intentionality, spontaneity, sensibility, control, and care). The new model provides a methodological guide and conceptual basis for future studies of critical review in any genre. PMID- 25741296 TI - Syntactic mixing across generations in an environment of community-wide bilingualism. AB - A quantitative analysis of a trans-generational, conversational corpus of Chintang (Tibeto-Burman) speakers with community-wide bilingualism in Nepali (Indo-European) reveals that children show more code-switching into Nepali than older speakers. This confirms earlier proposals in the literature that code switching in bilingual children decreases when they gain proficiency in their dominant language, especially in vocabulary. Contradicting expectations from other studies, our corpus data also reveal that for adults, multi-word insertions of Nepali into Chintang are just as likely to undergo full syntactic integration as single-word insertions. Speakers of younger generations show less syntactic integration. We propose that this reflects a change between generations, from strongly asymmetrical, Chintang-dominated bilingualism in older generations to more balanced bilingualism where Chintang and Nepali operate as clearly separate systems in younger generations. This change is likely to have been triggered by the increase of Nepali presence over the past few decades. PMID- 25741297 TI - The coherent and fluent mind: how unified consciousness is constructed from cross modal inputs via integrated processing experiences. PMID- 25741298 TI - Control your mind, make affordance available. AB - Evaluating the affordance-control interpretation of the relationship between performance and object estimation has been proposed by psychophysical and psychonomic studies. This study examined the weight estimation-performance relationship. Individuals with visual impairment or blindness put shots that varied in weight among five scales. In Experiment 1, only the perceived weight was a significant performance constraint. In Experiment 2, the weight was perceived as heavier when the participants' actions were manipulated through cognitive interpretation. The increase in perceived weight appeared to be related to performance and intrinsically scaled to the action, even when the action was only mental rather than physical. The study's findings suggest that bodily experience and action are the basis for physical judgments and likely underlie other basic cognitive interpretations of sensory stimuli. This suggestion goes hand in hand with the biofunctional approaches which assume direct experience of the integrated wholeness of one's body is fundamental for developing other kinds of awareness. Different perspectives from oriental philosophy and psychology are also discussed. PMID- 25741299 TI - The "Facebook-self": characteristics and psychological predictors of false self presentation on Facebook. AB - In this study we present and empirically examine a new phenomenon related to social networking sites, such as Facebook, the "false Facebook-self." Arguably false self-presentation on Facebook is a growing phenomenon, and in extreme cases; i.e., when ones Facebook image substantially deviates from their true image, it may serve as a gateway behavior to more problematic behaviors which may lead to psychological problems and even pathologies. In this study we show that certain users are more vulnerable to such false self-presentation than others. The study involved 258 Facebook users. Applying ANOVA and SEM analyses we show that users with low self-esteem and low trait authenticity are more likely than others to present a Facebook-self which deviates from their true selves. These social-interaction-related traits are influenced by one's upbringing and the anxious and avoidant attachment styles he or she has developed. Several cases (7.5%) with large gaps between the true and false Facebook-self were detected, which implies that future research should consider the adverse consequences and treatments of high levels of false Facebook-self. PMID- 25741300 TI - The measurement of psychological literacy: a first approximation. AB - Psychological literacy, the ability to apply psychological knowledge to personal, family, occupational, community and societal challenges, is promoted as the primary outcome of an undergraduate education in psychology. As the concept of psychological literacy becomes increasingly adopted as the core business of undergraduate psychology training courses world-wide, there is urgent need for the construct to be accurately measured so that student and institutional level progress can be assessed and monitored. Key to the measurement of psychological literacy is determining the underlying factor-structure of psychological literacy. In this paper we provide a first approximation of the measurement of psychological literacy by identifying and evaluating self-report measures for psychological literacy. Multi-item and single-item self-report measures of each of the proposed nine dimensions of psychological literacy were completed by two samples (N = 218 and N = 381) of undergraduate psychology students at an Australian university. Single and multi-item measures of each dimension were weakly to moderately correlated. Exploratory and confirmatory factor analyses of multi-item measures indicated a higher order three factor solution best represented the construct of psychological literacy. The three factors were reflective processes, generic graduate attributes, and psychology as a helping profession. For the measurement of psychological literacy to progress there is a need to further develop self-report measures and to identify/develop and evaluate objective measures of psychological literacy. Further approximations of the measurement of psychological literacy remain an imperative, given the construct's ties to measuring institutional efficacy in teaching psychology to an undergraduate audience. PMID- 25741301 TI - Investigating the motivational behavior of pupils during outdoor science teaching within self-determination theory. AB - This paper presents data from a mixed-method pilot study (n = 84) searching into learning psychological aspects of an outdoor science teaching program. We use data from qualitative explorations into the pupils' learning motivation during field observation, a group interview, and open questionnaires, in order to understand quantitative measures from the Self-Determination Index (SDI), and the Practical Orientation (PO) of the program. Our data suggest that lower self regulated pupils in "normal" science classes show a significantly higher self regulated learning motivational behavior in the outdoor educational setting (p < 10(-4)), and that the outdoor-teaching has generally been perceived as more practical than teaching at the normal school context (p < 10(-4)), irrespective of gender or school culture. We are going to provide in-depth analyses of all quantitative findings with our qualitative data and thus explain the findings logically, with respect to the direction of the statistical interpretation, and substantially, with respect to the meaning of the discoveries. We conclude that outdoor programming appears to be a suitable tool to trigger interest in science in youngsters, especially for less motivated pupils. PMID- 25741302 TI - Lay perspectives on the social and psychological functions of heroes. AB - Declaring and thinking about heroes are common human preoccupations but surprisingly aspects of heroism that reinforce these behaviors are not well understood. In four thematically consistent studies, we attempt to identify lay perspectives about the psychological functions served by heroes. In Study 1, participants (n = 189) freely generated open-ended descriptions of hero functions, which were then sorted by independent coders into 14 categories (e.g., instill hope, guide others). In Study 2, in an attempt to identify the most important functions associated with heroes, participants (n = 249) rated how each function corresponded with their personal views about heroes. Results from a confirmatory factor analysis suggested that a three-factor model of hero functions fit the data well: participants thought that heroes enhanced the lives of others, promoted morals, and protected individuals from threats. In Study 3 (n = 242), participants rated heroes as more likely to fulfill a protecting function than either leaders or role models. In Studies 4A (n = 38) and 4B (n = 102), participants indicated that thinking about a hero (relative to a leader or an acquaintance) during psychological threat fulfilled personal enhancement, moral modeling, and protection needs. In all, these findings provide an empirical basis to spur additional research about the social and psychological functions that heroes offer. PMID- 25741304 TI - The causal cognition of wrong doing: incest, intentionality, and morality. AB - The paper concerns the role of intentionality in reasoning about wrong doing. Anthropologists have claimed that, in certain non-Western societies, people ignore whether an act of wrong doing is committed intentionally or accidentally. To examine this proposition, we look at the case of Madagascar. We start by analyzing how Malagasy people respond to incest, and we find that in this case they do not seem to take intentionality into account: catastrophic consequences follow even if those who commit incest are not aware that they are related as kin; punishment befalls on innocent people; and the whole community is responsible for repairing the damage. However, by looking at how people reason about other types of wrong doing, we show that the role of intentionality is well understood, and that in fact this is so even in the case of incest. We therefore argue that, when people contemplate incest and its consequences, they simultaneously consider two quite different issues: the issue of intentionality and blame, and the much more troubling and dumbfounding issue of what society would be like if incest were to be permitted. This entails such a fundamental attack on kinship and on the very basis of society that issues of intentionality and blame become irrelevant. Using the insights we derive from this Malagasy case study, we re-examine the results of Haidt's psychological experiment on moral dumbfoundedness, which uses a story about incest between siblings as one of its test scenarios. We suggest that the dumbfoundedness that was documented among North American students may be explained by the same kind of complexity that we found in Madagascar. In light of this, we discuss the methodological limitations of experimental protocols, which are unable to grasp multiple levels of response. We also note the limitations of anthropological methods and the benefits of closer cross-disciplinary collaboration. PMID- 25741303 TI - Exploratory multivariate analysis of the effect of fatty fish consumption and medicinal use on heart rate and heart rate variability data. AB - The overall aim of the present study was to explore the relationship between medicinal use and fatty fish consumption on heart rate variability (HRV) and heart rate (HR) in a group of forensic inpatients on a variety of medications. A total of 49 forensic inpatients, randomly assigned to a fish group (n = 27) or a control group (n = 22) were included in the present study. Before and by the end of the food intervention period HR and HRV were measured during an experimental test procedure. An additional aim of this paper is to show how multivariate data analysis can highlight differences and similarities between the groups, thus being a valuable addition to traditional statistical hypothesis testing. The results indicate that fish consumption may have a positive effect on both HR and HRV regardless of medication, but that the influence of medication is strong enough to mask the true effect of fish consumption. Without correcting for medication, the fish group and control group become indistinguishable (p = 0.0794, Cohen's d = 0.60). The effect of medication is demonstrated by establishing a multivariate regression model that estimates HR and HRV in a recovery phase based on HR and HRV data recorded during psychological tests. The model performance is excellent for HR data, but yields poor results for HRV when employed on participants undergoing the more severe medical treatments. This indicates that the HRV behavior of this group is very different from that of the participants on no or lower level of medication. When focusing on the participants on a constant medication regime, a substantial improvement in HRV and HR for the fish group compared to the control group is indicated by a principal component analysis and t-tests (p = 0.00029, Cohen's d = 2.72). In a group of psychiatric inpatients characterized by severe mental health problems consuming different kinds of medication, the fish diet improved HR and HRV, indices of both emotional regulation and physical health. PMID- 25741305 TI - Neuroscience illuminating the influence of auditory or phonological intervention on language-related deficits. AB - Remediation programs for language-related learning deficits are urgently needed to enable equal opportunities in education. To meet this need, different training and intervention programs have been developed. Here we review, from an educational perspective, studies that have explored the neural basis of behavioral changes induced by auditory or phonological training in dyslexia, specific language impairment (SLI), and language-learning impairment (LLI). Training has been shown to induce plastic changes in deficient neural networks. In dyslexia, these include, most consistently, increased or normalized activation of previously hypoactive inferior frontal and occipito-temporal areas. In SLI and LLI, studies have shown the strengthening of previously weak auditory brain responses as a result of training. The combination of behavioral and brain measures of remedial gains has potential to increase the understanding of the causes of language-related deficits, which may help to target remedial interventions more accurately to the core problem. PMID- 25741306 TI - How people explain their own and others' behavior: a theory of lay causal explanations. AB - A theoretical model is proposed that specifies lay causal theories of behavior; and supporting experimental evidence is presented. The model's basic assumption is that different types of behavior trigger different hypotheses concerning the types of causes that may have brought about the behavior. Seven categories are distinguished that are assumed to serve as both behavior types and explanation types: goals, dispositions, temporary states such as emotions, intentional actions, outcomes, events, and stimulus attributes. The model specifies inference rules that lay people use when explaining behavior (actions are caused by goals; goals are caused by higher order goals or temporary states; temporary states are caused by dispositions, stimulus attributes, or events; outcomes are caused by actions, temporary states, dispositions, stimulus attributes, or events; events are caused by dispositions or preceding events). Two experiments are reported. Experiment 1 showed that free-response explanations followed the assumed inference rules. Experiment 2 demonstrated that explanations which match the inference rules are generated faster and more frequently than non-matching explanations. Together, the findings support models that incorporate knowledge based aspects into the process of causal explanation. The results are discussed with respect to their implications for different stages of this process, such as the activation of causal hypotheses and their subsequent selection, as well as with respect to social influences on this process. PMID- 25741307 TI - The advantages of model fitting compared to model simulation in research on preference construction. PMID- 25741308 TI - Monitoring supports performance in a dual-task paradigm involving a risky decision-making task and a working memory task. AB - Performing two cognitively demanding tasks at the same time is known to decrease performance. The current study investigates the underlying executive functions of a dual-tasking situation involving the simultaneous performance of decision making under explicit risk and a working memory task. It is suggested that making a decision and performing a working memory task at the same time should particularly require monitoring-an executive control process supervising behavior and the state of processing on two tasks. To test the role of a supervisory/monitoring function in such a dual-tasking situation we investigated 122 participants with the Game of Dice Task plus 2-back task (GDT plus 2-back task). This dual task requires participants to make decisions under risk and to perform a 2-back working memory task at the same time. Furthermore, a task measuring a set of several executive functions gathered in the term concept formation (Modified Card Sorting Test, MCST) and the newly developed Balanced Switching Task (BST), measuring monitoring in particular, were used. The results demonstrate that concept formation and monitoring are involved in the simultaneous performance of decision making under risk and a working memory task. In particular, the mediation analysis revealed that BST performance partially mediates the influence of MCST performance on the GDT plus 2-back task. These findings suggest that monitoring is one important subfunction for superior performance in a dual-tasking situation including decision making under risk and a working memory task. PMID- 25741309 TI - The effects of formalized and trained non-reciprocal peer teaching on psychosocial, behavioral, pedagogical, and motor learning outcomes in physical education. AB - Peer teaching is recognized as a powerful instructional method; however, there is a paucity of studies that have evaluated the outcomes experienced by peer teachers and their student recipients in the context of trained, non-reciprocal, high school physical education (PE). Accordingly, the effectiveness of a formalized and trained non-reciprocal peer teaching (T-PT) program upon psychosocial, behavioral, pedagogical, and student learning outcomes within high school PE classes was investigated. Students from eight intact classes (106 males, 94 females, Mage = 12.46, SD = 0.59) were randomly assigned to either a T PT intervention group (taught by a volunteer peer-teacher who was trained in line with a tactical games approach) or untrained group (U-PT; where volunteer peer teachers received no formal training, but did receive guidance on the game concepts to teach). Data were collected over 10 lessons in a 5-week soccer unit. Mixed-model ANOVAs/MANOVAs revealed that, in comparison to U-PT, the T-PT program significantly enhanced in-game performance actions and academic learning time among student recipients. Those in the T-PT also provided greater levels of feedback and structured learning time, as well as reporting more positive feelings about peer teaching and fewer perceived barriers to accessing learning outcomes. These findings show that non-reciprocal peer-teachers who receive formalized support through training and tactical games approach-based teaching resources can enhance behavioral, pedagogical, and motor performance outcomes in PE. PMID- 25741310 TI - Future-minded: the role of prospection in Agency, Control, and other goal directed processes. PMID- 25741311 TI - The effects of family support and gender on mature student engagement in higher education. PMID- 25741312 TI - Toward a general theoretical framework for judgment and decision-making. PMID- 25741313 TI - Lessons from the first two years of operating a study registry. PMID- 25741314 TI - To have and to hold: looking vs. touching in the study of categorization. PMID- 25741315 TI - Systemic, local, and imaging biomarkers of brain injury: more needed, and better use of those already established? AB - Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge. PMID- 25741316 TI - Maladaptive neural synchrony in tinnitus: origin and restoration. AB - Tinnitus is the conscious perception of sound heard in the absence of physical sound sources external or internal to the body, reflected in aberrant neural synchrony of spontaneous or resting-state brain activity. Neural synchrony is generated by the nearly simultaneous firing of individual neurons, of the synchronization of membrane-potential changes in local neural groups as reflected in the local field potentials, resulting in the presence of oscillatory brain waves in the EEG. Noise-induced hearing loss, often resulting in tinnitus, causes a reorganization of the tonotopic map in auditory cortex and increased spontaneous firing rates and neural synchrony. Spontaneous brain rhythms rely on neural synchrony. Abnormal neural synchrony in tinnitus appears to be confined to specific frequency bands of brain rhythms. Increases in delta-band activity are generated by deafferented/deprived neuronal networks resulting from hearing loss. Coordinated reset (CR) stimulation was developed in order to specifically counteract such abnormal neuronal synchrony by desynchronization. The goal of acoustic CR neuromodulation is to desynchronize tinnitus-related abnormal delta band oscillations. CR neuromodulation does not require permanent stimulus delivery in order to achieve long-lasting desynchronization or even a full-blown anti-kindling but may have cumulative effects, i.e., the effect of different CR epochs separated by pauses may accumulate. Unlike other approaches, acoustic CR neuromodulation does not intend to reduce tinnitus-related neuronal activity by employing lateral inhibition. The potential efficacy of acoustic CR modulation was shown in a clinical proof of concept trial, where effects achieved in 12 weeks of treatment delivered 4-6 h/day persisted through a preplanned 4-week therapy pause and showed sustained long-term effects after 10 months of therapy, leading to 75% responders. PMID- 25741317 TI - Drug resistance in cortical and hippocampal slices from resected tissue of epilepsy patients: no significant impact of p-glycoprotein and multidrug resistance-associated proteins. AB - Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue. PMID- 25741318 TI - Autophagy in thyroid cancer: present knowledge and future perspectives. AB - Thyroid cancer is the most common endocrine malignancy. Despite having a good prognosis in the majority of cases, when the tumor is dedifferentiated it does no longer respond to conventional treatment with radioactive iodine, the prognosis worsens significantly. Treatment options for advanced, dedifferentiated disease are limited and do not cure the disease. Autophagy, a process of self-digestion in which damaged molecules or organelles are degraded and recycled, has emerged as an important player in the pathogenesis of different diseases, including cancer. The role of autophagy in thyroid cancer pathogenesis is not yet elucidated. However, the available data indicate that autophagy is involved in several steps of thyroid tumor initiation and progression as well as in therapy resistance and therefore could be exploited for therapeutic applications. The present review summarizes the most recent data on the role of autophagy in the pathogenesis of thyroid cancer and we will provide a perspective on how this process can be targeted for potential therapeutic approaches and could be further explored in the context of multimodality treatment in cancer and personalized medicine. PMID- 25741319 TI - Pediatric adrenocortical tumors: what they can tell us on adrenal development and comparison with adult adrenal tumors. AB - Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal. PMID- 25741321 TI - Chemicals to enhance microalgal growth and accumulation of high-value bioproducts. AB - Photosynthetic microalgae have attracted significant attention as they can serve as important sources for cosmetic, food and pharmaceutical products, industrial materials and even biofuel biodiesels. However, current productivity of microalga based processes is still very low, which has restricted their scale-up application. In addition to various efforts in strain improvement and cultivation optimization, it was proposed that the productivity of microalga-based processes can also be increased using various chemicals to trigger or enhance cell growth and accumulation of bioproducts. Herein, we summarized recent progresses in applying chemical triggers or enhancers to improve cell growth and accumulation of bioproducts in algal cultures. Based on their enhancing mechanisms, these chemicals can be classified into four categories:chemicals regulating biosynthetic pathways, chemicals inducing oxidative stress responses, phytohormones and analogs regulating multiple aspects of microalgal metabolism, and chemicals directly as metabolic precursors. Taken together, the early researches demonstrated that the use of chemical stimulants could be a very effective and economical way to improve cell growth and accumulation of high value bioproducts in large-scale cultivation of microalgae. PMID- 25741320 TI - Malaria and the liver: immunological hide-and-seek or subversion of immunity from within? AB - During the pre-erythrocytic asymptomatic phase of malarial infection, sporozoites develop transiently inside less than 100 hepatocytes that subsequently release thousands of merozoites. Killing of these hepatocytes by cytotoxic T cells (CTLs) confers protection to subsequent malarial infection, suggesting that this bottleneck phase in the parasite life cycle can be targeted by vaccination. During natural transmission, although some CTLs are generated in the skin draining lymph nodes, they are unable to eliminate the parasite, suggesting that the liver is important for the sporozoite to escape immune surveillance. The contribution of the organ to this process is unclear. Based on the known ability of several hepatic antigen-presenting cells (APCs) to induce primary activation of CD8 T cells and tolerance, malarial antigens presented by both infected hepatocytes and/or hepatic cross-presenting APCs should result in tolerance. However, our latest model predicts that due to the low frequency of infected hepatocytes, some T cells recognizing sporozoite epitopes with high affinity should differentiate into CTLs. In this review, we discuss two possible models to explain why CTLs generated in the liver and skin draining lymph nodes are unable to eliminate the parasite: (1) sporozoites harness the tolerogenic property of the liver; (2) CTLs are not tolerized but fail to detect infected cells due to sparse infection of hepatocytes and the very short liver stage. We propose that while malaria sporozoites might use the ability of the liver to tolerize both naive and effector cells, they have also developed strategies to decrease the probability of encounter between CTLs and infected liver cells. Thus, we predict that to achieve protection, vaccination strategies should aim to boost intrahepatic activation and/or increase the chance of encounter between sporozoite-specific CTLs and infected hepatocytes. PMID- 25741322 TI - Role of integrons, plasmids and SXT elements in multidrug resistance of Vibrio cholerae and Providencia vermicola obtained from a clinical isolate of diarrhea. AB - The isolates of Vibrio cholerae and Providencia vermicola obtained from a diarrheal patient were investigated for genetic elements governing their drug resistance phenotypes. Out of 14 antibiotics tested, V. cholerae Vc IDH02365 isolate showed resistance to nine antibiotics, while P. vermicola Pv NBA2365 was found to be resistant to all the antibiotics except polymyxin B. Though SXT integrase was depicted in both the bacteria, class 1 integron was found to be associated only with Pv NBA2365. Integrons in Pv NBA2365 conferred resistance to beta-lactams, aminoglycosides, and trimethoprim. Pv NBA2365 carried two transformable plasmids imparting distinct antibiotic resistance traits to their Escherichia coli transformants. In rabbit ileal loop assays, Pv NBA2365 did not show any fluid accumulation (FA) in contrast with Vc IDH02365 that showed high FA. To the best of our knowledge, this is the first report of a highly drug resistant P. vermicola and additionally co-existence of multidrug resistant V. cholerae and P. vermicola. Both the microbes appeared to possess a wide array of mobile genetic elements for a large spectrum of antimicrobial agents, some of which are being used in the treatment of acute diarrhea. PMID- 25741324 TI - Escherichia coli O157:H7 bacteriophage Phi241 isolated from an industrial cucumber fermentation at high acidity and salinity. AB - A novel phage, Phi241, specific for Escherichia coli O157:H7 was isolated from an industrial cucumber fermentation where both acidity (pH <= 3.7) and salinity (>=5% NaCl) were high. The phage belongs to the Myoviridae family. Its latent period was 15 min and average burst size was 53 phage particles per infected cell. The phage was able to lyse 48 E. coli O157:H7 strains, but none of the 18 non-O157 strains (including E. coli O104:H7) or the 2 O antigen-negative mutants of O157:H7 strain, 43895Deltaper (also lacking H7 antigen) and F12 (still expressing H7 antigen). However, the phage was able to lyse a per-complemented strain (43895DeltaperComp) which expresses O157 antigen. These results indicated that phage Phi241 is specific for O157 antigen, and E. coli strains lacking O157 antigen were resistant to the phage infection, regardless of the presence or absence of H7 antigen. SDS-PAGE profile revealed at least 13 structural proteins of the phage. The phage DNA was resistant to many commonly used restriction endonucleases, suggesting the presence of modified nucleotides in the phage genome. At the multiplicity of infection of 10, 3, or 0.3, the phage caused a rapid cell lysis within 1 or 2 h, resulting in 3.5- or 4.5-log-unit reduction in cell concentration. The high lytic activity, specificity and tolerance to low pH and high salinity make phage Phi241 a potentially ideal biocontrol agent of E. coli O157:H7 in various foods. To our knowledge, this is the first report on E. coli O157:H7 phage isolated from high acidity and salinity environment. PMID- 25741326 TI - Algal extracellular release in river-floodplain dissolved organic matter: response of extracellular enzymatic activity during a post-flood period. AB - River-floodplain systems are susceptible to rapid hydrological events. Changing hydrological connectivity of the floodplain generates a broad range of conditions, from lentic to lotic. This creates a mixture of allochthonously and autochthonously derived dissolved organic matter (DOM). Autochthonous DOM, including photosynthetic extracellular release (PER), is an important source supporting bacterial secondary production (BSP). Nonetheless, no details are available regarding microbial extracellular enzymatic activity (EEA) as a response to PER under variable hydrological settings in river-floodplain systems. To investigate the relationship between bacterial and phytoplankton components, we therefore used EEA as a tool to track the microbial response to non chromophoric, but reactive and ecologically important DOM. The study was conducted in three floodplain subsystems with distinct hydrological regimes (Danube Floodplain National Park, Austria). The focus was on the post-flood period. Enhanced %PER (up to 48% of primary production) in a hydrologically isolated subsystem was strongly correlated with beta-glucosidase, which was related to BSP. This shows that-in disconnected floodplain backwaters with high terrestrial input-BSP can also be driven by autochthonous carbon sources (PER). In a semi-isolated section, in the presence of fresh labile material from primary producers, enhanced activity of phenol oxidase was observed. In frequently flooded river-floodplain systems, BSP was mainly driven by enzymatic degradation of particulate primary production. Our research demonstrates that EEA measurements are an excellent tool to describe the coupling between bacteria and phytoplankton, which cannot be deciphered when focusing solely on chromophoric DOM. PMID- 25741325 TI - The importance of mass spectrometric dereplication in fungal secondary metabolite analysis. AB - Having entered the Genomic Era, it is now evident that the biosynthetic potential of filamentous fungi is much larger than was thought even a decade ago. Fungi harbor many cryptic gene clusters encoding for the biosynthesis of polyketides, non-ribosomal peptides, and terpenoids - which can all undergo extensive modifications by tailoring enzymes - thus potentially providing a large array of products from a single pathway. Elucidating the full chemical profile of a fungal species is a challenging exercise, even with elemental composition provided by high-resolution mass spectrometry (HRMS) used in combination with chemical databases (e.g., AntiBase) to dereplicate known compounds. This has led to a continuous effort to improve chromatographic separation in conjunction with improvement in HRMS detection. Major improvements have also occurred with 2D chromatography, ion-mobility, MS/MS and MS(3), stable isotope labeling feeding experiments, classic UV/Vis, and especially automated data-mining and metabolomics software approaches as the sheer amount of data generated is now the major challenge. This review will focus on the development and implementation of dereplication strategies and will highlight the importance of each stage of the process from sample preparation to chromatographic separation and finally toward both manual and more targeted methods for automated dereplication of fungal natural products using state-of-the art MS instrumentation. PMID- 25741323 TI - Discovering probiotic microorganisms: in vitro, in vivo, genetic and omics approaches. AB - Over the past decades the food industry has been revolutionized toward the production of functional foods due to an increasing awareness of the consumers on the positive role of food in wellbeing and health. By definition probiotic foods must contain live microorganisms in adequate amounts so as to be beneficial for the consumer's health. There are numerous probiotic foods marketed today and many probiotic strains are commercially available. However, the question that arises is how to determine the real probiotic potential of microorganisms. This is becoming increasingly important, as even a superficial search of the relevant literature reveals that the number of proclaimed probiotics is growing fast. While the vast majority of probiotic microorganisms are food-related or commensal bacteria that are often regarded as safe, probiotics from other sources are increasingly being reported raising possible regulatory and safety issues. Potential probiotics are selected after in vitro or in vivo assays by evaluating simple traits such as resistance to the acidic conditions of the stomach or bile resistance, or by assessing their impact on complicated host functions such as immune development, metabolic function or gut-brain interaction. While final human clinical trials are considered mandatory for communicating health benefits, rather few strains with positive studies have been able to convince legal authorities with these health claims. Consequently, concern has been raised about the validity of the workflows currently used to characterize probiotics. In this review we will present an overview of the most common assays employed in screening for probiotics, highlighting the potential strengths and limitations of these approaches. Furthermore, we will focus on how the advent of omics technologies has reshaped our understanding of the biology of probiotics, allowing the exploration of novel routes for screening and studying such microorganisms. PMID- 25741327 TI - A metagenomic approach to characterize temperate bacteriophage populations from Cystic Fibrosis and non-Cystic Fibrosis bronchiectasis patients. AB - Pseudomonas aeruginosa (Pa), normally a soil commensal, is an important opportunistic pathogen in Cystic Fibrosis (CF) and non-Cystic Fibrosis Bronchiectasis (nCFBR). Persistent infection correlates with accelerated decline in lung function and early mortality. The horizontal transfer of DNA by temperate bacteriophages can add gene function and selective advantages to their bacterial host within the constrained environment of the lower lung. In this study, we chemically induce temperate bacteriophages from clonal cultures of Pa and identify their mixed viral communities employing metagenomic approaches. We compared 92 temperate phage metagenomes stratified from these clinical backgrounds (47 CF and 45 nCFBR Pa isolates) using MG-RAST and GeneWise2. KEGG analysis shows the complexity of temperate phage accessory gene carriage increases with duration and severity of the disease. Furthermore, we identify the presence of Ig-like motifs within phage structural genes linked to bacterial adhesion and carbohydrate binding including Big_2, He_Pig, and Fn3. This study provides the first clinical support to the proposed bacteriophage adherence to mucus (BAM) model and the evolution of phages interacting at these mucosal surfaces over time. PMID- 25741328 TI - Growth and location of bacterial colonies within dairy foods using microscopy techniques: a review. AB - The growth, location, and distribution of bacterial colonies in dairy products are important factors for the ripening and flavor development of cheeses, yogurts, and soured creams. Starter, non-starter, spoilage, and pathogenic bacteria all become entrapped in the developing casein matrix of dairy foods. In order to visualize these bacterial colonies and the environments surrounding them, microscopy techniques are used. The use of various microscopy methods allow for the rapid detection, enumeration, and distribution of starter, non-starter and pathogenic bacteria in dairy foods. Confocal laser scanning microscopy is extensively utilized to identify bacteria location via the use of fluorescent dyes. Further study is needed in relation to the development of micro- gradients and localized ripening parameters in dairy products due to the location of bacteria at the protein-fat interface. Development in the area of bacterial discrimination using microscopy techniques and fluorescent dyes/tags is needed as the benefits of rapidly identifying spoilage/pathogenic bacteria early in product manufacture would be of huge benefit in relation to both safety and financial concerns. PMID- 25741329 TI - Characterization of the E. coli proteome and its modifications during growth and ethanol stress. AB - We set out to provide a resource to the microbiology community especially with respect to systems biology based endeavors. To this end, we generated a comprehensive dataset monitoring the changes in protein expression, copy number, and post translational modifications in a systematic fashion during growth and ethanol stress in E. coli. We utilized high-resolution mass spectrometry (MS) combined with the Super-SILAC approach. In a single experiment, we have identified over 2300 proteins, which represent approximately 88% of the estimated expressed proteome of E. coli and estimated protein copy numbers using the Intensity Based Absolute Quantitation (iBAQ). The dynamic range of protein expression spanned up to six orders of magnitude, with the highest protein copy per cell estimated at approximately 300,000. We focused on the proteome dynamics involved during stationary phase growth. A global up-regulation of proteins related to stress response was detected in later stages of growth. We observed the down-regulation of the methyl directed mismatch repair system containing MutS and MutL of E. coli growing in long term growth cultures, confirming that higher incidence of mutations presents an important mechanism in the increase in genetic diversity and stationary phase survival in E. coli. During ethanol stress, known markers such as alcohol dehydrogenase and aldehyde dehydrogenase were induced, further validating the dataset. Finally, we performed unbiased protein modification detection and revealed changes of many known and unknown protein modifications in both experimental conditions. Data are available via ProteomeXchange with identifier PXD001648. PMID- 25741330 TI - Nitrogen addition, not initial phylogenetic diversity, increases litter decomposition by fungal communities. AB - Fungi play a critical role in the degradation of organic matter. Because different combinations of fungi result in different rates of decomposition, determining how climate change will affect microbial composition and function is fundamental to predicting future environments. Fungal response to global change is patterned by genetic relatedness, resulting in communities with comparatively low phylogenetic diversity (PD). This may have important implications for the functional capacity of disturbed communities if lineages sensitive to disturbance also contain unique traits important for litter decomposition. Here we tested the relationship between PD and decomposition rates. Leaf litter fungi were isolated from the field and deployed in microcosms as mock communities along a gradient of initial PD, while species richness was held constant. Replicate communities were subject to nitrogen fertilization comparable to anthropogenic deposition levels. Carbon mineralization rates were measured over the course of 66 days. We found that nitrogen fertilization increased cumulative respiration by 24.8%, and that differences in respiration between fertilized and ambient communities diminished over the course of the experiment. Initial PD failed to predict respiration rates or their change in response to nitrogen fertilization, and there was no correlation between community similarity and respiration rates. Last, we detected no phylogenetic signal in the contributions of individual isolates to respiration rates. Our results suggest that the degree to which PD predicts ecosystem function will depend on environmental context. PMID- 25741332 TI - Syntrophic growth via quinone-mediated interspecies electron transfer. AB - The mechanisms by which microbial species exchange electrons are of interest because interspecies electron transfer can expand the metabolic capabilities of microbial communities. Previous studies with the humic substance analog anthraquinone-2,6-disulfonate (AQDS) suggested that quinone-mediated interspecies electron transfer (QUIET) is feasible, but it was not determined if sufficient energy is available from QUIET to support the growth of both species. Furthermore, there have been no previous studies on the mechanisms for the oxidation of anthrahydroquinone-2,6-disulfonate (AHQDS). A co-culture of Geobacter metallireducens and G. sulfurreducens metabolized ethanol with the reduction of fumarate much faster in the presence of AQDS, and there was an increase in cell protein. G. sulfurreducens was more abundant, consistent with G. sulfurreducens obtaining electrons from acetate that G. metallireducens produced from ethanol, as well as from AHQDS. Co-cultures initiated with a citrate synthase-deficient strain of G. sulfurreducens that was unable to use acetate as an electron donor also metabolized ethanol with the reduction of fumarate and cell growth, but acetate accumulated over time. G. sulfurreducens and G. metallireducens were equally abundant in these co-cultures reflecting the inability of the citrate synthase-deficient strain of G. sulfurreducens to metabolize acetate. Evaluation of the mechanisms by which G. sulfurreducens accepts electrons from AHQDS demonstrated that a strain deficient in outer surface c-type cytochromes that are required for AQDS reduction was as effective at QUIET as the wild-type strain. Deletion of additional genes previously implicated in extracellular electron transfer also had no impact on QUIET. These results demonstrate that QUIET can yield sufficient energy to support the growth of both syntrophic partners, but that the mechanisms by which electrons are derived from extracellular hydroquinones require further investigation. PMID- 25741331 TI - Enriching distinctive microbial communities from marine sediments via an electrochemical-sulfide-oxidizing process on carbon electrodes. AB - Sulfide is a common product of marine anaerobic respiration, and a potent reactant biologically and geochemically. Here we demonstrate the impact on microbial communities with the removal of sulfide via electrochemical methods. The use of differential pulse voltammetry revealed that the oxidation of soluble sulfide was seen at +30 mV (vs. SHE) at all pH ranges tested (from pH = 4 to 8), while non-ionized sulfide, which dominated at pH = 4 was poorly oxidized via this process. Two mixed cultures (CAT and LA) were enriched from two different marine sediments (from Catalina Island, CAT; from the Port of Los Angeles, LA) in serum bottles using a seawater medium supplemented with lactate, sulfate, and yeast extract, to obtain abundant biomass. Both CAT and LA cultures were inoculated in electrochemical cells (using yeast-extract-free seawater medium as an electrolyte) equipped with carbon-felt electrodes. In both cases, when potentials of +630 or +130 mV (vs. SHE) were applied, currents were consistently higher at +630 then at +130 mV, indicating more sulfide being oxidized at the higher potential. In addition, higher organic-acid and sulfate conversion rates were found at +630 mV with CAT, while no significant differences were found with LA at different potentials. The results of microbial-community analyses revealed a decrease in diversity for both CAT and LA after electrochemical incubation. In addition, some bacteria (e.g., Clostridium and Arcobacter) not well-known to be capable of extracellular electron transfer, were found to be dominant in the electrochemical cells. Thus, even though the different mixed cultures have different tolerances for sulfide, electrochemical-sulfide removal can lead to major population changes. PMID- 25741333 TI - Non-selective regulation of peroxide and superoxide resistance genes by PerR in Campylobacter jejuni. AB - Campylobacter jejuni is an important foodborne pathogen. The molecular mechanisms for the regulation of oxidative stress resistance have not yet been understood fully in this bacterium. In this study, we investigated how PerR (peroxide stress regulator) modulates the transcriptional regulation of both peroxide and superoxide resistance genes in C. jejuni, particularly under oxidative stress conditions. The transcriptional levels of ahpC, katA, and sodB were substantially increased by aeration and oxidant exposure. Interestingly, a perR mutation completely abrogated the transcriptional response of ahpC, katA and sodB to oxidants. Furthermore, we demonstrated that perR transcription was reduced by aeration and oxidant exposure. In contrast to the unique role of PerR homologs in peroxide stress regulation in other bacteria, C. jejuni PerR directly regulates the transcription of sodB, the most important gene in superoxide defense, as evidenced by the alteration of sodB transcription by the perR mutation and direct binding of rPerR to the sodB promoter. In addition, we also observed notable morphological changes in C. jejuni from spiral rods to cocoid morphology under aerobic conditions. Based on the intracellular ATP levels, C. jejuni entered a viable-but-non-culturable (VBNC) state under aerobic conditions. These findings clearly demonstrate that C. jejuni possesses a unique regulatory mechanism of oxidative stress defense that does not specifically distinguish between peroxide and superoxide defense, and PerR plays a pivotal role in this non-selective regulation of oxidative stress resistance in C. jejuni. PMID- 25741334 TI - Fungal natural products-the mushroom perspective. PMID- 25741335 TI - Evaluating variation in human gut microbiota profiles due to DNA extraction method and inter-subject differences. AB - The human gut contains dense and diverse microbial communities which have profound influences on human health. Gaining meaningful insights into these communities requires provision of high quality microbial nucleic acids from human fecal samples, as well as an understanding of the sources of variation and their impacts on the experimental model. We present here a systematic analysis of commonly used microbial DNA extraction methods, and identify significant sources of variation. Five extraction methods (Human Microbiome Project protocol, MoBio PowerSoil DNA Isolation Kit, QIAamp DNA Stool Mini Kit, ZR Fecal DNA MiniPrep, phenol:chloroform-based DNA isolation) were evaluated based on the following criteria: DNA yield, quality and integrity, and microbial community structure based on Illumina amplicon sequencing of the V4 region of bacterial and archaeal 16S rRNA genes. Our results indicate that the largest portion of variation within the model was attributed to differences between subjects (biological variation), with a smaller proportion of variation associated with DNA extraction method (technical variation) and intra-subject variation. A comprehensive understanding of the potential impact of technical variation on the human gut microbiota will help limit preventable bias, enabling more accurate diversity estimates. PMID- 25741336 TI - Community-onset Klebsiella pneumoniae pneumonia in Taiwan: clinical features of the disease and associated microbiological characteristics of isolates from pneumonia and nasopharynx. AB - Klebsiella pneumoniae is an important cause of community-onset pneumonia in Asian countries and South Africa. We investigated the clinical characteristics of K. pneumoniae causing community-onset pneumonia, and the associated microbiological features between K. pneumoniae isolates from pneumonia and those from the nasopharynx in Taiwan. This study was conducted at the Taipei Veterans General Hospital during July, 2012 to February, 2014. The clinical characteristics in patients with community-onset K. pneumoniae pneumonia were analyzed. K. pneumoniae isolates from the nasopharynx of adults attending otorhinolaryngology outpatient clinics were collected to compare their microbiological features with those from pneumonia. Capsular genotypes, antimicrobial susceptibility, and multilocus sequence type (MLST) were determined among these strains. Ninety-one patients with community-onset K. pneumoniae pneumonia were enrolled. We found a high mortality (29.7%) among these patients. Capsular types K1, K2, K5, K20, K54, and K57 accounted for ~70% of the K. pneumoniae isolates causing pneumonia, and ~70% of all the K. pneumoniae strains isolated from the nasopharynx of patients in outpatient clinics. The MLST profiles further demonstrated the genetic relatedness between most pneumonia isolates and those from the nasopharynx. In conclusion, our results show that community-onset pneumonia caused by K. pneumoniae was associated with high mortality and could have a reservoir in the nasopharynx. To tackle this high-mortality disease, the distribution of capsular types in the nasopharynx might have implications for future vaccine development. PMID- 25741337 TI - Down Regulation of the TCR Complex CD3zeta-Chain on CD3+ T Cells: A Potential Mechanism for Helminth-Mediated Immune Modulation. AB - The CD3zeta forms part of the T cell receptor (TCR) where it plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways leading to T cell effector functions. Down regulation of CD3zeta leads to impairment of immune responses including reduced cell proliferation and cytokine production. In experimental models, helminth parasites have been shown to modulate immune responses directed against them and unrelated antigens, so called bystander antigens, but there is a lack of studies validating these observations in humans. This study investigated the relationship between expression levels of the TCR CD3zeta chain with lymphocyte cell proliferation during human infection with the helminth parasite, Schistosoma haematobium, which causes uro-genital schistosomiasis. Using flow cytometry, peripheral blood mononuclear cells (PBMCs) from individuals naturally exposed to S. haematobium in rural Zimbabwe were phenotyped, and expression levels of CD3zeta on T cells were related to intensity of infection. In this population, parasite infection intensity was inversely related to CD3zeta expression levels (p < 0.05), consistent with downregulation of CD3zeta expression during helminth infection. Furthermore, PBMC proliferation was positively related to expression levels of CD3zeta (p < 0.05) after allowing for confounding variables (host age, sex, and infection level). CD3zeta expression levels had a differing relationship between immune correlates of susceptibility and immunity, measured by antibody responses, indicating a complex relationship between immune activation status and immunity. The relationships between the CD3zeta chain of the TCR and schistosome infection, PBMC proliferation and schistosome-specific antibody responses have not previously been reported, and these results may indicate a mechanism for the impaired T cell proliferative responses observed during human schistosome infection. PMID- 25741339 TI - Is there a role for probiotics in the prevention of preterm birth? AB - Preterm birth (PTB) continues to be a global health challenge. An over-production of inflammatory cytokines and chemokines, as well as an altered maternal vaginal microbiome has been implicated in the pathogenesis of inflammation/infection associated PTB. Lactobacillus represents the dominant species in the vagina of most healthy pregnant women. The depletion of Lactobacillus in women with bacterial vaginosis (BV) has been associated with an increased risk of PTB. It remains unknown at what point an aberrant vaginal microbiome composition specifically induces the cascade leading to PTB. The ability of oral or vaginal lactobacilli probiotics to reduce BV occurrence and/or dampen inflammation is being considered as a means to prevent PTB. Certain anti-inflammatory properties of lactobacilli suggest potential mechanisms. To date, clinical studies have not been powered with sufficiently high rates of PTB, but overall, there is merit in examining this promising area of clinical science. PMID- 25741340 TI - Tumor Immunology, toward a Success Story? PMID- 25741341 TI - Interactions between CD44 and Hyaluronan in Leukocyte Trafficking. AB - Recruitment of leukocytes from the bloodstream to inflamed tissues requires a carefully regulated cascade of binding interactions between adhesion molecules on leukocytes and endothelial cells. Adhesive interactions between CD44 and hyaluronan (HA) have been implicated in the regulation of immune cell trafficking within various tissues. In this review, the biology of CD44-HA interactions in cell trafficking is summarized, with special attention to neutrophil recruitment within the liver microcirculation. We describe the molecular mechanisms that regulate adhesion between neutrophil CD44 and endothelial HA, including recent evidence implicating serum-derived hyaluronan-associated protein as an important co-factor in the binding of HA to CD44 under flow conditions. CD44-HA-mediated neutrophil recruitment has been shown to contribute to innate immune responses to invading microbes, as well as to the pathogenesis of many inflammatory diseases, including various liver pathologies. As a result, blockade of neutrophil recruitment by targeting CD44-HA interactions has proven beneficial as an anti inflammatory treatment strategy in a number of animal models of inflammatory diseases. PMID- 25741338 TI - The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome. AB - Regulatory T cells (Tregs) are suppressive T cells that have an essential role in maintaining the balance between immune activation and tolerance. Their development, either in the thymus, periphery, or experimentally in vitro, and stability and function all depend on the right mix of environmental stimuli. This review focuses on the effects of cytokines, metabolites, and the microbiome on both human and mouse Treg biology. The role of cytokines secreted by innate and adaptive immune cells in directing Treg development and shaping their function is well established. New and emerging data suggest that metabolites, such as retinoic acid, and microbial products, such as short-chain fatty acids, also have a critical role in guiding the functional specialization of Tregs. Overall, the complex interaction between distinct environmental stimuli results in unique, and in some cases tissue-specific, tolerogenic environments. Understanding the conditions that favor Treg induction, accumulation, and function is critical to defining the pathophysiology of many immune-mediated diseases and to developing new therapeutic interventions. PMID- 25741343 TI - Advances in bovine immunology - new tools and new insights to tackle old foes. PMID- 25741342 TI - T-bet Expression by Foxp3(+) T Regulatory Cells is Not Essential for Their Suppressive Function in CNS Autoimmune Disease or Colitis. AB - Accumulation of T regulatory (Treg) cells within the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) is essential for the resolution of disease. CNS Treg cells have been shown to uniformly express the Th1-associated molecules, T-bet and CXCR3. Here, we report that the expression of T-bet is not required for the function of these Treg within the CNS. Using mice that lacked T-bet expression specifically within the Treg compartment, we demonstrate that there was no deficit in Treg recruitment into the CNS during EAE and no difference in the resolution of disease compared to control mice. T-bet deficiency did not impact on the in vitro suppressive capacity of Treg. Transfer of T-bet-deficient Treg was able to suppress clinical signs of either EAE or colitis. These observations demonstrate that, although Treg can acquire characteristics associated with pathogenic T effector cells, this process is not necessarily required for their suppressive capacity and the resolution of autoimmune inflammation. PMID- 25741344 TI - Exosomes: tiny clues for mast cell communication. PMID- 25741345 TI - Protective immune responses to dengue virus infection and vaccines: perspectives from the field to the bench. PMID- 25741346 TI - Summarizing and exploring data of a decade of cytokinin-related transcriptomics. AB - The genome-wide transcriptional response of the model organism Arabidopsis thaliana to cytokinin has been investigated by different research groups as soon as large-scale transcriptomic techniques became affordable. Over the last 10 years many transcriptomic datasets related to cytokinin have been generated using different technological platforms, some of which are published only in databases, culminating in an RNA sequencing experiment. Two approaches have been made to establish a core set of cytokinin-regulated transcripts by meta-analysis of these datasets using different preferences regarding their selection. Here we add another meta-analysis derived from an independent microarray platform (CATMA), combine all the meta-analyses available with RNAseq data in order to establish an advanced core set of cytokinin-regulated transcripts, and compare the results with the regulation of orthologous rice genes by cytokinin. We discuss the functions of some of the less known cytokinin-regulated genes indicating areas deserving further research to explore cytokinin function. Finally, we investigate the promoters of the core set of cytokinin-induced genes for the abundance and distribution of known cytokinin-responsive cis elements and identify a set of novel candidate motifs. PMID- 25741347 TI - Agricultural practices altered soybean seed protein, oil, fatty acids, sugars, and minerals in the Midsouth USA. AB - Information on the effects of management practices on soybean seed composition is scarce. Therefore, the objective of this research was to investigate the effects of planting date (PD) and seeding rate (SR) on seed composition (protein, oil, fatty acids, and sugars) and seed minerals (B, P, and Fe) in soybean grown in two row-types (RTs) on the Mississippi Delta region of the Midsouth USA. Two field experiments were conducted in 2009 and 2010 on Sharkey clay and Beulah fine sandy loam soil at Stoneville, MS, USA, under irrigated conditions. Soybean were grown in 102 cm single-rows and 25 cm twin-rows in 102 cm centers at SRs of 20, 30, 40, and 50 seeds m(-2). The results showed that in May and June planting, protein, glucose, P, and B concentrations increased with increased SR, but at the highest SRs (40 and 50 seeds m(-2)), the concentrations remained constant or declined. Palmitic, stearic, and linoleic acid concentrations were the least responsive to SR increases. Early planting resulted in higher oil, oleic acid, sucrose, B, and P on both single and twin-rows. Late planting resulted in higher protein and linolenic acid, but lower oleic acid and oil concentrations. The changes in seed constituents could be due to changes in environmental factors (drought and temperature), and nutrient accumulation in seeds and leaves. The increase of stachyose sugar in 2010 may be due to a drier year and high temperature in 2010 compared to 2009; suggesting the possible role of stachyose as an environmental stress compound. Our research demonstrated that PD, SR, and RT altered some seed constituents, but the level of alteration in each year dependent on environmental factors such as drought and temperature. This information benefits growers and breeders for considering agronomic practices to select for soybean seed nutritional qualities under drought and high heat conditions. PMID- 25741348 TI - Integration of metabolomics data into metabolic networks. AB - Metabolite levels together with their corresponding metabolic fluxes are integrative outcomes of biochemical transformations and regulatory processes and they can be used to characterize the response of biological systems to genetic and/or environmental changes. However, while changes in transcript or to some extent protein levels can usually be traced back to one or several responsible genes, changes in fluxes and particularly changes in metabolite levels do not follow such rationale and are often the outcome of complex interactions of several components. The increasing quality and coverage of metabolomics technologies have fostered the development of computational approaches for integrating metabolic read-outs with large-scale models to predict the physiological state of a system. Constraint-based approaches, relying on the stoichiometry of the considered reactions, provide a modeling framework amenable to analyses of large-scale systems and to the integration of high-throughput data. Here we review the existing approaches that integrate metabolomics data in variants of constrained-based approaches to refine model reconstructions, to constrain flux predictions in metabolic models, and to relate network structural properties to metabolite levels. Finally, we discuss the challenges and perspectives in the developments of constraint-based modeling approaches driven by metabolomics data. PMID- 25741349 TI - Genomics-assisted breeding for boosting crop improvement in pigeonpea (Cajanus cajan). AB - Pigeonpea is an important pulse crop grown predominantly in the tropical and sub tropical regions of the world. Although pigeonpea growing area has considerably increased, yield has remained stagnant for the last six decades mainly due to the exposure of the crop to various biotic and abiotic constraints. In addition, low level of genetic variability and limited genomic resources have been serious impediments to pigeonpea crop improvement through modern breeding approaches. In recent years, however, due to the availability of next generation sequencing and high-throughput genotyping technologies, the scenario has changed tremendously. The reduced sequencing costs resulting in the decoding of the pigeonpea genome has led to the development of various genomic resources including molecular markers, transcript sequences and comprehensive genetic maps. Mapping of some important traits including resistance to Fusarium wilt and sterility mosaic disease, fertility restoration, determinacy with other agronomically important traits have paved the way for applying genomics-assisted breeding (GAB) through marker assisted selection as well as genomic selection (GS). This would accelerate the development and improvement of both varieties and hybrids in pigeonpea. Particularly for hybrid breeding programme, mitochondrial genomes of cytoplasmic male sterile (CMS) lines, maintainers and hybrids have been sequenced to identify genes responsible for cytoplasmic male sterility. Furthermore, several diagnostic molecular markers have been developed to assess the purity of commercial hybrids. In summary, pigeonpea has become a genomic resources-rich crop and efforts have already been initiated to integrate these resources in pigeonpea breeding. PMID- 25741350 TI - Phospholipase D affects translocation of NPR1 to the nucleus in Arabidopsis thaliana. AB - Phytohormone salicylic acid (SA) is a crucial component of plant-induced defense against biotrophic pathogens. Although the key players of the SA pathway are known, there are still gaps in the understanding of the molecular mechanism and the regulation of particular steps. In our previous research, we showed in Arabidopsis suspension cells that n-butanol, which specifically modulates phospholipase D activity, significantly suppresses the transcription of the pathogenesis related (PR-1) gene, which is generally accepted as the SA pathway marker. In the presented study, we have investigated the site of n-butanol action in the SA pathway. We were able to show in Arabidopsis plants treated with SA that n-butanol inhibits the transcription of defense genes (PR-1, WRKY38). Fluorescence microscopy of Arabidopsis thaliana mutants expressing 35S::NPR1-GFP (nonexpressor pathogenesis related 1) revealed significantly decreased nuclear localization of NPR1 in the presence of n-butanol. On the other hand, n-butanol did not decrease the nuclear localization of NPR1 in 35S::npr1C82A-GFP and 35S::npr1C216A-GFP mutants constitutively expressing NPR1 monomers. Mass spectrometric analysis of plant extracts showed that n-butanol significantly changes the metabolic fingerprinting while t-butanol had no effect. We found groups of the plant metabolites, influenced differently by SA and n-butanol treatment. Thus, we proposed several metabolites as markers for n-butanol action. PMID- 25741351 TI - Interpreting lemma and palea homologies: a point of view from rice floral mutants. AB - In contrast to eudicot flowers which typically exhibit sepals and petals at their periphery, the flowers of grasses are distinguished by the presence of characteristic outer organs. In place of sepals, grasses have evolved the lemma and the palea, two bract-like structures that partially or fully enclose the inner reproductive organs. With little morphological similarities to sepals, whether the lemma and palea are part of the perianth or non-floral organs has been a longstanding debate. In recent years, comparative studies of floral mutants as well as the availability of whole genome sequences in many plant species have provided strong arguments in favor of the hypothesis of lemma and palea being modified sepals. In rice, a feature of the palea is the bending of its lateral region into a hook-shaped marginal structure. This allows the palea to lock into the facing lemma region, forming a close-fitting lemma-palea enclosure. In this article, we focus on the rice lemma and palea and review some of the key transcription factors involved in their development and functional specialization. Alternative interpretations of these organs are also addressed. PMID- 25741352 TI - Mango (Mangifera indica L.) cv. Kent fruit mesocarp de novo transcriptome assembly identifies gene families important for ripening. AB - Fruit ripening is a physiological and biochemical process genetically programmed to regulate fruit quality parameters like firmness, flavor, odor and color, as well as production of ethylene in climacteric fruit. In this study, a transcriptomic analysis of mango (Mangifera indica L.) mesocarp cv. "Kent" was done to identify key genes associated with fruit ripening. Using the Illumina sequencing platform, 67,682,269 clean reads were obtained and a transcriptome of 4.8 Gb. A total of 33,142 coding sequences were predicted and after functional annotation, 25,154 protein sequences were assigned with a product according to Swiss-Prot database and 32,560 according to non-redundant database. Differential expression analysis identified 2,306 genes with significant differences in expression between mature-green and ripe mango [1,178 up-regulated and 1,128 down regulated (FDR <= 0.05)]. The expression of 10 genes evaluated by both qRT-PCR and RNA-seq data was highly correlated (R = 0.97), validating the differential expression data from RNA-seq alone. Gene Ontology enrichment analysis, showed significantly represented terms associated to fruit ripening like "cell wall," "carbohydrate catabolic process" and "starch and sucrose metabolic process" among others. Mango genes were assigned to 327 metabolic pathways according to Kyoto Encyclopedia of Genes and Genomes database, among them those involved in fruit ripening such as plant hormone signal transduction, starch and sucrose metabolism, galactose metabolism, terpenoid backbone, and carotenoid biosynthesis. This study provides a mango transcriptome that will be very helpful to identify genes for expression studies in early and late flowering mangos during fruit ripening. PMID- 25741353 TI - Hierarchical traits distances explain grassland Fabaceae species' ecological niches distances. AB - Fabaceae species play a key role in ecosystem functioning through their capacity to fix atmospheric nitrogen via their symbiosis with Rhizobium bacteria. To increase benefits of using Fabaceae in agricultural systems, it is necessary to find ways to evaluate species or genotypes having potential adaptations to sub optimal growth conditions. We evaluated the relevance of phylogenetic distance, absolute trait distance and hierarchical trait distance for comparing the adaptation of 13 grassland Fabaceae species to different habitats, i.e., ecological niches. We measured a wide range of functional traits (root traits, leaf traits, and whole plant traits) in these species. Species phylogenetic and ecological distances were assessed from a species-level phylogenetic tree and species' ecological indicator values, respectively. We demonstrated that differences in ecological niches between grassland Fabaceae species were related more to their hierarchical trait distances than to their phylogenetic distances. We showed that grassland Fabaceae functional traits tend to converge among species with the same ecological requirements. Species with acquisitive root strategies (thin roots, shallow root systems) are competitive species adapted to non-stressful meadows, while conservative ones (coarse roots, deep root systems) are able to tolerate stressful continental climates. In contrast, acquisitive species appeared to be able to tolerate low soil-P availability, while conservative ones need high P availability. Finally we highlight that traits converge along the ecological gradient, providing the assumption that species with similar root-trait values are better able to coexist, regardless of their phylogenetic distance. PMID- 25741354 TI - ROS-mediated abiotic stress-induced programmed cell death in plants. AB - During the course of their ontogenesis plants are continuously exposed to a large variety of abiotic stress factors which can damage tissues and jeopardize the survival of the organism unless properly countered. While animals can simply escape and thus evade stressors, plants as sessile organisms have developed complex strategies to withstand them. When the intensity of a detrimental factor is high, one of the defense programs employed by plants is the induction of programmed cell death (PCD). This is an active, genetically controlled process which is initiated to isolate and remove damaged tissues thereby ensuring the survival of the organism. The mechanism of PCD induction usually includes an increase in the levels of reactive oxygen species (ROS) which are utilized as mediators of the stress signal. Abiotic stress-induced PCD is not only a process of fundamental biological importance, but also of considerable interest to agricultural practice as it has the potential to significantly influence crop yield. Therefore, numerous scientific enterprises have focused on elucidating the mechanisms leading to and controlling PCD in response to adverse conditions in plants. This knowledge may help develop novel strategies to obtain more resilient crop varieties with improved tolerance and enhanced productivity. The aim of the present review is to summarize the recent advances in research on ROS-induced PCD related to abiotic stress and the role of the organelles in the process. PMID- 25741355 TI - Characterization of the serine acetyltransferase gene family of Vitis vinifera uncovers differences in regulation of OAS synthesis in woody plants. AB - In higher plants cysteine biosynthesis is catalyzed by O-acetylserine(thiol)lyase (OASTL) and represents the last step of the assimilatory sulfate reduction pathway. It is mainly regulated by provision of O-acetylserine (OAS), the nitrogen/carbon containing backbone for fixation of reduced sulfur. OAS is synthesized by Serine acetyltransferase (SERAT), which reversibly interacts with OASTL in the cysteine synthase complex (CSC). In this study we identify and characterize the SERAT gene family of the crop plant Vitis vinifera. The identified four members of the VvSERAT protein family are assigned to three distinct groups upon their sequence similarities to Arabidopsis SERATs. Expression of fluorescently labeled VvSERAT proteins uncover that the sub cellular localization of VvSERAT1;1 and VvSERAT3;1 is the cytosol and that VvSERAT2;1 and VvSERAT2;2 localize in addition in plastids and mitochondria, respectively. The purified VvSERATs of group 1 and 2 have higher enzymatic activity than VvSERAT3;1, which display a characteristic C-terminal extension also present in AtSERAT3;1. VvSERAT1;1 and VvSERAT2;2 are evidenced to form the CSC. CSC formation activates VvSERAT2;2, by releasing CSC-associated VvSERAT2;2 from cysteine inhibition. Thus, subcellular distribution of SERAT isoforms and CSC formation in cytosol and mitochondria is conserved between Arabidopsis and grapevine. Surprisingly, VvSERAT2;1 lack the canonical C-terminal tail of plant SERATs, does not form the CSC and is almost insensitive to cysteine inhibition (IC50 = 1.9 mM cysteine). Upon sulfate depletion VvSERAT2;1 is strongly induced at the transcriptional level, while transcription of other VvSERATs is almost unaffected in sulfate deprived grapevine cell suspension cultures. Application of abiotic stresses to soil grown grapevine plants revealed isoform-specific induction of VvSERAT2;1 in leaves upon drought, whereas high light- or temperature- stress hardly trigger VvSERAT2;1 transcription. PMID- 25741356 TI - Promotion of arsenic phytoextraction efficiency in the fern Pteris vittata by the inoculation of As-resistant bacteria: a soil bioremediation perspective. AB - A greenhouse pot experiment was carried out to evaluate the efficiency of arsenic phytoextraction by the fern Pteris vittata growing in arsenic-contaminated soil, with or without the addition of selected rhizobacteria isolated from the polluted site. The bacterial strains were selected for arsenic resistance, the ability to reduce arsenate to arsenite, and the ability to promote plant growth. P. vittata plants were cultivated for 4 months in a contaminated substrate consisting of arsenopyrite cinders and mature compost. Four different experimental conditions were tested: (i) non-inoculated plants; (ii) plants inoculated with the siderophore-producing and arsenate-reducing bacteria Pseudomonas sp. P1III2 and Delftia sp. P2III5 (A); (iii) plants inoculated with the siderophore and indoleacetic acid-producing bacteria Bacillus sp. MPV12, Variovorax sp. P4III4, and Pseudoxanthomonas sp. P4V6 (B), and (iv) plants inoculated with all five bacterial strains (AB). The presence of growth-promoting rhizobacteria increased plant biomass by up to 45% and increased As removal efficiency from 13% without bacteria to 35% in the presence of the mixed inoculum. Molecular analysis confirmed the persistence of the introduced bacterial strains in the soil and resulted in a significant impact on the structure of the bacterial community. PMID- 25741358 TI - Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges. AB - Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by a multi-systemic vascular dysplasia and hemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). Both genes are associated with TGFbeta/BMP signaling, and loss of function mutations in the co-receptor ENG are causal in HHT1, while HHT2 is associated with mutations in the signaling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis and heart development. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the future. PMID- 25741359 TI - Oxytocin, vasopressin, and Williams syndrome: epigenetic effects on abnormal social behavior. AB - Williams syndrome (WS) is a condition caused by a deletion of ~26-28 genes on chromosome 7q11.23 often characterized by abnormal social behavior and disrupted oxytocin (OT) and vasopressin (AVP) functioning. The observation that individuals with WS exhibit OT and AVP dysregulation is compelling. There is currently a lack of evidence that any of the genes typically deleted in WS have any direct effect on either OT or AVP. In this perspective article, we present a novel epigenetic model describing how DNA methylation may impact the expression of key genes within the OT and AVP systems, which may ultimately influence the social behavior observed in WS. We draw support from data pooled from a prior empirical research study (Henrichsen et al., 2011), demonstrating that OXTR is overexpressed in WS. These preliminary findings may create new opportunities to target the OT and AVP systems with the specific goal of improving outcomes in WS and other psychiatric conditions. PMID- 25741357 TI - Recent advances in the dissection of drought-stress regulatory networks and strategies for development of drought-tolerant transgenic rice plants. AB - Advances have been made in the development of drought-tolerant transgenic plants, including cereals. Rice, one of the most important cereals, is considered to be a critical target for improving drought tolerance, as present-day rice cultivation requires large quantities of water and as drought-tolerant rice plants should be able to grow in small amounts of water. Numerous transgenic rice plants showing enhanced drought tolerance have been developed to date. Such genetically engineered plants have generally been developed using genes encoding proteins that control drought regulatory networks. These proteins include transcription factors, protein kinases, receptor-like kinases, enzymes related to osmoprotectant or plant hormone synthesis, and other regulatory or functional proteins. Of the drought-tolerant transgenic rice plants described in this review, approximately one-third show decreased plant height under non-stressed conditions or in response to abscisic acid treatment. In cereal crops, plant height is a very important agronomic trait directly affecting yield, although the improvement of lodging resistance should also be taken into consideration. Understanding the regulatory mechanisms of plant growth reduction under drought stress conditions holds promise for developing transgenic plants that produce high yields under drought stress conditions. Plant growth rates are reduced more rapidly than photosynthetic activity under drought conditions, implying that plants actively reduce growth in response to drought stress. In this review, we summarize studies on molecular regulatory networks involved in response to drought stress. In a separate section, we highlight progress in the development of transgenic drought-tolerant rice plants, with special attention paid to field trial investigations. PMID- 25741360 TI - Multi-model inference in comparative phylogeography: an integrative approach based on multiple lines of evidence. AB - Comparative phylogeography has its roots in classical biogeography and, historically, relies on a pattern-based approach. Here, we present a model-based framework for comparative phylogeography. Our framework was initially developed for statistical phylogeography based on a multi-model inference approach, by coupling ecological niche modeling, coalescent simulation and direct spatio temporal reconstruction of lineage diffusion using a relaxed random walk model. This multi-model inference framework is particularly useful to investigate the complex dynamics and current patterns in genetic diversity in response to processes operating on multiple taxonomic levels in comparative phylogeography. In addition, because of the lack, or incompleteness of fossil record, the understanding of the role of biogeographical events (vicariance and dispersal routes) in most regions worldwide is barely known. Thus, we believe that the expansion of that framework for multiple species under a comparative approach may give clues on genetic legacies in response to Quaternary climate changes and other biogeographical processes. PMID- 25741361 TI - Social parasitism and the molecular basis of phenotypic evolution. AB - Contrasting phenotypes arise from similar genomes through a combination of losses, gains, co-option and modifications of inherited genomic material. Understanding the molecular basis of this phenotypic diversity is a fundamental challenge in modern evolutionary biology. Comparisons of the genes and their expression patterns underlying traits in closely related species offer an unrivaled opportunity to evaluate the extent to which genomic material is reorganized to produce novel traits. Advances in molecular methods now allow us to dissect the molecular machinery underlying phenotypic diversity in almost any organism, from single-celled entities to the most complex vertebrates. Here we discuss how comparisons of social parasites and their free-living hosts may provide unique insights into the molecular basis of phenotypic evolution. Social parasites evolve from a eusocial ancestor and are specialized to exploit the socially acquired resources of their closely-related eusocial host. Molecular comparisons of such species pairs can reveal how genomic material is re-organized in the loss of ancestral traits (i.e., of free-living traits in the parasites) and the gain of new ones (i.e., specialist traits required for a parasitic lifestyle). We define hypotheses on the molecular basis of phenotypes in the evolution of social parasitism and discuss their wider application in our understanding of the molecular basis of phenotypic diversity within the theoretical framework of phenotypic plasticity and shifting reaction norms. Currently there are no data available to test these hypotheses, and so we also provide some proof of concept data using the paper wasp social parasite/host system (Polistes sulcifer-Polistes dominula). This conceptual framework and first empirical data provide a spring-board for directing future genomic analyses on exploiting social parasites as a route to understanding the evolution of phenotypic specialization. PMID- 25741362 TI - Use of pharmacogenomics in pediatric renal transplant recipients. AB - Transplant recipients receive potent immunosuppressive drugs in order to prevent graft rejection. Therapeutic drug monitoring is the current approach to guide the dosing of calcineurin inhibitors, mammalian target of rapamycin inhibitors (mTORi) and mofetil mycophenolate. Target concentrations used in pediatric patients are extrapolated from adult studies. Gene polymorphisms in metabolizing enzymes and drug transporters such as cytochromes CYP3A4 and CYP3A5, UDP glucuronosyl transferase, and P-glycoprotein are known to influence the pharmacokinetics and dose requirements of immunosuppressants. The implications of pharmacogenomics in this patient population is discussed. Genetic information can help with achieving target concentrations in the early post-transplant period, avoiding adverse drug reactions and drug-drug interactions. Evidence about genetic studies and transplant outcomes is revised. PMID- 25741363 TI - Rapid evolution of silver nanoparticle resistance in Escherichia coli. AB - The recent exponential increase in the use of engineered nanoparticles (eNPs) means both greater intentional and unintentional exposure of eNPs to microbes. Intentional use includes the use of eNPs as biocides. Unintentional exposure results from the fact that eNPs are included in a variety of commercial products (paints, sunscreens, cosmetics). Many of these eNPs are composed of heavy metals or metal oxides such as silver, gold, zinc, titanium dioxide, and zinc oxide. It is thought that since metallic/metallic oxide NPs impact so many aspects of bacterial physiology that it will difficult for bacteria to evolve resistance to them. This study utilized laboratory experimental evolution to evolve silver nanoparticle (AgNP) resistance in the bacterium Escherichia coli (K-12 MG1655), a bacterium that does not harbor any known silver resistance elements. After 225 generations of exposure to the AgNP environment, the treatment populations demonstrated greater fitness vs. control strains as measured by optical density (OD) and colony forming units (CFU) in the presence of varying concentrations of 10 nm citrate-coated silver nanoparticles (AgNP) or silver nitrate (AgNO3). Genomic analysis shows that changes associated with AgNP resistance were already accumulating within the treatment populations by generation 100, and by generation 200 three mutations had swept to high frequency in the AgNP resistance stocks. This study indicates that despite previous claims to the contrary bacteria can easily evolve resistance to AgNPs, and this occurs by relatively simple genomic changes. These results indicate that care should be taken with regards to the use of eNPs as biocides as well as with regards to unintentional exposure of microbial communities to eNPs in waste products. PMID- 25741364 TI - Characterization of genetic diversity and gene mapping in two Swedish local chicken breeds. AB - The aim of this paper is to study genetic diversity in the two Swedish local chicken breeds Bohuslan-Dals svarthona and Hedemorahona. The now living birds of both of these breeds (about 500 for Bohuslan-Dals svarthona and 2600 for Hedemorahona) originate from small relicts of earlier larger populations. An additional aim was to make an attempt to map loci associated with a trait that are segregating in both these breeds. The 60k SNP chip was used to genotype 12 Bohuslan-Dals svarthona and 22 Hedemorahona. The mean inbreeding coefficient was considerably larger in the samples from Hedemorahona than in the samples from Bohuslan-Dals svarthona. Also the proportion of homozygous SNPs in individuals was larger in Hedemorahona. In contrast, on the breed level, the number of segregating SNPs were much larger in Hedemorahona than in Bohuslan-Dals svarthona. A multidimensional scaling plot shows that the two breeds form clusters well-separated from each other. Both these breeds segregate for the dermal hyperpigmentation phenotype. In Bohuslan-Dals svarthona most animals have dark skin, but some individuals with lighter skin exists (most easily detected by their red comb). An earlier study of the Fm locus showed that this breed has the same complex rearrangement involving the EDN3 gene as Silkie chicken and two other studied Asian breeds. In the breed Hedemorahona, most individuals have normal skin pigmentation (and red comb), but there are some birds with darker skin and dark comb. In this study the involvement of the EDN3 gene is confirmed also in Hedemorahona. In addition we identify a region on chromosome 21 that is significantly associated with the trait. PMID- 25741366 TI - Evaluation of patients' expectations and benefits in the treatment of allergic rhinitis with a new tool: the patient benefit index - the benefica study. AB - BACKGROUND: Symptoms of allergic rhinitis (AR) have a detrimental effect on quality of life. The AR-Patient Benefit Index (AR-PBI), a specific self assessment tool has been developed to assess treatment-related benefit in two separate sections: the Patient Needs Questionnaire (PNQ) which explores the patient's expectations before treatment and the Patient Benefit Questionnaire (PBQ) which evaluates treatment benefit. For the PNQ, three dimensions summarize patients' expectations: symptoms, social life and emotional state, thus covering a larger field than symptomatic relief. The aim of the study was to validate the French language version of the AR-PBI and to assess the treatment-related expectations and benefits provided in patients with allergic rhinitis treated with H1-antihistamines in a real-life study. METHODS: BENEFICA was a prospective, observational study involving patients with allergic rhinitis who were starting treatment with H1-antihistamines. The Patient Needs Questionnaire (PNQ) was administered before treatment (D0) and the Patient Benefit Questionnaire (PBQ) was collected after a 14-day course of H1-antihistamines (D15). Discomfort (visual analog scale), and quality of life (miniRQLQ) were measured on D0 and D15. RESULTS: Three thousands and eighty-nine patients were enrolled in the study: mean age 39 +/- 14 years, women 52%, 81% of patients with moderate to severe persistent rhinitis (Allergic Rhinitis and its Impact on Asthma, ARIA); 19% had (a) concomitant condition(s), 18% were asthmatic, and 12% had atopic dermatitis. Discomfort and quality of life improved between D0 and D15. AR-PBI was 2.7 +/- 0.8, superior to 1 (threshold for clinically relevant benefit) for 97% of patients and greater in patients willing to continue the treatment. PBI was moderately correlated to change in miniRQLQ (r = -0.45, p < 0.0001) and change in discomfort (r = -0.38, p < 0.0001), suggesting a richer conceptual content than symptoms relief. CONCLUSIONS: The French version of the Allergic Rhinitis-Patient Benefit Index (AR-PBI) has been validated. It complements the discomfort and quality of life tools and assesses the needs and benefits in patients suffering from allergic rhinitis. This new tool may help physicians to better understand patients' expectations and to discuss treatment issues with their patients. PMID- 25741365 TI - Identification of copy number variants in whole-genome data using Reference Coverage Profiles. AB - The identification of DNA copy numbers from short-read sequencing data remains a challenge for both technical and algorithmic reasons. The raw data for these analyses are measured in tens to hundreds of gigabytes per genome; transmitting, storing, and analyzing such large files is cumbersome, particularly for methods that analyze several samples simultaneously. We developed a very efficient representation of depth of coverage (150-1000* compression) that enables such analyses. Current methods for analyzing variants in whole-genome sequencing (WGS) data frequently miss copy number variants (CNVs), particularly hemizygous deletions in the 1-100 kb range. To fill this gap, we developed a method to identify CNVs in individual genomes, based on comparison to joint profiles pre computed from a large set of genomes. We analyzed depth of coverage in over 6000 high quality (>40*) genomes. The depth of coverage has strong sequence-specific fluctuations only partially explained by global parameters like %GC. To account for these fluctuations, we constructed multi-genome profiles representing the observed or inferred diploid depth of coverage at each position along the genome. These Reference Coverage Profiles (RCPs) take into account the diverse technologies and pipeline versions used. Normalization of the scaled coverage to the RCP followed by hidden Markov model (HMM) segmentation enables efficient detection of CNVs and large deletions in individual genomes. Use of pre-computed multi-genome coverage profiles improves our ability to analyze each individual genome. We make available RCPs and tools for performing these analyses on personal genomes. We expect the increased sensitivity and specificity for individual genome analysis to be critical for achieving clinical-grade genome interpretation. PMID- 25741367 TI - HBV vaccination status and response to hepatitis B vaccine among Iranian dentists, correlation with risk factors and preventive measures. AB - BACKGROUND: Studies showed that HBV vaccination and consequent level of antibody are not completely adequate among dentists despite performance of highly exposure prone procedures. OBJECTIVES: The objectives of the study were to evaluate the levels of responsiveness to HBV vaccine and to determine the occupational factors associated among dental staff. MATERIALS AND METHODS: In total, 1612 dental health care workers were recruited. The level of anti-HBs was tested using a commercially enzyme-linked immunosorbent assay (ELISA). Data on demographic, risk factors associated with dental practice and level of protective procedures and occupational exposure aspects were collected through self-reported questionnaires. RESULTS: Of 1538 vaccinated individuals, 55 (3.7%), 126 (8.4%) and 1309 (87.9%) had received one, two and full three doses of vaccine, respectively. One-hundred-seventy-six (11.5%) were nonimmune (anti-HBs < 10 IU/mL) and 1362 (88.5%) were immune (anti-HBs > 10 IU/ mL). 392/542 (72.3%) of dentists who received their third dose of vaccination less than five years before the commencement of study were completely immune compared to those who had completed all three recommended doses in a longer period (308/491, 64.3%) (P = 0.001). Fifty-eight (3.59%) of participants did not receive any HBV vaccine at all; however, they had positive results for anti-HBs, indicating a past HBV infection. Statistically, the levels of anti-HBs were significantly associated with gender, age, duration of dental practice engagement and regularly use of mask, glasses and shield. CONCLUSIONS: Since dental care workers have a high risk of exposure to hepatitis virus, they should be advised to receive hepatitis B vaccine and it should be confirmed if they have acquired immunity to HBV by testing the level of anti-HBs. PMID- 25741368 TI - Mutations of Basal core promoter and precore regions in hepatitis B virus genotypes B and C. AB - BACKGROUND: Mutations in basal core promoter (BCP) and precore regions of hepatitis B virus (HBV) are associated with course and treatment outcomes of chronic HBV infection. While BCP and precore mutation analysis have been carried out in adult patients between different genotypes, this analysis has rarely been performed for chronically infected children. OBJECTIVES: The aim of this study was to assess the mutation profiles of BCP and precore regions in different HBV genotypes in chronically infected children. PATIENTS AND METHODS: A cohort of 245 children and 92 adults with chronic HBV infection was included in this study. BCP and precore regions were analyzed by PCR amplification and sequenced. RESULTS: Ten nucleotide positions, including nt1679, nt1721, nt1753, nt1757, nt1758, nt1762, nt1764, nt1775, nt1856 and nt1858 in BCP/precore regions of HBV genome, showed obviously higher frequencies of mutation in genotype C subjects than in genotype B subjects among children, while there were only three positions, including nt1679, nt1758 and nt1775 showing higher mutation frequencies in genotype C subjects than in genotype B subjects in adults. Several combined mutations were obviously highly distributed in children with chronic HBV genotype C infection, such as G1721A/A1775G/T1858C triple mutation; a novel combined mutation type, exclusively detected in children with chronic HBV genotype C infection. In addition, G1721A/A1775G/T1858C combined mutation was associated with higher viral load and lower age distribution. CONCLUSIONS: The mutation ratio difference between genotypes B and C in children was higher than that of adults and several combined mutations were exclusively detected in children with chronic HBV genotype C infection associated with higher viral load. PMID- 25741369 TI - Insulin resistance provides the connection between hepatitis C virus and diabetes. PMID- 25741370 TI - Evaluation of prevalence and risk factors of hepatitis g virus infection among hemodialysis patients referred to Iranian army hospitals in tehran during 2012 2013. AB - BACKGROUND: GB virus C (GBV-C) or hepatitis G virus (HGV) is a newly discovered and enveloped RNA positive-stranded flavivirus-like particle, which has not yet been proven to have major negative effects on liver. OBJECTIVES: Increasing the risk of blood-borne infections in hemodialysis patients is a main health care concern in different countries. Therefore, it is important to estimate the prevalence and risk factors of hepatitis G virus infection in Iranian hemodialysis patients to design standard prevention and treatment plans. PATIENTS AND METHODS: In this multicenter observational or epidemiologic study, 138 patients who underwent hemodialysis in Iranian Army hospitals in Tehran were included. Serum HIV antibody (Ab), HCV antibody and HBS antigen (Ag) were assessed. Demographic data such as gender, age, blood group, cause of renal failure, dialysis onset and duration were collected from medical files. GBV-C/HGV was evaluated by nested reverse transcription polymerase chain reaction (RT-PCR) method. Then, all data were analyzed by SPSS ver. 13. RESULTS: In total, 81 males and 57 females were included. The mean age of patients was 62.16 +/- 14.86 years. Six (4.3%) had positive results for GBV-C/HGV by RT-PCR. Except gender (P = 0.045) and duration of dialysis in a week (P < 0.001), other demographic factors revealed no significant difference (P > 0.05). All patients had negative results for HIV Ab, HCV Ab and HBS Ag. CONCLUSIONS: Overall, 4.3% of patients had positive results for GBV-C/HGV and all negative for HIV, HCV and HBV. Further studies are needed to elucidate real prevalence, risk factors and characteristics of HGV infection in Iranian hemodialysis patients. PMID- 25741371 TI - Efficacy of Prolonged Treatment With Pegylated Interferon (Peg-IFN) and Ribavirin in Thalassemic Patients With Hepatitis C Who Relapsed After Previous Peg-IFN Based Therapy. AB - BACKGROUND: Most thalassemic patients with chronic hepatitis C virus (HCV) infection do not respond to therapy with pegylated interferon (Peg-IFN) plus ribavirin (RBV) due to hepatic siderosis and RBV dose reduction caused by RBV induced anemia. OBJECTIVES: In the present study, we recruited HCV genotype 1 infected thalassemic patients who had relapsed after a 48-week treatment with Peg IFN plus RBV in order to evaluate the efficacy of a 72-week regimen of Peg-IFN plus RBV. PATIENTS AND METHODS: In this retrospective study, 23 thalassemic patients with HCV genotype 1 infection who had prior relapse after treatment with Peg-IFN and RBV for 48 weeks were consecutively enrolled in this study for evaluation of the efficacy of a 72-week treatment regimen. RESULTS: For the 21 included cases, mean age was 29.7 years; 81% were men and 28.6% had cirrhosis. At the end of the treatment, nine (42.9%) patients had an undetectable level of HCV RNA in their sera. However, six months after treatment completion four of these patients relapsed and a sustained virological response (SVR) was found in five (23.8%) patients. Undetectable HCV RNA level at week 4 (P = 0.03) and undetectable HCV RNA level at week 12 (P < 0.01) were found to be predictors of SVR. There was an average 47.9% increase in blood transfusion during therapy and treatment was discontinued for 12 (57.1%) patients prematurely. CONCLUSIONS: The present study suggests that thalassemic patients with chronic hepatitis C genotype 1 infection who did not achieve SVR after a course of therapy with Peg IFN and RBV may benefit from being retreated with a 72-week regimen. PMID- 25741372 TI - Development of magnetic capture hybridization and quantitative polymerase chain reaction for hepatitis B virus covalently closed circular DNA. AB - BACKGROUND: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) served as a vital role in the life cycle of the virus and persistent infection. However, specific and quantitative methods for cccDNA detection have not been available. OBJECTIVES: Our aim was to develop and primarily evaluate a quantitative method for HBV cccDNA based on magnetic capture hybridization and quantitative PCR technology. MATERIALS AND METHODS: The functionalized nanoparticles specifically to capture HBV cccDNA, located on both sides of relaxed circle DNA (rcDNA) gap, were designed. Then, magnetic capture hybridization and quantitative PCR (MCH-qPCR) assay were developed and its performance was primarily evaluated with cccDNA standards and serum samples of patients with chronic hepatitis B. RESULTS: Specific nanoparticles of cccDNA capture were prepared and a magnetic capture hybridization and quantitative assay method for cccDNA was developed successfully. The limit of detection was 90 IU/mL, and a good linear relationship in the range of 10(2)-10(6) IU/mL was revealed (r(2) = 0.994) with the MCH-qPCR. Compared with directly real-time PCR, a high content of HBV DNA did not affect the detection of cccDNA for the MCH-qPCR method, and there was no cross-reactivity between cccDNA and rcDNA. CONCLUSIONS: The novel MCH-qPCR method has good sensitivity and specificity. It could meet the requirement of clinical routine detection. PMID- 25741373 TI - Association between platelet count as a noninvasive marker and ultrasonographic grading in patients with nonalcoholic Fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease has become a worldwide challenge. Liver biopsy remains the single most reliable approach to determine the severity of this disease. As patients with nonalcoholic fatty liver disease require close follow-up, performing this invasive method repeatedly seems impractical; therefore, designing a noninvasive system to follow up patients has become a common interest. OBJECTIVES: We intended to investigate the association between platelet counts of patients with nonalcoholic fatty liver disease and the severity of their disease based on serum levels of liver enzymes and grade of fatty liver on ultrasonography. PATIENTS AND METHODS: One thousand, three hundred and five patients with nonalcoholic fatty liver disease were included in this descriptive study. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and platelet counts of patients were measured. The grade of fatty liver was determined by abdominal ultrasonography. RESULTS: Of our study population, 54.3% (n = 708) were women. Patients with mild fatty liver on ultrasonography had lower platelet counts than those with moderate and severe fatty liver. However, no cutoff value of platelet count could reliably distinguish different grades of fatty liver. We found no significant association between platelet counts and serum levels of AST, ALT or ALP. However, we showed that male patients with abnormal levels of ALT had higher platelet counts. CONCLUSIONS: Platelet count in nonalcoholic fatty liver disease can serve as a clue to the severity of disease, but it cannot be considered as a sole test to follow up patients. PMID- 25741374 TI - Efficacy of 24-week pegylated interferon alpha and ribavirin combination therapy in highly selected patients infected with hepatitis C virus genotype 1. AB - BACKGROUND: Previous studies using pegylated interferon (Peg-IFN) and ribavirin (RBV) combination therapy suggested that patients with hepatitis C virus (HCV) genotype 1 and low pretreatment HCV RNA level who achieved rapid virological response (RVR) can be treated for 24 weeks without compromising sustained virological response (SVR) rate. OBJECTIVES: The current study aimed to investigate the efficacy of Peg-IFN-alfa-2a plus RBV administered for a 24-week treatment course in patients with chronic HCV genotype 1 infection and possessing the following criteria: low baseline serum HCV RNA level, absence of significant fibrosis and achievement of RVR. PATIENTS AND METHODS: In this case-control study, 20 patients with HCV genotype 1 infection and favorable baseline characteristics and on-treatment response were treated with Peg-IFN and RBV for 24 weeks as the case group. Furthermore, 23 patients with the same characteristics who underwent a 48-week treatment course were selected as the control group. RESULTS: The majority of patients had no fibrosis on liver elastography. There was no statistical difference regarding age, gender, alanine transaminase (ALT) level, rs12979860 polymorphism and the level of fibrosis between the two studied groups. All patients in the 24-week treatment course achieved SVR and all the subjects who received the 48-week treatment course achieved SVR as well (P > 0.99). CONCLUSIONS: The current study confirmed that the efficacy of a 24-week regimen of Peg-IFN-alfa-2a plus RBV was similar to the 48-week treatment in the patients infected with HCV genotype 1, and low baseline HCV RNA level who achieved RVR. Response guided therapy can be efficient and cost effective among the selected HCV genotype 1-infected patients. PMID- 25741375 TI - Respiratory symptoms, fractional exhaled nitric oxide & endotoxin exposure among female flower farm workers in Ethiopia. AB - BACKGROUND: Greenhouse workers are exposed to organic dusts, and they are thereby at risk of developing airway disorders. This study aims to measure personal endotoxin exposure, assess respiratory symptoms and measure fractional exhaled nitric oxide (FeNO) among female flower farm workers in Ethiopia. METHODS: A cross-sectional study involving female workers (n = 248) from four flower farms was conducted. The workers were interviewed for respiratory symptoms using a standard questionnaire. Workers from two of these farms also participated in personal endotoxin sampling (46 workers, 75 measurements) on glass fiber filters (0.2 MUm pore size) inside conductive 25 mm Millipore cassettes for sampling of the "total dust" fraction. They also participated in FeNO (n = 114) measurements with a portable electrochemistry-based sensor. Chi-square and independent t-tests were used to compare categorical and continuous variables respectively. A mixed effects model was used to analyze exposure determinants. RESULTS: Endotoxin exposure had a geometric mean (GM) of 22.8 endotoxin units (EU)/m(3) with a maximum of 180 EU/m(3). Greenhouse workers had significantly higher endotoxin exposure than workers outside the greenhouses (GM = 26.7 vs. 19.3 EU/m(3) respectively; p < 0.05). The mean age of the workers was 24 years, and their mean working time in the flower farm was 21 months. Greenhouse workers had higher prevalence of self-reported respiratory symptoms than those outside greenhouses. However, after adjusting for education only blocked nose remained significant. The FeNO concentration ranged 5-166 ppb (GM = 14 ppb). Two workers had FeNO concentration above 50 ppb. FeNO levels differs significantly between the farms but there was no difference between workers inside and outside greenhouses. CONCLUSION: Greenhouse workers at flower farms had higher prevalence of blocked nose than workers outside, which may indicate the presence of rhinitis. Endotoxin exposure was low. There were few workers with objective signs of airway inflammation; this might be because the mean working time in the greenhouses was only two years. We suggest further studies to evaluate the effect of longer employment and exposure time as well as to investigate possible exposure to pesticides and other components in the bio-aerosols. PMID- 25741376 TI - Cyclin E2 is the predominant E-cyclin associated with NPAT in breast cancer cells. AB - BACKGROUND: The cyclin E oncogene activates CDK2 to drive cells from G1 to S phase of the cell cycle to commence DNA replication. It coordinates essential cellular functions with the cell cycle including histone biogenesis, splicing, centrosome duplication and origin firing for DNA replication. The two E-cyclins, E1 and E2, are assumed to act interchangeably in these functions. However recent reports have identified unique functions for cyclins E1 and E2 in different tissues, and particularly in breast cancer. FINDINGS: Cyclins E1 and E2 localise to distinct foci in breast cancer cells as well as co-localising within the cell. Both E-cyclins are found in complex with CDK2, at centrosomes and with the splicing machinery in nuclear speckles. However cyclin E2 uniquely co-localises with NPAT, the main activator of cell-cycle regulated histone transcription. Increased cyclin E2, but not cyclin E1, expression is associated with high expression of replication-dependent histones in breast cancers. CONCLUSIONS: The preferential localisation of cyclin E1 or cyclin E2 to distinct foci indicates that each E-cyclin has unique roles. Cyclin E2 uniquely interacts with NPAT in breast cancer cells, and is associated with higher levels of histones in breast cancer. This could explain the unique correlations of high cyclin E2 expression with poor outcome and genomic instability in breast cancer. PMID- 25741377 TI - Prospective study and new concepts based on scoliosis detorsion of the first 225 early in-brace radiological results with the new Lyon brace: ARTbrace. AB - BACKGROUND: The symmetrical Lyon brace is a brace, usually used to maintain correction after a plaster cast reduction in the Cotrel's EDF (Elongation Derotation-Flexion) frame. The new Lyon brace or ARTbrace is an immediate corrective brace based on some of the principles of the plaster cast which are improved due to advances in CAD/CAM technology. The aim of this paper is to describe concepts of this new brace to be not only a replacement of the plaster cast, but also a definitive brace. METHODS: Instead of a plaster cast, three segmental CAD/CAM moulds are made with the instantaneous full 3D raster stereography digitizer (Orten):In self axial elongationIn shift and lumbar lordosisIn shift and thoracic kyphosis A specific software (OrtenShape) makes up the overlay of the three moulds. Mould 1 is used for the pelvis and the shoulders mould 2 for the lumbar segment and mould 3 for the thoracic segment. The mathematical basis of the ARTbrace is the torso column which is a circled helicoid with horizontal circle generator. A torso column is reproduced in the opposite direction of the scoliosis. Like the plaster cast, the ARTbrace is worn for a "total time" of 24 hours 7 days a week without modifying the standard protocol of the Lyon brace reduction. The prospective controlled cohort observational study of the 225 first patients treated since May 2013 is reported below. RESULTS: The in-brace immediate reduction is: 0.7, i.e. 40% better with the ARTbrace than with a plaster cast. The correction of flat back is 9 degrees (from 18 degrees .4 to 28 degrees .5 kyphosis Cobb angle). The improved aesthetic appearance is equal for rib hump and ATR. CONCLUSION: This first paper is an introduction with very short results and does not prejudge the final outcome. The ARTbrace can be used not only to replace the plaster cast, but also as a definitive brace. The new segmental moulding with final detorsion is even more efficient and to this day the ARTbrace is the most effective to reduce the Cobb angle of scoliosis. PMID- 25741378 TI - Analysis of the correlation between blood glucose level and prognosis in patients younger than 18 years of age who had head trauma. AB - OBJECTIVE: To analyze the correlation between early-term blood glucose level and prognosis in patients with isolated head trauma. METHODS: This study included a total of 100 patients younger than 18 years of age who had isolated head trauma. The admission blood glucose levels of these patients were measured. Age at the time of the incident, sex, mode of occurrence of the trauma, computed tomography findings, and GCSs were recorded. Kruskall Wallis test was used compare of groups. A p value less than 0.05 was considered statistically significant. RESULTS: The median age of the study population was 7 years and the median GCS was 11. There was a significant negative correlation between blood glucose level and GCS (p < 0.05). A significant correlation in the negative direction was observed between GCS and blood glucose level (r = -0.658, p < 0.05). Seventy seven percent of the patients were admitted to hospital, while 6% died in ED. CONCLUSION: The results of the present study suggest that hyperglycemia at an early stage and a low GCS may be reliable predictors of the severity of head trauma and prognosis. A higher blood glucose level may be an ominous sign that predicts a poor prognosis and an increased risk of death. PMID- 25741379 TI - A multi-tiered approach for assessing the forestry and wood products industries' impact on the carbon balance. AB - BACKGROUND: The forestry and wood products industries play a significant role in CO2 emissions reduction by increasing carbon stocks in living forest biomass and wood products. Moreover, wood can substitute for fossil fuels. Different methods can be used to assess the impact of regional forestry and wood products industries on regional CO2 emissions. This article considers three of those methods and combines them into a multi-tiered approach. RESULTS: The multi-tiered approach proposed in this article combines: 1) a Kyoto-Protocol-oriented method focused on changes in CO2 emissions resulting from regional industrial production, 2) a consumer-oriented method focused on changes in CO2 emissions resulting from regional consumption, and 3) a value-creation-oriented method focused on changes in CO2 emissions resulting from forest management and wood usage strategies. North Rhine-Westphalia is both a typical German state and an example of a region where each of these three methods yields different results. It serves as a test case with which to illustrate the advantages of the proposed approach. CONCLUSIONS: This case study argues that the choice of assessment methods is essential when developing and evaluating a strategy for reducing CO2 emissions. Emissions can be reduced through various social and economic processes. Since none of the assessment methods considered above is suitable for all of these processes, only a multi-tiered approach may ensure that strategy development results in an optimal emissions reduction strategy. PMID- 25741380 TI - Parental stress and the onset and course of childhood asthma. AB - The influence of a caregiver's stress on the development of childhood asthma is an important aspect of the treatment and prevention of illness. Many cross sectional studies have investigated the association between parenting attitude and/or caregiver's stress and childhood asthma morbidity, but prospective studies are more advantageous than cross-sectional studies in interpreting a causal relationship from the results. We here present an overview of prospective studies that have reported a relationship between parental stress and the morbidity or course of childhood asthma and discuss the role of parental mental health in its prevention and treatment. Almost all of the studies referred to in this paper show that caregiver (mostly mothers) stress contributed to the onset and to a poor prognosis, while only a few studies have examined the adverse effect of paternal stress on childhood asthma. Their results are inconsistent, and there is insufficient data examining specific stress-related properties that can be targeted in intervention studies. Not only maternal but also paternal influence should be considered in future studies, and it will be important to assess specific stress-related properties that can be the foundation of specific intervention methods. PMID- 25741381 TI - An assessment of antenatal care among Syrian refugees in Lebanon. AB - BACKGROUND: After more than three years of violence in Syria, Lebanon hosts over one million Syrian refugees creating significant public health concerns. Antenatal care delivery to tens of thousands of pregnant Syrian refugee women is critical to preventing maternal and fetal mortality but is not well characterized given the multiple factors obtaining health data in a displaced population. This study describes antenatal care access, the scope of existing antenatal care, and antenatal and family planning behaviors and practice among pregnant Syrian refugees in various living conditions and multiple geographic areas of Lebanon. METHODS: A field-based survey was conducted between July and October 2013 in 14 main geographic sites of refugee concentration. The assessment evaluated antenatal services among a non-randomized sample of 420 self-identified pregnant Syrian refugee women that included demographics, gestational age, living accommodation, antenatal care coverage, antenatal care content, antenatal health behaviors, antenatal health literacy, and family planning perception and practices. RESULTS: In total, 420 pregnant Syrian refugees living in Lebanon completed the survey. Of these, 82.9% (348) received some antenatal care. Of those with at least one antenatal visit, 222 (63.8%) received care attended by a skilled professional three or more times, 111 (31.9%) 1-2 times, and 15 (4.3%) had never received skilled antenatal care. We assessed antenatal care content defined by blood pressure measurement, and urine and blood sample analyses. Of those who had received any antenatal care, only 31.2% received all three interventions, 18.2% received two out of three, 32.1% received one out of three, and 18.5% received no interventions. Only (41.2%) had an adequate diet of vitamins, minerals, and folic acid. Access, content and health behaviors varied by gestational age, type of accommodation and location in Lebanon. CONCLUSIONS: Standards of antenatal care are not being met for pregnant Syrian refugee women in Lebanon. This descriptive analysis of relative frequencies suggests reproductive health providers should focus attention on increasing antenatal care visits, particularly to third trimester and late gestational age patients and to those in less secure sheltering arrangements. With this approach they can improve care content by providing early testing and interventions per accepted guidelines designed to improve pregnancy outcomes. PMID- 25741382 TI - Are submicroscopic chromosomal inversions predisposing factors for the t(9;22)(q34;q11.2) translocation in chronic myeloid leukemia? AB - A complex chromosomal rearrangement observed in a patient with chronic myeloid leukemia was explained as the consequence of a multistep process. The explanation involved an initial t(9;22) translocation with breakpoints distant from the BCR and ABL1 genes followed by genomic deletions that produced the BCR-ABL1 hybrid gene. We present an alternative model that fits the origin of the patient's rearrangement better. The present model links submicroscopic inversions with the occurrence of the t(9;22) translocation and opens a new approach on the research on the disease. PMID- 25741383 TI - Embolic suppurative thyroiditis with concurrent carcinoma in pregnancy: lessons in management through a case report. AB - BACKGROUND: The thyroid undergoes a variety of physiological changes during pregnancy. The relatively low iodine levels seen in pregnancy have been implicated in thyroid growth during this time. Management of thyroid cancer in pregnancy is not immediately apparent. Furthermore, acute suppurative thyroiditis is rare and this is attributed to the glands innate immunity. We thoroughly review the evidence regarding management of thyroid abscess and thyroid malignancy during pregnancy and illustrate it via an extremely rare case of an embolic thyroid abscess highlighting an underlying carcinoma in a pregnant woman. CASE: A 29-year old female was found to have a thyroid mass during an antenatal assessment. Following a wound infection from Caesarian section she developed a rapidly progressive thyroid abscess. Incision and drainage of the abscess, and subsequent histology revealed papillary carcinoma. She subsequently underwent both total thyroidectomy with level 6 dissection and radio-iodine ablation post natally. CONCLUSION: The literature is inconsistent regarding pregnancy as a risk factor for thyroid cancer, but overall it has been suggested as equally or slightly more frequent than in the non-pregnant population. Thyroid mass investigation should be as for the non-pregnant population. In the first trimester any endocrine surgery is associated with miscarriage, whereas these risks are reduced in second trimester. Importantly, there is no survival benefit in undergoing papillary carcinoma surgery in the third trimester versus early post partum and the risks of premature labour may outweigh any benefit gained by operating early. Most importantly, acute suppurative thyroiditis is rare entity and clinicians should have a low threshold for suspicion of underlying malignancy in these patients. This is especially true in the pregnant population who may be especially susceptible whilst undergoing hypertrophic thyroid changes. PMID- 25741384 TI - Dynamic navicular motion measured using a stretch sensor is different between walking and running, and between over-ground and treadmill conditions. AB - BACKGROUND: Non-invasive evaluation of in-shoe foot motion has traditionally been difficult. Recently a novel 'stretch-sensor' was proposed as an easy and reliable method to measure dynamic foot (navicular) motion. Further validation of this method is needed to determine how different gait analysis protocols affect dynamic navicular motion. METHODS: Potential differences in magnitude and peak velocity of navicular motion using the 'stretch sensor' between (i) barefoot and shod conditions; (ii) overground and treadmill gait; and/or (iii) running and walking were evaluated in 26 healthy participants. Comparisons were made using paired t-tests. RESULTS: Magnitude and velocity of navicular motion was not different between barefoot and shod walking on the treadmill. Compared to walking, velocity of navicular motion during running was 59% and 210% higher over ground (p < 0.0001) and on a treadmill (p < 0.0001) respectively, and magnitude of navicular motion was 23% higher during over-ground running compared to over ground walking (p = 0.02). Compared to over-ground, magnitude of navicular motion on a treadmill was 21% and 16% greater during walking (p = 0.0004) and running (p = 0003) respectively. Additionally, maximal velocity of navicular motion during treadmill walking was 48% less than walking over-ground (p < 0.0001). CONCLUSION: The presence of footwear has minimal impact on navicular motion during walking. Differences in navicular motion between walking and running, and treadmill and over-ground gait highlight the importance of task specificity during gait analysis. Task specificity should be considered during design of future research trials and in clinical practice when measuring navicular motion. PMID- 25741385 TI - Systems biology approaches for advancing the discovery of effective drug combinations. AB - Complex diseases like cancer are regulated by large, interconnected networks with many pathways affecting cell proliferation, invasion, and drug resistance. However, current cancer therapy predominantly relies on the reductionist approach of one gene-one disease. Combinations of drugs may overcome drug resistance by limiting mutations and induction of escape pathways, but given the enormous number of possible drug combinations, strategies to reduce the search space and prioritize experiments are needed. In this review, we focus on the use of computational modeling, bioinformatics and high-throughput experimental methods for discovery of drug combinations. We highlight cutting-edge systems approaches, including large-scale modeling of cell signaling networks, network motif analysis, statistical association-based models, identifying correlations in gene signatures, functional genomics, and high-throughput combination screens. We also present a list of publicly available data and resources to aid in discovery of drug combinations. Integration of these systems approaches will enable faster discovery and translation of clinically relevant drug combinations. Graphical abstractSpectrum of Systems Biology Approaches for Drug Combinations. PMID- 25741386 TI - High serum ferritin level is an independent risk factor for metabolic syndrome in a Chinese male cohort population. AB - BACKGROUND: Elevated serum ferritin levels have been reported to contribute to metabolic syndrome (MetS). We examined the association of serum ferritin levels with the development of MetS in a representative sample of Chinese male adult population. METHOD: The data came from the 2009-2013 Fangchenggang Area Males Health and Examination Survey (FAMHES). We combined a cross-sectional study of 2417 males and a longitudinal study of 857 males who participated in the FAMHES. RESULT: The serum ferritin level of MetS was higher than that of nonMetS (median and percentiles 25-75: 447.4 (294.1-612.4) vs. 302.4 (215.0-435.8) ng/ml, p < 0.01). A positive correlation between ferritin concentrations and blood pressure (Systolic BP: R = 0.110, Diastolic BP: R = 0.158), waist circumference (R = 0.333), fasting glucose (R = 0.089), triglyceride (R = 0.315) and low high density lipoprotein cholesterol (R = 0.130) was significant (all p < 0.001). Compared with the level of ferritin in the group with no MetS component, the group with all five MetS components had a higher ferritin level (554.7 (340.1 606.4) vs. 274.2 (198.2-384.4) ng/ml). The odd radio (OR) was higher for MetS in the highest ferritin quartile (OR = 2.29, 95% CI = 1.47-3.54) compared with the lowest ferritin quartile after adjustment for multi-factors. After 4-year follow up, 79 subjects newly diagnosed with MetS in 857 cohort male participants in 2013. Compared with the lowest ferritin quartile, the RR of the highest ferritin quartile was 2.55 (95% CI = 1.30-5.00) after multiple adjustments (p < 0.01). CONCLUSION: Our findings confirm that the serum ferritin level is associated with the independent components of MetS, and elevated ferritin level is an independent risk factor for MetS development in the Chinese male population during the 4-year follow-up period. PMID- 25741387 TI - Concomitant downregulation of the imprinted genes DLK1 and MEG3 at 14q32.2 by epigenetic mechanisms in urothelial carcinoma. AB - BACKGROUND: The two oppositely imprinted and expressed genes, DLK1 and MEG3, are located in the same gene cluster at 14q32. Previous studies in bladder cancer have suggested that tumor suppressor genes are located in this region, but these have not been identified. RESULTS: We observed that both DLK1 and MEG3 are frequently silenced in urothelial cancer tissues and cell lines. The concomitant downregulation of the two genes is difficult to explain by known mechanisms for inactivating imprinted genes, namely deletion of active alleles or epitype switching. Indeed, quantitative PCR revealed more frequent copy number gains than losses in the gene cluster that were, moreover, consistent within each sample, excluding gene losses as the cause of downregulation. Instead, we observed distinctive epigenetic alterations at the three regions controlling DLK1 and MEG3 expression, namely the DLK1 promoter; the intergenic (IG) and MEG3 differentially methylated regions (DMRs). Bisulfite sequencing and pyrosequencing revealed novel patterns of DNA methylation in tumor cells, which were distinct from that of either paternal allele. Furthermore, chromatin immunoprecipitation demonstrated loss of active and gain of repressive histone modifications at all regulatory sequences. CONCLUSIONS: Our data support the idea that the main cause of the prevalent downregulation of DLK1 and MEG3 in urothelial carcinoma is epigenetic silencing across the 14q32 imprinted gene cluster, resulting in the unusual concomitant inactivation of oppositely expressed and imprinted genes. PMID- 25741388 TI - Synthetic epigenetics-towards intelligent control of epigenetic states and cell identity. AB - Epigenetics is currently one of the hottest topics in basic and biomedical research. However, to date, most of the studies have been descriptive in nature, designed to investigate static distribution of various epigenetic modifications in cells. Even though tremendous amount of information has been collected, we are still far from the complete understanding of epigenetic processes, their dynamics or even their direct effects on local chromatin and we still do not comprehend whether these epigenetic states are the cause or the consequence of the transcriptional profile of the cell. In this review, we try to define the concept of synthetic epigenetics and outline the available genome targeting technologies, which are used for locus-specific editing of epigenetic signals. We report early success stories and the lessons we have learned from them, and provide a guide for their application. Finally, we discuss existing limitations of the available technologies and indicate possible areas for further development. PMID- 25741389 TI - Air pollution and health: emerging information on susceptible populations. AB - Outdoor air pollution poses risks to human health in communities around the world, and research on populations who are most susceptible continues to reveal new insights. Human susceptibility to adverse health effects from exposure to air pollution can be related to underlying disease; demographic or anthropometric characteristics; genetic profile; race and ethnicity; lifestyle, behaviors, and socioeconomic position; and location of residence or daily activities. In health research, an individual or group may have an enhanced responsiveness to a given, identical level of pollution exposure compared to those who are less susceptible. Or, people in these different groups may experience varying levels of exposure (for example, a theoretically homogeneous population whose members differ only by proximity to a road). Often the information available for health research may relate to both exposure and enhanced response to a given dose of pollution. This paper discusses the general direction of research on susceptibility to air pollution, with a general though not an exclusive focus on particulate matter, with specific examples of research on susceptibility related to cardiovascular disease, diabetes, asthma, and genetic and epigenetic features. We conclude by commenting how emerging knowledge of susceptibility can inform policy for controlling pollution sources and exposures to yield maximal health benefit and discuss two areas of emerging interest: studying air pollution and its connection to perinatal health, as well as land use and urban infrastructure design. PMID- 25741390 TI - Impacts of travel activity and urbanicity on exposures to ambient oxides of nitrogen and on exposure disparities. AB - Daily exposures to ambient oxides of nitrogen were estimated here for residents of Hillsborough County, FL. The 2009 National Household Travel Survey provided geocoded data on fixed activity locations during each person-day sampled. Routes between activity locations were calculated from transportation network data, assuming the quickest travel path. To estimate daily exposure concentrations for each person-day, the exposure locations were matched with diurnally and spatially varying ambient pollutant concentrations derived from CALPUFF dispersion model results. The social distribution of exposures was analyzed by comparing frequency distributions of grouped daily exposure concentrations and by regression modeling. To investigate exposure error, the activity-based exposure estimates were also compared with estimates derived using residence location alone. The mean daily activity-based exposure concentration for the study sample was 17 MUg/m3, with values for individual person-day records ranging from 7.0 to 43 MUg/m3. The highest mean exposure concentrations were found for the following groups: black (20 MUg/m3), below poverty (18 MUg/m3), and urban residence location (22 MUg/m3). Urban versus rural residence was associated with the largest increase in exposure concentration in the regression (8.3 MUg/m3). Time in nonresidential activities, including travel, was associated with an increase of 0.2 MUg/m3 per hour. Time spent travelling and at nonresidential locations contributed an average of 6 and 24 %, respectively, to the daily estimate. A mean error of 3.6 %, with range from -64 to 58 %, was found to result from using residence location alone. Exposure error was highest for those who travel most, but lowest for the sociodemographic subgroups with higher mean exposure concentrations (including blacks and those from below poverty households). This work indicates the importance of urbanicity to social disparities in activity based air pollution exposures. It also suggests that exposure error due to using residence location may be smaller for more exposed groups. PMID- 25741392 TI - ERRATUM to the article published in The Open Dentistry Journal, 2015, volume (9): page 60-64. PMID- 25741391 TI - Evaluation of hemoglobin concentration in pregnancy and correlation with different altitude: a study from balochistan plateau of pakistan. AB - BACKGROUND: Anemia refers to a condition having low hemoglobin concentration. Anemia is considered a major risk factor for unfavorable pregnancy outcomes. This is the first study describing the pattern of hemoglobin concentration during pregnancy and its relationship to areas of high and low altitudes in Balochistan (the largest of Pakistan's four provinces). The main objective of this study was to observe hemoglobin levels and prevalence of anemia among pregnant women living in the high or low altitude areas of Balochistan. METHODS: A randomized survey was conducted and blood samples were collected from 132 healthy full term pregnant women subjects and 110 unmarried females. The subjects of the current study were selected from two different areas of Balochistan (Quetta and Uthal). Hemoglobin levels of the subjects were analyzed on Microlab 300 by Merck kit. Dietary status of the subjects was assessed based on simplified associated food frequency questionnaire. The factors effecting hemoglobin in full term pregnancy at different altitudes were multi gravidity/parity (increased number of pregnancies/children), age, socio-economic and educational status. RESULTS: Anemia was highly prevalent in low-altitude region (68.33%). We found statistically significant difference in mean hemoglobin level at high-altitude region (11.81 +/- 1.02) and low-altitude region (10.20 +/- 1.28) in pregnant females of Balochistan plateau (P < 0.001). Higher maternal age (> 35 years) has shown significantly higher anemic frequency at both high (57.89%; p < 0.002) and low (41.46%; p = 0.067) altitudes. A balanced-diet that is rich in meat products has also shown significant correlation with reduced incidences of anemia among pregnant women at both altitudes. CONCLUSION: Hemoglobin concentration increases in the body with elevated altitudes and, thus, anemia was less frequent at high altitude region. Factors affecting hemoglobin concentration in full term pregnancy at different altitudes included old maternal age, low body-mass index, education and diet. PMID- 25741393 TI - Viral Profile of COPD Exacerbations According to Patients. AB - BACKGROUND: To compare the differences between elderly and non-elderly patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) due to viral infections. METHODS: Patients with chronic obstructive pulmonary disease (COPD) exacerbation were recruited and classified as elderly (>65 years) and non elderly (<= 65 years). Sputum and oropharyngeal samples were assessed, PCR for respiratory viruses and cultures for common pathogens were performed. RESULTS: 247 patients (median age: 69.3+/-9.5 years) were recruited and categorized into group A: non-elderly patients [n=81 (32.8%), median age 58+/-5.99] and group B: elderly patients [n=166 (67.2%), median age 74.8+/-4.8] years. In 133 (53.8%) patients a viral infection was identified and in 34 (13.8%) a bacterial pathogen was isolated from cultures. In 18 (7.3%) patients a double infection (bacterial+viral) was identified. In group B, the presence of cardiac failure (46.6% vs 28.3%, p<0.001), renal failure (10.5% vs 4%, p=0.03), bacterial co infection (13.8% vs 7.4%, p=0.04), influenza vaccination rates (45.5% vs 215, p<0.001), and longer hospital stay (8.4+/-4.4 vs 7.5+/-3.2 days, p=0.02) were higher than group A. The overall rate of viral infections did not differ according to age. A trend to higher rates of infection with parainfluenza 3 [19 (20%) patients in group B vs3 (7.5%) patients in group A, p=0.04] was observed in older patients. CONCLUSION: No differences on the rate and type of viral infections were noted for elderly vs non elderly patients. However, they tended to have more bacterial co-infections that led to AECOPD and longer hospitalization stays compared to non-elderly patients. PMID- 25741394 TI - Physical activity in adults with cystic fibrosis receiving intravenous antibiotics in hospital and in the community. AB - INTRODUCTION: Intravenous antibiotic therapy (IVAT) for CF acute pulmonary exacerbations (APE) can be delivered in hospital or in the community. This study aimed to compare physical activity in CF patients receiving hospital and community-delivered IVAT, as well as other health outcomes. MATERIALS AND METHODS: This was a non-randomised parallel group prospective observational study. Hospitalised and community-treated CF adults receiving IVAT for APE were asked to wear ActiGraph(r) activity monitors, complete the habitual activity estimation scale (HAES), food diary, modified shuttle test (MST) and CFQ-R at the start and end of therapy. Nutritional and clinical outcomes were also compared between the cohorts. The primary outcomes was physical activity measured by the ActiGraph(r) activity monitors at the beginning and end of treatment in both cohorts. RESULTS: Physical activity (measured and self-reported) was no different between the cohorts, with both hospitalised and community-treated subjects being generally sedentary. Body weight increased significantly in the hospitalised cohort, whereas no difference was seen in the community-treated cohort. FEV1 % predicted and FVC % predicted increased in community-treated subjects, whereas only FVC % predicted increased in hospitalised subjects. CFQ-R respiratory domain increased to a greater extent in community-treated subjects. CONCLUSION: CF adults receiving IVAT for APE, both in hospital and in the community, are generally sedentary and we found no difference in physical activity between the two groups. These findings suggests the need to further promote physical activity in suitable patients during APE where considered appropriate. PMID- 25741395 TI - Specific densified regions in the postlaminar human glaucomatous optic nerve. AB - PURPOSE: To describe 'densified regions' in human postlaminar optic nerves of donors with the clinical diagnosis of primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma (PEXG). METHODS: Optic nerves of 25 eyes with POAG and of 19 eyes with PEXG were investigated. Clinical data and axon counts of Epon embedded semi-thin sections were used to determine the stage of the disease. Ultrathin sections were performed of selected areas and studied with an electron microscope. Immunofluorescence staining of paraffin sections was performed including antibodies against glial fibrillary acidic protein (GFAP), neural cellular adhesion molecule, vimentin and laminin. RESULTS: Early changes in both types of glaucoma showed increased numbers of areas with a densified appearance. The lack of GFAP staining and of ultrastructurally light nuclei within these areas indicated loss of astroglia. CONCLUSION: For the first time, a special type of neurodegeneration in optic nerves with mild glaucomatous changes is described. PMID- 25741397 TI - The ABCDEF Rule: Combining the "ABCDE Rule" and the "Ugly Duckling Sign" in an Effort to Improve Patient Self-Screening Examinations. PMID- 25741398 TI - Comparison of the Distribution of Morphological Disorganization of Pigmented Lesions in a Community-based Practice versus a University-based Clinical Setting as Measured by a Multispectral Digital Skin Lesion Analysis Device: Impact on Diagnosis. AB - OBJECTIVE: To observe how a multispectral digital skin lesion analysis device was used by dermatologists in a community-based clinical setting and determine differences from a university-based environment. DESIGN: Use of multispectral digital skin lesion analysis was incorporated into a community-based practice by 12 dermatologists across six clinics over seven consecutive days with the data provided by the device integrated as an adjuvant to their clinical evaluation for their pigmented lesion management decisions. Multispectral digital skin lesion analysis results were collected electronically for lesions prior to biopsy, and histopathological evaluation was performed for the biopsied lesions. Multispectral digital skin lesion analysis and pathology results were then compared to assess the degree of morphological disorganization. SETTING/PARTICIPANTS: Study of 160 consecutive patients in community-based clinical setting. MEASUREMENTS: Proportion of "low" and "high" disorganization lesions identified by multispectral digital skin lesion analysis. RESULTS: Of the 344 pigmented skin lesions analyzed by multispectral digital skin lesion analysis, 255 were high disorganization, 113 of which were biopsied. Of the 89 lesions evaluated by multispectral digital skin lesion analysis to be low disorganization, seven were biopsied and all pathology was benign. Data demonstrate a higher rate of multispectral digital skin lesion analysis low disorganization readings for pigmented skin lesions (32% for single use per patient lesions, p<0.0001; 26% for all lesions, p<0.0001) than observed in the pigmented lesions clinics providing data for the university-based clinical study (10%). CONCLUSION: Multispectral digital skin lesion analysis in the community based clinical setting may outperform specificity results from the university based clinical trial study, perhaps because of a higher proportion of subtle lesions encountered at high-risk pigmented lesion clinics of participating major academic centers as compared with those in a community-based practice setting. PMID- 25741396 TI - Lipid Signaling in Tumorigenesis. AB - Lipids are important cellular building blocks and components of signaling cascades. Deregulation of lipid metabolism or signaling is frequently linked to a variety of human diseases such as diabetes, cardiovascular diseases, and cancer. It is widely believed that lipid molecules or their metabolic products are involved in tumorigenic inflammation and thus, lipids are implicated as significant contributors or even primary triggers of tumorigenesis. Lipids are believed to directly or indirectly activate growth promoting signals such as those involving LPA, insulin, IGF-1 and EGF to promote cancer cell growth. Cellular levels of certain lipids, including sphingosine-1-phosphate and ceramide, maintain a delicate balance between cell death and survival and alterations in their levels lead to unfavorable consequences including tumorigenesis. This article provides an overview of current knowledge that implicates lipids in tumorigenesis and explores the potential mechanisms that support a positive link between obesity and cancer. PMID- 25741399 TI - Safety and Efficacy of Oral Polypodium leucotomos Extract in Healthy Adult Subjects. AB - OBJECTIVE: The objective of this study was to determine the safety of oral Polypodium leucotomos extract administered twice daily to healthy adults for 60 days and assess its ability to provide protection against exposure to ultraviolet radiation. DESIGN: This was a randomized, double-blind, placebo-controlled study. SETTING: A single clinical research center. PARTICIPANTS: Healthy adult men and women between 18 and 65 years of age with Fitzpatrick skin types I to IV. MEASUREMENTS: Safety assessments included a physical examination, vital signs, and clinical laboratory parameters including hematology, comprehensive metabolic panel, and prothrombin time-partial thromboplastin time were obtained at baseline and at the end of the study. Reports of adverse events were recorded. Efficacy assessments were changes in minimal erythema dose testing, ultraviolet-induced erythema intensity response, and sunburn history during the prior 60 days. RESULTS: After two months of treatment, there were no changes in any safety assessments. The subjects in the placebo group showed a greater likelihood of experiencing >1 episodes of sunburn (2 vs. 8 subjects; p=0.04) At Day 28, Polypodium leucotomos extract-treated subjects showed greater likelihood of an increased minimal erythema dose (8 vs. 1 subject; p=0.01) and greater likelihood of decreased ultraviolet-induced erythema intensity (10 subjects vs. 3 subjects; p<0.01). CONCLUSION: Polypodium leucotomos extract 240mg taken twice daily for 60 days was a safe and effective means for reducing the damaging effects of ultraviolet radiation. Based on the excellent safety profile of Polypodium leucotomos, additional studies using higher doses may be warranted. PMID- 25741400 TI - Fast Absorbing Gut Suture versus Cyanoacrylate Tissue Adhesive in the Epidermal Closure of Linear Repairs Following Mohs Micrographic Surgery. AB - BACKGROUND: Cyanoacrylate topical adhesives and fast absorbing gut sutures are increasingly utilized by dermatologic surgeons as they provide satisfactory surgical outcomes while eliminating an additional patient visit for suture removal. To date, no head-to-head studies have compared the wound healing characteristics of these epidermal closure techniques in the repair of facial wounds after Mohs micrographic surgery. OBJECTIVE: To compare the cosmetic outcome of epidermal closure by cyanoacrylate topical adhesive with fast absorbing gut suture in linear repairs of the face following Mohs micrographic surgery. METHODS: Fourteen patients with wound length greater than 3cm who underwent Mohs micrographic surgery for nonmelanoma skin cancer of the face were enrolled in this randomized right-left comparative study. Following placement of dermal sutures, half of the wound was randomly selected for closure with cyanoacrylate and the contralateral side with fast absorbing gut suture. Using photographs from the three-month postoperative visit, six blinded individuals rated the overall cosmetic outcome. RESULTS: The present study shows no significant difference in cosmetic outcomes between cyanoacrylate and fast absorbing gut suture for closure of linear facial wounds resulting from Mohs micrographic surgery. Cyanoacrylate tissue adhesive may not be as effective in achieving optimal cosmesis for wounds on the forehead or of longer repair lengths. The majority of patients did not have a preference for wound closure techniques, but when a preference was given, cyanoacrylate was significantly favored over sutures. CONCLUSION: Cyanoacrylate tissue adhesive and fast absorbing gut suture both result in comparable aesthetic outcomes for epidermal closure of linear facial wounds following Mohs micrographic surgery. Consideration should be given to factors such as need for eversion, hemostasis, and wound tension when selecting an epidermal wound closure method. (ClinicalTrials.gov, Identifier: NCT01298167, http://clinicaltrials.gov/show/NCT01298167). PMID- 25741401 TI - Biologic safety in psoriasis: review of long-term safety data. AB - The development of targeted biologic agents has revolutionized the treatment of psoriasis. In this review, the authors focus on the published long-term (>= one year) safety data for the use of tumor necrosis factor-alpha antagonists etanercept, infliximab, and adalimumab, as well as the IL-12/IL-23 antagonist ustekinumab, in adult patients with moderate-to-severe psoriasis. The efficacy of these currently available biologic therapies has been demonstrated in several studies, and their safety profiles are also reassuring. PMID- 25741402 TI - A review of common tanning methods. AB - Tanning in the United States has become an increasingly popular activity in our culture. Tanning methods have evolved through the years to become more readily accessible and easier to use for all consumers, regardless of geographic location. With the rising incidence of skin cancer, the demand for safe and efficient tanning methods remains high. There are currently many different tanning methods being utilized, and still more are being researched. This article serves to summarize some of the most common tarining methods used in the United States today as well as some potential methods currently under study. PMID- 25741403 TI - Real-life effectiveness of topical vitamin d and corticosteroid combination therapy in psoriasis : moving beyond clinical trials. AB - To provide successful care for psoriasis patients, treatments must be efficacious and safe as well as improve the patients' overall well-being. Efficacy and safety are generally established by randomized, controlled clinical trials. However, because of the rigid conditions under which randomized, controlled clinical trials are conducted, they do not reflect patient experience in real-life clinical practice; that is, they do not measure treatment effectiveness in the real world. Factors such as adherence to therapy, treatment satisfaction, and quality of life may be rated unrealistically high in randomized, controlled clinical trials. Observational studies using real-life patient populations, and capturing patient-reported outcomes, are useful at better assessing a treatment's effectiveness. Healthcare professionals and payers may gain valuable insights from patient-reported outcomes data that can be used in making treatment decisions. For localized plaque psoriasis, topical vitamin D analog and corticosteroid combination therapy is recommended as a first-line treatment. This commentary addresses the concept of clinical trial efficacy versus real-life effectiveness in psoriasis treatment using vitamin D and corticosteroid topical combination therapy as a model. PMID- 25741404 TI - Blue-violet light irradiation dose dependently decreases carotenoids in human skin, which indicates the generation of free radicals. AB - In contrast to ultraviolet and infrared irradiation, which are known to facilitate cutaneous photoaging, immunosuppression, or tumour emergence due to formation of free radicals and reactive oxygen species, potentially similar effects of visible light on the human skin are still poorly characterized. Using a blue-violet light irradiation source and aiming to characterize its potential influence on the antioxidant status of the human skin, the cutaneous carotenoid concentration was measured noninvasively in nine healthy volunteers using resonance Raman spectroscopy following irradiation. The dose-dependent significant degradation of carotenoids was measured to be 13.5% and 21.2% directly after irradiation at 50 J/cm2 and 100 J/cm2 (P < 0.05). The irradiation intensity was 100 mW/cm2. This is above natural conditions; the achieved doses, though, are acquirable under natural conditions. The corresponding restoration lasted 2 and 24 hours, respectively. The degradation of cutaneous carotenoids indirectly shows the amount of generated free radicals and especially reactive oxygen species in human skin. In all volunteers the cutaneous carotenoid concentration dropped down in a manner similar to that caused by the infrared or ultraviolet irradiations, leading to the conclusion that also blue-violet light at high doses could represent a comparably adverse factor for human skin. PMID- 25741405 TI - Association of the apolipoprotein E 2 allele with concurrent occurrence of endometrial hyperplasia and endometrial carcinoma. AB - Genes encoding proteins with antioxidant properties may influence susceptibility to endometrial hyperplasia (EH) and endometrial carcinoma (ECa). Patients with EH (n = 89), EH concurrent with ECa (n = 76), ECa (n = 186), and healthy controls (n = 1110) were genotyped for five polymorphic variants in the genes involved in metabolism of lipoproteins (APOE Cys112Arg and Arg158Cys), iron (HFE Cys282Tyr and His63Asp), and catecholamines (COMT Val158Met). Patients and controls were matched by ethnicity (all Caucasians), age, body mass index (BMI), and incidence of hypertension and diabetes. The frequency of the APOE E 2 allele (158Cys) was higher in patients with EH + ECa than in controls (P = 0.0012, P(Bonferroni) = 0.018, OR = 2.58, 95% CI 1.49-4.45). The APOE E 4 allele (112Arg) was more frequently found in patients with EH than in controls and HFE minor allele G (63Asp) had a protective effect in the ECa group, though these results appeared to be nonsignificant after correction for multiple comparisons. The results of the study indicate that E 2 allele might be associated with concurrent occurrence of EH and ECa. PMID- 25741406 TI - Cancer as a Criterion A Traumatic Stressor for Veterans: Prevalence and Correlates. AB - The diagnosis of cancer is an uncontrollable stressor posing the threat of death and disfigurement, often followed by repeated exposure to aversive reminders in the form of noxious treatments, persisting side effects, reengagement at times of surveillance, and the threat of recurrence. The phenomenon of cancer as a traumatic stressor is explored in this study, with a focus on the prevalence and correlates of posttraumatic stress disorder (PTSD) Criterion A in a sample of 170 mostly male adults who received health care at VA Medical Centers in Boston or Houston. Participants were interviewed 6 months after diagnosis with head and neck, gastro-esophageal, or colorectal cancers. Approximately half-42.9% to 65.9% depending on cut-score used-perceived cancer to be a traumatic stressor involving actual/threatened death or injury or threat to physical integrity as well as fear, helplessness, or horror. Younger veterans and those with current combat PTSD symptoms were more likely to perceive cancer as a traumatic stressor, as were those who perceived their prognosis as uncertain; 12% had PTSD symptoms above a PCLC cut score of 50, which is similar to incidence rates of PTSD associated with other traumatic stressors. Cancer, therefore, appears to be a serious and for some, traumatic stressor, suggesting the importance of screening for cancer related PTSD in cancer survivors, particularly those most at risk. PMID- 25741407 TI - SEGMENTATION-FREE MEASURING OF CORTICAL THICKNESS FROM MRI. AB - Estimating the thickness of cerebral cortex is one of the most essential measurements performed in MR brain imaging. In this work we present a new approach to measure the cortical thickness which is based on minimizing line integrals over the probability map of the gray matter in the MRI volume. Previous methods often perform a pre-segmentation of the gray matter before measuring the thickness. Considering the noise and the partial volume effects, there are underlying class probabilities allocated to each voxel that this hard classification ignores, a result of which is a loss of important available information. Following the introduction of the proposed framework, the performance of our method is demonstrated on both artificial volumes and real MRI data for normal and Alzheimer affected subjects. PMID- 25741408 TI - Ambient pollution and respiratory outcomes among schoolchildren in Durban, South Africa. AB - OBJECTIVE: To examine associations between ambient air pollutants and respiratory outcomes among schoolchildren in Durban, South Africa. METHODS: Primary schools from within each of seven communities in two regions of Durban (the highly industrialised south compared with the non-industrial north) were selected. Children from randomly selected grade 4 classrooms were invited to participate. Standardised interviews, spirometry, methacholine challenge testing and skin prick testing were conducted. Particulate matter (PM), sulphur dioxide (SO2) and carbon monoxide were monitored at each school, while nitrogen oxides (NOx) and other pollutants were monitored at other sites. RESULTS: SO2 was significantly higher in the south than in the north, while PM concentrations were similar across the city. The prevalence of symptoms consistent with asthma of any severity was 32.1%. Covariate-adjusted prevalences were higher among children from schools in the south than among those from the north for persistent asthma (12.2% v. 9.6 %) and for marked airway hyperreactivity (AHR) (8.1% v. 2.8%), while SO2 resulted in a twofold increased risk of marked AHR (95% confidence interval 0.98 - 4.66; p=0.056). CONCLUSIONS: Schoolchildren from industrially exposed communities experienced higher covariate-adjusted prevalences of persistent asthma and marked AHR than children from communities distant from industrial sources. Our findings are strongly suggestive of industrial pollution related adverse respiratory health effects among these children. PMID- 25741409 TI - Comparison of Effect of One Course of Intense Exercise (Wingate test) on Serum Levels of Interleukin-17 in Different Groups of Athletes. AB - BACKGROUND: Research on the effects of exercise on immune function, has a wide range of sporting activities. Study on the long-term effects of regular exercise on serum levels of cytokines such as interleukin-17 have shown that moderate and regular exercise, has an important role in the prevention and treatment of many diseases. OBJECTIVES: Exhaustive exercise has a deep effect on cellular, humoral, innate immunity and the amount of cytokines of an athlete's immune system. So this study was designed to compare the effect of one course of exhaustive exercise on serum levels of interleukin (IL)-17 in different groups of athletes. PATIENTS AND METHODS: Forty professional athletes with a mean age of 25.1 +/- 5.0 years, divided equally in 4 groups (handball, volleyball, Sepak-takraw and climbing) were selected for this purpose. 30 second Wingate test for each athlete was used to assess anaerobic power. Blood samples before, immediately after and 2 hours after exercise was collected and the amount of serum IL-17 was measured. RESULTS: The results showed that the level of IL-17 in the study groups before and after the two hours exercise did not significantly change in all four groups. CONCLUSIONS: The results showed that short anaerobic exercise has no effect on the level of IL-17. PMID- 25741410 TI - Designing an electronic personal health record for professional Iranian athletes. AB - BACKGROUND: By providing sports organizations with electronic records and instruments that can be accessed at any time or place, specialized care can be offered to athletes regardless of injury location, and this makes the follow-up from first aid through to full recovery more efficient. OBJECTIVES: The aim of this study was to develop an electronic personal health record for professional Iranian athletes. PATIENTS AND METHODS: First, a comparative study was carried out on the types of professional athletes'existing handheld and electronic health information management systems currently being used in Iran and leading countries in the field of sports medicine including; Australia, Canada and the United States. Then a checklist was developed containing a minimum dataset of professional athletes' personal health records and distributed to the people involved, who consisted of 50 specialists in sports medicine and health information management, using the Delphi method. Through the use of data obtained from this survey, a basic paper model of professional athletes' personal health record was constructed and then an electronic model was created accordingly. RESULTS: Access to information in the electronic record was through a web-based, portal system. The capabilities of this system included: access to information at any time and location, increased interaction between the medical team, comprehensive reporting and effective management of injuries, flexibility and interaction with financial, radiology and laboratory information systems. CONCLUSIONS: It is suggested that a framework should be created to promote athletes' medical knowledge and provide the education necessary to manage their information. This would lead to improved data quality and ultimately promote the health of community athletes. PMID- 25741411 TI - Anthropometric characteristics and physical performance of colombian elite male wrestlers. AB - BACKGROUND: Wrestling was an important part of the ancient Olympic Games and is still one of the most popular events of the modern Olympic Games. Studies indicate that general physiologic profile of successful wrestlers is high anaerobic power and capacity, muscular strength, above average aerobic power, exceptional flexibility, fat free mass, and a mesomorphic somatotype. OBJECTIVES: The objective of the present study was to evaluate anthropometric characteristics and physical performance of elite male wrestlers. PATIENTS AND METHODS: The Colombian Wrestling Team was evaluated while in preparation for the Olympic Games (n = 21; age, 27.9 +/- 6.7 years). Athletes were tested on anthropometric and fitness parameters: body composition, somatotype distribution according to Heath Carter, aerobic capacity, vertical jump, and anaerobic power. RESULTS: The evaluations showed a mean body fat percentage of 13.6% +/- 3.0% (95% CI, 12.2% 15%), muscle mass of 46.4% +/- 2.2% (95% CI, 45.4%-47.4%), Ponderal index of 41.0 +/- 1.8 (95% CI, 40.2-41.8), body adiposity index (BAI) 25.1 +/- 3.6 (95% CI, 23.5-26.8), and somatotype distribution mesomorphic-ectomorph (5.3-1.6-3.8). Mean aerobic capacity was 45.9 +/- 6.6 mL/kg/min (95% CI, 42.8-48.9), vertical jump was 36.4 +/- 6.6 cm (95% CI, 11.8-16.6), and anaerobic power was 92.6 +/- 19.5 kg/s (95% CI, 83.7-101.5). CONCLUSIONS: These results provided a profile of elite wrestlers that could be used as training targets for developing athletes. The results may also provide information for training and tactical planning. PMID- 25741412 TI - Lifespan perspective of professional footballers' health. PMID- 25741413 TI - Recovery of powerful kick biomechanics after intense running fatigue in male and female soccer players. AB - BACKGROUND: Fatigue seems to have a significant effect on soccer kick performance. However, the duration of these effects has not been previously investigated. OBJECTIVES: The purpose of the present study was to investigate the duration of the acute effects of fatigue on soccer kick performance in males and females. PATIENTS AND METHODS: Ten male (age: 26.3 +/- 4.9 years, height: 178.1 +/- 5.1 cm, mass: 81.3 +/- 8.1 kg) and ten female (age: 24.4 +/- 4.2 years, height: 169.7 +/- 5.7 cm, mass: 61.8 +/- 5.1 kg) amateur soccer players performed three instep kicks prior to and after running on a treadmill till exhaustion. Three-dimensional kinematics were collected pre- and post-fatigue. RESULTS: Analysis of variance indicated a statistically significant decline in ball speed during the first and the second trial after fatigue (P < 0.05), but recovered to pre-fatigue levels during the third post-fatigue kicking trial (P > 0.05). Similarly, maximum ankle, knee and hip linear velocity and ankle angular displacement were significantly lower during the first two trials (P < 0.05), but not during the third trial after fatigue (P > 0.05). CONCLUSIONS: Soccer kick parameters recovered to pre-fatigue levels approximately within a minute after the end of the protocol. These findings have a practical meaning for players who have to perform set piece kicks under fatigue conditions and for coaches who have to guide their players. PMID- 25741415 TI - Acute shortness of breath in an adult. PMID- 25741414 TI - Return to rugby after brain concussion: a prospective study in 35 high level rugby players. AB - BACKGROUND: Although guidelines based on expert opinions have been developed for the immediate management and return to play of athletes after a concussion, data are lacking on this issue. OBJECTIVES: Evaluate a standardized management of brain concussion among rugby players to prevent the recurrence. PATIENTS AND METHODS: A prospective study was performed from September 2009 to June 2012. All rugby players who had a concussion when playing rugby were included. Patients were managed by a specialized hospital team with a specific protocol developed in collaboration with the medical staff of the rugby clubs included in the study. The series included 35 rugby players, with 23 professionals and 12 high-level players, 30 men and 5 women, mean age 23.1 +/- 5.5 years old. The median number of previous concussions was 2 (0-30) episodes. According to the Cantu concussion severity classification, 3 athletes were grade 1, 12 were grade 2 and 20 were grade 3. None of the injured athletes was lost to follow-up. The primary endpoint was the occurrence of a new concussion within 3 months after the first in patients who returned to rugby. RESULTS: Thirty-three patients returned to rugby after a mean 22.1 +/- 10 days. The recurrence rate within 3 months was 2/33 (6.1%). The median delay before returning to rugby was 21 (7-45) days. Factors associated with a delayed return to play were young age, initial loss of consciousness, severity Cantu grade 3 and post-concussive syndrome of more than 5 days. Analysis of two failures showed that the initial injury was grade 3 and that both were professional athletes and had a history of concussion. CONCLUSIONS: This prospective study validated the study protocol for the management of concussion in rugby players. PMID- 25741416 TI - Myocardial scar detected by cardiovascular magnetic resonance in a competitive bodybuilder with longstanding abuse of anabolic steroids. AB - INTRODUCTION: The self-administration intake of anabolic-androgenic steroids (AAS) is a widespread practice in competitive bodybuilders. Structural changes within the myocardium following AAS abuse including hypertrophy, restricted diastolic function as well as systolic dysfunction and impaired ventricular inflow have been reported. CASE PRESENTATION: We present the case of a 39-year old bodybuilder with a more than 20-year history of anabolic-androgenic steroids (AAS) abuse presenting with increasing exertional dyspnoea and fatigue. Diagnostic work-up of the patient's current symptoms included a cine cardiovascular magnetic resonance (CMR). Using a T1-weighted inversion-recovery sequence 10 minutes after application of 0.1 mmol/kg gadolinium with diethylenetriaminepentaacetic acid (gadolinium DTPA), patchy midwall enhancement in the septal and posterolateral region of the left ventricle was demonstrated. This enhancement pattern is different from the enhancement pattern found in patients with ischemic heart disease. CONCLUSIONS: The present case illustrates for the first time, by CMR, myocardial scarring with severe left ventricular hypertrophy in a patient with normal coronary arteries after long lasting abuse of AAS. With that finding we could demonstrate a link between AAS abuse and the occurrence of myocardial scarring in humans. This finding may help raise awareness of the consequences of AAS use. PMID- 25741417 TI - Low back pain functional disability in athletes; conceptualization and initial development of a questionnaire. AB - BACKGROUND: Low Back Pain (LBP) is one of the most prevalent causes of disability not only in the general population but also in athletes. Despite a large number of self-reported back specific disability questionnaires, there is no specific, well documented, outcome measure for athletes suffering from back pain. OBJECTIVES: This study aimed to identify the main descriptive themes representing functional disability in athletes due to LBP. PATIENTS AND METHODS: We conducted a qualitative study using in-depth interviews to characterize the experiences of athletes with LBP. Twenty athletes with LBP were recruited and the main descriptive elements of their LBP related disability were extracted. Then a preliminary questionnaire using these themes was proposed. RESULTS: The main disability indicators were pain intensity; stretching exercises, strengthening exercises, sport specific skills, back range of motion (ROM), sitting, walking, sleep patterns, self-care, and recreational activities, fear of pain and avoidance behavior, and changes in sexual activity. CONCLUSIONS: The findings of this study suggest that apart from non-sports items, some sport related items should be included in the assessment of LBP disability levels in athletes. Our results have also been organized as a preliminary LBP disability questionnaire for athletes. PMID- 25741418 TI - An exploratory examination of the association between altered lumbar motor control, joint mobility and low back pain in athletes. AB - BACKGROUND: Low back pain (LBP) is a common cause of lost playing time and can be a challenging clinical condition in competitive athletes. LBP in athletes may be associated with joint and ligamentous hypermobility and impairments in activation and coordination of the trunk musculature, however there is limited research in this area. OBJECTIVES: To determine if there is an association between altered lumbar motor control, joint mobility and low back pain (LBP) in a sample of athletes. MATERIALS AND METHODS: Fifteen athletes with LBP were matched by age, gender and body mass index (BMI) with controls without LBP. Athletes completed a questionnaire with questions pertaining to demographics, activity level, medical history, need to self-manipulate their spine, pain intensity and location. Flexibility and lumbar motor control were assessed using: active and passive straight leg raise, lumbar range of motion (ROM), hip internal rotation ROM (HIR), Beighton ligamentous laxity scale, prone instability test (PIT), observation of lumbar aberrant movements, double leg lowering and Trendelenburg tests. Descriptive statistics were compiled and the chi square test was used to analyze results. RESULTS: Descriptive statistics showed that 40% of athletes with LBP exhibited aberrant movements (AM), compared to 6% without LBP. 66% of athletes with LBP reported frequently self-manipulating their spine compared to 40% without LBP. No significant differences in motor control tests were found between groups. Athletes with LBP tended to have less lumbar flexion (63 +/- 11 degrees ) compared to those without LBP (66 +/- 13 degrees ). Chi-Square tests revealed that the AM were more likely to be present in athletes with LBP than those without (X2 = 4.66, P = 0.03). CONCLUSIONS: The presence of aberrant movement patterns is a significant clinical finding and associated with LBP in athletes. PMID- 25741419 TI - Spine surgery in athletes with low back pain-considerations for management and treatment. AB - While degenerative lumbar spine conditions are common in the general population, there are unique considerations when diagnosed in high-level athletes. Genetic factors have been identified as a more significant contributor to the development of degenerative disc disease than occupational risks, however, some have postulated that the incessant training of young, competitive athletes may put them at a greater risk for accelerated disease. The evidence-based literature regarding lumbar disc herniation in elite athletes suggests that it is reasonable to expect excellent clinical outcomes and successful return-to-sport after either operative or non-operative treatment regardless of sport played. However, those athletes who require repetitive torque on their lumbar spines may have poorer long-term outcomes if surgical treatment is required for this condition. Painful spondylolysis in the athlete can often be treated successfully with non-operative treatment, however, if surgery is required, pars repair techniques provides a motion-sparing alternative that may lead to successful return to sport. PMID- 25741420 TI - Golf-related low back pain: a review of causative factors and prevention strategies. AB - Golf is a popular sport with both perceived and real health benefits. However, certain injury risks are also prevalent, particularly to the lower back. Epidemiological studies have shown that lower back pain (LBP) from golf account for between 18% and 54% of all documented ailments, leading many researchers to regard the condition as the most common golf injury. The purpose of this review was to examine the scientific literature to ascertain the risk factors associated with the development of LBP from playing golf and suggest methods to modify or limit these factors. Results of the review indicate that the high frequency of LBP appears multi-factorial although the asymmetrical and forceful nature of the swing along with excessive play and practice, particularly amongst elite players, appear to be common factors. Other factors include swing flaws leading to excessive side-bend and over-rotation of the spine, abnormal muscle recruitment, poor trunk endurance, restricted lead hip internal rotation and the use of unnecessarily stressful club transportation methods. Methods to help control or eliminate excessive stress on the lower back would include reducing the amount spent playing or practicing, seeking professional assistance to assess and adjust swing mechanics, improve trunk and hip flexibility, increase the strength and endurance of the trunk musculature, consider different footwear options and avoid carrying the golf bag. Adopting some or all of these recommendations should allow players to continue to enjoy the sport of golf well into their senior years. PMID- 25741421 TI - Are Fast-Bowlers Prone to Back Injuries? Prevalence of Lumbar Spine Injuries in Fast-Bowlers: Review of MRI-Based Studies. AB - BACKGROUND: Fast-bowlers in cricket subject their spines to repetitive stress. OBJECTIVES: The aim of this study was to review the prevalence of lumbar spine injuries among fast-bowlers. MATERIALS AND METHODS: Medline and embase searches were performed. Further, the authors canvassed the reference list of available articles and used other search engines such as Google Scholar to identify a total of nine studies. RESULTS: The prevalence of lumbar disc degeneration in fast bowlers ranges from 21-65% with an incidence rate of 15% per year, and the prevalence of lumbar spine bony abnormalities ranges from 24-81%. Factors associated with lumbar spine injury in fast-bowlers are classified into un modifiable (age) and modifiable (more intense bowling workload and mixed-bowling technique). CONCLUSIONS: Fast-bowlers have a high prevalence of lumbar spine injuries. Appropriate interventions, such as educational sessions, may be able to modify risk factors such as bowling workload and bowling technique and thus reduce injury prevalence. PMID- 25741422 TI - Lower back injuries in rowing national level compared to international level rowers. AB - BACKGROUND: Rowing injuries are common, with lower back injuries having the highest incidence. OBJECTIVES: This study was to investigate the major rowing injuries seen at a single high performance rowing sports program over a 5 years training period and establish if any relationship exists between these injuries and the level of competition that the rower is partaking in. PATIENTS AND METHODS: All rowers at the South Australian Sports Institute (SASI) programs were designated as being either international or national level rowers. Injuries that caused greater than 5 days training loss during any one training year were recorded. The number of lower back injuries and rib stress injuries causing training time loss were analysed to assess whether there was any association between the level of rower and the nature and type of injury causing training time loss. RESULTS: Forty-five national rowers (97 training years) had 15 lower back injuries compared to 12 international rowers 35 training years) with 1 lower back injury. Thus a national level rower was more likely to have a lower back injury compared to an international rower P = 0.05. In contrast an international level was more likely to have a rib stress fracture compared to a national rower P = 0.04. 21% of all injuries in this study were a consequence of cycling injuries. CONCLUSIONS: Lower back injuries are a significant cause of training time lost in rowers. These injuries are much more likely to occur in national level rowers when compared to international level rowers. In contrast rib stress injuries are associated with international compared to national level rowers. PMID- 25741423 TI - U.S. Cohort Differences in Body Composition Outcomes of a 6-Month Pedometer-Based Physical Activity Intervention: The ASUKI Step Study. AB - BACKGROUND: Regular physical activity (PA) enhances health and is an important factor in disease prevention and longevity. The 2008 U.S. Physical Activity Guidelines recommends that all healthy adults attain at least 150 minutes per week of moderate intensity aerobic PA (e.g., brisk walking) to maintain and promote PA. OBJECTIVES: This study determined the effects of a 6-month pedometer based worksite walking intervention with participants focusing on a goal of achieving 10,000 steps per day, on body composition in adults with a wide range of body mass index (BMI) values and compares the changes with outcomes of similar studies. MATERIALS AND METHODS: The design was a single group, quasi-experimental study. All participants received a pedometer and were asked to register the daily number of steps. Men and women (n = 142; age = 41 +/- 11.5 years; BMI = 27.2 +/- 7.25 kg.m(-2)) received body composition measures at 1, 3, and 6 months. A multilevel growth modeling approach was used to explore change over time and to predict change by steps, age, gender, and fat category categorized as normal and overweight/obese. RESULTS: Significant individual differences in linear slopes and change over time were observed for waist circumference (WC) (-3.0 cm) only in unconditional model (t = -0.67, P = 0.02). CONCLUSIONS: A 3.0 cm loss in WC shows that a 10,000 step per day walking program has the potential to influence changes in body composition measures that are correlated with adverse health outcomes. While significant changes did occur there are some limitations. The analysis did not consider the data regarding completing of 10,000 steps per day and other potential factors that could influence the results. Compliance to the walking dose and initial physical activity and body composition levels are important to consider when studying body composition changes in such programs. PMID- 25741424 TI - Seminal Levels of Pro-inflammatory (CXCL1, CXCL9, CXCL10) and Homeostatic (CXCL12) Chemokines in Men With Asymptomatic Chlamydia trachomatis Infection. AB - BACKGROUND: Chemokines play important roles in immune system activation against microbial infections. OBJECTIVES: The current study aimed to evaluate seminal levels of CXC chemokines CXCL1, CXCL9, CXCL10 and CXCL12 in Chlamydia trachomatis infected patients. MATERIALS AND METHODS: The C. trachomatis infection was determined employing Polymerase Chain Reaction (PCR)-based methods. Seminal concentrations of CXCL1, CXCL9, CXCL10 and CXCL12 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: The current study results demonstrated that the semen levels of CXCL1 and CXCL9, but not CXCL10 and CXCL12, significantly increased in C. trachomatis infected patients compared to the healthy controls. CONCLUSIONS: Based on the current study results, it may be concluded that both CXCL1 and CXCL9 play more important roles than CXCL10 and CXCL12 in induction of immune responses against C. trachomatis and could possibly be considered as future targets for immunotherapy of C. trachomatis infection. PMID- 25741425 TI - Characterizing novel thermophilic amylase producing bacteria from taptapani hot spring, odisha, India. AB - BACKGROUND: Amylases play a vital role in biotechnological studies and rank an important position in the world enzyme market (25% to 33%). Bioprocess method of amylase production is more effective than the other sources, since the technique is easy, cost effective, fast, and the enzymes of required properties can be procured. OBJECTIVES: The current study aimed to report the characteristics of novel amylase producing bacterial strains isolated from Taptapani hot spring, Odisha, India. MATERIALS AND METHODS: Bacterial strains were isolated by dilution plating method from the water samples collected from Taptapani Hot Spring, Odisha and screened for amylase production through starch hydrolysis. The bacterial isolates were identified morphologically, biochemically, and finally by 16S rDNA profiling. RESULTS: Based on the morphological, physiological, biochemical characteristics and the molecular characterization, the isolates SS1, SS2, and SS3 were identified as Bacillus barbaricus, Aeromonas veroni, and Stenotrophomonas maltophilia, respectively. The approximate molecular weight of enzymes from SS1, SS2, and SS3 strains were 19 kDa, 56 kDa and 49 kDa, respectively. CONCLUSIONS: The current report isolates, characterizes, and demonstrates the novel heat-adapted amylase-producing bacteria SS1, SS2 and SS3 from Taptapani hot spring, indicating its potentiality and stability under acidic conditions. PMID- 25741426 TI - Acute nonbacterial gastroenteritis in hospitalized children: a cross sectional study. AB - BACKGROUND: Viral acute gastroenteritis (AGE) is a major cause of morbidity in childhood and leads to hospitalization in developed countries, such as Iran. OBJECTIVES: The aim of this study was to determine the prevalence and viral types (rotavirus, adenovirus, human parechoviruses-1, and human bocavirus) of acute nonbacterial gastroenteritis in hospitalized children. PATIENTS AND MATERIALS: This was a across-sectional prospective study performed at the Pediatric Department of Rasoul Hospital, Tehran, Iran (2009-2011) on 80 hospitalized children with viral AGE. All Stool samples were collected on viral transport media. Human bocavirus (HBoV) was detected using the Real-time PCR TaqMan method. Molecular detection of human parechovirus type 1 (HPeV-1) RNA in stool samples was done using a specific nested reverse transcription PCR (RT-PCR). Rota and adeno virus antigens were sought by rapid chromatographic tests. P values less than 0.05 were considered statistically significant. RESULTS: Fever was determined in 47.5% of cases (38), nausea and vomiting in 42.5% (34), respiratory symptoms in 16.3% (13), abdominal pain in 76%. Duration of diarrhea was 1-30 days (mean = 6.3 + 4.3 days). No dehydration was observed in 43.5% of subjects, mild dehydration in 33.8%, moderate dehydration in 17.5% and severe dehydration in 5% of cases. Positive rotavirus was found in 48.8% of cases (39), adenovirus in 20% (16), HBoV in 8% (6) and HPeV-1 in 23.2% (19), and adeno and rotaviruses co infection in 6% (4). The frequency of positive HBoV was significantly lower than adeno and rotaviruses infection (P value = 0.0001). Rotavirus was more frequent in males (P value = 0.003) and in young children (17.49 months vs. 21.44 months) [P value = 0.03, CI = -13.4, 5.5]. Rotavirus infection was related to the degree of dehydration (P value = 0.001) but was not related to the presence of vomiting or fever (P value > 0.5). CONCLUSIONS: This study indicates that viral agents, especially rotavirus (48.8%), HPeV-1 (23.2%) and adenovirus (20%) are the most important causes for viral AGE in children while HBoV (8%) is infrequent during childhood. Determination of various viral pathogens of AGE is very important in planning diarrhea disease control strategies in our country where rotavirus vaccination in not routinely used. PMID- 25741427 TI - Inducible Clindamycin Resistance in Methicillin-Resistant and-Susceptible Staphylococcus aureus Isolated From South East of Iran. AB - BACKGROUND: Clindamycin is a frequently used antimicrobial therapeutic medicine used for the treatment of skin and soft tissue infections caused by Staphylococcus aureus strains. Resistance to this antibiotic is either constitutive or inducible. Constitutive resistance to clindamycin could be detected by standard susceptibility testing methods. Inducible clindamycin resistance could not be detected by in vitro routine tests. This type of resistance can be identified by D-test. OBJECTIVES: The outbreak of inducible resistance to clindamycin in methicillin resistant and-susceptible S. aureus isolates were investigated in this study. MATERIALS AND METHODS: Totally 162 S. aureus isolates were evaluated for inducible clindamycin resistance by D-test in accordance with clinical and laboratory standards institute (CLSI) guidelines. RESULTS: Inducible clindamycin resistance was detected in 8.64% of S. aureus isolates. Inducible and constitutive resistance to clindamycin was found to be higher in methicillin resistant S. aureus (11.95% and 47.8% respectively) compared to methicillin susceptible S. aureus (4.28% and 2.85% respectively) isolates. CONCLUSIONS: Our results showed that inducible resistance to clindamycin in S. aureus isolates is relatively higher in this region. Therefore, D-test should be performed to prevent treatment failures against infections caused by S. aureus, which are resistant to erythromycin and the sensitive ones against clindamycin. PMID- 25741428 TI - Nocardia co-infection in patients with pulmonary tuberculosis. AB - BACKGROUND: Tuberculosis (TB) remains as one of the most serious infectious diseases in the world. Pulmonary tuberculosis can occur with other pulmonary diseases caused by opportunistic organisms such as Nocardia spp. particularly in immunocompromised patients. Therefore, diagnosis of co-infection at the early stage of the disease could be lifesaving. OBJECTIVES: The goal of this study was to detect Mycobacterium tuberculosis and Nocardia spp. in sputum specimens in order to assess the concomitant nocardiosis and tuberculosis in patients with suspected pulmonary tuberculosis. PATIENTS AND METHODS: From March 2011 to April 2012, 189 sputum specimens were obtained from patients who were suspected of having pulmonary tuberculosis. Out of 189 samples, 32 of the samples belonged to hospitalized HIV-infected patients. Samples were examined by Gram and Ziehl Nelsen staining, culture and PCR methods. RESULTS: From 157 sputum specimens, positive samples by acid fast staining, culture and PCR for M. tuberculosis were reported for 7.6% (12/157), 10.1% (16/157) and 7% (11/157) of samples, respectively. No results were obtained by the described methods for Nocardia spp. Among 32 samples of HIV-infected patients, four (12.5%) had positive results for acid fast staining, culture and PCR detecting M. tuberculosis while only two samples had positive results for Nocardia spp. by PCR and no results were reported by culture, Gram and acid fast staining for this organism. CONCLUSIONS: Concurrent pulmonary nocardiosis and tuberculosis is frequent in HIV-infected patients. Rapid and sensitive methods such as PCR are recommended for detection of such co-infections. PMID- 25741429 TI - Comparison of the in vitro Effect of Chemical and Herbal Mouthwashes on Candida albicans. AB - BACKGROUND: During the recent decades research has focused to find scientific evidence for the effects of herbal medicines. Researchers are interested in herbal remedies for medication and aim to substitute herbal material instead of chemical formula with limited side effects for human being. OBJECTIVES: The aim of the current study was to compare the in vitro effect of herbal and chemical mouthwashes against Candida albicans. MATERIALS AND METHODS: In this research, we used a standard strain of C. albicans, PTCC 5027. The suspension was made by a fresh culture of C. albicans (24 hours) and the optical density (turbidity equating to a McFarland standard of 0.5) was read at 530 nm. The C. albicans suspension was cultured on Sabouraud dextrose agar plate. Next, two wells were filled with mouthwashes and after incubation at 30oC for 24 hours, the inhibition zone was measured. Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of mouthwashes were determined. Data were analyzed using the SPSS software, independent T-tests and one-sided variance analysis (ANOVA-one way). RESULTS: Based on these findings on agar diffusion with (P = 0.764), MIC and MFC tests (P = 0.879), there were no significant differences between the antifungal effect of herbal and chemical mouthwashes. CONCLUSIONS: This study showed that, chemical mouthwashes acted better than herbal mouthwashes and among different chemical mouthwashes, Oral B was most effective. PMID- 25741430 TI - Bioassay Guided Fractionation of an Anti-Methicillin-Resistant Staphylococcus aureus Flavonoid From Bromus inermis Leyss Inflorescences. AB - BACKGROUND: Plants are considered as promising sources of new antibacterial agents as well as bioassay guided fractionation. OBJECTIVES: In the present work, the antibacterial properties, especially against methicillin-resistant Staphylococcus aureus (MRSA), of Bromus inermis inflorescence was studied, using the bioassay guided fractionation as well as the bio-autographic method. MATERIALS AND METHODS: The plant organic extract was prepared via maceration in methanol, followed by the fractionation using n-hexane. The extracts were subjected for minimum inhibitory concentrations (MICs) against some human pathogenic bacteria via standard broth micro-dilution assay. Thereafter, a bio autographical method was applied using the high performance thin layer chromatography (HPTLC) coupled with agar overlay assays for the primary characterization and identification of bioactive substance (s). RESULTS: Through the bioassay guided fractionation method, the greatest antibacterial activities were related to the n-hexane extract. It was also revealed that the effective anti-MRSA agent of the assessed plant was a relatively polar substance with an MIC value of about 8 MUg/mL against the tested MRSA strain (in comparison with the MIC value of 32 MUg/mL for chloramphenicol). CONCLUSIONS: As a result of the full range UV-Vis scanning of the responsible band in the HPTLC experiments (200 700 nm), the flavonoid was the most imaginable natural compound. PMID- 25741431 TI - A Novel Reduction Strategy of Clarithromycin Resistance in Helicobacter pylori. AB - BACKGROUND: Antibiotic resistance is a major therapeutic problem in patients infected with Helicobacter pylori. H. pylori clarithromycin resistant mutants have been evolved during antibiotic therapy, this is mainly due to 23s rRNA point mutations. OBJECTIVES: In the present study, we investigated anti-mutational features of four traditionally Iranian medicinal plants on three local isolated H. pylori strains. MATERIALS AND METHODS: In this study clarithromycin resistance was used as a mutation indicator. Frequencies of such mutations in the presence and absence of plant extracts were evaluated. Mutation incidence was evaluated by Luria Delbruck fluctuation assay. RESULTS: The mean mutation frequency in H. pylori isolates was 27 * 10(-9) which decreased at the presence of Mirtus communis, Teucrium polium, Achillea millefolium and Thymus vulgaris of plant extract, this amount was 97.4%, 95.2%, 63.7% and 19.6% respectively. Moreover, A to-G transition at 2143 position (A2143G) was detected by PCR-sequencing as major point mutation causing clarithromycin resistant mutants. CONCLUSIONS: The efficacy of these plant extracts in prohibiting resistance showed considerable results. This finding should be considered to use plant extracts with antibiotics to develop more effective eradication regimens. PMID- 25741432 TI - Distribution of yeast-like fungi at a university hospital in Turkey. AB - BACKGROUND: The increased life span has led to application of more invasive procedures for diagnosis and treatment of particularly immunosuppressed individuals. This situation drew more attention to fungal infections due to existence of yeast-like fungi. Candida infections have increased due to transplant in patients, prolonged intensive care unit (ICU) stays, and invasive procedures. Recently, identification of yeast-like fungi as well as antifungal susceptibility test has been gaining more importance. OBJECTIVES: In our study, we aimed to evaluate the distribution of yeast-like fungi strains isolated from blood, urine, wound and respiratory specimens, which were sent from various departments of Izmir University School of Medicine University Hospital. MATERIALS AND METHODS: The 262 yeast strains (of 13860 clinical specimens), isolated during 30.05.2012-20.05.2013, which were sent from various departments of Izmir University School of Medicine to Medical Microbiology Laboratory, were included in this study. Blood, wound, respiratory (sputum, tracheal secretion), and urine specimens were cultivated on blood agar and Sabouraud dextrose agar and incubated for 24-48 hours at 37 degrees C. The isolates were cultivated on CHROMagar Candida and Cornmeal Tween 80 medium for identification. Besides, the automatized Vitek version 2.0 system was used for identification of the yeast strains as well as the antifungal susceptibility of blood culture strains. RESULTS: A total of 262 strains, isolated from the Anesthesiology and Reanimation Unit, as well as from the departments of Hematology, Urology, Infectious Diseases, Gynecology and Obstetrics, and Ear Nose and Throat, were included in this study. The most common isolated yeast-like species was Candida albicans. C. parapsilosis was the most common yeast-like fungus isolated from blood cultures. All the blood culture strains were susceptible to amphotericin B, flucytosine, fluconazole and voriconazole. CONCLUSIONS: Candida strains isolated from newborns, elderly patients, and intensive care patients, identified and isolates from blood cultures, should be studied for antifungal susceptibility for management of the treatment. Our University Hospital is a recently opened center and these are the first data of our center. Gradually, as the number of patients increases, this data will be evaluated further. PMID- 25741433 TI - Antimicrobial Susceptibilities of Clinical Acinetobacter baumannii Isolates With Different Genotypes. AB - BACKGROUND: The treatment of Acinetobacter baumannii infections is difficult. Carbapenems, sulbactam, and colistin are the most effective antibiotics. OBJECTIVES: The aim of this study was to evaluate the susceptibilities of genotypically different A. baumannii isolates to sulbactam, amikacin, netilmicin, meropenem, tigecycline and colistin. PATIENTS AND METHODS: Isolates from various clinical samples of patients with hospital-acquired infections that were identified by the VITEK 2 Compact system in our hospital's microbiology laboratory between January 2010 and March 2012 were included in the study. To determine genetic relatedness of the isolates, the rep-PCR method was used. The broth microdilution method was used for amikacin, netilmicin, meropenem and colistin, while E-test was used for sulbactam and tigecycline. RESULTS: Among the 300 isolates, 30 were found to be genotypically different and were evaluated in terms of their antimicrobial susceptibilities. All isolates were susceptible to colistin. The susceptibility rates were 66.6%, 50%, 36.6%, 30%, and 10% for netilmicin, tigecycline, sulbactam, amikacin, and meropenem, respectively. For carbapenem resistant isolates, the susceptibility rates were 66.6%, 51.8%, 33.3%, and 25.9% for netilmicin, tigecycline, sulbactam, and amikacin, respectively. The sulbactam minimum inhibitory concentration (MIC) 50 and MIC 90 were 8 MUg/mL and 12 MUg/mL, respectively. CONCLUSIONS: In this study, it was concluded that determining the cut-off value for MIC breakpoints for sulbactam alone has a critical impact on the susceptibility results. PMID- 25741434 TI - The Prevalence of Pneumocystis jiroveci in Bronchoalveolar Lavage Specimens of Lung Transplant Recipients Examined by the Nested PCR. AB - BACKGROUND: The use of immune suppressive drugs for organ transplant recipients predisposes them to opportunistic infections, especially by fungal agents. Pneumocystis jiroveci, as an opportunistic pathogen, endangers the patients' life in those with immune system disorders. Early detection of latent Pneumocystis infection in susceptible patients may help choose the optimal treatment for these patients. OBJECTIVES: The aim of this study was to identify and determine the colonization of latent P. jiroveci infection among lung transplant recipients. PATIENTS AND METHODS: This cross-sectional descriptive study was conducted on lung transplant recipients. Bronchoalveolar lavage (BAL) specimens were collected from 32 patients undergoing bronchoscopy. The samples were aseptically homogenized by 10 mM dithiothreitol, and their DNA was extracted. The mtLSUrRNA gene of P. jiroveci was amplified using nested PCR in two stages. Nested PCR was performed using external primers of pAZ-102-E and pAZ102-H followed by using the PCR product of the first stage and internal primers of pAZ-102-E and pAZ102-L2. RESULTS: The genome of P. jiroveci was revealed by a 346 bp PCR product in the initial amplification and a 120 bp product in the nested PCR. The results showed that seven BAL specimens (21.9%) from lung transplant recipients were positive for P. jiroveci. CONCLUSIONS: In molecular epidemiology studies, nested PCR has higher sensitivity than PCR. Results of this study support the colonization of P. jiroveci in patients receiving lung transplantation. Patients who are carriers of P. jiroveci are at a higher risk of P. jiroveci pneumonia. PMID- 25741435 TI - A comparative study on the prevalence and risk factors of tuberculosis among the prisoners in khuzestan, South-west iran. AB - BACKGROUND: High prevalence of Tuberculosis (TB) among prisoners is reported as an alarming public health problem in the world, especially in the developing countries. OBJECTIVES: Since there is almost no information from TB in this population in Khuzestan province, the current study aimed to assess the prevalence and identify risk factors of TB among the prisoners of this region. PATIENTS AND METHODS: In a retrospective study, medical files of patients with Tuberculosis in Khuzestan Health Center (KHC), from 2005 to 2010, were studied. Patients with Pulmonary TB were placed in two groups as the Inmate Prison (IP) and Non-Inmate Prison (NIP) groups. Data extracted from the patients' records in the two groups were compared by SPSS software system using Chi square and Fisher exact tests. P-value was considered less than 0.05. RESULTS: From the reported 4562 patients with Tuberculosis, 363 (7.9%) were prison inmates at the time of TB diagnosis. Prevalence of TB cases among the prison inmates was 403.3 per 100'000.The annual TB case rate in the general population during this period was 16.4 per 100,000. Among the TB risk factors close contact [odds ratio (OR), 95% confidence interval (CI), 19.4, 8.9-41.8, P < 001] especially in the recent 2 years, injection drug use (IDU) [OR, 95% CI, 4.61, 1.7-12.4, P = 006], and Human Immunodeficiency Virus (HIV) infection [OR, 95% CI, 2.4, 1.1-5.0, P = 025] were more frequent in the prisoners than in the general population with TB. CONCLUSIONS: In the region under study the prevalence of TB among the prisoners was higher than the general population. The main risk factors for Pulmonary TB in this population were close contact, IDU and HIV infection. PMID- 25741436 TI - Zn(2+) reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder. AB - Our laboratory recently characterized a novel autism spectrum disorder (ASD) associated de novo missense mutation in the human dopamine transporter (hDAT) gene SLC6A3 (hDAT T356M). This hDAT variant exhibits dysfunctional forward and reverse transport properties that may contribute to DA dysfunction in ASD. Here, we report that Zn(2+) reverses, at least in part, the functional deficits of ASD associated hDAT variant T356M. These data suggest that the molecular mechanism targeted by Zn(2+) to restore partial function in hDAT T356M may be a novel therapeutic target to rescue functional deficits in hDAT variants associated with ASD. PMID- 25741438 TI - Evaluation of the applicability of the Immuno-solid-phase allergen chip (ISAC) assay in atopic patients in Singapore. AB - BACKGROUND/OBJECTIVE: Molecular-based allergy diagnostics are gaining popularity in clinical practice. Our aim was to evaluate their role in the tropics, given the inherent genetic and environmental differences. METHODS: We recruited subjects with history of atopy and collected data on demographics and atopic symptoms using validated questionnaires. Subjects underwent a series of skin prick tests (SPT). Serum total and specific IgE levels were measured using ImmunoCAP FEIA and ImmunoCAP ISAC(r), respectively. We describe their pattern of sensitization and agreement between test methods. RESULTS: A total of 135 subjects were recruited; mean +/- SD age of 31.18 +/- 12.72 years, 52.7% female. Allergic rhinitis (AR) was the most prevalent clinical manifestation of atopy (70.7%), followed by atopic dermatitis (AD) (50.5%) and asthma (26.2%). Polysensitization was seen in 51.1% of subjects by both SPT and ISAC. House dust mites (HDM) were the dominant allergen, with sensitization in 67.8% and 62% of subjects on SPT and ISAC, respectively. A group of subjects with monosensitization to B. tropicalis was identified. HDM sensitization was strongly associated with AR, while AD and asthma were not associated with sensitization to any allergen. Agreement between SPT and ISAC was mostly suboptimal. Greatest agreement was documented for the measurement of HDM sensitization with both methods (kappa = 0.64). Sensitization to the bulk of the remaining allergens in the ISAC panel was infrequent. CONCLUSION: Multiplex methods should not be used as a screening tool, especially in a population with lower rates of polysensitization and a dominant sensitizing allergen. There may be a role in adjusting the antigen spectrum in the ISAC panel to regional differences. PMID- 25741439 TI - Perioperative clinical and economic outcomes associated with replacing first generation high molecular weight hydroxyethyl starch (Hextend(r)) with low molecular weight hydroxyethyl starch (Voluven(r)) at a large medical center. AB - BACKGROUND: Several plasma volume expander alternatives exist to enhance intravascular volume status in patients undergoing surgery. The optimal intravascular volume expander in the perioperative setting is currently unknown. Low molecular weight hetastarch, Voluven(r) (130/0.4), may have a better safety profile than high molecular weight hetastarch, Hextend(r) (450/0.7). We examined the clinical and cost outcomes of converting from Hextend(r) to Voluven(r) in a large tertiary medical center. METHODS: Using a large electronic database, we retrospectively compared two different time periods (2009 and 2010) where the availability of semisynthetic colloids changed. Perioperative and postoperative outcomes including the use of red blood cells (RBC), platelets and coagulation factors, length of stay in the postoperative acute care unit (PACU), intensive care unit and hospital, as well as 30-day and 1-year mortality were compared. In addition, direct acquisition costs of all intraoperative and PACU colloids and crystalloid use were determined. RESULTS: A total of 4,888 adult subjects were compared of which 1,878 received Hextend(r) (pre-conversion) and 2,759 received Voluven(r) (post-conversion) during two separate 7-month periods within 1 year apart, with the remainder receiving Plasmanate. The patients were similar in terms of patient demographics, preoperative comorbidities, ASA status, emergency surgery, types of surgery, intraoperative, and PACU times. In unadjusted outcomes, patients in the Hextend(r) group received more lactated Ringer's than in the Voluven(r) group (2,220 + 1,312 vs. 1,946 +/- 1,097 ml; P < 0.0001). The use of albumin (Plasmanate) was reduced from 10.5% of patients to 1.1% when Voluven(r) was substituted for Hextend(r). Unadjusted outcomes were similar in each group including hospital LOS, percent change from baseline creatinine and receipt of intraoperative and PACU blood product administration. However, overall unadjusted total fluid costs were greater in the Voluven(r) compared to Hextend(r) group ($116.7 compared to $59.3; P < 0.001). CONCLUSIONS: Conversion from Hextend(r) to Voluven(r) in the perioperative period resulted in decreased albumin use and was not associated with changes in clinical outcomes and short- and long-term mortality. The conversion was associated with decreases in crystalloid use and an increase in colloid use and hence IV fluid acquisition costs in the Voluven(r) group. PMID- 25741437 TI - The development of a standardised diet history tool to support the diagnosis of food allergy. AB - The disparity between reported and diagnosed food allergy makes robust diagnosis imperative. The allergy-focussed history is an important starting point, but published literature on its efficacy is sparse. Using a structured approach to connect symptoms, suspected foods and dietary intake, a multi-disciplinary task force of the European Academy of Allergy and Clinical Immunology developed paediatric and adult diet history tools. Both tools are divided into stages using traffic light labelling (red, amber and green). The red stage requires the practitioner to gather relevant information on symptoms, atopic history, food triggers, foods eaten and nutritional issues. The amber stage facilitates interpretation of the responses to the red-stage questions, thus enabling the practitioner to prepare to move forward. The final green stage provides a summary template and test algorithm to support continuation down the diagnostic pathway. These tools will provide a standardised, practical approach to support food allergy diagnosis, ensuring that all relevant information is captured and interpreted in a robust manner. Future work is required to validate their use in diverse age groups, disease entities and in different countries, in order to account for differences in health care systems, food availability and dietary norms. PMID- 25741441 TI - Implementing the European Core Health Indicators (ECHI) in the Netherlands: an overview of data availability. AB - BACKGROUND: The European Commission, together with the European Union (EU) Member States, developed a core set of indicators for monitoring public health in the EU, the European Core Health Indicators (ECHI) shortlist. From 2009 to 2012 developmental work on the ECHI indicators continued within the framework of the Joint Action for European Community Health Indicators and Monitoring (ECHIM). In this article, we give the current state of affairs on the availability of data for the ECHI indicators in the Netherlands and show what progress has been made over the past 5 years. The information provided serves as an illustration of the challenges encountered in a European country when working on harmonising national data collections with international data delivery requirements. METHODS: To assess data availability, we consulted Dutch data experts and relevant websites and reports on health monitoring activities. We compared the available Dutch data with the definitions, preferred data sources and relevant dimensions as requested by ECHI. RESULTS: The Netherlands can provide data for 66 of the 75 ECHI indicators for which availability could be assessed: for all of the 48 ECHI indicators that can be extracted from international databases and for 18 of the 27 indicators not available from international databases. Breakdowns by socio economic status and region are not possible for 23 (35%) of the total of 66 indicators for which data are available and for 21 (32%) of these 66 indicators the definition is not exactly the same as requested by ECHIM. Since 2009, better estimates have become available for low birth weight, practising physicians and practising nurses. Moreover, several European initiatives to improve harmonised data collection are expected to have a positive effect on data availability for the Netherlands. Such initiatives should become sustainable in order to provide possibilities for monitoring trends. The scattered data ownership in the Netherlands complicates the coordination work for international data deliveries. CONCLUSION: Data availability in the Netherlands is good. Since 2009, several Dutch and European developments in harmonising data collection have contributed or will significantly contribute to improvements in the data situation for the ECHI indicators in the Netherlands. PMID- 25741442 TI - Percutaneous embolization: a viable treatment option for varicocele. PMID- 25741443 TI - Provider beliefs about diabetes treatment have little impact on glycemic control of their patients with diabetes. AB - OBJECTIVE: To improve the health of people with diabetes, it is essential to identify why patients experience extended periods of poor glycemic control before therapeutic intensification. RESEARCH DESIGN AND METHODS: We surveyed 252 primary care providers at Kaiser Permanente Northwest to determine their beliefs about the glycemic goals of their patients, treatment intensification behavior, and barriers to achieving optimal glycemic control. We linked the responses of 149 providers to the health records of their 18 346 patients with diabetes. RESULTS: Patient glycemic levels were not related to either individualized glycemic goals or provider intensification behavior. Providers' beliefs about diabetic treatment and glycated hemoglobin (HbA1c) goals were poorly associated with patient HbA1c levels. Providers identified patients' resistance to lifestyle behaviors and taking insulin, lack of medication adherence, and psychosocial issues as the main barriers to optimal glycemic control. Lack of time to care for complex patients was also a barrier. Providers who agreed that "current research did not support A1C levels <7%" were less likely to have patients with HbA1c levels <7% (OR=0.87, 95% CI 0.78 to 0.97) and patients of providers who disagreed that "some patients will have an A1C >9% no matter what I do" were 16% more likely to have patients with HbA1c <7% (1.16, 1.03 to 1.30) compared with providers who were neutral about those statements. CONCLUSIONS: Given the consistency of HbA1c levels across providers despite differences in beliefs and intensification behaviors, these barriers may be best addressed by instituting changes at the system level (ie, instituting institutional glycemic targets or outreach for dysglycemia) rather than targeting practice patterns of individual providers. PMID- 25741444 TI - Obesity is associated with an increase in pharmaceutical expenses among university employees. AB - OBJECTIVE: To examine costs associated with obesity in an employee population and factors associated with increased costs. METHODS: We used data from the Physical Activity and Life Style (PALS) study, a randomized prospective design evaluating three interventions to increase physical activity among physically inactive nonfaculty university employees (n = 454). The primary exposure variable, obesity (measured by body mass index), was obtained from the in-person baseline survey. Covariates were obtained from the baseline survey and included demographic characteristics and health status. Data from the baseline survey was linked with administrative data to determine pharmaceutical, inpatient, outpatient, and total health care costs for three years. Average monthly expenditures for obese and nonobese individuals were compared using t-tests and a two-part multivariate regression model adjusted for demographic and socioeconomic characteristics and health behaviors. RESULTS: Although in-patient and outpatient expenses were not associated with obesity, pharmaceutical expenditures were $408 or 87.2% higher per year ($468 versus $876) for obese individuals than for nonobese individuals, which reflected poorer health behaviors and health status of obese adults. CONCLUSION: Awareness of the costs associated with obesity among employees can stimulate employers to make the investment in providing employer-sponsored wellness and health improvement programs to address obesity. PMID- 25741440 TI - Phylogenomic analyses data of the avian phylogenomics project. AB - BACKGROUND: Determining the evolutionary relationships among the major lineages of extant birds has been one of the biggest challenges in systematic biology. To address this challenge, we assembled or collected the genomes of 48 avian species spanning most orders of birds, including all Neognathae and two of the five Palaeognathae orders. We used these genomes to construct a genome-scale avian phylogenetic tree and perform comparative genomic analyses. FINDINGS: Here we present the datasets associated with the phylogenomic analyses, which include sequence alignment files consisting of nucleotides, amino acids, indels, and transposable elements, as well as tree files containing gene trees and species trees. Inferring an accurate phylogeny required generating: 1) A well annotated data set across species based on genome synteny; 2) Alignments with unaligned or incorrectly overaligned sequences filtered out; and 3) Diverse data sets, including genes and their inferred trees, indels, and transposable elements. Our total evidence nucleotide tree (TENT) data set (consisting of exons, introns, and UCEs) gave what we consider our most reliable species tree when using the concatenation-based ExaML algorithm or when using statistical binning with the coalescence-based MP-EST algorithm (which we refer to as MP-EST*). Other data sets, such as the coding sequence of some exons, revealed other properties of genome evolution, namely convergence. CONCLUSIONS: The Avian Phylogenomics Project is the largest vertebrate phylogenomics project to date that we are aware of. The sequence, alignment, and tree data are expected to accelerate analyses in phylogenomics and other related areas. PMID- 25741445 TI - Pelvic exenteration: experience from a rural cancer center in developing world. AB - BACKGROUND: Pelvic exenteration (PE) is a morbid procedure. Ours is a rural based cancer center limited trained surgical oncology staff. Hence, this audit was planned to evaluate morbidity and outcomes of all patients undergoing PE at our center. METHODS: This is a IRB approved retrospective audit of all patients who underwent PE at our center from January 2010 to August 2013. The toxicity grades were retrospectively assigned according to the CTCAE version 4.02 criteria. Chi square test was done to identify factors affecting grades 3-5 morbidity. Kaplan Meier survival analysis has been used for estimation of median PFS and OS. RESULTS: 34 patients were identified, with the median age of 52 years (28-73 years). Total, anterior, posterior, and modified posterior exenterations were performed in 4 (11.8%), 5 (14.7%), 14 (41.2%), and 11 (32.4%) patients, respectively. The median time for surgery was 5.5 hours (3-8 hours). The median blood loss was 500 mL (200-4000 mL). CTCAE version 4.02 grades 3-4 toxicity was seen in nine patients (25.7%). The median estimated progression free survival was 31.76 months (25.13-38.40 months). The 2-year overall survival was 97.14%. CONCLUSION: PE related grades 3-5 morbidity of 25.7% and mortality of 2.9% at our resource limited center are encouraging. PMID- 25741446 TI - Using community informants to estimate maternal mortality in a rural district in Pakistan: a feasibility study. AB - BACKGROUND: We aimed to assess the feasibility of using community-based informants' networks to identify maternal deaths that were followed up through verbal autopsies (MADE-IN MADE-FOR technique) to estimate maternal mortality in a rural district in Pakistan. METHODS: We used 4 community networks to identify deaths in women of reproductive age in the past 2 years in Chakwal district, Pakistan. The deaths recorded by the informants were followed up through verbal autopsies. RESULTS: In total 1,143 Lady Health Workers (government employees who provide primary health care), 1577 religious leaders, 20 female lady councilors (elected representatives), and 130 nikah registrars (persons who register marriages) identified 2001 deaths in women of reproductive age. 1424 deaths were followed up with verbal autopsies conducted with the relatives of the deceased. 169 pregnancy-related deaths were identified from all reported deaths. Through the capture-recapture technique probability of capturing pregnancy-related deaths by LHWs was 0.73 and for religious leaders 0.49. Maternal mortality in Chakwal district was estimated at 309 per 100,000 live births. CONCLUSION: It is feasible and economical to use community informants to identify recent deaths in women of reproductive age and, if followed up through verbal autopsies, obviate the need for conducting large scale surveys. PMID- 25741447 TI - Knowledge of pregnant women on mother-to-child transmission of HIV in Meket District, Northeast Ethiopia. AB - Knowledge of pregnant women on the three periods of mother-to-child transmission (MTCT) of HIV has implication for child HIV acquisition. This study aims to assess the knowledge of pregnant women on mother-to-child transmission of HIV and to identify associated factors in Meket district, northeast Ethiopia. Logistic regression models were fitted to identify associated factors. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) were used to determine the presence and strength of association. About one-fifth (19%) of women were knowledgeable on mother-to-child transmission of HIV (95% CI: 15.5%, 22.4%). Being urban resident (AOR: 2.69, 95% CI: 1.48, 4.87), having primary education (AOR: 2.41, 95% CI: 1.03, 5.60), reporting receiving information on HIV from health care providers (AOR: 3.24, 95% CI: 1.53, 6.83), having discussion with partner about mother-to-child transmission of HIV (AOR: 2.64, 95% CI: 1.59, 4.39), and attending antenatal care (AOR: 5.80, 95% CI: 2.63, 12.77) were positively associated with increased maternal knowledge of mother-to-child transmission of HIV. Knowledge of mother-to-child transmission of HIV among pregnant women was low. Providing information, especially for rural women and their partners, is highly recommended. PMID- 25741448 TI - Leishmaniasis in central morocco: seasonal fluctuations of phlebotomine sand fly in aichoun locality, from sefrou province. AB - Cutaneous leishmaniases (CL) are endemic in Morocco. They are common in the human population in different localities such as Aichoun in Sefrou province, Morocco. This study was carried out in Aichoun locality from April to October 2012 in order to study the spatiotemporal trends of the main Leishmania phlebotomine vectors in this focus. Overall, 1171 sand flies, belonging to four species, were collected by sticky traps. Phlebotomus sergenti was the predominant species (78.4%) followed by Ph. perniciosus (10.5%), Ph. papatasi (7.94%), and Ph. longicuspis (3.16%). Sandflies were active during 6 months (May-October). Ph. sergenti, Ph. perniciosus, and Ph. papatasi displayed a bimodal distribution with a first peak in July and a second peak in September, while Ph. longicuspis showed a monophasic trend with a peak in August. The high abundance and the lengthy period of activity of Ph. sergenti and Ph. perniciosus, vectors of L. tropica and L. infantum, respectively, are a cause for concern as they indicate the high potential risk of Leishmania transmission in the studied areas. PMID- 25741449 TI - Expression of Prostanoid EP3 Receptors in Oral Squamous Epithelium and Oral Squamous Cell Carcinoma. AB - Objectives. To carry out a descriptive analysis of the expression of the EP3 receptors of PGE2 in different histological grades of OSCC and adjacent normal epithelium. Material and Methods. A total of 46 patients presenting with various histological subtypes and grades of OSCC were recruited from Maxillofacial Surgery Department of Nishtar Institute of Dentistry Multan. Microscopically tumour subtyping and histological grading according to Anneroth's grading system were carried out. Immunohistochemical staining with rabbit polyclonal EP3 receptor antibody was performed and sections were scored for intensity and proportion of positive adjacent squamous epithelial and tumour cells. Results. Out of 46 patients n = 28 (60.9%) were well differentiated, n = 15 (32.6%) were moderately differentiated, and only n = 3 (6.5%) were poorly differentiated. All n = 46 cases of OSCC were positive for EP3 receptor antibody, n = 14 (30.4%) cases had strong intensity of anti EP3 antibody staining in tumour tissue, n = 17 (37%) cases showed moderate intensity, and n = 15 (32.6%) cases showed weak intensity. Conclusion. Prostanoid EP3 receptors are widely but variably expressed in OSCC. Most of well differentiated OSCC cases show a moderate to strong expression of EP3 receptors. However, insignificant statistical relation to histological grades of OSCC has been observed. This might be due to small sample size of the study. PMID- 25741450 TI - Systematic HPLC/ESI-High Resolution-qTOF-MS Methodology for Metabolomic Studies in Nonfluorescent Chlorophyll Catabolites Pathway. AB - Characterization of nonfluorescent chlorophyll catabolites (NCCs) and dioxobilane type nonfluorescent chlorophyll catabolite (DNCC) in peel extracts of ripened lemon fruits (Citrus limon L.) was performed by HPLC/ESI-high resolution-qTOF-MS method. Compounds were identified in samples on the basis of measured accurate mass, isotopic pattern, and characteristic fragmentation profile with an implemented software postprocessing routine. Three NCC structures already identified in other vegetal tissues were present in the lemon fruit peels (Cl NCC1; Cl-NCC2; Cl-NCC4) while a new structure not defined so far was characterized (Cl-NCC3). This catabolite exhibits an exceptional arrangement of the peripheral substituents, allowing concluding that the preferences for the NCC modifications could be a species-related matter. PMID- 25741451 TI - Voltammetric Determination of Codeine on Glassy Carbon Electrode Modified with Nafion/MWCNTs. AB - A glassy carbon electrode modified with a Nafion/MWCNTs composite is shown to enable the determination of codeine using differential pulse voltammetry in phosphate buffer of pH 3.0. At a preconcentration time of 15 s, the calibration graph is linear in the 0.5 uM (0.15 mg.L(-1)) to 15 uM (4.5 mg.L(-1)) concentration range with a correlation coefficient of 0.998. The detection limit at a preconcentration time of 120 s is as low as 4.5 MUg.L(-1). The repeatability of the method at a 0.6 MUg.L(-1) concentration level, expressed as the RSD, is 3.7% (for n = 5). The method was successfully applied and validated by analyzing codeine in drug, human plasma, and urine samples. PMID- 25741452 TI - Computational methodology for ChIP-seq analysis. AB - Chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq) is a powerful technology to identify the genome-wide locations of DNA binding proteins such as transcription factors or modified histones. As more and more experimental laboratories are adopting ChIP-seq to unravel the transcriptional and epigenetic regulatory mechanisms, computational analyses of ChIP-seq also become increasingly comprehensive and sophisticated. In this article, we review current computational methodology for ChIP-seq analysis, recommend useful algorithms and workflows, and introduce quality control measures at different analytical steps. We also discuss how ChIP-seq could be integrated with other types of genomic assays, such as gene expression profiling and genome-wide association studies, to provide a more comprehensive view of gene regulatory mechanisms in important physiological and pathological processes. PMID- 25741454 TI - The Role of Food Parenting Skills and the Home Food Environment in Children's Weight Gain and Obesity. AB - This paper presents an overview to provide readers with an update on the literature about the relation between parental influences (general parenting and food parenting practices) and children's weight-related outcomes. It first summarizes the evidence regarding the role of food parenting practices in shaping and maintaining children's nutritional and weight status. It then describes empirical evidence on the relation between general parenting and children's weight status. This evidence is less convincing, possibly because general parenting has a different, more distal role in influencing child behavior than parenting practices. General parenting may moderate the impact of food parenting practices on children's nutrition behaviors. Finally, we discuss studies on interventions targeting childhood overweight and obesity. There is no consensus on the optimal intervention targets (i.e., general parenting and/or food parenting practices). Based on the overview, we offer suggestions for future research. PMID- 25741453 TI - The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. AB - In contrast to a majority of cancer types, the initiation of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue, with one of the most prevalent etiological factors being hepatitis B virus (HBV). Transformation of the liver in HBV-associated HCC often follows from or accompanies long-term symptoms of chronic hepatitis, inflammation and cirrhosis, and viral load is a strong predictor for both incidence and progression of HCC. Besides aiding in transformation, HBV plays a crucial role in modulating the accumulation and activation of both cellular components of the microenvironment, such as immune cells and fibroblasts, and non-cellular components of the microenvironment, such as cytokines and growth factors, markedly influencing disease progression and prognosis. This review will explore some of these components and mechanisms to demonstrate both underlying themes and the inherent complexity of these interacting systems in the initiation, progression, and metastasis of HBV-positive HCC. PMID- 25741456 TI - Rituximab Treatment for Nephrotic Syndrome in Children. AB - In the past 10 years, many reports have suggested that rituximab, a chimeric anti CD20 monoclonal antibody, is effective for children with complicated, frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, those reports were case reports, case series, retrospective surveys, and single-arm or short-term trials. Therefore, well-designed controlled trials are required to establish the value of rituximab in this condition. To evaluate the efficacy and safety of rituximab in childhood-onset, complicated FRNS/SDNS, a multicenter, double-blind, randomized, placebo-controlled trial was carried out by the Research Group of Childhood-onset Refractory Nephrotic Syndrome (RCRNS) in Japan (RCRNS01). RCRNS01 showed that rituximab is safe and effective for the treatment of childhood-onset, complicated FRNS/SDNS. In 2014, the use of rituximab for patients with complicated FRNS/SDNS was approved, first in the world, by the Ministry of Health, Labour and Welfare, Japan. PMID- 25741457 TI - Cuscuta reflexa and Carthamus Oxyacantha: potent sources of alternative and complimentary drug. AB - The present study was designed to evaluate the biological potential of Cuscuta reflexa and Carthamus oxyacantha. The ethanolic crude extract (C. reflexa; 9.1% and C. oxyacantha; 10.4%) was partitioned with different solvents at pH 3.0, 9.0 and 7.0. Phytochemical study showed that n-hexane fractions were rich source of terpenoids and ethyl acetate fractions were phenolic in nature while chloroform fractions contained alkaloidal skeleton. Total phenols were calculated with FC method and ranged 3.5 to 71.4 mg GAE/100 g DW. Antioxidant (DPPH & FRAP), enzyme inhibition potential (Protease & AChE) and antimicrobial activities were examined by the standard protocols. It was observed that about all extracts exhibited significant DPPH activity range (IC50 09 +/- 0.5 to 62 +/- 1.2 MUg/ml). The DPPH active extracts/fractions also showed remarkable reducing potential. A strong correlation has been found between phenolics and antioxidant activities. Antimicrobial assay that was performed against four microbes and results revealed that FMC-6 and FMP-8 were active against all the tested microbes, while FMP-2 was inactive. Eight extracts/fractions of these plants expressed more than 50% inhibition of the targeted enzymes. PMID- 25741455 TI - Alcohol Consumption and Obesity: An Update. AB - Recreational alcohol intake is a widespread activity globally and alcohol energy (7 kcal/g) can be a contributing factor to weight gain if not compensated for. Given that both excessive alcohol intake and obesity are of public health interest, the present paper provides an update on the association between alcohol consumption and body weight. In general, recent prospective studies show that light-to-moderate alcohol intake is not associated with adiposity gain while heavy drinking is more consistently related to weight gain. Experimental evidence is also mixed and suggests that moderate intake of alcohol does not lead to weight gain over short follow-up periods. However, many factors can explain the conflicting findings and a better characterization of individuals more likely to gain weight as a result of alcohol consumption is needed. In particular, individuals who frequently drink moderate amounts of alcohol may enjoy a healthier lifestyle in general that may protect them from weight gain. In conclusion, despite the important limitations of current studies, it is reasonable to say that alcohol intake may be a risk factor for obesity in some individuals, likely based on a multitude of factors, some of which are discussed herein. PMID- 25741459 TI - Modeling inflation rates and exchange rates in Ghana: application of multivariate GARCH models. AB - This paper was aimed at investigating the volatility and conditional relationship among inflation rates, exchange rates and interest rates as well as to construct a model using multivariate GARCH DCC and BEKK models using Ghana data from January 1990 to December 2013. The study revealed that the cumulative depreciation of the cedi to the US dollar from 1990 to 2013 is 7,010.2% and the yearly weighted depreciation of the cedi to the US dollar for the period is 20.4%. There was evidence that, the fact that inflation rate was stable, does not mean that exchange rates and interest rates are expected to be stable. Rather, when the cedi performs well on the forex, inflation rates and interest rates react positively and become stable in the long run. The BEKK model is robust to modelling and forecasting volatility of inflation rates, exchange rates and interest rates. The DCC model is robust to model the conditional and unconditional correlation among inflation rates, exchange rates and interest rates. The BEKK model, which forecasted high exchange rate volatility for the year 2014, is very robust for modelling the exchange rates in Ghana. The mean equation of the DCC model is also robust to forecast inflation rates in Ghana. PMID- 25741458 TI - Comparison of false positive rates for screening breast magnetic resonance imaging (MRI) in high risk women performed on stacked versus alternating schedules. AB - PURPOSE: Breast MRI added to mammography increases screening sensitivity for high risk women but false-positive (FP) rates are higher and the optimal screening schedule for coordination with mammography is unclear. We compare rates of FP MRI when studies were performed on two different schedules. PATIENTS AND METHODS: High-risk women at the University of Vermont who had at least 1 MRI and 1 mammogram performed within one year between 2004-2012 were eligible for inclusion in this study. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined in one of three ways. RESULTS: 137 women had screening which met inclusion criteria and 371 MRIs were reviewed. The FP rates were similar for the two schedules when considering BI-RAD 4, 5, 0 or biopsy as a positive test. FP rates were significantly higher for the stacked schedule (18.2 vs. 10.2%, p = 0.026) when considering BI-RADS 3-4-5-0 as positive test, due to the elevated rate of BI-RADS 3 assessments among stacked exams. CONCLUSION: False positive rates differ based on the type of exam (baseline or subsequent) and definition of positive but do not differ based on imaging schedule (stacked or alternating); suggesting that women and their providers may choose the imaging schedule they prefer. This is significant as a randomized clinical trial comparing the two schedules is not likely to be performed, given the high cost and large number of women needed for such a study. PMID- 25741460 TI - Multiphoton microscopy: applications in Urology and Andrology. AB - Multiphoton microscopy (MPM) enables real-time imaging of various cellular processes at submicron resolution. MPM is currently being used in neuroscience, oncology, and immunology. MPM has demonstrated promising results in urology. MPM has been used in the identification of spermatogenesis, evaluation of bladder cancer, and tissue identification in prostate cancer surgery. MPM has allowed the visualization of seminiferous tubules within the testis in a rat model and identified areas of spermatogenesis. MPM could potentially improve the efficacy of testicular sperm extraction. In bladder cancer evaluation, MPM has proven to be an effective imaging tool in identifying areas suspicious for malignancy. The imaging technology could be utilized in the future to provide urologists with an immediate impression of extracted bladder tissue, or as part of a cystoscopic device to evaluate the bladder in real time. Similarly, MPM has proven to be a useful imaging technique to evaluate prostate cancer. MPM could be utilized during a prostatectomy to help differentiate prostate from cavernous nerves that are closely adherent to the prostate. MPM uses a laser and safety studies will need to be performed prior to its utilization in the clinical setting. PMID- 25741461 TI - Cryopreservation of dental tissue and subsequent isolation of mesenchymal stem cells. PMID- 25741462 TI - Relationship between mandibular condyle and angle fractures and the presence of mandibular third molars. AB - OBJECTIVES: We retrospectively evaluated the impact of mandibular third molars on the occurrence of angle and condyle fractures. MATERIALS AND METHODS: This was a retrospective investigation using patient records and radiographs. The sample set consisted of 440 patients with mandibular fractures. Eruption space, depth and angulation of the third molar were measured. RESULTS: Of the 144 angle fracture patients, 130 patients had third molars and 14 patients did not. The ratio of angle fractures when a third molar was present (1.26 : 1) was greater than when no third molar was present (0.19 : 1; odds ratio, 6.58; P<0.001). Of the 141 condyle fractures patients, the third molar was present in 84 patients and absent in 57 patients. The ratio of condyle fractures when a third molar was present (0.56 : 1) was lower than when no third molar was present (1.90 : 1; odds ratio, 0.30; P<0.001). CONCLUSION: The increased ratio of angle fractures with third molars and the ratio of condyle fractures without a third molar were statistically significant. The occurrence of angle and condyle fractures was more affected by the continuity of the cortical bone at the angle than by the depth of a third molar. These results demonstrate that a third molar can be a determining factor in angle and condyle fractures. PMID- 25741463 TI - Expression of vascular endothelial growth factor in oral squamous cell carcinoma. AB - OBJECTIVES: The goal of this study was to determine the correlation of clinicopathological factors and the up-regulation of vascular endothelial growth factor (VEGF) expression in oral squamous cell carcinoma. MATERIALS AND METHODS: Immunohistochemical staining of VEGF and quantitative real-time polymerase chain reaction (RT-PCR) of VEGF mRNA were performed in 20 specimens from 20 patients with oral squamous cell carcinoma and another 20 specimens from 20 patients with carcinoma in situ as a controlled group. RESULTS: The results were as follows: 1) In immunohistochemical study of poorly differentiated and invasive oral squamous cell carcinoma, high-level staining of VEGF was observed. Significant correlation was observed between immunohistochemical VEGF expression and histologic differentiation, tumor size of specimens (Pearson correlation analysis, significance r>0.6, P<0.05). 2) In VEGF quantitative RT-PCR analysis, progressive cancer showed more VEGF expression than carcinoma in situ. Paired-samples analysis determined the difference of VEGF mRNA expression level between cancer tissue and carcinoma in situ tissue, between T1 and T2-4 (Student's t-test, P<0.05). CONCLUSION: These findings suggest that up-regulation of VEGF may play a role in the angiogenesis and progression of oral squamous cell carcinoma. PMID- 25741464 TI - Quality of life following surgical treatment of oral cancers. AB - INTRODUCTION: Quality of life (QoL) studies provide information about the impact of disease, the treatment of symptoms, and outcomes following treatment. The present study aims to evaluate the postoperative QoL of patients treated for oral cancer in a Nigerian government tertiary hospital. MATERIALS AND METHODS: A prospective study on consenting patients with oral cancer was undertaken at Aminu Kano Teaching Hospital, Kano, Nigeria. The subjects completed the University of Washington QoL (UW-QoL) questionnaire one day prior to surgery and postoperatively after 7 days, 1 month, 3 months, and 6 months. RESULTS: Sixty eight patients with oral cancer were recruited. Of these, 38 were males, and 30 were females (male : female, 1.3 : 1). Twenty-four patients (12 males and 12 females) underwent surgery and completed postoperative QoL assessment using the UW-QoL questionnaire. Preoperative QoL mean score was 2.21, while postoperative mean scores after 1 week, 1 month, 3 months, and 6 months were 3.67, 3.46, 2.82, and 2.61, respectively. CONCLUSION: An improvement in QoL following surgical treatment for patients with oral cancer was observed. 'Appearance,' 'recreation,' and 'chewing' were identified as the most important determinants of postoperative QoL in patients with oral cancer in our study. PMID- 25741465 TI - Complication rates in patients using absorbable collagen sponges in third molar extraction sockets: a retrospective study. AB - OBJECTIVES: The purpose of this study is to retrospectively evaluate the postoperative complication rates for absorbable type-I collagen sponge (Ateloplug; Bioland) use in third molar extraction. MATERIALS AND METHODS: From January to August 2013, 2,697 total patients undergoing third molar extraction and type-I collagen sponge application in the Department of Oral and Maxillofacial Surgery at Yonsei University Dental Hospital (1,163 patients) and Dong-A University Hospital (1,534 patients) were evaluated in a retrospective study using their operation and medical records. RESULTS: A total of 3,869 third molars in 2,697 patients were extracted and the extraction sockets packed with type-I collagen sponges to prevent postoperative complications. As a result, the overall complication rate was 4.52%, with 3.00% experiencing surgical site infection (SSI), 1.14% showing alveolar osteitis, and 0.39% experiencing hematoma. Of the total number of complications, SSI accounted for more than a half at 66.29%. CONCLUSION: Compared to previous studies, this study showed a relatively low incidence of complications. The use of type-I collagen sponges is recommended for the prevention of complications after third molar extraction. PMID- 25741466 TI - The incidence and morphology of maxillary sinus septa in dentate and edentulous maxillae: a cadaveric study with a brief review of the literature. AB - OBJECTIVES: The aim of this study is to determine the incidence, location, and orientation of maxillary sinus septa in formalin embalmed cadavers. MATERIALS AND METHODS: The study was conducted on 210 cadaveric heads available in our department. After taking the mid-sagittal section the specimens were opened from the medial aspect and the sinus cavity was explored for the presence of maxillary sinus septa, their anatomical plane, location and dimensions. RESULTS: The mean linear distance between maxillary sinus floor and its anatomical ostium was 26.76+/-5.21 mm and 26.91+/-4.96 mm on right and left side, respectively. A total of 59 maxillary sinus septa (28.1%) were observed in 210 maxillary specimens. Septae were most common, 33 septa (55.9%), in the middle region (between first and second molar tooth) of the sinus cavity. The maxillary sinus membrane (Schneiderian membrane) adhered tightly to the maxillary sinus and over the septae. Significantly more maxillary sinus septa were observed in edentulous maxillae in comparison to the dentate upper jaw. CONCLUSION: Knowledge of location of maxillary sinus ostium is mandatory for the rhinologist for drainage of secretions in maxillary sinusitis. The morphological details of maxillary sinus septa, particularly their location and anatomical planes, will guide dentists in performance of safe implant surgeries. The maxillary antrum septa of category I and II may complicate the procedure of inversion of bone plate and elevation of sinus membrane during maxillary augmentation surgeries. The category III septa observed in the sagittal plane were embedded by one of the branches of the infraorbital nerve in it, and if accidentally cut will lead to infraorbital nerve palsy in maxillary sinus surgeries. PMID- 25741467 TI - Conservative surgical approach to aggressive benign odontogenic neoplasm: a report of three cases. AB - Aggressive benign odontogenic neoplasms have substantial potential to grow to an enormous size with resulting bone deformities, and they often invade adjacent tissues and spread beyond their normal clinical and radiographic margins; as such, they have a high rate of recurrence. Historically, management (conservative versus aggressive) on the basis of clinical, radiographic and/or histopathologic characteristics has been controversial. However, recent advances in the understanding of the biological features of these lesions may provide greater evidence of the benefits of conservative management. Three patients with different complaints and final histopathologic diagnoses were enrolled in the study. All three cases were treated by a single operator with similar conservative surgical procedures. During follow-up, the patients had uneventful secondary healing and bone regeneration, less packing time than previously reported, no clinical or radiographic evidence of recurrence and no apparent deformity. The aggressive behavior of these lesions requires long clinical and radiographic follow-up. Conservative surgical management may be an option to reduce recurrence and morbidity and increase the probability of uneventful secondary healing and bone regeneration. PMID- 25741468 TI - Cavernous sinus thrombosis progression from trismus. AB - In the Department of Oral and Maxillofacial Surgery, patients with trismus can be easily identified. If the cause of trismus is infection of the masticatory space near the pterygoid plexus, the possibility of cavernous sinus thrombosis should be considered. We report the case of a patient who presented with limited mouth opening and progressed to cavernous sinus thrombosis, along with a review of the relevant literature. PMID- 25741469 TI - Low-grade osteosarcoma arising from cemento-ossifying fibroma: a case report. AB - Cemento-ossifying fibromas are benign tumors, and, although cases of an aggressive type have been reported, no cases of cemento-ossifying fibroma transforming into osteosarcoma have been documented previously. Low-grade osteosarcoma is a rare type of primary bone tumor, representing 1%-2% of all osteosarcomas. A 45-year-old female patient was diagnosed with cemento-ossifying fibroma, treated with mass excision several times over a period of two years and eight months, and followed up. After biopsy gathered because of signs of recurrence, she was diagnosed with low-grade osteosarcoma. The patient underwent wide excision, segmental mandibulectomy, and reconstruction with fibula free flap. The aim of this report is to raise awareness of the possibility that cemento-ossifying fibroma can transform into osteosarcoma and of the consequent necessity for careful diagnosis and treatment planning. PMID- 25741470 TI - An unusual abscess formation in the masticator space after acupressure massage: a case report. AB - Clinical features of masticator-space abscess (MSA) are very similar to those of parotitis or temporomandibular disorder (TMD), making early differential diagnosis difficult. Local causes of MSA include nerve block anesthesia, infection after tooth extraction, and trauma to the temporomandibular joint (TMJ); the systemic cause is immunodeficiency. Odontogenic causes account for most etiologies, but there are also unusual causes of MSA. A 66-year-old male patient visited the emergency room (ER) presenting with left-side TMJ pain three days after receiving an acupressure massage. He was tentatively diagnosed with conventional post-trauma TMD and discharged with medication. However, the patient returned to the ER with increased pain. At this time, his TMD diagnosis was confirmed. He made a third visit to the ER during which facial computed tomographic (CT) images were taken. CT readings identified an abscess or hematoma in the left masticator space. After hospitalizing the patient, needle aspiration confirmed pus in the infratemporal and temporal fossa. Antibiotics were administered, and the abscess was drained through an incision made by the attending physician. The patient's symptoms decreased, and he was discharged. PMID- 25741471 TI - Locally advanced breast implant-associated anaplastic large-cell lymphoma: a case report of successful treatment with radiation and chemotherapy. AB - The development of breast implant-associated anaplastic large-cell lymphoma (ALCL) is a rare phenomenon. A typical presentation is an effusion associated with a breast implant. Less commonly, disease can be more advanced locoregionally or distantly. The optimal treatment schema is a topic of debate: localized ALCL can potentially be cured with implant removal alone, while other cases in the literature, including those that are more advanced, have been treated with varying combinations of surgery, chemotherapy, and external beam radiotherapy. This is a case report of breast implant ALCL with pathologically proven lymph node involvement, the fifth such patient reported. Our patient experienced a favorable outcome with radiation therapy and chemotherapy. PMID- 25741472 TI - A multi-institutional experience in pediatric high-grade glioma. AB - INTRODUCTION: Pediatric high-grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes. MATERIALS AND METHODS: Fifty-one patients treated from 1984 to 2008 at the Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progression-free survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and sub-total resection/biopsy subgroup. RESULTS: Median OS was 27.6 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation (CRT) were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or CRT were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent CRT independently correlated with improved PFS, while higher radiation dose (>=59.4 Gy) and adjuvant chemotherapy were independently associated with improved OS. DISCUSSION: Total resection and receiving chemotherapy adjuvant to radiation or CRT are most closely associated with improved PFS and OS. For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes. PMID- 25741473 TI - MRI-Derived Restriction Spectrum Imaging Cellularity Index is Associated with High Grade Prostate Cancer on Radical Prostatectomy Specimens. AB - PURPOSE: We evaluate a novel magnetic resonance imaging (MRI) technique to improve detection of aggressive prostate cancer (PCa). MATERIALS AND METHODS: We performed a retrospective analysis of pre-surgical prostate MRI scans using an advanced diffusion-weighted imaging technique called restriction spectrum imaging (RSI), which can be presented as a normalized z-score statistic. Scans were acquired prior to radical prostatectomy. Prostatectomy specimens were processed using whole-mount sectioning and regions of interest (ROIs) were drawn around individual PCa tumors. Corresponding ROIs were drawn on the MRI imaging and paired with ROIs in regions with no pathology. RSI z-score and conventional apparent diffusion coefficient (ADC) values were recorded for each ROI. Paired t test, ANOVA, and logistic regression analyses were performed. RESULTS: We evaluated 28 patients with 64 ROIs (28 benign and 36 PCa). The mean difference in RSI z-score (PCa ROI-Benign ROI) was 2.17 (SE = 0.11; p < 0.001) and in ADC was 551 mm(2)/s (SE = 80 mm(2)/s; paired t-test, p < 0.001). The differences in the means among all groups (benign, primary Gleason 3, and primary Gleason 4) was significant for both RSI z-score (F 3,64 = 97.7, p < 0.001) and ADC (F 3,64 = 13.9, p < 0.001). A t-test was performed on only PCa tumor ROIs (n = 36) to determine PCa aggressiveness (Gleason 3 vs. Gleason 4) revealing that RSI z-score was still significant (p = 0.03), whereas, ADC values were no longer significant (p = 0.08). In multivariable analysis adjusting for age and race, RSI z-score was associated with PCa aggressiveness (OR 10.3, 95% CI: 1.4-78.0, p = 0.02) while ADC trended to significance (p = 0.07). CONCLUSION: The RSI-derived normalized cellularity index is associated with aggressive PCa as determined by pathologic Gleason scores. Further utilization of RSI techniques may serve to enhance standardized reporting systems for PCa in the future. PMID- 25741474 TI - Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. AB - Breast cancer is a common diagnosis in women. Breast radiation has become critical in managing patients who receive breast conserving surgery, or have certain high-risk features after mastectomy. Most patients have an excellent prognosis, therefore understanding the late effects of radiation to the chest is important. Radiation-induced heart disease (RIHD) comprises a spectrum of cardiac pathology including myocardial fibrosis and cardiomyopathy, coronary artery disease, valvular disease, pericardial disease, and arrhythmias. Tissue fibrosis is a common mediator in RIHD. Multiple pathways converge with both acute and chronic cellular, molecular, and genetic changes to result in fibrosis. In this article, we review the pathophysiology of cardiac disease related to radiation therapy to the chest. Our understanding of these mechanisms has improved substantially, but much work remains to further refine radiation delivery techniques and develop therapeutics to battle late effects of radiation. PMID- 25741475 TI - Current role of radiation therapy for multiple myeloma. AB - BACKGROUND: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors. METHODS: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale. RESULTS: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group. CONCLUSION: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT. PMID- 25741477 TI - Kidney injury molecule-1 as a predicting factor for inflamed kidney, diabetic and diabetic nephropathy Egyptian patients. AB - BACKGROUND: Kidney injury molecule-1 (KIM-1), a recently discovered transmembrane protein, is expressed in dedifferentiated proximal renal tubular epithelial cells in damaged regions. Kidney injury early detection in diabetic patients has great importance for therapy and prognosis. Therefore, the aim of the present study is to predict, validate and evaluate the presence of KIM-1 in kidney inflammation, dialectic and diabetic nephropathy diseases. METHODS: Sixty males and females subjects (30-52 years) were selected for this study. They were subdivided into three main groups; kidney injury, diabetic and diabetic nephropathy patients. The work was extended to evaluate KIM-1 after treatment of each disease. RESULTS: The results revealed significant elevation of KIM-1 in the diseased groups and a noticeable reduction after treatment. Diabetic nephropathy recorded the highest KIM-1 level than the AKI state or the diabetic patients. We noticed an association between KIM-1 and sex and a positive correlation (p < 0.0001) with the disease severity. CONCLUSIONS: In conclusion, urinary KIM-1 has been reported to be a noninvasive, rapid, sensitive, and reproducible biomarker to detect early kidney injury. We speculate that KIM-1 is expected to be a therapeutic target for kidney injury. PMID- 25741478 TI - Risky behaviors and life status as risk factors for spontaneous abortion. AB - BACKGROUND: The Health outcomes of an individual depend on his /her life position. OBJECTIVES: The purpose of the present paper aimed to study spontaneous abortion (as a high risk factor among rural pregnant) due to their life status. PATIENTS AND METHODS: The study was conducted among 40 young rural pregnant women, 12 to 20 years old by implementing a questionnaire during 2012 to 2013 in four villages in southeast of Iran. The women were exposed to high-risk factors such as shortage or lack of drinking water, high pressure electric power sources and chemicals released from burning gas both from cooking and cars as a fuel. The data were collected from the pregnant women coming into clinics. Results of the t test and chi-square identified significant (P < 0.05; 95% CI) and adjustment for birth variables. RESULTS: The findings revealed that pregnant women were without spontaneous abortion (100%) in villages of Iranshahr; while the pregnant women in Sarbaz villages experienced spontaneous abortion (30%). The houses were built from brick (80%), wood (15%) and fiber (5%) in villages of Iranshahr district; and from brick (45%), and stone (55%), in villages of Sarbaz district. Twenty percent of residents in the villages of Iranshahr were exposed to high-risk situations, while none in Sarbaz villages. Although all villages had 100% electric power source, pregnant women had 95% and 20% piped drinking water in villages of Iranshahr and Sarbaz, respectively. No houses in both villages were equipped with the gas fuel system. CONCLUSIONS: The findings suggest that a completely programmed surveillance program should be undertaken to implemented remedy in environmental shortages for pregnant rural women. PMID- 25741476 TI - Structural basis of Staphylococcus epidermidis biofilm formation: mechanisms and molecular interactions. AB - Staphylococcus epidermidis is a usually harmless commensal bacterium highly abundant on the human skin. Under defined predisposing conditions, most importantly implantation of a medical device, S. epidermidis, however, can switch from a colonizing to an invasive life style. The emergence of S. epidermidis as an opportunistic pathogen is closely linked to the biofilm forming capability of the species. During the past decades, tremendous advance regarding our understanding of molecular mechanisms contributing to surface colonization has been made, and detailed information is available for several factors active during the primary attachment, accumulative or dispersal phase of biofilm formation. A picture evolved in which distinct factors, though appearing to be redundantly organized, take over specific and exclusive functions during biofilm development. In this review, these mechanisms are described in molecular detail, with a highlight on recent insights into multi-functional S. epidermidis cell surface proteins contributing to surface adherence and intercellular adhesion. The integration of distinct biofilm-promoting factors into regulatory networks is summarized, with an emphasis on mechanism that could allow S. epidermidis to flexibly adapt to changing environmental conditions present during colonizing or invasive life-styles. PMID- 25741479 TI - Six-month follow-up study of ultrarapid opiate detoxification with naltrexone. AB - BACKGROUND: Illicit opiate use has an increasing incidence and prevalence, which increases mortality and morbidity, marginalization, and criminal behaviors, and causes major adverse effects on society. OBJECTIVES: This study aimed to investigate and follow the outcome of patients who underwent ultrarapid opiate detoxification (UROD) prospectively. PATIENTS AND METHODS: In this randomized clinical trial, 64 patients who underwent UROD were evaluated. The opiate antagonist regimen of naloxone was administered intravenously under general anesthesia, and detoxification was confirmed by naloxone challenge test. All patients were cared in intensive care unit (ICU) for 24 hours, and oral naltrexone was prescribed the next day, after recovery and discharge. Patients were followed up for one month after the procedure. Relapse was considered if routine use of opiates (daily use for at least two weeks) was reported by the patient after detoxification. The data was analyzed by SPSS 16.5 and the study was performed using descriptive analysis and Chi square test. RESULTS: All 64 participants were opiate-dependent males (ASA physical status of I or II) who aged over 18 years with a mean age of 31.11 +/- 8.93 years at the time of UROD. One month after UROD, 48 patients (75%) reported relapse and 16 (25%) reported abstinence; however, four patients of the non-relapsed group reported one episode of opiate use. There was no significant difference between relapsed and non relapsed patients regarding their marital status, level of education, and family history of opiate dependency (P > 0.05). CONCLUSIONS: Although UROD by naloxone is a safe and effective method of detoxification, if used alone, it has a very high relapse rate in long term. PMID- 25741480 TI - Predicting addiction potential on the basis of early traumatic events, dissociative experiences, and suicide ideation. AB - BACKGROUND: There is a great deal of medical literature suggesting that substance use disorder is a serious clinical concern, affecting general population and associated with considerable economic, societal, and personal costs. OBJECTIVES: This study sought to clarify the relationship between early trauma, dissociative experience, and suicide ideation as predictive factors of active and passive addiction potential (A/PAP) in high-school students. PATIENTS AND METHODS: Three hundred students with the mean age of 15.72 y were selected via multistage random sampling. All participants were asked to complete Iranian addiction potential scale, early trauma inventory, dissociative experiences scale, and Beck's suicide ideation scale. Analyzing data was done using canonical correlation. RESULTS: Structural coefficients showed that the pattern of high scores in A/PAP correlates with the pattern of high scores in early trauma, dissociative experience and suicide ideation. The findings of the study showed that the combination of low A/PAP can probably decrease the likelihood of early trauma, dissociative experience and suicide ideation. CONCLUSIONS: Early trauma, dissociative experience, and suicide ideation can predict A/PAP and explain the considerable variance of survival index. PMID- 25741481 TI - The effects of ecstasy on liver function tests, blood glucose, and lipids profile of male rats. AB - BACKGROUND: Ecstasy is used to improve mood and cordiality; however, based on some reports, it is neurotoxic to human users. OBJECTIVES: Because of the euphoria induced by MDMA (3,4-methylenedioxymethamphetamine) on the users, its consumption is increasing in almost all countries. This study was carried out to determine the effects of ecstasy administration in rats' blood sugar, lipids profile, and liver function tests. MATERIALS AND METHODS: The experiment was performed using 50 mature Wistar-Albino male rats. The rats were divided into five groups (n = 10). Sham control group (A), received tap water and ordinary rodent diet. The control (B) was administered saline but tests group C, D1, and D2 received single dose and multiple doses of MDMA, respectively. After experimental period, animals were deeply anesthetized by diethyl ether, sacrificed and the blood samples were collected for the evaluation of blood glucose, serum lipid and aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALK-P). Data were expressed as mean +/- SD and statistical difference was considered significant at P < 0.05. RESULTS: In C group, the values of blood sugar (193.8 +/- 11.6 mg/dL), low density lipoprotein (LDL) (19.2 +/- 7.9 mg/dL), and cholesterol (76.1 +/- 10.6 mg/dL), were significantly increased compared with those of control A and B (135 +/- 12.7), (140 +/- 18.8), and (45.4 +/- 9.8), (49.8 +/- 2.1) (49.4 +/- 10.6) groups. However, aspartate transaminase (AST) and alanine transaminase (ALT) were significantly increased in groups D1 (145.8 +/- 14.7 U/L), (91.1 +/- 8.1 U/L), and D2 (159.4 +/- 13.8 U/L) and (75.4 +/- 7.8) compared with those of group A (107.2 +/- 8.1), (45.4 +/- 9.8), B (79.8 +/- 12.1), (49.8 +/- 2.1), and C (115.6 +/- 17.5), (52.1 +/- 7.6 U/L). Cholesterol and LDL increased in groups C and D compared with group A. CONCLUSIONS: These results indicated that chronic administration of MDMA affects liver as well as lipoprotein profile in male rats. The exact mechanism of action needs further investigation. PMID- 25741482 TI - Compulsory maintenance treatment program amongst Iranian injection drug users and its side effects. AB - BACKGROUND: Psychoactive substance use can cause a broad variety of mental health disorders and social health problems for the drug users, their family and society. OBJECTIVES: The Ministry of Health, Treatment, and Medical Education of Iran has recently proclaimed an estimated number of 2 million drug abusers and 200,000 injecting drug users (IDUs). PATIENTS AND METHODS: For data collection, the directory of mental, social health, and Addiction designed a questionnaire in cooperation with Drug Control Headquarters of Iran. RESULTS: Among 402 IDUs patients, a large amount of them were male, single, and younger than 39 years. Regarding psychotic and somatic symptoms caused by methadone therapy, most of the participants had no problem with methadone maintenance treatment (MMT). CONCLUSIONS: There is a need to train health staff, and the community, concerning preventive measures, treatment, and reducing harm for substance drug users. PMID- 25741483 TI - Child dental neglect: a short review. AB - CONTEXT: Child dental neglect is a terrible tragedy with a high prevalence. Dealing with this issue is important regarding psychological and physical health policies. The current review was conducted to provide health professionals insight into the different aspects of child dental neglect as reported in previous literature. EVIDENCE ACQUISITION: Our review was prepared through an electronic search using Pub Med, Science Direct, Medline, Google, Cochran Library, Google Scholar and EMBASE databases. Relevant papers published since 2000 until now in English, discussing child dental neglect were retrieved. Both original and review papers were included. Eligible articles were fully read by the author. A data form was used to record useful findings. RESULTS: Distinguishing the direct and indirect signs of dental neglect is the first step for improvement of this matter. The dental team are the main professionals who can improve parental knowledge about the consequences of child dental neglect. Victims suffer from short and long-term adverse outcomes. Collaborative attempts need to be made by different health professionals to deal with this problem. CONCLUSIONS: Child dental neglect has many long-term impacts. The main professionals who are responsible for identification, intervention and treatment of child dental neglect are dental practitioners. However, other professionals cannot ignore this task. Finally, child dental neglect, despite its derivative outcomes, may be a presentation of a broader maltreatment. PMID- 25741484 TI - An analytical study on the common type of smokeless tobacco available in the Iranian market. AB - BACKGROUND: The use of smokeless tobacco is considered as a risk factor for oral cancer. OBJECTIVES: The current study aimed to chemically analyze, separate and measure the existing substances in a type of chewing tobacco. MATERIALS AND METHODS: In the current descriptive study, the investigated sample was a type of smokeless tobacco, known as BT, manufactured in India. First steam distillation method and Clevenger machine were used to separate and extract the essential oil of the sample. The presence of the desired compounds was evaluated in the essential oil, using gas chromatography (GC) and then gas chromatography coupled to mass spectrometry (GC/MS) analysis. RESULTS: Based on the results obtained by the applied technique, the presence of carcinogenic compounds, N-nitrosomethyl vinylamine (162 ug/g), N-nitrosonornicotine (6.3 ug/g), and Acetaldehyde (117 ug/g) was confirmed in the sample. CONCLUSIONS: Chemical analysis of the sample confirmed the existence of carcinogenic compounds. PMID- 25741485 TI - Therapeutic intervention and parenting style of abusive parents. AB - BACKGROUND: Victims of abuse comprise a significant proportion of all child psychiatric admissions, with an estimated 30% incidence of lifetime of physical and sexual abuse among child and adolescent outpatients, and as high as 55% among psychiatric inpatients. OBJECTIVES: The present study was conducted to examine the effects of therapeutic intervention and parent management training on parenting skill of abusive parents. PATIENTS AND METHODS: The study population consisted of all children who were referred to Child Psychiatric and Pediatric Departments of Imam Hossein Hospital, Tehran, IR Iran diagnosed with child abuse. Children and their families were visited by a psychiatrist for psychiatric problems. Later, the necessary interventions were taken for the children. To study the effect of intervention, parents completed 'Being a Parent and Parenting Scale' before intervention, and then again, in the third and sixth months following the intervention. The interventions included 8 weekly parent management training sessions for all of the involved parents and additional pharmacologic and psychological interventions according to the subjects' needs. RESULTS: Participants included 73 children with the mean age of 6.9 +/- 4.3 year, while the mean age of parents was 31.76 +/- 6.52 year for the mothers and 38.07 +/- 8.45 year for the fathers. General anxiety disorder (30.1%) and depression (27.4%) were the most common psychiatric disorders among mothers. In parenting scale, there were significant differences between the zero and third month in all subscales (P = 0.008), but there was no significant difference in verbosity and overreactivity after 6 months. Laxness showed significant changes over the period (P = 0.03). In viewing the 'Being a Parent Scale', there was no significant difference in satisfaction and competency subscales before and after the intervention. CONCLUSIONS: Therapeutic intervention and parent management training improves parenting skill of abusive parents, and this might lead to fewer incidents of abuse or neglect. PMID- 25741486 TI - Epidemiology of Suicide and its Associated Socio-demographic Factors in Patients Admitted to Emergency Department of Zahedan Khatam-Al-Anbia Hospital. AB - BACKGROUND: Suicide is a growing public health problem all over the world. Understanding the prevalence of suicide and its correlates is of great importance in planning programs to reduce the risk in different societies. OBJECTIVES: The present study was conducted to assess the epidemiology of suicide and its associated risk factors in Sistan and Balouchestan Province, southeast of Iran. PATIENTS AND METHODS: We investigated a total of 369 suicide cases admitted to the emergency department of Zahedan Khatam- Al- Anbia hospital between March 2010 and February 2012. Data was collected from the hospital information system (HIS) using a semi-structured questionnaire. Descriptive statistics and chi-square tests were used to identify the factors associated with suicidal behaviors. RESULTS: A greater proportion of the study subjects (65%) were female. They were more likely to be young (43.5% in the age group of 16 to 25 years) and illiterate or have a primary school education (20.9% and 48.8%, respectively). Housewives and self-employed individuals and those with a low or medium income dominated the suicide cases. The most common method of suicide was burning (53.4%) followed by drug ingestion (23.8%). One third of the suicide cases occurred during spring. The case fatality rate was 49.6% and it was significantly associated with low income, summer time suicides, burning as a method of suicide. CONCLUSIONS: This study highlights the burden of suicide and itspotential socio-demographic risk factors in Sistan and Blouchestan Province. This information has an implication for planning the preventive measures, policy making and future research. PMID- 25741487 TI - Djinnati syndrome in baluchestan: the role of traumatic and abuse experiences on individual vulnerability. PMID- 25741488 TI - Beta-amyloid imaging with florbetaben. AB - Florbetaben is a fluorine-18 (18F)-labeled stilbene derivative that was developed as a positron emission tomography (PET) tracer for routine clinical application to visualize beta-amyloid plaques in the Alzheimer's disease (AD) brain. The tracer successfully completed a global multicenter phase 0-III development program and was, as a consequence, recently approved by the US Food and Drug Administration and the European Medicines Agency. This review provides an overview on the florbetaben tracer characteristics and preclinical data leading to its human testing. Further, the favorable results of human pharmacokinetics, safety, and dosimetry evaluation of florbetaben are presented. Next, the results of the clinical testing of florbetaben are discussed, in which the tracer was shown to sensitively and specifically detect beta-amyloid neuritic plaques, as evidenced by employing different gold standards (from clinical diagnosis to post mortem histopathology). The potential of florbetaben to predict AD dementia in cases of mild cognitive impairment and to assist in the differential diagnosis in cases of dementia is also described. Finally, potential clinical impact and clinical routine PET image acquisition and analysis protocols for florbetaben are discussed. Taken together, the evidence shows that florbetaben is a valuable beta amyloid-targeting PET tracer in the clinic with great potential to serve as a biomarker supporting clinical AD diagnosis. PMID- 25741490 TI - A preliminary study for the development of indices and the current state of surgical site infections (SSIs) in Korea: the Korean Surgical Site Infection Surveillance (KOSSIS) program. AB - PURPOSE: We aimed to develop an effective system for surgical site infection (SSI) surveillance and examine the current domestic state of SSIs for common abdominal surgeries in Korea. METHODS: The Korean Surgical Site Infection Surveillance (KOSSIS) program was developed as an SSI surveillance system. A prospective multicenter study in nine university-affiliated or general hospitals was conducted for patients who underwent gastrectomy, cholecystectomy, appendectomy, colectomy, or proctectomy between August 16 and September 30 in 2012. Patients were monitored for up to 30 days by combining direct observation and a postdischarge surgeon survey. Data on SSIs were prospectively collected with KOSSIS secretarial support according to a common protocol. Operation specific SSI rates were stratified according to risk factors and compared with data from the Korean Nosocomial Infections Surveillance System (KONIS) and National Healthcare Safety Network. A focus group interview was conducted with participating hospitals for feedback. RESULTS: A total of 1,088 operations were monitored: 207 gastrectomies, 318 cholecystectomies, 270 appendectomies, 197 colectomies, and 96 proctectomies. Operation-specific SSI rates determined by the KOSSIS program were substantially higher than those found in KONIS (7.73% [95% confidence interval, 4.5%-12.3%] vs. 3.4% for gastrectomies, 10.15% [95% confidence interval, 6.1%-15.2%] vs. 4.0% for colectomy, and 13.5% [95% confidence interval, 7.4%-22.0%] vs. 4.2% for proctectomy). CONCLUSION: Despite a short surveillance period and heterogenous group of hospitals, our results suggest that KOSSIS could be a useful program to enhance SSI surveillance in Korea. PMID- 25741489 TI - Amyloid PET imaging: applications beyond Alzheimer's disease. AB - As a biomarker of beta-amyloid, positron emission tomography (PET) amyloid imaging offers a unique opportunity to detect the presence of this protein in the human body during life. Besides Alzheimer's disease (AD), deposits of beta amyloid in the brain are also present in other neurodegenerative diseases associated to dementia, such as Parkinson's disease and dementia with Lewy bodies, as well as in other processes affecting brain function, such as cerebral amyloid angiopathy, brain trauma, Down's syndrome and meningiomas, as shown by post-mortem pathology studies. Furthermore, in systemic amyloidosis other organs besides the brain are affected, and amyloid PET imaging may be suitable for the identification of these extra-cerebral amyloid depositions. Finally, the potential use of amyloid PET tracer accumulation in cerebral white matter (WM) as a marker of myelin is being investigated, leading to some promising results in patients with WM lesions and multiple sclerosis. In this article, a review of the ongoing research pointing to a broader application of amyloid PET imaging in clinical practice beyond AD is provided. PMID- 25741491 TI - Early outcome of the Korean Diagnosis-Related Groups payment system for appendectomy. AB - PURPOSE: The implementation of the Korean diagnosis-related groups (DRG) payment system has been recently introduced in selected several diseases including appendectomy in Korea. Here, we report the early outcomes with regard to clinical aspects and medical costs of the Korean DRG system for appendectomies in Seoul Metropolitan Government - Seoul National University Boramae Medical Center throughout comparing before and after introduction of DRG system. METHODS: The DRG system was applied since January 2013 at our institute. After the DRG system, we strategically designed and applied our algorithm for the treatment of probable appendicitis. We reviewed the patients who were treated with a procedure of appendectomy for probable appendicitis between July 2012 and June 2013, divided two groups based on before and after the application of DRG system, and compared clinical outcomes and medical costs. RESULTS: Total 416 patients were included (204 patients vs. 212 patients in the group before vs. after DRG). Shorter hospital stays (2.98 +/- 1.77 days vs. 3.82 +/- 1.84 days, P < 0.001) were found in the group after DRG. Otherwise, there were no significant differences in the perioperative outcomes and medical costs including costs for first hospitalization and operation, costs for follow-up after discharge, frequency of visits of out-patient's clinic or Emergency Department or rehospitalization. CONCLUSION: In the Korean DRG system for appendectomy, there were no significant differences in perioperative outcomes and medical costs, except shorter hospital stay. Further studies should be continued to evaluate the current Korean DRG system for appendectomy and further modifications and supplementations are needed in the future. PMID- 25741492 TI - The reality in the follow-up of breast cancer survivors: survey of Korean Breast Cancer Society. AB - PURPOSE: Follow-up after primary treatment for breast cancer is an important component of survivor care and various international guidelines exist for the surveillance. However, little is known about current actual practice patterns of physicians whether they adhere to or deviate from recommended guidelines. The aim of this study was to determine how physicians follow-up their patients after primary treatment for breast cancer in Korea. METHODS: A questionnaire survey with 34 questions in 4 categories was e-mailed to the members of Korean Breast Cancer Society from November to December 2013. Respondents were asked how they use follow-up modalities after primary treatment of breast cancer and we compared the survey results with present guidelines. RESULTS: Of the 129 respondents, 123 (95.3%) were breast surgeons. The most important consideration in follow-up was tumor stage. History taking, physical examinations, and mammography were conducted in similar frequency recommended by other guidelines while breast ultrasonography was performed more often. The advanced imaging studies such as CT, MRI, and bone scan, which had been recommended to be conducted only if necessary, were also examined more frequently. Regular screenings for secondary malignancy were performed in 38 respondents (29.5%). Five years later after primary treatment, almost the whole respondents (94.6%) themselves monitored their patients. CONCLUSION: A majority of respondents have been performed more intensive follow-up modalities in comparison with present guidelines and less frequently screenings for secondary malignancy. For optimal follow-up of breast cancer survivors, tailored delivery system should be considered. PMID- 25741493 TI - Role of charcoal tattooing in localization of recurred papillary thyroid carcinoma: initial experiences. AB - PURPOSE: Surgical excision is the definitive treatment for localized recurrence of papillary thyroid carcinoma. Reoperation for recurrence, however, is challenging and associated with increased operative times and complication rates. For safe and effective reoperation, ultrasound-guided charcoal tattooing localization can be used. The aim of this study was to investigate the feasibility and safety of the ultrasound-guided charcoal tattooing localization. METHODS: Between November 2012 and August 2013, ten patients underwent preoperative charcoal tattooing localization for twelve recurrent lesions. Patient demographics, pathologic features, and operation results were reviewed. RESULTS: The technical success rate of charcoal tattooing was 100%. Eight patients had one recurrent lesion, and two patients had double lesions. Among these 12 recurrent lesions, three (25%) were found in level II, four (33%) in level IV, four (33%) in level VI, and one (8%) was found in the thyroidectomy bed site. The mean size of lesions was 0.87 +/- 0.35 cm. Of these 10 patients, eight patients underwent selective lymph node dissection, one patient underwent modified radical neck dissection, and one patient underwent recurrent mass excision. Transient hypocalcemia developed in one patient, and no recurrent laryngeal nerve palsy occurred. There were no major complications related to the injection of the charcoal. The mean follow-up period after reoperation was 8.6 +/ 2.7 months; in the follow-up ultrasound, there were no remnant lesions in all patients. CONCLUSION: Preoperative ultrasound-guided charcoal tattooing localization for recurrent thyroid cancer appears to be a feasible and safe procedure for reoperation. Further evaluation is warranted in larger patients' cohorts. PMID- 25741494 TI - Clinical outcome for laparoscopic cholecystectomy in extremely elderly patients. AB - PURPOSE: Extremely elderly patients who present with complicated gallstone disease are less likely to undergo definitive treatment. The use of laparoscopic cholecystectomy (LC) in older patients is complicated by comorbid conditions that are concomitant with advanced age and may increase postoperative complications and the frequency of conversion to open surgery. We aimed to evaluate the results of LC in patients (older than 80 years). METHODS: We retrospectively analyzed 302 patients who underwent LC for acute cholecystitis between January 2011 and December 2013. Total patients were divided into three groups: group 1 patients were younger than 65 years, group 2 patients were between 65 and 79 years, and group 3 patients were older than 80 years. Patient characteristics were compared between the different groups. RESULTS: The conversion rate was significantly higher in group 3 compared to that in the other groups. Hematoma in gallbladder fossa and intraoperative bleeding were higher in group 3, the difference was not significant. Wound infection was not different between the three groups. Operating time and postoperative hospital stay were significantly higher in group 3 compared to those in the other groups. There was no reported bile leakage and operative mortality. Preoperative percutaneous transhepatic gallbladder drainage and endoscopic retrograde cholangiopancreatography were performed more frequently in group 3 than in the other groups. CONCLUSION: LC is safe and feasible. It should be the gold-standard approach for extremely elderly patients with acute cholecystitis. PMID- 25741495 TI - Effect of imatinib mesylate and rapamycin on the preformed intimal hyperplasia in rat carotid injury model. AB - PURPOSE: Intimal hyperplasia (IH) is the main cause of restenosis or occlusion after vascular procedures. Imatinib mesylate and rapamycin are known to prevent IH. The purpose of this study was to evaluate the effect of these drugs on the regression of preformed IH in rat carotid injury model. METHODS: IH was established in rat carotid arteries using a balloon catheter. The drug effects were assessed in vitro on proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMC) in the neointima. And in vivo studies were carried out in 4 groups: imatinib, rapamycin, combined, and no medication. After 2-week oral medication, morphometric analysis evaluated the number and density of neointimal cells, intima-to-media (I/M) ratio and cross-sectional area. Cell proliferation, apoptosis, and collagen changes were also investigated by immunohistochemical staining (IHCS). RESULTS: Imatinib and rapamycin significantly inhibited VSMC proliferation and migration, and promoted apoptosis in vitro. In morphometric analysis, the number and density of neointimal cells decreased significantly in all medication groups compared with control group (P < 0.01). However, there was no significant difference in neointimal cross-sectional area and I/M ratio among groups. In IHCS, imatinib and rapamycin inhibited neointimal cell proliferation significantly. However, there was no significant change in cell apoptosis and collagen composition. CONCLUSION: Combined treatment of with imatinib and rapamycin induced reduction of cell mass in preformed intimal hyperplasia, but failed to induce regression of intimal mass in this short-term medication study. Further studies will be needed with additional strategies of inducing lysis of the extracellular matrix. PMID- 25741497 TI - An idiopathic gigantomastia. AB - Gigantomastia is a rare condition characterized by excessive breast growth. It has been reported that the majority of gigantomastia cases occur during either pregnancy or puberty. We were presented with a rare case of gigantomastia associated with neither pregnancy nor puberty, and successfully treated it with reduction mammaplasty and free nipple graft. This idiopathic gigantomastia is the very first case in Korea, and adds to the worldwide total of 9 reported cases. PMID- 25741496 TI - Clinical outcome of early relaparotomy after elective open repair of abdominal aortic aneurysms. AB - PURPOSE: The aim of this study was to retrospectively evaluate the association of need for early relaparotomy with clinical outcomes after elective open repair of abdominal aortic aneurysms (AAAs). METHODS: A total of 292 consecutive patients who underwent elective open AAA repair at Asan Medical Center from January 2001 to December 2010 were included in this study, and we compared the demographics, clinical characteristics, related risk factors, and clinical outcomes of early relaparotomy versus nonrelaparotomy patients. RESULTS: The incidence of early relaparotomy during a single hospital stay was 4.1% (n = 12), and the most common causes were bowel ischemia (n = 5, 41.7%) and postoperative bleeding (n = 3, 25.0%). Among the demographics and clinical characteristics significantly associated with relaparotomy were: age (P = 0.025), chronic obstructive pulmonary disease (COPD) (P = 0.010), number of RBC units transfused during the AAA repair (P = 0.022) and in the following week (P = 0.005), and length of intensive care (P < 0.001) and overall hospital stay (P < 0.001). On multivariate analysis, presence of COPD (P = 0.009) and number of RBC units transfused during the AAA repair (P = 0.006) were statistically significantly associated with relaparotomy. Furthermore, early relaparotomy was associated with perioperative (within 30 days) (P = 0.048) and overall in-hospital mortality (P = 0.001). CONCLUSION: Early relaparotomy has an adverse effect on clinical outcomes: increased mortality and hospital length of stay. Presence of COPD and need for RBC transfusion are associated with early relaparotomy. PMID- 25741498 TI - Complicated benign cystic mesothelioma of mesoappendix misdiagnosed as an appendiceal abscess in a postpartum period woman. AB - Benign cystic mesothelioma is an uncommon tumor arising from the peritoneal mesothelium. It is characterized by multilocular grapelike, thin-, and translucent-walled cysts, or a unilocular cyst lined by benign mesothelial cells. It occurs predominantly in women of reproductive age, and shows a predilection for the surface of the pelvic peritoneum or visceral peritoneum. Patients usually present abdominal pain and palpable mass, but many cases have been found incidentally during laparotomy. Definite preoperative diagnosis is known to be difficult. Benign cystic mesothelioma has a tendency towards local recurrence, although the gross microscopic features are benign. Moreover, there is controversy over whether this disease is neoplastic or reactive. Initial complete surgical resection and cytoreductive surgery for recurred cases are standard treatments. In the following report, we describe a case of complicated benign cystic mesothelioma in a postpartum woman, involving the pelvic peritoneum and mesoappendix, which was initially misdiagnosed as a periappendiceal abscess. PMID- 25741499 TI - Dual-incision laparoscopic spleen-preserving distal pancreatectomy. AB - Laparoscopic spleen-preserving distal pancreatectomy has been widely performed for benign and borderline malignancy in the body or tail of the pancreas when there are not oncologic indications for splenectomy. As the need for minimally invasive procedures to reduce postoperative morbidity and improve the quality of life is increasing, many surgeons have attempted to reduce the number of trocars and incision size to minimize access trauma and scarring. Single-port laparoscopic spleen-preserving distal pancreatectomy is the result of these efforts; however it has many limitations such as technical difficulty and prolonged operation time. In this article, we report the first case of dual incision laparoscopic spleen-preserving distal pancreatectomy, proving that it can be a safe and feasible minimally invasive procedure for benign or borderline malignant tumors in the body or tail of the pancreas. PMID- 25741500 TI - ERRATUM: Correction of the 1st and 2nd authors' affiliation: Transfusion free radical antegrade modular pancreaticosplenectomy of metastatic neuroendocrine tumor of the pancreas in Jehovah's Witness patient. AB - [This corrects the article on p. 106 in vol. 88, PMID: 25692122.]. PMID- 25741501 TI - ERRATUM: Correction of affiliation: Posterior triangle approach for lateral in plane technique during hemodialysis catheter insertion via the internal jugular vein. AB - [This corrects the article on p. 114 in vol. 88, PMID: 25692124.]. PMID- 25741502 TI - Toward making inroads in reducing the disparity of lung health in Australian indigenous and new zealand maori children. PMID- 25741503 TI - Developing an undergraduate applied learning experience. AB - To foster student development, critical thinking, and application skills among public health students at the University of Hawai'i at Manoa, a three-course capstone series was developed as a key component of the public health Bachelor of Arts degree program. Over the course of 1.5 academic years students are actively involved in developing an interdisciplinary project proposal, then executing and presenting an independent, supervised, applied learning project. In the first course, students are introduced to a diverse range of public health projects and methods while working to develop their own project proposal - the foundation for the applied learning experience. The project execution course is designed to allow students to execute their proposed applied learning projects. This experience focuses on the application and integration of public health knowledge, skills, and practice acquired during the bachelor's degree course of study. Finally, students will be involved in reflecting on, finalizing, and sharing their completed projects in an undergraduate capstone seminar. Through implementation of this series, the program hopes to provide students with the opportunity to actively apply academic skills to real-world application. PMID- 25741504 TI - An undergraduate curriculum in public health benchmarked to the needs of the workforce. PMID- 25741505 TI - Cases of ergotism in livestock and associated ergot alkaloid concentrations in feed. AB - Ergot-induced disease in humans was known long before Biblical times and has been the root cause for countless human epidemics spanning from the early fourteenth century to the late sixteenth century. In contrast, many of these same ergot alkaloids have been utilized for their medicinal properties to mitigate migraine headaches and have had indications as anti-carcinogens. Although ergot alkaloids have been used for centuries by humans, basic pharmacokinetic data has not been documented for clinical disease in livestock. Consequently, a threshold dose and accurate dose-response data have yet to be established. Throughout the past several years, new detection techniques have emerged to detect these alkaloids at the parts per billion (ppb) level which has allowed for new efforts to be made with respect to determining threshold levels and making accurate clinical diagnoses in affected animals. This perspectives article provides a critical initial step for establishing a uniform interpretation of ergot toxicosis from limited existing data. PMID- 25741506 TI - Aqueous microwave-assisted cross-coupling reactions applied to unprotected nucleosides. AB - Metal catalyzed cross-coupling reactions have been the preferred tools to access to modified nucleosides (on the C5-position of pyrimidines and on the C7- or C8 positions of purines). Our objective is to focus this mini-review on the Suzuki Miyaura and on the Heck cross-couplings of nucleosides using microwave irradiations which is an alternative technology compatible with green chemistry and sustainable development. PMID- 25741508 TI - Concerning consequences of blocking Notch signaling in satellite muscle stem cells. PMID- 25741507 TI - Engineering Sugar Utilization and Microbial Tolerance toward Lignocellulose Conversion. AB - Production of fuels and chemicals through a fermentation-based manufacturing process that uses renewable feedstock such as lignocellulosic biomass is a desirable alternative to petrochemicals. Although it is still in its infancy, synthetic biology offers great potential to overcome the challenges associated with lignocellulose conversion. In this review, we will summarize the identification and optimization of synthetic biological parts used to enhance the utilization of lignocellulose-derived sugars and to increase the biocatalyst tolerance for lignocellulose-derived fermentation inhibitors. We will also discuss the ongoing efforts and future applications of synthetic integrated biological systems used to improve lignocellulose conversion. PMID- 25741509 TI - Prophylactic tracheal intubation for upper GI bleeding: A meta-analysis. AB - AIM: To evaluate usefulness of prophylactically intubating upper gastrointestinal bleeding (UGIB) patients. METHODS: UGIB results in a significant number of hospital admissions annually with endoscopy being the key intervention. In these patients, risks are associated with the bleeding and the procedure, including pulmonary aspiration. However, very little literature is available assessing the use of prophylactic endotracheal intubation on aspiration in these patients. A comprehensive search was performed in May 2014 in Scopus, CINAHL, Cochrane databases, PubMed/Medline, Embase, and published abstracts from national gastroenterology meetings in the United States (2004-2014). Included studies examined UGIB patients and compared prophylactic intubation to no intubation before endoscopy. Meta-analysis was conducted using RevMan 5.2 by Mantel-Haenszel and DerSimonian and Laird models with results presented as odds ratio for aspiration, pneumonia (within 48 h), and mortality. Funnel plots were utilized for publication bias and I2 measure of inconsistency for heterogeneity assessments. RESULTS: Initial search identified 571 articles. Of these articles, 10 relevant peer-reviewed articles in English and two relevant abstracts were selected to review by two independent authors (Almashhrawi AA and Bechtold ML). Of these studies, eight were excluded: Five did not have a control arm, one was a letter the editor, one was a survey study, and one was focused on prevention of UGIB. Therefore, four studies (N = 367) were included. Of the UGIB patients prophylactically intubated before endoscopy, pneumonia (within 48 h) was identified in 20 of 134 (14.9%) patients as compared to 5 of 95 (5.3%) patients that were not intubated prophylactically (P = 0.02). Despite observed trends, no significant differences were found for mortality (P = 0.18) or aspiration (P = 0.11). CONCLUSION: Pneumonia within 48 h is more likely in UGIB patients who received prophylactic endotracheal intubation prior to endoscopy. PMID- 25741510 TI - The relationship between serum 25-hydroxy vitamin D and insulin sensitivity and beta-cell function in newly diagnosed type 2 diabetes. AB - The aim of this study was to investigate the relationship between serum 25 hydroxy vitamin D (25-OHD) and insulin sensitivity and beta-cell function in newly diagnosed type 2 diabetes. 395 newly diagnosed type 2 diabetes patients were enrolled in this study. Venous blood samples were collected at 0 min, 30 min, and 120 min of OGTT to measure serum glucose and insulin. Matsuda ISI and HOMA-IR were used to determine insulin sensitivity. The ratio of 0-120 min area under curve of insulin to glucose (insulin release index, INSR) was calculated as surrogate index of beta-cell insulin secretion function. The products of insulin secretion indices multiplied by Matsuda insulin sensitivity index were used as disposition indices. Patients were divided into three groups according to tertiles (T1, T2, and T3) of 25-OHD concentration. There was significant difference among three groups for HOMA-IR, Matsuda ISI, and INSR. HOMA-IR, Matsuda ISI, INSR, and DI were undifferentiated among three groups in male patients. But HOMA-IR, Matsuda ISI, and INSR were significantly different among three groups in female patients after being adjusted by confounding factors. In conclusion, serum 25-OHD is associated with insulin sensitivity and beta-cell function for female newly diagnosed type 2 diabetes patients, and the association is ambiguous in males. PMID- 25741511 TI - The Nursing Students' Views About the Patient's Rights at the West Black Sea Universities in Turkey. AB - BACKGROUND: The members of healthcare team have an important role in implementation and protection of patient's rights. Contemporary nursing entails an ethical responsibility to advocate and protect the patients' rights. OBJECTIVES: This study was designed to evaluate how ready nursing students, at the end of their education, were to play the role of patient's rights advocates and to discuss ethics education in nursing. MATERIALS AND METHODS: This descriptive study was performed on nursing students at Black Sea Universities in the academic year 2010-2011. Data were collected using a structured questionnaire about students' attitudes regarding patients' rights including patient's rights regulations. The association between gender and students' attitudes was analyzed using Chi-square test. RESULTS: The mean age of the 238 participants was 22.11 +/ 1.21 years and 82.8% of them were female. The majority of the nursing students held desirable attitudes toward patient information, truth telling, and protection of patients' privacy and medical records. However, the students' views about the rights of patients to refuse treatment, children's active participation in treatment, prioritization of the quality of life in treatment, and respect for the rights of dying patients were less satisfactory. CONCLUSIONS: The results of this study was concerning with regard to nursing students' readiness for duties such as patient's rights advocacy. Therefore, it proposes ethics education that covers both patient's rights and the obligations of nurses to defend these rights. PMID- 25741512 TI - Content analysis of articles published in Iranian scientific nursing journals from 2009 through 2011. AB - BACKGROUND: Little is known about the features of Iranian nursing journals, specifically the subject areas used in articles, study designs, sampling methods, international collaboration of Iranian nursing scholars, specialty and academic rank of authors, and the most frequently contributing academic institutions in articles. OBJECTIVES: The aim of this study was to analyze the content of the articles published in Iranian scientific nursing journals. MATERIALS AND METHODS: Quantitative content analysis was implemented to study Iranian nursing journals, which were approved by the commission for accreditation and improvement of Iranian medical journals in 2011. Thus, 763 articles from six journals, published from 2009 through 2011, were investigated. Data were extracted from the abstracts and when necessary, from the full-text of articles by visiting the websites of these journals. Descriptive statistics were used to analyze the data. RESULTS: The main subjects of published articles in Iranian scientific nursing journals were consecutively renal dialysis (n = 21), intensive care unit (n = 16), nursing education (n = 15), patient satisfaction (n = 13), quality of life (n = 12), health education (n = 11), patient education (n = 11), pain (n = 10), and education (n = 9). The majority of authors had nursing and midwifery specialty (52.59%) followed by epidemiology/biostatistics specialty (7.72%). Isfahan, Tehran, Shahid Beheshti, Iran, Baqiyatallah, and Urmia universities of medical sciences had consecutively the largest number of publications in the studied journals. Only three papers (0.39%) were published by the international collaboration. CONCLUSIONS: Iranian nursing journals should publish special issues in the neglected subject areas. These journals should encourage authors to publish research evidence with higher quality. PMID- 25741513 TI - Barriers to Pap-smear Testing From the Viewpoint of Postmenopausal Women in Kashan. PMID- 25741514 TI - Success rate and complications of internal jugular vein catheterization with and without ultrasonography guide. AB - BACKGROUND: Central venous catheterization (CVC) is an important procedure in emergency departments (EDs). Despite existence of ultrasonography (US) devices in every ED, CVC is done using anatomical landmarks in many EDs in Iran. OBJECTIVES: This study aimed to compare the traditional landmark method vs. US-guided method of CVC placement in terms of complications and success rate. PATIENTS AND METHODS: In this randomized controlled trial, patients who were candidate for internal jugular vein catheterization, and referred to Baqiyatallah Hospital ED were randomly allocated into US-guided CVC and anatomical landmarks guided CVC groups. Central vein access time, number of attempts, success rate, and complications in each group were evaluated. Mann-Whitney U, chi-square and Fisher exact tests along with Pearson and Spearman correlation coefficients were used to analyze the data. RESULTS: Out of 100 patients, 56 were male and 44 were female. No significant differences were found between the US-guided and traditional landmark methods of CVC insertion in terms of age, gender, BMI, and site of catheter insertion. The mean access time was significantly lower in the US-guided group (37.12 +/- 17.33 s vs. 63.42 +/- 35.19 s, P < 0.001). The mean number of attempts was also significantly lower in the US-guided group (1.12 +/- 0.3 vs. 1.58 +/- 0.64 times, P < 0.001). Eighty-eight percent of patients in the US guided group were catheterized in the first attempt, while 50% of patients in the traditional landmark group were catheterized in the second or more attempts (P < 0.001). The success rate was 100% in the US-guided group, while it was 88% in the landmark group (P = 0.013). Moreover, the rate of complications was significantly lower in the US-guided group (4% vs. 24%, P = 0.004). CONCLUSIONS: The US-guided method for CVC placement was superior to the traditional landmark method in terms of access time, number of attempts, success rate, and fewer complications. PMID- 25741515 TI - Intensive care nurses' knowledge of radiation safety and their behaviors towards portable radiological examinations. AB - BACKGROUND: Radiological examinations for patients who are hospitalized at intensive care units are usually performed using portable radiography devices. However they may require knowledge and safety precautions of nurses. OBJECTIVES: The aim of the study was to investigate ICU nurses' knowledge of radiation safety and their behaviors towards portable radiological examinations. MATERIALS AND METHODS: In total, 44 intensive care nurses were recruited for this cross sectional descriptive study using census sampling during April and May 2014. The study setting was at intensive care units of Shahid Beheshti Hospital of Kashan, Iran. An eleven-item questionnaire and a five-item checklist were used for evaluating nurses' radiation protection knowledge and behaviors, respectively. An expert panel consisting of ten nursing and radiology faculty members confirmed the content validity of the questionnaire and the checklist. Moreover, a Geiger Muller counter was used for measuring ionizing radiation during portable radiological examinations. Study data were analyzed using the SPSS software version 13.0. Mean, standard deviation, frequency and one-sample t test were used for description of the data. The level of significance was set at below 0.05. RESULTS: The mean of participants' radiation protection knowledge was 4.77 +/- 1.38. The most prevalent radiation protection behavior of nurses was leaving the intensive care unit during portable radiological examinations. Only 6.8% of nurses stayed at the nursing station during radiological examinations. The highest dose of radiation was 0.11 micro Sievert per hour (MUSv/h), which was much lower than the highest permitted level of radiation exposure i.e. 0.25 MUSv/h. CONCLUSIONS: Portable radiological examinations did not expose healthcare providers to high doses of ionizing radiation. Nurses' radiation protection knowledge was limited and hence, they require in-service education programs. PMID- 25741516 TI - Behind the scenes of surrogacy. PMID- 25741517 TI - Predictors of prehospital delay in patients with acute myocardial infarction in kashan city. AB - BACKGROUND: The prehospital delay might result in death in patients with acute myocardial infarction (AMI). OBJECTIVES: This study aimed to investigate the prehospital delay and its related factors in patients with AMI admitted to Kashan's Shahid Beheshti Hospital. PATIENTS AND METHODS: This cross-sectional study was conducted on 117 patients with AMI in the second half of 2013. The interval between the onset of symptoms and arrival at the hospital was noted and in cases of delay, the factors leading to the delay were investigated using a questionnaire. The content validity of the questionnaire was confirmed through content validity method and its internal consistency was confirmed using Cronbach's alpha coefficient. Chi-square test, odds ratio, and logistic regression analysis were used in data analysis. RESULTS: The median delay was 129 minutes (mean +/- SD, 240.44 +/- 295.30). Overall, 32.5% of patients were admitted within 90 minutes of symptom onset. The long distance between living locations to the hospital was the most common cause of delay to hospital admission (31.7%). Significant associations were observed between the delay time and location of residency (P = 0.00) and type of transportation vehicle (P = 0.003). Multivariate logistic regression analysis showed that the location of residency and type of transportation vehicle could significantly predict the delay time in patients with AMI (P = 0.039 and 0.036, respectively). CONCLUSIONS: The delay time from symptom onset to hospital admission was high in patients with AMI. It is necessary to create emergency medical system (EMS) stations in suburbs and train the public on the importance of quick contact with the EMS when the symptoms of an AMI are observed. PMID- 25741518 TI - Comparing the effects of hot pack and lukewarm-water-soaked gauze on postoperative urinary retention; a randomized controlled clinical trial. AB - BACKGROUND: Urinary retention is a common postoperative complication that mandates urinary catheterization. Urinary catheterization is associated with different physical, mental, and financial problems for both patients and healthcare systems. The patient inconvenience, urinary tract infections, and increase in hospital stay and expenses are common problems of urinary retention and urinary catheterization. Therefore, alternative ways of relieving urinary retention, preferably noninvasive interventions, are of great interest. OBJECTIVES: The aim of this study was to compare the effects of placing hot pack and lukewarm-water-soaked gauze on the suprapubic region on male patients with postoperative urinary retention. PATIENTS AND METHODS: This was a three-group, randomized, controlled trial. A convenience sample of 126 male patients who had undergone general, orthopedic, or urologic surgeries were recruited. The block randomization method was used for allocating patients to either the two experimental groups (the hot pack and the lukewarm-water-soaked gauze groups) or the control one. Patients in the experimental groups were treated by placing either hot pack or lukewarm-water-soaked gauze on the suprapubic region. All patients were monitored for 20 minutes for urinary retention relief. If they did not experience urinary retention relief (starting urine flow and bladder evacuate), urinary catheterization would be performed. The data was collected using information sheet. Elimination of urinary retention was compared among study groups. The one-way analysis of variance and the Chi-square tests were used for analyzing data. RESULTS: Respectively, 59.5%, 71.4%, and 7.1% of patients in the hot pack, the soaked gauze, and the control groups experienced relief from urinary retention and the bladder was emptied. There was a significant difference among study groups in percentage of patients who experienced urinary retention relief. However, the difference between the two experimental groups was not significant. The time to urinary retention relief in hot pack, soaked gauze, and control groups was 15.45 +/- 3.15, 13.83 +/- 3.80, and 14.59 +/- 3.29 minutes, respectively. The difference among the study groups in time to urinary retention relief was not statistically significant. CONCLUSIONS: Both the lukewarm-water soaked gauze and the hot pack techniques had significant effects on postoperative urinary retention and significantly reduced the need for urinary catheterization. Using these two simple and cost-effective techniques for managing postoperative urinary retention is recommended. PMID- 25741519 TI - Effect of a self-management and follow-up program on self-efficacy in patients with multiple sclerosis: a randomized clinical trial. AB - BACKGROUND: Multiple sclerosis (MS) is the most common autoimmune disorder of the central nervous system with profound effects on patients' independence and self efficacy. Then, it is still questionable whether self-management programs in patients with MS affect the patients' self-efficacy. OBJECTIVES: The present study aimed to investigate the effect of a self-management program plus regular follow-up on self-efficacy in patients with MS. PATIENTS AND METHODS: A quasi experimental study was performed on 80 patients with relapsing remitting MS who were randomly allocated to an intervention (n = 40) and a control group (n = 40). The MS self-efficacy scale was completed before and after the intervention. The intervention group was divided into four small subgroups of ten. Then, each subgroup was invited to participate in four training sessions about self management. During the two months after the self-management sessions, a weekly telephone follow-up was conducted for each patient in the intervention group. The control group did not receive any intervention other than routine care. Data were analyzed using SPSS 11.5. Descriptive statistics, Chi-square, and independent samples t-testes were used to analyze the data. RESULTS: No significant difference in mean scores of baseline self-efficacy was found between the control (52.90 +/- 8.03) and the intervention groups (54.90 +/- 9.51) (P = 0.313). However, a significant difference was observed between the control (50.90 +/- 5.71) and the intervention groups (59.80 +/- 5.27) regarding mean scores of self efficacy at the end of the study (P < 0.001). CONCLUSIONS: Implementing the self management program plus regular follow-up increased the perception of self efficacy in patients with MS. Similar self-management programs are recommended to be integrated in the regular caring of patients with MS. PMID- 25741520 TI - Self-efficacy in nursing students. PMID- 25741521 TI - Think Out of the Box, Think Out of the Eye Reappraisal of HIV/AIDS Retinopathy. PMID- 25741522 TI - Juxtapapillary retinal capillary hemangioma: new therapeutic strategies. AB - The treatment of juxtapapillary retinal capillary hemangiomas (JRCHs) is still a therapeutic dilemma without established guidelines. Because of the location of these hemangiomas on or adjacent to the optic nerve, treatment is difficult and complex, especially when JRCHs are located in the papillomacular bundle. This manuscript reviews the clinically relevant data on literature regarding the treatment of JRCHs, focusing on novel combined therapies that have shown promising results in these lesions. PMID- 25741523 TI - Punctate inner choroidopathy: a systematic review. AB - This article reviews clinically relevant data regarding punctate inner choroidopathy, mainly the various treatment options. Punctate inner choroidopathy is an uncommon, inflammatory, multifocal chorioretinopathy affecting mostly young myopic women. It is characterized by the presence of multiple, small, well defined, yellow-white fundus lesions, in the absence of intraocular inflammation. We describe etiology, clinical findings and ancillary tests that help in the diagnosis and detection of complications. Treatment options that have been used to manage patients with PIC and CNV include immunosuppressants, corticoids, laser photocoagulation, photodynamic therapy, intravitreal anti-VEGF agents and submacular surgery. PMID- 25741524 TI - Physiology and psychology of vision and its disorders: a review. AB - The purpose of this review is to bring together to the physiology and psychology of vision and to analyze, based on our own data and on the available literature, the relationship between sight loss and individual reactions. As recent treatments for depression are often effective and have few side-effects, ophthalmologists should consider referral for treatment of depression in patients suffering from vision impairment. For this reason, vision rehabilitation should be more readily available and recommended. PMID- 25741525 TI - Eyes with large disc cupping and normal intraocular pressure: using optical coherence tomography to discriminate those with and without glaucoma. AB - We evaluated the ability of spectral-domain optic coherence tomography (SD-OCT) to differentiate large physiological optic disc cupping (LPC) from glaucomatous cupping in eyes with intraocular pressure (IOP) within the normal range. We prospectively enrolled patients with glaucoma or presumed LPC. Participants had optic discs with confirmed or suspected glaucomatous damage (defined as a vertical cup-to-disc ratio>=0.6), and all eyes had known untreated IOP<21 mmHg. For glaucomatous eyes, a reproducible glaucomatous visual field (VF) defect was required. LPC eyes required normal VF and no evidence of progressive glaucomatous neuropathy (follow-up>=30 months). Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell complex (GCC) thicknesses were obtained using SD-OCT. For all studied parameters of pRNFL and GCC thicknesses, eyes with glaucoma (n=36) had significantly thinner values compared to eyes with LPC (n=71; P<0.05 for all comparisons). In addition, pRNFL parameters had sensitivity of 66.7% and specificity of 83.1%, and GCC parameters had sensitivity of 61.2% and specificity of 81.7%. The combination of the two analyses increased the sensitivity to 80.6%. In conclusion, while evaluating patients with large optic disc cupping and IOP in the statistically normal range, SD-OCT had only limited diagnostic ability to differentiate those with and without glaucoma. Although the diagnostic ability of the pRNFL and the GCC scans were similar, these parameters yielded an increase in sensitivity when combined, suggesting that both parameters could be considered simultaneously in these cases. PMID- 25741526 TI - Recurrent Amyloid Material in Grafts Used in Patients with Lattice Corneal Dystrophy 2 (Meretoja's Syndrome). PMID- 25741527 TI - Estimating screening test utilization using electronic health records data. AB - BACKGROUND: Electronic health records (EHRs) are increasingly used by medical providers and offer a wide-reaching source of information on utilization of preventive services. Numerous measures used for quality assessment and public reporting are estimated based on EHR data. However, sources of error and misclassification can lead to over- or under-estimation of true utilization rates. EHR-derived measures of screening test use are subject to error due to misclassification of screening and diagnostic tests. The implications of this misclassification for EHR-based screening utilization estimates have not been well explored. OBJECTIVES: We calculated the bias in estimates of screening test utilization associated with several published EHR-based algorithms for identifying screening colonoscopies and propose two simple methods to correct this bias. We apply these corrections to obtain adjusted estimates of screening colonoscopy utilization using EHR data from Group Health, an integrated healthcare system in Washington-state. FINDINGS: The bias in screening colonoscopy utilization estimates ranged from an under-estimate of 3 to an over estimate of 12 percentage points across classification methods. If the operating characteristics of the classification method are known or if a statistical model that returns predicted probabilities of screening indication is applied in the population of interest, this information can be used to obtain unbiased estimates through simple corrections to the utilization rates with little loss of precision. When applied to data on colonoscopies received at Group Health, we found that an unadjusted estimate was 4 percentage points higher than our adjusted estimate. DISCUSSION: Error in classification of tests as screening when using EHR data to study screening utilization should be accounted for in order to eliminate bias and prevent spurious findings. PMID- 25741528 TI - Optical coherence tomography visualizes neurons in human entorhinal cortex. AB - The cytoarchitecture of the human brain is of great interest in diverse fields: neuroanatomy, neurology, neuroscience, and neuropathology. Traditional histology is a method that has been historically used to assess cell and fiber content in the ex vivo human brain. However, this technique suffers from significant distortions. We used a previously demonstrated optical coherence microscopy technique to image individual neurons in several square millimeters of en-face tissue blocks from layer II of the human entorhinal cortex, over 50 um in depth. The same slices were then sectioned and stained for Nissl substance. We registered the optical coherence tomography (OCT) images with the corresponding Nissl stained slices using a nonlinear transformation. The neurons were then segmented in both images and we quantified the overlap. We show that OCT images contain information about neurons that is comparable to what can be obtained from Nissl staining, and thus can be used to assess the cytoarchitecture of the ex vivo human brain with minimal distortion. With the future integration of a vibratome into the OCT imaging rig, this technique can be scaled up to obtain undistorted volumetric data of centimeter cube tissue blocks in the near term, and entire human hemispheres in the future. PMID- 25741529 TI - Improving a Case-Control Study of Multiple Sclerosis Using Formative Research. AB - Formative research (i.e. focus groups and key informant interviews) was conducted to understand risk perceptions and identify barriers to participation in a case control study of environmental exposures and genetic susceptibility as risk factors for multiple sclerosis (MS). Individuals with MS were recruited to participate in a focus group discussion and individual interviews. Participants were asked to review and comment on study materials and process including participation, interview, genetic testing, confidentiality, and questionnaire. A structured discussion guide was used with all participants to ensure uniformity and coverage of all predetermined topics. Participants reported an increased likelihood of participation if they were informed about the study by their neurologist and not a government agency. All participants expressed willingness to provide a blood sample for genotyping but disagreed about the setting for the blood draw (at home or in a lab). Participants were concerned that they would not receive their individual genotyping results. The study protocol and materials were revised based on comments from the focus group participants. Formative research is an under-utilized resource for researchers conducting epidemiologic studies. Even with limited resources, piloting study materials with individuals similar to the proposed study population can provide opportunities to make modifications to effectively meet the needs of participants and promote participation and retention. PMID- 25741530 TI - Interaction of HLA-DRB1*1501 and TNF-Alpha in a Population-based Case-control Study of Multiple Sclerosis. AB - This study was conducted to determine whether single nucleotide polymorphisms (SNPs) in nine genes (human leukocyte antigen (HLA), T cell receptor beta (TCA receptor beta), tumor necrosis factor alpha (TNF alpha), tumor necrosis factor beta (TNF beta), apolipoprotein E (APOE), interleukin 7 receptor alpha chain (IL7RA) interleukin 2 receptor alpha chain (IL2RA) myelin basic protein (MBP) and vitamin D receptor (VDR)) associated with multiple sclerosis (MS) could be replicated in a population-based sample, and to determine if these associations are modified by presence of HLA DRB1*1501. DNA was available from 722 individuals (223 with MS and 499 controls) who participated in a population-based case control study. Cases and controls were matched on ancestry, age, gender and geographic area. HLA DRB1*1501 risk allele (T) was confirmed in this population using a genotypic test, controlling for multiple comparisons. Examining the effect of each SNP in the presence or absence of the HLA DRB1*1501 risk allele identified significant associations with TNF alpha -1031 (rs1799964) among those without the HLA risk allele. No additional interactions were significant in a cases-only analysis. Our results indicate that an interaction between SNPs in TNF alpha and HLA DRB1*1501 may influence the risk of developing MS. PMID- 25741531 TI - Effects of high intensity interval versus moderate continuous training on markers of ventilatory and cardiac efficiency in coronary heart disease patients. AB - BACKGROUND: We tested the hypothesis that high intensity interval training (HIIT) would be more effective than moderate intensity continuous training (MIT) to improve newly emerged markers of cardiorespiratory fitness in coronary heart disease (CHD) patients, as the relationship between ventilation and carbon dioxide production (VE/VCO2 slope), oxygen uptake efficiency slope (OUES), and oxygen pulse (O2P). METHODS: Seventy-one patients with optimized treatment were randomly assigned into HIIT (n = 23, age = 56 +/- 12 years), MIT (n = 24, age = 62 +/- 12 years), or nonexercise control group (CG) (n = 24, age = 64 +/- 12 years). MIT performed 30 min of continuous aerobic exercise at 70-75% of maximal heart rate (HRmax), and HIIT performed 30 min sessions split in 2 min alternate bouts at 60%/90% HRmax (3 times/week for 16 weeks). RESULTS: No differences among groups (before versus after) were found for VE/VCO2 slope or OUES (P > 0.05). After training the O2P slope increased in HIIT (22%, P < 0.05) but not in MIT (2%, P > 0.05), while decreased in CG (-20%, P < 0.05) becoming lower versus HIIT (P = 0.03). CONCLUSION: HIIT was more effective than MIT for improving O2P slope in CHD patients, while VE/VCO2 slope and OUES were similarly improved by aerobic training regimens versus controls. PMID- 25741533 TI - Genetic and biochemical diversity among Valeriana jatamansi populations from Himachal Pradesh. AB - Valeriana jatamansi Jones is an important medicinal plant that grows wild in Himachal Pradesh, India. Molecular and biochemical diversity among 13 natural populations from Himachal Pradesh was assessed using RAPD and GC-MS to know the extent of existing variation. A total of seven genetically diverse groups have been identified based on RAPD analysis which corroborated well with the analysis based on chemical constituents. The essential oil yield ranged from 0.6% to 1.66% (v/w). A negative correlation between patchouli alcohol and viridiflorol, the two major valued constituents, limits the scope of their simultaneous improvement. However, other few populations like Chamba-II and Kandi-I were found promising for viridiflorol and patchouli alcohol, respectively. The analysis of chemical constitution of oil of the populations from a specific region revealed predominance of specific constituents indicating possibility of their collection/selection for specific end uses like phytomedicines. The prevalence of genetically diverse groups along with sufficient chemical diversity in a defined region clearly indicates the role of ecology in the maintenance of evolution of this species. Sufficient molecular and biochemical diversity detected among natural populations of this species will form basis for the future improvement. PMID- 25741532 TI - Radiotracers used for the scintigraphic detection of infection and inflammation. AB - Over the last forty years, a small group of commercial radiopharmaceuticals have found their way into routine medical use, for the diagnostic imaging of patients with infection or inflammation. These molecular radiotracers usually participate in the immune response to an antigen, by tagging leukocytes or other molecules/cells that are endogenous to the process. Currently there is an advancing effort by researchers in the preclinical domain to design and develop new agents for this application. This review discusses radiopharmaceuticals used in the nuclear medicine clinic today, as well as those potential radiotracers that exploit an organism's defence mechanisms to an infectious or inflammatory event. PMID- 25741535 TI - [From the editor]. PMID- 25741534 TI - The Core Promoter and Redox-sensitive Cis-elements as Key Targets for Inactivation of the Lysyl Oxidase Gene by Cadmium. AB - Exposure of humans to cadmium (Cd) either from environmental contamination or from cigarette smoke, often induces lung emphysema and cancers. Lysyl oxidase (LOX), a copper-dependent enzyme essential for crosslinking of the extracellular matrix, displays antagonistic effects on emphysema and cancer pathogenesis. Our previous studies showed down-regulation of LOX in Cd-resistant (CdR) rat fetal lung fibroblasts (RFL6) derived from parental cells via long-term Cd exposure. The cloned rat LOX gene promoter -804/-1 (relative to ATG) with the maximal promoter activity contains the Inr-DPE core promoter, putative NFI binding sites, metal response elements (MRE) and antioxidant response elements (ARE). ChIP assays reported here further characterize the rat LOX gene promoter in response to Cd. CdR cells exhibited enhanced methylation of CpG at the LOX core promoter region and reduced activities of the NFI binding sites and MRE, but increased activity of the ARE in a dose-dependent manner. The collective effect of Cd on the LOX promoter is trans-inhibition of the LOX gene as shown by suppression of histone H3 acetylation in the LOX core promoter region. Thus, the LOX core promoter and redox-sensitive cis-elements are key Cd targets for down-regulation of LOX relevant to mechanisms for Cd-induced emphysema and lung cancers. PMID- 25741536 TI - Community-acquired vs. nosocomial spontaneous bacterial peritonitis in patients with liver cirrhosis. AB - BACKGROUND/AIMS: Spontaneous bacterial peritonitis (SBP) is a common complication in patients with end-stage liver disease, but reports comparing community acquired SBP (CA-SBP) with nosocomial SBP (N-SBP) are rare. This study compared the clinical characteristics, microbiological characteristics, and treatment outcomes of patients with CA-SBP and N-SBP. METHODOLOGY: Records for 248 patients (173 men, 75 women) with cirrhosis who experienced SBP were retrospectively reviewed. RESULTS: The study population included 202 (81.5%) patients with CA-SBP and 46 (18.5%) patients with N-SBP. Patients with CA-SBP or N-SBP showed no significant differences in baseline or microbiological characteristics, except for a high frequency of previous SBP history in the N-SBP population (P=0.020). During hospitalization, antibiotic switching and in-hospital mortality were significantly higher for patients with N-SBP than CA-SBP (35.6% vs. 8.9%; P=0.001 and 30.4% vs. 12.9%; P=0.028). There were 202 (81.5%) deaths during the follow-up period, with longer overall survival time in patients with CA-SBP (7.9 vs. 3.9 months; P=0.041). However, time to recurrence was not significantly different between the two groups (4.7 vs. 3.6 months; P=0.910). CONCLUSIONS: N-SBP was significantly associated with increased antibiotic switching, higher in-hospital mortality and shorter overall survival. Third-generation cephalosporin may be inappropriate as first-line empirical antibiotics for patients with N-SBP. PMID- 25741537 TI - Scholarly vanity press: why you should judge the book by its cover. PMID- 25741538 TI - Reply by the authors of the original article. PMID- 25741539 TI - Reply by the authors of the original article. PMID- 25741540 TI - Affirming and investing in our intellectual community. PMID- 25741541 TI - Retraction notice to "Toward an optimal oligosaccharide ligand for rat natural killer cell activation receptor NKR-P1" [Biochem. Biophys. Res. Commun. 287 (2001) 11-20]. PMID- 25741542 TI - Next-generation analysis of cataracts: determining knowledge driven gene-gene interactions using biofilter, and gene-environment interactions using the Phenx Toolkit*. AB - Investigating the association between biobank derived genomic data and the information of linked electronic health records (EHRs) is an emerging area of research for dissecting the architecture of complex human traits, where cases and controls for study are defined through the use of electronic phenotyping algorithms deployed in large EHR systems. For our study, cataract cases and controls were identified within the Marshfield Personalized Medicine Research Project (PMRP) biobank and linked EHR, which is a member of the NHGRI-funded electronic Medical Records and Genomics (eMERGE) Network. Our goal was to explore potential gene-gene and gene-environment interactions within these data for 527,953 and 527,936 single nucleotide polymorphisms (SNPs) for gene-gene and gene environment analyses, respectively, with minor allele frequency > 1%, in order to explore higher level associations with cataract risk beyond investigations of single SNP-phenotype associations. To build our SNP-SNP interaction models we utilized a prior-knowledge driven filtering method called Biofilter to minimize the multiple testing burden of exploring the vast array of interaction models possible from our extensive number of SNPs. Using Biofilter, we developed 57,376 prior-knowledge directed SNP-SNP models to test for association with cataract status. We selected models that required 6 sources of external domain knowledge. We identified 13 statistically significant SNP-SNP models with an interaction with p-value < 1 * 10(-4), as well as an overall model with p-value < 0.01 associated with cataract status. We also conducted gene-environment interaction analyses for all GWAS SNPs and a set of environmental factors from the PhenX Toolkit: smoking, UV exposure, and alcohol use;these environmental factors have been previously associated with the formation of cataracts. We found a total of 782 gene-environment models that exhibit an interaction with a p-value < 1 * 10( 4) associatedwith cataract status. Our results show these approaches enable advanced searches for epistasis and gene-environment interactions beyond GWAS, and that the EHR based approach provides an additional source of data for seeking these advanced explanatory models of the etiology of complex disease/outcome such as cataracts. PMID- 25741543 TI - Author's response. PMID- 25741544 TI - Initial treatment of well-differentiated neuroendocrine tumors. PMID- 25741545 TI - Low-risk and very-low-risk prostate cancer: is there a role for focal therapy in the era of active surveillance? Yes, the two approaches complement each other. PMID- 25741546 TI - Low-risk and very-low-risk prostate cancer: is there a role for focal therapy in the era of active surveillance? No, focal therapy provides a false sense of security and no proven benefits. PMID- 25741548 TI - [Alexithymia - baseline trends of research]. AB - In this review, we considered current conceptions on the development of alexithymia. We analyzed the possibility of its development in different somatic and psychosomatic diseases as well as a role in the development of some psychoneurological diseases. The data on the relationship between alexithymia and behavioral disorders, disorders interpersonal relations are presented. Methods of diagnosis of alexithymia in clinical practice in patients with different lesions of the central nervous system are considered. PMID- 25741549 TI - [Current pharmacotherapy of overactive bladder in neurological patients]. AB - The literature data on the urgent neurological problem - overactive bladder (OAB) are summarized. The OAB prevalence, current conceptions on the physiology and pathophysiology of urination and pathogenetic mechanisms of OAB development are presented. Main groups of pharmacological agents used in OAB treatment are described. Special attention is drawn to rationale of using anticholinergic (antimuscarinic) drugs. The authors present the results of their own comparative analysis on the efficacy and tolerability of these drugs in treatment of patients with cerebral vascular diseases including the use of solifenacin succinate (VESIcare). PMID- 25741550 TI - [A.V. Snezhnveskii - physician, researcher, teacher on the occasion of the 100 birthday]. PMID- 25741551 TI - People's corner: Marie-Claude Morice MD FESC FACC. 'Une grande dame' of interventional cardiology received the Transcatheter Cardiovascular Therapeutics 2014 Geoffrey O. Hartzler Master Clinical Operator Award in 2014. PMID- 25741552 TI - Advising patients about electronic cigarettes. PMID- 25741553 TI - Electronic cigarettes: the pulmonologist's point of view. PMID- 25741554 TI - Physician, engineer, inventor and entrepreneur: Dr Johannes Muller has contributed to Berlin's reputation as a hot-spot for Med-Tech companies. PMID- 25741555 TI - Dr Sabine Ernst, FESC presented the latest innovations to improve atrial fibrillation therapies at European Society of Cardiology Congress 2014. PMID- 25741556 TI - Visualizing a safe place reduces pain during ablation of atrial fibrillation. PMID- 25741557 TI - Alzheimers Association update. PMID- 25741558 TI - Autonomic effects after anterior-to-posterior cervical mobilization. PMID- 25741559 TI - Response. PMID- 25741560 TI - Nobody's poster child. PMID- 25741561 TI - Relevance of pCR in breast cancer trials. PMID- 25741562 TI - Sleep disorders and headache. PMID- 25741563 TI - Re: Sore throat consultations in general practice prior to tonsillectomy among eight hundred and sixty-three children in England: is this in accordance with the SIGN guidelines? PMID- 25741564 TI - Response to Asimakopoulos et al. PMID- 25741565 TI - Tinnitus sound therapy: from the Sony Walkman to the Apple iPhone. PMID- 25741566 TI - A simple method to create an aperture using an antral washout trochar whilst fixing dorsal cartilage grafts to nasal bones using the tongue-in-groove technique. PMID- 25741567 TI - Electrocautery smoke evacuation simplified. PMID- 25741568 TI - Diagnosing amyotrophic lateral sclerosis (ALS) in ENT. PMID- 25741569 TI - Variation in tonsillectomy rates between Scottish health boards--implications for emergency admissions? PMID- 25741570 TI - Clinical otolaryngology news. PMID- 25741572 TI - Photoinduced isomerization-driven structural transformation between decanuclear and octadecanuclear gold(I) sulfido clusters. AB - Upon photoirradiation, isomerization of the ligands, 1,2 bis(diphenylphosphino)ethene (dppee) from the cis to the trans form in polynuclear gold(I) sulfido clusters, led to the structural transformation of the decagold(I) cluster to the octadecagold(I) cluster. Both polynuclear MU3-sulfido gold(I) clusters have been fully characterized by NMR, mass spectrometry, elemental analysis, and single crystal X-ray diffraction analysis. The transformation process could be readily detected and monitored by UV-vis absorption, emission, and (31)P NMR spectroscopy in solution. Supported and driven by Au(I)...Au(I) bonding interactions, the nuclearity and symmetry of these clusters were largely different from each other, resulting in completely distinct photophysical features. PMID- 25741573 TI - Control of heterogeneous nucleation and growth kinetics of dopamine-melanin by altering substrate chemistry. AB - Dopamine-melanin (DM or "polydopamine") can be deposited on virtually any substrate from solution through autoxidation of dopamine. The versatility of this process has allowed surface-mediated assembly of DM for a wide variety of functional coatings. Here we report the impact of well-defined surface chemistries on the nucleation and growth of such films. DM was deposited on silicon dioxide (SiO2) and SiO2 substrates modified with self-assembled monolayers (SAMs) bearing octadecyl (C18), phenethyl, and aminopropyl functional groups. Atomic force microscopy revealed three-dimensional islands whose areal density and surface coverage are lowest on bare SiO2 substrates and highest on the neutral aromatic and aliphatic substrates. Increasing the pH of the solution from 8.2 to 10 dissociates catechol moieties in DM and inhibits adsorption on negatively charged SiO2 substrates. The growth rate of DM films on SAM-modified SiO2 is maximized at pH 9.5 and almost completely abolished at pH 10 because of increased DM solubility. The initial rates of DM adsorption were measured using quartz crystal microbalance with dissipation measurements. The initial adsorption rate is proportional to the nucleation density, which increases as the hydrophobicity of the substrate increases. Taken together, these data provide insight into the rates of heterogeneous nucleation and growth of DM on substrates with well-defined chemistries. PMID- 25741574 TI - Energy cascades, excited state dynamics, and photochemistry in cob(III)alamins and ferric porphyrins. AB - Porphyrins and the related chlorins and corrins contain a cyclic tetrapyrrole with the ability to coordinate an active metal center and to perform a variety of functions exploiting the oxidation state, reactivity, and axial ligation of the metal center. These compounds are used in optically activated applications ranging from light harvesting and energy conversion to medical therapeutics and photodynamic therapy to molecular electronics, spintronics, optoelectronic thin films, and optomagnetics. Cobalt containing corrin rings extend the range of applications through photolytic cleavage of a unique axial carbon-cobalt bond, permitting spatiotemporal control of drug delivery. The photochemistry and photophysics of cyclic tetrapyrroles are controlled by electronic relaxation dynamics including internal conversion and intersystem crossing. Typically the electronic excitation cascades through ring centered pipi* states, ligand to metal charge transfer (LMCT) states, metal to ligand charge transfer (MLCT) states, and metal centered states. Ultrafast transient absorption spectroscopy provides a powerful tool for the investigation of the electronic state dynamics in metal containing tetrapyrroles. The UV-visible spectrum is sensitive to the oxidation state, electronic configuration, spin state, and axial ligation of the central metal atom. Ultrashort broadband white light probes spanning the range from 270 to 800 nm, combined with tunable excitation pulses, permit the detailed unravelling of the time scales involved in the electronic energy cascade. State of-the-art theoretical calculations provide additional insight required for precise assignment of the states. In this Account, we focus on recent ultrafast transient absorption studies of ferric porphyrins and corrin containing cob(III)alamins elucidating the electronic states responsible for ultrafast energy cascades, excited state dynamics, and the resulting photoreactivity or photostability of these compounds. Iron tetraphenyl porphyrin chloride (Fe((III))TPPCl) exhibits picosecond decay to a metal centered d -> d* (4)T state. This state decays on a ca. 16 ps time scale in room temperature solution but persists for much longer in a cryogenic glass. The photoreactivity of the (4)T state may lead to novel future applications for these compounds. In contrast, the nonplanar cob(III)alamins contain two axial ligands to the central cobalt atom. The upper axial ligand can be an alkyl group as in the two biologically active coenzymes or a nonalkyl ligand such as -CN in cyanocobalamin (vitamin B12) or -OH in hydroxocobalamin. The electronic structure, energy cascade, and bond cleavage of these compounds is sensitive to the details of the axial ligand. Nonalkylcobalamins exhibit ultrafast internal conversion to a low lying state of metal to ligand or ligand to metal charge transfer character. The compounds are generally photostable with ground state recovery complete on a time scale of 2-7 ps in room temperature aqueous solution. Alkylcobalamins exhibit ultrafast internal conversion to an S1 state of d/pi -> pi* character. Most compounds undergo bond cleavage from this state with near unit quantum yield within ~100 ps. Recent theoretical calculations provide a potential energy surface accounting for these observations. Conformation dependent mixing of the corrin pi and cobalt d orbitals plays a significant role in the observed photochemistry and photophysics. PMID- 25741575 TI - Efficient C(sp3)-H bond functionalization of isochroman by AZADOL catalysis. AB - A novel organocatalytic C(sp(3))-H bond functionalization of isochroman under practical conditions has been developed. In the presence of 5.0 mol % of AZADOL, the catalysis proceeded successfully with a broad range of substrates and nucleophiles in excellent yields. PMID- 25741576 TI - Enhanced proliferation and osteogenic differentiation of mesenchymal stem cells on graphene oxide-incorporated electrospun poly(lactic-co-glycolic acid) nanofibrous mats. AB - Currently, combining biomaterial scaffolds with living stem cells for tissue regeneration is a main approach for tissue engineering. Mesenchymal stem cells (MSCs) are promising candidates for musculoskeletal tissue repair through differentiating into specific tissues, such as bone, muscle, and cartilage. Thus, successfully directing the fate of MSCs through factors and inducers would improve regeneration efficiency. Here, we report the fabrication of graphene oxide (GO)-doped poly(lactic-co-glycolic acid) (PLGA) nanofiber scaffolds via electrospinning technique for the enhancement of osteogenic differentiation of MSCs. GO-PLGA nanofibrous mats with three-dimensional porous structure and smooth surface can be readily produced via an electrospinning technique. GO plays two roles in the nanofibrous mats: first, it enhances the hydrophilic performance, and protein- and inducer-adsorption ability of the nanofibers. Second, the incorporated GO accelerates the human MSCs (hMSCs) adhesion and proliferation versus pure PLGA nanofiber and induces the osteogenic differentiation. The incorporating GO scaffold materials may find applications in tissue engineering and other fields. PMID- 25741577 TI - Aromatic saddles containing two heptagons. AB - Soluble derivatives of C70H26 (1a,b) and C70H30 (2a,b), two new saddle-shaped polycyclic arenes containing two heptagons, were successfully synthesized from saddle-shaped diketones (3a,b), whose carbonyl groups are the key in the reactions to extend the polycyclic pi-framework. As found from the crystal structures, the polycyclic backbone of 1b has a deep saddle shape, while that of 2b is even more distorted because of the existence of two [4]-helicene moieties. On the basis of crystal structures, local aromaticity and nonplanarity of individual rings in the saddle-shaped pi-backbone were analyzed, and were found to follow Clar's rule in general. It was found that 1b and 3b behaved as p-type semiconductors in solution-processed thin film transistors while the amorphous films of 2b appeared insulating. PMID- 25741578 TI - The utility of gingival crevicular fluid matrix metalloproteinase-8 response patterns in prediction of site-level clinical treatment outcome. AB - BACKGROUND: Different gingival crevicular fluid (GCF) matrix metalloproteinase (MMP)-8 response patterns were studied among non-smoking and smoking patients with chronic periodontitis (CP) and generalized aggressive periodontitis (GAgP) to test the utility of GCF MMP-8 levels predicting the site-level treatment outcome. METHODS: Data from four independent longitudinal studies were combined. Altogether, the studies included 158 periodontal sites from 67 patients with CP and 32 patients with GAgP, and GCF samples were collected at baseline, after the treatment, and during the 6-month maintenance period. All GCF samples were analyzed by immunofluorometric assay for MMP-8. Different site-level MMP-8 response patterns were explored by the cluster analysis. Most optimal MMP-8 cutoff levels were searched with receiver operating characteristic analyses, and the predictive utility of defined levels was tested. RESULTS: Distinct types of MMP-8 response patterns were found in both smokers and non-smokers. MMP-8 levels exceeding the optimal cutoff levels separately defined for smokers and non smokers indicated increased risk for compromised treatment outcome at baseline and during the maintenance period. Seventy-one percent of non-smokers (positive likelihood ratio of 4.22) and 88% of smokers (positive likelihood ratio of 5.00) with positive test results at both baseline and the maintenance period had compromised treatment outcome. The double-positive result indicated 46% and 39% point risk increase for the compromised outcome, respectively. CONCLUSION: GCF MMP-8 analysis with defined cutoff levels could be used to predict the site-level treatment outcome and for longitudinal monitoring of the disease status during the maintenance period. PMID- 25741579 TI - Associations Among Oral Hygiene Behavior and Hypertension Prevalence and Control: The 2008 to 2010 Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Recently, a positive association has been reported between hypertension and periodontitis. The authors hypothesized that oral hygiene promotion activities could have an effect on hypertension prevention or the degree of hypertension control. Therefore, this study examines the relationship between oral hygiene behaviors and hypertension using data from a nationally representative survey, the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: Using data from the KNHANES (2008 to 2010), 19,560 adults with complete data sets were included. The authors analyzed the relationship of the prevalence and control rate of hypertension and numerous variables, including oral hygiene behavior. RESULTS: As the frequency of toothbrushing increased, the prevalence of hypertension decreased in multivariate analysis after adjusting for various factors, including the presence of periodontitis. In a subgroup analysis, this relationship was also observed in individuals without periodontitis. In particular, systolic blood pressure levels progressively decreased as the frequency of toothbrushing and the number of secondary oral products used increased. The adjusted odds ratio of hypertension prevalence was 1.195 (95% confidence interval 1.033 to 1.383) for individuals who brushed their teeth hardly ever or once daily compared with those who brushed after every meal. CONCLUSIONS: Individuals with poor oral hygiene behavior are more likely to have a higher prevalence of hypertension, even before periodontitis is shown. Oral hygiene behavior may be considered an independent risk indicator for hypertension, and maintaining good oral hygiene may help to prevent and control hypertension. PMID- 25741580 TI - Clinical and Biochemical Evaluation of Lozenges Containing Lactobacillus reuteri as an Adjunct to Non-Surgical Periodontal Therapy in Chronic Periodontitis. AB - BACKGROUND: This study evaluates the effects on clinical and biochemical parameters of Lactobacillus reuteri-containing probiotic supplementation adjunctive to initial periodontal therapy in patients with chronic periodontitis (CP). METHODS: Thirty patients with CP were included and divided into two groups. Every patient had, in each quadrant, >=2 teeth each with approximal sites with a probing depth (PD) of 5 to 7 mm and gingival index (GI) of >=2. The test group received scaling and root planing (SRP) and probiotic-containing lozenges. The control group received SRP and placebo lozenges. Plaque index (PI), GI, bleeding on probing (BOP), PD, and attachment gain were measured. Gingival crevicular fluid (GCF) was sampled for the analysis of matrix metalloproteinase (MMP)-8 and tissue inhibitor of metalloproteinase (TIMP)-1 by enzyme-linked immunosorbent assay. All evaluations were performed at baseline and on days 21, 90, 180, and 360. RESULTS: Differences in intergroup comparisons of PI, GI, BOP, and PD were found to be significant (P <0.05) in favor of the test group at all time points. Decreased GCF MMP-8 levels and increased TIMP-1 levels were found to be significant up to day 180 (P <0.05). Mean values of attachment gain were significantly higher in the test group compared with the control group on days 90, 180, and 360. CONCLUSIONS: Lozenges containing L. reuteri may be a useful supplement in moderately deep pockets of patients with CP. Low MMP-8 and high TIMP-1 levels may indicate the role of the lozenges in reduction of inflammation associated markers up to day 180. PMID- 25741581 TI - Effects of electroacupuncture on experimental periodontitis in rats. AB - BACKGROUND: Acupuncture has shown the capability of modulating the immuno inflammatory response of the host. This study aims to evaluate the effects of electroacupuncture (EA) on ligature-induced periodontitis in rats. METHODS: Thirty-two animals were divided into four groups: 1) control; 2) experimental periodontitis (EP); 3) sham-treated (EP/EA-sham); and 4) treated with EA (EP/EA). For the EP groups, a ligature was placed around the right mandibular first molars at day 1. Sessions of EA or EA-sham were assigned every other day. For EA treatment, large intestine meridian points LI4 and LI11 and stomach meridian points ST36 and ST44 were used. EA-sham was performed in off-meridian points. Animals were euthanized at day 11. Histomorphometric and microtomographic analyses were performed. Immunolabeling patterns for the receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), and tartrate resistant acid phosphatase (TRAP) were assessed. Expressions of interleukin (IL) 1beta, matrix metalloproteinase (MMP)-8, IL-6, and cyclooxygenase (COX)-2 messenger RNAs (mRNAs) were evaluated by quantitative reverse transcription polymerase chain reaction. Data were analyzed statistically (P <0.05, analysis of variance). RESULTS: Histomorphometric and microtomographic analyses demonstrated that group EP/EA presented reduced alveolar bone loss when compared to group EP (P <0.05). Reduced RANKL immunolabeling and fewer TRAP-positive multinucleated cells were observed in the EA-treated group in relation to group EP. No differences were observed in OPG expression among groups. EA treatment decreased the genic expression of IL-1beta and MMP-8 (P <0.05), increased the mRNA expression of IL-6 (P <0.05), and did not modify the genic expression of COX-2 in animals with EP (P >0.05). CONCLUSION: It can be concluded that EA reduced periodontal tissue breakdown and the expression of some proinflammatory mediators and a proresorptive factor in EP in rats. PMID- 25741582 TI - The Influence of Triclosan on Biomarkers of Cardiovascular Risk in Patients in the Cardiovascular and Periodontal Study (CAPS): A Randomized Controlled Trial. AB - BACKGROUND: Triclosan toothpaste is effective in controlling plaque and gingivitis and slowing progression of periodontitis; however, its influence on inflammatory biomarkers of cardiovascular disease (CVD), as well as on kidney and liver function, is unknown. METHODS: Patients recruited from the Cardiovascular Unit at Prince Charles Hospital, Brisbane, Australia, were randomized to triclosan (n = 193) or placebo (n = 190) groups and assessed for total cholesterol (TC), high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, triglycerides, C-reactive protein, erythrocyte sedimentation rate (ESR), hemoglobin, total white cell count (WCC), estimated glomerular filtration rate (eGFR), and liver function enzymes, annually for 5 years. A standard mixed model for each marker included group, sex, age, hypertension, diabetes, periodontal status, statin and anti-inflammatory drug use, and smoking as covariates. Changes in eGFR, WCC, and ESR were further analyzed using transition modeling. RESULTS: Triclosan toothpaste led to a greater decrease in TC (P = 0.03), LDL cholesterol (P = 0.04), and HDL cholesterol (P = 0.05) than placebo toothpaste. ESR increased at a slower rate in the triclosan group (P ~ 0.06) and was less likely to increase and more likely to improve in males on statins but not anti-inflammatory drugs in the triclosan group versus the placebo group. Markov modeling of the binary response for eGFR (greater than or less than/equal to the baseline median value) showed that patients with diabetes in the placebo group were significantly (P ~ 0.05) more likely to deteriorate than either patients with diabetes in the triclosan group or patients without diabetes in each group. CONCLUSIONS: These data suggest that triclosan toothpaste may influence some inflammatory biomarkers of CVD, but not kidney or liver function. However, it is unclear if this influence is clinically significant. PMID- 25741583 TI - Meta-Analysis of Association Between Interleukin-1beta C-511T Polymorphism and Chronic Periodontitis Susceptibility. AB - BACKGROUND: Many studies have been conducted to explore the association between interleukin (IL)-1beta C-511T polymorphism and risk of chronic periodontitis (CP) but with different or even contradictory results. A meta-analysis was performed to further explore their association. METHODS: PubMed, Chinese National Knowledge Infrastructure, and EMBASE were searched up to September 30, 2014 for relevant case-control studies. Two authors (D-YL and L-YX) independently selected studies and extracted data from included studies. The meta-analysis was performed using comprehensive meta-analysis software. RESULTS: Nineteen case-control studies involving 2,173 patients with CP and 3,900 healthy controls were included. Using a random-effects meta-analysis model, a non-significant association between IL 1beta C-511T polymorphism and CP was identified (T versus C: odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.85 to 1.25; TT versus CC: OR = 1.03, 95% CI = 0.72 to 1.46; CT versus CC: OR = 0.96, 95% CI = 0.71 to 1.30; CT + TT versus CC: OR = 1.00, 95% CI = 0.74 to 1.34; TT versus CT + CC: OR = 1.05, 95% CI = 0.81 to 1.38), and sensitivity analysis indicated that the results were robust. Subgroup analyses also revealed a non-significant association. No publication bias was detected. CONCLUSIONS: Based on currently available evidence, IL-1beta C 511T polymorphism is not associated with the risk of developing CP. Additional research is warranted to further explore and confirm the association of genetic polymorphism and CP. PMID- 25741584 TI - Unfolding and folding internal friction of beta-hairpins is smaller than that of alpha-helices. AB - By the forced unfolding of polyglutamine and polyalanine homopeptides in competing alpha-helix and beta-hairpin secondary structures, we disentangle equilibrium free energetics from nonequilibrium dissipative effects. We find that alpha-helices are characterized by larger friction or dissipation upon unfolding, regardless of whether they are free energetically preferred over beta-hairpins or not. Our analysis, based on MD simulations for atomistic peptide models with explicit water, suggests that this difference is related to the internal friction and mostly caused by the different number of intrapeptide hydrogen bonds in the alpha-helix and beta-hairpin states. PMID- 25741585 TI - Nuclear membrane R-type calcium channels mediate cytosolic ET-1-induced increase of nuclear calcium in human vascular smooth muscle cells. AB - The objective of this work was to verify whether, as in the case of the plasma membrane of human vascular smooth muscle cells (hVSMCs), cytosolic ET-1-induced increase of nuclear calcium is mediated via the activation of calcium influx through the steady-state R-type calcium channel. Pharmacological tools to identify the R-type calcium channels, as well as real 3-D confocal microscopy imaging techniques coupled to calcium fluorescent probes, were used to study the effect of cytosolic ET-1 on nuclear calcium in isolated nuclei of human hepatocytes and plasma membrane perforated hVSMCs. Our results showed that pre treatment with pertussis toxin (PTX) or cholera toxin (CTX) prevented cytosolic ET-1 (10(-9) mol/L) from inducing a sustained increase in nuclear calcium. Furthermore, the L-type calcium channel blocker nifedipine did not prevent cytosolic ET-1 from inducing an increase in nuclear calcium, as opposed to the dual L- and R-type calcium channel blocker isradipine (PN200-110) (in the presence of nifedipine). In conclusion, the preventative effect with PTX and CTX, and the absence of an effect with nifedipine, as well as the blockade by isradipine on cytosolic ET-1-induced increase in nuclear calcium, suggest that this nuclear calcium influx in hVSMCs is due to activation of the steady-state R type calcium channel. The sarcolemmal and nuclear membrane R-type calcium channels in hVSMCs are involved in ET-1 modulation of vascular tone in physiology and pathology. PMID- 25741586 TI - Unlike catalyzing error-free bypass of 8-oxodGuo, DNA polymerase lambda is responsible for a significant part of Fapy.dG-induced G -> T mutations in human cells. AB - 8-OxodGuo and Fapy.dG induced 10-22% mutations, predominantly G -> T transversions, in human embryonic kidney 293T cells in four TG*N sequence contexts, where N = C, G, A, or T. siRNA knockdown of pol lambda resulted in 34 and 55% increases in the level of mutations in the progeny from the 8-oxodGuo construct in the TG*T and TG*G sequences, respectively, suggesting that pol lambda is involved in error-free bypass of 8-oxodGuo. For Fapy.dG, in contrast, the level of G -> T mutations was reduced by 27 and 46% in the TG*T and TG*G sequences, respectively, suggesting that pol lambda is responsible for a significant fraction of Fapy.dG-induced G -> T mutations. PMID- 25741587 TI - EFFECT OF INDIVIDUAL AND COMMUNITY FACTORS ON MATERNAL HEALTH CARE SERVICE USE IN INDIA: A MULTILEVEL APPROACH. AB - This study aimed to assess empirically the influence of individual and community (neighbourhood) factors on the use of maternal health care services in India through three outcomes: utilization of full antenatal care (ANC) services, safe delivery and utilization of postnatal care services. Data were from the third round of the National Family Health Survey (2005-06). The study sample constituted ever-married women aged 15-49 from 29 Indian states. Multilevel logistic regression analysis was performed for the three outcomes of interest accounting for individual- and community-level factors associated with the use of maternal health care services. A substantial amount of variation was observed at the community level. About 45%, 51% and 62% of the total variance in the use of full ANC, safe delivery and postnatal care, respectively, could be attributed to differences across the community. There was significant variation in the use of maternal health care services at the individual level, with socioeconomic status and mother's education being the most prominent factors associated with the use of maternal health care services. At the community level, urban residence and poverty concentration were found to be significantly associated with maternal health care service use. The results suggest that an increased focus on community level interventions could lead to an increase in the utilization of maternal health care services in India. PMID- 25741588 TI - Divergent responses of soil buffering capacity to long-term N deposition in three typical tropical forests with different land-use history. AB - Elevated anthropogenic nitrogen (N) deposition has become an important driver of soil acidification at both regional and global scales. It remains unclear, however, how long-term N deposition affects soil buffering capacity in tropical forest ecosystems and in ecosystems of contrasting land-use history. Here, we expand on a long-term N deposition experiment in three tropical forests that vary in land-use history (primary, secondary, and planted forests) in Southern China, with N addition as NH4NO3 of 0, 50, 100, and 150 kg N ha(-1) yr(-1), respectively. Results showed that all three forests were acid-sensitive ecosystems with poor soil buffering capacity, while the primary forest had higher base saturation and cation exchange capacity than others. However, long-term N addition significantly accelerated soil acidification and decreased soil buffering capacity in the primary forest, but not in the degraded secondary and planted forests. We suggest that ecosystem N status, influenced by different land use history, is primarily responsible for these divergent responses. N-rich primary forests may be more sensitive to external N inputs than others with low N status, and should be given more attention under global changes in the future, because lack of nutrient cations is irreversible. PMID- 25741589 TI - Protein-templated biomimetic silica nanoparticles. AB - Biomimetic silica particles can be synthesized as a nanosized material within minutes in a process mimicked from living organisms such as diatoms and sponges. In this work, we have studied the effect of bovine serum albumin (BSA) as a template to direct the synthesis of silica nanoparticles (NPs) with the potential to associate proteins on its surface. Our approach enables the formation of spheres with different physicochemical properties. Particles using BSA as a protein template were smaller (~250-380 nm) and were more monodisperse than those lacking the proteic core (~700-1000 nm) as seen by dynamic light scattering (DLS), scanning electron microscopy (SEM), and environmental scanning electron microscopy (ESEM) analysis. The absence of BSA during synthesis produced silica nanoparticles without any porosity that was detectable by nitrogen adsorption, whereas particles containing BSA developed porosity in the range of 4 to 5 nm which collapsed on the removal of BSA, thus producing smaller pores. These results were in accordance with the pore size calculated by high-resolution transmission electron microscopy (HTEM). The reproducibility of the BSA-templated nanoparticle properties was determined by analyzing four batches of independent synthesizing experiments that maintained their properties. The high positive superficial charge of the nanoparticles facilitated adsorption under mild conditions of a range of proteins from an E. coli extract and a commercial preparation of laccase from Trametes versicolor. All of the proteins were quantitatively desorbed. Experiments conducted showed the reusability of the particles as supports for the ionic adsorption of the biomolecules. The protein loading capacity of the BSA-based biomimetic particles was determined using laccase as 98.7 +/- 6.6 mg.g(-1) of particles. PMID- 25741590 TI - Chlorination and monochloramination of 3-aminophenol: kinetics and formation of first by-products. AB - Aminophenols (AP) are synthetic intermediates in pharmaceutical, photographic and chemical dye industry. They can be released into the environment from wastewater and can react during water treatment processes. Therefore, it was interesting to study the oxidation of AP with chlorine and monochloramine in aqueous solution. In particular, the chlorination and monochloramination of 3-aminophenol (3AP) were investigated, and the formation of first by-products and kinetic rates were determined. The chlorination rate was 3.6 * 10(5) times greater than the monochloramination rate at pH 8.6. Two reaction pathways can explain the variation of the monochloramination apparent rate constant with pH. The first one was an electrophilic substitution of Cl(+) on the aromatic ring of the non ionized 3AP, leading to the formation of chloroaminophenol, with an individual rate constant of 6.7 * 10(2) M(-1) h(-1). The second reaction pathway was a monochloramine attack on the amino group of 3AP catalyzed at acidic pH with an individual rate constant of 9.2 * 10(9) * M(-2) * h(-1). PMID- 25741591 TI - RanBP9 at the intersection between cofilin and Abeta pathologies: rescue of neurodegenerative changes by RanBP9 reduction. AB - Molecular pathways underlying the neurotoxicity and production of amyloid beta protein (Abeta) represent potentially promising therapeutic targets for Alzheimer's disease (AD). We recently found that overexpression of the scaffolding protein RanBP9 increases Abeta production in cell lines and in transgenic mice while promoting cofilin activation and mitochondrial dysfunction. Translocation of cofilin to mitochondria and induction of cofilin-actin pathology require the activation/dephosphorylation of cofilin by Slingshot homolog 1 (SSH1) and cysteine oxidation of cofilin. In this study, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates Abeta-induced translocation of cofilin to mitochondria and induction of cofilin-actin pathology in cultured cells, primary neurons, and in vivo. Endogenous level of RanBP9 was also required for Abeta-induced collapse of growth cones in immature neurons (days in vitro 9 (DIV9)) and depletion of synaptic proteins in mature neurons (DIV21). In vivo, amyloid precursor protein (APP)/presenilin-1 (PS1) mice exhibited 3.5-fold increased RanBP9 levels, and RanBP9 reduction protected against cofilin-actin pathology, synaptic damage, gliosis, and Abeta accumulation associated with APP/PS1 mice. Brains slices derived from APP/PS1 mice showed significantly impaired long-term potentiation (LTP), and RanBP9 reduction significantly enhanced paired pulse facilitation and LTP, as well as partially rescued contextual memory deficits associated with APP/PS1 mice. Therefore, these results underscore the critical importance of endogenous RanBP9 not only in Abeta accumulation but also in mediating the neurotoxic actions of Abeta at the level of synaptic plasticity, mitochondria, and cofilin-actin pathology via control of the SSH1-cofilin pathway in vivo. PMID- 25741592 TI - Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model. AB - Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130(Deltahepa)) and control animals (gp130(f/f)) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130(Deltahepa) animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130(Deltahepa) mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130(f/f) and gp130(Deltahepa) animals. However, gp130(Deltahepa) livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-beta (TGFbeta), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC. PMID- 25741593 TI - LincRNA-p21 acts as a mediator of ING1b-induced apoptosis. AB - ING1b is a tumor suppressor that affects transcription, cell cycle control and apoptosis. ING1b is deregulated in disease, and its activity is closely linked to that of p53. In addition to regulating protein-coding genes, we found that ING1b also influences the expression of large intergenic non-coding RNAs (lincRNAs). In particular, lincRNA-p21 was significantly induced after DNA-damage stress or by ING1b overexpression. Furthermore, lincRNA-p21 expression in response to DNA damage was significantly attenuated in cells lacking ING1b. LincRNA-p21 is also a target of p53 and can trigger apoptosis in mouse cell models. We found that this function of lincRNA-p21 is conserved in human cell models. Moreover, ING1b and p53 could function independently to influence lincRNA-p21 expression. However, their effects become more additive under conditions of stress. In particular, ING1b regulates lincRNA-p21 levels by binding to its promoter and is required for induction of lincRNA-p21 by p53. The ability of ING1b to cause apoptosis is also impaired in the absence of lincRNA-p21. Surprisingly, deletion of the ING1b plant homeodomain, which allows it to bind histones and regulate chromatin structure, did not alter regulation of lincRNA-p21. Our findings suggest that ING1b induces lincRNA-p21 expression independently of histone 3 lysine 4 trimethylation mark recognition and that lincRNA-p21 functions downstream of ING1b. Thus, regulation at the level of lincRNA-p21 may represent the point at which ING1b and p53 pathways converge to induce apoptosis under specific stress conditions. PMID- 25741594 TI - T-cell intracellular antigens function as tumor suppressor genes. AB - Knockdown of T-cell intracellular antigens TIA1 and TIAR in transformed cells triggers cell proliferation and tumor growth. Using a tetracycline-inducible system, we report here that an increased expression of TIA1 or TIAR in 293 cells results in reduced rates of cell proliferation. Ectopic expression of these proteins abolish endogenous TIA1 and TIAR levels via the regulation of splicing of their pre-mRNAs, and partially represses global translation in a phospho eukaryotic initiation factor 2 alpha-dependent manner. This is accompanied by cell cycle arrest at G1/S and cell death through caspase-dependent apoptosis and autophagy. Genome-wide profiling illustrates a selective upregulation of p53 signaling pathway-related genes. Nude mice injected with doxycycline-inducible cells expressing TIA1 or TIAR retard, or even inhibit, growth of xenotumors. Remarkably, low expressions of TIA1 and TIAR correlate with poor prognosis in patients with lung squamous cell carcinoma. These findings strongly support the concept that TIA proteins act as tumor suppressor genes. PMID- 25741595 TI - MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway. AB - This study aims to investigate the expression status of miRNA-216b in familial hepatocellular carcinoma (HCC) and the correlation between miRNA-216b expression and pathogenesis, as well as the progression of HCC. The expression profile of miRNAs in plasma of peripheral blood between HCC patients with HCC family history and healthy volunteers without HCC family history was determined by microarray. Using real-time quantitative PCR to detect the expression in paired tissues from 150 patients with HCC, miR-216b was selected as its expression value in HCC patients was significantly lower compared with healthy volunteers. Next, miR-216b expression and the clinicopathological features of HCC were evaluated. The effect of miR-216b expression on tumor cells was investigated by regulating miR-216b expression in SMMC-7721 and HepG2 in vitro and in vivo. Finally, we explored mRNA targets of miR-216b. In 150 HCC, 37 (75%) tumors showed reduced miR-216b expression comparing with their adjacent liver tissues. The decreased expression of miR-216b was significantly correlated with tumor volume (P=0.044), HBV infection (P=0.026), HBV DNA quantitative (P=0.001) and vascular invasion (P=0.032). The 5-year disease-free survival and overall rates after liver resection in low expression and high expression groups of miR-216b are 62% and 54%, 25% and 20%, respectively. MiR-216b overexpression inhibited cell proliferation, migration and invasion, and miR-216b inhibition did the opposite. The expression of hepatitis B virus x protein (HBx) has tight correlation with downregulation of miR-216b. Furthermore, miR-216b downregulated the expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and exerted its tumor-suppressor function through inhibition of protein kinase B and extracellular signal-regulated kinase signaling downstream of IGF2. MiR-216b inhibits cell proliferation, migration and invasion of HCC by regulating IGF2BP2 and it is regulated by HBx. PMID- 25741596 TI - DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function. AB - Death-associated protein kinase (DAPK) 2 is a serine/threonine kinase that belongs to the DAPK family. Although it shows significant structural differences from DAPK1, the founding member of this protein family, DAPK2 is also thought to be a putative tumour suppressor. Like DAPK1, it has been implicated in programmed cell death, the regulation of autophagy and diverse developmental processes. In contrast to DAPK1, however, few mechanistic studies have been carried out on DAPK2 and the majority of these have made use of tagged DAPK2, which almost invariably leads to overexpression of the protein. As a consequence, physiological roles of this kinase are still poorly understood. Using two genetically distinct cancer cell lines as models, we have identified a new role for DAPK2 in the regulation of mitochondrial integrity. RNA interference-mediated depletion of DAPK2 leads to fundamental metabolic changes, including significantly decreased rate of oxidative phosphorylation in combination with overall destabilised mitochondrial membrane potential. This phenotype is further corroborated by an increase in the production of mitochondrial superoxide anions and increased oxidative stress. This then leads to the activation of classical stress-activated kinases such as ERK, JNK and p38, which is observed on DAPK2 genetic ablation. Interestingly, the generation of oxidative stress is further enhanced on overexpression of a kinase-dead DAPK2 mutant indicating that it is the kinase domain of DAPK2 that is important to maintain mitochondrial integrity and, by inference, for cellular metabolism. PMID- 25741598 TI - The ratio of Mcl-1 and Noxa determines ABT737 resistance in squamous cell carcinoma of the skin. PMID- 25741597 TI - Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. AB - Activation of the PERK branch of the unfolded protein response (UPR) in response to protein misfolding within the endoplasmic reticulum (ER) results in the transient repression of protein synthesis, mediated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). This is part of a wider integrated physiological response to maintain proteostasis in the face of ER stress, the dysregulation of which is increasingly associated with a wide range of diseases, particularly neurodegenerative disorders. In prion-diseased mice, persistently high levels of eIF2alpha cause sustained translational repression leading to catastrophic reduction of critical proteins, resulting in synaptic failure and neuronal loss. We previously showed that restoration of global protein synthesis using the PERK inhibitor GSK2606414 was profoundly neuroprotective, preventing clinical disease in prion-infected mice. However, this occured at the cost of toxicity to secretory tissue, where UPR activation is essential to healthy functioning. Here we show that pharmacological modulation of eIF2alpha-P-mediated translational inhibition can be achieved to produce neuroprotection without pancreatic toxicity. We found that treatment with the small molecule ISRIB, which restores translation downstream of eIF2alpha, conferred neuroprotection in prion-diseased mice without adverse effects on the pancreas. Critically, ISRIB treatment resulted in only partial restoration of global translation rates, as compared with the complete restoration of protein synthesis seen with GSK2606414. ISRIB likely provides sufficient rates of protein synthesis for neuronal survival, while allowing some residual protective UPR function in secretory tissue. Thus, fine-tuning the extent of UPR inhibition and subsequent translational de-repression uncouples neuroprotective effects from pancreatic toxicity. The data support the pursuit of this approach to develop new treatments for a range of neurodegenerative disorders that are currently incurable. PMID- 25741599 TI - TRPC1-mediated Ca2+ entry is essential for the regulation of hypoxia and nutrient depletion-dependent autophagy. AB - Autophagy is a cellular catabolic process needed for the degradation and recycling of protein aggregates and damaged organelles. Although Ca(2+) is suggested to have an important role in cell survival, the ion channel(s) involved in autophagy have not been identified. Here we demonstrate that increase in intracellular Ca(2+) via transient receptor potential canonical channel-1 (TRPC1) regulates autophagy, thereby preventing cell death in two morphologically distinct cells lines. The addition of DMOG or DFO, a cell permeable hypoxia mimetic agents, or serum starvation, induces autophagy in both epithelial and neuronal cells. The induction of autophagy increases Ca(2+) entry via the TRPC1 channel, which was inhibited by the addition of 2APB and SKF96365. Importantly, TRPC1-mediated Ca(2+) entry resulted in increased expression of autophagic markers that prevented cell death. Furthermore, hypoxia-mediated autophagy also increased TRPC1, but not STIM1 or Orai1, expression. Silencing of TRPC1 or inhibition of autophagy by 3-methyladenine, but not TRPC3, attenuated hypoxia induced increase in intracellular Ca(2+) influx, decreased autophagy, and increased cell death. Furthermore, the primary salivary gland cells isolated from mice exposed to hypoxic conditions also showed increased expression of TRPC1 as well as increase in Ca(2+) entry along with increased expression of autophagic markers. Altogether, we provide evidence for the involvement of Ca(2+) influx via TRPC1 in regulating autophagy to protect against cell death. PMID- 25741601 TI - In situ conjugation of dithiophenol maleimide polymers and oxytocin for stable and reversible polymer-peptide conjugates. AB - The in situ one-pot synthesis of peptide-polymer bioconjugates is reported. Conjugation occurs efficiently without the need for purification of dithiophenol maleimide functionalized polymer as a disulfide bridging agent for the therapeutic oxytocin. Conjugation of polymers was demonstrated to be reversible and to significantly improve the solution stability of oxytocin. PMID- 25741602 TI - Dielectrophoretic stretching of DNA tethered to a fiber tip. AB - In this work, we studied the stretching of lambda phage DNA molecules immobilized on an optical fiber tip attached to a force sensitive tuning fork under ac electric fields. We designed a two electrodes stretching system in a small chamber: one is a gold-coated optical fiber tip electrode, and the other is a gold-coated flat electrode. By applying a dielectrophoretic (DEP) force, the immobilized lambda DNA molecules on the tip are stretched and the stretching process is monitored by a fluorescent microscope. The DNA stretching in three dimensional space is optimized by varying electrode shape, electrode gap distance, ac frequency, and solution conductivity. By observing the vibrational amplitude change of a quartz tuning fork, we measured the effects due to Joule heating and the DEP force on the tethered DNA molecules in solution. This work demonstrates a method to manipulate and characterize immobilized lambda DNA molecules on a probe tip for further study of single DNA molecules. PMID- 25741600 TI - How cell death shapes cancer. AB - Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury- or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis. PMID- 25741603 TI - Chronic activation of pattern recognition receptors suppresses brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes. AB - Brown adipose tissue (BAT) holds promise to combat obesity through energy spending, non-shivering thermogenesis. Understanding of regulation of BAT development can lead to novel strategies to increase BAT mass and function for obesity treatment and prevention. Here, we report the effects of chronic activation of PRR on brown adipogenesis of multipotent mesodermal stem C3H10T1/2 cells and immortalized brown pre-adipocytes from the classical interscapular BAT of mice. Activation of NOD1, TLR4, or TLR2 by their respective synthetic ligand suppressed brown marker gene expression and lipid accumulation during differentiation of brown-like adipocytes of C3H10T1/2. Activation of the PRR only during the commitment was sufficient to suppress the differentiation. PRR activation suppressed PGC-1alpha mRNA, but induced PRDM16 mRNA at the commitment. Consistently, PRR activation suppressed the differentiation of immortalized brown pre-adipocytes. Activation of PRR induced NF-kappaB activation in both cells, which correlated with their abilities to suppress PPARgamma transactivation, a critical event for brown adipogenesis. Taken together, our results demonstrate that chronic PRR activation suppressed brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes, possibly through suppression of PPARgamma transactivation. The results suggest that anti- inflammatory therapies targeting PRRs may be beneficial for the BAT development. PMID- 25741604 TI - Therapeutic Role of Innovative Anti-Inflammatory Medications in the Prevention of Acute Coronary Syndrome. AB - An improved understanding of the pathogenesis of acute coronary syndromes and its relationship to atherosclerotic plaque rupture and thrombosis has contributed to the investigation of novel therapies for prevention and treatment. New data ascribe an increasingly important role of active inflammation in contributing to thinning of the atherosclerotic fibrous cap and plaque instability. Despite this understanding, there are currently no therapeutic approaches to specifically target the unstable plaque. Multiple randomized trials investigating treatment strategies have recently been completed or are currently being conducted, using anti-inflammatory medications, such as methotrexate, colchicine, darapladib, varespladib, losmapimod, and canakinumab, to reduce the incidence of cardiovascular events including acute coronary syndromes. These anti-inflammatory medications differ in their mechanism of action from having widespread targets (as is the case for methotrexate and colchicine) to having specific targets (as is the case for darapladib, varespladib, losmapimod, and canakinumab). The trials investigating the efficacy of darapladib in reducing cardiovascular events revealed no significant benefit when compared with the current standard of care. The varespladib studies were terminated early because of adverse outcomes. However, the outcomes of the remaining drug studies may still contribute to novel therapeutic approaches in the treatment of patients with unstable coronary artery disease. PMID- 25741605 TI - Frequent Premature Ventricular Contractions: An Electrical Link to Cardiomyopathy. AB - Heart failure is common and is associated with significant morbidity and mortality. Identifying potentially modifiable risk factors for the development of ventricular dysfunction is important in both the prevention and the treatment of this condition. Arrhythmia disorders are increasingly recognized as contributory to the development of ventricular failure. Poorly controlled supraventricular tachyarrhythmias, altered left ventricular activation due to left bundle branch block or right ventricular pacing, and frequent premature ventricular contractions (PVCs) constitute the main subtypes of arrhythmia disorders that are associated with the development of ventricular dysfunction. PVCs are common and are considered benign in the absence of structural heart disease. Frequent PVCs, defined as greater than 20% of all QRS complexes on standard 24-hour Holter monitoring, are associated with the presence or subsequent development of left ventricular dilatation and dysfunction. Catheter ablation of frequent PVCs has been demonstrated to be effective at PVC suppression and is associated with improvement or normalization of ventricular function; thus defining a specific, reversible form of ventricular dysfunction termed PVC cardiomyopathy. In patients presenting with high burden PVCs, an assessment for symptoms and associated cardiomyopathy is warranted and, in the appropriate clinical setting, PVC catheter ablation may be a reasonable treatment option. PMID- 25741606 TI - Catheterization of the carotid artery and jugular vein to perform hemodynamic measures, infusions and blood sampling in a conscious rat model. AB - The success of a small animal model to study critical illness is, in part, dependent on the ability of the model to simulate the human condition. Intra tracheal inoculation of a known amount of bacteria has been successfully used to reproduce the pathogenesis of pneumonia which then develops into sepsis. Monitoring hemodynamic parameters and providing standard clinical treatment including infusion of antibiotics, fluids and drugs to maintain blood pressure is critical to simulate routine supportive care in this model but to do so requires both arterial and venous vascular access. The video details the surgical technique for implanting carotid artery and common jugular vein catheters in an anesthetized rat. Following a 72 hr recovery period, the animals will be re anesthetized and connected to a tether and swivel setup attached to the rodent housing which connects the implanted catheters to the hemodynamic monitoring system. This setup allows free movement of the rat during the study while continuously monitoring pressures, infusing fluids and drugs (antibiotics, vasopressors) and performing blood sampling. PMID- 25741607 TI - Deriving retinal pigment epithelium (RPE) from induced pluripotent stem (iPS) cells by different sizes of embryoid bodies. AB - Pluripotent stem cells possess the ability to proliferate indefinitely and to differentiate into almost any cell type. Additionally, the development of techniques to reprogram somatic cells into induced pluripotent stem (iPS) cells has generated interest and excitement towards the possibility of customized personal regenerative medicine. However, the efficiency of stem cell differentiation towards a desired lineage remains low. The purpose of this study is to describe a protocol to derive retinal pigment epithelium (RPE) from iPS cells (iPS-RPE) by applying a tissue engineering approach to generate homogenous populations of embryoid bodies (EBs), a common intermediate during in vitro differentiation. The protocol applies the formation of specific size of EBs using microwell plate technology. The methods for identifying protein and gene markers of RPE by immunocytochemistry and reverse-transcription polymerase chain reaction (RT-PCR) are also explained. Finally, the efficiency of differentiation in different sizes of EBs monitored by fluorescence-activated cell sorting (FACS) analysis of RPE markers is described. These techniques will facilitate the differentiation of iPS cells into RPE for future applications. PMID- 25741608 TI - Federal workers' compensation programs: Department of Defense and Veterans Health Administration experiences. AB - OBJECTIVE: The objective of this article is to introduce the reader to this special supplement to the Journal of Occupational and Environmental Medicine regarding Federal Workers' Compensation Programs. METHODS: The short history of both the VHA and DoD Federal Workers' Compensation Programs are provided and a short synopsis of each author's article is provided. RESULTS: The lessons learned from the articles in the supplement are summarized in this article and 6 key findings are highlighted. CONCLUSIONS: Cooperation between human resources workers' compensation personnel, safety and occupational health personnel is a must for successful management of the WC program. Information and data sharing are critical for root cause and injury prevention, case management, and cost containment efforts. Enhancing efforts in these areas will save an estimated $100 million through cost avoidance efforts. PMID- 25741609 TI - Managing federal workers' compensation injuries and costs. AB - BACKGROUND: Federal Employees' Compensation Act injury rates and claim costs benefit from injury prevention and case management efforts. The Department of Labor Protecting Our Workers and Ensuring Reemployment data on lost time injuries and illnesses do support injury prevention and case management activities. METHODS: The management efforts of the Department of Defense, Veterans Administration, and Department of Labor were examined to determine whether more is needed to support injury prevention and case management efforts. RESULTS: Data on Protecting Our Workers and Ensuring Reemployment goal 3 metrics should be provided to safety and occupational health (SOH) personnel to support injury prevention and case management efforts. DISCUSSION: Injury prevention and case management data need to be made available to SOH team members to prevent injuries and lower claims costs. CONCLUSION: Actionable information must be provided to SOH that will facilitate case management and injury prevention programs and lower costs. PMID- 25741610 TI - Analysis of new workers' compensation claims in the Department of Defense civilian workforce, 2000-2012. AB - OBJECTIVE: This study of Department of Defense (DoD) civilian employees Workers' Compensation (WC) claims for chargeback year 2000 through 2012 aimed to analyze the frequency, rates, and costs of WC claims representing 5% of the DoD annual personnel budget. METHODS: A multiyear cross-sectional study of WC claims data identified the top five most frequent causes, natures, and anatomical sites; changes in frequency, worker age, costs, and time were evaluated for trends. RESULTS: The annual frequency and rate of new DoD WC claims decreased over time, whereas costs per new claim have increased. New claim frequencies, rates, and costs aggregated in older age groups. CONCLUSIONS: The increasing trend in costs of each claim and the overall program costs presents a need for case management. Analysis of WC claims data is necessary to help target injury prevention efforts and reduce program costs. PMID- 25741611 TI - Investigating the relationship between worker demographics and nature of injury on Federal Department of Defense workers' compensation injury rates and costs from 2000 to 2008. AB - OBJECTIVE: This is the first study of workers' compensation injuries and costs in Department of Defense workers that examined whether any demographic factors including age, sex, occupation, and nature of injury altered the risks or costs of an injury or illness over time. METHODS: Department of Defense Workers' Compensation claims for period 2000 to 2008 were analyzed (n = 142,115) using Defense Portal Analysis and Defense Manpower Data Center to calculate injury rates and costs. Regression analysis was done using SPSS to examine the change in the risk of injury or illness over time from 2000 to 2008. RESULTS: The age group of 30 to 34 years had the lowest costs per claim and highest claims rate, 332 per 10,000. The age group of 65 to 70 years had the lowest claims rate of 188 per 10,000 but the highest costs per claim. Claims cost increased $69 for each 5-year group, and older workers had a threefold increase in costs per claim. CONCLUSION: Younger workers get hurt more often, but older workers tend to have more expensive claims. PMID- 25741612 TI - Impact of clinical quality on employee choice of providers for workers' compensation-related medical care. AB - OBJECTIVE: The study examined the relationship between onsite occupational health practice characteristics, provider choice, and workers' compensation outcome metrics. METHODS: Cross-sectional survey of 140 medical center occupational health clinics within the Department of Veterans Affairs. Multivariate regression models examined how specific clinical quality factors influenced provider choice and workers' compensation measures. RESULTS: Several practice characteristics were associated with higher rates of in-house care selection-longer hours of operation, greater availability of workers' compensation-related medical services, clinic administration by a board certified physician, physician tenure, and adherence to clinical practice guidelines. Access to onsite, occupational and environmental medicine certified physician-directed care was associated with reductions in disability duration among injured healthcare workers. CONCLUSIONS: These findings suggest that occupational medicine board certification can positively impact provider choice among fully insured patients, which may have implications for other healthcare systems. PMID- 25741613 TI - Quality management and federal workers' compensation: the Veterans Health Administration workers' compensation program model. AB - OBJECTIVE: The federal workers' compensation program includes under a single employer five commonly encountered roles and responsibilities-injured patient, clinical provider, third-party administrator, adjudicator, and insurer. Data within the Veterans Health Administration (VHA) provide a unique opportunity to apply a simple model of health care quality improvement, exploring interactions between structures, processes, and outcomes. METHODS: A facility survey identified reporting structures, levels of education and training, policies and processes, tool availability and use, and perceptions of role adherence. Administrative data included process and outcome metrics, including short-term disability, long-term disability, and lost time cases. RESULTS: Improved collaboration between clinical and administrative staff within VHA and with the Department of Labor was associated with improved performance. CONCLUSIONS: Applying a clinical quality improvement model clarifies roles, expectations, and likely relationships for improved program management. PMID- 25741614 TI - Federal workers' compensation program basics. AB - OBJECTIVE: Primary health care providers may not be familiar with the Federal Employees' Compensation Act (FECA) and Department of Defense regulations that govern injured workers' rights, benefits, and procedures to follow when an injured employee is seen in the military medical treatment facility. METHODS: The FECA program was examined and each section reviewed to facilitate provider involvement from time of injury to final disposition of a claim and employee return to work. The best practices in case management are highlighted as well. RESULTS: Several areas of the FECA program require coordination between members of the installation Federal Worker's Compensation team. Areas requiring extensive communication by all team members were emphasized. CONCLUSIONS: Successful installation FECA programs engage all members of the FECA team in a collaborative fashion to share information, prevent injuries, and keep costs low. PMID- 25741615 TI - A brief summary of workers' compensation performance improvement projects 2008 to 2012 in the Veterans Health Administration. AB - BACKGROUND: The Veterans Health Administration undertook a series of performance improvement projects (PIP) using local initiatives identified through a national committee of regional workers' compensation representatives. METHODS: A steering committee identified five types of risks and interventions that were considered worthwhile. They defined performance metrics as outcome measures and distinguished short-term from long-term disability management success. RESULTS: Eight specific PIPs were implemented. No statistically significant differences in the planned outcome metrics were identified, although cost-benefit evaluations did identify a benefit. CONCLUSIONS: Conducting quantitative PIPs in a large system requires top management commitment, sequestration of funds, and mature systems. PMID- 25741616 TI - How can multielectron transfer be realized? A case study with keggin-type polyoxometalates in acetonitrile. AB - Theoretical consideration and computational simulation have been performed on the voltammetric properties of Keggin polyoxometalates (POMs), and the conversion from successive one-electron transfer in unacidified media to four-electron transfer (through two-electron transfer) in acidified media has been discussed. Perfect simulation of the cyclic voltammograms of POMs could be achieved using the standard formal potentials and the protonation constants, systematically evaluated by the equations, in which "simple (intrinsic)" and "synergistic (extrinsic)" electron-withdrawing effects of the MU4-oxygen were taken into consideration. In the proposed model, the formal potential of the one-electron redox waves for the ith reduction step is presented by Ei degrees (z0, s) = Ei** + 0.51(z0 - i + 1) + 1.067s (i = 1, 2, 3, 4; E1** = E2** = 0.577 V; E3** = E4** = 0.377 V), where z0 is the initial ionic charge of a Keggin POM and s is the mean bond valence of the MU4-O-W bonds in the POM. The values of Ei**s are related to the energy levels of the two lowest unoccupied molecular orbitals (LUMOs) of a hypothetical Keggin POM with null charge and null bond valence. Then it was revealed that the LUMOs have small on-site repulsion, which may be an important factor that makes multielectron transfer feasible. These findings would give a big clue in developing novel redox materials exhibiting multielectron transfers. PMID- 25741617 TI - Three-dimensional Co-culture model for tumor-stromal interaction. AB - Cancer progression (initiation, growth, invasion and metastasis) occurs through interactions between malignant cells and the surrounding tumor stromal cells. The tumor microenvironment is comprised of a variety of cell types, such as fibroblasts, immune cells, vascular endothelial cells, pericytes and bone-marrow derived cells, embedded in the extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs) have a pro-tumorigenic role through the secretion of soluble factors, angiogenesis and ECM remodeling. The experimental models for cancer cell survival, proliferation, migration, and invasion have mostly relied on two dimensional monocellular and monolayer tissue cultures or Boyden chamber assays. However, these experiments do not precisely reflect the physiological or pathological conditions in a diseased organ. To gain a better understanding of tumor stromal or tumor matrix interactions, multicellular and three-dimensional cultures provide more powerful tools for investigating intercellular communication and ECM-dependent modulation of cancer cell behavior. As a platform for this type of study, we present an experimental model in which cancer cells are cultured on collagen gels embedded with primary cultures of CAFs. PMID- 25741618 TI - Cost and physician effort analysis of invasive vs. noninvasive respiratory management of Duchenne muscular dystrophy. AB - BACKGROUND: Continuous tracheostomy mechanical ventilation users with Duchenne muscular dystrophy are institutionalized or have home nursing services (licensed practical nurse/registered nurse), whereas patients dependent on continuous noninvasive ventilatory support (CNVS) can avoid hospitalizations and publically paid services. DESIGN AND OBJECTIVE: This is a retrospective analysis comparing cost and physician effort for managing CNVS and continuous tracheostomy mechanical ventilation users with Duchenne muscular dystrophy. RESULTS: Compared with ongoing personal care, physician services and intercurrent hospitalization costs were negligible. Ten home continuous tracheostomy mechanical ventilation users had 16.4 hrs per day of licensed practical nurse/registered nurse care costing $269,370 per year; 14 were institutionalized at $237,350 per year; and 8 were decannulated to CNVS, with 5 subsequently returning home, costing only $9,800 per year for respiratory equipment. For 93 CNVS users, costs ranged from $9,800 per year for 37 without publically funded assistance, $44,968 per year for 3 with nurses' aides, $81,395 per year for 35 with unskilled personal assistance services, and $239,805 per year for 12 with licensed practical nurses/registered nurses. Twenty-eight became CNVS dependent without hospitalization or evaluation for home care. CONCLUSIONS: Noninvasive management permits cost-effective living at home but is disincentivized by fixed hospital diagnosis-related groups compensation that encourages rapid tracheotomy as well as expensive institutionalization and nursing care. PMID- 25741619 TI - Effects of Treadmill Training with Load on Gait in Parkinson Disease: A Randomized Controlled Clinical Trial. AB - OBJECTIVE: The aim of this study was to assess the effects of 3% of body weight loads (0%, 5%, and 10%) on treadmill gait training in subjects with Parkinson disease. DESIGN: This study used a randomized controlled single-blind trial. RESULTS: Spatiotemporal variables demonstrated significant intragroup alterations in all three groups at pretraining and posttraining, with an increase in speed (m/sec; F = 4.73, P = 0.04), stride length (m; F = 12.00, P = 0.002), and step length (m; F = 16.16, P = 0.001) and a decrease in the double-stance phase (%; F = 6.59, P = 0.02) and stance phase (%; F = 4.77, P = 0.04). Intergroup pretraining and posttraining did not exhibit significant differences (F < 2.18, P > 0.14). Angular variables showed significant intragroup alterations, with an increase in knee range of motion (F = 5.18, P = 0.03), and intergroup comparison revealed no significant changes (F = 1.87, P = 0.17). CONCLUSIONS: Posttraining improvements in speed, stride length, step length, double-stance, stance phase, and knee range of motion were observed in all groups, where no load (0%, 5%, or 10%) had any significant effect, suggesting that the influence of load did not make one experimental condition better than another. All participants benefitted from treadmill gait training, irrespective of the use of load. PMID- 25741620 TI - Isokinetic Assessment and Musculoskeletal Complaints in Paralympic Athletes: A Longitudinal Study. AB - OBJECTIVE: The aim of this study was to assess and monitor the peak torque of the knee extensor and flexor muscles in flexion and extension and the reports of musculoskeletal complaints in members of the main Brazilian Paralympic athletics team through 1 yr. DESIGN: Fourteen healthy athletes from both sexes were assessed three times in 1 yr. The volunteers were assessed for the presence of musculoskeletal complaints and muscle strength at three time points: (1) at the onset of the preparatory phase on December 2009, (2) at a follow-up assessment on June 2010, and (3) before actual competition on December 2010. The athletes' self reported musculoskeletal complaints were assessed in structured interviews, and the muscle strength was assessed by means of isokinetic dynamometry. RESULTS: The knee flexor and extensor muscle strength exhibited significant increase in both the right and left lower limbs at the second and third assessments compared with the first one (P < 0.05). Muscle imbalance was associated with knee and thigh complaints at all three assessments (P < 0.05). CONCLUSIONS: The knee flexor and extensor muscle strength exhibited a gradual increase in both lower limbs during the course of the three assessments. In parallel, muscle imbalance was associated with the occurrence of knee and thigh complaints. PMID- 25741621 TI - Review of the evidence of lymphedema treatment effect. AB - Lymphedema treatment aims to alleviate symptoms, prevent progression, and reduce risk for skin infection. Mainstream treatment options have been investigated in more than 160 studies. Findings from these studies have been included in at least 1 of more than 20 literature reviews. A critique of these reviews was undertaken to summarize efficacy findings. The quality of the reviews was evaluated, and gaps in the research were identified to better guide clinical practice. Overall, there was wide variation in review methods. The quality of studies included in reviews, in study design and reporting overall, has been poor. Reviews consistently concluded that complex physical therapy is effective at reducing limb volume. Volume reductions were also reported after the use of compression garments, pumps, and manual lymphatic drainage. However, greatest improvements were reported when these treatments formed a combined treatment program. Large, well-designed, evaluated, and reported randomised, controlled trials are needed to evaluate and compare treatments. Consistent outcome measures will allow better quality reviews and meta-analysis in the future. PMID- 25741622 TI - Virtual environments and virtual humans for military mild traumatic brain injury and posttraumatic stress disorder: an emerging concept. PMID- 25741624 TI - Surface-enhanced spectroscopies. PMID- 25741623 TI - Association between anterior open bite and impact on quality of life of preschool children. AB - The aim of this study was to evaluate the association between different types of malocclusion and the impact on quality of life among preschoolers and their families. A cross-sectional study was carried out involving 451 children 3-5 years of age. A clinical exam was performed to evaluate the malocclusions according to criteria proposed by Foster and Hamilton. This examination was conducted by a calibrated dentist. Parents/caregivers answered the Early Childhood Oral Health Impact Scale (ECOHIS) for the assessment of Oral Health Related Quality of Life (OHRQoL) and the questionnaire on socioeconomic and demographic characteristics. Data analysis involved descriptive statistics, chi square, Mann-Whitney and hierarchically adjusted Poisson regression. The prevalence of malocclusion was 28.4%. The most frequent conditions were posterior crossbite (20.4%), anterior open bite (9.5%) and increased overjet (8.4%). A significant association was found between anterior open bite and OHRQoL (p < 0.001). The adjusted analysis confirmed the association between anterior open bite and a negative impact on quality of life (PR = 2.55; 95%CI: 1.87 to 3.47; p < 0.001). Anterior open bite was associated with a negative impact on the quality of life of preschoolers. PMID- 25741625 TI - Live imaging of innate immune and preneoplastic cell interactions using an inducible Gal4/UAS expression system in larval zebrafish skin. AB - Here we describe a method to conditionally induce epithelial cell transformation by the use of the 4-Hydroxytamoxifen (4-OHT) inducible KalTA4-ERT2/UAS expression system(1) in zebrafish larvae, and the subsequent live imaging of innate immune cell interaction with HRASG12V expressing skin cells. The KalTA4-ERT2/UAS system is both inducible and reversible which allows us to induce cell transformation with precise temporal/spatial resolution in vivo. This provides us with a unique opportunity to live image how individual preneoplastic cells interact with host tissues as soon as they emerge, then follow their progression as well as regression. Recent studies in zebrafish larvae have shown a trophic function of innate immunity in the earliest stages of tumorigenesis(2,3). Our inducible system would allow us to live image the onset of cellular transformation and the subsequent host response, which may lead to important insights on the underlying mechanisms for the regulation of oncogenic trophic inflammatory responses. We also discuss how one might adapt our protocol to achieve temporal and spatial control of ectopic gene expression in any tissue of interest. PMID- 25741626 TI - Reliable energy level alignment at physisorbed molecule-metal interfaces from density functional theory. AB - A key quantity for molecule-metal interfaces is the energy level alignment of molecular electronic states with the metallic Fermi level. We develop and apply an efficient theoretical method, based on density functional theory (DFT) that can yield quantitatively accurate energy level alignment information for physisorbed metal-molecule interfaces. The method builds on the "DFT+Sigma" approach, grounded in many-body perturbation theory, which introduces an approximate electron self-energy that corrects the level alignment obtained from conventional DFT for missing exchange and correlation effects associated with the gas-phase molecule and substrate polarization. Here, we extend the DFT+Sigma approach in two important ways: first, we employ optimally tuned range-separated hybrid functionals to compute the gas-phase term, rather than rely on GW or total energy differences as in prior work; second, we use a nonclassical DFT-determined image-charge plane of the metallic surface to compute the substrate polarization term, rather than the classical DFT-derived image plane used previously. We validate this new approach by a detailed comparison with experimental and theoretical reference data for several prototypical molecule-metal interfaces, where excellent agreement with experiment is achieved: benzene on graphite (0001), and 1,4-benzenediamine, Cu-phthalocyanine, and 3,4,9,10-perylene tetracarboxylic-dianhydride on Au(111). In particular, we show that the method correctly captures level alignment trends across chemical systems and that it retains its accuracy even for molecules for which conventional DFT suffers from severe self-interaction errors. PMID- 25741627 TI - Molecular Simulation of Conformational Pre-Organization in Cyclic RGD Peptides. AB - To test the ability of molecular simulations to accurately predict the solution state conformational properties of peptidomimetics, we examined a test set of 18 cyclic RGD peptides selected from the literature, including the anticancer drug candidate cilengitide, whose favorable binding affinity to integrin has been ascribed to its pre-organization in solution. For each design, we performed all atom replica-exchange molecular dynamics simulations over several microseconds and compared the results to extensive published NMR data. We find excellent agreement with experimental NOE distance restraints, suggesting that molecular simulation can be a useful tool for the computational design of pre-organized solution-state structure. Moreover, our analysis of conformational populations estimates that, despite the potential for increased flexibility due to backbone amide isomerizaton, N-methylation provides about 0.5 kcal/mol of reduced conformational entropy to cyclic RGD peptides. The combination of pre organization and binding-site compatibility explains the strong binding affinity of cilengitide to integrin. PMID- 25741628 TI - Does food vendor density mediate the association between neighborhood deprivation and BMI?: a G-computation mediation analysis. AB - BACKGROUND: In previous research, neighborhood deprivation was positively associated with body mass index (BMI) among adults with diabetes. We assessed whether the association between neighborhood deprivation and BMI is attributable, in part, to geographic variation in the availability of healthful and unhealthful food vendors. METHODS: Subjects were 16,634 participants of the Diabetes Study of Northern California, a multiethnic cohort of adults living with diabetes. Neighborhood deprivation and healthful (supermarket and produce) and unhealthful (fast food outlets and convenience stores) food vendor kernel density were calculated at each participant's residential block centroid. We estimated the total effect, controlled direct effect, natural direct effect, and natural indirect effect of neighborhood deprivation on BMI. Mediation effects were estimated using G-computation, a maximum likelihood substitution estimator of the G-formula that allows for complex data relations such as multiple mediators and sequential causal pathways. RESULTS: We estimated that if neighborhood deprivation was reduced from the most deprived to the least deprived quartile, average BMI would change by -0.73 units (95% confidence interval: -1.05, -0.32); however, we did not detect evidence of mediation by food vendor density. In contrast to previous findings, a simulated reduction in neighborhood deprivation from the most deprived to the least deprived quartile was associated with dramatic declines in both healthful and unhealthful food vendor density. CONCLUSIONS: Availability of food vendors, both healthful and unhealthful, did not appear to explain the association between neighborhood deprivation and BMI in this population of adults with diabetes. PMID- 25741629 TI - The development of a community-based spirometry service in the Canterbury region of New Zealand: observations on new service delivery. AB - In 2008, as part of the changes to develop integrated health care services in the Canterbury region of New Zealand, the local health board in collaboration with general practitioners, respiratory specialists and scientists introduced a programme for general practices to provide laboratory-quality spirometry in the community. The service adhered to the 2005 ATS/ERS international spirometry standards. The spirometry service was provided by trained practice nurses and community respiratory nurses, and was monitored and quality assured by certified respiratory scientists in the Respiratory Physiology Laboratory, Christchurch Hospital and CISO (Canterbury Initiative Services Organisation). These two organisations were responsible for organising training seminars and refresher courses on spirometry technique and interpretation of results. A total of 10 practices have now become approved spirometry providers, with the number of tests carried out in the primary care setting increasing gradually. Consistently high quality spirometry tests have been obtained and are now presented on a centrally available results database for all hospital and community clinicians to review. Although the service has proved to be more convenient for patients, the tests have not been delivered as quickly as those carried out by the Respiratory Physiology Laboratory. However, the time scales for testing achieved by the community service is considered suitable for investigation of chronic disease. The success of the service has been dependent on several key factors including hospital and clinical support and a centralised quality assurance programme, a comprehensive training schedule and online clinical guidance and close integration between primary and secondary care clinicians. PMID- 25741630 TI - Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. AB - In most vertebrates, the liver produces bile that is necessary to emulsify absorbed fats and enable the digestion of lipids in the small intestine as well as to excrete bilirubin and other metabolic products. In the liver, the experimental obstruction of the extrahepatic biliary system initiates a complex cascade of pathological events that leads to cholestasis and inflammation resulting in a strong fibrotic reaction originating from the periportal fields. Therefore, surgical ligation of the common bile duct has become the most commonly used model to induce obstructive cholestatic injury in rodents and to study the molecular and cellular events that underlie these pathophysiological mechanisms induced by inappropriate bile flow. In recent years, different surgical techniques have been described that either allow reconnection or reanastomosis after bile duct ligation (BDL), e.g., partial BDL, or other microsurgical methods for specific research questions. However, the most frequently used model is the complete obstruction of the common bile duct that induces a strong fibrotic response after 21 to 28 days. The mortality rate can be high due to infectious complications or technical inaccuracies. Here we provide a detailed surgical procedure for the BDL model in mice that induce a highly reproducible fibrotic response in accordance to the 3R rule for animal welfare postulated by Russel and Burch in 1959. PMID- 25741631 TI - The role of material deprivation and consumerism in the decisions to engage in transactional sex among young people in the urban slums of Blantyre, Malawi. AB - Transactional sex has been associated with a high risk of HIV acquisition and unintended pregnancy among young women in urban slums in sub-Saharan Africa. However, few studies have explored the structural drivers of transactional sex from the perspective of both genders in these settings. This paper explores how young men and women understand the factors that lead to transactional sex among their peers, and how deprivation of material resources (housing, food and health care access) and consumerism (a desire for fashionable goods) may instigate transactional sex in the urban slums of Blantyre, Malawi. Data from 5 focus group discussions and 12 in-depth interviews undertaken with a total of 60 young men and women aged 18-23 years old, conducted between December 2012 and May 2013, were analysed using anticipated and grounded codes. Housing and food deprivation influenced decisions to engage in transactional sex for both young men and women. Poor health care access and a desire for fashionable goods (such as the latest hair or clothing styles and cellular phones) influenced the decisions of young women that led to transactional sex. Interventions that engage with deprivations and consumerism are essential to reducing sexual and reproductive health risks in urban slums. PMID- 25741632 TI - Electroluminescence from localized defects in zinc oxide: toward electrically driven single photon sources at room temperature. AB - Single photon sources are required for a wide range of applications in quantum information science, quantum cryptography, and quantum communications. However, the majority of room temperature emitters to date are only excited optically, which limits their proper integration into scalable devices. In this work, we overcome this limitation and present room temperature electrically driven light emission from localized defects in zinc oxide (ZnO) nanoparticles and thin films. The devices emit in the red spectral range and show excellent rectifying behavior. The emission is stable over an extensive period of time, providing an important prerequisite for practical devices. Our results open possibilities for building new ZnO-based quantum integrated devices that incorporate solid-state single photon sources for quantum information technologies. PMID- 25741633 TI - Bilateral retinal ischemic vasculopathy in a pregnant patient. AB - PURPOSE: To present the case of a young Turkish pregnant patient with bilateral, sight-threatening retinal ischemic vasculopathy and systemic signs suggestive of Behcet disease (oral ulceration, arthritis, and pseudofolliculitis). METHODS: Case report. RESULTS: Multiple areas of superficial, retinal white lesions and few hemorrhages related to occlusions of small retinal vessels were observed at presentation in the macular zone of both eyes. There was gradual improvement of retinal lesions after the administration of corticosteroids and immunosuppressive treatment. CONCLUSION: We report the case of a young pregnant patient with bilateral, sight-threatening retinal ischemic vasculopathy and systemic signs of Behcet disease. Although the systemic signs were highly suggestive of Behcet disease, the ocular presentation was unusual for this multisystemic inflammatory disorder. The differential diagnosis included a number of causes of ischemic retinal vasculopathy, such as systemic vasculitis, antiphospholipid syndrome, Susac syndrome, Purtscher-like retinopathy, and a new variant of acute macular neuroretinopathy (paracentral, acute middle maculopathy), which are further discussed. PMID- 25741634 TI - Acute, posterior multifocal placoid pigment epitheliopathy: a case of 11 recurrences over 15 years. AB - PURPOSE: To report the case of a patient with recurrent, acute posterior multifocal placoid pigment epitheliopathy. To the best of our knowledge, this is the longest documented course with the greatest number of recurrences reported. METHODS: Observational case report of one patient. A 27-year-old otherwise healthy male patient presented with recurrence of new scotomata over 15 years. Fundus photography, fluorescein angiography, indocyanine green angiography, fundus autofluorescence, and optical coherence tomography documented his clinical course. RESULTS: Over the course of 15 years, the patient developed 11 symptomatic (5 imaging-documented) recurrences of acute, posterior multifocal placoid pigment epitheliopathy affecting both eyes. Each episode manifested with new subjective scotomata and new lesions noted on imaging. Symptoms mostly resolved after each episode, and visual outcome remained excellent (20/20 in the right eye and 20/25 left eye at the last follow-up). CONCLUSION: Although typically monophasic, acute posterior multifocal placoid pigment epitheliopathy can rarely present with a recurrent course over a prolonged period of time and should be considered as a diagnosis in patients presenting with recurrent visual symptoms and new placoid lesions on imaging. In recurrent cases, visual recovery may still remain excellent. PMID- 25741635 TI - Acute vision loss after ocriplasmin use. AB - PURPOSE: There have been reports in the literature of transient vision loss after ocriplasmin injection and ellipsoid layer disruption on spectral domain optical coherence tomography. The authors report a patient with transient vision loss and more prolonged ellipsoid layer dysfunction. PATIENT: The authors present a 55 year-old woman with vitreomacular traction and a small foveal schisis who received ocriplasmin injection and experienced sudden transient vision loss. Spectral domain optical coherence tomography imaging revealed significantly increased schisis, new subretinal cavity, and prolonged ellipsoid layer disruption at 9 months. DISCUSSION: Previous reports suggested that acute vision loss after ocriplasmin injection may be due to ellipsoid layer disruption. This case showed vision loss, which may due to increased foveal schisis and a new subretinal cavity on spectral domain optical coherence tomography imaging. There was little correlation between ellipsoid layer loss and visual function. PMID- 25741636 TI - Super-resolution imaging of the natural killer cell immunological synapse on a glass-supported planar lipid bilayer. AB - The glass-supported planar lipid bilayer system has been utilized in a variety of disciplines. One of the most useful applications of this technique has been in the study of immunological synapse formation, due to the ability of the glass supported planar lipid bilayers to mimic the surface of a target cell while forming a horizontal interface. The recent advances in super-resolution imaging have further allowed scientists to better view the fine details of synapse structure. In this study, one of these advanced techniques, stimulated emission depletion (STED), is utilized to study the structure of natural killer (NK) cell synapses on the supported lipid bilayer. Provided herein is an easy-to-follow protocol detailing: how to prepare raw synthetic phospholipids for use in synthesizing glass-supported bilayers; how to determine how densely protein of a given concentration occupies the bilayer's attachment sites; how to construct a supported lipid bilayer containing antibodies against NK cell activating receptor CD16; and finally, how to image human NK cells on this bilayer using STED super resolution microscopy, with a focus on distribution of perforin positive lytic granules and filamentous actin at NK synapses. Thus, combining the glass supported planar lipid bilayer system with STED technique, we demonstrate the feasibility and application of this combined technique, as well as intracellular structures at NK immunological synapse with super-resolution. PMID- 25741637 TI - A methodological approach to non-invasive assessments of vascular function and morphology. AB - The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis. Damage to the endothelium may predispose the vessel to atherosclerosis and increase the risk for cardiovascular disease. Assessments of peripheral endothelial function are good indicators of early abnormalities in the vascular wall and correlate well with assessments of coronary endothelial function. The present manuscript details the important methodological steps necessary for the assessment of microvascular endothelial function using laser Doppler imaging with iontophoresis, large vessel endothelial function using flow-mediated dilatation, and carotid atherosclerosis using carotid artery ultrasound. A discussion on the methodological considerations for each of the techniques is also presented, and recommendations are made for future research. PMID- 25741638 TI - Association of PNC, BC, and PM2.5 measured at a central monitoring site with blood pressure in a predominantly near highway population. AB - Elevated blood pressure is an indicator of cardiovascular stress and increased risk of cardiovascular-related morbidity and mortality. There is emerging evidence suggesting air pollutants, including particulate matter (PM), could promote hypertension, thereby increasing cardiovascular disease risk. Repeated measurement analyses were conducted to examine the associations of three types of PM with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) in 220 participants, (mean age=58.5 years) from the Community Assessment of Freeway Exposure and Health study (CAFEH), most of whom live near a major highway. Ambient levels of air pollutants including particle number concentration (PNC; a measure of ultrafine particle (UFP) concentration), fine PM (PM2.5, Particle diameter<2.5 um), and black carbon (BC) were measured at a central site<7 km from the study areas. Central sites are good at capturing short term temporal trends in pollution associated with meteorological changes over regional areas. Linear mixed-effect models that accounted for repeated measures within one person were used to examine the associations between blood pressure variables and daily average of ambient PNC, PM2.5, or BC, controlling for demographic characteristics and major confounders including temperature. Our PNC model predicted that a higher PNC of 10,000 particles/cm3 was associated with higher DBP of 2.40 mmHg (p=0.03), independent of other factors in the model. There were no significant associations for PM2.5 or BC. Post hoc subgroup analyses by obesity status showed that positive associations of DBP with PNC were more pronounced among obese individuals than non-obese individuals. These results suggested that PNC levels are associated with increased blood pressure, which may contribute to cardiovascular disease risk. More research is needed to assess the relationship between PNC and blood pressure and to address possible residual confounding. PMID- 25741639 TI - Association between experience of child abuse and severity of drug addiction measured by the Addiction Severity Index among Japanese drug-dependent patients. AB - The aim of the present study was to clarify the association between child abuse experiences and drug addiction severity among Japanese drug-dependent patients using the Addiction Severity Index-Japanese version (ASI-J). One hundred and eleven inpatients and outpatients with drug dependence participated in the study. Some of the questions on the ASI-J asked about lifetime experiences of abuse. A higher percentage of female participants experienced child abuse compared with male participants. Male participants who experienced child abuse (MEA) had a significantly higher severity of drug use than men who did not experience it (MNEA). Female participants who experienced child abuse (FEA) had significantly more serious problems in family/social relationships than female participants who did not experience it (FNEA). Patients in the MEA group were arrested less frequently for drug charges, experienced more serious problems with their fathers, and experienced more severe anxiety in their lifetime compared with the MNEA group. The FEA group experienced more serious troubles with their sexual partners, close friends, and families and experienced more severe psychiatric problems in their lifetime compared with the FNEA group. These results suggest gender differences in the problems experienced by drug-dependent patients with child abuse experiences, and gender-specific interventions may be more effective in treating their drug dependence. PMID- 25741640 TI - Treatment intensification with insulin glargine in patients with inadequately controlled type 2 diabetes improves glycaemic control with a high treatment satisfaction and no weight gain. AB - PRINCIPLES: We aimed to evaluate the efficacy of, and treatment satisfaction with, insulin glargine administered with SoloSTAR(r) or ClikSTAR(r) pens in patients with type 2 diabetes mellitus managed by primary care physicians in Switzerland. METHODS: A total of 327 patients with inadequately controlled type 2 diabetes were enrolled by 72 physicians in this prospective observational study, which aimed to evaluate the efficacy of a 6-month course of insulin glargine therapy measured as development of glycaemic control (glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG]) and weight change. We also assessed preference for reusable or disposable pens, and treatment satisfaction. RESULTS: After 6 months, the mean daily dose of insulin glargine was 27.7+/-14.3 U, and dose titration was completed in 228 (72.4%) patients. Mean HbA1c decreased from 8.9%+/-1.6% (n=327) to 7.3%+/-1.0% (n=315) (p<0.0001), and 138 (43.8%) patients achieved an HbA1c<=7.0%. Mean FPG decreased from 10.9+/-4.5 to 7.3+/-1.8 mmol/l (p<0.0001). Mean body weight did not change (85.4+/-17.2 kg vs 85.0+/-16.5 kg; p=0.11). Patients' preference was in favour of the disposable SoloStar(r) pen (80%), as compared with the reusable ClickStar(r) pen (20%). Overall, 92.6% of physicians and 96.3% of patients were satisfied or very satisfied with the insulin glargine therapy. CONCLUSIONS: In patients with type 2 diabetes insulin glargine administered by SoloSTAR(r) or ClikSTAR(r) pens, education on insulin injection and on self-management of diabetes was associated with clinically meaningful improvements in HbA1c and FPG without a mean collective weight gain. The vast majority of both patients and primary care physicians were satisfied with the treatment intensification. PMID- 25741641 TI - Evaluating the effectiveness of cancer drug sensitization in vitro and in vivo. AB - Due to the high level of heterogeneity and mutations inherent in human cancers, single agent therapies, or combination regimens which target the same pathway, are likely to fail. Emphasis must be placed upon the inhibition of pathways that are responsible for intrinsic and/or adaptive resistance to therapy. An active field of investigation is the development and testing of DNA repair inhibitors that promote the action of, and prevent resistance to, commonly used chemotherapy and radiotherapy. We used a novel protocol to evaluate the effectiveness of BRCA2 inhibition as a means to sensitize tumor cells to the DNA damaging drug cisplatin. Tumor cell metabolism (acidification and respiration) was monitored in real-time for a period of 72 hr to delineate treatment effectiveness on a minute by minute basis. In combination, we performed an assessment of metastatic frequency using a chicken embryo chorioallantoic membrane (CAM) model of extravasation and invasion. This protocol addresses some of the weaknesses of commonly used in vitro and in vivo methods to evaluate novel cancer therapy regimens. It can be used in addition to common methods such as cell proliferation assays, cell death assays, and in vivo murine xenograft studies, to more closely discriminate amongst candidate targets and agents, and select only the most promising candidates for further development. PMID- 25741642 TI - Standardizing Predicted Body Weight Equations for Mechanical Ventilation Tidal Volume Settings. AB - BACKGROUND: Recent recommendations for lung protective mechanical ventilation include a tidal volume target of 6 mL/kg predicted body weight (PBW). Different PBW equations might introduce important differences in tidal volumes delivered to research subjects and patients. METHODS: PBW equations use height, age, and sex as input variables. We compared National Institutes of Health (NIH) ARDS Network (ARDSNet), actuarial table (ACTUARIAL), and Stewart (STEWART) PBW equations used in clinical trials, across physiologic ranges for age and height. We used three dimensional and two-dimensional surface analysis to compare these PBW equations. We then used age and height from actual clinical trial subjects to quantify PBW equation differences. RESULTS: Significant potential differences existed between these PBW predictions. The ACTUARIAL and ARDSNet surfaces for women were the only surfaces that intersected and produced both positive and negative differences. Mathematical differences between PBW equations at limits of height and age exceeded 30% in women and 24% in men for ACTUARIAL vs ARDSNet and about 25% for women and 15% for men for STEWART vs ARDSNet. The largest mathematical differences were present in older, shorter subjects, especially women. Actual differences for clinical trial subjects were as high as 15% for men and 24% for women. CONCLUSIONS: Significant differences between PBW equations for both men and women could be important sources of interstudy variation. Studies should adopt a standard PBW equation. We recommend using the NIH National Heart, Lung, and Blood Institute ARDS Network PBW equation because it is associated with the clinical trial that identified 6 mL/kg PBW as an appropriate target. PMID- 25741643 TI - Loop-mediated isothermal amplification (LAMP) assays for the species-specific detection of Eimeria that infect chickens. AB - Eimeria species parasites, protozoa which cause the enteric disease coccidiosis, pose a serious threat to the production and welfare of chickens. In the absence of effective control clinical coccidiosis can be devastating. Resistance to the chemoprophylactics frequently used to control Eimeria is common and sub-clinical infection is widespread, influencing feed conversion ratios and susceptibility to other pathogens such as Clostridium perfringens. Despite the availability of polymerase chain reaction (PCR)-based tools, diagnosis of Eimeria infection still relies almost entirely on traditional approaches such as lesion scoring and oocyst morphology, but neither is straightforward. Limitations of the existing molecular tools include the requirement for specialist equipment and difficulties accessing DNA as template. In response a simple field DNA preparation protocol and a panel of species-specific loop-mediated isothermal amplification (LAMP) assays have been developed for the seven Eimeria recognised to infect the chicken. We now provide a detailed protocol describing the preparation of genomic DNA from intestinal tissue collected post-mortem, followed by setup and readout of the LAMP assays. Eimeria species-specific LAMP can be used to monitor parasite occurrence, assessing the efficacy of a farm's anticoccidial strategy, and to diagnose sub-clinical infection or clinical disease with particular value when expert surveillance is unavailable. PMID- 25741644 TI - Effects of acupressure on progress of labor and cesarean section rate: randomized clinical trial. AB - OBJECTIVE To analyze the effects of acupressure at the SP6 point on labor duration and cesarean section rates in parturients served in a public maternity hospital. METHODS This controlled, randomized, double-blind, pragmatic clinical trial involved 156 participants with gestational age >= 37 weeks, cervical dilation >= 4 cm, and >= 2 contractions in 10 min. The women were randomly divided into an acupressure, placebo, or control group at a university hospital in an inland city in the state of Sao Paulo, Brazil, in 2013. Acupressure was applied to the SP6 point during contractions for 20 min. RESULTS The average labor duration was significantly different between the SP6 acupressure group [221.5 min (SD = 162.4)] versus placebo [397.9 min (SD = 265.6)] and versus control [381.9 min (SD = 358.3)] (p = 0.0047); however, the groups were similar regarding the cesarean section rates (p = 0.2526) and Apgar scores in the first minute (p = 0.9542) and the fifth minute (p = 0.7218) of life of the neonate. CONCLUSIONS The SP6 acupressure point proved to be a complementary measure to induce labor and may shorten the labor duration without causing adverse effects to the mother or the newborn. However, it did not affect the cesarean section rate. PMID- 25741645 TI - Polio inactivated vaccine costs into routine childhood immunization in Brazil. AB - OBJECTIVE To analyze the costs of vaccination regimens for introducing inactivated polio vaccine in routine immunization in Brazil. METHODS A cost analysis was conducted for vaccines in five vaccination regimens, including inactivated polio vaccine, compared with the oral polio vaccine-only regimen. The costs of the vaccines were estimated for routine use and for the "National Immunization Days", during when the oral polio vaccine is administered to children aged less than five years, independent of their vaccine status, and the strategic stock of inactivated polio vaccine. The presented estimated costs are of 2011. RESULTS The annual costs of the oral vaccine-only program (routine and two National Immunization Days) were estimated at US$19,873,170. The incremental costs of inclusion of the inactivated vaccine depended on the number of vaccine doses, presentation of the vaccine (bottles with single dose or ten doses), and number of "National Immunization Days" carried out. The cost of the regimen adopted with two doses of inactivated vaccine followed by three doses of oral vaccine and one "National Immunization Day" was estimated at US$29,653,539. The concomitant replacement of the DTPw/Hib and HepB vaccines with the pentavalent vaccine enabled the introduction of the inactivated polio without increasing the number of injections or number of visits needed to complete the vaccination. CONCLUSIONS The introduction of the inactivated vaccine increased the annual costs of the polio vaccines by 49.2% compared with the oral vaccine-only regimen. This increase represented 1.13% of the expenditure of the National Immunization Program on the purchase of vaccines in 2011. PMID- 25741646 TI - Access to continued-use medication among older adults, Brazil. AB - OBJECTIVE To determine the prevalence and associated access factors for all continued-use prescription drugs and the ways in which they can be obtained. METHODS Data was obtained from the 2008 Household National Survey. The sample comprised 27,333 individuals above 60 years who reported that they used continued use prescription drugs. A descriptive analysis and binary and multiple multinomial logistic regressions were performed. RESULTS 86.0% of the older adults had access to all the medication they needed, and among them, 50.7% purchased said medication. Those who obtained medication from the public health system were younger (60-64 years), did not have health insurance plans, and belonged to the lower income groups. It is remarkable that 14.0% of the subjects still had no access to any continued-use medication, and for those with more than four chronic diseases, this amount reached 22.0%. Those with a greater number of chronic diseases ran a higher risk of not having access to all the medication they needed. CONCLUSIONS There are some groups of older adults with an increased risk of not obtaining all the medication they need and of purchasing it. The results of this study are expected to contribute to guide programs and plans for access to medication in Brazil. PMID- 25741647 TI - HIV testing and clinical status upon admission to a specialized health care unit in Para, Brazil. AB - OBJECTIVE To analyze the clinical and laboratory characteristics of HIV-infected individuals upon admission to a reference health care center. METHODS This cross sectional study was conducted between 1999 and 2010 on 527 individuals with confirmed serological diagnosis of HIV infection who were enrolled in an outpatient health care service in Santarem, PA, Northern Brazil. Data were collected from medical records and included the reason for HIV testing, clinical status, and count of peripheral CD4+ T lymphocytes upon enrollment. The data were divided into three groups, according to the patient's year of admission - P1 (1999-2002), P2 (2003-2006), and P3 (2007-2010) - for comparative analysis of the variables of interest. RESULTS In the study group, 62.0% of the patients were assigned to the P3 group. The reason for undergoing HIV testing differed between genders. In the male population, most tests were conducted because of the presence of symptoms suggesting infection. Among women, tests were the result of knowledge of the partner's seropositive status in groups P1 and P2. Higher proportion of women undergoing testing because of symptoms of HIV/AIDS infection abolished the difference between genders in the most recent period. A higher percentage of patients enrolling at a more advanced stage of the disease was observed in P3. CONCLUSIONS Despite the increased awareness of the number of HIV/AIDS cases, these patients have identified their serological status late and were admitted to health care units with active disease. The HIV/AIDS epidemic in Para presents specificities in its progression that indicate the complex characteristics of the epidemic in the Northern region of Brazil and across the country. PMID- 25741648 TI - Cyclosporine versus tacrolimus: cost-effectiveness analysis for renal transplantation in Brazil. AB - OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. Moreover, regimens containing cyclosporine were more cost-effective [corrected]. PMID- 25741649 TI - Factors associated with smoking cessation. AB - OBJECTIVE To analyze the prevalence and factors associated with smoking abstinence among patients who were treated in a reference unit for smoking cessation. METHODS This cross-sectional study examined the medical records of 532 patients treated in a reference unit for smoking cessation in Belem, PA, Northern Brazil, between January 2010 and June 2012. Sociodemographic variables and those related to smoking history and treatment were analyzed. Statistical significance was set at p < 0.05. RESULTS The mean age of the participants was 50 years; 57.0% of the patients were women. The mean tobacco load was 30 packs/year, and the mean smoking duration was approximately 32 years. Most patients remained in treatment for four months. The rate of smoking abstinence was 75.0%. Regression analysis indicated that maintenance therapy, absence of relapse triggers, and lower chemical dependence were significantly associated with smoking cessation. CONCLUSIONS The smoking abstinence rate observed was 75.0%. The cessation process was associated with several aspects, including the degree of chemical dependence, symptoms of withdrawal, and period of patient follow-up in a multidisciplinary treatment program. Studies of this nature contribute to the collection of consistent epidemiological data and are essential for the implementation of effective smoking prevention and cessation strategies. PMID- 25741650 TI - Inequalities in health: living conditions and infant mortality in Northeastern Brazil. AB - OBJECTIVE To analyze the variation of infant mortality as per condition of life in the urban setting. METHODS Ecological study performed with data regarding registered deaths of children under the age of one who resided in Aracaju, SE, Northeastern Brazil, from 2001 to 2010. Infant mortality inequalities were assessed based on the spatial distribution of the Living Conditions Index for each neighborhood, classified into four strata. The average mortality rates of 2001-2005 and 2006-2010 were compared using the Student's t-test. RESULTS Average infant mortality rates decreased from 25.3 during 2001-2005 to 17.7 deaths per 1,000 live births in 2006-2010. Despite the decrease in the rates in all the strata during that decade, inequality of infant mortality risks increased in neighborhoods with worse living conditions compared with that in areas with better living conditions. CONCLUSIONS Infant mortality rates in Aracaju showed a decline, but with important differences among neighborhoods. The assessment based on a living condition perspective can explain the differences in the risks of infant mortality rates in urban areas, highlighting health inequalities in infant mortality as a multidimensional issue. PMID- 25741651 TI - Validity and reliability of a health care service evaluation instrument for tuberculosis. AB - OBJECTIVE To evaluate the validity and reliability of an instrument that evaluates the structure of primary health care units for the treatment of tuberculosis. METHODS This cross-sectional study used simple random sampling and evaluated 1,037 health care professionals from five Brazilian municipalities (Natal, state of Rio Grande do Norte; Cabedelo, state of Paraiba; Foz do Iguacu, state of Parana; Sao Jose do Rio Preto, state of Sao Paulo, and Uberaba, state of Minas Gerais) in 2011. Structural indicators were identified and validated, considering different methods of organization of the health care system in the municipalities of different population sizes. Each structure represented the organization of health care services and contained the resources available for the execution of health care services: physical resources (equipment, consumables, and facilities); human resources (number and qualification); and resources for maintenance of the existing infrastructure and technology (deemed as the organization of health care services). The statistical analyses used in the validation process included reliability analysis, exploratory factor analysis, and confirmatory factor analysis. RESULTS The validation process indicated the retention of five factors, with 85.9% of the total variance explained, internal consistency between 0.6460 and 0.7802, and quality of fit of the confirmatory factor analysis of 0.995 using the goodness-of-fit index. The retained factors comprised five structural indicators: professionals involved in the care of tuberculosis patients, training, access to recording instruments, availability of supplies, and coordination of health care services with other levels of care. Availability of supplies had the best performance and the lowest coefficient of variation among the services evaluated. The indicators of assessment of human resources and coordination with other levels of care had satisfactory performance, but the latter showed the highest coefficient of variation. The performance of the indicators "training" and "access to recording instruments" was inferior to that of other indicators. CONCLUSIONS The instrument showed feasibility of application and potential to assess the structure of primary health care units for the treatment of tuberculosis. PMID- 25741652 TI - Determinants of the use of health care services: multilevel analysis in the Metropolitan Region of Sao Paulo. AB - OBJECTIVE To evaluate the individual and contextual determinants of the use of health care services in the metropolitan region of Sao Paulo. METHODS Data from the Sao Paulo Megacity study - the Brazilian version of the World Mental Health Survey multicenter study - were used. A total of 3,588 adults living in 69 neighborhoods in the metropolitan region of Sao Paulo, SP, Southeastern Brazil, including 38 municipalities and 31 neighboring districts, were selected using multistratified sampling of the non-institutionalized population. Multilevel Bayesian logistic models were adjusted to identify the individual and contextual determinants of the use of health care services in the past 12 months and presence of a regular physician for routine care. RESULTS The contextual characteristics of the place of residence (income inequality, violence, and median income) showed no significant correlation (p > 0.05) with the use of health care services or with the presence of a regular physician for routine care. The only exception was the negative correlation between living in areas with high income inequality and presence of a regular physician (OR: 0.77; 95%CI 0.60;0.99) after controlling for individual characteristics. The study revealed a strong and consistent correlation between individual characteristics (mainly education and possession of health insurance), use of health care services, and presence of a regular physician. Presence of chronic and mental illnesses was strongly correlated with the use of health care services in the past year (regardless of the individual characteristics) but not with the presence of a regular physician. CONCLUSIONS Individual characteristics including higher education and possession of health insurance were important determinants of the use of health care services in the metropolitan area of Sao Paulo. A better understanding of these determinants is essential for the development of public policies that promote equitable use of health care services. PMID- 25741653 TI - Trends in healthy life expectancy among older Brazilian women between 1998 and 2008. AB - OBJECTIVE To analyze conditional and unconditional healthy life expectancy among older Brazilian women. METHODS This cross-sectional study used the intercensal technique to estimate, in the absence of longitudinal data, healthy life expectancy that is conditional and unconditional on the individual's current health status. The data used were obtained from the Pesquisa Nacional por Amostra de Domicilios (National Household Sample Survey) of 1998, 2003, and 2008. This sample comprised 11,171; 13,694; and 16,259 women aged 65 years or more, respectively. Complete mortality tables from the Brazilian Institute of Geography and Statistics for the years 2001 and 2006 were also used. The definition of health status was based on the difficulty in performing activities of daily living. RESULTS The remaining lifetime was strongly dependent on the current health status of the older women. Between 1998 and 2003, the amount of time lived with disability for healthy women at age 65 was 9.8%. This percentage increased to 66.2% when the women already presented some disability at age 65. Temporal analysis showed that the active life expectancy of the women at age 65 increased between 1998-2003 (19.3 years) and 2003-2008 (19.4 years). However, life years gained have been mainly focused on the unhealthy state. CONCLUSIONS Analysis of conditional and unconditional life expectancy indicated that live years gained are a result of the decline of mortality in unhealthy states. This pattern suggests that there has been no reduction in morbidity among older women in Brazil between 1998 and 2008. PMID- 25741654 TI - Economic analysis of surgical treatment of hip fracture in older adults. AB - OBJECTIVE To analyze the incremental cost-utility ratio for the surgical treatment of hip fracture in older patients. METHODS This was a retrospective cohort study of a systematic sample of patients who underwent surgery for hip fracture at a central hospital of a macro-region in the state of Minas Gerais, Southeastern Brazil between January 1, 2009 and December 31, 2011. A decision tree creation was analyzed considering the direct medical costs. The study followed the healthcare provider's perspective and had a one-year time horizon. Effectiveness was measured by the time elapsed between trauma and surgery after dividing the patients into early and late surgery groups. The utility was obtained in a cross-sectional and indirect manner using the EuroQOL 5 Dimensions generic questionnaire transformed into cardinal numbers using the national regulations established by the Center for the Development and Regional Planning of the State of Minas Gerais. The sample included 110 patients, 27 of whom were allocated in the early surgery group and 83 in the late surgery group. The groups were stratified by age, gender, type of fracture, type of surgery, and anesthetic risk. RESULTS The direct medical cost presented a statistically significant increase among patients in the late surgery group (p < 0.005), mainly because of ward costs (p < 0.001). In-hospital mortality was higher in the late surgery group (7.4% versus 16.9%). The decision tree demonstrated the dominance of the early surgery strategy over the late surgery strategy: R$9,854.34 (USD4,387.17) versus R$26,754.56 (USD11,911.03) per quality-adjusted life year. The sensitivity test with extreme values proved the robustness of the results. CONCLUSIONS After controlling for confounding variables, the strategy of early surgery for hip fracture in the older adults was proven to be dominant, because it presented a lower cost and better results than late surgery. PMID- 25741655 TI - Cervical cancer screening coverage in a high-incidence region. AB - OBJECTIVE To analyze the coverage of a cervical cancer screening program in a city with a high incidence of the disease in addition to the factors associated with non-adherence to the current preventive program. METHODS A cross-sectional study based on household surveys was conducted. The sample was composed of women between 25 and 59 years of age of the city of Boa Vista, RR, Northern Brazil who were covered by the cervical cancer screening program. The cluster sampling method was used. The dependent variable was participation in a women's health program, defined as undergoing at least one Pap smear in the 36 months prior to the interview; the explanatory variables were extracted from individual data. A generalized linear model was used. RESULTS 603 women were analyzed, with an mean age of 38.2 years (SD = 10.2). Five hundred and seventeen women underwent the screening test, and the prevalence of adherence in the last three years was up to 85.7% (95%CI 82.5;88.5). A high per capita household income and recent medical consultation were associated with the lower rate of not being tested in multivariate analysis. Disease ignorance, causes, and prevention methods were correlated with chances of non-adherence to the screening system; 20.0% of the women were reported to have undergone opportunistic and non-routine screening. CONCLUSIONS The informed level of coverage is high, exceeding the level recommended for the control of cervical cancer. The preventive program appears to be opportunistic in nature, particularly for the most vulnerable women (with low income and little information on the disease). Studies on the diagnostic quality of cervicovaginal cytology and therapeutic schedules for positive cases are necessary for understanding the barriers to the control of cervical cancer. PMID- 25741656 TI - Intimate partner violence after the diagnosis of sexually transmitted diseases. AB - OBJECTIVE To assess the prevalence and factors associated with intimate partner violence after the diagnosis of sexually transmitted diseases. METHODS This cross sectional study was conducted in Fortaleza, CE, Northeastern Brazil, in 2012 and involved 221 individuals (40.3% male and 59.7% female) attended to at reference health care units for the treatment of sexually transmitted diseases. Data were collected using a questionnaire applied during interviews with each participant. A multivariate analysis with a logistic regression model was conducted using the stepwise technique. Only the variables with a p value < 0.05 were included in the adjusted analysis. The odds ratio (OR) with 95% confidence interval (CI) was used as the measure of effect. RESULTS A total of 30.3% of the participants reported experiencing some type of violence (27.6%, psychological; 5.9%, physical; and 7.2%, sexual) after the diagnosis of sexually transmitted disease. In the multivariate analysis adjusted to assess intimate partner violence after the revelation of the diagnosis of sexually transmitted diseases, the following variables remained statistically significant: extramarital relations (OR = 3.72; 95%CI 1.91;7.26; p = 0.000), alcohol consumption by the partner (OR = 2.16; 95%CI 1.08;4.33; p = 0.026), history of violence prior to diagnosis (OR = 2.87; 95%CI 1.44;5.69; p = 0.003), and fear of disclosing the diagnosis to the partner (OR = 2.66; 95%CI 1.32;5.32; p = 0.006). CONCLUSIONS Individuals who had extramarital relations, experienced violence prior to the diagnosis of sexually transmitted disease, feared disclosing the diagnosis to the partner, and those whose partner consumed alcohol had an increased likelihood of suffering violence. The high prevalence of intimate partner violence suggests that this population is vulnerable and therefore intervention efforts should be directed to them. Referral health care services for the treatment of sexually transmitted diseases can be strategic places to identify and prevent intimate partner violence. PMID- 25741657 TI - Violence against metropolitan bus drivers and fare collectors in Brazil. AB - OBJECTIVE To analyze the correlation between sociodemographic factors and working conditions of bus workers in a metropolitan area and violence against them. METHODS This cross-sectional study used a nonprobabilistic sample estimated according to the number of workers employed in bus companies located in three cities in the Belo Horizonte metropolitan region in 2012 (N = 17,470). Face-to face interviews were conducted using a digital questionnaire. The factors associated with violence were analyzed in two stages using Poisson regression, according to each level. The magnitude of the association was evaluated using prevalence ratios with robust variance and a statistical significance of 5%, and 95% confidence intervals were obtained. RESULTS The study sample comprised 782 drivers and 691 fare collectors; 45.0% participants reported at least one act of violence in the workplace in the last 12 months, with passengers being predominantly responsible. The age of the bus workers was inversely associated with violence. Chronic diseases, sickness absenteeism, and working conditions were also associated with violence. CONCLUSIONS The findings on the correlation between violence and working conditions are essential for implementing prevention strategies by transportation service managers. PMID- 25741658 TI - Screening for frailty in older adults using a self-reported instrument. AB - OBJECTIVE To validate a screening instrument using self-reported assessment of frailty syndrome in older adults. METHODS This cross-sectional study used data from the Saude, Bem-estar e Envelhecimento study conducted in Sao Paulo, SP, Southeastern Brazil. The sample consisted of 433 older adult individuals (>= 75 years) assessed in 2009. The self-reported instrument can be applied to older adults or their proxy respondents and consists of dichotomous questions directly related to each component of the frailty phenotype, which is considered the gold standard model: unintentional weight loss, fatigue, low physical activity, decreased physical strength, and decreased walking speed. The same classification proposed in the phenotype was utilized: not frail (no component identified); pre frail (presence of one or two components), and frail (presence of three or more components). Because this is a screening instrument, "process of frailty" was included as a category (pre-frail and frail). Cronbach's alpha was used in psychometric analysis to evaluate the reliability and validity of the criterion, the sensitivity, the specificity, as well as positive and negative predictive values. Factor analysis was used to assess the suitability of the proposed number of components. RESULTS Decreased walking speed and decreased physical strength showed good internal consistency (alpha = 0.77 and 0.72, respectively); however, low physical activity was less satisfactory (alpha = 0.63). The sensitivity and specificity for identifying pre-frail individuals were 89.7% and 24.3%, respectively, while those for identifying frail individuals were 63.2% and 71.6%, respectively. In addition, 89.7% of the individuals from both the evaluations were identified in the "process of frailty" category. CONCLUSIONS The self reported assessment of frailty can identify the syndrome among older adults and can be used as a screening tool. Its advantages include simplicity, rapidity, low cost, and ability to be used by different professionals. PMID- 25741659 TI - Profile and follow-up of patients with tuberculosis in a priority city in Brazil. AB - OBJECTIVE To analyze the cases of tuberculosis and the impact of direct follow-up on the assessment of treatment outcomes. METHODS This open prospective cohort study evaluated 504 cases of tuberculosis reported in the Sistema de Informacao de Agravos de Notificacao (SINAN - Notifiable Diseases Information System) in Juiz de Fora, MG, Southeastern Brazil, between 2008 and 2009. The incidence of treatment outcomes was compared between a group of patients diagnosed with tuberculosis and directly followed up by monthly consultations during return visits (287) and a patient group for which the information was indirectly collected (217) through the city's surveillance system. The Chi-square test was used to compare the percentages, with a significance level of 0.05. The relative risk (RR) was used to evaluate the differences in the incidence rate of each type of treatment outcome between the two groups. RESULTS Of the outcomes directly and indirectly evaluated, 18.5% and 3.2% corresponded to treatment default and 3.8% and 0.5% corresponded to treatment failure, respectively. The incidence of treatment default and failure was higher in the group with direct follow-up (p < 0.05) (RR = 5.72, 95%CI 2.65;12.34, and RR = 8.31, 95%CI 1.08;63.92, respectively). CONCLUSIONS A higher incidence of treatment default and failure was observed in the directly followed up group, and most of these cases were neglected by the disease reporting system. Therefore, effective measures are needed to improve the control of tuberculosis and data quality. PMID- 25741660 TI - Readability of medicinal package leaflets: a systematic review. AB - OBJECTIVE To review studies on the readability of package leaflets of medicinal products for human use. METHODS We conducted a systematic literature review between 2008 and 2013 using the keywords "Readability and Package Leaflet" and "Readability and Package Insert" in the academic search engine Biblioteca do Conhecimento Online, comprising different bibliographic resources/databases. The preferred reporting items for systematic reviews and meta-analyses criteria were applied to prepare the draft of the report. Quantitative and qualitative original studies were included. Opinion or review studies not written in English, Portuguese, Italian, French, or Spanish were excluded. RESULTS We identified 202 studies, of which 180 were excluded and 22 were enrolled [two enrolling healthcare professionals, 10 enrolling other type of participants (including patients), three focused on adverse reactions, and 7 descriptive studies]. The package leaflets presented various readability problems, such as complex and difficult to understand texts, small font size, or few illustrations. The main methods to assess the readability of the package leaflet were usability tests or legibility formulae. Limitations with these methods included reduced number of participants; lack of readability formulas specifically validated for specific languages (e.g., Portuguese); and absence of an assessment on patients literacy, health knowledge, cognitive skills, levels of satisfaction, and opinions. CONCLUSIONS Overall, the package leaflets presented various readability problems. In this review, some methodological limitations were identified, including the participation of a limited number of patients and healthcare professionals, the absence of prior assessments of participant literacy, humor or sense of satisfaction, or the predominance of studies not based on role-plays about the use of medicines. These limitations should be avoided in future studies and be considered when interpreting the results. PMID- 25741661 TI - Distractive Auditory Stimuli in the Form of Music in Individuals With COPD: A Systematic Review. AB - BACKGROUND: Music has been used as a distractive auditory stimulus (DAS) in patients with COPD, but its effects are unclear. This systematic review aimed to establish the effect of DAS on exercise capacity, symptoms, and health-related quality of life (HRQOL) under three conditions: (1) during exercise training, (2) during exercise testing, and (3) for symptom management at rest. METHODS: Randomized controlled or crossover trials as well as cohort studies of DAS during exercise training, during formal exercise testing, and for symptom management among individuals with COPD were identified from a search of seven databases. Two reviewers independently assessed study quality. Weighted mean differences (WMDs) with 95% CIs were calculated using a random-effects model. RESULTS: Thirteen studies (12 of which were randomized controlled or crossover trials) in 415 participants were included. DAS increased exercise capacity when applied over at least 2 months of exercise training (WMD, 98 m; 95% CI, 47-150 m). HRQOL improved only after a training duration of 3 months. Less dyspnea was noted with DAS during exercise training, but this was not consistently observed in short-term exercise testing or as a symptom management strategy at rest. CONCLUSIONS: DAS appears to reduce symptoms of dyspnea and fatigue when used during exercise training, with benefits observed in exercise capacity and HRQOL. When applied during exercise testing, the effects on exercise capacity and symptoms and as a strategy for symptom management at rest are inconsistent. PMID- 25741662 TI - Structure tensor analysis of serial optical coherence scanner images for mapping fiber orientations and tractography in the brain. AB - Quantitative investigations of fiber orientation and structural connectivity at microscopic resolution have led to great challenges for current neuroimaging techniques. Here, we present a structure tensor (ST) analysis of ex vivo rat brain images acquired by a multicontrast (MC) serial optical coherence scanner. The ST considers the gradients of images in local neighbors to generate a matrix whose eigen-decomposition can estimate the local features such as the edges, anisotropy, and orientation of tissue constituents. This computational analysis is applied on the conventional- and polarization-based contrasts of optical coherence tomography. The three-dimensional (3-D) fiber orientation maps are computed from the image stacks of sequential scans both at mesoresolution for a global view and at high-resolution for the details. The computational orientation maps demonstrate a good agreement with the optic axis orientation contrast which measures the in-plane fiber orientation. Moreover, tractography is implemented using the directional information extracted from the 3-D ST. The study provides a unique opportunity to leverage MC high-resolution information to map structural connectivity of the whole brain. PMID- 25741663 TI - Ultrasensitive, real-time analysis of biomarkers in breath using tunable external cavity laser and off-axis cavity-enhanced absorption spectroscopy. AB - A robust biomedical sensor for ultrasensitive detection of biomarkers in breath based on a tunable external cavity laser (ECL) and an off-axis cavity-enhanced absorption spectroscopy (OA-CEAS) using an amplitude stabilizer is developed. A single-mode, narrow-linewidth, tunable ECL is demonstrated. A broadly coarse wavelength tuning range of 720 cm-1 for the spectral range between 6890 and 6170 cm-1 is achieved by rotating the diffraction grating forming a Littrow-type external-cavity configuration. A mode-hop-free tuning range of 1.85 cm-1 is obtained. The linewidths below 140 kHz are recorded. The ECL is combined with an OA-CEAS to perform laser chemical sensing. Our system is able to detect any molecule in breath at concentrations to the ppbv range that have absorption lines in the spectral range between 1450 and 1620 nm. Ammonia is selected as target molecule to evaluate the performance of the sensor. Using the absorption line of ammonia at 6528.76 cm-1, a minimum detectable absorption coefficient of approximately 1*10-8 cm-1 is demonstrated for 256 averages. This is achieved for a 1.4-km absorption path length and a 2-s data-acquisition time. These results yield a detection sensitivity of approximately 8.6*10-10 cm-1 Hz(-1/2). Ammonia in exhaled breath is analyzed and found in a concentration of 870 ppb for our example. PMID- 25741665 TI - Study of tissue oxygen supply rate in a macroscopic photodynamic therapy singlet oxygen model. AB - An appropriate expression for the oxygen supply rate (Gamma(s)) is required for the macroscopic modeling of the complex mechanisms of photodynamic therapy (PDT). It is unrealistic to model the actual heterogeneous tumor microvascular networks coupled with the PDT processes because of the large computational requirement. In this study, a theoretical microscopic model based on uniformly distributed Krogh cylinders is used to calculate Gamma(s) = g (1 - [3O2]/[3O2]0) that can replace the complex modeling of blood vasculature while maintaining a reasonable resemblance to reality; g is the maximum oxygen supply rate and [3O2]/[3O2]0 is the volume-average tissue oxygen concentration normalized to its value prior to PDT. The model incorporates kinetic equations of oxygen diffusion and convection within capillaries and oxygen saturation from oxyhemoglobin. Oxygen supply to the tissue is via diffusion from the uniformly distributed blood vessels. Oxygen can also diffuse along the radius and the longitudinal axis of the cylinder within tissue. The relations of Gamma(s) to [3O2]/[3O2]0 are examined for a biologically reasonable range of the physiological parameters for the microvasculature and several light fluence rates (phi). The results show a linear relationship between Gamma(s) and [3O2]/[3O2]0, independent of phi and photochemical parameters; the obtained g ranges from 0.4 to 1390 MUM/s. PMID- 25741666 TI - Long-term Comparative Effectiveness of Telemedicine in Providing Diabetic Retinopathy Screening Examinations: A Randomized Clinical Trial. AB - IMPORTANCE: Minimal information exists regarding the long-term comparative effectiveness of telemedicine to provide diabetic retinopathy screening examinations. OBJECTIVE: To compare telemedicine to traditional eye examinations in their ability to provide diabetic retinopathy screening examinations. DESIGN, SETTING, AND PARTICIPANTS: From August 1, 2006, through September 31, 2009, 567 participants with diabetes were randomized and followed up to 5 years of follow up (last date of patient follow-up occurred on August 6, 2012) as part of a multicenter randomized clinical trial with an intent to treat analysis. We assigned participants to telemedicine with a nonmydriatic camera in a primary care medical clinic (n = 296) or traditional surveillance with an eye care professional (n = 271). Two years after enrollment, we offered telemedicine to all participants. MAIN OUTCOMES AND MEASURES: Percentage of participants receiving annual diabetic retinopathy screening examinations, percentage of eyes with worsening diabetic retinopathy during the follow-up period using a validated scale from stage 0 (none) to stage 4 (proliferative diabetic retinopathy), and percentage of telemedicine participants who would require referral to an eye care professional for follow-up care using a cutoff of moderate diabetic retinopathy or worse, the presence of macular edema, or an unable-to-determine result for retinopathy or macular edema. RESULTS: The telemedicine group was more likely to receive a diabetic retinopathy screening examination when compared with the traditional surveillance group during the 6-month or less (94.6% [280/296] vs 43.9% [119/271]; 95% CI, 46.6%-54.8%; P < .001) and greater than 6-month through 18-month (53.0% [157/296] vs 33.2% [90/271]; 95% CI, 16.5%-23.1%; P < .001) time bins. After we offered telemedicine to both groups, we could not identify a difference between the groups in the percentage of diabetic retinopathy screening examinations. Diabetic retinopathy worsened by 2 stages or more in 35 (8.6%) of 409 participants (95% CI, 5.8%-11.2%) and improved by 2 stages or more in 5 (1.2%) of 409 participants (95% CI, 0.1%-2.3%) during the 4-year period. The percent of telemedicine participants requiring referral ranged from 19.2% (52/271) to 27.9% (58/208). CONCLUSIONS AND RELEVANCE: Telemedicine increased the percentage of diabetic retinopathy screening examinations, most participants did not require referral to an eye care professional, and diabetic retinopathy levels were generally stable during the study period. This finding suggests that primary care clinics can use telemedicine to screen for diabetic retinopathy and monitor for disease worsening over a long period. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01364129. PMID- 25741667 TI - Bilateral Fetal Hexadactyly Combined with Transient Dacryocystocele. PMID- 25741668 TI - Feasibility of Imaging and Treatment Monitoring of Breast Lesions with Three Dimensional Shear Wave Elastography. AB - Purpose Firstly to evaluate the feasibility and diagnostic performance of three dimensional (3 D) shear wave elastography (SWE) volume measurements in patients with breast lesions compared to breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) lesion volumes and 3D-US B-mode volumes. Secondly to assess the treatment monitoring performance of 3D-SWE in patients under neoadjuvant chemotherapy for breast cancer by comparing it to 3D-US lesion volume. Materials and Methods This prospective study was approved by the institutional review board. Informed consent was provided. 33 patients with 33 lesions were included. The feasibility of 3D-SWE was evaluated in 23 patients. In the 10 remaining patients receiving neoadjuvant chemotherapy, 3D-SWE was evaluated before and during treatment. Tumor volume and qualitative and quantitative elasticity analysis measurements were performed and compared to the tumor volume as estimated by 3D-US and DCE-MRI. Statistical analysis was performed using the Pearson correlation coefficient. Results 3D-SWE was feasible in patients with breast lesions. Tumor volume calculated with 3D-US and 3D-SWE showed very good and moderate concordances with DCE-MRI volume, respectively (Pearson correlation coefficients equal to rho = r = 0.88, p < 0.00 002 and rho = r = 0.5, p = 0.32, respectively). Modification of tumor elasticity and heterogeneity was correlated with response to treatment. In good responders, elasticity and elasticity heterogeneity diminished. Conclusion Tumor 3D-US volume measurements showed very good concordance with DCE-MRI volume. 3D-SWE can provide valuable information: reduction of tissue stiffness during treatment could be a potential indicator of response. These preliminary results should be confirmed on a larger number of patients. PMID- 25741669 TI - High-Resolution Ultrasound Including Contrast-Enhanced Ultrasound (CEUS) for the Detection of Gas Formation during Aspergillus Fumigatus Infection in Mice. AB - PURPOSE: A. fumigatus infections represent a major threat for patients with a suppressed immune system. Early diagnosis is of importance for a favorable outcome but appears to be difficult due to limited diagnostic procedures. Here we investigated the sensitivity of high-resolution ultrasound (HRU) for the detection of A. fumigatus infection in the liver. MATERIALS AND METHODS: BALB/c mice were intravenously infected with A. fumigatus and monitored by HRU, Doppler sonography (CCDS), contrast-enhanced ultrasound (CEUS), and real-time strain color-coded elastography (CCE) using a multi-frequency probe (6 - 15 MHz). Contrast media bolus injection of sulfur-hexafluoride micro-bubbles was applied and digital cine-loops from the arterial phase, as well as the portal venous phase up to the late phase of the whole liver were analyzed. All data were correlated to the histopathological findings. RESULTS: Using HRU and CEUS, a sonic shadow was detected in all infected animals. All Aspergillus-infected nodes from 3 - 6 mm in the liver showed a shadow with rim enhancement and no intranodal enhancement when using CEUS. A. fumigatus infection was confirmed by CFU assessment and histopathological analysis. Granulomas were not associated with shadowing on B-mode. In contrast, granulomas with a diameter above 5 mm and a higher stiffness in CCE generated particularly an arterial rim enhancement and portal venous washout without contrast media uptake in the late phase. In addition, CEUS was able to define dynamic capillary microvascularization of infected liver areas. CONCLUSION: Liver lesions associated with A. fumigatus infection can be detected in mice when combined with CEUS and CCE in vivo. PMID- 25741670 TI - Higher risk of developing sudden sensorineural hearing loss in patients with chronic otitis media. AB - IMPORTANCE: Several sources have suggested an association between chronic sensory hearing impairment and chronic otitis media (COM). However, to our knowledge, no studies have evaluated the risk of sudden sensorineural hearing loss (SSNHL) in patients with COM (COM-positive). OBJECTIVE: To examine the risk of developing SSNHL in COM-positive patients. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study; we compared 10 248 patients with newly diagnosed COM from January 1, 2001, through December 31, 2008, with 30 744 age- and sex-matched controls using data from Taiwan's National Health Insurance Research Database. METHODS: We followed each patient and evaluated the incidence of SSNHL. MAIN OUTCOMES AND MEASURES: The incidence of SSNHL at the end of 2011. RESULTS: The incidence of SSNHL was 3 times higher in the COM-positive cohort than in the COM negative cohort (14.47 vs 4.83 per 10 000 person-years). Cox proportional hazard regressions showed that the adjusted hazard ratio (AHR) was 3.02 (95% CI, 2.30 3.98). A stratified analysis showed that the highest risk of developing SSNHL was in the first follow-up year (incidence rate ratio [IRR], 3.87; 95% CI, 1.93 7.79). Thereafter, the risk declined during years 1 to 5 and then peaked (IRR, 3.01; 95% CI, 1.89-4.79). Patients who needed surgery had a higher incidence of SSNHL (AHR, 2.69; 95% CI, 1.62-4.48) compared with patients who needed only medication and observation. CONCLUSIONS AND RELEVANCE: Chronic otitis media was significantly associated with a higher risk of developing SSNHL. PMID- 25741671 TI - A small volume procedure for viral concentration from water. AB - Small-scale concentration of viruses (sample volumes 1-10 L, here simulated with spiked 100 ml water samples) is an efficient, cost-effective way to identify optimal parameters for virus concentration. Viruses can be concentrated from water using filtration (electropositive, electronegative, glass wool or size exclusion), followed by secondary concentration with beef extract to release viruses from filter surfaces, and finally tertiary concentration resulting in a 5 30 ml volume virus concentrate. In order to identify optimal concentration procedures, two different electropositive filters were evaluated (a glass/cellulose filter [1MDS] and a nano-alumina/glass filter [NanoCeram]), as well as different secondary concentration techniques; the celite technique where three different celite particle sizes were evaluated (fine, medium and large) followed by comparing this technique with that of the established organic flocculation method. Various elution additives were also evaluated for their ability to enhance the release of adenovirus (AdV) particles from filter surfaces. Fine particle celite recovered similar levels of AdV40 and 41 to that of the established organic flocculation method when viral spikes were added during secondary concentration. The glass/cellulose filter recovered higher levels of both, AdV40 and 41, compared to that of a nano-alumina/glass fiber filter. Although not statistically significant, the addition of 0.1% sodium polyphosphate amended beef extract eluant recovered 10% more AdV particles compared to unamended beef extract. PMID- 25741672 TI - Human brown adipose tissue depots automatically segmented by positron emission tomography/computed tomography and registered magnetic resonance images. AB - Reliably differentiating brown adipose tissue (BAT) from other tissues using a non-invasive imaging method is an important step toward studying BAT in humans. Detecting BAT is typically confirmed by the uptake of the injected radioactive tracer 18F-Fluorodeoxyglucose (18F-FDG) into adipose tissue depots, as measured by positron emission tomography/computed tomography (PET-CT) scans after exposing the subject to cold stimulus. Fat-water separated magnetic resonance imaging (MRI) has the ability to distinguish BAT without the use of a radioactive tracer. To date, MRI of BAT in adult humans has not been co-registered with cold activated PET-CT. Therefore, this protocol uses 18F-FDG PET-CT scans to automatically generate a BAT mask, which is then applied to co-registered MRI scans of the same subject. This approach enables measurement of quantitative MRI properties of BAT without manual segmentation. BAT masks are created from two PET CT scans: after exposure for 2 hr to either thermoneutral (TN) (24 degrees C) or cold-activated (CA) (17 degrees C) conditions. The TN and CA PET-CT scans are registered, and the PET standardized uptake and CT Hounsfield values are used to create a mask containing only BAT. CA and TN MRI scans are also acquired on the same subject and registered to the PET-CT scans in order to establish quantitative MRI properties within the automatically defined BAT mask. An advantage of this approach is that the segmentation is completely automated and is based on widely accepted methods for identification of activated BAT (PET-CT). The quantitative MRI properties of BAT established using this protocol can serve as the basis for an MRI-only BAT examination that avoids the radiation associated with PET-CT. PMID- 25741673 TI - Sensitive colorimetric detection of cyromazine in cucumber samples by using label free gold nanoparticles and polythymine. AB - Cyromazine (CYR) can cause serious damage to the organs of animals or human beings, and it was found to bind to polythymine (polyT10) via multiple hydrogen bonding interactions. Based on this novel finding, a highly sensitive and simple colorimetric method was developed for CYR detection by using label-free gold nanoparticles (AuNPs) and polyT10. Under the optimized conditions, excellent linearity was acquired for CYR within the range of 1-500 ng mL(-1). In addition, the spectra and color changes of the AuNP solution were measured by spectrophotometry and observed by the naked eye, and the results showed that as low as 1 and 5 ng mL(-1) of CYR could be detected, depending upon the measurement methods. Afterwards, cucumber was selected to investigate the sample matrix effect and a sample pretreatment procedure was developed with simple homogenization and filtration. Even after 200 times dilution, the limit of detection (LOD) and limit of quantitation (LOQ) reached 252 ng g(-1) and 500 ng g(-1), respectively. The LOD and LOQ satisfied the Chinese requirement for the maximum residue limit (MRL), which is 0.5-1 MUg g(-1) of CYR in most vegetables. The assay also showed a good average recovery of 83.7-104.8% with the RSD of less than 7% and good selectivity for cyromazine over other pesticides that may exist in vegetable samples. The method proposed in this study was simple, fast, and highly sensitive and accurate, and the test result with this method was visible to the naked eye. Therefore, it could be used for routine determination of CYR residues in cucumber samples. PMID- 25741674 TI - Cigarette smoking and cognitive health in elderly Japanese. AB - OBJECTIVE: To examine the relationships between smoking status and various domains of cognitive function in community-dwelling elderly subjects. METHODS: Participants (N = 4348) were asked about smoking status, demographic variables, and lifestyle factors, and underwent multidimensional neurocognitive tests. RESULTS: All analyses were conducted separately by sex. Women never smokers exhibited significantly better scores than past and/or current smokers in some neurocognitive tests. Among men, never smokers had significantly higher scores, such as in the Symbol Digit Substitution Test. Multiple linear regression analysis showed that pack-years (history of smoking) were significantly associated with the Symbol Digit Substitution Test in men. CONCLUSIONS: Smoking status may be associated with a decline in processing speed, and this decline varies by sex. PMID- 25741675 TI - Cervical cancer screening behavior among Hmong-American immigrant women. AB - OBJECTIVES: To investigate Hmong-American immigrant women's utilization of cervical cancer screening, including the impact of cultural health beliefs on screening use. METHODS: Overall, 164 Hmong-American immigrant women 21 to 65 years of age were recruited from a large metropolitan area in the Midwest. We used logistic regression, guided by Andersen's Behavior Model, to examine factors associated with the receipt of Pap test. RESULTS: About 67.1% had received a Pap test within the last 3 years. Fatalism, modesty, education, and marital status were significantly correlated with receiving a Pap test. CONCLUSION: The provision of cervical cancer literacy education and related preventive guidelines to this population are urgently needed to reduce cancer-screening disparity. PMID- 25741676 TI - Use of marijuana and changing risk perceptions. AB - OBJECTIVES: To improve understanding of which adolescents were most likely to perceive marijuana as not harmful. METHODS: Analyses were based on the SHARP survey, conducted in 3 large school districts in Utah in 2009, 2011, and 2013, among students in grades 6, 8, 10, and 12. RESULTS: Across school grades, students who viewed marijuana as not harmful were >=9 times more likely to have used marijuana. The perception that marijuana has no risk was higher in males, Hispanics, youth not living with their mother or father, and increased with school grade and decreased with the education of the student's guardian. CONCLUSIONS: Those historically identified as high risk for marijuana use also were most likely to view marijuana as not harmful. PMID- 25741677 TI - Factors associated with discrimination among minority college students. AB - OBJECTIVES: To assess minority college undergraduate and graduate students' self reported stress, ethnic identity, and skin complexion as predictors of perceptions of racial discrimination. METHODS: The participants (N = 172) were college-aged minority students. A hierarchical multiple regression analysis was conducted to examine the predictive relationship of the study variables on perceived racial discrimination. RESULTS: Skin complexion (beta = .34, p < .05) and ethnic identity (beta = .25, p < .05) had a positive (increased frequency) relationship with racial discrimination. When separated by sex, stress was a statistically significant predictor beta = .24, p < .05) of racial discrimination for males only. CONCLUSIONS: Understanding the predictors of perceived racial discrimination may allow for the development of interventions that alleviate the stress associated with discrimination. PMID- 25741678 TI - Maternal misperceptions of children's overweight in an indigenous Argentinean community. AB - OBJECTIVE: To compare the prevalence of misperception between 2 groups of mothers towards their children's weight status from an indigenous population in San Antonio de los Cobres (SAC) and a Buenos Aires (BA) mixed population. METHODS: Questionnaires regarding mothers' perceptions about their children's shape were performed during 2014. RESULTS: Overall, 152 SAC children (80 males) aged 9.0+2.1 years and 119 BA children (59 males) aged 8.1+1.7 years were evaluated. There was a significant difference in the prevalence of maternal misperception of normal weight vs overweight children in both ethnicities: SAC (38.8% vs 66.7%) and BA (33.3% vs 62.9%). CONCLUSION: These results suggest that maternal misperception of children's overweight was poor in both communities despite having different socio-economic and ethnic backgrounds. PMID- 25741679 TI - Health behaviors and work-related outcomes among school employees. AB - OBJECTIVE: To determine the association between selected health behaviors and work-related outcomes among 2398 school-based employees who voluntarily enrolled in a worksite wellness program. METHODS: This study presents participants' baseline data collected from a personal health assessment used by Well-Steps, a third-party wellness company. RESULTS: Employees with high levels of exercise, fruit/vegetable consumption, or restful sleep exhibited higher job-performance and job-satisfaction, and lower absenteeism (p < .05). When all 3 behaviors occurred simultaneously, there was higher job-performance (Prevalence Ratio=1.09; 95% CI=1.05-1.13), job-satisfaction (Prevalence Ratio=1.53; 95% CI=1.30-1.80), and lower absenteeism (Prevalence Ratio=1.16; 95% CI=1.08-1.325). Further, number of co-occurring health behaviors influenced other satisfaction and emotional health outcomes. CONCLUSION: Selected healthy behaviors, individually or co occurring, are associated with health outcomes potentially important at the worksite. PMID- 25741680 TI - Factors affecting Taiwanese smokers' identification of smuggled cigarettes. AB - OBJECTIVES: To analyze whether the perception that smuggled cigarettes are a greater health risk than legal cigarettes affects Taiwanese smokers' intention to distinguish smuggled cigarettes from legal cigarettes. METHODS: The study used the Recursive Bivariate Probit Model to analyze data from a survey conducted in 2013 of 450 smokers of smuggled cigarettes. RESULTS: The study found that when smokers believe they are more likely to get lung cancer from consuming smuggled cigarettes than they are from consuming legal cigarettes, the probability of the intention to identify smuggled cigarettes increased by 42.46%. CONCLUSIONS: The government should strengthen educational policies and programs that teach consumers about the health risks of smoking in general and the even greater health risks of smoking smuggled cigarettes in particular. PMID- 25741681 TI - E-cigarette marketing and older smokers: road to renormalization. AB - OBJECTIVES: To describe older smokers' perceptions of risks and use of e cigarettes, and their responses to marketing and knowledge of, and opinions about, regulation of e-cigarettes. METHODS: Eight 90-minute focus groups with 8 to 9 participants met in urban and suburban California to discuss topics related to cigarettes and alternative tobacco products. RESULTS: Older adults are using e cigarettes for cessation and as a way to circumvent no-smoking policies; they have false perceptions about the effectiveness and safety of e-cigarettes. They perceive e-cigarette marketing as a way to renormalize smoking. CONCLUSIONS: To stem the current epidemic of nicotine addiction, the FDA must take immediate action because e-cigarette advertising promotes dual use and may contribute to the renormalization of smoking. PMID- 25741682 TI - Contextual factors, indoor tanning, and tanning dependence in young women. AB - OBJECTIVES: To investigate the association of contextual factors such as cost, tanning accessibility, regulations, or marketing and indoor tanning or tanning dependence. METHODS: One hundred thirty-nine college-aged female indoor tanners completed a questionnaire between 2009 and 2011. RESULTS: Higher scores on tanning dependence and assessment in the spring/summer (versus the fall/winter) were associated with more frequent indoor tanning in the last 30 days (ps < .05). More frequent indoor tanning, greater session length, and more trouble paying for tanning were associated with higher scores on tanning dependence (ps < .05). CONCLUSIONS: Public health research and practice could benefit from attention to such contextual factors as tanning cost and regulations regarding session length. PMID- 25741683 TI - Multiple health behavior change in adults with or at risk for cancer: a systematic review. AB - OBJECTIVES: To identify components of efficacious interventions for multiple health behavior change (MHBC) in adult cancer survivors or adults at high risk for cancer. METHODS: A systematic review of MHBC interventions was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework. RESULTS: Ten studies met inclusion criteria. Most studies changed at least 2 health behaviors. Diet, exercise, and smoking cessation were consistently changed with in-person interventions. Longer duration interventions using phone or mail contact had a positive association with changing diet and exercise. CONCLUSIONS: MHBC interventions positively influenced behavior change in adults with cancer and those at high risk for cancer. Future studies should focus on increasing dissemination and implementation of efficacious interventions. PMID- 25741684 TI - mHealth text messaging for physical activity promotion in college students: a formative participatory approach. AB - OBJECTIVES: To develop mobile-based physical activity promotion text messages, understand users' preferences, and assess feasibility and acceptability in a college student sample. METHODS: Five focus groups (N = 33) were conducted using a participatory approach. An Audience Response System was adopted for data collection to ensure confidentiality and for directing the discussion foci. A framework analysis of transcribed focus group discussions was conducted. Atlas. ti qualitative analysis software was used to manage the data. RESULTS: Participants were uniformly enthusiastic about a text message-based intervention to encourage regular physical activity. They also preferred positive, supportive personally tailored messages. Participants placed a high value on messages related to establishing and monitoring realistic and achievable goals. CONCLUSIONS: mHealth text messaging was well received. The results support the feasibility and acceptance of such an intervention. PMID- 25741685 TI - Engagement indicators predict health changes in a lifestyle intervention. AB - OBJECTIVE: To evaluate the utility of several participant engagement indicators for predicting health changes in a church-based lifestyle intervention shown effective for improving dietary, physical activity, and clinical outcomes. METHODS: Descriptive indicators were constructed using 2 participant engagement measures - education session attendance (EDA) and exercise class attendance (EXA) - separately and combined. Relationships of 6 engagement indicators to health outcomes were tested using generalized linear mixed models. RESULTS: EDA predicted 5 dietary and 1 clinical outcome, whereas EXA predicted one physical activity and one clinical outcome. The combined indicator predicted the same 7 outcomes. CONCLUSION: Use of single engagement indicators specific to each intervention component is advocated for predicting relevant health outcome. PMID- 25741686 TI - Conditional risk assessment of adolescents' electronic cigarette perceptions. AB - OBJECTIVES: To adapt an established instrument for measuring adolescents' cigarette-related perceptions for new application with electronic cigarettes (e cigarettes). METHODS: In this exploratory study, 104 male high school students (40% tobacco ever-users) estimated the probability of potential e-cigarette risks (eg, lung cancer) or benefits (eg, look cool). We calculated associations between risk/benefit composite scores, ever-use, and use intention for e-cigarettes, and analogously, for combustible cigarettes. RESULTS: E-cigarette ever-use was associated with lower perceived risks, with adjusted differences versus never users greater for e-cigarettes than for cigarettes. Risk composite score was inversely associated, and benefit score positively associated, with e-cigarette ever-use and use intention. CONCLUSION: Conditional risk assessment characterized adolescents' perceived e-cigarette risk/benefit profile, with potential utility for risk-perception measurement in future studies. PMID- 25741687 TI - Patients', caregivers', and providers' perceived strategies for diabetes care. AB - OBJECTIVES: To explore strategies to improve type 2 diabetes mellitus (T2DM) self management among low-income and minority groups. METHODS: Focus groups centered on T2DM self-care behaviors were conducted using convenient sample of patients with T2DM (N = 17), caregivers (N = 5) and healthcare providers (N = 15). RESULTS: Patients and caregivers perceived strategies included improving patient provider communication, providers' accessibility and compassion, and flexible clinic hours. Strategies identified by providers were realistic patient's expectations, family support, and community resources. CONCLUSIONS: To our knowledge, this study is the first to elicit strategies to improve T2DM self management through a joint meeting of patients, caregivers, and healthcare providers. Study findings could help inform future efforts to assist patients better manage their T2DM. PMID- 25741689 TI - Wavelet transform based on the optimal wavelet pairs for tunable diode laser absorption spectroscopy signal processing. AB - This paper presents a novel methodology-based discrete wavelet transform (DWT) and the choice of the optimal wavelet pairs to adaptively process tunable diode laser absorption spectroscopy (TDLAS) spectra for quantitative analysis, such as molecular spectroscopy and trace gas detection. The proposed methodology aims to construct an optimal calibration model for a TDLAS spectrum, regardless of its background structural characteristics, thus facilitating the application of TDLAS as a powerful tool for analytical chemistry. The performance of the proposed method is verified using analysis of both synthetic and observed signals, characterized with different noise levels and baseline drift. In terms of fitting precision and signal-to-noise ratio, both have been improved significantly using the proposed method. PMID- 25741688 TI - Health literacy, information seeking, and trust in information in Haitians. AB - OBJECTIVES: To assess heath literacy, health information seeking, and trust in health-related information among Haitian immigrants seen in primary care. METHODS: Health literacy was measured by the Brief Health Literacy Screen (BHLS); items on health information use were from the 2007 Health Information National Trends Survey. RESULTS: BHLS scores differed according to age, education, and survey language. Participants with lower levels of health literacy tended to be more likely to place "a lot" or "some" trust in family and friends and religious organizations and leaders as sources of information about health or medical topics. CONCLUSIONS: Constructing a culturally-tailored and appropriate intervention regarding health promotion requires understanding how the population accesses and conveys health information. PMID- 25741690 TI - Correction: Galpha(i2)- and Galpha(i3)-deficient mice display opposite severity of myocardial ischemia reperfusion injury. PMID- 25741691 TI - Subgingival microbial communities in Leukocyte Adhesion Deficiency and their relationship with local immunopathology. AB - Leukocyte Adhesion Deficiency I (LAD-I) is a primary immunodeficiency caused by single gene mutations in the CD18 subunit of beta2 integrins which result in defective transmigration of neutrophils into the tissues. Affected patients suffer from recurrent life threatening infections and severe oral disease (periodontitis). Microbial communities in the local environment (subgingival plaque) are thought to be the triggers for inflammatory periodontitis, yet little is known regarding the microbial communities associated with LAD-I periodontitis. Here we present the first comprehensive characterization of the subgingival communities in LAD-I, using a 16S rRNA gene-based microarray, and investigate the relationship of this tooth adherent microbiome to the local immunopathology of periodontitis. We show that the LAD subgingival microbiome is distinct from that of health and Localized Aggressive Periodontitits. Select periodontitis associated species in the LAD microbiome included Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy and Treponema species. Pseudomonas aeruginosa, a bacterium not typically found in subgingival plaque is detected in LAD-I. We suggest that microbial products from LAD-associated communities may have a role in stimulating the local inflammatory response. We demonstrate that bacterial LPS translocates into the lesions of LAD-periodontitis potentially triggering immunopathology. We also show in in vitro assays with human macrophages and in vivo in animal models that microbial products from LAD-associated subgingival plaque trigger IL-23-related immune responses, which have been shown to dominate in patient lesions. In conclusion, our current study characterizes the subgingival microbial communities in LAD-periodontitis and supports their role as triggers of disease pathogenesis. PMID- 25741693 TI - Correction: NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein. PMID- 25741692 TI - Protein topology determines cysteine oxidation fate: the case of sulfenyl amide formation among protein families. AB - Cysteine residues have a rich chemistry and play a critical role in the catalytic activity of a plethora of enzymes. However, cysteines are susceptible to oxidation by Reactive Oxygen and Nitrogen Species, leading to a loss of their catalytic function. Therefore, cysteine oxidation is emerging as a relevant physiological regulatory mechanism. Formation of a cyclic sulfenyl amide residue at the active site of redox-regulated proteins has been proposed as a protection mechanism against irreversible oxidation as the sulfenyl amide intermediate has been identified in several proteins. However, how and why only some specific cysteine residues in particular proteins react to form this intermediate is still unknown. In the present work using in-silico based tools, we have identified a constrained conformation that accelerates sulfenyl amide formation. By means of combined MD and QM/MM calculation we show that this conformation positions the NH backbone towards the sulfenic acid and promotes the reaction to yield the sulfenyl amide intermediate, in one step with the concomitant release of a water molecule. Moreover, in a large subset of the proteins we found a conserved beta sheet-loop-helix motif, which is present across different protein folds, that is key for sulfenyl amide production as it promotes the previous formation of sulfenic acid. For catalytic activity, in several cases, proteins need the Cysteine to be in the cysteinate form, i.e. a low pKa Cys. We found that the conserved motif stabilizes the cysteinate by hydrogen bonding to several NH backbone moieties. As cysteinate is also more reactive toward ROS we propose that the sheet-loop-helix motif and the constraint conformation have been selected by evolution for proteins that need a reactive Cys protected from irreversible oxidation. Our results also highlight how fold conservation can be correlated to redox chemistry regulation of protein function. PMID- 25741694 TI - Characterization of cellulase secretion and Cre1-mediated carbon source repression in the potential lignocellulose-degrading strain Trichoderma asperellum T-1. AB - Trichoderma asperellum, a traditional bio-control species, was demonstrated to be an excellent candidate for lignocellulose degradation in this work. Comparing to the representatively industrial strain of Trichoderma reeseiQM6a, T. asperellum T 1 showed more robust growth, stronger spore production, faster secretion of lignocellulose-decomposing enzymes and better pH tolerance. The reducing sugar released by strain T-1 on the second day of fermentation was 87% higher than that of strain QM6a, although the maximum reducing sugar yield and the cellulase production persistence of the strain T-1 were lower. Our experiment found that the cellulase secretion was strongly inhibited by glucose, suggesting the existence of carbon source repression pathway in T. asperellum T-1. The inhibiting effect was enhanced with an increase in glucose concentration and was closely related to mycelium growth. SDS-PAGE and secondary mass-spectrum identification confirmed that the expression of endo-1,4-beta-xylanase I in T. asperellum T-1 was down-regulated when glucose was added. The factor Cre1, which plays an important role in the down-regulation of the endo-1,4-beta-xylanase I gene, was investigated by bioinformatics methods. The protein structure of Cre1, analyzed using multiple protein sequence alignment, indicates the existence of the Zn-fingers domain. Then, the binding sites of Cre1 on the endo-1,4-beta xylanase I gene promoter were further elucidated. This study is the first report about Cre1-mediated carbon repression in the bio-control strain T. asperellum T 1. All of the above results provided good references for better understanding T. asperellum T-1 and improving its application for lignocellulose degradation. PMID- 25741696 TI - Lincosamide synthetase--a unique condensation system combining elements of nonribosomal peptide synthetase and mycothiol metabolism. AB - In the biosynthesis of lincosamide antibiotics lincomycin and celesticetin, the amino acid and amino sugar units are linked by an amide bond. The respective condensing enzyme lincosamide synthetase (LS) is expected to be an unusual system combining nonribosomal peptide synthetase (NRPS) components with so far unknown amino sugar related activities. The biosynthetic gene cluster of celesticetin was sequenced and compared to the lincomycin one revealing putative LS coding ORFs shared in both clusters. Based on a bioassay and production profiles of S. lincolnensis strains with individually deleted putative LS coding genes, the proteins LmbC, D, E, F and V were assigned to LS function. Moreover, the newly recognized N-terminal domain of LmbN (LmbN-CP) was also assigned to LS as a NRPS carrier protein (CP). Surprisingly, the homologous CP coding sequence in celesticetin cluster is part of ccbZ gene adjacent to ccbN, the counterpart of lmbN, suggesting the gene rearrangement, evident also from still active internal translation start in lmbN, and indicating the direction of lincosamide biosynthesis evolution. The in vitro test with LmbN-CP, LmbC and the newly identified S. lincolnensis phosphopantetheinyl transferase Slp, confirmed the cooperation of the previously characterized NRPS A-domain LmbC with a holo-LmbN CP in activation of a 4-propyl-L-proline precursor of lincomycin. This result completed the functional characterization of LS subunits resembling NRPS initiation module. Two of the four remaining putative LS subunits, LmbE/CcbE and LmbV/CcbV, exhibit low but significant homology to enzymes from the metabolism of mycothiol, the NRPS-independent system processing the amino sugar and amino acid units. The functions of particular LS subunits as well as cooperation of both NRPS-based and NRPS-independent LS blocks are discussed. The described condensing enzyme represents a unique hybrid system with overall composition quite dissimilar to any other known enzyme system. PMID- 25741695 TI - Individualizing pharmacotherapy in patients with renal impairment: the validity of the Modification of Diet in Renal Disease formula in specific patient populations with a glomerular filtration rate below 60 ml/min. A systematic review. AB - BACKGROUND: The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus. METHODS AND FINDINGS: We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73 m2), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P30% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used. CONCLUSION: In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity. PMID- 25741697 TI - Diversification of the light-harvesting complex gene family via intra- and intergenic duplications in the coral symbiotic alga Symbiodinium. AB - The light-harvesting complex (LHC) is an essential component in light energy capture and transduction to facilitate downstream photosynthetic reactions in plant and algal chloroplasts. The unicellular dinoflagellate alga Symbiodinium is an endosymbiont of cnidarian animals, including corals and sea anemones, and provides carbohydrates generated through photosynthesis to host animals. Although Symbiodinium possesses a unique LHC gene family, called chlorophyll a-chlorophyll c2-peridinin protein complex (acpPC), its genome-level diversity and evolutionary trajectories have not been investigated. Here, we describe a phylogenetic analysis revealing that many of the LHCs are encoded by highly duplicated genes with multi-subunit polyprotein structures in the nuclear genome of Symbiodinium minutum. This analysis provides an extended list of the LHC gene family in a single organism, including 80 loci encoding polyproteins composed of 145 LHC subunits recovered in the phylogenetic tree. In S. minutum, 5 phylogenetic groups of the Lhcf-type gene family, which is exclusively conserved in algae harboring secondary plastids of red algal origin, were identified. Moreover, 5 groups of the Lhcr-type gene family, of which members are known to be associated with PSI in red algal plastids and secondary plastids of red algal origin, were identified. Notably, members classified within a phylogenetic group of the Lhcf type (group F1) are highly duplicated, which may explain the presence of an unusually large number of LHC genes in this species. Some gene units were homologous to other units within single loci of the polyprotein genes, whereas intergenic homologies between separate loci were conspicuous in other cases, implying that gene unit 'shuffling' by gene conversion and/or genome rearrangement might have been a driving force for diversification. These results suggest that vigorous intra- and intergenic gene duplication events have resulted in the genomic framework of photosynthesis in coral symbiont dinoflagellate algae. PMID- 25741698 TI - Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. AB - Necrotizing enterocolitis (NEC) is an inflammatory disease of the newborn bowel, primarily affecting premature infants. Early intestinal colonization has been implicated in the pathogenesis of NEC. The objective of this prospective case control study was to evaluate differences in the intestinal microbiota between infants who developed NEC and unaffected controls prior to disease onset. We conducted longitudinal analysis of the 16S rRNA genes of 312 samples obtained from 12 NEC cases and 26 age-matched controls with a median frequency of 7 samples per subject and median sampling interval of 3 days. We found that the microbiome undergoes dynamic development during the first two months of life with day of life being the major factor contributing to the colonization process. Depending on when the infant was diagnosed with NEC (i.e. early vs. late onset), the pattern of microbial progression was different for cases and controls. The difference in the microbiota was most overt in early onset NEC cases and controls. In proximity to NEC onset, the abundances of Clostridium sensu stricto from Clostridia class were significantly higher in early onset NEC subjects comparing to controls. In late onset NEC, Escherichia/Shigella among Gammaproteobacteria, showed an increasing pattern prior to disease onset, and was significantly higher in cases than controls six days before NEC onset. Cronobacter from Gammaproteobacteria was also significantly higher in late onset NEC cases than controls 1-3 days prior to NEC onset. Thus, the specific infectious agent associated with NEC may vary by the age of infant at disease onset. We found that intravenously administered antibiotics may have an impact on the microbial diversity present in fecal material. Longitudinal analysis at multiple time points was an important strategy utilized in this study, allowing us to appreciate the dynamics of the premature infant intestinal microbiome while approaching NEC at various points. PMID- 25741699 TI - Correction: In situ IgM production and clonal expansion of B-1 cells in peritoneal cavity promote elimination of C. albicans infection in IgH transgenic mice with VH derived from a natural antibody. PMID- 25741700 TI - Erratum: Pleiotropic functions for transcription factor Zscan10. PMID- 25741701 TI - Correction: Gene expression and pathway analysis of effects of the CMAH deactivation on mouse lung, kidney and heart. PMID- 25741702 TI - Consequences of seed origin and biological invasion for early establishment in restoration of a North American grass species. AB - Local, wild-collected seeds of native plants are recommended for use in ecological restoration to maintain patterns of adaptive variation. However, some environments are so drastically altered by exotic, invasive weeds that original environmental conditions may no longer exist. Under these circumstances, cultivated varieties selected for improved germination and vigor may have a competitive advantage at highly disturbed sites. This study investigated differences in early establishment and seedling performance between wild and cultivated seed sources of the native grass, Poa secunda, both with and without competition from the invasive exotic grass, Bromus tectorum. We measured seedling survival and above-ground biomass at two experimental sites in western Montana, and found that the source of seeds selected for restoration can influence establishment at the restoration site. Cultivars had an overall advantage when compared with local genotypes, supporting evidence of greater vigor among cultivated varieties of native species. This advantage, however, declined rapidly in the presence of B. tectorum and most accessions were not significantly different for growth and survival in competition plots. Only one cultivar had a consistent advantage despite a strong decline in its performance when competing with invasive plants. As a result, cultivated varieties did not meet expectations for greater establishment and persistence relative to local genotypes in the presence of invasive, exotic species. We recommend the use of representative local or regional wild seed sources in restoration to minimize commercial selection, and a mix of individual accessions (wild, or cultivated when necessary) in highly invaded settings to capture vigorous genotypes and increase the odds native plants will establish at restoration sites. PMID- 25741703 TI - Evidences of basal lactate production in the main white adipose tissue sites of rats. Effects of sex and a cafeteria diet. AB - Female and male adult Wistar rats were fed standard chow or a simplified cafeteria diet for one month. Then, the rats were killed and the white adipose tissue (WAT) in four sites: perigonadal, retroperitoneal, mesenteric and subcutaneous (inguinal) were sampled and frozen. The complete WAT weight in each site was measured. Gene expression analysis of key lipid and glucose metabolism enzymes were analyzed, as well as tissue and plasma lactate and the activity of lactate dehydrogenase. Lactate gradients between WAT and plasma were estimated. The influence of sex and diet (and indirectly WAT mass) on lactate levels and their relationships with lactate dehydrogenase activity and gene expressions were also measured. A main conclusion is the high production of lactate by WAT, practically irrespective of site, diet or sex. Lactate production is a direct correlate of lactate dehydrogenase activity in the tissue. Furthermore, lactate dehydrogenase activity is again directly correlated with the expression of the genes Ldha and Ldhb for this enzyme. In sum, the ability to produce lactate by WAT is not directly dependent of WAT metabolic state. We postulate that, in WAT, a main function of the lactate dehydrogenase path may be that of converting excess available glucose to 3C fragments, as a way to limit tissue self utilization as substrate, to help control glycaemia and/or providing short chain substrates for use as energy source elsewhere. More information must be gathered before a conclusive role of WAT in the control of glycaemia, and the full existence of a renewed glucose-lactate-fatty acid cycle is definitely established. PMID- 25741704 TI - Blockade of PD-1/PD-L1 promotes adoptive T-cell immunotherapy in a tolerogenic environment. AB - Adoptive cellular immunotherapy using in vitro expanded CD8+ T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC). The co-inhibitory receptor programmed death-1 (PD-1), in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8+ T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD L1 blockade on Tcm-like CD8+ T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8+ T cells. Blockade of PD-1/PD-L1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcm-like cells. PMID- 25741705 TI - Raising the political profile of the neglected zoonotic diseases: three complementary European commission-funded projects to streamline research, build capacity and advocate for control. PMID- 25741706 TI - Challenges with using primer IDs to improve accuracy of next generation sequencing. AB - Next generation sequencing technologies, like ultra-deep pyrosequencing (UDPS), allows detailed investigation of complex populations, like RNA viruses, but its utility is limited by errors introduced during sample preparation and sequencing. By tagging each individual cDNA molecule with barcodes, referred to as Primer IDs, before PCR and sequencing these errors could theoretically be removed. Here we evaluated the Primer ID methodology on 257,846 UDPS reads generated from a HIV 1 SG3Deltaenv plasmid clone and plasma samples from three HIV-infected patients. The Primer ID consisted of 11 randomized nucleotides, 4,194,304 combinations, in the primer for cDNA synthesis that introduced a unique sequence tag into each cDNA molecule. Consensus template sequences were constructed for reads with Primer IDs that were observed three or more times. Despite high numbers of input template molecules, the number of consensus template sequences was low. With 10,000 input molecules for the clone as few as 97 consensus template sequences were obtained due to highly skewed frequency of resampling. Furthermore, the number of sequenced templates was overestimated due to PCR errors in the Primer IDs. Finally, some consensus template sequences were erroneous due to hotspots for UDPS errors. The Primer ID methodology has the potential to provide highly accurate deep sequencing. However, it is important to be aware that there are remaining challenges with the methodology. In particular it is important to find ways to obtain a more even frequency of resampling of template molecules as well as to identify and remove artefactual consensus template sequences that have been generated by PCR errors in the Primer IDs. PMID- 25741707 TI - Spindle assembly checkpoint acquisition at the mid-blastula transition. AB - The spindle assembly checkpoint (SAC) maintains the fidelity of chromosome segregation during mitosis. Nonpathogenic cells lacking the SAC are typically only found in cleavage stage metazoan embryos, which do not acquire functional checkpoints until the mid-blastula transition (MBT). It is unclear how proper SAC function is acquired at the MBT, though several models exist. First, SAC acquisition could rely on transcriptional activity, which increases dramatically at the MBT. Embryogenesis prior to the MBT relies primarily on maternally loaded transcripts, and if SAC signaling components are not maternally supplied, the SAC would depend on zygotic transcription at the MBT. Second, checkpoint acquisition could depend on the Chk1 kinase, which is activated at the MBT to elongate cell cycles and is required for the SAC in somatic cells. Third, SAC function could depend on a threshold nuclear to cytoplasmic (N:C) ratio, which increases during pre-MBT cleavage cycles and dictates several MBT events like zygotic transcription and cell cycle remodeling. Finally, the SAC could by regulated by a timer mechanism that coincides with other MBT events but is independent of them. Using zebrafish embryos we show that SAC acquisition at the MBT is independent of zygotic transcription, indicating that the checkpoint program is maternally supplied. Additionally, by precociously lengthening cleavage cycles with exogenous Chk1 activity, we show that cell cycle lengthening and Chk1 activity are not sufficient for SAC acquisition. Furthermore, we find that SAC acquisition can be uncoupled from the N:C ratio. Together, our findings indicate that SAC acquisition is regulated by a maternally programmed developmental timer. PMID- 25741708 TI - Correction: Reduction of acute rejection by bone marrow mesenchymal stem cells during rat small bowel transplantation. PMID- 25741710 TI - Potential and limitations of intervertebral disc endogenous repair. AB - Intervertebral disc (IVD) disorders, especially degenerative disc disease, reduce the quality of life, and are short of effective therapy. A new direction for treatment of chronic tissue and organ diseases is to promote regeneration by harnessing endogenous repair mechanisms. In this review, we discuss the potential of endogenous repair in the IVD, the recent findings on endogenous IVD progenitor cells, and stem cell niches involved in IVD endogenous repair. We also highlight the factors which may restrict IVD self-healing. Ultimately, advanced therapeutic attempts to boost endogenous repair in the IVD are discussed, including bioactive factor delivery, gene therapy, activation of endogenous IVD progenitor cells and chemokine mediated stem cell homing. PMID- 25741711 TI - Epigenetic Control of Gene Function in Enamel Development. AB - Amelogenesis consists of various development phases that are tightly controlled by the exquisitely sequential and reciprocal interactions between tooth epithelium and mesenchyme. Subtle alterations during this complex physiological and biochemical development events could lead to severe enamel defects in shape, color and structure. Modulations in microRNA, DNA methylation and chromatin modifications are emerging as important regulatory mechanisms during tooth development. The growing field of epigenetic regulations in enamel development provides excellent opportunities to identify novel enamel-related disease makers and to explore the potential therapeutic methods. The present review will give an overview in the current research progress in epigenetic regulation events during tooth development with a highlight in the aspects of enamel formation. PMID- 25741709 TI - Profiling of microRNAs involved in retinal degeneration caused by selective Muller cell ablation. AB - Dysfunction of Muller cells has been implicated in the pathogenesis of several retinal diseases. In order to understand the potential contribution of Muller cells to retinal disease better, we have developed a transgenic model in which foci of Muller cell ablation can be selectively induced. MicroRNAs (miRNAs), small non-coding RNAs that are involved in post-transcriptional modulation, have critical functions in various biological processes. The aim of this study was to profile differential expression of miRNAs and to examine changes in their target genes 2 weeks after Muller cell ablation. We identified 20 miRNAs using the miScript HC PCR array. Data analysis using two target gene prediction databases (TargetScan and mirTarBase) revealed 78 overlapping target genes. DAVID and KEGG pathway analysis suggested that the target genes were generally involved in cell apoptosis, p53, neurotrophin, calcium, chemokine and Jak-STAT signalling pathways. Changes in seven target genes including Cyclin D2, Caspase 9, insulin like growth factor 1, IL-1 receptor-associated kinase (IRAK), calmodulin (CALM) and Janus kinase 2 (Jak2), were validated with qRT-PCR and western blots. The cellular localisation of cleaved-caspase 9, Cyclin D2, Jak2 and CALM was examined by immunofluorescence studies. We found that the transcription of some miRNAs was positively, rather than negatively, correlated with their target genes. After confirming that overexpressed miR-133a-3p was localised to the outer nuclear layer in the damaged retina, we validated the correlation between miR-133a-3p and one of its predicted target genes, cyclin D2, with a luciferase assay in 661 photoreceptor cells. Results revealed by miRNA profiling, target gene analysis and validation were generally consistent with our previous findings that selective Muller cell ablation causes photoreceptor degeneration and neuroinflammation. Our data on alterations of miRNAs and their target gene expression after Muller cell ablation provide further insights into the potential role of Muller cell dysfunction in retinal disease. PMID- 25741712 TI - Enamel Regeneration in Making a Bioengineered Tooth. AB - Overall enamel is the hard tissue overlying teeth that is vulnerable to caries, congenital defects, and damage due to trauma. Not only is enamel incapable of self-repair in most species, but it is also subject to attrition. Besides the use of artificial materials to restore enamel, enamel regeneration is a promising approach to repair enamel damage. In order to comprehend the progression and challenges in tissue-engineered enamel, this article elaborates alternative stem cells potential for enamel secretion and expounds fined strategies for enamel regeneration in bioengineered teeth. Consequently, more and more cell types have been induced to differentiate into ameloblasts and to secrete enamel, and an increasing number of reports have emerged to provide various potential approaches to induce cells to secrete enamel based on recombination experiments, artificial bioactive nano-materials, or gene manipulation. Accordingly, it is expected to further project more optimal conditions for enamel formation in bioengineering based on a more thorough knowledge of reciprocal epithelial-mesenchymal interactions, by which the procedures of enamel regeneration are able to be practically recapitulated and widely spread for the potential clinical value of enamel repair. PMID- 25741713 TI - Correction: Dynamic approximate entropy electroanatomic maps detect rotors in a simulated atrial fibrillation model. PMID- 25741714 TI - Overexpression of galectin-7 in mouse epidermis leads to loss of cell junctions and defective skin repair. AB - BACKGROUND: The proteins of the galectin family are implicated in many cellular processes, including cell interactions, polarity, intracellular trafficking, and signal transduction. In human and mouse, galectin-7 is almost exclusively expressed in stratified epithelia, notably in the epidermis. Galectin-7 expression is also altered in several human tumors of epithelial origin. This study aimed at dissecting the consequences of galectin-7 overexpression on epidermis structure and functions in vivo. METHODS: We established transgenic mice specifically overexpressing galectin-7 in the basal epidermal keratinocytes and analyzed the consequences on untreated skin and after UVB irradiation or mechanical injury. RESULTS: The intercellular cohesion of the epidermis is impaired in transgenic animals, with gaps developing between adjacent keratinocytes, associated with loss of adherens junctions. The epidermal architecture is aberrant with perturbations in the multilayered cellular organisation of the tissue, and structural defects in the basement membrane. These transgenic animals displayed a reduced re-epithelialisation potential following superficial wound, due to a defective collective migration of keratinocytes. Finally, a single mild dose of UVB induced an abnormal apoptotic response in the transgenic epidermis. CONCLUSION: These results indicate that an excess of galectin-7 leads to a destabilisation of adherens junctions associated with defects in epidermal repair. As this phenotype shares similarities with that of galectin-7 null mutant mice, we conclude that a critical level of this protein is required for maintaining proper epidermal homeostasis. This study brings new insight into the mode of action of galectins in normal and pathological situations. PMID- 25741715 TI - Structure-function correlations in stroke. AB - A variety of behavioral deficits can result from stroke. In this issue of Neuron, Corbetta et al. (2015) report that the deficits tend to cluster into just a few sets and are mostly associated with subcortical damage disrupting inter-regional connectivity. PMID- 25741716 TI - Intersectional illumination of neural circuit function. AB - In this issue of Neuron, Madisen et al. (2015) report the construction of several new transgenic mouse lines that apply intersectional genetic tools to achieve high levels of expression and cell-type specificity, providing a useful resource for future studies. PMID- 25741717 TI - More than a FAD: the in vivo effects of disease-linked presenilin-1 mutations. AB - Mutations in presenilins are linked to familial autosomal dominant Alzheimer's disease. In this issue of Neuron, Xia et al. (2015) show that a disease-linked mutation leads to loss of gamma-secretase function, cognitive decline, and neurodegeneration when knocked into the mouse genome. PMID- 25741718 TI - Short circuiting the circadian system with a new generation of precision tools. AB - Circadian behavior in mammals is coordinated by neurons within the suprachiasmatic nucleus (SCN). In this issue, Lee et al. (2015) and Mieda et al. (2015) applied state-of-the-art genetic tools to dissect the microcircuits within the SCN generating circadian rhythmic behavior. PMID- 25741719 TI - From intrinsic firing properties to selective neuronal vulnerability in neurodegenerative diseases. AB - Neurodegenerative diseases (NDDs) involve years of gradual preclinical progression. It is widely anticipated that in order to be effective, treatments should target early stages of disease, but we lack conceptual frameworks to identify and treat early manifestations relevant to disease progression. Here we discuss evidence that a focus on physiological features of neuronal subpopulations most vulnerable to NDDs, and how those features are affected in disease, points to signaling pathways controlling excitation in selectively vulnerable neurons, and to mechanisms regulating calcium and energy homeostasis. These hypotheses could be tested in neuronal stress tests involving animal models or patient-derived iPS cells. PMID- 25741720 TI - Homeoprotein signaling in the developing and adult nervous system. AB - Signaling classically involves the secretion of diverse molecules that bind specific cell-surface receptors and engage intracellular transduction cascades. Some exceptions-namely, lipophilic agents-can cross plasma membranes to bind intracellular receptors and be carried to the nucleus to regulate transcription. Homeoprotein transcription factors are among the few proteins with such a capacity. Here, we review the signaling activities of homeoproteins in the developing and adult nervous system, with particular emphasis on axon/cell migration and postnatal critical periods of cerebral cortex plasticity. We also describe homeoprotein non-cell-autonomous mechanisms and explore how this "novel" signaling pathway impacts emerging research in brain development and physiology. In this context, we explore hypotheses on the evolution of signaling, the role of homeoproteins as early morphogens, and their therapeutic potential for neurological and psychiatric diseases. PMID- 25741721 TI - Common behavioral clusters and subcortical anatomy in stroke. AB - A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first time stroke patients with heterogeneous lesions at 1-2 weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlas of white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition. PMID- 25741722 TI - Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. AB - An increasingly powerful approach for studying brain circuits relies on targeting genetically encoded sensors and effectors to specific cell types. However, current approaches for this are still limited in functionality and specificity. Here we utilize several intersectional strategies to generate multiple transgenic mouse lines expressing high levels of novel genetic tools with high specificity. We developed driver and double reporter mouse lines and viral vectors using the Cre/Flp and Cre/Dre double recombinase systems and established a new, retargetable genomic locus, TIGRE, which allowed the generation of a large set of Cre/tTA-dependent reporter lines expressing fluorescent proteins, genetically encoded calcium, voltage, or glutamate indicators, and optogenetic effectors, all at substantially higher levels than before. High functionality was shown in example mouse lines for GCaMP6, YCX2.60, VSFP Butterfly 1.2, and Jaws. These novel transgenic lines greatly expand the ability to monitor and manipulate neuronal activities with increased specificity. VIDEO ABSTRACT: PMID- 25741724 TI - Area-specific reestablishment of damaged circuits in the adult cerebral cortex by cortical neurons derived from mouse embryonic stem cells. AB - Pluripotent stem-cell-derived neurons constitute an attractive source for replacement therapies, but their utility remains unclear for cortical diseases. Here, we show that neurons of visual cortex identity, differentiated in vitro from mouse embryonic stem cells (ESCs), can be transplanted successfully following a lesion of the adult mouse visual cortex. Reestablishment of the damaged pathways included long-range and reciprocal axonal projections and synaptic connections with targets of the damaged cortex. Electrophysiological recordings revealed that some grafted neurons were functional and responsive to visual stimuli. No significant integration was observed following grafting of the same neurons in motor cortex, or transplantation of embryonic motor cortex in visual cortex, indicating that successful transplantation required a match in the areal identity of grafted and lesioned neurons. These findings demonstrate that transplantation of mouse ESC-derived neurons of appropriate cortical areal identity can contribute to the reconstruction of an adult damaged cortical circuit. PMID- 25741723 TI - Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. AB - Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer's disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1(-/-) mice. Neither mutation altered Psen1 mRNA expression, but both abolished gamma-secretase activity. Heterozygosity for the KI mutation decreased production of Abeta40 and Abeta42, increased the Abeta42/Abeta40 ratio, and exacerbated Abeta deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism. PMID- 25741725 TI - Sip1 downstream Effector ninein controls neocortical axonal growth, ipsilateral branching, and microtubule growth and stability. AB - Sip1 is an important transcription factor that regulates several aspects of CNS development. Mutations in the human SIP1 gene have been implicated in Mowat Wilson syndrome (MWS), characterized by severe mental retardation and agenesis of the corpus callosum. In this study we have shown that Sip1 is essential for the formation of intracortical, intercortical, and cortico-subcortical connections in the murine forebrain. Sip1 deletion from all postmitotic neurons in the neocortex results in lack of corpus callosum, anterior commissure, and corticospinal tract formation. Mosaic deletion of Sip1 in the neocortex reveals defects in axonal growth and in ipsilateral intracortical-collateral formation. Sip1 mediates these effects through its direct downstream effector ninein, a microtubule binding protein. Ninein in turn influences the rate of axonal growth and branching by affecting microtubule stability and dynamics. PMID- 25741726 TI - Toll receptors instruct axon and dendrite targeting and participate in synaptic partner matching in a Drosophila olfactory circuit. AB - Our understanding of the mechanisms that establish wiring specificity of complex neural circuits is far from complete. During Drosophila olfactory circuit assembly, axons of 50 olfactory receptor neuron (ORN) classes and dendrites of 50 projection neuron (PN) classes precisely target to 50 discrete glomeruli, forming parallel information-processing pathways. Here we show that Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively. The canonical ligands and downstream partners of Toll receptors in embryonic patterning and innate immunity are not required for the function of Toll-6/Toll-7 in wiring specificity, nor are their cytoplasmic domains. Interestingly, both Toll-6 and Toll-7 participate in synaptic partner matching between ORN axons and PN dendrites. Our investigations reveal that olfactory circuit assembly involves dynamic and long-range interactions between PN dendrites and ORN axons. PMID- 25741727 TI - ON and OFF unipolar brush cells transform multisensory inputs to the auditory system. AB - Unipolar brush cells (UBCs) of the dorsal cochlear nucleus (DCN) and vestibular cerebellar cortex receive glutamatergic mossy fiber input on an elaborate brush like dendrite. Two subtypes of UBC have been established based on immunohistochemical markers and physiological profiles, but the relation of these subtypes to the response to mossy fiber input is not clear. We examined the synaptic physiology of auditory UBCs in mouse brain slices, identifying two response profiles, and correlated each with a specific UBC subtype. One subtype had a striking biphasic excitatory response mediated by AMPAR and mGluR1alpha. The second was mGluR1alpha negative and was dominated by a strongly inhibitory outward K(+) current. These two subtypes upregulated or downregulated spontaneous firing, respectively. By analogy to the retina, we propose that UBCs comprise ON and OFF cells with respect to their response to glutamatergic input and may therefore provide distinct parallel processing of multisensory input to their targets. PMID- 25741728 TI - Melanopsin tristability for sustained and broadband phototransduction. AB - Mammals rely upon three ocular photoreceptors to sense light: rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). Rods and cones resolve details in the visual scene. Conversely, ipRGCs integrate over time and space, primarily to support "non-image" vision. The integrative mechanisms of ipRGCs are enigmatic, particularly since these cells use a phototransduction motif that allows invertebrates like Drosophila to parse light with exceptional temporal resolution. Here, we provide evidence for a single mechanism that allows ipRGCs to integrate over both time and wavelength. Light distributes the visual pigment, melanopsin, across three states, two silent and one signaling. Photoequilibration among states maintains pigment availability for sustained signaling, stability of the signaling state permits minutes-long temporal summation, and modest spectral separation of the silent states promotes uniform activation across wavelengths. By broadening the tuning of ipRGCs in both temporal and chromatic domains, melanopsin tristability produces signal integration for physiology and behavior. PMID- 25741730 TI - Cellular clocks in AVP neurons of the SCN are critical for interneuronal coupling regulating circadian behavior rhythm. AB - The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, is a network structure composed of multiple types of neurons. Here, we report that mice with a Bmal1 deletion specific to arginine vasopressin (AVP)-producing neurons showed marked lengthening in the free-running period and activity time of behavior rhythms. When exposed to an abrupt 8-hr advance of the light/dark cycle, these mice reentrained faster than control mice did. In these mice, the circadian expression of genes involved in intercellular communications, including Avp, Prokineticin 2, and Rgs16, was drastically reduced in the dorsal SCN, where AVP neurons predominate. In slices, dorsal SCN cells showed attenuated PER2::LUC oscillation with highly variable and lengthened periods. Thus, Bmal1-dependent oscillators of AVP neurons may modulate the coupling of the SCN network, eventually coupling morning and evening behavioral rhythms, by regulating expression of multiple factors important for the network property of these neurons. PMID- 25741729 TI - Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. AB - Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu, do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission. PMID- 25741732 TI - Is epidural analgesia during labor related to retained placenta? AB - OBJECTIVES: To explore the influence of epidural analgesia on the course of the third stage of labor and on the incidence of the complete retained placenta as well as retained parts of the placenta. STUDY DESIGN: This is a population-based cohort study in a tertiary medical center. We collected data from all 4227 spontaneous singleton vaginal deliveries during 6 months and compared the incidence of retained placenta in deliveries with epidural analgesia with those without analgesia. Multivariable logistic regression was used to control for possible confounders. RESULTS: More than two-thirds of the women (69.25%) used epidural analgesia during their delivery. A need for intervention due to placental disorder during the third stage of labor was noted in 4.2% of all deliveries. Epidural analgesia appeared to be significantly (P=0.028) related to placental disorders compared with no analgesia: 4.8% vs. 3%, respectively. Deliveries with manual interventions during the third stage, for either complete retained placenta or suspected retained parts of the placenta, were associated with the use of epidural analgesia (P=0.008), oxytocin (P=0.002) and older age at delivery (P=0.000), but when including all factors in a multivariable analysis, using a stepwise logistic regression, the factors that were independently associated with interventions for placental disruption during the third stage of delivery were previous cesarean section, oxytocin use and, marginally, older age. CONCLUSIONS: Complete retained placenta and retained parts of the placenta share the same risk factors. Epidural analgesia does not directly influence the incidence of complete retained placenta or retained parts, though clinically linked through increased oxytocin use. The factors that were independently associated with interventions for placental disruption during the third stage of delivery were previous cesarean section, oxytocin use and older age. PMID- 25741731 TI - Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations. AB - Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome. VIDEO ABSTRACT: PMID- 25741733 TI - Neurological disease or intellectual disability among sons of female Swedish dental personnel. AB - OBJECTIVE: Prenatal exposure to elemental mercury may be a potential hazard for the offspring of female dental personnel working with dental amalgam. The aim of this study was to investigate whether potential in utero exposure to mercury might have affected the development of nervous system of the sons of Swedish female dental personnel leading to an increased risk of neurological disease or intellectual disability. MATERIAL AND METHODS: We used national Swedish registers to investigate risks for diseases potentially related to adverse effects on neurodevelopment. Sons of female dentists (n=1690) and dental nurses (n=10,420) were compared with cohorts consisting of sons of other female healthcare personnel. Due to changes in mercury exposure in dentistry during the study period, analyses were stratified by decade of birth. Hazard ratios (HRs) were calculated using Cox proportional hazard models. RESULTS: We found no elevated risk for neurological disease, epilepsy or intellectual disability among the sons of dental personnel during any of the decades studied. HRs for neurological disease among the dental nurse cohort were even below 1.00 during the 1970s and 1980s. A low number of events resulted in uncertainty regarding results in the dentist cohort. CONCLUSIONS: We did not find any support for the hypothesis that mercury exposure in Swedish dentistry during the 1960s, 1970s or 1980s had any effect on the incidence of neurological disease or intellectual disability among the sons of female dental personnel. Our results imply that current use of dental amalgam should not represent an elevated risk for neurological disease or intellectual disability among the offspring of dental personnel. PMID- 25741734 TI - What do patients with epilepsy tell us about language dynamics? A review of fMRI studies. AB - The objective of this review is to resume major neuroimaging findings on language organization and plasticity in patients with focal and refractory epilepsy, to discuss the effect of modulatory variables that should be considered alongside patterns of reorganization, and to propose possible models of language reorganization. The focal and refractory epilepsy provides a real opportunity to investigate various types of language reorganization in different conditions. The 'chronic' condition (induced by the epileptogenic zone or EZ) is associated with either recruitment of homologous regions of the opposite hemisphere or recruitment of intrahemispheric, nonlinguistic regions. In the 'acute' condition (neurosurgery and EZ resection), the initial interhemispheric shift (induced by the chronic EZ) could follow a reverse direction, back to the initial hemisphere. These different patterns depend on several modulatory factors and are associated with various levels of language performance. As a neuroimaging tool, functional magnetic resonance imaging enables the detailed investigation of both hemispheres simultaneously and allows for comparison with healthy controls, potentially creating a more comprehensive and more realistic picture of brain-language relations. Importantly, functional neuroimaging approaches demonstrate a good degree of concordance on a theoretical level, but also a considerable degree of individual variability, attesting to the clinical importance with these methods to establish, empirically, language localization in individual patients. Overall, the unique features of epilepsy, combined with ongoing advances in technology, promise further improvement in understanding of language substrate. PMID- 25741735 TI - Detection of thiol-based redox switch processes in parasites - facts and future. AB - Malaria and African trypanosomiasis are tropical diseases caused by the protozoa Plasmodium and Trypanosoma, respectively. The parasites undergo complex life cycles in the mammalian host and insect vector, during which they are exposed to oxidative and nitrosative challenges induced by the host immune system and endogenous processes. Attacking the parasite's redox metabolism is a target mechanism of several known antiparasitic drugs and a promising approach to novel drug development. Apart from this aspect, oxidation of cysteine residues plays a key role in protein-protein interaction, metabolic responses to redox events, and signaling. Understanding the role and dynamics of reactive oxygen species and thiol switches in regulating cellular redox homeostasis is crucial for both basic and applied biomedical approaches. Numerous techniques have therefore been established to detect redox changes in parasites including biochemical methods, fluorescent dyes, and genetically encoded probes. In this review, we aim to give an insight into the characteristics of redox networks in the pathogens Plasmodium and Trypanosoma, including a comprehensive overview of the consequences of specific deletions of redox-associated genes. Furthermore, we summarize mechanisms and detection methods of thiol switches in both parasites and discuss their specificity and sensitivity. PMID- 25741736 TI - Ultrasound-stimulated microbubble enhancement of radiation response. AB - Cancer therapies result in the killing of cancer cells but remain largely ineffective, with most patients dying of their disease. The methodology described here is a new image-guided cancer treatment under development that relies on physical methods to alter tumour biology. It enhances tumour responses to radiation significantly by synergistically destroying tumour blood vessels using microbubbles. It achieves tumour specificity by confining the ultrasonic fields that stimulate microbubbles to tumour location only. By perturbing tumour vasculature and activating specific genetic pathways in endothelial cells, the technique has been demonstrated to sensitise the targeted tissues to subsequent therapeutic application of radiation, resulting in significantly enhanced cell killing through a ceramide-dependent pathway initiated at the cell membrane. The treatment reviewed here destroys blood vessels, significantly enhancing the anti vascular effect of radiation and improving tumour cure. The significant enhancement of localised tumour cell kill observed with this method means that radiation-based treatments can be potentially made more potent and lower doses of radiation utilised. The technique has the potential to have a profound impact on the practice of radiation oncology by offering a novel and safe means of reducing normal tissue toxicity while at the same time significantly increasing treatment effectiveness. PMID- 25741737 TI - Redox diversity in ERAD-mediated protein retrotranslocation from the endoplasmic reticulum: a complex puzzle. AB - Misfolded and incorrectly assembled proteins in the secretory pathway are eliminated by ubiquitylation and proteasomal degradation in a process known as ER associated degradation (ERAD). Retrotranslocation of diverse substrates including misfolded proteins and viruses occurs through channels in the ER membrane, which are also utilized for host cell penetration by A/B class protein toxins such as cholera toxin, ricin or K28. According to the current view, disulfide-bonded proteins must either be reduced or rearranged to ensure translocation competence and entry into the cytosol from the ER. As the underlying mechanisms are still largely mysterious, we here focus on the redox status and disulfide isomerization of ERAD substrates and the role of oxidoreductases in the essential process of ER to-cytosol retrotranslocation. PMID- 25741738 TI - "Personalized" sepsis care with the help of specific biomarker levels on admission and during follow up: are we there yet? PMID- 25741739 TI - Procalcitonin-guided antibiotic therapy: a potentially effective and efficient strategy. PMID- 25741740 TI - Increased level of circulating U2 small nuclear RNA fragments indicates metastasis in melanoma patients. AB - Background: Melanoma is the most aggressive skin cancer and, despite recent advances in therapy, about 20% of the patients die of their disease. Early relapse detection and monitoring of therapy response are crucial for efficient treatment of advanced melanoma. Thus, there is a need for blood-based biomarkers in melanoma management. Serum-derived U2 small nuclear RNA fragments (RNU2-1f) were previously shown to be blood-based biomarkers for gastrointestinal and gynecologic malignancies. Here we examined whether RNU2-1f may also serve as diagnostic biomarker in advanced melanoma. METHODS: Circulating RNU2-1f levels were quantified by comparative reverse transcription PCR in a training cohort of patients with metastatic melanoma (n=33, thereof regionally metastasized to skin and lymph nodes, n=23, and distantly metastasized, n=10) vs. patients with benign naevi (n=16) vs. healthy controls (n=39). RESULTS were validated in an independent patient cohort with distant metastasis (n=16) vs. controls (n=18). RESULTS: Circulating RNU2-1f levels in the training cohort were significantly increased in serum of regionally and distantly metastatic patients, compared with patients with benign naevi or healthy controls (p<0.0001) and allowed accurate detection of regional (AUC 0.80) as well as distant (AUC 0.84) metastasis. In the validation cohort, increased RNU2-1f levels were confirmed and enabled highly specific detection of distant metastasis (sensitivity 81%, specificity 100%, AUC 0.94). CONCLUSIONS: This is the first report to suggest a blood-based snRNA serving as a diagnostic biomarker for melanoma metastasis. Our data provide a rationale for further defining clinical utility of circulating RNU2-1f in metastasis detection in the management of melanoma patients at risk of relapse and/or with advanced disease. PMID- 25741741 TI - Ranking prestige of medical and laboratory technology journals. PMID- 25741742 TI - Spatio-temporal model for multiple ChIP-seq experiments. AB - The increasing availability of ChIP-seq data demands for advanced statistical tools to analyze the results of such experiments. The inherent features of high throughput sequencing output call for a modelling framework that can account for the spatial dependency between neighboring regions of the genome and the temporal dimension that arises from observing the protein binding process at progressing time points; also, multiple biological/technical replicates of the experiment are usually produced and methods to jointly account for them are needed. Furthermore, the antibodies used in the experiment lead to potentially different immunoprecipitation efficiencies, which can affect the capability of distinguishing between the true signal in the data and the background noise. The statistical procedure proposed consist of a discrete mixture model with an underlying latent Markov random field: the novelty of the model is to allow both spatial and temporal dependency to play a role in determining the latent state of genomic regions involved in the protein binding process, while combining all the information of the replicates available instead of treating them separately. It is also possible to take into account the different antibodies used, in order to obtain better insights of the process and exploit all the biological information available. PMID- 25741743 TI - Detection of DNA and poly-l-lysine using CVD graphene-channel FET biosensors. AB - A graphene channel field-effect biosensor is demonstrated for detecting the binding of double-stranded DNA and poly-l-lysine. Sensors consist of chemical vapor deposition graphene transferred using a clean, etchant-free transfer method. The presence of DNA and poly-l-lysine are detected by the conductance change of the graphene transistor. A readily measured shift in the Dirac voltage (the voltage at which the graphene's resistance peaks) is observed after the graphene channel is exposed to solutions containing DNA or poly-l-lysine. The 'Dirac voltage shift' is attributed to the binding/unbinding of charged molecules on the graphene surface. The polarity of the response changes to positive direction with poly-l-lysine and negative direction with DNA. This response results in detection limits of 8 pM for 48.5 kbp DNA and 11 pM for poly-l-lysine. The biosensors are easy to fabricate, reusable and are promising as sensors of a wide variety of charged biomolecules. PMID- 25741744 TI - Modulating cognition using transcranial direct current stimulation of the cerebellum. AB - Numerous studies have emerged recently that demonstrate the possibility of modulating, and in some cases enhancing, cognitive processes by exciting brain regions involved in working memory and attention using transcranial electrical brain stimulation. Some researchers now believe the cerebellum supports cognition, possibly via a remote neuromodulatory effect on the prefrontal cortex. This paper describes a procedure for investigating a role for the cerebellum in cognition using transcranial direct current stimulation (tDCS), and a selection of information-processing tasks of varying task difficulty, which have previously been shown to involve working memory, attention and cerebellar functioning. One task is called the Paced Auditory Serial Addition Task (PASAT) and the other a novel variant of this task called the Paced Auditory Serial Subtraction Task (PASST). A verb generation task and its two controls (noun and verb reading) were also investigated. All five tasks were performed by three separate groups of participants, before and after the modulation of cortico-cerebellar connectivity using anodal, cathodal or sham tDCS over the right cerebellar cortex. The procedure demonstrates how performance (accuracy, verbal response latency and variability) could be selectively improved after cathodal stimulation, but only during tasks that the participants rated as difficult, and not easy. Performance was unchanged by anodal or sham stimulation. These findings demonstrate a role for the cerebellum in cognition, whereby activity in the left prefrontal cortex is likely dis-inhibited by cathodal tDCS over the right cerebellar cortex. Transcranial brain stimulation is growing in popularity in various labs and clinics. However, the after-effects of tDCS are inconsistent between individuals and not always polarity-specific, and may even be task- or load-specific, all of which requires further study. Future efforts might also be guided towards neuro enhancement in cerebellar patients presenting with cognitive impairment once a better understanding of brain stimulation mechanisms has emerged. PMID- 25741745 TI - Reductive electropolymerization of a vinyl-containing poly-pyridyl complex on glassy carbon and fluorine-doped tin oxide electrodes. AB - Controllable electrode surface modification is important in a number of fields, especially those with solar fuels applications. Electropolymerization is one surface modification technique that electrodeposits a polymeric film at the surface of an electrode by utilizing an applied potential to initiate the polymerization of substrates in the Helmholtz layer. This useful technique was first established by a Murray-Meyer collaboration at the University of North Carolina at Chapel Hill in the early 1980s and utilized to study numerous physical phenomena of films containing inorganic complexes as the monomeric substrate. Here, we highlight a procedure for coating electrodes with an inorganic complex by performing reductive electropolymerization of the vinyl containing poly-pyridyl complex onto glassy carbon and fluorine doped tin oxide coated electrodes. Recommendations on electrochemical cell configurations and troubleshooting procedures are included. Although not explicitly described here, oxidative electropolymerization of pyrrole-containing compounds follows similar procedures to vinyl-based reductive electropolymerization but are far less sensitive to oxygen and water. PMID- 25741746 TI - Methods to test visual attention online. AB - Online data collection methods have particular appeal to behavioral scientists because they offer the promise of much larger and much more representative data samples than can typically be collected on college campuses. However, before such methods can be widely adopted, a number of technological challenges must be overcome--in particular in experiments where tight control over stimulus properties is necessary. Here we present methods for collecting performance data on two tests of visual attention. Both tests require control over the visual angle of the stimuli (which in turn requires knowledge of the viewing distance, monitor size, screen resolution, etc.) and the timing of the stimuli (as the tests involve either briefly flashed stimuli or stimuli that move at specific rates). Data collected on these tests from over 1,700 online participants were consistent with data collected in laboratory-based versions of the exact same tests. These results suggest that with proper care, timing/stimulus size dependent tasks can be deployed in web-based settings. PMID- 25741748 TI - Optical Emission Studies of Copper Plasma Induced Using Infrared Transversely Excited Atmospheric (IR TEA) Carbon Dioxide Laser Pulses. AB - Spatially resolved, time-integrated optical emission spectroscopy was applied for investigation of copper plasma produced by a nanosecond infrared (IR) transversely excited atmospheric (TEA) CO2 laser, operating at 10.6 MUm. The effect of surrounding air pressure, in the pressure range 0.1 to 1013 mbar, on plasma formation and its characteristics was investigated. A linear dependence of intensity threshold for plasma formation on logarithm of air pressure was found. Lowering of the air pressure reduces the extent of gas breakdown, enabling better laser-target coupling and thus increases ablation. Optimum air pressure for target plasma formation was 0.1 mbar. Under that pressure, the induced plasma consisted of two clearly distinguished and spatially separated regions. The maximum intensity of emission, with sharp and well-resolved spectral lines and negligibly low background emission, was obtained from a plasma zone 8 mm from the target surface. The estimated excitation temperature in this zone was around 7000 K. The favorable signal to background ratio obtained in this plasma region indicates possible analytical application of TEA CO2 laser produced copper plasma. Detection limits of trace elements present in the Cu sample were on the order of 10 ppm (parts per million). Time-resolved measurements of spatially selected plasma zones were used to find a correlation between the observed spatial position and time delay. PMID- 25741747 TI - Protocol for studying extinction of conditioned fear in naturally cycling female rats. AB - Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females. PMID- 25741749 TI - Stable knock-down of efflux transporters leads to reduced glucuronidation in UGT1A1-overexpressing HeLa cells: the evidence for glucuronidation-transport interplay. AB - Efflux of glucuronide is facilitated by the membrane transporters including BCRP and MRPs. In this study, we aimed to determine the effects of transporter expression on glucuronide efflux and cellular glucuronidation. Single efflux transporter (i.e., BCRP, MRP1, MRP3, or MRP4) was stably knocked-down in UGT1A1 overexpressing HeLa cells. Knock-down of transporters was performed by stable transfection of short-hairpin RNA (shRNA) using lentiviral vectors. Glucuronidation and glucuronide transport in the cells were characterized using three different aglycones (i.e., genistein, apigenin, and emodin) with distinct metabolic activities. BCRP knock-down resulted in significant reductions in excretion of glucuronides (42.9% for genistein glucuronide (GG), 21.1% for apigenin glucuronide (AG) , and 33.7% for emodin glucuronide (EG); p < 0.01) and in cellular glucuronidation (38.3% for genistein, 38.6% for apigenin, and 34.7% for emodin; p < 0.01). Knock-down of a MRP transporter led to substantial decreases in excretion of GG (32.3% for MRP1, 36.7% for MRP3, and 36.6% for MRP4; p < 0.01) and AG (59.3% for MRP1, 24.7% for MRP3, and 34.1% for MRP4; p < 0.01). Also, cellular glucuronidation of genistein (38.3% for MRP1, 32.3% for MRP3, and 31.1% for MRP4; p < 0.01) and apigenin (40.6% for MRP1, 32.4% for MRP3, and 34.6% for MRP4; p < 0.001) was markedly suppressed. By contrast, silencing of MRPs did not cause any changes in either excretion of EG or cellular glucuronidation of emodin. In conclusion, cellular glucuronidation was significantly altered by decreasing expression of efflux transporters, revealing a strong interplay of glucuronidation with efflux transport. PMID- 25741750 TI - Identification of a key catalytic intermediate demonstrates that nitrogenase is activated by the reversible exchange of N2 for H2. AB - Freeze-quenching nitrogenase during turnover with N2 traps an S = 1/2 intermediate that was shown by ENDOR and EPR spectroscopy to contain N2 or a reduction product bound to the active-site molybdenum-iron cofactor (FeMo-co). To identify this intermediate (termed here EG), we turned to a quench-cryoannealing relaxation protocol. The trapped state is allowed to relax to the resting E0 state in frozen medium at a temperature below the melting temperature; relaxation is monitored by periodically cooling the sample to cryogenic temperature for EPR analysis. During -50 degrees C cryoannealing of EG prepared under turnover conditions in which the concentrations of N2 and H2 ([H2], [N2]) are systematically and independently varied, the rate of decay of EG is accelerated by increasing [H2] and slowed by increasing [N2] in the frozen reaction mixture; correspondingly, the accumulation of EG is greater with low [H2] and/or high [N2]. The influence of these diatomics identifies EG as the key catalytic intermediate formed by reductive elimination of H2 with concomitant N2 binding, a state in which FeMo-co binds the components of diazene (an N-N moiety, perhaps N2 and two [e(-)/H(+)] or diazene itself). This identification combines with an earlier study to demonstrate that nitrogenase is activated for N2 binding and reduction through the thermodynamically and kinetically reversible reductive elimination/oxidative-addition exchange of N2 and H2, with an implied limiting stoichiometry of eight electrons/protons for the reduction of N2 to two NH3. PMID- 25741751 TI - Reservoir condition pore-scale imaging of multiple fluid phases using X-ray microtomography. AB - X-ray microtomography was used to image, at a resolution of 6.6 um, the pore scale arrangement of residual carbon dioxide ganglia in the pore-space of a carbonate rock at pressures and temperatures representative of typical formations used for CO2 storage. Chemical equilibrium between the CO2, brine and rock phases was maintained using a high pressure high temperature reactor, replicating conditions far away from the injection site. Fluid flow was controlled using high pressure high temperature syringe pumps. To maintain representative in-situ conditions within the micro-CT scanner a carbon fiber high pressure micro-CT coreholder was used. Diffusive CO2 exchange across the confining sleeve from the pore-space of the rock to the confining fluid was prevented by surrounding the core with a triple wrap of aluminum foil. Reconstructed brine contrast was modeled using a polychromatic x-ray source, and brine composition was chosen to maximize the three phase contrast between the two fluids and the rock. Flexible flow lines were used to reduce forces on the sample during image acquisition, potentially causing unwanted sample motion, a major shortcoming in previous techniques. An internal thermocouple, placed directly adjacent to the rock core, coupled with an external flexible heating wrap and a PID controller was used to maintain a constant temperature within the flow cell. Substantial amounts of CO2 were trapped, with a residual saturation of 0.203+/-0.013, and the sizes of larger volume ganglia obey power law distributions, consistent with percolation theory. PMID- 25741752 TI - Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficiency. AB - Encapsulation of small-molecule drugs in hydrophobic polymers or amphiphilic copolymers has been extensively used for preparing polymeric nanoparticles (NPs). The loadings and loading efficiencies of a wide range of drugs in polymeric NPs, however, tend to be very low. In this Communication, we report a strategy to prepare polymeric NPs with exceptionally high drug loading (>50%) and quantitative loading efficiency. Specifically, a dimeric drug conjugate bearing a trigger-responsive domain was designed and used as the core-constructing unit of the NPs. Upon co-precipitation of the dimeric drug and methoxypoly(ethylene glycol)-block-polylactide (mPEG-PLA), NPs with a dimeric drug core and a polymer shell were formed. The high-drug-loading NPs showed excellent stability in physiological conditions. No premature drug or prodrug release was observed in PBS solution without triggering, while external triggering led to controlled release of drug in its authentic form. PMID- 25741753 TI - Cyclopentanone as a cation-stabilizing electron-pair donor in the calcium catalyzed intermolecular carbohydroxylation of alkynes. AB - Although they have been used as reactivity-controlling additives in cationic polymerizations for decades, Lewis basic "electron pair donor" (ED) compounds were never used for the stabilization of cationic intermediates in transformations of small molecules. As such an ED, cyclopentanone proved highly efficient for the stabilization of allyl and vinyl cations in combination with our calcium-based catalyst system. Therefore, the first general transition-metal free intermolecular carbohydroxylation of alkynes with allyl and propargyl alcohols was realized. PMID- 25741754 TI - Fluorescence array-based sensing of metal ions using conjugated polyelectrolytes. AB - Array-based sensing offers several advantages for detecting a series of analytes with common structures or properties. In this study, four anionic conjugated polyelectrolytes (CPEs) with a common poly(p-pheynylene ethynylene) (PPE) backbone and varying pendant ionic side chains were designed. The conjugation length, repeat unit pattern, and ionic side chain composition were the main factors affecting the fluorescence patterns of CPE polymers in response to the addition of different metal ions. Eight metal ions, including Pb(2+), Hg(2+), Fe(3+), Cr(3+), Cu(2+), Mn(2+), Ni(2+), and Co(2+), categorized as water contaminants by the Environmental Protection Agency, were selected as analytes in this study. Fluorescence intensity response patterns of the four-PPE sensor array toward each of the metal ions were recorded, analyzed, and transformed into canonical scores using linear discrimination analysis (LDA), which permitted clear differentiation between metal ions using both two-dimensional and three dimensional graphs. In particular, the array could readily differentiate between eight toxic metal ions in separate aqueous solutions at 100 nM. Our four-PPE sensor array also provides a practical application to quantify Pb(2+) and Hg(2+) concentrations in blind samples within a specific concentration range. PMID- 25741755 TI - Dynamic Kerr effect study on six-membered-ring molecular liquids: benzene, 1,3 cyclohexadiene, 1,4-cyclohexadiene, cyclohexene, and cyclohexane. AB - The intermolecular dynamics of five six-membered-ring molecular liquids having different aromaticities-benzene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cyclohexene, and cyclohexane-measured by femtosecond Raman-induced Kerr effect spectroscopy have been compared in this study. The line shapes of the Fourier transform low-frequency spectra, which arise from the intermolecular vibrational dynamics, are trapezoidal for benzene and 1,3-cyclohexadiene, triangular for 1,4 cyclohexadiene and cyclohexene, and monomodal for cyclohexane. The trapezoidal shapes of the low-frequency spectra of benzene and 1,3-cyclohexadiene are due to the librational motions of their aromatic planar structures, which cause damped nuclear response features. The time integrals of the nuclear responses of the five liquids correlate to the squares of the polarizability anisotropies of the molecules calculated on the basis of density functional theory. The first moments of the low-frequency spectra roughly linearly correlate to the bulk parameters of the square roots of the surface tensions divided by the densities and the square roots of the surface tensions divided by the molecular weights, but the plots for cyclohexene deviate slightly from the correlations. The picosecond overdamped transients of the liquids are well fitted by a biexponential function. The fast time constants of all of the liquids are approximately 1.1-1.4 ps, and they do not obey the Stokes-Einstein-Debye hydrodynamic model. On the other hand, the slow time constants are roughly linearly proportional to the products of the shear viscosities and the molar volumes. The observed intramolecular vibrational modes at less than 700 cm(-1) for all of the liquids are also assigned on the basis of quantum chemistry calculations. PMID- 25741757 TI - Enrichment of cesium and rubidium in weathered micaceous materials at the Savannah River Site, South Carolina. AB - The enrichment of Cs and Rb relative to Ba, Sr, and K in three soils representing a range of soil maturities was determined to investigate the long-term sorption behavior of these elements in upland soils of the Savannah River Site (SRS). Elemental mass fractions normalized to upper continental crust (UCC) decreased in the order Cs > Rb > Ba > K > Sr in the soil fine fractions. Only the UCC normalized amount of Cs was greater than unity. The UCC-normalized amounts in strong-acid extracts decreased as Cs > Rb > Ba > K ~ Sr. In all three soil cores, the trends of the UCC-normalized amounts of acid-extractable metals were similar to trends of cation-exchange capacity (CEC) calculated from synchrotron-X-ray diffractometry measurements of soil mineralogy. Consequently, the relative enrichment of Cs and Rb is largely controlled by selective sorption to micaceous minerals, including hydroxy-interlayered vermiculite, that dominate the CEC. Where high clay content had caused retention of soil solution, amounts of acid extractable K, Sr, and Ba were enhanced. The retention of natural Cs by these three soils, which developed over many thousands of years, is a strong indicator that radiocesium will likewise be retained in SRS soils. PMID- 25741756 TI - Chemistry with an artificial primer of polyhydroxybutyrate synthase suggests a mechanism for chain termination. AB - Polyhydroxybutyrate (PHB) synthases (PhaCs) catalyze the conversion of 3-(R) hydroxybutyryl CoA (HBCoA) to PHB, which is deposited as granules in the cytoplasm of microorganisms. The class I PhaC from Caulobacter crescentus (PhaC(Cc)) is a highly soluble protein with a turnover number of 75 s(-1) and no lag phase in coenzyme A (CoA) release. Studies with [1-(14)C]HBCoA and PhaC(Cc) monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography reveal that the rate of elongation is much faster than the rate of initiation. Priming with the artificial primer [(3)H]sTCoA and monitoring for CoA release reveal a single CoA/PhaC, suggesting that the protein is uniformly loaded and that the elongation process could be studied. Reaction of sT PhaC(Cc) with [1-(14)C]HBCoA revealed that priming with sTCoA increased the uniformity of elongation, allowing distinct polymerization species to be observed by SDS-PAGE and autoradiography. However, in the absence of HBCoA, [(3)H]sT-PhaC unexpectedly generates [(3)H]sDCoA with a rate constant of 0.017 s(-1). We propose that the [(3)H]sDCoA forms via attack of CoA on the oxoester of the [(3)H]sT-PhaC chain, leaving the synthase attached to a single HB unit. Comparison of the relative rate constants of thiolysis by CoA and elongation by PhaC(Cc), and the size of the PHB polymer generated in vivo, suggests a mechanism for chain termination and reinitiation. PMID- 25741758 TI - Highly fluorescent, near-infrared-emitting Cd2+-tuned HgS nanocrystals with optical applications. AB - Bulk HgS itself has proven to be a technologically important material; however, the poor stability and weak emission of HgS nanocrystals have greatly hindered their promising applications. Presently, a critical problem is the uncontrollable growth of HgS NCs and their intrinsic surface states which are susceptible to the local environment. Here, we address the issue by an ion-tuning approach to fabricating stable, highly fluorescent Cd:HgS/CdS NCs for the first time, which efficiently tuned the band-gap level of HgS NCs, pushing their intrinsic states far away from the surface, reducing the strong interaction of the environment with surface states and hence drastically boosting the exciton transition. As compared to bare HgS NCs, the obtained Cd:HgS/CdS NCs exhibited tunable luminescence peaks from 724 to 825 nm with an unprecedentedly high quantum yield up to 40% at room temperature and excellent thermal and photostability. Characterized by TEM, XRD, XPS, and AAS, the resultant Cd:HgS/CdS NCs possessed a zinc-blende structure and was composed of a homogeneous alloyed HgCdS structure coated with a thin-layer CdS shell. The formation mechanism of Cd:HgS/CdS NCs was proposed. These bright, stable HgS-based NCs presented promising applications as fluorescent inks for anticounterfeiting and as excellent light converters when coated onto a blue-light-emitting diode. PMID- 25741759 TI - Polymeric iminosugars improve the activity of carbohydrate-processing enzymes. AB - Multivalent iminosugars have recently emerged as powerful tools to inhibit the activities of specific glycosidases. In this work, biocompatible dextrans were coated with iminosugars to form linear and ramified polymers with unprecedently high valencies (from 20 to 900) to probe the evolution of the multivalent inhibition as a function of ligand valency. This study led to the discovery that polyvalent iminosugars can also significantly enhance, not only inhibit, the enzymatic activity of specific glycoside-hydrolase, as observed on two galactosidases, a fucosidase, and a bacterial mannoside phosphorylase for which an impressive 70-fold activation was even reached. The concept of glycosidase activation is largely unexplored, with a unique recent example of small-molecules activators of a bacterial O-GlcNAc hydrolase. The possibility of using these polymers as "artificial enzyme effectors" may therefore open up new perspectives in therapeutics and biocatalysis. PMID- 25741760 TI - Transfection, selection, and colony-picking of human induced pluripotent stem cells TALEN-targeted with a GFP gene into the AAVS1 safe harbor. AB - Targeted transgene addition can provide persistent gene expression while circumventing the gene silencing and insertional mutagenesis caused by viral vector mediated random integration. This protocol describes a universal and efficient transgene targeted addition platform in human iPSCs based on utilization of validated open-source TALENs and a gene-trap-like donor to deliver transgenes into a safe harbor locus. Importantly, effective gene editing is rate limited by the delivery efficiency of gene editing vectors. Therefore, this protocol first focuses on preparation of iPSCs for transfection to achieve high nuclear delivery efficiency. When iPSCs are dissociated into single cells using a gentle-cell dissociation reagent and transfected using an optimized program, >50% cells can be induced to take up the large gene editing vectors. Because the AAVS1 locus is located in the intron of an active gene (PPP1R12C), a splicing acceptor (SA)-linked puromycin resistant gene (PAC) was used to select targeted iPSCs while excluding random integration-only and untransfected cells. This strategy greatly increases the chance of obtaining targeted clones, and can be used in other active gene targeting experiments as well. Two weeks after puromycin selection at the dose adjusted for the specific iPSC line, clones are ready to be picked by manual dissection of large, isolated colonies into smaller pieces that are transferred to fresh medium in a smaller well for further expansion and genetic and functional screening. One can follow this protocol to readily obtain multiple GFP reporter iPSC lines that are useful for in vivo and in vitro imaging and cell isolation. PMID- 25741761 TI - Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care. AB - Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care. PMID- 25741762 TI - Troubleshooting in extracorporeal life support. AB - Since the first clinical use of extracorporeal circulation in the last century by John Gibbon and the first successful mechanical support of the left ventricular function by Forest Dodrill, the progress of techniques and technologies has helped to develop minimised systems for extracorporeal circulatory and respiratory support. However, the fact is that, despite the advanced technologies used for extracorporeal support, successful application in order to be benefit a critically ill population requires highly trained and skilled teams. Application of these highly sophisticated techniques in life-saving situations inside and/or outside the operating room is a procedure with certain pitfalls and dangers. The aim of this review is to provide a short overview of the technical aspects of extracorporeal circulation, with a look at the recent literature and clinical experiences focusing on technical as well surgical considerations regarding the urgent and/or emergent usage of a central as well as peripheral extracorporeal system. PMID- 25741763 TI - Generation of a three-dimensional full thickness skin equivalent and automated wounding. AB - In vitro models are a cost effective and ethical alternative to study cutaneous wound healing processes. Moreover, by using human cells, these models reflect the human wound situation better than animal models. Although two-dimensional models are widely used to investigate processes such as cellular migration and proliferation, models that are more complex are required to gain a deeper knowledge about wound healing. Besides a suitable model system, the generation of precise and reproducible wounds is crucial to ensure comparable results between different test runs. In this study, the generation of a three-dimensional full thickness skin equivalent to study wound healing is shown. The dermal part of the models is comprised of human dermal fibroblast embedded in a rat-tail collagen type I hydrogel. Following the inoculation with human epidermal keratinocytes and consequent culture at the air-liquid interface, a multilayered epidermis is formed on top of the models. To study the wound healing process, we additionally developed an automated wounding device, which generates standardized wounds in a sterile atmosphere. PMID- 25741764 TI - Efficient prediction of progesterone receptor interactome using a support vector machine model. AB - Protein-protein interaction (PPI) is essential for almost all cellular processes and identification of PPI is a crucial task for biomedical researchers. So far, most computational studies of PPI are intended for pair-wise prediction. Theoretically, predicting protein partners for a single protein is likely a simpler problem. Given enough data for a particular protein, the results can be more accurate than general PPI predictors. In the present study, we assessed the potential of using the support vector machine (SVM) model with selected features centered on a particular protein for PPI prediction. As a proof-of-concept study, we applied this method to identify the interactome of progesterone receptor (PR), a protein which is essential for coordinating female reproduction in mammals by mediating the actions of ovarian progesterone. We achieved an accuracy of 91.9%, sensitivity of 92.8% and specificity of 91.2%. Our method is generally applicable to any other proteins and therefore may be of help in guiding biomedical experiments. PMID- 25741765 TI - Real-time duplex applications of loop-mediated AMPlification (LAMP) by assimilating probes. AB - Isothermal nucleic-acid amplification methods such as Loop-Mediated isothermal AMPlification (LAMP) are increasingly appealing alternatives to PCR for use in portable diagnostic system due to the low cost, weight, and power requirements of the instrumentation. As such, interest in developing new probes and other functionality based on the LAMP reaction has been intense. Here, we report on the development of duplexed LAMP assays for pathogen detection using spectrally unique Assimilating Probes. As proof of principle, we used a reaction for Salmonella enterica as a model coupled with a reaction for lambda-phage DNA as an internal control, as well as a duplexed assay to sub-type specific quarantine strains of the bacterial wilt pathogen Ralstonia solanacearum. Detection limits for bacterial DNA analyzed in individual reactions was less than 100 genomic equivalents in all cases, and increased by one to two orders of magnitude when reactions were coupled in duplexed formats. Even so, due to the more robust activity of newly available strand-displacing polymerases, the duplexed assays reported here were more powerful than analogous individual reactions reported only a few years ago, and represent a significant advance for incorporation of internal controls to validate assay results in the field. PMID- 25741766 TI - Extracellular vesicles in Alzheimer's disease: friends or foes? Focus on abeta vesicle interaction. AB - The intercellular transfer of amyloid-beta (Abeta) and tau proteins has received increasing attention in Alzheimer's disease (AD). Among other transfer modes, Abeta and tau dissemination has been suggested to occur through release of Extracellular Vesicles (EVs), which may facilitate delivery of pathogenic proteins over large distances. Recent evidence indicates that EVs carry on their surface, specific molecules which bind to extracellular Abeta, opening the possibility that EVs may also influence Abeta assembly and synaptotoxicity. In this review we focus on studies which investigated the impact of EVs in Abeta mediated neurodegeneration and showed either detrimental or protective role for EVs in the pathology. PMID- 25741767 TI - Chemical structure, property and potential applications of biosurfactants produced by Bacillus subtilis in petroleum recovery and spill mitigation. AB - Lipopeptides produced by microorganisms are one of the five major classes of biosurfactants known and they have received much attention from scientific and industrial communities due to their powerful interfacial and biological activities as well as environmentally friendly characteristics. Microbially produced lipopeptides are a series of chemical structural analogues of different families and, among them, 26 families covering about 90 lipopeptide compounds have been reported in the last two decades. This paper reviews the chemical structural characteristics and molecular behaviors of surfactin, one of the representative lipopeptides of the 26 families. In particular, two novel surfactin molecules isolated from cell-free cultures of Bacillus subtilis HSO121 are presented. Surfactins exhibit strong self-assembly ability to form sphere like micelles and larger aggregates at very low concentrations. The amphipathic and surface properties of surfactins are related to the existence of the minor polar and major hydrophobic domains in the three 3-D conformations. In addition, the application potential of surfactin in bioremediation of oil spills and oil contaminants, and microbial enhanced oil recovery are discussed. PMID- 25741768 TI - Nanoparticles of copper stimulate angiogenesis at systemic and molecular level. AB - Copper is a key element affecting blood vessel growth and muscle development. However, the ions released from Cu salts are toxic. Given their specific physicochemical properties, nanoparticles of Cu (NanoCu) may have different bioactivity and affect the development of blood vessel and muscles in a different manner than Cu salts. The objective of the study was to evaluate the influence of NanoCu on embryo development and angiogenesis at the systemic and molecular level, in experiments using a chick embryo model. Fertilized chicken eggs were divided into a control group, and groups injected with a placebo, CuSO4 or NanoCu. Embryo development at the whole body level and molecular indices using an embryo chorioallantoic membrane model were measured during embryogenesis. The present study indicated for the first time that NanoCu have pro-angiogenic properties at the systemic level, to a greater degree than CuSO4 salt. The properties of NanoCu were confirmed at the molecular level, demonstrating significant effects on mRNA concentration and on mRNA gene expression of all pro angiogenic and pro-proliferative genes measured herein. PMID- 25741770 TI - Thermodynamically metastable thiocyanato coordination polymer that shows slow relaxations of the magnetization. AB - Reaction of cobalt thiocyanate with 4-acetylpyridine leads to the formation of [Co(NCS)2(4-acetylpyridine)2]n (3/I). In its crystal structure the Co cations are connected by pairs of MU-1,3-bridging thiocyanato ligands into dimers that are further connected into layers by single anionic ligands. DTA-TG measurements of Co(NCS)2(4-acetyl-pyridine)4 (1) led to the formation of 3/I. In contrast, when the hydrate Co(NCS)2(4-acetyl-pyridine)2(H2O)2 (2) is decomposed, a mixture of 3/I and a thermodynamically metastable form 3/II is obtained. Further investigations reveal that thermal annealing of 2 leads to the formation of 3/II, that contains only traces of the stable form 3/I. DSC and temperature dependent X ray powder diffraction (XRPD) measurements prove that 3/II transforms into 3/I on heating. The crystal structure of 3/II was determined ab initio from XRPD data. In its crystal structure the Co cations are linked by pairs of bridging thiocyanato anions into a 1D coordination polymer, and thus, 3/II is an isomer of 3/I. Magnetic measurements disclose that the stable form 3/I only shows paramagnetism without any magnetic anomaly down to 2 K. In contrast, the metastable form 3/II shows ferromagnetic behavior. The phase transition into ordered state at Tc = 3.8 K was confirmed by specific heat measurements. Alternating current susceptibility measurements show frequency dependent maxima in chi' and chi", which is indicative for a slow relaxation of the magnetization. PMID- 25741769 TI - Expression of IL-8, IL-6 and IL-1beta in tears as a main characteristic of the immune response in human microbial keratitis. AB - Corneal infections are frequent and potentially vision-threatening diseases, and despite the significance of the immunological response in animal models of microbial keratitis (MK), it remains unclear in humans. The aim of this study was to describe the cytokine profile of tears in patients with MK. Characteristics of ocular lesions such as size of the epithelial defect, stromal infiltration, and hypopyon were analyzed. Immunological evaluation included determination of interleukine (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF) alpha in tear samples obtained from infected eyes of 28 patients with MK and compared with their contralateral non-infected eyes. Additionally, frequency of CD4+, CD8+, CD19+ and CD3-CD56+ cells was also determined in peripheral blood mononuclear cells in patients with MK, and compared with 48 healthy controls. Non significant differences were observed in the size of the epithelial defect, stromal infiltration, and hypopyon. Nevertheless, we found an immunological profile apparently related to MK etiology. IL-8 > IL-6 in patients with bacterial keratitis; IL-8 > IL-6 > IL-1beta and increased frequency of circulating CD3 CD56+ NK cells in patients with gram-negative keratitis; and IL-8 = IL-6 > IL 1beta in patients with fungal keratitis. Characterization of tear cytokines from patients with MK could aid our understanding of the immune pathophysiological mechanisms underlying corneal damage in humans. PMID- 25741771 TI - Transient characteristics for proton gating in laterally coupled indium-zinc oxide transistors. AB - The control and detection over processing, transport and delivery of chemical species is of great importance in sensors and biological systems. The transient characteristics of the migration of chemical species reflect the basic properties in the processings of chemical species. Here, we observed the field-configurable proton effects in a laterally coupled transistor gated by phosphorosilicate glass (PSG). The bias on the lateral gate would modulate the interplay between protons and electrons at the PSG/indium-zinc-oxide (IZO) channel interface. Due to the modulation of protons flux within the PSG films, the IZO channel current would be modified correspondingly. The characteristic time for the proton gating is estimated to be on the order of 20 ms. Such laterally coupled oxide based transistors with proton gating are promising for low-cost portable biosensors and neuromorphic system applications. PMID- 25741772 TI - Correction to Critical review of low-density polyethylene's partitioning and diffusion coefficients for trace organic contaminants and implications for its use as a passive sampler. PMID- 25741773 TI - Tobacco Smoke Exposure, Airway Resistance, and Asthma in School-age Children: The Generation R Study. AB - BACKGROUND: Tobacco smoke exposure has been associated with early childhood asthma symptoms. We assessed the associations of tobacco smoke exposure during pregnancy and childhood with wheezing patterns, asthma, airway interrupter resistance (Rint), and fractional exhaled nitric oxide (Feno) in school-age children and whether birth characteristics explained the associations. METHODS: This study was embedded in a population-based prospective cohort study among 6,007 children. Paternal and maternal smoking during pregnancy (never, first trimester only, continued), secondhand tobacco smoke exposure during childhood, wheezing patterns, and asthma were prospectively assessed by questionnaires. Wheezing patterns were defined as never, early (<= 3 years only), late (> 3 years only), and persistent (<= 3 and > 3 years) wheezing. Rint and Feno were measured at age 6 years. Birth characteristics were available from registries. RESULTS: Continued maternal smoking during pregnancy was associated with increased risks of early and persistent wheezing (OR: 1.24 [1.01, 1.52]; 1.48 [1.13, 1.95]) and asthma (1.65 [1.07, 2.55], for at least five cigarettes per day), but not with Rint or Feno. Birth characteristics did not explain these associations. Childhood tobacco smoke exposure was associated with higher Rint (difference z score: 0.45 [0.00, 0.90]), but this effect attenuated after adjustment for birth characteristics. Maternal smoking during first trimester only or paternal smoking during pregnancy was not associated with Rint, Feno, wheezing, or asthma. CONCLUSIONS: Continued maternal smoking during pregnancy was associated with increased risks of asthma outcomes in school-age children, whereas childhood tobacco smoke exposure was associated with higher Rint. Birth characteristics may explain part of these associations. PMID- 25741774 TI - Topographical estimation of visual population receptive fields by FMRI. AB - Visual cortex is retinotopically organized so that neighboring populations of cells map to neighboring parts of the visual field. Functional magnetic resonance imaging allows us to estimate voxel-based population receptive fields (pRF), i.e., the part of the visual field that activates the cells within each voxel. Prior, direct, pRF estimation methods(1) suffer from certain limitations: 1) the pRF model is chosen a-priori and may not fully capture the actual pRF shape, and 2) pRF centers are prone to mislocalization near the border of the stimulus space. Here a new topographical pRF estimation method(2) is proposed that largely circumvents these limitations. A linear model is used to predict the Blood Oxygen Level-Dependent (BOLD) signal by convolving the linear response of the pRF to the visual stimulus with the canonical hemodynamic response function. PRF topography is represented as a weight vector whose components represent the strength of the aggregate response of voxel neurons to stimuli presented at different visual field locations. The resulting linear equations can be solved for the pRF weight vector using ridge regression(3), yielding the pRF topography. A pRF model that is matched to the estimated topography can then be chosen post-hoc, thereby improving the estimates of pRF parameters such as pRF-center location, pRF orientation, size, etc. Having the pRF topography available also allows the visual verification of pRF parameter estimates allowing the extraction of various pRF properties without having to make a-priori assumptions about the pRF structure. This approach promises to be particularly useful for investigating the pRF organization of patients with disorders of the visual system. PMID- 25741776 TI - Tip-enhanced Raman nanographs: mapping topography and local electric fields. AB - We report tip-enhanced Raman imaging experiments in which information on sample topography and local electric fields is simultaneously obtained using an all optical detection scheme. We demonstrate how a Raman-active 4,4' dimercaptostilbene (DMS)-coated gold tip of an atomic force microscope can be used to simultaneously map the topography and image the electric fields localized at nanometric (20 and 5 nm wide) slits lithographically etched in silver, all using optical signals. Bimodal imaging is feasible by virtue of the frequency resolved optical response of the functionalized metal probe. Namely, the probe position-dependent signals can be subdivided into two components. The first is a 500-2250 cm(-1) Raman-shifted signal, characteristic of the tip-bound DMS molecules. The molecules report on topography through the intensity contrast observed as the tip scans across the nanoscale features. The variation in molecular Raman activity arises from the absence/formation of a plasmonic junction between the scanning probe and patterned silver surface, which translates into dimmed/enhanced Raman signatures of DMS. Using these molecular signals, we demonstrate that sub-15 nm spatial resolution is attainable using a 30 nm DMS-coated gold tip. The second response consists of two correlated sub-500 cm(-1) signals arising from mirror-like reflections of (i) the incident laser field and (ii) the Raman scattered response of an underlying glass support (at 100-500 cm(-1)) off the gold tip. We show that both the reflected low-wavenumber signals trace the local electric fields in the vicinity of the nanometric slits. PMID- 25741775 TI - Radial mobility and cytotoxic function of retroviral replicating vector transduced, non-adherent alloresponsive T lymphocytes. AB - We report a novel adaptation of the Radial Monolayer Cell Migration assay, first reported to measure the radial migration of adherent tumor cells on extracellular matrix proteins, for measuring the motility of fluorescently-labeled, non adherent human or murine effector immune cells. This technique employs a stainless steel manifold and 10-well Teflon slide to focally deposit non-adherent T cells into wells prepared with either confluent tumor cell monolayers or extracellular matrix proteins. Light and/or multi-channel fluorescence microscopy is used to track the movement and behavior of the effector cells over time. Fluorescent dyes and/or viral vectors that code for fluorescent transgenes are used to differentially label the cell types for imaging. This method is distinct from similar-type in vitro assays that track horizontal or vertical migration/invasion utilizing slide chambers, agar or transwell plates. The assay allows detailed imaging data to be collected with different cell types distinguished by specific fluorescent markers; even specific subpopulations of cells (i.e., transduced/nontransduced) can be monitored. Surface intensity fluorescence plots are generated using specific fluorescence channels that correspond to the migrating cell type. This allows for better visualization of the non-adherent immune cell mobility at specific times. It is possible to gather evidence of other effector cell functions, such as cytotoxicity or transfer of viral vectors from effector to target cells, as well. Thus, the method allows researchers to microscopically document cell-to-cell interactions of differentially-labeled, non-adherent with adherent cells of various types. Such information may be especially relevant in the assessment of biologically manipulated or activated immune cell types, where visual proof of functionality is desired with tumor target cells before their use for cancer therapy. PMID- 25741777 TI - Vitamin D receptor signaling and its therapeutic implications: Genome-wide and structural view. AB - Vitamin D3 is one of the few natural compounds that has, via its metabolite 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. For efficiently applying the therapeutic and disease-preventing potential of 1,25(OH)2D3 and its synthetic analogs, the key steps in vitamin D signaling need to be understood. These are the different types of molecular interactions with the VDR, such as (i) the complex formation of VDR with genomic DNA, (ii) the interaction of VDR with its partner transcription factors, (iii) the binding of 1,25(OH)2D3 or its synthetic analogs within the ligand-binding pocket of the VDR, and (iv) the resulting conformational change on the surface of the VDR leading to a change of the protein-protein interaction profile of the receptor with other proteins. This review will present the latest genome-wide insight into vitamin D signaling, and will discuss its therapeutic implications. PMID- 25741778 TI - Corrigendum: Acid-base transport in pancreatic cancer: Molecular mechanisms and clinical potential. PMID- 25741779 TI - Ultrasound Imaging is a Valid Method of Measuring the Cross-Sectional Area of the Quadratus Femoris Muscle. AB - Atrophy of the stabilizing muscles of the hip, such as quadratus femoris (QF), may predispose the hip joint to dysfunction. Ultrasound imaging (USI) has been shown to be a valid and reliable method of measuring the size of several hip muscles, but QF size has not been investigated. The objectives of this study were to establish the criterion validity of USI against the "gold standard" magnetic resonance imaging (MRI) for measuring the QF cross-sectional area (CSA) and to investigate intra-rater reliability of USI. Eleven current or retired professional ballet dancers (six women, five men) volunteered for USI of their QF within 1 week of MRI. The mean CSAs of QF were compared between the two imaging modalities, and the mean USI CSAs from two different trials were compared. Mean CSA with MRI (4.8 cm(2), +/- 1.54) was significantly larger than mean CSA with USI (4.29 cm(2) +/- 1.56; t = 5.82; p < 0.001), and the mean difference was 0.41 cm2 (9%). However, the measures were highly correlated for intra-class reliability (r = 0.96, p < 0.001), and intra-class correlation coefficients (ICC) demonstrated excellent agreement (ICC = 0.90; 95% confidence interval [CI]: 0.20 0.97) and consistency of measures (ICC = 0.96; 95% CI: 0.90- 0.98). Intra-rater reliability of measuring QF with USI was excellent between two trials (ICC = 0.98; 95% CI: 0.96- 0.99). The minimal detectable change at a 95% CI (MDC95) was 0.38 cm(2) (9.5%). It is concluded that USI is a valid and reliable measure of QF muscle size and can be used to measure QF CSA in a research or clinical setting. PMID- 25741780 TI - Motor control of rhythmic dance from a dynamical systems perspective: a review. AB - While dancers and dance educators express great interest in motor control as it relates to rhythmic dance, the subject remains largely uninvestigated. In order to advance our understanding of motor control, a theoretical framework called the dynamical systems approach (DSA) has been used. The DSA was originally developed to describe mathematically the principle of synchronization patterns in nature and their change over time. In recent decades, researchers studying human motor control have attempted to describe the synchronization of rhythmic movement using a DSA. More recently, this approach has been applied specifically to rhythmic dance movements. A series of studies that used the DSA revealed that when people synchronize rhythmic movement of a body part 1. with a different body part, 2. with other people's movement, or 3. with an auditory beat with some phase differences, unintentional and autonomous entrainment to a specific synchronization pattern occurs. However, through practice dancers are able to overcome such entrainment and dance freely. These findings provide practical suggestions for effective ways of training in dance education. The DSA can potentially be an effective tool for furthering our understanding of the motor control utilized in rhythmic dance. PMID- 25741781 TI - The effect of manipulated and accurate assessment feedback on the self-efficacy of dance students. AB - Research undertaken with athletes has shown that lower-evaluated feedback is related to low self-efficacy levels. However, the relationship between teacher feedback and self-efficacy has not been studied in the dance setting. In sports or dance contexts, very few studies have manipulated feedback content to examine its impact on performers' self-efficacy in relation to the execution of a specific movement. Therefore, the aim of this investigation was to explore the effect of manipulated upper, lower, and accurate grade feedback on changes in dancers' self-efficacy levels for the execution of the "Zapateado" (a flamenco foot movement). Sixty-one students (56 female, 5 male, ages 13 to 22 +/- 3.25 years) from a Spanish dance conservatory participated in this experimental study. They were randomly divided into four feedback groups: 1. upper-evaluated, 2. objective and informational, 3. lower-evaluated, and 4. no feedback-control. Participants performed three trials during a 1-hour session and completed questionnaires tapping self-efficacy pre-feedback and post-feedback. After each trial, teachers (who were confederates in the study) were first asked to rate their perception of each dancer's competence level at performing the movement according to conventional criteria (scores from 0 to 10). The results were then manipulated, and students accurate, lower-evaluated, or upper-evaluated scores were given. Those in the accurate feedback group reported positive change in self efficacy, whereas those in the lower-evaluated group showed no significant change in self-efficacy during the course of the trial. Findings call into question the common perception among teachers that it can be motivating to provide students with inaccurate feedback that indicates that the students' performance level is much better or much worse than they actually perceive it to be. Self-efficacy appears most likely to increase in students when feedback is accurate. PMID- 25741782 TI - A cross-sectional study of elite adult Irish dancers: biopsychosocial traits, pain, and injury. AB - Despite its growing popularity, scant research exists concerning musculoskeletal pain and injury in Irish dancing (ID). This study aimed to record the biopsychosocial characteristics of elite adult Irish dancers and to investigate potential relationships between these characteristics and musculoskeletal pain and injury. One hundred and four professional Irish dancers, elite competitive Irish dancers, and dancers in full time education studying ID completed a questionnaire providing data on dance and activity levels, physical and psychological health, and pain and injury history. Of these subjects, 84 underwent 1. a physical screening of lower limb flexibility, which involved balance and endurance; 2. a number of functional tests; and 3. anthropometric, biomechanical, and anatomical assessments. Subjects were divided into "significantly injured (SI)" and "not significantly injured (NSI)" categories based on the severity and impact of self-reported pain and injury. Thirty-three (31.7%) subjects were classified as SI and 71 (68.3%) as NSI. The factors significantly associated with being SI were female sex (p = 0.036), higher number of subjective general health (p = 0.001) and psychological (p = 0.036) complaints, low mood (p = 0.01), heightened catastrophizing (p = 0.047), and failure always to complete a warm-up (p = 0.006). A self-reported injury rate of 76.9% over the previous 5 years was reported. The mean number of injuries sustained to all body parts over the previous 5 years was 1.49, with a mean of 126.1 days lost annually to injury. Foot and ankle injuries were most prevalent. It was concluded that there is a significant level of musculoskeletal pain and injury in elite adult ID. A complex combination of biopsychosocial factors appears to be associated with pain and injury. PMID- 25741783 TI - Pain and Tingling in a Dancer's Ankle and Foot During Port de Bras: Looking Proximally to Treat Distal Pain. PMID- 25741785 TI - ZnO nanowires growth via reduction of ZnO powder by H2. AB - A unique approach of ZnO nanowire growth mediated via reduction of ZnO by H2 is presented. It is less complex and more controllable than the conventional carbothermal method (reduction of ZnO by C). The chemical vapor deposition system employed allows precise control of all deposition parameters: (1) source and substrate temperatures, (2) carrier gas compositions, flow and pressure of several gases, (3) growth along a large range of distances from the source. In situ residual gas analysis allows real-time feedback of the process reactions. Controlled, stabilized, homogenous growth (characterized by scanning electron microscopy and x-ray diffraction) over relatively large areas is demonstrated. PMID- 25741784 TI - Co-Deposition of Gold Nanoparticles and Metalloporphyrin Using the Langmuir Blodgett (LB) Technique for Surface-Enhanced Raman Scattering (SERS). AB - The synergistic effect produced by metallic nanoparticles when incorporated into different systems empowers a research field that is growing rapidly. In addition, organometallic materials are at the center of intensive research with diverse applications such as light-emitting devices, transistors, solar cells, and sensors. The Langmuir-Blodgett (LB) technique has proven to be suitable to address challenges inherent to organic devices, since the film properties can be tuned at the molecular level. Here we report a strategy to incorporate gold nanoparticles (AuNPs) into the LB film by co-deposition in order to achieve surface-enhanced Raman scattering (SERS) of the zinc(II)-protoporphyrin (IX) dimethyl ester (ZnPPIX-DME). Prior to the LB co-deposition, the properties of the Langmuir monolayer of ZnPPIX-DME at the air-water interface, containing AuNPs in the subphase, are studied through the surface-pressure versus mean molecular area (pi-A) isotherms. The ZnPPIX-DME+AuNPs pi-A isotherm presented a significant shift to higher molecular area, suggesting an interaction between both ZnPPIX-DME molecules and AuNPs. Those interactions are a key factor allowing the co deposition of both AuNPs and ZnPPIX-DME molecules onto a solid substrate, thus forming the LB film. SERS of ZnPPIX-DME was successfully attained, ensuring the spatial distribution of the AuNPs. Higher enhancement factors were found at AuNP aggregates, as a result of the intense local electromagnetic field found in the metal nanoparticle aggregates. The main vibrational bands observed in the SERS spectra suggest a physical adsorption of the ZnPPIX-DME onto the surface of AuNPs. The latter is not only in agreement with the interactions pointed out by the pi-A isotherms but also suggests that this interaction is kept upon LB film co-deposition. PMID- 25741786 TI - Donohue syndrome: a new case with a new complication. AB - Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million live births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor gene. DS is characterized by pre- and postnatal growth retardation with failure to thrive, lipoatrophy, muscle wasting, acanthosis nigricans, hypertrichosis, and dysmorphic features. Glucose homeostasis is affected with hyperinsulinemia, fasting hypoglycemia, and postprandial hyperglycemia. We report a Jordanian patient with genetically proven DS who had the classical physical features, progressive hypertrophic cardiomyopathy, cholestasis, and hyperglycemia, followed by hypoglycemia. In addition, the patient developed polyuria and uremia despite normal creatinine levels, hypernatremia, and hypertension. To our knowledge, these metabolic derangements were not previously reported in patients with DS. PMID- 25741787 TI - Osteocalcin is inversely associated with adiposity and leptin in adolescent boys. AB - BACKGROUND/AIMS: Recently, osteocalcin (OC), an osteoblast-derived hormone, has been found to correlate with adiposity, adipocytokines and insulin resistance in adults, but few studies have investigated this in children. The aim of this study was to investigate these associations in adolescent boys, for whom it is a time of significant bone mineral accrual, taking into account possible confounders related to adipose and bone tissues. PARTICIPANTS/METHODS: Participants were 141 adolescent boys (mean age 13.9+/-0.7 years), who were divided into tertiles according to OC levels. Across these groups, differences in total body fat mass (FM), body fat distribution, adiponectin, leptin and insulin resistance values were examined with relation to age, pubertal stage, daily energy and calcium intakes, and physical activity. RESULTS: Mean body mass index (BMI), FM, body fat% and leptin differed significantly between subjects in the three OC tertiles after adjustment for age, pubertal stage, energy and calcium intakes, and physical activity. There were no differences in fat free mass (FFM), bone mineral content, energy and calcium intakes, physical activity, adiponectin and insulin resistance values between study groups. For the entire cohort, mean serum OC was 130.2+/-45.2 ng/mL and was related to body mass, BMI, FM, body fat distribution and leptin. Circulating OC was not associated with FFM, daily energy and calcium intakes, physical activity, adiponectin or insulin resistance (insulin, glucose, homeostasis model assessment-insulin resistance) values. CONCLUSIONS: In male adolescents, OC is inversely related to body adiposity and leptin values, even after consideration of several factors that may affect bone and adipose tissues. PMID- 25741788 TI - Rickets and vitamin D deficiency in Alaska native children. AB - BACKGROUND: Rickets and vitamin D deficiency appeared to increase in Alaskan children starting in the 1990s. We evaluated the epidemiology of rickets and vitamin D deficiency in Alaska native (AN) children in 2001-2010. METHODS: We analyzed 2001-2010 visits with rickets or vitamin D deficiency diagnosis for AN and American Indian children and the general US population aged <10 years. We conducted a case-control study of AN rickets/vitamin D deficient cases and age- and region-matched controls. RESULTS: In AN children, annual rickets-associated hospitalization rate (2.23/100,000 children/year) was higher than the general US rate (1.23; 95% CI 1.08-1.39). Rickets incidence increased with latitude. Rickets/vitamin D deficiency cases were more likely to have malnutrition (OR 38.1; 95% CI 4.9-294), had similar breast-feeding prevalence, and were less likely to have received vitamin D supplementation (OR 0.23; 95% CI 0.1-0.87) than controls. CONCLUSIONS: Our findings highlight the importance of latitude, malnutrition, and lack of vitamin D supplementation as risk factors for rickets. PMID- 25741789 TI - Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. AB - BACKGROUND: Recently, whole exome sequencing identified heterozygous defects in the aggrecan (ACAN) gene in three families with short stature and advanced bone age. OBJECTIVE: We report a novel frameshift mutation in ACAN in a family with dominantly inherited short stature, advanced bone age, and premature growth cessation. This is the first case of targeted sequencing of ACAN in this phenotype and confirms that ACAN sequencing is warranted in patients with this rare constellation of findings. RESULTS: We present a 5 1/2-year-old male with a family history of short stature in three generations. The maternal grandfather stands 144.5 cm (Ht SDS -4.7), mother 147.7 cm (Ht SDS -2.6), and index case 99.2 cm (Ht SDS -2.7). Our prepubertal patient has significant bone age advancement (bone age 8 years at chronologic age 5 1/2 years) resulting in a poor predicted adult height of 142 cm (Ht SDS -5.1). DNA sequencing identified a novel heterozygous variant in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The mutation (p.Gly1797Glyfs*52) results in premature truncation and presumed loss of protein function. CONCLUSION: Mutations in the ACAN gene should be included in the differential diagnosis of the child with idiopathic short stature or familial short stature and bone age advancement. PMID- 25741790 TI - Nerve growth factor-induced myoprotection in C2C12 muscle cells is mediated by alpha9beta1 integrin via release of PGE2. AB - BACKGROUND: Nerve growth factor (NGF) mediates a wide range of activities in the central nervous system including neuronal differentiation, synaptic plasticity, and neuroprotection. In addition, NGF places an important role in skeletal muscle physiology by some unknown mechanisms. We recently demonstrated that NGF conferred myoprotection toward ischemia in C2C12 skeletal muscle cell model, establishing an important trophic role for NGF in skeletal muscle. METHODS: In this report, using ELISA and oxygen-glucose deprivation (OGD) assays, we investigated the potential contribution of prostaglandin E2 (PGE2) to NGF myoprotective effects toward C2C12 cultures exposed to OGD insults. Vipera lebetina obtusa disintegrin 5 (VLO5), a selective antagonist of alpha9beta1 integrin, was used as an experimental tool to clarify alpha9beta1 integrin role in NGF action. RESULTS: NGF-induced mitogen-activated protein kinase type 1 or 2 (ERK1/2) phosphorylation in C2C12 cells and in a dose-response fashion stimulated PGE2 release, both effects antagonized by VLO5 and PD98059. NGF-induced myoprotection of the cells exposed for 7 h to OGD, followed by 18 h of reoxygenation, was reversed by VLO5 treatment. CONCLUSIONS: These results suggest that NGF activation of alpha9beta1 integrin induced myoprotection by stimulation of ERK phosphorylation and release of cytoprotective PGE2 mediator. This effect may be also relevant for NGF-induced pain and hyperalgesia in the skeletal muscle. PMID- 25741793 TI - Mnk kinases in cytokine signaling and regulation of cytokine responses. PMID- 25741792 TI - Epigenetic considerations of the APOE gene. [corrected]. AB - The apolipoprotein E (APOE) gene is robustly linked with numerous physiological conditions, including healthy aging, altered cardiovascular fitness, and cognitive function. These connections have been established primarily by phenotype-genotype association studies using APOE's three common genetic variants (epsilon2, epsilon3, and epsilon4). These variants encode for the three apoE protein isoforms (E2, E3, and E4), which have slightly different structures and, consequently, distinct functions in lipid metabolism. However, the differential lipid binding and transferring properties of these isoforms cannot fully explain the association of APOE with such a wide range of physiological phenotypes. One potential explanation for APOE's pleiotropic roles may lie in its unique epigenetic properties. In this article, we present a brief review of the APOE gene and protein, its disease associations, and epigenetic components, with a focus on DNA methylation. We close with a discussion of the prospective epigenetic implications of APOE in disease. PMID- 25741794 TI - Method of isolated ex vivo lung perfusion in a rat model: lessons learned from developing a rat EVLP program. AB - The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and "pearls of wisdom"/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible. PMID- 25741791 TI - The emerging role of the first 17 amino acids of huntingtin in Huntington's disease. AB - Huntington's disease (HD) is caused by a polyglutamine (polyQ) domain that is expanded beyond a critical threshold near the N-terminus of the huntingtin (htt) protein, directly leading to htt aggregation. While full-length htt is a large (on the order of ~350 kDa) protein, it is proteolyzed into a variety of N terminal fragments that accumulate in oligomers, fibrils, and larger aggregates. It is clear that polyQ length is a key determinant of htt aggregation and toxicity. However, the flanking sequences around the polyQ domain, such as the first 17 amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, influence other important biochemical properties of the protein and ultimately its role in pathogenesis. Here, we review the impact of Nt17 on htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of posttranslational modifications (PTMs) that occur in Nt17 in HD, and the function of Nt17 as a membrane targeting domain. PMID- 25741795 TI - Economic Evaluation of a Web-Based Guided Self-Help Intervention for Employees With Depressive Symptoms: Results of a Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the cost-effectiveness of a Web-based guided intervention compared with care as usual for employees with depressive symptoms. METHODS: A total of 231 employees with depressive symptoms were randomized. Data were collected at baseline, 8 weeks, 6 months, and 12 months. Analyses were conducted from the societal and employer's perspective. RESULTS: At 12 months, a significant intervention effect on depressive symptoms was found. At a willingness to pay of 0 (?/unit of effect), the intervention's probabilities of cost-effectiveness were 0.62 (societal perspective) and 0.55 (employer's perspective). There was a 0.63 probability that the intervention resulted in a positive financial return for the employer. CONCLUSIONS: The intervention's cost effectiveness with regard to depressive symptoms depends on the willingness to pay of societal and company decision makers as well as the probability of cost effectiveness that they consider acceptable. The intervention is not cost-saving to the employer. PMID- 25741796 TI - Critical care telemedicine: evolution and state of the art: erratum. AB - [This corrects the article on p. 2429 in vol. 42, issue 11, PMID: 25080052]. PMID- 25741797 TI - Individualized early goal-directed therapy in systemic inflammation: is full utilization of preload reserve the optimal strategy? Erratum. AB - [This corrects the article on p. e741 in vol. 42, issue 12, PMID: 25402295]. PMID- 25741798 TI - Isolation, culture and long-term maintenance of primary mesencephalic dopaminergic neurons from embryonic rodent brains. AB - Degeneration of mesencephalic dopaminergic (mesDA) neurons is the pathological hallmark of Parkinson's diseae. Study of the biological processes involved in physiological functions and vulnerability and death of these neurons is imparative to understanding the underlying causes and unraveling the cure for this common neurodegenerative disorder. Primary cultures of mesDA neurons provide a tool for investigation of the molecular, biochemical and electrophysiological properties, in order to understand the development, long-term survival and degeneration of these neurons during the course of disease. Here we present a detailed method for the isolation, culturing and maintenance of midbrain dopaminergic neurons from E12.5 mouse (or E14.5 rat) embryos. Optimized cell culture conditions in this protocol result in presence of axonal and dendritic projections, synaptic connections and other neuronal morphological properties, which make the cultures suitable for study of the physiological, cell biological and molecular characteristics of this neuronal population. PMID- 25741799 TI - TIRFM and pH-sensitive GFP-probes to evaluate neurotransmitter vesicle dynamics in SH-SY5Y neuroblastoma cells: cell imaging and data analysis. AB - Synaptic vesicles release neurotransmitters at chemical synapses through a dynamic cycle of fusion and retrieval. Monitoring synaptic activity in real time and dissecting the different steps of exo-endocytosis at the single-vesicle level are crucial for understanding synaptic functions in health and disease. Genetically-encoded pH-sensitive probes directly targeted to synaptic vesicles and Total Internal Reflection Fluorescence Microscopy (TIRFM) provide the spatio temporal resolution necessary to follow vesicle dynamics. The evanescent field generated by total internal reflection can only excite fluorophores placed in a thin layer (<150 nm) above the glass cover on which cells adhere, exactly where the processes of exo-endocytosis take place. The resulting high-contrast images are ideally suited for vesicles tracking and quantitative analysis of fusion events. In this protocol, SH-SY5Y human neuroblastoma cells are proposed as a valuable model for studying neurotransmitter release at the single-vesicle level by TIRFM, because of their flat surface and the presence of dispersed vesicles. The methods for growing SH-SY5Y as adherent cells and for transfecting them with synapto-pHluorin are provided, as well as the technique to perform TIRFM and imaging. Finally, a strategy aiming to select, count, and analyze fusion events at whole-cell and single-vesicle levels is presented. To validate the imaging procedure and data analysis approach, the dynamics of pHluorin-tagged vesicles are analyzed under resting and stimulated (depolarizing potassium concentrations) conditions. Membrane depolarization increases the frequency of fusion events and causes a parallel raise of the net fluorescence signal recorded in whole cell. Single-vesicle analysis reveals modifications of fusion-event behavior (increased peak height and width). These data suggest that potassium depolarization not only induces a massive neurotransmitter release but also modifies the mechanism of vesicle fusion and recycling. With the appropriate fluorescent probe, this technique can be employed in different cellular systems to dissect the mechanisms of constitutive and stimulated secretion. PMID- 25741800 TI - An ex vivo model of an oligodendrocyte-directed T-cell attack in acute brain slices. AB - Death of oligodendrocytes accompanied by destruction of neurons and axons are typical histopathological findings in cortical and subcortical grey matter lesions in inflammatory demyelinating disorders like multiple sclerosis (MS). In these disorders, mainly CD8+ T-cells of putative specificity for myelin- and oligodendrocyte-related antigens are found, so that neuronal apoptosis in grey matter lesions may be a collateral effect of these cells. Different types of animal models are established to study the underlying mechanisms of the mentioned pathophysiological processes. However, although they mimic some aspects of MS, it is impossible to dissect the exact mechanism and time course of ''collateral'' neuronal cell death. To address this course, here we show a protocol to study the mechanisms and time response of neuronal damage following an oligodendrocyte directed CD8+ T cell attack. To target only the myelin sheath and the oligodendrocytes, in vitro activated oligodendrocyte-specific CD8+ T-cells are transferred into acutely isolated brain slices. After a defined incubation period, myelin and neuronal damage can be analysed in different regions of interest. Potential applications and limitations of this model will be discussed. PMID- 25741801 TI - Management of Kawasaki disease in resource-limited settings. PMID- 25741802 TI - The fast route to microbe identification: matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). AB - Rapid identification of bacterial and fungal microorganisms is critical for early and targeted antimicrobial therapy. Conventional methods for bacterial identification are time consuming. Matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) has revolutionized the daily process of identification in modern microbiological laboratories. The technique and its multiple current and future applications will be discussed. PMID- 25741803 TI - Panuveitis caused by Borrelia burgdorferi sensu lato infection. AB - A 13-year-old boy who presented with a red left eye, painful eye movement, blurred vision, photophobia and increased lacrimation, was diagnosed with 1-sided panuveitis with optic disk edema. Diagnostic work-up revealed borrelial antibodies in serum. Diagnosis of Lyme borreliosis was substantiated by demonstration of lymphocytic pleocytosis, intrathecal borrelial antibody synthesis, improvement after treatment with ceftriaxone and exclusion of other causes. PMID- 25741804 TI - Minimal inhibitory concentration drift of glycopeptides and linezolid against S. Aureus at a Chinese children's center, 2009-2013. AB - We analyzed the drift in the minimum inhibitory concentration (MIC) of glycopeptides and linezolid against 793 methicillin-resistant Staphylococcus aureus (MRSA) and 4696 methicillin-susceptible S. aureus (MSSA) isolates from Chinese children. For vancomycin and teicoplanin, no significant change occurred in different years for MIC values >= 2 MUg/mL, either in MRSA or MSSA. For linezolid, there was an MIC drift in MRSA and in MSSA. PMID- 25741805 TI - A teenager with abdominal pain after completing treatment for endocarditis. PMID- 25741806 TI - Two cases of extensive limb swelling after influenza vaccination. PMID- 25741807 TI - Risk of Rotavirus Vaccination for Children with SCID. PMID- 25741808 TI - Rotavirus-specific IgG antibodies from mothers' serum may inhibit infant immune responses to the pentavalent rotavirus vaccine. PMID- 25741809 TI - Treatment of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome. PMID- 25741811 TI - PRIMARY SCLERAL BUCKLING FOR PEDIATRIC RHEGMATOGENOUS RETINAL DETACHMENT. AB - PURPOSE: To evaluate the anatomical outcomes of primary scleral buckling (SB) procedures for pediatric rhegmatogenous retinal detachments. METHODS: Retrospective consecutive case series. One hundred and four eyes of 99 consecutive nonselected pediatric patients undergoing primary SB were identified. Baseline factors recorded were demographics, presenting clinical examination findings, previous ocular surgery, predisposing factors. Intraoperative factors recorded were the type of buckle, number and distribution of retinal breaks, number of retinal quadrants detached, macular status (involved vs. uninvolved), the use of subretinal fluid drainage, and surgical complications. Anatomical reattachment rate at last follow-up. Subgroup analysis was carried out to identify any predisposing factors for failure of primary surgery, effect of age on outcome, intraoperative pathology, effect of posterior versus anterior SB, and redetachment and secondary-procedure complications specific to SB. RESULTS: The initial surgery was segmental SB alone in 87 eyes (83.6%). Retinal reattachment was achieved with 1 operation in 73% (76 of 104 eyes). Of the 28 cases that redetached, 14 eyes underwent a repeat SB procedure (success rate of this second operation: 85.7% [12 of 14 eyes]), 13 eyes underwent vitrectomy (success rate of this second operation: 38.4% [5 of 13 eyes]), and 1 case was not reoperated. Overall, the final success rate was 94% (98 of 104 eyes). Factors associated with a statistically significant increased risk of failure included more than one break; three or more quadrants of detachment; horseshoe tears; no breaks seen on preoperative examination; Stickler syndrome. CONCLUSION: In selected cases, primary SB is an effective treatment for pediatric, rhegmatogenous retinal detachment. PMID- 25741812 TI - Diagnostic and Therapeutic Challenges. PMID- 25741813 TI - EFFICACY AND SAFETY OF DEXAMETHASONE INTRAVITREAL IMPLANT FOR PERSISTENT UVEITIC CYSTOID MACULAR EDEMA. AB - PURPOSE: To investigate dexamethasone intravitreal implant (DEX Implant 0.7 mg, Ozurdex; Allergan, Inc, Irvine, CA) as a treatment for persistent cystoid macular edema (CME) secondary to uveitis. METHODS: Treatment and outcomes data were collected retrospectively for 18 eyes from 13 consecutive patients treated with the DEX Implant for persistent, noninfectious uveitic CME. Outcome measures included the cumulative incidence of resolution of CME, visual acuity, central retinal thickness (measured by spectral domain optical coherence tomography), and vitreous haze score. RESULTS: After a single DEX Implant, there was no detectable CME in 89% and 72% of eyes at 1 month and 3 months, respectively. The median time to recurrence of CME (+/-standard error) was 201 +/- 62 days. The percentage of eyes with no recurrence of CME was 35% at 6 months and 30% at 12 months. At 3 months, there was a significant improvement from baseline in mean visual acuity (+2.1 lines, P < 0.01). Eyes with an epiretinal membrane at baseline had shorter time to recurrence of CME and smaller improvements in visual acuity and central retinal thickness than eyes without an epiretinal membrane. At least 1 episode of intraocular pressure >25 mmHg occurred within the first 3 months in 11% (2 of 18) of eyes; all effectively managed with topical hypotensive medications. CONCLUSION: A single DEX Implant produced sustained improvements in both visual acuity and retinal thickness in the majority of eyes with persistent uveitic CME. Uveitic CME did gradually recur in most eyes; however, close posttreatment monitoring is recommended. PMID- 25741814 TI - PATHOGENESIS OF PERSISTENT PLACOID MACULOPATHY: A Multimodal Imaging Analysis. AB - PURPOSE: To describe previously unreported clinical characteristics of persistent placoid maculopathy, suggest a pathogenesis of persistent placoid maculopathy using multimodal imaging, and provide evidence supporting high-dose immunosuppression for short-term management. METHODS: Retrospective case series. RESULTS: The cohort included 3 men with ages ranging from 55 years to 68 years. Persistent placoid maculopathy was bilateral in all 3 patients and characterized by recurrence and choroidal neovascularization in 1 patient. The median time to presentation was 3 months (range, 2-24 months), and follow-up was 8 months (range, 3-24 months). Previously unreported findings of far-peripheral lesions and optic nerve hyperfluorescence on fluorescein angiography were noted in separate individuals. In addition, findings from multimodal imaging supported an inflammatory pathogenesis of the inner choroid and the outer retina. Finally, all patients experienced substantial improvement to structural and functional measures in at least one eye within days to weeks of initiating high-dose corticosteroids (0.75-1 mg/kg/day). CONCLUSION: Multimodal imaging suggests that persistent placoid maculopathy has an inflammatory pathogenesis that may affect the inner choroid with secondary changes to the retinal pigment epithelium and the outer retina. High-dose corticosteroids may provide short-term benefit. PMID- 25741815 TI - ENDOPHTHALMITIS CAUSED BY SERRATIA MARCESCENS: Clinical Features, Antibiotic Susceptibilities, and Treatment Outcomes. AB - PURPOSE: To report the clinical features, antibiotic sensitivities, and visual outcomes associated with endophthalmitis caused by Serratia marcescens. METHODS: A consecutive case series of patients with vitreous culture-positive endophthalmitis caused by S. marcescens from July 1, 1993, to June 30, 2012, at a large university referral center. Findings from this study were compared with those of a previous study (January 1980-June 1993) from our institution. RESULTS: Of the 10 study patients who were identified, clinical settings included trabeculectomy bleb-associated (n = 3), post-cataract surgery (n = 2), post penetrating keratoplasty (n = 2), post-scleral buckle (n = 1), glaucoma drainage implant-associated (n = 1), and post-keratoprosthesis (n = 1). Clinical features included pain (n = 10) and hypopyon (n = 5). Presenting visual acuity was hand motions or worse in seven cases. All isolates were sensitive to gentamicin, ceftazidime, imipenem, and levofloxacin. The MIC 90s of isolates for antibiotics tested in the current period compared with isolates from January 1980 to June 1993 were unchanged. All isolates were resistant to vancomycin. Initial treatment strategies were vitreous tap and intravitreal antibiotic injection (n = 8), pars plana vitrectomy with intravitreal antibiotic injection (n = 1), and evisceration (n = 1). When repeat vitreous fluid was obtained, persistent positive cultures were present in 1 (10%) of 10 patients in this study, compared with 5 (50%) of 10 patients in the previous study. Final visual acuity was no light perception in 6 of 10 patients (60%). CONCLUSION: Outcomes were generally poor with a high rate of complete visual loss in the affected eye. PMID- 25741816 TI - Association between anatomical resolution and functional outcomes in the mivi trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole. AB - PURPOSE: To evaluate visual function in patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction including when associated with macular hole after ocriplasmin treatment, and the association between resolution of the underlying condition and improvement in visual function. METHODS: Six hundred and fifty-two patients from 2 Phase 3 trials received a single intravitreal injection of ocriplasmin 125 MUg (n = 464) or placebo (n = 188). Mean and categorical changes from baseline in best-corrected visual acuity and 25-item Visual Function Questionnaire scores were used to evaluate visual function. Subgroups with VMA resolution and full-thickness macular hole closure were compared. RESULTS: Overall, 42% of patients who achieved VMA resolution at Day 28 had a >=2-line improvement in best-corrected visual acuity at Month 6, and 20% had a >=3-line improvement. Likewise, 69% of patients with nonsurgical full-thickness macular hole closure at Day 28 had a >=2-line improvement at Month 6, and 48% had a >=3 line best-corrected visual acuity improvement. Mean improvements in 25-item Visual Function Questionnaire scores were associated with achieving VMA resolution and nonsurgical full-thickness macular hole closure. CONCLUSION: In patients with symptomatic VMA/vitreomacular traction, VMA resolution and nonsurgical full-thickness macular hole closure were each associated with improvements in visual function. Resolving the underlying anatomical condition in symptomatic VMA/vitreomacular traction will increase the probability of achieving a clinically meaningful improvement in visual function. PMID- 25741817 TI - Reduction of Platelet Aggregation From Ingestion of Oleic and Linoleic Acids Found in Vitis vinifera and Arachis hypogaea Oils. AB - The purpose of this study was to evaluate the effect of the consumption of seed oils from Vitis vinifera and Arachis hypogaea in platelet aggregation. The initial hypothesis suggested that subjects who have consumed these seed oils undergo modified platelet aggregation. This study was performed using a pre-post test design, with a control group, and double blind. The effects of the consumption of grape seed and peanut oils were measured for platelet aggregation in clinical and laboratory tests in 30 healthy subjects. In addition to this group, a control group of 4 health subjects received no treatment with oils, just 500 mg oral administration acetylsalicylic acid for 7 days. Platelet aggregation was assessed by the Born turbidimetric method, using 3 different concentrations of adenosine diphosphate as agonists (2, 54; 1, 17; and 0, 58 MUM). The study subjects had very similar results; both oils were shown to have a significant reduction in platelet aggregation. Grape seed oil showed a decrease of 8.4 +/- 1% in aggregation, compared with peanut oil, which decreased aggregation by 10.4 +/- 1%. The control group, taking 500 mg OD aspirin for 7 days, showed a significant decrease in platelet aggregation, similar to that of oil ingestion. Each of the oils was analyzed for fatty acids, to determine which particular acids were presents in greater levels, which could explain the reduction in platelet aggregation. The oil found to be most abundant in grape seeds was linoleic acid (omega-6), and in peanuts, it was oleic acid (omega-9). However, in fact, both acids reduced platelet aggregation. Consumption of plant oils from grape seeds and peanuts had a lowering effect on platelet aggregation, in addition to containing a high content of unsaturated fatty acids. However, omega-3, omega-6, and omega-9 fatty acids were not specifically responsible for the reductions mentioned above. PMID- 25741819 TI - New achievements: from submission to disclosure. PMID- 25741820 TI - Systematic review and meta-analysis: what are the implications in the clinical practice? PMID- 25741818 TI - Inhibition of cancer cell proliferation and breast tumor targeting of pHLIP monomethyl auristatin E conjugates. AB - Localized delivery is vital for the successful development of novel and effective therapeutics for the treatment of cancer. The targeting and delivery described herein is based on the pH (low) insertion peptide (pHLIP), a unique delivery peptide that can selectively target tumors in mice and translocate and release cargo molecules intracellularly based solely on the low extracellular pH intrinsic to cancer cells. In this study, we investigate the efficacy of pHLIP to target and deliver the highly potent and clinically validated microtubule inhibitor monomethyl auristatin E (MMAE) to cancer cells and breast tumors. We show that pHLIP-MMAE conjugates induce a potent cytotoxic effect (>90% inhibition of cell growth) in a concentration- and pH-dependent manner after only 2 h incubation without any apparent disruption of the plasma membrane. pHLIP-MMAE conjugates exhibit between an 11- and 144-fold higher antiproliferative effect at low pH than that at physiological pH and a pronounced pH-dependent cytotoxicity as compared to that of free drug. Furthermore, we demonstrate that a pHLIP-MMAE drug conjugate effectively targets triple-negative breast tumor xenografts in mice. These results indicate that pHLIP-based auristatin conjugates may have an enhanced therapeutic window as compared to that of free drug, providing a targeting mechanism to attenuate systemic toxicity. PMID- 25741821 TI - Why are mini-implants lost: the value of the implantation technique! AB - The use of mini-implants have made a major contribution to orthodontic treatment. Demand has aroused scientific curiosity about implant placement procedures and techniques. However, the reasons for instability have not yet been made totally clear. The aim of this article is to establish a relationship between implant placement technique and mini-implant success rates by means of examining the following hypotheses: 1) Sites of poor alveolar bone and little space between roots lead to inadequate implant placement; 2) Different sites require mini implants of different sizes! Implant size should respect alveolar bone diameter; 3) Properly determining mini-implant placement site provides ease for implant placement and contributes to stability; 4) The more precise the lancing procedures, the better the implant placement technique; 5) Self-drilling does not mean higher pressures; 6) Knowing where implant placement should end decreases the risk of complications and mini-implant loss. PMID- 25741822 TI - An interview with Eiji Tanaka. PMID- 25741823 TI - Perception of adults' smile esthetics among orthodontists, clinicians and laypeople. AB - OBJECTIVE: Smile esthetics has become a major concern among patients and orthodontists. Therefore, the aim of this study was: (1) To highlight differences in perception of smile esthetics by clinicians, orthodontists and laypeople; (2) To assess factors such as lip thickness, smile height, color gradation, tooth size and crowding, and which are associated with smile unpleasantness. METHODS: To this end, edited photographs emphasizing the lower third of the face of 41 subjects were assessed by three groups (orthodontists, laypeople and clinicians) who graded the smiles from 1 to 9, highlighting the markers that evince smile unpleasantness. Kruskall-Wallis test supplemented by Bonferroni test was used to assess differences among groups. Additionally, the prevailing factors in smile unpleasantness were also described. RESULTS: There was no significant difference (P = 0.67) among groups rates. However, the groups highlighted different characteristics associated with smile unpleasantness. Orthodontists emphasized little gingival display, whereas laypeople emphasized disproportionate teeth and clinicians emphasized yellow teeth. CONCLUSION: Orthodontists, laypeople and clinicians similarly assess smile esthetics; however, noticing different characteristics. Thus, the orthodontist must be careful not to impose his own perception of smile esthetics. PMID- 25741824 TI - Perception of the relationship between TMD and orthodontic treatment among orthodontists. AB - INTRODUCTION: The consensus about the relationship between TMD and orthodontic treatment has gone from a cause and effect association between TMD and orthodontic treatment to the idea that there is no reliable evidence supporting this statement. OBJECTIVE: To assess the beliefs, despite scientific evidence, of Brazilian orthodontists about the relationship between TMD and orthodontic treatment with regards to treatment, prevention and etiology of TMD. METHODS: A survey about the relationship between TMD and orthodontic treatment was prepared and sent to Brazilian orthodontists by e-mail and social networks. Answers were treated by means of descriptive statistics and strong associations between variables were assessed by qui-square test. RESULTS: The majority of orthodontists believe that orthodontic treatment not only is not the best treatment option for TMD, but also is not able to prevent TMD. Nevertheless, the majority of orthodontists believe that orthodontic treatment can cause TMD symptoms. CONCLUSION: This study suggests that orthodontists' beliefs about the relationship between orthodontic treatment and TMD are in accordance with scientific evidence only when referring to treatment and prevention of TMD. The majority of orthodontists believe that, despite scientific evidence, orthodontic treatment can cause TMD. PMID- 25741825 TI - Severe root resorption resulting from orthodontic treatment: prevalence and risk factors. AB - OBJECTIVE: To assess the prevalence of severe external root resorption and its potential risk factors resulting from orthodontic treatment. METHODS: A randomly selected sample was used. It comprised conventional periapical radiographs taken in the same radiology center for maxillary and mandibular incisors before and after active orthodontic treatment of 129 patients, males and females, treated by means of the Standard Edgewise technique. Two examiners measured and defined root resorption according to the index proposed by Levander et al. The degree of external apical root resorption was registered defining resorption in four degrees of severity. To assess intra and inter-rater reproducibility, kappa coefficient was used. Chi-square test was used to assess the relationship between the amount of root resorption and patient's sex, dental arch (maxillary or mandibular), treatment with or without extractions, treatment duration, root apex stage (open or closed), root shape, as well as overjet and overbite at treatment onset. RESULTS: Maxillary central incisors had the highest percentage of severe root resorption, followed by maxillary lateral incisors and mandibular lateral incisors. Out of 959 teeth, 28 (2.9%) presented severe root resorption. The following risk factors were observed: anterior maxillary teeth, overjet greater than or equal to 5 mm at treatment onset, treatment with extractions, prolonged therapy, and degree of apex formation at treatment onset. CONCLUSION: This study showed that care must be taken in orthodontic treatment involving extractions, great retraction of maxillary incisors, prolonged therapy, and/or completely formed apex at orthodontic treatment onset. PMID- 25741826 TI - Comparison of clinical bracket point registration with 3D laser scanner and coordinate measuring machine. AB - OBJECTIVE: The aim of the present study was to assess the diagnostic value of a laser scanner developed to determine the coordinates of clinical bracket points and to compare with the results of a coordinate measuring machine (CMM). METHODS: This diagnostic experimental study was conducted on maxillary and mandibular orthodontic study casts of 18 adults with normal Class I occlusion. First, the coordinates of the bracket points were measured on all casts by a CMM. Then, the three-dimensional coordinates (X, Y, Z) of the bracket points were measured on the same casts by a 3D laser scanner designed at Shahid Beheshti University, Tehran, Iran. The validity and reliability of each system were assessed by means of intraclass correlation coefficient (ICC) and Dahlberg's formula. RESULTS: The difference between the mean dimension and the actual value for the CMM was 0.0066 mm. (95% CI: 69.98340, 69.99140). The mean difference for the laser scanner was 0.107 +/- 0.133 mm (95% CI: -0.002, 0.24). In each method, differences were not significant. The ICC comparing the two methods was 0.998 for the X coordinate, and 0.996 for the Y coordinate; the mean difference for coordinates recorded in the entire arch and for each tooth was 0.616 mm. CONCLUSION: The accuracy of clinical bracket point coordinates measured by the laser scanner was equal to that of CMM. The mean difference in measurements was within the range of operator errors. PMID- 25741827 TI - Interproximal wear versus incisors extraction to solve anterior lower crowding: a systematic review. AB - OBJECTIVE: To determine by means of a systematic review the best treatment, whether interproximal wear or incisor extraction, to correct anterior lower crowding in Class I patients in permanent dentition. METHODS: A literature review was conducted using MEDLINE, Scopus and Web of Science to retrieve studies published between January 1950 and October 2013. In selecting the sample, the following inclusion criteria were applied: studies involving interproximal wear and/or extraction of mandibular incisors, as well as Class I cases with anterior lower crowding in permanent dentition. RESULTS: Out of a total of 943 articles found after excluding duplicates, 925 were excluded after abstract analysis. After full articles were read, 13 were excluded by the eligibility criteria and one due to methodological quality; therefore, only fours articles remained: two retrospective and two randomized prospective studies. Data were collected, analyzed and organized in tables. CONCLUSION: Both interproximal wear and mandibular incisor extraction are effective in treating Class I malocclusion in permanent dentition with moderate anterior lower crowding and pleasant facial profile. There is scant evidence to determine the best treatment option for each case. Clinical decision should be made on an individual basis by taking into account dental characteristics, crowding, dental and oral health, patient's expectations and the use of set-up models. PMID- 25741828 TI - Influence of the socioeconomic status on the prevalence of malocclusion in the primary dentition. AB - OBJECTIVE: To assess the influence of socioeconomic background on malocclusion prevalence in primary dentition in a population from the Brazilian Amazon. METHODS: This cross-sectional study comprised 652 children (males and females) aged between 3 to 6 years old. Subjects were enrolled in private preschools (higher socioeconomic status - HSS, n = 312) or public preschools (lower socioeconomic status - LSS, n = 340) in Belem, Para, Brazil. Chi-square and binomial statistics were used to assess differences between both socioeconomic groups, with significance level set at P < 0.05. RESULTS: A high prevalence of malocclusion (81.44%) was found in the sample. LSS females exhibited significantly lower prevalence (72.1%) in comparison to HSS females (84.7%), particularly with regard to Class II (P < 0.0001), posterior crossbite (P = 0.006), increased overbite (P = 0.005) and overjet (P < 0.0001). Overall, malocclusion prevalence was similar between HSS and LSS male children (P = 0.36). Early loss of primary teeth was significantly more prevalent in the LSS group (20.9%) in comparison to children in the HSS group (0.9%), for both males and females (P < 0.0001). CONCLUSION: Socioeconomic background influences the occurrence of malocclusion in the primary dentition. In the largest metropolitan area of the Amazon, one in every five LSS children has lost at least one primary tooth before the age of seven. PMID- 25741829 TI - Base of the skull morphology and Class III malocclusion in patients with unilateral cleft lip and palate. AB - OBJECTIVE: The aim of the present study was to determine the morphological differences in the base of the skull of individuals with cleft lip and palate and Class III malocclusion in comparison to control groups with Class I and Class III malocclusion. METHODS: A total of 89 individuals (males and females) aged between 5 and 27 years old (Class I, n = 32; Class III, n = 29; and Class III individuals with unilateral cleft lip and palate, n = 28) attending PUC-MG Dental Center and Cleft Lip/Palate Care Center of Baleia Hospital and PUC-MG (CENTRARE) were selected. Linear and angular measurements of the base of the skull, maxilla and mandible were performed and assessed by a single calibrated examiner by means of cephalometric radiographs. Statistical analysis involved ANCOVA and Bonferroni correction. RESULTS: No significant differences with regard to the base of the skull were found between the control group (Class I) and individuals with cleft lip and palate (P > 0.017). The cleft lip/palate group differed from the Class III group only with regard to CI.Sp.Ba (P = 0.015). Individuals with cleft lip and palate had a significantly shorter maxillary length (Co-A) in comparison to the control group (P < 0.001). No significant differences were found in the mandible (Co-Gn) of the control group and individuals with cleft lip and palate (P = 1.000). CONCLUSION: The present findings suggest that there are no significant differences in the base of the skull of individuals Class I or Class III and individuals with cleft lip and palate and Class III malocclusion. PMID- 25741830 TI - Cephalometric variables used to predict the success of interceptive treatment with rapid maxillary expansion and face mask. A longitudinal study. AB - INTRODUCTION: Prognosis is the main limitation of interceptive treatment of Class III malocclusions. The interceptive procedures of rapid maxillary expansion (RME) and face mask therapy performed in early mixed dentition are capable of achieving immediate overcorrection and maintenance of facial and occlusal morphology for a few years. Individuals presenting minimal acceptable faces at growth completion are potential candidates for compensatory orthodontic treatment, while those with facial involvement should be submitted to orthodontic decompensation for orthognathic surgery. OBJECTIVES: To investigate cephalometric variables that might predict the outcomes of orthopedic treatment with RME and face mask therapy (FM). METHODS: Cephalometric analysis of 26 Class III patients (mean age of 8 years and 4 months) was performed at treatment onset and after a mean period of 6 years and 10 months at pubertal growth completion, including a subjective facial analysis. Patients was divided into two groups: success group (21 individuals) and failure group (5 individuals). Discriminant analysis was applied to the cephalometric values at treatment onset. Two predictor variables were found by stepwise procedure. RESULTS: Orthopedic treatment of Class III malocclusion may have unfavorable prognosis at growth completion whenever initial cephalometric analysis reveals increased lower anterior facial height (LAFH) combined with reduced angle between the condylar axis and the mandibular plane (CondAx.MP). CONCLUSION: The results of treatment with RME and face mask therapy at growth completion in Class III patients could be predicted with a probability of 88.5%. PMID- 25741831 TI - Alternative treatment for open bite Class III malocclusion in a child with Williams-Beuren syndrome. AB - Williams-Beuren syndrome (WBS) is a rare genetic condition that affects approximately 1 in every 20,000 - 50,000 live births. WBS children have specific skeletal deformities, dental malformations and rare lingual muscle dysfunction. The need for orthodontic and orthognathic therapy has arisen and has been considered a real clinical challenge even for experienced professionals, once it requires a complex and individualized treatment plan. This study reports a case of orthopedic expansion of the maxilla, in which a modified facial mask was used for protraction of the maxillary complex associated with clockwise rotation of the maxilla. In addition, special considerations about treatment time and orthopedic outcomes are discussed. PMID- 25741832 TI - Orthodontic treatment in patient with idiopathic root resorption: a case report. AB - Multiple idiopathic external root resorption is a rare pathological condition usually detected as an incidental radiographic finding. External root resorption of permanent teeth is a multifactorial process related to several local and systemic factors. If an etiological factor cannot be identified for root resorption, the term "idiopathic" is applied. This report presents a case of multiple idiopathic apical root resorption. The condition was found in a young female patient seeking orthodontic treatment due to malocclusion. This kind of resorption starts apically and progresses coronally, causing a gradual shortening and rounding of the remaining root. Patients with this condition are not the ideal candidates for orthodontic treatment; however, the aim of this report is to describe an unusual case of idiopathic root resorption involving the entire dentition, and to present the orthodontic treatment of this patient. It describes the progress and completion of orthodontic therapy with satisfactory end results. PMID- 25741833 TI - Orthodontic retreatment of a Class III patient with significant midline asymmetry and bilateral posterior crossbite. AB - Posterior crossbite might cause serious long-term functional problems if not early treated. Nevertheless, in older patients, treatment might include palatal expansion in order to correct such malocclusion. In view of the above, this article aims at reporting late correction of bilateral posterior crossbite associated with Angle Class III malocclusion, right subdivision, with consequent midline shift (good skeletal pattern). The case was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO), with DI equal to or greater than 10, as a requirement for the title of certified by the BBO. PMID- 25741835 TI - [Anemia caused by parasites]. AB - Anemia is a major public health problem and concerns the World Health Organization. It is more common in developing countries particularly in South Asia and Africa. The causes of anemia are varied and parasites can cause it. We propose to study the anemia caused by parasites after a brief hematology and pathophysiology of anemia in general. PMID- 25741834 TI - TMD and chronic pain: a current view. AB - This review aims at presenting a current view on the physiopathologic mechanisms associated with temporomandibular disorders (TMDs). While joint pain is characterized by a well-defined inflammatory process mediated by tumor necrosis factor-alpha and interleukin, chronic muscle pain presents with enigmatic physiopathologic mechanisms, being considered a functional pain syndrome similar to fibromyalgia, irritable bowel syndrome, interstitial cystitis and chronic fatigue syndrome. Central sensitization is the common factor unifying these conditions, and may be influenced by the autonomic nervous system and genetic polymorphisms. Thus, TMDs symptoms should be understood as a complex response which might get worse or improve depending on an individual's adaptation. PMID- 25741836 TI - [Carcinogenesis of non small cell lung cancer and therapeutic implications]. AB - The occurrence of a lung cancer is a consequence of a long-lasting process dealing with a transformation of a normal cell to a malignant one. The four steps of transformation reflect the genetic modifications of the cells. The molecular studies of pre-invasive lesions have already established a correlation between the lesion continuum and the multi-step carcinogenesis. Gradual genetic alterations are correlated with the increase of the cell's malignant potential. We tried to present the carcinogenesis of the lung non microcellular carcinomas and to highlight the main therapeutic targets. PMID- 25741837 TI - [Limits of quantitative coronary angiography (QCA) in intermediate stenosis measuring: a correlation and concordance study with intravascular ultrasound (IVUS)]. AB - BACKGROUND: Although coronarography is still the gold standard to evaluate coronary lesions, it remains a bidimensional representation of a tridimensional complex structure, which can represent a source of error in measurements. AIMS: to perform a correlation and concordance study between quantitative coronary angiography (QCA) and intravascular ultrasound measurements for intermediate and ambiguous lesions. METHODS: We analysed 40 patients' coronary arteries from March 2009 to November 2011 by both QCA and intravascular ultrasound to perform then a correlation and concordance study. RESULTS: the correlation study confirmed the limits of the angiogram in providing accurate measurements. The correlation coefficient was yet high in reference diameters (r=0,78, p<0,001) and minimal lumen diameters (r=0,58, p<0,001), but was middling for stenosis percentages (r=0,23, p=0,03). This coefficient was also high for lesions lengths (r=0,51, p=0,01). Bland &Altaman diagrams showed however wide limits of agreement, reflecting possibility of large measurements error and confirming the absence of concordance between the two techniques. CONCLUSION: Coronarography though being the most widespread mean of evaluating coronary lesions lacks to provide accurate measurements, which can influence patient's management, especially in case of intermediate lesions. PMID- 25741838 TI - [The Tunisian Revolution in the eyes of children]. AB - BACKGROUND: The child uses drawing as a language. By reflecting faithfully all that is involved in the psychic life of the child, the drawing participates in the diagnosis and plays a role in the therapeutic management of young people suffering from psychological difficulties. AIM: To analyze the drawings of children and adolescents followed at the department of Child and Adolescent Psychiatry, further to the events of the Tunisian Revolution. METHOD: it is about a cross sectional study conducted among outpatients consulting the department of Child and Adolescent Psychiatry at Razi hospital in Manouba during the period from January 25 to February 28, 2011. These patients were divided into two groups with a specific instruction for each, to represent the events experienced by the patient and his family for the first group and to do a free drawing for the second. RESULTS: both groups consisted of 16 patients each with successively average age of 10, 5 and 10.33 years and sex ratio of 2.20 and 1.25. Patients in both groups were exposed to different stressors. The first group of children used in their drawings few colors, mostly black and red. The instruments of war such as bullets, guns, tanks and military helicopters were well represented. The characters were mostly male who were angry and looking for leakage. The drawings depicted scenes of war and conflict with people in distress or dead. The drawings of the second group were essentially about nature. CONCLUSION: We find that the instruction has significantly changed the behavior of children from the sheet. The instruction in this context seems to be a necessary to help these children overcome their concerns and express their pain. PMID- 25741839 TI - [Implementation of the safe surgery checklist of the World Health Organization at the University Hospital of Monastir (Tunisia)]. AB - OBJECTIVE: To evaluate the impact of introduction of the WHO safe surgery checklist in the university hospital of Monastir over a period of five months. METHODS: We conducted a longitudinal study (before - after) with evaluation of five result indicators which were: percentage of surgical site infections, not prescribed antibioprophylaxis, unplanned return to the operating room, postoperative length of stay and postoperatively death. RESULTS: We identified 185 patients during the period and 323 patients after the introduction of the WHO checklist. The proportion of surgical site infection decreased significantly from 13.5% in the reference period to 1.3% after the introduction of the checklist (p < 0.001). The proportion of unplanned return to the operative room was 10.3% before the introduction of the checklist and deceased significantly to 1.3% at the intervention period (p = 0.003). The proportion of not prescribed antibioprophylaxis and median post-operative length of stay deceased also significantly during the study period (p < 0.001). CONCLUSION: The surgical checklist control contributes to the development of a safety culture in the operating room. Maintaining its use should be supported by incentives such as certification and accreditation. PMID- 25741840 TI - [Epidemiological, clinical features, therapeutic results and evolution of gastrointestinal stromal tumour: about 25 cases]. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) are mesenchymal tumors occuring in the majority of cases in the stomach and small intestine, rarely in rectum, colon, esophagus or mesentery. They are derived from cells of cajal or their precursor, and are typically CD117/KIT + (95%), CD34 + (70%). AIMS: is to study the epidemiological, clinical, therapeutic and evolution of gastrointestinal stromal tumors. METHODS: retrospective study including all patients with the diagnosis of GIST supported in the department of gastroenterology and surgery in universital hospital of Monastir. RESULTS: 25 patients were included, 12 men and 13 women with an average age of 60.5 years. Digestive symptomatology was dominated by gastrointestinal bleeding (n = 12) and abdominal pain (n = 12). The tumor was discovered incidentally in two patients. The small intestine was the most common site of the tumor (n = 10), followed by the stomach in 9 patients, rectum in two patients, the colon (n = 1), the bulb of water (n = 1), duodenum (n = 1) and liver in a patient. The tumor size ranged from 0.8 to 24 cm. GIST was localized in 16 patients, in whom therapeutic care based mainly on surgery and optimal broad. It was metastatic in 9 patients, in whom treatment using imatinib as first-line in 4 of them with a good response in 3 patients and the possibility of R0 surgery in one patient, initial stabilization and then a secondary exhaust in a patient. The first surgery was necessary in 5 patients in complicated situation or if diagnostic doubt. CONCLUSION: The best characterization of GIST thanks to advances in cancer research has led to improved treatment of these tumors. Surgery is the standard treatment in localized forms. Imatinib is the standard treatment in metastatic GIST first line as well as adjuvant after surgery. PMID- 25741841 TI - [Survival prognosis factors in multiple myeloma]. AB - BACKGROUND: Outcome in multiple myeloma (MM) is very heterogeneous in survival and therapeutic response, constantly fatale despite her therapy progress. AIM: To determine the prognostic factors and survival in MM. METHODS: We carried out a transversal study of 100 patients in the rheumatology department of hospital Monastir between 1991 and 2010. In each case we determinate the survival delay and also the clinical, laboratory, radiological data at diagnosis and therapeutic response. RESULTS: The mean age was 64.4 years and sex ratio H/F=1.27. MM is IgG type in 57%, IgA in 28% and light chain in 11% of cases. The survival mean is 34 months and the survival median is 26 months. Univariate analysis showed five prognostic factors: age (p = 0.016), anaemia (p=0.033), beta2 microglobulin ( p < 0.0001) , CRP (p = 0.0001), albumin (p = 0.002), LDH (p=0.001), plasmocyte proliferation rate (p=0.003) and rapidly therapeutic response (p <0.001). beta2 microgrobulin-CRP classification and the international staging system (ISS) presented a high prognosis signification (p < 0.0001). Multivariate analysis demonstrated two prognostic factors: beta2 microglobulin and CRP. CONCLUSIONS: Our study showed that MM presented many prognostic factors, which easily realised in daly practice. These prognostic factors are essentially to evaluate prognosis and select patients for appropriate therapeutic indication. beta2 microgrobulin- CRP classification and the international staging system (ISS) are more predictive than Durie Salmon classification in MM survival. PMID- 25741842 TI - Lower incidence of hypotension following spinal anesthesia with 6% hydroxyethyl starch preload compared to 9 0/00 saline solution in caesarean delivery. AB - BACKGROUND: Hypotension is a common complication following spinal anesthesia for cesarean delivery. Techniques to prevent hypotension include preloading intravenous fluid. AIM: To compare the effect of two preloading regimens: 6% hydroxyethyl starch (HES) and 90/00 saline solution, to prevent hypotension after spinal anesthesia in cesarean delivery. METHODS: 105 patients undergoing intrathecal anesthesia for elective cesarean delivery were randomized and allocated to receive a preload of 500 ml HES 130/0.4 (HES Group) or a preload of 1500 ml 90/00 saline solution (CR group). Blood pressure and heart rate were recorded at baseline and after spinal anesthesia (every minute for the first 10 min, every 3 min for the next 10 min, and then every 5 min for the last 20 min). The primary outcome was to compare the incidence of hypotension (defined as a 20% reduction in systolic arterial pressure from baseline) between the two preloading regimens. Vasopressor requirements (i.v. bolus of 6 mg ephedrine) were also compared. RESULTS: The incidence of hypotension was 87% in the CR group and 69% in the HES group (p= 0.028). Ephedrine requirement, incidence of nausea, and/or vomiting and neonatal outcome did not significantly differ between the two groups. CONCLUSION: The incidence of hypotension was lower after preloading of 500 mL of HES 130/0.4 than preloading with 1500 mL of 90/00 saline solution. PMID- 25741843 TI - Borderline tumors of the ovary. AB - BACKGROUND: Borderline tumors of the ovary (BOT) were described for the first time by Taylor in 1929. These lesions have a more favorable outcome than do other ovarian cancers. Their prognosis and treatment are still subject of discussion since they occurred more often in young women where the sparing fertility surgery is always considered primarily. AIM: Evaluate the management of patients with borderline ovarian tumors. METHODS: A retrospective study was conducted in 40 patients with borderline ovarian tumors treated between January 1, 1991 and December 31, 2004. RESULTS: Median follow-up was 43 months, mean age was 44 years. Initial surgery was conservative in 17 patients and radical in 23 cases. Six patients had residual disease. Serous, mucinous and mixte tumors were observed in 18, 21 and 1 cases respectively. Staging was I, II, III in 26, 5, and 9 cases respectively with two pseudomyxomas. Adjuvant Chemotherapy was given in 3 patients. There was a recurrence in 13 patients and seven died. The 5-year overall survival rate was 78 %. Prognostic factors with an impact on survival rate were age, stage of the disease, histological subtype and residual tumor. Factors with a negative impact on recurrence were age, type of surgery and residual disease. With Cox multivariate analysis, residual tumor is an independent factor for overall survival, on the other hand age and type of surgery were significant for recurrence free survival. CONCLUSION: Careful staging followed by complete and radical surgery is mandatory. Unilateral salpingo-oophorectomy with omentectomy and multiple peritoneal biopsies and washing could be indicated in patients with child bearing age. Radical surgery after pregnancy is advised. PMID- 25741844 TI - Severe acute hepatitis induced by a DRESS syndrome to piroxicam. PMID- 25741845 TI - [Cutaneous epidermotropic cytotoxic T cell lymphoma]. PMID- 25741846 TI - A case of genital radionecrosis: the forgotten complication. PMID- 25741847 TI - [A diffuse bony Ewing's sarcoma]. PMID- 25741848 TI - [Pheochromocytoma during pregnancy: a diagnosis not to be missed]. PMID- 25741849 TI - Acute pancreatitis secondary to long-term 5- aminosalicylic acid therapy in a patient with ulcerative colitis: a case-report. PMID- 25741850 TI - [Non small-cell lung cancer revealed by retinal vasculitis]. PMID- 25741851 TI - [Primitif colonic lymphoma: a rare digestive tumor]. PMID- 25741852 TI - Spontaneous intrathoracic gastric volvulus: a rare emergency easily overlooked. PMID- 25741853 TI - [Benzylthiouracil induced ANCA-positive vasculitis]. PMID- 25741854 TI - Anesthetic management of a giant extracranial internal carotid artery aneurysm. PMID- 25741855 TI - [Malignant melanoma of the rectus abdominis muscle : a case report]. PMID- 25741856 TI - AzoCholine Enables Optical Control of Alpha 7 Nicotinic Acetylcholine Receptors in Neural Networks. AB - Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal alpha7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR. AzoCholine could be used to modulate cholinergic activity in a brain slice and in dorsal root ganglion neurons. In addition, we demonstrate light-dependent perturbation of behavior in the nematode, Caenorhabditis elegans. PMID- 25741857 TI - Characterization of nitrazine yellow as a photoacoustically active pH reporter molecule. AB - Throughout the fields of biomedical imaging, materials analysis, and routine chemical analysis, it is desirable to have a toolkit of molecules that can allow noninvasive/remote chemical sensing with minimal sample preparation. Here, we describe the photophysical properties involved in photoacoustic (PA) measurements and present a detailed analysis of the requirements and complications involved in PA sensing. We report the use of nitrazine yellow (NY) as a well-behaved PA pH reporter molecule. Both the basic and acidic forms of NY are photoacoustically well-behaved and allow for rapid and noninvasive measurement of pH in either transparent or turbid media. We also find that the serum protein-bound form of NY is photoacoustically well-behaved and should permit applications in noninvasive 3D imaging (e.g., the lymphatic system). PMID- 25741858 TI - Why aren't we doing better in asthma: time for personalised medicine? AB - After decades of improvement, asthma outcomes have stalled. Mortality, hospitalisations, exacerbations and symptom control remain sub-optimal. In controlled trials, most patients gain high levels of control, but in 'real-life' routine clinical practice most patients do not. Avoidable factors are found in most asthma deaths and hospital admissions. This perspective paper considers and contextualises the factors underlying poor asthma outcomes, and it suggests approaches that could improve the situation. Factors discussed include severe, therapy-resistant disease and the role of new and upcoming pharmacological therapies in improving outcomes. These are likely to be beneficial when targeted on patients with severe disease and discrete phenotypic characteristics, identified through biomarkers. However, for the majority of patients treated in the community, they are unlikely to be used widely, and better use of current therapy classes will be more important. Non-adherence with regular inhaled corticosteroid treatment and over-use of rescue bronchodilators are common, and many patients have poor inhaler technique. Self-management is frequently poor, particularly in those with psychosocial disadvantages and co-morbidities. Communication between clinicians and patients is sometimes poor, with failure to detect avoidable poor control and non-adherence, and failure to provide the necessary information and education to support efficient self-management. Strategies for improving monitoring and clinician-patient interactions to allow personalised treatment are considered. These strategies have the potential to allow individual patient needs to be recognised and efficient targeting of the variety of effective pharmacological and non-pharmacological interventions that we possess, which has the potential to improve both individual and population outcomes. PMID- 25741860 TI - Legislation in the genomic era: the Affordable Care Act and genetic testing for cancer risk assessment. PMID- 25741859 TI - Transposon mediated integration of plasmid DNA into the subventricular zone of neonatal mice to generate novel models of glioblastoma. AB - An urgent need exists to test the contribution of new genes to the pathogenesis and progression of human glioblastomas (GBM), the most common primary brain tumor in adults with dismal prognosis. New potential therapies are rapidly emerging from the bench and require systematic testing in experimental models which closely reproduce the salient features of the human disease. Herein we describe in detail a method to induce new models of GBM with transposon-mediated integration of plasmid DNA into cells of the subventricular zone of neonatal mice. We present a simple way to clone new transposons amenable for genomic integration using the Sleeping Beauty transposon system and illustrate how to monitor plasmid uptake and disease progression using bioluminescence, histology and immuno-histochemistry. We also describe a method to create new primary GBM cell lines. Ideally, this report will allow further dissemination of the Sleeping Beauty transposon system among brain tumor researchers, leading to an in depth understanding of GBM pathogenesis and progression and to the timely design and testing of effective therapies for patients. PMID- 25741861 TI - Assessing multilevel determinants of adoption and implementation of genomic medicine: an organizational mixed-methods approach. AB - PURPOSE: Adoption and implementation of evidence-based genetic and genomic medicine have been slow. We describe a methodology for identifying the influence of organizational factors on adoption and implementation of these services in health-care organizations. METHODS: We illustrate a three-component, mixed methods health services research approach, including expert panels, qualitative interviews with key informants, and quantitative surveys completed by key informants. RESULTS: This research approach yielded a baseline assessment of existing genetic health-care models in the Veterans Health Administration and identified organizational barriers to and facilitators of adoption. In aggregate, the panel and key informant strategies created a communication network of relevant organizational stakeholders and a detailed foundation of organizational knowledge from which to design tools and models for implementation-level genetic/genomic translation. CONCLUSION: Expert panel and key informant strategies can be used to create a backdrop of stakeholder involvement and baseline organizational knowledge within which to plan translation research and to inform strategic planning and policies for adoption and implementation of genetic services in health-care organizations. PMID- 25741862 TI - The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia. AB - PURPOSE: Familial hypercholesterolemia (FH) is one of the most common monogenic disorders, and the high concentrations of low-density lipoprotein (LDL) cholesterol presented since birth confers on these patients an increased cardiovascular risk. More than 1,600 alterations have been described in the LDL receptor gene (LDLR), but a large number need to be validated as mutations causing disease to establish a diagnosis of FH. This study aims to characterize, both at the phenotypic and genotypic levels, families with a clinical diagnosis of FH and present evidence for the importance of the integration of clinical, molecular, and functional data for the correct diagnosis of patients with FH. METHODS: A detailed analysis of the phenotype and genotype presented by 55 families with 13 different alterations in the LDLR was conducted. For eight of these, an extensive functional characterization was performed by flow cytometry, confocal microscopy, and reverse transcriptase polymerase chain reaction. RESULTS: Carriers of neutral alterations presented a significantly lower incidence of premature cardiovascular disease, lower levels of atherogenic lipoproteins and a large number of these individuals had LDL-cholesterol values below the 75(th) percentile. presented a significantly lower incidence of premature cardiovascular disease, lower levels of atherogenic lipoproteins and a large number of these individuals had LDL-cholesterol values below the 75th percentile However, the functional study was essential to determine the pathogenicity of variants. CONCLUSION: The data collected illustrate the importance of this integrated analysis for the correct assessment of patients with FH who can otherwise be misdiagnosed. PMID- 25741863 TI - Determining the prevalence of McArdle disease from gene frequency by analysis of next-generation sequencing data. AB - PURPOSE: McArdle disease is one of the most common glycogen storage disorders. Although the exact prevalence is not known, it has been estimated to be 1 in 100,000 patients in the United States. More than 100 mutations in PYGM have been associated with this disorder. McArdle disease has significant clinical variability: Some patients present with severe muscle pain and weakness; others have only mild, exercise-related symptoms. METHODS: Next-generation sequencing data allow estimation of disease prevalence with minimal ascertainment bias. We analyzed gene frequencies in two cohorts of patients based on exome sequencing results. We categorized variants into three groups: a curated set of published mutations, variants of uncertain significance, and likely benign variants. RESULTS: An initial estimate based on the frequency of six common mutations predicts a disease prevalence of 1/7,650 (95% confidence interval (CI) 1/5,362 1/11,108), which greatly deviates from published estimates. A second method using the two most common mutations predicts a prevalence of 1/42,355 (95% CI 1/24,536 1/76,310) in Caucasians. CONCLUSIONS: These results suggest that the currently accepted prevalence of McArdle disease is an underestimate and that some of the currently considered pathogenic variants are likely benign. PMID- 25741864 TI - CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. AB - PURPOSE: Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN patients with IPD receiving ERT monotherapy. METHODS: A chart review identified 20 CN patients with IPD treated with ERT monotherapy for >=6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT; >=51,200) at least twice; low titers (LT; <6,400) throughout treatment; or sustained intermediate titers (SIT; 6,400-25,600). RESULTS: Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, whereas the LT group exclusively carried splice-site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. CONCLUSION: Immunological responses are a significant risk in CN IPD; thus induction of immune tolerance in the naive setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease. PMID- 25741865 TI - Development of clinical decision support alerts for pharmacogenomic incidental findings from exome sequencing. AB - PURPOSE: Electronic health records (EHRs) and their associated decision support tools are potentially important means of disseminating a patient's pharmacogenomic profile to his or her health-care providers. We sought to create a proof-of-concept decision support alert system generated from pharmacogenomic incidental findings from exome sequencing. METHODS: A pipeline for alerts from exome sequencing tests was created for patients in the New EXome Technology in (NEXT) Medicine study at the University of Washington. Decision support rules using discrete, machine-readable incidental finding results were programmed into a commercial EHR rules engine. An evaluation plan to monitor the alerts in real medical interactions was established. RESULTS: Alerts were created for 48 actionable pharmacogenomic variants in 11 genes and were launched on 24 September 2014 for University of Washington inpatient care. Of the 94 participants enrolled in the NEXT Medicine study, 49 had one or more pharmacogenomic variants identified for return. CONCLUSION: Reflections on the process reveal that while incidental findings can be used to generate decision support alerts, substantial resources are required to ensure that each alert is consistent with rapidly evolving pharmacogenomic literature and is customized to fit in the clinical workflow unique to each incidental finding. PMID- 25741866 TI - Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia. AB - PURPOSE: High myopia is one of the leading causes of blindness worldwide, with high heritability. However, only a few causative genes have been identified, and the pathogenesis is still unclear. Our aim was to identify a novel causative gene in a family with autosomal-dominant, nonsyndromic high myopia. METHODS: Whole genome linkage and whole-exome sequencing were conducted on the family. Real-time quantitative polymerase chain reaction and immunoblotting were applied to test the functional consequence of the candidate mutation. Sanger sequencing was performed to screen for the candidate gene in other families or sporadic cases. RESULTS: A heterozygous missense mutation, c.871G>A (p.Glu291Lys), within P4HA2 was cosegregating with the phenotype in the family. The segregating mutation caused premature degradation of unstable messenger RNA. Subsequent screening for P4HA2 in 186 cases identified an additional four mutations in 5 cases, including the frameshift mutation c.1349_1350delGT (p.Arg451Glyfs*8), the nonsense mutation c.1327A>G (p.Lys443*), and two deleterious missense mutations, c.419A>G (p.Gln140Arg) and c.448A>G (p.Ile150Val). The missense mutation c.419A>G (p.Gln140Arg) was recurrently identified in a sporadic case and was segregating in a three-generation family. CONCLUSION: P4HA2 was identified as a novel causative gene for nonsyndromic high myopia. This study also indicated that the disruption of posttranslational modifications of collagen is an important factor in the pathogenesis of high myopia. PMID- 25741867 TI - Lysosomal storage disease in the brain: mutations of the beta-mannosidase gene identified in autosomal dominant nystagmus. AB - PURPOSE: Genetic etiology of congenital/infantile nystagmus remains largely unknown. This study aimed to identify genomic mutations in patients with infantile nystagmus and an associated disease network. METHODS: Patients with inherited and sporadic infantile nystagmus were recruited for whole-exome and Sanger sequencing. beta-Mannosidase activities were measured. Gene expression, protein-protein interaction, and nystagmus-associated lysosomal storage disease (LSD) genes were analyzed. RESULTS: A novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA, which encodes lysosomal beta-mannosidase, was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. MANBA was expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Functional validation of these mutations demonstrated a significant decrease of beta-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. Further analysis revealed that nystagmus is present in at least 24 different LSDs involving the brain. CONCLUSION: This is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity. Because beta-mannosidase activities are required for development of the oculomotor nervous system, our findings shed new light on the role of LSD associated genes in the pathogenesis of infantile nystagmus. PMID- 25741869 TI - Facile, rapid, and large-area periodic patterning of semiconductor substrates with submicron inorganic structures. AB - The development of high-throughput and scalable techniques for patterning inorganic structures is useful for the improved function and efficiency of photonic and energy conversion devices. Here we demonstrate a facile and rapid electrochemical method for patterning periodic metallic and nonmetallic submicron structures over large areas. Si substrates have been patterned with arrays of periodically spaced lines, rings, squares, and terraces of main-group and transition-metal oxides. In addition to planar substrates, three-dimensional surfaces and their vertical sidewalls have been patterned. The features are 20(+/ 1) nm high and 360(+/-15) nm wide, and their period is finely tunable in situ from 500 nm to 7 MUm. These features exhibit <3% variation in period and are rapidly patterned in <2 min. We demonstrate the versatility of the technique by rapidly patterning an efficient water splitting catalyst, Co phosphate oxide (CoPi), and show that the integrated materials system performs water splitting with complete Faradaic efficiency. More generally, the ability to pattern submicron structures over large areas in a facile, reliable, and timely manner may be useful for the fabrication of devices for energy, meta-material, and sensing applications. PMID- 25741868 TI - Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. AB - The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes, and epigenetic assays for genetic disorders. By virtue of increased complexity, this shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context the ACMG convened a workgroup in 2013 comprising representatives from the ACMG, the Association for Molecular Pathology (AMP), and the College of American Pathologists to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP, and College of American Pathologists stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. This report recommends the use of specific standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified in genes that cause Mendelian disorders. Moreover, this recommendation describes a process for classifying variants into these five categories based on criteria using typical types of variant evidence (e.g., population data, computational data, functional data, segregation data). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments-approved laboratory, with results interpreted by a board certified clinical molecular geneticist or molecular genetic pathologist or the equivalent. PMID- 25741870 TI - Predicting nursing home placement among home- and community-based services program participants. AB - BACKGROUND: Several states offer publicly funded-care management programs to prevent long-term care placement of high-risk Medicaid beneficiaries. Understanding participant risk factors and services that may prevent long-term care placement can facilitate efficient allocation of program resources. OBJECTIVES: To develop a practical prediction model to identify participants in a home- and community-based services program who are at highest risk for long-term nursing home placement, and to examine participant-level and program-level predictors of nursing home placement. STUDY DESIGN: In a retrospective observational study, we used deidentified data for participants in the Connecticut Home Care Program for Elders who completed an annual assessment survey between 2005 and 2010. METHODS: We analyzed data on patient characteristics, use of program services, and short-term facility admissions in the previous year. We used logistic regression models with random effects to predict nursing home placement. The main outcome measures were long-term nursing home placement within 180 days or 1 year of assessment. RESULTS: Among 10,975 study participants, 1249 (11.4%) had nursing home placement within 1 year of annual assessment. Risk factors included Alzheimer's disease (odds ratio [OR], 1.30; 95% CI, 1.18-1.43), money management dependency (OR, 1.33; 95% CI, 1.18 1.51), living alone (OR, 1.53; 95% CI, 1.31-1.80), and number of prior short-term skilled nursing facility stays (OR, 1.46; 95% CI, 1.31-1.62). Use of a personal care assistance service was associated with 46% lower odds of nursing home placement. The model C statistic was 0.76 in the validation cohort. CONCLUSIONS: A model using information from a home- and community-based service program had strong discrimination to predict risk of long-term nursing home placement and can be used to identify high-risk participants for targeted interventions. PMID- 25741871 TI - Improving medication understanding among Latinos through illustrated medication lists. AB - OBJECTIVES: Strategies are needed to improve medication management among vulnerable populations. We tested the effect of providing illustrated, plain language medication lists on medication understanding, adherence, and satisfaction among Latino patients with diabetes in a safety net clinic. STUDY DESIGN: Randomized controlled trial. METHODS: Intervention patients received a PictureRx illustrated medication list that depicted the medication, indication, and dosing instructions, accompanied by plain language bilingual text. Usual care patients received a written list of their medications in their preferred language, with indication but no images. Outcomes were assessed by telephone approximately 1 week later. The Medication Understanding Questionnaire measured patients' ability to report the indication, strength, dosing, and frequency for their medication regimen. Self-reported adherence and satisfaction were secondary outcomes. Analysis was performed by intention to treat. RESULTS: Of 200 enrolled participants, 197 (98.5%) completed follow-up. Most (71%) had not graduated high school, and 59% had low health literacy. Patients randomized to illustrated medication instructions had better overall understanding of their medications (P<.001), including greater ability to report the drug indication (P<.01), strength (P<.05), dosing (P<.01), and frequency of administration (P<.001). Self reported adherence did not differ significantly between study groups. Patients who received illustrated medication lists were very satisfied with them. CONCLUSIONS: In this randomized controlled trial, patients who received illustrated, plain-language medication lists demonstrated significantly greater understanding of their medication regimen. Such tools have the potential to improve medication use and chronic disease control, as well as reduce health disparities-although this requires further study. PMID- 25741872 TI - Preconsultation exchange in the United States: use, awareness, and attitudes. AB - OBJECTIVES: Demand for specialty care exceeds supply in many healthcare systems in the United States. Preconsultation exchange has the potential to increase access to specialty care, and increase its timeliness and efficiency, by triaging need and urgency and streamlining the previsit workup. We sought to characterize attitudes toward, use of, and concerns regarding preconsultation exchange among US internists. STUDY DESIGN: Prospective cross-sectional survey. METHODS: We administered a Web-based survey to a large national panel of US internists maintained by the American College of Physicians. RESULTS: Response rate was 55% (N=451) with minimal differences between responders and nonresponders. Of responders, only 13% were initially familiar with the term "preconsultation exchange," but once defined, 28% were classified as frequent users, 40% as occasional users, and 32% as rare/never users. Internists used preconsultation exchange to: guide the prespecialty visit workup (78%), answer clinical questions without a patient visit to the specialist (71%), triage referral urgency (67%), and transfer referrals to a more appropriate specialty (47%). Responders supported multiple benefits of preconsultation exchange, but also reported concerns regarding reimbursement, liability, physicians taking personal responsibility for patient care, and inadequate exchange of clinical information. Compared with primary care physicians, specialists recognized more benefits of preconsultation exchange, but also expressed more concerns. The majority of responders reported increased willingness to use preconsultation exchange if specific remedies were applied. CONCLUSIONS: Most US internists participate in preconsultation exchange and agree with its potential benefits. However, important concerns and barriers exist. Methods to reduce barriers to preconsultation exchange should be identified. PMID- 25741873 TI - Addressing cost barriers to medications: a survey of patients requesting financial assistance. AB - OBJECTIVES: Given that many patients with chronic diseases face cost-related barriers to care, we evaluated patients' views on which providers (both physicians and nonphysicians) to involve and which methods to use to screen for those barriers. We also examined patients' preferences for how physicians consider cost-efficacy trade-offs in decisions. STUDY DESIGN: A national survey of 1400 randomly sampled adults with a chronic disease seeking financial assistance (842 respondents). METHODS: Participants rated their comfort with various providers and tools for identifying cost barriers. Then they rated a randomly assigned clinical vignette that described how a clinical decision was made in the context of a cost-efficacy tradeoff. Vignettes depicted 3 decision types: cost-conscious physician, cost-indifferent physician, or patient-directed. Comfort was rated from 1 to 10-ratings above 7 indicated high comfort. RESULTS: More respondents reported high comfort with physicians screening for cost barriers (81.1%) than with pharmacists (74.8%; P=.002), nurses (69.4%; P<.001), professional counselors (68.3%; P<.001), and trained volunteers (50.5%; P<.001). Regarding screening for cost barriers using administrative records, more respondents reported higher comfort with doctors' offices (58.8%) than with insurance companies (53.3%; P=.03), but similar levels of comfort compared to pharmacies (62.1%; P=.17). Participants favored "patient-directed" decisions with physician input (odds ratio, 4.64; 95% CI, 3.14-6.84; P<.001) compared with "cost conscious" decisions in which physicians unilaterally decided how to manage cost efficacy tradeoffs. CONCLUSIONS: Patients were open to a range of cost-barrier screening approaches, but most favor direct conversations with their doctor and shared decision making in decisions involving cost-efficacy trade-offs. PMID- 25741875 TI - There's more than one way to build a medical home. AB - OBJECTIVES: The patient-centered medical home (PCMH) is a critical aspect of delivery system reform. The purpose of this study was to examine variations in achievement of PCMH requirements across different types of practices. STUDY DESIGN: We used data on the points awarded, by standard and element, to 2369 practices recognized by September 2013 under the National Committee for Quality Assurance PCMH program, 2011 version. METHODS: We tested for differences across practice types in the percentage of practices achieving full credit for 27 element scores using likelihood ratio chi2 tests with an adjustment for multiple comparisons. RESULTS: Of the practices, 45% were affiliated with health systems, 22.6% were community health centers, and 5.3% were military treatment facilities. The remaining practices were physician-owned, 10% with at least 5 clinicians and 17.3% with less than 5. Even among Level 3 practices, there were significant differences across the practice types in the percentage of practices achieving full credit for 19 of 27 elements. Different types of practices demonstrated strengths in different medical home capabilities. CONCLUSIONS: Even among practices with the highest level of PCMH achievement, there are variations in key medical home capabilities. While research is needed to identify PCMH components having the greatest impact on outcomes, this research shows that the NCQA model is flexible enough to adapt to the strengths and needs of practices and the patients they serve. Efforts to support widespread dissemination of the PCMH model and practice transformation should recognize and build on these variations. PMID- 25741876 TI - Synthesis of Zn:Cu2O thin films using a single step electrodeposition for photovoltaic applications. AB - Zinc-doped cuprous oxide (Zn:Cu2O) thin films have been prepared via single step electrodeposition from an aqueous solution containing sodium perchlorate. The Zn/Cu molar ratio in the Zn:Cu2O films can be tuned between 0.006 and 0.236 by adjusting the magnitude of the applied potential and the sodium perchlorate concentration. Electrical characterization reveals that zinc dopants increase the Fermi level in Zn:Cu2O films, enabling a 3-fold improvement in the power conversion efficiency of a fully electrodeposited Cu2O homojunction photovoltaic device. PMID- 25741874 TI - Medicare Star excludes diabetes patients with poor CVD risk factor control. AB - OBJECTIVES: CMS recently added medication adherence to antihypertensives, antihyperlipidemics, and oral antihyperglycemics to its Medicare Star quality measures. These CMS metrics exclude patients with <2 medication fills (ie, "early nonadherence") and patients concurrently taking insulin. This study examined the proportion of patients with diabetes prescribed cardiovascular disease (CVD) medications excluded from Star adherence metrics and assessed the relationship of both Star-defined adherence and exclusion from Star metrics with CVD risk factor control. STUDY DESIGN: Cross-sectional, population-based analysis of 129,040 patients with diabetes aged >=65 years in 2010 from 3 Kaiser Permanente regions. METHODS: We estimated adjusted risk ratios to assess the relationship between achieving Star adherence and being excluded from Star adherence metrics, with CVD risk factor control (glycated hemoglobin [A1C]<8.0%, low-density lipoprotein cholesterol [LDL-C]<100 mg/dL, and systolic blood pressure [SBP]<130 mm Hg) in patients with diabetes. RESULTS: Star metrics excluded 27% of patients with diabetes prescribed oral medications. Star-defined nonadherence was negatively associated with CVD risk factor control (risk ratio [RR], 0.95, 0.84, 0.96 for A1C, LDL-C, and SBP control, respectively; P<.001). Exclusion from Star metrics due to early nonadherence was also strongly associated with poor control (RR, 0.83, 0.56, 0.87 for A1C, LDL-C, and SBP control, respectively; P<.001). Exclusion for insulin use was negatively associated with A1C control (RR, 0.78; P<.0001). CONCLUSIONS: Medicare Star adherence measures underestimate the prevalence of medication nonadherence in diabetes and exclude patients at high risk for poor CVD outcomes. Up to 3 million elderly patients with diabetes may be excluded from these measures nationally. Quality measures designed to encourage effective medication use should focus on all patients treated for CVD risk. PMID- 25741877 TI - Spatial filtering of a diode laser beam for confocal Raman microscopy. AB - With the development of single-longitudinal mode diode lasers, there has been an increase in using these sources for Raman spectroscopy. This is largely due to the cost-effectiveness of diode lasers, which offer savings not only in initial capital cost, but also electrical, cooling, and replacement costs over time, when compared with ion lasers. The use of diode-lasers in confocal Raman microscopy has remained a challenge, however, due to poor transverse beam quality. In this work, we present the design and implementation of a simple spatial filter capable of adapting a single-mode diode laser source to confocal Raman microscopy, yielding comparable spatial resolution as a gas-ion laser beam for profiling and optical-trapping applications. For profiling applications, spatial filtering improved x,y resolution of the beam by a factor 10, which in turn increased optical-trapping forces by ~90 times and yielded sevenfold greater Raman scattering signal intensity from an optically trapped phospholipid vesicle. PMID- 25741878 TI - Achieving high performance electric field induced strain: a rational design of hyperbranched aromatic polyamide functionalized graphene-polyurethane dielectric elastomer composites. AB - Dielectric elastomers have great potentials as flexible actuators in micro electromechanical systems (MEMS) due to their large deformation, light weight, mechanical compliancy, and low cost. The low dielectric constant of these elastomers requires a rather high voltage electric field, which has greatly limited their applications. In this work, a diaphragm-type flexible microactuator comprising a hyperbranched aromatic polyamide functionalized graphene (HAPFG) filler embedded into the polyurethane (PU) dielectric elastomer matrix is described. The rational designed HAPFG sheets exhibits uniform dispersion in PU matrix and strong adhesion with the matrix by hydrogen-bond coupling. Consequently, the HAPFG-PU composites possess high dielectric performance and low loss modulus. The effect of hyperbranched aromatic polyamide functionalized graphene on high voltage electric field induced strain was experimentally investigated using the Fotonic sensor. The high electric field response of the composite was discussed by applying different kinds of alternating-current field. In addition, a comparison of the breakdown strength between the HAPFG-PU composite and the pure PU was carried out. PMID- 25741879 TI - Zooplankton community changes confound the biodilution theory of methylmercury accumulation in a recovering mercury-contaminated lake. AB - In this study, the biodilution hypothesis of methylmercury (MeHg) accumulation was examined in a Hg-contaminated ecosystem that has undergone concurrent changes in nutrient loading and zooplankton community composition. Using a long-term record of 17 years (between 1980 and 2009), we demonstrate that zooplankton MeHg concentrations in Onondaga Lake, NY, are strongly driven by changes in the zooplankton community and body size. MeHg concentrations in zooplankton increased with an increase in body size and biomass. The highest concentrations of MeHg were observed under eutrophic and hypereutrophic conditions when large-bodied Daphnia species, Daphnia pulicaria and Daphnia galeata mendotae, were present. Bioconcentration rather than biodilution was governing the accumulation of MeHg in zooplankton without apparent growth dilution or zooplankton biomass dilution. Algal-bloom dilution controlled the variability in the MeHg concentration only under hypereutrophic conditions when Ceriodaphnia predominated the cladoceran population. Our study demonstrates that changes in zooplankton community composition confound the biodilution theory in Onondaga Lake and that the presence of large-bodied zooplankton species drives elevated MeHg concentrations. PMID- 25741881 TI - In silico Screening for Identification of Novel Anti-malarial Inhibitors by Molecular Docking, Pharmacophore Modeling and Virtual Screening. AB - OBJECTIVE: Drug resistance from affordable drugs has increased the number of deaths from malaria globally. This problem has raised the requirement to design new drugs against multidrug-resistant Plasmodium falciparum parasite. METHODS: In the current project, we have focused on four important proteins of Plasmodium falciparum and used them as receptors against a dataset of four anti-malarial drugs. In silico analysis of these receptors and ligand dataset was carried out using Autodock 4.2. A pharmacophore model was also established using Ligandscout. RESULTS: Analysis of docking experiments showed that all ligands bind efficiently to four proteins of Plasmodium falciparum. We have used ligand-based pharmacophore modeling and developed a pharmacophore model that has three hydrophobic regions, two aromatic rings, one hydrogen acceptor and one hydrogen donor. Using this pharmacophore model, we have screened a library of 50,000 compounds. The compounds that shared features of our pharmacophore model and exhibited interactions with the four proteins of our receptors dataset are short listed. CONCLUSION: As there is a need of more anti-malarial drugs, therefore, this research will be helpful in identifying novel anti-malarial drugs that exhibited bindings with four important proteins of Plasmodium falciparum. The hits obtained in this study can be considered as useful leads in anti-malarial drug discovery. PMID- 25741880 TI - Chronic Bronchitis Is Associated With Worse Symptoms and Quality of Life Than Chronic Airflow Obstruction. AB - BACKGROUND: COPD includes the chronic bronchitis (CB) and emphysema phenotypes. Although it is generally assumed that emphysema or chronic airflow obstruction (CAO) is associated with worse quality of life (QOL) than is CB, this assumption has not been tested. METHODS: The current study's analyses from the Lovelace Smokers' Cohort (LSC) were validated in the COPD Gene Cohort (COPDGene). CB without CAO (CB only) was defined as self-reported cough productive of phlegm for >= 3 mo/y for 2 consecutive years and postbronchodilator FEV1/FVC >= 70%. CAO without CB (CAO only) was defined as a postbronchodilator FEV1/FVC < 70% with no evidence of CB. QOL outcomes were obtained from the St. George's Respiratory Questionnaire (SGRQ) and the 36-Item Short Form Health Survey (SF-36) questionnaires. A priori covariates included age, sex, pack-years of smoking, current smoking, and FEV1. RESULTS: Smokers with CB without CAO (LSC = 341; COPDGene = 523) were younger and had a greater BMI and less smoking exposure than did those with CAO only (LSC = 302; COPDGene = 2,208). Compared with the latter group, QOL scores were worse for those with CB only. Despite similar SGRQ Activity and SF-36 Role Physical and Physical Functioning, SGRQ Symptoms and Impact scores and SF-36 emotional and social measures were worse in the CB-only group, in both cohorts. After adjustment for covariates, the CB-only group remained a significant predictor for "worse" symptoms and emotional and social measures. CONCLUSIONS: To our knowledge, this analysis is the first to suggest that among subjects with COPD, those with CB only present worse QOL symptoms and mental well-being than do those with CAO only. PMID- 25741882 TI - Recognition and Impact of Host-derived Molecules on Bacterial Cell-to-cell Signalling Pathways. AB - Microbe-host signalling is now a well accepted concept and an intensively studied research field. Although some of the observed bacterial phenotypes are attributed to host-recognition and inter-kingdom signalling, most of them are not relying on a proved molecular mechanism. Recent progress revealed some recognition and signalling pathways for host molecules in bacterial cells, which try to explain their modulatory effect on growth and virulence. Since the current knowledge on the field is poor and debatable, the purpose of this paper is to review and discuss the research performed in order to elucidate the ways by which microbial cells recognize and decode the host molecule signals. PMID- 25741883 TI - High-speed photorefractive keratectomy with femtosecond ultraviolet pulses. AB - Femtosecond near-infrared lasers are widely used for a number of ophthalmic procedures, with flap cutting in the laser-assisted in situ keratomileusis (LASIK) surgery being the most frequent one. At the same time, lasers of this type, equipped with harmonic generators, have been shown to deliver enough ultraviolet (UV) power for the second stage of the LASIK procedure, the stromal ablation. However, the speed of the ablation reported so far was well below the currently accepted standards. Our purpose was to perform high-speed photorefractive keratectomy (PRK) with femtosecond UV pulses in rabbits and to evaluate its predictability, reproducibility and healing response. The laser source delivered femtosecond 206 nm pulses with a repetition rate of 50 kHz and an average power of 400 mW. Transepithelial PRK was performed using two different ablation protocols, to a total depth of 110 and 150 MUm. The surface temperature was monitored during ablation; haze dynamics and histological samples were evaluated to assess outcomes of the PRK procedure. For comparison, analogous excimer ablation was performed. Increase of the ablation speed up to 1.6 s/diopter for a 6 mm optical zone using femtosecond UV pulses did not significantly impact the healing process. PMID- 25741884 TI - Clinical Worsening as Composite Study End Point in Pediatric Pulmonary Arterial Hypertension. AB - BACKGROUND: Clinical worsening (CW), an increasingly used composite end point in adult pulmonary arterial hypertension (PAH), has not yet been evaluated in pediatric PAH. This study aims to evaluate the usefulness of CW in pediatric PAH by assessing the event incidence and prognostic value of each separate component of CW and of the composite CW end point. METHODS: Seventy pediatric patients with PAH from the Dutch National Network for Pediatric Pulmonary Hypertension, who started PAH-targeted therapy between January 2000 and January 2014, were included in the study and underwent standardized follow-up. The following CW components were prospectively registered: death, lung transplantation (LTx), PAH-related hospitalizations, initiation of IV prostanoids, and functional deterioration (World Health Organization functional-class deterioration, >= 15% decrease in 6 min walk distance, or both). The longitudinal event incidence and prognostic value were assessed for each separate component and their combination. RESULTS: The end-point components of death, LTx, hospitalizations, initiation of IV prostanoids, and functional deterioration occurred with a longitudinal event rate of 10.1, 2.5, 21.4, 9.4 and 48.1 events per 100 person-years, respectively. The composite CW end point occurred 91.5 times per 100 person-years. The occurrences of either hospitalization, initiation of IV prostanoids, or functional deterioration were predictive of death or LTx (P < .001 for each component). In this cohort, 1-, 3-, and 5-year transplant-free survival was 76%, 64%, and 56%, respectively. Freedom from CW at 1, 3, and 5 years was 43%, 22%, and 17%, respectively. CONCLUSIONS: CW occurred with a high event incidence and each of the soft end-point components was predictive of death or LTx. This supports the usefulness of CW as a study end point in clinical trials in pediatric PAH. PMID- 25741885 TI - Initial mechanisms for the decomposition of electronically excited energetic salts: TKX-50 and MAD-X1. AB - Decomposition of energetic salts TKX-50 and MAD-X1 (dihydroxylammonium 5,5' bistetrazole-1,1'-diolate and dihydroxylammonium 3,3'-dinitro-5,5'-bis-1,2,4 triazole-1,1'-diol, respectively), following electronic state excitation, is investigated both experimentally and theoretically. The NO and N2 molecules are observed as initial decomposition products from the two materials subsequent to UV excitation. Observed NO products are rotationally cold (<25 K) and vibrationally hot (>1500 K). The vibrational temperature of the NO product from TKX-50 is (2600 +/- 250) K, (1100 +/- 250) K hotter than that produced from MAD X1. Observed N2 products of these two species are both rotationally cold (<30 K). Initial decomposition mechanisms for these two electronically excited salts are explored at the complete active space self-consistent field (CASSCF) level. Potential energy surface calculations at the CASSCF(8,8)/6-31G(d) level illustrate that conical intersections play an essential role in the decomposition mechanisms. Electronically excited S1 molecules can nonadiabatically relax to the lower electronic state through (S1/S0)CI conical intersections. Both TKX-50 and MAD-X1 have two (S1/S0)CI conical intersections between S1 and S0 states, related to and leading to two different reaction paths, forming N2 and NO products. N2 products are released by the opening of the tetrazole or triazole rings of TKX-50 and MAD-X1. NO products are released from the amine N-oxide moiety of TKX-50, and for MAD-X1, they are produced through nitro-nitrite isomerizations. The observed rotational energy distributions for NO and N2 products are consistent with the final structures of the respective transition states for each molecule on its S0 potential energy surface. PMID- 25741886 TI - Comparative Cost-effectiveness of the Baerveldt Implant, Trabeculectomy With Mitomycin, and Medical Treatment. AB - IMPORTANCE: The Tube vs Trabeculectomy Trial (TVT) found that the 350-mm2 Baerveldt implant (tube) and trabeculectomy with mitomycin may be similarly effective in lowering intraocular pressure in primary open-angle glaucoma. However, to date, there are no published long-term clinical data on the cost effectiveness of trabeculectomy with mitomycin vs tube insertion. OBJECTIVE: To assess the cost-effectiveness of these procedures compared with maximal medical treatment. DESIGN, SETTING, AND PARTICIPANTS: We used the Markov cohort model with a 5-year time horizon to study a hypothetical cohort of 100 000 patients who required glaucoma surgery. MAIN OUTCOMES AND MEASURES: Quality-adjusted life years (QALYs) gained, costs from the societal perspective, and the incremental cost-effectiveness ratio of medical treatment, trabeculectomy, and tube insertion. Costs were identified from Medicare Current Procedural Terminology and Ambulatory Payment Classification reimbursement codes and Red Book medication costs. The QALYs were based on visual field and visual acuity outcomes. The hypothetical societal limit to resources was included using a willingness-to-pay threshold of $50 000 per QALY. Costs and utilities were discounted at 3% per year. Uncertainty was assessed using deterministic sensitivity analyses. RESULTS: The mean costs for medical treatment, trabeculectomy, and tube insertion were $6172, $7872 and $10 075, respectively; these amounts resulted in a cost difference of $1700 (95% CI, $1644-$1770) for medical treatment vs trabeculectomy, $3904 (95% CI, $3858-$3953) for medical treatment vs tube insertion, and $2203 (95% CI, $2121-$2261) for trabeculectomy vs tube insertion. The mean 5-year probability of blindness was 4% for both surgical procedures and 15% for medical treatment. The utility gained after medical treatment, trabeculectomy, and tube insertion was 3.10, 3.30, and 3.38 QALYs, respectively. The incremental cost-effectiveness ratio was $8289 per QALY for trabeculectomy vs medical treatment, $13 896 per QALY for tube insertion vs medical treatment, and $29 055 per QALY for tube insertion vs trabeculectomy. The cost-effectiveness of each surgical procedure was most sensitive to early and late surgical failure rates and was minimally affected by adverse events, rates of visual field progression, or medication costs. CONCLUSIONS AND RELEVANCE: Assuming a willingness to pay of $50 000 per QALY, trabeculectomy and tube insertion are cost-effective compared with medical treatment alone. Trabeculectomy, however, is cost-effective at a substantially lower cost per QALY compared with tube insertion. More research is necessary to reliably account for patient preferences between the 2 operations. PMID- 25741887 TI - Effect of HIV Infection and Highly Active Antiretroviral Therapy on Hearing Function: A Prospective Case-Control Study From Cameroon. AB - IMPORTANCE: Human immunodeficiency virus (HIV) infection remains a major cause of morbidity and mortality worldwide. Many studies have found a higher prevalence of hearing impairment among HIV-positive individuals. OBJECTIVE: To investigate the effect of HIV and highly active antiretroviral treatment (HAART) on the hearing function in a Cameroonian population. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective case-control study from March 1, 2012, through January 31, 2013. The study took place at the National Social Insurance Fund Hospital in Yaounde, Cameroon, a public health facility. We included 90 HIV-positive case patients and 90 HIV-negative control patients aged 15 to 49 years without any history of hearing loss or treatment with a known ototoxic drug. The case group was further divided into 3 subgroups: 30 HAART-naive patients, 30 patients receiving first-line HAART, and 30 patients receiving second-line HAART. INTERVENTIONS: Hearing function was assessed by pure-tone audiometry and classified according to the criteria of the Bureau International d'Audio Phonologie. MAIN OUTCOMES AND MEASURES: Hearing loss due to HIV and HAART. RESULTS: The HIV-positive patients had more otologic symptoms (hearing loss, dizziness, tinnitus, and otalgia) than HIV-negative patients (41 vs 13, P = .04). There were 49 cases (27.2%) of hearing loss in the HIV-positive group vs 10 (5.6%) in the HIV-negative group (P = .04). Compared with HIV-negative individuals, the odds of hearing loss were higher among HIV-infected HAART-naive patients (right ear: odds ratio [OR], 6.7; 95% CI, 4.3-9.7; P = .004; left ear: OR, 6.2; 95% CI, 3.5-8.3; P = .006), patients receiving first-line HAART (right ear: OR, 5.6; 95% CI, 1.9-10.5; P = .01; left ear: OR, 12.5; 95% CI, 8.5-15.4; P < .001), and patients receiving second-line HAART (right ear: OR, 6.7; 95% CI, 3.3-9.6; P = .004; left ear: OR, 3.7; 95% CI, 3.0-5.0; P = .08). CONCLUSIONS AND RELEVANCE: Hearing loss is more frequent in HIV-infected patients compared with uninfected patients. Therefore, HIV-infected patients need special audiologic care. Further studies are needed because controversy remains regarding the factors that lead to ear damage. PMID- 25741888 TI - Fabrication of freestanding nanoparticle membranes over wells. AB - Freestanding nanoparticle membranes over circular wells are prepared by utilizing surface engineering. The crucial step of this method is the hydrophobic treatment of the substrate surface, which causes the water droplet to be suspended over wells during drying. Consequently, the nanoparticle monolayer self-assembled at the surface of the water droplet would drape itself over wells instead of being dragged into wells and ruptured into patches after the evaporation of water. This scenario was confirmed by the results of control experiments with changes in the hydrophobicity of the surface and the depth of wells. Moreover, the NaCl crystallization experiment provides additional evidence for the dynamic process of drying. Freestanding nanoparticle membranes with different nanoparticle core sizes and different lengths of ligands have been successfully prepared using the same route. The Young's modulus of one typical kind of prepared freestanding nanoparticle membrane was measured with force microscopy. PMID- 25741889 TI - Peptide-nanoparticle ligation mediated by cutinase fusion for the development of cancer cell-targeted nanoconjugates. AB - The relationship between the positioning of ligands on the surface of nanoparticles and the structural features of nanoconjugates has been underestimated for a long time, albeit of primary importance to promote specific biological recognition at the nanoscale. In particular, it has been formerly observed that a proper molecular orientation can play a crucial role, first optimizing ligand immobilization onto the nanoparticles and, second, improving the targeting efficiency of the nanoconjugates. In this work, we present a novel strategy to afford peptide-oriented ligation using genetically modified cutinase fusion proteins, which combines the presence of a site-directed "capture" module based on an enzymatic unit and a "targeting" moiety consisting of the ligand terminal end of a genetically encoded polypeptide chain. As an example, the oriented presentation of U11 peptide, a sequence specific for the recognition of urokinase plasminogen activator receptor (uPAR), was achieved by enzyme-mediated conjugation with an irreversible inhibitor of cutinase, an alkylphosphonate p nitrophenol ester linker, covalently bound to the surface of iron oxide nanoparticles. The targeting efficiency of the resulting protein-nanoparticle conjugates was assessed using uPAR-positive breast cancer cells exploiting confocal laser scanning microscopy and quantitative fluorescence analysis of confocal images. Ultrastructural analysis of transmission electron micrographs provided evidence of a receptor-mediated pathway of endocytosis. Our results showed that, despite the small average number of targeting peptides presented on the nanoparticles, our ligand-oriented nanoconjugates proved to be very effective in selectively binding to uPAR and in promoting the uptake in uPAR-positive cancer cells. PMID- 25741891 TI - Theoretical analysis of reactivity patterns in Diels-Alder reactions of cyclopentadiene, cyclohexadiene, and cycloheptadiene with symmetrical and unsymmetrical dienophiles. AB - The Diels-Alder reactions of cyclopentadiene, cyclohexadiene, and cycloheptadiene with a series of dienophiles were studied with quantum mechanical calculations (M06-2X density functional theory) and analyzed with the distortion/interaction model. The poor reactivities of cyclohexadiene and cycloheptadiene with dienophiles that give relatively synchronous transition states result from the substantial distortion required to achieve a transition state involving the formation of two bonds of the diene simultaneously. However, highly asynchronous or stepwise reactions result in less distortion of the diene and less differences in reactivities of different dienes. The transition state geometry of cyclopentadiene is less distorted in the asynchronous reaction with 1,1 dicyanoethylene compared to that with cis- and trans-1,2-dicyanoethylenes, which react through synchronous transition states. PMID- 25741890 TI - The bioconjugation and radiosynthesis of 89Zr-DFO-labeled antibodies. AB - The exceptional affinity, specificity, and selectivity of antibodies make them extraordinarily attractive vectors for tumor-targeted PET radiopharmaceuticals. Due to their multi-day biological half-life, antibodies must be labeled with positron-emitting radionuclides with relatively long physical decay half-lives. Traditionally, the positron-emitting isotopes 124I (t1/2=4.18 d), 86Y (t1/2=14.7 hr), and 64Cu (t1/2=12.7 hr) have been used to label antibodies for PET imaging. More recently, however, the field has witnessed a dramatic increase in the use of the positron-emitting radiometal 89Zr in antibody-based PET imaging agents. 89Zr is a nearly ideal radioisotope for PET imaging with immunoconjugates, as it possesses a physical half-life (t1/2=78.4 hr) that is compatible with the in vivo pharmacokinetics of antibodies and emits a relatively low energy positron that produces high resolution images. Furthermore, antibodies can be straightforwardly labeled with 89Zr using the siderophore-derived chelator desferrioxamine (DFO). In this protocol, the prostate-specific membrane antigen targeting antibody J591 will be used as a model system to illustrate (1) the bioconjugation of the bifunctional chelator DFO-isothiocyanate to an antibody, (2) the radiosynthesis and purification of a 89Zr-DFO-mAb radioimmunoconjugate, and (3) in vivo PET imaging with an 89Zr-DFO-mAb radioimmunoconjugate in a murine model of cancer. PMID- 25741892 TI - Preparation and respirometric assessment of mitochondria isolated from skeletal muscle tissue obtained by percutaneous needle biopsy. AB - Respirometric profiling of isolated mitochondria is commonly used to investigate electron transport chain function. We describe a method for obtaining samples of human Vastus lateralis, isolating mitochondria from minimal amounts of skeletal muscle tissue, and plate based respirometric profiling using an extracellular flux (XF) analyzer. Comparison of respirometric profiles obtained using 1.0, 2.5 and 5.0 MUg of mitochondria indicate that 1.0 MUg is sufficient to measure respiration and that 5.0 MUg provides most consistent results based on comparison of standard errors. Western blot analysis of isolated mitochondria for mitochondrial marker COX IV and non-mitochondrial tissue marker GAPDH indicate that there is limited non-mitochondrial contamination using this protocol. The ability to study mitochondrial respirometry in as little as 20 mg of muscle tissue allows users to utilize individual biopsies for multiple study endpoints in clinical research projects. PMID- 25741893 TI - In utero intra-cardiac tomato-lectin injections on mouse embryos to gauge renal blood flow. AB - The formation and perfusion of developing renal blood vessels (apart from glomeruli) are greatly understudied. As vasculature develops via angiogenesis (which is the branching off of major vessels) and vasculogenesis (de novo vessel formation), perfusion mapping techniques such as resin casts, in vivo ultrasound imaging, and micro-dissection have been limited in demonstrating the intimate relationships between these two processes and developing renal structures within the embryo. Here, we describe the procedure of in utero intra-cardiac ultrasound guided FITC-labeled tomato lectin microinjections on mouse embryos to gauge the ontogeny of renal perfusion. Tomato lectin (TL) was perfused throughout the embryo and kidneys harvested. Tissues were co-stained for various kidney structures including: nephron progenitors, nephron structures, ureteric epithelium, and vasculature. Starting at E13.5 large caliber vessels were perfused, however peripheral vessels remained unperfused. By E15.5 and E17.5, small peripheral vessels as well as glomeruli started to become perfused. This experimental technique is critical for studying the role of vasculature and blood flow during embryonic development. PMID- 25741894 TI - The proportion of correct diagnoses is low in emergency patients with nonspecific complaints presenting to the emergency department. AB - OBJECTIVE: To determine the proportion of correct emergency department (ED) diagnoses and of hospital discharge diagnoses, in comparison with final diagnoses at the end of a 30-day follow-up, in patients presenting with nonspecific complaints (NSCs) to the ED; to determine differences between male and female patients in the proportion of missed diagnoses. METHODS: Prospective observational study. Diagnoses made at the ED, hospital discharge diagnoses, and final diagnoses were compared. RESULTS: Of 22,782 nontrauma patients presenting to the ED from May 2007 until May 2009, 9,926 were triaged as emergency severity index level 2 or 3, of whom 789 presented with NSCs. After exclusion of 217 patients, 572 were included for final analysis. The final diagnosis at the end of follow-up was taken to be the correct "gold standard" diagnosis. In 263 (46.0%) patients, this corresponded to the primary ED diagnosis, and in 292 (51%) patients to the hospital discharge diagnosis. The most frequent final diagnoses were urinary tract infections (n=49), electrolyte disorders (n=40) and pneumonia (n=37), and were correctly diagnosed at the ED in 23, 21 and 27 patients, respectively. Of the twelve most common diagnoses (corresponding to 354 patients), functional impairment was most frequently missed. Among these 354 patients, diagnoses were significantly more often missed in women than in men (142 of 231 [62%] women vs 57 of 123 [46%] men, p=0.004). CONCLUSION: Patients presenting to the ED with NSCs present a diagnostic challenge. New diagnostic tools are needed to help in the diagnosis of these patients. PMID- 25741895 TI - Analysis of autophagy in Penicillium chrysogenum by using starvation pads in combination with fluorescence microscopy. AB - The study of cellular quality control systems has emerged as a highly dynamic and relevant field of contemporary research. It has become clear that cells possess several lines of defense against damage to biologically relevant molecules like nucleic acids, lipids and proteins. In addition to organelle dynamics (fusion/fission/motility/inheritance) and tightly controlled protease activity, the degradation of surplus, damaged or compromised organelles by autophagy (cellular 'self-eating') has received much attention from the scientific community. The regulation of autophagy is quite complex and depends on genetic and environmental factors, many of which have so far not been elucidated. Here a novel method is presented that allows the convenient study of autophagy in the filamentous fungus Penicillium chrysogenum. It is based on growth of the fungus on so-called 'starvation pads' for stimulation of autophagy in a reproducible manner. Samples are directly assayed by microscopy and evaluated for autophagy induction / progress. The protocol presented here is not limited for use with P. chrysogenum and can be easily adapted for use in other filamentous fungi. PMID- 25741896 TI - Image monitoring of pharmaceutical blending processes and the determination of an end point by using a portable near-infrared imaging device based on a polychromator-type near-infrared spectrometer with a high-speed and high resolution photo diode array detector. AB - In the present study we have developed a new version (ND-NIRs) of a polychromator type near-infrared (NIR) spectrometer with a high-resolution photo diode array detector, which we built before (D-NIRs). The new version has four 5 W halogen lamps compared with the three lamps for the older version. The new version also has a condenser lens with a shorter focal point length. The increase in the number of the lamps and the shortening of the focal point of the condenser lens realize high signal-to-noise ratio and high-speed NIR imaging measurement. By using the ND-NIRs we carried out the in-line monitoring of pharmaceutical blending and determined an end point of the blending process. Moreover, to determinate a more accurate end point, a NIR image of the blending sample was acquired by means of a portable NIR imaging device based on ND-NIRs. The imaging result has demonstrated that the mixing time of 8 min is enough for homogeneous mixing. In this way the present study has demonstrated that ND-NIRs and the imaging system based on a ND-NIRs hold considerable promise for process analysis. PMID- 25741897 TI - Hybridisation potential of 1',3'-Di-O-methylaltropyranoside nucleic acids. AB - In further study of our series of six-membered ring-containing nucleic acids, different 1',3'-di-O-methyl altropyranoside nucleoside analogs (DMANA) were synthesized comprising all four base moieties, adenine, cytosine, uracil and guanine. Following assembly into oligonucleotides (ONs), their affinity for natural oligonucleotides was evaluated by thermal denaturation of the respective duplexes. Data were compared with results obtained previously for both anhydrohexitol (HNAs) and 3'-O-methylated altrohexitol modified ONs (MANAs). We hereby demonstrate that ONs modified with DMANA monomers, unlike some of our previously described analogues with constrained 6-membered hexitol rings, did not improve thermodynamic stability of dsRNA complexes, most probably in view of an energetic penalty when forced in the required 1C4 pairing conformation. Overall, a single incorporation was more or less tolerated or even positive for the adenine congener, but incorporation of a second modification afforded a slight destabilization (except for A), while a fully modified sequence displayed a thermal stability of -0.3 degrees C per modification. The selectivity of pairing remained very high, and the new modification upon incorporation into a DNA strand, strongly destabilized the corresponding DNA duplexes. Unfortunately, this new modification does not bring any advantage to be further evaluated for antisense or siRNA applications. PMID- 25741898 TI - Theoretical and experimental electrostatic potential around the m-nitrophenol molecule. AB - This work concerns a comparison of experimental and theoretical results of the electron charge density distribution and the electrostatic potential around the m nitrophenol molecule (m-NPH) known for its interesting physical characteristics. The molecular experimental results have been obtained from a high-resolution X ray diffraction study. Theoretical investigations were performed using the Density Functional Theory at B3LYP level of theory at 6-31G* in the Gaussian program. The multipolar model of Hansen and Coppens was used for the experimental electron charge density distribution around the molecule, while we used the DFT methods for the theoretical calculations. The electron charge density obtained in both methods allowed us to find out different molecular properties such us the electrostatic potential and the dipole moment, which were finally subject to a comparison leading to a good match obtained between both methods. The intramolecular charge transfer has also been confirmed by an HOMO-LUMO analysis. PMID- 25741899 TI - In situ EPR studies of reaction pathways in Titania photocatalyst-promoted alkylation of alkenes. AB - In situ EPR spectroscopy at cryogenic temperatures has been used to observe and identify paramagnetic species produced when titania is irradiated in the presence of reactants used in the photocatalytic alkylation of maleimide with t-butyl carboxylic acid or phenoxyacetic acid. It is shown that maleimide acts as an acceptor of conduction band electrons. Valence band holes oxidise t-butyl carboxylic acid to the t-butyl radical and phenoxyacetic acid to the phenoxyacetic acid radical cation. In the presence of maleimide, the phenoxymethyl radical is formed from phenoxyacetic acid. The relevance of these observations to the mechanisms of titania photocatalyst-promoted alkylation of alkenes is discussed. PMID- 25741900 TI - Cationic iridium(III) complexes with two carbene-based cyclometalating ligands: cis versus trans isomers. AB - A series of cationic iridium(III) complexes with two carbene-based cyclometalating ligands and five different N^N bipyridine and 1,10-phenanthroline ancillary ligands is presented. For the first time--in the frame of a rarely studied class of bis(heteroleptic) iridium complexes with two carbene-based cyclometalating ligands--a pair of cis and trans isomers has been isolated. All complexes (trans-1-5 and cis-3) were characterized by (1)H NMR, (13)C NMR, (31)P NMR, and HRMS (ESI-TOF); in addition, crystal structures of cis-3 and trans-4 are reported and discussed. Cyclic voltammetric studies show that the whole series exhibits highly reversible oxidation and reduction processes, suggesting promising potential for optoelectronic applications. Ground-state DFT and TD-DFT calculations nicely predict the blue shift experimentally observed in the room temperature absorption and emission spectra of cis-3, compared to the trans complexes. In CH3CN, cis-3 displays a 4-fold increase in photoluminescence quantum yield (PLQY) with respect to trans-3, as a consequence of drastically slower nonradiative rate constant. By contrast, at 77 K, the emission properties of all the compounds, including the cis isomer, are much more similar, with a pronounced hypsochromic shift for the trans complexes. A similar behavior is found in solid state (1% w/w poly(methyl methacrylate) matrix), with all complexes displaying PLQY of ~70-80%, comparable emission lifetimes (tau ~ 1.3 MUs), and a remarkable rigidochromic shift. To rationalize the more pronounced nonradiative deactivation (and smaller PLQY) observed for photoexcited trans complexes, comparative temperature-dependent emission studies in the range of 77 450 K for cis-3 and trans-3 were made in propylene glycol, showing that solvation effects are primarily responsible for the observed behavior. PMID- 25741901 TI - Investigation of fluoroethylene carbonate effects on tin-based lithium-ion battery electrodes. AB - Electroless plating of tin on copper foil (2-D) and foams (3-D) was used to create carbon- and binder-free thin films for solid electrolyte interphase (SEI) property investigation. When electrochemically cycled vs lithium metal in coin cells, the foam electrodes exhibited better cycling performance than the planar electrodes due to electrode curvature. The effect of the additive/cosolvent fluoroethylene carbonate (FEC) was found to drastically improve the capacity retention and Coulombic efficiency of the cells. The additive amount of 2% FEC is enough to derive the benefits in the cells at a slow (C/9) cycling rate. The interfacial properties of Sn thin film electrodes in electrolyte with/without FEC additive were investigated using in situ electrochemical quartz crystal microbalance with dissipation (EQCM-D). The processes of the decomposition of the electrolyte on the electrode surface and Li alloying/dealloying with Sn were characterized quantitatively by surface mass change at the molecular level. FEC containing electrolytes deposited less than electrolyte without FEC on the initial reduction sweep, yet increased the overall thickness/mass of SEI after several cyclic voltammetry cycles. EQCM-D studies demonstrate that the mass accumulated per mole of electrons (mpe) was varied in different voltage ranges, which reveals that the reduction products of the electrolyte with/without FEC are different. PMID- 25741902 TI - Dynamic structure elucidation of chemical reactivity by laser pulses and X-ray probes. AB - Visualising chemical reactions by X-ray methods is a tantalising prospect. New light sources provide the prospect for studying atomic, electronic and energy transfers accompanying chemical change by X-ray spectroscopy and inelastic scattering. Here we assess how this adventure can illuminate inorganic and catalytic chemistry. In particular X-ray inelastic scattering provides a means of exploiting X-ray free electron lasers, as a parallel to laser Raman spectroscopy. PMID- 25741904 TI - Recording light-evoked postsynaptic responses in neurons in dark-adapted, mouse retinal slice preparations using patch clamp techniques. AB - The retina is the gateway to the visual system. To understand visual signal processing mechanisms, we investigate retinal neural network functions. Retinal neurons in the network comprise of numerous subtypes. More than 10 subtypes of bipolar cells, ganglion cells, and amacrine cells have been identified by morphological studies. Multiple subtypes of retinal neurons are thought to encode distinct features of visual signaling, such as motion and color, and form multiple neural pathways. However, the functional roles of each neuron in visual signal processing are not fully understood. The patch clamp method is useful to address this fundamental question. Here, a protocol to record light-evoked synaptic responses in mouse retinal neurons using patch clamp recordings in dark adapted conditions is provided. The mouse eyes are dark-adapted O/N, and retinal slice preparations are dissected in a dark room using infrared illumination and viewers. Infrared light does not activate mouse photoreceptors and thus preserves their light responsiveness. Patch clamp is used to record light-evoked responses in retinal neurons. A fluorescent dye is injected during recordings to characterize neuronal morphological subtypes. This procedure enables us to determine the physiological functions of each neuron in the mouse retina. PMID- 25741903 TI - Complications Following Therapeutic Bronchoscopy for Malignant Central Airway Obstruction: Results of the AQuIRE Registry. AB - BACKGROUND: There are significant variations in how therapeutic bronchoscopy for malignant airway obstruction is performed. Relatively few studies have compared how these approaches affect the incidence of complications. METHODS: We used the American College of Chest Physicians (CHEST) Quality Improvement Registry, Evaluation, and Education (AQuIRE) program registry to conduct a multicenter study of patients undergoing therapeutic bronchoscopy for malignant central airway obstruction. The primary outcome was the incidence of complications. Secondary outcomes were incidence of bleeding, hypoxemia, respiratory failure, adverse events, escalation in level of care, and 30-day mortality. RESULTS: Fifteen centers performed 1,115 procedures on 947 patients. There were significant differences among centers in the type of anesthesia (moderate vs deep or general anesthesia, P < .001), use of rigid bronchoscopy (P < .001), type of ventilation (jet vs volume cycled, P < .001), and frequency of stent use (P < .001). The overall complication rate was 3.9%, but significant variation was found among centers (range, 0.9%-11.7%; P = .002). Risk factors for complications were urgent and emergent procedures, American Society of Anesthesiologists (ASA) score > 3, redo therapeutic bronchoscopy, and moderate sedation. The 30-day mortality was 14.8%; mortality varied among centers (range, 7.7%-20.2%, P = .02). Risk factors for 30-day mortality included Zubrod score > 1, ASA score > 3, intrinsic or mixed obstruction, and stent placement. CONCLUSIONS: Use of moderate sedation and stents varies significantly among centers. These factors are associated with increased complications and 30-day mortality, respectively. PMID- 25741905 TI - The attentional set shifting task: a measure of cognitive flexibility in mice. AB - Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity. PMID- 25741907 TI - Crystal field effect induced topological crystalline insulators in monolayer IV VI semiconductors. AB - Two-dimensional (2D) topological crystalline insulators (TCIs) were recently predicted in thin films of the SnTe class of IV-VI semiconductors, which can host metallic edge states protected by mirror symmetry. As thickness decreases, quantum confinement effect will increase and surpass the inverted gap below a critical thickness, turning TCIs into normal insulators. Surprisingly, based on first-principles calculations, here we demonstrate that (001) monolayers of rocksalt IV-VI semiconductors XY (X = Ge, Sn, Pb and Y = S, Se, Te) are 2D TCIs with the fundamental band gap as large as 260 meV in monolayer PbTe. This unexpected nontrivial topological phase stems from the strong crystal field effect in the monolayer, which lifts the degeneracy between p(x,y) and p(z) orbitals and leads to band inversion between cation pz and anion px,y orbitals. This crystal field effect induced topological phase offers a new strategy to find and design other atomically thin 2D topological materials. PMID- 25741906 TI - An update on the association of vitamin D deficiency with common infectious diseases. AB - Vitamin D plays an important role in modulating the immune response to infections. Deficiency of vitamin D is a common condition, affecting both the general population and patients in health care facilities. Over the last decade, an increasing body of evidence has shown an association between vitamin D deficiency and an increased risk for acquiring several infectious diseases, as well as poorer outcomes in vitamin D deficient patients with infections. This review details recent developments in understanding the role of vitamin D in immunity, the antibacterial actions of vitamin D, the association between vitamin D deficiency and common infections (like sepsis, pneumonia, influenza, methicillin-resistant Staphylococcus aureus, human immunodeficiency virus type-1 (HIV), and hepatitis C virus (HCV)), potential therapeutic implications for vitamin D replacement, and future research directions. PMID- 25741908 TI - Cuspal Flexure and Extent of Cure of a Bulk-fill Flowable Base Composite. AB - OBJECTIVES: To investigate a bulk-fill flowable base composite (Surefil SDR Flow) in terms of cuspal flexure and cure when used in incremental or bulk techniques. METHODS: Mesio-occluso-distal cavities (4 mm deep, 4 mm wide) were prepared in 24 extracted molars. The slot-shaped cavities were etched, bonded, and restored in 1) two 2-mm increments Esthet-X HD (control), 2) two 2-mm increments Surefil SDR Flow, or 3) 4-mm bulk Surefil SDR Flow (N=8). The teeth were digitized after preparation (baseline) and restoration and were precisely aligned to calculate cuspal flexure. Restored teeth were placed in fuchsin dye for 16 hours to determine occlusal bond integrity from dye penetration. Extent of cure was assessed by hardness at 0.5-mm increments through the restoration depth. Results were analyzed with analysis of variance and Student-Newman-Keuls post hoc tests (alpha=0.05). RESULTS: Surefil SDR Flow, either incrementally or bulk filled, demonstrated significantly less cuspal flexure than Esthet-X HD. Dye penetration was less than 3% of cavity wall height and was not statistically different among groups. The hardness of Surefil SDR Flow did not change throughout the depth for both incrementally and bulk filled restorations; the hardness of Esthet-X HD was statistically significantly lower at the bottom of each increment than at the top. CONCLUSIONS: Filling in bulk or increments made no significant difference in marginal bond quality or cuspal flexure for the bulk-fill composite. However, the bulk-fill composite caused less cuspal flexure than the incrementally placed conventional composite. The bulk-fill composite cured all the way through (4 mm), whereas the conventional composite had lower cure at the bottom of each increment. PMID- 25741909 TI - Socioeconomic disadvantage increasing risk for depression among recently diagnosed HIV patients in an urban area in Brazil: cross-sectional study. AB - Depression is the most common psychiatric co-morbidity among people living with HIV (PLHIV), with prevalence rates ranging from 25% to 36%. Depression impacts negatively upon adherence and response to combined antiretroviral therapy (CART) and the transmission of HIV infection through increased sexually risky behavior. This cross-sectional study presents data from a reference HIV-outpatient service in Dourados (Brazil) that evaluated the association between depressive symptoms, health-related quality of life, and clinical, socioeconomic, and demographic factors in newly diagnosed HIV/AIDS patients. Using the Beck Depression Inventory (BDI), the prevalence of depressive symptoms was 61% with a predominance of self deprecating and cognitive-affective factors. Depressive symptoms were associated with lower income (p=0.019) and disadvantaged social class (p=0.005). Poorer quality of life was related to depressive symptoms (p<0.0001), low educational level (p=0.05), and lower income (p=0.03). These data suggest that socioeconomic factors, including level of income and education, are mediating the risk of depression and poor quality of life of PLHIV. Possible explanations for this effect are discussed, including the possible role of stigma. PMID- 25741910 TI - Polypropylene/Layered Double Hydroxide (LDH) Nanocomposites: Influence of LDH Particle Size on the Crystallization Behavior of Polypropylene. AB - Highly dispersed isotactic polypropylene (iPP) nanocomposites were prepared by incorporating two different sized Mg-Al LDH nanoparticles with different loadings from 1 to 10 wt % using a modified solvent mixing method. Larger sized LDH nanoparticles (~3-4 MUm) were prepared from the gel form of Mg-Al LDH, and the smaller sized nanoparticles (~50-200 nm) were prepared by sonication of as synthesized LDH particles. Such obtained LDH nanoparticles were carefully characterized using wide-angle X-ray diffraction (WAXD), transmission electron microscopy, and scanning electron microscopy. WAXD and atomic force microscopy results indicate that the LDH nanoparticles were highly dispersed in the iPP matrix. The influence of LDH nanoparticles size and concentration on the thermal stability, spherulitic morphology, melting behavior, isothermal crystallization kinetics, and lamellar structure of iPP were investigated. Incorporation of low loadings of sonicated LDH particles (e.g., 1-2.5 wt %) show substantial effect on thermal stability, spherulite size, crystallinity, and crystallization half-time and lamellar morphology of iPP compared to the pure iPP and that of nanocomposites with larger LDH particles with same loadings. The better nucleation ability of iPP in the presence of sonicated LDH can be attributed to the high surface area of LDH nanoparticles along with its better dispersibility within the polymer matrix. The incorporation of LDH nanoparticles does not change the crystallization growth mechanism and crystal structure of iPP. PMID- 25741911 TI - The role of metabolomics in osteoarthritis for early diagnosis, monitoring prognosis and treatment. PMID- 25741912 TI - Definition of a quantitative measurement method for acetabular version in a plain radiograph in the healthy adult hip. AB - OBJECTIVES: This study aims to define a quantitative measurement method for acetabular version in a standard anteroposterior hip radiograph, assess the intraobserver and interobserver agreements of this method, and compare it with the gold standard computed tomography (CT). PATIENTS AND METHODS: Anteroposterior standard hip radiographs and simultaneously taken transverse acetabular CT sections of 78 hips of 39 patients (10 males, 29 females; mean age 60 years; range 40 to 81 years) were used in the study. In standard anteroposterior hip radiographs, "acetabular anterior wall line" was identified as the line between the most lateral edge of the acetabulum and the inferolateral edge of the teardrop. "Acetabular posterior wall line" was identified as the line between the most lateral edge of the subchondral sclerosis and the outmost point of acetabulum posterior lunate surface sclerosis. To assess the reliability of this technique, mentioned angles in 78 hips were measured by two authors independently two weeks apart. Direct radiographic values were compared with the acetabular version measurement values in CT examination. RESULTS: Mean acetabular version angles of 78 hips in plain radiographs and CT were 18.0 degrees (9-25 degrees ) and 17.2 degrees (12-25 degrees ), respectively. Mean intraobserver measurement differences were 1.3 degrees (0-5 degrees ) and 1.5 degrees (0-6 degrees ). Mean interobserver measurement difference was 1.4 degrees (0-5 degrees ). The mean difference between plain radiography measurements and CT measurements was 2.5 degrees (0-6 degrees ). A significant correlation was detected between plain radiographic measurements and CT measurements. CONCLUSION: By this quantitative method, acetabular morphology may be measured less invasively, easily, quickly and reliably in plain radiograph in transverse plane. PMID- 25741913 TI - [Arthroscopic dorsal ligamento capsulodesis results in Geissler grade 2 and 3 scapholunate interosseous ligament injuries]. AB - OBJECTIVES: This study aims to retrospectively evaluate results of arthroscopic dorsal ligamento capsulodesis in Geissler grade 2 and 3 scapholunate ligament injuries. PATIENTS AND METHODS: Thirty-two patients (20 males, 12 females; mean age 30.1 years; range 21 to 42 years) who were performed arthroscopic dorsal ligamento capsulodesis due to Geissler grade 2 and 3 scapholunate ligament injuries between February 2011 and July 2013 were included in this study. Mean duration between the onset of complaints and surgery was 13.7 (range 6-20) months. Joint ranges of motion were compared to wrist motions on the healthy side. Patients were evaluated postoperatively by Mayo Wrist Scoring Test. Pain was assessed by visual analog scale (VAS). RESULTS: Mean follow-up period was 15.12 (range 6-24) months. According to Mayo Wrist Scoring Test, results were excellent in 20 patients, and good in 12 patients. Compared to the healthy extremity, preoperative mean flexion gap range was 2.18 degrees (range 0 degrees -5 degrees ), and mean extension gap range was 4.37 degrees (range 0 degrees -15 degrees ). Compared to the healthy extremity, postoperative mean flexion gap range was 1.71 degrees (range 0 degrees -5 degrees ), and extension gap range was 1.09 degrees (range 0 degrees -10 degrees ). Compared to the healthy hand, preoperative and postoperative mean grip strengths were 86% and 94%, respectively. While preoperative VAS score was 6.59 (range 4-9), postoperative VAS score was 1.21 (range 0-6). CONCLUSION: According to the study results, arthroscopic dorsal ligamento capsulodesis is an effective method for the elimination of pain and range of motion limitation, and recovery of grip strength. PMID- 25741914 TI - Hypothenar hammer syndrome: a case series and literature review. AB - OBJECTIVES: This study aims to report our experience regarding patients who were surgically treated due to hypothenar hammer syndrome and review the related literature. PATIENTS AND METHODS: The study included 11 hands of eight patients (5 males, 3 females; mean age 48 years; range 29 to 60 years) who underwent surgery due to hypothenar hammer syndrome between September 2004 and March 2013. Mean follow-up period was 50 months (range 3-103 months). The time of symptom onset, occupational history, and detailed physical examination findings were recorded. Surgery was performed under sedation and axillary anesthesia. Distal segment of the forearm, all thrombosed segments of the Guyon and superficial arch were removed. Reconstruction of the ulnar artery and the superficial arch was performed using vein grafts obtained from the forearm. RESULTS: While all patients' dominant hand was affected, both hands were affected in three patients. All patients complained of pain and color change in one finger or multiple fingers. While minimal amputation and debridement of fingertip pulp was performed in two patients, all other patients recovered uneventfully. Patency of the ulnar artery was uneventful at follow-up in five of the eight patients, whereas three patients were performed revision surgery for a new vein graft. Most patient complaints resolved during the follow-up period. CONCLUSION: Hypothenar hammer syndrome is a disease of the upper extremities that should be considered in patients with digital ischemia, and a history of manual labor and smoking. Although this disease can be treated with conservative therapy, advance-stage patients who fail to respond to conservative treatment can be treated surgically with vein grafts. PMID- 25741915 TI - Comparison of subacromial tenoxicam and steroid injections in the treatment of impingement syndrome. AB - OBJECTIVES: This study aims to assess and compare the efficacy of subacromial tenoxicam and steroid injections in treating patients with shoulder impingement syndrome. PATIENTS AND METHODS: Forty patients having shoulder impingement syndrome with findings of rotator cuff tendinitis or subacromial bursitis on magnetic resonance imaging were included in the study. Patients were randomized into two subacromial injection groups: patients in the first group (10 males, 10 females; mean age 45.3 years; range 32 to 67 years) were administered 20 mg tenoxicam three times by weekly intervals, and patients in the second group (8 males, 12 females; mean age 46.5 years; range 29 to 73 years) were administered 40 mg methylprednisolone acetate just for once. Visual analog scale (VAS), active range of motion (ROM) of the shoulder joint, and Disabilities of Arm, Shoulder and Hand (DASH) questionnaire scores were evaluated at baseline, six weeks after treatment, and first year. RESULTS: Visual analog scale, DASH, and active ROM scores in both groups were statistically significantly improved. No statistically significant difference was detected between subacromial tenoxicam and steroid injections in terms of post-treatment VAS, DASH, and active ROM scores. Mean pre- and post-treatment VAS scores in tenoxicam group were 7.8 (range, 3-9) and 2.6 (range, 2-4), respectively. Mean pre- and post-treatment VAS scores in steroid group were 6.2 (range, 3-10) and 3.6 (range, 0-7), respectively. Mean pre- and post-treatment DASH scores in tenoxicam group were 59.4 (range, 45-80) and 14.7 (range, 8.3-25.8), respectively. Mean pre- and post-treatment DASH scores in steroid group were 56.7 (range, 33.3-85.8) and 18.1 (range, 0-69.2), respectively. Although the improvement in active ROM was higher in the steroid group, difference between two groups was not statistically significant. CONCLUSION: Both subacromial tenoxicam and steroid injections may be successfully used in the treatment of patients with impingement syndrome. Subacromial tenoxicam injection may be preferred as a first-line intervention in these patients thanks to its safe profile. PMID- 25741916 TI - Combination of anatomical locking plate and retrograde intramedullary nail in distal femoral fractures: comparison of mechanical stability. AB - OBJECTIVES: This study aims is to investigate mechanical properties of intramedullary (IM) nailing and anatomical locking plate in a bone model based on the hypothesis that their combined usage increases safety of fixation stabilization. MATERIALS AND METHODS: Twenty-one left distal femoral fracture models were used in the study. Bones were divided into three equal groups. Group 1 specimens were fixed laterally by distal femoral anatomical locking plate. Group 2 specimens were fixed with retrograde distal femoral IM nail. Group 3 specimens were fixed with both distal femoral anatomical locking plate and retrograde distal femoral IM nail. In mechanical tests, alterations in axial loading, torsion angles, and load to failure values were measured and compared between groups. RESULTS: Compared to group 1, group 2 was relatively more resistant in axial load tests (p=0.225), and significantly more resistant in load to failure tests (p=0.048). Group 1 was relatively more resistant in torsional load tests (p=0.949) compared to group 2. Group 3 was significantly more resistant than group 1 in axial (p=0.001), torsional (p=0.012) load tests and load to failure tests (p=0.008). Group 3 was significantly more resistant compared to group 2 in axial (p=0.003), torsional (p=0.008) load tests, and relatively more resistant (p=0.059) in load to failure tests. CONCLUSION: Thanks to its high mechanical strength and early mobilization capability, distal femoral anatomical locking plate and IM nail combination might be a choice of treatment in complicated osteoporotic or distal femoral fractures from high-energy trauma in young adults. PMID- 25741917 TI - [Morphometric anatomic study and clinical significance of lunate fossa]. AB - OBJECTIVES: This study aims to investigate the depth, transverse and sagittal diameters of lunate fossa which is a significant structure of the wrist in terms of reducing the risk for volar plate screws, which are administered in distal radius fractures, from penetrating into the joint. MATERIALS AND METHODS: Depth, transverse and sagittal diameters of lunate fossa in 50 right and 50 left adult dried radius bones without distal tip damage were measured by using MicroscribeG2X from the MicroScribe G series. RESULTS: Mean lunate fossa depth: left 2.419886+/-0.51 mm/right 2.543052+/-0.78 mm, mean lunate fossa sagittal diameter: left 19.656+/-1.57 mm/right 18.796+/-1.53 mm, mean lunate fossa transverse diameter: left 11.382+/-0.65 mm/right 11.106+/-0.91 mm. There was no statistically significant difference between right and left depth values of lunate fossa (p=0.320), whereas there was statistically significant difference between right and left transverse and sagittal diameters (p=0.006, p=0.048). CONCLUSION: Measurements involving depth of lunate fossa may guide the development of new anatomic plates and decrease complications like the penetration of screw into joint whilst volar plate administrations. PMID- 25741918 TI - Effect of Ankaferd blood stopper(r) on tendon healing: an experimental study in a rat model of Achilles tendon injury. AB - OBJECTIVES: This in vivo study aims to investigate the effects of Ankaferd Blood Stopper(r) (ABS) which is a recently developed topical hemostatic agent on tendon healing using a rat Achilles tendon injury model. MATERIALS AND METHODS: Twelve male Wistar-Albino rats were used in the study. Right legs of the rats were assigned as the study group, and left legs were assigned as the control group. Under anesthesia, bilateral Achilles tendon injuries were created and repaired surgically. To the surgical sites, 1 mL of ABS for the right side and 1 mL of serum physiologic solution for the left side were applied. Animals were euthanized on the 21st postoperative day, and tendon samples were collected from the extremities. Histological analyses were performed according to the semiquantitative tendon scoring system (Bonar Scale). RESULTS: Total tendon healing scores were significantly poorer in the study group compared to the control group. Although there were no significant differences between the groups in terms of tenocyte morphology, degree of ground substance staining, and vascularity, the collagen morphology scores were significantly poorer in the study group. CONCLUSION: In our study, application of ABS had histologically negative effect on tendon healing in rats. However, further biomechanical and immune histochemical studies are required to support these results. PMID- 25741919 TI - Is magnetic resonance imaging reliable for the evaluation of the ruptured or healed anterior cruciate ligament? AB - Magnetic resonance imaging (MRI) is the preferred imaging technique to evaluate the intact, ruptured or healed anterior cruciate ligament (ACL). However, its effectiveness in the diagnosis of chronic tears with synovialization has not been searched. During conservative treatment of torn ACL, there is a reparative process with proliferation of synovial scar tissue which may produce a bridge. This healing, so called synovialization, may cause ACL to be misdiagnosed as intact on MRI. This is true for old ruptures of ACL. Magnetic resonance imaging is reliable in the evaluation of acute ACL ruptures. However, MRI is not reliable to evaluate the stability of the healed ACL after conservative treatment, and the ruptures due to degenerated ACLs. PMID- 25741920 TI - Total wrist arthrodesis with wrist fusion rod in patients with rheumatoid arthritis. AB - OBJECTIVES: This study aims to retrospectively review the short-term surgical outcome of wrist fusion using wrist fusion rod (WFR). PATIENTS AND METHODS: Six wrists of four female patients (mean age 56 years; range 51 to 62 years) with advanced stage rheumatoid arthritis of Larsen IV or V were performed total wrist fusion using WFR. Clinical outcome was assessed using a numeric rating scale of pain satisfaction level. Bony fusion, correction of palmar subluxation and ulnar deviation, rod bending angle, wrist fusion angle, and complications were assessed from radiographs. RESULTS: All wrists achieved painless wrist stability with bony fusion of the radiocarpal joint. Both the palmar subluxation and ulnar deviation were corrected in all patients. Two radiographic complications were observed: rod fracture in one patient and a radiolucent line in proximal metacarpal bone in another patient. Both complications might have occurred as a result of instability of the third carpometacarpal joint, but neither influenced clinical outcome. Wrist fusion angle was smaller than rod bending angle at final observation. CONCLUSION: Wrist fusion using WFR is an option for the treatment of advanced stage rheumatoid arthritis of wrist. According to our experience, the stability of third carpometacarpal joint should be assessed before surgery, and this joint should be fused if required. The bending angle of the intramedullary rod does not directly form the wrist fusion angle in contrast to the case with a dorsal wrist fusion plate. PMID- 25741921 TI - [Neglected ipsilateral simultaneous ruptures of patellar and quadriceps tendon]. AB - Neglected patellar and quadriceps tendon rupture is a rare injury, but ipsilateral simultaneous patellar and quadriceps tendon rupture was not described in the literature to our knowledge. In this article, we report a 40-year-old healthy male patient with neglected ipsilateral patellar and quadriceps tendon ruptures treated by peroneus longus tendon autograft. Patient had received some conservative and surgical treatments for patellar fracture before applying to our clinic. After our treatment using peroneus longus autograft and interference nails, patient was immobilized for six weeks in cylindrical cast. Flexion exercises and full weight bearing were started after cast removal. Patient had no complaint at postoperative second year. Patient was a neglected case. Surgical repair and early rehabilitation enabled us to achieve a satisfactory outcome. PMID- 25741922 TI - Bilateral, locked, recurrent anterior shoulder dislocation: case report. AB - Bilateral anterior dislocation of the shoulder is a rare condition. Most of the cases are seen as posterior dislocations which generally occur during diffuse tonic-clonic contractions of epileptic seizures or after being exposed to strong electric shock. In this article, we report a 21-year-old epileptic patient who had severe bilateral shoulder pain and joint restriction. Diagnoses of bilateral, locked, anterior shoulder dislocation and Hill-Sachs lesions were made with shoulder X-rays and computed tomography. Arthroscopic Bankart repair and remplissage technique were applied in surgical treatment of both shoulders. Posterior dislocations of shoulder usually occur during epileptic seizures but anterior dislocations are rare in the literature. This may lead to delay in diagnosis. Computed tomography scan may be helpful in making diagnosis in uncertain patients. It should not be forgotten that recurrent anterior dislocations may be seen in epileptic patients. Such dislocations should be followed up regularly and instability must be treated to prevent excessive damage to the shoulder. PMID- 25741923 TI - [Acute myeloid leukemia diagnosed with soft tissue mass in the right thigh]. AB - Myeloid sarcoma is a very rare solid tumor which frequently accompanies myeloproliferative disorders and consists of immature myeloid cells. A 47-year old male patient admitted to our clinic with complaints of swelling and pain in the right thigh. After diagnosis of myeloid sarcoma was made with tru-cut biopsy, acute myeloid leukemia was diagnosed by hematology clinic as a result of peripheral smear and bone marrow biopsy. No surgical intervention was performed. Patient was treated with chemotherapy for acute myeloid leukemia, and allogeneic bone marrow transplantation. In the follow-up period, patient was asymptomatic at 14 months and magnetic resonance imaging showed almost complete regression of the tumor. PMID- 25741925 TI - Enhancement in photoluminescence performance of carbon-decorated T-ZnO. AB - The facile preparation of ZnO possessing high visible luminescence intensity remains challenging due to an unclear luminescence mechanism. Here, two basic approaches are proposed to enhance the luminescent intensity based on the theoretical analysis over surface defects. Based on the deduction, we introduce a methodology for obtaining hybrid tetrapod-like zinc oxide (T-ZnO), decorated by carbon nanomarterials on T-ZnO surfaces through the catalytic chemical vapor deposition approach. The intensity of the T-ZnO green emission can be modulated by topography and the proportion of carbon. Under proper experiment conditions, the carbon decorating leads to dramatically enhanced luminescence intensity of T ZnO from 400 to 700 nm compared with no carbon decorated, which elevates this approach to a simple and effective method for the betterment of fluorescent materials in practical applications. PMID- 25741924 TI - [Situs inversus of the fibula: medialized fibula]. AB - Congenital extremity anomalies are caused by pathological changes during the development process of the embryo. Exposure to toxins during 4-12 weeks of pregnancy may lead to extremity anomalies. In this article, we present a girl patient born as one of triplets at the 31st week and fifth day of pregnancy with meningomyelocele, Arnold-Chiari type 2 malformation, developmental dysplasia of the right hip, hypothyroidism, and lower extremity anomaly. Mother had a history of antenatal usage of sodium valproate. Radiographic examination of the lower extremity showed medial location of the fibula. PMID- 25741926 TI - Optical Absorption Microspectroscopy (MU-OAS) Based on Schwarzschild-Type Cassegrain Optics. AB - A new experimental setup, combining a custom-designed Schwarzschild-type Cassegrain-based microscope and an ultraviolet-visible-near infrared (UV-Vis-NIR) spectrophotometer, has been developed, focusing the light beam down to 20 MUm diameter. Optical absorption spectra (in the 300-2500 nm range) have been measured on micrometer-sized natural glass inclusions providing information on iron speciation in magmatic melts. The absence of contribution from the host crystal matrix provides a test of the efficiency of micro-focusing. A microthermometric stage has been adapted on the microscope for measuring optical absorption spectra up to 900 K with application to the thermochromism of minute natural spinel crystals (MgAl2O4:Fe(2+),Cr(3+)). This experimental setup provides an easy and fast way to follow the evolution of spectral properties and color of glasses or crystals with temperature as well as the possibility of measuring spatially resolved optical absorption spectra. PMID- 25741928 TI - [Collaboration networks in nursing]. PMID- 25741927 TI - Impact assessment of repeated exposure of organotypic 3D bronchial and nasal tissue culture models to whole cigarette smoke. AB - Cigarette smoke (CS) has a major impact on lung biology and may result in the development of lung diseases such as chronic obstructive pulmonary disease or lung cancer. To understand the underlying mechanisms of disease development, it would be important to examine the impact of CS exposure directly on lung tissues. However, this approach is difficult to implement in epidemiological studies because lung tissue sampling is complex and invasive. Alternatively, tissue culture models can facilitate the assessment of exposure impacts on the lung tissue. Submerged 2D cell cultures, such as normal human bronchial epithelial (NHBE) cell cultures, have traditionally been used for this purpose. However, they cannot be exposed directly to smoke in a similar manner to the in vivo exposure situation. Recently developed 3D tissue culture models better reflect the in vivo situation because they can be cultured at the air-liquid interface (ALI). Their basal sides are immersed in the culture medium; whereas, their apical sides are exposed to air. Moreover, organotypic tissue cultures that contain different type of cells, better represent the physiology of the tissue in vivo. In this work, the utilization of an in vitro exposure system to expose human organotypic bronchial and nasal tissue models to mainstream CS is demonstrated. Ciliary beating frequency and the activity of cytochrome P450s (CYP) 1A1/1B1 were measured to assess functional impacts of CS on the tissues. Furthermore, to examine CS-induced alterations at the molecular level, gene expression profiles were generated from the tissues following exposure. A slight increase in CYP1A1/1B1 activity was observed in CS-exposed tissues compared with air-exposed tissues. A network-and transcriptomics-based systems biology approach was sufficiently robust to demonstrate CS-induced alterations of xenobiotic metabolism that were similar to those observed in the bronchial and nasal epithelial cells obtained from smokers. PMID- 25741930 TI - Understanding diabetes self-management behaviors among Hispanics in New York City. AB - Diabetes mellitus is a public health concern disproportionately affecting Hispanics. Because Hispanics are greatly affected by a high prevalence of diabetes, a qualitative study was conducted, which explored how Hispanics understand, perceive, and experience behavioral change and how they maintain such change while managing their diabetes. Twenty Caribbean (Dominican and Puerto Rican) Hispanic adults with diabetes, who were either English- or Spanish speaking, participated in the study. Twenty individual interviews were conducted, audiotaped, and transcribed and translated. Structured questions were used in the interviews which covered the meaning of certain terms (e.g., healthy eating, exercise), motivators and barriers to changing behaviors related to diabetes management, and a question to explore ways nurses can assist them in changing behaviors. Content analysis was used to analyze the text of the interviews. Three themes (diabetes management, behavior change, and nurse's role) emerged from the data, including apparent gaps in the participants' perception of adapting their cultural foods into healthier dietary habits. PMID- 25741932 TI - The adapted model of institutional support for Hispanic student degree completion: revisions and recommendations. AB - This article describes the historical development of the adapted model of institutional support (AMIS) for Hispanic student degree completion. The model was developed using 6 major categories of support: financial support, emotional and moral support, mentoring, professional socialization, academic advising, and technical support. Studies used to validate the inclusion of each of the components are presented. Two self-assessment instruments based on the model, the Institutional Self-Assessment for Factors Supporting Hispanic Student Recruitment and Persistence and the Healthcare Professions Education Program Self-Assessment (PSA), used to evaluate institutional supports for Hispanic student degree completion are described. This article describes the results of 2 studies using the PSA. The findings from these studies provide support for the AMIS. Limitations of the model and recommendations for further research are presented. PMID- 25741931 TI - Preferences for intervention among Peruvian women in intimate partner violence relationships. AB - We sought to identify what abused Peruvian women want or need as intervention strategies. We conducted five focus groups with 30 women with prior or current experience with intimate partner violence. Participants noted that abused women need compassionate support, professional counseling, and informational and practical (e.g., work skills training, employment, shelter, financial support) interventions. We propose a 2-tiered intervention strategy that includes community support groups and individual professional counseling. This strategy is intended to offer broad coverage, meeting the needs of large groups of women who experience abuse, whereas providing specialized counseling for those requiring intensive support. Respect for each woman's autonomy in the decision-making process is a priority. Interventions targeted toward women and men should address structural factors that contribute to violence against women. PMID- 25741929 TI - Latino community-based participatory research studies: a model for conducting bilingual translations. AB - Many behavioral health materials have not been translated into Spanish. Of those that are available in Spanish, some of them have not been translated correctly, many are only appropriate for a subgroup of Latinos, and/or multiple versions of the same materials exist. This article describes an innovative model of conducting bilingual English-Spanish translations as part of community-based participatory research studies and provides recommendations based on this model. In this article, the traditional process of conducting bilingual translations is reviewed, and an innovative model for conducting translations in collaboration with community partners is described. Finally, recommendations for conducting future health research studies with community partners are provided. Researchers, health care providers, educators, and community partners will benefit from learning about this innovative model that helps produce materials that are more culturally appropriate than those that are produced with the most commonly used method of conducting translations. PMID- 25741933 TI - An integrated review of directly observed therapy for tuberculosis in Latin America. AB - Tuberculosis (TB) continues to be one of the main causes of death in adults globally. Failure to complete TB treatment can lead to treatment-resistant TB and continued transmission of the infection. Directly observed therapy (DOT) is the treatment recommended by the World Health Organization. This article sought to synthesize DOT data to identify important variables in DOT research, including original research studies conducted in a Latin American country on pulmonary TB. Medication supervisors included family members or health professionals who provided support, education, and counseling. Age, past treatment, drug abuse, and housing in poor neighborhoods were negatively correlated to DOT adherence. Community-based DOT programs were more successful than clinic-based programs. Cost and convenience of DOT treatment seem to be barriers to treatment completion. TB rates have fallen since the inception of DOT, but studies have not shown a significant difference between DOT and self-administered therapy. PMID- 25741935 TI - Health protection and risks for rescuers in cases of floods. AB - Floods can pose a number of safety and health hazards for flood-affected populations and rescuers and bring risk of injuries, infections, and diseases due to exposure to pathogenic microorganisms and different biological and chemical contaminants. The risk factors and possible health consequences for the rescuers involved in evacuation and rescuing operations during the May 2014 flood crisis in Croatia are shown, as well as measures for the prevention of injuries and illnesses. In cases of extreme floods, divers play a particularly important role in rescuing and first-response activities. Rescuing in contaminated floodwaters means that the used equipment such as diving suits should be disinfected afterwards. The need for securing the implementation of minimal health and safety measures for involved rescuers is paramount. Data regarding injuries and disease occurrences among rescuers are relatively scarce, indicating the need for medical surveillance systems that would monitor and record all injuries and disease occurrences among rescuers in order to ensure sound epidemiological data. The harmful effects of flooding can be reduced by legislation, improvement of flood forecasting, establishing early warning systems, and appropriate planning and education. PMID- 25741936 TI - Organophosphate pesticides exposure among farmworkers: pathways and risk of adverse health effects. AB - Organophosphate (OP) compounds are the most widely used pesticides with more than 100 OP compounds in use around the world. The high-intensity use of OP pesticides contributes to morbidity and mortality in farmworkers and their families through acute or chronic pesticides-related illnesses. Many factors contributing to adverse health effects have been investigated by researchers to determine pathways of OP-pesticide exposure among farmers in developed and developing countries. Factors like wind/agricultural pesticide drift, mixing and spraying pesticides, use of personal protective equipment (PPE), knowledge, perceptions, washing hands, taking a shower, wearing contaminated clothes, eating, drinking, smoking, and hot weather are common in both groups of countries. Factors including low socioeconomic status areas, workplace conditions, duration of exposure, pesticide safety training, frequency of applying pesticides, spraying against the wind, and reuse of pesticide containers for storage are specific contributors in developing countries, whereas housing conditions, social contextual factors, and mechanical equipment were specific pathways in developed countries. This paper compares existing research in environmental and behavioural exposure modifying factors and biological monitoring between developing and developed countries. The main objective of this review is to explore the current depth of understanding of exposure pathways and factors increasing the risk of exposure potentially leading to adverse health effects specific to each group of countries. PMID- 25741934 TI - Levels of soya aeroallergens during dockside unloading as measured by personal and static sampling. AB - Soya is an important worldwide agricultural product widely shipped and imported in bulk. It contains a number of recognised allergens and the use of soya products and its dockside unloading have been associated with occupational asthma and community episodes of asthma. Two recognised inhalation soya allergens, soya trypsin inhibitor (STI) and hydrophobic soya protein (HSP), were measured in personal and static air samples collected at a United Kingdom (UK) dock during 3 days of unloading three bulks of processed soya beans and soya pelletised husk. Static samples included task-related and those taken at the workplace perimeter and neighbouring sites. Soluble total protein (STP) and gravimetric dust analyses were also undertaken. While gravimetric dust results in personal air samples were below half of the current UK exposure limit of 10 mg m(-3) for grain dust, and generally less than 0.5 mg m(-3) for the static samples, airborne concentrations for STI and HSP ranged between 0-3,071 and 11-12,629 ng m(-3), respectively, while the correlation between the two specific allergen measurements was generally good (Rank Spearman coefficient 0.74). The data from this investigation suggest that HSP is a more sensitive indicator of soya exposure than STI, but only for soya husk, while STI may be equipotent in detecting exposure to both hull and bean derived soya products. Both assays appear sensitive techniques for investigating the control of exposure to allergenic soy material. The endotoxin level in the husk bulk was 15-60-fold that found in the two chipped bean bulks. PMID- 25741937 TI - Umbilical cord plasma interferon-induced protein 10 (IP-10) and interferon induced T-cell alpha chemoattractant (ITAC) levels are lower in women with severe preeclampsia. AB - BACKGROUND: Higher 1st trimester maternal serum levels of interferon-induced protein 10 (IP-10) and interferon inducible T-cell alpha chemoattractant (ITAC) are reported in gestations complicated with preeclampsia. However, parallel results in the fetal circulation are lacking. OBJECTIVE: To compare IP-10 and ITAC levels in neonatal cord blood from gestations complicated by severe preeclampsia vs. gestational age-matched controls. METHOD: Umbilical cord vessels were sampled following delivery of women with severe preeclampsia (n=30) >=36 weeks to measure plasma IP-10 and ITAC levels and compared to corresponding controls matched for parity as well as maternal and gestational age. Chemokines were measured by specific ELISAs and expressed as pg/mL. Rho Spearman's coefficients were calculated to establish correlations between chemokine values and various numeric variables. RESULTS: Preeclamptic cases displayed significantly lower median plasma umbilical artery and vein levels of both chemokines when compared to controls (IP-10: 23.4 vs. 31.4 and 2.0 vs. 24.6 pg/mL, P<0.05; and ITAC: 2.0 vs. 13.9 and 11.9 vs. 31.6 pg/mL, P<0.05, in artery and vein, respectively). There was a significant correlation between levels of both chemokines (r2=0.616, P=0.0001), but not with other variables. CONCLUSION: In contrast to elevated 1st trimester levels of IP-10 previously found in the maternal serum of women who later developed preeclampsia, this study found lower umbilical cord IP-10 and ITAC plasma levels in near-term gestations with established severe preeclampsia. PMID- 25741938 TI - Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1. AB - Autosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (ENPP1) causes a wide spectrum of phenotypes, ranging from lethal generalized arterial calcification of infancy to hypophosphatemic rickets with hypertension. Hearing loss was not previously thought to be one of the features of the disease entities and was merely regarded as a complication rather than a part of the disease. We report two children who presented in mid to late childhood with progressive varus deformity of their legs due to hypophosphatemic rickets caused by mutations in the ENPP1 gene. Both children had evidence of progressive hearing loss requiring the use of hearing aids. This report of two unrelated infants with compound heterozygous mutations in ENPP1 and previously published cases confirms that mild to moderate hearing loss is frequently associated with ARHR2. Early onset conductive hearing loss may further distinguish the autosomal recessive ENPP1 related type from other types of hypophosphatemia. PMID- 25741939 TI - Metabolic syndrome in obese children and adolescents in Serbia: prevalence and risk factors. AB - OBJECTIVE: To assess the prevalence of metabolic syndrome (MS) in obese children and adolescents in Serbia. SUBJECTS AND METHODS: The study group consisted of 254 subjects (148 female and 106 male), aged 4.6-18.9 years with diet-induced obesity (body mass index >=95th percentile). Presence of MS using the International Diabetes Federation definition was assessed in all subjects, as well as oral glucose tolerance test and insulin resistance indices. RESULTS: Overall prevalence of MS in all subjects aged >=10 years was 31.2%, namely, 28.7% in children aged 10 to <16 years and 40.5% in adolescents >=16 years. When adjusted for age, gender and pubertal development, higher degree of obesity was a strong predictor of MS. Multivariate analysis showed that taller subjects and those with higher degree of insulin resistance were at significantly higher risk of MS, independent of the degree of obesity. CONCLUSIONS: High prevalence of MS emphasizes the need for prevention and treatment of childhood obesity. PMID- 25741940 TI - Antenatal Bartter syndrome presenting as hyperparathyroidism with hypercalcemia and hypercalciuria: a case report and review. AB - Antenatal type I Bartter syndrome (ABS) is usually identified by the presence of polyhydramnios, premature delivery, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis caused by mutations in the Na-K-2Cl cotransporter (NKCC2)-encoding SLC12A1 gene. In this report, we describe a novel presentation of this syndrome with hypercalcemic hypercalciuric hyperparathyroidism, and review the literature of the variable atypical presentations of ABS. PMID- 25741941 TI - Perrault syndrome with growth hormone deficiency: a rare autosomal recessive disorder. AB - Perrault syndrome is a rare genetically heterogeneous autosomal recessive group of disorders described in 1951 by Perrault as gonadal dysgenesis with deafness. Here we present a rare case of sporadic Perrault syndrome with short stature and growth hormone deficiency (GHD). Although there was a report on partial GHD in Perrault, our case is a first of its kind with documented GHD (Nishi Y, Hamamoto K, Kajiyama M, Kawamura I. The Perrault syndrome: clinical report and review. Am J Med Genet 1988;31:623-9). We report this case because of the rarity of keeping this condition as a differential diagnosis while evaluating for short stature with amenorrhea. PMID- 25741942 TI - Consciousness, awareness of insight and neural mechanisms of schizophrenia. AB - According to recent research, disturbances of self-awareness and conscious experience have a critical role in the pathophysiology of schizophrenia, and in this context, schizophrenia is currently understood as a disorder characterized by distortions of acts of awareness, self-consciousness, and self-monitoring. Together, these studies suggest that the processes of disrupted awareness and conscious disintegration in schizophrenia might be related and represented by similar disruptions on the brain level, which, in principle, could be explained by various levels of disturbed connectivity and information disintegration that may negatively affect usual patterns of synchronous activity constituting adaptive integrative functions of consciousness. On the other hand, mental integration based on self-awareness and insight may significantly increase information integration and directly influence neural mechanisms underlying basic pathophysiological processes in schizophrenia. PMID- 25741944 TI - Normal spirometric standards in young adult Indian population. AB - BACKGROUND: The appropriateness of spirometric reference value depends on all its features matching those of the person being assessed, like ethnicity, environment, nutrition, absence of disease, measurement protocol, as well as equipment used. The present study determines the lung function parameters in normal young healthy Indians and derives reliable prediction formulae for Indian population. METHODS: Computerized spirometry was done in 298 nonsmoking medical students of both genders studying in MKCG Medical College, Berhampur. All the data were statistically analyzed, and prediction equations for the young Indian population were derived. RESULTS: All the lung parameters showed significant gender difference. Height showed the greatest effect on the predicted value of FEV1 and FVC in males and females. Height has the greatest effect on the predicted value of FEV1% in females, whereas weight has the least effect. We formulated univariate and multivariate regression models for prediction of lung parameters in the young Indian adults. The predicted values of pulmonary function parameters for men were 4%-17% higher than most studies, except for Kashmiri population where it was 9% lower. For females, lung parameters were 1%-29% higher in comparison to study groups in other Indian studies. The lung parameters for males were found to be lower than Iranian and Caucasian population study, but higher than Pakistani population. For females, lung parameters were 3%-8% lower than Iranian and Caucasian population, but higher in comparison to Pakistani population. CONCLUSIONS: The computed regression norms may be used to predict the spirometric values in young Indian population of similar age group as the study population. PMID- 25741945 TI - Thiol switches in redox regulation of chloroplasts: balancing redox state, metabolism and oxidative stress. AB - In photosynthesizing chloroplasts, rapidly changing energy input, intermediate generation of strong reductants as well as oxidants and multiple participating physicochemical processes and pathways, call for efficient regulation. Coupling redox information to protein function via thiol modifications offers a powerful mechanism to activate, down-regulate and coordinate interdependent processes. Efficient thiol switching of target proteins involves the thiol-disulfide redox regulatory network, which is highly elaborated in chloroplasts. This review addresses the features of this network. Its conditional function depends on specificity of reduction and oxidation reactions and pathways, thiol redox buffering, but also formation of heterogeneous milieus by microdomains, metabolite gradients and macromolecular assemblies. One major player is glutathione. Its synthesis and function is under feedback redox control. The number of thiol-controlled processes and involved thiol switched proteins is steadily increasing, e.g., in tetrapyrrole biosynthesis, plastid transcription and plastid translation. Thus chloroplasts utilize an intricate and versatile redox regulatory network for intraorganellar and retrograde communication. PMID- 25741946 TI - Sense of coherence in young people with congenital heart disease. AB - OBJECTIVE: Patient-reported outcomes (PROs) have been found to play a role in the development of clinical complications. Hence, it is crucial to understand why some patients do well in terms of PROs and others do not and to identify these groups of patients. Sense of coherence (SOC), capturing a person's outlook on life, is associated with PROs in adolescents with congenital heart disease (CHD). Therefore, we (1) examine how SOC develops in young people with CHD, (2) identify subgroups of SOC development, and (3) characterize subgroups in terms of demographic and clinical variables and PROs. METHOD: In this 4-wave longitudinal study, 429 adolescents with CHD (53.4% boys; median age = 16.3 years) completed assessments of SOC (SOC-13). PROs included quality of life (linear analog scale), loneliness (UCLA-8), depression (CES-D), and perceived health (PedsQL). Latent class growth analysis was used to identify clinically meaningful subgroups of SOC development. RESULTS: Patients with CHD had a moderate SOC that slightly decreased over the first 18 months. Four subgroups of SOC development emerged: Consistently High (27%), Intermediate Stable (41%), Intermediate Decreasing (25%), and Chronically Low (7%). Subgroups differed in terms of sex and PROs, but not in terms of age, disease complexity, primary diagnosis, or surgical history. CONCLUSION: Patients with a strong and stable SOC over time showed a better adaptation than patients with a lower and/or decreasing SOC. Our results can guide the identification of patients at risk for adverse health outcomes and the development of interventions to enhance optimal living in patients with CHD. PMID- 25741943 TI - Role of protein kinase A in regulating mitochondrial function and neuronal development: implications to neurodegenerative diseases. AB - In neurons, enhanced protein kinase A (PKA) signaling elevates synaptic plasticity, promotes neuronal development, and increases dopamine synthesis. By contrast, a decline in PKA signaling contributes to the etiology of several brain degenerative diseases, including Alzheimer's disease and Parkinson's disease, suggesting that PKA predominantly plays a neuroprotective role. A-kinase anchoring proteins (AKAPs) are large multidomain scaffold proteins that target PKA and other signaling molecules to distinct subcellular sites to strategically localize PKA signaling at dendrites, dendritic spines, cytosol, and axons. PKA can be recruited to the outer mitochondrial membrane by associating with three different AKAPs to regulate mitochondrial dynamics, structure, mitochondrial respiration, trafficking, dendrite morphology, and neuronal survival. In this review, we survey the myriad of essential neuronal functions modulated by PKA but place a special emphasis on mitochondrially localized PKA. Finally, we offer an updated overview of how loss of PKA signaling contributes to the etiology of several brain degenerative diseases. PMID- 25741947 TI - Parent health beliefs, social determinants of health, and child health services utilization among U.S. school-age children with autism. AB - OBJECTIVE: Substantial variation exists in autism spectrum disorder (ASD) care by race, ethnicity, and socioeconomic status; however, the role of parent health beliefs in this variation is poorly understood. Study goals were to (1) examine variation in parent beliefs about ASD prognosis and treatment according to social determinants of health (SDH) and (2) assess whether this variation was associated with variable health services utilization, among 1420 children with special health care needs (CSHCN) having ASD. METHODS: We used linked data from the 2011 Survey of Pathways to Diagnosis and Treatment and the 2009-2010 National Survey of Children with Special Health Care Needs. Bivariate and multivariate analyses assessed variation in parent beliefs according to race/ethnicity, household income, and parent educational attainment. Further analyses assessed whether variation in beliefs was associated with the use of psychotropic medication, traditional therapy, or complementary/alternative therapy for ASD. RESULTS: Parents of lower educational attainment or who had lower income were more likely to think that their child's condition was a mystery. Near-poor families were less likely to believe that they had the power to change the child's condition. Parents of minority children were more likely than white children to view their child's condition as temporary. However, these differences in beliefs only had modest associations with variation in use of the health services analyzed. CONCLUSIONS: Some SDH-related variation exists in health beliefs among parents of children with ASD, but these differences may not be the main factors accounting for ASD health care disparities. PMID- 25741949 TI - Sleep differences among children with autism spectrum disorders and typically developing peers: a meta-analysis. AB - OBJECTIVE: Sleep problems such as difficulties in sleep initiation, nighttime awakening, and shortened sleep time are often subjectively reported in children with autism spectrum disorder (ASD). However, results of objective studies have been mixed. Our goal was to evaluate the existing data from objective measures using a systematic approach to identify and describe the differences in sleep parameters by comparing total sleep time (TST), sleep latency (SL), and sleep efficiency (SE) in children with ASD with those of typically developing (TD) peers. METHODS: Studies that used objective measures such as actigraphy or polysomnography (PSG) to describe the sleep parameters of TST, SL, and SE in children with ASD compared with children with TD were identified. A meta-analysis was performed for the 10 studies that met inclusion criteria with evaluation of differences in means using random effects models. A total of 343 children with ASD and 221 children with TD were included. Assessments for sources of heterogeneity and publication bias were undertaken. RESULTS: TST for children with ASD was on average 32.8 minutes less per day (95% confidence interval [CI]: 16.6-49.0 minutes) than their TD peers. Average SL was 10.9 minutes longer (95% CI: 6.7-15.0 minutes), and average SE was 1.9% less (95% CI: 0.7%-3.1%) than their TD peers. Notable heterogeneity was found within studies for TST, and mild heterogeneity was found for SE. Concurrent intellectual disability was a moderator of TST. Children with ASD and normal intelligence had a small and nonsignificant decrease in TST as compared with TD peers, whereas those with ASD and intellectual disability (ID) had a significant decrease in TST as compared with TD peers. The magnitude of the difference in mean SL and SE increased as compared with TD peers as age increased. Studies that used PSG and those that did not include children on medications were more likely to report mean decreases in SE. CONCLUSIONS: Children with ASD have small but measurable objective differences in their sleep parameters that are consistent with subjective reporting. Children with ASD have shorter TST, longer SL periods, and decreased SE as compared with TD peers. Concurrent ID, medication use, method of data collection, and age of subjects significantly moderated these results. The decrease in TST in children with ASD and normal intelligence was not significant as compared with TD peers, suggesting that ID may help explain the shortened TST in children with ASD. PMID- 25741951 TI - Predicting, identifying, and managing sepsis. PMID- 25741952 TI - Sepsis and septic shock: a review. AB - Sepsis and septic shock are a continuum of disease resulting from a complex host response to infection. They are major health issues in the United States, causing significant financial burden to the health care system in addition to multisystem morbidity and high rates of mortality. In recent decades, landmark trials in sepsis management have demonstrated improved mortality. Although the value of protocol-driven care is currently under question, it is clear that early recognition, prompt resuscitation, and timely use of antibiotics are of utmost importance. PMID- 25741948 TI - Perceptions of siblings' sexual activity predict sexual attitudes among at-risk adolescents. AB - OBJECTIVE: Most American youth have siblings. This study examined the influence of early adolescents' perceptions of their older sibling's sexual activity on their own sexual attitudes and behaviors. METHODS: Early adolescents (ages 12-14) at risk for emotional/behavioral problems reported on attitudes towards sex, sexual behaviors, and perception of older siblings' and peers' sexual activity and perceived parental approval toward sex. The sample was divided into 3 groups: teens who thought their older sibling was not having sex (N = 119), teens who believed their sibling was sexually active (N = 55), and teens without an older sibling (N = 170). RESULTS: Teens who thought their older sibling was not having sex scored higher in valuing abstinence and lower on perceptions of peer sex and maternal approval toward sex than teens who perceived their sibling to be having sex and teens without an older sibling. Regarding behaviors, teens who thought their older sibling was not having sex were less likely to endorse making out, touching genitals, oral sex, and vaginal sex compared with teens who thought their older sibling was having sex. CONCLUSIONS: Perceptions that older siblings abstain from sexual activity may be a protective factor for more conservative attitudes towards sex and decreased sexual activity among young at-risk teens. A single question about perceptions of siblings' sexual behaviors can be integrated into health care visits to introduce conversations about age-appropriate sexual decision-making. PMID- 25741950 TI - Persisting behavior problems in extremely low birth weight adolescents. AB - OBJECTIVE: To describe behavior problems in extremely low birth weight (ELBW, <1000 g) adolescents born 1992 through 1995 based on parent ratings and adolescent self-ratings at age 14 years and to examine changes in parent ratings from ages 8-14. METHOD: Parent ratings of behavior problems and adolescent self ratings were obtained for 169 ELBW adolescents (mean birth weight 815 g, gestational age 26 wk) and 115 normal birth weight (NBW) controls at 14 years. Parent ratings of behavior at age 8 years were also available. Behavior outcomes were assessed using symptom severity scores and rates of scores above DSM-IV symptom cutoffs for clinical disorder. RESULTS: The ELBW group had higher symptom severity scores on parent ratings at age 14 years than NBW controls for inattentive attention-deficit hyperactivity disorder (ADHD), anxiety, and social problems (all p's < .01). Rates of parent ratings meeting DSM-IV symptom criteria for inattentive ADHD were also higher for the ELBW group (12% vs. 1%, p < .01). In contrast, the ELBW group had lower symptom severity scores on self-ratings than controls for several scales. Group differences in parent ratings decreased over time for ADHD, especially among females, but were stable for anxiety and social problems. CONCLUSIONS: Extremely low birth weight adolescents continue to have behavior problems similar to those evident at a younger age, but these problems are not evident in behavioral self-ratings. The findings suggest that parent ratings provide contrasting perspectives on behavior problems in ELBW youth and support the need to identify and treat these problems early in childhood. PMID- 25741954 TI - Surviving sepsis in the critical care environment. AB - The management of sepsis and septic shock in the intensive care environment is a complex task requiring the cooperation of a multidisciplinary team. The Surviving Sepsis Campaign provides systematic guidelines for the recognition, early intervention, and supportive management of sepsis. Critical care nurses are instrumental in ensuring that these guidelines and other sources of evidence based practice are used for patients with severe sepsis or septic shock. This article discusses the pathophysiologic processes in severe sepsis and septic shock and discusses the appropriate interventions as recommended by the Surviving Sepsis Campaign. Recommended early treatments are reviewed along with interventions related to hemodynamics, perfusion, and supportive care in the critical care environment. PMID- 25741953 TI - Pharmacotherapy of sepsis. AB - Treatment of sepsis involves prompt recognition and treatment to optimize outcome. Several medication considerations are pertinent to patients with sepsis, severe sepsis, and septic shock. Medications play a crucial role in providing resuscitation, hemodynamic support, resolution of infection, and reduction of complications of the disease. Over the past 20 years, significant focus has been devoted to the pharmacologic treatment of septic shock, resulting in significant advances and controversies. Ongoing research will continue to focus on this disease process and will continue to shape treatment in the future. The use of medication therapies directed at treatment of sepsis will be reviewed in this article. PMID- 25741955 TI - Recognition of risk factors and prognostic indicators in Fournier's gangrene. AB - Fournier's gangrene is a rare but rapidly progressive necrotizing infection that results from the synergistic action of multiple aerobic and anaerobic organisms colonized on the skin and in the anogenital area. This is a case report of a middle-aged man with late presentation of Fournier's gangrene that was treated aggressively by a team of infectious disease specialists, surgeons, intensivists, and intensive care unit specialty nurses over a 3-week period. Despite heroic efforts by the multidisciplinary team, the patient's condition deteriorated and he died of multisystem failure. The purpose of this article was to alert clinicians to the etiology, pathophysiology, risk factors for invasive necrosis, prognostic indicators, and current diagnostic and treatment recommendations. Fournier's gangrene represents a true medical and surgical emergency and requires early recognition and a team approach to management. PMID- 25741956 TI - Osteomyelitis: an overview of imaging modalities. AB - Diagnosis, early intervention, and treatment of patients who have an infection are the basic foundations of patient care. Early, appropriate interventions are associated with decreased patient morbidity and mortality. Diagnostic procedures with clinical information and laboratory results are integral in the assessment of inflammatory diseases and the prevention of sepsis. Some of the imaging modalities currently used for the assessment of inflammation include computed tomography, plain radiography, positron emission tomography, technetium Tc 99m bone scintigraphy, magnetic resonance imaging, and leukocyte scintigraphy. In the case of patients who exhibit signs of osteomyelitis, it is necessary to understand that acute and chronic conditions are not based on the duration of the disease but on the histopathologic features of the disease. Although several imaging modalities are considered appropriate, there is not one singular procedure that is considered ideal. Rather, it is a combination of procedures and various other clinical factors. This article addresses some of the advantages and disadvantages of the modalities, with a focus on molecular imaging and the assessment of osteomyelitis. PMID- 25741957 TI - Managing oncology neutropenia and sepsis in the intensive care unit. AB - Neutropenic sepsis results as a post-cancer treatment complications and is considered an oncologic emergency. Neutropenic sepsis can result in mortality, especially if it is not identified at an early stage. Septic syndrome is the leading cause of nonrelapse mortality in patients with hematologic malignancies and solid tumors. Therefore, intensive care unit (ICU) nurses must possess a thorough understanding of cancer treatments, hematopoiesis, neutropenia, sepsis, risk factors, and the ability to perform a comprehensive assessment of the oncology patient. Each of these components plays a vital role in the patient's overall management following treatments with chemotherapy, radiation, and stem cell transplantation. The ICU nurse who encompasses this understanding will be able to identify neutropenic sepsis in a timely manner. The early identification of neutropenic sepsis will enable the ICU nurse to expeditiously implement preventive treatment and management to prevent mortality. PMID- 25741960 TI - Physician-led sepsis quality improvement team. AB - Over the last decade, hospitalizations for sepsis have more than doubled and the incidence of postsurgical sepsis tripled between 1997 and 2006. This upward trend is expected to continue for several reasons, including population-specific characteristics (e.g., age, chronic disease status) and health care-specific characteristics (eg, lack of understanding of sepsis, medical treatments that leave patients susceptible). Highly effective, focused, quality improvement teams need to be established in order to successfully manage this condition. Quality improvement, and specifically quality improvement in health care, has evolved substantially over the past few decades. This evolution has been pushed by government initiatives and private accrediting bodies that have exposed concerns regarding quality of care. Hospitals have responded with not only corrective actions but also actions that improve quality despite a lack of noted deficiencies (i.e., taking quality from "good" to "better"). Key components of a successful quality improvement program have been identified, as have components of successful quality improvement teams. By applying these components to a physician-led sepsis quality improvement team, hospitals can successfully decrease sepsis mortality and increase compliance with the application of sepsis best practice in the emergency department, intensive care unit, or non-intensive care unit nursing units. PMID- 25741959 TI - Reduction in time to first action as a result of electronic alerts for early sepsis recognition. AB - The use of an electronic alerting system to notify practitioners when a patient meets modified systemic inflammatory response syndrome criteria was hypothesized to decrease the time to goal-directed therapy initiation. This retrospective, before-and-after study analyzed adult patients identified with sepsis or septic shock and compared 30 patients prior to electronic alert initiation with 30 patients after initiation. The primary endpoint was time to any sepsis-related intervention. Patients in the post-alert group demonstrated a shorter time to any sepsis-related intervention by a median difference of 3.5 hours (P = .02). Using computerized medical records to create an electronic alerting system has the potential to identify high-risk patients and initiate interventions sooner. At our institution, the creation of an alerting system with real-time data has decreased the time it takes to begin sepsis workup and treatment. PMID- 25741958 TI - The older adult experiencing sepsis. AB - Sepsis is a potentially fatal response to infection affecting patients across the life span. Sepsis can progress from systemic inflammatory response to severe sepsis and septic shock if not recognized promptly and managed effectively. Risk factors for sepsis include age, gender, the presence of invasive devices (eg, urinary catheters), and chronic medical conditions (eg, chronic obstructive pulmonary disease). Sepsis awareness is essential and includes identification of population-focused risk factors, recognition of clinical signs and symptoms, and timely implementation of interventions. The purpose of this article was to examine sepsis in older adults, including prevalence, atypical presentation of the condition, and considerations for sepsis management in the elderly population. PMID- 25741962 TI - Follow me down the K-hole: ketamine and its modern applications. AB - Ketamine is a versatile anesthetic agent that has been in use since the Vietnam War. Its popularity grew in war time due to its unique pharmacological properties, yet its use dwindled because of some of its adverse effects. However, in specialty areas, ketamine remains the drug of choice and its benefit far outweighs its risk. In our review, we outline the history of ketamine, its pharmacological properties, and its modern applications in various arenas. PMID- 25741961 TI - Anesthetic choices and breast cancer recurrence: a retrospective pilot study of patient, disease, and treatment factors. AB - The purpose of this work was to investigate differences in patient, disease, and treatment factors between women who received outpatient surgical treatment of breast cancer with paravertebral and general anesthesia compared with women who received general anesthesia alone. A total of 358 patients with stage 0-III disease received a partial or total mastectomy without axillary node dissection at a large academic cancer center. Study median follow-up time was 28.8 months. Patient demographic characteristics were equally represented across anesthesia groups. Mean body mass index (kg/m) was greater in those who received general anesthesia alone (mean = 29, SD = 6.8) than in those who received paravertebral regional block with general anesthesia (mean = 28, SD = 5.1) (P = .001). The paravertebral regional block with general anesthesia group contained advanced stages of disease (P = .01) and had longer surgical procedures (P = .01) than the general anesthesia alone group. Breast cancer recurrence was detected in 1.7% of the study population (paravertebral regional block with general anesthesia: n = 4; and general anesthesia alone: n = 2). Overall, no association between anesthesia type and recurrence was detected (P = .53), with an unadjusted estimated hazard ratio of 1.84 (95% confidence interval, 0.34-10.08). The overall rate of recurrence was very small in this population. A larger study is needed to detect significant differences in rates of recurrence attributable to type of anesthesia. PMID- 25741965 TI - The Effects of a Diet and Exercise Program for Older Adults With Metabolic Syndrome. AB - BACKGROUND: The prevalence of metabolic syndrome is high among older adults in Taiwan. However, few studies have studied the effect of a combined diet and exercise program on managing metabolic syndrome (MetS) in individuals 65 years and older and living in Taiwan's rural areas. PURPOSE: This study tests the effectiveness of a diet and exercise program on the MetS biomarkers in older community residents with MetS. METHODS: This study used a quasiexperimental study design. All participants were 65 years and older and were diagnosed with MetS. The outcome variables included biomarkers (blood pressure, waist circumference, hip circumference, body mass index, blood sugar, cholesterol, and triglycerides) and demographic characteristics. The participants were distributed into a diet and-exercise group (n = 163) and a nondiet-and-nonexercise group (n = 138). The outcome variables were examined 3 months after the start of the intervention program. RESULTS: The participants in the diet-and-exercise group had lower values than the nondiet-and-nonexercise group for blood pressure, waist circumference, hip circumference, body mass index, blood sugar, cholesterol, and triglyceride (all ps < .001). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The diet and exercise program is an effective intervention for treating older individuals with MetS. Clear and concise information concerning the effects of diet and exercise in promoting the health of older residents with MetS is helpful to improve the health of the older adults inTaiwan. PMID- 25741963 TI - A study in scarlet: restrictive red blood cell transfusion strategy. AB - Anemia due to various etiologies occurs in critically ill patients requiring blood transfusion. Traditional transfusion goals guide our transfusion to achieve a hemoglobin goal of at least 10 g/dL. However, it is becoming increasingly evident that a restrictive transfusion goal of 7 g/dL may improve survival outcome, reduce infection, and reduce health care expenditure. Moreover, this strategy has been proven to be effective in a variety of patient population, including those who are critically ill, septic patients, those with a history of cardiac disease, those with gastrointestinal bleed, or those who suffered traumatic injury. This article reviews some of the evidence supporting the restrictive transfusion strategy. PMID- 25741966 TI - Targeted DNA methylation analysis by next-generation sequencing. AB - The role of epigenetic processes in the control of gene expression has been known for a number of years. DNA methylation at cytosine residues is of particular interest for epigenetic studies as it has been demonstrated to be both a long lasting and a dynamic regulator of gene expression. Efforts to examine epigenetic changes in health and disease have been hindered by the lack of high-throughput, quantitatively accurate methods. With the advent and popularization of next generation sequencing (NGS) technologies, these tools are now being applied to epigenomics in addition to existing genomic and transcriptomic methodologies. For epigenetic investigations of cytosine methylation where regions of interest, such as specific gene promoters or CpG islands, have been identified and there is a need to examine significant numbers of samples with high quantitative accuracy, we have developed a method called Bisulfite Amplicon Sequencing (BSAS). This method combines bisulfite conversion with targeted amplification of regions of interest, transposome-mediated library construction and benchtop NGS. BSAS offers a rapid and efficient method for analysis of up to 10 kb of targeted regions in up to 96 samples at a time that can be performed by most research groups with basic molecular biology skills. The results provide absolute quantitation of cytosine methylation with base specificity. BSAS can be applied to any genomic region from any DNA source. This method is useful for hypothesis testing studies of target regions of interest as well as confirmation of regions identified in genome-wide methylation analyses such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing, and methylated DNA immunoprecipitation sequencing. PMID- 25741967 TI - In situ Ca2+ imaging of the enteric nervous system. AB - Reflex behaviors of the intestine are controlled by the enteric nervous system (ENS). The ENS is an integrative network of neurons and glia in two ganglionated plexuses housed in the gut wall. Enteric neurons and enteric glia are the only cell types within the enteric ganglia. The activity of enteric neurons and glia is responsible for coordinating intestinal functions. This protocol describes methods for observing the activity of neurons and glia within the intact ENS by imaging intracellular calcium (Ca(2+)) transients with fluorescent indicator dyes. Our technical discussion focuses on methods for Ca(2+) imaging in whole mount preparations of the myenteric plexus from the rodent bowel. Bulk loading of ENS whole-mounts with a high-affinity Ca(2+) indicator such as Fluo-4 permits measurements of Ca(2+) responses in individual neurons or glial cells. These responses can be evoked repeatedly and reliably, which permits quantitative studies using pharmacological tools. Ca(2+) responses in cells of the ENS are recorded using a fluorescence microscope equipped with a cooled charge-coupled device (CCD) camera. Fluorescence measurements obtained using Ca(2+) imaging in whole-mount preparations offer a straightforward means of characterizing the mechanisms and potential functional consequences of Ca(2+) responses in enteric neurons and glial cells. PMID- 25741970 TI - Virologic failure among children taking lopinavir/ritonavir-containing first-line antiretroviral therapy in South Africa. AB - OBJECTIVE: To report the outcomes, clinical management decisions and results of resistance testing among a group of children who developed virologic failure on first-line lopinavir/ritonavir (LPV/r)-based therapy from a large cohort of antiretroviral therapy-treated children in Soweto. DESIGN: Historical cohort study. METHODS: Children with virologic failure were identified from a group of 1692 children <3 years who had initiated first-line LPV/r-containing therapy since 2000 up to the end November 2011. Genotyping was conducted in some children, and outcomes, management decisions and resistance results were described. RESULTS: A total of 152 children with virologic failure on first-line LPV/r-containing antiretroviral therapy were included. Resistance testing was performed in 75/152 (49%), and apart from a younger age (11.1 vs. 15.1 months, P = 0.04), the children with versus those without resistance testing were similar for baseline characteristics (weight, CD4, viral load and time to failure). Genotyping revealed that 8/75 (10.7%) had significant LPV/r-associated resistance mutations, including 2 with intermediate darunavir resistance. Among 63/75 (84%) children remaining on LPV/r-based therapy, 32/63 (51%) achieved virologic suppression, and 2 of these children with significant LPV mutations. In accordance with the local guidelines at the time, 12/152 (8%) children were switched to non-nucleoside reverse-transcriptase inhibitors-based therapy. Of these, 4/12 (33%) resuppressed, and the rest did not achieve virologic suppression including the 2 with lopinavir mutations. CONCLUSIONS: Virologic failure of LPV/r-containing first-line regimens is associated with accumulation of LPV/r mutations in children. The implications are unclear, and surveillance at selected sites is warranted for long-term virologic outcomes and development of resistance. PMID- 25741972 TI - Changing trends of acute otitis media bacteriology in central Israel in the pneumococcal conjugate vaccines era. AB - BACKGROUND: The widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has changed acute otitis media (AOM) bacteriology. Only scattered data with regard to this effect of PCV13 have been published so far. METHODS: We retrospectively identified children <6 years of age who presented to our hospital with AOM, and had middle ear fluid (MEF) cultures obtained during tympanocentesis or from spontaneous otorrhea during 2008-2013, when PCV7 (2009) and PCV13 (2010) were gradually introduced in the Israeli National Immunization Program. Data were extracted for demographics, clinical and microbiologic parameters, according to vaccination status. RESULTS: Of the 295 eligible AOM episodes reported in 279 children, 224 (76%) had MEF cultures from tympanocentesis and 71 (24%) from spontaneous otorrhea. Boys and children <2 years of age contributed 178 (60%) and 219 (74%) AOM episodes, respectively. Acute mastoiditis complicated 58 (20%) of these episodes. None of the children were PCV immunized in 2008, but >90% had received >=1 PCV dose(s) by 2011 or later. Of the 106 (36%) MEF cultures which tested positive for otopathogens, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and multiple bacteria grew in 60 (57%), 39 (37%), 2 (2%) and 5 (5%) episodes, respectively. S. pneumonia-positive MEF culture rate in unimmunized children (31, 69%) was significantly higher than in PCV7-immunized children (22, 59%) or PCV13-immunized children (12, 50%), P = 0.04 and P = 0.02, respectively. CONCLUSION: PCV7 and PCV13 implementations in the Israeli National Immunization Program were associated with a rapid reduction of "severe" pneumococcal AOM episodes. PMID- 25741971 TI - Safety, tolerability and immunogenicity of 15-valent pneumococcal conjugate vaccine in toddlers previously vaccinated with 7-valent pneumococcal conjugate vaccine. AB - BACKGROUND: Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) in children has led to significant reduction in pneumococcal disease in children and adults. However, diseases caused by serotypes not included in PCV7 have increased. A 15-valent pneumococcal conjugate vaccine (PCV15) containing serotypes in PCV7 and 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in toddlers 12 to 15 months of age. METHODS: Ninety toddlers who completed an infant series with PCV7 received a single dose of either aluminum-adjuvanted PCV15, nonadjuvanted PCV15, or PCV7. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination and serious AEs (SAEs) were collected for 30 days postvaccination. Solicited AEs included local (pain/tenderness, swelling, nodule and redness) and systemic (fatigue, arthralgia and myalgia) AEs. Serotype-specific immunoglobulin G (IgG) and opsonophagocytic (OPA) responses were measured immediately prior and 30 days postvaccination. RESULTS: Incidences of local and systemic AEs were comparable across vaccine groups. The majority of reported events, regardless of vaccine received, were transient and of mild to moderate intensity. No clinically significant differences were observed when comparing duration and severity of AEs. No vaccine-related SAEs or discontinuations from the study due to AEs were reported. Pneumococcal IgG concentrations and OPA titers increased postvaccination, with appreciable fold rises for all serotypes. Antibody levels were comparable between both PCV15 formulations and generally comparable to PCV7 for the shared serotypes. CONCLUSION: Both formulations of PCV15 display acceptable safety profiles and induce IgG and OPA responses to all vaccine serotypes. PMID- 25741968 TI - Internalization and observation of fluorescent biomolecules in living microorganisms via electroporation. AB - The ability to study biomolecules in vivo is crucial for understanding their function in a biological context. One powerful approach involves fusing molecules of interest to fluorescent proteins such as GFP to study their expression, localization and function. However, GFP and its derivatives are significantly larger and less photostable than organic fluorophores generally used for in vitro experiments, and this can limit the scope of investigation. We recently introduced a straightforward, versatile and high-throughput method based on electroporation, allowing the internalization of biomolecules labeled with organic fluorophores into living microorganisms. Here we describe how to use electroporation to internalize labeled DNA fragments or proteins into Escherichia coli and Saccharomyces cerevisiae, how to quantify the number of internalized molecules using fluorescence microscopy, and how to quantify the viability of electroporated cells. Data can be acquired at the single-cell or single-molecule level using fluorescence or FRET. The possibility of internalizing non-labeled molecules that trigger a physiological observable response in vivo is also presented. Finally, strategies of optimization of the protocol for specific biological systems are discussed. PMID- 25741969 TI - Early infant feeding patterns and HIV-free survival: findings from the Kesho-Bora trial (Burkina Faso, Kenya, South Africa). AB - OBJECTIVE: To investigate the association between feeding patterns and HIV-free survival in children born to HIV-infected mothers and to clarify whether antiretroviral (ARV) prophylaxis modifies the association. METHODS: From June 2005 to August 2008, HIV-infected pregnant women were counseled regarding infant feeding options, and randomly assigned to triple-ARV prophylaxis (triple ARV) until breastfeeding cessation (BFC) before age 6 months or antenatal zidovudine with single-dose nevirapine (short-course ARV). Eighteen-month HIV-free survival of infants HIV-negative at 2 weeks of age was assessed by feeding patterns (replacement feeding from birth, BFC <3 months, BFC >=3 months). RESULTS: Of the 753 infants alive and HIV-negative at 2 weeks, 28 acquired infection and 47 died by 18 months. Overall HIV-free survival at 18 months was 0.91 [95% confidence interval (CI): 0.88-0.93]. In the short-course ARV arm, HIV-free survival (0.88; CI: 0.84-0.91) did not differ by feeding patterns. In the triple ARV arm, overall HIV-free survival was 0.93 (CI: 0.90-0.95) and BFC <3 months was associated with lower HIV-free survival than BFC >=3 months (adjusted hazard ratio: 0.36; CI: 0.15-0.83) and replacement feeding (adjusted hazard ratio: 0.20; CI: 0.04-0.94). In the triple ARV arm, 4 of 9 transmissions occurred after reported BFC (and 5 of 19 in the short-course arm), indicating that some women continued breastfeeding after interruption of ARV prophylaxis. CONCLUSIONS: In resource-constrained settings, early weaning has previously been associated with higher infant mortality. We show that, even with maternal triple-ARV prophylaxis during breastfeeding, early weaning remains associated with lower HIV-free survival, driven in particular by increased mortality. PMID- 25741973 TI - Clinicoradiologic response of neurologic tuberculous mass lesions in children treated with thalidomide. AB - Neurologic tuberculous pseudoabscesses that clinically progress despite conventional antituberculosis therapy may be responsive to adjuvant thalidomide, a potent tumor necrosis factor-alpha inhibitor. In this study, the addition of thalidomide provided substantial clinical benefit in the majority of patients, and magnetic resonance imaging evolution of lesions from early-stage "T2 bright" with edema to "T2 black" represented a marker of cure. PMID- 25741974 TI - Bradycardia in children with Crimean-Congo hemorrhagic fever. PMID- 25741975 TI - Herpes zoster multiplex and bilateral in an immunocompetent child. PMID- 25741976 TI - Atypical cystic echinococcosis in a young child. PMID- 25741977 TI - Intestinal parasites among children with diarrhea younger than 5 years of age in rural Ethiopia. PMID- 25741978 TI - Cesarean section and hospitalization for respiratory syncytial virus infection. PMID- 25741979 TI - Health care changes and research gaps. PMID- 25741980 TI - Effect of a Comprehensive School Physical Activity Program on School Day Step Counts in Children. AB - BACKGROUND: Comprehensive School Physical Activity Programming (CSPAP) has the potential to increase physical activity (PA) in children over time. The purpose of this study was to examine the effect of CSPAP on school day step counts in children. METHODS: Participants were 327 fourth and fifth grade children recruited from 4 elementary schools. The study was conducted within an Interrupted Time-Series Design framework. School day step counts were collected for 5 days across preintervention and postintervention time-points (10 days total) using NL-1000 piezoelectric pedometers. Robust piecewise regression examined pre- and postintervention intercepts and slopes, and the change in these parameters using postestimation statistics. RESULTS: The slope coefficient was statistically significant across preintervention (beta = -105.23, P < .001) but not postintervention time-points (beta = -63.23, P = .347), suggesting decreases in steps counts across preintervention and stability of step counts across postintervention school days. Postestimation statistics yielded increases in school day step counts from the end of preintervention (day 5) to the start of postintervention (day 6; t(319) = -4.72, P < .001, Cohen's d = 4.72). CONCLUSIONS: The CSPAP intervention increased average school day step counts and attenuated decreases in step counts throughout the school week in children. PMID- 25741988 TI - Porphyrin-encapsulated metal-organic frameworks as mimetic catalysts for electrochemical DNA sensing via allosteric switch of hairpin DNA. AB - A sensitive electrochemical sensor is designed for DNA detection based on mimetic catalysis of metal-organic framework (MOF) and allosteric switch of hairpin DNA. The functional MOFs are synthesized as signal probes by a one-pot encapsulation of iron(III) meso-5,10,15,20-tetrakis(4-carboxyphenyl) porphyrin chloride (FeTCPP) into a prototypal MOF, HKUST-1(Cu), and sequentially conjugated with streptavidin (SA) as a recognition element. The resulting FeTCPP@MOF composites can mimetically catalyze the oxidation of o-phenylenediamine (o-PD) to 2,2' diaminoazobenzene, which is a good electrochemical indicator for signal readout. The presence of target DNA introduces the allosteric switch of hairpin DNA to form SA aptamer, and thus, FeTCPP@MOF-SA probe is brought on the electrode surface via the specific recognition between SA and the corresponding aptamer, resulting in the enhancement of electrochemical signal. The "signal-on" electrochemical sensor can detect target DNA down to 0.48 fM with the linear range of 10 fM to 10 nM. Moreover, the MOF-based electrochemical sensor exhibits acceptable selectivity against even a single mismatched DNA and good feasibility in complex serum matrixes. This strategy opens up a new direction of porphyrin functionalized MOF for signal transduction in electrochemical biosensing. PMID- 25741986 TI - Standard versus biofilm antimicrobial susceptibility testing to guide antibiotic therapy in cystic fibrosis. AB - BACKGROUND: The antibiotics used to treat pulmonary infections in people with cystic fibrosis are typically chosen based on the results of antimicrobial susceptibility testing performed on bacteria traditionally grown in a planktonic mode (grown in a liquid). However, there is considerable evidence to suggest that Pseudomonas aeruginosa actually grows in a biofilm (or slime layer) in the airways of people with cystic fibrosis with chronic pulmonary infections. Therefore, choosing antibiotics based on biofilm rather than conventional antimicrobial susceptibility testing could potentially improve response to treatment of Pseudomonas aeruginosa in people with cystic fibrosis. This is an update of a previously published Cochrane Review. OBJECTIVES: To compare biofilm antimicrobial susceptibility testing-driven therapy to conventional antimicrobial susceptibility testing-driven therapy in the treatment of Pseudomonas aeruginosa infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched a registry of ongoing trials and the reference lists of relevant articles and reviews.Most recent search: 19 November 2014. SELECTION CRITERIA: Randomized controlled trials of antibiotic therapy based on biofilm antimicrobial susceptibility testing compared to antibiotic therapy based on conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infection in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed their risk of bias and extracted data from eligible trials. Additionally, the review authors contacted the trial investigators to obtain further information. MAIN RESULTS: The searches identified two multicentre, randomized, double-blind controlled clinical trials eligible for inclusion in the review with a total of 78 participants; one trial was done in people who were clinically stable, the other in people experiencing pulmonary exacerbations. These trials prospectively assessed whether the use of biofilm antimicrobial susceptibility testing improved microbiological and clinical outcomes in participants with cystic fibrosis who were infected with Pseudomonas aeruginosa. The primary outcome was the change in sputum Pseudomonas aeruginosa density from the beginning to the end of antibiotic therapy.Although the intervention was shown to be safe, the data from these two trials did not provide evidence that biofilm susceptibility testing was superior to conventional susceptibility testing either in terms of microbiological or lung function outcomes. One of the trials also measured risk and time to subsequent exacerbation as well as quality of life measures and did not demonstrate any difference between groups in these outcomes. Both trials had an overall low risk of bias. AUTHORS' CONCLUSIONS: The current evidence is insufficient to recommend choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than conventional antimicrobial susceptibility testing in the treatment of Pseudomonas aeruginosa pulmonary infections in people with cystic fibrosis. Biofilm antimicrobial susceptibility testing may be more appropriate in the development of newer, more effective formulations of drugs which can then be tested in clinical trials. PMID- 25741987 TI - Comprehensive assessment of germline chemical toxicity using the nematode Caenorhabditis elegans. AB - Identifying the reproductive toxicity of the thousands of chemicals present in our environment has been one of the most tantalizing challenges in the field of environmental health. This is due in part to the paucity of model systems that can (1) accurately recapitulate keys features of reproductive processes and (2) do so in a medium- to high-throughput fashion, without the need for a high number of vertebrate animals. We describe here an assay in the nematode C. elegans that allows the rapid identification of germline toxicants by monitoring the induction of aneuploid embryos. By making use of a GFP reporter line, errors in chromosome segregation resulting from germline disruption are easily visualized and quantified by automated fluorescence microscopy. Thus the screening of a particular set of compounds for its toxicity can be performed in a 96- to 384 well plate format in a matter of days. Secondary analysis of positive hits can be performed to determine whether the chromosome abnormalities originated from meiotic disruption or from early embryonic chromosome segregation errors. Altogether, this assay represents a fast first-pass strategy for the rapid assessment of germline dysfunction following chemical exposure. PMID- 25741989 TI - Focal embolic cerebral ischemia in the rat. AB - Animal models of focal cerebral ischemia are well accepted for investigating the pathogenesis and potential treatment strategies for human stroke. Occlusion of the middle cerebral artery (MCA) with an endovascular filament is a widely used model to induce focal cerebral ischemia. However, this model is not amenable to thrombolytic therapies. As thrombolysis with recombinant tissue plasminogen activator (rtPA) is a standard of care within 4.5 h of human stroke onset, suitable animal models that mimic cellular and molecular mechanisms of thrombosis and thrombolysis of stroke are required. By occluding the MCA with a fibrin-rich allogeneic clot, we previously developed an embolic model of MCA occlusion in the rat, which recapitulates the key components of thrombotic development and of thrombolytic therapy of rtPA observed from human ischemic stroke. Here we describe in detail the surgical procedures of our model, including preparing emboli from rat donors. These procedures can be typically completed within ~30 min, and they are highly adaptable to other strains of rats, as well as mice, in both sexes. Thus, this model provides a powerful tool for translational stroke research. PMID- 25741992 TI - Chemoselective hydrogenation of carbonyl compounds and acceptorless dehydrogenative coupling of alcohols. AB - OsHCl(CO)[kappa(3)-PyCH2NHC2H4NHPtBu2] is the first efficient catalyst for chemoselective reduction of challenging unsaturated esters to enols and for acceptorless coupling of amines with MeOH and EtOH affording formamides and acetamides. The NMR, ESI-MS, and DFT data indicate a mechanism proceeding in the metal coordination sphere and producing no free organic intermediates. PMID- 25741990 TI - Hydrogenation using iron oxide-based nanocatalysts for the synthesis of amines. AB - In this protocol, we describe the preparation of nanoscale iron oxide-based materials and their use in the catalysis of different hydrogenation reactions. Pyrolysis of a Fe(OAc)2-phenanthroline complex on carbon at 800 degrees C under argon atmosphere results in the formation of nanoscale Fe2O3 particles surrounded by nitrogen-doped graphene layers. By applying these catalysts, the hydrogenation of structurally diverse and functionalized nitroarenes to anilines proceeds with excellent selectivity. Furthermore, we have shown that one-pot reductive amination of carbonyl compounds with nitroarenes is also possible in the presence of these iron oxide catalysts. We report herein the synthesis of more than 40 amines, which are important feedstocks and key intermediates for pharmaceuticals, agrochemicals and polymers. The detailed preparation of the catalysts and the procedures for the hydrogenation processes are presented. The overall time required for the catalyst preparation and for the hydrogenation reactions are 35 h and 20-35 h, respectively. PMID- 25741995 TI - Unraveling the folding mechanism of the smallest knotted protein, MJ0366. AB - Understanding the mechanism by which polypeptide chains thread themselves into topologically knotted structures has emerged to be a challenging subject not least because of the additional complexity associated with the spontaneous and efficient knotting and folding events. While recent theoretical calculations have made significant progress in establishing the atomistic folding pathways for a number of knotted proteins, experimental data on the folding stabilities and kinetic pathways of knotted proteins has been sparse. Using MJ0366 from Methanocaldococcus jannaschii, the smallest knotted protein known to date, as a model system, we set out to systematically investigate its folding equilibrium, kinetics, and internal dynamics under native and chemically denatured states. NMR hydrogen-deuterium exchange analysis indicates that the knotted region is the most stable structural element within the novel fold. Additionally, (15)N spin relaxation analysis reveals the presence of residual structures in urea-denatured MJ0366. Despite the apparent two-state equilibrium unfolding behavior during chemical denaturation, the kinetic unfolding pathway of MJ0366 involves the dissociation of the homodimeric native state into a native-like monomeric intermediate followed by unfolding into a denatured state. Our results provide comprehensive structural information regarding the folding dynamics and kinetic pathways of MJ0366, whose small size is ideal for converging experimental and theoretical findings to better understand the underlying principles of the folding of knotted proteins. PMID- 25741991 TI - Preparation of chiral quantum dots. AB - Chiral quantum dots (QDs) are expected to have a range of potential applications in photocatalysis, as specific antibacterial and cytotoxic drug-delivery agents, in assays, as sensors in asymmetric synthesis and enantioseparation, and as fluorescent chiral nanoprobes in biomedical and analytical technologies. In this protocol, we present procedures for the synthesis of chiral optically active QD nanostructures and their quality control using spectroscopic studies and transmission electron microscopy imaging. We closely examine various synthetic routes for the preparation of chiral CdS, CdSe, CdTe and doped ZnS QDs, as well as of chiral CdS nanotetrapods. Most of these nanomaterials can be produced by a very fast (70 s) microwave-induced heating of the corresponding precursors in the presence of D- or L-chiral stabilizing coating ligands (stabilizers), which are crucial to generating optically active chiral QDs. Alternatively, chiral QDs can also be produced via the conventional hot injection technique, followed by a phase transfer in the presence of an appropriate chiral stabilizer. We demonstrate that the properties, structure and behavior of chiral QD nanostructures, as determined by various spectroscopic techniques, strongly depend on chiral stabilizers and that the chiral effects induced by them can be controlled via synthetic procedures. PMID- 25741994 TI - Triple cathode buffer layers composed of PCBM, C60, and LiF for high-performance planar perovskite solar cells. AB - In this paper, triple cathode buffer layers (CBLs) composed of phenyl-C61-butyric acid methyl ester (PCBM), C60, and LiF layers were introduced into the planar p-i n perovskite solar cells (p-i-n PSCs) with a device structure of ITO/PEDOT:PSS/CH3NH3PbI3-xClx/CBLs/Al. For comparison, a single CBL of PCBM and a double CBL of PCBM/LiF were also investigated in the p-i-n PSCs. On the basis of the PCBM buffer layer, the addition of a thin LiF layer facilitated the charge collection process and led to the dramatic improvement of the power conversion efficiency (PCE) of the PSCs up to 14.69% under an illumination of AM 1.5G, 100 mW/cm(2), which is to date one of the highest efficiencies of the p-i-n PSCs. By further insertion of a C60 layer between PCBM and LiF in the triple CBLs, a PCE of 14.24% was obtained, and more importantly, the PCBM/C60/LiF triple CBLs are very helpful for improving the stability of the devices and making the LiF layer less thickness-sensitive for achieving high performances of the p-i-n PSCs. PMID- 25741993 TI - Corneodesmosomal water content in frozen-hydrated porcine skin. PMID- 25741998 TI - Correction: Histidine-rich glycoprotein uptake and turnover is mediated by mononuclear phagocytes. PMID- 25741997 TI - Interactions between paraoxonase 1 genetic polymorphisms and smoking and their effects on oxidative stress and lung cancer risk in a Korean population. AB - BACKGROUND: Few studies in epidemiology have evaluated the effects of gene environment interaction on oxidative stress, even though this interaction is an important etiologic factor in lung carcinogenesis. We investigated the effects of the genetic polymorphisms of paraoxonase 1 (PON1), smoking, and the interaction between the two on lung cancer risk and oxidative stress. METHODS: This study's subjects consisted of 416 newly diagnosed lung cancer patients and an equal number of matched controls. The GoldenGate assay was used for genotypic analyses of the PON1 gene. Urinary 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances levels were measured as indicators of oxidative stress. RESULTS: The PON1 rs662 AA genotype showed a significantly lower risk of lung cancer than the GG genotype (OR = 0.60, 95% CI: 0.36-0.99). The protective effect of the PON1 rs662 AA genotype on lung cancer risk was limited to non-smokers. Lung cancer patients who had the rs662 A allele showed a dose-dependent association between smoking status and oxidative stress markers. Among non smoking lung cancer patients, urinary 8-OHdG levels were significantly lower in individuals with the rs662 GA and AA genotypes than in those with the GG genotype. Furthermore, we found a significant interaction effect between PON1 rs662 and smoking status on urinary 8-OHdG levels in lung cancer patients. CONCLUSIONS: Our results suggest that the protective effect of PON1 rs662 SNP against lung carcinogenesis and the induction of oxidative stress might be modulated by the interaction between PON1 genetic polymorphisms and tobacco smoking. PMID- 25742000 TI - Sarsaparilla (Smilax Glabra Rhizome) extract inhibits migration and invasion of cancer cells by suppressing TGF-beta1 pathway. AB - Sarsaparilla, also known as Smilax Glabra Rhizome (SGR), was shown to modulate immunity, protect against liver injury, lower blood glucose and suppress cancer. However, its effects on cancer cell adhesion, migration and invasion were unclear. In the present study, we found that the supernatant of water-soluble extract from SGR (SW) could promote adhesion, inhibit migration and invasion of HepG2, MDA-MB-231 and T24 cells in vitro, as well as suppress metastasis of MDA MB-231 cells in vivo. Results of F-actin and vinculin dual staining showed the enhanced focal adhesion in SW-treated cells. Microarray analysis indicated a repression of TGF-beta1 signaling by SW treatment, which was verified by real time RT-PCR of TGF-beta1-related genes and immunoblotting of TGFBR1 protein. SW was also shown to antagonize TGF-beta1-promoted cell migration. Collectively, our study revealed a new antitumor function of Sarsaparilla in counteracting invasiveness of a subset of cancer cells by inhibiting TGF-beta1 signaling. PMID- 25742001 TI - Intrapleural Fibrinolysis for the Treatment of Indwelling Pleural Catheter Related Symptomatic Loculations: A Multicenter Observational Study. AB - BACKGROUND: Indwelling pleural catheters (IPCs) are an effective option in the management of malignant pleural effusion. Up to 14% of patients with IPCs develop symptomatic pleural loculations causing ineffective fluid drainage and breathlessness. To our knowledge, this is the first study to describe intrapleural fibrinolytic therapy for IPC-related symptomatic loculations. METHODS: All patients who received intrapleural fibrinolytic therapy for symptomatic loculations between January 1, 2002, and June 30, 2014, in four established IPC centers were retrospectively included. Patient outcomes, treatment effectiveness, and adverse events were recorded. RESULTS: Sixty-six patients (mean age, 64.7 +/- 14.2 years; 52% women) were included. Lung cancer (31.3%) and malignant pleural mesothelioma (20.3%) were the most common malignancies. Fibrinolytic instillation was performed in outpatient (61%) and inpatient settings. Tissue-plasminogen activator (n = 52), urokinase (n = 12), and streptokinase (n = 2) were used. The majority (69.7%) received only one fibrinolytic dose (range, one to six). Pleural fluid drainage increased in 93% of patients, and dyspnea improved in 83% following therapy. The median cumulative pleural fluid volume drained at 24 h posttreatment was 500 mL (interquartile range 300-1,034 mL). The area of opacity caused by pleural effusion on chest radiograph decreased from (mean, SD) 52% (14%) to 31% (21%) of the hemithorax (n = 13; P = .001). There were two cases of nonfatal pleural bleed (3%). CONCLUSIONS: Intrapleural fibrinolytic therapy can improve pleural fluid drainage and symptoms in selected patients with IPC and symptomatic loculation, but it carries a small risk of pleural bleeding. There is significant heterogeneity in its use currently, and further studies are needed to determine patient selection and optimal dosing regimen and to define its safety profile. PMID- 25742004 TI - Implementation of a neural network for multispectral luminescence imaging of lake pigment paints. AB - Luminescence multispectral imaging is a developing and promising technique in the fields of conservation science and cultural heritage studies. In this article, we present a new methodology for recording the spatially resolved luminescence properties of objects. This methodology relies on the development of a lab-made multispectral camera setup optimized to collect low-yield luminescence images. In addition to a classic data preprocessing procedure to reduce noise on the data, we present an innovative method, based on a neural network algorithm, that allows us to obtain radiometrically calibrated luminescence spectra with increased spectral resolution from the low-spectral resolution acquisitions. After preliminary corrections, a neural network is trained using the 15-band multispectral luminescence acquisitions and corresponding spot spectroscopy luminescence data. This neural network is then used to retrieve a megapixel multispectral cube between 460 and 710 nm with a 5 nm resolution from a low spectral-resolution multispectral acquisition. The resulting data are independent from the detection chain of the imaging system (filter transmittance, spectral sensitivity of the lens and optics, etc.). As a result, the image cube provides radiometrically calibrated emission spectra with increased spectral resolution. For each pixel, we can thus retrieve a spectrum comparable to those obtained with conventional luminescence spectroscopy. We apply this method to a panel of lake pigment paints and discuss the pertinence and perspectives of this new approach. PMID- 25742009 TI - Correction: Epstein-Barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PMID- 25742002 TI - Conformational dynamics and antigenicity in the disordered malaria antigen merozoite surface protein 2. AB - Merozoite surface protein 2 (MSP2) of Plasmodium falciparum is an abundant, intrinsically disordered protein that is GPI-anchored to the surface of the invasive blood stage of the malaria parasite. Recombinant MSP2 has been trialled as a component of a malaria vaccine, and is one of several disordered proteins that are candidates for inclusion in vaccines for malaria and other diseases. Nonetheless, little is known about the implications of protein disorder for the development of an effective antibody response. We have therefore undertaken a detailed analysis of the conformational dynamics of the two allelic forms of MSP2 (3D7 and FC27) using NMR spectroscopy. Chemical shifts and NMR relaxation data indicate that conformational and dynamic properties of the N- and C-terminal conserved regions in the two forms of MSP2 are essentially identical, but significant variation exists between and within the central variable regions. We observe a strong relationship between the conformational dynamics and the antigenicity of MSP2, as assessed with antisera to recombinant MSP2. Regions of increased conformational order in MSP2, including those in the conserved regions, are more strongly antigenic, while the most flexible regions are minimally antigenic. This suggests that modifications that increase conformational order may offer a means to tune the antigenicity of MSP2 and other disordered antigens, with implications for vaccine design. PMID- 25742006 TI - Preclinical assessment of adjunctive tPA and DNase for peritoneal dialysis associated peritonitis. AB - A major complication of peritoneal dialysis is the development of peritonitis, which is associated with reduced technique and patient survival. The inflammatory response elicited by infection results in a fibrin and debris-rich environment within the peritoneal cavity, which may reduce the effectiveness of antimicrobial agents and predispose to recurrence or relapse of infection. Strategies to enhance responses to antimicrobial agents therefore have the potential to improve patient outcomes. This study presents pre-clinical data describing the compatibility of tPA and DNase in combination with antimicrobial agents used for the treatment of PD peritonitis. tPA and DNase were stable in standard dialysate solution and in the presence of antimicrobial agents, and were safe when given intraperitoneally in a mouse model with no evidence of local or systemic toxicity. Adjunctive tPA and DNase may have a role in the management of patients presenting with PD peritonitis. PMID- 25742007 TI - Nickel ions selectively inhibit lipopolysaccharide-induced interleukin-6 production by decreasing its mRNA stability. AB - Nickel (Ni) ions easily elute from many alloys and elicit inflammation and allergies. Previous studies have shown that infections due to the implantation of medical devices cause inflammation and enhance the elution of Ni ions (Ni2+). However, cross-talk between infection- and Ni2+-induced signaling pathways has not yet been elucidated in detail. In the present study, we investigated the effects of Ni2+ on the lipopolysaccharide (LPS)-induced production of cytokines in a LPS-induced air pouch-type inflammation model in BALB/c mice and the murine macrophage cell line RAW264. We demonstrated that Ni2+ inhibited the LPS-induced production of interleukin (IL)-6, but not that of tumor necrosis factor (TNF) alpha both in vivo and in vitro. This inhibitory effect was also observed with cobalt ion (Co2+), but not with chloride ion (Cl-), zinc ion (Zn2+), or palladium ion (Pd2+), and was highly selective to the production of IL-6. Ni2+ did not inhibit the activation of ERK1/2, p38 MAPK, or JNK. Although Ni2+ decreased IL-6 mRNA levels, it failed to inhibit the LPS-induced activation of the IL-6 promoter. An experiment using actinomycin D, a transcription inhibitor, revealed that Ni2+ decreased the stability of IL-6 mRNA. Moreover, Ni2+ inhibited the LPS induced expression of Arid5a, but not regnase-1. These results demonstrated that Ni2+ may have selectively inhibited the LPS-induced production of IL-6 by decreasing the Arid5a-dependent stabilization of IL-6 mRNA. PMID- 25742008 TI - Should we have blind faith in bioinformatics software? Illustrations from the SNAP web-based tool. AB - Bioinformatics tools have gained popularity in biology but little is known about their validity. We aimed to assess the early contribution of 415 single nucleotide polymorphisms (SNPs) associated with eight cardio-metabolic traits at the genome-wide significance level in adults in the Family Atherosclerosis Monitoring In earLY Life (FAMILY) birth cohort. We used the popular web-based tool SNAP to assess the availability of the 415 SNPs in the Illumina Cardio Metabochip genotyped in the FAMILY study participants. We then compared the SNAP output with the Cardio-Metabochip file provided by Illumina using chromosome and chromosomal positions of SNPs from NCBI Human Genome Browser (Genome Reference Consortium Human Build 37). With the HapMap 3 release 2 reference, 201 out of 415 SNPs were reported as missing in the Cardio-Metabochip by the SNAP output. However, the Cardio-Metabochip file revealed that 152 of these 201 SNPs were in fact present in the Cardio-Metabochip array (false negative rate of 36.6%). With the more recent 1000 Genomes Project release, we found a false-negative rate of 17.6% by comparing the outputs of SNAP and the Illumina product file. We did not find any 'false positive' SNPs (SNPs specified as available in the Cardio Metabochip by SNAP, but not by the Cardio-Metabochip Illumina file). The Cohen's Kappa coefficient, which calculates the percentage of agreement between both methods, indicated that the validity of SNAP was fair to moderate depending on the reference used (the HapMap 3 or 1000 Genomes). In conclusion, we demonstrate that the SNAP outputs for the Cardio-Metabochip are invalid. This study illustrates the importance of systematically assessing the validity of bioinformatics tools in an independent manner. We propose a series of guidelines to improve practices in the fast-moving field of bioinformatics software implementation. PMID- 25741999 TI - Determination of methanogenic pathways through carbon isotope (delta13C) analysis for the two-stage anaerobic digestion of high-solids substrates. AB - This study used carbon isotope (delta(13)C)-based calculations to quantify the specific methanogenic pathways in a two-stage experimental biogas plant composed of three thermophilic leach bed reactors (51-56 degrees C) followed by a mesophilic (36.5 degrees C) anaerobic filter. Despite the continuous dominance of the acetoclastic Methanosaeta in the anaerobic filter, the methane (CH4) fraction derived from carbon dioxide reduction (CO2), fmc, varied significantly over the investigation period of 200 days. At organic loading rates (OLRs) below 6.0 gCOD L(-1) d(-1), the average fmc value was 33%, whereas at higher OLRs, with a maximum level of 17.0 gCOD L(-1) d(-1), the fmc values reached 47%. The experiments allowed for a clear differentiation of the isotope fractionation related to the formation and consumption of acetate in both stages of the plant. Our data indicate constant carbon isotope fractionation for acetate formation at different OLRs within the thermophilic leach bed reactors as well as a negligible contribution of homoacetogenesis. These results present the first quantification of methanogenic pathway (fmc values) dynamics for a continually operated mesophilic bioreactor and highlight the enormous potential of delta(13)C analysis for a more comprehensive understanding of the anaerobic degradation processes in CH4-producing biogas plants. PMID- 25742005 TI - Dopaminergic control of the globus pallidus through activation of D2 receptors and its impact on the electrical activity of subthalamic nucleus and substantia nigra reticulata neurons. AB - The globus pallidus (GP) receives dopaminergic afferents from the pars compacta of substantia nigra and several studies suggested that dopamine exerts its action in the GP through presynaptic D2 receptors (D2Rs). However, the impact of dopamine in GP on the pallido-subthalamic and pallido-nigral neurotransmission is not known. Here, we investigated the role of dopamine, through activation of D2Rs, in the modulation of GP neuronal activity and its impact on the electrical activity of subthalamic nucleus (STN) and substantia nigra reticulata (SNr) neurons. Extracellular recordings combined with local intracerebral microinjection of drugs were done in male Sprague-Dawley rats under urethane anesthesia. We showed that dopamine, when injected locally, increased the firing rate of the majority of neurons in the GP. This increase of the firing rate was mimicked by quinpirole, a D2R agonist, and prevented by sulpiride, a D2R antagonist. In parallel, the injection of dopamine, as well as quinpirole, in the GP reduced the firing rate of majority of STN and SNr neurons. However, neither dopamine nor quinpirole changed the tonic discharge pattern of GP, STN and SNr neurons. Our results are the first to demonstrate that dopamine through activation of D2Rs located in the GP plays an important role in the modulation of GP-STN and GP-SNr neurotransmission and consequently controls STN and SNr neuronal firing. Moreover, we provide evidence that dopamine modulate the firing rate but not the pattern of GP neurons, which in turn control the firing rate, but not the pattern of STN and SNr neurons. PMID- 25742003 TI - How attention can create synaptic tags for the learning of working memories in sequential tasks. AB - Intelligence is our ability to learn appropriate responses to new stimuli and situations. Neurons in association cortex are thought to be essential for this ability. During learning these neurons become tuned to relevant features and start to represent them with persistent activity during memory delays. This learning process is not well understood. Here we develop a biologically plausible learning scheme that explains how trial-and-error learning induces neuronal selectivity and working memory representations for task-relevant information. We propose that the response selection stage sends attentional feedback signals to earlier processing levels, forming synaptic tags at those connections responsible for the stimulus-response mapping. Globally released neuromodulators then interact with tagged synapses to determine their plasticity. The resulting learning rule endows neural networks with the capacity to create new working memory representations of task relevant information as persistent activity. It is remarkably generic: it explains how association neurons learn to store task relevant information for linear as well as non-linear stimulus-response mappings, how they become tuned to category boundaries or analog variables, depending on the task demands, and how they learn to integrate probabilistic evidence for perceptual decisions. PMID- 25742012 TI - Enabling big geoscience data analytics with a cloud-based, MapReduce-enabled and service-oriented workflow framework. AB - Geoscience observations and model simulations are generating vast amounts of multi-dimensional data. Effectively analyzing these data are essential for geoscience studies. However, the tasks are challenging for geoscientists because processing the massive amount of data is both computing and data intensive in that data analytics requires complex procedures and multiple tools. To tackle these challenges, a scientific workflow framework is proposed for big geoscience data analytics. In this framework techniques are proposed by leveraging cloud computing, MapReduce, and Service Oriented Architecture (SOA). Specifically, HBase is adopted for storing and managing big geoscience data across distributed computers. MapReduce-based algorithm framework is developed to support parallel processing of geoscience data. And service-oriented workflow architecture is built for supporting on-demand complex data analytics in the cloud environment. A proof-of-concept prototype tests the performance of the framework. Results show that this innovative framework significantly improves the efficiency of big geoscience data analytics by reducing the data processing time as well as simplifying data analytical procedures for geoscientists. PMID- 25742010 TI - PKCeta/Rdx-driven phosphorylation of PDK1: a novel mechanism promoting cancer cell survival and permissiveness for parvovirus-induced lysis. AB - The intrinsic oncotropism and oncosuppressive activities of rodent protoparvoviruses (PVs) are opening new prospects for cancer virotherapy. Virus propagation, cytolytic activity, and spread are tightly connected to activation of the PDK1 signaling cascade, which delays stress-induced cell death and sustains functioning of the parvoviral protein NS1 through PKC(eta)-driven modifications. Here we reveal a new PV-induced intracellular loop-back mechanism whereby PKCeta/Rdx phosphorylates mouse PDK1:S138 and activates it independently of PI3-kinase signaling. The corresponding human PDK1phosphoS135 appears as a hallmark of highly aggressive brain tumors and may contribute to the very effective targeting of human gliomas by H-1PV. Strikingly, although H-1PV does not trigger PDK1 activation in normal human cells, such cells show enhanced viral DNA amplification and NS1-induced death upon expression of a constitutively active PDK1 mimicking PDK1phosphoS135. This modification thus appears as a marker of human glioma malignant progression and sensitivity to H-1PV-induced tumor cell killing. PMID- 25741996 TI - Let's Talk Critical. Development and Evaluation of a Communication Skills Training Program for Critical Care Fellows. AB - RATIONALE: Although expert communication between intensive care unit clinicians with patients or surrogates improves patient- and family-centered outcomes, fellows in critical care medicine do not feel adequately trained to conduct family meetings. OBJECTIVES: We aimed to develop, implement, and evaluate a communication skills program that could be easily integrated into a U.S. critical care fellowship. METHODS: We developed four simulation cases that provided communication challenges that critical care fellows commonly face. For each case, we developed a list of directly observable tasks that could be used by faculty to evaluate fellows during each simulation. We developed a didactic curriculum of lectures/case discussions on topics related to palliative care, end-of-life care, communication skills, and bioethics; this month-long curriculum began and ended with the fellows leading family meetings in up to two simulated cases with direct observation by faculty who were not blinded to the timing of the simulation. Our primary measures of effectiveness were the fellows' self-reported change in comfort with leading family meetings after the program was completed and the quality of the communication as measured by the faculty evaluators during the family meeting simulations at the end of the month. MEASUREMENTS AND MAIN RESULTS: Over 3 years, 31 critical care fellows participated in the program, 28 of whom participated in 101 family meeting simulations with direct feedback by faculty facilitators. Our trainees showed high rates of information disclosure during the simulated family meetings. During the simulations done at the end of the month compared with those done at the beginning, our fellows showed significantly improved rates in: (1) verbalizing an agenda for the meeting (64 vs. 41%; Chi-square, 5.27; P = 0.02), (2) summarizing what will be done for the patient (64 vs. 39%; Chi-square, 6.21; P = 0.01), and (3) providing a follow-up plan (60 vs. 37%; Chi-square, 5.2; P = 0.02). More than 95% of our participants (n = 27) reported feeling "slightly" or "much" more comfortable with discussing foregoing life-sustaining treatment and leading family discussions after the month-long curriculum. CONCLUSIONS: A communication skills program can be feasibly integrated into a critical care training program and is associated with improvements in fellows' skills and comfort with leading family meetings. PMID- 25742014 TI - Correction: Angiotensin II upregulates endothelial lipase expression via the NF kappa B and MAPK signaling pathways. PMID- 25742011 TI - Systematic artifacts in support vector regression-based compound potency prediction revealed by statistical and activity landscape analysis. AB - Support vector machines are a popular machine learning method for many classification tasks in biology and chemistry. In addition, the support vector regression (SVR) variant is widely used for numerical property predictions. In chemoinformatics and pharmaceutical research, SVR has become the probably most popular approach for modeling of non-linear structure-activity relationships (SARs) and predicting compound potency values. Herein, we have systematically generated and analyzed SVR prediction models for a variety of compound data sets with different SAR characteristics. Although these SVR models were accurate on the basis of global prediction statistics and not prone to overfitting, they were found to consistently mispredict highly potent compounds. Hence, in regions of local SAR discontinuity, SVR prediction models displayed clear limitations. Compared to observed activity landscapes of compound data sets, landscapes generated on the basis of SVR potency predictions were partly flattened and activity cliff information was lost. Taken together, these findings have implications for practical SVR applications. In particular, prospective SVR-based potency predictions should be considered with caution because artificially low predictions are very likely for highly potent candidate compounds, the most important prediction targets. PMID- 25742015 TI - Correction: Midazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis. PMID- 25742019 TI - Correction: The effectiveness of teleglaucoma versus in-patient examination for glaucoma screening: a systematic review and meta-analysis. PMID- 25742017 TI - Circulation of Crimean-Congo Hemorrhagic Fever Virus in the former Yugoslav Republic of Macedonia revealed by screening of cattle sera using a novel enzyme linked immunosorbent assay. AB - BACKGROUND: There are only few assays available for the detection of Crimean Congo Hemorrhagic Fever Virus (CCHFV)-specific antibodies in animals, and data about diagnostic sensitivity and specificity are incompletely documented for most of these tests. This is unfortunate since CCHFV antibodies in animals can be used as indicator for virus circulation in a geographic area and therewith potential risk of human exposure. This paper therefore reports on a novel ELISA for the detection of CCHFV-specific antibodies in cattle and on its application for testing ruminant sera from the Former Yugoslav Republic of Macedonia. PRINCIPAL FINDINGS: A highly sensitive and specific ELISA was developed to detect CCHFV specific IgG antibodies in cattle. The assay was validated by using 503 negative serum samples from a country where CCHFV has never been detected until now, and by using 54 positive serum samples. The positive sera were verified by using two commercially available assays (for testing human serum) which we have adapted for use in animals. The sensitivity of the novel ELISA was 98% and its specificity 99%. The presence of Hyalomma ticks was demonstrated in the Former Yugoslav Republic of Macedonia and depending on the region antibody prevalence rates up to 80% were detected in the cattle population. CONCLUSION: This article describes a fully validated, highly sensitive and specific ELISA for the detection of CCHFV specific IgG antibodies in cattle. Using this assay, CCHFV-specific antibodies were detected for the first time in cattle in the Former Yugoslav Republic of Macedonia, giving evidence for an active circulation of this virus in the country. Supporting this conclusion, the occurrence of the main vector of CCHFV was demonstrated in the present work for the first time in Former Yugoslav Republic of Macedonia. PMID- 25742013 TI - Progressive gender differences of structural brain networks in healthy adults: a longitudinal, diffusion tensor imaging study. AB - Sexual dimorphism in the brain maturation during childhood and adolescence has been repeatedly documented, which may underlie the differences in behaviors and cognitive performance. However, our understanding of how gender modulates the development of structural connectome in healthy adults is still not entirely clear. Here we utilized graph theoretical analysis of longitudinal diffusion tensor imaging data over a five-year period to investigate the progressive gender differences of brain network topology. The brain networks of both genders showed prominent economical "small-world" architecture (high local clustering and short paths between nodes). Additional analysis revealed a more economical "small world" architecture in females as well as a greater global efficiency in males regardless of scan time point. At the regional level, both increased and decreased efficiency were found across the cerebral cortex for both males and females, indicating a compensation mechanism of cortical network reorganization over time. Furthermore, we found that weighted clustering coefficient exhibited significant gender-time interactions, implying different development trends between males and females. Moreover, several specific brain regions (e.g., insula, superior temporal gyrus, cuneus, putamen, and parahippocampal gyrus) exhibited different development trajectories between males and females. Our findings further prove the presence of sexual dimorphism in brain structures that may underlie gender differences in behavioral and cognitive functioning. The sex specific progress trajectories in brain connectome revealed in this work provide an important foundation to delineate the gender related pathophysiological mechanisms in various neuropsychiatric disorders, which may potentially guide the development of sex-specific treatments for these devastating brain disorders. PMID- 25742020 TI - Trends and outcome from radical therapy for primary non-metastatic prostate cancer in a UK population. AB - BACKGROUND: Increasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed. PATIENT AND METHODS: Non-metastatic cancers diagnosed from 2000-2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755]. RESULTS: Over the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men >= 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9-22.2], p<0.0001] and use of RT [HR 1.9 [1.0-3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [<= 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort. CONCLUSION: This study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men. PMID- 25742024 TI - Unusual Temperature Dependence of Magnetization and Possible Magnetic Noncollinearity in Tm and Pr Clusters. AB - Rare-earth metals in their bulk form possess rather similar crystallographic structures, which is due to the very similar features of their outer electronic states. On the other hand, their magnetic properties are of rich variety, which is related to the specific form of the indirect magnetic exchange interaction between the inner electronic shells. In cluster form, this interplay may lead to very unusual magnetic structures. Here we show how the magnetic moments vary with size and temperature in Tm and Pr clusters. While in Pr clusters clear atom-by atom oscillations indicate antiferromagnetic ordering, smooth variation and anomalous temperature behavior in Tm is representative for an essentially non collinear spin arrangement. Their electric behavior is also very different, with a metallic-like behavior of Pr and localized electronic states in Tm. PMID- 25742018 TI - Fecal calprotectin concentrations in healthy children aged 1-18 months. AB - OBJECTIVE: Fecal calprotectin (FC) is an established biomarker of gut inflammation. The aim of this study was to evaluate FC concentrations in healthy children between 1 and 18 months of age. METHODS: Healthy children aged 1-18 months were enrolled in this study at the Department of Children's Health Care in Shanghai, China. Children's stool samples were collected and analyzed, and FC concentration was determined using a commercially available enzyme-linked immunosorbent assay (ELISA). The children's weights and lengths were measured. Parents were asked to complete a brief questionnaire regarding several clinical and sociodemographic factors. RESULTS: The FC concentrations were unevenly distributed; the median FC concentration was 174.3 MUg/g (range: 6.0-1097.7 MUg/g) or 2.241 log10 MUg/g (range: 0.775-3.041 log10 MUg/g) for all 288 children. The children were divided into several age groups: 1-3 months, 3-6 months, 6-9 months, 9-12 months and 12-18 months. The median FC concentrations for these age groups were 375.2 MUg/g (2.574 log10 MUg/g), 217.9 MUg/g (2.338 log10 MUg/g), 127.7 MUg/g (2.106 log10 MUg/g), 96.1 MUg/g (1.983 log10 MUg/g) and 104.2 MUg/g (2.016 log10 MUg/g), respectively. A significant correlation between age and FC concentration was found (r=-0.490, p<0.001). A simple correlation analysis of weight-for-length Z-scores or weight-for-age Z-scores vs. FC concentrations showed that these variables were negatively correlated (Spearman's rho=-0.287, p<0.001; Spearman's rho=-0.243, p<0.001, respectively). CONCLUSIONS: The FC levels of children aged 1-18 months exhibit a downward trend with increasing age and are greater than the normal levels observed in healthy adults. In healthy children aged <6 months, FC levels are high. In children aged 6-18 months, FC concentrations are relatively low but are still higher than those of children aged >4 years. PMID- 25742016 TI - Comparative genomics of Cluster O mycobacteriophages. AB - Mycobacteriophages--viruses of mycobacterial hosts--are genetically diverse but morphologically are all classified in the Caudovirales with double-stranded DNA and tails. We describe here a group of five closely related mycobacteriophages- Corndog, Catdawg, Dylan, Firecracker, and YungJamal--designated as Cluster O with long flexible tails but with unusual prolate capsids. Proteomic analysis of phage Corndog particles, Catdawg particles, and Corndog-infected cells confirms expression of half of the predicted gene products and indicates a non-canonical mechanism for translation of the Corndog tape measure protein. Bioinformatic analysis identifies 8-9 strongly predicted SigA promoters and all five Cluster O genomes contain more than 30 copies of a 17 bp repeat sequence with dyad symmetry located throughout the genomes. Comparison of the Cluster O phages provides insights into phage genome evolution including the processes of gene flux by horizontal genetic exchange. PMID- 25742021 TI - Identifying individual risk factors and documenting the pattern of heat-related illness through analyses of hospitalization and patterns of household cooling. AB - BACKGROUND: As climate change increases the frequency and intensity of extreme heat events researchers and public health officials must work towards understanding the causes and outcomes of heat-related morbidity and mortality. While there have been many studies on both heat-related illness (HRI), there are fewer on heat-related morbidity than on heat-related mortality. OBJECTIVE: To identify individual and environmental risk factors for hospitalizations and document patterns of household cooling. METHODS: We performed a pooled cross sectional analysis of secondary U.S. data, the Nationwide Inpatient Sample. Risk ratios were calculated from multivariable models to identify risk factors for hospitalizations. Hierarchical modeling was also employed to identify relationships between individual and hospital level predictors of hospitalizations. Patterns of air conditioning use were analyzed among the vulnerable populations identified. RESULTS: Hospitalizations due to HRI increased over the study period compared to all other hospitalizations. Populations at elevated risk for HRI hospitalization were blacks, males and all age groups above the age of 40. Those living in zip-codes in the lowest income quartile and the uninsured were also at an increased risk. Hospitalizations for HRI in rural and small urban clusters were elevated, compared to urban areas. CONCLUSIONS: Risk factors for HRI include age greater than 40, male gender and hospitalization in rural areas or small urban clusters. Our analysis also revealed an increasing pattern of HRI hospitalizations over time and decreased association between common comorbidities and heat illnesses which may be indicative of underreporting. PMID- 25742029 TI - Metal-free oxidative functionalization of a C(sp(3))-H bond adjacent to nitrogen and intramolecular aromatic cyclization for the preparation of 6 amidophenanthridines. AB - A metal-free cyclization reaction of 2-isocyanobiphenyls with amide derivatives by using tert-butyl peroxybenzoate (TBPB) as oxidant was developed, which provided an access to pharmacologically interesting 6-amidophenanthridine compounds. The reactions proceeded through a sequence of functionalization of the C(sp(3))-H bond adjacent to the nitrogen atom and intramolecular radical aromatic cyclization with good chemistry yields. PMID- 25742026 TI - Imidazolium-based zwitterionic surfactants: characterization of normal and reverse micelles and stabilization of nanoparticles. AB - This paper presents the physicochemical properties of micellar aggregates formed from a series of zwitterionic surfactants of the type 3-(1-alkyl-3 imidazolio)propane-sulfonate (ImS3-n), with n = 10, 12, 14, and 16. The ImS3-n dipolar ionic surfactants represent a versatile class of dipolar ionic compounds, which form normal and reverse micelles. Furthermore, they are able to stabilize nanoparticles in water and in organic media. Aqueous solubility is too low at room temperature to allow characterization of micellar aggregates but increases with addition of salts, allowing determination of aggregation number and cmc. As expected, these parameters depend on the length of the alkyl chain, and cmc values follow Klevens equation. In the presence of NaClO4, all ImS3-n micelles become anionoid by incorporating ClO4(-) on the micellar interface. A special feature of these surfactants is the ability to form reverse micelles and solubilize copious amounts of saline solutions in chloroform. (1)H NMR and infrared spectroscopic evidence showed that the maximum water to surfactant molar ratio w0 achievable depends on the concentration and type of salt dissolved. Reverse micelles of the ImS3-n surfactants can be used to stabilize metallic nanoparticles, whose size may be tuned by the amount of water dissolved. PMID- 25742023 TI - Trabeculectomy-related complications in Olmsted County, Minnesota, 1985 through 2010. AB - IMPORTANCE: Trabeculectomy is the surgical standard of care for patients with medically refractory glaucoma. The use of antimetabolite agents, such as mitomycin, has increased the rate of complications after trabeculectomy. OBJECTIVE: To determine the rate of trabeculectomy-related complications during a 25-year study. DESIGN, SETTING, AND PARTICIPANTS: For this retrospective, population-based study, we enrolled the residents of Olmsted County, Minnesota, who underwent a trabeculectomy from January 1, 1985, through December 31, 2010, at the Mayo Clinic and Olmsted Community Hospital. Data were collected from August 2012 to September 2013 followed by data analysis through January 2014. EXPOSURES: After reviewing the patient records, we determined the occurrence of complications, including bleb leak, hypotony, hyphema, choroidal effusion, choroidal hemorrhage, blebitis, and endophthalmitis, as they relate to the mitomycin concentration administered during the operation. We reviewed relevant publications in Ovid, MEDLINE, and PubMed to identify studies representative of the reported trabeculectomy complication rate. MAIN OUTCOMES AND MEASURES: Cumulative probabilities of short- and long-term complications, determined using the Kaplan-Meier method, and the relation to mitomycin concentration applied during trabeculectomy. RESULTS: In 334 patients, 460 eyes underwent trabeculectomy (mean [SD; range] follow-up, 7.7 [5.7; 0-27.7] years). Among them, 159 eyes had complications, with early complications (<3 months) in 100 eyes and late complications (>=3 months) in 59 eyes during the follow-up. Ten eyes had an early and a late complication. The 20-year cumulative chances of early, late, or any complication were 19.7% (95% CI, 16.2%-23.6%), 26.0% (95% CI, 15.0%-36.0%), and 45.0% (95% CI, 38.0%-52.0%), respectively. The cumulative probabilities of vision-threatening complications during 20 years were 2.0% (95% CI, 0%-4.0%) for blebitis and 5.0% (95% CI, 1.0%-9.0%) for endophthalmitis. Association between the rate of trabeculectomy complications and mitomycin dose used was P = .77. In total, 98 cases (21.3%) underwent further surgical procedures related directly to the complication. CONCLUSIONS AND RELEVANCE: The rate of trabeculectomy-related complications does not appear to be associated with mitomycin use during a mean follow-up of 7.7 years. The rate of vision-threatening complications appears to be comparable to those of previous studies of shorter duration. PMID- 25742028 TI - Single-step immobilization of cell adhesive peptides on a variety of biomaterial substrates via tyrosine oxidation with copper catalyst and hydrogen peroxide. AB - Immobilization of biologically active peptides which were isolated from extracellular matrix proteins is a powerful strategy for the design and functionalization of biomaterial substrates. However, the method of peptide immobilization was restricted, that is, peptide is often immobilized through the reactive groups inherent in substrates with multistep reactions. Here, we report a single-step immobilization of fibronectin-derived cell adhesive peptide (Arg Glu-Asp-Val; REDV) onto polymer materials by use of tyrosine oxidation with copper catalyst and hydrogen peroxide. REDV peptide was successfully immobilized on tissue culture polystyrene, poly(ethylene terephthalate), poly(vinyl chloride), expanded-poly(tetrafluoroethylene), and poly(l-lactic acid), resulting in enhanced adhesion of human umbilical vein endothelial cells. This method is a single-step reaction under very mild conditions and is available for the biological functionalization of various medical devices. PMID- 25742022 TI - The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis. AB - OBJECTIVE: This study aimed to determine whether inhaled prostaglandins are associated with improvement in pulmonary physiology or mortality in patients with ARDS and assess adverse effects. METHODS: The following data sources were used: PubMed, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, reference lists, conference proceedings, and ClinicalTrials.gov. Studies selected included randomized controlled trials and nonrandomized studies. For data extraction, two reviewers independently screened titles and abstracts for eligibility. With regard to data synthesis, 25 studies (two RCTs) published over 21 years (1993-2014) were included. The PROSPERO registration number was CRD42014013180. RESULTS: One randomized controlled trial showed no difference in the change in mean Pao2 to Fio2 ratio when comparing inhaled alprostadil to placebo: 141.2 (95% CI, 120.8-161.5) to 161.5 (95% CI, 134.6-188.3) vs 163.4 (95% CI, 140.8-186.0) to 186.8 (95% CI, 162.9-210.7), P = .21. Meta-analysis of the remaining studies demonstrated that inhaled prostaglandins were associated with improvement in Pao2 to Fio2 ratio (16 studies; 39.0% higher; 95% CI, 26.7%-51.3%), and Pao2 (eight studies; 21.4% higher; 95% CI, 12.2%-30.6%), and a decrease in pulmonary artery pressure (-4.8 mm Hg; 95% CI, -6.8 mm Hg to -2.8 mm Hg). Risk of bias and heterogeneity were high. Meta-regression found no association with publication year (P = .862), baseline oxygenation (P = .106), and ARDS etiology (P = .816) with the treatment effect. Hypotension occurred in 17.4% of patients in observational studies. CONCLUSIONS: In ARDS, inhaled prostaglandins improve oxygenation and decrease pulmonary artery pressures and may be associated with harm. Data are limited both in terms of methodologic quality and demonstration of clinical benefit. The use of inhaled prostaglandins in ARDS needs further study. PMID- 25742025 TI - Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy. AB - IMPORTANCE: Important differences exist in the pattern and timing of distant metastases between human papillomavirus-initiated (HPV+) and HPV- oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE: To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS: All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS: Thirty seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV- disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV- disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV- disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV- disease (HPV+ group, 23 of 28 patients [82%]; HPV- group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE: This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV- disease. Human papillomavirus-initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies. PMID- 25742027 TI - Genome-wide snapshot of chromatin regulators and states in Xenopus embryos by ChIP-Seq. AB - The recruitment of chromatin regulators and the assignment of chromatin states to specific genomic loci are pivotal to cell fate decisions and tissue and organ formation during development. Determining the locations and levels of such chromatin features in vivo will provide valuable information about the spatio temporal regulation of genomic elements, and will support aspirations to mimic embryonic tissue development in vitro. The most commonly used method for genome wide and high-resolution profiling is chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq). This protocol outlines how yolk-rich embryos such as those of the frog Xenopus can be processed for ChIP-Seq experiments, and it offers simple command lines for post-sequencing analysis. Because of the high efficiency with which the protocol extracts nuclei from formaldehyde-fixed tissue, the method allows easy upscaling to obtain enough ChIP material for genome-wide profiling. Our protocol has been used successfully to map various DNA-binding proteins such as transcription factors, signaling mediators, components of the transcription machinery, chromatin modifiers and post-translational histone modifications, and for this to be done at various stages of embryogenesis. Lastly, this protocol should be widely applicable to other model and non-model organisms as more and more genome assemblies become available. PMID- 25742030 TI - Functional evaluation of biological neurotoxins in networked cultures of stem cell-derived central nervous system neurons. AB - Therapeutic and mechanistic studies of the presynaptically targeted clostridial neurotoxins (CNTs) have been limited by the need for a scalable, cell-based model that produces functioning synapses and undergoes physiological responses to intoxication. Here we describe a simple and robust method to efficiently differentiate murine embryonic stem cells (ESCs) into defined lineages of synaptically active, networked neurons. Following an 8 day differentiation protocol, mouse embryonic stem cell-derived neurons (ESNs) rapidly express and compartmentalize neurotypic proteins, form neuronal morphologies and develop intrinsic electrical responses. By 18 days after differentiation (DIV 18), ESNs exhibit active glutamatergic and gamma-aminobutyric acid (GABA)ergic synapses and emergent network behaviors characterized by an excitatory:inhibitory balance. To determine whether intoxication with CNTs functionally antagonizes synaptic neurotransmission, thereby replicating the in vivo pathophysiology that is responsible for clinical manifestations of botulism or tetanus, whole-cell patch clamp electrophysiology was used to quantify spontaneous miniature excitatory post-synaptic currents (mEPSCs) in ESNs exposed to tetanus neurotoxin (TeNT) or botulinum neurotoxin (BoNT) serotypes /A-/G. In all cases, ESNs exhibited near complete loss of synaptic activity within 20 hr. Intoxicated neurons remained viable, as demonstrated by unchanged resting membrane potentials and intrinsic electrical responses. To further characterize the sensitivity of this approach, dose-dependent effects of intoxication on synaptic activity were measured 20 hr after addition of BoNT/A. Intoxication with 0.005 pM BoNT/A resulted in a significant decrement in mEPSCs, with a median inhibitory concentration (IC50) of 0.013 pM. Comparisons of median doses indicate that functional measurements of synaptic inhibition are faster, more specific and more sensitive than SNARE cleavage assays or the mouse lethality assay. These data validate the use of synaptically coupled, stem cell-derived neurons for the highly specific and sensitive detection of CNTs. PMID- 25742031 TI - Experimental glaucoma induced by ocular injection of magnetic microspheres. AB - Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present here a protocol for elevating intraocular pressure (IOP) in the rat, by injecting magnetic microspheres into the anterior chamber of the eye. The use of magnetic particles allows the user to manipulate the beads into the iridocorneal angle, thus providing a very effective blockade of fluid outflow from the trabecular meshwork. This leads to long-lasting IOP rises, and eventually neuronal death in the ganglion cell layer (GCL) as well as optic nerve pathology, as seen in patients with the disease. This method is simple to perform, as it does not require machinery, specialist surgical skills, or many hours of practice to perfect. Furthermore, the pressure elevations are very robust, and reinjection of the magnetic microspheres is not usually required unlike in some other models using plastic beads. Additionally, we believe this method is suitable for adaptation for the mouse eye. PMID- 25742032 TI - [Overcoming the limitations of the descriptive and categorical approaches in psychiatric diagnosis: a proposal based on Bayesian networks]. AB - Efforts to overcome the problems of descriptive and categorical approaches have not yielded results. In the present article, psychiatric diagnosis using Bayesian networks is proposed. Instead of a yes/no decision, Bayesian networks give the probability of diagnostic category inclusion, thereby yielding both a graded, i.e., dimensional diagnosis, and a value of the certainty of the diagnosis. With the use of Bayesian networks in the diagnosis of mental disorders, information about etiology, associated features, treatment outcome, and laboratory results may be used in addition to clinical signs and symptoms, with each of these factors contributing proportionally to their own specificity and sensitivity. Furthermore, a diagnosis (albeit one with a lower probability) can be made even with incomplete, uncertain, or partially erroneous information, and patients whose symptoms are below the diagnostic threshold can be evaluated. Lastly, there is no need of NOS or "unspecified" categories, and comorbid disorders become different dimensions of the diagnostic evaluation. Bayesian diagnoses allow the preservation of current categories and assessment methods, and may be used concurrently with criteria-based diagnoses. Users need not put in extra effort except to collect more comprehensive information. Unlike the Research Domain Criteria (RDoC) project, the Bayesian approach neither increases the diagnostic validity of existing categories nor explains the pathophysiological mechanisms of mental disorders. It, however, can be readily integrated to present classification systems. Therefore, the Bayesian approach may be an intermediate phase between criteria-based diagnosis and the RDoC ideal. PMID- 25742033 TI - [Clinical and cognitive predictors of psychosocial functioning during the euthymic period in bipolar disorder type II]. AB - AIM: Review of clinical and cognitive predictors of psychosocial functioning during the euthymic period in patients with bipolar disorder type II (BD II) was aimed in this paper. Psychosocial functioning status, clinical and cognitive predictors of psychosocial functioning and assessment of psychosocial functioning during the euthymic period in patients with BD-II were discussed. METHOD: Studies investigated psychosocial functioning and its clinical and cognitive predictors were reviewed. Studies conducted between 1990 and 2013 were scanned. RESULTS: It's been seen that there were limited studies investigating psychosocial functioning and predictors of psychosocial functioning. Findings from these limited studies indicated that patients with BD-II experienced psychosocial disability as much as BD-I did. It was reported that subclinical depressive symptoms and cognitive impairment were the prominent predictors of psychosocial functioning during the euthymic periods in patients with BD-II. CONCLUSION: There are limited studies conducted in euthymic BD-II patients. There are various findings among the studies. Nevertheless, subclinical depressive symptoms and cognitive impairments are the prominent predictors of psychosocial functioning in euthymic BD-II patients. However, follow-up and cross-sectional studies are needed in this area. PMID- 25742034 TI - [Relationships between well-being and social support: a meta analysis of studies conducted in Turkey]. AB - OBJECTIVE: The purpose of this study was to investigate overall relationships between well-being and social support through meta-analysis. Studies which investigated associations between social support and life satisfaction, subjective well-being, self-esteem, depression, loneliness were included in the meta-analysis. METHOD: By doing literature review to assess studies for potential inclusion; studies were included which met the inclusion criteria. Inclusion criteria were that studies must be conducted in Turkey and must report a correlation coefficient between study variables. Data were analyzed using a random effect model. RESULTS: It was found that there was a positive relationship between overall well-being and social support; level of social support was negatively correlated with depression and loneliness. For well-being variables, the mean effect size of perceived support from family and for depression/loneliness, the mean effect size of perceived support from friends were significantly stronger than other support sources. For both well-being variables and depression/loneliness variables, mean effect size of studies conducted with older people was significantly stronger than studies conducted with other age groups. Also, mean effect size of theses were significantly stronger than articles. CONCLUSION: The findings are expected to contribute to a better understanding of relationships between social support and well-being. PMID- 25742035 TI - [Eyes test performance among unaffected mothers of patients with schizophrenia]. AB - OBJECTIVE: Theory of Mind (ToM) deficit is a widely accepted feature of schizophrenia. A number of studies have examined ToM deficits of first degree relatives of schizophrenic patients as genetic markers of schizophrenia. Examination of mentalization capacity among mothers of schizophrenia patients may improve our understanding of theory of mind impairments in schizophrenia. The aim of this study is to use Reading Mind in the Eyes test to examine theory of mind capacity among mothers of schizophrenic patients. METHOD: Performance during the test "Reading the Mind in the Eyes" (Eyes Test) was compared between the mothers of schizophrenic patients (n=47) and mothers whose children have no psychotic mental illness (n=47). Test results were analyzed based on the categorization of test items as positive, negative, and neutral. RESULTS: Mothers of schizophrenic patients displayed poorer performance during the Eyes Test compare to mothers in the control group, particularly in the recognition of positive and neutral mental representations. There was no statistically significant difference in the recognition of negative mental representations between mothers of patients and the control groups. CONCLUSION: The results of this study indicate that mothers of schizophrenic patients differ in some theory of mind patterns. Theory of mind may be an important developmental or endophenotipic factor in the pathogenesis of schizophrenia and should be further evaluated using other biological markers. PMID- 25742036 TI - [The mediating role of early maladaptive schemas in the relationship between maternal rejection and psychological problems]. AB - OBJECTIVE: The aim of this study was to explore the mediating role of early maladaptive schemas (EMSs) in the relationship between perceived maternal rejection during childhood and current psychological problems, such as anxiety and depression, in Turkish university students. EMSs were categorized according to 3 schema domains; impaired limits-exaggerated standards, disconnection rejection, and impaired autonomy-other directedness. MATERIALS AND METHODS: The study included 266 undergraduate university students (188 female and 78 male) aged 18-27 years. All the participants were administered the Young Schema Questionnaire-Short Form 3 (YSQ-SF3), Trait Anxiety Inventory (STAI-T), Beck Depression Inventory (BDI), and Parental Acceptance-Rejection Questionnaire (Adult PARQ: Mother). RESULTS: Disconnection-rejection schema domain mediated the relationship between perceived maternal rejection during childhood and anxiety, but not depression. Furthermore, impaired autonomy-other directedness schema domain mediated the relationship between perceived maternal rejection, and both anxiety and depression. CONCLUSION: The present findings facilitate greater understanding of the possible mechanisms by which perceived maternal rejection during childhood might affect adult psychology. Furthermore, representations of the self that are internalized during childhood are centrally connected to psychological adjustment later in life; therefore, an understanding of these internalized representations may be important for developing targeted interventions and prevention strategies for those that have experienced maternal rejection. PMID- 25742037 TI - [Validation of the World Health Organization-5 Well-Being Index; assessment of maternal well-being and its associated factors]. AB - OBJECTIVE: The aim of this study was to validate the World Health Organization-5 Well-Being Index (WHO-5) in a sample of pregnant Iranian women, to explore the changes in maternal well-being from pregnancy to postpartum, and to determine the factors associated with maternal well-being. MATERIALS AND METHODS: This study included 341 pregnant women that presented to healthcare centers affiliated with Shahroud University of Medical Sciences, Iran, in 2011. The participants completed the General Health Questionnaire (GHQ-28) and Farsi version of WHO-5 during the third trimester of pregnancy and at 2 months postpartum. RESULTS: Cronbach's alpha coefficient for WHO-5 items was 0.85. The correlation coefficient between WHO-5 and GHQ-28 was -0.64 (P < 0.001). Exploratory factor analysis yielded 1 factor with an eigen value equal to 3.15, which explained 63.1% of the total variance. Confirmatory factor analysis confirmed the 1-factor structure. The area under ROC curve was 0.82. A WHO-5 cut-off score of <50 exhibited optimal sensitivity (0.84) and specificity (0.59) for identifying psychological symptoms (GHQ-28 score >=24). There was a significant difference between third trimester (58.4 +/- 22) and postpartum (64.1 +/- 22.3) mean WHO-5 scores (P < 0.001). Maternal level of education (OR = 1.130; 95% CI: 1.307, 1.232) was the only predictor of maternal well-being during third trimester. Breastfeeding difficulty (OR = 0.923; 95% CI: 0.882, 0.965) and maternal well being scores during third trimester (OR = 1.038; 95% CI: 1.019, 1.058) were predictors of maternal well-being during the postpartum period. CONCLUSIONS: The Farsi version of WHO-5 was observed to be a reliable and valid instrument for screening psychological symptoms in pregnant Iranian women. The present findings show that maternal well-being improved following childbirth. PMID- 25742038 TI - [The validity and reliability of the Social Communication Questionnaire- Turkish form in autistics aged 4-18 years]. AB - OBJECTIVE: The Social Communication Questionnaire (SCQ) is a valid and reliable 40- item scale used to assess of pervasive developmental disorders (PDDs). The aim of this study was to determine the validity and reliability of the SCQ Turkish Form (SCQ-TF). MATERIALS AND METHODS: The study included 100 children and adolescents aged 4-18 years 50 were diagnosed as PDD and 50 were diagnosed with intellectual disability (ID) based on DSM-IV-TR criteria. The consistency, test retest reliability, content validity, and discriminant validity of SCQ-TF for the groups in the study sample were evaluated. SCQ-TF was compared to the Childhood Autism Rating Scale (CARS), Autism Behavioural Checklist (ABC), and Clinical Global Impression Severity of Illness (CGI-SI). The most appropriate SCQ-TF cut off point was determined via ROC analysis. RESULTS: The 4-factor structure of SCQ TF accounted for 43% of the observed total variance. Correlations between the Social Communication Questionnaire -Turkish Form and the other measures were significant. The Cronbach's alpha value for the SCQ-TF total score was 0.80. Intraclass correlation coefficient (ICC) varied between 0.87 and 0.96, and the cut-off point was 15. CONCLUSION: The findings show that SCQ-TF is valid and reliable for use in Turkey in those aged 4-18 years. PMID- 25742039 TI - [Differential diagnosis between Schizotypal Personality Disorder and Autism Spectrum Disorders: a case report]. AB - Schizotypal personality disorder is characterized by social and interpersonal deficits marked by discomfort with, and reduced capacity for, close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior. Inappropriate or constricted affect, reduced capacity for relationships, lack of close friends and reduced capacity for social life are the symptoms that overlap both schizotypal personality disorder and autism spectrum disorders. The making of differential diagnosis may be difficult since several symptoms are similar between these disorders. In this study, we discussed the differential diagnosis issues on the basis of an adolescent case. Odd appearance, magical thoughts, reference thoughts suggests Schizotypal Personality Disorder whereas lack of eye contact at 2 years old, a preference to be isolated and play alone and referral to a child psychiatrist at 4 years old suggest Autism Spectrum Disorders. Based on the results of psychological assessment, Wechsler Intelligence Scale for Children-Revised (WISC-R) profile is compatible with autistic children's profiles. Based on Schizotypal Personality Questionnaire, the patient's anxiety, lack of close friends, constricted affect symptoms which take place in the category of interpersonal schizotypy seems to overlap with lack of communication of Autism Spectrum Disorders. This case report indicates that, separation of autism and schizophrenia, a very important historical breakthrough in autism research, may be blurred in cases with less typical clinical pictures representing autistic and schizophrenic "spectrum" diagnosis. PMID- 25742040 TI - [Anxiety disorder due to epilepsy: a case report]. AB - Epileptic patients present with psychiatric disorders more frequently than the general population and patients with other chronic medical conditions. Psychiatric disorders can co-occur with epilepsy and can be caused by epilepsy. Personality changes, as well as psychosis, and mood or anxiety disorders can occur in association with epilepsy. Anxiety disorders due to epilepsy can manifest as generalized anxiety disorder, panic disorder, phobias, or obsessive compulsive disorder. The risk of an anxiety disorder is higher in patients with focal epilepsy, especially those with temporal lobe epilepsy, but an anxiety disorder can also occur in patients with frontal lobe epilepsy or generalized tonic-clonic epilepsy. Herein we present a 41-year-old female patient with comorbid anxiety disorder and epilepsy that improved following initiation of antiepileptic medication. The patient's EEG showed abnormalities, particularly in the frontal lobe. Epileptic activation-associated anxiety disorder presented as phobia of swallowing and the patient exhibited features of generalized anxiety disorder. Following initiation of antiepileptic medication, the seizures stopped and the symptoms of anxiety disappeared in two weeks. The patient was receiving psychotherapy once every 2 weeks. The patient remained asymptomatic during 2 years of follow-up. This case highlights the importance of differential diagnosis of underlying epilepsy in patients with acute severe anxiety and the efficacy of proper medical treatment, which was given in the presented case for the underling pathology of anxiety. PMID- 25742041 TI - [Editorial]. PMID- 25742042 TI - Associations between yogurt, dairy, calcium, and vitamin D intake and obesity among U.S. children aged 8-18 years: NHANES, 2005-2008. AB - The aim of this study was to investigate associations of yogurt and dairy consumption with energy, macronutrient, calcium, and vitamin D intakes, and associations with indicators of overweight/obesity in U.S. children in the National Health and Nutrition Examination Survey (NHANES 2005-2008). Using 24 hour recall data, children 8-18 years of age were classified to dairy consumption groups of <1, 1 to <2, or 2+ dairy servings, and yogurt consumers were those who reported eating yogurt during at least one of two dietary intake interviews. NHANES anthropometric measurements were used, and BMI and BMI-for-age percentiles were calculated. Yogurt and dairy consumption were associated with higher intakes of calcium, vitamin D and protein. Yogurt intake was associated with lower total fat and saturated fat intakes and body fat as measured by subscapular skinfold thickness. This study supports consumption of yogurt and higher amounts of dairy as eating patterns associated with greater intake of specific shortfall nutrients, and lower body fat in U.S. children. PMID- 25742044 TI - Purification, characterization and in vitro application of a thermostable oxidant and SDS-stable uricase from a newly isolated Bacillus firmus DWD-33. AB - A thermostable oxidant- and SDS-stable uricase was produced from a newly isolated B. firmus DWD-33. Maximum enzyme productivity was obtained in medium containing 0.8% maltose and 1.2% soybean powder as carbon and nitrogen sources, respectively. Enzyme purification increased the specific activity to 24-fold with 27% recovery and molecular weight of 33.5 kDa. As compared with other microbial uricases, the pure enzyme showed high thermostability and other unique characters. The Vmax was 387 uM/min, the turnover number (Kcat) was 21.8*103 s-1 and the catalytic efficiency (Kcat /Km) was 2.76*108 s-1M-1. The enzyme was stable at pH 7.0-10.0 and up to 70 oC. The optimal reaction temperature and pH of enzyme were 50 oC and pH 8.0, respectively. Mg2+ significantly enhanced the enzymatic activity, while Hg2+, EDTA and o-phenanthroline greatly suppressed the activity. Mg2+ might be the uricase cofactor as the enzyme activity was restored after its addition to EDTA-chelated enzyme. The enzyme inhibition by the copper chelating agent 2,9-dimethyl-1,10-phenanthroline suggests that this enzyme is a cuprouricase-type. The purified uricase retained 72 and 82% of its original activity even after incubation with 0.5% H2O2 and 0.5% SDS for 6 h, respectively. The application of enzyme in the in vitro measurement of uric acid in human sera was promising and none of uric acid analogs was a competitive substrate for enzyme, indicative of the high specificity of uricase with respect to uric acid measurement in vitro. The reaction can be applied in clinical laboratory for 10 min only due to the absorbances are lineary related to uric acid concentration up to 500 uM. PMID- 25742043 TI - Two-photon imaging of cellular dynamics in the mouse spinal cord. AB - Two-photon (2P) microscopy is utilized to reveal cellular dynamics and interactions deep within living, intact tissues. Here, we present a method for live-cell imaging in the murine spinal cord. This technique is uniquely suited to analyze neural precursor cell (NPC) dynamics following transplantation into spinal cords undergoing neuroinflammatory demyelinating disorders. NPCs migrate to sites of axonal damage, proliferate, differentiate into oligodendrocytes, and participate in direct remyelination. NPCs are thereby a promising therapeutic treatment to ameliorate chronic demyelinating diseases. Because transplanted NPCs migrate to the damaged areas on the ventral side of the spinal cord, traditional intravital 2P imaging is impossible, and only information on static interactions was previously available using histochemical staining approaches. Although this method was generated to image transplanted NPCs in the ventral spinal cord, it can be applied to numerous studies of transplanted and endogenous cells throughout the entire spinal cord. In this article, we demonstrate the preparation and imaging of a spinal cord with enhanced yellow fluorescent protein expressing axons and enhanced green fluorescent protein-expressing transplanted NPCs. PMID- 25742045 TI - Location of Ge and extra-framework species in the zeolite ITQ-24. AB - The germanosilicate ITQ-24 (IWR framework type) was synthesized in fluoride medium using 1,3,5-tris(1,2-dimethylimidazolium) benzene as the structure directing agent (SDA). A structure analysis of the as-synthesized ITQ-24 material using synchrotron powder diffraction data and difference electron density calculations have allowed the fluoride ions and the germanium atoms to be located and the conformation of the SDA to be determined. The benzyl ring is perpendicular to the b axis with the three imidazolium moieties forming a "T shaped" arrangement. Ge atoms replace some of the Si in the double-4-ring (d4r) and in one of the single-4-rings (s4r). The other s4r contains only Si. Fluoride ions are in the d4r units. Initially, the space group Cmmm (highest possible symmetry) was assumed, but the framework geometry was strained. An independent evaluation of the symmetry using the powder charge flipping algorithm in Superflip led to a successful refinement with reasonable geometry and a refined composition of |[(C6H3)(C7H10N2)3]2F2|[Si(40.2)Ge(15.8)O112] in the space group Pban. PMID- 25742046 TI - Exposing the intermolecular nature of the second relaxation pathway in a mononuclear cobalt(II) single-molecule magnet with positive anisotropy. AB - The investigation of a pentagonal bipyramidal Co(ii) complex with large positive anisotropy (D ~ +30 cm(-1)) revealed field induced Single-Molecule Magnet behaviour with Ueff ~ 50 K at 1.0 kOe. This compound belongs to a group of only a handful of complexes which exhibit this unique magnetic property while possessing easy-plane anisotropy. At high applied fields, a second relaxation process with an intermolecular nature has been exposed using magnetic dilution studies with varying percentages of Zn(ii) analogue. The disappearance of the second relaxation process at low frequency can be followed using magnetically diluted samples at 25%, 10% and 5% Co(ii) concentrations. PMID- 25742047 TI - Duplex DNA and DNA-RNA hybrids with parallel strand orientation: 2'-deoxy-2' fluoroisocytidine, 2'-deoxy-2'-fluoroisoguanosine, and canonical nucleosides with 2'-fluoro substituents cause unexpected changes on the double helix stability. AB - Oligonucleotides with parallel or antiparallel strand orientation incorporating 2'-fluorinated 2'-deoxyribonucleosides with canonical nucleobases or 2'-deoxy-2' fluoroisocytidine ((F)iCd, 1c) and 2'-deoxy-2'-fluoroisoguanosine ((F)iGd, 3c) were synthesized. To this end, the nucleosides 1c and 3c as well as the phosphoramidite building blocks 19 and 23 were prepared and employed in solid phase oligonucleotide synthesis. Unexpectedly, (F)iCd is not stable during oligonucleotide deprotection (55 degrees C, aq NH3) and was converted to a cyclonucleoside (14). Side product formation was circumvented when oligonucleotides were deprotected under mild conditions (aq ammonia-EtOH, rt). Oligonucleotides containing 2'-fluoro substituents ((F)iCd, (F)iGd and fluorinated canonical 2'-deoxyribonucleosides) stabilize double-stranded DNA, RNA, and DNA-RNA hybrids with antiparallel strand orientation. Unexpected strong stability changes are observed for oligonucleotide duplexes with parallel chains. While fluorinated oligonucleotides form moderately stable parallel stranded duplexes with complementary DNA, they do not form stable hybrids with RNA. Furthermore, oligoribonucleotide duplexes with parallel strand orientation are extremely unstable. It is anticipated that nucleic acids with parallel chains might be too rigid to accept sugar residues in the N-conformation as observed for ribonucleosides or 2'-deoxy-2'-fluororibonucleosides. These observations might explain why nature has evolved the principle of antiparallel chain orientation and has not used the parallel chain alignment. PMID- 25742049 TI - CO2 adsorption on amine-functionalized periodic mesoporous benzenesilicas. AB - CO2 adsorption was investigated on amine-functionalized mesoporous silica (SBA 15) and periodic mesoporous organosilica (PMO) samples. Hexagonally (p6mm) ordered mesoporous SBA-15 and benzene-PMO (BPMO) samples were prepared in the presence of Pluronic P123 block copolymer template under acidic conditions. Three kinds of amine-containing organosilanes and polyethylenimine were used to functionalize SBA-15 and BPMO. Small-angle X-ray scattering and nitrogen adsorption isotherms showed that these samples featured ordered mesostructure, high surface area, and narrow pore size distributions. Solid-state (13)C- and (29)Si cross-polarization magic-angle spinning NMR spectra showed chemical linkage between amine-containing modifiers and the surface of mesoporous materials. The chemically linked amine-containing modifiers were found to be on both the inner and outer surfaces. N-[3-(trimethoxysilyl)propyl]ethylenediamine modified BPMO (A2-BPMO) sample exhibited the highest CO2 uptake (i.e., ~3.03 mmol/g measured on a volumetric adsorption analyzer) and the fastest adsorption rate (i.e., ~13 min to attain 90% of the maximum amount) among all the samples studied. Selectivity and reproducibility measurements for the A2-BPMO sample showed quite good performance in flowing N2 gas at 40 mL/min and CO2 gas of 60 mL/min at 25 degrees C. PMID- 25742048 TI - Construct validity and minimal important difference of 6-minute walk distance in survivors of acute respiratory failure. AB - OBJECTIVE: The 6-min walk distance (6MWD), a widely used test of functional capacity, has limited evidence of construct validity among patients surviving acute respiratory failure (ARF) and ARDS. The objective of this study was to examine construct validity and responsiveness and estimate minimal important difference (MID) for the 6MWD in patients surviving ARF/ARDS. METHODS: For this secondary data analysis of four international studies of adult patients surviving ARF/ARDS (N = 641), convergent and discriminant validity, known group validity, predictive validity, and responsiveness were assessed. MID was examined using anchor- and distribution-based approaches. Analyses were performed within studies and at various time points after hospital discharge to examine generalizability of findings. RESULTS: The 6MWD demonstrated good convergent and discriminant validity, with moderate to strong correlations with physical health measures (|r| = 0.36-0.76) and weaker correlations with mental health measures (|r| = 0.03 0.45). Known-groups validity was demonstrated by differences in 6MWD between groups with differing muscle strength and pulmonary function (all P < .01). Patients reporting improved function walked farther, supporting responsiveness. 6MWD also predicted multiple outcomes, including future mortality, hospitalization, and health-related quality of life. The 6MWD MID, a small but consistent patient-perceivable effect, was 20 to 30 m. Findings were similar for 6MWD % predicted, with an MID of 3% to 5%. CONCLUSIONS: In patients surviving ARF/ARDS, the 6MWD is a valid and responsive measure of functional capacity. The MID will facilitate planning and interpretation of future group comparison studies in this population. PMID- 25742051 TI - A stereological analysis of NPY, POMC, Orexin, GFAP astrocyte, and Iba1 microglia cell number and volume in diet-induced obese male mice. AB - The hypothalamic arcuate nucleus (ARC) contains 2 key neural populations, neuropeptide Y (NPY) and proopiomelanocortin (POMC), and, together with orexin neurons in the lateral hypothalamus, plays an integral role in energy homeostasis. However, no studies have examined total neuronal number and volume after high-fat diet (HFD) exposure using sophisticated stereology. We used design based stereology to estimate NPY and POMC neuronal number and volume, as well as glial fibrillary acidic protein (astrocyte marker) and ionized calcium-binding adapter molecule 1 (microglia marker) cell number in the ARC; as well as orexin neurons in the lateral hypothalamus. Stereological analysis indicated approximately 8000 NPY and approximately 9000 POMC neurons in the ARC, and approximately 7500 orexin neurons in the lateral hypothalamus. HFD exposure did not affect total neuronal number in any population. However, HFD significantly increased average NPY cell volume and affected NPY and POMC cell volume distribution. HFD reduced orexin cell volume but had a bimodal effect on volume distribution with increased cells at relatively small volumes and decreased cells with relatively large volumes. ARC glial fibrillary acidic protein cells increased after 2 months on a HFD, although no significant difference after 6 months on chow diet or HFD was observed. No differences in ARC ionized calcium binding adapter molecule 1 cell number were observed in any group. Thus, HFD affects ARC NPY or POMC neuronal cell volume number not cell number. Our results demonstrate the importance of stereology to perform robust unbiased analysis of cell number and volume. These data should be an empirical baseline reference to which future studies are compared. PMID- 25742050 TI - Strategies for tracking anastasis, a cell survival phenomenon that reverses apoptosis. AB - Anastasis (Greek for "rising to life") refers to the recovery of dying cells. Before these cells recover, they have passed through important checkpoints of apoptosis, including mitochondrial fragmentation, release of mitochondrial cytochrome c into the cytosol, activation of caspases, chromatin condensation, DNA damage, nuclear fragmentation, plasma membrane blebbing, cell shrinkage, cell surface exposure of phosphatidylserine, and formation of apoptotic bodies. Anastasis can occur when apoptotic stimuli are removed prior to death, thereby allowing dying cells to reverse apoptosis and potentially other death mechanisms. Therefore, anastasis appears to involve physiological healing processes that could also sustain damaged cells inappropriately. The functions and mechanisms of anastasis are still unclear, hampered in part by the limited tools for detecting past events after the recovery of apparently healthy cells. Strategies to detect anastasis will enable studies of the physiological mechanisms, the hazards of undead cells in disease pathology, and potential therapeutics to modulate anastasis. Here, we describe effective strategies using live cell microscopy and a mammalian caspase biosensor for identifying and tracking anastasis in mammalian cells. PMID- 25742052 TI - Iodoarene-catalyzed cyclizations of unsaturated amides. AB - The cyclization of N-alkenylamides catalyzed by iodoarenes under oxidative conditions is presented. Five-, six-, and seven-membered rings with a range of substitutions can be prepared by this route. Preliminary data from the use of chiral iodoarenes as precatalysts show that enantiocontrol is feasible. PMID- 25742053 TI - Using cell-substrate impedance and live cell imaging to measure real-time changes in cellular adhesion and de-adhesion induced by matrix modification. AB - Cell-matrix adhesion plays a key role in controlling cell morphology and signaling. Stimuli that disrupt cell-matrix adhesion (e.g., myeloperoxidase and other matrix-modifying oxidants/enzymes released during inflammation) are implicated in triggering pathological changes in cellular function, phenotype and viability in a number of diseases. Here, we describe how cell-substrate impedance and live cell imaging approaches can be readily employed to accurately quantify real-time changes in cell adhesion and de-adhesion induced by matrix modification (using endothelial cells and myeloperoxidase as a pathophysiological matrix modifying stimulus) with high temporal resolution and in a non-invasive manner. The xCELLigence cell-substrate impedance system continuously quantifies the area of cell-matrix adhesion by measuring the electrical impedance at the cell substrate interface in cells grown on gold microelectrode arrays. Image analysis of time-lapse differential interference contrast movies quantifies changes in the projected area of individual cells over time, representing changes in the area of cell-matrix contact. Both techniques accurately quantify rapid changes to cellular adhesion and de-adhesion processes. Cell-substrate impedance on microelectrode biosensor arrays provides a platform for robust, high-throughput measurements. Live cell imaging analyses provide additional detail regarding the nature and dynamics of the morphological changes quantified by cell-substrate impedance measurements. These complementary approaches provide valuable new insights into how myeloperoxidase-catalyzed oxidative modification of subcellular extracellular matrix components triggers rapid changes in cell adhesion, morphology and signaling in endothelial cells. These approaches are also applicable for studying cellular adhesion dynamics in response to other matrix modifying stimuli and in related adherent cells (e.g., epithelial cells). PMID- 25742054 TI - Trauma history in African-American women living with HIV: effects on psychiatric symptom severity and religious coping. AB - Women living with HIV (WLHIV) have rates of post-traumatic stress disorder (PTSD) up to 5 times higher than the general population. Individuals living with HIV and a concurrent diagnosis of PTSD have poorer HIV-related outcomes; however, the prevalence and impact of PTSD on African-American WLHIV seeking mental health treatment is unknown. The aim of this study is to examine the associations between PTSD symptoms with psychiatric symptom severity and psychological/religious coping strategies in African-American WLHIV who are seeking mental health treatment. This is a cross-sectional study of 235 African American WLHIV attending an urban community mental health clinic. Bivariate analyses were conducted to evaluate associations between a PTSD symptoms scale (PSS>=21 versus PSS<21) and (1) psychiatric severity, (2) coping strategies, and (3) religious coping strategies. Thirty-six percent reported symptoms consistent with PTSD (PSS>=21). These women were significantly more likely to have worse mental health symptoms and were more likely to employ negative psychological and religious coping strategies. On the contrary, women with a PSS<21 reported relatively low levels of mental health symptoms and were more likely to rely on positive psychological and religious coping strategies. Over one-third of African American WLHIV attending an outpatient mental health clinic had symptoms associated with PTSD. These symptoms were associated with worse mental health symptoms and utilization of dysfunctional religious and nonreligious coping strategies. Untreated PTSD in WLHIV predicts poorer HIV-related health outcomes and may negatively impact comorbid mental health outcomes. Screening for PTSD in WLHIV could identify a subset that would benefit from evidence-based PTSD specific therapies in addition to mental health interventions already in place. PTSD-specific interventions for WLHIV with PTSD may improve outcomes, improve coping strategies, and allow for more effective treatment of comorbid mental health disorders. PMID- 25742055 TI - Experimental Infection of the Mayan Cichlid Cichlasoma urophthalmus with the Oomycete Aphanomyces invadans. AB - This study aimed to determine the susceptibility of the Mayan cichlid Cichlasoma urophthalmus to infection with the fungus Aphanomyces invadans (also known as epizootic ulcerative syndrome [EUS]). A total of 27 C. urophthalmus were exposed to the original A. Invadans 2006/86/EC strain by intramuscularly injecting the fish with 25,000 zoospores/ml or exposing the fish to a suspension of 25,000 zoospores/ml in 6-L aquaria for 30 days. To assess the infectious capacity of A. invadans, 3 golden barbs (Puntius semifasciolatus) were infected intramuscularly with 200,000 zoospores/ml. A second experiment using 100 C. urophthalmus was performed for 60 days with 50 fish in each treatment group. A polymerase chain reaction (PCR)-based diagnostic method was used; muscle and gills were the target tissues. In the first experiment, none of the exposed C. urophthalmus developed skin lesions related to A. invadans infection. However, PCR analysis revealed that infection had occurred. For the intramuscular treatment, there were significant differences between the controls and the muscle samples (Fisher's exact test; P < 0.05) but not between the controls and the gill samples (P > 0.05). All golden barbs became infected, as indicated by PCR, and developed skin lesions typical of A. invadans infection. We concluded that C. urophthalmus was infected with A. invadans but was an asymptomatic carrier because skin lesions did not develop. In the second experiment, all fish were negative, suggesting that the fish had cleared the infection by the end of the experiment. PMID- 25742057 TI - Pick-up and drop transfer of diamond nanosheets. AB - Nanocrystalline diamond (NCD) is a promising material for electronic and mechanical micro- and nanodevices. Here we introduce a versatile pick-up and drop technique that makes it possible to investigate the electrical, optical and mechanical properties of as-grown NCD films. Using this technique, NCD nanosheets, as thin as 55 nm, can be picked-up from a growth substrate and positioned on another substrate. As a proof of concept, electronic devices and mechanical resonators are fabricated and their properties are characterized. In addition, the versatility of the method is further explored by transferring NCD nanosheets onto an optical fiber, which allows measuring its optical absorption. Finally, we show that NCD nanosheets can also be transferred onto two-dimensional crystals, such as MoS2, to fabricate heterostructures. Pick-up and drop transfer enables the fabrication of a variety of NCD-based devices without requiring lithography or wet processing. PMID- 25742056 TI - Prenatal and Postnatal Exposure to Persistent Organic Pollutants and Infant Growth: A Pooled Analysis of Seven European Birth Cohorts. AB - BACKGROUND: Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects. OBJECTIVES: We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). METHODS: We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure. RESULTS: We found a significant increase in growth associated with p,p' DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted beta = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (beta = -0.10; 95% CI: 0.19, -0.01). CONCLUSION: To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p'-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels. PMID- 25742058 TI - Isolated extraocular muscle infiltration with plasmacytoma treated with localized injection of dexamethasone. AB - Plasmacytoma of the orbit secondary to multiple myeloma is rare and has not previously been reported limited to an extraocular muscle. Conventional treatment is either localized radiotherapy or systemic chemotherapy. We report a case of plasmacytoma within the medial rectus muscle, which regressed completely with localized infiltration of dexamethasone. PMID- 25742059 TI - Adding Vision to Concussion Testing: A Prospective Study of Sideline Testing in Youth and Collegiate Athletes. AB - BACKGROUND: Sports-related concussion commonly affects the visual pathways. Current sideline protocols test cognition and balance but do not include assessments of visual performance. We investigated how adding a vision-based test of rapid number naming could increase our ability to identify concussed athletes on the sideline at youth and collegiate levels. METHODS: Participants in this prospective study included members of a youth ice hockey and lacrosse league and collegiate athletes from New York University and Long Island University. Athletes underwent preseason baseline assessments using: 1) the King-Devick (K-D) test, a <2-minute visual performance measure of rapid number naming, 2) the Standardized Assessment of Concussion (SAC), a test of cognition, and 3) a timed tandem gait test of balance. The SAC and timed tandem gait are components of the currently used Sport Concussion Assessment Tool, 3rd Edition (SCAT3 and Child-SCAT3). In the event of a concussion during the athletic season, injured athletes were retested on the sideline/rink-side. Nonconcussed athletes were also assessed as control participants under the same testing conditions. RESULTS: Among 243 youth (mean age 11 +/- 3 years, range 5-17) and 89 collegiate athletes (age 20 +/- 1 years, range 18-23), baseline time scores for the K-D test were lower (better) with increasing participant age (P < 0.001, linear regression models). Among 12 athletes who sustained concussions during their athletic season, K-D scores worsened from baseline by an average of 5.2 seconds; improvement by 6.4 seconds was noted for the nonconcussed controls (n = 14). The vision-based K-D test showed the greatest capacity to distinguish concussed vs control athletes based on changes from preseason baseline to postinjury (receiver operating characteristic [ROC] curve areas from logistic regression models, accounting for age = 0.92 for K-D, 0.87 for timed tandem gait, and 0.68 for SAC; P = 0.0004 for comparison of ROC curve areas). CONCLUSIONS: Adding a vision-based performance measure to cognitive and balance testing enhances the detection capabilities of current sideline concussion assessment. This observation in patients with mild traumatic brain injury reflects the common involvement and widespread distribution of brain pathways dedicated to vision. PMID- 25742060 TI - Retinal atrophy in eyes with resolved papilledema detected by optical coherence tomography. AB - BACKGROUND: To apply automated spectral domain optical coherence tomography (SD OCT) segmentation to eyes with resolving papilledema. METHODS: Ninety-four patients with idiopathic intracranial hypertension seen at the Duke Eye Center neuro-ophthalmology clinic between November 2010 and October 2011 were reviewed. Excluded were eyes with papilledema with Frisen grade >2, other optic neuropathies or retinopathies, and those that did not have SD-OCT imaging. The remaining 43 patients were split into 2 groups: non-atrophic papilledema and atrophic papilledema. Automated SD-OCT segmentation was performed on patients with non-atrophic papilledema and age-matched controls for each of the 9 regions of the Early Treatment Diabetic Retinopathy Study map. Bonferroni correction was used for multiple comparisons. All SD-OCT scans were reviewed for retinal structural abnormalities. RESULTS: Total macular thickness was significantly thinner within the fovea and inner macular ring in non-atrophic papilledema vs control eyes (266 vs 276 MUm, P = 0.04; 333 vs 344 MUm P < 0.01, n = 26 non atrophic papilledema, 30 controls). SD-OCT demonstrated thinning within the fovea, inner macular ring, and outer macular ring of the outer plexiform layer plus nuclear layer in non-atrophic papilledema vs control (124 vs 131 MUm, P < 0.01; 112 vs 118 MUm, P = 0.03; 95 vs 100 MUm, P = 0.03). Retinal structural changes were seen in 21/33 eyes with atrophic papilledema vs none of the eyes with non-atrophic papilledema or controls. CONCLUSIONS: SD-OCT shows qualitative and quantitative changes in the macula of eyes with resolved papilledema. PMID- 25742061 TI - Bilateral Intracranial Optic Nerve and Chiasmal Involvement in IgG4-Related Disease. PMID- 25742062 TI - Medication Review and Patient Outcomes in an Orthopedic Department: A Randomized Controlled Study. AB - OBJECTIVE: We investigated the health-related effect of systematic medication review performed by a clinical pharmacist and a clinical pharmacologist on nonelective elderly orthopedic patients. METHODS: This is a nonblinded randomized controlled study of 108 patients 65 years or older treated with at least 4 drugs. For the intervention, the clinical pharmacist reviewed the participants' medication after completion of the usual medication routine. Information was collected from medical charts, interviews with participants, and database registrations of drug purchase. Results were conferred with the clinical pharmacologist, and recommendations were delivered directly to the ward physicians. The control was usual medication routine, that is, physicians prescribing admitting orders. The primary outcome was time to the first unplanned contact to a physician after discharge (i.e., general practitioner, emergency department visit, or readmission) during 3-month follow-up. Secondary outcomes included other health-related outcomes, for example, length of in-hospital stay, mortality, and quality of life. RESULTS: Time to the first unplanned contact to a physician was 14.9 days (95% confidence interval, 8.9-21.0) in the intervention group compared with 27.3 days (95% confidence interval, 18.9-35.7) in the controls (P = 0.05). Overall, no statistically significant differences were seen in the secondary outcomes apart from "number of" and "time to first" emergency department visits, which were in favor of the intervention group. A marked hesitation of the ward physicians to comply with recommendations was noted (18%). CONCLUSIONS: The study showed that the patients receiving usual care had a significantly longer time to the first unplanned contact to a physician after discharge; however, the fact that less than 1 of 5 recommendations was adopted by the physicians raises concerns as to whether this finding could be attributable to the intervention. PMID- 25742063 TI - When Doing Wrong Feels So Right: Normalization of Deviance. AB - Normalization of deviance is a term first coined by sociologist Diane Vaughan when reviewing the Challenger disaster. Vaughan noted that the root cause of the Challenger disaster was related to the repeated choice of NASA officials to fly the space shuttle despite a dangerous design flaw with the O-rings. Vaughan describes this phenomenon as occurring when people within an organization become so insensitive to deviant practice that it no longer feels wrong. Insensitivity occurs insidiously and sometimes over years because disaster does not happen until other critical factors line up. In clinical practice, failing to do time outs before procedures, shutting off alarms, and breaches of infection control are deviances from evidence-based practice. As in other industries, health care workers do not make these choices intending to set into motion a cascade toward disaster and harm. Deviation occurs because of barriers to using the correct process or drivers such as time, cost, and peer pressure. As in other industries, operators will often adamantly defend their actions as necessary and justified. Although many other high-risk industries have embraced the normalization of deviance concept, it is relatively new to health care. It is urgent that we explore the impact of this concept on patient harm. We can borrow this concept from other industries and also the steps these other high-risk organizations have found to prevent it. PMID- 25742064 TI - Modifying the Bank Erosion Hazard Index (BEHI) protocol for rapid assessment of streambank erosion in northeastern Ohio. AB - Understanding the source of pollution in a stream is vital to preserving, restoring, and maintaining the stream's function and habitat it provides. Sediments from highly eroding streambanks are a major source of pollution in a stream system and have the potential to jeopardize habitat, infrastructure, and stream function. Watershed management practices throughout the Cleveland Metroparks attempt to locate and inventory the source and rate the risk of potential streambank erosion to assist in formulating effect stream, riparian, and habitat management recommendations. The Bank Erosion Hazard Index (BEHI), developed by David Rosgen of Wildland Hydrology is a fluvial geomorphic assessment procedure used to evaluate the susceptibility of potential streambank erosion based on a combination of several variables that are sensitive to various processes of erosion. This protocol can be time consuming, difficult for non professionals, and confined to specific geomorphic regions. To address these constraints and assist in maintaining consistency and reducing user bias, modifications to this protocol include a "Pre-Screening Questionnaire", elimination of the Study Bank-Height Ratio metric including the bankfull determination, and an adjusted scoring system. This modified protocol was used to assess several high priority streams within the Cleveland Metroparks. The original BEHI protocol was also used to confirm the results of the modified BEHI protocol. After using the modified assessment in the field, and comparing it to the original BEHI method, the two were found to produce comparable BEHI ratings of the streambanks, while significantly reducing the amount of time and resources needed to complete the modified protocol. PMID- 25742065 TI - Engagement of adolescents in a health communications program to prevent noncommunicable diseases: Multiplicadores Jovenes, Lima, Peru, 2011. AB - BACKGROUND: Several risk factors for noncommunicable diseases (NCDs), including obesity, are associated with behaviors established in infancy that persist throughout adolescence and adulthood. As such, adolescents should be engaged in the design and implementation of NCD prevention strategies. COMMUNITY CONTEXT: In Lima, Peru's capital, the proportion of adolescents aged 15 to 19 is 9.3% of the city's population, and school enrollment rates are high. The prevalence of excess weight in Peruvian adolescents is 14.2%, and prevalence has not declined in recent years. Also recently, NCDs and their risk factors have gained more attention in public health and policy areas, with regulatory action focusing on healthful nutrition to address obesity and related NCDs. The Multiplicadores Jovenes (Young Multipliers) project was conducted among adolescents aged 15 to 17 from 9 public secondary schools in peri-urban areas of Lima, Peru. METHODS: The project provided basic communication tools and knowledge of NCD prevention and public health research to adolescents during 16 weekly participatory sessions to enable them to design and disseminate healthful lifestyle promotion messages to their school peers. OUTCOME: Thirty of 45 participants finished the program. Seven communications campaigns were designed and implemented in schools, reaching 1,200 students. The participants gained motivation, increased knowledge, and developed communication skills that were combined to implement healthful lifestyle promotion campaigns. INTERPRETATION: Engaging young people in public health promotion activities was feasible and advantageous for the design of tailored prevention-related content and its dissemination among peers. PMID- 25742066 TI - Increased confusion and memory loss in households, 2011 Behavioral Risk Factor Surveillance System. AB - Using data from the 2011 Behavioral Risk Factor Surveillance System (BRFSS), we examined households in 13 states (N = 81,012) in which the respondent or another adult household member experienced increased confusion or memory loss (ICML) in the preceding 12 months. A total of 12.6% of households reported at least 1 adult who experienced ICML, and in 5.4% of households all adults experienced ICML. Based on these results, an estimated 4 million households in these 13 states have a member with ICML, potentially affecting more than 10 million people. This study can inform public health communication campaigns aimed at increasing awareness of the signs and symptoms of cognitive decline and augment community planning efforts so that the needs of households in which 1 or more adults has cognitive decline are considered. PMID- 25742067 TI - Demographic and health status differences among people aged 45 or older with and without functional difficulties related to increased confusion or memory loss, 2011 Behavioral Risk Factor Surveillance System. AB - We examined the demographic and health characteristics of people aged 45 years or older in 21 states with self-reported increased confusion or memory loss (ICML) (n = 10,583) by whether or not they also reported functional difficulties related to ICML. We used data from the 2011 Behavioral Risk Factor Surveillance System optional module on impact of cognitive impairment. After adjusting for demographic differences, we found that respondents with ICML and functional difficulties were significantly more likely than those with ICML and no functional difficulties to report frequent poor physical health, frequent poor mental health, limited activity due to poor physical or mental health, and a need for more help. Further understanding of the implications for long-term services and supports is needed. PMID- 25742068 TI - Zebrafish keratocyte explants to study collective cell migration and reepithelialization in cutaneous wound healing. AB - Due to their unique motile properties, fish keratocytes dissociated from explant cultures have long been used to study the mechanisms of single cell migration. However, when explants are established, these cells also move collectively, maintaining many of the features which make individual keratocytes an attractive model to study migration: rapid rates of motility, extensive actin-rich lamellae with a perpendicular actin cable, and relatively constant speed and direction of migration. In early explants, the rapid interconversion of cells migrating individually with those migrating collectively allows the study of the role of cell-cell adhesions in determining the mode of migration, and emphasizes the molecular links between the two modes of migration. Cells in later explants lose their ability to migrate rapidly and collectively as an epithelial to mesenchymal transition occurs and genes associated with wound healing and inflammation are differentially expressed. Thus, keratocyte explants can serve as an in vitro model for the reepithelialization that occurs during cutaneous wound healing and can represent a unique system to study mechanisms of collective cell migration in the context of a defined program of gene expression changes. A variety of mutant and transgenic zebrafish lines are available, which allows explants to be established from fish with different genetic backgrounds. This allows the role of different proteins within these processes to be uniquely addressed. The protocols outlined here describe an easy and effective method for establishing these explant cultures for use in a variety of assays related to collective cell migration. PMID- 25742070 TI - Capturing tissue repair in zebrafish larvae with time-lapse brightfield stereomicroscopy. AB - The zebrafish larval tail fin is ideal for studying tissue regeneration due to the simple architecture of the larval fin-fold, which comprises of two layers of skin that enclose undifferentiated mesenchyme, and because the larval tail fin regenerates rapidly within 2-3 days. Using this system, we demonstrate a method for capturing the repair dynamics of the amputated tail fin with time-lapse video brightfield stereomicroscopy. We demonstrate that fin amputation triggers a contraction of the amputation wound and extrusion of cells around the wound margin, leading to their subsequent clearance. Fin regeneration proceeds from proximal to distal direction after a short delay. In addition, developmental growth of the larva can be observed during all stages. The presented method provides an opportunity for observing and analyzing whole tissue-scale behaviors such as fin development and growth in a simple microscope setting, which is easily adaptable to any stereomicroscope with time-lapse capabilities. PMID- 25742072 TI - The burden of norovirus disease in children in the European Union. AB - BACKGROUND: Noroviruses (NoVs) are the leading cause of acute gastroenteritis across all age groups. Because a vaccine is in clinical development, burden of disease data are required to guide the eventual introduction of this vaccine. In this study, we estimate the burden of NoV disease in children less than 5 years of age in the European Union (EU). METHODS: We carried out a literature search using PubMed to identify studies providing incidence or prevalence data for NoV disease in the EU. We applied the pooled average NoV incidence and prevalence rates to the EU population less than 5 years of age to obtain the annual number of NoV illnesses, medical visits, hospitalizations and deaths occurring in the EU among children younger than 5 years. RESULTS: Data from 12 studies were included. We estimate that NoV infection may cause up to 5.7 million illnesses in the community, 800,000 medical visits, 53,000 hospitalizations and 102 deaths every year in children younger than 5 years in the EU. CONCLUSION: The burden of NoV disease in children in the EU is substantial, and will grow in relative importance as rotavirus (RV) vaccines are rolled out in the EU. This burden of disease is comparable with the burden of RV disease in the EU before RV vaccine introduction. More country-specific studies are needed to better assess this burden and guide the potential introduction of a vaccine against NoV at the national level. PMID- 25742073 TI - Mortality due to bloodstream infections and necrotizing enterocolitis in very low birth weight infants. AB - BACKGROUND: We evaluated the mortality due to nosocomial bloodstream infection (BSI) and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants in 229 neonatal departments participating in the German national neonatal infection surveillance system between 2000 and 2011. METHODS: For each infection type, we conducted a retrospective cohort study and a case-control study. In the cohort studies, the mortality risk due to BSI and/or NEC was estimated by calculating adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) using Cox proportional hazard regression with time the dependent variable infection. In the matched case-control studies, the attributable mortality was calculated. RESULTS: A total of 43,116 VLBW infants, of which 6911 patients had at least 1 BSI and 1271 patients had at least 1 NEC, were analyzed. Overall mortality was 6.6%. Patients with at least 1 BSI had a mortality of 5.6%, and patients with at least 1 NEC had a mortality of 19.2%. The cohort studies revealed that BSI (AHR=1.83; 95% CI: 1.61-2.08) and NEC (AHR=6.35; 95% CI: 5.47 7.37) are independently associated with increased mortality. In the case-control study for BSI, 5187 (75.1%) patients with BSI were matched. Attributable mortality was 1.4% (95% CI: 0.7-2.2). In the case-control study for NEC, 1092 (85.9%) patients with NEC were matched. Attributable mortality was 14.7% (95% CI: 12.2-17.1). CONCLUSIONS: Nosocomial BSI and NEC increased mortality in VLBW infants. BSI, however, was associated with a relatively small attributable mortality of 1.4%, whereas NEC had a high attributable mortality of 14.7%. PMID- 25742071 TI - Generation of plasmid vectors expressing FLAG-tagged proteins under the regulation of human elongation factor-1alpha promoter using Gibson assembly. AB - Gibson assembly (GA) cloning offers a rapid, reliable, and flexible alternative to conventional DNA cloning methods. We used GA to create customized plasmids for expression of exogenous genes in mouse embryonic stem cells (mESCs). Expression of exogenous genes under the control of the SV40 or human cytomegalovirus promoters diminishes quickly after transfection into mESCs. A remedy for this diminished expression is to use the human elongation factor-1 alpha (hEF1alpha) promoter to drive gene expression. Plasmid vectors containing hEF1alpha are not as widely available as SV40- or CMV-containing plasmids, especially those also containing N-terminal 3xFLAG-tags. The protocol described here is a rapid method to create plasmids expressing FLAG-tagged CstF-64 and CstF-64 mutant under the expressional regulation of the hEF1alpha promoter. GA uses a blend of DNA exonuclease, DNA polymerase and DNA ligase to make cloning of overlapping ends of DNA fragments possible. Based on the template DNAs we had available, we designed our constructs to be assembled into a single sequence. Our design used four DNA fragments: pcDNA 3.1 vector backbone, hEF1alpha promoter part 1, hEF1alpha promoter part 2 (which contained 3xFLAG-tag purchased as a double-stranded synthetic DNA fragment), and either CstF-64 or specific CstF-64 mutant. The sequences of these fragments were uploaded to a primer generation tool to design appropriate PCR primers for generating the DNA fragments. After PCR, DNA fragments were mixed with the vector containing the selective marker and the GA cloning reaction was assembled. Plasmids from individual transformed bacterial colonies were isolated. Initial screen of the plasmids was done by restriction digestion, followed by sequencing. In conclusion, GA allowed us to create customized plasmids for gene expression in 5 days, including construct screens and verification. PMID- 25742074 TI - Effect of mupirocin decolonization on subsequent methicillin-resistant Staphylococcus aureus infection in infants in neonatal intensive care units. AB - OBJECTIVE: To evaluate whether topical mupirocin treatment can effectively decolonize methicillin-resistant Staphylococcus aureus (MRSA) carriage and reduce subsequent MRSA infection in neonates. METHODS: During a 1-year period, the infants admitted to our neonatal intensive care units (NICUs)-1 and NICU-2 were included, and specimens from the nares and umbilicus were obtained within 24 hours, and specimen collection was repeated weekly for 2 weeks. Mupirocin was administered for 5 days to the infants with MRSA colonization in NICU-1 during the first half of the year and then switched to those in NICU-2 during the second half of the year. RESULTS: A total of 525 infants were recruited: 257 infants in the treatment group and 268 in the control group. MRSA colonization was detected in 130 infants (25%) during NICU stay, which is a similar rate in both groups. Twenty-two (4.2%) episodes of MRSA infection were identified. The rate of MRSA infection was significantly higher in infants with prior colonization than in those without (10.2% vs. 2.3%, P<0.001). Among the infants with prior colonization, the rate of MRSA infection in the treatment group was significantly lower than that in the control group (3.2% vs. 16%, P=0.014), and the rate in the treatment group was comparable to that in those without colonization (P=0.7804). Of the 15 infants with both clinical and colonizing isolates, indistinguishable strains between the paired isolates from the same infant by molecular methods were identified in 14 infants (93%). CONCLUSION: Administering mupirocin topical therapy to MRSA-colonized infants in NICUs might reduce subsequent MRSA infections during hospitalization in these infants. A large-scale study should be conducted. PMID- 25742075 TI - An outbreak of Kingella kingae infections associated with hand, foot and mouth disease/herpangina virus outbreak in Marseille, France, 2013. AB - BACKGROUND: Outbreaks of invasive Kingella kingae infections recently emerged as a new public health concern in daycare centers in Europe, USA and Israel. Despite this, no trigger factor has been yet identified, preventing the setting up of rational measures of control and prevention. We report an outbreak of K. kingae infections associated with hand, foot and mouth disease/herpangina outbreak, and we define the research and policy priorities. METHODS: From April 22 to May 07, 2013, 5 toddlers presented successive osteo-articular infections in a daycare center in Marseille, France. Real-time polymerase chain reaction targeting the cpn60 gene of K. kingae was used to investigate suspected cases and the prevalence of oropharyngeal K. kingae carriage of their close contacts. RESULTS: The attack rate of the K. kingae infections outbreak was 23.7% (5/21) with no fatality. Positive real-time polymerase chain reaction targeting the cpn60 gene of K. kingae confirmed the diagnosis in 3 cases and revealed a rate of K. kingae oropharynx carriage in the index classroom of 94.4% (17/18) among daycare attendees not given antibiotic during the previous month, and of 76.9% (10/13) among staff in close contact. The eradication rate of K. kingae was 21.4% (3/14) among classmates after oral administration of rifampicin, and eradication occurred spontaneously in 83.3% (5/6) of the staff. Clinical and epidemiological features of the herpangina outbreak were consistent with that of an emerging European Coxsackievirus-A6 outbreak. CONCLUSIONS: Hand, foot and mouth disease/herpangina virus outbreak enables triggering a K. kingae infections outbreak. Our findings offer support for new guidelines of K. kingae infections outbreaks management and emphasize the need for further research. PMID- 25742076 TI - Barriers to successful early infant diagnosis of HIV infection at primary care level in Malawi. AB - HIV-infected women seeking early infant HIV diagnosis (EID) services in Malawi were asked about factors potentially associated with returning for EID results. Many (33.3%) infants failed to complete the EID process because of time and costs required for multiple visits. Infants of mothers receiving antiretroviral treatment were less likely to drop out (adjusted risk ratio 0.51), suggesting that EID completion may improve in programs providing antiretroviral treatment to all pregnant women. PMID- 25742078 TI - Antibody persistence in Australian adolescents following meningococcal C conjugate vaccination. AB - BACKGROUND: In Australia, following the introduction of serogroup C meningococcal (MenC) conjugate vaccine for toddlers and catch-up immunization through adolescence, MenC disease incidence plummeted and remains low. However, individual protection following MenC conjugate vaccination, particularly in young children, may be short-lived. We investigated the persistence of MenC serum bactericidal antibody (SBA) titers in adolescents, more than 7 years after a single "catch-up" dose of MenC conjugate vaccine. We also investigated their exposure and susceptibility to meningococcal serogroups A, W and Y. METHODS: MenC SBA titers and Men A, C, W and Y IgG geometric mean concentration were measured in 240 healthy 11- to 16-year-old adolescents. The correlate of protection was an rSBA titer of >=8. RESULTS: An rSBA>=8 was observed in 105 [44% (95% confidence interval {CI}, 37-50%)] of 240 adolescents (mean age, 13.2 years, mean interval since MenC immunization, 8.2 years). The proportion with an rSBA>=8, geometric mean rSBA titer and geometric mean IgG concentration increased with age, from 22% to 75%, 3.7 to 33.4 and 0.13 to 0.52 MUg/mL, in participants who received MenC vaccine at mean age 2.8 to 7.5 years, respectively. Natural acquired antibody to Men A, W and Y was low with IgG geometric mean concentrations of 1.26, 0.38 and 0.47 MUg/mL, respectively. CONCLUSIONS: More than half of Australian adolescents have inadequate serological protection against MenC disease and low natural immunity to MenA, W and Y. PMID- 25742077 TI - Distortion product otoacoustic emission data in perinatally HIV-infected and HIV exposed but uninfected children and adolescents in the Pediatric HIV/AIDS Cohort Study. AB - The effect of perinatal HIV infection and exposure on sub-clinical auditory function can be measured with distortion product otoacoustic emissions (DPOAEs). DPOAEs were obtained at 4 frequency bins (1, 2, 3 and 4 kHz) and categorized by a signal-to-noise ratio. HIV infection was not associated with poorer DPOAEs. Among HIV-infected children, HIV viral load>=400 copies/mL had significantly lower odds of better DPOAEs. PMID- 25742079 TI - Impact of the 13-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae among children attending group daycare in southeastern France. AB - Regular surveys of pneumococcal nasopharyngeal carriage have been conducted among children attending daycare centers in Southeastern France from 1999 to 2012. We compared carriage rate, susceptibility patterns and serotype distribution in 2012, following implementation of the 13-valent pneumococcal conjugate vaccine, with findings from 5 previous surveys. Carriage rate was stable, antibiotic susceptibility improved and only serotype 19A persisted among vaccine-types. PMID- 25742080 TI - Prevalence of congenital cytomegalovirus infection in Nigeria: a pilot study. AB - Dried saliva specimens from 263 neonates in Lagos, Nigeria, were tested for cytomegalovirus (CMV) using real-time polymerase chain reaction. The results for 10 infants (3.8%, 95% confidence interval, 2.1-6.8) were found to be positive. Congenital CMV infection was not associated with any of the demographic or maternal factors including HIV. These data demonstrate the high prevalence of congenital CMV infection and the feasibility of CMV screening by real-time polymerase chain reaction testing. PMID- 25742081 TI - Subacute osteomyelitis of the femur due to Fusobacterium nucleatum in a 7-year old boy. AB - Subacute hematogenous osteomyelitis is an insidious infection, which commonly has a delayed diagnosis. We describe the case of a 7-year-old boy with subacute osteomyelitis, which was initially considered to be a bone tumor. Infection should be considered in all cases of bone pain, especially in children, even in the absence of typical systemic features of inflammation. PMID- 25742082 TI - Rotavirus vaccine virus shedding, viremia and clearance in infants with severe combined immune deficiency. AB - We report for the first time Rotarix vaccine-acquired rotavirus infections with viremia in 2 infants vaccinated before being diagnosed with severe combined immune deficiency. Monitoring the first infant revealed that persistent rotavirus infection resolved after complete immune reconstitution was achieved by gene therapy. PMID- 25742083 TI - Staphylococcus schleiferi meningitis in a child. PMID- 25742084 TI - Neonatal pityriasis versicolor. PMID- 25742085 TI - Corneal melting caused by Neisseria gonorrhoeae in an adolescent. PMID- 25742086 TI - Intensive care unit admission rates for respiratory syncytial virus infection as a function of age in preterm infants born at 32-35-week gestation and not receiving immunoprophylaxis. PMID- 25742087 TI - Pasteurella canis peritonitis in a child on peritoneal dialysis. PMID- 25742088 TI - Rapid viral rebound after 4 years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth. AB - Attention has focused on the possibility of cure for HIV infected infants if treated promptly after delivery. The "Mississippi baby," who had very prolonged remission after antiretroviral discontinuation, may represent a unique situation. We report an infant treated from birth, who seroreverted, remained virologically suppressed, and had undetectable HIV-1 RNA and DNA at 4 years of age, yet experienced virologic rebound within days of discontinuation of antiretroviral therapy. PMID- 25742091 TI - Design of a haptic model for the training of cleft treatment procedures. AB - INTRODUCTION: Cleft lip and palate (CLP) defects are considered to be the most common facial birth defect. Despite the relevance of this global health issue, the knowledge level on CLP is alarmingly low. Therefore, it was our aim to construct a realistic haptic anatomic CLP model that can be used for 3 dimensional visualizing CLP and practicing the first steps of CLP treatment. METHODS: Models of newborns with CLP are not commercially available so far. Therefore, construction was based on a purchased baby doll of a healthy newborn. After fabrication of the model, we used it in a hands-on course for medical students. A total of 138 students were asked to perform practical tasks such as like taking intraoral impressions and fixating drinking and nasoalveolar plates on the CLP model. To evaluate the didactic benefit, preteaching and postteaching multiple-choice tests were performed. RESULTS: A suitable patient's plaster model from our archive served as a template for shaping a unilateral CLP in the face of a baby doll by means of a scalpel and a handheld rotating milling machine. Hard and soft palate were milled out and replaced by a hard stone cast of a patient with cleft palate. When analyzing the preteaching and postteaching scores of the students' multiple-choice tests, an improvement was achieved in 69.6%, which proved to be statistically significant (P < 0.001). CONCLUSIONS: In our opinion, the CLP model is a useful teaching tool with a high potential to improve the level of knowledge and practical expertise in the field of CLP. PMID- 25742092 TI - Adapting the joint commission's seven foundations of safe and effective transitions of care to home. AB - The purpose of this article is to describe The Joint Commission's 7 foundations of safe and effective transitions of care to home: (a) leadership support; (b) multidisciplinary collaboration; (c) early identification of patients/clients at risk; (d) transitional planning; (e) medication management; (f) patient and family action/engagement; and (g) transfer of information. These foundations were identified by The Joint Commission after a review of published research; focus groups with healthcare professionals involved in transitions of care; and visits to diverse healthcare organizations. The author, who is the executive director of The Joint Commission's Home Care Accreditation Program, illustrates how healthcare organizations are adapting the 7 foundations of safe and effective transitions of care to home. PMID- 25742090 TI - The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. AB - BACKGROUND: Malnutrition may impact the pharmacokinetics (PKs) of antiretroviral medications and virologic responses in HIV-infected children. The authors therefore evaluated the PK of nevirapine (NVP), efavirenz (EFV) and lopinavir (LPV) in associations with nutritional status in a cohort of HIV-infected Ugandan children. METHODS: Sparse dried blood spot samples from Ugandan children were used to estimate plasma concentrations. Historical PK data from children from 3 resource-rich countries (RRC) were utilized to develop the PK models. RESULTS: Concentrations in 330 dried blood spot from 163 Ugandan children aged 0.7-7 years were analyzed in reference to plasma PK data (1189 samples) from 204 children from RRC aged 0.5-12 years. Among Ugandan children, 48% was malnourished (underweight, thin or stunted). Compared to RRC, Ugandan children exhibited reduced bioavailability of EFV and LPV; 11% (P=0.045) and 18% (P=0.008), respectively. In contrast, NVP bioavailability was 46% higher in Ugandan children (P<0.001) with a trend toward greater bioavailability when malnourished. Children receiving LPV, EFV or NVP had comparable risk of virologic failure. Among children on NVP, low height and weight for age Z scores were associated with reduced risk of virologic failure (P=0.034, P=0.068, respectively). CONCLUSIONS: Ugandan children demonstrated lower EFV and LPV and higher NVP exposure compared to children in RRC, perhaps reflecting the consequence of malnutrition on bioavailability. In children receiving NVP, the relation between exposure, malnutrition and outcome turned out to be marginally significant. Further investigations are warranted using more intensive PK measurements and adequate adherence assessments, to further assess causes of virologic failure in Ugandan children. PMID- 25742089 TI - Syphilis in HIV-infected mothers and infants: results from the NICHD/HPTN 040 study. AB - BACKGROUND: Untreated syphilis during pregnancy is associated with spontaneous abortion, stillbirth, prematurity and infant mortality. Syphilis may facilitate HIV transmission, which is especially concerning in low- and middle-income countries where both diseases are common. METHODS: We performed an analysis of data available from NICHD/HPTN 040 (P1043), a study focused on the prevention of intrapartum HIV transmission to 1684 infants born to 1664 untreated HIV-infected women. This analysis evaluates risk factors and outcomes associated with a syphilis diagnosis in this cohort of HIV-infected women and their infants. RESULTS: Approximately, 10% of women (n=171) enrolled had serological evidence of syphilis without adequate treatment documented and 1.4% infants (n=24) were dually HIV and syphilis infected. Multivariate logistic analysis showed that compared with HIV-infected women, co-infected women were significantly more likely to self-identify as non-white (adjusted odds ratio [AOR] 2.5, 95% CI: 1.5 4.2), to consume alcohol during pregnancy (AOR 1.5, 95% CI: 1.1-2.1) and to transmit HIV to their infants (AOR 2.1, 95% CI: 1.3-3.4), with 88% of HIV infections being acquired in utero. As compared with HIV-infected or HIV-exposed infants, co-infected infants were significantly more likely to be born to mothers with venereal disease research laboratory titers>=1:16 (AOR 3, 95% CI: 1.1-8.2) and higher viral loads (AOR 1.5, 95% CI: 1.1-1.9). Of 6 newborns with symptomatic syphilis, 2 expired shortly after birth, and 2 were HIV-infected. CONCLUSION: Syphilis continues to be a common co-infection in HIV-infected women and can facilitate in utero transmission of HIV to infants. Most infants are asymptomatic at birth, but those with symptoms have high mortality rates. PMID- 25742093 TI - Neddylation Pathway as a Novel Anti-cancer Target: Mechanistic Investigation and Therapeutic Implication. AB - Protein neddylation, a newly characterized posttranslational modification that adds the ubiquitin-like molecule NEDD8 to substrates, modulates important biological processes, whereas dysfunction of neddylation may cause several serious diseases, such as cancer. Inhibition of neddylation pathway has emerged as a promising anticancer strategy, as evidenced by development of the NEDD8 activating enzyme (NAE) inhibitor MLN4924. Due to its potent anti-cancer efficacy and well-tolerated toxicity, MLN4924 has been evaluated in multiple Phase I clinical trials for solid tumors and hematologic malignancies. Recently, accumulating evidences indicate that neddylation pathway also plays a pivotal role in the regulation of multiple processes of tumor microenvironment (TME), such as tumor angiogenesis and the function of immune cells. In this review, we briefly summarize the latest progresses in this field and highlight neddylation pathway as an attractive therapeutic target against human cancer. PMID- 25742094 TI - Ligustrazine Suppresses the Growth of HRPC Cells through the Inhibition of Cap- Dependent Translation Via Both the mTOR and the MEK/ERK Pathways. AB - Ligustrazine (TMP) has recently been used for the treatment of various cancers. However, its exact mechanisms of action, particularly the functions and the mechanisms of Ligustrazine in human hormone-refractory prostate cancer (HRPC), have not yet been extensively studied. Recently, our findings suggest that Ligustrazine dose- and time-dependently inhibits the growth of HRPC cells by reducing their proliferation and promoting apoptosis. Interestingly, the treatment of hormone-refractory prostate cancer (PC-3) cells with Ligustrazine results in a significant inhibition of the activation of mTOR and related downstream targets, which are critical for cell growth. Furthermore, pull-down assays with 7-methyl- GTP Sepharose 4B beads indicate that Ligustrazine reduces the available eIF4E for translation initiation. Accordingly, the results from the translation assay using a luciferase reporter system further demonstrate that Ligustrazine indeed inhibits cap-dependent translation. In addition, the transient overexpression of eIF4E or MNK1 prevents the Ligustrazine-induced inhibition of proliferation and confers significant protection against Ligustrazine-induced apoptosis. Therefore, the present study provides evidences that Ligustrazine may be a candidate for therapeutic reagent for the treatment of HRPC and certifies that Ligustrazine modulates the availability of eIF4E mainly through the mTOR and MEK/ERK signaling pathways to inhibit cap-dependent translation. Taken together, our results indicate that the inhibition of cap dependent translation is likely an essential mechanism in Ligustrazine-induced apoptosis. PMID- 25742095 TI - Synthesis of Isoxazole Moiety Containing Thieno[2,3-d]pyrimidine Derivatives and Preliminarily in vitro Anticancer Activity (Part II). AB - 21 new structures of isoxazole-moiety-containing thieno[2,3-d]pyrimidine derivatives(3a~3u) were synthesized for the first time and characterized using IR, (1)H NMR, (13)C NMR, ESI-MS and elemental analysis techniques. And then their in vitro anticancer activity against lung cancer A549, colorectal HCT116 and breast cancer MCF-7 cell lines was preliminarily evaluated using the MTT method. Among them, most compounds exhibited good to excellent anticancer activity. In particular, 3g, 3j and 3n exhibited a broad spectrum and more potent anticancer activity against A549, HCT116 and MCF-7 cell lines, which can be regarded as the promising anticancer drug-candidates. PMID- 25742096 TI - Editor's letter. PMID- 25742097 TI - Bioethics and diplomacy in the health dossier--presentation. PMID- 25742099 TI - International cooperation for science and technology development: a way forward for equity in health. AB - Since 1990, international organizations have been increasingly involved in building an international sub-regime for research, development and innovation in health. This article analyzes the priorities of developing countries in health since the 1990s. It is a descriptive and analytical study that investigates the literature and contributions of key informants. Calling for the end of global inequities in the support for science and technology in health, international organizations recommend that developing countries focus their efforts on neglected diseases and operational research, an insufficient agenda for science and technology cooperation to effectively overcome the vulnerabilities between countries. PMID- 25742098 TI - South-South Cooperation: Brazilian experiences in South America and Africa. AB - Over recent years Brazil has played an increasingly active role internationally, the result of its model of integration and its foreign policy directives. The health sector is a valuable and strategic area for Brazilian technical cooperation to achieve various objectives, including its development goals. This article describes the main directives of Brazilian foreign policy, conceptually defining and characterizing South-South Cooperation, illustrated through an analysis of two Brazilian technical cooperation initiatives in healthcare: one in South America, the other in Africa. The study concludes that, irrespective of the interests and power asymmetries existing in South-South Cooperation, the objectives of this cooperation were achieved through the technical work. PMID- 25742100 TI - Health at the dawn of development: the thought of Abraham Horwitz. AB - The article explores the ideas of Pan American Health Organization director Abraham Horwitz on the relations between health and development at the time the Alliance for Progress was established, in 1961. Taking development discourse as a public philosophy of international cooperation, the discussion centers on how Horwitz worked to mediate between health and development. Horwitz endeavored to establish arguments that highlighted the importance of social policy, especially in health; he also strove to reach different audiences and drew connections between elements like health, illness, and labor productivity, without ignoring the humanistic considerations so dear to the public health tradition. PMID- 25742101 TI - The Juscelino Kubitschek government and the Brazilian Malaria Control and Eradication Working Group: collaboration and conflicts in Brazilian and international health agenda, 1958-1961. AB - Malaria, a disease which was under control in the beginning of Juscelino Kubitschek government, became the most important endemic disease in 1958, when Brazil made a commitment with the World Health Organization to convert its control programs into eradication programs. For this purpose a Malaria Control and Eradication Group was set up under the leadership of the malaria specialist Mario Pinotti. Malaria would become an important bargaining chip in the context of the development policies of Kubitschek. This article focuses on path of the Malaria Control and Eradication Working Group in Brazil, in its varying relationships with the arguments and guidelines established at international level. PMID- 25742102 TI - International cooperation and health policy implementation in a post-conflict situation: the case of East Timor. AB - This study centers on relationships among national and international actors in preparation of the first health policy document for East Timor, under the United Nations transitional administration, between 1999 and 2002. International cooperation support for the health system rehabilitation process during the post conflict period is analyzed as part of reconstruction of the State in parallel with construction of the country's political and institutional framework. Knowledge, ideas, "ways of doing," and induced and accepted practices permeate an interplay of power relationships that condition both national political alliance building and the architecture of international aid, pointing to input to a discussion of how these mechanisms interact at different conjunctures and times in different negotiating frameworks. PMID- 25742103 TI - Education, ethics, and solidarity in international cooperation. AB - The article analyzes an experience in technical cooperation between Brazil and Andean countries in the form of the International Course in the Management of Human Resource Policies in Health. This exploratory documental study encompassed a number of Latin American countries whose institutions of higher education had partnerships with the Federal University of Rio Grande do Norte, mediated by the Pan American Health Organization Representation in Brazil. The course experience shows that fundamental values like ethics and solidarity are determinant to the success of technical cooperation processes. PMID- 25742104 TI - Fiocruz as an actor in Brazilian foreign relations in the context of the Community of Portuguese-Speaking Countries: an untold story. AB - Brazilian foreign policy paradigms and changes in the global scenario since the Cold War created conditions for stronger ties between Brazil and Portuguese speaking African countries. Recently, Brazil took the lead in regional integration processes and in South-South cooperation initiatives. These strategies and Fiocruz's acknowledged technical expertise resulted in its direct involvement in Brazilian foreign public health policy in the Community of Portuguese-Speaking Countries. Fiocruz developed cooperation projects in various areas, sharing its know-how and best practices in the most critical fields in partner countries, consolidating "public health framework cooperation" and contributing to diversifying Brazil's partners and promoting Brazil as a global actor. PMID- 25742105 TI - International health/global health dossier--presentation. PMID- 25742106 TI - Between the foreign and the local: French midwifery, traditional practitioners, and vernacular medical knowledge about childbirth in Lima, Peru. AB - This article examines the politics of midwifery and the persecution of untitled female assistants in childbirth in early republican Peru. A close reading of late colonial publications and the works of Benita Paulina Cadeau Fessel, a French obstetriz director of a midwifery school in Lima, demonstrates both trans Atlantic and local influences in the campaign against untitled midwives. Cadeau Fessel's efforts to promote midwifery built upon debates among writers in Peru's enlightened press, who vilified untrained midwives' and wet nurses' vernacular medical knowledge and associated them with Lima's underclass. One cannot understand the transfer of French knowledge about professional midwifery to Peru without reference to the social, political, and cultural context. PMID- 25742107 TI - Transnational dialogues between specialist and institutional knowledge in occupational accident legislation, first half of the twentieth century. AB - In the early twentieth century, Argentina began legislating occupational safety. Law no.9.688 legislated accidents in the workplace (1915) and granted legal jurisdiction to work-related problems. The approval of this legislation was in dialogue with proposals being produced in other regions. The links established between local figures and colleagues elsewhere are useful for examining the circulation, reception and legitimation of knowledge on a regional scale. The objective of this article is to examine the transnational references in local discussions about occupational accidents in Peru and Chile during the first half of the twentieth century. PMID- 25742108 TI - From gynaecology offices to screening campaigns: a brief history of cervical cancer prevention in Brazil. AB - This paper discusses the knowledge and medical practices relating to cervical cancer in Brazil. It analyses the growing medical interest in the disease at the beginning of the twentieth century, the development of prevention techniques in the 1940s, and the emergence of screening programs in the 1960s. It argues that the development of knowledge on cervical cancer was related simultaneously to a number of factors: transformations in medical knowledge, the development of the idea that the disease should be treated as a public health problem, the increased concerns with women's health, and major changes to the Brazilian healthcare system. The article concludes by identifying a number of issues that are still proving to be obstacles to control of the disease. PMID- 25742109 TI - [The Caribbean origins of the National Public Health System in the USA: a global approach to the history of medicine and public health in Latin America]. AB - This article defines global history in relation to the history of medicine and public health. It argues that a global approach to history opens up a space for examining the reverberations transmitted from the geographic periphery towards western regions, which have traditionally dominated modern historiography. It analyzes two medical interventions in the Caribbean in the late nineteenth and early twentieth century, showing how these events had profound consequences in the USA. The successes achieved in the Caribbean in terms of yellow fever and ancylostoma control, as well as providing a model for health campaigns in the southern USA, inspired the centralization of public health in North America under the centralizing control of the federal government. PMID- 25742110 TI - [The "culture of survival" and international public health in Latin America: the Cold War and the eradication of diseases in the mid-twentieth century]. AB - This article analyzes the main campaigns run by international agencies and national health bodies to eradicate infectious diseases in rural Latin America in the 1940s and 1950s. The political dimensions of the period have been studied but there has been little attention as yet to the health dimensions. This article proposes the concept of a "culture of survival" to explain the official public health problems of states with limited social policies that did not allow the exercise of citizenship. Public health, as part of this culture of survival, sought a temporary solution without confronting the social problems that led to infections and left a public health legacy in the region. PMID- 25742111 TI - The impact that the influenza A (H1N1) pandemic had on news reporting in the state of Parana, Brazil. AB - This study aims to analyze how influenza A (H1N1) in 2009 was reported in the state of Parana. A total of 189 articles were analyzed in two newspapers from Parana. Pursuant to analysis, four themes were identified: the spread of the virus; the pandemic and fear; influenza in the health service; and influenza in public policies. By studying how influenza A was reported in the media, it was possible to see the social impact that the H1N1 pandemic represented for society, presenting challenges for public institutions and ordinary citizens, who sensed that they were in a high-risk group exposed to a potentially lethal virus. This disease radically changed the habits of a globalized community seeking to escape from vulnerability. PMID- 25742112 TI - [Washington and Geneva arrive in Buenos Aires: notes on the history of the habit of smoking and its medicalization]. AB - For much of the twentieth century both the civilian and military governments did not consider smoking a priority concern. It was only in the last decade of the twentieth century that the international movement against cigarettes, led by the World Health Organization, US organizations and academics, began to have some impact on Argentina's political scene. It was in this context that a new professional group managed to foment the creation of a broad anti-smoking political bloc. In this process, voluntarism focused on individual programs to quit smoking that had marked much of the initiatives of the twentieth century, ended up being replaced by public policies designed to ensure smoke free environments and combat passive smoking. PMID- 25742116 TI - In vitro enrichment of ovarian cancer tumor-initiating cells. AB - Evidence suggests that small subpopulations of tumor cells maintain a unique self renewing and differentiation capacity and may be responsible for tumor initiation and/or relapse. Clarifying the mechanisms by which these tumor-initiating cells (TICs) support tumor formation and progression could lead to the development of clinically favorable therapies. Ovarian cancer is a heterogeneous and highly recurrent disease. Recent studies suggest TICs may play an important role in disease biology. We have identified culture conditions that enrich for TICs from ovarian cancer cell lines. Growing either adherent cells or non-adherent 'floater' cells in a low attachment plate with serum free media in the presence of growth factors supports the propagation of ovarian cancer TICs with stem cell markers (CD133 and ALDH activity) and increased tumorigenicity without the need to physically separate the TICs from other cell types within the culture. Although the presence of floater cells is not common for all cell lines, this population of cells with innate low adherence may have high tumorigenic potential.Compared to adherent cells grown in the presence of serum, TICs readily form spheres, are significantly more tumorigenic in mice, and express putative stem cell markers. The conditions are easy to establish in a timely manner and can be used to study signaling pathways important for maintaining stem characteristics, and to identify drugs or combinations of drugs targeting TICs. The culture conditions described herein are applicable for a variety of ovarian cancer cells of epithelial origin and will be critical in providing new information about the role of TICs in tumor initiation, progression, and relapse. PMID- 25742117 TI - Differentiation of mesenchymal stem cells under hypoxia and normoxia: lipid profiles revealed by time-of-flight secondary ion mass spectrometry and multivariate analysis. AB - Mesenchymal stem cells (MSC) have the ability to self-renew and differentiate into multiple cell types valuable for clinical treatment of rheumatic pathologies. To study the chondrogenic potential of MSC and identify the conditions that recreate the native cartilage environment, we used time-of-flight secondary ion mass spectrometry (TOF-SIMS) for label-free detection of cell-type- and environmental-condition-specific molecular profiles. We observed that coculture of human MSC and chondrocytes under standard culture conditions leads to improved extracellular matrix (ECM) deposition. In marked contrast, this effect was lost under low oxygen tension. This improved extracellular matrix deposition was associated with a significant decrease in lipids and in particular cholesterol under low oxygen tension as revealed by TOF-SIMS coupled to principal component analysis and discriminant analysis. We furthermore demonstrate that the higher cholesterol levels under normoxia might regulate fibroblast growth factor 1 (FGF-1) gene expression which was previously implemented in increased ECM production in the cocultures. In conclusion, our study shows an unexpected role of lipids as orchestrators of chondrogenesis in response to oxygen tension which is, at least in part, mediated through FGF-1. PMID- 25742118 TI - Combined iNO and endothelial progenitor cells improve lung alveolar and vascular structure in neonatal rats exposed to prolonged hyperoxia. AB - BACKGROUND: Stem cells or inhaled nitric oxide (iNO) are reported to improve lung structures in bronchopulmonary dysplasia (BPD) models. We hypothesized that combined iNO and transplanted endothelial progenitor cells (EPCs) might restore lung structure in rats after neonatal hyperoxia. METHODS: Litters were separated into eight groups: room air, hyperoxia, hyperoxia + iNO, hyperoxia + iNO + L NAME, hyperoxia + EPCs, hyperoxia + EPCs + L-NAME, hyperoxia + EPCs + iNO, and hyperoxia + EPCs + iNO + L-NAME. Litters were exposed to hyperoxia from the 21st day, then, sacrificed. EPCs were injected on the 21st day. L-NAME was injected daily for 7 d from the 21st day. Serum vascular endothelial growth factor (VEGF), radial alveolar count (RAC), VIII factor, EPCs engraftment, lung VEGF, VEGFR2, endothelial nitric oxide (eNOS) and SDF-1 expression, and NO production were examined. RESULTS: Hyperoxia exposure led to air space enlargement, loss of lung capillaries, and low expression of VEGF and eNOS. Transplanted EPCs, when combined with iNO, had significantly increased engraftment in lungs, compared to EPCs alone, upon hyperoxia exposure. There was improvement in alveolarization, microvessel density, and upregulation of VEGF and eNOS proteins in the hyperoxia exposed EPCs with iNO group, compared to hyperoxia alone. CONCLUSION: Combined EPCs and iNO improved lung structures after neonatal hyperoxia. This was associated with the upregulation of VEGF and eNOS expression. PMID- 25742119 TI - Chemoenzymatic synthesis of thiazolyl peptide natural products featuring an enzyme-catalyzed formal [4 + 2] cycloaddition. AB - Thiocillins from Bacillus cereus ATCC 14579 are members of the well-known thiazolyl peptide class of natural product antibiotics, the biosynthesis of which has recently been shown to proceed via post-translational modification of ribosomally encoded precursor peptides. It has long been hypothesized that the final step of thiazolyl peptide biosynthesis involves a formal [4 + 2] cycloaddition between two dehydroalanines, a unique transformation that had eluded enzymatic characterization. Here we demonstrate that TclM, a single enzyme from the thiocillin biosynthetic pathway, catalyzes this transformation. To facilitate characterization of this new class of enzyme, we have developed a combined chemical and biological route to the complex peptide substrate, relying on chemical synthesis of a modified C-terminal fragment and coupling to a 38 residue leader peptide by means of native chemical ligation (NCL). This strategy, combined with active enzyme, provides a new chemoenzymatic route to this promising class of antibiotics. PMID- 25742121 TI - Visible-light-responsive TiO2-coated ZnO:I nanorod array films with enhanced photoelectrochemical and photocatalytic performance. AB - Control of structural and compositional characteristics during fabrication of a versatile visible-light active ZnO-based photocatalyst is a crucial step toward improving photocatalytic pollutant degradation processes. In this work, we report a multifunctional photocatalytic electrode, i.e., TiO2 coated ZnO:I nanorods (ZnO:I/TiO2 NRs) array films, fabricated via a hydrothermal method and a subsequent wet-chemical process. This type of hybrid photocatalytic film not only enhances light absorption with the incorporation of iodine but also possesses increased electron transport capability and excellent chemical stability arising from the unique TiO2-coated 1D structure. Owing to these synergic advantages, the degradation efficiency of the ZnO:I samples reached ~97% after irradiation for 6 h, an efficiency 62% higher than that of pure ZnO. For RhB photocatalytic degradation experiments in both acidic (pH = 3) and alkaline (pH = 11) solutions, as well as in repeat photodegradation experiments, the ZnO:I/TiO2 NRs films demonstrated high stability and durability under visible-light irradiation. Thus, ZnO:I/TiO2 NRs are considered a promising photocatalytic material to degrade organic pollutants in aqueous eco-environments. PMID- 25742120 TI - Psoriasis and the Risk of Major Cardiovascular Events: Cohort Study Using the Clinical Practice Research Datalink. AB - The association between psoriasis and risk of major cardiovascular (CV) events (myocardial infarction, acute coronary syndrome, unstable angina, and stroke) is unclear. A cohort study with 48,523 patients with psoriasis and 208,187 controls was conducted. During a median follow-up of 5.2 years, 1,257 patients with psoriasis (2.59%) had a major CV event, compared with 4,784 controls (2.30%). In the multivariable analysis, inflammatory arthritis hazard ratio (HR) 1.36 (1.18 1.58), diabetes HR 1.18 (1.06-1.31), chronic kidney disease HR 1.18 (1.07-1.31), hypertension HR 1.37 (1.29-1.45), transient ischemic attack HR 2.74 (2.41-3.12), atrial fibrillation HR 1.54 (1.36-1.73), valvular heart disease HR 1.23 (1.05 1.44), thromboembolism 1.32 (1.17-1.49), congestive heart failure HR 1.57 (1.39 1.78), depression HR 1.16 (1.01-1.34), current smoker HR 2.18 (2.03-2.33), age (year) HR 1.07 (1.07-1.07), and male gender HR 1.83 (1.69-1.98) were statistically significant for the risk of major CV events. The age- and gender adjusted HRs of a major CV event for psoriasis were 1.10 (1.04-1.17) and for severe psoriasis 1.40 (1.07-1.84), whereas the fully adjusted HRs were attenuated to 1.02 (0.95-1.08) and 1.28 (0.96-1.69). In conclusion, neither psoriasis nor severe psoriasis were associated with the short-to-medium term (over 3-5 years) risk of major CV events after adjusting for known cardiovascular disease risk factors. PMID- 25742122 TI - Racial Differences in Weight Loss Among Adults in a Behavioral Weight Loss Intervention: Role of Diet and Physical Activity. AB - BACKGROUND: African-Americans lose less weight during a behavioral intervention compared with Whites, which may be from differences in dietary intake or physical activity. METHODS: Subjects (30% African American, 70% White; n = 346; 42.4 +/- 9.0 yrs.; BMI = 33.0 +/- 3.7 kg/m2) in an 18-month weight loss intervention were randomized to a standard behavioral (SBWI) or a stepped-care (STEP) intervention. Weight, dietary intake, self-report and objective physical activity, and fitness were assessed at 0, 6, 12, and 18 months. RESULTS: Weight loss at 18 months was greater in Whites (-8.74 kg with 95% CI [-10.10, -7.35]) compared with African Americans (-5.62 kg with 95% CI [-7.86, -3.37]) (P = .03) in the SBWI group and the STEP group (White: -7.48 kg with 95% CI [-8.80, -6.17] vs. African American: 4.41kg with 95% CI [-6.41, -2.42]) (P = .01). Patterns of change in dietary intake were not different between groups. Objective physical activity (PA) changed over time (P < .0001) and was higher in Whites when compared with African Americans (P = .01). CONCLUSIONS: Whites lost more weight (3.10 kg) than African American adults. Although there were no differences in dietary intake, Whites had higher levels of objective PA and fitness. Thus, the discrepancy in weight loss may be due to differences in PA rather than dietary intake. However, the precise role of these factors warrants further investigation. PMID- 25742124 TI - OGP functionalized phenylalanine-based poly(ester urea) for enhancing osteoinductive potential of human mesenchymal stem cells. AB - Amino acid-based poly(ester urea)s (PEU) are high modulus, resorbable polymers with many potential uses, including the surgical repair of bone defects. In vitro and in vivo studies have previously shown that phenylalanine-based PEUs have nontoxic hydrolytic byproducts and tunable degradation times. Phenylalanine PEUs (poly(1-PHE-6)) have been further modified by tethering osteogenic growth peptide (OGP) to tyrosine-based monomer subunits. These OGP-tethered PEUs have been fabricated into porous scaffolds and cultured in vitro to examine their effect on differentiation of human mesenchymal stem cells (hMSCs) toward the osteogenic lineage. The influence of tethered OGP on the hMSC proliferation and differentiation profile was measured using immunohistochemistry, biochemistry, and quantitative real time polymerase chain reaction (qRT-PCR). In vitro data indicated an enhanced expression of BSP by 130-160% for hMSCs on OGP-tethered scaffolds compared to controls. By 4 weeks, there was a significant drop (60-85% decrease) in BSP expression on OGP-functionalized scaffolds, which is characteristic of osteogenic differentiation. ALP and OSC expression was significantly enhanced for OGP-functionalized scaffolds by week 4, with values reaching 145% and 300% greater, respectively, compared to nonfunctionalized controls. In vivo subcutaneous implantation of poly(1-PHE-6) scaffolds revealed significant tissue-scaffold integration, as well as the promotion of both osteogenesis and angiogenesis. PMID- 25742125 TI - Synthesis and reactivity of NHC-supported Ni2(MU(2)-eta(2),eta(2)-S2)-bridging disulfide and Ni2(MU-S)2-bridging sulfide complexes. AB - The (IPr)Ni scaffold stabilizes low-coordinate, mononuclear and dinuclear complexes with a diverse range of sulfur ligands, including MU(2)-eta(2),eta(2) S2, eta(2)-S2, MU-S, and MU-SH motifs. The reaction of {(IPr)Ni}2(MU-Cl)2 (1, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) with S8 yields the bridging disulfide species {(IPr)ClNi}2(MU(2)-eta(2),eta(2)-S2) (2). Complex 2 reacts with 2 equiv of AdNC (Ad = adamantyl) to yield a 1:1 mixture of the terminal disulfide compound (IPr)(AdNC)Ni(eta(2)-S2) (3a) and trans-(IPr)(AdNC)NiCl2 (4a). 2 also reacts with KC8 to produce the Ni-Ni-bonded bridging sulfide complex {(IPr)Ni}2(MU-S)2 (6). Complex 6 reacts with H2 to yield the bridging hydrosulfide compound {(IPr)Ni}2(MU-SH)2 (7), which retains a Ni-Ni bond. 7 is converted back to 6 by hydrogen atom abstraction by 2,4,6-(t)Bu3-phenoxy radical. The 2,6-diisopropylphenyl groups of the IPr ligand provide lateral steric protection of the (IPr)Ni unit but allow for the formation of Ni-Ni-bonded dinuclear species and electronically preferred rather than sterically preferred structures. PMID- 25742123 TI - The Role of Surfactant in Lung Disease and Host Defense against Pulmonary Infections. AB - Pulmonary surfactant is essential for life as it lines the alveoli to lower surface tension, thereby preventing atelectasis during breathing. Surfactant is enriched with a relatively unique phospholipid, termed dipalmitoylphosphatidylcholine, and four surfactant-associated proteins, SP-A, SP B, SP-C, and SP-D. The hydrophobic proteins, SP-B and SP-C, together with dipalmitoylphosphatidylcholine, confer surface tension-lowering properties to the material. The more hydrophilic surfactant components, SP-A and SP-D, participate in pulmonary host defense and modify immune responses. Specifically, SP-A and SP D bind and partake in the clearance of a variety of bacterial, fungal, and viral pathogens and can dampen antigen-induced immune function of effector cells. Emerging data also show immunosuppressive actions of some surfactant-associated lipids, such as phosphatidylglycerol. Conversely, microbial pathogens in preclinical models impair surfactant synthesis and secretion, and microbial proteinases degrade surfactant-associated proteins. Deficiencies of surfactant components are classically observed in the neonatal respiratory distress syndrome, where surfactant replacement therapies have been the mainstay of treatment. However, functional or compositional deficiencies of surfactant are also observed in a variety of acute and chronic lung disorders. Increased surfactant is seen in pulmonary alveolar proteinosis, a disorder characterized by a functional deficiency of the granulocyte-macrophage colony-stimulating factor receptor or development of granulocyte-macrophage colony-stimulating factor antibodies. Genetic polymorphisms of some surfactant proteins such as SP-C are linked to interstitial pulmonary fibrosis. Here, we briefly review the composition, antimicrobial properties, and relevance of pulmonary surfactant to lung disorders and present its therapeutic implications. PMID- 25742127 TI - Correction: Tumor suppressors TSC1 and TSC2 differentially modulate actin cytoskeleton and motility of mouse embryonic fibroblasts. PMID- 25742126 TI - Mechanical Ventilation and ARDS in the ED: A Multicenter, Observational, Prospective, Cross-sectional Study. AB - BACKGROUND: There are few data regarding mechanical ventilation and ARDS in the ED. This could be a vital arena for prevention and treatment. METHODS: This study was a multicenter, observational, prospective, cohort study aimed at analyzing ventilation practices in the ED. The primary outcome was the incidence of ARDS after admission. Multivariable logistic regression was used to determine the predictors of ARDS. RESULTS: We analyzed 219 patients receiving mechanical ventilation to assess ED ventilation practices. Median tidal volume was 7.6 mL/kg predicted body weight (PBW) (interquartile range, 6.9-8.9), with a range of 4.3 to 12.2 mL/kg PBW. Lung-protective ventilation was used in 122 patients (55.7%). The incidence of ARDS after admission from the ED was 14.7%, with a mean onset of 2.3 days. Progression to ARDS was associated with higher illness severity and intubation in the prehospital environment or transferring facility. Of the 15 patients with ARDS in the ED (6.8%), lung-protective ventilation was used in seven (46.7%). Patients who progressed to ARDS experienced greater duration in organ failure and ICU length of stay and higher mortality. CONCLUSIONS: Lung protective ventilation is infrequent in patients receiving mechanical ventilation in the ED, regardless of ARDS status. Progression to ARDS is common after admission, occurs early, and worsens outcome. Patient- and treatment-related factors present in the ED are associated with ARDS. Given the limited treatment options for ARDS, and the early onset after admission from the ED, measures to prevent onset and to mitigate severity should be instituted in the ED. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01628523; URL: www.clinicaltrials.gov. PMID- 25742128 TI - Correction: Large, omega-3 rich, pelagic diatoms under Arctic sea ice: sources and implications for food webs. PMID- 25742130 TI - Determination of the recovered-fiber content in paperboard samples by applying mid-infrared spectroscopy. AB - Paperboard is widely used in different applications, such as packaging and graphic printing, among others. Consumption of recycled paper is growing, which has led the paper-mill packaging industry to apply strict quality controls. This means that it is very important to develop methods to test the quality of recycled products. In this article, we focus on determining the recovered-fiber content of paperboard samples by applying Fourier transform mid-infrared (FT-MIR) spectroscopy in combination with multivariate statistical methods. To this end, two very fast, nondestructive approaches were applied: classification and quantification. The first approach is based on classifying unknown paperboard samples into two groups: high and low recovered-fiber content. Conversely, under the quantification approach, the content of recovered fiber in the incoming paperboard samples is determined. The experimental results presented in this article show that the classification approach, which classifies unknown incoming paperboard samples, is highly accurate and that the quantification approach has a root mean square error of prediction of about 4.1. PMID- 25742129 TI - Significant in vivo anti-inflammatory activity of Pytren4Q-Mn a superoxide dismutase 2 (SOD2) mimetic scorpiand-like Mn (II) complex. AB - BACKGROUND: The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight. BACKGROUND/METHODOLOGY: We have recently reported that two SOD mimetic compounds, the Mn(II) complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q Mn(II) complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin. PRINCIPAL FINDINGS: In this report we show that the Mn(II) complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules. CONCLUSION/SIGNIFICANCE: The effective anti-inflammatory activity of the Mn(II) complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies. PMID- 25742131 TI - Correction: Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PMID- 25742132 TI - Presynaptic plasticity as a hallmark of rat stress susceptibility and antidepressant response. AB - Two main questions are important for understanding and treating affective disorders: why are certain individuals susceptible or resilient to stress, and what are the features of treatment response and resistance? To address these questions, we used a chronic mild stress (CMS) rat model of depression. When exposed to stress, a fraction of rats develops anhedonic-like behavior, a core symptom of major depression, while another subgroup of rats is resilient to CMS. Furthermore, the anhedonic-like state is reversed in about half the animals in response to chronic escitalopram treatment (responders), while the remaining animals are resistant (non-responder animals). Electrophysiology in hippocampal brain slices was used to identify a synaptic hallmark characterizing these groups of animals. Presynaptic properties were investigated at GABAergic synapses onto single dentate gyrus granule cells. Stress-susceptible rats displayed a reduced probability of GABA release judged by an altered paired-pulse ratio of evoked inhibitory postsynaptic currents (IPSCs) (1.48 +/- 0.25) compared with control (0.81 +/- 0.05) and stress-resilient rats (0.78 +/- 0.03). Spontaneous IPSCs (sIPSCs) occurred less frequently in stress-susceptible rats compared with control and resilient rats. Finally, a subset of stress-susceptible rats responding to selective serotonin reuptake inhibitor (SSRI) treatment showed a normalization of the paired-pulse ratio (0.73 +/- 0.06) whereas non-responder rats showed no normalization (1.2 +/- 0.2). No changes in the number of parvalbumin-positive interneurons were observed. Thus, we provide evidence for a distinct GABAergic synaptopathy which associates closely with stress susceptibility and treatment-resistance in an animal model of depression. PMID- 25742133 TI - Prevalence and incidence of memory complaints in employed compared to non employed aged 55-64 years and the role of employment characteristics. AB - OBJECTIVES: To examine the association of employment status and characteristics with prevalent and incident memory complaints (MC) in 55-64-year-olds. METHODS: Subjects were participants of the Longitudinal Aging Study Amsterdam (LASA). Respondents with baseline data were selected to examine the association of employment status (n = 1525) and employment characteristics (n = 1071) with prevalent MC (i.e., MC at baseline). Respondents without MC at baseline were selected to examine the association of employment (n = 526) and employment characteristics (n = 379; working hours, job prestige, job level, psychological job demands, iso-strain) with incident MC (i.e., no MC at baseline and MC at three-year follow-up). Associations were adjusted for relevant covariates (demographics, memory performance, physical health, mental health, personality traits). Logistic regression was applied. Data were weighed according to gender and age of the Dutch population. RESULTS: At baseline 20.5% reported MC. At three year follow-up, 15.4% had incident MC. No associations were found between employment status and MC. Adjusted analysis revealed that individuals with high occupational cognitive demands were more likely to have prevalent MC. CONCLUSIONS: Middle-aged workers are equally as likely to experience MC as non working age-peers. Among workers, those with cognitively demanding work were more likely to experience MC, independent of memory performance. Memory decline due to ageing may be noticed sooner in 55-64-year-olds performing cognitively demanding work. PMID- 25742134 TI - Health effects from swimming training in chlorinated pools and the corresponding metabolic stress pathways. AB - Chlorination is the most popular method for disinfecting swimming pool water; however, although pathogens are being killed, many toxic compounds, called disinfection by-products (DBPs), are formed. Numerous epidemiological publications have associated the chlorination of pools with dysfunctions of the respiratory system and with some other diseases. However, the findings concerning these associations are not always consistent and have not been confirmed by toxicological studies. Therefore, the health effects from swimming in chlorinated pools and the corresponding stress reactions in organisms are unclear. In this study, we show that although the growth and behaviors of experimental rats were not affected, their health, training effects and metabolic profiles were significantly affected by a 12-week swimming training program in chlorinated water identical to that of public pools. Interestingly, the eyes and skin are the organs that are more directly affected than the lungs by the irritants in chlorinated water; instead of chlorination, training intensity, training frequency and choking on water may be the primary factors for lung damage induced by swimming. Among the five major organs (the heart, liver, spleen, lungs and kidneys), the liver is the most likely target of DBPs. Through metabolomics analysis, the corresponding metabolic stress pathways and a defensive system focusing on taurine were presented, based on which the corresponding countermeasures can be developed for swimming athletes and for others who spend a lot of time in chlorinated swimming pools. PMID- 25742135 TI - Two adenine nucleotide translocase paralogues involved in cell proliferation and spermatogenesis in the silkworm Bombyx mori. AB - Mitochondrial adenine nucleotide translocase (ANT) specifically acts in ADP/ATP exchange through the mitochondrial inner membrane. This transporter protein thereby plays a significant role in energy metabolism in eukaryotic cells. Most mammals have four paralogous ANT genes (ANT1-4) and utilize these paralogues in different types of cells. The fourth paralogue of ANT (ANT4) is present only in mammals and reptiles and is exclusively expressed in testicular germ cells where it is required for meiotic progression in the spermatocytes. Here, we report that silkworms harbor two ANT paralogues, the homeostatic paralogue (BmANTI1) and the testis-specific paralogue (BmANTI2). The BmANTI2 protein has an N-terminal extension in which the positions of lysine residues in the amino acid sequence are distributed as in human ANT4. An expression analysis showed that BmANTI2 transcripts were restricted to the testis, suggesting the protein has a role in the progression of spermatogenesis. By contrast, BmANTI1 was expressed in all tissues tested, suggesting it has an important role in homeostasis. We also observed that cultured silkworm cells required BmANTI1 for proliferation. The ANTI1 protein of the lepidopteran Plutella xylostella (PxANTI1), but not those of other insect species (or PxANTI2), restored cell proliferation in BmANTI1 knockdown cells suggesting that ANTI1 has similar energy metabolism functions across the Lepidoptera. Our results suggest that BmANTI2 is evolutionarily divergent from BmANTI1 and has developed a specific role in spermatogenesis similar to that of mammalian ANT4. PMID- 25742136 TI - Dysregulation of X chromosome inactivation in high grade ovarian serous adenocarcinoma. AB - BACKGROUND: One of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction. MATERIALS AND METHODS: We used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward's hierarchical clustering method was used to classify the methylation status of the X chromosome. RESULTS: We grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1-2.5, two copies of active X group: HR 1.4, 95% CI 1.0-1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI. CONCLUSIONS: Loss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness. PMID- 25742137 TI - Ancestry dependent DNA methylation and influence of maternal nutrition. AB - There is extensive variation in DNA methylation between individuals and ethnic groups. These differences arise from a combination of genetic and non-genetic influences and potential modifiers include nutritional cues, early life experience, and social and physical environments. Here we compare genome-wide DNA methylation in neonatal cord blood from African American (AA; N = 112) and European American (EA; N = 91) participants of the CANDLE Study (Conditions Affecting Neurocognitive Development and Learning in Early Childhood). Our goal is to determine if there are replicable ancestry-specific methylation patterns that may implicate risk factors for diseases that have differential prevalence between populations. To identify the most robust ancestry-specific CpG sites, we replicate our results in lymphoblastoid cell lines from Yoruba African and CEPH European panels of HapMap. We also evaluate the influence of maternal nutrition- specifically, plasma levels of vitamin D and folate during pregnancy--on methylation in newborns. We define stable ancestry-dependent methylation of genes that include tumor suppressors and cell cycle regulators (e.g., APC, BRCA1, MCC). Overall, there is lower global methylation in African ancestral groups. Plasma levels of 25-hydroxy vitamin D are also considerably lower among AA mothers and about 60% of AA and 40% of EA mothers have concentrations below 20 ng/ml. Using a weighted correlation analysis, we define a network of CpG sites that is jointly modulated by ancestry and maternal vitamin D. Our results show that differences in DNA methylation patterns are remarkably stable and maternal micronutrients can exert an influence on the child epigenome. PMID- 25742138 TI - Yip1A, a novel host factor for the activation of the IRE1 pathway of the unfolded protein response during Brucella infection. AB - Brucella species replicate within host cells in the form of endoplasmic reticulum (ER)-derived vacuoles. The mechanisms by which the bacteria are sequestered into such vacuoles and obtain a continuous membrane supply for their replication remain to be elucidated. In the present study, we provided several lines of evidence that demonstrate the mechanism by which B. abortus acquires the ER derived membrane. First, during Brucella infection, the IRE1 pathway, but not the PERK and ATF6 pathways, of the unfolded protein response (UPR) was activated in a time-dependent manner, and the COPII vesicle components Sar1, Sec23, and Sec24D were upregulated. Second, a marked accretion of ER-derived vacuoles was observed around replicating bacteria using fluorescent microscopy and electron microscopy. Third, we identified a novel host factor, Yip1A, for the activation of the IRE1 pathway in response to both tunicamycin treatment and infection with B. abortus. We found that Yip1A is responsible for the phosphorylation of IRE1 through high order assembly of Ire1 molecules at ER exit sites (ERES) under the UPR conditions. In Yip1A-knockdown cells, B. abortus failed to generate the ER derived vacuoles, and remained in endosomal/lysosomal compartments. These results indicate that the activation of the IRE1 pathway and the subsequent formation of ER-derived vacuoles are critical for B. abortus to establish a safe replication niche, and that Yip1A is indispensable for these processes. Furthermore, we showed that the autophagy-related proteins Atg9 and WIPI1, but not DFCP1, were required for the biogenesis of the ER-derived membrane compartments. On the basis of our findings, we propose a model for intracellular Brucella replication that exploits the host UPR and ER-derived vacuole formation machineries, both of which depend on Yip1A-mediated IRE1 activation. PMID- 25742139 TI - Sentinel Events, Serious Reportable Events, and Root Cause Analysis. PMID- 25742140 TI - Palliative Care in Advanced Lung Disease: The Challenge of Integrating Palliation Into Everyday Care. AB - The tendency toward "either/or" thinking (either cure or comfort) in traditional biomedical care paradigms does little to optimize care in advancing chronic illness. Calls for improved palliation in chronic lung disease mandate a review of related care gaps and current clinical practices. Although specialist palliative services have their advocates, adding yet another element to an already fragmented, often complex, care paradigm can be a challenge. Instead, we propose a more holistic, patient-centered approach based on elements fundamental to palliative and best care practices generally and integrated as needed across the entire illness trajectory. To support this approach, we review the concept of primary palliative care competencies, identify vulnerability specific to those living with advanced COPD (an exemplar of chronic lung disease), and describe the need for care plans shaped by patient-centered communication, timely palliative responsiveness, and effective advance care planning. A costly systemic issue in the management of chronic lung disease is patients' increasing dependency on episodic ED care to deal with preventable episodic crises and refractory dyspnea. We address this issue as part of a proposed model of care that provides proactive, collaborative case management and the appropriate and carefully monitored use of opioids. We encourage and support a renewed primary care resolve to integrate palliative approaches to care in advanced lung disease that, in concert with judicious referral to appropriate specialist palliative care services, is fundamental to what should be a more sustainable systematic improvement in palliative care delivery. PMID- 25742142 TI - Ebola in West Africa: who pays for what in the outbreak? PMID- 25742141 TI - Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of survival and metastasis for recurrent hepatocellular carcinoma after transarterial chemoembolization. AB - PURPOSE: To evaluate whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to lymphocyte ratio (PLR) predict survival and metastasis in patients after transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (RHCC). MATERIALS AND METHODS: Clinical and laboratory data from 132 RHCC patients treated with TACE from January 2003 to December 2012 were retrospectively reviewed. Prognostic factors were assessed by multivariate analysis, and the predictive values of NLR and PLR for overall survival (OS) and extrahepatic metastases were compared. RESULTS: Pretreatment mean NLR and PLR were 3.1 and 137, respectively. The 0.5-, 1-, and 2-year OS rates were 93.7%, 67.1%, and 10.1% in the low NLR group and 81.1%, 18.9%, and 3.8% in the high NLR group, respectively (P = 0.017). The corresponding OS rates in the low and high PLR groups were 92.5%, 58.1%, and 9.7% and 84.6%, 23.1%, and 2.6%, respectively (P = 0.030). The discriminatory performance predicting 1-year survival probability was significantly poorer for NLR (area under the curve [AUC] = 0.685, 95% confidence interval [CI] 0.598-0.763) than for PLR (AUC = 0.792, 95% CI 0.712 0.857; P = 0.0295), but was good for both ratios for predicting post-TACE extrahepatic metastasis. Multivariate analysis indicated that high PLR (hazard ratio [HR] = 0.373, 95% CI = 0.216-0.644, P < 0.001, vascular invasion (HR = 0.507, 95% CI = 0.310-0.832, P = 0.007), and multiple tumors (HR= 0.553, 95% CI = 0.333-0.919, P = 0.022) were independent prognostic factors for OS. CONCLUSIONS: High NLR and PLR were both associated with poor prognosis and metastasis in RHCC patients treated with TACE, but high PLR was a better predictor of 1-year OS. High PLR, vascular invasion, and multiple tumors were independent, unfavorable prognostic factors. PMID- 25742143 TI - The interferon-inducible DNA-sensor protein IFI16: a key player in the antiviral response. AB - IFI16, a member of the IFN-inducible PYHIN-200 gene family, displays multifaceted activity due to its ability to bind to various target proteins and, in turn, modulate a variety cell functions including proliferation, differentiation, apoptosis/pyroptosis, senescence, and in? ammation. The last few year have seen major advances in our knowledge of IFI16 antiviral activity and its role in the immune response. Indeed, a wealth of evidence now supports a key role of IFI16 in the activation of innate immunity and viral restriction against Herpesviruses and Lentiviruses, such that the definition of IFI16 as a "restriction factor" is now widely accepted. However, most viruses have developed their own unique strategy to antagonize IFI16, leading to a modification or disruption of its function. This review summarizes our current understanding of how viral replication is sensed and then inhibited by IFI16 protein and the viral strategies employed to defeat this host defense mechanism. We will focus mainly on Herpesviruses, although recent discoveries on the role of IFI16 in lentiviral infection will also be considered. PMID- 25742144 TI - Real life experience in treatment of HIV-1/HCV-coinfected patients with pegylated interferon alpha and ribavirin: predictors of SVR. AB - Single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 near the interleukin 28B gene are predictors of virological response (SVR) to IFN-based therapy for monoinfected chronic hepatitis C patients. We retrospectively evaluated the impact of IL28B SNPs and other factors on SVR in a cohort of 102 HIV-1/HCV-coinfected patients treated with pegylated interferon-? (peg-INF?) and ribavirin. Data on baseline features and virological response at different time points were collected. Overall, 89/102 patients (87%) were males, 44 (43%) of whom infected with HCV genotype 1; SVR was achieved by 50 patients (49%). A univariate logistic regression analysis demonstrated that rs129679860 SNP genotype CC (p<0.034), rs8099917 SNP genotype TT (p<0.01), HCV genotype 2 or 3 (p<0.0001), low HCV viral load (p<0.028) and RVR (rapid virological response) (p<0.0001) were associated with a higher likelihood of SVR. Multivariate analysis confirmed only RVR and HCV genotype as independent predictors of SVR. In a real life setting, the importance of RVR and IL28B SNPs was confirmed as predictive of SVR to identify patients with a higher likelihood of SVR to Peg-INF?+RBV, and also to designate a deferred therapy for patients with a low likelihood of SVR for whom it is preferable to wait for more successful options. PMID- 25742145 TI - Clinical course of chronic hepatitis B patients receiving nucleos(t)ide analogues after virological breakthrough during monotherapy with lamivudine. AB - Little is known about the optimal management of patients with chronic hepatitis B (CHB) who develop drug resistance. The aim of this study was to investigate the effectiveness of different drug regimens in chronically HBV-infected patients. HBV viral load was determined using a bDNA assay and the substitutions in HBV-DNA were studied by polymerase sequencing test. The study involved 38 patients who experienced a therapeutic failure to lamivudine (LAM). The sequential treatments used were: LAM + adefovir (ADV), LAM + tenofovir (TDF), entecavir (ETV) monotherapy, ADV monotherapy and TDF monotherapy. Similar activity against HBV replication was observed with all drug regimens. Of the patients treated with LAM, 44% developed resistance mutations. The rt M204I mutation was observed more frequently. Sequential ADV add-on LAM and TDF therapy induced the appearance of resistance in 3/18 (16.6%) and in 1/8 (5.5%) treated patients, respectively. Genotype D was the most prevalent (78.9%), followed by genotype A (13%), genotype E (5.2%) and genotype C (2.6%). Our study showed that baseline serum HBV DNA is an important predictor of virologic response and that virologic breakthrough is significantly associated with the insurgence of genotypic resistance. PMID- 25742146 TI - a statistical model based on serological parameters for predicting occult HBV infection: implications for organ/ blood donations. AB - The transmission of hepatitis B virus by donors with occult HBV infection (OBI) is a threat for blood transfusion and organ/tissue transplantation. The risk of carrying HBV DNA is currently not predictable by simple serologic markers, while HBV DNA testing is not universally deployed. This study evaluated an integrated serologic approach for assessing this risk. Anti-HBc positive subjects (461 HIV negative, 262 HIV-positive) were selected for the study. Serology was analyzed by a commercial CMIA technique. HBV DNA was analyzed by both commercial and home brew real-time amplification assays. A penalized maximum likelihood logistic approach was used to analyze the data. In HBsAg-negative subjects (HIV-negative), anti-HBc signal/cut off values, the presence of anti-HBc IgM, the absence of anti HBsAg, and the absence of anti-HCV were correlated to the probability of finding circulating HBV DNA. A model for predicting HBV DNA presence by 4 serological parameters is therefore proposed. The predictive value of the logistic model based on simple serologic markers may represent a reasonable tool for the assessment of HBV transmission risk by transfusion or organ/tissue donation in the context of limited resources and where nucleic acid testing is not performed. In addition, it may be helpful for assessing the risk of reactivation in immunosuppressed OBI patients. PMID- 25742147 TI - Comparison of Seeplex PneumoBacter aCE detection assay and in-house multiplex PCR for the identification of Streptococcus pneumoniae. AB - Rapid and accurate identification of Streptococcus pneumoniae is important for appropriate and prudent antimicrobial use in the treatment of lower respiratory tract infection. It is difficult to separate S. pneumoniae from commensal viridans group streptococci either by classical techniques or molecular methods. Aim of this study was to compare a commercially available multiplex PCR assay Seeplex PneumoBacter ACE Detection assay (Seegene, Seoul, South Korea), and in house multiplex PCR using primer sets for lytA and cpsA for ability to differentiate S. pneumoniae in a known set of bacteria (S. pneumoniae and viridans group streptococci) and clinical samples. Of 20 viridans streptococcal isolates, 8 were misidentified as S. pneumoniae by commercial PCR test. Of 209 throat swabs tested with Seeplex PneumoBacter ACE Detection assay, 122 (58,4%) were positive for S. pneumoniae while only 11 (5.3%) samples were positive with lytA and cpsA primers. Therefore, the commercial multiplex PCR test appears to have low specificity in diagnosing S. pneumoniae. PMID- 25742148 TI - Enzymatic characterization of Chlamydophila pneumoniae phospholipase D. AB - Chlamydophila pneumoniae, an aetiological agent of respiratory infection, is also thought to play an immuno-pathogenetic role in atherosclerosis by contributing to inflammation and plaque instability. Phospholipase D (PLD) is an enzyme involved in lipid metabolism and may have a direct or indirect impact on virulence and the inflammatory response. Some aspects of the developmental cycle of C. pneumoniae suggest a direct implication of its PLD (CpPLD) in the pathogenesis, specifically by affecting the regulation of lipid metabolism and lipid exchange between C. pneumoniae and host cells. Our previous studies disclosed a specific anti-CpPLD antibody response in patients with acute coronary syndromes chronically infected with C. pneumoniae, and demonstrated that this antigen is a factor able to drive the inflammatory process in atherosclerosis. Due to the intriguing aspects of the CpPLD, the present study investigated CpPLD enzymatic activity of the protein and the two domains that include one HKD motif each polypeptide. Our results showed that CpPLD was able to synthesize the cardiolipin (CL) but unable to hydrolyze phospholipids. It was also observed that each single HKD motif has an independent CL synthetase activity. This enzymatic activity of CpPLD could be important in the inflammatory process within the atherothrombotic events. PMID- 25742150 TI - Detection of Pneumocystis jirovecii and Aspergillus spp. DNa in bronchoalveolar lavage fluids by commercial real-time PCr assays: comparison with conventional diagnostic tests. AB - The present study employed two commercial real-time PCR kits, MycAssay? Pneumocystis (PJ-PCR) and MycAssay? Aspergillus (ASP-PCR), for the search of fungal DNA on 44 bronchoalveolar lavage (BAL) fluids from patients at risk of invasive fungal disease. Operationally, on the basis of clinical diagnosis and according to the European Organization for Research and Treatment Cancer/Mycoses Study Group (EORTC/MSG) criteria, patients were clustered in 3 groups: a P. jirovecii pneumonia (PCP) group, an invasive aspergillosis (IA) group and a control (CTRL) group, consisting of 8, 10 and 24 patients, respectively. The results were compared to those obtained with conventional diagnostic assays, including BAL culture, galactomannan-ELISA (GM) and immunofluorescence (IF). The PJ-PCR assay returned a sensitivity and specificity of 100% and 94.4%, respectively. The ASP-PCR assay showed a sensitivity and specificity of 80% and 97.1%. When compared to the culture assay, the ASP-PCR showed enhanced sensitivity, and a good level of agreement (kappa = 0.63) was observed between ASP-PCR and GM assays. Overall, our data emphasize the diagnostic usefulness of the two commercial real-time PCR assays, especially in high-risk patients where timing is critical and a low fungal burden may hamper correct and prompt diagnosis by conventional tests. PMID- 25742149 TI - Antimicrobial efficacy of doripenem and its combinations with sulbactam, amikacin, colistin, tigecycline in experimental sepsis of carbapenem-resistant Acinetobacter baumannii. AB - Acinetobacter baumannii is the most common species to have developed resistance to antibiotics. Due to increasing levels of drug resistance, the available therapeutic options are insufficient in A. baumannii infections. This study investigated the efficacy of doripenem monotherapy versus doripenem combination therapy with sulbactam, amikacin, colistin and tigecycline in experimental sepsis. A carbapenem-resistant A. baumannii was used to develop a sepsis model in 8-10-week-old Balb/c mice by intraperitoneal injection. Antibiotic therapies were initiated two hours after injection of bacterial suspension. Necropsy was performed at 24, 48 and 72 hours and cultures were made from heart, lung, liver and spleen samples. Bacterial loads of lung and liver were calculated as CFU/g. Combination therapies with doripenem were more effective than monotherapy at 24 and 48 hours of infection but no differences between groups were detected at 72 hours. The combination of doripenem with tigecycline and amikacin began to eradicate the bacterial load of lung and liver after 48 hours of infection, whereas doripenem+sulbactam and doripenem+colistin were started to eradication at 72 hours. The results of the study showed that combination therapies with doripenem are more effective than monotherapy and the combination of doripenem with tigeycline or amikacin has more rapid bactericidal effect than that with sulbactam or colistin. PMID- 25742151 TI - JCV-specific T-cells producing IFN-gamma are differently associated with PmL occurrence in HIV patients and liver transplant recipients. AB - Aim of this work was to investigate a possible correlation between the frequency of JCV-specific T-cells and PML occurrence in HIV-infected subjects and in liver transplant recipients. A significant decrease of JCV-specific T-cells was observed in HIV-PML subjects, highlighting a close relation between JCV-specific T-cell immune impairment and PML occurrence in HIV-subjects. Interestingly, liver transplant recipients (LTR) showed a low frequency of JCV-specific T-cells, similar to HIV-PML subjects. Nevertheless, none of the enrolled LTR developed PML, suggesting the existence of different immunological mechanisms involved in the maintenance of a protective immune response in LTR. PMID- 25742152 TI - L1 gene sequence of a putative novel type human papillomavirus in an immunocompetent patient with glans lichen sclerosus. AB - The identification of a putative novel type human papillomaviruses (HPV) strain related to HPV-RTRX3 in a subject with penile skin warts and glans lichen sclerosus is reported. A beta-HPV-RTRX3-like strain was detected in a immunocompetent patient with glans lichen sclerosus. HPV screening was performed by PCR in L1 gene. The MY fragment showed 99% nt identity with HPV-RTRX3 and 64.5% nt identity with HPV-37. The remaining part of the L1 gene showed similarity with HPV 80, 15, 17, and 37. Based on the presence of penile lichen sclerosus and the HPV-RTRX3-like strain found in our patient, a potential correlation was hypothesized. PMID- 25742153 TI - Characterization of the tripartite drug efflux pumps of Porphyromonas gingivalis aTCC 33277. AB - The periodontal pathogen, Porphyromonas gingivalis ATCC 33277 has six gene clusters that encode tripartite drug efflux pumps. To examine the effects of the drug efflux pumps on its antibiotic sensitivity, six mutants were constructed, each defective in the membrane fusion protein gene of each gene cluster. Compared to the wild-type strain, all mutants exhibited an elevated sensitivity to tetracycline, and two mutants with deletions in the PGN_1431 and PGN_1680 genes showed an increased sensitivity to various types of antibiotics. These results suggest that the activity of drug efflux systems may affect antibiotic sensitivity in P. gingivalis. PMID- 25742154 TI - Waterborne norovirus outbreak during a summer excursion in Northern Italy. AB - In September 2011, an acute gastroenteritis outbreak affected 33 children in Northern Italy. Patients had drunk river water during an excursion. Identical GI.4 norovirus genomes were detected from one patient's stools and from the river water. Improper discharge of human sewage into the river may have caused this waterborne outbreak. PMID- 25742155 TI - Listeria monocytogenes meningitis in an immunocompromised patient. AB - This report describes a case of meningitis caused by Listeria monocytogenes in a stem cell transplant recipient on immunosuppressive therapy for cutaneous chronic graft-versus host disease. A 59-year-old woman had undergone allogeneic stem cell transplantation (from a matched unrelated donor) 13 months previously for chronic lymphocytic leukemia. She was on regular hematologic follow-up. Though her previous malignancy has been in remission, she was immunosuppressed due to the pharmacological treatment. We describe a meningitis caused by a typical food borne pathogen, dangerous in patients with impaired cell-mediated immunity. Moreover the bacterium had a multidrug resistance, a rare characteristic in clinical listeriosis. Rapid diagnosis and treatment are key factors in these cases. We chose ampicillin and rifampicin that allowed a complete resolution of the clinical manifestations. PMID- 25742156 TI - Hepatitis A virus in a medical setting in Madagascar: a lesson for public health. PMID- 25742157 TI - Expression of concern: Thakur A, Kadam R, Kompella UB. Trabecular meshwork and lens partitioning of corticosteroids: implications for elevated intraocular pressure and cataracts. Arch Ophthalmol. 2011:129(7):914-920. AB - JAMA Ophthalmology has been notified by the University of Colorado Denver Anschutz Medical Campus that the university completed a scientific misconduct investigation involving research published by Rajendra Kadam, MPharm, and has determined that 10 papers with Kadam as an author contain falsified and/or fabricated data. For the article published in 2011 by Kadam et al in JAMA Ophthalmology, then known as Archives of Ophthalmology, the original liquid chromatographic/mass spectrometric data were not available to compare with the data used in the analysis, and the investigative committee was unable to validate the data reported in the study. Therefore, the committee was unable to reach any definitive conclusion related to the integrity or reliability of the data in this report. This Editorial Expression of Concern is to inform readers about possible concerns related to data therein. If additional information becomes available about the integrity of the data reported in this article, we will determine whether additional action is warranted. PMID- 25742158 TI - Controlling factors in the rates of oxidation of anilines and phenols by triplet methylene blue in aqueous solution. AB - Anilines and phenols are structurally similar compound classes that both are susceptible to oxidation by excited state triplet sensitizers but undergo oxidation by different mechanisms. To gain an understanding of the factors that control the rate of oxidation of anilines and phenols by triplet excited states, a kinetic study was performed on the oxidation of substituted anilines and phenols by methylene blue. The rate constants of one-electron transfer from anilines to triplet state methylene blue and their dependence on the reaction free energy are well fit to a Sandros-Boltzmann model. The observed rate constants are also well modeled when aniline oxidation potentials derived computationally are used. For phenols, the proton-coupled electron transfer rate constants were found to correlate primarily with O-H bond dissociation free energy and secondarily with phenol pKa. Rate constants for phenols could be modeled using computed bond dissociation free energies. These results provide a basis for predicting aniline and phenol oxidation rates, which could be valuable, for example, in assessing the likely persistence and fate of aniline- and phenol based aqueous environmental pollutants. PMID- 25742159 TI - Association between low-grade albuminuria and cardiovascular risk in Korean adults: the 2011-2012 Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Recent studies have indicated that low UACR levels (<30 MUg/mg) previously considered to be in the normal range ('low-grade albuminuria') are associated with cardiovascular morbidity and mortality in the general population. METHODS: We studied 9,736 participants with albuminuria in the normal range from the 2011-2012 Korea National Health and Nutrition Examination Survey (KNHANES). RESULTS: The weighted prevalences of metabolic syndrome (MS) and the 10-year risk for coronary heart disease measured using the Framingham risk score (FRS) >= 20% (high risk) were 22.5 +/- 0.7% and 14.5 +/- 0.7%, respectively, in males and 23.3 +/- 0.8% and 8.5 +/- 0.4%, respectively in females. Weighted comparisons among the tertiles of UACR revealed that the prevalences of MS and high-risk FRS increased with increasing UACR (MS: males, 15.9 +/- 1.1, 20.2 +/- 1.2, 32.4 +/- 1.5%, respectively; P < 0.001; and females, 17.6 +/- 1.0, 22.7 +/- 1.0, 30.2 +/- 1.4%, respectively; P < 0.001. High-risk FRS: males, 9.5 +/- 0.7, 12.3 +/- 0.9, 22.5 +/- 1.2, respectively; P < 0.001; and females, 5.8 +/- 0.6, 7.9 +/- 0.7, 12.0 +/- 0.9%, respectively; P < 0.001). The positive association persisted after adjusting for hypertension and diabetes. The weighted comparisons among the deciles of UACR revealed that the prevalences of MS and high-risk FRS began to increase at the ranges of 3.89-5.15 and 5.16-7.36 mg/g Cr, respectively. CONCLUSION: Low-grade albuminuria was significantly associated with estimated cardiovascular risk and MS in a nationally representative sample of Koreans. PMID- 25742160 TI - Gated mesoporous silica nanoparticles for the controlled delivery of drugs in cancer cells. AB - In recent years, mesoporous silica nanoparticles (MSNs) have been used as effective supports for the development of controlled-release nanodevices that are able to act as multifunctional delivery platforms for the encapsulation of therapeutic agents, enhancing their bioavailability and overcoming common issues such as poor water solubility and poor stability of some drugs. In particular, redox-responsive delivery systems have attracted the attention of scientists because of the intracellular reductive environment related to a high concentration of glutathione (GSH). In this context, we describe herein the development of a GSH-responsive delivery system based on poly(ethylene glycol)- (PEG-) capped MSNs that are able to deliver safranin O and doxorubicin in a controlled manner. The results showed that the PEG-capped systems designed in this work can be maintained closed at low GSH concentrations, yet the cargo can be delivered when the concentration of GSH is increased. Moreover, the efficacy of the PEG-capped system in delivering the cytotoxic agent doxorubicin in cells was also demonstrated. PMID- 25742161 TI - Efficacy of Chinese eye exercises on reducing accommodative lag in school-aged children: a randomized controlled trial. AB - PURPOSE: To evaluate the efficacy of Chinese eye exercises on reducing accommodative lag in children by a randomized, double-blinded controlled trial. METHODS: A total of 190 children aged 10 to 14 years with emmetropia to moderate myopia were included. They were randomly allocated to three groups: standard Chinese eye exercises group (trained for eye exercises by doctors of traditional Chinese medicine); sham point eye exercises group (instructed to massage on non acupoints); and eyes closed group (asked to close their eyes without massage). Primary outcome was change in accommodative lag immediately after intervention. Secondary outcomes included changes in corrected near and distant visual acuity, and visual discomfort score. RESULTS: Children in the standard Chinese eye exercises group had significantly greater alleviation of accommodative lag (-0.10 D) than those in sham point eye exercises group (-0.03 D) and eyes closed group (0.07 D) (P = 0.04). The proportion of children with alleviation of accommodative lag was significantly higher in the standard Chinese eye exercises group (54.0%) than in the sham point eye exercises group (32.8%) and the eyes closed group (34.9%) (P = 0.03). No significant differences were found in secondary outcomes. CONCLUSION: Chinese eye exercises as performed daily in primary and middle schools in China have statistically but probably clinically insignificant effect in reducing accommodative lag of school-aged children in the short-term. Considering the higher amounts of near work load of Chinese children, the efficacy of eye exercises may be insufficient in preventing myopia progression in the long-term. TRIAL REGISTRATION: ClinicalTrials.gov NCT01756287. PMID- 25742164 TI - Correction: The release rate of environmental DNA from juvenile and adult fish. PMID- 25742163 TI - Th17 inflammation model of oropharyngeal candidiasis in immunodeficient mice. AB - Oropharyngeal Candidiasis (OPC) disease is caused not only due to the lack of host immune resistance, but also the absence of appropriate regulation of infection-induced immunopathology. Although Th17 cells are implicated in antifungal defense, their role in immunopathology is unclear. This study presents a method for establishing oral Th17 immunopathology associated with oral candidal infection in immunodeficient mice. The method is based on reconstituting lymphopenic mice with in vitro cultured Th17 cells, followed by oral infection with Candida albicans (C. albicans). Results show that unrestrained Th17 cells result in inflammation and pathology, and is associated with several measurable read-outs including weight loss, pro-inflammatory cytokine production, tongue histopathology and mortality, showing that this model may be valuable in studying OPC immunopathology. Adoptive transfer of regulatory cells (Tregs) controls and reduces the inflammatory response, showing that this model can be used to test new strategies to counteract oral inflammation. This model may also be applicable in studying oral Th17 immunopathology in general in the context of other oral diseases. PMID- 25742162 TI - Generation of influenza virus from avian cells infected by Salmonella carrying the viral genome. AB - Domestic poultry serve as intermediates for transmission of influenza A virus from the wild aquatic bird reservoir to humans, resulting in influenza outbreaks in poultry and potential epidemics/pandemics among human beings. To combat emerging avian influenza virus, an inexpensive, heat-stable, and orally administered influenza vaccine would be useful to vaccinate large commercial poultry flocks and even migratory birds. Our hypothesized vaccine is a recombinant attenuated bacterial strain able to mediate production of attenuated influenza virus in vivo to induce protective immunity against influenza. Here we report the feasibility and technical limitations toward such an ideal vaccine based on our exploratory study. Five 8-unit plasmids carrying a chloramphenicol resistance gene or free of an antibiotic resistance marker were constructed. Influenza virus was successfully generated in avian cells transfected by each of the plasmids. The Salmonella carrier was engineered to allow stable maintenance and conditional release of the 8-unit plasmid into the avian cells for recovery of influenza virus. Influenza A virus up to 107 50% tissue culture infective doses (TCID50)/ml were recovered from 11 out of 26 co-cultures of chicken embryonic fibroblasts (CEF) and Madin-Darby canine kidney (MDCK) cells upon infection by the recombinant Salmonella carrying the 8-unit plasmid. Our data prove that a bacterial carrier can mediate generation of influenza virus by delivering its DNA cargoes into permissive host cells. Although we have made progress in developing this Salmonella influenza virus vaccine delivery system, further improvements are necessary to achieve efficient virus production, especially in vivo. PMID- 25742165 TI - The anti-(+)-methamphetamine monoclonal antibody mAb7F9 attenuates acute (+) methamphetamine effects on intracranial self-stimulation in rats. AB - Passive immunization with monoclonal antibodies (mAbs) against (+) methamphetamine (METH) is being evaluated for the treatment of METH addiction. A human/mouse chimeric form of the murine anti-METH mAb7F9 has entered clinical trials. This study examined the effects of murine mAb7F9 on certain addiction related behavioral effects of METH in rats as measured using intracranial self stimulation (ICSS). Initial studies indicated that acute METH (0.1-0.56 mg/kg, s.c.) lowered the minimal (threshold) stimulation intensity that maintained ICSS. METH (0.3 mg/kg, s.c.) also blocked elevations in ICSS thresholds (anhedonia-like behavior) during spontaneous withdrawal from a chronic METH infusion (10 mg/kg/day x 7 days). In studies examining effects of i.v. pretreatment with mAb7F9 (at 30, 100, or 200 mg/kg), 200 mg/kg blocked the ability of an initial injection of METH (0.3 mg/kg, s.c.) to reduce baseline ICSS thresholds, but was less capable of attenuating the effect of subsequent daily injections of METH. MAb7F9 (200 mg/kg) also produced a small but significant reduction in the ability of METH (0.3 mg/kg, s.c.) to reverse METH withdrawal-induced elevations in ICSS thresholds. These studies demonstrate that mAb7F9 can partially attenuate some addiction-related effects of acute METH in an ICSS model, and provide some support for the therapeutic potential of mAb7F9 for the treatment of METH addiction. PMID- 25742167 TI - Room-temperature transition-metal-free one-pot synthesis of 3-aryl imidazo[1,2 a]pyridines via iodo-hemiaminal intermediate. AB - A mild and efficient one-pot synthesis of 3-aryl imidazo[1,2-a]pyridines in up to 88% yield was developed. An adduct was formed after the simple mixing of 2-amino 4-methylpyridine, 2-phenylacetaldehyde, and N-iodosuccinimide in CH2Cl2, and the structure of the adduct was characterized by 2D NMR, IR, and high-resolution mass analysis. The adduct was readily cyclized by treatment with a saturated aqueous solution of NaHCO3. The reactions proceeded to completion after several hours at room temperature. PMID- 25742168 TI - Detection of foodborne bacterial pathogens from individual filth flies. AB - There is unanimous consensus that insects are important vectors of foodborne pathogens. However, linking insects as vectors of the pathogen causing a particular foodborne illness outbreak has been challenging. This is because insects are not being aseptically collected as part of an environmental sampling program during foodborne outbreak investigations and because there is not a standardized method to detect foodborne bacteria from individual insects. To take a step towards solving this problem, we adapted a protocol from a commercially available PCR-based system that detects foodborne pathogens from food and environmental samples, to detect foodborne pathogens from individual flies.Using this standardized protocol, we surveyed 100 wild-caught flies for the presence of Cronobacter spp., Salmonella enterica, and Listeria monocytogenes and demonstrated that it was possible to detect and further isolate these pathogens from the body surface and the alimentary canal of a single fly. Twenty-two percent of the alimentary canals and 8% of the body surfaces from collected wild flies were positive for at least one of the three foodborne pathogens. The prevalence of Cronobacter spp. on either body part of the flies was statistically higher (19%) than the prevalence of S. enterica (7%) and L.monocytogenes (4%). No false positives were observed when detecting S. enterica and L. monocytogenes using this PCR-based system because pure bacterial cultures were obtained from all PCR-positive results. However, pure Cronobacter colonies were not obtained from about 50% of PCR-positive samples, suggesting that the PCR-based detection system for this pathogen cross-reacts with other Enterobacteriaceae present among the highly complex microbiota carried by wild flies. The standardized protocol presented here will allow laboratories to detect bacterial foodborne pathogens from aseptically collected insects, thereby giving public health officials another line of evidence to find out how the food was contaminated when performing foodborne outbreak investigations. PMID- 25742166 TI - Moving protons and electrons in biomimetic systems. AB - An enormous variety of biological redox reactions are accompanied by changes in proton content at enzyme active sites, in their associated cofactors, in substrates and/or products, and between protein interfaces. Understanding this breadth of reactivity is an ongoing chemical challenge. A great many workers have developed and investigated biomimetic model complexes to build new ways of thinking about the mechanistic underpinnings of such complex biological proton coupled electron transfer (PCET) reactions. Of particular importance are those model reactions that involve transfer of one proton (H(+)) and one electron (e( )), which is equivalent to transfer of a hydrogen atom (H(*)). In this Current Topic, we review key concepts in PCET reactivity and describe important advances in biomimetic PCET chemistry, with a special emphasis on research that has enhanced efforts to understand biological PCET reactions. PMID- 25742169 TI - Metal-free synthesis of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts. AB - Ynones are a valuable functional group and building block in organic synthesis. Ynones serve as a precursor to many important organic functional groups and scaffolds. Traditional methods for the preparation of ynones are associated with drawbacks including harsh conditions, multiple purification steps, and the presence of unwanted byproducts. An alternative method for the straightforward preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts is described herein. The adoption of organotrifluoroborate salts as an alternative to organometallic reagents for the formation of new carbon-carbon bonds has a number of advantages. Potassium organotrifluoroborate salts are shelf stable, have good functional group tolerance, low toxicity, and a wide variety are straightforward to prepare. The title reaction proceeds rapidly at ambient temperature in the presence of a Lewis acid without the exclusion of air and moisture. Fair to excellent yields may be obtained via reaction of various aryl and alkyl acid chlorides with alkynyltrifluoroborate salts in the presence of boron trichloride. PMID- 25742170 TI - Novel atomic force microscopy based biopanning for isolation of morphology specific reagents against TDP-43 variants in amyotrophic lateral sclerosis. AB - Because protein variants play critical roles in many diseases including TDP-43 in Amyotrophic Lateral Sclerosis (ALS), alpha-synuclein in Parkinson's disease and beta-amyloid and tau in Alzheimer's disease, it is critically important to develop morphology specific reagents that can selectively target these disease specific protein variants to study the role of these variants in disease pathology and for potential diagnostic and therapeutic applications. We have developed novel atomic force microscopy (AFM) based biopanning techniques that enable isolation of reagents that selectively recognize disease-specific protein variants. There are two key phases involved in the process, the negative and positive panning phases. During the negative panning phase, phages that are reactive to off-target antigens are eliminated through multiple rounds of subtractive panning utilizing a series of carefully selected off-target antigens. A key feature in the negative panning phase is utilizing AFM imaging to monitor the process and confirm that all undesired phage particles are removed. For the positive panning phase, the target antigen of interest is fixed on a mica surface and bound phages are eluted and screened to identify phages that selectively bind the target antigen. The target protein variant does not need to be purified providing the appropriate negative panning controls have been used. Even target protein variants that are only present at very low concentrations in complex biological material can be utilized in the positive panning step. Through application of this technology, we acquired antibodies to protein variants of TDP 43 that are selectively found in human ALS brain tissue. We expect that this protocol should be applicable to generating reagents that selectively bind protein variants present in a wide variety of different biological processes and diseases. PMID- 25742171 TI - Low energy physical activity recognition system on smartphones. AB - An innovative approach to physical activity recognition based on the use of discrete variables obtained from accelerometer sensors is presented. The system first performs a discretization process for each variable, which allows efficient recognition of activities performed by users using as little energy as possible. To this end, an innovative discretization and classification technique is presented based on the chi2 distribution. Furthermore, the entire recognition process is executed on the smartphone, which determines not only the activity performed, but also the frequency at which it is carried out. These techniques and the new classification system presented reduce energy consumption caused by the activity monitoring system. The energy saved increases smartphone usage time to more than 27 h without recharging while maintaining accuracy. PMID- 25742172 TI - Continuous human action recognition using depth-MHI-HOG and a spotter model. AB - In this paper, we propose a new method for spotting and recognizing continuous human actions using a vision sensor. The method is comprised of depth-MHI-HOG (DMH), action modeling, action spotting, and recognition. First, to effectively separate the foreground from background, we propose a method called DMH. It includes a standard structure for segmenting images and extracting features by using depth information, MHI, and HOG. Second, action modeling is performed to model various actions using extracted features. The modeling of actions is performed by creating sequences of actions through k-means clustering; these sequences constitute HMM input. Third, a method of action spotting is proposed to filter meaningless actions from continuous actions and to identify precise start and end points of actions. By employing the spotter model, the proposed method improves action recognition performance. Finally, the proposed method recognizes actions based on start and end points. We evaluate recognition performance by employing the proposed method to obtain and compare probabilities by applying input sequences in action models and the spotter model. Through various experiments, we demonstrate that the proposed method is efficient for recognizing continuous human actions in real environments. PMID- 25742173 TI - In-vitro activity of avermectins against Mycobacterium ulcerans. AB - Mycobacterium ulcerans causes Buruli ulcer (BU), a debilitating infection of subcutaneous tissue. There is a WHO-recommended antibiotic treatment requiring an 8-week course of streptomycin and rifampicin. This regime has revolutionized the treatment of BU but there are problems that include reliance on daily streptomycin injections and side effects such as ototoxicity. Trials of all-oral treatments for BU show promise but additional drug combinations that make BU treatment safer and shorter would be welcome. Following on from reports that avermectins have activity against Mycobacterium tuberculosis, we tested the in vitro efficacy of ivermectin and moxidectin on M. ulcerans. We observed minimum inhibitory concentrations of 4-8 MUg/ml and time-kill assays using wild type and bioluminescent M. ulcerans showed a significant dose-dependent reduction in M. ulcerans viability over 8-weeks. A synergistic killing-effect with rifampicin was also observed. Avermectins are well tolerated, widely available and inexpensive. Based on our in vitro findings we suggest that avermectins should be further evaluated for the treatment of BU. PMID- 25742175 TI - Root plasticity of Populus euphratica seedlings in response to different water table depths and contrasting sediment types. AB - Riparian plants in arid regions face a highly variable water environment controlled by hydrological processes. To understand whether riparian plants adapt to such environments through plastic responses, we compared the root traits, biomass allocation and growth of Populus euphratica Oliv. Seedlings grown in lysimeters filled with clay or clay/river sand sediments under inundation and varying water table conditions. We hypothesized that adaptive phenotypic plasticity is likely to develop or be advantageous in seedlings of this species to allow them to adapt desert floodplain environments. Growth was significantly reduced by inundation. However, rather than following relatively fixed trait and allocation patterns, the seedlings displayed adaptive mechanisms involving the development of adventitious roots to enhance plant stability and obtain oxygen, together with a lower proportion of root biomass. At the whole-plant level, at deeper water table depths, seedlings allocated more biomass to the roots, and total root length increased with decreasing water table depths, regardless of the sediment, consistent with optimal partitioning theory. The sediment type had a significant effect on seedling root traits. P. euphratica displayed very different root traits in different sediment types under the same hydrological conditions, showing a greater first-order root number in clay sediment under shallower water table conditions, whereas rooting depth was greater in clay/river sand sediment under deep water table conditions. In clay sediment, seedlings responded to lower water availability via greater root elongation, while the root surface area was increased through increasing the total root length in clay/river sand sediment, suggesting that seedlings facing deeper water tables are not always likely to increase their root surface area to obtain more water. Our results indicate that P. euphratica seedlings are able to adapt to a range of water table conditions through plastic responses in root traits and biomass allocation. PMID- 25742174 TI - Bioenergetic programming of macrophages by the apolipoprotein A-I mimetic peptide 4F. AB - The apoA-I (apolipoprotein A-I) mimetic peptide 4F favours the differentiation of human monocytes to an alternatively activated M2 phenotype. The goal of the present study was to test whether the 4F-mediated differentiation of MDMs (monocyte-derived macrophages) requires the induction of an oxidative metabolic programme. 4F treatment induced several genes in MDMs that play an important role in lipid metabolism, including PPARgamma (peroxisome-proliferator-activated receptor gamma) and CD36. Addition of 4F was associated with a significant increase in FA (fatty acid) uptake and oxidation compared with vehicle treatment. Mitochondrial respiration was assessed by measurement of the OCR (oxygen consumption rate). 4F increased basal and ATP-linked OCR as well as maximal uncoupled mitochondrial respiration. These changes were associated with a significant increase in DeltaPsim (mitochondrial membrane potential). The increase in metabolic activity in 4F-treated MDMs was attenuated by etomoxir, an inhibitor of mitochondrial FA uptake. Finally, addition of the PPARgamma antagonist T0070907 to 4F-treated MDMs reduced the expression of CD163 and CD36, cell-surface markers for M2 macrophages, and reduced basal and ATP-linked OCR. These results support our hypothesis that the 4F-mediated differentiation of MDMs to an anti-inflammatory phenotype is due, in part, to an increase in FA uptake and mitochondrial oxidative metabolism. PMID- 25742176 TI - Polyphosphatase PPN1 of Saccharomyces cerevisiae: switching of exopolyphosphatase and endopolyphosphatase activities. AB - The polyphosphatase PPN1 of Saccharomyces cerevisiae shows an exopolyphosphatase activity splitting phosphate from chain end and an endopolyphosphatase activity fragmenting high molecular inorganic polyphosphates into shorter polymers. We revealed the compounds switching these activities of PPN1. Phosphate release and fragmentation of high molecular polyphosphate prevailed in the presence of Co2+ and Mg2+, respectively. Phosphate release and polyphosphate chain shortening in the presence of Co2+ were inhibited by ADP but not affected by ATP and arginine. The polyphosphate chain shortening in the presence of Mg2+ was activated by ADP and arginine but inhibited by ATP. PMID- 25742177 TI - [Uncommon Complication of a Common Infection of the Upper Airways]. PMID- 25742178 TI - [Intralesional therapy of a postoperatively originated ranula]. PMID- 25742180 TI - Environmental behavior of the chiral herbicide haloxyfop. 2. Unchanged enantiomer composition in blackgrass (Alopecurus myosuroides) and garden cress (Lepidium sativum). AB - Haloxyfop-methyl is a chiral herbicide against grasses in dicotyledonous crops. In plants and soil, haloxyfop-methyl is rapidly hydrolyzed to haloxyfop-acid, whose R-enantiomer carries the actual herbicidal activity. In soil, S-haloxyfop acid is converted within less than 1 day and almost completely into R-haloxyfop acid. In this study, we investigated the possible interconversion of the enantiomers of haloxyfop-methyl and haloxyfop-acid in blackgrass and garden cress. Racemic or enantiopure haloxyfop-methyl was applied to the leaves of plants grown in agar. The metabolism was followed during 4 days using enantioselective GC-MS. In contrast to soils, no interconversion was observed in plants, and metabolism was nonenantioselective. These findings are consistent with the fact that after pre-emergence application to soil and uptake by roots, the observed herbicidal effect is basically independent of the enantiomer composition of the applied substance, whereas after postemergence application, the efficacy clearly is different for the two enantiomers. PMID- 25742181 TI - A hypoxia efficient imidazole-based Ru(II) arene anticancer agent resistant to deactivation by glutathione. AB - A slow hydrolyzing imidazole-based Ru(II)-arene complex [(L)Ru(II)(eta(6)-p cym)(Cl)](PF6) (1) with excellent stability in the extracellular chloride concentration shows better activity under hypoxia and strong resistance to glutathione (GSH) in vitro under hypoxic conditions. 1 arrests the cell cycle in sub G1 and G2/M phases and leads to apoptosis. PMID- 25742179 TI - HBV genotypic variability in Cuba. AB - The genetic diversity of HBV in human population is often a reflection of its genetic admixture. The aim of this study was to explore the genotypic diversity of HBV in Cuba. The S genomic region of Cuban HBV isolates was sequenced and for selected isolates the complete genome or precore-core sequence was analyzed. The most frequent genotype was A (167/250, 67%), mainly A2 (149, 60%) but also A1 and one A4. A total of 77 isolates were classified as genotype D (31%), with co circulation of several subgenotypes (56 D4, 2 D1, 5 D2, 7 D3/6 and 7 D7). Three isolates belonged to genotype E, two to H and one to B3. Complete genome sequence analysis of selected isolates confirmed the phylogenetic analysis performed with the S region. Mutations or polymorphisms in precore region were more common among genotype D compared to genotype A isolates. The HBV genotypic distribution in this Caribbean island correlates with the Y lineage genetic background of the population, where a European and African origin prevails. HBV genotypes E, B3 and H isolates might represent more recent introductions. PMID- 25742182 TI - One step synthesis of quantum dot-magnetic nanoparticle heterodimers for dual modal imaging applications. AB - Dual modal nanoprobes are promising tools for accurately detecting target molecules as part of the diagnosis of diseases including cancers. We have explored a new dual modal bioimaging probe that is comprised of a quantum dot (QD)-magnetic nanoparticle (MNP) hybrid. The MNP-QD heterodimers explored are fabricated by using a platinum-guanine coordination bonding guided self-assembly process, employing the metal-DNA conjugation method. Investigations utilizing energy dispersive spectroscopy (EDS) equipped high resolution transmission electron microscopy (HRTEM) demonstrate that the heterodimer contains an iron (Fe) dominant MNP and a cadmium (Cd) dominant QD. Finally, the results of cell studies show that the MNP-QD conjugates display good HeLa cell uptake in the absence of non-specific binding to the cell membrane and, as such, they can be used to label cells in vitro and in vivo as part of a new cell imaging technique. PMID- 25742183 TI - Pollen dispersal in fragmented populations of the dioecious wind-pollinated tree, Allocasuarina verticillata (drooping sheoak, drooping she-oak; Allocasuarinaceae). AB - Vegetation clearing, land modification and agricultural intensification have impacted on many ecological communities around the world. Understanding how species respond to fragmentation and the scales over which functionality is retained, can be critical for managing biodiversity in agricultural landscapes. Allocasuarina verticillata (drooping sheoak, drooping she-oak) is a dioecious, wind-pollinated and -dispersed species with key conservation values across southeastern Australia. But vegetation clearing associated with agricultural expansion has reduced the abundance and spatial distribution of this species in many regions. Spatial genetic structure, relatedness among trees, pollen dispersal and mating patterns were examined in fragmented A. verticillata populations selected to represent the types of remnants that now characterise this species. Short scale spatial genetic structure (5-25 m) and relatedness among trees were observed in most populations. Unexpectedly, the two male trees closest to each female did not have a reproductive advantage accounting for only 4-15% of the seed produced in larger populations. Biparental inbreeding was also generally low (<4%) with limited evidence of seed crop domination by some male trees. More male trees contributed to seed crops in linear remnants (mean 17) compared to those from patch remnants (mean 11.3) which may reflect differences in pollen dispersal within the two remnant types. On average, pollen travels ~100 m irrespective of remnant type but was also detected to have dispersed as far as 1 km in open landscapes. Low biparental inbreeding, limited reproductive assurance for near-neighbour and probably related males and variability in the distances over which females sample pollen pools suggest that some mechanism to prevent matings between relatives exists in this species. PMID- 25742184 TI - (3 + 1)-Dimensional commensurately modulated structure and photoluminescence properties of diborate KSbOB2O5. AB - Single-crystal diborate KSbOB2O5 has been prepared under a high temperature molten-salt method and its structure has been determined by single crystal X-ray diffraction analysis. The diffraction pattern shows strong main reflections and weak satellite reflections, clearly indicating a modulated structure. Using the four-dimensional superspace formalism for aperiodic structures, its reflections could be indexed as orthorhombic superspace group Pmn21(0beta0)s00 with the modulation vector q = 5/12b*, and then the structure solution and refinement reached a final commensurately modulated model that was refined extremely well and did not show any unusual features. On the other hand, the powder sample of KSbOB2O5 was synthesized by the high-temperature solid-state reaction method, and the powder X-ray diffraction pattern fits very well with the simulated from the single-crystal data. In addition, photoluminescence properties of diborate KSbOB2O5 activated by 4.5 mol% Dy(3+) have been studied, indicating an extraordinary phenomenon that the red emission at around 635 nm ((4)F(9/2) -> (6)H(11/2)) is much stronger than the yellow emission at around 581 nm ((4)F(9/2) -> (6)H(13/2)). PMID- 25742185 TI - Orthotopic injection of breast cancer cells into the mammary fat pad of mice to study tumor growth. AB - Breast cancer growth can be studied in mice using a plethora of models. Genetic manipulation of breast cancer cells may provide insights into the functions of proteins involved in oncogenic progression or help to discover new tumor suppressors. In addition, injecting cancer cells into mice with different genotypes might provide a better understanding of the importance of the stromal compartment. Many models may be useful to investigate certain aspects of disease progression but do not recapitulate the entire cancerous process. In contrast, breast cancer cells engraftment to the mammary fat pad of mice better recapitulates the location of the disease and presence of the proper stromal compartment and therefore better mimics human cancerous disease. In this article, we describe how to implant breast cancer cells into mice orthotopically and explain how to collect tissues to analyse the tumor milieu and metastasis to distant organs. Using this model, many aspects (growth, angiogenesis, and metastasis) of cancer can be investigated simply by providing a proper environment for tumor cells to grow. PMID- 25742186 TI - Therapist-supported Internet cognitive behavioural therapy for anxiety disorders in adults. AB - BACKGROUND: Cognitive behavioural therapy (CBT) is an evidence-based treatment for anxiety disorders. Many people have difficulty accessing treatment, due to a variety of obstacles. Researchers have therefore explored the possibility of using the Internet to deliver CBT; it is important to ensure the decision to promote such treatment is grounded in high quality evidence. OBJECTIVES: To assess the effects of therapist-supported Internet CBT on remission of anxiety disorder diagnosis and reduction of anxiety symptoms in adults as compared to waiting list control, unguided CBT, or face-to-face CBT. Effects of treatment on quality of life and patient satisfaction with the intervention were also assessed. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group Specialized Register (CCDANCTR) to 12 April 2013. The CCDANCTR includes relevant randomised controlled trials from EMBASE (1974 -), MEDLINE (1950 -) and PsycINFO (1967 -). We also searched online clinical trial registries and reference lists of included studies. We contacted authors to locate further trials. An update of an initial search (April 2013), conducted in September 2014, identified seven new completed studies, seven previously ongoing studies now completed, and four new ongoing studies. This is a fast-moving area; we plan to update this review shortly, incorporating these new studies. SELECTION CRITERIA: Each identified study was independently assessed for inclusion by two authors. To be included, studies had to be randomised controlled trials of therapist-supported ICBT compared to a waiting list, attention, information, or online discussion group; unguided CBT (that is, self-help); or face-to-face CBT. We included studies that treated adults with an anxiety disorder (panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, obsessive compulsive disorder, and specific phobia) defined according to the Diagnostic and Statistical Manual of Mental Disorders III, III-R, IV, IV-TR or the International Classification of Disesases 9 or 10. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of included studies and judged overall study quality. We used data from intention-to-treat analyses wherever possible. We assessed treatment effect for the dichotomous outcome of clinically important improvement in anxiety using a risk ratio (RR) with 95% confidence interval (CI). For disorder-specific and general anxiety symptom measures and quality of life we assessed continuous scores using standardized mean differences (SMD). We examined statistical heterogeneity using the I(2) statistic. MAIN RESULTS: We screened 1000 citations and selected 30 studies (2181 participants) for inclusion. The studies examined social phobia (11 trials), panic disorder with or without agoraphobia (8 trials), generalized anxiety disorder (4 trials), post-traumatic stress disorder (1 trial), and specific phobia (1 trial). Five remaining studies included a range of anxiety disorder diagnoses. Studies were conducted in Sweden (15 trials), Australia (12 trials), Switzerland (2 trials), and the Netherlands (1 trial) and investigated a variety of ICBT protocols. Three primary comparisons were identified, experimental versus waiting list control, experimental versus unguided ICBT, and experimental versus face-to-face CBT.Moderate quality evidence from 9 studies (644 participants) contributed to a pooled RR of 4.18 (95% CI 2.42 to 7.22) for clinically important improvement in anxiety at post-treatment, favouring therapist-supported ICBT over a waiting list, attention, information, or online discussion group only. Similarly, the SMD for disorder-specific symptoms at post-treatment (22 studies, 1573 participants; SMD -1.12, 95% CI 1.39 to -0.85) and general anxiety symptoms at post-treatment (14 studies, 1004 participants; SMD -0.79, 95% CI -1.10 to -0.48) favoured therapist-supported ICBT. The quality of the evidence for both outcomes was low.One study compared unguided CBT to therapist-supported ICBT for clinically important improvement in anxiety at post-treatment, showing no difference in outcome between treatments (54 participants; very low quality evidence). At post-treatment there were no clear differences between unguided CBT and therapist-supported ICBT for disorder specific anxiety symptoms (4 studies, 253 participants; SMD -0.24, 95% CI -0.69 to 0.21; low quality evidence) or general anxiety symptoms (two studies, 138 participants; SMD 0.28, 95% CI -2.21 to 2.78; low quality evidence).Compared to face-to-face CBT, therapist-supported ICBT showed no significant differences in clinically important improvement in anxiety at post-treatment (4 studies, 365 participants; RR 1.09, 95% CI 0.89 to 1.34; moderate quality evidence). There were also no clear differences between face-to-face and therapist supported ICBT for disorder-specific anxiety symptoms at post-treatment (6 studies, 424 participants; SMD 0.09, 95% CI -0.26 to 0.43; low quality evidence) or general anxiety symptoms at post-treatment (5 studies, 317 participants; SMD 0.17, 95% CI -0.35 to 0.69; low quality evidence).Overall, risk of bias in included studies was low or unclear for most domains. However, due to the nature of psychosocial intervention trials, blinding of participants and personnel, and outcome assessment tended to have a high risk of bias. Heterogeneity across a number of the meta-analyses was substantial, some was explained by type of anxiety disorder or may be meta-analytic measurement artefact due to combining many assessment measures. Adverse events were rarely reported. AUTHORS' CONCLUSIONS: Therapist supported ICBT appears to be an efficacious treatment for anxiety in adults. The evidence comparing therapist-supported ICBT to waiting list, attention, information, or online discussion group only control was low to moderate quality, the evidence comparing therapist-supported ICBT to unguided ICBT was low to very low quality, and comparisons of therapist-supported ICBT to face-to-face CBT was low to moderate quality. Further research is needed to better define and measure any potential harms resulting from treatment. These findings suggest that therapist-supported ICBT is more efficacious than a waiting list, attention, information, or online discussion group only control, and that there may not be a significant difference in outcome between unguided CBT and therapist-supported ICBT; however, this latter finding must be interpreted with caution due to imprecision. The evidence suggests that therapist-supported ICBT may not be significantly different from face-to-face CBT in reducing anxiety. Future research should involve equivalence trials comparing ICBT and face-to-face CBT, examine the importance of the role of the therapist in ICBT, and include effectiveness trials of ICBT in real-world settings. A timely update to this review is needed given the fast pace of this area of research. PMID- 25742187 TI - Understanding the Concept of Health Care-Associated Pneumonia in Lung Transplant Recipients. AB - BACKGROUND: Limited data are available regarding the etiologic impact of health care-associated pneumonia (HCAP) in lung transplant recipients. Therefore, our aim was to evaluate the microbiologic differences between HCAP and hospital acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in lung transplant recipients with a radiographically confirmed diagnosis of pneumonia. METHODS: We performed a retrospective cohort study of lung transplant recipients with pneumonia at one transplant center over a 7-year period. Eligible patients included lung transplant recipients who developed a first episode of radiographically confirmed pneumonia >= 48 h following transplantation. HCAP, HAP, and VAP were classified according to the American Thoracic Society/Infectious Diseases Society of America 2005 guidelines. chi2 and Student t tests were used to compare categorical and continuous variables, respectively. RESULTS: Sixty-eight lung transplant recipients developed at least one episode of pneumonia. HCAP (n = 42; 62%) was most common, followed by HAP/VAP (n = 26; 38%) stratified in HAP (n = 20; 77%) and VAP (n = 6; 23%). Pseudomonas aeruginosa was the predominantly isolated organism (n = 22; 32%), whereas invasive aspergillosis was uncommon (< 10%). Multiple-drug resistant (MDR) pathogens were less frequently isolated in patients with HCAP compared with HAP/VAP (5% vs 27%; P = .009). Opportunistic pathogens were less frequently identified in lung transplant recipients with HCAP than in those with HAP/VAP (7% vs 27%; P = .02). Lung transplant recipients with HCAP had a similar mortality at 90 days (n = 9 [21%] vs n = 4 [15%]; P = .3) compared with patients with HAP/VAP. CONCLUSIONS: HCAP was the most frequent infection in lung transplant recipients. MDR pathogens and opportunistic pathogens were more frequently isolated in HAP/VAP. There were no differences in 30- and 90-day mortality between lung transplant recipients with HCAP and those with HAP/VAP. PMID- 25742188 TI - Strong electroactive biodegradable shape memory polymer networks based on star shaped polylactide and aniline trimer for bone tissue engineering. AB - Preparation of functional shape memory polymer (SMP) for tissue engineering remains a challenge. Here the synthesis of strong electroactive shape memory polymer (ESMP) networks based on star-shaped polylactide (PLA) and aniline trimer (AT) is reported. Six-armed PLAs with various chain lengths were chemically cross linked to synthesize SMP. After addition of an electroactive AT segment into the SMP, ESMP was obtained. The polymers were characterized by (1)H NMR, GPC, FT-IR, CV, DSC, DMA, tensile test, and degradation test. The SMP and ESMP exhibited strong mechanical properties (modulus higher than GPa) and excellent shape memory performance: short recovery time (several seconds), high recovery ratio (over 94%), and high fixity ratio (almost 100%). Moreover, cyclic voltammetry test confirmed the electroactivity of the ESMP. The ESMP significantly enhanced the proliferation of C2C12 cells compared to SMP and linear PLA (control). In addition, the ESMP greatly improved the osteogenic differentiation of C2C12 myoblast cells compared to PH10 and PLA in terms of ALP enzyme activity, immunofluorescence staining, and relative gene expression by quantitative real time polymerase chain reaction (qRT-PCR). These intelligent SMPs and electroactive SMP with strong mechanical properties, tunable degradability, good electroactivity, biocompatibility, and enhanced osteogenic differentiation of C2C12 cells show great potential for bone regeneration. PMID- 25742189 TI - Chojalactones A-C, cytotoxic butanolides isolated from Streptomyces sp. cultivated with mycolic acid containing bacterium. AB - The soil-derived bacterium, Streptomyces sp. CJ-5, was cocultured with the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596. The combined culture method significantly enhanced the production of the secondary metabolites in Streptomyces sp. CJ-5, leading to the isolation of three novel butanolide chojalactones A-C (1-3), with unusual gamma-butyrolactone scaffolds. The complete structures, including the absolute configurations of 1-3, were determined based on spectroscopic data and total syntheses. In methylthiazole tetrazolium (MTT) assays, 1 and 2 showed moderate cytotoxicity against P388 cells. PMID- 25742190 TI - Congenital cytomegalovirus infections and glycoprotein B genotypes in live-born infants: a prevalence study in Turkey. AB - BACKGROUND: Cytomegalovirus (CMV) infections are the leading cause of infectious hearing loss and central nervous system disease among children worldwide. In this study, we aimed to determine the birth prevalence of congenital CMV infection in live-born infants in Turkey. METHODS: In total, 944 consecutive live-born infants born from 926 pregnant women were included in this study. CMV-DNA was investigated in saliva samples of all newborns within the first 3 days after birth using TaqMan-based real-time PCR. RESULTS: The birth prevalence of congenital CMV infection in live-born infants was 1.91% (18/944), and all congenitally infected infants were asymptomatic at birth. The prevalence of congenital CMV infection was 16.7% (3/18) in twin pregnancies and 1.32% (12/908) in single pregnancies (p = 0.002). Genotyping analysis showed glycoprotein B-1 (gB1) to be the most frequently detected genotype at 83.3%. CONCLUSION: The study results suggest that the majority of congenital CMV infection in Turkey occurs following nonprimary maternal infection. We believe that congenital CMV infection and its long-term effects have been underestimated in our country, as infected infants are usually asymptomatic at birth. PMID- 25742191 TI - Growth-based determination and biochemical confirmation of genetic requirements for protein degradation in Saccharomyces cerevisiae. AB - Regulated protein degradation is crucial for virtually every cellular function. Much of what is known about the molecular mechanisms and genetic requirements for eukaryotic protein degradation was initially established in Saccharomyces cerevisiae. Classical analyses of protein degradation have relied on biochemical pulse-chase and cycloheximide-chase methodologies. While these techniques provide sensitive means for observing protein degradation, they are laborious, time consuming, and low-throughput. These approaches are not amenable to rapid or large-scale screening for mutations that prevent protein degradation. Here, a yeast growth-based assay for the facile identification of genetic requirements for protein degradation is described. In this assay, a reporter enzyme required for growth under specific selective conditions is fused to an unstable protein. Cells lacking the endogenous reporter enzyme but expressing the fusion protein can grow under selective conditions only when the fusion protein is stabilized (i.e. when protein degradation is compromised). In the growth assay described here, serial dilutions of wild-type and mutant yeast cells harboring a plasmid encoding a fusion protein are spotted onto selective and non-selective medium. Growth under selective conditions is consistent with degradation impairment by a given mutation. Increased protein abundance should be biochemically confirmed. A method for the rapid extraction of yeast proteins in a form suitable for electrophoresis and western blotting is also demonstrated. A growth-based readout for protein stability, combined with a simple protocol for protein extraction for biochemical analysis, facilitates rapid identification of genetic requirements for protein degradation. These techniques can be adapted to monitor degradation of a variety of short-lived proteins. In the example presented, the His3 enzyme, which is required for histidine biosynthesis, was fused to Deg1-Sec62. Deg1-Sec62 is targeted for degradation after it aberrantly engages the endoplasmic reticulum translocon. Cells harboring Deg1-Sec62-His3 were able to grow under selective conditions when the protein was stabilized. PMID- 25742192 TI - Health and carcinogenic risk evaluation for cohorts exposed to PAHs in petrochemical workplaces in Rawalpindi city (Pakistan). AB - This study presents the analyses of urinary biomarkers (1-OHPyr, alpha- and beta naphthols) of polycyclic aromatic hydrocarbons (PAHs) exposure and biomarkers of effect (i.e. blood parameters) in petroleum-refinery workers (RFs) and auto repair workers (MCs). Exposed subjects had higher concentrations of white blood cell (WBC) count than control subjects (CN) subjects (5.31 * 10(3) MUL(-1) in exposed vs. 5.15 * 10(3) MUL(-1) in CN subjects), while the biomarker of oxidative DNA damage (8-OHdG) was significantly higher in MCs. The exposure among these two cohorts could be influenced by the ambience of the workplaces; in fact, MCs' shops are relatively damp and enclosed workplaces in comparison with the indoor environment of refineries. PAHs in the dust samples from mechanical workshops probably originated from mixed sources (traffic exhaust and petroleum spills), while the incremental lifetime cancer risk (ILCR) for MCs showed moderate-to-low cancer risk from exposure to dust-bound PAHs. The study shows that increasing PAH exposure can be traced in MC workstations and needs to be investigated for the safety of public health. PMID- 25742193 TI - Silylated precision particles for controlled release of proteins. AB - With the recent advances in the development of novel protein based therapeutics, controlled delivery of these biologics is an important area of research. Herein, we report the synthesis of microparticles from bovine serum albumin (BSA) as a model protein using Particle Replication in Non-wetting Templates (PRINT) with specific size and shape. These particles were functionalized at room temperature using multifunctional chlorosilane that cross-link the particles to render them to slowly-dissolving in aqueous media. Mass spectrometric study of the reaction products of diisopropyldichlorosilane with individual components of the particles revealed that they are capable of reacting and forming cross-links. Energy dispersive spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) were also used to confirm the functionalization of the particles. Cross sectional analysis using focused ion beam (FIB) and EDS proved that the functionalization occurs throughout the bulk of the particles and is not just limited to the surface. Circular dichroism data confirmed that the fraction of BSA molecules released from the particles retains its secondary structure thereby indicating that the system can be used for delivering protein based formulations while controlling the dissolution kinetics. PMID- 25742194 TI - Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. AB - PURPOSE: To determine if repeated intravenous exposures to gadolinium-based contrast agents (GBCAs) are associated with neuronal tissue deposition. MATERIALS AND METHODS: In this institutional review board-approved single-center study, signal intensities from T1-weighted magnetic resonance (MR) images and postmortem neuronal tissue samples from 13 patients who underwent at least four GBCA enhanced brain MR examinations between 2000 and 2014 (contrast group) were compared with those from 10 patients who did not receive GBCA (control group). Antemortem consent was obtained from all study participants. Neuronal tissues from the dentate nuclei, pons, globus pallidus, and thalamus of these 23 deceased patients were harvested and analyzed with inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy, and light microscopy to quantify, localize, and assess the effects of gadolinium deposition. Associations between cumulative gadolinium dose, changes in T1-weighted MR signal intensity, and ICP-MS-derived tissue gadolinium concentrations were examined by using the Spearman rank correlation coefficient (rho). RESULTS: Compared with neuronal tissues of control patients, all of which demonstrated undetectable levels of gadolinium, neuronal tissues of patients from the contrast group contained 0.1 58.8 MUg gadolinium per gram of tissue, in a significant dose-dependent relationship that correlated with signal intensity changes on precontrast T1 weighted MR images (rho = 0.49-0.93). All patients in the contrast group had relatively normal renal function at the time of MR examination. Gadolinium deposition in the capillary endothelium and neural interstitium was observed only in the contrast group. CONCLUSION: Intravenous GBCA exposure is associated with neuronal tissue deposition in the setting of relatively normal renal function. Additional studies are needed to investigate the clinical significance of these findings and the generalizability to other GBCAs. Online supplemental material is available for this article. PMID- 25742195 TI - Enhanced photocatalytic performance of sandwiched ZnO@Ag@Cu2O nanorod films: the distinct role of Ag NPs in the visible light and UV region. AB - Sandwiched ZnO@Ag@Cu2O nanorod films were synthesized by successive electrodeposition, magnetron sputtering and the second electrodeposition. The as synthesized composites were characterized by x-ray diffraction patterns, field emission scanning electron microscopy, low- and high-resolution transmission electron microscopy and a UV-vis spectrophotometer. Their photocatalytic performance was estimated by the degradation of a methyl orange solution under UV or visible-light irradiation, respectively. In the visible region, due to localized surface plasmon resonance absorption of Ag NPs, ZnO@Ag@Cu2O showed a significantly enhanced photocatalytic performance. The enhancement factor of Ag NPs on the catalytic performance of ZnO@Ag@Cu2O was estimated as a function of the Cu2O deposition time, and the corresponding enhancement mechanism was also evaluated by the monochromatic photocatalytic experiment and discrete dipole approximation simulation. In the UV region, due to the formation of a Schottky junction (e.g. Ag/ZnO, Ag/Cu2O), a limited enhanced photocatalytic performance was also realized for ZnO@Ag@Cu2O photocatalysts. PMID- 25742196 TI - Pediatric Ferroportin Disease. PMID- 25742197 TI - Correlation of clinical profile and specific histopathological features of temporal artery biopsies. AB - BACKGROUND: This study sought to correlate the clinical features of patients with giant cell arteritis (GCA) who present with ophthalmic symptoms and signs, with 2 specific histopathological findings-the presence of giant cells and arterial wall neoangiogenesis. The goal was to assess if these pathological features might be useful in guiding the approach to patient management. METHODS: Medical charts were retrospectively reviewed from 58 patients who underwent a temporal artery biopsy at a single institution. Detailed information was collected about the clinical presentation and course, with an emphasis on visual function. Histopathological and immunohistochemical techniques were used to examine temporal artery biopsies for evidence of inflammation. Correlations were made between the clinical data and the presence of giant cells and neoangiogenesis. RESULTS: Twenty-one (34%) biopsies were positive for inflammation consistent with GCA. Although the percentage of positive biopsies with giant cells was high, neither the presence of giant cells nor neoangiogenesis was predictive of a patient's presenting visual symptoms, severity and bilaterality of vision loss, other ophthalmic manifestations of GCA, presence of headache or jaw claudication, or erythrocyte sedimentation rate. Giant cells were more common in patients with recent weight loss. Immunohistochemistry confirmed diagnoses but did not alter the clinical course or treatment plan. CONCLUSIONS: There was no correlation between the clinical, specifically visual, features of GCA and the presence or absence of giant cells or neoangiogenesis in temporal artery biopsy specimens. Although the presence of neoangiogenesis may be important in the pathogenesis of GCA, our study showed no correlation between this finding and the clinical course. PMID- 25742198 TI - Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas. AB - BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms. PMID- 25742199 TI - Harnessing the bioorthogonal inverse electron demand Diels-Alder cycloaddition for pretargeted PET imaging. AB - Due to their exquisite affinity and specificity, antibodies have become extremely promising vectors for the delivery of radioisotopes to cancer cells for PET imaging. However, the necessity of labeling antibodies with radionuclides with long physical half-lives often results in high background radiation dose rates to non-target tissues. In order to circumvent this issue, we have employed a pretargeted PET imaging strategy based on the inverse electron demand Diels-Alder cycloaddition reaction. The methodology decouples the antibody from the radioactivity and thus exploits the positive characteristics of antibodies, while eschewing their pharmacokinetic drawbacks. The system is composed of four steps: (1) the injection of a mAb-trans-cyclooctene (TCO) conjugate; (2) a localization time period during which the antibody accumulates in the tumor and clears from the blood; (3) the injection of the radiolabeled tetrazine; and (4) the in vivo click ligation of the components followed by the clearance of excess radioligand. In the example presented in the work at hand, a (64)Cu-NOTA-labeled tetrazine radioligand and a trans-cyclooctene-conjugated humanized antibody (huA33) were successfully used to delineate SW1222 colorectal cancer tumors with high tumor-to background contrast. Further, the pretargeting methodology produces high quality images at only a fraction of the radiation dose to non-target tissue created by radioimmunoconjugates directly labeled with (64)Cu or (89)Zr. Ultimately, the modularity of this protocol is one of its greatest assets, as the trans cyclooctene moiety can be appended to any non-internalizing antibody, and the tetrazine can be attached to a wide variety of radioisotopes. PMID- 25742200 TI - The feasibility of utilizing plasma MiRNA107 and BACE1 messenger RNA gene expression for clinical diagnosis of amnestic mild cognitive impairment. AB - OBJECTIVE: To investigate the relationship between microRNA107 (miRNA107) and BACE1 messenger RNA (mRNA) gene expressions in plasma and their diagnostic capability to distinguish subjects with amnestic mild cognitive impairment from healthy controls. METHOD: We recruited 97 patients with Alzheimer's disease according to diagnostic criteria of DSM-IV and National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association, 116 subjects with amnestic mild cognitive impairment, and 81 healthy controls from January 2012 to December 2012. The real-time PCR was used to quantify miRNA107 and BACE1 mRNA. The power of classification accuracies between patients with amnestic mild cognitive impairment and healthy controls was performed using linear discriminate analysis single or combining both the expression miRNA107 and BACE1 mRNA. RESULTS: For patients with Alzheimer's disease, the miRNA107 expressions in plasma and cerebral spinal fluid were correlated (Pearson correlation = 0.665, P = .034). There were statistically significant correlations between plasma miRNA107 and BACE1 mRNA gene expression in Alzheimer's disease, amnestic mild cognitive impairment, and healthy control groups (r value = -0.316 [P = .002], -0.615 [P < .001], and -0.367 [P = .001], respectively). The overall classification accuracy of miRNA107 to discriminate between patients with amnestic mild cognitive impairment and healthy controls was 91.9%, with sensitivity of 98.3% and specificity of 82.7%. CONCLUSIONS: The miRNA107 expression in plasma has a high capability to discriminate between patients with amnestic mild cognitive impairment and healthy controls. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01819545. PMID- 25742201 TI - C-reactive protein alterations in bipolar disorder: a meta-analysis. AB - OBJECTIVE: There is growing evidence that bipolar disorder (BD) is associated with inflammation, including abnormal levels of acute-phase C-reactive protein (CRP). Our meta-analysis was conducted to estimate the size of the association between CRP levels and BD, accounting also for subgroup differences (mood phases and treatment). DATA SOURCES: MEDLINE, EMBASE, PsycINFO, and ISI Web of Science and references of identified articles were searched up to June 2013 using the keywords (bipolar disorder) AND (C-reactive protein OR CRP). STUDY SELECTION: English language studies measuring blood levels of CRP in patients with BD and control subjects were selected, 136 abstracts were reviewed, 20 articles retrieved, and 11 studies included. DATA EXTRACTION: Two independent reviewers extracted data. All studies were included in the primary analyses, and between group differences for subanalyses were also reported. This meta-analysis was performed using random-effects models. RESULTS: Eleven studies comprising 1,618 subjects were eligible for inclusion. Overall, CRP levels were significantly elevated in patients with BD versus controls (standardized mean difference [SMD] = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (SMD = 0.73; 95% CI, 0.44 to 1.02; P < .001) and euthymic (SMD = 0.26; 95% CI, 0.01 to 0.51; P = .04), but not in depressed (SMD = 0.28; 95% CI, -0.17 to 0.73; P = .22) patients with BD compared to controls. CRP levels were unrelated to use of lithium or antipsychotic medication. CONCLUSIONS: This meta-analysis supports an association between increased CRP levels and BD. Given that an elevated level of CRP is a marker of low-grade inflammation and a risk factor for cardiovascular and malignant diseases, measurement of CRP level might be relevant to the clinical care of bipolar patients. PMID- 25742202 TI - The economic burden of adults with major depressive disorder in the United States (2005 and 2010). AB - BACKGROUND: The economic burden of depression in the United States--including major depressive disorder (MDD), bipolar disorder, and dysthymia--was estimated at $83.1 billion in 2000. We update these findings using recent data, focusing on MDD alone and accounting for comorbid physical and psychiatric disorders. METHOD: Using national survey (DSM-IV criteria) and administrative claims data (ICD-9 codes), we estimate the incremental economic burden of individuals with MDD as well as the share of these costs attributable to MDD, with attention to any changes that occurred between 2005 and 2010. RESULTS: The incremental economic burden of individuals with MDD increased by 21.5% (from $173.2 billion to $210.5 billion, inflation-adjusted dollars). The composition of these costs remained stable, with approximately 45% attributable to direct costs, 5% to suicide related costs, and 50% to workplace costs. Only 38% of the total costs were due to MDD itself as opposed to comorbid conditions. CONCLUSIONS: Comorbid conditions account for the largest portion of the growing economic burden of MDD. Future research should analyze further these comorbidities as well as the relative importance of factors contributing to that growing burden. These include population growth, increase in MDD prevalence, increase in treatment cost per individual with MDD, changes in employment and treatment rates, as well as changes in the composition and quality of MDD treatment services. PMID- 25742203 TI - Excessive and premature new-onset cardiovascular disease among adults with bipolar disorder in the US NESARC cohort. AB - BACKGROUND: Cross-sectional studies demonstrate increased prevalence of cardiovascular disease (CVD) among adults with bipolar disorder. However, there is a paucity of prospective data regarding new-onset CVD among adults with bipolar disorder. METHOD: Analyses compared the 3-year incidence of CVD (via participant-reported physician diagnoses) among participants with DSM-IV diagnoses of bipolar I disorder (n = 1,047), bipolar II disorder (n = 392), major depressive disorder (MDD; n = 4,396), or controls (n = 26,266), who completed Wave 1 (2001-2002) and Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Analyses also compared the age of participants with new-onset CVD across groups. Multivariable analyses controlled for age, sex, race, cigarette smoking, hypertension, obesity, and alcohol and drug use disorders. RESULTS: The 3-year incidence of CVD among adults with bipolar I disorder, bipolar II disorder, MDD, and among controls was 6.30%, 5.74%, 3.98%, and 3.70%, respectively. The covariate-adjusted incidence of CVD was significantly greater among participants with bipolar I and II disorders versus controls and versus participants with MDD. Adjusted odds ratios (95% CI) were 2.58 (1.84-3.61; P < .0001) for bipolar I disorder vs controls; 2.76 (1.60 4.74; P = .0004) for bipolar II disorder vs controls; 2.11 (1.46-3.04; P = .0001) for bipolar I disorder vs MDD; 2.25 (1.26-4.01; P = .007) for bipolar II disorder vs MDD; and 1.22 (0.99-1.51; P = .06) for MDD vs controls. Bipolar I disorder participants with new-onset CVD were 10.70 +/- 2.77 years younger than MDD participants with new-onset CVD and 16.78 +/- 2.51 years younger than controls. Bipolar II disorder participants with new-onset CVD were 7.92 +/- 3.27 years younger than MDD participants with new-onset CVD and 13.99 +/- 2.79 years younger than controls. DISCUSSION: Adults with bipolar disorder are at significantly and meaningfully increased risk to develop CVD over the course of 3 years, even as compared to adults with MDD, and despite controlling for multiple potential confounds. Combined with very early age of CVD onset, this finding underscores the need for early and assertive CVD prevention strategies for people with bipolar disorder. PMID- 25742204 TI - Solutions for treating Hispanic adults with ADHD. PMID- 25742205 TI - Efficacy of acamprosate for the treatment of alcohol dependence long after recovery from withdrawal syndrome: a randomized, double-blind, placebo-controlled study conducted in Japan (Sunrise Study). AB - OBJECTIVE: To undertake a double-blind, randomized, placebo-controlled trial to examine the efficacy of acamprosate in maintaining complete abstinence in Japanese patients with alcohol dependence. METHOD: We enrolled 327 patients with ICD-10-defined alcohol dependence and randomly assigned them to treatment with either acamprosate (1,998 mg/d orally) or placebo for 24 weeks. The primary endpoint was complete abstinence after 24 weeks of administration. The study was performed at 34 medical institutions between 2009 and 2011. RESULTS: The acamprosate group demonstrated significantly superior efficacy versus the placebo group on the primary endpoint: the proportion maintaining complete abstinence in the acamprosate group was 47.2% (77/163 subjects), compared with 36.0% (59/164 subjects) in the placebo group (P = .039). The difference in complete abstinence rates between the 2 groups was 11.3% (95% CI, 0.6%-21.9%). CONCLUSIONS: Acamprosate is superior to placebo in maintaining abstinence in Japanese patients with alcohol dependence. These findings concur with 11 randomized, blinded, placebo-controlled clinical trials conducted in Europe. This study was designed to reflect clinical practice in Japan and is therefore a meaningful addition to the available evidence in this field. TRIAL REGISTRATION: JapicCTI identifier: 090694. PMID- 25742206 TI - Buprenorphine-naloxone treatment of prescription opioid abuse: does past performance predict future results? PMID- 25742207 TI - MDDScore: confirmation of a blood test to aid in the diagnosis of major depressive disorder. AB - BACKGROUND: Previously, a biomarker panel was developed for use as an aid to major depressive disorder (MDD) diagnosis; it consisted of 9 biomarkers associated with the neurotrophic, metabolic, inflammatory, and hypothalamic pituitary-adrenal axis pathways. This panel and associated algorithm produced good clinical sensitivity and specificity (92% and 81%, respectively) in differentiating MDD patients from individuals without MDD. To further validate the panel, we performed a prospective study using a larger set of new prospectively acquired MDD patients and a similarly collected population of nondepressed subjects. The addition of gender and body mass index (BMI) effects to the algorithm was also evaluated. METHOD: Blood samples were obtained from MDD patients (n = 68) clinically evaluated at multiple sites in 2011 and 2012 using standard psychiatric assessment tools and structured clinical interviews according to DSM-IV criteria. Blood samples (n = 86) from nondepressed subjects were obtained as controls. MDD and nondepressed samples were randomized into independent training (n = 102) and validation sets (n = 52). Analytes in sera were quantified by immunoassay. RESULTS: Training set biomarker data were used to develop a logistic regression model that included gender and BMI in a manner that allowed for their interaction with the biochemical analytes. For the training set, the sensitivity and specificity of the test (with 95% CI) were 93% (0.80 0.98) and 95% (0.85-0.99), respectively. This method (designated the MDDScore) was then applied to the independent validation set and had a sensitivity and specificity of 96% (0.77-0.98) and 86% (0.66-0.95), respectively. The overall accuracy for the training set was 94%; the validation set accuracy was 91%. CONCLUSION: Examination of a randomized independent set of samples confirms the ability of the previously established biomarker panel to identify persons with MDD; the accuracy was over 90%. The improved model that adds gender and BMI to the previously established panel of 9 biomarkers is robust and simple; it provides the most rigorously tested, objective diagnostic test for MDD to date. PMID- 25742209 TI - Lumpers, splitters, and statistics: bipolar disorder, schizophrenia, and their relationship to seasonality. PMID- 25742208 TI - Reduction of alcohol drinking in young adults by naltrexone: a double-blind, placebo-controlled, randomized clinical trial of efficacy and safety. AB - OBJECTIVE: Naltrexone, an opioid antagonist, may facilitate reduction in drinking among young adults. We compared the efficacy and safety of naltrexone administered daily plus targeted dosing with placebo to reduce drinking in young adults who engage in heavy drinking. METHOD: A randomized, double-blind, placebo controlled study was conducted in an outpatient research center in March 2008 January 2012. Participants were aged 18-25 years and reported >= 4 heavy drinking days in the prior 4 weeks. Interventions included naltrexone 25 mg daily plus 25 mg targeted (at most daily) in anticipation of drinking (n = 61) or daily/targeted placebo (n = 67). All participants received a personalized feedback session and brief counseling every other week. Primary outcomes were percent heavy drinking days and percent days abstinent over the 8-week treatment period. Secondary outcomes included number of drinks per drinking day and percentage of days with estimated blood alcohol concentration (BAC) levels >= 0.08 g/dL. RESULTS: Of 140 randomized patients, 128 began treatment, comprising the evaluable sample. During treatment, percent heavy drinking days (naltrexone: mean = 21.60, SD = 16.05; placebo: mean = 22.90, SD = 13.20) (P = .58) and percent days abstinent (naltrexone: mean = 56.60, SD = 22.52; placebo: mean = 62.50, SD = 15.75) (P = .39) did not differ by group. Naltrexone significantly reduced the number of drinks per drinking day (naltrexone: mean = 4.90, SD = 2.28; placebo: mean = 5.90, SD = 2.51) (P = .009) and percentage of drinking days with estimated BAC >= 0.08 g/dL (naltrexone: mean = 35.4, SD = 28.40; placebo: mean = 45.7, SD = 26.80) (P = .042). There were no serious adverse events. Sleepiness was more common with naltrexone. CONCLUSIONS: Naltrexone did not reduce frequency of drinking or heavy drinking days, but reduced secondary measures of drinking intensity. While effects were modest, the risk-benefit ratio favors offering naltrexone to help young adult heavy drinkers reduce the amount of alcohol they drink. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00568958. PMID- 25742210 TI - Reducing the cost and burden of depression: incorporate heart and get an early start. PMID- 25742211 TI - A blood test for depression? PMID- 25742212 TI - Medical test development and implementation: a multistep journey. PMID- 25742213 TI - Bipolar II disorder: reasons to recognize. PMID- 25742214 TI - Acamprosate, alcoholism, and abstinence. PMID- 25742215 TI - Naltrexone reduces heavy drinking in problem drinkers across the spectrum of dependence. PMID- 25742216 TI - A primer on confidence intervals in psychopharmacology. AB - Research papers and research summaries frequently present results in the form of data accompanied by 95% confidence intervals (CIs). Not all students and clinicians know how to interpret CIs. This article provides a nontechnical, nonmathematical discussion on how to understand and glean information from CIs; all explanations are accompanied by simple examples. A statistically accurate explanation about CIs is also provided. CIs are differentiated from standard deviations, standard errors, and confidence levels. The interpretation of narrow and wide CIs is discussed. Factors that influence the width of a CI are listed. Explanations are provided for how CIs can be used to assess statistical significance. The significance of overlapping and nonoverlapping CIs is considered. It is concluded that CIs are far more informative than, say, mere P values when drawing conclusions about a result. PMID- 25742217 TI - Renal toxicity of long-term lithium treatment for mild cognitive impairment. PMID- 25742218 TI - Drs Aprahamian and Forlenza reply. PMID- 25742219 TI - Health care-seeking behaviors of African American ADHD patients and their families: overcoming economic and cultural barriers. PMID- 25742220 TI - Treating depression in primary care: initial and follow-up treatment strategies. PMID- 25742221 TI - Switching therapies in MS: what are the options? PMID- 25742223 TI - Value of FDG PET/CT in staging of oral cancer: four simultaneous primary malignancies. AB - Patients with squamous cell cancer (SCC) of the head and neck are at increased risk for second primary malignancies (SPMs). We report on a 53-year-old patient with primary diagnosis of SCC in the anterior floor of the mouth. Panendoscopy suspected an SPM of the right vocal cord. FDG PET/CT, as a whole-body imaging method, confirmed this suspicion and raised concern for further SPM of both esophagus and colon. All malignancies were confirmed by biopsy. Subsequently, the patient underwent radiochemotherapy. In summary, FDG PET/CT revealed unexpected multiple SPMs, prevented unnecessary resection of the oral SCC, and enabled individualized therapeutic management. PMID- 25742222 TI - A guide to generating and using hiPSC derived NPCs for the study of neurological diseases. AB - Post-mortem studies of neurological diseases are not ideal for identifying the underlying causes of disease initiation, as many diseases include a long period of disease progression prior to the onset of symptoms. Because fibroblasts from patients and healthy controls can be efficiently reprogrammed into human induced pluripotent stem cells (hiPSCs), and subsequently differentiated into neural progenitor cells (NPCs) and neurons for the study of these diseases, it is now possible to recapitulate the developmental events that occurred prior to symptom onset in patients. We present a method by which to efficiently differentiate hiPSCs into NPCs, which in addition to being capable of further differentiation into functional neurons, can also be robustly passaged, freeze-thawed or transitioned to grow as neurospheres, enabling rapid genetic screening to identify the molecular factors that impact cellular phenotypes including replication, migration, oxidative stress and/or apoptosis. Patient derived hiPSC NPCs are a unique platform, ideally suited for the empirical testing of the cellular or molecular consequences of manipulating gene expression. PMID- 25742224 TI - Ovarian hyperstimulation and breast cancer on PET imaging with sonographic correlation. AB - We present interesting PET/CT and ultrasound findings in a 36-year-old lactating woman with stage T2 N0 M0 right breast cancer undergoing oocyte retrieval for fertility preservation. Her cancer treatment plan included neoadjuvant chemotherapy; therefore, the patient wanted to undergo an oocyte retrieval procedure for fertility preservation. She underwent a transvaginal ultrasound guided oocyte retrieval procedure in the morning and a staging F-FDG PET/CT later the same day. At the time of PET imaging, she had been breast-feeding her 9-month old infant with only her left breast. PMID- 25742225 TI - The role of routine clinical pretreatment 18F-FDG PET/CT in predicting outcome of colorectal liver metastasis. AB - OBJECTIVE: The aim of this study was to determine the value of SUV-based metabolic parameters derived from pretreatment F-FDG PET/CT of colorectal liver metastases in predicting disease response, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: We retrospectively reviewed 70 colorectal patients with liver metastases who underwent pretreatment F-FDG PET/CT. SUVmean, SUVmax, TLG (total lesion glycolysis), metabolic tumor volume, and metabolic tumor diameter were the metabolic parameters derived from volume of interest analysis of the most FDG-avid liver lesion in each subject. Clinical and laboratory parameters were recorded. Tumor response was assessed by response evaluation criteria in solid tumors 1.1 criteria at 12 weeks after treatment. Associations between tumor response, metabolic parameters, and clinical/laboratory parameters were examined by 1-way analysis of variance. The relationship of the metabolic parameters with PFS and OS was determined by Kaplan Meier analyses and further confirmed with multivariate Cox regression analyses. RESULTS: SUVmean less than 4.48, SUVmax less than 6.59, TLG less than 75.2, metabolic tumor volume less than 4.49 cm, and hemoglobin level greater than or equal to 11 g/dL were associated with longer PFS (P < 0.05). Prior surgery or radiofrequency ablation to the liver metastases was the only additional factor shown to be associated with longer OS. CONCLUSIONS: SUV-based metabolic parameters derived from pretreatment F-FDG PET/CT can predict PFS in colorectal liver metastases. PMID- 25742226 TI - Etiology of amyloidosis determines myocardial 99mTc-DPD uptake in amyloidotic cardiomyopathy. AB - Tc-DPD (Tc-3,3-diphosphono-1,2-propanodicarboxylic acid) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light chain cardiac amyloidosis and other nonamyloidotic cardiomyopathies with a hypertrophic phenotype, in which myocardial tracer uptake is low or absent. Myocardial bone tracer uptake in the rarer forms of amyloidosis (eg, apolipoprotein-related) has been rarely studied. We present 4 cases of cardiac amyloidosis that underwent Tc-DPD scintigraphy; myocardial DPD uptake was present in patients with ATTR, wtTTR and apolipoprotein AI and negative in cases with AL and apolipoprotein AII-related disease. PMID- 25742227 TI - Radio-guided surgery and postoperative PET/CT scan of a surgical specimen of an intraosseous meningioma in a patient with neuroendocrine tumor of the pancreas. AB - A 63-year-old man with a previously resected neuroendocrine tumor of the pancreas underwent Ga DOTATOC PET/CT, which showed intense Ga DOTATOC uptake in the left calvarium. Radio-guided surgery and subsequent histology revealed an intraosseous meningioma. Complete removal was proven by a PET/CT scan of the surgical specimen. PMID- 25742228 TI - Anakinra injection site reaction on FDG PET/CT. AB - Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology, mainly characterized by fever, arthritis, skin rash, and raised ferritin concentration. FDG PET/CT scan of a 29-year-old woman with AOSD showed extensive lymphadenopathy, hypermetabolic splenomegaly, and increased bone marrow uptake consistent with AOSD activity. In addition, large dense lesions with high FDG uptake in the subcutaneous fat in the thighs corresponding to injection sites were seen. She had been treated with prednisone and daily subcutaneous injection of 100 mg anakinra before the scan indicating the subcutaneous lesions as injection site reactions to anakinra. PMID- 25742229 TI - (18)FDG PET/CT appearance in primary cutaneous diffuse large B-cell lymphoma, leg type. AB - We report the case of a 70-year-old woman who presented with a small and painless red skin nodule in the right lower leg, which rapidly and significantly increased in size over few weeks and developed a central eschar. Skin biopsy was consistent with primary cutaneous diffuse large B-cell lymphoma, leg type (PCDBCL-LT), an aggressive and rare cutaneous lymphoma. F-FDG PET/CT showed a hypermetabolic soft tissue mass in the right leg with no evidence of systemic involvement of disease. PMID- 25742230 TI - Diffuse Large B-Cell Lymphoma Infiltrating Limb Bones With a Few Lymphadenopathy Revealed on Whole-Body 18F-FDG PET/CT. AB - A 74-year-old man presented to our hospital for a 2-month history of worsening feet and left hand swelling pain. Computed tomography reconstruction image and sagittal images of the left foot demonstrated multiple and irregular bone destruction. Orthopedic surgeon suspected tuberculosis or primary skeletal malignancy. 18F-FDG PET/CT revealed bone destruction and abnormal activity mainly in bones of both upper and lower extremities and a few lymphadenopathy at the region of left axilla and groin. Diagnosis of diffuse large B-cell lymphoma was eventually made. Subsequently, the patient was transferred to the department of oncology and responded well to antilymphoma therapy. PMID- 25742231 TI - Comparison of 131I-MIBG, 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT scans in a patient with extra adrenal paraganglioma associated with SDH-B gene mutation. AB - Paragangliomas (PGLs) due to succinate dehydrogenase subunit B (SDH-B) mutation can be aggressive. A 40-year-old woman with normetanephrine-secreting, extra adrenal, abdominal PGL due to SDH-B genetic mutation underwent surgical excision of primary, followed by whole-body I-MIBG scan after 6 months, which showed no abnormality. However, Ga-DOTANOC and F-FDG PET/CT scans showed primary site recurrence, hepatic and skeletal metastasis, with latter scan revealing more lesions. We suggest that F-FDG PET should be done in all patients with PGL due to SDH-B mutations, as it may show additional unsuspected lesions that may be missed by other tracers. PMID- 25742232 TI - (99m)Tc disphosphonate uptake due to splenosis: incidental finding 60 years after splenectomy. AB - A 72-year-old man was referred for a triphasic bone scintigraphy to evaluate painful prosthetic implant of the knee. In all the study phases, images showed abnormal uptake close to the tibial portion of the implant. Interestingly, later whole-body images revealed high radiopharmaceutical accumulation in the left hypochondrium. Subsequent radiolabeled leukocyte scintigraphy confirmed radiotracer accumulation in the same localizations. As an important background the patient underwent splenectomy owing to Banti syndrome 60 years earlier. A Tc labeled heat-damaged red blood cell scintigraphy was then performed, which confirmed radiopharmaceutical accumulation in the left hypochondrium being consistent with splenosis. PMID- 25742233 TI - (18)F-FDOPA accumulation in traumatic rib fractures: a potential pitfall. AB - F-FDOPA (6-[F]fluoro-L-DOPA) is used for the detection and staging of neuroendocrine tumors by visualizing the uptake of amine precursors in these tumors with high sensitivity and specificity. However, as this tracer is only available in a limited number of centers worldwide and the minority of the nuclear medicine specialists and referring clinicians is familiar with the distribution pattern of F-FDOPA, some physiological uptake patterns and pitfalls remain to be fully elucidated. Here, we present 2 cases of markedly increased uptake in the ribs after traumatic injury. PMID- 25742234 TI - (18)F-FDG PET/CT mean SUV and metabolic tumor volume for mean survival time in non-small cell lung cancer. AB - OBJECTIVE: The study was designed to determine the relationship between survival time of standardized uptake value (SUVmax and SUVmean) and metabolic tumor volume (MTV) in patients with non-small cell lung cancer (NSCLC), and examine the impact of demographic, clinical, and radiological data of these patients on survival. MATERIALS AND METHODS: We performed a retrospective analysis of the records of 79 patients with NSCLC who presented to our hospital between May 2010 and March 2013, received a final diagnosis, and underwent F-FDG PET/CT for staging. Clinical, radiological, and F-FDG PET/CT parameters with an impact on prognosis such as the SUVmax of the primary tumor as calculated by the volumetric region of interest in the F-FDG PET/CT scans during initial diagnosis, mean SUV of the tumor, and MTV obtained with a threshold of SUVmax greater than 2.5 were recorded and statistically analyzed. A statistical analysis was carried out based on the clinical, radiological, and PET/CT findings of the patients who were divided into 2 groups: survivors and nonsurvivors. RESULTS: Seventy patients (88.6%) were men, and 9 (11.4%) were women. The mean age was 63.65 +/- 11.51 years in the nonsurvivor group (n = 40) versus 62.74 +/- 10.60 years in the survivor group (n = 39) (Table 1). The mean survival time from diagnosis was 7.9 +/- 6.52 months in the nonsurvivor group versus 14.09 +/- 7.41 months in the survivor group. The mean survival time was 12.9 +/- 7.9 months for those aged 60 or younger, whereas it was 9.9 +/- 7.2 years for those aged 60 or older. According to the Cox regression analysis, higher MTV [relative risk (RR), 1.006; P = 0.03] and mean SUVmax (mSUV) (RR, 1.302; P = 0.03) had a significant impact on shortening of the mean survival time. However, no statistical significance was reached for SUVmax measurements (RR, 0.970; P = 0.39). Furthermore, there was a significant relationship between increased tumor size (<2 cm, 2-4 cm, and >=4 cm) and shortened mean survival time (P = 0.03). CONCLUSION: The present study showed that MTV and mSUV of FDG PET/CT scans of the tumor, but not SUVmax, had a significant impact on survival time of patients with NSCLC. Based on this result, we believe that we might have more accurate information about the survival time of our patients if we also evaluate mSUV and MTV in combination with mSUV, which is frequently used for diagnosis and monitoring of patients with NSCLC during our daily practice. PMID- 25742235 TI - Human Biodistribution and Radiation Dosimetry of S-11C-Methyl-L-Cysteine Using Whole-Body PET. AB - PURPOSE: S-C-Methyl-L-cysteine (C-MCYS) is a recently developed amino acid PET tracer for tumor imaging. The present study estimated human radiation absorbed dose of C-MCYS in healthy volunteers based on whole-body PET imaging. METHODS: Five sequential whole-body PET scans were performed on 6 healthy volunteers after injection of C-MCYS. Each scan contained of approximately 7 to 10 bed positions, and total scan time of each volunteer was approximately 70 to 85 minutes. Regions of interest were drawn on PET images of source organs. Residence times of 13 source organs for men and 14 source organs for women were calculated from the organ-specific time-activity curves. Absorbed dose estimates were performed from organ residence time by using the medical internal radiation dosimetry method. RESULTS: All volunteers showed initial high uptake in liver, heart, kidneys, pancreas, spleen, and uterus (only women), and followed by rapid clearance. There was very little activity residual in most of the organs except for the liver at the last emission scan time (approximately 75 minutes). The liver was the dose limiting critical organ with the highest radiation-absorbed dose (1.01E-02 +/- 2.64E-03 mGy/MBq), followed by the heart (9.09E-03 +/- 1.40E-03 mGy/MBq), and the kidneys (7.12E-03 +/- 9.44E-04 mGy/MBq). The effective dose to the whole body was 4.03E-03 +/- 1.65E-04 mSv/MBq. A routine injection of 555 MBq (15 mCi) of C-MCYS would lead to an estimated effective dose of 2.24 +/- 0.092 mSv. CONCLUSIONS: The potential radiation risks associated with C-MCYS PET imaging are within accepted limits. C-MCYS is a safe amino acid PET tracer for tumor imaging and can be used in further clinical studies. PMID- 25742236 TI - Optimized protocol for (18)F-choline PET/CT in patients with biochemically relapsed prostate cancer: experiences on 250 consecutive cases. AB - PURPOSE: We review acquisition F-choline PET/CT methodology, evaluate a new F choline acquisition protocol for prostate cancer (PC), and propose a standardized acquisition protocol on F-choline in PC patients. MATERIALS: Two hundred fifty consecutive PC patients (mean age 72 years, mean PSA 7.9 ng/mL) were prospectively evaluated with F-choline PET/CT. An early scan of the pelvis (1 bed position of 4 minutes) was followed by a whole-body scan at 1 hour. Early and 1 delayed hour images of the pelvis were compared. RESULTS: Twenty-one percent of patients (n = 57) with positive F-choline demonstrated abnormal local uptake; 18% of patients (n = 45) showed distant localization only; 23% of patients (n = 53) had both local and distant localization; 38% of patients (n = 38) did not show any pathological uptake. All early images showed absence of radioactive urine in ureters, bladder, or urethra with satisfactory visualization of the prostatic region. Considering the group of patients with local uptake only, the prostatic region uptake, confirmed by late images, was better visualized in the early phase in 32/57 cases (SUVmax 12.4 +/- 3.2 vs. 7.3 +/- 5.2, P <0.01). Instead distant lesions were visualized on both early and late images with similar uptakes values (SUVmax 9.8 +/- 4.1 vs. 10.3 +/- 4.5, P = N.S.). CONCLUSION: Early F-choline images improve pelvic prostate cancer lesion clarity. All pathologic pelvic deposits (prostate, lymph nodes, bone) were visualized both in the early and late images. PMID- 25742237 TI - Therapeutic Algorithm Guided by Sequential 11C-Choline PET/CT in a Patient With Metastatic Castration-Resistant Prostate Cancer. AB - Antiandrogen therapy alone or combined with radical therapy is the first choice in diagnosis and recurrence of patients with metastatic prostate cancer. However, patients on androgen deprivation frequently show treatment resistance. In recent years, new treatments for metastatic castration-resistant prostate cancer have been developed. Clinical studies with docetaxel have shown its usefulness for first-line therapy, and different therapeutic algorithms with second-line drugs like abiraterone or cabazitaxel have also been proposed. Sequential metabolic study with PET/CT imaging with 11C-choline may be important for assessing the right moment for administration each one of the therapeutic options. PMID- 25742238 TI - Incidental Detection of Solitary Hepatic Metastasis by 99mTc-MDP and 18F-NaF PET/CT in a Patient With Osteosarcoma of the Tibia. AB - A 36-year-old woman with a history of left above-knee amputation caused by tibial osteosarcoma 3 years ago underwent static Tc-MDP bone scintigraphy to evaluate osseous metastases. Although no lesion in the bone was identified, the images showed an intense activity in the region of the liver. This activity was also shown subsequently by F-NaF and F-FDG PET/CT imaging as a partially calcified lesion in the anterior segment of the right lobe of the liver. Solitary hepatic metastasis form osteosarcoma was suspected and further implied by follow-up studies. PMID- 25742239 TI - Sentinel lymph node biopsy of oral/oropharyngeal squamous cell carcinoma: techniques, indications, advantages, and accuracy. PMID- 25742240 TI - Asymmetric thoracic metaiodobenzylguanidine (MIBG) activity due to prior radiation therapy. AB - A 5-year-old patient suffered Horner syndrome, which was caused by a neuroblastoma in the left apex of the lung shown on the initial I-MIBG scan. After the surgical resection and external radiation to the left lung field, a follow-up I-MIBG scan revealed significantly less MIBG activity in the left upper chest compared to the contralateral right upper chest. PMID- 25742241 TI - State of the art cranial ultrasound imaging in neonates. AB - Cranial ultrasound (CUS) is a reputable tool for brain imaging in critically ill neonates. It is safe, relatively cheap and easy to use, even when a patient is unstable. In addition it is radiation-free and allows serial imaging. CUS possibilities have steadily expanded. However, in many neonatal intensive care units, these possibilities are not optimally used. We present a comprehensive approach for neonatal CUS, focusing on optimal settings, different probes, multiple acoustic windows and Doppler techniques. This approach is suited for both routine clinical practice and research purposes. In a live demonstration, we show how this technique is performed in the neonatal intensive care unit. Using optimal settings and probes allows for better imaging quality and improves the diagnostic value of CUS in experienced hands. Traditionally, images are obtained through the anterior fontanel. Use of supplemental acoustic windows (lambdoid, mastoid, and lateral fontanels) improves detection of brain injury. Adding Doppler studies allows screening of patency of large intracranial arteries and veins. Flow velocities and indices can be obtained. Doppler CUS offers the possibility of detecting cerebral sinovenous thrombosis at an early stage, creating a window for therapeutic intervention prior to thrombosis-induced tissue damage. Equipment, data storage and safety aspects are also addressed. PMID- 25742242 TI - Measurement of dynamic scapular kinematics using an acromion marker cluster to minimize skin movement artifact. AB - The measurement of dynamic scapular kinematics is complex due to the sliding nature of the scapula beneath the skin surface. The aim of the study was to clearly describe the acromion marker cluster (AMC) method of determining scapular kinematics when using a passive marker motion capture system, with consideration for the sources of error which could affect the validity and reliability of measurements. The AMC method involves placing a cluster of markers over the posterior acromion, and through calibration of anatomical landmarks with respect to the marker cluster it is possible to obtain valid measurements of scapular kinematics. The reliability of the method was examined between two days in a group of 15 healthy individuals (aged 19-38 years, eight males) as they performed arm elevation, to 120 degrees , and lowering in the frontal, scapular and sagittal planes. Results showed that between-day reliability was good for upward scapular rotation (Coefficient of Multiple Correlation; CMC = 0.92) and posterior tilt (CMC = 0.70) but fair for internal rotation (CMC = 0.53) during the arm elevation phase. The waveform error was lower for upward rotation (2.7 degrees to 4.4 degrees ) and posterior tilt (1.3 degrees to 2.8 degrees ), compared to internal rotation (5.4 degrees to 7.3 degrees ). The reliability during the lowering phase was comparable to results observed during the elevation phase. If the protocol outlined in this study is adhered to, the AMC provides a reliable measurement of upward rotation and posterior tilt during the elevation and lowering phases of arm movement. PMID- 25742243 TI - Impact of adenoviral stool load on adenoviremia in pediatric hematopoietic stem cell transplant recipients. AB - BACKGROUND: Adenoviremia adversely affects prognosis in the post-hematopoietic stem cell transplant setting. METHODS: We sought to determine retrospectively the cutoff load of adenovirus in the stool as a predictor of adenoviremia, in children who underwent an allogeneic hematopoietic stem cell transplant. The prevalence of sapovirus, norovirus and astrovirus in the stool was also studied. RESULTS: The study cohort consisted of 117 patients, of which 71 (60%) had diarrhea. Adenovirus was detected in the stool in 39 of 71 (55%) patients. Age <=10 years (P = 0.05; odds ratio: 2.57; 95% confidence interval: 0.98-6.75) and male sex (P = 0.04; odds ratio: 2.67; 95% confidence interval: 1.02-6.99) increased risk for detection of adenovirus in stool on univariate analysis. Coinfections with enteric pathogens were infrequent. Viral load >10 copies/g stool predicted adenoviremia with a sensitivity and specificity of 82%. Sapovirus, norovirus and astrovirus were detected in 3, 4 and 1 patient, respectively. CONCLUSIONS: Quantitative detection of adenovirus in stool may have implications for preemptive therapy. Testing for other enteric viruses may have implications for infection control. PMID- 25742244 TI - The effect of early life antibiotic exposures on diarrheal rates among young children in Vellore, India. AB - BACKGROUND: Antibiotic treatment of childhood illnesses is common in India. In addition to contributing to antimicrobial resistance, antibiotics might result in increased susceptibility to diarrhea through interactions with the gastrointestinal microbiota. Breast milk, which enriches the microbiota early in life, may increase the resilience of the microbiota against perturbations by antibiotics. METHODS: In a prospective observational cohort study, we assessed whether antibiotic exposures from birth to 6 months affected rates of diarrhea up to age 3 years among 465 children from Vellore, India. Adjusting for treatment indicators, we modeled diarrheal rates among children exposed and unexposed to antibiotics using negative binomial regression. We further assessed whether the effect of antibiotics on diarrheal rates was modified by exclusive breastfeeding at 6 months. RESULTS: More than half of the children (n = 267, 57.4%) were given at least one course of antibiotics in the first 6 months of life. The adjusted relative incidence rate of diarrhea was 33% higher among children who received antibiotics under 6 months of age compared with those who did not (incidence rate ratio: 1.33, 95% confidence interval: 1.12, 1.57). Children who were exclusively breastfed until 6 months of age did not have increased diarrheal rates following antibiotic use. CONCLUSIONS: Antibiotic exposures early in life were associated with increased rates of diarrhea in early childhood. Exclusive breastfeeding might protect against this negative impact. PMID- 25742246 TI - Outcomes of trauma care at centers treating a higher proportion of older patients: the case for geriatric trauma centers. AB - BACKGROUND: The burden of injury among older patients continues to grow and accounts for a disproportionate number of trauma deaths. We wished to determine if older trauma patients have better outcomes at centers that manage a higher proportion of older trauma patients. METHODS: The National Trauma Data Bank years 2007 to 2011 was used. All high-volume Level 1 and Level 2 trauma centers were included. Trauma centers were categorized by the proportion of older patients seen. Adult trauma patients were categorized as older (>=65 years) and younger adults (16-64 years). Coarsened exact matching was used to determine differences in mortality and length of stay between older and younger adults. Risk-adjusted mortality ratios by proportion of older trauma patients seen were analyzed using multivariate logistic regression models and observed-expected ratios. RESULTS: A total of 1.9 million patients from 295 centers were included. Older patients accounted for one fourth of trauma visits. Matched analysis revealed that older trauma patients were 4.2 times (95% confidence interval, 3.99-4.50) more likely to die than younger patients. Older patients were 34% less likely to die if they presented at centers treating a high versus low proportion of older trauma (odds ratio, 0.66; 95% confidence interval, 0.54-0.81). These differences were independent of trauma center performance. CONCLUSION: Geriatric trauma patients treated at centers that manage a higher proportion of older patients have improved outcomes. This evidence supports the potential advantage of treating older trauma patients at centers specializing in geriatric trauma. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25742245 TI - Genomics of injury: The Glue Grant experience. PMID- 25742247 TI - Feasibility of screening for preinjury frailty in hospitalized injured older adults. AB - BACKGROUND: Frailty assessment of injured older adults (IOAs) is important for clinical management; however, the feasibility of screening for preinjury frailty has not been established in a Level I trauma center. The aims of our study were to assess enrollment rates of IOAs and their surrogates as well as completion rates of selected brief frailty screening instruments. METHODS: We conducted a prospective cohort study on patients, age 65 years and older with a primary injury diagnosis. Patients and/or surrogates were interviewed within 48 hours of admission using the Vulnerable Elders Survey (VES-13), Barthel Index (BI), and the Life Space Assessment (LSA). Data analysis included frequency distributions, chi statistics, Mann-Whitney and Kruskal-Wallis tests, and general linear modeling (analysis of variance). RESULTS: Of 395 admitted patients, 188 were enrolled with subsequent surrogate screening. Corresponding patient interviews were conducted for 77 patients (41%). Screening time was less than 5 minutes for each instrument, and item completion was 100%. Forty-two enrolled patients (22%) had nurse-reported delirium, and 69 (37%) patients either did not feel like answering questions or were unable to be interviewed secondary to their medical condition. The median score of surrogate responses for the VES-13 was 3.5 (interquartile range, 2-7), with 64% of the sample having a score of 3 or greater, indicating vulnerability or frailty. Median scores for the BI (19.0) and LSA (56.0) indicated high numbers with limitations in activities of daily living and limitations in mobilization. CONCLUSION: Screening for preinjury frailty in IOAs is feasible yet highly dependent on the presence of a surrogate respondent. A clinically significant percentage of patients have functional deficits consistent with frailty, dependence in activities of daily living, and limitations in mobilization. Implementation of validated brief screening instruments to identify frailty in clinical settings is warranted for targeting timely, efficient, and effective care interventions. LEVEL OF EVIDENCE: Epidemiologic study, level II. PMID- 25742248 TI - Survival of severe blunt trauma patients treated with resuscitative endovascular balloon occlusion of the aorta compared with propensity score-adjusted untreated patients. AB - BACKGROUND: Despite a growing call for use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for critically uncontrolled hemorrhagic shock, there is limited evidence of treatment efficacy. We compared the mortality between patients who received a REBOA with those who did not, adjusting for the likelihood of treatment and injury severity, to measure efficacy. METHODS: We analyzed observational prospective data from the Japan Trauma Data Bank (2004 2011) to compare the mortality between adult patients who received a REBOA with those who did not. To adjust for potential treatment bias, we calculated the likelihood of REBOA treatment via a propensity score (PS) using available pretreatment variables (vital signs, age, sex, as well as anatomic and physiologic injury severity) and matched treated patients to up to five similar PS untreated patients. We compared survival to discharge between treated and untreated groups using conditional logistic regression and Cox proportional hazards regression. RESULTS: Of 45,153 patients who met inclusion, 452 patients (1.0%) received REBOA placement. These patients were seriously injured (median Injury Severity Score [ISS], 35) and had high mortality (76%). Patients who did not receive a REBOA had significantly lower injury severity (median ISS, 13; p < 0.0001) and lower mortality (16%). After matching REBOA patients with controls with similar PSs for treatment, the crude conditional odds ratio of survival by REBOA treatment was 0.30 (95% confidence interval, 0.23-0.40). CONCLUSION: REBOA treatment is associated with higher mortality compared with similarly ill trauma patients who did not receive a REBOA. The higher observed mortality among REBOA treated patients may signal "last ditch" efforts for severity not otherwise identified in the trauma registry. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV. PMID- 25742249 TI - Paraplegic and quadriplegic patients undergoing emergency abdominal surgery: sicker presentations, worse outcomes. AB - BACKGROUND: Patients with paraplegia or quadriplegia presenting with abdominal surgical emergencies pose major clinical challenges. Difficulties in prompt diagnosis and treatment may influence patient outcomes. METHODS: This is an American College of Surgeons National Surgical Quality Improvement Program study of patients undergoing an emergent abdominal operation. Patients were stratified into paraplegic (PARA), quadriplegic (QUAD), and control (CONT). PARA and QUAD groups were matched with controls by 1:2 ratio. Regression models were used to analyze the effect of paraplegia and quadriplegia on outcome. RESULTS: A total of 76,766 patients underwent emergent abdominal operations: 274 PARA, 132 QUAD, and 76,356 CONT patients. Lower gastrointestinal operations were the most common procedures in PARA and QUAD groups; appendectomy was the most common in the CONT group. After cohort matching, patients with cord paralysis were significantly more likely to present with severe sepsis, have "infected" wounds at operation, and have increased rates of postoperative sepsis and need for reoperation. CONCLUSION: Patients with paraplegia or quadriplegia with acute abdominal surgical emergencies are more likely to present late and have a significantly higher incidence of postoperative septic complications and longer hospital stay. Early surgical consultation and aggressive evaluation and postoperative management are warranted in these populations. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV. PMID- 25742250 TI - Beyond the hospital doors: Improving long-term outcomes for elderly trauma patients. AB - BACKGROUND: Elderly trauma patients (TPs) are the fastest growing trauma population, increasing the need for postacute care rehabilitation. For TP, discharge to skilled nursing facilities (SNFs) has been associated with higher 1 year mortality compared with discharge to inpatient rehabilitation facilities (IRFs) or home. The availability of IRF beds has been decreasing, but the proportion occupied by non-TPs, specifically stroke patients (SPs), has increased. We wanted to better characterize trends in trauma discharges and compare them with a population that is equally dependent on postdischarge rehabilitation. We hypothesized that discharge to SNF is rapidly increasing, while discharge to IRF is declining for trauma, but not for SPs. METHODS: This is retrospective cohort study of adult trauma and SPs discharged from 2003 to 2009. The National Trauma Data Bank and National Inpatient Sample were used to study TPs and SPs, respectively. RESULTS: Falls became the leading cause of injury, and the proportion of older TPs increased from 23% to 30%. Older TPs discharged to SNF increased from 30.7% in 2003 to 40.8% in 2009 (p < 0.001). TPs were 34% (adjusted relative risk [RR], 1.34; 95% confidence interval [CI], 1.15-1.57) more likely to be discharged to an SNF and 36% (adjusted RR, 0.64; 95% CI, 0.48-0.85) less likely to be discharged to an IRF. From 2003 to 2009, SPs were 78% more likely to be discharged to an IRF (adjusted RR, 1.78; 95% CI, 1.74-1.82). The largest absolute increase in SP discharges to IRFs occurred the year following implementation of the stroke center certification program. CONCLUSION: For TPs, there was a significant increase in SNF discharges and a decrease in IRF discharges. During the same period, after implementation of stroke center certification, SPs were more likely to be discharged to an IRF. Future research should focus on evaluating which postacute care setting is most effective in providing rehabilitation for TPs and adjusting our discharge efforts to improve long-term outcomes. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25742251 TI - Secondary brain injury in trauma patients: the effects of remote ischemic conditioning. AB - BACKGROUND: Management of traumatic brain injury (TBI) is focused on preventing secondary brain injury. Remote ischemic conditioning (RIC) is an established treatment modality that has been shown to improve patient outcomes secondary to inflammatory insults. The aim of our study was to assess whether RIC in trauma patients with severe TBI could reduce secondary brain injury. METHODS: This prospective consented interventional trial included all TBI patients admitted to our Level 1 trauma center with an intracranial hemorrhage and a Glasgow Coma Scale (GCS) score of 8 or lower on admission. In each patient, four cycles of RIC were performed within 1 hour of admission. Each cycle consisted of 5 minutes of controlled upper limb (arm) ischemia followed by 5 minutes of reperfusion using a blood pressure cuff. Serum biomarkers of acute brain injury, S-100B, and neuron specific enolase (NSE) were measured at 0, 6, and 24 hours. Outcome measure was reduction in the level of serum biomarkers after RIC. RESULTS: A total of 40 patients (RIC, 20; control, 20) were enrolled. The mean (SD) age was 46.15 (18.64) years, the median GCS score was 8 (interquartile range, 3-8), and the median head Abbreviated Injury Scale (AIS) score was 3 (interquartile range, 3 5), and there was no difference between the RIC and control groups in any of the baseline demographics or injury characteristics including the type and size of intracranial bleed or skull fracture patterns. There was no difference in the 0 hour S-100B (p = 0.9) and NSE (p = 0.72) level between the RIC and the control group. There was a significant reduction in the mean levels of S-100B (p = 0.01) and NSE (p = 0.04) at 6 hours and 24 hours in comparison with the 0-hour level in the RIC group. CONCLUSION: This study showed that RIC significantly decreased the standard biomarkers of acute brain injury in patients with severe TBI. Our study highlights the novel therapeutic role of RIC for preventing secondary brain insults in TBI patients. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 25742252 TI - Early versus delayed same-admission laparoscopic cholecystectomy for acute cholecystitis in elderly patients with comorbidities. AB - BACKGROUND: The optimal timing of same-admission laparoscopic cholecystectomy (LC) for acute cholecystitis (AC) in elderly patients, especially those with significant comorbidities, is not clear. METHODS: This is a National Surgical Quality Improvement Program study, which included patients older than 65 years undergoing LC for AC. Patients with choledocholithiasis were excluded. Patients were divided into two subgroups as follows: no significant comorbidities (American Society of Anesthesiologists [ASA] score <= 2) and significant comorbidities (ASA score > 2). Patients undergoing LC within 24 hours of admission (early LC) were compared with patients undergoing LC later than 24 hours after admission (delayed LC), using univariable and multivariable regression analyses. RESULTS: A total of 4,011 patients were included in the study. Early LC was performed in 38.0% and delayed LC in 62.0% of the patients. Regression analysis identified early LC as an independent predictor for shorter anesthesia time and postoperative length of stay, overall and in the subgroup with an ASA score greater than 2. CONCLUSION: Early, within 24 hours of admission, LC for AC in patients older than 65 years with significant comorbidities is associated with shorter postoperative stay and no increase in postoperative complications or conversion to open cholecystectomy. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 25742253 TI - Stimulation of Wnt/beta-catenin signaling pathway with Wnt agonist reduces organ injury after hemorrhagic shock. AB - BACKGROUND: Hemorrhagic shock is a leading cause of morbidity and mortality in surgery and trauma patients. Despite a large number of preclinical trials conducted to develop therapeutic strategies against hemorrhagic shock, there is still an unmet need for effective therapy for hemorrhage patients. Wnt/beta catenin signaling controls developmental processes and cellular regeneration owing to its central role in cell survival and proliferation. We therefore hypothesized that the activation of Wnt signaling reduces systemic injury caused by hemorrhagic shock. METHODS: Adult male Sprague-Dawley rats underwent hemorrhagic shock by controlled bleeding of the femoral artery to maintain a mean arterial pressure of 30 mm Hg for 90 minutes, followed by resuscitation with crystalloid equal to two times the shed blood volume. After resuscitation, animals were infused with Wnt agonist (5 mg/kg) or vehicle (20% dimethyl sulfoxide in saline). Blood and tissue samples were collected 6 hours after resuscitation for analysis. RESULTS: Hemorrhagic shock increased serum levels of aspartate aminotransferase, lactate, and lactate dehydrogenase. Treatment with Wnt agonist significantly reduced these levels by 40%, 36%, and 77%, respectively. Wnt agonist also decreased blood urea nitrogen and creatinine by 34% and 56%, respectively. The treatment reduced lung myeloperoxidase activity and interleukin 6 messenger RNA by 55% and 68%, respectively, and significantly improved lung histology. Wnt agonist treatment increased Bcl-2 protein to sham values and decreased cleaved caspase 3 by 46%, indicating attenuation of hemorrhage-induced apoptosis in the lungs. Hemorrhage resulted in significant reductions of beta-catenin protein levels in the lungs as well as down-regulation of a Wnt target gene, cyclin D1, while Wnt agonist treatment preserved these levels. CONCLUSION: The administration of Wnt agonist attenuated hemorrhage induced organ injury, inflammation, and apoptosis. This was correlated with the preservation of the Wnt signaling pathway. Thus, Wnt/beta-catenin activation could be protective in hemorrhagic shock. PMID- 25742254 TI - Hypotensive resuscitation in combination with arginine vasopressin may prolong the hypotensive resuscitation time in uncontrolled hemorrhagic shock rats. AB - BACKGROUND: The optimal resuscitation strategy for traumatic hemorrhagic shock is not completely determined. The objective of the present study was to investigate whether hypotensive resuscitation in combination with arginine vasopressin (AVP) can prolong the hypotensive resuscitation time by minimizing blood loss and stabilizing hemodynamics for uncontrolled hemorrhagic shock. METHODS: With an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions. RESULTS: Hypotensive resuscitation in combination with AVP maintenance for 3 hours significantly reduced total blood loss and fluid requirement during hypotensive resuscitation period and significantly improved the survival of shock rats as compared with hypotensive resuscitation alone. Among the four concentrations of AVP, 5 * 10 U/mL had the best effect: it significantly improved hemodynamics and increased cardiac function, oxygen delivery, as well as hepatic blood flow and hepatic function in the shock rats. However, renal blood flow in the hypotensive resuscitation + AVP group was lower than that in the hypotensive resuscitation alone group. CONCLUSION: Hypotensive resuscitation in combination with early application of AVP could prolong the tolerance time of hypotensive resuscitation and "buy" longer safe prehospital transport time by reducing blood loss and stabilizing hemodynamics. This strategy may be a promising strategy for the early management of trauma patients with active bleeding. PMID- 25742255 TI - Surgical stabilization of severe rib fractures. PMID- 25742256 TI - Rapid measurement of fibrinogen concentration in whole blood using a steel ball coagulometer. AB - BACKGROUND: Fibrinogen plays a key role in hemostasis and is the first coagulation factor to reach critical levels in bleeding patients. Current European guidelines on the management of traumatic or perioperative bleeding recommend fibrinogen supplementation at specific threshold levels. Whole blood viscoelastic tests provide fast evaluation of fibrin deficits. Fast measurement of plasma fibrinogen concentration is not yet available. We investigated a method to rapidly determine whole blood fibrinogen concentration using standard Clauss assays and a steel ball coagulometer and provide an estimate of the "plasma equivalent" fibrinogen concentration within minutes by adjustment of the measured whole blood fibrinogen concentration with a quickly measureable hemoglobin derived hematocrit. METHODS: The feasibility of this approach was tested with a Clauss assay using multiple porcine fresh blood samples obtained during in vivo bleeding, hemodilution, and after treatment with hemostatic therapy. Two different Clauss assays were then tested using multiple human volunteers' blood samples diluted in vitro and supplemented with fibrinogen concentrate. Comparative measurements with fibrin-based thromboelastometry tests were performed. RESULTS: Regression and Bland-Altman analyses of derived "plasma equivalent" fibrinogen and measured plasma fibrinogen concentration was excellent in porcine and human blood samples, especially in the ranges relevant to traumatic or perioperative bleeding. CONCLUSION: Fast whole blood fibrinogen measurements could be considered as an alternative to plasma fibrinogen measurement for acute bleeding management in trauma and perioperative care settings. Further studies are needed to prove this concept and determine the turnaround times for its clinical application in emergency departments and operating theaters. PMID- 25742258 TI - Intraoperative ultrasound to assess for pancreatic duct injuries. PMID- 25742257 TI - Differences in degree, differences in kind: characterizing lung injury in trauma. AB - BACKGROUND: Acute lung injury following trauma remains a significant source of morbidity and mortality. Although multiple trauma studies have used hypoxemia without radiographic adjudication as a surrogate for identifying adult respiratory distress syndrome (ARDS) cases, the differences between patients with hypoxemia alone and those with radiographically confirmed ARDS are not well described in the literature. We hypothesized that nonhypoxemic, hypoxemic, and ARDS patients represent distinct groups with unique characteristics and predictors. METHODS: Laboratory, demographic, clinical, and outcomes data were prospectively collected from 621 intubated, critically injured patients at an urban Level 1 trauma center from 2005 to 2013. Hypoxemia was defined as PaO2/FIO2 ratio of 300 or lower. ARDS was adjudicated using Berlin criteria, with blinded two-physician consensus review of chest radiographs. Group comparisons were performed by hypoxemia and ARDS status. Logistic regression analyses were performed to separately assess predictors of hypoxemia and ARDS. RESULTS: Of the 621 intubated patients, 64% developed hypoxemia; 46% of these hypoxemic patients developed ARDS by chest radiograph. Across the three groups (no hypoxemia, hypoxemia, ARDS), there were no significant differences in age, sex, or comorbidities. However, there was an increase in severity of shock, injury, and chest injury by group, with corresponding trends in transfusion requirements and volume of early fluid administration. Outcomes followed a similar stepwise pattern, with pneumonia, multiorgan failure, length of intensive care unit stay, number of ventilator days, and overall mortality highest in ARDS patients. In multiple logistic regression, early plasma transfusion, delayed crystalloid administration, body mass index, and head and chest injury were independent predictors of hypoxemia, while head and chest injury, early crystalloid infusion, and delayed platelet transfusion were independent predictors of ARDS. CONCLUSION: Hypoxemia and ARDS exist on a spectrum of respiratory dysfunction following trauma, with increasing injury severity profiles and resuscitation requirements. However, they also represent distinct clinical states with unique predictors, which require directed research approaches and targeted therapeutic strategies. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 25742259 TI - Responsibility. PMID- 25742260 TI - Importance of spatial and spectral data reduction in the detection of internal defects in food products. AB - Despite the importance of data reduction as part of the processing of reflection based classifications, this study represents one of the first in which the effects of both spatial and spectral data reductions on classification accuracies are quantified. Furthermore, the effects of approaches to data reduction were quantified for two separate classification methods, linear discriminant analysis (LDA) and support vector machine (SVM). As the model dataset, reflection data were acquired using a hyperspectral camera in 230 spectral channels from 401 to 879 nm (spectral resolution of 2.1 nm) from field pea (Pisum sativum) samples with and without internal pea weevil (Bruchus pisorum) infestation. We deployed five levels of spatial data reduction (binning) and eight levels of spectral data reduction (40 datasets). Forward stepwise LDA was used to select and include only spectral channels contributing the most to the separation of pixels from non infested and infested field peas. Classification accuracies obtained with LDA and SVM were based on the classification of independent validation datasets. Overall, SVMs had significantly higher classification accuracies than LDAs (P < 0.01). There was a negative association between pixel resolution and classification accuracy, while spectral binning equivalent to up to 98% data reduction had negligible effect on classification accuracies. This study supports the potential use of reflection-based technologies in the quality control of food products with internal defects, and it highlights that spatial and spectral data reductions can (1) improve classification accuracies, (2) vastly decrease computer constraints, and (3) reduce analytical concerns associated with classifications of large and high-dimensional datasets. PMID- 25742261 TI - Bats and zoonotic viruses: can we confidently link bats with emerging deadly viruses? AB - An increasingly asked question is 'can we confidently link bats with emerging viruses?'. No, or not yet, is the qualified answer based on the evidence available. Although more than 200 viruses - some of them deadly zoonotic viruses have been isolated from or otherwise detected in bats, the supposed connections between bats, bat viruses and human diseases have been raised more on speculation than on evidence supporting their direct or indirect roles in the epidemiology of diseases (except for rabies). However, we are convinced that the evidence points in that direction and that at some point it will be proved that bats are competent hosts for at least a few zoonotic viruses. In this review, we cover aspects of bat biology, ecology and evolution that might be relevant in medical investigations and we provide a historical synthesis of some disease outbreaks causally linked to bats. We provide evolutionary-based hypotheses to tentatively explain the viral transmission route through mammalian intermediate hosts and to explain the geographic concentration of most outbreaks, but both are no more than speculations that still require formal assessment. PMID- 25742263 TI - Mechanisms of growth inhibition of Phytomonas serpens by the alkaloids tomatine and tomatidine. AB - Phytomonas serpens are flagellates in the family Trypanosomatidae that parasitise the tomato plant (Solanum lycopersicum L.), which results in fruits with low commercial value. The tomato glycoalkaloid tomatine and its aglycone tomatidine inhibit the growth of P. serpens in axenic cultures. Tomatine, like many other saponins, induces permeabilisation of the cell membrane and a loss of cell content, including the cytosolic enzyme pyruvate kinase. In contrast, tomatidine does not cause permeabilisation of membranes, but instead provokes morphological changes, including vacuolisation. Phytomonas treated with tomatidine show an increased accumulation of labelled neutral lipids (BODYPY-palmitic), a notable decrease in the amount of C24-alkylated sterols and an increase in zymosterol content. These results are consistent with the inhibition of 24-sterol methyltransferase (SMT), which is an important enzyme that is responsible for the methylation of sterols at the 24 position. We propose that the main target of tomatidine is the sterols biosynthetic pathway, specifically, inhibition of the 24-SMT. Altogether, the results obtained in the present paper suggest a more general effect of alkaloids in trypanosomatids, which opens potential therapeutic possibilities for the treatment of the diseases caused by these pathogens. PMID- 25742264 TI - Quantification of C4d deposition and hepatitis C virus RNA in tissue in cases of graft rejection and hepatitis C recurrence after liver transplantation. AB - Histology is the gold standard for diagnosing acute rejection and hepatitis C recurrence after liver transplantation. However, differential diagnosis between the two can be difficult. We evaluated the role of C4d staining and quantification of hepatitis C virus (HCV) RNA levels in liver tissue. This was a retrospective study of 98 liver biopsy samples divided into four groups by histological diagnosis: acute rejection in patients undergoing liver transplant for hepatitis C (RejHCV+), HCV recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+), acute rejection in patients undergoing liver transplant for reasons other than hepatitis C and chronic hepatitis C not transplanted (HCVTx-). All samples were submitted for immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of C4d was observed in the portal vessels and was highest in the HCVTx- group. There was no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However, tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+ group samples. Additionally, there was a significant correlation between tissue and serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to be an efficient diagnostic test for the recurrence of HCV infection. PMID- 25742262 TI - An overview of malaria transmission from the perspective of Amazon Anopheles vectors. AB - In the Americas, areas with a high risk of malaria transmission are mainly located in the Amazon Forest, which extends across nine countries. One keystone step to understanding the Plasmodium life cycle in Anopheles species from the Amazon Region is to obtain experimentally infected mosquito vectors. Several attempts to colonise Anopheles species have been conducted, but with only short lived success or no success at all. In this review, we review the literature on malaria transmission from the perspective of its Amazon vectors. Currently, it is possible to develop experimental Plasmodium vivax infection of the colonised and field-captured vectors in laboratories located close to Amazonian endemic areas. We are also reviewing studies related to the immune response to P. vivax infection of Anopheles aquasalis, a coastal mosquito species. Finally, we discuss the importance of the modulation of Plasmodium infection by the vector microbiota and also consider the anopheline genomes. The establishment of experimental mosquito infections with Plasmodium falciparum, Plasmodium yoelii and Plasmodium berghei parasites that could provide interesting models for studying malaria in the Amazonian scenario is important. Understanding the molecular mechanisms involved in the development of the parasites in New World vectors is crucial in order to better determine the interaction process and vectorial competence. PMID- 25742265 TI - Bioactive endophytic fungi isolated from Caesalpinia echinata Lam. (Brazilwood) and identification of beauvericin as a trypanocidal metabolite from Fusarium sp. AB - Aiming to identify new sources of bioactive secondary metabolites, we isolated 82 endophytic fungi from stems and barks of the native Brazilian tree Caesalpinia echinata Lam. (Fabaceae). We tested their ethyl acetate extracts in several in vitro assays. The organic extracts from three isolates showed antibacterial activity against Staphylococcus aureus and Escherichia coli [minimal inhibitory concentration (MIC) 32-64 MUg/mL]. One isolate inhibited the growth of Salmonella typhimurium (MIC 64 MUg/mL) and two isolates inhibited the growth of Klebsiella oxytoca (MIC 64 MUg/mL), Candida albicans and Candida tropicalis (MIC 64-128 MUg/mL). Fourteen extracts at a concentration of 20 MUg/mL showed antitumour activities against human breast cancer and human renal cancer cells, while two isolates showed anti-tumour activities against human melanoma cancer cells. Six extracts were able to reduce the proliferation of human peripheral blood mononuclear cells, indicating some degree of selective toxicity. Four isolates were able to inhibit Leishmania (Leishmania) amazonensis and one isolate inhibited Trypanosoma cruzi by at least 40% at 20 MUg/mL. The trypanocidal extract obtained from Fusarium sp. [KF611679] culture was subjected to bioguided fractionation, which revealed beauvericin as the compound responsible for the observed toxicity of Fusarium sp. to T. cruzi. This depsipeptide showed a half maximal inhibitory concentration of 1.9 MUg/mL (2.43 MUM) in a T. cruzi cellular culture assay. PMID- 25742266 TI - BAY 41-2272 activates host defence against local and disseminated Candida albicans infections. AB - In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41 2272 might occur primarily by the modulation of the host immune response through macrophage activation. PMID- 25742268 TI - Experimental infection with the Toxoplasma gondii ME-49 strain in the Brazilian BR-1 mini pig is a suitable animal model for human toxoplasmosis. AB - Toxoplasma gondii causes toxoplasmosis, a worldwide disease. Experimentation with pigs is necessary for the development of new therapeutic approaches to human diseases. BR-1 mini pigs were intramuscularly infected with T. gondii with tachyzoites (RH strain) or orally infected with cysts (ME-49 strain). Haematology and serum biochemistry were analysed and buffy coat cells were inoculated in mice to determine tachyzoite circulation. No alterations were observed in erythrocyte and platelet values; however, band neutrophils increased seven days after infection with ME-49. Serology of the mice inoculated with pig blood leucocytes revealed circulating ME-49 or RH strain tachyzoites in the pigs' peripheral blood at two and seven or nine days post-infection. The tachyzoites were also directly observed in blood smears from the infected pigs outside and inside leucocytes for longer periods. Alanine-aminotransferase was high at days 21 and 32 in the RH infected pigs. After 90 days, the pigs were euthanised and their tissue samples were processed and inoculated into mice. The mice serology revealed the presence of parasites in the hearts, ileums and mesenteric lymph nodes of the pigs. Additionally, cysts in the mice were only observed after pig heart tissue inoculation. The infected pigs presented similar human outcomes with relatively low pathogenicity and the BR-1 mini pig model infected with ME-49 is suitable to monitor experimental toxoplasmosis. PMID- 25742267 TI - Experimental benznidazole treatment of Trypanosoma cruzi II strains isolated from children of the Jequitinhonha Valley, Minas Gerais, Brazil, with Chagas disease. AB - Trypanosoma cruzi strains from distinct geographic areas show differences in drug resistance and association between parasites genetic and treatment response has been observed. Considering that benznidazole (BZ) can reduce the parasite burden and tissues damage, even in not cured animals and individuals, the goal is to assess the drug response to BZ of T. cruzi II strains isolated from children of the Jequitinhonha Valley, state of Minas Gerais, Brazil, before treatment. Mice infected and treated with BZ in both phases of infection were compared with the untreated and evaluated by fresh blood examination, haemoculture, polymerase chain reaction, conventional (ELISA) and non-conventional (FC-ALTA) serologies. In mice treated in the acute phase, a significant decrease in parasitaemia was observed for all strains. Positive parasitological and/or serological tests in animals treated during the acute and chronic (95.1-100%) phases showed that most of the strains were BZ resistant. However, beneficial effect was demonstrated because significant reduction (p < 0.05%) and/or suppression of parasitaemia was observed in mice infected with all strains (acute phase), associated to reduction/elimination of inflammation and fibrosis for two/eight strains. BZ offered some benefit, even in not cured animals, what suggest that BZ use may be recommended at least for recent chronic infection of the studied region. PMID- 25742269 TI - Oseltamivir-resistant influenza A(H1N1)pdm2009 strains found in Brazil are endowed with permissive mutations, which compensate the loss of fitness imposed by antiviral resistance. AB - The 2009 pandemic influenza A virus outbreak led to the systematic use of the neuraminidase (NA) inhibitor oseltamivir (OST). Consequently, OST-resistant strains, carrying the mutation H275Y, emerged in the years after the pandemics, with a prevalence of 1-2%. Currently, OST-resistant strains have been found in community settings, in untreated individuals. To spread in community settings, H275Y mutants must contain additional mutations, collectively called permissive mutations. We display the permissive mutations in NA of OST-resistant A(H1N1)pdm09 virus found in Brazilian community settings. The NAs from 2013 are phylogenetically distinct from those of 2012, indicating a tendency of positive selection of NAs with better fitness. Some previously predicted permissive mutations, such as V241I and N369K, found in different countries, were also detected in Brazil. Importantly, the change D344N, also predicted to compensate loss of fitness imposed by H275Y mutation, was found in Brazil, but not in other countries in 2013. Our results reinforce the notion that OST-resistant A(H1N1)pdm09 strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in different countries. Systematic circulation of these viral strains may jeopardise the use of the first line of anti-influenza drugs in the future. PMID- 25742270 TI - Therapeutic switching: from antidermatophytic essential oils to new leishmanicidal products. AB - This study examined whether the antidermatophytic activity of essential oils (EOs) can be used as an indicator for the discovery of active natural products against Leishmania amazonensis. The aerial parts of seven plants were hydrodistilled. Using broth microdilution techniques, the obtained EOs were tested against three strains of dermatophytes (Trichophyton mentagrophytes, Microsporum gypseum and Microsporum canis). To compare the EOs antifungal and antiparasitic effects, the EOs activities against axenic amastigotes of L. amazonensis were concurrently evaluated. For the most promising EOs, their antileishmanial activities against parasites infecting peritoneal macrophages of BALB/c mice were measured. The most interesting antifungal candidates were the EOs from Cymbopogon citratus, Otacanthus azureus and Protium heptaphyllum, whereas O. azureus, Piper hispidum and P. heptaphyllum EOs exhibited the lowest 50% inhibitory concentration (IC50) values against axenic amastigotes, thus revealing a certain correspondence between both activities. The P. hispidum EO was identified as the most promising product in the results from the infected macrophages model (IC50: 4.7 ug/mL, safety index: 8). The most abundant compounds found in this EO were sesquiterpenes, notably curzerene and furanodiene. Eventually, the evaluation of the antidermatophytic activity of EOs appears to be an efficient method for identifying new potential drugs for the treatment of L. amazonensis. PMID- 25742271 TI - Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation--technological development issues. AB - This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints. PMID- 25742272 TI - Neutralising antibodies for Mayaro virus in Pantanal, Brazil. AB - The Pantanal hosts diverse wildlife species and therefore is a hotspot for arbovirus studies in South America. A serosurvey for Mayaro virus (MAYV), eastern (EEEV), western (WEEV) and Venezuelan (VEEV) equine encephalitis viruses was conducted with 237 sheep, 87 free-ranging caimans and 748 equids, including 37 collected from a ranch where a neurologic disorder outbreak had been recently reported. Sera were tested for specific viral antibodies using plaque-reduction neutralisation test. From a total of 748 equids, of which 264 were immunised with vaccine composed of EEEV and WEEV and 484 had no history of immunisation, 10 (1.3%) were seropositive for MAYV and two (0.3%) for VEEV using criteria of a >= 4-fold antibody titre difference. Among the 484 equids without history of immunisation, 48 (9.9%) were seropositive for EEEV and four (0.8%) for WEEV using the same criteria. Among the sheep, five were sero- positive for equine encephalitis alphaviruses, with one (0.4%) for EEEV, one (0.4%) for WEEV and three (1.3%) for VEEV. Regarding free-ranging caimans, one (1.1%) and three (3.4%), respectively, had low titres for neutralising antibodies to VEEV and undetermined alphaviruses. The neurological disorder outbreak could not be linked to the alphaviruses tested. Our findings represent strong evidence that MAYV and all equine encephalitis alphaviruses circulated in the Pantanal. PMID- 25742273 TI - The use of halloysite clay and carboxyl-functionalised multi-walled carbon nanotubes for recombinant LipL32 antigen delivery enhanced the IgG response. AB - We studied the feasibility of using halloysite clay nanotubes (HNTs) and carboxyl functionalised multi-walled carbon nanotubes (COOH-MWCNTs) as antigen carriers to improve immune responses against a recombinant LipL32 protein (rLipL32). Immunisation using the HNTs or COOH-MWCNTs significantly increased the rLipL32 specific IgG antibody titres (p < 0.05) of Golden Syrian hamsters. None of the vaccines tested conferred protection against a challenge using a virulent Leptospira interrogans strain. These results demonstrated that nanotubes can be used as antigen carriers for delivery in hosts and the induction of a humoral immune response against purified leptospiral antigens used in subunit vaccine preparations. PMID- 25742274 TI - Genetic variability in G2 and F2 region between biological clones of human respiratory syncytial virus with or without host immune selection pressure. AB - Human respiratory syncytial virus (HRSV) is an important respiratory pathogens among children between zero-five years old. Host immunity and viral genetic variability are important factors that can make vaccine production difficult. In this work, differences between biological clones of HRSV were detected in clinical samples in the absence and presence of serum collected from children in the convalescent phase of the illness and from their biological mothers. Viral clones were selected by plaque assay in the absence and presence of serum and nucleotide sequences of the G2 and F2 genes of HRSV biological clones were compared. One non-synonymous mutation was found in the F gene (Ile5Asn) in one clone of an HRSV-B sample and one non-synonymous mutation was found in the G gene (Ser291Pro) in four clones of the same HRSV-B sample. Only one of these clones was obtained after treatment with the child's serum. In addition, some synonymous mutations were determined in two clones of the HRSV-A samples. In conclusion, it is possible that minor sequences could be selected by host antibodies contributing to the HRSV evolutionary process, hampering the development of an effective vaccine, since we verify the same codon alteration in absence and presence of human sera in individual clones of BR-85 sample. PMID- 25742275 TI - Sandfly (Diptera: Psychodidae: Phlebotominae) species diversity in an urban area of the municipality of Tapachula, Chiapas, Mexico. AB - Monitoring phlebotomine sandflies in urban areas is key for epidemiological studies in susceptible populations. This paper describes sandfly fauna that were present in an urban area of the municipality of Tapachula, Chiapas, Mexico, and were captured with Shannon and CDC light traps. During February and March of 2014, 1,442 sandflies were captured, specifically Lutzomyia cruciata (Coquillet) (98.8%), Lutzomyia cayennensis cayennensis (Floch and Abonnenc) (0.8%), Lutzomyia chiapanensis (Dampf) (0.3%) and Lutzomyia atulapai (De Leon) (0.1%). Lu. cruciata was the most abundant and the most frequently trapped species. This is the first record of its remarkable ability to adapt to urban green areas. The three other species trapped represent new records of geographic distribution for the study region. These results indicate the need to establish measures for reducing both human contact with this vector and the risk of possible sites of infection. PMID- 25742276 TI - Trichuris trichiura in a post-Colonial Brazilian mummy. AB - Trichuris trichiura is a soil-transmitted helminth which is prevalent in warm, moist, tropical and subtropical regions of the world with poor sanitation. Heavy whipworm can result either in Trichuris dysenteric syndrome - especially in children - or in a chronic colitis. In heavy infections, worms can spread proximally and may cause ileitis. Here we provide first microscopic evidence for a T. trichiura adult worm embedded in the rectum of a post-Colonial Brazilian adult mummy. During Colonial and post-Colonial times, many European chroniclers described a parasitic disease named Maculo whose symptomatology coincides with heavy helminthiasis. Based on our findings and on comparison of ancient textual evidence with modern description of heavy whipworm, we feel confident in considering that the two syndromes are expressions of the same pathological condition. PMID- 25742277 TI - Whole-genome sequences of influenza A(H3N2) viruses isolated from Brazilian patients with mild illness during the 2014 season. AB - The influenza A(H3N2) virus has circulated worldwide for almost five decades and is the dominant subtype in most seasonal influenza epidemics, as occurred in the 2014 season in South America. In this study we evaluate five whole genome sequences of influenza A(H3N2) viruses detected in patients with mild illness collected from January-March 2014. To sequence the genomes, a new generation sequencing (NGS) protocol was performed using the Ion Torrent PGM platform. In addition to analysing the common genes, haemagglutinin, neuraminidase and matrix, our work also comprised internal genes. This was the first report of a whole genome analysis with Brazilian influenza A(H3N2) samples. Considerable amino acid variability was encountered in all gene segments, demonstrating the importance of studying the internal genes. NGS of whole genomes in this study will facilitate deeper virus characterisation, contributing to the improvement of influenza strain surveillance in Brazil. PMID- 25742278 TI - Full-genome sequences of hepatitis B virus subgenotype D3 isolates from the Brazilian Amazon Region. AB - The Brazilian Amazon Region is a highly endemic area for hepatitis B virus (HBV). However, little is known regarding the genetic variability of the strains circulating in this geographical region. Here, we describe the first full-length genomes of HBV isolated in the Brazilian Amazon Region; these genomes are also the first complete HBV subgenotype D3 genomes reported for Brazil. The genomes of the five Brazilian isolates were all 3,182 base pairs in length and the isolates were classified as belonging to subgenotype D3, subtypes ayw2 (n = 3) and ayw3 (n = 2). Phylogenetic analysis suggested that the Brazilian sequences are not likely to be closely related to European D3 sequences. Such results will contribute to further epidemiological and evolutionary studies of HBV. PMID- 25742279 TI - The metabogenic role of iron in chronic chagasic cardiac failure. PMID- 25742280 TI - Determination of Antiproliferative Activities of Volatile Contents and HPLC Profiles of Dicranum scoparium (Dicranaceae, Bryophyta). AB - The aim of this study was to examine the anticancer activities and phytochemical profiles of Dicranum scoparium against HeLa cell lines. The bio-guided fractionation studies of dichloromethane extract have high antiproliferative activities. Fractions 7, 9, 19, 20 are rich source of unsaturated fatty acids, and- in the case of Fr-19 may improve the antiproliferative activities as well as increase the unsaturated fatty acid content. The effect of proliferative activities in hexane extract can be attributed to the saturated fatty acid composition of D. scoparium. The Fr-9 exhibited strong antiproliferative activity at concentrations of 100 and 50 MUg mL(-1) compared to 5-FU. The fractions of 7, 9, 19 and 20 from dichloromethane extracts exhibited antiproliferative activities at a concentration of 100 MUg mL(-1). The HPLC-TOF/MS studies gave nine compounds from the most active fraction of dichloromethane at concentrations of 250 and 100 MUg mL(-1). The lower activities were obtained from the fractions including steroid derivatives. PMID- 25742281 TI - Site of reactivity models predict molecular reactivity of diverse chemicals with glutathione. AB - Drug toxicity is often caused by electrophilic reactive metabolites that covalently bind to proteins. Consequently, the quantitative strength of a molecule's reactivity with glutathione (GSH) is a frequently used indicator of its toxicity. Through cysteine, GSH (and proteins) scavenges reactive molecules to form conjugates in the body. GSH conjugates to specific atoms in reactive molecules: their sites of reactivity. The value of knowing a molecule's sites of reactivity is unexplored in the literature. This study tests the value of site of reactivity data that identifies the atoms within 1213 reactive molecules that conjugate to GSH and builds models to predict molecular reactivity with glutathione. An algorithm originally written to model sites of cytochrome P450 metabolism (called XenoSite) finds clear patterns in molecular structure that identify sites of reactivity within reactive molecules with 90.8% accuracy and separate reactive and unreactive molecules with 80.6% accuracy. Furthermore, the model output strongly correlates with quantitative GSH reactivity data in chemically diverse, external data sets. Site of reactivity data is nearly unstudied in the literature prior to our efforts, yet it contains a strong signal for reactivity that can be utilized to more accurately predict molecule reactivity and, eventually, toxicity. PMID- 25742282 TI - Committing to place: the potential of open collaborations for trusted environmental governance. AB - Conventional modes of environmental governance, which typically exclude those stakeholders that are most directly linked to the specific place, frequently fail to have the desired impact. Using the example of lake water management in Loweswater, a small hamlet within the English Lake District, we consider the ways in which new "collectives" for local, bottom-up governance of water bodies can reframe problems in ways which both bind lay and professional people to place, and also recast the meaning of "solutions" in thought-provoking ways. PMID- 25742283 TI - An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder. AB - BACKGROUND: To use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. RESULTS: We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. CONCLUSIONS: This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies. PMID- 25742284 TI - Mechanical vessel injury in zebrafish embryos. AB - Zebrafish (Danio rerio) embryos have proven to be a powerful model for studying a variety of developmental and disease processes. External development and optical transparency make these embryos especially amenable to microscopy, and numerous transgenic lines that label specific cell types with fluorescent proteins are available, making the zebrafish embryo an ideal system for visualizing the interaction of vascular, hematopoietic, and other cell types during injury and repair in vivo. Forward and reverse genetics in zebrafish are well developed, and pharmacological manipulation is possible. We describe a mechanical vascular injury model using micromanipulation techniques that exploits several of these features to study responses to vascular injury including hemostasis and blood vessel repair. Using a combination of video and timelapse microscopy, we demonstrate that this method of vascular injury results in measurable and reproducible responses during hemostasis and wound repair. This method provides a system for studying vascular injury and repair in detail in a whole animal model. PMID- 25742285 TI - Hepatitis C related chronic liver cirrhosis: feasibility of texture analysis of MR images for classification of fibrosis stage and necroinflammatory activity grade. AB - PURPOSE: To assess the feasibility of texture analysis for classifying fibrosis stage and necroinflammatory activity grade in patients with chronic hepatitis C on T2-weighted (T2W), T1-weighted (T1W) and Gd-EOB-DTPA-enhanced hepatocyte-phase (EOB-HP) imaging. MATERIALS AND METHODS: From April 2008 to June 2012, MR images from 123 patients with pathologically proven chronic hepatitis C were retrospectively analyzed. Texture parameters derived from histogram, gradient, run-length matrix, co-occurrence matrix, autoregressive model and wavelet transform methods were estimated with imaging software. Fisher, probability of classification error and average correlation, and mutual information coefficients were used to extract subsets of optimized texture features. Linear discriminant analysis in combination with 1-nearest neighbor classifier (LDA/1-NN) was used for lesion classification. In compliance with the software requirement, classification was performed based on datasets from all patients, the patient group with necroinflammatory activity grade 1, and that with fibrosis stage 4, respectively. RESULTS: Based on all patient dataset, LDA/1-NN produced misclassification rates of 28.46%, 35.77% and 20.33% for fibrosis staging and 34.15%, 25.20% and 28.46% for necroinflammatory activity grading in T2W, T1W and EOB-HP images. In the patient group with necroinflammatory activity grade 1, LDA/1-NN yielded misclassification rates of 5.00%, 0% and 12.50% for fibrosis staging in T2W, T1W and EOB-HP images respectively. In the patient group with fibrosis stage 4, LDA/1-NN yielded misclassification rates of 5.88%, 12.94% and 11.76% for necroinflammatory activity grading in T2W, T1W and EOB-HP images respectively. CONCLUSION: Texture quantitative parameters of MR images facilitate classification of the fibrosis stage as well as necroinflammatory activity grade in chronic hepatitis C, especially after categorizing the input dataset according to the activity or fibrosis degree in order to remove the interference between the fibrosis stage and necroinflammatory activity grade on texture features. PMID- 25742286 TI - Reference ranges for uterine artery pulsatility index during the menstrual cycle: a cross-sectional study. AB - BACKGROUND: Cyclic endometrial neoangiogenesis contributes to changes in local vascular patterns and is amenable to non-invasive assessment with Doppler sonography. We hypothesize that the uterine artery (UtA) impedance, measured by its pulsatility index (PI), exhibits a regular pattern during the normal menstrual cycle. Therefore, the main study objective was to derive normative new day-cycle-based reference ranges for the UtA-PI during the entire cycle from days 1 to 34 according to the isolated time effect and potential confounders such as age and parity. METHODS: From January 2009 to December 2012, a cross-sectional study of 1,821 healthy women undergoing routine gynaecological ultrasound was performed. The Doppler flow of the right and left UtA-PI was studied transvaginally by colour and pulsed Doppler imaging. The mean right and left values and the presence or absence of a bilateral protodiastolic notch were recorded. Reference intervals for the PI according to the cycle day were generated by classical linear regression. RESULTS: The majority of patients (97.5%) presented unilateral or bilateral UtA notches. The crude 5th, 50th, and 95th reference percentile curves of the UtA-PI at 1-34 days of the normal menstrual cycle were derived. In all curves, a progressive significant decrease occurred during the first 13 days, followed by an increase and recovery in the UtA-PI. The adjusted 5th, 50th, and 95th reference percentile curves for the effects of age and parity were also obtained. These two conditions generated an approximately identical UtA-PI pattern during the cycle, except with small but significant reductions at the temporal extremes. CONCLUSIONS: The median, 5th, and the 95th percentiles of the UtA-PI decrease during the first third of the menstrual cycle and recover to their initial values during the last two thirds of the cycle. The rates of decrease and recovery depend significantly on age and parity. PMID- 25742288 TI - Validation of noninvasive hemoglobin measurement by pulse co-oximeter in newborn infants. AB - OBJECTIVE: To describe the accuracy of noninvasive hemoglobin (Hb) obtained with pulse co-oximeter (SpHb) compared with total Hb (tHb) from laboratory co-oximeter in neonates. STUDY DESIGN: Neonates with birth weight (BW) <3000 g admitted to LAC+USC Medical Center neonatal intensive care unit were included. SpHb was recorded using Masimo Radical-7 and compared with tHb. A total of three data sets were obtained for each patient. Regression analysis and Bland-Altman analysis were performed. RESULT: Sixty-one patients (mean+/-s.d., BW 1177+/-610 g and gestational age 28.7+/-3.9 weeks) were enrolled. The mean tHb value was 13.9+/ 2.0 g dl(-1) and the mean SpHb was 14.0+/-2.0 g dl(-1). There was a moderately positive correlation between SpHb and tHb (r=0.66, P<0.001) with a bias and precision of -0.09+/-1.67 g dl(-1). Data from a subgroup of infants with gestational age ?32 weeks (52/61 patients) were analyzed, and the correlation coefficient was moderately positive (r=0.69, P<0.001) with a bias and precision of -0.23+/-1.60 g dl(-1). CONCLUSION: Our results suggest that noninvasive SpHb may be considered as an adjunct to invasive tHb measurements in newborn infants <3000 g especially in preterm infants ?32 weeks of gestation. PMID- 25742287 TI - Influence of H-HOPE intervention for premature infants on growth, feeding progression and length of stay during initial hospitalization. AB - OBJECTIVE: To examine whether premature infants receiving the maternally administered H-HOPE (Hospital to Home Transition-Optimizing Premature Infant's Environment) intervention had more rapid weight gain and growth, improved feeding progression and reduced length of hospital stay, compared with controls. STUDY DESIGN: Premature infants born at 29-34 weeks gestational age and their mothers with at least two social-environmental risk factors were randomly assigned to H HOPE intervention (n=88) or an attention control (n=94) groups. H-HOPE consists of a 15-min multisensory intervention (Auditory, Tactile, Visual and Vestibular stimuli) performed twice daily prior to feeding plus maternal participatory guidance on preterm infant behavioral cues. RESULT: H-HOPE group infants gained weight more rapidly over time than infants in the control group and grew in length more rapidly than control infants, especially during the latter part of the hospital stay. CONCLUSION: For healthy preterm infants, the H-HOPE intervention appears to improve weight gain and length over time from birth to hospital discharge. PMID- 25742290 TI - Correction: Glutathione S-transferase P influences redox and migration pathways in bone marrow. PMID- 25742289 TI - Detection of ROS1 gene rearrangement in lung adenocarcinoma: comparison of IHC, FISH and real-time RT-PCR. AB - AIMS: To compare fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative real-time reverse transcription-PCR (qRT-PCR) assays for detection of ROS1 fusion in a large number of ROS1-positive lung adenocatcinoma (ADC) patients. METHODS: Using IHC analysis, sixty lung ADCs including 16 cases with ROS1 protein expression and 44 cases without ROS1 expression were selected for this study. The ROS1 fusion status was examined by FISH and qRT-PCR assay. RESULTS: Among 60 cases, 16 (26.7%), 13 (21.7%) and 20 (33.3%) cases were ROS1 positive revealed by IHC, FISH and qRT-PCR, respectively. Using FISH as a standard method for ROS1 fusion detection, the sensitivity and specificity of IHC were 100% and 93.6%, respectively. Three IHC-positive cases, which showed FISH negative, were demonstrated with ROS1 fusion by qRT-PCR analysis. The sensitivity and specificity of qRT-PCR for detection for ROS1 fusion were 100% and 85.1%, respectively. The total concordance rate between IHC and qRT-PCR were 93.3%. CONCLUSION: IHC is a reliable and rapid screening tool in routine pathologic laboratories for the identification of suitable candidates for ROS1-targeted therapy. Some ROS1 IHC-positive but FISH-negative cases did harbor the translocation events and may benefit from crizotinib. PMID- 25742291 TI - Correction: Re-meandering of lowland streams: will disobeying the laws of geomorphology have ecological consequences? PMID- 25742292 TI - Genome-wide association study of parity in Bangladeshi women. AB - Human fertility is a complex trait determined by gene-environment interactions in which genetic factors represent a significant component. To better understand inter-individual variability in fertility, we performed one of the first genome wide association studies (GWAS) of common fertility phenotypes, lifetime number of pregnancies and number of children in a developing country population. The fertility phenotype data and DNA samples were obtained at baseline recruitment from individuals participating in a large prospective cohort study in Bangladesh. GWAS analyses of fertility phenotypes were conducted among 1,686 married women. One SNP on chromosome 4 was non-significantly associated with number of children at P <10(-7) and number of pregnancies at P <10(-6). This SNP is located in a region without a gene within 1 Mb. One SNP on chromosome 6 was non-significantly associated with extreme number of children at P <10(-6). The closest gene to this SNP is HDGFL1, a hepatoma-derived growth factor. When we excluded hormonal contraceptive users, a SNP on chromosome 5 was non-significantly associated at P <10(-5) for number of children and number of pregnancies. This SNP is located near C5orf64, an open reading frame, and ZSWIM6, a zinc ion binding gene. We also estimated the heritability of these phenotypes from our genotype data using GCTA (Genome-wide Complex Trait Analysis) for number of children (hg2 = 0.149, SE = 0.24, p-value = 0.265) and number of pregnancies (hg2 = 0.007, SE = 0.22, p-value = 0.487). Our genome-wide association study and heritability estimates of number of pregnancies and number of children in Bangladesh did not confer strong evidence of common variants for parity variation. However, our results suggest that future studies may want to consider the role of 3 notable SNPs in their analysis. PMID- 25742293 TI - Synthesis and characterization of mid-infrared transparency compounds: acentric BaHgS2 and centric Ba8Hg4S5Se7. AB - Two mid-IR transparency compounds, namely, acentric BaHgS2 (BHS) and centric Ba8Hg4S5Se7 (BHSSe), were successfully synthesized by a conventional solid-state reaction method. The space group of BHS is orthorhombic Pmc21 with [HgS4] tetrahedra and isolated dumbbell-shaped [HgS2] units, while BHSSe belongs to the orthorhombic space group Pnma with infinite isolated infinity[HgSe2(S/Se)2](4-) chains. Raman spectra and thermal analysis of the titled materials were measured. In addition, their band gaps are found to be 1.93 (BHS) and 1.98 eV (BHSSe) from the measured diffuse reflectance spectra. Significantly, the powder BHS sample exhibits a good second harmonic generation (SHG) response of ~6.5 times compared with that of reference AgGaS2 at a fundamental wavelength (2.09 MUm). The calculated SHG coefficients of BHS are also reported, and the maximum result agrees well with the test observation. PMID- 25742294 TI - Correction: fitness landscape transformation through a single amino acid change in the rho terminator. PMID- 25742296 TI - Preparing for Fellowship in Internal Medicine. Steps for Success with a Focus on Pulmonary and/or Critical Care Programs. AB - This paper outlines specific tips for those applying to pulmonary and/or critical care medicine fellowship training in the United States using the PAIR-Match steps: preparation, application, interview, ranking, and match. Preparation for fellowship begins long before the application process with an assessment of one's long-term goals (to the extent that these are known). The cornerstone of the application is the curriculum vitae, which should highlight applicants' pulmonary and critical care-related experiences and scholarly work. Applicants should obtain letters of recommendation from faculty members who know them well and can write a letter that speaks to their strengths in clinical, scholarly, or leadership areas. The personal statement is an opportunity to share experiences not otherwise shared in the application and is an opportunity to explain any breaks in training or performance lapses. When selecting programs to which they will apply, applicants should pay close attention to the areas of education and curriculum, clinical experience, scholarly opportunity, and personal factors. Preparing for interviews should include a review of the program at which one is interviewing and development of relevant questions regarding details of the program. The interview day is the applicant's opportunity to see the "personality" of the program by meeting with the program director, faculty, and current fellows and to assess whether the program is a good fit for their goals. Applicants should only rank those programs they are willing to attend, in order of preference; they should be aware that the match process is binding. PMID- 25742295 TI - Specific dephosphorylation at tyr-554 of git1 by ptprz promotes its association with paxillin and hic-5. AB - G protein-coupled receptor kinase-interactor 1 (Git1) is involved in cell motility control by serving as an adaptor that links signaling proteins such as Pix and PAK to focal adhesion proteins. We previously demonstrated that Git1 was a multiply tyrosine-phosphorylated protein, its primary phosphorylation site was Tyr-554 in the vicinity of the focal adhesion targeting-homology (FAH) domain, and this site was selectively dephosphorylated by protein tyrosine phosphatase receptor type Z (Ptprz). In the present study, we showed that Tyr-554 phosphorylation reduced the association of Git1 with the FAH-domain-binding proteins, paxillin and Hic-5, based on immunoprecipitation experiments using the Tyr-554 mutants of Git1. The Tyr-554 phosphorylation of Git1 was higher, and its binding to paxillin was consistently lower in the brains of Ptprz-deficient mice than in those of wild-type mice. We then investigated the role of Tyr-554 phosphorylation in cell motility control using three different methods: random cell motility, wound healing, and Boyden chamber assays. The shRNA-mediated knockdown of endogenous Git1 impaired cell motility in A7r5 smooth muscle cells. The motility defect was rescued by the exogenous expression of wild-type Git1 and a Git1 mutant, which only retained Tyr-554 among the multiple potential tyrosine phosphorylation sites, but not by the Tyr-554 phosphorylation-defective or phosphorylation-state mimic Git1 mutant. Our results suggested that cyclic phosphorylation-dephosphorylation at Tyr-554 of Git1 was crucial for dynamic interactions between Git1 and paxillin/Hic-5 in order to ensure coordinated cell motility. PMID- 25742297 TI - DNA-carbon dots function as fluorescent vehicles for drug delivery. AB - Carbon dots (CDs) are a new representative in the carbon-based material family, attracting tremendous interest in a large variety of fields, including biomedicine. In this report, we described a facile and green system for synthesizing DNA-CDs using genomic DNA isolated from Escherichia coli. DNA-CDs can be purified using a simple column centrifugation-based system. During DNA-CD synthesis, ribose was collapsed, accompanied by the release of nitrogen, and several new bonds (C-OH, N-O, and N-P) were formed, while the other covalent bonds of DNA were largely maintained. The presence of abundant chemical groups, such as amino or hydroxyl groups on DNA-CDs, may facilitate their future functionalization. These highly biocompatible DNA-CDs can serve as a new type of fluorescent vehicle for cell imaging and drug delivery studies. Our research may hasten the development of CDs for prominent future biomedical applications. PMID- 25742298 TI - Correction: predicting non return to work after orthopaedic trauma: the Wallis occupational rehabilitation risk (WORRK) model. PMID- 25742299 TI - The human toxome project. AB - The Human Toxome Project, funded as an NIH Transformative Research grant 2011 2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectroscopy-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies. PMID- 25742301 TI - Correction: Multi year observations reveal variability in residence of a tropical demersal fish, Lethrinus nebulosus: implications for spatial management. PMID- 25742300 TI - An increase in mean platelet volume from baseline is associated with mortality in patients with severe sepsis or septic shock. AB - INTRODUCTION: Mean platelet volume (MPV) is suggested as an index of inflammation, disease activity, and anti-inflammatory treatment efficacy in chronic inflammatory disorders; however, the effect of MPV on sepsis mortality remains unclear. Therefore, we investigated whether the change in MPV between hospital admission and 72 hours (DeltaMPV72h-adm) predicts 28-day mortality in severe sepsis and/or septic shock. METHODS: We prospectively enrolled 345 patients admitted to the emergency department (ED) who received standardized resuscitation (early goal-directed therapy) for severe sepsis and/or septic shock between November 2007 and December 2011. Changes in platelet indices, including DeltaMPV72h-adm, were compared between survivors and non-survivors by linear mixed model analysis. The prognostic value of DeltaMPV72h-adm for 28-day mortality was ascertained by Cox proportional hazards model analysis. RESULTS: Thirty-five (10.1%) patients died within 28 days after ED admission. MPV increased significantly during the first 72 hours in non-survivors (P = 0.001) and survivors (P < 0.001); however, the rate of MPV increase was significantly higher in non-survivors (P = 0.003). Nonetheless, the difference in the platelet decline rate over the first 72 hours did not differ significantly between groups (P = 0.360). In multivariate analysis, DeltaMPV72h-adm was an independent predictor of 28-day mortality, after adjusting for plausible confounders (hazard ratio, 1.44; 95% confidence interval, 1.01-2.06; P = 0.044). CONCLUSIONS: An increase in MPV during the first 72 hours of hospitalization is an independent risk factor for adverse clinical outcomes. Therefore, continuous monitoring of MPV may be useful to stratify mortality risk in patients with severe sepsis and/or septic shock. PMID- 25742302 TI - Correction: Determinants of acceptance and subsequent uptake of the HPV vaccine in a cohort in Eldoret, Kenya. PMID- 25742303 TI - Correction: EGFR, HER-2 and KRAS in canine gastric epithelial tumors: a potential human model? PMID- 25742304 TI - Correction: Long non-coding RNA BANCR promotes proliferation in malignant melanoma by regulating MAPK pathway activation. PMID- 25742306 TI - Emergency treatment for exposure to Ebola virus: the need to fast-track promising vaccines. PMID- 25742305 TI - Aberrant splicing in transgenes containing introns, exons, and V5 epitopes: lessons from developing an FSHD mouse model expressing a D4Z4 repeat with flanking genomic sequences. AB - The DUX4 gene, encoded within D4Z4 repeats on human chromosome 4q35, has recently emerged as a key factor in the pathogenic mechanisms underlying Facioscapulohumeral muscular dystrophy (FSHD). This recognition prompted development of animal models expressing the DUX4 open reading frame (ORF) alone or embedded within D4Z4 repeats. In the first published model, we used adeno associated viral vectors (AAV) and strong viral control elements (CMV promoter, SV40 poly A) to demonstrate that the DUX4 cDNA caused dose-dependent toxicity in mouse muscles. As a follow-up, we designed a second generation of DUX4-expressing AAV vectors to more faithfully genocopy the FSHD-permissive D4Z4 repeat region located at 4q35. This new vector (called AAV.D4Z4.V5.pLAM) contained the D4Z4/DUX4 promoter region, a V5 epitope-tagged DUX4 ORF, and the natural 3' untranslated region (pLAM) harboring two small introns, DUX4 exons 2 and 3, and the non-canonical poly A signal required for stabilizing DUX4 mRNA in FSHD. AAV.D4Z4.V5.pLAM failed to recapitulate the robust pathology of our first generation vectors following delivery to mouse muscle. We found that the DUX4.V5 junction sequence created an unexpected splice donor in the pre-mRNA that was preferentially utilized to remove the V5 coding sequence and DUX4 stop codon, yielding non-functional DUX4 protein with 55 additional residues on its carboxyl terminus. Importantly, we further found that aberrant splicing could occur in any expression construct containing a functional splice acceptor and sequences resembling minimal splice donors. Our findings represent an interesting case study with respect to AAV.D4Z4.V5.pLAM, but more broadly serve as a note of caution for designing constructs containing V5 epitope tags and/or transgenes with downstream introns and exons. PMID- 25742307 TI - Development of a pHrodo-based assay for the assessment of in vitro and in vivo erythrophagocytosis during experimental trypanosomosis. AB - Extracellular trypanosomes can cause a wide range of diseases and pathological complications in a broad range of mammalian hosts. One common feature of trypanosomosis is the occurrence of anemia, caused by an imbalance between erythropoiesis and red blood cell clearance of aging erythrocytes. In murine models for T. brucei trypanosomosis, anemia is marked by a very sudden non hemolytic loss of RBCs during the first-peak parasitemia control, followed by a short recovery phase and the subsequent gradual occurrence of an ever-increasing level of anemia. Using a newly developed quantitative pHrodo based in vitro erythrophagocytosis assay, combined with FACS-based ex vivo and in vivo results, we show that activated liver monocytic cells and neutrophils as well as activated splenic macrophages are the main cells involved in the occurrence of the early stage acute anemia. In addition, we show that trypanosomosis itself leads to a rapid alteration of RBC membrane stability, priming the cells for accelerated phagocytosis. PMID- 25742308 TI - A randomized controlled trial comparing the ventilation duration between adaptive support ventilation and pressure assist/control ventilation in medical patients in the ICU. AB - BACKGROUND: Adaptive support ventilation (ASV) is a closed loop mode of mechanical ventilation (MV) that provides a target minute ventilation by automatically adapting inspiratory pressure and respiratory rate with the minimum work of breathing on the part of the patient. The aim of this study was to determine the effect of ASV on total MV duration when compared with pressure assist/control ventilation. METHODS: Adult medical patients intubated and mechanically ventilated for > 24 h in a medical ICU were randomized to either ASV or pressure assist/control ventilation. Sedation and medical treatment were standardized for each group. Primary outcome was the total MV duration. Secondary outcomes were the weaning duration, number of manual settings of the ventilator, and weaning success rates. RESULTS: Two hundred twenty-nine patients were included. Median MV duration until weaning, weaning duration, and total MV duration were significantly shorter in the ASV group (67 [43-94] h vs 92 [61-165] h, P = .003; 2 [2-2] h vs 2 [2-80] h, P = .001; and 4 [2-6] days vs 4 [3-9] days, P = .016, respectively). Patients in the ASV group required fewer total number of manual settings on the ventilator to reach the desired pH and Paco2 levels (2 [1 2] vs 3 [2-5], P < .001). The number of patients extubated successfully on the first attempt was significantly higher in the ASV group (P = .001). Weaning success and mortality at day 28 were comparable between the two groups. CONCLUSIONS: In medical patients in the ICU, ASV may shorten the duration of weaning and total MV duration with a fewer number of manual ventilator settings. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01472302; URL: www.clinicaltrials.gov. PMID- 25742309 TI - Generation of lymphocytic microparticles and detection of their proapoptotic effect on airway epithelial cells. AB - Interest in the biological roles of cell membrane-derived vesicles in cell-cell communication has increased in recent years. Microparticles (MPs) are one such type of vesicles, ranging in diameter from 0.1 MUm to 1 MUm, and typically shed from the plasma membrane of eukaryotic cells undergoing activation or apoptosis. Here we describe the generation of T lymphocyte-derived microparticles (LMPs) from apoptotic CEM T cells stimulated with actinomycin D. LMPs are isolated through a multistep differential centrifugation process and characterized using flow cytometry. This protocol also presents an in situ cell death detection method for demonstrating the proapoptotic effect of LMPs on bronchial epithelial cells derived from mouse primary respiratory bronchial tissue explants. Methods described herein provide a reproducible procedure for isolating abundant quantities of LMPs from apoptotic lymphocytes in vitro. LMPs derived in this manner can be used to evaluate the characteristics of various disease models, and for pharmacology and toxicology testing. Given that the airway epithelium offers a protective physical and functional barrier between the external environment and underlying tissue, use of bronchial tissue explants rather than immortalized epithelial cell lines provides an effective model for investigations requiring airway tract tissue. PMID- 25742310 TI - Curcumin analog DM-1 in monotherapy or combinatory treatment with dacarbazine as a strategy to inhibit in vivo melanoma progression. AB - Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects. PMID- 25742311 TI - Organ-level analysis of idioblast patterning in Egeria densa Planch. leaves. AB - Leaf tissues of plants usually contain several types of idioblasts, defined as specialized cells whose shape and contents differ from the surrounding homogeneous cells. The spatial patterning of idioblasts, particularly of trichomes and guard cells, across the leaf epidermis has received considerable attention as it offers a useful biological model for studying the intercellular regulation of cell fate and patterning. Excretory idioblasts in the leaves of the aquatic monocotyledonous plant Egeria densa produced light blue autofluorescence when irradiated with ultraviolet light. The use of epifluorescence microscopy to detect this autofluorescence provided a simple and convenient method for detecting excretory idioblasts and allowed tracking of those cells across the leaf surfaces, enabling quantitative measurement of the clustering and spacing patterns of idioblasts at the whole leaf level. Occurrence of idioblasts was coordinated along the proximal-distal, medial-lateral, and adaxial-abaxial axes, producing a recognizable consensus spatial pattern of idioblast formation among fully expanded leaves. Idioblast clusters, which comprised up to nine cells aligned along the proximal-distal axis, showed no positional bias or regularity in idioblast-forming areas when compared with singlet idioblasts. Up to 75% of idioblasts existed as clusters on every leaf side examined. The idioblast-forming areas varied between leaves, implying phenotypic plasticity. Furthermore, in young expanding leaves, autofluorescence was occasionally detected in a single giant vesicle or else in one or more small vesicles, which eventually grew to occupy a large portion of the idioblast volume as a central vacuole. Differentiation of vacuoles by accumulating the fluorescence substance might be an integral part of idioblast differentiation. Red autofluorescence from chloroplasts was not detected in idioblasts of young expanding leaves, suggesting idioblast differentiation involves an arrest in chloroplast development at a very early stage, rather than transdifferentiation of chloroplast-containing epidermal cells. PMID- 25742312 TI - Hemin-functionalized WS2 nanosheets as highly active peroxidase mimetics for label-free colorimetric detection of H2O2 and glucose. AB - Hemin-functionalized WS2 nanosheets (hemin/WS2-NSs) were first obtained by hemin assembled on the surface of few-layered WS2 nanosheets (WS2-NSs) via van der Waals interactions. Significantly, this new material possessed the advantages of both hemin and WS2 nanosheets and exhibited some unique properties. Firstly, hemin/WS2-NSs had intrinsic peroxidase-like activity, which could effectively catalyze oxidation of the substrate 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to produce a typical blue colored reaction. Secondly, the activity of hemin/WS2 NSs was much higher than the activity of hemin or WS2-NSs alone. The catalytic activity followed the typical Michaelis-Menten kinetics and was dependent on the temperature, pH, H2O2 concentration, as well as reaction time. Based on this finding, a new highly sensitive and selective colorimetric method for H2O2 and glucose detection was developed. This method was simple and inexpensive for glucose detection using glucose oxidase (GOx) and hemin/WS2-NSs with a linear range of 0.5 * 10(-5) to 2.0 * 10(-4) mol L(-1) with a detection limit of 1.5 * 10(-6) mol L(-1). The good catalytic activity and low-cost make the hemin/WS2-NSs a useful biocatalyst for a wide range of potential applications in environmental chemistry, biotechnology and clinical diagnostics. PMID- 25742313 TI - Intensity- and Domain-Specific Levels of Physical Activity and Sedentary Behavior in 10- to 14-Year-Old Children. AB - BACKGROUND: to investigate levels of physical activity (PA) and sedentary behavior (SB) in 10- to 14-year-olds and to determine PA differences between week weekend days, genders and school stages. METHODS: 241 children were recruited from 15 primary and 15 secondary schools. PA was assessed for 7 days using the SenseWear Mini Armband and an electronic diary. Week-weekend and gender differences were determined using 2-way repeated-measures ANOVA. Combined intensity- and domain-specific PA differences between genders and school stages were examined using 2-way ANOVA. RESULTS: Weekdays were more active compared with weekend days. Physical activity level (PAL) of boys was higher compared with girls. Boys showed more moderate (+15 min/day) and vigorous PA (+9 min/day), no differences were found for SB and light PA. Secondary school children showed more SB (+111 min/day), moderate (+8 min/day) and vigorous (+9 min/day) PA and less light PA (-66 min/day) compared with primary school children. No difference was found for PAL. The results of the combined intensity- and domain-specific parameters revealed more nuanced differences between genders and school stages. CONCLUSIONS: Our results demonstrate the complexity of PA and SB behavior of children, indicating the need for a multidimensional and differentiated approach in PA promotion. PMID- 25742315 TI - Copper-catalyzed trans-carbohalogenation of terminal alkynes with functionalized tertiary alkyl halides. AB - A highly trans-selective Cu-catalyzed carbohalogenation including carbobromination, carboiodination, and carbochlorination of terminal alkynes with activated tertiary alkyl halides has been realized, providing quaternary-carbon containing alkenyl halides in good yields with excellent regio- and stereoselectivity. Meanwhile, an unprecedented alkyne trans-carboalkynylation process has been achieved via the tandem trans-carbohalogenation/Sonogashira coupling reaction, which furnishes highly functionalized 1,3-enynes in a single chemical transformation. PMID- 25742314 TI - Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation. AB - Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-beta, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-beta1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, beta1-integrin, calponin and alpha-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-beta signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-beta-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-beta-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation. PMID- 25742316 TI - Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. AB - Metformin is the mainstay therapy for type 2 diabetes (T2D) and many patients also take salicylate-based drugs [i.e., aspirin (ASA)] for cardioprotection. Metformin and salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) and salicylate interacting directly at the AMPK beta1 drug-binding site. AMPK activation by both drugs results in phosphorylation of ACC (acetyl-CoA carboxylase; P-ACC) and inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme controlling fatty acid synthesis (lipogenesis). We find doses of metformin and salicylate used clinically synergistically activate AMPK in vitro and in vivo, resulting in reduced liver lipogenesis, lower liver lipid levels and improved insulin sensitivity in mice. Synergism occurs in cell-free assays and is specific for the AMPK beta1 subunit. These effects are also observed in primary human hepatocytes and patients with dysglycaemia exhibit additional improvements in a marker of insulin resistance (proinsulin) when treated with ASA and metformin compared with either drug alone. These data indicate that metformin-salicylate combination therapy may be efficacious for the treatment of non-alcoholic fatty liver disease (NAFLD) and T2D. PMID- 25742318 TI - Physical Models for Charge Transfer at Single Crystal Oxide Semiconductor Surfaces as Revealed by the Doping Density Dependence of the Collection Efficiency of Dye Sensitized Photocurrents. AB - The doping density dependence of photocurrents has been experimentally measured at single crystal rutile TiO2 electrodes sensitized with the N3 chromophore and a trimethine dye. As the doping density of the electrodes was varied from 10(15) to 10(20) cm(-3), three different regimes of behavior were observed for the magnitude and shape of the dye sensitized current-voltage curves. Low-doped crystals produced current-voltage curves with a slow rise of photocurrent with potential. At intermediate doping levels, Schottky barrier behavior was observed producing a photocurrent plateau at electrode bias in the depletion region. At highly doped electrodes, tunneling currents played a significant role especially in the recombination processes. These different forms of the current-voltage curves could be fit to an Onsager-based model for charge collection at a semiconductor electrode. The fitting revealed the role of the various physical parameters that govern photoinduced charge collection in sensitized systems. PMID- 25742317 TI - Amyloid precursor protein mediated changes in intestinal epithelial phenotype in vitro. AB - BACKGROUND: Although APP and its proteolytic metabolites have been well examined in the central nervous system, there remains limited information of their functions outside of the brain. For example, amyloid precursor protein (APP) and amyloid beta (Abeta) immunoreactivity have both been demonstrated in intestinal epithelial cells. Based upon the critical role of these cells in absorption and secretion, we sought to determine whether APP or its metabolite amyloid beta (Abeta), had a definable function in these cells. METHODOLOGY/PRINCIPAL FINDINGS: The human colonic epithelial cell line, Caco-2 cells, were cultured to examine APP expression and Abeta secretion, uptake, and stimulation. Similar to human colonic epithelium stains, Caco-2 cells expressed APP. They also secreted Abeta 1 40 and Abeta 1-42, with LPS stimulating higher concentrations of Abeta 1-40 secretion. The cells also responded to Abeta 1-40 stimulation by increasing IL-6 cytokine secretion and decreasing cholesterol uptake. Conversely, stimulation with a sAPP-derived peptide increased cholesterol uptake. APP was associated with CD36 but not FATP4 in co-IP pull down experiments from the Caco-2 cells. Moreover, stimulation of APP with an agonist antibody acutely decreased CD36 mediated cholesterol uptake. CONCLUSIONS/SIGNIFICANCE: APP exists as part of a multi-protein complex with CD36 in human colonic epithelial cells where its proteolytic fragments have complex, reciprocal roles in regulating cholesterol uptake. A biologically active peptide fragment from the N-terminal derived, sAPP, potentiated cholesterol uptake while the beta secretase generated product, Abeta1 40, attenuated it. These data suggest that APP is important in regulating intestinal cholesterol uptake in a fashion dependent upon specific proteolytic pathways. Moreover, this biology may be applicable to cells beyond the gastrointestinal tract. PMID- 25742319 TI - Environmental behavior of the chiral herbicide haloxyfop. 1. Rapid and preferential interconversion of the enantiomers in soil. AB - Haloxyfop-methyl is a chiral herbicide that was first introduced as racemate and later replaced by "haloxyfop-P-methyl", mainly consisting of the R-enantiomer, which carries the herbicidal activity. We studied the ester cleavage of haloxyfop methyl and further degradation and chiral inversion of the acid enantiomers in three different soils using enantioselective gas chromatography-mass spectrometry. Our results confirm the rapid ester hydrolysis of haloxyfop-methyl with half-lives of a few hours and indicate that hydrolysis is weakly enantioselective. Further degradation of haloxyfop was slower with half-lives of several days. In all three soils, S-haloxyfop was rapidly converted to R haloxyfop. In sterile soil, no degradation and no inversion were observed, indicating that both processes are biologically mediated. In soil where 50% of the water had been replaced by deuterium oxide, significant H-D exchange in haloxyfop was observed, pointing to a reaction mechanism involving abstraction of the proton at the chiral center of the molecule. PMID- 25742321 TI - Heated Humidified High-Flow Nasal Oxygen in Adults: Mechanisms of Action and Clinical Implications. AB - Traditionally, nasal oxygen therapy has been delivered at low flows through nasal cannulae. In recent years, nasal cannulae designed to administer heated and humidified air/oxygen mixtures at high flows (up to 60 L/min) have been gaining popularity. These high-flow nasal cannula (HFNC) systems enhance patient comfort and tolerance compared with traditional high-flow oxygenation systems, such as nasal masks and nonrebreathing systems. By delivering higher flow rates, HFNC systems are less apt than traditional oxygenation systems to permit entrainment of room air during patient inspiration. Combined with the flushing of expired air from the upper airway during expiration, these mechanisms assure more reliable delivery of high Fio2 levels. The flushing of upper airway dead space also improves ventilatory efficiency and reduces the work of breathing. HFNC also generates a positive end-expiratory pressure (PEEP), which may counterbalance auto-PEEP, further reducing ventilator work; improve oxygenation; and provide back pressure to enhance airway patency during expiration, permitting more complete emptying. HFNC has been tried for multiple indications, including secretion retention, hypoxemic respiratory failure, and cardiogenic pulmonary edema, to counterbalance auto-PEEP in patients with COPD and as prophylactic therapy or treatment of respiratory failure postsurgery and postextubation. As of yet, very few high-quality studies have been published evaluating these indications, so recommendations regarding clinical applications of HFNC remain tentative. PMID- 25742322 TI - Telemedicine and eye examinations for diabetic retinopathy: a time to maximize real-world outcomes. PMID- 25742323 TI - Professional development session for early career scientists at SITC 2012. AB - The Society for Immunotherapy of Cancer (SITC) 2012 Professional Development Session was held as part of the SITC 27th Annual Meeting, Washington, DC, on October 24, 2012. The session was designed as a new opportunity for early career investigators to learn about relevant career development topics in a didactic setting. PMID- 25742320 TI - Effect of mobile telephone reminders on treatment outcome in HIV: evidence from a randomised controlled trial in India. AB - OBJECTIVE: To assess whether customised mobile phone reminders would improve adherence to therapy and thus decrease virological failure among HIV infected patients starting antiretroviral treatment (ART). DESIGN: Randomised controlled trial among HIV infected patients initiating antiretroviral treatment. SETTING: Three diverse healthcare delivery settings in south India: two ambulatory clinics within the Indian national programme and one private HIV healthcare clinic. PARTICIPANTS: 631 HIV infected, ART naive, adult patients eligible to initiate first line ART were randomly assigned to mobile phone intervention (n=315) or standard care (n=316) and followed for 96 weeks.. INTERVENTION: The intervention consisted of customised, interactive, automated voice reminders, and a pictorial message that were sent weekly to the patients' mobile phones for the duration of the study. MAIN OUTCOME MEASURES: The primary outcome was time to virological failure (viral load >400 copies/mL on two consecutive measurements). Secondary outcomes included ART adherence measured by pill count, death rate, and attrition rate. Suboptimal adherence was defined as mean adherence <95%. RESULTS: Using an intention-to-treat approach we found no observed difference in time to virological failure between the allocation groups: failures in the intervention and standard care arms were 49/315 (15.6%) and 49/316 (15.5%) respectively (unadjusted hazard ratio 0.98, 95% confidence interval 0.67 to 1.47, P=0.95). The rate of virological failure in the intervention and standard care groups were 10.52 and 10.73 per 100 person years respectively. Comparison of suboptimal adherence was similar between both groups (unadjusted incidence rate ratio 1.24, 95% CI 0.93 to 1.65, P=0.14). Incidence proportion of patients with suboptimal adherence was 81/300 (27.0%) in the intervention arm and 65/299 (21.7%) in the standard care arm. The results of analyses adjusted for potential confounders were similar, indicating no significant difference between the allocation groups. Other secondary outcomes such as death and attrition rates, and subgroup analysis also showed comparable results across allocation groups. CONCLUSIONS: In this multicentre randomised controlled trial among ART naive patients initiating first line ART within the Indian national programme, we found no significant effect of the mobile phone intervention on either time to virological failure or ART adherence at the end of two years of therapy.Trial registration Current Controlled Trials ISRCTN79261738. PMID- 25742324 TI - Facial nerve axotomy in mice: a model to study motoneuron response to injury. AB - The goal of this surgical protocol is to expose the facial nerve, which innervates the facial musculature, at its exit from the stylomastoid foramen and either cut or crush it to induce peripheral nerve injury. Advantages of this surgery are its simplicity, high reproducibility, and the lack of effect on vital functions or mobility from the subsequent facial paralysis, thus resulting in a relatively mild surgical outcome compared to other nerve injury models. A major advantage of using a cranial nerve injury model is that the motoneurons reside in a relatively homogenous population in the facial motor nucleus in the pons, simplifying the study of the motoneuron cell bodies. Because of the symmetrical nature of facial nerve innervation and the lack of crosstalk between the facial motor nuclei, the operation can be performed unilaterally with the unaxotomized side serving as a paired internal control. A variety of analyses can be performed postoperatively to assess the physiologic response, details of which are beyond the scope of this article. For example, recovery of muscle function can serve as a behavioral marker for reinnervation, or the motoneurons can be quantified to measure cell survival. Additionally, the motoneurons can be accurately captured using laser microdissection for molecular analysis. Because the facial nerve axotomy is minimally invasive and well tolerated, it can be utilized on a wide variety of genetically modified mice. Also, this surgery model can be used to analyze the effectiveness of peripheral nerve injury treatments. Facial nerve injury provides a means for investigating not only motoneurons, but also the responses of the central and peripheral glial microenvironment, immune system, and target musculature. The facial nerve injury model is a widely accepted peripheral nerve injury model that serves as a powerful tool for studying nerve injury and regeneration. PMID- 25742325 TI - Synthetic progestins medroxyprogesterone acetate and dydrogesterone and their binary mixtures adversely affect reproduction and lead to histological and transcriptional alterations in zebrafish (Danio rerio). AB - Medroxyprogesterone acetate (MPA) and dydrogesterone (DDG) are synthetic progestins widely used in human and veterinary medicine. Although aquatic organisms are exposed to them through wastewater and animal farm runoff, very little is known about their effects in the environment. Here we provide a comprehensive analysis of the responses of zebrafish (Danio rerio) to MPA, DDG, and their binary mixtures at measured concentrations between 4.5 and 1663 ng/L. DDG and both mixtures impaired reproductive capacities (egg production) of breeding pairs and led to histological alterations of ovaries and testes and increased gonadosomatic index. Transcriptional analysis of up to 28 genes belonging to different pathways demonstrated alterations in steroid hormone receptors, steroidogenesis enzymes, and specifically, the circadian rhythm genes, in different organs of adult zebrafish and eleuthero-embryos. Alterations occurred even at environmentally relevant concentrations of 4.5-4.8 ng/L MPA, DDG and the mixture in eleuthero-embryos and at 43-89 ng/L in adult zebrafish. Additionally, the mixtures displayed additive effects in most but not all parameters in adults and eleuthero-embryos, suggesting concentration addition. Our data suggest that MPA and DDG and their mixtures induce multiple transcriptional responses at environmentally relevant concentrations and adverse effects on reproduction and gonad histology at higher levels. PMID- 25742326 TI - Manipulation and in vitro maturation of Xenopus laevis oocytes, followed by intracytoplasmic sperm injection, to study embryonic development. AB - Amphibian eggs have been widely used to study embryonic development. Early embryonic development is driven by maternally stored factors accumulated during oogenesis. In order to study roles of such maternal factors in early embryonic development, it is desirable to manipulate their functions from the very beginning of embryonic development. Conventional ways of gene interference are achieved by injection of antisense oligonucleotides (oligos) or mRNA into fertilized eggs, enabling under- or over-expression of specific proteins, respectively. However, these methods normally require more than several hours until protein expression is affected, and, hence, the interference of gene functions is not effective during early embryonic stages. Here, we introduce an experimental system in which expression levels of maternal proteins can be altered before fertilization. Xenopus laevis oocytes obtained from ovaries are defolliculated by incubating with enzymes. Antisense oligos or mRNAs are injected into defolliculated oocytes at the germinal vesicle (GV) stage. These oocytes are in vitro matured to eggs at the metaphase II (MII) stage, followed by intracytoplasmic sperm injection (ICSI). By this way, up to 10% of ICSI embryos can reach the swimming tadpole stage, thus allowing functional tests of specific gene knockdown or overexpression. This approach can be a useful way to study roles of maternally stored factors in early embryonic development. PMID- 25742327 TI - Giving patients what they need and want. PMID- 25742328 TI - Preparing patients to care for themselves. PMID- 25742329 TI - Blaming patients. PMID- 25742330 TI - RN networking. PMID- 25742331 TI - RN networking. PMID- 25742332 TI - Alternative therapies. PMID- 25742335 TI - FDA warns against power morcellation for hysterectomy and fibroids. PMID- 25742336 TI - The joint commission addresses health care worker fatigue. PMID- 25742338 TI - Diabetes trends: 20 years of progress and paradox. PMID- 25742341 TI - Senior managers in work areas: do they improve performance? PMID- 25742343 TI - Health screening: conflicting findings, dueling recommendations. PMID- 25742347 TI - Postsurgical chemotherapy vs. surgery alone for resectable gastric cancer. PMID- 25742348 TI - Ana's story. PMID- 25742352 TI - JBI's systematic reviews: data extraction and synthesis. AB - This article is the fifth in a series on the systematic review from the Joanna Briggs Institute, an international collaborative supporting evidence-based practice in nursing, medicine, and allied health fields. The purpose of the series is to describe how to conduct a systematic review-one step at a time. This article details the data extraction and data synthesis stages, with an emphasis on conducting a meta-analysis of quantitative data. PMID- 25742357 TI - The new world of health care quality and measurement. AB - This column is designed to provide a nursing perspective on the new hospital quality measurements. Future articles will cover the various quality indicators hospitals face and the role of the nurse in meeting mandated benchmarks. Reader responses to this column are welcome and will help to make it more useful to nurses in meeting the challenges posed by health care reform and changing Medicare reimbursement programs. PMID- 25742358 TI - Lessons learned from litigation: maintaining professional boundaries. PMID- 25742359 TI - Infection prevention practices in ambulatory surgery centers. AB - The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, and birthing centers, as well as some abortion facilities, must file information on medical errors.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID- 25742360 TI - From candy striper to chief nurse. PMID- 25742362 TI - Isolation of human mesenchymal stem cells and their cultivation on the porous bone matrix. AB - Mesenchymal stem cells (MSCs) have a differentiation potential towards osteoblastic lineage when they are stimulated with soluble factors or specific biomaterials. This work presents a novel option for the delivery of MSCs from human amniotic membrane (AM-hMSCs) that employs bovine bone matrix Nukbone (NKB) as a scaffold. Thus, the application of MSCs in repair and tissue regeneration processes depends principally on the efficient implementation of the techniques for placing these cells in a host tissue. For this reason, the design of biomaterials and cellular scaffolds has gained importance in recent years because the topographical characteristics of the selected scaffold must ensure adhesion, proliferation and differentiation into the desired cell lineage in the microenvironment of the injured tissue. This option for the delivery of MSCs from human amniotic membrane (AM-hMSCs) employs bovine bone matrix as a cellular scaffold and is an efficient culture technique because the cells respond to the topographic characteristics of the bovine bone matrix Nukbone (NKB), i.e., spreading on the surface, macroporous covering and colonizing the depth of the biomaterial, after the cell isolation process. We present the procedure for isolating and culturing MSCs on a bovine matrix. PMID- 25742363 TI - Perspectives on social media in and as research: A synthetic review. AB - With the growth of social media use in both the private and public spheres, researchers are currently exploring the new opportunities and practices offered by these tools in the research lifecycle. This area is still in its infancy: As methodological approaches and methods are being tested - mainly through pragmatic and exploratory approaches - practices are being shaped and negotiated by the actors involved in research. A further element of complexity is added by the ambivalent status of social media within research activities. They can be both a tool - for recruitment, data collection, analysis - and data - as what constitutes the corpus to be analysed - both in an observational and interactive domain. This synthetic analysis of the literature is aimed at identifying how social media are currently being used in research and how they fit into the research lifecycle. We identify and discuss emerging evidence and trends in the adoption of social media in research, which can be used and applied by psychiatry research practitioners as a framework to inform the development of a personalized research network and social media strategy in research. PMID- 25742364 TI - Determination of Strong Absorption Band Profiles of Low-Temperature Liquids from Reflection Spectra: The nu3 Band of Liquefied Tetrafluoromethane (CF4). AB - An experimental unit for recording the combined reflection-absorption spectra of low-temperature liquids was designed and manufactured and an algorithm for obtaining the extinction coefficient was developed. The manufactured experimental unit and the algorithm were tested by recording, for the first time, the absorption spectrum of liquefied CF4. The band parameters derived from the experimental data are compared with estimates available in the literature. PMID- 25742365 TI - Correction: a new framework for cortico-striatal plasticity: behavioural theory meets in vitro data at the reinforcement-action interface. PMID- 25742367 TI - Correction: combined anti-inflammatory and anti-AGE drug treatments have a protective effect on intervertebral discs in mice with diabetes. PMID- 25742366 TI - Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method. AB - The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min(-1) M(-1) k(inact)/K(I) values and >=10-fold selectivity for PAD3 over PADs 1, 2, and 4. PMID- 25742368 TI - Murine model of femoral artery wire injury with implantation of a perivascular drug delivery patch. AB - Percutaneous interventions including balloon angioplasty and stenting have been used to restore blood flow in vessels with occlusive vascular disease. While these therapies lead to the rapid restoration of blood flow, these technologies remain limited by restenosis in the case of bare metal stents and angioplasty, or reduced healing and possibly enhanced risk of thrombosis in the case of drug eluting stents. A key pathophysiological mechanism in the formation of restenosis is intimal hyperplasia caused by the activation of vascular smooth muscle cells and inflammation due to arterial stretch and injury. Surgeries that induce arterial injury in genetically modified mice are useful for the mechanistic study of the vascular response to injury but are often technically challenging to perform in mouse models due to the their small size and lack of appropriate sized devices. We describe two approaches for a surgical technique that induces endothelial denudation and arterial stretch in the femoral artery of mice to produce robust neointimal hyperplasia. The first approach creates an arteriotomy in the muscular branch of the femoral artery to obtain vascular access. Following wire injury this arterial branch is ligated to close the arteriotomy. A second approach creates an arteriotomy in the main femoral artery that is later closed through localized cautery. This method allows for vascular access through a larger vessel and, consequently, provides a less technically demanding procedure that can be used in smaller mice. Following either method of arterial injury, a degradable drug delivery patch can be placed over or around the injured artery to deliver therapeutic agents. PMID- 25742369 TI - The nature and role of the gold-krypton interactions in small neutral gold clusters. AB - We investigate the nature and role of krypton embedding in small neutral gold clusters. For some of these clusters, we observe a particular site-dependent character of the Kr binding that does not completely follow the criterion of binding at low-coordinated sites, widely accepted for interaction of a noble gas with closed-shell metal systems such as metal surfaces. We aim at understanding the effect of low dimensionality and open-shell electronic structure of the odd numbered clusters on the noble gas-metal cluster interaction. First, we investigate the role of attractive and repulsive forces, and the frontier molecular orbitals. Second, we investigate the Au-Kr interaction in terms of reactivity and bonding character. We use a reactivity index derived from Fukui formalism, and criteria provided by the electron localization function (ELF), in order to classify the type of bonding. We carry out this study on the minimum energy structures of neutral gold clusters, as obtained using pseudo potential plane-wave density functional theory (DFT). A model is proposed that includes the effect of attractive electrostatic, van der Waals and repulsive forces, together with effects originating from orbital overlap. This satisfactorily explains minimum configurations of the noble gas-gold cluster systems, the site preference of the noble gas atoms, and changes in electronic properties. PMID- 25742370 TI - Exercise and medication effects on persons with Parkinson disease across the domains of disability: a randomized clinical trial. AB - BACKGROUND AND PURPOSE: Hypokinesia and bradykinesia as movement deficits of Parkinson disease are thought to be mediated by both basal ganglia dysfunction and a loss of muscle mass and strength commensurate with aging and decreased levels of physical activity. For these reasons, we sought to utilize resistance training as a means to increase muscle force and minimize hypokinesia and bradykinesia in persons with Parkinson disease and examine the effects of exercise and medication on Body Structure and Function (muscle force production and muscle cross-sectional area), Activity (mobility), and Participation (Health Status) outcomes. METHODS: Forty-two participants were enrolled in a 12-week randomized clinical trial that compared 2 active exercise interventions: a standard care control group (Active Control) and an experimental group that underwent Resistance Exercise via Negative Eccentric Work (RENEW). RESULTS: Participants in both groups improved in muscle force production and mobility as a result of exercise and medication (P < 0.02). There were no significant interaction or between-group differences and no significant changes in muscle cross-sectional area or health status were observed. Effect sizes for exercise and medication combined exceeded the effect sizes of either intervention in isolation. DISCUSSION AND CONCLUSIONS: Taken together, these results point to the complementary effects of exercise and medication on the Body Structure and Function and Activity outcomes but little effect on Participation outcomes.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A92). PMID- 25742371 TI - Pressure-controlled treadmill training in chronic stroke: a case study with AlterG. AB - BACKGROUND AND PURPOSE: Body-weight-supported treadmill training has been shown to be an effective intervention to improve walking characteristics for individuals who have experienced a stroke. A pressure-controlled treadmill utilizes a sealed chamber in which air pressure can be altered in a controlled manner to counteract the effects of gravity. The focus of this case study was to assess the immediate and short-term impact of a pressure-controlled treadmill to improve gait parameters, reduce fall risk, improve participation, and reduce the self-perceived negative impact of stroke in an individual with chronic stroke. CASE DESCRIPTION: The subject was an 81-year-old man (14.5 months poststroke). He had slow walking speed, poor endurance, and multiple gait deviations. INTERVENTION: The subject trained 4 times per week for 4 weeks (40 minutes per session) on a pressure-controlled treadmill (AlterG M320) to counter the influence of gravity on the lower extremities. OUTCOMES: Following training, self selected gait speed increased from 0.50 m/s to 0.96 m/s, as measured by the 10 meter walk test. Stride length increased from 0.58 m to 0.95 m after training and to 1.00 m at 1-month follow-up. Peak hip flexion increased from 3.7 degrees to 24.6 degrees after training and to 19.4 degrees at 1-month follow-up. Peak knee flexion increased from 19.4 degrees to 34.3 degrees after training and to 42.7 degrees at 1-month follow-up. Measures of endurance, fall risk, and percentage of perceived recovery also were found to improve posttraining. DISCUSSION: Training with a pressure-controlled treadmill may be a viable alternative to traditional body-weight-supported treadmill training for persons poststroke. Additional studies with larger sample sizes are needed to elucidate the role of pressure-controlled treadmill training in this population. Video abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A97). PMID- 25742374 TI - What is backward disequilibrium and how do i treat it? A complex patient case study. AB - BACKGROUND AND PURPOSE: Postural vertical refers to a component of an individual's perception of verticality that is derived from information about the direction of gravitational forces. Backward disequilibrium (BD) is a postural disorder observed in some older adults who have a distortion in their perception of postural vertical. Individuals with BD sustain their center of mass (COM) posterior to their base of support and resist correction of COM alignment. The purposes of this case study are to describe a patient with BD and propose a physical therapy management program for this condition. CASE DESCRIPTION AND INTERVENTION: The patient was an 83-year-old woman admitted for home care services 4 months after falling and sustaining a displaced right femoral neck fracture and subsequent hemiarthroplasty. Details of the clinical examination, diagnosis, and intervention are provided and a treatment protocol for physical therapy management is suggested. OUTCOMES: During the episode of care, the patient (1) decreased her dependence on caregivers, (2) surpassed minimal detectable change or minimal clinically important improvements in gait speed and on the Short Physical Performance Battery and Performance-Oriented Mobility Assessment, and (3) achieved her primary goal of staying in her own apartment at an assisted living facility. DISCUSSION: Knowledge of BD coupled with a thorough clinical examination may assist physical therapists in identifying this condition and employing the specific intervention we have proposed. We believe that failure to recognize and manage our patient's condition appropriately would have led to nursing home placement.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A94). PMID- 25742375 TI - Relationships among physical inactivity, deconditioning, and walking impairment in persons with multiple sclerosis. AB - BACKGROUND AND PURPOSE: We have previously proposed a conceptual model of physical inactivity, physiological deconditioning, and walking impairment in persons with multiple sclerosis (MS) that suggests engaging in physical activity and improving physiological conditioning may lead to improvements in walking performance. This cross-sectional study examined the nature of associations among physical activity, aerobic capacity, and walking performance in persons with MS and healthy controls. METHODS: The sample included 31 persons with MS and 31 controls matched by age, sex, height, and weight. Participants completed the 6 minute walk (6MW), wore an ActiGraph model GT3X accelerometer for 7 days as an objective measure of physical activity (expressed as time spent in moderate-to vigorous physical activity [MVPA]), and completed an incremental exercise test on a cycle ergometer as a measure of aerobic capacity (VO2peak). RESULTS: Hierarchical linear regression analyses indicated that MVPA and VO2peak partially explained group differences in 6MW performance (R = 0.782), although group remained a significant predictor of 6MW performance (beta = 0.304; P < 0.001). Path analysis indicated that group had both statistically significant direct and indirect effects on 6MW performance, and the indirect effect operated through pathways involving MVPA and VO2peak. DISCUSSION AND CONCLUSIONS: These results provide direct preliminary evidence that physiological deconditioning, perhaps occurring as a result of physical inactivity, may explain variability in walking impairment in persons with MS. These findings support the design and implementation of targeted interventions for improving walking impairment in this population. VIDEO ABSTRACT AVAILABLE: for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A93). PMID- 25742376 TI - Exercise for persons with Parkinson disease: important considerations of medication, assessment, and training. PMID- 25742377 TI - Lost in translation: priorities in the application of evidence to practice. PMID- 25742378 TI - Validity of body-worn sensor acceleration metrics to index upper extremity function in hemiparetic stroke. AB - BACKGROUND AND PURPOSE: Accelerometers have been used to capture real-world use of the paretic upper extremity in people with stroke. It may be possible to characterize different aspects of the recorded acceleration to gain insight about movement capabilities during task-specific behavior. These measures may be of value for guiding rehabilitation. We undertook a study to identify the acceleration characteristics that have a stable association with upper extremity function and sensitivity to within-participant fluctuations in function over multiple sessions of task-specific training. METHODS: Twenty-seven adults 6 months or more poststroke with upper extremity paresis participated. Signals from wrist-worn accelerometers were sampled at 30 Hz during 7 sessions of task specific training. Paretic upper extremity function was evaluated with the Action Research Arm Test. We used Spearman correlations to examine within-session associations between acceleration metrics and Action Research Arm Test performance. A mixed model was used to determine which metrics were sensitive to within-participant fluctuations in upper extremity function across the 7 training sessions. RESULTS: Upper extremity function correlated with bilateral acceleration variability and use ratio during 5 and 6 sessions, respectively. Time accelerating between 76% and 100% of peak acceleration correlated with function in 6 sessions. Variability of the paretic upper extremity acceleration and the ratio of acceleration variability between upper extremities were associated with function during all 7 sessions. Variability in both the acceleration of the paretic upper extremity, and acceleration of the paretic and nonparetic extremities combined were sensitive to within-participant fluctuations in function across training sessions. DISCUSSION AND CONCLUSIONS: Multiple features of the acceleration profile track with upper extremity function within and across sessions of task-specific training. It may be possible to monitor these features with accelerometers to index upper extremity function outside of clinical settings.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A91). PMID- 25742379 TI - Suicide trends among persons aged 10-24 years--United States, 1994-2012. AB - Suicide is the second leading cause of death among persons aged 10-24 years in the United States and accounted for 5,178 deaths in this age group in 2012. Firearm, suffocation (including hanging), and poisoning (including drug overdose) are the three most common mechanisms of suicide in the United States. Previous reports have noted that trends in suicide rates vary by mechanism and by age group in the United States, with increasing rates of suffocation suicides among young persons. To test whether this increase is continuing and to determine whether it varies by demographic subgroups among persons aged 10-24 years, CDC analyzed National Vital Statistics System mortality data for the period 1994 2012. Trends in suicide rates were examined by sex, age group, race/ethnicity, region of residence, and mechanism of suicide. Results of the analysis indicated that, during 1994-2012, suicide rates by suffocation increased, on average, by 6.7% and 2.2% annually for females and males, respectively. Increases in suffocation suicide rates occurred across demographic and geographic subgroups during this period. Clinicians, hotline staff and others who work with young persons need to be aware of current trends in suffocation suicides in this group so that they can accurately assess risk and educate families. Media coverage of suicide incidents and clusters should follow established guidelines to avoid exacerbating risk for "suicide contagion" among vulnerable young persons.* Suicide contagion is a process by which exposure to the suicide or suicidal behavior of one or more persons influences others who are already vulnerable and thinking about suicide to attempt or die by suicide. Early prevention strategies are needed to reduce the likelihood of young persons developing suicidal thoughts and behavior. PMID- 25742380 TI - Update: Influenza activity--United States, September 28, 2014-February 21, 2015. AB - Influenza activity in the United States began to increase in mid-November, remained elevated through February 21, 2015, and is expected to continue for several more weeks. To date, influenza A (H3N2) viruses have predominated overall. As has been observed in previous seasons during which influenza A (H3N2) viruses predominated, adults aged >=65 years have been most severely affected. The cumulative laboratory-confirmed influenza-associated hospitalization rate among adults aged >=65 years is the highest recorded since this type of surveillance began in 2005. This age group also accounts for the majority of deaths attributed to pneumonia and influenza. The majority of circulating influenza A (H3N2) viruses are different from the influenza A (H3N2) component of the 2014-15 Northern Hemisphere seasonal vaccines, and the predominance of these antigenically and genetically drifted viruses has resulted in reduced vaccine effectiveness. This report summarizes U.S. influenza activity* since September 28, 2014, and updates the previous summary. PMID- 25742381 TI - Infant and maternal characteristics in neonatal abstinence syndrome--selected hospitals in Florida, 2010-2011. AB - Neonatal abstinence syndrome (NAS) is a constellation of physiologic and neurobehavioral signs exhibited by newborns exposed to addictive prescription or illicit drugs taken by a mother during pregnancy. The number of hospital discharges of newborns diagnosed with NAS has increased more than 10-fold (from 0.4 to 4.4 discharges per 1,000 live births) in Florida since 1995, far exceeding the three-fold increase observed nationally. In February 2014, the Florida Department of Health requested the assistance of CDC to 1) assess the accuracy and validity of using Florida's hospital inpatient discharge data, linked to birth and infant death certificates, as a means of NAS surveillance and 2) describe the characteristics of infants with NAS and their mothers. This report focuses only on objective two, describing maternal and infant characteristics in the 242 confirmed NAS cases identified in three Florida hospitals during a 2-year period (2010-2011). Infants with NAS experienced serious medical complications, with 97.1% being admitted to an intensive care unit, and had prolonged hospital stays, with a mean duration of 26.1 days. The findings of this investigation underscore the important public health problem of NAS and add to current knowledge on the characteristics of these mothers and infants. Effective June 2014, NAS is now a mandatory reportable condition in Florida. Interventions are also needed to 1) increase the number and use of community resources available to drug-abusing and drug-dependent women of reproductive age, 2) improve drug addiction counseling and rehabilitation referral and documentation policies, and 3) link women to these resources before or earlier in pregnancy. PMID- 25742382 TI - Vital signs: seat belt use among long-haul truck drivers--United States, 2010. AB - BACKGROUND: Motor vehicle crashes were the leading cause of occupational fatalities in the United States in 2012, accounting for 25% of deaths. Truck drivers accounted for 46% of these deaths. This study estimates the prevalence of seat belt use and identifies factors associated with nonuse of seat belts among long-haul truck drivers (LHTDs), a group of workers at high risk for fatalities resulting from truck crashes. METHODS: CDC analyzed data from its 2010 national survey of LHTD health and injury. A total of 1,265 drivers completed the survey interview. Logistic regression was used to examine the association between seat belt nonuse and risk factors. RESULTS: An estimated 86.1% of LHTDs reported often using a seat belt, 7.8% used it sometimes, and 6.0% never. Reporting never using a belt was associated with often driving >=10 mph (16 kph) over the speed limit (adjusted odds ratio [AOR] = 2.9), working for a company with no written safety program (AOR = 2.8), receiving two or more tickets for moving violations in the preceding 12 months (AOR = 2.2), living in a state without a primary belt law (AOR = 2.1); and being female (AOR = 2.3). CONCLUSIONS: Approximately 14% of LHTDs are at increased risk for injury and death because they do not use a seat belt on every trip. Safety programs and other management interventions, engineering changes, and design changes might increase seat belt use among LHTDs. IMPLICATIONS FOR PUBLIC HEALTH: Primary state belt laws can help increase belt use among LHTDs. Manufacturers can use recently collected anthropometric data to design better-fitting and more comfortable seat belt systems. PMID- 25742383 TI - Systems for rapidly detecting and treating persons with ebola virus disease- United States. AB - The U.S. Department of Health and Human Services (HHS), CDC, other U.S. government agencies, the World Health Organization (WHO), and international partners are taking multiple steps to respond to the current Ebola virus disease (Ebola) outbreak in West Africa to reduce its toll there and to reduce the chances of international spread. At the same time, CDC and HHS are working to ensure that persons who have a risk factor for exposure to Ebola and who develop symptoms while in the United States are rapidly identified and isolated, and safely receive treatment. HHS and CDC have actively worked with state and local public health authorities and other partners to accelerate health care preparedness to care for persons under investigation (PUI) for Ebola or with confirmed Ebola. This report describes some of these efforts and their impact. PMID- 25742384 TI - Notes from the field: Adverse events associated with administration of simulation intravenous fluids to patients--United States, 2014. AB - On December 23, 2014, the New York State Department of Health (NYSDOH) was notified of adverse health events in two patients who had been inadvertently administered nonsterile, simulation 0.9% sodium chloride intravenous (IV) fluids at an urgent care facility. Simulation saline is a nonsterile product not meant for human or animal use; it is intended for use by medical trainees practicing IV administration of saline on mannequins or other training devices. Both patients experienced a febrile illness during product administration and were hospitalized; one patient developed sepsis and disseminated intravascular coagulation. Neither patient died. Staff members at the clinic reported having ordered the product through their normal medical supply distributor and not recognizing during administration that it was not intended for human use. PMID- 25742385 TI - Notes from the field: Increase in reported Crimean-Congo hemorrhagic fever cases- country of Georgia, 2014. AB - During January-September 2014, Georgia's National Centers for Disease Control and Public Health (NCDC) detected 22 cases of Crimean-Congo hemorrhagic fever (CCHF) in the country. CCHF is caused by infection with a tickborne virus of the Bunyaviridae family. Transmission occurs from the bite of an infected tick or from crushing an infected tick with bare skin. Secondary transmission can result from contact with blood or tissues of infected animals and humans. CCHF initially manifests as a nonspecific febrile illness that progresses to a hemorrhagic phase, marked by rapidly developing symptoms leading to multiorgan failure, shock, and death in severe cases. The clinical severity, transmissibility, and infectiousness of CCHF are responsible for its categorization as a viral hemorrhagic fever high-priority bioterrorism agent. PMID- 25742386 TI - [AGNP Prize for research in psychopharmacology]. PMID- 25742387 TI - Decentration of optical zone center and its impact on visual outcomes following SMILE. AB - PURPOSE: To evaluate decentration from pupil center and corneal vertex normal following femtosecond laser small incision lenticule extraction (SMILE) for the treatment of myopia and myopic astigmatism. METHODS: This study evaluated 101 eyes of 101 patients with a spherical equivalent (SE) of -5.30 +/- 1.72 diopters (D). Decentration was measured in the pupil-centered group (PC group) by video capture images and in the vertex normal-centered group (VNC group) using the WaveLight Oculyzer II (Alcon). The PC and VNC groups were further divided into 4 subgroups (1 PC, 2 PC and 1 VNC, 2 VNC) based on the displacement of the lenticule center. Uncorrected and corrected distance visual acuities, manifest refraction, and wavefront errors were measured preoperatively, and at 1 day, 1 week, 1 month, and 3 and 6 months postoperatively. RESULTS: Regarding efficacy and safety, at 6 months postoperatively, 65, 71, 83, and 53% of eyes had unchanged corrected distance visual acuity in 1 PC, 1 VNC, 2 PC and 2 VNC groups, respectively. Also, 97, 98, 100, and 97% of treated eyes had a postoperative uncorrected distance visual acuity 20/20 or better in the subgroups, respectively. In the groups mentioned above, 96, 100, 100, and 95% of eyes, respectively, were within +/-0.5 D of the targeted SE. In terms of total higher order aberrations, the 1 PC group was significantly higher than the 1 VNC group (P = 0.04), whereas the 2 VNC group was significantly higher than the 2 PC group (P = 0.02). CONCLUSIONS: Our results demonstrate that better refractive outcomes will be achieved when the lenticule center is closer to the corneal vertex normal. PMID- 25742388 TI - In vivo confocal microscopic analysis of normal human anterior limbal stroma. AB - PURPOSE: To characterize the microarchitecture of anterior limbal stroma in healthy individuals using in vivo confocal microscopy (IVCM) and to correlate it with mesenchymal stem cells (MSCs), a component of the limbal niche. METHODS: The corneal side of the superior limbus was scanned in 30 eyes of 17 normal subjects beyond the basal epithelium, deep into the stroma using an HRT III laser scanning microscope. The IVCM findings were correlated with the immunohistochemical features of MSCs in the anterior limbal stroma. RESULTS: Clusters of hyperreflective structures were observed in the anterior limbal stroma, subjacent to the basal epithelium (depth, 50.2 +/- 8.7 MUm to 98 +/- 12.8 MUm), but not in the corneal stroma. The structures showed unique morphology compared with epithelial cells, keratocytes, neurons, and dendritic cells. In parallel, confocal analysis of immunostained sections showed clusters of cells, double positive for MSC-specific markers (CD90 and CD105) in the anterior limbal stroma at a depth of 55.3 +/- 12.7 MUm to 72 +/- 37.6 MUm. The organization and distribution of the MSC clusters locates them within the hyperreflective region in the anterior limbal stroma. CONCLUSIONS: The hyperreflective structures, demonstrated for the first time in the human anterior limbal stroma, probably represent an important component of the limbal niche. Our approach of in vivo imaging may pave the way for assessing the limbal stromal health. PMID- 25742389 TI - Long-term resolution of immunological graft rejection after a dexamethasone intravitreal implant. AB - PURPOSE: To present the results of the injection of an intravitreal implant of dexamethasone 0.7 mg (DEX 0.7 mg) in 4 patients with an immunologic graft rejection after penetrating keratoplasty. METHODS: Two of the patients received DEX 0.7 mg because inflammation and corneal edema not related to endothelial cell loss persisted despite the administration of topical prednisolone acetate, subconjunctival betamethasone, and systemic methylprednisolone. The other 2 cases received DEX 0.7 mg at the time rejection was diagnosed. RESULTS: At 1 and 6 months after implantation, all rejection episodes resolved with improvement in uncorrected and best-corrected visual acuity, restoration of graft transparency, reduction of central corneal thickness, and no significant increase in intraocular pressure. CONCLUSIONS: In 4 eyes with an immunologic graft rejection after penetrating keratoplasty, the dexamethasone 0.7 mg intravitreal implant was an effective treatment option, even in cases refractory to standard topical and systemic therapy. PMID- 25742390 TI - Solitary epibulbar neurofibroma in older adult patients. AB - PURPOSE: To report a solitary epibulbar neurofibroma in 2 elderly patients without systemic neurofibromatosis. METHODS: Case reports and literature review. RESULTS: A 67-year-old man presented with a 2-month history of left epibulbar mass. On slit-lamp examination, an 8- * 8-mm amelanotic, translucent, gelatinous, circumscribed lesion was present deep to the nasal bulbar conjunctiva. A 60-year old otherwise healthy man presented with a 6-week history of a subconjunctival growth causing pain and photophobia in his right eye. On slit-lamp examination, an 8- * 8-mm amelanotic, translucent, gelatinous, circumscribed subconjunctival lesion, causing a delle was present near the nasal limbus. In each case, excisional biopsy was performed and histopathologic study revealed the diagnosis of neurofibroma. In both cases, after 12 months of follow-up, there was no evidence of recurrence or systemic disease. CONCLUSIONS: Solitary epibulbar neurofibroma in older adult patients without systemic neurofibromatosis is rare but should be considered in the differential diagnosis of epibulbar tumors. PMID- 25742391 TI - Trigeminal involvement in parry-romberg syndrome: an in vivo confocal microscopy study of the cornea. PMID- 25742392 TI - Pressure-temperature phase behavior of mixtures of natural sphingomyelin and ceramide extracts. AB - Ceramides are a group of sphingolipids that act as highly important signaling molecules in a variety of cellular processes including differentiation and apoptosis. The predominant in vivo synthetic pathway for ceramide formation is via sphingomyelinase catalyzed hydrolysis of sphingomyelin. The biochemistry of this essential pathway has been studied in detail; however, there is currently a lack of information on the structural behavior of sphingomyelin- and ceramide rich model membrane systems, which is essential for developing a bottom-up understanding of ceramide signaling and platform formation. We have studied the lyotropic phase behavior of sphingomyelin-ceramide mixtures in excess water as a function of temperature (30-70 degrees C) and pressure (1-200 MPa) by small- and wide-angle X-ray scattering. At low ceramide concentrations the mixtures form the ripple gel phase (P(beta)') below the gel transition temperature for sphingomyelin, and this observation has been confirmed by atomic force microscopy. Formation of the ripple gel phase can also be induced at higher temperatures via the application of hydrostatic pressure. At high ceramide concentration an inverse hexagonal phase (HII) is formed coexisting with a cubic phase. PMID- 25742393 TI - The multifaceted benefits of protein co-expression in Escherichia coli. AB - We report here that the expression of protein complexes in vivo in Escherichia coli can be more convenient than traditional reconstitution experiments in vitro. In particular, we show that the poor solubility of Escherichia coli DNA polymerase III epsilon subunit (featuring 3'-5' exonuclease activity) is highly improved when the same protein is co-expressed with the alpha and theta subunits (featuring DNA polymerase activity and stabilizing epsilon, respectively). We also show that protein co-expression in E. coli can be used to efficiently test the competence of subunits from different bacterial species to associate in a functional protein complex. We indeed show that the alpha subunit of Deinococcus radiodurans DNA polymerase III can be co-expressed in vivo with the epsilon subunit of E. coli. In addition, we report on the use of protein co-expression to modulate mutation frequency in E. coli. By expressing the wild-type epsilon subunit under the control of the araBAD promoter (arabinose-inducible), and co expressing the mutagenic D12A variant of the same protein, under the control of the lac promoter (inducible by isopropyl-thio-beta-D-galactopyranoside, IPTG), we were able to alter the E. coli mutation frequency using appropriate concentrations of the inducers arabinose and IPTG. Finally, we discuss recent advances and future challenges of protein co-expression in E. coli. PMID- 25742394 TI - Generation of murine cardiac pacemaker cell aggregates based on ES-cell programming in combination with Myh6-promoter-selection. AB - Treatment of the "sick sinus syndrome" is based on artificial pacemakers. These bear hazards such as battery failure and infections. Moreover, they lack hormone responsiveness and the overall procedure is cost-intensive. "Biological pacemakers" generated from PSCs may become an alternative, yet the typical content of pacemaker cells in Embryoid Bodies (EBs) is extremely low. The described protocol combines "forward programming" of murine PSCs via the sinus node inducer TBX3 with Myh6-promoter based antibiotic selection. This yields cardiomyocyte aggregates consistent of >80% physiologically functional pacemaker cells. These "induced-sinoatrial-bodies" ("iSABs") are spontaneously contracting at yet unreached frequencies (400-500 bpm) corresponding to nodal cells isolated from mouse hearts and are able to pace murine myocardium ex vivo. Using the described protocol highly pure sinus nodal single cells can be generated which e.g. can be used for in vitro drug testing. Furthermore, the iSABs generated according to this protocol may become a crucial step towards heart tissue engineering. PMID- 25742395 TI - Iron-catalyzed N-arylsulfonamide formation through directly using nitroarenes as nitrogen sources. AB - One-step, catalytic synthesis of N-arylsulfonamides via the construction of N-S bonds from the direct coupling of sodium arylsulfinates with nitroarenes was realized in the presence of FeCl2 and NaHSO3 under mild conditions. In this process, stable and readily available nitroarenes were used as nitrogen sources, and NaHSO3 acted as a reductant to provide N-arylsulfonamides in good to excellent yields. A broad range of functional groups were very well-tolerated in this reaction system. In addition, mechanistic studies indicated that the N-S bond might be generated through direct coupling of nitroarene with sodium arylsulfinate prior to the reduction of nitroarenes by NaHSO3. Accordingly, a reaction mechanism involving N-aryl-N-arenesulfonylhydroxylamine as an intermediate was proposed. PMID- 25742397 TI - Utility of CT in the emergency department in patients with ulcerative colitis. AB - BACKGROUND: Computed tomography (CT) is used in the emergency department (ED) for triage of patients with gastrointestinal complaints. Patients with inflammatory bowel disease undergo radiologic studies for gastrointestinal symptoms and are at risk for excessive ionizing radiation exposure; however, the utility of CT in the ED in patients with ulcerative colitis (UC) is not clear. In this study, we assess the frequency and risk factors for clinically significant CT findings in patients with UC in the ED. METHODS: We retrospectively reviewed 163 consecutive cases of patients with UC who presented to a tertiary care ED and underwent abdominopelvic CT between June 2008 and December 2011. Using logistic regression, we identified predictors of significant CT findings and derived a model to predict CT scans without clinically significant findings. RESULTS: Of note, 63.2% (103/163) of CT scans had no clinically significant findings. Less than 2% of scans revealed complications related to UC. Predictors of CT scans without clinically significant findings included rectal bleeding or diarrhea (P < 0.001), use of 5-aminosalicylate (P = 0.011), or immunomodulator (P = 0.032). Alternatively, predictors of clinically significant CT findings included nausea and vomiting (P < 0.001), history of colectomy (P < 0.001), history of abdominal or pelvic surgery (P < 0.001), surgery within 1 month (P < 0.001), age (P = 0.004), elevated white blood cell count (P = 0.003), and no UC medications (P = 0.001). CONCLUSIONS: Most patients with UC who presented to the ED and underwent CT had no clinically significant findings. We devised a model to predict lack of clinically significant CT findings, which may assist in reducing cost and radiation exposure in patients with UC. PMID- 25742396 TI - Racial disparities in readmission, complications, and procedures in children with Crohn's disease. AB - BACKGROUND: Racial disparities in care and outcomes contribute to mortality and morbidity in children; however, the role in pediatric Crohn's disease is unclear. In this study, we compared cohorts of black and white children with Crohn's disease to determine the extent race is associated with differences in readmissions, complications, and procedures among hospitalizations in the United States. METHODS: Data were extracted from the Pediatric Health Information System (January 1, 2004-June 30, 2012) for patients with 21 years or younger hospitalized with a diagnosis of Crohn's disease. White and black cohorts were randomly selected in a 2:1 ratio by hospital. The primary outcome was time from index hospital discharge to readmission. The most frequent complications and procedures were evaluated by race. RESULTS: There were 4377 patients. Black children had a shorter time to first readmission and higher probability of readmission (P = 0.009) and a 16% increase in risk of readmission compared with white children (P = 0.01). Black children had longer length of stay and higher frequency of overall and late (30-d to 12-mo postdischarge) readmissions (P < 0.001). During index hospitalization, more black children had perianal disease and anemia (P < 0.001). During any hospitalization, black children had higher incidence of perianal disease, anemia, and vitamin D deficiency, and greater number of perianal procedures, endoscopies, and blood product transfusion (P < 0.001). CONCLUSIONS: There are differences in hospital readmissions, complications, and procedures among hospitalized children related to race. It is unclear whether these differences are due to genetic differences, worse intrinsic disease, adherence, access to treatment, or treatment disparities. PMID- 25742398 TI - Short health scale: a valid, reliable, and responsive measure of health-related quality of life in children with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) presents a growing medical and epidemiological problem. In respect to patients, health-related quality of life (HRQOL) emerged as informative means to evaluate the impact of disease burden on health. The Short Health Scale (SHS), a disease-specific HRQOL instrument with only 4 questions (symptoms, functioning, worry, and general well-being), was demonstrated as valid, reliable, and responsive in adults. Aim of this study was to assess its psychometric properties in children with IBD. METHODS: In a multicentric prospective study, HRQOL was assessed in 104 children with IBD by generic (PedsQL) and disease-specific questionnaires (IMPACT-III (HR) and SHS), which were cross-culturally adapted for Croatian. Forty-one patients completed the questionnaires at the second visit 6 to 12 months later. Of them, 27 patients changed from remission to active disease or vice versa and were included in responsiveness to change analysis. RESULTS: Patients in remission had significantly better scores for symptoms (P = 0.022) and functioning (P = 0.003) than those with active disease. Each of the 4 SHS questions was strongly correlated with the corresponding dimensions of PedsQL and IMPACT-III (HR) questionnaires (rs = 0.50-0.72, P < 0.001). Reliability was confirmed with Cronbach's alpha = 0.74. Patients who changed from remission to active disease or vice versa showed significant change in following SHS scores: symptoms (P = 0.032), functioning (P = 0.008), and worry (P = 0.021). CONCLUSIONS: SHS appears to be valid, reliable, and responsive tool to measure HRQOL in children with IBD. Simplicity of use, compactness, and the possibility of immediate interpretation make SHS well suited for both clinical practice and research studies. PMID- 25742400 TI - CARD3 deficiency protects against colitis through reduced epithelial cell apoptosis. AB - BACKGROUND: Caspase activation and recruitment domain 3 (CARD3) is a 61-kDa protein kinase. Recent evidence shows the importance of CARD3 in the immune response and inflammatory diseases. To elucidate its impact on inflammatory bowel disease, we studied the effects of the loss of CARD3 in the acute dextran sodium sulfate-induced colitis. METHODS: Colitis was induced by administration of dextran sodium sulfate to wild-type and CARD3 mice. Colon tissues were analyzed. RESULTS: CARD3 mice were less susceptible to the development of colitis than wild type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of CARD3 mice to colitis was closely related to increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Finally, CARD3 levels were increased in intestinal tissue from patients with IBD. CONCLUSIONS: These results imply a role for CARD3 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of CARD3 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted CARD3 inhibition may represent a new therapeutic approach in IBD. PMID- 25742399 TI - Colitis induces enteric neurogenesis through a 5-HT4-dependent mechanism. AB - BACKGROUND: The intestine is known to contain enteric neuronal progenitors, but their precise identity and the mechanisms that activate them remain unknown. Based on the evidence for the neurogenic role of serotonin (5-HT) in the postnatal gut and the observation of enteric neuronal hyperplasia in inflammatory bowel disease, we hypothesized that colitis induces a neurogenic response through 5-HT4 receptor signaling. METHODS: We examined the effects of 5-HT4 agonism on colonic neurogenesis and gliogenesis in vitro and in vivo in adult mice using dextran sodium sulfate to experimentally induce colitis. RESULTS: In vitro, 5-HT4 agonism led to increased neuronal proliferation and density. Induction of experimental colitis in vivo similarly resulted in increased numbers of myenteric neurons, and this was inhibited by 5-HT4 antagonism. Interestingly, both in vitro and in vivo, 5-HT4 signaling increased glial cell proliferation but did not increase glial cell numbers, leading us to hypothesize that glia may give rise to neurons. After induction of colitis in normal, Nestin-GFP and Sox2-GFP transgenic mice, it was revealed that multiple glial markers (Sox2, Nestin, and CD49b) became strongly expressed by enteric neurons. Immunoselected enteric glia were found to give rise to neurons in culture, and this was inhibited in the presence of 5-HT4 blockade. Finally, isolated glia gave rise to a neuronal network upon transplantation into aganglionic embryonic avian hindgut. CONCLUSIONS: These results show that colitis promotes enteric neurogenesis in the adult colon through a serotonin-dependent mechanism that drives glial cells to transdifferentiate into neurons. PMID- 25742401 TI - Helicobacter pylori-specific protection against inflammatory bowel disease requires the NLRP3 inflammasome and IL-18. AB - BACKGROUND: The Gram-negative bacterium Helicobacter pylori is a constituent of the human gastric microbiota. Chronic infection with H. pylori causes gastritis and predisposes to gastric carcinoma but has also been inversely linked to various allergic and chronic inflammatory conditions. In particular, large meta analyses have documented an inverse association between H. pylori infection and the risk of developing ulcerative colitis and Crohn's disease. METHODS: We investigated possible protective effects of experimental H. pylori infection and of regular treatment with H. pylori extract in 2 mouse models of colitis and in mouse models of type I diabetes and multiple sclerosis. The mechanism of protection was examined in mouse strains lacking specific innate immune recognition pathways and cytokines. RESULTS: We show here that experimental infection with H. pylori and administration of regular doses of H. pylori extract both alleviate the clinical and histopathological features of dextran sodium sulfate-induced chronic colitis and of T-cell transfer-induced colitis. High resolution endoscopy of the protected animals revealed the accumulation of large amounts of colonic mucus upon H. pylori exposure, which could be attributed to transcriptional activation of the mucin 2 gene. The protection against dextran sodium sulfate-induced colitis was dependent on the NLRP3 inflammasome and interleukin-18 signaling. Other autoimmune diseases, i.e., experimental autoimmune encephalomyelitis and type I diabetes, were not controlled by H. pylori. CONCLUSIONS: In summary, we propose here that the immunomodulatory activity of an ancient constituent of the gut microbiota, H. pylori, may be exploited for the prevention and/or treatment of inflammatory bowel diseases. PMID- 25742402 TI - Is the transition possible? PMID- 25742403 TI - CFH Y402H polymorphism and response to intravitreal ranibizumab in Brazilian patients with neovascular age-related macular degeneration. AB - OBJECTIVE: To investigate the association between CFH gene polymorphism and response to ranibizumab in Brazilian patients with neovascular age-related macular degeneration (AMD). METHODS: 95 patients were genotyped for the CFH rs1061170 (Y402H) single nucleotide polymorphism. Patients with neovascular AMD initially received intravitreal ranibizumab injections for three months and were retreated as needed. Visual acuity (VA) and central retinal thickness (CRT) were measured before treatment and at 1, 3, 6, and 12 months post-treatment. RESULTS: For patients with the TT and TC genotypes, paired comparisons of VA showed a statistically significant improvement when the data obtained at all visits were compared with baseline. Patients homozygous for the risk genotype (CC) did not show a statistically significant improvement when VA obtained at visits 1, 3, 6 and 12 were compared with baseline. For all genotypes, paired comparisons of CRT showed a statistically significant improvement when the data obtained at visits 1, 3, 6 and 12 were compared with baseline. CONCLUSION: Patients with the CC genotype showed poorer long-term functional response to intravitreal ranibizumab. PMID- 25742404 TI - Safety and tolerability of controlled-release oxycodone on postoperative pain in patients submitted to the oncologic head and neck surgery. AB - OBJECTIVE: To evaluate the safety and tolerability of controlled-release oxycodone in the treatment of postoperative pain of head and neck oncologic resections. METHODS: We conducted a prospective, observational and open study, with 83 patients with moderate to severe pain after head and neck oncological operations. All patients received general anesthesia with propofol, fentanyl and sevoflurane. Postoperatively, should they have moderate or severe pain, we began controlled-release oxycodone 20 mg 12/12 b.i.d on the first day and 10 mg b.i.d. on the second. We assessed the frequency and intensity of adverse effects, the intensity of postoperative pain by a verbal numeric scale and the use of rescue analgesia from 12 hours after administration of the drug and between 7 and 13 days after the last oxycodone dose. RESULTS: The most common adverse events were nausea, vomiting, dizziness, pruritus, insomnia, constipation and urinary retention, most mild. No serious adverse events occurred. In less than 12 hours after the use of oxycodone, there was a significant decrease in the intensity of postoperative pain, which remained until the end of the study. The rescue medication was requested at a higher frequency when the opioid dose was reduced, or after its suspension. CONCLUSION: Controlled release oxycodone showed to be safe and well tolerated and caused a significant decrease in post-operative pain. PMID- 25742405 TI - Nuss procedure for pectus excavatum repair: critical appraisal of the evidence. AB - OBJECTIVE: To evaluate the effectiveness and safety of correction of pectus excavatum by the Nuss technique based on the available scientific evidence. METHODS: We conducted an evidence synthesis following systematic processes of search, selection, extraction and critical appraisal. Outcomes were classified by importance and had their quality assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: The process of selection of items led to the inclusion of only one systematic review, which synthesized the results of nine observational studies comparing the Nuss and Ravitch procedures. The evidence found was rated as poor and very poor quality. The Nuss procedure has increased the incidence of hemothorax (RR = 5.15; 95% CI: 1.07; 24.89), pneumothorax (RR = 5.26; 95% CI: 1.55; 17.92) and the need for reintervention (RR = 4.88; 95% CI: 2.41; 9.88) when compared to the Ravitch. There was no statistical difference between the two procedures in outcomes: general complications, blood transfusion, hospital stay and time to ambulation. The Nuss operation was faster than the Ravitch (mean difference [MD] = -69.94 minutes, 95% CI: -139.04, -0.83). CONCLUSION: In the absence of well-designed prospective studies to clarify the evidence, especially in terms of aesthetics and quality of life, surgical indication should be individualized and the choice of the technique based on patient preference and experience of the team. PMID- 25742407 TI - Bariatric surgery: impact on sexuality of the obese person. AB - OBJECTIVE: To assess the impact of surgical treatment in the sexuality of the obese. METHODS: We conducted a qualitative / quantitative research with 30 patients who had undergone Fobi-Capella Roux-Y gastric bypass for at least one year. We collected data through individual interviews using a questionnaire with 10 mixed questions and one open, between May and June 2011. The objective data were quantified in absolute numbers and percentages, and the subjective ones were analyzed using the Discourse of the Collective Subject (DCS) and discussed in view of reference published on the subject. RESULTS: 30 patients were enrolled, with a mean age 44 +/- 12 years, 24 (80%) were female and six (20%) were male, 23 (77%) were married, 23 (96%) were hypertensive and eight (33%) were diagnosed with Diabetes Mellitus. After the operation, 11 (37%) individuals reported no change in the number sexual intercourses, but 19 (63%) reported that this number was altered, 16 (53%) informed increased frequency, one (3%) reported a decrease in frequency, one (3%) did not practice sexual intercourse anymore and one (3%) did not report the frequency. The central ideas (CI) raised originated four DCSs: Experience of female sexuality; No experience of female sexuality; Experience of male sexuality; and improvements of comorbidities and psychological factor. CONCLUSION: there are positive repercussions of physical and emotional orders of the surgical treatment of obesity, favoring the quality of life, including sexuality. PMID- 25742406 TI - Complex pulmonary aspergilloma treated by cavernostomy. AB - OBJECTIVE: To evaluate the effectiveness of cavernostomy in patients with complex fungal balls. METHODS: We analyzed the medical records of patients undergoing cavernostomy between January 2005 and May 2013, evaluating: age, gender, preoperative signs and symptoms, predisposing disease, preoperative tests, location of the aspergilloma, etiologic agent, cavernostomy indication, postoperative outcome. RESULTS: Ten patients were male. The mean age was 42.9 years (34-56). The most frequent symptom was repeated pulmonary bleeding. Cavernostomy was proposed for patients at high risk for lung resection. It was performed in 17 patients and all of them had pulmonary tuberculosis sequelae, with cavitations. The indication in all cases was hemoptysis and elimination of phlegm. The cavernostomies were performed in a single surgical procedure. In all 17 patients the cavity was left open after the withdrawal of the mycetoma. In all patients hemoptysis ceased immediately. Operative mortality was 9.5% (1). CONCLUSION: cavernostomy is an effective treatment alternative in patients at high risk. It may be useful in some patients with complex aspergilloma, irrespective of lung function or bilateral disease. It is technically easy, has low-risk, saves parenchyma, and may be performed in a single operative time. PMID- 25742408 TI - Hypothalamic-pituitary-gonadal function in men with liver cirrhosis before and after liver transplantation. AB - OBJECTIVE: To evaluate the influence of end-stage liver disease and orthotopic liver transplantation in the pituitary function and hormone metabolism before and after liver transplantation. METHODS: In a prospective study, serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and prolactin (PRL) of 30 male patients with cirrhosis were determined two to four hours before and six months after liver transplantation. The results were compared according to the Model for End-stage Liver Disease (MELD). RESULTS: male patients with liver cirrhosis have hypogonadism. FSH was normal, but inappropriately low due to androgen failure; E2 and PRL, on their turn, were high. After liver transplantation, FSH and LH levels increased (p < 0.05), whereas E2 and PRL normalized (p < 0.05). The MELD score did not influence changes in FSH, PRL and LH, however, the more severe the cirrhosis was, the more significant was the normalization of E2 (p = 0.01). CONCLUSION: Patients with cirrhosis and male hypogonadism have inappropriately normal levels of FSH and LH, associated with an increase in E2 and LRP. After liver transplantation, FSH and LH increased, while E2 and PRL returned to normal. Changes in E2 levels were most pronounced in patients with MELD > 18. The severity of cirrhosis had no influence on FSH, PRL and LH. PMID- 25742409 TI - Ultrasound evaluation on carpal tunnel syndrome before and after bariatric surgery. AB - OBJECTIVE: To evaluate the prevalence of carpal tunnel syndrome in candidates for bariatric surgery comparing with the non-obese population and verify the effects on it of bariatric treatment. METHODS: We studied three groups of individuals: 1) patients waiting for bariatric surgery (preoperative); 2) individuals who had already undergone the procedure (postoperative); and 3) control group. We collected demographic and clinical data of carpal tunnel syndrome. The Ultrasound examination was carried out to diagnose the syndrome by measuring the median nerve area. RESULTS: We included 329 individuals (114 in the preoperative group, 90 in the postoperative group and 125 controls). There was a higher prevalence of paresthesias (p=0.0003), clinical tests (p=0.0083) on the preoperative group when compared with controls (p<0.00001). There were lowe levels of paresthesias (p=0.0002) and median nerve area (p=0.04) in postoperative patients but with no significant difference in general. A significant difference was found between the preoperative and postoperative groups (p=0.05) in those who performed non-manual work. CONCLUSION: There was a higher prevalence of carpal tunnel syndrome in the preoperative group compared with the control one, but no significant difference was observed between the pre and postoperative groups in general. There was difference between pre and postoperative groups for non-manual workers. PMID- 25742410 TI - Use of local muscle flaps to cover leg bone exposures. AB - OBJECTIVE: To evaluate the use of the medial gastrocnemius muscle and/or soleus muscle flaps as surgical treatment of the leg bone exposure. METHODS: We retrospectively analyzed the medical records of patients undergoing transposition of the medial gastrocnemius and / or soleus for treating exposed bone in the leg, from January 1976 to July 2009, gathering information on epidemiological data, the etiology the lesion, the time between the initial injury and muscle transposition, the muscle used to cover the lesion, the healing evolution of the skin coverage and the function of the gastrocnemius-soleus unit. RESULTS: 53 patients were operated, the ages varying between nine and 84 years (mean age 41); 42 were male and 11 female. The main initial injury was trauma (84.8%), consisting of tibia and / or fibula fracture. The most frequently used muscle was the soleus, in 40 cases (75.5%). The rank of 49 patients (92.5%) was excellent or good outcome, of three (5.6%) as regular and of one (1.9%) as unsatisfactory. CONCLUSION: the treatment of bone exposure with local muscle flaps (gastrocnemius and/or soleus) enables obtaining satisfactory results in covering of exposed structures, favoring local vascularization and improving the initial injury. It offers the advantage of providing a treatment in only one surgical procedure, an earlier recovery and reduced hospital stay. PMID- 25742411 TI - Topographic anatomical study of the sciatic nerve relationship to the posterior portal in hip arthroscopy. AB - OBJECTIVE: To evaluate the anatomic topographic relation between the sciatic nerve in relation to the piriform muscle and the posterior portal for the establishment of hip arthroscopy. METHODS: We dissected 40 hips of 20 corpses of adult Brazilians, 17 male and three female, six black, six brown and eight white. We studied the anatomical relationship between the sciatic nerve and the piriform muscle with their variations and the distance between the lateral edge of the sciatic nerve and the posterior portal used in hip arthroscopy. We then classified the anatomical alterations found in the path of the sciatic nerve on the piriform muscle. RESULTS: Seventeen corpses had bilateral relationship between the sciatic nerve and the piriform muscle, i.e., type A. We found the following anatomical variations: 12.5% of variant type B; and an average distance between the sciatic nerve and the portal for arthroscopy of 2.98cm. One body had type B anatomical variation on the left hip and type A on the right. CONCLUSION: the making of the posterior arthroscopic portal to the hip joint must be done with careful marking of the trochanter massive; should there be difficult to find it, a small surgical access is recommended. The access point to the portal should not exceed two centimeters towards the posterior superior aspect of the greater trochanter, and must be made with the limb in internal rotation of 15 degrees. PMID- 25742412 TI - Papillary neoplasias of the biliary tract. AB - The authors conducted a revisional study of intraepithelial papillary lesions of the bile ducts, characterized by being a kind of rare, intraductal growing cholangiocarcinoma. Articles published in the last 10 years were reviewed. The authors considered that the adenoma-carcinoma development is an important feature to warrant prophylactic measures through excisions. The histological type and biomolecular behavior may have relevance in the postoperative course of such lesions, which have a better prognosis when compared with other histological types. PMID- 25742413 TI - The introduction of navigation in liver surgery in Brazil. AB - The authors thoroughly report the development, the technical aspects and the performance of the first navigated liver resections, by laparotomy and laparoscopy, in Brazil, done at the National Cancer Institute, Ministry of Health, using a surgical navigator. PMID- 25742414 TI - Ureteral reconstruction with abdominal wall muscle flap: experimental study in rabbits. AB - The authors detail the experimental development of a technique for the reconstruction of the ureter using a tubular shape, muscle flap of the abdominal wall. the preliminary results indicate the feasibility of this surgical technique. PMID- 25742415 TI - Evaluation of zebrafish kidney function using a fluorescent clearance assay. AB - The zebrafish embryo offers a tractable model to study organogenesis and model human genetic disease. Despite its relative simplicity, the zebrafish kidney develops and functions in almost the same way as humans. A major difference in the construction of the human kidney is the presence of millions of nephrons compared to the zebrafish that has only two. However, simplifying such a complex system into basic functional units has aided our understanding of how the kidney develops and operates. In zebrafish, the midline located glomerulus is responsible for the initial blood filtration into two pronephric tubules that diverge to run bilaterally down the embryonic axis before fusing to each other at the cloaca. The pronephric tubules are heavily populated by motile cilia that facilitate the movement of filtrate along the segmented tubule, allowing the exchange of various solutes before finally exiting via the cloaca. Many genes responsible for CKD, including those related to ciliogenesis, have been studied in zebrafish. However, a major draw back has been the difficulty in evaluating zebrafish kidney function after genetic manipulation. Traditional assays to measure kidney dysfunction in humans have proved non translational to zebrafish, mainly due to their aquatic environment and small size. For example, it is not physically possible to extract blood from embryonic staged fish for analysis of urea and creatinine content, as they are too small. In addition, zebrafish do not produce enough urine for testing on a simple proteinuria 'dipstick', which is often performed during initial patient examinations. We describe a fluorescent assay that utilizes the optical transparency of the zebrafish to quantitatively monitor the clearance of a fluorescent dye, over time, from the vasculature and out through the kidney, to give a read out of renal function. PMID- 25742416 TI - Aberrant liver insulin receptor isoform a expression normalises with remission of type 2 diabetes after gastric bypass surgery. AB - Type 2 diabetes mellitus (T2DM) results from a combination of progressive insulin resistance and loss of pancreatic beta cell function and/or mass. Insulin signalling occurs through the insulin receptor, (INSR) which is alternatively spliced into two isoforms: INSRA (-exon 11) and INSRB (+exon 11). Because the INSR isoforms have different functional characteristics, their relative expression ratio has been implicated in the pathogenesis of insulin resistance and T2DM. We studied levels of INSR isoform mRNA in liver samples taken from 46 individuals with or without T2DM at Roux-en-Y (RYGB) surgery, and on average 17 (+/- 5.6) months later in 16 of the same individuals (8 diabetic and non-diabetic patients). INSRA or INSRB was also overexpressed in HepG2 cells to ascertain their effect on AKT phosphorylation and PCK1 expression as markers of insulin mediated metabolic signalling. We found the INSRB:A isoform ratio was reduced in individuals with T2DM in comparison to those with normal glucose tolerance and normalised with remission of diabetes. The INSRB:A ratio increased due to a reduction in the alternatively spliced INSRA isoform following remission of diabetes. Overexpressing INSRA isoform in HepG2 hepatoma cells reduced inhibition of PCK1 transcription and did not increase AKT phosphorylation in response to insulin load compared to the effect of overexpressing the B isoform. Data presented here revitalizes the role of the INSR isoforms in the pathogenesis of T2DM, and suggests that an abrogated INSRB:A ratio that favours the INSRA isoform may negatively impact insulin-mediated metabolic signalling. PMID- 25742417 TI - Charge reduction and thermodynamic stabilization of substrate RNAs inhibit RNA editing. AB - African trypanosomes cause a parasitic disease known as sleeping sickness. Mitochondrial transcript maturation in these organisms requires a RNA editing reaction that is characterized by the insertion and deletion of U-nucleotides into otherwise non-functional mRNAs. Editing represents an ideal target for a parasite-specific therapeutic intervention since the reaction cycle is absent in the infected host. In addition, editing relies on a macromolecular protein complex, the editosome, that only exists in the parasite. Therefore, all attempts to search for editing interfering compounds have been focused on molecules that bind to proteins of the editing machinery. However, in analogy to other RNA driven biochemical pathways it should be possible to stall the reaction by targeting its substrate RNAs. Here we demonstrate inhibition of editing by specific aminoglycosides. The molecules bind into the major groove of the gRNA/pre-mRNA editing substrates thereby causing a stabilization of the RNA molecules through charge compensation and an increase in stacking. The data shed light on mechanistic details of the editing process and identify critical parameters for the development of new trypanocidal compounds. PMID- 25742418 TI - Tetrachlorobenzoquinone activates Nrf2 signaling by Keap1 cross-linking and ubiquitin translocation but not Keap1-Cullin3 complex dissociation. AB - Tetrachlorobenzoquinone (TCBQ), a metabolite of industrial herbicide pentachlorophenol, showed hepatotoxicity and genotoxicity through reactive oxygen species (ROS) mechanism in vivo and in vitro models. Nuclear factor erythroid derived 2-like 2 (Nrf2) is a cellular sensor of oxidative or electrophilic stress, which controls the expression of detoxifying enzymes and antioxidant proteins. Using the human hepatoma HepG2 cell line as an in vitro model, we demonstrated a significant induction of Nrf2 but not its negative regulator Kelch like ECH-associated protein 1 (Keap1), following exposure to TCBQ. Also, our results clearly demonstrated the translocation of cytosolic Nrf2 into the nucleus. After translocation, Nrf2 subsequently binds to the antioxidant response element (ARE), up-regulated heme oxygenase-1 (HO-1), and NADH quinone oxidoreductase subunit 1 (NQO1), which may be considered as an antioxidative response to TCBQ-intoxication. The luciferase reporter assay confirmed the formation of the Nrf2-ARE complex. Furthermore, mechanism studies proposed that TCBQ promoted the formation of the Keap1 cross-linking dimer, a ubiquitination switch from Nrf2 to Keap1 but not the dissociation of the Keap1-Cullin3 (Cul3) complex. PMID- 25742419 TI - Association Between Hemodynamic Profile, Physical Capacity and Quality of Life in Pulmonary Hypertension. AB - BACKGROUND: No studies have described and evaluated the association between hemodynamics, physical limitations and quality of life in patients with pulmonary hypertension (PH) without concomitant cardiovascular or respiratory disease. OBJECTIVE: To describe the hemodynamic profile, quality of life and physical capacity of patients with PH from groups I and IV and to study the association between these outcomes. METHODS: Cross-sectional study of patients with PH from clinical groups I and IV and functional classes II and III undergoing the following assessments: hemodynamics, exercise tolerance and quality of life. RESULTS: This study assessed 20 patients with a mean age of 46.8 +/- 14.3 years. They had pulmonary capillary wedge pressure of 10.5 +/- 3.7 mm Hg, 6-minute walk distance test (6MWDT) of 463 +/- 78 m, oxygen consumption at peak exercise of 12.9 +/- 4.3 mLO2.kg-1.min-1 and scores of quality of life domains < 60%. There were associations between cardiac index (CI) and ventilatory equivalent for CO2 (r=-0.59, p <0.01), IC and ventilatory equivalent for oxygen (r=-0.49, p<0.05), right atrial pressure (RAP) and 'general health perception' domain (r=-0.61, p<0.01), RAP and 6MWTD (r=-0.49, p<0.05), pulmonary vascular resistance (PVR) and 'physical functioning' domain (r=-0.56, p<0.01), PVR and 6MWTD (r=-0.49, p<0.05) and PVR index and physical capacity (r=-0.51, p<0.01). CONCLUSION: Patients with PH from groups I and IV and functional classes II and III exhibit a reduction in physical capacity and in the physical and mental components of quality of life. The hemodynamic variables CI, diastolic pulmonary arterial pressure, RAP, PVR and PVR index are associated with exercise tolerance and quality of life domains. PMID- 25742420 TI - Hypertension in patients with cancer. AB - There is a known association between chemotherapy and radiotherapy for treatment of cancer patients and development or worsening of hypertension. The aim of this article is to review this association. A literature search was conducted for articles reporting this association on the databases PubMed, SciELO and LILACS between 1993 and 2013. There was a high coprevalence of hypertension and cancer, since both diseases share the same risk factors, such as sedentary lifestyle, obesity, smoking, unhealthy diet and alcohol abuse. The use of chemotherapy and adjuvant drugs effective in the treatment of cancer increased the survival rate of these patients and, consequently, increased the incidence of hypertension. We described the association between the use of angiogenesis inhibitors (bevacizumab, sorafenib and sunitinib), corticosteroids, erythropoietin and non steroidal anti-inflammatory drugs with the development of hypertension. We also described the relationship between hypertension and carotid baroreceptor injury secondary to cervical radiotherapy. Morbidity and mortality increased in patients with cancer and hypertension without proper antihypertensive treatment. We concluded that there is need for early diagnosis, effective monitoring and treatment strategies for hypertension in cancer patients in order to reduce cardiovascular morbidity and mortality. PMID- 25742422 TI - Deletion of the PDR16 gene influences the plasma membrane properties of the yeast Kluyveromyces lactis. AB - The plasma membrane is the first line of cell defense against changes in external environment, thus its integrity and functionality are of utmost importance. The plasma membrane properties depend on both its protein and lipid composition. The PDR16 gene is involved in the control of Kluyveromyces lactis susceptibility to drugs and alkali metal cations. It encodes the homologue of the major K. lactis phosphatidylinositol transfer protein Sec14p. Sec14p participates in protein secretion, regulation of lipid synthesis, and turnover in vivo. We report here that the plasma membrane of the Klpdr16Delta mutant is hyperpolarized and its fluidity is lower than that of the parental strain. In addition, protoplasts prepared from the Klpdr16Delta cells display decreased stability when subjected to hypo-osmotic conditions. These changes in membrane properties lead to an accumulation of radiolabeled fluconazole and lithium cations inside mutant cells. Our results point to the fact that the PDR16 gene of K. lactis (KlPDR16) influences the plasma membrane properties in K. lactis that lead to subsequent changes in susceptibility to a broad range of xenobiotics. PMID- 25742423 TI - Primary Cardiac Allograft Dysfunction-Validation of a Clinical Definition. AB - BACKGROUND: Heart transplantation is an established treatment for advanced heart failure. Primary allograft dysfunction (PGD) is reported in up to 40% of transplants and is associated with a poor outcome. METHODS: As part of Heart Evaluation and Retrieval for Transplantation study, an investigation of the assessment of donor hearts for transplantation, we proposed a clinical definition for cardiac PGD comprising severely impaired systolic function affecting one or both ventricles accompanied by hypotension, low cardiac output, and high filling pressures occurring in the first 72 hours (in the absence of hyper acute rejection and technical surgical factors, such as cardiac tamponade). Here, we examine the prospective application of this definition to 290 heart transplants. We compared the clinical outcome of PGD and non-PGD cases. RESULTS: Ninety-four of 290 transplants developed PGD (32.4%). Inotrope use (score) was higher in the PGD group at 24, 48, and 72 hours after transplantation (P < 0.01). In the PGD group, there was a greater requirement for, intra-aortic balloon pump (50% vs 15%, P < 0.01), mechanical support (27% vs 0%, P < 0.01), and renal replacement therapy (61% vs 26%, P < 0.01). Intensive care stay was longer for recipients with PGD (median 14 vs 5 days, P < 0.01) and early mortality was higher (37% vs 4% at 30 days, 42% vs 8% at 1 year, P < 0.01). CONCLUSIONS: In conclusion, our definition of PGD could be applied in a national multicenter study, and the cases it defined had more frequent complications and higher mortality. PMID- 25742424 TI - Perspectives of Transplant Professionals on the Values, Ethics, and Challenges of Living Kidney Donor Evaluation in Asia. AB - BACKGROUND: Deceased donor rates in Asia are among the lowest in the world. This has necessitated a reliance on living kidney donation, which has given rise to concerns about donor motivation and assessment in this region. We aimed to describe transplant professional perspectives on living kidney donor evaluation in Asia. METHODS: Face-to-face, semistructured interviews were conducted with 53 transplant professionals (nephrologists [n = 21], surgeons/urologists [n = 17], coordinators [n = 7], social workers [n = 5], ethicists [n = 2], psychologist [n = 1]) from 20 centers in 10 countries. Transcripts were analyzed thematically to identify themes. RESULTS: The theme of traversing vulnerability overarched 4 themes. Vigilance against exploitation of the vulnerable meant mitigating the threat of commercial transplantation, combating disparities, and verifying volunteerism. Maintaining clarity of professional roles encompassed the perceived necessity of legal safeguards to determine legitimacy of relationships, ensuring informed consent, demarcating responsibilities, minimizing conflict of interest, meeting community expectations, and resolving ambivalence regarding donor risk. Societal plight driving caution about living kidney donor assessment was emphasized in the context of poverty and desperation, higher risk of disease, and lack of social security. Navigating sociocultural barriers acknowledged the centrality of the family, economic priorities, distrust in modern medicine, generational traditions, and emotional opacity limiting their ability to gauge donor motivation. CONCLUSIONS: Moral, professional, sociocultural and societal vulnerabilities contribute to the barriers and ethical quandaries in living kidney donation in Asia. Strategies are needed to address culturally based anxieties and disparities in living donation. Transplant professionals depend on strong legislation and policies to prevent exploitation of living donors. PMID- 25742425 TI - Array comparative genomic hybridization (array CGH) for detection of genomic copy number variants. AB - Array CGH for the detection of genomic copy number variants has replaced G-banded karyotype analysis. This paper describes the technology and its application in a clinical diagnostic service laboratory. DNA extracted from a patient's sample (blood, saliva or other tissue types) is labeled with a fluorochrome (either cyanine 5 or cyanine 3). A reference DNA sample is labeled with the opposite fluorochrome. There follows a cleanup step to remove unincorporated nucleotides before the labeled DNAs are mixed and resuspended in a hybridization buffer and applied to an array comprising ~60,000 oligonucleotide probes from loci across the genome, with high probe density in clinically important areas. Following hybridization, the arrays are washed, then scanned and the resulting images are analyzed to measure the red and green fluorescence for each probe. Software is used to assess the quality of each probe measurement, calculate the ratio of red to green fluorescence and detect potential copy number variants. PMID- 25742426 TI - Atomic resolution observation of conversion-type anode RuO2 during the first electrochemical lithiation. AB - Transition metal oxides have attracted great interest as alternative anode materials for rechargeable lithium-ion batteries. Among them, ruthenium dioxide is considered to be a prototype material that reacts with the Li ions in the conversion type. In situ transmission electron microscopy reveals a two-step process during the initial lithiation of the RuO2 nanowire anode at atomic resolution. The first step is characterized by the formation of the intermediate phase LixRuO2 due to the Li-ion intercalation. The following step is manifested by the solid-state amorphization reaction driven by advancing the reaction front. The crystalline/amorphous interface is consisted of {011} atomic terraces, revealing the orientation-dependent mobility. In the crystalline matrix, lattice disturbance and dislocation are identified to be two major stress-induced distortions. The latter can be effective diffusion channels, facilitating transportation of the Li ions inside the bulk RuO2 crystal and further resulting in non-uniform Li-ion distribution. It is expected that the local enrichment of the Li ions may account for the homogeneous nucleation of dislocations in the bulk RuO2 crystal and the special island-like structures. These results elucidate the structural evolution and the phase transformation during electrochemical cycling, which sheds light on engineering RuO2 anode materials. PMID- 25742427 TI - Correction: SynPAnal: software for rapid quantification of the density and intensity of protein puncta from fluorescence microscopy images of neurons. PMID- 25742428 TI - CRISPR multitargeter: a web tool to find common and unique CRISPR single guide RNA targets in a set of similar sequences. AB - Genome engineering has been revolutionized by the discovery of clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR-associated system genes (Cas) in bacteria. The type IIB Streptococcus pyogenes CRISPR/Cas9 system functions in many species and additional types of CRISPR/Cas systems are under development. In the type II system, expression of CRISPR single guide RNA (sgRNA) targeting a defined sequence and Cas9 generates a sequence-specific nuclease inducing small deletions or insertions. Moreover, knock-in of large DNA inserts has been shown at the sites targeted by sgRNAs and Cas9. Several tools are available for designing sgRNAs that target unique locations in the genome. However, the ability to find sgRNA targets common to several similar sequences or, by contrast, unique to each of these sequences, would also be advantageous. To provide such a tool for several types of CRISPR/Cas system and many species, we developed the CRISPR MultiTargeter software. Similar DNA sequences in question are duplicated genes and sets of exons of different transcripts of a gene. Thus, we implemented a basic sgRNA target search of input sequences for single-sgRNA and two-sgRNA/Cas9 nickase targeting, as well as common and unique sgRNA target searches in 1) a set of input sequences; 2) a set of similar genes or transcripts; or 3) transcripts a single gene. We demonstrate potential uses of the program by identifying unique isoform-specific sgRNA sites in 71% of zebrafish alternative transcripts and common sgRNA target sites in approximately 40% of zebrafish duplicated gene pairs. The design of unique targets in alternative exons is helpful because it will facilitate functional genomic studies of transcript isoforms. Similarly, its application to duplicated genes may simplify multi-gene mutational targeting experiments. Overall, this program provides a unique interface that will enhance use of CRISPR/Cas technology. PMID- 25742429 TI - Chemoenzymatically prepared heparan sulfate containing rare 2-O-sulfonated glucuronic acid residues. AB - The structural diversity of natural sulfated glycosaminoglycans (GAGs) presents major promise for discovery of chemical biology tools or therapeutic agents. Yet, few GAGs have been identified so far to exhibit this promise. We reasoned that a simple approach to identify such GAGs is to explore sequences containing rare residues, for example, 2-O-sulfonated glucuronic acid (GlcAp2S). Genetic algorithm-based computational docking and filtering suggested that GlcAp2S containing heparan sulfate (HS) may exhibit highly selective recognition of antithrombin, a key plasma clot regulator. HS containing only GlcAp2S and 2-N sulfonated glucosamine residues, labeled as HS2S2S, was chemoenzymatically synthesized in just two steps and was found to preferentially bind antithrombin over heparin cofactor II, a closely related serpin. Likewise, HS2S2S directly inhibited thrombin but not factor Xa, a closely related protease. The results show that a HS containing rare GlcAp2S residues exhibits the unusual property of selective antithrombin activation and direct thrombin inhibition. More importantly, HS2S2S is also the first molecule to activate antithrombin nearly as well as the heparin pentasaccharide although being completely devoid of the critical 3-O-sulfonate group. Thus, this work shows that novel functions and mechanisms may be uncovered by studying rare GAG residues/sequences. PMID- 25742430 TI - Nicotine ameliorates experimental severe acute pancreatitis via enhancing immunoregulation of CD4+ CD25+ regulatory T cells. AB - OBJECTIVES: Activation of "nicotinic anti-inflammatory pathway" could reduce severity of inflammation and injury induced by acute pancreatitis. However, the role of regulatory T (Treg) cells in this pathway is unclear. METHODS: Severe acute pancreatitis (SAP) was induced in mice through retrograde injection of 50 MUL 2% Na-taurocholate into the pancreatic duct of the mouse. In nicotine treatment group, nicotine (50, 100, and 300 MUg/kg) was administered 1 hour before and after SAP operation through intraperitoneal injection. We compared the properties of Treg cell percentage and specific marker such as cytotoxic T lymphocyte antigen 4 and forkhead box transcription factor forkhead/winged helix transcription factor p3 on Treg using quantitative reverse transcription polymerase chain reaction and flow cytometry. All experiment animal serum cytokines were measured using enzyme-linked immunosorbent assay. One-way analysis of variance was applied to evaluate the experimental data and for statistical comparisons. The survival rate data were analyzed using the log-rank test. RESULTS: Nicotine significantly protected mice from lethal SAP in a dose dependent fashion by inhibiting tissue injury, digestive enzyme production, and proinflammatory cytokines production. Moreover, nicotine up-regulated the number and suppressive capacity of CD4 CD25 Treg via inducing the expression of immunoregulatory molecules and transforming growth factor beta1 elevation. CONCLUSIONS: Modulating immunoregulation of CD4 CD25 Treg is a critical mechanism for nicotinic anti-inflammatory pathway and it may be feasible to use selective agonists as an immunotherapy for SAP. PMID- 25742431 TI - Nutritional status in children with Shwachman-diamond syndrome. AB - OBJECTIVE: In Shwachman-Diamond syndrome (SDS), pancreatic insufficiency can lead to malabsorption of fat-soluble vitamins and trace elements. The aim of this study was to assess the serum concentrations of vitamins A and E, zinc, copper, and selenium and their deficiencies. METHODS: This retrospective review was performed in 21 children (12 were male; median age, 7.8 years) with genetically confirmed SDS at a tertiary pediatric hospital. Pancreatic enzyme replacement therapy (PERT) and vitamin or trace elements supplements were documented. RESULTS: Twenty patients (95%) had pancreatic insufficiency receiving PERT, 10 (47%) had a combined vitamin and trace element deficiency, 6 (29%) had an isolated vitamin deficiency, and 4 (19%) had an isolated trace element deficiency. Vitamins A and E deficiency occurred in 16 (76%) and 4 (19%) of 21, respectively. Low serum selenium was found in 10 (47%), zinc deficiency in 7 (33%), and copper deficiency in 5 (24%). Eleven patients (52%) were on multivitamin supplementation, and 2 (10%) on zinc and selenium supplements. No statistical differences were found between repeated measurements for all micronutrients. CONCLUSIONS: More than 50% of the children had vitamin A and selenium deficiencies despite adequate supplementation of PERT and supplements. Micronutrients should be routinely measured in SDS patients to prevent significant complications. PMID- 25742432 TI - Effectiveness of influenza vaccination programme in preventing hospital admissions, Valencia, 2014/15 early results. AB - Preliminary results for the 2014/15 season indicate low to null effect of vaccination against influenza A(H3N2)-related disease. As of week 5 2015, there have been 1,136 hospital admissions, 210 were due to influenza and 98% of subtype A strains were H3. Adjusted influenza vaccine effectiveness was 33% (range: 6 53%) overall and 40% (range: 13% to 59%) in those 65 years and older. Vaccination reduced by 44% (28-68%) the probability of admission with influenza. PMID- 25742433 TI - Trivalent inactivated seasonal influenza vaccine effectiveness for the prevention of laboratory-confirmed influenza in a Scottish population 2000 to 2009. AB - To evaluate seasonal trivalent inactivated influenza vaccine effectiveness (VE) in Scotland, we performed a Scotland-wide linkage of patient-level primary care, hospital and virological swab data from 3,323 swabs (pooling data over nine influenza seasons: 2000/01 to 2008/09). We estimated the VE for reducing realtime RT-PCR-confirmed influenza using a test-negative study design. Vaccination was associated with a 57% (95% confidence interval (CI): 31-73) reduction in the risk of PCR-confirmed influenza. VE was 60% (95% CI:22-79) for patients younger than 65 years and clinically at risk of serious complications from influenza, and 19% (95% CI: -104 to 68) for any individual 65 years and older. Vaccination was associated with substantial, sustained reductions in laboratory-confirmed influenza in the general population and younger patients in clinical at-risk groups. PMID- 25742434 TI - A pilot validation in 10 European Union Member States of a point prevalence survey of healthcare-associated infections and antimicrobial use in acute hospitals in Europe, 2011. AB - We present a pilot validation study performed on 10 European Union (EU) Member States, of a point prevalence survey (PPS) of healthcare-associated infections (HAIs) and antimicrobial use in Europe in 2011 involving 29 EU/European Economic Area (EEA) countries and Croatia. A total of 20 acute hospitals and 1,950 patient records were included in the pilot study, which consisted of validation and inter rater reliability (IRR) testing using an in-hospital observation approach. In the validation, a sensitivity of 83% (95% confidence interval (CI): 79-87%) and a specificity of 98% (95% CI: 98-99%) were found for HAIs. The level of agreement between the primary PPS and validation results were very good for HAIs overall (Cohen's kappaappa (kappa):0.81) and across all the types of HAIs (range: 0.83 for bloodstream infections to 1.00 for lower respiratory tract infections). Antimicrobial use had a sensitivity of 94% (95% CI: 93-95%) and specificity of 97% (95% CI: 96-98%) with a very good level of agreement (kappa:0.91). Agreement on other demographic items ranged from moderate to very good (kappa: 0.57-0.95): age (kappa:0.95), sex (kappa: 0.93), specialty of physician (kappa: 0.87) and McCabe score (kappa: 0.57). IRR showed a very good level of agreement (kappa: 0.92) for both the presence of HAIs and antimicrobial use. This pilot study suggested valid and reliable reporting of HAIs and antimicrobial use in the PPS dataset. The lower level of sensitivity with respect to reporting of HAIs reinforces the importance of training data collectors and including validation studies as part of a PPS in order for the burden of HAIs to be better estimated. PMID- 25742435 TI - Post-discharge surveillance (PDS) for surgical site infections: a good method is more important than a long duration. AB - Post-discharge surveillance (PDS) for surgical site infections (SSIs) normally lasts 30 days, or one year after implant surgery, causing delayed feedback to healthcare professionals. We investigated the effect of shortened PDS durations on SSI incidence to determine whether shorter PDS durations are justified. We also studied the impact of two national PDS methods (those mandatory since 2009 ('mandatory') and other methods acceptable before 2009 ('other')) on SSI incidence. From Dutch surveillance (PREZIES) data (1999-2008), four implant-free surgeries (breast amputation, Caesarean section, laparoscopic cholecystectomy and colectomy) and two implant surgeries (knee replacement and total hip replacement) were selected. We studied the impact of PDS duration and method on SSI incidences by survival and Cox regression analyses. We included 105,607 operations. Shortened PDS duration for implant surgery from one year to 90 days resulted in 6 14% of all SSIs being missed. For implant-free procedures, PDS reduction from 30 to 21 days caused similar levels of missed SSIs. In contrast, up to 62% of SSIs (for cholecystectomy) were missed if other instead of mandatory PDS methods were used. Inferior methods of PDS, rather than shortened PDS durations, may lead to greater underestimation of SSI incidence. Our data validate international recommendations to limit the maximum PDS duration (for implant surgeries) to 90 days for surveillance purposes, as this provides robust insight into trends. PMID- 25742436 TI - Correction: integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD. PMID- 25742437 TI - Enhanced reduced representation bisulfite sequencing for assessment of DNA methylation at base pair resolution. AB - DNA methylation pattern mapping is heavily studied in normal and diseased tissues. A variety of methods have been established to interrogate the cytosine methylation patterns in cells. Reduced representation of whole genome bisulfite sequencing was developed to detect quantitative base pair resolution cytosine methylation patterns at GC-rich genomic loci. This is accomplished by combining the use of a restriction enzyme followed by bisulfite conversion. Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) increases the biologically relevant genomic loci covered and has been used to profile cytosine methylation in DNA from human, mouse and other organisms. ERRBS initiates with restriction enzyme digestion of DNA to generate low molecular weight fragments for use in library preparation. These fragments are subjected to standard library construction for next generation sequencing. Bisulfite conversion of unmethylated cytosines prior to the final amplification step allows for quantitative base resolution of cytosine methylation levels in covered genomic loci. The protocol can be completed within four days. Despite low complexity in the first three bases sequenced, ERRBS libraries yield high quality data when using a designated sequencing control lane. Mapping and bioinformatics analysis is then performed and yields data that can be easily integrated with a variety of genome-wide platforms. ERRBS can utilize small input material quantities making it feasible to process human clinical samples and applicable in a range of research applications. The video produced demonstrates critical steps of the ERRBS protocol. PMID- 25742438 TI - Laser capture microdissection--a demonstration of the isolation of individual dopamine neurons and the entire ventral tegmental area. AB - Laser capture microdissection (LCM) is used to isolate a concentrated population of individual cells or precise anatomical regions of tissue from tissue sections on a microscope slide. When combined with immunohistochemistry, LCM can be used to isolate individual cells types based on a specific protein marker. Here, the LCM technique is described for collecting a specific population of dopamine neurons directly labeled with tyrosine hydroxylase immunohistochemistry and for isolation of the dopamine neuron containing region of the ventral tegmental area using indirect tyrosine hydroxylase immunohistochemistry on a section adjacent to those used for LCM. An infrared (IR) capture laser is used to both dissect individual neurons as well as the ventral tegmental area off glass slides and onto an LCM cap for analysis. Complete dehydration of the tissue with 100% ethanol and xylene is critical. The combination of the IR capture laser and the ultraviolet (UV) cutting laser is used to isolate individual dopamine neurons or the ventral tegmental area when using PEN membrane slides. A PEN membrane slide has significant advantages over a glass slide as it offers better consistency in capturing and collecting cells, is faster collecting large pieces of tissue, is less reliant on dehydration and results in complete removal of the tissue from the slide. Although removal of large areas of tissue from a glass slide is feasible, it is considerably more time consuming and frequently leaves some residual tissue behind. Data shown here demonstrate that RNA of sufficient quantity and quality can be obtained using these procedures for quantitative PCR measurements. Although RNA and DNA are the most commonly isolated molecules from tissue and cells collected with LCM, isolation and measurement of microRNA, protein and epigenetic changes in DNA can also benefit from the enhanced anatomical and cellular resolution obtained using LCM. PMID- 25742439 TI - Secondhand Smoking Is Associated With Vascular Inflammation. AB - BACKGROUND: The relative risk for cardiovascular diseases in passive smokers is similar to that of active smokers despite almost a 100-fold lower dose of inhaled cigarette smoke. However, the mechanisms underlying the surprising susceptibility of the vascular tissue to the toxins in secondhand smoke (SHS) have not been directly investigated. The aim of this study was to investigate directly vascular endothelial cell function in passive smokers. METHODS: Using a minimally invasive method of endothelial biopsy, we investigated directly the vascular endothelium in 23 healthy passive smokers, 25 healthy active smokers, and 23 healthy control subjects who had never smoked and had no regular exposure to SHS. Endothelial nitric oxide synthase (eNOS) function (expression of basal eNOS and activated eNOS [phosphorylated eNOS at serine1177 (P-eNOS)]) and expression of markers of inflammation (nuclear factor-kappaB [NF-kappaB]) and oxidative stress (nitrotyrosine) were assessed in freshly harvested venous endothelial cells by quantitative immunofluorescence. RESULTS: Expression of eNOS and P-eNOS was similarly reduced and expression of NF-kappaB was similarly increased in passive and active smokers compared with control subjects. Expression of nitrotyrosine was greater in active smokers than control subjects and similar in passive and active smokers. Brachial artery flow-mediated dilation was similarly reduced in passive and active smokers compared with control subjects, consistent with reduced endothelial NO bioavailability. CONCLUSIONS: Secondhand smoking increases vascular endothelial inflammation and reduces active eNOS to a similar extent as active cigarette smoking, indicating direct toxic effects of SHS on the vasculature. PMID- 25742440 TI - Step-by-step strategy from achiral precursors to polyoxometalates-based chiral organic-inorganic hybrids. AB - Using two types of triol ligands, several novel asymmetrically triol functionalized Anderson organic hybrids have been efficiently synthesized in high purity and good yields via a convenient two-step esterification reaction. These organic-inorganic hybrids are chiral and can be spontaneously resolved with suitable solvents. Their molecular and crystal structures have been confirmed by single-crystal X-ray diffraction studies. Stable solid-state chirality of the corresponding enantiopure crystals has also been confirmed definitively by CD spectra. Interestingly, these organic-inorganic hybrids possess a layer-by-layer structure, forming solvent-accessible nanoscale chiral channels via a 1D infinite helical chain substructure. TGA measurements indicated that the species of the central heteroatoms significantly effects the stability of these compounds. PMID- 25742441 TI - Donor/acceptor indenoperylene dye for highly efficient organic dye-sensitized solar cells. AB - An N-annulated indenoperylene electron-donor decorated with photochemically inactive segments is synthesized and further conjugated via triple bond with electron-acceptor benzothiadiazolylbenzoic acid for a metal-free donor/acceptor dye. Without use of any coadsorbate, the judiciously tailored indenoperylene dye achieves a high-power conversion efficiency of 12.5% under irradiance of 100 mW cm(-2) AM1.5G sunlight. PMID- 25742442 TI - Correction: A streamlined system for species diagnosis in Caenorhabditis (Nematoda: Rhabditidae) with name designations for 15 distinct biological species. PMID- 25742443 TI - Debating male circumcision for HIV prevention: a one-sided argument does not represent a legitimate 'controversy' analysis--reply to de Camargo et al. PMID- 25742445 TI - Threat of interim data leaks prompts call for international rules. PMID- 25742446 TI - New technologies take root in the search for antibiotics from soil. PMID- 25742448 TI - Insurance companies are slow to cover next-generation sequencing. PMID- 25742449 TI - Copy number variations' effect on drug response still overlooked. PMID- 25742450 TI - Natural killers: cataloging immune cells for immunotherapy. PMID- 25742451 TI - Training on trials: patients taught the language of drug development. PMID- 25742452 TI - Timing is everything for compassionate use of delamanid. PMID- 25742453 TI - Metabolic-epigenetic coupling in osteoclast differentiation. PMID- 25742454 TI - Taming the inflammasome. PMID- 25742455 TI - Toward recreating colon cancer in human organoids. PMID- 25742456 TI - Understanding biomarkers of neurodegeneration: Ultrasensitive detection techniques pave the way for mechanistic understanding. PMID- 25742457 TI - Understanding biomarkers of neurodegeneration: Novel approaches to detecting tau pathology. PMID- 25742459 TI - Glottal Aperture and Buccal Airflow Leaks Critically Affect Forced Oscillometry Measurements. AB - BACKGROUND: The forced oscillation technique (FOT) measures respiratory resistance and reactance; however, the upper airways may affect the results. We quantified the impact of glottal aperture and buccal air leaks. METHODS: In the glottal aperture study (1) 10 healthy subjects (aged 34 +/- 2 years) performed a total lung capacity maneuver followed by 10-s breath-hold with and without total glottal closure and (2) the effects of humming (incomplete glottal narrowing) on FOT measurements were studied in six healthy subjects. Glottal narrowing was confirmed by direct rhinolaryngoscopy. In the air leak study, holes of increasing diameter (3.5, 6.0, and 8.5 mm) were made to the breathing filters. Eleven healthy subjects (aged 33 +/- 2 years) and five patients with COPD (aged 69 +/- 3 years) performed baseline FOT measurements with the three modified filters. RESULTS: Narrow glottal apertures and humming generated whole-breath resistance at 5 Hz (R5) peaks, increased R5 (1.49 +/- 0.37 kPa/L/s vs 0.34 +/- 0.01 kPa/L/s, P < .001), and decreased whole-breath reactance at 5 Hz (X5) values (-2.10 +/- 0.51 kPa/L/s vs -0.09 +/- 0.01 kPa/L/s, P < .001). The frequency dependency of resistance was increased. Holes in the breathing filters produced indentations on the breathing trace. Even the smaller holes reduced R5 in healthy subjects (0.33 +/- 0.02 to 0.24 +/- 0.02 kPa/L/s, P < .01) and patients with COPD (0.50 +/- 0.04 to 0.41 +/- 0.04 kPa/L/s, P < .05), whereas X5 became less negative (from -0.09 +/- 0.01 to -0.05 +/- 0.01 in healthy subjects, P < .01; from -0.22 +/- 0.06 to 0.11 +/- 0.03 kPa/L/s in patients with COPD, P < .05). CONCLUSIONS: Visual inspection of the data is required to exclude glottal narrowing and buccal air leaks identified as R5 peaks and volume indentations, respectively, because these significantly affect FOT measurements. PMID- 25742458 TI - Anemia: progress in molecular mechanisms and therapies. AB - Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to both the understanding of frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that are likely to benefit from new advances include the hemoglobinopathies (beta-thalassemia and sickle cell disease); rare genetic disorders of RBC production; and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new approaches to treatment include drugs that target recently defined pathways in RBC production, iron metabolism, and fetal globin-family gene expression, as well as gene therapies that use improved viral vectors and newly developed genome editing technologies. PMID- 25742460 TI - A tetO Toolkit To Alter Expression of Genes in Saccharomyces cerevisiae. AB - Strategies to optimize a metabolic pathway often involve building a large collection of strains, each containing different versions of sequences that regulate the expression of pathway genes. Here, we develop reagents and methods to carry out this process at high efficiency in the yeast Saccharomyces cerevisiae. We identify variants of the Escherichia coli tet operator (tetO) sequence that bind a TetR-VP16 activator with differential affinity and therefore result in different TetR-VP16 activator-driven expression. By recombining these variants upstream of the genes of a pathway, we generate unique combinations of expression levels. Here, we built a tetO toolkit, which includes the I-OnuI homing endonuclease to create double-strand breaks, which increases homologous recombination by 10(5); a plasmid carrying six variant tetO sequences flanked by I-OnuI sites, uncoupling transformation and recombination steps; an S. cerevisiae optimized TetR-VP16 activator; and a vector to integrate constructs into the yeast genome. We introduce into the S. cerevisiae genome the three crt genes from Erwinia herbicola required for yeast to synthesize lycopene and carry out the recombination process to produce a population of cells with permutations of tetO variants regulating the three genes. We identify 0.7% of this population as making detectable lycopene, of which the vast majority have undergone recombination at all three crt genes. We estimate a rate of ~20% recombination per targeted site, much higher than that obtained in other studies. Application of this toolkit to medically or industrially important end products could reduce the time and labor required to optimize the expression of a set of metabolic genes. PMID- 25742461 TI - Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka. AB - The use of laparoscopy for liver surgery is increasing rapidly. The Second International Consensus Conference on Laparoscopic Liver Resections (LLR) was held in Morioka, Japan, from October 4 to 6, 2014 to evaluate the current status of laparoscopic liver surgery and to provide recommendations to aid its future development. Seventeen questions were addressed. The first 7 questions focused on outcomes that reflect the benefits and risks of LLR. These questions were addressed using the Zurich-Danish consensus conference model in which the literature and expert opinion were weighed by a 9-member jury, who evaluated LLR outcomes using GRADE and a list of comparators. The jury also graded LLRs by the Balliol Classification of IDEAL. The jury concluded that MINOR LLRs had become standard practice (IDEAL 3) and that MAJOR liver resections were still innovative procedures in the exploration phase (IDEAL 2b). Continued cautious introduction of MAJOR LLRs was recommended. All of the evidence available for scrutiny was of LOW quality by GRADE, which prompted the recommendation for higher quality evaluative studies. The last 10 questions focused on technical questions and the recommendations were based on literature review and expert panel opinion. Recommendations were made regarding preoperative evaluation, bleeding controls, transection methods, anatomic approaches, and equipment. Both experts and jury recognized the need for a formal structure of education for those interested in performing major laparoscopic LLR because of the steep learning curve. PMID- 25742462 TI - Consensus conference on laparoscopic liver resection: a jury-based evaluation. PMID- 25742463 TI - Beyond "a chance to cut is a chance to cure": surgical quality in the cancer care continuum. PMID- 25742464 TI - MoS2 nanolayers grown on carbon nanotubes: an advanced reinforcement for epoxy composites. AB - In the present study, carbon nanotubes (CNTs) wrapped with MoS2 nanolayers (MoS2 CNTs) were facilely synthesized to obtain advanced hybrids. The structure of the MoS2-CNT hybrids was characterized by X-ray diffraction, Raman spectroscopy, scanning electron microscopy, and transmission electron microscopy measurements. Subsequently, the MoS2-CNT hybrids were incorporated into EP for reducing fire hazards. Compared with pristine CNTs, MoS2-CNT hybrids showed good dispersion in EP matrix and no obvious aggregation of CNTs was observed. The obtained nanocomposites exhibited significant improvements in thermal properties, flame retardancy and mechanical properties, compared with those of neat EP and composites with a single CNT or MoS2. With the incorporation of 2.0 wt % of MoS2 CNT hybrids, the char residues and glass transition temperature (Tg) of the EP composite was significantly increased. Also, the addition of MoS2-CNT hybrids awarded excellent fire resistance to the EP matrix, which was evidenced by the significantly reduced peak heat release rate and total heat release. Moreover, the amount of organic volatiles from EP decomposition was obviously decreased, and the formation of toxic CO was effectively suppressed, implying the toxicity of the volatiles was reduced and smoke production was obviously suppressed. The dramatically reduced fire hazards were generally ascribed to the synergistic effect of MoS2 and CNTs, containing good dispersion of MoS2-CNT hybrids, catalytic char function of MoS2 nanolayers, and physical barrier effects of MoS2 nanolayers and CNT network structure. PMID- 25742465 TI - Emergency postexposure vaccination with vesicular stomatitis virus-vectored Ebola vaccine after needlestick. AB - IMPORTANCE: Safe and effective vaccines and drugs are needed for the prevention and treatment of Ebola virus disease, including following a potentially high-risk exposure such as a needlestick. OBJECTIVE: To assess response to postexposure vaccination in a health care worker who was exposed to the Ebola virus. DESIGN AND SETTING: Case report of a physician who experienced a needlestick while working in an Ebola treatment unit in Sierra Leone on September 26, 2014. Medical evacuation to the United States was rapidly initiated. Given the concern about potentially lethal Ebola virus disease, the patient was offered, and provided his consent for, postexposure vaccination with an experimental vaccine available through an emergency Investigational New Drug application. He was vaccinated on September 28, 2014. INTERVENTIONS: The vaccine used was VSVDeltaG-ZEBOV, a replicating, attenuated, recombinant vesicular stomatitis virus (serotype Indiana) whose surface glycoprotein gene was replaced by the Zaire Ebola virus glycoprotein gene. This vaccine has entered a clinical trial for the prevention of Ebola in West Africa. RESULTS: The vaccine was administered 43 hours after the needlestick occurred. Fever and moderate to severe symptoms developed 12 hours after vaccination and diminished over 3 to 4 days. The real-time reverse transcription polymerase chain reaction results were transiently positive for vesicular stomatitis virus nucleoprotein gene and Ebola virus glycoprotein gene (both included in the vaccine) but consistently negative for Ebola virus nucleoprotein gene (not in the vaccine). Early postvaccination cytokine secretion and T lymphocyte and plasmablast activation were detected. Subsequently, Ebola virus glycoprotein-specific antibodies and T cells became detectable, but antibodies against Ebola viral matrix protein 40 (not in the vaccine) were not detected. CONCLUSIONS AND RELEVANCE: It is unknown if VSVDeltaG-ZEBOV is safe or effective for postexposure vaccination in humans who have experienced a high-risk occupational exposure to the Ebola virus, such as a needlestick. In this patient, postexposure vaccination with VSVDeltaG-ZEBOV induced a self-limited febrile syndrome that was associated with transient detection of the recombinant vesicular stomatitis vaccine virus in blood. Strong innate and Ebola-specific adaptive immune responses were detected after vaccination. The clinical syndrome and laboratory evidence were consistent with vaccination response, and no evidence of Ebola virus infection was detected. PMID- 25742466 TI - Management of primary anterior shoulder dislocations using immobilization. AB - Reference/Citation : Paterson WH, Throckmorton TW, Koester M, Azar FM, Kuhn JE. Position and duration of immobilization after primary anterior shoulder dislocation: a systemic review and meta-analysis of the literature. J Bone Joint Surg Am. 2010;92(18):2924-2933. CLINICAL QUESTION: Does an optimum duration and position of immobilization after primary anterior shoulder dislocation exist for reducing recurrence rates? DATA SOURCES: MEDLINE/PubMed, EMBASE, and Cochrane databases were searched up to December 2009 without limitations. The search terms for all databases used were shoulder AND dislocation and shoulder AND immobilization. STUDY SELECTION: Criteria used to include articles were (1) English language, (2) prospective level I or level II studies (according to Journal of Bone & Joint Surgery guidelines), (3) nonoperative management of initial anterior shoulder dislocation, (4) minimum follow-up of 1 year, and (5) rate of recurrent dislocation as a reported outcome. DATA EXTRACTION: A standardized evaluation method was used to extract data to allow assessment of methods issues and statistical analysis to determine sources of bias. The primary outcome was the recurrence rate after nonoperative management of anterior shoulder dislocation. Additional data extracted and used in subanalyses included duration and position of immobilization and age at the time of initial dislocation. Data were analyzed to determine associations among groups using 2 tailed Fisher exact tests. For pooled categorical data, relative risk of recurrent dislocation, 95% confidence intervals, and heterogeneity using the I(2) statistic and chi(2) tests were calculated for individual studies. The Mantel Haenszel method was used to combine studies and estimate overall relative risk of recurrent dislocation and 95% confidence intervals. The statistical difference between duration of immobilization and position was determined using z tests for overall effect. Pooled results were presented as forest plots. MAIN RESULTS: In the initial search of the databases, the authors identified 2083 articles. A total of 9 studies met all of the criteria and were included in this review. In most of the studies, age was a risk factor for recurrence. Patients less than 30 years of age were more likely to sustain a recurrent dislocation than patients more than 30 years of age. In 5 studies (n = 1215), researchers found no difference in recurrence of shoulder dislocation when immobilized in internal rotation (IR) for less than 1 week (41%, 40 of 97) compared with more than 3 weeks (37%, 34 of 93) in patients less than 30 years of age (P = .52). Authors of 3 studies (n = 289) compared the effect of immobilization in IR versus external rotation (ER), and whereas they found no statistical difference, a trend appeared toward reduced recurrence rates in ER but not IR (P = .07). The rate of recurrent dislocation was 40% (25 of 63) in patients treated with IR sling immobilization and 25% (22 of 88) in patients immobilized in ER. CONCLUSIONS: Overall, the investigators found that younger age (<30 years) was a predictor of recurrent dislocations, immobilization for more than 1 week did not improve recurrence rates, and an apparent trend existed toward decreased recurrence rates with ER rather than IR. According to the review and meta-analysis by Paterson et al, the level of evidence for recommendations regarding optimal duration and position of immobilization to reduce the risk of recurrent dislocation was therapeutic level II. This level of evidence was appropriate because the review included only prospective studies of level I or II and a minimum follow-up of 1 year. PMID- 25742467 TI - Mitochondrial apoptosis: killing cancer using the enemy within. AB - Apoptotic cell death inhibits oncogenesis at multiple stages, ranging from transformation to metastasis. Consequently, in order for cancer to develop and progress, apoptosis must be inhibited. Cell death also plays major roles in cancer treatment, serving as the main effector function of many anti-cancer therapies. In this review, we discuss the role of apoptosis in the development and treatment of cancer. Specifically, we focus upon the mitochondrial pathway of apoptosis-the most commonly deregulated form of cell death in cancer. In this process, mitochondrial outer membrane permeabilisation or MOMP represents the defining event that irrevocably commits a cell to die. We provide an overview of how this pathway is regulated by BCL-2 family proteins and describe ways in which cancer cells can block it. Finally, we discuss exciting new approaches aimed at specifically inducing mitochondrial apoptosis in cancer cells, outlining their potential pitfalls, while highlighting their considerable therapeutic promise. PMID- 25742468 TI - Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. AB - BACKGROUND: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. METHODS: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. RESULTS: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2). CONCLUSIONS: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy. PMID- 25742469 TI - ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels. AB - BACKGROUND: Ataxia telangiectasia mutated (ATM) is a kinase that has a central role in the maintenance of genomic integrity by activating cell cycle checkpoints and promoting repair of DNA double-strand breaks (DSB). In breast cancer, a low level of ATM was correlated with poor outcome; however, the molecular mechanism of this downregulation is still unclear. METHODS: We used qRT-PCR assay to quantify mRNA levels of ATM gene in 454 breast tumours from patients with known clinical/pathological status and outcome; reverse phase protein arrays (RPPA) were used to assess the levels of ATM and 14 proteins in 233 breast tumours. RESULTS: ATM mRNA was associated with poor metastasis-free survival (MFS) (P=0.00012) on univariate analysis. ATM mRNA and protein levels were positively correlated (P=0.00040). A low level of ATM protein was correlated with poorer MFS (P=0.000025). ATM expression at mRNA or protein levels are independent prognostic factors on multivariate analysis (P=0.00046 and P=0.00037, respectively). The ATM protein level was positively correlated with the levels of six proteins of the DSB repair pathway: H2AX (P<0.0000001), XRCC5 (P<0.0000001), NBN (P<0.0000001), Mre11 (P=0.0000029), Rad50 (P=0.0064), and TP53BP1 (P=0.026), but not with proteins involved in other pathways that are altered in cancer. Low expression of ATM protein was significantly associated with high miR-203 expression (P=0.011). CONCLUSION: We confirmed that ATM expression is an independent prognostic marker at both RNA and protein levels. We showed that alteration of ATM is involved in dysregulation of the DSB repair pathway. Finally, miR-203 may be responsible for downregulation of ATM in breast cancers. PMID- 25742470 TI - Nationwide bowel cancer screening programme in England: cohort study of lifestyle factors affecting participation and outcomes in women. AB - BACKGROUND: In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60-69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of screening, and we studied this association by linking NHSBCSP data to a large prospective cohort of women. METHODS: Electronic linkage of the NHSBCSP and Million Women Study records identified 899 166 women in the study cohort with at least one invitation for screening. NHSBCSP provided information on screening acceptance, FOBt results, screen-detected colorectal cancer and other outcomes. The Million Women Study provided prospectively collected information on personal and lifestyle factors. Multiple regression was used to estimate relative risks (RRs) of factors associated with acceptance and outcomes of screening. RESULTS: Overall, 70% of women (628 976/899 166) accepted their first invitation for bowel cancer screening, of whom 9133 (1.5%) were FOBt-positive, 743 (0.1%) had screen detected colorectal cancer and 3056 (0.5%) had screen-detected colorectal adenoma. Acceptance was lower in women from the most than the least deprived tertile, in South Asians and in Blacks than in Whites, in current than in never smokers and in obese than in normal weight women: adjusted RRs (95% confidence interval) for acceptance vs not, 0.90 (0.90-0.90); 0.77 (0.75-79); 0.94 (0.92 0.96); 0.78 (0.77-0.78); and 0.88 (0.88-0.89), respectively: P<0.001 for each. These factors were also associated with an increased risk of being FOBt-positive and of having screen-detected adenoma, but were not strongly associated with the risk of screen-detected colorectal cancer. Relative risks for screen-detected adenoma were 1.22 (1.12-1.34), 2.46 (1.75-3.45), 1.61 (1.05-2.48), 1.53 (1.38 1.68) and 1.77 (1.60-1.95), respectively (P<0.001 for all, except for Blacks vs Whites P=0.03). Use of hormone therapy for menopause was associated with reduced risk of screen-detected adenoma, RR ever vs never use, 0.87 (0.81-0.93), P<0.001 and colorectal cancer, 0.78 (0.68-0.91), P=0.001. INTERPRETATION: Among women in England, socioeconomic and lifestyle factors strongly affect participation in routine bowel cancer screening, risk of being FOBt-positive and risk of having screen-detected colorectal adenoma. However, screen-detected colorectal cancer risk is not strongly related to these factors. PMID- 25742471 TI - Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients. AB - INTRODUCTION: Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system. METHODS: Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel. RESULTS: Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified. CONCLUSIONS: Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients. PMID- 25742473 TI - Occupational exposure to endocrine disruptors and lymphoma risk in a multi centric European study. AB - BACKGROUND: Incidence rates of lymphoma are usually higher in men than in women, and oestrogens may protect against lymphoma. METHODS: We evaluated occupational exposure to endocrine disrupting chemicals (EDCs) among 2457 controls and 2178 incident lymphoma cases and subtypes from the European Epilymph study. RESULTS: Over 30 years of exposure to EDCs compared to no exposure was associated with a 24% increased risk of mature B-cell neoplasms (P-trend=0.02). Associations were observed among men, but not women. CONCLUSIONS: Prolonged occupational exposure to endocrine disruptors seems to be moderately associated with some lymphoma subtypes. PMID- 25742472 TI - Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer. AB - BACKGROUND: Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (+/-mitomycin C) in the randomised phase III MAX study. METHODS: DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM. RESULTS: Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71 1.17)) or OS (HR 0.95 (0.71-1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37-0.85) for RAS MT and HR 0.69 (0.5-0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic. CONCLUSION: Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC. PMID- 25742474 TI - Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression. AB - BACKGROUND: Activation of the Notch pathway has been reported in various types of cancers. However, the role of the hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) in osteosarcoma is unknown. We examined the function of HEY1 in osteosarcoma. METHODS: Expression of HEY1 was studied in human osteosarcoma. The effects of HEY1 in osteosarcoma were evaluated in vitro and in a xenograft model. Moreover, we examined the function of matrix metallopeptidase 9 (MMP9) as a downstream effector of HEY1. RESULTS: HEY1 was upregulated in human osteosarcoma. Knockdown of HEY1 inhibited the invasion of osteosarcoma cell lines. In contrast, the forced expression of HEY1 increased the invasion of mesenchymal stem cell. In addition, lung metastases were significantly inhibited by the knockdown of HEY1. We found that MMP9 was a downstream effector of HEY1 that promotes the invasion of osteosarcoma cells. Knockdown of HEY1 decreased the expression of MMP9. Addition of MMP9 rescued the invasion of osteosarcoma cells that had been rendered less invasive by knockdown of HEY1 expression. CONCLUSIONS: Our findings suggested that HEY1 augmented the metastasis of osteosarcoma via upregulation of MMP9 expression. Therefore, inhibition of HEY1 may be a novel therapeutic strategy for preventing osteosarcoma metastasis. PMID- 25742475 TI - Reproductive factors, exogenous hormone use and risk of hepatocellular carcinoma among US women: results from the Liver Cancer Pooling Project. AB - BACKGROUND: Hepatocellular carcinoma (HCC) occurs less commonly among women than men in almost all regions of the world. The disparity in risk is particularly notable prior to menopause suggesting that hormonal exposures during reproductive life may be protective. Exogenous oestrogenic exposures such as oral contraceptives (OCs), however, have been reported to increase risk, suggesting that estrogens may be hepatocarcinogenic. To examine the effects of reproductive factors and exogenous hormones on risk, we conducted a prospective analysis among a large group of US women. METHODS: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, data from 799,500 women in 11 cohorts were pooled and harmonised. Cox proportional hazards regression models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of reproductive factors and exogenous hormones with HCC (n=248). RESULTS: Bilateral oophorectomy was associated with a significantly increased risk of HCC (HR=2.67, 95% CI=1.22-5.85), which did not appear to be related to a shorter duration of exposure to endogenous hormones or to menopausal hormone therapy use. There was no association between OC use and HCC (HR=1.12, 95% CI=0.82-1.55). Nor were there associations with parity, age at first birth, age at natural menopause, or duration of fertility. CONCLUSIONS: The current study suggests that bilateral oophorectomy increases the risk of HCC but the explanation for the association is unclear. There was no association between OC use and HCC risk. Examination of endogenous hormone levels in relation to HCC may help to clarify the findings of the current study. PMID- 25742476 TI - Prognostic and predictive value of immunological parameters for chemoradioimmunotherapy in patients with pancreatic adenocarcinoma. AB - BACKGROUND: Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon-alpha in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes. METHODS: The following methods were used: tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot. Immunological parameters were correlated with patients' survival using the Kaplan-Meier method. RESULTS: Irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8(+) T cells in peripheral blood of the patients were associated with patients' survival. Amount of CD3(+) and effector-memory CD8(+) blood lymphocytes, expression of CD152 and interleukin (IL)-2 serum level showed a predictive value for chemoradioimmunotherapy. Tumoural accumulation of CD3(+) and CD8(+) cells was predictive for outcome of chemotherapy alone. Besides, we identified the frequencies of CD3(+) lymphocytes, effCD8(+) T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy. CONCLUSIONS: Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients. PMID- 25742477 TI - Mitochondrial dysfunction and risk of cancer. AB - BACKGROUND: Mitochondrial mutations are commonly reported in tumours, but it is unclear whether impaired mitochondrial function per se is a cause or consequence of cancer. To elucidate this, we examined the risk of cancer in a nationwide cohort of patients with mitochondrial dysfunction. METHODS: We used nationwide results on genetic testing for mitochondrial disease and the Danish Civil Registration System, to construct a cohort of 311 patients with mitochondrial dysfunction. A total of 177 cohort members were identified from genetic testing and 134 genetically untested cohort members were matrilineal relatives to a cohort member with a genetically confirmed maternally inherited mDNA mutation. Information on cancer was obtained by linkage to the Danish Cancer Register. Standardised incidence ratios (SIRs) were used to assess the relative risk of cancer. RESULTS: During 7334 person-years of follow-up, 19 subjects developed a primary cancer. The corresponding SIR for any primary cancer was 1.06 (95% confidence interval 0.68-1.63). Subgroup analyses according to mutational subtype yielded similar results, for example, a SIR of 0.94 (95% CI 0.53 to 1.67) for the m.3243A>G maternally inherited mDNA mutation, cases=13. CONCLUSIONS: Patients with mitochondrial dysfunction do not appear to be at increased risk of cancer compared with the general population. PMID- 25742478 TI - Cancer spectrum and frequency among children with Noonan, Costello, and cardio facio-cutaneous syndromes. AB - BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours. PMID- 25742479 TI - An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study. AB - BACKGROUND: Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. METHODS: We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202,206 women in the European Prospective Investigation into Cancer and Nutrition study. RESULTS: Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration. CONCLUSION: Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model. PMID- 25742481 TI - Age-specific risk of breast cancer in women with neurofibromatosis type 1. AB - BACKGROUND: Young women with neurofibromatosis type 1 (NF1) are reported to have a higher risk of breast cancer than others, and this might have implications for screening programmes. Our aim was to calculate this risk. METHODS: An all-England linked data set of hospital admissions and deaths was analysed to determine age specific rates of breast cancer in women with NF1 and controls. RESULTS: The age specific excess risk of breast cancer, comparing the NF1 cohort with the control cohort, was elevated 6.5-fold (95% confidence interval 2.6-13.5) in women aged 30 39 years. There was a 4.4 (2.5-7.0) times higher risk among women aged 40-49. CONCLUSIONS: Women with NF1 develop breast cancer at younger ages than the general population. PMID- 25742480 TI - Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study. AB - BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease. PMID- 25742482 TI - Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer. AB - BACKGROUND: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). METHODS: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. RESULTS: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA 1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. CONCLUSIONS: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy. PMID- 25742483 TI - Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS: In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS: A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median DeltaQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ?470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS: These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended. PMID- 25742484 TI - Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours. AB - BACKGROUND: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management. METHODS: Here we use human head and neck squamous cell carcinoma (HNSCC) models and nuclear magnetic resonance (NMR) spectroscopy to assess the metabolic changes that follow acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), and which could serve as potential metabolic biomarkers of drug resistance. RESULTS: Comparison of NMR metabolite profiles obtained from control (CAL(S)) and EGFR TKI-resistant (CAL(R)) cells grown as 2D monolayers, 3D spheroids or xenograft tumours in athymic mice revealed a number of differences between the sensitive and drug-resistant models. In particular, we observed elevated levels of glycerophosphocholine (GPC) in CAL(R) relative to CAL(S) monolayers, spheroids and tumours, independent of the growth rate or environment. In addition, there was an increase in alanine, aspartate and creatine+phosphocreatine in resistant spheroids and xenografts, and increased levels of lactate, branched-chain amino acids and a fall in phosphoethanolamine only in xenografts. The xenograft lactate build-up was associated with an increased expression of the glucose transporter GLUT-1, whereas the rise in GPC was attributed to inhibition of GPC phosphodiesterase. Reduced glycerophosphocholine (GPC) and phosphocholine were observed in a second HNSCC model probably indicative of a different drug resistance mechanism. CONCLUSIONS: Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models. These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic. PMID- 25742485 TI - The significant survival advantage of female sex in nasopharyngeal carcinoma: a propensity-matched analysis. AB - BACKGROUND: Whether females have better survival than males in nasopharyngeal carcinoma is barely acknowledged and the exact explanations remain unknown. METHODS: Overall, 5929 patients receiving treatment between January 2005 and December 2010 were separately stratified by stage into early and advanced stage groups, and by age into premenopausal (?45 years), menopausal (46-54 years) and postmenopausal (?55 years) groups. Matched males and females in each group were identified using the propensity score matching method. Differences in disease free survival (DSS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRFS) were estimated by the Kaplan Meier method and Cox regression model. RESULTS: Overall, 398, 923, 744, 319 and 313 pairs of males and females were matched in early stage, advanced stage, premenopausal, menopausal and postmenopausal group, respectively. Females showed significant advantage over males across all end points in both early and advanced stage groups (P?0.042). However, this advantage persisted at premenopausal age (P?0.042), declined during menopause (DMFS, P=0.021; DSS, P=0.100; OS, P=0.693; LRFS, P=0.330) and totally disappeared at postmenopausal age (P?0.344). CONCLUSIONS: Sex significantly affects NPC survival, with a definite female advantage regardless of tumour stage. Intrinsic biologic traits appear to be the exact explanation according to the declining magnitude of sex effect with age. PMID- 25742487 TI - Correction: Adaptive robotic control driven by a versatile spiking cerebellar network. PMID- 25742488 TI - Mechanism and functional implications of the heme-induced binding promiscuity of IgE. AB - A fraction of antibodies from healthy immune repertoires binds to heme and acquires the ability to recognize multiple antigens. The mechanism and functional consequences of heme-mediated antigen binding promiscuity (polyreactivity) are not understood. Here, we used SPE7, a mouse monoclonal IgE specific for dinitrophenyl that has been thoroughly characterized at the molecular level, as a model antibody to elucidate the mechanism and functional consequences of heme mediated polyreactivity. We first demonstrate that exposure of SPE7 to heme results in a substantial increase in its antigen binding polyreactivity. Comparison of the binding kinetics and thermodynamics of interaction of native and heme-bound SPE7 indicates that the binding of heme to SPE7 confers binding affinities in the low nanomolar range toward several antigens but has no influence on the mechanism of recognition of dinitrophenyl. In vitro cellular assays further demonstrate that heme-bound SPE7 does not promote the degranulation of basophils in the presence of new target antigens, while degranulation is observed in the presence of dinitrophenyl. Molecular docking and fluorescence spectroscopy revealed binding of heme to the variable region of SPE7 at a distance from the conventional binding site for dinitrophenyl, explaining the extension of binding polyreactivity without abrogation of the interaction with its cognate antigen. In addition, our data suggest that heme, when bound to IgE, is solvent-exposed and may serve as an interfacial cofactor mediating binding to diverse proteins. This study contributes to the understanding of the mechanisms of heme-induced antibody polyreactivity. It also paves the way toward the delineation of the functional impact of polyreactivity and cross-reactivity of IgE. PMID- 25742489 TI - Correction: negligible immunogenicity of induced pluripotent stem cells derived from human skin fibroblasts. PMID- 25742490 TI - Palladium-catalyzed intramolecular aminoacetoxylation of unactivated alkenes with hydrogen peroxide as oxidant. AB - A palladium-catalyzed intramolecular aminoacetoxylation of unactivated alkenes was developed in which H2O2 was used as the sole oxidant. A variety of 3 acetoxylated piperidines were obtained in good yields with good to excellent regio- and diastereoselectivities. Mechanistic study revealed that the addition of di(2-pyridyl) ketone (dpk) ligand was crucial to promote the oxidative cleavage of the C-Pd(II) bond by H2O2 to give the C-OAc bond. PMID- 25742491 TI - An in situ growth approach to the fabrication of zeolite imidazolate framework-90 bonded capillary column for gas chromatography separation. AB - The unique properties of metal-organic frameworks, such as diversity in structures and pore sizes, high surface area, shape selectivity and available to functionality make them as potential materials of the stationary phase for gas chromatography. Here we show an in situ growth approach to the fabrication of zeolite imidazolate framework-90 (ZIF-90) bonded capillary column for gas chromatography separation. ZIF-90 was directly grown onto the inner wall of the carboxyl modified capillary via the coordination between Zn(II) and carboxyl group. The fabricated ZIF-90 bonded capillary column acted as a weak polar stationary phase. It not only exhibits high capacity in the separation of linear molecules, but also offers excellent features for the separation of 2- and 3 substituted ketones. PMID- 25742492 TI - Periodic Change in Sufficient Physical Activity: A 2-Year Study of a Multi-Ethnic Cohort. AB - BACKGROUND: Measuring the way people vary across time in meeting recommended levels of physical activity is a prerequisite to quantifying exposure in outcome studies or identifying determinants of sufficient physical activity. The study determined whether distinct patterns of change in sufficient physical activity could be identified in a population. METHODS: A cohort (N = 497) from a random, multiethnic sample of adults living in Hawaii was assessed every 6 months for 2 years beginning spring 2004. Latent transition analysis classified people as sufficiently or insufficiently active each time. RESULTS: In the total cohort, odds that people would move from insufficient to sufficient activity (45% to 59%) at each 6-month transition were higher than odds they would move from sufficient to insufficient activity (8% to 13%). However, those odds, as well as types and amounts of physical activity, differed widely among and within 3 of 4 transition classes that represented 21% of the cohort. CONCLUSIONS: Point-prevalence of sufficient physical activity in the total cohort was similar to contemporary U.S. estimates. However, physical activity varied between and within subgroups of the cohort. Further research is needed using self-report and objective measures to determine patterns of change in sufficient physical activity in other representative cohorts. PMID- 25742493 TI - Bora downregulation results in radioresistance by promoting repair of double strand breaks. AB - Following DNA double-strand breaks cells activate several DNA-damage response protein kinases, which then trigger histone H2AX phosphorylation and the accumulation of proteins such as MDC1, p53-binding protein 1, and breast cancer gene 1 at the damage site to promote DNA double-strand breaks repair. We identified a novel biomarker, Bora (previously called C13orf34), that is associated with radiosensitivity. In the current study, we set out to investigate how Bora might be involved in response to irradiation. We found a novel function of Bora in DNA damage repair response. Bora down-regulation increased colony formation in cells exposed to irradiation. This increased resistance to irradiation in Bora-deficient cells is likely due to a faster rate of double strand breaks repair. After irradiation, Bora-knockdown cells displayed increased G2-M cell cycle arrest and increased Chk2 phosphorylation. Furthermore, Bora specifically interacted with the tandem breast cancer gene 1 C-terminal domain of MDC1 in a phosphorylation dependent manner, and overexpression of Bora could abolish irradiation induced MDC1 foci formation. In summary, Bora may play a significant role in radiosensitivity through the regulation of MDC1 and DNA repair. PMID- 25742494 TI - Synthesis, structural and antioxidant studies of some novel N-ethyl phthalimide esters. AB - A series of N-ethyl phthalimide esters 4(a-n) were synthesized and characterized by spectroscopic studies. Further, the molecular structure of majority of compounds were analysed by single crystal X-ray diffraction studies. The X-ray analysis revealed the importance of substituents on the crystal stability and molecular packing. All the synthesized compounds were tested for in vitro antioxidant activity by DPPH radical scavenging, FRAP and CUPRAC methods. Few of them have shown good antioxidant activity. PMID- 25742496 TI - Correction: Urotensin II inhibits doxorubicin-induced human umbilical vein endothelial cell death by modulating ATF expression and via the ERK and Akt pathway. PMID- 25742495 TI - Molecular and Biochemical Analysis of Chalcone Synthase from Freesia hybrid in flavonoid biosynthetic pathway. AB - Chalcone synthase (CHS) catalyzes the first committed step in the flavonoid biosynthetic pathway. In this study, the cDNA (FhCHS1) encoding CHS from Freesia hybrida was successfully isolated and analyzed. Multiple sequence alignments showed that both the conserved CHS active site residues and CHS signature sequence were found in the deduced amino acid sequence of FhCHS1. Meanwhile, crystallographic analysis revealed that protein structure of FhCHS1 is highly similar to that of alfalfa CHS2, and the biochemical analysis results indicated that it has an enzymatic role in naringenin biosynthesis. Moreover, quantitative real-time PCR was performed to detect the transcript levels of FhCHS1 in flowers and different tissues, and patterns of FhCHS1 expression in flowers showed significant correlation to the accumulation patterns of anthocyanin during flower development. To further characterize the functionality of FhCHS1, its ectopic expression in Arabidopsis thaliana tt4 mutants and Petunia hybrida was performed. The results showed that overexpression of FhCHS1 in tt4 mutants fully restored the pigmentation phenotype of the seed coats, cotyledons and hypocotyls, while transgenic petunia expressing FhCHS1 showed flower color alteration from white to pink. In summary, these results suggest that FhCHS1 plays an essential role in the biosynthesis of flavonoid in Freesia hybrida and may be used to modify the components of flavonoids in other plants. PMID- 25742497 TI - Human vascular model with defined stimulation medium - a characterization study. AB - The formation of blood vessels is a vital process in embryonic development and in normal physiology. Current vascular modelling is mainly based on animal biology leading to species-to-species variation when extrapolating the results to humans. Although there are a few human cell based vascular models available these assays are insufficiently characterized in terms of culture conditions and developmental stage of vascular structures. Therefore, well characterized vascular models with human relevance are needed for basic research, embryotoxicity testing, development of therapeutic strategies and for tissue engineering. We have previously shown that the in vitro vascular model based on co-culture of human adipose stromal cells (hASC) and human umbilical vein endothelial cells (HUVEC) is able to induce an extensive vascular-like network with high reproducibility. In this work we developed a defined serum-free vascular stimulation medium (VSM) and performed further characterization in terms of cell identity, maturation and structure to obtain a thoroughly characterized in vitro vascular model to replace or reduce corresponding animal experiments. The results showed that the novel vascular stimulation medium induced intact and evenly distributed vascular-like network with morphology of mature vessels. Electron microscopic analysis assured the three-dimensional microstructure of the network containing lumen. Additionally, elevated expressions of the main human angiogenesis-related genes were detected. In conclusion, with the new defined medium the vascular model can be utilized as a characterized test system for chemical testing as well as in creating vascularized tissue models. PMID- 25742498 TI - NMR studies of the equilibria and reaction rates in aqueous solutions of formaldehyde. AB - Formaldehyde has an important role in the chemical industry and in biological sciences. In dilute aqueous solutions of formaldehyde only traces of the molecular formaldehyde are present and the predominant species are methylene glycol and in lower concentrations, dimethylene glycol. The chemical equilibria and reaction rates of the hydration of formaldehyde in H2O and D2O solutions at low concentrations were studied by (1)H and (13)C NMR at various conditions of pH (1.8-7.8) and temperature (278-333 K). These measurements became possible by direct detection of formaldehyde (13)C and (1)H peaks. The equilibrium and rate constants of the dimerization reaction of methylene glycol were also measured. The rate constants for both the hydration and the dimerization reactions were measured by a new version of the conventional selective inversion transfer method. This study, together with previous published work, completes the description of dynamics and equilibria of all the processes occurring in dilute aqueous formaldehyde solutions. PMID- 25742499 TI - miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of cancer cells. AB - MicroRNAs can function as key tumor suppressors or oncogenes and act as biomarkers for cancer diagnosis or prognosis. Although high-throughput assays have revealed many miRNA biomarkers for pancreatic ductal adenocarcinoma (PDAC), only a few have been validated in independent populations or investigated for functional significance in PDAC pathogenesis. In this study, we correlated the expression of 36 potentially prognostic miRNAs within PDAC tissue with clinico pathological features and survival in 151 Chinese patients. We then analyzed the functional roles and target genes of two miRNAs in PDAC development. We found that high expression of miR-186 and miR-326 predict poor and improved survival, respectively. miR-186 was over-expressed in PDAC patients compared with controls, especially in patients with large tumors (>2 cm), lymph node metastasis, or short term survival (< 24 months). In contrast, miR-326 was down-regulated in patients compared with controls and displayed relatively increased expression in the patients with long-term survival or without venous invasion. Functional experiments revealed that PDAC cell proliferation and migration was decreased following inhibition and enhanced following over-expression of miR-186. In contrast, it was enhanced following inhibition and decreased after over expression of miR-326. A luciferase assay indicated that miR-186 can bind directly to the 3'-UTR of NR5A2 to repress gene expression. These findings suggest that miR-186 over-expression contributes to the invasive potential of PDAC, likely via suppression of NR5A2, thereby leading to a poor prognosis; high miR-326 expression prolongs survival likely via the decreasing invasive potential of PDAC cells. These two miRNAs can be used as markers for clinical diagnosis and prognosis, and they represent therapeutic targets for PDAC. PMID- 25742500 TI - Volume regulation and renal function at high altitude across gender. AB - AIMS: We investigated changes in volume regulating hormones and renal function at high altitudes and across gender. METHODOLOGY: Included in this study were 28 subjects (n = 20 males; n = 8 females. ages: 19 - 65 yrs), who ascended to a height of 3440m (HA1), on the 3rd day and to 5050m (HA2), on the 14th day. Plasma and urinary creatinine and urinary osmolality as well as plasma levels of plasma renin activity (PRA), Aldosterone, antidiuretic hormone (ADH), and atrial natriuretic peptide (ANP) were measured. The plasma volume loss (PVL) was estimated from plasma density and hematocrit. Glomerular filtration rate (GFR) was measured based on nocturnal (9 hour) creatinine clearance; this was compared with various methods for estimation of GFR. RESULTS: The mean 24-hour urine production increased significantly in both sexes across the expedition. But PVL reached significance only in males. No changes in Na+ in plasma, urine or its fractional excretion were seen at both altitudes. Urinary osmolality decreased upon ascent to the higher altitudes. ADH and PRA decreased significantly at both altitudes in males but only at HA2 in females. However, no changes in aldosterone were seen across the sexes and at different altitudes. ANP increased significantly only in males during the expedition. GFR, derived from 9-h creatinine clearance (CreaCl), decreased in both sexes at HA1 but remained stable at HA2. Conventional Crea[p]-based GFR estimates (eGFR) showed only poor correlation to CreaCl. CONCLUSIONS: We report details of changes in hormonal patterns across high altitude sojourn. To our knowledge we are not aware of any study that has examined these hormones in same subjects and across gender during high altitude sojourn. Our results also suggest that depending on the estimation formula used, eGFR underestimated the observed decrease in renal function measured by CreaCl, thus opening the debate regarding the use of estimated glomerular filtration rates at high altitudes. PMID- 25742501 TI - Evidence of water molecules--a statistical evaluation of water molecules based on electron density. AB - Water molecules play important roles in many biological processes, especially when mediating protein-ligand interactions. Dehydration and the hydrophobic effect are of central importance for estimating binding affinities. Due to the specific geometric characteristics of hydrogen bond functions of water molecules, meaning two acceptor and two donor functions in a tetrahedral arrangement, they have to be modeled accurately. Despite many attempts in the past years, accurate prediction of water molecules-structurally as well as energetically-remains a grand challenge. One reason is certainly the lack of experimental data, since energetic contributions of water molecules can only be measured indirectly. However, on the structural side, the electron density clearly shows the positions of stable water molecules. This information has the potential to improve models on water structure and energy in proteins and protein interfaces. On the basis of a high-resolution subset of the Protein Data Bank, we have conducted an extensive statistical analysis of 2.3 million water molecules, discriminating those water molecules that are well resolved and those without much evidence of electron density. In order to perform this classification, we introduce a new measurement of electron density around an individual atom enabling the automatic quantification of experimental support. On the basis of this measurement, we present an analysis of water molecules with a detailed profile of geometric and structural features. This data, which is freely available, can be applied to not only modeling and validation of new water models in structural biology but also in molecular design. PMID- 25742502 TI - Correction: Changes in eating attitudes, body esteem and weight control behaviours during adolescence in a South African cohort. PMID- 25742503 TI - The role of botulinum toxin a in the establishment of symmetry in pediatric paralysis of the lower lip. AB - IMPORTANCE: Botulinum toxin A has been described as an effective adjunct treatment for achieving symmetry in adults with facial paralysis. Few investigators have described the use of botulinum toxin A in pediatric patients with facial paralysis. OBJECTIVE: To present our preliminary experience with botulinum toxin A in pediatric patients presenting with asymmetry of the lower lip. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective medical record review of all pediatric patients (age range, 4-17 years; mean [SD] age, 11.2 [4.7] years) with facial paralysis who were treated with botulinum toxin A injections from January 1, 2004, through December 31, 2012. Patients presented for treatment at The Hospital for Sick Children, Toronto, Ontario, Canada, or the Massachusetts Eye and Ear Infirmary, Boston. MAIN OUTCOMES AND MEASURES: Using facial analysis software, we measured lower lip asymmetry in the patients' photographs before and after treatment, at rest, and in a dynamic state. We performed analysis of variance to assess for improvement in symmetry. RESULTS: We identified 18 patients with the following 3 primary indications for treatment: focal lip asymmetry (n = 11), extensive hemifacial asymmetry (n = 5), and focal synkinesis (n = 2). We found no complications related to botulinum toxin A treatment. The mean (SD) dynamic deviation before the injection was 3.5 (1.7) mm, whereas the mean dynamic deviation after the injection was 1.5 (0.8) mm. The mean (SD) deviation correction was evaluated at 61% (6%) and was statistically significant (P = .04). CONCLUSIONS AND RELEVANCE: Botulinum toxin A injection is a safe procedure for improving localized asymmetry in pediatric patients with facial paralysis. Preliminary results indicate that botulinum toxin A may be an effective treatment for lower lip asymmetry in children and adolescents. LEVEL OF EVIDENCE: 4. PMID- 25742504 TI - The effect of meteorological variables on the transmission of hand, foot and mouth disease in four major cities of shanxi province, China: a time series data analysis (2009-2013). AB - Increased incidence of hand, foot and mouth disease (HFMD) has been recognized as a critical challenge to communicable disease control and public health response. This study aimed to quantify the association between climate variation and notified cases of HFMD in selected cities of Shanxi Province, and to provide evidence for disease control and prevention. Meteorological variables and HFMD cases data in 4 major cities (Datong, Taiyuan, Changzhi and Yuncheng) of Shanxi province, China, were obtained from the China Meteorology Administration and China CDC respectively over the period 1 January 2009 to 31 December 2013. Correlations analyses and Seasonal Autoregressive Integrated Moving Average (SARIMA) models were used to identify and quantify the relationship between the meteorological variables and HFMD. HFMD incidence varied seasonally with the majority of cases in the 4 cities occurring from May to July. Temperatures could play important roles in the incidence of HFMD in these regions. The SARIMA models indicate that a 1 degrees C rise in average, maximum and minimum temperatures may lead to a similar relative increase in the number of cases in the 4 cities. The lag times for the effects of temperatures were identified in Taiyuan, Changzhi and Yuncheng. The numbers of cases were positively associated with average and minimum temperatures at a lag of 1 week in Taiyuan, Changzhi and Yuncheng, and with maximum temperature at a lag of 2 weeks in Yuncheng. Positive association between the temperature and HFMD has been identified from the 4 cities in Shanxi Province, although the role of weather variables on the transmission of HFMD varied in the 4 cities. Relevant prevention measures and public health action are required to reduce future risks of climate change with consideration of local climatic conditions. PMID- 25742505 TI - Clinicopathological correlation of outer retinal tubulation in age-related macular degeneration. PMID- 25742506 TI - Operant procedures for assessing behavioral flexibility in rats. AB - Executive functions consist of multiple high-level cognitive processes that drive rule generation and behavioral selection. An emergent property of these processes is the ability to adjust behavior in response to changes in one's environment (i.e., behavioral flexibility). These processes are essential to normal human behavior, and may be disrupted in diverse neuropsychiatric conditions, including schizophrenia, alcoholism, depression, stroke, and Alzheimer's disease. Understanding of the neurobiology of executive functions has been greatly advanced by the availability of animal tasks for assessing discrete components of behavioral flexibility, particularly strategy shifting and reversal learning. While several types of tasks have been developed, most are non-automated, labor intensive, and allow testing of only one animal at a time. The recent development of automated, operant-based tasks for assessing behavioral flexibility streamlines testing, standardizes stimulus presentation and data recording, and dramatically improves throughput. Here, we describe automated strategy shifting and reversal tasks, using operant chambers controlled by custom written software programs. Using these tasks, we have shown that the medial prefrontal cortex governs strategy shifting but not reversal learning in the rat, similar to the dissociation observed in humans. Moreover, animals with a neonatal hippocampal lesion, a neurodevelopmental model of schizophrenia, are selectively impaired on the strategy shifting task but not the reversal task. The strategy shifting task also allows the identification of separate types of performance errors, each of which is attributable to distinct neural substrates. The availability of these automated tasks, and the evidence supporting the dissociable contributions of separate prefrontal areas, makes them particularly well-suited assays for the investigation of basic neurobiological processes as well as drug discovery and screening in disease models. PMID- 25742507 TI - Tracing copper derived from pig manure in calcareous soils and soil leachates by 65Cu labeling. AB - Copper is used as a growth promoter in animal husbandry, resulting in high Cu concentrations in animal manure. We tested whether Cu would be mobilized in soils receiving excessive loads of manure, both from recently added and from aged fractions. To discriminate between these Cu sources, manure was labeled with (65)Cu. After soil application of 0, 15, and 30 Mg manure ha(-1), leachate was collected in free-draining lysimeters (40 cm depth) under undisturbed soil over a 53 day period. Determining the total amounts of Cu and the fractions of (65)Cu in leachate and the soil profile enabled us to trace the translocation of Cu derived from labeled manure. More than 84% of the applied Cu was retained in the top 2 cm of soil. Less than 0.01% of the applied Cu was detected overall in the leachate. Of this amount, however, 38% (+/- 8.9 SE) was leached within 8 days after application. The total Cu concentration in leachates (32-164 MUg L(-1)) frequently exceeded the Chinese groundwater quality standard of 50 MUg L(-1). The added (65)Cu, however, accounted for less than 3.6% of the total Cu leaching load, suggesting that Cu from older sources and/or geological background controls contamination, regardless of current land management. PMID- 25742508 TI - Effect of substrate temperature on pattern formation of nanoparticles from volatile drops. AB - This study investigates pattern formation during evaporation of water-based nanofluid sessile droplets placed on a smooth silicon surface at various temperatures. An infrared thermography technique was employed to observe the temperature distribution along the air-liquid interface of evaporating droplets. In addition, an optical interferometry technique is used to quantify and characterize the deposited patterns. Depending on the substrate temperature, three distinctive deposition patterns are observed: a nearly uniform coverage pattern, a "dual-ring" pattern, and multiple rings corresponding to "stick-slip" pattern. At all substrate temperatures, the internal flow within the drop builds a ringlike cluster of the solute on the top region of drying droplets, which is found essential for the formation of the secondary ring deposition onto the substrate for the deposits with the "dual-ring" pattern. The size of the secondary ring is found to be dependent on the substrate temperature. For the deposits with the rather uniform coverage pattern, the ringlike cluster of the solute does not deposit as a distinct secondary ring; instead, it is deformed by the contact line depinning. In the case of the "stick-slip" pattern, the internal flow behavior is complex and found to be vigorous with rapid circulating flow which appears near the edge of the drop. PMID- 25742510 TI - Correction: Post-mortem tissue biopsies obtained at minimally invasive autopsy: an RNA-quality analysis. PMID- 25742509 TI - Urinary thrombin: a novel marker of glomerular inflammation for the diagnosis of crescentic glomerulonephritis (prospective observational study). AB - BACKGROUND: Crescentic glomerulonephritis (CresGN), an uncommon rapidly progressive disease, is characterized by severe glomerular inflammation with fibrin deposition. The lack of specific CresGN biomarkers delays diagnosis and threatens life. Because fibrin deposits in CresGN glomeruli indicate thrombin generation, we hypothesized that thrombin is excreted in urine and is a specific CresGN biomarker. METHODS: We measured urinary thrombin activity in 200 untreated patients (17 with CresGN, 183 with primary glomerulonephritis) and controls (8 patients with healed CresGN, 11 with nephrosclerosis, and 10 with tubulointerstitial nephritis, and 66 healthy volunteers). CresGN types included 15 pauci-immune and 2 immune complex. We assessed the diagnostic accuracy of thrombinuria in 169 patients with hematuria and proteinuria. Renal biopsy tissues were immunostained for tissue factor and fibrin. We analyzed the relationship of thrombinuria to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, glomerular fibrin deposition, antineutrophil cytoplasmic antibodies (ANCAs), and C-reactive protein (CRP). We studied changes in thrombin activities after glucocorticoid treatment in 12 patients with thrombinuria. RESULTS: The highest thrombinuria occurrence was in CresGN (70.6%), followed by membranoproliferative glomerulonephritis (41.7%), IgA nephropathy (9.2%), and acute glomerulonephritis (0%). More than 75% of patients with nonproliferative glomerulonephritis manifested no thrombinuria. No controls had thrombinuria. Thrombinuria showed high CresGN specificity (90.1%) and moderate sensitivity (70.6%) and was detected in 4 of 7 patients with ANCA-negative CresGN. In CresGN, thrombinuria was associated with fibrin deposition in glomerular extracapillary tissue, where monocytes/macrophages expressed tissue factor. Thrombinuria in CresGN was unrelated to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, and CRP. After glucocorticoid treatment, thrombinuria in patients with CresGN rapidly disappeared but proteinuria and hematuria persisted. CONCLUSIONS: Thrombinuria was specific for glomerular inflammation, was unaffected by systemic inflammation or coagulation, and demonstrated good diagnostic accuracy for CresGN including ANCA-negative cases. Thrombinuria measurement may provide risk-free diagnosis and screening for CresGN. PMID- 25742511 TI - Annotated differentially expressed salivary proteins of susceptible and insecticide-resistant mosquitoes of Anopheles stephensi. AB - Vector control is one of the major global strategies for control of malaria. However, the major obstacle for vector control is the development of multiple resistances to organochlorine, organophosphorus insecticides and pyrethroids that are currently being used in public health for spraying and in bednets. Salivary glands of vectors are the first target organ for human-vector contact during biting and parasite-vector contact prior to parasite development in the mosquito midguts. The salivary glands secrete anti-haemostatic, anti-inflammatory biologically active molecules to facilitate blood feeding from the host and also inadvertently inject malaria parasites into the vertebrate host. The Anopheles stephensi mosquito, an urban vector of malaria to both human and rodent species has been identified as a reference laboratory model to study mosquito-parasite interactions. In this study, we adopted a conventional proteomic approach of 2D electrophoresis coupled with MALDI-TOF mass spectrometry and bioinformatics to identify putative differentially expressed annotated functional salivary proteins between An. stephensi susceptible and multiresistant strains with same genetic background. Our results show 2D gel profile and MALDI-TOF comparisons that identified 31 differentially expressed putative modulated proteins in deltamethrin/DDT resistant strains of An. stephensi. Among these 15 proteins were found to be upregulated and 16 proteins were downregulated. Our studies interpret that An. stephensi (multiresistant) caused an upregulated expression of proteins and enzymes like cytochrome 450, short chain dehyrdogenase reductase, phosphodiesterase etc that may have an impact in insecticide resistance and xenobiotic detoxification. Our study elucidates a proteomic response of salivary glands differentially regulated proteins in response to insecticide resistance development which include structural, redox and regulatory enzymes of several pathways. These identified proteins may play a role in regulating mosquito biting behavior patterns and may have implications in the development of malaria parasites in resistant mosquitoes during parasite transmission. PMID- 25742512 TI - The Diabetes Risk Phenotype of Young Women With Recent Gestational Diabetes. AB - CONTEXT: The pathogenesis of type 2 diabetes (T2D) is still incompletely understood. In-depth phenotyping of young individuals at risk for T2D can contribute to the understanding of this process. OBJECTIVE: The purpose of this study was to metabolically characterize women with recent gestational diabetes (GDM), an at-risk cohort for T2D. STUDY PARTICIPANTS: Participants were 147 women consecutively recruited 3 to 16 months after pregnancy: women who had GDM and women after a normoglycemic pregnancy (control subjects) in a 2:1 ratio. DESIGN: This was a monocenter cross-sectional analysis (Prediction, Prevention and Subclassification of Type 2 Diabetes Study [PPS-Diab]). METHODS: A 5-point oral glucose tolerance test with calculation of the insulin sensitivity index and disposition index (validation by euglycemic clamp and intravenous glucose tolerance test) was performed. In addition, anthropometrics, medical and family history, clinical chemistry and biomarkers, statistical modeling, and a magnetic resonance imaging/magnetic resonance spectroscopy substudy (body fat distribution and liver and muscle fat; n = 66) were obtained. RESULTS: Compared with control subjects, women after GDM had a reduced disposition index, higher levels of plasma fetuin-A, and a lower insulin sensitivity index. A low insulin sensitivity index was also the major determinant of pathological glucose tolerance after GDM. The factors most strongly predictive of low insulin sensitivity were high plasma leptin, body mass index, triglycerides, and waist circumference. Ectopic lipids showed no body mass index-independent associations with having had GDM or low insulin sensitivity in a magnetic resonance imaging substudy. CONCLUSIONS: We found that beta-cell function is already impaired in women with recent GDM, a young at-risk cohort for T2D. In addition, our data suggest that fetuin-A and leptin signaling may be important early contributors to the pathogenesis of T2D, at this disease stage equally or more relevant than ectopic lipids and low-grade inflammation. PMID- 25742513 TI - Lipotoxicity, a potential risk factor for the increasing prevalence of subclinical hypothyroidism? AB - CONTEXT: Subclinical hypothyroidism (SCH) is an important public health problem worldwide for its increasing prevalence and potential deleterious effects, whereas its etiology has not been fully elucidated. Lipotoxicity exerts extensive and serious impact on human health, but so far, the potential effect of lipotoxicity on thyroid is unclear. OBJECTIVE: The objective of the study was to assess the association between serum triglyceride levels and the risk for SCH. DESIGN, PARTICIPANTS, AND METHODS: We conducted a population-based case-control study. A total of 24 100 subjects with similar and stable iodine nutrition status were recruited from China. Cases of 5033 SCH patients were identified and equal controls were matched by age, gender, and region. Conditional logistic regression was used to analyze the association between serum triglyceride levels and risk for SCH. RESULTS: Hypertriglyceridemia was associated with an approximately 35% increased risk for SCH in both men (odds ratio 1.325; 95% confidence interval 1.002-1.753) and women (odds ratio 1.397; 95% confidence interval 1.217-1.604), even after adjustment for potential confounders. Notably, the risk for SCH increased progressively following the elevation of serum triglyceride levels. Compared with individuals with serum triglyceride levels less than 0.97 mmol/L, the risk for SCH increased approximately 1.9-fold in men and 1.4-fold in women, respectively, when triglyceride levels were greater than 1.99 mmol/L. CONCLUSION: Our findings suggested that hypertriglyceridemia was positively associated with the risk for SCH. PMID- 25742514 TI - Recovery of the incretin effect in type 2 diabetic patients after biliopancreatic diversion. AB - CONTEXT: Bariatric surgery often results in remission of the diabetic state in obese patients. Increased incretin effect seems to play an important role in the glycemic improvements after Roux-en-Y gastric bypass, but the impact of biliopancreatic diversion (BPD) remains unexplored. OBJECTIVE: The objective was to elucidate the effect of BPD on the incretin effect and its interplay with beta cell function and insulin sensitivity (IS) in obese subjects with type 2 diabetes (T2DM). DESIGN, SETTING AND PATIENTS: Twenty-three women were studied: a control group of 13 lean, normal glucose-tolerant women (lean NGT) studied once and 10 obese patients with T2DM studied before, 1 and 12 months after BPD. INTERVENTION: The ObeseT2DM group underwent BPD. MAIN OUTCOME MEASURES: The main outcome measure was the change in incretin effect as measured by the isoglycemic intravenous glucose infusion test. Secondary outcomes encompassed IS and beta cell function. RESULTS: At baseline, the incretin effect was lower in obese T2DM compared to lean NGT (P < .05). One month after BPD, the incretin effect was not changed, but at 12 months it reached the level of the lean NGT group (P > .05). IS improved (P < .05) 1 month after BPD and at 12 months it resembled the levels of the lean NGT group. Insulin secretory rate and beta-cell glucose sensitivity increased after BPD and achieved levels similar to lean NGT group 1 month after BPD and even higher levels at 12 months (P < .05). CONCLUSIONS: BPD has no acute impact on the reduced incretin effect, but 12 months after surgery the incretin effect normalizes alongside normalization of glucose control, IS and beta-cell function. PMID- 25742515 TI - Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine disrupting chemicals in the European Union. AB - CONTEXT: Epidemiological studies and animal models demonstrate that endocrine disrupting chemicals (EDCs) contribute to cognitive deficits and neurodevelopmental disabilities. OBJECTIVE: The objective was to estimate neurodevelopmental disability and associated costs that can be reasonably attributed to EDC exposure in the European Union. DESIGN: An expert panel applied a weight-of-evidence characterization adapted from the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and approximate burden of disease. Cost estimation as of 2010 utilized lifetime economic productivity estimates, lifetime cost estimates for autism spectrum disorder, and annual costs for attention deficit hyperactivity disorder. Setting, Patients and Participants, and Intervention: Cost estimation was carried out from a societal perspective, ie, including direct costs (eg, treatment costs) and indirect costs such as productivity loss. RESULTS: The panel identified a 70-100% probability that polybrominated diphenyl ether and organophosphate exposures contribute to IQ loss in the European population. Polybrominated diphenyl ether exposures were associated with 873,000 (sensitivity analysis, 148,000 to 2.02 million) lost IQ points and 3290 (sensitivity analysis, 3290 to 8080) cases of intellectual disability, at costs of ?9.59 billion (sensitivity analysis, ?1.58 billion to ?22.4 billion). Organophosphate exposures were associated with 13.0 million (sensitivity analysis, 4.24 million to 17.1 million) lost IQ points and 59 300 (sensitivity analysis, 16,500 to 84,400) cases of intellectual disability, at costs of ?146 billion (sensitivity analysis, ?46.8 billion to ?194 billion). Autism spectrum disorder causation by multiple EDCs was assigned a 20-39% probability, with 316 (sensitivity analysis, 126-631) attributable cases at a cost of ?199 million (sensitivity analysis, ?79.7 million to ?399 million). Attention-deficit hyperactivity disorder causation by multiple EDCs was assigned a 20-69% probability, with 19 300 to 31 200 attributable cases at a cost of ?1.21 billion to ?2.86 billion. CONCLUSIONS: EDC exposures in Europe contribute substantially to neurobehavioral deficits and disease, with a high probability of >?150 billion costs/year. These results emphasize the advantages of controlling EDC exposure. PMID- 25742516 TI - Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European union. AB - CONTEXT: Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. OBJECTIVE: The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). DESIGN: A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. RESULTS: Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of ?157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of ?109 billion that differed modestly from base case probability inputs. CONCLUSIONS: EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs. PMID- 25742517 TI - Male reproductive disorders, diseases, and costs of exposure to endocrine disrupting chemicals in the European Union. AB - INTRODUCTION: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618,000 additional assisted reproductive technology procedures, costing ?4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of ?130 million (sensitivity analysis, ?117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of ?848 million annually (sensitivity analysis, ?313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of ?7.96 billion. CONCLUSIONS: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly ?15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs. PMID- 25742518 TI - Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European Union. AB - CONTEXT: Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. OBJECTIVE: The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. DESIGN: An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. RESULTS: The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of ?24.6 million (sensitivity analysis: ?24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of ?835 million (sensitivity analysis: ?835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and ?15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with ?607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of ?1.54 billion. CONCLUSIONS: EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of >?18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures. PMID- 25742519 TI - An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome. AB - CONTEXT: Severe short stature can be caused by defects in numerous biological processes including defects in IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of short stature are associated with medical comorbidities including hypogonadism and microcephaly. OBJECTIVE: To identify an underlying genetic etiology in two siblings with severe short stature and gonadal failure. DESIGN: Clinical phenotyping, genetic analysis, complemented by in vitro functional studies of the candidate gene. SETTING: An academic pediatric endocrinology clinic. PATIENTS OR OTHER PARTICIPANTS: Two adult siblings (male patient [P1] and female patient 2 [P2]) presented with a history of severe postnatal growth failure (adult heights: P1, 6.8 SD score; P2, -4 SD score), microcephaly, primary gonadal failure, and early onset metabolic syndrome in late adolescence. In addition, P2 developed a malignant gastrointestinal stromal tumor at age 28. INTERVENTION(S): Single nucleotide polymorphism microarray and exome sequencing. RESULTS: Combined microarray analysis and whole exome sequencing of the two affected siblings and one unaffected sister identified a homozygous variant in XRCC4 as the probable candidate variant. Sanger sequencing and mRNA studies revealed a splice variant resulting in an in-frame deletion of 23 amino acids. Primary fibroblasts (P1) showed a DNA damage repair defect. CONCLUSIONS: In this study we have identified a novel pathogenic variant in XRCC4, a gene that plays a critical role in non homologous end-joining DNA repair. This finding expands the spectrum of DNA damage repair syndromes to include XRCC4 deficiency causing severe postnatal growth failure, microcephaly, gonadal failure, metabolic syndrome, and possibly tumor predisposition. PMID- 25742520 TI - In vivo tractography of fetal association fibers. AB - Association fibers connect different cortical areas within the same hemisphere and constitute an essential anatomical substrate for a diverse range of higher cognitive functions. So far a comprehensive description of the prenatal in vivo morphology of these functionally important pathways is lacking. In the present study, diffusion tensor imaging (DTI) and tractography were used to visualize major association fiber tracts and the fornix in utero in preselected non-motion degraded DTI datasets of 24 living unsedated fetuses between 20 and 34 gestational weeks (GW). The uncinate fasciculus and inferior fronto-occipital fasciculus were depicted as early as 20 GW, while in vivo 3D visualization of the inferior longitudinal fasciculus, cingulum and fornix was successful in older fetuses during the third trimester. Provided optimal scanning conditions, in utero DTI and tractography have the potential to provide a more accurate anatomical definition of developing neuronal networks in the human fetal brain. Knowledge about the normal prenatal 3D association tract morphology may serve as reference for their assessment in common developmental diseases. PMID- 25742521 TI - Synergetic use of neural precursor cells and self-assembling peptides in experimental cervical spinal cord injury. AB - Spinal cord injuries (SCI) cause serious neurological impairment and psychological, economic, and social consequences for patients and their families. Clinically, more than 50% of SCI affect the cervical spine. As a consequence of the primary injury, a cascade of secondary mechanisms including inflammation, apoptosis, and demyelination occur finally leading to tissue scarring and development of intramedullary cavities. Both represent physical and chemical barriers to cell transplantation, integration, and regeneration. Therefore, shaping the inhibitory environment and bridging cavities to create a supportive milieu for cell transplantation and regeneration is a promising therapeutic target. Here, a contusion/compression model of cervical SCI using an aneurysm clip is described. This model is more clinically relevant than other experimental models, since complete transection or ruptures of the cord are rare. Also in comparison to the weight drop model, which in particular damage the dorsum columns, circumferential compression of the spinal cord appears advantageous. Clip closing force and duration can be adjusted to achieve different injury severity. A ring spring facilitates precise calibration and constancy of clip force. Under physiological conditions, synthetic self-assembling peptides (SAP) self-assemble into nanofibers and thus, are appealing for application in SCI. They can be injected directly into the lesion minimizing damage to the cord. SAPs are biocompatible structures erecting scaffolds to bridge intramedullary cavities and thus, equip the damaged cord for regenerative treatments. K2(QL)6K2 (QL6) is a novel SAP introduced by Dong et al. In comparison to other peptides, QL6 self assembles into beta-sheets at neutral pH. 14 days after SCI, after the acute stage, SAPs are injected into the center of the lesion and neural precursor cells (NPC) are injected into adjacent dorsal columns. In order to support cell survival, transplantation is combined with continuous subdural administration of growth factors by osmotic micro pumps for 7 days. PMID- 25742522 TI - A Cost-Utility Analysis Comparing the Sartorius versus the Rectus Femoris Flap in the Treatment of the Infected Vascular Groin Graft Wound. AB - BACKGROUND: The purpose of this study was to examine the sartorius and rectus femoris flaps as reasonable coverage options for the infected vascular groin graft wound. The authors' goal was to perform a cost-utility analysis of the sartorius flap versus the rectus femoris flap in the treatment of an infected vascular groin graft. METHODS: Cost-utility methodology involved a literature review compiling outcomes for specific flap interventions, obtaining utility scores for complications to estimate quality-adjusted life-years, accruing costs using Diagnosis-Related Group and Current Procedural Terminology codes for each intervention, and developing a decision tree that could portray the more cost effective strategy. The authors also performed sensitivity analysis to check the robustness of their data. Szilyagi III and Samson III and IV grades of infected groin grafts were included in the study. RESULTS: Twenty-six studies were used pooling 296 patients (234 sartorius flaps and 62 rectus flaps). Decision tree analysis noted that the rectus femoris flap was the more cost-effective option. It was the dominant treatment option given that it was more clinically effective by an additional 0.30 quality- adjusted life-years, with the sartorius flap option costing an additional $2241.88. The sartorius flap had a 13.68 percent major complication rate versus an 8.6 percent major complication rate for the rectus femoris flap. One-way sensitivity analysis showed that the sartorius flap became a cost-effective option if its major complication rate was less than or equal to 8.89 percent. CONCLUSION: The rectus femoris flap in the treatment of the infected vascular groin graft is a cost-effective option compared with the sartorius flap. PMID- 25742523 TI - What Is the Optimum Timing of Postmastectomy Radiotherapy in Two-Stage Prosthetic Reconstruction: Radiation to the Tissue Expander or Permanent Implant? AB - BACKGROUND: Postmastectomy radiotherapy is increasingly common for patients with advanced breast cancer. The optimal timing and sequence of mastectomy, reconstruction, and radiotherapy remains unresolved for patients choosing immediate two-stage prosthetic reconstruction. METHODS: Long-term outcomes were compared for all patients with prosthetic-based reconstruction without radiation, radiation to the tissue expander, or to the permanent implant from 2003 to 2012 performed by the senior author (P.G.C.). Surgeon-evaluated outcomes included reconstructive failure, aesthetic results, and capsular contracture. Odds of failure with radiotherapy at different times were evaluated with logistic regression and Kaplan-Meier analysis. Patient-reported outcomes were assessed using the BREAST-Q. RESULTS: A total of 1486 reconstructions without radiation, 94 reconstructions with tissue expander radiation, and 210 reconstructions with permanent implant radiation were included. Six-year predicted failure rates were greater for patients with tissue expander radiation than for patients with permanent implant radiation (32 percent versus 16.4 percent; p < 0.01). Patients undergoing radiation to the tissue expander had a greater proportion of very good to excellent aesthetic results compared to patients with permanent implant radiation (75.0 percent versus 67.6 percent; p < 0.01) and lower rates of grade IV capsular contracture (p < 0.01). BREAST-Q scores were similar for patients with the different radiation timings. CONCLUSIONS: Although the risk of reconstructive failure is significantly higher for patients with tissue expander radiation compared to patients with permanent implant radiation, the aesthetic results and capsular contracture rates are slightly better. Patient reported outcomes do not differ between patients with tissue expander or permanent implant radiation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25742524 TI - Distinct features in Koreans with involutional blepharoptosis. AB - BACKGROUND: The authors intended to present the distinct characteristics in Korean patients with involutional ptosis that deviate from typically defined features. METHODS: This is a prospective observational study of 162 Korean patients with involutional ptosis. The patients underwent levator aponeurosis advancement surgery from January of 2006 to June of 2013. Patient characteristics including eyelid crease, palpebral fissure width, levator function, and the shape and condition of the levator muscle and aponeurosis were assessed. RESULTS: Of 279 total eyes in 162 patients, high eyelid crease and levator aponeurosis disinsertion from the tarsal plate were observed in 19.7 percent and 13 percent of the eyes, respectively. Moderate to severe fat tissue infiltration on the levator muscle was noted in 90.6 percent of the eyes. Patients were older (p = 0.002) and the eyelid drooping was more severe (p < 0.001) in cases with more fat infiltration. Levator function was inversely proportional to the degree of fat tissue infiltration (p = 0.037). CONCLUSION: Slightly decreased levator function, infrequent high eyelid crease occurrence, thick and puffy eyelids, low incidence of levator aponeurosis disinsertion from the tarsal plate, and prominent fatty infiltration on the levator muscle are distinct and unique characteristics of involutional ptosis in Korean patients. PMID- 25742525 TI - Innervated Reverse Digital Artery Island Flap through Bilateral Neurorrhaphy using Direct Small Branches of the Proper Digital Nerve. AB - BACKGROUND: The reverse digital artery flap uses the radial or ulnar surface of the proximal phalanx of the involved digit and has been applied to sensate flaps using the superficial sensory nerve branch and the dorsal branch of the proper digital nerve. As these nerve branches innervate the dorsal surface of the finger, however, hypesthesia of the dorsal side of the middle phalanx is inevitable. METHODS: Thirty fingers of 25 patients who had the innervated reverse digital artery flap using direct small branches of the proper digital nerve were included in this study. The minimum follow-up duration was 24 months, and the average defect size was 2.8 cm(2). RESULTS: In all cases, the pulp defects were successfully reconstructed with this flap. The average size of the donor flap was 3.9 cm(2). At 6 months after surgery, the average static two-point discrimination value was 5.9 mm, the average moving two-point discrimination value was 5.0 mm, and the average Semmes-Weinstein monofilament score was 3.79. At 1 year postoperatively, the average Cold Intolerance Severity Score was 20. The percentage total active motion was measured at 99 percent 2 years after surgery. CONCLUSIONS: Because this flap does not sacrifice the proper digital nerve or dorsal branch of the nerve, the sensibility of the dorsal aspect of the proximal and middle phalanx can be preserved. This flap is cosmetically excellent, as it uses a donor flap similar to the injured fingertip and the donor scar can be hidden by adjacent fingers. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25742526 TI - Reply: simplifying the management of caudal septal deviation in rhinoplasty. PMID- 25742527 TI - An optogenetic approach for assessing formation of neuronal connections in a co culture system. AB - Here we describe a protocol to generate a co-culture consisting of 2 different neuronal populations. Induced pluripotent stem cells (iPSCs) are reprogrammed from human fibroblasts using episomal vectors. Colonies of iPSCs can be observed 30 days after initiation of fibroblast reprogramming. Pluripotent colonies are manually picked and grown in neural induction medium to permit differentiation into neural progenitor cells (NPCs). iPSCs rapidly convert into neuroepithelial cells within 1 week and retain the capability to self-renew when maintained at a high culture density. Primary mouse NPCs are differentiated into astrocytes by exposure to a serum-containing medium for 7 days and form a monolayer upon which embryonic day 18 (E18) rat cortical neurons (transfected with channelrhodopsin-2 (ChR2)) are added. Human NPCs tagged with the fluorescent protein, tandem dimer Tomato (tdTomato), are then seeded onto the astrocyte/cortical neuron culture the following day and allowed to differentiate for 28 to 35 days. We demonstrate that this system forms synaptic connections between iPSC-derived neurons and cortical neurons, evident from an increase in the frequency of synaptic currents upon photostimulation of the cortical neurons. This co-culture system provides a novel platform for evaluating the ability of iPSC-derived neurons to create synaptic connections with other neuronal populations. PMID- 25742528 TI - Association of worksite wellness center attendance with weight loss and health care cost savings: Mayo Clinic's experience. AB - OBJECTIVE: To assess the impact of wellness center attendance on weight loss and costs. METHODS: A retrospective analysis was conducted using employee data, administrative claims, and electronic health records. A total of 3199 employees enrolled for 4 years (2007 to 2010) were included. Attendance was categorized as follows: 1 to 60, 61 to 180, 181 to 360, and more than 360 visits. Weight loss was defined as moving to a lower body mass index category. Total costs included paid amounts for both medical and pharmacy services. RESULTS: Subjects with 181 to 360 and more than 360 visits were 46% (P = 0.05) and 72% (P = 0.01) more likely to have body mass index improvement compared with those with 1 to 60 visits. Compared with the mean annual cost of $13,267 for 1 to 60 visits, the mean for subjects with 61 to 180, 181 to 360, and more than 360 visits had significantly lower costs at $9538, $9332 and $8293, respectively (all P < 0.01). Higher attendance was associated with weight loss and significantly lower annual costs. PMID- 25742529 TI - Workplace exercise and educational program for improving fitness outcomes related to health in workers: a randomized controlled trial. AB - OBJECTIVE: To investigate the effects of a workplace fitness and education program intervention on physical fitness of workers. METHODS: Employees from a chemical plant (n = 60) participated in a 4-month longitudinal study. They were randomly distributed in control and experimental groups. The experimental group had 4 months of exercise training in 15-minute sessions. The following evaluations were performed before and after the training period: body composition, localized muscle strength, and flexibility. RESULTS: The experimental group showed a significant decrease in body fat (24.7%) and a significant increase in lean mass (6.1%), flexibility (17.9%), sit-up test performance (39.8%), and push-up test performance (29.8%) after the workplace fitness and education program compared with initial values. CONCLUSIONS: A structured program of physical exercise was effective in improving body composition, abdominal strength, upper limb strength, and flexibility in workers. PMID- 25742530 TI - Job satisfaction in the European union: the role of macroeconomic, personal, and job-related factors. AB - BACKGROUND: Job satisfaction is influenced by many factors. Most of them are attributed to personality or company features. Little research has been conducted identifying the relationship of job satisfaction with macroeconomic parameters. METHODS: We used data collected by European Commission (Eurostat, Eurofound) and World Health Organization (WHO) for personal (eg, subjective health, physical activity), company (eg, career advancement perspectives, negative health effects of work), or macroeconomic parameters (eg, Gross Domestic Product, unemployment rate) on state level. Correlation analysis and a stepwise linear regression model were obtained. RESULTS: Gross domestic product (GDP) was the best predictor for job satisfaction across the European Union member states ahead of good career perspectives, and WHO-5 score (depressive symptoms). CONCLUSIONS: Beside personal, job-related, and organizational factors that influence job satisfaction, the macroeconomic perspective has to be considered, too. PMID- 25742531 TI - Changes implemented during a workplace psychosocial intervention and their consistency with intervention priorities. AB - OBJECTIVES: To describe the changes implemented as part of a workplace psychosocial intervention. METHODS: The intervention was conducted in a public organization employing 1630 white-collar workers. The intervention was defined as all changes implemented to reduce adverse psychosocial work factors. A logbook was held to describe the changes implemented in the intervention group and in a comparable control group (N = 1282). RESULTS: Social support and reward were the psychosocial factors most targeted (41% to 83%). In comparison with the control group, the intervention group implemented four times more major changes and implemented changes, improving the employees' workload. CONCLUSIONS: Changes mainly targeted social support and reward. The intervention group implemented four times more major changes than the control group. The intervention group implemented changes targeting the workload, whereas no such changes were implemented in the control group. PMID- 25742532 TI - Psychosocial factors at work and occupational injury: results from the French national SUMER survey. AB - OBJECTIVE: This study aims at exploring the associations between psychosocial work factors and occupational injury. METHODS: The study was based on 46,962 employees of the French national representative survey SUMER 2010. The associations between psychosocial work factors and occupational injury/absence duration for injury within the last year were studied using weighted logistic and negative binomial regression models adjusted for covariates. RESULTS: Verbal abuse and low predictability for both sexes, psychological demands for women and low reward, physical violence, and bullying for men were associated with occupational injury. Low decision latitude and psychological demands for women were associated with absence duration for injury. CONCLUSIONS: Some psychosocial work factors may play a role in occurrences of occupational injury, but the role is unclear in relation to absence duration for injury. PMID- 25742533 TI - Stages of weight change among an occupational cohort. AB - OBJECTIVE: To assess the readiness to change dietary intake and body weight among production workers. We also ascertained differences between self-perceived and measured body mass index. METHODS: This cross-sectional study queried physical activity, psychosocial factors, fruit and vegetable intake, and readiness to change based on the transtheoretical model. RESULTS: Sixty-three (28%) workers were overweight, and 114 (50%) were obese. Obese workers were in the following stages of weight change: precontemplation (4%), contemplation (45%), preparation (13%), action (21%), and (17%) maintenance. Ten percent of overweight workers erroneously reported their body mass index to be normal. CONCLUSIONS: About half of overweight/obese workers were in the precontemplation or contemplation stages for healthy dietary changes or weight loss. Recognizing the stages of change with regard to weight and the self-perception of weight status may help tailor workplace health promotion programs. PMID- 25742534 TI - Demographic trends of sick leave absenteeism among civil service employees at a federal agency from 2004 to 2012. AB - OBJECTIVE: To investigate the associations between demographic variables and sick leave use. METHODS: We analyzed sick leave use among civil servants at a federal agency (FA) from 2004 to 2012 by demographic and FA-specific variables. We used a mixed methods approach and type III analysis to build a descriptive model of sick leave proportions and demographic variables. RESULTS: Sick absenteeism usage varied significantly (variation of greater than one sick day per year) by sex, Emergency Operations Center response tier, length of service at the FA, age, and general schedule pay grade level. Our final descriptive model contained age, sex, response tier and an interaction term between age and sex. CONCLUSIONS: Future studies should examine these associations on smaller time scales, perhaps breaking the data down by month or day of the week. PMID- 25742535 TI - Improving employee health: evaluation of a worksite lifestyle change program to decrease risk factors for diabetes and cardiovascular disease. AB - OBJECTIVE: To determine whether an evidence-based, behavioral lifestyle intervention program delivered at a worksite setting is effective in improving type 2 diabetes and cardiovascular disease risk factors. METHODS: A randomized 6 month delayed control design was utilized, with two thirds of the participants assigned to begin intervention immediately, and one third beginning 6 months later. The year-long program (weekly for 3 months transitioning to monthly) focused on weight loss and increasing physical activity. RESULTS: The immediate intervention group had greater mean weight loss (-10.4 lb, 5.1%, vs -2.3 lb, 1%; P = 0.0001) than the delayed control group at 6 months and relatively greater improvements in activity, HbA1c, and other risk factors. The delayed group experienced similar improvements after completing the intervention program. CONCLUSIONS: A worksite behavioral lifestyle intervention is feasible and effective in significantly improving risk factors for type 2 diabetes and cardiovascular disease. PMID- 25742536 TI - Work and health among Latina mothers in farmworker families. AB - BACKGROUND: Work organization is important for the health of vulnerable workers, particularly women. This analysis describes work organization for Latinas in farmworker families and delineates the associations of work organization with health indicators. METHODS: Up to 220 Latina women in farmworker families completed interviews from October 2012 to July 2013. Interviews addressed job structure, job demand, job control, and job support. Health measures included stress, depressive symptoms, physical activity, family conflict, and family economic security. RESULTS: Three fifths of the women were employed. Several work organization dimensions, including shift, psychological demand, work safety climate, and benefits, were associated with participant health as expected, on the basis of the work organization and job demands-control-support models. CONCLUSIONS: Research should address women's health and specific work responsibilities. Occupational safety policy must consider the importance of work organization in the health of vulnerable workers. PMID- 25742537 TI - Occupational UV exposure in French outdoor workers. AB - OBJECTIVES: Occupational ultraviolet (UV) exposure was evaluated in a population based sample in France. METHODS: A random survey was conducted in 2012 in individuals aged 25 to 69 years. The median daily standard erythemal UV dose (SED) was estimated from exposure time and place and matched to satellite UV records. RESULTS: A total of 889 individuals were exposed to solar UV with highest doses observed among gardeners (1.19 SED), construction workers (1.13 SED), agricultural workers (0.95 SED), and culture/art/social science workers (0.92 SED). Information and communication technology, industry, and transport workers were highly exposed (>0.70 SED). Significant factors associated with high occupational UV exposure were sex (P < 0.0001), phototype (P = 0.0003), and taking lunch outdoors (P < 0.0001). CONCLUSIONS: This study identified not only expected occupations with high UV exposure but also unexpected occupations with high exposures. This could serve as a basis for future prevention. PMID- 25742538 TI - The association between physical activity, sitting time, sleep duration, and sleep quality as correlates of presenteeism. AB - OBJECTIVE: This study aims to examine the relationship of lifestyle behaviors (physical activity, work and non-work sitting time, sleep quality, and sleep duration) with presenteeism while controlling for sociodemographics, work- and health-related variables. METHODS: Data were collected from 710 workers (aged 20 to 76 years; 47.9% women) from randomly selected Australian adults who completed an online survey. Linear regression was used to examine the relationship between lifestyle behaviors and presenteeism. RESULTS: Poorer sleep quality (standardized regression coefficients [B] = 0.112; P < 0.05), suboptimal duration (B = 0.081; P < 0.05), and lower work sitting time (B = -0.086; P < 0.05) were significantly associated with higher presenteeism when controlling for all lifestyle behaviors. Engaging in three risky lifestyle behaviors was associated with higher presenteeism (B = 0.150; P < 0.01) compared with engaging in none or one. CONCLUSIONS: The results of this study highlight the importance of sleep behaviors for presenteeism and call for behavioral interventions that simultaneously address sleep in conjunction with other activity-related behaviors. PMID- 25742542 TI - Genetic screening in the workplace. PMID- 25742539 TI - Guidance to employers on integrating e-cigarettes/electronic nicotine delivery systems into tobacco worksite policy. AB - In recent years, new products have entered the marketplace that complicate decisions about tobacco control policies and prevention in the workplace. These products, called electronic cigarettes (e-cigarettes) or electronic nicotine delivery systems, most often deliver nicotine as an aerosol for inhalation, without combustion of tobacco. This new mode of nicotine delivery raises several questions about the safety of the product for the user, the effects of secondhand exposure, how the public use of these products should be handled within tobacco free and smoke-free air policies, and how their use affects tobacco cessation programs, wellness incentives, and other initiatives to prevent and control tobacco use. In this article, we provide a background on e-cigarettes and then outline key policy recommendations for employers on how the use of these new devices should be managed within worksite tobacco prevention programs and control policies. PMID- 25742543 TI - Certified medical examiners and screening for obstructive sleep apnea. PMID- 25742544 TI - What are some of the features of worksite wellness interventions in the United States? AB - The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney. PMID- 25742546 TI - Saphenous Vein Graft Wrapping by Nitinol Mesh: A Word of Caution. PMID- 25742545 TI - Rapid genotyping of animals followed by establishing primary cultures of brain neurons. AB - High-resolution analysis of the morphology and function of mammalian neurons often requires the genotyping of individual animals followed by the analysis of primary cultures of neurons. We describe a set of procedures for: labeling newborn mice to be genotyped, rapid genotyping, and establishing low-density cultures of brain neurons from these mice. Individual mice are labeled by tattooing, which allows for long-term identification lasting into adulthood. Genotyping by the described protocol is fast and efficient, and allows for automated extraction of nucleic acid with good reliability. This is useful under circumstances where sufficient time for conventional genotyping is not available, e.g., in mice that suffer from neonatal lethality. Primary neuronal cultures are generated at low density, which enables imaging experiments at high spatial resolution. This culture method requires the preparation of glial feeder layers prior to neuronal plating. The protocol is applied in its entirety to a mouse model of the movement disorder DYT1 dystonia (DeltaE-torsinA knock-in mice), and neuronal cultures are prepared from the hippocampus, cerebral cortex and striatum of these mice. This protocol can be applied to mice with other genetic mutations, as well as to animals of other species. Furthermore, individual components of the protocol can be used for isolated sub-projects. Thus this protocol will have wide applications, not only in neuroscience but also in other fields of biological and medical sciences. PMID- 25742547 TI - Isolated Tricuspid Valve Surgery: A Single Institutional Experience with the Technique of Minimally Invasive Surgery via Right Minithoracotomy. AB - Background Minimally invasive cardiac surgery via right lateral minithoracotomy is a well-described approach. However, reports on isolated tricuspid valve surgery (TVS) in this technique are rare. Therefore, we like to give a contribution by reporting our experience. Methods We retrospectively reviewed 25 tricuspid valve operations via right lateral minithoracotomy with femoral cannulation between August 2009 and September 2013 (18 repairs, 7 replacements, and 72% repair rate). Three patients (12%) presented for a re-do operation, and nine patients (36%) suffered from active endocarditis at admission. All patients underwent TVS as single valve procedure. Ten patients received additional procedures such as removal of infected leads, resection of atrial tumors, or closure of atrial septal defects. An annuloplasty ring was inserted in 12 cases. We investigated the short-term morbidity and mortality with regard to the surgical procedure. Results Repair rate was 72%. Thirty-day and 1-year mortality were 4 and 20%, respectively. The only patient with early mortality received the surgical procedure on the tricuspid valve as fourth cardiac-related surgery and postoperative mortality was due to intracranial air embolism. Perioperative morbidity included reoperation for bleeding (8%) and stroke (4%). No disturbance of wound healing occurred. Durations of intensive care unit stay and hospital stay were 2.3 +/- 2.4 and 17.4 +/- 13.1 days, respectively. Endocarditis-caused surgery did not reveal any significant difference in the intra- or perioperative course compared with other indications. Conclusion Minimally invasive TVS via right lateral minithoracotomy is feasible with good results. Even in a cohort of patients suffering from elevated rate of active endocarditis, a high repair rate can be achieved. PMID- 25742548 TI - Extracorporeal Life Support in "Awake" Patients as a Bridge to Lung Transplant. AB - BACKGROUND: Traditionally, patients on extracorporeal membrane oxygenation (ECMO) are sedated and mechanically ventilated, which increases risk of complications related to immobility and mechanical ventilation. The purpose of this study was to assess the feasibility and highlight the benefits of a bridge to lung transplant (LTx) using "awake ECMO" support. METHODS: The peripheral venovenous or venoarterial ECMO was implanted at a bedside. A retrospective study of patients undergoing LTx between January 2007 and March 2013 was performed. Outcomes in patients supported on ECMO as a bridge to LTx and kept "awake" (Group 1) were compared with the rest of the LTx patients (Group 2). RESULTS: In this period, 249 LTx were performed and in them 7 patients were bridged to LTx using "awake ECMO" strategy. Two patients were awake at ECMO implantation and throughout the therapy, and two patients were on ventilator support at the time of ECMO implantation who were extubated later and maintained awake until LTx. The remaining three patients were awake for some time during the ECMO. There was no statistically significant difference in most donor characteristics and recipient baseline characteristics as well as post-LTx parameters between the two groups. One-year survival estimate was not different between the groups: Group 1, 85.7% vs. Group 2, 86.3% (log rank p = 0.99). CONCLUSION: In end-stage lung disease, the ECMO can be commenced in "awake" patients and patients can be awakened on ECMO. The "awake ECMO" strategy may avoid complications related to mechanical ventilation, sedation, and immobilization and provide comparable outcomes in the high-risk LTx patients. PMID- 25742549 TI - Use of del Nido Cardioplegia in Adult Cardiac Surgery. AB - Background: del Nido cardioplegia was developed to protect pediatric hearts, and similar to pediatric hearts, older adult hearts tolerate ischemia-reperfusion poorly. This study investigates the feasibility of del Nido cardioplegia as an alternative to conventional Buckberg cardioplegia in adult cardiac surgery. METHODS: A total of 142 adult patients undergoing cardiopulmonary bypass with del Nido cardioplegia and conventional Buckberg cardioplegia were retrospectively reviewed. RESULTS: Fewer doses of cardioplegia and fewer defibrillations were noted with del Nido cardioplegia, and there were no significant differences in incidence of postoperative events. CONCLUSION: del Nido cardioplegia may be a feasible alternative to conventional Buckberg cardioplegia. PMID- 25742550 TI - The midterm results of radiofrequency ablation and vagal denervation in the surgical treatment of long-standing atrial fibrillation associated with rheumatic heart disease. AB - BACKGROUND: Though maze III procedure is an effective surgical treatment for atrial fibrillation (AF), the complexity and complications prevent its widespread application. Radiofrequency ablation (RA) has become an accepted therapy, but its chronic effects are still unclear. This retrospective clinical study describes our experience of RA and vagal denervation (VD) in surgical treatment of long standing AF associated with rheumatic heart disease (RHD) during a 5-year follow up. METHODS: Between June 2006 and December 2007, a total of 173 consecutive patients with long-standing AF-associated RHD underwent mitral valve replacement and ablation maze procedure. In total, 92 cases had RA alone and 81 had RA + VD. Patients were followed up with clinical examination and electrocardiography, and the data were analyzed by multivariable analysis with Cox hazard model. RESULTS: The average follow-up time was 5.0 +/- 0.6 years. Multivariable analysis with Cox hazard model revealed that the duration of AF, the size of the left atrium, and tricuspid regurgitation are risk factors for AF recurrence. In addition, long standing AF >= 7 years, left atrium diameter >= 58 mm, and severe tricuspid regurgitation may increase the risk of AF recurrence by 2.16-, 2.37-, and 2.67 fold, respectively. Although the freedom from AF during 2 to 5 postoperative years in the RA and RA + VD groups were similar, the percentage of antiarrhythmic drug therapy was higher in the RA group during the early postoperative period (4th month, 54.1 vs. 34.7%, p = 0.017; 5th month, 39.2 vs. 21.3%, p = 0.018; 6th month, 23.0 vs. 10.7%, p = 0.044). Furthermore, the percentage of those free from AF was lower during the 1st year (6th month, 82.2 vs 93.8%, p = 0.023; 1st year, 76.1 vs. 89.9%, p = 0.019). CONCLUSION: RA is effective for the surgical treatment of long-standing AF associated with rheumatic valve disease. Though vagal denervation helped to maintain a stable sinus rhythm at an early stage, there was no additional benefit after the 1st year of follow-up. PMID- 25742551 TI - Painful Chest Wall Swellings: Tietze Syndrome or Chest Wall Tumor? AB - BACKGROUND: Tietze syndrome (TS) is an inflammatory condition characterized by chest pain and swelling of costochondral junction. Primary chest wall tumors may mimic TS. In this article, we report our experience of approximately 121 patients initially diagnosed as TS and determined chest wall tumor in some cases at the follow-up. METHODS: This is a retrospective review of patients diagnosed as TS by clinical examination, chest X-ray, electrocardiogram, routine laboratory tests, and computed tomography (CT) of chest: all treated and followed up between March 2001 and July 2012. There were 121 cases (41 males and 80 females; mean age, 39.6 +/- 3.2 years) of TS. RESULTS: In 27 patients with initial normal radiological findings, the size of swellings had doubled during the follow-up period (mean, 8.51 +/- 2.15 months). These patients were reevaluated with chest CT and bone scintigraphy and then early diagnostic biopsy was performed. Pathologic examination revealed primary chest wall tumor in 13 patients (5 malignant, 8 benign). CT had a sensitivity of 92.3% and a specificity of 64.2% in detection of tumors (kappa: 0.56, p = 0.002), whereas the sensitivity and the specificity of bone scan were 84.6 and 35.7%, respectively (kappa: 0.199, p = 0.385). CONCLUSION: Primary chest wall tumors could mimic TS. Bone scintigraphy or CT is not specific enough to determine malignant and other benign disorders of costochondral junction. Therefore, clinicians should follow TS patients more closely, and in case of increasing size of swelling, early diagnostic biopsy should be considered. PMID- 25742552 TI - Survival following Pulmonary Metastasectomy for Sarcoma. AB - OBJECTIVES: The aim of this study is to report the overall survival after pulmonary metastasectomy in patients with metastatic sarcoma and prognostic factors for survival. METHODS: This is a retrospective observational study of consecutive patients having pulmonary metastasectomy for sarcoma over a 5-year period. Survival was calculated by Kaplan-Meier method. RESULTS: Between August 2007 and January 2014, a total of 80 pulmonary metastasectomies were performed on 66 patients with metastatic sarcoma. There were no postoperative in-hospital deaths. The median age was 51 years (range, 16-79) and 39 (59%) patients were male. Fourteen patients had bilateral lung operations and surgical access was by video-assisted thoracoscopic surgery in 48 (73%) cases. The median number of metastases resected was 3 (range, 1-9). The median disease-free interval was 25 months (range, 0-156). Median overall survival was 25.5 months (range, 1-60). At follow-up, 19 patients (29%) were dead with a median follow-up of 31 months (range, 1-60). Recurrence of metastases significantly affected survival: median of 25.5 months (95% confidence interval [CI], 17.7-33.4) versus 48.4 months (95% CI, 42.5-54.4) in patients with no recurrent metastases (p = 0.004). There was no significant difference in survival between patients with high-grade versus low grade tumors (p = 0.13), histological type (osteosarcoma vs. other soft tissue sarcoma types, p = 0.14), unilateral versus bilateral lung metastases (p = 0.48), or lung metastases alone versus lung and other sites of metastases (p = 0.5). CONCLUSION: In selected patients, pulmonary metastasectomy for sarcoma is safe and may confer a good medium-term survival. Recurrent metastasis after resection confers a poor prognosis. PMID- 25742554 TI - Mohs micrographic surgery for eccrine porocarcinoma: an update and review of the literature. AB - BACKGROUND: Eccrine porocarcinoma (EPC) is a rare malignancy of the eccrine sweat glands that is locally aggressive with a high propensity to metastasize. Most cases have been treated by wide local excision (WLE) with 20% local recurrence rate. There have been 20 cases of EPC treated with Mohs micrographic surgery (MMS) in the literature. OBJECTIVE: To review the literature regarding the management of this aggressive tumor using MMS. METHODS: A comprehensive literature review was conducted by searching the PubMed database using the keywords Mohs, porocarcinoma, malignant eccrine poroma, and eccrine neoplasms. RESULTS: Most of the reported cases of EPC were treated by WLE, and only 20 cases were treated with MMS. Of the 20 EPC cases treated with MMS, there was only 1 nodal recurrence and no local recurrence. Other reported treatment modalities include radiation and excision with frozen sections. The authors report the second case of EPC on the temple, and the 21st case successfully treated with MMS. CONCLUSION: Eccrine porocarcinoma is a rare neoplasm with potentially aggressive clinical behavior. In cases where tissue conservation is important, MMS should be considered. PMID- 25742553 TI - Bleeding and Thrombotic Events in Patients Undergoing Mechanical Circulatory Support: A Review of Literature. AB - Bleeding and thrombotic events are among the most common complications detected in patients with mechanical circulatory support (MCS). Herein, we reviewed the available evidence on the prevalence, etiology, and management of bleeding and thrombotic events in patients following MCS procedures, such as implantation of both intra- and paracorporeal devices that generate either pulsatile or nonpulsatile flow. Extracorporeal life support procedures providing support to the failing heart and lungs were also reviewed. Most bleeding and thromboembolic events occur despite appropriate hemostatic and anticoagulation management based on conventional coagulation laboratory parameters. Prevalence of bleeding events in this population ranges between 5 and 81%. Wide range in prevalence of bleeding reported in literature may be explained by different devices with different anticoagulation protocols being used, as well as different definitions of bleeding outcomes. Although bleeding events are more common than thromboembolic events, the consequences of thrombotic events are often detrimental. Management of bleeding events remains challenging and measures to prevent and treat bleeding events are often followed by thromboembolic events. Therefore, a personalized approach based on point-of-care hemostatic tests and adjusted to device type and patient comorbidities is therefore warranted. To provide advanced understanding of hemostatic disturbances during MCS, prospective trials focused on bleeding and thromboembolic events as primary endpoints should be conducted. Better understanding of the underlying pathophysiology and a shift towards a personalized approach based on functional point-of-care hemostatic properties assessment may provide more favorable clinical outcomes. This should, however, be coupled with further technological improvements providing better device surface hemocompatibility as interaction between blood and device surface affects the hemostatic equilibrium. PMID- 25742555 TI - Multicenter pivotal study of vacuum-assisted precise tissue release for the treatment of cellulite. AB - BACKGROUND: Cellulite refers to the dimpled appearance of skin occurring where the dermis is tethered by subcutaneous fibrous septa arranged perpendicularly to the skin surface. OBJECTIVE: To demonstrate the safety and efficacy of a new system for vacuum-assisted precise tissue release for the treatment of cellulite. MATERIALS AND METHODS: Adult women with moderate to severe cellulite (N = 55) underwent a single treatment. Post-treatment assessments were performed after 3 and 14 days; 1, 3, and 6 months; and at 1 year. Outcome measures included blinded assessments of subject photographs, a validated Cellulite Severity Scale (CSS), and the Global Aesthetic Improvement Scale. Subject satisfaction and pain ratings were also recorded. RESULTS: The mean baseline CSS score of 3.4 decreased to 1.3 at 3 months (p < .0001) and 1.4 at 1 year (p < .0001), with 47 subjects (93%) having >=1-point improvements. Subject satisfaction was 85% at 3 months and 94% at 1 year. Transient treatment-related adverse events were mild in severity. CONCLUSION: This study demonstrates the safety, efficacy, and subject satisfaction with vacuum-assisted precise tissue release in the treatment of cellulite. There was no reduction in treatment benefits for up to 1 year. These results supported the Food and Drug Administration clearance of the device for the long-term reduction in the appearance of cellulite. PMID- 25742556 TI - Can long-term alopecia occur after appropriate pulsed-dye laser therapy in hair bearing sites? Pediatric dermatologists weigh in. AB - BACKGROUND: The risk of long-term alopecia after pulsed-dye laser (PDL) therapy is unknown. To identify how many practitioners treat hair-bearing sites with PDL and how commonly long-term alopecia occurs, the authors queried pediatric dermatologists about their experiences using this modality. METHODS: A survey was designed to evaluate the frequency of and factors contributing to long-term alopecia after PDL treatment of port-wine stains (PWS). "Long-term" was defined as no sign of hair regrowth after several years of nontreatment. The survey was administered to attendees at the 2014 Society for Pediatric Dermatology biannual meeting. RESULTS: Sixty-four pediatric dermatologists completed the survey, 50 of whom had experience using PDL. Of these physicians, 86% have used PDL to treat PWS of the eyebrow and 80% have treated PWS of the scalp. Over one-quarter of respondents (25.5%) using PDL on hair-bearing areas had at least 1 of their patients develop long-term alopecia after PDL treatment. The incidence of long term alopecia after PDL treatment in the surveyed population was 1.5% to 2.6%. CONCLUSION: The occurrence of long-term alopecia at hair-bearing sites after treatment with PDL may be greater than previously thought. Because the majority of physicians using PDL treat hair-bearing areas, prospective studies are needed to more accurately determine the risk of long-term alopecia and the factors that contribute to it. PMID- 25742557 TI - Identification and management of mental health issues by dermatologic surgeons: a survey of American Society for Dermatologic Surgery members. AB - BACKGROUND: Dermatologists have long been interested in mental health issues of their patients. Some psychosocial distress likely motivates the pursuit of cosmetic dermatologic treatments. However, a percentage of patients seeking treatment suffer from significant psychopathology, such as body dysmorphic disorder (BDD), which may contraindicate treatment. OBJECTIVE: To assess dermatologic surgeons' strategies for identification and management of mental health issues among patients seeking cosmetic procedures. MATERIALS AND METHODS: A survey was sent to 2,855 practicing members of the American Society for Dermatologic Surgery by e-mail. RESULTS: Two hundred sixty members completed the survey (9.1%). Approximately, 60% of respondents indicated that they ask new patients about psychiatric treatment history, and 92% reported that they have declined to provide a cosmetic treatment because of concerns about mental health status. Most (94%) indicated that they were aware of BDD, and 62% indicated that they refused to treat a patient believed to have BDD. Respondents estimated that 13% of new patients had BDD and 63% considered BDD to be a contraindication to treatment. CONCLUSION: Approximately 60% of dermatologic surgeons inquire about the mental health issues of their cosmetic patients. Most are aware of BDD, but less than two-thirds consider it a contraindication to treatment. PMID- 25742558 TI - Optical coherence tomography for planning of follicular unit extraction. AB - BACKGROUND: As the subcutaneous course of the hair follicle cannot be extrapolated from the angle of hair emergence, the follicular unit extraction (FUE) method bears the risk of follicle transsection potentially affecting the success of the whole intervention. Histological examination can provide this angle information but are too time consuming and invasive to be integrated in the workflow. OBJECTIVE: In this work, the authors present an effective and noninvasive way to determine these subcutaneous follicle angles. METHODS AND MATERIALS: For this purpose, the authors use optical coherence tomography to provide images of the first 2 to 3 mm of the surface of the skin. RESULTS: On 3 probands, they scanned 2 regions. We computed the number of hair follicles in a certain angular region around a mean angle, representing an FUE tool, and found a considerable diversity of the angular deviations. CONCLUSION: As this angular distribution massively influences the transsection rate, the authors suggest such a method to be considered as a future improvement of preoperative assessment. PMID- 25742559 TI - A randomized, controlled clinical study to investigate the safety and efficacy of acoustic wave therapy in body contouring. AB - BACKGROUND: There is an increased demand for the reduction of localized adipose tissue by noninvasive methods. OBJECTIVE: The objective of this study was to determine the safety and efficacy of noninvasive lipolysis of excess adiposities overlying the lateral thigh region using acoustic wave therapy (AWT). This study incorporates 2 mechanical waves with varying properties in the same session: radial and planar AWT. METHODS AND MATERIALS: The treatment was performed using AWT on the lateral thigh areas of 15 female patients. The study was performed using the planar and radial pulse handpieces, with 8 sessions performed within 4 weeks. Follow-up visits were performed 1, 4, and 12 weeks after the last treatment. RESULTS: Reduction in both thigh circumference and subcutaneous fat layer thickness, measured through ultrasound, was observed. CONCLUSION: This study demonstrates that AWT is safe and efficacious for the treatment of localized adiposities in the saddlebag area. However, the results obtained were not statistically significant. Larger studies will be needed to further access the effects of AWT on thigh circumference reduction. Furthermore, the authors also found an improvement in the appearance of both cellulite and skin firmness after the treatments. PMID- 25742560 TI - Use of fractional CO2 laser decreases the risk of skin cancer development during ultraviolet exposure in hairless mice. AB - BACKGROUND: Nonmelanoma skin cancers are caused mainly by prolonged ultraviolet (UV) exposure. There is a growing interest in the prevention of skin cancer and antiaging treatment because of aging of the population. Currently, ablative fractional photothermolysis (FP) laser treatment is actively being performed for facial rejuvenation. OBJECTIVE: The objective of this study was to prove the suppressive effect of CO2 fractional laser (FL) on skin cancer development. MATERIALS AND METHODS: Two groups of hairless mice were treated with either CO2 FL or nothing at 3-week intervals during the 20 weeks of UV exposure period. The number of tumors was subsequently counted every 2 weeks over the 30-week period to the termination of the experiment. At 30 weeks, representative tumors were evaluated for tumor type. The authors also determined the messenger RNA (mRNA) expression levels of the matrix metalloproteinase 13 (MMP-13) and Type 1 procollagen. RESULTS: At 30 weeks, the UV- and FL-treated group showed a significantly lower tumor occurrence rate and a more benign progression of tumors than the UV-only treated group. The UV- and FL-treated group presented a higher mRNA level of Type 1 procollagen and a lower level of MMP-13 than the UV-only treated group. CONCLUSION: The occurrence of UV-induced skin tumors can be decreased by multiple sessions of ablative FP with CO2 laser. PMID- 25742561 TI - Important implications and new uses of ablative lasers in dermatology: fractional carbon dioxide laser prevention of skin cancer. PMID- 25742562 TI - Biodirected synthesis and nanostructural characterization of anisotropic gold nanoparticles. AB - Gold nanoparticles with anisotropic structures have tunable absorption properties and diverse bioapplications as image contrast agents, plasmonics, and therapeutic diagnostic materials. Amino acids with electrostatically charged side chains possess inner affinity for metal ions. Lysine (Lys) efficiently controlled the growing into star-shape nanoparticles with controlled narrow sizes (30-100 nm) and produced in high yields (85-95%). Anisotropic nanostructures showed tunable absorbance from UV to NIR range, with extraordinary colloidal stability (-26 to 42 mV) and surface-enhanced Raman scattering properties. Advanced electron microscopy characterization through ultra-high-resolution SEM, STEM, and HR-TEM confirmed the size, nanostructure, crystalline structure, and chemical composition. Molecular dynamics simulations revealed that Lys interacted preferentially with Au(I) through the -COOH group instead of their positive side chains with a binding free energy (BFE) of 3.4 kcal mol(-1). These highly monodisperse and colloidal stable anisotropic particles prepared with biocompatible compounds may be employed in biomedical applications. PMID- 25742563 TI - Evolution and phenotypic selection of cancer stem cells. AB - Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can change, and favorable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. We set out to investigate the emerging intratumoral heterogeneity and to determine the evolutionary trajectories of the combination of cell-intrinsic kinetics that yield aggressive tumor growth. We develop a cellular automaton model that tracks the temporal evolution of the malignant subpopulation of so-called cancer stem cells(CSC), as these cells are exclusively able to initiate and sustain tumors. We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of non-stem cancer cells(CC) that compete with CSC and thus inhibit CSC division while a reduction in proliferation potential loosens such inhibition and facilitates frequent CSC division. The sub-population of cancer stem cells in itself becomes highly heterogeneous dictating population level dynamics that vary from long-term dormancy to aggressive progression. Our study suggests that the clonal diversity that is captured in single tumor biopsy samples represents only a small proportion of the total number of phenotypes. PMID- 25742564 TI - Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. AB - Animal models have proven to be invaluable to researchers trying to answer questions regarding the mechanisms of behavior. The Open Field Maze is one of the most commonly used platforms to measure behaviors in animal models. It is a fast and relatively easy test that provides a variety of behavioral information ranging from general ambulatory ability to data regarding the emotionality of the subject animal. As it relates to rodent models, the procedure allows the study of different strains of mice or rats both laboratory bred and wild-captured. The technique also readily lends itself to the investigation of different pharmacological compounds for anxiolytic or anxiogenic effects. Here, a protocol for use of the open field maze to describe mouse behaviors is detailed and a simple analysis of general locomotor ability and anxiety-related emotional behaviors between two strains of C57BL/6 mice is performed. Briefly, using the described protocol we show Wild Type mice exhibited significantly less anxiety related behaviors than did age-matched Knock Out mice while both strains exhibited similar ambulatory ability. PMID- 25742565 TI - Correction: the exploration-exploitation dilemma: a multidisciplinary framework. PMID- 25742567 TI - Low estimated glomerular filtration rate is associated with high recurrence rate and poor prognosis of hemorrhage stroke. AB - This study investigated whether a low estimated glomerular filtration rate (eGFR) leads to a higher risk of stroke recurrence and a poor prognosis in hemorrhagic stroke patients. A total of 2000 stroke patients were recruited during 2000-2001 and prospectively followed up for a median of 4.5 years. The independent association of a low eGFR with stroke recurrence and poor prognosis was evaluated using Kaplan-Meier analysis and Cox regression models. Among the hemorrhagic stroke patients, the incidence rate of a low eGFR for the compound endpoints (stroke recurrence, myocardial infarction, and all-cause mortality) was greater than that of a normal eGFR (P=0.012). A similar result was observed for the incidence rate of recurrence and death caused by cardiovascular disease or stroke (Csdeath) (P=0.013, and P=0.001, respectively). After adjustment for age, sex, and other cardiovascular risk factors, a low eGFR was associated with a 2.93-fold increased risk of the compound endpoints (P=0.001, RR=2.93, 95% CI=1.58-5.43), 3.06-fold increased risk of recurrent stroke (P=0.003, RR=3.06, 95% CI=1.46 6.40), and 3.57-fold increased risk of Csdeath (P=0.005, RR=3.57, 95% CI=1.46 8.70) among hemorrhagic stroke patients. Among the hemorrhagic stroke patients, a low eGFR was a strong predictor of stroke recurrence and a poor prognosis. PMID- 25742568 TI - Cocaine dependence and stroke: pathogenesis and management. AB - Cocaine abuse remains a devastating medical problem for our society. Current concepts suggest that both hemorrhagic and ischemic stroke, particularly in young people, can result as a consequence of cocaine exposure. We provide an analysis of mechanisms of injury and a discussion of the pharmacological management of stroke following cocaine use. Preclinical research suggests that the cause of cocaine-mediated stroke is multifactorial and involves vasospasm, changes in cerebral vasculature, and platelet aggregation. We suggest that drugs able to induce vasospastic, thrombogenic, or neurotoxic effects of cocaine could be suitable as therapeutic agents. In contrast caution should be exerted when using anti-platelet and thrombolytic agents in cocaine users with stroke. PMID- 25742569 TI - Surgical treatment of microinvasive cervical cancer: analysis of pathologic features with implications on radicality. AB - OBJECTIVES: To evaluate pathologic features with implications on surgical radicality in women treated with radical hysterectomy and pelvic lymphadenectomy for cervical cancer stage IA1 with lymph vascular space invasion (LVSI) and stage IA2 by correlating findings in conization and hysterectomy specimens. METHODS: Women with cervical cancer stage IA1 with LVSI and stage IA2 diagnosed by loop electrosurgical excisional procedure or cold knife conization were treated with radical hysterectomy and pelvic lymphadenectomy from January 1999 to December 2011 in 2 institutions. RESULTS: Fifty patients were enrolled: 40 with stage IA2 and 10 with stage IA1 with LVSI. Median age was 43 (30-67) years. All patients underwent cervical conization for diagnosis (45 loop electrosurgical excisional procedure, 5 cold knife). Lymph vascular space invasion was detected in 15 patients (30%). Two patients had positive pelvic nodes. No parametrial involvement was detected in the entire cohort. Positive margins were present in 35 patients, and residual disease was detected in 22 patients (44%). Positive margins predicted residual disease at radical hysterectomy (P = 0.02). Medium follow-up time was 51 months. One patient developed a pelvic recurrence, and there were no disease-related deaths. CONCLUSIONS: Patients with positive margins in cone biopsy specimens have an increased risk of residual disease at radical hysterectomy and require careful evaluation before conservative surgery. Pelvic lymph node evaluation is essential because lymph node metastasis may occur even in early stages. The lack of parametrial invasion in this study reinforces the knowledge that the select group of patients with microinvasive cervical carcinoma stages IA1 LVSI and stage IA2 have a very low risk of parametrial infiltration. Less radical surgery can be carefully considered for these patients. PMID- 25742571 TI - Removal of arsenic from aqueous solutions using waste iron columns inoculated with iron bacteria. AB - Arsenic contamination of water resources is one of the serious risks threatening natural ecosystems and human health. This study investigates arsenic removal using a waste iron column with and without iron bacteria in continuous and batch phases. In batch experiments, the effects of pH, contact time, initial concentration of arsenic and adsorbent dose were investigated. Results indicated that the highest arsenate removal efficiency occurred at pH 7 (96.76%). On increasing the amount of waste iron from 0.25 to 1 g, the removal rate changed from about 42.37%-96.70%. The results of continuous experiments on the column containing waste iron showed that as the empty bed contact time increased from 5 to 60 min, the secondary arsenate concentration changed from 23 to 6 ug/l. In experiments involving a waste iron column with iron bacteria, an increase in residence time from 5 to 60 min decreased the secondary arsenate concentration from 14.97 to 4.86 ug/l. The results of this study showed that waste iron containing iron bacteria is a good adsorbent for removal of arsenic from contaminated water. PMID- 25742566 TI - Programming apoptosis and autophagy with novel approaches for diabetes mellitus. AB - According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe. PMID- 25742570 TI - Dorsal root ganglia neurons and differentiated adipose-derived stem cells: an in vitro co-culture model to study peripheral nerve regeneration. AB - Dorsal root ganglia (DRG) neurons, located in the intervertebral foramina of the spinal column, can be used to create an in vitro system facilitating the study of nerve regeneration and myelination. The glial cells of the peripheral nervous system, Schwann cells (SC), are key facilitators of these processes; it is therefore crucial that the interactions of these cellular components are studied together. Direct contact between DRG neurons and glial cells provides additional stimuli sensed by specific membrane receptors, further improving the neuronal response. SC release growth factors and proteins in the culture medium, which enhance neuron survival and stimulate neurite sprouting and extension. However, SC require long proliferation time to be used for tissue engineering applications and the sacrifice of an healthy nerve for their sourcing. Adipose-derived stem cells (ASC) differentiated into SC phenotype are a valid alternative to SC for the set-up of a co-culture model with DRG neurons to study nerve regeneration. The present work presents a detailed and reproducible step-by-step protocol to harvest both DRG neurons and ASC from adult rats; to differentiate ASC towards a SC phenotype; and combines the two cell types in a direct co-culture system to investigate the interplay between neurons and SC in the peripheral nervous system. This tool has great potential in the optimization of tissue-engineered constructs for peripheral nerve repair. PMID- 25742572 TI - Mesial temporal lobe epilepsy: an old and yet not entirely unfold story. PMID- 25742573 TI - Neurological examination: history, problems and facts in the 21st century. PMID- 25742575 TI - Etiological prevalence of epilepsy and epileptic seizures in hospitalized elderly in a Brazilian tertiary center - Salvador - Brazil. AB - Epilepsy in the elderly has high incidence and prevalence and is often underecognized. OBJECTIVE: To describe etiological prevalence of epilepsy and epileptic seizures in elderly inpatients. METHODS: Retrospective analysis was performed on elderly patients who had epilepsy or epileptic seizures during hospitalization, from January 2009 to December 2010. One hundred and twenty patients were enrolled. They were divided into two age subgroups (median 75 years) with the purpose to compare etiologies. RESULTS: The most common etiology was ischemic stroke (36.7%), followed by neoplasias (13.3%), hemorrhagic stroke (11.7%), dementias (11.4%) and metabolic disturbances (5.5%). The analysis of etiological association showed that ischemic stroke was predominant in the younger subgroup (45% vs 30%), and dementias in the older one (18.9% vs 3.8%), but with no statistical significance (p = 0.23). CONCLUSION: This study suggests that epilepsy and epileptic seizures in the elderly inpatients have etiological association with stroke, neoplasias and dementias. PMID- 25742574 TI - Patterns of seizure control in patients with mesial temporal lobe epilepsy with and without hippocampus sclerosis. AB - OBJECTIVE: Patients with mesial temporal lobe epilepsy (MTLE) may present unstable pattern of seizures. We aimed to evaluate the occurrence of relapse remitting seizures in MTLE with (MTLE-HS) and without (MTLE-NL) hippocampal sclerosis. METHOD: We evaluated 172 patients with MTLE-HS (122) or MTLE-NL (50). Relapse-remitting pattern was defined as periods longer than two years of seizure freedom intercalated with seizure recurrence. "Infrequent seizures" was considered as up to three seizures per year and "frequent seizures" as any period of seizures higher than that. RESULTS: Thirty-seven (30%) MTLE-HS and 18 (36%) MTLE-NL patients had relapse-remitting pattern (X2, p = 0.470). This was more common in those with infrequent seizures (X2, p < 0.001). Twelve MTLE-HS and one MTLE-NL patients had prolonged seizure remission between the first and second decade of life (X2, p = 0.06). CONCLUSION: Similar proportion of MTLE-HS or MTLE NL patients present relapse-remitting seizures and this occurs more often in those with infrequent seizures. PMID- 25742576 TI - Evaluation of the effects of group psychotherapy on cognitive function in patients with multiple sclerosis with cognitive dysfunction and depression. AB - OBJECTIVE: This study will evaluate how decreasing depression severity via group psychotherapy affects the cognitive function of patients with multiple sclerosis (MS) who are also diagnosed with depression and cognitive dysfunction. METHOD: MS patients completed the Brief Repeatable Battery of Neuropsychological Tests and Beck Depression Inventory (BDI). The group members diagnosed with depression and cognitive dysfunction underwent group psychotherapy for 3 months. Upon completion of psychotherapy, both tests were readministered. RESULTS: Depression and cognitive dysfunction were comorbid in 15 (13.9%) of patients. Although improvement was detected at the end of the 3-month group psychotherapy intervention, it was limited to the BDI and the Paced Auditory Test. CONCLUSION: Group psychotherapy might decrease cognitive impairment in MS patients. PMID- 25742577 TI - Clinical and neuropsychological assessment of attention and ADHD comorbidity in a sample of children and adolescents with idiopathic epilepsy. AB - Children with epilepsy present significant problems concerning attention and comorbidity with attention deficit hyperactivity disorder (ADHD). OBJECTIVE: To determine the prevalence of attention complaints, ADHD diagnosis and attention profile in a sample of children and adolescents with idiopathic epilepsy. METHOD: 36 children and adolescents with idiopathic epilepsy and 37 genre and age matched healthy controls underwent several procedures to diagnose their neuropsychological profile and comorbidity with ADHD. RESULTS: The prevalence of ADHD was higher in patients with epilepsy [chi2= 4.1, p = 0.043, 6 (16.7%) vs 1 (2.7%)], with worse results in attention related WISC items and factors in patients with epilepsy comparing to the controls, but not between patients with and without ADHD. Clinical characteristics did not influence those results. CONCLUSION: This study found a greater prevalence of problems wih attention in pediatric patients with idiopathic epilepsy, but not a distinct profile between those with or without ADHD. PMID- 25742578 TI - Waiting time to radiotherapy as a prognostic factor for glioblastoma patients in a scenario of medical disparities. AB - OBJECTIVE: To evaluate the effect of waiting time (WT) to radiotherapy (RT) on overall survival (OS) of glioblastoma (GBM) patients as a reliable prognostic variable in Brazil, a scenario of medical disparities. METHOD: Retrospective study of 115 GBM patients from two different health-care institutions (one public and one private) in Brazil who underwent post-operative RT. RESULTS: Median WT to RT was 6 weeks (range, 1.3-17.6). The median OS for WT <= 6 weeks was 13.5 months (95%CI , 9.1-17.9) and for WT > 6 weeks was 14.2 months (95%CI, 11.2-17.2) (HR 1.165, 95%CI 0.770-1.762; p = 0.470). In the multivariate analysis, the variables associated with survival were KPS (p < 0.001), extent of resection (p = 0.009) and the adjuvant treatment (p = 0.001). The KPS interacted with WT to RT (HR 0.128, 95%CI 0.034-0.476; p = 0.002), showing that the benefit of KPS on OS depends on the WT to RT. CONCLUSION: No prognostic impact of WT to RT could be detected on the OS. Although there are no data to ensure that delays to RT are tolerable, we may reassure patients that the time-length to initiate treatment does not seem to influence the control of the disease, particularly in face of other prognostic factors. PMID- 25742579 TI - Artificial gait in complete spinal cord injured subjects: how to assess clinical performance. AB - OBJECTIVE: Adapt the 6 minutes walking test (6MWT) to artificial gait in complete spinal cord injured (SCI) patients aided by neuromuscular electrical stimulation. METHOD: Nine male individuals with paraplegia (AIS A) participated in this study. Lesion levels varied between T4 and T12 and time post injured from 4 to 13 years. Patients performed 6MWT 1 and 6MWT 2. They used neuromuscular electrical stimulation, and were aided by a walker. The differences between two 6MWT were assessed by using a paired t test. Multiple r-squared was also calculated. RESULTS: The 6MWT 1 and 6MWT 2 were not statistically different for heart rate, distance, mean speed and blood pressure. Multiple r-squared (r2 = 0.96) explained 96% of the variation in the distance walked. CONCLUSION: The use of 6MWT in artificial gait towards assessing exercise walking capacity is reproducible and easy to apply. It can be used to assess SCI artificial gait clinical performance. PMID- 25742580 TI - Piribedil and pathological gambling in six parkinsonian patients. AB - Impulse control disorders (ICD) in Parkinson's disease (PD) have attracted increasing interest. They are characterized by the inability to control the impulse to perform an act that can be detrimental to them or to others. Although dopamine agonists (DA), as a group, have been associated with impulse control disorders (ICD), piribedil has rarely been reported to cause them. METHOD: Case reports of six parkinsonian patients on piribedil presenting pathological gambling (PG). RESULTS: All of the patients presented ICD associated with piribedil use. Two of them received this medication as first treatment and four of them who had developed ICDs secondary to other DA that reappeared with piribedil. CONCLUSION: Despite piribedil is commercially available in only a few countries, it should be considered in the differential diagnosis of PG in patients with PD. PMID- 25742581 TI - A case-control study of the prevalence of neurological diseases in inflammatory bowel disease (IBD). AB - Neurological diseases are common in inflammatory bowel disease (IBD) patients, but their exact prevalence is unknown. Method We prospectively evaluated the presence of neurological disorders in 121 patients with IBD [51 with Crohn's disease (CD) and 70 with ulcerative colitis (UC)] and 50 controls (gastritis and dyspepsia) over 3 years. Results Our standard neurological evaluation (that included electrodiagnostic testing) revealed that CD patients were 7.4 times more likely to develop large-fiber neuropathy than controls (p = 0.045), 7.1 times more likely to develop any type of neuromuscular condition (p = 0.001) and 5.1 times more likely to develop autonomic complaints (p = 0.027). UC patients were 5 times more likely to develop large-fiber neuropathy (p = 0.027) and 3.1 times more likely to develop any type of neuromuscular condition (p = 0.015). Conclusion In summary, this is the first study to prospectively establish that both CD and UC patients are more prone to neuromuscular diseases than patients with gastritis and dyspepsia. PMID- 25742582 TI - Effects of iodinated contrast media in a novel model for cerebral vasospasm. AB - OBJECTIVE: We developed an in vitro model for vasospasm post subarachnoid hemorrhage that was suitable for investigating brain vessel autoregulation. We further investigated the effects of iodinated contrast medium on the vascular tone and the myogenic response of spastic cerebral vessels. METHOD: We isolated and perfused the superior cerebellar arteries of rats. The vessels were pressurized and studied under isobaric conditions. Coagulated blood was used to simulate subarachnoid hemorrhage. The contrast medium iodixanol was applied intraluminally. RESULTS: Vessels exposed to blood developed significantly stronger myogenic tone (65.7 +/- 2.0% vs 77.1 +/- 1.2% of the maximum diameter, for the blood and the control group, respectively) and significantly decreased myogenic response, compared with the control groups. The contrast medium did not worsen the myogenic tone or the myogenic response in any group. CONCLUSION: Our results show that deranged myogenic response may contribute to cerebral blood flow disturbances subsequent to subarachnoid hemorrhage. The contrast medium did not have any negative influence on vessel tone or myogenic response in this experimental setting. PMID- 25742583 TI - Tamoxifen antagonizes the effects of ovarian hormones to induce anxiety and depression-like behavior in rats. AB - The effects of tamoxifen (TAM) on anxiety and depression-like behavior in ovariectomized (OVX) and naive female rats were investigated. The animals were divided into Sham-TAM, OVX-TAM, Sham and OVX groups. Tamoxifen (1 mg/kg) was administered for 4 weeks. In the forced swimming test, the immobility times in the OVX and Sham-TAM groups were higher than in the Sham group. In the open field, the numbers of central crossings in the OVX and Sham-TAM groups were lower than the number in the Sham group, and the number of peripheral crossings in the OVX group was lower than the number in the Sham group. In the elevated plus maze, the numbers of entries to the open arm among the animals in the Sham-TAM and OVX groups were lower than the number in the Sham group, while the number of entries to the open arm in the OVX-TAM group was higher than the number in the OVX group. It was shown that deletion of ovarian hormones induced anxiety and depression like behavior. Administration of tamoxifen in naive rats led to anxiety and depression-like behavior that was comparable with the effects of ovarian hormone deletion. It can be suggested that tamoxifen antagonizes the effects of ovarian hormones. It also seems that tamoxifen has anxiolytic effects on ovariectomized rats. PMID- 25742584 TI - Neurological examination: pioneering authors and their books. AB - The objective of this article is to highlight some of the most important pioneering books specifically focused on the neurological examination and their authors. During the XIX Century, Alexander Hammond, William Gowers and Charles Mills pioneered the neurological literature, followed in the XX Century by Aloysio de Castro, Monrad-Krohn, Derek Denny-Brown, Robert Wartenberg, Gordon Holmes, and Russel DeJong. With determination and a marked sense of observation and research, they competently developed and spread the technique and art of the neurological exam. PMID- 25742585 TI - Sleep deprivation, pain and prematurity: a review study. AB - The aim was to describe current reports in the scientific literature on sleep in the intensive care environment and sleep deprivation associated with painful experiences in premature infant. A systematic search was conducted for studies on sleep, pain, premature birth and care of the newborn. Web of Knowledge, MEDLINE, LILACS, Cochrane Library, PubMed, EMBASE, Scopus, VHL and SciELO databases were consulted. The association between sleep deprivation and pain generates effects that are observed in the brain and the behavioral and physiological activity of preterm infants. Polysomnography in intensive care units and pain management in neonates allow comparison with the first year of life and term infants. We have found few references and evidence that neonatal care programs can influence sleep development and reduce the negative impact of the environment. This evidence is discussed from the perspective of how hospital intervention can improve the development of premature infants. PMID- 25742586 TI - Andreas Vesalius as a renaissance innovative neuroanatomist: his 5th centenary of birth. AB - Andreas Vesalius (1514-1564) is considered the Father of Modern Anatomy, and an authentic representative of the Renaissance. His studies, founded on dissection of human bodies, differed from Galeno, who based his work on dissection of animals, constituted a notable scientific advance. Putting together science and art, Vesalius associated himself to artists of the Renaissance, and valued the images of the human body in his superb work De Humani Corporis Fabrica.This paper aims to honor this extraordinary European Renaissance physician and anatomist, who used aesthetic appeal to bind text and illustration, science and art. His achievements are highlighted, with an especial attention on neuroanatomy. Aspects about his personal life and career are also focused. PMID- 25742587 TI - Alzheimer's 100th anniversary of death and his contribution to a better understanding of Senile dementia. AB - Initially the trajectory of the historical forerunners and conceptions of senile dementia are briefly presented, being highlighted the name of Alois Alzheimer who provided clinical and neuropathological indicators to differentiate a group of patients with Senile dementia. Alzheimer's examination of Auguste D's case, studied by him with Bielschowsky's silver impregnation technique, permitted to identify a pathological marker, the intraneuronal neurofibrillary tangles, characterizing a new disease later named after him by Kraepelin - Alzheimer's disease. Over the time this disorder became one of the most important degenerative dementing disease, reaching nowadays a status that may be considered as epidemic. PMID- 25742588 TI - Aloysio de Castro and Uruguay. AB - Aloysio de Castro, when Director of the School of Medicine of Rio de Janeiro, and Americo Ricaldoni, when Dean of the School of Medicine of Montevideo, Uruguay, started a period of intense collaboration between both institutions. In this period, Aloysio visited Montevideo in many occasions, giving lectures, donating scientific material and publishing papers in Uruguay. Ricaldoni retributed his visits, distinguishing Aloysio as the first foreign Honorary Professor of the Medical School of Uruguay, participating in the inauguration of the new building of the School in Rio. Even after Ricaldoni's death in 1928, for many years, Aloysio continued with his visits. A poem by Aloysio de Castro dedicated to Montevideo is attached. PMID- 25742589 TI - Neurology at Escola Paulista de Medicina (1933-1995). From Fausto Guerner to Jose Geraldo Camargo Lima. AB - Escola Paulista de Medicina (EPM) was founded in 1933 and the first Professor of Neurology was Fausto Guerner, who could not effectively assume the teaching activities due to his premature death in 1938. Professor Guerner had had his neurological training at Paris. Professor Longo was his successor. Longo was one of the founders of Arquivos de Neuro-Psiquiatria the foremost journal of neurosciences in Latin American. Longo died in 1967 and Professor Paulo Pupo succeeded him. Pupo introduced electroencephalography in Brazil. After his death in 1970, Professor Dante Giorgi succeeded him until 1974. Professor Jose Geraldo Camargo Lima took over the position after Giorgi's death. He created the Neurological Emergency unit, initiated the Post-Graduation in Neurology and divided the Discipline in specialized units. During the 1980's and until his retirement in 1995, EPM had become one of most important centers of Brazil training neurologists and researchers in neurological sciences. PMID- 25742590 TI - The corneomandibular reflex: a light touch and wide conclusions. PMID- 25742591 TI - Megalencephalic leukoencephalopathy with subcortical cysts (MLC) - a case with clinical and magnetic resonance imaging (MRI) dissociation. PMID- 25742592 TI - Gasserian ganglion neurosarcoidosis mimicking trigeminal schwannoma. PMID- 25742593 TI - Michelangelo, mammillary bodies and the Creator. PMID- 25742594 TI - The relationship between neurocysticercosis and the development of mesial temporal lobe sclerosis. PMID- 25742595 TI - Seasonality of 278 neuromyelitis optica relapses in a Brazilian cohort. PMID- 25742596 TI - Surgical treatment of type I Chiari malformation: the role of Magendie's foramen opening e tonsils manipulation. AB - The treatment for type 1 Chiari malformation (CM 1) is one of the most controversial topics in the neurosurgical field. The present study evaluated two of the most applied surgical techniques to treat CM 1. Method 32 patients were evaluated and divided in two groups: group 1 had 16 patients that were submitted to decompression of occipital bone and dura mater of the craniovertebral junction (CVJ); group 2 also had 16 patients and in addition to the previous procedure, they were submitted to Magendie's foramen opening e tonsils manipulation. The comparison between the groups included neurological exam and cerebrospinal fluid flow imaging during pre and postoperative periods. Results Both techniques were equivalents in terms of neurological improvement of the patients (p > 0.05), but the group 2 had more surgical complications, with relative risk of 2.45 (CI 1.55 3.86) for adverse events. Whatever the cerebrospinal fluid flow at CVJ, the patients of the group 1 achieved greater amount of flow than the group 2 (p < 0.05) during the postoperative period. Conclusion The cranial and dural decompression of the CVJ without arachnoidal violation was the best surgical intervention for treatment of CM 1, between these two compared techniques. PMID- 25742597 TI - Dr Jose Alberto Goncalves da Silva March 18, 1938 -July 19, 2014. PMID- 25742598 TI - Molecular responses of Frankia sp. strain QA3 to naphthalene. AB - The Frankia-actinorhizal plant symbiosis plays a significant role in plant colonization in soils contaminated with heavy metals and toxic aromatic hydrocarbons. The molecular response of Frankia upon exposure to soil contaminants is not well understood. To address this issue, we subjected Frankia sp. strain QA3 to naphthalene stress and showed that it could grow on naphthalene as a sole carbon source. Bioinformatic analysis of the Frankia QA3 genome identified a potential operon for aromatic compound degradation as well as several ring-hydroxylating dioxygenases. Under naphthalene stress, the expression of these genes was upregulated. Proteome analysis showed a differential protein profile for cells under naphthalene stress. Several protein spots were analyzed and used to identify proteins involved in stress response, metabolism, and energy production, including a lignostilbene dioxygenase. These results provide a model for understanding the molecular response of Frankia to common soil pollutants, which may be required for survival and proliferation of the bacterium and their hosts in polluted environments. PMID- 25742599 TI - Function through synthesis-informed design. AB - In 1996, a snapshot of the field of synthesis was provided by many of its thought leaders in a Chemical Reviews thematic issue on "Frontiers in Organic Synthesis". This Accounts of Chemical Research thematic issue on "Synthesis, Design, and Molecular Function" is intended to provide further perspective now from well into the 21st century. Much has happened in the past few decades. The targets, methods, strategies, reagents, procedures, goals, funding, practices, and practitioners of synthesis have changed, some in dramatic ways as documented in impressive contributions to this issue. However, a constant for most synthesis studies continues to be the goal of achieving function with synthetic economy. Whether in the form of new catalysts, reagents, therapeutic leads, diagnostics, drug delivery systems, imaging agents, sensors, materials, energy generation and storage systems, bioremediation strategies, or molecules that challenge old theories or test new ones, the function of a target has been and continues to be a major and compelling justification for its synthesis. While the targets of synthesis have historically been heavily represented by natural products, increasingly design, often inspired by natural structures, is providing a new source of target structures exhibiting new or natural functions and new or natural synthetic challenges. Complementing isolation and screening approaches to new target identification, design enables one to create targets de novo with an emphasis on sought-after function and synthetic innovation with step-economy. Design provides choice. It allows one to determine how close a synthesis will come to the ideal synthesis and how close a structure will come to the ideal function. In this Account, we address studies in our laboratory on function oriented synthesis (FOS), a strategy to achieve function by design and with synthetic economy. By starting with function rather than structure, FOS places an initial emphasis on target design, thereby harnessing the power of chemists and computers to create new structures with desired functions that could be prepared in a simple, safe, economical, and green, if not ideal, fashion. Reported herein are examples of FOS associated with (a) molecular recognition, leading to the first designed phorbol-inspired protein kinase C regulatory ligands, the first designed bryostatin analogs, the newest bryologs, and a new family of designed kinase inhibitors, (b) target modification, leading to highly simplified but functionally competent photonucleases-molecules that cleave DNA upon photoactivation, (c) drug delivery, leading to cell penetrating molecular transporters, molecules that ferry other attached or complexed molecules across biological barriers, and (d) new reactivity-regenerating reagents in the form of functional equivalents of butatrienes, reagents that allow for back-to-back three component cycloaddition reactions, thus achieving structural complexity and value with step-economy. While retrosynthetic analysis seeks to identify the best way to make a target, retrofunction analysis seeks to identify the best targets to make. In essence, form (structure) follows function. PMID- 25742600 TI - Knowledge of HIV and willingness to conduct oral rapid HIV testing among dentists in Xi'an China. AB - INTRODUCTION: China is considered a country of low HIV prevalence (780,000 people living with HIV), however, HIV infections among high-risk populations continue to grow at alarming rates. Voluntary Counseling and Testing services were first implemented in 2003, and oral rapid HIV testing (ORHT) began in 2012. Dentists, as oral health experts, would be well placed to conduct ORHT. We assessed willingness of dentists to undertake ORHT in their clinical practice. METHODS: A cross-sectional, paper-based survey of dentists from the Xi'an region of China was conducted from April to June 2013. Dentists were recruited from Shaanxi Stomatological Association using a stratified sampling methodology. A 40-item survey was used to measure knowledge of HIV, attitudes toward people living with HIV and willingness to conduct ORHT. RESULTS: 477 dentists completed the survey with a mean HIV knowledge test score of 13.2/18 (SD 1.9). If made available in the dental setting, 276 (57.9%) preferred to use blood to diagnose HIV, only 190 (39.8%) preferred saliva or both. Four hundred and thirty-five (91.2%) thought that ORHT was needed in dental clinics. Female dentists felt more accepting of ORHT than males (93.8% vs. 87.8%; chi2=5.145; p<0.05). 42.6% of the participants who responded thought that lack of education on ORHT for dentists was the most urgent problem to solve for ORHT, 144 (31.3%) thought that lack of support for ORHT from patients was the most urgent problem. There was statistically significant difference among dental hospital, dentistry and department of dentistry (chi2=24.176; p<0.05). CONCLUSIONS: The majority of Chinese dentists thought that ORHT was needed in the dental setting. Providing opportunities for dentists and dental students to learn about HIV testing guidelines and practices is needed as well as feasibility and implementation science research. PMID- 25742601 TI - Oxygen and hydrogen stable isotope ratios of bulk needles reveal the geographic origin of Norway spruce in the European Alps. AB - BACKGROUND: Tracking timber is necessary in order to prevent illegal logging and protect local timber production, but there is as yet no suitable analytical traceability method. Stable isotope ratios in plants are known to reflect geographical variations. In this study we analysed four stable isotope ratios in order to develop a model able to identify the geographic origin of Norway spruce in the European Alps. METHODOLOGY AND PRINCIPAL FINDINGS: delta18O, delta2H, delta13C and delta15N were measured in bulk needles of Picea abies sampled in 20 sites in and around the European Alps. Environmental and spatial variables were found to be related to the measured isotope ratios. An ordinary least squares regression was used to identify the most important factor in stable isotope variability in bulk needles. Spatial autocorrelation was tested for all isotope ratios by means of Moran's I. delta18O, delta2H and delta15N values differed significantly between sites. Distance from the coast had the greatest influence on delta2H, while latitude and longitude were strongly related to delta18O. delta13C values did not appear to have any relationship with geographical position, while delta15N values were influenced by distance from the motorway. The regression model improved the explanatory power of the spatial and environmental variables. Positive spatial autocorrelations were found for delta18O and delta2H values. CONCLUSIONS: The delta 18O, delta2H and delta15N values in P. abies bulk needles are a suitable proxy to identify geographic origin as they vary according to geographical position. Although the regression model showed the explanatory variables to have significant power and stability, we conclude that our model might be improved by multivariate spatial interpolation of the delta 18O and delta2H values. PMID- 25742602 TI - Correction: Comparative transcriptome analysis of two oysters, Crassostrea gigas and Crassostrea hongkongensis provides insights into adaptation to hypo-osmotic conditions. PMID- 25742604 TI - The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase. AB - Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER) associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD. PMID- 25742605 TI - Auxin regulates SNARE-dependent vacuolar morphology restricting cell size. AB - The control of cellular growth is central to multicellular patterning. In plants, the encapsulating cell wall literally binds neighbouring cells to each other and limits cellular sliding/migration. In contrast to its developmental importance, growth regulation is poorly understood in plants. Here, we reveal that the phytohormone auxin impacts on the shape of the biggest plant organelle, the vacuole. TIR1/AFBs-dependent auxin signalling posttranslationally controls the protein abundance of vacuolar SNARE components. Genetic and pharmacological interference with the auxin effect on vacuolar SNAREs interrelates with auxin resistant vacuolar morphogenesis and cell size regulation. Vacuolar SNARE VTI11 is strictly required for auxin-reliant vacuolar morphogenesis and loss of function renders cells largely insensitive to auxin-dependent growth inhibition. Our data suggests that the adaptation of SNARE-dependent vacuolar morphogenesis allows auxin to limit cellular expansion, contributing to root organ growth rates. PMID- 25742606 TI - Induction of excessive endoplasmic reticulum stress in the Drosophila male accessory gland results in infertility. AB - Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the lumen of the ER. A cell responds to ER stress with the unfolded protein response (UPR), a complex program of transcriptional and translational changes aimed at clearing misfolded proteins. Secretory tissues and cells are particularly well adapted to respond to ER stress because their function requires high protein production and secretory load. The insect male accessory gland (AG) is a secretory tissue involved in male fertility. The AG secretes many seminal fluid proteins (SFPs) essential for male reproduction. Among adult Drosophila tissues, we find that genes upregulated by ER stress are most highly expressed in the AG, suggesting that the AG is already undergoing high levels of ER stress due to its normal secretory functions. We hypothesized that induction of excessive ER stress in the AG above basal levels, would perturb normal function and provide a genetic tool for studying AG and SFP biology. To test this, we genetically induced excessive ER stress in the AG by conditional 1) expression of a misfolded protein or 2) knockdown of the UPR regulatory protein, BiP. Both genetic manipulations induced excessive ER stress in the AG, as indicated by the increase in Xbp1 splicing, a marker of ER stress. Both models resulted in a large decrease in or loss of SFP production and male infertility. Sperm production, motility, and transfer appeared unaffected. The induction of strong ER stress in the insect male AG may provide a simple way for studying or manipulating male fertility, as it eliminates AG function while preserving sperm production. PMID- 25742603 TI - Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction. AB - Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood-brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. Furthermore, we found that ingestion of glucose after a primary injury increases the probability of death through a secondary injury mechanism that exacerbates intestinal barrier dysfunction. Our results indicate that natural variation in the probability of death following TBI is due in part to genetic differences that affect intestinal barrier dysfunction. PMID- 25742607 TI - Emergency department-based health insurance enrollment for children: does linkage lead to insurance retention and utilization? AB - OBJECTIVES: Although 40% of emergency departments (EDs) report having an insurance linkage program, no studies have evaluated the long-term success of these programs. This study aimed to examine insurance retention and utilization by children initially referred to insurance by our ED insurance linkage program. METHODS: We retrospectively examined insurance records of all uninsured children successfully enrolled in public insurance by the insurance linkage program established in our suburban academic ED between 2004 and 2009. Emergency department-enrolled children were matched by age, sex, program, and year of enrollment to a control group of children from the same county who were enrolled in non-ED settings. Wilcoxon signed rank and chi tests were used to compare enrollment and claims variables. RESULTS: Emergency department-enrolled children retained insurance for longer, had a higher reenrollment rate, and were higher users of insurance. The average length of enrollment for ED children was 734 days versus 597 days in the control group. Eighty percent of the ED cohort reenrolled in insurance after initial eligibility expiration versus 64% of the control group. Children enrolled via the ED averaged 26 claims (vs 12 claims) and $20,087 (vs $5216) in hospital charges per year of enrollment. This higher utilization was reflected in increased primary care, specialty care, ED visits, inpatient, and mental health claims in the ED group. CONCLUSIONS: Emergency department-based insurance enrollment programs have the potential to improve access to health care for children. Policies aimed at expanding insurance enrollment among the uninsured population, including the Affordable Care Act, may consider the ED's potential as an effective enrollment site. PMID- 25742608 TI - Correction: ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance. PMID- 25742610 TI - Correction: In vitro sensitivity of Plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes. PMID- 25742609 TI - Exercise end-tidal CO2 predicts central sleep apnea in patients with heart failure. AB - BACKGROUND: Increased CO2 chemosensitivity and augmented exercise ventilation are characteristic of patients with heart failure (HF) with central sleep apnea (CSA). The aim of this study was to test the hypothesis that decreased end-tidal CO2 by cardiopulmonary exercise testing predicts CSA in patients with HF. METHODS: Consecutive ambulatory patients with New York Heart Association II to III HF were prospectively evaluated by CO2 chemosensitivity by rebreathe, cardiopulmonary exercise testing, and polysomnography (PSG). Subjects were classified as having either CSA (n = 20) or no sleep apnea (n = 13) by PSG; a central apnea-hypopnea index (AHI) >= 5 was used to define CSA. Subgroups were compared by t test or Mann-Whitney test and data summarized as mean +/- SD. P < .05 was considered significant. RESULTS: At rest, subjects with CSA had higher central CO2 chemosensitivity (Deltaminute ventilation [V.e]/Deltapartial pressure of end-tidal CO2 [Petco2], 2.3 +/- 1.0 L/min/mm Hg vs 1.6 +/- 0.4 L/min/mm Hg, P = .02) and V.e (15 +/- 7 L/min vs 10 +/- 3 L/min, P = .02) and lower Petco2 (31 +/- 4 mm Hg vs 35 +/- 4 mm Hg, P < .01) than control subjects. At peak exercise, the ventilatory equivalents per expired CO2 (V.e/V.co2) was higher (43 +/- 9 vs 33 +/- 6, P < .01) and Petco2 lower (29 +/- 6 mm Hg vs 36 +/- 5 mm Hg, P < .01) in subjects with CSA. In addition, CO2 chemosensitivity, peak exercise V.e/V.co2, and Petco2 were independently correlated with CSA severity as quantified by the AHI (P < .05). Peak exercise Petco2 was most strongly associated with CSA (OR, 1.29; 95% CI, 1.08-1.54; P = .01; area under the curve, 0.88). CONCLUSIONS: In patients with HF and CSA, ventilatory drive is increased while awake at rest and during exercise and associated with heightened CO2 chemosensitivity and decreased arterial CO2 set point. PMID- 25742611 TI - Unpacking the 'structural' in a structural approach for HIV prevention among female sex workers: a case study from China. AB - Interventions for HIV prevention among female sex workers (FSWs) in China focus on HIV/sexually transmitted infection (STI) and individual behaviour change. An occupational health framework facilitates intervention across an array of health issues FSWs face including HIV/STI, violence, reproductive health, stigma and substance use. Through a case study of a community-based Jiaozhou (JZ) FSW programme, we developed a conceptual framework incorporating global discussions of structural approaches to HIV prevention with the specific social and structural contexts identified among FSWs in China. Based on ethnographic fieldwork between August 2010 and May 2013, we describe the evolution of this programme to its current occupational health focus and unpack the intervention strategies. We describe the critical features of the programme that have fostered success among FSWs including high-quality clinical services provided within a welcoming setting, responsive outreach work through staff and trained FSW peers, interpersonal and community-level engagement aimed at changing the local social and structural environments of sex work and tailored health education materials. This intervention differs from other projects in China by adopting a more holistic approach to FSW health that incorporates social issues. It also demonstrates the feasibility of structural interventions among FSWs even within an environment that has strong anti-prostitution policies. PMID- 25742613 TI - Correction: Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson's disease. PMID- 25742612 TI - Obesity and bronchodilator response in black and Hispanic children and adolescents with asthma. AB - BACKGROUND: Obesity is associated with poor asthma control, increased asthma morbidity, and decreased response to inhaled corticosteroids. We hypothesized that obesity would be associated with decreased bronchodilator responsiveness in children and adolescents with asthma. In addition, we hypothesized that subjects who were obese and unresponsive to bronchodilator would have worse asthma control and would require more asthma controller medications. METHODS: In the Study of African Americans, Asthma, Genes, and Environments (SAGE II) and the Genes environments and Admixture in Latino Americans (GALA II) study, two identical, parallel, case-control studies of asthma, we examined the association between obesity and bronchodilator response in 2,963 black and Latino subjects enrolled from 2008 to 2013 using multivariable logistic regression. Using bronchodilator responsiveness, we compared asthma symptoms, controller medication usage, and asthma exacerbations between nonobese (< 95th% BMI) and obese (>= 95th% BMI) subjects. RESULTS: The odds of being bronchodilator unresponsive were 24% (OR, 1.24; 95% CI, 1.03-1.49) higher among obese children and adolescents compared with their not obese counterparts after adjustment for age, race/ethnicity, sex, recruitment site, baseline lung function (FEV1/FVC), and controller medication. Bronchodilator-unresponsive obese subjects were more likely to report wheezing (OR, 1.38; 95% CI, 1.13-1.70), being awakened at night (OR, 1.34; 95% CI, 1.09 1.65), using leukotriene receptor inhibitors (OR, 1.33; 95% CI, 1.05-1.70), and using inhaled corticosteroid with long-acting beta2-agonist (OR, 1.37; 95% CI, 1.05-1.78) than were their nonobese counterpart. These associations were not seen in the bronchodilator-responsive group. CONCLUSIONS: Obesity is associated with bronchodilator unresponsiveness among black and Latino children and adolescents with asthma. The findings on obesity and bronchodilator unresponsiveness represent a unique opportunity to identify factors affecting asthma control in blacks and Latinos. PMID- 25742614 TI - Outcomes of group audiological rehabilitation for unaided adults with hearing impairment and their significant others. AB - PURPOSE: The purpose of this study was to evaluate the outcomes of a group audiological rehabilitation (GAR) program designed for working adults who do not use amplification and for their significant others. METHOD: A quasirandomized control design was used to measure outcomes of the GAR program. Twenty-four couples participated in weekly GAR group sessions designed to address communication problems encountered in the workplace and at home. Twelve couples were placed on a waiting list as a control group. Assessments were completed at time frames prior to the sessions, post-waiting list, immediately after the sessions, and 12 weeks after. These included direct measures for the adults with hearing impairment, proxy measures from the significant others, and direct measures for the significant others. RESULTS: Results indicated adults with hearing impairment and their significant others experienced significant improvements following participation in the GAR program. These improvements were maintained in the short term (12 weeks). CONCLUSIONS: Working adults with hearing impairment who do not use amplification can benefit from GAR sessions. Significant others of working adults with hearing impairment experience third party disability, which can also be alleviated through participation in GAR sessions. PMID- 25742615 TI - Is antigenic sin always "original?" Re-examining the evidence regarding circulation of a human H1 influenza virus immediately prior to the 1918 Spanish flu. PMID- 25742616 TI - Correction: fears and beliefs in rheumatoid arthritis and spondyloarthritis: a qualitative study. PMID- 25742617 TI - Metagenome of a microbial community inhabiting a metal-rich tropical stream sediment. AB - Here, we describe the metagenome and functional composition of a microbial community in a historically metal-contaminated tropical freshwater stream sediment. The sediment was collected from the Mina Stream located in the Iron Quadrangle (Brazil), one of the world's largest mining regions. Environmental DNA was extracted and was sequenced using SOLiD technology, and a total of 7.9 Gbp was produced. A taxonomic profile that was obtained by comparison to the Greengenes database revealed a complex microbial community with a dominance of Proteobacteria and Parvarcheota. Contigs were recruited by bacterial and archaeal genomes, especially Candidatus Nitrospira defluvii and Nitrosopumilus maritimus, and their presence implicated them in the process of N cycling in the Mina Stream sediment (MSS). Functional reconstruction revealed a large, diverse set of genes for ammonium assimilation and ammonification. These processes have been implicated in the maintenance of the N cycle and the health of the sediment. SEED subsystems functional annotation unveiled a high degree of diversity of metal resistance genes, suggesting that the prokaryotic community is adapted to metal contamination. Furthermore, a high metabolic diversity was detected in the MSS, suggesting that the historical arsenic contamination is no longer affecting the prokaryotic community. These results expand the current knowledge of the microbial taxonomic and functional composition of tropical metal-contaminated freshwater sediments. PMID- 25742618 TI - Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) null polymorphisms and the risk of hypertension: a meta-analysis. AB - BACKGROUND: Some studies have recently focused on the association between glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms and hypertension; however, results have been inconsistent. OBJECTIVE: In order to drive a more precise estimation, the present systematic review and meta-analysis is performed to investigate the relationship between the GSTM1 and GSTT1 null polymorphisms and hypertension. METHODS: Eligible articles were identified by a search of several bibliographic databases for the period up to August 17, 2013. Odds ratios were pooled using either fixed-effects or random effects models. RESULTS: Regarding the GSTM1 null/present genotype, 14 case control studies were eligible (2773 hypertension cases and 3189 controls). The meta-analysis revealed that it might present a small increased risk for hypertension, although the effect was not statistically significant (odd ratio (OR) = 1.16, 95% confidence interval (CI): 0.96, 1.40; P = 0.002, I2 = 59.8%). Further subgroup analysis by ethnicity and control source suggested that the association was still not significant. Thirteen case-control studies were eligible for GSTT1 (2497 hypertension cases and 3078 controls). No statistically significant association was observed between the GSTT1 null genotype and hypertension risk (OR = 1.14, 95% CI: 0.85, 1.53; P = 0.000, I2 = 80.3%). Furthermore, stratification by ethnicity and control source indicated no association between the GSTT1 null genotype and hypertension risk. We further confirmed the association by sensitivity analysis. No publication bias was detected. CONCLUSION: This meta-analysis suggests that the GSTM1 and GSTT1 null polymorphisms are not associated with the risk of hypertension. Future large well designed epidemiological studies with individual information, lifestyle factors, and environmental factors are warranted to validate the present findings. PMID- 25742619 TI - Schisandrin B prevents doxorubicin induced cardiac dysfunction by modulation of DNA damage, oxidative stress and inflammation through inhibition of MAPK/p53 signaling. AB - Doxorubicin (Dox) is a highly effective antineoplastic drug. However, Dox-induced apoptosis in cardiomyocytes leads to irreversible degenerative cardiomyopathy, which limits Dox clinical application. Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In current study, we investigated possible protective effects of Sch B against Dox-induced cardiomyopathy in mice. Mice received a single injection of Dox (20 mg/kg IP). Five days after Dox administration, left ventricular (LV) performance was significantly depressed and was improved by Sch B treatment. Sch B prevented the Dox-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart. In addition, the increased expression of phospho-p38 MAPK and phospho-MAPK activated mitogen kinase 2 levels by Dox were significantly suppressed by Sch B treatment. Sch B also attenuated Dox-induced higher expression of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3 positive cells and phopho-p53 levels in mice. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species were significantly less in Sch B treatment mice after Dox injection. These findings suggest that Sch B attenuates Dox induced cardiotoxicity via antioxidative and anti-inflammatory effects. PMID- 25742621 TI - Correction: Low-rank and eigenface based sparse representation for face recognition. PMID- 25742620 TI - Application of VEGFA and FGF-9 enhances angiogenesis, osteogenesis and bone remodeling in type 2 diabetic long bone regeneration. AB - Although bone regeneration is typically a reliable process, type 2 diabetes is associated with impaired or delayed healing processes. In addition, angiogenesis, a crucial step in bone regeneration, is often altered in the diabetic state. In this study, different stages of bone regeneration were characterized in an unicortical bone defect model comparing transgenic type 2 diabetic (db-/db-) and wild type (WT) mice in vivo. We investigated angiogenesis, callus formation and bone remodeling at early, intermediate and late time points by means of histomorphometry as well as protein level analyses. In order to enhance bone regeneration, defects were locally treated with recombinant FGF-9 or VEGFA. Histomorphometry of aniline blue stained sections indicated that bone regeneration is significantly decreased in db-/db- as opposed to WT mice at intermediate (5 days post operation) and late stages (7 days post operation) of bone regeneration. Moreover, immunohistochemical analysis revealed significantly decreased levels of RUNX-2, PCNA, Osteocalcin and PECAM-1 in db-/db- defects. In addition, osteoclastogenesis is impaired in db-/db- indicating altered bone remodeling. These results indicate significant impairments in angiogenesis and osteogenesis in type 2 diabetic bones. Importantly, angiogenesis, osteogenesis and bone remodeling could be reconstituted by application of recombinant FGF-9 and, in part, by VEGFA application. In conclusion, our study demonstrates that type 2 diabetes affects angiogenesis, osteogenesis and subsequently bone remodeling, which in turn leads to decreased bone regeneration. These effects could be reversed by local application of FGF-9 and to a lesser degree VEGFA. These data could serve as a basis for future therapeutic applications aiming at improving bone regeneration in the type 2 diabetic patient population. PMID- 25742622 TI - Partition and poliomyelitis: an investigation of the polio disparity affecting Muslims during India's eradication program. AB - BACKGROUND: Significant disparities in the incidence of polio existed during its eradication campaign in India. In 2006, Muslims, who comprise 16% of the population in affected states, comprised 70% of paralytic polio cases. This disparity was initially blamed on the Muslims and a rumor that the vaccination program was a plot to sterilize their children. Using the framework of structural violence, this paper describes how the socio-political and historical context of Muslim populations in India shaped the polio disparity. METHODS AND FINDINGS: A qualitative study utilizing methods of rapid ethnography was conducted from May August 2009 in Aligarh, Uttar Pradesh, India. Field methods included participant observation of vaccination teams, historical document research, and 107 interviews with both Global Polio Eradication Initiative (GPEI) stakeholders and families with vaccine-eligible children. Almost all respondents agreed that Aligarh was a highly segregated city, mostly due to riots after Partition and during the 1990s. Since the formation of segregated neighborhoods, most respondents described that "Muslim areas" had been underdeveloped compared to "Hindu areas," facilitating the physical transmission of poliovirus. Distrust of the government and resistance to vaccination were linked to this disparate development and fears of sterilization influenced by the "Family Planning Program" from 1976-1977. CONCLUSIONS: Ethnic violence and social marginalization since the Partition and during the rise of Hindu nationalism led to distrust of the government, the formation of segregated slums, and has made Muslims victims of structural violence. This led to the creation of disease-spreading physical environments, lowered vaccine efficacy, and disproportionately higher levels of resistance to vaccination. The causes of the polio disparity found in this study elucidate the nature of possible other health disparities affecting minorities in India. LIMITATIONS: This study is limited by the manual coding of the transcribed data, size, and some dialectal difficulties in translation. PMID- 25742623 TI - Inverse Relationship Between Physical Activity, Adiposity, and Arterial Stiffness in Healthy Middle-Aged Subjects. AB - BACKGROUND: Several obesity related factors are reported to exacerbate premature arterial stiffening, including inactivity and metabolic disarray. The aim of the current study was to investigate the relationship between physical activity, arterial stiffness and adiposity using objective methods. To further explore the role of adiposity in this complex process, obesity associated anthropometric and humoral biomarkers were measured. METHODS: Seventy-nine healthy, lifelong nonsmoking subjects were recruited. Habitual physical activity was measured using accelerometry. Arterial stiffness [augmentation index (AIx) and pulse wave velocity (PWV)] was measured using tonometry. Body composition was estimated using bioimpedence. Adipose associated biomarkers, leptin and adiponectin, were also measured. RESULTS: Sedentary time was significantly associated with AIx (r = 0.38, P < .001), PWV (r = 0.33, P < .01), body fat composition (r = 0.40, P < .001) and age (r = 0.30, P < .01). Moderate-to-vigorous physical activity (MVPA) was inversely correlated with AIx (r = -0.28, P < .05), body fat composition (r = -0.30, P < .01), postprandial insulin (r = -0.35, P < .01), and leptin/adiponectin ratio (r = -0.28, P < .05). MVPA, body fat composition, and postprandial insulin remained independent predictors of AIx but not PWV. CONCLUSION: The more time healthy individuals spend being sedentary, the greater their body fat and arterial stiffness. Conversely higher activity levels are associated with reduced body fat and less arterial stiffness. PMID- 25742624 TI - Constitutively active signaling by the G protein betagamma-subunit mediates intrinsically increased phosphodiesterase-4 activity in human asthmatic airway smooth muscle cells. AB - Signaling by the Gbetagamma subunit of Gi protein, leading to downstream c-Src induced activation of the Ras/c-Raf1/MEK-ERK1/2 signaling pathway and its upregulation of phosphodiesterase-4 (PDE4) activity, was recently shown to mediate the heightened contractility in proasthmatic sensitized isolated airway smooth muscle (ASM), as well as allergen-induced airway hyperresponsiveness and inflammation in an in vivo animal model of allergic asthma. This study investigated whether cultured human ASM (HASM) cells derived from asthmatic donor lungs exhibit constitutively increased PDE activity that is attributed to intrinsically upregulated Gbetagamma signaling coupled to c-Src activation of the Ras/MEK/ERK1/2 cascade. We show that, relative to normal cells, asthmatic HASM cells constitutively exhibit markedly increased intrinsic PDE4 activity coupled to heightened Gbetagamma-regulated phosphorylation of c-Src and ERK1/2, and direct co-localization of the latter with the PDE4D isoform. These signaling events and their induction of heightened PDE activity are acutely suppressed by treating asthmatic HASM cells with a Gbetagamma inhibitor. Importantly, along with increased Gbetagamma activation, asthmatic HASM cells also exhibit constitutively increased direct binding of the small Rap1 GTPase-activating protein, Rap1GAP, to the alpha-subunit of Gi protein, which serves to cooperatively facilitate Ras activation and, thereby, enable enhanced Gbetagamma regulated ERK1/2-stimulated PDE activity. Collectively, these data are the first to identify that intrinsically increased signaling via the Gbetagamma subunit, facilitated by Rap1GAP recruitment to the alpha-subunit, mediates the constitutively increased PDE4 activity detected in asthmatic HASM cells. These new findings support the notion that interventions targeted at suppressing Gbetagamma signaling may lead to novel approaches to treat asthma. PMID- 25742625 TI - Genome-wide identification and expression profiling analysis of ZmPIN, ZmPILS, ZmLAX and ZmABCB auxin transporter gene families in maize (Zea mays L.) under various abiotic stresses. AB - The auxin influx carriers auxin resistant 1/like aux 1 (AUX/LAX), efflux carriers pin-formed (PIN) (together with PIN-like proteins) and efflux/conditional P glycoprotein (ABCB) are major protein families involved in auxin polar transport. However, how they function in responses to exogenous auxin and abiotic stresses in maize is largely unknown. In this work, the latest updated maize (Zea mays L.) reference genome sequence was used to characterize and analyze the ZmLAX, ZmPIN, ZmPILS and ZmABCB family genes from maize. The results showed that five ZmLAXs, fifteen ZmPINs, nine ZmPILSs and thirty-five ZmABCBs were mapped on all ten maize chromosomes. Highly diversified gene structures, nonconservative transmembrane helices and tissue-specific expression patterns suggested the possibility of function diversification for these genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression patterns of ZmLAX, ZmPIN, ZmPILS and ZmABCB genes under exogenous auxin and different environmental stresses. The expression levels of most ZmPIN, ZmPILS, ZmLAX and ZmABCB genes were induced in shoots and were reduced in roots by various abiotic stresses (drought, salt and cold stresses). The opposite expression response patterns indicated the dynamic auxin transport between shoots and roots under abiotic stresses. Analysis of the expression patterns of ZmPIN, ZmPILS, ZmLAX and ZmABCB genes under drought, salt and cold treatment may help us to understand the possible roles of maize auxin transporter genes in responses and tolerance to environmental stresses. PMID- 25742627 TI - Correction: Detection of colorectal cancer (CRC) by urinary volatile organic compound analysis. PMID- 25742626 TI - Post-amputation pain is associated with the recall of an impaired body representation in dreams-results from a nation-wide survey on limb amputees. AB - The experience of post-amputation pain such as phantom limb pain (PLP) and residual limb pain (RLP), is a common consequence of limb amputation, and its presence has negative effects on a person's well-being. The continuity hypothesis of dreams suggests that the presence of such aversive experiences in the waking state should be reflected in dream content, with the recalled body representation reflecting a cognitive proxy of negative impact. In the present study, we epidemiologically assessed the presence of post-amputation pain and other amputation-related information as well as recalled body representation in dreams in a sample of 3,234 unilateral limb amputees. Data on the site and time of amputation, residual limb length, prosthesis use, lifetime prevalence of mental disorders, presence of post-amputation pain, and presence of non-painful phantom phenomena were included in logistic regression analyses using recalled body representation in dreams (impaired, intact, no memory) as dependent variable. The effects of age, sex, and frequency of dream recall were controlled for. About 22% of the subjects indicated that they were not able to remember their body representation in dreams, another 24% of the amputees recalled themselves as always intact, and only a minority of less than 3% recalled themselves as always impaired. Almost 35% of the amputees dreamed of themselves in a mixed fashion. We found that lower-limb amputation as well as the presence of PLP and RLP was positively associated with the recall of an impaired body representation in dreams. The presence of non-painful phantom phenomena, however, had no influence. These results complement previous findings and indicate complex interactions of physical body appearance and mental body representation, probably modulated by distress in the waking state. The findings are discussed against the background of alterations in cognitive processes after amputation and hypotheses suggesting an innate body model. PMID- 25742628 TI - Stable isotope anatomy of tropical cyclone Ita, North-Eastern Australia, April 2014. AB - The isotope signatures registered in speleothems during tropical cyclones (TC) provides information about the frequency and intensity of past TCs but the precise relationship between isotopic composition and the meteorology of TCs remain uncertain. Here we present continuous delta18O and delta2H data in rainfall and water vapour, as well as in discrete rainfall samples, during the passage of TC Ita and relate the evolution in isotopic compositions to local and synoptic scale meteorological observations. High-resolution data revealed a close relationship between isotopic compositions and cyclonic features such as spiral rainbands, periods of stratiform rainfall and the arrival of subtropical and tropical air masses with changing oceanic and continental moisture sources. The isotopic compositions in discrete rainfall samples were remarkably constant along the ~450 km overland path of the cyclone when taking into account the direction and distance to the eye of the cyclone at each sampling time. Near simultaneous variations in delta18O and delta2H values in rainfall and vapour and a near equilibrium rainfall-vapour isotope fractionation indicates strong isotopic exchange between rainfall and surface inflow of vapour during the approach of the cyclone. In contrast, after the passage of spiral rainbands close to the eye of the cyclone, different moisture sources for rainfall and vapour are reflected in diverging d-excess values. High-resolution isotope studies of modern TCs refine the interpretation of stable isotope signatures found in speleothems and other paleo archives and should aim to further investigate the influence of cyclone intensity and longevity on the isotopic composition of associated rainfall. PMID- 25742629 TI - Nasal obstruction and epistaxis. Nasal alveolar soft part sarcoma. PMID- 25742630 TI - Electrokinetic preconcentration of particles and cells in microfluidic reservoirs. AB - Preconcentrating samples of dilute particles or cells to a detectable level is required in many chemical, environmental and biomedical applications. A variety of force fields have thus far been demonstrated to capture and accumulate particles and cells in microfluidic devices, which, however, all take place within the region of microchannels and may potentially cause channel clogging. This work presents a new method for the electrokinetic preconcentration of 1 MUm diameter polystyrene particles and E. coli cells in a very-low-conductivity medium inside a microfluidic reservoir. The entire microchannel can hence be saved for a post-concentration analysis. This method exploits the strong recirculating flows of induced-charge electroosmosis to concentrate particles and cells near the corners of the reservoir-microchannel interface. Positive dielectrophoresis is found to also play a role when small microchannels are used at high electric fields. Such an in-reservoir electrokinetic preconcentration method can be easily implemented in a parallel mode to increase the flow throughput, which may potentially be used to preconcentrate bacterial pathogens in water. PMID- 25742631 TI - The Disposition of Radiocontrast in the Interscalene Space in Healthy Volunteers. AB - BACKGROUND: We measured the spread of radiocontrast in the interscalene space after injection under low (<15 psi) and high (>20 psi) pressures. METHODS: Nine healthy volunteers received ultrasound-guided injections of 10 mL radio-opaque NaCl 0.9% in both interscalene spaces. Spread of injectate as assessed by computed tomography scan and discomfort on injection were recorded. RESULTS: Under both opening pressure conditions, injectate contacted 3 brachial plexus roots and spilled over the surface of the anterior and/or middle scalene muscles underneath the cervical fascia. CONCLUSIONS: Regardless of injection pressure, the interscalene space was filled with 10 mL of radiocontrast injectate. PMID- 25742632 TI - The influence of acute pulmonary hypertension on cardiac output measurements: calibrated pulse contour analysis, transpulmonary and pulmonary artery thermodilution against a modified Fick method in an animal model. AB - BACKGROUND: In critically ill patients with significant pulmonary hypertension (PH), close perioperative cardiovascular monitoring is mandatory, considering the increased morbidity and mortality in this patient group. Although the pulmonary artery catheter is still the standard for the diagnosis of PH, its use to monitor cardiac output (CO) in patients with PH is decreasing as a result of increased morbidity and possible influence of tricuspid regurgitation on the measurements. However, continuous CO measurement methods have never been evaluated under PH regarding their agreement and trending ability. In this study, we evaluated the influence of acute PH and different CO states on transpulmonary thermodilution (TPTD) and calibrated pulse contour analysis (PiCCO; both assessed with PiCCO plusTM), intermittent pulmonary artery thermodilution (PATD), and continuous thermodilution (CCO) compared with a modified Fick method (FICK) in an animal model. METHODS: Nine healthy pigs were studied under anesthesia. PH of 25 and 40 mm Hg (by administration of the thromboxane analog U46619), CO decreases, and CO increases were induced to test the different CO measurement techniques over a broad range of hemodynamic situations. Before each step, a new baseline data set was collected. CO values were compared using Bland-Altman analysis; trending abilities were assessed via concordance and polar plot analysis. The influence of pulmonary pressure on CO measurements was analyzed using linear mixed models. RESULTS: A mean bias of -0.26 L/min with prediction intervals of -0.88 to 1.4 L/min was measured between TPTD and FICK. Their concordance rate was 100% (94% 100% confidence interval), and the mean polar angle -3 degrees with radial limits of agreement of +/-28 degrees indicated good trending abilities. PATD compared with FICK also showed good trending ability. Comparisons of PiCCO and CCO versus FICK revealed low agreement and poor trending results with concordance rates of 84% (71%-93%) and 88% (74%-95%), mean polar angles from -17 degrees and -19 degrees , and radial limits of agreement of +/-45 degrees and 40 degrees . Pulmonary pressures influenced only the difference between FICK and PiCCO, as assessed by linear mixed models. CONCLUSIONS: TPTD compared with FICK was able to track all changes induced during the study period, including those by PH. It yielded better agreement than PATD both compared with FICK. PiCCO and CCO were not mapping all changes correctly, and when used clinically in unstable patients, regular controls with intermittent techniques are required. Acute pharmacologically induced PH did influence the difference between FICK and PiCCO. PMID- 25742633 TI - Kidney paired donation: a plea for a Swiss National Programme. AB - Growing incidence of end-stage renal disease, shortage of kidneys from deceased donors and a better outcome for recipients of kidneys from living donor have led many centres worldwide to favour living donor kidney transplantation programmes. Although criteria for living donation have greatly evolved in recent years with acceptance of related and unrelated donors, an immunological incompatibility, either due to ABO incompatibility and/or to positive cross-match, between a living donor and the intended recipient, could impede up to 40% of such procedures. To avoid refusal of willing and healthy living donors, a number of strategies have emerged to overcome immunological incompatibilities. Kidney paired donation is the safest way for such patients to undergo kidney transplantation. Implemented with success in many countries either as national or multiple regional independent programmes, it could include simple exchanges between any number of incompatible pairs, incorporate compatible pairs and non directed donors (NDDs) to start a chain of compatible transplantations, lead to acceptance of ABO-incompatible matching, and integrate desensitising protocols. Incorporating all variations of kidney paired donation, the Australian programme has been able to facilitate kidney transplantation in 49% of registered incompatible pairs. This review is a plea for implementing a national kidney paired donation programme in Switzerland. PMID- 25742634 TI - Correction: pea fiber and wheat bran fiber show distinct metabolic profiles in rats as investigated by a 1H NMR-based metabolomic approach. PMID- 25742635 TI - Closantel Poisoning Treated With Plasma Exchange. PMID- 25742636 TI - Peroxiredoxin isoforms are associated with cardiovascular risk factors in type 2 diabetes mellitus. AB - The production of oxygen free radicals in type 2 diabetes mellitus contributes to the development of complications, especially the cardiovascular-related ones. Peroxiredoxins (PRDXs) are antioxidant enzymes that combat oxidative stress. The aim of this study was to investigate the associations between the levels of PRDX isoforms (1, 2, 4, and 6) and cardiovascular risk factors in type 2 diabetes mellitus. Fifty-three patients with type 2 diabetes mellitus (28F/25M) and 25 healthy control subjects (7F/18M) were enrolled. We measured the plasma levels of each PRDX isoform and analyzed their correlations with cardiovascular risk factors. The plasma PRDX1, -2, -4, and -6 levels were higher in the diabetic patients than in the healthy control subjects. PRDX2 and -6 levels were negatively correlated with diastolic blood pressure, fasting blood sugar, and hemoglobin A1c. In contrast, PRDX1 levels were positively correlated with low density lipoprotein and C-reactive protein levels. PRDX4 levels were negatively correlated with triglycerides. In conclusion, PRDX1, -2, -4, and -6 showed differential correlations with a variety of traditional cardiovascular risk factors. These results should encourage further research into the crosstalk between PRDX isoforms and cardiovascular risk factors. PMID- 25742638 TI - Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence. AB - Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6 +/- 14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas. PMID- 25742640 TI - Probabilistic MRI tractography of the optic radiation using constrained spherical deconvolution: a feasibility study. AB - BACKGROUND AND PURPOSE: Imaging the optic radiation (OR) is of considerable interest in studying diseases affecting the visual pathway and for pre-surgical planning of temporal lobe resections. The purpose of this study was to investigate the clinical feasibility of using probabilistic diffusion tractography based on constrained spherical deconvolution (CSD) to image the optic radiation. It was hypothesized that CSD would provide improved tracking of the OR compared with the widely used ball-and-stick model. METHODS: Diffusion weighted MRI (30 directions) was performed on twenty patients with no known visual deficits. Tractography was performed using probabilistic algorithms based on fiber orientation distribution models of local white matter trajectories. The performance of these algorithms was evaluated by comparing computational times and receiver operating characteristic results, and by correlation of anatomical landmark distances to dissection estimates. RESULTS: The results showed that it was consistently feasible to reconstruct individual optic radiations from clinically practical (4.5 minute acquisition) diffusion weighted imaging data sets using CSD. Tractography based on the CSD model resulted in significantly shorter computational times, improved receiver operating characteristic results, and shorter Meyer's loop to temporal pole distances (in closer agreement with dissection studies) when compared to the ball-and-stick based algorithm. CONCLUSIONS: Accurate tractography of the optic radiation can be accomplished using diffusion MRI data collected within a clinically practical timeframe. CSD based tractography was faster, more accurate and had better correlation with known anatomical landmarks than ball-and-stick tractography. PMID- 25742639 TI - Manipulation of a quasi-natural cell block for high-efficiency transplantation of adherent somatic cells. AB - Recent advances have raised hope that transplantation of adherent somatic cells could provide dramatic new therapies for various diseases. However, current methods for transplanting adherent somatic cells are not efficient enough for therapeutic applications. Here, we report the development of a novel method to generate quasi-natural cell blocks for high-efficiency transplantation of adherent somatic cells. The blocks were created by providing a unique environment in which cultured cells generated their own extracellular matrix. Initially, stromal cells isolated from mice were expanded in vitro in liquid cell culture medium followed by transferring the cells into a hydrogel shell. After incubation for 1 day with mechanical agitation, the encapsulated cell mass was perforated with a thin needle and then incubated for an additional 6 days to form a quasi natural cell block. Allograft transplantation of the cell block into C57BL/6 mice resulted in perfect adaptation of the allograft and complete integration into the tissue of the recipient. This method could be widely applied for repairing damaged cells or tissues, stem cell transplantation, ex vivo gene therapy, or plastic surgery. PMID- 25742641 TI - The tail domain is essential but the head domain dispensable for C. elegans intermediate filament IFA-2 function. AB - The intermediate filament protein IFA-2 is essential for the structural integrity of the Caenorhabditis elegans epidermis. It is one of the major components of the fibrous organelle, an epidermal structure comprised of apical and basal hemidesmosomes linked by cytoplasmic intermediate filaments that serve to transmit force from the muscle to the cuticle. Mutations of IFA-2 result in epidermal fragility and separation of the apical and basal epidermal surfaces during postembryonic growth. An IFA-2 lacking the head domain fully rescues the IFA-2 null mutant, whereas an IFA-2 lacking the tail domain cannot. Conversely, an isolated IFA-2 head was able to localize to fibrous organelles whereas the tail was not. Taken together these results suggest that the head domain contains redundant signals for IF localization, whereas non-redundant essential functions map to the IFA-2, tail, although the tail is unlikely to be directly involved in fibrous organelle localization. PMID- 25742643 TI - A Comparison of Near- and Mid-Infrared Spectroscopic Methods for the Analysis of Several Nutritionally Important Chemical Substances in the Chinese Yam (Dioscorea opposita): Total Sugar, Polysaccharides, and Flavonoids. AB - The Chinese yam (Dioscorea opposita) is a basic food in Asia and especially China. Consequently, an uncomplicated, reliable method should be available for the analysis of the quality and origin of the yams. Thus, near-infrared (NIR) and mid-infrared (mid-IR) spectroscopic methods were developed to discriminate among Chinese yam samples collected from four geographical regions. The yam samples were analyzed also for total sugar, polysaccharides, and flavonoids. These three analytes were used to compare the performance of the analytical methods. Overlapping spectra were resolved using chemometrics methods. Such spectra were compared qualitatively using principal component analysis (PCA) and quantitatively using partial least squares (PLS) and least squares-support vector machine (LS-SVM) models. We discriminated among the four sets of yam data using PCA, and the NIR data performed somewhat better than the mid-IR data. We constructed the PLS and LS-SVM calibration models for the prediction of the three key variables, and the LS-SVM model produced better results. Also, the NIR prediction model produced better outcomes than the mid-IR prediction model. Thus, both infrared (IR) techniques performed well for the analysis of the three key analytes, and the samples were qualitatively discriminated according to their provinces of origin. Both techniques may be recommended for the analysis of Chinese yams, although the NIR technique would be preferred. PMID- 25742642 TI - Combined treatment with troglitazone and lovastatin inhibited epidermal growth factor-induced migration through the downregulation of cysteine-rich protein 61 in human anaplastic thyroid cancer cells. AB - Our previous studies have demonstrated that epidermal growth factor (EGF) can induce cell migration through the induction of cysteine-rich protein 61 (Cyr61) in human anaplastic thyroid cancer (ATC) cells. The aim of the present study was to determine the inhibitory effects of combined treatment with the peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand troglitazone and the cholesterol-lowering drug lovastatin at clinically achievable concentrations on ATC cell migration. Combined treatment with 5 MUM troglitazone and 1 MUM lovastatin exhibited no cytotoxicity but significantly inhibited EGF-induced migration, as determined using wound healing and Boyden chamber assays. Cotreatment with troglitazone and lovastatin altered the epithelial-to mesenchymal-transition (EMT) -related marker gene expression of the cells; specifically, E-cadherin expression increased and vimentin expression decreased. In addition, cotreatment reduced the number of filopodia, which are believed to be involved in migration, and significantly inhibited EGF-induced Cyr61 mRNA and protein expression as well as Cyr61 secretion. Moreover, the phosphorylation levels of 2 crucial signal molecules for EGF-induced Cyr61 expression, the cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), were decreased in cells cotreated with troglitazone and lovastatin. Performing a transient transfection assay revealed that the combined treatment significantly suppressed Cyr61 promoter activity. These results suggest that combined treatment with low doses of troglitazone and lovastatin effectively inhibits ATC cell migration and may serve as a novel therapeutic strategy for metastatic ATC. PMID- 25742644 TI - The nitric oxide production in the moss Physcomitrella patens is mediated by nitrate reductase. AB - During the last 20 years multiple roles of the nitric oxide gas (*NO) have been uncovered in plant growth, development and many physiological processes. In seed plants the enzymatic synthesis of *NO is mediated by a nitric oxide synthase (NOS)-like activity performed by a still unknown enzyme(s) and nitrate reductase (NR). In green algae the *NO production has been linked only to NR activity, although a NOS gene was reported for Ostreococcus tauri and O. lucimarinus, no other Viridiplantae species has such gene. As there is no information about *NO synthesis neither for non-vascular plants nor for non-seed vascular plants, the interesting question regarding the evolution of the enzymatic *NO production systems during land plant natural history remains open. To address this issue the endogenous *NO production by protonema was demonstrated using Electron Paramagnetic Resonance (EPR). The *NO signal was almost eliminated in plants treated with sodium tungstate, which also reduced the NR activity, demonstrating that in P. patens NR activity is the main source for *NO production. The analysis with confocal laser scanning microscopy (CLSM) confirmed endogenous NO production and showed that *NO signal is accumulated in the cytoplasm of protonema cells. The results presented here show for the first time the *NO production in a non vascular plant and demonstrate that the NR-dependent enzymatic synthesis of *NO is common for embryophytes and green algae. PMID- 25742646 TI - Transcriptomic responses of Atlantic salmon (Salmo salar) to environmental enrichment during juvenile rearing. AB - Captive rearing programs (hatcheries) are often used in conservation and management efforts for at-risk salmonid fish populations. However, hatcheries typically rear juveniles in environments that contrast starkly with natural conditions, which may lead to phenotypic and/or genetic changes that adversely affect the performance of juveniles upon their release to the wild. Environmental enrichment has been proposed as a mechanism to improve the efficacy of population restoration efforts from captive-rearing programs; in this study, we examine the influence of environmental enrichment during embryo and yolk-sac larval rearing on the transcriptome of Atlantic salmon (Salmo salar). Full siblings were reared in either a hatchery environment devoid of structure or an environment enriched with gravel substrate. At the end of endogenous feeding by juveniles, we examined patterns of gene transcript abundance in head tissues using the cGRASP-designed Agilent 4*44K microarray. Significance analysis of microarrays (SAM) indicated that 808 genes were differentially transcribed between the rearing environments and a total of 184 gene ontological (GO) terms were over- or under-represented in this gene list, several associated with mitosis/cell cycle and muscle and heart development. There were also pronounced differences among families in the degree of transcriptional response to rearing environment enrichment, suggesting that gene-by-environment effects, possibly related to parental origin, could influence the efficacy of enrichment interventions. PMID- 25742645 TI - Replicative DNA polymerase delta but not epsilon proofreads errors in Cis and in Trans. AB - It is now well established that in yeast, and likely most eukaryotic organisms, initial DNA replication of the leading strand is by DNA polymerase epsilon and of the lagging strand by DNA polymerase delta. However, the role of Pol delta in replication of the leading strand is uncertain. In this work, we use a reporter system in Saccharomyces cerevisiae to measure mutation rates at specific base pairs in order to determine the effect of heterozygous or homozygous proofreading defective mutants of either Pol epsilon or Pol delta in diploid strains. We find that wild-type Pol epsilon molecules cannot proofread errors created by proofreading-defective Pol epsilon molecules, whereas Pol delta can not only proofread errors created by proofreading-defective Pol delta molecules, but can also proofread errors created by Pol epsilon-defective molecules. These results suggest that any interruption in DNA synthesis on the leading strand is likely to result in completion by Pol delta and also explain the higher mutation rates observed in Pol delta-proofreading mutants compared to Pol epsilon-proofreading defective mutants. For strains reverting via AT->GC, TA->GC, CG->AT, and GC->AT mutations, we find in addition a strong effect of gene orientation on mutation rate in proofreading-defective strains and demonstrate that much of this orientation dependence is due to differential efficiencies of mispair elongation. We also find that a 3'-terminal 8 oxoG, unlike a 3'-terminal G, is efficiently extended opposite an A and is not subject to proofreading. Proofreading mutations have been shown to result in tumor formation in both mice and humans; the results presented here can help explain the properties exhibited by those proofreading mutants. PMID- 25742647 TI - Bacterial immune evasion through manipulation of host inhibitory immune signaling. PMID- 25742649 TI - Correction: methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles. PMID- 25742648 TI - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes esophageal squamous cell carcinoma growth via beta-adrenoceptors in vitro and in vivo. AB - Cigarette smoke is a risk factor for esophageal squamous cell carcinoma (ESCC). It contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) is one of the strongest carcinogens in tobacco and our previous studies have shown its proliferation-promoting role in the progression of ESCC. Recently, NNK was identified as an agonist for both beta1- and beta2 adrenoceptors. Thus, we hypothesized that the cancer-promoting effect of NNK was likely mediated through beta-adrenoceptors in ESCC. Therefore, we investigated the comprehensive role of NNK in ESCC in vitro and in vivo, and found that NNK promoted many oncogenic features including ESCC cell proliferation and xenograft tumor growth as well as ESCC cell migration and invasion. Western blotting showed that NNK induced significant up-regulation of phosphorylated ERK1/2, cyclin D1, Bcl-2, and vascular endothelial growth factor as well as down-regulation of Bax. Importantly, the oncogenic effects of NNK in ESCC and the altered protein expression were reversed to some extent by down-regulation of beta1- and beta2 adrenoceptors with the beta2-adrenoceptor showing a greater rescue effect. Taken together, our in vitro and in vivo results demonstrate that NNK plays an oncogenic role in ESCC through beta-adrenoceptors. Furthermore, beta2 adrenoceptor might play a more important role in this process. Our findings might provide a chemoprevention and therapy strategy for cigarette smoke-related ESCC carcinogenesis. PMID- 25742650 TI - p53 Status correlates with the risk of recurrence in non-muscle invasive bladder cancers treated with Bacillus Calmette-Guerin: a meta-analysis. AB - OBJECTIVE: Published studies have yielded inconsistent results on the relationship between p53 status and the prognosis of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG) intravesical therapy. Therefore, we performed a meta-analysis to evaluate the prognostic value of p53 in NMIBC treated with BCG. METHODS: We systematically searched for relevant literature in PubMed, EMBASE, CNKI, and Chinese Wanfang databases. Hazard ratios (HRs) with 95% confidence intervals (CIs) were combined as the effect size (ES) across studies for recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: A total of 11 studies, consisting of 1,049 participants, met the criteria. Overall, there was no clear relationship between p53 status and RFS or PFS for NMIBC patients treated with BCG (HR: 1.40, 95% CI: 0.91-2.16; HR: 1.37, 95% CI: 0.90-2.09, respectively). Obvious heterogeneity was observed across the studies (I2 = 69.5%, P = 0.001; I2 = 44.7%, P = 0.081, respectively). In stratified analysis by region, p53 overexpression was a predictor of poor RFS in Asian populations (HR: 1.57, 95% CI: 1.08-2.27). In addition, after excluding the studies that possibly contributed to the heterogeneity by the Galbraith plot, the overall association for RFS became statistically significant (HR: 1.38 95% CI: 1.08-1.77) without evidence of heterogeneity (I2 = 0.0%, P = 0.499). CONCLUSION: This meta-analysis suggests that p53 overexpression in NMIBC patients treated with BCG may be associated with RFS, especially in Asian populations. Because of the heterogeneity and other limitations, further studies with rigid criteria and large populations are still warranted to confirm our findings. PMID- 25742652 TI - Correction: An unusual occurrence of Nautilus macromphalus in a cenote in the Loyalty Islands (New Caledonia). PMID- 25742651 TI - Binding of subdomains 1/2 of PfEMP1-DBL1alpha to heparan sulfate or heparin mediates Plasmodium falciparum rosetting. AB - The capacity of Plasmodium falciparum parasitized erythrocytes (pRBC) to adhere to the endothelial lining in the microvasculature and to red blood cells (RBC) is associated with the virulence of the parasite, the pathogenesis and development of severe malaria. Rosetting, the binding of uninfected RBC to pRBC, is frequently observed in individuals with severe malaria and is mediated by the N terminal NTS-DBL1alpha domain of the adhesin Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed at the surface of the pRBC. Heparan sulfate has been suggested to be an important receptor for the NTS-DBL1alpha variant IT4(var60) expressed by the parasite FCR3S1.2. Here, we have determined the binding site of NTS-DBL1alpha (IT4(var60)) to the RBC and heparin using a set of recombinant, mutated proteins expressed in and purified from E. coli. All the variants were studied for their ability to bind to RBC, their capacities to disrupt FCR3S1.2 rosettes, their affinities for heparin and their binding to rosette-disruptive mAbs. Our results suggest that NTS-DBL1alpha mediates binding to RBC through a limited number of basic amino acid residues localized on the surface of subdomains 1 (SD1) and 2 (SD2). The SD2-binding site is localized in close proximity to one of two previously identified binding sites in the rosetting PfEMP1 of the parasite PaloAlto-varO. The binding site in SD2 of NTS DBL1alpha could represent a template for the development of anti-rosetting drugs. PMID- 25742653 TI - Correction: Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer. PMID- 25742654 TI - An ex vivo model for anti-angiogenic drug testing on intact microvascular networks. AB - New models of angiogenesis that mimic the complexity of real microvascular networks are needed. Recently, our laboratory demonstrated that cultured rat mesentery tissues contain viable microvascular networks and could be used to probe pericyte-endothelial cell interactions. The objective of this study was to demonstrate the efficacy of the rat mesentery culture model for anti-angiogenic drug testing by time-lapse quantification of network growth. Mesenteric windows were harvested from adult rats, secured in place with an insert, and cultured for 3 days according to 3 experimental groups: 1) 10% serum (angiogenesis control), 2) 10% serum + sunitinib (SU11248), and 3) 10% serum + bevacizumab. Labeling with FITC conjugated BSI-lectin on Day 0 and 3 identified endothelial cells along blood and lymphatic microvascular networks. Comparison between day 0 (before) and 3 (after) in networks stimulated by 10% serum demonstrated a dramatic increase in vascular density and capillary sprouting. Growing networks contained proliferating endothelial cells and NG2+ vascular pericytes. Media supplementation with sunitinib (SU11248) or bevacizumab both inhibited the network angiogenic responses. The comparison of the same networks before and after treatment enabled the identification of tissue specific responses. Our results establish, for the first time, the ability to evaluate an anti-angiogenic drug based on time-lapse imaging on an intact microvascular network in an ex vivo scenario. PMID- 25742656 TI - Correction: Psychological stress exerts effects on pathogenesis of hepatitis B via type-1/type-2 cytokines shift toward type-2 cytokine response. PMID- 25742655 TI - Quantification of cellular NEMO content and its impact on NF-kappaB activation by genotoxic stress. AB - NF-kappaB essential modulator, NEMO, plays a key role in canonical NF-kappaB signaling induced by a variety of stimuli, including cytokines and genotoxic agents. To dissect the different biochemical and functional roles of NEMO in NF kappaB signaling, various mutant forms of NEMO have been previously analyzed. However, transient or stable overexpression of wild-type NEMO can significantly inhibit NF-kappaB activation, thereby confounding the analysis of NEMO mutant phenotypes. What levels of NEMO overexpression lead to such an artifact and what levels are tolerated with no significant impact on NEMO function in NF-kappaB activation are currently unknown. Here we purified full-length recombinant human NEMO protein and used it as a standard to quantify the average number of NEMO molecules per cell in a 1.3E2 NEMO-deficient murine pre-B cell clone stably reconstituted with full-length human NEMO (C5). We determined that the C5 cell clone has an average of 4 x 10(5) molecules of NEMO per cell. Stable reconstitution of 1.3E2 cells with different numbers of NEMO molecules per cell has demonstrated that a 10-fold range of NEMO expression (0.6-6x10(5) molecules per cell) yields statistically equivalent NF-kappaB activation in response to the DNA damaging agent etoposide. Using the C5 cell line, we also quantified the number of NEMO molecules per cell in several commonly employed human cell lines. These results establish baseline numbers of endogenous NEMO per cell and highlight surprisingly normal functionality of NEMO in the DNA damage pathway over a wide range of expression levels that can provide a guideline for future NEMO reconstitution studies. PMID- 25742657 TI - Correction: Tetrahydrocurcumin protects against cadmium-induced hypertension, raised arterial stiffness and vascular remodeling in mice. PMID- 25742658 TI - Development of a high-throughput resequencing array for the detection of pathogenic mutations in osteogenesis imperfecta. AB - OBJECTIVE: Osteogenesis imperfecta (OI) is a rare inherited skeletal disease, characterized by bone fragility and low bone density. The mutations in this disorder have been widely reported to be on various exonal hotspots of the candidate genes, including COL1A1, COL1A2, CRTAP, LEPRE1, and FKBP10, thus creating a great demand for precise genetic tests. However, large genome sizes make the process daunting and the analyses, inefficient and expensive. Therefore, we aimed at developing a fast, accurate, efficient, and cheaper sequencing platform for OI diagnosis; and to this end, use of an advanced array-based technique was proposed. METHOD: A CustomSeq Affymetrix Resequencing Array was established for high-throughput sequencing of five genes simultaneously. Genomic DNA extraction from 13 OI patients and 85 normal controls and amplification using long-range PCR (LR-PCR) were followed by DNA fragmentation and chip hybridization, according to standard Affymetrix protocols. Hybridization signals were determined using GeneChip Sequence Analysis Software (GSEQ). To examine the feasibility, the outcome from new resequencing approach was validated by conventional capillary sequencing method. RESULT: Overall call rates using resequencing array was 96-98% and the agreement between microarray and capillary sequencing was 99.99%. 11 out of 13 OI patients with pathogenic mutations were successfully detected by the chip analysis without adjustment, and one mutation could also be identified using manual visual inspection. CONCLUSION: A high throughput resequencing array was developed that detects the disease-associated mutations in OI, providing a potential tool to facilitate large-scale genetic screening for OI patients. Through this method, a novel mutation was also found. PMID- 25742659 TI - Outer membrane protein U (OmpU) mediates adhesion of Vibrio mimicus to host cells via two novel N-terminal motifs. AB - Vibrio mimicus (V.mimicus) is a causative agent of ascites disease in aquatic animals. Our previous studies have demonstrated that the outer membrane protein U (OmpU) from V.mimicus is an immunoprotective antigen with six immunodominant linear B-cell epitopes. Although the N-terminus of OmpU contains potential binding motifs, it remained unclear whether OmpU possesses adhesion function. Here, the adhesive capacity of recombinant OmpU and V.mimicus to epithelioma papulosum cyprinid (EPC) cells was determined by immunofluorescence and adherence assay. The results showed that after co-incubated with rOmpU, an obvious visible green fluorescence could be observed on the EPC cell surface and the nuclei exhibited blue fluorescence; while the control cell surface did not show any signal, only nuclei exhibited blue fluorescence. The average number of wild-type strain adhered to each cell was 32.3 +/- 4.5. The average adhesion number of OmpU gene deletion mutant was significantly reduced to 10.8 +/- 0.5 (P < 0.01) and restored to 31.3 +/- 2.8 by complement strain (P >0.05). Pretreatment of cells with rOmpU reduced the average adhesion number of wild-type strain to 9.7 +/- 2.9 (P < 0.01). Likewise, binding was significantly decreased to 8.8 +/- 3.2 (P < 0.01) due to blocking role of OmpU antibodies. To determine binding motifs of OmpU, six immunodominant B-cell epitope peptides labeled with FITC were employed in flow cytometry-based binding assay. Two FITC-labeled epitope peptides (aa90 101 and aa173-192) showed strong binding to EPC cells (the fluorescence positive cell rate was 99 +/- 0.6% and 98 +/- 0.3%, respectively), which could be specifically competed by excess corresponding unlabeled peptides, whereas the remaining four showed a low level of background binding. This is the first demonstration that OmpU possesses adhesion function and its N terminal 90-101 and 173-192 amino acid regions are critical sites for cell surface binding. PMID- 25742660 TI - Rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients. AB - Cystic fibrosis patients are highly susceptible to infections with non tuberculous mycobacteria. Especially Mycobacterium abscessus infections are common but reliable diagnosis is hampered by non-specific clinical symptoms and insensitive mycobacterial culture. In the present study we established novel methods for rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients. We performed Mycobacterium abscessus specific DNA-strip- and quantitative PCR-based analyses of non-cultured sputum samples to detect and characterize Mycobacterium abscessus infections. Concomitantly in vitro T-cell reactivation with purified protein derivatives (PPDs) from different mycobacterial species was used to determine Mycobacterium abscessus specific T-cell cytokine expression of infected cystic fibrosis patients. Four of 35 cystic fibrosis patients (11.4%) were Mycobacterium abscessus culture positive and showed concordant DNA-strip-test results. Quantitative PCR revealed marked differences of mycobacterial burden between cystic fibrosis patients and during disease course. Tandem-repeat analysis classified distinct Mycobacterium abscessus strains of infected cystic fibrosis patients and excluded patient-to-patient transmission. Mycobacterium abscessus specific T-cells were detected in the blood of cystic fibrosis patients with confirmed chronic infection and a subgroup of patients without evidence of Mycobacterium abscessus infection. Comparison of cytokine expression and phenotypic markers revealed increased proportions of CD40L positive T-cells that lack Interleukin-2 expression as a marker for chronic Mycobacterium abscessus infections in cystic fibrosis patients. Direct sputum examination enabled rapid diagnosis and quantification of Mycobacterium abscessus in cystic fibrosis patients. T-cell in vitro reactivation and cytokine expression analyses may contribute to diagnosis of chronic Mycobacterium abscessus infection. PMID- 25742661 TI - Increasing research literacy: the community research fellows training program. AB - The Community Research Fellows Training (CRFT) Program promotes the role of underserved populations in research by enhancing the capacity for community-based participatory research (CBPR). CRFT consists of 12 didactic training sessions and 3 experiential workshops intended to train community members in research methods and evidence-based public health. The training (a) promotes partnerships between community members and academic researchers, (b) enhances community knowledge of public health research, and (c) trains community members to become critical consumers of research. Fifty community members participated in training sessions taught by multidisciplinary faculty. Forty-five (90%) participants completed the program. Findings demonstrate that the training increased awareness of health disparities, research knowledge, and the capacity to use CBPR as a tool to address disparities. PMID- 25742662 TI - Awareness of Federal Regulatory Mechanisms Relevant to Community-Engaged Research: Survey of Health Disparities-Oriented NIH-Funded Investigators. AB - Few studies or investigators involved in community-engaged research or community based participatory research have examined awareness and adoption of federal regulatory mechanisms. We conducted a survey of investigators affiliated with the 10 National Institutes of Health (NIH) Centers for Population Health and Health Disparities. A questionnaire designed to capture experience with the conduct and oversight of community-engaged research, and awareness of pertinent regulatory mechanisms, including Federalwide Assurances (FWAs), Individual Investigator Agreements (IIAs), and Institutional Review Board Authorization Agreements (IAAs), was completed by 101 respondents (68% response rate). Although most were aware of FWAs, only a minority of those surveyed reported knowledge of IAAs and IIAs and even fewer had used them in their research with community partners. Implications for future training and oversight are discussed. PMID- 25742663 TI - Ethical issues in patient-centered outcomes research and comparative effectiveness research: a pilot study of community dialogue. AB - Community bioethics dialogues were held on the topic of patient-centered outcomes research (PCOR) and comparative effectiveness research (CER). Participants were 65 and older and represented either a lower income, African American group (A) or a higher income White group (B). Participants were presented with a variety of background reading and study materials. Meetings were held 2 hr per week for 6 weeks. The groups showed both independence in judgment from the investigators and diversity of opinion between the two groups. Group B addressed more topics than Group A and in some instances explored additional policy nuances. Members of Group A appeared more cognizant of issues of social justice that affect vulnerable populations and appeared leery of approaches that suggested possible disrespect for their own personal experiences. Future plans call for both repeating the dialogue with additional, diverse community groups and repeating community bioethics dialogues on new topics with the same groups. PMID- 25742664 TI - An Analysis of Information Technology Adoption by IRBs of Large Academic Medical Centers in the United States. AB - The clinical research landscape has changed dramatically in recent years in terms of both volume and complexity. This poses new challenges for Institutional Review Boards' (IRBs) review efficiency and quality, especially at large academic medical centers. This article discusses the technical facets of IRB modernization. We analyzed the information technology used by IRBs in large academic institutions across the United States. We found that large academic medical centers have a high electronic IRB adoption rate; however, the capabilities of electronic IRB systems vary greatly. We discuss potential use cases of a fully exploited electronic IRB system that promise to streamline the clinical research work flow. The key to that approach utilizes a structured and standardized information model for the IRB application. PMID- 25742665 TI - The MICHR Genomic DNA BioLibrary: An Empirical Study of the Ethics of Biorepository Development. AB - In this article, we report on an effort to study the development and usefulness of a large, broad-use, opt-in biorepository for genomic research, focusing on three ethical issues: providing appropriate understanding, recruiting in ways that do not comprise autonomous decisions, and assessing costs versus benefits. We conclude the following: (a) Understanding can be improved by separating the task of informing subjects from documenting informed consent (Common Rule) and permission to use personal health information and samples for research (Health Insurance Portability and Accountability Act [HIPAA]); however, regulations might have to be changed to accommodate this approach. (b) Changing recruiting methods increases efficiency but can interfere with subject autonomy. (c) Finally, we propose a framework for the objective evaluation of the utility of biorepositories and suggest that more attention needs to be paid to use and sustainability. PMID- 25742666 TI - Contrasting views of risk perception and influence of financial compensation between adolescent research participants and their parents. AB - U.S. regulations governing pediatric research do not specify the assent process. To identify best practices, it is important to examine parents' and adolescents' views. The present study focuses on parents' and adolescents' views regarding possible research risks and the influence of financial compensation on their willingness to accept research procedures. Interviews were conducted with 177 adolescents participating in clinical research for a medical or psychiatric illness, or as healthy volunteers, and a parent. Significant discordance was found between how bothered the teen would feel from research-related side effects and procedures compared with parental report. Most teens were willing to accept non-beneficial procedures without compensation. Payment had significantly greater influence on healthy volunteers and their parents compared with those with a medical or psychiatric illness. Discordance between adolescent and parental views about risks recommends obtaining direct input from adolescents during the assent process. Modest payments should not raise concerns of undue inducement, especially in teens with pre-existing conditions. PMID- 25742667 TI - Motivational factors for participation in biomedical research: evidence from a qualitative study of biomedical research participation in Blantyre District, Malawi. AB - Obtaining effective informed consent from research participants is a prerequisite to the conduct of an ethically sound research. Yet it is believed that obtaining quality informed consent is generally difficult in settings with low socioeconomic status. This is so because of the alleged undue inducements and therapeutic misconception among participants. However, there is a dearth of data on factors that motivate research participants to take part in research. Hence, this study was aimed at filling this gap in the Malawian context. We conducted 18 focus group discussions with community members in urban and rural communities of Blantyre in Malawi. Most participants reported that they accepted the invitation to participate in research because of better quality treatment during study also known as ancillary care, monetary and material incentives given to participants, and thorough medical diagnosis. PMID- 25742668 TI - Using "clinical trial diaries" to track patterns of participation for serial healthy volunteers in U.S. phase I studies. AB - Phase I testing of investigational drugs relies on healthy volunteers as research participants. Many U.S. healthy volunteers enroll repeatedly in clinical trials for the financial compensation. Serial participants are incentivized to ignore restrictions on their participation, and no centralized clinical trial registry prevents dual enrollment. Little is currently known about how healthy volunteers participate in studies over time, hampering the development of policies to protect this group. We detail a methodology developed as part of a longitudinal study to track in real-time healthy volunteers' Phase I participation. Illustrating these data through three case studies, we document how healthy volunteers use strategies, such as qualifying for studies at more than one clinic and traveling significant distances, to maximize their participation. Our findings suggest that "clinical trial diaries" can generate critical information about serial research participation and point to ethical issues unique to healthy volunteers' involvement in Phase I clinical trials. PMID- 25742669 TI - Postpartum Women's Perspectives on the Donation of Placentas for Scientific Research in Campinas, Brazil. AB - Little is known about public perspectives of scientific and therapeutic uses of placentas. Gaps in knowledge potentiate ethical and clinical problems regarding collection and applications. As such, this study sought to assess the perspectives of placenta donation of a sample of women. Postpartum women's perspectives on placental donation were assessed at the State University of Campinas in the Centro de Atencao Integral a Saude da Mulher (CAISM) maternity hospital using a cross-sectional survey (n = 384) and semi-structured interviews (n = 12). Surveys were analyzed quantitatively and interviews were analyzed qualitatively using grounded coding; results were compared. The average age of respondents was 27. Fifty-six percent had more than one child, 45% were Caucasian, 38% were mixed-race, 74% identified with a Christian faith, 52% had high school education or higher, 13% regarded the placenta as spiritually important, 72% felt that knowing what happens to the placenta after birth was somewhat or very important, 78% supported the use of the placenta in research and medicine, 59% reported that consent to collect the placenta was very or somewhat important, 78% preferred their doctor to invite donation, and only 7% preferred the researcher to invite donation. Interviews suggested women appreciate being part of research and that receiving information about studies was important to them. Informed by these results, we argue that women support scientific and therapeutic uses of placentas, want to be included in decision making, and desire information about the placenta. Placentas should not be viewed as "throwaway" organs that are poised for collection without the involvement and permission of women. Women want to be meaningfully included in research processes. PMID- 25742670 TI - Parent perspectives on privacy and governance for a pediatric repository of non biological, research data. AB - Research data repositories (RDRs) are data storage entities where data can be submitted, stored, and subsequently accessed for purposes beyond the original intent. There is little information relating to non-biological RDRs, nor considerations regarding pediatric data storage and re-use. We examined parent perspectives on pediatric, non-biological RDRs. Qualitative, descriptive methods including both interviews and focus groups were used. Purposive sampling of adult participants in two provincial birth cohorts yielded 19 interviewees and 18 focus group participants (4 groups). Transcripts were analyzed by thematic content analysis. Parent research participants strongly supported the sharing of their own, and their child's, non-biological research data. Four themes emerged: that altruism has limits, that participants have ongoing privacy concerns, that some participants need the assurance of congruent values between themselves and researchers/research questions, and that opinions diverge for some governance issues. The establishment of RDRs is important and maximizes participants', researchers', and funders' investments. Participants as data donors have concerns relating to privacy, relationships, and governance that must be considered in RDR development. PMID- 25742671 TI - Simplifying the complexity of confidentiality in research. PMID- 25742672 TI - Measuring voluntariness of consent to research: an instrument review. AB - The conceptual complexity of the term voluntariness has resulted in relatively few empirical studies of the voluntariness component of consent to research. As the call for a formal assessment of voluntariness to be incorporated into the consent process intensifies, more researchers are responding to the challenge of developing a valid and reliable measure of voluntariness. The purpose of this article was to summarize and describe the empirical literature on voluntariness of consent. As part of a broader study on the voluntariness of consent to research, existing empirical studies of voluntariness of consent to research were reviewed to establish how voluntariness of consent to research has been assessed to date. Fifteen studies using different voluntariness assessment instruments were identified and included in the review. The review found that little attempt has been made to systematically collect data on the reliability and validity of voluntariness assessment instruments. No two instruments reviewed were found to be based on a shared conceptualization of voluntary consent to research. PMID- 25742673 TI - Analysis of research ethics board approval times in an academic department of medicine. AB - As part of an ongoing effort to better understand barriers to academic research, we reviewed and analyzed the process of research ethics applications, focusing on ethics approval time, within the Department of Medicine from 2006 to 2011. A total of 1,268 applications for approval to use human subjects in research were included in our analysis. Three variables, risk category (minimal vs. non-minimal risk), type of funding, and year of submission, were statistically significant for prediction of ethics approval time, with risk status being the most important of these. The covariate-adjusted mean time for approval for minimal risk studies (35.7 days) was less than half that of non-minimal risk protocols (76.5 days). Studies funded through a for-profit sponsor had significantly longer approval times than those funded through other means but were also predominantly (87%) non minimal risk protocols. Further investigations of the reasons underlying the observed differences are needed to determine whether improved training for research ethics board (REB) members and/or greater dialogue with investigators may reduce the lengthy approval times associated with non-minimal risk protocols. PMID- 25742674 TI - The views of quality improvement professionals and comparative effectiveness researchers on ethics, IRBs, and oversight. AB - Recently, there have been increasing numbers of activities labeled as either quality improvement (QI) or comparative effectiveness research (CER), both of which are designed to learn what works and what does not in routine clinical care settings. These activities can create confusion for researchers, Institutional Review Board members, and other stakeholders as they try to determine which activities or components of activities constitute clinical practices and which constitute clinical research requiring ethical oversight and informed consent. We conducted a series of semi-structured focus groups with QI and CER professionals to understand their experiences and views of the ethical and regulatory challenges that exist as well as the formal or informal practices and criteria they and their institutions use to address these issues. We found that most participants have experienced challenges related to the ethical oversight of QI and CER activities, and many believe that current regulatory criteria for distinguishing clinical practice from clinical research requiring ethical oversight are confusing. Instead, many participants described other criteria that they believe are more ethically appropriate. Many also described developing formal or informal practices at their institutions to navigate which activities require ethical oversight. However, these local solutions do not completely resolve the issues caused by the blurring of clinical practice and clinical research, raising the question of whether more foundational regulatory changes are needed. PMID- 25742675 TI - The development of a preference-setting model for the return of individual genomic research results. AB - Understanding participants' preferences for the return of individual research results (IRR) in genomic research may allow for the implementation of more beneficial result disclosure methods. We tested four preference-setting models through cognitive interviews of parents to explore how parents conceptualize the process of setting preferences and which disease characteristics they believe to be most important when deciding what results to receive on their child. Severity and preventability of a condition were highly influential in decision making and certain groups of research results were anticipated by participants to have negative psychological effects. These findings informed the development of an educational tool and preference-setting model that can be scaled for use in the return of IRR from large biobank studies. PMID- 25742676 TI - Let's get technical. PMID- 25742677 TI - Advances in laser dentistry: expanding beyond periodontal care. PMID- 25742678 TI - In memoriam: Morton Amsterdam, 1921-2014. PMID- 25742679 TI - Technology education and training: the need for a comprehensive plan. PMID- 25742680 TI - Digital intraoral imaging: a beneficial patient education tool. PMID- 25742681 TI - ScanX SwiftTM: comfortable, convenient, affordable PSP digital imaging. PMID- 25742682 TI - Benefits of Sirona's ORTHOPHOS XG 3D system extend far beyond implantology. PMID- 25742683 TI - SIMPLANT(r) computer-guided implant treatment software: unlocking digital potential. PMID- 25742684 TI - Responsive web design: online marketing mobility. PMID- 25742685 TI - Getting ahead: "Real-world" technologies give dental school grads an edge. PMID- 25742687 TI - Abortion 'on the NHS': the National Health Service and abortion stigma. PMID- 25742686 TI - Risk of dementia in peritoneal dialysis patients compared with hemodialysis patients. AB - BACKGROUND: Compared with similarly aged controls, patients with end-stage renal disease (ESRD) have a higher prevalence of cognitive impairment and more rapid cognitive decline, which is not explained by traditional risk factors alone. Since previous small studies suggest an association of cognitive impairment with dialysis modality, we compared incident dementia among patients initiating hemodialysis (HD) vs peritoneal dialysis (PD) in a large national cohort. METHODS: This is a retrospective cohort study of incident dialysis patients in the United States from 2006 to 2008 with no diagnosis of dementia prior to beginning dialysis. We evaluated the effect of initial dialysis modality on incidence of dementia, diagnosed by Medicare claims data, adjusted for baseline demographic and clinical data from the USRDS registry. RESULTS: Our analysis included 121,623 patients, of whom 8,663 initiated dialysis on PD. The mean age of our cohort was 69.2 years. Patients who initiated PD had a lower cumulative incidence of dementia than those who initiated HD (1.0% vs 2.7%, 2.5% vs 5.3%, and 3.9% vs 7.3% at 1, 2, and 3 years, respectively). The risk of dementia for patients who started on PD was lower compared with those who started on HD, with a hazard ratio (HR) = 0.46 [0.41, 0.53], in an unadjusted model and HR 0.74 [0.64, 0.86] in a matched model. CONCLUSIONS: Dialysis modality is associated with incident dementia in a cohort of older ESRD patients. This finding warrants further investigation of the effect of dialysis modality on cognitive function and evaluation for possible mechanisms. PMID- 25742688 TI - What investigations are needed to optimally monitor for malignancies in SLE? AB - OBJECTIVE: The overall cancer incidence risk in systemic lupus erythematosus (SLE) is approximately 15%-20% more than in the general population. Nevertheless, to date, the optimal malignancy screening measures in SLE remain undefined. Our objective is to determine what investigations are needed to optimally monitor for malignancies in SLE in order to inform upcoming Canadian Rheumatology Association recommendations. METHODS: We conducted a systematic search looking at three scientific sources, Embase, Medline and Cochrane, in an attempt to identify cancer screening recommendations for patients with SLE. We used a filter for observational studies and included articles published in 2000 and onward. RESULTS: The initial search strategy led to 986 records. After removal of duplicates and articles unrelated to SLE, we were left with 497 titles. From those, 79 research articles on cancer incidence in SLE were isolated and reviewed. Of the 79 original research papers, 25 offered screening recommendations, 14 suggested additional cancer screening whereas 11 studies simply promoted adherence to general population screening measures. The suggestions for more rigorous screening included recommending human papilloma virus testing in addition to routine cervical screening, and/or that cervical screening should be performed annually and/or suggested urine cancer screening in SLE patients with a history of cyclophosphamide exposure. CONCLUSIONS: We found no original research studies directly comparing cancer screening strategies in SLE. Generally, authors recommend adherence to general population screening measures, particularly cervical screening. This, possibly with adding targeted screening in special cases (e.g. annual urine cytology in patients with prior cyclophosphamide exposure, and considering existing lung cancer screening guidelines for past heavy smokers), may be a reasonable approach for cancer screening in SLE. PMID- 25742689 TI - Crowdfunding sought for study that will provide first images of human brain on LSD. PMID- 25742690 TI - VP5 autocleavage is required for efficient infection by in vitro-recoated aquareovirus particles. AB - Grass carp reovirus (GCRV) is a member of the genus Aquareovirus in the family Reoviridae, and contains five core proteins (VP1-VP4 and VP6) and two outer capsid proteins (VP5 and VP7) in its particle. Previous studies have revealed that the outer-capsid proteins of reovirus are responsible for initiating infection, but the mechanism is poorly understood. Using baculovirus-expressed VP5 and VP7 to recoat purified cores, in vitro assembly of GCRV was achieved in this study. Recoated GCRV (R-GCRV) closely resembled native GCRV (N-GCRV) in particle morphology, protein composition and infectivity. Similar to N-GCRV, the infectivity of R-GCRV could be inhibited by treating cells with the weak base NH4Cl. In addition, recoated particles carrying an Asn->Ala substitution at residue 42 of VP5 (VP5N42A/VP7 R-GCRV) were no longer infectious. These results provide strong evidence that autocleavage of VP5 is critical for aquareovirus to initiate efficient infection. PMID- 25742691 TI - Laser-assisted one-pot fabrication of calcium phosphate-based submicrospheres with internally crystallized magnetite nanoparticles through chemical precipitation. AB - In this paper, we have further developed our simple (one-pot) and rapid (short irradiation time) laser fabrication process of submicrometer spheres composed of amorphous calcium iron phosphate. In our previous process, laser irradiation was applied to a calcium phosphate (CaP) reaction mixture supplemented with ferric ions (Fe(3+)) as a light-absorbing agent. Because the intention of the present study was to fabricate magnetite-encapsulated CaP-based submicrometer spheres, ferrous ions (Fe(2+)) were used as a light-absorbing agent rather than ferric ions. The ferrous ions served as a light-absorbing agent and facilitated the fabrication of submicrometer and micrometer spheres of amorphous calcium iron phosphate. The sphere formation and growth were better promoted by the use of ferrous ions as compared with the use of ferric ions. The chemical composition of the spheres was controllable through adjustment of the experimental conditions. By the addition of sodium hydroxide to the CaP reaction mixture supplemented with ferrous ions, fabrication of CaP-based magnetic submicrometer spheres was successfully achieved. Numerous magnetite and wustite nanoparticles were coprecipitated or segregated into the CaP-based spherical amorphous matrix via light-material interaction during the CaP precipitation process. The magnetic properties of the magnetite and wustite formed in the CaP-based spheres were investigated by magnetization measurements. The present process and the resulting CaP-based spheres are expected to have great potential for biomedical applications. PMID- 25742692 TI - A facile method to establish human induced pluripotent stem cells from adult blood cells under feeder-free and xeno-free culture conditions: a clinically compliant approach. AB - Reprogramming human adult blood mononuclear cells (MNCs) cells by transient plasmid expression is becoming increasingly popular as an attractive method for generating induced pluripotent stem (iPS) cells without the genomic alteration caused by genome-inserting vectors. However, its efficiency is relatively low with adult MNCs compared with cord blood MNCs and other fetal cells and is highly variable among different adult individuals. We report highly efficient iPS cell derivation under clinically compliant conditions via three major improvements. First, we revised a combination of three EBNA1/OriP episomal vectors expressing five transgenes, which increased reprogramming efficiency by >=10-50-fold from our previous vectors. Second, human recombinant vitronectin proteins were used as cell culture substrates, alleviating the need for feeder cells or animal-sourced proteins. Finally, we eliminated the previously critical step of manually picking individual iPS cell clones by pooling newly emerged iPS cell colonies. Pooled cultures were then purified based on the presence of the TRA-1-60 pluripotency surface antigen, resulting in the ability to rapidly expand iPS cells for subsequent applications. These new improvements permit a consistent and reliable method to generate human iPS cells with minimal clonal variations from blood MNCs, including previously difficult samples such as those from patients with paroxysmal nocturnal hemoglobinuria. In addition, this method of efficiently generating iPS cells under feeder-free and xeno-free conditions allows for the establishment of clinically compliant iPS cell lines for future therapeutic applications. PMID- 25742694 TI - Acupuncture treatment for chronic knee pain: study by Hinman et al underestimates acupuncture efficacy. PMID- 25742693 TI - Peripheral blood-derived mesenchymal stem cells: candidate cells responsible for healing critical-sized calvarial bone defects. AB - Postnatal tissue-specific stem/progenitor cells hold great promise to enhance repair of damaged tissues. Many of these cells are retrieved from bone marrow or adipose tissue via invasive procedures. Peripheral blood is an ideal alternative source for the stem/progenitor cells because of its ease of retrieval. We present a coculture system that routinely produces a group of cells from adult peripheral blood. Treatment with these cells enhanced healing of critical-size bone defects in the mouse calvarium, a proof of principle that peripheral blood-derived cells can be used to heal bone defects. From these cells, we isolated a subset of CD45( ) cells with a fibroblastic morphology. The CD45(-) cells were responsible for most of the differentiation-induced calcification activity and were most likely responsible for the enhanced healing process. These CD45(-) fibroblastic cells are plastic-adherent and exhibit a surface marker profile negative for CD34, CD19, CD11b, lineage, and c-kit and positive for stem cell antigen 1, CD73, CD44, CD90.1, CD29, CD105, CD106, and CD140alpha. Furthermore, these cells exhibited osteogenesis, chondrogenesis, and adipogenesis capabilities. The CD45(-) fibroblastic cells are the first peripheral blood-derived cells that fulfill the criteria of mesenchymal stem cells as defined by the International Society for Cellular Therapy. We have named these cells "blood-derived mesenchymal stem cells." PMID- 25742695 TI - Estimating the burden of minor ailment consultations in general practices and emergency departments through retrospective review of routine data in North East Scotland. AB - BACKGROUND: Minor ailment attendances in general practices and emergency departments (EDs) place significant burden on health care resources. OBJECTIVES: To estimate the prevalence and type of minor ailment consultations for adults in general practice and ED that could be managed in a community pharmacy. METHODS: Retrospective review of routine data from general practices (n = 2) and one ED in North East Scotland. Two independent consensus panels assessed each consultation summary to determine whether it represented a minor ailment. Outcomes included prevalence of consultations for minor ailments in general practice and ED and frequency of different minor ailment type that could be managed in community pharmacies. RESULTS: In total, of the 494 general practice and 550 ED consultations assessed, 13.2% [95% confidence interval (CI): 18.6-25.9%] and 5.3% (95% CI: 4.0-8.0%), respectively, were categorized as minor ailments suitable for management in community pharmacies. Consensus among panel members was moderate for general practice consultations, but fair to poor for ED consultations. Agreement between uni- and multi-disciplinary panels was good. Applied to national data, these estimates would equate to ~18 million general practice and 6500000 ED consultations that could be redirected to community pharmacy, equating to ~L1.1 billion in resources. CONCLUSION: Minor ailment consultations still present a major burden on higher cost settings. Effective strategies are needed to raise awareness among patients and health professionals regarding conditions that can be managed effectively in pharmacies and to change patient health seeking behaviour for such conditions. PMID- 25742696 TI - Clinical and epidemiological characteristics of patients with early syphilis from three academic centres in Poland, Germany and Ireland: initial findings from the POETS study. AB - OBJECTIVES: Syphilis recognition in HIV-positive patients has important implications. Initial data from this study, established in June 2012 to better understand the natural history of syphilis and treatment response, examine the characteristics of patients including sexual behaviour, rates of concurrent sexually transmitted infections (STI) and type of treatment given. METHODS: Patients were recruited from Ireland, Poland and Germany. Data gathered included demographics, method of syphilis acquisition, stage of syphilis infection, HIV status, nadir and current CD4 counts and HIV viral suppression rates. Data were then subanalysed into HIV-positive and HIV-negative groups. RESULTS: Of 175 patients recruited, 68% were HIV-positive and 86.3% were men who have sex with men. Most HIV-positive patients presented with secondary syphilis (55.7% vs 13.2%) (p=0.0001) while the majority of HIV-negative patients had primary syphilis noted at the time of recruitment (47.2% vs18.9%, p=0.0002). Approximately half of all patients had a HIV RNA viral load <40 copies/mL (55%). Previous syphilis infection occurred more frequently in HIV-positive than HIV negative patients (p=0.0001). Concurrent STIs at the time of syphilis diagnosis were found in 26.8%, of whom 31 (25.4%) were HIV-positive (p=0.64). HIV-positive patients received doxycycline more frequently than their HIV-negative counterparts (33.6% vs 1.9%, p=0.0001) while HIV-negative patients were treated with long-acting penicillin in 88.7% of cases vs 58% of HIV-positive patients (p=0.0002). CONCLUSIONS: A 40% rate of unsuppressed viraemia, high levels of STIs and varying treatment regimens represent a public health risk for Europe, suggesting the model of sexual healthcare delivery in HIV-positive patients requires further evaluation. PMID- 25742697 TI - Patrick Vallance: Inquisitive and geeky. PMID- 25742698 TI - Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development. AB - Hematopoietic stem cells (HSCs) reside in regulatory niches in the bone marrow (BM). Although HSC niches have been extensively characterized, the role of endosteal osteoblasts (OBs) in HSC regulation requires further clarification, and the role of OBs in regulating leukemic stem cells (LSCs) is not well studied. We used an OB visualization and ablation mouse model to study the role of OBs in regulating normal HSCs and chronic myelogenous leukemia (CML) LSCs. OB ablation resulted in increase in cells with a LSK Flt3(-)CD150(+)CD48(-) long-term HSC (LTHSC) phenotype but reduction of a more highly selected LSK Flt3(-)CD34( )CD49b(-)CD229(-) LTHSC subpopulation. LTHSCs from OB-ablated mice demonstrated loss of quiescence and reduced long-term engraftment and self-renewal capacity. Ablation of OB in a transgenic CML mouse model resulted in accelerated leukemia development with reduced survival compared with control mice. The notch ligand Jagged-1 was overexpressed on CML OBs. Normal and CML LTHSCs cultured with Jagged 1 demonstrated reduced cell cycling, consistent with a possible role for loss of Jagged-1 signals in altered HSC and LSC function after OB ablation. These studies support an important role for OBs in regulating quiescence and self-renewal of LTHSCs and a previously unrecognized role in modulating leukemia development in CML. PMID- 25742699 TI - Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation. AB - Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here, we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived TSCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580. PMID- 25742701 TI - Patient-derived bladder cancer xenografts: a systematic review. AB - Patient-derived tumor xenografts (PDTXs) are said to accurately reflect the heterogeneity of human tumors. In the case of human bladder cancer, few studies are available featuring these models. The best methodology to develop and the real value of the model remain unclear. This systematic review aims to elucidate the best methodology to establish and use PDTXs to study the characteristics and behavior of human bladder tumors. The value and potential application of these models are also addressed. A comprehensive literature search was performed to identify published studies using xenograft models directly established from human bladder cancer samples into mice. A total of 12 studies were included in the final analysis. All studies differed in design; the reported take rate varied between 11% and 80%, with the implantation via dorsal incision and with matrigel obtaining the higher take rate. Advanced stage and high-grade tumors were associated with increased take rate. Xenografts preserved the original tumor identity in the establishment phase and after serial passages. Although some studies suggest a correlation between engraftment success and clinical prognosis, evidence about the association between the response of xenografts to treatment and the clinical response of the tumor of origin is still missing. All methodological approaches resulted in the establishment of tumor xenografts with preservation of the original tumor identity but variable take rate. The time needed to establish the model and propagate xenografts to a number suitable for drug testing is the main limitation of the model, along with the success rate and lack of consistency in the early passages. Comparison between tumor response in mice and clinical outcome remains to be assessed. PMID- 25742702 TI - [Bilateral chronic dislocation of the temporomandibular joints and Meige syndrome]. AB - INTRODUCTION: Chronic dislocation of the temporo-mandibular joint (TMJ) is rare. It occurs when an acute dislocation is left untreated, in certain situations, including severe illness, neurologic or psychiatric diseases or prolonged oral intubation. CASE REPORT: A 79 years old woman, with Meige syndrome, suffered from bilateral dislocation of the TMJ for over 1 year. Surgical repositioning of the mandibular condyles and temporal bone eminectomy were performed. At the 18 postoperative months control, no recurrence has been noted. DISCUSSION: Treatment of chronic TMJ dislocations often requires a surgical procedure. Manual reduction, even under general anaesthesia, often fails because of severe muscular spasm and periarticular fibrotic changes. The management of this disorder is still controversial. We review available surgical procedures. PMID- 25742700 TI - Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. AB - Epigenetic events that are essential drivers of lymphocyte transformation remain incompletely characterized. We used models of Epstein-Barr virus (EBV)-induced B cell transformation to document the relevance of protein arginine methyltransferase 5 (PRMT5) to regulation of epigenetic-repressive marks during lymphomagenesis. EBV(+) lymphomas and transformed cell lines exhibited abundant expression of PRMT5, a type II PRMT enzyme that promotes transcriptional silencing of target genes by methylating arginine residues on histone tails. PRMT5 expression was limited to EBV-transformed cells, not resting or activated B lymphocytes, validating it as an ideal therapeutic target. We developed a first in-class, small-molecule PRMT5 inhibitor that blocked EBV-driven B-lymphocyte transformation and survival while leaving normal B cells unaffected. Inhibition of PRMT5 led to lost recruitment of a PRMT5/p65/HDAC3-repressive complex on the miR96 promoter, restored miR96 expression, and PRMT5 downregulation. RNA sequencing and chromatin immunoprecipitation experiments identified several tumor suppressor genes, including the protein tyrosine phosphatase gene PTPROt, which became silenced during EBV-driven B-cell transformation. Enhanced PTPROt expression following PRMT5 inhibition led to dephosphorylation of kinases that regulate B-cell receptor signaling. We conclude that PRMT5 is critical to EBV driven B-cell transformation and maintenance of the malignant phenotype, and that PRMT5 inhibition shows promise as a novel therapeutic approach for B-cell lymphomas. PMID- 25742703 TI - [Towel clip reduction of zygomatic arch fracture]. AB - INTRODUCTION: Isolated fractures of the zygomatic arch (IFZA) are common in maxillofacial emergencies. They usually require a closed reduction. Several reduction techniques have been proposed. The reduction using a Ginestet-type hook is the gold standard technique. DISCUSSION: The reduction using a towel clip under local anesthesia is an economical, simple, reliable and safe alternative technique for the reduction of IFZA. We describe this procedure. PMID- 25742704 TI - [Reconstruction assisted by 3D printing in maxillofacial surgery]. AB - INTRODUCTION: 3-dimensional models (3D) appeared in the medical field 20 years ago. The recent development of consumer 3D printers explains the renewed interest in this technology. We describe the technical and practical modalities of this surgical tool, illustrated by concrete examples. TECHNICAL NOTE: The OsiriX((r)) software (version 5.8.5, Geneva, Switzerland) was used for 3D surface reconstruction of the area of interest, the generation and export of ".stl" file. The NetFabb((r)) software (Basic version 5.1.1, Lupburg, Germany) provided the preparation of ".stl" file. The 3D-printer was an Up plus 2 Easy 120((r)) (PP3DP, Beijing Technology Co. TierTime Ltd., Chine). The printer used fused deposition modeling. The softwar Up!((r)) allowed the 3d impression as required. RESULTS: The first case illustrated the value of 3D printing in the upper (frontal sinus and orbital roof). The second case concerned the preconfiguration of the osteosynthesis material for a complex fracture of the midface through the "mirroring" system. The third case showed the conformation of a prereconstruction for segmental mandibulectomy. DISCUSSION: Current 3D-printers are easy to use and represent a promising solution for medical prototyping. The 3D printing will quickly become undeniable because of its advantages: information sharing, simulation, surgical guides, pedagogy. PMID- 25742705 TI - Cost-Effectiveness Analysis of Incretin Therapy for Type 2 Diabetes in Spain: 1.8 mg Liraglutide Versus Sitagliptin. AB - OBJECTIVES: Metformin is the first-line therapy for most patients with type 2 diabetes, but the majority require treatment intensification at some stage due to the progressive nature of the disease. The 1860-LIRA-DPP-4 trial showed that liraglutide exhibited greater improvements compared with sitagliptin in glycated hemoglobin and body mass index in patients with type 2 diabetes inadequately controlled on metformin monotherapy. As a follow-up to a previously published cost-effectiveness analysis of 1.2 mg liraglutide versus sitagliptin in Spain, the aim of this analysis was to compare long-term projections of the clinical and cost implications associated with 1.8 mg liraglutide and sitagliptin. METHODS: For the modeling analysis, 52-week treatment effect data (as opposed to 26-week data in the previous analysis) were taken from the 1860-LIRA-DPP-4 trial, for adults with type 2 diabetes receiving 1.8 mg liraglutide or 100 mg sitagliptin daily in addition to metformin. Long-term (patient lifetime) projections of clinical outcomes and direct costs (2012 EUR) were made using a published and validated model of type 2 diabetes, with modeling assumptions as per the 1.2 mg liraglutide analysis. RESULTS: Liraglutide was associated with increased life expectancy (14.24 versus 13.87 years) and quality-adjusted life expectancy [9.24 versus 8.84 quality-adjusted life years (QALYs)] over sitagliptin. Improved clinical outcomes were attributable to the improvement in glycemic control, leading to a reduced incidence of diabetes-related complications, including renal disease, cardiovascular disease, ophthalmic and diabetic foot complications. Liraglutide was associated with increased direct costs (EUR 56,628 versus EUR 52,450), driven by increased pharmacy costs. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio of EUR 10,436 per QALY gained versus sitagliptin. CONCLUSIONS: A previous analysis has suggested that 1.2 mg liraglutide is cost-effective from a healthcare payer perspective in Spain, and the present analysis suggests that the 1.8 mg dose is also likely to be cost-effective. PMID- 25742707 TI - A surface curvature oscillation model for vapour-liquid-solid growth of periodic one-dimensional nanostructures. AB - While the vapour-liquid-solid process has been widely used for growing one dimensional nanostructures, quantitative understanding of the process is still far from adequate. For example, the origins for the growth of periodic one dimensional nanostructures are not fully understood. Here we observe that morphologies in a wide range of periodic one-dimensional nanostructures can be described by two quantitative relationships: first, inverse of the periodic spacing along the length direction follows an arithmetic sequence; second, the periodic spacing in the growth direction varies linearly with the diameter of the nanostructure. We further find that these geometric relationships can be explained by considering the surface curvature oscillation of the liquid sphere at the tip of the growing nanostructure. The work reveals the requirements of vapour-liquid-solid growth. It can be applied for quantitative understanding of vapour-liquid-solid growth and to design experiments for controlled growth of nanostructures with custom-designed morphologies. PMID- 25742706 TI - Assessing the Approximate Number System: no relation between numerical comparison and estimation tasks. AB - Whether our general numerical skills and the mathematical knowledge that we acquire at school are entwined is a debated issue, which many researchers are still striving to investigate. The findings reported in the literature are actually inconsistent; some studies emphasized the existence of a relationship between the acuity of the Approximate Number System (ANS) and arithmetic competence, while some others did not observe any significant correlation. One potential explanation of the discrepancy might stem from the evaluation of the ANS itself. In the present study, we correlated two measures used to index ANS acuity with arithmetic performance. These measures were the Weber fraction (w), computed from a numerical comparison task and the coefficient of variation (CV), computed from a numerical estimation task. Arithmetic performance correlated with estimation CV but not with comparison w. We further investigated the meaning of this result by taking the relationship between w and CV into account. We expected a tight relation as both these measures are believed to assess ANS acuity. Crucially, however, w and CV did not correlate with each other. Moreover, the value of w was modulated by the congruity of the relation between numerical magnitude and non-numerical visual cues, potentially accounting for the lack of correlation between the measures. Our findings thus challenge the overuse of w to assess ANS acuity and more generally put into question the relevance of correlating this measure with arithmetic without any deeper understanding of what they are really indexing. PMID- 25742708 TI - Enhanced visible light photocatalytic activity of ZnIn2S4 modified by semiconductors. AB - To improve the visible light photocatalytic activity of a ZnIn2S4 sample, we synthesized two kinds of coupled-photocatalysts: TiO2@ZnIn2S4 core-shell type heterostructure composites by a simple and flexible hydrothermal route using TiO2 as the precursor and CuO/ZnIn2S4 contact type heterostructure composites incorporated with different amounts of CuO by the impregnation-calcination method. These as-prepared samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV Visible absorption spectra (UV-Vis) and nitrogen adsorption measurements. An enhancement in photocatalytic activity was observed after the addition of TiO2 and CuO. It was found that the as-synthesized TiO2@ZnIn2S4 photocatalyst was more efficient than TiO2 and ZnIn2S4 in the photocatalytic degradation of methylene blue (MB). TEM images confirmed that the TiO2@ZnIn2S4 nanoparticles possessed a well-proportioned core-shell morphology. On the other hand, the effects of CuO loading amount on the crystal structure, and photocatalytic properties of CuO/ZnIn2S4 samples for MB degradation under visible light irradiation were investigated, suggesting that the introduction of CuO could influence the morphology and BET specific surface area of the ZnIn2S4 sample and enhance the visible light absorption of photocatalysts. The photocatalytic degradation performance of MB was remarkably improved in the presence of CuO/ZnIn2S4 compared to pure ZnIn2S4 and 10 mol% CuO/ZnIn2S4 was found to possess the optimal photocatalytic performance. Moreover, mechanisms for the enhanced photocatalytic activity of the TiO2@ZnIn2S4 and CuO/ZnIn2S4 composites were proposed. PMID- 25742709 TI - Parenting and environmental risk : an examination of child loss and maternal involvement among Bofi foragers in Central Africa. AB - The majority of adaptationist models and research related to parenting strategies have focused on extrinsic or population-level risk as predictors of parenting. However, some researchers have called for greater consideration of cultural factors as well as on intracultural variation in parenting. This study uses a biocultural approach to examine intracultural variation in environmental risk and parenting among the Bofi foragers in Central Africa. In particular, we examine 30 mothers' experiences of child loss as a predictor of variation in maternal involvement (proximity, holding, and affection) with their young children. Multivariate and univariate analyses indicate that child loss accounted for substantial variation in maternal behaviors and was predictive of maternal holding and the expression of physical affection. In sum, our findings indicate that intracultural variation in child loss is predictive of maternal involvement with young children and that a biocultural approach is useful in explaining this variation. PMID- 25742710 TI - Diffusion MRI properties of the human uncinate fasciculus correlate with the ability to learn visual associations. AB - The uncinate fasciculus (UF) is a cortico-cortico white matter pathway that links the anterior temporal and the orbitofrontal cortex (OFC). In the monkey, transection of the UF causes significant impairments in learning conditional visual-visual associations, while object discrimination remains intact, suggesting an important role for the UF in mediating the learning of complex visual associations. Whether this functional role extends to the human UF has not been tested directly. Here, we used diffusion tensor magnetic resonance imaging (dMRI) and behavioral experiments to examine the relation between learning visual associations and the structural properties of the human UF. In a group of healthy adults, we segmented the UF and the inferior longitudinal fasciculus (ILF) and derived dMRI measures of the structural properties of the two pathways. We also used a behavioral experiment adapted from the monkey studies to characterize the ability of these individuals to learn to associate a person's face with a group of specific scenes (conditional visual-visual association). We then tested whether the variability in the dMRI measures of the two pathways correlated with variability in the ability to rapidly learn the face-place associations. Our study suggests that in the human, the left UF may be important for mediating the rapid learning of conditional visual-visual associations whereas the right UF may play an important role in the immediate retrieval of visual-visual associations. These results provide preliminary evidence suggesting similarities and differences in the functional role of the UF in monkeys compared to humans. The findings presented here contribute to our understanding of the functional role of the UF in humans and the functional neuroanatomy of the brain networks involved in visual cognition. PMID- 25742711 TI - Statins associated with 46% rise in type 2 diabetes risk, study shows. PMID- 25742712 TI - Submarine fresh groundwater discharge into Laizhou Bay comparable to the Yellow River flux. AB - Near- and off-shore fresh groundwater resources become increasingly important with the social and economic development in coastal areas. Although large scale (hundreds of km) submarine groundwater discharge (SGD) to the ocean has been shown to be of the same magnitude order as river discharge, submarine fresh groundwater discharge (SFGD) with magnitude comparable to large river discharge is never reported. Here, we proposed a method coupling mass-balance models of water, salt and radium isotopes based on field data of (223)Ra, (226)Ra and salinity to estimate the SFGD, SGD. By applying the method in Laizhou Bay (a water area of ~6000 km(2)), we showed that the SFGD and SGD are 0.57 ~ 0.88 times and 7.35 ~ 8.57 times the annual Yellow River flux in August 2012, respectively. The estimate of SFGD ranges from 4.12 * 10(7) m(3)/d to 6.36 * 10(7) m(3)/d, while SGD ranges from 5.32 * 10(8) m(3)/d to 6.20 * 10(8) m(3)/d. The proportion of the Yellow River input into Laizhou Bay was less than 14% of the total in August 2012. Our method can be used to estimate SFGD in various coastal waters. PMID- 25742713 TI - Visualization of mouse induced pluripotent stem cells for evaluation of tracheal regeneration. AB - CONCLUSION: Visualization of mouse induced pluripotent stem (iPS) cells with the use of a fluorescent protein was successfully achieved for evaluation of tracheal regeneration. OBJECTIVES: Tracheal epithelial cells derived from iPS cells are expected to be a useful cell source for tracheal regeneration. Our previous study demonstrated that mouse iPS cells differentiated into tracheal epithelial cells. However, when they are implanted into tracheal defects in experimental animals, it is difficult to determine whether the regenerated tracheal epithelium is in fact derived from iPS cells. The purpose of this study was to develop a visualization technique for iPS cells for evaluation of tracheal regeneration. METHODS: Fluorescent marker tdTomato was transfected into iPS cells. Tracheal epithelial cells were generated from tdTomato-labeled iPS cells using embryoid body formation to detect the expression of tdTomato. The artificial material with tdTomato-labeled iPS cells was implanted into tracheal defects in nude rats. The survival and distribution of tdTomato-labeled iPS cell-derived cells were examined using the IVIS Imaging System and immunostaining. RESULTS: The expression of tdTomato was detected in both undifferentiated cells and tracheal epithelial cells in vitro. tdTomato-labeled iPS cell-derived cells were successfully detected in the tracheal defects by IVIS Imaging System and immunostaining. PMID- 25742716 TI - The growth hormone receptor exon 3-deleted/full-length polymorphism and response to growth hormone therapy in prepubertal idiopathic short children. AB - OBJECTIVE: The primary aim of the study was to evaluate d3-GHR as a possible cause of increased GH sensitivity in children with delayed infancy-childhood transition (DICT). The secondary aim was to investigate the impact of the GHR exon 3 deleted/full-length (d3/fl) polymorphism on GH treatment response in prepubertal children classified as having idiopathic short stature (ISS). DESIGN: Study subjects included 167 prepubescent longitudinally followed children classified as having ISS. Children were randomized to standard-dose GH treatment (33 MUg kg(-1) day(-1)), to double-dose treatment (67 MUg kg(-1) day(-1)), or to an untreated control group. Growth and metabolic outcome were evaluated at birth (n = 166), after one year of treatment (n = 59) and at adult height (n = 145). Genotyping of the GHR d3/fl polymorphism was performed using TaqMan SNP genotyping of tagSNP rs6873545. RESULTS: Birth and early growth data did not reach the predetermined level of statistical significance for difference between genotypes. Growth and IGF-1 response after one year of GH treatment did not differ between genotypes. IGFBP-3SDS was higher in untreated d3-GHR carriers than in untreated fl/fl individuals, whereas there was insufficient evidence for higher IGFBP-3SDS in treated d3-GHR carriers. Genotype did not explain the growth response to treatment, and no differences in heightSDS, height gain, or difference in height to midparental heightSDS between genotype groups were found at adult height. CONCLUSION: The common GHR d3/fl polymorphism is probably not a cause of DICT in children with ISS, and our results do not suggest that the d3 GHR genotype is associated with increased sensitivity to GH in children with ISS. PMID- 25742715 TI - Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity. AB - Herpes simplex virus (HSV) undergoes a lytic infection in epithelial cells and a latent infection in neuronal cells, and epigenetic mechanisms play a major role in the differential gene expression under the two conditions. HSV viron DNA is not associated with histones but is rapidly loaded with heterochromatin upon entry into the cell. Viral proteins promote reversal of the epigenetic silencing in epithelial cells while the viral latency-associated transcript promotes additional heterochromatin in neuronal cells. The cellular sensors that initiate the chromatinization of foreign DNA have not been fully defined. IFI16 and cGAS are both essential for innate sensing of HSV DNA, and new evidence shows how they work together to initiate innate signaling. IFI16 also plays a role in the heterochromatinization of HSV DNA, and this review will examine how IFI16 integrates epigenetic regulation and innate sensing of foreign viral DNA to show how these two responses are related. PMID- 25742718 TI - Risk factors for overweight and overfatness in rural South African children and adolescents. AB - BACKGROUND: To determine risk factors for overweight/overfatness in children and adolescents from rural KwaZulu-Natal, South Africa. METHODS: Anthropometric data were collected from a cross-sectional sample (n = 1519, ages 7, 11 and 15 years) and linked to demographic information (n = 1310 and n = 1317 in overweight and overfat analyses, respectively). Candidate risk factors for overweight/overfatness were identified and tested for associations with overweight (BMI-for-age >+1SD, WHO reference) and overfatness (>85th centile body fatness, McCarthy reference) as outcomes. Associations were examined using simple tests of proportions (chi(2)/Mann-Whitney U tests) and multivariable logistic regression. RESULTS: Sex was a consistent variable across both analyses; girls at significantly increased risk of overweight and overfatness (overweight: n = 180, 73.9 and 26.1% females and males, respectively (P < 0.0001); overfat: n = 187, 72.7 and 27.3% females and males, respectively (P < 0.0001)). In regression analyses, sex and age (defined by school grade) were consistent variables, with boys at lower risk of overweight (adjusted odds ratio (AOR) 0.40 (confidence interval (CI) -0.28-0.57)) and risk of overweight increasing with age (AOR 0.65 (CI- 0.44-0.96), 0.50 (CI-0.33-0.75) and 1.00 for school grades 1, 5 and 9, respectively). Results were similar for overfatness. CONCLUSIONS: This study suggests that pre-adolescent/adolescent females may be the most appropriate targets of future interventions aimed at preventing obesity in rural South Africa. PMID- 25742717 TI - UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. AB - Dietary methionine restriction (MR) by 80% increases energy expenditure (EE), reduces adiposity, and improves insulin sensitivity. We propose that the MR induced increase in EE limits fat deposition by increasing sympathetic nervous system-dependent remodeling of white adipose tissue and increasing uncoupling protein 1 (UCP1) expression in both white and brown adipose tissue. In independent assessments of the role of UCP1 as a mediator of MR's effects on EE and insulin sensitivity, EE did not differ between wild-type (WT) and Ucp1(-/-) mice on the control diet, but MR increased EE by 31% and reduced adiposity by 25% in WT mice. In contrast, MR failed to increase EE or reduce adiposity in Ucp1(-/ ) mice. However, MR was able to increase overall insulin sensitivity by 2.2-fold in both genotypes. Housing temperatures used to minimize (28 degrees C) or increase (23 degrees C) sympathetic nervous system activity revealed temperature independent effects of the diet on EE. Metabolomics analysis showed that genotypic and dietary effects on white adipose tissue remodeling resulted in profound increases in fatty acid metabolism within this tissue. These findings establish that UCP1 is required for the MR-induced increase in EE but not insulin sensitivity and suggest that diet-induced improvements in insulin sensitivity are not strictly derived from dietary effects on energy balance. PMID- 25742719 TI - Variations in Neisseria meningitidis carriage by socioeconomic status: a cross sectional study. AB - BACKGROUND: Deprivation is associated with an increased risk of invasive Neisseria meningitidis disease, but little is known about the relationship between deprivation and asymptomatic carriage of N. meningitidis. This analysis was conducted to examine the relationship between meningococcal carriage and deprivation. METHODS: As part of a rapid meningococcal carriage prevalence study conducted in West Cumbria to investigate an apparent cluster of invasive meningococcal disease, data were collected on lifestyle and social factors, including area-level indicators of socioeconomic status, to identify factors associated with meningococcal carriage. RESULTS: In a multivariable log binomial regression model adjusted for age, lower socioeconomic status was significantly associated with higher prevalence of meningococcal carriage. A 1-unit increase in Index of Multiple Deprivation (2010) score was associated with a 1.7% increase in meningococcal carriage prevalence (95% confidence interval 0.3-3.0%). Age was the only significant predictor of carriage of Neisseria lactamica. CONCLUSIONS: Living in a deprived area is associated with increased carriage of Group B meningococcus. Deprivation is an important factor to consider in the evaluation of the effectiveness and cost-effectiveness of the introduction of new meningococcal B vaccines and the development and implementation of immunization policies. Further work is required to understand whether deprivation has an effect on meningococcal carriage through other factors such as smoking. PMID- 25742720 TI - Accuracy of reporting abortions with Down syndrome in England and Wales: a data linkage study. AB - BACKGROUND: The number of abortions of fetuses with Down syndrome in England and Wales reported by the Department of Health (DH) differs from that reported by the National Down Syndrome Cytogenetic Register (NDSCR). The aim of this study was to investigate the reasons for this. METHODS: Abortions in 2011 and 2012 from DH were matched to those from NDSCR. The number of cases not reported to either source was estimated. RESULTS: An estimated 2240 abortions of fetuses with Down syndrome occurred in 2011/12; NDSCR estimated 2208 and DH 1100. One thousand and six abortions were identified in both data sets, including 145 (14%) which were not recorded by DH as having Down syndrome. Abortions in NDSCR that were not matched in DH occurred throughout England and Wales and at all gestational ages. An estimated 61 abortions of fetuses with Down syndrome were not reported to DH or NDSCR. CONCLUSIONS: The number of abortions of fetuses with Down syndrome reported by the NDSCR is more complete than that reported by the DH. DH data for abortions with other congenital anomalies are also likely to be underestimates, and more accurate estimates are available from BINOCAR regional congenital anomaly registers. PMID- 25742714 TI - Bacteriophage lambda: Early pioneer and still relevant. AB - Molecular genetic research on bacteriophage lambda carried out during its golden age from the mid-1950s to mid-1980s was critically important in the attainment of our current understanding of the sophisticated and complex mechanisms by which the expression of genes is controlled, of DNA virus assembly and of the molecular nature of lysogeny. The development of molecular cloning techniques, ironically instigated largely by phage lambda researchers, allowed many phage workers to switch their efforts to other biological systems. Nonetheless, since that time the ongoing study of lambda and its relatives has continued to give important new insights. In this review we give some relevant early history and describe recent developments in understanding the molecular biology of lambda's life cycle. PMID- 25742721 TI - High voltage supercapacitors based on carbon-grafted NiO nanowires interfaced with an aprotic ionic liquid. AB - The report provides a preliminary assessment of the charge storage prerogatives of an asymmetric electrochemical capacitor employing a carbon-grafted NiO electrode interfaced with 1-ethyl-3-methyl imidazoliumdicyanamide as an ionic liquid electrolyte. This configuration has been demonstrated to be potentially exploited for developing hybrid supercapacitors providing as high energy density as 21 W h Kg(-1). PMID- 25742722 TI - Metabolic syndrome in patients with bipolar disorder: comparison with major depressive disorder and non-psychiatric controls. AB - OBJECTIVE: We aimed to investigate the prevalence of the metabolic syndrome (MetS) and its individual components in subjects with bipolar disorder (BD) compared to those with major depressive disorder (MDD) and non-psychiatric controls. METHODS: We examined 2431 participants (mean age 44.3+/-13.0, 66.1% female), of whom 241 had BD; 1648 had MDD; and 542 were non-psychiatric controls. The MetS was ascertained according to NCEP ATP III criteria. Multivariable analyses were adjusted for age, sex, ethnicity, level of education, smoking status and severity of depressive symptoms, and in the case of BD subjects, also for psychotropic medication use. RESULTS: Subjects with BD had a significantly higher prevalence of MetS when compared to subjects with MDD and non-psychiatric controls (28.4% vs. 20.2% and 16.5%, respectively, p<0.001), also when adjusted for sociodemographic and lifestyle factors (OR 1.52, 95% CI: 1.09-2.12, p=0.02 compared to MDD; OR 1.79, 95% CI: 1.20-2.67, p=0.005 compared to non-psychiatric controls). The differences between BD subjects with controls could partly be ascribed to a higher mean waist circumference (91.0 cm vs. 88.8, respectively, p=0.03). In stratified analysis, the differences in the prevalence of MetS between patients with BD and MDD were found in symptomatic but not in asymptomatic cases. CONCLUSION: This study confirms a higher prevalence of MetS in patients with BD compared to both MDD patients and controls. Specifically at risk are patients with a higher depression score and abdominal obesity. PMID- 25742723 TI - Cytotoxicity and Synergistic Effect of the Constituents from Roots of Aglaia odorata (Meliaceae). AB - Twelve compounds were isolated from the roots of Aglaia odorata. Their structures were established on the basis of NMR and MS data as rocaglaol (1), rocaglamide (2), eichlerialactone (3), sapelins A (4), isofouquierone (5), eichlerianic acid (6), shoreic acid (7), agladupol E (8), 3-epimeliantriol (9), cleomiscosins B (10), 2beta,3beta-dihydroxy-5alpha-pregnane-16-one (11) and beta-D-glucopyranos-1 yl N-methylpyrrole-2-carboxylate (12). Among them, compounds 1 and 2 showed significant cytotoxicity against human cancer cell (HL-60, SMMC-7721, A-549, MCF 7 and SW480) with IC50 values of 0.007-0.095 MUM, while compounds 3-5 and 10 and 11 showed moderate to no cytotoxicity (IC50 0.43 to values >40 MUM). Compound 6 showed only weak cytotoxicity (IC50 6.87 to >40 MUM) and its epmier 7 was completely inactivite (IC50>40 MUM) in the assay. However, potent synergistic effect was observed when the molar ratio of 6 to 7 is between 4:1 and 1:1. PMID- 25742725 TI - Magnetic resonance elastography: evaluation of new inversion algorithm and quantitative analysis method. AB - PURPOSE: To assess mean shear hepatic stiffness calculations using various region of interest (ROI) techniques, a new inversion algorithm, and a confidence threshold mask. METHODS: Seventy-three patients (49 with abnormal liver function tests/known chronic liver disease and 24 healthy liver transplant donors) underwent liver biopsy and magnetic resonance elastography (MRE). MRE data processed with the current inversion algorithm [multiscale direct inversion (MSDI)] was assessed using 2 ROI methods (single vs. triple). The data were then reprocessed using the new inversion algorithm (multimodel direct inversion [MMDI]) Hepatic stiffness calculations were performed using a single (70%) ROI method, with/without a 95% confidence threshold mask, and compared with MSDI. RESULTS: For MSDI, average stiffness difference between single and triple ROI methods was not statistically significant by the 2-sample t test [0.15 kilopascals (kPa); P = .77]. For the 2 algorithms, there was little difference in average stiffness measurements of MSDI and MMDI (mean, 0.32 kPa; 9%) using a confidence mask with good agreement [intraclass correlation coefficient (ICC), 0.986 (95% CI 0.975-0.994)]. Use of the confidence mask showed excellent consistency and less variance [ICC, 0.995 (95% CI 0.993-0.998)] compared to either the inter-observer or intra-observer freehand technique. CONCLUSION: MRE analysis showed no significant difference between the 2 freehand ROI techniques. With a 9% average kPa variance, stiffness measurements for MSDI and MMDI were also not significantly different. The use of the confidence mask reduces calculated stiffness variability, which impacts the use of MRE for assessing therapy response and initial/longitudinal assessment of chronic liver disease. PMID- 25742724 TI - Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis. AB - Delayed healing or nonhealing of bone is an important clinical concern. Although bone, one of the two tissues with scar-free healing capacity, heals in most cases, healing is delayed in more than 10% of clinical cases. Treatment of such delayed healing condition is often painful, risky, time consuming, and expensive. Tissue healing is a multistage regenerative process involving complex and well orchestrated steps, which are initiated in response to injury. At best, these steps lead to scar-free tissue formation. At the onset of healing, during the inflammatory phase, stationary and attracted macrophages and other immune cells at the fracture site release cytokines in response to injury. This initial reaction to injury is followed by the recruitment, proliferation, and differentiation of mesenchymal stromal cells, synthesis of extracellular matrix proteins, angiogenesis, and finally tissue remodeling. Failure to heal is often associated with poor revascularization. Since blood vessels mediate the transport of circulating cells, oxygen, nutrients, and waste products, they appear essential for successful healing. The strategy of endogenous regeneration in a tissue such as bone is interesting to analyze since it may represent a blueprint of successful tissue formation. This review highlights the interdependency of the time cascades of inflammation, angiogenesis, and tissue regeneration. A better understanding of these inter-relations is mandatory to early identify patients at risk as well as to overcome critical clinical conditions that limit healing. Instead of purely tolerating the inflammatory phase, modulations of inflammation (immunomodulation) might represent a valid therapeutic strategy to enhance angiogenesis and foster later phases of tissue regeneration. PMID- 25742726 TI - Perceptual interactions between electrodes using focused and monopolar cochlear stimulation. AB - In today's cochlear implant (CI) systems, the monopolar (MP) electrode configuration is the most commonly used stimulation mode, requiring only a single current source. However, with an implant that will allow simultaneous activation of multiple independent current sources, it is possible to implement an all-polar (AP) stimulation mode designed to create a focused electrical field. The goal of this experiment was to study the potential benefits of this all-polar mode for reducing uncontrolled electrode interactions compared with the monopolar mode. The five participants who took part in the study were implanted with a research device that was connected via a percutaneous connector to a benchtop stimulator providing 22 independent current sources. The perceptual effects of the AP mode were tested in three experiments. In Experiment 1, the current level difference between loudness-matched sequential and simultaneous stimuli composed of 2 spatially separated pulse trains was measured as function of the electrode separation. Results indicated a strong current-summation interaction for simultaneous stimuli in the MP mode for separations up to at least 4.8 mm. No significant interaction was found in the AP mode beyond a separation of 2.4 mm. In Experiment 2, a forward-masking paradigm was used with fixed equally loud probes in AP and MP modes, and AP maskers presented on different electrode positions. Results indicated a similar spatial masking pattern between modes. In Experiment 3, subjects were asked to discriminate between across-electrode temporal delays. It was hypothesized that discrimination would decrease with electrode separation faster in AP compared to MP modes. However, results showed no difference between the two modes. Overall, the results indicated that the AP mode produced less current spread than MP mode but did not lead to a significant advantage in terms of spread of neuronal excitation at equally loud levels. PMID- 25742727 TI - Identification, molecular characterization, and gene expression analysis of a CD109 molecule in the Hawaiian bobtail squid Euprymna scolopes. AB - All organisms have unique immune systems that help them identify and eliminate invading microorganisms. A group of evolutionary ancient molecules, the thioester containing proteins (TEP) superfamily, are known to play an important immune role by aiding animal hosts in the recognition, destruction, and elimination of hazardous microorganisms and their products. Our laboratory focuses on studying the role of the immune system in the mutualistic relationship between the sepiolid squid, Euprymna scolopes and its bioluminescent symbiont Vibrio fischeri. In the present study, we report the identification of a novel TEP-like transcript expressed in the light organ of squid. Characterization of the full length coding sequence showed a molecule of 4218 nucleotides, corresponding to 1406 amino acids. Further sequence analysis revealed it contained structural characteristics of A2M molecules, including the thioester and receptor-binding domains. Analysis using the predicted amino acid sequence suggested this transcript was a homologue of CD109 molecules, thus we named it E. scolopes-CD109 (Es-CD109). In addition to the light organ, we were able to detect and amplify Es CD109 in 12 out of 14 adult squid tissues tested. Quantification experiments showed that Es-CD109 expression levels were significantly lower in the light organ of symbiotic compared to aposymbiotic juveniles, suggesting a possible down regulation of the host immune response in the presence of the bacterial symbiont. PMID- 25742728 TI - Complement receptor type 1 (CR1/CD35) expressed on activated human CD4+ T cells contributes to generation of regulatory T cells. AB - The role of complement in the regulation of T cell immunity has been highlighted recently by several groups. We were prompted to reinvestigate the role of complement receptor type 1 (CR1, CD35) [corrected] in human T cells based on our earlier data showing that activated human T cells produce C3 (Torok et al. (2012) [48]) and also by results demonstrating that engagement of Membrane Cofactor Protein (MCP, CD46) induces a switch of anti-CD35-activated [corrected] helper T cells into regulatory T cells (Kemper et al. (2003) [17]). We demonstrate here that co-ligation of CD46 and CD35, [corrected] the two C3b-binding structures present on activated CD4+ human T cells significantly enhances CD25 expression, elevates granzyme B production and synergistically augments cell proliferation. The role of CR1 in the development of the Treg phenotype was further confirmed by demonstrating that its engagement enhances IL-10 production and reduces IFNgamma release by the activated CD4+ T cells in the presence of excess IL-2. The functional in vivo relevance of our findings was highlighted by the immunohistochemical staining of tonsils, revealing the presence of CD4/CD35 [corrected] double positive lymphocytes mainly in the inter-follicular regions where direct contact between CD4+ T cells and B lymphocytes occurs. Regarding the in vivo relevance of the complement-dependent generation of regulatory T cells in secondary lymphoid organs we propose a scenario shown in the figure. The depicted process involves the sequential binding of locally produced C3 fragments to CD46 and CD35 [corrected] expressed on activated T cells, which - in the presence of excess IL-2 - leads to the development of Treg cells. PMID- 25742729 TI - Effect of bed characters on the direct synthesis of dimethyldichlorosilane in fluidized bed reactor. AB - This paper presents the numerical investigation of the effects of the general bed characteristics such as superficial gas velocities, bed temperature, bed heights and particle size, on the direct synthesis in a 3D fluidized bed reactor. A 3D model for the gas flow, heat transfer, and mass transfer was coupled to the direct synthesis reaction mechanism verified in the literature. The model was verified by comparing the simulated reaction rate and dimethyldichlorosilane (M2) selectivity with the experimental data in the open literature and real production data. Computed results indicate that superficial gas velocities, bed temperature, bed heights, and particle size have vital effect on the reaction rates and/or M2 selectivity. PMID- 25742730 TI - Effect of a modified saquinavir/ritonavir dosing regimen with lower dose lead-in phase on QTc interval, pharmacokinetics, antiviral activity and safety in treatment-naive HIV-1-infected patients. AB - BACKGROUND: Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations. OBJECTIVE: To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naive HIV-1 infected patients. METHODS: Twenty-three HIV-1-infected treatment-naive patients received saquinavir/ritonavir 500/100 mg BID on days 1-7 and 1000/100 mg BID on days 8-14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia's formula (?QTcFdense) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days. RESULTS: The mean maximum ?QTcFdense was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ?QTcFdense >=30 ms (on day 10); the highest mean ?QTcFdense was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated. CONCLUSION: Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naive HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment. PMID- 25742731 TI - [Microbiological diagnosis of viral hepatitis]. AB - Liver inflammation or hepatitis has many different causes, both infectious and non-infectious. Among the former, viral infection is responsible for at least half of all hepatitis worldwide. Different viruses have been described with primary tropism for liver tissue. These microorganisms have been successively named with letters of the alphabet: A, B, C, D, E and G. The aim of this paper is to review this heterogeneous group of viruses in its most basic aspects, including clinical implications, treatment, main control, and prophylactic measures and, of special interest, diagnostic approaches, both serological and molecular, which are used for their detection, quantification and characterization. PMID- 25742732 TI - Effects of hypoxia on proliferation of human cord blood-derived mesenchymal stem cells. AB - The purpose of our study was to examine the influence of hypoxia on proliferation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). The mononuclear cells were separated by density gradient centrifugation from human umbilical cord blood and then, respectively, cultured under hypoxia (5 % O2) or normoxia (20 % O2). Their cell morphology, cell surface markers, beta galactosidase staining, cell growth curve, DNA cycle, and the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) were evaluated. We found that hypoxia, in part via HIF-1alpha, improved the proliferation efficiency, and prevented senescence of hUCB-MSCs without altering their morphology and surface markers. These results demonstrated that hypoxia provides a favorable culture condition to promote hUCB-MSCs proliferation in vitro, which is a better way to obtain sufficient numbers of hUCB-MSCs for research and certainly clinical application. PMID- 25742733 TI - Real-time PCR assay is superior to other methods for the detection of mycoplasma contamination in the cell lines of the National Cell Bank of Iran. AB - Mycoplasmas are the most important contaminants of cell cultures throughout the world. They are considered as a major problem in biological studies and biopharmaceutical economic issues. In this study, our aim was to find the best standard technique as a rapid method with high sensitivity, specificity and accuracy for the detection of mycoplasma contamination in the cell lines of the National Cell Bank of Iran. Thirty cell lines suspected to mycoplasma contamination were evaluated by five different techniques including microbial culture, indirect DNA DAPI staining, enzymatic mycoalert((r)) assay, conventional PCR and real-time PCR. Five mycoplasma-contaminated cell lines were assigned as positive controls and five mycoplasma-free cell lines as negative controls. The enzymatic method was performed using the mycoalert((r)) mycoplasma detection kit. Real-time PCR technique was conducted by PromoKine diagnostic kits. In the conventional PCR method, mycoplasma genus-specific primers were designed to analyze the sequences based on a fixed and common region on 16S ribosomal RNA with PCR product size of 425 bp. Mycoplasma contamination was observed in 60, 56.66, 53.33, 46.66 and 33.33 % of 30 different cell cultures by real-time PCR, PCR, enzymatic mycoalert((r)), indirect DNA DAPI staining and microbial culture methods, respectively. The analysis of the results of the different methods showed that the real-time PCR assay was superior the other methods with the sensitivity, specificity, accuracy, predictive value of positive and negative results of 100 %. These values were 94.44, 100, 96.77, 100 and 92.85 % for the conventional PCR method, respectively. Therefore, this study showed that real time PCR and PCR assays based on the common sequences in the 16S ribosomal RNA are reliable methods with high sensitivity, specificity and accuracy for detection of mycoplasma contamination in cell cultures and other biological products. PMID- 25742734 TI - First study of pathogen load and localisation of ovine footrot using fluorescence in situ hybridisation (FISH). AB - Analysis of bacterial populations in situ provides insights into pathogen population dynamics and potential reservoirs for disease. Here we report a culture-independent study of ovine footrot (FR); a debilitating bacterial disease that has significant economic impact on sheep farming worldwide. Disease begins as an interdigital dermatitis (ID), which may then progress to separation of the hoof horn from the underlying epidermis causing severe footrot (SFR). Dichelobacter nodosus is the causative agent of ovine FR, however, the role of Fusobacterium necrophorum and other bacteria present in the environment and on the feet of sheep is less clear. The objective of this study was to use fluorescence in situ hybridisation (FISH) to detect, localise and quantify D. nodosus, F. necrophorum and the domain Bacteria from interdigital skin biopsies of healthy, ID- and SFR-affected feet. D. nodosus and F. necrophorum populations were restricted primarily to the epidermis, but both were detected more frequently in feet with ID or SFR than in healthy feet. D. nodosus cell counts were significantly higher in feet with ID and SFR (p<0.05) than healthy feet, whereas F. necrophorum cell counts were significantly higher only in feet with SFR (p<0.05) than healthy feet. These results, together with other published data, indicate that D. nodosus likely drives pathogenesis of footrot from initiation of ID to SFR; with D. nodosus cell counts increasing prior to onset of ID and SFR. In contrast, F. necrophorum cell counts increase after SFR onset, which may suggest an accessory role in disease pathogenesis, possibly contributing to the severity and duration of SFR. PMID- 25742735 TI - Upper-body resistance exercise augments vastus lateralis androgen receptor-DNA binding and canonical Wnt/beta-catenin signaling compared to lower-body resistance exercise in resistance-trained men without an acute increase in serum testosterone. AB - The purpose of the study was to determine the effect of single bouts of lower body (LB) and upper- and lower-body (ULB) resistance exercise on serum testosterone concentrations and the effects on muscle testosterone, dihydrotestosterone (DHT), androgen receptor (AR) protein content, and AR-DNA binding. A secondary purpose was to determine the effects on serum wingless-type MMTV integration site (Wnt4) levels and skeletal muscle beta-catenin content. In a randomized cross-over design, exercise bouts consisted of a LB and ULB protocol, and each bout was separated by 1 week. Blood and muscle samples were obtained before exercise and 3 and 24h post-exercise; blood samples were also obtained at 0.5, 1, and 2 h post-exercise. Statistical analyses were performed by separate two-way factorial analyses of variance (ANOVA) with repeated measures. No significant differences from baseline were observed in serum total and free testosterone and skeletal muscle testosterone and DHT with either protocol (p>0.05). AR protein was significantly increased at 3 h post-exercise and decreased at 24 h post-exercise for ULB, whereas AR-DNA binding was significantly increased at 3 and 24h post-exercise (p<0.05). In response to ULB, serum Wnt4 was significantly increased at 0.5, 1, and 2 h post-exercise (p<0.05) and beta catenin was significantly increased at 3 and 24 h post-exercise (p<0.05). It was concluded that, despite a lack of increase in serum testosterone and muscle androgen concentrations from either mode of resistance exercise, ULB resistance exercise increased Wnt4/beta-catenin signaling and AR-DNA binding. PMID- 25742736 TI - THP1 macrophages oxidized cholesterol, generating 7-derivative oxysterols specifically released by HDL. AB - Macrophages are well recognized as key pathophysiologic agents in many chronic inflammatory diseases, especially atherosclerosis. During atherogenesis process, low density lipoproteins (LDL) undergo oxidation (oxLDL) and become highly atherogenic as they induce a strong accumulation of cholesterol in subendothelial macrophages leading to the formation of foam cells, the major cellular component of fatty streaks. OxLDL are enriched in oxidation products of cholesterol called oxysterols involved in the regulation of cholesterol homeostasis, by their ability to induce cellular oxidative stress and cytotoxicity. Little is known about intracellular oxysterol production in macrophages. Using both radiochemical and mass analyzes, we showed that THP1 macrophages promote the intracellular oxidation of LDL derived-cholesterol as well as intracellular cholesterol, this later mechanism being enhanced by exposure with native or oxLDL. We demonstrated that in both THP1 and Raw 267.4 cells cholesterol oxidation occurs in the late endosomal compartment. Most oxysterols were produced by non-enzymatic routes (7 ketocholesterol and 7alpha/beta-hydroxycholesterol) but enzymatically formed 7alpha-, 27-hydroxycholesterol were also quantified. Incubation of THP1 macrophages with nLDL or oxLDL, induced a 2- and 100-fold increase in oxysterol production, respectively. Both oxysterols derived from LDL cholesterol and cellular cholesterol were readily exported to HDL whereas apoA1 was inefficient, showing that HDL plays a major role in the removal of excess oxysterols in THP1 macrophages. PMID- 25742737 TI - Mononucleotide repeats in the SMAD4 gene promoter in colon carcinoma tissue of Croatian patients. AB - This study was aimed at the analysis of mononucleotide repeats -462T(15) and 4T(12) in the SMAD4 gene promoter in sporadic colon adenocarcinoma tissue of Croatian patients. The analysis has included 60 pairs of samples of colon tumor and adjacent normal tissue. The number of thymidines in the tracts -462T(15) and 4T(12) of the SMAD4 gene promoter was determined by PCR with fluorescently labeled primers followed by the analysis of obtained DNA fragments by capillary electrophoresis. In the normal colon tissue two haplotypes were present: 462T(15)/-4T(12) in 51 patients (85%) and -462T(16)/-4T(12) in 9 patients (15%). Among the cases with haplotype -462T(15)/-4T(12) detected in normal colon tissue, in 5 cases (8%) malignant tissue displayed different haplotypes: 462T(10)/ 4T(10), -462T(12)/-4T(12), 462T(13)/-4T(11), -462T(14)/-4T(10) and -462T(15)/ 4T(11). Haplotype -462T(14)/-4T(10) was previously found to be associated with significantly decreased SMAD4 gene promoter activity in comparison to the wild type, while the other detected haplotypes remain to be functionally characterized. This study has shown that functionally relevant somatic alterations of the SMAD4 gene promoter are found in some colon cancer tumors. Although not as frequent in colon as in pancreatic cancer, they may be of significance for certain cases and their role in colon tumorigenesis should be investigated further. PMID- 25742738 TI - beta-Trefoil structure enables interactions between lectins and protease inhibitors that regulate their biological functions. AB - Fungal ricin B-like lectins and protease inhibitors, mycocypins and mycospins, are important mediators in fungal defence against antagonists and all possess the beta-trefoil fold. We demonstrate here that fungal beta-trefoil proteins interact with each other, in addition to their apparent targets, and that these interactions modulate their biological activity. Such regulation of carbohydrate binding or inhibitory activity is observed for the first time in beta-trefoil proteins and could constitute a mechanism for regulating their physiological functions. It could also have implications in molecular recognition of other combinations of beta-trefoil proteins in other species. PMID- 25742739 TI - Oxidation of translation factor EF-G transiently retards the translational elongation cycle in Escherichia coli. AB - In Escherichia coli, elongation factor G (EF-G), a key protein in translational elongation, is particularly susceptible to oxidation. We demonstrated previously that EF-G is inactivated upon formation of an intramolecular disulphide bond. However, the details of the mechanism by which the oxidation of EF-G inhibits the function of EF-G on the ribosome remain to be elucidated. When we oxidized EF-G with hydrogen peroxide, neither the insertion of EF-G into the ribosome nor single-cycle translocation activity in vitro was affected. However, the GTPase activity and the dissociation of EF-G from the ribosome were suppressed when EF-G was oxidized. The synthesis of longer peptides was suppressed to a greater extent than that of a shorter peptide when EF-G was oxidized. Thus, the formation of the disulphide bond in EF-G might interfere with the hydrolysis of GTP that is coupled with dissociation of EF-G from the ribosome and might thereby retard the turnover of EF-G within the translational machinery. When we added thioredoxin to the suppressed translation system that included oxidized EF-G, translational activity was almost immediately restored. We propose that oxidation of EF-G might provide a regulatory mechanism for transient and reversible suppression of translation in E. coli under oxidative stress. PMID- 25742740 TI - Impairment of the Pin1/E2F1 axis in the anti-proliferative effect of bortezomib in hepatocellular carcinoma cells. AB - BACKGROUND: The modest efficacy of available therapies for Hepatocellular carcinoma (HCC) indicates the need to develop novel therapeutic approaches. For the proteasome inhibitor Bortezomib (BZB), potentially attractive for HCC treatment, the mechanism of action is largely unknown. The BZB effect on E2Fs and the E2Fs control on the peptidylproline cis-trans isomerase (Pin1), prompted us to explore the BZB effect on the Pin1-E2F1 axis. METHODS: The tumorigenic cell line HuH7 together with the non-tumorigenic cells IHH and the human pluripotent stem cell derived hepatocytes (hPSC-H), were used as cellular models of HCC and normal liver cells, respectively. RESULTS: BZB reduces HuH7 growth as shown by cell counting, cell vitality test and cell cycle analysis; this is paralleled by the decrease of Pin1, E2F1, cyclin A2 and of the hyper-phosphorylated pRB. Pin1 E2F1 axis impairment justifies the anti-proliferative effect since Pin-E2F1 depletion decreases HuH7 growth while the over-expression rescues BZB-induced inhibition of proliferation. Moreover, Pin1-E2F1 promote HuH7 growth via the up regulation of cyclin D1, cyclin E, cyclin A2, E2F2 and in part E2F3. Finally, in the control cells IHH and hPSC-H, BZB effect on cell vitality is not irrelevant, a fact correlated to the cellular proliferation rate. Thus, BZB effect on healthy liver tissue may not be entirely negligible hence caution should be exercised in its use in liver regeneration processes. CONCLUSION: For the first time we prove the functional involvement of the Pin1-E2F1 axis in the anti-proliferative effect of BZB indicating Pin1-E2F as an attractive target to control HCC cell growth. PMID- 25742743 TI - Three dimensional in vitro human tissue models for ADME-Tox studies. PMID- 25742742 TI - The p110alpha isoform of phosphoinositide 3-kinase is essential for cone photoreceptor survival. AB - Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylates the 3'OH of the inositol ring of phosphoinositides (PIs). They are responsible for coordinating a diverse range of cellular functions. Class IA PI3K is a heterodimeric protein composed of a regulatory p85 and a catalytic p110 subunit. In this study, we conditionally deleted the p110alpha-subunit of PI3K in cone photoreceptor cells using the Cre-loxP system. Cone photoreceptors allow for color vision in bright light (daylight vision). Cone-specific deletion of p110alpha resulted in cone degeneration. Our studies suggest that PI3K signaling is essential for cone photoreceptor functions. PMID- 25742741 TI - Quantitative studies of mRNA recruitment to the eukaryotic ribosome. AB - The process of peptide bond synthesis by ribosomes is conserved between species, but the initiation step differs greatly between the three kingdoms of life. This is illustrated by the evolution of roughly an order of magnitude more initiation factor mass found in humans compared with bacteria. Eukaryotic initiation of translation is comprised of a number of sub-steps: (i) recruitment of an mRNA and initiator methionyl-tRNA to the 40S ribosomal subunit; (ii) migration of the 40S subunit along the 5' UTR to locate the initiation codon; and (iii) recruitment of the 60S subunit to form the 80S initiation complex. Although the mechanism and regulation of initiation has been studied for decades, many aspects of the pathway remain unclear. In this review, I will focus discussion on what is known about the mechanism of mRNA selection and its recruitment to the 40S subunit. I will summarize how the 43S preinitiation complex (PIC) is formed and stabilized by interactions between its components. I will discuss what is known about the mechanism of mRNA selection by the eukaryotic initiation factor 4F (eIF4F) complex and how the selected mRNA is recruited to the 43S PIC. The regulation of this process by secondary structure located in the 5' UTR of an mRNA will also be discussed. Finally, I present a possible kinetic model with which to explain the process of mRNA selection and recruitment to the eukaryotic ribosome. PMID- 25742744 TI - Transforming growth factor beta 3 involved in the pathogenesis of synovial chondromatosis of temporomandibular joint. AB - Synovial chondromatosis (SC) of temporomandibular joint is rare proliferative disorder featured by the formation of cartilaginous nodules in synovium and joint space. Transforming growth factor beta 3 (TGF-beta3) is closely related to chondrogenic differentiation, and might participate in pathogenesis of SC. We discovered that increased quantity of synoviocytes and blood vessels were observed in SC synovium. The vessel wall and sublining fibroblasts were stained positively by the antibodies against TGF-beta3, fibroblast growth factor 2 (FGF 2), and CD34. In loose bodies (LBs), TGF-beta3 was mainly expressed in chondrocytes and FGF-2 was expressed in chondrocytes, fibroblasts, and vessel walls. Expressions of TGF-beta1, TGF-beta3, FGF-2, Sox9, Wnt-4, Foxc2, and VEGF-A mRNA were significantly higher in SC synovium. Stimulation of TGF-beta3 on synoviocytes increased alkaline phosphatase (ALP) activity and expressions of chondrogenic genes (Sox9, Col2alpha1, Aggrecan, Wnt-4, and Wnt-11), osteogenic genes (Runx2, Foxc2, osteocalcin, and Col1alpha1), and VEGF-A, but failed to influence FGF-2 expression. However, the addition of FGF-2 increased TGF-beta3 expression. In conclusion, TGF-beta3 existed in synovium and LBs of SC, and was responsible for the pathogenesis of SC. PMID- 25742745 TI - Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family. AB - Lynch syndrome (LS) is an inherited predisposition cancer syndrome, typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. In the last years, a role for epimutations of the same genes has also been reported. MLH1 promoter methylation is a well known mechanism of somatic inactivation in tumors, and more recently, several cases of constitutional methylation have been identified. In four subjects affected by multiple tumors and belonging to a suspected LS family, we detected a novel secondary MLH1 gene epimutation. The methylation of MLH1 promoter was always linked in cis with a 997 bp-deletion (c.-168_c.116+713del), that removed exon 1 and partially involved the promoter of the same gene. Differently from cases with constitutional primary MLH1 inactivation, this secondary methylation was allele-specific and CpGs of the residual promoter region were totally methylated, leading to complete allele silencing. In the colon tumor of the proband, MLH1 and PMS2 expression was completely lost as a consequence of a pathogenic somatic point mutation (MLH1 c.199G>A, p.Gly67Arg) that also abrogated local methylation by destroying a CpG site. The evidences obtained highlight how MLH1 mutations and epimutations can reciprocally influence each other and suggest that an altered structure of the MLH1 locus results in epigenetic alteration. PMID- 25742746 TI - All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells. AB - Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells. PMID- 25742747 TI - An integrative approach identified genes associated with drug response in gastric cancer. AB - Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro. PMID- 25742748 TI - Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice. AB - CBFbeta-SMMHC (core-binding factor beta-smooth muscle myosin heavy chain), the fusion protein generated by the chromosome 16 inversion fusion gene, CBFB-MYH11, is known to initiate leukemogenesis. However, the mechanism through which CBFbeta SMMHC contributes to leukemia development is not well understood. Previously, it was proposed that CBFbeta-SMMHC acts by dominantly repressing the transcription factor RUNX1 (Runt-related protein 1), but we recently showed that CBFbeta-SMMHC has activities that are independent of RUNX1 repression. In addition, we showed that a modified CBFbeta-SMMHC with decreased RUNX1-binding activity accelerates leukemogenesis. These results raise questions about the importance of RUNX1 in leukemogenesis by CBFbeta-SMMHC. To test this, we generated mice expressing Cbfb MYH11 in a Runx1-deficient background, resulting from either homozygous Runx1 null alleles (Runx1(-/-)) or a single dominant-negative Runx1 allele (Runx1(+/lz)). We found that loss of Runx1 activity rescued the differentiation defects induced by Cbfb-MYH11 during primitive hematopoiesis. During definitive hematopoiesis, RUNX1 loss also significantly reduced the proliferation and differentiation defects induced by Cbfb-MYH11. Importantly, Cbfb-MYH11-induced leukemia had much longer latency in Runx1(+/lz) mice than in Runx1-sufficient mice. These data indicate that Runx1 activity is critical for Cbfb-MYH11-induced hematopoietic defects and leukemogenesis. PMID- 25742750 TI - Direct transformation of xylan-type hemicelluloses to furfural via SnCl4 catalysts in aqueous and biphasic systems. AB - Direct catalytic transformation of xylan-type hemicelluloses to furfural in the aqueous system and the biphasic system were comparatively investigated under mild conditions. Screening of several promising chlorides for conversion of beech xylan in the aqueous system revealed the Lewis acid SnCl4 was the most effective catalyst. Comparing to the single aqueous system, the bio-based 2 methyltetrahydrofuran (2-MTHF)/H2O biphasic system was more conducive to the synthesis of furfural, in which the highest furfural yield of 78.1% was achieved by using SnCl4 as catalysts under the optimized reaction conditions (150 degrees C, 120 min). Additionally, the influences of xylan-type hemicelluloses with different chemical and structural features from beech, corncob and bagasse on the furfural production were studied. It was found that furfural yield to some extent was determined by the xylose content in hemicelluloses and also had relationships with the molecular weight of hemicelluloses and the degree of crystallization. PMID- 25742749 TI - Notch-mediated expansion of cord blood progenitors: maintenance of transcriptional and epigenetic fidelity. PMID- 25742751 TI - Bed agglomeration characteristics of rice straw combustion in a vortexing fluidized-bed combustor. AB - To investigate bed agglomeration characteristics, the combustion of pelletized rice straw was conducted in a bench-scale vortexing fluidized bed. Effects of bed temperature, superficial velocity, secondary gas velocities, and mass blended ratio of coal on the defluidization time were investigated. The alkali concentrations in different sections of the bed zone were also studied. The bed materials and agglomerates were analyzed using SEM/EDX to obtain the surface morphology and the compositions. The results revealed that the defluidization time is increased with superficial gas velocity and is decreased with bed temperature. Eutectic composition with low melting point materials promote defluidization at high temperatures. Effect of the secondary gas velocity on the defluidization time indicates different trends at different bed temperatures. The highest value of alkali concentration appears at upper bubbling zone. Coal ash can avoid the existence of a certain eutectic composition, and increases its melting point. PMID- 25742752 TI - Biorefining strategy for maximal monosaccharide recovery from three different feedstocks: eucalyptus residues, wheat straw and olive tree pruning. AB - This work proposes the biorefining of eucalyptus residues (ER), wheat straw (WS) and olive tree pruning (OP) combining hydrothermal pretreatment (autohydrolysis) with acid post-hydrolysis of the liquid fraction and enzymatic hydrolysis of the solid fraction towards maximal recovery of monosaccharides from those lignocellulose materials. Autohydrolysis of ER, WS and OP was performed under non isothermal conditions (195-230 degrees C) and the non-cellulosic saccharides were recovered in the liquid fraction while cellulose and lignin remained in the solid fraction. The acid post-hydrolysis of the soluble oligosaccharides was studied by optimizing sulfuric acid concentration (1-4%w/w) and reaction time (10-60 min), employing a factorial (2(2)) experimental design. The solids resulting from pretreatment were submitted to enzymatic hydrolysis by applying commercial cellulolytic enzymes Celluclast(r) 1.5L and Novozyme(r) 188 (0.225 and 0.025 g/g solid, respectively). This strategy provides high total monosaccharide recovery or high glucose recovery from lignocellulosic materials, depending on the autohydrolysis conditions applied. PMID- 25742753 TI - Hydrothermal pretreatment of several lignocellulosic mixtures containing wheat straw and two hardwood residues available in Southern Europe. AB - This work studied the processing of biomass mixtures containing three lignocellulosic materials largely available in Southern Europe, eucalyptus residues (ER), wheat straw (WS) and olive tree pruning (OP). The mixtures were chemically characterized, and their pretreatment, by autohydrolysis, evaluated within a severity factor (logR0) ranging from 1.73 up to 4.24. A simple modeling strategy was used to optimize the autohydrolysis conditions based on the chemical characterization of the liquid fraction. The solid fraction was characterized to quantify the polysaccharide and lignin content. The pretreatment conditions for maximal saccharides recovery in the liquid fraction were at a severity range (logR0) of 3.65-3.72, independently of the mixture tested, which suggests that autohydrolysis can effectively process mixtures of lignocellulosic materials for further biochemical conversion processes. PMID- 25742754 TI - Development and characterization of activated hydrochars from orange peels as potential adsorbents for emerging organic contaminants. AB - Activated hydrochars obtained from the hydrothermal carbonization of orange peels (Citrus sinensis) followed by various thermochemical processing were assessed as adsorbents for emerging contaminants in water. Thermal activation under flows of CO2 or air as well as chemical activation with phosphoric acid were applied to the hydrochars. Their characteristics were analyzed and related to their ability to uptake three pharmaceuticals (diclofenac sodium, salicylic acid and flurbiprofen) considered as emerging contaminants. The hydrothermal carbonization and subsequent activations promoted substantial chemical transformations which affected the surface properties of the activated hydrochars; they exhibited specific surface areas ranging from 300 to ~620 m(2)/g. Morphological characterization showed the development of coral-like microspheres dominating the surface of most hydrochars. Their ability to adsorb the three pharmaceuticals selected was found largely dependent on whether the molecules were ionized or in their neutral form and on the porosity developed by the new adsorbents. PMID- 25742756 TI - Development of a smartphone application for the objective detection of attentional deficits in delirium. AB - BACKGROUND: Delirium is an acute, severe deterioration in mental functioning. Inattention is the core feature, yet there are few objective methods for assessing attentional deficits in delirium. We previously developed a novel, graded test for objectively detecting inattention in delirium, implemented on a computerized device (Edinburgh Delirium Test Box (EDTB)). Although the EDTB is effective, tests on universally available devices have potential for greater impact. Here we assessed feasibility and validity of the DelApp, a smartphone application based on the EDTB. METHODS: This was a preliminary case-control study in hospital inpatients (aged 60-96 years) with delirium (N = 50), dementia (N = 52), or no cognitive impairment (N = 54) who performed the DelApp assessment, which comprises an arousal assessment followed by counting of lights presented serially. Delirium was assessed using the Confusion Assessment Method and Delirium Rating Scale-Revised-98 (DRS-R98), and cognition with conventional tests of attention (e.g. digit span) and the short Orientation-Memory-Concentration Test (OMCT). RESULTS: DelApp scores (maximum score = 10) were lower in delirium (scores (median(IQR)): 6 (4-7)) compared to dementia (10 (9-10)) and control groups (10 (10-10), p-values < 0.001). Receiver operating characteristic (ROC) analyses revealed excellent accuracy of the DelApp for discriminating delirium from dementia (AUC = 0.93), and delirium from controls (AUC = 0.99, p-values < 0.001). DelApp and DRS-R98 severity scores were moderately well correlated (Kendall's tau = -0.60, p < 0.001). OMCT scores did not differ between delirium and dementia. CONCLUSIONS: The DelApp test showed good performance, supporting the utility of objectively measuring attention in delirium assessment. This study provides evidence of the feasibility of using a smartphone test for attentional assessment in hospital inpatients with possible delirium, with potential applications in research and clinical practice. PMID- 25742755 TI - In vitro biomechanical evaluation of four fixation techniques for distractive flexion injury stage 3 of the cervical spine. AB - PURPOSE: Anterior plate fixation has been reported to provide satisfactory results in cervical spine distractive flexion (DF) injuries stages 1 and 2, but will result in a substantial failure rate in more unstable stage 3 and above. The aim of this investigation was to determine the biomechanical properties of different fixation techniques in a DF-3 injury model where all structures responsible for the posterior tension band mechanism are torn. METHODS: The multidirectional three-dimensional stiffness of the subaxial cervical spine was measured in eight cadaveric specimens with a simulated DF-3 injury at C5-C6, stabilized with four different fixation techniques: anterior plate alone, anterior plate combined with posterior wire, transarticular facet screws, and a pedicle screw-rod construct, respectively. RESULTS: The anterior plate alone did not improve stability compared to the intact spine condition, thus allowing considerable range of motion around all three cardinal axes (p > 0.05). The anterior plate combined with posterior wire technique improved flexion-extension stiffness (p = 0.023), but not in axial rotation and lateral bending. When the anterior plate was combined with transarticular facet screws or with a pedicle screws-rod instrumentation, the stability improved in flexion-extension, lateral bending, and in axial rotation (p < 0.05). CONCLUSIONS: These findings imply that the use of anterior fixation alone is insufficient for fixation of the highly unstable DF-3 injury. In these situations, the use of anterior fixation combined with a competent posterior tension band reconstruction (e.g. transarticular screws or a posterior pedicle screws-rod device) improves segmental stability. PMID- 25742757 TI - Assessment of disease activity in Systemic Lupus Erythematosus: Lights and shadows. AB - The assessment of disease activity in patients affected by Systemic Lupus Erythematosus (SLE) represents an important issue, as recommended by the European League Against Rheumatism (EULAR). Two main types of disease activity measure have been proposed: the global score systems, providing an overall measure of activity, and the individual organ/system assessment scales, assessing disease activity in different organs. All the activity indices included both clinical and laboratory items, related to the disease manifestations. However, there is no gold standard to measure disease activity in patients affected by SLE. In this review, we will analyze the lights and shadows of the disease activity indices, by means of a critical approach. In particular, we will focus on SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), the most frequently used in randomized controlled trials and observational studies. The evaluation of data from the literature underlined some limitations of these indices, making their application in clinical practice difficult and suggesting the possible use of specific tools in the different subset of SLE patients, in order to capture all the disease features. PMID- 25742758 TI - Managing unwanted immunogenicity of biologicals. AB - All protein drugs (biologicals) have an immunogenic potential and we are armed with multiple guidelines, regulatory documents and white papers to assist us in assessing the level of risk for unwanted immunogenicity of new biologicals. However, for certain biologicals, significant immunogenicity becomes only apparent after their use in patients. Causes of immunogenicity are multifactorial but not yet fully understood. Within the pharmaceutical industry there are only a few opportunities to openly discuss the causes and consequences of immunogenicity with regard to the development of new biologicals. The annual Open Scientific Symposium of the European Immunogenicity Platform (EIP) is one such meeting that brings together scientists and clinicians from academia and industry to build know-how and expertise in the field of immunogenicity. The critical topics discussed at the last EIP meeting (February 2014) will be reviewed here. The current opinion of this expert group is that the assessment of unwanted immunogenicity can be improved by using prediction tools, optimizing the performance of immunogenicity assays and learning from the clinical impact of other biologicals that have already been administered to patients. A multidisciplinary approach is warranted to better understand and minimize drug immunogenicity and its clinical consequences. PMID- 25742759 TI - Early and late effects of high- versus low-dose angiotensin receptor blockade on renal function and outcomes in patients with chronic heart failure. AB - OBJECTIVES: This study investigated the dose-related effect of losartan on changes in renal function using data from the HEAAL (Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan) trial. BACKGROUND: Angiotensin receptor blockers adversely affect renal function in patients with heart failure (HF). The time course and dose dependency of this time course, as well as the clinical implications of these changes in renal function, are not well described. METHODS: Subjects in the HEAAL dataset (n = 3,843) were studied. Changes in estimated glomerular filtration rate (eGFR) over time were compared between dose groups. The association between the timing of incident increases in serum creatinine (SCr) >0.3 mg/dl and clinical outcomes was explored. RESULTS: Compared with 50 mg, 150 mg losartan led to a greater reduction in eGFR across time (mean difference:-3.76 ml/min/1.73 m(2); p < 0.0001). This difference was driven by early changes, and differences in eGFRafter 4 months were not significant (mean difference: 0.42 ml/min/1.73 m(2); p = 0.15) [corrected]. Although an increase in SCr >0.3 mg/dl from baseline was associated with increased risk of death or hospitalization for HF (hazard ratio [HR]: 1.36; p < 0.0001), the relationship was not significant if the change occurred before 4 months (HR: 1.09; p = 0.20). Despite increased risk of worsening renal function, 150 mg losartan was associated with reduced risk of death or hospitalization for HF compared with 50 mg (HR: 0.85; p < 0.0001). CONCLUSIONS: Compared with 50 mg, 150 mg losartan is associated with an increased risk of acute rise in SCr, as well as with greater long-term reductions in eGFR. Despite these effects, high-dose losartan retains its net clinical benefit and is associated with reduced risk of death or hospitalization for HF. (Study to Evaluate Potential Decrease in Hospitalization Events, Time Between Events, and Increasing Longevity in Patients With Symptomatic Heart Failure; NCT00090259). PMID- 25742760 TI - Incidence, temporal trends, and prognostic impact of heart failure complicating acute myocardial infarction. The SWEDEHEART Registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies): a study of 199,851 patients admitted with index acute myocardial infarctions, 1996 to 2008. AB - OBJECTIVES: The aim of this study was to examine temporal trends in the incidence and outcomes of heart failure (HF) complicating acute myocardial infarction (AMI) in a large national cohort. BACKGROUND: There are limited and conflicting data concerning temporal trends in the incidence and prognostic implication of in hospital HF that complicates AMI. METHODS: The nationwide coronary care unit registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) records baseline characteristics, treatments, and outcome of consecutive patients with AMIs admitted to all hospitals in Sweden. The diagnosis of HF requires the presence of crackles (Killip class >=II) or the use of intravenous diuretic agents or intravenous inotropes. This study included 199,851 patients admitted for index AMIs between 1996 and 2008. RESULTS: The incidence of HF declined from 46% to 28% (p < 0.001). This decrease was more pronounced in patients with ST-segment elevation myocardial infarctions and left bundle branch block (from 50% to 28%) compared with those with non-ST-segment elevation myocardial infarctions (from 42% to 28%) (p < 0.001). The in-hospital, 30-day, and 1-year mortality rates for patients who developed HF during the index myocardial infarction decreased over the years from 19% to 13%, from 23% to 17%, and from 36% to 31%, respectively (p < 0.001 for all). Thirteen-year survival analysis showed higher mortality in patients with HF compared with those without HF (adjusted hazard ratio: 2.1; 95% confidence interval: 2.06 to 2.13). CONCLUSIONS: A marked decrease was found in the incidence of HF complicating AMI between 1996 and 2008. However, HF continues to worsen the early-, intermediate-, and long-term adverse prognostic risk after AMI. PMID- 25742761 TI - Standing the test of time. PMID- 25742763 TI - Evolving role of galectin-3 as a cardiac biomarker: heart failure with preserved ejection fraction and renal function, important pieces of the puzzle. PMID- 25742762 TI - Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure). AB - OBJECTIVES: This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. BACKGROUND: Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. METHODS: Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. RESULTS: Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). CONCLUSIONS: In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF. PMID- 25742764 TI - Association of cardiomyopathy with adverse cardiac events in pregnant women at the time of delivery. AB - OBJECTIVES: The aim of this study was to determine the predictors of adverse events in pregnant women with cardiomyopathy (CDM) and CDM subtypes at the time of delivery. BACKGROUND: Investigation of patients' characteristics and outcomes in women with CDM at the time of delivery has been limited. METHODS: The Healthcare Cost and Utilization Project's National Inpatient Sample was screened for hospital admissions for delivery in pregnant women with CDM from 2006 to 2010. Clinical characteristics and maternal outcomes were identified in women with and without CDM and in CDM subtypes. The primary outcome of interest was major adverse clinical events (MACE), a composite of in-hospital death, acute myocardial infarction, heart failure, arrhythmia, cerebrovascular event, or embolic event. RESULTS: Our study population comprised 2,078 patients with CDM and 4,438,439 patients without CDM. Of those with CDM, 52 (2.5%) were hypertrophic, 1,039 (50.0%) were peripartum, and 987 (47.5%) were classified as other. Women with CDM were older, white, and insured by Medicaid. MACE rates were significantly higher in women with peripartum CDM (46%), compared with hypertrophic CDM (23%) and all others (39%) (p < 0.001). In multivariable analysis, the presence of peripartum cardiomyopathy (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.1 to 4.6), valvular disease (OR: 2.11; 95% CI: 1.6 to 2.9), and eclampsia (OR: 5.0; 95% CI: 1.6 to 1.9) was independently associated with MACE. CONCLUSIONS: Presence of CDM is independently predictive of MACE during hospitalization for delivery. Patients with peripartum CDM had the highest likelihood of MACE compared with other CDM subtypes. PMID- 25742765 TI - Risk prediction tools in patients with heart failure. PMID- 25742766 TI - Effect of ivabradine on early readmissions after hospitalization for worsening heart failure. PMID- 25742767 TI - Reply: effect of ivabradine on early readmissions after hospitalization for worsening heart failure. PMID- 25742768 TI - Coenzyme Q10: will this natural substance become a guideline-directed adjunctive therapy in heart failure? PMID- 25742770 TI - Hop, skip, and jump: do we need phase II cardiovascular clinical trials? PMID- 25742769 TI - Reply: Coenzyme q10: will this natural substance become a guideline-directed adjunctive therapy in heart failure? PMID- 25742771 TI - Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia. AB - Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure. PMID- 25742772 TI - Cardiac rehabilitation completion is associated with reduced mortality in patients with diabetes and coronary artery disease. AB - AIMS: Cardiac rehabilitation (CR) reduces the risks of mortality and hospitalisation in patients with coronary artery disease and without diabetes. It is unknown whether patients with diabetes obtain the same benefits from CR. METHODS: We retrospectively examined patients referred to a 12 week CR programme between 1996 and 2010. Associations between CR completion vs non-completion and death, hospitalisation rate and cardiac hospitalisation rate were assessed by survival analysis. RESULTS: Over the study period, 13,158 participants were referred to CR (mean +/- SD, age 59.9 +/- 11.1 years, 28.9% female, 2,956 [22.5%] with diabetes). Patients with diabetes were less likely to complete CR than those without diabetes (41% vs 56%, p < .0001). Over a median follow-up of 6.6 years, there were 379 deaths in patients with diabetes vs 941 deaths among those without diabetes (12.8% vs 8.9%). Of the non-completers, patients with diabetes had a higher mortality rate compared with those without diabetes (17.7% vs 11.3%). In patients who completed CR, mortality was lower: 11.1% in patients with diabetes vs 7.0% in those without diabetes. In patients with diabetes, CR completion was associated with reduced mortality (HR 0.46 [95% CI 0.37, 0.56]), reduced hospitalisation (HR 0.86 [95% CI 0.76, 0.96]) and reduced cardiac hospitalisation (HR 0.67 [95% CI 0.54, 0.84]). The protective associations were similar to those of patients without diabetes. In multivariable adjusted analyses, all of these associations remained significant. CONCLUSIONS: Patients with diabetes were less likely to complete CR than those without diabetes. However, patients with diabetes who completed CR derived similar apparent reductions in mortality and hospitalisation to patients without diabetes. PMID- 25742775 TI - [Where are we?]. PMID- 25742776 TI - Solution processed single-emission layer white polymer light-emitting diodes with high color quality and high performance from a poly(N-vinyl)carbazole host. AB - Low cost and high performance white polymer light-emitting diodes (PLEDs) are very important as solid-state lighting sources. In this research three commercially available phosphors were carefully chosen, bis[2-(4,6 difluorophenyl)pyridinato-N,C(2)](picolinate)iridium(III) (FIrpic), bis[2-(2 pyridinyl-N)phenyl-C](2,4-pentanedionato-O(2),O(4))iridium(III) [Ir(ppy)2(acac)], and bis(2-phenyl-benzothiazole-C(2),N)(acetylacetonate)iridium(III) [Ir(bt)2(acac)], plus a home-made red phosphor of tris[1-(2,6-dimethylphenoxy)-4 (4-chlorophenyl)phthalazine]iridium(III) [Ir(MPCPPZ)3], and their photophysical and morphological properties were systematically studied as well as their applications in single-emission layer white PLEDs comprising poly(N vinylcarbazole) as host. Additionally, the electrochemical properties and energy level alignment, possible energy transfer process, and thin-film morphology were also addressed. The binary blue/orange complementary white PLEDs exhibit stable electroluminescence spectra, wide spectrum-covering region range from 380-780 nm, and high color rendering index (CRI) over 70 with Commission Internationale de l'Eclairage coordinates x,y (CIEx,y) of (0.388, 0.440), correlated color temperature (CCT) of around 4400, plus high efficiency of 25.5 cd A(-1). The optimized red-green-blue white PLEDs showed a satisfactory CRI of around 82.4, maximum current efficiency of 20.0 cd A(-1) and external quantum efficiency (EQE) of 10.8%, corresponding to a CCT of 3700-2800, which is a warm-white hue. At last, stable and high color quality, red-green-orange-blue four component white PLEDs, with a CRI of over 82, a high efficiency of 24.0 cd A(-1), EQE of 11.5%, and high brightness of 43,569.9 cd m(-2) have been obtained. PMID- 25742773 TI - B cells responses and cytokine production are regulated by their immune microenvironment. AB - The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naive T cells produce multiple cytokines upon activation while naive activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN alpha, IFN-beta, IFN-gamma. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response. PMID- 25742774 TI - The role of Th17-associated cytokines in the pathogenesis of experimental autoimmune uveitis (EAU). AB - The proinflammatory and pathogenic function of Th17 cells in autoimmune diseases have been established but the mechanism by which such cells cause disease remains to be determined. Inflammatory cytokines produced by Th17 cells may either promote or inhibit disease development. The major cytokines produced by the uveitogenic T cells, such as IL-17 and IL-22, are not always pathogenic, and the disease-inducing ability of pathogenic T cells is not immediately correlated to the amount of cytokine they produce. Future studies identifying factors causing increased Th17 responses and determining the types of cells that regulating Th17 autoreactive T cells should facilitate our effort of understanding Th17-mediated disease pathogenesis. PMID- 25742777 TI - Frontal vitrification of PDMS using air plasma and consequences for surface wrinkling. AB - We study the surface oxidation of polydimethylsiloxane (PDMS) by air plasma exposure and its implications for the mechanically-induced surface wrinkling of the resulting glass-elastomer bilayers. The effect of plasma frequency (kHz and MHz), oxygen content (from O2 to air), pressure (0.5 <= P <= 1.5 mbar), as well as exposure time and power, is quantified in terms of the resulting glassy skin thickness h, inferred from wrinkling experiments. The glassy skin thickness is found to increase logarithmically with an exposure time t, for different induction powers p, and all data collapse in terms of a plasma dose, D = p * t. The kinetics of film propagation are found to increase with the oxygen molar fraction yO2 and decrease with the gas pressure P, allowing both the wrinkling wavelength lambda and amplitude A to be effectively controlled by gas pressure and composition. A generalised relationship for frontal vitrification is obtained by re-scaling all lambda and h data by D/P. A coarse-grained wave propagation model effectively describes and quantifies the process stages (induction, skin formation and propagation) under all the conditions studied. Equipped with this knowledge, we further expand the capabilities of plasma oxidation for PDMS wrinkling, and a wavelength of lambda ~ 100 nm is readily attained with a modest strain epsilonprestrain ~ 20%. PMID- 25742778 TI - Comment on "Tumour thickness as a predictor of nodal metastases in oral cancer: comparison between tongue and floor of mouth subsites" by Balasubramanian D et al. PMID- 25742781 TI - Endovascular stent-graft excision and surgical aortic reconstruction. AB - Endovascular aneurysm repair is being used more often and replacing open surgical repair as the treatment option for aortic aneurysm. Early results are better than those of open surgical repair, but the need for a second intervention is greater. Excision of a previously placed stent-graft by different surgical methods is very difficult and has high mortality and morbidity rates. We describe 3 patients who had previous endovascular aneurysm repair and were treated by an open surgical method with near total excision, leaving part of the stent-graft in the native aortic tissue. PMID- 25742782 TI - Lung adenocarcinoma with clear cell features producing carbohydrate antigen 19-9. AB - A 76-year-old man underwent surgery for lung cancer. Histopathologically, most of the resected tumor was composed of polygonal cells with foamy cytoplasm, and the cells were arranged predominantly in acinar patterns. In this case, although the carbohydrate antigen 19-9 level was high before surgery, it normalized after resection. The tumor was considered a carbohydrate antigen 19-9-producing tumor, which was further supported by the results of immunohistochemical analysis. Adenocarcinoma with clear cell features, producing carbohydrate antigen 19-9, is an exceedingly rare entity. PMID- 25742783 TI - Cardiac calcified amorphous tumor in a hemodialysis patient. AB - We present a case of cardiac calcified amorphous tumor, a rare intracardiac non neoplastic tumor, in a hemodialysis patient. A 72-year-old woman with no history of thromboembolic, malignant, or inflammatory disease presented with dyspnea. Echocardiography revealed a highly echoic, slightly mobile mass with an acoustic shadow originating from the mitral subvalvular apparatus, extending to the left ventricular outflow tract. She underwent surgical resection of the mass through the aortic valve, which was easily excised from the papillary muscle and chordae tendineae. Histopathologic examination revealed nodular calcium deposits on a background of amorphous degenerated fibrin material, consistent with calcified amorphous tumor. PMID- 25742784 TI - A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras. AB - The efficacy of anti-angiogenic therapies on cancer patients is limited by the emergence of drug resistance, urging the search for second-generation drugs. In this study, we screened an academic chemical library (DCM, University of Grenoble Alpes) and identified a leader molecule, COB223, that inhibits endothelial cell migration and proliferation. It inhibits also Lewis lung carcinoma (LLC/2) cell proliferation whereas it does not affect fibroblast proliferation. The anti angiogenic activity of COB223 was confirmed using several in vitro and in vivo assays. In a mouse LLC/2 tumor model, ip administration of doses as low as 4 mg/kg COB223 efficiently reduced the tumor growth rate. We observed that COB223 inhibits endothelial cell ERK1/2 phosphorylation induced by VEGF, FGF-2 or serum and that it acts downstream of PKC and upstream of Ras. This molecule represents a novel anti-angiogenic and anti-tumorigenic agent with an original mechanism of action that deserves further development as an anti-cancer drug. PMID- 25742785 TI - The significance of PIWI family expression in human lung embryogenesis and non small cell lung cancer. AB - The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression. PMID- 25742786 TI - A melanoma subtype with intrinsic resistance to BRAF inhibition identified by receptor tyrosine kinases gene-driven classification. AB - Dysregulation of receptor tyrosine kinases (RTKs) contributes to several aspects of oncogenesis including drug resistance. In melanoma, distinct RTKs have been involved in BRAF inhibitors (BRAFi) resistance, yet the utility of RTKs expression pattern to identify intrinsically resistant tumors has not been assessed. Transcriptional profiling of RTKs and integration with a previous classification, reveals three robust subtypes in two independent datasets of melanoma cell lines and one cohort of melanoma samples. This classification was validated by Western blot in a panel of patient-derived melanoma cell lines. One of the subtypes identified here for the first time displayed the highest and lowest expression of EGFR and ERBB3, respectively, and included BRAF-mutant tumors all intrinsically resistant to BRAFi PLX4720, as assessed by analysis of the Cancer Cell Line Encyclopedia pharmacogenomic study and by in vitro growth inhibition assays. High levels of EGFR were detected, even before therapy, in tumor cells of one of three melanoma patients unresponsive to BRAFi. Use of different pharmacological inhibitors highlighted the relevance of PI3K/mTOR signaling for growth of this PLX4720-resistant subtype. Our results identify a specific molecular profile of melanomas intrinsically resistant to BRAFi and suggest the PI3K/mTOR pathway as a potential therapeutic target for these tumors. PMID- 25742787 TI - The IgH 3' regulatory region governs MU chain transcription in mature B lymphocytes and the B cell fate. AB - We report that the IgH 3' regulatory region (3'RR) has no role on MU chain transcription and pre-BCR expression in B cell progenitors. In contrast, analysis of heterozygous IgH aDelta3'RR/bwt mice indicated that the 3'RR controls MU chain transcripts in mature splenocytes and impacts membrane IgM density without obvious effect on BCR signals (colocalisation with lipid rafts and phosphorylation of Erk and Akt after BCR crosslinking). Deletion of the 3'RR modulates the B cell fate to less marginal zone B cells. In conclusion, the 3'RR is dispensable for pre-BCR expression and necessary for optimal commitments toward the marginal zone B cell fate. These results reinforce the concept of a dual regulation of the IgH locus transcription and accessibility by 5' elements at immature B cell stages, and by the 3'RR as early as the resting mature B cell stage and then along further activation and differentiation. PMID- 25742788 TI - Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation. AB - Allyl isothiocyanate (AITC), a constituent of many cruciferous vegetables exhibits significant anticancer activities in many cancer models. Our studies provide novel insights into AITC-induced anticancer mechanisms in human A549 and H1299 non-small cell lung cancer (NSCLC) cells. AITC exposure induced replication stress in NSCLC cells as evidenced by gammaH2AX and FANCD2 foci, ATM/ATR-mediated checkpoint responses and S and G2/M cell cycle arrest. Furthermore, AITC-induced FANCD2 foci displayed co-localization with BrdU foci, indicating stalled or collapsed replication forks in these cells. Although PITC (phenyl isothiocyanate) exhibited concentration-dependent cytotoxic effects, treatment was less effective compared to AITC. Previously, agents that induce cell cycle arrest in S and G2/M phases were shown to sensitize tumor cells to radiation. Similar to these observations, combination therapy involving AITC followed by radiation treatment exhibited increased DDR and cell killing in NSCLC cells compared to single agent treatment. Combination index (CI) analysis revealed synergistic effects at multiple doses of AITC and radiation, resulting in CI values of less than 0.7 at Fa of 0.5 (50% reduction in survival). Collectively, these studies identify an important anticancer mechanism displayed by AITC, and suggest that the combination of AITC and radiation could be an effective therapy for NSCLC. PMID- 25742789 TI - Up-regulation of matrix metalloproteinases in a mouse model of chemically induced colitis-associated cancer: the role of microRNAs. AB - Emerging evidence has implicated microRNAs in regulating the production of multiple inflammatory mediators including cytokines and chemokines. We previously elucidated the dynamic activation of key signals that link colitis to colorectal cancer. In this study, we observed a sharp increase in the levels of matrix metalloproteinases (Mmps) that provided a basis for the inflammation-cancer link, and we questioned whether this was a consequence of the dysregulation of Mmp specific microRNAs, at least partly. We assayed a panel of murine microRNAs that were predicted to target Mmps and found they were downregulated in the inflammation-cancer link. Furthermore, we demonstrated that three murine microRNAs, namely miR-128, -134, and -330, can target the three Mmps Mmp3, Mmp10, and Mmp13, respectively. We also found that the level of the microRNA-processing enzyme Dicer1 was decreased in the inflammation-cancer link. These microRNAs functioned as tumor suppressors in colon cancer cells, attenuating the proliferation, migration, and invasion potential of murine colon cancer cells as well as angiogenesis and the growth of tumors derived from these cells. Our results suggest that microRNAs modulate the production of key inflammatory mediators and that microRNA dysfunction may contribute to the non-resolving inflammation associated with cancer. PMID- 25742790 TI - Induction of cellular prion protein (PrPc) under hypoxia inhibits apoptosis caused by TRAIL treatment. AB - Hypoxia decreases cytotoxic responses to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) protein. Cellular prion protein (PrPc) is regulated by HIF-1alpha in neurons. We hypothesized that PrPc is involved in hypoxia-mediated resistance to TRAIL-induced apoptosis. We found that hypoxia induced PrPc protein and inhibited TRAIL-induced apoptosis. Thus silencing of PrPc increased TRAIL induced apoptosis under hypoxia. Overexpression of PrPc protein using an adenoviral vector inhibited TRAIL-induced apoptosis. In xenograft model in vivo, shPrPc transfected cells were more sensitive to TRAIL-induced apoptosis than in shMock transfected cells. Molecular chemo-therapy approaches based on the regulation of PrPc expression need to address anti-tumor function of TRAIL under hypoxia. Molecular chemo-therapy approaches based on the regulation of PrPc expression need to address anti-tumor function of TRAIL under hypoxia. PMID- 25742791 TI - Identification of epipolythiodioxopiperazines HDN-1 and chaetocin as novel inhibitor of heat shock protein 90. AB - The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an important target for cancer treatment. HDN-1, an epipolythiopiperazine-2, 5-diones (ETPs) compound, was here identified as a new Hsp90 inhibitor. HDN-1 bound directly to C terminus of Hsp90alpha, resulting in a potential conformational change that interfered with the binding of 17-AAG and novobiocin to Hsp90alpha. In contrast, association of 17-AAG, novobiocin or ATP with Hsp90alpha did not prevent the binding HDN-1 to Hsp90alpha. HDN-1 in combination with 17-AAG exhibited an enhanced inhibitory effect on non-small lung cancer cell proliferation. Molecular docking analyses revealed that HDN-1 bound to Hsp90alpha at C-terminal 526-570 region. In addition, HDN-1 degraded multiple oncoproteins and promoted EGF induced wild type and mutated EGFR downregulation. Notably, chaetocin, used as a SUV39H1 inhibitor with similar structure to HDN-1, bound to Hsp90 and degraded Hsp90 client proteins and SUV39H1 as did HDN-1. These results indicate that HDN-1 and chaetocin are inhibitors of Hsp90 and that SUV39H1 is a novel client protein of Hsp90. PMID- 25742792 TI - Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer. AB - Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered. Thus, in this study, we computationally and experimentally screened a series of small-molecule inhibitors targeting ERK toward different types of human breast cancer cells. Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex. Moreover, we found that BL-EI001 induced breast cancer cell apoptosis via mitochondrial pathway but independent on Ras/Raf/MEK pathway. In addition, we carried out proteomics analyses for exploring some possible BL-EI001-induced apoptotic pathways, and further found that BL-EI001-induced apoptosis affected ERK phosphorylation in breast cancer. Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo. Taken together, these results demonstrate that in silico design and experimental discovery of a synthesized small-molecule ERK inhibitor (BL-EI001)as a potential novel apoptosis-inducing drug in the treatment of breast cancer. PMID- 25742793 TI - Cytokeratin 5/6 fingerprinting in HER2-positive tumors identifies a poor prognosis and trastuzumab-resistant basal-HER2 subtype of breast cancer. AB - There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy. Building on earlier studies suggesting that HER2+ tumors enriched with molecular and morpho-immunohistochemical features classically ascribed to basal-like tumors are highly aggressive and refractory to trastuzumab, we investigated the prognostic and predictive value of the basal-HER2+ phenotype in HER2 overexpressing tumors. Our retrospective cohort study of a consecutive series of 152 HER2+ primary invasive ductal breast carcinomas first confirmed the existence of a distinct subgroup co-expressing HER2 protein and basal cytokeratin markers CK5/6, the so-called basal-HER2+ phenotype. Basal-HER2+ phenotype (>=10% of cells showing positive CK5/6 staining), but not estrogen receptor status, was significantly associated with inferior overall survival by univariate analysis and predicted worsened disease free survival after accounting for strong prognostic variables such as tumor size at diagnosis in stepwise multivariate analysis. In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis. A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy. PMID- 25742794 TI - Comparison of anesthetic efficacy between lidocaine with and without magnesium sulfate USP 50% for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind, placebo controlled study was to compare the anesthetic efficacy between lidocaine with and without magnesium sulfate USP 50% for inferior alveolar nerve (IAN) blocks in patients with symptomatic irreversible pulpitis. METHODS: One hundred patients with symptomatic irreversible pulpitis of mandibular posterior teeth were selected for the study. The patients received 1 mL magnesium sulfate USP 50% or distilled water (placebo) 1 hour before administration of conventional IAN block. Endodontic access cavity preparation was initiated 15 minutes after the IAN block injection. Lip numbness was recorded for all the patients. Success of IAN block was defined as no or mild pain on the visual analogue scale during access cavity preparation and initial instrumentation. RESULTS: The success rate for the IAN block was 58% for magnesium sulfate group and 32% for the placebo group, with statistically significant difference between the 2 groups (P = .016). CONCLUSIONS: In mandibular posterior teeth diagnosed with symptomatic irreversible pulpitis, preoperative administration of 1 mL magnesium sulfate USP 50% resulted in statistically significant increase in success of IAN block compared with placebo. PMID- 25742795 TI - Survival of Intentionally Replanted Teeth and Implant-supported Single Crowns: A Systematic Review. AB - INTRODUCTION: Although nonsurgical initial root canal treatment and retreatment have high success rates, periapical disease can remain. The survival rates of 2 surgical procedures, intentionally replanted (IR) teeth and implant-supported single crowns (ISCs), have yet to be compared. The purpose of this systematic review and meta-analysis was to examine the literature and quantify the survival of IR teeth and compare it with that of ISCs. METHODS: Systematic searches were enriched by citation mining. Weighted survival means and 95% confidence intervals (CI) were estimated using a random-effects model and compared. RESULTS: The quality of the IR and ISC articles was only moderate. Data for ISCs were much more plentiful than for IR teeth. Meta-analysis revealed a weighted mean survival of 88% (95% CI, 81%-94%) for IR teeth. Root resorption was reported with a mean prevalence of 11%. The weighted mean survival of ISCs was 97% (95% CI, 96%-98%). The mean survival of ISCs was significantly higher than that of IR teeth (P < .001). A recent study on IR teeth indicated that orthodontic extrusion before intentional replantation improved survival rates. CONCLUSIONS: A systematic review and meta-analysis found that the mean survival of ISCs was significantly higher than IR teeth. However, treatment decisions must be based on a wide variety of treatment and patient-specific parameters. Intentional replantation may have a role when ISC is not practicable. Studies using contemporary treatment and analytic methods should be used to identify and measure intentional replant prognostic and treatment variables. PMID- 25742796 TI - Cellular analysis of cleavage-stage chick embryos reveals hidden conservation in vertebrate early development. AB - Birds and mammals, phylogenetically close amniotes with similar post-gastrula development, exhibit little conservation in their post-fertilization cleavage patterns. Data from the mouse suggest that cellular morphogenesis and molecular signaling at the cleavage stage play important roles in lineage specification at later (blastula and gastrula) stages. Very little is known, however, about cleavage-stage chick embryos, owing to their poor accessibility. This period of chick development takes place before egg-laying and encompasses several fundamental processes of avian embryology, including zygotic gene activation (ZGA) and blastoderm cell-layer increase. We have carried out morphological and cellular analyses of cleavage-stage chick embryos covering the first half of pre ovipositional development, from Eyal-Giladi and Kochav stage (EGK-) I to EGK-V. Scanning electron microscopy revealed remarkable subcellular details of blastomere cellularization and subgerminal cavity formation. Phosphorylated RNA polymerase II immunostaining showed that ZGA in the chick starts at early EGK-III during the 7th to 8th nuclear division cycle, comparable with the time reported for other yolk-rich vertebrates (e.g. zebrafish and Xenopus). The increase in the number of cell layers after EGK-III is not a direct consequence of oriented cell division. Finally, we present evidence that, as in the zebrafish embryo, a yolk syncytial layer is formed in the avian embryo after EGK-V. Our data suggest that several fundamental features of cleavage-stage development in birds resemble those in yolk-rich anamniote species, revealing conservation in vertebrate early development. Whether this conservation lends morphogenetic support to the anamniote-to-amniote transition in evolution or reflects developmental plasticity in convergent evolution awaits further investigation. PMID- 25742797 TI - Pericytes in the myovascular niche promote post-natal myofiber growth and satellite cell quiescence. AB - The satellite cells, which serve as adult muscle stem cells, are both located beneath myofiber basement membranes and closely associated with capillary endothelial cells. We observed that 90% of capillaries were associated with pericytes in adult mouse and human muscle. During post-natal growth, newly formed vessels with their neuroglial 2 proteoglycan (NG2)-positive pericytes became progressively associated with the post-natal muscle stem cells, as myofibers increased in size and satellite cells entered into quiescence. In vitro, human muscle-derived pericytes promoted myogenic cell differentiation through insulin like growth factor 1 (IGF1) and myogenic cell quiescence through angiopoietin 1 (ANGPT1). Diphtheria toxin-induced ablation of muscle pericytes in growing mice led both to myofiber hypotrophy and to impaired establishment of stem cells quiescence. Similar effects were observed following conditional in vivo deletion of pericyte Igf1 and Angpt1 genes, respectively. Our data therefore demonstrate that, by promoting post-natal myogenesis and stem cell quiescence, pericytes play a key role in the microvascular niche of satellite cells. PMID- 25742798 TI - Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis. AB - Bone morphogenetic protein (BMP) signaling plays many roles in skull morphogenesis. We have previously reported that enhanced BMP signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells causes craniosynostosis during postnatal development. Additionally, we observed that 55% of Bmpr1a mutant mice show neonatal lethality characterized by a distended gastrointestinal tract. Here, we show that severely affected mutants exhibit defective nasal cartilage, failure of fusion between the nasal septum and the secondary palate, and higher levels of phosphorylated SMAD1 and SMAD5 in the nasal tissue. TUNEL demonstrated an increase in apoptosis in both condensing mesenchymal tissues and cartilage of the nasal region in mutants. The levels of p53 (TRP53) tumor suppressor protein were also increased in the same tissue. Injection of pifithrin-alpha, a chemical inhibitor of p53, into pregnant mice prevented neonatal lethality while concomitantly reducing apoptosis in nasal cartilage primordia, suggesting that enhanced BMP signaling induces p53-mediated apoptosis in the nasal cartilage. The expression of Bax and caspase 3, downstream targets of p53, was increased in the mutants; however, the p53 expression level was unchanged. It has been reported that MDM2 interacts with p53 to promote degradation. We found that the amount of MDM2-p53 complex was decreased in all mutants, and the most severely affected mutants had the largest decrease. Our previous finding that the BMP signaling component SMAD1 prevents MDM2-mediated p53 degradation coupled with our new data indicate that augmented BMP signaling induces p53-mediated apoptosis by prevention of p53 degradation in developing nasal cartilage. Thus, an appropriate level of BMP signaling is required for proper craniofacial morphogenesis. PMID- 25742800 TI - Disruption of Th2a and Th2b genes causes defects in spermatogenesis. AB - The variant histones TH2A and TH2B are abundant in the testis, but their roles in spermatogenesis remain elusive. Here, we show that male mutant mice lacking both Th2a and Th2b genes were sterile, with few sperm in the epididymis. In the mutant testis, the lack of TH2B was compensated for by overexpression of H2B, whereas overexpression of H2A was not observed, indicating a decrease in the total histone level. Mutant mice exhibited two defects: incomplete release of cohesin at interkinesis after meiosis I and histone replacement during spermiogenesis. In the mutant testis, secondary spermatocytes at interkinesis accumulated and cohesin was not released normally, suggesting that the retained cohesion of sister chromatids delayed the subsequent entry into meiosis II. In addition, impaired chromatin incorporation of TNP2 and degenerated spermatids were observed in the mutant testis. These results suggest that a loss of TH2A and TH2B function in chromatin dynamics or a decrease in the total histone levels causes defects in both cohesin release and histone replacement during spermatogenesis. PMID- 25742801 TI - Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines. AB - The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into a 'halogen dance' phenomenon associated with these medicinally relevant architectures. PMID- 25742799 TI - Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains. AB - The genetic control of mammalian epithelial polarity and dynamics can be studied in vivo at cellular resolution during morphogenesis of the mouse neural tube. The mouse neural plate is a simple epithelium that is transformed into a columnar pseudostratified tube over the course of ~ 24 h. Apical F-actin is known to be important for neural tube closure, but the precise roles of actin dynamics in the neural epithelium are not known. To determine how the organization of the neural epithelium and neural tube closure are affected when actin dynamics are blocked, we examined the cellular basis of the neural tube closure defect in mouse mutants that lack the actin-severing protein cofilin 1 (CFL1). Although apical localization of the adherens junctions, the Par complex, the Crumbs complex and SHROOM3 is normal in the mutants, CFL1 has at least two distinct functions in the apical and basal domains of the neural plate. Apically, in the absence of CFL1 myosin light chain does not become phosphorylated, indicating that CFL1 is required for the activation of apical actomyosin required for neural tube closure. On the basal side of the neural plate, loss of CFL1 has the opposite effect on myosin: excess F-actin and myosin accumulate and the ectopic myosin light chain is phosphorylated. The basal accumulation of F-actin is associated with the assembly of ectopic basal tight junctions and focal disruptions of the basement membrane, which eventually lead to a breakdown of epithelial organization. PMID- 25742802 TI - Prevalence of overweight in children and adolescents with juvenile idiopathic arthritis. AB - OBJECTIVES: To assess the prevalence of overweight in patients with juvenile idiopathic arthritis (JIA) between 2003 and 2012 and to determine correlates of overweight relevant to the change in the overweight rate. METHOD: Annual overweight prevalence was determined in the National Paediatric Rheumatological Database (NPRD) between 2003 and 2012. The prevalence of overweight in JIA was compared to representative data from Germany in 2005. RESULTS: The median age of JIA patients was 11.5 years and the mean disease duration 4 years. Almost 50% of JIA patients had persistent oligoarthritis, followed by rheumatoid factor (RF) negative polyarthritis (14%). The overweight prevalence decreased significantly from 14.2% in 2003 to 8.3% in 2012 [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89-0.95]. Higher levels of physical activity and less frequent treatment with high-dose glucocorticoids (GCs) were associated with decreasing overweight rates. Systemic JIA had the highest decrease in the overweight rate over time. Patients with JIA had an overweight rate comparable to that of children and adolescents in the general population. However, systemic JIA and enthesitis related arthritis were more likely to be associated with overweight. The use of high-dose GCs, lower functional limitations, and a lower level (or lack) of participation in school sports were significant predictors of overweight in multivariable analyses. CONCLUSIONS: The prevalence of overweight in JIA was comparable to the general population and decreased significantly over time. The decrease was associated with higher functional ability and JIA patients should be encouraged to be more physically active. The role of an elevated body mass index (BMI) in the long-term outcome of JIA needs to be addressed in future studies. PMID- 25742804 TI - A study of whether automated Diabetic Retinopathy Image Assessment could replace manual grading steps in the English National Screening Programme. AB - OBJECTIVES: Diabetic retinopathy screening in England involves labour intensive manual grading of digital retinal images. We present the plan for an observational retrospective study of whether automated systems could replace one or more steps of human grading. METHODS: Patients aged 12 or older who attended the Diabetes Eye Screening programme, Homerton University Hospital (London) between 1 June 2012 and 4 November 2013 had macular and disc-centred retinal images taken. All screening episodes were manually graded and will additionally be graded by three automated systems. Each system will process all screening episodes, and screening performance (sensitivity, false positive rate, likelihood ratios) and diagnostic accuracy (95% confidence intervals of screening performance measures) will be quantified. A sub-set of gradings will be validated by an approved Reading Centre. Additional analyses will explore the effect of altering thresholds for disease detection within each automated system on screening performance. RESULTS: 2,782/20,258 diabetes patients were referred to ophthalmologists for further examination. Prevalence of maculopathy (M1), pre proliferative retinopathy (R2), and proliferative retinopathy (R3) were 7.9%, 3.1% and 1.2%, respectively; 4749 (23%) patients were diagnosed with background retinopathy (R1); 1.5% were considered ungradable by human graders. CONCLUSIONS: Retinopathy prevalence was similar to other English diabetic screening programmes, so findings should be generalizable. The study population size will allow the detection of differences in screening performance between the human and automated grading systems as small as 2%. The project will compare performance and economic costs of manual versus automated systems. PMID- 25742805 TI - Consultation rates in cervical screening non-attenders: opportunities to increase screening uptake in GP primary care. AB - OBJECTIVE: To estimate the proportion of cervical screening non-attenders presenting to general practice (GP) primary care over one year. SETTING: 137 practices in East London, UK. METHODS: Anonymous primary care records were downloaded using EMIS web (clinical software). Cervical screening nonattendance was defined as no recorded smear in the last 3.5 years (women aged 25-49) or 5.5 years (women aged 50-64). The last three consultation entries were used to estimate the proportion of non-attenders who consulted in GP over 3 months and 1 year using the Kaplan-Meier method. Newly registered women were assessed separately. Results were calculated for each practice and the median and interquartile range (IQR) across practices are presented. Heterogeneity was assessed using funnel plots. RESULTS: Of 261,810 women, 224,313 (86%) had been registered for >1 year. The proportion classified as non-attenders differed between those registered for >1 year (30%, IQR 27%--35%) and within the last year (49%, IQR 40%--57%), suggesting that screening records were less up-to-date in newly registered women. A median of 32% (IQR: 27%--37%) of non-attenders presented over 3 months, and 60% (IQR: 52%--67%) over 1 year. Funnel plots of the proportion of non-attenders presenting by the number of non-attenders showed substantial variation between practices. CONCLUSIONS: Over half of cervical screening non-attenders present to their GP at least once a year, in over 75% of practices. This represents a good opportunity for improving coverage by offering an alternative form of screening, such as self-sampling for human papillomavirus testing. PMID- 25742807 TI - Chronic implantable mechanical circulatory support 50 years later: still shooting for the stars! PMID- 25742806 TI - Evaluation by Citation: Trends in Publication Behavior, Evaluation Criteria, and the Strive for High Impact Publications. AB - Criteria for the evaluation of most scholars' work have recently received wider attention due to high-profile cases of scientific misconduct which are perceived to be linked to these criteria. However, in the competition for career advancement and funding opportunities almost all scholars are subjected to the same criteria. Therefore these evaluation criteria act as 'switchmen', determining the tracks along which scholarly work is pushed by the dynamic interplay of interests of both scholars and their institutions. Currently one of the most important criteria is the impact of publications. In this research, the extent to which publish or perish, a long standing evaluation criterion, led to scientific misconduct is examined briefly. After this the strive for high impact publications will be examined, firstly by identifying the period in which this became an important evaluation criterion, secondly by looking at variables contributing to the impact of scholarly papers by means of a non-structured literature study, and lastly by combining these data into a quantitative analysis. PMID- 25742803 TI - Inventory of current EU paediatric vision and hearing screening programmes. AB - OBJECTIVE: To examine the diversity in paediatric vision and hearing screening programmes in Europe. METHODS: Themes for comparison of screening programmes derived from literature were used to compile three questionnaires on vision, hearing, and public health screening. Tests used, professions involved, age, and frequency of testing seem to influence sensitivity, specificity, and costs most. Questionnaires were sent to ophthalmologists, orthoptists, otolaryngologists, and audiologists involved in paediatric screening in all EU full-member, candidate, and associate states. Answers were cross-checked. RESULTS: Thirty-nine countries participated; 35 have a vision screening programme, 33 a nation-wide neonatal hearing screening programme. Visual acuity (VA) is measured in 35 countries, in 71% of these more than once. First measurement of VA varies from three to seven years of age, but is usually before age five. At age three and four, picture charts, including Lea Hyvarinen, are used most; in children over four, Tumbling-E and Snellen. As first hearing screening test, otoacoustic emission is used most in healthy neonates, and auditory brainstem response in premature newborns. The majority of hearing testing programmes are staged; children are referred after 1 4 abnormal tests. Vision screening is performed mostly by paediatricians, ophthalmologists, or nurses. Funding is mostly by health insurance or state. Coverage was reported as >95% in half of countries, but reporting was often not first-hand. CONCLUSION: Largest differences were found in VA charts used (12), professions involved in vision screening (10), number of hearing screening tests before referral (1-4), and funding sources (8). PMID- 25742808 TI - 50th anniversary landmark commentary on Ankeney JL, O'Grady TJ. The treatment of transposition of the great vessels. Ann Thorac Surg 1968;5:262-76. PMID- 25742809 TI - 50th anniversary landmark commentary on Eloesser L. Of an operation for tuberculous empyema. Ann Thorac Surg 1969;8:355-7. PMID- 25742810 TI - 50th anniversary landmark commentary on Sealy WC, Hattler BG Jr, Blumenschein SD, Cobb FR. Surgical treatment of Wolff-Parkinson-White syndrome. Ann Thorac Surg 1969;8:1-11. PMID- 25742811 TI - Studies on postinfarct left ventricular remodeling: state of the art. PMID- 25742812 TI - A primer on using shrinkage to compare in-hospital mortality between centers. AB - Outcomes of cardiothoracic surgery are usually compared among hospitals or physicians by reporting the frequency of in-hospital mortality. Although there is agreement that these frequencies should be adjusted for case mix, there remains uncertainty about the value of using a statistical model that represents hospitals as random effects as opposed to the conventional approach of fixed effects. For years, the Northern New England Cardiovascular Disease Study Group has compared in-hospital mortality after coronary artery bypass graft surgery among centers using a fixed effects approach. An alternative method using random effects has become increasingly popular, and is the method used by cardiothoracic surgery registries such as the Massachusetts Data Analysis Center. The purpose of this report is to provide a short background on fixed versus random effects modeling, describe the use of shrinkage estimators including empirical Bayes, and illustrate them using data from the Northern New England Cardiovascular Disease Study Group. We conclude that both are acceptable approaches to hospital profiling if done in combination with appropriate risk adjustment. PMID- 25742813 TI - Invited commentary. PMID- 25742814 TI - Invited commentary. PMID- 25742815 TI - Invited commentary. PMID- 25742816 TI - Invited commentary. PMID- 25742817 TI - Invited commentary. PMID- 25742818 TI - Invited commentary. PMID- 25742819 TI - Invited commentary. PMID- 25742820 TI - Invited commentary. PMID- 25742821 TI - Invited commentary. PMID- 25742822 TI - Invited commentary. PMID- 25742823 TI - Invited commentary. PMID- 25742824 TI - Invited commentary. PMID- 25742825 TI - Dissecting intramyocardial hematoma after robotic mitral valve repair. AB - We report the first case of a dissecting intramyocardial hematoma discovered intraoperatively after robotic mitral valve repair, potential etiologies relevant to robotic surgery, and its successful management. PMID- 25742826 TI - Myocardial infarction and rupture after bronchial artery embolization. AB - Bronchial artery embolization is a well-known treatment for hemoptysis. Adverse events of this procedure include multiple systemic embolism and infarction. Myocardial infarction has been recently reported during bronchial artery embolization, owing to the presence of a coronary-to-bronchial artery fistula. We report the management of an ischemic left ventricular free wall rupture caused by bronchial artery embolization in a patient with massive hemoptysis, bronchiectasis, and undetected coronary-to-bronchial artery anomalous connection. PMID- 25742827 TI - Damaged right internal jugular venous catheter status after Cox Maze IV procedure. AB - The Cox-Maze IV (CM-IV) procedure was introduced as a modification of the Cox Maze III by using a bipolar radiofrequency clamp to replicate the majority of the long linear cut and sew lesions. The CM-IV maintained excellent success rates with low complication, and there are no reports of device-related complication in the literature. In this article, we present a patient who underwent aortic valve replacement with a concomitant CM-IV procedure. There was difficulty removing the right internal jugular catheter during the postoperative course, with evidence of catheter fracture on chest radiograph. Upon catheter removal by Interventional Radiology, the distal segment had sustained a radiofrequency burn strike that had melted the involved segment with significant loss of catheter integrity. Of the several events that have occurred in our high volume Maze program, this resulted in changing the anesthesia protocol by using shorter catheters that will be less likely to become caught in the jaws of the bipolar clamp during the performance of the intercaval line of the CM-IV. PMID- 25742828 TI - Isolated huge aneurysm of the left main coronary artery in a 22-year-old patient with type 1 neurofibromatosis. AB - A 22-year-old patient with neurofibromatosis type 1 presented with acute chest pain. A computed tomography scan and coronary angiography revealed a partially thrombosed huge aneurysm of the left main coronary artery. Despite medical treatment, the patient's angina recurred. The patient underwent a coronary bypass grafting operation and surgical exclusion of the aneurysm. Postoperative imaging disclosed good permeability of the 3 coronary artery bypass grafts and complete thrombosis of the excluded aneurysm. PMID- 25742829 TI - Extra-anatomic right ventricle to pulmonary artery conduit: the apical-aortic equivalent for complex right ventricular outflow tract reconstruction. AB - We describe the case of a 22-year-old with tetralogy of Fallot, who underwent complete repair with ventricular septal defect closure and right ventricle to pulmonary artery conduit placement. She has undergone numerous subsequent conduit changes, each complicated by early stenosis and failure. Unfortunately, serial conduit changes can become increasingly challenging. While extra-anatomic conduits have been described for complex left ventricular outflow tract obstruction, they have not been described for right-sided obstruction. Herein, we present a patient who underwent successful placement of an extra-anatomic valved right ventricle to pulmonary artery conduit in the setting of complex right ventricular outflow tract obstruction. PMID- 25742830 TI - Primary cardiac malignant lymphoma: survival for 13 years after surgical resection and adjuvant chemotherapy. AB - We report a patient who has survived for 13 years after surgical resection of a cardiac malignant lymphoma. A 73-year-old woman underwent partial resection of a tumor occluding the tricuspid valve, which arose from the right atrium. The pathologic diagnosis was diffuse large B cell lymphoma. She was treated with adjuvant chemotherapy for 6 months postoperatively. Since then, she has shown no evidence of recurrence, without any further treatment. To our knowledge, this is the longest surviving case of cardiac malignant lymphoma. The therapeutic strategy for this malignant cardiac tumor is discussed briefly. PMID- 25742831 TI - Fatal spontaneous dissection of a Contegra conduit in a child. AB - The Contegra bovine jugular vein conduit (Medtronic, Minneapolis, MN) is one of the most widely used grafts for surgical reconstruction of the right ventricular outflow tract in both pediatric and adult patients with congenital heart disease. In this report, we describe a case of acute dissection of a neointimal peel in a Contegra conduit resulting in conduit stenosis and death of a child. PMID- 25742832 TI - Intraoperative cardiac mapping in the treatment of an infant congenital fibroma. AB - Surgical treatment for ventricular tachycardia associated with congenital cardiac tumors is rare. Intraoperative electroanatomic mapping was performed in a 23 month-old female infant to identify the arrhythmogenic substrate of the epicardium before tumor resection. Verification of the localized abnormal electrocardiogram on the tumor in the treatment of ventricular tachycardia was useful for successful partial resection and cryoablation of the giant fibroma. PMID- 25742833 TI - Reversible compression of the left lower lobe vein after right pneumonectomy. AB - Herein we report the case of a 60-year-old female patient who developed severe respiratory failure after right-sided pneumonectomy starting 2 hours after uneventful surgery. A computed tomographic scan revealed a completely congested left lower lobe. The underlying pathomechanism of this unique finding was a kinking effect of the left lower lobe vein over the descending aorta, caused by the shifting of the heart toward the right side. Even with immediate reintubation and aggressive ventilation it was impossible to stabilize the patient and therefore an extracorporal membrane oxygenation (ECMO) had to be implanted. The ECMO support and right-lateral and prone positioning of the patient markedly improved oxygenation. After a stabilization period of 2 days the ECMO could be removed and the patient was extubated on the ninth postoperative day. To the best of our knowledge, this is the first reported case of a unilobar edema caused by a transiently impaired venous drainage after pneumonectomy. The combination of immediate ECMO support together with right-lateral and prone positioning resulted in restoration and stabilization of the patient's cardiorespiratory function. PMID- 25742834 TI - Hepatic capsular avulsion after video-assisted thoracic biopsy of the lung. AB - We report a life-threatening subcapsular hepatic hemorrhage after VATS, successfully treated with Gelfoam embolization of the right hepatic artery. The postprocedure course was complicated by infarction of the right hepatic lobe. PMID- 25742835 TI - Thymic flap for bronchial stump reinforcement after lobectomy. AB - Buttressing of the bronchial stump after pulmonary resection has been reported to decrease the prevalence of bronchopleural fistula. This adjuvant maneuver is most commonly performed in patients undergoing resection for infection or in those who have received preoperative radiation. The anatomic location of the upper lobe bronchus often makes it difficult to create a tension-free flap using muscle or pericardial fat. Parietal pleura is often mobilized for such cases. We present a case in which the parietal pleura was not available, and the right inferior pole of the thymus was used for bronchial coverage following upper lobectomy. PMID- 25742836 TI - Benign metachronous bilateral ovarian and mediastinal teratomas with an elevated alpha-fetoprotein. AB - Teratomas are a common form of non-seminomatous germ cell tumor histologically composed of tissues derived from multiple cell lines of the primary embryonic germ cell layers. There are few cases reported in the literature that describe multiple locations with recurrence of benign teratomas, none of which describe an elevated AFP. We describe a case of metachronous bilateral recurrent ovarian and mediastinal teratomas with a curiously elevated alpha-fetoprotein. We may be describing a novel syndrome of recurrent metachronous teratomas. Because of the uncertainty of this case, the patient will require close follow-up over the next several years. PMID- 25742837 TI - Catamenial pneumothorax with bullae. AB - The physiologic mechanisms and diagnostic approach of catamenial pneumothorax remain controversial. We report 3 patients with catamenial pneumothorax with bullae. Endometrial cells in these patients were located around the bullae, suggesting a possible new mechanism for catamenial pneumothorax in which cyclic endometrial shedding in the lung causes destruction of the lining of alveolar epithelial cells and forms bullae. Because intrathoracic endometriosis is considered an underrecognized cause of secondary spontaneous pneumothorax, we performed careful histologic examination for definitive diagnosis of thoracic endometriosis. PMID- 25742838 TI - Chest wall implantation metastasis caused by percutaneous radiofrequency ablation for hepatic tumor. AB - We report a very rare case of a 55-year-old man with chest wall metastatic tumor caused by seeding of hepatocellular carcinoma after percutaneous radiofrequency ablation (RFA) for hepatic tumor 42 months after the initial operation. The patient was managed with aggressive full-thickness chest wall resection and reconstruction with a Prolene (Ethicon, Somerville, NJ) and methyl methacrylate sandwich graft and subsequent musculocutaneous free-flap transposition. PMID- 25742839 TI - Resection of costal exostosis using piezosurgery associated with uniportal video assisted thoracoscopy. AB - We report a case of a 35-year-old woman affected by costal exostosis, originating from the posterior arc of the left fifth rib, who complained of a persistent intractable neuralgia in the left T5 dermatome. Both pain and the risk of visceral injury led us to resect exostosis. The procedure was performed using a uniportal videothoracoscopic approach without additional incisions. For bone resection, we used Piezosurgery, a soft tissue-sparing system based on ultrasound vibrations. Piezosurgery allowed the complete resection of exostosis without injuring the intercostal nerve and vessels. The histologic analysis confirmed the diagnosis of osteochondroma and showed no sign of malignancy. The patient was discharged 2 days after the operation. Considering the lack of symptoms, the low risk of degeneration, and the absence of recurrence at 12-month follow-up, the simple resection of exostosis without performing a more extensive rib resection was judged to be optimal. PMID- 25742840 TI - Aortic pseudoaneurysm eroding through the anterior chest wall. PMID- 25742841 TI - First report of chronic expanding intrapericardial hematoma caused by coronary to pulmonary artery fistulas. PMID- 25742842 TI - Direct access implantation of a Melody valve in native mitral valve: a hybrid approach in the presence of extensive mitral annular calcification. PMID- 25742843 TI - Hemothorax after delayed fracture of sternal wire. PMID- 25742844 TI - New method of posterior scallop augmentation for ischemic mitral regurgitation. AB - We report a new method of posterior middle scallop (P2) augmentation for ischemic mitral regurgitation to achieve deep coaptation. First, P2 was divided straight at the center and partially detached from the annulus in a reverse T shape. A narrow pentagon-shaped section of pericardium was sutured to the divided P2 and annular defect. The tip of the pentagon was attached directly to the papillary muscle, thus creating a very large P2 scallop. A standard-sized ring was placed. We adopted this technique in 2 patients with advanced ischemic cardiomyopathy, and no mitral regurgitation was observed during a 1-year follow-up. PMID- 25742845 TI - A simple technique for preparation of artificial chordal loops with a strip of paper. AB - Artificial chordal replacement with polytetrafluoroethylene suture lines is a well-accepted technique for mitral valve repair. This report presents a method of making chordal loops of the desired length using a strip of paper. This technique uses a simple, cost-free, and easily obtained material--a strip of paper--to prepare artificial chordal loops with its advantages. PMID- 25742846 TI - Four-stitch side-to-side anastomosis for sequential coronary artery bypass grafting. AB - Sequential bypass (SB) is an effective method of implementing complete myocardial revascularization of complex coronary stenoses. The SB allows a single graft to be used for bypass in several locations, which facilitates multi-branch revascularization. We have developed a simple SB technique, four-stitch side-to side anastomosis, and report its clinical effectiveness in 428 patients. PMID- 25742847 TI - Tricuspidization and reimplantation procedure for unicuspid aortic valve with annuloaortic ectasia. AB - Unicuspid aortic valve is a rare anomaly. We report 2 cases of successfully treated unicuspid valves with aortic dilatations by using a tricuspidization and reimplantation procedure. Two men, 35 and 39 years old, with severe aortic regurgitation and stenosis received this procedure. The sclerotic portion of a unicuspid valve, including 2 rudimentary commissures, was resected and reconstructed with autologous pericardium to create a tricuspid valve. An aortic root was replaced with a prosthetic graft. Postoperative echocardiogram showed trivial aortic regurgitation and minimal pressure gradient. Follow-up was 32 and 34 months, respectively. These valves remained stable in these periods. Tricuspidization and reimplantation is a promising procedure. PMID- 25742848 TI - Donald Nixon Ross, BS, MB, ChB, FRCS: pioneering surgeon and true gentleman. AB - Donald Nixon Ross, FRCS, was a master surgeon, a consummate scholar, and fine gentleman. Herein, are descriptions of his education, practice of cardiac surgery, and legacy contributions. He always will be known for developing and applying the aortic autograft "switch" procedure for aortic stenosis known in perpetuity as the Ross procedure. PMID- 25742849 TI - Reply: To PMID 25086946. PMID- 25742850 TI - Mild acute kidney injury and short-term outcomes after cardiac surgery. PMID- 25742851 TI - Reply: To PMID 23063198. PMID- 25742852 TI - The use of a rigid ring in aortic valve repair. PMID- 25742853 TI - Multifaceted approach to plastic bronchitis. PMID- 25742854 TI - A call for careful interpretation of outcome of nonsurgical approach in clinical stage IIIa non-small cell lung cancer in the National Cancer Database. PMID- 25742856 TI - Reply: To PMID 24929895. PMID- 25742855 TI - Influence of blood transfusion on clinical outcomes in resected lung cancer. PMID- 25742857 TI - Management of right atrial hemangioma in a patient with antithrombin deficiency. AB - Hereditary antithrombin (AT) deficiency is an autosomal dominant inheritance disorder. Patients with AT deficiency have a high risk of thromboembolism, and intraoperative cardiopulmonary bypass management is difficult. We present the case of a 53-year-old man who was diagnosed with AT deficiency and who underwent an open heart operation for a right atrial hemangioma. We administered AT-III concentrate perioperatively to maintain his AT-III level up to 80% to establish cardiopulmonary bypass and prevent thromboembolic events postoperatively. The right atrial hemangioma was successfully excised after right atriotomy. The patient had an uneventful postoperative course and was discharged on postoperative day 14. PMID- 25742858 TI - Pulmonary valve cusp augmentation for pulmonary regurgitation after repair of valvular pulmonary stenosis. AB - A 23-year-old female patient with a history of pulmonary valvectomy for pulmonary stenosis at 2 years of age underwent pulmonary valve repair, which consisted of remnant cusp extension using a fresh pericardium and commissural resuspension. An immediate postoperative computed tomographic scan showed full movement of the extended anterior cusp during systole, yet flail motion during diastole. However, follow-up magnetic resonance imaging at 10 months postoperatively revealed a small amount of pulmonary flow regurgitation (2.0%). PMID- 25742859 TI - A giant pseudoaneurysm of the left anterior descending coronary artery related to Behcet disease. AB - We report the case of a young patient with a recent diagnosis of Behcet disease, in whom the left anterior descending coronary artery was found fully open into a giant pseudoaneurysm, with occlusion of the distal segment. Surgical treatment included opening of the pseudoaneurysm with clot and fibrous tissue removal, proximal left anterior descending coronary artery closure, and distal left anterior descending coronary artery grafting. In patients with Behcet disease, it is advisable to perform computed tomography coronary angiography to rule out the presence of coronary artery disease and the occurrence of a rare but potentially life-threatening complication. PMID- 25742860 TI - Use of single-cannula venous-venous extracorporeal life support in the management of life-threatening airway obstruction. AB - The use of venous-venous extracorporeal life support (VV ECLS) for the endoscopic management of airway obstruction has been rarely reported. In most instances, ECLS has been used in the setting of cardiopulmonary resuscitation in which venoarterial ECLS was initiated as part of resuscitation. We report a patient with a bulky primary tumor of the tracheal carina presenting with airway obstruction who was managed with intraoperative single-cannula VV ECLS to facilitate endoscopic interventions leading to more definitive airway security. PMID- 25742861 TI - Early pneumonectomy for pulmonary mucormycosis. AB - Mucormycosis is a fungal infection caused by a rare pathogen most commonly affecting immunocompromised hosts. Successful treatment of pulmonary mucormycosis requires rapid diagnosis, reversal of predisposing factors, aggressive surgical excision, and antifungal therapy. We present a case of pulmonary mucormycosis affecting a young neutropenic male requiring a pneumonectomy. PMID- 25742862 TI - Complete resection of a giant mediastinal leiomyosarcoma. AB - Primary mediastinal leiomyosarcoma is an extremely rare malignancy, and the only opportunity for a cure lies with an aggressive surgical approach. We report a 66 year-old woman who underwent complete resection of a giant mediastinal leiomyosarcoma located on the bilateral diaphragm. The tumor encased the inferior vena cava and compressed the adjacent structures. Using cardiopulmonary bypass with 20 minutes of hepatic ischemia, the tumor was completely resected with combined resection and reconstruction of the surrounding structures. Because of the tumor size and location in the boundary area between thoracic and abdominal surgeries, the procedure necessitated the cooperation of many expert surgeons. PMID- 25742863 TI - Application of extracorporeal membrane oxygenation in giant bullae resection. AB - A patient with chronic obstructive pulmonary disease and lung bullae was admitted to our hospital. He suffered respiratory failure and was given mechanical ventilation. However, the bullae became more and more large and compressed the lungs on both sides. We managed extracorporeal membrane oxygenation (ECMO) to maintain the patient's blood oxygenation, and performed bullae resection surgery successfully. The patient's pulmonary function recovered gradually after the operation and he returned home. In our experience with this case, ECMO can be used in bullae resection. PMID- 25742864 TI - A novel treatment for pulmonary hemorrhage during thromboendarterectomy surgery. AB - Injury to the pulmonary artery during thromboendarterectomy is a rare but potentially fatal complication with no reported surgical techniques to combat it. Treatment is only supportive and morbidity is high. We report the intraoperative diagnosis and surgical management of pulmonary hemorrhage in 3 patients after pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. PMID- 25742865 TI - Blunted behavioral and molecular responses to chronic mild stress in adult rats with experience of infancy maternal separation. AB - Childhood adversity has profound and persistent effects on brain functions and has been implicated in the etiology of depression. Brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) play critical roles during brain development to maintain neuronal function and structural integrity in adulthood. We therefore investigated the long-term effects of early life adversity on the depression-related behavior and the expression of BDNF and CREB in the hippocampus. Male Sprague-Dawley newborn rats were subjected to maternal separation for 3 h/day on postnatal days 2-14. After the postnatal day 90, rats with or without the experience of infancy maternal separation received a series of unpredictable chronic mild stress (CMS) for 21 days. Sucrose preference and spontaneous activity in the open field test were recorded, and the expression of BDNF and CREB in the hippocampus was measured by real-time RT-PCR and Western blot analyses. Before exposure to CMS, the rats with maternal separation showed the significant decreases in sucrose preference, spontaneous activity, and hippocampal expression of BDNF and CREB, compared to the animals without maternal separation. In contrast, the rats without maternal separation showed greater decreases of the above indictors after CMS, the levels of which were lower than those observed in the rats with maternal separation. Thus, early life adversity leads to long-term decreases in the capacity of enjoying sweetness, spontaneous activity, and hippocampal expression of BDNF and CREB. Moreover, childhood neglect may decrease the neurobehavioral plasticity, thereby blunting the responses to adulthood stress and increasing the susceptibility to depression. PMID- 25742866 TI - Incorporation of gantry angle correction for 3D dose prediction in intensity modulated radiation therapy. AB - Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0 degrees using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0 degrees may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0 degrees gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0 degrees gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal. PMID- 25742867 TI - Synthesis of novel Schiff base ligands from gluco- and galactochloraloses for the Cu(II) catalyzed asymmetric Henry reaction. AB - A series of chiral Schiff base ligands has been prepared using aminochloralose derivatives of glucose and galactose. These ligands were used as catalysts in the asymmetric Henry reaction in the presence of Cu(II) ions giving yields of up to 95%. An interesting solvent dependency on enantiomeric control was observed with the best enantiomeric excesses (up to 91%) being obtained in the presence of water. PMID- 25742868 TI - Synthesis and biotinylation of oligosaccharide fragments of mannosylated and 5 deoxy-5-methylthio-xylofuranosylated lipoarabinomannan from Mycobacterium tuberculosis. AB - The attachment of biotin to a molecule provides a powerful tool in biology. Here, we report an efficient synthesis and biotinylation of mannosylated and 5-deoxy-5 methylthio-xylofuranosylated Lipoarabinomannan from Mycobacterium tuberculosis. Preparation of the oligosaccharides involved the sequential addition of thioglycoside donors with arabinofuranosyl-containing acceptors. Methylthio group was introduced near the end of the synthesis. PMID- 25742869 TI - Hemodynamics should be the primary approach to diagnosing, following, and managing pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a highly morbid cardiopulmonary disease characterized by plexogenic pulmonary arteriole remodelling. Importantly, PAH severity correlates inversely with cardiac output and directly with pulmonary vascular resistance and right atrial pressure, illustrating the importance of accurately measured hemodynamics to define the clinical profile of patients. Currently available noninvasive technology offers only hemodynamic estimates. In contrast, right heart catheterization is the principle diagnostic procedure in PAH and is required to: (1) definitively exclude alternative pulmonary vascular diseases; and (2) quantify hemodynamics at baseline, after vasoreactivity testing, or in response to therapy to prognosticate outcome and guide therapeutic escalation. PMID- 25742870 TI - 1H- and 13C-NMR spectroscopy of Thy-1-APPSL mice brain extracts indicates metabolic changes in Alzheimer's disease. AB - Biochemical alterations underlying the symptoms and pathomechanisms of Alzheimer's disease (AD) are not fully understood. However, alterations of glucose metabolism and mitochondrial dysfunction certainly play an important role. (1)H- and (13)C-NMR spectroscopy exhibits promising results in providing information about those alterations in vivo in patients and animals, especially regarding the mitochondrial tricarboxylic acid (TCA) cycle. Accordingly, transgenic mice expressing mutant human amyloid precursor protein (APP(SL)) serving as a model of neuropathological changes in AD-were examined with in vitro 1D (1)H- and 2D (1)H-(13)C-HSQC-NMR spectroscopy after oral administration of 1 (13)C-glucose and acquisition of brain material after 30 min. Perchloric acid extracts were measured using a 500 MHz spectrometer, providing more detailed information compared to in vivo spectra achievable nowadays. Area under curve (AUC) data of metabolite peaks were obtained and normalized in relation to the creatine signal, serving as internal reference. Besides confirming well-known metabolic alterations in AD like decreased N-acetylaspartate (NAA)/Creatine (Cr) ratio, new findings such as a decrease in phosphorylcholine (PC) are presented. Glutamate (Glu) and glutamine (Gln) concentrations were decreased while gamma aminobutyric acid (GABA) was elevated in Thy1-APP(SL) mice. (13)C-NMR spectroscopy revealed a shift in the Glx-2/Glx-4-ratio-where Glx represents a combined Glu/Gln-signal-towards Glx-2 in AD. These findings correlated well with the NAA/Cr-ratio. The Gln-4/Glu-4-ratio is altered in favor of Glu. Our findings suggest that glutamine synthetase (GS), which is predominantly present in glial cells may be impaired in the brain of Thy1-APP(SL) transgenic mice. Since GS is an ATP-dependent enzyme, mitochondrial dysfunction might contribute to reduced activity, which might also account for the increased metabolism of glutamate via the GABA shunt, a metabolic pathway to bypass intra-mitochondrial alpha ketoglutarate-dehydrogenase, resulting in elevated GABA levels. PMID- 25742871 TI - Effects of the Nanoparticle-Based Vaccine, SEL-068, on Nicotine Discrimination in Squirrel Monkeys. AB - A key feature of addiction to nicotine likely resides in its ability to produce subjective effects that, in turn, may be reflected in its discriminative-stimulus properties. Vaccination against such effects of nicotine offers an intriguing therapeutic approach for smoking cessation, but a reliably effective and immunologically safe vaccine remains to be identified. Here we report on the ability of SEL-068, a nanoparticle-based vaccine that targets nicotine, to modify the discriminative-stimulus effects of nicotine in a primate species. Results indicate that squirrel monkeys vaccinated with SEL-068 failed to acquire 0.1 mg/kg nicotine discrimination but readily learned to discriminate 0.001 mg/kg of the nicotinic full agonist (+)-epibatidine ((+)-EPI). After (+)-EPI training, doses of nicotine ? 0.32 mg/kg, which produced behaviorally adverse actions, still failed to substitute for the (+)-EPI training stimulus in immunized monkeys, whereas (+)-EPI and the partial agonist varenicline engendered, respectively, complete and partial substitution in all monkeys with potency comparable to their potency in non-immunized subjects. In other subjects, nicotine was trained as a discriminative-stimulus and then replaced by (+)-EPI. Subsequent vaccination with SEL-068 led to a threefold and long-lasting (>30 weeks) decrease in the potency of nicotine but not (+)-EPI or varenicline. Collectively, our results show that SEL-068 can block the development of nicotine discrimination and attenuate nicotine's effects in nicotine-experienced monkeys without altering the discriminative-stimulus properties of other nicotinic drugs. The difference in the vaccine's effects in naive and nicotine-experienced subjects provides important insight into the conditions under which immunotherapy may be effective in combating nicotine addiction. PMID- 25742872 TI - Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys. AB - Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model. PMID- 25742874 TI - A flexible and implantable microelectrode arrays using high-temperature grown vertical carbon nanotubes and a biocompatible polymer substrate. AB - This paper presents a novel microelectrode arrays using high-temperature grown vertically aligned carbon nanotubes (CNTs) integrated on a flexible and biocompatible parylene substrate. A simple microfabrication process is proposed to unite the high quality vertical CNTs grown at high temperature with the heat sensitive parylene substrate in a highly controllable manner. Briefly, the CNTs electrode is encapsulated by two layers of parylene and the device is released using xenon difluoride (XeF2). The process is compatible with wafer-scale post complementary metal oxide semiconductor integration. Lower impedance and larger interfacial capacitance have been demonstrated using CNTs compared to a Pt electrode. The flexible CNT electrodes have been utilized for extracellular neuronal recording and stimulation in rats. The signal-to-noise ratio of the device is about 12.5. The threshold voltage for initiating action potential is about 0.5 V. PMID- 25742873 TI - Reward Anticipation Is Differentially Modulated by Varenicline and Nicotine in Smokers. AB - Recidivism rates for cigarette smokers following treatment often exceed 80%. Varenicline is the most efficacious pharmacotherapy currently available with cessation rates of 25-35% following a year of treatment. Although the in vivo binding properties are well known, varenicline's neurobiological mechanisms of action are still poorly understood. Varenicline acts as a nicotinic receptor partial agonist or antagonist depending on the presence or absence of nicotine and has been implicated in the reduction of reward signaling more broadly. The current study probed anticipatory reward processing using a revised monetary incentive delay task during fMRI in cohorts of smokers and non-smokers who completed a two-drug, placebo-controlled, double-blind crossover study. All participants underwent ~17 days of order-balanced varenicline and placebo pill administration and were scanned under each condition wearing a transdermal nicotine or placebo patch. Consistent with nicotine's ability to enhance the rewarding properties of nondrug stimuli, acute nicotine administration enhanced activation in response to reward-predicting monetary cues in both smokers and non smokers. In contrast, varenicline reduced gain magnitude processing, but did so only in smokers. These results suggest that varenicline's downregulation of anticipatory reward processing in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation. PMID- 25742875 TI - Endolymphatic hydrops detected by 3-dimensional fluid-attenuated inversion recovery MRI following intratympanic injection of gadolinium in the asymptomatic contralateral ears of patients with unilateral Meniere's disease. AB - BACKGROUND: The aim of this study was to identify the incidence of endolymphatic hydrops using 3-dimensional fluid-attenuated inversion recovery (3D-FLAIR) magnetic resonance imaging (MRI) in the contralateral ear in patients with unilateral Meniere's disease (MD). MATERIAL AND METHODS: This was a prospective study. 3D-FLAIR MRI was performed with a 3 Tesla (3 T) unit 24 h after the intratympanic administration of gadolinium (Gd) in 30 unilateral MD patients with an asymptomatic contralateral ear. The incidence of contralateral involvement in unilateral MD patients and the potential correlations between the affected and contralateral ears were analyzed. RESULTS: Endolymphatic hydrops was observed in 7 of the 30 (23.3%) asymptomatic ears. The mean PTA of the asymptomatic ears in the contralateral hydrops patients (33.0+/-6.1 dB) was significantly higher compared with the non-hydrops patients (17.8+/-5.7 dB). The patients with observed contralateral hydrops exhibited a significantly longer duration of the disease compared with the non-hydrops patients (6.7+/-6.3 vs. 2.9+/-3.1 years, respectively). Furthermore, the patients with contralateral hydrops had a worse hearing level in the affected ears compared with the non-hydrops patients (70.3+/ 7.4 vs. 52.5+/-3.8 dB, respectively). CONCLUSIONS: Endolymphatic hydrops is closely related to hearing loss but does not necessarily result in Meniere's symptoms. Patients with a long history of MD and severe hearing loss in the affected ear are more likely to exhibit endolymphatic hydrops in the asymptomatic contralateral ear. Adequate attention should focus on unilateral MD patients with contralateral ear hydrops because of the potential to develop bilateral MD. PMID- 25742876 TI - Sensitivity analysis of a novel five-degrees-of-freedom user command controller in people with spinal cord injury and non-injured for full upper extremity neuroprosthesis, wearable powered orthoses and prosthetics. AB - Sensitivity analysis for a user command controller monitoring head position for artificial control of the proximal upper limb was performed. The controller was evaluated by having subjects complete target matching tasks manipulating a simulated on-screen hand representation to investigate the effects of target location and target speed on performance. Sixteen subjects took part in the study, 11 of whom had sustained cervical spinal cord injuries. The subjects were able to control the on-screen hand with overall low sensitivity of performance with the controller to target position in its five-degrees-of-freedom. The optimal speed was found to be a compromise between low speed and high accuracy but longer completion time and fast speed for short completion time with lower accuracy. The results demonstrated the robustness of the controller across a population of non-injured subjects and those with tetraplegia. PMID- 25742877 TI - Delayed diagnosis of childhood low-grade glioma: causes, consequences, and potential solutions. AB - PURPOSE: Diagnosis of childhood brain tumors is delayed more than diagnosis of other pediatric cancers. However, the contribution of the most common pediatric brain tumors, lowgrade gliomas (LGG), to this delay has never been investigated. METHODS: We retrospectively reviewed cases of childhood LGG diagnosed from January 1995 through December 2005 at our institution. The pre-diagnosis symptom interval (PSI) was conservatively calculated, and its association with race, sex, age, tumor site, tumor grade, and outcome measures (survival, disease progression, shunt use, seizures, extent of resection) was analyzed. Cases of neurofibromatosis type 1 were reported separately. RESULTS: The 258 children had a median follow-up of 11.1 years, and 226 (88 %) remained alive. Greater pre diagnosis symptom interval (PSI) was significantly associated with grade I (vs. grade II) tumors (p = 0.03) and age >10 years at diagnosis (p = 0.03). Half of the 16 spinal tumors had a PSI > 6 months. PSI was significantly associated with progression (p = 0.02) in grade I tumors (n = 195) and in grade I tumors outside the posterior fossa (n = 134, p = 0.03). Among children with grade I tumors, median PSI was longer in those who had seizures (10.3 months) than in those who did not (2.5 months) (p = 0.09). CONCLUSIONS: Delayed diagnosis of childhood LGG allows tumor progression. To reduce time to diagnosis, medical curricula should emphasize inclusion of LGG in the differential diagnosis of CNS neoplasm. PMID- 25742878 TI - Honey as a topical treatment for wounds. AB - BACKGROUND: Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee, Apis mellifera. Honey has been used since ancient times as a remedy in wound care. Evidence from animal studies and some trials has suggested that honey may accelerate wound healing. OBJECTIVES: The objective of this review was to assess the effects of honey compared with alternative wound dressings and topical treatments on the of healing of acute (e.g. burns, lacerations) and/or chronic (e.g. venous ulcers) wounds. SEARCH METHODS: For this update of the review we searched the Cochrane Wounds Group Specialised Register (searched 15 October 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 9); Ovid MEDLINE (1946 to October Week 1 2014); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 13 October 2014); Ovid EMBASE (1974 to 13 October 2014); and EBSCO CINAHL (1982 to 15 October 2014). SELECTION CRITERIA: Randomised and quasi randomised trials that evaluated honey as a treatment for any sort of acute or chronic wound were sought. There was no restriction in terms of source, date of publication or language. Wound healing was the primary endpoint. DATA COLLECTION AND ANALYSIS: Data from eligible trials were extracted and summarised by one review author, using a data extraction sheet, and independently verified by a second review author. All data have been subsequently checked by two more authors. MAIN RESULTS: We identified 26 eligible trials (total of 3011 participants). Three trials evaluated the effects of honey in minor acute wounds, 11 trials evaluated honey in burns, 10 trials recruited people with different chronic wounds including two in people with venous leg ulcers, two trials in people with diabetic foot ulcers and single trials in infected post-operative wounds, pressure injuries, cutaneous Leishmaniasis and Fournier's gangrene. Two trials recruited a mixed population of people with acute and chronic wounds. The quality of the evidence varied between different comparisons and outcomes. We mainly downgraded the quality of evidence for risk of bias, imprecision and, in a few cases, inconsistency.There is high quality evidence (2 trials, n=992) that honey dressings heal partial thickness burns more quickly than conventional dressings (WMD -4.68 days, 95%CI -5.09 to -4.28) but it is unclear if there is a difference in rates of adverse events (very low quality evidence) or infection (low quality evidence).There is very low quality evidence (4 trials, n=332) that burns treated with honey heal more quickly than those treated with silver sulfadiazine (SSD) (WMD -5.12 days, 95%CI -9.51 to -0.73) and high quality evidence from 6 trials (n=462) that there is no difference in overall risk of healing within 6 weeks for honey compared with SSD (RR 1.00, 95% CI 0.98 to 1.02) but a reduction in the overall risk of adverse events with honey relative to SSD. There is low quality evidence (1 trial, n=50) that early excision and grafting heals partial and full thickness burns more quickly than honey followed by grafting as necessary (WMD 13.6 days, 95%CI 9.82 to 17.38).There is low quality evidence (2 trials, different comparators, n=140) that honey heals a mixed population of acute and chronic wounds more quickly than SSD or sugar dressings.Honey healed infected post-operative wounds more quickly than antiseptic washes followed by gauze and was associated with fewer adverse events (1 trial, n=50, moderate quality evidence, RR of healing 1.69, 95%CI 1.10 to 2.61); healed pressure ulcers more quickly than saline soaks (1 trial, n= 40, very low quality evidence, RR 1.41, 95%CI 1.05 to 1.90), and healed Fournier's gangrene more quickly than Eusol soaks (1 trial, n=30, very low quality evidence, WMD -8.00 days, 95%CI -6.08 to -9.92 days).The effects of honey relative to comparators are unclear for: venous leg ulcers (2 trials, n= 476, low quality evidence); minor acute wounds (3 trials, n=213, very low quality evidence); diabetic foot ulcers (2 trials, n=93, low quality evidence); Leishmaniasis (1 trial, n=100, low quality evidence); mixed chronic wounds (2 trials, n=150, low quality evidence). AUTHORS' CONCLUSIONS: It is difficult to draw overall conclusions regarding the effects of honey as a topical treatment for wounds due to the heterogeneous nature of the patient populations and comparators studied and the mostly low quality of the evidence. The quality of the evidence was mainly downgraded for risk of bias and imprecision. Honey appears to heal partial thickness burns more quickly than conventional treatment (which included polyurethane film, paraffin gauze, soframycin-impregnated gauze, sterile linen and leaving the burns exposed) and infected post-operative wounds more quickly than antiseptics and gauze. Beyond these comparisons any evidence for differences in the effects of honey and comparators is of low or very low quality and does not form a robust basis for decision making. PMID- 25742879 TI - Influence of Bi(3+)-doping on the magnetic and Mossbauer properties of spinel cobalt ferrite. AB - The influence of Bi(3+)-doping on the magnetic and Mossbauer properties of cobalt ferrite (CoFe2O4), wherein the Fe(3+) ions are replaced by the Bi(3+) ions to form CoBixFe2-xO4 ferrites, where x = 0.0, 0.05, 0.1, 0.15 or 0.2, has been investigated. The structural and morphological properties of undoped and doped ferrites, synthesized chemically through a self-igniting sol-gel method, are initially screened using X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy measurements. The changes in magnetic moment of ions, their coupling with neighboring ions and cation exchange interactions are confirmed from the Mossbauer spectroscopy analysis. The effect of Bi(3+)-doping on the magnetic properties of CoFe2O4 ferrite is examined from the vibrating sample magnetometry spectra. Saturation magnetization and coercivity values are increased initially and then decreased, as result of Bi(3+) doping. The obtained results with improved saturation magnetization (from 26.36 to 44.96 emu g(-1)), coercivity (from 1457 to 1863 Oe) and remanence magnetization (from 14.48 to 24.63 emu g(-1)) on 0.1-0.15 mol Bi(3+)-doping of CoBixFe2-xO4 demonstrate the usefulness for magnetic recording and memory devices. PMID- 25742881 TI - Suicide in circumpolar regions: an introduction and overview. AB - This extended editorial introduces the Special Issue on Suicide and Resilience in Circumpolar Regions, the results of the knowledge synthesis project by an international research team funded by the Canadian Institutes of Health Research and endorsed by the Arctic Council. It focuses on the extent and magnitude of the problem of suicidal behaviours and thoughts from a circumpolar perspective - the variation across Arctic States and their northern regions, the excess risk among some indigenous groups and their demographic characteristics. Much remains to be learned about the design and implementation of youth-focused intervention programmes, especially in a circumpolar comparative framework. PMID- 25742880 TI - Improving Immigrant Populations' Access to Mental Health Services in Canada: A Review of Barriers and Recommendations. AB - This article emerges from a scoping review of over two decades of relevant literature on immigrants' access to mental health services in Canada. Key online databases were searched to explore the gaps and opportunities for improving access to mental health services using a review framework provided by Arksey and O'Malley (Int J Soc Res Methodol 8:19-32, 2005). Immigrants and refugees came from diverse religious and cultural backgrounds and had complex mental health related concerns that were not currently being adequately addressed by existing services. The major barriers to the utilization of mental health services included: those related to the uptake of existing health information and services; those that were related to the process of immigrant settlement; and barriers related to availability of appropriate services. A thematic analysis of the range of recommendations that emerge from these studies for improvement of research, practice and policy is provided. PMID- 25742883 TI - High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients. AB - BACKGROUND: The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III. FINDINGS: We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) by using the SPSS 2 step cluster function and Kaplan-Meier survival analysis. CONCLUSION: According to our results, patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation. Moreover, we demonstrated that the "Traditional pathway" with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis. This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation. PMID- 25742884 TI - Screening tests for tuberculosis before starting biological therapy. PMID- 25742882 TI - A scoping review of Indigenous suicide prevention in circumpolar regions. AB - BACKGROUND: Suicide is a serious public health challenge in circumpolar regions, especially among Indigenous youth. Indigenous communities, government agencies and health care providers are making concerted efforts to reduce the burden of suicide and strengthen protective factors for individuals, families and communities. The persistence of suicide has made it clear that more needs to be done. OBJECTIVE: Our aim was to undertake a scoping review of the peer-reviewed literature on suicide prevention and interventions in Indigenous communities across the circumpolar north. Our objective was to determine the extent and types of interventions that have been reported during past decade. We want to use this knowledge to support community initiative and inform intervention development and evaluation. DESIGN: We conducted a scoping review of online databases to identify studies published between 2004 and 2014. We included articles that described interventions in differentiated circumpolar Indigenous populations and provided evaluation data. We retained grey literature publications for comparative reference. RESULTS: Our search identified 95 articles that focused on suicide in distinct circumpolar Indigenous populations; 19 articles discussed specific suicide-related interventions and 7 of these described program evaluation methods and results in detail. The majority of publications on specific interventions were found in North American countries. The majority of prevention or intervention documentation was found in supporting grey literature sources. CONCLUSION: Despite widespread concern about suicide in the circumpolar world and active community efforts to promote resilience and mental well-being, we found few recorded programs or initiatives documented in the peer-reviewed literature, and even fewer focusing specifically on youth intervention. The interventions described in the studies we found had diverse program designs and content, and used varied evaluation methods and outcomes. The studies we included consistently reported that it was important to use community-based and culturally guided interventions and evaluations. This article summarizes the current climate of Indigenous circumpolar suicide research in the context of intervention and highlights how intervention-based outcomes have largely remained outside of peer reviewed sources in this region of the world. PMID- 25742885 TI - Diagnosis and management of takotsubo cardiomyopathy. PMID- 25742886 TI - Effects of dialysis solution on the cardiovascular function in peritoneal dialysis patients. AB - Objective Peritoneal dialysis (PD) patients have an increased cardiovascular burden. In this study, we aimed to compare certain PD solutions (Physioneal((r)) and Dianeal((r))) in terms of the ambulatory blood pressure, echocardiographic parameters (ECHO), carotid atherosclerosis, endothelial function and serum asymmetric dimethylarginine (ADMA) level. Methods A total of 45 PD patients were enrolled in this prospective randomized controlled study: 23 patients in the Dianeal((r)) group and 22 patients in the Physioneal((r)) group. Ambulatory blood pressure measurements, echocardiography, carotid artery intima-media thickness measurements and flow mediated dilatation (FMD) and ADMA values were obtained at baseline and 12 months. Results The baseline parameters were similar between the groups with respect to the echocardiographic parameters, 24-hour ambulatory blood monitoring measurements and ADMA and FMD levels. All 24-hour blood pressure monitoring measurements, except for the average daytime systolic blood pressure, were significantly decreased in both groups at the first year. In the Physioneal((r)) group, a significant decrease was observed with regard to the ADMA levels. Considering the FMD values, significant augmentation was seen at the end of the first year in both groups. Improvements in the FMD measurements were prominent in the Physioneal((r)) group; however, this finding was not statistically significant. Conclusion The use of solutions with a neutral pH in PD patients results in decreased ADMA levels, which may be an important contributor to reductions in the incidence of cardiovascular events and deaths in this population. PMID- 25742887 TI - Biliary tract infection or colonization with Elizabethkingia meningoseptica after endoscopic procedures involving the biliary tract. AB - OBJECTIVE: This study was performed to investigate the clinical significance of detecting Elizabethkingia meningoseptica in the bile. METHODS: We herein report a case series of biliary colonization or infection with E. meningoseptica. Twenty patients with E. meningoseptica recovered from the bile were treated at a 4,300 bed teaching hospital in China between January 2009 and December 2012. The clinical information for the cases of E. meningoseptica recovered from the bile and the microbiological data of the E. meningoseptica isolates were examined. RESULTS: Most of the 20 patients were not immunocompromised, although they had cholelithiasis and had recently received antimicrobial agents. All cases were treated with indwelling nasobiliary tubes and endoscopic retrograde cholangiopancreatography and/or endoscopic sphincterotomy prior to the detection of E. meningoseptica in the bile. The average time between the placement of the nasobiliary tube and the detection of E. meningoseptica in the bile was 6.6 days. E. meningoseptica caused cholangitis in five cases, one of which also involved secondary septicemia, and colonized the nasobiliary tubes or biliary tract in the remaining 15 cases. All but two patients recovered and were discharged. Two patients died of septicemia; E. meningoseptica and Escherichia coli were the causative pathogens in one case and other organisms were the causative pathogens in the other. CONCLUSION: E. meningoseptica is an unusual causative pathogen of healthcare-associated cholangitis. Cholangitis resulting from this bacterium is generally associated with good outcomes, although secondary septicemia can be life-threatening. PMID- 25742888 TI - Effects of combined enalapril and folic acid therapy on the serum uric acid levels in hypertensive patients: a multicenter, randomized, double-blind, parallel-controlled clinical trial. AB - Objective The efficacy of combined treatment consisting of enalapril and folic acid (FA) was compared to that of enalapril alone in reducing the serum uric acid (UA) levels in adult hypertensive patients in China. Methods Patients with mild to moderate hypertension (n=480) were randomly assigned to one of three treatment groups: (1) 10 mg enalapril (control group), (2) 10 mg enalapril plus 0.4 mg FA (low-FA group) or (3) 10 mg enalapril plus 0.8 mg FA (high-FA group) daily for eight weeks. The primary outcome was the UA ratio (week 8 UA: baseline UA). Results The final analysis included 450 patients (43.1% men, 27-75 years of age). An adjusted multivariable regression analysis revealed no significant differences in the UA ratio between the three groups after eight weeks of treatment. In the subgroup analysis stratified according to the baseline UA level, the high-FA group demonstrated a significantly greater UA-lowering response among the patients with an elevated baseline UA concentration (UA >=310 MUmol/L) [median UA ratio (25th percentile, 75th percentile): 0.94 (0.83, 1.01)], compared with that observed in the control group [0.97 (0.90, 1.00), p=0.025]. Similar results were found in the participants with baseline hyperuricemia (HUA; UA: men >420 MUmol/L, women >350 MUmol/L). Conclusion In this sample of adult hypertensive patients, the administration of a daily dose of 10 mg of enalapril combined with 0.8 mg of FA had a greater beneficial effect on the serum UA levels than did that of 10 mg of enalapril alone in patients with either an elevated UA concentration or HUA. PMID- 25742889 TI - Pathological evidence of the cause of spontaneous regression in a case of resected hepatocellular carcinoma. AB - A 67-year-old man presented for an evaluation after experiencing right hypochondrial pain lasting for two months. Abdominal ultrasonography showed a hepatic tumor in the right liver and extremely mild hepatic steatosis. The imaging findings indicated that the tumor (43 mm in size) was ischemic, and the lesion was surgically resected and examined. The histopathological findings demonstrated 95% necrosis with moderately differentiated hepatocellular carcinoma (HCC). The diagnosis was HCC with spontaneous regression. There was also pathological evidence of thrombus formation in the peripheral arteries and portal veins. In addition, the non-cancerous regions of the liver were diagnosed as exhibiting non-alcoholic steatohepatitis. The pathological findings obtained after resection of the HCC lesion showed spontaneous regression. PMID- 25742890 TI - Takotsubo cardiomyopathy with involvement of delayed-onset rhabdomyolysis and acute kidney injury after rosuvastatin treatment. AB - Takotsubo cardiomyopathy is a disorder characterized by left ventricular apical ballooning with preceding emotional and/or physical stressors. This condition is also an important differential diagnosis of acute coronary syndrome. We herein describe a case of Takotsubo cardiomyopathy, a significant clinical phenomenon, triggered by delayed-onset rhabdomyolysis following the administration of long term statin treatment, without any preceding stressors or changes in the patient's medical condition, in association with complaints of non-specific muscle-related symptoms. Although an electrocardiogram showed remarkable ST segment elevation, a careful reading of the electrocardiogram findings revealed the features of Takotsubo cardiomyopathy. Withdrawing the statin therapy improved the patient's cardiac function. PMID- 25742891 TI - Critical takotsubo cardiomyopathy complicated by ventricular septal perforation. AB - An 81-year-old woman was admitted with chest pain. An electrocardiogram demonstrated ST segment elevation in leads II, III and aVF, and echocardiography revealed left ventricular apical asynergy with a left-to-right ventricular shunt. Meanwhile, emergent coronary angiography showed no significant coronary artery stenosis, whereas left ventriculography indicated apical ballooning and a left-to right ventricular shunt. We therefore diagnosed the patient with Takotsubo cardiomyopathy complicated by ventricular septal perforation and cardiogenic shock. An electrocardiogram disclosed a prolonged QT interval over time, and the patient became hemodynamically stable under treatment with inotropes; however, she suddenly developed fatal ventricular fibrillation three days after hospitalization. Takotsubo cardiomyopathy complicated by ventricular septal perforation is a critical condition that requires careful monitoring. PMID- 25742892 TI - Endobronchial ultrasound-guided transbronchial needle aspiration in a patient with pericardial mesothelioma. AB - Pericardial mesothelioma is a very rare pericardial tumor. Diagnosing pericardial disease can be challenging, and obtaining an antemortem diagnosis of pericardial mesothelioma is particularly difficult. We herein report the case of a 60-year old man with pericardial mesothelioma diagnosed on endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). Chest computed tomography showed a mass surrounding the pericardium, and EBUS-TBNA of the right inferior paratracheal and subcarinal stations was consequently performed. No uptake was noted on (18)F-fluorodeoxy glucose positron emission tomography, other than in the pericardial mass. The results of histological and immunohistochemical examinations indicated the features of malignant mesothelioma. We therefore diagnosed the patient with pericardial mesothelioma, which was subsequently confirmed at autopsy. PMID- 25742893 TI - Successful recovery from an acute kidney injury due to amniotic fluid embolism. AB - A 33-year-old Japanese woman at 40 weeks gestation visited the maternity hospital after imminent labor had begun. After the delivery, persistent bleeding developed resulting in hemorrhagic shock. Although the hemorrhage was eventually controlled, hepatic and renal dysfunction occurred, leading to acute kidney injury (AKI). The patient's clinical presentation was suggestive of amniotic fluid embolism (AFE). We subsequently initiated continuous renal replacement therapy (RRT) for AKI. The patient's condition improved, she discontinued RRT, and her renal function recovered. We herein report a patient who successfully recovered from AKI caused by AFE. PMID- 25742894 TI - Advanced thymic cancer treated with carboplatin and paclitaxel in a patient undergoing hemodialysis. AB - A 53-year-old man with an asymptomatic anterior mediastinal tumor undergoing hemodialysis was referred to our institution. He was diagnosed with thymic basaloid carcinoma based on the findings of a chest tomography-guided biopsy and successfully treated with carboplatin (300 mg/m(2)/day) and paclitaxel (200 mg/m(2)/day) on day 1 for six three-week cycles. To our knowledge, this is the first report regarding the efficiency of a carboplatin dose-definition method based on the body surface area with paclitaxel in a hemodialysis patient. This report may therefore be useful for treating hemodialysis patients who are candidates for carboplatin and paclitaxel therapy. PMID- 25742895 TI - Metastatic embryonal carcinoma mimicking locally advanced non-small cell lung cancer. AB - A 50-year-old man with a history of smoking of 45 pack-years underwent right lower lobectomy after neoadjuvant chemoradiotherapy for locally advanced non small cell lung cancer diagnosed on a bronchial biopsy and standard imaging examinations, including chest-abdominal contrast-enhanced computed tomography (CT) and whole-body F-18 fluorodeoxyglucose positron emission tomography/CT. Left orchiectomy was performed simultaneously to treat the slightly swollen left testis, which had remained unchanged for over five years. The thoracic tumor was proven to be in pathological complete remission and the testicular lesion was pathologically diagnosed as an embryonal carcinoma. Furthermore, a pathological reevaluation of the preoperative bronchial biopsy specimen revealed the lung tumor to be a metastatic embryonal carcinoma. PMID- 25742896 TI - Evidence of unilateral metastatic pulmonary calcification with a prolonged Fever and arthralgia caused by acute lymphoblastic leukemia in a chronic dialysis patient. AB - A 55-year-old man was transferred to our hospital with unilateral lung lesions, a persistent fever and vague chest pain with arthralgia lasting for three months. He had been treated for end-stage renal disease with hemodialysis for 15 years and had a medical history of recurrent subcutaneous calciphylaxis due to secondary hyperparathyroidism. Transbronchial biopsied specimens demonstrated metastatic pulmonary calcification, and a bone marrow biopsy showed Philadelphia chromosome-positive acute lymphoblastic leukemia. Although metastatic calcification often lacks specific symptoms, the lungs is a primary site for deposition. This is the first report of unilateral metastatic pulmonary calcification associated with secondary hyperparathyroidism. PMID- 25742897 TI - Immune-mediated neuropathy with Epstein-Barr virus-positive T-cell lymphoproliferative disease. AB - A 47-year-old man with Epstein-Barr virus (EBV)-positive T/NK- cell lymphoproliferative disease (EBV-T/NK-LPD) developed acute-onset weakness. A nerve conduction study showed a conduction block in both the proximal and most distal segments. Although the patient's neuropathy transiently responded to intravenous immunoglobulin, it was progressive for at least 25 days until the start of prednisolone (PSL) administration, after which it remarkably improved. The neuropathy further improved after allogeneic bone marrow transplantation (BMT). The present patient's clinical course is not consistent with that of typical Guillain-Barre syndrome. This case suggests that EBV-T/NK-LPD can cause progressive immune-mediated neuropathy as a result of chronic EBV antigen presentation and can be treated with PSL and BMT. PMID- 25742898 TI - Human T lymphotropic virus type-1-associated myelopathy manifesting shortly after living-donor renal transplantation. AB - A 38-year-old woman experienced numbness in both lower extremities and spastic paralysis a few months after undergoing living-donor renal transplantation. The patient was negative for human T lymphotropic virus type-1 (HTLV-1) antibodies prior to the procedure; however, she was diagnosed with HTLV-1-associated myelopathy (HAM) based on positive serum and cerebrospinal fluid antibody titers after the surgery. Because the donor was also positive for HTLV-1 antibodies, the infection likely originated from the transplanted kidney. Clinical and imaging improvements were noted following the administration of interferon-alpha. HAM has been reported to occur after living-donor renal transplantation; however, there are no previous reports of onset within such a short period. PMID- 25742899 TI - Single photon emission computed tomography (SPECT) findings of a patient with a novel prion mutation. AB - We experienced a unique case of familial prion disease with a prion gene mutation that caused pan-autonomic failure, sensory neuropathy and mild cognitive impairment. No abnormal sites of intensity were observed on diffusion-weighted magnetic resonance image (MRI) over six to 11 years or fluid attenuated inversion recovery MRI at six or nine years. However, (99m)Tc-ethylcysteinate dimer single photon emission computed tomography (SPECT) showed a decreased cerebral blood flow in the bilateral parietal and occipital lobes at nine years, which then expanded at 11 years, corresponding to mild atrophy in these areas on MRI. In some cases of prion mutations, particularly the slowly progressive type, SPECT may show abnormalities, while MRI does not. PMID- 25742900 TI - Acute respiratory distress syndrome due to Strongyloides stercoralis infection in a patient with cervical cancer. AB - A 62-year-old woman complained of diarrhea and vomiting after receiving chemotherapy for cervical cancer in association with high doses of corticosteroids. Two months later, the patient developed acute respiratory distress syndrome, and numerous Strongyloides stercoralis parasites were found in the intrabronchial discharge. Ivermectin was administered daily until nematodes were no longer detected in the sputum, and the patient's condition was successfully rescued. Antibodies for human T-cell lymphotropic virus-1 (HTLV-1) were positive. HTLV-1 infection and the administration of corticosteroids are known risk factors for strongyloides hyperinfection syndrome. Therefore, physicians should consider this disease in the differential diagnosis of patients from endemic areas who present with gastrointestinal symptoms under these risk factors. PMID- 25742901 TI - Remission and worsening of claudication on MRI. PMID- 25742902 TI - Effects of end-capped acceptors subject to subtle structural changes on solution processable small molecules for organic solar cells. AB - Self-assembly is crucial for small molecular organic solar cells, which are extremely sensitive to the molecular structure. In this work, three subtle structural changed end-capped acceptors with increased electron withdrawing ability, named octyl 2-cyanoacetate (=CNCOOC8H17), 3-oxoundecanenitrile (=CNCOC8H17), and 2-(octylsulfonyl) acetonitrile (=CNSOOC8H17), were synthesized and introduced into a planar conjugated backbone using ethylhexyl-thiophene substituted benzodithiophene (TBDT) as a core and trithiophene as a pi-bridge (labelled M1, M2 and M3, respectively). Their effects on absorption, thermal properties, and morphologies were studied and compared. In particular, the molecular packing of the three materials varied significantly, and the hole mobilities differed by orders of magnitude. As a result, the fill factors of devices varied from 52% to 72%. Combining the effects of electron-withdrawing capability and molecular packing, the power conversion efficiencies of the optimized devices increased from 3.0% for M3 to 6.4% for M1 and M2. The relationship between end-capped acceptors and photovoltaic properties would generate valuable insights into further producing more efficient solution processable organic solar cells. PMID- 25742903 TI - Ultra-small Co3O4 nanoparticles-reduced graphene oxide nanocomposite as superior anodes for lithium-ion batteries. AB - Reducing the particle size of active component in electrode material could significantly improve the electrochemical performance of lithium-ion batteries. Herein, we report a facile method for preparing cobalt oxide nanoparticles reduced graphene oxide (Co3O4-RGO) nanocomposite, which was composed of ultra small Co3O4 nanoparticles (~12.5 nm in size) anchored on RGO nanosheets, as anode material for lithium-ion batteries. Both of the Co3O4-RGO nanocomposite and Co3O4 nanoparticles showed very high specific surface areas of ~149.5 m(2) g(-1) and ~107.4 m(2) g(-1). The Co3O4-RGO nanocomposite showed excellent coulombic efficiency, high lithium storage capacity and good rate capability. With an optimum weight percentage of RGO (~40 wt%), the nanocomposite displayed a high reversible discharge capacity of 830.7 mA h g(-1) after 75 cycles at 200 mA g( 1), and a reversible capacity of 680.9 mA h g(-1) after 30 cycles at 200 mA g(-1) and 100 consecutive cycles at 500 mA g(-1). After each eight cycles at 50, 100, 200, and 500 mA g(-1), the nanocomposite showed high reversible specific capacities of about 1153.2, 961.0, 851.4 and 736.4 mA h g(-1), respectively. These results show the importance of anchoring ultra-small nanoparticles on graphene nanosheets for maximum utilization of electrochemically active Co3O4 nanoparticles and graphene for energy storage applications in high-performance lithium-ion batteries. PMID- 25742904 TI - Does Measurement of Esophagogastric Junction Distensibility by EndoFLIP Predict Therapy- responsiveness to Endoluminal Fundoplication in Patients With Gastroesophageal Reflux Disease? AB - BACKGROUND/AIMS: In patients with gastroesophageal reflux disease (GERD), an increased esophagogastric junction (EGJ) distensibility has been described. Assessment of EGJ distensibility with the endoscopic functional luminal imaging probe (EndoFLIP) technique might identify patients responsive to transoral incisionless fundoplication (TIF), whereas postoperative measurement of EGJ distensibility might provide insight into the antireflux mechanism of TIF. Therefore, we investigated the value of the EndoFLIP technique in GERD patients treated by TIF. METHODS: Forty-two GERD patients underwent EGJ distensibility measurement before TIF using the EndoFLIP technique. In a subgroup of 25 patients, EndoFLIP measurement was repeated both postoperative and at 6 months follow-up. Treatment outcome was assessed according to esophageal acid exposure time (AET; objective outcome) and symptom scores (clinical outcome) 6 months after TIF. RESULTS: Multiple logistic regression analysis showed that preoperative EGJ distensibility (OR, 0.16; 95% CI, 0.03-0.78; P = 0.023) and preoperative AET (OR, 0.62; 95% CI, 0.42-0.90; P = 0.013) were independent predictors for objective treatment outcome but not for clinical outcome after TIF. The best cut-off value for objective outcome was 2.3 mm(2)/mmHg for preoperative EGJ distensibility and 11% for preoperative AET. EGJ distensibility decreased direct postoperative from 2.0 (1.2-3.3) to 1.4 (1.0-2.2) mm(2)/mmHg (P = 0.014), but increased to 2.2 (1.5-3.0) at 6 months follow-up (P = 0.925, compared to preoperative). CONCLUSIONS: Preoperative EGJ distensibility and preoperative AET were independent predictors for objective treatment outcome but not for clinical outcome after TIF. According to our data, the EndoFLIP technique has no added value either in the preoperative diagnostic work-up or in the post procedure evaluation of endoluminal antireflux therapy. PMID- 25742905 TI - Return to sport after muscle injury. AB - Skeletal muscle injuries are among the most common sports-related injuries that result in time lost from practice and competition. The cellular response to muscle injury can often result in changes made to the muscle fibers as well as the surrounding extracellular matrix during repair. This can negatively affect the force and range of the injured muscle even after the patient's return to play. Diagnosis of skeletal muscle injury involves both history and physical examinations; imaging modalities including ultrasound and magnetic resonance imaging (MRI) can also be used to assess the extent of injury. Current research is investigating potential methods, including clinical factors and MRI, by which to predict a patient's return to sports. Overall, function of acutely injured muscles seems to improve with time. Current treatment methods for skeletal muscle injuries include injections of steroids, anesthetics, and platelet-rich plasma (PRP). Other proposed methods involve inhibitors of key players in fibrotic pathways, such as transforming growth factor (TGF)-beta and angiotensin II, as well as muscle-derived stem cells. PMID- 25742906 TI - An Appraisal of Clinical Practice Guidelines for Diabetic Retinopathy. AB - The objective is to evaluate the methodological quality of clinical practice guidelines (CPGs) published by the American Academy of Ophthalmology (AAO), Canadian Ophthalmological Society (COS), and Royal College of Ophthalmologists (RCO) for diabetic retinopathy. Four evaluators independently appraised the CPGs using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, which covers 6 domains (Scope and Purpose, Stakeholder Involvement, Rigor of Development, Clarity of Presentation, Applicability, and Editorial Independence). Scores ranged from 35% to 78% (AAO), 60% to 92% (COS), and 35% to 82% (RCO). Intraclass correlation coefficients for the reliability of mean scores were 0.78, 0.78, and 0.79, respectively. The strongest domains were Scope and Purpose, and Clarity of Presentation (COS). The weakest were Stakeholder Involvement (AAO), Rigor of Development (AAO, RCO), Applicability, and Editorial Independence (RCO). Diabetic retinopathy practice guidelines can be improved by targeting Stakeholder Involvement, Rigor of Development, Applicability, and Editorial Independence. PMID- 25742907 TI - Microtubule-organizing center-mediated nuclear polarity in various normal and neoplastic human tissues. AB - Nuclear polarity is characterized by intracytoplasmic nuclear positioning and alignment in the tissue. The mechanisms responsible for maintaining nuclear polarity in normal cells and its disturbance in neoplastic cells are not understood. We studied microtubule-organizing center (MTOC) positioning-mediated nuclear polarity in various normal and neoplastic human tissues, as well as in cultured cells. To visualize the MTOC in cells, gamma-tubulin and pericentrin were immunohistochemically stained by fluorescence and non-fluorescence methods. Position of MTOC in normal and neoplastic tissue was assessed by spatial relationship with nucleus and apico-basal axis. We found MTOC positioning to be related to morphogenesis in various normal and neoplastic human tissues, as well as in cultured cells. MTOC positions were different between two-dimensional cultured isolated cells and three-dimensional cultured gland-formed cells. The MTOC position was specific depending on the cell type in the tissue structure. In particular, glandular and urothelial epithelium had a strong relationship with preservation of nuclear polarity and MTOC positioning. Carcinoma cells showed an irregular position or absence of the MTOC depending on poorer differentiation and higher grade of carcinomas. In conclusion, the position of the MTOC affects regulation of nuclear polarity and morphogenesis of normal and pathological tissue structure. PMID- 25742908 TI - Expression of proteins associated with hypoxia and Wnt pathway activation is of prognostic significance in hepatocellular carcinoma. AB - In the development and progression of hepatocellular carcinoma, tumor hypoxia plays an important role, as does activation of the Wnt pathway. The aim of this study was to characterize the expression and interrelationship between hypoxia and Wnt-pathway-associated proteins as prognostic factors for hepatocellular carcinoma. Expression of HIF-1alpha, CA-IX, E-cadherin, beta-catenin, and Ki-67 was assessed by immunohistochemistry in 179 primary hepatocellular carcinoma cases. Univariate and multivariate analyses were performed to assess the relationship between the clinicopathological factors, protein expression, overall survival (OS), and recurrence-free survival (RFS). By univariate analysis, tumor stage, size, satellitosis, and vascular invasion were confirmed as prognostic factors for worse OS and RFS. High expression of HIF-1alpha, CA-IX, beta-catenin, Ki-67, and E-cadherin was observed in 60, 15, 64, 8, and 64 % of tumors, respectively, and this was significantly associated with poor OS. CA-IX, HIF 1alpha, and E-cadherin were independent predictors of poor prognosis. We stratified 169 patients into four groups according to the expression level of hypoxia and Wnt pathway markers. The group with high expression of both hypoxia and Wnt-pathway-associated proteins showed worst OS. The poor survival of this group was also significant in patients with early stage disease and tumor size of less than 5 cm (p < 0.05). We identified a subgroup of hepatocellular carcinoma patients with high expression of both hypoxia and Wnt pathway proteins and found this predictive of poor survival. The therapeutic options for this group might need to be revisited. PMID- 25742909 TI - The UK: a nation of pill takers? PMID- 25742910 TI - A comparison of the pathological, clinical and radiographical, features of cryptogenic organising pneumonia, acute fibrinous and organising pneumonia and granulomatous organising pneumonia. AB - AIMS: Cryptogenic organising pneumonia (COP) and acute fibrinous and organising pneumonia (AFOP) are recognised patterns of organising pneumonia (OP), a condition that resembles pneumonia but is not caused by infection. We have recognised granulomatous organising pneumonia (GOP) to be a similar histopathological entity where non-necrotising granulomata are intimately associated with the organising connective tissue. To what degree COP, AFOP and GOP represent distinct clinical and pathological disorders is unknown. This cross sectional study sought to compare the pathological, clinical, and radiographical features of these OP patterns. METHODS: Surgical lung biopsy specimens were reviewed for consecutive patients referred with OP to a metropolitan cancer centre. Clinical information and CT images were acquired from the hospital electronic medical record to determine the clinical and CT characteristics of each OP pattern. RESULTS: Sixty-one patients (35 men, 26 women), mean age 61.5 years (range 8-85 years), were available for analysis. Of these, 43 patients (70%) had at least one prior cancer; 27 (44%) had received chemotherapy and 18 (30%) had received radiation. Approximately, half (32 patients) had respiratory symptoms, most commonly cough, dyspnoea and/or wheezing. While symptoms and mortality rates were not different among OP groups, AFOP patients more commonly had fever (p=0.04). GOP patients less commonly had received chemotherapy (p=0.03) and were more likely to present as masses/nodules (p=0.04). CONCLUSIONS: AFOP and GOP, a newly described OP form, possess clinical and pathological findings that set it apart from a COP, suggesting an emerging spectrum of OP. PMID- 25742911 TI - Testing implications of varying targets for Bordetella pertussis: comparison of the FilmArray Respiratory Panel and the Focus B. pertussis PCR assay. AB - BACKGROUND: The FilmArray Respiratory Panel (RP) detects multiple pathogens, including Bordetella pertussis. The multiplex PCR system is appropriate for a core laboratory or point of care due to ease of use. The purpose of this study is to compare the analytical sensitivity of the FilmArray RP, which targets the promoter region of the B. pertussis toxin gene, with the Focus real-time PCR assay, which targets the insertion sequence IS481. METHODS: Seventy-one specimens from patients aged 1 month to 18 years, which had tested positive for B. pertussis using the Focus assay, were analysed using the FilmArray RP. RESULTS: Forty-six specimens were positive for B. pertussis by both the Focus and the FilmArray RP assays. Twenty-five specimens were negative for B. pertussis using the FilmArray RP assay, but positive using the Focus assay. CONCLUSIONS: The FilmArray RP assays will detect approximately 1/3 less cases of B. pertussis than the Focus assay. PMID- 25742914 TI - Multi-responsible chameleon molecule with chiral naphthyl and azobenzene moieties. AB - A photochromic chiral molecule with azobenzene mesogens and a (R)-configuration naphthyl moiety (abbreviated as NCA2M) was specifically designed and synthesized for the demonstration of chameleon-like color changes responding to multitudinous external stimuli, such as temperature, light and electric field. The basic phase transition behaviors of NCA2M were first studied by the combination of differential scanning calorimetry (DSC) and polarized optical microscopy (POM). Based on the structure-sensitive X-ray diffraction results obtained at different temperatures, it was comprehended that the NCA2M molecule exhibited the tilted version of highly ordered smectic crystal phase with 5.45 nm layer thickness. Chiral nematic (N*) liquid crystals (LC) with helical superstructures were formed by doping the NCA2M photochromic chiral molecule in an achiral nematic (N) LC medium. By controlling the helical pitch length of N*-LC with respect to temperature, light and electric field, the wavelength of selectively reflected light from the N* photonic crystal was finely tuned. The light-induced color change of N*-LC film was the most efficient method for covering the whole visible region from blue to green and to red, which allowed us to fabricate remote controllable photo-responsive devices. PMID- 25742912 TI - Screening for Zinc Deficiency in Patients with Cirrhosis: When Should We Start? AB - BACKGROUND: Zinc deficiency has been observed in cirrhosis, but management guidelines do not address screening for zinc deficiency. We aim to determine the prevalence of zinc deficiency in different stages of cirrhosis and to correlate zinc levels with complications of cirrhosis and clinical outcomes. Patients who had a diagnosis of cirrhosis and had serum zinc levels drawn from 2007 to 2011 were identified. Demographics, laboratory data, presence of ascites, encephalopathy, and infection were obtained; Child-Pugh and MELD scores were calculated. Stata software was used for data analysis. A total of 163 patients were included in the study. RESULTS: The median serum zinc level was 0.47 mcg/ml (IQR 0.37-0.63); 83 % of patients were zinc deficient. Zinc deficiency was more prevalent in patients with Child-Pugh score B or C, and with MELD scores >=15. Zinc levels were lower in alcoholic, hepatitis C, and cholestatic diseases than in other etiologies of liver disease. Zinc levels correlated with INR (r = -0.56, p < 0.001), bilirubin (r = -0.51, p < 0.001), and albumin (r = 0.68, p < 0.001), and were lower in patients with ascites (0.40 vs. 0.57 mcg/ml, p < 0.001), encephalopathy (0.40 vs. 0.53 mcg/ml, p < 0.001), diuretic use (0.45 vs. 0.535 mcg/ml, p = 0.005), and infection (0.32 vs. 0.51 mcg/ml, p < 0.001). Ascites (p = 0.044) and infection (p = 0.009) were independently associated with zinc levels. Zinc-deficient patients had lower transplant-free survival rates than non deficient patients. CONCLUSION: Zinc deficiency is highly prevalent in cirrhotic patients with Child-Pugh score B or C, and with MELD score >=15. Zinc deficiency also correlates with disease severity, infection, and a worse transplant-free survival. Screening for zinc deficiency should be considered in this subset of patients. PMID- 25742915 TI - Direct sequencing of a disulfide-linked peptide with electrospray ionization tandem mass spectrometry. AB - Dissociation of disulfide is normally mandatory prior to disulfide peptide sequencing via electrospray ionization collision induced dissociation mass spectrometry (ESI-CID-MS). Herein, a facile method for directly sequencing intact disulfide peptides was proposed. The basic principles involved were electrolyte enhanced corona discharge in ESI and the following oxidative cleavage reaction. PMID- 25742913 TI - Distinct mPTP activation mechanisms in ischaemia-reperfusion: contributions of Ca2+, ROS, pH, and inorganic polyphosphate. AB - AIMS: The mitochondrial permeability transition pore (mPTP) plays a central role for tissue damage and cell death during ischaemia-reperfusion (I/R). We investigated the contribution of mitochondrial inorganic polyphosphate (polyP), a potent activator of Ca(2+)-induced mPTP opening, towards mPTP activation and cardiac cell death in I/R. METHODS AND RESULTS: A significant increase in mitochondrial free calcium concentration ([Ca(2+)]m), reactive oxygen species (ROS) generation, mitochondrial membrane potential depolarization (DeltaPsim), and mPTP activity, but no cell death, was observed after 20 min of ischaemia. The [Ca(2+)]m increase during ischaemia was partially prevented by the mitochondrial Ca(2+) uniporter (MCU) inhibitor Ru360 and completely abolished by the combination of Ru360 and the ryanodine receptor type 1 blocker dantrolene, suggesting two complimentary Ca(2+) uptake mechanisms. In the absence of Ru360 and dantrolene, mPTP closing by polyP depletion or CSA decreased mitochondrial Ca(2+) uptake, suggesting that during ischaemia Ca(2+) can enter mitochondria through mPTP. During reperfusion, a burst of endogenous polyP production coincided with a decrease in [Ca(2+)]m, a decline in superoxide generation, and an acceleration of hydrogen peroxide (H2O2) production. An increase in H2O2 correlated with restoration of mitochondrial pHm and an increase in cell death. mPTP opening and cell death on reperfusion were prevented by antioxidants Trolox and MnTBAP [Mn (III) tetrakis (4-benzoic acid) porphyrin chloride]. Enzymatic polyP depletion did not affect mPTP opening during reperfusion, but increased ROS generation and cell death, suggesting that polyP plays a protective role in cellular stress response. CONCLUSIONS: Transient Ca(2+)/polyP-mediated mPTP opening during ischaemia may serve to protect cells against cytosolic Ca(2+) overload, whereas ROS/pH-mediated sustained mPTP opening on reperfusion induces cell death. PMID- 25742916 TI - Biomechanical Outcomes of Bridge-enhanced Anterior Cruciate Ligament Repair Are Influenced by Sex in a Preclinical Model. AB - BACKGROUND: Despite the well-established role of sex on the anterior cruciate ligament (ACL) injury risk, its effects on ACL surgical outcomes remain controversial. This is particularly critical when developing novel surgical techniques to treat the injury because there are limited data existing on how these procedures will respond in each sex. One such approach is bridge-enhanced ACL repair, in which primary suture repair of the ACL is augmented with a bioactive scaffold saturated with autologous blood. It has shown comparable biomechanical outcomes to ACL reconstruction in preclinical models. QUESTIONS/PURPOSES: We asked (1) whether sex affects the biomechanical outcomes of bridge-enhanced ACL repair; and (2) if suture type (absorbable or nonabsorbable), used to repair the torn ACL, can minimize the potential sex discrepancies in outcomes after 15 weeks of healing in a large animal preclinical model. METHODS: Seventeen (eight males, nine females) Yorkshire pigs (Parson's Farms, Hadley, MA, USA) underwent bilateral ACL transection and received bridge enhanced ACL repair with an absorbable suture (n=17) on one side and with a nonabsorbable suture (n=17) on the other side. The leg receiving the absorbable suture was randomized within each animal. ACL structural properties and AP knee laxity for each knee were measured after 15 weeks of healing. Mixed linear models were used to compare the biomechanical outcomes between sexes and suture groups. RESULTS: When treated with absorbable suture, females had a lower ACL linear stiffness (females, 11 N/mm [range, 8-42]; males, 31 N/mm [range, 12-56]; difference, 20 N/mm [95% confidence interval {CI}, 4-36]; p=0.032), ACL yield (females, 121 N [range, 56-316]; males, 224 N [range, 55-538]; difference, 103 N [95% CI, 6-200]; p=0.078), and maximum load (females, 128 N [range, 63-332]; males, 241 N [range, 82-538]; difference, 114 N [95% CI, 15-212]; p=0.052) than males after 15 weeks of healing. Female knees treated with absorbable suture had a lower linear stiffness (absorbable, 11 N/mm [range, 8-42]; nonabsorbable, 25 N/mm [range, 8-64]; difference, 14 [95% CI, 2-26] N; p=0.054), ACL yield (absorbable, 121 N [range, 56-316]; nonabsorbable, 230 N [range, 149-573]; difference, 109 N [95% CI, 56-162]; p=0.002), and maximum load (absorbable, 128 N [range, 63-332]; nonabsorbable, 235 N [range, 151-593]; difference, 107 N [95% CI, 51-163]; p=0.002) along with greater AP knee laxity at 30 degrees (absorbable, 9 mm [range, 5-12]; nonabsorbable, 7 mm [range, 2-13]; difference, 2 mm [95% CI, 1-4]; p=0.034) than females treated with nonabsorbable suture. When repaired using nonabsorbable suture, the biomechanical outcomes were similar between female and male knees (p>0.10). CONCLUSIONS: Females had significantly worse biomechanical outcomes than males when the repairs were performed using absorbable sutures. However, the use of nonabsorbable sutures ameliorated these differences between males and females. CLINICAL RELEVANCE: The current findings highlight the critical role of sex on the biomechanical outcomes of bridge enhanced ACL repair in a relevant large animal model. Better understanding of the mechanisms responsible for these observations using preclinical models and concomitant clinical studies in human patients may allow for additional development of sex-specific surgical and rehabilitative strategies with potentially improved outcomes in women. PMID- 25742917 TI - CORR Insights((r)): Premature Therapeutic Antimicrobial Treatments Can Compromise the Diagnosis of Late Periprosthetic Joint Infection. PMID- 25742918 TI - Sorafenib: a review of its use in patients with radioactive iodine-refractory, metastatic differentiated thyroid carcinoma. AB - Sorafenib (Nexavar(r)) is the first tyrosine kinase inhibitor to be approved for the treatment of radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). In the pivotal phase III DECISION trial in patients with RAI refractory, locally advanced or metastatic DTC, oral sorafenib 400 mg twice daily significantly prolonged median progression-free survival (PFS) relative to placebo. The PFS benefit of sorafenib over placebo was evident in all pre specified clinical and genetic biomarker subgroups, and neither BRAF nor RAS mutation status was predictive of sorafenib benefit for PFS. The objective response rate was significantly higher in patients receiving sorafenib than in those receiving placebo; all objective responses were partial responses. The overall survival benefit of sorafenib is as yet unclear, with no significant benefit observed at the time of primary analysis or at 9 months following the primary analysis. Overall survival was possibly confounded by the crossover of patients in the placebo group to sorafenib upon disease progression. The adverse events associated with sorafenib in the DECISION trial were consistent with the known tolerability profile of the drug, with hand-foot skin reaction, diarrhea, and alopecia reported most commonly. Most treatment-emergent adverse events were grade 1 or 2 in severity and occurred early in treatment. However, a high proportion of patients discontinued sorafenib therapy or required dose reductions or interruptions because of toxicity. Although final overall survival data are awaited, current evidence suggests that sorafenib is a promising new treatment option for patients with RAI-refractory, metastatic DTC. PMID- 25742920 TI - The girls set the tone: gendered classroom norms and the development of aggression in adolescence. AB - In a four-wave longitudinal study with N = 1,321 adolescents in Germany, we examined the impact of class-level normative beliefs about aggression on aggressive norms and behavior at the individual level over the course of 3 years. At each data wave, participants indicated their normative acceptance of aggressive behavior and provided self-reports of physical and relational aggression. Multilevel analyses revealed significant cross-level interactions between class-level and individual-level normative beliefs at T1 on individual differences in physical aggression at T2, and the indirect interactive effects were significant up to T4. Normative approval of aggression at the class level, especially girls' normative beliefs, defined the boundary conditions for the expression of individual differences in aggressive norms and their impact on physically and relationally aggressive behavior for both girls and boys. The findings demonstrate the moderating effect of social norms on the pathways from individual normative beliefs to aggressive behavior in adolescence. PMID- 25742919 TI - A Double-Blinded, Randomized, Placebo-Controlled Trial to Evaluate Efficacy, Safety, and Tolerability of Single Doses of Tirasemtiv in Patients with Acetylcholine Receptor-Binding Antibody-Positive Myasthenia Gravis. AB - Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium and increases muscle force following subtetanic nerve input. In an animal model of myasthenia gravis (MG), single oral doses of tirasemtiv improved muscle force and reduced fatigability. The purpose of this study was to determine the effect of single doses of tirasemtiv on skeletal muscle function and fatigability in patients with generalized MG. Thirty-two patients with acetylcholine receptor antibody positive MG and muscle weakness received single doses of tirasemtiv (250 mg or 500 mg) or placebo in a double-blind, randomized treatment sequence with each treatment separated by at least 1 week. Outcome measures included the Quantitative MG Score (QMG), MG Composite, Manual Muscle Testing, and forced vital capacity. At 6 h after dosing, tirasemtiv produced dose-related improvements from baseline in the QMG score (slope: -0.49 QMG point per 250 mg; p = 0.02) and in percent predicted forced vital capacity (slope: 2.2% per 250 mg; p = 0.04). QMG improved >3 points in twice as many patients after 500 mg tirasemtiv than after placebo. Both doses of tirasemtiv were well tolerated; there were no premature terminations or serious adverse events. The results of this study suggest that tirasemtiv may improve muscle function in MG and will be used to support further development of tirasemtiv in neuromuscular diseases. PMID- 25742921 TI - New adsorption model -- theory, phenomena and new concept. AB - According to the conventional Gibbs adsorption model, which is a common assumption about the molecular concentration at surfaces, the adsorbed film of soluble amphiphiles is located at the air/solution interface just like Langmuir monolayer which is illustrated in many physical chemistry text books on "Colloid and Interface Science". According to many proofs of the experimental results here, the newer idea for the surface adsorption is confirmed and explained, which is quite different from the conventional Gibbs surface excess model at the air/solution interface. PMID- 25742922 TI - Factors affecting intestinal absorption of cholesterol and plant sterols and stanols. AB - Various factors affect intestinal absorption of cholesterol and plant sterols and stanols. Plant sterols and stanols are generally less absorptive than cholesterol. Differential absorption rates among various plant sterols and stanols have been also reported. Although it was suggested that differential absorption among cholesterol and various plant sterols was determined by difference in excretion rates of sterols and stanols through ATP-binding cassette transporter (ABC) G5/ABCG8 of intestinal cells, our study suggests that affinity for and solubility in bile salt micelles can be important determinants for differential absorption of plant sterols and stanols. It was also suggested that plant sterols were transiently incorporated into intestinal cells and then excreted to intestinal lumen through ABCG5/ABCG8. However, in a rat study, transient incorporation of sitosterol into intestinal cells was not observed, suggesting that sitosterol is differentiated from cholesterol at the incorporation site of intestinal cells. It is well established that plant sterols inhibit intestinal absorption of cholesterol and exert a hypocholesterolemic activity. Plant sterols are solubilized in bile salt micelles as cholesterol. Our study clearly showed that because the sterol-solubilizing capacity of bile salt micelles was limited, plant sterols solubilized in micelles reduced the solubility of cholesterol. This can be the major cause of inhibition of cholesterol absorption by plant sterols. Pancreatic cholesterol esterase accelerates intestinal absorption of unesterified cholesterol. Although it was suggested that cholesterol esterase accelerated esterification of cholesterol incorporated into intestinal cells and acted as a transporter at the surface of intestinal cells, our research revealed that the accelerated cholesterol absorption was caused by hydrolysis of phosphatidylcholine in bile salt micelles. It is thought that hydrolysis of phosphatidylcholine reduces the affinity of cholesterol for the micelles and accelerates the incorporation of cholesterol released from the micelles into intestinal cells. PMID- 25742923 TI - Enzymatic production of biodiesel from microalgal oil using ethyl acetate as an acyl acceptor. AB - Microalgae have become an important source of biomass for biodiesel production. In enzymatic transesterification reaction, the enzyme activity is decreased in presence of alcohols. The use of different acyl acceptors such as methyl/ethyl acetate is suggested as an alternative and effective way to overcome this problem. In this study, ethyl acetate was used for the first time in the enzymatic production of biodiesel by using microalga, Chlorella vulgaris, as a triglyceride source. Enzymatic conversion of such fatty acids to biodiesel was catalyzed by Novozym 435 as an efficient immobilized lipase which is extensively used in biodiesel production. The best conversion yield of 66.71% was obtained at the ethyl acetate to oil molar ratio of 13:1 and Novozym 435 concentration of 40%, based on the amount of oil, and a time period of 72 h at 40C. The results showed that ethyl acetate have no adverse effect on lipase activity and the biodiesel amount was not decreased even after seven transesterification cycles, so ethyl acetate has a great potential to be substituted for short-chain alcohols in transesterification reaction. PMID- 25742924 TI - Preparation of optically pure delta-lactones using diastereomeric resolution with amino acid as resolving agent. AB - Synthesis of optically pure delta-lactones by diastereomeric resolution was investigated. Amino acid derivatives, which can be obtained at a relatively low cost, were used as resolving agents. Six optically pure delta-lactones were efficiently synthesized using Cbz-L-alanine without other expensive resolving agents. Both enantiomers of delta-lactone obtained had over 98% enantiomeric excesses. This diastereomeric resolution is very efficient for the preparation of optically pure delta-lactones. PMID- 25742927 TI - Inappropriate use of ambulance services by elderly patients with less urgent medical needs. AB - Elderly patients with less urgent medical needs represent a high proportion of all emergency patients in Japan; this trend is gradually increasing, presenting a burden on the emergency medical system. To design effective interventions, it is important to understand the basic characteristics of emergency service use. For elderly Japanese patients, there is currently no detailed report on less urgent cases (LUC), or those cases that could be diagnosed by primary care physicians. Since there is a need for a timely reporting of detailed LUC data, we used data of 2004-2006 from an immediately available database at the Yao Tokushukai General Hospital. With a focus on LUC, we analyzed 7,800 cases of elderly patients, aged over 65 years, who were transported via ambulance to a secondary emergency hospital in Osaka. Of these, 3,354 patients (43.0%) were classified as having initial emergencies and were given outpatient care in the emergency department, and 1,544 patients (19.8%) were LUC, in which 541 subjects (6.9%) may have used ambulance services somewhat inappropriately owing to a lack of alternate transportation. In the remaining 1,003 patients, ambulance use could have been avoided if primary care clinics were available at night and during holidays. We therefore focus on three important points: awareness-raising activities to prevent inappropriate ambulance use, strengthening of transport services to healthcare facilities, and expanding primary care clinic office hours. This study is the first detailed report on the use of ambulance services in Japan by elderly patients with less urgent medical needs. PMID- 25742926 TI - Toxic effect of silver and platinum nanoparticles toward the freshwater microalga Pseudokirchneriella subcapitata. AB - The growing use of nanoparticles in a wide range of products has resulted in their release into the aquatic environment; therefore, an understanding of the toxic effects of nanoparticles on aquatic organisms is of permanent importance. The aim of this study was to evaluate the toxicity of silver and platinum nanoparticles toward the freshwater microalga, Pseudokirchneriella subcapitata. Algal growth and photosynthetic pigments were determined to quantitate the effects of varying concentrations of Ag and Pt nanoparticles. The silver nanoparticles were much more toxic than the platinum ones. The concentrations causing total inhibition of algal growth were 5.0 and 22.2 mg L(-1), respectively. Similar results were obtained by analyzing the concentration of photosynthetic pigments in P. subcapitata exposed to nanoparticles. Thus, simple spectrophotometric determination of chlorophyll is a convenient tool for the analysis of nanoparticle toxicity to algae. PMID- 25742925 TI - Management of retinoblastoma in children: current status. AB - In recent years, there have been dramatic changes in the management of intraocular retinoblastoma. Intraocular retinoblastoma is a highly curable malignancy and current treatments are aimed to preserve vision while reducing the late effects such as treatment-induced secondary malignancies. The advent of intra-arterial chemotherapy changed the treatment paradigm from systemic treatment with chemotherapy to local treatment, and new questions emerged. While intra-arterial chemotherapy achieved encouraging results, only experience from major referral centers is reported, so its indications, advantages and risks are still to be elucidated. Many factors should be considered when choosing the appropriate conservative therapy. When the disease has extended outside the eye, the chances of cure are significantly lower and treatment should be tailored by the presence of pathology risk factors such as invasion of the choroid, the optic nerve, and the sclera. Adjuvant therapy is decided upon this information. Children with overt extraocular disease are treated with higher dose neoadjuvant therapy followed by delayed enucleation and adjuvant therapy. PMID- 25742928 TI - Inter- and independent effects of region and race/ethnicity on variety of fruit and vegetable consumption in the USA: 2011 Behavioral Risk Factor Surveillance System (BRFSS). AB - OBJECTIVE: (i) To estimate the independent and combined effects of race/ethnicity and region on the variety of fruits and vegetables consumed in the USA in 2011; and (ii) to assess whether and to what extent race/ethnicity and region may synergistically influence variety of fruit and vegetable consumption. DESIGN: Cross-sectional analysis. Multivariate logistic regression predicted the likelihood of meeting fruit and vegetable variety indicators independently and in combination for each race/ethnicity and region. Interaction effects models were used to test for interaction effects between race/ethnicity and region on fruit and vegetable variety. SETTING: The 2011 Behavioral Risk Factor Surveillance System (BRFSS). SUBJECTS: The sample consisted of 275 864 adult respondents. RESULTS: Fewer than half of respondents consumed fruit and all vegetable subcategories at least once weekly. The adjusted likelihood of meeting fruit and vegetable variety indicators varied significantly by race/ethnicity and region (P<0.05). Significant interactions between race/ethnicity and region were found for at least once weekly consumption of beans, orange vegetables, all vegetables, and fruit and all vegetables (P<0.05). CONCLUSIONS: Our results reinforce previous findings that the variety of vegetable consumption is lacking and is particularly evident among some population subgroups, such as non-Hispanic blacks in the Midwest USA, who may benefit from targeted dietary interventions. PMID- 25742930 TI - Isolation, molecular characterization and evaluation of the pathogenicity of a porcine rotavirus isolated from Jiangsu Province, China. AB - In this study, a porcine rotavirus was isolated from a fecal sample from a diarrheic piglet in Jiangsu Province, China. Rotavirus-specific cytopathic effects were observed after 12 blind passages on MA-104 cells, yielding a virus titer of 10(6.125) TCID50/ml. By applying an 80 % nucleotide cutoff value and the RotaC(2.0) automated genotyping tool, the Vp4 genotype of the new isolate was identified as P[7]. The Vp7 genotype was identified as G[9], lineage VI, and sublineage c. Experimentally infected piglets showed severe diarrhea symptoms 16 24 h post-inoculation, indicating that this new porcine rotavirus isolate is a pathogenic strain. PMID- 25742929 TI - Overexpression of ADAMTS-7 leads to accelerated initiation and progression of collagen-induced arthritis in mice. AB - The aim of the present study is to determine whether ADAMTS-7 contributes to the onset and severity of joint inflammation in the pathogenesis of inflammatory arthritis. ADAMTS-7 was found to be elevated in the course of collagen-induced arthritis (CIA). ADAMTS-7 transgenic (TG) mice were more susceptible to the induction of CIA. The onset of CIA was accelerated and the arthritic severity was increased in TG mice compared to wild-type mice. The overall incidence was also significantly higher in TG mice. In addition, arthritic TG mice displayed significantly higher clinical and histological arthritis scores. The COMP degradative fragments were significantly elevated in articular cartilage and sera in CIA models of TG mice. Furthermore, the production of tumor necrosis factor alpha and interleukin-17 was also increased in serum and draining lymph nodes of arthritic TG mice. Therefore, these data provided the in vivo evidence, suggesting that ADAMTS-7 may play an important role in the pathogenesis of inflammatory arthritis, and that inhibition of ADAMTS-7 may be a potential target to ameliorate the severity of inflammatory arthritis. PMID- 25742931 TI - Prevalence of emerging porcine parvoviruses and their co-infections with porcine circovirus type 2 in China. AB - A total of 450 samples from domestic pigs in China were tested for porcine parvoviruses (PPVs) and co-infections with porcine circovirus type 2 (PCV2), and their complete capsid genes were sequenced. The prevalence of PPV1, PPV2, PPV3, PPV4, and PCV2 was 5.56 %, 39.56 %, 45.11 %, 21.56 %, and 47.33 %, respectively, and co-infection with PCV2 occurred in 4 % (PPV1), 22.44 % (PPV2), 24 % (PPV3), and 12 % (PPV4) of the samples. Phylogenetic analysis revealed two main lineages for each virus, and residues that differentiated these viruses were identified. The co-infections of emerging PPVs and PCV2 were prevalent, indicating their cooperative roles in porcine circovirus-associated diseases. PMID- 25742932 TI - First phylogenetic analysis of a Crimean-Congo hemorrhagic fever virus genome in naturally infected Rhipicephalus appendiculatus ticks (Acari: Ixodidae). AB - Crimean-Congo haemorrhagic fever (CCHF) is a potentially fatal systemic viral disease in many parts of the world, including Iran. The nationwide incidence of human CCHF in endemic areas was 870 confirmed cases with 126 deaths (case fatality rate, CFR = 17.6 %) in the decade leading to 2012. The detection of the CCHF virus (CCHFV) genome in tick vectors is of fundamental importance for identifying these ticks as potential reservoirs of CCHFV infection. From May to October 2013, following detection of four new clinical cases resulting in two deaths in the city of Mashhad (northeast Iran), hard ticks were recovered from infested livestock in 40 villages in Khorasan-Razavi province and examined by the microscopic method for species identification. About a quarter of the ticks were then subjected to reverse-transcription polymerase chain reaction (RT-PCR) to detect the CCHFV genome. The PCR products were then sequenced, and their phylogenetic lineages were determined. A total of 407 hard ticks were captured, representing seven different species in two distinct genera. Members of the genus Hyalomma were widely distributed in all but two of the villages studied, and this was also the most frequent (83.3 %) tick genus. Of 105 adult ticks subjected to RT-PCR, four (3.8 %) ticks were found positive for the CCHFV genome. One brown ear tick, Rhipicephalus appendiculatus, was found to be naturally infected for the first time anywhere in the world. Ticks of Hyalomma asiaticum, Hyalomma marginatum, and Rhipicephalus turanicus were also found to be naturally infected with CCHFV. CCHFV found in these four different tick species were clustered in the same lineage with the Matin and SR3 strains from Pakistan and some other strains from Iran, indicating that these tick species were naturally infected with genetically closely related CCHFV in the region. The presence of CCHFV infection in four different hard tick species was confirmed using RT-PCR in northeast Iran. Part of this infection was attributed to Rh. appendiculatus, which is thus a potential new natural vector of CCHFV in Iran. It is also confirmed by phylogenetic analysis that CCHFV in this region is genetically closely related, even in the different tick species. PMID- 25742933 TI - CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. AB - Bispecific T cell-engaging (BiTE) antibodies recruit polyclonal cytotoxic T cells (CTL) to tumors. One such antibody is carcinoembryonic antigen (CEA) BiTE that mediates T cell/tumor interaction by simultaneously binding CD3 expressed by T cells and CEA expressed by tumor cells. A widely operative mechanism for mitigating cytotoxic T cell-mediated killing is the interaction of tumor expressed PD-L1 with T cell-expressed PD-1, which may be partly reversed by PD 1/PD-L1 blockade. We hypothesized that PD-1/PD-L1 blockade during BiTE-mediated T cell killing would enhance CTL function. Here, we determined the effects of PD-1 and PD-L1 blockade during initial T cell-mediated killing of CEA-expressing human tumor cell lines in vitro, as well as subsequent T cell-mediated killing by T lymphocytes that had participated in tumor cell killing. We observed a rapid upregulation of PD-1 expression and diminished cytolytic function of T cells after they had engaged in CEA BiTE-mediated killing of tumors. T cell cytolytic activity in vitro could be maximized by administration of anti-PD-1 or anti-PD-L1 antibodies alone or in combination if applied prior to a round of T cell killing, but T cell inhibition could not be fully reversed by this blockade once the T cells had killed tumor. In conclusion, our findings demonstrate that dual blockade of PD-1 and PD-L1 maximizes T cell killing of tumor directed by CEA BiTE in vitro, is more effective if applied early, and provides a rationale for clinical use. PMID- 25742934 TI - Endovascular treatment of popliteal aneurysm. AB - Although traditional surgical repair by aneurysm exclusion and bypass is still considered the gold standard in the treatment of popliteal artery aneurysms (PAAs), the endovascular repair (ER) has been gaining great interest in the last decades. ER offers several advantages over open bypass, including lower morbidity and mortality, and faster functional recovery, but some concerns about migration, occlusion, or fracture remain when a stent graft is deployed across a joint that undergo constant flexion. This review summarizes the current evidence on ER for PAAs. Level I evidence is still very limited, while the majority of published data come from retrospective studies. Moreover the heterogeneity of PAA morphology seems to play a major role in the outcomes after popliteal endografts placement, so that many anatomical criteria should be taken into account to determine which patient is best treated endovascularly. In conclusion, while it is unlike that endovascular treatment may displace open surgical bypass in the near future, it indeed does provide a feasible option for selected patients with high surgical risk and good anatomical features. PMID- 25742935 TI - Pyranone natural products as inspirations for catalytic reaction discovery and development. AB - Natural products continue to provide a wealth of opportunities in the areas of chemical and therapeutic development. These structures are effective measuring sticks for the current state of chemical synthesis as a field and constantly inspire new approaches and strategies. Tetrahydropryans and tetrahydropyran-4 ones are found in numerous bioactive marine natural products and medicinal compounds. Our interest in exploring the therapeutic potential of natural products containing these motifs provided the impetus to explore new methods to access highly functionalized, chiral pyran molecules in the most direct and rapid fashion possible. This goal led to exploration and development of a Lewis acid mediated Prins reaction between a chiral beta-hydroxy-dioxinone and aldehyde to produce a pyran-dioxinone fused product that can be processed in a single pot operation to the desired tetrahydropyran-4-ones in excellent yield and stereoselectivity. Although the Prins reaction is a commonly employed approach toward pyrans, this method uniquely provides a 3-carboxy-trisubstituted pyran and utilizes dioxinones in a manner that was underexplored at the time. The 3-carboxy substituent served as a key synthetic handhold when this method was applied to the synthesis of highly functionalized pyrans within the macrocyclic natural products neopeltolide, okilactiomycin, and exiguolide. When employed in challenging macrocyclizations, this tetrahydropyranone forming reaction proved highly stereoselective and robust. Another major thrust in our lab has been the synthesis of benzopyranone natural products, specifically flavonoids, because this broad and diverse family of compounds possesses an equally broad range of biological and medicinal applications. With the goal of developing a broad platform toward the synthesis of enantioenriched flavonoid analogs and natural products, a biomimetic, asymmetric catalytic approach toward the synthesis of 2 aryl benzopyranones was developed. A bifunctional hydrogen bonding/Bronstead base catalyst was ultimately found to enable this transformation in analogous manner to the biosynthesis via the enzyme chalcone isomerase. Employing thiourea catalysts derived from the pseudoenantiomeric quinine and quinidine, alkylidene beta-ketoesters can be isomerized to 3-carboxy flavanones and decarboxylated in a single pot operation to stereodivergently provide highly enantioenriched flavanones in excellent yield. This method was applied to the synthesis of the abyssinone family of natural products, as well as the rotenoid, deguelin. An analogous method to isomerize chalcones was developed and applied to the synthesis of isosilybin A. In both of these related endeavors, the need for novel enabling methodologies toward the efficient creation of targeted molecular complexity drove the discovery, development and deployment of these stereoselective catalytic transformations. PMID- 25742937 TI - Solvent-free synthesis of new inorganic-organic hybrid solids with finely tuned manganese oxalate structures. AB - Three manganese phosphate-oxalates have been synthesized under solvent-free conditions. These inorganic-organic hybrid solids are based on a pcu-type topology with nanobelt-like, sql-, and cds-type manganese oxalate skeletons, respectively. The amine molecules play a novel structure-directing role for the formation of different metal-organic skeletons within a specific framework topology. PMID- 25742936 TI - Genetic and environmental factors in the aetiology of hypospadias. AB - This article reviews the current evidence and knowledge of the aetiology of hypospadias. Hypospadias remains a fascinating anomaly of the male phallus. It may be an isolated occurrence or part of a syndrome or field defect. The increasing use of assisted reproductive techniques and hormonal manipulation during pregnancy may have been associated with an apparent rise in the incidence of hypospadias. Genetic studies and gene analysis have suggested some defects that could result in hypospadias. New light has also been thrown on environmental factors that could modulate candidate genes, causing altered development of the male external genitalia. PMID- 25742938 TI - Evidence for a nematic component to the hidden-order parameter in URu2Si2 from differential elastoresistance measurements. AB - For materials that harbour a continuous phase transition, the susceptibility of the material to various fields can be used to understand the nature of the fluctuating order and hence the nature of the ordered state. Here we use anisotropic biaxial strain to probe the nematic susceptibility of URu2Si2, a heavy fermion material for which the nature of the low temperature 'hidden order' state has defied comprehensive understanding for over 30 years. Our measurements reveal that the fluctuating order has a nematic component, confirming reports of twofold anisotropy in the broken symmetry state and strongly constraining theoretical models of the hidden-order phase. PMID- 25742939 TI - Strategies for heart regeneration: approaches ranging from induced pluripotent stem cells to direct cardiac reprogramming. AB - Cardiovascular disease remains a leading cause of death for which current therapeutic regimens are limited. Following myocardial injury, endogenous cardiac fibroblasts, which account for more than half of the cells in the heart, proliferate and synthesize extracellular matrix, leading to fibrosis and heart failure. As terminally differentiated cardiomyocytes have little regenerative capacity following injury, development of cardiac regenerative therapy is highly desired. Embryonic stem (ES) and induced pluripotent stem (iPS) cells are promising tools for regenerative medicine; however, these stem cells demonstrate variable cardiac differentiation efficiency and tumorigenicity, which should be solved for clinical applications. Up until the last decade, it was an established theory that cardiomyocytes could only be produced from fibroblasts mediating through stem cells. However, in 2010, we reported for the first time a novel method of the direct reprogramming of fibroblasts into cardiomyocytes, demonstrating various reprogramming pathways exist. This review summarizes the latest trends in stem cell and regenerative research, touching upon iPS cells, partial reprogramming strategy, and direct cardiac reprogramming. Specifically, we examine the many recent advances in both in vitro and in vivo direct cardiac reprogramming, and explore the application of these methods to cardiovascular regenerative medicine. PMID- 25742940 TI - Neutrophil to lymphocyte ratio predicts SYNTAX score in patients with non-ST segment elevation myocardial infarction. AB - In this study we aimed to investigate whether there is an association between the neutrophil to lymphocyte ratio (NLR) and severity of coronary artery disease (CAD) in patients with non-ST segment elevation myocardial infarction (NSTEMI) using the SYNTAX score (SXscore). A total of 414 patients with NSTEMI who underwent coronary angiography were enrolled in the study. NLR was measured for all patients at presentation. The study population was then divided into 3 tertiles based on the SYNTAX trial results.(1)) The low syntax group (n = 329) was defined as those with an SXscore <= 22, the intermediate syntax group (n = 58) was defined as an SXscore >= 23 and < 33, and the high syntax group (n = 27) as those with an SXscore >= 33. NLR was significantly lower in patients with a low SXscore compared to patients with an intermediate SXscore or high SXscore (3.7 +/- 4 to 4.6 +/- 2 and 7.9 +/- 4, P < 0.001). Linear regression analysis revealed that NLR (coefficientbeta = 0.380, 95%CI: 1.165-1.917, P < 0.001) was significantly associated with the SXscore in patients with NSTEMI. Our results indicate that NLR is independently associated with the severity of CAD in patients with NSTEMI. PMID- 25742941 TI - Stent boost subtract imaging for the assessment of optimal stent deployment in coronary ostial lesion intervention: comparison with intravascular ultrasound. AB - Percutaneous coronary intervention (PCI) of ostial lesions is complex and is technically very demanding. Intravascular ultrasound (IVUS) is considered the gold standard method to guide PCI but has several limitations. Stent boost subtract (SBS) imaging is an enhancement of the radiologic edge of the stent by digital management of regular X-ray images. The purpose of this study was to determine the availability of stent enhancement with SBS during ostial PCI by comparison with IVUS.We investigated SBS and IVUS after stent implantation in 58 ostial lesions in 55 patients. SBS and IVUS were performed in all patients to obtain improved stent location and to detect optimal release and deployment. We defined the SBS and IVUS criteria for accuracy of stent location and adequate stent deployment. IVUS findings showed that stent location was generally good. The location was accurate in 48 (82.8%) and inadequate stent deployment was observed in 10 of 58 (17.2%). Eight SBS images showed inadequate stent expansion. SBS predicted inadequate findings of IVUS with 100% specificity and 80% sensitivity, while a significant positive correlation was observed between SBS MSA and MSA by IVUS with a regression coefficient of 0.95.Imaging techniques have a primary role during ostial PCI. SBS is a simple and quick method that offers several advantages, enabling improved stent location, adequate stent expansion, and optimal apposition of the struts to the wall. SBS imaging could be conventionally used during ostial PCI, especially in centers where IVUS is not used routinely. PMID- 25742942 TI - Influence of diabetes mellitus on long-term outcomes of patients with unprotected left main coronary artery disease treated with either drug-eluting stents or coronary artery bypass grafting. AB - Whether the effect of diabetes on patients with unprotected left main coronary artery (ULMCA) disease differs according to different strategies of revascularization was unknown. This study was conducted to evaluate the impact of diabetes on patients with ULMCA disease treated with either percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG).A total of 922 patients with ULMCA disease who received drug-eluting stent (DES) (n = 465) implantation or underwent CABG (n = 457) were retrospectively analyzed. We compared the effects of these 2 treatments on clinical outcomes (death, myocardial infarction, stroke, repeat revascularization, and the composite of death, myocardial infarction, or stroke), according to diabetic status.During the median follow-up of 7.1 years (interquartile range, 5.3 to 8.2 years), no difference was found between PCI and CABG in the adjusted occurrence of death (P = 0.112) and the composite endpoints of death, myocardial infarction, and stroke (P = 0.235). Significantly higher incidence of repeat revascularization (P < 0.001) was observed in the DES group, whereas the CABG group had a significantly higher rate of stroke (P = 0.001). These trends were consistent in both diabetic and nondiabetic patients. We did not observe significant interactions between treatment outcomes and the presence or absence of diabetes after adjustment for covariates (P(interaction) = 0.580 for the composite of death, MI and stroke, P(interaction) = 0.685 for death, P(interaction) = 0.416 for MI, P(interaction) = 0.470 for stroke, and P(interaction) = 0.502 for repeat revascularization).Presence of diabetes was not important for decision-making between CABG and PCI in patients with ULMCA disease. PMID- 25742943 TI - Impact of cystatin-C level on the prevalence and angiographic characteristics of vasospastic angina in Korean patients. AB - Cystatin-C, a marker of mild renal dysfunction, has been reported to be associated with cardiovascular diseases including vasospastic angina (VSA). We aimed to investigate the impact of cystatin-C level on the prevalence and angiographic characteristics of VSA in Korean patients.A total of 549 patients in the VA-KOREA (Vasospastic Angina in KOREA) registry who underwent ergonovine provocation tests were consecutively enrolled. Estimated glomerular filtration rate (eGFR) and levels of serum creatinine (Cr) and cystatin-C were assessed before angiography.The patients were classified into two groups: the VSA group (n = 149, 27.1%) and the non-VSA group (n = 400). Although eGFR and Cr levels were similar between the two groups, the VSA group had a significantly higher level of cystatin-C (P < 0.05). A high level of cystatin-C (second tertile, hazard ratio 1.432; 95% confidence interval [1.1491.805]; P = 0.026, third tertile, 1.947 [1.132-2.719]; P = 0.003) and current smoking (2.710 [1.415-4.098]; P < 0.001) were independently associated with the prevalence of VSA. Furthermore, the highest level of cystatin-C (> 0.96 ng/mL) had a significant impact on the incidence of multivessel spasm (2.608 [1.061-4.596]; P = 0.037).A high level of cystatin-C was independently associated with the prevalence of VSA and with a high-risk type of VSA in Korean patients, suggesting that proactive investigation of VSA should be considered for patients with mild renal dysfunction indicated by elevated cystatin-C. PMID- 25742944 TI - Plasma neutrophil gelatinase-associated lipocalin and worsening renal function during everolimus therapy after heart transplantation. AB - Recently, the mammalian target of rapamycin inhibitor everolimus (EVL) has been introduced as a novel immunosuppressant for heart transplant (HTx) recipients, and is expected to preserve renal function compared to conventional calcineurin inhibitors (CNIs). However, a considerable number of recipients treated with EVL were not free from worsening renal function regardless of CNI reduction. Data were collected retrospectively from 27 HTx recipients who had received EVL (trough concentration, 3.1-9.2 ng/mL) along with reduced CNIs (%decreases in trough concentration, 27.3 +/- 13.0%) because of switching from mycophenolate mophetil due to digestive symptoms or neutropenia, progressive coronary artery vasculopathy, or persistent renal dysfunction, and had been followed over 1 year between August 2008 and January 2013. Estimated glomerular filtration rate (eGFR) decreased in 5 recipients (18.5%) during the study period. Univariate logistic regression analysis demonstrated that a higher plasma neutrophil gelatinase associated lipocalin (P-NGAL) level was the only significant predictor for a decrease in eGFR over a 1-year EVL treatment period among all baseline parameters (P = 0.008). eGFR and proteinuria worsened almost exclusively in patients with baseline P-NGAL >= 85 ng/mL, which was the cutoff value calculated by an ROC analysis (area under the curve, 0.955; sensitivity, 1.000; specificity, 0.955). In conclusion, higher P-NGAL may be a novel predictor for the worsening of renal function after EVL treatment that is resistant to CNI reduction in HTx recipients. PMID- 25742945 TI - Targeted therapy is required for management of pulmonary arterial hypertension after defect closure in adult patients with atrial septal defect and associated pulmonary arterial hypertension. AB - BACKGROUND: Therapeutic strategies for pulmonary arterial hypertension (PAH) associated with atrial septal defect (ASD) remain a matter of debate. METHODS AND RESULTS: We identified 5 outpatients who had been diagnosed with ASD-PAH and undergone ASD closure in combination with targeted therapy with certified PAH drugs. We assessed changes in hemodynamic parameters and exercise capacity. The combination of ASD closure and targeted therapy significantly increased systemic blood flow (Qs) from the baseline (from 3.3 +/- 0.6 L/minute to 4.2 +/- 1.0 L/minute, P < 0.05) with a significant improvement in the World Health Organization Functional Class (WHO-FC; from 2.8 +/- 0.4 to 1.6 +/- 0.5, P < 0.05). The hemodynamic data before and after ASD closure without targeted therapy showed further elevation of pulmonary vascular resistance shortly after ASD closure (678 dyne . s/cm(5) to 926 dyne . s/cm(5)) in 1 case, as well as after a long time since ASD closure (491.0 +/- 53.7 dyne . s/cm(5) to 1045.0 +/- 217.8 dyne . s/cm(5)) in 2 cases. This worsening was reversed after the targeted therapy, accompanied by an increase in Qs and an improvement in WHO-FC in all cases. CONCLUSIONS: Targeted therapy should be added to ASD closure in adult patients with ASD-PAH. PMID- 25742946 TI - Usefulness of right ventricular basal free wall strain by two-dimensional speckle tracking echocardiography in patients with chronic thromboembolic pulmonary hypertension. AB - Recently two-dimensional (2D) speckle tracking echocardiography (STE) derived from right ventricular (RV) free wall has been shown to be a very useful tool for the estimation of RV performance. The purpose of this study was to examine whether RV basal free wall strain can detect increased mean pulmonary arterial pressure (mPAP) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We investigated a total of 126 patients with CTEPH (mean age, 56 +/- 12 years). They underwent echocardiography and right heart catheter examination. 2D STE-derived longitudinal strain was measured by placing 2 regions of interests (ROIs) on the RV basal free wall in RV-focused apical 4-chamber view. Peak strain (RV-PS) was acquired between the 2 ROIs. Conventional echocardiographic RV parameters (RV fractional area change, RV myocardial performance index, tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity, and tricuspid regurgitant pressure gradient) were evaluated as well. Right heart catheterization was performed on the day following of echocardiographic evaluation. Among RV echo parameters, RV-PS showed the best correlation with mPAP (r = 0.75, P < 0.0001). Receiver operating characteristic analysis revealed that a cut-off value of RV-PS -20.8% could detect mPAP ? 25 mmHg (sensitivity 78%, specificity 93%, area under the curve 0.90, P < 0.001). RV basal free wall strain was a useful tool for the non-invasive detection of increased mPAP in patients with CTEPH. PMID- 25742947 TI - Impact of supervised cardiac rehabilitation on urinary albumin excretion in patients with cardiovascular disease. AB - Urinary albumin excretion is a predictor of cardiovascular death. Cardiac rehabilitation (CR) with exercise training (ET) has been shown to improve exercise capacity and prognosis in patients with cardiovascular disease (CVD). However, it remains unclear whether CR reduces urinary albumin excretion in CVD patients. We performed a retrospective, observational study using data obtained from 98 male CVD patients without macroalbuminuria and estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m(2) who participated in CR with ET during hospitalization. Twenty-three patients continued supervised ET for 6 months (supervised group) and 75 patients quit supervised ET (non-supervised group). The supervised ET program consisted of 60 minutes of supervised sessions 1-3 times a week and 30-60 minutes of home exercise at least twice a week. Urinary albumin/creatinine ratio (ACR) was significantly decreased in the supervised group at 6 months after enrollment (43 +/- 71 mg/g to 17 +/- 20 mg/g creatinine, P < 0.05) but not in the non-supervised group. eGFR was unchanged in the supervised group but was significantly decreased in the non-supervised group (72 +/- 18 mL/minute/1.73 m(2) to 67 +/- 17 mL/minute/1.73 m(2), P < 0.001). The results of multiple regression analysis showed that only supervised ET was an independent contributor to DeltaACR. CR with supervised ET decreased urinary albumin excretion without deterioration of renal function. These findings suggest that continuation of a supervised ET program is associated with reduction in the development of CVD and reduction in cardiovascular morbidity and mortality in CVD patients. PMID- 25742948 TI - Rescue balloon pulmonary angioplasty under veno-arterial extracorporeal membrane oxygenation in a patient with acute exacerbation of chronic thromboembolic pulmonary hypertension. AB - We describe a case of a 41-year-old woman with acute exacerbation of chronic thromboembolic pulmonary hypertension (CTEPH) complicated by rapidly progressive respiratory failure and right heart failure with cardiogenic shock. A computed tomography (CT) showed thrombi in the right main pulmonary artery and bilateral peripheral pulmonary arteries, and echocardiography showed right ventricular dilatation and tricuspid regurgitation, with an estimated pressure gradient of 80 mmHg. The patient was initially diagnosed with acute pulmonary thromboembolism, and thrombolytic therapy was administered. Her condition subsequently deteriorated, however, necessitating mechanical ventilation and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We performed emergency catheter directed thrombectomy and thrombus aspiration. Pulmonary hypertension (PH) temporarily improved, but subsequently worsened, and the patient was diagnosed with CTEPH. Pulmonary endarterectomy (PEA) was performed. After PEA, we were unable to wean the patient off VA-ECMO, and rescue balloon pulmonary angioplasty (BPA) to the middle and inferior lobe branches of the right lung was performed. Five days after BPA, the patient was removed from VA-ECMO and on the 57th day of hospitalization, she was weaned off the ventilator. The patient was discharged after 139 days of hospitalization. Rescue BPA represents a useful intervention for improving PH and weaning off VA-ECMO in a patient with acute exacerbation of CTEPH. PMID- 25742949 TI - Monolayer graphene on nanostructured Ag for enhancement of surface-enhanced Raman scattering stable platform. AB - We have reported that the Ag nanostructure-based substrate is particularly suitable for surface-enhanced Raman scattering when it is coated with monolayer graphene, an optically transparent and chemistry-inertness material in the visible range. Ag bowtie nanoantenna arrays and Ag nanogrids were fabricated using plasma-assisted nanosphere lithography. Our measurements show that atmospheric sulfur containing compounds are powerless to break in the monolayer graphene to vulcanize the surfaces of the Ag bowtie nanoantenna arrays and Ag nanogrids by various means, including scanning electron microscopy (SEM) and x ray photoelectron spectroscopy (XPS). Furthermore, the Ag nanostructure substrate coated with the monolayer graphene film shows a larger enhancement of Raman activity and the electromagnetic field than the uncoated substrate. Compared with those of bare Ag nanostructures, the averaged EFs of graphene-film-coated Ag nanostructures were estimated to be about 21 and 5 for Ag bowtie nanoantenna arrays and nanogrids after one month later in air, respectively. These observations are further supported by theoretical calculations. PMID- 25742950 TI - Can clays ensure nuclear waste repositories? AB - Research on argillite as a possible host rock for nuclear waste disposal is still an open subject since many issues need to be clarified. In the Underground Research Laboratories constructed for this purpose, a damaged zone around the excavation has been systematically observed and characterized by the appearance of micro-fissures. We analyse here -at nanoscale level- the calcite/clay assembly, the main constituents of argillite, under storage conditions and show the fragility of the montmorillonite with respect to calcite. Under anisotropic stress, we have observed a shear deformation of the assembly with the presence of broken bonds in the clay mineral, localised in the octahedral rather than the tetrahedral layers. The stress/strain curve leads to a failure strength point at 18.5 MPa. The obtained in-plane response of the assembly to perpendicular deformation is characterized by smaller perpendicular moduli Ez = 48.28 GPa compared to larger in-plane moduli Ex = 141.39 GPa and Ey = 134.02 GPa. Our calculations indicate the instability of the assembly without water molecules at the interface in addition to an important shear deformation. PMID- 25742951 TI - Finding communities in sparse networks. AB - Spectral algorithms based on matrix representations of networks are often used to detect communities, but classic spectral methods based on the adjacency matrix and its variants fail in sparse networks. New spectral methods based on non backtracking random walks have recently been introduced that successfully detect communities in many sparse networks. However, the spectrum of non-backtracking random walks ignores hanging trees in networks that can contain information about their community structure. We introduce the reluctant backtracking operators that explicitly account for hanging trees as they admit a small probability of returning to the immediately previous node, unlike the non-backtracking operators that forbid an immediate return. We show that the reluctant backtracking operators can detect communities in certain sparse networks where the non backtracking operators cannot, while performing comparably on benchmark stochastic block model networks and real world networks. We also show that the spectrum of the reluctant backtracking operator approximately optimises the standard modularity function. Interestingly, for this family of non- and reluctant-backtracking operators the main determinant of performance on real world networks is whether or not they are normalised to conserve probability at each node. PMID- 25742952 TI - The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged recently as a new class of genes that regulate cellular processes, such as cell growth and apoptosis. The SPRY4 intronic transcript 1 (SPRY4-IT1) is a 708-bp lncRNA on chromosome 5 with a potential functional role in tumorigenesis. The clinical significance of SPRY4 IT1 and the effect of SPRY4-IT1 on cancer progression are unclear. METHODS: Quantitative reverse transcriptase PCR (qRT-PCR) was performed to investigate the expression of SPRY4-IT1 in 48 breast cancer tissues and four breast cancer cell lines. Gain and loss of function approaches were used to investigate the biological role of SPRY4-IT1 in vitro. Microarray bioinformatics analysis was performed to identify the putative targets of SPRY4-IT1, which were further verified by rescue experiments, and by western blotting and qRT-PCR. RESULTS: SPRY4-IT1 expression was significantly upregulated in 48 breast cancer tumor tissues comparedwith normal tissues. Additionally, increased SPRY4-IT1 expression was found to be associated with a larger tumor size and an advanced pathological stage in breast cancer patients. The knockdown of SPRY4-IT1 significantly suppressed proliferation and caused apoptosis of breast cancer cells in vitro. Furthermore, we discovered that ZNF703 was a target of SPRY4-IT1 and was downregulated by SPRY4-IT1 knockdown. Moreover, we provide the first demonstration that ZNF703 plays an oncogenic role in ER (-) breast carcinoma cells. CONCLUSIONS: SPRY4-IT1 is a novel prognostic biomarker and a potential therapeutic candidate for breast cancer. PMID- 25742953 TI - RNS60, a charge-stabilized nanostructure saline alters Xenopus Laevis oocyte biophysical membrane properties by enhancing mitochondrial ATP production. AB - We have examined the effects of RNS60, a 0.9% saline containing charge-stabilized oxygen nanobubble-based structures. RNS60 is generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. This study, implemented in Xenopus laevis oocytes, addresses both the electrophysiological membrane properties and parallel biological processes in the cytoplasm. Intracellular recordings from defolliculated X. laevis oocytes were implemented in: (1) air oxygenated standard Ringer's solution, (2) RNS60-based Ringer's solution, (3) RNS10.3 (TCP-modified saline without excess oxygen)-based Ringer's, and (4) ONS60 (saline containing high pressure oxygen without TCP modification)-based Ringer's. RNS60-based Ringer's solution induced membrane hyperpolarization from the resting membrane potential. This effect was prevented by: (1) ouabain (a blocker of the sodium/potassium ATPase), (2) rotenone (a mitochondrial electron transfer chain inhibitor preventing usable ATP synthesis), and (3) oligomycin A (an inhibitor of ATP synthase) indicating that RNS60 effects intracellular ATP levels. Increased intracellular ATP levels following RNS60 treatment were directly demonstrated using luciferin/luciferase photon emission. These results indicate that RNS60 alters intrinsic the electrophysiological properties of the X. laevis oocyte membrane by increasing mitochondrial-based ATP synthesis. Ultrastructural analysis of the oocyte cytoplasm demonstrated increased mitochondrial length in the presence of RNS60-based Ringer's solution. It is concluded that the biological properties of RNS60 relate to its ability to optimize ATP synthesis. PMID- 25742954 TI - Changes in myoplasmic Ca2+ during fatigue differ between FDB fibers, between glibenclamide-exposed and Kir6.2-/- fibers and are further modulated by verapamil. AB - One objective of this study was to document how individual FDB muscle fibers depend on the myoprotection of KATP channels during fatigue. Verapamil, a CaV1.1 channel blocker, prevents large increases in unstimulated force during fatigue in KATP-channel-deficient muscles. A second objective was to determine if verapamil reduces unstimulated [Ca(2+)]i in KATP-channel-deficient fibers. We measured changes in myoplasmic [Ca(2+)] ([Ca(2+)]i) using two KATP-channel-deficient models: (1) a pharmacological approach exposing fibers to glibenclamide, a channel blocker, and (2) a genetic approach using fibers from null mice for the Kir6.2 gene. Fatigue was elicited with one tetanic contraction every sec for 3 min. For all conditions, large differences in fatigue kinetics were observed from fibers which had greater tetanic [Ca(2+)]i at the end than at the beginning of fatigue to fibers which eventually completely failed to release Ca(2+) upon stimulation. Compared to control conditions, KATP-channel-deficient fibers had a greater proportion of fiber with large decreases in tetanic [Ca(2+)]i, fade and complete failure to release Ca(2+) upon stimulation. There was, however, a group of KATP-channel-deficient fibers that had similar fatigue kinetics to those of the most fatigue-resistant control fibers. For the first time, differences in fatigue kinetics were observed between Kir6.2(-/-) and glibenclamide-exposed muscle fibers. Verapamil significantly reduced unstimulated and tetanic [Ca(2+)]i. It is concluded that not all fibers are dependent on the myoprotection of KATP channels and that the decrease in unstimulated force by verapamil reported in a previous studies in glibenclamide-exposed fibers is due to a reduction in Ca(2+) load by reducing Ca(2+) influx through CaV1.1 channels between and during contractions. PMID- 25742955 TI - Slope walking causes short-term changes in soleus H-reflex excitability. AB - The purpose of this study was to test the hypothesis that downslope treadmill walking decreases spinal excitability. Soleus H-reflexes were measured in sixteen adults on 3 days. Measurements were taken before and twice after 20 min of treadmill walking at 2.5 mph (starting at 10 and 45 min post). Participants walked on a different slope each day [level (Lv), upslope (Us) or downslope (Ds)]. The tibial nerve was electrically stimulated with a range of intensities to construct the M-response and H-reflex curves. Maximum evoked responses (Hmax and Mmax) and slopes of the ascending limbs (Hslp and Mslp) of the curves were evaluated. Rate-dependent depression (RDD) was measured as the % depression of the H-reflex when measured at a rate of 1.0 Hz versus 0.1 Hz. Heart rate (HR), blood pressure (BP), and ratings of perceived exertion (RPE) were measured during walking. Ds and Lv walking reduced the Hmax/Mmax ratio (P = 0.001 & P = 0.02), although the reduction was larger for Ds walking (29.3 +/- 6.2% vs. 6.8 +/- 5.2%, P = 0.02). The reduction associated with Ds walking was correlated with physical activity level as measured via questionnaire (r = -0.52, P = 0.04). Us walking caused an increase in the Hslp/Mslp ratio (P = 0.03) and a decrease in RDD (P = 0.04). These changes recovered by 45 min. Exercise HR and BP were highest during Us walking. RPE was greater during Ds and Us walking compared to Lv walking, but did not exceed "Fairly light" for Ds walking. In conclusion, in healthy adults treadmill walking has a short-term effect on soleus H-reflex excitability that is determined by the slope of the treadmill surface. PMID- 25742956 TI - Rhythmic arm swing enhances patterned locomotor-like muscle activity in passively moved lower extremities. AB - The use of driven gait orthosis (DGO) has drawn attention in gait rehabilitation for patients after central nervous system (CNS) lesions. By imposing a passive locomotor-like kinematic pattern, the neural mechanisms responsible for locomotion can be activated as in a normal gait. To further enhance this activity, discussions on possible intervention are necessary. Given the possible functional linkages between the upper and lower limbs, we investigated in healthy subjects the degree of modification in the lower limb muscles during DGO-induced passive gait by the addition of swing movement in the upper extremity. The results clearly showed that muscle activity in the ankle dorsiflexor TA muscle was significantly enhanced when the passive locomotor-like movement was accompanied by arm swing movement. The modifications in the TA activity were not a general increase through the stride cycles, but were observed under particular phases as in normal gaits. Voluntary effort to swing the arms may have certain effects on the modification of the muscle activity. The results provide clinical implications regarding the usefulness of voluntary arm swing movement as a possible intervention in passive gait training using DGO, since ordinary gait training using DGO does not induce spontaneous arm swing movement despite its known influence on the lower limb movement. PMID- 25742957 TI - Differential expression and regional distribution of aquaporins in amnion of normal and gestational diabetic pregnancies. AB - The region of the amnion overlying the placenta plays an active role in fluid exchange between amniotic fluid and fetal blood perfusing the surface of the placenta, whereas little transfer occurs across the reflected amnion that contacts the membranous chorion. Because aquaporins (AQPs) facilitate rapid movement of water across cells, we hypothesized that AQP gene expression in placental amnion is higher than in reflected amnion. Furthermore, because gestational diabetes mellitus (GDM) is often associated with polyhydramnios, we hypothesized that amnion AQP gene expression is reduced when amniotic fluid volume is elevated. Human placental and reflected amnion were obtained at cesarean delivery and subjected to relative quantitation of AQP mRNA by real-time RT-qPCR and proteins by western immunoblot. Amnion mRNA levels of five AQPs differed by up to 400-fold (P < 0.001), with AQP1 and AQP3 most abundant, AQP8 least and AQP9 and AQP11 intermediately expressed. Aquaporin proteins showed a similar profile. Aquaporin mRNA abundance was higher (P < 0.001) in placental than reflected amnion, whereas protein levels were lower (P < 0.01). In GDM pregnancies, neither AQP mRNA nor protein levels were different from normal. There was no correlation between AQP mRNA or protein levels with the amniotic fluid index in normal or GDM subjects. We conclude that there is a strong differential expression profile among individual AQPs and between regions of the amnion. These findings suggest differences in contribution of individual AQPs to water transport in the two regions of the amnion. Furthermore, AQP expression in the amnion is not altered in patients with GDM. PMID- 25742958 TI - Significant association between glycemic status and increased estimated postglomerular resistance in nondiabetic subjects - study of inulin and para aminohippuric acid clearance in humans. AB - We investigated whether glomerular hemodynamic parameters in nondiabetic subjects, including healthy subjects, are associated with glycemic status indices, by simultaneous measurement of inulin (Cin) and para-aminohippuric acid (CPHA) clearance. Twenty-six subjects (age 49.5 +/- 13.3 years; 13 men and 13 women; 14 healthy subjects and 12 subjects with mild proteinuria) were enrolled. Cin and CPAH were measured simultaneously. All 26 subjects were nondiabetics. Estimated preglomerular resistance, estimated postglomerular resistance, and estimated glomerular hydrostatic pressure (Pglo) were calculated according to Gomez' formula. Pglo correlated significantly and positively with hemoglobin A1c (HbA1c) in both healthy subjects (r = 0.532, P = 0.0498) and subjects with mild proteinuria (r = 0.681, P = 0.015). While there was no significant correlation between estimated preglomerular resistance and HbA1c, estimated postglomerular resistance correlated significantly and positively with HbA1c both in healthy subjects (r = 0.643, P = 0.013) and subjects with mild proteinuria (r = 0.589, P = 0.044). Glomerular filtration fraction, estimated Pglo and estimated postglomerular resistance in total subjects were associated significantly with HbA1c after adjustment for age, gender, and body mass index. These results demonstrate that, even in nondiabetic subjects, glycemic status is associated with estimated postglomerular resistance, but not estimated preglomerular resistance. It is suggested that increased estimated postglomerular resistance associated with higher HbA1c levels, even within the normal range, causes increased estimated Pglo, leading to increased FF. Thus, hemodynamic abnormalities associated with higher HbA1c levels may be related to glomerular hypertension, even in nondiabetic subjects. PMID- 25742959 TI - Activity in descending dopaminergic neurons represents but is not required for leg movements in the fruit fly Drosophila. AB - Modulatory descending neurons (DNs) that link the brain to body motor circuits, including dopaminergic DNs (DA-DNs), are thought to contribute to the flexible control of behavior. Dopamine elicits locomotor-like outputs and influences neuronal excitability in isolated body motor circuits over tens of seconds to minutes, but it remains unknown how and over what time scale DA-DN activity relates to movement in behaving animals. To address this question, we identified DA-DNs in the Drosophila brain and developed an electrophysiological preparation to record and manipulate the activity of these cells during behavior. We find that DA-DN spike rates are rapidly modulated during a subset of leg movements and scale with the total speed of ongoing leg movements, whether occurring spontaneously or in response to stimuli. However, activating DA-DNs does not elicit leg movements in intact flies, nor do acute bidirectional manipulations of DA-DN activity affect the probability or speed of leg movements over a time scale of seconds to minutes. Our findings indicate that in the context of intact descending control, changes in DA-DN activity are not sufficient to influence ongoing leg movements and open the door to studies investigating how these cells interact with other descending and local neuromodulatory inputs to influence body motor output. PMID- 25742960 TI - Remote ischemic preconditioning delays the onset of acute mountain sickness in normobaric hypoxia. AB - Acute mountain sickness (AMS) is a neurological disorder occurring when ascending too fast, too high. Remote ischemic preconditioning (RIPC) is a noninvasive intervention protecting remote organs from subsequent hypoxic damage. We hypothesized that RIPC protects against AMS and that this effect is related to reduced oxidative stress. Fourteen subjects were exposed to 18 hours of normoxia (21% oxygen) and 18 h of normobaric hypoxia (12% oxygen, equivalent to 4500 m) on different days in a blinded, randomized order. RIPC consisted of four cycles of lower limb ischemia (5 min) and 5 min of reperfusion, and was performed immediately before the study room was entered. A control group was exposed to hypoxia (12% oxygen, n = 14) without RIPC. AMS was evaluated by the Lake Louise score (LLS) and the AMS-C score of the Environmental Symptom Questionnaire. Plasma concentrations of ascorbate radicals, oxidized sulfhydryl (SH) groups, and electron paramagnetic resonance (EPR) signal intensity were measured as biomarkers of oxidative stress. RIPC reduced AMS scores (LLS: 1.9 +/- 0.4 vs. 3.2 +/- 0.5; AMS-C score: 0.4 +/- 0.1 vs. 0.8 +/- 0.2), ascorbate radicals (27 +/- 7 vs. 65 +/- 18 nmol/L), oxidized SH groups (3.9 +/- 1.4 vs. 14.3 +/- 4.6 MUmol/L), and EPR signal intensity (0.6 +/- 0.2 vs. 1.5 +/- 0.4 * 10(6)) after 5 h in hypoxia (all P < 0.05). After 18 hours in hypoxia there was no difference in AMS and oxidative stress between RIPC and control. AMS and plasma markers of oxidative stress did not correlate. This study demonstrates that RIPC transiently reduces symptoms of AMS and that this effect is not associated with reduced plasma levels of reactive oxygen species. PMID- 25742961 TI - Heterogeneity in [18F]fluorodeoxyglucose positron emission tomography/computed tomography of non-small cell lung carcinoma and its relationship to metabolic parameters and pathologic staging. AB - To investigate the relationships between tumor heterogeneity, assessed by texture analysis of [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) images, metabolic parameters, and pathologic staging in patients with non-small cell lung carcinoma (NSCLC). A retrospective analysis of 38 patients with histologically confirmed NSCLC who underwent staging FDG-PET/computed tomography was performed. Tumor images were segmented using a standardized uptake value (SUV) cutoff of 2.5. Five textural features, related to the heterogeneity of gray level distribution, were computed (energy, entropy, contrast, homogeneity, and correlation). Additionally, metabolic parameters such as SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG), as well as pathologic staging, histologic subtype, and tumor diameter, were obtained. Finally, a correlation analysis was carried out. Of 38 tumors, 63.2% were epidermoid and 36.8% were adenocarcinomas. The mean +/- standard deviation values of MTV and TLG were 30.47 +/- 25.17 mL and 197.81 +/- 251.11 g, respectively. There was a positive relationship of all metabolic parameters (SUVmax, SUVmean, MTV, and TLG) with entropy, correlation, and homogeneity and a negative relationship with energy and contrast. The T component of the pathologic TNM staging (pT) was similarly correlated with these textural parameters. Textural features associated with tumor heterogeneity were shown to be related to global metabolic parameters and pathologic staging. PMID- 25742963 TI - Optical probes for the detection of protons, and alkali and alkaline earth metal cations. AB - Luminescent sensors and switches continue to play a key role in shaping our understanding of key biochemical processes, assist in the diagnosis of disease and contribute to the design of new drugs and therapies. Similarly, their contribution to the environment cannot be understated as they offer a portable means to undertake field testing for hazardous chemicals and pollutants such as heavy metals. From a physiological perspective, the Group I and II metal ions are among the most important in the periodic table with blood plasma levels of H(+), Na(+) and Ca(2+) being indicators of several possible disease states. In this review, we examine the progress that has been made in the development of luminescent probes for Group I and Group II ions as well as protons. The potential applications of these probes and the mechanism involved in controlling their luminescent response upon analyte binding will also be discussed. PMID- 25742962 TI - NKX2-5 mutations in an inbred consanguineous population: genetic and phenotypic diversity. AB - NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2 5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population. PMID- 25742964 TI - Diagnosis and management of asthma in children. PMID- 25742965 TI - Body mass index and progressive hand osteoarthritis: data from the Oslo hand osteoarthritis cohort. AB - OBJECTIVES: Few longitudinal studies have studied the association between body mass index (BMI) and hand osteoarthritis (OA). We aimed to explore the association between BMI and progressive hand OA in a longitudinal study of the Oslo hand OA cohort. METHOD: Participants with existing hand OA had hand radiographs and BMI data taken at baseline and 7-year follow-up (n = 103). The radiographs were read according to the Kellgren-Lawrence (KL) scale. First, we examined the association between baseline BMI and incident OA (KL grade >= 2) in joints without OA at baseline (adjusted for age and sex) using generalized estimating equation (GEE) analyses. Second, we examined whether changes in BMI from baseline to follow-up were associated with increasing KL sum score from baseline to follow-up using linear regression. We repeated the analyses using changes in number of joints with symptomatic OA and patient-reported pain and physical function as the outcome. RESULTS: The mean (SD) age at baseline was 61.6 (5.6) years and 91 (94%) of the cohort were women. The mean (SD) BMI was 25.7 (4.0) kg/m(2) at baseline and the mean (SD) BMI change was 1.1 (2.0) kg/m(2). There was no relationship between baseline BMI and development of more joints with OA during follow-up. Similarly, there was no association between change in BMI and hand OA progression, increasing hand pain or disability. CONCLUSIONS: In the Oslo hand OA cohort, higher BMI was not related to hand OA progression. PMID- 25742966 TI - Contralateral acute lower limb ischaemia following total hip replacement in a patient with an endovascular abdominal aortic aneurysm repair. AB - Total hip replacement (THR) is a common procedure to treat patients with a fractured neck of femur. Ipsilateral major vessel injury with acute lower limb ischaemia is a rare but potentially devastating complication. Contralateral acute limb ischaemia is unreported. We present the case of a contralateral, acute lower limb ischaemia following THR for a fractured neck of femur in the presence of an endovascular aortic aneurysm repair (EVAR) and femoro-femoral crossover grafts. We advise early vascular surgery consultation for patients undergoing THR with an EVAR stentgraft in situ to help minimize risks of peri- and postoperative graft occlusion and consequent acute lower limb ischaemia. PMID- 25742967 TI - Atypical fibroxanthoma?. AB - Atypical fibroxanthoma (AFX) is a rare skin neoplasm of low-grade malignancy and fibroblastic origin. AFX is a curable cutaneous disease and the diagnosis depends on knowledge of its clinical and histological features and combined immunohistochemistry markers. This study presents a case of a male patient, aged 90 years, presented with painless skin lesion in his ear. The lesion had been growing progressively for 2 months, measured ~1.5 cm, ulcerated, fixed and firm. After a biopsy, the patient underwent a complete resection with adequate surgical margins and showed favorable evolution without complications or recurrence. The histopathological evaluation showed a poorly circumscribed ulcerated dermal nodule, mesenchymal proliferation, with pleomorphic spindle cells. There was infiltration of the deep dermis and subcutis, showing malignant features, but there was no invasion of cartilage. The immunohistochemical analysis confirmed the diagnosis of AFX. PMID- 25742968 TI - Laparoscopic-assisted endoscopic retrograde cholangiopancreatography post bariatric surgery: how to overcome the technical challenges. AB - The prevalence of bariatric surgery is increasing worldwide and as a direct consequence, there shall be an increasing number of patients presenting with the complications of bariatric surgery, often to non-specialist units. The authors report a case of a 42-year-old Caucasian female who had previous laparoscopic Roux-en-Y gastric bypass, open cholecystectomy and abdominoplasty presenting with right upper quadrant pain in keeping with retained common bile duct stones. After the failure of conservative management, a laparoscopic-assisted transgastric endoscopic retrograde changiopancreatography and sphincterotomy was performed. We shall be describing our technique. PMID- 25742969 TI - Ocular disease in the cobalamin C defect: a review of the literature and a suggested framework for clinical surveillance. AB - The association between combined methylmalonic acidemia and homocystinuria of cblC type (cobalamin C defect, cblC) and ocular disease is now well recognized, and is a significant component of morbidity and disability associated with the condition. In this review, through collation of historically reported cases of early- and late-onset cblC and previously unreported cases, we have attempted to characterize the epidemiology, clinical features, and pathomechanisms of individual ocular features of cblC. These data suggest that maculopathy and nystagmus with abnormal vision are extremely common and affect the majority of children with early-onset cblC, usually before school age; strabismus and optic atrophy are also seen at relatively high frequency. The timing of progression of macular disease may coincide with a critical period of postnatal foveal development. Maculopathy and retinal disease may be subclinical and show only partial correlation with the extent of visual deficits, and visual deterioration may be relentlessly progressive in spite of aggressive treatment of biochemical abnormalities. In later-onset forms of the disease, visual loss and ocular complications appear to be infrequent. Finally, we discuss investigational strategies in diagnosing and characterizing eye disease in individuals with cblC, explore possible therapeutic avenues that may attenuate progression and severity of eye disease, and propose a clinical surveillance guideline for monitoring progression of ocular disease in children and adults with cblC. PMID- 25742970 TI - Characterization of a nitrilase from Arthrobacter aurescens CYC705 for synthesis of iminodiacetic acid. AB - A nitrilase gene cyc705 from Arthrobacter aurescens CYC705 for synthesis of iminodiacetic acid (IDA) was cloned. This gene contained a 930 bp ORF, which encoded a polypeptide of 310 amino acids. A recombinant Escherichia coli BL21(DE3)/pET28a-cyc705 was constructed to achieve the heterologous expression of cyc705. This recombinant nitrilase was purified to homogeneity with a molecular weight of 36.7 kDa on SDS-PAGE and mass spectrometry, and characterized to be an oligomer of 14 subunits by gel permeation chromatography. Using iminodiacetonitrile (IDAN) as the substrate, the Vmax, Km, kcat and kcat/Km were 9.05 U mg(-1), 43.17 mM(-1), 94.1 min(-1) and 2.18*10(3) min(-1) M(-1), respectively. The optimum temperature and pH were 25 degrees C and 5.8. The suitable substrates for the purified nitrilase were short-chain aliphatic dinitriles. High concentration of IDAN could be hydrolyzed to IDA in a shorter time. PMID- 25742971 TI - Characterization of some potentially probiotic Lactobacillus strains isolated from Iranian native chickens. AB - The objective of the present study was to isolate, identify and characterize new LAB strains with high probiotic potentials from Iranian (Isfahan) indigenous chickens. From 90 isolated LABs, 11 isolates had high growth rate under different stress conditions, including acid (pH 2.5), bile (0.5% oxgall), salt (6-15%) and temperatures 15 and 45 degrees C, and their aggregation time was less than 120 min. Based on the molecular identification using 16S rDNA sequencing and phylogenetic analysis, the isolates belonged to two Lactobacillus salivarius and L. reuteri species. The isolates showed different tolerance to 16 clinically and veterinary relevant antibiotics, and most of them were resistant to or semi tolerant of 7-15 different studied antibiotics. The Es11, Es12, Es3 and Es13 strains with resistance to or semi-tolerance of 15, 14 and 13 different antibiotics, respectively, were the most tolerant strains. The selected isolates showed a wide range of antimicrobial activity against 7 different pathogenic strains. All the isolates exhibited antagonistic activity against E. coli, Enterococcus hirae, Salmonella enterica and Staphylococcus aureus. The isolates Es6 and Es11 with high antagonistic activity and resistance against 6 of the studied pathogens were the most powerful antagonistic isolates. The values and types of adhesion to the Caco-2 cell cultures were significantly different (0-40 bacteria/Caco-2 cell), and the maximum adhesion was observed for the isolates Es6 and Es13 with 35 and 40 bacteria adhesion/cell, respectively. Finally, based on all the experiments, 7 strains, including Es1, Es6, Es7, Es11, Es12 and Es13, were selected for the further in vivo assays and possible use in the poultry industry. PMID- 25742972 TI - Short hairpin RNAs of designed sequences can be extracellularly produced by the marine bacterium Rhodovulum sulfidophilum. AB - Previously, we proposed a new method for production of RNA aptamers using the marine bacterium Rhodovulum sulfidophilum. A streptavidin RNA aptamer (an RNA which binds to streptavidin) was extracellularly produced by this bacterium containing engineered plasmid. The aptamer had full biological function. As a next step we attempted to produce another functional RNA, short hairpin RNAs (shRNAs) using this bacterial system. We have designed two types of shRNAs targeted to the luciferase gene. Here we report that shRNAs are successfully produced extracellularly by this system. Even if the shRNA has a long stem-loop structure which is thought to interfere with transcription in bacterial cells, the yield of the shRNA is almost the same as that of the streptavidin RNA aptamer. During the course of these experiments, we also found a new type of RNA processing for the double-stranded region of the shRNA. PMID- 25742973 TI - Pyrosequencing-based analysis of the bacterial community during fermentation of Alaska pollock sikhae: traditional Korean seafood. AB - We analyzed the bacterial community of Alaska pollock sikhae, a traditional Korean food made by natural fermentation with Alaska pollock, utilizing pyrosequencing. We fermented the Alaska pollock sikhae at two different temperatures (10 degrees C and 20 degrees C). Before fermentations, the bacterial community was varied. After fermentations, however, Lactobacillus sakei became dominant. The Alaska pollock sikhae sample before fermentations contained only 2% L. sakei, but the sample on day 6 of fermentation at 10 degrees C comprised 74% L. sakei (90% at 20 degrees C). In addition, we observed a reduction in the composition of unpreferred bacterial species for foods after fermentation. The composition of unpreferred bacterial species was more than 30% of total reads in samples before fermentation and decreased to less than 0.2% after fermentation. This result suggested that the fermentation of Alaska pollock sikhae can be beneficial for food safety. Alaska pollock sikhae might be a favorable habitat for L. sakei. Our study is the first report illustrating the alteration of the bacterial community of Alaska pollock sikhae during fermentation utilizing pyrosequencing analysis. PMID- 25742974 TI - Molecular cloning, sequence analysis and expression of a GHF 43 xylanase from Aspergillus niger in Escherichia coli. AB - A new xylanase gene (xyn43A) from Aspergillus niger XZ-3S was cloned and expressed in Escherichia coli BL21-CodonPlus (DE3)-RIL. The coding region of the gene was separated by only one intron 86 bp in length. It encoded 318 amino acid residues of a protein with a calculated molecular weight (MW) of 33.47 kDa plus a signal peptide of 19 amino acids. The amino acid sequence of the xyn43A gene showed 77.56% amino acid identity to A. nidulans xylanase, and the phylogenetic tree analysis revealed that xyn43A had close relationships with those of family 43 of glycosyl hydrolases reported from other microorganisms. Three-dimensional structure modeling showed that Xyn43A had a typical five-blade beta-propeller fold. The mature peptide encoding cDNA was subcloned into pET-28a (+) expression vector. The resultant recombinant plasmid pET-28a-xyn43A was transformed into Escherichia coli BL21-CodonPlus (DE3)-RIL, and xylanase activity was measured. A maximum activity of 61.43 U/mg was obtained from the cellular extract of E. coli BL21-CodonPlus (DE3)-RIL harboring pET-28a-xyn43A. The recombinant xylanase had optimal activity at pH5.0 and 45 degrees C. Fe(3+), Cu(2+) and EDTA had an obvious active effect on the enzyme. PMID- 25742975 TI - Vaccine efficacy of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Edwardsiella ictaluri against E. tarda in tilapia. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), derived from the outer-membrane protein (OMP) fraction, has been used as a potential candidate for vaccine development. The gene-encoding 37 kDa GAPDH outer membrane protein (OMP) from Edwardsiella ictaluri was amplified using polymerase chain reaction (PCR) and was cloned and expressed in Escherichia coli BL21 (DE3). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting, and nucleotide and amino acid sequencing were used to analyze the expressed antigenic protein and gene encoding this protein. Comparative DNA and protein sequence analysis of GAPDH from E. ictaluri GAPDHs from several Gram-negative bacterial species within the Enterobacteriaceae family revealed that the GAPDHs within this group are highly conserved and share a sequence similarity of 75-100% with E. ictaluri GDPDH. Rabbit antiserum raised against the E. ictaluri recombinant GAPDH (rGAPDH) protein recognized purified GADPH, indicating that it has a strong immunogenicity. Tilapia fish were intraperitoneally immunized with formalin killed E. ictaluri whole cells, and rGAPDH (30 MUg fish(-1)) from E. ictaluri, both of which were emulsified in ISA 763A adjuvant. At 3 months after immunization, fish were challenged with the E. tarda strain to assess vaccine efficacy; the relative percent survival (RPS) values were found to exceed 71.4%. The specific mean antibody titer log2 level of groups vaccinated with rGAPDH at 3 months was significantly higher than that of non-vaccinated fish (control group). Therefore, this recombinant protein can be considered a multi-purpose candidate vaccine against several pathogenic bacteria. PMID- 25742976 TI - Synergistic antimicrobial efficacy of mesoporous ZnO loaded with 4-(alpha-L rhamnosyloxy)-benzyl isothiocyanate isolated from the Moringa oleifera seed. AB - The antimicrobial activities of isolated compounds from seed extracts of Moringa oleifera and synergistic antimicrobial efficacy through hybridized complex of organic-inorganic composite materials were studied. The two main components of the Moringa oleifera seed were isolated and determined to be niazimicin and 4 (alpha-L-rhamnosyloxy)-benzyl isothiocyanate (RBI). The antimicrobial activity of the separated compounds of the Moringa oleifera seed were tested in vitro against 3 bacterial species and 2 fungal species by the paper disc diffusion assay and broth dilution methods. Both compounds showed antimicrobial activity against tested species and RBI was more effective than niazimicin. The MIC of RBI on S. aureus, E. coli, P. aeruginosa, C. albicans, and A. niger was 0.005%, 0.1%, 0.5%, 0.5%, and 0.5%, respectively, while the MIC of niazimicin on S. aureus was 0.1%. Next, we investigated the combined antimicrobial action of mesoporous ZnO and RBI by incorporating the compound within the pore of mesoporous ZnO. The MIC of mesoporous ZnO with RBI on S. aureus, E. coli, P. aeruginosa, C. albicans, and A. niger was 0.001%, 0.01%, 0.5%, 0.1%, and 0.1%, respectively. A synergistic effect of RBI with mesoporous ZnO was shown. From these results, the mesoporous ZnO could act as a reservoir for RBI and mesoporous ZnO with RBI could be used for cosmetic preservatives. PMID- 25742977 TI - Concentrated biosynthesis of tobramycin by genetically engineered Streptomyces tenebrarius. AB - Tobramycin is an important broad spectrum aminoglycoside antibiotic widely used against severe Gram-negative bacterial infections. It is produced by base catalyzed hydrolysis of carbamoyltobramycin (CTB) generated by S. tenebrarius. We herein report the construction of a genetically engineered S. tenebrarius for direct fermentative production of tobramycin by disruption of aprK and tobZ. A unique putative NDP-octodiose synthase gene aprK was disrupted to optimize the production of CTB, resulting in the blocking of apramycin biosynthesis and the obvious increase in CTB production of aprK disruption mutant S. tenebrarius ST316. Additional mutation on the carbamoyltransferase gene tobZ in S. tenebrarius ST316 generated a strain ST318 that produces tobramycin as a single metabolite. ST318 could be used for industrial fermentative production of tobramycin. PMID- 25742978 TI - Production of glucose oxidase and catalase by Aspergillus niger free and immobilized in alginate-polyvinyl alcohol beads. AB - The production of glucose oxidase (GOX) and catalase (CAT) by submerged fermentation of the free and immobilized xerophytic fungus Aspergillus niger under equal conditions was compared. To immobilize fungal spores, entrapment in PVA/alginate beads treated with NaNO3/CaCl2 was performed. The yield of immobilization in the beads with a diameter less than 1mm was equal to 100%. Fungus growth and substrate consumption were evaluated in both fermentation systems, demonstrating the lag-period presence in the case of the first cycle of immobilized fungus use. The enzyme production by immobilized fungus reuse was carried out. In these cases, greater enzymatic GOX activity was detected, while CAT activity decreased. SEM micrographs for the beads with immobilized fungus applied in the first and second fermentation cycles were obtained, presenting fungus spreading inside the sphere, spore presence and branching hyphae. Immobilization of A. niger on PVA/alginate beads is effective for GOX and CAT production at least on 2-3 repeated fermentative cycles. Thus, immobilization enables repeated use of microbial cells. PMID- 25742979 TI - Isolation of alkaliphilic bacteria for production of high optically pure L-(+) lactic acid. AB - Lactic acid bacteria that grow under alkaline conditions (pH 10) were isolated from various sources in Okinawa (Japan). These alkali-tolerant and alkaliphilic bacteria were classified as follows: Microbacterium sp. (1 strain), Enterococcus spp. (9 strains), Alkalibacterium spp. (3 strains), Exiguobacterium spp. (5 strains), Oceanobacillus spp. (3 strains) and Bacillus spp. (7 strains) by 16S rRNA gene sequencing. By fermentation, many strains were able to convert glucose into mainly L-(+)-lactic acid of high optical purity in alkaline broth. This result indicated that valuable L-(+)-lactic acid-producing bacteria could be isolated efficiently by screening under alkaline conditions. Six strains were selected and their ability to produce lactic acid at different initial pH was compared. Enterococcus casseliflavus strain 79w3 gave the highest lactic acid concentration. Lactic acid concentration and productivity were 103 g L(-1) (optical purity of 99.5% as L-isomer) and 2.2 g L(-1) h(-1), respectively when 129 g L(-1) of glucose was used by batch fermentation. PMID- 25742980 TI - Transcriptional analysis of genes encoding proteins significantly increased in Kitasatospora setae KM-6054(T) under submerged culture. PMID- 25742981 TI - Imaging biomarkers in ischemic stroke clinical trials: an opportunity for rigor. PMID- 25742982 TI - Validation of multisociety combined task force definitions of abnormal disk morphology. AB - BACKGROUND AND PURPOSE: The multisociety task force descriptively defined abnormal lumbar disk morphology. We aimed to use their definitions to provide a higher level of evidence for the validation of MR imaging in the evaluation of this pathology in patients who have undergone diskectomy by retrospectively classifying their preoperative MRI. MATERIALS AND METHODS: This retrospective, institutional review board-approved study included 54 of 86 consecutive patients (47 men; average age, 44 years) enrolled in an ongoing prospective trial of surgically treated lumbar disk herniation who had preoperative MRI and documented intraoperative classification of the abnormal disk as protrusion, extrusion, or sequestration by the treating surgeon. Preoperative MRI was classified by 2 blinded radiologists; discrepancies were resolved by a third reader. Statistical analysis of interobserver agreement and imaging compared with surgical findings was performed. RESULTS: The readers disagreed on only 1 of the 54 cases. The third reader resolved the disagreement. Eight protrusions and 46 extrusions were found on imaging, with no sequestrations. At surgery, there were 13 protrusions and 40 extrusions, with 2 of the extrusions also containing sequestrations; the remaining case had only sequestration. There were 16 discrepancies between imaging and surgery, resulting in 70% agreement. CONCLUSIONS: This study, which was intended to validate the multisociety combined task force definitions of abnormal disk morphology by using MR imaging with a surgical criterion standard, found 70% agreement between imaging diagnosis and surgical findings. Although reasonable, this finding highlights differences that often exist between intraoperative and preoperative imaging findings of lumbar disk herniation. PMID- 25742983 TI - Narrowing the Expertise Gap for Predicting Intracranial Aneurysm Hemodynamics: Impact of Solver Numerics versus Mesh and Time-Step Resolution. AB - BACKGROUND AND PURPOSE: Recent high-resolution computational fluid dynamics studies have uncovered the presence of laminar flow instabilities and possible transitional or turbulent flow in some intracranial aneurysms. The purpose of this study was to elucidate requirements for computational fluid dynamics to detect these complex flows, and, in particular, to discriminate the impact of solver numerics versus mesh and time-step resolution. MATERIALS AND METHODS: We focused on 3 MCA aneurysms, exemplifying highly unstable, mildly unstable, or stable flow phenotypes, respectively. For each, the number of mesh elements was varied by 320* and the number of time-steps by 25*. Computational fluid dynamics simulations were performed by using an optimized second-order, minimally dissipative solver, and a more typical first-order, stabilized solver. RESULTS: With the optimized solver and settings, qualitative differences in flow and wall shear stress patterns were negligible for models down to ~800,000 tetrahedra and ~5000 time-steps per cardiac cycle and could be solved within clinically acceptable timeframes. At the same model resolutions, however, the stabilized solver had poorer accuracy and completely suppressed flow instabilities for the 2 unstable flow cases. These findings were verified by using the popular commercial computational fluid dynamics solver, Fluent. CONCLUSIONS: Solver numerics must be considered at least as important as mesh and time-step resolution in determining the quality of aneurysm computational fluid dynamics simulations. Proper computational fluid dynamics verification studies, and not just superficial grid refinements, are therefore required to avoid overlooking potentially clinically and biologically relevant flow features. PMID- 25742984 TI - Disrupted Global and Regional Structural Networks and Subnetworks in Children with Localization-Related Epilepsy. AB - BACKGROUND AND PURPOSE: Structural connectivity has been thought to be a less sensitive measure of network changes relative to functional connectivity in children with localization-related epilepsy. The aims of this study were to investigate the structural networks in children with localization-related epilepsy and to assess the relation among structural connectivity, intelligence quotient, and clinical parameters. MATERIALS AND METHODS: Forty-five children with nonlesional localization-related epilepsy and 28 healthy controls underwent DTI. Global network (network strength, clustering coefficient, characteristic path length, global efficiency, and small-world parameters), regional network (nodal efficiency), and the network-based statistic were compared between patients and controls and correlated with intelligence quotient and clinical parameters. RESULTS: Patients showed disrupted global network connectivity relative to controls, including reduced network strength, increased characteristic path length and reduced global efficiency, and reduced nodal efficiency in the frontal, temporal, and occipital lobes. Connectivity in multiple subnetworks was reduced in patients, including the frontal-temporal, insula-temporal, temporal-temporal, frontal-occipital, and temporal-occipital lobes. The frontal lobe epilepsy subgroup demonstrated more areas with reduced nodal efficiency and more impaired subnetworks than the temporal lobe epilepsy subgroup. Network parameters were not significantly associated with intelligence quotient, age at seizure onset, or duration of epilepsy. CONCLUSIONS: We found disruption in global and regional networks and subnetworks in children with localization-related epilepsy. Regional efficiency and subnetworks were more impaired in frontal lobe epilepsy than in temporal lobe epilepsy. Future studies are needed to evaluate the implications of disrupted networks for surgical resection and outcomes for specific epileptogenic zones and the relation of disrupted networks to more complex cognitive function. PMID- 25742985 TI - Enhanced axonal metabolism during early natalizumab treatment in relapsing remitting multiple sclerosis. AB - BACKGROUND AND PURPOSE: The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging. MATERIALS AND METHODS: In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-beta or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter. RESULTS: At baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-beta/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased. CONCLUSIONS: Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism. PMID- 25742986 TI - Different spectral hounsfield unit curve and high-energy virtual monochromatic image characteristics of squamous cell carcinoma compared with nonossified thyroid cartilage. AB - BACKGROUND AND PURPOSE: The attenuation of normal nonossified thyroid cartilage can be similar to that of head and neck squamous cell carcinoma on CT. We compared dual-energy CT spectral Hounsfield unit attenuation characteristics of nonossified thyroid cartilage with that of squamous cell carcinoma to determine the optimal virtual monochromatic image reconstruction energy levels for distinguishing tumor from normal nonossified thyroid cartilage. MATERIALS AND METHODS: Dual-energy CT scans from 30 patients with histopathology-proved squamous cell carcinoma at different primary sites (laryngeal and nonlaryngeal) and 10 healthy patients were evaluated. Patients were scanned with a 64-section single-source scanner with fast-kilovolt (peak) switching, and scans were reconstructed at different virtual monochromatic energy levels ranging from 40 to 140 keV. Spectral attenuation curves of tumor and nonossified thyroid cartilage were quantitatively evaluated and compared. Any part of the tumor invading the cartilage, when present, was excluded from ROI analysis to avoid cross contamination from areas where there could be a mixture of cartilage and invading tumor. RESULTS: Normal nonossified thyroid cartilage had a characteristic, predictable spectral attenuation curve that was different from that of tumors. The greatest difference in attenuation of nonossified cartilage compared with tumor was on virtual monochromatic images of >=95 keV (P < .0001), with sharp contrast between the relatively high attenuation of nonossified cartilage compared with that of tumor. CONCLUSIONS: Head and neck squamous cell carcinoma has significantly different attenuation on virtual monochromatic images of >=95 keV, compared with nonossified thyroid cartilage. PMID- 25742987 TI - Teaching Lessons by MR CLEAN. PMID- 25742988 TI - MR imaging-detected carotid plaque hemorrhage is stable for 2 years and a marker for stenosis progression. AB - BACKGROUND AND PURPOSE: MR imaging-detected carotid plaque hemorrhage is associated with an increased risk of recurrent ischemic cerebrovascular events and could be an indicator of disease progression; however, there are limited data regarding the dynamics of the MR imaging-detected carotid plaque hemorrhage signal. We assessed the temporal change of this signal and its impact on carotid disease progression. MATERIALS AND METHODS: Thirty-seven symptomatic patients with 54 carotid stenoses of >30% on sonography underwent serial MR imaging during 24 months. A signal-intensity ratio of >1.5 between the carotid plaque and adjacent muscle was defined as plaque hemorrhage, and a change in signal intensity ratio of >0.31 between time points was considered significant. Sixteen patients underwent >=2 carotid sonography scans to determine the peak systolic velocities and degree of stenosis with time. RESULTS: Of the 54 carotids, 28 had the presence of hyperintense signal on an MR imaging sequence (PH+) and 26 had the absence of hyperintense signal on an MR imaging sequence (PH-) at baseline. The signal-intensity ratio was stable in 33/54 carotid plaques, but 39% showed a change. Plaque hemorrhage classification did not change in 87% of carotid plaques, but 4 became PH+, and 3, PH-. As a group, PH+ carotids did not change significantly in signal-intensity ratio (P = .585), whereas PH- showed an increased signal-intensity ratio at 24.5 months (P = .02). In PH+ plaques, peak systolic velocities significantly increased by 22 +/- 39.8 cm/s from baseline to last follow-up sonography (Z = 2.427, P = .013). CONCLUSIONS: During 2 years, MR imaging-detected carotid plaque hemorrhage status remained stable in most (87%) cases with 4 (7%) incident plaque hemorrhages. PH+ plaques were associated with increased flow velocity during the follow-up period. PMID- 25742989 TI - We know now: Mavridis atrophy is associated with cognitive impairment in Parkinson disease. PMID- 25742990 TI - A dual-process perspective on fluency-based aesthetics: the pleasure-interest model of aesthetic liking. AB - In this article, we develop an account of how aesthetic preferences can be formed as a result of two hierarchical, fluency-based processes. Our model suggests that processing performed immediately upon encountering an aesthetic object is stimulus driven, and aesthetic preferences that accrue from this processing reflect aesthetic evaluations of pleasure or displeasure. When sufficient processing motivation is provided by a perceiver's need for cognitive enrichment and/or the stimulus' processing affordance, elaborate perceiver-driven processing can emerge, which gives rise to fluency-based aesthetic evaluations of interest, boredom, or confusion. Because the positive outcomes in our model are pleasure and interest, we call it the Pleasure-Interest Model of Aesthetic Liking (PIA Model). Theoretically, this model integrates a dual-process perspective and ideas from lay epistemology into processing fluency theory, and it provides a parsimonious framework to embed and unite a wealth of aesthetic phenomena, including contradictory preference patterns for easy versus difficult-to-process aesthetic stimuli. PMID- 25742991 TI - In situ characterization of uranium and americium oxide solid solution formation for CRMP process: first combination of in situ XRD and XANES measurements. AB - Transmutation of americium in heterogeneous mode through the use of U1-xAmxO2+/ delta ceramic pellets, also known as Americium Bearing Blankets (AmBB), has become a major research axis. Nevertheless, in order to consider future large scale deployment, the processes involved in AmBB fabrication have to minimize fine particle dissemination, due to the presence of americium, which considerably increases the risk of contamination. New synthesis routes avoiding the use of pulverulent precursors are thus currently under development, such as the Calcined Resin Microsphere Pelletization (CRMP) process. It is based on the use of weak acid resin (WAR) microspheres as precursors, loaded with actinide cations. After two specific calcinations under controlled atmospheres, resin microspheres are converted into oxide microspheres composed of a monophasic U1-xAmxO2+/-delta phase. Understanding the different mechanisms during thermal conversion, that lead to the release of organic matter and the formation of a solid solution, appear essential. By combining in situ techniques such as XRD and XAS, it has become possible to identify the key temperatures for oxide formation, and the corresponding oxidation states taken by uranium and americium during mineralization. This paper thus presents the first results on the mineralization of (U,Am) loaded resin microspheres into a solid solution, through in situ XAS analysis correlated with HT-XRD. PMID- 25742992 TI - Fatal fungemia with Scedosporium prolificans in a patient with acute myeloid leukemia. AB - Scedosporium prolificans (S. prolificans) is a type of mold, which rarely affects immunocompromised people. We treated a 71-year-old woman with acute myeloid leukemia (AML-M5a) with low-dose cytarabine, acralubicin, and filgrastim as the induction therapy. On day 7 after the initiation of chemotherapy, she became febrile and agranulocytic, and developed anal pain ; therefore, we discontinued the chemotherapy on day 8. Broad-spectrum antibiotics, micafungin, and then liposomal amphotericin B were ineffective. The serum concentration of beta-D glucan was 525 pg/mL. She died of multiple organ failure on day 17. S. prolificans was detected from the blood culture on day 13. Physicians should consider Scedosporium spp. infection when principal antifungal agents are ineffective and fungal infection is strongly suspected. PMID- 25742993 TI - Superficial mycosis. PMID- 25742994 TI - [Oral health care by utilizing food function]. AB - We examined the effects of spices and herbs on Candida albicans to develop therapeutic tools against oral diseases such as oral candidiasis. C. albicans, a dimorphic fungus, is a component of the healthy human microbial flora. However, the excessive overgrowth of C. albicans causes oral candidiasis, and the symptoms, accompanied by severe inflammation, reduce the quality of life of elderly people. We found that spices such as clove (Syzygium aromaticum) and cassia (Cinnamomum aromaticum) exhibit inhibitory activity against Candida mycelial growth and show therapeutic efficacy in a murine oral candidiasis model. Our studies also demonstrated that the inhibitory activity of cinnamaldehyde was strengthened in parallel with a prolonged treatment time. Furthermore, when cinnamaldehyde in combination with methylcellulose was administered to the model mice, the therapeutic effect was potentiated. Here, we summarize up-to-date findings on how to use spices and herbs on a daily basis to improve or prevent oral problems such as oral candidiasis with the presentation of our recent data. PMID- 25742995 TI - [Phaeomycotic cyst caused by Exophiala xenobiotica in a patient with rheumatoid arthritis and lung cancer]. AB - In black fungal infections, Exophiala species are frequently encountered as causative agents of human mycosis, particularly in immunocompromised patients. Among them, Exophiala jenselmei was previously reported as the most common etiological agent. Advances in molecular taxonomy proved this taxon to be heterogeneous, and led to newly introduced or redefined species. Exophiala xenobiotica is one of the novel species differentiated from E. jenselmei on the basis of molecular phylogeny.Here, we report a case of pheomycotic cyst caused by E. xenobiotica, which was well controlled via drainage and local thermotherapy. A 70-year-old man developed a cystic nodular lesion on the dorsum of his right thumb over the previous 3 months. He had been treated with prednisolone and methotrexate for 4 years for rheumatoid arthritis. The patient also had lung cancer with vertebral bone metastasis. Direct microscopic examination of the greenish pus aspirated from the cyst revealed mycelial elements. Culture of the pus on blood and Sabouraud dextrose agar yielded numerous black colonies multiple times. Histopathological examination of a biopsy specimen showed subcutaneous abscess formation surrounded by granulomatous tissues. Faintly pigmented pseudohyphae were seen within the abscess. The presence of melanin in the fungal cells was determined by Fontana-Masson staining. Initial microscopic examination of the isolate revealed annellidic conidiogenous cells, suggestive of E. jenselmei. This strain was further identified as E. xenobiotica by sequence analysis of the internal transcribed spacer (ITS) region of ribosomal RNA, showing a 100% sequence homology with the strain type.Pheomycotic cysts should be considered on identifying a slowly developing chronic subcutaneous abscess in immunocompromised patients. Sequencing is recommended for accurate species identification of causative pathogens. PMID- 25742997 TI - Terminology. PMID- 25742996 TI - [In vitro antifungal activity of ravuconazole against isolates of dermatophytes and Candida species from patients with dermatomycoses]. AB - The in vitro activity of ravuconazole (RVCZ) was compared with those of itraconazole (ITCZ) and terbinafine (TBF) against 73 dermatophyte isolates and 18 Candida spp. isolates recovered from patients with dermatomycosis at 4 dermatological clinics in Japan in 2011. The dermatophyte isolates consisted of Trichophyton rubrum (n=51), Trichophyton mentagrophytes (n=20 : these strains were not identified by molecular phylogenetic analysis.), Trichophyton tonsurans (n=1), and Microsporum canis (n=1). The Candida spp. isolates comprised C. albicans (n=11), C. parapsilosis (n=5), C. guilliermondii (n=1), and C. pseudohaemulonii (n=1). RVCZ was highly active against all dermatophytes and all Candida spp. : the geometric mean (GM) MICs for T. rubrum and T. mentagrophytes were 0.035 MUg/mL and MICs for T. tonsurans and M. canis were <= 0.03 MUg/mL, and GM MICs for C. albicans and C. parapsilosis were <= 0.03 MUg/mL and MICs for C. guilliermondii and C. pseudohaemulonii were 0.25 and <= 0.03 MUg/mL, respectively. Compared to RVCZ, ITCZ showed similar anti-dermatophytic and anti Candida activities, while TBF had a slightly higher anti-dermatophytic but a markedly lower anti-Candida activity. These results suggest that RVCZ is a potential candidate systemic antifungal therapy against onychomycosis and other dermatomycoses that are refractory to topical antifungal therapy. PMID- 25742998 TI - Relationship between esophageal cardiac glands and gastroesophageal reflux disease. AB - OBJECTIVE: The role of esophageal cardiac glands has not been fully determined. This study was performed to clarify the protective role of esophageal cardiac glands against the development of gastroesophageal reflux disease (GERD). METHODS: The subjects included 2,656 Japanese individuals who visited our institution for a detailed medical checkup. GERD symptoms were assessed using the Japanese version of the Carlsson-Dent self-administered questionnaire (QUEST) and an upper gastrointestinal endoscopy examination in each subject. The presence of reflux esophagitis, size of diaphragmatic hiatus, degree of gastric mucosal atrophy and existence of visible esophageal cardiac glands in the distal esophagus, based on the detection of yellowish elevated areas, were determined using endoscopy. RESULTS: Esophageal cardiac glands were observed in 355 cases (13.4%). Reflux esophagitis was significantly less frequent in the cases with esophageal cardiac glands than in those without. The esophageal cardiac glands were mainly located on the left-posterior side of the esophageal wall of the distal esophagus. A multiple regression analysis showed that the presence of esophageal cardiac glands was an independent factor for preventing reflux esophagitis. On the other hand, the existence of these glands did not correlate with the presence of GERD symptoms (QUEST score of 6 or more). CONCLUSION: The presence of visible esophageal cardiac glands may have a protective role against the development of reflux esophagitis. PMID- 25742999 TI - Characteristics of refractory gastroesophageal reflux disease (GERD) symptoms -is switching proton pump inhibitors based on the patient's CYP2C19 genotype an effective management strategy? AB - OBJECTIVE: We investigated factors related to proton pump inhibitor (PPI) refractory gastroesophageal reflux disease (GERD) symptoms, particularly with respect to acid, the CYP2C19 genotype and psychological aspects. METHODS: Patients with an Frequency Scale for the Symptoms of GERD (FSSG) score of >=8 after the initial treatment were switched to therapy with rabeprazole at a dose of 20 mg once daily for eight weeks. We investigated the rate of improvement in PPI-refractory GERD symptoms, background factors, the Hospital Anxiety and Depression Scale (HADS) score and the CYP2C19 genotype. Patients Sixty patients endoscopically diagnosed with reflux esophagitis within the past six months who had received omeprazole at a dose of 20 mg once daily for eight weeks or longer were enrolled. RESULTS: In 71.6% of the patients, the FSSG score decreased to <8 after treatment with omeprazole at a dose of 20 mg once daily for >=8 weeks, resulting in improvements in their GERD symptoms. Significant factors related to omeprazole-refractory GERD symptoms included a longer disease duration (p=0.0004) and higher HADS score (p=0.01). Among the omeprazole-refractory cases, only 23.5% of the patients showed symptom improvement after switching to rabeprazole. There were no significant differences in the average scores for FSSG (p=0.089) or HADS (p=0.182), before or after the drug change. A total of 92% of the rabeprazole poor responders were homo/hetero extensive metabolizers for the CYP2C19 genotype. CONCLUSION: Our findings suggest that switching the PPI from omeprazole (20 mg once daily) to rabeprazole (20 mg once daily) is not a significant effective therapeutic strategy for improving PPI-refractory GERD symptoms, taking into consideration possible psychometric factors and patients who require stronger acid suppression than that achieved with a double dose of PPIs for PPI-refractory GERD symptoms. PMID- 25743000 TI - Incidence of hepatocellular carcinoma reduced by phlebotomy treatment in patients with chronic hepatitis C. AB - OBJECTIVE: To determine the impact of phlebotomy on the laboratory values and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. METHODS: Study patients with chronic hepatitis C were treated with glycyrrhizin injection and oral ursodeoxycholic acid and either with (n=52) or without (n=50) phlebotomy during the period of 2005-2012. Six phlebotomized patients had previously received interferon therapy and were subsequently excluded from the data analysis. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, lactate dehydrogenase, ferritin, iron and albumin, as well as the hemoglobin concentration, platelet count and prothrombin time, were determined. We compared the long-term outcomes based on the incidence of HCC and laboratory values, including the baseline serum ferritin levels, in patients treated with versus without phlebotomy. RESULTS: In the phlebotomy group, the mean AST and ALT levels decreased significantly at each one-year interval over five years (p<0.01), whereas the platelet counts did not. The incidence of HCC in the phlebotomized patients was significantly lower than that observed in the patients treated without phlebotomy: 10.3% vs. 43.7%, respectively, during the 8-year observation period (p=0.04). The incidence of HCC was also lower in the phlebotomized patients with a normal baseline ferritin level: 0.0% vs. 36.0% in the matched subgroup treated without phlebotomy at year 8. Phlebotomy offered a risk ratio of 0.13, thus suggesting protection against the development of HCC. CONCLUSION: The incidence of HCC can be reduced by phlebotomy treatment, which should be performed in patients with chronic hepatitis C not receiving or not responding to antiviral therapy. PMID- 25743001 TI - Safety and efficacy of partial splenic embolization in telaprevir-based triple therapy for chronic hepatitis C. AB - OBJECTIVE: Pegylated-interferon/ribavirin (peg-IFN/RBV) therapy with a protease inhibitor is the standard therapy for genotype 1b chronic hepatitis C. Despite improving treatment outcomes, patients with thrombocytopenia are often difficult to treat because interferon commonly exacerbates thrombocytopenia. In this study, partial splenic embolization (PSE) was performed in patients with hypersplenism induced thrombocytopenia to determine the effectiveness of this method as a potential treatment. METHODS: Patients were pretreated with PSE and then received triple combination therapy. The safety and efficacy of PSE was evaluated. RESULTS: Eighteen patients were analyzed, including 12 patients with the interleukin 28B (IL28B) major genotype and 12 patients with the inosine triphosphatase (ITPA) major genotype. The median embolization rate with PSE was 70% (range: 40-85%). PSE increased the patients' platelet counts from 71.5*10(3) /MUL (53-99*10(3) /MUL) to 121.5*10(3) /MUL (70-194*10(3) /MUL; p=0.0002). The patients' platelet counts fluctuated above 50*10(3) /MUL during the treatment. Specifically, the increase in the platelet count was significantly associated with the ITPA major genotype compared with the minor genotype (p=0.0057 at 2 weeks, p=0.0031 at 3 weeks, and p=0.0148 at 4 weeks). Adherence to peg-IFN alpha2b was sufficient (1.38 MUg/kg/week). The rapid viral response rate was 72.2% (13/18), the end of treatment response rate was 88.9% (16/18), and the sustained virological response (SVR) rate was 66.7% (12/18). The SVR rate for patients with the IL28B major genotype was 83.3% (10/12). No adverse effect due to PSE pretreatment was found in any patients. Furthermore, no patient discontinued treatment due to thrombocytopenia. CONCLUSION: PSE, in conjunction with triple combination therapy, is a useful and safe method to treat genotype 1b chronic hepatitis C patients with hypersplenism-induced thrombocytopenia. PMID- 25743002 TI - Background of the FIB-4 index in Japanese non-alcoholic fatty liver disease. AB - OBJECTIVE: We investigated the distribution and characteristics of the FIB-4 index of liver fibrosis in 1,441 Japanese men (age 50.7+/-10.2 years) and 304 women (age 53.9+/-10.3 years) who underwent comprehensive general health checkups and were identified as having non-alcoholic fatty liver disease. With respect to the FIB-4 index, differences according to sex, metabolic indices, and ultrasonic findings were investigated. METHODS: Among 9,255 individuals who underwent comprehensive general health checkups, 2,750 (29.8%) were found to have mild fatty liver or fatty liver based on ultrasound findings. After excluding patients who consumed >=150 g alcohol/week (818 individuals), those testing positive for hepatitis B surface antigens or hepatitis C virus antibody (184 individuals), and those for whom data were insufficient (three individuals), we investigated the FIB-4 indices in the remaining 1,745 subjects. RESULTS: There were no sex differences in the FIB-4 index. A total of 1,370 patients (78.5%) exhibited a low cut-off index (COI) (<1.30), 357 (20.5%), exhibited an indeterminate COI (1.30 2.67), and 18 (1.0%) exhibited a high COI (>2.67). There were no associations between the FIB-4 index and the constituent factors of metabolic syndrome. In contrast, there was a significant difference in the ln FIB-4 index between the patients with and without mild fatty liver or fatty liver on ultrasound among men (0.006+/-0.43 and -0.092+/-0.39, p<0.001), but not women. CONCLUSION: The FIB-4 index was is significantly lower in men, but not women, with fatty liver. The FIB 4 index must be calculated separately during medical checkups and evaluated in conjunction with ultrasound findings. PMID- 25743003 TI - Impact of early interventions by a cardiac rehabilitation team on the social rehabilitation of patients resuscitated from cardiogenic out-of-hospital cardiopulmonary arrest. AB - OBJECTIVE: We examined the effects of intervention performed by a multidisciplinary cardiac rehabilitation (CR) team on the social rehabilitation of patients with cardiogenic out-of-hospital cardiopulmonary arrest (OHCA) in the acute phase. METHODS: This study included 122 patients who were resuscitated after cardiogenic OHCA during a 10-year period. They were divided into two groups: including a non-CR group of patients (n=58) who were admitted before the CR team started performing systematic intervention and a CR group (n=64) who were admitted after the intervention was initiated. The following items were examined for each group: treatment condition at onset, contents of treatment, primary disease, presence or absence of underlying disease, presence or absence of complications, general physical and neurological outcome, duration of hospital stay, and status of social rehabilitation. RESULTS: Although the number of patients with cardiogenic OHCA did not markedly change, the number of bystanders participating in cardiopulmonary resuscitation (CPR) was significantly higher in the CR group versus the non-CR group (p<0.01). The effect of bystanders participating in CPR also significantly reduced the mortality outcome (p<0.05 versus the group without CPR), and patients in the CR group were more likely to achieve social rehabilitation (p<0.05 versus the group without CPR). Moreover, the number of patients who returned to society one year later was increased in the CR group versus the non-CR group (p<0.05). The incidence of respiratory complications was also significantly lower in the CR group versus the non-CR group (p<0.05). CONCLUSION: Along with the usefulness of rapid pre-hospital aid, our results suggest that systemic intervention performed by the CR team administered while the patient was in the acute phase may have promoted social rehabilitation of patients resuscitated after cardiogenic OHCA. PMID- 25743005 TI - Ultrastructural studies of IgG4-related kidney disease. AB - OBJECTIVE: Ultrastructural studies of IgG4-related kidney disease (IgG4-RKD) characterized by tubulointerstitial nephritis (TIN) are limited in previous reports due to the rarity of the condition. In the present report, we performed ultrastructural examinations and assessed the pathogenesis of this disease. PATIENTS: Clinicopathological studies were conducted in eight patients diagnosed with IgG4-RKD. Routine light, immunofluorescence and electron microscopy examinations and immunohistochemical assessments of IgG4 were performed using renal biopsy samples. RESULTS: Hypocomplementemia, positive anti-nuclear antibodies and eosinophilia were confirmed in more than half of the cases. Electron dense deposits (EDDs) were frequently found in the glomeruli and interstitium. The rate of deposition was 62.5% in both mesangial areas and Bowman's capsule. EDDs were frequently detected on the tubular basement membrane (TBM) (87.5% of patients). The interstitium also contained EDDs on collagen fibers in 87.5% of the cases and on basement membrane-like materials in areas of fibrosis in 37.5% of the cases. The creatinine clearance levels were significantly lower in the patients with the latter pattern. Meanwhile, the rate of immunoglobulin and/or complement deposition on the TBM was observed in less than 37.5% of patients, and these findings were not entirely coincident with the cases of EDDs on the TBM. CONCLUSION: EDDs are frequently found in the glomeruli and interstitium in patients with IgG4-RKD; however, immunohistological studies do not provide evidence that IgG4-RKD involves TIN with immune complex nephropathy. The presence of interstitial EDDs may be related to the progression of interstitial fibrosis in the setting of IgG4-RKD. PMID- 25743004 TI - The duration of diabetes is inversely associated with the physiological serum bilirubin levels in patients with type 2 diabetes. AB - OBJECTIVE: The aim of this study was to assess the relationship between the duration of diabetes and the physiological serum bilirubin concentration in association with antioxidant properties in patients with type 2 diabetes. METHODS: A total of 1,746 patients with type 2 diabetes were investigated in this cross-sectional study. An analysis of covariance was performed after adjusting for other covariates. Simple correlation analyses and a multivariate regression model were used to assess the association between the duration of diabetes and the serum bilirubin concentration. RESULTS: The mean total bilirubin value differed significantly according to the tertile of diabetes duration (<5 years, 12.38 MUmol/L, 95% confidence interval (CI) 12.02-12.76; 5-11.9 years, 12.33 MUmol/L, 95% CI 11.97-12.69; >=12 years, 11.73 MUmol/L, 95% CI 11.35-12.11; p for trend =0.033), after adjustment for other covariates. In addition, an inverse correlation was found between the serum bilirubin concentration and diabetes duration (rho=-0.211, p<0.001). According to a multivariate model, the association between the diabetes duration and serum bilirubin concentration remained significant, even after adjustment for confounding factors (beta=-0.074, p=0.008). CONCLUSION: The duration of diabetes is inversely associated with a serum bilirubin concentration within the physiologic range in patients with type 2 diabetes. PMID- 25743006 TI - CC16 gene A38G polymorphism and susceptibility to asthma: an updated meta analysis. AB - OBJECTIVE: To comprehensively evaluate the association between the CC16 gene A38G polymorphism and the risk of asthma. METHODS: Studies were retrieved from databases including PubMed, EMBASE, Web of Science and the Chinese Biomedical Literature Database according to the inclusive and exclusive criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. MATERIALS: Fifteen case-control studies with 1,623 cases and 3,294 controls were recruited for the analysis of the association between the CC16 gene A38G polymorphism and the risk of asthma. RESULTS: The overall ORs showed no significant associations between the CC16 gene A38G polymorphism and the risk of asthma (AA vs. GG: OR=1.04, 95%CI=0.86-1.25; AG vs. GG: OR=1.08, 95%CI=0.94-1.24; AA + AG vs. GG: OR=1.07, 95%CI=0.94-1.22; AA vs. AG + GG: OR=1.01, 95%CI=0.85-1.19; A vs. G: OR=1.04, 95%CI=0.95-1.14). Moreover, similar results were obtained in the subgroup analysis stratified by ethnicity (Asian: AG vs. GG: OR=1.02, 95%CI=0.87-1.21; Caucasian: AG vs. GG: OR=1.22, 95%CI=0.94-1.57) and age (Child: AG vs. GG: OR=1.21, 95%CI=0.84-1.74; Adult: AG vs. GG: OR=1.06, 95%CI=0.91-1.23). CONCLUSION: CC16 gene A38G polymorphism is not associated with the risk of asthma. PMID- 25743007 TI - Effect of a chronic obstructive pulmonary disease (COPD) intervention on COPD awareness in a regional city in Japan. AB - OBJECTIVE: The purpose of this study was to examine the effect of an intervention for chronic obstructive pulmonary disease (COPD) on COPD awareness in a regional city in Japan. METHODS: Self-administered questionnaires were completed by the residents of the city of Matsuura, Japan. Residents (>=50 years) of the mainland in Matsuura were included in a COPD intervention project (mainland group), while residents of the islands district received no intervention due to geographical issues (island group). The rates of COPD awareness and accuracy of responses to the questions about COPD were compared between the two groups. MATERIALS: The study included 5,891 residents 40 to 74 years of age of Matsuura in 2013. The mainland group comprised 4,419 subjects, and the island group 1,472 included subjects. RESULTS: The overall response rate to the questionnaire was 24.6%, with similar response rates between the two groups. The rate of COPD awareness in the mainland group was 24.5%, which was significantly higher than that observed in the island group (11.8%) (p<0.01). The rate of awareness tended to decrease in association with increasing age. Among 276 responders who stated they were aware of COPD, the accuracy rate for responses to the questions about COPD was not significantly different between the groups. CONCLUSION: In the present study, there was a difference in COPD awareness between the two groups, suggesting that COPD interventions may increase awareness of the disease. However, the level of knowledge regarding COPD remained low and modifications to the intervention are required to improve awareness of the condition, especially among elderly subjects. PMID- 25743008 TI - Prehospital delay and stroke-related symptoms. AB - OBJECTIVE: Prehospital delay is the major cause of treatment delay in stroke. This study was conducted to clarify the contribution of specific stroke-related symptoms to prehospital delay. METHODS: A consecutive series of 469 patients hospitalized within 2 weeks of stroke onset was collected. In this study, prehospital delay was defined as the time interval from recognition of stroke related symptoms to hospital arrival. The prevalence of each symptom or sign and prehospital delay were analyzed. RESULTS: Weakness of the lower limb (43.5%) was the most common symptom followed by weakness of the upper limb (37.1%) and dysarthria (31.6%). Conversely, the most common sign was weakness of the upper limb (54.1%) followed by dysarthria (53.3%), weakness of the lower limb (53.1%), and sensory disturbance (39.0%). The presence of confusion/decreased level of consciousness (p<0.001), aphasia (p<0.001), headache (p=0.017), and nausea/vomiting (p=0.035) were associated with earlier hospital visitation compared with the absence of these symptoms in univariate analyses. Conversely, the presence of sensory disturbance (p=0.0017) and vertigo/dizziness (p=0.044) were associated with a significant delay in hospital visitation compared with the absence of these symptoms. There was a discrepancy in the prevalence between symptoms recognized by the patients or bystanders and signs diagnosed by the physicians. CONCLUSION: There was a significant overall correlation between prehospital delay and the National Institute of Health Stroke Scale scores. Public education is therefore necessary to encourage early hospital visitation even with the appearance of mild symptoms. PMID- 25743009 TI - Paragonimiasis in Japan: a twelve-year retrospective case review (2001-2012). AB - OBJECTIVE: Paragonimiasis, or lung fluke infection, is a food-borne parasitic disease caused by infection with trematodes belonging to the genus Paragonimus. Although paragonimiasis was once considered successfully controlled in the 1970s, new cases began to emerge in the late 1980s. To apprehend the current-day situation of the re-emergent cases of paragonimiasis in Japan, we conducted a retrospective review of 443 patients who were referred to our laboratory and diagnosed as having paragonimiasis during 2001-2012. METHODS: Patients were diagnosed as having paragonimiasis based primarily on immunodiagnostic methods in addition to clinical, laboratory, and radiographic findings. Patient data were extracted from consultation sheets from attending physicians and were analyzed. RESULTS: Majority of the patients were residents of Kyushu Island. However, a substantial number of cases were also from other parts of Japan. Immigrants (mostly from China, Thailand, and Korea) accounted for a quarter of the cases. Native Japanese contracted paragonimiasis by consuming wild boar meat or freshwater crabs, whereas immigrants contracted the infection almost exclusively by consumption of freshwater crabs. Eosinophilia and elevated serum IgE levels were found in around 80% of the patients. Parasite egg detection was documented only in 11.7% of the cases, showing the reliance on serological tests for diagnosing paragonimiasis in current clinical practice. CONCLUSION: Paragonimiasis remains a public health issue in Japan, and the situation should be closely monitored. PMID- 25743010 TI - The CYVADIC regimen as a combination chemotherapy treatment option for advanced soft tissue sarcomas originating from the non-extremities. AB - OBJECTIVE: Soft tissue sarcoma (STS) originating from the non-extremities has a poor prognosis and risk for visceral crisis; therefore, combination chemotherapy with a high response rate is desired. METHODS: We retrospectively reviewed the cases of 30 patients with advanced STS that originated from the non-extremities who were treated between October 2005 and February 2012 at our institute with the CYVADIC chemotherapy regimen, which consists of cyclophosphamide, vincristine, doxorubicin, and dacarbazine. The patients' objective responses, progression-free survival (PFS), and overall survival (OS) were evaluated, and a statistical analysis was conducted to identify the predictive factors related to response and survival. RESULTS: The median follow-up time was 16.5 months. The response rate was 33%, the median PFS was 7.4 months, and the 1-year OS was 81% (the OS did not reach the median). The median number of treatment cycles was six. Eleven patients failed to complete 6 cycles due to disease progression. The number of involved organs (>3) was a significant predictive factor of early refractoriness by the logistic regression analysis. Thirteen patients had an objective response or PFS longer than 1 year, and an alkaline phosphatase (ALP) level within the normal limits were the significant predictive factors of a good response. CONCLUSION: The patients' responses to the CYVADIC therapy for advanced STS originating from the non-extremities were moderate; therefore, CYVADIC therapy may be a treatment option of choice as combination chemotherapy for such patients. We propose that the number of involved organs and ALP concentration may be useful measures to predict the response to the CYVADIC therapy. PMID- 25743011 TI - Successful conservative treatment of emphysematous gastritis. AB - Emphysematous gastritis is an extremely rare disease with an unfavorable prognosis. To date, very few studies have been conducted regarding the intragastric recovery process based on endoscopic findings. We herein report a case of emphysematous gastritis that improved with long-term (five months) conservative treatment in which we were able to observe the intragastric recovery process endoscopically. In cases in which emphysematous gastritis is suspected, it is important to provide prompt diagnostic imaging (including CT) and early appropriate treatment in order to improve the prognosis. PMID- 25743012 TI - De novo Crohn's disease following orthotopic liver transplantation: a case report and literature review. AB - The development of de novo Crohn's disease (CD) after orthotopic liver transplantation (OLT) is rare, possibly due to the continuous use of immunosuppressive treatment. Although several cases of CD following OLT have been reported worldwide, there are currently so such cases in Japan. We herein report the case of a patient who newly developed CD after undergoing OLT for congenital biliary atresia. The patient subsequently underwent ileocecal resection and has since maintained clinical remission. This is the first report of this condition in Japan. We also review the literature concerning cases of de novo inflammatory bowel disease (IBD) developing after OLT, and discuss the causes of and role of immunosuppressive agents in treating IBD. PMID- 25743013 TI - A second pedigree with amyloid-less familial Alzheimer's disease harboring an identical mutation in the amyloid precursor protein gene (E693delta). AB - A 59-year-old woman developed early-onset, slowly progressive dementia and spastic paraplegia. positron emission tomography (PET) imaging revealed a large reduction in the level of glucose uptake without amyloid deposition in the cerebral cortex. We identified a homozygous microdeletion within the amyloid beta (Abeta) coding sequence in the amyloid precursor protein (APP) gene (c.2080_2082delGAA, p.E693del) in three affected siblings and a heterozygous microdeletion in an unaffected sibling. The identical mutation was previously reported in the first Alzheimer's pedigree without amyloid deposits. Furthermore, an increase in high-molecular-weight Abeta-reactive bands was detected in the patient's CSF. Our findings suggest that soluble Abeta-oligomers induce neuronal toxicity, independent of insoluble Abeta fibrils. PMID- 25743014 TI - Refractory status epilepticus caused by anti-NMDA receptor encephalitis that markedly improved following combination therapy with rituximab and cyclophosphamide. AB - We herein describe the case of a 48-year-old woman who presented with nonconvulsive status epilepticus refractory to antiepileptic drugs caused by anti N-methyl-D-aspartate receptor (NMDAR) encephalitis without any tumors. She developed nausea and psychiatric symptoms, followed by fever and an acute progressive disturbance of consciousness. On admission to our hospital, she presented with involuntary orofacial movements and central hypoventilation, and an electroencephalogram showed a generalized slow activity consistent with nonconvulsive status epilepticus. The patient's drug-resistant status epilepticus markedly improved following second-line immunotherapy with rituximab and cyclophosphamide. Physicians should consider the early initiation of second-line therapy in certain cases of anti-NMDAR encephalitis. PMID- 25743015 TI - Voriconazole-responsive disseminated nodular lesions on spinal MRI. AB - A 74-year-old woman was hospitalized due to dysuria, weakness and dysesthesia of the lower extremities. She was in an immunosuppressed state following the administration of methylprednisolone therapy for idiopathic interstitial pneumonia. Cerebrospinal fluid and blood cultures were negative, and no infectious biomarkers were found. A gadolinium (Gd)-enhanced T1-weighted image of magnetic resonance imaging (MRI) revealed disseminated nodular lesions along the spinal cord. We suspected a diagnosis of seronegative deep mycosis and initiated anti-fungal therapy with voriconazole, which subsequently alleviated all of the patient's symptoms and MRI findings. Therefore, the presence of Gd-enhanced disseminated nodules on spinal MRI may be a good marker of deep meningeal mycosis. PMID- 25743016 TI - Successful immune moderation treatment for progressive encephalomyelitis with rigidity and myoclonus. AB - Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disease. PERM consists of the same symptoms as stiff person syndrome, in addition to sensory, brainstem and autonomic features. We herein report a case of PERM in a 48-year-old woman who initially presented with spasticity of the lower limbs and subsequently developed upper limb spasticity, perioral myoclonus and restlessness after three months. The onset of potentially fatal dysautonomia was observed at the peak of the disease. Treatment with high-dose immunoglobulin (400 mg/kg, 5 days), levetiracetam and azathioprine resulted in a drastic and sustained improvement of these symptoms. This is an interesting case of PERM in which the patient showed a dramatic improvement following immune moderation. PMID- 25743017 TI - Corticoid therapy for overlapping syndromes in an HIV-positive patient. AB - Human immunodeficiency virus (HIV) infection disturbs the host's immune function and often coexists with various autoimmune and/or systemic rheumatic diseases with manifestations that sometimes overlap with each other. We herein present the case of a 43-year-old Japanese man infected with HIV who exhibited elevated serum creatine kinase and transaminases levels without any symptoms. He was diagnosed with autoimmune hepatitis, polymyositis and Sjogren's syndrome and received combined antiretroviral therapy (cART); however, the laboratory abnormalities persisted. We successfully administered cART with the addition of oral prednisolone, and the patient's condition recovered without side effects related to the metabolic or immunosuppressive effects of these drugs. PMID- 25743018 TI - Relapsing polychondritis with encephalitis: a case report and literature review. AB - We herein report the case of a 39-year-old man who developed bilateral auricular chondritis, conjunctivitis, and central neurological symptoms. He was diagnosed with encephalitis associated with relapsing polychondritis (RP) based on the findings of an ear cartilage biopsy, cerebrospinal fluid examination and magnetic resonance imaging. Although oral prednisolone (60 mg/day) was administered, the initial steroid therapy did not improve his symptoms. In contrast, methylprednisolone (mPSL) pulse therapy followed by prednisolone gradually ameliorated his condition. There were no episodes of recurrence during the two year follow-up period. A review of the literature revealed that meningoencephalitis and encephalitis are rare, but important, complications of RP responsive to mPSL pulse therapy. PMID- 25743019 TI - Treatment of mediastinitis due to methicillin-resistant Staphylococcus aureus in a renal dysfunction patient undergoing adjustments to the linezolid dose. AB - This study is the first case report of the treatment of methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis using therapeutic drug monitoring of the serum and wound exudate concentrations of linezolid in a renal dysfunction patient. In the present study, the serum trough concentration of linezolid was maintained between 2 and 7 MUg/mL. Therapeutic drug monitoring dosage adjustments may be especially useful in patients with renal dysfunction and severe MRSA infection. PMID- 25743020 TI - Gastric ulcer caused by the retention of rice cakes. PMID- 25743021 TI - Genetic analysis of four European huchen (Hucho hucho Linnaeus, 1758) broodstocks from Poland, Germany, Slovakia, and Ukraine: implication for conservation. AB - Four broodstocks of European huchen (Hucho hucho) from: Poland, Germany, Slovakia, and Ukraine were investigated using ten microsatellite DNA loci. Microsatellite DNA analysis was successfully applied for the first time in the Polish broodstock of this fish species. The genetic variation and genetic distance between these broodstocks were evaluated. In addition, we examined the potential effects of a genetic bottleneck on the genetic variation of the broodstocks. The European huchen broodstocks exhibited moderate genetic diversity (PIC = 0.405-0.496 and I = 0.831-1.047) with the exception of German broodstock which presented higher genetic diversity (PIC = 0.590 and I = 1.254). Observed (Ho) and expected (He) heterozygosity across the investigated loci in all broodstocks ranged from 0.434 to 0.686 and from 0.452 to 0.650, respectively. Overall, the studied broodstocks were in Hardy-Weinberg equilibrium (HWE); however, from 8 to 42% of the loci deviated from HWE in each stock. The Garza Williamson index (M = 0.146-0.279) and values of the heterozygosity excess revealed a reduction of genetic variation in all studied broodstocks because of the founder or bottleneck effect. The analysis of genetic differentiation (Fst) and Nei's genetic distance between pairs of broodstocks revealed that Polish and Ukrainian broodstocks of European huchen were characterized by the closest genetic distance. In contrast, the highest genetic divergence parameters (Fst and Nei's distance) were observed among German, Slovak, and Ukrainian broodstocks. PMID- 25743022 TI - Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. AB - The prognosis of patients with gastric carcinomas at an advanced stage still remains dismal, and therefore novel therapeutic modalities are urgently needed. Since the successful targeting of amplified ERBB2 with a humanized monoclonal antibody, the amplified genes of other receptor tyrosine kinases such as EGFR, FGFR2, and MET, as well as those of other cell regulator genes, are being considered as candidate targets of molecular therapy. The aim of the present study was to determine the amplification status of 26 genes, which are frequently amplified in solid cancers, in advanced gastric cancers. A total of 93 formalin fixed and paraffin-embedded advanced gastric cancer tissues were examined by multiple ligation-dependent probe amplification, and 32 cases with 'gain' or 'amplified' status of 16 genes were further examined for the respective gene amplification by fluorescence in situ hybridization (FISH) and for the respective protein overexpression by immunohistochemistry. The frequencies of gene amplifications in advanced gastric cancers were as follows: ERBB2 (13 cases, 14%), FGFR2 (7 cases, 8%), MYC (7 cases, 8%), TOP2A (7 cases, 8%), MET (4 cases, 4%), MDM2 (4 cases, 4%), CCND1 (3 cases, 3%), FGF10 (2 cases, 3%), and EGFR (1 case, 1%). Amplification of the receptor tyrosine kinases genes occurred in a mutually exclusive manner except for one tumor in which ERBB2 and FGFR2 were both amplified but in different cancer cells. Co-amplification of ERBB2 and MYC, and EGFR and CCND1, in single nuclei but on different amplicons, was confirmed in one case each. Attempts at correlating the FISH status with the immunohistochemical staining pattern showed variable results from complete concordance to no correlation. In conclusion, combination of multiple ligation-dependent probe amplification and FISH analysis is a feasible approach for obtaining the semi comprehensive genetic information that is necessary for personalized molecular targeted therapy. PMID- 25743023 TI - CD5-positive follicular lymphoma: clinicopathologic correlations and outcome in 88 cases. AB - Follicular lymphoma is a low-grade B-cell lymphoma of germinal center B-cell origin that typically lacks CD5 expression. We describe the clinicopathologic features of 88 cases of CD5+ follicular lymphoma (53 men, 35 women; median age, 60 years; range, 31-86). Follicular lymphoma was diagnosed initially in lymph nodes in 66 and extranodal sites in 22 patients. Eighty-one patients had lymphadenopathy, 66 had more than one involved site, 46 had bone marrow involvement, and 7 had splenomegaly. Staging information was available for 84 patients: 52 stage IV, 18 stage III, 12 stage II, and 2 stage I. Sixty-one cases were grade 1 or 2 and 27 were grade 3. The median proliferation index (Ki-67) was 30%. CD5 expression was detected by flow cytometry in 69, immunohistochemistry in 8, and both methods in 11 cases. The presence of t(14;18)(q32;q21)/IGH-BCL2 or other BCL2 translocation was detected in 28/44 (64%) cases. A total of 38 (43%) patients also had diffuse large B-cell lymphoma, concurrent with (n=20), subsequent to (n=13), or developing before CD5+ follicular lymphoma (n=5). All patients received chemotherapy; 12 also received stem-cell transplantation. With a median follow-up of 55 months (range, 0.5-207), 15 patients died, 46 were alive with disease, and 20 were in clinical remission. Compared with a matched group of patients with CD5- follicular lymphoma, patients with CD5+ follicular lymphoma more commonly had an International Prognostic Index >2 (35/80 vs 10/99, P<0.001), more often developed diffuse large B-cell lymphoma (38/88 vs 17/99; P<0.001), and had a shorter median progression-free survival (44 vs 89 months, P=0.0042). Higher Ki-67 and International Prognostic Index were identified as poor prognostic factors in both the groups. We conclude that CD5 expression in follicular lymphoma is associated with a higher International Prognostic Index, higher rate of transformation to diffuse large B-cell lymphoma, and shorter progression-free survival. PMID- 25743024 TI - Mode of lysozyme protein adsorption at end-tethered polyethylene oxide brushes on gold surfaces determined by neutron reflectivity. AB - The mode of lysozyme protein adsorption at end-tethered thiol-terminated polyethylene oxide brushes grafted upon gold was determined in situ by neutron reflectivity using the INTER instrument at target station 2, ISIS, RAL, UK. It was found that the most probable position of protein adsorption at these weakly protein resistive brushes was at the gold-brush interface in the so-called primary protein position. PMID- 25743025 TI - Thinning and thickening of free-standing smectic films revisited. AB - We present a theoretical explanation of the remarkable thickness instabilities that occur in free-standing smectic films (FSSF) upon changing the external conditions: i) upon heating the film above the bulk smectic disordering temperature, generally the film does not rupture but instead shows successive layer-by-layer thinning transitions; ii) thickening of FSSF, which occurs within the thermal range of the smectic phase upon local heating. All observations reported so far can be explained on the basis of the Landau-de Gennes theory of the smectic state in combination with nucleation theory. In overheated smectic films (thinning) or locally heated FSSF (thickening) an additional normal tensile force appears due to a change of the mean density of the film. In the case of an overheated FSSF the free energy has oscillatory character, and upon heating the balance of tensile and elastic forces breaks down spontaneously. This leads to thinning of the film, which proceeds via thermal nucleation and growing of dislocation loops in the middle plane of the film. The expression for the envelope of the points of thinning as well as estimates of the dynamics of growth of dislocation loops, are in good agreement with experiments. Local heating of a FSSF within the smectic temperature range induces thermal expansion, which shifts the system to a metastable state. This favors nucleation and growth of dislocation loops of excess smectic layers in the middle plane of the film. The activation energy of such dislocation loops attains values below the threshold energy and decreases upon further heating. This leads to local film thickening by many tens of layers. Realization of this scenario depends crucially on the energy dissipated locally in the film. Estimates of the thickness of the growing "island" in the film and of the velocity of the dislocation loop growth are in reasonable agreement with experiments. PMID- 25743026 TI - Applying GSH to a wide range of experiments in granular media. AB - Granular solid hydrodynamics (GSH) is a continuum-mechanical theory for granular media, whose wide range of applicability is shown in this paper. Simple, frequently analytic solutions are related to classic observations at different shear rates, including: i) static stress distribution, clogging; ii) elasto plastic motion: loading and unloading, approach to the critical state, angle of stability and repose; iii) rapid dense flow: the MU-rheology, Bagnold scaling and the stress minimum; iv) elastic waves, compaction, wide and narrow shear band. Less conventional experiments have also been considered: shear jamming, creep flow, visco-elastic behavior and non-local fluidization. With all these phenomena ordered, related, explained and accounted for, though frequently qualitatively, we believe that GSH may be taken as a unifying framework, providing the appropriate macroscopic vocabulary and mindset that help one coming to terms with the breadth of granular physics. PMID- 25743027 TI - Coverage dependent water dissociative adsorption on Fe(110) from DFT computation. AB - Using density functional theory calculations and ab initio atomistic thermodynamics, H2O adsorption and dissociation on the Fe(110) p(4 * 4) surface at different coverages have been computed. At the lowest coverage, the adsorbed H2O, OH, O and H species can migrate easily on the surface. For (H2O)n adsorption, H2O molecules donating H atoms for H-bonding adsorb more strongly than those accepting H atoms for H-bonding. Monomeric H2O dissociation is favored both thermodynamically and kinetically. On nO pre-covered Fe(110) surfaces (n = 1 8), H2O dissociation is accessible for nO + H2O (n = 1-7) both kinetically and thermodynamically, while H2O desorption instead of dissociation occurs at n = 8. With the increased number of surface O atoms, H2 dissociative adsorption energies vary in a narrow range for n = 1-4 and decrease for n = 5-7, while at n = 8, the surface does not adsorb H2. At low OH coverage (n = 2, 4), OH groups are perpendicularly adsorbed without H-bonding, while for n>= 6, adsorbed OH groups are linearly arranged and stabilized by H-bonding. The maximal OH coverage (n = 12) is 0.75 ML and the reasonable O coverage (n = 7) is 0.44 ML, in line with the experiment. The calculated desorption temperatures of H2O and H2 agree well with the available experimental data. These results provide fundamental insights into water-involved reactions catalyzed by iron and interaction mechanisms of water interaction with metal surfaces. PMID- 25743028 TI - High-grade soft tissue sarcomas of the extremities: surgical margins influence only local recurrence not overall survival. AB - PURPOSE: After surgical treatment of high-grade soft tissue sarcomas, local recurrences, metastases and survival remain a great concern. Further knowledge on factors with a possible impact on these endpoints, specifically resection margins, is relevant for decision-making regarding the aggressiveness of local treatment. The aim of this study is to investigate the impact of prognostic factors on local recurrence and overall survival for patients with high-grade soft tissue sarcomas of the extremities. METHODS: In a retrospective cohort study of 127 patients (mean age 48 years, range five to 91; median follow-up 71 months) the prognostic effect of margin status and other clinicopathologic characteristics on local recurrence and overall survival were analysed by employing a multivariate Cox regression. RESULTS: Five-year cumulative incidence of local recurrence and distant metastases was 26% and 40%, respectively. The estimated five-year overall survival was 59%. Tumour size proved a consistent adverse prognostic factor for local recurrence (hazard ratio (HR) 3.9), distant metastasis (HR 4.9) and overall survival (HR 2.4). The significant association of resection margins with local recurrence (HR 10.2) was confirmed. Margins were however not significantly associated with the occurrence of distant metastasis or overall survival. The occurrence of local recurrence had a significant impact on overall survival (HR 2.0). CONCLUSIONS: The results of this study confirm the critical role of tumour size on survival and margins on local recurrence, and stress the need for further investigation concerning the association between margins, local recurrence and survival. PMID- 25743029 TI - Historical descriptions of physicians' personal pathologies. AB - There were many instances in the history of medicine when doctors reported on their suffering from diseases or injuries and how they were managed. Orthopaedic surgery saw many examples of such self-reports. Do surgeons describe their own pathologies in the same way they do those of their patients? Also what did such self reports change in the orthopaedic practice of their times and thereafter? The aim of this paper is to review some historical self-reports in which eminent general and orthopaedic surgeons reported their own orthopaedic ailments. Many such reports broke prevalent myths and made significant changes in the orthopaedic thought and methodology. PMID- 25743030 TI - Risk for chronic kidney disease increases with obesity: Health Survey for England 2010. AB - OBJECTIVE: Studies of the relationship between obesity and chronic kidney disease (CKD) in nationally representative population samples are limited. Our study aimed to determine if overweight and obesity were independently associated with the risk for CKD in the 2010 Health Survey for England (HSE). DESIGN: The HSE is an annually conducted cross-sectional study. In 2010 serum creatinine was included to determine the incidence of CKD in the population. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Multivariable logistic regression models were developed to calculate odds ratios and 95% confidence intervals for CKD risk by BMI (reference category: BMI=18.5 24.9 kg/m2) and adjusted for age, gender, ethnicity, smoking, diabetes and hypertension. SETTING: A random sample of nationally representative households in England. SUBJECTS: Adults (n 3463) with calculable eGFR and BMI were included. RESULTS: The prevalence of CKD was 5.9%. The risk of CKD was over 2.5 times higher in obese participants compared with normal-weight participants in the fully adjusted model (BMI=30.0-39.9 kg/m2: adjusted OR=2.78 (95% CI 1.75, 4.43); BMI >= 40.0 kg/m2: adjusted OR=2.68 (95% CI 1.05, 6.85)). CONCLUSIONS: Obesity is associated with an increased risk of CKD in a national sample of the UK population, even after adjustment for known CKD risk factors, which may have implications for CKD screening and future national health service planning and delivery. PMID- 25743031 TI - The effect of serum, intestinal and peritoneal visfatin levels on early diagnosis of acute mesenteric ischemia. AB - BACKGROUND: Acute mesenteric ischemia (AMI) is a rapidly progressive disease where early diagnosis is life-saving. As a new cytokine, levels of thevisfatin might be affected during the ischema and reperfusion. In our study, we obtained changes of visfatin levels in the serum, peritoneal and intestinal lavage samples in rats, to investigate the effectiveness of these changes in the early diagnosis of AMI. METHODS: In group 1 (Sham group) the intestine was exteriorated after the laparotomy was performed and allowed to stand for 3 hours without ischemia. In group 2 (acute mesenteric ischemia-reperfusion group) the mesenteric artery was ligated and, mesenteric blood flow was restored after 60-minute ischemia. To compare with intestinal injury, in group 3 (acute pancreatitis group) the ductus pancreaticus was ligated, and the abdomen was closed for 3 days in expectation of the formation of pancreatitis. In all of the groups, the intestinal lavage, peritoneal lavage and blood samples were analyzed to evaluate the levels of visfatin, TNF-alpha, IL-6 and IL-8. Samples were taken before the procedure in all groups; additionally 60 minutes after ischemia and 120 minutes after reperfusion in group 2; and after the development of the pancreatitis in group 3. RESULTS: Serum, intestinal and peritoneal lavage visfatin levels were found to be increased in group 2 and group 3 (P<0.05). In group 2, while serum TNF-alpha levels were increased in both ischemia and reperfusion; in intestinal lavage sample the increase was only in the ischemic phase (P<0.05). In group 2, IL-8 levels were significantly increased after ischemia in serum (P=0.03) and after reperfusion in intestinal lavage (P=0.004) samples. CONCLUSIONS: Serum, intestinal and peritoneal visfatin levels were increased not only in the case of mesenteric ischemia, but also in acute pancreatitis. In these two clinical pathologies, the visfatin levels of the intestinal and peritoneal cavitiesmay increase parallel to the serum visfatin levels. PMID- 25743032 TI - Typical symptoms for prediction of outcome and risk stratification in acute pulmonary embolism. AB - BACKGROUND: Clinical presentation of pulmonary embolism (PE) comprises a wide spectrum from asymptomatic incidental finding to typical symptoms with chest pain, dyspnea, hemoptysis and syncope/collapse. We aimed to investigate typical symptoms of PE and increasing number of these symptoms to predict outcome in acute PE. METHODS: Data of PE patients were analysed retrospectively. According to the typical symptoms patients were subdivided in groups with 0, 1, 2, or >=3 symptoms, which were compared with Kruskal-Wallis-Test. Logistic regression models were computed to investigate the association between the symptoms as well as the groups with the outcome parameters in-hospital death, myocardial necrosis, Shock-Index >=1.0 and (right ventricular dysfunction (RVD). ROC curves were calculated to test the effectiveness of increasing number of symptoms to predict the outcome parameters. RESULTS: One hundred eighty-two PE patients (61.5% female, mean age 68.5+/-15.3 years) were included in this study. 5 patients (2.7%) died in-hospital. Logistic regression models revealed associations between syncope/collapse and in-hospital death (OR 7.269, 95%CI 0.894-59.130, P=0.0636), myocardial necrosis (OR2.872, 0.904-9.130, P=0.0738), Shock-Index >=1.0 (OR 4.906, 1.440-16.721, P=0.00110) and RVD (OR 5.265, 1.078-25.708, P=0.0401). Dyspnea and myocardial necrosis were also associated (OR 3.245, 1.127-9.348, P=0.0292). Increasing number of symptoms were not associated with in-hospital death, but absence of typical symptoms was associated with lower frequency of myocardial necrosis (OR 0.212, 0.046-0.976, P=0.0464). Effectiveness of increasing number of symptoms to predict myocardial necrosis was only moderate (AUC 0.608). CONCLUSIONS: The symptom syncope/collapse is connected with poorer outcome in acute PE. An increasing number of symptoms failed to be useful for outcome prediction and risk stratification in acute PE. PMID- 25743033 TI - Relating the steady-state visual evoked potential to single-stimulus responses derived from m-sequence stimulation. AB - PURPOSE: Steady-state visual evoked potentials have various applications, including objective acuity testing. However, a non-monotonous spatial-frequency tuning (a "notch") occurs at intermediate spatial frequencies in about half of the examinees. One possible reason lies in the temporal superposition of single stimulus responses. This was investigated in 20 subjects. METHODS: Single stimulus responses to checkerboard onsets were estimated through deconvolution of responses to m-sequence stimulation. Based on these, steady-state responses were predicted through superposition of temporally overlapping single-stimulus responses and compared to normally recorded steady-state responses. Discrepancies were analyzed in both the time and frequency domains. RESULTS: The agreement between predicted and recorded steady-state responses varied greatly among subjects, ranging from a good match including non-monotonous features of the tuning curve to substantial deviations. Although in some subjects the tuning of the recorded responses was better matched by the predicted responses than by the deconvolved m-sequence responses from which the prediction was computed, the correlation was not significantly different at the group level. In most subjects, there was only a small to moderate contribution of higher harmonics. The match between predicted and recorded responses was not always uniform across electrode locations. CONCLUSIONS: Our data are consistent with temporal superposition explaining an interindividually variable part of the checksize tuning curve without being its primary determinant. PMID- 25743034 TI - Association of Kawasaki disease with tropospheric winds in Central Chile: is wind borne desert dust a risk factor? AB - It has been found that Kawasaki disease (KD) cases diagnosed in Japan, Hawaii and San Diego, USA increase when tropospheric wind patterns arrive from central Asia, suggesting a common, wind-borne causal agent. We analyzed KD cases hospitalized in Santiago, Chile to look for associations with local, regional and large scale meteorological variables. We compiled monthly data of KD incidence rates, local meteorological variables, large scale wind patterns and several El Nino Southern Oscillation (ENSO) indices for 2001-2010; we considered standardized anomalies in all analyses and used linear time series models to account for data autocorrelation. We found that meteorological variables explain 38% of variance in KD rates. A unit increase in northerly wind at 3 lagged months, temperature at 1 and 3 lagged months and monthly change of ENSO 4 index are associated with changes in KD rates of 0.203 (95% CI 0.049-0.358), 0.181 (95% CI 0.014-0.347), 0.192 (95% CI 0.030-0.353) and -0.307 (95% CI -0.458-0.156), respectively. These results are robust when northerly wind level is changed or when a shorter period (2005-2010) is used to estimate model parameters. We found a statistical association of KD at Santiago, Chile with tropospheric, northerly wind patterns suggesting that dust transported from the Atacama Desert could include a causative agent. A novel result is that ENSO dynamics also explain part of KD variability with a decrease in KD when La Nina is dissipating or El Nino is on the rise; hence climate scale dynamics might be taken into account in future studies worldwide - at least as a potential explanatory variable that may confound KD seasonality on a global scale. PMID- 25743035 TI - [Axillary pathologic response after neoadjuvant chemotherapy in locally advanced breast cancer with axillary involvement]. AB - AIM: To compare axillary involvement (N+) at initial staging in locally advanced breast cancer (LABC) with axillary lymphadenectomy histologic results after neoadjuvant chemotherapy treatment (NeoChemo). MATERIAL AND METHODS: Retrospective study between November 2011 and September 2013 of LABC cases treated with neoadjuvant chemotherapy based on docetaxel (associated with trastuzumab in HER2 positive cases and carboplatin/adriamycin in HER2 negative cases). Those clinically or radiologically suspected cases of axillary involvement were histologically confirmed. When there was no suspicion of axillary involvement, sentinel lymph node radioguided biopsy (SLNRB) was performed using intradermal injection of (99m)Tc-nanocolloid albumin prior to neoadjuvant treatment. Axillary lymphadenectomy after NeoChemo was undertaken in all cases with positive axilla. Final pathologic response was classified as complete (pCR) when there was no evidence of tumoral disease and as non pathologic complete response (no pCR) in the opposite case. RESULTS: A total of 346 patients treated with docetaxel were reviewed, identifying 105 LABC. Axillary involvement at initial staging was detected in 70 (67%) before starting NeoChemo. From these 70, 73% (n=51) were N+ (fine needle biopsy and/or biopsy) and the remaining 19 (27%) were occult N+ detected by SLNRB. Axillary lymphadenectomy detected pCR in 56% (39/70), increasing up to 84% pCR when initial N+ status was reached using SNLB. On the other hand, when N+ was detected using fine needle biopsy/lymph biopsy, pCR was only 45%. CONCLUSION: More than 50% of women affected by locally advanced breast cancer with tumoral axillary involvement at initial diagnosis present free metastatic axilla after therapeutic neoadjuvant chemotherapy effect. This increases up to almost 90% in case of occult metastatic axilla detected with sentinel node biopsy prior starting neoadjuvant chemotherapy. PMID- 25743037 TI - The investigation on phytochemicals from Ferulago angulata (Schlecht) Boiss, indigenous to central parts of Iran. AB - Ferulago angulata (Schlecht) Boiss (Apiaceae) is a perennial herb distributed in the central parts of Iran. In this work, the essential oil of Ferulago angulata aerial parts collected from the central parts of Iran was obtained by using hydrodistillation analysed by GC and GC-MS. Air-dried and powdered plant roots were extracted with n-hexane, dichloromethane and methanol, respectively, using a Soxhlet apparatus. The n-hexane extract was subjected to preparative thin-layer chromatography using chloroform-acetone (95:5) as solvent system to yield two linear furanocoumarins, prantschimgin and oxypeucedanin. The structure of theisolated compounds was elucidated by using spectroscopic data such as (1)H NMR, (13)C NMR, UV and IR. The results of GC-MS analyses showed that gamma terpinolene (11.97%), alpha-pinene (10.00%), sabinene (6.89%), linalool (5.56%) and cis-ocimene (4.41%) were the main components among 51 constituents characterised in the oil. The oil exhibits considerable phytotoxic activity. PMID- 25743036 TI - [Use of radioguided surgery in the surgical treatment of osteoid osteoma]. AB - OBJECTIVE: Osteoid osteoma is the third most common benign bone tumor and complete surgical resection is definitive treatment. There are a limited number of publications on the use of radioguided surgery in this type of lesion. To assess the utility of radioguided surgery in our environment as a method of surgical treatment of this tumor. MATERIAL AND METHODS: We retrospectively evaluated 12 patients (2 women and 10 men, age range 9-44 years) with clinical and radiological suspicion of osteoid osteoma. Bone scintigraphy showed foci of pathology uptake compatible with suspected lesion in the femur (4 cases), tibia (3), vertebral column (3), humerus (1) and talus (1). Subsequently patients underwent surgical treatment by radioguided surgery after injection of a dose of (99m)Tc-hydroxy diphosphonate. The nidus was removed using gamma probe and mini gamma camera, considering the technique to be completed when its counts decreased to the levels of the surrounding bone counts. RESULTS: Lesions were located in all patients (12 of 12), and were confirmed histologically in 8 of them, including an osteoblastoma. The cure rate was 100%, based on the disappearance of pain after a minimum follow-up of 6 months. CONCLUSION: Use of radioguided surgery in the surgical treatment of osteoid osteoma showed satisfactory results, with 100% efficiency in both lesion location and outcome of treatment and without major postoperative complications. PMID- 25743038 TI - Induction of host defences by Rhizobium during ineffective nodulation of pea (Pisum sativum L.) carrying symbiotically defective mutations sym40 (PsEFD), sym33 (PsIPD3/PsCYCLOPS) and sym42. AB - Rhizobia are able to establish a beneficial interaction with legumes by forming a new organ, called the symbiotic root nodule, which is a unique ecological niche for rhizobial nitrogen fixation. Rhizobial infection has many similarities with pathogenic infection and induction of defence responses accompanies both interactions, but defence responses are induced to a lesser extent during rhizobial infection. However, strong defence responses may result from incompatible interactions between legumes and rhizobia due to a mutation in either macro- or microsymbiont. The aim of this research was to analyse different plant defence reactions in response to Rhizobium infection for several pea (Pisum sativum) mutants that result in ineffective symbiosis. Pea mutants were examined by histochemical and immunocytochemical analyses, light, fluorescence and transmission electron microscopy and quantitative real-time PCR gene expression analysis. It was observed that mutations in pea symbiotic genes sym33 (PsIPD3/PsCYCLOPS encoding a transcriptional factor) and sym40 (PsEFD encoding a putative negative regulator of the cytokinin response) led to suberin depositions in ineffective nodules, and in the sym42 there were callose depositions in infection thread (IT) and host cell walls. The increase in deposition of unesterified pectin in IT walls was observed for mutants in the sym33 and sym42; for mutant in the sym42, unesterified pectin was also found around degrading bacteroids. In mutants in the genes sym33 and sym40, an increase in the expression level of a gene encoding peroxidase was observed. In the genes sym40 and sym42, an increase in the expression levels of genes encoding a marker of hypersensitive reaction and PR10 protein was demonstrated. Thus, a range of plant defence responses like suberisation, callose and unesterified pectin deposition as well as activation of defence genes can be triggered by different pea single mutations that cause perception of an otherwise beneficial strain of Rhizobium as a pathogen. PMID- 25743039 TI - Expression of developmentally regulated plasma membrane polypeptide (DREPP2) in rice root tip and interaction with Ca(2+)/CaM complex and microtubule. AB - The cytoplasmic free Ca(2+) could play an important role for salt tolerance in rice root (Oryza sativa L.). Here, we compared the expression profiles of two putative developmentally regulated plasma membrane polypeptides (DREPP1 and DREPP2) in rice roots of salt-tolerant cv. Pokkali and salt-sensitive cv. IR29. The messenger RNA (mRNA) for OsDREPP1 could be detected in all parts of root and did not change upon salt stress, whereas the mRNA for OsDREPP2 was detected only in root tips. The transcript level of OsDREPP2 first disappeared upon salt stress, then recovered in Pokkali, but not recovered in IR29. The gene-encoding OsDREPP2 was cloned from cv. Pokkali and expressed in Escherichia coli, and its biochemical properties were studied. It was found that OsDREPP2 is a Ca(2+) binding protein and binds also to calmodulin (CaM) as well as microtubules. The mutation of Trp4 and Phe16 in OsDREPP2 to Ala decreased the binding of DREPP2 to Ca(2+)/CaM complex, indicating the N-terminal basic domain is involved for the binding. The binding of OsDREPP2 to microtubules was inhibited by Ca(2+)/CaM complex, while the binding of double-mutant OsDREPP2 protein to microtubules was not inhibited by Ca(2+)/CaM complex. We propose that CaM inhibits the binding of DREPP2 to cortical microtubules, causes the inhibition of microtubule depolymerization, and enhances the cell elongation. PMID- 25743040 TI - Preparation of antibacterial and radio-opaque dental resin with new polymerizable quaternary ammonium monomer. AB - OBJECTIVE: A new polymerizable quaternary ammonium monomer (IPhene) with iodine anion was synthesized and incorporated into Bis-GMA/TEGDMA (50/50, wt/wt) to prepare antibacterial and radio-opaque dental resin. METHODS: IPhene was synthesized through a 2-steps reaction route, and its structure was confirmed by FT-IR and (1)H-NMR spectra. IPhene was incorporated into Bis-GMA/TEGDMA (50/50, wt/wt) with a series of mass fraction (from 10 wt.% to 40 wt.%). Degree of monomer conversion (DC) was determined by FT-IR analysis. Polymerization shrinkage was determined according to the variation of density before and after polymerization. The flexural strength, modulus of elasticity, and fracture energy were measured using a three-point bending set up. Radiograph was taken to evaluate the radio-opacity of the polymer. A single-species biofilm model with Streptococcus mutans (S. mutans) as the tests organism was used to evaluate the antibacterial activity of the polymer. Bis-GMA/TEGDMA resin system without IPhene was used as a control group. RESULTS: FT-IR and (1)H-NMR spectra of IPhene revealed that IPhene was the same as the designed structure. ANOVA analysis showed that when mass fraction of IPhene was more than 10 wt.%, the obtained resin formulation had lower DC, polymerization shrinkage, FS, and FM than control resin (p<0.05). Polymers with 20 wt.% and 30 wt.% IPhene had higher fracture energies than control polymer (p<0.05). IPhene containing samples had higher radio-opacity than control group (p<0.05), and radio-opacity of IPhene containing sample increased with the increasing of IPhene mass fraction (p<0.05). Only polymers with 30 wt.% and 40 wt.% of IPhene showed antibacterial activity (p<0.05). SIGNIFICANCE: IPhene could endow dental resin with both antibacterial and radio-opaque activity when IPhene reached 30 wt.% or more. Though sample with 30 wt.% of IPhene had lower FS and FM than control group, its lower volumetric shrinkage, higher fracture energy, higher radio-opacity, and antibacterial activity still made it having potential to be used in dentistry. PMID- 25743041 TI - Long-term effects on subscapularis integrity and function following arthroscopic shoulder stabilization with a low anteroinferior (5:30 o'clock) portal. AB - PURPOSE: The use of a low anteroinferior (5:30 o'clock) portal for arthroscopic shoulder stabilization allows an anatomical refixation of the capsulolabral complex. This anteroinferior portal, however, penetrates the inferior subscapularis (SSC), which is criticized. Therefore, the aim of the study was to evaluate the functional and structural properties of the SSC in patients with anteroinferior shoulder stabilization. The hypothesis was that it does not harm the SSC by demonstrating full muscular function and imaging-based normal structure at a long-term follow-up. METHODS: Twenty patients were examined (14 males and six females; mean age 37.0 years) retrospectively after a mean follow up of 9.6 years. At final follow-up, clinical examination and clinical scores (ASES, Constant-Murley, WOSI, and Rowe score) were documented. Additionally, SSC strength was evaluated with a custom-made electronic force measurement plate. All patients underwent bilateral magnetic resonance imaging to assess structural integrity and fatty infiltration (grading according to Fuchs et al.) of the SSC. Furthermore, vertical and transversal (superior and inferior) diameters of the muscle and the muscle area in a parasagittal plane were measured. RESULTS: Clinical scores revealed good-to-excellent long-term results (ASES 92 points, Constant-Murley 82 points, WOSI 85 %, and Rowe 84 points). Force measurement in comparison with the contralateral side showed no significant (p > 0.05) differences for the 'belly-press' test (ipsilateral 102 N vs. contralateral 101 N) and the 'lift-off' test (73 vs. 69 N). There were also no significant differences between the mean diameters and the areas of the SSC muscle belly (vertical diameter ipsilateral 92 mm vs. contralateral 94 mm; superior transversal 28 vs. 29 mm; inferior transversal 34 vs. 34 mm; area 2336 vs. 2526 mm(2)). CONCLUSION: Arthroscopic labral repair with a low anteroinferior portal demonstrates no signs of structural and functional impairment of the SSC after 9.6 year follow-up. For clinical relevance, the lower part of the SSC can be penetrated for an optimal anchor placement in shoulder instabilities or Bankart fractures without concerns of a negative long-term effect on the SSC. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 25743042 TI - The effect of distal tibial rotation during high tibial osteotomy on the contact pressures in the knee and ankle joints. AB - PURPOSE: Intraoperative fracture of the lateral cortex fractures of the tibia is a potential complication of high tibial osteotomy (HTO), which may result in inadequate rotational alignment of the distal tibia. Our aim was to determine how rotational malalignment of the distal tibial segment distal would affect intraarticular contact pressure distribution in the knee and ankle joints. METHODS: A medial, L-shaped opening-wedge HTO was performed on seven human lower body specimens. A stainless steel device with integrated load cell was used to axially load the leg. Pressure-sensitive sensors were used to measure intraarticular contact pressures. Intraoperative changes in alignment were monitored in real time using computer navigation. Measurements were performed in the native knee alignment, after 10 degrees and 15 degrees of alignment correction and with the distal tibia fixed at 15 degrees of external rotation. RESULTS: Moderate-to-large alignment changes after medial opening-wedge HTO resulted in a shift in intraarticular contact pressures from the medial compartment of the knee towards the lateral compartment. However, fixation of the distal tibial segment at 15 degrees of external rotation neutralized this intended beneficial effect. In the ankle, external rotation of the distal tibia also caused a reduction in contact pressures and tibiotalar contact area. CONCLUSION: Malrotation of the distal tibial fragment negates the intended effect of offloading the diseased compartment of the knee, with the contact pressures remaining similar to those of the native knee. Furthermore, malrotation leads to abnormal ankle contact pressures. Care should be taken to ensure appropriate rotational alignment of the distal tibial segment during intraoperative fixation of HTO procedures. PMID- 25743043 TI - What are the important manoeuvres for beginners to minimize surgical time in primary total knee arthroplasty? AB - PURPOSE: It was hypothesized that surgical time of beginners would be much longer than that of experts. Our purpose was to investigate and clarify the important manoeuvres for beginners to minimize surgical time in primary total knee arthroplasty (TKA) as a multicentre study. METHODS: A total of 300 knees in 248 patients (averaged 74.6 years) were enrolled. All TKAs were done using the same instruments and the same measured resection technique at 14 facilities by 25 orthopaedic surgeons. Surgeons were divided into three surgeon groups (four experts, nine medium-volume surgeons and 12 beginners). The surgical technique was divided into five phases. Detailed surgical time and ratio of the time in each phase to overall surgical time were recorded and compared among the groups in each phase. A total of 62, 119, and 119 TKAs were done by beginners, medium volume surgeons, and experts, respectively. RESULTS: Significant differences in surgical time among the groups were seen in each phase. Concerning the ratio of the time, experts and medium-volume surgeons seemed cautious in fixation of the permanent component compared to other phases. Interestingly, even in ratio, beginners and medium-volume surgeons took more time in exposure of soft tissue compared to experts. (0.14 in beginners, 0.13 in medium-volume surgeons, 0.11 in experts, P < 0.05). CONCLUSION: Beginners took more time in exposure and closure of soft tissue compared to experts. Improvement in basic technique is essential to minimize surgical time among beginners. First of all, surgical instructors should teach basic techniques in primary TKA for beginners. LEVEL OF EVIDENCE: Therapeutic studies, Level IV. PMID- 25743044 TI - Differences in evaluation between geriatric and adult patients requiring pulmonary consultation. AB - OBJECTIVE: The main aim of the study was to investigate the effects of age in pulmonary consultation and to evaluate differences between geriatric and adult patients. MATERIAL AND METHODS: Consultation referrals to the clinic of chest diseases for patients from emergency, inpatient and outpatient clinics of a tertiary care general hospital between December 2010 and April 2011 were examined retrospectively. The patients were divided into two groups, namely those aged 65 years and over (geriatric patients) and those under the age of 65 years (adults). RESULTS: Out of 272 patients 135 (49.6%) were geriatric patients and 137 (50.4%) were adult patients. The mean age of the geriatric patients and adults was 75.6+/ 7.1 years and 49.7+/-11.8 years, respectively. While the geriatric patients showed a significantly higher presence of pathologies in chest radiography, respiratory complaints and concomitant diseases compared to the adult group, the respiratory function test results were lower. The complaint of shortness of breath was higher in the geriatric group compared to the adult group (71% in geriatric patients and 59.1% in adults). The most common diagnosis was chronic obstructive pulmonary disease (COPD, 37%) in the geriatric patients and asthma (27.7%) in the adult patients. As to the results of consultations, treatment oriented recommendations were given for 63 (46.6%) geriatric patients and approval for operation was given for 75 (54.7%) adult patients. CONCLUSION: Consultants should take the age of patients into consideration during evaluation in order to achieve the most appropriate treatment plan for these patients and reduce the potential postoperative complications to a minimum. PMID- 25743045 TI - Enhanced identification of BOLD-like components with multi-echo simultaneous multi-slice (MESMS) fMRI and multi-echo ICA. AB - The recent introduction of simultaneous multi-slice (SMS) acquisitions has enabled the acquisition of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) data with significantly higher temporal sampling rates. In a parallel development, the use of multi-echo fMRI acquisitions in conjunction with a multi-echo independent component analysis (ME ICA) approach has been introduced as a means to automatically distinguish functionally-related BOLD signal components from signal artifacts, with significant gains in sensitivity, statistical power, and specificity. In this work, we examine the gains that can be achieved with a combined approach in which data obtained with a multi-echo simultaneous multi-slice (MESMS) acquisition are analyzed with ME-ICA. We find that ME-ICA identifies significantly more BOLD-like components in the MESMS data as compared to data acquired with a conventional multi-echo single-slice acquisition. We demonstrate that the improved performance of MESMS derives from both an increase in the number of temporal samples and the enhanced ability to filter out high-frequency artifacts. PMID- 25743046 TI - Public goods and procreation. AB - Procreation is the ultimate public goods problem. Each new child affects the welfare of many other people, and some (but not all) children produce uncompensated value that future people will enjoy. This essay addresses challenges that arise if we think of procreation and parenting as public goods. These include whether individual choices are likely to lead to a socially desirable outcome, and whether changes in laws, social norms, or access to genetic engineering and embryo selection might improve the aggregate outcome of our reproductive choices. PMID- 25743047 TI - Distributive justice and cognitive enhancement in lower, normal intelligence. AB - There exists a significant disparity within society between individuals in terms of intelligence. While intelligence varies naturally throughout society, the extent to which this impacts on the life opportunities it affords to each individual is greatly undervalued. Intelligence appears to have a prominent effect over a broad range of social and economic life outcomes. Many key determinants of well-being correlate highly with the results of IQ tests, and other measures of intelligence, and an IQ of 75 is generally accepted as the most important threshold in modern life. The ability to enhance our cognitive capacities offers an exciting opportunity to correct disabling natural variation and inequality in intelligence. Pharmaceutical cognitive enhancers, such as modafinil and methylphenidate, have been shown to have the capacity to enhance cognition in normal, healthy individuals. Perhaps of most relevance is the presence of an 'inverted U effect' for most pharmaceutical cognitive enhancers, whereby the degree of enhancement increases as intelligence levels deviate further below the mean. Although enhancement, including cognitive enhancement, has been much debated recently, we argue that there are egalitarian reasons to enhance individuals with low but normal intelligence. Under egalitarianism, cognitive enhancement has the potential to reduce opportunity inequality and contribute to relative income and welfare equality in the lower, normal intelligence subgroup. Cognitive enhancement use is justifiable under prioritarianism through various means of distribution; selective access to the lower, normal intelligence subgroup, universal access, or paradoxically through access primarily to the average and above average intelligence subgroups. Similarly, an aggregate increase in social well-being is achieved through similar means of distribution under utilitarianism. In addition, the use of cognitive enhancement within the lower, normal intelligence subgroup negates, or at the very least minimises, several common objections to cognitive enhancement. Subsequently, this paper demonstrates that there is a compelling case for cognitive enhancement use in individuals with lower, normal intelligence. PMID- 25743048 TI - How to insure against utilitarian overconfidence. AB - This paper addresses two examples of overconfident presentations of utilitarian moral conclusions. First, there is Peter Singer's widely discussed claim that if the consequences of a medical experiment are sufficiently good to justify the use of animals, then we should be prepared to perform the experiment on human beings with equivalent mental capacities. Second, I consider defences of infanticide or after-birth abortion. I do not challenge the soundness of these arguments. Rather, I accuse those who seek to translate these conclusions into moral advice of a dangerous overconfidence. This paper offers an insurance policy that protects against some of the costs of mistaken moral reasoning. An interest in moral insurance is motivated by the recognition that, in the event that overconfident ethicists have reasoned incorrectly, some actions recommended by their conclusions are not just bad, but very bad. We should reject suggestions that we conduct medical experiments on humans or kill newborns. PMID- 25743049 TI - The value of respect in human research ethics: a conceptual analysis and a practical guide. AB - In order to continue to maintain public trust and confidence in human research, participants must be treated with respect. Researchers and Human Research Ethics Committee members need to be aware that modern considerations of this value include: the need for a valid consenting process, the protection of participants who have their capacity for consent compromised; the promotion of dignity for participants; and the effects that human research may have on cultures and communities. This paper explains the prominence of respect as a value when considering the ethics of human research and provides practical advice for both researchers and Human Research Ethics Committee members in developing respectful research practices. PMID- 25743050 TI - The limits of evidence: evidence based policy and the removal of gamete donor anonymity in the UK. AB - This paper will critically examine the use of evidence in creating policy in the area of reproductive technologies. The use of evidence in health care and policy is not a new phenomenon. However, codified strategies for evidence appraisal in health care technology assessments and attempts to create evidence based policy initiatives suggest that the way evidence is used in practice and policy has changed. This paper will examine this trend by considering what is counted as 'good' evidence, difficulties in translating evidence into policy and practice and how evidence interacts with principles. To illustrate these points the removal of gamete donor anonymity in the UK in 2005 and the debates that preceded this change in the law will be examined. It will be argued that evidence will only ever take us so far and attention should also be paid to the underlying principles that guide policy. The paper will conclude with suggestions for how underlying principles can be more rigorously used in policy formation. PMID- 25743051 TI - Gamete donation, information sharing and the best interests of the child: an overview of the psychosocial evidence. AB - This paper overviews key empirical findings from social science research regarding the impact of gamete donation on child wellbeing. In particular, the paper addresses current regulatory debates concerning information sharing and the best interests of the child by considering psychosocial aspects of telling--or not telling--children about their donor conception and the identity of their donor. The paper identifies three core sets of empirical, ethical and policy concerns underpinning these debates relating to (i) the psychosocial impact of gamete donation per se on child wellbeing, (ii) the psychosocial impact of parental disclosure decisions on child wellbeing, and (iii) the psychosocial implications of donor identification for donor-conceived offspring. The paper illustrates how these concerns are framed by ideas about the significance-or not of 'genetic relatedness'; ideas which have come to the fore in contemporary discussions about the potential consequences of donor-conceived individuals gaining access to their donor's identity. By drawing together research findings that may be pertinent to the regulation of gamete donation and information sharing, a further aim of this paper is to explore the potential use and misuse of empirical 'evidence' in ethical and policy debates. Whilst this paper starts from the premise that psychosocial data has a vital role in grounding normative discussions, it seeks to contribute to this dialogue by highlighting both the value and limitations of social science research. In particular, the paper argues for a cautious approach to applying psychosocial evidence to ethical issues that is sensitive to the caveats and nuances of research findings and the changing cultural and regulatory context. PMID- 25743052 TI - Central role of altruism in the recruitment of gamete donors. AB - This paper explores problems associated with using altruism as the central value in gamete donation, and in doing so draws on empirical data that sheds light on why gamete donors choose to donate. Donation of bodily material is, arguably, supposed to be motivated by altruism, and this is the view taken by many European governments. Other values are often ignored or rejected as morally inappropriate. This paper analyses some conceptual and practical problems with the use of altruism as the motivation to determine moral acceptability-drawing on empirical data that suggests gamete donors are not motivated purely by altruism, and that motivations are in fact quite complex. Two problems are first analysed: (1) how do we distinguish altruistic from non-altruistic donations and (2) how do we distinguish between removing barriers and providing incentives. A final question, triggered by the Nuffield Council on Bioethics' report, is whether the meaning of the payment should be decided on the basis of an a priori definition or on the basis of the donors' subjective experience. It is concluded that there are different legitimate core values in donation, which should be balanced. In order to value the good generated by donation, donors with mixed motives should be accepted, as long as helping others is an important motive and also features in their motivation. PMID- 25743053 TI - The use of empirical evidence in formulating reproductive policy advice and policy. AB - The focus of this paper is an analysis and discussion of what kind of empirical evidence bodies that advise on or set public policy in the area of reproduction and reproductive technologies are looking for when developing new advice or policy, but the analysis has implications for other areas of 'bioethics policy making' as well. The paper outlines some important differences between policy making and philosophical analysis, provides an account of 'policy relevance' and discusses ways in which evidence may be misused in policy making. The scope of the paper is, for the most part restricted to considerations of empirical evidence of a social scientific nature. PMID- 25743054 TI - Can significant differences in regulating medical and non-medical research be justified? AB - It is now typical for human subjects research to be regulated by review by an independent research ethics committee in most jurisdictions. However it is common for countries to opt to only compulsorily regulate medical research while leaving some or all non-medical research either unregulated or only regulated on a voluntary basis. In this paper I will argue, using regulation in the UK as an example, that it is difficult to justify this sharp distinction in practices. While I won't come to any definitive conclusions in this paper as to whether research ought to be regulated compulsorily I will suggest that we would be better to regulate all research, albeit perhaps with a lighter touch than the present UK system if we want to prevent some highly risky research avoiding appropriate regulation. I will examine several arguments to defend making such a distinction; that medical professionals have special moral duties, that medical research has a higher magnitude/frequency of risks and that regulating non medical research constitutes the inappropriate imposition of the medical model onto non-medical research. Having critiqued these objections I will then discuss the advantages of harmonizing the regulation of research and conclude that there is not a good reason to treat medical and non-medical research as fundamentally different in kind. PMID- 25743055 TI - The ambiguous lessons of the Iranian model of paid living kidney donation : Fry Revere, S. (2014). The kidney sellers: a journey of discovery in Iran. (Durham: Carolina Academic Press). PMID- 25743056 TI - Descendants and advance directives. AB - Some of the concerns that have been raised in connection to the use of advance directives are of the epistemic variety. Such concerns highlight the possibility that adhering to an advance directive may conflict with what the author of the directive actually wants (or would want) at the time of treatment. However, at least one objection to the employment of advance directives is metaphysical in nature. The objection to be discussed here, first formulated by Rebecca Dresser and labeled by Allen Buchanan as the slavery argument and David DeGrazia the someone else problem, aims to undermine the legitimacy of certain uses of advance directives by concluding that such uses rest upon an incorrect assumption about the identity over time of those ostensibly governed by the directives. There have been numerous attempts to respond to this objection. This paper aims to assess two strategies that have been pursued to cope with the problem. PMID- 25743057 TI - Epidemics of Ebola virus infection. Introduction. PMID- 25743058 TI - Dual-use decision making: relational and positional issues. AB - Debates about dual-use research often turn on the potential for scientific research to be used to benefit or harm humanity. This dual-use potential is conventionally understood as the product of the magnitude of the harms and benefits of dual-use research, multiplied by their likelihood. This account, however, neglects important social aspects of the use of science and technology. In this paper, I supplement existing conceptions of dual-use potential to account for the social context of dual-use research. This account incorporates relational and positional concerns that feature in the success or failure of dual-use. I then defend this account against foreseeable objections. PMID- 25743059 TI - Evaluating human enhancements: the importance of ideals. AB - Is it necessary to have an ideal of perfection in mind to identify and evaluate true biotechnological human "enhancements", or can one do without? To answer this question we suggest employing the distinction between ideal and non-ideal theory, found in the debate in political philosophy about theories of justice: the distinctive views about whether one needs an idea of a perfectly just society or not when it comes to assessing the current situation and recommending steps to increase justice. In this paper we argue that evaluating human enhancements from a non-ideal perspective has some serious shortcomings, which can be avoided when endorsing an ideal approach. Our argument starts from a definition of human enhancement as improvement, which can be understood in two ways. The first approach is backward-looking and assesses improvements with regard to a status quo ante. The second, a forward-looking approach, evaluates improvements with regard to their proximity to a goal or according to an ideal. After outlining the limitations of an exclusively backward-looking view (non-ideal theory), we answer possible objections against a forward-looking view (ideal theory). Ultimately, we argue that the human enhancement debate would lack some important moral insights if a forward-looking view of improvement is not taken into consideration. PMID- 25743060 TI - Factors associated with length of stay following an emergency medical admission. AB - BACKGROUND: Hospitals are under pressure to use resources in the most efficient manner. We have examined the factors predicting Length of Stay (LOS) in one institution, using a database of all episodes of emergency medical admissions prospectively collected over 12 years. AIM: To examine the ability to predict hospital LOS following an emergency medical hospital admission. METHODS: All emergency admissions (66,933 episodes; 36,271 patients) to St. James's Hospital, Dublin, Ireland over a 12-year period (2002-2013) were evaluated in relation to LOS. Predictor variables (identified univariately) were entered into a multiple logistic regression model to predict a longer or shorter LOS (bivariate at the median). The data was also modelled as count data (absolute LOS), using zero truncated Poisson regression methodology. Appropriate post-estimation techniques for model fit were then applied to assess the resulting model. RESULTS: The major predictors of LOS included Acute Illness Severity (biochemical laboratory score at admission), Charlson co-morbidity, Manchester Triage Category at admission, Diagnosis Related Group, sepsis status (based on blood culture result), and Chronic Disease Score Indicator. The full model to predict a LOS above or below the median had an Area Under Receiver Operating Characteristic (AUROC) of 0.71 (95% CI: 0.70, 0.71). The truncated Poisson model appeared to achieve a good model fit (R(2) statistic=0.76). CONCLUSION: Predictor variables strongly correlated with LOS; there were linear increases within categories and summation between variables. More predictor variables may improve model reliability but predicting LOS ranges or quantiles may be more realistic, based on these results. PMID- 25743062 TI - Medium effect on the characteristics of the coupled seismic and electromagnetic signals. AB - Recently developed numerical simulation technique can simulate the coupled seismic and electromagnetic signals for a double couple point source or a finite fault planar source. Besides the source effect, the simulation results showed that both medium structure and medium property could affect the coupled seismic and electromagnetic signals. The waveform of coupled signals for a layered structure is more complicated than that for a simple uniform structure. Different from the seismic signals, the electromagnetic signals are sensitive to the medium properties such as fluid salinity and fluid viscosity. Therefore, the co-seismic electromagnetic signals may be more informative than seismic signals. PMID- 25743061 TI - Challenge to the suppression of tumor growth by the beta4-galactosyltransferase genes. AB - It has been well established that structural changes in glycans attached to proteins and lipids are associated with malignant transformation of cells. We focused on galactose residues among the sugars since they are involved in the galectin-mediated biology, and many carbohydrate antigens are frequently expressed on this sugar. We found changes in the expression of the beta4 galactosyltransferase (beta4GalT) 2 and 5 genes in cancer cells: decreased expression of the beta4GalT2 gene and increased expression of the beta4GalT5 gene. The growth of mouse melanoma cells showing enhanced expression of the beta4GalT2 gene or reduced expression of the beta4GalT5 gene is inhibited remarkably in syngeneic mice. Tumor growth inhibition is probably caused by the induction of apoptosis, inhibition of angiogenesis, and/or reduced MAPK signals. Direct transduction of human beta4GalT2 cDNA together with the adenovirus vector into human hepatocellular carcinoma cells grown in SCID mice results in marked growth retardation of the tumors. beta4GalT gene-transfer appears to be a potential tool for cancer therapy. PMID- 25743063 TI - Criticality features in ULF magnetic fields prior to the 2011 Tohoku earthquake. AB - The criticality of ULF (Ultra-low-frequency) magnetic variations is investigated for the 2011 March 11 Tohoku earthquake (EQ) by natural time analysis. For this attempt, some ULF parameters were considered: (1) Fh (horizontal magnetic field), (2) Fz (vertical magnetic field), and (3) Dh (inverse of horizontal magnetic field). The first two parameters refer to the ULF radiation, while the last parameter refers to another ULF effect of ionospheric signature. Nighttime (L.T. = 3 am +/- 2 hours) data at Kakioka (KAK) were used, and the power of each quantity at a particular frequency band of 0.03-0.05 Hz was averaged for nighttime hours. The analysis results indicate that Fh fulfilled all criticality conditions on March 3-5, 2011, and that the additional parameter, Dh reached also a criticality on March 6 or 7. In conclusion, criticality has reached in the pre EQ fracture region a few days to one week before the main shock of the Tohoku EQ. PMID- 25743064 TI - Errata to "reminiscence of phospholipase B in Penicillium notatum". PMID- 25743065 TI - pH-responsive water-in-water Pickering emulsions. AB - The structure and stability of water-in-water emulsions was investigated in the presence of spherical, pH-sensitive microgels. The emulsions were formed by mixing aqueous solutions of dextran and PEO. The microgels consisted of cross linked, synthetic polymers with a radius that steeply increased from 60 to 220 nm with increasing pH within a narrow range around 7.0. At all pH values between 5.0 and 7.5, the microgels were preferentially situated at the interface, but only in a narrow range between pH 7.0 and 7.5, the emulsions were stable for at least 1 week. The droplet size was visualized with confocal laser scanning microscopy and was found to be smallest in the stable pH range. Emulsions could be stabilized or destabilized by small changes of the pH. Addition of small amounts of salt led to a shift of the pH range where the emulsions were stable. The effects of varying the microgel concentration and the polymer composition were investigated. PMID- 25743067 TI - The gastrointestinal phage communities of the cultivated freshwater fishes. AB - The phage communities in the gut of 62 cultivated freshwater fish were investigated by culture-based methods. Using three selective media, 445 pathogenic bacilli strains were isolated and used as indicators for subsequent phage isolations. Totally, 63 phages were detected and the respective host strains were identified with the comparative sequence analysis of 16S rRNA gene, including Aeromonas (29), Vibrio (1), Citrobacter (16), Serratia (4), Enterobacter (2), Proteus (3), Buttiauxella (2), Plesiomonas (2), Kluyvera (1), Morgenella (2) and Providencia (1). The diversity of Aeromonas phages was assessed by discrimination of their host strains with random amplified polymorphic DNA method. Furthermore, the isolated Aeromonas phages were characterized by host range and growth inhibition assay. The results demonstrated that there were abundant and diverse phage populations in the gut environment of the cultivated freshwater fishes. The phages could contribute to the microbiota balance in the gut ecosystem of fishes and provide reliable phage sources for future applications. PMID- 25743066 TI - MicroRNA-146a regulates ICOS-ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres. AB - Tight control of T follicular helper (Tfh) cells is required for optimal maturation of the germinal centre (GC) response. The molecular mechanisms controlling Tfh-cell differentiation remain incompletely understood. Here we show that microRNA-146a (miR-146a) is highly expressed in Tfh cells and peak miR-146a expression marks the decline of the Tfh response after immunization. Loss of miR 146a causes cell-intrinsic accumulation of Tfh and GC B cells. MiR-146a represses several Tfh-cell-expressed messenger RNAs, and of these, ICOS is the most strongly cell autonomously upregulated target in miR-146a-deficient T cells. In addition, miR-146a deficiency leads to increased ICOSL expression on GC B cells and antigen-presenting cells. Partial blockade of ICOS signalling, either by injections of low dose of ICOSL blocking antibody or by halving the gene dose of Icos in miR-146a-deficient T cells, prevents the Tfh and GC B-cell accumulation. Collectively, miR-146a emerges as a post-transcriptional brake to limit Tfh cells and GC responses. PMID- 25743068 TI - Significant enhancement of methionol production by co-expression of the aminotransferase gene ARO8 and the decarboxylase gene ARO10 in Saccharomyces cerevisiae. AB - Methionol is an important volatile sulfur flavor compound, which can be produced via the Ehrlich pathway in Saccharomyces cerevisiae. Aminotransferase and decarboxylase are essential enzymes catalyzing methionol biosynthesis. In this work, two aminotransferase genes ARO8 and ARO9 and one decarboxylase gene ARO10 were introduced into S. cerevisiae S288c, respectively, via an expression vector. Over-expression of ARO8 resulted in higher aminotransferase activity than that of ARO9. And the cellular decarboxylase activity was remarkably increased by over expression of ARO10. A co-expression vector carrying both ARO8 and ARO10 was further constructed to generate the recombinant strain S810. Shaking flask experiments showed that the methionol yield from S810 reached 1.27 g L(-1), which was increased by 51.8 and 68.8% compared to that from the wild-type strain and the control strain harboring the empty vector. The fed-batch fermentation by strain S810 produced 3.24 g L(-1) of methionol after 72 h of cultivation in a bioreactor. These results demonstrated that co-expression of ARO8 and ARO10 significantly boosted the methionol production. It is the first time that more than 3.0 g L(-1) of methionol produced by genetically engineered yeast strain was reported by co-expression of the aminotransferase and decarboxylase via the Ehrlich pathway. PMID- 25743069 TI - Bacterial diversity in native habitats of the medicinal fungus Ophiocordyceps sinensis on Tibetan Plateau as determined using Illumina sequencing data. AB - Ophiocordyceps sinensis is one of the most well-known traditional Chinese medicinal fungi. In this study, bacterial diversity in the soils of native habitats of O. sinensis was investigated using Illumina sequencing data. A total of 525,000 sequences of V6-16S rRNA were analyzed. The number of OTUs from each sample ranged from 13,858 to 15,978 at 97% sequence similarity cut-off. The results demonstrated that the deep sequencing approach provides improved access to rare genotypes. Richness indices and Shannon's diversity index did not differ significantly between samples collected from locations where O. sinensis was present (Os1-3) and not present (NOs1-3). Classified bacterial sequences were grouped into 23 phyla including Proteobacteria, Actinobacteria, Acidobacteria, Verrucomicrobia, etc. The Venn diagram revealed that 7183 OTUs belonging to 14 phyla were shared by Os, NOs and MP (mycelial pellicle wrapping the sclerotium of O. sinensis) samples, possibly representing a core microbiome existing in native habitats of O. sinensis, and that 863 belonging to 12 phyla were shared by Os and MP samples, possibly related to the occurrence of O. sinensis. Overall, the results revealed a high bacterial diversity in the soil samples and the relationships between the bacterial diversity and O. sinensis merit further investigation. PMID- 25743070 TI - Draft genome sequence of the Chilean isolate Aeromonas salmonicida strain CBA100. AB - We report the draft genome sequence from Aeromonas salmonicida sp. strain CBA100, which was characterized as an antibiotic-resistant bacterium isolated from infected rainbow trout. The total size of the genome is 4,788,109 bp, with a G + C content of 60.55%. Comparison of its open reading frames shows that the closest homologue to one third of the genes of strain CBA100 are found in A. hydrophila. The strain contains several efflux pumps and putative genes that confer resistance to multiclass antibiotics, including macrolide, beta-lactamics, florfenicol and quinolones. The antibiogram profile suggests that efflux pumps are the main mechanism of resistance to non-beta-lactamic antibiotics. This is the first genome of a Chilean isolate of A. salmonicida, which should shed light on the design of strain-specific vaccines against this pathogen and reduce the use of antibiotics for preventive treatment in Chilean aquaculture. PMID- 25743071 TI - Mineral phosphate solubilization by Streptomyces sp. CTM396 involves the excretion of gluconic acid and is stimulated by humic acids. AB - The actinomycetes isolates (128) which were taken from agricultural soil samples and collected near a rock phosphate processing unit were screened for mineral phosphate-solubilizing (MPS) ability. A significant MPS activity was observed for 30 isolates on various phosphate sources when grown in the National Botanical Research Institute's phosphate broth. CTM396 and CTM397 strains which showed the highest MPS abilities were identified by 16S rDNA sequencing as members of the genus Streptomyces. Their MPS activity was proved to be concomitant with a drop in pH due to the secretion of gluconic acid (GA). This was correlated with the simultaneous detection by PCR of genes gdh [encoding the glucose dehydrogenase (GDH) responsible for GA production from glucose] and pqq (involved in biosynthesis of the pyrroloquinoline quinone cofactor of GDH), as well as the highlighting of GHD enzyme activity, for the first time in a Streptomyces sp. strain producing GA. Furthermore, the 0.05% of humic acids proved to have a stimulatory effect on the growth and the ability of CTM396 to solubilize Gafsa rock phosphate. According to this study, it is possible to use humic acids and Gafsa rock phosphate in association with spores of ad hoc Streptomyces strains as natural and efficient amendments to improve plant growth with no need of costly and pollutant transformation of Gafsa rock phosphate. PMID- 25743072 TI - Toxigenic Vibrio cholerae identified in estuaries of Tanzania using PCR techniques. AB - The current study assessed the occurrence of the Vibrio cholerae serogroups O1 and O139 in environmental samples along salinity gradients in three selected estuaries of Tanzania both through culture independent methods and by cultured bacteria. Occurrence of V. cholerae was determined by PCR targeting the V. cholerae outer membrane protein gene ompW. Furthermore, the presence of toxigenic strains and serogroups O1 and O139 was determined using multiplex PCR with specific primers targeting the cholera toxin gene subunit A, ctxA, and serotype specific primers, O1-rfb and O139-rfb, respectively. Results showed that V. cholerae occurred in approximately 10% (n = 185) of both the environmental samples and isolated bacteria. Eight of the bacteria isolates (n = 43) were confirmed as serogroup O1 while one belonged to serogroup O139, the first reported identification of this epidemic strain in East African coastal waters. All samples identified as serogroup O1 or O139 and a number of non-O1/O139 strains were ctxA positive. This study provides in situ evidence of the presence of pathogenic V. cholerae O1 and O139 and a number of V. cholerae non-O1/O139 that carry the cholera toxin gene in estuaries along the coast of Tanzania. PMID- 25743073 TI - Characterization of the highly active fragment of glyceraldehyde-3-phosphate dehydrogenase gene promoter for recombinant protein expression in Pleurotus ostreatus. AB - Developing efficient native promoters is important for improving recombinant protein expression by fungal genetic engineering. The promoter region of glyceraldehyde-3-phosphate dehydrogenase gene in Pleurotus ostreatus (Pogpd) was isolated and optimized by upstream truncation. The activities of these promoters with different lengths were further confirmed by fluorescence, quantitative real time PCR and Western blot analysis. A truncated Pogpd-P2 fragment (795 bp) drove enhanced green fluorescence protein (egfp) gene expression in P. ostreatus much more efficiently than full-length Pogpd-P1. Further truncating Pogpd-P2 to 603, 403 and 231 bp reduced the eGFP expression significantly. However, the 403-bp fragment between -356 bp and the start codon was the minimal but sufficient promoter element for eGFP expression. Compact native promoters for genetic engineering of P. ostreatus were successfully developed and validated in this study. This will broaden the preexisting repertoire of fungal promoters for biotechnology application. PMID- 25743076 TI - Effects of terminal chain length in hydrogen-bonded chiral switches on phototunable behavior of chiral nematic liquid crystals: helicity inversion and phase transition. AB - A novel series of photoresponsive chiral switches are fabricated by a facile hydrogen-bonded (H-bonded) assembly method, in which the binaphthyl azobenzene molecule is used as the proton acceptor, and binaphthyl acids with opposite chiral configuration are proton donors. We find that the helical twisted power of H-bonded chiral switches and the helical handedness of induced chiral nematic liquid crystals (N*-LCs) are mainly determined by the terminal flexible chain length in proton donors of binaphthyl acids. Controlling the lengths of the terminal flexible chain leads to different photoswitching behaviors by light irradiation, such as a helical inversion in the N*-LCs and a phase transition from N*-LCs to nematic LCs. This is mainly because of chiral counteraction and intensity attenuation of opposite chiral configurations between the proton acceptor and proton donor during UV-vis irradiation. Additionally, the thermal switching behavior of N*-LCs doped with H-bonded chiral switches is also demonstrated, and the related tuning mechanism may be attributed to the H-bonded effect and the changes in a dihedral angle of the binaphthyl rings. This facile assembly approach provides a new way for the fabrication of functional chiral switches for photonic applications. PMID- 25743074 TI - The genome of Shigella dysenteriae strain Sd1617 comparison to representative strains in evaluating pathogenesis. AB - We sequenced and analyzed Shigella dysenteriae strain Sd1617 serotype 1 that is widely used as model strain for vaccine design, trials and research. A combination of next-generation sequencing platforms and assembly yielded two contigs representing a chromosome size of 4.34 Mb and the large virulence plasmid of 177 kb. This genome sequence is compared with other Shigella genomes in order to understand gene complexity and pathogenic factors. PMID- 25743077 TI - On the number of perceivable blur levels in naturalistic images. AB - Blur is a useful cue for depth. Natural images contain objects at a range of depths whose depth can be signaled by their perceived blur. Here, to evaluate the usefulness of blur as a depth cue, we estimate the number blur levels that observers can perceive simultaneously. To estimate this value, observers discriminated and classified dead leaves patterns that contained a controlled distribution of blur levels but are more complex or naturalistic than stimuli typically used in blur research. We used a 2-IFC discrimination task, in which observers reported the interval that contained more blur levels and a classification task, in which observers reported the number of perceived blur levels. In both tasks, observers could not discriminate or classify more than four levels of blur in the stimulus reliably. In isolation from other cues, blur may provide only a coarse cue to depth and add limited depth information when present in natural scenes with complex distributions of blur and multiple depth cues. PMID- 25743078 TI - Contrast and stimulus duration dependence of perceptual surround suppression in older adults. AB - Most natural visual tasks involve the extraction of visual features from suprathreshold contrast backgrounds, hence an understanding of how ageing impacts on contrast mechanisms is essential to understand elderly visual function. Previous studies have revealed increased perceptual surround suppression of contrast in older adults. We aimed to determine whether such age-related effects depend on the centre or surround stimulus contrast as the neurophysiological mechanisms underpinning contrast-contrast suppression depend on such contrast relationships. We also measured surround suppression of contrast for longer duration and shorter duration stimuli to explore for effects of surround adaptation Fifteen younger and 15 older adults performed a centre-surround contrast discrimination task for a variety of centre-surround contrast combinations (20%, 40% and 80% contrast). Stimulus duration was 500ms. The 40% centre, 80% surround condition was also presented for 100ms duration. Relative to younger adults, perceptual surround suppression was increased for the older group for low, but clearly suprathreshold, central contrasts (20% contrast), whilst both groups performed similarly for stimuli with high centre contrasts. Data was best fit by a model with both increased inhibitory and excitatory weightings in the older group. Reduced stimulus duration increased perceptual surround suppression for both groups consistent with reduced adaptation to the surround, and did not explain the difference in suppression magnitude between groups. Understanding the stimulus parameters that elicit increased surround suppression in older adults is key to directing future work exploring underlying neural substrates, in addition to potentially being useful for predicting performance on more complicated natural visual tasks such as object and scene perception. PMID- 25743079 TI - Anisotropy in spatial summation properties of human Ocular-Following Response (OFR). AB - Using sinusoidal gratings we show that an increase in stimulus size confined to the dimension orthogonal to the axis of motion leads to stronger Ocular Following Responses (OFRs) up to a certain optimal size. An increase beyond this optimum produces smaller responses, indicating suppressive interactions. In sharp contrast, when the stimulus growth occurs parallel to the axis of motion OFR magnitudes increase monotonically both for horizontal and vertical directions of motion. Similar results are obtained with 1D white noise patterns. However, the OFR spatial anisotropy is minimal with 2D white noise patterns, revealing a pivotal role of orientation-selective (i.e., cortical) mechanisms in mediating this phenomenon. The lack of anisotropy for 2D patterns suggests that directional signals alone are not sufficient to elicit this suppression. The OFR spatial anisotropy is potentiated if a stationary grating is presented for 600-1000ms before its motion commences, further emphasizing the importance of static orientation signals. These results suggest that the strength of cortical spatial interactions is asymmetric-i.e., larger in the direction of the ends than the flanks of an orientation-selective receptive field-which corroborates the existing neurophysiological evidence. PMID- 25743080 TI - Compliance and patching and atropine amblyopia treatments. AB - In the past 20 years, there has been a great advancement in knowledge pertaining to compliance with amblyopia treatments. The occlusion dose monitor introduced quantitative monitoring methods in patching, which sparked our initial understanding of the dose-response relationship for patching amblyopia treatment. This review focuses on current compliance knowledge and the impact it has on patching and atropine amblyopia treatment. PMID- 25743082 TI - Sharing pharma compounds with academia: experiences with providing vitamin D receptor ligands. PMID- 25743083 TI - Using ethnographic approaches to explore care home medicine management systems. PMID- 25743084 TI - Cone beam computed tomography after round window vibroplasty: do the radiological findings match the auditory outcome? AB - CONCLUSION: The cone beam computed tomography (CBCT) imaging technique has proved to be reliable for assessing the appropriate positioning of the floating mass transducer (FMT) in the round window (RW) niche, although some parameters do not seem to be essential for achieving a satisfactory functional outcome. OBJECTIVES: To evaluate the role that specific imaging parameters derived from CBCT of the temporal bone have for predicting the functional outcome after RW vibroplasty (RW VP). METHODS: CBCT imaging was carried out in a homogeneous group of patients who presented with a mixed type of hearing loss after open tympanoplasty. Three arbitrary radiological parameters were taken into account: the FMT/RW membrane contact, bony contacts of the FMT margins, and the inferior FMT tissue support. The audiological assessment took into consideration the PTA4 (500-4000 Hz), the PTA2 (125-250 Hz), and the word recognition score (WRS) in quiet and in noise. RESULTS: One subject presented with all positive CBCT parameters and showed a good, but not the best auditory performance among the study group. In the majority of the subjects, with a satisfactory postoperative hearing improvement, at least two of the three radiological parameters were present. In comparison with the unaided condition, an improvement in both the PTA4 and PTA2 was found in all the subjects. PMID- 25743081 TI - Targeting the translation machinery in cancer. AB - Dysregulation of mRNA translation is a frequent feature of neoplasia. Many oncogenes and tumour suppressors affect the translation machinery, making aberrant translation a widespread characteristic of tumour cells, independent of the genetic make-up of the cancer. Therefore, therapeutic agents that target components of the protein synthesis apparatus hold promise as novel anticancer drugs that can overcome intra-tumour heterogeneity. In this Review, we discuss the role of translation in cancer, with a particular focus on the eIF4F (eukaryotic translation initiation factor 4F) complex, and provide an overview of recent efforts aiming to 'translate' these results to the clinic. PMID- 25743085 TI - Functional interaction of nicotinic acetylcholine receptors and Na+/K+ ATPase from Locusta migratoria manilensis (Meyen). AB - Associated proteins are important for the correct functioning of nicotinic acetylcholine receptors (nAChRs). In the present study, a neonicotinoid-agarose affinity column was used to isolate related proteins from a solubilized membrane preparation from the nervous system of Locusta migratoria manilensis (Meyen). 1530 peptides were identified and most of them were involved in the membranous structure, molecular interaction and cellular communication. Among these peptides, Na(+)/K(+) ATPase had the highest MASCOT score and were involved in the molecular interaction, which suggested that Na(+)/K(+) ATPase and nAChRs might have strong and stable interactions in insect central nervous system. In the present study, functional interactions between nAChRs and Na(+)/K(+) ATPase were examined by heterologous expression in Xenopus oocytes. The results showed that the activated nAChRs increased pump currents of Na(+)/K(+) ATPase, which did not require current flow through open nAChRs. In turn, Na(+)/K(+) ATPase significantly increased agonist sensitivities of nAChRs in a pump activity independent manner and reduced the maximum current (Imax) of nAChRs. These findings provide novel insights concerning the functional interactions between insect nAChRs and Na(+)/K(+) ATPase. PMID- 25743086 TI - Cryopreservation of the Hair Follicle Maintains Pluripotency of Nestin-Expressing Hair Follicle-Associated Pluripotent Stem Cells. AB - Hair follicles contain nestin-expressing pluripotent stem cells, the origin of which is above the bulge area, below the sebaceous gland. We have termed these cells hair follicle-associated pluripotent (HAP) stem cells. In the present study, we established efficient cryopreservation methods of the hair follicle that maintained the pluripotency of HAP stem cells. We cryopreserved the whole hair follicle from green fluorescent protein transgenic mice by slow-rate cooling in TC-Protector medium and storage in liquid nitrogen. After thawing, the upper part of the hair follicle was isolated and cultured in Dulbecco's Modified Eagle's Medium (DMEM) with fetal bovine serum (FBS). After 4 weeks of culture, cells from the upper part of the hair follicle grew out. The growing cells were transferred to DMEM/F12 without FBS. After 1 week of culture, the growing cells formed hair spheres, each containing ~1*10(2) HAP stem cells. The hair spheres contained cells that differentiated to neurons, glial cells, and other cell types. The thawed and cultured upper part of the hair follicle produced almost as many pluripotent hair spheres as fresh follicles. The hair spheres derived from slow-cooling cryopreserved hair follicles were as pluripotent as hair spheres from fresh hair follicles. In contrast, rapid-cooling (vitrification) cryopreservation poorly preserved the pluripotency of the hair follicle stem cells. Stem cell marker genes (nestin, Sox2, and SSEA-1) were as highly expressed in slow-rate cooled cryopreserved follicles, after thawing, as in fresh follicles. However, in the vitrification cryopreserved follicles, the expression of the stem cell marker genes was greatly reduced. Direct cryopreservation of hair spheres by either the rapid-cooling, or slow-cooling method, resulted in loss of pluripotency. These results suggest that the slow-rate cooling cryopreservation of the whole hair follicle is effective to store HAP stem cells. Stored HAP stem cells would be very useful in personalized regenerative medicine, enabling any individual to maintain a bank of pluripotent stem cells for future clinical use. PMID- 25743087 TI - Age, period and cohort effects on time trends in alcohol consumption in the Swedish adult population 1979-2011. AB - AIMS: In Sweden, alcohol abstention has increased over the last 20 years and consumption has recently decreased after a peak in 2004. To understand the dynamics of these trends the present study aims at estimating age, period and cohort (APC) effects on trends in alcohol use prevalence as well as overall and beverage-specific volume of drinking over the last three decades. METHODS: APC analysis of seven cross-sectional surveys from 1979 to 2011 was conducted using cross-classified random effects models (CCREMs) by gender. The nationally representative samples comprised 77,598 respondents aged 16-80 years. Outcome measures were 30-day prevalence of alcohol use and overall as well as beverage specific alcohol volume. RESULTS: Trends in prevalence, overall and beverage specific volume were significantly affected by APC. The period effects of prevalence and overall volume show a small decline after an increase up to the year 2005. Mean beer and wine volume levelled off after a peak in 2005 and volume of spirits drinking decreased constantly. Predicted alcohol prevalence rates in male cohorts (1945-1985) remained generally at the same level, while they declined in post-World War II female generations. Results point to high overall and beverage-specific consumption among cohorts born in the 1940s, 1950s and 1980s. CONCLUSIONS: High consuming cohorts of the 1940-1950s were key in rising consumption up to 2005. Progression through the life course of these cohorts, a decrease in prevalence and drinking volume in successive cohorts seem to have contributed to the recent downward trend in alcohol use in Sweden. PMID- 25743088 TI - On bioinformatic resources. PMID- 25743090 TI - Liver parenchyma access and lesion marker via the endovascular route. AB - BACKGROUND: Neoadjuvant chemotherapeutic regimens for metastatic colorectal cancer are now so effective that they can cause "vanishing" lesions. With new advances such as local ablation, intra-arterial treatments in bolus with pumps or with beads, and isolation of hepatic perfusion, the need for a working channel to the liver may be warranted, ideally reducing the risk of spreading neoplastic cells. MATERIALS AND METHODS: The endovascular trans-vessel wall Extroducer device makes it possible to gain direct access to the liver parenchyma. The distal tip is then detached, to act as both a marker and a securing plug in the vessel defect. We used ex vivo and in vivo tests to evaluate the device as a working channel for local administration of substances to the parenchyma and as a marker for detection with both transabdominal and intraoperative ultrasonography. RESULTS: We could deploy the Extroducer device without any hemorrhagic or thromboembolic complications in vivo, and we were able to detect all markers ex vivo and in vivo using both transabdominal and intraoperative ultrasonography. Furthermore, we found that it is possible to administer substances to the liver parenchyma using the catheter. CONCLUSIONS: The trans-vessel wall technique can be used to establish a working channel to the liver parenchyma for administration of any substance, such as chemotherapeutic agents or cells. The detached device can also be used as a marker for ultrasound-guided partial liver resection in "vanishing lesions." The technique should have a low risk of seeding of neoplastic cells. This study in large animals forms a strong basis for translation to clinical studies. PMID- 25743091 TI - Progress in the preparation and application of three-dimensional graphene-based porous nanocomposites. AB - Due to high specific surface area, excellent conductivity, low mass density, good compatibility and elegant flexibility, three-dimensional graphene composites with interconnected porous structures possess unusual and novel physical and electronic properties, unsurpassed chemical functionalities and other attractive features. Therefore, different three-dimensional graphene-based nanoporous scaffolds have been extensively designed, prepared and investigated for practical applications in lithium-ion batteries, super-capacitors, solar cells, catalysis, thermal management, environment pollution enrichment and separation, and chemical sensors with high performance from both fundamental and technological viewpoints. To present readers with a better understanding of this kind of important porous material, in this feature article, we will highlight the main achievements made in the preparation of 3D graphene micro- and/or nano-architectures and their potential applications in the aforementioned fields. PMID- 25743089 TI - Nanopore-based fourth-generation DNA sequencing technology. AB - Nanopore-based sequencers, as the fourth-generation DNA sequencing technology, have the potential to quickly and reliably sequence the entire human genome for less than $1000, and possibly for even less than $100. The single-molecule techniques used by this technology allow us to further study the interaction between DNA and protein, as well as between protein and protein. Nanopore analysis opens a new door to molecular biology investigation at the single molecule scale. In this article, we have reviewed academic achievements in nanopore technology from the past as well as the latest advances, including both biological and solid-state nanopores, and discussed their recent and potential applications. PMID- 25743092 TI - Induction of fibronectin by HER2 overexpression triggers adhesion and invasion of breast cancer cells. AB - Fibronectin (FN), an extracellular matrix ligand, plays a pivotal role in cell adhesion, migration, and oncogenic transformation. Aberrant FN expression is associated with poor prognoses in various types of cancer, including breast cancer. In the current study, we investigated the relationship between FN induction and HER2 expression in breast cancer cells. Our results showed that the level of FN expression increased in response to HER family ligands, EGF and TGF alpha in a time- and dose-dependent manner. On the other hand, EGF-induced FN expression decreased in response to trastuzumab, which is a HER2-targeted monoclonal antibody. However, EGF-induced FN expression was not affected by trastuzumab in JIMT-1 breast cancer cells, which are trastuzumab insensitive cells. Next, we introduced the HER2 gene into MDA-MB231 cells to verify the relationship between FN and HER2. The level of FN expression significantly increased in HER2-overexpressed MDA-MB231 cells. In contrast, the induction of FN by HER2 was significantly decreased in response to trastuzumab treatment. In addition, the induction of FN by HER2 was down-regulated by the MEK 1/2 specific inhibitor, U0126. Using conditioned culture media of vec- and HER2-overexpressed MDA-MB231 cells, we observed the cell morphology, adhesion, and invasion of MDA MB231 cells. Interestingly, in conditioned culture media of HER2-overexpressed MDA-MB231 cells, the cell morphology was altered, and adhesion and invasion of MDA-MB231 cells significantly increased. In addition, our results showed that recombinant human FN augmented cell adhesion and invasion of MDA-MB231 cells while these inductions decreased in response to an FN inhibitor. Therefore, we demonstrated that the induction of FN by HER2 triggers cell adhesion and invasion capacities. PMID- 25743093 TI - Growth and gene expression differ over time in alpha-linolenic acid treated breast cancer cells. AB - SCOPE: Heterogeneity of breast cancer (BC) subtypes makes BC treatment difficult. alpha-linolenic acid (ALA), rich in flaxseed oil, has been shown to reduce growth and increase apoptosis in several BC cell lines, but the mechanism of action needs further understanding. METHODS AND RESULTS: Four BC cell lines (MCF-7, BT 474, MDA-MB-231 and MDA-MB-468) were incubated with 75 MUM ALA+1 nM 17-beta estradiol (E2) or 1 nM E2 only (control) for 24 h. MDA-MB-231 cells were additionally incubated at 6 and 12 h. Viable cell number was measured, and expression of genes related to BC (signaling pathways, cell cycle, apoptosis) was quantified by real-time PCR array. There was a reduction in growth of all ALA treated cell lines after 24 h, and in MDA-MB-231 cells this was time-dependent. Many genes were altered after 24 h, and these differed between cell lines. In MDA MB-231 cells, several gene expression changes were time-dependent. CONCLUSIONS: ALA reduces growth of BC cell lines, by modifying signaling pathways, which differ between BC molecular subtypes. The ALA effect on gene expression is dynamic and changes over time, indicating the significance of incubation period in detecting gene changes. PMID- 25743094 TI - The impact of a mental health clinical placement on the clinical confidence of nursing students in Jordan. AB - OBJECTIVES: To examine the impact of clinical placement in a mental health setting on the clinical confidence of nursing students in Jordan. DESIGN AND SETTING: A non-experimental descriptive survey design was used. Data was collected using the Mental Health Nursing Clinical Confidence Scale (MHNCCS) in Jordan. RESULTS: Data indicates that, as a result of clinical placement, nursing students had improved perceived confidence regarding the concept of mental health and mental illness, felt better able to conduct a mental health status examination, create nursing care plans, administer medication and provide health education to patients in mental health settings. CONCLUSIONS: Improving the clinical confidence among Jordanian nursing students in relation to mental health nursing skills may provide a safer environment for students and patients as well as lead to enhanced well-being and function of patients. In addition, the results of this study may have practical implications for positive changes to the mental health nursing curriculum clinical placement goals. PMID- 25743095 TI - Knowledge level assessment and change among nursing students regarding administering intra-muscular injection at Al-Balqa'a Applied University: an interventional study. AB - BACKGROUND: Intra-muscular injection is a widely used technique for administering parenteral medication, so education about correct techniques of administering intra-muscular injections is important to prevent complications associated with intra-muscular injection. OBJECTIVES: To assess the knowledge level of nursing students regarding administering intra-muscular injection and to determine if knowledge level change after joining an educational session about administering intra-muscular injection. DESIGNS: This study used pretest and posttest control group designs. SETTINGS: Regular class in which a pretest and an educational session was conducted followed by a posttest after 2weeks. PARTICIPANTS: Nursing students of Al-Balqa'a Applied University/Zarqa University College participated in this study. METHODS: Data were collected through self-administered questionnaire. RESULTS: Experimental group did not do better in the posttest than the control group after they joined an educational session about administering intra-muscular injection. The level of students (first year vs. second year) has been identified as a covariate that may have distorted the results. CONCLUSION: One educational session is insufficient to change level of knowledge regarding administering intra-muscular injection, in addition to considering the level of nursing students when conducting the educational session, as well as the follow up and feedback during administering intra-muscular injection at clinical sites. PMID- 25743098 TI - Dielectrophoretic investigation of Bi2Te3 nanowires-a microfabricated thermoelectric characterization platform for measuring the thermoelectric and structural properties of single nanowires. AB - In this article a microfabricated thermoelectric nanowire characterization platform to investigate the thermoelectric and structural properties of single nanowires is presented. By means of dielectrophoresis (DEP), a method to manipulate and orient nanowires in a controlled way to assemble them onto our measurement platform is introduced. The thermoelectric platform fabricated with optimally designed DEP electrodes results in a yield of nanowire assembly of approximately 90% under an applied peak-to-peak ac signal Vpp = 10 V and frequency f = 20 MHz within a series of 200 experiments. Ohmic contacts between the aligned single nanowire and the electrodes on the platform are established by electron beam-induced deposition. The Seebeck coefficient and electrical conductivity of electrochemically synthesized Bi2Te3 nanowires are measured to be -51 MUV K(-1) and (943 +/- 160)/(Omega(-1) cm(-1)), respectively. Chemical composition and crystallographic structure are obtained using transmission electron microscopy. The selected nanowire is observed to be single crystalline over its entire length and no grain boundaries are detected. At the surface of the nanowire, 66.1 +/- 1.1 at.% Te and 34.9 +/- 1.1 at.% Bi are observed. In contrast, chemical composition of 64.2 at.% Te and 35.8 at.% Bi is detected in the thick center of the nanowire. PMID- 25743099 TI - Screening for salt-responsive proteins in two contrasting alfalfa cultivars using a comparative proteome approach. AB - A comparative proteomic approach was carried out between two contrasting alfalfa cultivars, nonomu (NM-801; salt tolerant) and vernal (VN; salt intolerant) in terms of salt tolerance. Seedlings were subjected to salt stress (50 and 100 mM NaCl) for three days. Several physiological parameters (leaf water, chlorophyll, root Na(+), K(+), and Ca(2+)) and root proteome profile were analyzed. Comparison of physiological status revealed that NM-801 is more tolerant to salt than VN. Eighty three differentially expressed proteins were found on 2-DE maps, of which 50 were identified by MALDI-TOF or MALDI-TOF/TOF mass spectrometry. These proteins were involved in ion homeostasis, protein turnover and signaling, protein folding, cell wall components, carbohydrate and energy metabolism, reactive oxygen species regulation and detoxification, and purine and fatty acid metabolism. The comparative proteome analysis showed that 33 salt-responsive proteins were significantly changed in both cultivars, while 17 (14 in VN and 3 in NM-801) were cultivar-specific. Peroxidase, protein disulfide-isomerase, NAD synthetase, and isoflavone reductase were up-regulated significantly only in NM 801 in all salt concentrations. In addition, we identified novel proteins including NAD synthetase and biotin carboxylase-3 that were not reported previously as salt-responsive. Taken together, these results provide new insights of salt stress tolerance in alfalfa. PMID- 25743100 TI - HIV Sexual Risk and Syndemics among Women in Three Urban Areas in the United States: Analysis from HVTN 906. AB - Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions. PMID- 25743101 TI - Safety and efficacy of adenotonsillectomy for obstructive sleep apnea in infants, toddlers and preschool children. AB - OBJECTIVE: To investigate and compare the safety and efficacy of adenotonsillectomy (AT) on obstructive sleep apnea (OSA) in infants and toddlers (IT) with preschool children (PS), and charts of 147 children between the ages of 11 months and 6 years were reviewed. METHODS: Harmonic Scalpel (HS) was introduced into AT to reduce the operative duration and intraoperative hemorrhage. Preoperative and postoperative apnea-hypopnea indices (AHI) values obtained by the type 3 portable monitoring device, and the change achieved by AT were statistically compared between IT group (N=50) and PS group (N=97). The mean operative duration, the mean amount of intraoperative hemorrhage, the incidence of postoperative hemorrhage, the frequency of abnormal postoperative chest X-ray findings, and the length of hospital stay were also compared between the two groups. All statistical analyses were conducted using either the Student's t test or Fischer's exact test, and p-values <0.05 were considered statistically significant. RESULTS: In the IT group, the mean preoperative AHI value was 13.5+/ 7.1 and decreased to 4.7+/-3.4 postoperatively. In the PS group, the mean AHI value changed from 16.0+/-10.2 to 4.4+/-2.4. There were statistically significant differences between the preoperative and postoperative AHI values in both the IT and PS groups, but there were no statistically significant differences between the IT and PS groups. The mean operative durations in the IT group for tonsillectomy and adenoidectomy were 12.8+/-6.7 min and 19.5+/-8.1 min, respectively. The corresponding values in the PS group were 14.5+/-6.6 min and 22.9+/-9.7 min, respectively. The mean tonsillectomy durations were comparable, but the adenoidectomy duration was statistically shorter in the IT group. In the IT group, the mean amounts of intraoperative hemorrhage during tonsillectomy and during adenoidectomy were 6.0+/-5.1 and 18.9+/-10.6 g, respectively. The corresponding values in the PS group were 6.4+/-5.4 g and 26.2+/-13.4 g, respectively. The mean tonsillectomy blood loss was comparable between the groups but was statistically less during adenoidectomy in the IT group. There were no statistical differences between the two groups in the incidence of postoperative hemorrhage and of abnormal findings in the postoperative chest X-ray, and in the length of hospital stay. CONCLUSION: AT in IT can be performed without major perioperative complications and should be considered the primary treatment of OSA from infancy to early childhood. Ultrasonic devices may contribute to increasing the safety of this surgical treatment. PMID- 25743103 TI - Gold nanoparticle/polymer nanocomposite for highly sensitive drug-DNA interaction. AB - The interaction of the anticancer drug mitomycin C (MC) and DNA immobilized on gold a nanoparticle/polyvinylferrocenium (AuNP/PVF(+)) coated electrode is presented. This is the first attempt to prepare a biocompatible nanoparticle/redox polymer composite in a one-step and easy electropolymerization procedure and then use the coated electrode for MC-DNA interaction. The prepared electrode exhibits high sensitivity for the investigation of drug-DNA interaction. PMID- 25743102 TI - Rescue of the temperature-sensitive, autosomal-recessive mutation R298S in the sodium-bicarbonate cotransporter NBCe1-A characterized by a weakened dimer and abnormal aggregation. AB - BACKGROUND: Band keratopathy, an ocular disease that is characterized by hypercalcemia and opaque bands across the cornea, has been associated with kidney disease. Type-II renal tubular acidosis (RTA), a condition in which the kidneys fail to recover bicarbonate (HCO3-) in the proximal tubule of the nephron, results in HCO3- wastage in the urine and low blood pH. The development of these diseases is associated with autosomal-recessive mutations in the Na+-coupled HCO3 cotransporter NBCe1-A located at the basolateral membranes of either cell type. METHODS: We provide insight into the devastating R298S mutation found in type-II RTA-afflicted individuals using confocal-microscopy imaging of fluorescently tagged NBCe1-A and NBCe1-A-R298S molecules expressed in human corneal endothelial and proximal tubule cells and from in-depth biophysical studies of their cytoplasmic N-terminal domains (Nt and Nt-R298S), including Nt crystal structure, melting-temperature, and homodimer dissociation constant (KD) analyses. RESULTS: We illuminate and rescue trafficking defects of the R298S mutation of NBCe1-A. The KD for Nt monomer-dimer equilibrium is established. The KD for Nt-R298S is significantly higher, but immeasurable due to environmental factors (pH, temperature, concentration) that result in dimer instability leading to precipitation. The crystal structure of Nt-dimer shows that R298 is part of a putative substrate conduit and resides near the dimer interface held together by hydrogen-bond networks. CONCLUSIONS: The R298S is a temperature-sensitive mutation in Nt that results in instability of the colloidal system leading to abnormal aggregation. GENERAL SIGNIFICANCE: Our findings provide new perspectives to the aberrant mechanism of certain ocular pathologies and type-II RTA associated with the R298S mutation. PMID- 25743104 TI - Lipid droplets hypertrophy: a crucial determining factor in insulin regulation by adipocytes. AB - Lipid droplets (LDs) hypertrophy in adipocytes is the main cause of energy metabolic system dysfunction, obesity and its afflictions such as T2D. However, the role of adipocytes in linking energy metabolic disorders with insulin regulation is unknown in humans. Human adipocytes constitutively synthesize and secrete insulin, which is biologically functional. Insulin concentrations and release are fat mass- and LDs-dependent respectively. Fat reduction mediated by bariatric surgery repairs obesity-associated T2D. The expression of genes, like PCSK1 (proinsulin conversion enzyme), GCG (Glucagon), GPLD1, CD38 and NNAT, involved in insulin regulation/release were differentially expressed in pancreas and adipose tissue (AT). INS (insulin) and GCG expression reduced in human AT-T2D as compared to AT-control, but remained unchanged in pancreas in either state. Insulin levels (mRNA/protein) were higher in AT derived from prediabetes BB rats with destructed pancreatic beta-cells and controls than pancreas derived from the same rats respectively. Insulin expression in 10 human primary cell types including adipocytes and macrophages is an evidence for extrapancreatic insulin producing cells. The data suggest a crosstalk between AT and pancreas to fine tune energy metabolic system or may minimize the metabolic damage during diabetes. This study opens new avenues towards T2D therapy with a great impact on public health. PMID- 25743105 TI - Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas. AB - Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy. PMID- 25743106 TI - Is There A Difference in Bone Ingrowth in Modular Versus Monoblock Porous Tantalum Tibial Trays? AB - Contemporary total knee designs incorporating highly porous metallic surfaces have demonstrated promising clinical outcomes. However, stiffness differences between modular and monoblock porous tantalum tibial trays may affect bone ingrowth. This study investigated effect of implant design, spatial location and clinical factors on bone ingrowth. Three modular and twenty-one monoblock retrieved porous tantalum tibial trays were evaluated for bone ingrowth. Nonparametric statistical tests were used to investigate differences in bone ingrowth by implant design, tray spatial location, substrate depth and clinical factors. Modular trays (5.3 +/- 3.2%) exhibited higher bone ingrowth than monoblock trays (1.6 +/- 1.9%, P = 0.032). Bone ingrowth in both designs was highest in the initial 500 MUm from the surface. Implantation time was positively correlated with bone ingrowth for monoblock trays. PMID- 25743107 TI - Study of the Influence of Bone Cement Type and Mixing Method on the Bioactivity and the Elution Kinetics of Ciprofloxacin. AB - The objectives of this study were to examine ciprofloxacin release from three trademarks of bone cements (Simplex(r), Lima(r) and Palacos(r)) and its bioactivity using as variables, the mixing method, the chemical form of the antibiotic and the antibiotic combination. The antibiotic amount released in base form represents 35% of antibiotic amount released when hydrochloride form is incorporated. Moreover, the combination (vancomycin and ciprofloxacin) shows a stronger release (132%) than hydrochloride ciprofloxacin alone. Three cements show equal drug release profile (P > 0.05). A bioactivity simulation exercise showed that until 72 hours post-surgery, ciprofloxacin concentrations in the implant would be higher than 0.1 MUg/mL in 100% of the patients. After drain removal, it is expected that bioactivity would increase since drug clearance from implant would decrease. PMID- 25743108 TI - Complementary use of bioluminescence imaging and contrast-enhanced micro-computed tomography in an orthotopic brain tumor model. AB - Small animal models are crucial to link molecular discoveries and implementation of clinically relevant therapeutics in oncology. Using these models requires noninvasive imaging techniques to monitor disease progression and therapy response. Micro-computed tomography (CT) is less studied for the in vivo monitoring of murine intracranial tumors and traditionally suffers from poor soft tissue contrast, whereas bioluminescence imaging (BLI) is known for its sensitivity but is not frequently employed for quantifying tumor volume. A widely used orthotopic glioblastoma multiforme (GBM) tumor model was applied in nude mice, and tumor growth was evaluated by BLI and contrast-enhanced microCT imaging. A strong correlation was observed between CT volume and BLI-integrated intensity (Pearson coefficient (r) = .85, p = .0002). Repeated contouring of contrast-enhanced microCT-delineated tumor volumes achieved an intraobserver average pairwise overlap ratio of 0.84 and an average tumor volume coefficient of variance of 0.11. MicroCT-delineated tumor size was found to correlate with tumor size obtained via histologic analysis (Pearson coefficient (r) = .88, p = .005). We conclude that BLI intensity can be used to derive tumor volume but that the use of both contrast-enhanced microCT and BLI provides complementary tumor growth information, which is particularly useful for modern small animal irradiation devices that make use of microCT and BLI for treatment planning, targeting, and monitoring. PMID- 25743110 TI - Histological characterization of human breast implant capsules. AB - BACKGROUND: This study investigated the relationships between histomorphological aspects of breast capsules, including capsule thickness, collagen fiber alignment, the presence of alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts, and clinical observations of capsular contracture. METHODS: Breast capsule samples were collected at the time of implant removal in patients undergoing breast implant replacement or revision surgery. Capsular contracture was scored preoperatively using the Baker scale. Histological analysis included hematoxylin and eosin staining, quantitative analysis of capsule thickness, collagen fiber alignment, and immunohistochemical evaluation for alpha-SMA and CD68. RESULTS: Forty-nine samples were harvested from 41 patients. A large variation in histomorphology was observed between samples, including differences in cellularity, fiber density and organization, and overall structure. Baker I capsules were significantly thinner than Baker II, III, and IV capsules. Capsule thickness positively correlated with implantation time for all capsules and for contracted capsules (Baker III and IV). Contracted capsules had significantly greater collagen fiber alignment and alpha-SMA-positive immunoreactivity than uncontracted capsules (Baker I and II). Capsules from textured implants had significantly less alpha-SMA-positive immunoreactivity than capsules from smooth implants. CONCLUSION: The histomorphological diversity observed between the breast capsules highlights the challenges of identifying mechanistic trends in capsular contracture. Our findings support the role of increasing capsule thickness and collagen fiber alignment, and the presence of contractile myofibroblasts in the development of contracture. These changes in capsule structure may be directly related to palpation stiffness considered in the Baker score. Approaches to disrupt these processes may aid in decreasing capsular contracture rates. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25743109 TI - Apoptosis, autophagy, necroptosis, and cancer metastasis. AB - Metastasis is a crucial hallmark of cancer progression, which involves numerous factors including the degradation of the extracellular matrix (ECM), the epithelial-to-mesenchymal transition (EMT), tumor angiogenesis, the development of an inflammatory tumor microenvironment, and defects in programmed cell death. Programmed cell death, such as apoptosis, autophagy, and necroptosis, plays crucial roles in metastatic processes. Malignant tumor cells must overcome these various forms of cell death to metastasize. This review summarizes the recent advances in the understanding of the mechanisms by which key regulators of apoptosis, autophagy, and necroptosis participate in cancer metastasis and discusses the crosstalk between apoptosis, autophagy, and necroptosis involved in the regulation of cancer metastasis. PMID- 25743113 TI - Accelerator mass spectrometry analysis of ultra-low-level (129)I in carrier-free AgI-AgCl sputter targets. AB - Separation of carrier-free iodine from low-level iodine samples and accurate measurement of ultra-low-level (129)I in microgram iodine target are essential but a bottleneck in geology and environment research using naturally produced (129)I. This article presents a detection technique of accelerator mass spectrometry (AMS) for accurate determination of ultra-low-level (129)I in carrier-free AgI-AgCl sputter targets. Copper instead of aluminum was selected as the suitable sample holder material to avoid the reaction of AgI-AgCl powder with aluminum. Niobium powder was selected as thermally and electrically conductive matrix to be mixed with AgI-AgCl powder, in order to obtain and maintain a stable and high iodine ion current intensity, as well as less memory effect and low background level of (129)I. The most optimal ratio of the Nb matrix to the AgI AgCl powder was found to be 5:1 by mass. The typical current of (127)I(5+) using AgI-AgCl targets with iodine content from 5 to 80 MUg was measured to be 5 to 100 nA. Four-year AMS measurements of the (129)I/(127)I ratios in standards of low iodine content and the machine blanks showed a good repeatability and stability. PMID- 25743112 TI - Opportunity cost in the economic evaluation of da Vinci robotic assisted surgery. AB - OBJECTIVE: This study aims to demonstrate the importance of the opportunity cost in using da Vinci robotic surgery, assisted by a comprehensive review of the literature to determine the differences in the total cost of surgery and operative time in traditional laparoscopic surgery and da Vinci robotic surgery. METHODOLOGY: We identified the studies comparing the use of traditional laparoscopic surgery with robotics during the period 2002-2012 in the electronic economic evaluation databases, and another electronic search was performed for publications by Spanish hospitals in the same period to calculate the opportunity cost. A meta-analysis of response variables considering the total cost of the intervention and surgical time was completed using the items selected in the first revision, and their differences were analyzed. We then calculated the opportunity cost represented by these time differences using the data obtained from the studies in the second review of the literature. RESULTS: Nine items were selected in the first review and three in the second. Traditional laparoscopic surgery has a lower cost than the da Vinci (p < 0.00001). Robotic surgery takes longer (8.0-65.5 min) than traditional surgery (p < 0.00001), and this difference represents an average opportunity cost for robot use of ? 489.98, with a unit cost factor/time which varies according to the pathology dealt with, from ? 8.2 to 18.7/min. CONCLUSIONS: The opportunity cost is a quantity that must be included in the total cost of using a surgical technology within an economic cost analysis in the context of an economic evaluation. PMID- 25743111 TI - Long Noncoding RNA Arid2-IR Is a Novel Therapeutic Target for Renal Inflammation. AB - Increasing evidence shows that microRNAs play an important role in kidney disease. However, functions of long noncoding RNAs (lncRNAs) in kidney diseases remain undefined. We have previously shown that TGF-beta1 plays a diverse role in renal inflammation and fibrosis and Smad3 is a key mediator in this process. In this study, we used RNA-sequencing to identify lncRNAs related to renal inflammation and fibrosis in obstructive nephropathy induced in Smad3 wild-type and knockout mice. We found that Arid2-IR was a Smad3-associated lncRNA as a Smad3 binding site was found in the promoter region of Arid2-IR and deletion of Smad3 abolished upregulation of Arid2-IR in the diseased kidney. In vitro knockdown of Arid2-IR from tubular epithelial cells produced no effect on TGF beta-induced Smad3 signaling and fibrosis but inhibited interleukin-1beta stimulated NF-kappaB-dependent inflammatory response. In contrast, overexpression of Arid2-IR promoted interleukin-1beta-induced NF-kappaB signaling and inflammatory cytokine expression without alteration of TGF-beta1-induced fibrotic response. Furthermore, treatment of obstructed kidney with Arid2-IR shRNA blunted NF-kappaB-driven renal inflammation without effect on TGF-beta/Smad3-mediated renal fibrosis. Thus, Arid2-IR is a novel lncRNA that functions to promote NF kappaB-dependent renal inflammation. Blockade of Arid2-IR may represent a novel and specific therapy for renal inflammatory disease. PMID- 25743114 TI - Serum cystatin C levels are associated with asymptomatic peripheral arterial disease in type 2 diabetes mellitus patients without overt nephropathy. AB - AIMS: We investigated the association between serum cystatin C and asymptomatic peripheral artery disease (PAD) in type 2 diabetes mellitus patients with normal renal function or mild renal impairment and we compared cystatin C with albuminuria and estimated glomerular filtration rate (eGFR) for prediction of PAD. METHODS: We enrolled 272 patients with type 2 diabetes. Patients were excluded if they had an eGFR<60mL/min per 1.73m(2), 24-h urine albumin (24h uAlb)>=300mg/day, serum creatinine (Cr)>1.3mg/dL, or previous history of cardiovascular disease. PAD was defined as having an ankle brachial index (ABI)<=0.9. RESULTS: Patients with PAD were more likely to have a lower eGFR and higher values of 24h-uAlb, cystatin C, and serum Cr than subjects without PAD. Cystatin C was independently associated with age, current smoking, HDL, eGFR, and PAD. Odds ratios (ORs) for PAD after adjustment for age, gender, smoking, and hypertension were 1.71 (95% CI, 1.02-2.85), 1.51 (95% CI, 0.93-2.44), and 0.78 (95% CI, 0.41-1.49) for a one standard deviation increase in cystatin C, 24h uAlb, and eGFR, respectively. CONCLUSIONS: Cystatin C was independently associated with PAD in type 2 diabetes mellitus patients without overt nephropathy. PMID- 25743115 TI - Microcanonical molecular simulations of methane hydrate nucleation and growth: evidence that direct nucleation to sI hydrate is among the multiple nucleation pathways. AB - The results of six high-precision constant energy molecular dynamics (MD) simulations initiated from methane-water systems equilibrated at 80 MPa and 250 K indicate that methane hydrates can nucleate via multiple pathways. Five trajectories nucleate to an amorphous solid. One trajectory nucleates to a structure-I hydrate template with long-range order which spans the simulation box across periodic boundaries despite the presence of several defects. While experimental and simulation data for hydrate nucleation with different time- and length-scales suggest that there may exist multiple pathways for nucleation, including metastable intermediates and the direct formation of the globally stable phase, this work provides the most compelling evidence that direct formation to the globally stable crystalline phase is one of the multiple pathways available for hydrate nucleation. PMID- 25743116 TI - What keeps female problematic Internet users busy online? AB - While problematic Internet use is recognized to be predominant among male adolescents, a female trend is gradually becoming apparent. Our study aimed at investigating the characteristics of female Internet users and distinguishing between the online activities of problematic and regular Internet users' on school days. Data were retrieved from a cross-sectional survey of a representative sample of 3067 8th graders in the canton of Vaud, Switzerland, that completed an online questionnaire in 2012. Only females were included. Based on the Internet addiction test, the sample was divided into regular (RUs) (IAT < 50, n = 1339) and problematic users (PIUs) (IAT >= 50, n = 201). Groups were compared regarding sociodemographic variables, online activities, devices used to access the Internet, substance use, and physical activity. Significant variables were included in a backward logistic regression. At the multivariate level, PIUs were more prone to spend time online for leisure activities (odds ratio [OR] 2.38) and to access the Internet through a smartphone (OR 1.79) or tablet (OR 1.84). PIUs were less likely to be physically active (OR 0.86) and more likely to present poor emotional well-being (OR 2.67) and to smoke (OR 1.88). CONCLUSION: A sizeable percentage of female adolescents are problematic Internet users. When performing a comprehensive biopsychosocial assessment, teenagers owning numerous devices to access the Internet, presenting other health-compromising behaviors or poor emotional well-being should be specifically targeted. PMID- 25743117 TI - Evaluating the feasibility of integrating salivary testing for congenital CMV into the Newborn Hearing Screening Programme in the UK. AB - Congenital cytomegalovirus (cCMV) accounts for 20% of all childhood sensorineural hearing loss (SNHL) but is not routinely tested for at birth. Valganciclovir has been shown to prevent hearing deterioration and improve neurocognitive outcomes if started in the first month of life. This study aimed to assess the feasibility of integrating testing for cCMV using salivary swabs into the Newborn Hearing Screening Programme (NHSP). Parents of newborns <22 days old in South West London, who were referred after their initial newborn hearing screen for further audiological testing, were approached by hearing screeners to obtain a saliva sample for CMV DNA polymerase chain reaction (PCR). Eighty percent (203/255) of newborns who were eligible had a saliva swab taken by the hearing screener. Over 99% of results were delivered within the first month of life. Two newborns were identified with cCMV and both seen on day 10 of life by the paediatric specialist. All saliva samples tested delivered a result using real-time PCR. CONCLUSION: It is feasible for hearing screeners to obtain saliva swabs to test for CMV DNA using real-time PCR in newborns referred after their initial hearing screen. Rapid diagnostic testing for cCMV needs a more detailed clinical and cost effectiveness analysis. PMID- 25743118 TI - Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice. AB - The aim of this research was to assess the antinociceptive activity of the transient receptor potential (TRP) channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate (AITC), or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal administration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxel-treated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 ug/20 ul, this effect was 51% (P<0.001) for capsazepine and 37% (P<0.05) for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% (P<0.05) in the AITC test and by 54% (P<0.001) in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2 thienylmethyl) benzamide hydrochloride salt (AMTB), a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% (P<0.05) and 51% (P<0.01), respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test (62%; P<0.001). In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used. PMID- 25743119 TI - Moringa oleifera extract enhances sexual performance in stressed rats. AB - Aphrodisiacs are required to improve male sexual function under stressful conditions. Due to the effects of oxidative stress and dopamine on male sexual function, we hypothesized that Moringa oleifera leaves might improve male sexual dysfunction induced by stress. Therefore, the effects on various factors playing important roles in male sexual behavior, such as antioxidant effects, the suppression of monoamine and phosphodiesterase type 5 (PDE-5) activities, serum testosterone and corticosterone levels, and histomorphological changes in the testes, of a hydroethanolic extract of M. oleifera leaves were investigated. Various doses of extract including 10, 50, and 250 mg/kg body weight (BW) were given orally to male Wistar rats before exposure to 12 h-immobilization stress for 7 d. The results demonstrated that the extract showed both antioxidant and monoamine oxidase type B (MAO-B) suppression activities. At 7 d of treatment, the low dose of extract improved sexual performance in stress-exposed rats by decreasing intromission latency and increasing intromission frequency. It also suppressed PDE-5 activity, decreased serum corticosterone level, but increased serum testosterone, numbers of interstitial cells of Leydig and spermatozoa. The increased numbers of interstitial cells of Leydig and spermatozoa might have been due to the antioxidant effect of the extract. The increased sexual performance during the intromission phase might have been due to the suppression of MAO-B and PDE-5 activities and increased testosterone. Therefore, M. oleifera is a potential aphrodisiac, but further research concerning the precise underlying mechanisms is still needed. PMID- 25743120 TI - Genetic polymorphisms of CYP2D6*10 and the effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in infertile men with idiopathic oligozoospermia. AB - Tamoxifen citrate, as the first line of treatment for infertile men with idiopathic oligozoospermia, was proposed by the World Health Organization (WHO), and testosterone undecanoate has shown benefits in semen values. Our objective was to assess the effectiveness of treatment with tamoxifen citrate and testosterone undecanoate in infertile men with idiopathic oligozoospermia, and whether the results would be affected by polymorphisms of CYP2D6*10. A total of 230 infertile men and 147 controls were included in the study. Patients were treated with tamoxifen citrate and testosterone undecanoate. Sex hormone, sperm parameters, and incidence of spontaneous pregnancy were detected. There were no significant differences between the control and patient groups with respect to CYP2D6*10 genotype frequencies (P>0.05). The follicle-stimulation hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were raised, and sperm concentration and motility were increased at 3 months and became significant at 6 months, and they were higher in the wild-type allele (C/C) than in the heterozygous variant allele (C/T) or homozygous variant allele (T/T) subgroups (P<0.05). In addition, the percentage of normal morphology was raised at 6 months, and represented the highest percentage in the C/C subgroup (P<0.05). The incidence of spontaneous pregnancy in the C/C subgroup was higher than that in the C/T or T/T subgroups (P<0.01). This study showed that the CYP2D6*10 variant genotype demonstrated worse clinical effects in infertile men with idiopathic oligozoospermia. PMID- 25743121 TI - Clinical effect of postconditioning in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the clinical effect of postconditioning on patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). METHODS: Randomized controlled trials were identified by searching relevant databases published up to April 2nd, 2014. A meta-analysis of eligible studies was performed by Stata 12.0 and Review Manager 5.2 with a fixed-effect model. RESULTS: Ten studies providing adverse cardiac events in a total of 1346 STEMI patients treated with primary PCI were identified. The occurrence of heart failure was significantly reduced in patients treated with postconditioning compared with usual care (risk ratio (RR) 0.533; 95% confidence intervals (CI) 0.368-0.770), whereas non-fatal reinfarction slightly increased in the postconditioning group (RR 2.746; 95% CI 1.007-7.488). No significant difference in total major adverse cardiac events (MACEs) was observed between the two groups (RR 0.876; 95% CI 0.671-1.144). CONCLUSIONS: Postconditioning in STEMI patients undergoing primary PCI significantly reduces the risk of heart failure, but fails to decrease the incidence of total MACEs and the risk of non-fatal reinfarction. PMID- 25743122 TI - Evaluation of the safety and efficacy of transcatheter aortic valve implantation in patients with a severe stenotic bicuspid aortic valve in a Chinese population. AB - OBJECTIVE: The purpose of this study is to evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with a severe stenotic bicuspid aortic valve (BAV) in a Chinese population. While several groups have reported the feasibility, efficacy, and safety of TAVI for patients with a BAV, worldwide experience of the technique is still limited, especially in China. METHODS: From March 2013 to November 2014, high surgical risk or inoperable patients with symptomatic severe aortic stenosis (AS) who had undergone TAVI at our institution were selected for inclusion in our study. RESULTS were compared between a BAV group and a tricuspid aortic valve (TAV) group. RESULTS: Forty patients were included in this study, 15 (37.5%) of whom were identified as having a BAV. In the BAV group, the aortic valve area was smaller ((0.47+/-0.13) vs. (0.59+/-0.14) cm(2)), the ascending aortic diameter was larger ((40.4+/-4.4) vs. (36.4+/-4.3) mm), and the concomitant aortic regurgitation was lower. No significant differences were found between the groups in the other baseline characteristics. No differences were observed either in the choice of access or valve size. The procedural success achieved in this study was 100%. There were no differences between groups in device success (86.7% vs. 88.0%), 30-d mortality (6.7% vs. 8.0%), or 30-d combined end point (13.3% vs. 12.0%). The incidences of new pacemaker implantation, paravalvular regurgitation and other complications, recovery of left ventricle ejection fraction and heart function were similar in both groups. CONCLUSIONS: Patients with a severely stenotic BAV can be treated with TAVI, and their condition after treatment should be similar to that of people with a TAV. PMID- 25743123 TI - Clinical assessment and polysomnographic study of sleep apnea in a Chinese population of snorers. AB - BACKGROUND AND OBJECTIVES: While an increasing number of people who snore are seeking medical consultations, the clinical characteristics of snorers are rarely reported. The aim of this study is to characterize the clinical and polysomnographic features in a population of snorers. METHODS: A total of 490 subjects were examined retrospectively. The clinical history, Epworth Sleepiness Scale (ESS) scores, physical examination, and full-night polysomnography (PSG) data were obtained for all the subjects. The correlations between the neck circumference, waist circumference, ESS scores, body mass index (BMI), and apnea hypopnea index (AHI) of obstructive sleep apnea (OSA) patients were explored. The gender and age differences in OSA patients were analyzed. RESULTS: OSA was diagnosed in 84.7% of the sample, with 21.2% of the patients having a mild form, 15.4% having a moderate form, and 63.4% having a severe form of OSA. The ESS scores, neck circumference, waist circumference, and BMI were positively correlated with AHI in OSA patients. The ESS scores and BMI were negatively correlated with nadir oxygen saturation (SaO2). A greater number of men than women exhibited moderate to severe forms of the disease. OSA affects the work of males more commonly compared with females. Nocturia was a more common complaint in elderly OSA patients. Heart diseases coexisted more frequently with OSA in elderly patients. CONCLUSIONS: In a population of snorers, OSA is the most common condition identified. The ESS scores and BMI were well correlated with the severity of the disease. Men had a more severe form of OSA than women. Nocturia frequently occurred in elderly OSA patients, as did the coexistence of heart disease. PMID- 25743124 TI - Intraperitoneal administration of butyrate prevents the severity of acetic acid colitis in rats. AB - Intrarectal infusion of butyrate improves colorectal disorders including ulcerative colitis (UC). However, it is not established whether systemically administered butyrate benefits such patients. The current study aimed at exploring and comparing the potential of intraperitoneally, intrarectally, and orally administered butyrate against acetic acid (AA)-induced UC in rats. Intrarectal administration of 2 ml of 50% AA was done after or without prior treatment of rats for 7 consecutive days with 100 mg/kg sodium butyrate (SB) intraperitoneally, intrarectally, or orally. Rats were sacrificed after 48 h of AA-treatment. Subsequently, colon sections were processed routinely for histopathological examination. We clinically observed diarrhea, loose stools, and hemoccult-positive stools, and histologically, epithelial loss and ulceration, crypt damage, goblet cell depletion, hemorrhage, and mucosal infiltration of inflammatory cells. The changes were significantly reduced by intraperitoneal, intrarectal, or oral butyrate, with intraperitoneal butyrate exhibiting the highest potency. It is concluded that intraperitoneal administration of butyrate abrogates the lesions of AA-induced UC and its potency surpasses that of intrarectal or oral butyrate. PMID- 25743125 TI - Identification of microRNAs and their target genes in Alport syndrome using deep sequencing of iPSCs samples. AB - MicroRNAs (miRNAs) are a class of small RNA molecules that are implicated in post transcriptional regulation of gene expression during development. The discovery and understanding of miRNAs has revolutionized the traditional view of gene expression. Alport syndrome (AS) is an inherited disorder of type IV collagen, which most commonly leads to glomerulonephritis and kidney failure. Patients with AS inevitably reach end-stage renal disease and require renal replacement therapy, starting in young adulthood. In this study, Solexa sequencing was used to identify and quantitatively profile small RNAs from an AS family. We identified 30 known miRNAs that showed a significant change in expression between two individuals. Nineteen miRNAs were up-regulated and eleven were down regulated. Forty-nine novel miRNAs showed significantly different levels of expression between two individuals. Gene target predictions for the miRNAs revealed that high ranking target genes were implicated in cell, cell part and cellular process categories. The purine metabolism pathway and mitogen-activated protein kinase (MAPK) signaling pathway were enriched by the largest number of target genes. These results strengthen the notion that miRNAs and their target genes are involved in AS and the data advance our understanding of miRNA function in the pathogenesis of AS. PMID- 25743126 TI - Non-specific anti-viral approach towards Ebola virus infection: a comment on "Against Ebola: type I interferon guard risk and mesenchymal stromal cell combat sepsis". PMID- 25743127 TI - Epidural steroid injections in the management of cervical disc herniations with radiculopathy. AB - OBJECTIVES: To evaluate the efficacy and safety of cervical epidural steroid injection (CESI) in the management of cervical disc herniations with radiculopathy. METHOD: We conducted a prospective interventional study with a 1 year follow-up comprising 33 consecutive patients presenting symptoms of cervicobrachial pain; positive neurological signs; corresponding cervical disc herniation/protrusion as verified by magnetic resonance imaging (MRI); insufficient improvement on prior conservative therapy; and no claims for financial compensation. Symptoms and clinical findings were registered in validated questionnaires before the procedure. Blind midline interlaminar CESI at the level of disc herniation was administered utilizing the loss of resistance (LOR) technique. Outcome was assessed during the first 3 months by telephone interview or clinical examination and final outcome measures were obtained at 1 year using validated questionnaires. RESULTS: The study included 20 men (60%) and 13 women (40%); median age was 51 (range 30-63) years. Median duration of neck and arm pain was 72 (7-450) and 64 (5-443) days, respectively. On average, patients received 1.7 CESIs (range 1-3). Sixteen patients (49%) had only one injection. All 33 patients were potentially surgical candidates. Only two (6%) needed surgical intervention during follow-up. There was significant improvement in pain intensity and functional outcome. Intake of analgesics was significantly reduced. Eighty-two per cent would say 'yes' to receiving the same treatment again. No serious adverse events were observed. CONCLUSIONS: CESI appears to be a safe and efficient part of the treatment of patients with symptomatic cervical disc herniations and may be considered before patients are referred to surgery. PMID- 25743128 TI - Clinical significance of hemodynamic cerebral ischemia on cognitive function in carotid artery stenosis: a prospective study before and after revascularization. AB - BACKGROUND: Carotid stenosis is known to have negative impacts on cognitive function. However, it is still unclear through which mechanisms cognitive function is impaired in patients with carotid stenosis. This study was aimed to clarify the impact of cerebral hemodynamics on cognitive function in carotid stenosis. METHODS: This prospective study included totally 109 patients with carotid stenosis who underwent carotid endarterectomy (CEA) or carotid artery stenting (CAS). Using N-isopropyl-p-[123I]-iodoamphetamine SPECT, cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to acetazolamide were quantitatively measured in all patients before and after CEA/CAS. Based on preoperative data, the patients were categorized into three groups: Type 1 (CBF >=32 mL/min/100 g, CVR >=10%), Type 2 (CBF >=32 mL/min/100 g and CVR <10%), and Type 3 (CBF <32 mL/min/100 g and CVR <10%). White matter lesions were categorized according to Wahlund grading. Cognitive function was evaluated with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and 3 months after CEA/CAS. RESULTS: Before CEA/CAS, total RBANS score was significant lower than the age-matched controls, 84+/-14 in Type 1 group (N.=56), 82+/-12 in Type 2 group (N.=43), and 70+/-12 in Type 3 group (N.=10). Especially, Type 3 patients had further lower score than Type 1 (P=0.008) and Type 2 (P=0.039) patients. There were no significant differences in white matter lesions among three groups. Total RBANS scores significantly improved at 3 months after CEA/CAS in all three groups, and the difference among them completely disappeared. CONCLUSIONS: These findings strongly suggest that carotid stenosis itself impairs cognitive function and compromised hemodynamic ischemia further declines it. CEA/CAS significantly improve cognitive function. The beneficial effects are most notable in patients with reduced CBF/CVR. PMID- 25743129 TI - The preventive effect of breast-feeding for longer than 6 months on early pubertal development among children aged 7-9 years in Korea. AB - OBJECTIVE: The present study was performed to investigate whether breast-feeding is associated with early pubertal development among children 7-9 years old in Korea. DESIGN: Children were divided into those who did and did not receive breast-feeding for 6 months or longer in accordance with the recommendations of the WHO. Pubertal status was determined by clinical examination using Tanner staging. SETTING: Prospective observational study. SUBJECTS: We conducted a follow-up study of children aged 7-9 years in 2011 who had taken part in the Ewha Birth & Growth Cohort study. RESULTS: Fifty (22.8%) of the total of 219 children were in early puberty, with the proportion being slightly higher for girls (24.1%) than boys (21.4%). Children who had entered early puberty were taller, weighed more and had a higher concentration of insulin-like growth factor 1. Moreover, the change in weight Z-score from birth to follow-up was significantly lower in children who were breast-fed than in those who were not (weight Z-score change: 0.32 (sd 1.59) v. 0.77 (sd 1.61), respectively, P=0.04). Comparison of breast-feeding by puberty status indicated a preventive association with early puberty in children who were breast-fed for 6 months or longer (OR=0.37; 95% CI 0.18, 0.74). This association remained significant after adjustment for relevant covariates. CONCLUSIONS: These results demonstrate a beneficial association between breast-feeding and early pubertal development, especially in those breast fed for 6 months or longer. The study suggests that interventions would need to start early in life to prevent early pubertal development. PMID- 25743131 TI - [Application of iPSC technology to cancer treatment]. AB - Induced pluripotent stem cells(iPSCs)can be generated via reprogramming of somatic cells into pluripotent stem cells by introducing defined factors with appropriate culture conditions. iPSCs have 4 key properties. iPSCs have pluripotency and self-renewal ability, which are properties in common with embryonic stem cells. Additionally, iPSCs can be generated from various donor individuals with particular characteristics and also from various types of cells in a single donor. Regarding the medical applications of the technology, the best use of iPSCs should be based on a better understanding of these properties in accordance to different purposes. At present, the technology has been applied in various research fields. In cancer research, the technology has been expected to be useful, especially in immunotherapy, disease modeling, drug development. Thus, iPSC technology is a promising tool even in the field. Continuous challenges raise the hope for the development of novel cancer treatments using iPSC technologies in the future. PMID- 25743130 TI - Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance. AB - OBJECTIVE: Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. STUDY DESIGN: We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year. RESULTS: One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis (P = .78). CONCLUSION: Ovarian vein thrombosis is commonly encountered after debulking surgery for ovarian cancer. Anticoagulation is usually not indicated, and clinically meaningful thrombus progression rarely occurs. PMID- 25743132 TI - [Proton beam therapy with concurrent chemotherapy for non-small cell lung cancer - our experiences and future direction]. AB - Concurrent chemoradiotherapy is the gold standard of care for patients with unresectable locally advanced non-small cell lung cancer (NSCLC). Proton beam therapy (PBT) can reduce the doses for normal lungs because of the penetration energy peak. PBT with concurrent chemotherapy for locally advanced NSCLC has been introduced in National Cancer Center Hospital East since December 2011. Thirty three patients received PBT with concurrent chemotherapy for 2 years. Nine patients received PBT because they were not suited for radical photon radiotherapy due to excessive V20 Gy or doses to the spinal cord. Thirty-one patients received cisplatin plus vinorelbine; the remaining 2 patients received weekly carboplatin and paclitaxel, or daily carboplatin. All but 1 patient received the planned PBT dose (60 GyE[n=15]or 66 GyE[n=17]). PBT was terminated in 1 patient after the delivery of 36 GyE because of the development of liver metastases. PBT was suspended in 8 patients because of the development of febrile neutropenia (n=6) and esophagitis (n=3). Two patients (6%) experienced grade 3 esophagitis. The grade 2 toxicities included esophagitis (n=12), dermatitis (n=10), and pneumonitis (n=2). Grade 3 pneumonitis was not observed. Disease progression was observed in 17 patients. In-field recurrence was observed in 4 patients, distant metastases were observed in 14 patients, and both types of recurrence were observed in 1 patient. With a median follow-up time of 6.0 months for censored cases, the median progression-free survival time was 9.9 months (95% confidence interval: 5.2-14.6). Our retrospective study demonstrates that PBT with concurrent chemotherapy is feasible, although the possible complications, such as radiation esophagitis and dermatitis, might be rather severe compared with standard chemoradiotherapy using photons. PMID- 25743133 TI - [Concurrent proton therapy and chemotherapy for locally advanced cancers]. AB - Charged particles such as protons and carbon-ions offer advantageous physical properties to radiation therapy (RT) for the treatment of various cancers when compared with photons, because they exhibit a spread-out Bragg peak, and may be utilized to achieve a desirable dose distribution to the target volume by using specified beam modulation. Interestingly, the cytocidal effect of protons is almost equal to that of photons, because both protons and photons are considered low-linear energy transfer radiations. Hence, proton beam therapy (PBT) is an attractive RT option, especially in the treatment of locally advanced cancers, as irradiation doses can be safely escalated while sparing the surrounding normal tissues, and because PBT may be concurrently combined with chemotherapy for treating such cancers. Recent advances in PBT techniques including a spot scanning method, as well as an increase in the number of particle therapy institutes are anticipated to yield favorable results through future multi institutional prospective studies. The University of Tsukuba has carried out several studies to validate the effectiveness of PBT for many types of cancers since 1983. Here, we present our findings on the clinical outcomes of PBT for esophageal cancer, non-small cell lung cancer, intrahepatic biliary tract cancer, pancreas cancer, and bladder cancer; future aspects of PBT concurrently combined with chemotherapy for treating locally advanced cancers are also discussed. PMID- 25743134 TI - [Treatment with carbon-ion radiotherapy and its combinations -- basic biological studies and investigations at the National Institute of Radiological Sciences]. AB - The clinical application of carbon ions generated by the heavy ion medical accelerator in Chiba (HIMAC) reached its 20th anniversary in 2014. More than 9,000 cancer patients have been treated at the National Institute of Radiological Sciences (NIRS). Carbon-ion radiotherapy has been applied for treating various types of tumors that were considered difficult to control with existing modalities. Our experience to date has indicated that carbon-ion radiotherapy is advantageous for head and neck cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, bone/soft tissue sarcomas of the pelvis, uterine cervix adenocarcinomas, and other cancers. However, some cancer types (such as those in close proximity to radiosensitive normal organs) require additional treatments to sensitize the target cancer because of limitation of the irradiation dose. Furthermore, systemic combined therapy is also utilized to suppress possible metastasis. Currently, some anticancer agents are utilized with carbon-ion radiotherapy, including dacarbazine, nimustine hydrochloride, vincristine (DAV), gemcitabine, cisplatin, and 5-fluorouracil. Interesting reagents such as PARP and HSP90 inhibitors have been proposed as cancer cell- specific sensitizers for carbon-ion irradiation during basic biological studies, especially those from the Research Project with Heavy Ions at NIRS-HIMAC. In our laboratory, we have focused our studies on the suppression of metastasis. We have proposed the concurrent use of reagents to inhibit the invasive potential of cancer cells under carbon-ion irradiation. Recently, we have also shown that combining carbon ion radiotherapy with the local injection of dendritic cells inhibits lung metastases in an in vivo murine model. PMID- 25743135 TI - [Heavy ion radiotherapy for prostate cancer -- the role of hormone therapy]. AB - The role of androgen deprivation therapy combined with heavy ion radiotherapy involving carbon ions was reviewed. In conventional radiotherapy, short- and long term androgen deprivation therapies were recommended for patients with intermediate- and high-risk prostate cancers, respectively. The rationale for using a combination androgen deprivation therapy can be partially explained by prostatic tissue oxygenation and the effect on DNA-repair molecules via the androgen receptor. Heavy ion radiotherapy and androgen deprivation therapy were performed in combination according to risk criteria. Further studies are warranted to determine the optimal method and duration of androgen deprivation therapy during heavy ion radiotherapy for prostate cancer. PMID- 25743136 TI - [Efficacy and safety of cisplatin plus pemetrexed as a first-line treatment for Japanese patients with advanced non-squamous non-small-cell lung cancer -- a retrospective analysis]. AB - BACKGROUND: Cisplatin plus pemetrexed is considered the standard of care for the first-line treatment of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). However, little is known about the efficacy and safety of this regimen in Japanese patients in a daily clinical setting. METHODS: We retrospectively analyzed 40 patients who received cisplatin (75 mg/m/(2)) and pemetrexed (500 mg/m(2)) as a first-line treatment for advanced non-squamous NSCLC. RESULTS: Recorded Grade 3 or 4 hematological toxicities included neutropenia in 7 cases (17.5%), leukopenia in 5 cases (12.5%), anemia in 1 case (2.5%), thrombocytopenia in 1 case (2.5%), and febrile neutropenia in 1 case (2.5%). Grade 3 or 4 nonhematological toxicities included anorexia in 3 cases (7.5%), infection in 1 case (2.5%), rash in 1 case (2.5%), and increased transaminase expression in 1 case (2.5%). Therefore, the adverse events were mostly mild. There were no treatment related deaths. The overall response rate was 37.5%, median progression free survival was 5.6 months, and median overall survival (OS) was 18.8 months. In an epidermal growth factor receptor (EGFR) mutation status subgroup analysis, the median OS of patients with wild-type EGFR or unknown status (n=28)was 16.8 months. CONCLUSION: Cisplatin plus pemetrexed was well tolerated as a first-line treatment and effective in Japanese patients with advanced non-squamous NSCLC. PMID- 25743137 TI - [A retrospective analysis of cetuximab or panitumumab monotherapy for KRAS wild type metastatic colorectal cancer in clinical practice]. AB - We performed a retrospective study on the use of cetuximab or panitumumab alone in patients with KRAS wild-type metastatic colorectal cancer between November 2008 and February 2012. Twenty-two patients were analyzed and classified as PS 0/1 (good PS group)and PS 2/3/4 (poor PS group)with 11 patients in each group. The response rate, disease control rate, median progression-free survival, and median overall survival were 9%, 73%, 5.1 months (95%confidence interval[CI]: 1.5 8.7), and 16 months (95% CI: 8.8-24), respectively, in the good PS group, and the corresponding values in the poor PS group were 0%, 18%, 0.7 months (95% CI: 0.3 1.0), and 1.5 months (95% CI: 0.7-2.4). Grade 3 or 4 adverse events were skin toxicities (2 patients with grade 3 toxicities), panitumumab-related interstitial lung disease (1 patient with grade 4 toxicity), and cetuximab infusion-related reaction (1 patient with grade 4 toxicity). No treatment-related deaths were observed. In conclusion, the efficacy and safety of cetuximab or panitumumab monotherapy in patients with a good PS in our study were similar to those reported in previous clinical trials, whereas patients with a poor PS showed poorer outcomes. PMID- 25743138 TI - [A feasibility study of adjuvant therapy with capecitabine plus oxaliplatin (XELOX) for Japanese patients with advanced colorectal cancer]. AB - We prospectively evaluated the feasibility of XELOX(oxaliplatin 130 mg/m/(2) on day 1 plus capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks) for adjuvant treatment in 15 patients with stage III/IV (Japanese classification) colorectal cancer and pathological curability A or B after D2-D3 lymph node dissection. Patients were seen at our institute between September 2009 and January 2012. In the current study, no severe adverse events occurred, including hand-foot syndrome greater than Grade 3, as compared with the MOSAIC, NSABP C-07, and NO16968/XELOXA trials. We confirm that XELOX is a feasible treatment option and discuss the benefits of evaluating the safety and efficacy of XELOX in more patients. PMID- 25743139 TI - [Effect of tolvaptan on ascites due to malignancy]. AB - Ascites accompanying a malignancy is often refractory to conventional treatment with saline diuretics, making it difficult to control. We administered a new diuretic, Tolvaptan, to 10 individuals with malignancy and heart failure accompanied by ascites, which was refractory to saline diuretics, and assessed its efficacy and adverse events. We observed a significant reduction in abdominal distension following 2 weeks of Tolvaptan administration. However, we also observed significant increases in serum potassium, urea nitrogen, and creatinine levels, but no serious adverse events. This suggests that Tolvaptan may also be effective as treatment for ascites. PMID- 25743140 TI - [Evaluation of the pharmaceutical stability of polaprezinc/sodium alginate gargle solution containing lidocaine]. AB - OBJECTIVE: A gargle solution(L-P/AG)for the treatment of painful stomatitis was prepared by adding lidocaine to a polaprezinc/sodium alginate gargle solution(P/AG), and its pharmaceutical stability was evaluated. METHODS: L-P/AG was stored at 5, 25, and 40 degrees C. The strengths of polaprezinc and lidocaine were determined. The viscosity and pH of L-P/AG were also determined, and its appearance was evaluated. RESULTS: When stored at 5 or 25 degrees C in a dark place, L-P/AG showed neither reduction in the strength of either drug nor did it show a change in the viscosity, pH, or appearance. When stored exposed to light at 40 degrees C, L-P/AG showed reductions in the strength of both drugs, as well as in viscosity and pH; furthermore, a change in appearance was noted. DISCUSSION: L-P/AG prepared for the treatment of painful stomatitis remains pharmaceutically stable for 28 days when stored at 25 degrees C in a dark place. PMID- 25743141 TI - [Appropriate dosing of fosaprepitant for colon cancer patients]. AB - After fosaprepitant (FOS)was added to the National Health Insurance drug reimbursement price list, we switched the route of administration of antiemetics from oral to intravenous in chemotherapy regimens for colon cancer to improve patient medication adherence. However, because the number of patients reporting application-site disorders after administration of FOS increased, we monitored the incidence of these disorders in patients with colon cancer to identify ways to avoid them. In our prospective study, patients receiving conventional FOS dosing regimens (control group)were compared with those receiving diluted FOS solutions (study group). There were no significant differences between the two groups with respect to the incidence of application-site disorders, and contrary to expectations, the incidence was higher in the study group than in the control group. On the basis of the principle of non-maleficence and the availability of alternative therapies using oral aprepitant (APR), we terminated this study early and adopted the basic strategy that all patients with application-site disorders, except for those with central venous access devices, should be treated with oral APR after confirming their preferences. PMID- 25743142 TI - [Subcutaneous myeloid sarcoma in a patient with essential thrombocythemia that transformed into acute myeloid leukemia]. AB - Since November 2008, an 80-year-old man had been administered hydroxyurea and aspirin for the treatment of essential thrombocythemia (ET). In January 2012, his white blood cell count was markedly elevated, and he was treated with busulfan and cytarabine. In October 2012, he was hospitalized because of fever and general malaise, and a central venous port was placed in the right anterior chest owing to difficulty obtaining peripheral vascular access. Approximately 2 weeks after port placement, a subcutaneous mass was observed near the port. The patient died in November 2012 owing to exacerbation of the original disease. Autopsy revealed transformation to acute myeloid leukemia( AML; M2 subtype) and myeloid sarcoma (MS) in lymph nodes and the right anterior chest. The incidence of transformation of ET to AML is low, and MS as a comorbidity is rare. However, the risk of MS complications should be considered in patients with hematological malignancies due to recent increases in the use of central venous ports in such cases. PMID- 25743143 TI - [A case of stage IV gastric cancer resected after chemotherapy with capecitabine plus cisplatin]. AB - A 64-year-old woman was diagnosed with Stage IV gastric cancer with lymph node and multiple liver metastases. She was treated with 6 courses of chemotherapy, in 3-week courses, with capecitabine (1,000 mg/m/(2)) plus cisplatin(80 mg/m(2)) administered for 2 weeks, followed by a drug-free week. She underwent curative total gastrectomy with D2 lymph node dissection and reconstruction by using the Roux-en-Y method. The postoperative pathological findings revealed a T3 (SE), N1M1, Stage II B tumor; the tumor was determined to be Grade 1b owing to the chemotherapeutic effect. Postoperatively, only S-1 therapy was administered, because of the development of Grade 3 hand-foot syndrome. The patient is alive 1 year and 8 months after the initial gastrectomy. PMID- 25743144 TI - [A case of renal salt-wasting syndrome during chemotherapy for advanced gastric cancer]. AB - A 66-year-old woman was admitted to our hospital with heartburn and liver dysfunction. She was diagnosed with advanced gastric cancer. After the initiation of chemotherapy with trastuzumab, capecitabine, and cisplatin, she developed hyponatremia and renal failure with renal salt-wasting syndrome (RSWS). She recovered from these conditions after infusion of hypertonic saline. A diagnosis of RSWS should be considered in patients with hyponatremia who receive cisplatin based chemotherapy. PMID- 25743145 TI - [A case of appendix cancer treated as cancer of unknown primary origin]. AB - A 57-year-old man initially presented with chief complaints of abdominal distension and anorexia. Positron emission tomography- computed tomography (PET CT) scan showed ascites and multiple peritoneal metastases with abnormal uptake of fluorodeoxyglucose (FDG). The patient underwent endoscopy, biopsy, and cytology and was diagnosed with adenocarcinoma of unknown primary origin. He was treated with systematic chemotherapy, including carboplatin/paclitaxel (CBDCA/ PTX) and gemcitabine regimens. However, progressive disease (PD) complicated by intestinal obstruction was indicated. He was referred to our department for management. We performed surgery to resolve the intestinal obstruction and confirm the diagnosis. Appendix cancer was diagnosed intraoperatively. He was administered a modified fluorouracil plus Leucovorin and oxaliplatin(mFOLFOX6) /panitumumab regimen following surgery. The tumor had a good response to treatment, and the primary lesion was resected. After resection , the tumor was controlled by systemic chemotherapy for six months. However, the patient unfortunately died owing to arrhythmia. Most patients with cancer of unknown primary origin have a very poor prognosis because it is difficult to select appropriate treatment. Laparotomy can be effective in making a definitive diagnosis, as in the case described here. PMID- 25743146 TI - [Stevens-Johnson syndrome induced by regorafenib in a patient with progressive recurrent rectal carcinoma]. AB - A 55-year-old man with rectal carcinoma underwent lower anterior resection. Eight years after surgery, multiple metastases were detected in the liver, lung, and abdominal lymph nodes. The metastatic cancers were resistant to standard chemotherapy. Thus, regorafenib was administered to the patient. The patient presented symptoms of Stevens-Johnson syndrome (SJS) nine days after regorafenib administration, and hence, treatment was terminated. To treat SJS, he received oral and topical steroid therapies. SJS is an important adverse event that hinders the continuation of regorafenib treatment. Thus, it is necessary to continually check the patient's skin condition carefully, especially at early stages of treatment. To our knowledge, this is the first report of SJS arising during the course of regorafenib treatment. PMID- 25743147 TI - [A successful multimodality therapy for a case of recurrent rectal cancer with KRAS mutation]. AB - A man in his 50s underwent high anterior resection for rectosigmoid cancer in January 2010. The primary tumor was diagnosed as a moderately differentiated adenocarcinoma with KRAS mutation, pStage III a. In May 2011, the patient had a recurrent lung tumor detected by computed tomography(CT); the tumor was resected using video-assisted thoracoscopic surgery. However, additional recurrent lung tumors arose, and radiofrequency ablation (RFA) was performed to treat these in February 2012. After RFA therapy, capecitabine was administered as adjuvant chemotherapy. Unfortunately, 10 months later, positron emission tomography (PET) /CT suggested a new recurrence in a left lateral lymph node. Although the pelvic lymph node was surgically removed immediately, a new lung recurrence was found on CT three months after the surgery. RFA was again used to treat this lung lesion. After the second RFA, the patient is doing well without any evidence of recurrence. We describe a case of recurrent rectal cancer successfully treated with multimodality therapy. The combination of appropriate local therapy with systemic chemotherapy is an essential strategy to treat advanced colorectal cancer, especially in patients with KRAS mutation when anti-EGFR antibodies are not effective. PMID- 25743148 TI - [A case of advanced pancreas cancer successfully treated by using combined modality therapy]. AB - A 62-year-old woman visited a nearby hospital with chief complaints of diarrhea and weight loss.A computed tomography (CT)scan showed a hypovascular tumor approximately 2 cm in diameter in the pancreatic uncus, and the patient was referred to our department for thorough examination and treatment.The patient was diagnosed with cT4 (A) N0M0, cStage IV a cancer of the pancreatic uncus.The treatment consisted of 3 weeks of gemcitabine and 1 week of drug withdrawal; after completion of 4 courses, concomitant administration of S-1 (ie GS therapy) was initiated.The tumor gradually shrank, and it was not observed on a CT scan 1 year and 8 months later.Although no obvious distant metastasis was observed, a low density area around the superior mesenteric artery still remained.Possibility of viable tumor could not be completely ruled out; therefore, a pancreaticoduodenectomy was scheduled.However, because sclerosis around the superior mesenteric artery was quite severe, bled easily, and was difficult to separate, we decided that excision was impossible and resumed the GS therapy. The primary lung cancer that developed subsequently was resected, and the GS therapy was continued.The tumor in the pancreatic uncus was resected after growth was observed 3 years and 9 months after the initiation of chemotherapy.The patient is currently receiving chemotherapy as an outpatient. PMID- 25743149 TI - [A case of pleomorphic malignant fibrous histiocytoma with multiple lung metastases with bilateral pneumothorax after chemotherapy]. AB - A 70-year-old man diagnosed with pleomorphic malignant fibrous histiocytoma of the left thigh underwent tumor resection. After 10 months, he underwent extended resection due to local recurrence. However, because multiple lung metastases was detected at this time, chemotherapy with ifosfamide and doxorubicin was administered. After three courses of chemotherapy, the lung metastases enlarged and the patient received ifosfamide and etoposide as second line chemotherapy. Even after three courses of second line treatment, the disease progressed, for which docetaxel and gemcitabine were administered as third line chemotherapy. After three courses of third line treatment, multiple lung metastases reduced and were replaced with scar and cystic lesions (reduction ratio 85.9%). After four courses of treatment, the patient developed left pneumothorax. Partial resection of the left upper lobe was performed by thoracoscopic surgery. Histopathological examination revealed rupture of the visceral pleura in a scar lesion leading to air leakage. After 13 courses of treatment, he developed right pneumothorax. Partial resection of the right middle lobe was performed. Histopathological examination revealed a cystic lesion without tumor remnants. After 15 courses of third line treatment, lung metastasis could be controlled. Chemotherapy with docetaxel and gemcitabine resulted in few adverse effects that were within tolerance limits. PMID- 25743150 TI - [A case of metastatic cancer of unknown primary origin that progressed rapidly after complete remission via second-line chemotherapy]. AB - Leptomeningeal metastasis occurs in approximately 5% of patients with metastatic solid carcinomas, and it is often diagnosed in patients with breast cancer, lung cancer, malignant melanoma, and digestive cancer. Herein, we report a case of a metastatic cancer of unknown primary origin. The leptomeningeal metastasis progressed quite rapidly, and the patient died despite achieving complete remission via second-line chemotherapy. PMID- 25743151 TI - Enzyme-histochemical investigations on the lymphatics oe the intrinsic uterine wall in the monkey. PMID- 25743152 TI - Monitoring and trend mapping of sea surface temperature (SST) from MODIS data: a case study of Mumbai coast. AB - Sea surface temperature (SST) is one of the most important parameters in monitoring ecosystem health in the marine and coastal environment. Coastal ecosystem is largely dependent on ambient temperature and temperature fronts for marine/coastal habitat and its sustainability. Hence, thermal pollution is seen as a severe threat for ecological health of coastal waters across the world. Mumbai is one of the largest metropolises of the world and faces severe domestic and industrial effluent disposal problem, of which thermal pollution is a major issue with policy-makers and environmental stakeholders. This study attempts to understand the long-term SST variation in the coastal waters off Mumbai, on the western coast of India, and to identify thermal pollution zones. Analysis of SST trends in the near-coastal waters for the pre- and post-monsoon seasons from the year 2004 to the year 2010 has been carried out using Moderate Resolution Imaging Spectro-radiometer (MODIS) Thermal Infra-red (TIR) bands. SST is calculated with the help of bands 31 and 32 using split window method. Several statistical operations were then applied to find the seasonal averages in SST and the standard deviation of SST in the study area. Maximum variation in SST was found within a perpendicular distance of 5 km from the shoreline during the study period. Also, a warm water mass was found to form consistently off coast during the winter months. Several anthropogenic sources of thermal pollution could be identified which were found to impact various locations along the coast. PMID- 25743153 TI - Patterns and trends in sources of information about sex among young people in Britain: evidence from three National Surveys of Sexual Attitudes and Lifestyles. AB - OBJECTIVE: To assess progress in meeting young people's sex education needs in Britain by examining the current situation and changes over the past 20 years in sources of information about sexual matters and unmet information needs. DESIGN: Cross-sectional probability sample surveys. SETTING: British general population. PARTICIPANTS: 3869 men and women aged 16-24 years, interviewed 2010-2012 for the third National Survey of Sexual Attitudes & Lifestyles (Natsal-3), compared with 16-24 year-olds in Natsal-1 (1990-1991; 792 men and women) and Natsal-2 (1999 2001; 2673 men and women). MAIN OUTCOME MEASURES: Reported source of information about sexual matters, unmet information needs and preferred source of additional information. RESULTS: Between 1990 and 2012, the proportion citing school lessons as their main source of information about sexual matters increased from 28.2% (95% CI 24.6 to 32.1) to 40.3% (95% CI 38.6 to 42.1). In 2010-2012, parents were reported as a main source by only 7.1% (95% CI 5.8 to 8.7) of men and 14.1% (95% CI 12.6 to 15.7) of women and, for women, were less commonly reported than in 1999-2001 (21.7%; 95% CI 19.6 to 24.0). Most young people reported not knowing enough when they first felt ready for sexual experience (68.1% men, 70.6% women), and this did not change substantially over time. They wanted more information about psychosexual matters (41.6% men, 46.8% women), as well as sexually transmitted infections (27.8% men, 29.8% women) and, for women, contraception (27.5%). Young people primarily wanted this information from school, parents or health professionals. CONCLUSIONS: Over the past 20 years, young people have increasingly identified school lessons as their main source of information about sex, although they continue to report needing more information on a broad range of topics. The findings support the expressed need for improved sex and relationships education in schools alongside greater involvement of parents and health professionals. PMID- 25743154 TI - Associations between source of information about sex and sexual health outcomes in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - OBJECTIVES: To examine variation in source of information about sexual matters by sociodemographic factors, and associations with sexual behaviours and outcomes. DESIGN: Cross-sectional probability sample survey. SETTING: British general population. PARTICIPANTS: 3408 men and women, aged 17-24 years, interviewed from 2010-2012 for third National Survey of Sexual Attitudes and Lifestyles. MAIN OUTCOME MEASURES: Main source of information (school, a parent, other); age and circumstances of first heterosexual intercourse; unsafe sex and distress about sex in past year; experience of sexually transmitted infection (STI) diagnoses, non-volitional sex or abortion (women only) ever. RESULTS: Citing school was associated with younger age, higher educational level and having lived with both parents. Citing a parent was associated, in women, with lower educational level and having lived with one parent. Relative to other sources, citing school was associated with older age at first sex (adjusted HR 0.73 (95% CI 0.65 to 0.83) men, 0.73 (0.65 to 0.82) women), lower likelihood of unsafe sex (adjusted OR 0.58 (0.44 to 0.77) men, 0.69 (0.52 to 0.91) women) and previous STI diagnosis (0.55 (0.33 to 0.91) men, 0.58 (0.43 to 0.80) women) and, in women, with lower likelihood of lack of sexual competence at first sex; and experience of non volitional sex, abortion and distress about sex. Citing a parent was associated with lower likelihood of unsafe sex (0.53 (0.28 to 1.00) men; 0.69 (0.48 to 0.99) women) and, in women, previous STI diagnosis. CONCLUSIONS: Gaining information mainly from school was associated with lower reporting of a range of negative sexual health outcomes, particularly among women. Gaining information mainly from a parent was associated with some of these, but fewer cited parents as a primary source. The findings emphasise the benefit of school and parents providing information about sexual matters and argue for a stronger focus on the needs of men. PMID- 25743155 TI - Excess of threonine compared with serine promotes threonine aldolase activity in Lactococcus lactis IL1403. AB - Lactococcus lactis is an important lactic acid starter for food production as well as a cell factory for production of food grade additives, among which natural flavour production is one of the main interests of food producers. Flavour production is associated with the degradation of amino acids and comprehensive studies are required to elucidate mechanisms behind these pathways. In this study using chemically defined medium, labelled substrate and steady state cultivation, new data for the catabolism of threonine in Lc. lactis have been obtained. The biosynthesis of glycine in this organism is associated with the catabolic pathways of glucose and serine. Nevertheless, if threonine concentration in the growth environment exceeds that of serine, threonine becomes the main source for glycine biosynthesis and the utilization of serine decreases. Also, the conversion of threonine to glycine was initiated by a threonine aldolase and this was the principal pathway used for threonine degradation. As in Streptococcus thermophilus, serine hydroxymethyltransferase in Lc. lactis may possess a secondary activity as threonine aldolase. Other catabolic pathways of threonine (e.g. threonine dehydrogenase and threonine dehydratase) were not detected. PMID- 25743156 TI - Identification of antigen Ag43 in uropathogenic Escherichia coli Dr+ strains and defining its role in the pathogenesis of urinary tract infections. AB - Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are amongst the most common bacterial infectious diseases in the developed world. The urovirulence of UPEC is mainly associated with the surface-exposed fimbrial adhesins and adhesins of the autotransporter (AT) family. The best studied of these proteins is antigen Ag43 mediating cell aggregation, adhesion and biofilm development as the causes of chronic UTIs. The E. coli IH11128 Dr(+) (dra (+)) strain of the Dr/Afa(+) family of adhesins possesses two major surface-exposed virulence factors: Dr fimbrial polyadhesin and DraD protein (fimbrial tip subunit or protein component of the adhesive sheath). Here, we identified for the first time, to our knowledge, the agn43 gene encoding Ag43 in the WT clinical isolate of UPEC Dr(+) as a new virulence factor not yet tested. We also found that Dr fimbrial expression, which like Ag43 is under the control of a phase-variable mechanism, did not exclude Ag43 surface presentation. However, the presence of Dr fimbriae supported by other structures on the cell surface caused a physical neutralization of Ag43-mediated autoaggregation during in vitro growth. The fimbrial bundling further increased the distance between the adjacent Ag43(+) cells, thus preventing head-to-tail association between surface-exposed Ag43 subunits and their interactions with the host cells. The investigations showed that Ag43 did not act as a specific adhesin and invasin, conversely to the major virulence factors of E. coli Dr(+), but played significant roles in the viability and metabolic activity of bacterial cells forming biofilm, and in the survival of bacteria within invaded epithelial cells. PMID- 25743158 TI - Immunoreactive cortisone in droppings reflect stress levels, diet and growth rate of gull-billed tern chicks. AB - Blood levels of corticosterone have been traditionally analyzed to assess stress levels in birds; however, measuring steroid hormone metabolites in feces and droppings has gained much interest as a noninvasive technique successfully used for such purposed in vertebrates. Diet may affect these fecal metabolite levels (e.g., due to nutritional stress), however, this variable has not been taken into account in studies with chicks despite the great dietary flexibility of many avian species. In this study, we addressed for the first time this key issue and validated the technique in wild gull-billed tern chicks (Gelochelidon nilotica). Several enzyme immunoassays were used to determine the most appropriate test to measure the stress response. Subsequently, we performed an experiment in captivity to assess adrenocortical activity in gull-billed tern chicks fed with two diets: piscivorous vs. insectivorous. Finally, the relation between the chicks' growth rate and excreted immunoreactive glucocorticoid metabolites (EGMs) was also evaluated. We found the immunoreactive cortisone metabolites to be a good index of stress (as being an index of adrenocortical reactivity) in chicks of this species. Fish-fed chicks had higher levels of cortisone metabolites when comparing both concentration and total daily excreted metabolites. Within each treatment diet, cortisone metabolite levels and growth rates were negatively correlated. These findings suggest that the diet should be considered when using this technique for comparative purposes and highlight the trade-off between stress levels and chicks growth rates. PMID- 25743157 TI - Crystal structures of immunoglobulin Fc heterodimers reveal the molecular basis for heterodimer formation. AB - We determined the X-ray crystal structure of an immunoglobulin fragment crystallizable (Fc) heterodimer, EW-RVT, at a resolution of 2.5A and found that the designed asymmetric interaction residues located in the heterodimeric CH3 interface favor Fc heterodimer formation. We further generated an inter-CH3 disulfide-bonded heterodimeric Fc variant, EW-RVT(S-S), which exhibited improved heterodimer formation and thermodynamic stability compared with the parent EW-RVT variant. The crystal structure of EW-RVTS-S superimposed very closely with the wild-type Fc structure. Our results provide the detailed structure of heterodimeric Fc scaffolds, which will be useful for the generation of immunoglobulin G (IgG)-like bispecific antibodies. PMID- 25743159 TI - ALTERNATIVE OXIDASE1a modulates the oxidative challenge during moderate Cd exposure in Arabidopsis thaliana leaves. AB - This study aims to unravel the functional significance of alternative oxidase1a (AOX1a) induction in Arabidopsis thaliana leaves exposed to cadmium (Cd) by comparing wild-type (WT) plants and aox1a knockout mutants. In the absence of AOX1a, differences in stress-responsive transcript and glutathione levels suggest an increased oxidative challenge during moderate (5 uM) and prolonged (72h) Cd exposure. Nevertheless, aox1a knockout leaves showed lower hydrogen peroxide (H2O2) accumulation as compared to the WT due to both acute (24h) and prolonged (72h) exposure to 5 uM Cd, but not to 10 uM Cd. Taken together, we propose a working model where AOX1a acts early in the response to Cd and activates or maintains a mitochondrial signalling pathway impacting on cellular antioxidative defence at the post-transcriptional level. This fine-tuning pathway is suggested to function during moderate (5 uM) Cd exposure while being overwhelmed during more severe (10 uM) Cd stress. Within this framework, ethylene is required - either directly or indirectly via NADPH oxidase isoform C - to fully induce AOX1 expression. In addition, reciprocal crosstalk between these components was demonstrated in leaves of A. thaliana plants exposed to Cd. PMID- 25743160 TI - Housing helpful invaders: the evolutionary and molecular architecture underlying plant root-mutualist microbe interactions. AB - Plant root rhizosphere interactions with mutualistic microbes are diverse and numerous, having evolved over time in response to selective pressures on plants to attain anchorage and nutrients. These relationships can be considered to be formed through a combination of architectural connections: molecular architecture interactions that control root-microbe perception and regulate the balance between host and symbiont and developmental architecture interactions that enable the microbes to be 'housed' in the root and enable the exchange of compounds. Recent findings that help to understand the common architecture that exists between nodulation and mycorrhizal interactions, and how this architecture could be re-tuned to develop new symbioses, are discussed here. PMID- 25743162 TI - New oxygenated himachalenes in male-specific odor of the Chinese windmill butterfly, Byasa alcinous alcinous. AB - Male adults of the Chinese windmill Byasa alcinous alcinous (Papilionidae) are well known to have a strong musk-like odor, in which two oxygenated himachalene compounds, together with six sesquiterpene hydrocarbons, were newly discovered. gamma-Himachalen-4-yl acetate (1) was the predominant compound isolated from the solvent extract of the males. The structure of 1 was determined using MS and NMR, and its relative configuration was established as 1S*,4R*,6R* by NOE analysis with the help of quantum mechanical computation. Interestingly, the amount of 1 in males increased until 7 days after eclosion, suggesting that this compound is involved in sexual maturation for mating. Another new compound was identified as gamma-himachalen-4-ol (2) by comparison with the retention time and mass spectrum of the hydrolysate of 1. Since males of other papilionid species have general volatiles omnipresent in plants and insects, the presence of species-specific volatiles in males is characteristic of B. alcinous alcinous. PMID- 25743161 TI - Disruption of both chloroplastic and cytosolic FBPase genes results in a dwarf phenotype and important starch and metabolite changes in Arabidopsis thaliana. AB - In this study, evidence is provided for the role of fructose-1,6-bisphosphatases (FBPases) in plant development and carbohydrate synthesis and distribution by analysing two Arabidopsis thaliana T-DNA knockout mutant lines, cyfbp and cfbp1, and one double mutant cyfbp cfbp1 which affect each FBPase isoform, cytosolic and chloroplastic, respectively. cyFBP is involved in sucrose synthesis, whilst cFBP1 is a key enzyme in the Calvin-Benson cycle. In addition to the smaller rosette size and lower rate of photosynthesis, the lack of cFBP1 in the mutants cfbp1 and cyfbp cfbp1 leads to a lower content of soluble sugars, less starch accumulation, and a greater superoxide dismutase (SOD) activity. The mutants also had some developmental alterations, including stomatal opening defects and increased numbers of root vascular layers. Complementation also confirmed that the mutant phenotypes were caused by disruption of the cFBP1 gene. cyfbp mutant plants without cyFBP showed a higher starch content in the chloroplasts, but this did not greatly affect the phenotype. Notably, the sucrose content in cyfbp was close to that found in the wild type. The cyfbp cfbp1 double mutant displayed features of both parental lines but had the cfbp1 phenotype. All the mutants accumulated fructose-1,6-bisphosphate and triose-phosphate during the light period. These results prove that while the lack of cFBP1 induces important changes in a wide range of metabolites such as amino acids, sugars, and organic acids, the lack of cyFBP activity in Arabidopsis essentially provokes a carbon metabolism imbalance which does not compromise the viability of the double mutant cyfbp cfbp1. PMID- 25743163 TI - Proteome changes during yeast-like and pseudohyphal growth in the biofilm-forming yeast Pichia fermentans. AB - The Pichia fermentans strain DISAABA 726 is a biofilm-forming yeast that has been proposed as biocontrol agent to control brown rot on apple. How ever, when inoculated on peach, strain 726 shows yeast-like to pseudohyphal transition coupled to a pathogenic behaviour. To identify the proteins potentially involved in such transition process, a comparative proteome analysis of P. fermentans 726 developed on peach (filamentous growth) vs apple (yeast-like growth) was carried out using two-dimensional gel electrophoresis coupled with mass spectrometry analysis. The proteome comparison was also performed between the two different cell morphologies induced in a liquid medium amended with urea (yeast-like cells) or methionine (filamentous cells) to exclude fruit tissue impact on the transition. Seventy-three protein spots showed significant variations in abundance (+/-twofold, p < 0.01, confidence intervals 99 %) between pseudohyphal vs yeast-like morphology produced on fruits. Among them, 30 proteins changed their levels when the two morphologies were developed in liquid medium. The identified proteins belong to several pathways and functions, such as glycolysis, amino acid synthesis, chaperones, and signalling transduction. The possible role of a group of proteins belonging to the carbohydrate pathway in the metabolic re organisation during P. fermentans dimorphic transition is discussed. PMID- 25743164 TI - Radiolabeled new somatostatin analogs conjugated to DOMA chelator used as targeted tumor imaging agent: synthesis and radiobiological evaluation. AB - Several receptor-specific radiopeptides have been developed and effective in the diagnosis of malignant diseases. Among them, somatostatin receptor (SSTR) scintigraphy with (111)In-DTPA-octreotide has become a tumor diagnostic radiopharmaceutical in nuclear medicine. However, it suffers some drawbacks concerning the imaging properties and elevated radiation burden of (111)In. Here, we report the synthesis of radiolabeled two new octapeptides with improved uptake in SSTR2-positive tumors in comparison with (99m)Tc-HYNIC-Tyr(3)-octreotide (HYNIC-TOC). Octapeptides were synthesized in high yield by Fmoc solid-phase synthesis and coupling the macrocyclic chelator DOMA(1,4,7-Tri-Boc-10 (carboxymethyl)-1,4,7,10-tetraazocyclododecane-1-yl-monoacetic acid) to these peptides for (99m)Tc labeling. New peptides DOMA-Asn(3)-octreotate(DOMA-AATE) and DOMA-Pro(3)-octreotate(DOMA-PATE) were purified, characterized by RP-HPLC, MALDI mass, (1)H-NMR, (13)C-NMR. Labeling was performed by SnCl2 method to get products with excellent radiochemical purity (97 %). Radiopeptides were found to be substantially stable under physiological condition for 24 h. Internalization and receptor-binding studies were determined in somatostatin receptor-expressing C6 glioma cell line and rat brain cortex membrane and the results compared with HYNIC-TOC as standard. The IC50 values of (99m)Tc-DOMA-AATE(1.10 +/- 0.48 nM) and (99m)Tc-DOMA-PATE(1.76 +/- 0.06 nM) showed high affinity binding for SSTR2 receptor and they internalized rapidly in C6 cells. Biodistribution and imaging studies were performed in C6 tumor-bearing rat under gamma camera showing significant uptake in kidney, urine and C6 tumor. Radiopeptides exhibited fast blood clearance and rapid elimination through the urinary systems. However, (99m)Tc-DOMA-AATE exhibited the highest tumor to muscle and tumor to blood uptake ratios among three. These favorable characteristics validate (99m)Tc-DOMA-AATE as a more promising (99m)Tc-radiotracer than (99m)Tc-DOMA-PATE, (99m)Tc-HYNIC-TOC for SSTR2-positive tumor scintigraphy. PMID- 25743165 TI - Targeting rho guanine nucleotide exchange factor ARHGEF5/TIM with auto-inhibitory peptides in human breast cancer. AB - The oncogenic protein ARHGEF5/TIM has long been known to express specifically in human breast cancer and other tumors, which is an important member of Rho guanine nucleotide exchange factors that activate Rho-family GTPases by promoting GTP/GDP exchange. The activation capability of TIM is auto-inhibited by a putative helix N-terminal to Dbl homology (DH) domain, which is stabilized by intramolecular interaction of Src homology 3 domain with a poly-proline sequence that locates between the helix and DH domain. Here, we attempted to target TIM DH domain using the modified versions of its auto-inhibitory helix. In the procedure, bioinformatics techniques were used to investigate the intramolecular interaction of DH domain with auto-inhibitory helix and, based on obtained knowledge, to optimize physicochemical property and structural conformation for the helix. We also performed affinity assay to determine the binding strength of modified peptides to DH domain. Consequently, two modified peptides, namely, DALYEEYNLVV and EVLYEEYQLVV were found as good binders of DH domain with dissociation constants K d of 0.35 and 2 uM, respectively. Structural analysis revealed that the charge neutralization and electrostatic interaction confer additional stability for these two peptide complexes with DH domain. PMID- 25743166 TI - Acute Q fever and the risk of developing endocarditis. AB - OBJECTIVES: Assess clinical and serological data as parameters indicative of a possible evolution to endocarditis after an episode of acute Q fever. PATIENTS AND METHODS: Retrospective cohort study of evolution to endocarditis after an acute Q fever episode, analyzing the clinical and serological evolution and the antibiotic treatment administered. RESULTS: Eighty patients were recruited, 20% of whom had phase i IgG antibody levels >= 1:1024 in the first 3 months. Only 44% of the patients underwent antibiotherapy in the acute phase; only 2 patients underwent extended antibiotherapy. Fifteen percent of the patients underwent an echocardiogram. None of the patients had symptoms suggestive of chronic infection or progressed to endocarditis after a median follow-up of 100 months, regardless of the early increase in phase i IgG antibodies. CONCLUSIONS: The early increase in phase i IgG antibodies in asymptomatic patients is not associated with progression to endocarditis despite not undergoing prolonged antibiotic treatment. PMID- 25743167 TI - Occlusive vasculopathy due to type I cryoglobulinemia in IgG-lambda type multiple myeloma. PMID- 25743168 TI - Digital ischemia as a presentation of granulomatosis with polyangiitis. PMID- 25743169 TI - Similar clinical outcomes but more healthcare use in shoulder impingement patients following corticosteroid injection compared with physical therapy. PMID- 25743170 TI - There is no good evidence for the effectiveness of commonly used over-the-counter medicine to alleviate acute cough. PMID- 25743171 TI - Prolonged dual antiplatelet therapy after drug-eluting stent reduces the risk of stent thrombosis and major cardiovascular events but increases the rate of bleeding. PMID- 25743172 TI - Anacetrapib in familial hypercholesterolaemia: pros and cons. PMID- 25743173 TI - Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. AB - BACKGROUND: Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2.59 mmol/L or higher without cardiovascular disease or 1.81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. FINDINGS: Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3.3 mmol/L (SD 0.8) to 2.1 mmol/L (0.8; percentage change 36.0% [95% CI -39.5 to -32.5] compared with an increase with placebo from 3.4 mmol/L (1.2) to 3.5 mmol/L (1.6; percentage change 3.7% [-1.2 to 8.6], with a difference in percentage change between anacetrapib and placebo of -39.7% (95% CI -45.7 to -33.7; p<0.0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0.1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. FUNDING: Merck & Co, Inc. PMID- 25743174 TI - Hearing loss: a global health issue. PMID- 25743175 TI - Cortisol and the muscle-bone axis: response to comments by Molfino et al. PMID- 25743176 TI - The impact of glucocorticoid therapy on trabecular bone score in older women. AB - We propose that trabecular bone score could be a useful tool for the study of glucocorticoid-associated bone effects. Trabecular bone score alone and lumbar spine bone mineral density (BMD) used in combination with trabecular bone score, but not lumbar spine BMD alone was able to discriminate between glucocorticoid treated and glucocorticoid-naive women. INTRODUCTION: Glucocorticoids result in rapid bone loss and an increase in fracture risk that cannot be fully explained by changes in BMD. Trabecular bone score (TBS) correlates with three-dimensional bone micro-architectural parameters and can be derived from grey-level variations within dual energy X-ray absorptiometry (DXA) scans. We propose that TBS could be a useful tool for the study of glucocorticoid-associated bone effects. METHODS: We assessed the ability of lumbar spine BMD (LS-BMD), TBS, and LS-BMD with TBS (LS-BMD + TBS) to discriminate between healthy women and (i) glucocorticoid treated women, and (ii) glucocorticoid-naive women with recent fractures. Older women (n = 484, ages 55-79 years) who had (i) taken prednisolone >=5 mg/day for >3 months (n = 64), (ii) sustained a recent fracture of the distal forearm (n = 46), proximal humerus (n = 37), vertebra (n = 30) or proximal femur (n = 28), or (iii) were healthy population-based women (n = 279) were recruited. LS-BMD was measured by DXA and TBS values were derived. RESULTS: Compared to healthy, population-based women, women with recent fractures had lower LS-BMD (-0.34 to 1.38) and TBS (-0.38 to -1.04) Z-scores. Glucocorticoid-treated women had lower TBS Z-scores than glucocorticoid-naive women (-0.80 versus 0) but their LS-BMD Z scores did not differ (-0.13 versus 0). TBS alone (area under the receiver operating characteristic curve (AUC) = 0.721) and LS-BMD + TBS (AUC = 0.721), but not LS-BMD alone (AUC = 0.572) was able to discriminate between glucocorticoid treated and glucocorticoid-naive women. CONCLUSIONS: TBS provides additional information regarding glucocorticoid-associated alterations in bone quality. We conclude that TBS may be a useful tool for the further study of glucocorticoid induced osteoporosis. PMID- 25743177 TI - Tako-tsubo cardiomyopathy in two sisters: a chance finding or familial predisposition? PMID- 25743178 TI - Altered Quality of Life and Psychological Health (SCL-90-R) in Patients With Chronic Rhinosinusitis With Nasal Polyps. AB - OBJECTIVES: To investigate the impact of olfactory dysfunction on quality of life (QOL) and psychological status in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: A retrospective observational study was conducted from January 2011 to May 2012 with 130 patients with septal deviation (SD) (n = 59) and CRSwNP (n = 71). All patients underwent computed tomography (CT), allergy tests, and sniffin' stick olfactory test. Anosmia was defined by Threshold Discrimination-Identification (TDI) scores less than 16. QOL and psychological symptoms were assessed with the Sinonasal Outcome Test-20 (SNOT-20) and Symptom Checklist-90-Revised (SCL-90-R). RESULTS: Odor discrimination and identification scores were significantly lower in CRSwNP than in SD (P = .008 and P = .005, respectively). In CRSwNP, identification score decreased with higher CT score (r = -0.29, P = .014). CRSwNP with anosmia showed a decreased QOL (P = .044), and SNOT-20 negatively correlated with TDI in severe CRSwNP (CT score >=15, r = 0.714, P = .001). Anosmia patients had higher anxiety and phobia scores of SCL-90 R in both SD and CRSwNP. However, depression score increased only in CRSwNP with anosmia (P = .025). CONCLUSION: Olfactory dysfunction may have significant effects on QOL and psychological health. CRSwNP with anosmia is a distinct phenotype having mixed type of olfactory loss that might have a detrimental effect on depression. PMID- 25743179 TI - Identification of a novel CLRN1 gene mutation in Usher syndrome type 3: two case reports. AB - OBJECTIVE: This study examines the CLRN1 gene mutation analysis in Japanese patients who were diagnosed with Usher syndrome type 3 (USH3) on the basis of clinical findings. METHODS: Genetic analysis using massively parallel DNA sequencing (MPS) was conducted to search for 9 causative USH genes in 2 USH3 patients. RESULTS: We identified the novel pathogenic mutation in the CLRN1 gene in 2 patients. The missense mutation was confirmed by functional prediction software and segregation analysis. Both patients were diagnosed as having USH3 caused by the CLRN1 gene mutation. CONCLUSION: This is the first report of USH3 with a CLRN1 gene mutation in Asian populations. Validating the presence of clinical findings is imperative for properly differentiating among USH subtypes. In addition, mutation screening using MPS enables the identification of causative mutations in USH. The clinical diagnosis of this phenotypically variable disease can then be confirmed. PMID- 25743180 TI - Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf blindness. AB - OBJECTIVE: This study examines ABHD12 mutation analysis in 2 PHARC patients, originally thought to be Usher syndrome. METHODS: The ABHD12 gene of 2 patients, who suffered from deaf-blindness and dysfunctional central and peripheral nervous systems, were sequenced. RESULTS: We identified that both cases carried the same novel splice site mutation in the ABHD12 gene. However, 1 had epilepsy and the other had peripheral neuropathy. Based on haplotype analysis, the mutation is likely not a hot spot, but rather could be attributable to a common ancestor. CONCLUSION: This study shows that PHARC has phenotypic variability, even within a family, which is consistent with previous reports. Differential diagnosis of "deaf-blindness" diseases is crucial. Confirming the presence of associated symptoms is necessary for differentiating some deaf-blindness syndromes. In addition, mutation analysis is a useful tool for confirming the diagnosis. PMID- 25743181 TI - USH2 caused by GPR98 mutation diagnosed by massively parallel sequencing in advance of the occurrence of visual symptoms. AB - OBJECTIVE: We present 2 patients who were identified with mutations in the GPR98 gene that causes Usher syndrome type 2 (USH2). METHODS: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were used to identify the genetic causes of hearing loss. RESULTS: We identified causative mutations in the GPR98 gene in 1 family (2 siblings). The patients had moderate sloping hearing loss, and no progression was observed over a period of 10 years. Fundus examinations were normal. However, electroretinograms revealed impaired responses in both patients. CONCLUSION: Early diagnosis of Usher syndrome has many advantages for patients and their families. This study supports the use of comprehensive genetic diagnosis for Usher syndrome, especially prior to the onset of visual symptoms, to provide the highest chance of diagnostic success in early life stages. PMID- 25743182 TI - Molecular genetic diversity and characterization of conjugation genes in the fish parasite Ichthyophthirius multifiliis. AB - Ichthyophthirius multifiliis is the etiologic agent of "white spot", a commercially important disease of freshwater fish. As a parasitic ciliate, I. multifiliis infects numerous host species across a broad geographic range. Although Ichthyophthirius outbreaks are difficult to control, recent sequencing of the I. multifiliis genome has revealed a number of potential metabolic pathways for therapeutic intervention, along with likely vaccine targets for disease prevention. Nonetheless, major gaps exist in our understanding of both the life cycle and population structure of I. multifiliis in the wild. For example, conjugation has never been described in this species, and it is unclear whether I. multifiliis undergoes sexual reproduction, despite the presence of a germline micronucleus. In addition, no good methods exist to distinguish strains, leaving phylogenetic relationships between geographic isolates completely unresolved. Here, we compared nucleotide sequences of SSUrDNA, mitochondrial NADH dehydrogenase subunit I and cox-1 genes, and 14 somatic SNP sites from nine I. multifiliis isolates obtained from four different states in the US since 1995. The mitochondrial sequences effectively distinguished the isolates from one another and divided them into at least two genetically distinct groups. Furthermore, none of the nine isolates shared the same composition of the 14 somatic SNP sites, suggesting that I. multifiliis undergoes sexual reproduction at some point in its life cycle. Finally, compared to the well-studied free living ciliates Tetrahymena thermophila and Paramecium tetraurelia, I. multifiliis has lost 38% and 29%, respectively, of 16 experimentally confirmed conjugation-related genes, indicating that mechanistic differences in sexual reproduction are likely to exist between I. multifiliis and other ciliate species. PMID- 25743183 TI - Emergence of infectious malignant thrombocytopenia in Japanese macaques (Macaca fuscata) by SRV-4 after transmission to a novel host. AB - We discovered a lethal hemorrhagic syndrome arising from severe thrombocytopenia in Japanese macaques kept at the Primate Research Institute, Kyoto University. Extensive investigation identified that simian retrovirus type 4 (SRV-4) was the causative agent of the disease. SRV-4 had previously been isolated only from cynomolgus macaques in which it is usually asymptomatic. We consider that the SRV 4 crossed the so-called species barrier between cynomolgus and Japanese macaques, leading to extremely severe acute symptoms in the latter. Infectious agents that cross the species barrier occasionally amplify in virulence, which is not observed in the original hosts. In such cases, the new hosts are usually distantly related to the original hosts. However, Japanese macaques are closely related to cynomolgus macaques, and can even hybridize when given the opportunity. This lethal outbreak of a novel pathogen in Japanese macaques highlights the need to modify our expectations about virulence with regards crossing species barriers. PMID- 25743184 TI - Integration of disease association and eQTL data using a Bayesian colocalisation approach highlights six candidate causal genes in immune-mediated diseases. AB - The genes and cells that mediate genetic associations identified through genome wide association studies (GWAS) are only partially understood. Several studies that have investigated the genetic regulation of gene expression have shown that disease-associated variants are over-represented amongst expression quantitative trait loci (eQTL) variants. Evidence for colocalisation of eQTL and disease causal variants can suggest causal genes and cells for these genetic associations. Here, we used colocalisation analysis to investigate whether 595 genetic associations to ten immune-mediated diseases are consistent with a causal variant that regulates, in cis, gene expression in resting B cells, and in resting and stimulated monocytes. Previously published candidate causal genes were over-represented amongst genes exhibiting colocalisation (odds ratio > 1.5), and we identified evidence for colocalisation (posterior odds > 5) between cis eQTLs in at least one cell type and at least one disease for six genes: ADAM15, RGS1, CARD9, LTBR, CTSH and SYNGR1. We identified cell-specific effects, such as for CTSH, the expression of which in monocytes, but not in B cells, may mediate type 1 diabetes and narcolepsy associations in the chromosome 15q25.1 region. Our results demonstrate the utility of integrating genetic studies of disease and gene expression for highlighting causal genes and cell types. PMID- 25743186 TI - Rigid therapies, rigid minds: italian professionals' perspectives on autism interventions. AB - Many therapies, interventions, and programs seek to improve outcomes and quality of life for people diagnosed with autism spectrum conditions. This paper addresses Italian professionals' perspectives on a variety of such interventions, including TEACCH, ABA, Defeat Autism Now!, and Doman-Delacato. Drawing on participant-observation and interviews collected in 2012-2013 in a northern region of Italy, it highlights the theme of "rigidity" that appears in professionals' discourses about both the characteristics of people with autism and the potential risks of adhering too strictly to any particular treatment protocol. The co-occurrence of the theme of rigidity across different domains demonstrates a way in which diagnostic characteristics become metaphors for medical practice. This paper proposes that such discursive moves may help bridge the gap between people with autism and people who work with them because a key attribute of people with autism-thinking and/or acting rigidly-is also a potential pitfall for people without autism. PMID- 25743185 TI - Mask loss-of-function rescues mitochondrial impairment and muscle degeneration of Drosophila pink1 and parkin mutants. AB - PTEN-induced kinase 1 (Pink1) and ubiquitin E3 ligase Parkin function in a linear pathway to maintain healthy mitochondria via regulating mitochondrial clearance and trafficking. Mutations in the two enzymes cause the familial form of Parkinson's disease (PD) in humans, as well as accumulation of defective mitochondria and cellular degeneration in flies. Here, we show that loss of function of a scaffolding protein Mask, also known as ANKHD1 (Ankyrin repeats and KH domain containing protein 1) in humans, rescues the behavioral, anatomical and cellular defects caused by pink1 or parkin mutations in a cell-autonomous manner. Moreover, similar rescue can also be achieved if Mask knock-down is induced in parkin adult flies when the mitochondrial dystrophy is already manifested. We found that Mask genetically interacts with Parkin to modulate mitochondrial morphology and negatively regulates the recruitment of Parkin to mitochondria. We also provide evidence that loss of Mask activity promotes co-localization of the autophagosome marker with mitochondria in developing larval muscle, and that an intact autophagy pathway is required for the rescue of parkin mutant defects by mask loss of function. Together, our data strongly suggest that Mask/ANKHD1 activity can be inhibited in a tissue- and timely-controlled fashion to restore mitochondrial integrity under PD-linked pathological conditions. PMID- 25743187 TI - Ethanol impairment of spontaneous alternation behaviour and associated changes in medial prefrontal glutamatergic gene expression precede putative markers of dependence. AB - Cognitive impairments are observable in over half of cases with alcoholism, deficits in spatial working memory being particularly common. Previously we observed that rats make more alternation errors in a Y-maze test of spontaneous alternation behaviour/spatial working memory after 5-day intermittent ethanol. Here we used qPCR to quantify changes in gene expression accompanying this behavioural impairment. Male Wistar rats were treated with either saline or ethanol (1 or 2.5g/kg) for 5days followed by 2 drug-free days. Brains were dissected after Y-maze analysis and RNA was extracted from the medial prefrontal cortex, hippocampus and nucleus accumbens. Using the Qiagen GABA & Glutamate PCR array we measured changes in these two neurotransmitter systems. A dose of 1g/kg ethanol did not affect spontaneous alternation behaviour or any other behavioural variable. 2.5g/kg significantly decreased % correct alternations (p=0.028) without affecting total distance (p=0.54) and increased time in the choice area (p=0.023) at the Y-maze centre, indicating a possible impairment in decision making. In the medial prefrontal cortex, 2.5g/kg ethanol decreased mRNA expression of brain-derived neurotrophic factor, NMDA NR2A subunit, mGluR8 receptor, Homer1, the glutamate transporters SLC1a1 and SLC1a6 and Srr. In the nucleus accumbens this dose did not affect mRNA expression of the dopamine D1 or D2 receptors but did upregulate the GABA transporter GAT-3. Even if only correlational, these data suggest that gene expression changes in the medial prefrontal cortex and associated cognitive impairment occur before adaptation of the dopaminergic system and, presumably, drug dependence. PMID- 25743188 TI - Development and leading-edge application of innovative photoaffinity labeling. AB - Photoaffinity labeling has become increasingly important with the development of powerful specific probes that are synthesized by installing a photo-activatable functional group (photophore) on the framework of biological ligands. The present review summarizes the development of diazirine-based photoaffinity labeling by focusing on its application to the structural elucidation of ligand-accepting sites within proteins. PMID- 25743189 TI - Complex formation with layered double hydroxides for the remediation of hygroscopicity. AB - Layered double hydroxides (LDHs) have been used commercially as antacids, to stabilize drugs, to allow the controlled release of incorporated drugs, and to act as drug carriers to reduce drug accumulation within the body. Several types of LDH were investigated: nitrate type (LDH-NO3); chloride type (LDH-Cl); and carbonate type (LDH-CO3). Each type was added to an aqueous or methanol (MeOH) solution containing a drug (pravastatin or nateglinide). With pravastatin sodium, the interlayer distance expanded after reaction with LDH-NO3 and LDH-Cl in aqueous solution. In contrast, the interlayer distance of LDH-CO3 increased in methanol with nateglinide. Each drug was intercalated into the interlayer space of LDH by ion exchange. The hygroscopicity of the drug substances, complexes, and physical mixtures were determined at 70% relative humidity. Increases in weight (%) of the complexes were less than those of the physical mixtures, which demonstrates that hygroscopicity was reduced upon complexation with LDH due to the layer of LDH over the drugs. PMID- 25743190 TI - Stability order of caffeine co-crystals determined by co-crystal former exchange reaction and its application for the validation of in silico models. AB - The purpose of the present study was to determine the thermodynamic stability orders of co-crystals by co-crystal former (CCF) exchange reactions. Caffeine (CA) was employed as a model drug. The CCF exchange reaction was performed by liquid-assisted grinding using ethanol. When oxalic acid (OX) was added to CA citric acid co-crystal (CA-CI), CA-CI converted to CA-OX, suggesting that CA-OX is more stable than CA-CI. The stability orders of other co-crystals were determined in the same manner. The stability order of CA co-crystals was determined as CA-OX~CA-p-hydroxybenzoic acid (HY)>CA-CI>CA-malonic acid>CA-maleic acid. The stability order correlated with the difference in hydrogen bond energy estimated in silico, except for CA-HY. The pi-pi stacking in CA-HY was suggested as a reason for this discrepancy. The CCF exchange reaction was demonstrated as a useful method to determine the stability order of co-crystals, which can be used for the validation of in silico parameters to predict co-crystal formation. PMID- 25743191 TI - Quantitative comparison of caffeoylquinic acids and flavonoids in Chrysanthemum morifolium flowers and their sulfur-fumigated products by three-channel liquid chromatography with electrochemical detection. AB - For the determination of seven caffeoylquinic acids [neochlorogenic acid (NcA), cryptochlorogenic acid (CcA), chlorogenic acid (CA), caffeic acid (CfA), isochlorogenic acid A (Ic A), isochlorogenic acid B (Ic B), isochlorogenic acid C (Ic C)] and two flavonoids [luteolin 7-O-glucoside (LtG) and luteolin (Lt)], a three-channel liquid chromatography with electrochemical detection (LC-3ECD) method was established. Chromatographic peak heights were proportional to each concentration, ranging from 2.5 to 100 ng/mL for NcA, CA, CcA, and CfA, and ranging from 2.5 to 250 ng/mL for LtG, Ic B, Ic A, Ic C, and Lt, respectively. The present LC-3ECD method was applied to the quantitative analysis of caffeoylquinic acids and flavonoids in four cultivars of Chrysanthemum morifolium flowers and their sulfur-fumigated products. It was found that 60% of LtG and more than 47% of caffeoylquinic acids were lost during the sulfur fumigation processing. Sulfur fumigation showed a destructive effect on the C. morifolium flowers. In addition, principle component analyses (PCA) were performed using the results of the quantitative analysis of caffeoylquinic acids and flavonoids to compare the "sameness" and "differences" of these analytes in C. morifolium flowers and the sulfur-fumigated products. PCA score plots showed that the four cultivars of C. morifolium flowers were clearly classified into four groups, and that significant differences were also found between the non-fumigated C. morifolium flowers and the sulfur-fumigated products. Therefore, it was demonstrated that the present LC-3ECD method coupled with PCA is applicable to the variation analysis of different C. morifolium flower samples. PMID- 25743192 TI - Synthesis and antibacterial activities of Yanglingmycin analogues. AB - The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with minimum inhibitory concentration (MIC) values ranging from 3.91 to 15.62 ug/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides. PMID- 25743193 TI - Function of rayon fibers with metallophthalocyanine derivatives: potential of low molecular weight polycyclic aromatic hydrocarbon removal and Bacillus sp. removal. AB - Polycyclic aromatic hydrocarbons (PAHs) are known as carcinogenic and/or mutagenic substances, and are present at high concentration in polluted environments. It has recently been reported that spore-forming bacteria (e.g., Bacillus spp.) can be transported long distances alive in the atmosphere, which raises the possibility that some of the transported bacteria could have adverse effects on human health. There is thus a need for filters that can remove gaseous PAHs from the air that people breathe and that can inhibit bacterial growth on the filters. We focused on metallophthalocyanine derivatives (M-Pc) which are known to adsorb PAHs as well as to inhibit the growth of bacteria as a potential filtering agent. In this study, we developed different types of M-Pc-supported rayon fibers by changing central metals, functional groups, concentrations of M Pc and rayon types, and evaluated their removal effects by measuring adsorption rates of 3- and 4-ring PAHs with a HPLC and growth curves of Bacillus sp. with a spectrophotometer. The results showed that both the effects depended on functional groups and concentrations of M-Pc, and rayon types. The most effective combination was observed in Fe-Pc with sulfo group supported on cationized rayon fiber at the concentration of 2 to 3.3 wt%. Central metal species of M-Pc were influenced only on the antibacterial properties. This fiber would be applicable to filtering agents and textiles. PMID- 25743194 TI - Nitrile-containing phenolic glucosides from the leaves of Glochidion acuminatum. AB - From the EtOAc-soluble fraction of a MeOH extract of the leaves of Glochidion acuminatum, six new compounds along with five known ones were isolated. The structures of the new compounds were elucidated to be two gallates, a p hydroxybenzoate and an (S)-2-(4-hydroxycyclohex-1-en-1-yl)acetate of a nitrile containing phenolic glucoside, methyl 2-(2-hydroxyphenyl)acetate beta-D glucopyranoside, and (S)-methyl 2-[4-sulfooxycyclohex-1-en-1-yl]acetate on the basis of spectroscopic evidence. PMID- 25743196 TI - Editor's choice, volume 113. PMID- 25743195 TI - Physicochemical stability study on cyclosporine A loaded dry-emulsion formulation with enhanced solubility. AB - The main purpose of the present study was to evaluate the physicochemical stability of cyclosporine A (CsA)-loaded glycerol monooleate-based dry emulsion (DE). DE formulations containing 5-25% CsA (DE5-25) were stored at 25 degrees C/60% relative humidity for 4 weeks, and freeze-dried solid dispersion formulations containing 5-30% CsA (FD5-30) were also prepared as reference formulations. Even after the storage, no significant changes were observed in the appearance of any formulations. In the dissolution study, both DE and FD exhibited marked enhancement of solubility and there was at least 2.0-fold improvement in the initial dissolution rate of DE formulations compared with that of FD formulations. After storage, DE5, DE15 and FD5 maintained relatively high solubility, with 10% reduction compared with the initial state. However, the solubility of DE25 gradually decreased during storage, as evidenced by 76% reduction of the dissolution amount. No significant changes were seen in DE5-25 using powder X-ray diffraction, although thermal analysis revealed moderate changes in crystallinity in DE25 after storage, possibly leading to the decreased dissolution. Furthermore, particle size distributions of micelles in DE5 and DE15 were almost unchanged after storage for 4 weeks. From these findings, it appears that the physicochemical stability of CsA-loaded DE might vary depending on the manufacturing method and that further optimization could improve physical properties and stability. PMID- 25743197 TI - Glucuronic Acid Moieties on Xylan Are Functionally Equivalent to O-Acetyl Substituents. PMID- 25743198 TI - A Solution to the C-Value Paradox and the Function of Junk DNA: The Genome Balance Hypothesis. AB - The Genome Balance Hypothesis originated from a recent study that provided a mechanism for the phenomenon of genome dominance in ancient polyploids: unique 24nt RNA coverage near genes is greater in genes on the recessive subgenome irrespective of differences in gene expression. 24nt RNAs target transposons. Transposon position effects are now hypothesized to balance the expression of networked genes and provide spring-like tension between pericentromeric heterochromatin and microtubules. The balance (coordination) of gene expression and centromere movement is under selection. Our hypothesis states that this balance can be maintained by many or few transposons about equally well. We explain known balanced distributions of junk DNA within genomes and between subgenomes in allopolyploids (and our hypothesis passes "the onion test" for any so-called solution to the C-value paradox). Importantly, when the allotetraploid maize chromosomes delete redundant genes, their nearby transposons are also lost; this result is explained if transposons near genes function. The Genome Balance Hypothesis is hypothetical because the position effect mechanisms implicated are not proved to apply to all junk DNA, and the continuous nature of the centromeric and gene position effects have not yet been studied as a single phenomenon. PMID- 25743199 TI - Executive function and cortical thickness in youths prenatally exposed to cocaine, alcohol and tobacco. AB - Small and detrimental, albeit inconsistent, effects of prenatal cocaine exposure (PCE) during early childhood have been reported. The teratogenic effects of prenatal alcohol (PAE) and tobacco exposure (PTE) on neurobehavior are more firmly established than PCE. We tested if co-exposure to all three drugs could be related to greater differences in brain structure than exposure to cocaine alone. Participants (n=42, PCE=27; age range=14-16 years) received an executive function battery prior to a T1-weighted 3T structural MRI scan. Cortical thickness was measured using FreeSurfer (v5.1). Fetal drug exposure was quantified through maternal self-reports usage during pregnancy. Using general linear modeling, we found no main effects of PCE on cortical thickness, but significant main effects of PAE and PTE in superior and medial frontal regions, after co-varying for the effects of age, sex, and each drug of exposure. Significant alcohol-by-tobacco interactions, and significant cocaine-by-alcohol interactions on cortical thickness in medial parietal and temporal regions were also observed. Poly-drug exposure and cognitive function also showed significant interactions with cortical thickness: lower cortical thickness was associated with better performance in PCE-exposed adolescents. Results suggest that although children with PCE have subtle but persistent brain cortical differences until mid-to-late adolescence. PMID- 25743201 TI - Stroke risk in atrial fibrillation: Do we anticoagulate CHADS2 or CHA2DS2-VASc >=1, or higher? PMID- 25743200 TI - Improving bone mineral density reporting to patients with an illustration of personal fracture risk. AB - BACKGROUND: To determine patients' preferences for, and understanding of, FRAX(r) fracture risk conveyed through illustrations. METHODS: Drawing on examples from published studies, four illustrations of fracture risk were designed and tested for patient preference, ease of understanding, and perceived risk. We enrolled a convenience sample of adults aged 50 and older at two medical clinics located in the Midwestern and Southern United States. In-person structured interviews were conducted to elicit patient ranking of preference, ease of understanding, and perceived risk for each illustration. RESULTS: Most subjects (n = 142) were female (64%), Caucasian (76%) and college educated (78%). Of the four risk depictions, a plurality of participants (37%) listed a bar graph as most preferred. Subjects felt this illustration used the stoplight color system to display risk levels well and was the most "clear," "clean," and "easy to read". The majority of subjects (52%) rated the pictogram as the most difficult to understand as this format does not allow people to quickly ascertain their individual risk category. CONCLUSIONS: Communicating risk to patients with illustrations can be done effectively with clearly designed illustrations responsive to patient preference. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01507662. PMID- 25743202 TI - Psychiatry's Next Generation: Teaching College Students About Mental Health. AB - OBJECTIVE: The authors describe an integrated area of study for undergraduate college students that targets an increase in knowledge of mental health issues in children, adolescents, and emerging adults; encourages mental health service utilization on college campuses; and exposes young minds to the possibilities of working with children and adolescents in the mental health field. METHODS: An overview of the program is provided, including the resources required to oversee and manage the program, student requirements, a description of the role that clinicians and researchers play as the program faculty, and an explanation of the tuition model. RESULTS: The program currently includes 40 courses with an annual enrollment of over 3000 students, resulting in departmental revenues that currently exceed $11 million per year. Student evaluations of the courses are very positive, and in a program survey students reported that their participation in the program had a positive impact on their life (84.2%) and impacted their career choice (60.2%). CONCLUSIONS: The benefits of the program include a valuable outreach to college students regarding the importance of seeking help for mental health issues, a positive influence on early career decision-making, opportunities for clinical and research educators to develop their scholarly areas of interest, and a significant source of departmental discretionary revenues. PMID- 25743203 TI - Psychiatrists' and Psychiatry Residents' Attitudes Toward Transgender People. AB - OBJECTIVE: Gender minority groups, such as transgender individuals, frequently encounter stigma, discrimination, and negative mental health outcomes, which can result in contact with mental health professionals. Recent studies suggest that negative attitudes toward transgender individuals are prevalent and measurable within the general population. The Genderism and Transphobia scale (GTS) measures anti-transgender feelings, thoughts, and behaviors. The purpose of this study was to use the GTS to conduct an investigation of psychiatrists' attitudes toward transgender individuals. METHODS: A cross-sectional survey of n = 142 faculty members and residents from the Department of Psychiatry at the University of Manitoba was conducted. Respondents completed an online survey consisting of demographic questions and the GTS. Responses were analyzed descriptively and compared to previously published data on the GTS. RESULTS: There was a trend for psychiatrists and psychiatry residents within this sample to endorse less negative attitudes toward transgender people compared to other published data using a sample of undergraduate students. Descriptive analyses suggest that psychiatrists' and psychiatry residents' GTS scores may be related to gender identity, political ideology, religiosity, and levels of both professional and personal contact. CONCLUSIONS: These data evoke optimism regarding psychiatrists' and psychiatry residents' attitudes toward transgender individuals. Additional larger-scale studies comparing this medical specialty group with other specialty groups will further elucidate factors that modify physician attitudes toward this patient population. These findings may contribute to the development of educational strategies to ensure that the transgender population receives medical treatment without stigma or attitudinal compromise. PMID- 25743204 TI - Production of pyroxene ceramics from the fine fraction of incinerator bottom ash. AB - Incinerator bottom ash (IBA) is normally processed to extract metals and the coarse mineral fraction is used as secondary aggregate. This leaves significant quantities of fine material, typically less than 4mm, that is problematic as reuse options are limited. This work demonstrates that fine IBA can be mixed with glass and transformed by milling, calcining, pressing and sintering into high density ceramics. The addition of glass aids liquid phase sintering, milling increases sintering reactivity and calcining reduces volatile loss during firing. Calcining also changes the crystalline phases present from quartz (SiO2), calcite (CaCO3), gehlenite (Ca2Al2SiO7) and hematite (Fe2O3) to diopside (CaMgSi2O6), clinoenstatite (MgSiO3) and andradite (Ca3Fe2Si3O12). Calcined powders fired at 1080 degrees C have high green density, low shrinkage (<7%) and produce dense (2.78 g/cm(3)) ceramics that have negligible water absorption. The transformation of the problematic fraction of IBA into a raw material suitable for the manufacture of ceramic tiles for use in urban paving and other applications is demonstrated. PMID- 25743205 TI - Chromokinesin Kid and kinetochore kinesin CENP-E differentially support chromosome congression without end-on attachment to microtubules. AB - Chromosome congression is the alignment of chromosomes at the spindle equator, and is a prerequisite for faithful chromosome segregation. Recent data suggest that before kinetochores attach to the end of microtubules (end-on attachment), chromosomes can move along microtubules towards the spindle equator through attachment of kinetochores to the lateral surface of microtubules (lateral attachment). Here we address this mechanism, focusing on the contribution of two mitotic motors, Kid and CENP-E. In cells depleted of Hec1, which is essential for end-on attachment, chromosomes show partial and transient congression. This transient congression is further perturbed by co-depletion of Kid, suggesting its role in chromosome congression. In comparison, CENP-E suppresses chromosome congression, probably by tethering kinetochores to short, unstable microtubules, and works in congression only when microtubules are stabilized. Our results may reflect the differential contributions of Kid and CENP-E in chromosome congression in physiological conditions where stabilized microtubules are becoming increased. PMID- 25743207 TI - Laparoscopic Radical Cystectomy Versus Extraperitoneal Radical Cystectomy: Is the Extraperitoneal Technique Rewarding? AB - BACKGROUND: To study whether extraperitoneal radical cystectomy (EORC) accelerates the postoperative recovery of bowel function compared with laparoscopic radical cystectomy (LRC). PATIENTS AND METHODS: All the patients with bladder cancer who underwent EORC or LRC with an ileal conduit by a single surgeon from January 2009 to June 2014 were investigated. The perioperative outcomes and follow-up data were analyzed, with a focus on postoperative ileus (POI). RESULTS: A total of 41 LRCs and 53 EORCs met the inclusion criteria. LRC was associated with a significant reduction in the estimated blood loss (278 vs. 356 mL, P = .017) and a shorter hospital stay (8.1 vs. 9.2 days, P = .003). However, LRC was also associated with longer operative times (349 vs. 316 minutes, P = .022). The incidence of paralytic POI was 7.3% (3 of 41) and 7.5% (4 of 53; P = .966) and the obstructive POI rate was 4.9% (2 of 41) and 3.8% (2 of 53; P = .792) for the LRC and EORC groups, respectively. No significant differences were noted in blood transfusion requirements, interval to flatus or liquid intake, or opioid dosage. No patient in either group had positive surgical margins, and no significant differences were observed in the lymph node count (P = .112). At a median follow-up period of 28.7 months (range, 3-62 months), no significant differences were seen between the LRC and EORC groups in the 3-year overall, cancer-specific, or cancer-free survival rates. CONCLUSION: EORC resulted in a POI rate similar to that of LRC, despite factors favoring LRC. Our results suggest that extraperitoneal LRC could improve the perioperative outcomes. PMID- 25743206 TI - Sequencing of Cabazitaxel and Abiraterone Acetate After Docetaxel in Metastatic Castration-Resistant Prostate Cancer: Treatment Patterns and Clinical Outcomes in Multicenter Community-Based US Oncology Practices. AB - BACKGROUND: Optimal sequencing of cabazitaxel (C) and abiraterone acetate (A) after docetaxel (D) for metastatic castration-resistant prostate cancer (mCRPC) is unclear. We assessed treatment patterns and outcomes in patients with mCRPC receiving different sequences of A or C, or both, after administration of D. METHODS: Retrospective analysis was conducted of US Oncology Network iKnowMed (iKM) electronic health record (EHR) data to assess patients with mCRPC who received treatment with D and were subsequently treated with C or A, or both, between April 2011 and May 2012. Patients received 2 or 3 drugs: DA, DC, DAC, or DCA. Overall survival (OS) and time to treatment failure (TTF) were analyzed by the Kaplan-Meier method from the start to the end of second-line therapy after administration of D (TTF1) and to the end of combined second- and third-line therapy (TTF2) for 3-drug sequences. Multivariable Cox proportional hazard models evaluated the impact of baseline clinical prognostic factors and treatment sequence on OS and TTF. RESULTS: Of 350 patients who were treated with D and subsequent therapies, 183 (52.3%) received DA, 54 (15.4%) received DC, 77 (22.0%) received DCA, and 36 (10.3%) received DAC. In a multivariable analysis, adjusted comparisons suggested that 3-drug sequences were associated with improved OS versus 2-drug sequences (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.092-0.476; P = .0002). There were no statistically significant differences in OS and TTF for DC versus DA, and OS was significantly greater for DCA versus DAC (HR, 0.13; 95% CI, 0.022-0.733; P = .0210). More cycles of C were administered in DCA than in DAC (median 6 vs. 4; t test P < .0001), whereas the duration of A treatment was similar. CONCLUSION: Administration of 3 agents in the DCA sequence was more optimal for treating mCRPC in this hypothesis-generating study. PMID- 25743208 TI - Usefulness of regional distribution of coronary artery calcium to improve the prediction of all-cause mortality. AB - Although the traditional Agatston coronary artery calcium (CAC) score is a powerful predictor of mortality, it is unknown if the regional distribution of CAC further improves cardiovascular risk prediction. We retrospectively studied 23,058 patients referred for Agatston CAC scoring, of whom 61% had CAC (n=14,084). CAC distribution was defined as the number of vessels with CAC (0 to 4, including left main). For multivessel CAC, "diffuse" CAC was defined by decreasing percentage of CAC in the single most affected vessel and by <=75% total Agatston CAC score in the most calcified vessel. All-cause mortality was ascertained through the social security death index. The mean age was 55+/-11 years, with 69% men. There were 584 deaths (2.5%) over 6.6+/-1.7 years. Considerable heterogeneity existed between the Agatston CAC score group and the number of vessels with CAC. In each CAC group, increasing number of vessels with CAC was associated with an increased mortality rate. After adjusting for age, gender, Agatston CAC score, and cardiovascular risk factors, increasing number of vessels with CAC was associated with higher mortality risk compared with single vessel CAC (2-vessel: HR 1.61 [95% CI 1.14 to 2.25], 3-vessel: 1.99 [1.44 to 2.77], and 4-vessel: 2.22 [1.53 to 3.23]). "Diffuse" CAC was associated with a higher mortality rate in the CAC 101 to 400 and >400 groups. Left main CAC was associated with increased mortality risk. In conclusion, increasing number of vessels with CAC and left main CAC predict increased all-cause mortality and improve the prognostic power of the traditional Agatston CAC score. PMID- 25743209 TI - Comparison of outcomes in patients with probable versus definite cardiac sarcoidosis. AB - Patients with probable cardiac sarcoidosis (CS) who satisfy only clinical cardiac findings for CS are not uncommon. The aim of this study was to compare outcomes between patients with probable CS and those with definite CS treated with steroids. The study population consisted of 101 consecutive patients who satisfied clinical cardiac findings for CS. Patients with definite CS were defined as having histologic or clinical confirmation of CS according to the guidelines and were treated with steroids. Patients with probable CS were defined as having only clinical cardiac findings but not definite CS because of no histologic confirmation or extracardiac sarcoidosis and were not treated with steroids. The end point was major adverse cardiac events. Forty-seven patients had definite CS, and the other 54 had probable CS. Except for serum angiotensin converting enzyme levels and left ventricular dysfunction, clinical characteristics were similar between the 2 groups. Over a median follow-up period of 15 months, major adverse cardiac events occurred more frequently in patients with probable CS than in those with definite CS (74% vs 53%, p=0.029). The event free survival rate was worse in patients with probable CS than in those with definite CS (log-rank test, p=0.006). Cox proportional-hazards analysis showed that probable CS was an independent predictor of major adverse cardiac events. In conclusion, outcomes were worse in patients with probable CS than in those with definite CS treated with steroids. The initiation of steroid treatment may be considered for patients who satisfy only clinical cardiac findings for CS. PMID- 25743210 TI - Ethnic differences among implantable cardioverter defibrillators recipients in Israel. AB - Heart failure is an increasingly common condition arising from a variety of different pathophysiological processes. Little is known about the unique features of Israeli Arabs who present with heart failure and who undergo cardiac device implantation. The study population comprised of 4,671 patients who were enrolled in the national Israeli Implantable Cardioverter Defibrillator registry. We compared demographic, clinical, and echocardiographic characteristics; device related indications; and outcomes between Israeli Arabs (n = 733) and Jews (n = 3,938), who were enrolled in the registry from July 2010 through December 2013. Israeli Arabs constituted 15.7% of the study population. They were younger at presentation compared with Jews (57 +/- 15 vs 66 +/- 12 years, respectively; p <0.001), with a greater burden of co-morbidities, including diabetes mellitus and chronic obstructive lung disease and smoking. In addition, Arab patients had a greater frequency of non-ischemic cardiomyopathy (40.2% vs 24.6%, respectively; p <0.001), which was associated with a greater frequency of familial history of sudden cardiac death. During 15 +/- 9 month follow-up, the mortality rates and appropriate device therapy were similar in both ethnic groups. In conclusion, Israeli Arab patients implanted with implantable cardioverter defibrillators display unique clinical features with greater prevalence of non-ischemic cardiomyopathy characterized by an early-onset and rapid deterioration. PMID- 25743211 TI - Association of hypothyroidism with adverse events in patients with heart failure receiving cardiac resynchronization therapy. AB - Hypothyroidism is associated with an adverse prognosis in cardiac patients in general and in particular in patients with heart failure (HF). The aim of this study was to evaluate the impact of hypothyroidism on patients with HF receiving cardiac resynchronization therapy (CRT). Additionally, the impact of level of control of hypothyroidism on risk of adverse events after CRT implantation was also evaluated. We included consecutive patients in whom a CRT device was implanted from April 2004 to April 2010 at our institution with sufficient follow up data available for analysis; 511 patients were included (age 68.5+/-12.4 years, women 20.4%); 84 patients with a clinical history of hypothyroidism, on treatment with thyroid hormone repletion or serum thyroid-stimulating hormone level>=5.00 MUU/ml, were included in the hypothyroid group. The patients were followed for up to 3 years after implant for a composite end point of hospitalization for HF, left ventricular assist device placement, or heart transplant and cardiac death; 215 composite end point events were noted in this period. In a multivariate model, hypothyroidism (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.027 to 2.085, p=0.035), female gender (HR 0.64, 95% CI 0.428 to 0.963, p=0.032), and creatinine (HR 1.26, 95% CI 1.145 to 1.382, p<0.001) were significantly associated with occurrence of the composite end point; 53.6% of patients with hypothyroidism at baseline developed the composite end point compared with 39.8% of those with euthyroidism (p=0.02). In conclusion, hypothyroidism is associated with a worse prognosis after CRT implantation. PMID- 25743212 TI - Dietary intake, resting energy expenditure, and eating behavior in women with and without polycystic ovary syndrome. AB - BACKGROUND: Data on dietary intake, meal patterns, and eating attitudes from women with polycystic ovary syndrome (PCOS) is limited despite the fact that PCOS is associated with obesity. We aimed to test the hypothesis that women with PCOS display altered dietary intakes and eating behaviors compared to controls. METHODS: Women with PCOS (n = 72) as defined according to the modified Rotterdam criteria were compared with healthy controls (n = 30). Anthropometry included measurement of waist circumference and determination of the resting metabolic rate via indirect calorimetry. All women completed questionnaires regarding eating behavior; Three-Factor Eating Questionnaire (TFEQ-R21) and eating attitudes; Eating Attitudes Test (EAT). Group comparisons were done by Mann Whitney U test and logistic regression analysis was used for adjustments of age and BMI in a non-parametric way. RESULTS: BMI was higher in women with PCOS compared to controls. Resting metabolic rate did not differ between women with women with and without PCOS after adjustment for age and BMI [1411 +/- 229 kcal/day versus 1325 +/- 193 kcal per day (P = 0.07)], whereas the respiratory exchange ratio was higher in women with PCOS than in controls [0.83 +/- 0.07 versus 0.78 +/- 0.08 (P = 0.02 after adjustments for age and BMI)]. Energy percent (E%) carbohydrates was higher in women with PCOS compared to controls (P = 0.017), but E% alcohol was lower (P = 0.036) after adjustment for age and BMI. The average total EAT scores and EAT dieting subscale scores were higher in women with PCOS compared with controls (P = 0.001 and P = 0.024, respectively) after adjustment for age and BMI. No difference was found for previous or current symptoms of bulimia nervosa. CONCLUSIONS: Independent of BMI and age, the resting metabolic rate did not differ between women with and without PCOS indicating that women with PCOS should have equal abilities in terms of energy metabolism to lose weight as women without PCOS. Women with PCOS showed greater concerns about their weight and dieting, and this indicates that anxiety about weight is one of the psychological symptoms of PCOS. PMID- 25743213 TI - Multiple binding modes of isothiocyanates that inhibit macrophage migration inhibitory factor. AB - Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has roles in the innate immune response, and also contributes to inflammatory disease. While the biological properties of MIF are closely linked to protein protein interactions, MIF also has tautomerase activity. Inhibition of this activity interferes with the interaction of MIF with protein partners e.g. the CD74 receptor, and tautomerase inhibitors show promise in disease models including multiple sclerosis and colitis. Isothiocyanates inhibit MIF tautomerase activity via covalent modification of the N-terminal proline. We systematically explored variants of benzyl and phenethyl isothiocyanates, to define determinants of inhibition. In particular, substitution with hydroxyl, chloro, fluoro and trifluoro moieties at the para and meta positions were evaluated. In assays on treated cells and recombinant protein, the IC50 varied from 250 nM to >100 MUM. X ray crystal structures of selected complexes revealed that two binding modes are accessed by some compounds, perhaps owing to strain in short linkers between the isothiocyanate and aromatic ring. The variety of binding modes confirms the existence of two subsites for inhibitors and establishes a platform for the development of potent inhibitors of MIF that only need to target one of these subsites. PMID- 25743214 TI - LEADOPT: an automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors. AB - Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT. PMID- 25743215 TI - Recent advances of chroman-4-one derivatives: synthetic approaches and bioactivities. AB - Chroman-4-one scaffold is a privileged structure in heterocyclic chemistry and drug discovery. Also, chroman-4-ones are important intermediates and interesting building blocks in organic synthesis and drug design. The structural diversity found in the chroman-4-one family led to their division into several categories including benzylidene-4-chromanones, flavanones (2-phenyl-4-chromanones), isoflavanones (3-phenyl-4-chromanones), spirochromanones, and C-4 modified chroman-4-ones such as hydrazones and oxime derivatives. This review addresses the most significant synthetic methods reported on 4-chromanone-derived compounds and consequently emphasizes on the biological relevance of such compounds. PMID- 25743216 TI - Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity. AB - A series of novel chalcone-triazole derivatives were synthesized and screened for in vitro anticancer activity on the human cancer cell lines IMR32 (neuroblastoma), HepG2 (hepatoma) and MCF-7 (breast adenocarcinoma), DU-145 (prostate carcinoma), and A549 (lung adenocarcinoma). Among the tested compounds, 4r showed the most promising anticancer activity in all the cell lines whereas, compounds 4c (IC50 65.86 MUM), 4e (IC50 66.28 MUM), 4o (IC50 35.81 MUM), 4q (IC50 50.82 MUM) and 4s (IC50 48.63 MUM) showed better activity than the standard doxorubicin (IC50 69.33 MUM) in A549 cell line alone. Rat intestinal alpha glucosidase inhibitory activity of the synthesized derivatives showed 4m (IC50 67.77 MUM), 4p (IC50 74.94 in MUM) and 4s (IC50 102.10 MUM) as most active compared to others. The in silico docking of synthesized derivatives 4a-4t with DNA topoisomerase IIalpha revealed the LibDock score in the range of 71.2623 118.29 whereas, compounds 4h, 4m, 4p and 4s with docking target alpha-glucosidase were in the range of 100.372-107.784. PMID- 25743217 TI - Guidelines for pre-clinical assessment of the acetylcholine receptor--specific passive transfer myasthenia gravis model-Recommendations for methods and experimental designs. AB - Antibodies against the muscle acetylcholine receptor (AChR) are the most common cause of myasthenia gravis (MG). Passive transfer of AChR antibodies from MG patients into animals reproduces key features of human disease, including antigenic modulation of the AChR, complement-mediated damage of the neuromuscular junction, and muscle weakness. Similarly, AChR antibodies generated by active immunization in experimental autoimmune MG models can subsequently be passively transferred to other animals and induce weakness. The passive transfer model is useful to test therapeutic strategies aimed at the effector mechanism of the autoantibodies. Here we summarize published and unpublished experience using the AChR passive transfer MG model in mice, rats and rhesus monkeys, and give recommendations for the design of preclinical studies in order to facilitate translation of positive and negative results to improve MG therapies. PMID- 25743218 TI - Evidence for the role of phosphatidylcholine-specific phospholipase in experimental subarachnoid hemorrhage in rats. AB - Neuron apoptosis and inflammatory responses contribute to subarachnoid hemorrhage (SAH)-induced early brain injury (EBI), which is the main aspect that affects patients' outcome. Previous research has demonstrated that phosphatidylcholine specific phospholipase C (PC-PLC) plays critical roles in cell apoptosis and various inflammatory responses, and that tricyclodecan-9-yl-xanthogenate (D609), a well known PC-PLC inhibitor, is a powerful agent to protect brain from cerebral ischemic injury and SAH-induced cerebral vasospasm. However, the association between PC-PLC and SAH-induced EBI is undetermined. Therefore, we sought to investigate whether PC-PLC was implicated in SAH-induced EBI. Compared with sham group, an upregulation of PC-PLC activity was detected in the brain tissue and serum of SAH group. Pharmacological blockade of PC-PLC by D609 attenuated neurological behavior impairment, brain edema and blood-brain barrier (BBB) damage induced by SAH. In addition, D609 treatment significantly inhibited SAH induced inflammatory response and neuron apoptosis. Furthermore, inhibition of PC PLC in primary-cultured rat cortical neurons attenuated oxyhemoglobin (OxyHb) induced apoptosis morphology and decrease in survival rate. In conclusion, our data suggest that PC-PLC participates in SAH-induced EBI. PMID- 25743220 TI - Mucosal immunology: food additives feed the fire. PMID- 25743219 TI - Balancing natural killer cell activation through paired receptors. AB - Natural killer (NK) cells are innate lymphocytes that are crucial for the control of infections and malignancies. NK cells express a variety of inhibitory and activating receptors that facilitate fine discrimination between damaged and healthy cells. Among them, a family of molecules that bind nectin and nectin-like proteins has recently emerged and has been shown to function as an important regulator of NK cell functions. These molecules include CD226, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), CD96, and cytotoxic and regulatory T cell molecule (CRTAM). In this Review, we focus on the recent advances in our understanding of how these receptors regulate NK cell biology and of their roles in pathologies such as cancer, infection and autoimmunity. PMID- 25743221 TI - Inflammasome: starving inflammation. PMID- 25743223 TI - Salivary testosterone and cortisol responses to four different rugby training exercise protocols. AB - This study assessed the acute response of salivary testosterone and cortisol concentrations to four exercise protocols in 27 elite male rugby players. Each athlete completed four protocols in random order on separate in-season weeks. Two protocols were resistance training based consisting of four exercises (high pull, bench press, squat and chin-ups/prone row): Protocol 1 consisted of 5 sets of 15 repetitions at 55% of 1 repetition maximum (1 RM) with 1-minute rest (5 * 15 55%). Protocol 2 consisted of three sets of five repetitions at 85% 1 RM with 2 minute rest (3 * 5-85%). Protocol 3 was a strongman (STRNG) session consisting of three stations within a circuit of exercises that included exercises such as battling ropes, prowler push, farmer's walk and tyre flips. Protocol 4 was based on boxing and wrestling inspired exercises (combative--COMB). Salivary testosterone and cortisol concentrations were measured before (PRE) and immediately after exercise (POST). Testosterone did not significantly change as a result of any intervention, whereas cortisol declined and the testosterone to cortisol (T/C) ratio increased significantly in both the 5 * 15-55% and 3 * 5-85% protocol. When results were retrospectively grouped and analysed according to the protocol that demonstrated the greatest absolute testosterone response, significant (P < 0.01) increases for the 5 * 15-55%, STRNG and COMB protocols were observed. The individualised hormone response to exercise observed in this study highlights the importance of recognising a protocol-dependent approach to training athletes. Furthermore this study also highlights a potential usefulness of employing STRNG and COMB training protocols as an alternative stimulus to resistance training. PMID- 25743222 TI - The role of sex hormones in immune protection of the female reproductive tract. AB - Within the human female reproductive tract (FRT), the challenge of protection against sexually transmitted infections (STIs) is coupled with the need to enable successful reproduction. Oestradiol and progesterone, which are secreted during the menstrual cycle, affect epithelial cells, fibroblasts and immune cells in the FRT to modify their functions and hence the individual's susceptibility to STIs in ways that are unique to specific sites in the FRT. The innate and adaptive immune systems are under hormonal control, and immune protection in the FRT varies with the phase of the menstrual cycle. Immune protection is dampened during the secretory phase of the cycle to optimize conditions for fertilization and pregnancy, which creates a 'window of vulnerability' during which potential pathogens can enter and infect the FRT. PMID- 25743224 TI - Prevalence of autoimmune disease in moyamoya disease patients in Western Chinese population. AB - The pathogenesis of moyamoya remains to be elucidated and an immunologic basis has been suggested. For gaining further insight into the pathogenesis of moyamoya, we explored the epidemiological characteristics of autoimmune disease in moyamoya disease (MMD) in Western Chinese population. Retrospective clinical characteristic analysis of patients with angiographically confirmed MMD was performed and compared with the general Chinese population. A significantly higher prevalence of autoimmune disease was observed, particularly type 1 diabetes mellitus (P<0.001, 7.0% vs 1.2%, chi(2) test) and Graves disease (P<0.001, 7.0% vs 0.34%, chi(2) test) in the general Chinese population. The overall prevalence of autoimmune disease in MMD was up to 31.0% (44/142). This study suggested higher overall prevalence of autoimmune disease in MMD in Western China when compared with the general Chinese population. The findings further supported that autoimmune abnormality might associate with MMD and autoimmune component to pathogenesis of moyamoya vasculopathy. PMID- 25743225 TI - Invasive procedures in Parkinson's disease: let's be aware we are dealing with prion-like proteins. PMID- 25743226 TI - 1,2-Dichloroethane-induced toxic encephalopathy: a case series with morphological investigations. AB - 1,2-Dichloroethane (DCE) is commonly used as an industrial organic solvent and causes occupational diseases. Toxic encephalopathy is the most common and serious disorder resulting from DCE intoxication. Five patients who worked in shoemaking, pipemaking or a paint factory were identified as suffering from severe encephalopathy due to DCE intoxication. DCE-induced toxic encephalopathy manifests as various neurological deficits, with changes observable by neuroimaging. The main clinical manifestation is headache accompanied by intracranial hypertension. The typical cranial CT/MR scan of DCE toxic encephalopathy shows extensive brain edema and diffuse, symmetric, abnormal signal intensities in the cerebellar dentate nucleus, basal ganglia, and white matter in the bilateral cerebral hemispheres. The diagnosis of DCE toxic encephalopathy can be confirmed by the typical clinical and neuroimaging characteristics together with a history of exposure to substances contaminated with DCE. Dehydrating agents and glucocorticoids are the primary treatments. With early diagnosis and prompt treatment, promising results and recovery can be achieved. Effective prevention is expected to reduce the incidence of DCE toxic encephalopathy. PMID- 25743227 TI - An isotope hydrochemical approach to understand fluoride release into groundwaters of the Datong Basin, Northern China. AB - The hydrogeochemical and isotopic investigations of high fluoride (up to 8.26 mg L(-1)) groundwater in the Datong Basin, Northern China were carried out in order to evaluate the geochemical controls on fluoride enrichment. The groundwater fluoride concentration tends to increase along with the regional groundwater flow path away from the basin margins, towards the central parts of the basin. Groundwater with high F concentrations has a distinctive major ion chemistry, being generally HCO3(-)-rich, Na-rich, Ca-poor, and having weak alkaline pH values (7.2 to 8.2) and Na-HCO3 waters. These data indicate that variations in the groundwater major ion chemistry and possibly pH, which are controlled by water-rock interaction processes in the aquifer, are important in mobilizing F. Positive correlations between fluoride with lithogenic sodium (LNa) and HCO3(-) in groundwater show that the high fluoride content and alkaline sodic characteristics of groundwater result from dissolution of fluorine-bearing minerals. The occurrence and behavior of fluorine in groundwater are mainly controlled by fluorite precipitation as a function of Ca(2+) concentration. A positive correlation between fluoride and delta(18)O, low F(-)/Cl(-) ratios, and the low tritium level in the fluoride-rich groundwater indicate the effects of long-term water-rock interactions and intensive evapotranspiration. PMID- 25743228 TI - Kinetics of enzymatic reactions in lipid membranes containing domains. AB - An appreciable part of enzymes operating in vivo is associated with lipid membranes. The function of such enzymes can be influenced by the presence of domains containing proteins and/or composed of different lipids. The corresponding experimental model-system studies can be performed under well controlled conditions, e.g., on a planar supported lipid bilayer or surface immobilized vesicles. To clarify what may happen in such systems, we propose general kinetic equations describing the enzyme-catalyzed substrate conversion occurring via the Michaelis-Menten (MM) mechanism on a membrane with domains which do not directly participate in reaction. For two generic situations when a relatively slow reaction takes place primarily in or outside domains, we take substrate saturation and lateral substrate-substrate interactions at domains into account and scrutinize the dependence of the reaction rate on the average substrate coverage. With increasing coverage, depending on the details, the reaction rate reaches saturation via an inflection point or monotonously as in the conventional MM case. In addition, we show analytically the types of reaction kinetics occurring primarily at domain boundaries. In the physically interesting situation when the domain growth is fast on the reaction time scale, the latter kinetics are far from conventional. The opposite situation when the reaction is fast and controlled by diffusion has been studied by using the Monte Carlo technique. The corresponding results indicate that the dependence of the reaction kinetics on the domain size may be weak. PMID- 25743229 TI - [Ubiquitination-regulated receptor trafficking of endothelin type A and type B receptors]. PMID- 25743230 TI - [Regulation of G protein-coupled receptor kinase by nitrosylation]. PMID- 25743231 TI - [Identification of a new molecule that promotes clearance of apoptotic cells - G protein-coupled receptor kinase 6 is involved in engulfment of apoptotic cells]. PMID- 25743232 TI - [Trends in functions and inhibitors of p38]. PMID- 25743233 TI - [Pharmacological and clinical profile of dexrazoxane (SAVENE(r) Intravenous Infusion 500 mg), a therapeutic agent for anthracycline extravasation]. PMID- 25743235 TI - [Network activity controls adult neurogenesis]. PMID- 25743234 TI - [Pharmacological and clinical profile of ipragliflozin (Suglat(r)): a new therapeutic agent for type 2 diabetes]. PMID- 25743236 TI - [A new topical gene C9orf72 in neurodegenerative diseases]. PMID- 25743237 TI - Flexible prototype thermoelectric devices based on Ag2Te and PEDOT:PSS coated nylon fibre. AB - p- and n-type Ag2Te nanocrystals are coated separately onto nylon fibres to create flexible composites. A prototype thermoelectric device made using such fibres produces ~0.8 nW in a 20 K temperature difference. This is improved to over 5 nW by using a conducting polymer as the p-type material. PMID- 25743238 TI - T2 shine-through phenomena in diffusion-weighted MR imaging of lumbar discs after oxygen-ozone discolysis: a randomized, double-blind trial with steroid and O2-O3 discolysis versus steroid only. AB - PURPOSE: To evaluate the discal morpho-structural changes as predictive sign in the clinical outcome after Ozone Therapy in lumbar disc herniation using the T2 shine-through effect in DWI. METHODS: One hundred and fifty-four patients suffering from lumbosciatica (89 men and 65 women; range 23-62 years) were included in previous MR study performed with FSE-T2 and T2-fat, SE-T1 and DWI sequences and were randomly assigned to two groups. Seventy-seven patients (Control Group) underwent conservative treatment with intraforaminal injection of steroid and anesthetic. The remaining 77 patients (Study Group) underwent the same treatment with the addiction of oxygen-ozone (O2-O3). During the coming 6 months, an MRI follow-up with the same sequences was performed. An intervertebral disc volumetric analysis (IDVA), DWI signal score and post treatment clinical outcome evaluation were performed for an assessment of hernia reduction. chi (2) test, Student's t test and analysis of covariance were used for comparison of variables. RESULTS: In the Study Group, 58 over 77 patients had a successful outcome (Responders). In the Responders group, DWI T2 shine-through effect was present during MRI follow-up and in particular in 53 of 77 patients in the 6 months of follow-up (P < 0.05). Moreover, in the same group was present a statistically significant discs' shrinkage in the sixth month of follow-up (P < 0.05) as showed by IDVA. CONCLUSIONS: T2 shine-through effect in DWI is present before morphological disc reduction and moreover could be considered as a predictive sign of response to oxygen-ozone treatment. PMID- 25743239 TI - Idiopathic interstitial pneumonias: do HRCT criteria established by ATS/ERS/JRS/ALAT in 2011 predict disease progression and prognosis? AB - PURPOSE: The objective of the study was to determine whether HRCT criteria for Usual Interstitial Pneumonia (UIP), possible UIP or no-UIP pattern recommended by ATS/ERS/JRS/ALAT guidelines 2011 are able to predict progression and prognosis of the disease in a group of patients with fibrotic idiopathic interstitial pneumonia (IIP). MATERIALS AND METHODS: This was a retrospective study conducted with the approval of the ethics committee. Two radiologists at baseline HRCT distributed 70 patients with fibrotic IIP into three groups on the basis of the 2011 guidelines: UIP pattern (group 1), possible UIP pattern (group 2), inconsistent with UIP pattern (group 3). The different abnormalities (honeycombing, reticulation, ground-glass and traction bronchiectasis), fibrotic score (reticulation + honeycombing) and overall CT score were visually scored at baseline and during the follow-up (total HRCT 178). The mortality rate of the three groups was compared. The baseline abnormalities were then correlated with the mortality rate in the UIP group. RESULTS: The inter-observer agreement in the classification of the abnormalities in the three groups was almost perfect (k = 0.92). After consensus, 44 patients were classified into group 1, 13 into group 2 and 13 into group 3. During a mean follow-up of 1386 days, overall CT score, fibrotic score, honeycombing and traction bronchiectasis showed a significant progression in group 1. The mortality rate was significantly higher in group 1 (18 deaths) versus group 2 and 3 (1 death each). In group 1, baseline honeycombing rate higher than 25 %, fibrotic score higher than 30, overall CT score greater than 45 and traction bronchiectasis in more than 4 lobes defined the worst prognosis. CONCLUSION: HRCT classification based on 2011 guidelines showed high accuracy in stratifying fibrotic changes because in our study UIP, possible UIP and inconsistent with UIP pattern seem to be correlated with different disease progression and mortality rate. PMID- 25743240 TI - Serum levels of interleukin-2 predict the recurrence of atrial fibrillation after pulmonary vein ablation. AB - AIMS: Interleukin-2 has a significant antitumor activity in some types of cancer, and has been associated with the development of atrial fibrillation (AF). In addition, IL-2 serum levels in recent onset AF have been related with pharmaceutical cardioversion outcomes. We evaluated the hypothesis that a relationship exists between inflammation and the outcome of catheter ablation of AF. METHODS: We studied 44 patients with paroxysmal AF who underwent catheter ablation. Patients with structural heart disease, coronary artery or valve disease, active inflammatory disease, known or suspected neoplasm, endocrinopathies, or exposure to anti-inflammatory drugs were excluded. All study participants underwent evaluation with a standardized protocol, including echocardiography, and cytokine levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumour necrosis factor-alpha, and gamma-interferon determination before procedure. Clinical and electrocardiographic follow-up were performed with Holter-ECG at 3, 6 and 12months in order to know if sinus rhythm was maintained. RESULTS: After catheter ablation of the 44 patients included (53+/-10years, 27.3% female), all patients returned to sinus rhythm. During the first year of follow-up seven patients (15.9%) experienced recurrence of AF. The demographics, clinical and echocardiographic features, and pharmacological treatments of these patients were similar to those who maintained sinus rhythm. The only independent factor predictive of recurrence of AF was an elevated level of IL-2 (OR 1.18, 95% CI 1.12-1.38). CONCLUSIONS: High serum levels of interleukin-2, a pro-inflammatory non-vascular cytokine, are associated with the recurrence of AF in patients undergoing catheter ablation. PMID- 25743241 TI - Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease. AB - BACKGROUND: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the rest of the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described. IL-18 could potentially amplify the process by inducing increased expression of IFN-gamma which in turn can increase the production of IL 18, thereby creating a positive feedback mechanism. In order to assess the contribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the association between a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developing Chagas cardiomyopathy. METHODS AND RESULTS: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas disease cardiomyopathy patients (n=849) and asymptomatic subjects (n=202). We found a significant difference in genotype frequencies among moderate and severe CCC patients with ventricular dysfunction. CONCLUSIONS: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkage disequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome. PMID- 25743242 TI - Application of multiplex arrays for cytokine and chemokine profiling of bile. AB - BACKGROUND: Gallbladder disease is highly related to inflammation, but the inflammatory processes are not well understood. Bile provides a direct substrate in assessing the local inflammatory response that develops in the gallbladder. To assess the reproducibility of measuring inflammatory markers in bile, we designed a methods study of 69 multiplexed immune-related markers measured in bile obtained from gallstone patients. METHODS: To evaluate assay performance, a total of 18 bile samples were tested twice within the same plate for each analyte, and the 18 bile samples were tested on two different days for each analyte. We used the following performance parameters: detectability, coefficient of variation (CV), intraclass correlation coefficient (ICC), and percent agreement (concordance among replicate measures above and below detection limit). Furthermore, we examined the association of analyte levels with gallstone characteristics such as type, numbers, and size. RESULTS: All but 3 analytes (Stem Cell Factor, SCF; Thrombopoietin, TPO; sIL-1RI) were detectable in bile. 52 of 69 (75.4%) analytes had detectable levels for at least 50% of the subjects tested. The within-plate CVs were ?25% for 53 of 66 (80.3%) detectable analytes, and across-plate CVs were ?25% for 32 of 66 (48.5%) detectable analytes. Moreover, 64 of 66 (97.0%) analytes had ICC values of at least 0.8. Lastly, the percent agreement was high between replicates for all of the analytes (median; within plate, 97.2%; across plate, 97.2%). In exploratory analyses, we assessed analyte levels by gallstone characteristics and found that levels for several analytes decreased with increasing size of the largest gallstone per patient. CONCLUSIONS: Our data suggest that multiplex assays can be used to reliably measure cytokines and chemokines in bile. In addition, gallstone size was inversely related to the levels of select analytes, which may aid in identifying critical pathways and mechanisms associated with the pathogenesis of gallbladder diseases. PMID- 25743243 TI - The effect of Indomethacin and Betamethasone on the cytokine response of human neonatal mononuclear cells to gram-positive bacteria. AB - Intrauterine infections with gram-positive bacteria pose a serious threat to neonates since they can result in neonatal sepsis, induce a fetal inflammatory response and also cause preterm birth. Despite intensive care, prematurity remains a leading cause of neonatal death, and is often accompanied by a number of morbidities. In order to prevent premature birth, tocolytic agents like Indomethacin are administered. Betamethasone is used to promote lung maturation and prevent respiratory distress syndrome. A combination of both drugs is assumed to prevent premature delivery while simultaneously facilitating lung maturation. This study investigates the effect of Betamethasone, Indomethacin and a combination of both on the cytokine production of neonatal cord blood mononuclear cells (CBMC) after stimulation with lysates of the gram-positive pathogens Streptococcus agalactiae and Enterococcus faecalis. The aim of the study is to determine the impact of these drugs on the function of the neonatal immune system which should aid clinicians in choosing the optimal therapy in case of preterm birth associated with intrauterine infection. Betamethasone reduced the production of the pro-inflammatory cytokines IL-6, IL-12p40, MIP-1alpha and TNF and increased the expression of the anti-inflammatory cytokine IL-10, depending on the pathogen used for stimulation. In contrast to Betamethasone, Indomethacin almost exclusively increased IL-10 production. The combination of both drugs decreased the expression of IL-6, IL-12p40, MIP-1alpha and TNF while increasing IL-10 production, depending on the concentration of Indomethacin and the pathogen used for stimulation. Based on our results, the combination therapy with Indomethacin and Betamethasone has a similar effect on cytokine production as Betamethasone alone, which is generally administered in case of impending preterm birth. However, the combination therapy has the advantage of promoting lung maturation while simultaneously blocking preterm labor effectively. PMID- 25743244 TI - Constitutively high-level expression of TGFbeta isoforms in cord blood and its relationship to perinatal findings. AB - BACKGROUND: The clinical significance of TGFbeta isoforms in cord blood is not well understood. METHODS: We obtained cord blood samples from 37 term infants and 85 preterm infants who were born in several clinical settings. The serum levels of 3 TGFbeta isoforms and of the other 17 cytokines in cord blood were investigated using cytometric bead array technology. RESULTS: Very high levels of TGFbeta1 and TGFbeta2 isoforms compared to the level of other cytokines were found; mean levels were 44,180 and 1871pg/mL, respectively. The levels of all 3 isoforms of TGFbeta were significantly correlated with birth weight, and the levels of TGFbeta1 and TGFbeta3 were correlated with gestational age. The levels of TGFbeta1 and beta2 isoforms were strongly correlated with each other, but not with levels of other cytokines. The levels of TGFbeta1 and TGFbeta2 were significantly higher in male infants and significantly lower in infants with fetal growth restriction. The prevalence of chronic lung disease was related to a low level of TGFbeta1, and that of patent ductus arteriosus was related to a high level of TGFbeta1 in preterm infants. CONCLUSIONS: TGFbeta1 and TGFbeta2 appeared to play a significant role in physiological and pathological conditions in the fetus. TGFbeta isoform levels appear to be regulated independently of those of other cytokines and do not appear to be influenced by inflammation in the fetal period. The role of TGFbeta3 in cord blood and the postnatal chronological changes of the TGFbeta isoforms should be investigated in the future. PMID- 25743246 TI - Adenoid cystic carcinoma of the larynx: a report of six cases with review of the literature. AB - CONCLUSION: Adenoid cystic carcinoma (ACC) in the larynx is an extremely rare entity. Although the 5-year disease-specific survival rates for laryngeal ACC are high, distant metastasis might occur up to more than 5 years post treatment. Therefore patients with ACC require long-term follow-up. OBJECTIVE: To summarize the characteristics of laryngeal ACC by analyzing six cases in a single center. METHODS: This was a retrospective analysis of six patients with laryngeal ACC who were treated in Beijing Tongren Hospital between 1998 and 2013. RESULTS: The mean age at diagnosis was 44 years, ranging from 15 to 61 years. Dyspnea was the most common complaint. All patients underwent combined-modality treatment with surgical resection and external beam radiation. The range of follow-up time varied from 1 to 7 years (median 5 years). Follow-up inspections indicated that none of them had local or regional recurrence. Distant metastasis occurred in 33.7% (2/6) of the patients, with one lung metastasis 5 years after operation and one liver metastasis 4 years after operation. PMID- 25743245 TI - Plasma immune analytes in patients with epithelial ovarian cancer. AB - OBJECTIVES: Inflammation is a common feature of epithelial ovarian cancer (EOC), and measurement of plasma markers of inflammation might identify candidate markers for use in screening or presurgical evaluation of patients with adnexal masses. METHODS: Plasma specimens from cohorts of 100 patients with advanced EOC (AJCC Stage III and IV), 50 patients with early stage EOC (Stage I and II), and 50 patients with benign surgical conditions were assayed for concentrations of multiple cytokines, toll-like receptor agonists, and vascular growth factors via ELISA and electrochemiluminescence. Immune proteins were then analyzed for association with EOC. Differences in plasma protein levels between benign, early, and advanced EOC patient groups were assessed with and without adjustment for plasma cancer antigen 125 (CA-125) levels. RESULTS: Out of 23 proteins tested, six-including interferon gamma (IFNgamma), interleukin 6 (IL-6), IL-8, IL-10, tumor necrosis factor alpha (TNFalpha), and placental growth factor (PlGF)-were univariately associated with EOC (all p<0.005), and one-IL-6-was associated with early stage EOC (p<0.0001). Heat shock protein 90kDa beta member 1 (HSP90B1, gp96) was associated with EOC and early stage EOC with borderline statistical significance (p=0.039 and p=0.026, respectively). However, when adjusted for (CA 125), only HSP90B1 independently predicted EOC (p=0.008), as well as early stage EOC (p=0.014). CONCLUSIONS: Multiple plasma cytokines, including IFNgamma, IL-6, IL-8, IL-10, TNFalpha, PlGF, and HSP90B1 are associated with EOC. Of these, HSP90B1 is associated with EOC independent from the biomarker CA-125. PMID- 25743247 TI - High-definition computed tomography for coronary artery stents imaging: Initial evaluation of the optimal reconstruction algorithm. AB - OBJECTIVE: The aim of this study was to evaluate the in vivo performance of four image reconstruction algorithms in a high-definition CT (HDCT) scanner with improved spatial resolution for the evaluation of coronary artery stents and intrastent lumina. MATERIALS AND METHODS: Thirty-nine consecutive patients with a total of 71 implanted coronary stents underwent coronary CT angiography (CCTA) on a HDCT (Discovery CT 750 HD; GE Healthcare) with the high-resolution scanning mode. Four different reconstruction algorithms (HD-stand, HD-detail; HD-stand plus; HD-detail-plus) were applied to reconstruct the stented coronary arteries. Image quality for stent characterization was assessed. Image noise and intrastent luminal diameter were measured. The relationship between the measurement of inner stent diameter (ISD) and the true stent diameter (TSD) and stent type were analysed. RESULTS: The stent-dedicated kernel (HD-detail) offered the highest percentage (53.5%) of good image quality for stent characterization and the highest ratio (68.0+/-8.4%) of visible stent lumen/true stent lumen for luminal diameter measurement at the expense of an increased overall image noise. The Pearson correlation coefficient between the ISD and TSD measurement and spearman correlation coefficient between the ISD measurement and stent type were 0.83 and 0.48, respectively. CONCLUSIONS: Compared with standard reconstruction algorithms, high-definition CT imaging technique with dedicated high-resolution reconstruction algorithm provides more accurate stent characterization and intrastent luminal diameter measurement. PMID- 25743248 TI - Comparison of cardiovascular magnetic resonance feature tracking and tagging for the assessment of left ventricular systolic strain in acute myocardial infarction. AB - AIMS: To assess the feasibility of feature tracking (FT)-measured systolic strain post acute ST-segment elevation myocardial infarction (STEMI) and compare strain values to those obtained with tagging. METHODS: Cardiovascular MRI at 1.5T was performed in 24 patients, 2.2 days post STEMI. Global and segmental circumferential (Ecc) and longitudinal (Ell) strain were assessed using FT and tagging, and correlated with total and segmental infarct size, area at risk and myocardial salvage. RESULTS: All segments tracked satisfactorily with FT (p<0.001 vs. tagging). Total analysis time per patient was shorter with FT (38.2+/-3.8 min vs. 63.7+/-10.3 min, p<0.001 vs. tagging). Global Ecc and Ell were higher with FT than with tagging, apart from FT Ecc using the average of endocardial and epicardial contours (-13.45+/-4.1 [FT] vs. -13.85+/-3.9 [tagging], p=0.66). Intraobserver and interobserver agreement for global strain were excellent for FT (ICC 0.906-0.990) but interobserver agreement for tagging was lower (ICC<0.765). Interobserver and intraobserver agreement for segmental strain was good for both techniques (ICC>0.7) apart from tagging Ell, which was poor (ICC=0.15). FT derived Ecc significantly correlated with total infarct size (r=0.44, p=0.03) and segmental infarct extent (r=0.44, p<0.01), and best distinguished transmurally infarcted segments (AUC 0.77) and infarcted from adjacent and remote segments. FT derived Ecc correlated strongest with segmental myocardial salvage (rs=-0.406). CONCLUSIONS: FT global Ecc and Ell measurement in acute STEMI is feasible and robust. FT-derived strain is quicker to analyse, tracks myocardium better, has better interobserver variability and correlated more strongly with infarct, area at risk (oedema), myocardial salvage and infarct transmurality. PMID- 25743249 TI - Template-directed construction of conformational supramolecular isomers for bilayer porous metal-organic frameworks with distinct gas sorption behaviors. AB - A pair of supramolecular isomers of Co(II)-based metal-organic frameworks can be directionally constructed in virtue of solvent templates, which show diverse bilayer networks and lattice packing with the same Co3 SBUs and organic linkers. The two porous materials show distinct gas sorption behaviors at different temperatures, especially their CO2 sorption selectivity. PMID- 25743250 TI - Somatosensory feedback refines the perception of hand shape with respect to external constraints. AB - Motor commands issued by the CNS are based upon memories of past experiences with similar objects, the current state of the hand and arm postures, and sensory input. Thus widespread somatosensory information is available to form precise representations of hand shape on which to base motor commands to match a desired posture or movement. The aim of this study was to examine the extent to which somatosensory information reflecting external influences on independent finger movement is incorporated into the perception of hand shape driving the motor command. To address this issue, a matching task was performed while pairs of fingers in the grasping hand were constrained to move in tandem when grasping familiar objects. The hypothesis was that motor commands would be driven by comparison of the online sensory information from the matching hand to a desired somatosensory state determined by the current somatosensory input from the grasping hand. The results demonstrated that multi-muscle patterns of activation and hand postures were altered with respect to the external constraint on independent finger movement. A secondary aim of this study was to examine the influence of sensory information on the structure of the multi-muscle patterns. The hypothesis was that the same synergies (patterns of activation across muscles) would be used to complete the task but would be rescaled with respect to condition. The results demonstrated that rescaling the patterns of multi-muscle activity from the unconstrained condition could not equivalently represent those from the constrained conditions. Thus it appears that external restriction of independent finger movement was signaled by somatosensory feedback and incorporated into the desired state driving the motor command resulting in selective activation of groups of muscles. PMID- 25743251 TI - Involvement of apoptosis and calcium accumulation through TRPV1 channels in neurobiology of epilepsy. AB - Calcium ion accumulation into the cytosol of the hippocampus and dorsal root ganglion (DRG) are main reasons in etiology of epilepsy. Transient receptor potential vanilloid type 1 (TRPV1) channel is a cation-permeable calcium channel found in the DRG and hippocampus. Although previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been investigated. We tested the effects of TRPV1 specific antagonists, capsazepine (CPZ) and 5'-iodoresiniferatoxin (IRTX) on the modulation of calcium accumulation, apoptosis and anticonvulsant properties in the hippocampus and DRG of pentylentetrazol (PTZ) and capsaicin (CAP) administrated rats. Forty rats were divided into five groups as follows; control, PTZ, CAP+PTZ, IRTX, and IRTX+PTZ. Fura-2 and patch-clamp experiments were performed on neurons dissected from treated animals by CAP and CPZ. PTZ and CAP+PTZ administrations increased intracellular free Ca(2+) concentrations, TRPV1 current densities, apoptosis, caspase 3 and 9 values although the values were reduced by IRTX and CPZ treatments. Latency time was extended by application CPZ and IRTX although CAP produced acceleration of epileptic seizures. Taken together, these results support a role for TRPV1 channels in the inhibition of apoptosis, epileptic seizures and calcium accumulation, indicating that TRPV1 inhibition may possibly be a novel target in the DRG and hippocampus for prevention of epileptic seizures and peripheral pain. PMID- 25743252 TI - Ascending parabrachio-thalamo-striatal pathways: potential circuits for integration of gustatory and oral motor functions. AB - The medial parabrachial nucleus (MPB) and external part of the medial parabrachial nucleus (MPBE) relay gustatory, oral mechanosensory and other visceral information in the rat brain and reportedly project not only to the parvicellular part of the posteromedial ventral thalamic nucleus (VPMpc) but also to the ventrocaudal part of the intralaminar thalamic nuclei. Generally, the intralaminar thalamic nuclei project topographically to the caudate putamen (CPu); however, it is unclear where the ventrocaudal part of the intralaminar thalamic nuclei projects within the CPu. Thus, we visualized neural pathways from the MPB and MPBE to the CPu via the ventrocaudal part of the intralaminar thalamic nuclei using an anterograde tracer, biotinylated dextran amine, and a retrograde tracer, cholera toxin B subunit. We found that the MPB and MPBE sent a relatively stronger input to the ventrocaudal part of the intralaminar thalamic nuclei such as the oval paracentral thalamic nucleus (OPC), central medial thalamic nucleus (CM) and parafascicular thalamic nucleus (PF) and retroreuniens area (RRe) as compared to the VPMpc. In turn, these thalamic nuclei projected to the ventral part of the CPu with the topographical arrangement as follows: the OPC to the ventrocentral part of the CPu; ventrolateral part of the PF to the ventrolateral part of the CPu; and the caudal part of the CM, ventromedial part of the PF and RRe to the ventromedial part of the CPu. Further, we found that the VPMpc rather projected to the interstitial nucleus of the posterior limb of the anterior commissure than the CPu. The ventral part of the CPu is reported to be involved in jaw movement as well as food and water intake functions. Therefore, these parabrachio-thalamo-striatal pathways that we demonstrated here suggest that gustatory and oral mechanosensory information affects feeding behavior within the ventral part of the CPu. PMID- 25743253 TI - Altered nociception in mice with genetically induced hypoglutamatergic tone. AB - Extensive pharmacological evidence supports the idea that glutamate plays a key role in both acute and chronic pain. In the present study, we investigated the implication of the excitatory amino acid in physiological nociception by using mutant mice deficient in phosphate-activated glutaminase type 1 (GLS1), the enzyme that synthesizes glutamate in central glutamatergic neurons. Because homozygous GLS1-/- mutants die shortly after birth, assays for assessing mechanical, thermal and chemical (formalin) nociception were performed on heterozygous GLS1+/- mutants, which present a clear-cut decrease in glutamate synthesis in central neurons. As compared to paired wild-type mice, adult male GLS1+/- mutants showed decreased responsiveness to mechanical (von Frey filament and tail-pressure, but not tail-clip, tests) and thermal (Hargreaves' plantar, tail-immersion and hot-plate tests) nociceptive stimuli. Genotype-related differences were also found in the formalin test for which GLS1+/- mice exhibited marked decreases in the nociceptive responses (hindlimb lift, lick and flinch) during both phase 1 (0-5 min) and phase 2 (16-45 min) after formalin injection. On the other hand, acute treatment with memantine (1mg/kg i.p.), an uncompetitive antagonist at NMDA glutamate receptors, reduced nociception responses in wild type but not GLS1+/- mice. Conversely, antinociceptive response to acute administration of a low dose (1mg/kg s.c.) of morphine was significantly larger in GLS1+/- mutants versus wild-type mice. Our findings indicate that genetically driven hypoactivity of central glutamatergic neurotransmission renders mice hyposensitive to nociceptive stimulations, and promotes morphine antinociception, further emphasizing the critical role of glutamate in physiological nociception and its opioid-mediated control. PMID- 25743254 TI - Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport. AB - Transactive response DNA-binding protein 43 (TDP-43) is a predominantly nuclear, ubiquitously expressed RNA and DNA-binding protein. It recognizes and binds to UG repeats and is involved in pre-mRNA splicing, mRNA stability and microRNA metabolism. TDP-43 is essential in early embryonic development but accumulates in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal lobar degeneration (FTLD). It is not known yet whether cytoplasmic aggregates of TDP-43 are toxic or protective but they are often associated with a loss of TDP-43 from the nucleus and neurodegeneration may be caused by a loss of normal TDP-43 function or a gain of toxic function. Here we present a proteomic study to analyze the effect of loss of TDP-43 on the proteome. MS data are available via ProteomeXchange with identifier PXD001668. Our results indicate that TDP-43 is an important regulator of RNA metabolism and intracellular transport. We show that Ran-binding protein 1 (RanBP1), DNA methyltransferase 3 alpha (Dnmt3a) and chromogranin B (CgB) are downregulated upon TDP-43 knockdown. Subsequently, transportin 1 level is increased as a result of RanBP1 depletion. Improper regulation of these proteins and the subsequent disruption of cellular processes may play a role in the pathogenesis of the TDP-43 proteinopathies ALS and FTLD. PMID- 25743255 TI - Activation of the Wnt/beta-catenin signaling cascade after traumatic nerve injury. AB - Recent data have shown that preservation of the neuromuscular junction (NMJ) after traumatic nerve injury helps to improve functional recovery with surgical repair via matrix metalloproteinase-3 (MMP3) blockade. As such, we sought to explore additional pathways that may augment this response. Wnt3a has been shown to inhibit acetylcholine receptor (AChR) clustering via beta-catenin-dependent signaling in the development of the NMJ. Therefore, we hypothesized that Wnt3a and beta-catenin are associated with NMJ destabilization following traumatic denervation. A critical size nerve defect was created by excising a 10-mm segment of the sciatic nerve in mice. Denervated muscles were then harvested at multiple time points for immunofluorescence staining, quantitative real-time PCR, and western blot analysis for Wnt3a and beta-catenin levels. Moreover, a novel Wnt/beta-catenin transgenic reporter mouse line was utilized to support our hypothesis of Wnt activation after traumatic nerve injury. The expression of Wnt3a mRNA was significantly increased by 2 weeks post-injury and remained upregulated for 2 months. Additionally, beta-catenin was activated at 2 months post-injury relative to controls. Correspondingly, immunohistochemical analysis of denervated transgenic mouse line TCF/Lef:H2B-GFP muscles demonstrated that the number of GFP-positive cells was increased at the motor endplate band. These collective data support that post-synaptic AChRs destabilize after denervation by a process that involves the Wnt/beta-catenin pathway. As such, this pathway serves as a potential therapeutic target to prevent the motor endplate degeneration that occurs following traumatic nerve injury. PMID- 25743256 TI - Single-trial multisensory memories affect later auditory and visual object discrimination. AB - Multisensory memory traces established via single-trial exposures can impact subsequent visual object recognition. This impact appears to depend on the meaningfulness of the initial multisensory pairing, implying that multisensory exposures establish distinct object representations that are accessible during later unisensory processing. Multisensory contexts may be particularly effective in influencing auditory discrimination, given the purportedly inferior recognition memory in this sensory modality. The possibility of this generalization and the equivalence of effects when memory discrimination was being performed in the visual vs. auditory modality were at the focus of this study. First, we demonstrate that visual object discrimination is affected by the context of prior multisensory encounters, replicating and extending previous findings by controlling for the probability of multisensory contexts during initial as well as repeated object presentations. Second, we provide the first evidence that single-trial multisensory memories impact subsequent auditory object discrimination. Auditory object discrimination was enhanced when initial presentations entailed semantically congruent multisensory pairs and was impaired after semantically incongruent multisensory encounters, compared to sounds that had been encountered only in a unisensory manner. Third, the impact of single trial multisensory memories upon unisensory object discrimination was greater when the task was performed in the auditory vs. visual modality. Fourth, there was no evidence for correlation between effects of past multisensory experiences on visual and auditory processing, suggestive of largely independent object processing mechanisms between modalities. We discuss these findings in terms of the conceptual short term memory (CSTM) model and predictive coding. Our results suggest differential recruitment and modulation of conceptual memory networks according to the sensory task at hand. PMID- 25743257 TI - An experimental investigation of evolutionary dynamics in the Rock-Paper-Scissors game. AB - Game theory describes social behaviors in humans and other biological organisms. By far, the most powerful tool available to game theorists is the concept of a Nash Equilibrium (NE), which is motivated by perfect rationality. NE specifies a strategy for everyone, such that no one would benefit by deviating unilaterally from his/her strategy. Another powerful tool available to game theorists are evolutionary dynamics (ED). Motivated by evolutionary and learning processes, ED specify changes in strategies over time in a population, such that more successful strategies typically become more frequent. A simple game that illustrates interesting ED is the generalized Rock-Paper-Scissors (RPS) game. The RPS game extends the children's game to situations where winning or losing can matter more or less relative to tying. Here we investigate experimentally three RPS games, where the NE is always to randomize with equal probability, but the evolutionary stability of this strategy changes. Consistent with the prediction of ED we find that aggregate behavior is far away from NE when it is evolutionarily unstable. Our findings add to the growing literature that demonstrates the predictive validity of ED in large-scale incentivized laboratory experiments with human subjects. PMID- 25743259 TI - Interleukin-10 Induces Both Plasma Cell Proliferation and Angiogenesis in Multiple Myeloma. AB - In multiple myeloma the angiogenic process is enhanced by various mediators. Among them interleukin-10 (IL-10), secreted mainly by myeloma-associated macrophages seems to participate in myeloma progression with variable manners. The aim of the study was to measure serum levels of IL-10 in various stages of MM patients and to correlate them with various angiogenic cytokines, such as vascular endothelial growth factor and angiopoietin-2 and with known proliferation parameters, such as serum levels of B-cell activating factor and bone marrow infiltration by myeloma plasma cells, in order to explore their clinical significance. We measured serum levels of the above parameters by ELISA in 54 newly diagnosed MM patients. All of them were higher in MM patients and were increasing in parallel with disease progression. Furthermore, IL-10 correlated positively with both angiogenic cytokines and proliferation markers. This correlation of IL-10 with both angiogenic cytokines and markers of disease activity implicates that they all have an important role in MM pathogenesis and progression. PMID- 25743258 TI - Methylation of Integrin alpha4 and E-Cadherin Genes in Human Prostate Cancer. AB - Prostate cancer is the second most common malignancy in men worldwide. Abnormal epigenetic alterations such as DNA methylation and histone modification play an important role in tumor initiation, progression and regulation of cancer-related genes such as integrin alpha4 and E-cadherin. Expression of these genes was determined by semi-quantitative reverse transcriptase-PCR in prostate cancer cell lines, DU145 and PC3, before and after treatment with 5-aza-2-deoxycytidine and trichostatin A. Laser capture microdissection microscopy was used to obtain exclusively affected epithelial cells from prostate gland biopsies of 30 patients with prostate cancer and 40 with benign prostate hyperplasia. DNA bisulfite modifications followed by methylation-specific PCR were used to evaluate the promoter methylation status of E-cadherin and alpha4 integrin genes in extracted DNA from patients and aforementioned cell lines. The integrin alpha4 promoter in DU145 was fully methylated, whereas in PC3 cells, partial methylation was detected. E-cadherin was expressed in both cell lines; trichostatin A and 5-aza-2 deoxycytidine treatment had no effect on E-cadherin expression, however the combined treatment of both drugs or 5-aza-2-deoxycytidine alone increased integrin alpha4 expression. Integrin alpha4 and E-cadherin were hypermethylated in 66.6 % and 6.6 % of prostate cancer cases, respectively; no hypermethylation was observed in patients with benign prostate hyperplasia. These results together suggest that aberrant DNA methylation is one of the mechanisms involved in integrin alpha4 expression and may play an important role in human prostate carcinogenesis. In addition, the higher rate of integrin alpha4 gene methylation in prostate cancer patients elects it as a potential molecular tumor marker. PMID- 25743260 TI - Single Nucleotide Polymorphisms (SNPs) of RAD51-G172T and XRCC2-41657C/T Homologous Recombination Repair Genes and the Risk of Triple- Negative Breast Cancer in Polish Women. AB - Double strand DNA breaks are the most dangerous DNA damage which, if non-repaired or misrepaired, may result in genomic instability, cancer transformation or cell death. RAD51 and XRCC2 encode proteins that are important for the repair of double-strand DNA breaks by homologous recombination. Therefore, genetic variability in these genes may contribute to the occurrence and progression of triple-negative breast cancer. The polymorphisms of the XRCC2 gene -41657C/T (rs718282) and of the RAD51 gene, -172G/T (rs1801321), were investigated by PCR RFLP in 70 patients with triple-negative breast cancer and 70 age- and sex matched non-cancer controls. The obtained results demonstrated a significant positive association between the RAD51 T/T genotype and TNBC, with an adjusted odds ratio (OR) of 4.94 (p = 0.001). The homozygous T/T genotype was found in 60 % of TNBC cases and in 14 % of the used controls. Variant 172 T allele of RAD51 increased cancer risk (OR = 2.81 (1.72-4.58), p < .0001). No significant associations were observed between -41657C/T genotype of XRCC2 and the incidence of TNBC. There were no significant differences between the distribution of XRCC2 41657C/T genotypes in the subgroups assigned to histological grades. The obtained results indicate that the polymorphism of RAD51, but not of XRCC2 gene, may be positively associated with the incidence of triple-negative breast carcinoma in the population of Polish women. PMID- 25743261 TI - Postmortem disclosure of genetic information to family members: active or passive? AB - Advances in next-generation DNA sequencing (NGS) now make it possible, and affordable, to sequence the entire genome of an individual. Routine clinical application is on the horizon. There is a consensus that some subsets of genetic information should be disclosed to patients, but disclosure to their relatives is less consensual. This issue becomes especially salient after a patient's death, when permission can no longer be sought. There has however been little debate on postmortem disclosure. We identify and explain the arguments in favor of and against disclosure of genetic information to the relatives of a deceased patient. We conclude that there are valid reasons to communicate some subsets of genetic information to family members after death, and we propose a passive postmortem disclosure policy. PMID- 25743262 TI - Substitution-induced spin-splitted surface states in topological insulator (Bi 1 x Sbx)2Te3. AB - We present a study on surface states of topological insulator (Bi 1-x Sbx)2Te3 by imaging quasiparticle interference patterns (QPI) using low temperature scanning tunneling microscope. Besides the topological Dirac state, we observed another surface state with chiral spin texture within the conduction band range. The quasiparticle scattering in this state is selectively suppressed. Combined with first-principles calculations, we attribute this state to a spin-splitted band induced by the substitution of Bi with Sb atoms. Our results demonstrate that the coexistence of topological order and alloying may open wider tunability in quantum materials. PMID- 25743263 TI - The treatment with pasireotide in Cushing's disease: effects of long-term treatment on tumor mass in the experience of a single center. AB - Pasireotide is the first medical therapy officially approved for the treatment of adult patients with Cushing's disease (CD) who experienced a failure of pituitary surgery or are not candidates for surgery and require medical therapeutic intervention. The current study aimed at investigating the effects of long-term treatment with pasireotide (up to 24 months) on tumor mass in a group of patients with CD, participating to a phase III study. Fourteen CD patients entered the phase III clinical trial CSOM230B2305 at Naples Center, and eight (seven women, one man, aged 38.9 +/- 17.6 years), including seven with a microadenoma and one with a macroadenoma, received treatment with pasireotide at the dose of 600-1200 ug bid for at least 6 months, and were considered for the analysis of the study. These eight patients were subjected to the evaluation of pituitary tumor volume by pituitary MRI, together with the evaluation of urinary cortisol levels, at baseline and every 6 months for the entire period of treatment. Pasireotide treatment induced full disease control in 37.5 % and partial disease control in 37.5 % after 6 months, whereas full and partial disease control after 12 months was obtained in 28.6 % and in 57.1 % of patients, respectively. A significant (>25 %) reduction in tumor volume was found in 62.5 % and in 100 % of patients, after 6 and 12 months, respectively. In particular, after 6 months, a slight tumor shrinkage (between 25.1 and 50 %) was observed in 25 %, moderate (50.1-75 %) in 25 %, and marked (>75 %) in 12.5 % of patients, whereas after 12 months, a slight tumor shrinkage was observed in 43 %, moderate in 14 %, and marked in 43 % of patients. In 25 % of patients (two patients), a marked tumor shrinkage was recorded, with tumor mass disappearance in one case; this tumor shrinkage was associated to rapid and sustained biochemical remission up to 24 months of continuous pasireotide treatment. These two cases represent the first cases with a documentation of such a notable effect of pasireotide on tumor mass. Pasireotide induces significant tumor shrinkage in 62.5 % of patients after 6 months and in 100 % of patients after 12 months, and occasionally induces a radiological disappearance of the tumor. This evidence supports and strengthens the role of pasireotide as medical treatment specifically addressed to patients with CD, particularly in those who had unsuccessful pituitary surgery, or are not candidates for surgery. PMID- 25743264 TI - Maternal hypothyroidism and subsequent neuropsychological outcome of the progeny: a family portrait. PMID- 25743266 TI - Precise localization of ulnar neuropathy at the elbow. AB - OBJECTIVE: To report the utility of short-segment nerve conduction studies (SSNCSs) and ultrasonography (US) in the precise localization of ulnar neuropathy at the elbow (UNE) and differentiation between lesions in the retroepicondylar (RTC) groove and under the humeroulnar aponeurotic arcade (HUA; i.e., cubital tunnel). METHODS: In a group of prospectively recruited patients with suspected UNE, four blinded examiners took a history and performed neurologic, electrodiagnostic (EDx) and ultrasonographic (US) examinations. Precise UNE localization was determined by SSNCSs criteria (conduction slowing and conduction block), and by US criteria (changes in cross-sectional area - CSA). Localizations obtained by EDx and US studies were compared. RESULTS: We included 83 patients (86 arms) with SSNCSs or US diagnosis of UNE. US confirmed the SSNCSs localization in 45%, provided localization alone in 24%, and was unable to confirm SSNCSs localization in 23% of arms. Lesions in RTC (76%) were mainly demyelinating (63%), and localized at the medial epicondyle (29%) or 2 cm proximal to it (69%). By contrast, lesions at HUA (17%) were mainly axonal (73%), and localized 2 cm (57%) or 3 cm (43%) distal to the medial epicondyle. CONCLUSION: SSNCSs and US are able to precisely localize UNE in the majority (93%) of arms with pathologic SSNCSs or US. UNE in RTC are predominantly demyelinating, and approx. 5-times more common than UNE at HUA that are more commonly axonal. SIGNIFICANCE: SSNCSs and US are of similar utility and complement each other in precise UNE localization. PMID- 25743265 TI - GLP-1 reduces metalloproteinase-14 and soluble endoglin induced by both hyperglycemia and hypoglycemia in type 1 diabetes. PMID- 25743267 TI - Potential cognitive decline linked to angiotensin-converting enzyme gene but not hypertension: Evidence from cognitive event-related potentials. AB - OBJECTIVES: The aims of the present study were to investigate the effect of hypertension and angiotensin-converting enzyme (ACE) genotypes on cognitive event related potentials (ERPs), and whether the impact of ACE genotypes on P300 is related to the influence of hypertension. METHODS: Using the Cognitive Abilities Screening Instrument (CASI), we recruited 97 mentally healthy middle-aged and older adults. Medical histories were collected, and blood pressure, ACE insertion/deletion polymorphisms and ERPs in an auditory oddball task were measured for all participants. RESULTS: When the participants were stratified according to the presence or absence of hypertension, there were no differences in CASI score, percentage of ACE genotypes and ERPs. The subjects with the D/D homozygote displayed lower amplitude and longer latency of P300, although there were no differences in CASI score and the percentage of hypertension. CONCLUSIONS: The subjects with the D/D genotype tended to have decreased amplitude and prolonged latency of P300 ERPs which reflected subtle cognitive impairment. There were no associations between hypertension, CASI score and P300 measurements. SIGNIFICANCE: Using ERPs, potential cognitive decline was linked to ACE genotypes, independently of the effect of hypertension. PMID- 25743268 TI - Resting-state sensorimotor rhythm (SMR) power predicts the ability to up-regulate SMR in an EEG-instrumental conditioning paradigm. AB - OBJECTIVE: Instrumental conditioning of EEG activity (EEG-IC) is a promising method for improvement and rehabilitation of cognitive functions. However, it has been found that even healthy adults are not always able to learn how to regulate their brain activity during EEG-IC. In the present study, the role of a neurophysiological predictor of EEG-IC learning performance, the resting-state power of sensorimotor rhythm (rs-SMR, 12-15Hz), was investigated. METHODS: Eyes open and eyes-closed rs-SMR power was assessed before N=28 healthy adults underwent 10 training sessions of instrumental SMR conditioning (ISC), in which participants should learn to voluntarily increase their SMR power by means of audio-visual feedback. A control group of N=19 participants received gamma (40 43Hz) or sham EEG-IC. RESULTS: N=19 of the ISC participants could be classified as "responders" as they were able to increase SMR power during training sessions, while N=9 participants ("non-responders") were not able to increase SMR power. Rs SMR power in responders before start of ISC was higher in widespread parieto occipital areas than in non-responders. A discriminant analysis indicated that eyes-open rs-SMR power in a central brain region specifically predicted later ISC performance, but not an increase of SMR in the control group. CONCLUSIONS: Together, these findings indicate that rs-SMR power is a specific and easy-to measure predictor of later ISC learning performance. SIGNIFICANCE: The assessment of factors that influence the ability to regulate brain activity is of high relevance, as it could be used to avoid potentially frustrating and expensive EEG IC training sessions for participants who have a low chance of success. PMID- 25743269 TI - Sural-sparing is seen in axonal as well as demyelinating forms of Guillain-Barre syndrome. AB - OBJECTIVE: The "sural-sparing pattern" of Guillain-Barre syndrome (GBS) is believed to reflect demyelinating pathology. We asked if it is present in non demyelinating GBS-subtypes, namely acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN) and Miller Fisher syndrome (MFS), in addition to acute inflammatory demyelinating polyneuropathy (AIDP). METHODS: We studied the occurrence of sural-sparing pattern in clinically defined GBS and MFS patients. Using serial electrodiagnostic studies, GBS patients were divided into AIDP, according to appearance of demyelination-remyelination and AMAN/AMSAN, if there were signs of reversible conduction failure or Wallerian-like degeneration. Equivocal cases were left unclassified. We defined sural-sparing as a greater decrease in median and or ulnar sensory nerve action potential than that of the sural, compared to age and height-matched normal controls. RESULTS: Twelve of 30 GBS and 7 of 20 MFS patients had sural-sparing. This pattern was seen in 4 of 8 AIDP, 5 of 13 AMAN/AMSAN and 3 of 9 unclassified cases. Sequential studies uncovered sural-sparing, initially covert, in additional 1 MFS, 1 unclassified, 1 AIDP and 1 AMAN/AMSAN patient. CONCLUSIONS: Sural-sparing occurs in axonal and demyelinating GBS subtypes. SIGNIFICANCE: The sural-sparing pattern reflects a pathological process common to axonal and demyelinating GBS-subtypes alike. PMID- 25743270 TI - Breast cancer imaging using the near-infrared fluorescent agent, CLR1502. AB - Positive margins after breast conservation surgery represent a significant problem in the treatment of breast cancer. The near-infrared fluorescence agent CLR1502 (Cellectar Biosciences, Madison, WI) was studied in a preclinical breast cancer model to determine imaging properties and ability to detect small islands of malignancy. Nude mice bearing human breast cancer flank xenografts were given a systemic injection of CLR1502, and imaging was performed using LUNA (Novadaq Technologies Inc., Richmond, BC) and Pearl Impulse (LI-COR Biosciences, Lincoln, NE) devices. Normal tissues were examined for fluorescence signal, and conventional and fluorescence histology was performed using the Odyssey scanner. Peak tumor to background ratio occurred 2 days after injection with CLR1502. The smallest amount of tumor that was imaged and detected using these devices was 1.9 mg, equivalent to 1.9 * 106 cells. The highest fluorescence signal was seen in tumor and normal lymph node tissue, and the lowest fluorescence signal was seen in muscle and plasma. Human breast cancer tumors can be imaged in vivo with multiple optical imaging platforms using CLR1502. This pilot study supports further investigations of this fluorescent agent for improving surgical resection of malignancies, with the goal of eventual clinical translation. PMID- 25743271 TI - Study of structures and thermodynamics of CuNi nanoalloys using a new DFT-fitted atomistic potential. AB - Shape, stability and chemical ordering patterns of CuNi nanoalloys are studied as a function of size, composition and temperature. A new parametrization of an atomistic potential for CuNi is developed on the basis of ab initio calculations. The potential is validated against experimental bulk properties, and ab initio results for nanoalloys of sizes up to 147 atoms and for surface alloys. The potential is used to determine the chemical ordering patterns of nanoparticles with diameters of up to 3 nm and different structural motifs (decahedra, truncated octahedra and icosahedra), both in the ground state and in a wide range of temperatures. The results show that the two elements do not intermix in the ground state, but there is a disordering towards solid-solution patterns in the core starting from room temperature. This order-disorder transition presents different characteristics in the icosahedral, decahedral and fcc nanoalloys. PMID- 25743272 TI - Predicting ecological responses of the Florida Everglades to possible future climate scenarios: introduction. AB - Florida's Everglades stretch from the headwaters of the Kissimmee River near Orlando to Florida Bay. Under natural conditions in this flat landscape, water flowed slowly downstream as broad, shallow sheet flow. The ecosystem is markedly different now, altered by nutrient pollution and construction of canals, levees, and water control structures designed for flood control and water supply. These alterations have resulted in a 50% reduction of the ecosystem's spatial extent and significant changes in ecological function in the remaining portion. One of the world's largest restoration programs is underway to restore some of the historic hydrologic and ecological functions of the Everglades, via a multi billion dollar Comprehensive Everglades Restoration Plan. This plan, finalized in 2000, did not explicitly consider climate change effects, yet today we realize that sea level rise and future changes in rainfall (RF), temperature, and evapotranspiration (ET) may have system-wide impacts. This series of papers describes results of a workshop where a regional hydrologic model was used to simulate the hydrology expected in 2060 with climate changes including increased temperature, ET, and sea level, and either an increase or decrease in RF. Ecologists with expertise in various areas of the ecosystem evaluated the hydrologic outputs, drew conclusions about potential ecosystem responses, and identified research needs where projections of response had high uncertainty. Resource managers participated in the workshop, and they present lessons learned regarding how the new information might be used to guide Everglades restoration in the context of climate change. PMID- 25743279 TI - [Report from Hannover. Family practitioners in emergency admission]. PMID- 25743274 TI - Adherence, exposure and patients' experiences with the use of erlotinib in non small cell lung cancer. AB - PURPOSE: Erlotinib is an orally administered tyrosine kinase inhibitor used for treatment of non-small cell lung cancer. Understanding actual use of medication is essential for optimizing treatment conditions. METHODS: In this multicentre prospective observational study, patients starting erlotinib treatment were followed for 4 months. Adherence was assessed using a medication event monitoring system (MEMS). Area under the curve (AUC) was determined after 1, 2 and 4 months. Before start and at monthly intervals, patients filled out questionnaires about attitude towards medication and disease, quality of life, symptoms and use in daily practice. RESULTS: Sixty-two patients (median age 63.5 years, 53 % male) were included of whom 15 were still on treatment after 4 months. MEMS data of 55 patients revealed a mean adherence of 96.8 +/- 4.0 %. Over one-third of patients had an adherence rate <95 %. At 1 month, 21 % of patients did not always correctly take erlotinib without food. Associated risk factors were older age, suboptimal adherence, ocular symptoms and stomatitis (all p < 0.05). After 1 month of treatment, fatigue (91 %) and rash (86 %) were the most common symptoms reported. AUCss of erlotinib was higher in patients with rash and patients with moderate-severe anorexia (both p < 0.05). CONCLUSION: Though adherence to erlotinib treatment is generally high, non-adherence might be an issue in a considerable number of patients. To support optimal erlotinib intake, clinicians need to take adequate measures to ameliorate symptoms and to address adherence and correct intake without food. Especially older patients and those who experience stomatitis may need extra attention. PMID- 25743273 TI - Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) have been reported to play an important role in tumorigenesis. In this study, the role of miR-15a and miR-16-1 in gastric adenocarcinoma (GAC) was investigated. METHODS: The expression of miR-15a and miR 16-1 in cell lines and primary tumors was examined by miRNA qRT-PCR. Proliferative assays, colony formation, cell invasion and migration, flow cytometry analysis and in vivo study were performed by ectopic expression of miR 15a and miR-16-1. The putative target genes of miR-15a and miR-16-1 were explored by TargetScan and further validated. RESULTS: We found that miR-15a and miR-16-1 were down-regulated in GAC cell lines and primary tumor samples compared with normal gastric epithelium. Functional study demonstrated that ectopic expression of miR-15a and miR-16-1 suppressed cell proliferation, monolayer colony formation, invasion and migration, and xenograft formation in vivo. In addition, miR-15a and miR-16-1 induced G0/G1 cell cycle arrest which was further confirmed by Western blot and qRT-PCR of related cell cycle regulators. YAP1 was confirmed to be a functional target of miR-15a and miR-16-1 in GAC. YAP1 re-expression partly abrogated the inhibitory effect of miR-15a and miR-16-1 in GAC cells. In clinical samples, YAP1 protein expression shows negative correlation with miR-15a and miR-16-1 expression. CONCLUSION: In conclusion, targeting YAP1 by tumor suppressor miRNA miR-15a and miR-16-1 plays inhibitory effect and this might have a therapeutic potential in GAC. PMID- 25743280 TI - [Living as once the Callas did - almost anyway]. PMID- 25743281 TI - [Value of the physician identity card in a foreign country]. PMID- 25743285 TI - [Seeking a cause for monoarthritis. Why does the joint hurt?]. PMID- 25743286 TI - [Interval, strength, vibration. Which sports are especially suitable for patients with COPD?]. PMID- 25743288 TI - [Pneumococcal vaccination. What is the general practice protocol?]. PMID- 25743289 TI - [New oral anticoagulants in venous thromboembolism. General practice information on switching, monitoring, pausing]. PMID- 25743290 TI - [In acid reflux diet habits should be intensively discussed]. PMID- 25743291 TI - [Hepatic encephalopathy causes permanent damage]. PMID- 25743292 TI - [Type 1 diabetes is dangerous even with good HbA1c values]. PMID- 25743297 TI - [Carotid stenosis: endarterectomy is superior to stent]. PMID- 25743298 TI - [Further development of the child protection ambulatory services]. PMID- 25743299 TI - [Sexual medicine in clinical practice--instructions for simple questions]. PMID- 25743300 TI - [Dengue fever and chikungunya fever: travel associated viral infections]. PMID- 25743301 TI - [Urolithiasis]. PMID- 25743302 TI - [Health care]. PMID- 25743303 TI - [Checklist: wrist fractures]. PMID- 25743304 TI - [The role of SGLT-2 inhibitors in the treatment of type 2 diabetes]. PMID- 25743322 TI - Invited commentary: future of population studies--defining research priorities and processes. AB - In this issue of the Journal, an expert panel offers 7 recommendations on how population studies supported by National Heart, Lung, and Blood Institute contracts might be strategically transformed (Am J Epidemiol. 2015;181(6):363 368). The Institute and its external advisors seemingly established this panel of epidemiologists and nonepidemiologists primarily to find ways to save research costs. Although the working group's recommendations offer reasonable approaches, we believe that, even in tough fiscal times, the main drivers of cardiovascular epidemiologic research must remain 1) scientific questions that are important and 2) study designs to match these. Although cardiovascular epidemiology admittedly is often redundant and needs to be more efficient, undue focus on administrative efficiency and cost savings will not necessarily guarantee cutting-edge population research. PMID- 25743323 TI - Roger et al. respond to "future of population studies". PMID- 25743324 TI - Strategic transformation of population studies: recommendations of the working group on epidemiology and population sciences from the National Heart, Lung, and Blood Advisory Council and Board of External Experts. AB - In 2013, the National Heart, Lung, and Blood Institute assembled a working group on epidemiology and population sciences from its Advisory Council and Board of External Experts. The working group was charged with making recommendations to the National Heart, Lung, and Blood Advisory Council about how the National Heart, Lung, and Blood Institute could take advantage of new scientific opportunities and delineate future directions for the epidemiology of heart, lung, blood, and sleep diseases. Seven actionable recommendations were proposed for consideration. The themes included 1) defining the compelling scientific questions and challenges in population sciences and epidemiology of heart, lung, blood, and sleep diseases; 2) developing methods and training mechanisms to integrate "big data" science into the practice of epidemiology; 3) creating a cohort consortium and inventory of major studies to optimize the efficient use of data and specimens; and 4) fostering a more open, competitive approach to evaluating large-scale longitudinal epidemiology and population studies. By building on the track record of success of the heart, lung, blood, and sleep cohorts to leverage new data science opportunities and encourage broad research and training partnerships, these recommendations lay a strong foundation for the transformation of heart, lung, blood, and sleep epidemiology. PMID- 25743325 TI - Survival is Better After Breast Conserving Therapy than Mastectomy for Early Stage Breast Cancer: A Registry-Based Follow-up Study of Norwegian Women Primary Operated Between 1998 and 2008. AB - BACKGROUND: Breast-conserving therapy (BCT) and mastectomy (MTX) has been considered to have a similar long-time survival. However, better survival in women undergoing BCT compared with MTX is found in two recent register studies from the United States. The purpose of this study was to compare survival after BCT and MTX for women with early-stage breast cancer in Norway. METHODS: Women with invasive, early-stage breast cancer (1998-2008) where BCT and MTX were considered as equally beneficial treatments were included for a total of 13,015 women. Surgery was divided in two main cohorts (primary BCT, primary MTX) and five subcohorts. Analyses were stratified into T1N0M0, T2N0M0, T1N1M0, T2N1M0, and age groups (<50, 50-69, >=70). Overall survival and breast cancer-specific survival (BCSS) were calculated in life tables, hazard ratios by Cox regression, and sensitivity analyses. RESULTS: Five-year BCSS for women who underwent primary BCT or primary MTX was 97 and 88 %, respectively. Women who underwent primary MTX had a hazard ratio of 1.64 (95 % confidence interval 1.43-1.88) for breast cancer death compared with women who underwent primary BCT after adjusting for the year of diagnosis, age at diagnosis, stage, histology, and grade. CONCLUSIONS: Survival was better or equal after breast-conserving therapy than mastectomy in all early stages, surgical subcohorts, and age groups. This advantage could not only be attributed to differences in tumor biology. PMID- 25743326 TI - Factors Affecting the Locoregional Recurrence of Conventional Papillary Thyroid Carcinoma After Surgery: A Retrospective Analysis of 3381 Patients. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) does recur, despite its favorable long-term outcome. The incidence of thyroid cancer in South Korea increased during the 1990s, then increased rapidly after the turn of the century. In 2011, the rate of thyroid cancer diagnoses was 15 times that observed in 1993. The present study aimed to identify factors associated with the locoregional recurrence of recently increasing conventional PTC. METHODS: The records of 3381 patients with conventional PTC were reviewed for this retrospective cohort study. Between January 2004 and January 2012, these patients underwent ultrasonography, computed tomography, and preoperative and total thyroidectomy with central neck dissection. Disease recurrence was defined as structural evidence of disease following the remission period. RESULTS: Median length of follow-up was 5.6 (range 2.1-10.1) years. Of 3381 patients, 75 (2.2 %) experienced recurrence. The univariate analysis suggested that locoregional recurrence was associated with tumor size, multifocality, extrathyroidal extension (ETE), lymph node metastasis, lymphatic invasion, vascular invasion, and positive surgical margin. However, multivariate analysis showed that only tumor size (p < 0.001), bilaterality (p < 0.001), gross ETE (p = 0.049), lymph node metastasis (p < 0.001), and vascular invasion (p = 0.013) were independently associated with locoregional recurrence. CONCLUSIONS: Tumor size, bilaterality, gross ETE, lymph node metastasis, and vascular invasion were associated with locoregional recurrence. Evaluation of these prognostic factors appears to help identify patients who require close monitoring. PMID- 25743327 TI - Radiation-Associated Undifferentiated Pleomorphic Sarcoma is Associated with Worse Clinical Outcomes than Sporadic Lesions. AB - BACKGROUND: Radiation therapy is used increasingly as a component of multidisciplinary treatment for many solid tumors. One complication of such treatment is the development of radiation-associated sarcoma (RAS). Undifferentiated pleomorphic sarcoma (UPS), previously termed "malignant fibrous histiocytoma" (MFH) is the most common histologic subtype of RAS. This study investigated the clinical outcomes for patients with radiation-associated UPS (RA UPS/MFH). METHODS: The study identified 1068 patients with UPS/MFH treated at the authors' institution. Patient and tumor factors were collected and compared. Regression analysis was performed to identify independent predictors of survival. A matched-cohort survival and recurrence analysis was performed for radiation associated and sporadic UPS/MFH. RESULTS: The findings showed that RA-UPS/MFH comprised 5.1 % of the UPS population. The median latency to the development of RA-UPS/MFH was 9.3 years. The 5-year disease-specific survival (DSS) was 52.2 % for patients identified with RA-UPS/MFH (n = 55) compared with 76.4 % for patients with unmatched sporadic UPS/MFH (n = 1,013; p < 0.001). A matched-cohort analysis also demonstrated that the 5-year DSS was significantly worse for RA UPS/MFH (52.2 vs 73.4 %; p = 0.002). Furthermore, higher local recurrence rates were observed for patients with RA-UPS/MFH than for patients with sporadic lesions (54.5 vs 23.5 %; p < 0.001). Radiation-associated status and incomplete resection were identified as independent predictors of local recurrence. CONCLUSION: This study demonstrated worse clinical outcomes for patients with RA UPS/MFH than for patients with sporadic UPS/MFH. Local recurrence was significantly higher for patients with RA-UPS/MFH, suggesting a unique tumor biology for this challenging disease. PMID- 25743328 TI - Distant Metastases in Patients with Carcinoma of the Major Salivary Glands. AB - BACKGROUND: This study aimed to show the incidence of distant metastases (DM) in salivary gland cancer as well as the types of histology most commonly associated with it and to identify factors predictive of DM. METHODS: The study identified 301 patients who underwent surgery for cancer of the major salivary glands at Memorial Sloan-Kettering Cancer center between 1985 and 2009. Clinical, tumor, and treatment characteristics were recorded. Tumors were categorized as low-, intermediate-, and high-risk pathology based on histologic subtype and grade. Factors predictive of distant recurrence-free probability (DRFP) were determined by uni- and multivariable analyses. RESULTS: The primary tumor was parotid in 266 patients (88 %), and 96 tumors (32 %) were clinical T3/T4. For 57 patients (18.9 %), DM developed with a 5-year DRFP of 72.7 %. The most common site of metastasis was the lung (50 %). The clinical predictors were male gender, cT4 stage, cN+ stage, and clinical overall stage. The multivariable analysis of clinical variables showed male gender (p = 0.018), cT4 stage (p < 0.001), and cN+ stage (p = 0.004) to be significant. The pathologic predictors were high-risk and high grade pathology, vascular invasion, perineural invasion, positive margins, pT4 stage, pN+ stage, and overall stage. The multivariable analysis of pathologic variables showed high-grade pathology (p < 0.001), perineural invasion (p = 0.005), and pN+ stage (p = 0.002) to be significant. CONCLUSIONS: Distant metastases developed in approximately 20 % of the patients with salivary gland cancer. The most common site of metastases was the lung. The significant predictors of DM were cT4, cN+, male gender, high-grade pathology, perineural invasion, and positive nodal disease. PMID- 25743330 TI - The Expression of Melanoma-Associated Antigen D2 Both in Surgically Resected and Serum Samples Serves as Clinically Relevant Biomarker of Gastric Cancer Progression. AB - BACKGROUND: Sensitive biomarkers are necessary for risk classification of patients with gastric cancer (GC), especially ones at risk of distant metastases. Melanoma-associated antigen (MAGE)-D2 has been reported to play a role in the process of cell adhesion and metastatic potential of tumor cells in colorectal cancer. The purpose of this study was to identify a novel clinically relevant biomarker of GC. METHODS: Expression analysis of MAGE-D2 was conducted in GC cell lines and clinical samples (surgical specimen and serum) in both mRNA and protein level. Correlations between MAGE-D2 expression status and clinicopathological factors were evaluated. RESULTS: MAGE-D2 mRNA expression levels were similar between GC tissues and the corresponding normal adjacent tissues and were independent of GC differentiation or subtype. In 101 (45 %) of 225 patients, the expression level of MAGE-D2 mRNA was increased in GC tissues compared with the corresponding normal adjacent tissues. Increased expression of MAGE-D2 mRNA in GC tissues was associated with distant metastasis and early recurrence and was an independent prognostic factor (hazard ratio 2.27, 95 % confidence interval 1.39 3.74, P = 0.001). There was a stepwise increase in serum MAGE-D2 level going from healthy volunteers to patients with localized GC and then to those with extended GC (stage IV). Patients with preoperative serum MAGE-D2 levels >130 pg/ml had a more unfavorable prognosis than those with levels <=130 pg/ml. CONCLUSION: MAGE D2 was associated with metastatic potential of GC and may represent a promising biomarker, both in gastric tissues and serum samples, for malignant behavior of GC. PMID- 25743329 TI - Characterizing Breast Cancer in a Population with Increased Prevalence of Triple Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women. AB - BACKGROUND: The androgen receptor (AR) is a commonly-expressed hormone receptor in breast cancer and may be a marker of response to targeted anti-androgen therapy, a particularly attractive option for triple-negative breast cancer (TNBC). Gene expression studies suggest that ARs may distinguish a luminal/AR TNBC subtype from stem cell-like subtypes. TNBC frequency is two to three times higher in African American and African breast cancers compared with White American and European breast cancers, yet little is known regarding TNBC subtypes in high-frequency African-ancestry populations. We evaluated ARs and the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) among breast cancers from Ghana, Africa. METHODS: Overall, 147 formalin-fixed, paraffin-embedded invasive breast cancers from the Komfo Anoyke Teaching Hospital in Ghana were studied at the University of Michigan, and analyzed immunohistochemically for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, ALDH1, and AR expression. RESULTS: The median age of patients was 45 years. Only 31 cases (21 %) were ER positive, and 14 (10 %) were HER2-positive; 89 (61 %) were TNBCs. For the entire group, 44 % were AR-positive and 45 % were ALDH1-positive. ER/PR-positive tumors were more likely to be AR-positive compared with ER/PR-negative tumors (87 vs. 26 %; p < 0.0001), but there was no association between ALDH1 and AR expression. Among the TNBC cases, 45 % were ALDH1-positive and 24 % were AR-positive. ALDH1 positivity was associated with AR positivity within the subset of TNBC (36 vs. 14 %; p = 0.019). CONCLUSION: We confirmed other studies showing a high frequency of TNBC in Africa. Surprisingly, ALDH1 was found to correlate with AR expression among TNBC, suggesting that novel TNBC subtypes may exist among populations with African ancestry. PMID- 25743331 TI - Tumor-Associated Macrophages Extend Along Lymphatic Flow in the Pre-metastatic Lymph Nodes of Human Gastric Cancer. AB - BACKGROUND: Tumor-associated macrophages (TAMs) correlate with lymphangiogenesis in primary lesions and with lymph node (LN) metastasis of several cancers. However, the association of TAMs in regional LNs with lymphatic spread of cancer remains unclear. The purpose of this study was to evaluate the distribution of TAMs in draining LNs and the impact of TAMs on the establishment of LN metastasis of gastric cancer. METHODS: The number and distribution of TAMs in regional LNs that were obtained from 49 patients who underwent radical surgery for gastric cancer at Osaka City University Hospital in 2011 were assessed. TAMs were defined as immunohistochemically CD163 positive cells. The association of the TAM density with lymph node metastasis and the lymphatic drainage route of the stomach were investigated. RESULTS: A high density of TAMs was significantly associated with pathologically positive lymph nodes and pathological TNM stage. The density of TAMs was increased in LNs with micro metastasis compared with those without metastasis. There was a significant, positive correlation between TAM number and lymphatic vessel density in LNs. In nonmetastatic LNs, TAMs were likely to accumulate in the neighborhood of the primary lesion. In addition, the density of TAMs in distant LNs was significantly increased in patients in whom LN metastasis was observed in perigastric LNs. CONCLUSIONS: Accumulated TAMs may induce lymphangiogenesis and prepare an environment that facilitates cancer proliferation in LNs. Our findings might provide a conceptual framework for understanding the lymphatic spreading of cancer and for designing future therapeutic strategies for gastric cancer. PMID- 25743332 TI - Risk Factors for Anastomotic Leakage After Intersphincteric Resection Without a Protective Defunctioning Stoma for Lower Rectal Cancer. AB - BACKGROUND: Intersphincteric resection (ISR) is performed as an alternative to abdominoperineal resection for super-low rectal cancer. The purpose of this study was to evaluate risk factors for anastomotic leakage (AL) after ISR without a defunctioning stoma for lower rectal cancer. METHODS: Between 1995 and 2012, 135 consecutive patients with lower rectal cancer underwent curative ISR without a protective defunctioning stoma. Univariate and multivariate analyses were performed to determine the risk factors for AL. RESULTS: The radiological and symptomatic AL rate was 17.0 % (23/135). Univariate analysis demonstrated that male sex (P = 0.030), preoperative chemotherapy (P = 0.016), partial ISR (P < 0.001), lateral lymph-node dissection (P = 0.042), distal tumor distance from the dentate line (P = 0.007), and straight reconstruction (P < 0.001) were significantly associated with AL. Severe AL requiring re-laparotomy developed in 13 (9.6 %) patients. Univariate analysis demonstrated that male sex (P = 0.006), partial ISR (P < 0.001), distal tumor distance from the dentate line (P = 0.002), and straight reconstruction (P < 0.001) were significantly associated with AL requiring relaparotomy. Multivariate analysis demonstrated that partial ISR [odds ratio (OR) 6.701; P = 0.001] and straight reconstruction (OR 5.552; P = 0.002) were independently predictive of AL. CONCLUSIONS: Partial ISR and straight reconstruction increased the risk of AL after ISR without a protective defunctioning stoma. A defunctioning stoma might be mandatory in patients with the risk factors identified in this analysis. PMID- 25743333 TI - Age, Preoperative Subcutaneous Fat Area, and Open Laparotomy are Risk Factors for Incisional Hernia following Colorectal Cancer Surgery. AB - BACKGROUND: Although incisional hernia (IH) is a common complication of abdominal surgery, the incidence rate and risk factors are not well known. The objectives of this study are to determine the incidence rate of IH following colorectal cancer surgery and to describe the associated risk factors. METHODS: Between 2005 and 2010, patients who underwent surgery to treat colorectal cancer were examined. The diagnosis of IH was performed by CT scan, and the visceral fat area (VFA) and subcutaneous fat area (SFA) at the level of the umbilicus were calculated using a 3D-image analysis system. Survival analysis was used to assess the incidence and risk factors of IH. RESULTS: A total of 626 patients (326 open, 300 laparoscopic) were included in this study, with median follow-up of 54 (range 2-97) months. Forty patients were diagnosed with postoperative IH, and the cumulative, 5-year incidence of IH was 7.3 %. Univariate analysis revealed that age, body mass index, waist circumference, hip circumference, open laparotomy, wound infection, VFA, and SFA were significantly associated with incidence of IH. Multivariate analysis revealed that age [hazard ratio (HR) 1.043 (1.005-1.083), p = 0.027], open laparotomy [HR 4.410 (1.018-19.095), p = 0.047], and SFA [HR 1.013 (1.004-1.022), p = 0.005] were significant risk factors for developing IH. CONCLUSIONS: Higher age and SFA, along with open surgery, are risk factors for developing IH. PMID- 25743334 TI - Preoperative Cardiac Risk Assessment and Surgical Outcomes of Patients with Gastric Cancer. AB - PURPOSE: To evaluate the incidence of major adverse cardiac events (MACE) and long-term surgical outcomes after gastrectomy for gastric cancer using the revised cardiac risk index (RCRI), which is based on preoperative insulin use, serum creatinine >2.0 mg/dL, and history of ischemic or congestive heart failure or cerebrovascular disease. METHODS: We allocated 1000 patients who underwent elective gastrectomy to three groups with >=3 (group A, n = 32), 2 (group B, n = 142), or 1 (group C, n = 826) of these factors and compared surgical complications and prognoses. RESULTS: Groups A and B had older patients than group C. Group B had more male patients than groups A and C. Tumor staging and gastrectomy type were similar among all groups. D1 lymph node dissection was more frequent in group A than in groups B or C. The incidence of MACE in groups A, B, and C was 25.0, 9.9, and 1.1 %, respectively. RCRI was associated with MACE. Furthermore, the incidence of pneumonia and in-hospital mortality was associated with RCRI risk factors. However, the incidence of anastomotic leakage, intra abdominal abscess, wound infection, and pancreas-related infection were similar among the groups. The 5-year overall survival rates of the three groups were 44.3, 65.2, and 80.8 %, which were significantly different. CONCLUSIONS: Patients with RCRI factors have an increased risk of MACE, pneumonia, and higher mortality after gastrectomy; thus, careful patient selection and meticulous perioperative care are crucial for successful gastrectomy. PMID- 25743336 TI - Effects of FGF-2 and FGF receptor antagonists on MMP enzymes, aggrecan, and type II collagen in primary human OA chondrocytes. AB - OBJECTIVES: Fibroblast growth factor (FGF)-2 is a member of the FGF family and is found in the synovial fluid of patients with osteoarthritis (OA). The aim of this study was to investigate the effects of FGF-2 on human OA cartilage/chondrocytes by examining the association between FGF-2 and the cartilage degrading enzymes matrix metalloproteinase (MMP)-1 and MMP-13 and the major cartilage matrix components aggrecan and collagen II. METHOD: Cartilage samples were obtained from 97 OA patients undergoing total knee replacement surgery. Cartilage tissue cultures were conducted and levels of FGF-2, MMP-1, and MMP-13 released into the culture medium were measured by immunoassay. The effects of FGF-2 on the expression of MMP-1, MMP-13, aggrecan, and collagen II were further investigated in cultures of primary human OA chondrocytes. RESULTS: FGF-2, MMP-1, and MMP-13 were released into the culture medium from cartilage samples obtained from patients with OA. FGF-2 concentrations correlated positively with the concentrations of MMP-1 (r = 0.414, p < 0.001) and MMP-13 (r = 0.362, p < 0.001). FGF-2 also up-regulated the production of MMP-1 and MMP-13, and down-regulated the expression of aggrecan and collagen II, in human OA chondrocyte cultures. Furthermore, FGF receptor antagonists AZD4547 and NVP-BGJ398 down-regulated the expression of MMP-1 and MMP-13 and up-regulated aggrecan and collagen II both in the absence and in the presence of exogenous FGF-2. CONCLUSIONS: Our results suggest that, in contrast to its growth factor-like effects in some other tissues, FGF-2 induces catabolic effects in human OA cartilage. Moreover, FGF receptor antagonists showed promising beneficial effects on the balance of catabolic and anabolic factors within OA cartilage. PMID- 25743337 TI - A dietary dairy/yeast prebiotic and flaxseed oil enhance growth, hematological and immunological parameters in channel catfish at a suboptimal temperature (15 degrees C). AB - Channel catfish raised in the southern United States require two growing seasons to reach market size. Growing seasons are separated by a cool period of about 3 months when feed intake and growth are greatly reduced. A cool-weather feeding strategy to improve feed intake, growth or health of catfish might improve survival and reduce the time needed to achieve market size. We conducted a feeding trial with channel catfish at a suboptimal temperature (15 degrees C) to determine the effects of supplementing diets with either a dairy/yeast prebiotic or flaxseed oil (high in 18:3n-3) compared with a control with soybean oil (high in 18:2n-6). The trial was conducted in recirculating systems with 1140-l tanks containing 100 fish each (mean initial weight 61.4 g+/-0.43 s.e.m.). A 28% protein basal diet was supplemented with 20 g/kg cellulose and 20 g/kg soybean oil (SBO, control), 20 g/kg cellulose and 20 g/kg flaxseed oil (FLAX) or 20 g/kg of a dairy/yeast prebiotic and 20 g/kg soybean oil (PREB). Fish were fed once daily to satiation and weighed every 3 weeks to track growth. Hematology, non specific immune responses, proximate and fatty acid composition of muscle were determined to assess diet effects. Catfish-fed FLAX or PREB had higher weight gain, feed consumption and lysozyme activity than fish fed SBO. Total n-3 fatty acids in muscle were higher in fish fed SBO or FLAX than those fed PREB. Total n 6 long-chain polyunsaturated acids were higher in muscle of fish fed PREB than those fed SBO. Fatty acids in the PREB and SBO diets were similar, so the PREB appeared to increase elongation and desaturation of n-6 fatty acids in muscle. Flaxseed oil and the dairy/yeast prebiotic both have potential to increase catfish performance at a low temperature. PMID- 25743338 TI - Ocular Involvement Following Postnatally Acquired Toxoplasma gondii Infection in Southern Brazil: A 28-Year Experience. AB - PURPOSE: To determine the incidence of, and risk factors for, ocular involvement among people known to have postnatally acquired Toxoplasma gondii infection in a region of southern Brazil where there is a high prevalence of endemic disease. DESIGN: Retrospective longitudinal cohort study. METHODS: Records of 302 patients with serologic evidence of recent T gondii infection (a positive anti-T gondii IgM antibody test) from Erechim, Rio Grande do Sul state, Brazil (1974-2002) were analyzed. The incidence of ocular involvement was calculated in terms of person years (PY) of follow-up. Risk factors for ocular involvement were analyzed using log-rank and Fisher exact tests. RESULTS: At initial ocular examination (baseline), 30 patients (9.9%) had intraocular inflammation only (anterior chamber cells and flare, vitreous inflammatory reactions, retinal whitening), without clinically apparent necrotizing retinochoroiditis. At baseline, men were more likely to have ocular involvement (P = .043) and antiparasitic treatment was associated with less ocular involvement (P = .015). Follow-up examinations were performed on 255 patients (median follow-up, 13.7 months [range 0.4-261.9 months]). Among those without ocular involvement at baseline, the incidence of necrotizing retinochoroiditis was 6.4/100 PY. Patients >40 years of age at first IgM test had a greater risk of incident necrotizing retinochoroiditis (hazard ratio = 4.47, 95% CI = 1.67-11.93, P = .003) than younger patients. The incidence of recurrent necrotizing retinochoroiditis was 10.5/100 PY. CONCLUSION: Isolated intraocular inflammatory reactions can be an initial manifestation of T gondii infection, with necrotizing retinochoroiditis occurring months or years later. Male sex and older age are risk factors for toxoplasmic retinochoroiditis. Antitoxoplasmic treatment may protect against early ocular involvement. PMID- 25743339 TI - Posterior vitreous mobility delineated by tracking of optical coherence tomography images in eyes with idiopathic macular holes. AB - PURPOSE: To demonstrate the posterior vitreous mobility following eye movements in patients forming macular holes, using an optical coherence tomography (OCT) eye-tracking system. DESIGN: Prospective consecutive interventional case series. METHODS: Twenty-four eyes of 17 consecutive patients with idiopathic macular hole and the remaining fellow eyes were recruited. Following acquisition of baseline fundus scans, all patients were instructed to perform sets of standardized full excursion vertical and horizontal eye movements. Immediately after each set of movements an OCT scan registered to the baseline fundus image was obtained using the eye-tracking system. Three images were then overlaid using picture-editing software, thereby documenting the changing configuration of the posterior vitreous as well as its position relative to the static retinal structures. RESULTS: In patients with macular hole, 22 of 24 eyes (92%) had duplication of the posterior cortical vitreous in overlaid images. The extent of duplication (indicating mobility) was increased with increasing vitreous separation and as the stage of macular hole increased (75% in stage 0; 80% in stage 1; 100% in both stage 2 and stage 3). In all eyes in which there was a wavy configuration to the vitreous face, or in which there was a greater angle of vitreous insertion into the peripheral retina, vitreous mobility was evident on overlaid images (P = 2.7 * 10(-17) and P = 1.7 * 10(-13), respectively). CONCLUSION: By dynamically evaluating patients, we offer potential mechanistic insights that may further implicate mobile vitreous and associated fluid currents in the pathogenesis and progression of macular holes. PMID- 25743340 TI - Ocular Involvement Following an Epidemic of Toxoplasma gondii Infection in Santa Isabel do Ivai, Brazil. AB - PURPOSE: To investigate ocular involvement (prevalence, incidence, lesion characteristics) following postnatally acquired infection with an "atypical" genotype of Toxoplasma gondii during a well-characterized 2001 outbreak in Santa Isabel do Ivai, Brazil, attributed to a contaminated municipal reservoir. DESIGN: Prospective longitudinal cohort study. METHODS: We performed ophthalmic examinations on 290 of 454 individuals with serologic evidence of T gondii infection during the epidemic (positive IgM antibody tests). Prevalence of ophthalmic findings (intraocular inflammatory reactions [including transient, isolated retinal whitening without clinically apparent retinal necrosis] and necrotizing retinochoroiditis) at initial examination (baseline) and incidence of new findings during 10.5 months of follow-up were calculated. Cumulative risks of ophthalmic events were determined (Kaplan-Meier technique). RESULTS: Ocular involvement was present in 33 of 288 IgM+ individuals (11.5%) at baseline, including 17 with focal retinal whitening only and 13 with necrotizing retinochoroiditis. Incidence of new ocular involvement was estimated to be 1.73 events per 100 person-months (PM); cumulative risk at 10.5 months was 30.1%. Incident necrotizing retinochoroiditis was more common among those with focal retinal whitening at baseline (6.7/100 PM) than among those with no ocular involvement at baseline (1.11/100 PM; hazard ratio 6.07 [1.94-19.01]; P < .0001). CONCLUSIONS: Waterborne infection with an atypical genotype of T gondii is associated with substantial risk of ocular involvement. Lesions may continue to develop during the first year after infection. The increased risk of late necrotizing retinochoroiditis associated with isolated focal retinal whitening at presentation suggests the early presence of parasites in the retina, despite initial lack of observable retinal necrosis. PMID- 25743341 TI - Serum expression of S100A6 is a potential detection marker in patients with urothelial carcinoma in the urinary bladder. AB - To investigate the level of serum S100A6 in patients with bladder cancer and in healthy controls and compare these levels with clinicopathologic findings, we evaluated the level of serum S100A6 in 30 healthy controls and 50 patients with bladder cancer diagnosed via transurethral resection of bladder tumor and/or radical cystectomy. S100A6 in sera was detected by employing automatic dot blot systems, and the micro Dot Blot array with a 256-solid pin configuration. The normalized signal of serum S100A6 expression in bladder cancer patients was significantly higher than that of healthy controls (P = 0.001). Serum S100A6 expression of non-muscle-invasive cancer (NMIC) was significantly higher than that of healthy controls (P = 0.04). Furthermore, the S100A6 serum level in patients with muscle-invasive bladder cancer was significantly higher than that in patient with NMIC (P = 0.004). The sensitivity and specificity were 48.0% (95% CI: 0.337-0.626) and 93.3% (95% CI: 0.779-0.992), respectively. The area under the curve was 0.727. Serum S100A6 expression is a potentially effective detection marker for bladder cancer. Applying this serum marker to clinical practice would require less-invasive examinations of patients and would help to detect life threatening cancerous lesions earlier than current modalities. PMID- 25743342 TI - Behavioral palatability of dietary fatty acids correlates with the intracellular calcium ion levels induced by the fatty acids in GPR120-expressing cells. AB - We recently reported that G-protein-coupled receptor 120 (GPR120) is expressed on taste buds, and that rodents showed preference for long-chain fatty acids (LCFA) at a low concentration. We also showed that the LCFA (1% linoleic acid) increased the extracellular dopamine (DA) level in the nucleus accumbens (NAc), which participates in reward behavior. However, the mechanism underlying the involvement of the GPR120-agonistic activity of LCFA in the palatability of dietary fat remains elusive. Therefore, we examined the association between the GPR120-agonistic activity and palatability of LCFA. First, we measured Ca(2+) signaling in HEK293 cells stably expressing GPR120 under stimulation by various LCFAs. We then assessed the palatability of the various LCFAs by testing the licking behavior in mice and measured the changes in the NAc-DA level by in vivo microdialysis. Consequently, 14- to 22-carbon unsaturated LCFAs showed strong GPR120-agonistic activity. Additionally, mice displayed high licking response to unsaturated 16- and 18-carbon LCFAs, and unsaturated 18-carbon LCFA significantly increased the DA level. The licking rate and the LCFA-dependent increase in DA level also correlated well with the GPR120- agonistic activity. These findings demonstrate that chemoreception of LCFA by GPR120 is involved in the recognition and palatability of dietary fat. PMID- 25743343 TI - A low, non-toxic dose of paclitaxel can prevent dendritic cell-precursors from becoming tolerogenic dendritic cells with impaired functions. AB - Tumor infiltrating dendritic cells (TIDCs) are thought to be potent antigen presenting cells able to activate tumor-specific cytotoxic T lymphocytes (CTLs) or tolerogenic DCs that suppress immune reaction against tumors to escape. We have recently reported that majority of these TIDCs were DEC-205(+) DCs having a cross-presenting ability of captured tumor antigens to CD8(+) T cells via class I MHC (MHC-I) molecules, nevertheless, when the TIDCs expressed down-modulated costimulatory molecules, such as CD80 and CD86, they will inhibit the priming and activation of immune effectors (Immunol. Cell Biol., 91: 545-555, 2013). Here, we show that DC-precursors (preDCs) but not the established DCs become tolerogenic DCs expressing down-regulated costimulatory molecules having low responsiveness to LPS or tumor cells, when exposed to soluble factors released from the encountered ovarian tumors in the early phase of their development. However, we found that we could reduce the secretion of those soluble factors with a low, nontoxic concentration of paclitaxel (PTX) and we could stop the preDCs to be tolerogenic DCs and maintain DC functions. These findings indicate that we could prevent the induction of tolerogenic DCs from preDCs by using low, non-toxic doses of anti-cancer drugs to establish DCs that effectively elicit tumor specific CTLs. PMID- 25743335 TI - Whole-genome sequence-based analysis of thyroid function. AB - Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF>=1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 * 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 * 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 * 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 * 10(-11)). All common variants explain >=20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function. PMID- 25743345 TI - Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose. AB - Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (*OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or *OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury. PMID- 25743344 TI - Fasudil, a Rho kinase inhibitor, suppresses tumor growth by inducing CXCL14/BRAK in head and neck squamous cell carcinoma. AB - CXCL14/BRAK (BRAK) is a secreted chemokine with anti-tumor activity, and its expression is suppressed in tumor cells. We previously reported the anti-tumor activity of BRAK in cell lines of head and neck squamous cell carcinoma (HNSCC) and the suppression of BRAK secretion in these cells. BRAK secretion in fibrosarcoma cells is restored by Fasudil, which is a Rho-kinase (ROCK) inhibitor. In this study, we examined the anti-tumor effect of BRAK by evaluating its gene expression and protein secretion in HNSCC cell lines. We found that BRAK mediated the suppressive effect of Fasudil against HNSCC cells. Tumor development in female BALB/cAJclnu/nu mice was suppressed by Fasudil. Also secretion of BRAK protein by tumor cell lines in vitro was significantly stimulated by Fasudil treatment. Similarly, the production of BRAK protein was significantly increased by the addition of Fasudil to cultured tumor cells. Furthermore Fasudil significantly increased BRAK gene expression at the mRNA level in HNSCC cell line. Inhibition of the RhoA/ROCK pathway by siRNAs significantly stimulated BRAK gene expression. These results show that the tumor-suppressive effect of Fasudil was mediated by BRAK, suggesting that Fasudil may therefore be useful for the treatment of HNSCC. PMID- 25743346 TI - VEGF secretion by adipose tissue-derived regenerative cells is impaired under hyperglycemic conditions via glucose transporter activation and ROS increase. AB - Transplantation of cultured adipose-derived regenerative cells (ADRCs) into ischemic tissues promotes neovascularization and blood perfusion recovery. These effects are attenuated in diabetes patients. We examined the effects of hyperglycemia on the angiogenic capacity of ADRCs derived from Wistar rats both in vivo and in vitro. Cultured ADRCs were predominantly composed of CD90 positive cells; prevalence of CD90 positive cells was not affected by hyperglycemia. mRNA and protein levels of vascular endothelial growth factor (VEGF) were significantly decreased in ADRCs under hyperglycemic conditions independent of osmolarity, whereas mRNA levels of hepatocyte growth factor and fibroblast growth factor were unaffected. Since ADRCs express glucose transporter proteins GLUT1, 3 and 4, we examined the effects of the glucose transporter inhibitor phloretin on reactive oxygen species (ROS) and angiogenic factors. Phloretin decreased the glucose uptake rate, reduced ROS, and increased VEGF mRNA in ADRCs exposed to a hyperglycemic condition. In vivo transplantation of ADRCs cultured under hyperglycemic conditions into mouse ischemic limbs resulted in significantly decreased blood perfusion and capillary density in ischemic regions compared with transplantation of ADRCs cultured under normoglycemic conditions. These results suggest that hyperglycemia impaired VEGF production in ADRCs via an increase of ROS, impairing the angiogenic capacity of ADRCs transplanted into ischemic limbs. PMID- 25743347 TI - Implementation of individualized medicine for cancer patients by multiomics-based analyses-the Project HOPE-. AB - The Project HOPE (High-tech Omics-based Patient Evaluation) for cancer medicine aims to evaluate biological characteristics of each cancer tissue as well as diathesis of each patient in around 1,000 consecutive cases per year, who receive operations at the Shizuoka Cancer Center. Cancer tissues are investigated by whole-exome sequencing for 18,835 genes, focusing on 12,776 in-house cancer hotspots from 483 cancer-associated genes. To confirm cancer-specific genetic changes, we analyzed blood cells to collate with data of cancer tissues, and we reevaluate cancer tissues by comprehensive cancer panel for 409 genes. In order to investigate diathesis of the patients, we evaluate 43,015 hotspots associated with non-cancerous diseases. In terms of gene expression profiling, we analyze cancer-specific alterations for 29,833 genes using tumor and adjacent normal tissues. If and when necessary, we investigate tumor and normal tissues by proteomics and metabolomics. The model experiments using glioblastoma cell lines demonstrated that the method is appropriate for clinical application. The Project HOPE makes it possible to implement individualized medicine and to practice preventive and presymptomatic medicine for cancer patients. Furthermore, the project can create important seeds for research and development in cancer medicine. PMID- 25743348 TI - [Ectopic Adrenocorticotropic Hormone-producing Pulmonary Carcinoid Tumor Presenting as Cushing Syndrome]. AB - The patient was a 57-year-old female who felt muscle weakness and visited a physician. Hypokalemia was pointed out, and she was referred to our hospital for detailed examination and treatment. Hormone-related tests and imaging were performed, and the patient was diagnosed as Cushing syndrome. Moreover, an ectopic adrenocorticotropic hormone (ACTH)-producing tumor was suspected. The whole body was examined to find a tumor, but no apparent lesion was found, except for a small nodule of 5-mm in size was present in the right middle pulmonary lobe on chest computed tomography (CT). It was decided to perform surgical resection for both diagnosis and treatment. Pathological diagnosis was a typical carcinoid. On immunostaining, ACTH-positive cells were detected, and the lesion was definitely diagnosed as an ectopic ACTH-producing tumor. Since the ACTH level after surgery returned to normal, the lesion was concluded to be completely excised. PMID- 25743349 TI - [W-shaped Resection and Suture of the Posterior Mitral Leaflet in a Patient with Barlow's Disease]. AB - A 72-year-old female presented with congestive heart failure. Ultrasound cardiogram revealed billowing mitral leaflets and severe mitral regurgitation. We diagnosed her with Barlow's disease and performed mitral valve repair. The posterior leaflet was large, and the leaflet height was more than 26 mm. Leaflet height reduction was necessary in order to prevent systolic anterior movement (SAM). The middle scallop was resected in a" W" shape, and its center vertex was designed to have a height of 18 mm, which was the final height of the posterior leaflet. SAM and major leaks were not seen by transesophageal echocardiography after weaning the patient from cardiopulmonary bypass. The use of a W-shaped resection is a simple technique that can be used to reduce the volume and height of the posterior mitral leaflet. PMID- 25743350 TI - [Mitral valve replacement for a manifesting carrier of duchenne muscular dystrophy]. AB - Duchenne muscular dystrophy (DMD) is an X-linked disease, but female carriers infrequently have some symptoms, who are called manifesting carriers. Here we report a case of a manifesting carrier of DMD with skeletal muscle weakness and cardiac abnormalities such as deterioration of cardiac function and left ventricular dilatation, who successfully underwent cardiac surgery. A 79-year-old female with acute heart failure for severe mitral regurgitation was admitted to our hospital. Surgical replacement of the mitral valve was performed under general anesthesia with intravenous anesthetics and non-depolarizing muscle relaxant. Cardiac surgery on a manifesting carrier of DMD is rare and requires a careful preoperative assessment of the heart function and anesthetic management. PMID- 25743351 TI - [Thoracic and abdominal and limb wounds by gun shot]. AB - In Japan, we are permitted to own fire arms only for hunting and clay pigeon shooting, but gunshot wound victims have neen rarely seen due to the strict laws against owing guns, and the lack of related crimes. Therefore, surgeons should be familiar with ballistics, practical gunshot wound management, and the possibility of delayed lead poisoning ssociated with bullet residue. A 69-year-old man was brought to our hospital because he was accidentally shot by his companion's shotgun during hunting. On admission, although he had stable vital sign and multiple gunshot wounds on his right forearm and femur, chest X-ray and computed tomography (CT) revealed a few of bullets and its flagments on his back, into spleen and pericardium. Following local debridment after removal of the bullets in his right forearm and femur at an emergency room, broken heart muscle and diaphragm were repaired and hematoma in the anterior mediastinum was removed at the operating room. The patient was discharged on the 25th post-operative day and his post-operative course was uneventful. In case of gunshot injuries, in addition to prompt diagnosis and evaluation of organ injuries, careful follow up for possible delayed lead poisoning is important. PMID- 25743352 TI - [Valve Replacement for Tricuspid Valve Regurgitation due to Pacemaker Lead Adherence;Report of Two Cases]. AB - We experienced tricuspid valve regurgitation (TR) due to pacemaker lead adherence in an 81-year-old woman and in a 68-year-old woman, who both had right heart failure. The cause of TR was deformation of the tricuspid valve by pacemaker leads. Because of strong adherence between the lead and the leaflet or the tendinous cord, lead extraction and valve replacement were performed. The living lead was preserved by fixation at the septum wall outside the valve cuff in 1 patient. In the other patient, the epicardial lead was used for implantation because it was easier compared to intravenous lead implantation. The heart failure and TR improved after the operation in both patients. PMID- 25743353 TI - [Repair of Cardiac and Pulmonary Damage caused by Stabbing with a Kitchen Knife;Report of a Case]. AB - A 51-year-old woman was stabbed in the chest with a kitchen knife. Twenty minutes after arrival at our hospital by ambulance, she was transferred to the operating room, and a cardiopulmonary bypass was established from the right femoral artery and vein, and a median sternotomy was performed. The knife had damaged the surface of the heart and penetrated the lingular segment of the left lung. Both wounds were directly sutured. Chest X-rays taken after closing the chest showed bleeding in the left lung probably because of the administration of heparin. Bleeding was controlled by lingulectomy. The postoperative course was uneventful. PMID- 25743354 TI - [Traumatic injury of the proximal aortic arch after blunt chest trauma;report of a case]. AB - We report a rare case of an proximal aortic arch injury caused by blunt chest trauma. A 48-year-old woman was transferred to our hospital because of traffic accident. Computed tomography (CT) showed a small ulcer-like projection (ULP) at the proximal part of the aortic arch. An elective surgery for aortic repair was performed because of significant enlargement of the ULP in the aortic arch revealed by follow-up CT. The patient's postoperative course was uneventful, and she was discharged on the 14th postoperative day. PMID- 25743355 TI - [Surgical treatment for aortic valve endocarditis combined with bacterial meningitis and vertebral osteomyelitis;report of a case]. AB - A 59-year-old man was referred to our hospital with disturbance of consciousness. Bacterial meningitis was diagnosed by a spinal tap, and penicillin sensitive Streptococcus pneumonia was detected by blood culture. Magnetic resonance imaging revealed a vertebral osteomyelitis. Treatment with antibiotics was started immediately. Four days after admission, congestive heart failure suddenly occurred. Echocardiography showed mobile vegetation on the aortic valve, and severe regurgitation. As acute heart failure could not be controlled, the aortic valve was replaced by ATS 22AP valve on the 7th day after admission. Antibiotic therapy was continued for 8 weeks. The postoperative course was uneventful. PMID- 25743356 TI - [Surgical treatment for pseudoaneurysm of the sinus of valsalva ruptured into the right atrium after mycotic right coronary artery aneurysm repair;report of a case]. AB - A 67-year-old man was admitted to our hospital by ambulance after syncope due to complete A-V block. He had received surgical treatment for mycotic aneurysm of the right coronary artery 3 months before, with patch plasty of the right sinus of Valsalva and bypass grafting to the right coronary artery (RCA) as well as the left anterior descending branch. Computed tomography revealed pseudoaneurysm of the right Valsalva sinus of about 8 cm in diameter and a shunt flow to the right atrium. The previous bypass graft to RCA had been occluded due to compression by the aneurysm. As he was in a shock state, emergency operation was performed. Cardiopulmonary bypass was first established, and after the rectal temperature reached to 26 degrees centigrade, the chest was opened. The pseudoaneurysm burst out when the sternum was re-opened. Under circulatory arrest, the ascending aorta was clamped, and then the circulation was resumed. The previous bovine pericardium patch repairing the Valsalva sinus was detached due to infection, and mural thrombus and pus were observed in the aneurysm. At the bottom of the aneurysm, a fistula connected to the right atrium was found. Debridement around the aneurysm was performed as much as possible. The defect of the Valsalva sinus was repaired with a Dacron patch immersed in gentian violet. The postoperative course was uneventful without any recurrence of infection. PMID- 25743357 TI - [Valve replacement after omentum flap for medicastinitis;report of a case]. AB - A 71-year-old woman presented with heart failure due to aortic and mitral valve regurgitation. She had developed midiastinitis and graft infection, 15 months before, following replacement of the ascending aorta for acute aortic dissection. Omentum flap operation had been performed and the infection had been controlled. This time, she underwent re-thoracotomy, and replacement of ascending aorta, aortic valve replacement and mitral valve plasty were performed. The omenal tissue was exfoliated without any damage to the heart or the great vessels by using an ultrasonic scalpel. As the omental tissue was viable, it was placed back in the mediastinal space. PMID- 25743358 TI - [Adult congenital aortic coarctaion;report of a case]. AB - A 63-year-old man with a history of hypertension from 20-year-old complained of dyspnea on effort. He was diagnosed as an adult congenital aortic coarctaion by computed tomography (CT). The CT showed the many collaterals from the subclavian artery, the internal thoracic artery and the intercostal artery to the descending aorta. The coarctation was totally replaced with prosthetic graft through 3rd left thoracotomy under partial cardiopulmonary bypass. The operation was successful and the postoperative course was uneventful. To avoid postoperative paradoxical hypertension, total prosthetic replacement is preferable. PMID- 25743359 TI - [Successful management of nonocclusive mesenteric ischemia after aortic valve replacement;report of a case]. AB - Non-occlusive mesenteric ischemia (NOMI) is a fatal complication after cardiovascular surgery, but early diagnosis is difficult because the clinical symptoms are not specific. We report a case of NOMI with successful management due to early diagnosis and treatment. A 78-year-old male complained of sudden abdominal pain after aortic valve replacement. NOMI was suspected because his laboratory work-up showed elevated serum transaminase, and computed tomography showed no mesenteric artery obstruction. We started a continuous intravenous infusion of prostaglandin E1, and performed emergency arterial angiography. Since angiography showed vasospasm of the mesenteric artery, we also started a continuous intra-arterial infusion of papaverine. Each vasodilator drug was started within a few hours after the onset of NOMI. His subsequent hospital course was uneventful, and he was discharged without enterectomy or fatal intestinal necrosis. PMID- 25743360 TI - [Successful Primary Endovascular Repair for Aortoesophageal Fistula due to Ruptured Tuberculous Pseudoaneurysm of the Thoracoabdominal Aorta;Report of a Case]. AB - We report a successful case of 50-year-old woman with aortoesophageal fistula due to tuberculous pseudoaneurysm of the thoracoabdominal aorta. We underwent endovascular repair with stent graft. Her clinical course improved without additional surgical repair or postoperative complications. The patient remains well at 3-year follow-up. PMID- 25743361 TI - [Incidentally detected bronchial artery aneurysm with combined operation for mitral regurgitation;report of a case]. AB - A 77-year-old woman was admitted to the hospital for heart failure with orthopnea. Echocardiography revealed massive mitral regurgitation. During preoperative cardiac catheterization, an aneurysm was indentified incidentally just below the tracheal carina. Three dimensional computed tomography showed three bronchial artery aneurysms behind the pulmonary artery and the left atrium. The proximal aneurysm was the largest and was 22 mm in diameter. It was resected by retracting the ascending aorta to the left, the superior vana cava to the right and right pulmonary artery cranially under cardiopulmonary bypass, and mitral valve plasty was performed. We believed that resection of the proximal aneurysm would cause thrombotic occlusion of the other 2 aneurysms. Bronchial artery aneurysm is a rare entity that is observed in fewer than 1% of those who undergo selective bronchial arteriography. In addition, because bronchial artery aneurysm is a potentially life-threatening lesion, it should be treated promptly when diagnosed. PMID- 25743362 TI - [Infectious endocarditis complicated with preoperative infectious intracranial aneurysm;report of a case]. AB - A 44-year-old man was admitted with the diagnosis of active infective endocarditis( IE) due to Streptococcus mitis, complicated with infectious intracranial aneurysm. Preoperative echocardiography showed mobile vegetation on the mitral leaflet, size of which was 20 mm. The magnetic resonance imaging( MRI) demonstrated that the size of aneurysm was increasing, and infectious intracranial aneurysm was treated surgically. Twenty one days after the operation, the mitral valve plasty was performed. He was discharged on foot without any neurological findings. The duration between the brain surgery and the cardiac surgery was thought to be important to prevent the new neurological complication. PMID- 25743363 TI - [Preoperative spontaneous regression of type B3 thymoma;report of a case]. AB - A 65-year-old man experiencing chest oppression was admitted to our hospital. Contrast-enhanced chest computed tomography (CT) showed a 71*52-mm cystic mass with an enhanced wall in the thymus. The CT-guided needle biopsy of the tumor only revealed the presence of necrotic tissue. However, the tumor spontaneously decreased in size significantly to 33*21 mm in 2 months. The patient underwent right hemi-lobectomy of the thymus, which showed necrotic tissue in the center of the mass;the fibrotic cystic wall included several masses of type B3 thymoma cells( so called" well-differentiated thymic carcinoma", Masaoka stage II). Because of avoiding local recurrence, extended thymectomy including lymph node resection was additionally performed. The patient received radiation therapy postoperatively and has shown no sign of recurrence in 3 years of follow-up care. PMID- 25743364 TI - [Wide resection of chest wall for intramuscular lipoma in serratus anterior muscle reconstructed by autologous tissue;report of a case]. AB - A 60-years-old man with a right lateral chest wall mass visited our hospital. There was a mass of 50*45 mm on the 5th rib. The mild atypical cells were detected by the percutaneous needle biopsy, and the tumor was resected with the chest wall of which detect was reconstructed with fascia lata and latissimus dorsi muscle cutaneous flap. Pathological diagnosis was lipoma in the serratus anterior muscle. The postoperative course was uneventful without paradoxical respiration and surgical site infection. Since intramuscular lipoma is very rare and is reported to have a risk of recurrence, careful observation is necessary. PMID- 25743365 TI - Evaluation of potential internal references for quantitative real-time RT-PCR normalization of gene expression in red drum (Sciaenops ocellatus). AB - Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) has been used extensively for studying gene expression in diverse organisms including fish. In this study, with an aim to identify reliable reference genes for qRT-PCR in red drum (Sciaenops ocellatus), an economic fish species, we determined the expression stability of seven housekeeping genes in healthy and bacterium-infected red drum. Each of the selected candidate genes was amplified by qRT-PCR from the brain, gill, heart, intestine, kidney, liver, muscle, and spleen of red drum infected with or without a bacterial pathogen for 12 and 48 h. The mRNA levels of the genes were analyzed with the geNorm and NormFinder algorithms. The results showed that in the absence of bacterial infection, translation initiation factor 3, NADH dehydrogenase 1, and QM-like protein may be used together as internal references across the eight examined tissues. Bacterial infection caused variations in the rankings of the most stable genes in a tissue dependent manner. For all tissues, two genes sufficed for reliable normalization at both 12 and 48 h post-infection. However, the optimal gene pairs differed among tissues and, for four of the examined eight tissues, between infection points. These results indicate that when studying gene expression in red drum under conditions of bacterial infection, the optimal reference genes should be selected on the basis of tissue type and, for accurate normalization, infection stage. PMID- 25743366 TI - Spectroscopic identification of an Fe(III) center, not Fe(IV), in the crystalline Sc-O-Fe adduct derived from [Fe(IV)(O)(TMC)]2+. AB - The apparent Sc(3+) adduct of [Fe(IV)(O)(TMC)](2+) (1, TMC = 1,4,8,11-tetramethyl 1,4,8,11-tetraazacyclotetradecane) has been synthesized in amounts sufficient to allow its characterization by various spectroscopic techniques. Contrary to the earlier assignment of a +4 oxidation state for the iron center of 1, we establish that 1 has a high-spin iron(III) center based on its Mossbauer and EPR spectra and its quantitative reduction by 1 equiv of ferrocene to [Fe(II)(TMC)](2+). Thus, 1 is best described as a Sc(III)-O-Fe(III) complex, in agreement with previous DFT calculations (Swart, M. Chem. Commun. 2013, 49, 6650.). These results shed light on the interaction of Lewis acids with high-valent metal-oxo species. PMID- 25743367 TI - Effects of adjunctive exercise on physiological and psychological parameters in depression: a randomized pilot trial. AB - OBJECTIVE: Major depressive disorder (MDD) is associated with decreased physical activity and increased rates of the metabolic syndrome (MetS), a risk factor for the development of type 2 diabetes and cardiovascular disorders. Exercise training has been shown to improve cardiorespiratory fitness and metabolic syndrome factors. Therefore, our study aimed at examining whether patients receiving an exercise program as an adjunct to inpatient treatment will benefit in terms of physiological and psychological factors. METHOD: Fourty-two inpatients with moderate to severe depression were included. Twenty-two patients were randomized to additional 3x weekly exercise training (EXERCISE) and compared to treatment as usual (TAU). Exercise capacity was assessed as peak oxygen uptake (VO2peak), ventilatory anaerobic threshold (VAT) and workload expressed as Watts (W). Metabolic syndrome was defined according to NCEP ATPIII panel criteria. RESULTS: After 6 weeks of treatment, cardiorespiratory fitness (VO2peak, VAT, Watt), waist circumference and HDL cholesterol were significantly improved in EXERCISE participants. Treatment response expressed as >=50% MADRS reduction was more frequent in the EXERCISE group. CONCLUSIONS: Adjunctive exercise training in depressed inpatients improves physical fitness, MetS factors, and psychological outcome. Given the association of depression with cardiometablic disorders, exercise training is recommended as an adjunct to standard antidepressant treatment. PMID- 25743368 TI - A systematic review of the efficacy of cognitive behavioral therapy for treating and preventing perinatal depression. AB - BACKGROUND: Cognitive behavioral therapy (CBT) is an empirically supported treatment for treating and preventing depression that has been widely studied in perinatal populations. Previous meta-analytic reviews of CBT interventions in this population have not investigated potential moderators of treatment efficacy specific to this type of therapy. METHOD: Forty randomized and quasi-randomized controlled trials assessing the efficacy of CBT during pregnancy and the first year postpartum were included in the meta-analyses. Change in depressive symptoms from pre-treatment to post-treatment was assessed in both treatment and prevention trials, and the difference in prevalence of postpartum depressive episodes was assessed in prevention trials. Characteristics of included studies, interventions and samples were assessed as potential moderators of effect sizes. RESULTS: CBT interventions resulted in significant reductions in depressive symptoms compared to control conditions in both treatment and prevention studies. In prevention studies, individuals who received CBT had significantly lower rates of postpartum depressive episodes compared to control conditions. In both treatment and prevention trials, interventions initiated during the postpartum period were more effective than antenatal interventions. In prevention trials, individually-administered treatments were more effective than group interventions and greater reductions in depressive symptoms were found in studies that included higher proportions of nonwhite, single, and multiparous participants. LIMITATIONS: The methodological quality of included studies varied widely among studies eligible for inclusion in the meta-analysis. CONCLUSIONS: There is strong evidence that CBT interventions are effective for treating and preventing depression during the perinatal period. Further methodologically rigorous studies are needed to further investigate potential moderators of treatment efficacy. PMID- 25743369 TI - Postoperative evaluation of drill holes for arthroscopic Bankart repair with suture anchors by the use of computed tomography. AB - BACKGROUND: Here we investigated the angle and placement of bone holes for suture anchors using postoperative computed-tomography scapula scans. METHODS: The study group comprised 20 shoulders from 20 consecutive patients (13 males and seven females; mean age 23.4 years) who underwent arthroscopic Bankart repair. All anchors were inserted through the anterior portal after establishing a bone hole at the edge of the glenoid articular surface using a drill. Computed tomography images of the scapula were taken 1 month postoperatively and used to create three dimensional scapula models with Mimics and Magics software. Bone holes in the anterior-inferior (3:00-6:00) position were assigned either to the non-perforated group if they were positioned entirely inside the glenoid bone or to the perforated group if the far cortex of the glenoid was penetrated by the drill. The angle between the glenoid articular surface and the bone hole was measured in the oblique coronal and transverse plane views. The length of the bone hole was also assessed. RESULTS: Of the 85 bone holes investigated, 42 were in the 3:00 6:00 position. Perforation was detected in 16 of these 42 holes (38.2%). The angle in the oblique coronal plane view and the length of the bone hole were significantly larger in the non-perforated group than in the perforated group; however, the angle in the transverse plane view did not significantly differ between the two groups. CONCLUSIONS: Before inserting an implant in the anterior inferior area, the angle between the drill guide and the glenoid surface in the oblique coronal plane view should be carefully checked to ensure that the length of the hole inside the glenoid bone is adequate. PMID- 25743370 TI - Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner. AB - PURPOSE: Uroguanylin (UGN) is a 16 amino acid peptide produced mainly by intestinal epithelial cells. Nutrients intake increases circulating levels of prouroguanylin that is processed and converted to UGN to activate the guanylyl cyclase 2C receptor (GUCY2C). Given that the UGN-GUCY2C system has been proposed as a novel gut-brain endocrine axis regulating energy balance, the aim of the present study was to investigate the regulation of UGN protein levels in duodenum and circulating levels in lean and obese mice under different nutritional conditions and its potential interaction with leptin. METHODS: Swiss, C57BL/6 wild-type and ob/ob male adult mice under different nutritional conditions were used: fed ad libitum standard diet (control); 48 h fasting (fasted); 48 h fasting followed by 24 h of feeding (refed); and fed high-fat diet (45 %) during 10 weeks. In addition, peripheral leptin administration was performed. Intestinal uroguanylin expression was studied by Western blot analysis; plasma levels were measured by ELISA. RESULTS: Food deprivation significantly reduced plasma UGN levels, which were correlated with the lower protein levels of UGN in duodenum. These effects were reverted after refeeding and leptin challenge. Consistently, in ob/ob mice UGN expression was decreased, whereas leptin treatment up-regulated UGN levels in duodenum in these genetically modified mice compared to WT. Diet induced obese mice displayed increased UGN levels in intestine and plasma in comparison with lean mice. CONCLUSIONS: Our findings suggest that UGN levels are correlated with energy balance status and that the regulation of UGN by nutritional status is leptin-dependent. PMID- 25743372 TI - Mitochondria: key players in the neurotoxic effects of amphetamines. AB - Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers. PMID- 25743371 TI - Childhood emotional abuse, negative emotion-driven impulsivity, and alcohol use in young adulthood. AB - Childhood emotional abuse has been linked to problematic alcohol use in later life but there is a paucity of empirically based knowledge about the developmental pathways linking emotional abuse and alcohol use in young adulthood. Using a community sample of young individuals aged 18-25 (N=268; female 52%), we performed structural equation modeling to investigate whether emotional abuse influences alcohol use through urgent personality trait and to determine pathways for these effects in a multivariate context. We also examined variations in these pathways by four different alcohol use outcomes including frequency of alcohol use, binge drinking, alcohol-related problems, and alcohol use disorders (AUD). The present study found that emotional abuse was related to urgency, which in turn influenced four types of alcohol use. Urgency may play a significant role in linking childhood maltreatment to alcohol use in young adulthood. PMID- 25743373 TI - Resolving pathways of interaction of mipafox and a sarin analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches. AB - The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here, our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF/TOF. The ACP was detected with a diethyl-phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl-phosphonylated and a methyl-phosphonylated adduct after Flu MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diisopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However, with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand calculated in modeling was lower and, consequently, aging appeared as a more likely reaction. We document here direct evidence for a phosphorylated hAChE refractory to oxime reactivation, although we observed no aging. PMID- 25743374 TI - Perfluorooctanoic acid disrupts the blood-testis barrier and activates the TNFalpha/p38 MAPK signaling pathway in vivo and in vitro. AB - Perfluorooctanoic acid (PFOA) is correlated with male reproductive dysfunction in animals and humans, but the underlying mechanisms for this remain unknown. To explore the potential reproductive toxicity of PFOA, we studied blood-testis barrier (BTB) damage using in vivo and in vitro models. Male mice were gavage administered PFOA (0-20 mg/kg/d) for 28 consecutive days, and breeding capacity and permeability of the Sertoli cell-based BTB were estimated. Primary Sertoli cells (SCs) were exposed to PFOA (0-500 MUM) for 48 h, and transepithelial electrical resistance (TER) was assessed. Furthermore, BTB-associated protein expression, TNFalpha content, and phosphorylation and protein levels of the mitogen-activated protein kinase (MAPK) pathway were detected. An apparent decrease in mated and pregnant females per male mouse as well as litter weight was observed. Marked BTB damage was evidenced by increased red biotin fluorescence in the lumen tubular of the testes and the decrease in TER in SCs in vitro. The protein levels of claudin-11, connexin-43, N-cadherin, beta-catenin, and occludin were significantly decreased in the testes and also in the SCs in vitro except for N-cadherin and beta-catenin. TNFalpha content showed a dose dependent increase in the testes and a dose- and time-dependent increase in the SCs, with the p-p38/p38 MAPK ratio also increasing in testes and SCs after PFOA exposure. Moreover, PFOA altered expressions of claudin-11, connexin-43, TNFalpha, and p-p38 MAPK were recovered 48 h after PFOA removal in the SCs. The SCs appeared to be target to PFOA, and the disruption of the BTB may be crucial to PFOA-induced reproductive dysfunction in mice. PMID- 25743375 TI - Hepatitis C virus structural proteins can exacerbate or ameliorate acetaminophen induced liver injury in mice. AB - Chronic hepatitis C virus (HCV) infection predisposes patients to develop liver failure after acetaminophen (APAP) overdose. Mechanisms involved in this were explored using transgenic mice expressing the HCV structural proteins core, E1 and E2. Treatment of C57BL/6J mice with 200 mg/kg body weight APAP resulted in significant liver injury at 6 h as indicated by elevated ALT levels, focal centrilobular necrosis and nuclear DNA fragmentation. HCV transgenic mice showed a variable response, with approximately half the animals showing exacerbation of all parameters of liver injury, while the other half was protected. HCV transgenic mice with higher liver injury had lower liver glutathione levels, elevated mitochondrial oxidative stress and enhanced release of apoptosis inducing factor (AIF) from the mitochondria. This was accompanied by induction of a higher ER stress response and induction of autophagy. Transgenic animals showing protection against liver injury had a robust recovery of liver glutathione content at 6 h when compared to wild-type animals, accompanied by reduction in mitochondrial oxidative stress and AIF release. This was accompanied by an elevation in glutathione S-transferase mRNA levels and activity, which suggests that an efficient clearance of the reactive intermediate may contribute to the protection against APAP hepatotoxicity in these mice. These results demonstrate that while HCV infection could exacerbate APAP-induced liver injury due to induction and amplification of mitochondrial oxidant stress, it could also protect against injury by activation of APAP scavenging mechanisms. PMID- 25743376 TI - The impact of treatment with indacaterol in patients with COPD: A post-hoc analysis according to GOLD 2011 categories A to D. AB - BACKGROUND: Indacaterol is an inhaled, once-daily, ultra-long-acting beta2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). We report on the effectiveness of indacaterol and other bronchodilators compared with placebo in patients across the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 categories A to D. METHODS: A post-hoc, subgroup pooled analysis of 6-month efficacy data from three randomized, placebo-controlled, parallel-group studies involving 3862 patients was performed across GOLD 2011 categories A to D, according to baseline forced expiratory volume in 1 s (FEV1) % predicted, modified Medical Research Council (mMRC) dyspnea scale, and exacerbation history in the 12 months prior to entry. Efficacy of once-daily indacaterol 150 and 300 MUg, open-label tiotropium 18 MUg, twice-daily salmeterol 50 MUg, and formoterol 12 MUg was compared with placebo. End points analysed were trough FEV1, transition dyspnea index (TDI), and St George's Respiratory Questionnaire (SGRQ) total score, all at Week 26, and mean rescue medication use over 26 weeks. RESULTS: Indacaterol 150 and 300 MUg significantly improved FEV1, compared with placebo across all GOLD groups. Indacaterol 150 and 300 MUg also significantly improved TDI, SGRQ total score, and mean rescue medication use compared with placebo across most GOLD subgroups. CONCLUSIONS: Treatment selection according to patient's symptoms as well as lung function is an important consideration in maintenance treatment of COPD. Indacaterol 150 and 300 MUg effectively improved lung function and symptoms in patients across all GOLD 2011 categories. PMID- 25743377 TI - Origin of 1/f noise in hydration dynamics on lipid membrane surfaces. AB - Water molecules on lipid membrane surfaces are known to contribute to membrane stability by connecting lipid molecules and acting as a water bridge. Although water structures and diffusivities near the membrane surfaces have been extensively studied, hydration dynamics on the surfaces has remained an open question. Here we investigate residence time statistics of water molecules on the surface of lipid membranes using all-atom molecular dynamics simulations. We show that hydration dynamics on the lipid membranes exhibits 1/f noise. Constructing a dichotomous process for the hydration dynamics, we find that residence times in each state follow a power-law with exponential cutoff and that the process can be regarded as a correlated renewal process where interoccurrence times are correlated. The results imply that the origin of the 1/f noise in hydration dynamics on the membrane surfaces is a combination of a power-law distribution with cutoff of interoccurrence times of switching events and a long-term correlation between the interoccurrence times. These results suggest that the 1/f noise attributed to the correlated renewal process may contribute to the stability of the hydration layers and lipid membranes. PMID- 25743378 TI - Lymphnodal Co-infection of Cryptococcus and Histoplasma in a HIV-Infected Patient and Review of Published Reports. AB - Human infection with Histoplasma capsulatum and Cryptococcus runs the gamut from asymptomatic illness to disseminated disease. Though both are the most prevalent systemic mycoses in HIV-infected patients, simultaneous infection by both the pathogens rarely occurs. We document the first case from Asian subcontinent with concurrent infection with disseminated cryptococcosis and histoplasmosis infections in a HIV-infected Indian patient diagnosed by morphological examination of fine-needle aspiration cytology samples obtained from the enlarged lymph nodes on light microscopy and were later confirmed by culture studies. A prompt, accurate and timely diagnosis of the disseminated form of dual mycosis (or either of the mycosis as well) is of utmost importance which has obvious impact on early initiation of treatment. Fine-needle aspiration cytology is a rapid, cost-effective and reliable method to identify infection with Cryptococcus and Histoplasma and is comparable with the essential culture studies. PMID- 25743379 TI - Identification of SHIP-1 and SHIP-2 homologs in channel catfish, Ictalurus punctatus. AB - Src homology domain 2 (SH2) domain-containing inositol 5'-phosphatases (SHIP) proteins have diverse roles in signal transduction. SHIP-1 and SHIP-2 homologs were identified in channel catfish, Ictalurus punctatus, based on sequence homology to murine and human SHIP sequences. Full-length cDNAs for catfish SHIP-1 and SHIP-2 (IpSHIP-1 and IpSHIP-2) were obtained using 5' and 3' RACE protocols. Catfish SHIP molecules share a high degree of sequence identity to their respective SHIP sequences from diverse taxa and both are encoded by single copy genes. IpSHIP-1 and IpSHIP-2 transcripts were expressed in all catfish tissues analyzed except for skin, and IpSHIP-1 message was more abundant than IpSHIP-2 message in lymphoid tissues. Catfish clonal B, cytotoxic T, and macrophage cell lines also expressed message for both molecules. IpSHIP-1 and IpSHIP-2 SH2 domains were expressed as recombinant proteins and were both found to be bound by cross-reacting rabbit anti-mouse SHIP-1 pAb. The anti-mouse SHIP-1 pAb also reacted with cell lysates from the cytotoxic T cell lines, macrophages and stimulated PBL. SHIP-1 is also phosphorylated at a conserved tyrosine residue, as shown by immunoprecipitation studies. PMID- 25743380 TI - Immune response of peroxinectin of Chinese mitten crab Eriocheir sinensis to exterior stimulation. AB - Peroxinectin possesses the features of both peroxidase activity and adhesive property and plays important roles in innate immune system of crustaceans. In this study, the sequence of peroxinectin of Eriocheir sinensis (EsPX) was analyzed and its expression in response to exterior stimulation was detected in both in vivo and in vitro examination. We showed that the full-length cDNA sequence was composed of 2701 bp and owned a molecular mass of 85.2 kDa and a theoretical pI (isoelectric point) of 6.91. Real-time PCR revealed that the EsPX was mainly distributed in the muscle, hemocytes and stomach. Furthermore, the EsPX was verified to be located in hyalinocytes, semigranulocytes and granulocytes, and was distributed throughout the cytoplasm and nucleus, especial in cytoplasm. After injected with beads, lipopolysaccharide (LPS) and Aeromonas hydrophila, the EsPX mRNA expression was significantly up-regulated and peaked up at 4, 2 and 16 h respectively (P <0.05). In the in vitro experiment, the stimulation of LPS and beads also induced a prominent boost of EsPX protein in primary cultured hemocytes. The expression of EsPX was peaked up at 4 and 8 h for LPS and beads challenged groups respectively, followed by remarkable release of the incremental EsPX into the extracellular matrix. These findings suggested that the expression of EsPX was susceptible to exterior stimulation, and that the highly expressional EsPX would be released into extracellular matrix by the exterior stimulus. PMID- 25743381 TI - The distribution of lymphoid cells in the small intestine of germ-free and conventional piglets. AB - Porcine ileum is populated with a high proportion of B cells but previous studies have shown that they are not developed there. While B cells prevail in the ileum even in germ-free animals, microbial colonization is a major factor that causes even a greater prevalence of B cells in the ileum and further differential representation of lymphoid cells throughout small intestine. Analysis of lymphoid subpopulations showed that the effector cells appear only after colonization. These include class-switched IgM(+)IgA(+) B cells, primed CD2(-)CD21(+) B cells, antibody-producing/memory CD2(+)CD21(-) B cells, and effector/memory CD4(+)CD8(+) alphabeta Th cells. While colonization resulted in a uniform distribution of effector cells throughout the gut, it caused a decrease in the frequency of cytotoxic alphabeta and CD2(+)CD8(+) gammadelta T cells. These results suggest that the ileum is a site where naive B cells expand presumably to increase antibody repertoire but the entire small intestine is immunofunctionally comparable. PMID- 25743382 TI - [Application of electron spin resonance spectroscopy for the detection of irradiated crustaceans (prawn, shrimp, and crabs)]. AB - Prawn, shrimp and crabs sold in Japan are mostly imported from overseas. Detection of irradiated crustaceans is very important for quality assurance. In this study, we used ESR to detect radiation-induced radicals after irradiation of prawn, shrimp and crabs of major species. No radiation-induced radicals were detected in prawn (black tiger prawn) or shrimp (white leg shrimp). Radiation induced radicals due to hydroxyapatite were detected in the claws of snow crab, red king crab, and swimming crab. Our results indicate that ESR measurement on the claw parts of these three species of crab can be used to determine their irradiation history. PMID- 25743383 TI - Development and validation of an event-specific quantitative PCR method for genetically modified maize MIR162. AB - A novel real-time PCR-based analytical method was developed for the event specific quantification of a genetically modified (GM) maize event, MIR162. We first prepared a standard plasmid for MIR162 quantification. The conversion factor (Cf) required to calculate the genetically modified organism (GMO) amount was empirically determined for two real-time PCR instruments, the Applied Biosystems 7900HT (ABI7900) and the Applied Biosystems 7500 (ABI7500) for which the determined Cf values were 0.697 and 0.635, respectively. To validate the developed method, a blind test was carried out in an interlaboratory study. The trueness and precision were evaluated as the bias and reproducibility of relative standard deviation (RSDr). The determined biases were less than 25% and the RSDr values were less than 20% at all evaluated concentrations. These results suggested that the limit of quantitation of the method was 0.5%, and that the developed method would thus be suitable for practical analyses for the detection and quantification of MIR162. PMID- 25743384 TI - [Formation of trans-1,3-pentadiene in off-flavor food]. AB - The purpose of the present study is to investigate the production of trans-1,3 pentadiene in a sorbic acid-containing food which was the subject of a complaint that it was off-flavor. Penicillium sp. was isolated from the off-flavor food. The isolated Penicillium sp. was identified as Penicillium chrysogenum by DNA sequencing of the internal transcribed spacer region and the D1/D2 region of the 28S subunit. When P. chrysogenum was cultured in the presence of potassium sorbate, trans-1,3-pentadiene was produced and detected by GC-MS after solid phase micro extraction. The production of trans-1,3-pentadiene by P. chrysogenum in the culture solution was pH-dependent. These results suggest that the production of trans-1,3-pentadiene in the off-flavor food was mainly due to the decomposition of sorbic acid by P. chrysogenum. PMID- 25743385 TI - [Validation study on a multi-residue method for determination of pesticide residues in agricultural products by new automatic pretreatment equipment (FASRAC) and GC-MS/MS]. AB - A validation study was performed on a multiresidue method for determination of pesticide residues in agricultural products according to the method validation guideline of the Ministry of Health, Labour and Welfare of Japan. FASRAC (Food Automatic Analytical Systems for Residual Agricultural Chemicals) automatically performs extraction of pesticide residues from agricultural products with acetonitrile, filtration, constant volume, mixing with the use of air, mixing acetonitrile with buffer solvent, separation, and dehydration with sodium sulfate. The extract was purified with a GC/NH2 column. For wheat flour and soybeans, a purification step with a C18 column was added before a GC/NH2 column. After removal of the solvent, the extract was resolved in n-hexane/acetone solvent for GC-MS/MS analysis. In the case of manual analysis, pesticide residues were analyzed according to official multiresidue methods and purification steps were the same as in FASRAC. Recovery tests were performed with wheat flour, soybeans, spinach and apples, by addition of 302 pesticides at the concentrations 0.01 mg/kg. The results indicate that automatic extraction using FASRAC is superior to manual analysis in trueness, repeatability and within-run reproducibility. Specially, automatic extraction using FASRAC is superior to manual analysis in trueness because it is optimized in various respects, for example reextraction at salting-out. PMID- 25743386 TI - A case-control study of treatment choices made by doctors diagnosed with early breast cancer. AB - INTRODUCTION: Doctors who are diagnosed with breast cancer form a small subset of women with unique insight into their disease. The aim of this study was to compare key treatment decisions in medically-qualified doctors with equivalent degree-educated, matched controls diagnosed with early breast cancer. METHODS: Patients diagnosed with breast cancer between 01/01/2006 and 31/12/2011 were included and screened for occupation by 2 independent investigators. Allied health professionals with a medical background (e.g. nurses, physiotherapists) were excluded. Patient controls were matched by age, nodal status and grade. If there were more than 5 possible matches then those patients with the closest tumour size were selected. RESULTS: 5259 of 8623 patients had signed the generic research consent form. 619 of these were either doctors, or had received tertiary level education and could form appropriate controls. After exclusions, 46 medically-qualified doctors and 230 matched control patients were included in the analysis. No statistical differences in age or tumour characteristics were identified between doctors with breast cancer and matched controls. No differences were identified between the two groups in the uptake of mastectomy, chemotherapy, immediate breast reconstruction or post-mastectomy radiotherapy. CONCLUSION: Medically-qualified patients diagnosed with early breast cancer are no more likely to opt for mastectomy, chemotherapy, immediate breast reconstruction or post-mastectomy radiotherapy than non-medically-qualified controls. The level of information generally provided to patients with breast cancer is adequate for a similar decision to be made by control patients with equivalent levels of education, independent of any knowledge of pathology or understanding of the medical system that medically-qualified patients may possess. PMID- 25743387 TI - Analysis of prognostic factors of endovascular therapy in 59 patients with acute anterior circulation stroke: a retrospective cohort study - observational. AB - INTRODUCTION: Endovascular therapy (ET) is increasingly used for stroke patients out of the time window, based on the multimodal treatment (MMT) it can be used alone or in combination. The purpose of this study was to assess the outcome of intra-arterial thrombolysis (IAT) and MMT for acute anterior circulation ischemic stroke (ACIS), and reveal prognostic factors of ET in the authors' stroke center. METHODS: A retrospective analysis of the data of 59 patients with ACIS who received ET from 2010 to 2014 in the stroke center was performed. A univariate analysis was conducted to reveal the differences between IAT and MMT, and the distinctions between favorable and unfavorable outcomes, logistic regression analysis was performed to determine the predictors of outcomes. RESULTS: Thirty four patients who accepted MMT had a higher baseline National Institutes of Health Stroke Scale score on admission (18.3 +/- 4.2) compared with 25 patients who were treated with IAT (12.6 +/- 4.3). The MMT group had a higher patent flow (23/34) (thrombolysis in myocardial infarction grade 2-3) compared with the IAT group (10/25). Moreover, the MMT group had a longer time for emergency department (ED) (5.8 +/- 1.4) than the IAT group (5.2 +/- 0.8). In multivariate analysis, age, time to ED, and NIHSS score at discharge are predictors for poor outcome, whereas perfect recanalization was associated with favorable outcome. CONCLUSION: MMT might be suitable for patients with a severe admission NIHSS and a higher patency rate than IAT. Vessel recanalization was the only predictor for favorable outcome. PMID- 25743388 TI - Multimodal treatment of abdominal and pelvic desmoplastic small round cell tumor with relative good prognosis. AB - OBJECTIVE: To investigate the clinicopathologic features and survival outcomes of desmoplastic small round cell tumor (DSCRT). METHODS: The retrospective cohort study was performed on clinical and pathological data of 18 DSCRT patients. Among them, two subgroups were classified according to treatment modalities. 10 cases underwent operation and adjuvant chemotherapy (group 1, 10/18, 55.6%) and 8 cases were diagnosed by fine needle aspiration biopsy without surgical intervention (group 2, 8/18, 44.4%). All cases received six courses of multiple agents chemotherapy. RESULTS: All cases were histologically confirmed as DSRCT and Cox regression revealed that sex, tumor localization and treatment modality affected patient outcomes. Kaplan-Meier analysis revealed that the median survival time was 22.0 +/- 4.0 mo in group 1 versus 9.0 +/- 0.7 mo in group 2. CONCLUSION: DSRCT is highly aggressive malignance with poor prognosis, surgical excision with combination of chemotherapy can significantly improve the survival outcomes. PMID- 25743389 TI - Application of laparoscopy in the combined surgical procedures of gynecological and digestive disorders in obese women: a retrospective cohort study. AB - BACKGROUND: Laparoscopy surgery has been widely used for many decades and combined laparoscopic procedures have become favorable choices for concomitant pathologies in the abdomen. However, the type of combination procedures and their safety in obese women have not been well elucidated in obese women. METHODS: Here we retrospectively reported 147 obese women underwent combined laparoscopic gynecological surgery and cholecystectomy/appendicectomy in our hospital from January 2003 to December 2011. Of the total number of patients (n = 147), various laparoscopic gynecological surgeries were combined with laparoscopic cholecystectomy in 93 patients, and were combined with laparoscopic appendectomy in the rest 54 patients. Patients' ages ranged from 24 to 55 years with an average of 33 years. RESULTS: Our results showed that combined procedures caused various operative time and blood loss, with no difference considering the time to resume oral intake and length of hospital stay. Intraoperative complications occurred in a total of 7 patients (4.8%). None of the patients suffered from major complications after laparoscopic surgery, and minor postoperative complications occurred in 30 patients (20.4%). The follow-up period ranged from 6 to 24 months (average, 18.5 months). None of the patients developed complications during follow-up, except that one patient suffered from colporrhagia. CONCLUSIONS: Our results further suggest that the combined abdominal laparoscopic procedures of gynecologic and general surgery are safe and economic choices for obese women, and benefit patients in many ways including lesser pain, shorter hospital stays and earlier recovery. PMID- 25743391 TI - Impact of pre-transplant antiaggregant and anticoagulant therapies on early hemorrhagic and cardiovascular events after kidney transplantation. AB - BACKGROUND: Oral anticoagulation with vitamin K antagonists (VKA) and antiaggregant therapy (AAT) are common among dialysis patients, but it is not known if they increase the risk of hemorrhagic (HE) or cardiovascular events (CVE) in the early post-transplant weeks. METHODS: We conducted a retrospective analysis on 911 consecutive kidney transplants (KTxs) in order to analyze the impact of AAT and VKA on early HE and CVE-which might be related to their withdrawal-and to identify the main risk factors for these complications. RESULTS: We observed 21/911 HE (2.3%; 1 death, 4 allograft loss); risk factors for HE at multivariate analysis were: KTx before 2004 (when anti-factor Xa activity measurement was not available; odds ratio, OR 5.835, [95% confidence interval, 1.241-27.436], p = 0.026), and VKA (OR 7.090 [2.030-24.772], p = 0.002), while AAT was not a risk factor. CVE were 32/911 (3.5%; 3 deaths, 11 allograft loss): risk factors for CVE at multivariate analysis were: previous cardiovascular events (OR 4.180 [1.615-10.948], p = 0.0032) and cinacalcet use (OR 7.930 [3.002-20.945], p < 0.0001), while neither VKA nor AAT had any impact. CONCLUSIONS: In conclusion, HE and CVE are relatively rare but can be severe, but there are no pre-KTx modifiable risk factors. If an anticoagulant therapy with low molecular weight heparins has to be started soon after surgery, monitoring of anti-Xa activity is highly recommended. PMID- 25743390 TI - The role of the insulin-like growth factor-1 system in breast cancer. AB - IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis. IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies. PMID- 25743392 TI - Editorial overview: Plant biotechnology. PMID- 25743394 TI - The usefulness of discerning patterns. AB - The health care domain is highly fluid, with new developments and discoveries occurring at a steady rate. The announcement that President Barack Obama made in his 2015 State of the Union Address to Congress regarding the launch of a new Precision Medicine Initiative offers an illustration of the considerable interest that exists in achieving greater progress in treating disease. Given such initiatives, it may be worth pondering what impact they will have on the composition of the health workforce. PMID- 25743395 TI - Investigation into health science students' awareness of occupational therapy: implications for interprofessional education. AB - OBJECTIVE: To investigate the level of awareness of the occupational therapy profession among final-year health sciences students at Kuwait University. METHODS: This study utilized a survey targeting final-year students in the Health Sciences Center at Kuwait University schools of medicine, pharmacy, dentistry, and allied health sciences. The survey addressed awareness of occupational therapy, its scope of practice, work environments, and preference for learning more about the profession. RESULTS: Of the 244 surveys distributed, 132 were returned, for a 54% response rate. The proportion of those who knew about occupational therapy ranged from 94% (radiologic science) to a low of 17% (medicine). Most respondents learned about occupational therapy from colleagues (77.1%), rather than from their academic programs (28.1%). RESULTS indicated that about one fifth of students (21.4%) were unsure about the role of occupational therapists as members of the health care team. Preferences for learning more about the profession were consistent with interprofessional opportunities, such as observing an occupational therapy session (64.5%) and attending a workshop (63.6%) or presentation (59.8%). CONCLUSION: Although most respondents had some awareness of occupational therapy, specifics about its scope of practice and relevance to the health care team were lacking. Preferences for learning more about occupational therapy were consistent with the current trend for interprofessional education in health care. Implications for interprofessional education are presented. PMID- 25743393 TI - CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling. AB - The mechanisms governing apical membrane assembly during biological tube development are poorly understood. Here, we show that extension of the C. elegans excretory canal requires cerebral cavernous malformation 3 (CCM-3), independent of the CCM1 orthologue KRI-1. Loss of ccm-3 causes canal truncations and aggregations of canaliculular vesicles, which form ectopic lumen (cysts). We show that CCM-3 localizes to the apical membrane, and in cooperation with GCK-1 and STRIPAK, promotes CDC-42 signalling, Golgi stability and endocytic recycling. We propose that endocytic recycling is mediated through the CDC-42-binding kinase MRCK-1, which interacts physically with CCM-3-STRIPAK. We further show canal membrane integrity to be dependent on the exocyst complex and the actin cytoskeleton. This work reveals novel in vivo roles of CCM-3.STRIPAK in regulating tube extension and membrane integrity through small GTPase signalling and vesicle dynamics, which may help explain the severity of CCM3 mutations in patients. PMID- 25743396 TI - The value of traditional cognitive variables for predicting performance in graduate speech-language pathology programs. AB - BACKGROUND: Student performance on the Praxis examination and in clinical settings is considered indicative of university graduate program quality. Utilization of admission variables most predictive of graduate school performance in speech-language pathology is therefore critical. This study evaluated the relationship between cognitive variables (GRE scores, undergraduate GPA, and course-specific grades) and performance on the Praxis and between the cognitive variables and first-year clinical performance. METHODS: Admissions data for 230 students from four graduate programs in two states were analyzed. Participants were assigned to three groups based on Praxis scores (high performance, moderate performance, low performance/fail) and two groups based on clinical performance (low need supervision, high need supervision). RESULTS: Statistically significant relationships were found between all independent variables and the dependent variables (Praxis scores and first-year clinical performance). Participants' pass fail status on the Praxis was predicted with a high degree of accuracy based on speech-hearing science grades, physical science grades, and the GRE-Total (GRE-T) scores alone. The low need supervision group for clinical performance demonstrated statistically higher group means for GRE-T and GRE-Quantitative (GRE Q) scores compared to the high need supervision group. CONCLUSIONS: The use of the GRE and American Speech-Language-Hearing Association-required science course grades in graduate admissions is warranted. PMID- 25743397 TI - Assessing the effectiveness of a clinical instructor online training module as measured by student perception and sustained best practices. AB - Due to current scrutiny of physical therapy (PT) clinical education, clinical education models require revisions with close examination of current practice, including best practices in clinical instructor (CI) education. Unfortunately, depth of research currently available to support these revisions is minimal, particularly in areas of research that investigate maintaining recently taught skills in CI training and students' perceived CI effectiveness following training. This study's purpose was to explore these areas. CIs (n=21) were assigned to either a control or treatment group. Treatment group-CIs completed an online module prior to supervising a Doctor of Physical Therapy (DPT) student during a 9-week clinical rotation and then participated in data collection activities following the rotation. Data from control group-CIs established a baseline. Data from students' assessments of their CIs' performances yielded qualitative themes demonstrating differentiated learning environments and module taught best practices for treatment group-students. Quantitative findings did not make a distinction between the two student groups. Lastly, treatment group-CIs maintained best practices after an inactive period. This study suggests CIs were able to maintain best practices using just-in-time education, distributed clinical practice, and reflection. By continuing examination of online CI education, PT clinical education can move toward new models through evidence based CI best practices. PMID- 25743398 TI - Using twitter in health professional education: a case study. AB - PURPOSE: The vast majority of health care students, providers, and organizations utilize social media to access and share information. However, there is little research exploring integration of social media into health professional education. This case study describes how the social media site Twitter was used in a first-year physical therapy professionalism course to teach, support, and model professional online communication. METHODS: Twitter was used for discussion and sharing among 36 doctor of physical therapy (DPT) students enrolled in a first-year professionalism course. Participants completed four Twitter assignments. Outcome measures included student surveys of overall social media use, perceptions of Twitter use in the course, Twitter use during the course, and student engagement measured using a subset of questions from the National Survey of Student Engagement (NSSE). OUTCOMES: During the course, students posted a total of 337 tweets (mean 9.36 tweets/student). Pre- and post-course surveys showed an increase in academic and professional social media use. Perception of Twitter use in the course was generally positive. There was a small increase in mean NSSE score that was not statistically significant. DISCUSSION: Using Twitter in a physical therapy professionalism course was a positive experience for students and was associated with increased academic and professional social media use. Future studies are needed to determine whether deliberate teaching of social media as a professional technology competency will result in meaningful increases in professional online engagement and improved digital professionalism in health professional students and providers. PMID- 25743399 TI - A survey of student involvement in the american physical therapy association. AB - PURPOSE: Students in professional programs are influenced to participate in professional associations by faculty, which may have long-term implications for participation and membership. The purpose of this study is to describe the participation of Doctor of Physical of Therapy (DPT) students in the American Physical Therapy Association (APTA). PROCEDURES: Eighty randomly chosen DPT education program directors were asked to forward a survey link to their students. Twenty program directors agreed and 242 students completed the survey. FINDINGS: Over one-half of the respondents were required by their program to be an association member, with 43.7% holding a position and 45.7% reporting conference attendance. Students who were required to be members were equally likely to be involved. Students did not join specialty sections within the organization. CONCLUSIONS: Students are not taking advantage of all the benefits of membership. Requiring student membership does not influence participation in the professional association. PMID- 25743401 TI - Do health professions graduate programs increase diversity by not requiring the graduate record examination for admission? AB - PURPOSE: Seeking to increase the diversity of the health care workforce, prominent national commissions have called on health professions graduate schools to deemphasize standardized tests in admissions. Have programs that do not require standardized tests observed an increase in students from under represented minority groups? METHODS: The websites of the centralized application services for occupational therapy, physical therapy, physician assistant studies, and speech-language pathology programs were reviewed, and programs were identified that do not require the Graduate Record Examination (GRE) for admissions. Representatives were then invited to participate in a hypothesis generating interview. The transcripts were coded using grounded theory to identify emerging themes. STUDY SAMPLE: Faculty and administrators with admissions responsibilities representing 30 graduate programs in the health professions participated. RESULTS: Fewer than one-third of programs in each health profession surveyed do not require the GRE for admission. While test optional programs attract students who might otherwise not apply to graduate school, the lack of a GRE requirement does not automatically increase the representation of under-represented minority students in the matriculated class. The programs most successful in meeting their diversity goals also engage in deliberate recruitment activities. PMID- 25743400 TI - A survey of physical therapists' perception and attitude about sleep. AB - PURPOSE: The purpose of this study was to assess the attitude and perception of physical therapists (PTs) on the perceived need to assess sleep of their patients and provide education about sleep to their patients, as well as to determine the perceived need for PTs to be educated on sleep topics. METHODS: An electronic survey was sent to internship site coordinators. Descriptive analyses and logistic regressions were conducted. RESULTS: The response rate was 28% (n=76). Most respondents (93%) agreed poor sleep is associated with impaired function. Eighty-two percent agreed that PTs should assess patients' sleep habits and sleep quality, and 95% agreed that addressing sleep issues may impact PT outcomes. The majority did not receive education about sleep during entry-level PT education (75%) or following graduation (86%). Most respondents (95%) thought PTs should receive education about sleep. CONCLUSION: PTs recognize that sleep impacts outcomes, and patients' sleep should be assessed. However, PTs have not received education about sleep, although the majority thought PTs should receive education about sleep. Therefore, entry-level PT education programs may consider incorporating education about sleep, and the development of continuing education courses is also needed. PMID- 25743402 TI - A Call for Action: Advocating for Increased Funding for the Allied Health Professions: ASAHP Leadership Development Program. AB - Allied health professionals are a diverse group of health care workers who provide necessary services to patients in addition to, or in place of, services provided by physicians, nurses, and medical paraprofessionals. Two forces generating increased demand for allied health professionals are the aging of the US population and health care reform associated with the implementation of the Patient Protection and Affordable Care Act. Although the allied health professions comprise nearly 60% of the health care workforce, the funding to support workforce training, faculty development, and research in the allied health fields lags substantially behind funding for the physician and nursing professions. Increased advocacy efforts are needed to increase the awareness of what the allied health professions contribute to health care and to expand funding across all health care professions. PMID- 25743403 TI - An emerging pathway for physician assistant employment: podiatric PA. AB - PURPOSE: The physician assistant (PA) profession was created in the mid-1960s to expand access to primary care providers in critical shortage areas. The scope of the profession has evolved since then to include the majority of medical subspecialties. Historically, only allopathic medical doctors and doctors of osteopathic medicine have been allowed to supervise PAs. Podiatric medicine may prove to be another emerging job market if state legislatures will allow doctors of podiatric medicine (DPMs) to supervise PAs. METHODS: A bivariate analysis was done with PAs and DPMs in Tennessee who completed general surveys to assess their level of interest in working with the other and comparing that with the number of years each group had been in practice. RESULTS: Surveys were completed by 217 PAs or PA students and by 25 DPMs. Both groups showed a clear interest for DPMs to be authorized to supervise PAs in the practice of podiatr ic medicine. Eighty percent of PAs and 83% of DPMs responded that their respective state associations should devote funds to support a legislative initiative to permit DPMs to supervise PAs in Tennessee. Sixty-two percent of PAs responded that they would consider working with a DPM, while 80% of DPMs responded that they would hire a PA if given the opportunity. Eighty-eight percent of DPMs surveyed felt that their practice would operate more efficiently if they were able to utilize PAs. CONCLUSIONS: The addition of a PA to podiatric medicine is a logical extension of the PA's role in healthcare, and the inclusion of PAs into the field would help to satisfy the increasing demand for podiatric medical care. PMID- 25743404 TI - Can the communities of practice model explain the complex organization of an interprofessional student-led health clinic? AB - Interprofessional collaborative practice (IPCP) in healthcare has been shown to improve patient safety and healthcare staff satisfaction. However providing opportunities for pre-registration healthcare students to develop the skills required to practise in an interprofessional manner is challenging. Furthermore there is little theory-based literature exploring or describing the organization of these interprofessional student learning opportunities. This paper explores the organization of a student-led interprofessional healthcare clinic using Wenger's Communities of Practice (CoP) model as a framework. It modifies the CoP model to incorporate the routine yet shifting roles of students and patients, and builds on an earlier account of a Community of Clinical Practice (CoCP) by taking a different perspective. The CoCP model could act as a guide for the development of similar student-led interprofessional university clinics. PMID- 25743405 TI - Implementation of simulation-based learning in a physician assistant curriculum. AB - PURPOSE: This article describes the implementation of high-fidelity simulation into the physical diagnosis courses in a Physician Assistant Studies Program and notes the outcomes. METHODS: Six scenarios were developed based on a variety of clinical settings and presentations to complement the didactic education in the physical diagnosis course. Thirty-nine first-year students participated in the simulation labs in addition to the course. Students were given a pre- and post course survey regarding their confidence in evaluating/treating a patient, identifying medical equipment, interpreting physiologic information, responding to changes in a patient's status, and their interest in practicing in acute care. Students were also surveyed following each scenario to assess whether the training was sufficiently realistic, comprehensive, and useful in their training. RESULTS/CONCLUSIONS: The results demonstrated increased confidence levels in all skills assessed at the end of the course as compared to the beginning. Additionally, students strongly agreed that the simulation training was sufficiently realistic, comprehensive, and useful to their training. Interestingly, there appeared to be a decreased interest in practicing in acute care, perhaps due to new/additional exposure to this practice setting. PMID- 25743406 TI - Pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The best reconstruction method for the pancreatic remnant after pancreaticoduodenectomy remains debatable. We aimed to investigate the perioperative outcomes of 2 popular reconstruction methods: pancreaticogastrostomy and pancreaticojejunostomy. DATA SOURCES: Randomized controlled trials comparing pancreaticogastrostomy versus pancreaticojejunostomy were identified from literature databases (MEDLINE/PubMed, EMBASE, Web of Science, Cochrane Library). The meta-analysis included 8 studies: 607 patients who underwent pancreaticogastrostomy and 604 who underwent pancreaticojejunostomy. Postoperative pancreatic fistula and intra-abdominal fluid collection rates were significantly lower after pancreaticogastrostomy compared with pancreaticojejunostomy. No statistically significant differences were found in the incidence of delayed gastric emptying, biliary fistula, hemorrhage, reoperation, wound infection, overall morbidity, mortality, and length of hospital stay. CONCLUSIONS: Our meta-analysis suggests that pancreaticogastrostomy not only reduces the rate of postoperative pancreatic fistula but also decreases its severity. Pancreaticogastrostomy is associated with a lower rate of intra-abdominal fluid collection. Our results suggest that pancreaticogastrostomy should be the preferred reconstruction method. PMID- 25743407 TI - Two senior surgeons' view: prevention of surgical site infection associated with colorectal operations. AB - Preventing surgical site infection is perhaps the most direct method of decreasing medical expenses. The following is an attempt at comprehensive ways of decreasing surgical site infection as well as decreasing patient discomfort. PMID- 25743408 TI - No difference between unicompartmental versus total knee arthroplasty for the management of medial osteoarthtritis of the knee in the same patient: a systematic review and pooling data analysis. AB - INTRODUCTION: One-third of patients with knee osteoarthritis (OA) has involvement of only one compartment, especially the medial one. SOURCES OF DATA: We performed a comprehensive search of studies comparing unicompartmental knee arthoplasty (UKA) and total knee arthroplasty (TKA) in the same patient on PubMed, OVID/Medline, Cochrane, CINAHL, Google scholar and Embase databases. AREAS OF AGREEMENT: UKA is indicated in knee with medial OA, no flexion deformity, no joint instability and no varus deformity. AREAS OF CONTROVERSY: Although high tibial osteotomy, UKA and TKA have been proposed to address medial OA of the knee, the best management is still controversial. GROWING POINTS: Studies investigating surgical management of medial OA of the knee are increasingly frequent. AREAS TIMELY FOR DEVELOPING RESEARCH: Large, multicentre, powered, randomized trials comparing UKA and TKA are needed to identify the best management for medial OA of the knee. Moreover, new score systems for satisfaction of the patient should be formulated. PMID- 25743409 TI - Estimation of air-water gas exchange coefficient in a shallow lagoon based on 222Rn mass balance. AB - The radon-222 mass balance is now commonly used to quantify water fluxes due to Submarine Groundwater Discharge (SGD) in coastal areas. One of the main loss terms of this mass balance, the radon evasion to the atmosphere, is based on empirical equations. This term is generally estimated using one among the many empirical equations describing the gas transfer velocity as a function of wind speed that have been proposed in the literature. These equations were, however, mainly obtained from areas of deep water and may be less appropriate for shallow areas. Here, we calculate the radon mass balance for a windy shallow coastal lagoon (mean depth of 6m and surface area of 1.55*10(8) m(2)) and use these data to estimate the radon loss to the atmosphere and the corresponding gas transfer velocity. We present new equations, adapted to our shallow water body, to express the gas transfer velocity as a function of wind speed at 10 m height (wind range from 2 to 12.5 m/s). When compared with those from the literature, these equations fit particularly well with the one of Kremer et al. (2003). Finally, we emphasize that some gas transfer exchange may always occur, even for conditions without wind. PMID- 25743410 TI - A new accurate and flexible index to assess the contribution of building materials to indoor gamma exposure. AB - The role of building materials as a source of gamma radiation has been recognized in the new EU Basic Safety Standards Directive which introduces an index I to screen building materials of radiological concern. This index was developed to account for average concrete values of thickness and density, the main structural characteristics of building materials that have an effect on gamma irradiation. Consequently, this screening procedure could be unfit in case of significantly different density and/or thickness of the building materials under examination. The paper proposes a more accurate and flexible activity concentration index, accounting for the actual density and thickness of building materials. PMID- 25743411 TI - The histone acetyltransferase Myst2 regulates Nanog expression, and is involved in maintaining pluripotency and self-renewal of embryonic stem cells. AB - The histone acetyltransferase Myst2 plays an important role in embryogenesis, but its function in undifferentiated ES cells remains poorly understood. Here, we show that Myst2 plays a role in pluripotency and self-renewal of ES cells. Myst2 deficiency results in loss of characteristic morphology, decreased alkaline phosphatase staining and reduced histone acetylation, as well as aberrant expression of pluripotency and differentiation markers. Our ChIP data reveal a direct association of Myst2 with the Nanog promoter and Myst2-dependent Oct4 binding on the Nanog promoter. Together our data suggest that Myst2-mediated histone acetylation may be required for recruitment of Oct4 to the Nanog promoter, thereby regulating Nanog transcription in ES cells. PMID- 25743412 TI - Coaches' attitudes towards placebo interventions in sport. AB - Placebo-induced performance enhancement is a new controversial issue in competitive sports. Coaches have control over the use of placebos, but their practices and attitudes were barely studied to date. In this survey 96 coaches from regional, national and international levels were asked about their practices and attitudes concerning placebo use in sports. Results revealed that 90% of the respondents were aware of placebo effects. Many (44%) coaches admitted to administering a placebo to their athletes. Those working at international level have administered placebos more often than the others (P = .02). Two thirds of the coaches agreed to the wider use of placebos in sport. Respondents who have used placebos in the past reported improved athletic performance. They also agreed more to the wider use of placebos than the coaches who previously did not use a placebo (P = .001). Team sport coaches use more often placebos than coaches working with individual athletes (P = .05). Only 10% of the sample thought that their athletes would refuse a hypothetical performance enhancer supplied by them. After a successful placebo intervention, only 15% of the coaches would administer it again without consulting the athlete. Overall, the coaches are optimistic about placebo use in sports. Close to half of them, especially those coaching at higher levels of competition, may use it regularly while achieving positive results. PMID- 25743413 TI - Optical forces in nanoplasmonic systems: how do they work, what can they be useful for? AB - In this article, we share our vision for a future nanofactory, where plasmonic trapping is used to control the different manufacturing steps associated with the transformation of initial nanostructures to produce complex compounds. All the different functions existing in a traditional factory can be translated at the nanoscale using the optical forces produced by plasmonic nanostructures. A detailed knowledge of optical forces in plasmonic nanostructures is however essential to design such a nanofactory. To this end, we review the numerical techniques for computing optical forces on nanostructures immersed in a strong optical field and show under which conditions approximate solutions, like the dipole approximation, can be used in a satisfactory manner. Internal optical forces on realistic plasmonic antennas are investigated and the reconfiguration of a Fano-resonant plasmonic system using such internal forces is also studied in detail. PMID- 25743414 TI - Effect of hen age and maternal vitamin D source on performance, hatchability, bone mineral density, and progeny in vitro early innate immune function. AB - The metabolite 25-hydroxy vitamin D3 (25-OHD) can complement or replace vitamin D3 in poultry rations, and may influence broiler production and immune function traits. The effect of broiler breeder dietary 25-OHD on egg production, hatchability, and chick early innate immune function was studied. We hypothesized that maternal dietary 25-OHD would support normal broiler breeder production and a more mature innate immune system of young chicks. Twenty-three-week-old Ross 308 hens (n=98) were placed in 4 floor pens and fed either 2,760 IU vitamin D3 (D) or 69 MUg 25-OHD/kg feed. Hen weights were managed according to the primary breeder management guide. At 29 to 31 wk (Early), 46 to 48 wk (Mid), and 61 to 63 wk (Late), hens were artificially inseminated and fertile eggs incubated and hatched. Chicks were placed in cages based on maternal treatment and grown to 7 d age. Innate immune function and plasma 25-OHD were assessed at 1 and 4 d post hatch on 15 chicks/treatment. Egg production, hen BW, and chick hatch weight were not affected by diet (P>0.05). Total in vitro Escherichia coli (E. coli) killing by 25-OHD chicks was greater than the D chicks at 4 d for the Early and Mid hatches, and 1 and 4 d for the Late hatch. This can be partly explained by the 25 OHD chicks from the Late hatch also having a greater E. coli phagocytic capability. No consistent pattern of oxidative burst response was observed. Chicks from the Mid hatch had greater percent phagocytosis, phagocytic capability, and E. coli killing than chicks from Early and Late hatches. Overall, maternal 25-OHD increased hatchability and in vitro chick innate immunity towards E. coli. Regardless of treatment, chicks from Late and Early hens had weaker early innate immune responses than chicks from Mid hens. The hen age effect tended to be the greatest factor influencing early chick innate immunity, but maternal 25-OHD also increased several measures relative to D. PMID- 25743415 TI - Histopathological and morphometric changes induced by a dextran sodium sulfate (DSS) model in broilers. AB - Oral administration of dextran sodium sulfate (DSS) is commonly used as an inducer of enteric inflammation in rodents. However, there is a dearth of knowledge regarding appropriate dosage, timing, or ageresponses in broilers for this potential inducer of inflammation without necrosis. Two experiments were conducted in day-of-hatch chicks to analyze clinical parameters and enteric histological changes induced by DSS when administered via drinking water ( DW: ). In both experiments, birds were distributed into nontreated control or varying concentrations of DSS in DW. For both experiments, only 0.75% DSS in DW was histologically evaluated. In Experiment 1, chicks received DSS from day 3 to 11, and at 3, 6, and 8 d of treatment, chicks were weighed, and sections of the duodenum, ileum, and ceca were formalin fixed. The addition of 0.75% DSS caused depression, anemia, and watery bloody diarrhea, plus significantly (P < 0.05) decreased BW gain at all times. Shortened ileal villi at 6 d and duodenal villi at 8 d of treatment, reduced duodenal and ileal epithelial cell height at 3, 6, and 8 d, and increased duodenal goblet cell density at 6 and 8 d were observed in response to DSS administration (P < 0.05). In Experiment 2, birds received DSS from days 10 to 16 and were sampled at 3 and 6 d of treatment. Similar changes were found in ceca of treated birds. There was no significant change in the duodenal villus height and goblet cell density by 6 d of treatment, suggesting that 6 d of 0.75% DSS in DW was not sufficient for the reproduction of duodenal symptoms in these older birds. However, there was a significant decrease in ilealvillus height and decreased ileal epithelial cell height at 3 and 6 d of treatment, as well as a significant decrease in BW compared to the control group. These findings indicate that DW administration of 0.75% DSS caused generalized mild and non-necrotic enteritis in broilers and that this compound may be useful for enteric inflammation modeling in poultry. PMID- 25743416 TI - Survival of turkey arthritis reovirus in poultry litter and drinking water. AB - Turkey reoviruses (TRVs) can cause arthritis, tenosynovitis, and enteric diseases in turkeys, leading to huge economic losses. The TRVs are tentatively divided into turkey arthritis reoviruses (TARVs) and turkey enteric reoviruses (TERVs) depending on the type of disease they produce. This study was conducted to determine the survival of these viruses in autoclaved and nonautoclaved poultry litter and drinking water at room temperature (approx. 25 degrees C). Three isolates of TARV (TARV-O'Neil, TARV-MN2, and TARV-MN4) and one each of TERV (TERV MN1) and chicken arthritis reovirus (CARV) were used in this study. The viruses were propagated and titrated on QT-35 cells. In autoclaved dechlorinated tap water, all 5 viruses were able to survive for 9 to 13 wk. In nonautoclaved water, all 5 viruses survived for at least 2 wk. In autoclaved litter, the viruses survived for 6 to 8 wk, and in nonautoclaved litter, they survived for 6 to 8 d only. The implications of these results are discussed below. PMID- 25743417 TI - Genetic relations between natural antibodies binding keyhole limpet hemocyanin and production traits in a purebred layer chicken line. AB - Natural antibodies (NAb) are an important component of the first line of immune defense. Selective breeding for enhanced NAb levels in chickens may improve general disease resistance. It is unknown what the consequences of selection for NAb will be on the productive performance of laying hens. In this paper we describe the genetic relations between NAb titers binding keyhole limpet hemocyanin at 19 wk age and production traits in a white purebred leghorn chicken line observed in several time periods. A linear animal model was used to estimate (co)variance components, heritabilities, and correlations. Negative genetic correlations were found between egg weight and NAb titers, and between egg breaking strength and NAb titers. Positive genetic correlations were found between the feed conversion ratio (consumed feed/egg mass produced) and NAb titers, and egg production and NAb titers. Negative phenotypic correlations were found between body weight and NAb titers, between egg weight and NAb titers, and between egg breaking strength and NAb titers. Positive phenotypic correlations were found between egg production and NAb titers, and feed conversion ratio and NAb titers. In general, phenotypic correlations were more often significant, but less pronounced than genetic correlations. Other production traits were not found to be significant related to NAb titers. These findings suggest that there is a genetic tradeoff between levels of immunity and some production traits, although the underlying mechanism(s) remain(s) unclear. The results suggest possible consequences for production efficiency as a result of selective breeding for improved general disease resistance by natural antibodies. PMID- 25743418 TI - Efficacy of a novel prebiotic and a commercial probiotic in reducing mortality and production losses due to cold stress and Escherichia coli challenge of broiler chicks 1. AB - Prebiotics consisting of resistant starch may alter intestinal ecology, thus modulating inflammation and increasing intestinal health through increased cecal production of short-chain fatty acids (SCFA). Probiotics may directly alter the intestinal microbiome, resulting in the same effects. We hypothesize that adding prebiotics and probiotics to feed may protect the gut of young chicks under stress. Studies 1, 2, and 3 evaluated treatments in a cold stress (CS) and Escherichia coli (EC) oral challenge to 430 day-old broiler chicks for 3 wk. In study 1, prebiotics were administered as 15% of the diet during the first week only and consisted of the following: Hi-Maize resistant starch (HM), potato starch (PS), or raw potato (RP). In studies 2 and 3, the PS treatment was identical to study 1, and an additional probiotic treatment (PRO) was administered in feed and water. In study 1, PS protected BW during the first week and decreased the mortality of CS/EC-challenged birds during the first week and wk 3, while RP decreased the mortality of warm-brooded birds challenged with EC during the first week. In study 2, PS decreased and PRO increased the main effect mean (MEM) of the first week BW. PS and PRO numerically decreased the feed conversion ratio (FCR) by 23 and 29 points, respectively, in CS/EC-challenged birds with no effects on mortality. In study 3, PS decreased and PRO increased the first week and wk 3 MEM BW. PS numerically increased FCR by 16 points, while PRO decreased FCR by 2 points. Both PS and PRO tended to increase overall mortality, and PRO significantly increased mortality in the CS/EC challenge. These results suggest that the effects of PS may be too variable in this challenge model for further study; however, the PRO treatment improved production values and may have potential as an alternative to antibiotics during the first weeks after hatch. PMID- 25743419 TI - Comparison of different sampling types across the rearing period in broiler flocks for isolation of Campylobacter spp. AB - Campylobacter is the most common bacterial cause of human gastrointestinal disease in most developed countries. It is generally accepted that poultry products are a significant source of foodborne Campylobacter infections in humans. Assessing the effectiveness of any potential intervention at farm level requires monitoring of the Campylobacter status of broiler flocks, using appropriate sampling methods. The aim of this study was to assess the influence of the sample type across the rearing period for the detection of Campylobacter spp. at farm level. During this study, 21 commercial broiler farms were intensively sampled. Each farm was visited and sampled at different times during the rearing period (d 1, 7, 14, 21, 28, 35, and 42). On the first day of rearing, the status of the house and the day-old flock was evaluated, and environmental and cecal samples were collected. During rearing, 4 different sample types were collected: feces with sock swabs (sock swabs), feces directly from the litter (feces), cloacal swabs, and cecal content. All samples were analyzed according to ISO 10272-1:2006 (Annex E) and also by direct culture. The results of this study showed that Campylobacter spp. were detected in all of the sample types on d 14 of rearing. From this point on, the detection increased significantly, with a maximum detection rate by the end of rearing, regardless of the sample type. All samples that were negative upon direct culture were also negative after pre enrichment. At the end of rearing, the percentage of samples positive for Campylobacter spp. was 71.4% for cecal samples, 61.9% for cloacal swabs, 45.2% for sock swabs, and 69.1% for fecal samples. C. jejuni was detected in all the sample types, with positive rates ranging from 67.1 to 76.0% for cecal samples and cloacal content, respectively. Cecal samples, cloacal swabs, and fecal samples cultured by direct plating onto modified charcoal cefoperazone deoxycholate agar (mCCDA) without pre-enrichment have the same sensitivity for detection of Campylobacter spp. in broiler flocks independent of the day of rearing. PMID- 25743420 TI - Efficacy of beer fermentation residue containing Saccharomyces cerevisiae cells for ameliorating aflatoxicosis in broilers. AB - This study aimed to determine the aflatoxin B1 (AFB1) binding capacity of a beer fermentation residue (BFR) containing Saccharomyces cerevisiae cells, and the efficacy of BFR to ameliorate the toxic effects of AFB1 on performance, serum biochemistry, and histology of broilers. The BFR was collected from a microbrewery, and the yeast cells were counted, dried, and milled before it was used in the study. In vitro evaluation of the BFR was conducted using different concentrations of AFB1 (2.0, 4.0, 8.0, 16.0, and 32.0 MUg AFB1/mL) and 100 mg/10 mL of BFR at pH 3.0 or 6.0. Two hundred 1-day-old male broilers (Ross 308) were assigned to chick batteries and allowed ad libitum access to feed and water. A completely randomized design was used with 5 replicate pens of 5 chicks assigned to each of 4 dietary treatments from hatch to 21 d, which included: 1) basal diet (BD), with no BFR or AFB1; 2) BD supplemented with 1% BFR; 3) BD supplemented with 2 mg AFB1/kg of feed; and 4) BD supplemented with 2 mg AFB1/kg feed and 1% BFR. Performance variables were determined weekly, while serum analyses were performed on d 14 and 21. At the end of the study, chicks were anesthetized with carbon dioxide, euthanized by cervical dislocation, and the kidney, liver, and bursa of Fabricius were removed for determination of relative weights, and for histological evaluation. In vitro assays showed that the higher the initial AFB1 concentration in solution, the greater the AFB1 amount adsorbed by BFR at both pHs tested. Feed intake, BW gain, and concentrations of albumin, total protein, and globulin increased (P < 0.05) in broilers fed BFR+AFB1 (Diet 4), when compared to the birds receiving only AFB1 (Diet 2). Although BFR was not able to reduce or prevent the effects of AFB1 on relative weights of kidneys and liver, it reduced the severity of histological changes in the liver and kidney caused by AFB1. PMID- 25743421 TI - Botanical alternatives to antibiotics for use in organic poultry production. AB - The development of antibiotic resistant pathogens has resulted from the use of sub-therapeutic concentrations of antibiotics delivered in poultry feed. Furthermore, there are a number of consumer concerns regarding the use of antibiotics in food animals including residue contamination of poultry products and antibiotic resistant bacterial pathogens. These issues have resulted in recommendations to reduce the use of antibiotics as growth promoters in livestock in the United States. Unlike conventional production, organic systems are not permitted to use antibiotics. Thus, both conventional and organic poultry production need alternative methods to improve growth and performance of poultry. Herbs, spices, and various other plant extracts are being evaluated as alternatives to antibiotics and some do have growth promoting effects, antimicrobial properties, and other health-related benefits. This review aims to provide an overview of herbs, spices, and plant extracts, currently defined as phytobiotics as potential feed additives. PMID- 25743423 TI - The 65th regional meeting (kita area). PMID- 25743422 TI - Genetic evolution of H5 highly pathogenic avian influenza virus in domestic poultry in Vietnam between 2011 and 2013. AB - In spite of highly pathogenic avian influenza H5N1 vaccination campaigns for domestic poultry, H5N1 viruses continue to circulate in Vietnam. To estimate the prevalence of avian influenza virus in Vietnam, surveillance was conducted between November 2011 and February 2013. Genetic analysis of 312 highly pathogenic avian influenza H5 viruses isolated from poultry in Vietnam was conducted and possible genetic relationships with strains from neighboring countries were investigated. As previously reported, phylogenetic analysis of the avian influenza virus revealed two H5N1 HPAI clades that were circulating in Vietnam. Clade 1.1, related to Cambodian strains, was predominant in the southern provinces, while clade 2.3.2.1 viruses were predominant in the northern and central provinces. Sequence analysis revealed evidence of active genetic evolution. In the gene constellation of clade 2.3.2.1, genotypes A, B, and B(II) existed during the 2011/2012 winter season. In June 2012, new genotype C emerged by reassortment between genotype A and genotype B(II), and this genotype was predominant in 2013 in the northern and central provinces. Interestingly, enzootic Vietnamese clade 2.3.2.1C H5 virus subsequently reassorted with N2, which originated from wild birds, to generate H5N2 highly pathogenic avian influenza, which was isolated from duck in the northeast region. This investigation indicated that H5N1 outbreaks persist in Vietnam and cause genetic reassortment with circulating viruses. It is necessary to strengthen active influenza surveillance to eradicate highly pathogenic avian influenza viruses and sever the link between highly pathogenic avian influenza and other circulating influenza viruses. PMID- 25743424 TI - The 131th regional meeting (kanto area). PMID- 25743425 TI - Facile synthesis of three-dimensional Pt-Pd alloyed multipods with enhanced electrocatalytic activity and stability for ethylene glycol oxidation. AB - A facile one-pot solvothermal method was developed for the fabrication of well defined three-dimensional highly branched Pt-Pd alloyed multipods, using ethylene glycol as a solvent and a reducing agent, along with N-methylimidazole as a structure-directing agent, without any seed, template, or surfactant. The as prepared nanocrystals exhibited a relatively large electrochemically active surface area, improved electrocatalytic activity and superior stability for ethylene glycol oxidation in alkaline media, compared with commercial Pt black and Pd black, making them promising electrocatalysts in fuel cells. PMID- 25743426 TI - Arthroscopic brostrom technique. AB - Surgical strategy regarding chronic lateral ankle instability is undergoing an evolution from traditional open procedures to minimally invasive and arthroscopic techniques. The development of arthroscopic techniques for the ankle mirrors the processes witnessed for the shoulder and knee over the last 30 years. The arthroscopic Brostrom is a novel technique that allows the surgeon to use an arthroscope to perform a lateral ankle ligament reconstruction that was previously thought possible only through open surgical technique. Indications and contraindications for the arthroscopic technique are essentially the same as those for an open Brostrom type of procedure. The arthroscopic Brostrom procedure is easy to remember and relatively simple to perform for the surgeon who has mastered basic ankle arthroscopy. The authors' results discussed in this article reveal that the arthroscopic Brostrom is a safe and effective procedure with outcomes at least equal to published results for traditional open techniques. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 25743427 TI - Double-Row Bridging Suture Fixation Augmented With Double Krackow Suture for the Repair of Avulsion of the Ossified Achilles Tendon: A Technical Tip. PMID- 25743429 TI - A Problematic Palsy: An Exercise in Clinical Reasoning. PMID- 25743428 TI - Vaginal Cytomegalovirus Shedding Before and After Initiation of Antiretroviral Therapy in Rakai, Uganda. AB - Vaginal shedding of cytomegalovirus (CMV) DNA was determined longitudinally among 96 women coinfected with human immunodeficiency virus (HIV), herpes simplex virus 2, and CMV starting antiretroviral therapy (ART) during a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Vaginal CMV was detected in 75 of 96 women (78.0%) and 379 of 1080 individual visits (35.1%). ART status, higher HIV RNA viral load before ART initiation, and younger age were significantly associated with increased frequency of CMV shedding (P < .01). Compared to pre-ART, CMV shedding peaked from month 2 to month 4 after ART initiation, suggesting possible immune reconstitution inflammatory syndrome. Further studies need to determine the clinical significance of asymptomatic CMV shedding. PMID- 25743430 TI - Capsule Commentary on Stevens et al., Variation in Inpatient Consultation Among Older Adults in the United States. PMID- 25743431 TI - Opening the door to transgender care. PMID- 25743432 TI - An ontogenetic framework linking locomotion and trabecular bone architecture with applications for reconstructing hominin life history. AB - The ontogeny of bipedal walking is considered uniquely challenging, due in part to the balance requirements of single limb support. Thus, locomotor development in humans and our bipedal ancestors may track developmental milestones including the maturation of the neuromuscular control system. Here, we examined the ontogeny of locomotor mechanics in children aged 1-8, and bone growth and development in an age-matched skeletal sample to identify bony markers of locomotor development. We show that step-to-step variation in mediolateral tibia angle relative to the vertical decreases with age, an indication that older children increase stability. Analyses of trabecular bone architecture in the distal tibia of an age-matched skeletal sample (the Norris Farms #36 archaeological skeletal collection) show a bony signal of this shift in locomotor stability. Using a grid of eleven cubic volumes of interest (VOI) in the distal metaphysis of each tibia, we show that the degree of anisotropy (DA) of trabecular struts changes with age. Intra-individual variation in DA across these VOIs is generally high at young ages, likely reflecting variation in loading due to kinematic instability. With increasing age, mean DA converges on higher values and becomes less variable across the distal tibia. We believe the ontogeny of distal tibia trabecular architecture reflects the development of locomotor stability in bipeds. We suggest this novel bony marker of development may be used to assess the relationship between locomotor development and other life history milestones in fossil hominins. PMID- 25743433 TI - Encephalization and diversification of the cranial base in platyrrhine primates. AB - The cranial base, composed of the midline and lateral basicranium, is a structurally important region of the skull associated with several key traits, which has been extensively studied in anthropology and primatology. In particular, most studies have focused on the association between midline cranial base flexion and relative brain size, or encephalization. However, variation in lateral basicranial morphology has been studied less thoroughly. Platyrrhines are a group of primates that experienced a major evolutionary radiation accompanied by extensive morphological diversification in Central and South America over a large temporal scale. Previous studies have also suggested that they underwent several evolutionarily independent processes of encephalization. Given these characteristics, platyrrhines present an excellent opportunity to study, on a large phylogenetic scale, the morphological correlates of primate diversification in brain size. In this study we explore the pattern of variation in basicranial morphology and its relationship with phylogenetic branching and with encephalization in platyrrhines. We quantify variation in the 3D shape of the midline and lateral basicranium and endocranial volumes in a large sample of platyrrhine species, employing high-resolution CT-scans and geometric morphometric techniques. We investigate the relationship between basicranial shape and encephalization using phylogenetic regression methods and calculate a measure of phylogenetic signal in the datasets. The results showed that phylogenetic structure is the most important dimension for understanding platyrrhine cranial base diversification; only Aotus species do not show concordance with our molecular phylogeny. Encephalization was only correlated with midline basicranial flexion, and species that exhibit convergence in their relative brain size do not display convergence in lateral basicranial shape. The evolution of basicranial variation in primates is probably more complex than previously believed, and understanding it will require further studies exploring the complex interactions between encephalization, brain shape, cranial base morphology, and ecological dimensions acting along the species divergence process. PMID- 25743434 TI - Changes in salivary secretion and sense of taste following cochlear implantation: a prospective study. AB - CONCLUSION: A set of methods for evaluating changes in salivary secretion and sense of taste following cochlear implantation (CI) was applied and tested. No association between implantation and objectively assessed sense of taste was found. However, a statistically significant decrease in non-stimulated salivary flow on the day after surgery was found. OBJECTIVES: To develop and test a research method describing the course of changes in salivary secretion and sense of taste following CI. METHODS: This was a longitudinal study examining 13 patients undergoing CI at Odense University Hospital in 2012. Questionnaires, sialometry and gustatory testing were applied. RESULTS: A general postoperative decrease in salivary secretion could not be found. However, a 29.9% mean reduction in non-stimulated salivary flow was observed when looking specifically at the visit the day after surgery (p = 0.001). When adjusting for perioperative administration of glycopyrrolate (p < 0.001) and atropine (p = 0.178), the former was highly associated with a 69.7% mean decrease in non-stimulated salivary flow at the visit the day after surgery. The third examination was still, independent of glycopyrrolate administration, borderline significantly associated with a 14.5% mean decrease (p = 0.054). We did not find any significant decrease in sense of taste following implantation. PMID- 25743435 TI - Estimating the association between metabolic risk factors and marijuana use in U.S. adults using data from the continuous National Health and Nutrition Examination Survey. AB - PURPOSE: More research is needed on the health effects of marijuana use. Results of previous studies indicate that marijuana could alleviate certain factors of metabolic syndrome, such as obesity. METHODS: Data on 6281 persons from National Health and Nutrition Examination Survey from 2005 to 2012 were used to estimate the effect of marijuana use on cardiometabolic risk factors. The reliability of ordinary least squares (OLS) regression models was tested by replacing marijuana use as the risk factor of interest with alcohol and carbohydrate consumption. Instrumental variable methods were used to account for the potential endogeneity of marijuana use. RESULTS: OLS models show lower fasting insulin, insulin resistance, body mass index, and waist circumference in users compared with nonusers. However, when alcohol and carbohydrate intake substitute for marijuana use in OLS models, similar metabolic benefits are estimated. The Durbin-Wu Hausman tests provide evidence of endogeneity of marijuana use in OLS models, but instrumental variables models do not yield significant estimates for marijuana use. CONCLUSION: These findings challenge the robustness of OLS estimates of a positive relationship between marijuana use and fasting insulin, insulin resistance, body mass index, and waist circumference. PMID- 25743436 TI - Design of polystyrene latex particles covered with polyoxometalate clusters via multiple covalent bonding. AB - Polyoxometalates (POMs) covalently functionalized with methyl methacrylate groups were applied as surfactants in the emulsion polymerization reaction of styrene. Due to the copolymerization of the methyl methacrylate groups and the styrene monomers, the polyoxometalate clusters are covalently grafted onto the surface of polystyrene latex nanoparticles. Such latex particles are fully covered with catalytic POM clusters and might serve as quasi-homogeneous catalysts. PMID- 25743437 TI - Out-of-hours palliative care: what are the educational needs and preferences of general practitioners? AB - OBJECTIVES: Offering genuine choice to patients over place of care and death requires the provision of high-quality palliative care 24/7. This study examines the confidence of out-of-hours general practitioners (GPs) in symptom control and end of life prescribing, and identifies their educational needs and preferences in order to inform recommendations for future education. METHODS: A self completion postal survey was designed and sent to 1005 GPs working for an independent provider of out-of-hours services across England. Quantitative data were analysed using descriptive statistics and non-parametric tests. RESULTS: 203 (20.3%) GPs completed the survey questionnaire; 13.3% (n=27) worked exclusively out-of-hours. Confidence in assessing palliative care emergencies (42.8%, n=87: 'not so confident' or 'not at all confident'), managing symptoms in non-cancer patients (39.4%, n=80) and prescribing a new syringe driver (39.0%, n=79) was lowest. Lower confidence was associated with infrequent exposure to palliative patients (p<0.05) and lack of training in palliative care (p<0.05); 12.8% (n=26) had never received formal training. Educational preferences were closely associated with confidence (p<0.0005); the topics above were most requested. E learning was the preferred method (67.5%, n=137). 82.1% (n=165) believed training focused on out-of-hours work would be beneficial. CONCLUSIONS: We identify that confidence in key palliative care competences is severely lacking. Educational strategies to address this concern must be targeted at GPs preferences for content and mode of delivery. Regular e-learning is favoured, but should be blended with other approaches that promote engagement including out-of-hours themed workshops and case discussion. Specialist palliative care services should engage with out-of-hours providers to support education. PMID- 25743438 TI - A survey of patients' experience of pain and other symptoms while receiving care from palliative care services. AB - CONTEXT: In Australia, patients at the end of life with complex symptoms and needs are often referred to palliative care services (PCSs), but little is known about the symptoms of patients receiving palliative care in different settings. OBJECTIVE: To explore patients' levels of pain and other symptoms while receiving care from PCSs. METHOD: PCSs registered through Australia's national Palliative Care Outcomes Collaboration (PCOC) were invited to participate in a survey between 2008 and 2011. Patients (or if unable, a proxy) were invited to complete the Palliative Care Outcome Scale. RESULTS: Questionnaires were completed for 1800 patients. One-quarter of participants reported severe pain, 20% reported severe 'other symptoms', 20% reported severe patient anxiety, 45% reported severe family anxiety, 66% experienced depressed feelings and 19% reported severe problems with self-worth. Participants receiving care in major cities reported higher levels of depressed feelings than participants in inner regional areas. Participants receiving care in community and combined service settings reported higher levels of need for information, more concerns about wasted time, and lower levels of family anxiety and depressed feelings when compared to inpatients. Participants in community settings had lower levels of concern about practical matters than inpatients. CONCLUSIONS: Patients receiving care from Australian PCSs have physical and psychosocial concerns that are often complex and rated as 'severe'. Our findings highlight the importance of routine, comprehensive assessment of patients' concerns and the need for Specialist Palliative Care clinicians to be vigilant in addressing pain and other symptoms in a timely, systematic and holistic manner, whatever the care setting. PMID- 25743440 TI - Assessing the internal consistency and temporal stability of advance directives generated by an interactive, online computer program. AB - OBJECTIVE: Evaluate the internal consistency and temporal stability of advance directives (ADs) generated by an interactive, online computer program. METHODS: 33 participants completed the program at three visits, 2 weeks apart. Agreement rates were calculated for the General Wishes component of the AD. The test-retest method was used to examine the temporal stability of the Specific Wish for Treatment component which contains five clinical scenarios. RESULTS: General Wishes remained stable with 94% selecting the identical response at each visit. For the Specific Wish for Treatment scale, significant variations in test-retest correlations existed (ie, rho=0.32-0.78, between time points 1 and 2); however within scenario, correlations did not significantly vary between time points. Temporal stability was lower in the Specific Wish for Treatment scale compared with General Wishes (average rho=0.59, between time points 1 and 2; and rho=0.75, between time points 2 and 3). CONCLUSIONS: ADs generated by an online decision aid demonstrate good temporal stability, with highest stability for General Wishes and moderate stability for Specific Wish for Treatment regarding medical treatments in specific clinical scenarios. Internal consistency for wish for treatment across all time points and scenarios was high (Cronbach alpha>0.90). PMID- 25743439 TI - The online use of Violence and Journey metaphors by patients with cancer, as compared with health professionals: a mixed methods study. AB - OBJECTIVE: To compare the frequencies with which patients with cancer and health professionals use Violence and Journey metaphors when writing online; and to investigate the use of these metaphors by patients with cancer, in view of critiques of war-related metaphors for cancer and the adoption of the notion of the 'cancer journey' in UK policy documents. DESIGN: Computer-assisted quantitative and qualitative study of two data sets totalling 753 302 words. SETTING: A UK-based online forum for patients with cancer (500 134 words) and a UK-based website for health professionals (253 168 words). PARTICIPANTS: 56 patients with cancer writing online between 2007 and 2012; and 307 health professionals writing online between 2008 and 2013. RESULTS: Patients with cancer use both Violence metaphors and Journey metaphors approximately 1.5 times per 1000 words to describe their illness experience. In similar online writing, health professionals use each type of metaphor significantly less frequently. Patients' Violence metaphors can express and reinforce negative feelings, but they can also be used in empowering ways. Journey metaphors can express and reinforce positive feelings, but can also be used in disempowering ways. CONCLUSIONS: Violence metaphors are not by default negative and Journey metaphors are not by default a positive means of conceptualising cancer. A blanket rejection of Violence metaphors and an uncritical promotion of Journey metaphors would deprive patients of the positive functions of the former and ignore the potential pitfalls of the latter. Instead, greater awareness of the function (empowering or disempowering) of patients' metaphor use can lead to more effective communication about the experience of cancer. PMID- 25743441 TI - Observation on the traditional phytotherapy among the Malayali tribes in Eastern Ghats of Tamil Nadu, South India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicine remained as the most affordable and easily accessible source of treatment for many ailments. The Malayali tribes living in the Kolli hills region of Eastern Ghats of Tamil Nadu has long history of ethnomedicinal knowledge has been remained unexplored hither to. Hence, this study was initiated with an aim to record the ethnomedicinal plants of Malayali tribes and to document and analyse the local knowledge on phytotherapy before environmental and cultural changes deplete the resources. METHODS: In order to document the phytotherapical knowledge, a field study was carried out between August 2012 and February 2014. The ethnomedicinal knowledge was recorded through interviews among the Malayali tribes, and traditional healers. In addition a semi structure questionnaire was used to collect information on the local name of the plant, plant part used for curing, method of preparation in phytoremedies and any other plants/agents used as ingredients. Factor of informant consensus (Fic), use value (UV), fidelity level (FL), relative importance (RI) and novelty index were employed in data analysis. RESULTS: Current research work reports total of 86 medicinal plant species belonging to 76 genera of 46 different families. Herbs constituted the largest growth habit (48 species, 56%) followed by trees (13 species, 15%) and shrubs (9 species, 11%) etc. Leaf 43 (46%) is the plant part widely used followed by whole plant 9 (10%), seeds and fruits 9 (10%) and root 7 (8%). Paste was the most common preparation method use in herbal recipes. These plants were used to treat various human diseases and ailments grouped under 19 disease categories with the highest number of species (31) being used for dermatological infections/diseases followed by gastro-intestinal ailments (28) and general health (15). Asystasia chelonoides (UV of 2.76) and Piper nigrum (UV of 2.12) are the most frequently and popularly used medicinal plant species in the study area. CONCLUSION: The result of the study revealed that there was high diversity of medicinal plants and traditional knowledge about the use, preparation, and application of which is still maintained in the study area. However, the knowledge of herbal medicine was held by elders. The decline in the use of plants by the younger generation may gradually lead to the fading away of indigenous knowledge associated with the plants. PMID- 25743442 TI - Enhanced spin-orbit coupling and charge carrier density suppression in LaAl1 xCrxO3/SrTiO3 hetero-interfaces. AB - We report a gradual suppression of the two-dimensional electron gas (2DEG) at the LaAlO(3)/SrTiO(3) interface on substitution of chromium at the Al sites. The sheet carrier density at the interface (n?) drops monotonically from ~2.2 * 10(14) cm(-2) to ~2.5 * 10(13) cm(-2) on replacing ~60% of the Al sites by Cr and the sheet resistance (R?) exceeds the quantum limit for localization (h/2e(2)) in the concentrating range 40-60% of Cr. The samples with Cr ?40% show a distinct minimum (T(m)) in metallic R?(T) whose position shifts to higher temperatures on increasing the substitution. Distinct signatures of Rashba spin-orbit interaction (SOI) induced magnetoresistance (MR) are seen in R? measured in out of plane field (H?) geometry at T ? 8 K. Analysis of these data in the framework of Maekawa-Fukuyama theory allows extraction of the SOI critical field (H(SO)) and time scale (tau(SO)) whose evolution with Cr concentration is similar as with the increasing negative gate voltage in LAO/STO interface. The MR in the temperature range 8 K ? T ? T(m) is quadratic in the field with a +ve sign for H? and -ve sign for H?. The behaviour of H? MR is consistent with Kondo theory which in the present case is renormalized by the strong Rashba SOI at T < 8 K. PMID- 25743443 TI - Representing visual recursion does not require verbal or motor resources. AB - The ability to form and use recursive representations while processing hierarchical structures has been hypothesized to rely on language abilities. If so, linguistic resources should inevitably be activated while representing recursion in non-linguistic domains. In this study we use a dual-task paradigm to assess whether verbal resources are required to perform a visual recursion task. We tested participants across 4 conditions: (1) Visual recursion only, (2) Visual recursion with motor interference (sequential finger tapping), (3) Visual recursion with verbal interference--low load, and (4) Visual recursion with verbal interference--high load. Our results show that the ability to acquire and use visual recursive representations is not affected by the presence of verbal and motor interference tasks. Our finding that visual recursion can be represented without access to verbal resources suggests that recursion is available independently of language processing abilities. PMID- 25743444 TI - Defining the light emitting area for displays in the unipolar regime of highly efficient light emitting transistors. AB - Light-emitting field effect transistors (LEFETs) are an emerging class of multifunctional optoelectronic devices. It combines the light emitting function of an OLED with the switching function of a transistor in a single device architecture. The dual functionality of LEFETs has the potential applications in active matrix displays. However, the key problem of existing LEFETs thus far has been their low EQEs at high brightness, poor ON/OFF and poorly defined light emitting area - a thin emissive zone at the edge of the electrodes. Here we report heterostructure LEFETs based on solution processed unipolar charge transport and an emissive polymer that have an EQE of up to 1% at a brightness of 1350 cd/m(2), ON/OFF ratio > 10(4) and a well-defined light emitting zone suitable for display pixel design. We show that a non-planar hole-injecting electrode combined with a semi-transparent electron-injecting electrode enables to achieve high EQE at high brightness and high ON/OFF ratio. Furthermore, we demonstrate that heterostructure LEFETs have a better frequency response (f cut off = 2.6 kHz) compared to single layer LEFETs. The results presented here therefore are a major step along the pathway towards the realization of LEFETs for display applications. PMID- 25743445 TI - Cardiac findings and events observed in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis. AB - A phase 2, open-label study in 21 patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis showed that tafamidis (20 mg daily for 12 months) stabilized these transthyretin variants. We assessed cardiac amyloid infiltration and cardiac abnormalities in this same study population. At baseline, median age was 64.3 years, 11 patients were in NYHA class II, 13 had conduction abnormalities, 14 N-terminal pro-hormone brain natriuretic peptide concentrations >300 pg/ml, and 17 interventricular septal thickness >12 mm. Mean (SD) left ventricular ejection fraction was 60.3% (9.96). Patients with normal heart rate variability increased from 4/19 at baseline to 8/19 at month 12 (p < 0.05). Cardiac biomarkers remained stable. Although four patients had increases in interventricular septal thickness >= 2 mm, the remainder had stable septal wall thickness. There were no clinically relevant changes in mean echocardiographic/electrocardiographic variables and no safety concerns. PMID- 25743447 TI - More evidence of an association between antipsychotic drugs and the risk of diabetes in children and adolescents: a population-based study. PMID- 25743446 TI - Vectorcardiography for optimization of stimulation intervals in cardiac resynchronization therapy. AB - Current optimization of atrioventricular (AV) and interventricular (VV) intervals in cardiac resynchronization therapy (CRT) is time consuming and subject to noise. We aimed to prove the principle that the best hemodynamic effect of CRT is achieved by cancelation of opposing electrical forces, detectable from the QRS morphology in the 3D vectorcardiogram (VCG). Different degrees of left (LV) and right ventricular (RV) pre-excitation were induced, using variation in AV intervals during LV pacing in 20 patients with left bundle branch block (LBBB) and variation in VV intervals during biventricular pacing in 18 patients with complete AV block or atrial fibrillation. The smallest QRS vector area identified stimulation intervals with minimal systolic stretch (median difference [IQR] 20 ms [-20, 20 ms] and maximal hemodynamic response (10 ms [-20, 40 ms]). Reliability of VCG measurements was superior to hemodynamic measurements. This study proves the principle that VCG analysis may allow easy and reliable optimization of stimulation intervals in CRT patients. PMID- 25743448 TI - Depressed older adults who are adherent to medications have a lower risk of hospitalisation for coronary artery disease. PMID- 25743449 TI - New use of antipsychotics associated with a small increased risk of acute kidney injury in older adults with mental disorders. PMID- 25743450 TI - Depressive symptoms are associated with late life cognitive decline independent of common age-related pathologies. PMID- 25743451 TI - Barrett's oesophagus: sharpening the view. PMID- 25743452 TI - Mechanisms of Barrett's oesophagus: intestinal differentiation, stem cells, and tissue models. AB - Barrett's oesophagus (BE) is defined as any metaplastic columnar epithelium in the distal oesophagus which replaces normal squamous epithelium and which predisposes to cancer development. It is this second requirement, the predisposition to cancer, which makes this condition both clinically highly relevant and an important area for ongoing research. While BE has been defined pathologically since the 1950's (Allison and Johnstone, Thorax 1955), and identified as a risk factor for esophageal adenocarcinoma since the 1970's (Naef A.P., et al J Thorac Cardiovasc Surg. 1975), our understanding of the molecular events giving rise to this condition remains limited. Herein we will examine what is known about the intestinal features of BE and how well it recapitulates the intestinal epithelium, including stem identity and function. Finally, we will explore laboratory models of this condition presently in use and under development, to identify new insights they may provide into this important clinical condition. PMID- 25743453 TI - Mechanisms of Barrett's oesophagus (clinical): LOS dysfunction, hiatal hernia, peristaltic defects. AB - Barrett's oesophagus, with the potential to develop into oesophageal adenocarcinoma (OAC), is a major complication of gastrooesophageal reflux disease (GORD). However, about 50% of patients developing OAC had no known GORD beforehand. Hence, while GORD symptoms, oesophagitis, and Barrett's have a number of common determinants (oesophagogastric junction (OGJ) incompetence, impaired oesophageal clearance mechanisms, hiatus hernia) they also have some independent determinants. Further, although excess oesophageal acid exposure plays a major role in the genesis of long-segment Barrett's oesophagus there is minimal evidence supporting this for short-segment Barrett's. Hence, these may have unique pathophysiological features as well. Long-segment Barrett's seems to share most, if not all, of the risk factors for oesophagitis, particularly high-grade oesophagitis. However, it is uncertain if OGJ function and acid clearance are more severely impaired in patients with long-segment Barrett's compared to patients with high-grade oesophagitis. With respect to short-segment Barrett's, the acid pocket may play an important pathogenic role. Conceptually, extension of the acid pocket into the distal oesophagus, also known as intra-sphincteric reflux, provides a mechanism or acid exposure of the distal osophageal mucosa without the occurrence of discrete reflux events, which are more likely to prompt reflux symptoms and lead to the development of oesophagitis. Hence, intra sphincteric reflux related to extension of the acid/no acid interface at the proximal margin of the acid pocket may be key in the development of short segment Barrett's. However, currently this is still somewhat speculative and further studies are required to confirm this. PMID- 25743455 TI - Risk factors and populations at risk: selection of patients for screening for Barrett's oesophagus. AB - Screening for Barrett's oesophagus is an attractive notion due to the rising incidence of oesophageal adenocarcinoma, the relative ease of acquiring tissue from the oesophagus, and the availability of endoscopic therapy for early neoplastic lesions. If screening is recommended, the question remains: which patients should be screened? Endoscopy is frequently performed in patients with symptoms of gastro-oesophageal reflux disease, but the vast majority of patients diagnosed with oesophageal adenocarcinoma have never undergone a prior endoscopy. The efficiency of screening needs to be improved. A number of tools for predicting the presence of Barrett's oesophagus or future risk of developing oesophageal adenocarcinoma are available. More research is needed to validate these tools and to identify the thresholds at which screening should be offered. PMID- 25743454 TI - A review of the epidemiology of Barrett's oesophagus and oesophageal adenocarcinoma. AB - While the incidence rates of many cancers have decreased in past decades, the incidence of oesophageal adenocarcinoma continues to increase. The only known precursor for oesophageal adenocarcinoma is Barrett's oesophagus. Studies conducted have identified white race, male sex, GORD, cigarette smoking, obesity, and the absence of Helicobacter pylori status as risk factors for oesophageal adenocarcinoma. Other potential associations include dietary factors and the absence of non-steroidal anti-inflammatory drug use. Many individual studies have been limited by sample size and several meta-analyses have pooled data from studies to address this limitation. In this review we present a synthesis of these studies and summarize current knowledge of risk factors for both oesophageal adenocarcinoma and Barrett's oesophagus. PMID- 25743456 TI - Cost considerations in implementing a screening and surveillance strategy for Barrett's oesophagus. AB - There is increasing concern over the rising costs of healthcare leading to debate regarding the use of resources to implement preventive strategies. Oesophageal adenocarcinoma and its precursor, Barrett's oesophagus provides an excellent opportunity to highlight this issue since cancer is uncommon even among individuals with documented Barrett's oesophagus. This review provides a brief introduction to economic analysis in healthcare and summarizes published studies of the cost-effectiveness of strategies to reduce mortality from cancer. Current best estimates highlight the cost-effectiveness of endoscopic ablation among patients with Barrett's oesophagus and high-grade dysplasia and the low cost effectiveness of ablation among patients without dysplasia. The cost effectiveness of ablation among patients with Barrett's and low-grade dysplasia is poorly defined due to the ambiguity of diagnosing dysplasia, the unknown risk of cancer among patients with low-grade dysplasia, and the uncertain durability of ablation to maintain remission from metaplasia and dysplasia and prevent cancer. PMID- 25743457 TI - Barrett's oesophagus: can meaningful screening and surveillance guidelines be formulated based on new data and rejigging the old paradigm? AB - Gastro-oesophageal reflux disease (GORD) and Barrett's oesophagus (BO) have been considered to be the most important known risk factors for oesophageal adenocarcinoma (OAC). It has been the fastest growing cancer in the Western World and has occurred against a backdrop of progressive reduction in the risk estimate of malignancy associated with BO and no reduction in mortality from OAC using the prevailing screening and surveillance guidelines. The recently published link between high risk HPV and Barrett's dysplasia/cancer may be the 'missing' strong risk factor responsible for the significant rise of OAC since the 1970's, as has been the case with head and neck tumours, another viral associated cancer. P53 immunohistochemistry has been proposed as a good molecular marker for predicting disease progression in BD. Nevertheless, significant negative staining for this mutation in BD remains a major hurdle to widespread routine clinical use as a sole molecular marker. Recent data raises the distinct possibility of at least 2 (probably more) carcinogenic pathways operating in OAC. One is HPV mediated devoid largely of p53 mutations and the other p53 dependent. The joint use of both these markers as part of a molecular panel may represent the best bet yet of detecting the high risk group of progressors to OAC. Patients who are positive for either or both biomarkers i.e p53 or/and transcriptional markers of HPV may warrant more intensive screening. In future, genome wide technology may provide molecular signatures to aid diagnosis and risk stratification in BO. PMID- 25743458 TI - Barrett's oesophagus diagnostic criteria: endoscopy and histology. AB - This review summarizes the endoscopic and histologic features of Barrett's oesophagus(BO) as well as some of the recent advancements and controversies. BO represents metaplastic conversion of normal squamous epithelium of tubular oesophagus to columnar epithelium. The diagnosis of BO requires a combination of endoscopic and histopathologic findings. There is worldwide controversy regarding the exact definition of BO, particularly with regard to the requirement to histologically identify goblet cells in biopsies. The presence and detectability of goblet cells might vary depending on a variety of factors and is subject to sampling error. Therefore, a systematic biopsy sampling with sufficient number of biopsies is currently recommended to limit the likelihood of a false negative result for detection of goblet cells. There are both endoscopic and pathologic challenges in evaluating gastro-oesophageal junction biopsies in patients with irregular Z lines to determine the exact location of the sample (i.e., oesophagus versus stomach). Recently, several novel endoscopic techniques have been developed to improve BO detection. However, none have been validated yet in clinical practice. The surveillance of patients with BO relies on histologic evaluation of dysplasia. However, there are significant pathologic limitations and diagnostic variability in evaluating the presence and grading of BO dysplasia, particularly with regard to the more recently recognized non intestinal types of dysplasia. All BO dysplasia samples should be reviewed by an expert gastrointestinal pathologist to confirm the diagnosis. Finally, it is important to emphasize that close interaction between gastroenterologists and pathologists is essential to ensure proper evaluation of endoscopic biopsies in order to optimize the surveillance and clinical management of patients with BO. PMID- 25743459 TI - Diagnosis by endoscopy and advanced imaging. AB - Evaluation of patients with Barrett's oesophagus (BO) using dye-based chromoendoscopy, optical chromoendoscopy, autofluorescence imaging, or confocal laser endomicroscopy does not significantly increase the number of patients with a diagnosis of early neoplasia compared with high-definition white light endoscopy (HD-WLE) with random biopsy analysis. These newer imaging techniques are not more effective in standard surveillance of patients with BO because the prevalence of early neoplasia is low and HD-WLE with random biopsy analysis detects most cases of neoplasia. The evaluation and treatment of patients with BO and early-stage neoplasia should be centralized in tertiary referral centers, where procedures are performed under optimal conditions, by expert endoscopists. Lesions that require resection are almost always detected by HD-WLE, although advanced imaging techniques can detect additional flat lesions. However, these are of limited clinical significance because they are effectively eradicated by ablation therapy. No endoscopic imaging technique can reliably assess submucosal or lymphangio-invasion. Endoscopic resection of early-stage neoplasia in patients with BO is important for staging and management. Optical chromoendoscopy can also be used to evaluate lesions before endoscopic resection and in follow-up after successful ablation therapy. PMID- 25743460 TI - The use of molecular markers in predicting dysplasia and guiding treatment. AB - The ability to stratify patients based on the risk of progression to oesophageal adenocarcinoma would provide benefit to patients as well as deliver a more cost effective surveillance programme. Current practice is to survey all patients with Barrett's oesophagus (BO) and use histological diagnoses to guide further management. However, reliance on histology alone has its drawbacks. We are currently unable to reliably stratify the risk of progression of patients with non-dysplastic BO based on any particular histological feature. There is also considerable variability in histological interpretation. An obvious recourse has been to rely on identifying molecular features possibly as an adjunct to histology, to better diagnose and stratify patients. To this end, p53 immunohistochemistry can be used as a useful adjunct to risk stratify and clarify histological grades, particularly low-grade dysplasia. Other markers of progression, although not yet in a clinically applicable format, are promising. Measurements of promoter methylation and also genomic instability such as loss of heterozygosity and copy number alterations show promise especially as high throughput genetic technologies reach maturity. The enduring hope is that these molecular biomarkers will make the transition to clinical applicability either in the direct endoscopic setting or even using non-endoscopic methods. PMID- 25743462 TI - Acid suppression and surgical therapy for Barrett's oesophagus. AB - Gastro-oesophageal reflux disease is a common medical problem in developed countries, and is a risk factor for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Both proton pump inhibitor therapy and antireflux surgery are effective at controlling endoscopic signs and symptoms of gastro oesophageal reflux in patients with Barrett's oesophagus, but often fail to eliminate pathological oesophageal acid exposure. The current available studies strongly suggest that acid suppressive therapy, both pharmacological as well as surgical acid suppression, can reduce the risk the development and progression in patients with Barrett's oesophagus, but are not capable of complete prevention. No significant differences have been found between pharmacological and surgical therapy. For clinical practice, patients should be prescribed a proton pump inhibitor once daily as maintenance therapy, with the dose guided by symptoms. Antireflux surgery can be a good alternative to proton pump inhibitor therapy, but should be primarily offered to patients with symptomatic reflux, and not to asymptomatic patients with the rationale to protect against cancer. PMID- 25743463 TI - Chemoprevention in Barrett's oesophagus. AB - Increasing incidence of oesophageal adenocarcinoma along with poor survival entails novel preventive strategies. Agents that target pro-oncogenic pathways in Barrett's mucosa could halt this neoplastic transformation. In this review, we will use epidemiological associations and molecular mechanisms to identify novel chemoprevention targets in Barrett's oesophagus. We will also discuss recent chemoprevention trials. PMID- 25743461 TI - Barrett's oesophagus: frequency and prediction of dysplasia and cancer. AB - The incidence of oesophageal adenocarcinoma is continuing to increase at an alarming rate in the Western world today. Barrett's oesophagus is a clearly recognized risk factor for the development of oesophageal adenocarcinoma, but the overwhelming majority of patients with Barrett's oesophagus will never develop oesophageal cancer. A number of endoscopic, histologic and epidemiologic risk factors identify Barrett's oesophagus patients at increased risk for progression to high-grade dysplasia and oesophageal adenocarcinoma. Endoscopic factors include segment length, mucosal abnormalities as seemingly trivial as oesophagitis and the 12 to 6 o'clock hemisphere of the oesophagus. Both intestinal metaplasia and low grade dysplasia, the latter only if confirmed by a pathologist with expertise in Barrett's oesophagus pathologic interpretation are the histologic risk factors for progression. Epidemiologic risk factors include ageing, male gender, obesity, and smoking. Factors that may protect against the development of adenocarcinoma include a diet rich in fruits and vegetables, and the use of proton pump inhibitors, aspirin/NSAIDs and statins. PMID- 25743464 TI - Endoscopic therapy for Barrett's oesophagus. AB - Barrett's oesophagus (BO) is thought to progress through the development of dysplasia (low grade and high grade) to oesophageal adenocarcinoma, a lethal cancer with poor survival. The overall goal of endoscopic therapy of BO is to eliminate metaplastic and dysplastic epithelium, to prevent and/or reduce the risk of progression to OAC. Endoscopic therapy techniques can be divided into two broad complementary techniques: tissue acquiring (endoscopic mucosal resection and endoscopic submucosal dissection) and ablative. Endoscopic therapy has been established as safe and effective for the subjects with intra-mucosal cancer (IMC), high-grade dysplasia (HGD) and more recently in treating low-grade dysplasia (LGD). Challenges to endoscopic therapy are being recognized, such as incomplete response and recurrence. While eradication of intestinal metaplasia is the immediate goal of endoscopic therapy, surveillance must continue after complete elimination of intestinal metaplasia, to detect and treat recurrences. PMID- 25743465 TI - Preoperative evaluation of oesophageal adenocarcinoma. AB - The preoperative evaluation of oesophageal adenocarcinoma involves endoscopic ultrasound (EUS), computed tomography (CT), and positron emission tomography (PET). With routine Barrett's oesophagus surveillance, superficial cancers are often identified. EUS, CT and PET have a limited role in the staging of superficial tumours. Standard EUS has limited accuracy, but high frequency ultrasound miniprobes are valuable for assessing tumour stage in superficial tumours. However, the best method for determining depth of invasion, and thereby stage of disease, is endoscopic mucosal resection. In contrast, in advanced oesophageal cancers, a multi-modality approach is crucial. Accurate tumour staging is very important since the treatment of advanced cancers involves a combination of chemotherapy, radiation, and surgery. EUS is very useful for staging of the tumour and nodes. High frequency ultrasound miniprobes provide the ability to perform staging when the lesion is obstructing the oesophageal lumen. CT and PET provide valuable information regarding node and metastasis staging. PMID- 25743466 TI - Chemoradiation in oesophageal cancer. AB - Oesophageal cancer is the 8th most common cancer worldwide, and has significant mortality and morbidity rates. The two most common histological types, squamous cell carcinoma and adenocarcinoma, have different localizations, distinctive risk factors, and molecular mechanisms. Survival for patients with locoregional oesophageal cancer is poor when treated with surgery only, with 5-year survival less than 10-15%. Radiation therapy has limited efficacy when given alone. Concurrent chemoradiation improves local-regional control and facilitates margin free resection when delivered preoperatively. Chemoradiation prolongs survival when given as definitive treatment or combined with surgery. Neoadjuvant chemoradiation also reduces risk of distant recurrence. To date, there is no data supporting the addition of targeted therapy to concurrent chemoradiation. Understanding molecular pathways regulating both radiosensitivity and tumorigenesis/invasion may lead to the discovery of new targeted agents, improving outcome of chemoradiation in terms of both locoregional and systemic control, ultimately resulting in prolonged survival. PMID- 25743467 TI - Barrett's oesophagus: treatment with surgery. AB - Barrett's oesophagus develops as a consequence of gastro-oesophageal reflux disease and may progress to oesophageal adenocarcinoma. Antireflux surgery is an option for patients with reflux disease, but the efficacy and impact on the natural history of disease in patients with Barrett's oesophagus is controversial. This review addresses the existing data on these important issues. PMID- 25743468 TI - Microrheology with optical tweezers: measuring the relative viscosity of solutions 'at a glance'. AB - We present a straightforward method for measuring the relative viscosity of fluids via a simple graphical analysis of the normalised position autocorrelation function of an optically trapped bead, without the need of embarking on laborious calculations. The advantages of the proposed microrheology method are evident when it is adopted for measurements of materials whose availability is limited, such as those involved in biological studies. The method has been validated by direct comparison with conventional bulk rheology methods, and has been applied both to characterise synthetic linear polyelectrolytes solutions and to study biomedical samples. PMID- 25743469 TI - Immunoreactive antigens recognized in serum samples from mice intranasally immunized with Porphyromonas gingivalis outer membrane vesicles. AB - Outer membrane vesicles (OMVs) of the periodontopathic bacterium Porphyromonas gingivalis contain a wide range of virulence factors including lipopolysaccharide (LPS), fimbriae and gingipains. We have recently reported strong immunogenicity of OMVs using an intranasal vaccine mouse model. In the present study, we performed sub-immunoproteome analysis of OMV-immunized mouse serum samples from six different mice in order to identify immunodominant antigens. The combination of two-dimensional (2D) gel electrophoresis and mass spectrometry analysis identified OMV proteins of 53 spots on a 2D map, and it was notable that OMV proteins were largely distributed within a low pH range, in marked contrast to the ubiquitous distribution of outer membrane proteins. Western blot using the six serum samples after 2D electrophoresis revealed that all showed immunoreactivity to some diffuse signals at extremely low pH, which was similar to the distribution of immunoreactive signals when the A-LPS antibody was used. Mass spectrometry analysis also demonstrated that the signals corresponded to a wide range of virulence factors including A-LPS-modified proteins such as gingipains. Absorption of serum with LPS resulted in a dramatic reduction of immmunoreactivity. We conclude that LPS and A-LPS-modified proteins in OMVs carry immunodominant determinants and eventually elicit P. gingivalis-specific antibodies in mice. PMID- 25743470 TI - Mce4F Mycobacterium tuberculosis protein peptides can inhibit invasion of human cell lines. AB - This work was aimed at studying the Mycobacterium tuberculosis H37Rv Rv3494c protein, taking into account that it belongs to the mammalian cell entry family (mce) which is thought to have important functions in the disease's pathogenesis. The protein was characterized in silico; its presence on mycobacterial surface was confirmed by immunoelectron microscopy. High-activity binding peptides (HABPs) were identified by binding assays with (125)I; their ability to inhibit mycobacterial entry to two cell lines (U937 alveolar macrophages and A549 epithelial cells) was ascertained and their role in bacterial entry was confirmed by fluorescent microsphere internalization assay. This protein's predicted alpha helix structure was confirmed by circular dichroism of its peptides. All HABPs inhibited mycobacterial entry to cells and that the 38379 peptide ((201)IDQAGPFLQAQIRAGGDIKSY(220)) had high binding ability and inhibited the mycobacterial entry to both cell lines assayed here. Rv3494c peptides 38370 ((21)LSVMAIFYLRLPATFGIGTY(40)), 38373 ((81)HMRLNSGTAIPSNVTATVRSY(100)) and 38379 ((201)IDQAGPFLQAQIRAGGDIKSY(220)) showed to be HABP and inhibited mycobacterial entry to A549 cells and peptide 38382 ((261)RPSFPALAASLANLGRVGVIY(280)) bind to U937 and inhibited the mycobacterial entry to this cell line; all of these sequences play an important role in cell line recognition and invasion, and may thus be considered in the search for prophylactic candidates against tuberculosis. PMID- 25743471 TI - Novel effects of Helicobacter pylori CagA on key genes of gastric cancer signal transduction: a comparative transfection study. AB - Helicobacter pylori (H. pylori) infection is now recognized as a worldwide problem. Helicobacter pylori CagA is the first bacterial oncoprotein to be identified in relation to human cancer. Helicobacter pylori CagA is noted for structural diversity in its C-terminal region (contains EPIYA motifs), with which CagA interacts with numerous host cell proteins. Deregulation of host signaling by translocated bacterial proteins provides a new aspect of microbial-host cell interaction. The aim of this study is to compare the cellular effects of two different CagA EPIYA motifs on identified signaling pathways involve in gastric carcinogenesis. To investigate the effects of CagA protein carboxyl region variations on the transcription of genes involved in gastric epithelial carcinogenesis pathways, the eukaryotic vector carrying the cagA gene (ABC and ABCCC types) was transfected into gastric cancer cell line. The 42 identified key genes of signal transduction involved in gastric cancer were analyzed at the transcription level by real-time PCR. The results of real-time PCR provide us important clue that the ABCCC oncoprotein variant can change the fate of the cell completely different from ABC type. In fact, these result proposed that the ABCCC type can induce the intestinal metaplasia, IL-8, perturbation of Crk adaptor proteins, anti-apoptotic effect and carcinogenic effect more significantly than ABC type. These data support our hypothesis of a complex interaction of host cell and these two different H. pylori effector variants that determines host cellular fate. PMID- 25743473 TI - Bactericidal, opsonophagocytic and anti-adhesive effectiveness of cross-reactive antibodies against Moraxella catarrhalis. AB - Moraxella catarrhalis is a human-restricted significant respiratory tract pathogen. The bacteria accounts for 15-20% of cases of otitis media in children and is an important causative agent of infectious exacerbations of chronic obstructive pulmonary disease in adults. The acquisition of new M. catarrhalis strains plays a central role in the pathogenesis of both mentioned disorders. The antibody-dependent immune response to this pathogen is critical for its effective elimination. Thus, the knowledge about the protective threshold of cross-reactive antibodies with defined functionality seems to be important. The complex analysis of broad-spectrum effectiveness of cross-reactive antibodies against M. catarrhalis has never been performed. The goal of the present study was to demonstrate and compare the bactericidal, opsonophagocytic and blocking function of cross-reacting antibodies produced in response to this bacterium or purified outer membrane proteins incorporated in Zwittergent-based micelles. The multivalent immunogens were used in order to better mimic the natural response of the host. The demonstrated broad-spectrum effectiveness of cross-reactive antibodies in pathogen eradication or inhibition strongly indicates that this pool of antibodies by recognition of pivotal shared M. catarrhalis surface epitopes seems to be an essential additional source to control host-microbe interaction. PMID- 25743472 TI - Protective and therapeutic effects of the resuscitation-promoting factor domain and its mutants against Mycobacterium tuberculosis in mice. AB - The resuscitation-promoting factor (Rpf), a secretory protein first reported in Micrococcus luteus, plays a critical role in mycobacterial survival and infection. There are five functionally redundant Rpf-like proteins identified in M. tuberculosis (Mtb). All these Rpfs share a conserved Rpf domain (Rpfd) composed of approximately 70 amino acids, which possesses the same biological functions as the full-length Rpf protein. Glutamic acid at position 54 in Rpfd (E54) has been implicated in mediating multiple physiological processes, and a single amino acid substitution at residue E54 can affect the protein biological activity. In order to determine the effects of different amino acid substitutions of E54 in Rpfd on its immunogenic activity, we generated three recombinant Rpfd mutants, Rpfd1 (E54K), Rpfd2 (E54A) and Rpfd3 (E54K and D48A), based on T-cell epitope prediction and tested their potential protective/therapeutic effects against Mtb in mice. Our results demonstrated that replacement of E54 by different amino acids in Rpfd distinctively influenced its resuscitation promoting activities and Th1-type immune responses induced in mice. Administration of Rpfd2 mutant enhanced Th1-type cellular responses (IFN-gamma and IL-2) in mice (P < 0.05, Rpfd2 versus control) and provided effective protection against Mtb in mice by significantly inhibiting the growth of Mtb during the initial stage of infection. Four weeks after the challenge, the slightest pathological injury in lung was observed in the Rpfd2-immunized group among all three Rfpd mutant-immunized groups. Furthermore, Rpfd2 therapy significantly decreased the bacterial load in lung and alleviated histopathological damage in Mtb-infected mice. Together, our results suggest Rpfd2 as a novel effective vaccine candidate against Mtb. PMID- 25743474 TI - Aggregatibacter actinomycetemcomitans induces Th17 cells in atherosclerotic lesions. AB - Th17 cells have been linked to the pathogenesis of several chronic inflammatory and autoimmune diseases. However, the role of Th17 cells and IL-17 in atherosclerosis remains poorly understood. We previously reported that Aggregatibacter actinomycetemcomitans (Aa) bacteremia accelerated atherosclerosis accompanied by inflammation in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. In this study, we investigated whether Aa promotes the Th17 inducing pathway in Aa-challenged Apoe(shl) mice. Mice were intravenously injected with live Aa HK1651 or vehicles. Time-course analysis of splenic IL-17(+)CD4(+) cell frequencies, the proximal aorta lesion area, serum IL 17, IL-6, TGF-beta and IL-1beta levels, the mRNA expression of Th17-related molecules such as IL-1beta, IL-6, IL17RA, STAT3, IL-21, IL-23, TGF-beta and RORgammat, Th17-related microRNA levels and the levels of AIM-2, Mincle and NLRP3 were examined. Challenge with Aa time dependently induced tropism of Th17 cells in the spleen and increase in atheromatous lesions in the aortic sinus of Apoe(shl) mice. Serum IL-17, IL-6, TGF-beta and IL-1beta levels were significantly enhanced by Aa. The gene expression of IL-1beta, IL-6, IL-17RA, IL 21, IL-23, TGF-beta, STAT3, RORgammat, AIM-2, Mincle and NLRP3 was also time dependently stimulated in the aorta of Aa-challenged mice. Furthermore, Aa challenge significantly increased the expression of miR-146b and miR-155 in the aorta. Based on the results, it seems that Aa stimulates Th17 induction that affects the progression of Aa-accelerated atherosclerosis. PMID- 25743475 TI - Proteomic analyses of iron-responsive, Clp-dependent changes in Staphylococcus aureus. AB - Staphylococcus aureus is a frequent human pathogen that is capable of causing a wide range of life-threatening infections. A promising antibacterial target is the Clp proteolytic system, which performs the vital function of maintaining protein turnover within the cell. This system primarily impacts the bacterial response to various stresses by degrading specific proteins but can also regulate a number of physiological processes through protein degradation. A critical stress to which S. aureus must adapt during infection of a vertebrate host is nutrient iron limitation. We have previously shown that the Clp system impacts expression of genes required for heme-iron acquisition during iron limitation and is required for staphylococcal infection. Based on these data, we sought to further define the Clp-dependent impact on S. aureus during iron limitation by characterizing the proteomic profiles of mutants inactivated for components of the Clp protease, including ClpP, ClpC and ClpX, in high- and low-iron conditions. Our results reveal numerous proteins altered in abundance in the clp mutants and provide new insights into the staphylococcal proteolytic network during nutrient iron limitation. PMID- 25743476 TI - Clostridium difficile toxin B intoxicated mouse colonic epithelial CT26 cells stimulate the activation of dendritic cells. AB - Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis mainly through two exotoxins TcdA and TcdB that target intestinal epithelial cells. Dendritic cells (DCs) play an important role in regulating intestinal inflammatory responses. In the current study, we explored the interaction of TcdB-intoxicated epithelial cells with mouse bone marrow-derived DCs. TcdB induced cell death and heat shock protein translocation in mouse intestinal epithelial CT26 cells. The intoxicated epithelial cells promoted the phagocytosis and the TNF-alpha secretion by DCs. Incubation with TcdB-intoxicated CT26 cells stimulated DC maturation. Moreover, TcdB-treated CT26 cells induced DC immigration when they were injected into mice subcutaneously. Taken together, these data demonstrate that TcdB-intoxicated intestinal epithelial cells are able to stimulate DC activation in vitro and attract DCs in vivo, indicating that epithelial cells may be able to regulate DC activation under the exposure of TcdB during C. difficile infection. PMID- 25743477 TI - Predictors of In-hospital Adverse Events in Patients with Prosthetic Valve Infective Endocarditis. AB - BACKGROUND: We aimed to study patients with prosthetic valve endocarditis (PVE) and analyse factors associated with in-hospital adverse events. METHODS: A review of all patients who underwent echocardiography at a local university hospital with definite PVE (modified Duke's criteria) was performed. Adverse events of in hospital mortality and redo valve surgery were identified. RESULTS: There were 23 patients with PVE (median age 53 years (IQR:38-66), 12 males (52%)). Twelve adverse events occurred including seven (30%) in-hospital mortalities and five (21%) redo valve surgery. Factors associated with in-hospital mortality include Staphylococcus aureus-PVE (86% vs 31%, p=0.027), presence of shock (86% vs 19%, p=0.005) and intensive care unit admission (72% vs 19%, p=0.026). Factors associated with the need for redo valve surgery include a younger median age (37 vs 61 years, p=0.012), longer median length of stay (58 vs 17 days, p=0.004), history of intravenous drug abuse (IVDA) (60% vs 6%, p=0.021) and right-sided valvular involvement (40% vs 0%, p=0.040). Using a composite endpoint of both outcomes, factors associated with in-hospital adverse events were a history of IVDA (36% vs 0%, p=0.037) and presence of shock (64% vs 17%, p=0.036). CONCLUSION: PVE carries a high risk of poor clinical outcome in terms of in hospital mortality and the need for redo surgery. PMID- 25743478 TI - Circumferential Calcified Thrombus in a Basal Lateral Wall Pseudo-aneurysm. PMID- 25743479 TI - Does frailty lie in the eyes of the beholder? PMID- 25743480 TI - Resistive switching in high-density nanodevices fabricated by block copolymer self-assembly. AB - Bipolar resistive switching memories based on metal oxides offer a great potential in terms of simple process integration, memory performance, and scalability. In view of ultrahigh density memory applications, a reduced device size is not the only requirement, as the distance between different devices is a key parameter. By exploiting a bottom-up fabrication approach based on block copolymer self-assembling, we obtained the parallel production of bilayer Pt/Ti top electrodes arranged in periodic arrays over the HfO2/TiN surface, building memory devices with a diameter of 28 nm and a density of 5 * 10(10) devices/cm(2). For an electrical characterization, the sharp conducting tip of an atomic force microscope was adopted for a selective addressing of the nanodevices. The presence of devices showing high conductance in the initial state was directly connected with scattered leakage current paths in the bare oxide film, while with bipolar voltage operations we obtained reversible set/reset transitions irrespective of the conductance variability in the initial state. Finally, we disclosed a scalability limit for ultrahigh density memory arrays based on continuous HfO2 thin films, in which a cross-talk between distinct nanodevices can occur during both set and reset transitions. PMID- 25743481 TI - Ramsay Hunt syndrome. PMID- 25743482 TI - Soft nano-wrapping on graphene oxide by using metal-organic network films composed of tannic acid and Fe ions. AB - Graphene oxide (GO) nanosheets were easily covered with uniform metal-organic network films composed of tannic acid and Fe ions. The surface morphology of the wrapped GO sheets was elucidated using atomic force, scanning electron, and transmission electron microscopy measurements. The GO sheets covered with the TA Fe films on a substrate were reduced chemically without the collapse of the wrapped nanostructure of the TA-Fe/GO sheets. The modified GO sheets covered with TA-Fe were highly stable in water and easy to handle, which made it possible for placing on a microelectrode array for conductivity measurements. PMID- 25743483 TI - ALPPS Offers a Better Chance of Complete Resection in Patients with Primarily Unresectable Liver Tumors. Results of a Multicentre Analysis: Reply. PMID- 25743484 TI - Clinicopathologic features and outcomes in patients with diffuse sclerosing variant of papillary thyroid carcinoma. AB - BACKGROUND: Diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare variant more common among younger patients. MATERIALS AND METHODS: Excluding patients with microcarcinoma, 5848 patients with PTC underwent initial surgery between 1995 and 2011. Twenty-two patients (0.4 %) were histologically diagnosed with DSV, of whom 20 (91 %) were <45 years old. We compared clinicopathologic characteristics and outcomes between patients with DSV and those with classical PTC <45 years old. Univariate analysis by the Kaplan-Meier method in relation to cause-specific survival (CSS) and disease-free survival (DFS) rates was performed with regard to the following variables: sex; anti thyroglobulin antibody (TgAb) positivity; presence of distant metastasis; pathological lymph node metastasis; extra-thyroidal invasion; and pathological variant (classical vs. DSV). RESULTS: The 20 patients with DSV <45 years old comprised 18 females and 2 males. Frequencies of TgAb, pN1b, and local recurrence were higher in the DSV group than in the classical PTC group. Ten-year CSS and DFS rates for PTC patients <45 years old were 99.7 and 88.6 % in the classical PTC group and 100 and 60.5 % in the DSV group. CSS rate did not differ between groups, but DFS rate was significantly lower in the DSV group than in the classical PTC group (p < 0.0001, log-rank test). Multivariate analysis identified DSV group and pN1b as prognostic factors for recurrence in young PTC patients. CONCLUSIONS: Most DSV patients were young and had a background of chronic thyroiditis. Outcomes for DSV were very good, but recurrence was more common than in classical PTC. PMID- 25743485 TI - Predictive factors for occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma by preoperative ultrasonographic and pathological features. AB - BACKGROUND: The surgical extent and indication for treatment in patients with papillary thyroid microcarcinoma (PTMC) remain a controversial issue. The aim of this study was to investigate the predictive factor for contralateral occult carcinoma in patients with unilateral PTMC by preoperative ultrasonographic and pathological features. METHODS: Of the total patients who underwent thyroidectomy, 455 patients with PTMC confined to one unilateral lobe as diagnosed using preoperative ultrasonography (US) were enrolled in the study. Occult contralateral carcinoma was defined as tumor foci in the contralateral lobe that was not detected preoperatively, but was detected pathologically. All patients underwent preoperative US review to investigate the US features of PTMC such as laterality, location, size, internal component, echogenicity, margin, calcification shape, multifocality, bilaterality, extrathyroidal extension, and location with respect to the trachea. Clinicopathological data were also analyzed. RESULTS: Of the total of 455 patients who underwent total thyroidectomy for preoperatively detected unilateral PTMC, 71 patients (15.6 %) had contralateral occult carcinoma. Clinicopathological characteristics did not significantly differ between patients with and without contralateral occult carcinoma. Multivariate analysis showed that the absence of a well-defined margin and the presence of a probably benign nodule in the contralateral lobe were independent predictive factors for contralateral occult carcinoma in patients with unilateral PTMC in preoperative US images. CONCLUSION: We demonstrated that an absence of a well-defined margin and the presence of a probably benign nodule in the contralateral lobe were independent predictive factors for contralateral occult carcinoma in patients with unilateral PTMC in preoperative US. The prediction of contralateral occult carcinoma in unilateral PTMC using preoperative US features could be useful for determining the optical extent of surgery. PMID- 25743487 TI - Long noncoding RNAs in organogenesis: making the difference. AB - A large proportion of the cellular transcriptome of higher vertebrates consists of non-protein coding transcripts, among them the long noncoding RNAs (lncRNAs). Although lncRNAs are functionally extremely divergent, many ncRNAs have been shown to interact with chromatin modifying complexes and/or with transcriptional regulators. Via such interactions, many lncRNAs are involved in controlling the activity and expression level of target genes, including important regulators of embryonic processes, and thereby fine-tune gene regulatory networks controlling cell fate, lineage balance, and organogenesis. Intriguingly, an increase in organ complexity during evolution parallels a rise in lncRNA abundance. The current data suggest that lncRNAs support the generation of cell diversity and organ complexity during embryogenesis, and thereby have promoted the evolution of more complex organisms. PMID- 25743486 TI - Effect of bovine colostrum feeding in comparison with milk replacer and natural feeding on the immune responses and colonisation of enterotoxigenic Escherichia coli in the intestinal tissue of piglets. AB - The present study investigated the effect of feeding bovine colostrum (BC) to piglets in comparison with feeding a milk replacer (MR) and conventional rearing by the sow on the intestinal immune system and number of enterotoxigenic Escherichia coli (ETEC) colonising the intestinal tissue. Piglets (23-d-old) were allocated to one of the following four groups: (1) killed at the beginning of the experiment (Base); (2) separated from the sow and fed BC (BC-fed); (3) separated from the sow and fed a MR (MR-fed); (4) kept with the sow (Sow-Milk). Blood was sampled on days 1 and 8, and faecal samples were collected on days 1, 3, 5 and 8. On day 8, piglets were killed and gastrointestinal digesta and intestinal segments were collected. The frequency of diarrhoea was found to be higher (P<= 0.019) in MR-fed piglets than in BC-fed and Sow-Milk piglets. Piglets from the MR fed group had the lowest lactic acid bacteria:haemolytic E. coli ratio (P(treat)= 0.064) in the faeces. The number of E. coli colonising the intestinal tissue was higher (P< 0.001) in piglets from the MR-fed group than in those from the BC-fed and Sow-Milk groups. Piglets from the Sow-Milk group had a higher (P= 0.020) mucosal IgG concentration than those from the MR-fed group, but did not exhibit any difference when compared with piglets from the Base and BC-fed groups. Piglets from the BC-fed group exhibited a reduced (P<= 0.037) expression level of Toll-like receptor-4 in the intestinal mucosa when compared with those from the MR-fed and Sow-Milk groups. The expression level of IL-2 was higher (P<= 0.051) in piglets from the MR-fed group than in those from the other treatment groups. In conclusion, feeding BC rather than MR to the piglets reduced the colonisation of intestine by ETEC and modulated the intestinal immune system, whereas no differences were observed in piglets fed BC and conventionally reared by the sows. PMID- 25743488 TI - Shortening trinucleotide repeats using highly specific endonucleases: a possible approach to gene therapy? AB - Trinucleotide repeat expansions are involved in more than two dozen neurological and developmental disorders. Conventional therapeutic approaches aimed at regulating the expression level of affected genes, which rely on drugs, oligonucleotides, and/or transgenes, have met with only limited success so far. An alternative approach is to shorten repeats to non-pathological lengths using highly specific nucleases. Here, I review early experiments using meganucleases, zinc-finger nucleases (ZFN), and transcription-activator like effector nucleases (TALENs) to contract trinucleotide repeats, and discuss the possibility of using CRISPR-Cas nucleases to the same end. Although this is a nascent field, I explore the possibility of designing nucleases and effectively delivering them in the context of gene therapy. PMID- 25743489 TI - Erratum to: The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review. PMID- 25743492 TI - [Bouveret syndrome. What is obstructing the duodenum?]. PMID- 25743495 TI - [The doctor's new vanity vehicle]. PMID- 25743496 TI - [Futuristic imaging in the Bavarian forest]. PMID- 25743497 TI - [An unusual career. An Oxford researcher becomes country doctor]. PMID- 25743498 TI - [Shortage of rural physicians. How to "seduce" first semester students]. PMID- 25743502 TI - [Prevention ruling. Screening program only with evidence!]. PMID- 25743503 TI - [Therapy of chronic renal failure. Family practitioner and nephrologist hand in hand]. PMID- 25743505 TI - [Consider recurrence prevention in kidney calculi. After colic is before colic]. PMID- 25743504 TI - [Terminal renal failure. Planning renal replacement early!]. PMID- 25743506 TI - [Two drugs inhibit disease progression. Idiopathic lung fibrosis treatable for the first time]. PMID- 25743507 TI - [Cough, runny nose, musculoskeletal pain. What you can recommend for the common cold]. PMID- 25743508 TI - [Progress and new challenges. HIV: the cure moves closer]. PMID- 25743510 TI - [Paroxysmal atrial fibrillation well controlled. Why the sudden patient syncope?]. PMID- 25743512 TI - [A second opiate poisoning often follow the first one]. PMID- 25743513 TI - [No information can help hardcore vaccination skeptics]. PMID- 25743515 TI - [A new era in therapy of chronic hepatitis C]. PMID- 25743516 TI - [Pregnancy: problems after kidney donation]. PMID- 25743517 TI - [Also atrial fibrillation without symptoms carries risks]. PMID- 25743519 TI - [No missed lesions in index colonoscopy]. PMID- 25743521 TI - [Medical therapy of ulcerative colitis]. PMID- 25743522 TI - [Ulcerative colitis--surgical treatment and aftercare]. PMID- 25743523 TI - [Multinodular goiter. "My blood tests have always been in best order"]. PMID- 25743524 TI - [Edema--kidney disease to heart failure]. PMID- 25743525 TI - [Headaches diary, weekends, chocolate and red wine: are expectations the leading migraine trigger?]. PMID- 25743538 TI - [Clostridium difficile, are all our patients diagnosed?]. AB - BACKGROUND: A close correlation between clinical and microbiological diagnosis in Clostridium difficile infection (CDI) is very important to identify how severe is this health problem, and to approach its correct management of it, individually and as a population problem. OBJETIVES: a) To evaluate if there is an adequate correlation between the microbiological and clinical diagnosis in CDI patients; b) to determine if the discordance between the microbiological and clinical diagnosis could be associated with different clinical patient characteristics, therapeutic attitudes, and outcomes. PATIENTS AND METHODS: A retrospective study was conducted, using clinical and epidemiologic data, on inpatients with a microbiological diagnosis of CDI in 2013 in the Hospital Clinico San Carlos in Madrid (Spain), depending on whether their clinical ICD diagnosis was included. RESULTS: From a total of 33,317 discharged patients, 204 patients had a CDI diagnosis. Only 51.5% patients had this diagnosis stated in their discharge report. Patients on whom the clinical diagnosis was included, were older, had higher level of dependence (P<.05), and received treatment for CDI more frequently (P<.001) than patients who did not have the clinical diagnosis included. A lower treatment rate was associated with a higher mortality (P=.032) CONCLUSIONS: Nearly half of patients with a microbiological diagnosis of CDI did not have the clinical diagnosis included in their clinical report. Patients without the clinical diagnosis were younger, had less disability, and received specific antibiotics for CDI less frequently. Not receiving specific antibiotics for CDI was associated with higher mortality. PMID- 25743539 TI - Adhesion, invasion, intracellular survival and cytotoxic activity of strains of Aeromonas spp. in HEp-2, Caco-2 and T-84 cell lines. AB - The genus Aeromonas contains important pathogen for both humans and other animals, being responsible for the etiology of intestinal and extraintestinal diseases. The pathology caused by these bacteria involves several virulence factors, such as the ability to produce toxins, adhesion and invasion. The properties conferred by these factors have been extensively studied in experiments of interaction between bacterial strains and cell culture. We evaluate the interaction of eight Aeromonas spp. strains, previously isolated from human faeces, food and water with HEp-2, Caco-2 and T-84 cell lines. Cytotoxic effects, the pattern of adhesion, invasive capacity and intracellular survival were analyzed. The results showed that Aeromonas strains were adherent to three cells lines in 6 h of incubation, displaying the aggregative adherence pattern. Among eight strains studied, 50% produced cytotoxic effects on HEp-2 cells, while none of the strains produced cytotoxic effects on Caco-2 and T-84 cells at 48 h. This study demonstrated that subsets of Aeromonas isolated from different sources were able to invade intestinal (T-84, Caco-2) and epithelial (HEp-2) cell lines cultivated in vitro surviving in intracellular environments up to 72 h. Finally, our results support the pathogenic potential of Aeromonas, especially those of food and clinical sources. PMID- 25743540 TI - Corrigendum: The immune synapse clears and excludes molecules above a size threshold. PMID- 25743541 TI - Home advantage in soccer--A matter of expectations, goal setting and tactical decisions of coaches? AB - In soccer, home teams win about 67% of decided games. The causes for this home advantage are still unresolved. There is a shortage of research on the psychological states of actors involved. In this study, we examined soccer coaches' expectations, goal setting and tactical decisions in relation to game location. Soccer coaches (N = 297) with different expertise levels participated in an experimental, online management game and were randomly assigned to one of two groups, "home game (HG)" or "away game." Participants received information on the game for which they were asked to make decisions in multiple points. The only differing information between groups was game location. Regardless of expertise, HG coaches had higher expectations to win, set more challenging goals and decided for more offensive and courageous playing tactics. Possible consequences of these findings concerning home advantage in soccer are discussed. PMID- 25743542 TI - Anthropometric profile of elite acrobatic gymnasts and prediction of role performance. AB - BACKGROUND: This study is aimed at determining the anthropometric profile of acrobatic gymnasts, differentiating on the basis of their role. METHODS: The sample consisted of 150 gymnasts (129 women and 21 men) from throughout Spain. The anthropometric measurements were taken according to the International Society for the Advancement of Kinanthropometry (ISAK) procedures. Morphological measurements, proportionality and somatotype were analyzed in both groups. A comparative analysis between groups and a prediction model were used to analyze the specific profile of each role. RESULTS: All morphological measurements showed significant differences (P<0.05) between tops and bases, the latter presenting higher values. The endomorphic element of the bases presented higher values than the tops, for whom the ectomorphy scores were higher. Bases have an endo mesomorphic somatotype and tops present a balanced mesomorphic. There are no mesomorphy differences between the tops and bases. BMI was significantly higher in the bases (BMI=20.28 kg/m2). Proportionality differences between roles are shown. Both roles present negatives values for almost all variables studied except for the trochlear condyle of the humerus, the bicondyle of the femur and the wrist bistyloid breadth in tops and the wrist bistyloid breadth, the upper arm relaxed girths and maximum calf in bases. The best prediction model included thigh girth as the best explanatory covariate of role performance. CONCLUSIONS: Here are differences between both roles, bases being gymnasts of larger size than tops. However, they present no differences in the muscular component, as it might be expected. PMID- 25743543 TI - Neighboring Genes Show Correlated Evolution in Gene Expression. AB - When considering the evolution of a gene's expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (<100 kb) but extends much further. Sex-specific expression change is also genomically clustered. As genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5 hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. PMID- 25743546 TI - The multihued palette of dye-decolorizing peroxidases. AB - Dye-decolorizing peroxidases (DyPs; EC 1.11.1.19) are heme enzymes that comprise a family of the dimeric alpha+beta barrel structural superfamily of proteins. The first DyP, identified relatively recently in the fungus Bjerkandera adusta, was characterized for its ability to catalyze the decolorization of anthraquinone based industrial dyes. These enzymes are now known to be present in all three domains of life, but do not appear to occur in plants or animals. They are involved in a range of physiological processes, although in many cases their roles remain unknown. This has not prevented the development of their biocatalytic potential, which includes the transformation of lignin. This review highlights the functional diversity of DyPs in the light of phylogenetic, structural and biochemical data. The phylogenetic analysis reveals the existence of at least five classes of DyPs. Their potential physiological roles are discussed based in part on synteny analyses. Finally, the considerable biotechnological potential of DyPs is summarized. PMID- 25743545 TI - Multispecies Analysis of Expression Pattern Diversification in the Recently Expanded Insect Ly6 Gene Family. AB - Gene families often consist of members with diverse expression domains reflecting their functions in a wide variety of tissues. However, how the expression of individual members, and thus their tissue-specific functions, diversified during the course of gene family expansion is not well understood. In this study, we approached this question through the analysis of the duplication history and transcriptional evolution of a rapidly expanding subfamily of insect Ly6 genes. We analyzed different insect genomes and identified seven Ly6 genes that have originated from a single ancestor through sequential duplication within the higher Diptera. We then determined how the original embryonic expression pattern of the founding gene diversified by characterizing its tissue-specific expression in the beetle Tribolium castaneum, the butterfly Bicyclus anynana, and the mosquito Anopheles stephensi and those of its duplicates in three higher dipteran species, representing various stages of the duplication history (Megaselia abdita, Ceratitis capitata, and Drosophila melanogaster). Our results revealed that frequent neofunctionalization episodes contributed to the increased expression breadth of this subfamily and that these events occurred after duplication and speciation events at comparable frequencies. In addition, at each duplication node, we consistently found asymmetric expression divergence. One paralog inherited most of the tissue-specificities of the founder gene, whereas the other paralog evolved drastically reduced expression domains. Our approach attests to the power of combining a well-established duplication history with a comprehensive coverage of representative species in acquiring unequivocal information about the dynamics of gene expression evolution in gene families. PMID- 25743547 TI - [Operative Results of Total Arch Replacement with Arch First Technique using a Trifurcated Graft]. AB - In aortic arch surgery, we reconstruct branches before opening the arch to avoid cerebral embolism of the debris derived from the aortic wall. We made a trifurcated graft for branch reconstruction using 10 mm and 8 mm polyester grafts. Cardiopulmonary bypass started under right axillary perfusion and venous drainage through the right atrium. While cooling, the left subclavian artery was clamped and anastomosed to the end of the trifurcated graft. Then the ascending aorta was cross-clamped and cardioplegic solution was infused. At 25 degrees centigrade of the tympanic temperature, the left carotid artery is clamped and anastomosed to the branch of the trifurcated graft with or without perfusion into the left carotid artery. Subsequently the brachiocephalic artery was reconstructed in the same manner. After antegrade cerebral perfusion was established through the trifurcated graft via right axillary perfusion, distal anastomosis of the aortic arch was done with the open distal technique. Graft graft anastomosis was followed to reperfuse the lower half of the body. Finally proximal anastomosis was performed to complete total arch replacement. Forty-four patients underwent total arch replacement in this technique. In-hospital mortality was 4.5%. Cerebral infarction occurred in 4.5% of the patients probably due to embolization of the debris derived from the branches of the aortic arch. PMID- 25743544 TI - Ancient Duplications and Expression Divergence in the Globin Gene Superfamily of Vertebrates: Insights from the Elephant Shark Genome and Transcriptome. AB - Comparative analyses of vertebrate genomes continue to uncover a surprising diversity of genes in the globin gene superfamily, some of which have very restricted phyletic distributions despite their antiquity. Genomic analysis of the globin gene repertoire of cartilaginous fish (Chondrichthyes) should be especially informative about the duplicative origins and ancestral functions of vertebrate globins, as divergence between Chondrichthyes and bony vertebrates represents the most basal split within the jawed vertebrates. Here, we report a comparative genomic analysis of the vertebrate globin gene family that includes the complete globin gene repertoire of the elephant shark (Callorhinchus milii). Using genomic sequence data from representatives of all major vertebrate classes, integrated analyses of conserved synteny and phylogenetic relationships revealed that the last common ancestor of vertebrates possessed a repertoire of at least seven globin genes: single copies of androglobin and neuroglobin, four paralogous copies of globin X, and the single-copy progenitor of the entire set of vertebrate-specific globins. Combined with expression data, the genomic inventory of elephant shark globins yielded four especially surprising findings: 1) there is no trace of the neuroglobin gene (a highly conserved gene that is present in all other jawed vertebrates that have been examined to date), 2) myoglobin is highly expressed in heart, but not in skeletal muscle (reflecting a possible ancestral condition in vertebrates with single-circuit circulatory systems), 3) elephant shark possesses two highly divergent globin X paralogs, one of which is preferentially expressed in gonads, and 4) elephant shark possesses two structurally distinct alpha-globin paralogs, one of which is preferentially expressed in the brain. Expression profiles of elephant shark globin genes reveal distinct specializations of function relative to orthologs in bony vertebrates and suggest hypotheses about ancestral functions of vertebrate globins. PMID- 25743548 TI - [Full Recovery from Cardiopulmonary Arrest caused by Traumatic Asphyxia]. AB - Traumatic asphyxia is a crush injury of the chest characterized by facial edema, cyanosis, conjunctival hemorrhage, and petechiae on the face and chest. The prognosis depends on the duration of chest compression and early cardiopulmonary resuscitation after cardiopulmonary arrest. Here we report a case of full recovery from cardiopulmonary arrest caused by traumatic asphyxia. The chest of a 56-year-old man was compressed by a machine while working. Immediately, his colleague started cardiopulmonary resuscitation, which was successful. When he was admitted to our hospital, his consciousness level was E1V2M2(Glasgow coma scale). Our treatment included therapeutic hypothermia, the duration of which was 24 hours at 34 degrees C. Rewarming his body to 36 degrees C took place over 48 hours. Thereafter, he recovered completely and was discharged on the 12th hospital day without neurologic sequela. Therapeutic hypothermia was possibly effective in this case. PMID- 25743549 TI - [Two cases of fulminant myocarditis with mesenteric ischemia]. AB - Fulminant myocarditis (FM) can lead to a refractory cardiogenic shock and multiple organ failure. Mechanical circulatory support (MCS) is not infrequency required to salvage patients in a profound shock. Advanced technology in MCS such as a temporary ventricular assist device can yield improved early outcome. However, incessant mesenteric ischemia remains a challenge to be resolved even with MCS. We here-in report 2 cases of FM associated with mesenteric ischemia that was extremely difficult to diagnose and treat. Therapeutic strategy for FM with mesenteric ischemia is discussed. PMID- 25743550 TI - [Stanford type B aortic dissection associated with coarctation of the aorta]. AB - We report a rare case of type B aortic dissection associated with coarctation of the aorta. A 35-year-old man had sudden dyspnea and severe back pain. Computed tomography revealed aortic coarctation at the distal aortic arch, and aortic dissection below the coarctation. The diameter of proximal descending aorta was enlarged to 52 mm. We electively performed excision of aortic coarctation and descending aortic graft replacement. Coarctation of the aorta has a poor prognosis, The risk of aortic rupture due to aortic dissection is very high, and the histological abnormality is also pointed out. Therefore we should perform aggressive surgical treatment. PMID- 25743551 TI - [One-stage resection of intravenous leiomyomatosis extending into the right atrium]. AB - Intravenous leiomyomatosis (IVL) is a benign tumor that originates from a uterine myoma and rarely extends to the heart through the inferior vena cava (IVC). Echocardiography revealed an abnormal mass in the right atrium in a 63-year-old asymptomatic woman. Preoperative examination revealed a tumor extending from a myoma through the right internal iliac vein to the right atrium, and the patient was diagnosed with IVL. She underwent sternotomy combined with laparotomy, and the intravenous and intracardiac tumor was removed under normothermic cardiopulmonary bypass without cardiac arrest. Hysterectomy and bilateral adnexectomy were also performed. No additional therapy was required after surgery. PMID- 25743552 TI - [Clear Cell Tumor of the Lung Showing Gradual Growth for 6 years]. AB - Clear cell tumor of the lung (CCTL) is a rare benign tumor that originates from the lung. We report a case of CCTL which had grown for 6 years. The patient was a 25-year-old woman and her chest roentgenogram detected a well-circumscribed coin like shadow in the left lower lung field. Its size was 30 mm in diameter at consultation, and retrospectively we recognized a nodule of 13 mm in diameter in the same location on the health checkup roentgenogram 6 years before. The growth of the tumor suggested the possibility of malignancy, and the tumor was surgically resected by partial resection of the lung. Post operative course was uneventful. The tumor was clearly separated from pulmonary parenchyma, and was immunohistochemically diagnosed as CCTL. PMID- 25743553 TI - [Hemorrhage from the subclavian artery after lung cancer resection treated by stent graft placement]. AB - We present a case of a 79-year-old man with right apical invasive lung cancer which was treated by induction radiotherapy followed by right upper lobectomy with chest wall resection. Four days after the operation, hemorrhage from the funicular structure in the cupula of the parietal pleura was observed, and hemostasis was achieved by ligation and fibrin sheet pasting. At the time, we were not able to detect the hemorrhage from the subclavian artery. Two days after the 1st hemostasis, hemorrhage reccurred. Hemorrhage from the inferior border of the subclavian artery was observed, and hemostasis was achieved by direct suture and fibrin sheet pasting. One day after the 2nd hemostasis, re-recurrent hemorrhage occurred. Stent graft placement was performed under local anesthesia. No hemorrhage occurred after the stent graft placement. PMID- 25743554 TI - [Intrapulmonary hematoma masquerading as metastatic carcinoma of lung cancer]. AB - We herein report a case of intrapulmonary hematoma after lobectomy for lung cancer. A 51-year-old male underwent right upper lobectomy for lung cancer in a thoracoscopic procedure. Three months after the operation, chest computed tomography showed a 16-mm well-circumscribed nodule in the right lower lobe suggesting metastatic carcinoma for lung cancer. We performed the partial resection of the right lower lobe. The histological examination confirmed the diagnosis of an intrapulmonary hematoma. When pulmonary shadow appears after lung operations, intrapulmonary hematoma is one of a choice of differential diagnosis. Magnetic resonance imaging may be useful in establishing the diagnosis when intrapulmonary hematoma is suspicious clinically. PMID- 25743555 TI - [Present and aspects for cadaver surgical training in Japan]. AB - In overseas countries the cadaver surgical training (CST) has been very common as evaluation systems for new operative method and medical devices. However, in Japan basic autopsy training is indispensable for nurturing doctors at schools of medicine, while the clinical doctors have been using cadavers for the progress and technique, or the like, of a surgery with the scope of clinical autopsy. In the consequence, in 2013 the guideline "Autopsy for clinical medicine training and research" was put in effect over a series of discussions for the purpose of society acknowledgement of CST. The subsidized project "Training for the development of practical technique of a surgery" by the Ministry of Health and Labor has been offered publicly for private organizations and expected a nationwide expansion. I review the current situation of CST in Japan and introduce CST at Ehime University School of Medicine. This editorial is based on the background of CST in Japan and referred to the outlook for the future. PMID- 25743556 TI - [Cadiac lipoma of the right atrium;report of a case]. AB - Cardiac lipoma is a rare benign tumor. A 42-year-old male was referred to our hospital to undergo thorough examination and treatment of a space-occupying right atrial lesion, detected incidentally by chest computed tomography(CT). After admission, it was diagnosed as cardiac lipoma by echocardiography, CT, and magnetic resonance imaging. We resected the tumor under cardiopulmonary bypass and reconstructed the right atrium using a bovine pericardial patch. The histopathological examination reveaed that the tumor was lipoma. The postoperative course has been uneventful without recurrence for nearly 2 years. PMID- 25743557 TI - [Surgical excision of left atrial myxoma shortly after cerebral embolism;report of a case]. AB - A 48-year-old male visited the emergency room suffering from acute dysarthria and right hemiplegia. Brain magnetic resonance imaging (MRI) revealed multiple cerebral infarctions. Echocardiography showed a mass in the left atrium. He was diagnosed with cerebral embolism due to left atrial myxoma. Open heart surgery immediately after the attack is generally considered contraindicated because of such problems as hemorrhagic infarction or brain edema. However, relapse of embolism may make the condition worse and miss the timing of surgery. Eventually, we electively performed excision of the myxoma 20 days after the onset of cerebral infarction. The postoperative course was uneventful. This is a report about a rare case of open heart surgery shortly after the attack. The indication and the appropriate timing of open heart surgery following cerebral embolism were discussed. PMID- 25743558 TI - [Vacuum-assisted Closure (VAC) Treatment for Sternal Infection in a Patient after Cardiovascular Surgery; Report of a Case]. AB - One year ago, a 42-year-old woman underwent aortic root replacement because of a pseudoaneurysm that developed at the site of an anastomosis after ascending aortic replacement for acute aortic dissection. Six months later, she complained of fever and cough. A computed tomography revealed recurrence of the peudoaneurysm at the proximal anastomosis of the aortic root replacement. After emergency re-do aortic root replacement, she was admitted to intensive care unit (ICU) without sternal closure because of mediastinitis. The mediastinitis was managed by debridement and lavage drainage, followed by vacuum-assisted closure (VAC) treatment. The VAC treatment facilitated wound healing and active rehabilitation using a portable device. Finally, the wound was closed completely using a skin graft. VAC treatment is considered very useful in a case of post sternotomy madiastinitis. PMID- 25743559 TI - [Restenosis following descending aortic replacement for coarctation of the aorta; report of a case]. AB - We report a case of a 44-year-old man with restenosis of coarctation of aorta (CoA). He had a history of descending aortic replacement for CoA using a graft 14 mm in diameter at 29 years ago. He had reoperation because of pressure gradient of 61 mmHg across the graft and intermittent claudication. Reoperation was done under unilateral lung ventilation with lung collapsed, through 3th and 5th interspace thoracotomy. Left lung adhesion was carefully released with an ultrasonically vibrating scalpel. After full heparinization, femoro-femoral bypass was started and descending aorta was clamped. The old graft was excised, and descending aortic replacement was done with a new graft of 26 mm in a diameter. His postoperative course was uneventful. The intermittent claudication disappeared. PMID- 25743560 TI - [Successful mitral valve replacement in a patient with functional mitral regurgitation induced by cardiac sarcoidosis;report of a case]. AB - We report a case of cardiac sarcoidosis associated with mitral valve regurgitation. A 62-year-old woman with cardiac sarcoidosis was admitted for the treatment of an intractable mitral regurgitation. She had been treated for cardiac sarcoidosis with prednisolone, and she had undergone pacemaker implantation because of advanced complete A-V block 5 years before. However, her hemodynamics deteriorated, and echocardiography revealed severe functional mitral regurgitation, thinning of the ventricular septum, and left ventricular dysfunction. The patient underwent mitral valve replacement with a mechanical prosthetic valve, and her postoperative course was uneventful. She is currently well without exacerbation of heart failure at 2 years after operation. Functional mitral regurgitation is a relatively common complication in patients with cardiac sarcoidosis. Mitral valve replacement should be considered in patients with medically intractable mitral valve dysfunction due to cardiac sarcoidosis. PMID- 25743561 TI - [Parathyroid Hormone-related Peptide (PTHrP) Producing Lung Cancer Presenting Hypercalcemia; Report of a Case]. AB - An 82-year-old man was admitted to our hospital with hemoptysis and weight loss. Chest computed tomography(CT) showed a 90 mm mass with cavity formation in the right lower lobe adjacent to chest wall. Laboratory data revealed hypercalcemia and elevation of parathyroid hormone-related protein C (PTHrP). He was diagnosed as squamous cell carcinoma of lung by transbronchial lung biopsy (TBLB) [cT3aN1M0]. Nausea and anorexia due to hypercalcemia became worse and a right middle and lower lobectomy was performed because of difficult control of symptoms by medicine and worsening of his general condition. His symptoms were improved immediately after surgery. PMID- 25743562 TI - Non-invasive methods for the determination of body and carcass composition in livestock: dual-energy X-ray absorptiometry, computed tomography, magnetic resonance imaging and ultrasound: invited review. AB - The ability to accurately measure body or carcass composition is important for performance testing, grading and finally selection or payment of meat-producing animals. Advances especially in non-invasive techniques are mainly based on the development of electronic and computer-driven methods in order to provide objective phenotypic data. The preference for a specific technique depends on the target animal species or carcass, combined with technical and practical aspects such as accuracy, reliability, cost, portability, speed, ease of use, safety and for in vivo measurements the need for fixation or sedation. The techniques rely on specific device-driven signals, which interact with tissues in the body or carcass at the atomic or molecular level, resulting in secondary or attenuated signals detected by the instruments and analyzed quantitatively. The electromagnetic signal produced by the instrument may originate from mechanical energy such as sound waves (ultrasound - US), 'photon' radiation (X-ray-computed tomography - CT, dual-energy X-ray absorptiometry - DXA) or radio frequency waves (magnetic resonance imaging - MRI). The signals detected by the corresponding instruments are processed to measure, for example, tissue depths, areas, volumes or distributions of fat, muscle (water, protein) and partly bone or bone mineral. Among the above techniques, CT is the most accurate one followed by MRI and DXA, whereas US can be used for all sizes of farm animal species even under field conditions. CT, MRI and US can provide volume data, whereas only DXA delivers immediate whole-body composition results without (2D) image manipulation. A combination of simple US and more expensive CT, MRI or DXA might be applied for farm animal selection programs in a stepwise approach. PMID- 25743563 TI - Biological effects of inorganic phosphate: potential signal of toxicity. AB - Inorganic phosphate (Pi) plays crucial roles in several biological processes and signaling pathways. Pi uptake is regulated by sodium-dependent phosphate (Na/Pi) transporters (NPTs). Moreover, Pi is used as a food additive in food items such as sausages, crackers, dairy products, and beverages. However, the high serum concentration of phosphate (> 5.5 mg/dL) can cause adverse renal effects, cardiovascular effects including vascular or valvular calcification, and stimulate bone resorption. In addition, Pi can also alter vital cellular signaling, related to cell growth and cap-dependent protein translation. Moreover, intake of dietary Pi, whether high (1.0%) or low (0.1%), affects organs in developing mice, and is related to tumorigenesis in mice. The recommended dietary allowance (RDA) of Pi is the daily dietary intake required to maintain levels above the lower limit of the range of normal serum Pi concentration (2.7 mg/dL) for most individuals (97-98%). Thus, adequate intake of Pi (RDA; 700 mg/day) and maintenance of normal Pi concentration (2.7-4.5 mg/dL) are important for health and prevention of diseases caused by inadequate Pi intake. PMID- 25743564 TI - Characterization of nicardipine hydrochloride-induced cell injury in human vascular endothelial cells. AB - Nicardipine hydrochloride (NIC), a dihydropyridine calcium-channel blocking agent, has been widely used for the treatment of hypertension. Especially, nicardipine hydrochloride injection is used as first-line therapy for emergency treatment of abnormally high blood pressure. Although NIC has an attractive pharmacological profile, one of the dose-limiting factors of NIC is severe peripheral vascular injury after intravenous injection. The goal of this study was to better understand and thereby reduce NIC-mediated vascular injury. Here, we investigated the mechanism of NIC-induced vascular injury using human dermal microvascular endothelial cells (HMVECs). NIC decreased cell viability and increased percent of dead cells in a dose-dependent manner (10-30 MUg/mL). Although cell membrane injury was not significant over 9 hr exposure, significant changes of cell morphology and increases in vacuoles in HMVECs were observed within 30 min of NIC exposure (30 MUg/mL). Autophagosome labeling with monodansylcadaverine revealed increased autophagosomes in the NIC-treated cells, whereas caspase 3/7 activity was not increased in the NIC-treated cells (30 MUg/mL). Additionally, NIC-induced reduction of cell viability was inhibited by 3 methyladenine, an inhibitor of autophagosome formation. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy could contribute to the reduction of NIC-induced vascular injury. PMID- 25743565 TI - Antiseptic Effects of New 3'-N-Substituted Carbazole Derivatives In Vitro and In Vivo. AB - Inhibition of high-mobility group box 1 (HMGB1) protein and restoration of endothelial integrity are emerging as attractive therapeutic strategies in the management of sepsis. Here, new five structurally related 3'-N-substituted carbazole derivatives were examined for their effects on lipopolysaccharide (LPS) mediated or cecal ligation and puncture (CLP)-mediated release of HMGB1 and on modulation of HMGB1-mediated inflammatory responses. We accessed this question by monitoring the effects of posttreatment carbazole derivatives on LPS- and CLP mediated release of HMGB1 and HMGB1-mediated regulation of proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. The new 3'-N-substituted carbazole derivatives 1-5 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. New compounds also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with each compound reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice. These results indicate that the new 3'-N-substituted carbazole derivatives could be candidate therapeutic agents for various severe vascular inflammatory diseases owing to their inhibition of the HMGB1 signaling pathway. PMID- 25743566 TI - Work Tasks as Determinants of Grain Dust and Microbial Exposure in the Norwegian Grain and Compound Feed Industry. AB - OBJECTIVES: The grain and compound feed industry entails inevitable risks of exposure to grain dust and its microbial content. The objective of this study was therefore to investigate task-dependent exposure differences in order to create knowledge basis for awareness and exposure reducing measures in the Norwegian grain and compound feed industry. METHODS: A total of 166 samples of airborne dust were collected by full-shift personal sampling during work in 20 grain elevators and compound feed mills during one autumn season and two winter seasons. The personal exposure to grain dust, endotoxins, beta-1->3-glucans, bacteria, and fungal spores was quantified and used as individual outcomes in mixed models with worker nested in company as random effect and different departments and tasks as fixed effects. RESULTS: The exposure levels were highest in grain elevator departments. Exposure to endotoxins was particularly high. Tasks that represented the highest and lowest exposures varied depending on the bioaerosol component. The most important determinants for elevated dust exposure were cleaning and process controlling. Cleaning increased the dust exposure level by a factor of 2.44 of the reference, from 0.65 to 1.58mg m(-3), whereas process controlling increased the dust exposure level by a factor of 2.97, from 0.65 to 1.93mg m(-3). Process controlling was associated with significantly less grain dust exposure in compound feed mills and the combined grain elevators and compound feed mills, than in grain elevators. The exposure was reduced by a factor of 0.18 and 0.22, from 1.93 to 0.34mg m(-3) and to 0.42mg m(-3), respectively, compared with the grain elevators. Inspection/maintenance, cleaning, and grain rotation and emptying were determinants of higher exposure to both endotoxin and beta-1->3-glucans. Seed winnowing was in addition a strong determinant for endotoxin, whereas mixing of animal feed implied higher beta-1->3 glucan exposure. Cleaning was the only task that contributed significantly to higher exposure to bacteria and fungal spores. CONCLUSION: Cleaning in all companies and process controlling in grain elevators were the strongest determinants for overall exposure, whereas seed winnowing was a particular strong determinant of endotoxin exposure. Exposure reduction by technical intervention or personal protective equipment should therefore be considered at work places with identified high exposure tasks. PMID- 25743568 TI - Influence of material surface on the scanning error of a powder-free 3D measuring system. AB - OBJECTIVES: This study aims to evaluate the accuracy of a powder-free three dimensional (3D) measuring system (CEREC Omnicam, Sirona), when scanning the surface of a material at different angles. Additionally, the influence of water was investigated. MATERIALS AND METHODS: Nine different materials were combined with human tooth surface (enamel) to create n = 27 specimens. These materials were: Controls (InCoris TZI and Cerec Guide Bloc), ceramics (Vitablocs(r) Mark II and IPS Empress CAD), metals (gold and amalgam) and composites (Tetric Ceram, Filtek Supreme A2B and A2E). The highly polished samples were scanned at different angles with and without water. The 216 scans were then analyzed and descriptive statistics were obtained. RESULTS: The height difference between the tooth and material surfaces, as measured with the 3D scans, ranged from 0.83 MUm (+/-2.58 MUm) to -14.79 MUm (+/-3.45 MUm), while the scan noise on the materials was between 3.23 MUm (+/-0.79 MUm) and 14.24 MUm (+/-6.79 MUm) without considering the control groups. Depending on the thickness of the water film, measurement errors in the order of 300-1,600 MUm could be observed. CONCLUSIONS: The inaccuracies between the tooth and material surfaces, as well as the scan noise for the materials, were within the range of error for measurements used for conventional impressions and are therefore negligible. The presence of water, however, greatly affects the scan. CLINICAL RELEVANCE: The tested powder-free 3D measuring system can safely be used to scan different material surfaces without the prior application of a powder, although drying of the surface prior to scanning is highly advisable. PMID- 25743567 TI - Tooth preparation for full-coverage restorations-a literature review. AB - OBJECTIVES: The objective of this review was to assess the current knowledge about tooth preparation for full-coverage restorations regarding the following aspects: biological parameters, preparation geometry, and technical conditions. METHODS: A systematic literature search was conducted using three electronic databases (MEDLINE, DIMDI, and Cochrane databases) in order to identify relevant citations; additionally, the process was augmented by a hand search. RESULTS: A number of 117 citations were relevant; 11 of these were reviews, 23 were clinical studies, 82 were in vitro investigations, and one was animal research. CONCLUSION: The basic form of a preparation has not changed substantially over the years, although new materials like all-ceramic systems have their own demands with regard to the details of the preparation's geometry. Estimating how much of the tooth structure can be removed without harming the tooth remains one of the biggest problems, if not the main difficulty, during tooth preparation. As the periodontal tissues may be affected by the restoration margin, a supragingival position of the margin should be preferred whenever possible. No finish line design has yet proven to be superior with regard to the marginal accuracy of the subsequent restoration. Instead, good detectability of the margin for the dental technician or intraoral scanning devices appears to be of primary importance in order to achieve a good fitting restoration. CLINICAL SIGNIFICANCE: A detailed look at the covered aspects regarding tooth preparations can help to improve clinical outcomes in daily practice. PMID- 25743570 TI - Effectiveness and safety of arthroscopic versus open Bankart repair for recurrent anterior shoulder dislocation: a meta-analysis of clinical trial data. AB - PURPOSE: To evaluate the effectiveness and safety of arthroscopic and open Bankart repair for recurrent anterior shoulder dislocation using meta-analysis of data from clinical trials. MATERIALS AND METHODS: Cochrane Register of Controlled Trials, PUBMED and EMBASE were used to search and identify clinical trials that evaluated arthroscopic and open Bankart repair for recurrent anterior shoulder dislocation. Methodological qualities of studies were assessed by Cochrane Collaboration tool for assessing risk of bias and Newcastle-Ottawa Scale. Publication bias was detected using Begg's test and Egger's test. RESULTS: Sixteen trials involving 827 shoulders were included in the study. Based on Cochrane Collaboration tool for assessing risk of bias, three studies were rated as high quality and one study was rated as moderate quality among the randomized controlled trials. Another twelve case-control studies were rated as high quality based on Newcastle-Ottawa Scale. No significant publication bias was detected by Begg's test or Egger's test. Meta-analysis results indicated that arthroscopic repair has a significantly better recovery rate for external rotation at 90 degrees of abduction, external rotation at side (P > 0.05) and forward flexion. However, arthroscopic repair had higher rates of recurrence and reoperation than open Bankart repair. CONCLUSION: Meta-analysis of available randomized controlled trials and case-control studies demonstrated that arthroscopic repair and open Bankart repair were similar in safety. Arthroscopic repair resulted in better recovery of range of motion, but recurrence and reoperation rates were higher than open Bankart repair. PMID- 25743571 TI - Femoroacetabular impingement inducing non-union of a femoral neck fracture: a case report. AB - INTRODUCTION: We describe a case in which femoroacetabular impingement (FAI) was identified as the cause of non-union of a femoral neck fracture and the subsequent treatment strategy. MATERIALS AND METHODS: Retrospective review of a 35-year-old patient, without any risk factors for non-union, who sustained a femoral neck fracture. Pre-existing FAI was identified as the cause for the non union of the femoral neck fracture, with successful treatment of the non-union according to established arthroscopic treatment of the hip. RESULTS: After treatment of the FAI, the non-union healed uneventfully within 3 months. CONCLUSIONS: FAI may be a less common but potential cause of delayed union or non union in the setting of femoral neck fracture in the young. PMID- 25743569 TI - Relationship between viral load and behavioral measures of adherence to antiretroviral therapy in children living with human immunodeficiency virus in Latin America. AB - Few studies have examined antiretroviral therapy adherence in Latin American children. Standardized behavioral measures were applied to a large cohort of human immunodeficiency virus-infected children in Brazil, Mexico, and Peru to assess adherence to prescribed antiretroviral therapy doses during the three days prior to study visits, assess timing of last missed dose, and evaluate the ability of the adherence measures to predict viral suppression. Time trends in adherence were modeled using a generalized estimating equations approach to account for possible correlations in outcomes measured repeatedly in the same participants. Associations of adherence with human immunodeficiency virus viral load were examined using linear regression. Mean enrollment age of the 380 participants was 5 years; 57.6% had undetectable' viral load (<400 copies/mL). At enrollment, 90.8% of participants were perfectly (100%) adherent, compared to 87.6% at the 6-month and 92.0% at the 12-month visit; the proportion with perfect adherence did not differ over time (p=0.1). Perfect adherence was associated with a higher probability of undetectable viral load at the 12-month visit (odds ratio=4.1, 95% confidence interval: 1.8-9.1; p<0.001), but not at enrollment or the 6-month visit (p>0.3). Last time missed any antiretroviral therapy dose was reported as "never" for 52.0% at enrollment, increasing to 60.7% and 65.9% at the 6- and 12-month visits, respectively (p<0.001 for test of trend). The proportion with undetectable viral load was higher among those who never missed a dose at enrollment and the 12-month visit (p<=0.005), but not at the 6-month visit (p=0.2). While antiretroviral therapy adherence measures utilized in this study showed some association with viral load for these Latin American children, they may not be adequate for reliably identifying non-adherence and consequently children at risk for viral resistance. Other strategies are needed to improve the evaluation of adherence in this population. PMID- 25743572 TI - Effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart. AB - Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 MUM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N',N'-tetrakis(2 pyridylmethyl)ethylene diamine (TPEN; 10 MUM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion. PMID- 25743573 TI - Longikaurin E induces apoptosis of pancreatic cancer cells via modulation of the p38 and PI3K/AKT pathways by ROS. AB - Pancreatic cancer is a devastating disease with a poor prognosis. It ranks as the fourth or fifth most common cancer in men and women and has the lowest 5-year survival rate. Therefore, there is an urgent need to develop novel therapeutic agents for pancreatic cancer. Longikaurin E (LE), which is derived from the traditional herbal medicine Rabdosia longituba, had been reported to have anti proliferative and pro-apoptotic properties in several types of cancers. In this study, we investigated the cytotoxic properties of LE against pancreatic cancer cells and explored the mechanism behind the observed apoptosis. Pancreatic cancer cell lines cultured in the presence of LE exhibited dose- and time-dependent growth suppression by clone formation, methylthiazoltetrazolium assay, lactate dehydrogenase cytotoxicity assay, and fluorescence-activated cell sorting analysis, respectively. In addition, these culture conditions also induced the generation of cellular reactive oxygen species (ROS). In order to determine the mechanisms underlying LE-induced cytotoxicity, we used reverse transcription polymerase chain reaction and Western blot analysis in the pancreatic cancer cell line PANC1. The results showed that the expression of Bax was noticeably upregulated and the expression levels of Bcl-2, Bcl-XL, survivin, and c-Myc were significantly downregulated. We also observed increased p38 phosphorylation and decreased phosphorylation of the PI3K/AKT pathway. Interestingly, we also found that LE activated caspase-3. However, N-acetyl-L-cysteine, a kind of antioxidant, reversed all of these cellular activities. In conclusion, this study suggested that LE induced apoptosis of pancreatic cancer cells via ROS generation to modulate the p38 and PI3K/AKT pathways and could be a promising anti-pancreatic agent. PMID- 25743574 TI - Cortisone and hydrocortisone inhibit human Kv1.3 activity in a non-genomic manner. AB - Glucocorticoids are hormones released in response to stress that are involved in various physiological processes including immune functions. One immune-modulating mechanism is achieved by the Kv1.3 voltage-dependent potassium channel, which is expressed highly in lymphocytes including effector memory T lymphocytes (TEM). Although glucocorticoids are known to inhibit Kv1.3 function, the detailed inhibitory mechanism is not yet fully understood. Here we studied the rapid non genomic effects of cortisone and hydrocortisone on the human Kv1.3 channel expressed in Xenopus oocytes. Both cortisone and hydrocortisone reduced the amplitude of the Kv1.3 channel current in a concentration-dependent manner. Both cortisone and hydrocortisone rapidly and irreversibly inhibited Kv1.3 currents, eliminating the possibility of genomic regulation. Inhibition rate was stable relative to the degree of depolarization. Kinetically, cortisone altered the activating gate of Kv1.3 and hydrocortisone interacted with this channel in an open state. These results suggest that cortisone and hydrocortisone inhibit Kv1.3 currents via a non-genomic mechanism, providing a mechanism for the immunosuppressive effects of glucocorticoids. PMID- 25743576 TI - Development of the MAE/UHPLC-MS-TOF method for determination of benzodiazepines in human bio-fluids for toxicological analysis. AB - A rapid method of microwave-assisted extraction (MAE) followed by ultrahigh performance liquid chromatography with mass spectrometry with time of flight detection (UHPLC-MS-TOF) was optimized and validated for the purpose of determination of five benzodiazepines in human serum and blood samples. Extraction parameters and conditions of the UHPLC-MS-TOF method were defined. Validation of the developed method was performed at three concentration levels: 10, 100 and 250 ng/mL of each drug for both serum and blood samples. For serum and blood the limit of detection was found in the ranges 0.46-2.58 ng/mL and 0.43 1.87 ng/mL, precision (RSD): 0.3-6.7% and 0.9-8.4%, accuracy of the assay (RE): 5.3 to +2.4% and -5.7 to +7.6%, recovery: 80.5-104.3% and 79.9-106.9%, matrix effects: 95.9-110.5% and 97.5-114.2%, respectively. Moreover, the optimized and validated MAE/UHPLC-MS-TOF method was applied to analysis of blood samples. PMID- 25743575 TI - Experimental colitis in mice is attenuated by topical administration of chlorogenic acid. AB - Epidemiological data suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease, and inflammation. Chlorogenic acid (CGA), an ester of caffeic and quinic acids, is one of the most abundant polyphenol compounds in human diet with proven biological effectiveness both in vitro and in vivo. The aim of the study is to investigate the possible anti-inflammatory effect of CGA in the gastrointestinal (GI) tract and its mechanism of action. We used a well-established model of colitis, induced by intracolonic (i.c.) administration of trinitrobenzenesulfonic acid (TNBS) in mice. The anti-inflammatory effect of CGA in the colon was evaluated based on the clinical and macroscopic and microscopic parameters. To investigate the mechanism of protective action of CGA, myeloperoxidase (MPO), H2O2, and NF-kappaB levels were assessed in the colon tissue. CGA administered i.c. at the dose of 20 mg/kg (two times daily) protected against TNBS-induced colitis more effectively than the same dose administered orally (p.o.), as evidenced by significantly lower macroscopic and ulcer scores. Furthermore, CGA (20 mg/kg, i.c.) reduced neutrophil infiltration, as demonstrated by decreased MPO activity. Moreover, CGA suppressed activation of NF-kappaB, as evidenced by lower levels of phospho-NF kappaB/NF-kappaB ratio in the tissue. CGA did not affect the oxidative stress pathways. CGA exhibits anti-inflammatory properties through reduction of neutrophil infiltration and inhibition of NF-kappaB-dependent pathways. Our results suggest that CGA may have the potential to become a valuable supplement in the treatment of GI diseases. PMID- 25743577 TI - Development of an HPLC/UV assay for the evaluation of inhibitors of human recombinant monoacylglycerol lipase. AB - Monoacylglycerol lipase (MAGL) is a membrane-associated cytosolic serine hydrolase which catalyses the hydrolysis of the endocannabinoid 2 arachidonoylglycerol into arachidonic acid and glycerol. MAGL represents the link between the endocannabinoid and the eicosanoid system indeed its inhibition enhances endocannabinoid signalling and lowers eicosanoid production. Here we present a radioactive-free, sensitive and solid HPLC-UV based method to evaluate MAGL activity by using 4-nitrophenylacetate (4-NPA) as substrate. The enzymatic activity is measured by quantifying the 4-nitrophenol (PNP) (lambda = 315 nm) formation on a C18 stationary phase. The method was validated by calculating IC50 values of the reference inhibitors JZL184, CAY10499 and JW642 and confirming the irreversible and non-competitive mechanism of inhibition for JZL184. Furthermore in order to resemble the catalytic conditions of MAGL at cell membrane level, the surfactant Triton X-100 was added, as a micelle forming agent and 4 nitrophenyldodecanoate (4-NPDo) was used as lipophilic substrate for MAGL. The data obtained confirmed that the HPLC method is an alternative, radioactive-free approach for the screening and characterization of new MAGL inhibitors. Finally this assay prevents, in an unequivocal manner, any interference related to the intrinsic absorbance of screened compounds or metabolites generated upon enzymatic cleavage which could seriously affect the assay readout. PMID- 25743578 TI - Combined stool-based multiplex PCR and microscopy for enhanced pathogen detection in patients with persistent diarrhoea and asymptomatic controls from Cote d'Ivoire. AB - Infectious diarrhoea ranks among the leading causes of morbidity worldwide. Although most acute diarrhoeal episodes are self-limiting, the diagnosis and treatment of persistent diarrhoea (>=2 weeks) are cumbersome and require laboratory identification of the causative pathogen. Stool-based PCR assays have greatly improved the previously disappointing pathogen detection rates in high income countries, but there is a paucity of quality data from tropical settings. We performed a case-control study to elucidate the spectrum of intestinal pathogens in patients with persistent diarrhoea and asymptomatic controls in southern Cote d'Ivoire. Stool samples from 68 patients and 68 controls were obtained and subjected to molecular multiplex testing with the Luminex((r)) Gastrointestinal Pathogen Panel (GPP), microscopy and rapid antigen detection tests for the diagnosis of diarrhoeagenic pathogens. Overall, 20 different bacteria, parasites and viruses were detected by the suite of diagnostic methods employed. At least one pathogen was observed in 84% of the participants, and co infections were observed in >50% of the participants. Enterotoxigenic Escherichia coli (32%), Giardia intestinalis (29%) and Shigella species (20%) were the predominant pathogens, and Strongyloides stercoralis (10%) was the most prevalent helminth. Pathogen frequencies and numbers of co-infections were similar in patients and controls. Although the Luminex((r)) GPP detects a broad range of pathogens, microscopy for helminths and intestinal protozoa remains necessary to cover the full aetiological spectrum in tropical settings. We conclude that highly sensitive multiplex PCR assays constitute a useful screening tool, but that positive results might need to be confirmed by independent methods to discriminate active infection from asymptomatic faecal shedding of nucleic acids. PMID- 25743579 TI - Epstein-Barr virus (EBV) DNA in whole blood as a superior prognostic and monitoring factor than EBV-encoded small RNA in situ hybridization in diffuse large B-cell lymphoma. AB - Epstein-Barr virus (EBV) status was retrospectively analysed by the use of EBV encoded small RNA (EBER) in situ hybridization (ISH) and EBV DNA analysis in whole blood with diffuse large B-cell lymphoma, to assess the clinical significance for diagnosis, prognostication, and monitoring of tumour burden. Three hundred and twenty-nine patients were retrospectively enrolled, with 232 patients being available for EBER ISH analysis, 189 patients for EBV DNA analysis, and 138 patients for both analyses. EBER was positive in 24 (10.3%) patients, and EBV DNA was positive in 18 (9.5%) patients; the two analyses had 92.8% concordance. Patients with pretreatment EBER positivity had worse overall survival (OS) than those without EBER positivity (p 0.03); the same pattern was observed for EBV DNA (p < 0.01). A significant p-value was also observed for OS when EBER and EBV DNA were combined (p < 0.01). On multivariate analysis, both EBV DNA (hazard ratio 3.71, 95% CI 1.78-7.74, p < 0.01) and EBER (hazard ratio 2.03, 95% CI 1.03-4.00, p 0.04) remained independent predictive factors for OS. Regarding the dynamic changes in copy number of elevated EBV DNA, the transformation from positive to negative after cycle 3 with chemotherapy may have the most capacity to distinguish a superior from an inferior outcome. These findings suggest that EBV DNA in whole blood has good concordance with EBER ISH, and that it may be a better prognostic and monitoring biomarker than EBER. PMID- 25743580 TI - Increase in pre-seasonal community-acquired Legionnaire's disease due to increased precipitation. PMID- 25743581 TI - Common marmosets show social plasticity and group-level similarity in personality. AB - The social environment influences animal personality on evolutionary and immediate time scales. However, studies of animal personality rarely assess the effects of the social environment, particularly in species that live in stable groups with individualized relationships. We assessed personality experimentally in 17 individuals of the common marmoset, living in four groups. We found their personality to be considerably modified by the social environment. Marmosets exhibited relatively high plasticity in their behaviour, and showed 'group personality', i.e. group-level similarity in the personality traits. In exploratory behaviour this was maintained only in the social environment but not when individuals were tested alone, suggesting that exploration tendency is subjected to social facilitation. Boldness, in contrast, showed higher consistency across the social and solitary conditions, and the group-level similarity in trait scores was sustained also outside of the immediate social environment. The 'group-personality' was not due to genetic relatedness, supporting that it was produced by social effects. We hypothesize that 'group personality' may be adaptive for highly cooperative animals through facilitating cooperation among individuals with similar behavioural tendency. PMID- 25743583 TI - Temporal trends in herpes zoster-related hospitalizations in Madrid (Spain), 2003 2013. AB - OBJECTIVES: This study aimed to estimate herpes zoster (HZ) related hospitalization rates in the Autonomous Community of Madrid (Spain), considering both total and complicated cases, and to analyze their temporal trends by sex and age. METHODS: Population based cross-sectional study of all hospital admissions with an HZ diagnosis in any position from 2003 to 2013. Annual crude, age adjusted and age-specific hospitalization rates were calculated by sex and year. Joinpoint Regression models were used to analyze time trends. RESULTS: The incidence of hospitalizations with HZ increased significantly during the study period from 10.81 to 16.97 per 100,000 person-year, with an average annual rise of 2.80%. The rate of hospitalization of complicated HZ increased from 4.67 to 8.99 per 100,000 person-year. No 'breakthrough points' of the time trends were detected. The proportion of complicated HZ was similar in both sexes, and increased from 43.2% to 53.0%. By age and sex significant increases affecting women from age 85 and men from age 75 and in the group of 45-64 years were observed. CONCLUSIONS: Hospitalizations related to HZ are increasing, with a significant rise of complicated cases. Long term and more detailed studies are required to monitor HZ. PMID- 25743584 TI - False-positive Aspergillus galactomannan and its kinetics in allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVES: We evaluated the incidence of and risk factors for false-positive Aspergillus galactomannan (GM) antigenemia in allogeneic hematopoietic stem cell transplantation (HSCT). We also focused on the GM index value and its kinetics. METHODS: Patients who underwent their first allogeneic HSCT at our center between June 2007 and December 2012 were included (n = 172). Episodes of positive GM tests were classified as either "true-positive", which fulfilled the EORTC criteria for proven or probable invasive aspergillosis (IA), or "false-positive", which was not accompanied by clinical findings. The remaining cases were regarded as "inconclusive". RESULTS: The one-year cumulative incidences of IA and positive GM tests were 10.1% and 48.1%, respectively. Among 148 episodes of positive GM tests, 97(65.5%), 23(15.5%), and 28(19.0%) were classified as false-positive, true-positive and inconclusive, respectively. In the first episodes of positive GM tests in each patient (false-positive = 67, others = 30), an increase in the GM value in the first two measurements, neutropenia, and use of anti-mold agents at positive GM episode were associated with a significantly lower possibility of false-positive results according to a multivariate analysis. CONCLUSIONS: A false positive GM test was frequently seen after allogeneic HSCT. An increase in the GM value may increase its positive predictive value. PMID- 25743585 TI - Anti-acetylcholinesterase and Antioxidant Activities of Inhaled Juniper Oil on Amyloid Beta (1-42)-Induced Oxidative Stress in the Rat Hippocampus. AB - Juniper volatile oil is extracted from Juniperus communis L., of the Cupressaceae family, also known as common juniper. Also, in aromatherapy the juniper volatile oil is used against anxiety, nervous tension and stress-related conditions. In the present study, we identified the effects of the juniper volatile oil on amyloid beta (1-42)-induced oxidative stress in the rat hippocampus. Rats received a single intracerebroventricular injection of amyloid beta (1-42) (400 pmol/rat) and then were exposed to juniper volatile oil (200 MUl, either 1 or 3 %) for controlled 60 min period, daily, for 21 continuous days. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Additionally, the acetylcholinesterase activity in the hippocampus was assessed. The amyloid beta (1-42)-treated rats exhibited the following: increase of the acetylcholinesterase, superoxide dismutase and catalase specific activities, decrease of glutathione peroxidase specific activity and the total content of the reduced glutathione along with an elevation of malondialdehyde and protein carbonyl levels. Inhalation of the juniper volatile oil significantly decreases the acetylcholinesterase activity and exhibited antioxidant potential. These findings suggest that the juniper volatile oil may be a potential candidate for the development of therapeutic agents to manage oxidative stress associated with Alzheimer's disease through decreasing the activity of acetylcholinesterase and anti-oxidative mechanism. PMID- 25743586 TI - [Scientific review on novel genome editing techniques]. PMID- 25743587 TI - [Examination of processed vegetable foods for the presence of common DNA sequences of genetically modified tomatoes]. AB - The contamination of processed vegetable foods with genetically modified tomatoes was investigated by the use of qualitative PCR methods to detect the cauliflower mosaic virus 35S promoter (P35S) and the kanamycin resistance gene (NPTII). DNA fragments of P35S and NPTII were detected in vegetable juice samples, possibly due to contamination with the genomes of cauliflower mosaic virus infecting juice ingredients of Brassica species and soil bacteria, respectively. Therefore, to detect the transformation construct sequences of GM tomatoes, primer pairs were designed for qualitative PCR to specifically detect the border region between P35S and NPTII, and the border region between nopaline synthase gene promoter and NPTII. No amplification of the targeted sequences was observed using genomic DNA purified from the juice ingredients. The developed qualitative PCR method is considered to be a reliable tool to check contamination of products with GM tomatoes. PMID- 25743588 TI - [Studies on rapid multi-residue analysis of pesticides in agricultural products by LC-MS/MS]. AB - Rapid multi-residue analysis of pesticides in agricultural products was studied by using LC-MS/MS. Pesticide residues in 10 g of homogenized agricultural products were extracted with 30 mL of acetonitrile and salted out with 4 g of anhydrous magnesium sulfate and 1 g of sodium chloride in the presence of citrate salts for buffering in a disposable tube. Co-extractives were removed by use of our original triple layered column (C18/GC/PSA; 60/30/60 mg). According to the method validation guideline of the Ministry of Health, Labour and Welfare of Japan, we conducted recovery tests in 5 kinds of agricultural products (brown rice, kiwi, cabbage, sweet potato and spinach) spiked with 60 pesticides at the level of 0.01 or 0.1 MUg/g. Each concentration of pesticide spiked was extracted from 2 samples per day on 5 days. Pesticides in the test solution were determined by two types of LC-MS/MS using scheduled MRM. Using this method, 58 out of 60 pesticides satisfied the guideline criteria in brown rice, 59 in kiwi, 55 in cabbage, 55 in sweet potato and 56 in spinach. This method is applicable for routine examination of pesticide residues in agricultural products. PMID- 25743589 TI - [Structure identification of contaminants in a beverage product by liquid chromatography coupled with quadrupole time-of-flight mass spectrometry]. AB - The contaminants in a beverage product that had been reported to have a strange taste were identified. By comparative analysis with the normal product using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS), six unknown compounds were detected in the total ion current chromatograms of the product in question. Detailed analysis of the mass spectra and product ion spectra of these compounds strongly suggested that the compounds were capric acid diethanolamide, lauric acid diethanolamide, myristic acid diethanolamide, lauryl dimethylaminoacetic acid, lauryl sulfate, and lauric acid, all of which are surfactants commonly used as ingredients of household detergents and shampoos. We searched commercially available detergent products to check for the presence of these six surfactants, and identified products that might have been intentionally or unintentionally mixed into the beverage product after opening. PMID- 25743582 TI - MRI evaluation and safety in the developing brain. AB - Magnetic resonance imaging (MRI) evaluation of the developing brain has dramatically increased over the last decade. Faster acquisitions and the development of advanced MRI sequences, such as magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), perfusion imaging, functional MR imaging (fMRI), and susceptibility-weighted imaging (SWI), as well as the use of higher magnetic field strengths has made MRI an invaluable tool for detailed evaluation of the developing brain. This article will provide an overview of the use and challenges associated with 1.5-T and 3-T static magnetic fields for evaluation of the developing brain. This review will also summarize the advantages, clinical challenges, and safety concerns specifically related to MRI in the fetus and newborn, including the implications of increased magnetic field strength, logistics related to transporting and monitoring of neonates during scanning, and sedation considerations, and a discussion of current technologies such as MRI conditional neonatal incubators and dedicated small-foot print neonatal intensive care unit (NICU) scanners. PMID- 25743590 TI - [Performance comparison of material tests for cadmium and lead in food contact plastics]. AB - Based on the Japanese Food Sanitation Law, the performances of official and alternative material test methods for cadmium (Cd) and lead (Pb) in food contact plastics were compared. Nineteen laboratories participated to an interlaboratory study, and quantified Cd and Pb in three PVC pellets. in the official method, a sample is digested with H2SO4, taken up in HCl, and evaporated to dryness on a water bath, then measured by atomic absorption spectrometry (AAS) or inductively coupled plasma-optical emission spectrometry (ICP-OES). Statistical treatment revealed that the trueness, repeatability (RSDr) and reproducibility (RSDr) were 86-95%, 3.1-9.4% and 8.6-22.1%, respectively. The values of the performance parameters fulfilled the requirements , and the performances met the test specifications. The combination of evaporation to dryness on a hot plate and measurement by AAS or ICP-OES is applicable as an alternative method. However, the trueness and RSDr were inferior to those of the official method. The performance parameters obtained by using the microwave digestion method (MW method) to prepare test solution were better than those of the official method. Thus, the MW method is available as an alternative method. Induced coupled plasma mass spectrometry (ICP-MS) is also available as an alternative method. However, it is necessary to ensure complete digestion of the sample. PMID- 25743591 TI - [Simultaneous analysis of residual pesticides in fruit, vegetables, brown rice, and oolong tea by LC-MS/MS]. AB - According to "The validity evaluation guideline of the testing methodology on the residual pesticides in food" of the Ministry of Health, Labour and Welfare of Japan, we carried out validity evaluation of a simultaneous analysis method for residual pesticides in various products with the QuEChERS method using a C18 mini column and/or an EnviCarb/PSA mini column for purification. Multi-ingredient simultaneous analysis with high sensitivity in a short time was achieved with LC MS/MS. Validation was achieved for 269 pesticides among 302 pesticides in eight kinds of fruit, vegetables, and brown rice and 204 pesticides among 233 pesticides in oolong tea. Finally, 151 pesticides in oolong tea and from 234 to 259 pesticides in fruit, vegetables, and brown rice met the values specified in the guideline. PMID- 25743592 TI - [Validation study on a multi-residue method for determination of pesticides in agricultural products by LC-MS/MS]. AB - A multi-residue method for 122 pesticides in agricultural products was validated in accordance with Japanese guidelines for residual agricultural chemicals in food. The sample was extracted with acetonitrile. Co-extractives were removed by GPC-graphitized carbon column SPE, followed by silica gel/PSA cartridge column SPE. The pesticides in the test solution were determined by LC-MS/MS using scheduled MRM in combination with polarity switching. Validation tests were performed on spinach, brown rice, soybean, orange and tomato fortified at 0.01 and 0.1 MUg/g. The pesticides at each level were analyzed in two samples per day on five different days. In conclusion, among 122 pesticides tested for each level, 121 pesticides (but not disulfoton) were found to meet all of the guideline criteria. PMID- 25743593 TI - Dynamic wetting: status and prospective of single particle based experiments and simulations. AB - The fundamental molecular and microscopic properties of materials leading to dynamic wetting and relaxation effects have been subject to numerous studies in the past decades, but a thorough understanding is still missing. While most previous experiments utilize fluids deposited on planar substrates, this article focuses on an attractive alternative based on single colloidal particles: colloidal particles have the ability to strongly interact with fluid-fluid interfaces and the behavior strongly depends on the surface properties of the particles and the fluids used. Recent progress in the manipulation and synthesis of colloidal particles with well-defined surface properties and shapes makes them ideal candidates to probe the fundamental surface properties leading to dynamic wetting effects. In this paper we review and discuss the status of experimental and numerical techniques to characterize the dynamic wetting of single particles at fluid-fluid interfaces, with the aim to assist scientists and engineers in the design of new experimental techniques and particle-based (bio)analytical tools. PMID- 25743594 TI - Inhibition of nucleoporin member Nup214 expression by miR-133b perturbs mitotic timing and leads to cell death. AB - BACKGROUND: Nucleoporins mediate nucleocytoplasmic exchange of macromolecules and several have been assigned active mitotic functions. Nucleoporins can participate in various mitotic functions like spindle assembly, kinetochore organisation and chromosome segregation- important for genome integrity. Pathways to genome integrity are frequently deregulated in cancer and many are regulated in part by microRNAs. Indeed, altered levels of numerous microRNAs have frequently been associated with tumorigenesis. Here, we unveil a microRNA-mediated regulation of the nucleoporin Nup214 and its downstream effect on genome integrity. METHODS: Databases/bioinformatic tools such as miRBase, Oncomine and RNAhybrid predicted Nup214 as a miR-133b target. To validate this, we used luciferase reporter assays, Real-Time PCR and immuno-blotting. Flow cytometry and immuno-blots of mitotic markers were used to analyse cell cycle pattern upon thymidine synchronization and miR-133b treatment. Mitotic indices and chromosomal abnormalities were assessed by immuno-fluorescence for FITC-tagged phospho-H3 as well as video-microscopy for GFP-tagged histone H4. Annexin V/propidium iodide staining, caspase3/PARP cleavage and colony formation assays were done to investigate cell death upon either miR-133b transfection or NUP214 knockdown by siRNA. UPCI:SCC084, HCT116, HeLa-H4-pEGFP and HEK293 (human oral squamous cell carcinoma, colorectal, cervical carcinomas and embryonic kidney cell lines, respectively) were used. miR-133b and NUP214 expressions were validated in cancer cell lines and tissues by Real-Time PCR. RESULTS: Examination of head and neck tumour tissues and cancer cell lines revealed that Nup214 and miR-133b expressions are negatively correlated. In vitro, Nup214 was significantly downregulated by ectopic miR-133b. This downregulation elevated mitotic indices and delayed degradation of mitotic marker proteins cyclinB1 and cyclinA and dephosphorylation of H3. Moreover, this mitotic delay enhanced chromosomal abnormalities and apoptosis. CONCLUSIONS: We have identified NUP214, a member of the massive nuclear pore complex, as a novel miR-133b target. Thus, we have shown a hitherto unknown microRNA regulation of mitosis mediated by a member of the nucleoporin family. Based on observations, we also raise some hypotheses regarding transport-dependent/independent functions of Nup214 in this study. Our results hence attempt to explain why miR-133b is generally downregulated in tumours and lay out the potential for Nup214 as a therapeutic target in the treatment of cancer. PMID- 25743595 TI - Traumatic ophthalmoplegia. PMID- 25743596 TI - The Incidence of Respiratory Tract Infections in Vertically HIV-Infected Children in Lower Silesia in Poland and the Approach to Infection Prevention. AB - Human immunodeficiency virus (HIV) is a risk factor associated with respiratory tract infections. However little is known about the prevalence of these infections in HIV-infected children in Poland. We investigated the incidence of respiratory tract infections in 26 HIV-infected children (aged 4-18, mean 10.3 years, including 17 girls) treated in our center and compared it with the age matched control group of 70 children. The prevalence of chronic diseases and other factors such as cigarette smoking by household members or attending educational institutions were also taken into consideration. Among the HIV infected children, 48 respiratory infections were observed, including 4 cases of pneumonia and 44 other respiratory infections for 312 person-month observations vs. 256 infections including 13 cases of pneumonia and 243 other respiratory infections for 840 person-month observations in the control group. Thus, incidence of respiratory infections per month was lower in HIV-infected children (14%) compared with the control group (29%), i.e., 0.14 95% CI (0.10-0.18) infections per month vs. 0.29 95% CI (0.26-0.32). There was no difference in the incidence of pneumonia. The lower incidence of respiratory infections in HIV infected children may be explained by their avoiding sick people, taking influenza vaccination on the annual basis, and possibly antiviral medication. We conclude that the influence of modifiable environmental factors that reduce the risk of respiratory tract infections is more significant than the HIV infection itself. PMID- 25743597 TI - Stagnating Low Influenza Vaccine Coverage Rates in the Polish Elderly Population in 2008-2013. AB - Although annual vaccination is the most effective way of preventing the disease and its severe outcomes, influenza vaccine coverage rates have always been at suboptimal levels in Poland. A retrospective analysis was conducted on influenza vaccine coverage rates among patients older than 65 years at local and national levels. Influenza vaccine coverage rates among the elderly in the capital city of Warsaw ranged from 20.5% in 2013 to 31.5% in 2010 and these rates were higher than those reported at the national level (from 7.6% in 2012 to 11.3% in 2009). At a local level the proportion of vaccines given to the elderly compared to all vaccinated individuals varied from 40 to 52% which was comparable to the proportions reported at the national level (37-48.5%). 69% of the elderly were only vaccinated once during the observation period, and only 0.5% of them repeated the vaccination in each subsequent year. The chance of being vaccinated against influenza more than once was statistically higher among women than men (OR 4.9; 95% CI 4.2-5.8). Influenza vaccine coverage rates are low at both local and national levels and ought to be improved in Poland in future. PMID- 25743598 TI - Nurses' experiences of caring for critically ill, non-sedated, mechanically ventilated patients in the Intensive Care Unit: a qualitative study. AB - OBJECTIVE: The objective was to explore nurses' experiences of caring for non sedated, critically ill patients requiring mechanical ventilation. DESIGN AND SETTING: The study had a qualitative explorative design and was based on 13 months of fieldwork in two intensive care units in Denmark where a protocol of no sedation is implemented. Data were generated during participant observation in practice and by interviews with 16 nurses. Data were analysed using thematic interpretive description. FINDINGS: An overall theme emerged: "Demanding, yet rewarding". The demanding aspects of caring for more awake intubated patients included unpredictability, ambiguous needs and complex actions, while the rewarding aspects included personal interaction. Three sub-themes were identified: (i) caring for and with the patient, (ii) negotiating relational and instrumental care and (iii) managing physical and emotional closeness. CONCLUSION: Despite the complexity of care, nurses preferred to care for more awake rather than sedated patients and appreciated caring for just one patient at a time. The importance of close collaboration between nurses and doctors to ensure patient comfort during mechanical ventilation was valued. Caring for more awake non-sedated patients required the nurses to act at the interface between ambiguous possibilities and needs, which was perceived as both demanding and rewarding. PMID- 25743600 TI - Musical theatre: the hazards of the performer's workplace. AB - Being a musical theatre performer requires excellence in the combined skills of dancing, singing, and acting, and artists undergo rigorous training in these disciplines in order to achieve the professional standards expected by a discerning audience. However, the performer has more to do than just execute the choreography, vocal repertoire, and dialogue--he or she will also be navigating the often highly complex on-stage and off-stage areas which are fraught with hazards. This article seeks to highlight the challenges that lie beyond the visible part of the performance and to raise questions of how best to equip our musical theatre performers to safely negotiate these issues. PMID- 25743601 TI - Pain prevalence in instrumental musicians: a systematic review. AB - OBJECTIVE: To investigate current prevalence of pain among different musician groups, sex, and body region. METHODS: Studies were sought from PubMed, Web of Science, Academic Search Complete, Science Direct, and Scielo. Databases were searched from 1 January 2000 until December 2012. Two reviewers screened titles and abstracts and assessed full reports for potentially eligible studies. One reviewer extracted information on musicians' characteristics, study methods, and study quality. When possible, a meta-analysis of pain prevalence estimates was performed. RESULTS: A total of 18 studies were included in this systematic review. Studies assessed pain prevalence in general and the prevalence of pain affecting playing capacity for different time periods: point, 1-week, 1-year, month, and lifetime prevalence. The prevalence of pain in general, across all groups of musicians and periods of interest over which pain was assessed, varied between 29.0 and 90.0%, whereas the prevalence of pain affecting playing capacity varied between 25.8 and 84.4%. There was a tendency for guitar players to have the highest pain prevalence. The most affected body regions were the low back (9.8 to 66.7%) and neck (9.8 to 48.5%). CONCLUSIONS: Pain prevalence is high among musicians, independent of the pain definition and time period used. Health and educational policy makers should become aware of the high prevalence of pain affecting performance practices, so that pain-associated mechanisms are investigated and preventive strategies are tested and implemented. PMID- 25743602 TI - Effect of height on motor coordination in college students participating in a dancesport program. AB - OBJECTIVE: Athlete screening tools combine measures of physical performance and morphometric parameters unique to each sport. Given the increasing competitiveness of dancesport, we designed the present quasi-experimental study to analyze the relationship between body height and motor coordination in college students. METHODS: Six hundred eighty-six students were randomly selected to participate in a dancing sport program that consisted of 16 weeks (32 hrs) of training. The program included an assessment of basic skills (rhythm, movement specificity, intensity, expressive force, and action coherence) and skills related to a doubles dance routine. Male and female students were divided into four single-sex groups based on their heights (each group had a 5-cm range), and the average scores for each performance indicator were analyzed. RESULTS: A one way ANOVA revealed significant differences in performance scores for each indicator of basic skills and double routine skills between the different height groups. Male in the 175-179 cm group and female students in the 165-169 cm group had the best performance scores on each indicator, while the shortest students had the worst performance scores. CONCLUSION: The height of students participating in sport dancing training had an impact on dancesport performance and motor coordination, counter to the traditional belief that shorter people have better coordination. PMID- 25743603 TI - Risk factors for injuries in competitive Irish dancers enrolled in dance schools in Calgary, Canada. AB - OBJECTIVES: Irish dancing has become a popular activity following international exposure to touring dance companies. Previous studies have reported high injury incidence rates in dancers. The objective of this study was to examine risk factors for injuries in competitive Irish dancers in Calgary, Canada. DESIGN: This is a cross-sectional study. Competitive dancers over 12 years of age in Calgary, Canada, were eligible to participate. METHODS: A pen-and-paper survey was administered to gather information on demographics, risk factors for injury, and injuries in the past year. Potential risk factors included age, competitive level, participation in other physical activities, years of participation in Irish dance, and performing a warm-up or cool-down. Incidence proportions (IP) and odds ratios (OR) were estimated. RESULTS: Three of the five accredited dance schools in Calgary participated and a total of 36 questionnaires were completed. Twenty-six dancers (IP=72.2%; 95% CI 54.8-85.8%) reported at least one Irish dance-related injury in the past year. There were 60 injuries reported and the majority (57%) were foot or ankle injuries. Elite level dancers (OR= 6.33; CI 1.27-31.57) and dancers over 18 years of age (OR= 24.43; CI 2.60-229.56) were at greater risk of injury in the past year than non-elite and younger dancers. CONCLUSIONS: Elite dancers and dancers over 18 years of age are at the greatest risk of injury in Irish dance in Calgary, Canada. PMID- 25743604 TI - Music performance anxiety in young musicians: comparison of playing classical or popular music. AB - OBJECTIVES: Music performance anxiety (MPA) is an issue frequently experienced by musicians. It occurs not only in experienced musicians but also in children and adolescents. Furthermore, most research on MPA has been done with musicians who specialized in classical music. This study investigated the development of MPA across the ages in young musicians focusing on the classical and popular genres. METHODS: In a cross-sectional survey, 239 students at German music schools, aged between 7 and 20 yrs, were asked about their perceived MPA and musical background. The data were analyzed according to musical genre and age. Multiple regression analyses were performed to investigate the influences of musical experiences on MPA. RESULTS: The analyses yielded high levels of MPA for classical musicians between 7 and 16 yrs, which was reduced in older students; for popular musicians, low MPA was seen in the younger (7-11 yrs) and high MPA in the older (16+ yrs) musicians. MPA was influenced by gender and the number of performances in the classical music group and only by gender and age in the popular music group. CONCLUSION: The results showed clear different trends for the development of MPA between musical genres that should be taken into account for educational aspects in musical training. PMID- 25743605 TI - Musician's dystonia is highly task specific: no strong evidence for everyday fine motor deficits in patients. AB - OBJECTIVES: 1) To examine the fine motor skills used everyday by patients suffering from musician's dystonia (MD) in the upper limb in order to verify whether MD is task-specific; and 2) to compare the affected and non-affected hands of MD musicians vs healthy musicians in performance of these tasks in order to clarify whether dystonic symptoms can be found in the non-affected side of MD patients. BACKGROUND: MD is typically considered to be focal and task specific, but patients often report impairment in everyday life activities. Furthermore, in the course of MD, about 15% of patients complain of dystonic symptoms in other parts of the body. METHODS: Twenty-seven musicians affected by MD and 27 healthy musicians were studied using 1) the Motor Performance Test Series, 2) a kinematic analysis of handwriting, and 3) an assessment of the grip force regulation while lifting and moving a manipulandum. RESULTS: Patients performed most fine motor tasks without any evidence of a deficit. Exclusively in the handwriting tasks (2), they exhibited fewer frequencies of the written trace and a prolonged overall writing time. CONCLUSION: MD is highly task specific and does not strongly affect other motor skills. The subtle deficits in handwriting may be explained as a consequence of a general psychological disposition rather than as compensatory mechanisms to avoid the appearance of dystonic symptoms. Furthermore, we did not find signs of multifocal motor deficits in the unaffected hands of MD patients. PMID- 25743599 TI - Regulation of translesion DNA synthesis: Posttranslational modification of lysine residues in key proteins. AB - Posttranslational modification of proteins often controls various aspects of their cellular function. Indeed, over the past decade or so, it has been discovered that posttranslational modification of lysine residues plays a major role in regulating translesion DNA synthesis (TLS) and perhaps the most appreciated lysine modification is that of ubiquitination. Much of the recent interest in ubiquitination stems from the fact that proliferating cell nuclear antigen (PCNA) was previously shown to be specifically ubiquitinated at K164 and that such ubiquitination plays a key role in regulating TLS. In addition, TLS polymerases themselves are now known to be ubiquitinated. In the case of human polymerase eta, ubiquitination at four lysine residues in its C-terminus appears to regulate its ability to interact with PCNA and modulate TLS. Within the past few years, advances in global proteomic research have revealed that many proteins involved in TLS are, in fact, subject to a previously underappreciated number of lysine modifications. In this review, we will summarize the known lysine modifications of several key proteins involved in TLS; PCNA and Y-family polymerases eta, iota, kappa and Rev1 and we will discuss the potential regulatory effects of such modification in controlling TLS in vivo. PMID- 25743606 TI - Nasendoscopic evaluation of stress velopharyngeal insufficiency in wind musicians: a pilot study. AB - OBJECTIVE: To investigate the anatomy and function of the velopharyngeal mechanism in musicians who experience symptoms of stress velopharyngeal insufficiency (VPI) compared to musicians who do not. METHODS: The velopharyngeal mechanism of 13 musicians, 8 with reported symptoms of stress VPI and 5 without, were evaluated using video nasendoscopy before and after 30 minutes of playing. All nasendoscopic recordings were rated by an external speech-language pathologist and ear, nose and throat surgeon for maintenance of velopharyngeal closure, type of velopharyngeal closure pattern, and velopharyngeal gap. RESULTS: Six out of 8 cases with stress VPI had nasal air leak during the assessment, 2 of whom had fatigue-related increased symptoms. Three controls had mild nasal air leak without affecting the consistency of soft palate seal nor quality of playing, suggesting that evidence of nasal air leak is not always symptomatic of stress VPI. All cases had unusual anatomical characteristics, such as the soft palate closing against an irregular surface on the posterior nasopharyngeal wall, which may cause insufficient velopharyngeal closure. Typically the soft palate contacted the nasopharyngeal wall higher when playing a wind instrument compared to during speech. CONCLUSION: Specific anatomical features and factors such as fatigue and stress may affect maintenance of velopharyngeal closure in persons with stress VPI. It is important that musicians with stress VPI are evaluated while playing their instrument. Future studies into stress VPI would benefit by including objective assessment components and some degree of quantifiable measurements. PMID- 25743607 TI - Physical and mental workloads in professional dance teachers. AB - OBJECTIVE: The aim of this cross-sectional study was to investigate the level of mental and physical workloads in professional dance teachers depending on the trained students' age, technique level, or dance style. METHODS: A total number of 133 professional dance pedagogues responded to an online cross-sectional questionnaire survey on self-assessment of physical and mental workloads occurring during dance units. RESULTS: The majority of dance teachers estimated their level of physical and mental workload to be almost as high as that of their students, with differences in physical and mental workloads observed depending on dance style, age of students, and technical level. More than 60% of the teachers were convinced that their occupation implies positive effects on their own health in terms of self-realization (78.2%), musculoskeletal system (66.9%), and social relationships (61.7%). Of all respondents, 58.6% stated that their musculoskeletal system was jeopardized by the physically demanding activity. This is followed by the fear of financial insecurity (50.4%). The majority of all dance teachers (males 65.4%, females 63.9%) would like to obtain further education on prevention against or dealing with physical workload. CONCLUSION: Physical and mental workloads play an important role in dance teaching. Coping with or preventing these loads could be keys to a lifelong, healthy career as a professional dance teacher. Future trials should look at clinical parameters of physical and mental load. PMID- 25743608 TI - Pointing the foot without sickling: an examination of ankle movement during jumping. AB - The saute is a relatively simple dance jump that can be performed by both highly skilled dancers and non-dancers. However, there are characteristics of jumping unique to trained dancers, especially in terms of foot and ankle movement during flight. Dancers are trained not to "sickle, " or to avoid the anatomically coupled ankle inversion that occurs with plantar flexion, maintaining the appearance of a straight line through the lower leg and foot. The purpose of this study was to examine ankle movements in elite dancers compared to non-dancers. Twenty healthy females, 10 with no prior dance training and 10 professional dancers, performed 20 consecutive sautes while three-dimensional kinematic data were collected. Sagittal and frontal plane kinematics were calculated and vector coding methods were used to quantify coordination patterns within the ankle in the sagittal and frontal planes. This pattern was chosen for analysis to identify the avoidance of a sickled foot by trained dancers. Peak ankle positions and coordination patterns between groups were examined using independent t-tests (a <0.05). Dancers demonstrated greater peak plantar flexion (p<0.01) and less change in ankle angle during the flight phase (p= 0.01), signifying holding the pointed foot position during flight. There was no statistically significant difference in sagittal and frontal plane ankle coupling (p= 0.15); however, the Cohen's d effect size for the difference in coupling was medium-to-large (0.73). Dynamic analysis of the foot and ankle during jumping demonstrates how elite dancers achieve the aesthetic requirements of dance technique. PMID- 25743609 TI - Bacterial killing via a type IV secretion system. AB - Type IV secretion systems (T4SSs) are multiprotein complexes that transport effector proteins and protein-DNA complexes through bacterial membranes to the extracellular milieu or directly into the cytoplasm of other cells. Many bacteria of the family Xanthomonadaceae, which occupy diverse environmental niches, carry a T4SS with unknown function but with several characteristics that distinguishes it from other T4SSs. Here we show that the Xanthomonas citri T4SS provides these cells the capacity to kill other Gram-negative bacterial species in a contact dependent manner. The secretion of one type IV bacterial effector protein is shown to require a conserved C-terminal domain and its bacteriolytic activity is neutralized by a cognate immunity protein whose 3D structure is similar to peptidoglycan hydrolase inhibitors. This is the first demonstration of the involvement of a T4SS in bacterial killing and points to this special class of T4SS as a mediator of both antagonistic and cooperative interbacterial interactions. PMID- 25743610 TI - The fluid and electrolyte balance of New Zealand European and Maori/Pacific Island athletes: An observational study. AB - Observational research on professional athletes from the USA suggests differences may exist in sweat sodium loss based on ethnic differences. The New Zealand (NZ) sporting population is mainly of European or Maori/Pacific Island origin. Therefore, this study aimed to describe the fluid-electrolyte balance of athletes by ethnicity. A total of 20 Maori/Pacific Islanders (MP; body mass 100.97 +/- 13.05 kg) and 29 NZ European (NZE; body mass 89.11 +/- 11.56 kg) elite male athletes were recruited. Sweat rates were determined by body mass change during a 1-h spin cycle exercise session, during which fluid intakes and heart rate were recorded. Sweat samples were analysed for sodium concentration. Mean +/- SD sweat sodium concentrations were 73.4 +/- 27.2 mmol.L(-1) and 55.5 +/- 26.8 mmol.L(-1) for the MP and NZE groups, respectively (p = 0.070). Sweat rate was 0.93 +/- 0.26 L.h(-1) for the MP group and 0.89 +/- 0.33 L.h(-1) for the NZE group (p = 0.357). Fluid intake was 1.05 +/- 0.48 L and 0.93 +/- 0.49 L for MP and NZE, respectively (p = 0.395). Half of the MP group gained weight during the exercise session compared to 37% of the NZE group. Pre-exercise urine specific gravity was significantly lower amongst the NZE group (1.016 +/- 0.009 g mL(-1)) than the MP group (1.024 +/- 0.008 g mL(-1)) p = 0.001. There was no significant difference in heart rate between the groups, p = 0.082. Hydration practices of athletes in NZ may differ by ethnicity, and this may highlight the need for more targeted education by ethnicity. PMID- 25743611 TI - Tungsten trioxide nanoplate array supported platinum as a highly efficient counter electrode for dye-sensitized solar cells. AB - A tungsten trioxide (WO3) nanoplate array is fabricated directly on the FTO/glass substrate and used as a platinum (Pt) nanoscale supporter for a highly efficient and low Pt-consumption counter electrode (CE) in dye-sensitized solar cells (DSCs). A Pt/WO3 composite structure, with Pt nanoparticles having a diameter of 2-3 nm, increases the electrochemical catalytic activity in catalyzing the reduction of triiodide. Accordingly, the power conversion efficiency is increased from less than 1% for WO3 CE and 8.1% for Pt CE, respectively, to 8.9% for Pt/WO3 CE. Moreover, the use of Pt/WO3 CE can dramatically reduce the consumption of scarce Pt material, with a relatively low Pt-loading of ~2 MUg cm(-2), while maintaining a much better performance. The excellent performance of Pt/WO3 CE is attributed to the efficient electron injection and transport via WO3 supporters, as well as the nanostructure array morphology of WO3 for deposition of fine Pt nanoparticles. This work provides an approach for developing highly catalytic and low-cost Pt based CEs, which also has implications for the development of Pt/WO3 nanoplate arrays for other applications. PMID- 25743612 TI - Templated assembly of BiFeO3 nanocrystals into 3D mesoporous networks for catalytic applications. AB - The self-assembly of uniform nanocrystals into large porous architectures is currently of immense interest for nanochemistry and nanotechnology. These materials combine the respective advantages of discrete nanoparticles and mesoporous structures. In this article, we demonstrate a facile nanoparticle templating process to synthesize a three-dimensional mesoporous BiFeO3 material. This approach involves the polymer-assisted aggregating assembly of 3 aminopropanoic acid-stabilized bismuth ferrite (BiFeO3) nanocrystals followed by thermal decomposition of the surfactant. The resulting material consists of a network of tightly connected BiFeO3 nanoparticles (~6-7 nm in diameter) and has a moderately high surface area (62 m(2) g(-1)) and uniform pores (ca. 6.3 nm). As a result of the unique mesostructure, the porous assemblies of BiFeO3 nanoparticles show an excellent catalytic activity and chemical stability for the reduction of p-nitrophenol to p-aminophenol with NaBH4. PMID- 25743613 TI - The challenges of studying the anaerobic microbial world. PMID- 25743614 TI - A comparative study of the bacterial community in denitrifying and traditional enhanced biological phosphorus removal processes. PMID- 25743615 TI - Directional cell elongation through filopodia-steered lamellipodial extension on patterned silk fibroin films. AB - Micropatterned biomaterials have been used to direct cell alignment for specific tissue engineering applications. However, the understanding of how cells respond to guidance cues remains limited. Plasticity in protrusion formation has been proposed to enable cells to adapt their motility mode to microenvironment. In this study, the authors investigated the key role of protrusion response in cell guidance on patterned silk fibroin films. The results revealed that the ability to transform between filopodia and small lamellipodia played important roles in directional cell guidance. Filopodia did not show directional extension on patterned substrates prior to spreading, but they transduced topographical cues to the cell to trigger the formation of small lamellipodia along the direction of a microgrooved or parallel nanofiber pattern. The polar lamellipodia formation provided not only a path with directionality, but a driving force for directional cell elongation. Moreover, aligned nanofibers coating provided better mechanical support for the traction of filopodia and lamellipodia, promoting cell attachment, spreading, and migration. This study provides new insight into how cells respond to guidance cues and how filopodia and lamellipodia control cell contact guidance on micropatterned biomaterial surfaces. PMID- 25743616 TI - Relationship between surface chemistry, biofilm structure, and electron transfer in Shewanella anodes. AB - A better understanding of how anode surface properties affect growth, development, and activity of electrogenic biofilms has great potential to improve the performance of bioelectrochemical systems such as microbial fuel cells. The aim of this paper was to determine how anodes with specific exposed functional groups (-N(CH3)3 (+), -COOH, -OH, and -CH3), created using omega-substituted alkanethiolates self-assembled monolayers attached to gold, affect the surface properties and functional performance of electrogenic Shewanella oneidensis MR-1 biofilms. A combination of spectroscopic, microscopic, and electrochemical techniques was used to evaluate how electrode surface chemistry influences morphological, chemical, and functional properties of S. oneidensis MR-1 biofilms, in an effort to develop improved electrode materials and structures. Positively charged, highly functionalized, hydrophilic surfaces were beneficial for growth of uniform biofilms with the smallest cluster sizes and intercluster diffusion distances, and yielding the most efficient electron transfer. The authors derived these parameters based on 3D morphological features of biofilms that were directly linked to functional properties of the biofilm during growth and that, during polarization, were directly connected to the efficiency of electron transfer to the anode. Our results indicate that substratum chemistry affects not only primary attachment, but subsequent biofilm development and bacterial physiology. PMID- 25743617 TI - GPs should identify and visit people at risk from cold homes, says NICE. PMID- 25743618 TI - Obstructive sleep apnea and sickle cell disease: Towards hemorheological abnormalities and vascular dysfunction worsening. PMID- 25743619 TI - The role of partial parotidectomy for benign parotid tumors: A case-control study. AB - OBJECTIVE: To evaluate the results and complications after partial parotidectomy vs superficial parotidectomy, as primary treatment of benign parotid tumors. STUDY DESIGN: Case-control study. SETTING: University hospital. SUBJECTS AND METHODS: A case-control study is presented on parotidectomy, comparing a group of 25 patients treated by partial parotidectomy vs a similar group of 25 patients treated by superficial parotidectomy. All patients had primary benign parotid tumors, were matched by sex and age, and had a minimum follow-up of 4 years. Independent variables included sex, age, medical history, intra-operative variables (surgical time, estimated blood loss, type of drainage, use of collagen), fine-needle aspiration cytology, computed tomography findings, and final histopathological diagnosis. Outcome measures were early and late complications, such as facial nerve paralysis, seroma, sialocele, Frey syndrome, and recurrence. RESULTS: Partial parotidectomy resulted in less early and late complications than superficial parotidectomy, with similar recurrence rates. Temporal facial paresis was found in 4% of partial surgeries, vs 12% of superficial parotidectomies, a significant difference. Three months after surgery, only one patient has a persistent marginal nerve paresis. In contrast, sialocele was more common after partial parotidectomy (28% vs 16%), a significant difference. CONCLUSIONS: Partial parotidectomy achieves less early and late complications than superficial parotidectomy, with similar recurrence rates. PMID- 25743620 TI - Analytical techniques for characterization of cyclodextrin complexes in the solid state: A review. AB - Cyclodextrins are cyclic oligosaccharides able to form inclusion complexes with a variety of hydrophobic guest molecules, positively modifying their physicochemical properties. A thorough analytical characterization of cyclodextrin complexes is of fundamental importance to provide an adequate support in selection of the most suitable cyclodextrin for each guest molecule, and also in view of possible future patenting and marketing of drug-cyclodextrin formulations. The demonstration of the actual formation of a drug-cyclodextrin inclusion complex in solution does not guarantee its existence also in the solid state. Moreover, the technique used to prepare the solid complex can strongly influence the properties of the final product. Therefore, an appropriate characterization of the drug-cyclodextrin solid systems obtained has also a key role in driving in the choice of the most effective preparation method, able to maximize host-guest interactions. The analytical characterization of drug cyclodextrin solid systems and the assessment of the actual inclusion complex formation is not a simple task and involves the combined use of several analytical techniques, whose results have to be evaluated together. The objective of the present review is to present a general prospect of the principal analytical techniques which can be employed for a suitable characterization of drug-cyclodextrin systems in the solid state, evidencing their respective potential advantages and limits. The applications of each examined technique are described and discussed by pertinent examples from literature. PMID- 25743621 TI - The stereoselective separation of serine containing peptides by zwitterionic ion exchanger type chiral stationary phases and the study of serine racemization mechanisms by isotope exchange and tandem mass spectrometry. AB - The occurrence of d-amino acids (D-AAs) in higher-developed organisms in their free form, and within peptides and proteins, has been investigated with an increasing number of studies. Often the inversion of the stereochemical configuration of an individual amino acid drastically changes its biological activity. Alongside Asn and Asp, Ser is most prone to racemization within peptides. Specific enzymes catalyzing D-Ser generation and breakdown have been described. Hence, the applicability of enantioselective ZWIX(+)((r)) and ZWIX( )((r)) chiral stationary phases (CSPs) to peptide separations was assessed and a set of 14 pairs of diastereomeric and enantiomeric Ser and Thr containing di-, tri- and tetra-peptides was chromatographically separated without prior hydrolysis to the individual amino acids. To a certain extent, RP chromatography also enabled the separation of peptide diastereomers. The ZWIX CSPs delivered chromatographic selectivities between 1.04 and 7.23, allowing a change of elution order by switching between the ZWIX(+) and the ZWIX(-) CSP. Coupling these highly selective chromatographic columns with an LTQ-Orbitrap XLTM mass spectrometer and performing high resolution MS(2) measurements enabled us to investigate mechanistic aspects of chemically induced racemization of Ser embedded in short peptides. As reaction medium an alkaline aqueous solution (pH 12.3) was selected. Proton/deuterium exchange experiments provided evidence of a fast Calpha proton exchange with simultaneous racemization. Additionally, (18)O/(16)O exchange allowed the identification of an alternative, and somewhat retarded racemization via a reversible beta-elimination and reintroduction of water at the hydroxymethyl side chain of Ser. This involved the intermediate generation of the prochiral didehydro alanine unit. PMID- 25743622 TI - SK channels and ventricular arrhythmias in heart failure. AB - Small-conductance Ca(2+)-activated K(+) (SK) currents are important in the repolarization of normal atrial (but not ventricular) cardiomyocytes. However, recent studies showed that the SK currents are upregulated in failing ventricular cardiomyocytes, along with increased SK channel protein expression and enhanced sensitivity to intracellular Ca(2+). The SK channel activation may be either anti arrhythmic or pro-arrhythmic, depending on the underlying clinical situations. While the SK channel is a new target of anti-arrhythmic therapy, drug safety is still one of the major concerns. PMID- 25743623 TI - Access to polysubstituted indoles or benzothiophenes via palladium-catalyzed cross-coupling of furfural tosylhydrazones with 2-iodoanilines or 2 iodothiophenols. AB - Palladium-catalyzed cross-coupling of furfural tosylhydrazones with 2 iodoanilines or 2-iodothiophenols produces polysubstituted indoles or benzothiophenes, respectively. The reaction proceeds through 2-furylmethylene palladium iodide intermediates, which undergo furan ring opening followed by ring closure to form indoles or benzothiophenes. This reaction will expand the synthetic applications of furfural derivatives. PMID- 25743624 TI - Using age- and sex-specific risk thresholds to guide statin therapy: one size may not fit all. AB - BACKGROUND: New cholesterol guidelines emphasize 10-year risk of cardiovascular disease (CVD) to identify adults eligible for statin therapy as primary prevention. Whether these CVD risk thresholds should be individualized by age and sex has not been explored. OBJECTIVES: This study evaluated the potential impact of incorporating age- and sex-specific CVD risk thresholds into current cholesterol guidelines. METHODS: Using data from the Framingham Offspring Study, this study assessed current treatment recommendations among age- and sex-specific groups in 3,685 participants free of CVD. Then, it evaluated how varying age- and sex-specific 10-year CVD risk thresholds for statin treatment affect the sensitivity and specificity for incident 10-year CVD events. RESULTS: Basing statin therapy recommendations on a 10-year fixed risk threshold of 7.5% results in lower statin consideration among women than men (63% vs. 33%; p<0.0001), yet most of the study participants who were 66 to 75 years of age were recommended for statin treatment (90.3%). The fixed 7.5% threshold had relatively low sensitivity for capturing 10-year events in younger women and men (40 to 55 years of age). Sensitivity of the recommendations was substantially improved when the treatment threshold was reduced to 5% in participants who were 40 to 55 years of age. Among older adults (66 to 75 years of age), specificity was poor, but when the treatment threshold was raised to 10% in women and 15% in men, specificity significantly improved, with minimal loss in sensitivity. CONCLUSIONS: Cholesterol treatment recommendations could be improved by using individualized age- and sex-specific CVD risk thresholds. PMID- 25743625 TI - South Georgia and the Southern Ocean. PMID- 25743627 TI - Interpretation of surface diffusion data with Langevin simulations: a quantitative assessment. AB - Diffusion studies of adsorbates moving on a surface are often analyzed using 2D Langevin simulations. These simulations are computationally cheap and offer valuable insight into the dynamics, however, they simplify the complex interactions between the substrate and adsorbate atoms, neglecting correlations in the motion of the two species. The effect of this simplification on the accuracy of observables extracted using Langevin simulations was previously unquantified. Here we report a numerical study aimed at assessing the validity of this approach. We compared experimentally accessible observables which were calculated using a Langevin simulation with those obtained from explicit molecular dynamics simulations. Our results show that within the range of parameters we explored Langevin simulations provide a good alternative for calculating the diffusion procress, i.e. the effect of correlations is too small to be observed within the numerical accuracy of this study and most likely would not have a significant effect on the interpretation of experimental data. Our comparison of the two numerical approaches also demonstrates the effect temperature dependent friction has on the calculated observables, illustrating the importance of accounting for such a temperature dependence when interpreting experimental data. PMID- 25743626 TI - Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. AB - IPF is a progressive lung disorder characterized by fibroblast proliferation and myofibroblast differentiation. Although neutrophil accumulation within IPF lungs has been negatively correlated with outcomes, the role played by neutrophils in lung fibrosis remains poorly understood. We have demonstrated previously that NE promotes lung cancer cell proliferation and hypothesized that it may have a similar effect on fibroblasts. In the current study, we show that NE(-/-) mice are protected from asbestos-induced lung fibrosis. NE(-/-) mice displayed reduced fibroblast and myofibroblast content when compared with controls. NE directly both lung fibroblast proliferation and myofibroblast differentiation in vitro, as evidenced by proliferation assays, collagen gel contractility assays, and alphaSMA induction. Furthermore, alphaSMA induction occurs in a TGF-beta independent fashion. Treatment of asbestos-recipient mice with ONO-5046, a synthetic NE antagonist, reduced hydroxyproline content. Thus, the current study points to a key role for neutrophils and NE in the progression of lung fibrosis. Lastly, the study lends rationale to use of NE-inhibitory approaches as a novel therapeutic strategy for patients with lung fibrosis. PMID- 25743629 TI - Hydrogen-deuterium exchange mass spectrometry for determining protein structural changes in drug discovery. AB - Protein structures are dynamically changed in response to post-translational modifications, ligand or chemical binding, or protein-protein interactions. Understanding the structural changes that occur in proteins in response to potential candidate drugs is important for predicting the modes of action of drugs and their functions and regulations. Recent advances in hydrogen/deuterium exchange mass spectrometry (HDX-MS) have the potential to offer a tool for obtaining such understanding similarly to other biophysical techniques, such as X ray crystallography and high resolution NMR. We present here, a review of basic concept and methodology of HDX-MS, how it is being applied for identifying the sites and structural changes in proteins following their interactions with other proteins and small molecules, and the potential of this tool to help in drug discovery. PMID- 25743628 TI - New potential eukaryotic substrates of the mycobacterial protein tyrosine phosphatase PtpA: hints of a bacterial modulation of macrophage bioenergetics state. AB - The bacterial protein tyrosine phosphatase PtpA is a key virulence factor released by Mycobacterium tuberculosis in the cytosol of infected macrophages. So far only two unrelated macrophage components (VPS33B, GSK3alpha) have been identified as PtpA substrates. As tyrosine phosphatases are capable of using multiple substrates, we developed an improved methodology to pull down novel PtpA substrates from an enriched P-Y macrophage extract using the mutant PtpA D126A. This methodology reduced non-specific protein interactions allowing the identification of four novel putative PtpA substrates by MALDI-TOF-MS and nano LC MS: three mitochondrial proteins - the trifunctional enzyme (TFP), the ATP synthase, and the sulfide quinone oxidoreductase - and the cytosolic 6 phosphofructokinase. All these proteins play a relevant role in cell energy metabolism. Using surface plasmon resonance, PtpA was found to bind immunopurified human TFP through its catalytic site since TFP-PtpA association was inhibited by a specific phosphatase inhibitor. Moreover, PtpA wt was capable of dephosphorylating immunopurified human TFP in vitro supporting that TFP may be a bona fide PtpA susbtrate. Overall, these results suggest a novel scenario where PtpA-mediated dephosphorylation may affect pathways involved in cell energy metabolism, particularly the beta oxidation of fatty acids through modulation of TFP activity and/or cell distribution. PMID- 25743630 TI - Flavonoids from the aerial parts of Houttuynia cordata attenuate lung inflammation in mice. AB - The aerial parts of Houttuynia cordata used for treating inflammation-related disorders contain flavonoids as major constituents. Since certain flavonoids possess anti-inflammatory activity, especially in the lung, the pharmacological activities of H. cordata and the flavonoid constituents were evaluated using in vitro and in vivo models of lung inflammation. The 70 % ethanol extract of the aerial parts of H. cordata inhibited the production of inflammatory biomarkers IL 6 and NO in lung epithelial cells (A549) and alveolar macrophages (MH-S), respectively. And the same plant material, administered orally (100 and 400 mg/kg), significantly inhibited lung inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury. From the extract, major flavonoids including afzelin, hyperoside and quercitrin were successfully isolated and they also attenuated LPS-induced lung inflammation in mice by oral administration. In particular, quercitrin showed most potent activity at 100 mg/kg. These results demonstrate for the first time that H. cordata and three flavonoid constituents have a therapeutic potential for treating lung inflammatory disorders. PMID- 25743631 TI - Comparison of laser and intense pulsed light sintering (IPL) for inkjet-printed copper nanoparticle layers. AB - In this contribution we discuss the sintering of an inkjet-printed copper nanoparticle ink based on electrical performance and microstructure analysis. Laser and intense pulsed light (IPL) sintering are employed in order to compare the different techniques and their feasibility for electronics manufacturing. A conductivity of more than 20% of that of bulk copper material has been obtained with both sintering methods. Laser and IPL sintering techniques are considered to be complementary techniques and are highly suitable in different application fields. PMID- 25743632 TI - Safety and efficacy study of lung cancer stem cell vaccine. AB - In this trial, lung cancer stem cells (CSCs) were separated and cultured to produce a vaccine; its safety and efficacy were prospectively evaluated in low-, medium-, and high-dose groups. Between February and September 2014, we enrolled 90 patients who met the enrollment criteria and assigned them to three groups (n = 30). Throughout the trial, injection site reaction was the most common reaction (63 %), and fever was least common (16 %); however, there was no difference among the three groups. When the immune responses pre- and post-vaccination were compared, we found that the CSC-nonspecific and CSC-specific responses were both significantly enhanced in the medium- and high-dose groups. This study is the first clinical trial of a lung CSC vaccine and preliminarily proves its safety and efficacy. PMID- 25743633 TI - Murine adipose-derived mesenchymal stromal cell vesicles: in vitro clues for neuroprotective and neuroregenerative approaches. AB - BACKGROUND AIMS: Adipose-derived mesenchymal stromal cells (ASC) are known to promote neuroprotection and neuroregeneration in vitro and in vivo. These biological effects are probably mediated by paracrine mechanisms. In recent years, nanovesicles (NV) and microvesicles (MV) have been shown to play a major role in cell-to-cell communication. We tested the efficacy of NV and MV obtained from ASC in mediating neuroprotection and neuroregeneration in vitro. METHODS: We exposed neuronal cells (both cell line and primary cultures) to oxidative stress in the presence or not of NV or MV. RESULTS: In this experimental setting, we found that low doses of NV or MV protected neurons from apoptotic cell death. We then assessed the neuroregenerative effect of NV/MV in cerebellar slice cultures demyelinated with lysophosphatidylcholine. We observed that low but not higher doses of NV and MV increased the process of remyelination and activated nestin positive oligodendroglial precursors. CONCLUSIONS: Taken together, our data in vitro support the relevance of ASC vesicles as a source of protecting and regenerating factors that might modulate the microenvironment in neuro inflammatory as well as in neurodegenerative disorders. The present findings may suggest that stromal cell-derived vesicles might represent a potential therapeutic tool, enabling the safe administration of stromal cell effector factors, avoiding the cellular counterpart. PMID- 25743634 TI - Clumps of a mesenchymal stromal cell/extracellular matrix complex can be a novel tissue engineering therapy for bone regeneration. AB - BACKGROUND AIMS: The transplantation of mesenchymal stromal cells (MSCs) to damaged tissue has attracted attention in scientific and medical fields as an effective regenerative therapy. Nevertheless, additional studies are required to develop an MSC transplant method for bone regeneration because the use of an artificial scaffold restricts the number of transplanted cells and their function. Furthermore, regulating the degree of cell differentiation in vitro is desirable for a more effective regenerative therapy. To address these unresolved issues, with the use of a self-produced extracellular matrix (ECM), we developed clumps of an MSC/ECM complex (C-MSCs). METHODS: MSCs isolated from rat femur were cultured in growth medium supplemented with 50 MUg/mL of ascorbic acid for 7 days. To obtain C-MSCs, confluent cells were scratched with the use of a micropipette tip to roll up the cellular sheet, which consisted of ECM produced by the MSCs. The biological properties of C-MSCs were assessed in vitro and their bone regenerative activity was tested by use of a rat calvarial defect model. RESULTS: Immunofluorescent confocal microscopic analysis revealed that type I collagen formed C-MSCs. Osteopontin messenger RNA expression and amount of calcium content were higher in C-MSCs cultured in osteo-inductive medium than those of untreated C-MSCs. The transplantation of osteogenic-differentiated C MSCs led to rapid bone regeneration in the rat calvarial defect model. CONCLUSIONS: These results suggest that the use of C-MSCs refined by self produced ECM, which contain no artificial scaffold and can be processed in vitro, may represent a novel tissue engineering therapy. PMID- 25743636 TI - One-step detection of pathogens and viruses: combining magnetic relaxation switching and magnetic separation. AB - We report a sensing methodology that combines magnetic separation (MS) and magnetic relaxation switching (MS-MRS) for one-step detection of bacteria and viruses with high sensitivity and reproducibility. We first employ a magnetic field of 0.01 T to separate the magnetic beads of large size (250 nm in diameter) from those of small size (30 nm in diameter) and use the transverse relaxation time (T2) of the water molecules around the 30 nm magnetic beads (MB30) as the signal readout of the immunoassay. An MS-MRS sensor integrates target enrichment, extraction, and detection into one step, and the entire immunoassay can be completed within 30 min. Compared with a traditional MRS sensor, an MS-MRS sensor shows enhanced sensitivity, better reproducibility, and convenient operation, thus providing a promising platform for point-of-care testing. PMID- 25743637 TI - In vivo brain delivery of v-myc overproduced human neural stem cells via the intranasal pathway: tumor characteristics in the lung of a nude mouse. AB - We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc) were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%), and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%). In the mice with initial lung signals (4 of 9, 44.4%), the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally. PMID- 25743635 TI - Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia. AB - Major theories on the neural basis of schizophrenic core symptoms highlight aberrant salience network activity (insula and anterior cingulate cortex), prefrontal hypoactivation, sensory processing deficits as well as an impaired connectivity between temporal and prefrontal cortices. The mismatch negativity is a potential biomarker of schizophrenia and its reduction might be a consequence of each of these mechanisms. In contrast to the previous electroencephalographic studies, functional magnetic resonance imaging may disentangle the involved brain networks at high spatial resolution and determine contributions from localized brain responses and functional connectivity to the schizophrenic impairments. Twenty-four patients and 24 matched control subjects underwent functional magnetic resonance imaging during an optimized auditory mismatch task. Haemodynamic responses and functional connectivity were compared between groups. These data sets further entered a diagnostic classification analysis to assess impairments on the individual patient level. In the control group, mismatch responses were detected in the auditory cortex, prefrontal cortex and the salience network (insula and anterior cingulate cortex). Furthermore, mismatch processing was associated with a deactivation of the visual system and the dorsal attention network indicating a shift of resources from the visual to the auditory domain. The patients exhibited reduced activation in all of the respective systems (right auditory cortex, prefrontal cortex, and the salience network) as well as reduced deactivation of the visual system and the dorsal attention network. Group differences were most prominent in the anterior cingulate cortex and adjacent prefrontal areas. The latter regions also exhibited a reduced functional connectivity with the auditory cortex in the patients. In the classification analysis, haemodynamic responses yielded a maximal accuracy of 83% based on four features; functional connectivity data performed similarly or worse for up to about 10 features. However, connectivity data yielded a better performance when including more than 10 features yielding up to 90% accuracy. Among others, the most discriminating features represented functional connections between the auditory cortex and the anterior cingulate cortex as well as adjacent prefrontal areas. Auditory mismatch impairments incorporate major neural dysfunctions in schizophrenia. Our data suggest synergistic effects of sensory processing deficits, aberrant salience attribution, prefrontal hypoactivation as well as a disrupted connectivity between temporal and prefrontal cortices. These deficits are associated with subsequent disturbances in modality-specific resource allocation. Capturing different schizophrenic core dysfunctions, functional magnetic resonance imaging during this optimized mismatch paradigm reveals processing impairments on the individual patient level, rendering it a potential biomarker of schizophrenia. PMID- 25743638 TI - Size and edge roughness dependence of thermal conductivity for vacancy-defective graphene ribbons. AB - By incorporating the phonon-phonon scattering, phonon-boundary scattering and phonon-vacancy scattering into the linearized Boltzmann transport equation, we theoretically investigate the effects of size and edge roughness on thermal conductivity of single vacancy-defective graphene ribbons. Due to the severe suppression of high-frequency phonons by phonon-vacancy scattering which includes the impacts of missing mass and linkages, as well as the variation of the force constant of bonds associated with vacancies, the low-frequency ballistic phonons have a higher contribution to the thermal conductivity, which results in the stronger length, weaker width and weaker edge roughness dependence on thermal conductivity of vacancy-defective graphene ribbons than that of pristine ones. Our findings are helpful to understand and manipulate thermal conductivity of graphene by phononic engineering. PMID- 25743639 TI - [Is the troponin threshold for women too high?]. PMID- 25743641 TI - [Spiral esophageal contractions]. PMID- 25743643 TI - ["Sun is an almost totally disregarded occupational risk"]. PMID- 25743644 TI - [The medical building as country doctor magnet]. PMID- 25743645 TI - [Honest money for honest explanation]. PMID- 25743648 TI - [Nonmedical practice assistants are possible even in new practices]. PMID- 25743651 TI - [The obligation for vaccination counseling is far too limited]. PMID- 25743653 TI - [Is the patient no longer the focus?]. PMID- 25743652 TI - [Triple anticoagulant therapy - now what can I give for pain?]. PMID- 25743654 TI - [However, a stroke it was not!]. PMID- 25743655 TI - [Basic principles of tumor pain therapy]. PMID- 25743656 TI - [Naturopathy consultation. Who benefits from a fasting cure?]. PMID- 25743657 TI - [Meditation: a true winner in hypertension]. PMID- 25743658 TI - [The interval carcinoma challenge]. PMID- 25743660 TI - [Weight loss via the lung]. PMID- 25743662 TI - [Going to Babylon with Google]. PMID- 25743663 TI - [What assistant physicians unfortunately do not learn]. PMID- 25743664 TI - [Gamer pain from nintendinitis to waii knee]. PMID- 25743665 TI - [Only old literature in the waiting room]. PMID- 25743666 TI - [How to help patients with ear nose throat problems]. PMID- 25743667 TI - [Blocked nose: differential diagnosis]. PMID- 25743668 TI - [The therapy of dysphonia]. PMID- 25743669 TI - [Emergency checklist panic attack]. PMID- 25743670 TI - [Current management of midshaft clavicle fractures]. PMID- 25743671 TI - [Reducing and maintaining body weight - trends and evidence]. PMID- 25743672 TI - [Stool transplantation - gut bacteria as a novel therapeutic option]. PMID- 25743673 TI - [Optimizing antihypertensive therapy]. PMID- 25743674 TI - [New freedoms in insulin therapy]. PMID- 25743675 TI - [Favorable effects on health related quality of life]. PMID- 25743676 TI - [It need not always be an antibiotic]. PMID- 25743677 TI - [Synthetic antithrombotic drug with broad approval profile]. PMID- 25743678 TI - [Bones are often weaker than one (man) expects]. PMID- 25743679 TI - [Antidote to dabigatran]. PMID- 25743680 TI - [New formulation with improved pharmacokinetics]. PMID- 25743681 TI - [New flexibility in diabetes therapy]. PMID- 25743682 TI - [New combination therapy increases chances of recovery]. PMID- 25743684 TI - [Effective anticoagulation also in advanced age]. PMID- 25743685 TI - An increase in hemoglobin, platelets and white blood cells levels by iron chelation as single treatment in multitransfused patients with myelodysplastic syndromes: clinical evidences and possible biological mechanisms. AB - Iron chelation therapy can improve hematopoiesis in myelodysplastic syndromes. Only few studies showed hematologic improvement with deferoxamine, and the erythroid responses were correlated with good compliance to long-term treatment. Indeed, single-case reports and data from clinical trials testing the efficacy of deferasirox reported hematologic improvements with varying rates of response in different lineages. Overall, about 760 myelodysplastic syndrome (MDS) patients with iron overload receiving deferasirox were included in six different studies, and an increase in hemoglobin level was reported to range from 6 to 44.5%, an increase in platelet count from 13 to 61%, and in neutrophil count from 3 to 76%. In all the published studies, hematologic improvements were not related to serum ferritin or to non-total binding iron changes; indeed, other pathways were indicated as possible pathogenetic mechanisms, such as decreased NF-kB activity, modulation of mTOR signalling, and reduced reactive oxygen species. The aims of this review are to provide all available information relating clinical and hematologic changes after chelation therapy and to discuss potential mechanisms involved in such responses. PMID- 25743687 TI - Heparanase procoagulant activity, factor Xa, and plasminogen activator inhibitor 1 are increased in shift work female nurses. AB - Epidemiologic studies indicate on an increased risk of cardiovascular disease and cancer in shift workers, although the underlying mechanism is obscure. Heparanase directly enhances tissue factor (TF) activity leading to increased factor Xa production and subsequent activation of the coagulation system. In the present study, a comparison of coagulation markers among healthy shift working (SW) vs. healthy daytime working (DW) female nurses was performed. Thirty SW and 30 DW female nurses were enrolled. For each of the 60 participants, blood was drawn between 7:00 and 8:00 a.m. and at least 8 h after the last work shift. Plasma was studied for coagulation marker that included TF/heparanase procoagulant activity, TF activity, heparanase procoagulant activity, heparanase level, factor Xa level, plasminogen activator inhibitor 1 (PAI-1), plasminogen, alpha2-antiplasmin, fibrinogen, global protein C, von Willebrand factor, and D-dimer by chromogenic assays and enzyme-linked immunosorbent assays (ELISAs). Sleep quality was assessed by self-report according to the Pittsburgh Sleep Quality Index. The heparanase procoagulant activity increased by 2-fold and the TF/heparanase procoagulant activity increased by 1.5-fold in SW nurses compared to DW nurses (P < 0.05). Factor Xa levels and PAI-1 levels were significantly higher among SW nurses compared to the DW group (22 vs. 18 ng/ml, P < 0.05, and 32 vs. 22 ng/ml, P < 0.005, respectively). No significant differences were found in the other tested coagulation markers between the study groups. Heparanase procoagulant activity, factor Xa level, and PAI-1 level were significantly higher in SW nurses compared to the DW group. These alterations of blood coagulation activation may potentially contribute to cardiovascular and cancer morbidity. PMID- 25743686 TI - Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P). AB - Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in >=3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time. PMID- 25743688 TI - Effects of the 1, 4-dihydropyridine L-type calcium channel blocker benidipine on bone marrow stromal cells. AB - Osteoporosis (OP) often increases the risk of bone fracture and other complications and is a major clinical problem. Previous studies have found that high blood pressure is associated with bone formation abnormalities, resulting in increased calcium loss. We have investigated the effect of the antihypertensive drug benidipine on bone marrow stromal cell (BMSC) differentiation into osteoblasts and bone formation under osteoporotic conditions. We used a combination of in vitro and in vivo approaches to test the hypothesis that benidipine promotes murine BMSC differentiation into osteoblasts. Alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), beta-catenin, and low-density lipoprotein receptor-related protein 5 (LRP5) protein expression was evaluated in primary femoral BMSCs from C57/BL6 mice cultured under osteogenic conditions for 2 weeks to examine the effects of benidipine. An ovariectomized (OVX) mouse model was used to investigate the effect of benidipine treatment for 3 months in vivo. We found that ALP, OCN, and RUNX2 expression was up-regulated and WNT/beta-catenin signaling was enhanced in vitro and in vivo. In OVX mice that were intragastrically administered benidipine, bone parameters (trabecular thickness, bone mineral density, and trabecular number) in the distal femoral metaphysis were significantly increased compared with control OVX mice. Consistently, benidipine promoted BMSC differentiation into osteoblasts and protected against bone loss in OVX mice. Therefore, benidipine might be a suitable candidate for the treatment of patients with postmenopausal osteoporosis and hypertension. PMID- 25743690 TI - Expression analysis of octopamine and tyramine receptors in Drosophila. AB - The monoamines octopamine and tyramine, which are the invertebrate counterparts of epinephrine and norepinephrine, transmit their action through sets of G protein-coupled receptors. Four different octopamine receptors (Oamb, Octbeta1R, Octbeta2R, Octbeta3R) and 3 different tyramine receptors (TyrR, TyrRII, TyrRIII) are present in the fruit fly Drosophila melanogaster. Utilizing the presumptive promoter regions of all 7 octopamine and tyramine receptors, the Gal4/UAS system is utilized to elucidate their complete expression pattern in larvae as well as in adult flies. All these receptors show strong expression in the nervous system but their exact expression patterns vary substantially. Common to all octopamine and tyramine receptors is their expression in mushroom bodies, centers for learning and memory in insects. Outside the central nervous system, the differences in the expression patterns are more conspicuous. However, four of them are present in the tracheal system, where they show different regional preferences within this organ. On the other hand, TyrR appears to be the only receptor present in the heart muscles and TyrRII the only one expressed in oenocytes. Skeletal muscles express octbeta2R, Oamb and TyrRIII, with octbeta2R being present in almost all larval muscles. Taken together, this study provides comprehensive information about the sites of expression of all octopamine and tyramine receptors in the fruit fly, thus facilitating future research in the field. PMID- 25743689 TI - Stress signaling in mammalian oocytes and embryos: a basis for intervention and improvement of outcomes. AB - Oocytes and early stage embryos are highly sensitive to variation in diverse exogenous factors such as temperature, osmolarity, oxygen, nutrient restriction, pH, shear stress, toxins, amino acid availability, and lipids. It is becoming increasingly apparent that many such factors negatively affect the endoplasmic reticulum, protein synthesis and protein processing, initiating ER stress and unfolded protein responses. As a result, ER stress signaling serves as a common mediator of cellular responses to diverse stressors. In oocytes and embryos, this leads to developmental arrest and epigenetic changes. Recent studies have revealed that preventing ER stress or inhibiting ER stress signaling can preserve or even enhance oocyte and embryo developmental potential. This review examines ER stress signaling, how it arises, how it affects oocytes and embryos, and how its occurrence can be managed or prevented. PMID- 25743691 TI - Confocal stereology: an efficient tool for measurement of microscopic structures. AB - Quantitative measurements of geometric forms or counting of objects in microscopic specimens is an essential tool in studies of microstructure. Confocal stereology represents a contemporary approach to the evaluation of microscopic structures by using a combination of stereological methods and confocal microscopy. 3-D images acquired by confocal microscopy can be used for the estimation of geometrical characteristics of microscopic structures by stereological methods, based on the evaluation of optical sections within a thick slice and using computer-generated virtual test probes. Such methods can be used for estimating volume, number, surface area and length using relevant spatial probes, which are generated by specific software. The interactions of the probes with the structure under study are interactively evaluated. An overview of the methods of confocal stereology developed during the past 30 years is presented. Their advantages and pitfalls in comparison with other methods for measurement of geometrical characteristics of microscopic structures are discussed. PMID- 25743692 TI - Update on stereology for light microscopy. AB - The quantitative investigation of images taken from light microscopy observation is one of the pillars of biological and biomedical investigation. The main objective is the count of objects, usually cells. In addition, the measurement of several morphological parameters, such as the diameter of cells, the length of vessels, etc., can also be important for the quantitative assessment of the features of a tissue. Whereas counting and measuring histological elements may appear easy, especially today with the availability of dedicated software, in fact it is not, since what we can count and measure on light microscopy images are not the true histological elements but actually profiles of them. Obviously, the number and size of profiles of an object do not correspond to the object number and size and thus significant mistakes can be made in the interpretation of the quantitative data obtained from profiles. To cope with this problem, over the last decades, a number of design-based stereological tools have been developed in order to obtain unbiased and reliable quantitative estimates of cell and tissue elements that originate from light microscopy images. This paper reviews the basic principles of the stereological tools from the first disector applications through some of the most recently devised methods. PMID- 25743693 TI - Light sheet-based fluorescence microscopy (LSFM) for the quantitative imaging of cells and tissues. AB - In light sheet-based fluorescence microscopy (LSFM), only the focal plane is illuminated by a laser light sheet. Hence, only the fluorophores within a thin volume of the specimen are excited. This reduces photo-bleaching and photo-toxic effects by several orders of magnitude compared with any other form of microscopy. Therefore, LSFM (aka single/selective-plane illumination microscopy [SPIM] or digitally scanned light sheet microscopy [DSLM]) is the technique of choice for the three-dimensional imaging of live or fixed and of small or large three-dimensional specimens. The parallel recording of millions of pixels with modern cameras provides an extremely fast acquisition speed. Recent developments address the penetration depth, the resolution and the recording speed of LSFM. The impact of LSFM on research areas such as three-dimensional cell cultures, neurosciences, plant biology and developmental biology is increasing at a rapid pace. The development of high-throughput LSFM is the next leap forward, allowing the application of LSFM in toxicology and drug discovery screening. PMID- 25743695 TI - STED nanoscopy: a glimpse into the future. AB - The well-known saying of "Seeing is believing" became even more apt in biology when stimulated emission depletion (STED) nanoscopy was introduced in 1994 by the Nobel laureate S. Hell and coworkers. We presently stand at a juncture. Nanoscopy represented a revolution in fluorescence microscopy but now is a mature technique applied to many branches of biology, physics, chemistry, and materials science. We are currently looking ahead to the next generation of optical nanoscopes, to the new key player that will arise in the forthcoming years. This article gives an overview of the various cutting-edge implementations of STED nanoscopy and tries to shine a light into the future: imaging everything faster with unprecedented sensitivity and label-free. PMID- 25743694 TI - Advances in chemical labeling of proteins in living cells. AB - The pursuit of quantitative biological information via imaging requires robust labeling approaches that can be used in multiple applications and with a variety of detectable colors and properties. In addition to conventional fluorescent proteins, chemists and biologists have come together to provide a range of approaches that combine dye chemistry with the convenience of genetic targeting. This hybrid-tagging approach amalgamates the rational design of properties available through synthetic dye chemistry with the robust biological targeting available with genetic encoding. In this review, we discuss the current range of approaches that have been exploited for dye targeting or for targeting and activation and some of the recent applications that are uniquely permitted by these hybrid-tagging approaches. PMID- 25743697 TI - [Argyll-Robertson pupil]. PMID- 25743696 TI - Survival of auditory hair cells. AB - The inability of mammals to regenerate auditory hair cells creates a pressing need to understand the means of enhancing hair cell survival following insult or injury. Hair cells are easily damaged by noise exposure, by ototoxic medications and as a consequence of aging processes, all of which lead to progressive and permanent hearing impairment as hair cells are lost. Significant efforts have been invested in designing strategies to prevent this damage from occurring since permanent hearing loss has a profound impact on communication and quality of life for patients. In this mini-review, we discuss recent progress in the use of antioxidants, anti-inflammatories and apoptosis inhibitors to enhance hair cell survival. We conclude by clarifying the distinction between protection and rescue strategies and by highlighting important areas of future research. PMID- 25743698 TI - Association between 24 h urinary sodium and potassium excretion and the metabolic syndrome in Chinese adults: the Shandong and Ministry of Health Action on Salt and Hypertension (SMASH) study. AB - The association of 24 h urinary Na and potassium excretion with the risk of the metabolic syndrome (MetS) has not been studied in China. The aim of the present study was to examine this association by analysing the data from 1906 study participants living in north China. To this end, 24 h urine samples were collected. Of the 1906 participants, 471 (24.7 %) had the MetS. The mean urinary Na and K excretion was 228.7 and 40.8 mmol/d, respectively. After multivariate adjustment, the odds of the MetS significantly increased across the increasing tertiles of urinary Na excretion (1.00, 1.40 and 1.54, respectively). For the components of the MetS, the odds of central obesity, elevated blood pressure and elevated TAG, but not the odds of low HDL-cholesterol and elevated fasting glucose, significantly increased with the successive tertiles of urinary Na excretion. Furthermore, for every 100 mmol/d increase in urinary Na excretion, the odds of the MetS, central obesity, elevated blood pressure and elevated TAG was significantly increased by 29, 63, 22 and 21 %, respectively. However, urinary K excretion was not significantly associated with the risk of the MetS. These findings suggest that high Na intake might be an important risk factor for the MetS in Chinese adults. PMID- 25743699 TI - Bioavailability and pharmacokinetics profile of helicid in beagle dogs using gradient elution high performance liquid chromatography electrospray ionization mass spectrometry. AB - A simple, sensitive and reliable gradient elution high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS) method was developed for quantifying helicid in dog plasma. The limit of detection (LOD) and the lower limit of quantitation (LLOQ) were 0.3 and 1 ng/mL, respectively. This method was validated for selectivity, linearity, accuracy and precision, extraction recoveries, matrix effects, carry-over, cross-talk, dilution integrity, stability and incurred sample reanalysis (ISR). Bioavailability and pharmacokinetic parameters of helicid in beagle dogs were researched from a two period crossover design study. After intravenous administration (i.v.), helicid had a mean (+/- SD) AUC0-infinity of 12062.06 +/- 2482.69 ng/mL h and terminal half-life (t1/2 z) of 2.91 +/- 1.37 h, while Cmax was 35613.23 +/- 8157.18 ng/mL. Following intragastric gavage administration (i.g.), AUC0-infinity was 7589.16 +/ 1797.20 ng/mL h along with a longer t1/2 z of 4.10 +/- 4.35 h. Cmax was researched at 0.58 +/- 0.20 h. The absolute bioavailability (F) of helicid was 15.74 +/- 1.87%. PMID- 25743700 TI - In vitro evaluation of Sun Protection Factor and stability of commercial sunscreens using mass spectrometry. AB - Sunlight exposure causes several types of injury to humans, especially on the skin; among the most common harmful effects due to ultraviolet (UV) exposure are erythema, pigmentation and lesions in DNA, which may lead to cancer. These long term effects are minimized with the use of sunscreens, a class of cosmetic products that contains UV filters as the main component in the formulation; such molecules can absorb, reflect or diffuse UV rays, and can be used alone or as a combination to broaden the protection on different wavelengths. Currently, worldwide regulatory agencies define which ingredients and what quantities must be used in each country, and enforce companies to conduct tests that confirm the Sun Protection Factor (SPF) and the UVA (Ultraviolet A) factor. Standard SPF determination tests are currently conducted in vivo, using human subjects. In an industrial mindset, apart from economic and ethical reasons, the introduction of an in vitro method emerges as an interesting alternative by reducing risks associated to UV exposure on tests, as well as providing assertive analytical results. The present work aims to describe a novel methodology for SPF determination directly from sunscreen formulations using the previously described cosmetomics platform and mass spectrometry as the analytical methods of choice. PMID- 25743701 TI - Bioremediation using Novosphingobium strain DY4 for 2,4-dichlorophenoxyacetic acid-contaminated soil and impact on microbial community structure. AB - The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is commonly used for weed control. The ubiquity of 2,4-D has gained increasing environmental concerns. Biodegradation is an attractive way to clean up 2,4-D in contaminated soil. However, information on the bioaugmentation trial for remediating contaminated soil is still very limited. The impact of bioaugmentation using 2,4-D-degraders on soil microbial community remains unknown. The present study investigated the bioremediation potential of a novel degrader (strain DY4) for heavily 2,4-D polluted soil and its bioaugmentation impact on microbial community structure. The strain DY4 was classified as a Novosphingobium species within class Alphaproteobacteria and harbored 2,4-D-degrading TfdAalpha gene. More than 50 and 95 % of the herbicide could be dissipated in bioaugmented soil (amended with 200 mg/kg 2,4-D) respectively in 3-4 and 5-7 days after inoculation of Novosphingobium strain DY4. A significant growth of the strain DY4 was observed in bioaugmented soil with the biodegradation of 2,4-D. Moreover, herbicide application significantly altered soil bacterial community structure but bioaumentation using the strain DY4 showed a relatively weak impact. PMID- 25743706 TI - Images of the month: Dentures in the cecum. PMID- 25743703 TI - Human Placenta-Derived CD146-Positive Mesenchymal Stromal Cells Display a Distinct Osteogenic Differentiation Potential. AB - Mesenchymal stromal cells (MSCs) are multipotent cells that can be differentiated in vitro into a variety of cell types, including adipocytes or osteoblasts. Our recent studies indicated that a high expression of CD146 on MSCs from bone marrow correlates with their robust osteogenic differentiation potential. We therefore investigated if expression of CD146 on MSCs from the placenta correlates with a similar osteogenic differentiation potential. The MSCs were isolated specifically from the endometrial and fetal parts of human term placenta and expanded in separate cultures and compared with MSCs from bone marrow as controls. The expression of cell surface antigens was investigated by flow cytometry. Differentiation of MSCs was documented by cytochemistry and analysis of typical lineage marker genes. CD146-positive MSCs were separated from CD146-negative cells by magnet-assisted cell sorts (MACS). We report that the expression of CD146 is associated with a higher osteogenic differentiation potential in human placenta-derived MSCs (pMSCs) and the CD146(pos) pMSCs generated a mineralized extracellular matrix, whereas the CD146(neg) pMSCs failed to do so. In contrast, adipogenic and chondrogenic differentiation of pMSCs was not different in CD146(pos) compared with CD146(neg) pMSCs. Upon enrichment of pMSCs by MACS, the CD146(neg) and CD146(pos) populations maintained their expression levels for this antigen for several passages in vitro. We conclude that CD146(pos) pMSCs either respond to osteogenic stimuli more vividly or, alternatively, CD146(pos) pMSCs present a pMSC subset that is predetermined to differentiate into osteoblasts. PMID- 25743707 TI - Images of the month: Duplication of gallbladder. PMID- 25743702 TI - Genomic landscape of paediatric adrenocortical tumours. AB - Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis. PMID- 25743708 TI - Video of the month: Endoscopic ultrasound-guided drainage for liver abscess using a fully covered metallic stent. PMID- 25743712 TI - Characterization of inflammation and fibrosis in Crohn's disease lesions by magnetic resonance imaging. PMID- 25743713 TI - Response to Levy. PMID- 25743714 TI - Response to Chalassani et al. PMID- 25743715 TI - Adalimumab trough levels and response to biological treatment in patients with inflammatory bowel disease: a useful cutoff in clinical practice. PMID- 25743716 TI - Response to Bodini et al. PMID- 25743717 TI - Many factors affecting the quality of bowel preparation need to be discussed when comparing different regimes. PMID- 25743718 TI - Response to Syed. PMID- 25743719 TI - Response to Feuerstein. PMID- 25743720 TI - The ideal insertion method for colonoscopy is in the eye of the beholder. PMID- 25743721 TI - An unusual presentation of malignant melanoma: amelanotic gastric metastasis. PMID- 25743723 TI - Erratum: the risks of thromboembolism vs. recurrent gastrointestinal bleeding after interruption of systemic anticoagulation in hospitalized inpatients with gastrointestinal bleeding: a prospective study. PMID- 25743724 TI - Corrigendum: Characterization of inflammation and fibrosis in Crohn's disease lesions by magnetic resonance imaging. PMID- 25743725 TI - Effects of hyperbaric oxygen therapy on rat facial skin. AB - INTRODUCTION: We used immunohistochemistry to investigate the histopathologic effects of hyperbaric oxygen (HBO) on the facial skin of rats. MATERIAL AND METHODS: Rats in the HBO group (n = 6) were placed in a 20 L HBO chamber at 2.5 atmospheres absolute at 25-26 degrees C with 100% oxygen for 90 min/day for 7 days. Following euthanasia, sections of facial skin were removed for examination. RESULTS: Epidermal hyperplasia and degeneration, basal-cell hypertrophy, subepithelial fibrosis, and increased connective tissue were observed in the HBO group. E-cadherin expression was reduced in the epidermis, hair follicles, and sebaceous glands in HBO-treated rats relative to control animals. HBO treatment was associated with vimentin immunoreactivity in fibroblasts, endothelial cells, and the bulbus pilorum of a subset of hair follicles. It also resulted in increased type IV collagen expression within the connective tissue in the hair follicles and sebaceous glands. CONCLUSION: The HBO group demonstrated epidermal hyperplasia and degeneration, basal-cell hypertrophy, and subepithelial fibrosis. In addition, HBO decreased E-cadherin expression, which suggests that HBO may impair intracellular adhesion. Expression of vimentin and type IV collagen was also observed in the dermis. Increased connective tissue, hemorrhage, and mononuclear cell infiltration were observed in the dermis of HBO-treated animals. Thus, HBO has effects on the structures of the epidermis and dermis. PMID- 25743726 TI - Effect of palonosetron (5HT-3 antagonist) and pantoprazole (proton pump inhibitor) against surgical esophagitis induced by forestomach and pylorus ligation in albino rats. AB - This study was embarked upon to evaluate the effects of pantoprazole and palonosetron on experimental esophagitis in albino wistar rats. Groups of rats, fasted for 36 h, were subjected to pylorus and forestomach ligation, supervened by treatment with normal saline (3 ml/kg, po, sham control), esophagitis control (3 ml/kg, po), pantoprazole (30 mg/kg, po), palonosetron (0.5 mg/kg, po), and their combination. Animals were sacrificed after 12 h and appraised for the volume of gastric juices, total acidity, free acidity, and esophagitis index. Esophageal tissues were further figured out biochemically for markers of oxidative stress and inflammatory mediators. The combination therapy comparably inhibited the esophagitis index (52.86%), gastric volume (66.04%), free acidity (43.76%), and total acidity (42.60%) in comparison with toxic control. The combination therapy also subsidized the biochemical and inflammatory markers to the purview less than toxic control. The morphological changes were scrutinized by scanning electron microscopy and were observed to demonstrate momentous protection by the amalgamation therapy. Combination therapy with pantoprazole and palonosetron flaunted sententious protection against experimental esophagitis. PMID- 25743727 TI - Neurotoxicity of mycotoxins produced in vitro by Penicillium roqueforti isolated from maize and grass silage. AB - Fungal growth in human foods and animal feeds causes profound damage indicating a general spoilage, nutritional losses, and the formation of mycotoxins. Thirty apparently contaminated maize and grass silage samples were analyzed for the presence of total fungi. Penicillium roqueforti were isolated from all (100%) moldy silage samples on general and selective culture media. Furthermore, P. roqueforti-positive samples culture media subjected to the toxin extraction and toxins of patulin, penicillic acid, mycophenolic acid, and roquefortin-C (ROQ-C) were identified by means of high-performance liquid chromatography method. Cytotoxicity of identified toxins was investigated on neuro-2a cells. Alamar blue reduction, neutral red uptake, and intracellular adenosine triphosphate (ATP) content assays indicated that patulin and ROQ-C exert the strongest and weakest toxicity, respectively. Reactive oxygen species (ROS) generation by the toxins exposed cells was measured, and the results supported the mitochondrial and lysosomal dysfunction and ATP depletion in exposed cells. Our data suggest that P. roqueforti is the widely present mold in analyzed maize and grass silage samples, which is able to produce toxins that cause neurotoxicity. This finding may explain in part some neuronal disorders in animals, which are fed contaminated feedstuffs with mentioned fungus. Moreover, mitochondrial and lysosomal dysfunction, intracellular ATP depletion, and the excessive ROS generation were found as the mechanisms of cytotoxicity for P. roqueforti produced toxins. PMID- 25743728 TI - International retrospective comparison of inpatient rehabilitation for patients with spinal cord dysfunction epidemiology and clinical outcomes. AB - OBJECTIVE: To describe and compare epidemiologic characteristics of patients with spinal cord dysfunction admitted to spinal rehabilitation units (SRUs) in 9 countries (Australia, Canada, Italy, India, Ireland, The Netherlands, Switzerland, United Kingdom, and United States). DESIGN: Retrospective multicenter open-cohort case series. SETTING: SRUs. PARTICIPANTS: Patients (N=956) with initial onset of spinal cord dysfunction consecutively admitted between January 1, 2008, and December 31, 2010. Median age on admission was 59 years (interquartile range [IQR], 46-70), and 60.8% of patients were men. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Demographic characteristics (eg, age, sex), time frame over which clinical symptoms of spinal cord dysfunction developed, etiology, length of stay in hospital, level of lesion and American Spinal Injury Association Impairment Scale (AIS) grade, discharge destination, and inpatient mortality. RESULTS: The time frame of onset of spinal cord dysfunction symptoms was as follows: <=1 day (28.5%); <=1 week (13.8%); >1 week but <=1 month (10.5%), and >1 month (47.2%). Most common etiologies were degenerative conditions (30.8%), malignant tumors (16.2%), ischemia (10.9%), benign tumors (8.7%), and bacterial infections (7.1%). Most patients (72.3%) had paraplegia. The AIS grade on SRU admission was grade A in 14%, grade B in 6.5%, grade C in 24%, grade D in 52.4%, grade E in 0.2%, and missing in 2.9%. AIS grade significantly improved by discharge (z=-10.1, P<.0001). Median length of stay in the SRU was 46.5 days (IQR, 17-89.5). Most (80.5%) patients were discharged home. Differences between countries were found for most variables. CONCLUSIONS: This international study of spinal cord dysfunction showed substantial variation of etiology, demographic, and clinical characteristics across countries. Further research, including multiple centers per country, are needed to separate country effects from center effects. PMID- 25743729 TI - Dysphagia screening measures for use in nursing homes: a systematic review. AB - PURPOSE: The purpose of this study was to evaluate the psychometric quality and feasibility of measurements for screening dysphagia in older adults to identify the 'right tool' for nurses to use in nursing homes. METHODS: A systematic review was done. Electronic databases were searched for studies related to dysphagia screening measurements. A checklist was used to evaluate the psychometric quality and applicability. Tools were evaluated for feasible incorporation into routine care by nurses. RESULTS: 29 tools from 31 studies were identified. Dysphagia screening tools with an acceptable validity and reliability had sensitivity between 68% and 100% and specificity between 52% and 100%. The Gugging Swallowing Screen (GUSS) and the Standardized Swallowing Assessment (SSA) were the tools with high psychometric quality, especially with high sensitivity, that nurses could perform feasibly to identify the risk and to grade the severity of dysphagia and aspiration of nursing home residents. CONCLUSION: Results show that GUSS and SSA are reliable and sensitive tools for screening dysphagia which nurses can use in nursing homes. Further research is needed to examine feasibility of screening with identified tools, and also, to establish effective and standardized protocols for these tools so they can be effectively incorporated into routine care. PMID- 25743730 TI - [Relationship between expectations regarding aging and physical activity among middle aged adults in urban areas: based on the Pender's Health Promotion Model]. AB - PURPOSE: The purpose of this study was to measure the level of expectations regarding aging (ERA) and identify relationship between ERA and physical activity of middle aged adults. METHODS: Participants were middle aged adults who resided in the community in three cities in Korea. Data were collected using questionnaires that contained items on individual characteristic, International Physical Activity Questionnaires (IPAQ), and behavior-specific cognitive factors including ERA-12. Hierarchical multiple regression was conducted to examine whether ERA would predict physical activity by controlling other factors. RESULTS: The mean age of the participants was 51.1+/-6.9 years. The mean score for ERA (possible range=0 to 100) was 40.04+/-14.31. More than half of the participants (62.6%) were not engaged in health promoting physical activity. Gender, employment status and exercise confidence were associated with level of physical activity (F=7.14, p<.001, R2=.36). After controlling for individual factors and behavior-specific cognitive factors, ERA was independently related to physical activity (F=7.19, p<.001, R2=.38). CONCLUSION: The results demonstrate that individuals' belief about aging has effects on physical activity in Korean middle aged adults. Thus, nursing interventions which focused on ERA could help enhance physical activity in middle aged adults. PMID- 25743731 TI - [Effects of a cardiocerebrovascular disease prevention education program for postmenopausal middle-aged women]. AB - PURPOSE: This study was conducted to examine effects of a cardiocerebrovascular disease (CVD) prevention education program on knowledge, self-efficacy and health behavior among postmenopausal middle-aged women. METHODS: A non-equivalent control group pretest-posttest design was used. Participants were 53 postmenopausal middle-aged women who registered in two community culture centers in G metropolitan city. Experimental group (n=26) received a CVD prevention education program 8 times over 8 weeks. Knowledge, self-efficacy and health behavior of the participants were examined with self-report structured questionaries. Data were collected between October 15 and December 11, 2013, and were analyzed using chi-square test, Fisher's exact test, independent t-test, and analysis of covariance with SPSS/PC version 21.0. RESULTS: After the intervention the experimental group showed significant increases in the knowledge of CVD symptoms (p<.001) and CVD risk factors (p<.001), level of self-efficacy (p=.028) and health behavior (p<.001) compared to the control group. However, no significant difference was found between groups for knowledge of CVD prevention (p<.133). CONCLUSION: Results suggest that a CVD prevention education program can be an effective strategy to improve knowledge on CVD symptoms and risk factors, self-efficacy and health behavior for postmenopausal middle-aged women. PMID- 25743732 TI - [Effect of muscle strength training on urinary incontinence and physical function: a randomized controlled trial in long-term care facilities]. AB - PURPOSE: This study was done to determine whether muscle strength training programs have an impact on improving symptoms of urinary incontinence (UI) and physical function among elderly women with UI who reside in long-term care facilities. METHODS: A randomized controlled trial was conducted. Participants had to be over 65 years, score over 15 score on the mini-mental state examination, and be able to walk alone or with an assistant. Seventy residents were randomly allocated to either the training group (n=35) or control group (n=35). The program consisted of 50 minutes, twice a week for 8 weeks, and included Kegel's exercise, Thera-band training and indoor walking. Main outcomes were UI symptoms, peak vaginal pressure and physical functions measured with timed up and go test (TUG), one leg standing test (OLST), activities of daily living (ADL) and grip strength. Changes in outcome measurements were calculated from baseline to 4 weeks and to 8 weeks using repeated measures ANOVA. RESULTS: There were significant differences in peak vaginal pressure (p<.001), TUG (p<.001), OLST (p=.012) and grip strength (p<.001) in the interaction between groups and time. CONCLUSION: Future studies are suggested to confirm the effect of muscle strength training in long-term care facilities where elderly women with UI reside. PMID- 25743733 TI - [Effects of special mouth care with an aroma solution on oral status and oral cavity microorganism growth in elderly stroke patients]. AB - PURPOSE: This study was conducted to examine the effect of oral care with an aroma solution on oral status and oral cavity microorganism growth in elderly patients with stroke. METHODS: A non-equivalent control group, with a pretest posttest design was used in this study. The participants were assigned to the experimental group (n=30) that received oral care with an aroma solution or the control group (n=31) that received 0.9% saline solution. To identify the effect of the experimental treatments, objective/subjective assessments of oral status and oral cavity microorganism growth were performed using the oral assessment guide, oral perception guide, and oral swab culture. Data were analyzed using Chi square test, Fisher's exact test, and t-test with the SPSS version 21.0 program. RESULTS: The objective oral status was significantly lower in the experimental group than in the control group (t= -3.64, p<.001). There was no significant difference between the subjective oral status of the experimental group and control groups (t= -1.24, p=.109). Oral microorganism growth was significantly lower in the experimental group than in the control group (t= -7.39, p<.001). CONCLUSION: These findings indicate that special mouth care using an aroma solution could be an effective oral health nursing intervention for elderly patients with stroke. PMID- 25743734 TI - [Development and evaluation of the Empowering A Self-Efficacy (EASE) program for children with epilepsy]. AB - PURPOSE: The purpose of this study was to verify effects of the Empowering A Self Efficacy (EASE) program on self-efficacy, self-management, and child attitude toward illness in children with epilepsy. METHODS: This was a quasi-experimental study with a non-equivalent control group pre-post test design. Participants were 10 to 15 year old children with epilepsy (11 in the experimental group and 10 in the control group) who were registered at one hospital in S city. The experimental group received the EASE program for 3 weeks. In the first week, a group meeting lasting 570 minutes was conducted on a single day. Over the next two weeks, telephone counselling was conducted twice a week. Data were analyzed using SPSS 18.0. RESULTS: There was a significant difference of pre-post evaluation of the epilepsy self-management scores in the experimental group. However, differences between the experimental group and the control group for seizure self-efficacy and child attitude toward illness were not significant. CONCLUSION: This is the first study in Korea to develop and evaluate an intervention program for children with epilepsy. Further studies are needed to confirm the effects of the EASE program. PMID- 25743735 TI - [Structural equation modeling on healthy menopausal transition]. AB - PURPOSE: This study was designed to construct and test structural equation modeling on healthy menopausal transition in middle-aged women in order to identify variables affecting healthy menopausal transition. METHODS: Participants, 276 women, 45 to 60 years of age, with menopausal symptom score higher than 5 on the Korean version of Menopause Rating Scale, were recruited in three cities and one county of Gyeongnam Province. Research data were collected via questionnaires and analysed using SPSS version 18.0 and AMOS version 20.0. RESULTS: After confirmatory factor analysis, one of the observed variables was excluded due to relatively low factor loading. The model fit indices for the hypothetical model were suitable for the recommended level: GFI=.93, CFI=.92, RMSEA=.05. Self-efficacy, self-differentiation, and menopausal symptoms explained 67.7% of variance in menopausal transition, and self-differentiation was the most influential factor for menopausal transition. Self efficacy and menopausal symptoms explained 9.6% of variance in menopausal management, although "menopausal symptoms" was not significant. CONCLUSION: These results suggest that nursing interventions to improve self-differentiation, self efficacy, menopausal management and decrease menopausal symptoms are critical for healthy menopausal transition in middle-aged women. Continued development of a variety of community based nursing interventions to facilitate healthy menopausal transition is suggested. PMID- 25743736 TI - [Factors that influence sexual intercourse among middle school students: using data from the 8th (2012) Korea Youth Risk Behavior Web-based Survey]. AB - PURPOSE: The purpose of this study was to investigate factors that influence sexual intercourse among middle school students in South Korea. METHODS: Using statistics from the 8th (2012) Korea Youth Risk Behavior Web-based Survey, hierarchical logistic regression analysis was conducted. The study sample comprised 37,297 middle school students aged primarily 12 to 15. RESULTS: The significant predictors of sexual intercourse were grade, ever smoking, ever drinking, habitual or purposeful drug use, economic status, weekly allowance, cohabitation with family, and type of school. CONCLUSION: The results suggest that intensified sex education is needed not only in the 1st grade of middle school, but also in the upper grades of elementary school. Sexual health interventions for high-risk groups may be needed, given the factors predicting sexual intercourse. PMID- 25743737 TI - [Effects of a physical activity program using exergame with elderly women]. AB - PURPOSE: This study was done to investigate the motivational, physical and affective benefits of exergaming in community dwelling older adult women. METHODS: The research design was a nonequivalent control group pre-test and post test design. Sixty-one older adult women over the age of 65 were recruited from 6 community senior centers to participate in the 8 week exercise intervention or control group. Six centers were divided into one of three groups: exergame, qigong exercise, or control. The exergame and the qigong exercise group received 16 sessions, scheduled twice a week, with each session lasting 50 minutes. Test measures were completed before and after the 8 week intervention period for all participants. Measures included: Grip strength, chair stand, 6 m walking, balance, geriatric depression scale, vitality and intrinsic motivation. RESULTS: There were significant improvements in the exergame and qigong exercise group for grip strength, chair stand, 6m walking, balance, vitality and intrinsic motivation at the end the 8-week program compared with the control group. CONCLUSION: The exergame could be an effective alternative for older adult women to group exercise classes. PMID- 25743738 TI - [Structural equation model for caregiving experience of families providing care for family members with mental disorders]. AB - PURPOSE: This study was done to develop and test a structural model for caregiving experience including caregiving satisfaction and caregiving strain in families providing care for family members with a mental disorder. METHODS: The Stress-appraisal-coping model was used as the conceptual framework and the structural equation model to confirm the path that explains what and how variables affect caregiving experience in these families. In this hypothesis model, exogenous variables were optimism, severity of illness and uncertainty. The endogenous variables were self efficacy, social support, caregiving satisfaction and caregiving strain. Data were collected using structured questionnaires. RESULTS: Optimism and caregiving self-efficacy had significant direct and indirect effects on caregiving satisfaction. Optimism, severity of illness and uncertainty had significant direct and indirect effects on caregiving strain. The modified path model explained effects of optimism on caregiving self efficacy with social support in the path structure as a mediator. Also, there were direct and indirect effects of optimism and uncertainty on caregiving satisfaction with social support and caregiving self-efficacy in the path structure as a mediators. CONCLUSION: Results suggest the need to improve caregiving self-efficacy of these families, establish support systems such as a mental health professional support programs for caregiving self-efficacy. Optimism, severity of illness and uncertainty perceived by families need to be considered in the development of support programs in order to increase their effectiveness. PMID- 25743739 TI - [Psychometric properties of the Alzheimer's Disease Knowledge Scale--Korean Version]. AB - PURPOSE: The purpose of this study was to evaluate the psychometric properties of the Korean version of the Alzheimer's Disease Knowledge Scale (ADKS-K) to determine its applicability to Korean adults. METHODS: Cross-cultural validity was performed according to Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). The Kuder-Richardson Formula 20 for internal consistency and Intraclass Correlation Coefficient (ICC) for test-retest reliability were conducted. Content validity, criterion related validity and construct validity were evaluated. The Classical Test Theory (CTT) model and the Item Response Theory (IRT) model were applied in performing the item analysis. RESULTS: The KR 20 was .71, and the ICC was .90, indicating that the ADKS-K has internal consistency and stability reliability. Thirty items of the ADKS-K had significant Content Validity Ratio (CVR) values, i.e., mean of 0.82 and range of 0.60~1.00. Mean item difficulty and discrimination indices calculated by TestAn program were 0.63 and 0.23, respectively. Mean item difficulty and discrimination indices calculated by BayesiAn program were -0.60 and 0.77, respectively. These tests indicate that ADKS-K has an acceptable level of difficulty and discriminating efficiency. CONCLUSION: Results suggest that ADKS-K has the potential to be a proper instrument for assessing AD knowledge in Korean adults. PMID- 25743740 TI - [Prevalence and characteristics of chemotherapy-related cognitive impairment in patients with breast cancer]. AB - PURPOSE: Evidence suggests that some patients with breast cancer experience cognitive difficulties following chemotherapy. This longitudinal study was done to examine the prevalence of cognitive impairment and trajectory of cognitive function over time in women with breast cancer, who received adjuvant chemotherapy. METHODS: Participants were 137 patients with breast cancer. They completed neuropsychological tests and the Functional Assessment of Cancer Therapy-Cognitive Function before adjuvant therapy (pretest), toward the end of adjuvant therapy (posttest), and 6 months after the completion of adjuvant therapy (follow-up test). Of the patients, 91 were treated with adjuvant chemotherapy and 46 patients who did not receive chemotherapy made up the comparison group. A reliable-change index and repeated-measure ANOVA were used for statistical analyses. RESULTS: At the posttest point, over 30% of patients showed complex cognitive impairment and reported greater difficulty in subjective cognitive function. At the follow-up test point, 22.0% of patients exhibited complex cognitive impairment and 30.8% of patients complained of subjective cognitive impairment. Repeated-measure ANOVA showed significant decreases after receiving chemotherapy followed by small improvements 6 months after the completion of chemotherapy in cognitive domains of change for attention and concentration, memory, executive function, and subjective cognitive function. CONCLUSION: These results suggest that chemotherapy in patients with breast cancer may be associated with objective and subjective cognitive impairments. Further studies are needed to explore the potential risk factors and predictor of chemotherapy-related cognitive changes. Also nursing interventions for prevention and intervention of cognitive impairments should be developed and tested. PMID- 25743741 TI - Cross-cultural validation of instruments measuring health beliefs about colorectal cancer screening among Korean Americans. AB - PURPOSE: The purpose of this study was to report the instrument modification and validation processes to make existing health belief model scales culturally appropriate for Korean Americans (KAs) regarding colorectal cancer (CRC) screening utilization. METHODS: Instrument translation, individual interviews using cognitive interviewing, and expert reviews were conducted during the instrument modification phase, and a pilot test and a cross-sectional survey were conducted during the instrument validation phase. Data analyses of the cross sectional survey included internal consistency and construct validity using exploratory and confirmatory factor analysis. RESULTS: The main issues identified during the instrument modification phase were (a) cultural and linguistic translation issues and (b) newly developed items reflecting Korean cultural barriers. Cross-sectional survey analyses during the instrument validation phase revealed that all scales demonstrate good internal consistency reliability (Cronbach's alpha=.72~.88). Exploratory factor analysis showed that susceptibility and severity loaded on the same factor, which may indicate a threat variable. Items with low factor loadings in the confirmatory factor analysis may relate to (a) lack of knowledge about fecal occult blood testing and (b) multiple dimensions of the subscales. CONCLUSION: Methodological, sequential processes of instrument modification and validation, including translation, individual interviews, expert reviews, pilot testing and a cross-sectional survey, were provided in this study. The findings indicate that existing instruments need to be examined for CRC screening research involving KAs. PMID- 25743742 TI - Development and evaluation of an education program for professional palliative care nursing. AB - PURPOSE: This study aimed to develop a "Palliative Care Professional" education program and evaluate its effects on the recognition of good death, palliative care, and the meaning of life for nurses. METHODS: It was developed based on the hospice care program for volunteers being used in the Hospice Palliative Care Research Center of S University in Seoul. It was also based on the studies which investigated the educational needs of nurses in palliative care. This program consisted of 5 sessions and 16 content items for 2 weeks. A non-equivalent control group non-synchronized design was utilized and participants were assigned to the experimental group (n=42) or the control group (n=44). RESULTS: The recognition of a good death (F=11.44, p=.001), palliative care (F=4.15, p=.045), and the meaning of life (F=5.12, p=.026) increased more significantly for participants in the experimental group than in the control group. Participants felt that they gained further knowledge in palliative patient management and refined their clinical practice. CONCLUSION: The results of the study indicate that this program could serve as a practical program for palliative care nursing in the nursing field and suggests that more attention should be directed to the diverse educational needs of nurses. PMID- 25743743 TI - Return to work experience among military officers with cancer. AB - PURPOSE: This study was done to describe the return to work experience of military officers with cancer. METHODS: Individual in-depth interviews with 15 participants were conducted between September 2013 and April 2014. Participants were interviewed 1~4 times; interviews continued until the data became saturated. Data were analyzed using Strauss and Corbin's grounded theory. RESULTS: The core category emerged as "living a new life after enduring difficulties". The return to work process consisted of four sequential phases: chaos, positive thought formation, behavior practices, and reformation. Action/interaction strategies used by military officers with cancer to resolve enduring difficulties were controlling emotions, accepting reality, prioritizing health, making efforts to improve relationships, and looking for future jobs. CONCLUSION: These results will promote understanding of military officers' return to work experience following cancer survival, and will be helpful in developing more effective nursing interventions through enhanced perspectives and insights of practitioners. PMID- 25743744 TI - Retraction: Risk factors and features of critically ill patients with deep vein thrombosis in lower extremities. AB - This article is being retracted as a part of the manuscript was a 'duplicate publication' from an earlier publication. The authors have acknowledged duplicate publication of parts of the above article and requested retraction from JKAN. PMID- 25743745 TI - On the Genetic and Environmental Correlations between Trait Emotional Intelligence and Vocational Interest Factors. AB - The phenotypic (observed), genetic, and environmental correlations were examined in a sample of adult twins between the four factors and global score of the trait emotional intelligence questionnaire (TEIQue) and the seven vocational interest factors of the Jackson Career Explorer (JCE). Multiple significant correlations were found involving the work style vocational interest factor (consisting of job security, stamina, accountability, planfulness, and interpersonal confidence) and the social vocational interest factor (which included interests in the social sciences, personal services, teaching, social services, and elementary education), both of which correlated significantly with all of the TEIQue variables (well-being, self-control, emotionality, sociability, and global trait EI). Following bivariate genetic analyses, most of the significant phenotypic correlations were found to also have significant genetic correlations as well as significant non-shared (unique) environmental correlations. PMID- 25743746 TI - Are all the 18 DSM-IV and DSM-5 criteria equally useful for diagnosing ADHD and predicting comorbid conduct problems? AB - In view of ICD-11 revision, we evaluate whether the 18 DSM-IV diagnostic items retained by DSM-5 could be further improved (i) in predicting ADHD 'caseness' and 'impairment' and (ii) discriminating ADHD without CD (ADHD - CD) cases from ADHD with CD (ADHD + CD) cases. In a multi-centre study sample consisting of 1497 ADHD probands and 291 unaffected subjects, 18 diagnostic items were examined for redundancy; then each item was evaluated for association with caseness, impairment and CD status using Classical Test Theory, Item-Response Theory and logistic regression methods. First, all 18 DSM-IV items contributed significantly and independently to the clinical diagnosis of ADHD. Second, not all the DSM-IV items carried equal weighting. "Often loses things", "forgetfulness" and "difficulty sustaining attention" mark severity for Inattentiveness (IA) items and "often unduly noisy", "exhibits a persistent pattern of restlessness", "leaves seat in class" and "often blurts out answers" for Hyperactivity/Impulsivity (HI) items. "Easily distracted", "inattentive to careless mistakes", "often interrupts" and "often fidgets" are associated with milder presentations. In the IA domain, "distracted" yields most information in the low-severity range of the latent trait, "careless" in the mid-severity range and "loses" in the high-severity range. In the HI domains, "interrupts" yields most information in the low-severity range and "motor" in the high-severity range. Third, all 18 items predicted impairment. Fourth, specific ADHD items are associated with ADHD + CD status. The DSM-IV diagnostic items were valid and not redundant; however, some carried more weight than others. All items were associated with impairment. PMID- 25743748 TI - Prediction of genotoxic potential of cosmetic ingredients by an in silico battery system consisting of a combination of an expert rule-based system and a statistics-based system. AB - Genotoxicity is the most commonly used endpoint to predict the carcinogenicity of chemicals. The International Conference on Harmonization (ICH) M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk offers guidance on (quantitative) structure activity relationship ((Q)SAR) methodologies that predict the outcome of bacterial mutagenicity assay for actual and potential impurities. We examined the effectiveness of the (Q)SAR approach with the combination of DEREK NEXUS as an expert rule-based system and ADMEWorks as a statistics-based system for the prediction of not only mutagenic potential in the Ames test, but also genotoxic potential in mutagenicity and clastogenicity tests, using a data set of 342 chemicals extracted from the literature. The prediction of mutagenic potential or genotoxic potential by DEREK NEXUS or ADMEWorks showed high values of sensitivity and concordance, while prediction by the combination of DEREK NEXUS and ADMEWorks (battery system) showed the highest values of sensitivity and concordance among the three methods, but the lowest value of specificity. The number of false negatives was reduced with the battery system. We also separately predicted the mutagenic potential and genotoxic potential of 41 cosmetic ingredients listed in the International Nomenclature of Cosmetic Ingredients (INCI) among the 342 chemicals. Although specificity was low with the battery system, sensitivity and concordance were high. These results suggest that the battery system consisting of DEREK NEXUS and ADMEWorks is useful for prediction of genotoxic potential of chemicals, including cosmetic ingredients. PMID- 25743747 TI - Synthesis and evaluation of hydroponically alginate nanoparticles as novel carrier for intravenous delivery of propofol. AB - Commercial lipid emulsion of propofol (CLE) has several drawbacks including pain on injection and emulsion instability. In this paper, a novel nanocarrier system is introduced to improve stability and solubility of the poorly soluble anesthetic drug, propofol, for intravenous administration. In this paper, alginate is modified using a facile method in which the carboxylic group of alginate is grafted to octanol. The octanol-grafted alginate (Alg-C8) is then employed to prepare nanoparticles which are subsequently used for encapsulation of propofol. The nanoparticles are analyzed for their pH, osmolarity, particle size, stability, morphology and sleep recovery and the results are compared with CLE as control. It is revealed that nanoparticles have the average particle size of 180 nm +/- 1.2 and spherical morphology which is less than CLE while their pH, osmolarity and profile of release of formulated nanoparticles are similar to those of CLE. In addition, the results show good chemical and physical storage stability for the nanoparticles at room temperature for at least 6 months compared to CLE as control. The animal sleep recovery test on rats shows no significant difference in time of unconsciousness and recovery of the righting reflex between nanoparticles and CLE. It is concluded that encapsulated nanoparticles introduced here could be a promising clinical intravenous system for delivery of poorly soluble anesthetic propofol. In addition, this study provides an efficient and facile method for preparing a carrier system for water insoluble drugs. PMID- 25743749 TI - Uranium modifies or not behavior and antioxidant status in the hippocampus of rats exposed since birth. AB - In view of the known sensitivity of the developing central nervous system to pollutants, we sought to assess the effects of exposure to uranium (U) - a heavy metal naturally present in the environment - on the behavior of young rats and the impact of oxidative stress on their hippocampus. Pups drank U (in the form of uranyl nitrate) at doses of 10 or 40 mg.L(-1) for 10 weeks from birth. Control rats drank mineral water. Locomotor activity in an open field and practice effects on a rotarod device decreased in rats exposed to 10 mg.L(-1) (respectively, -19.4% and -51.4%) or 40 mg.L(-1) (respectively, -19.3% and 55.9%) in compared with control rats. Anxiety (+37%) and depressive-like behavior (-50.8%) were altered by U exposure only at 40 mg.L(-1). Lipid peroxidation (+35%) and protein carbonyl concentration (+137%) increased significantly after exposure to U at 40 mg.L(-1). A significant increase in superoxide dismutase (SOD, +122.5%) and glutathione peroxidase (GPx, +13.6%) activities was also observed in the hippocampus of rats exposed to 40 mg.L(-1). These results demonstrate that exposure to U since birth alters some behaviors and modifies antioxidant status. PMID- 25743750 TI - Effect of buprenorphine on genotoxicity evaluation of chemicals by the rat liver micronucleus test with partial hepatectomy. AB - In the view of animal welfare considerations, we investigated the suitability of modifying the rat liver micronucleus test with partial hepatectomy to include administration of an analgesic drug to minimize pain and distress as much as possible. The effects of the analgesic, buprenorphine, on the genotoxicity evaluation of structural chromosome aberration inducers (cyclophosphamide, diethylnitrosamine and 1,2-dimethylhydrazine) and numerical chromosome aberration inducers (colchicine and carbendazim) were examined. The genotoxicants were given orally to 8-week-old male F344 rats a day before or after partial hepatectomy and hepatocytes were isolated 4 days after the partial hepatectomy. Buprenorphine was injected subcutaneously twice a day with at least a 6-hr interval for 2 days from just after partial hepatectomy. As results, buprenorphine caused neither change in clinical signs (except for one animal death) nor increase in the incidence of micronucleated hepatocytes of vehicle treated animals. In the case of concomitant treatment of buprenorphine and a genotoxicant, one out of 8 animals died in each group given buprenorphine with cyclophosphamide, carbendazim or colchicine (lower dose level only). Slight changes in clinical signs were noted in the group given buprenorphine with cyclophosphamide or carbendazim. A statistically significant increase in the incidence of micronucleated hepatocytes was obtained in concomitant treatment of buprenorphine and genotoxicant compared with genotoxicant alone for 1,2-dimethylhydrazine, colchicine and carbendazim. It is concluded that use of buprenorphine as an analgesic drug to minimize pain and distress for rats that are given partial hepatectomy is not appropriate under the present experimental conditions, because it could enhance the general toxicity and genotoxicity of the test chemical. PMID- 25743751 TI - Spiroquinazolinone-induced cytotoxicity and apoptosis in K562 human leukemia cells: alteration in expression levels of Bcl-2 and Bax. AB - Spiroquinazolinone compounds have been considered as a new series of potent apoptosis-inducing agents. In this study, anti-proliferative and apoptotic effects of the derivatives from the spiroquinazolinone family were investigated in the human chronic myeloid leukemia K562 cells. The K562 cells were treated with various concentrations of the spiroquinazolinone (10-300 uM) for 3 days and cell viability was determined by MTT growth inhibition assay. 4t-QTC was more active among these compounds with IC50 of 50 +/- 3.6 uM and was selected for further studies. Apoptosis, as the mechanism of cell death was investigated morphologically by acridine orange/ethidium bromide (AO/EtBr) double staining, cell surface expression assay of phosphatidyl serine by Annexin V/PI technique, as well as the formation of DNA ladder. The K562 cells underwent apoptosis upon a single dose (at IC50 value) of the 4t-QTC compound, and over-expressed caspase-3 expression by more than 1.7-fold, following a 72 hr treatment. Furthermore, RT PCR and Western blot analysis revealed that treatment of the K562 cells with 4t QTC down-regulates and up-regulates the expression of Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), respectively. Based on the present data, it seems that these compounds from the spiroquinazolinone family are good candidates for further evaluation as an effective chemotherapeutic family acting through induction of apoptosis in chronic myeloid leukemia. PMID- 25743752 TI - Aspirin regulates hepatocellular lipid metabolism by activating AMPK signaling pathway. AB - Aspirin has been reported to regulate lipid metabolism. However, the mechanism underlying the regulation is not clear. We presently investigated aspirin's promotion of AMP-activated protein kinase (AMPK) pathway activation in human hepatoma HepG2 cells by examining AMPK expression, the promotion of AMPK activation. Then we investigated the influence of aspirin-promoted AMPK signaling on fatty acid oxidation in HepG2 cells. The results demonstrated that aspirin treatment did not regulate the expression of AMPK and its downstream target, Acetyl-Coenzyme A Carboxylase (ACC), but activated the AMPK signaling pathway by promoting the phosphorylation of AMPK and ACC. And, interestingly, the promotion by aspirin is dependent of cellular esterase, which catalyzes aspirin to salicylate. Moreover, the activated AMPK signaling promoted the fatty acid oxidation, by promoting expression of Carnitine palmitoyltransferase I (CPT1) and Medium-Chain Acyl-CoA Dehydrogenase (MCAD) in both mRNA and protein levels. Thus, we confirmed in this study that aspirin promoted lipid oxidation by upregulating the AMPK signaling pathway. PMID- 25743753 TI - Cyclo-pnicta-triazanes: biradicaloids or zwitterions? AB - Bulky triazenides were utilized in the reaction with pnictogen(III) chlorides (ECl3, E = P, As, Sb, and Bi) yielding triaza-pnicta-butene analogues of the type R-N?N-N(R)-ECl2 (R = Ter = 2,6-bis(2,4,6-trimethylphenyl)phenyl). Subsequent reduction of these dichloro-species afforded unprecedented four-membered group 15 heterocycles [E(MU-NTer)2N] bearing one dicoordinate pnictogen and nitrogen atom. These N3E rings represent species at the borderline between singlet biradicaloids and zwitterions with diminished reactivity compared to known singlet biradicaloids. The N3P compound could be identified, while N3As and N3Sb species as well as the precursor compounds were fully characterized. PMID- 25743754 TI - Legal liability in South Korea. PMID- 25743755 TI - Response to: "Legal liability in South Korea". PMID- 25743756 TI - Postnatal MK-801 treatment of female rats impairs acquisition of working memory, but not reference memory in an eight-arm radial maze; no beneficial effects of enriched environment. AB - RATIONALE: Memory impairment has been documented in MK-801 (NMDA receptor antagonist) model of schizophrenia, but less is known on the rescue and/or differential effects of MK-801 on short- and long-term memories. OBJECTIVES: We determined the effects of MK-801 treatment and/or enriched environment (EE) on acquisition of reference and working memory in developing rats. METHODS: Female Wistar rats were injected with MK-801 (1 mg/kg) from postnatal days (P) 6-10. Task acquisition, working memory error (WME), and reference memory error (RME) were assessed in an eight-arm radial maze task. Behavioral performance of rats was also tested in an open field test before (P35-P40) and after (P65-P70) radial maze training to assess anxiety and locomotion. EE was applied from birth up to the end of experiments. RESULTS: MK-801 treatment did not influence task acquisition in the radial maze; however, by the end of training, MK-801-treated rats made significantly more WME, but not RME, compared to control rats. Ratio of WME to total error was also significantly higher in MK-801 group. EE prevented MK 801-associated behaviors in the open field but did not exert beneficial effects on working memory deficit in the radial maze task. EE per se affected behavioral performance of rats only in the open field test. CONCLUSIONS: Our results suggest that postnatal MK-801 treatment differentially affects working and reference memory in a young brain. Anxiety and hyperactivity associated with MK-801 are observed more severely in adulthood. Dissociation of the positive effects of EE may suggest selective modification of distinct pathways. PMID- 25743757 TI - Hypofunction of prefrontal cortex NMDA receptors does not change stress-induced release of dopamine and noradrenaline in amygdala but disrupts aversive memory. AB - RATIONALE: A dysfunction of prefrontal cortex has been associated with the exacerbated response to stress observed in schizophrenic patients and high-risk individuals to develop psychosis. The hypofunction of NMDA glutamatergic receptors induced by NMDA antagonists produces cortico-limbic hyperactivity, and this is used as an experimental model to resemble behavioural abnormalities observed in schizophrenia. OBJECTIVES: The aim of the present study was to investigate whether injections of NMDA antagonists into the medial prefrontal cortex of the rat change (1) the increases of dopamine, noradrenaline and corticosterone concentrations produced by acute stress in amygdala, and (2) the acquisition of aversive memory related to a stressful event. METHODS: Male Wistar rats were implanted with guide cannulae to perform microdialysis and bilateral microinjections (0.5 MUl/side) of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4 yl]-propyl-1-phophonic acid (CPP) (25 and 100 ng). Prefrontal injections were performed 60 min before restraint stress in microdialysis experiments, or training (footshock; 0.6 mA, 2 s) in inhibitory avoidance test. Retention latency was evaluated 24 h after training as an index of aversive memory. RESULTS: Acute stress increased amygdala dialysate concentrations of dopamine (160% of baseline), noradrenaline (145% of baseline) and corticosterone (170% of baseline). Prefrontal injections of CPP did not change the increases of dopamine, noradrenaline or corticosterone produced by stress. In contrast, CPP significantly reduced the retention latency in the inhibitory avoidance test. CONCLUSIONS: These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory. PMID- 25743758 TI - Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat. AB - RATIONALE: Evidence suggests that the noradrenergic system mediates ethanol reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. METHODS: This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer seeking and self-administration. Male alcohol preferring (P) rats (n = 20/experiment) were trained to complete a response requirement (RR) resulting in access to 1 % sucrose (n = 10) or 10 % ethanol (n = 10) for 20 min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, and 1.0 mg/kg, intraperitoneally (IP)), or prazosin in combination with propranolol (5 mg/kg (IP); Exp. 1) or in combination with naltrexone (0.03 mg/kg, subcutaneously (SC); Exp. 2). RESULTS: For Exp. 1, prazosin alone effectively decreased sucrose seeking more than ethanol seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol seeking more than sucrose seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp. 2, prazosin alone and naltrexone alone were effective in decreasing ethanol seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol seeking and consumption and sucrose intake, but not sucrose seeking. CONCLUSIONS: Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone and also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers. PMID- 25743760 TI - "Not Just Right Experiences" are specific to obsessive-compulsive disorder: further evidence from Italian clinical samples. AB - Not Just Right Experiences (NJREs) are considered to be a perceptually tinged phenomenon mainly related to obsessive-compulsive disorder (OCD). The evidence of an association between NJREs and OCD or OC symptoms have been accumulating in the last few years, whereas there is a paucity of studies about the role of this construct in other clinical conditions considered part of the "OCD spectrum". In the current study, the NJRE-Q-R Severity scale (a well-validated measure of NJREs) was administered to 41 patients with OCD, 53 with hair-pulling disorder (HPD), 38 with gambling disorder (GD) and 43 with eating disorders (ED) along with measures of OC symptoms and general distress. In each group, NJREs were consistently associated with OC symptoms; moreover, the pattern of associations appeared coherent with the main clinical features of each disorder. The OCD group reported higher levels of NJREs severity than GD and ED, whereas there were no differences between the OCD and HPD groups. However, HPD patients did not have higher scores of NJREs severity than GD and ED counterparts. NJREs appear to be specific to OCD, but further study is needed to establish the role of this construct in OCD-related disorders. PMID- 25743759 TI - Dopamine D1-like receptor signalling in the hippocampus and amygdala modulates the acquisition of contextual fear conditioning. AB - RATIONALE: Dopamine D1-like receptor signalling is involved in contextual fear conditioning, but the brain regions involved and its role in other contextual fear memory processes remain unclear. OBJECTIVES: The objective of this study was to investigate (1) the effects of SCH 23390, a dopamine D1/D5 receptor antagonist, on contextual fear memory encoding, retrieval and reconsolidation, and (2) if the effects of SCH 23390 on conditioning involve the dorsal hippocampus (DH) and/or basolateral amygdala (BLA). METHODS: Rats were used to examine the effects of systemically administering SCH 23390 on the acquisition, consolidation, retrieval and reconsolidation of contextual fear memory, and on locomotor activity and shock sensitivity. We also determined the effects of MK 801, an NMDA receptor antagonist, on contextual fear memory reconsolidation. The effects of infusing SCH 23390 locally into DH or BLA on contextual fear conditioning and locomotor activity were also examined. RESULTS: Systemic administration of SCH 23390 impaired contextual fear conditioning but had no effects on fear memory consolidation, retrieval or reconsolidation. MK-801 was found to impair reconsolidation, suggesting that the behavioural parameters used allowed for the pharmacological disruption of memory reconsolidation. The effects of SCH 23390 on conditioning were unlikely the result of any lasting drug effects on locomotor activity at memory test or any acute drug effects on shock sensitivity during conditioning. SCH 23390 infused into either DH or BLA impaired contextual fear conditioning and decreased locomotor activity. CONCLUSIONS: These findings suggest that dopamine D1-like receptor signalling in DH and BLA contributes to the acquisition of contextual fear memory. PMID- 25743761 TI - Current clinical, laboratory, and treatment outcome characteristics of visceral leishmaniasis: results from a seven-year retrospective study in Greece. AB - OBJECTIVES: Visceral leishmaniasis (VL) is re-emerging in endemic areas. The epidemiological, clinical, laboratory, and treatment outcome characteristics in a large cohort of VL patients is described herein. METHODS: The cases of 67 VL patients (57% male, mean age 56 years) treated in two Greek hospitals over the last 7 years were identified and evaluated retrospectively. RESULTS: Forty-six percent of patients reported contact with animals. Seventeen patients (25%) were immunocompromised, and 22% were co-infected with another pathogen. Sixty-four percent of patients had fever, 57% had weakness, 37% had sweats, 21% had weight loss, and 13% had a dry cough, while 6% developed haemophagocytic syndrome. The median duration of symptoms was 28 days. Fifty-eight percent of patients had splenomegaly, 49% had hepatomegaly, and 36% had lymphadenopathy. The diagnosis was established by positive PCR in peripheral blood (73%) and/or bone marrow specimens (34%). Sixty-one patients (91%) received liposomal amphotericin (L AMB). Six patients (10%) did not respond or relapsed but were eventually cured after a second cycle of L-AMB. During a 6-month follow-up, the overall mortality was 9%, although none of these deaths was attributed to VL. CONCLUSIONS: VL is still a common disease in endemic areas, affecting immunocompetent and immunocompromised patients. Its diagnosis is challenging, and molecular techniques are valuable and helpful tools to achieve this. Treatment with L-AMB is safe and very effective. PMID- 25743762 TI - NDM-1-producing Enterobacteriaceae in a teaching hospital in Shanghai, China: IncX3-type plasmids may contribute to the dissemination of blaNDM-1. AB - OBJECTIVES: To provide the epidemiological dissemination and the genetic characteristics of bla(NDM-1) in a teaching hospital in Shanghai, China. METHODS: Here, the carbapenemase genes of 114 CRE isolates were evaluated by polymerase chain reaction (PCR). Clonal relatedness was assessed by pulsed-field gel electrophoresis (PFGE). Conjugation experiments and Southern blot hybridization were performed to determine the transferability of plasmids. Then plasmids were completely sequenced by the shotgun method. RESULTS: Two Klebsiella pneumoniae strains (RJA1227 and RJF866) and one Raoultella planticola strain (RJA274) were identified as NDM-1 positive. The two K. pneumoniae isolates belonged to ST11 and exhibited highly similar PFGE patterns. Shotgun sequencing showed that plasmid pRJF866 (ca. 110 kb) contained genes associated with the IncFII-FIB group and was highly similar to plasmid pKOX_NDM1. RJA274 (ca. 50 kb) harbored bla(NDM-1) on an IncX3 plasmid, which was nearly identical to plasmid pNDM-HN380 except that part of the ISAba125 element is missing. CONCLUSION: This is the first report of NDM-1 positive Enterobacteriaceae from Shanghai, China. IncX3 plasmids, reported in various species in the United Arab Emirates and China, may contribute to the dissemination of bla(NDM-1.). More attention should be devoted to monitoring the dissemination of the NDM-1 gene due to its potential horizontal transfer via mobile genetic elements. PMID- 25743763 TI - Majorana fermions in ferromagnetic chains on the surface of bulk spin-orbit coupled s-wave superconductors. AB - Majorana fermion (MF) excitations in solid state system have non-Abelian statistics which is essential for topological quantum computation. Previous proposals to realize MF, however, generally requires fine-tuning of parameters. Here we explore a platform which avoids the fine-tuning problem, namely a ferromagnetic chain deposited on the surface of a spin-orbit coupled s-wave superconductor. We show that it generically supports zero-energy topological MF excitations near the two ends of the chain with minimal fine-tuning. Depending on the strength of the ferromagnetic moment in the chain, the number of MFs at each end, n, can be either one or two, and should be revealed by a robust zero-bias peak (ZBP) of height 2 ne(2)/h in scanning tunneling microscopy (STM) measurements which would show strong (weak) signals at the ends (middle) of the chain. The role of an approximate chiral symmetry which gives an integer topological invariant to the system is discussed. PMID- 25743765 TI - Prebiotic petroleum. AB - This short communication summarizes a global and continuous reflection on the origins of life. "Prebiotic Petroleum" assumes that "the class of most complex molecules of life that may have geochemical and abiotic origin is the class of fatty acids with long aliphatic chains" and proposes a physical process for the formation of liposomes. Developments following the workshop start from the idea that the liposomes also acquire ion exchange channels physically during their forming process. PMID- 25743764 TI - Photocatalytic degradation of pharmaceutical wastes by alginate supported TiO2 nanoparticles in packed bed photo reactor (PBPR). AB - In recent years deposal of pharmaceutical wastes has become a major problem globally. Therefore, it is necessary to removes pharmaceutical waste from the municipal as well as industrial effluents before its discharge. The convectional wastewater and biological treatments are generally failed to separate different drugs from wastewater streams. Thus, heterogeneous photocatalysis process becomes lucrative method for reduction of detrimental effects of pharmaceutical compounds. The main disadvantage of the process is the reuse or recycle of photocatalysis is a tedious job. In this work, the degradation of aqueous solution of chlorhexidine digluconate (CHD), an antibiotic drug, by heterogeneous photocatalysis was study using supported TiO2 nanoparticle. The major concern of this study is to bring down the limitations of suspension mode heterogeneous photocatalysis by implementation of immobilized TiO2 with help of calcium alginate beads. The alginate supported catalyst beads was characterized by scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM/EDAX) as well as the characteristic crystalline forms of TiO2 nanoparticle was confirmed by XRD. The degradation efficiency of TiO2 impregnated alginate beads (TIAB) was compared with the performance of free TiO2 suspension. Although, the degradation efficiency was reduced considerably using TIAB but the recycle and reuse of catalyst was increased quite appreciably. The kinetic parameters related to this work have also been measure. Moreover, to study the susceptibility of the present system photocatalysis of other three drugs ibuprofen (IBP), atenolol (ATL) and carbamazepine (CBZ) has been carried out using immobilized TiO2. The continuous mode operation in PBPR has ensured the applicability of alginate beads along with TiO2 in wastewater treatment. The variation of residence time has significant impact on the performance of PBPR. PMID- 25743766 TI - Cyclophilin A in cardiovascular homeostasis and diseases. AB - Vascular homeostasis is regulated by complex interactions between many vascular cell components, including endothelial cells, vascular smooth muscle cells (VSMCs), adventitial inflammatory cells, and autonomic nervous system. The balance between oxidant and antioxidant systems determines intracellular redox status, and their imbalance can cause oxidative stress. Excessive oxidative stress is one of the important stimuli that induce cellular damage and dysregulation of vascular cell components, leading to vascular diseases through multiple pathways. Cyclophilin A (CyPA) is one of the causative proteins that mediate oxidative stress-induced cardiovascular dysfunction. CyPA was initially discovered as the intracellular receptor of the immunosuppressive drug cyclosporine 30 years ago. However, recent studies have established that CyPA is secreted from vascular cell components, such as endothelial cells and VSMCs. Extracellular CyPA augments the development of cardiovascular diseases. CyPA secretion is regulated by Rho-kinase, which contributes to the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. We recently reported that plasma CyPA levels are significantly higher in patients with coronary artery disease, which is associated with increased numbers of stenotic coronary arteries and the need for coronary intervention in such patients. Furthermore, we showed that the vascular erythropoietin (Epo)/Epo receptor system plays an important role in production of nitric oxide and maintenance of vascular redox state and homeostasis, with a potential mechanistic link to the Rho-kinase-CyPA pathway. In this article, I review the data on the protective role of the vascular Epo/Epo receptor system and discuss the roles of the CyPA/Rho-kinase system in cardiovascular diseases. PMID- 25743767 TI - A Spontaneous Coronary Dissection Successfully Treated With Bioabsorbable Scaffolds. PMID- 25743768 TI - Clinical treatment and prognosis in patients with acute coronary syndrome and anemia. Response. PMID- 25743769 TI - Pathogenesis and clinical presentation of acute heart failure. AB - Acute heart failure constitutes a heterogeneous clinical syndrome, whose pathophysiology is complex and not completely understood. Given the diversity of clinical presentations, several different pathophysiological mechanisms along with factors triggering circulatory decompensation are involved. This article discusses the available evidence on the pathophysiological phenomena attributed or/and associated with episodes of acute heart failure and describes different clinical profiles, which, from a clinical perspective, constitute a key element for therapeutic decision-making. PMID- 25743770 TI - Endophthalmitis and a Heart Murmur. PMID- 25743771 TI - Giant Intrapericardial Cyst Causing Compression of the Left Ventricle. PMID- 25743772 TI - Plasma QconCATs reveal a gender-specific proteomic signature in apheresis platelet plasma supernatants. AB - Clinical translation of proteomic technologies is often hampered by technical limitations, including inter-laboratory inconsistencies of label-free derived relative quantification, time-consuming analytical approaches and the subsequent challenge of performing proteomic analyses on large cohorts of subjects. Here we introduce plasma QconCAT-based targeted proteomics, an approach that allows the simultaneous absolute quantitation down to the picogram level of hundreds of proteins in a single liquid chromatography-selected reaction monitoring mass spectrometry run. We demonstrate the robustness of the approach by analyzing apheresis platelet concentrate supernatants at storage day 1 and the end of the shelf life for this blood-derived therapeutic, day 5. The targeted approach was repeatable and robust revealing potential gender-specific signatures across a set of three male and female donors. This technical note represents a proof-of principle of the application of QconCAT-based MRM strategies to transfusion medicine relevant issues, such as storage and gender-dependent proteomic signatures in blood-derived therapeutics. BIOLOGICAL SIGNIFICANCE: Gender differences in the proteome composition of apheresis platelet supernatants have always been postulated, and might underlie a higher risk of adverse reactions when transfusing apheresis products from female donors. Preliminary proteomic studies provided an overview of gender-dependent relative compositional differences in the proteome of apheresis platelet supernatants during routine storage in the blood bank. Here we apply a proteomics approach for absolute quantitation of approximately 100 proteins in apheresis platelet supernatants from male and female donors at storage days 1 and 5. Absolute quantitative proteomic analyses allowed us to confirm and expand on previous observations about gender and storage-dependency of platelet supernatant protein profiles. PMID- 25743774 TI - A color-code based method for the interpretation of plantar pressure measurements in clinical gait analysis. AB - Comparing plantar pressure measurements (PPM) of a patient following an intervention or between a reference group and a patient-group is common practice in clinical gait analysis. However, this process is often time consuming and complex, and commercially available software often lacks powerful visualization and interpretation tools. In this paper, we propose a simple method for displaying pixel-level PPM deviations relative to a so-called reference PPM pattern. The novel method contains 3 distinct stages: (1) a normalization of pedobarographic fields (for foot length and width), (2) a pixel-level z-score based calculation and, (3) color coding of the normalized pedobarographic fields. The methodological steps associated to this novel method are precisely described and clinical output illustrated. We believe that the advantages of the novel method cover several domains. The strongest advantage of the novel method is that it provides a straightforward visual interpretation of PPM without decreasing the resolution perspective. A second advantage is that it may guide the selection of a local mapping technique (data reduction technique). Finally, it may be easily used as education tool during the therapist-patient interaction. PMID- 25743773 TI - MicroRNA modulators of epigenetic regulation, the tumor microenvironment and the immune system in lung cancer. AB - Cancer is an exceedingly complex disease that is orchestrated and driven by a combination of multiple aberrantly regulated processes. The nature and depth of involvement of individual events vary between cancer types, and in lung cancer, the deregulation of the epigenetic machinery, the tumor microenvironment and the immune system appear to be especially relevant. The contribution of microRNAs to carcinogenesis and cancer progression is well established with many reports and investigations describing the involvement of microRNAs in lung cancer, however most of these studies have concentrated on single microRNA-target relations and have not adequately addressed the complexity of their interactions. In this review, we focus, in part, on the role of microRNAs in the epigenetic regulation of lung cancer where they act as active molecules modulating enzymes that take part in methylation-mediated silencing and chromatin remodeling. Additionally, we highlight their contribution in controlling and modulating the tumor microenvironment and finally, we describe their role in the critical alteration of essential molecules that influence the immune system in lung cancer development and progression. PMID- 25743775 TI - Biomechanics of uphill walking using custom ankle-foot orthoses of three different stiffnesses. AB - Ankle-foot orthoses (AFOs) can provide support and improve walking ability in individuals with plantarflexor weakness. Passive-dynamic AFO stiffness can be optimized for over-ground walking, however little research exists for uphill walking, when plantarflexor contributions are key. PURPOSE: Compare uphill walking biomechanics (1) between dynamic AFO users and able-bodied control subjects. (2) between injured and sound limbs (3) across different AFO stiffnesses. METHODS: Twelve patients with unilateral limb-salvage and twelve matched, able-bodied controls underwent biomechanical gait analysis when walking up a 10 degrees incline. Three AFO stiffnesses were tested in the patient group: Nominal (clinically prescribed), Compliant (20% less stiff), and Stiff (20% more stiff). RESULTS AND DISCUSSION: AFO users experienced less ankle motion and power generation, lower knee extensor moments, and greater hip flexion and power generation than controls during uphill walking. Despite these deviations, they walked at equivalent self-selected velocities and stride lengths. Asymmetries were present at the ankle and knee with decreased ankle motion and power, and lower knee extensor moments on the AFO limb. Stiffer AFOs increased knee joint flexion but a 40% range in AFO stiffness had few other effects on gait. Therefore, a wide range of clinically prescribed AFO stiffnesses may adequately assist uphill walking. PMID- 25743776 TI - Motion analysis of Chinese normal knees during gait based on a novel portable system. AB - Normative tibiofemoral data of Chinese or Asian subjects during gait is rarely reported. This study is aimed at investigating the six-degree-of-freedom (6DOF) knee kinematics of adult Chinese during gait, based on a novel portable system. Twenty-eight healthy Chinese subjects (56 knees) were studied during their treadmill gaits. A set of optical marker clusters were attached to the thighs and shanks of each subject, who was tracked by an optical joint kinematics measurement system. Knee landmarks were initially digitized with respect to the marker cluster sets to determine the local coordinate systems for calculation of 6DOF knee joint kinematics. The range of motion (ROM) in 6DOF and 5 kinematic parameters were calculated and compared between bilateral knees and genders. We discovered that knee rotations, as well as motion in proximodistal and mediolateral translations, showed similar patterns in flexion and extension. However, the anteroposterior translations did not show a clear pattern. The results of ROM in 6DOF obtained in this study are comparable with those reported in existing literature. No statistical difference was found between left and right knees either in the ROMs or in the 5 kinematic parameters. However, the ROM in the mediolateral direction during gait was found to be higher in men than women (P=0.014). In addition, the femurs of female subjects rotated more internally than the femurs of male during the stance phase (P=0.011). We concluded that normal Chinese knees exhibited distinct gait patterns, except for anteroposterior motion. Women and men exhibit different axial rotations and mediolateral translation patterns during their treadmill gait. PMID- 25743777 TI - Phacoemulsification with toric IOL implantation in Alport syndrome with anterior lenticonus having spontaneously ruptured anterior capsule. AB - PURPOSE: To report the outcome of phacoemulsification with toric intraocular lens (IOL) implantation in Alport syndrome with spontaneously ruptured capsule. METHODS: Case report and literature review. RESULTS: A 2.2-mm clear corneal phacoemulsification with toric lens implantation was done in anterior lenticonus with spontaneously ruptured anterior capsule. The toric IOL was well-centered with good visual outcome. CONCLUSIONS: Safe phacoemulsification with toric IOL implantation is possible in cases with spontaneous rupture of anterior lens capsule. Ability to achieve compact and complete capsulorhexis is one of the key steps to achieve favorable results. PMID- 25743778 TI - Intraocular pressure after intravitreal injection of dexamethasone implant for macular edema resulting from retinal vein occlusion. AB - PURPOSE: A recognized side effect of corticosteroids intravitreal injections (IVT) is the onset of ocular hypertension. The aim of our study was to analyze changes in short-term intraocular pressure (IOP) after IVT of sustained-release dexamethasone implant in order to provide an appropriate monitoring scheme. METHODS: In this retrospective study, the charts of 44 eyes of 42 patients treated by IVT of dexamethasone implant for macular edema resulting from retinal vein occlusion were reviewed. The IOP measurements were performed at baseline and at 15 minutes, 7 days (D7), 1 month (M1), 2 months (M2), and 4 months (M4) after IVT. RESULTS: Mean IOP was 13.4 +/- 2.5 mm Hg at baseline. Twelve eyes out of 44 (27.3%) were treated with antihypertensive eyedrops for a well-controlled glaucoma at baseline. Following IVT, mean IOP was 11.5 +/- 3.6 mm Hg at 15 minutes, 14.7 +/- 3.1 mm Hg at D7, 16.4 +/- 7.0 mm Hg at M1, 19.3 +/- 7.9 mm Hg at M2, and 13.5 +/- 3.1 mm Hg at M4. An IOP >=25 mm Hg or increased by 10 mm Hg or more was not observed in any eye at 15 minutes, D7, or M4 after IVT, but in 8.6% of cases at M1 and in 25% at M2. CONCLUSIONS: It seems reasonable to perform the first IOP monitoring 1 month after IVT of dexamethasone implant and at each efficacy assessment visit (M2, M4). Special attention should be given to patients at risk, such as glaucoma patients. An IOP measurement immediately after IVT and in the following days (1 week) does not seem to be appropriate on a routine basis. PMID- 25743779 TI - Elschnig's spots in the acute and remission stages in preeclampsia: spectral domain optical coherence tomographic features. AB - PURPOSE: Preeclampsia is a multisystem disorder defined as new onset of hypertension and proteinuria during the second half of pregnancy. Serous retinal detachment (SRD) is a known complication of preeclampsia caused by choroidal ischemia and subsequent disruption of blood-retinal barrier. Poor perfusion of the choriocapillaris causes Elschnig's spots. We aim to describe distinctive optical coherence tomography (OCT) features of a cluster of Elschnig's spots in a patient with severe preeclampsia during the acute and remission stages. We also present a summary of OCT features of preeclampsia patients with SRD. METHODS: Descriptive case report. RESULTS: V-shaped adhesions were observed at the location of each of the Elschnig's spots, the center of which showed disruption of the outer retinal bands (external limiting membrane, inner segment/outer segment junction layer), and the V-shaped outer parts remained tethered to retinal pigment epithelium (RPE)-Bruch's complex by hyperreflective exudate on the surface of RPE. These features parallel the histopathologic features described earlier. In an experimental model, Elschnig's spots showed a gradient of RPE damage from the center to the periphery, where RPE was necrotic in the center and edematous in the periphery. Three months later, spectral-domain OCT (SD-OCT) showed focal RPE elevations at the location of each of the Elschnig's spots. CONCLUSIONS: We illustrate the distinctive SD-OCT features of a cluster of Elschnig's spots in the acute and chronic stages of preeclampsia and demonstrate the correlation with the previously described histopathologic features. Despite the favorable visual outcome, irreversible tissue damage may occur, necessitating prompt diagnosis and immediate therapeutic intervention. PMID- 25743780 TI - Presumed bilateral acute retinal necrosis 11 years apart, atypical presentation, and early vitrectomy. AB - PURPOSE: To report a case of presumed bilateral acute retinal necrosis with delayed onset caused by herpes simplex virus type 2, medical treatment, and surgical approach. METHODS: Retrospective, interventional case described in a 51 year-old patient who complained of unilateral blurred vision with history of nonoperated retinal detachment in his fellow eye after posterior uveitis 11 years earlier. RESULTS: Ocular examination suggested diagnosis of acute retinal necrosis involving the posterior pole and sparing periphery. The causative agent was demonstrated using polymerase chain reaction analysis of the aqueous humor. Intensive medical treatment with intravenous acyclovir, intravitreous foscarnet, and corticosteroids was administered, slowing down but not stopping progression of the disease. Due to the monocular status of the patient and high probability of secondary retinal detachment, early vitrectomy was indicated. CONCLUSIONS: Rapid and aggressive medical treatment is necessary in this condition. Bilateral involvement often occurs within weeks, but can also happen more rarely after several months or years, requiring long-term follow-up. Early surgical treatment is controversial but it is an option to be considered in certain cases. PMID- 25743781 TI - Psychological aspects and depression in patients with retinitis pigmentosa. AB - PURPOSE: To assess the psychological impact and the potential relationship between depression and visual impairment in patients with retinitis pigmentosa (RP). METHODS: Our study included 34 patients with RP and 35 age- and sex-matched controls. All participants underwent a thorough ophthalmic examination including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, and dilated funduscopy, and they completed the Zung Depression Inventory questionnaire and the Patient Health Questionnaire-9 (PHQ-9). Questionnaires were rated according to specific guidelines. Statistical analysis was performed using SPSS 20.0 software. RESULTS: There was a statistically significant difference in PHQ-9 score and Zung score between patients with RP and controls. The BCVA differed significantly between the 2 groups as well. Older subjects presented significantly higher Zung score and PHQ-9 score, as well as worse BCVA in both eyes. Sex did not show any significant correlation as far as Zung score, PHQ-9 score, or BCVA. Zung score was correlated positively with PHQ-9 score, while both Zung and PHQ-9 score were positively correlated with BCVA. CONCLUSIONS: Patients with RP seem to present mild to moderate depressive symptoms in comparison with healthy control subjects without visual impairment. These symptoms were found to be correlated with BCVA and age, suggesting that visual loss and older age in patients with RP could be predictive factors of their emotional status. Therefore, there is need for close monitoring and supportive management of this population, so as to detect depression and to treat it promptly. PMID- 25743782 TI - Melanoma risk after ovarian stimulation for in vitro fertilization. AB - STUDY QUESTION: Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? SUMMARY ANSWER: Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. WHAT IS KNOWN ALREADY: Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. STUDY DESIGN, SIZE, DURATION: In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non significant risk increases (5-6 cycles HR = 1.92; >=7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07 10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). LIMITATIONS, REASONS FOR CAUTION: Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. STUDY FUNDING/COMPETING INTEREST: This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health. PMID- 25743783 TI - Increased levels of dioxin-like substances in adipose tissue in patients with deep infiltrating endometriosis. AB - STUDY QUESTION: Are the levels of biologically active and the most toxic dioxin like substances in adipose tissue of patients with deep infiltrating endometriosis (DIE) higher than in a control group without endometriosis? SUMMARY ANSWER: DIE patients have higher levels of dioxins and polychlorinated biphenyls (PCBs) in adipose tissue compared with controls without endometriosis. WHAT IS KNOWN ALREADY: Some studies have investigated the levels of dioxin-like substances, in serum samples, in patients with endometriosis, with inconsistent results. STUDY DESIGN, SIZE, DURATION: Case-control study including two groups of patients. The study group (DIE group) consisted of 30 patients undergoing laparoscopic surgery because of DIE. In all patients, an extensive preoperative work-up was performed including clinical exploration, magnetic resonance imaging (MRI) and transvaginal sonography. All patients with DIE underwent a confirmatory histological study for DIE after surgery. The non-endometriosis control group (control group), included the next consecutive patient undergoing laparoscopic surgery in our center due to adnexal benign gynecological disease (ovarian or tubal procedures other than endometriosis) after each DIE patient, and who did not present any type of endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: During the surgical procedure 1-2 g of adipose tissue from the omentum were obtained. Dioxin-like substances were analyzed in adipose tissue in DIE patients and controls without endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: The total toxic equivalence and concentrations of both dioxins and PCBs were significantly higher in patients with DIE in comparison with the control group (P < 0.05), mainly due to the significantly higher values of the two most toxic dioxins (2,3,7,8-tetrachlorodibenzo-p-dioxin [2,3,7,8-TCDD] and 1,2,3,7,8 pentachlorodibenzo-p-dioxin [1,2,3,7,8-PeCDD]) (P < 0.01 for each compound). The levels of furan 2,3,4,7,8-PeCDF were statistically higher in the DIE group compared with controls. Only four congeners of PCBs had toxic equivalence values and concentrations that were statistically higher in patients with DIE, but these included the most toxic and carcinogenic PCB-126 (PCB-114 P < 0.05; PCB-156 P < 0.05; PCB-189 P = 0.04; PCB-126 P < 0.01). LIMITATIONS, REASONS FOR CAUTION: Since few patients were recruited, the study is only exploratory. Our results need to be confirmed in larger and more heterogeneous population studies since environmental and even genetic factors involved in determining dioxins and PCBs widely vary in different countries. Furthermore, the strict eligibility criteria used may preclude generalization of the results to other populations and the surgery-based sampling frame may induce a selection bias. Finally, adipose tissue was obtained only from the omentum, and not from other adipose tissue of the body. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest a potential role of dioxin-like substances in the pathogenesis of DIE. Further studies are warranted to confirm our findings. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 25743784 TI - Dynamic changes in hyperglycosylated human chorionic gonadotrophin throughout the first trimester of pregnancy and its role in early placentation. AB - STUDY QUESTION: What is the in situ localization and function of hyperglycosylated hCG (hCG-H) in first trimester pregnancy tissues? SUMMARY ANSWER: HCG-H localizes to the syncytiotrophoblast, cytotrophoblast and invasive extravillous trophoblast within the maternal decidua and promotes invasion during the first trimester of pregnancy. WHAT IS KNOWN ALREADY: Serum levels of hCG-H decline dramatically throughout the first trimester of pregnancy. As hCG-H is produced by choriocarcinoma cells, it is proposed to regulate trophoblast invasion. STUDY DESIGN, SIZE, DURATION: Tissues were collected from elective first trimester pregnancy terminations. Placental villous and decidua basalis were collected from Week 6 to Week 12 of gestation (n = 49). PARTICIPANTS/MATERIALS, SETTING, METHODS: Tissues were collected from elective first trimester surgical pregnancy terminations to determine localization, abundance and function of hCG-H. Placental villous outgrowth studies determined the impact of neutralizing endogenous hCG-H on trophoblast function. Real-time proliferation, migration and invasion assays using JEG-3 choriocarcinoma cells further elucidated the role of hCG-H in trophoblast function. MAIN RESULTS AND THE ROLE OF CHANCE: HCG-H localized to syncytiotrophoblast layer of the placental villous from gestational weeks 6-9; thereafter hCG-H localized as a discrete layer between syncytio- and cyto-trophoblast layers. Immunoreactive hCG-H was also observed within the cytotrophoblast layer in Week 7-8 of gestation. HCG-H abundance decreased within placental villous from Weeks 6-12 of gestation (n = 3 placentas per gestational weeks 6-12). HCG-H also localized to anchoring villi within maternal decidua, extravillous trophoblasts invading into the maternal decidua and endovascular trophoblasts remodeling maternal blood vessels. Treatment of primary first trimester villous explants with hCG-H neutralizing antibody reduced trophoblast outgrowth (n = 3 placentas, P < 0.05). Treatment of a trophoblast cell line with neutralizing antibody reduced trophoblast invasion (n = 4, P < 0.05) but did not affect migration or proliferation. LIMITATIONS, REASONS FOR CAUTION: Functional invasion and migration assays performed using cell lines. Not possible to perform such assays with primary human material. WIDER IMPLICATIONS OF THE FINDINGS: HCG-H is an important autocrine factor facilitating trophoblast invasion in the first trimester of pregnancy. Targeting hCG-H may prove useful in the treatment of pathologic pregnancies, such as ectopic pregnancies, or pregnancy complications including pre-eclampsia and gestational trophoblast diseases. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Victorian Government Operational Infrastructure Support Program. J.E. is supported by NHMRC project grant #1047756, L.A.S. and E.D. by NHMRC Fellowships #1002018 and #550905 respectively and E.M. by an NHMRC Early Career Fellowship #611827. The authors have no conflicts of interest relating to this work. PMID- 25743786 TI - CRISPR/Cas9: a molecular Swiss army knife for simultaneous introduction of multiple genetic modifications in Saccharomyces cerevisiae. AB - A variety of techniques for strain engineering in Saccharomyces cerevisiae have recently been developed. However, especially when multiple genetic manipulations are required, strain construction is still a time-consuming process. This study describes new CRISPR/Cas9-based approaches for easy, fast strain construction in yeast and explores their potential for simultaneous introduction of multiple genetic modifications. An open-source tool (http://yeastriction.tnw.tudelft.nl) is presented for identification of suitable Cas9 target sites in S. cerevisiae strains. A transformation strategy, using in vivo assembly of a guideRNA plasmid and subsequent genetic modification, was successfully implemented with high accuracies. An alternative strategy, using in vitro assembled plasmids containing two gRNAs, was used to simultaneously introduce up to six genetic modifications in a single transformation step with high efficiencies. Where previous studies mainly focused on the use of CRISPR/Cas9 for gene inactivation, we demonstrate the versatility of CRISPR/Cas9-based engineering of yeast by achieving simultaneous integration of a multigene construct combined with gene deletion and the simultaneous introduction of two single-nucleotide mutations at different loci. Sets of standardized plasmids, as well as the web-based Yeastriction target sequence identifier and primer-design tool, are made available to the yeast research community to facilitate fast, standardized and efficient application of the CRISPR/Cas9 system. PMID- 25743787 TI - Metabolic gene clusters encoding the enzymes of two branches of the 3-oxoadipate pathway in the pathogenic yeast Candida albicans. AB - The pathogenic yeast Candida albicans utilizes hydroxyderivatives of benzene via the catechol and hydroxyhydroquinone branches of the 3-oxoadipate pathway. The genetic basis and evolutionary origin of this catabolic pathway in yeasts are unknown. In this study, we identified C. albicans genes encoding the enzymes involved in the degradation of hydroxybenzenes. We found that the genes coding for core components of the 3-oxoadipate pathway are arranged into two metabolic gene clusters. Our results demonstrate that C. albicans cells cultivated in media containing hydroxybenzene substrates highly induce the transcription of these genes as well as the corresponding enzymatic activities. We also found that C. albicans cells assimilating hydroxybenzenes cope with the oxidative stress by upregulation of cellular antioxidant systems such as alternative oxidase and catalase. Moreover, we investigated the evolution of the enzymes encoded by these clusters and found that most of them share a particularly sparse phylogenetic distribution among Saccharomycotina, which is likely to have been caused by extensive gene loss. We exploited this fact to find co-evolving proteins that are suitable candidates for the missing enzymes of the pathway. PMID- 25743789 TI - Outcome after simultaneous resection of gastric primary tumour and synchronous liver metastases: survival analysis of a single-center experience in China. AB - BACKGROUND: The optimal surgical strategy for the treatment of synchronous resectable gastric cancer liver metastases remains controversial. The aims of this study were to analyze the outcome and overall survival of patients presenting with gastric cancer and liver metastases treated by simultaneous resection. MATERIALS AND METHODS: Between January 1990 and June 2009, 35 patients diagnosed with synchronous hepatic metastases from gastric carcinoma received simultaneous resection of both primary gastric cancer and synchronous hepatic metastases. The clinicopathologic features and the surgical results of the 35 patients were retrospectively analyzed. RESULTS: The 5-year overall survival rate after surgery was 14.3%. Five patients survived for more than 5 years after surgery. No mortality has occurred within 30 days after resection, although two patients (5.7%) developed complications during the peri-operative course. Univariate analysis revealed that patients with the presence of lymphovascular invasion of the primary tumor, bilateral liver metastasis and multiple liver metastases suffered poor survival. Lymphovascular invasion by the primary lesion and multiple liver metastases were significant prognostic factors that influenced survival in the multivariate analysis (p=0.02, p=0.001, respectively). CONCLUSIONS: The presence of lymphovascular invasion of the primary tumor and multiple liver metastases are significant prognostic determinants of survival. Gastric cancer patients without lymphovascular invasion and with a solitary synchronous liver metastasis may be good candidates for hepatic resection. Simultaneous resection of both primary gastric cancer and synchronous hepatic metastases may effectively prolong survival in strictly selected patients. PMID- 25743788 TI - S. cerevisiae * S. eubayanus interspecific hybrid, the best of both worlds and beyond. AB - Saccharomyces pastorianus lager-brewing yeasts have descended from natural hybrids of S. cerevisiae and S. eubayanus. Their alloploidy has undoubtedly contributed to successful domestication and industrial exploitation. To understand the early events that have led to the predominance of S. pastorianus as lager-brewing yeast, an interspecific hybrid between S. cerevisiae and S. eubayanus was experimentally constructed. Alloploidy substantially improved the performance of the S. cerevisiae * S. eubayanus hybrid as compared to either parent regarding two cardinal features of brewing yeasts: tolerance to low temperature and oligosaccharide utilization. The hybrid's S. eubayanus subgenome conferred better growth rates and biomass yields at low temperature, both on glucose and on maltose. Conversely, the ability of the hybrid to consume maltotriose, which was absent in the S. eubayanus CBS12357 type strain, was inherited from its S. cerevisiae parent. The S. cerevisiae * S. eubayanus hybrid even outperformed its parents, a phenomenon known as transgression, suggesting that fast growth at low temperature and oligosaccharide utilization may have been key selective advantages of the natural hybrids in brewing environments. To enable sequence comparisons of the parental and hybrid strains, the genome of S. eubayanus CBS12357 type strain (Patagonian isolate) was resequenced, resulting in an improved publicly available sequence assembly. PMID- 25743785 TI - Temperature and host preferences drive the diversification of Saccharomyces and other yeasts: a survey and the discovery of eight new yeast species. AB - Compared to its status as an experimental model system and importance to industry, the ecology and genetic diversity of the genus Saccharomyces has received less attention. To investigate systematically the biogeography, community members and habitat of these important yeasts, we isolated and identified nearly 600 yeast strains using sugar-rich enrichment protocols. Isolates were highly diverse and contained representatives of more than 80 species from over 30 genera, including eight novel species that we describe here: Kwoniella betulae f.a. (yHKS285(T) = NRRL Y-63732(T) = CBS 13896(T)), Kwoniella newhampshirensis f.a. (yHKS256(T) = NRRL Y-63731(T) = CBS 13917(T)), Cryptococcus wisconsinensis (yHKS301(T) = NRRL Y-63733(T) = CBS 13895(T)), Cryptococcus tahquamenonensis (yHAB242(T) = NRRL Y-63730(T) = CBS 13897(T)), Kodamaea meredithiae f.a. (yHAB239(T) = NRRL Y-63729(T) = CBS 13899(T)), Blastobotrys buckinghamii (yHAB196(T) = NRRL Y-63727(T) = CBS 13900(T)), Candida sungouii (yHBJ21(T) = NRRL Y-63726(T) = CBS 13907(T)) and Cyberlindnera culbertsonii f.a. (yHAB218(T) = NRRL Y-63728(T) = CBS 13898(T)), spp. nov. Saccharomyces paradoxus was one of the most frequently isolated species and was represented by three genetically distinct lineages in Wisconsin alone. We found a statistically significant association between Quercus (oak) samples and the isolation of S. paradoxus, as well as several novel associations. Variation in temperature preference was widespread across taxonomic ranks and evolutionary timescales. This survey highlights the genetic and taxonomic diversity of yeasts and suggests that host and temperature preferences are major ecological factors. PMID- 25743790 TI - Current insights on cholangiocarcinoma research: a brief review. AB - Colangiocarcinoma (CCA) is a progressively fatal disease which generally occurs due to malignant transformation of hepatic biliary cholangiocytes. The incidence of CCA has been increasing worldwide and there is an urgent requirement for effective diagnosis and treatment strategies against this devastating disease. Different factors including liver-fluke infestation, viral hepatitis, exogenous nitrosamine-mediated DNA damage, and chronic inflammation have been linked to CCA genesis. However, the risk factors and underlying complex mechanisms leading to development of CCA are not sufficiently understood to devise an effective targeted treatment therapy. In this review, we summarize currently known epidemiological and pathological aspects of the disease and briefly describe various potential biomarkers and experimental anticancer phytochemicals related to CCA research. In addition, we also sum up recent findings that link chronic inflammation of hepatic biliary cholangiocytes with CCA. The collective information concisely presented in this article would provide useful insights into the current understanding of this cancer. PMID- 25743791 TI - Proton pump inhibitors and helicobacter pylori-associated pathogenesis. AB - The fact that long-term use of proton pump inhibitors (PPIs) aggravates corpus atrophic gastritis in patients with Helicobacter pylori infection has been proven clinically and experimentally. Corpus atrophic gastritis is a known risk factor for gastric cancer. Therefore, gastric neoplasia might be associated with the long-term use of PPIs. One of the causes of worsening corpus atrophic gastritis, leading to the development of adenocarcinoma, might be bacterial overgrowth under conditions of hypochlorhydria. The production of potentially carcinogenic N nitrosocompounds by nitrosating organisms under conditions of hypochlorhydria might be associated with carcinogenesis. Interactions between bile acids, pH, and H. pylori might also contribute to carcinogenicity, especially in patients with gastro-esophageal reflux disease (GERD). The concentration of soluble bile acids, which have bactericidal or chemorepellent properties toward H. pylori, in gastric contents is considerably higher in patients undergoing continuous PPI therapy than in healthy individuals with normal acid production. Under these circumstances, H. pylori might colonize the stomach body rather than the pyloric antrum. Hypergastrinemia induced by PPI administration might promote the development of gastric cancer. Because the main cause of corpus atrophic gastritis is H. pylori infection, and not PPI administration, H. pylori infection should be eradicated before starting long-term PPI therapy. PMID- 25743792 TI - From self-care for healthy people to self-management for cancer patients with cancer portals. AB - Self-care to prevent cancer and self-management to cope with the disease are two discrete effective mechanisms for improving of control and management of neoplasia. Both them have certain strategies and practices. Often the two are used interchangeably despite their different approaches. Strategies of self-care usually refer to prevention at different levels include primary, secondary and tertiary. In contrast, strategies of self-management are related to management and alleviation of unpleasant cancer-related symptoms and treatment-related side effects for improving the quality of life of cancer survivors. Successful promoting of self-care and self-management strategies need people and survivor empowerment. Within this context, innovative approaches open a new window. In this paper after a brief review of related strategies and practices, we provide an explanation of how cancer portals may play an important role in the empowerment process and what are key potentials for implementing of self- care and self-management strategies for cancer. PMID- 25743793 TI - Serum levels of MMP9 and MMP2 in patients with oral squamous cell carcinoma. AB - BACKGROUND: Squamous cell carcinoma (SCC) is the most common cancer in the oral area. Matrix metalloproteinases (MMPs) and especially MMP-2 and MMP-9 are increased in malignancy and lymph node involvement in oral SCCs. We aimed to evaluate the serum levels of MMP-2 and MMP-9 in patients with oral SCC compared to normal subjects and their relation with clinicopathological findings. MATERIALS AND METHODS: In this case control study, 20 patients with oral SCC and 20 healthy subjects were included and serum levels of MMP-2 and MMP-9 were compared between groups. Also, the correlation between these markers with clinicopathological findings including grade (T) and node (N) were evaluated. RESULTS: Patients with oral SCC had significantly higher serum levels of MMP-2 (p=0.01) and MMP-9 (p<0.001) compared to healthy subjects. With increase in grade T, MMP-2 was significantly increased (p=0.001), but in the MMP-9 case this was not significant (p=0.27). The levels of MMP-2 (p=0.002) and MMP-9 (p=0.01) in cases with lymph node involvement and that of MMP-2 in subjects with smoking history (p=0.001) were significantly high. There was significantly positive correlation between MMP-2 with grade T tumor (r=0.598, p=0.005), lymph node involvement (r=0.737, p<0.001) and smoking (r=0.674, p=0.001) and also between MMP-9 and lymph node involvement (r=0.474, p=0.03). CONCLUSIONS: Both markers are significantly increased in oral SCC compared to healthy subjects. However, MMP-2 was better for evaluating lymph node involvement and tumor grade. PMID- 25743794 TI - Exogenous natural glycoprotein multiple mechanisms of anti-tumor activity. AB - Natural glycoproteins can induce apoptosis of tumor cells and exert anti-tumor activity by immunomodulatory functions, cytotoxic and anti-inflammation effects, and inhibition of endothelial growth factor. Given their prospects as novel agents, sources of natural antitumor glycoproteins have attracted attention and new research directions in glycoprotein biology are gradually shifting to the direction of cancer treatment and prevention of neoplastic disease. In this review, we summarize the latest findings with regard to the tumor suppressor signature of glycoproteins and underlying regulatory mechanisms. PMID- 25743795 TI - Breast cancer prevention information seeking behavior and interest on cell phone and text use: a cross-sectional study in Malaysia. AB - BACKGROUND: Breast cancer is the most common cancer and the second principal cause of cancer deaths among women worldwide, including Malaysia. This study focused on media choice and attempted to determine the communication channels mostly used and preferred by women in seeking information and knowledge about breast cancer. MATERIALS AND METHODS: A cross sectional study was carried out to examine the breast cancer prevention information seeking behavior among 450 students at one private university in Malaysia. RESULTS: The mean age of respondents was 25+/-4.3 years. Common interpersonal information sources were doctors, friends, and nurses and common channel information sources were television, brochure, and internet. Overall, 89.9% used cell phones, 46.1% had an interest in receiving cell phone breast cancer prevention messages, 73.9% used text messaging, and 36.7% had an interest in receiving text breast cancer prevention messages. Bivariate analysis revealed significant differences among age, eduation, nationality and use of cell phones. CONCLUSIONS: Assessment of health information seeking behavior is important for community health educators to target populations for program development. PMID- 25743796 TI - Knockdown of UHRF1 by lentivirus-mediated shRNA inhibits ovarian cancer cell growth. AB - Human UHRF1 (ubiquitin-like PHD and RING finger domain-containing 1) has been reported to be over-expressed in many cancers, but its role in ovarian cancer remains elusive. Here, we determined whether knockdown of UHRF1 by lentivirus mediated shRNA could inhibit ovarian cancer cell growth. Lentivirus- mediated short hairpin RNAs (lv-shRNAs-UHRF1) were designed to trigger the gene silencing RNA interference (RNAi) pathway. The efficiency of lentivirus-mediated shRNA infection into HO-8910 and HO-8910 PM cells was determined using fluorescence microscopy to observe lentivirus-mediated GFP expressionand was confirmed to be over 80 percent. UHRF1 expression in infected HO-8910 and HO-8910 PM was evaluated by real-time PCR and Western blot analysis. The Cell Counting Kit-8 (CCK-8) assay was used to measure cell viability; flow cytometry and Hoechst 33342 assay was applied to measure cell cycle arrest and apoptosis. Cell invasion was assessed using transwell chambers. Our results demonstrated that the loss of UHRF1 promoted HO-8910 and HO-8910 PM cell apoptosis, while inhibiting cell proliferation. In addition, UHRF1 knockdown significantly inhibited the invasion of human ovarian cancer cells. In the present study, we also showed that depleting HO-8910 cells of UHRF1 caused activation of the DNA damage response pathway, with the cell cycle arrested in G2/M-phase. The DNA damage response in cells depleted of UHRF1 was illustrated by phosphorylation of CHK (checkpoint kinase) 2 on Thr68, phosphorylation of CDC25 (cell division control 25) on Ser 216 and phosphorylation of CDK1 (cyclin-dependent kinase 1) on Tyr 15. PMID- 25743797 TI - Increased expression of HOXB2 and HOXB13 proteins is associated with HPV infection and cervical cancer progression. AB - BACKGROUND: Cervical cancer (CeCa) is the second most common cancer in women in developing countries, and human papilloma virus (HPV) is the primary etiological factor. Aberrant expression of HOX transcription factors has been observed in several types of cancer. To date, however, no reports exist on the expression of HOXB2 and HOXB13 proteins during neoplastic progression in CeCa and its correlation with HPV infection. MATERIALS AND METHODS: Expression of HOXB2 and HOXB13 proteins was assessed in tissue microarrays from normal cervical epithelium, cervical intraepithelial neoplasias grade 1-3, and CeCa. HPV was detected by PCR and sequencing. Expression of HOX-positive cells was determined in each diagnostic group. RESULTS: Percentage of HOXB2- and HOXB13-positive cells gradually increased from means of 10.9% and 16.7%, respectively, in samples from healthy women, to 75.2% and 88.6% in those from CeCa patients. Frequency of HPV infection also increased from 13% in healthy tissue samples to 92.3% in CeCa. Both HOXB2 and HOXB13 proteins were preferentially expressed in HPV+ samples. CONCLUSIONS: The present study represents the first report on the expression of both HOXB2 and HOXB13 proteins through cervix tumorigenesis, providing evidence that increased expression of such proteins is a common event during progression to CeCa. PMID- 25743798 TI - Cancer survivors aged 40 years or elder are associated with high risk of chronic kidney disease: the 2010-2012 Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: The number of cancer survivors is increasing globally and recently, higher rates of comorbidities in cancer survivors have been reported. However, no studies have investigated whether cancer survivors have a higher risk of chronic kidney disease (CKD). Accordingly, our study evaluated the association between cancer survivors and the risk of CKD using the 2010-2012 Korean National Health and Nutrition Examination Survey. MATERIALS AND METHODS: A total of 11,407 participants aged 40 years and over were categorized into two groups according to cancer experience. Multiple variables were compared and the odds ratios (ORs) for CKD prevalence were calculated using a weighted logistic regression analysis between the two groups. RESULTS: Cancer survivors were older than were those in the non-cancer group, on average, the percentages of glomerular filtration rate(GFR) lower than 60mL/min/1.73m2, proteinuria, and CKD were significantly higher in cancer survivors when compared to controls. Weighted logistic regression analyses demonstrated that cancer survivors had a higher risk for CKD after adjusting for multiple variables (OR (95% confidence interval), 2.88 (1.48- 5.59)). CONCLUSIONS: Our study demonstrated a possible association between CKD and cancer survival in Korean adults. Identifying and correcting risk factors for cancer survivors would positively affect prevention of CKD and result in a better cancer prognosis. PMID- 25743799 TI - Identification of biomarkers for diagnosis of gastric cancer by bioinformatics. AB - BACKGROUND: We aimed to discover potential gene biomarkers for gastric cancer (GC) diagnosis. MATERIALS AND METHODS: Genechips of 10 GC tissues and 10 gastric mucosa (GM, para-carcinoma tissue, normal control) tissues were generated using an exon array of Affymetrix containing 30,000 genes. The differentially expressed genes (DEGs) between GC tissues and normal control were identified by the Limma package and analyzed by hierarchical clustering analysis. Gene ontology (GO) and pathway enrichment analyses were performed for investigating the functions of DEGs. Receiver operating characteristics (ROC) analysis was performed to measure the effects of biomarker candidates for diagnosis of GC. RESULTS: Totals of 896 up-regulated and 60 down-regulated DEGs were identified to be differentially expressed between GC samples and normal control. Hierarchical clustering analysis showed that DEGs were highly differentially expressed and most DEGs were up regulated. The most significantly enriched GO-BP term was revealed to be mitotic cell cycle and the most significantly enriched pathway was cell cycle. The intersection analysis showed that most significant DEGs were cyclin B1 (CCNB1) and cyclin B2 (CCNB2). The sensitivities and specificities of CCNB1 and CCNB2 were both high (p<0.0001). Areas under the ROC curve for CCNB1 and CCNB2 were both greater than 0.9 (p<0.0001). CONCLUSIONS: CCNB1 and CCNB2, which were involved in cell cycle, played significant roles in the progression and development of GC and these genes may be potential biomarkers for diagnosis and prognosis of GC. PMID- 25743800 TI - Total serum bile acid as a potential marker for the diagnosis of cholangiocarcinoma without jaundice. AB - Diagnosis of cholangiocarcinoma (CCA) is difficult when patients do not show jaundice. The aim of this study was to examine the feasibility of using the total serum bile acid (TSBA) level as an aid for the diagnosis of CCA in patients without jaundice. For this purpose, TSBA of the following groups were measured using a Beckman Synchron CX4 clinical chemistry analyzer: 60 cases of CCA with total serum bilirubin <=2 mg/dL (low total bilirubin group, LTB); 32 cases of CCA with total serum bilirubin >2 mg/dL (high total bilirubin group, HTB); and 115 healthy controls. Liver function parameters such as serum cholesterol, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were also examined. The results showed that the TSBA of both LTB and HTB groups of the CCA patients were significantly higher than that of the healthy controls. Also, significant correlation was observed between TSBA and total bilirubin levels in the HTB group of CCA patients. However, no such correlation was seen in the LTB group. The cut-off value of TSBA was determined for the LTB group of CCA patients using the receiver operating characteristic curve analysis, and it was 6.05 MUmol/L with the sensitivity and specificity of 46.7% and 84.4%, respectively. In addition, the ALP level was correlated well with the TSBA level and ALP in HTB group was significantly higher than that of LTB group. Moreover, the combination of high TSBA and high ALP levels gave higher specificity up to 97.4%. TSBA might be useful for the diagnosis of CCA patients without jaundice. PMID- 25743801 TI - Characteristics of oral tongue and base of the tongue cancer: a hospital cancer registry based analysis. AB - BACKGROUND: Tongue cancer is one of the leading sites of cancer in our population. AIM: To evaluate the socio-demographic profiles and stages at diagnosis of oral tongue (OT) and base of tongue (BT) cancers, and identify any possible variations in characteristics. MATERIALS AND METHODS: A retrospective analysis was conducted on tongue cancer cases, divided into OT and BT, registered at the hospital cancer registry of North-East India during January 2010 to May 2013. Cases were analyzed for age, gender, residential status and different levels of education for patients, the stage at diagnosis and presence of distant metastasis. RESULTS: A total of 1,113 cases of tongue cancers were registered, 846(76.1%) of BT and 267(23.9%) of OT. While 33.9% of BT cancer patients were above 65 years of age, the figure for OT cancers was 18.4%, stages III and IV accounting for 90.8% and 77%, respectively. The relative risk for distant metastasis in OT cancers was 3.3 (95% CI 1.08-10.1, p=0.03). CONCLUSIONS: In the subsites of tongue cancers in our population, the majority arose from the base of tongue, these tending to occur in older individuals and presenting at late stage. PMID- 25743802 TI - The expression of MRTF-A and AQP1 play important roles in the pathological vascular remodeling. AB - BACKGROUND: Objective Myocardin-related transcription factor (MRTF)-A is a Rho signaling-responsive co-activator of serum response factor (SRF). The purpose of this study is to investigate the role of MRTF-A and AQP1 (aquaporin 1) in pathological vascular remodeling. MATERIALS AND METHODS: MRTF-A, AQP1 and neointima expression was detected both in the wire injured femoral arteries of wild-type mice and the atherosclerotic aortic tissues of ApoE-/- mice. Expression of ICAM-1, matrix metallopeptidase 9 (MMP-9) and integrin beta1 were also assayed. The intercourse relationship between the molecules were investigated by interfering RNA and inhibitor assay. RESULTS: MRTF-A and AQP1 expression were significantly higher in the wire injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE-/- mice than in healthy control tissues. Both in wire-injured femoral arteries in MRTF-A knockout (Mkl1-/-) mice and atherosclerotic lesions in Mkl1-/-; ApoE-/- mice, neointima formation were significantly attenuated and the expression of AQP1 were significantly decreased. Expression of ICAM-1, matrix metallopeptidase 9 (MMP-9) and integrin beta1, three SRF targets and key regulators of cell migration, and AQP1 in injured arteries was significantly weaker in Mkl1-/- mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs were the down-regulation of microRNA 300. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. CONCLUSIONS: MRTF-A could be a novel therapeutic target for the treatment of vascular diseases. PMID- 25743803 TI - Sun protection use behaviour among University students from 25 low, middle income and emerging economy countries. AB - The aim of this study was to investigate the sun protection use behaviour among university students from 25 low, middle income and emerging economy countries. Using anonymous questionnaires, data were collected from 18,687 undergraduate university students aged 18-30 years (mean age 20.8, SD=2.8) from 26 universities in 25 countries across Asia, Africa and the Americas. Overall, 57.2% of university students reported liking to sunbathe and of those only 48.1% used sun protection when sunbathing. In multivariate logistic regression, younger age, being female, coming from a wealthy or quite well off economic family background, living in an upper middle or high income country, lighter skin tone, and other health behaviours were found to be associated with sun protection use behaviour. Low sun protection use calls for health promotion programmes to prevent unprotected sun exposure. PMID- 25743804 TI - Chemopreventive effects of hydatid disease on experimental breast cancer. AB - Breast cancer is one of the most common and letal cancers in all over the world. Since there have been significant improvements in treatment of breast cancer, there is still a big need for alternative approaches. In this study, we aimed to investigate protective role of hydatid disease against breast cancer. Twenty Wistar rats were divided into two groups of 10 rats each Group I (control) and Group II. In Group II intraperitoneal hydatidosis was performed. Then DMBA was applied to mammary tissues of all rats. Immunohistochemistry studies for Ki-67 and S-100 in the tumoral tissue sections of DMBA induced mammary tumor in rats were performed. TUNEL Assay was used to detect apoptotic cells of tumoral tissue. In vivo anticancer activity testing was carried out by preventing the tumorigenesis by DMBA in mammary tissue of rats. The expressions of the Ki-67 and S-100 protein decreased in rats who had Hydatid Disease (HD) (Group II), compared with the control rats (Group I). TUNEL positive cells were higher in rats with HD (Group II), compared with the control rats (Group I). In vivo studies showed that HD prevented the tumorigenesis by DMBA in mammary tissue of rats with 50 percent.In the light of the evidence the present study showed that HD may have chemopreventive effects on DMBA induced breast cancer. PMID- 25743805 TI - Overexpression of Tbx3 predicts poor prognosis of patients with resectable pancreatic carcinoma. AB - BACKGROUND: To determine the expressions of Tbx3, a member of subgroup belonging to T-box family, and its prognostic value in pancreatic carcinoma. MATERIALS AND METHODS: We determined the expression levels of Tbx3 on both mRNA and protein levels in 30 pairs of fresh tumor tissues and paratumor tissues by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. In addition, protein level of Tbx3 were identified using immunochemistry in 80 pairs of paraffin-embedded specimen. The correlations between Tbx3 expression and various clinicopathological parameters as well as overall survival were evaluated. RESULTS: Tbx3 mRNA and protein levels in tumor tissues were significantly higher than in the paratumor tissues by qRT-PCR (0.05 +/-0.007 vs. 0.087+/-0.001, p<0.001) and western blotting (1.134+/-0.043 vs. 0.287+/-0.017, p<0.001). The statistical analysis based on immunohistochemical evaluation suggested that Tbx3 aberrant expression was significantly associated with several conventional clinicopathological variables, such as gender, age, tumor position, preoperative CA19-9 level, pathological T staging and N staging. Univariate and multivariate analyses revealed that Tbx3 expression was an independent prognostic factor for overall survival (<0.001). CONCLUSIONS: Our results suggest that overexpression of Tbx3 is associated with poor prognosis of pancreatic cancer patients. However, additional clinical trials are needed to accurately validate this observation. PMID- 25743806 TI - Fibulin-3 as a diagnostic biomarker in patients with malignant mesothelioma. AB - BACKGROUND: New tumour biomarkers are being intensely investigated for malignant mesothelioma (MM). Fibulin-3 is produced in MM but its role remains uncertain. The aim of this study was to evaluate the validity of measuring serum fibulin-3 in the diagnosis and prognosis of MM. MATERIALS AND METHODS: This prospective study was performed on 43 patients and 40 healthy controls who were admitted to our hospital between January 2012 and January 2014. Data from MM patients, including demographic and clinical features, routine laboratory data, levels of serum fibulin-3, and treatment outcomes were defined as potential prognostic factors. The receiver operating characteristic (ROC) curve for fibulin-3 was used to detect the cut-off value with highest sensitivity and specificity. Univariate survival analysis was performed using the Kaplan-Meier method in patients with MM. Afterwards, the possible factors identified with univariate analyses were entered into the cox regression analysis. RESULTS: Our results revealed that patients with MM had significantly higher serum levels of fibulin-3 than controls. The results showed that the best cut-off point was 36.6 ng/ml with an AUC (area under the curve)=0.976, sensitivity=93.0% and specificity=90.0. In our study, the initial significant poor prognostic factors were advanced stage, high white blood cell count, high platelet count, high C-reactive protein (p<0.05 for each variable). Later, according to multivariate analysis the results showed only advanced stage as significant parameter (p=0.040). CONCLUSIONS: We determined that real use for serum fibulin-3 was not for prognosis but for diagnosis in MM. Also advanced stage was associated with poor MM prognosis. PMID- 25743807 TI - Epidemiology and trend of cancers in the province of Kerman: southeast of Iran. AB - BACKGROUND: According to increase in elderly populations, and change in lifestyle and cancer-causing behavior, the global burden of cancer is increasing. For prevention and control of disease, knowledge of population statistics of cancers and their trends is essential. This study aimed to investigate the epidemiology and trends of cancer in the province of Kerman: southeast of Iran. MATERIALS AND METHODS: This analytical and cross-sectional study was carried out based on cancer registry data at the Disease Management Center of the Health Ministry from 2004 to 2009 in the province of Kerman in Iran. Common cancers were defined as the number of reported cases and standardized incidence rates. To compute the annual percentage change (APC), joinpoint 4.1.1.1 software was applied. RESULTS: Of 10,595 registered cases, 45.3% (4802 cases) were in women and 56.7% (5,793 cases) occurred in men. The standardized incidence rates for both females and males were increasing during the six years studied. The most common cancers in both sexes during six years of studied were skin (13.4%), breast (9.35%), bladder (7.8%), stomach (7.45%), leukemia (7.05%), colorectal(5.57%), lung(4.92%), trachea(3.51%) and prostate(2.48%). CONCLUSIONS: Our findings revealed that the cancer incidence is demonstrating increasing trends in both sexes in the province of Kerman. This may be because of changes in lifestyle, increasing exposure to risk factors for cancer and increase of life expectancy. If this is the case, increasing public awareness of cancer risk factors is a high priority, together with introduction of large-scale screening techniques. PMID- 25743808 TI - Do long term cancer survivors have better health-promoting behavior than non cancer populations?: case-control study in Korea. AB - BACKGROUND: We compared the health-promoting behavior of long-term cancer survivors with those of the general population to identify necessary behavioral interventions to reduce the health risk among cancer patients. MATERIALS AND METHODS: We used data from the 2007 and 2012 Korea National Health and Nutrition Examination Surveys (KNHANES IV [2007~2009] and KNHANES V [2010~2012]) on smoking status, alcohol use, physical exercise, and disease screening. We compared long term cancer survivors with members of the general population; the controls were matched by propensity score matching. A multiple logistic regression model was used to investigate the association between cancer status and health-promoting behavior. RESULTS: Long-term cancer survivors had a lower risk of smoking than the general population controls (OR: 0.42, 95%CI: 0.25-0.71). In addition, the long-term cancer survivors had a lower risk of alcohol use than the general population controls (OR: 0.70, 95%CI: 0.50-0.98). However, in terms of physical exercise and disease screening, no statistically significant differences were detected (physical exercise OR: 1.01, 95%CI: 0.75-1.35; disease screening OR: 1.27, 95%CI: 0.93-1.74). All covariates were adjusted. CONCLUSIONS: The long-term cancer survivors had a much lower risk of smoking and alcohol use than the general population controls. However, almost no differences in physical exercise and screening for cancer recurrence or secondary disease were detected between the long-term cancer survivors and general population controls. To reduce the health risks and challenges facing long-term cancer survivors, interventions to encourage physical exercise and screening for cancer recurrence and secondary disease should be implemented. PMID- 25743809 TI - Serum pleiotrophin could be an early indicator for diagnosis and prognosis of non small cell lung cancer. AB - AIMS: Pleiotrophin (PTN), an angiogenic factor, is associated with various types of cancer, including lung cancer. Our aim was to investigate the possibility of using serum PTN as an early indicator regarding disease diagnosis, classification and prognosis, for patients with non-small cell lung cancer (NSCLC). METHODS: Significant differences among PTN levels in patients with small cell lung cancer (SCLC, n=40), NSCLC (n=136), and control subjects with benign pulmonary lesions (n=21), as well as patients with different pathological subtypes of NSCLC were observed. RESULTS: A serum level of PTN of 300.1 ng/ml, was determined as the cutoff value differentiating lung cancer patients and controls, with a sensitivity and specificity of 78.4% and 66.7%, respectively. Negative correlations between serum PTN level and pathological differentiation level, stage, and survival time were observed in our cohort of patients with NSCLC. In addition, specific elevation of PTN levels in pulmonary tissue in and around NSCLC lesions in comparison to normal pulmonary tissue obtained from the same subjects was also observed (n=2). CONCLUSION: This study suggests that the serum PTN level of patients with NSCLC could be an early indicator for diagnosis and prognosis. This conclusion should be further assessed in randomized clinical trials. PMID- 25743810 TI - Prevalence and predicting factors for anxiety in thai women with abnormal cervical cytology undergoing colposcopy. AB - AIM: To compare prevalence of anxiety in women with abnormal cervical cytology (Pap) undergoing colposcopy to that of women attending the outpatient clinic for check-up and to examine predicting factors. MATERIALS AND METHODS: In this cross sectional analytical study, 100 women with abnormal cervical cytology (abnormal Pap group) and 100 women who attended our outpatient clinic for check-up (control group) were recruited from June 2013 to January 2014. The Hospital Anxiety and Depression Scale (HADS) was employed to determine anxiety in the participants with the score of >= 11 suggestive of clinically significant anxiety. The prevalence of anxiety and the mean HADS scores for anxiety were compared between the groups. For those with abnormal Pap, association between clinical factors and anxiety was assessed. A p-value of < 0.05 was considered significant. RESULTS: Median age was different between the groups, 44.0 years in the abnormal Pap group and 50.0 years in the control group (p=0.01). The proportion of participants who had more than one sexual partner was higher in the abnormal Pap group, 39.2% vs. 24.7% (p=0.03) and the prevalence of anxiety was significantly higher 14/100 (14.0%) vs. 3/100 (3.0%) (p < 0.01). The prevalence of depression was comparable between the groups. The mean HADS scores for anxiety and depression subscales were significantly higher in the abnormal Pap group, 6.6 vs. 4.8 (P < 0.01) and 3.9 vs. 3.1 (p=0.05), respectively. For the abnormal Pap group, no definite association between clinical factors and anxiety was demonstrated. CONCLUSIONS: The prevalence of anxiety in women with abnormal Pap awaiting colposcopy was significantly higher than that of normal controls. Special attention including thorough counselling, with use of information leaflets and psychological support, should be directed to these women. PMID- 25743811 TI - Role of HER2 in brain metastasis of breast cancer: a systematic review and meta analysis. AB - BACKGROUND: Breast cancer is one of the most common cancers among women worldwide and the HER2 receptor plays an important role in its development and progression. This systematic review aimed to summarize the role of HER2 in brain metastasis in patients with breast cancer. MATERIALS AND METHODS: We conducted a literature search by advanced search in title field using the Scopus, Pubmed, and Google scholar databases until the end of June 2014. With metastasis, metastatic, HER2, brain, and breast cancer, as terms of search we selected 31 articles, which were reviewed by two independent and blinded expert reviewers. The studies were first selected according to their titles and abstracts. Quality of the studies were then assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) protocol for observational studies and CONSORT(Consolidation of Standards for Reporting Trials) protocol for clinical trials. For statistical analyses, we used STATA, version 11.0 software. Forest and funnel diagrams were drawn and for heterogeneity, index was also considered. Also we used meta regression analysis. RESULTS: Finally, we reviewed 10 studies. The prevalence of brain metastasis in HER2- positive breast cancer patients was 24.9%. There was publication bias in the reviewed studies. Meta regression analysis showed that follow up time had no significant effect (p=0.396) on the prevalence of brain metastasis. CONCLUSIONS: The results showed a high prevalence of brain metastasis in HER2 positive breast cancer patients. PMID- 25743812 TI - Radiotherapy for brain metastases in southern Thailand: workload, treatment pattern and survival. AB - PURPOSE: To study the patient load, treatment pattern, survival outcome and its predictors in patients with brain metastases treated by radiotherapy. MATERIALS AND METHODS: Data for patients with brain metastases treated by radiotherapy between 2003 and 2007 were collected from medical records, the hospital information system database, and a population-based tumor registry database until death or at least 5 years after treatment and retrospectively reviewed. RESULTS: The number of treatments for brain metastases gradually increased from 48 in 2003 to 107 in 2007, with more than 70% from lung and breast cancers. The majority were treated with whole brain radiation of 30 Gy (3 Gy X 10 fractions) by cobalt 60 machine, using radiation alone. The overall median survival of the 418 patients was 3.9 months. Cohort analysis of relative survival after radiotherapy was as follows: 52% at 3 months, 18% at 1 year and 3% at 5 years in males; and 66% at 3 months, 26% at 1 year and 7% at 5 years in females. Multivariate analysis demonstrated that the patients treated with combined modalities had a better prognosis. Poor prognostic factors included primary cancer from the lung or gastrointestinal tract, emergency or urgent consultation, poor performance status (ECOG 3-4), and a hemoglobin level before treatment of less than 10 g/dl. CONCLUSIONS: This study identified an increasing trend of patient load with brain metastases. Possible over-treatment and under-treatment were demonstrated with a wide range of survival results. Practical prognostic scoring systems to assist in decision-making for optimal treatment of different patient groups is absolutely necessary; it is a key strategy for balancing good quality of care and patient load. PMID- 25743813 TI - Expression and prognostic implications of FOXO3a and Ki67 in lung adenocarcinomas. AB - To investigate the significance of FOXO3a and Ki67 in human lung adenocarcinomas. Envision immunohistochemical staining and Western blotting were used to examine the protein expression of FOXO3a in 127 cases of human lung adenocarcinoma specimens. The positive rate in lung adenocarcinoma (55.9%) was lower than that in normal tissues (80%). We found that the expression of FOXO3a was closely related with the degree of differentiation, TNM staging, lymph node metastasis and survival. In addition, significant differences in the different pathological types of lung adenocarcinoma cases (P<0.01). The FOXO3a positive rate of the acini as the main type (APA) (86.7%) and the lepidic as the main type (LPA) (82.4%) was higher than the solid as the main type (SPA) (50.0%), the papilla as the main type (PPA) (42.9%) and the micropapilla as the main type (MPA) (9.4%). Moreover, the expression of FOXO3a was negatively related with Ki67 expression. Our results suggested that the expression of FOXO3a is closely correlated with the aggressiveness of lung adenocarcinoma. It was indicated that disregulation of FOXO3a might play key roles in the occurrence and development of lung adenocarcinoma and joint detection of the two markers might play an important role in diagnosing tumors. PMID- 25743814 TI - Capecitabine pattern of usage, rate of febrile neutropaenia and treatment related death in asian cancer patients in clinical practice. AB - BACKGROUND: Oral capecitabine is increasingly replacing intravenous 5 fluorouracil in many chemotherapy regimens. However, data on the risk of febrile neutropaenia (FN) and treatment related death (TRD) with the drug remain sparse outside of clinical trial settings despite its widespread usage. This study aimed to determine these rates in a large cohort of patients treated in the University of Malaya Medical Centre (UMMC). MATERIALS AND METHODS: We reviewed the clinical notes of all patients prescribed with oral capecitabine chemotherapy for any tumour sites in University Malaya Medical Centre (UMMC) from 1st January 2009 till 31st June 2010. Information collected included patient demographics, histopathological features, treatment received including the different chemotherapy regimens and intent of treatment whether the chemotherapy was given for neoadjuvant, concurrent with radiation, adjuvant or palliative intent. The aim of this study is to establish the pattern of usage, FN and TRD rates with capecitabine in clinical practice outside of clinical trial setting. FN is defined as an oral temperature >38.5 degrees or two consecutive readings of >38.0 degrees for 2 hours and an absolute neutrophil count <0.5 x 109/L, or expected to fall below 0.5 x 109/L (de Naurois et al., 2010). Treatment related death was defined as death occurring during or within 30 days of last chemotherapy treatment. RESULTS: Between 1st January 2009 and 30th June 2010, 274 patients were treated with capecitabine chemotherapy in UMMC. The mean age was 58 years (range 22 to 82 years). Capecitabine was used in 14 different tumour sites with the colorectal site predominating with a total of 128 cases (46.7%), followed by breast cancer (35.8%). Capecitabine was most commonly used in the palliative setting accounting for 63.9% of the cases, followed by the adjuvant setting (19.7%). The most common regimen was single agent capecitabine with 129 cases (47.1%). The other common regimens were XELOX (21.5%) and ECX (10.2%). The main result of this study showed an overall FN rate of 2.2% (6/274). The overall TRD rate was 5.1% (14/274). The FN rate for the single agent capecitabine regimen was 1.6% (2/129) and the TRD rate was 5.4% (7/129). All the TRDs were with single agent capecitabine regimen were used for palliative intent. CONCLUSIONS: Oral capecitabine is used widely in clinical practice in a myriad of tumour sites and bears a low risk of febrile neutropaenia. However, capecitabine like any other intravenous chemotherapeutic agent carries a significant risk of treatment related death. PMID- 25743815 TI - Breast cancer at extreme ages--a comparative analysis in Chile. AB - BACKGROUND: Young onset breast cancer (BC) has a worse outcome as compared to in the elderly. However, some studies have shown that BC in the elderly, despite indolent features, does also cause increase in mortality. In an attempt to compare clinic-pathological characteristics, BC subtypes and survival in patients with BC presenting at extremes of age, we performed a retrospective study. MATERIALS AND METHODS: Patients were either <=40 or >=70 years old. Subtypes were defined using immunohistochemistry and histological grade. Chi-Square test was used for evaluation of categorical variables, and Kaplan-meier and log-rank for disease-specific survival (DSS) and disease free survival (DFS) . RESULTS: We analyzed 256 patients <=40 and 366 patients >=70. Younger patients presented with more aggressive disease, with less luminal A but more luminal B and triple negative (TN) subtype. With a median follow-up of 57.5 months, DFS at 5 years in younger patients was 72.3% vs 84.6% in the elderly (p=0.007). Luminal A and B disease presented with worse DFS in younger patients. The opposite was seen in the TN subgroup. Although we found no significant differences in DSS, older patients with TN tumors died of BC more frequently. This group also received less chemotherapy. CONCLUSIONS: Young patients present with more aggressive disease, this translating into worse DFS. However, elderly patients with TN disease represent a particular subpopulation with worse DFS and DSS, suggesting that chemotherapy should not be withheld only because of age. PMID- 25743816 TI - Feasibility and efficacy of concurrent chemoradiotherapy in elderly patients with esophageal squamous cell carcinoma: a respective study of 116 cases from a single institution. AB - BACKGROUND: To evaluate the safety and efficacy of combined chemoradiotherapy or radiotherapy alone in elderly patients with esophageal carcinoma to identify the best method of treatment. MATERIALS AND METHODS: One hundred and sixteen patients with esophageal carcinoma aged 70 and older who received definitive radiotherapy or chemoradiotherapy entered the study. Overall survival (OS), disease-free survival (DFS) and treatment- related toxicities were assessed. RESULTS: The median OS of the overall population was 17.9 months. For patients treated with cCRT, sCRT and radiotherapy alone, the median OS was 22.3 months, 18.0 months and 12.4 months respectively(P=0.044). Median OS for patients treated with radiotherapy dose >=60Gy and <60Gy was 20.2 months and 10.9 months respectively (p=0.017). By univariate analysis, Chemoradiotherapy (include cCRT and sCRT) and radiotherapy dose >=60Gy were found to achieve higher survival rates compared with radiotherapy alone and radiotherapy dose <60Gy (P=0.015, P=0.017). By multivariate analysis, chemoradiotherapy (HR=1.645, P=0.022) and radiotherapy dose >=60Gy (HR=1.642, P=0.025) were identified as independent prognostic factors of OS. CONCLUSIONS: Definitive concurrent chemoradiotherapy could be considered as a feasible and effective treatment in esophageal carcinoma patients aged 70 and older. Radiotherapy dose 60Gy is an effective treatment option compared with standard dose radiotherapy, while higher doses are not beneficial to improve survival. PMID- 25743818 TI - Socio-demography and medical history as predictors of health-related quality of life of breast cancer survivors. AB - BACKGROUND: Even after completion of conventional treatment, breast cancer survivors continue to exhibit a variety of psychological and physical symptoms, affecting their quality of life. The study aimed to investigate the relationship between socio-demography, medical characteristics and health-related quality of life (HR-QOL) of a sample of breast cancer survivors in Malaysia. MATERIALS AND METHODS: This pilot cross-sectional survey was conducted among breast cancer survivors (n=40) who were members of Breast Cancer Support Group Centre Johor Bahru. A validated self-administered questionnaire was used to identify the relationships between socio-demography, medical characteristics and HR-QOL of the participants. RESULTS: Living with family and completion of treatment were significant predictive factors of self-rated QOL, while living with family and ever giving birth significantly predicted satisfaction with health and physical health. Psychological health had moderate correlations with number of children and early cancer stage. Survivors' higher personal income (>MYR4,500) was the only significant predictor of social relationship, while age, income more than MYR4,500 and giving birth significantly predicted environment domain score. CONCLUSIONS: The findings suggested the survivors coped better in all four HR-QOL domains if they were married, lived with family, had children and were employed. PMID- 25743817 TI - Efficacy of dose dense doxorubicin and cyclophosphamide followed by paclitaxel versus conventional dose doxorubicin, cyclophosphamide followed by paclitaxel or docetaxel in patients with node-positive breast cancer. AB - BACKGROUND: Adding taxanes to adjuvant antracycline and cyclophosphamide (AC) in combination may provide significant improvement in node-positive and high risk node-negative breast cancer (BC) patients. However, the optimal dose and the role of dose-dense (DD) chemotherapy have yet to be determined. The aim of this study was to compare the efficacy of a DD paclitaxel (P)-AC combination with conventional weekly P-AC or docetaxel D-AC combinations in patients with node positive breast cancer. MATERIALS AND METHODS: Newly diagnosed 280 node-positive BC patients diagnosed from 1998 to 2013 in three clinics were retrospectively analyzed. Demographic and medical data were collected from the medical charts. Patients were categorized to 3 groups according to treatment arms: arm A, ddAC-P; arm B, weekly P and AC combination; and arm C; T and AC combination. Adjuvant trastuzumab was added for HER2-positive patients. Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). The log-rank test was used to examine the statistical significance of the differences observed between the groups. Two-sided P values <0.05 were considered statistically significant. RESULTS: Of the total of 280 patients, 101 were in arm A, 114 in arm B and 65 in arm C.The median ages were 49, 50 and 46, respectively (p=0.11). Median follow-up was 39 (3-193) months. Stage, lymphovascular and perineural invasion, receptor patern, and menopausal status were similar in the 3 treatment arms, but HER2 positivity was significantly lower in arm A, compared to arms B and C (25.7%, 53.1%, 41.5% in arms A, B and C, respectively; p<0.001). Also grade 3 tumors were significantly less frequent in treatment arm A compared to arm B and C (27.3%, 56.8% and 49.2% , respectively, p=0.01). Afterunivariate and multivariate analysis were performed, 3-year DFS rates were 89%, 81%, and 75%, respectively (p=0.12) and three year OS rates were 96.6%, 89%, and 75% (p=0.62). CONCLUSIONS: In this study, no significant difference was found between adjuvant dose dense and conventional taxane treatment regimens. PMID- 25743819 TI - Adoptive immunotherapy for small cell lung cancer by expanded activated autologous lymphocytes: a retrospective clinical analysis. AB - BACKGROUND: To investigate the clinical efficacy of expanded activated autologous lymphocytes (EAAL) in patients with small cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 32 SCLC patients were selected and randomly divided into EAAL treatment and control groups, 16 cases in each. EAAL were obtained by proliferation of peripheral blood mononuclear cells (PBMCs) of patients followed by phenotype determination. Clinical data of all patients were recorded. Patients of both groups were followed up and the overall survival (OS) were compared retrospectively. RESULTS: After culture and proliferation in vitro, the percentages of CD3+, CD3+CD8+, CD45RO+, CD28+, CD29+, CD8+CD28+ and CD3+CD16+/CD56+ cells increased markedly (p<0.05). The OS of the EAAL treatment group was longer than that of control group, but the difference was not statistically significant (p=0.060, HR=0.487, 95%CI 0.228~1.037). 1- to 3-year survival rates in EAAL treatment group were longer than those in control group, but there was still no significant difference (p>0.05). COX multivariate regression analysis showed that the number of chemotherapy cycles and the application of EAAL immunotherapy were independent prognostic factors for SCLC patients. The OS in females and chemotherapy<=6 cycles were obviously prolonged after EAAL immunotherapy. CONCLUSIONS: In vitro induction and proliferation of EAAL is easy and biologically safe. Generally, EAAL adoptive immunotherapy can evidently prolong the OS of SCLC patients. PMID- 25743820 TI - Relationships between C-kit expression and mean platelet volume in benign, preneoplastic and neoplastic endometrium. AB - BACKGROUND: c-Kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117). Mean platelet volume (MPV) is a useful marker for demonstrating thrombocyte function. We aimed to investigate whether c-kit is expressed in benign, preneoplastic and neoplastic endometrial tissues and whether MPV has a relation with c-kit expression and its intensity. MATERIALS AND METHODS: c-Kit expression was investigated immunohistochemically in 10 samples of normal endometrium (n=10), simple endometrial hyperplasia (5 cases with atypia and 10 cases without atypia), complex endometrial hyperplasia (10 cases with atypia and 10 cases without atypia) and endometrial cancer (EC) (10 cases grade I and 10 cases grade II) and MPV of all cases was checked. RESULTS: c-Kit expression was observed at very low rates in cases with normal endometrial tissues (NE) and in hyperplasia without atypia. c-Kit expression and immunostaining were strong in endometrial atypia and EC. MPV levels of complex atypical endometrial hyperplasia (CAEH) (p:0.002), EC grade I (ECG I) (p<0.001) and EC grade II (ECG II) (p<0.001) were significantly elevated when compared with the NE group. Both c-kit expression and intensity of immunostaining had a positive correlation with MPV level. CONCLUSIONS: While c-kit expression and intensity of immunostaining were mildly positive in NE and hyperplasia without atypia, they were clearly observed in EC and hyperplasia with atypia. As c-kit expression is related to the mutagenesis a long-term follow- up may be needed in these cases. A high MPV level may be a good test for demonstrating c-kit expression and intensity of immunostaining. PMID- 25743821 TI - Anti-mutagenic activity of Salvia merjamie extract against gemcitabine. AB - Gemcitabine is an anti-cancer drug with clinically uses in the treatment of various neoplasms, including breast, ovarian, non-small cell lung, pancreaticand cervical cancers, T-cell malignancies, germ cell tumours, and hepatocellular carcinomas. However, it has also been reported to have many adverse effects. Naturally occurring anti-mutagenic effects, especially those of plant origin, have recently become a subject of intensive research. The present study was therefore designed to investigate the anti-mutagenic effects of Salvia merjamie (Family: Lamiaceae) plant extracts against the mutagenic effects of gemcitabine. The anti-mutagenic properties of Salvia merjamie were tested in Inbred SWR/J male and female mice bone marrow cells. The mice were treated in four groups; a control group treated with 30 mg/kg body weight gemcitabine and three treatment groups, each with 30 mg/kg body weight gemcitabine together with, respectively, 50, 100 and 150 mg/kg body weight Salvia merjamie extract. Chromosomal aberration and mitotic index assays were performed with the results demonstrating that Salvia merjamie extract protects bone marrow cells in mice against gemcitabine induced mutagenicity. This information can be used for the development of a potential therapeutic anti-mutagenic agents. PMID- 25743822 TI - Pemetrexed induces G1 phase arrest and apoptosis through inhibiting Akt activation in human non small lung cancer cell line A549. AB - Pemetrexed is an antifolate agent which has been used for treating malignant pleural mesothelioma and non small lung cancer in the clinic as a chemotherapeutic agent. In this study, pemetrexed inhibited cell growth and induced G1 phase arrest in the A549 cell line. To explore the molecular mechanisms of pemetrexed involved in cell growth, we used a two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics approach to analyze proteins changed in A549 cells treated with pemetrexed. As a result, twenty differentially expressed proteins were identified by ESI-Q-TOF MS/MS analysis in A549 cells incubated with pemetrexed compared with non-treated A549 cells. Three key proteins (GAPDH, HSPB1 and EIF4E) changed in pemetrexed treated A549 cells were validated by Western blotting. Accumulation of GAPDH and decrease of HSPB1 and EIF4E which induce apoptosis through inhibiting phosphorylation of Akt were noted. Expression of p-Akt in A549 cells treated with pemetrexed was reduced. Thus, pemetrexed induced apoptosis in A549 cells through inhibiting the Akt pathway. PMID- 25743823 TI - Tobacco use and oral leukoplakia: cross-sectional study among the Gond tribe in Madhya Pradesh. AB - BACKGROUND: Leukoplakia is an asymptomatic and potentially malignant change in the oral mucosa and high frequencies have been reported among smokers. The present study concerned the prevalence of tobacco use and leukoplakia and also associations between the two. STUDY DESIGN: This cross sectional survey was conducted amongst the Gond tribal population of Kundam Block, Jabalpur district, Madhya Pradesh state, Central India during 2007 to 2009. Screening for leukoplakia was conducted by a medical officer with two mouth mirrors. It is only based on visual inspection and oral pathology was not performed. A semi structured questionnaire was used to collect information on socio-demographic and smoking habits. Prevalence of leukoplakia among users and non-users of tobacco was calculated in terms of percentages. RESULTS: Of 1,552 individuals aged more than 12 years of age who were screened, 144 (9.3%) were found to have oral leukoplakia. The prevalence of leukoplakia was significantly elevated among tobacco users as compared to non-users (11% vs 2.5%; p<0.001). The percentage of leukoplakia was almost similar in both tobacco smokers and chewers (9% vs 11%; p=0.304). However, the percentage of leukoplakia was especially high among those chewers who also smoked tobacco (21.9%). CONCLUSIONS: The findings of the present study showed a positive effect of tobacco use and prevalence of leukoplakia. Also the prevalence was very high among Gond tribe, a marginalized population living in central India. There is a need for effective screening and treatment of leukoplakia in this area. PMID- 25743824 TI - Distribution of human papilloma virus infections of uterine cervix among women of reproductive age--a cross sectional hospital-based study from North East India. AB - Infection of the uterine cervix by human papilloma viruses (HPV) may be associated with cervical pre-cancer and invasive cervical carcinoma if left untreated. With advance in molecular techniques, it has become easier to detect the resence of HPV DNA long before the appearance of any lesion. This study concerned cervical scrape samples of 310 married non-pregnant women attending a gynecology outpatient department for both Pap and PCR testing to detect HPV DNA. Nested PCR using primers for L1 consensus gene with My9/My11 and GP6+/ GP5+followed by multiplex PCR were carried out to detect HPV 16 and HPV18. RESULT: HPV prevalence was 11.9% out of which 3.67% cases of negative for intra epithelial lesion or malignancy (NILM) and in 71.1% (27/38) of atypical cervical smears were HPV positive. There was increasing trend of high-risk-HPV positivity (HR HPV 16 and 18), from 20% in benign cytology (NILM) to 42.9 % in LSIL, 71.41% in HSIL and 100% in SCC. There was highly significant association of HPV infection with cervical lesion (x2=144.0, p<0.01) and also with type specific HPV prevalence (x2=7.761*(p<0.05). PMID- 25743825 TI - Clinical investigation in effect of riboflavin sodium phosphate on prevention and treatment for patients with radiotherapy related esophagitis. AB - OBJECTIVE: To investigate the clinical effect of riboflavin sodium phosphate on prevention of radiotherapy related esophagitis (RRE). METHODS: This retrospective study involved 55 patients with middle and advanced esophageal cancer who were divided into an experimental group of 28 and a control group of 27 patients. Those in the experimental group were treated with riboflavin sodium phosphate combined with conventional symptomatic treatment during radiotherapy; while patients in control group received the latter alone. The incidence and degree of RRE were compared after radiotherapy. RESULTS: The incidences of RRE in experimental and control group were 53.5% and 81.4%, respectively (p<0.05); the incidence of stages III and IV RRE in the experimental group was 17.8%, while in the control group it was 44.4% (p<0.05). CONCLUSION: Riboflavin sodium phosphate could significantly prevent RRE and reduce the incidence of stage III and IV disease. These results were worthy of further confirmation by randomized controlled trials. PMID- 25743826 TI - Sun burn incidence and knowledge of greek elementary and high school children about sun protection. AB - INTRODUCTION: Overexposure to sun radiation and particularly its accumulation during childhood and adolescence is a significant risk factor for skin cancer development. The sun burn is particularly important. AIM: To estimate sun burn incidence in young pupils in a coastal area of Greece. MATERIALS AND METHODS: Two surveys were conducted in a school population in the same district in Greece, over different periods of time, in young people 9 to 18 years old (n=2 977). Anonymous questionnaires were completed. Levels of significance were two- tailed and statistical significance was set at p=0.05. SPSS 17.0 software was used for statistical analysis. RESULTS: From the individual characteristics of the participants it was shown that the majority of them had dark hair and fair skin, whereas a significant percentage reported the existence of moles on face and their body (83.4% vs 68.1%). The sun burn incidence was high in adolescents and the younger pupils (41.9% vs 55.6%). The younger aged children who were living in an urban area had significantly higher rates of sun burn than those living in semi-urban areas (33.8% vs 24.8%, p=0.020). As far as the knowledge of pupils about the risks of sun radiation it was shown that the elementary school pupils had better knowledge than those at high school. Finally, those with better knowledge had the fewer sun burns (Mean 2.83 SD 0.87, p<0.001). CONCLUSIONS: The contribution of knowledge to the decrease of sun burn incidence is important as long as this is continuous. Therefore, the education should concern not only children but also teachers and parents in the context of continuous and systematic programs of health education. PMID- 25743827 TI - Is it necessary to submit grossly normal looking gall bladder specimens for histopathological examination? AB - BACKGROUND: The objectives of the study were to: 1) determine the frequency of incidental malignancy in unsuspected/grossly normal looking gall bladders; 2) determine the frequency of malignancy in suspected/grossly abnormal looking gall bladders. MATERIALS AND METHODS: This prospective, cross sectional study was carried out at a tertiary care hospital in Pakistan, during a four year period (Jan 2009-dec2012). All the cholecystectomy cases performed for gallstone diseases were examined initially by a surgeon and later on by a pathologist for macroscopic abnormalities and accordingly assigned to one of the three categories i.e. grossly normal, suspicious, abnormal/malignant. Frequency of incidental carcinoma in these categories was observed after receiving the final histopathology report. RESULTS: A total of 426 patients underwent cholecystectomy for cholelithiasis, with a 1:4 male: female ratio. Mean age of the patients was 45 years with a range of 17-80 years. The frequency of incidental gallbladder carcinoma was found to be 0.70 %(n=3). All the cases of gallbladder carcinoma were associated with some macroscopic abnormality. Not a single case of incidental carcinoma gallbladder was diagnosed in 383 'macroscopically normal looking' gallbladders. CONCLUSIONS: Incidental finding of gall bladder cancer was not observed in any of macroscopically normal looking gall bladders and all the cases reported as carcinoma gallbladder had some gross abnormality that made them suspicious. We suggest histopathologic examination of only those gall bladders with some gross abnormality. PMID- 25743828 TI - High expression level of preoperative serum Uroplakin III is associated with biologically aggressive bladder cancer. AB - BACKGROUND: Uroplakins have been widely investigated as potential markers in patients with bladder cancer because these proteins are specific to the urothelium. However, the role of uroplakin proteins in bladder cancer remains unknown. In this study, preoperative serum levels of uroplakin III were measured in patients with urothelial carcinoma of the urinary bladder and examined for possible association with clinicopathological features and clinical outcomes. MATERIALS AND METHODS: This study included 52 bladder cancer patients at various stages and 28 healthy controls. Uroplakin III levels were detected in preoperative sera using an automated dot blot system and a micro-dot blot array. RESULTS: There was a significant increase in serum uroplakin III levels in patients with bladder cancer as compared to healthy controls (p<0.05). In addition, serum uroplakin III levels were associated with muscle-invasive status, high grade and lymphovascular invasion (p<0.02). Log-rank tests indicated high serum uroplakin III to be significantly associated with cancer-specific mortality. CONCLUSIONS: Determination of serum uroplakin III level could be valuable for identifying patients with biologically aggressive bladder cancer. PMID- 25743829 TI - Carcinoma microsatellite instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for stage II rectal cancer. AB - PURPOSE: Rectal cancers with high microsatellite-instable have clinical and pathological features that differentiate them from microsatellite-stable or low- frequency carcinomas, which was studied rarely in stage II rectal cancer, promoting the present investigation of the usefulness of microsatellite instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II rectal cancer. PATIENTS AND METHODS: Data of 460 patients who underwent primary anterior resection with a double stapling technique for rectal carcinoma at a single institution from 2008 to 2012 were retrospectively collected. All patients experienced a total mesorectal excision (TME) operation. Survival analysis were analyzed using the Cox regression method. RESULTS: Five-year rate of disease-free survival (DFS) was noted in 390 (84.8%) of 460 patients with stage II rectal cancer. Of 460 tissue specimens, 97 (21.1%) exhibited high-frequency microsatellite instability. Median age of the patients was 65 (50-71) and 185 (40.2%) were male. After univariate and multivariate analysis, microsatellite instability (p= 0.001), female sex (p< 0.05) and fluorouracil-based adjuvant chemotherapy (p< 0.001), the 3 factors were attributed to a favorable survival status independently. Among 201 patients who did not receive adjuvant chemotherapy, those cancers displaying high-frequency microsatellite instability had a better 5-year rate of DFS than tumors exhibiting microsatellite stability or low-frequency instability (HR, 13.61 [95% CI, 1.88 to 99.28]; p= 0.010), while in 259 patients who received adjuvant chemotherapy, there was no DFS difference between the two groups (p= 0.145). Furthermore, patients exhibiting microsatellite stability or low-frequency instability who received adjuvant chemotherapy had a better 5-year rate of DFS than patients did not (HR, 5.16 [95% CI, 2.90 to 9.18]; p< 0.001), while patients exhibiting high frequency microsatellite instability were not connected with increased DFS (p= 0.696). It was implied that female patients had better survival than male. CONCLUSION: Survival status after anterior resection of rectal carcinoma is related to the microsatellite instability status, adjuvant chemotherapy and gender. Fluorouracil-based adjuvant chemotherapy benefits patients of stage II rectal cancer with microsatellite-stable or low microsatellite-instable, but not those with high microsatellite- instable. Additionally, free of adjuvant chemotherapy, carcinomas with high microsatellite-instable have a better 5-year rate of DFS than those with microsatellite-stable or low microsatellite-instable, and female patients have a better survival as well. PMID- 25743830 TI - Cyclooxygenase-2 expression in invasive breast carcinomas of no special type and correlation with pathological profiles suggest a role in tumorigenesis rather than cancer progression. AB - BACKGROUND: COX-2 has been shown to play an important role in the development of breast cancer and increased expression has been mooted as a poor prognostic factor. The purpose of this study was to investigate the relationship between COX 2 immunohistochemical expression and known predictive and prognostic factors in breast cancer in a routine diagnostic histopathology setting. MATERIALS AND METHODS: Formalin-fixed paraffin- embedded tumour tissue of 144 no special type (NST) invasive breast carcinomas histologically diagnosed between January 2009 and December 2012 in Hospital Sultanah Bahiyah, Alor Setar, Kedah were immunostained with COX-2 antibody. COX-2 overexpression was analysed against demographic data, hormone receptor status, HER2- neu overexpression, histological grade, tumour size and lymph node status. RESULTS: COX-2 was overexpressed in 108/144 (75%) tumours and was significantly more prevalent (87%) in hormone receptor-positive tumours. There was no correlation between COX-2 overexpression and HER2/neu status. Triple negative cancers had the lowest prevalence (46%) (p<0.05). A rising trend of COX-2 overexpression with increasing age was observed. There was a significant inverse relationship with tumour grade (p<0.05), prevalences being 94%, 83% and 66% in grades 1, 2 and 3 tumours, respectively. A higher prevalence of COX-2 overexpression in smaller size tumours was observed but this did not reach statistical significance. There was no relationship between COX-2 expression and lymph node status. CONCLUSIONS: This study did not support the generally held notion that COX-2 overexpression is linked to poor prognosis, rather supporting a role in tumorigenesis. Larger scale studies with outcome data and basic studies on cancer pathogenetic pathways will be required to cast further light on whether COX-2 inhibitors would have clinical utility in cancer prevention or blockage of cancer progression. In either setting, the pathological assessment for COX-2 overexpression in breast cancers would have an important role in the selection of cancer patients for personalized therapy with COX-2 inhibitors. PMID- 25743831 TI - Male breast cancer: a 24 year experience of a tertiary care hospital in Pakistan. AB - BACKGROUND: Male breast cancer accounts for less than 1% of all cancers found in men. It usually presents at a later age and stage as compared to female breast cancer. Treatment strategies are extrapolated from the management of female breast cancer. Our study here looked at 18 patients diagnosed with and treated for male breast cancer at The Aga Khan University Hospital in Pakistan. We compared our findings with the existing data from Asian and Western countries. MATERIALS AND METHODS: A retrospective study was conducted looking at patients with male breast cancer between January 1986 and December 2009. Patient and disease characteristics were analyzed and 5 year overall survival was calculated using Microsoft Excel and SPSS. RESULTS: The average age at diagnosis was 52 years (38-67 years). Twelve (66.7%) patients had axillary lymphadenopathy. Stage II disease was the most common stage at presentation (9 patients, 50%). Infiltrating ductal carcinoma was seen in 16 patients (88.8%). Seven lesions were positive for both estrogen and progesterone receptors. Sixteen patients had surgery in the form of either modified radical mastectomy or radical mastectomy. Radiation was used in 7 patients in an adjuvant setting. The five year overall survival for stage I, II, III and IV disease was 100% vs 78% vs 50% vs 0%( p<0.05). Five year overall survival was 61%. None of the other prognostic factors were statistically significant. Median follow up was 15 months (3-202 months). CONCLUSIONS: Male breast cancer may be on a slow rise but is still an uncommon disease. Tumor stage and lymph node status are important prognostic markers. Public awareness and screening may help in detecting the disease at an earlier stage. Prospective trials are needed to improve the management of this disease. PMID- 25743832 TI - Barriers to cervical screening among Pacific women in a New Zealand Urban Population. AB - BACKGROUND: In Aotearoa/New Zealand cervical screening programmes have reduced cervical cancer; however, half of cervical cancer cases among Pacific women are found among clients who had not attended cervical screening. Hence, we set out to determine health provider perspectives on barriers that prevent their services reaching Pacific women within Aotearoa/New Zealand. MATERIALS AND METHODS: Twenty semi-structured interviews were conducted with health care providers, Pap smear takers and community workers in the Wellington region. Participants were asked their views on factors that enabled and/or constrained the participation of Pacific women in their cervical screening services. RESULTS: Six interrelated themes influencing participation in cervical screening among Pacific women in the Wellington region were apparent: the funding and practice of service delivery; family always coming first; the cost of screening services; type of employment; the appropriateness of information; and attitudes to self and screening. CONCLUSIONS: Determining specific ethnic group actual health needs and meeting them contributes to overall improvement in New Zealand's health status. The results identified the need for improvements to the delivery of screening services including adapting cervical screening services to the requirements of Pacific women through more outreach services at alternate clinic hours; culturally appropriate practitioners; the ability to take up opportunities for health checks and foster long-term relationships; as well as appropriate monitoring and evaluation of approaches. Funding and reporting relationships also need to be compatible with the goal of improving outcomes for Pacific women. Further research into client voices for their particular needs to compliment the service provider perspective as well as minority groups is called for. PMID- 25743833 TI - Does treatment of Helicobacter pylori infection reduce gastric precancerous lesions? AB - BACKGROUND: Treatment of Helicobacter pylori (H. pylori) decreases the prevalence of gastric cancer, and may inhibit gastric precancerous lesions progression into gastric cancer. The aim of this study was to determine the effect of treatment on subsequent gastric precancerous lesion development. MATERIALS AND METHODS: We prospectively studied 27 patients who had low grade dysplasia at the time of enrollment, in addition to dysplasia atrophic gastritis and intestinal metaplasia observed in all patients. All were prescribed quadruple therapy to treat H. Pylori infection for 10 days. Patients underwent endoscopy with biopsy at enrollment and then at follow up two years later. Biopsy samples included five biopsies from the antrum of lesser curvature, antrum of greater curvature, angularis, body of stomach and fundus. RESULTS of these biopsies were compared before and after treatment. RESULTS: Overall, the successful eradication rate after two years was 15/27 (55.6%). After antibiotic therapy, the number of patients with low grade dysplasia decreased significantly (p=0.03), also with reduction of the atrophic lesions (p=0.01), but not metaplasia. CONCLUSIONS: Treatment of H. pylori likely is an effective therapy in preventing the development of subsequent gastric premalignant lesions. PMID- 25743834 TI - MicroRNA-328 inhibits proliferation of human melanoma cells by targeting TGFbeta2. AB - Some microRNAs (miRNAs) have been shown to act as oncogenes or tumor suppressor genes in human melanomas. miR-328 is upregulated in blood cells of melanoma patients compared to in healthy controls. This suggests a role for miR-328 in melanoma that warrants investigation. In this study, we demonstrated miR-328 levels to be dramatically decreased in human melanoma cell lines. Moreover, forced expression of miR-328 inhibited proliferation and induced G1-phase arrest of the SK-MEL-1 melanoma cell line. We identified TGFbeta2 as a direct target gene for miR-328 using a fluorescent reporter assay and western blotting. Levels of TGFbeta2 were dramatically increased in human melanoma cell lines and were inversely correlated with the miR-328 expression level. Our findings provide new insights into the mechanisms of human melanoma development, indicating that miR 328 has therapeutic potential for this disease. PMID- 25743835 TI - Knowledge of human papillomavirus and its association with head and neck benign and malignant lesions in a group of dental patients in pakistan. AB - Human papillomaviruses (HPVs) remain a serious world health problem due to their association with cervical and head and neck cancers. While over 100 HPV types have been identified, only a few subtypes are associated with malignancies. HPV 16 and 18 are the most prevalent oncogenic types in head and neck cancers. Although it has been proven that some subsets of benign and malignant head and neck lesions are associated with HPV, the general population have very little awareness and knowledge of their association with HPV. Therefore, the purpose of this study was to determine the knowledge of HPV and its links with head and neck benign and malignant lesions in a group of Pakistani dental patients who attended the Dental Department of the Sandeman provincial hospital in Quetta, Pakistan. One hundred and ninety-two patients were recruited and requested to answer a questionnaire. It was revealed that there was a low level of knowledge about HPV and its association with head and neck benign and malignant lesions among the participants. This result suggested that more education regarding the relationship of HPV in inducing head and neck benign and malignant lesions is required in this group of patients. PMID- 25743836 TI - ZAP-70 protein expression in B-cell chronic lymphoid leukemia: a single center experience from Pakistan. AB - BACKGROUND: Chronic lymphoid leukemia (CLL) is the most frequent type of adult leukemia. The Rai and Binet staging systems have been well recognized as standards for assessing the treatment requirements and overall survival in CLL patients. However, there is a need to seek newer prognostic markers to identify stable or progressive forms of CLL that will facilitate risk-adapted treatment strategies. Currently a molecular biomarker ZAP-70 has attracted interest as providing prognostic information in CLL patients. OBJECTIVE: To determine the frequency of ZAP-70 positivity in B-CLL patients at disease presentation. MATERIALS AND METHODS: From January 2011 to September 2014, 89 patients were diagnosed to have chronic lymphoid leukemia. Complete blood count was done on an automated analyzer (Cell Dyne, Abott Architect, USA), while immunophenotyping was conducted for each patient to establish the diagnosis of the disease. ZAP-70 expression was evaluated by flow cytometry. Data were compiled and analyzed by SPSS version 21. RESULTS: Out of the total of 89 B-CLL patients, 62 (69.7%) were male and 27 (30.3%) were females with a male to female ratio of 2:1. The mean age was 57.5+/-12.1 years. The frequency of ZAP-70 positivity in our B-CLL patients was found to be 13.5%. ZAP- 70 positivity was significantly correlated with stage III disease and high absolute lymphocytic count (P<0.05). No correlation of ZAP 70 could be established with age and gender (p>0.05). CONCLUSIONS: The frequency of ZAP-70 in our patients appears low. It is approximately half that in international data. We would recommend to screen all the newly diagnosed patients with CLL for ZAP-70 protein expression for risk stratification, family counseling and to predict overall survival. PMID- 25743837 TI - The Health Examinees (HEXA) study: rationale, study design and baseline characteristics. AB - BACKGROUND: Korea has experienced rapid economic development in a very short period of time. A mixture of traditional and modern risk factors coexists and the rapid change in non-genetic factors interacts with genetic constituents. With consideration of these unique aspects of Korean society, a large-scale genomic cohort study-the Health Examinees (HEXA) Study-has been conducted to investigate epidemiologic characteristics, genomic features, and gene-environment interactions of major chronic diseases including cancer in the Korean population. MATERIALS AND METHODS: Following a standardized study protocol, the subjects were prospectively recruited from 38 health examination centers and training hospitals throughout the country. An interview- based questionnaire survey was conducted to collect information on socio-demographic characteristics, medical history, medication usage, family history, lifestyle factors, diet, physical activity, and reproductive factors for women. Various biological specimens (i.e., plasma, serum, buffy coat, blood cells, genomic DNA, and urine) were collected for biorepository according to the standardized protocol. Skilled medical staff also performed physical examinations. RESULTS: Between 2004 and 2013, a total of 167,169 subjects aged 40-69 years were recruited for the HEXA study. Participants are being followed up utilizing active and passive methods. The first wave of active follow-up began in 2012 and it will be continued until 2015. The principal purpose of passive follow-up is based on data linkages with the National Death Certificate, the National Cancer Registry, and the National Health Insurance Claim data. CONCLUSIONS: The HEXA study will render an opportunity to investigate biomarkers of early health index and the chronological changes associated with chronic diseases. PMID- 25743838 TI - Hypermethylation of promoter region of LATS1--a CDK interacting protein in oral squamous cell carcinomas--a pilot study in India. AB - BACKGROUND: Epigenetic silencing of tumor suppressor genes due to promoter hypermethylation is one of the frequent mechanisms observed in cancers. Hypermethylation of several tumor suppressor genes involved in cell cycle regulation has been reported in many types of tumors including oral squamous cell carcinomas. LATS1 (Large Tumor Suppressor, isoform 1) is a novel tumor suppressor gene that regulates cell cycle progression by forming complexes with the cyclin dependent kinase, CDK1. Promoter hypermethylation of the LATS1 gene has been observed in several carcinomas and also has been linked with prognosis. However, the methylation status of LATS1 in oral squamous cell carcinomas is not known. As oral cancer is one of the most prevalent forms of cancer in India, the present study was designed to investigate the methylation status of LATS1 promoter and associate it with histopathological findings in order to determine any associations of the genetic status with stage of differentiation. MATERIALS AND METHODS: Tumor chromosomal DNA isolated from biopsy tissues of thirteen oral squamous cell carcinoma biopsy tissues were subjected to digestion with methylation sensitive HpaII enzyme followed by amplification with primers flanking CCGG motifs in promoter region of LATS1 gene. The PCR amplicons were subsequently subjected to agarose gel electrophoresis along with undigested amplification control. RESULTS: HpaII enzyme based methylation sensitive PCR identified LATS1 promoter hypermethylation in seven out of thirteen oral squamous cell carcinoma samples. CONCLUSIONS: The identification of LATS1 promoter hypermethylation in seven oral squamous cell carcinoma samples (54%), which included one sample with epithelial dysplasia, two early invasive and one moderately differentiated lesions indicates that the hypermethylation of this gene may be one of the early event during carcinogenesis. To the best of our knowledge, this is the first study to have explored and identified positive association between LATS1 promoter hypermethylation with histopathological features in oral squamous cell carcinomas. PMID- 25743839 TI - Expression of ki67 in papillary thyroid microcarcinoma and its clinical significance. AB - PURPOSE: To investigate the expression of Ki67 protein in papillary thyroid microcarcinoma(PTMC), and to analyze its clinical significance. MATERIALS AND METHODS: Ki67 protein expression was evaluated in the tissues of 108 human PTMC and 50 other benign papillary hyperplasia of thyroid specimens using immunohistochemistry. RESULTS: The expression intensity of Ki67 in PTMC and benign papillary hyperplasia of thyroid specimens were 1.45+/-1.83% and 0.46+/ 0.46%.The positive expression rates were 46.3% and 14%. There were significant differences between these two groups (p<0.01). There was no significant variation of the expression intensity and positive expression rates of Ki67 in PTMC with gender, age, position of the tumor and the level of TSH pre-operation (p>0.05), but these parameters varied with tumor size, invasion by membrane and cervical lymph node metastasis (p<0.05 or p<0.01). CONCLUSIONS: The expression of Ki67 in PTMC was related to tumor size, invasion by membrane and cervical lymph node metastasis, and could be the important indicator for judging clinical progress and estimating prognosis. PMID- 25743840 TI - 8-year analysis of the prevalence of lymph nodes metastasis, oncologic and pregnancy outcomes in apparent early-stage malignant ovarian germ cell tumors. AB - PURPOSE: To determine the rate of lymph node metastasis, oncologic and pregnancy outcomes in apparent early-stage malignant ovarian germ cell tumor (MOGCT). MATERIALS AND METHODS: Medical records of apparent early-stage MOGCT patients undergoing primary surgical treatment at Siriraj Hospital, Bangkok, Thailand, between January 2006 and December 2013, were retrospectively reviewed. RESULTS: Thirty-eight patients had apparent stage I-II MOGCT. The mean age was 22.1+/-7.7 years (median, 20.8 years; range, 7.7-35.6 years). The mean tumor size was 17.8+/ 6.5 cm with a median of 20 (range 4-30) cm. Three most common histopathologies were dysgerminoma (12 patients, 31.6%), immature teratoma (12 patients, 31.6%), and endodermal sinus tumor (6 patients, 15.8%). Twenty-seven of 38 patients underwent lymphadenectomy; 13 patients (48.2%) were stage IA and 8 patients (29.6%) were stage IC. The rate of retroperitoneal nodes metastasis was 7.4% (2/27 patients). At 26.1 months of median follow-up time (range 1.9-88.5 months), 9 patients retained fertility functions, with uneventful pregnancies in 3 of these. Only one patient (2.6%) had progression of disease at 4.9 months after surgery. The 5-year survival rate was 97.4%. CONCLUSION: As the rate of pelvic or para-aortic node metastasis in MOGCT is considerable, lymphadenectomy should be incorporated in surgical staging procedures. PMID- 25743841 TI - BRD7 promoter hypermethylation as an indicator of well differentiated oral squamous cell carcinomas. AB - BACKGROUND: Promoter hypermethylation mediated gene silencing of tumor suppressor genes is considered as most frequent mechanism than genetic aberrations such as mutations in the development of cancers. BRD7 is a single bromodomain containing protein that functions as a subunit of SWI/SNF chromatin-remodeling complex to regulate transcription. It also interacts with the well know tumor suppressor protein p53 to trans- activate genes involved in cell cycle arrest. Loss of expression of BRD7 has been observed in breast cancers and nasopharyngeal carcinomas due to promoter hypermethylation. However, the genetic status of BRD7 in oral squamous cell carcinomas (OSCCs) is not known, although OSCC is one of the most common among all reported cancers in the Indian population. Hence, in the present study we investigated OSCC samples to determine the occurrence of hypermethylation in the promoter region of BRD7 and understand its prevalence. MATERIALS AND METHODS: Genomic DNA extracted from biopsy tissues of twenty three oral squamous cell carcinomas were digested with methylation sensitive HpaII type2 restriction enzyme that recognizes and cuts unmethylated CCGG motifs. The digested DNA samples were amplified with primers flanking the CCGG motifs in promoter region of BRD7 gene. The PCR amplified products were analyzed by agarose gel electrophoresis along with undigested amplification control. RESULTS: Methylation sensitive enzyme technique identified methylation of BRD7 promoter region seventeen out of twenty three (74%) well differentiated oral squamous cell carcinoma samples. CONCLUSIONS: The identification of BRD7 promoter hypermethylation in 74% of well differentiated oral squamous cell carcinomas indicates that the methylation dependent silencing of BRD7 gene is a frequent event in carcinogenesis. To the best of our knowledge, the present study is the first to report the occurrence of BRD7and its high prevalence in oral squamous cell carcinomas. PMID- 25743842 TI - Financial distress and its predicting factors among iranian cancer patients. AB - BACKGROUND: Financial distress due to the cost of cancer treatments is prevalent among cancer patients. Identifying the level of financial distress and its affecting factors has an important role in providing supportive services. Accordingly, the aims of this study were to determine these parameters among Iranian cancer patients. MATERIALS AND METHODS: This descriptive-correlational study was undertaken among 262 cancer patients admitted to both private and public hospitals in East Azerbaijan province, Iran. The financial distress/financial well being scale was used to determine financial distress. The data were analyzed using SPSS software using descriptive and inferential statistics (multiple linear regression). RESULTS: Among the 262 cancer patients, 57.3% were male and their mean age was 47.0 years. The mean score for financial distress was 4.12 (2.01). The final regression model demonstrated that the independent variables (predictors) of income less than living expenses, income equal to living expenses, having an employed spouse in governmental job and living with parents, with regression coefficients of -1.029, -0.515, 0.198, and 0.096, respectively, were predictors of financial distress among cancer patients. These variables accounted for 50% of changes in variance of financial distress. CONCLUSIONS: Iranian cancer patients have moderate to high levels of financial distress. Considering policies for managing direct and indirect costs of cancer treatments must be followed. PMID- 25743843 TI - Associations of demographic and socioeconomic factors with stage at diagnosis of breast cancer. AB - BACKGROUND: Stage at diagnosis is one of the most important prognostic factors of breast cancer survival. Because in the breast cancer case this may vary with socioeconomic characteristics, this study was performed to recognize the relationship between demographic and socioeconomic factors with stage at diagnosis in Iran. MATERIALS AND METHODS: This cross-sectional, descriptive study conducted on 526 patients suffering from breast cancer and registered in Cancer Research Center of Shahid Beheshti University of Medical Sciences from 2008 to 2013. A reliable and valid questionnaire about family levels of socioeconomic status filled in by interviewing the patients via phone. For analyzing the data, Multinomial logistic regression, Kendal tau-b correlation coefficient and Contingency Coefficient tests were executed by SPSS22. Economic status, educational attainment of patient and household head and/or a combination of these were considered as parameters for socioeconomic status. First, the relationship between stage at diagnosis and demographic and socioeconomic status was assessed in univariate analysis then these relationships assessed in two different models of multinomial logistic regression. RESULTS: The mean age of the patients was 48.3 (SD=11.4). According to the results of this study, there were significant relationships between stage at diagnosis of breast cancer with patient education (p=0.011), living place (p=0.044) and combined socioeconomic status (p=0.024). These relationships persisted in multiple multinomial logistic regressions. Other variables, however, had no significant correlation. CONCLUSIONS: Patient education, combined socioeconomic status and living place are important variables in stage at diagnosis of breast cancer in Iranian women. Interventions have to be applied with the aim of raising women's accessibility to diagnostic and medical facilities and also awareness in order to reducing delay in referring. In addition, covering breast cancer screening services by insurance is recommended. PMID- 25743844 TI - Planning aspects of volumetric modulated arc therapy and intensity modulated radio therapy in carcinoma left breast--a comparative study. AB - BACKGROUND: The advantages of Rapid Arc plans versus Intensity modulated radiotherapy plans for Carcinoma left breast were analyzed. MATERIALS AND METHODS: In this study 20 Post mastectomy carcinoma left breast patients were analyzed. Both Intensity modulated Radiotherapy and Rapid Arc plans were generated for these patients. IMRT plans with 7 beams in an arc fashion and VMAT plans with two semi arcs were made to achieve 95% dose coverage to 100% volume. The plans were evaluated using Dose volume Histograms. RESULTS: The mean Conformity and Homogeneity index in VMAT is found to be 1.05 and 0.065 respectively whereas in IMRT it was 1.07 and 0.069. The 20% volume of Heart received a mean dose of 960cGy in VMAT and 1300cGy in IMRT. The mean dose was 1236cGy in VMAT and 1870cGy in IMRT. The ipsilateral Lung received 3395cGy to 5% volume and 1840cGy to 20% volume on an average and the mean dose was 1205cGy in VMAT, while the same were found to be 3525cGy, 2012cGy and 1435cGy respectively in IMRT. The Contralateral Lung received a mean dose of 505cGy in VMAT and 553cGy in IMRT. The mean Monitor units in VMAT were 512MU and 1170MU in IMRT. The NTID in VMAT is 108.8 x 105 Gycm3 and 110.1 x 105 Gycm3 in IMRT. CONCLUSIONS: The target coverage, homogeneity and Conformity index were better in VMAT plans. The Ipsilateral Lung and heart dose were very less in VMAT plans. The Contralateral Lung dose and the Normal Tissue Integral Dose were also lesser in VMAT plans however the difference is not very appreciable. The MU in VMAT plans is almost 50% that of the IMRT plans which results in the reduction of treatment time. On the whole VMAT proves to be a better modality for treating Ca. Left Breast Patients. PMID- 25743845 TI - H2O2 inhibits proliferation and mediates suppression of migration via DLC1/RhoA signaling in cancer cells. AB - BACKGROUND: RhoGTPase-activating proteins (RhoGAPs) regulate RhoGTPases in cells, but whether individual reactive oxygen species (ROS) regulate RhoGAPs is unknown. Our previous published papers have shown that deleted in liver cancer 1 (DLC1) inhibits cancer cell migration by its RhoGAP activity. The present study was designed to explore the role of H2O2 in regulation of DLC1. MATERIALS AND METHODS: We treated cells with H2O2 for 24h and phenotypic changes were analyzed by MTT, RT-PCR, Western blotting, immunofluorescence staining and wound healing assays. RESULTS: H2O2 downregulated cyclin D1 and cyclin E to inhibit proliferation, and upregulated BAX to induce apoptosis in MCF-7 cells. Compared with non-tumorigenic cells, H2O2 increased expression of DLC1 and reduced activity of RhoA in cancer cells. Stress fiber production and migration were also suppressed by H2O2 in MDA-MB-231 cells. CONCLUSIONS: Our study suggests that H2O2 inhibits proliferation through modulation of cell cycle and apoptosis-related genes, and inhibits migration by decreasing stress fibers via DLC1/RhoA signaling. PMID- 25743846 TI - Patients with HER2-positive early breast cancer receiving adjuvant trastuzumab: clinicopathological features, efficacy, and factors affecting survival. AB - BACKGROUND: The aim of the present study was to evaluate clinicopathological characteristics of our early stage breast cancer patients who are epidermal growth factor receptor 2 (HER2) overexpressed/ amplified (HER2+), the efficacy of trastuzumab treatment and survival results. MATERIALS AND METHODS: Patients with HER2- positive early stage breast cancer receiving adjuvant trastuzumab were investigated retrospectively. Clinicopathological features of 210 patients and treatment outcome were analysed. To evaluate survival rates, the Kaplan-Meier method was used. Univariate and multivariate analyses were conducted with the Cox regression model. RESULTS: Mean age of the patients was 51.8, 71.9% being postmenopausal. Some 37.6% of patients were node negative, and 31% had T1 tumor size and 52.4% were positive for estrogen receptor. Of 210 patients, 89.5% completed planned 52 weeks adjuvant trastuzumab treatment. The median follow up was 27.5 months (6.0-86.0 ). Relapse free survival (RFS) was 68.0 months (95% CI: 62.1-74.0) and overall survival (OS) was 74.8 months (95% CI: 69.5-80.1). The 3 year OS for all patients was 92.0% and RFS was 79.6%. During follow up, relapse was detected at the rate of 14.3%. Trastuzumab associated cardiotoxicity was found at the rate of 3.3%. In univariate analyses, larger tumor size and grade III were significantly associated (p<0.05) with RFS. Multivariate analyses of covariates displaying p<0.05 identified grade III as an independent prognostic factor. CONCLUSIONS: In the present study, it was established that trastuzumab had a satisfactory safety profile and treatment efficacy as in other clinical studies and that among clinicopathological factors evaluated, only being grade 3 had a significant effect on RFS. The occurrence of relapse with adjuvant trastuzumab makes it necessary to identify molecular predictors, which will define this group better and help explain resistance to anti HER2 based therapies. PMID- 25743847 TI - Increased UGT1A3 and UGT1A7 expression is associated with pancreatic cancer. AB - UGT1A play important roles in the glucuronidation of a variety of endogenous and exogenous compounds. UGT1A isoforms are expressed tissue specifically. The aim of this study was to examine the relationship between UGT1A3 and UGT1A7 mRNA expression and pancreatic cancer. Paired healthy and tumor tissue samples of 43 patients with pancreatic cancer were included in this study. UGT1A3 and UGT1A7 mRNA expressions were analyzed by real time-PCR. In the result of study, UGT1A3 and UGT1A7 mRNA expressions were significantly higher in tumor tissue than normal tissue of pancreatic cancer patients (p<0.05). In addition, high mRNA expression of UGT1A3 and UGT1A7 was significantly associated with larger tumor size (p<0.05). The data suggested that UGT1A3 and UGT1A7 may play roles in the progression of pancreatic cancer. Consequently, UGT1A3 and UGT1A7 are potential prognostic indicators. PMID- 25743848 TI - Plasma nuclear factor kappa B and serum peroxiredoxin 3 in early diagnosis of hepatocellular carcinoma. AB - BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) is the most important step in successful treatment. However, it is usually rare due to the lack of a highly sensitive specific biomarker so that the HCC is usually fatal within few months after diagnosis. The aim of this work was to study the role of plasma nuclear factor kappa B (NF-?B) and serum peroxiredoxin 3 (PRDX3) as diagnostic biomarkers for early detection of HCC in a high-risk population. MATERIALS AND METHODS: Plasma nuclear factor kappa B level (NF-?B) and serum peroxiredoxin 3 (PRDX3) levels were measured using enzyme linked immunosorbent assay (ELISA), in addition to alpha-fetoprotein (AFP) in 72 cirrhotic patients, 64 patients with HCC and 29 healthy controls. RESULTS: NF-?B and PRDX3 were significantly elevated in the HCC group in relation to the others. Higher area under curve (AUC) of 0.854 (for PRDX3) and 0.825 (for NF-?B) with sensitivity of 86.3% and 84.4% and specificity of 75.8% and 75.4% respectively, were found compared to AUC of alpha-fetoprotein (AFP) (0.65) with sensitivity of 72.4% and specificity of 64.3%. CONCLUSIONS: NF-?B and PRDX3 may serve as early and sensitive biomarkers for early detection of HCC facilitating improved management. The role of nuclear factor kappa B (NF-?B) as a target for treatment of liver fibrosis and HCC must be widely evaluated. PMID- 25743849 TI - TRAIL and Bortezomib: killing cancer with two stones. AB - Cancer genomics and proteomics have undergone considerable broadening in the past decades and increasingly it is being realized that solid/liquid phase microarrays and high-throughput resequencing have provided platforms to improve our existing knowledge of determinants of cancer development, progression and survival. Loss of apoptosis is a widely and deeply studied process and different approaches are being used to restore apoptosis in resistant cancer phenotype. Modulating the balance between pro-apoptotic and anti-apoptotic proteins is essential to induce apoptosis. It is becoming more understood that pharmacological inhibition of the proteasome might prove to be an effective option in improving TRAIL induced apoptosis in cancer cells. Keeping in view rapidly accumulating evidence of carcinogenesis, metastasis, resistance against wide ranging therapeutics and loss of apoptosis, better knowledge regarding tumor suppressors, oncogenes, pro apoptotic and anti-apotptic proteins will be helpful in translating the findings from benchtop to bedside. PMID- 25743850 TI - Morinda citrifolia plays a central role in the primary prevention of mitochondrial-dependent degenerative disorders. PMID- 25743851 TI - Visually induced initiation of Drosophila innate courtship-like following pursuit is mediated by central excitatory state. AB - The courtship ritual of male Drosophila represents an innate behaviour that is initiated by female-derived sensory stimuli. Here we report that moving light spots can induce courtship-like following pursuit in tethered wild-type male flies provided the fly is primed by optogenetic stimulation of specific dsx expressing neuronal clusters in the lateral protocerebrum (LPR). Namely, stimulation of the pC1 neuronal cluster initiates unilateral wing extension and vibration of both sides, whereas stimulation of the pC2l cluster initiates only contralateral wing displays. In addition, stimulation of pC2l but not pC1 neurons induced abdominal bending and proboscis extension. Ca(2+) imaging of the pC1 cluster revealed periodic Ca(2+) rises, each corresponding to a turn of the male fly during courtship. In contrast, group-reared fru mutant males exhibit light spot-induced courtship pursuit without optogenetic priming. Ca(2+) imaging revealed enhanced responses of LPR neurons to visual stimuli in the mutants, suggesting a neural correlate of the light spot-induced courtship behaviour. PMID- 25743852 TI - CD107a as a marker of activation in chicken cytotoxic T cells. AB - The study aimed to evaluate cell surface mobilisation of CD107a as a general activation marker on chicken cytotoxic T cells (CTL). Experiments comprised establishment of an in vitro model for activation-induced CD107a mobilisation and design of a marker panel for the detection of CD107a mobilisation on chicken CTL isolated from different tissues. Moreover, CD107a mobilisation was analysed on CTL isolated from airways of infectious bronchitis virus (IBV)-infected birds direct ex vivo and upon in vitro stimulation. Results showed that phorbol 12 myristate 13-acetate (PMA) in combination with ionomycin was a consistent inducer of CD107a cell surface mobilisation on chicken CTL in a 4h cell culture model. In chickens experimentally infected with IBV, higher frequencies of CTL isolated from respiratory tissues were positive for CD107a on the cell surface compared to those from uninfected control chickens indicating in vivo activation. Moreover, upon in vitro PMA+ ionomycin stimulation, higher proportions of CTL isolated from the airways of IBV-infected chickens showed CD107a mobilisation compared to those from uninfected control chickens. Monitoring of CD107a cell surface mobilisation may thus be a useful tool for studies of chicken CTL cytolytic potential both in vivo and in vitro. PMID- 25743853 TI - Biomass and lipid accumulation of three new screened microalgae with high concentration of carbon dioxide and nitric oxide. AB - Three species of indigenous microalgae species were isolated from an artificial lake. They were identified as Scenedesmus sp., through the molecular phylogenetic and morphological method and named SDEC-12, SDEC-13 and SDEC-14. To evaluate their tolerance to the harmful composition in the exhaust gas and the potential to produce biodiesel, they were cultured with 15% CO2 and 200 ppm NO. The SDEC-13 and SDEC-14 strains were able to grow well under 15% CO2 with the maximum biomass productivity of 0.087 and 0.090 g L(-1) d(-1), respectively. When cultured with 15% CO2, the three strains showed a similar total lipid content (25.7-28.25%) and the fatty acid of SDEC-14 strain showed the highest saturated level (76.59%). SDEC-13 was the only strain that could tolerate 200 ppm NO and 15% CO2, while its total lipid content remained unaffected by the NO, so the SDEC-13 strain had the potential to produce biodiesel with flue gas. PMID- 25743854 TI - Harness technology to produce real change. PMID- 25743856 TI - Prosthodontic rehabilitation of a patient with aggressive periodontitis. AB - Aggressive periodontitis previously termed as juvenile periodontitis is characterised by rapid destruction of the periodontium at a relatively young age. Rehabilitation of these patients is often challenging and difficult. Controlling the disease and restoring periodontal health is essential for successful prosthodontic rehabilitation. This clinical report describes an interdisciplinary approach in the rehabilitation of a young adult patient with generalised aggressive periodontitis. Treatment objectives included plaque control, prevention of further attachment loss, reduction/elimination of pockets, and prosthetic rehabilitation to enhance aesthetics and restore masticatory function. One year recall evaluation revealed stable periodontal support with no further loss of attachment and no other complications. PMID- 25743855 TI - Aprepitant versus metoclopramide, both combined with dexamethasone, for the prevention of cisplatin-induced delayed emesis: a randomized, double-blind study. AB - BACKGROUND: A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. PATIENTS AND METHODS: A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. RESULTS: Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments. CONCLUSIONS: In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity. CLINICALTRIALSGOV NUMBER: NCT00869310. PMID- 25743858 TI - A ruthless sarcoma of the foot. PMID- 25743857 TI - 'Triplication' defect in deciduous teeth: an unusual odontogenic anomaly. AB - Developmental odontogenic anomalies can occur in primary as well as in permanent dentition leading to morphological variations in shape, size and structure and numerical variations such as hypodontia. The most commonly reported odontogenic anomaly in primary dentition is conjoined teeth. Conjoined teeth can be due to fusion or gemination. Relevant clinical and radiographic evaluation is a must to differentiate between the two. Occurrence of double fusion as an anomaly may not be infrequent, but triple fusion is a rare odontogenic anomaly. We report a case of a 7.5-year-old girl who clinically had a large crown due to triple fusion in her dentition, between two normal primary teeth and a supernumerary tooth. This paper gives a brief insight into the incidence, associated quandaries and diagnosis and treatment modalities of a triple fusion. PMID- 25743859 TI - Chronic pancreatitis presenting as superior mesenteric artery syndrome. PMID- 25743860 TI - Difficulty with cuff deflation of reinforced tracheal tube caused by inflation line occlusion with silk thread ligation and fixation. AB - A reinforced tracheal tube, ligated with silk threads, was inserted into a tracheostomy orifice and fixed to the skin. The cuff inflation line of the reinforced tracheal tube became occluded. Reinforced 'armoured' tracheal tubes have a spiral of wire embedded into the wall of the tube to give strength and flexibility, and may be sharply bent without compromising the tube lumen. The tracheal cuff attached to the tube is inflated by injecting air through a narrow diameter tube welded to the outside of the tracheal tube. When a reinforced tracheal tube is ligated and fixed with silk threads, it should be confirmed whether the tracheal tube cuff can be deflated and inflated after fixation. Moreover, because occlusion can be eliminated by removing all silk threads used to ligate a tracheal tube, they should be removed before extubation. PMID- 25743861 TI - Patellar ligament rupture in an adolescent. AB - Rupture of the patellar tendon is a well-known injury in the orthopaedic literature. However, it is unusual and rarely reported in adolescent children. On the one hand, in the immature skeleton, the most frequent lesion above the kneecap is the sleeve fracture. On the other hand, in the distal region, avulsion of the tibial tuberosity is more common. Patellar tendon rupture in an adolescent is a rare lesion. We report a case in which an adolescent sustained a fall when jumping. No predisposing factors have been found. The injury was treated with surgical repair with transosseous suturing and reinforcement with semitendinosus tendon. The aim of this study is to present a case of traumatic rupture of the extensor mechanism of the knee in an adolescent and the therapy used. PMID- 25743862 TI - Infantile osteopetrosis associated with osteomyelitis. AB - Osteopetrosis is a rare inherited disorder characterised by the inability to reabsorb and remodel bone due to an osteoclast dysfunction. An increase in bone mass and density results in severe skeletal malformation and bone marrow failure, which may be fatal. The aim of this study was to report a case of infantile osteopetrosis in a 6-year-old boy, who primarily complained of dental problems. The patient developed an osteomyelitis after a primary tooth extraction. We also reviewed the literature about this genetic bone disease, since the management of dental problems of these patients can be a challenge to the dentist. The diagnosis, clinical and radiographic features and treatment of the case were discussed in this work. PMID- 25743863 TI - Major ischaemic stroke caused by an air embolism from a ruptured giant pulmonary bulla. AB - We report an extremely rare complication of a major ischaemic cerebral event caused by an air embolism due to spontaneous rupture of a giant pulmonary bulla that occurred during an airline flight. Shortly after take-off, the patient experienced sudden right-sided hemiplegia and dyspnoea. Following an emergency landing in Reykjavik, a CT scan of the brain showed minute air bubbles consistent with air emboli within the left-sided intracerebral arteries, and MRI showed signs of acute ischaemic cerebral infarction in the left hemisphere. The patient later underwent a pulmonary lobectomy and survived this life-threatening complication with relatively mild neurological sequelae. PMID- 25743864 TI - Neuropsychiatric systemic lupus erythematosus: a diagnostic challenge. AB - A 58-year-old woman presented to neuropsychiatric services with increased frequency of confusional episodes and intermittent psychotic symptoms. She had a 19-year history of atypical epileptic seizures and cognitive decline. Detailed review of history and clinical investigations revealed that she had accumulated sufficient features to meet diagnostic criteria for systemic lupus erythematosus (SLE). She had previously had lymphopenia and a malar rash; she had positive antinuclear, anti-Ro (anti-Sjogren's-syndrome-related antigen A) and anti-SM (anti-Smith Antibody) antibodies, and elevated erythrocyte sedimentation rate. The seizures, cognitive impairment and psychosis were attributable to neuropsychiatric SLE. Treatment with immune-modulating therapy, cyclophosphamide, resulted in significant improvement in subjective and objective clinical presentation. Neuropsychiatric SLE should be considered a potential differential diagnosis for patients presenting with seizures, psychotic symptoms or cognitive decline. A detailed clinical evaluation with review of the medical history and appropriate laboratory analyses allows this diagnosis to be made, and appropriate treatment to be initiated. PMID- 25743865 TI - Traumatically shattered kidney without urine extravasation or vascular amputation. AB - The American Association for the Surgery of Trauma (AAST) injury scoring scale is commonly used for genitourinary injuries. Normally, grade 4-5 lacerations of the kidney show involvement of the pelvicalyceal system (PCS) with urine extravasation (UE). We present a case of a 41-year-old woman who was hospitalised with macrohaematuria and retroperitoneal haematoma after severe blunt acceleration flank trauma. CT scan showed an extended laceration of the left kidney with separation of upper pole. This is the first case of an extended kidney laceration without UE due to rupture within the dichotomous PCS, which healed up after selective embolisation. If possible, severe renal bleeding should be treated with selective embolisation as an alternative to surgery. Any suspected involvement of the PCS should undergo retrograde ureteropyelography and urinary diversion. PMID- 25743866 TI - Dislocated trial femoral head during total hip arthroplasty: review of the literature and the new algorithm for treatment. AB - Dislocation of the trial femoral head is a rare and unpleasant event that can compromise the success of the total hip arthroplasty. A 62-year-old Caucasian woman with osteoarthritis was admitted to our Department and underwent an elective total hip arthroplasty. While performing the dislocation manoeuver the trial femoral head dissociated from the taper in the superior and anterior direction in the soft tissue and could not be retrieved immediately. The operation was then executed and finished in an ordinary manner. Three months after discharge from our department patient presented with the pain in the hip and groin and periprosthetic joint infection was diagnosed. The successful second operation for the retrieval of the dislocated trial femoral head was conducted through ilioinguinal approach. In this paper we reviewed the published literature and developed the algorithm for the decision-making while dealing with the dislocated and lost trial femoral head. PMID- 25743867 TI - Takotsubo cardiomyopathy case series: typical, atypical and recurrence. AB - Takotsubo cardiomyopathy (TCM) is characterised by a transient left ventricular (LV) dysfunction, ECG changes that can imitate acute myocardial infarction and positive cardiac biomarkers in the absence of obstructive coronary artery disease. The exact pathogenesis of TCM is unclear but emotional or physical stress is a common denominator. We present three cases encompassing a spectrum of the disease: A typical TCM with apical LV dyskinesis, an atypical TCM with mid ventricular regions affected and a TCM recurrence. Our cases show that TCM symptoms vary between individuals and may vary in the same patient. All our patients reported acute emotional stress prior to the onset of symptoms, had LV systolic dysfunction, positive cardiac biomarkers and non-obstructed coronary arteries. In all cases, LV systolic dysfunction eventually improved. TCM may account for 0.7-2.5% of acute coronary syndromes. It is more prevalent in the female population and can reoccur. Treatment is mainly supportive. PMID- 25743869 TI - Tourniquet-associated povidone-iodine-induced chemical burns. PMID- 25743868 TI - Implantable collamer lens in a case of corneal scar with anisometropic amblyopia in an adult: an expanded indication. AB - A 35-year-old man, a unilateral high myope with corneal scarring, presented for evaluation. He had a stromal scar that started temporally, traversed along the pupillary zone partially and extended across the horizontal diameter of the cornea. The Descemet's membrane appeared intact even though the scar was extending into deep stroma towards the nasal end, as seen in the optical coherence tomography image. The patient had an uncorrected distance visual acuity (UDVA) of 4/60 OD, which improved with a refraction of -9.0 DS/-1.50 DC at 15 to 6/18p and 6/6p OS. He underwent an uneventful toric implantable collamer lens (ICL) implantation of -15.0 D/-2.0 D at 102 after preoperative yttrium-aluminium garnet (YAG) laser iridotomy in the right eye. The postoperative UDVA and corrected distance visual acuity for the right eye were 6/12 and 6/9p (with a refraction of +0.50 D/-0.50 D at 85), respectively. The corneal scar and topography were stable. This case reports an expanded indication for toric ICL in cases with corneal scar/opacity but good spectacle corrected visual acuity. PMID- 25743870 TI - Atrial enlargement associated with non-valvular atrial fibrillation: an unusual cause of dysphagia and weight loss. PMID- 25743871 TI - Pseudomyxoma peritonei: a rare tumour mimicking primary ovarian neoplasia. PMID- 25743872 TI - Healing the orphaned heart: heart failure in a patient with glucose-6-phosphate dehydrogenase deficiency. AB - Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are not represented in clinical trials for heart failure. Moreover, many of the recommended medications can cause haemolysis in this group of patients. We present the case of a 71-year-old woman with G6PD deficiency admitted for acute non-ischemic heart failure with reduced ejection fraction. Our experience showed that a combination of ethacrynic acid and spironolactone is safe and effective for relief of volume overload in this group of patients. Studies are needed to determine whether the morbidity and mortality benefits of established heart failure regimens extend to patients with G6PD deficiency. PMID- 25743873 TI - Polyarteritis nodosa: an atypical presentation. PMID- 25743874 TI - Changes in alcohol drinking and subsequent sickness absence. AB - AIMS: The aim was to examine whether changes in alcohol drinking are associated with sickness absence. METHODS: Repeated postal questionnaires on alcohol drinking were conducted among employees of the City of Helsinki in 2000-2 and 2007 to assess changes in drinking habits between these two time points. Data on the number of self-certified and medically confirmed sickness absences were derived from the employer's register. Sickness absences were followed from 2007 until the end of 2010 among employees participating in both questionnaire surveys. The study includes 3252 female and 682 male employees 40-60 years old at baseline. Poisson regression was used in the data analysis and population attributable fractions (PAFs) were calculated. RESULTS: Alcohol drinking was associated especially with self-certified sickness absence. Rate ratios (RRs) and 95% confidence intervals (CIs) for increasing weekly average drinking were 1.38, 1.18-1.62 among women and 1.58, 1.18-2.12 among men. Also stable problem drinking (for women 1.39, 1.26-1.54, for men 1.44, 1.10-1.87) and among women stable heavy drinking (1.53, 1.20-1.94) increased self-certified sickness absence. There were associations between alcohol drinking and medically confirmed sickness absence but these were mainly explained by health and health behaviours. Also, a decrease in weekly average drinking was associated with sickness absence among women whereas among men former problem drinking increased sickness absence. According to the PAF values, problem drinking had a stronger contribution to sickness absence than weekly average drinking. CONCLUSIONS: Alcohol drinking is particularly associated with self-certified sickness absence. Reducing adverse drinking habits is likely to prevent sickness absence. PMID- 25743875 TI - Abstinence and current or former alcohol use as predictors of disability retirement in Finland. AB - AIM: According to previous studies, abstinence from alcohol increases the risk of disability retirement (DR). We studied whether former alcohol users' poor mental or physical health might have contributed to this result. METHODS: Prospective population-based study of 3621 occupationally active Finns aged 30-55 years at baseline. Disability pension data for 2000-2011 was retrieved from national pension records. We examined medically certified disability retirement due to all causes and due to mental disorders among lifelong abstainers, former drinkers, those with an alcohol use disorder irrespective of consumption and current users, further classified according to weekly intake of alcohol. Chronic somatic diseases were evaluated in a clinical examination and common mental and alcohol use disorders using the Composite International Diagnostic Interview. Cox regression was used. RESULTS: Neither lifelong abstinence nor alcohol consumption, even at hazardous levels, without alcohol use disorder was associated with disability retirement. Compared with light drinkers, former drinkers' hazard ratio for DR due to mental disorders was 2.67 (95% CI 1.39 5.13), allowing for somatic and mental morbidity, physical and psychosocial workload, health behaviour and socio-demographic factors. The respective hazard ratio of DR due to all causes for those with alcohol use disorder was 2.17 (1.49 3.16) and of DR due to mental disorders 4.04 (2.02 to 8.06). CONCLUSIONS: Lifelong abstinence did not predict disability retirement. Former drinkers and people with alcohol use disorders were at a multi-fold risk of work disability due to mental disorders compared with light drinkers, thus it is important to support their work ability. PMID- 25743876 TI - Designing for health in school buildings: between research and practice. AB - AIM: To investigate the kinds of knowledge practitioners use when planning and designing for health in school buildings. METHODS: Twelve semi-structured qualitative interviews were conducted with architects, teachers and officials to investigate use of knowledge in the making of school buildings. RESULTS: Practitioners drew on many kinds and sources of knowledge, but in particular they made use of concepts, examples or pictures or thought-provoking knowledge. However, the interviews indicate a number of hurdles for efficient knowledge sharing between research and practice: (1) a considerable discrepancy between kinds of knowledge used by practice and knowledge traditionally produced by research; (2) research-knowledge and practice-knowledge form two circuits and the flow from one circuit to the other is weak; (3) practitioners' knowledge was often based on experience and therefore person-dependent. It makes the knowledge vulnerable. CONCLUSIONS: Special attention has to be paid by research to concepts and principles to guide the decision-making in practice. Further is recommended to consider new kinds of collaboration between researchers and practitioners. PMID- 25743877 TI - Mothers' and their daughters' use of preventive measures against cervical cancer. AB - AIMS: Vaccination against human papillomavirus (HPV) and screening are complementary preventive measures against cervical cancer. In Denmark, screening and vaccination are free of charge for the women. In total, 75% of women are screened and about 90% of girls are vaccinated with at least one dose. Our aim was to determine whether, in Denmark, daughters of unscreened mothers are less likely to be vaccinated against HPV than are daughters of screened mothers. METHODS: We used population-based data from the Danish Patient Register, Health Service Registration, Pathology Data Bank, and Civil Registration System. Individual-level data on screening, vaccination, and vital status until 31 December 2010 were retrieved. Daughters were linked to their mothers through the link provided in the Civil Registration System. The study population included 149,147 girls born in 1993-1997 and their mothers. We calculated birth cohort specific relative risks (RRs) of non-initiation of HPV vaccination in daughters depending on their mothers' screening status. RESULTS: In total, 8% of girls did not receive any vaccination, and 35% of their mothers were unscreened. Among the 92% of girls receiving at least one vaccine dose, 14% of mothers were unscreened. The birth cohort-specific RRs of non-initiation of vaccination given an unscreened mother varied between 2.16 (95% CI: 2.00-2.33) and 2.83 (95% CI: 2.63 3.05). CONCLUSIONS: The observed association between screening and vaccination suggest that it will be difficult to increase the vaccination coverage by, for example, counselling at the mother's cervical screening appointment. Other measures to increase the coverage with vaccination will be important. PMID- 25743878 TI - Associations across spatial patterns of disease incidences, socio-demographics, and land use in Finland 1991-2010. AB - AIMS: The epidemiological aim was to draw a general picture of spatial patterns of diseases, socio-demographics, and land use in Finland to detect possible under recognized associations between the patterns. The methodological purpose was to compare and combine two statistical techniques to approach the data from different viewpoints. METHODS: Two different statistical methods, the self organizing map and principal coordinates of neighbor matrices with variation partitioning, were used to search for spatial patterns of 15 non-infectious diseases and 17 direct or indirect risk factors. The dataset was gathered from five Finnish registries and pooled over the years 1991-2010. The statistical unit in the analyses was a municipality (n=303). RESULTS: Variables referring to urban living were related to low incidences of all other diseases but cancer, whereas variables referring to rural living were related to low incidences of cancer and high incidences of other diseases, especially coronary heart disease (CHD), hypertension, diabetes, asthma/chronic obstructive pulmonary disease, and serious mental illnesses at the municipal level. The relationships between diseases other than cancer and risk factors related to socio-demographics and land use variables were stronger than those between cancer and risk factors. CONCLUSIONS: The structuration of spatial patterns was dominated by CHD together with land use features and unemployment rate. The relationship between unemployment and spatial health inequalities was emphasized. On the basis of the present study, it is suggested that large heterogeneous datasets are clustered and analyzed simultaneously with more than one statistical method to recognize the most significant and generalizable results. PMID- 25743879 TI - Review of the state-of-the-art of exhaust particulate filter technology in internal combustion engines. AB - The increasingly stringent emission regulations, such as US 2010, Tier 2 Bin 5 and beyond, off-road Tier 4 final, and Euro V/5 for particulate matter (PM) reduction applications, will mandate the use of the diesel particulate filters (DPFs) technology, which is proven to be the only way that can effectively control the particulate emissions. This paper covers a comprehensive overview of the state-of-the-art DPF technologies, including the advanced filter substrate materials, the novel catalyst formulations, the highly sophisticated regeneration control strategies, the DPF uncontrolled regenerations and their control methodologies, the DPF soot loading prediction, and the soot sensor for the PM on board diagnostics (OBD) legislations. Furthermore, the progress of the highly optimized hybrid approaches, which involves the integration of diesel oxidation catalyst (DOC) + (DPF, NOx reduction catalyst), the selective catalytic reduction (SCR) catalyst coated on DPF, as well as DPF in the high-pressure exhaust gas recirculation (EGR) loop systems, is well discussed. Besides, the impacts of the quality of fuel and lubricant on the DPF performance and the maintenance and retrofit of DPF are fully elaborated. Meanwhile, the high efficiency gasoline particulate filter (GPF) technology is being required to effectively reduce the PM and particulate number (PN) emissions from the gasoline direct injection (GDI) engines to comply with the future increasingly stricter emissions regulations. PMID- 25743880 TI - Paper and flexible substrates as materials for biosensing platforms to detect multiple biotargets. AB - The need for sensitive, robust, portable, and inexpensive biosensing platforms is of significant interest in clinical applications for disease diagnosis and treatment monitoring at the point-of-care (POC) settings. Rapid, accurate POC diagnostic assays play a crucial role in developing countries, where there are limited laboratory infrastructure, trained personnel, and financial support. However, current diagnostic assays commonly require long assay time, sophisticated infrastructure and expensive reagents that are not compatible with resource-constrained settings. Although paper and flexible material-based platform technologies provide alternative approaches to develop POC diagnostic assays for broad applications in medicine, they have technical challenges integrating to different detection modalities. Here, we address the limited capability of current paper and flexible material-based platforms by integrating cellulose paper and flexible polyester films as diagnostic biosensing materials with various detection modalities through the development and validation of new widely applicable electrical and optical sensing mechanisms using antibodies and peptides. By incorporating these different detection modalities, we present selective and accurate capture and detection of multiple biotargets including viruses (Human Immunodeficiency Virus-1), bacteria (Escherichia coli and Staphylococcus aureus), and cells (CD4(+) T lymphocytes) from fingerprick volume equivalent of multiple biological specimens such as whole blood, plasma, and peritoneal dialysis effluent with clinically relevant detection and sensitivity. PMID- 25743881 TI - Results of a feasibility study: barriers and facilitators in implementing the Sherbrooke model in France. AB - OBJECTIVES: Return-to-work interventions associated with the workplace environment are often more effective than conventional care. The Sherbrooke model is an integrated intervention that has proved successful in preventing work disability due to low-back pain. Implementation, however, runs up against many obstacles, and failure has been reported in many countries. The present study sought to identify barriers to and facilitators of the implementation of the Sherbrooke model within the French health system. METHODS: A multiple case study with nested levels of analysis was performed in two regions of France. A conceptual framework was designed and refined to identify barriers and facilitators at the individual, organizational and contextual levels. Qualitative data were collected via semi-structured interview (N=22), focus groups (N=7), and observation and from the gray literature. Participants (N=61) belonged to three fields: healthcare, social insurance, and the workplace. RESULTS: Numerous barriers and facilitators were identified in each field and at each level, some specific and others common to workers in all fields. Individual and organizational barriers comprised lack of time and resources, discordant professional values, and perceived risk. Legal barriers comprised medical confidentiality, legal complexity, and priority given to primary prevention. Individual-level facilitators comprised needs and perceived benefits. Some organizations had concordant values and practices. Legal facilitators comprised possibilities of collaboration and gradual return to work. CONCLUSION: The present feasibility analysis of implementing the Sherbrooke model revealed numerous barriers and facilitators suggesting a new implementation strategy be drawn up if failure is to be avoided. PMID- 25743882 TI - Reduction in the soles of graduated compression stockings prevents falls without reducing the preventive effect for venous stasis. AB - INTRODUCTION: Graduated compression stockings (GCS) are widely used to prevent venous thromboembolism; however, GCS are slippery and a fall hazard owing to the synthetic fibers. Therefore, we investigated whether changing the sole's shape decreased slipping. MATERIALS AND METHODS: We designed four GCS types with varying sole shapes and normal slipperiness to compare with normal GCS and a barefoot model without GCS (control). A mannequin foot with a GCS type or the control was placed on a ramp at 0 degrees , and the angle was slowly increased. When the mannequin foot had moved >=100% from the original position, the angle of slide-out (AS) was measured, and the forward and backward AS values were compared. Next, we investigated whether sole modification influenced the effectiveness of the normal GCS for preventing venous stasis. The same GCS type (Torenka) was given to 30 healthy volunteers. Peak systolic velocities (PSV) of the popliteal vein prior to wearing GCS and 20 and 40min after wearing GCS were measured using Doppler ultrasound, and the changes were compared with those of the normal GCS. RESULTS: Only the AS of the GCS type with the smallest sole area (Torenka) was not significantly different from the control's AS, which was significantly larger than the normal GCS' AS. Normal and Torenka GCS resulted in significantly increased PSV after 20 and 40min compared with no GCS, with no significant difference between the two groups. CONCLUSION: Torenka-type GCS were the least slippery but were as effective as normal GCS for venous stasis. PMID- 25743883 TI - Prediction of thrombotic and hemorrhagic events during polycythemia vera or essential thrombocythemia based on leukocyte burden. AB - BACKGROUND: Evidences suggest an association between leukocytosis and thrombotic or hemorrhagic complication in polycythemia vera (PV) and essential thrombocythemia (ET), but clinical implication is not well known. OBJECTIVE: To evaluate whether leukocyte burden during follow-up is related to thrombotic or hemorrhagic events in PV and ET. PATIENTS/METHODS: We retrospectively analyzed patients with PV or ET treated at Seoul National University Bundang Hospital, Korea. Time-weighted averages of leukocytes during the follow-up period were defined as leukocyte burden and were calculated for each patient and compared between patient subgroups. In each patient with events, leukocyte burden for the 3-month period before the event was compared with that for the entire follow-up period. RESULTS: In 102 patients with PV or ET, 35 events (16 thrombotic, 19 hemorrhagic) occurred in 29 patients (median follow-up, 54months). Leukocyte burden were significantly higher in patients with events than in event-free patients (12,015*10(3) /MUL vs. 9,567*10(3)/MUL, P=0.003). The difference was more prominent in ET patients than in PV patients, and in patients with hemorrhagic events than in those with thrombotic events. In patients with events, the leukocyte burden in the pre-event period was higher than in the entire follow up period (16,767*10(3)/MUL vs. 12,015*10(3)/MUL, P=0.002). In all patients, leukocyte burden during entire follow-up period of 11,000*10(3)/MUL or higher was an independent risk factor for vascular events. CONCLUSION: In PV or ET patients, leukocyte burden during disease course is related to increased incidence of thrombotic or hemorrhagic events. PMID- 25743884 TI - Cancer-associated thrombosis: investigating the role of new oral anticoagulants. AB - Venous thromboembolism (VTE) is a common complication of cancer and has a significant impact on morbidity and mortality in patients with malignancies. Low molecular weight heparins (LMWHs) currently represent the drug of choice for both initial and long-term treatment of cancer-associated thrombosis. In recent years, however, a new class of novel oral anticoagulants (NOACs) inhibiting directly thrombin or activated factor X have been proposed as an alternative therapeutic option on the basis the results of subgroup analyses of phase III randomized controlled trials, including few cases of patients with cancer. After analysis of the available literature data, we conclude that although potentially interesting, future research specifically conducted in cancer patients is needed to clarify the role of these newer anticoagulant agents in prevention and treatment of cancer-related VTE. PMID- 25743885 TI - Treatment-related frequency of venous thrombosis in lower esophageal, gastro esophageal and gastric cancer--a clinical prospective study of outcome and prognostic factors. AB - INTRODUCTION: Prospective studies of chemotherapy-associated VTE in cancer patients undergoing neoadjuvant chemotherapy in combination with curative intended surgery have not been reported for upper gastrointestinal cancer. In this clinical prospective study, we sought to estimate the incidence of VTE in esophagogastric cancer (OEC) patients scheduled for a specific perioperative chemotherapy regime: oxaliplatin, capecitabine, and epirubicin, (EXE) and curative intended surgery. MATERIAL AND METHODS: A total of 129 consecutive OEC patients were examined using state-of-the-art bilateral compression ultrasound (biCUS) for deep vein thrombosis (DVT) before undergoing preoperative chemotherapy, surgery, and postoperative chemotherapy. In addition 79 were also consecutively scanned at baseline for pulmonary embolism (PE) using state-of-the art computer tomography pulmonary angiography (CTPA). RESULTS: There were 21 VTE cases throughout the course of treatment (16%, 95% confidence interval [95% CI]: 10 - 24%) among the patients examined using both biCUS and CTPA. Fourteen of 21 VTE was incidental (68%, 95% CI: 43 -85) and 7 VTE events was symptomatic (33%, 15 - 57). The median overall survival was 18months (95% CI: 13 - 24) in patients without any VTE and 14months (95% CI: 7 -30, P = 0.820) in patients with VTE. The cancer stage (adjusted odds ratio [OR]: 5.2, 95% CI: 1 - 21, p=0.002) and gastric cancer (OR 6.4, 95% CI: 2 - 21, P = 0.002) was a significant predictor of VTE. CONCLUSION: The incidence of VTE in patients undergoing EXE neoadjuvant chemotherapy was high, particularly among patients with initial stage III and IV cancers. In addition, a substantial number of chemotherapy-related VTE cases were asymptomatic. PMID- 25743886 TI - Identification of anti-moesin antibodies in the serums of patients with antiphospholipid syndrome. AB - INTRODUCTION: The antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by recurrent vascular thrombosis and obstetric complications. However, the precise mechanisms by which the autoantibodies mediate disease remain to be elucidated. Moesin is an intracellular protein that links the cell membrane and cytoskeleton, mediating the formation of microtubules and cell adhesion sites as well as ruffling of the cell membrane, which is crucial for platelet activation. MATERIALS AND METHODS: We screened the serums from patients with APS for the presence of anti-moesin antibodies (anti-moesin Abs) recognizing antigens derived from prokaryotic expression system, and investigated the effect of murine monoclonal anti-moesin Abs (anti-moesin mAbs) on platelet activation and aggregation by flow cytometry and platelet aggregation assay in vitro to study their potential pathogenic role in APS. RESULTS: The presence of anti-amino (N)-terminal portion of moesin antibodies (anti-moesin-N Abs) was observed in 73% (73/100) patients with APS, which was significantly higher than anti-cardiolipin antibodies (aCL, 49%) and anti-beta2 glycoprotein I antibodies (anti-beta2GPI, 43%). Moreover, the elevated anti-moesin-N Abs levels significantly correlated with plasma levels of anti-beta2GPI (rs=0.474, P<0.001) rather than aCL (P=0.203). The murine anti-moesin mAbs promote platelet activation and aggregation in vitro, which could be effectively neutralized by moesin-N. CONCLUSIONS: In combination of the detection of aCL and anti-beta2GPI, screening for the presence of anti-moesin-N Abs might has its value in facilitating the laboratory diagnosis of APS. The pathogenic role of anti-moesin N Abs in the serums of APS patients needs to be further studied. PMID- 25743888 TI - Efficient asymmetric transfer hydrogenation of ketones in ethanol with chiral iridium complexes of spiroPAP ligands as catalysts. AB - Highly efficient iridium catalyzed asymmetric transfer hydrogenation of simple ketones with ethanol as a hydrogen donor has been developed. By using chiral spiro iridium catalysts (S)- a series of alkyl aryl ketones were hydrogenated to chiral alcohols with up to 98% ee. PMID- 25743887 TI - Does the Russell Viper Venom time test provide a rapid estimation of the intensity of oral anticoagulation? A cohort study. AB - BACKGROUND: Dilute Russell Viper Venom Time (DRVV-T) might be useful in urgent settings for screening patients on Non-VKA Oral Anticoagulants (NOACs). AIM: To compare the accuracy of DRVV-T with gold standard assays for the assessment of pharmacodynamics of dabigatran, rivaroxaban and vitamin K antagonist (VKA) in plasma samples from patients. METHODS: Sixty rivaroxaban, 48 dabigatran and 50 VKA samples from patients were included. DRVV-T was performed in all groups using STA(r)-Staclot(r)DRVV-Screen and -Confirm. For NOACs, PT and aPTT were performed using different reagents while plasma drug concentrations were measured by liquid mass-spectrometry (LC-MS/MS). For VKA, INR was performed using RecombiPlasTin 2G(r). RESULTS: For NOACs, correlations between calibrated STA(r)-Staclot(r)DRVV Confirm and LC-MS/MS (rs=0.88 and 0.97 for rivaroxaban and dabigatran, respectively) were higher than the ones obtained with STA(r)-Staclot(r)DRVV Screen (rs=0.87 and 0.91), PT (rs=0.83 to 0.86) or aPTT (rs=0.84 to 0.89). Bland Altman analyses showed that calibrated DRVV-T methods tend to overestimate plasma concentrations of NOACs. ROC curves revealed that cut-off to exclude supra therapeutic levels at Ctrough (i.e. 200ng/mL) are different for dabigatran and rivaroxaban. Neither STA(r)-Staclot(r)DRVV-Screen nor -Confirm correlated sufficiently with the intensity of VKA therapy (rs=0.35 and 0.52). CONCLUSIONS: STA(r)-Staclot(r)DRVV-Confirm provides a rapid estimation of the intensity of anticoagulation with rivaroxaban or dabigatran without specific calibrators. At Ctrough, thresholds for rivaroxaban and dabigatran can be used to identify supra therapeutic plasma level. However, this test cannot differentiate the nature of the NOACs. The development of a point-of-care device optimising this method would be of particular interest in emergency situations. PMID- 25743889 TI - Pulmonary embolism and stroke as the initial manifestation of advanced metastatic pancreatic adenocarcinoma. PMID- 25743890 TI - Surface charge effects in protein adsorption on nanodiamonds. AB - Understanding the interaction of proteins with charged diamond nanoparticles is of fundamental importance for diverse biomedical applications. Here we present a thorough study of protein binding, adsorption kinetics and structure on strongly positively (hydrogen-terminated) and negatively (oxygen-terminated) charged nanodiamond particles using a quartz crystal microbalance by dissipation and infrared spectroscopy. By using two model proteins (bovine serum albumin and lysozyme) of different properties (charge, molecular weight and rigidity), the main driving mechanism responsible for the protein binding to the charged nanoparticles was identified. Electrostatic interactions were found to dominate the protein adsorption dynamics, attachment and conformation. We developed a simple electrostatic model that can qualitatively explain the observed adsorption behaviour based on charge-induced pH modifications near the charged nanoparticle surfaces. Under neutral conditions, the local pH around the positively and negatively charged nanodiamonds becomes very high (11-12) and low (1-3) respectively, which has a profound impact on the protein charge, hydration and affinity to the nanodiamonds. Small proteins (lysozyme) were found to form multilayers with significant conformational changes to screen the surface charge, while larger proteins (albumin) formed monolayers with minor conformational changes. The findings of this study provide a step forward toward understanding and eventually predicting nanoparticle interactions with biofluids. PMID- 25743891 TI - [New frontiers of epigenetics researches in pharmaceutical sciences]. PMID- 25743892 TI - [Structure basis of versatile base recognition of MBD4]. AB - DNA methylation is one of the major epigenetic marks in the mammalian genome to define chromatin higher-order structure, and plays essential roles in various developmental processes. In the mammalian genome, DNA methylation mainly occurs at the 5th position of cytosine bases in a palindromic 5'-CG-3'dinucleotide sequence. Methyl CpG binding domain (MBD) proteins recognize symmetrically methylated CpG sites (5mCG/5mCG) through a conserved MBD, and recruit transcriptional repressors or chromatin modifiers. One of the MBD proteins, MBD4, uniquely contains a C-terminal glycosylation domain together with an N-terminal MBD, and functions as a mismatch DNA repair enzyme specific for T/G or U/G mismatch bases generated by spontaneous deamination of 5-methylcytosine. The base excision activity of MBD4 is also implicated in active DNA demethylation initiated by the conversion of 5-methylcytosine to thymine by deaminases. Unlike other MBD proteins, MBD4 recognizes not only 5mCG/5mCG but also T/G mismatched sites generated by spontaneous deamination of 5-methylcytosine (5mCG/TG). In addition, our biochemical data demonstrate that MBD also binds to intermediates in DNA demethylation pathways, such as 5-hydroxymethyl-cytosine (hmC), 5-carboxyl cytosine and 5-hydroxy-uracil. The crystal structures of MBDMBD4 in complex with 5mCG/TG, 5mCG/5mCG or 5mCG/hmCG provide new structural insights into the versatility of base recognition by MBD4. A DNA interface of MBD4 has flexible structural features, in which an extensive hydration water network supports the versatile base specificity of MBD4. The versatile base recognition by MBDMBD4 implies multi-functional roles of MBD4 in the regulation of dynamic DNA methylation patterns. PMID- 25743894 TI - [Development of fluorogenic probes for the detection of histone deacetylase activity]. AB - Fluorescence imaging using synthetic probes is becoming increasingly popular as a chemistry-based technique for the analysis of biomolecules. Real-time visual information on various biological molecules can be obtained by designing probes with high flexibility. The focus of our research is to design fluorogenic probes which are non-fluorescent in their initial intact form, but exhibit enhanced fluorescence intensity upon reactions with target biomolecules. The fluorescence switch of these probes allows the detection of the function and the localization of biomolecules with a high signal-to-noise ratio. Thus far, we have succeeded in designing and synthesizing fluorogenic probes that visualize molecules involved in epigenetics. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression. A significant amount of epigenetic information can be obtained by the detection of enzyme activity. However, the existing methods require complicated multistep procedures. To overcome this limitation, we developed fluorogenic probes for the detection of HDAC activity in a one-step procedure. In this review, the details of the strategy for probe design and the detection method have been described. PMID- 25743893 TI - [A CxxC domain that binds to unmethylated CpG is required for KDM2A to control rDNA transcription]. AB - Dysfunction of ribosome biogenesis is commonly found in cancers. Because the transcription of ribosomal RNA genes (rDNA) is a rate-limiting step in ribosome biogenesis and is elevated in many cancer cells, ribosomal RNA transcription can be a target for cancer therapy. In eukaryotes, ribosomal RNA is transcribed specifically in nucleoli by RNA polymerase I but not by RNA polymerase II. Therefore, ribosomal RNA transcription by RNA polymerase I would have a distinct nature compared to transcription by RNA polymerase II. Genomic DNA with proteins including histones constitutes chromatin. The structure of chromatin has plasticity and is regulated by chemical modifications of chromatin's components. We had reported that histone demethylase KDM2A reduced ribosomal RNA transcription in response to starvation. In this symposium, we reported our recent results showing the mechanism by which KDM2A was recruited to rDNA chromatin. We found that KDM2A bound to a rDNA promoter with unmethylated CpG dinucleotides via KDM2A CxxC-zinc finger motif. This binding was required for KDM2A to demethylate histone in the rDNA promoter and reduce rDNA transcription resulting from starvation. Further, this binding was detected before starvation, independent of the demethylase activity. We also found that the histone demethylation by KDM2A in response to starvation was detected only in the rDNA promoter, but not in a gene promoter transcribed by Pol II, the P2RX4 promoter. These results suggest that it is important to consider genome regions and cell conditions when developing epigenetic drugs. PMID- 25743895 TI - [Recent advances in the functionality of foods: aging and stress]. PMID- 25743896 TI - [An overview of current research of the effect of foods on aging and stress]. AB - The aging process is largely influenced by dietary factors. For example, caloric restriction can slow age-related functional deterioration and the onset or progression of age-related diseases, as well as prolong mean and maximum life span in laboratory animals. However, the dietary factors that affect the aging process comprise not only calories, but also various nutrients, such as proteins, carbohydrates, fats, and vitamins. Phytochemicals, which are found in plants, are non-nutritive, yet many phytochemicals are known to act as antioxidants and prevent diseases associated with free radical production. Furthermore, certain phytochemicals can help prevent or reduce the risk of cancer, inflammation, and cardiovascular disease by alteration of several signal transduction pathways in cells. Therefore, much focus is being placed on the effects of dietary phytochemicals on aging and stress response. This paper reviews recent advances in the study of two major dietary phytochemicals, resveratrol and curcumin, on aging and stress response. PMID- 25743897 TI - [Prevention of senescence and stress by food composition]. AB - The high prevalence of dementia in aged individuals suggests that aging is the most important risk factor and that senescence further enhances dementia. We have searched for dietary factors that prevent brain senescence using a mouse model of age-related neurodegeneration (SAMP10). This mouse line is suitable for studying brain senescence because brain atrophy and cognitive dysfunction are observed with aging, similar to humans. The production of reactive oxygen species and oxidative damage are high in the brains of aged SAMP10. We found that green tea catechin and beta-cryptoxanthin in Japanese mandarin oranges prevented brain atrophy and cognitive dysfunction. In addition, psychosocially chronically stressed mice exhibited a shortened life span and accelerated cognitive dysfunction. These deficiencies were prevented by the ingestion of theanine, an amino acid in tea, under stressed conditions. While a number of factors affect brain senescence, our results suggest that non-nutritive food components such as catechin, beta-cryptoxanthin and theanine may be useful for preventing brain senescence. PMID- 25743898 TI - [Mechanisms underlying physiological functions of food factors via non-specific interactions with biological proteins]. AB - We previously reported that zerumbone, a sesquiterpene found in Zingiber zerumbet SMITH, showed notable cancer preventive effects in various organs of experimental rodents. This agent up-regulated nuclear factor-E2-related factor (Nrf2)-dependent expressions of anti-oxidative and xenobiotics-metabolizing enzymes, leading to an increased self-defense capacity. On the other hand, zerumbone markedly suppressed the expression of cyclooxygenase-2, an inducible pro-inflammatory enzyme, by disrupting mRNA stabilizing processes. Binding experiments using a biotin derivative of zerumbone demonstrated that Keap1, an Nrf2 repressive protein, is one of its major binding proteins that promotes their dissociation for inducing Nrf2 transactivation. We then generated a specific antibody against zerumbone-modified proteins and found that zerumbone modified numerous cellular proteins in a non-specific manner, with global distribution of the modified proteins seen not only in cytoplasm but also the nucleus. Based on those observations, zerumbone was speculated to cause proteo-stress, a notion supported by previous findings that it increased the C-terminus of Hsc70 interacting protein-dependent protein ubiquitination and also promoted aggresome formation. Interestingly, zerumbone counteracted proteo-stress and heat stress via up-regulation of the protein quality control systems (PQCs), e.g., heat shock proteins (HSPs), ubiquitin-proteasome, and autophagy. Meanwhile, several phytochemicals, including ursolic acid and curcumin, were identified as marked HSP70 inducers, whereas most nutrients tested were scarcely active. Recent studies have revealed that PQCs play important roles in the prevention of many lifestyle related diseases, such as cancer, thus non-specific binding of phytochemicals to cellular proteins may be a novel and unique mechanism underlying their physiological activities. PMID- 25743899 TI - [Influence of Japanese food on senility and health maintenance]. AB - One of the factors that is believed to contribute to Japanese longevity is their dietary life, which is unique and distinct from Westerners. However, there has been no study that examined whether Japanese food in itself is effective for health maintenance. Therefore, we investigated in rats whether Japanese food is beneficial to health maintenance compared with American food. As a result, we revealed that modern Japanese food is useful for health maintenance compared with modern American food. We subsequently investigated the health benefits of Japanese food from different eras. The menus of Japanese foods from 4 different years, 2005, 1990, 1975 and 1960 were prepared, cooked, and powderized. Each of the Japanese foods was provided to mice. We found that the Japanese food from 1975 exhibited health benefits with respect to the stages of growth, adolescence, maturity and old age. Furthermore, we focused on fish oil, which is one of the beneficial ingredients of Japanese food, and investigated the effect of its long term intake on lifespan in mice. Surprisingly, long-term intake of large amounts of fish oil shortened the lifespan of these mice. By contrast, intake of small amounts of fish oil with antioxidants extended the lifespan. Moreover, while intake of large amounts of fish oil also shortened the lifespan of Caenorhabditis elegans (C. elegans), intake of small amounts of fish oil extended the lifespan. Thus, it was suggested that even when foods have been reported to have health benefits, ingestion of large amounts of individual foods is undesirable for health maintenance. PMID- 25743900 TI - [beta-Cryptoxanthin and the risk for lifestyle-related disease: findings from recent nutritional epidemiologic studies]. AB - Antioxidant micronutrients, such as vitamins and carotenoids, exist in abundance in fruits and vegetables and have been known to contribute to the body's defense against reactive oxygen species. Numerous recent epidemiologic studies have demonstrated that a high dietary consumption of fruit and vegetables rich in carotenoids or with high serum carotenoid concentrations results in lower risks of certain cancers, diabetes, and cardiovascular disease. These epidemiologic studies have suggested that antioxidant carotenoids may have a protective effect against several lifestyle-related diseases. beta-Cryptoxanthin is a carotenoid pigment found in Japanese mandarin (Citrus unshiu MARC.) fruit, which is mainly produced in Japan. Our nutritional epidemiologic survey, the Mikkabi Study, utilized data derived from health examinations of inhabitants performed in the town of Mikkabi in Shizuoka, Japan. In this survey, we measured serum beta-cryptoxanthin as a specific biomarker to estimate the consumption of Japanese mandarin fruit. From the cross-sectional analyses from the Mikkabi Study, we found inverse associations of serum beta-cryptoxanthin with the risks for atherosclerosis, insulin resistance, liver dysfunction, metabolic syndrome, low bone mineral density, and oxidative stress. In this review, recent epidemiologic studies about the associations between serum beta-cryptoxanthin with the risk for several lifestyle-related diseases were reviewed. PMID- 25743901 TI - [Faculty-led pharmaceutical educational reform--reform from the view of third party evaluation of pharmaceutical education]. PMID- 25743902 TI - [Perspectives of pharmaceutical education--while explaining the related evaluation standards and their viewpoints of "evaluation of pharmaceutical education programs"]. AB - In 2013, a program to be implemented by the Japan Accreditation Board for Pharmaceutical Education, Third-party Pharmaceutical Education Evaluation, was initiated. The purposes of this program are: 1) to ensure the quality of education programs; 2) to promote their improvement; and 3) to provide support to actively obtain public understanding and cooperation. In the next 7 years, all pharmaceutical departments and universities will undergo this third-party evaluation. The evaluation standards specify the necessity of establishing indices to evaluate goal achievement levels and to ensure appropriate evaluation based on standards in a number of very important domains of pharmaceutical education. They also emphasize that it is necessary to similarly evaluate overall learning achievement levels in undergraduate degree accreditation. On the other hand, the revision of pharmaceutical education models and core curricula was also proposed and considered in 2013, and preparations for the adoption of revised curricula are currently proceeding. The revised models and core curricula are mainly characterized by setting learning goals within a learning-achievement based education approach, taking into consideration the 10 qualities to be achieved before graduating. In line with this, in order to nurture pharmacists who appropriately meet social needs by enhancing the quality of their education and training, it is crucial for universities to establish methods to appropriately evaluate learning goal achievement levels as a basis for the realization of these qualities. In this article, appropriate pharmaceutical education curricula, particularly evaluation methods, will be discussed from the above-mentioned perspectives, while explaining the related third-party evaluation standards and their viewpoints. PMID- 25743903 TI - [Current and ideal stages of pharmaceutical education]. AB - Education in university is commonly based on active learning by the students themselves. Lectures, exercises, and training are major learning strategies in a university. Self-study is one of the methods of active learning and is considered to be a major part of the classes when calculating the credits. When the six-year pharmaceutical education program was started, degree of attitude education was increased dramatically. New learning strategies considered to be suitable for attitude education, such as small group discussion (SGD), World Cafe, team-based learning (TBL), and problem-based learning (PBL)-Tutorials, were introduced in the classes, and the students were very much attracted by these methods. Not only the tactics but also the skills and abilities of teachers are greatly influenced by using such strategies to realize efficient education. Therefore, the most important point becomes faculty development. The degree of learning and the satisfaction of the students are not always mutually related. The evaluation of learning strategies has become difficult because of ambiguous criteria. Whereas an integrated educational program of drug therapies stimulates the motivation for learning of the students, a well-designed program may ruin the delight in learning of students. PMID- 25743904 TI - [Education reform with the support of the faculty--introduction of a supplementary education program including teacher support and individual guidance]. AB - To deal with declining levels of academic ability and motivation among students (a situation attributable to fewer high school graduates, a greater number of universities, and the diversification of entrance examination methods), one must comprehend the conditions of faculties collectively, and take appropriate measures. Using the results of examinations carried out in each grade as indices, we examined levels of academic ability and established various support programs based on the results. Basic chemistry, biology, and physics courses were designed to help first-year students acquire essential academic skills. For second, third, and fourth-year students, two types of support programs were implemented: supplementary instruction to help students improve their understanding of basic topics in pharmaceutical sciences, and an e-learning system to promote self study, requiring minimal assistance from teachers. Although educational benefits were observed in many students, the number of learners whose understanding failed to improve as a result of the support programs continued to increase. Consequently, The Support Section for Pharmaceutical Education opened in October 2011 to address these concerns. The support section functions mainly to provide individual assistance to students who lack strong academic abilities, and provides teachers with information useful for educational reform. Here, we describe the educational support provided by our faculty and its effectiveness. PMID- 25743905 TI - [Concept extraction of graduate research by modified grounded theory approach and creating of rubric oriented to performance evaluation]. AB - A revised core curriculum model for pharmaceutical education, developed on the basis of the principles of outcome-based education, will be introduced in 2015. Inevitably, appropriate assessments of students' academic achievements will be required. Although evaluations of the cognitive domain can be carried out by paper tests, evaluation methods for the attitude domain and problem-solving abilities need to be established. From the viewpoint of quality assurance for graduates, pharmaceutical education reforms have become vital to evaluation as well as learning strategies. To evaluate student academic achievements on problem solving abilities, authentic assessment is required. Authentic assessment is the evaluation that mimics the context tried in work and life. Specifically, direct evaluation of performances, demonstration or the learners' own work with integrated variety knowledge and skills, is required. To clarify the process of graduate research, we obtained qualitative data through focus group interviews with six teachers and analyzed the data using the modified grounded theory approach. Based on the results, we clarify the performance students should show in graduate research and create a rubric for evaluation of performance in graduate research. PMID- 25743906 TI - [Importance of the pharmacist education program to build the effective interprofessional collaboration]. PMID- 25743907 TI - [The pharmacist-physician collaboration for IPW: from physician's perspective]. AB - Interprofessional work (IPW) is increasingly important in various settings including primary care, in which the role of pharmacists is particularly important. Many studies have shown that in cases of hypertension, diabetes, dyslipidemia, and metabolic syndrome, physician-pharmacist collaboration can improve medication adherence and help to identify drug-related problems. Some surveys and qualitative studies revealed barriers and key factors for effective physician-pharmacist collaboration, including trustworthiness and role clarification. In Japan, some cases of good collaborative work between pharmacists and physicians in hospitals and primary care settings have been reported. Still, community pharmacists in particular have difficulties collaborating with primary care doctors because they have insufficient medical information about patients, they feel hesitant about contacting physicians, and they usually communicate by phone or fax rather than face to face. Essential competencies for good interprofessional collaboration have been proposed by the Canadian Interprofessional Health Collaborative (CIHC): interprofessional communication; patient/client/family/community-centered care; role clarification; team functioning; collaborative leadership; and interprofessional conflict resolution. Our interprofessional education (IPE) team regularly offers educational programs to help health professionals learn interprofessional collaboration skills. We expect many pharmacists to learn those skills and actively to facilitate interprofessional collaboration. PMID- 25743908 TI - [The pharmacist-nurse collaboration for IPW: from nurse's perspective]. AB - The concept of interprofessional work (IPW) is becoming increasingly important recently and the role of nurses in IPW seems critical. In Japan, the problem of burnout and turnover of nurses has been recognized, and the solution seems embedded in the scheme of IPW, because it appears to improve their job satisfaction and recognition as health professionals. However, many obstacles lie ahead, such as "tribal conflict" between health professionals including between pharmacists and nurses. Although failure to understand the roles of other professionals or competencies may seem to hamper with the promotion of collaboration, we must realize that even a lack of understanding among nurses exists. The authors believe that the solution is to understand and respect not only other professionals but also colleagues of the same profession. PMID- 25743909 TI - [Elucidating obstructive factors for IPW from the pharmacist position in clinical practice]. AB - In Japan, many health professionals do not seem to have adequate understandings of the competencies and specialties of other professionals. The competencies of pharmacists are especially overlooked because their expected roles have been changing rapidly in recent years and may vary depending on context in various settings. Due to this lack of understanding physicians themselves often perform therapeutic drug monitoring (TDM), and pharmacists sometimes suggest unnecessary prescription proposals to physicians without considering their treatment plans. Although "community and hospital pharmacist collaboration" has been emphasized for many years, many pharmacists in both settings still do not understand one another's situation. How can we make pharmacists' competencies appropriately understood and respected by other health professionals? What should we do to promote interprofessional work (IPW) with more incorporation of pharmacists so as to pursue patient/client/family-centered care? The key to success in IPW seems to lie in the answers to these questions. PMID- 25743910 TI - [Trial of interprofessional education for effective IPW]. AB - To work collaboratively in healthcare practice, health professionals should learn not only the competencies of their own specialties but also those of other professions so as to promote effective interprofessional work (IPW), thus optimizing patient/client outcomes. For this reason interprofessional education (IPE) is urgently needed. Since the establishment of Centre for the Advancement of Interprofessional Education (CAIPE) in 1987, many IPE programs have been developed and implemented worldwide. Currently, our Japan Society for Instructional Systems in Healthcare (JSISH) IPE program project team is conducting a study to develop an effective and versatile IPE program according to the framework of instructional design (ID). The main categories of learning goals of our program are intellectual skills and attitudes among Gagne's five categories. Therefore we designed our program to start from the drama (skit or video) of a bad example of IPW for learners to see and discuss the barriers of interprofessional collaboration. The drama of IPW seems to enhance attention and relevance for learners; both of which are components of the ARCS model. We expect every health professional including pharmacists to learn about IPW competencies through participating in our IPE program, enabling us further to pursue the ideal patient/client/family-centered care together. PMID- 25743911 TI - [Integration of pharmacokinetics and pharmacodynamics based on the in vivo analysis of drug-receptor binding]. AB - As I was deeply interested in the effects of drugs on the human body, I chose pharmacology as the subject of special study when I became a 4th year student at Shizuoka College of Pharmacy. I studied abroad as a postdoctoral fellow for two years, from 1978, under the tutelage of Professor Henry I. Yamamura (pharmacology) in the College of Medicine at the University of Arizona, USA. He taught me a variety of valuable skills such as the radioreceptor binding assay, which represented the most advanced technology developed in the US at that time. After returning home, I engaged in clarifying receptor abnormalities in pathological conditions, as well as in drug action mechanisms, by making the best use of this radioreceptor binding assay. In 1989, following the founding of the University of Shizuoka, I was invited by Professor Ryohei Kimura to join the Department of Pharmacokinetics. This switch in discipline provided a good opportunity for me to broaden my perspectives in pharmaceutical sciences. I worked on evaluating drug-receptor binding in vivo as a combined index for pharmacokinetics and pharmacological effect manifestation, with the aim of bridging pharmacology and pharmacokinetics. In fact, by focusing on data from in vivo receptor binding, it became possible to clearly rationalize the important consideration of drug dose-concentration-action relationships, and to study quantitative and kinetic analyses of relationships among pharmacokinetics, receptor binding and pharmacological effects. Based on this concept, I was able to demonstrate the utility of dynamic analyses of drug-receptor binding in drug discovery, drug fostering, and the proper use of pharmacokinetics with regard to many drugs. PMID- 25743912 TI - [Effects of 15-day chronic stress on behavior and neurological changes in the hippocampus of ICR mice]. AB - Numerous rodent models of depression have been reported, most requiring a long experimental period and significant effort. We explored a new potential mouse model for depression by investigating whether exposure to a 15-day chronic stress paradigm could induce depression-like behavior in ICR mice. Animals in the stress exposed groups were subjected to 3 h of restraint while immersed in a 28 degrees C water bath daily for 15 consecutive days. Immobility time in the forced swim test was increased in the chronic stress-exposed mice compared with the controls. Serum corticosterone levels were also much higher in the stressed mice than in the control mice. Hippocampal cell survival (BrdU-positive cells) and neurotrophic factor (NGF, TrkA) mRNA levels were significantly decreased in the chronic stress-exposed mice compared with controls. Administration of the anti depressant drugs clomipramine (20 mg/kg/d) or imipramine (30 mg/kg/d) did not change the immobility time in the forced swim test, but treatment with lithium (100 mg/kg/d) did result in slight improvement. These results suggest that this 15-day chronic stress paradigm can induce depression-like behavior and neurological changes, in a short time and with minimal effort, facilitating the assessment of treatments for depression. PMID- 25743913 TI - [Errata: Education effect of the simple suspension method training for fifth-year medical students]. PMID- 25743915 TI - Networks under pressure: the development of in situ high-pressure neutron diffraction for glassy and liquid materials. AB - The pressure-driven collapse in the structure of network-forming materials will be considered in the gigapascal (GPa) regime, where the development of in situ high-pressure neutron diffraction has enabled this technique to obtain new structural information. The improvements to the neutron diffraction methodology are discussed, and the complementary nature of the results is illustrated by considering the pressure-driven structural transformations for several key network-forming materials that have also been investigated by using other experimental techniques such as x-ray diffraction, inelastic x-ray scattering, x ray absorption spectroscopy and Raman spectroscopy. A starting point is provided by the pressure-driven network collapse of the prototypical network-forming oxide glasses B2O3, SiO2 and GeO2. Here, the combined results help to show that the coordination number of network-forming structural motifs in a wide range of glassy and liquid oxide materials can be rationalised in terms of the oxygen packing fraction over an extensive pressure and temperature range. The pressure driven network collapse of the prototypical chalcogenide glass GeSe2 is also considered where, as for the case of glassy GeO2, site-specific structural information is now available from the method of in situ high-pressure neutron diffraction with isotope substitution. The application of in situ high-pressure neutron diffraction to other structurally disordered network-forming materials is also summarised. In all of this work a key theme concerns the rich diversity in the mechanisms of network collapse, which drive the changes in physico-chemical properties of these materials. A more complete picture of the mechanisms is provided by molecular dynamics simulations using theoretical schemes that give a good account of the experimental results. PMID- 25743916 TI - Appropriate use of medical imaging shouldn't always mean less imaging. PMID- 25743914 TI - Kruppel-like factors in an endothelial and vascular smooth muscle cell coculture model: impact of a diabetic environment and vitamin D. AB - Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are involved in the development of local and diffuse vasculopathies by participating in inflammatory processes that can lead to uncontrolled vascular complications. Our aim was to study the possible interactions of EC and VSMC in an in vitro coculture model exposed to diabetic-like conditions and the effect of vitamin D on cellular pathways that might lead to an inflammatory response. EC and VSMC were isolated from different umbilical cords and stimulated in an in vitro coculture model in a diabetic-like environment and calcitriol for 24 h. Total RNA and protein were extracted from cells and analyzed for the expression of selected inflammatory-related markers. The EC-VSMC coculture in a diabetic-like environment induced the expression of inflammatory markers such as Kruppel-like factors, thioredoxin-interacting protein (TXNIP), IL-6, and IL-8. Addition of vitamin D to the EC-VSMC coculture induced selective changes in the inflammatory response. This model could lead to a better understanding of the interactions between EC and VSMC in the inflammatory processes involved in diabetes and emphasizes the role of vitamin D in the inflammatory response. The use of different donors strengthens the significance of our findings showing that genetic variations do not affect the impact of vitamin D on the expression of inflammatory-related proteins in our model. PMID- 25743917 TI - Laying down the burdensome cross. PMID- 25743918 TI - Risk-sharing programs. PMID- 25743919 TI - ACR Appropriateness Criteria acute trauma to the ankle. AB - Acute ankle injuries are frequently diagnosed and treated in emergency departments and outpatient clinics. Recent evidence-based clinical treatment guidelines and systematic review of economic analyses support the use of 3-view (anteroposterior, lateral, and mortise) radiographic evaluation of patients meeting the criteria of the Ottawa ankle rules. Cross-sectional imaging has a limited secondary role primarily as a tool for preoperative planning and as a problem-solving technique in patients with persistent symptoms and suspected of having occult fractures. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25743920 TI - Reengineering the radiology enterprise: a summary of the 2014 Intersociety Committee Summer Conference. AB - The current initiative to reform health care from both a quality and a cost perspective has already had a profound impact on the radiology enterprise. We have seen a decrease in the utilization of imaging studies, a reduction in reimbursement, a declining payer mix, shrinking incomes, a proliferation of performance indices, creation of radiology mega-groups, growth of national radiology companies, and increasing turf incursions. Our cheese is clearly on the move, and we must take action to reengineer the radiology enterprise. In keeping with general health care reform, we must be patient-centric, data driven, and outcome based. We must create a radiology enterprise that adheres to the value equation of providing the highest quality health care, for the lowest possible cost, for all citizens. PMID- 25743921 TI - Retirement issues for radiologists: consensus statement on successful planning by the Commission on Human Resources of the ACR. AB - Successful retirement planning requires a determination of which activities and relationships may replace those associated with the current full-employment position. Next, there must be acceptance of leaving the profession behind. Finally, the individual must determine the specific decisions and actions that must be made to transition to successful retirement in the future. To be successful, the entire process should occur over a period of several years. Alternatively, bridge employment may play a significant role in the transition from full-employment to full-time retirement. PMID- 25743922 TI - Patient awareness of breast density and interest in supplemental screening tests: comparison of an academic facility and a county hospital. AB - PURPOSE: The aim of this study was to measure women's knowledge of breast density and their attitudes toward supplemental screening tests in the setting of the California Breast Density Notification Law at an academic facility and a county hospital, serving women with higher and lower socioeconomic status, respectively. METHODS: Institutional review board exemptions were obtained. A survey was administered during screening mammography at two facilities, assessing women's awareness of and interest in knowing their breast density and interest in and willingness to pay for supplemental whole breast ultrasound and contrast-enhanced spectral mammography (CEMG). The results were compared by using Fisher exact tests between groups. RESULTS: A total of 105 of 130 and 132 of 153 women responded to the survey at the academic and county facilities, respectively. Among respondents at the academic and county facilities, 23% and 5% were aware of their breast density, and 94% and 79% wanted to know their density. A majority were interested in supplemental ultrasonography and CEMG at both sites; however, fewer women had a willingness to pay for the supplemental tests at the county hospital compared with those at the academic facility (22% and 70%, respectively, for ultrasound, P < .0001; 20% and 65%, respectively, for CEMG, P < .0001). CONCLUSIONS: Both groups of women were interested in knowing their breast density and in supplemental screening tests. However, women at the county hospital were less willing to incur out-of-pocket expenses, suggesting a potential for a disparity in health care access for women of lower socioeconomic status after the enactment of breast density notification legislation. PMID- 25743924 TI - Stories from the kitchen: lessons for radiology from the restaurant business. PMID- 25743923 TI - Monitoring of clinical imaging guidelines part 3: norms, standards, and regulations. AB - It is known that the use of imaging in clinical situations is not always optimal, leading to suboptimal health care and potential radiation risk. There may be overuse of imaging, underuse, or use of the wrong modality. The use of clinical imaging guidelines is likely to improve the use of imaging, but roadblocks exist. Some of these relate to regulatory oversight and mandates. There is wide variation by country and region in the regulatory setting, ranging from actual absence of regulatory authorities to mandated availability of clinical imaging guidelines in the European Community. Collaborative efforts to ensure that clinical imaging guidelines are at least available is a good starting point. Regulatory oversight and support are necessary to ensure the use of clinical imaging guidelines. Regulations should address 3 areas: availability, clinical utilization, and adherence to and revision of guidelines. The use of both internal and external audits, with the aim of both use of and adherence to guidelines and quality improvement, is the best tool for enhancing use. The major challenges that need to be addressed, collaboratively, to ensure the dissemination and use of clinical imaging guidelines are the development of regulations, of regulatory structures that can be effectively deployed, and of benchmarks for adherence and for utility. PMID- 25743925 TI - Safety's perils. PMID- 25743926 TI - Implementation of the ACR Dose Index Registry. PMID- 25743927 TI - Fulfilling the health care economics milestones: adopting an online curriculum for radiology residency programs. PMID- 25743928 TI - A comparison of the effects of tributyltin chloride and triphenyltin chloride on cell proliferation, proapoptotic p53, Bax, and antiapoptotic Bcl-2 protein levels in human breast cancer MCF-7 cell line. AB - In recent years it was disclosed, that numerous organotin(IV) derivatives have remarkable cytotoxicity against several types of cancer cells. The property to inhibit cell growth makes these compounds promising for antitumor therapy, as the clinical effectiveness of cisplatin is limited by drug resistance and significant side effects. Tributyltin and triphenyltin are known as endocrine disruptors. Moreover, the compounds exert their toxicity in mammals predominantly through nuclear receptor signaling. Here we present the effects of tributyltin chloride (TBT-Cl) and triphenyltin chloride (TPT-Cl) on cell proliferation, expression of proapoptotic p53, Bax, and antiapoptotic Bcl-2 proteins in human breast cancer MCF-7 cell line. Dose and time dependent (24, 48 and 72 h) cell expositions have demonstrated TBT-Cl as more effective in inhibiting MCF-7 cell proliferation than TPT-Cl. Short time treatment with TBT-Cl displayed marked stimulation of p53 protein expression when compared to TPT-Cl. Both organotin compounds displayed similar mild enhancement of Bax protein expression. The 24h exposition of TPT-Cl induced substantial diminution of Bcl-2 protein expression in comparison with both, untreated cells and TBT-Cl treated cells. Our observations indicate that TBT-Cl and TPT-Cl have different antiproliferative potency and distinct impact on expression of apoptosis marker proteins. PMID- 25743929 TI - Serum osteopontin concentrations in relation to coronary artery disease. AB - BACKGROUND AND AIMS: Coronary artery disease (CAD) is a common form of vascular disease and is associated with high mortality and morbidity globally. It has been suggested that serum osteopontin (OPN) may be a useful biomarker of atherosclerosis and vascular calcification. The aim of this study was to assess the association between serum OPN levels and severity of CAD. METHODS: Three hundred and four subjects were studied, 111 with clinically significant angiographically defined CAD (CAD+) (>50% stenosis), 96 with negative angiography (CAD-) (<50% stenosis) and 97 healthy controls. Fasting blood samples were collected from all patients before coronary angiography and serum OPN levels were determined using ELISA. RESULTS: Serum concentrations of OPN were significantly higher in both CAD+ (72.99 [51.05-103.64]) and CAD- (11.11 [8.11-18.23]) (p = 0.001) groups compared with the control group (5.99 [4.26-7.91]) (p = 0.001). CAD+ subjects also had higher serum OPN levels compared with CAD-subjects (p = 0.001). However, OPN levels were comparable between subgroups of CAD+ subjects stratified according to the number of narrowed vessels in angiography. CONCLUSIONS: The present results suggest a positive association between circulating OPN concentrations and the presence but not the extent of CAD. PMID- 25743931 TI - Organohalogens and their hydroxylated metabolites in the blood of pigs from an open waste dumping site in south India: association with hepatic cytochrome P450. AB - The concentrations of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and their hydroxylated metabolites (OH-PCBs and OH-PBDEs) were measured in the blood of Eurasian wild pigs (Sus scrofa) from a municipal waste open dumping site (DS) and a reference site (RS) in South India. We showed that contamination with OH-PCBs was higher in female pigs from the DS than in all other adult pigs. The highest OH-PCB concentrations were found in piglets from the DS. Moreover, the hepatic expression levels of CYP1A and CYP2B were higher in piglets than in their dam, implying metabolism of PCBs by cytochrome P450 (CYP) enzymes. The OH-PCB congener profiles differed according to sex and collection sites, possibly because of variations in the expression levels of phase I and phase II enzymes among individual pigs, differences in the exposure sources, and maternal transfer of parent PCBs. The hepatic CYP1A expression levels were positively correlated with the blood concentrations of 4OH-CB107, 4OH-CB162, and 4OH-CB187, implying CYP1A-dependent formation of these OH-PCBs in the pig liver. We found no significant correlations between the blood concentrations of OH-PCBs and thyroid hormones (THs); however, the thyroxin (T4) levels were lower in pigs from the DS than in pigs from the RS. Our limited dataset suggest that induced CYP enzymes accelerate the metabolism of xenobiotics and endogenous molecules in pigs. Thus, besides parental compounds, the risk of hydroxylated metabolites entering wildlife and humans living in and around municipal open waste dumping sites should be considered. PMID- 25743930 TI - Streptococcus pneumoniae Serotypes Identified in Mexican Children with Invasive Disease Before and After the Introduction of PCV7 (1993-2012). AB - BACKGROUND AND AIMS: Streptococcus pneumoniae is the leading cause of acute otitis media, pneumonia, meningitis, and sepsis. The heptavalent pneumococcal conjugate vaccine (PCV7) was incorporated into the national immunization program in Mexico in 2008. The aim of the study was to analyze the frequency of S. pneumoniae serotypes isolated from children <=5 years of age with invasive diseases before and after the introduction of PCV7. METHODS: Isolates from sterile fluids, tissues and other body fluids were obtained from 1993 to 2012. Isolates collected in hospitals for the surveillance network were sent to the Instituto Nacional de Salud Publica. Serotyping was done using the Quellung reaction. The pre-vaccination period was considered from 1993-2007. RESULTS: A total of 1346 isolates were collected during 1993-2012. In the pre-vaccination era, serotypes included in PCV7 accounted for 59.7% of the strains, whereas in 2012 they represented only 21% of cases. There was a significant decrease in all PCV7-included serotypes. A gradual increase of the 19A serotype was detected during the vaccination period from 7% in 2008 to 39% of the isolates in 2012. In this year, 29% of the serotypes causing invasive disease were not included in any of the pneumococcal conjugate vaccines. CONCLUSION: The emergence of PCV7 non included serotypes after vaccination demands increased surveillance. Currently in Mexico, the 13-valent conjugate vaccine (PCV13) offers better coverage than the 10-valent pneumococcal conjugate vaccine (PCV10). PMID- 25743933 TI - Physiotherapy after subacromial decompression surgery: development of a standardised exercise intervention. AB - This paper describes the development and details of a standardised physiotherapy exercise intervention designed to address pain and disability in patients with difficulty returning to usual activities after arthroscopic decompression surgery for subacromial impingement syndrome. To develop the intervention, the literature was reviewed with respect to the effectiveness of postoperative exercises, components of previous exercise programmes were extracted, and input from clinical physiotherapists in the field was obtained through a series of workshops. The physiotherapy exercise intervention is currently being evaluated within the framework of the Shoulder Intervention Project (ISRCTN55768749). PMID- 25743932 TI - Prenatal phthalate exposure and reproductive function in young men. AB - BACKGROUND: Prenatal exposure to phthalates is suggested to negatively impact male reproductive function, but human data are lacking. OBJECTIVES: To study associations between prenatal exposure to diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP), and reproductive parameters of adolescent men. METHODS: Using linear regression models adjusted for potential confounders, we studied associations between levels of DEHP- and DiNP metabolites in maternal sera from mean 12 weeks of pregnancy, and testicular size, semen quality and reproductive hormones in 112 adolescent sons, recruited from the general population. RESULTS: Men in the highest exposure tertile of one DiNP metabolite [mono-(carboxy-iso-octyl) phthalate], compared with men in the lowest tertile had: 4.3mL (95% CI: 0.89, 7.6mL; p<0.001) lower total testicular volume; 30% (95% CI: 3.6, 63%; p=0.02) higher levels of follicle-stimulating hormone; and 0.87mL (95% CI: 0.28, 1.5mL; p=0.004) lower semen volume. Men in the highest exposure tertile of one DEHP metabolite [mono-(2-ethyl-5-hydroxylhexyl) phthalate] had 0.70mL (95% CI: 0.090, 1.3mL; p=0.03) lower semen volume than men in the lowest exposure tertile. The levels of two DiNP metabolites [mono-(hydroxy-iso-nonyl) phthalate and mono-(oxo-iso-nonyl) phthalate] were linearly associated with luteinizing hormone (p<0.01). CONCLUSION: Prenatal levels of some metabolites of DEHP and DiNP seemed negatively associated with reproductive function of adolescent men. PMID- 25743934 TI - Parameterization of temperature sensitivity of spring phenology and its application in explaining diverse phenological responses to temperature change. AB - Existing evidence of plant phenological change to temperature increase demonstrates that the phenological responsiveness is greater at warmer locations and in early-season plant species. Explanations of these findings are scarce and not settled. Some studies suggest considering phenology as one functional trait within a plant's life history strategy. In this study, we adapt an existing phenological model to derive a generalized sensitivity in space (SpaceSens) model for calculating temperature sensitivity of spring plant phenophases across species and locations. The SpaceSens model have three parameters, including the temperature at the onset date of phenophases (Tp), base temperature threshold (Tb) and the length of period (L) used to calculate the mean temperature when performing regression analysis between phenology and temperature. A case study on first leaf date of 20 plant species from eastern China shows that the change of Tp and Tb among different species accounts for interspecific difference in temperature sensitivity. Moreover, lower Tp at lower latitude is the main reason why spring phenological responsiveness is greater there. These results suggest that spring phenophases of more responsive, early-season plants (especially in low latitude) will probably continue to diverge from the other late-season plants with temperatures warming in the future. PMID- 25743935 TI - Localizing exciton recombination sites in conformationally distinct single conjugated polymers by super-resolution fluorescence imaging. AB - To thoroughly elucidate how molecular conformation and photophysical properties of conjugated polymers (CPs) are related requires simultaneous probing of both. Previous efforts used fluorescence imaging with one nanometer accuracy (FIONA) to image CPs, which allowed simultaneous estimation of molecular conformation and probing of fluorescence intensity decay. We show that calculating the molecular radius of gyration for putative folded and unfolded poly(2-methoxy-5-(2' ethylhexyloxy)1,4-phenylenevinylene) (MEH-PPV) molecules using FIONA underestimates molecular extension by averaging over emitters during localization. In contrast, employing algorithms based on single molecule high resolution imaging with photobleaching (SHRImP), including an approach we term all-frames SHRImP, allows localization of individual emitters. SHRImP processing corroborates that compact MEH-PPV molecules have distinct photophysical properties from extended ones. Estimated radii of gyration for isolated 168 kDa MEH-PPV molecules immobilized in polystyrene and exhibiting either stepwise or continuous intensity decays are found to be 12.6 and 25.3 nm, respectively, while the distance between exciton recombination sites is estimated to be ~10 nm independent of molecular conformation. PMID- 25743936 TI - The MAINSAIL trial: an expected failure. PMID- 25743938 TI - Self-reported medication adherence for heart failure is associated with lower risk of all-cause hospitalisation and death. PMID- 25743937 TI - Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. AB - BACKGROUND: Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208. FINDINGS: 1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17.7 months (95% CI 14.8-18.8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1.53, 95% CI 1.17-2.00, p=0.0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group. INTERPRETATION: Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted. FUNDING: Celgene Corporation. PMID- 25743939 TI - Carers providing end-of-life care at home have limited formal support in managing medications. PMID- 25743940 TI - Review suggests mobile phone interventions improve medication adherence; rigorous longer term studies are needed to confirm effects. PMID- 25743941 TI - Low-dose aspirin reduces morbidity and mortality in pregnant women at high-risk for preeclampsia. PMID- 25743942 TI - Review: structured physical activity during pregnancy reduces risk of caesarean delivery. PMID- 25743943 TI - Effects of dimethyl sulfoxide on the NLRP3 inflammasome. PMID- 25743944 TI - Photodissociation dynamics of ethanethiol in clusters: complementary information from velocity map imaging, mass spectrometry and calculations. AB - We investigate the solvent effects on photodissociation dynamics of the S-H bond in ethanethiol CH3CH2SH (EtSH). The H fragment images are recorded by velocity map imaging (VMI) at 243 nm in various expansion regimes ranging from isolated molecules to clusters of different sizes and compositions. The VMI experiment is accompanied by electron ionization mass spectrometry using a reflectron time-of flight mass spectrometer (RTOFMS). The experimental data are interpreted using ab initio calculations. The direct S-H bond fission results in a peak of fast fragments at Ekin(H) ~ 1.25 eV with a partly resolved structure corresponding to vibrational levels of the CH3CH2S cofragment. Clusters of different nature ranging from dimers to large (EtSH)N, N >= 10, clusters and to ethanethiol clusters embedded in larger argon "snowballs" are investigated. In the clusters a sharp peak of near-zero kinetic energy fragments occurs due to the caging. The dynamics of the fragment caging is pictured theoretically, using multi-reference ab initio theory for the ethanethiol dimer. The larger cluster character is revealed by the simultaneous analysis of the VMI and RTOFMS experiments; none of these tools alone can provide the complete picture. PMID- 25743947 TI - The effect of surface passivation on the structure of sulphur-rich PbS colloidal quantum dots for photovoltaic application. AB - The use of PbS colloidal quantum dots in photovoltaic devices is very promising because of their simple and low cost production processes and their unique properties, such as bandgap tunability and potential multiple exciton generation. Here we report the synthesis of PbS nanocrystals used for application in solar cells. The sulphur-rich nature of their surface appears to be caused by the exposure to ambient conditions. The use of methanol as medium during the ligand exchange process has a crucial role in the removal of native oleate ligands. Without proper ligand exchange, the unpassivated surface is subject to ambient hydroxylation leading to the depletion of Pb atoms and the formation of a polysulfide phase. Devices assembled with this material showed good performance with an efficiency of 3.2%. PMID- 25743950 TI - [Is the patient allergic - or moribund?]. PMID- 25743951 TI - [GKV takes over HPV vaccination starting at age 9]. PMID- 25743945 TI - Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia. AB - Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis. In this study we aimed to compare pattern of gastric corpus microbiota in ESCC with normal esophagus. Cases were included subjects with early ESCC (stage I-II) and esophageal squamous dysplasia (ESD) as the cancer precursor. Control groups included age and sex matched subjects with mid-esophagus esophagitis (diseased-control), and histologically normal esophagus (healthy-control). DNA was extracted from snap frozen gastric corpus tissues and 16S rRNA was sequenced on GS-FLX Titanium. After noise removal, an average of 3004 reads per sample was obtained from 93 subjects. We applied principal coordinate analysis to ordinate distances from beta diversity data. Pattern of gastric microbiota using Unifrac (p = 0.004) and weighted Unifrac distances (p = 0.018) statistically varied between cases and healthy controls. Sequences were aligned to SILVA database and Clostridiales and Erysipelotrichales orders were more abundant among cases after controling for multiple testing (p = 0.011). No such difference was observed between mid esophagitis and healthy controls. This study is the first to show that composition of gastric corpus mucosal microbiota differs in early ESCC and ESD from healthy esophagus. PMID- 25743952 TI - [A quasi family practitioner model keeps private patients in the network]. PMID- 25743953 TI - [Physician who employs colleagues can remain a freelancer]. PMID- 25743954 TI - [Minimum wage also applies to physician practices!]. PMID- 25743955 TI - [Then the emergency physician shrinks down to normal size]. PMID- 25743956 TI - [Hands up - or I shoot!]. PMID- 25743957 TI - [KBV representatives jeopardize family physician reimbursement fee increase]. PMID- 25743958 TI - [Bureaucracy frustration over long-term treatment needs]. PMID- 25743959 TI - [Referral also applies in the following quarter]. PMID- 25743960 TI - [Alcoholics and smokers get poor treatment]. PMID- 25743961 TI - [Elderly patient fights hemorrhages and hematomas after operation]. PMID- 25743962 TI - [Intensive blood glucose reduction: yes or no?]. PMID- 25743963 TI - [An autoimmune disease often does not come alone]. PMID- 25743964 TI - [Antibiotics only in clinical signs of infection]. PMID- 25743965 TI - [Do not forget about gonococcal infection!]. PMID- 25743966 TI - [Small surgical interventions: when is bridging necessary?]. PMID- 25743967 TI - [Medications for respiratory insufficiency and exacerbations]. PMID- 25743970 TI - [Opioids not as monotherapy]. PMID- 25743971 TI - [Sex without backache: this is how it works]. PMID- 25743972 TI - [Is prostate cancer screening only an illusion?]. PMID- 25743973 TI - [An avocado a day keeps the doctor away]. PMID- 25743975 TI - [Madame blue finger]. PMID- 25743974 TI - [In diarrhea of unknown origin also think of olmesartan!]. PMID- 25743976 TI - [New score for lung cancer risk in COPD]. PMID- 25743977 TI - [A sticky obstruction in the terminal esophagus]. PMID- 25743978 TI - [Freed from actinomycetoma and wheelchair]. PMID- 25743979 TI - [NSAID in antithrombotic treatment increases risk of bleeding]. PMID- 25743980 TI - [Does vitamin D prevent colorectal cancers?]. PMID- 25743981 TI - [Saved from infertility in maturity?]. PMID- 25743982 TI - [This allergy is not a minor issue!]. PMID- 25743983 TI - [Rectal prolapse]. PMID- 25743984 TI - [Abusing the skin]. PMID- 25743985 TI - [Why does the knee hurt?]. PMID- 25743986 TI - [With evidence the recommendation level also increases]. PMID- 25743987 TI - [How poor blood glucose values damage the brain]. PMID- 25743988 TI - [2 step inhaler for twice daily use]. PMID- 25743989 TI - [What children want to know about palliative medicine]. PMID- 25743990 TI - [Bronchitis Severity Score indicates therapy success]. PMID- 25743991 TI - [Interferon free recovery for almost all patients]. PMID- 25743992 TI - [Reliable phytotherapy drug with multiple target effect]. PMID- 25743993 TI - [The cancer that came in out of the cold]. PMID- 25743994 TI - [Hawthorn is also effective in diastolic heart failure]. PMID- 25743995 TI - Sequential treatment with epirubicin, oxaliplatin and 5FU (EOF) followed by docetaxel, oxaliplatin and 5FU (DOF) in patients with advanced gastric or gastroesophageal cancer: a single-institution experience. AB - PURPOSE: The aim of this study was to evaluate the activity and safety of epirubicin (EPI), oxaliplatin (l-OHP) and 5fluorouracil (5FU) (EOF) followed by docetaxel (D), l-OHP and 5FU (DOF) in patients with advanced gastric or gastroesophageal junction (GEJ) cancer. METHODS: Forty-five patients were enrolled: 26 gastric and 19 GEJ cancer. Median age was 69 years (range 34-83); ECOG performance status was 0-1 in 37 patients. Treatment consisted of EPI 50 mg/m(2) combined with l-OHP 130 mg/m(2) on day 1 and continuous infusion 5FU 750 mg/m(2) days 1-5 (EOF), every 3 weeks for a maximum of 4 cycles. After EOF completion, patients received D 70 mg/m(2) combined with l-OHP 130 mg/m(2) on day 1 and continuous infusion 5FU 750 mg/m(2) days 1-5 (DOF), every 3 weeks for a maximum of 4 cycles. RESULTS: After sequential EOF/DOF, the overall response rate was 51.1 % (95 % CI 35.7-66.2 %) and 93.3 % of patients were progression free 6 months after the onset of chemotherapy. The median progression-free survival was 9.5 months (95 % CI 8.0-11.9 months), and the median overall survival was 15.8 months (95 % CI 13.6-18.9 months). Grade 3 neutropenia was observed in 15 patients (33.3 %) after sequential EOF/DOF. CONCLUSIONS: The sequential treatment EOF/DOF is feasible in well-selected patients with advanced gastric or GEJ cancer and shows encouraging survival results. PMID- 25743997 TI - 2015 Scientific Session of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Nashville, Tennessee, USA, 15-18 April 2015 : Top Posters of Distinction. PMID- 25743996 TI - Clinical risk factors for anastomotic leakage after laparoscopic anterior resection for rectal cancer: a systematic review and meta-analysis. AB - BACKGROUND: Anastomotic leakage (AL) is a serious complication in laparoscopic rectal cancer surgery, and risk factors for AL are not well defined. Herein, we conducted a systematic review to quantify the clinicopathologic factors predictive for AL in patients who underwent laparoscopic anterior resection (LAR) for rectal cancer. METHODS: A systematic search of electronic databases (PubMed, Embase, Cochrane CENTRAL, Scopus Database, and Wanfang Database) for studies published until August 2014 was performed. Cohort, case-control studies, and randomized controlled trials that examined clinical risk factors for AL were included. RESULTS: Fourteen studies (seven prospective and seven retrospective studies) involving 4580 patients met final inclusion criteria. From the pooled analyses, five demographic factors were found to be significantly associated with the development of AL, including male gender (OR 2.04, 95% CI 1.50-2.77), BMI >=25 kg/m(2) (OR 1.46, 95% CI 1.00-2.14), ASA score >2 (OR 1.74, 95% CI 1.04 2.93, P = 0.04), tumor size >5 cm (OR 1.63, 95% CI 1.01-2.64, P = 0.05), and preoperative chemotherapy (OR 1.67, 95% CI 1.10-2.55, P = 0.02). Four operative factors were significantly associated with increased risk of AL, including longer operative time (95% CI 1.71-5.77, P = 0.0002), number of stapler firings >=3 (OR 0.17, 95% CI 0.07-0.41, P < 0.001), intra-operative transfusions/blood loss >100 mL (OR 3.79, 95% CI 2.48-5.49, P < 0.001), and anastomosis level within 5 cm from the anal verge (OR 9.63, 95% CI 3.05-30.43, P = 0.0001), while pelvic drain (OR 0.43, 95% CI 0.19-0.94, P = 0.04) was significantly associated with a lower AL rate. CONCLUSION: Our analysis identified several clinicopathologic factors associated with AL in patients who underwent LAR. The knowledge of these risk factors may influence treatment- and procedure-related decisions and possibly reduce the leakage rate. PMID- 25743998 TI - Neglected zoonotic helminths: Hymenolepis nana, Echinococcus canadensis and Ancylostoma ceylanicum. AB - The majority of helminth parasites that are considered by WHO to be the cause of 'neglected diseases' are zoonotic. In terms of their impact on human health, the role of animal reservoirs and polyparasitism are both emerging issues in understanding the epidemiology of a number of these zoonoses. As such, Hymenolepis (Rodentolepis) nana, Echinococcus canadensis and Ancylostoma ceylanicum all qualify for consideration. They have been neglected and there is increasing evidence that all three parasite infections deserve more attention in terms of their impact on public health as well as their control. PMID- 25743999 TI - Appropriate antimicrobial therapy in the era of multidrug-resistant human pathogens. AB - The past decade has brought a significant rise in antimicrobial resistance, and the ESKAPE pathogens have become a significant threat to public health. Three epidemiological features that negatively impact patients, which are consistently seen with the ESKAPE pathogens, are the following: 1) there has been a rise in incidence of these organisms as causative human pathogens, 2) there has been a significant increase in antimicrobial resistance in these bacterial species, and 3) the infections caused by these resistant strains are associated with worse outcomes when compared with infections caused by their susceptible counterparts. Significant delays in time to appropriate antimicrobial therapy of up to 5 days have been reported in infections due to these organisms and this is the strongest predictor of mortality with ESKAPE pathogens, particular in critically ill patients, where every hour delay has an incremental survival disadvantage for patients. Strategies to decrease these delays are urgently needed. Although routine broad-spectrum empiric coverage for these organisms would ideally limit this delay, agents with activity against these organisms are sometimes less effective, have significant toxicity risk, and their use can result in the development of resistance. Therefore, strategies to optimize therapy, although limiting unnecessary use of broad-spectrum antimicrobials, are urgently needed. This review will discuss potential strategies to optimize empiric therapy in the age of multi-drug resistance, the limitations of these strategies, and will discuss future directions and opportunities. PMID- 25744001 TI - Wrong-site nerve blocks: 10 yr experience in a large multihospital health-care system. AB - INTRODUCTION: Although wrong-site surgery has garnered extensive scrutiny, the incidence of wrong-site blocks remains unknown. Our study thus sought to quantify the incidence of wrong-site blocks and examine some of their associated risk factors in our multihospital health-care system. METHODS: Using quality improvement and billing data, we quantified the total number of blocks and wrong site blocks occurring between July 1, 2002 and June 30, 2012 within the University of Pittsburgh Medical Center Health System. The incidence of wrong site block was determined by block type, hospital, and type of service involved in performing the block. The incidence of wrong-site block was compared with that of wrong-site surgery. Fisher's exact tests were performed to determine associations between the incidence of wrong-site block and any of the aforementioned variables. A root-cause analysis was performed to determine the source of wrong-site blocks after the implementation of a timeout policy. RESULTS: Of the 85 915 patients receiving blocks, 70 441 received only unilateral blocks, yielding an overall incidence of wrong-site block of 1.28 (95% confidence interval 0.43-2.13) per 10 000 patients receiving unilateral blocks. The incidence of wrong-site block was highest with femoral blocks, and differed from the incidence of wrong-site surgery. All occurrences of wrong-site block after the implementation of the timeout policy involved policy violations. CONCLUSIONS: Our study provides the first incidence data on wrong-site block in a large patient population and can help hospitals to develop policies based on these data. It is yet to be determined whether active intervention can eliminate this adverse event. PMID- 25744000 TI - Synergistic effects of high dietary calcium and exogenous parathyroid hormone in promoting osteoblastic bone formation in mice. AB - In the present study, we investigated whether high dietary Ca and exogenous parathyroid hormone 1-34 fragments (PTH 1-34) have synergistic effects on bone formation in adult mice, and explored the related mechanisms. Adult male mice were fed a normal diet, a high-Ca diet, a PTH-treated diet, or a high-Ca diet combined with subcutaneously injected PTH 1-34 (80 MUg/kg per d) for 4 weeks. Bone mineral density, trabecular bone volume, osteoblast number, alkaline phosphatase (ALP)- and type I collagen-positive areas, and the expression levels of osteoblastic bone formation-related genes and proteins were increased significantly in mice fed the high-Ca diet, the PTH-treated diet, and, even more dramatically, the high-Ca diet combined with PTH. Osteoclast number and surface and the ratio of receptor activator for nuclear factor-kappaB ligand (RANKL):osteoprotegerin (OPG) were decreased in the high-Ca diet treatment group, increased in the PTH treatment group, but not in the combined treatment group. Furthermore, third-passage osteoblasts were treated with high Ca (5 mM), PTH 1-34 (10-8 M) or high Ca combined with PTH 1-34. Osteoblast viability and ALP activity were increased in either the high Ca-treated or PTH-treated cultures and, even more dramatically, in the cultures treated with high Ca plus PTH, with consistent up-regulation of the expression levels of osteoblast proliferation and differentiation-related genes and proteins. These results indicate that dietary Ca and PTH play synergistic roles in promoting osteoblastic bone formation by stimulating osteoblast proliferation and differentiation. PMID- 25744002 TI - Human graft-derived mesenchymal stromal cells potently suppress alloreactive T cell responses. AB - After organ transplantation, recipient T cells contribute to graft rejection. Mesenchymal stromal cells from the bone marrow (BM-MSCs) are known to suppress allogeneic T-cell responses, suggesting a possible clinical application of MSCs in organ transplantation. Human liver grafts harbor resident populations of MSCs (L-MSCs). We aimed to determine the immunosuppressive effects of these graft derived MSCs on allogeneic T-cell responses and to compare these with the effects of BM-MSCs. BM-MSCs were harvested from aspirates and L-MSCs from liver graft perfusates. We cultured them for 21 days and compared their suppressive effects with the effects of BM-MSCs on allogeneic T-cell responses. Proliferation, cytotoxic degranulation, and interferon-gamma production of alloreactive T cells were more potently suppressed by L-MSCs than BM-MSCs. Suppression was mediated by both cell-cell contact and secreted factors. In addition, L-MSCs showed ex vivo a higher expression of PD-L1 than BM-MSCs, which was associated with inhibition of T-cell proliferation and cytotoxic degranulation in vitro. Blocking PD-L1 partly abrogated the inhibition of cytotoxic degranulation by L-MSCs. In addition, blocking indoleamine 2,3-dioxygenase partly abrogated the inhibitive effects of L MSCs, but not BM-MSCs, on T-cell proliferation. In conclusion, liver graft derived MSC suppression of allogeneic T-cell responses is stronger than BM-MSCs, which may be related to in situ priming and mobilization from the graft. These graft-derived MSCs may therefore be relevant in transplantation by promoting allohyporesponsiveness. PMID- 25744003 TI - Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. AB - BACKGROUND: Transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation (AF) in canines. OBJECTIVES: This study examined the antiarrhythmic and anti-inflammatory effects of LLTS in humans. METHODS: Patients with paroxysmal AF who presented for AF ablation were randomized to either 1 h of LLTS (n = 20) or sham control (n = 20). Attaching a flat metal clip onto the tragus produced LLTS (20 Hz) in the right ear (50% lower than the voltage slowing the sinus rate). Under general anesthesia, AF was induced by burst atrial pacing at baseline and after 1 h of LLTS or sham treatment. Blood samples from the coronary sinus and the femoral vein were collected at those time points and then analyzed for inflammatory cytokines, including tumor necrosis factor alpha and C-reactive protein, using a multiplex immunoassay. RESULTS: There were no differences in baseline characteristics between the 2 groups. Pacing-induced AF duration decreased significantly by 6.3 +/- 1.9 min compared with baseline in the LLTS group, but not in the control subjects (p = 0.002 for comparison between groups). AF cycle length increased significantly from baseline by 28.8 +/- 6.5 ms in the LLTS group, but not in control subjects (p = 0.0002 for comparison between groups). Systemic (femoral vein) but not coronary sinus tumor necrosis factor (TNF)-alpha and C-reactive protein levels decreased significantly only in the LLTS group. CONCLUSIONS: LLTS suppresses AF and decreases inflammatory cytokines in patients with paroxysmal AF. Our results support the emerging paradigm of neuromodulation to treat AF. PMID- 25744004 TI - Looking beyond the ablation shore, treating atrial fibrillation from afar: integrating anatomic, physiologic, neurologic, and cardiovascular principles into novel therapies. PMID- 25744005 TI - Implantable cardioverter-defibrillator therapy in Brugada syndrome: a 20-year single-center experience. AB - BACKGROUND: Patients with Brugada syndrome and aborted sudden cardiac death or syncope have higher risks for ventricular arrhythmias (VAs) and should undergo implantable cardioverter-defibrillator (ICD) placement. Device-based management of asymptomatic patients is controversial. ICD therapy is associated with high rates of inappropriate shocks and device-related complications. OBJECTIVES: The objective of this study was to investigate clinical features, management, and long-term follow-up of ICD therapy in patients with Brugada syndrome. METHODS: Patients presenting with spontaneous or drug-induced Brugada type 1 electrocardiographic findings, who underwent ICD implantation and continuous follow-up at a single institution, were eligible for this study. RESULTS: A total of 176 consecutive patients were included. During a mean follow-up period of 83.8 +/- 57.3 months, spontaneous sustained VAs occurred in 30 patients (17%). Eight patients (4.5%) died. Appropriate ICD shocks occurred in 28 patients (15.9%), and 33 patients (18.7%) had inappropriate shocks. Electrical storm occurred in 4 subjects (2.3%). Twenty-eight patients (15.9%) experienced device-related complications. In multivariate Cox regression analysis, aborted sudden cardiac death and VA inducibility on electrophysiologic studies were independent predictors of appropriate shock occurrence. CONCLUSIONS: ICD therapy was an effective strategy in Brugada syndrome, treating potentially lethal arrhythmias in 17% of patients during long-term follow-up. Appropriate shocks were significantly associated with the presence of aborted sudden cardiac death but also occurred in 13% of asymptomatic patients. Risk stratification by electrophysiologic study may identify asymptomatic patients at risk for arrhythmic events and could be helpful in investigating syncope not related to VAs. ICD placement is frequently associated with device-related complications, and rates of inappropriate shocks remain high regardless of careful device programming. PMID- 25744006 TI - Programmed electrical stimulation for patients with asymptomatic Brugada syndrome? The shock-filled debate continues. PMID- 25744008 TI - Amyloid beta and cardiovascular disease: intriguing questions indeed. PMID- 25744007 TI - Amyloid-beta (1-40) and the risk of death from cardiovascular causes in patients with coronary heart disease. AB - BACKGROUND: The amyloid beta peptide is the major protein constituent of neuritic plaques in Alzheimer disease and appears to play a central role in vascular inflammation pathophysiology. OBJECTIVES: This study sought to determine the clinical value of amyloid-beta 1-40 (Abeta40) measurement in predicting cardiovascular (CV) mortality in patients with coronary heart disease (CHD) and arterial stiffness progression in young healthy subjects. METHODS: Abeta40 was retrospectively measured in blood samples collected from 3 independent prospective cohorts and 2 case-control cohorts (total N = 1,464). Major adverse cardiac events (MACE) were assessed in the 2 prospective cohorts (n = 877) followed for a median of 4.4 years. To look at effects on subclinical disease, arterial stiffness was evaluated at baseline and after 5-year follow-up (n = 107) in young healthy subjects. The primary endpoint was the predictive value of Abeta40 for CV mortality and outcomes in patients with CHD. RESULTS: In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, high-sensitivity C-reactive protein, and high-sensitivity troponin T, Abeta40 independently predicted CV death and MACE in patients with CHD (p < 0.05 for all). After multivariate adjustment, Abeta40 levels conferred a substantial enhancement of net reclassification index and integrated discrimination improvement of individuals at risk in the total combined CHD cohort over the best predictive model. Further cohort-based analysis revealed that Abeta40 levels were significantly and independently associated with arterial stiffness progression, incident subclinical atherosclerosis, and incident CHD. CONCLUSIONS: Measuring blood levels of Abeta40 identified patients at high risk for CV death. PMID- 25744009 TI - Trends in settings for peripheral vascular intervention and the effect of changes in the outpatient prospective payment system. AB - BACKGROUND: Peripheral vascular intervention (PVI) is an effective treatment option for patients with peripheral artery disease (PAD). In 2008, Medicare modified reimbursement rates to encourage more efficient outpatient use of PVI in the United States. OBJECTIVES: The purpose of this study was to evaluate trends in the use and clinical settings of PVI and the effect of changes in reimbursement. METHODS: Using a 5% national sample of Medicare fee-for-service beneficiaries from 2006 to 2011, we examined age- and sex-adjusted rates of PVI by year, type of procedure, clinical setting, and physician specialty. RESULTS: A total of 39,339 Medicare beneficiaries underwent revascularization for PAD between 2006 and 2011. The annual rate of PVI increased slightly from 401.4 to 419.6 per 100,000 Medicare beneficiaries (p = 0.17), but the clinical setting shifted. The rate of PVI declined in inpatient settings from 209.7 to 151.6 (p < 0.001), whereas the rate expanded in outpatient hospitals (184.7 to 228.5; p = 0.01) and office-based clinics (6.0 to 37.8; p = 0.008). The use of atherectomy increased 2-fold in outpatient hospital settings and 50-fold in office-based clinics during the study period. Mean costs of inpatient procedures were similar across all types of PVI, whereas mean costs of atherectomy procedures in outpatient and office-based clinics exceeded those of stenting and angioplasty procedures. CONCLUSIONS: From 2006 to 2011, overall rates of PVI increased minimally. However, after changes in reimbursement, PVI and atherectomy in outpatient facilities and office-based clinics increased dramatically, neutralizing cost savings to Medicare and highlighting the possible unintended consequences of coverage decisions. PMID- 25744010 TI - Incentives for clinical decisions where evidence is lacking. PMID- 25744012 TI - A proposal to incorporate trial data into a hybrid ACC/AHA algorithm for the allocation of statin therapy in primary prevention. AB - Current algorithms for statin allocation in primary prevention use epidemiologic estimates of absolute risk. However, a global risk prediction score has not been used as an enrollment criterion in any randomized trial of statin therapy. Moreover, completed statin trials show greater relative risk reductions for those patients at lower levels of absolute risk. Thus, risk calculators that rely solely on epidemiologic modeling do not ensure that those who will benefit are selected for treatment. We propose a hybrid approach to statin prescription for apparently healthy men and women that strongly endorses pharmacologic treatment for those who have estimated 10-year risks >=7.5% and for whom trial-based evidence supports statin efficacy in primary prevention. Although individuals could still be treated on the basis of absolute risk alone, the hybrid approach is evidence-based, is easily applied in clinical practice, and may increase the transparency of physician-patient interactions concerning prescription of statin therapy in primary prevention. PMID- 25744011 TI - Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus definitions from Peripheral Academic Research Consortium (PARC). AB - The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines to inform clinical decisions in patients with lower extremity peripheral artery disease. PMID- 25744013 TI - The state of the States: American College of Cardiology chapter successes, challenges, and future focus. PMID- 25744014 TI - Women in cardiology: fellows' perspective. PMID- 25744015 TI - Same-day discharge and risks of mortality and readmission after elective ICD placement for primary prevention. PMID- 25744016 TI - Cost effectiveness of continued-warfarin versus heparin-bridging therapy during pacemaker and defibrillator surgery. PMID- 25744017 TI - A mechanistic explanation for the minimal impact of renal denervation on 24-h ambulatory blood pressure in SIMPLICITY HTN-3. PMID- 25744018 TI - Reply: A mechanistic explanation for the minimal impact of renal denervation on 24-h ambulatory blood pressure in SIMPLICITY HTN-3. PMID- 25744019 TI - Aspiration thrombectomy: timing should be considered. PMID- 25744020 TI - Reply: Aspiration thrombectomy: timing should be considered. PMID- 25744021 TI - Presence of plicidentine in the oral teeth of the coelacanth Latimeria chalumnae Smith 1939 (Sarcopterygii; Actinistia). AB - The extant coelacanth Latimeria is a sarcopterygian predatory fish with caniniform teeth on its upper and lower jaws. The teeth are constituted of a cone of dentine with an apical cap of enamel, and they are fixed to the osseous component of the jaws by an attachment bone. Internal walls of the tooth base show folds that have been firstly interpreted in the past as radial vascular canals. Three-dimensional visualisation of these foldings using X-ray tomographic techniques and new histological interpretation lead to reconsider these structures as true plicidentine. The folds of the dentine do not invade the whole pulp cavity of the tooth contrary to the plicated condition of most fossil sarcopterygian fishes (e.g., Eusthenopteron, Porolepis, Megalichthys) certain fossil marine reptiles (ichthyosaurs) and extant varanids; in Latimeria they are limited to the lower third to the half of the pulp cavity. The presence of plicidentine in Latimeria's teeth is proposed to be a plesiomorphic character for sarcopterygians. PMID- 25744022 TI - The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs. AB - To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity. PMID- 25744023 TI - Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. AB - Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1(-/ ) and Casp1(-/-) mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-beta-mediated neuroinflammation and Casp6-mediated axonal degeneration. PMID- 25744024 TI - Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass. AB - The interplay between osteoblasts and osteoclasts has a crucial role in maintaining bone homeostasis. In this study, we reveal that osteoblasts are capable of inducing osteoclast apoptosis by FAS ligand (FASL)/FAS signaling. Conditional knockout of FASL in osteoblasts results in elevated osteoclast numbers and activity, along with reduced bone mass, suggesting that osteoblast produced FASL is required to maintain physiological bone mass. More interestingly, we show that osteoblasts from ovariectomized (OVX) osteoporotic mice exhibit decreased FASL expression that results from the IFN-gamma- and TNF alpha-activated NF-kappaB pathway, leading to reduced osteoclast apoptosis and increased bone resorption. Systemic administration of either IFN-gamma or TNF alpha ameliorates the osteoporotic phenotype in OVX mice and rescues FASL expression in osteoblasts. In addition, ovariectomy induces more significant bone loss in FASL conditional knockout mice than in control group with increased osteoclast activity in which the levels of RANKL and OPG remain unchanged. Taken together, this study suggests that osteoblast-induced osteoclast apoptosis via FASL/FAS signaling is a previously unrecognized mechanism that has an important role in the maintenance of bone mass in both physiological conditions and OVX osteoporosis. PMID- 25744025 TI - Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing. AB - Prelamin A accumulation and persistent DNA damage response (DDR) are hallmarks of vascular smooth muscle cell (VSMC) ageing and dysfunction. Although prelamin A is proposed to interfere with DNA repair, our understanding of the crosstalk between prelamin A and the repair process remains limited. The extracellular signal regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM) activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing. We show both prelamin A accumulation and increased DNA damage occur concomitantly, before VSMC replicative senescence, and induce the localisation of ERK1/2 to promyelocytic leukaemia protein nuclear bodies (PML NBs) at the sites of DNA damage via nesprin-2 and lamin A interactions. Importantly, VSMCs treated with DNA damaging agents also displayed prelamin A accumulation and ERK compartmentalisation at PML NBs, suggesting that prelamin A and nesprin-2 are novel components of the DDR. In support of this, disruption of ERK compartmentalisation at PML NBs, by either depletion of nesprin-2 or lamins A/C, resulted in the loss of ATM from DNA lesions. However, ATM signalling and DNA repair remained intact after lamins A/C depletion, whereas nesprin-2 disruption ablated downstream Chk2 activation and induced genomic instability. We conclude that lamins A/C and PML act as scaffolds to organise DNA-repair foci and compartmentalise nesprin-2/ERK signalling. However, nesprin-2/ERK signalling fidelity, but not their compartmentalisation at PML NBs, is essential for efficient DDR in VSMCs. PMID- 25744026 TI - Caspases shutdown nonsense-mediated mRNA decay during apoptosis. AB - Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that plays integral roles in eliminating mRNAs with premature termination codons to prevent the synthesis of truncated proteins that could be pathogenic. One response to the accumulation of detrimental proteins is apoptosis, which involves the activation of enzymatic pathways leading to protein and nucleic acid cleavage and culminating in cell death. It is not clear whether NMD is required to ensure the accurate expression of apoptosis genes or is no longer necessary since cytotoxic proteins are not an issue during cell death. The present study shows that caspases cleave the two NMD factors UPF1 and UPF2 during apoptosis impairing NMD. Our results demonstrate a new regulatory pathway for NMD that occurs during apoptosis and provide evidence for role of the UPF cleaved fragments in apoptosis and NMD inhibition. PMID- 25744028 TI - Accumulation of alkaline earth metals by the green macroalga Bryopsis maxima. AB - Twenty-five days after the disaster at the Fukushima Daiichi nuclear power plant in 2011, we collected samples of the green macroalga Bryopsis maxima from the Pacific coast of Japan. Bryopsis maxima is a unicellular, multinuclear, siphonous green macroalga. Radiation analysis revealed that B. maxima emitted remarkably high gamma radiation of (131)I, (134)Cs, (137)Cs, and (140)Ba as fission products of (235)U. Interestingly, B. maxima contained naturally occurring radionuclides derived from (226)Ra and (228)Ra. Analysis of element content revealed that B. maxima accumulates many ocean elements, especially high quantities of the alkaline earth metals Sr (15.9 g per dry-kg) and Ba (3.79 g per dry-kg), whereas Ca content (12.5 g per dry-kg) was lower than that of Sr and only 61 % of the mean content of 70 Japanese seaweed species. Time-course analysis determined the rate of radioactive (85)Sr incorporation into thalli to be approximately 0.13 g Sr per dry-kg of thallus per day. Subcellular fractionation of B. maxima cells showed that most of the (85)Sr was localized in the soluble fraction, predominantly in the vacuole or cytosol. Given that (85)Sr radioactivity was permeable through a dialysis membrane, the (85)Sr was considered to be a form of inorganic ion and/or bound with a small molecule. Precipitation analysis with sodium sulfate showed that more than 70% of the Sr did not precipitate as SrSO4, indicating that a proportion of the Sr may bind with small molecules in B. maxima. PMID- 25744027 TI - Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains. AB - Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak alpha9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that alpha9 does not line a pore. Bak (and Bax) activation allowed linkage of alpha9 to neighboring alpha9 segments, identifying an alpha9:alpha9 interface in Bak (and Bax) oligomers. Although the linkage pattern along alpha9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The alpha9:alpha9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high order oligomers were generated when alpha9:alpha9 linkage in the membrane was combined with alpha6:alpha6 linkage on the membrane surface, the alpha6-alpha9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore. PMID- 25744029 TI - Prospective validation of DACH2 as a novel biomarker for prediction of metastasis and prognosis in muscle-invasive urothelial carcinoma of the bladder. AB - Metastasis is the main cause of death from muscle-invasive urothelial carcinoma of the bladder (UCB), and the metastatic potential of tumors is often unpredictable. The role of Dachshund homolog 2 gene (DACH2) in tumorigenesis remains unexplored. We aimed to investigate whether DACH2 can be used as a biomarker to predict metastasis and prognosis of muscle-invasive UCB in a sequential training and validation fashion. For the training set (n = 40), compared with UCB patients without lymph node (LN) metastasis, both DACH2 protein and mRNA expression were greatly increased in case-matched patients with LN metastasis. For the independent validation set (n = 243), patients with primary UCB that did not express DACH2 had a longer metastasis-free survival (MFS) and overall survival (OS) than did those with tumors expressing DACH2 (5-year MFS: 88% [95% CI 80-96] versus 19% [95% CI 7-31], p < 0.001; 5-year OS: 93% [95% CI 87 99] versus 37% [95% CI 23-51], p < 0.001). Multivariable analysis of DACH2 status showed hazard ratios of 7.34 (95% CI 3.15-11.87, p < 0.001) for MFS and 3.96 (95% CI 2.04-7.16, p < 0.001) for OS which were much higher than hazard ratios associated with other independent risk factors. Collectively, DACH2 is an independent prognostic marker that can be used at initial diagnosis of UCB to identify patients who have a high potential to develop metastasis. PMID- 25744030 TI - Platelet-derived growth factor receptors form complexes with neuropilin-1 during megakaryocytic differentiation of thrombopoietin-dependent UT-7/TPO cells. AB - Neuropilin-1 (NRP-1) is involved in angiogenesis, but the role of NRP-1 in megakaryocytopoiesis is not yet fully understood. In this study, we investigated whether thrombopoietin (TPO) regulates the expression of platelet-derived growth factor (PDGF) and its receptors (PDGFRs) on TPO-dependent UT-7/TPO cells and whether PDGFRs and NRP-1 on UT-7/TPO cells form complexes during megakaryocytic differentiation. When UT-7/TPO cells were starved of TPO for 24 h and then stimulated with 5 ng/ml TPO, the expression of PDGF-B, PDGFRalpha, and PDGFRbeta were significantly up-regulated after the addition of TPO. TPO also induced tyrosine phosphorylation of PDGFRalpha but not PDGFRbeta, and promoted the formation of PDGFRalphabeta heterodimer complexes. Furthermore, megakaryocytic differentiation of UT-7/TPO cells on treatment with phorbol myristate acetate (PMA) was accompanied by a marked up-regulation of PDGFRbeta and NRP-1 protein expression, complex formation between PDGFRs and NRP-1, PDGFRalphabeta heterodimer complexes, and an increase in PDGF-BB-binding activity. Immunocytochemistry confirmed complex formation between PDGFRs and NRP-1 and PDGFRalphabeta heterodimer complexes in PMA-differentiated UT-7/TPO cells. Our observations suggest that NRP-1 is involved in megakaryocytopoiesis through complex formation with PDGFRs, and that NRP-1-PDGFR-complexes may contribute to effective cellular functions mediated by TPO and PDGF in megakaryocytic cells. PMID- 25744031 TI - A newly discovered neurotoxin ADTIQ associated with hyperglycemia and Parkinson's disease. AB - BACKGROUND: Diabetes is associated with an increased risk of Parkinson's disease (PD). Number of studies have suggested that methylglyoxal (MGO) induced by diabetes is related to PD. However, very little is known about its molecular mechanism. On other hand, 1-acetyl-6, 7- dihydroxyl-1, 2, 3, 4- Tetrahydroisoquinoline(ADTIQ) is a dopamine (DA)-derived tetrahydroisoquinoline (TIQ), a novel endogenous neurotoxins, which was first discovered in frozen Parkinson's disease human brain tissue. While ADTIQ precursor methylglyoxal was also found in diabetic patients related to the glucose metabolism and diabetic patients. METHODS: LC-MS/MS, 1H NMR and infrared spectroscopy identified the structure of ADTIQ. The Annexin V-FITC/PI, MTT and western blot analysis were used to measure the neurotoxicity of ADTIQ. The levels of ADTIQ and methylglyoxal were detected by LC-MS/MS. RESULTS: Here we report the chemical synthesis of ADTIQ, demonstrate its biosynthesis in SH-SY5Y neuroblastoma cell line and investigate its role in the pathogenesis of PD. In addition, a significant increase in the level of ADTIQ was detected in the brains of transgenic mice expressing mutant forms (A53T or A30P) of alpha-synuclein. ADTIQ also reduced the cell viability and induced mitochondrial apoptosis in dopaminergic cells, suggesting that ADTIQ acts as an endogenous neurotoxin and potentially involved in the pathogenesis of PD. Methylglyoxal, a major byproduct of glucose metabolism and abnormalities in glucose metabolism could influence the levels of ADTIQ. Consistent with the hypothesis, increased levels of ADTIQ and methylglyoxal were detected in the striatum of diabetic rats and SH-SY5Y cells cultured in the presence of high glucose concentrations. CONCLUSIONS: Increased levels of ADTIQ could be related with Hyperglycemia and death of dopaminergic neurons. GENERAL SIGNIFICANCE: The increased levels of ADTIQ could be a reason of dopamine neuron dysfunction in diabetes. Therefore, ADTIQ may play a key role in increasing the risk for PD in patients with diabetes. PMID- 25744032 TI - Low Birth Weight in MZ Twins Discordant for Birth Weight is Associated with Shorter Telomere Length and lower IQ, but not Anxiety/Depression in Later Life. AB - Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial sample from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication samples from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both samples and also in the Melbourne sample. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight. PMID- 25744033 TI - Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature. AB - Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17 years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder. PMID- 25744034 TI - Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs. AB - An established means of improving the pharmacokinetics properties of oligoribonucleotides (ORNs) is to exchange their phosphodiester linkages for phosphorothioates (PSs). However, this strategy has not been pursued for small interfering RNAs (siRNAs), possibly because of sporadic reports that PS siRNAs show reduced inhibitory activity. The PS group is chiral at phosphorous (Rp/Sp centres), and conventional solid-phase synthesis of PS ORNs produces a population of diastereoisomers. Here we show that the choice of the activating agent for the synthesis of a PS ORN influences the Rp/Sp ratio of PS linkages throughout the strand. Furthermore, PS siRNAs composed of ORNs with a higher fraction of Rp centres show greater resistance to nucleases in serum and are more effective inhibitors in cells than their Sp counterparts. The finding that a stereochemically biased population of ORN diastereoisomers can be synthesized and exploited pharmacologically is important because uniform PS modification of siRNAs may provide a useful compromise of their pharmacokinetics and pharmacodynamics properties in RNAi therapeutics. PMID- 25744035 TI - Characterisation of de novo mutations in the C-terminal domain of proprotein convertase subtilisin/kexin type 9. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the hepatic low-density lipoprotein receptor (LDL-R) and is therefore a prominent therapeutic target for reducing LDL-cholesterol. The C-terminal domain of PCSK9 is unlikely to be involved in a direct extracellular interaction with the LDL-R. We probed the importance of the C-terminus for the degradation of the LDL-R by designing seven de novo mutants of PCSK9 that fill potential druggable cavities. The mutants were tested for their ability to diminish LDL uptake in human HepG2 cells and for affinity towards a calcium independent mutant of the EGF(A) domain of the human LDL-R. The later was done by a newly developed surface plasmon resonance-based assay format. We identified three mutant proteins (G517R, V610R and V644R) with decreased ability to block LDL uptake into HepG2 cells. These mutations define areas outside the direct interaction area between PCSK9 and the LDL-R that could be targeted to inhibit the PCSK9 triggered degradation of the LDL-R. We also describe the mechanistic rationalisation of the affinity changes seen with the natural occurring human D374Y (gain of function) mutation causing severe hypercholesterolaemia. The action of this mutant is due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant. PMID- 25744036 TI - Improvement of the soy formate dehydrogenase properties by rational design. AB - Previous experiments on substitution of the residue Phe290 to Asp, Asn and Ser in NAD(+)-dependent formate dehydrogenase from soya Glycine max (SoyFDH) showed important role of the residue in enzyme thermal stability and catalytic properties (Alekseeva et al. Prot. Eng. Des. Sel., 2012a; 25: :781-88). In this work, we continued site-directed mutagenesis experiments of the Phe290 and the residue was changed to Ala, Thr, Tyr, Glu and Gln. All amino acid changes resulted in increase of catalytic constant from 2.9 to 3.5-4.7 s(-1). The substitution Phe290Ala led to KM (NAD+) decrease from 13.3 to 8.6 MUM, and substitutions Phe290Tyr and Phe290Glu resulted in decrease and increase of KM (HCOO-) from 1.5 to 0.9 and -2.9 mM, respectively. The highest improvement of catalytic properties was observed for SoyFDH Phe290Ala which showed 2-fold higher catalytic efficiency with both substrates. Stability of mutants was examined by study of thermal inactivation kinetics and differential scanning calorimetry (DSC). All five amino acids provided increase of thermal stability of mutant SoyFDH in comparison with wild-type enzyme. Mutant SoyFDH Phe290Glu showed the highest improvement-the stabilization effect was 43 at 56 degrees C. The DSC data agree with results of thermal inactivation kinetics. Substitutions Phe290Tyr, Phe290Thr, Phe290Gln and Phe290Glu provided Tm value increase 0.6 degrees -6.6 degrees . SoyFDH Phe290Glu and previously prepared SoyFDH Phe290Asp show similar thermal stability as enzymes from Candida boidinii and Mycobacterium vaccae N10 and have higher catalytic efficiency with NAD(+) compared with all described FDHs. Therefore, these mutants are very perspective enzymes for coenzyme regeneration in processes of chiral synthesis with dehydrogenases. PMID- 25744038 TI - [Picture in clinical hematology no. 78]. PMID- 25744037 TI - A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed towards the wild-type XIAP allele. AB - X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI. PMID- 25744039 TI - [Hematopoietic cell transplantation in Japan: nationwide survey 2013]. PMID- 25744040 TI - [Usefulness of quantitative PCR in biopsy specimens for early therapeutic intervention in gastro-intestinal cytomegalovirus infections after allogeneic stem cell transplantation]. AB - Gastro-intestinal cytomegalovirus infection (GI-CMV), which occurs after allogeneic stem cell transplantation (allo-SCT), is diagnosed by immunostaining of biopsied tissues obtained using a fiberscope. However, the sensitivity of this pathological diagnostic test is poor. We evaluated the suitability of using quantitative polymerase chain reaction (qPCR) to test GI-mucosal tissues for CMV. We analyzed adult patients who had undergone allo-SCT at our institute. Twenty seven specimens were collected from patients undergoing GI-fibers-copy for upper GI-symptoms after allo-SCT. Of these patients, 9 tested positive for CMV by qPCR; their symptoms resolved soon after receiving antiviral therapies for CMV. Pathological procedures detected GI-CMV in only 3 cases. In contrast, CMV qPCR was positive for 12 of 30 specimens collected from patients with lower GI symptoms by using colon fibers-copy. Antiviral therapies were effective in all but one case. GI-CMV was diagnosed pathologically in only 5 cases. Therefore, CMV qPCR is effective for early therapeutic intervention in CMV-GI patients after allo-SCT. PMID- 25744041 TI - [Sustained remission over 10 years after rituximab-monotherapy in a patient with primary duodenal follicular lymphoma]. AB - A 79-year-old man received gastrointestinal endoscopy for reexamination of a gastric submucosal tumor in May 2002 and whitish granular mucosa was found near the ampulla of Vater of the duodenum, though biopsy specimens showed only lymphocyte infiltrations. In December 2002, a second gastrointestinal endoscopy revealed an irregular granular elevated lesion around the ampulla of Vater and biopsy specimens showed pathological findings of follicular lymphoma. No other abnormal findings raising suspicion of tumor formation were observed on systemic examinations and the diagnosis of duodenal follicular lymphoma was confirmed. Systemic chemotherapy using rituximab at 375 mg/m(2) weekly for 4 consecutive weeks was started in January 2003. Six months later, endoscopic findings of the lesions revealed nearly normal mucosa around the ampulla of Vater, though histologically the biopsy specimens showed residual lymphoma cells. The same rituximab therapy as before was started in November. There has been no evidence of recurrence and a prolonged, more than 10 years, complete remission has been achieved. PMID- 25744042 TI - [Sustained deep molecular response over eight years after discontinuation of imatinib for chronic myeloid leukemia]. AB - A 72-year-old female was diagnosed with chronic phase chronic myeloid leukemia (CML) in 2001. After a short course of treatment with hydroxycarbamide, imatinib (IM) 400 mg was started. A major molecular response was presumably acquired 10 months later. IM was discontinued after treatment for 47 months in November 2005. At the same time, BCR-ABL transcript was undetectable by nested RT-PCR assay, which was equivalent to <0.00138% BCR-ABL according to the international scale. The patient is still under observation with no additional therapy, and BCR-ABL has remained negative for 102 months, to date. Furthermore, interferon was never used in this patient. IM has dramatically improved the prognosis of CML. Since no cure has yet been established, patients are recommended to continue treatment even after achieving deep molecular responses. There are several ongoing clinical trials challenging the discontinuation of IM, but long-term observation is still lacking. The sustained deep molecular response, exceeding eight years, experienced in this patient is potentially encouraging. PMID- 25744043 TI - [Epileptic encephalopathy associated with human herpes virus 6 (HHV-6) encephalitis after the second cord blood transplantation in a patient with pediatric acute lymphoblastic leukemia]. AB - The incidence of HHV-6 encephalitis during hematopoietic stem cell transplantation (HSCT) in children is thought to be less than that in adults and risk factors, prognosis and complications are virtually unknown. Herein, we report a pediatric case developing epileptic encephalopathy following HHV-6 encephalitis after a second cord blood transplantation (CBT). A 7-year-old boy with relapsed B-precursor acute lymphoblastic leukemia in second remission underwent CBT. However, he received a second CBT due to graft failure. On day 25 after the second CBT, he developed short-term memory defects and seizures. He was diagnosed with HHV-6 encephalitis because HHV-6 DNA was detected in his blood and cerebrospinal fluid and abnormal hippocampal signals were seen on cranial magnetic resonance imaging (MRI). After treatment with foscarnet, HHV-6 DNA levels and MRI findings improved; however, he developed epileptic encephalopathy five months after the onset of encephalitis. There are very few reports on pediatric epileptic encephalopathy associated with HHV-6 encephalitis after HSCT. Detailed studies are needed to analyze risk factors, prognosis, and complications. PMID- 25744044 TI - [Successful treatment of Bing-Neel syndrome using combination therapy with fludarabine and rituximab]. AB - Bing-Neel syndrome is known as Waldenstrom's macroglobulinemia with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells. A 74-year-old man was admitted because of progressive cognitive impairment. Serum immunoelectrophoresis showed a monoclonal IgM-kappa component. Bone marrow aspiration revealed 59% small lymphocytes showing plasmacytoid differentiation. Bone marrow flow cytometry disclosed a population of kappa light-chain positive lymphoid cells expressing CD19, CD20, CD38, and CD138. Magnetic resonance imaging of the brain demonstrated gadolinium-enhancement in the right temporo-parieto occipital meninges with sulcal enhancement. Cerebrospinal fluid cytology showed a population of lymphoplasmacytoid cells, positive for CD19, CD20, CD25, and kappa light-chain. Based on these findings, Bing-Neel syndrome was diagnosed. Although combination chemotherapy consisting of intrathecal methotrexate and oral cyclophosphamide was started, his symptoms continued to worsen. Then, we initiated treatment with a regimen consisting of fludarabine/rituximab (FR). After 6 courses of this FR regimen, a complete remission was achieved. Our case suggests the FR regimen to potentially be an effective treatment option for Bing Neel syndrome of the scattered type. PMID- 25744045 TI - [Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP]. AB - We report a 77-year-old Japanese man with idiopathic thrombocytopenic purpura (ITP) which developed into chronic myelogenous leukemia (CML) during treatment with eltrombopag, a thrombopoetin (TPO) receptor agonist, because the disease was refractory to prednisolone. Eltrombopag can induce a good reaction in terms of the platelet count. However, CML in the chronic phase developed in about 19 months in our present case. Dasatinib was administered because he had diabetes. However, a blastic crisis immediately occurred. He died despite switching to Nilotinib. Recently, the occurrence of myelofibrosis and hematological malignancies due to long-term use of TPO receptor agonists has become a concern. This is the first report of a TPO receptor agonist possibly contributing to CML onset and crisis. PMID- 25744046 TI - [Septic shock and necrotizing fasciitis due to Aeromonas hydrophila after chemotherapy in a patient with mantle cell lymphoma accompanied by liver cirrhosis]. AB - A 78-year-old man with liver cirrhosis was admitted to our hospital because of persistent diarrhea and abdominal pain. Colonoscopy revealed erosions and submucosal tumors in portions of the sigmoid colon and rectum, which were diagnosed as mantle cell lymphoma with biopsy. After chemotherapy consisting of vincristine and prednisone, he developed Aeromonas hydrophila septicemia, resulting in septic shock and necrotizing fasciitis despite prescribing antimicrobial agents to which this organism was susceptible. Whenever we intend to treat patients with hematological malignancies and an underlying chronic liver disease, we must keep this bacterium in mind. PMID- 25744048 TI - Effects of endocrine therapy on the prognosis of elderly patients after surgery for papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is a common thyroid malignancy. Elderly patients have more severe disease and more complications following postoperative endocrine therapy to control thyroid-stimulating hormone (TSH) levels. We aimed to identify optimal postoperative serum TSH levels in elderly patients to prevent recurrence and metastasis and minimize complications. This retrospective cohort study collected data of 87 consecutive elderly patients (age >75) who underwent surgery for PTC with postoperative levothyroxine therapy (50-150 MUg/d) between January 2006 and June 2008 and were followed until 2013. After 24 patients with TSH fluctuations and incomplete data were excluded, 73 patients were grouped based on postoperative TSH levels: Group A, 0.3-0.5 mIU/mL; Group B, 0.1-0.3 mIU/mL; and Group C <0.1 mIU/mL (n = 24, 25, 24, respectively). Subjects' baseline, preoperative data, postoperative complications and 1-, 3- and 5-year follow-up data were compared between groups. No significant differences in gender, age (median age of 80 years old), surgery type or clinical characteristics were found between groups (all p value >0.05). Postoperatively, all subjects had normal ECG and neck ultrasound, no osteoporosis, and no differences in survival rate or metastasis. Five-year follow-up revealed significant differences in development of arrhythmias, osteoporosis, insomnia and anxiety between Groups B (0.1-0.3 mIU/mL) and C (<0.1 mIU/mL) compared to Group A (0.3-0.5 mIU/mL). Postoperative incidence of PTC recurrence and metastasis remained stable in elderly patients undergoing thyroid surgery and endocrine therapy but complications increased significantly with increasing TSH levels. Controlling TSH to lower limits of normal may help prevent PTC recurrence and metastasis and reduce complications in this high-risk population. PMID- 25744049 TI - Hunger state affects both olfactory abilities and gustatory sensitivity. AB - Chemical senses such as odor, taste and appearance are directly related with appetite. Understanding the relation between appetite and flavor is getting more important due to increasing number of obese patients worldwide. The literature on the studies investigating the change in olfactory abilities and gustatory sensitivity mostly performed using food-related odors and tastes rather than standardized tests were developed to study olfaction and gustation. Therefore, results are inconsistent and the relationship between olfactory and gustatory sensitivity with respect to the actual state of human satiety is still not completely understood. Here, for the first time in literature, we investigated the change in both olfactory abilities and gustatory sensitivity in hunger and in satiety using 123 subjects (37 men, 86 women; mean age 31.4 years, age range 21 41 years). The standardized Sniffin' Sticks Extended Test and Taste Strips were used for olfactory testing and gustatory sensitivity, respectively. TDI score (range 1-48) was calculated as the collective scores of odor threshold (T), odor discrimination (D) and odor identification (I). The evaluation was performed in two successive days where the hunger state of test subjects was confirmed by blood glucose test strips (mean blood glucose level 90.0 +/- 5.6 mg/dl in hunger and 131.4 +/- 8.1 mg/dl in satiety). The results indicated statistically significant decrease in olfaction in satiety compared to hunger (mean TDI 39.3 +/ 1.1 in hunger, 37.4 +/- 1.1 in satiety, p < 0.001). The comparison of gustatory sensitivity indicated significantly higher sensitivity to sweet, sour and salty in hunger (p < 0.001), but significantly higher sensitivity to bitter tastant in satiety (p < 0.001). With this prospective study, we were able to show that both olfactory abilities and gustatory sensitivity were affected by hunger state. PMID- 25744050 TI - The NADPH oxidase inhibitor DPI can abolish hypoxia-induced apoptosis of human kidney proximal tubular epithelial cells through Bcl2 up-regulation via ERK activation without ROS reduction. AB - AIMS: Ischemia/reperfusion injury (IRI), resulting from hypoxic damage within a graft, is the leading cause of cell death and graft rejection. In this study, we investigated whether a HIF-1alpha inhibitor or various antioxidants were able to prevent ischemic injury in a cellular model in which experimental hypoxia was induced using CoCl2. MAIN METHODS: The ischemic injury induced in HK-2 cells by CoCl2 was validated by increased reactive oxygen species (ROS) production, reduced cell viability, and increased apoptosis at different times and doses. The preventative effects of various anti-oxidants on ischemic injury were evaluated using ROS levels, cell viability, and apoptosis. The MAPK phosphorylation status and Bcl2/Bax expression levels were evaluated after treatment with various antioxidants. KEY FINDINGS: The increase in ROS induced by hypoxia was significantly inhibited by NAC and CAPE, but not by any other treatment. The reduction in cell viability induced by CoCl2 was significantly inhibited by NAC and DPI, but not by any other treatment. The apoptosis induced by CoCl2 was also significantly inhibited by NAC and DPI, but not by any other treatment. Moreover, NAC and DPI prevented CoCl2-induced apoptosis in HK-2 cells in a dose- and time dependent manner. Treatment of CoCl2 and HK-2 cells treated with DPI, but not NAC, significantly induced ERK activation and Bcl2 expression. NAC and DPI treatment prevented the apoptosis of cells cultured under hypoxic conditions. SIGNIFICANCE: Our results suggest that DPI should be investigated further as a novel protective agent that prevents kidney ischemia. PMID- 25744051 TI - Leptin, 20 years of searching for glucose homeostasis. AB - Leptin was discovered in 1994 (20 years ago). In addition to having well characterized effects on the regulation of energy homeostasis, leptin clearly also plays a major role in metabolic homeostasis. In fact, leptin plays an important role in the regulation of glucose homeostasis independent of food intake and body weight. The mechanism underlying the modulation of glucose metabolism by leptin is not completely understood, although evidence indicates that the effect occurs at both the central and peripheral levels. In this review, we will focus on the role of leptin in glucose homeostasis at the central level and its role in insulin secretion and in counteracting hormones, such as glucagon, growth hormone, cortisol and catecholamines. PMID- 25744052 TI - Stochastic stability of sigma-point Unscented Predictive Filter. AB - In this paper, the Unscented Predictive Filter (UPF) is derived based on unscented transformation for nonlinear estimation, which breaks the confine of conventional sigma-point filters by employing Kalman filter as subject investigated merely. In order to facilitate the new method, the algorithm flow of UPF is given firstly. Then, the theoretical analyses demonstrate that the estimate accuracy of the model error and system for the UPF is higher than that of the conventional PF. Moreover, the authors analyze the stochastic boundedness and the error behavior of Unscented Predictive Filter (UPF) for general nonlinear systems in a stochastic framework. In particular, the theoretical results present that the estimation error remains bounded and the covariance keeps stable if the system's initial estimation error, disturbing noise terms as well as the model error are small enough, which is the core part of the UPF theory. All of the results have been demonstrated by numerical simulations for a nonlinear example system. PMID- 25744053 TI - Robust model reference adaptive output feedback tracking for uncertain linear systems with actuator fault based on reinforced dead-zone modification. AB - In this paper, robust model reference adaptive tracking controllers are considered for Single-Input Single-Output (SISO) and Multi-Input Multi-Output (MIMO) linear systems containing modeling uncertainties, unknown additive disturbances and actuator fault. Two new lemmas are proposed for both SISO and MIMO, under which dead-zone modification rule is improved such that the tracking error for any reference signal tends to zero in such systems. In the conventional approach, adaption of the controller parameters is ceased inside the dead-zone region which results tracking error, while preserving the system stability. In the proposed scheme, control signal is reinforced with an additive term based on tracking error inside the dead-zone which results in full reference tracking. In addition, no Fault Detection and Diagnosis (FDD) unit is needed in the proposed approach. Closed loop system stability and zero tracking error are proved by considering a suitable Lyapunov functions candidate. It is shown that the proposed control approach can assure that all the signals of the close loop system are bounded in faulty conditions. Finally, validity and performance of the new schemes have been illustrated through numerical simulations of SISO and MIMO systems in the presence of actuator faults, modeling uncertainty and output disturbance. PMID- 25744054 TI - High-gain visual feedback exacerbates ankle movement variability in children. AB - The purpose was to compare the effect of low- and high-gain visual feedback on ankle movement variability and muscle activation in children and young adults. Six young adults (19.8 +/- 0.6 years) and nine children (9.4 +/- 1.6 years) traced a sinusoidal target by performing ankle plantar/dorsiflexion movements. The targeted range of motion was 10 degrees , and the frequency of the sinusoidal target was 0.4 Hz for 35 s. Low-gain visual feedback was 0.66 degrees , and high gain visual feedback was 4.68 degrees . Surface EMG was recorded from the tibialis anterior (TA) muscle. Movement variability amplitude was quantified as the standard deviation of the position fluctuations after the task frequency was removed with a notch filter (second-order; 0.3-0.5 Hz). We quantified the oscillations in movement variability and TA EMG burst using the following frequency bands: 0-0.3, 0.3-0.6, 0.6-0.9, 0.9-1.2, and 1.2-1.5 Hz. Children exhibited greater movement variability than young adults, which was exacerbated during the high-gain visual feedback condition (P < 0.05). The greater ankle movement variability in children at the high-gain visual feedback condition was predicted by greater power within the 0-0.3 Hz of their movement variability (R (2) = 0.51, P < 0.001). The greater power in movement variability from 0 to 0.3 Hz in children was predicted by greater power within the 0-0.3 Hz in their TA EMG burst activity (R (2) = 0.6, P < 0.001). The observed deficiency in movement control with amplified visual feedback in children may be related to an ineffective use of visual feedback and the immaturity of the cortico-motor systems. PMID- 25744056 TI - Fluctuating expression of microRNAs in adenovirus infected cells. AB - The changes in cellular microRNA (miRNA) expression during the course of an adenovirus type 2 infection in human lung fibroblast were studied by deep RNA sequencing. Expressions of 175 miRNAs with over 100 transcripts per million nucleotides were changed more than 1.5-fold. The expression patterns of these miRNAs changed dramatically during the course of the infection, from upregulation of the miRNAs known as tumor suppressors (such as miR-22, miR-320, let-7, miR 181b, and miR-155) and down-regulation of oncogenic miRNAs (such as miR-21 and miR-31) early to downregulation of tumor suppressor miRNAs (such as let-7 family, mir-30 family, 23/27 cluster) and upregulation of oncogenic miRNAs (include miR 125, miR-27, miR-191) late after infection. The switch in miRNA expression pattern occurred when adenovirus DNA replication started. Furthermore, deregulation of cellular miRNA expression was a step-wise and special sets of miRNAs were deregulated in different phases of infection. PMID- 25744055 TI - Neural processes mediating the preparation and release of focal motor output are suppressed or absent during imagined movement. AB - Movements that are executed or imagined activate a similar subset of cortical regions, but the extent to which this activity represents functionally equivalent neural processes is unclear. During preparation for an executed movement, presentation of a startling acoustic stimulus (SAS) evokes a premature release of the planned movement with the spatial and temporal features of the tasks essentially intact. If imagined movement incorporates the same preparatory processes as executed movement, then a SAS should release the planned movement during preparation. This hypothesis was tested using an instructed-delay cueing paradigm during which subjects were required to rapidly release a handheld weight while maintaining the posture of the arm or to perform first-person imagery of the same task while holding the weight. In a subset of trials, a SAS was presented at 1500, 500, or 200 ms prior to the release cue. Task-appropriate preparation during executed and imagined movements was confirmed by electroencephalographic recording of a contingent negative variation waveform. During preparation for executed movement, a SAS often resulted in premature release of the weight with the probability of release progressively increasing from 24 % at -1500 ms to 80 % at -200 ms. In contrast, the SAS rarely (<2 % of trials) triggered a release of the weight during imagined movement. However, the SAS frequently evoked the planned postural response (suppression of bicep brachii muscle activity) irrespective of the task or timing of stimulation (even during periods of postural hold without preparation). These findings provide evidence that neural processes mediating the preparation and release of the focal motor task (release of the weight) are markedly attenuated or absent during imagined movement and that postural and focal components of the task are prepared independently. PMID- 25744057 TI - Distinctive binding modes and inhibitory mechanisms of two peptidic inhibitors of urokinase-type plasminogen activator with isomeric P1 residues. AB - Two isomeric piperidine derivatives (meta and para isomers) were used as arginine mimics in the P1 position of a cyclic peptidic inhibitor (CPAYSRYLDC) of urokinase-type plasminogen activator. The two resulting cyclic peptides showed vastly different affinities (~70 fold) to the target enzyme. X-ray crystal structure analysis showed that the two P1 residues were inserted into the S1 specificity pocket in indistinguishable manners. However, the rest of the peptides bound in entirely different ways on the surface of the enzyme, and the two peptides have different conformations, despite the highly similar sequence. These results demonstrate how the subtle difference in P1 residue can dictate the exosite interactions and the potencies of peptidic inhibitors, and highlight the importance of the P1 residue for protease inhibition. This study provides important information for the development of peptidic agents for pharmacological intervention. PMID- 25744058 TI - An evolutionary inspection game with labour unions on small-world networks. AB - We study an evolutionary inspection game where agents can chose between working and shirking. The evolutionary process is staged on a small-world network, through which agents compare their incomes and, based on the outcome, decide which strategy to adopt. Moreover, we introduce union members that have certain privileges, of which the extent depends on the bargaining power of the union. We determine how the union affects the overall performance of the firm that employs the agents, and what are its influences on the employees. We find that, depending on its bargaining power, the union has significant leverage to deteriorate the productivity of a firm, and consequently also to lower the long-run benefits of the employees. PMID- 25744059 TI - Fast and robust estimation of spectro-temporal receptive fields using stochastic approximations. AB - BACKGROUND: The receptive field (RF) represents the signal preferences of sensory neurons and is the primary analysis method for understanding sensory coding. While it is essential to estimate a neuron's RF, finding numerical solutions to increasingly complex RF models can become computationally intensive, in particular for high-dimensional stimuli or when many neurons are involved. NEW METHOD: Here we propose an optimization scheme based on stochastic approximations that facilitate this task. The basic idea is to derive solutions on a random subset rather than computing the full solution on the available data set. To test this, we applied different optimization schemes based on stochastic gradient descent (SGD) to both the generalized linear model (GLM) and a recently developed classification-based RF estimation approach. RESULTS AND COMPARISON WITH EXISTING METHOD: Using simulated and recorded responses, we demonstrate that RF parameter optimization based on state-of-the-art SGD algorithms produces robust estimates of the spectro-temporal receptive field (STRF). Results on recordings from the auditory midbrain demonstrate that stochastic approximations preserve both predictive power and tuning properties of STRFs. A correlation of 0.93 with the STRF derived from the full solution may be obtained in less than 10% of the full solution's estimation time. We also present an on-line algorithm that allows simultaneous monitoring of STRF properties of more than 30 neurons on a single computer. CONCLUSIONS: The proposed approach may not only prove helpful for large scale recordings but also provides a more comprehensive characterization of neural tuning in experiments than standard tuning curves. PMID- 25744060 TI - Human JC virus small tumour antigen inhibits nucleotide excision repair and sensitises cells to DNA-damaging agents. AB - The human JC virus (JCV) is potentially carcinogenic to humans as a Group 2B carcinogen, and it is ubiquitous in human populations. To investigate whether the small tumour (ST) antigen of the JCV contributes to genomic instability, we established cell lines stably expressing the JCV ST and examined its role in DNA repair. Results from host cell reactivation (HCR) assay revealed that the established cell lines exhibited lower nucleotide excision repair (NER) activity than the vector control cells did. The presence of gamma-H2AX, a marker of DNA damage, indicated that the established cell line contained more DNA damage foci compared with vector control cells. Furthermore, the results of clonogenic analyses indicated that the JCV ST-expressing cells were more sensitive than the vector control cells to ultraviolet (UV) irradiation and cisplatin treatment. Micronuclei formation assay revealed that the JCV ST-positive cells presented more chromosomal breakages than did the JCV ST-negative cells, particularly after exposure to DNA-damaging agents. The xeroderma pigmentosum Group D protein, a DNA helicase involved in NER, was downregulated in the JCV ST-positive cells in response to UV irradiation. The effect of the protein phosphatase 2A (PP2A) inhibitor okadaic acid on NER was similar to that of the ST, which is a PP2A binding protein. Therefore, the deactivation of the PP2A might underlie ST mediated NER inhibition. The results of this study indicate that exposing JCV ST positive cells to DNA-damaging agents causes genomic instability, which contributes to carcinogenesis. Our data provide further evidence on the association between the JCV ST and human cancer. PMID- 25744061 TI - Functional restoration of exhausted CD4(+) and CD8(+) T cells in chronic viral infection by vinegar-processed flos of Daphne genkwa. AB - T-cell exhaustion has become an important issue in chronic infection because exhausted antigen-specific T cells show impaired abilities to eradicate persistently infected pathogens and produce effector cytokines, such as IFN-gamma and TNF-alpha. Thus, strategies to either restore endogenous exhausted T cell responses or provide functional T cells are needed for therapeutics of chronic infection. Despite promising developments using antibodies and cell immunotherapy, there have been no reported attempts to restore exhausted T cells using treatment with materials derived from natural resources. Here, using a mouse model of chronic infection with lymphocytic choriomeningitis virus (LCMV), we found that vinegar-processed flowers (flos) of Daphne genkwa (vp-genkwa), which was composed mainly of four index components, restored exhausted CD4(+) and CD8(+) T cells significantly, as corroborated by evidence that vp-genkwa treatment enhanced functional LCMV-specific CD4(+) and CD8(+) T cells, both quantitatively and qualitatively. Furthermore, pretreatment with vp-genkwa prevented the generation of exhausted LCMV-specific CD8(+) T cells. Such restorations of exhausted LCMV-specific CD4(+) and CD8(+) T cells by vp-genkwa were closely associated with reduced viral burden in sera and tissues. More interestingly, vp-genkwa treatment induced down-regulation of negative molecules, such as PD-1 and Tim-3, in exhausted CD4(+) and CD8(+) T cells with more apparent down-regulation of Tim-3, suggesting that Tim-3 molecule may be a major target in restoring exhausted T cell responses. Collectively, these results provide valuable new insights into the use of vp-genkwa to develop a therapeutic strategy for chronic human diseases, such as hepatitis B and C virus, human immunodeficiency virus, and cancers. PMID- 25744062 TI - Reducing pain from heel lances in neonates following education on oral sucrose. AB - BACKGROUND: Heel lances are common painful procedures performed in the neonatal intensive care unit (NICU). Upon observation, pain relieving methods were not consistently applied during such procedures in our institution. OBJECTIVE: The objective of this three-phase quality improvement project was to improve pain management for heel lance-induced pain in the NICU. SETTING: This study took place in a 27-bed NICU in a level IV perinatal regional center at a 591 bed university affiliated teaching hospital in New York, United States. METHOD: Study Phase 1, involving 25 neonates, documented baseline pain management strategies and pain scores, which were measured before, during, and after heel lancing using the Neonatal Pain Agitation and Sedation Scale (N-PASS). In Study Phase 2, nurses and physicians were educated on the use of sucrose and non-pharmacological measures to prevent and manage heel lance-induced pain. Study Phase 3 (Post education evaluation), had the same procedure as Study Phase 1, and involved another host of 25 neonates. MAIN OUTCOME MEASURE: Pain scores were compared in groups of neonates in Phase 1 (before education) and Phase 3 (after education) before, during and after heel lancing. Other outcome measures included quantifying the use of sucrose and documenting any adverse effects. RESULTS: We found an 84 % increase in the use of sucrose post-education (Phase 3), and most importantly, an 11.2 % reduction in pain scores from heel lances in neonates. Four neonates who did not receive sucrose in Phase 3 had higher pain scores during heel lancing than those who did (3.5 and 2.38, respectively). There were no adverse effects reported with sucrose. CONCLUSION: Health care providers were aware of sucrose but were not using this treatment modality, despite its availability on nursing units. Education was effective in the adoption of sucrose use, leading to a reduction in pain from heel lances in neonates. PMID- 25744063 TI - Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix. AB - E3 ubiquitin ligase Cbl-b and c-Cbl play important roles in bone formation and maintenance. Cbl-b and c-Cbl regulate the activity of various receptor tyrosine kinases and intracellular protein tyrosine kinases mainly by regulating the degradation of target proteins. However, the precise mechanisms of how Cbl-b and c-Cbl regulate osteoblast differentiation are not well known. In this study, we investigated potential targets of Cbl-b and c-Cbl. We found that Cbl-b and c-Cbl inhibit BMP2-induced osteoblast differentiation in mesenchymal cells. Among various osteogenic transcription factors, we identified that Cbl-b and c-Cbl suppress the protein stability and transcriptional activity of Osterix. Our results suggest that Cbl-b and c-Cbl inhibit the function of Osterix by enhancing the ubiquitin-proteasome-mediated degradation of Osterix. Taken together, we propose novel regulatory roles of Cbl-b and c-Cbl during osteoblast differentiation in which Cbl-b and c-Cbl regulate the degradation of Osterix through the ubiquitin-proteasome pathway. PMID- 25744064 TI - Lectin-like oxidized low-density lipoprotein receptor-1 abrogation causes resistance to inflammatory bone destruction in mice, despite promoting osteoclastogenesis in the steady state. AB - Inflammatory bone diseases have been attributed to increased bone resorption by augmented and activated bone-resorbing osteoclasts in response to inflammation. Although the production of diverse proinflammatory cytokines is induced at the inflamed sites, the inflammation also generates reactive oxygen species that modify many biological compounds, including lipids. Among the oxidized low density lipoprotein (LDL) receptors, lectin-like oxidized LDL receptor-1 (LOX-1), which is a key molecule in the pathogenesis of multifactorial inflammatory atherosclerosis, was downregulated with osteoclast differentiation. Here, we demonstrate that LOX-1 negatively regulates osteoclast differentiation by basically suppressing the cell-cell fusion of preosteoclasts. The LOX-1-deleted (LOX-1(-/-)) mice consistently decreased the trabecular bone mass because of elevated bone resorption during the growing phase. In contrast, when the calvaria was inflamed by a local lipopolysaccharide-injection, the inflammation-induced bone destruction accompanied by the elevated expression of osteoclastogenesis related genes was reduced by LOX-1 deficiency. Moreover, the expression of receptor activator of NF-kappaB ligand (RANKL), a trigger molecule for osteoclast differentiation, evoked by the inflammation was also abrogated in the LOX-1(-/-) mice. Osteoblasts, the major producers of RANKL, also expressed LOX-1 in response to proinflammatory agents, interleukin-1beta and prostaglandin E2. In the co culture of LOX-1(-/-) osteoblasts and wild-type osteoclast precursors, the osteoclastogenesis induced by interleukin-1beta and prostaglandin E2 decreased; this process occurred in parallel with the downregulation of osteoblastic RANKL expression. Collectively, LOX-1 abrogation results in resistance to inflammatory bone destruction, despite promoting osteoclastogenesis in the steady state. Our findings indicate the novel involvement of LOX-1 in physiological bone homeostasis and inflammatory bone diseases. PMID- 25744065 TI - The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis. AB - BACKGROUND: Tumor-induced lymphangiogenesis facilitates breast cancer progression by generating new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes and beyond. Given the recent evidence suggesting the implication of C-C chemokine ligand 21/chemokine receptor 7 (CCL21/CCR7) in lymph node metastasis, the aim of our study was to define the role of this chemokine pair in breast cancer-associated lymphangiogenesis. METHODS: The expression analysis of CCL21/CCR7 pair and lymphatic endothelial cell (LEC) markers in breast cancer specimens was performed by means of quantitative real-time PCR. By utilizing CCR7 and CCL21 gene manipulated breast cancer cell implants into orthotopic sites of nude mice, lymphatic vessel formation was assessed through quantitative real-time PCR, immunohistochemistry and immunofluorescence assays. Finally, the lymphangiogenic potential of CCL21/CCR7 was assessed in vitro with primary LECs through separate functional assays, each attempting to mimic different stages of the lymphangiogenic process. RESULTS: We found that CCR7 mRNA expression in human breast cancer tissues positively correlates with the expression of lymphatic endothelial markers LYVE-1, podoplanin, Prox-1, and vascular endothelial growth factor-C (VEGF-C). We demonstrated that the expression of CCL21/CCR7 by breast cancer cells has the ability to promote tumor induced lymph-vascular recruitment in vivo. In vitro, CCL21/CCR7 chemokine axis regulates the expression and secretion of lymphangiogenic factor VEGF-C and thereby promotes proliferation, migration, as well as tube formation of the primary human LECs. Finally, we showed that protein kinase B (AKT) signaling pathway is the intracellular mechanism of CCR7-mediated VEGF-C secretion by human breast cancer cells. CONCLUSIONS: These results reveal that CCR7 and VEGF-C display a significant crosstalk and suggest a novel role of the CCL21/CCR7 chemokine axis in the promotion of breast cancer-induced lymphangiogenesis. PMID- 25744066 TI - An atypical presentation of visual conversion disorder. AB - Nonorganic vision loss accounts for up to 5% of patients and presents in two forms, malingering and visual conversion disorder (VCD). It is described a case of VCD in a new mother struggling both with her husband being deployed overseas and the recent death of her father. In addition, she had been evaluated for a concussion secondary to a motor vehicle accident three months prior. An inexpensive series of clinical tests were performed to rule out organic disease and obtained equivocal results. Some tests revealed intact vision in the affected eye while others supported a neurological cause for the vision loss. However, the patient quickly recovered normal visual acuity when encouraged to discuss situations that have been causing emotional stress. This almost immediate recovery of vision confirmed the diagnosis of VCD. This report should make primary eye care professionals more aware of visual conversion disorder and its clinical evaluation. PMID- 25744067 TI - Literature and art therapy in post-stroke psychological disorders. AB - Stroke is one of the leading causes of morbidity and long-term disability worldwide, and post-stroke depression (PSD) is a common and serious psychiatric complication of stroke. PSD makes patients have more severe deficits in activities of daily living, a worse functional outcome, more severe cognitive deficits and increased mortality as compared to stroke patients without depression. Therefore, to reduce or prevent mental problems of stroke patients, psychological treatment should be recommended. Literature and art therapy are highly effective psychological treatment for stroke patients. Literature therapy divided into poetry and story therapy is an assistive tool that treats neurosis as well as emotional or behavioral disorders. Poetry can add impression to the lethargic life of a patient with PSD, thereby acting as a natural treatment. Story therapy can change the gloomy psychological state of patients into a bright and healthy story, and therefore can help stroke patients to overcome their emotional disabilities. Art therapy is one form of psychological therapy that can treat depression and anxiety in stroke patients. Stroke patients can express their internal conflicts, emotions, and psychological status through art works or processes and it would be a healing process of mental problems. Music therapy can relieve the suppressed emotions of patients and add vitality to the body, while giving them the energy to share their feelings with others. In conclusion, literature and art therapy can identify the emotional status of patients and serve as a useful auxiliary tool to help stroke patients in their rehabilitation process. PMID- 25744068 TI - Resolution of polyserositis after removal of appendix mucinous cystadenoma. AB - Mucinous cystadenoma is a rare benign neoplasm and is usually discovered incidentally. Pleuritis and pericarditis, inflammation of the pleura and pericardium, may represent manifestations of autoimmune disorders especially in female subjects. We report a patient with polyserositis that was resolved after removal of the mucinous cystadenoma. To the best of our knowledge, this is a first report describing pleuritis and pericarditis as an initial presentation of mucinous cystadenoma of an appendix. A forty-year-old Caucasian female patient with a history of pleuritis and recurrent pericarditis was admitted to the hospital due to acute abdomen. At that time she was taking indomethacin and colchicine due to pericarditis that was controlled only with the combination of these two drugs. The patient had elevated erythrocyte sedimentation rate (ESR), increased C-reactive protein (CRP) and normocytic anemia. Immunological tests, including antinuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies, were repeatedly negative. Emergency surgery revealed acute appendicitis with perforation and subsequent diffuse peritonitis. Histopathological examination showed acute appendicitis and mucinous cystadenoma. Following the surgery the patient did not take any drugs. Fourteen months later the patient was symptom free. Pleuritis and pericarditis in female patients are most often associated with autoimmune diseases. We assume that increased ESR and CRP with anemia detected in the patient may reflect the altered immunity that is due to mucinous cystadenoma. We believe that this report has a broader clinical impact, implying that benign tumor could alter immunity, which can lead to unusual presentation such as polyserositis. PMID- 25744069 TI - Current understanding of pathogenesis and treatment of TMJ osteoarthritis. AB - Osteoarthritis is a common disease that can cause severe pain and dysfunction in any joint, including the temporomandibular joint (TMJ). TMJ osteoarthritis (TMJOA) is an important subtype in the classification of temporomandibular disorders. TMJOA pathology is characterized by progressive cartilage degradation, subchondral bone remodeling, and chronic inflammation in the synovial tissue. However, the exact pathogenesis and process of TMJOA remain to be understood. An increasing number of studies have recently focused on inflammation and remodeling of subchondral bone during the early stage of TMJOA, which may elucidate the possible mechanism of initiation and progression of TMJOA. The treatment strategy for TMJOA aims at relieving pain, preventing the progression of cartilage and subchondral bone destruction, and restoring joint function. Conservative therapy with nonsteroidal anti-inflammatory drugs, splint, and physical therapy, such as low-energy laser and arthrocentesis, are the most common treatments for TMJOA. These therapies are effective in most cases in relieving the signs and symptoms, but their long-term therapeutic effect on the pathologic articular structure is unsatisfactory. A treatment that can reverse the damage of TMJOA remains unavailable to date. Treatments that prevent the progression of cartilage degradation and subchondral bone damage should be explored, and regeneration for the TMJ may provide the ideal long-term solution. This review summarizes the current understanding of mechanisms underlying the pathogenesis and treatment of TMJOA. PMID- 25744070 TI - PPARgamma Maintains Homeostasis through Autophagy Regulation in Dental Pulp. AB - This study investigated the relevance between pulp vitality and autophagy in aged human dental pulp cells (HDPCs) and whether peroxisome proliferator-activated receptor gamma (PPARgamma) affects autophagy regulation for homeostasis in the aging progress. In vivo experiments were used in human and Sprague-Dawley rat teeth obtained from young and adult individuals. Aging- and autophagy-related molecules were determined by immunohistochemistry and hematoxylin and eosin staining. HDPCs were serially subcultured until spontaneously arrested for in vitro aging, and the replication deficiency adenovirus was introduced for PPARgamma overexpression. Subsequently, the effect of PPARgamma on regulation of autophagy molecules, mitochondria activity, and cell viability was assessed using Western blotting, confocal microscopy, and the MTT assay, respectively. In adult pulp tissue, autophagy molecules (autophagy protein 5, microtubule-associated protein 1A/1B light chain, and Beclin-1) were increased, but aging-related (PPARgamma and heme oxygenase 1 [HO-1]) and dentinogenesis (dentin sialophosphoprotein and dentin matrix acidic phosphoprotein) molecules were decreased. In aged HDPCs, autophagy and intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were increased, while PPARgamma and HO-1 were decreased. Under stimulation with lipopolysaccharide, autophagy- and aging related molecules were differentially expressed between young and aged cells. PPARgamma induced HO-1 and autophagy molecules but reduced inflammatory molecules in aged cells. In addition, PPARgamma activated strong mitochondrial activity and cell viability in aging cells. Inhibition of HO-1 by tin protoporphyrin IX exacerbated autophagy and mitochondrial activity as well as cell viability in young cells. This study indicates that PPARgamma maintains pulp homeostasis through the regulation of autophagy molecules during the life span of HDPCs. PMID- 25744071 TI - [Comparison of differentiated thyroid carcinoma staging systems in a Spanish population]. AB - BACKGROUND AND OBJECTIVE: Differentiated thyroid carcinoma staging is increasingly important due to the current trends to a less intensive therapy in low-risk patients. The TNM system is most widely used, but other systems based on follow-up of several patient cohorts have been developed. When these systems have been applied to other populations, results have been discordant. Our study evaluates the suitability of several differentiated thyroid carcinoma staging systems in a Spanish population. MATERIAL AND METHOD: 729 patients with differentiated thyroid carcinoma and staging data available were enrolled. Mean follow-up time was 10.8 years. The TNM, EORTC, AMES, Clinical class, MACIS, Ohio, NTCTCS, and Spanish systems were applied to all histological types. The Kaplan Meier survival curves for each system were analyzed, and compared using the proportion of explained variation (PEV). RESULTS: The demographic and clinical characteristics of our population were similar to those of other Spanish and international cohorts reported. The best systems were NTCTCS, with 74.7% PEV, and TNM (68.3%), followed by the Ohio, MACIS, EORTC, and AMES systems with minimal differences between them, while the least adequate were the Spanish (55.2%) and Clinical class (47.1%) systems. CONCLUSION: The NTCTCS staging system was found to be better than TNM in our population but, because of its simplicity and greater dissemination, the TNM appears to be recommended for staging of patients with differentiated thyroid carcinoma. PMID- 25744072 TI - Intrasellar ependymoma: clinical, imaging, pathological, and surgical findings. AB - Ependymomas arising in the intrasellar compartment are extremely rare and most often are not included in the differential diagnosis of an intrasellar tumor mass. We review the literature to further advance awareness regarding unusual presentations of this type of tumor and present an illustrative case of an intrasellar cystic ependymoma that developed in an uncommon location. In our illustrative case, the patient had a 2 year history of hypopituitarism, but no headaches or visual disturbance. Preoperatively, the lesion was thought to be a pituitary macroadenoma. PMID- 25744073 TI - Endoscopic lumbar foraminotomy. AB - Foraminal stenosis frequently causes radiculopathy in lumbar degenerative spondylosis. Endoscopic transforaminal techniques allow for foraminal access with minimal tissue disruption. However, the effectiveness of foraminal decompression by endoscopic techniques has yet to be studied. We evaluate radiographic outcome of endoscopic transforaminal foraminotomies performed at L3-L4, L4-L5, and L5-S1 on cadaveric specimens. Before and after the procedures, three dimensional CT scans were obtained to measure foraminal height and area. Following the foraminotomies, complete laminectomies and facetectomies were performed to assess for dural tears or nerve root damage. L3-L4 preoperative foraminal height increased by 8.9%, from 2.12+/-0.13cm to 2.27+/-0.14cm (p<0.01), and foraminal area increased by 24.8% from 2.21+/-0.18cm(2) to 2.72+/-0.19cm(2) (p<0.01). At L4 L5, preoperative foraminal height was 1.87+/-0.17cm and area was 1.78+/ 0.18cm(2). Endoscopic foraminotomies resulted in a 15.3% increase of foraminal height (2.11+/-0.15cm, p<0.05) and 44.8% increase in area of (2.51+/-0.21cm(2), p<0.01). At L5-S1, spondylitic changes caused diminished foraminal height (1.26+/ 0.14cm) and foraminal area (1.17+/-0.18cm(2)). Postoperatively, foraminal height increased by 41.6% (1.74+/-0.09cm, p<0.05) and area increased by 98.7% (2.08+/ 0.17cm(2), p<0.01). Subsequent inspection via a standard midline approach revealed one dural tear of an S1 nerve root. Endoscopic foraminotomies allow for effective foraminal decompression, though clinical studies are necessary to further evaluate complications and efficacy. PMID- 25744074 TI - High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery. AB - Intracranial atherosclerosis is associated with recurrent ischemic stroke. High resolution MRI (HR MRI) can provide information about atheroma in vivo. We aimed to analyze and compare vascular wall imaging characteristics between patients with symptomatic and asymptomatic atherosclerotic stenosis of the middle cerebral artery (MCA) using 3.0 Tesla HR MRI. The HR MRI protocol included four different scans: black blood T1-weighted, T2-weighted and proton density-weighted MRI, as well as three-dimensional turbo spin echo imaging techniques with multiplanar reconstruction. Plaque characteristics, including location, morphology, and signal intensity, were analyzed in 51 patients (29 symptomatic, 22 asymptomatic) with atherosclerotic stenosis of the middle cerebral artery. The vessel wall area, lumen area, and plaque area (PA) were also calculated and compared between the symptomatic and asymptomatic groups. We found that PA, remodeling index (RI), and positive remodeling (PR) prevalence were significantly greater in the symptomatic group than in the asymptomatic group (PA: p=0.033; RI: p=0.020; PR: p=0.032). Plaque location in the superior aspect of the vessel wall and irregular plaque surface were more frequently observed in the symptomatic group than in the asymptomatic group (superior location: p=0.031; irregular surface: p=0.036). Moreover, multivariate logistic regression identified plaque location on the superior wall as an independent predictor of symptomatic MCA stenosis (odds ratio: 4.471; p=0.039). Therefore, we can conclude that patients with symptomatic atherosclerotic stenosis of the MCA are more likely to have larger plaques, PR, superiorly located plaques, and irregular plaque surface. These characteristics are promising factors for stratifying stroke risk. PMID- 25744075 TI - Analysis of prognostic factors and treatment of anaplastic meningioma in China. AB - Meningioma is the most frequently reported primary brain and central nervous system tumor. However, malignant meningioma is rare with the anaplastic subtype the most common. This subtype of meningioma is fatal with a high recurrence rate and poor survival. A retrospective review of anaplastic meningioma patients treated in one of the largest neurosurgical centers in China between 2003 and 2008 was conducted. From 70 identified patients, seven were lost to follow-up, but the remaining 63 patients were studied for prognostic factors. The mean follow-up time was 84.9+/-standard deviation (SD) of 19.7months. Tumor recurred in 35 out of 63 (55.6%) patients. Thirty-three (52.4%) patients had died by the most recent follow-up, and the median overall survival (OS) was 70.0+/-9.7months. The 3year and 5year survival rates were 68.3% and 54.7%, respectively. The median progression-free survival (PFS) was 52.0+/-9.9months, whereas the 3year and 5year PFS rates were 60.2% and 43.9%, respectively. We found that preoperative KPS, extent of tumor resection, radiotherapy, tumor location and previous history of meningioma were factors related to PFS. In the non-recurrent group, the preoperative Karnofsky Performance Scale (KPS), extent of tumor resection and radiotherapy correlated with PFS. However, multivariate analysis identified radiotherapy as the only independent factor affecting PFS (p=0.007). Additionally, MIB-1 proliferation index failed to identify a cut-off point to predict the prognosis for anaplastic meningioma. This study provides an overview of the epidemiology and treatment of anaplastic meningioma in China using a large population. PMID- 25744076 TI - Multimodal treatment and management strategies for intracranial hemangiopericytoma. AB - Intracranial hemangiopericytoma (HPC) is a rare malignant meningothelial tumor. The authors retrospectively reviewed the long-term clinical outcomes of patients with HPC with regard to treatment modalities and histopathological grades. Eighteen women and 20 men (mean age 38.5 years, range, 18-62 years) were observed over an average follow-up period of 61 months (range, 15-133 months) between 2003 and 2013. The initial treatment modalities included total tumor resection followed by conventional radiotherapy (RT) (n=27), and subtotal tumor resection followed by stereotactic radiosurgery (n=11). One patient (3%) had permanent neurological deficits, and six patients (16%) died. Thirteen patients (34%) suffered recurrence. One year, 5 year, and 10 year recurrence-free survival rates were 100%, 70%, and 39%, respectively. Five patients (13%) developed metastasis. One year, 5 year, and 10 year metastasis-free survival rates were 100%, 89%, 74%, respectively. Low grade tumors were associated with longer overall survival, recurrence-free interval and metastasis-free interval (log-rank, p<0.05). Radical resection with RT was associated with longer overall survival and recurrence-free interval (log-rank, p<0.05), but had no effect on the metastasis-free interval (log-rank, p=0.245). Thus, radical surgery followed by adjuvant RT is the primary treatment of HPC, but recurrence and metastasis remain a common treatment outcome regardless of initial strategy. It is necessary to maintain long-term follow-up and serial imaging for all patients with intracranial HPC after treatment, regardless of extent of resection. PMID- 25744077 TI - Quantification of subconcussive impact forces to the head using a forensic model. AB - Concussive and subconcussive head injury is a global phenomenon that affects millions of people each year. Concussive injury has been extensively studied in sport, which has led to a greater understanding of the biomechanical forces involved and guidelines aimed at preventing athletes from playing while concussed. Subconcussive forces by definition do not meet the threshold for concussion but nonetheless may have significant long term consequences due to the repetitive pattern of injury to the head. Quantifying these impact forces using a forensic head model provides the groundwork for future studies by establishing a range or threshold of subconcussive impact forces that could be correlated with clinical assessments. The use of a forensic head model has distinct advantages in terms of ethics and safety. PMID- 25744079 TI - Correction to ADC values in diffusion-weighted MRI and their relationship with age, gender and BMI in healthy people's pancreases. PMID- 25744078 TI - Induction of burst suppression or coma using intravenous anesthetics in refractory status epilepticus. AB - General anesthetic-induced coma therapy has been recommended for the treatment of refractory status epilepticus (RSE). However, the influence of electroencephalographic (EEG) burst suppression (BS) on outcomes still remains unclear. This study investigated the impact of intravenous anesthetic-induced BS on the prognosis of RSE using a retrospective analysis of all consecutive adult patients who received intravenous anesthetic treatment for RSE at the Seoul National University Hospital between January 2006 and June 2011. Twenty-two of the 111 episodes of RSE were enrolled in this study. Of the 22 RSE patients, 12 (54.5%) were women and 18 (81.4%) exhibited generalized convulsive status epilepticus. Sixteen patients (72.7%) were classified as having acute symptomatic etiology, including three patients with anoxic encephalopathy, and others with remote symptomatic etiology. Only two patients (9.1%) had a favorable Status Epilepticus Severity Score (0-2) at admission. All patients received midazolam (MDZ) as a primary intravenous anesthetic drug for RSE treatment; three (13.6%) received MDZ and propofol, and one (4.5%) received MDZ and pentobarbital. The rates of mortality and poor outcome at discharge were 13.6% (n=3) and 54.5% (n=12), respectively. While BS was achieved in six (27.5%) patients, it was not associated with mortality or poor outcome. Induced BS was associated with prolonged hospital stay in subgroup analysis when excluding anoxic encephalopathy. Our results suggest that induction of BS for treating RSE did not affect mortality or outcome at discharge and may lead to an increased length of hospital stay. PMID- 25744080 TI - Partially coherent ultrafast spectrography. AB - Modern ultrafast metrology relies on the postulate that the pulse to be measured is fully coherent, that is, that it can be completely described by its spectrum and spectral phase. However, synthesizing fully coherent pulses is not always possible in practice, especially in the domain of emerging ultrashort X-ray sources where temporal metrology is strongly needed. Here we demonstrate how frequency-resolved optical gating (FROG), the first and one of the most widespread techniques for pulse characterization, can be adapted to measure partially coherent pulses even down to the attosecond timescale. No modification of experimental apparatuses is required; only the processing of the measurement changes. To do so, we take our inspiration from other branches of physics where partial coherence is routinely dealt with, such as quantum optics and coherent diffractive imaging. This will have important and immediate applications, such as enabling the measurement of X-ray free-electron laser pulses despite timing jitter. PMID- 25744081 TI - Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart. AB - Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. (13)C6 glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart. PMID- 25744082 TI - Experimental treatment of a refinery waste air stream, for BTEX removal, by water scrubbing and biotrickling on a bed of Mitilus edulis shells. AB - The paper presents the results of a two-stage pilot plant for the removal of benzene, toluene, ethylbenzene and xylene (BTEX) from a waste air stream of a refinery wastewater treatment plant (WWTP). The pilot plant consisted of a water scrubber followed by a biotrickling filter (BTF). The exhausted air was drawn from the main works of the WWTP in order to prevent the free migration to the atmosphere of these volatile hazardous contaminants. Concentrations were detected at average values of 12.4 mg Nm(-3) for benzene, 11.1 mg Nm(-3) for toluene, 2.7 mg Nm(-3) for ethylbenzene and 9.5 mg Nm(-3) for xylene, with considerable fluctuation mainly for benzene and toluene (peak concentrations of 56.8 and 55.0 mg Nm(-3), respectively). The two treatment stages proved to play an effective complementary task: the water scrubber demonstrated the ability to remove the concentration peaks, whereas the BTF was effective as a polishing stage. The overall average removal efficiency achieved was 94.8% while the scrubber and BTF elimination capacity were 37.8 and 15.6 g BTEX d(-1) m(-3), respectively. This result has led to outlet average concentrations of 1.02, 0.25, 0.32 and 0.26 mg Nm(-3) for benzene, toluene, ethylbenzene and xylene, respectively. The paper also compares these final concentrations with toxic and odour threshold concentrations. PMID- 25744083 TI - Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization. AB - BACKGROUND: In a growth phase occurring during most of folliculogenesis, the oocyte produces and accumulates molecules and organelles that are fundamental for the development of the preimplantation embryo. At ovulation, growth is followed by a phase of maturation that, although confined within a short temporal window, encompasses modifications of the oocyte chromosome complement and rearrangements of cytoplasmic components that are crucial for the achievement of developmental competence. Cumulus cells (CCs) are central to the process of maturation, providing the oocyte with metabolic support and regulatory cues. METHODS: PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews concerning oocyte maturation in mammals. Searches were performed adopting 'oocyte' and 'maturation' as main terms, in association with other keywords expressing concepts relevant to the subject. The most relevant publications, i.e. those concerning major phenomena occurring during oocyte maturation in established experimental models and the human species, were assessed and discussed critically to offer a comprehensive description of the process of oocyte maturation. RESULTS: By applying the above described search criteria, 6165 publications were identified, of which 543 were review articles. The number of publications increased steadily from 1974 (n = 7) to 2013 (n = 293). In 2014, from January to the time of submission of this manuscript, 140 original manuscripts and reviews were published. The studies selected for this review extend previous knowledge and shed new and astounding knowledge on oocyte maturation. It has long been known that resumption of meiosis and progression to the metaphase II stage is intrinsic to oocyte maturation, but novel findings have revealed that specific chromatin configurations are indicative of a propensity of the oocyte to resume the meiotic process and acquire developmental competence. Recently, genetic integrity has also been characterized as a factor with important implications for oocyte maturation and quality. Changes occurring in the cytoplasmic compartment are equally fundamental. Microtubules, actin filaments and chromatin not only interact to finalize chromosome segregation, but also crucially co-operate to establish cell asymmetry. This allows polar body extrusion to be accomplished with minimal loss of cytoplasm. The cytoskeleton also orchestrates the rearrangement of organelles in preparation for fertilization. For example, during maturation the distribution of the endoplasmic reticulum undergoes major modifications guided by microtubules and microfilaments to make the oocyte more competent in the generation of intracellular Ca(2+) oscillations that are pivotal for triggering egg activation. Cumulus cells are inherent to the process of oocyte maturation, emitting regulatory signals via direct cell-to-cell contacts and paracrine factors. In addition to nurturing the oocyte with key metabolites, CCs regulate meiotic resumption and modulate the function of the oocyte cytoskeleton. CONCLUSIONS: Although the importance of oocyte maturation for the achievement of female meiosis has long been recognized, until recently much less was known of the significance of this process in relation to other fundamental developmental events. Studies on chromatin dynamics and integrity have extended our understanding of female meiosis. Concomitantly, cytoskeletal and organelle changes and the ancillary role of CCs have been better appreciated. This is expected to inspire novel concepts and advances in assisted reproduction technologies, such as the development of novel in vitro maturation systems and the identification of biomarkers of oocyte quality. PMID- 25744084 TI - Idiopathic optic perineuritis: disguised as recurrent optic neuritis. PMID- 25744085 TI - An organic transistor-based system for reference-less electrophysiological monitoring of excitable cells. AB - In the last four decades, substantial advances have been done in the understanding of the electrical behavior of excitable cells. From the introduction in the early 70's of the Ion Sensitive Field Effect Transistor (ISFET), a lot of effort has been put in the development of more and more performing transistor-based devices to reliably interface electrogenic cells such as, for example, cardiac myocytes and neurons. However, depending on the type of application, the electronic devices used to this aim face several problems like the intrinsic rigidity of the materials (associated with foreign body rejection reactions), lack of transparency and the presence of a reference electrode. Here, an innovative system based on a novel kind of organic thin film transistor (OTFT), called organic charge modulated FET (OCMFET), is proposed as a flexible, transparent, reference-less transducer of the electrical activity of electrogenic cells. The exploitation of organic electronics in interfacing the living matters will open up new perspectives in the electrophysiological field allowing us to head toward a modern era of flexible, reference-less, and low cost probes with high-spatial and high-temporal resolution for a new generation of in-vitro and in vivo monitoring platforms. PMID- 25744086 TI - Local muscle endurance is associated with fatigue-based changes in electromyographic spectral properties, but not with conduction velocity. AB - The purpose of this study was to examine the associations amongst muscle fiber action potential conduction velocity (CV), spectral characteristics of the surface electromyographic (EMG) signal, and endurance time during a sustained submaximal isometric muscle action. Eleven men (mean+/-SD age=23+/-4yrs) performed a sustained, submaximal isometric muscle action of the dominant forearm flexors at 60% of the maximum voluntary contraction (MVC) until the designated force level could no longer be maintained. Sixteen separate bipolar surface EMG signals were detected from the biceps brachii with a linear electrode array during this contraction. Two channels from this array were used to measure CV, and one of these two channels was used for further EMG signal processing. The channels that provided the highest signal quality were used for the CV measurements and further data analysis. A wavelet analysis was then used to analyze the bipolar EMG signal, and the resulting wavelet spectrum was decomposed with a nonparametric spectral decomposition procedure. The results showed that the time to exhaustion during the sustained contraction was not correlated with the rate of decrease in CV, but it was highly correlated with both the decrease in high-frequency spectral power (r=0.947) and the increase in low-frequency spectral power (r=0.960). These findings are particularly interesting, considering that the decrease in traditional EMG spectral variables (e.g., mean frequency or median frequency) with fatigue is generally attributed to reductions in CV. While this may indeed be true, the present results suggested that other factors (i.e., other than CV) that can affect the shape of the EMG frequency spectrum during fatigue are more important in determining the endurance capabilities of the muscle than is CV. PMID- 25744087 TI - Work stressors, perseverative cognition and objective sleep quality: a longitudinal study among Dutch Helicopter Emergency Medical Service (HEMS) Pilots. AB - OBJECTIVES: This longitudinal study examined the associations between work stressors, perseverative cognition and subjective and objective sleep quality. We hypothesized work stressors to be associated with (i) poor nocturnal sleep quality and (ii) higher levels of perseverative cognition during a free evening. We further hypothesized (iii) perseverative cognition to be associated with poor nocturnal sleep quality and (iv) the association between work stressors and sleep quality to be mediated by perseverative cognition. METHODS: The participants were 24 pilots working for the Dutch Helicopter Emergency Medical Service (HEMS). They completed six questionnaires: at the end of three consecutive day shifts and each morning following the shifts. The questionnaires addressed work stressors (workload, distressing shifts and work-related conflicts), subjective sleep quality and perseverative cognition. Participants wore actigraphs to assess sleep onset latency, total sleep time and number of awakenings. RESULTS: Correlation analysis revealed that (i) distressing shifts were related to delayed sleep onset (r=0.50, p=0.026) and that workload was related to impaired sleep quality (e.g., subjective sleep quality: r=-0.42, p=0.044). Moreover, (ii) distressing shifts were positively related to perseverative cognition (r=0.62, p=0.002), (iii) perseverative cognition delayed sleep onset (r=0.74, p<0.001) and (iv) mediated the association between distressing shifts and sleep onset latency. CONCLUSIONS: Perseverative cognition may be an explanatory mechanism in the association between work stressors and poor sleep. PMID- 25744088 TI - An empirical study on the wake around a squatting worker in a confined space. AB - OBJECTIVES: When an air current flows from behind a worker, the contaminant level in the breathing zone may increase due to the wake around the worker. Researchers have been investigating about this wake, and much knowledge has been provided about the wake that appears around a standing worker. However, the wake around a squatting worker has not been addressed. This study aimed to describe the wake in front of a worker squatting in a confined space by using a model worker and a chamber and investigate the conditions in which this wake develops easily. METHODS: A mannequin was employed as a model worker and was placed in the chamber to simulate a squatting worker in a confined space. Then, air was sent from behind under various conditions with a fan, and the wake was observed. RESULTS: A wake appeared when smoke was emitted at 0-0.1 m from the point just below the breathing zone, and most of the wake region was in the range between the point just below the model worker's breathing zone and body. A wake did not appear when a fan of 0.15 m in diameter was used. The flow rate and velocity of the airflow were almost irrelevant with respect to wake development. CONCLUSIONS: The following are recommended based on the results of the present study. i) The distance between a source of contaminants and the point just below the breathing zone should be more than 0.2 m. ii) An air duct with a cross-section of less than 0.02 m(2) is desirable to avoid producing a wake. PMID- 25744089 TI - Immunocytochemical detection of beta-defensins and cathelicidins in the secretory granules of the tongue in the lizard Anolis carolinensis. AB - Previous molecular studies indicated that antimicrobial peptides in lizard are expressed in the skin and tongue among other epithelial organs. The present ultrastructural immunogold study aimed to detect the specific location of three broadly expressed antimicrobial peptides in the tongue of the lizard Anolis carolinensis. The immunocytochemical study indicated that beta-defensin-15, the likely main defensin of granulocytes and skin, is poorly expressed in some dense and medium-dense granules of glandular cells of the papillated tongue. Conversely beta-defensin-27 appears highly expressed in numerous pale and cribriform dense granules of glandular cells and is also secreted on the tongue surface. The immunostaining for cathelicidin-1 indicated a variable but however positive immunolabeling in numerous granules in the tongue glands, suggesting that this antimicrobial peptide previously found on the epidermal surface is also present in the tongue secretions and participates to the formation of the anti-microbial oral barrier. The study suggests that among the numerous beta-defensins and cathelicidins identified in the genome of this lizard is present a specific distribution of different peptide subtypes in various body regions, including the tongue, and that these peptides contribute to the formation of local antimicrobial barriers. PMID- 25744090 TI - Head and neck solitary infantile myofibroma: Clinicopathological and immunohistochemical features of a case series. AB - Infantile myofibroma is a rare mesenchymal benign tumor mostly found in the head and neck region. The aim of this study was to describe a small case series of head and neck solitary infantile myofibroma, emphasizing the importance of the histopathological and immunohistochemical features, and the potential diagnostic challenges. For the study, clinical and imaging data were obtained from the medical records. All cases were histologically reviewed, and immunohistochemical analyses were performed to confirm the diagnosis. Four cases of head and neck solitary infantile myofibroma were identified. All patients were females and presented a mean age of 3 years old (ranging from 2 to 6 years). The site of the tumors were the mandible, right cheek, subcutaneous tissue adjacent to basal cortical of the mandible and upper anterior gingiva. No symptoms, such as pain or paresthesia, were reported. Computerized tomography revealed well-delimited tumors. All tumors were positive for vimentin and alpha-smooth muscle actin. All patients underwent surgical excision and no signs of recurrence were observed after long-term follow-up. In summary, head and neck solitary infantile myofibromas are rare and present excellent prognosis. The correlation between clinical, histopathological and immunohistochemical features are essential for a correct diagnosis. PMID- 25744091 TI - Skeletal anchorage for everybody? a questionnaire study on frequency of use and clinical indications in daily practice. AB - AIM: The purpose of this survey was to determine how commonly, and in what clinical situations, German-based orthodontists use skeletal anchorage devices in daily clinical practice. METHOD: In early 2013, a set of questionnaires on the subject of skeletal anchorage devices was mailed to 2459 members of the German Orthodontic Society (Deutsche Gesellschaft fur Kieferorthopadie, DGKFO). The questions dealt separately with mini screws (MSCs) and osseointegrated palatal implants (OPIs). The addresses were asked whether or not, as well as how frequently and in what clinical situations, they used these MSCs and/or OPIs, what their experience was, and to elaborate on their reasons for using or not using these devices. RESULTS: The rate of returned questionnaires was 48 %. To correctly interpret our data, it should be kept in mind that an unknown number of respondents did not distinguish between OPIs and palatally inserted MSCs. Overall, 62 % indicated that they did use MSCs and/or OPIs, although most of them (> 50 %) infrequently (<= 2 new patients/3 months). Only <= 2 % were frequent users (> 2 new patients/week). While most users (> 70 %) indicated that their experience was mostly good, only <= 50 % considered the devices easy and trouble free to use in daily clinical practice. The median percentage of insertion procedures conducted by the respondents themselves was 2 % for MSCs and 0 % for OPIs. Many of the non-users indicated that their treatment concept did not include suitable clinical indications (>= 50 %), expressed skepticism about the success rates (56 % of MSC and 21 % of OPI non-users), or thought that the insertion procedures involved were too complex or time-consuming (33 % of MSC and 56 % of OPI non-users). CONCLUSION: A total of 62 % of German-based orthodontists participating in this survey indicated using skeletal anchorage devices, although most of them infrequently. Major reasons for non-use were lack of clinical indications, skepticism about the success rate of MSCs, and overly complex or time-consuming procedures of surgical OPI insertion. PMID- 25744092 TI - Effect of archwire qualities and bracket designs on the force systems during leveling of malaligned teeth. AB - OBJECTIVES: The force systems during multiband treatment are influenced by the selection of the bracket-archwire combinations. Resin models replicated from casts reflecting the pretreatment intraoral situation of a patient's mandible were used to explore how different bracket systems and archwire qualities would affect the force systems developing during simulated orthodontic leveling of several malaligned teeth. MATERIALS AND METHODS: Leveling movements of the malaligned teeth 32, 33, and 34 were simulated using the orthodontic measurement and simulation system (OMSS). Two bracket types and three archwire qualities were compared, the former featuring a slot width of 0.022" (0.56 mm) and including one conventional (Freedom MIM Roth by ODS) and one passive self-ligating (Carriere MBT by ODS) design. Both were combined with three NiTi round 0.014" (0.36 mm) archwire products, two of them standard products (CuNiTi by Ormco; EuroArch by ODS) and one being a low-cost (NiTi Superelastic by Modern Arch) product. Measured parameters included force, torque, translation, and rotation. RESULTS: Archwire qualities are critical to the force systems developing in the leveling stage. On the other hand, the finding that lower force/torque values result in less tooth movement is not primarily due to wire selection. Our most striking result was that the ODS EuroArch wire resulted in very low force and torque values both with the conventional and with the self-ligating brackets. Almost identical patterns with these two bracket designs were found, and none of the measured parameters revealed a significant advantage for any of the bracket archwire combinations over the others. CONCLUSION: In our experimental simulations of tooth leveling, wire-quality selection was found to be a key modifier of force, torque, translation, and rotation. Clearly, however, neither the wire qualities nor the bracket designs made a decisive difference to the amounts of leveling movement induced to malaligned teeth; other factors like tooth class or nature of the malalignment seem to be more important in this regard. A therapeutic benefit of self-ligating over conventional brackets was not demonstrable. PMID- 25744093 TI - Artifacts in orthodontic bracket systems in cone-beam computed tomography and multislice computed tomography. AB - OBJECTIVES: The purpose of this study was to quantify artifacts caused by different bracket systems in cone-beam computed tomography (CBCT) and multislice computed tomography (MSCT) scans. METHODS: Orthodontic brackets of four different systems were consecutively bonded to the surface of a residual molar on a human cadaveric mandible. One MSCT system and three CBCT units were used to scan each of the four bonded brackets, in addition to obtaining a blank reference scan of the tooth surface. All datasets were registered to the reference dataset using visualization software (Analyze 11.0(r) by AnalyzeDirect). Artifact-related reductions in image quality were expressed in percent of theoretical maximum standard deviations (SD) obtained for the gray values of the adjacent voxels, with higher percentages correlating more pronounced artifacts. RESULTS: Both the SD percentages for three defined line profiles and their mean values were almost invariably higher with the MSCT system than with the CBCT units. Looking into the individual SD percentages, two of the CBCT units (Pax Zenith 3D(r) and Picasso Trio(r); both Vatech) produced higher values than the MSCT system (SOMATOM Definition AS+(r); Siemens) in some line profiles. The titanium bracket, in particular, was associated with marked differences between the two scanner technologies, as the mean artifact intensities from this bracket were particularly high with the MSCT unit and relatively low with the CBCT units. The artifact intensities observed with the other three bracket systems varied widely depending on which scanner was used. CONCLUSION: Different artifact intensities were noted depending on the composition of the bracket system and on the scanner technology (MSCT/CBCT). While the artifacts manifested themselves differently with different scanners, their adverse effects were comparable. However, given the variable severity of the artifacts observed depending on the materials scanned and the scanners used, a blanket recommendation for or against MSCT or CBCT units cannot be given on the basis of this study. PMID- 25744094 TI - Novel lingual retainer created using CAD/CAM technology: evaluation of its positioning accuracy. AB - OBJECTIVES: Permanent retention is currently the method of choice to stabilize orthodontic treatment results. Frequently, permanent retention schemes are adopted to prevent posttreatment changes in the esthetic zone of the anterior teeth. With increasingly prolonged times of intraoral device use, and retention to be provided in the maxilla despite limited space, the demands placed on well planned and precise retainer positioning are becoming more exacting. The aim of the present study was to analyze the intraoral precision of lingual retainers made using computer-aided design and machining (CAD/CAM). MATERIALS AND METHODS: A custom manufacturer (Retaintechnology; Cologne, Germany) employing innovative CAD/CAM technology was commissioned to fabricate 16 lingual retainers. Following intraoral insertion using the manufacturer's recommended transfer system, impressions of the intraoral situations were taken and scanned for digitization. On this basis, the intraoral retainer positions were compared to the preceding virtual setups by superimposition with the manufacturer's datasets. Three dimensional processing software (Geomagic Qualify 2012; Geomagic) was used to analyze the retainers, based on a total of 80 interproximal sites, for deviations from their planned positions along the horizontal (x-), sagittal (y-), and vertical (z-) axes. These deviations of the achieved from the intended positions were considered clinically relevant if >= 0.5 mm and, based on this premise, were subjected to a t-test with statistical software (Prism; GraphPad). RESULTS: The intraoral retainer positions were found to correlate closely with the preceding virtual setups (i.e., the positions as they had been planned by the custom manufacturer). Positional deviations were significantly less than 0.5 mm. They were very small in the horizontal and sagittal planes and moderately larger in the vertical plane. CONCLUSION: Highly precise intraoral results may be achieved by transferring three-dimensional virtual setups for lingual retainers to the actual patients. This CAD/CAM strategy of making retainers can offer high predictability even in anatomically demanding regions and in the presence of limited space. PMID- 25744095 TI - Shear bond strength of different adhesives tested in accordance with DIN 13990-1/ 2 and using various methods of enamel conditioning. AB - OBJECTIVES: The purpose of this work was to analyze the shear bond strength (SBS) of different adhesives for orthodontic brackets in accordance with DIN 13990-1/ 2, also taking into consideration potential effects arising from different scenarios of enamel conditioning and specimen storage. MATERIALS AND METHODS: A total of 390 experiments were performed, with groups of 10 specimens subjected to identical treatments. Three adhesives were tested: TransbondTM XT (3M Unitek, Monrovia, USA), Beauty Ortho Bond (Shofu, Kyoto, Japan), and Fuji Ortho LC (GC Europe, Leuven, Belgium). SBS was evaluated separately at the bracket-adhesive and adhesive-enamel interfaces, as well as the total (enamel-adhesive-bracket) interface. The brackets were metal brackets for upper right central incisors (Discovery(r) from Dentaurum, Ispringen, Germany). A universal testing machine (Zwick Z010, Ulm, Germany) was used for testing the SBS after 15 min, or after storage in distilled water at 37 degrees C for 24 h, or after 24 h followed by 500 thermocycles alternating between 5 and 55 degrees C. RESULTS: TransbondTM XT produced the highest levels of SBS. The least favorable performance was observed with Fuji Ortho LC after enamel conditioning with 10 % polyacrylic acid. Thermocycling did not have a significant influence. CONCLUSION: TransbondTM XT and Beauty Ortho Bond (but not Fuji Ortho LC) yielded levels of SBS adequate for clinical application (>= 7 MPa). PMID- 25744096 TI - Regioselective annulation of nitrosopyridine with alkynes: straightforward synthesis of N-oxide-imidazopyridines. AB - We have developed a novel method for the regioselective annulation of 2 nitrosopyridines with variably substituted alkynes under mild reaction conditions. This approach allows the annulation of alkynes with 2 nitrosopyridines under reagent- and catalyst-free reaction conditions. The developed method shows excellent functional group tolerance and provides easy access to N-oxide-imidazo[1,2-a]pyridines. PMID- 25744097 TI - Experts question how India will meet promises on public health after cut in budget for 2015-16. PMID- 25744098 TI - Inhibition of miR-134 Protects Against Hydrogen Peroxide-Induced Apoptosis in Retinal Ganglion Cells. AB - MicroRNAs (miRNAs) have been suggested to play an important role in neurological diseases. Particularly, miR-134 is reportedly involved in regulating neuron survival. However, the association between miR-134 and retinal ganglion cell (RGC) survival under adverse stimulus has not been extensively investigated. In this study, we aimed to explore the role and underlying mechanism of miR-134 in regulating RGC apoptosis in response to hydrogen peroxide (H2O2) treatment. Results showed that the expression of miR-134 dose- and time-dependently increased in RGC after H2O2 treatment. H2O2-induced RGC apoptosis was significantly attenuated by the inhibition of miR-134 expression by antagomiR-134 and was enhanced by miR-134 overexpression. Luciferase reporter assay revealed a direct interaction between miR-134 and the 3'-untranslated region of cyclic AMP response element-binding protein (CREB), a critical transcription factor for neuronal protection. In H2O2-treated RGCs, the inhibition of miR-134 significantly elevated the expression of CREB and its downstream genes, including brain-derived neurotrophic factor (BDNF) and Bcl-2. Furthermore, the inhibition of miR-134 also increased the expression of miR-132, a rapid response gene downstream of CREB. In addition, the target gene of miR-132, acetylcholinesterase was expectedly decreased by miR-134 inhibition. However, the overexpression of miR-134 exerted an opposite effect. The knockdown of CREB apparently abolished the protective effect of miR-134 inhibition against H2O2-induced RGC apoptosis. The increased expression of BDNF and Bcl-2 induced by miR-134 inhibition was also abrogated by CREB knockdown. Overall, our results suggested that the downregulation of miR-134 can effectively protect against H2O2-induced RGC apoptosis by negatively modulating CREB expression. PMID- 25744099 TI - Humanin Does Not Protect Against STZ-Induced Spatial Memory Impairment. AB - [Gly14]-Humanin (HNG) is a 24-amino acid peptide which was first identified in the brains of patients diagnosed with Alzheimer's disease (AD). In this region, some neurons were protected against cell damage occurring in this disease. Further studies suggested a neuroprotective role for humanin against Abeta and some other insults. Intraventricularly administered streptozotocin (STZ) disrupts insulin signaling pathway which leads to behavioral and biochemical changes resemble to early signs of AD; therefore, STZ model has been proposed as a model for sporadic Alzheimer's disease (sAD). Regarding the reported beneficial effects of humanin in AD, this study was aimed to investigate if this peptide prevents spatial memory and hippocampal PI3/Akt signaling impairment induced by centrally injected STZ. Adult male Sprague-Dawely rats weighting 250-300 g were used, and cannuls were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3 mg/kg), and humanin (0.01, 0.05, 0.1, and 1 nmol) or saline were injected from day 4 and continued till day 14. The animal's learning and memory capability was assessed on days 15-18 using Morris water maze. After complement of behavioral studies, the hippocampi were isolated, and the level of phosphorylated Akt (pAkt) was assessed through Western blot analysis. The results showed that STZ significantly impaired spatial memory, and humanin in a wide range of doses (0.01, 0.05, 0.1, and 1 nmol) failed to restore STZ-induced deficit. It was also revealed that humanin was not efficient in restoring pAkt disruption. It seems that humanin is not capable in restoring memory deterioration that resulted from insulin signaling disruption. PMID- 25744100 TI - Self-powered electrospinning apparatus based on a hand-operated Wimshurst generator. AB - A conventional electrospinning setup cannot work without a plug (electricity supply). In this article, we report a self-powered electrospinning setup based on a hand-operated Wimshurst generator. The new device has better applicability and portability than a typical conventional electrospinning setup because it is lightweight and can work without an external power supply. Experimental parameters of the apparatus such as the minimum number of handle turns to generate enough energy to spin, rotation speed of the handle and electrospinning distance were investigated. Different polymers such as polystyrene (PS), poly(vinylidene fluoride) (PVDF), polycaprolactone (PCL) and polylactic acid (PLA) were electrospun into ultrathin fibers successfully by this apparatus. The stability, reliability, and repeatability of the new apparatus demonstrate that it can be used as not only a demonstrator for an electrospinning process, but also a beneficial complement to conventional electrospinning especially where or when without a power supply, and may be used in wound healing and rapid hemostasis, etc. PMID- 25744103 TI - Sensory tricks for isolated speech-induced lingual dystonia. PMID- 25744101 TI - ERBB4 polymorphism and family history of psychiatric disorders on age-related cortical changes in healthy children. AB - Genetic variations in ERBB4 were associated with increased susceptibility for schizophrenia (SCZ) and bipolar disorders (BPD). Structural imaging studies showed cortical abnormalities in adolescents and adults with SCZ or BPD. However, less is known about subclinical cortical changes or the influence of ERBB4 on cortical development. 971 healthy children (ages 3-20 years old; 462 girls and 509 boys) were genotyped for the ERBB4-rs7598440 variants, had structural MRI, and cognitive evaluation (NIH Toolbox (r)). We investigated the effects of ERBB4 variants and family history of SCZ and/or BPD (FH) on cortical measures and cognitive performances across ages 3-20 years using a general additive model. Variations in ERBB4 and FH impact differentially the age-related cortical changes in regions often affected by SCZ and BPD. The ERBB4-TT-risk genotype children with no FH had subtle cortical changes across the age span, primarily located in the left temporal lobe and superior parietal cortex. In contrast, the TT-risk genotype children with FH had more pronounced age-related changes, mainly in the frontal lobes compared to the non-risk genotype children. Interactive effects of age, FH and ERBB4 variations were also found on episodic memory and working memory, which are often impaired in SCZ and BPD. Healthy children carrying the risk-genotype in ERBB4 and/or with FH had cortical measures resembling those reported in SCZ or BPD. These subclinical cortical variations may provide early indicators for increased risk of psychiatric disorders and improve our understanding of the effect of the NRG1-ERBB4 pathway on brain development. PMID- 25744102 TI - Malignant progression of precancerous lesions of the uterine cervix following biological DMARD therapy in patients with arthritis. PMID- 25744104 TI - First-principles determination of defect energy levels through hybrid density functionals and GW. AB - In this topical review, we discuss recent progress in electronic-structure methods for calculating defect energy levels in semiconductors and insulators. We concentrate mainly on two advanced electronic-structure schemes, namely hybrid density functional theory and many-body perturbation theory in the GW approximation. These two schemes go beyond standard density functional theory in the semilocal approximation providing a more realistic description of band gaps. In particular, we address important aspects underlying the GW scheme and highlight the correspondence between the defect levels as obtained in the various schemes. We further assess the quality of the band-edge positions determined with hybrid functionals and GW through the calculation of band-offsets at semiconductor heterojunctions and of ionization potentials at semiconductor surfaces. PMID- 25744105 TI - Social rejection following neonatal inflammation is mediated by olfactory scent cues. AB - Early-life exposure to inflammation has been associated with several behavioral and cognitive deficits detected in adulthood. However, early behavioral changes have not been well described in rodent models of infection, specifically with respect to social behavior. In the present work we show that lipopolysaccharide (LPS) challenge at 3 and 5days of age reduced overall social contact time in male juvenile rats, primarily mediated by the amount of contact they received from a novel conspecific. Given that there are important sensory, motor, and motivational components that underlie social interaction we sought to uncover the mechanism(s) responsible for the reduced social contact directed towards neonatal (n)LPS treated animals. Using an intranasal perfusion procedure, we induced a ZnSO4 lesion in a subset of novel conspecifics, effectively disrupting their olfactory processing via olfactory neuroepithelium degeneration. Overall, this procedure equalized the amount of social contact directed towards nLPS animals compared to nsaline rats. To determine whether nLPS disrupted auditory communication we evaluated ultrasonic vocalizations (USVs) for the total number and duration of calls, and the average duration and frequency from each vocalization recording. There were no differences in USVs across treatment groups. Treating nLPS rats with diazepam maintained the level of social contact they initiated, compared to the stress-induced decrease observed in their saline treated counterparts. However, diazepam did not stabilize the amount of contact directed towards them. Together, this indicates that neither vocalized motor pathways nor anxiety cues, mediated by auditory/motor communication, are involved in the social deficits following nLPS. Instead, our data suggest that olfactory indicators, likely mediated through microbiota/immunomodulatory scent signals underlie the reductions in social contact that follow neonatal inflammation. PMID- 25744106 TI - Sample size determination for logistic regression on a logit-normal distribution. AB - Although the sample size for simple logistic regression can be readily determined using currently available methods, the sample size calculation for multiple logistic regression requires some additional information, such as the coefficient of determination ([Formula: see text]) of a covariate of interest with other covariates, which is often unavailable in practice. The response variable of logistic regression follows a logit-normal distribution which can be generated from a logistic transformation of a normal distribution. Using this property of logistic regression, we propose new methods of determining the sample size for simple and multiple logistic regressions using a normal transformation of outcome measures. Simulation studies and a motivating example show several advantages of the proposed methods over the existing methods: (i) no need for [Formula: see text] for multiple logistic regression, (ii) available interim or group sequential designs, and (iii) much smaller required sample size. PMID- 25744107 TI - Experimental design and statistical analysis for three-drug combination studies. AB - Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line. To our best knowledge, this is the first ever three drug combinations study performed based on the original 4D dose-response surface formed by dose ranges of three drugs. PMID- 25744108 TI - Age, sex and marital status are associated with self-reported liver condition in adults: national surveys in the UK and USA, 2009-2010. PMID- 25744109 TI - Loneliness and health in Eastern Europe: findings from Moscow, Russia. AB - OBJECTIVES: To examine which factors are associated with feeling lonely in Moscow, Russia, and to determine whether loneliness is associated with worse health. STUDY DESIGN: Cross-sectional study. METHODS: Data from 1190 participants were drawn from the Moscow Health Survey. Logistic regression analysis was used to examine which factors were associated with feeling lonely and whether loneliness was linked to poor health. RESULTS: Almost 10% of the participants reported that they often felt lonely. Divorced and widowed individuals were significantly more likely to feel lonely, while not living alone and having greater social support reduced the risk of loneliness. Participants who felt lonely were more likely to have poor self-rated health (odds ratio [OR]: 2.28; 95% confidence interval [CI]: 1.38-3.76), and have suffered from insomnia (OR: 2.43; CI: 1.56-3.77) and mental ill health (OR: 2.93; CI: 1.88-4.56). CONCLUSIONS: Feeling lonely is linked to poorer health in Moscow. More research is now needed on loneliness and the way it affects health in Eastern Europe, so that appropriate interventions can be designed and implemented to reduce loneliness and its harmful impact on population well-being in this setting. PMID- 25744110 TI - Improving wellbeing and self-efficacy by social prescription. PMID- 25744111 TI - Effectiveness of public health practices against shaken baby syndrome/abusive head trauma in Japan. AB - OBJECTIVES: Previous studies have demonstrated the effectiveness of educational materials on infant crying to change caregivers' knowledge and behaviours related to shaken baby syndrome or abusive head trauma (SBS/AHT) using selected samples in randomized controlled trials. This study investigated the impact of public health practices to prevent SBS/AHT in Japan through the use of educational materials. STUDY DESIGN: Cross-sectional study. METHODS: The intervention was comprised of two parts: (1) the screening of an educational DVD at a prenatal class; and (2) the distribution of a public health pamphlet at a postnatal home visit. Expectant parents watched a DVD (The Period of PURPLE Crying) about the features of infant crying and recommended behaviours (walking away if frustrated in the event of unsoothable crying, sharing information on crying with other caregivers) at a preterm parenting class held at eight months' gestation. A postnatal home-visit service was implemented in which a maternity nurse distributed a pamphlet to explain information about infant crying. Before the four-month health check-up, a self-administered questionnaire was distributed to assess exposure to these public health practices and outcome variables (i.e. infant crying knowledge, walk-away and information-sharing behaviours), and responses were collected at the four-month health check-up (n = 1316). The impacts of these interventions on outcome variables were analysed by comparing those exposed to both interventions, either intervention and neither intervention after adjusting for covariates. RESULTS: Crying and shaking knowledge were significantly higher among women exposed to the public health practices, with a dose-response relationship (both P < 0.001). Further, walk-away behaviour during periods of unsoothable crying was higher among the intervention group. However, sharing information about infant crying with other caregivers was less likely among the intervention group. CONCLUSIONS: The impact of educational materials in public health practice on knowledge of crying and shaking, and walk-away behaviour in Japan had a dose-response relationship; however, an increase in sharing information with other caregivers was not observed. PMID- 25744112 TI - A first study on the incidence and prevalence of IBD in Malaysia--results from the Kinta Valley IBD Epidemiology Study. AB - BACKGROUND: Inflammatory bowel disease [IBD] is known to be rare in the Asia Pacific region but epidemiological studies are scarce. METHODS: Kinta Valley [Ipoh] was chosen as the sample population. Malaysia has a multiethnic population consisting of Malays, Chinese, and Indians. New cases over 2 years were prospectively captured as well as all known existing cases. Total numbers of the population as a whole and of each ethnic group were obtained. Incidence, prevalence, and mean incidence over two decades were then calculated. RESULTS: There were 10 new cases of IBD diagnosed from April 2011 to April 2013. The crude incidence rates of IBD, ulcerative colitis [UC], and Crohn's disease[CD], respectively, were 0.68, 0.46, and 0.20 per 100,000 persons. The highest incidence was among the Indians, 1.91 compared with 0.35 and 0.63 per 100,000 persons among the Malays and the Chinese, respectively. The mean incidence of IBD has increased steadily from 0.07 to 0.69 per 100,000 person-years over the past two decades. The UC:CD ratio was 8:1 from 1990 to 2000 and 3.6:1 from 2000 to 2010. The prevalence rates of IBD, UC, and CD, respectively, were 9.24, 6.67, and 2.17 per 100,000 persons. The highest prevalence also was among the Indians: 24.91 compared with 7.00 and 6.90 per 100,000 persons among the Malay and Chinese races, respectively. CONCLUSIONS: The incidence and prevalence rates of IBD are low in Malaysia but the incidence appears to be increasing and marked racial differences exist. As in other Asian countries, the incidence of CD is increasing at a more rapid rate relative to UC. PMID- 25744113 TI - Lattice-mismatch-induced twinning for seeded growth of anisotropic nanostructures. AB - Synthesis of anisotropic nanostructures from materials with isotropic crystal structures often requires the use of seeds containing twin planes to break the crystalline symmetry and promote the preferential anisotropic growth. Controlling twinning in seeds is therefore critically important for high-yield synthesis of many anisotropic nanostructures. Here, we demonstrate a unique strategy to induce twinning in metal nanostructures for anisotropic growth by taking advantage of the large lattice mismatch between two metals. By using Au-Cu as an example, we show, both theoretically and experimentally, that deposition of Cu to the surface of single-crystalline Au seeds can build up strain energy, which effectively induces the formation of twin planes. Subsequent seeded growth allows the production of Cu nanorods with high shape anisotropy that is unachievable without the use of Au seeds. This work provides an effective strategy for the preparation of anisotropic metal nanostructures. PMID- 25744114 TI - Maximal exercise testing variables and 10-year survival: fitness risk score derivation from the FIT Project. AB - OBJECTIVE: To determine which routinely collected exercise test variables most strongly correlate with survival and to derive a fitness risk score that can be used to predict 10-year survival. PATIENTS AND METHODS: This was a retrospective cohort study of 58,020 adults aged 18 to 96 years who were free of established heart disease and were referred for an exercise stress test from January 1, 1991, through May 31, 2009. Demographic, clinical, exercise, and mortality data were collected on all patients as part of the Henry Ford ExercIse Testing (FIT) Project. Cox proportional hazards models were used to identify exercise test variables most predictive of survival. A "FIT Treadmill Score" was then derived from the beta coefficients of the model with the highest survival discrimination. RESULTS: The median age of the 58,020 participants was 53 years (interquartile range, 45-62 years), and 28,201 (49%) were female. Over a median of 10 years (interquartile range, 8-14 years), 6456 patients (11%) died. After age and sex, peak metabolic equivalents of task and percentage of maximum predicted heart rate achieved were most highly predictive of survival (P<.001). Subsequent addition of baseline blood pressure and heart rate, change in vital signs, double product, and risk factor data did not further improve survival discrimination. The FIT Treadmill Score, calculated as [percentage of maximum predicted heart rate + 12(metabolic equivalents of task) - 4(age) + 43 if female], ranged from -200 to 200 across the cohort, was near normally distributed, and was found to be highly predictive of 10-year survival (Harrell C statistic, 0.811). CONCLUSION: The FIT Treadmill Score is easily attainable from any standard exercise test and translates basic treadmill performance measures into a fitness-related mortality risk score. The FIT Treadmill Score should be validated in external populations. PMID- 25744115 TI - Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. AB - OBJECTIVE: To evaluate the 5-year efficacy and safety of once weekly exenatide. PATIENTS AND METHODS: The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 MUg of exenatide twice daily) with an open ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 MUg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate. RESULTS: Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, -1.6%; 95% CI, -1.8% to 1.4%; vs -1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (-28.8 mg/dL; 95% CI, -36.2 to -21.5 mg/dL), weight (-3.0 kg; 95% CI, -4.6 to -1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed. CONCLUSION: Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00308139. PMID- 25744116 TI - Emerging issues in gram-negative bacterial resistance: an update for the practicing clinician. AB - The rapid and global spread of antimicrobial-resistant organisms in recent years has been unprecedented. Although resistant gram-positive infections have been concerning to clinicians, the increasing incidence of antibiotic-resistant gram negative infections has become the most pressing issue in bacterial resistance. Indiscriminate antimicrobial use in humans and animals coupled with increased global connectivity facilitated the transmission of gram-negative infections harboring extended-spectrum beta-lactamases in the 1990s. Carbapenemase-producing Enterobacteriaceae, such as those containing Klebsiella pneumoniae carbapenemases and New Delhi metallo-beta-lactamases, have been the latest scourge since the late 1990s to 2000s. Besides beta-lactam resistance, these gram-negative infections are often resistant to multiple drug classes, including fluoroquinolones, which are commonly used to treat community-onset infections. In certain geographic locales, these pathogens, which have been typically associated with health care-associated infections, are disseminating into the community, posing a significant dilemma for clinicians treating community-onset infections. In this Concise Review, we summarize emerging trends in antimicrobial resistance. We also review the current knowledge on the detection, treatment, and prevention of infection with these organisms, with a focus on the carbapenemase-producing gram-negative bacilli. Finally, we discuss emerging therapies and areas that need further research and effort to stem the spread of antimicrobial resistance. PMID- 25744117 TI - 73-year-old man with dyspnea on exertion. PMID- 25744118 TI - Best practices for patients with chronic migraine: burden, diagnosis, and management in primary care. AB - Headache and migraine are common medical complaints among patients visiting primary care physicians (PCPs). A number of these patients may have chronic migraine, which is more difficult to diagnose and manage than many other headache disorders. Identification of those at risk, correct diagnosis, and establishment of a comprehensive management plan for patients with chronic migraine will require a joint effort between the PCP and the headache specialist. Together, the PCP and headache specialist will need to assess the patient for modifiable exacerbating factors and comorbidities while managing prophylactic and as-needed therapies. Herein, we provide a review of chronic migraine for the PCP and describe tools for improving patient care. PMID- 25744119 TI - In reply--What is the optimal timing for surgical treatment of infective endocarditis? PMID- 25744120 TI - What is the optimal timing for surgical treatment of infective endocarditis? PMID- 25744121 TI - Electronic cigarettes are efficacious. PMID- 25744122 TI - In reply--Electronic cigarettes are efficacious. PMID- 25744123 TI - In reply--Time to focus on preventing coronary artery disease through exercise training in normoglycemic individuals. PMID- 25744124 TI - Time to focus on preventing coronary artery disease through exercise training in normoglycemic individuals. PMID- 25744125 TI - Coenzyme Q10 and statin-induced myopathy--I. PMID- 25744126 TI - Coenzyme Q10 and statin-induced myopathy--II. PMID- 25744127 TI - In reply--Coenzyme Q10 and statin-induced myopathy. PMID- 25744128 TI - Type A aortic dissection in fibromuscular dysplasia. PMID- 25744129 TI - Multiple painful nodules and uterine leiomyomas. PMID- 25744130 TI - 79-year-old woman with dyspnea, cough, and renal failure. PMID- 25744132 TI - A reliable and valid questionnaire was developed to measure computer vision syndrome at the workplace. AB - OBJECTIVES: To design and validate a questionnaire to measure visual symptoms related to exposure to computers in the workplace. STUDY DESIGN AND SETTING: Our computer vision syndrome questionnaire (CVS-Q) was based on a literature review and validated through discussion with experts and performance of a pretest, pilot test, and retest. Content validity was evaluated by occupational health, optometry, and ophthalmology experts. Rasch analysis was used in the psychometric evaluation of the questionnaire. Criterion validity was determined by calculating the sensitivity and specificity, receiver operator characteristic curve, and cutoff point. Test-retest repeatability was tested using the intraclass correlation coefficient (ICC) and concordance by Cohen's kappa (kappa). RESULTS: The CVS-Q was developed with wide consensus among experts and was well accepted by the target group. It assesses the frequency and intensity of 16 symptoms using a single rating scale (symptom severity) that fits the Rasch rating scale model well. The questionnaire has sensitivity and specificity over 70% and achieved good test-retest repeatability both for the scores obtained [ICC = 0.802; 95% confidence interval (CI): 0.673, 0.884] and CVS classification (kappa = 0.612; 95% CI: 0.384, 0.839). CONCLUSION: The CVS-Q has acceptable psychometric properties, making it a valid and reliable tool to control the visual health of computer workers, and can potentially be used in clinical trials and outcome research. PMID- 25744133 TI - On mixture models for diagnostic meta-analyses. PMID- 25744134 TI - Radiolabeled BMIPP for imaging hepatic fatty acid metabolism: evaluation of hepatic distribution and metabolism in mice at various metabolic statuses induced by fasting in comparison with palmitic acid. AB - Abnormalities in hepatic fatty acid metabolism are involved in various diseases. In order to clarify the use of 123I-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid ([123I]BMIPP) for imaging hepatic fatty acid metabolism, we determined the hepatic distribution/metabolism of [125I]BMIPP in mice at various metabolic statuses induced by fasting, and compared the results with those of [1 (14)C]palmitic acid ([1-(14)C]PA). Fed or fasted (6, 12, and 24 hour-fasted) mice were intravenously injected with [125I]BMIPP or [1-(14)C]PA. Hepatic radioactivity was measured at 1 to 120 minutes after the injection (n = 5 to 15/time points), and radioactive lipid metabolites were analyzed by thin-layer chromatography (n = 3/time points). The areas under the curves (AUCs) were calculated. In mice given [125I]BMIPP, the hepatic radioactivity was increased with the fasting time (AUC: 35.1, 45.5, 57.6, and 59.0 [% injected dose (ID)/g/kg]?min for fed, 6, 12, and 24 hour-fasted). Similar characteristic changes were observed in mice given [1-(14)C]PA (100.6, 101.0, 116.5, and 121.5 [%ID/g/kg]?min). Metabolite analysis showed that the triglyceride-fraction was increased by fasting in both groups (5.7, 12.8, 32.0, and 37.9 [%ID/g/kg]?min for [125I]BMIPP groups; 20.6, 39.2, 66.0, and 67.9 [%ID/g/kg]?min for [1-(14)C]PA groups). Thus, [125I]BMIPP demonstrated the changes in hepatic fatty acid metabolism induced by fasting, indicating the potential of [123I]BMIPP for imaging hepatic fatty acid metabolism. PMID- 25744135 TI - Geometrical tradeoffs in graphene-based deeply-scaled electrically reconfigurable metasurfaces. AB - In this work we study the terahertz light propagation through deeply-scaled graphene-based reconfigurable metasurfaces, i.e. metasurfaces with unit-cell dimensions much smaller than the terahertz wavelength. These metasurfaces are analyzed as phase modulators for constructing reconfigurable phase gradients along an optical interface for the purpose of beam shaping. Two types of deeply scaled metacell geometries are analyzed and compared, which consist of: (i) multi split ring resonators, and (ii) multi spiral resonators. Two figures of merit, related to: (a) the loss and (b) the degree of reconfigurability achievable by such metamaterials -when applied in beam shaping applications-, are introduced and discussed. Simulations of these two types of deep-subwavelength geometries, when changing the metal coverage-fraction, show that there is an optimal coverage fraction that gives the best tradeoff in terms of loss versus degree of reconfigurability. For both types of geometries the best tradeoff occurs when the area covered by the metallic region is around 40% of the metacell total area. From this point of view, reconfigurable deeply-scaled metamaterials can indeed provide a superior performance for beam shaping applications when compared to not deeply-scaled ones; however, counterintuitively, employing very highly-packed structures might not be beneficial for such applications. PMID- 25744136 TI - Quantitatively probing propensity for structural transitions in engineered virus nanoparticles by single-molecule mechanical analysis. AB - Viruses are increasingly being studied from the perspective of fundamental physics at the nanoscale as biologically evolved nanodevices with many technological applications. In viral particles of the minute virus of mice (MVM), folded segments of the single-stranded DNA genome are bound to the capsid inner wall and act as molecular buttresses that increase locally the mechanical stiffness of the particle. We have explored whether a quantitative linkage exists in MVM particles between their DNA-mediated stiffening and impairment of a heat induced, virus-inactivating structural change. A series of structurally modified virus particles with disrupted capsid-DNA interactions and/or distorted capsid cavities close to the DNA-binding sites were engineered and characterized, both in classic kinetics assays and by single-molecule mechanical analysis using atomic force microscopy. The rate constant of the virus inactivation reaction was found to decrease exponentially with the increase in elastic constant (stiffness) of the regions closer to DNA-binding sites. The application of transition state theory suggests that the height of the free energy barrier of the virus inactivating structural transition increases linearly with local mechanical stiffness. From a virological perspective, the results indicate that infectious MVM particles may have acquired the biological advantage of increased survival under thermal stress by evolving architectural elements that rigidify the particle and impair non-productive structural changes. From a nanotechnological perspective, this study provides proof of principle that determination of mechanical stiffness and its manipulation by protein engineering may be applied for quantitatively probing and tuning the conformational dynamics of virus-based and other protein-based nanoassemblies. PMID- 25744137 TI - Perturbation theory of a superconducting 0 - pi impurity quantum phase transition. AB - A single-level quantum dot with Coulomb repulsion attached to two superconducting leads is studied via the perturbation expansion in the interaction strength. We use the Nambu formalism and the standard many-body diagrammatic representation of the impurity Green functions to formulate the Matsubara self-consistent perturbation expansion. We show that at zero temperature second order of the expansion in its spin-symmetric version yields a nearly perfect agreement with the numerically exact calculations for the position of the 0 - pi phase boundary at which the Andreev bound states reach the Fermi energy as well as for the values of single-particle quantities in the 0-phase. We present results for phase diagrams, level occupation, induced local superconducting gap, Josephson current, and energy of the Andreev bound states with the precision surpassing any (semi)analytical approaches employed thus far. PMID- 25744139 TI - Why I blog and tweet. PMID- 25744138 TI - Apolipoprotein epsilon 4 genotype is associated with less improvement in cognitive function five years after cardiac surgery: a retrospective cohort study. AB - PURPOSE: Cognitive performance after cardiac surgery can be impaired, and genetic risk factors have previously been suggested. When compared with other isoforms of the gene, the apolipoprotein epsilon 4 (APOE4) allele is associated with worse outcomes in many neurologic disorders. We hypothesized that the APOE4 allele is associated with less favourable cognitive function five years after surgery. METHODS: Caucasian patients enrolled in previously reported prospective cognitive trials in both cardiac and non-cardiac surgery participated in this retrospective cohort study. Neuropsychological function was assessed at baseline and five years postoperatively. The relationship between change in cognitive index score and APOE was evaluated using multivariable linear regression. An additive genetic model toward the epsilon 4 allele was applied with adjustment for baseline cognition, years of education, age, presence of diabetes in both cohorts, and presence of coronary artery disease in the non-cardiac surgery cohort. RESULTS: A total of 357 patients were included in this study. In the cardiac surgery group (n = 233), baseline cognitive index (P < 0.001), years of education (P = 0.04), age at time of surgery (P < 0.001), and the APOE4 allele (P = 0.009), were associated with a five-year change in cognitive index. Patients carrying the APOE4 allele showed less improvement in cognitive index scores five years after cardiac surgery compared with patients without the APOE4 allele. In the non cardiac surgery (n = 124) group, no association was found between APOE4 allele status and change in cognitive index. CONCLUSION: We report an association between APOE4 and neurocognitive function five years following cardiac surgery. Preoperative identification of patients with the APOE4 genotype may improve stratification of cardiac surgery patients at risk for a less favourable cognitive trajectory. PMID- 25744140 TI - Just who is "Skeptical Scalpel"? PMID- 25744141 TI - Perineural steroids for trauma and compression-related peripheral neuropathic pain: a systematic review and meta-analysis. AB - PURPOSE: Perineural steroids are often used to treat chronic peripheral neuropathic pain (NP) secondary to trauma or compression. Nevertheless, when compared with local anesthetics (LA) or conventional medical management (CMM), their efficacy and safety in patients with trauma or compression-related neuropathic pain syndromes is unclear. The purpose of this systematic review and meta-analysis was to determine the efficacy and safety of perineural steroids in compression or trauma-related NP after one to three months of injection. SOURCE: We reviewed randomized controlled trials from MEDLINE((r)), EMBASETM, Cochrane central register of controlled trials, Cochrane database of systematic reviews, and Google Scholar (first 200 hits) up to April 2014 that compared perineural injections of steroids with LA or CMM in adult patients with trauma or compression-related chronic peripheral NP. A meta-analysis was performed on the data on pain scores measured at one to three months after the interventions. Quality of evidence was classified using the GRADE system. Two authors independently reviewed all identified titles and abstracts for eligibility. PRINCIPAL FINDINGS: Five trials comprising 353 patients (177 in the steroid group and 176 in the comparator groups) were included. At one to three months after the interventions, patients who received perineural steroids reported lower pain scores than those who received LA or CMM (mean difference: -1.31 points on a 0-10 numerical rating scale for pain; 95% confidence interval: -2.50 to -0.13; quality of evidence: low; I(2) = 89%). None of the studies reported any significant adverse effects. CONCLUSIONS: Perineural steroids may provide analgesic efficacy for one to three months in patients with chronic peripheral NP of traumatic or compressive origin; however, the strength of this recommendation is weak. Well designed large randomized studies are required. PMID- 25744142 TI - Current concepts in negative pressure wound therapy. AB - Negative pressure wound therapy (NPWT) is becoming recognized in veterinary medicine as a viable option for the management of complex wounds. NPWT has many advantages over traditional wound care and results in quicker and improved wound healing in many instances. This article discusses the art and science of NPWT, as well as the many current indications, complications, advantages and disadvantages, and future directions of NPWT in small animal veterinary medicine. This therapy will likely have a growing role in veterinary medical practice for complicated wound management and other usages in coming years. PMID- 25744143 TI - Current concepts in hepatobiliary surgery. AB - The most common hepatic procedures performed in companion animals are liver biopsies and partial hepatectomies. Surgery of the biliary tract most often involves the gallbladder, although surgical intervention of the bile duct may also be performed. Hepatobiliary surgery is often challenging, being performed in patients with significant systemic illness and associated with potentially life threatening complications. An in-depth understanding of the regional anatomy, use of a team concept for patient management, particularly for patients undergoing partial hepatectomy surgery, and provision of intensive perioperative monitoring and support helps minimize complications and maximize outcome. PMID- 25744144 TI - Current concepts in wound management and wound healing products. AB - Current concepts in wound management are summarized. The emphasis is on selection of the contact layer of the bandage to promote a moist wound environment. Selection of an appropriate contact layer is based on the stage of wound healing and the amount of wound exudate. The contact layer can be used to promote autolytic debridement and enhance wound healing. PMID- 25744145 TI - Ischemia-modified albumin is not better than creatine kinase-MB and cardiac troponin I in predicting a cardiac injury in nontraumatic subarachnoid hemorrhage. AB - BACKGROUND: The aims were to investigate the role of serum ischemia-modified albumin (IMA), tumor necrosis factor alpha (TNF-alpha), and myeloperoxidase (MPO) and to evaluate the relationship between IMA and cardiac markers (creatine kinase myocardial isoenzyme [CK-MB] and cardiac troponin I [cTnI]) related to cardiac abnormalities in adult patients after nontraumatic subarachnoid hemorrhage (SAH). METHODS: Twenty-nine patients with nontraumatic SAH admitted to the emergency department and 20 healthy adults as the control group were included in the study. Ischemia-modified albumin, TNF-alpha, MPO, CK-MB, cTnI, and leukocyte count (white blood cell [WBC]) in the circulation were measured on admission. RESULTS: Ischemia-modified albumin, TNF-alpha, and MPO levels were higher by mean values of 11.6%, 9.5%, and 2.9%, respectively, in patients with SAH compared with control group. However, levels of these parameters were not statistically different between the groups (P > .05). However, WBC, CK-MB, and cTnI values were significantly higher in patients with SAH compared with healthy control (P < .001, P < .01, and P < .05, respectively). White blood cell and cTnI levels in the circulation were positively correlated with patients' clinical severity (r = 0.598, P = .001 and r = 0.461, P = .012, respectively). Ischemia-modified albumin has a poor diagnostic value in comparison with WBC, CK-MB, and cTnI tests to differentiate between patients after SAH and controls according to receiver operating characteristic curve. CONCLUSIONS: The results suggest that IMA is not better than CK-MB and cTnI in predicting a cardiac injury in patients after nontraumatic SAH. PMID- 25744146 TI - N-terminal pro-B-type natriuretic peptide is also related to increased mortality. PMID- 25744147 TI - Clinical profile of injection drug users presenting to the ED. AB - BACKGROUND: Injection drug users (IDUs) commonly use the emergency department (ED) as their primary health care access point. OBJECTIVE: We sought to characterize infectious disease clinical presentations and laboratory results of IDUs admitted to the hospital from the ED and contrast them with those of non IDUs. METHODS: We enrolled all admitted adult patients with infectious disease related diagnoses at a county level 1 trauma center from June 2010 to January 2011 and used a structured chart abstraction tool to record patient characteristics and clinical outcomes. We compared clinical presenting features, laboratory data, and microbiological culture results of IDUs with concomitantly enrolled non-IDUs. RESULTS: Of 603 total participants, 189 were IDUs, and 414 were non-IDUs. Injection drug users had higher rates of skin and soft tissue infection admission but had similar hospital length of stay (7.5 vs 6.1 days) and mortality (2.1% vs 2.9%). Compared with non-IDUs, IDUs more commonly had hyponatremia, 38.1% vs 27.1% (mean difference, 11.4%; 95% confidence intervals [CIs], 3.4%-19.6%) and thrombocytopenia, 18.5% vs 11.0% (mean difference, 7.5%; 95% CI, 1.5%-14.2%) but less frequently had leukocytosis, 36.0% vs 52.7% (mean difference, 16.7%; 95% CI, 8.2%-24.8%). Injection drug users and non-IDUs had similar rates of positive ED-derived blood cultures, 16.5% vs 22.6% (mean difference, 6.1%; 95% CI, -13.3 to 1.7%). CONCLUSIONS: When admitted from the ED for infectious disease-related diagnoses, IDUs had similar rates of fever, higher rates of hyponatremia and thrombocytopenia, and lower rates of leukocytosis than non-IDUs. Although they had similar rates of bacteremia, only IDUs were positive for methicillin-resistant Staphylococcus aureus. PMID- 25744148 TI - Isolated testicular pain mimicking ruptured abdominal aortic aneurysm in a nonagenarian. AB - Ruptured abdominal aortic aneurysm commonly presents as acute abdominal or lower back pain and hemodynamic instability. We discuss the case of a 90-year-old patient who presented to the emergency unit with a 3-day history of left testicular pain. Ultrasound scan demonstrated and a computed tomography scan confirmed a 6 cm in diameter ruptured abdominal aortic aneurysm with enlargement and hematoma of the left psoas muscle causing the symptoms. This atypical presentation highlights the need for clinical vigilance and emergency physician performed ultrasound scan in the older patients with seemingly benign testicular symptoms. PMID- 25744149 TI - Minimal impact of an electronic medical records system. AB - BACKGROUND: Electronic medical records (EMRs) implementation in hospitals and emergency departments (EDs) is becoming increasingly more common. The purpose of this study was to determine the impact of an EMR system on patient-related factors that correlate to ED workflow efficiency. METHODS: A retrospective chart review assessed monthly census reports of all patients who registered and were treated to disposition during conversion from paper charts to an EMR system. The primary outcome measurement was an analysis of the time of registration to discharge or total ED length of stay as well as rate of those who left without being seen, eloped, or left against medical advice. These data were recorded from 3 periods, for 18 months: before installation of the EMR system (pre-EMR), during acclimation to the EMR, and post acclimation (post-EMR). RESULTS: A total of 61626 individual patient records were collected and analyzed. The total ED length of stay across all patient subtypes was not significantly affected by the installation of the hospital-wide EMR system (P = .481); however, a significant decrease was found for patients who were admitted to the hospital from the ED (P < .00001). The percentage of patients who left without being seen between the pre EMR and post-EMR periods was 1.8% and 2.7%, respectively, representing a significant increase (P < .0001). The number of patients who left against medical advice did not change across the periods of the present investigation (P > .25). CONCLUSIONS: Installation of a hospital-wide EMR system had minimal impact on workflow efficiency parameters in an ED. PMID- 25744150 TI - Can mean platelet volume predict the prognosis of patients with community acquired pneumonia? PMID- 25744151 TI - Questions regarding the utility of the 30-degree test in measuring optic nerve sheath diameters in ED patients. PMID- 25744152 TI - Hydration structure of strongly bound water on the sulfonic acid group in a Nafion membrane studied by infrared spectroscopy and quantum chemical calculation. AB - The hydration structure of the 'strongly bound water' around the sulfonic acid (SA) groups in Nafion, which has recently been revealed by (1)H NMR spectroscopy (Anal. Chem., 2013, 85, 7581), is studied using infrared spectroscopy with the aid of quantum chemical (QC) calculations. During a heated drying process, bulky water is firstly dehydrated, which is followed by the disappearance of the hydronium ion and the appearance of bands that have been assigned to the fully dehydrated species at 140 degrees C. However, a spectral simulation based on QC reveals that the spectrum at 140 degrees C comes from the SA group associated with a single-water molecule via two H-bonds. This implies that a thoroughly dried membrane is unavailable even at 140 degrees C, and the involved water corresponds to the 'strongly bound water.' The QC-analytical results are experimentally confirmed by evolved gas analysis mass spectrometry (EGA-MS). At ca. 300 degrees C, which is the temperature where the SA group is selectively decomposed, the molecular fragment of SO2 is observed accompanying water molecules as expected. This confirms that the last single-water molecule can remain on the SA group until the thermal decomposition. PMID- 25744154 TI - Divergent spatial regulation of duplicated fatty acid-binding protein (fabp) genes in rainbow trout (Oncorhynchus mykiss). AB - The increased use of plant oil as a dietary supplement with the resultant high dietary lipid loads challenges the lipid transport, metabolism and storage mechanisms in economically important aquaculture species, such as rainbow trout. Fatty acid-binding proteins (Fabp), ubiquitous in tissues highly active in fatty acid metabolism, participate in lipid uptake and transport, and overall lipid homeostasis. In the present study, searches of nucleotide sequence databases identified mRNA transcripts coded by 14 different fatty acid-binding protein (fabp) genes in rainbow trout (Oncorhynchus mykiss), which include the complete minimal suite of seven distinct fabp genes (fabp1, 2, 3, 6, 7, 10 and 11) discovered thus far in teleost fishes. Phylogenetic analyses suggest that many of these extant fabp genes in rainbow trout exist as duplicates, which putatively arose owing to the teleost-specific whole genome duplication (WGD); three pairs of duplicated fabp genes (fabp2a.1/fabp2a.2, fabp7b.1/fabp7b.2 and fabp10a.1/fabp10a.2) most likely were generated by the salmonid-specific WGD subsequent to the teleost-specific WGD; and fabp3 and fabp6 exist as single copy genes in the rainbow trout genome. Assay of the steady-state levels of fabp gene transcripts by RT-qPCR revealed: (1) steady-state transcript levels differ substantially between fabp genes and, in some instances, by as much as 30*10(4) fold; (2) some fabp transcripts are widely distributed in many tissues, whereas others are restricted to one or a few tissues; and (3) divergence of regulatory mechanisms that control spatial transcription of duplicated fabp genes in rainbow trout appears related to length of time since their duplication. The suite of fabp genes described here provides the foundation to investigate the role(s) of fatty acid-binding proteins in the uptake, mobilization and storage of fatty acids in cultured fish fed diets differing in lipid content, especially the use of plant oil as a dietary supplement. These nutritional dietary supplements may well lead to high lipid loads with the resultant challenges to lipid homeostasis and, thus, health of cultivated fish which may be mediated by appropriate transcriptional control of fabp genes. PMID- 25744153 TI - Contrasting patterns of hot spell effects on morbidity and mortality for cardiovascular diseases in the Czech Republic, 1994-2009. AB - The study examines effects of hot spells on cardiovascular disease (CVD) morbidity and mortality in the population of the Czech Republic, with emphasis on differences between ischaemic heart disease (IHD) and cerebrovascular disease (CD) and between morbidity and mortality. Daily data on CVD morbidity (hospital admissions) and mortality over 1994-2009 were obtained from national hospitalization and mortality registers and standardized to account for long-term changes as well as seasonal and weekly cycles. Hot spells were defined as periods of at least two consecutive days with average daily air temperature anomalies above the 95% quantile during June to August. Relative deviations of mortality and morbidity from the baseline were evaluated. Hot spells were associated with excess mortality for all examined cardiovascular causes (CVD, IHD and CD). The increases were more pronounced for CD than IHD mortality in most population groups, mainly in males. In the younger population (0-64 years), however, significant excess mortality was observed for IHD while there was no excess mortality for CD. A short-term displacement effect was found to be much larger for mortality due to CD than IHD. Excess CVD mortality was not accompanied by increases in hospital admissions and below-expected-levels of morbidity prevailed during hot spells, particularly for IHD in the elderly. This suggests that out-of hospital deaths represent a major part of excess CVD mortality during heat and that for in-hospital excess deaths CVD is a masked comorbid condition rather than the primary diagnosis responsible for hospitalization. PMID- 25744155 TI - The role of plasma, albumin, and fibronectin in Staphylococcus epidermidis adhesion to polystyrene surface. AB - The influence of soluble and immobilized plasma, albumin, and fibronectin (Fn) on the adhesion of three Staphylococcus epidermidis strains to polystyrene was investigated. Both soluble and immobilized plasma and albumin cause to 7-fold reduction of the amounts of adhered cells, regardless of the strain used. The soluble Fn exhibited the adhesion for one strain and did not affect the bacterial sorption for remaining strains, whereas on Fn-coated polystyrene two of the three strains showed about 1.5-fold increase in the number of adsorbed bacteria. The plasma- and albumin-coated surfaces became much more hydrophilic as the contact angle changed from 78 +/- 2 degrees for control to 18 +/- 2 degrees for plasma and 21 +/- 3 degrees for albumin. The ligand-receptor specific interactions strains S. epidermidis with Fn-coated surfaces were proved by measuring the adhesion forces between cell surface and Fn-coated AFM tip. The surface roughness measured using AFM after the plasma and proteins immobilization was changed within 10 nm and not correlate with changes in bacterial adhesion. PMID- 25744157 TI - A microfluidic device for efficient chemical testing using Caenorhabditis elegans. AB - The nematode worm Caenorhabditis elegans has been employed as a popular model organism in many fields of biological research. In this paper, we present a microfluidic device for facilitating chemical testing using C. elegans. For testing chemicals on chip, the device houses single nematodes in microfluidic chambers and precisely adjusts the chamber's chemical environment during experiments. Eight nematodes can be readily loaded into the chambers through separate loading channels in a quick and gentle manner. In addition, a custom made software with a graphic user interface is also created for quantitative analysis of locomotion parameters (swimming frequency and bend amplitude) of the nematodes in response to chemical stimuli, thus greatly enhancing the efficiency of data collection. We perform proof-of-concept experiments using two chemicals, zinc ion (Zn(2+)) and glucose, to demonstrate the effectiveness of the microfluidic device. PMID- 25744156 TI - Novel markers of endothelial dysfunction and inflammation in Behcet's disease patients with ocular involvement: epicardial fat thickness, carotid intima media thickness, serum ADMA level, and neutrophil-to-lymphocyte ratio. AB - The etiology of Behcet's disease (BD) has not been fully elucidated. However, immunological and environmental factors, endothelial dysfunction (ED), and genetic susceptibility have been proposed to play a role. In this study, we aimed to evaluate epicardial fat thickness (EFT) together with serum asymmetric dimethylarginine (ADMA), carotid intima media thickness (CIMT), and neutrophil-to lymphocyte ratio (NLR) in BD patients with ocular involvement. Thirty-six ocular BD patients (17 active and 19 inactive ocular involvement), and 35 age and sex matched healthy controls were enrolled to this cross-sectional study. All patients underwent examinations with transthoracic echocardiography and carotid Doppler ultrasound. Serum ADMA levels, CIMT, EFT, and NLR were compared between groups, and their association with disease activity was evaluated. Behcet's disease patients had higher WBC counts, neutrophil counts, NLR, CIMT, EFT values, and serum ADMA levels than do healthy controls. The other biochemical, hematological, and echocardiographic parameters were comparable between the two groups. Behcet's disease duration was positively correlated with EFT and CIMT. Multivariate logistic regression analysis revealed that increased serum ADMA concentration and CIMT are independently associated with BD. Neutrophil counts, NLR, and serum ADMA level were higher, and lymphocyte count was lower in patients with active ocular BD compared to those of inactive ocular BD group. Carotid intima media thickness, serum ADMA level, EFT, and NLR were increased in ocular BD patients compared to healthy subjects. In addition, both serum ADMA level and NLR were associated with disease activity of ocular involvement. Increase in disease duration was associated with increase in CIMT and EFT which suggests that anatomical changes occur in time during the disease course. Increased CIMT, serum ADMA level, EFT, and NLR may provide new clues about the role of ED and inflammation in the etiopathogenesis of BD. PMID- 25744158 TI - Gastrointestinal tolerance of erythritol-containing beverage in young children: a double-blind, randomised controlled trial. AB - BACKGROUND/OBJECTIVE: To determine gastrointestinal (GI) responses and maximum tolerated dose of erythritol in young children given as a single oral dose in a 250-ml non-carbonated fruit-flavoured beverage in between meals. This is a multicentre double-blind study with sequential design for multiple dose groups and randomised crossover for comparators of placebo vs dose. SUBJECTS/METHODS: A total of 185 healthy young children aged 4-6 years were recruited at three clinical investigation centres after informed consent of both parents; 184 children completed the study. Children were included in one of the four dose groups (5, 15, 20 or 25 g erythritol) and exposed randomly to only one single dose vs an isosweet sucrose placebo. After consumption in the clinic and an observation period, GI symptoms and stooling patterns were recorded during the next 48 h. RESULTS: Statistically significantly more episodes of diarrhoea and/or severe GI symptoms were observed in the 20 and 25 g groups compared with placebo, but not in the 5 and 15 g groups. Stool consistency, as measured by Bristol stool scale, was lower in the 15-, 20- and 25 g groups for the first 24 h period, but not at later time points. Incidences of nausea, vomiting, borborygmi, excess flatus and abdominal pain were not significantly different from the placebo controls at all doses of erythritol. CONCLUSIONS: Rapid ingestion of up to and including 15 g (6% w/v) of erythritol in a beverage in between meals by young children aged 4-6 years was well tolerated. The no observed effect level for diarrhoea and/or severe GI symptoms was 15 g (0.73 g/kg body weight (bw)). Children appeared not to be more sensitive to the GI effects of erythritol than published for adults on a g/kg bw basis. PMID- 25744159 TI - Distinguishing Mast Cell Progenitors from Mature Mast Cells in Mice. AB - Mast cells originate from the bone marrow and develop into c-kit(+) FcERI(+) cells. Both mast cell progenitors (MCp) and mature mast cells express these cell surface markers, and ways validated to distinguish between the two maturation forms with flow cytometry have been lacking. Here, we show that primary peritoneal MCp from naive mice expressed high levels of integrin beta7 and had a low side scatter (SSC) light profile; whereas mature mast cells expressed lower levels of integrin beta7 and had a high SSC light profile. The maturation statuses of the cells were confirmed using three main strategies: (1) MCp, but not mature mast cells, were shown to be depleted by sublethal whole-body gamma irradiation. (2) The MCp were small and immature in terms of granule formation, whereas the mature mast cells were larger and had fully developed metachromatic granules. (3) The MCp had fewer transcripts of mast cell-specific proteases and the enzyme responsible for sulfation of heparin than mature mast cells. Moreover, isolated peritoneal MCp gave rise to mast cells when cultured in vitro. To summarize, we have defined MCp and mature mast cells in naive mice by flow cytometry. Using this strategy, mast cell maturation can be studied in vivo. PMID- 25744160 TI - Intervention effects on dietary intake among children by maternal education level: results of the Copenhagen School Child Intervention Study (CoSCIS). AB - Dietary intake among Danish children, in general, does not comply with the official recommendations. The objectives of the present study were to evaluate the 3-year effect of a multi-component school-based intervention on nutrient intake in children, and to examine whether an intervention effect depended on maternal education level. A total of 307 children (intervention group: n 184; comparison group: n 123) were included in the present study. All had information on dietary intake pre- and post-intervention (mean age 6.8 and 9.5 years for intervention and comparison groups, respectively) assessed by a 7-d food record. Analyses were conducted based on the daily intake of macronutrients (energy percentage (E%)), fatty acids (E%), added sugar (E%) and dietary fibre (g/d and g/MJ). Analyses were stratified by maternal education level into three categories. Changes in nutrient intake were observed in the intervention group, mainly among children of mothers with a short education ( < 10 years). Here, intake of dietary fibre increased (beta = 2.1 g/d, 95 % CI 0.5, 3.6, P= 0.01). Intake of protein tended to increase (beta = 0.6 E%, 95 % CI -0.01, 1.2, P= 0.05), while intake of fat (beta = -1.7 E%, 95 % CI -3.8, 0.3, P= 0.09) and SFA (beta = -0.9, 95 % CI -2.0, 0.2, P= 0.10) tended to decrease. Also, a significant intervention effect was observed on the intake of SFA among children of mothers with a long education (beta = -0.8, 95 % CI -1.5, -0.03, P= 0.04). This multi component school-based intervention resulted in changes in the dietary intake, particularly among children of mothers with a short education. As the dietary intake of this subgroup generally differs most from the recommendations, the results of the present study are particularly encouraging. PMID- 25744161 TI - Maximizing the effect of an alpha7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits. AB - Positive allosteric modulators (PAMs) for the alpha7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the alpha7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal alpha7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective alpha7 nicotinic receptor agonist, choline chloride (10 or 33mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal alpha7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the alpha7 receptors. These data may have implications for further clinical testing of putative alpha7 nicotinic receptor PAMs. PMID- 25744162 TI - Dextran-based hydrogel formed by thiol-Michael addition reaction for 3D cell encapsulation. AB - Cell encapsulation in three-dimensional (3D) hydrogels can mimic native cell microenvironment and plays a major role in cell-based transplantation therapies. In this contribution, a novel in situ-forming hydrogel, Dex-l-DTT hydrogel ("l" means "linked-by"), by cross-linking glycidyl methacrylate derivatized dextran (Dex-GMA) and dithiothreitol (DTT) under physiological conditions, has been developed using thiol-Michael addition reaction. The mechanical properties, gelation process and degree of swelling of the hydrogel can be easily adjusted by changing the pH of phosphate buffer saline. The 3D cell encapsulation ability is demonstrated by encapsulating rat bone marrow mesenchymal stem cells (BMSCs) and NIH/3T3 fibroblasts into the in situ-forming hydrogel with maintained high viability. The BMSCs also maintain their differentiation potential after encapsulation. These results demonstrate that the Dex-l-DTT hydrogel holds great potential for biomedical field. PMID- 25744163 TI - Permanent upper trunk plexopathy after interscalene brachial plexus block. AB - Interscalene brachial plexus block (IBPB) has been widely used in shoulder surgical procedures. The incidence of postoperative neural injury has been estimated to be as high as 3 %. We report a long-term neurologic deficit after a nerve stimulator assisted brachial plexus block. A 55 year-old male, with right shoulder impingement syndrome was scheduled for elective surgery. The patient was given an oral dose of 10 mg of diazepam prior to the nerve stimulator assisted brachial plexus block. The patient immediately complained, as soon as the needle was placed in the interscalene area, of a sharp pain in his right arm and he was sedated further. Twenty-four hours later, the patient complained of severe shoulder and arm pain that required an increased dose of analgesics. Severe peri scapular atrophy developed over the following days. Electromyography studies revealed an upper trunk plexus injury with severe denervation of the supraspinatus, infraspinatus and deltoid muscles together with a moderate denervation of the biceps brachii muscle. Chest X-rays showed a diaphragmatic palsy which was not present post operatively. Pulmonary function tests were also affected. Phrenic nerve paralysis was still present 18 months after the block as was dysfunction of the brachial plexus resulting in an inability to perform flexion, abduction and external rotation of the right shoulder. Severe brachial plexopathy was probably due to a local anesthetic having been administrated through the perineurium and into the nerve fascicles. Severe brachial plexopathy is an uncommon but catastrophic complication of IBPB. We propose a clinical algorithm using ultrasound guidance during nerve blocks as a safer technique of regional anesthesia. PMID- 25744164 TI - Two linked pairs of Arabidopsis TNL resistance genes independently confer recognition of bacterial effector AvrRps4. AB - Plant immunity requires recognition of pathogen effectors by intracellular NB-LRR immune receptors encoded by Resistance (R) genes. Most R proteins recognize a specific effector, but some function in pairs that recognize multiple effectors. Arabidopsis thaliana TIR-NB-LRR proteins RRS1-R and RPS4 together recognize two bacterial effectors, AvrRps4 from Pseudomonas syringae and PopP2 from Ralstonia solanacearum. However, AvrRps4, but not PopP2, is recognized in rrs1/rps4 mutants. We reveal an R gene pair that resembles and is linked to RRS1/RPS4, designated as RRS1B/RPS4B, which confers recognition of AvrRps4 but not PopP2. Like RRS1/RPS4, RRS1B/RPS4B proteins associate and activate defence genes upon AvrRps4 recognition. Inappropriate combinations (RRS1/RPS4B or RRS1B/RPS4) are non-functional and this specificity is not TIR domain dependent. Distinct putative orthologues of both pairs are maintained in the genomes of Arabidopsis thaliana relatives and are likely derived from a common ancestor pair. Our results provide novel insights into paired R gene function and evolution. PMID- 25744166 TI - ? PMID- 25744167 TI - ? PMID- 25744165 TI - The formation of electronically excited species in the human multiple myeloma cell suspension. AB - In this study, evidence is provided on the formation of electronically excited species in human multiple myeloma cells U266 in the growth medium exposed to hydrogen peroxide (H2O2). Two-dimensional imaging of ultra-weak photon emission using highly sensitive charge coupled device camera revealed that the addition of H2O2 to cell suspension caused the formation of triplet excited carbonyls (3)(R = O)*. The kinetics of (3)(R = O)* formation in the real time, as measured by one dimensional ultra-weak photon emission using low-noise photomultiplier, showed immediate enhancement followed by a slow decay. In parallel to the formation of (3)(R = O)*, the formation of singlet oxygen ((1)O2) in U266 cells caused by the addition of H2O2 was visualized by the imaging of (1)O2 using the green fluorescence of singlet oxygen sensor green detected by confocal laser scanning microscopy. Additionally, the formation of (1)O2 after the addition of H2O2 to cell suspension was detected by electron paramagnetic resonance spin-trapping spectroscopy using 2,2,6,6-tetramethyl-4-piperidone. Presented results indicate that the addition of H2O2 to cell suspension results in the formation of (3)(R = O)* and (1)O2 in U266 cell suspension. The contribution of the cell-free medium to the formation of electronically excited species was discussed. PMID- 25744168 TI - Genetic contribution to the variance of blood pressure and heart rate: a systematic review and meta-regression of twin studies. AB - The genetic contribution of blood pressure and heart rate (HR) varied widely between studies. Demographic factors such as ethnicity, age and/or sex might explain some of the heterogeneity. We performed a systematic review focusing on four phenotypes: systolic blood pressure (SBP), diastolic blood pressure (DBP), HR and pulse pressure (PP). Meta-regression was conducted to analyze potential factors in relation to SBP and DBP heritability. A total of 10,613 independent twins that came from 17 studies were included in the analysis. The weighted mean value of heritability for SBP and DBP was 0.54 (95% CIs: 0.48-0.60) and 0.49 (95% CIs: 0.42-0.56). Comparatively, three studies of HR and four studies of PP heritability were limited for the heterogeneity test. Meta-regression showed that, on average, SBP heritability with additive genes/unique environment (AE) model tend to have a higher heritability than additive genes/shared environment/unique environment (ACE) model (coefficient = 0.0947, p = .0142). A similar result was found for DBP as well. No other factors such as sex, age, ethnicity, publication year were significantly associated with heritability variance. Our study shows heritability estimates based on twin studies of both SBP and DBP are around 50%, using an AE rather than an ACE model; the variance due to C ended up in A, suggesting that the AE model may overestimate heritability if a small contribution of shared environment exists. PMID- 25744169 TI - Anti-RANKL treatment improves screw fixation in cancellous bone in rats. AB - Bisphosphonates improve implant fixation in randomised clinical trials of knee prostheses, hip prostheses and dental implants. However, a limited amount of bone resorption is required for bisphosphonates to exert an effect. Anti-RANKL treatment does not have this limitation, and we therefore tested whether if they might be more effective for improvement of implant fixation. This is of interest, as anti-RANKL treatment with denosumab is now in common clinical use. Male SD rats received a stain-less steel screw in the right proximal tibia and a drill hole in the left (n = 42). They were randomised to subcutaneous injections of either alendronate (20 MUg/kg/day), alendronate (200 MUg/kg/day), osteoprotegerin with an Fc tag (OPG-Fc; 8 mg/kg, twice weekly), or saline control. After 4 weeks, the fixation of the steel screw was measured by pull-out test. The tibia with the drill hole was evaluated with MUCT. OPG-Fc increased the pull-out force compared to saline controls by 153% (p < 0.001). There was no significant difference between OPG-Fc and the alendronate groups. OPG-Fc increased the bone density (BV/TV) in the previous drill hole compared to controls 7-fold (p < 0.001). This increase was higher than with any alendronate dose (p < 0.001). OPG-Fc increased the bone density of the L5 vertebral body, but there was no significant difference between OPG-Fc and alendronate. Our results suggest that screw fixation in cancellous bone can be dramatically improved by an anti-RANKL agent. The effect was comparable to very high bisphosphonate doses. Screw insertion in cancellous bone elicits a metaphyseal fracture healing response, and our findings might be relevant not only for implant fixation, but also for fracture healing in cancellous bone. PMID- 25744171 TI - The impact of race on the development of severe heterotopic ossification following acetabular fracture surgery. AB - OBJECTIVES: To determine the association between race on severe heterotopic ossification (HO) following acetabular fracture surgery. DESIGN: Retrospective case control study. SETTING: Level I university trauma centre. METHODS: Two hundred and fifty-three patients who were surgically treated for acetabular fractures were retrospectively evaluated. Postoperative radiographs were evaluated for HO by a blinded musculoskeletal radiologist, and classified based on a modified Brooker classification. RESULTS: Of the 253 patients that met inclusion and exclusion criteria, 175 (69%) were male and 78 (31%) were female. One hundred and fifty-four (61%) patients were Caucasian, and 99 (39%) were African American (AA). Fifty-five (21%) patients developed severe HO. Of those who developed severe HO, 25 were Caucasian (45%), 30 were African American (55%). Forty-one patients (75%) with severe HO were male, and 14 (25%) were female. No statistical differences (p>0.05) were found between groups in terms of age, days to surgery, GCS at presentation, surgical approach, perioperative HO prophylaxis, or AO/OTA fracture classification. The patient population was then stratified by race, gender, and race/gender. AA were more likely than Caucasians to develop severe HO (odds ratio [OR], 2.24; confidence interval [CI], 1.22-4.11). When gender was considered independent of race, no statistical differences (p>0.05) were observed (OR, 1.40; CI, 0.71-2.75). AA males were much more likely to develop severe HO when compared to Caucasian females (OR, 4.4; CI, 1.38-14.06). CONCLUSION: Race is associated with different rates of severe HO formation following acetabular fracture surgery. AA patients are significantly more likely to develop severe HO following acetabular fracture surgery when compared to Caucasian patients. PMID- 25744170 TI - Risk factors associated with the severity of injury outcome for paediatric road trauma. AB - Road trauma is one of the most common causes of injury for children. Yet risk factors associated with different levels of injury severity for childhood road trauma have not been examined in-depth. This study identifies crash and injury risk factors associated with the severity of non-fatal injury outcome for paediatric road trauma. A retrospective analysis was conducted of paediatric road trauma identified in linked police-reported and hospitalisation records during 1 January 2001 to 31 December 2011 in New South Wales (NSW), Australia. The linkage rate was 54%. Injury severity was calculated from diagnosis classifications in hospital records using the International Classification of Disease Injury Severity Score. Univariate and multi-variable logistic regression was conducted. There were 2412 car occupants, 1701 pedestrians and 612 pedal cyclists hospitalised where their hospital record linked to a police report. For car occupants, unauthorised vehicle drivers had twice the odds (OR: 2.21, 95%CI 1.47 3.34) and learner/provisional drivers had one and a half times higher odds (OR: 1.54, 95%CI 1.15-2.07) of a child car occupant sustaining a serious injury compared to a minor injury. For pedal cyclists and pedestrians, there were lower odds of a crash occurring during school commuting time and higher odds of a crash occurring during the weekend or on a dry road for children who sustained a serious versus a minor injury. Injury prevention initiatives, such as restraint and helmet use, that should reduce injury and/or crash severity are advocated. PMID- 25744172 TI - Evaluating the efficiency of local municipalities in providing traffic safety using the Data Envelopment Analysis. AB - The purpose of this study was to estimate the relative efficiency of 197 local municipalities in traffic safety in Israel during 2004-2009, using Data Envelopment Analysis (DEA). DEA efficiency is based on multiple inputs and multiple outputs, when their weights are unknown. We used here inputs reflecting the resources allocated to the local municipalities (such as funding), outputs include measures that reflect reductions in accidents (such as accidents per population), and intermediate variables known as safety performance indicators (SPI): measures that are theoretically linked to crash and injury reductions (such as use of safety belts). Some of the outputs are undesirable. Using DEA, the local municipalities were rank-scaled from the most efficient to the least efficient and required improvements for inefficient municipalities were calculated. We found that most of the improvements were required in two intermediate variables related to citations for traffic violations. Several DEA versions were used including a two-stage model where in the first stage the intermediate variables are the outputs, and in the second stage they are the inputs. Further analyses utilizing multiple regressions were performed to verify the effect of various demographic parameters on the efficiency of the municipalities. The demographic parameters tested for each local municipality were related to the size, age, and socio-economic level of the population. The most significant environmental variable affecting the efficiency of local municipalities in preventing road accidents is the population size of the local authority; the size has a negative effect on the efficiency. As far as we could determine, this is the first time that the DEA is used to measure the efficiency of local municipalities in improving traffic safety. PMID- 25744173 TI - Nature and etiology of hollow-organ abdominal injuries in frontal crashes. AB - Injuries to the hollow organs of the lower digestive system carry substantial risk of complication due to infection and blood loss, and commonly require invasive abdominal surgery to diagnose and treat. The causes of, and risk factors for, lower abdomen injury in automobile collisions are poorly understood. The goal of this study was to investigate the risk factors and potential mechanisms of hollow-organ, lower abdomen injury in belted automobile occupants in frontal collisions. A field survey data analysis was performed to examine the relationship between various occupant and collision factors and the risk of moderate or greater severity injury (i.e., Abbreviated Injury Scale, AIS 2+) to the small intestine, large intestine, or mesentery among belted occupants involved in frontal collisions. Descriptive and comparative risk factor analyses were performed with data originating from that National Automotive Sampling System Crashworthiness Data System (NASS-CDS) over the years 2000-2011. Multivariable logistic regression models were developed to describe the effects of these factors on hollow-organ injury risk. Potential injury mechanisms were further investigated through in-depth examination of select cases exhibiting hollow-organ injuries from the Crash Investigation Research and Engineering Network (CIREN). The inclusion criteria yielded 25,407 individual cases from NASS CDS, representing a weighted population of 11,373,358 exposed automobile occupants. Within this dataset, 143 cases (weighted frequency: 7962 occupants) exhibited AIS 2+ injury to hollow abdominal organs. Multivariable regression analysis indicated a statistically significant increased risk of moderate or greater severity injuries to the hollow organs of the abdomen with increased in DeltaV (odds ratio (OR) 1.07, 95% confidence interval: 1.06-1.09) and age (OR: 1.03, 1.01-1.06). Albeit non-statistically significant, a positive association between BMI and injury risk was observed, especially among obese individuals (OR: 3.55, 0.82-15.2). No association was observed for gender or seated location within the vehicle. RESULT: from this study indicate that hollow abdominal organ injury is a universal problem in frontal collisions, not confined to a specific gender or seating location. Examination of CIREN cases suggests these types of injuries are associated with direct loading of the lower abdomen by the lap belt, either through poor initial belt positioning or through a "submarining" type of kinematic where the lap belt slips off of the pelvis and loads into the abdomen. Potential countermeasures against hollow-organ abdominal injury should include measures to improve initial lap belt fit, and to retain engagement of the lap belt on the pelvis throughout the collision event. PMID- 25744174 TI - EPR investigation of thermal decay of radiation-induced species of benzoic acid and its sodium and potassium salts. AB - The structural and kinetic features of the radiation-induced radicals of benzoic acid and its sodium and potassium salts were investigated using electron paramagnetic resonance (EPR) spectroscopy. Two main different radicals were found to be responsible for the measured spectra of the irradiated samples. It is concluded that these two radicals have a structure similar to that of cyclohexadienyl-type (CHD) and benzyl-type (BNZ) radicals. The relative contributions of the CHD and BNZ radicals to the measured peak-to-peak amplitude and to the total spectra were calculated. The room-temperature stability of the EPR signals and the decay kinetic features of the radiation-induced radicals derived from annealing at high temperatures were determined. PMID- 25744175 TI - Direct infusion MS-based lipid profiling reveals the pharmacological effects of compound K-reinforced ginsenosides in high-fat diet induced obese mice. AB - The serum lipid metabolites of lean and obese mice fed normal or high-fat diets were analyzed via direct infusion nanoelectrospray-ion trap mass spectrometry followed by multivariate analysis. In addition, lipidomic biomarkers responsible for the pharmacological effects of compound K-reinforced ginsenosides (CK), thus the CK fraction, were evaluated in mice fed high-fat diets. The obese and lean groups were clearly discriminated upon principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) score plot, and the major metabolites contributing to such discrimination were triglycerides (TGs), cholesteryl esters (CEs), phosphatidylcholines (PCs), and lysophosphatidylcholines (LPCs). TGs with high total carbon number (>50) and low total carbon number (<50) were negatively and positively associated with high-fat diet induced obesity in mice, respectively. When the CK fraction was fed to obese mice that consumed a high-fat diet, the levels of certain lipids including LPCs and CEs became similar to those of mice fed a normal diet. Such metabolic markers can be used to better understand obesity and related diseases induced by a hyperlipidic diet. Furthermore, changes in the levels of such metabolites can be employed to assess the risk of obesity and the therapeutic effects of obesity management. PMID- 25744176 TI - Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. AB - Glioblastoma multiforme (GBM) is a devastating disease and the most lethal of adult brain tumors. Treatment is based on surgery, radiotherapy and chemotherapy by oral temozolomide (TMZ), which is the most potent chemotherapy agent for the treatment of GBM. Despite TMZ efficiency, the prognosis of these tumors remains poor. This is because of inherent or acquired resistance of glioma tumor cells to TMZ. This resistance is caused by DNA repair enzyme activity, overexpression of epidermal growth factor receptor (EGFR), galectin-1, murine double minute 2 (Mdm2), p53 and phosphatase and tensin homolog (PTEN) mutations. Many strategies to overcome this resistance have been developed. In this review, we will describe the main mechanisms of GBM resistance to TMZ and different strategies developed to reverse the phenotype of these tumor cells. Finally, we will discuss the drawbacks and limitations of these strategies. PMID- 25744184 TI - Nitrogen transforming community in a horizontal subsurface-flow constructed wetland. AB - Constructed wetlands are important ecosystems with respect to nitrogen cycling. Here we studied the activity and abundance of nitrogen transforming bacteria as well as the spatial distribution of nitrification, anaerobic ammonium oxidation (anammox), and denitrification processes in a horizontal subsurface-flow constructed wetland. The functional genes of the nitrogen cycle were evenly distributed in a linear way along the flow path with prevalence at the superficial points. The same trend was observed for the nitrification and denitrification turnover rates using isotope labeling techniques. It was also shown that only short-term incubations should be used to measure denitrification turnover rates. Significant nitrate consumption under aerobic conditions diminishes nitrification rates and should therefore be taken into account when estimating nitrification turnover rates. This nitrate consumption was due to aerobic denitrification, the rate of which was comparable to that for anaerobic denitrification. Consequently, denitrification should not be considered as an exclusively anaerobic process. Phylogenetic analysis of hydrazine synthase (hzsA) gene clones indicated the presence of Brocadia and Kuenenia anammox species in the constructed wetland. Although anammox bacteria were detected by molecular methods, anammox activity could not be measured and hence this process appears to be of low importance in nitrogen transformations in these freshwater ecosystems. PMID- 25744185 TI - Assessing interdependent operational, tactical and strategic risks for improved utility master plans. AB - Risk management plays a key role in water utilities. Although risk tools are well established at operational levels, approaches at the strategic level are rarely informed by systemic assessments of the water supply and lack a long-term perspective. Here, we report a baseline strategic risk analysis, founded on a systemic analysis of operational risks developed 'bottom-up' and validated in a large water utility. Deploying an action-oriented research method, supported by semi- structured interviews with in-house water utility risk experts, deep connections are established between operational risk and strategic risk that surpass those existing elsewhere in the sector. Accessible presentational formats - influence diagrams, risk "heat-maps" and supporting narratives are used to promote Board-level risk discussions, and characterise a baseline set of strategic risks core to forward utility master planning. Uniquely, the influence of operational events, exposures and potential harms, together with the mitigating measures in place to mediate these risks are linked to corporate objectives on business sustainability, profitability, water quality, water quantity, supply disruption and reputation. PMID- 25744186 TI - Destruction of microcystins (cyanotoxins) by UV-254 nm-based direct photolysis and advanced oxidation processes (AOPs): influence of variable amino acids on the degradation kinetics and reaction mechanisms. AB - Hepatotoxic microcystins (MCs) are the most frequently detected group of cyanobacterial toxins. This study investigated the degradation of common MC variants in water, MC-LR, MC-RR, MC-YR and MC-LA, by UV-254 nm-based processes, UV only, UV/H2O2, UV/S2O8(2-) and UV/HSO5(-). Limited direct photolysis of MCs was observed, while the addition of an oxidant significantly improved the degradation efficiency with an order of UV/S2O8(2-) > UV/HSO5(-) > UV/H2O2 at the same initial molar concentration of the oxidant. The removal of MC-LR by UV/H2O2 appeared to be faster than another cyanotoxin, cylindrospermopsin, at either the same initial molar concentration or the same initial organic carbon concentration of the toxin. It suggested a faster reaction of MC-LR with hydroxyl radical, which was further supported by the determined second-order rate constant of MCs with hydroxyl radical. Both isomerization and photohydration byproducts were observed in UV only process for all four MCs; while in UV/H2O2, hydroxylation and diene-Adda double bond cleavage byproducts were detected. The presence of a tyrosine in the structure of MC-YR significantly promoted the formation of monohydroxylation byproduct m/z 1061; while the presence of a second arginine in MC-RR led to the elimination of a guanidine group and the absence of double bond cleavage byproducts. It was therefore demonstrated in this study that the variable amino acids in the structure of MCs influenced not only the degradation kinetics but also the preferable reaction mechanisms. PMID- 25744188 TI - Identification of anti-HIV agents with a novel benzo[4,5]isothiazolo[2,3 a]pyrimidine scaffold. AB - 3,4-Dihydro-2H-benzo[4,5]isothiazolo[2,3-a]pyrimidine is a newly identified antiviral agent against human immunodeficiency virus type 1 (HIV-1) infection, derived from 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182). The introduction of the hydrophobic 8-aryl substituent on the benzene substructure improved its anti-HIV activity, resulting in the identification of 6 fold more potent analogs. In addition, it was demonstrated that these isothiazolopyrimidine derivatives exert anti-HIV effects at an early stage of viral infection. PMID- 25744187 TI - Chromatin organization at the nuclear pore favours HIV replication. AB - The molecular mechanisms that allow HIV to integrate into particular sites of the host genome are poorly understood. Here we tested if the nuclear pore complex (NPC) facilitates the targeting of HIV integration by acting on chromatin topology. We show that the integrity of the nuclear side of the NPC, which is mainly composed of Tpr, is not required for HIV nuclear import, but that Nup153 is essential. Depletion of Tpr markedly reduces HIV infectivity, but not the level of integration. HIV integration sites in Tpr-depleted cells are less associated with marks of active genes, consistent with the state of chromatin proximal to the NPC, as analysed by super-resolution microscopy. LEDGF/p75, which promotes viral integration into active genes, stabilizes Tpr at the nuclear periphery and vice versa. Our data support a model in which HIV nuclear import and integration are concerted steps, and where Tpr maintains a chromatin environment favourable for HIV replication. PMID- 25744189 TI - Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni. AB - Praziquantel is currently the only drug available to treat schistosomiasis. Since drug resistance would be a major barrier for the increasing global attempts to eliminate schistosomiasis as a public health problem, efforts should go hand in hand with the discovery of novel treatment options. Synthetic peroxides might offer a good direction since their antischistosomal activity has been demonstrated in the laboratory. We studied 19 bridged 1,2,4,5-tetraoxanes, 2 tricyclic monoperoxides, 11 bridged 1,2,4-trioxolanes, 12 silyl peroxides, and 4 hydroxylamine derivatives against newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Schistosomicidal compounds were tested for cytotoxicity followed by in vivo studies of the most promising compounds. Tricyclic monoperoxides, trioxolanes, and tetraoxanes revealed the highest in vitro activity against NTS (IC50s 0.4-20.2 MUM) and adult schistosomes (IC50s 1.8 22.8 MUM). Tetraoxanes showed higher cytotoxicity than antischistosomal activity. Selected trioxolane and tricyclic monoperoxides were tested in mice harboring an adult S. mansoni infection. The highest activity was observed for two trioxolanes, which showed moderate worm burden reductions (WBR) of 44.3% and 42.9% (p>0.05). Complexation of the compounds with beta-cyclodextrin with the aim to improve solubility and gastrointestinal absorption did not increase in vivo antischistosomal efficacy. The high in vitro antischistosomal activity of trioxolanes and tricyclic monoperoxides is a promising basis for future investigations, with the focus on improving in vivo efficacy. PMID- 25744190 TI - Synthesis and antitumor activity of novel per-butyrylated glycosides of podophyllotoxin and its derivatives. AB - A series of perbutyrylated glycosides of podophyllotoxin and its derivatives were synthesized and evaluated for their antitumor activity in vitro. Most of them exhibit cytotoxic activity against a panel of five human cancer cell lines (HL 60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Among the synthesized compounds, epipodophyllotoxin alpha-d-galactopyranoside 8b, epipodophyllotoxin alpha-d-arabinopyranoside 8e, and podophyllotoxin beta-d-glucopyranoside 11a show the highest potency of anticancer activity with their IC50 values ranging from 0.14 to 1.69MUM. Structure activity relationship analysis indicates that the type of glycosidic linkage, the configuration at C-4 of the podophyllotoxin scaffold, and the substitution at 4'-position (OH vs OCH3) can all have significant effect on the potency of their anticancer activity. Several compounds are more active than the control drugs Etoposide and Cisplatin, suggesting their potential as anticancer agents for further development. PMID- 25744191 TI - Does conventional intra-aortic balloon pump trigger timing produce optimal hemodynamic effects in vivo? AB - PURPOSE: The intra-aortic balloon pump (IABP) provides circulatory support through counterpulsation. The hemodynamic effects of the IABP may vary with assisting frequency and depend on IAB inflation/deflation timing. We aimed to assess in vivo the IABP benefits on coronary, aortic, and left ventricular hemodynamics at different assistance frequencies and trigger timings. METHODS: Six healthy, anesthetized, open-chest sheep received IABP support at 5 timing modes (EC, LC, CC, CE, CL, corresponding to early/late/conventional/conventional/conventional inflation and conventional/conventional/conventional/early/late deflation, respectively) with frequency 1:3 and 1:1. Aortic (Q(ao)) and coronary (Q(cor)) flow, and aortic (P(ao)) and left ventricular (PLV) pressure were recorded simultaneously, with and without IABP support. Integrating systolic Q(ao) yielded stroke volume (SV). RESULTS: EC at 1:1 produced the lowest end-diastolic P(ao) (59.5 +/- 7.8 mmHg [EC], 63.4 +/- 11.1 mmHg [CC]), CC at 1:1 the lowest systolic PLV (69.1 +/- 6.5 mmHg [CC], 76.4 +/- 6.5 mmHg [control]), CC at 1:1 the highest SV (88.5 +/- 34.4 ml [CC], 76.6 +/- 31.9 ml [control]) and CC at 1:3 the highest diastolic Qcor (187.2 +/- 25.0 ml/min [CC], 149.9 +/- 16.6 ml/min [control]). Diastolic P(ao) augmentation was enhanced by both assistance frequencies alike, and optimal timings were EC for 1:3 (10.4 +/- 2.8 mmHg [EC], 6.7 +/- 3.8 mmHg [CC]) and CC for 1:1 (10.8 +/- 6.7 mmHg [CC], -3.0 +/- 3.8 mmHg [control]). CONCLUSIONS: In our experiments, neither a single frequency nor a single inflation/deflation timing, including conventional IAB timing, has shown superiority by uniformly benefiting all studied hemodynamic parameters. A choice of optimal frequency and IAB timing might need to be made based on individual patient hemodynamic needs rather than as a generalized protocol. PMID- 25744192 TI - A novel peritoneum derived vascular prosthesis formed on a latex catheter in an SDF-1 chemokine enriched environment: a pilot study. AB - INTRODUCTION: Although saphenous vein grafts are widely used conduits for coronary artery bypass graft surgery, their clinical value remains limited due to high failure rates. The aim of the study was to evaluate feasibility, safety, and biocompatibility of peritoneal derived vascular grafts (PDVG) formed on a silicone-coated, latex, Foley catheter in a stromal cell-derived factor (SDF-1)- enriched environment. METHODS: Foley catheters were implanted into the parietal wall of 8 sheep. After 21 days the peritoneal cavity was re-opened and the newly formed tissue fragments were harvested. The animals were randomly assigned into: (1) study group in which conduits were incubated in a solution containing SDF-1, (2) control group without SDF-1 incubation. Left carotid arteries were accessed and "end-to-side" anastomoses were performed. Biological materials for histological examination were taken at 4, 7, 10, and 14 days. RESULTS AND CONCLUSIONS: The study proved safety, feasibility, and biocompatibility of PDVG formed on the basis of a silicone-coated, latex catheter in an SDF-1 chemokine enriched environment. These biological grafts effectively integrated with the native high-pressure arterial environment in an ovine model and provided favorable vascular profile. The potential clinical value of this technology needs to be further elucidated in long-term preclinical and clinical studies. PMID- 25744193 TI - Evaluation of a pseudo-one-compartment model for phosphorus kinetics by later phase dialysate collection during blood purification. AB - PURPOSE: Phosphorus removal is a major issue to assess for physicians engaging in hemodialysis. A pseudo-one-compartment model was reported as a novel model for phosphorus kinetics. We aimed to evaluate the adequacy of this model from the standpoint of the total mass of removed phosphorus during prolonged treatment. METHODS: Dialysate was collected during 6-h hemodialysis and hemodiafiltration treatment in 5 patients. Later-phase (from 4 to 6 h) dialysate was collected separately. Mobilization clearance (K(m)) and dialyzer clearance (K) were calculated by simple arithmetic operations utilizing stable serum phosphorus concentrations in this later phase. Volume of the accessible compartment (V(0)) was estimated by a fitting method. Amounts of removed phosphorus were calculated with these parameters and compared with measured values. The best sampling time points during treatment were also assessed, when the parameters were determined by serial serum phosphorus concentrations alone. RESULTS: Pearson's correlation coefficient (R) between calculated and measured values of removed phosphorus was 0.991 and the concordance correlation coefficient (rho) was 0.987. When K(m), K and V(0) were determined by serial serum concentrations alone, including those at 0, 1, 4, and 6 h, the calculated mass of removed phosphorus had high R (0.974 0.975) or rho (0.966-0.972) with the measured values. CONCLUSIONS: We confirmed that a pseudo-one-compartment model is useful for the estimation of removed phosphorus mass during prolonged blood purification by collecting dialysate. When the parameters are determined by a fitting method using serial serum concentrations alone, sampling at 0, 1, 4, and 6 h seems to be adequate. PMID- 25744194 TI - Buccal mucosa repair with electrospun silk fibroin matrix in a rat model. AB - INTRODUCTION: Biomimic electrospun matrix derived from silk fibroin nanofiber solution was recently prepared in our group. The feasibility of the matrix as mucosa repair scaffold was evaluated in a rat model in the present study. METHODS: Full thickness wound was established on the buccal mucosa of male Wister rats via microscopic oral surgery. 80 rats were randomly assigned into 4 groups: (1) silk fibroin matrix, (2) commercial cowhide acellular dermal matrix (Heal All), (3) commercial acellular dermal matrix of human skin (RENOV), and (4) vaseline gauze, respectively. RESULTS: The silk fibroin matrix showed similar repair performance compared to the commercial acellular dermal matrices, implying promising applications in mucosa regeneration. More importantly, the silk fibroin matrix showed better wound healing ability, improved wound shrinkage inhibition, and reduced local immunological incompatibility. CONCLUSIONS: The silk fibroin scaffold performed satisfied in scar tissue inhibition and epidermis regeneration. Taking into account its improved mechanical properties, the biomimic electrospun silk matrix could become a promising substitute of acellular dermal matrix in clinical applications. PMID- 25744195 TI - Construction of a biocompatible decellularized porcine hepatic lobe for liver bioengineering. AB - OBJECTIVE: One of the major obstacles in applying decellularized organs for clinical use is the recellularization step, during which huge numbers of cells are required to develop whole livers. We established a simple protocol for constructing a bioartificial hepatic lobe and investigated its biocompatibility. METHODS: The right lateral lobe of porcine liver was decellularized using 0.1% sodium dodecyl sulfate through the right branch of the portal vein. Decellularized lobes were evaluated by histological and biochemical analyses. DNA content was quantified to validate the decellularization protocol. The presence of immunogenic and pathogenic antigens was checked to exclude potential rejection and thrombosis after xenotransplantation. Xeno-reactivity of decellularized tissue against human peripheral blood mononuclear cells was examined. Cytotoxicity was evaluated against hepatocarcinoma cells. Finally, scaffolds were incubated in collagenase for biodegradation testing. RESULTS: The decellularized lobe preserved the three-dimensional architecture, ultrastructure, extracellular matrix components, and vasculature. Scaffolds were almost depleted of DNA in addition to antigenic and pathogenic antigens, which are considered barriers to xenotransplantation. The human immune response against scaffolds was considered non-significant. Our matrices were biocompatible and biodegradable. CONCLUSIONS: We successfully developed a non-cytotoxic, non-immunogenic, and biodegradable porcine hepatic lobe for future liver regeneration and bioengineering. PMID- 25744196 TI - NT-proBNP and troponin T levels differ after haemodialysis with a low versus high flux membrane. AB - BACKGROUND: Brain natriuretic peptide (BNP), N-terminal-proBNP (NT-proBNP), and high sensitive cardiac troponin T (TnT) are markers that are elevated in chronic kidney disease and correlate with increased risk of mortality. Data are conflicting on the effect of biomarker levels by hemodialysis (HD).Our aim was to clarify to what extent HD with low-flux (LF) versus high-flux (HF) membranes affects the plasma levels of BNP, NT-proBNP, and TnT. METHODS AND MATERIALS: 31 HD patients were included in a crossover design, randomized to start dialysis with a LF-HD or HF-HD dialyzer. Each patient was his/her own control. The dialyses included in the study were the first treatments of two consecutive weeks with each mode of dialysis. Patients normally on hemodiafiltration (HDF) also performed a HDF the third week. Values after HD were corrected for extent of ultrafiltration. RESULTS: During LF-HD the biomarkers NT-proBNP and TnT increased (15 versus 6%, P <= .001) while there was a slight decrease in BNP (P<.05). During HF-HD the NT-proBNP, BNP and TnT levels decreased (P <= .01 for all). During HDF all three markers decreased (P<.01 for all). The rise in TnT during LF HD correlated with dialysis vintage (months on HD, r = .407, P = .026), Kt/V-urea (r = .383, P = .037), HD time in hours/treatment (r = .447, P = .013) and inversely with residual urinary output (r = -.495, P = .005). The baseline levels of BNP and NT-proBNP correlated with blood pressure. CONCLUSIONS: Cardiac biomarkers increase slightly during LF-HD. A HF-HD eliminates the biomarkers and can mask increases caused by, e.g., myocardial infarction. PMID- 25744197 TI - Factors associated with albumin loss in post-dilution hemodiafiltration and nutritional consequences. AB - INTRODUCTION: Hemodiafiltration is currently one of the most effective techniques of extra-renal purification but results in an increase of albumin loss in dialysate. We aimed to determine the factors associated with albumin loss during post-dilution hemodiafiltration, compare an "automatic" mode of infusate flow control versus a "manual" control, and assess the potential nutritional impact. METHODS: This prospective observational study included all hemodialysis patients in our institution who underwent post-dilution hemodiafiltration 3 times a week on a Fresenius 5008 for at least 2 months. At each session, albumin content was measured in a representative effluent dialysate volume. The automatic mode of the Fresenius 5008 was used for automatic infusate flow control. RESULTS: In all, 18 patients (mean age 60.7 +/- 15 years) underwent 85 post-dilution hemodiafiltration sessions. The mean albumin loss was 3134 +/- 2450 mg/session. Albumin loss was significantly affected by infusate flow, infusate volume, transmembrane pressure and ultrafiltration volume. The loss was greater with Toraysulfone and FX 1000 membranes rather than FX 80 or FX 100 membranes. With AutoSub rather than manual control, infusate flow was greater (P<.001), transmembrane pressure was higher (P = .004), and the albumin loss was greater (P = .010). However, there was no correlation between albumin loss and nutritional variables. CONCLUSIONS: Albumin loss during post-dilution hemodiafiltration was correlated with increased transmembrane pressure and infusate flow, especially AutoSub flow control, and type of membrane. However, this loss, when moderate, did not seem to affect nutritional aspects and should not limit the use of hemodiafiltration. PMID- 25744198 TI - Tissue engineering of the temporomandibular joint disc: current status and future trends. AB - INTRODUCTION: Temporomandibular joint disorders are extremely prevalent and there is no ideal treatment clinically for the moment. For severe cases, a discectomy often need to be performed, which will further result in the development of osteoarthritis. In the past thirty years, tissue engineering has provided a promising approach for the effective remedy of severe TMJ disease through the creation of viable, effective, and biological functional implants. METHODS: Although TMJ disc tissue engineering is still in early stage, unremitting efforts and some achievements have been made over the past decades. In this review, a comprehensive summary of the available literature on the progress and status in tissue engineering of the TMJ disc regarding cell sources, scaffolds, biochemical and biomechanical stimuli, and other prospects relative to this field is provided. RESULTS AND CONCLUSIONS: Even though research studies in this field are too few compared to other fibrocartilage (e.g., knee meniscus) and numerous, difficult tasks still exist, we believe that our ultimate goal of regenerating a biological implant whose histological, biochemical, and biomechanical properties parallel native TMJ discs for clinical therapy will be achieved in the near future. PMID- 25744199 TI - ABCA1 expression in macrophages of allogeneic hematopoietic stem cell transplantation patients with severe infection undergoing continuous blood purification. AB - BACKGROUND: Excessive activation of the inflammatory mediator cascade after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients is associated with high mortality. Many studies have shown that continuous blood purification (CBP) could improve the prognosis of allo-HSCT patients with severe infection. However, the exact mechanism remains unclear. The aim of this study was to observe the effect of CBP on the expression of ATP-binding cassette transporter A1 (ABCA1) in macrophages, and to investigate the interventional effects of CBP on serum cytokine in allo-HSCT patients with severe infection. METHODS: A total of 26 allo-HSCT patients with severe infection were included in this study. Before CBP and after CBP, blood samples were collected to observe hepatic and renal function, and the serum levels of TNF-alpha, IL-1, IL-6, and IL 10 were detected via ELISA. The THP-1 macrophages were exposed to serum samples obtained from patients at specific time points during CBP to test the changes of ABCA1 in macrophages by real-timePCR and Western blotting. RESULTS: Serum creatinine, alanine aminotransferase, and C reaction protein (CRP) levels decreased significantly after CBP. Moreover, TNF-alpha, IL-1, and IL-6 serum levels decreased significantly, but IL-10 level increased significantly after CBP (P<.05). After CBP, ABCA1 expression levels were higher than those before CBP, and ABCA1 expression was significantly increased with the supplementation of CBP (P<.05). CONCLUSIONS: CBP improved the condition of allo-HSCT patients with severe infection. CBP may be a potent up-regulator of the ABCA1 levels in macrophages of allo-HSCT patients with severe infection. PMID- 25744200 TI - The impact of reliable prebolus T 1 measurements or a fixed T 1 value in the assessment of glioma patients with dynamic contrast enhancing MRI. AB - INTRODUCTION: Accurate quantification of hemodynamic parameters using dynamic contrast enhanced (DCE) MRI requires a measurement of tissue T 1 prior to contrast injection (T 1). We evaluate (i) T 1 estimation using the variable flip angle (VFA) and the saturation recovery (SR) techniques and (ii) investigate if accurate estimation of DCE parameters outperform a time-saving approach with a predefined T 1 value when differentiating high- from low-grade gliomas. METHODS: The accuracy and precision of T 1 measurements, acquired by VFA and SR, were investigated by computer simulations and in glioma patients using an equivalence test (p > 0.05 showing significant difference). The permeability measure, K trans, cerebral blood flow (CBF), and - volume, V p, were calculated in 42 glioma patients, using fixed T 1 of 1500 ms or an individual T 1 measurement, using SR. The areas under the receiver operating characteristic curves (AUCs) were used as measures for accuracy to differentiate tumor grade. RESULTS: The T 1 values obtained by VFA showed larger variation compared to those obtained using SR both in the digital phantom and the human data (p > 0.05). Although a fixed T 1 introduced a bias into the DCE calculation, this had only minor impact on the accuracy differentiating high-grade from low-grade gliomas, (AUCfix = 0.906 and AUCind = 0.884 for K trans; AUCfix = 0.863 and AUCind = 0.856 for V p; p for AUC comparison > 0.05). CONCLUSION: T 1 measurements by VFA were less precise, and the SR method is preferable, when accurate parameter estimation is required. Semiquantitative DCE values, based on predefined T 1 values, were sufficient to perform tumor grading in our study. PMID- 25744201 TI - Tooth loss early in life accelerates age-related bone deterioration in mice. AB - Both osteoporosis and tooth loss are health concerns that affect many older people. Osteoporosis is a common skeletal disease of the elderly, characterized by low bone mass and microstructural deterioration of bone tissue. Chronic mild stress is a risk factor for osteoporosis. Many studies showed that tooth loss induced neurological alterations through activation of a stress hormone, corticosterone, in mice. In this study, we tested the hypothesis that tooth loss early in life may accelerate age-related bone deterioration using a mouse model. Male senescence-accelerated mouse strain P8 (SAMP8) mice were randomly divided into control and toothless groups. Removal of the upper molar teeth was performed at one month of age. Bone response was evaluated at 2, 5 and 9 months of age. Tooth loss early in life caused a significant increase in circulating corticosterone level with age. Osteoblast bone formation was suppressed and osteoclast bone resorption was activated in the toothless mice. Trabecular bone volume fraction of the vertebra and femur was decreased in the toothless mice with age. The bone quality was reduced in the toothless mice at 5 and 9 months of age, compared with the age-matched control mice. These findings indicate that tooth loss early in life impairs the dynamic homeostasis of the bone formation and bone resorption, leading to reduced bone strength with age. Long-term tooth loss may have a cumulative detrimental effect on bone health. It is important to take appropriate measures to treat tooth loss in older people for preventing and/or treating senile osteoporosis. PMID- 25744202 TI - Treatment of table olive processing wastewaters using novel photomodified ultrafiltration membranes as first step for recovering phenolic compounds. AB - Table olive processing wastewaters (TOPW) have high salt concentration and total phenolic content (TPC) causing many environmental problems. To reduce them, ultrafiltration (UF) was applied for treating TOPW. However, NaCl, which is the main responsible of salinity in TOPW, and phenols are small molecules that cannot be separated by conventional UF membranes. They have serious problems caused by fouling, which can be overcome using membrane modification techniques. For these reasons, photomodification may be an effective technique to obtain a stream rich in TPC due to the changes in membrane surface properties. UV-modification in the presence of two hydrophilic compounds (polyethylene glycol and aluminium oxide) was performed to achieve membranes with high reductions of organic matter and to keep the TPC as high as possible. Commercial polyethersulfone (PES) membranes of 30 kDa were used. Surface modification was evaluated using FTIR-ATR spectroscopy and membrane performance was studied by calculating the rejection ratios of colour, chemical oxygen demand (COD) and TPC. Results demonstrated that UF is a useful pre-treatment to reduce organic matter from TOPW, obtaining a permeate rich in TPC. PES/Al2O3 membranes displayed superior antifouling properties and rejection values, keeping high the TPC (>95%). Therefore, UF using modified membranes is an appropriate and sustainable technique for treating TOPW. PMID- 25744204 TI - Mice lacking the cerebral cortex develop normal song: insights into the foundations of vocal learning. AB - Mouse models play an increasingly important role in the identification and functional assessment of speech-associated genes, with a focus on genes involved in vocal production, and possibly vocal learning. Moreover, mice reportedly show direct projections from the cortex to brainstem vocal motor neurons, implying a degree of volitional control over vocal output. Yet, deaf mice did not reveal differences in call structures compared to their littermates, suggesting that auditory input is not a prerequisite for the development of species-specific sounds. To elucidate the importance of cortical structures for the development of mouse ultrasonic vocalizations (USVs) in more detail, we studied Emx1 CRE;Esco2(fl/fl) mice, which lack the hippocampus and large parts of the cortex. We conducted acoustic analyses of the USVs of 28 pups during short-term isolation and 23 adult males during courtship encounters. We found no significant differences in the vocalizations of Emx1-CRE;Esco2(fl/fl) mice, and only minor differences in call type usage in adult mice, compared to control littermates. Our findings question the notion that cortical structures are necessary for the production of mouse USVs. Thus, mice might be less suitable to study the mechanisms supporting vocal learning than previously assumed, despite their value for studying the genetic foundations of neurodevelopment more generally. PMID- 25744203 TI - OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy. AB - BACKGROUND: Glioblastoma is the most malignant human brain tumor and has a dismal prognosis; however, some patients show long-term survival. The interaction between the costimulatory molecule OX40 and its ligand OX40L generates key signals for T-cell activation. The augmentation of this interaction enhances antitumor immunity. In this present study, we explored whether OX40 signaling is responsible for antitumor adaptive immunity against glioblastoma and also established therapeutic antiglioma vaccination therapy. METHODS: Tumor specimens were obtained from patients with primary glioblastoma (n = 110) and grade III glioma (n = 34). Quantitative polymerase chain reaction (PCR), flow cytometry, and immunohistochemistry were used to analyze OX40L expression in human glioblastoma specimens. Functional consequences of OX40 signaling were studied using glioblastoma cell lines, mouse models of glioma, and T cells isolated from human subjects and mice. Cytokine production assay with mouse regulatory T cells was conducted under hypoxic conditions (1.5% O2). RESULTS: OX40L mRNA was expressed in glioblastoma specimens and higher levels were associated with prolonged progression-free survival of patients with glioblastoma, who had undergone gross total resection. In this regard, OX40L protein was expressed in A172 human glioblastoma cells and its expression was induced under hypoxia, which mimics the microenvironment of glioblastoma. Notably, human CD4 T cells were activated when cocultured in anti-CD3-coated plates with A172 cells expressing OX40L, as judged by the increased production of interferon-gamma. To confirm the survival advantage of OX40L expression, we then used mouse glioma models. Mice bearing glioma cells forced to express OX40L did not die during the observed period after intracranial transplantation, whereas all mice bearing glioma cells lacking OX40L died. Such a survival benefit of OX40L was not detected in nude mice with an impaired immune system. Moreover, compared with systemic intraperitoneal injection, the subcutaneous injection of the OX40 agonist antibody together with glioma cell lysates elicited stronger antitumor immunity and prolonged the survival of mice bearing glioma or glioma-initiating cell-like cells. Finally, OX40 triggering activated regulatory T cells cultured under hypoxia led to the induction of the immunosuppressive cytokine IL10. CONCLUSION: Glioblastoma directs immunostimulation or immunosuppression through OX40 signaling, depending on its microenvironment. PMID- 25744205 TI - Fixation times in differentiation and evolution in the presence of bottlenecks, deserts, and oases. AB - Cellular differentiation and evolution are stochastic processes that can involve multiple types (or states) of particles moving on a complex, high-dimensional state-space or "fitness" landscape. Cells of each specific type can thus be quantified by their population at a corresponding node within a network of states. Their dynamics across the state-space network involve genotypic or phenotypic transitions that can occur upon cell division, such as during symmetric or asymmetric cell differentiation, or upon spontaneous mutation. Here, we use a general multi-type branching processes to study first passage time statistics for a single cell to appear in a specific state. Our approach readily allows for nonexponentially distributed waiting times between transitions, reflecting, e.g., the cell cycle. For simplicity, we restrict most of our detailed analysis to exponentially distributed waiting times (Poisson processes). We present results for a sequential evolutionary process in which L successive transitions propel a population from a "wild-type" state to a given "terminally differentiated," "resistant," or "cancerous" state. Analytic and numeric results are also found for first passage times across an evolutionary chain containing a node with increased death or proliferation rate, representing a desert/bottleneck or an oasis. Processes involving cell proliferation are shown to be "nonlinear" (even though mean-field equations for the expected particle numbers are linear) resulting in first passage time statistics that depend on the position of the bottleneck or oasis. Our results highlight the sensitivity of stochastic measures to cell division fate and quantify the limitations of using certain approximations (such as the fixed-population and mean-field assumptions) in evaluating fixation times. PMID- 25744206 TI - Onsite and online FT-NIR spectroscopy for the estimation of total nitrogen and moisture content in poultry manure. AB - The nitrogen and moisture of manure are highly variable parameters and depend on animal type, husbandry techniques, environmental conditions and storage time. The precision in manure dose estimation for crops fertilization depends on the total nitrogen and moisture content just before its incorporation in the field. The aim of the study is to develop a Fourier Transform Near Infrared (FT-NIR) spectroscopy method to determine the total Kjeldhal nitrogen (TKN%) and moisture (M%) of different types of poultry manure prior to land application. Samples covering a wide range of poultry types and different husbandry conditions were obtained from farms of North-Eastern Italy in order to develop the method. The method was calibrated (R(2) = 0.94 for TKN%, R(2) = 0.99 for M%) and validated (R(2) = 0.82 for TKN%, R(2) = 0.95 for M%) in the laboratory. An external validation was also performed in situ with independent samples, of similar origin to the previous data set, which were collected just before application in the field. Spectra acquisitions for these samples were carried out using the same instrumentation which was placed in a special vehicle for monitoring campaigns. The results showed satisfactory prediction accuracy (R(2) = 0.82 for TKN%, R(2) = 0.93 for M%). Finally, an additional analysis was performed to discriminate the different types of poultry effluents. The TKN and M measurements in the disposal areas indicated that current agronomic practices lead to more than double poultry manure oversupply. The proposed FT-NIR methodology aims to improve the current fertilization management and environmental protection by providing fast and precise estimations of poultry manure doses prior to land application. PMID- 25744207 TI - A temperature induced lipocalin gene from Medicago falcata (MfTIL1) confers tolerance to cold and oxidative stress. AB - Temperature-induced lipocalins (TIL) are plasmalemma-localized proteins and responsive to environmental stresses. Physiological functions of MfTIL1 from Medicago sativa subsp. falcata (L.) Arcang. (hereafter falcata), a forage legume with cold and drought tolerance, were investigated in this study. MfTIL1 expression was greatly induced by 4-96 h of cold treatment, while transcript levels of the orthologs in Medicago truncatula, a model legume plant with lower cold tolerance than falcata, were reduced or not altered within 48-96 h. MfTIL1 expression was not responsive to dehydration and salinity. Compared to the wild type, transgenic tobacco plants overexpressing MfTIL1 had lower temperature (LT50) that resulted in 50 % lethal and elevated survival rate in response to freezing, elevated F v/F m and decreased ion leakage after treatments with chilling, high light and methyl viologen (MV). H2O2 and O2 (-) were less accumulated in transgenic plants than in the wild type after treatments with chilling, high light and MV, while antioxidant enzyme activities showed no difference between the two types of plants prior to or following treatments. Higher transcript levels of NtDREB3 and NtDREB4 genes were observed in transgenic plants than in the wild type under non-stressed conditions, but higher transcript levels of NtDREB1, NtDREB2, NtDREB4 and NtCOR15a genes under chilling conditions. It is suggested that MfTIL1 plays an important role in plant tolerance to cold and oxidative stress through promoted scavenging of reactive oxygen species and up-regulating expression of multiple cold responsive genes. PMID- 25744208 TI - Health-risk behaviors in teens investigated by U.S. Child Welfare Agencies. AB - PURPOSE: The aim of this study was to examine prevalence and correlates of health risk behaviors in 12- to 17.5-year-olds investigated by child welfare and compare risk-taking over time and with a national school-based sample. METHODS: Data from the National Survey of Child and Adolescent Well-Being (NSCAW II) were analyzed to examine substance use, sexual activity, conduct behaviors, and suicidality. In a weighted sample of 815 adolescents aged 12-17.5 years, prevalence and correlates for each health-risk behavior were calculated using bivariate analyses. Comparisons to data from NSCAW I and the Youth Risk Behavior Survey were made for each health-risk behavior. RESULTS: Overall, 65.6% of teens reported at least one health-risk behavior with significantly more teens in the 15- to 17.5-year age group reporting such behaviors (81.2% vs. 54.4%; p <= .001). Almost 75% of teens with a prior out-of-home placement and 77% of teens with child behavior checklist scores >=64 reported at least one health-risk behavior. The prevalence of smoking was lower than in NSCAW I (10.5% vs. 23.2%; p <= .05) as was that of sexual activity (18.0% vs. 28.8%; p <= .05). Prevalence of health risk behaviors was lower among older teens in the NSCAW II sample (n = 358) compared with those of the 2011 Youth Risk Behavior Surveillance System high school-based sample with the exception of suicidality, which was approximately 1.5 times higher (11.3% [95% confidence interval, 6.5-19.0] vs. 7.8% [95% confidence interval, 7.1-8.5]). CONCLUSIONS: Health-risk behaviors in this population of vulnerable teens are highly prevalent. Early efforts for screening and interventions should be part of routine child welfare services monitoring. PMID- 25744209 TI - Preventing drug use among sexual-minority youths: findings from a tailored, web based intervention. AB - PURPOSE: Rates of drug use among sexual-minority youths are disproportionately high. Yet, expressly designed prevention programs targeting this population are absent. This study developed and tested a web-based drug abuse prevention program for sexual-minority youths. METHODS: A sample (N = 236) of sexual-minority youths was recruited via Facebook. Online, all youths completed pretests; youths randomly assigned to the intervention received a 3-session prevention program; and all youths completed posttest and 3-month follow-up measurements. RESULTS: At 3-month follow-up and compared to youths in the control arm, intervention-arm youths reported less stress, reduced peer drug use, lower rates of past 30-day other drug use, and higher coping, problem solving, and drug-use refusal skills. CONCLUSIONS: Outcome data suggest the potential of tailored intervention content to address sexual-minority youths' drug use rates and related risk factors. Moreover, study procedures lend support to the feasibility of using the Internet to recruit sexual-minority youths, collect data, and deliver intervention. PMID- 25744211 TI - Bioadsorption strategies with yeast molecular display technology. AB - Molecular display techniques using microbial cell surfaces have been widely developed in the past twenty years, and are useful tools as whole cell catalysts for various applications such as bioconversion, bioremediation, biosensing, and the screening system of protein libraries. Furthermore, different types of microbial cells among eukaryotic and prokaryotic strains have been investigated for their use in surface display technologies. Recently, several kinds of protein displaying yeasts have been utilized as bioadsorbents in this platform technology. In particular, these trials have successfully expanded the possibility of applications to metal binding, affinity purification, and receptor ligand interaction by using the yeast cell surface. In this mini review, we describe the general principles of molecular display technology using yeast cells and its applications, with a particular focus on bioadsorption. PMID- 25744210 TI - Physical exercise and epigenetic adaptations of the cardiovascular system. AB - During the last decade, epigenetics became one of the fastest growing research fields in numerous clinical and basic science disciplines. Evidence suggests that chromatin modifications (e.g., histone modifications and DNA methylation) as well as the expression of micro-RNA molecules play a crucial role in the pathogenesis of several cardiovascular diseases. On the one hand, they are involved in the development of general risk factors like chronic inflammation, but on the other hand, epigenetic modifications are conducive to smooth muscle cell, cardiomyocyte, and endothelial progenitor cell proliferation/differentiation as well as to extracellular matrix processing and endothelial function (e.g., endothelial nitric oxide synthase regulation). Therefore, epigenetic medical drugs have gained increased attention and provided the first promising results in the context of cardiovascular malignancies. Beside other lifestyle factors, physical activity and sports essentially contribute to cardiovascular health and regeneration. In this review we focus on recent research proposing physical activity as a potent epigenetic regulator that has the potential to counteract pathophysiological alterations in almost all the aforementioned cardiovascular cells and tissues. As with epigenetic medical drugs, more knowledge about the molecular mechanisms and dose-response relationships of exercise is needed to optimize the outcome of preventive and rehabilitative exercise programs and recommendations. PMID- 25744212 TI - Evaluation of the adequacy of the consume-by date of rice balls sold at convenience stores. AB - The adequacy of the consume-by date was validated for rice balls sold at convenience stores (CVSs),taking into account the process of distribution. The results indicated that the increase in the viable cell counts differed significantly depending on the type of rice balls and the storage temperature. At 19 h after delivery, Staphylococcus spp. were detected in 4 samples (26.7%) of the Tunamayo samples of Company A and in the majority of the Plum samples of Company B. Results showed there was a strong correlation between the elapsed time after delivery and the viable cell counts for all samples except for the Plum samples of Company B. The regression equations varied for the different types of rice balls and the different storage temperatures. Using the obtained regression equations and assuming a safety factor of 0.7, the appropriate consume-by date was determined to be 11 h for the Tunamayo and 38 h for the Plum of Company A, and 21 h for the Tunamayo of Company B. Among 14 strains of isolated Gram negative bacteria, 11 strains (78.6%) belonged to the genus Serratia. PMID- 25744213 TI - Characterization of microorganisms isolated from the black dirt of toilet bowls and componential analysis of the black dirt. AB - We have previously conducted a microflora analysis and examined the biofilm forming activity of bacteria isolated from toilet bowl biofilms. In the present investigation, to reveal the strain involved in the formation of black dirt in toilet bowls, we performed a microflora analysis of the bacteria and fungi isolated from the black dirt of toilet bowls at ten homes. Among samples from different isolation sites and sampling seasons, although a similar tendency was not seen in bacterial microflora, Exophiala sp. was detected in the fungal microflora from all samples of black dirt except for one, and constituted the major presence. By scanning electron microscope (SEM) analysis of the formed black dirt, SEM image at * 1,000 and * 5,000 magnification showed objects like hyphae and many bacteria adhering to them, respectively. Micro fourier transform infrared spectroscopy (micro FT-IR) and SEM with X-ray microanalysis (SEM-XMA) were used to investigate the components of black dirt. IR spectra of micro-FT-IR showed typical absorptions associated with amide compounds and protein, and the elements such as C, N, O, Na, Mg, Al, Si, P, S, K, and Ba were detected with SEM XMA. These results showed that black dirt had living body ingredients. Furthermore, Exophiala sp. and Cladosporium sp. strains, which were observed at a high frequency, accumulated 2-hydroxyjuglone (2-HJ) and flaviolin as one of the intermediates in the melanin biosynthetic pathway by the addition of a melanin synthesis inhibitor (tricyclazole) at the time of cultivation. These results suggested strongly that the pigment of black dirt in toilet bowls was melanin produced by Exophiala sp. and Cladosporium sp. strains. PMID- 25744214 TI - Isolation and identification of Enterobacteriaceae from raw horsemeat intended for human consumption (Basashi). AB - The status of Enterobacteriaceae contamination was investigated in a total of 131 samples of raw horsemeat (Basashi) intended for human consumption purchased from a general meat shop or by mail-order from October 2012 to December 2013. The bacteria were isolated from 105 of the 112 samples (93.8%). Prominent differences in the isolation rate due to the place of manufacture/sale or by the cut of the meat were not observed. Moreover, in a comparison between domestic (92.6%) and imported (100%) samples, the isolation rate was slightly higher in the imported samples. When Enterobacteriaceae isolated from raw horsemeat was identified, it was highly diverse, with 14 species identified in total. From among these species, Hafnia alvei was the most common, with 33 strains (19.8%),followed by 27 strains (16.2%) of Klebsiella pneumoniae and 26 strains (15.6%) of Enterobacter cloacae, indicating that these three species were dominant. A trend was observed, with the dominant strain differing depending on the place of manufacture/sale or the cut of the meat. H. alvei was isolated at an especially high frequency from imported samples. An investigation was carried out regarding raw horsemeat intended for human consumption from Yamanashi Prefecture and Canada, regularly purchased from one store in Kanagawa Prefecture. Enterobacteriaceae were isolated during five of nine (55.6%) trials, in which the isolated bacteria were H. alvei, K. pneumoniae, etc. Moreover, they were isolated at a very high isolation rate of seven among 10 trials for the Canadian meat, and H. alvei was the most commonly isolated bacteria. Accordingly, when an investigation was carried out regarding the differences in the strain level in the six isolates of H. alvei periodically isolated from raw horsemeat from Canada by the pulsed-field gel electrophoresis (PFGE) pattern using a restriction enzyme, SfiI, there was a possibility that these were the same H-38 strain (November 2013) and H-64 strain (April 2014) as well as the same H-104 strain (July 2014) and H-131 strain (December 2014). As mentioned above, it has been demonstrated that a variety of Enterobacteriaceae were isolated from raw horsemeat (Basashi) intended for human consumption, and at a high frequency. Moreover, based on the fact that the same species or strain was chronologically isolated, the possibility of contamination by the same contamination source at different times was suggested. PMID- 25744215 TI - The synergistic effect of two formulated biofungicides in the biocontrol of root and bottom rot of lettuce. AB - The aim of this study was to evaluate the synergistic effect of two formulated biofungicides (Rhizoleen-T and Rhizoleen-B) in the suppression of root and bottom rot of lettuce caused by Rhizoctonia solani, as well as the consequent effect on the phytosanitarian status of the plants.The results proved that application of the biofungicides either singly or in combination increased the germination and survival of the lettuce up to 61.67% and 100%, respectively. The phytosanitarian status of the plants, which was indicated by morphological and physiological parameters, was improved as the result of the application of the biofungicides. The noteworthy valuable result was the increase in fresh weight by 52.5% of the control when the two biofungicides were applied as a mixture. Interestingly, the mixture of the two biofungicides brought about a significant increase in most parameters compared to either of them in single preparation. Proline and phenols significantly increased as a result of the application of the biofungicides compared to the control. This means that the treated plants were more resistant against the pathogens. The study concludes that application of the biofungicides protects the lettuce plants against root and bottom rot, and in addition they increase the strength of the defense system of the plants. It is recommended that the application of a biofungicide mixture is a good and effective strategy in the biocontrol of plant diseases. PMID- 25744216 TI - Defensive effects of human intestinal antimicrobial peptides against infectious diseases caused by Vibrio mimicus and V. vulnificus. AB - Of human pathogenic Vibrio species, V. mimicus causes gastroenteritis whereas V. vulnificus causes fatal septicemia after consumption of contaminated seafood. These two pathogens produce hemolytic toxins termed V. mimicus hemolysin (VMH) and V. vulnificus hemolysin (VVH), respectively. These toxins elicit the cytolysis of various eukaryotic cells, as well as erythrocytes. The human intestine secretes cationic antimicrobial peptides (AMPs) to prevent infectious diseases. Paneth cells in the small intestine secrete alpha-defensin 5 (HD-5) and epithelial cells in the large intestine produce LL-37. In the present study, we examined the bactericidal activities of AMPs against V. mimicus and V. vulnificus. Although HD-5 showed no bactericidal activity, LL-37 revealed significant activity against both Vibrio species, suggesting that neither V. mimicus nor V. vulnificus can multiply in the large intestine. We also tested whether AMPs had the ability to inactivate the hemolytic toxins. Only HD-5 was found to inactivate VMH, but not VVH, in a dose-dependent manner through the direct binding to VMH. Therefore, it is considered that V. mimicus cannot penetrate the small intestinal epithelium because the cytolytic action of VMH is inactivated by HD-5. PMID- 25744217 TI - Evaluation of the immunochromatographic device for the detection of verotoxins in cultures of food materials. AB - The immunochromatographic assay, which targets Shiga toxin 1/verotoxin 1 (VT1) and/or Shiga toxin 2/verotoxin 2 (VT2) independently with same test device, was used for easily, rapidly and specifically detecting verotoxin-producing Escherichia coli among E. coli strains from food and fecal materials. All 10 strains of VT 1 and/or VT 2- producing E. coli among E. coli isolates from various sources showed a positive reaction to VT1- or VT2- antibodies, but other gram-negative and positive bacterial species had a negative reaction. Bacterial counts of 10(8) cfu/ml in enrichment broth and food suspension were required for the detection of VT-producing E. coli. The IC assay described here could detect easily and specifically the verotoxin-producing E. coli within 20 min by pure culture. PMID- 25744218 TI - Cronobacter spp. in commercially available dried food in Japan. AB - A total of 140 samples of dried food sold in Japan were surveyed and tested for the presence of viable bacteria, distribution of coliform bacteria, and contamination with Cronobacter spp. The samples were purchased from retail stores in Tokyo and Kanagawa Prefecture. Out of the 140 samples tested, viable bacteria were found in 135 samples and coliform bacteria were found in 23 samples. Qualitative and quantitative testing revealed the presence of Cronobacter spp. in 35 (25.0%) and 11 samples (7.9%), respectively. The most commonly found Cronobacter species were C. sakazakii, with the next most common, in order, being C. muytjensii and C. turicensis. The actual numbers of Cronobacter species in the tested dried foods were low, but the widespread contamination particularly in dried herbs and vegetables was confirmed. PMID- 25744219 TI - A cyclic octithiophene containing beta,beta'-linkages. AB - A cyclic octithiophene containing two beta,beta'-linkages was synthesized. Due to the large structural change in the excited state, this compound exhibited bathochromically shifted fluorescence. It also showed a small difference between the first and second oxidation potentials, indicative of spin delocalization through the beta,beta'-linkage in the one electron-oxidized state. PMID- 25744220 TI - The influence of the neighborhood physical environment on early child health and development: A review and call for research. AB - This review examines evidence of the association between the neighborhood built environment, green spaces and outdoor home area, and early (0-7 years) child health and development. There was evidence that the presence of child relevant neighborhood destinations and services were positively associated with early child development domains of physical health and wellbeing and social competence. Parents' perceptions of neighborhood safety were positively associated with children's social-emotional development and general health. Population representative studies using objective measures of the built environment and valid measures of early child development are warranted to understand the impact of the built environment on early child health and development. PMID- 25744221 TI - Contact angle and adsorption energies of nanoparticles at the air-liquid interface determined by neutron reflectivity and molecular dynamics. AB - Understanding how nanomaterials interact with interfaces is essential to control their self-assembly as well as their optical, electronic, and catalytic properties. We present here an experimental approach based on neutron reflectivity (NR) that allows the in situ measurement of the contact angles of nanoparticles adsorbed at fluid interfaces. Because our method provides a route to quantify the adsorption and interfacial energies of the nanoparticles in situ, it circumvents problems associated with existing indirect methods, which rely on the transport of the monolayers to substrates for further analysis. We illustrate the method by measuring the contact angle of hydrophilic and hydrophobic gold nanoparticles, coated with perdeuterated octanethiol (d-OT) and with a mixture of d-OT and mercaptohexanol (MHol), respectively. The contact angles were also calculated via atomistic molecular dynamics (MD) computations, showing excellent agreement with the experimental data. Our method opens the route to quantify the adsorption of complex nanoparticle structures adsorbed at fluid interfaces featuring different chemical compositions. PMID- 25744222 TI - Hubs of Anticorrelation in High-Resolution Resting-State Functional Connectivity Network Architecture. AB - A major focus of brain research recently has been to map the resting-state functional connectivity (rsFC) network architecture of the normal brain and pathology through functional magnetic resonance imaging. However, the phenomenon of anticorrelations in resting-state signals between different brain regions has not been adequately examined. The preponderance of studies on resting-state fMRI (rsFMRI) have either ignored anticorrelations in rsFC networks or adopted methods in data analysis, which have rendered anticorrelations in rsFC networks uninterpretable. The few studies that have examined anticorrelations in rsFC networks using conventional methods have found anticorrelations to be weak in strength and not very reproducible across subjects. Anticorrelations in rsFC network architecture could reflect mechanisms that subserve a number of important brain processes. In this preliminary study, we examined the properties of anticorrelated rsFC networks by systematically focusing on negative cross correlation coefficients (CCs) among rsFMRI voxel time series across the brain with graph theory-based network analysis. A number of methods were implemented to enhance the neuronal specificity of resting-state functional connections that yield negative CCs, although at the cost of decreased sensitivity. Hubs of anticorrelation were seen in a number of cortical and subcortical brain regions. Examination of the anticorrelation maps of these hubs indicated that negative CCs in rsFC network architecture highlight a number of regulatory interactions between brain networks and regions, including reciprocal modulations, suppression, inhibition, and neurofeedback. PMID- 25744223 TI - Mitochondrial phylogeny of grey mullets (Acanthopterygii: Mugilidae) suggests high proportion of cryptic species. AB - The low level of morphometric variability and the poor phylogenetic information borne by the morpho-anatomical characters used thus far in the systematics of grey mullets (Mugilidae) emphasize the utility of molecular systematics in this family. A recent mitochondrial phylogeny of grey mullets has uncovered multiple deep lineages within several species, flagging putative cryptic species. Here, we considered that several of the deeply divergent lineages represent separate species based on either the tree topology, independent data from nuclear markers, geographic distributions, or a combination of the foregoing. By analogy with these well-documented cases, we considered other deep lineages in seven genera we focused on to represent putative cryptic species. Up to two cryptic species were thus potentially detected in the genus Chelon, three in Crenimugil (including two within the single Crenimugil seheli), two in Dajaus, one in Ellochelon, 16 in Mugil (including 13 within the single M. cephalus), two in Osteomugil, and 10 in Planiliza. Wherever possible, we kept the current species epithets to designate those lineages that unambiguously correspond to the type material, based on type locality, and we assigned arbitrary letters (sp. A, B, etc.) to the other lineages. We present a molecular diagnosis for 24 of the species analysed in this work, as well as for 25 putative cryptic species. PMID- 25744224 TI - Antibody persistence 5 years after vaccination at 2 to 10 years of age with Quadrivalent MenACWY-CRM conjugate vaccine, and responses to a booster vaccination. AB - BACKGROUND: In a multi-center extension study, children 2-10 years of age, initially vaccinated with one or two doses (2-5 year-olds) or one dose (6-10 year olds) of quadrivalent meningococcal CRM197-conjugate vaccine (MenACWY-CRM), were assessed five years later for antibody persistence and booster response using serum bactericidal assay with human complement (hSBA). METHODS: Children 7-10 and 11-15 years of age, who received MenACWY-CRM in the original study, and age matched vaccine-naive children, were enrolled in this extension study. After an initial blood draw, children received one dose of MenACWY-CRM as booster or primary dose, with a second blood draw 28 days later. RESULTS: hSBA titers decreased five years after primary vaccination, but were higher than in non vaccinated controls against serogroups C, W and Y, with substantial proportions having titers >=8: 7-22% for A, 32-57% for C, 74-83% for W, and 48-54% for Y. Previously-vaccinated children demonstrated booster responses to revaccination against all four serogroups. Responses to primary vaccination in vaccine-naive controls were lower and similar to primary responses observed in the original study. All vaccinations were generally well tolerated, with no safety concern raised. CONCLUSIONS: Approximately half the children vaccinated as 2-10 year-olds maintained protective antibodies against serogroups C, W and Y five years later, but fewer did against serogroup A. Declining titers five years after vaccination and robust booster responses suggest that five years may be an appropriate interval to revaccinate children, subject to epidemiology and delivery considerations. PMID- 25744225 TI - Parental vaccine hesitancy and acceptance of seasonal influenza vaccine in the pediatric emergency department. AB - BACKGROUND: Providing influenza vaccine to patients in the pediatric emergency department (PED) is one strategy to increase childhood influenza vaccine uptake. The Parent Attitudes about Childhood Vaccines (PACV) survey is a new tool to identify vaccine-hesitant parents that may facilitate influenza vaccine uptake in the PED. OBJECTIVE: To assess the feasibility of administering the PACV modified for influenza vaccination in the PED setting and to determine whether parental PACV scores are associated with patient receipt of influenza vaccine in the PED. METHODS: We conducted a cross-sectional study in the PED of a tertiary pediatric hospital in Seattle, WA during the 2013-2014 influenza season. English-speaking parents of children aged 6 months to 7 years who were afebrile, medically stable to be discharged home from the PED, and had not already received an influenza vaccine this season were administered a modified version of the PACV. PACV scores (0-100, higher score=higher hesitancy) were dichotomized (<50 and >=50) consistent with previous validation studies. Feasibility was assessed by determining time to complete the PACV. Our primary outcome was influenza vaccine refusal in the PED. We used multivariable logistic regression to estimate unadjusted and adjusted odds ratios for association between vaccine refusal and dichotomized PACV scores. RESULTS: 152 parent participants were included in the analysis. The median time for administering the PACV was 7 min. The median PACV score was 28, with 74% scoring <50. Parents who scored >=50 on the PACV had increased odds of refusing the influenza vaccine compared to parents who scored <50 (adjusted OR [95% CI]: 6.58 [2.03-21.38]). CONCLUSION: Administration of the PACV in the PED is feasible, and higher PACV scores in this setting are associated with increased influenza vaccine refusal. PMID- 25744226 TI - Rapid impact of rotavirus vaccine introduction to the National Immunization plan in southern Israel: comparison between 2 distinct populations. AB - BACKGROUND: Rotavirus vaccines were licensed in Israel in 2007, and in 2011 the pentavalent-vaccine (RV5) was introduced into the Israeli National Immunization plan. AIM: To determine the effect of rotavirus-vaccines on the incidence of hospital visits due to rotavirus gastroenteritis (RVGE) and all-cause diarrhea in Jewish and Bedouin children <5 year residing in southern Israel. METHODS: We conducted a population-based, prospective, observational study. Data from 2006 through 2013 were analyzed. Our hospital is the only medical center in the region, enabling age-specific incidences calculation. RESULTS: In the pre-vaccine period, the overall RVGE hospital visits rates per 1000 in children <12, 12-23 and 24-59 m were 16.1, 18.6 and 1.4 in Jewish children, respectively. The respective rates in Bedouin children were 26.4, 12.5 and 0.7 (P<0.001 for <12 m). Hospitalization rates were higher among Bedouin than among Jewish children (60.0% vs. 39.7%, P<0.001). Vaccine uptake was faster in the Jewish vs. the Bedouin population. In the year following RV5 introduction, RVGE hospital visits rates declined by 82%, 70% (P<0.001 both) and 36% (P=0.092) in Jewish children <12, 12 23 and 24-59 m, respectively. In Bedouin children, the respective RVGE rates declined by 70% (P<0.001), 21% (P=ns) and 14% (P=ns). Throughout the study, RVGE rates declined significantly in children <12, and 12-23 m by 80% and 88% in Jewish children, respectively, and by 62 and 75% in Bedouin children, respectively (P<0.001 for all declines). In children 24-59 m, RVGE rates declined by 46% (P=0.025) in Jewish children, but no reduction was observed in Bedouin children. The dynamics of all-cause diarrhea rates were similar to that of RVGE. CONCLUSIONS: Significant reductions of RVGE rates were observed, following Rota vaccine introduction in southern Israel in both Jewish and Bedouin children. However, the impact was faster and more profound in Jewish children, probably related to higher vaccine uptake and possibly to lifestyle differences. PMID- 25744227 TI - Immunization of pregnant women against pertussis: the effect of timing on antibody avidity. AB - BACKGROUND: The Centers for Disease Control and Prevention recommend tetanus diphteria-acellular pertussis (Tdap) immunization during pregnancy, preferably at 27-36 weeks gestation. AIMS: First, to assess the relative avidity index (RAI) of umbilical cord immunoglobulin G (IgG) to pertussis toxin (PT) for newborns of women immunized with Tdap during late pregnancy as compared to unimmunized women. Second, to assess whether there is a preferential period of gestational Tdap immunization that provides the highest RAI of umbilical cord IgG to PT. METHODS: RAI of IgG to PT was assessed via an adapted ELISA using NH4SCN as a dissociating agent. RESULTS: We found that newborns of women immunized with Tdap during late pregnancy (n=52) had higher mean RAI of umbilical cord IgG to PT than those of unimmunized women (n=8), 73.77%+/-12.08 (95% CI, 70.41-77.13) vs. 50.23%+/-21.32 (95% CI, 32.41-68.06), p<0.001. Further, the RAI of umbilical cord IgG to PT was significantly higher in newborns of women immunized at 27-30(+6) weeks gestation (n=20) when compared with newborns of women immunized at 31-36 weeks (n=22) and >36 weeks (n=7), 79.53%+/-5.61 (95% CI, 76.91-82.16) vs. 71.56%+/-12.58 (95% CI, 65.98-77.14) vs. 63.93%+/-17.98 (95% CI, 47.31-80.56), p<0.03. CONCLUSION: Gestational Tdap immunization between 27 and 30(+6) weeks resulted in the highest avidity of IgG to PT conveyed at delivery as compared with immunization beyond 31 weeks gestation. Future studies should be conducted to confirm our findings to optimize pertussis-controlling strategies. PMID- 25744229 TI - Antibody responses among adolescent females receiving the quadrivalent HPV vaccine series corresponding to standard or non-standard dosing intervals. AB - Quadrivalent human papillomavirus vaccine (HPV4) is recommended as a 3-dose series administered at 0, 1-2, and 6 months. However, this dosing schedule is often not followed leading to longer dosing intervals. We conducted a prospective study to assess antibody titers to HPV4 when dose 2 and/or dose 3 were administered on schedule or delayed. Healthy females (N=331) aged 9-18 years were enrolled at the time of receipt of HPV4 dose 2 or 3. Participants were classified as belonging to one of four groups depending upon timing of receipt of HPV4: both doses on time; only dose 2 delayed later than 90 days; only dose 3 delayed later than 180 days; or both doses 2 and 3 delayed. Pre- and post-dose 3 blood samples were assayed for HPV antibody titers (types 6, 11, 16, and 18). Post-dose 3 geometric mean titers (GMTs) for all HPV types were not significantly lower for any of the delayed dosing groups when compared to the on time group. When compared to the on time group, the post dose 3 GMTs in the delayed dose 3 group were significantly higher (p<0.05) for HPV types 6, 11, and 16. Our findings suggest that delays of dose 2 or 3 do not interfere with immune responses after completion of the 3-dose series. These results support current recommendations to not administer additional doses of HPV4 vaccine if dose 2, dose 3, or both doses have been administered late. PMID- 25744228 TI - Enhanced immune responses by skin vaccination with influenza subunit vaccine in young hosts. AB - Skin has gained substantial attention as a vaccine target organ due to its immunological properties, which include a high density of professional antigen presenting cells (APCs). Previous studies have demonstrated the effectiveness of this vaccination route not only in animal models but also in adults. Young children represent a population group that is at high risk from influenza infection. As a result, this group could benefit significantly from influenza vaccine delivery approaches through the skin and the improved immune response it can induce. In this study, we compared the immune responses in young BALB/c mice upon skin delivery of influenza vaccine with vaccination by the conventional intramuscular route. Young mice that received 5 MUg of H1N1 A/Ca/07/09 influenza subunit vaccine using MN demonstrated an improved serum antibody response (IgG1 and IgG2a) when compared to the young IM group, accompanied by higher numbers of influenza-specific antibody secreting cells (ASCs) in the bone marrow. In addition, we observed increased activation of follicular helper T cells and formation of germinal centers in the regional lymph nodes in the MN immunized group, rapid clearance of the virus from their lungs as well as complete survival, compared with partial protection observed in the IM-vaccinated group. Our results support the hypothesis that influenza vaccine delivery through the skin would be beneficial for protecting the high-risk young population from influenza infection. PMID- 25744230 TI - Radiation-induced rupture of the superficial femoral artery: a case report. AB - BACKGROUND: Radiation-induced necrosis and arteriopathy are well-known iatrogenic pathologic entities. However, radiation-induced rupture of the superficial femoral artery is an exceptional life-threatening event. REPORT: We hereby report a case of radiation-induced rupture of the superficial femoral artery that was successfully treated by fascial stitching then by an endovascular approach by stenting. RESULTS: Infection, skin stiffness, and major tissue loss in a previously irradiated field are important limiting factors to an open surgical approach. CONCLUSION: It is important to consider using a combined approach for selected patients. PMID- 25744231 TI - Leiomyosarcoma of the thoracic aorta in a patient with hypertrophic cardiomyopathy. AB - We report a case of leiomyosarcoma of the thoracic aorta in a 49-year-old male patient with history of hypertrophic cardiomyopathy. The only presenting symptom was back pain localized under the left scapula with the frequency and severity of the pain increasing with time. Imaging studies detected the presence of an aortic tumor. The tumor was excised en bloc, and an interposition graft was implanted. The histology showed a fully excised grade 3 leiomyosarcoma. This article discusses features of this rare condition. PMID- 25744232 TI - Effects of combination therapy using basic fibroblast growth factor and mature adipocyte-derived dedifferentiated fat (DFAT) cells on skin graft revascularisation. AB - BACKGROUND: Although the benefits of basic fibroblast growth factor (bFGF) for wound healing and angiogenesis are well known, its effects on the process of skin graft revascularisation have not been clarified. It was hypothesised that bFGF would be beneficial to promote taking of skin grafts, but that the effect might be limited in the case of bFGF monotherapy. Therefore, this study investigated the efficacy of combination therapy using bFGF and dedifferentiated fat (DFAT) cells. DFAT cells have multilineage differentiation potential, including into endothelial cells, similar to the case of mesenchymal stem cells (MSC). METHODS: Commercially available human recombinant bFGF was used. DFAT cells were prepared from SD strain rats as an adipocyte progenitor cell line from mature adipocytes. Full-thickness skin was lifted from the back of SD strain rats and then grafted back to the original wound site. Four groups were established prior to skin grafting: control group (skin graft alone), bFGF group (treated with bFGF), DFAT group (treated with DFAT cells), and combination group (treated with both bFGF and DFAT cells). Tissue specimens for histological examination were harvested 48 hours after grafting. RESULTS: The histological findings for the bFGF group showed vascular augmentation in the grafted dermis compared with the control group. However, the difference in the number of revascularised vessels per unit area did not reach statistical significance against the control group. In contrast, in the combination group, skin graft revascularisation was significantly promoted, especially in the upper dermis. CONCLUSION: The results suggest that replacement of the existing graft vessels was markedly promoted by the combination therapy using bFGF and DFAT cells, which may facilitate skin graft taking. PMID- 25744233 TI - Investigation of possible prophylactic, renoprotective, and cardioprotective effects of thromboprophylactic drugs against ischemia-reperfusion injury. AB - The aim of this study was to investigate whether anticoagulant and antiaggregant agents have protective effects against oxidative damage induced by peripheral ischemia-reperfusion (I/R). Groups were created as follows: control group, I/R group (sham group), I/R plus acetylsalicylic acid (Group I), I/R+clopidogrel (Group II), I/R+rivaroxaban (Group III), I/R+bemiparin sodium (Group IV), and I/R+enoxaparin sodium (Group V). In Groups I, II, III, IV, and V, drugs were administered daily for 1 week before I/R creation. Peripheral I/R was induced in the I/R groups by clamping the right femoral artery. The rats were sacrificed 1 hour after reperfusion. Nitrogen oxide levels, malondialdehyde (MDA) levels, paraoxonase-1 (PON1) activity, and prolidase activity were evaluated in both cardiac and renal tissues. There was no significant difference in nitrogen oxide levels between the groups. However, cardiac and renal MDA were significantly higher and PON1 activity was markedly lower in the I/R groups compared with the control group (p<0.05). Although elevated prolidase activity was detected in both the cardiac and renal tissue of the I/R groups, only the sham group and Group V had significantly higher renal prolidase activity (p<0.05). Group V had significantly higher cardiac MDA, PON1, prolidase levels, and renal prolidase activity compared with the sham group (p<0.05). Significant improvement in renal MDA levels was only observed in Group III, and marked improvement was observed in the cardiac MDA levels of Group II when compared with the sham group (p<0.05). Thromboprophylactic agents appear to provide partial or prominent protection against I/R injury. PMID- 25744234 TI - TGF-beta1 and IL-10 single nucleotide polymorphisms as risk factors for oral cancer in Taiwanese. AB - Cytokine production capacity varies among individuals and depends on cytokine gene polymorphisms. Transforming growth factor-beta 1 (TGF-beta1) plays a significant role in regulating the proliferation and apoptosis of epithelial cells. Interleukin 10 (IL-10) is an immunoregulatory cytokine with biological functions of anti-inflammation, immunosuppression, allergy, and anti-agenesis. The two cytokines are supposed to play an important role in carcinogenesis. The association between cytokine gene polymorphisms with oral cancer (OC) was investigated. We studied the association between the polymorphism in TGF-beta1 (G to C polymorphism at codon 25 <+915>) and IL-10 (-1082 G/A, -819 C/T, and -592 C/A) and the risk of OC in patients (n = 162) and healthy controls (n = 118) in Taiwan. All genotyping experiments were performed using the polymerase chain reaction sequence-specific primer (PCR-SSP) method. It was found that the codon 25 GC genotype of TGF-beta1 is significantly higher in frequency in patients with OC compared with a healthy control group (p < 0.0001). People with the GC genotype in codon 25 had an 11.09-fold increased risk of OC [odds ratio (OR) = 11.09; 95% confidence interval (CI) = 6.16-113.23]. IL-10 polymorphisms in -819 and -592 positions correlated with the risk of OC (p < 0.0001). The IL-10 -592 C allele-containing genotypes posed an increased risk of OC (OR = 1.79, 95% CI = 1.11-2.91). People with the CT genotype in IL-10 -819 had a 3.32-fold increased risk of OC (OR = 3.32; 95% CI = 1.64-6.94). The results suggest that polymorphisms in TGF-beta1 and IL-10 may have a significant influence on the development of OC. PMID- 25744235 TI - Utilization of 18F-FDG PET/CT as a staging tool in patients with newly diagnosed lymphoma. AB - The aim of this study was to investigate the role of 2-fluorine-18-fluoro-2-deoxy D-glucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in the initial staging and prediction of bone marrow involvement in patients with newly diagnosed lymphoma. A total of 185 patients with newly diagnosed lymphoma were enrolled. All patients received PET/CT and bone marrow biopsy as part of a staging work-up. At the initial staging, 17 patients (9.2%) with occult nodal or extranodal lesions were upstaged after a review of the PET/CT studies. PET/CT was found to be useful in the differentiation of aggressive lymphoma subtypes from the indolent subtype based on higher standardized uptake value (SUV) (16.67 vs. 7.98, p < 0.001). The results of bone marrow biopsy and PET/CT in the detection of bone marrow involvement were concordant in 152 patients (82.1%); positive concordance was observed in 21 patients, and negative concordance was observed in 131 patients. A high concordance rate was found between aggressive B cell lymphoma and Hodgkin's lymphoma (88.1% and 93.8%, respectively). High negative predictive values (NPVs) for excluding bone marrow involvement were observed in aggressive B-cell lymphoma (93.2%) and Hodgkin's lymphoma (100%). Diffuse bone marrow FDG uptake accurately predicted bone marrow in aggressive B-cell lymphoma with a positive predictive value (PPV) of 100%. The concordance rate was lower in indolent B-cell lymphoma (66.0%). In conclusion, PET/CT resulted in the upstaging of patients with occult extranodal or nodal lesions. A high SUV level can predict aggressive subtype of lymphoma and detect aggressive components in indolent lymphoma. PET/CT had a high PPV for aggressive B-cell lymphoma with diffuse bone marrow FDG uptake and high NPVs for excluding bone marrow involvement in aggressive B-cell lymphoma and Hodgkin's lymphoma. Bone marrow biopsy may be omitted for the above subgroups of patients with medical conditions not suitable for this procedure. For patients with indolent B-cell lymphoma, bone marrow biopsy is still an indispensable procedure for staging. PMID- 25744236 TI - Diagnostic value of contrast-enhanced ultrasound in thyroid nodules with calcification. AB - The aim of this study was to investigate the diagnostic values of conventional ultrasound and contrast-enhanced ultrasound (CEUS) in benign and malignant thyroid nodules with calcification. Conventional ultrasound and CEUS were performed in 122 patients with thyroid nodules with calcification. The thyroid nodules were characterized as benign or malignant by pathological diagnosis. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accordance rate of the two imaging methods were determined. The area under the receiver operating characteristics curve (AUC) was used to assess the diagnostic values of the two imaging methods. In 122 cases of thyroid nodules with calcification, 73 benign nodules and 49 malignant nodules were verified by pathological diagnosis. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accordance rate of conventional ultrasound were 50%, 77%, 59%, 69%, and 66%, respectively, and those of CEUS were 90%, 92%, 88%, 93%, and 91%, respectively. There were significant differences between the two imaging methods. AUCs of conventional ultrasound and CEUS were 0.628 +/- 0.052 and 0.908 +/- 0.031, suggesting low and high diagnostic values, respectively. CEUS has high diagnostic values, being significantly greater than those of conventional ultrasound, in differential diagnosis of benign and malignant thyroid nodules with calcification. PMID- 25744237 TI - Usefulness of admission hematologic parameters as diagnostic tools in acute pulmonary embolism. AB - The purpose of this study was to determine the role of red cell distribution width (RDW), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) in the diagnostic phase of acute pulmonary embolism (PE). We screened 248 consecutive patients who were admitted to the emergency service with PE foremost in the differential diagnosis. Based on spiral computed chest tomography, the patients were divided into two groups. There were 112 confirmed cases of acute PE and 138 patients without PE. Blood samples were obtained within 2 hours of presentation and before starting any medication. There were no significant differences between the PE and the non-PE groups with respect to sex, age, frequency of disease, serum creatinine, sodium, and potassium (p > 0.05 for all). NLR, RDW, and PLR were higher in patients with PE than those without PE. High sensitivity C-reactive protein, D-dimer, and troponin levels were also higher in patients with PE. RDW values were positively correlated with troponin levels (r = 0.147, p = 0.021). There were no correlations between RDW and NLR, PLR, or D dimer. NLR had a highly positive correlation with PLR (r = 0.488, p < 0.001). In multivariate logistic regression analysis, troponin I, D-dimer, high-sensitivity C-reactive protein, and RDW were found to be independent predictors of PE [odds ratio (95% confidence interval) respectively: 5.208 (2.534-10.704), 1.242 (1.094 1.409), 1.005 (1.000-1.010), 1.175 (1.052-1.312)]. In receiver operating characteristic analysis of the patients in the study, RDW >18.9 predicted acute PE with a sensitivity of 20.7% and a specificity of 93.4%. In conclusion, RDW can be considered useful as a diagnostic measure for patients with suspected acute PE. PMID- 25744238 TI - A comparison of propofol target controlled infusion-based and sevoflurane-based anesthesia in adults undergoing elective anterior cervical discectomy and fusion. AB - The target controlled infusion (TCI) of propofol with fentanyl facilitates easy titration of the depth of anesthesia, and thereby may improve the quality of anesthesia. The aim of this study is to investigate if propofol TCI-based anesthesia is practical for anterior cervical discectomy and fusion (ACDF), one of the most common surgical interventions in spine procedures, when compared with sevoflurane-based anesthesia with respect to the quality of anesthesia. Patients were classified into two groups according to the anesthesia regimen of maintenance of anesthesia with fentanyl and either propofol TCI (group FP) or inhalational sevoflurane (group FS), respectively. The primary endpoint was to evaluate quality of anesthesia and extubation time. Secondary endpoints were hemodynamic stability during the operation, operative fentanyl consumption, and postoperative complications. The study results revealed there were comparable results on time to extubation, changes in intraoperative hemodynamic parameters, and the occurrence of postoperative complications between the groups. No differences in average length of intensive care unit (ICU) stay and hospital stay were noticed. However, opioid consumption and blood loss during the operation for patients in group FP were significantly higher than those of patients in group FS (551.28 +/- 193.98 vs. 446.86 +/- 177.15 MUg, p = 0.005; 52.06 +/- 58.25 vs. 28.33 +/- 40.74 mL, p = 0.019, respectively). In these adult patients undergoing ACDF, propofol TCI-based anesthesia appears to be as efficacious as sevoflurane based anesthesia but consumed more fentanyl and experienced higher blood loss. PMID- 25744239 TI - Cerebral venous etiology of intracranial hypertension and differentiation from idiopathic intracranial hypertension. AB - This study presents the characteristics that distinguish between idiopathic intracranial hypertension (ICH) and ICH caused by intracranial vascular damage. Twenty-one patients with ICH were included in this study. The analysis of the symptomatology correlated with the values of intracranial pressure, and the imaging findings revealed significant differences between these two types of ICH. ICH caused by intracranial venous vascular damage is named vascular ICH. Vascular ICH has a known etiology, such as cerebral vascular illness, and a relatively rapid increase in intracranial pressure of approximately 21 cmH2O and imaging findings show characteristic images of thrombosis or stenosis of the intracranial venous system, while all brain images (computed tomography, magnetic resonance imaging, angio-magnetic resonance imaging) are normal in idiopathic ICH. The treatment of vascular ICH is etiologic, pathogenic, and symptomatic, but that of idiopathic ICH is only symptomatic. PMID- 25744240 TI - Henoch-Schonlein purpura triggered by Mycoplasma pneumoniae in a female infant. PMID- 25744241 TI - Reversible dasatinib-related pulmonary arterial hypertension diagnosed by noninvasive echocardiography. PMID- 25744242 TI - Pulmonary radiofrequency ablation (Part 2): Procedure and follow-up. AB - Pulmonary radiofrequency ablation requires more than just interventional radiology skills. Patients must be selected carefully, and the acts that need to be done before, during, and after the procedure must be coordinated. To guarantee patient safety, radiologists need to know the variants of the technique, the precautions that must be taken, the complications that can occur, and the risks involved. Early differentiation between tumor tissue and normal changes secondary to treatment on imaging tests will make it possible to repeat the treatment without delays, and this will increase survival. This article describes how to coordinate and carry out pulmonary radiofrequency ablation, the complications of the technique, and the current evidence in follow-up. PMID- 25744244 TI - Downregulation of ABCE1 via siRNA affects the sensitivity of A549 cells against chemotherapeutic agents. AB - ATP-binding cassette E1 (ABCE1) is involved in several biological functions in cancer cells such as tumor proliferation, antiapoptotic pathway and chemoresistance mechanism. This work aimed to investigate the alterations in chemosensitivity of A549 lung cancer cells for 5-Fluorouracil (5-FU) and irinotecan by silencing ABCE1 using specific small interfering RNAs (siRNA). The cells were treated with low doses of drugs, alone and also their combinations with ABCE1 siRNA. Cytotoxicity, cell proliferation and apoptosis/necrosis evaluations were performed in order to examine the effects of the combined treatment. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to confirm the downregulation of ABCE1. We also investigated the levels of B cell lymphoma 2 (Bcl-2) and mammalian target of rapamycin (mTOR) after the treatments by RT-PCR. Downregulation of ABCE1 improved the anticancer effects of 5-FU in inducing cell viability/proliferation inhibition and apoptosis/necrosis, whereas interestingly, almost did not change or slightly reduced the anticancer effects of irinotecan. ABCE1 expression significantly decreased by transfecting the cells with ABCE1 siRNA. Moreover, Bcl-2 and mTOR levels changed after the single or combined therapy in parallel with the apoptotic and antiproliferation effect. In conclusion, the simultaneous treatment of lung cancer cells with ABCE1 siRNA and 5-FU exhibited synergistic or additive effects; however, ABCE1 siRNA and irinotecan had unexpected antagonistic effects. Our findings demonstrate that the strategy of downregulation of ABCE1 may be included in conventional 5-FU chemotherapy for lung cancer, minimizing the usage of 5-FU at high dosages. PMID- 25744243 TI - Enhanced expression of suppresser of cytokine signaling 3 inhibits the IL-6 induced epithelial-to-mesenchymal transition and cholangiocarcinoma cell metastasis. AB - It was recently demonstrated that interleukin-6 (IL-6) induces the epithelial-to mesenchymal transition (EMT) in cholangiocarcinoma (CCA), but the underlying molecular mechanism remains to be explored. In this study, we studied the role of suppresser of cytokine signaling 3 (SOCS3), a negative feedback regulator of IL 6/STAT3, in the IL-6-induced EMT in CCA. Treatment with IL-6 induced the EMT by decreasing the E-cadherin expression and increasing the expression of N-cadherin and vimentin. Using wound healing and invasion assays, we found that IL-6 promoted cell motility. Further, a stably transfected cell line overexpressing SOCS3 was constructed. Enhanced SOCS3 expression decreased IL-6-induced cell invasion and EMT in parallel with downregulating the IL-6/STAT3 pathway. In contrast, SOCS3 silencing using siRNA exhibited no effect on the cell invasive ability and EMT. Finally, an in vivo study indicated that the enhancement of SOCS3 expression decreased metastasis compared with the control, and this effect was achieved by the repression of p-STAT3, N-cadherin and vimentin, and the induction of E-cadherin assessed by Western blot analysis. Our results suggest that enhanced expression of SOCS3 can antagonize IL-6-induced EMT and cell metastasis by abrogating the IL-6/STAT3 pathway. These data establish that SOCS3 plays a role in the EMT in CCA and may provide novel therapeutic strategies for CCA. PMID- 25744245 TI - G protein-coupled estrogen receptor (GPER) mediates NSCLC progression induced by 17beta-estradiol (E2) and selective agonist G1. AB - Estrogen classically drives lung cancer development via estrogen receptor beta (ERbeta). However, fulvestrant, an anti-estrogen-based endocrine therapeutic treatment, shows limited effects for non-small cell lung cancer (NSCLC) in phase II clinical trials. G protein-coupled estrogen receptor (GPER), a third estrogen receptor that binds to estrogen, has been found to be activated by fulvestrant, stimulating the progression of breast, endometrial, and ovarian cancers. We here demonstrated that cytoplasm-GPER (cGPER) (80.49 %) and nucleus-GPER (53.05 %) were detected by immunohistochemical analysis in NSCLC samples. cGPER expression was related to stages IIIA-IV, lymph node metastasis, and poorly differentiated NSCLC. Selective agonist G1 and 17beta-estradiol (E2) promoted the GPER-mediated proliferation, invasion, and migration of NSCLC cells. Additionally, in vitro administration of E2 and G1 increased the number of tumor nodules, tumor grade, and tumor index in a urethane-induced adenocarcinoma model. Importantly, the pro tumorigenic effects of GPER induced by E2 were significantly reduced by co administering the GPER inhibitor G15 and the ERbeta inhibitor fulvestrant, as compared to administering fulvestrant alone both in vitro and in vivo. Moreover, the phosphorylation of MAPK and Akt was involved in E2/G1-induced GPER activation. In conclusion, our results indicated that a pro-tumor function of GPER exists that mediated E2-/G1-dependent NSCLC progression and showed better efficiency regarding the co-targeting of GPER and ERbeta, providing a rationale for further investigation of anti-estrogen clinical therapy. PMID- 25744246 TI - Better Catalysts through Microscopy: Mesoscale M1/M2 Intergrowth in Molybdenum Vanadium Based Complex Oxide Catalysts for Propane Ammoxidation. AB - In recent decades, catalysis research has transformed from the predominantly empirical field to one where it is possible to control the catalytic properties via characterization and modification of the atomic-scale active centers. Many phenomena in catalysis, such as synergistic effect, however, transcend the atomic scale and also require the knowledge and control of the mesoscale structure of the specimen to harness. In this paper, we use our discovery of atomic-scale epitaxial interfaces in molybdenum-vanadium based complex oxide catalysts systems (i.e., Mo-V-M-O, M = Ta, Te, Sb, Nb, etc.) to achieve control of the mesoscale structure of this complex mixture of very different active phases. We can now achieve true epitaxial intergrowth between the catalytically critical M1 and M2 phases in the system that are hypothesized to have synergistic interactions, and demonstrate that the resulting catalyst has improved selectivity in the initial studies. Finally, we highlight the crucial role atomic scale characterization and mesoscale structure control play in uncovering the complex underpinnings of the synergistic effect in catalysis. PMID- 25744247 TI - US hospital rating systems rarely agree, study finds. PMID- 25744248 TI - Preparative Separation of N-Feruloyl Serotonin and N-(p-Coumaroyl) Serotonin from Safflower Seed Meal Using High-Speed Counter-Current Chromatography. AB - High-speed counter-current chromatography (HSCCC) was successfully applied for the preparative separation and purification of N-feruloyl serotonin (NF) and N-(p coumaroyl) serotonin (NP) from safflower seed meal. After the measurement of partition coefficient of the two target compounds in the two-phase solvent systems, the HSCCC was performed well with a two-phase solvent system composed of CHCl3-methanol-0.1 M HCl at a volume ratio of 1 : 1 : 1, v/v. The upper phase was used as stationary phase and the lower phase was used as mobile phase. Under the optimized condition, 7.5 mg NF and 6.9 mg NP were separated from 40 mg crude sample with the purity of 98.8 and 97.3%, respectively. The structures of the isolated compounds were identified by (1)H NMR and (13)C NMR. PMID- 25744249 TI - Failed Back Surgery Syndrome: from pathophysiology to recent therapeutic advances in neurostimulation--conclusion. PMID- 25744250 TI - Failed back surgery syndrome: from pathophysiology to recent therapeutic advances in neurostimulation--introduction. PMID- 25744252 TI - [Since 30 years and tomorrow too: publishing biomedical science in French]. PMID- 25744251 TI - Allosteric modulation of proteinase 3 activity by anti-neutrophil cytoplasmic antibodies in granulomatosis with polyangiitis. AB - Anti-neutrophil cytoplasmic antibodies (ANCA) with proteinase 3 (PR3) specificity are a useful laboratory biomarker for the diagnosis of Granulomatosis with Polyangiitis (GPA) and are believed to be implicated in the pathogenesis. It has been repeatedly suggested that disease activity of GPA is more closely related to the appearance and rise of PR3-inhibiting ANCA than to an increase of total ANCA. Previous studies on a limited number of patient samples, however, have yielded inconclusive results. To overcome the previous methodological limitations, we established a new ultrasensitive method to quantify the inhibitory capacity of PR3-ANCA using small volumes of plasma from patients with GPA. A large collection of longitudinally-collected samples from the Wegener Granulomatosis Etanercept Trial (WGET) became available to us to determine the functional effects of ANCA on PR3 in comparison to clinical disease manifestations. In these patient samples we not only detected PR3-ANCA with inhibitory capacity, but also PR3-ANCA with enhancing effects on PR3 activity. However no correlation of these activity modulating PR3-ANCA with disease activity at either the time of enrollment or over the course of disease was found. Only patients with pulmonary involvement, especially patients with nodule formation in the respiratory tract, showed a slight, but not significant, decrease of inhibitory capacity. Epitope mapping of the activity-modulating PR3-ANCA revealed a binding on the active site surface of PR3. Yet these ANCA were able to bind to PR3 with an occupied active site cleft, indicating an allosteric mechanism of inhibition. The recently described signal ratio between the MCPR3-3 and MCPR3-2 capture ELISA was consistent with the binding of activity-modulating ANCA to the active site surface. Evidence for a shared epitope between activity-modulating PR3-ANCA and MCPR3-7, however, was very limited, suggesting that a majority of PR3-ANCA species do not inhibit PR3 by the same mechanism as previously reported for MCPR3-7. PMID- 25744253 TI - [The radiotherapy FLASH to save healthy tissues]. PMID- 25744254 TI - [Bovine tubercle bacilli: evolution associated with loss of transmission capacity in humans]. PMID- 25744255 TI - [Mast cells aggravate sepsis in mice by inhibiting peritoneal macrophage phagocytosis]. PMID- 25744256 TI - [STAG3 in premature ovarian failure]. PMID- 25744257 TI - [Passive Tau immunotherapy for prevention of Tau pathology progression]. PMID- 25744258 TI - [A novel role for the TRPV1 ion channel in CD4 T cell activation]. PMID- 25744259 TI - [Application of Cas9/CRISPR to the study of synaptic function]. PMID- 25744260 TI - [Haemostasis dysregulation in filovirus infections]. AB - Filoviruses are responsible for highly lethal infections. Those viruses are found in intertropical areas of Africa and Asia where they circulate in their supposed natural reservoir, fruit bats. During filovirus outbreaks and depending on the strains, various modifications in hemostasis have been observed in patients. The disseminated intravascular coagulation identified in these infections is multicausal and involves both viral factors and abnormal physiological responses. In this review we will describe the mechanisms responsible for these disturbances and we will highlight some aspects of the basis of filovirus high pathogenicity. PMID- 25744261 TI - [Human dendritic cells in allergic asthma and rhinitis]. AB - The role of dendritic cells (DC) in the pathogenesis of allergic asthma and rhinitis has been highlighted for 15 years. In this review, we summarize key findings concerning DC function in airway allergy and focus on studies performed in human. DC coming from allergic patients have specific characteristics, including significant expression of high affinity receptor for IgE as well as a propensity for Th2 responses induction following priming with allergen and/or epithelial cytokines. Mechanistic data concerning this DC dysfunction in asthma also provide perspectives for innovating therapies. PMID- 25744262 TI - [Gene silencing approaches for the treatment of Huntington's disease]. AB - Huntington's disease is a rare neurodegenerative disease caused by a pathologic CAG expansion in the exon 1 of the huntingtin (HTT) gene. Aggregation and abnormal function of the mutant HTT (mHTT) cause motor, cognitive and psychiatric symptoms in patients, which lead to death in 15-20 years. Currently, there is no treatment for HD. Experimental approaches based on drug, cell or gene therapy are developed and reach progressively to the clinic. Among them, mHTT silencing using small non-coding nucleic acids display important physiopathological benefit in HD experimental models. PMID- 25744263 TI - [Glucose homeostasis and gut-brain connection]. AB - Since the XIX(th) century, the brain has been known for its role in regulating food intake (via the control of hunger sensation) and glucose homeostasis. Further interest has come from the discovery of gut hormones, which established a clear link between the gut and the brain in regulating glucose and energy homeostasis. The brain has two particular structures, the hypothalamus and the brainstem, which are sensitive to information coming either from peripheral organs or from the gut (via circulating hormones or nutrients) about the nutritional status of the organism. However, the efforts for a better understanding of these mechanisms have allowed to unveil a new gut-brain neural axis as a key regulator of the metabolic status of the organism. Certain nutrients control the hypothalamic homeostatic function via this axis. In this review, we describe how the gut is connected to the brain via different neural pathways, and how the interplay between these two organs drives the energy balance. PMID- 25744264 TI - [Optimal permeability of aquaporins: a question of shape?]. AB - Aquaporins are transmembrane proteins, ubiquitous in the human body. Inserted into the cell membranes, they play an important role in filtration, absorption and secretion of fluids. However, the excellent compromise between selectivity and permeability of aquaporins remains elusive. In this review, we focus on the hourglass shape of aquaporins, and we investigate its influence on water permeability, using numerical calculations and a simple theoretical model. We show that there is an optimum opening angle that maximizes the hydrodynamic permeability, and whose value is close to the angles observed in aquaporins. PMID- 25744266 TI - [High content screening in chemical biology: overview and main challenges]. AB - The last two decades have seen the development of high content screening (HCS) methodology and its adaptation for the evaluation of small molecules as drug candidates or their use as chemical tools for research purpose. HCS was initially set-up for the understanding of the mechanism of action of compounds by testing them on cell based-assays for pharmacological and toxicological studies. Since the last decade, the use of HCS has been extended to academic research laboratories and this technology has become the starting point for numerous projects aiming at the identification of molecular targets and cellular pathways for a given disease on which novel type of drugs could act. This screening approach relies on image capture of fluorescently labeled cells therefore generating a large amount of data that must be handled by appropriate automated image analysis methods and storage instrumentation. These latter in addition to the integration and data sharing are current challenges that HCS must still tackle. PMID- 25744265 TI - [Digital PCR compartmentalization II. Contribution for the quantitative detection of circulating tumor DNA]. AB - Genetic markers are now widely used in the clinics, particularly in cancer patient management. Indeed, these tumor markers can help in the diagnosis and prognosis of the disease, and provide valuable information for treatment orientation in the context of personalized medicine. The presence of circulating cell-free tumor DNA (cftDNA) and thus of tumor markers in the blood can be considered to partly avoid the use of solid biopsies. The use of blood samples, as liquid biopsies, is less invasive and described as more representative of tumor heterogeneity. However, cftDNA can be found in blood in low proportion that can vary according to the nature and the progression of the tumor. For these reasons, the use of highly sensitive, specific and ideally quantitative methods for its detection are required. These requirements constituted until recently a technological limit, which now can be overcome thanks to digital PCR. This technology could now become a very efficient and non-invasive tool in oncology, complementary to conventional diagnostic techniques. PMID- 25744267 TI - [Fragment-based screening: a promising avenue for drug design]. AB - Fragment-based screening is now recognised as a powerful method for the design of novel potent molecules against therapeutic protein targets including challenging targets. Here, the main concepts used in the fragment-based drug design approach are reviewed, together with the reasons for its success. Methods and strategies used to identify, validate and select fragments are discussed. Future challenges and developments that are expected for the next decade are presented. PMID- 25744268 TI - [Space coding: a Nobel prize diary]. AB - The Nobel Prize in Medecine or Physiology for 2014 has been awarded to three neuroscientists: John O'Keefe, May-Britt Moser and Edvard Moser for "their discoveries of cells that constitute a positioning system in the brain". This rewards innovative ideas which led to the development of intracerebral recording techniques in freely moving animals, thus providing links between behavior and physiology. This prize highlights how neural activity sustains our ability to localize ourselves and move around in the environment. This research provides key insights on how the brain drives behavior. PMID- 25744269 TI - [The Supreme Court free genes - economic and legal justifications - impacts on innovation and the healthcare offer]. PMID- 25744270 TI - [Desperately seeking targets]. AB - In clinical oncology, obtaining sequence data from tumour samples has become practical in terms of logistics, turnover time and costs. The major issue now is the interpretation of this sequence to define actionable targets, i.e. genome changes that are involved in tumorogenesis and that predict the efficacy of existing and available targeted treatments. This is the focus of major efforts from public clinical centres and from companies that see it as a promising commercial activity. PMID- 25744272 TI - Role of let-7b in the regulation of N-acetylgalactosaminyltransferase 2 in IgA nephropathy. AB - BACKGROUND: IgA nephropathy (IgAN) is characterized by aberrant O-glycosylation in the hinge region of IgA1. The early step in O-glycan formation is the attachment of N-acetylgalactosamine (GalNAc) to the serine/threonine of the hinge region; the process is catalysed by UDP-N-acetyl-alpha-d galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). In our previous work, the microarray analysis on peripheral blood mononuclear cells (PBMCs) identified an upregulated miRNA called let-7b. METHODS: To study the molecular mechanisms in which let-7b was involved, we performed a bioinformatic analysis to predict their target genes. To validate biologically let-7b targets, we performed transient transfection experiments ex vivo using PBMCs from an independent group of IgAN patients and healthy blood donors (HBDs). RESULTS: Bioinformatic analysis revealed that GALNT2 is the potential target of let-7b. We found this miRNA significantly upregulated in PBMCs of IgAN patients compared with HBDs. Then, we demonstrated in ex-vivo experiments that let-7b decreased GALNT2 levels in PBMCs of IgAN patients, whereas the loss of let-7b function in PBMCs of HBDs led to an increase of GALNT2 mRNA and its protein level. Finally, we found that upregulation of let-7b occurred also in B-lymphocytes from IgAN patients. CONCLUSIONS: Our results give novel additional information on the abnormal O-glycosylation process of IgA1 in IgAN patients. This study provides evidence for another important miRNA-based regulatory mechanism of the O glycosylation process in which the deregulated expression of let-7b is associated with altered expression of GALNT2. This finding could be taken into consideration for new therapeutic approaches in IgAN because other serum glycosylated proteins do not display abnormal glycosylation. PMID- 25744273 TI - The vulnerable patient with chronic kidney disease. AB - Patients with chronic kidney disease (CKD) exhibit an increased cardiovascular risk. The high susceptibility to cardiovascular disease renders CKD patients 'vulnerable patients'. The overall cardiovascular risk of a vulnerable patient with CKD is determined by the components of the vulnerable myocardium, the vulnerable vessel and the vulnerable blood which in sum contribute to the increased morbidity and mortality risk in CKD patients. Future therapeutic strategies to reduce cardiovascular morbidity and mortality in this high-risk population should address all three aspects of vulnerability in CKD patients. PMID- 25744274 TI - Vitamin D receptor activator and dietary sodium restriction to reduce residual urinary albumin excretion in chronic kidney disease (ViRTUE study): rationale and study protocol. AB - Optimal albuminuria reduction is considered essential to halting chronic kidney disease (CKD) progression. Both vitamin D receptor activator (VDRA) treatment and dietary sodium restriction potentiate the efficacy of renin-angiotensin aldosterone-system (RAAS) blockade to reduce albuminuria. The ViRTUE study addresses whether a VDRA in combination with dietary sodium restriction provides further albuminuria reduction in non-diabetic CKD patients on top of RAAS blockade. The ViRTUE study is an investigator-initiated, prospective, multi centre, randomized, double-blind (paricalcitol versus placebo), placebo controlled trial targeting stage 1-3 CKD patients with residual albuminuria of >300 mg/day due to non-diabetic glomerular disease, despite angiotensin converting enzyme inhibitor or angiotensin receptor blocker use. During run-in, all subjects switched to standardized RAAS blockade (ramipril 10 mg/day) and blood pressure titrated to <140/90 mmHg according to a standardized protocol. Eligible patients are subsequently enrolled and undergo four consecutive study periods in random order of 8 weeks each: (i) paricalcitol (2 ug/day) combined with a liberal sodium diet (~200 mmol Na(+)/day, i.e. mean sodium intake in the general population), (ii) paricalcitol (2 ug/day) combined with dietary sodium restriction (target: 50 mmol Na(+)/day), (iii) placebo combined with a liberal sodium diet and (iv) placebo combined with dietary sodium restriction. Data are collected at the end of each study period. The primary outcome is 24-h urinary albumin excretion. Secondary study outcomes are blood pressure, renal function (estimated glomerular filtration rate), plasma renin activity and, in a sub population (N = 9), renal haemodynamics (measured glomerular filtration rate and effective renal plasma flow). A sample size of 50 patients provides 90% power to detect a 23% reduction in albuminuria, assuming a 25% dropout rate. Further reduction of residual albuminuria by combination of VDRA treatment and sodium restriction during single-agent RAAS-blockade will justify long-term studies on cardiorenal outcomes and safety. CLINICAL TRIAL REGISTRATION: NTR2898 (Dutch trial register). PMID- 25744275 TI - Surface properties of atomically flat poly-crystalline SrTiO3. AB - Comparison between single- and the poly-crystalline structures provides essential information on the role of long-range translational symmetry and grain boundaries. In particular, by comparing single- and poly-crystalline transition metal oxides (TMOs), one can study intriguing physical phenomena such as electronic and ionic conduction at the grain boundaries, phonon propagation, and various domain properties. In order to make an accurate comparison, however, both single- and poly-crystalline samples should have the same quality, e.g., stoichiometry, crystallinity, thickness, etc. Here, by studying the surface properties of atomically flat poly-crystalline SrTiO3 (STO), we propose an approach to simultaneously fabricate both single- and poly-crystalline epitaxial TMO thin films on STO substrates. In order to grow TMOs epitaxially with atomic precision, an atomically flat, single-terminated surface of the substrate is a prerequisite. We first examined (100), (110), and (111) oriented single crystalline STO surfaces, which required different annealing conditions to achieve atomically flat surfaces, depending on the surface energy. A poly crystalline STO surface was then prepared at the optimum condition for which all the domains with different crystallographic orientations could be successfully flattened. Based on our atomically flat poly-crystalline STO substrates, we envision expansion of the studies regarding the TMO domains and grain boundaries. PMID- 25744276 TI - Comparison of the Responsiveness of the Long-Form and Simplified Stroke Rehabilitation Assessment of Movement: Group- and Individual-Level Analysis. AB - BACKGROUND: The group-level responsiveness of the original, 30-item Stroke Rehabilitation Assessment of Movement measure (STREAM-30) is similar to that of the simplified STREAM (STREAM-15), even though the STREAM-30 has twice as many items as those of the STREAM-15. OBJECTIVE: The purpose of this study was to compare the responsiveness of the STREAM-30 and STREAM-15 at both group and individual levels in patients with stroke. For the latter level, the Rasch calibrated 27-item STREAM (STREAM-27) was used because the individual-level indexes of the STREAM-30 could not be estimated. DESIGN: A repeated-measurements design was used. In total, 195 patients were assessed with the STREAM-30 at both admission and discharge. METHODS: The Rasch scores of the STREAM-27 and STREAM-15 were estimated from the participants' responses on the STREAM-30. We calculated the paired t-test value, effect size, and standardized response mean as the indexes of group-level responsiveness. The significance of change for each participant was estimated as the individual-level responsiveness index, and the paired t test and test of marginal homogeneity were used for individual-level comparisons between the STREAM-27 and STREAM-15. RESULTS: At the group level, the STREAM-30, STREAM-27, and STREAM-15 showed sufficient and comparable responsiveness. At the individual level, the STREAM-27 detected significantly more participants with significant improvement and fewer participants with no change or deterioration compared with the STREAM-15. LIMITATIONS: Few patients with subacute stroke showed deterioration at discharge, so the abilities of the 2 measures to detect deterioration remain inconclusive. CONCLUSIONS: The STREAM-27 detected more participants with significant recovery compared with the STREAM-15, although the group-level responsiveness of the 2 measures was the same. The STREAM-27 is recommended as an outcome measure to demonstrate the treatment effects of movement and mobility for patients with stroke. PMID- 25744277 TI - One-pot synthesis of meso-structured Pd-CeOx catalyst for efficient low temperature CO oxidation under ambient conditions. AB - A facile one-pot co-precipitation approach was applied to fabricate a meso structured Pd-CeOx composite for low temperature CO oxidation. The as-prepared material had a much higher specific area and highly dispersed noble metal species, and thus showed excellent catalytic activity and stability for CO oxidation, especially under ambient conditions. Complete CO conversion could be achieved at as low as 25 degrees C for 5.9 wt% Pd doped catalyst, when 3.0 vol% H2O was introduced into the feed gas. The reaction mechanism on such a catalyst has been proposed through in situ DRIFTS and kinetic analysis. PMID- 25744278 TI - Is it possible to diagnose TB in ancient bone using microscopy? AB - In paleopathology, light microscopy, particularly the use of polarized transmission light, is highly valued for the establishment of reliable diagnoses. Recently, there has been a considerable widening of our experience in the diagnosis of pathological conditions at the micro-level using thin-ground sections prepared from archaeological bone. Thus, the question has arisen as to whether it might also be possible to diagnose tuberculous disease in archaeological bone using microscopy. As a rule, the reliability of a diagnosis established on the basis of thin-ground sections depends on the state of preservation of the selected sample (e.g., pseudopathology). However, sometimes, although the preservation is fairly good, a diagnosis cannot easily be established because the characteristic criteria (e.g., mosaic structure, in Paget's disease) are not clearly observable or seem to be ambiguous. In this case, we assumed that the pathophysiological nature of the morphological structures should be analyzed (e.g., the speed of growth of pathological newly built bone formations) which might help to differentiate between nonspecific (e.g., hematogenous osteomyelitis) and specific inflammatory bone diseases (e.g., tuberculous bone disease). To verify this assumption, samples were taken from recent bone collection materials with known disease diagnoses and from archaeological specimens which show lesions suspicious of bone tuberculosis (e.g., bone tuberculosis, tuberculous meningitis). PMID- 25744279 TI - Antibiotic stewardship programmes and the surgeon's role. AB - Inappropriate antibiotic use is a frequent occurrence, especially in surgical units. Among the unnecessary costs of such usage are unfavourable outcomes for patients and the emergence and spread of resistant bacteria. Antibiotic stewardship programmes aim to limit the spread of antibiotic resistance by promoting thoughtful prescribing of antibiotics. Such programmes usually try to control inappropriate use of antibiotics; to optimize the choice of drug, dosing, route, and duration of therapy; to maximize clinical cure or prevention of infection; and to limit unwanted effects and excess cost. In this paper, I discuss the impact of improper use of antibiotics and outline why I believe that antibiotic stewardship is likely to be the best way of dealing with it. Engagement of surgeons in antibiotic stewardship programmes is crucial to their success. PMID- 25744280 TI - Cross-sectional correlation of single-item health literacy screening questions with established measures of health literacy in patients with rheumatoid arthritis. AB - Research suggests that health literacy (HL) is associated with rheumatoid arthritis (RA) patients' functional status. Single-item health literacy screening (SILS) questionnaires may establish patients' HL; however, the wording of SILS may be misinterpreted by RA patients as a query regarding physical limitations. Despite this threat to validity, multiple publications have employed the SILSs as a measure of health literacy. We assessed the construct validity of two SILS's versions by correlating scores with standardized HL measures. English-speaking adult RA patients at a hospital serving low-income patients were enrolled in a cross-sectional study. Subjects completed two SILS versions, as well as two longer HL measurement tools [short test of functional health literacy in adults (s-TOFHLA) and the rapid estimate of adult literacy in medicine (REALM)]. Spearman correlation was used to compare these tools. The study enrolled 110 subjects. There was a good correlation between the two SILS versions (r = 0.705). The correlation of SILS2 and REALM or s-TOFHLA was less robust. The distribution of scores within each SILS2 category demonstrated substantial variation. The SILS2 has construct validity in the assessment of HL in patients with RA, though its correlation with traditional methods of assessing HL is weak. PMID- 25744281 TI - The association between patient activation and medication adherence, hospitalization, and emergency room utilization in patients with chronic illnesses: a systematic review. AB - OBJECTIVE: A systematic review of the published literature on the association between the PAM (Patient Activation Measure) and hospitalization, emergency room use, and medication adherence among chronically ill patient populations. METHODS: A literature search of several electronic databases was performed. Studies published between January 1, 2004 and June 30, 2014 that used the PAM measure and examined at least one of the outcomes of interest among a chronically ill study population were identified and systematically assessed. RESULTS: Ten studies met the eligibility criteria. Patients who scored in the lower PAM stages (Stages 1 and 2) were more likely to have been hospitalized. Patients who scored in the lowest stage were also more likely to utilize the emergency room. The relationship between PAM stage and medication adherence was inconclusive in this review. CONCLUSION: Chronically ill patients reporting low stages of patient activation are at an increased risk for hospitalization and ER utilization. PRACTICAL IMPLICATIONS: Future research is needed to further understand the relationship between patient activation and medication adherence, hospitalization and/or ER utilization in specific chronically ill (e.g. diabetic, asthmatic) populations. Research should also consider the role of patient activation in the development of effective interventions which seek to address the outcomes of interest. PMID- 25744283 TI - Enantioselective femtosecond laser photoionization spectrometry of limonene using photoelectron circular dichroism. AB - Limonene is ionized by circularly polarized 420 nm femtosecond laser pulses. Ion mass and photoelectron energy spectra identify the dominant (2 + 1) multiphoton ionization mechanism, aided by TDDFT calculations of the Rydberg excitations. Photoelectron circular dichroism measurements on pure enantiomers reveal a chiral asymmetry of +/-4 %. PMID- 25744282 TI - Resting-state functional connectivity of antero-medial prefrontal cortex sub regions in major depression and relationship to emotional intelligence. AB - BACKGROUND: Major depressive disorder has been associated with abnormal resting state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals. METHODS: Twenty-one medication-free, non-treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10 m, 10r, and 10p were created and compared between the two groups. RESULTS: Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence. CONCLUSIONS: These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence. PMID- 25744284 TI - General Anil Chandra Anand, incoming President, Indian Society of Gastroenterology 2014- 2015. PMID- 25744285 TI - Validation of the Hindi version of the Multidimensional Fatigue Inventory-20 (MFI 20) in Indian cancer patients. AB - OBJECTIVE: The present study was designed to validate the Hindi version of the Multidimensional Fatigue Inventory-20 (MFI-20) in Indian oncology population. METHODS: The original English version of the MFI-20 was translated into Hindi (hMFI-20) using the translation and back translation processes. The hMFI-20 was administered to 200 cancer patients. The item analysis for hMFI-20 was carried out using the corrected item-total correlation. The confirmatory factor analysis (CFA) was employed to test whether the original factor structure of MFI-20 is confirmed for the hMFI-20. Further, convergent and discriminant validities were also tested. The reliability of the hMFI-20 was evaluated by computing composite reliability and Cronbach's alpha coefficient. RESULTS: Corrected item-total correlation value for each of the items of hMFI-20 was greater than 0.6. Results of the CFA (comparative fit indices (CFI) = 0.91, root mean squared residual (RMR) = 0.04, root mean square error of approximation (RMSEA) = 0.028, and chi (2) = 45.68, p > 0.05) indicated that the five-factor model provided a good fit to the data. The findings indicated that hMFI-20 has a good convergent (composite reliability (CR) >0.7; average variance extracted value (AVE) >0.5) and discriminant (maximum shared variance (MSV) < AVE; average shared variance (ASV) < AVE; square root of AVE > inter-factor correlations) validities. The Cronbach's alpha coefficient for the total hMFI-20 was 0.8 and was more than 0.7 for each of the five factors. CONCLUSIONS: We conclude that the hMFI-20 has a high internal consistency and reasonable construct validity. Therefore, the hMFI-20 is a reliable and valid tool to assess the multidimensional fatigue in Indian oncology population. However, we recommend further validation of hMFI-20 in population of cancer patients of different linguistic settings and regions of India. PMID- 25744286 TI - Lymphoedema and health-related quality of life by early treatment in long-term survivors of breast cancer. A comparative retrospective study up to 15 years after diagnosis. AB - PURPOSE: The purpose was to compare progression/regression of arm lymphoedema, health-related quality of life and medical background data among women who discontinued their treatment (non-continued treatment group, NCTG) with these factors among women who continued treatment (continued treatment group, CTG). METHODS: Seventy-two women were included in the NCTG and 58 women in the CTG. Women in the NCTG were invited to an examination and measurement of affected arm volume at the clinic in 2008. Medical background data and arm volume values, measured using the water displacement method, were collected from patient records and the Breast Cancer Quality Register of the Uppsala Orebro Region. The functional assessment of cancer therapy for breast cancer (FACT-B) was used to assess health-related quality of life in both groups. RESULTS: There were no differences with regard to progression/regression of arm lymphoedema or health related quality of life. The CTG had experienced more advanced disease and received more extensive surgical and oncological treatment. The CTG had significantly larger arm volume due to lymphoedema at diagnosis (mean 422 ml) compared to the NCTG (mean 283 ml; p < 0.001), and at the last visit at the clinic (CTG mean 414 ml versus NCTG mean 239 ml; p < 0.001). CONCLUSIONS: The results indicate that there might be a spontaneous regression of lymphoedemas in the NCTG but there is a need for more research to make it possible to draw firm conclusions regarding this. PMID- 25744287 TI - Variations in intensity of end-of-life cancer therapy by cancer type at a Canadian tertiary cancer centre between 2003 and 2010. AB - BACKGROUND: Aggressive medical management of cancer patients at the end of life (EOL) is an indicator of health services quality. We evaluated the variations in EOL cancer therapy utilization and in acute care hospital deaths across different types of cancer within the setting of a regionalized cancer program. METHODS: Intravenous chemotherapy and radiotherapy use within the last 14 and 30 days of life was identified through the Alberta Cancer Registry and then verified by chart review for cancer decedents residing within 50 km of the Tom Baker Cancer Centre between 2003 and 2010. Multivariable logistic regression was used to examine variations in outcomes of interest by cancer, adjusting for age and other factors in prespecified models. RESULTS: Of the 9863 decedents included in the study, 3.0 and 6.3 % received chemotherapy within the final 14 and 30 days of life, respectively. In multivariable model, breast, hematological, and gynecological cancers were at least 2.5 times more likely than other cancers to undergo EOL chemotherapy. Radiotherapy was given to 4.6 % of decedents within 14 days of death, but only 66 % (359/542 courses) were completed as prescribed. Acute care admission within 14 days of death was seen in 44 % of decedents and 34 % died in the hospital. CONCLUSIONS: In our regional cancer program, the intensity of cancer therapies near the end of life varied considerably across different cancer types. Such variations may be unwarranted. A substantial proportion of cancer deaths occurred in the acute care setting. Greater efforts to integrate palliative care in outpatient cancer services are needed. PMID- 25744288 TI - Enhancing the experience of carers in the chemotherapy outpatient setting: an exploratory randomised controlled trial to test impact, acceptability and feasibility of a complex intervention co-designed by carers and staff. AB - PURPOSE: Supporting someone through chemotherapy can be emotionally and physically demanding. However, research has yet to establish the type of support carers require or the best way to provide this. This study tested the feasibility and acceptability of a complex intervention for carers that was co-designed by staff and carers of patients starting chemotherapy. METHODS: Forty-seven carers were recruited, randomised between the intervention (n = 24) and control (n = 23) groups. A questionnaire was completed pre- and post-intervention measuring knowledge of chemotherapy and its side effects, experience of care, satisfaction with outpatient services, coping and emotional wellbeing. The intervention process was evaluated by carers and healthcare professionals (HCPs) in focus groups. RESULTS: Recruitment to the study was unproblematic and attrition from it was low, suggesting the intervention and study processes were acceptable to patients and carers. Carers in receipt of the 'Take Care' intervention reported statistically significantly better understanding of symptoms and side effects and their information needs being more frequently met than carers in the control. Confidence in coping improved between baseline and follow-up for the intervention group and declined for the control although differences were insufficient to achieve statistical significance. There was no significant difference between the two groups' emotional wellbeing. HCP and carer focus groups confirmed the feasibility and acceptability of the intervention. CONCLUSIONS: The 'Take Care' intervention proved acceptable to carers and HCPs and demonstrates considerable promise and utility in practice. Study findings support the conduct of a fully powered RCT to determine the intervention's effectiveness and cost-effectiveness. PMID- 25744289 TI - Exercise compliance among patients with multiple myeloma undergoing chemotherapy: a retrospective study. AB - PURPOSE: Multiple myeloma (MM) is often associated with osteolytic bone disease and anemia, resulting in skeletal fragility and persistent fatigue, pain, and reduced quality of life. Exercise is considered safe and beneficial for this population. Our objectives were to evaluate the extent to which MM patients undergoing chemotherapy complied with exercise recommendations and to identify factors associated with noncompliance. METHODS: This retrospective study included 41 MM patients referred to a hospital-based rehabilitation program while undergoing chemotherapy. Variables collected at baseline (T1) and follow-up (T2) included: (a) demographics and medical history, (b) exercise levels (MET hours/week), preferences and barriers, and (c) fatigue severity scores (0-10). Statistical analyses included logistic regression to identify factors associated with exercise noncompliance and t-tests and chi-squared tests to compare outcomes between the groups according to compliance. RESULTS: The mean age of the participants was 61 years; 73 % were male and 81 % had bone lesions. Overall exercise compliance at T2 was 71 %, with an observed increase in exercise levels (mean group difference: 6.5 MET-hours/week; p < 0.001) and decrease in fatigue severity scores (mean group difference -1.2; p = 0.003). Factors associated with exercise noncompliance included history of pathological fracture (odds ratio [OR] 4.7; p = 0.049), spinal cord compression (SCC) (OR 14.1; p = 0.023), and radiation (OR 28.0; p < 0.001). CONCLUSIONS: In this sample of MM patients, high compliance with exercise and associated improvements in fatigue were observed. However, participants with a history of pathological fracture, SCC, or radiation are at increased risk of noncompliance and may require additional supervision to improve exercise compliance. PMID- 25744290 TI - Women's experiences of hormonal therapy for breast cancer: exploring influences on medication-taking behaviour. AB - PURPOSE: Five to 10 years of adjuvant hormonal therapy is recommended to prevent breast cancer recurrence. This study investigated modifiable influences on adjuvant hormonal therapy medication-taking behaviour (MTB) in women with stage I III breast cancer. METHODS: Semi-structured face-to-face interviews among women with stage I-III breast cancer prescribed adjuvant hormonal therapy purposively sampled by their MTB at two cancer centres. Thematic analysis was conducted based on the Framework approach, with the Theoretical Domains Framework (TDF) informing the analysis framework; the TDF is an integrative framework consisting of 14 domains of behavioural change to inform intervention design. RESULTS: Thirty-one women participated in interviews (14 adherent/persistent; 7 non adherent/persistent; 10 non-persistent). Three domains identified both barriers and enablers to hormonal therapy MTB across the three MTB strata: beliefs about consequences, intentions and goals and behaviour regulation, but their influence was different across the strata. Other domains influenced individual MTB strata. Key enablers for adherent/persistent women were identified within the domain beliefs about consequences (breast cancer recurrence), intentions and goals (high priority), beliefs about capabilities (side effects) and behaviour regulation (managing medication). Barriers were identified within the domain behaviour regulation (no routine), memory, attention and decision processes (forgetting) and environmental context and resources (stressors) for non-adherent/persistent women and intentions and goals (quality of life), behaviour regulation (temporal self-regulation), reinforcement, beliefs about consequences (non-necessity) and social influences (clinical support) for non-persistent women. CONCLUSION: This study identified modifiable influences on hormonal therapy MTB. Targeting these influences in clinical practice may improve MTB and hence survival in this population. PMID- 25744291 TI - Accuracy of diagnostic demarcation of undifferentiated-type early gastric cancers for magnifying endoscopy with narrow-band imaging: endoscopic submucosal dissection cases. AB - BACKGROUND: The usefulness of magnifying endoscopy with narrow-band imaging (ME NBI) for undifferentiated-type early gastric cancers (UD-type EGCs) is unclear. The present study examined the accuracy of the diagnostic demarcation of lesions using ME-NBI. METHODS: The study population consisted of 76 patients with UD-type EGC lesions measuring <=20 mm in diameter using white-light imaging (WLI) and endoscopic ultrasonography and diagnosed as intramucosa and UL(-); all the lesions were confirmed as early gastric cancer based on postoperative pathological examination. All the patients had undergone an initial endoscopic submucosal dissection (ESD) at this hospital between January 2010 and January 2014. After marking with demarcation lines at the utmost oral and anal sites of the lesion using argon plasma coagulation under ME-NBI for intervention, the cases with demarcations that were consistent with the postoperative pathological findings were defined as having been accurately diagnosed. The inflammatory cell infiltration (Updated Sydney System, USS) were also assessed. RESULTS: The diagnostic demarcations of the lesion were consistent in 62 cases (81.6 %). The accurate diagnosis rate was higher for the USS cases with mild neutrophil and monocyte infiltration (P < 0.05). The addition of ME-NBI to WLI improved the accurate diagnosis rate by 27.6 %. CONCLUSION: The use of ME-NBI in diagnostic demarcation of UD-type EGCs is recommended. PMID- 25744292 TI - Outlier-resilient complexity analysis of heartbeat dynamics. AB - Complexity in physiological outputs is believed to be a hallmark of healthy physiological control. How to accurately quantify the degree of complexity in physiological signals with outliers remains a major barrier for translating this novel concept of nonlinear dynamic theory to clinical practice. Here we propose a new approach to estimate the complexity in a signal by analyzing the irregularity of the sign time series of its coarse-grained time series at different time scales. Using surrogate data, we show that the method can reliably assess the complexity in noisy data while being highly resilient to outliers. We further apply this method to the analysis of human heartbeat recordings. Without removing any outliers due to ectopic beats, the method is able to detect a degradation of cardiac control in patients with congestive heart failure and a more degradation in critically ill patients whose life continuation relies on extracorporeal membrane oxygenator (ECMO). Moreover, the derived complexity measures can predict the mortality of ECMO patients. These results indicate that the proposed method may serve as a promising tool for monitoring cardiac function of patients in clinical settings. PMID- 25744293 TI - A comparison between different prediction models for invasive breast cancer occurrence in the French E3N cohort. AB - Breast cancer remains a global health concern with a lack of high discriminating prediction models. The k-nearest-neighbor algorithm (kNN) estimates individual risks using an intuitive tool. This study compares the performances of this approach with the Cox and the Gail models for the 5-year breast cancer risk prediction. The study included 64,995 women from the French E3N prospective cohort. The sample was divided into a learning (N = 51,821) series to learn the models using fivefold cross-validation and a validation (N = 13,174) series to evaluate them. The area under the receiver operating characteristic curve (AUC) and the expected over observed number of cases (E/O) ratio were estimated. In the two series, 393 and 78 premenopausal and 537 and 98 postmenopausal breast cancers were diagnosed. The discrimination values of the best combinations of predictors obtained from cross-validation ranged from 0.59 to 0.60. In the validation series, the AUC values in premenopausal and postmenopausal women were 0.583 [0.520; 0.646] and 0.621 [0.563; 0.679] using the kNN and 0.565 [0.500; 0.631] and 0.617 [0.561; 0.673] using the Cox model. The E/O ratios were 1.26 and 1.28 in premenopausal women and 1.44 and 1.40 in postmenopausal women. The applied Gail model provided AUC values of 0.614 [0.554; 0.675] and 0.549 [0.495; 0.604] and E/O ratios of 0.78 and 1.12. This study shows that the prediction performances differed according to menopausal status when using parametric statistical tools. The k-nearest-neighbor approach performed well, and discrimination was improved in postmenopausal women compared with the Gail model. PMID- 25744294 TI - The CCL2 chemokine is a negative regulator of autophagy and necrosis in luminal B breast cancer cells. AB - Luminal A and B breast cancers are the most prevalent forms of breast cancer diagnosed in women. Compared to luminal A breast cancer patients, patients with luminal B breast cancers experience increased disease recurrence and lower overall survival. The mechanisms that regulate the luminal B subtype remain poorly understood. The chemokine CCL2 is overexpressed in breast cancer, correlating with poor patient prognosis. The purpose of this study was to determine the role of CCL2 expression in luminal B breast cancer cells. Breast tissues, MMTV-PyVmT and MMTV-Neu transgenic mammary tumors forming luminal B-like lesions, were immunostained for CCL2 expression. To determine the role of CCL2 in breast cancer cells, CCL2 gene expression was silenced in mammary tumor tissues and cells using TAT cell-penetrating peptides non-covalently cross linked to siRNAs (Ca-TAT/siRNA). CCL2 expression was examined by ELISA and flow cytometry. Cell growth and survival were analyzed by flow cytometry, immunocytochemistry, and fluorescence microscopy. CCL2 expression was significantly increased in luminal B breast tumors, MMTV- PyVmT and MMTV-Neu mammary tumors, compared or normal breast tissue or luminal A breast tumors. Ca-TAT delivery of CCL2 siRNAs significantly reduced CCL2 expression in PyVmT mammary tumors, and decreased cell proliferation and survival. CCL2 gene silencing in PyVmT carcinoma cells or BT474 luminal B breast cancer cells decreased cell growth and viability associated with increased necrosis and autophagy. CCL2 expression is overexpressed in luminal B breast cancer cells and is important for regulating cell growth and survival by inhibiting necrosis and autophagy. PMID- 25744295 TI - Breast cancer incidence after hormonal treatments for infertility: systematic review and meta-analysis of population-based studies. AB - The increasing practice of hormonal infertility treatments (HITs) raised concerns about their effects on breast cancer (BC) risk. Available evidence reported conflicting results. The aim of this study was to assess the potential association between HITs and BC risk. The literature was searched through November 2014. Eligible studies included cohort studies reporting BC incidence in women undergone HITs. Data were analyzed with standard meta-analytic techniques. Subgroup analyses were performed by type of intervention (IVF vs. NO IVF), follow up duration (<10 vs. >10 years), and type of control (population vs. infertile). 20 eligible studies (207.914 women, 2347 BC) were retrieved: no increased risk was detected (SRR = 1.05, 95 % CI 0.96-1.14), with a significant heterogeneity (I (2) = 59 %, p = 0.001) among studies. In the seven studies with the in vitro fertilization (IVF) procedure, no increase in BC risk was observed (SRR = 0.96, 95 % CI 0.80-1.14); in the three NO IVF studies, an increased BC risk was identified (SRR = 1.26, 95 %CI 1.06-1.50). A borderline interaction between type of intervention (IVF vs. NO IVF) and BC risk was observed (p = 0.06). An increased risk with longer follow-up (>=10 vs. <10 years) was detected (SRR = 1.13, 95 % CI 1.02-1.26 vs. SRR = 0.95, 95 % CI 0.85-1.06). Overall, HITs are not associated with an increased BC risk. In particular, no increased risk was observed in women undergoing IVF. Conversely, an increased in BC risk cannot be ruled out with older treatment protocols based on clomiphene. The long-term administration of clomiphene outside the current indications should be discouraged because of a possible increase in BC risk. PMID- 25744296 TI - Oligoadenylate synthase-like (OASL) proteins: dual functions and associations with diseases. AB - The study of antiviral pathways to reveal methods for the effective response and clearance of virus is closely related to understanding interferon (IFN) signaling and its downstream target genes, IFN-stimulated genes. One of the key antiviral factors induced by IFNs, 2'-5' oligoadenylate synthase (OAS), is a well-known molecule that regulates the early phase of viral infection by degrading viral RNA in combination with RNase L, resulting in the inhibition of viral replication. In this review, we describe OAS family proteins from a different point of view from that of previous reviews. We discuss not only RNase L-dependent (canonical) and independent (noncanonical) pathways but also the possibility of the OAS family members as biomarkers for various diseases and clues to non-immunological functions based on recent studies. In particular, we focus on OASL, a member of the OAS family that is relatively less well understood than the other members. We will explain its anti- and pro-viral dual roles as well as the diseases related to single-nucleotide polymorphisms in the corresponding gene. PMID- 25744297 TI - Scoparone interferes with STAT3-induced proliferation of vascular smooth muscle cells. AB - Scoparone, which is a major constituent of Artemisia capillaries, has been identified as an anticoagulant, hypolipidemic, vasorelaxant, anti-oxidant and anti-inflammatory drug, and it is used for the traditional treatment of neonatal jaundice. Therefore, we hypothesized that scoparone could suppress the proliferation of VSMCs by interfering with STAT3 signaling. We found that the proliferation of these cells was significantly attenuated by scoparone in a dose dependent manner. Scoparone markedly reduced the serum-stimulated accumulation of cells in the S phase and concomitantly increased the proportion of cells in the G0/G1 phase, which was consistent with the reduced expression of cyclin D1, phosphorylated Rb and survivin in the VSMCs. Cell adhesion markers, such as MCP-1 and ICAM-1, were significantly reduced by scoparone. Interestingly, this compound attenuated the increase in cyclin D promoter activity by inhibiting the activities of both the WT and active forms of STAT3. Similarly, the expression of a cell proliferation marker induced by PDGF was decreased by scoparone with no change in the phosphorylation of JAK2 or Src. On the basis of the immunofluorescence staining results, STAT3 proteins phosphorylated by PDGF were predominantly localized to the nucleus and were markedly reduced in the scoparone treated cells. In summary, scoparone blocks the accumulation of STAT3 transported from the cytosol to the nucleus, leading to the suppression of VSMC proliferation through G1 phase arrest and the inhibition of Rb phosphorylation. This activity occurs independent of the form of STAT3 and upstream of kinases, such as Jak and Src, which are correlated with abnormal vascular remodeling due to the presence of an excess of growth factors following vascular injury. These data provide convincing evidence that scoparone may be a new preventative agent for the treatment of cardiovascular diseases. PMID- 25744298 TI - Utilizing the resource of twins reared apart: their distribution across nine provinces or cities of China. AB - Twins reared apart provide a fascinating experiment to distinguish genetic from environmental influences. However, there is as yet no broad report on distribution of twins reared apart, especially in the Chinese population. In this study, information on 18,295 volunteer twin pairs of all age groups was compiled in nine provinces or cities of China, and questionnaires were used for zygosity determination. It was discovered that twins reared apart from 0 to 10 years of age accounted for 2.2% of all twin interviewees, with the proportion of this 0-10 group separated before 1, 2, and 5 years old, accounting for 65.3%, 76.1%, and 91.3%, respectively. The proportion of twins reared apart is not significantly related to zygosity or gender, but it is related to region and twin age. As the age of twins lowers, the proportion of those reared apart gradually decreases. Twins reared apart will become rarer in the future and therefore should be cherished as a resource. PMID- 25744299 TI - Interactive human protein atlas launches. AB - Researchers in Sweden have completed a major analysis of the human proteome and presented their results in a free, interactive web portal that allows researchers to visualize the distribution of proteins across all of the body's major tissues and organs. PMID- 25744304 TI - Contraceptive Use Before and After Gastric Bypass: a Questionnaire Study. AB - BACKGROUND: At present, women are recommended to avoid pregnancy 12-18 months after bariatric surgery. Our aim in this study was to describe patterns of contraceptive use before and after gastric bypass in Sweden, and to describe the contraceptive counseling given preoperatively to women undergoing gastric bypass. METHODS: In October 2012, a questionnaire was sent to 1000 Swedish women who all had undergone gastric bypass during 2010. The women had been included in the Scandinavian Obesity Surgery Register at time of surgery. The main outcome measures were patterns of use of contraception before and after bariatric surgery. RESULTS: The response rate was 57 %. The most commonly used contraceptive methods were intrauterine devices, 29 % preoperatively and 26 % postoperatively even though there was a postoperative switch from the copper intrauterine device to the levonorgestrel intrauterine system. Thirty percent did not use any contraceptive during the first 12 months after surgery. Sixty percent of the responders were aware of the recommendations to avoid pregnancy after surgery. CONCLUSIONS: Many women who undergo bariatric surgery are not using any contraceptive method despite the recommendation that they should avoid pregnancy for at least 12 months. There is a great need to improve contraceptive counseling for this growing group of women. PMID- 25744305 TI - The Magnitude of Antral Resection in Laparoscopic Sleeve Gastrectomy and its Relationship to Excess Weight Loss. AB - BACKGROUND: The objective of this study was to evaluate the effect of antral resection on weight loss and complications after laparoscopic sleeve gastrectomy (LSG). METHODS: This was a retrospective study of the prospectively collected data of patients who underwent LSG at Jordan University Hospital from February 2011 to February 2012. Patients were divided into two groups based on antral resection: group A underwent a 6-cm antral resection, and group B underwent a 2 cm antral resection. The percentage of excess weight loss (%EWL) was calculated at 3, 6, 12, and 24 months postoperatively. RESULTS: One hundred and ten patients were included in the study, all of whom completed at least 24 months of follow-up (mean follow-up, 33 months). Their mean body mass index was 46.1 +/- 7.9 kg/m(2). In group A, the mean %EWL was 38.1 +/- 14.1, 54.9 +/- 19.9, 65.6 +/- 22.8, and 66.8 +/- 28.4% at 3, 6, 12, and 24 months, respectively. However, in group B, the mean %EWL was 42.1 +/- 13.4, 63.8 +/- 19.8, 80.0 +/- 22.1, and 81.5 +/- 22.9% at 3, 6, 12, and 24 months, respectively. Patients in group B experienced statistically significant greater weight loss than patients in group A. Statistically significant greater weight regain was seen in group A. Group A had a higher incidence of reflux symptoms (six patients; 11%) than group B (four patients; 7.1%). CONCLUSIONS: Radical antral resection in association with LSG safely potentiates the restrictive effect achieved and may result in greater and better maintained weight loss. PMID- 25744306 TI - High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes. AB - The aim of the present study was to identify the genes differentially expressed in the visceral adipose tissue in a well-characterised mouse model of high-fat diet (HFD)-induced obesity. Male C57BL/6J mice (n 20) were fed either HFD (189 % of energy from fat) or low-fat diet (LFD, 42 % of energy from fat) for 16 weeks. HFD-fed mice exhibited obesity, insulin resistance, dyslipidaemia and adipose collagen accumulation, along with higher levels of plasma leptin, resistin and plasminogen activator inhibitor type 1, although there were no significant differences in plasma cytokine levels. Energy intake was similar in the two diet groups owing to lower food intake in the HFD group; however, energy expenditure was also lower in the HFD group than in the LFD group. Microarray analysis revealed that genes related to lipolysis, fatty acid metabolism, mitochondrial energy transduction, oxidation-reduction, insulin sensitivity and skeletal system development were down-regulated in HFD-fed mice, and genes associated with extracellular matrix (ECM) components, ECM remodelling and inflammation were up regulated. The top ten up- or down-regulated genes include Acsm3, mt-Nd6, Fam13a, Cyp2e1, Rgs1 and Gpnmb, whose roles in the deterioration of obesity-associated adipose tissue are poorly understood. In conclusion, the genes identified here provide new therapeutic opportunities for prevention and treatment of diet induced obesity. PMID- 25744307 TI - Cadmium at nanomolar concentrations activates Raf-MEK-ERK1/2 MAPKs signaling via EGFR in human cancer cell lines. AB - Cadmium (Cd) is an environmental contaminant classified as carcinogenic to humans by the International Agency for Research on Cancer, supported by data from occupational exposure. Environmentally relevant dietary exposure to Cd has recently been associated with osteoporosis and cancers of the prostate, endometrium, and breast in the general population. The low exposure effects have been proposed to result from endocrine modulative properties of Cd, which mimic the physiological actions of estrogen and androgen. However, the mechanism of action of Cd is an unanswered question. We have shown previously, using mouse models, that canonical estrogen receptor signaling is not involved in estrogen mimicry effects of Cd. Instead, low-level Cd exposure stimulated the mitogen activated protein kinases (MAPKs) ERK1/2 in these mice. Here we investigate further the ERK1/2 MAPK signaling activation by Cd in vitro by using nanomolar concentrations of cadmium chloride (CdCl2) in three different human carcinoma cell lines: HepG2, MCF-7, and ECC-1. The findings also were confirmed in previously collected mouse tissue samples. We show that 10(-8)M levels of CdCl2 activate ERK1/2 (Tyr 204) and the p53 specific ubiquitin ligase Mdm2 (Ser 166) via Raf and MEK by acting through the epidermal growth factor receptor (EGFR). Furthermore, our results suggest that the CdCl2-induced activation of ERK1/2 and Mdm2 may interfere with the p53 response to genotoxic compounds in cancer cell lines. Our data collectively suggest that nanomolar levels of CdCl2 activate Raf MEK-ERK1/2 via EGFR. We hypothesize that this signaling cascade may be involved in observed low exposure effects of Cd in certain human populations. PMID- 25744308 TI - Dose response chemopreventive potential of allyl isothiocyanate against 7,12 dimethylbenz(a)anthracene induced mammary carcinogenesis in female Sprague-Dawley rats. AB - The present study aimed to investigate the dose response chemopreventive potential of allyl isothiocyanate (AITC) against 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinogenesis in female Sprague-Dawley rats. Mammary tumor was induced by a single dose of DMBA (25 mg/rat) injected subcutaneously near mammary gland. We observed reduced body weight and increased in total number of tumors, tumor incidence and tumor volume in DMBA-induced rats. We also observed decreased antioxidant status (SOD, CAT, GPX and GSH) and increased lipid peroxidation (TBARS and LOOH) in plasma and mammary tissues. Increased levels of CYP450, Cyt-b5 and decreased levels of phase II (GST and GR) biotransformation enzymes noticed in liver and mammary tissues of DMBA-induced rats. Further, increased levels of lipid profile (TC, TG, PL and FFA) and lipoprotein (LDL and VLDL) were noticed. Whereas, decreased level of HDL in plasma and decreased levels of PL and FFA in mammary tissue. Oral administration of AITC different doses (10, 20 and 40 mg/kg bw) inhibited the tumor incidence and restored levels of biochemical markers. Biochemical findings are supported by histopathological studies. These results suggested that AITC at a dose of 20 mg/kg bw significantly exert chemopreventive potential against DMBA-induced mammary carcinogenesis. PMID- 25744309 TI - Asbestos between science and myth. A 6,000-year story. AB - Asbestos was used in making pottery in Eastern Finland from around 4000 B.C. In the ancient era and in the Middle Ages, magic properties were frequently attributed to this mineral. In the first century A.D., the Latin encyclopaedist Pliny the Elder reported in his Historia Naturalis that asbestos protects against all poisonings, particularly that of magicians. Moreover, asbestos was often found in places of worship, in Rome as well as in Athens and in Jerusalem. In the Middle Ages asbestos was identified with some animals, such as the salamander and certain white rodents. With such appearance, the mineral had a huge success in Western as well as in Eastern literature and the fine arts. Marco Polo (1254 1324) in the Milione tried to deny that asbestos was a salamander. Despite its noxious effects, asbestos continues to be used in much of the world. In the 21st century it seems to be maintaining its quality as a magic stone. PMID- 25744310 TI - [Work ability, psycho-physical health, burnout, and age among nursery school and kindergarten teachers: a cross-sectional study]. AB - INTRODUCTION: Although well-being and psychophysical health of nursery school and kindergarten teachers have important implications also on the health and well being of their recipients, studies dedicated to these workers are quite rare, particularly in Italy. AIM: The aim of the study was to observe psychophysical health conditions in a sample of nursery school and kindergarten teachers employed in the Education Services Division of the Municipality of Turin. METHOD: The study was cross-sectional; 884 self-reporting questionnaires were distributed and 734 teachers (representing 53% of those employed at the Education Services of the Municipality of Turin) correctly filled out the questionnaire. RESULTS: Respectively 53.4% and 50% of participants reported medium or high levels of emotional exhaustion and depersonalization, while 18.5% showed low levels of personal accomplishment. Responders reported moderate levels of work ability in 38.9% and poor levels in 5.6%. The majority of the respondents (98.7%) did not report depressive symptoms; 42.9% of the sample suffered moderate to severe limiting musculoskeletal pain. Age and profession were associated with emotional exhaustion, personal accomplishment, and musculoskeletal pain. However, work ability and depression were only associated with age. No associations were found with depersonalization. CONCLUSIONS: The present study shows that health conditions of nursery school and kindergarten teachers were critical and that age contributed to the explanation of these conditions. PMID- 25744311 TI - [Cross-sectional study of the variability of work-related stress among post graduate medical residents at the main University Polyclinic of Sicily]. AB - BACKGROUND: Among health care workers (HCWs), work-related stress is one of the main topics in risk assessment and prevention at the workplace. Post-graduate medical residents (MRs) are a group of HCWs comparable to medical doctors in terms of occupational exposure and occurrence of work-related stress syndromes. OBJECTIVES: Risk assessment of work-related stress among MRs attending the major University Hospital of Sicily. METHODS: A cross-sectional survey via an anonymous and self-administered questionnaire. RESULTS: 45% of clinical MRs and 37% of surgical MRs had access to compensatory rest days against 92% of MRs of the services area (p<0.001). A work attendance recording system for MRs was available in 80% of the postgraduate medical schools of the services area, in 60% of the clinical postgraduate schools and in 50% of the surgical postgraduate schools (p<0.001). MRs of the postgraduate surgical schools reported having access to work breaks (41%) with less frequency compared to clinical (60%) and services MRs (74%) (p<0.001). Both clinical (47%) and surgical MRs (47%) were more exposed to work-related stress than MRs of the services area (27%) (p<0.001). CONCLUSIONS: The survey demonstrated excess exposure to work-related stress for all the considered variables in MRs of the surgical area, compared with MRs of clinical and services areas. It is strongly recommended to provide specific training programmes aimed at managing the MRs' risk of exposure to work-related stress, focusing both on the workers and the work environment. PMID- 25744312 TI - Hospitalization for cancer among radiologists in Taiwan. AB - BACKGROUND: Population aging and the incremental use of high-tech instruments increase the demand for radiological examinations and treatments in medical services. The exposure of radiologists and other medical workers to medical treatment radiation may thus be increased. OBJECTIVES: The aim of the study was to explore the average number of cancer hospitalizations and use of hospitalization as cancer treatment for radiologists compared with that for family medicine physicians, as well as the trends in the annual average number of cancer hospitalizations among radiologists. METHODS: Research data were obtained from the 2000-2010 Taiwan National Health Insurance Research Database. These samples collected for this study were unbalanced panel data. RESULTS: The average number of cancer hospitalizations for radiologists from 2000 to 2010 ranged between 3.67 and 28.260/00. After controlling the effects of gender, age, hospital accreditation level and year using generalized estimating equations with a binomial distribution and logit link function, our study found that radiologists had non significant higher risk of cancer hospitalizations compared with family medicine physicians. However, the average number of cancer hospitalizations for radiologists showed an annual decline from 2000 to 2010. CONCLUSIONS: Compared with family medicine physicians, radiologists had non significant higher risk of cancer hospitalizations. The data period examined in this study was only 11 years. Considering the numerous new radiological procedures currently in use in modern medical treatments, the health status of medical radiation workers should be continuously monitored in the future. PMID- 25744313 TI - [Job satisfaction and work ability index in nurses]. AB - BACKGROUND: Job satisfaction and work ability are important in the nursing profession to ensure good working conditions and to reduce work-related diseases and illness. Psychosocial factors such as social support and decision latitude (autonomy) could have a role in cardiovascular diseases, low back pain, injuries and sick leave. AIM: To evaluate work ability, job satisfaction, psychosocial factors and diseases in 10 departments of the Monfalcone Hospital. MATERIAL AND METHODS: The Work Ability Index (WAI) questionnaire and Karasek Job Content Questionnaire with other questions related to working conditions and diseases were administered to 160 nurses working in 10 departments. The response rate was 90%. SPSS Statistic packaging was used for statistical analysis. RESULTS: The study population had a mean age of 41.1 +/- 7 years and the majority were female (81.25%). WAI gave a rating of over 37 points (good and excellent) for 86.4%, with an average of 39.9 +/- 5.9 in women and 40.6 +/- 6.4 in men. The WAI differences between the departments were significant with Medicine and Surgery showing lower values (p=0.012). WAI was significantly lower in subjects with sick leave higher than 10 days per year (p=0.000) and in subjects with cardiovascular diseases (p=0.031). CONCLUSION: Our study showed very good working conditions for nurses. A follow-up of the analyzed population over time will add further information on this aspect. PMID- 25744314 TI - [The gender gap in Italian medicine]. AB - BACKGROUND: This study is collocated in the debate about the gender gap in Medicine giving voice to female physicians who have damaged the "glass ceiling". OBJECTIVES: Our research offers a contribute to the exploration about the motivations of persistence of gender gap in Medicine despite current changes. METHODS: This study is based on 21 biographical interviews to female physicians who are managers in Italian hospitals. The themes emerged by data analysis concerned the participants 'discrimination experiences in their hierarchical advancement, the evidences of a persistence of horizontal segregation in some medical specializations, the difficult to find a work-life balance and the effects of this difficult on the female physicians' health. RESULTS: Our research confirmed a persistence of gender gap in the medical world, which disadvantages women in their career choices and in their hierarchical advancement and which appears in the form of invisible barriers impregnated of stereotypes and prejudices that are taken for granted by many men and women, especially those who have the power; these barriers make the female doctors 'health more vulnerable to the event of work-related stress. CONCLUSIONS: By the dates emerged the necessity of cultural and institutional interventions, actions for deconstruction of gender stereotypes, and the necessity of intervention for a more flexible and functioning work organization that satisfies the female physicians' needs. PMID- 25744315 TI - "Bernardino Ramazzini, three hundred years after his death", Padua (Italy), October 18th, 2014. AB - The year 2014 has marked the tercentenary from the death of Bernardino Ramazzini (1633-1714), universally credited as the founder of Occupational Health (5, 9, 10, 11). Indeed, the renowned physician died on November 5th 1714 in Padua, where he had been appointed as Professor of Practical Medicine at the local prestigious University from the year 1700. To commemorate this anniversary, the professors of Occupational Health of the University of Padua, the Italian Society of Occupational Health and Industrial Hygiene (Societa Italiana di Medicina del Lavoro eIgiene Industriale, SIMLII), the International Commission on Occupational Health (ICOH) and the University of Padua organized a conference in the wonderful location of Palazzo Bo (Main Hall) under the patronage of the Padua Municipality, the Workers' Compensation Authority (INAIL), the Venetian Region and the Societas Internationalis Historiae Medicinae.[...]. PMID- 25744317 TI - Arthroscopic arthritis options are on the horizon. AB - Arthroscopic treatment options are on the horizon for cartilage defects and arthritis. While arthroscopy is not a "cure" for osteoarthritis, arthroscopic and related surgery is of significant benefit to many patients with intra-articular pathology including osteoarthritis and articular cartilage disease. However, arthroscopy alone is insufficient, and arthroscopic treatment of patients with arthritis is a salvage procedure requiring an approach where arthroscopy must be combined with additional procedures. There are degrees of osteoarthritis severity, and arthroscopy is more effective in combination with additional procedures in younger patients, in more active patients, and in patients with less severe disease, or smaller lesions. On another note, we continue to be fascinated by the knee anterolateral ligament, although to date its clinical relevance is entirely speculative. PMID- 25744318 TI - Authors' reply. PMID- 25744319 TI - The relevance of the latarjet procedure for the management of humeral bone defects in anterior shoulder instability. PMID- 25744320 TI - Distinguishing venous thrombosis from venous thromboembolism. PMID- 25744321 TI - Authors' reply. PMID- 25744322 TI - Abandoning microfracture of the knee: has the time come? AB - Marrow stimulation has been performed for more than 45 years beginning with the simple drilling of bony surfaces, burring or "abrading" the sclerotic lesion, and more recently using awls to penetrate eburnated bone to promote blood flow to the bony surface. Multiple authors have promoted these procedures as "helpful," but others have confirmed only short-term relief with destruction of the subchondral surface. Unfortunately, proponents do not compare their marrow stimulation results to a control group that had debridement alone. A recent study confirmed that microfracture (MF) is equivalent to debridement and does not affect the subchondral bone, which therefore does not reduce the success rates of future surgery subsequent to MF. This brief review summarizes some of the factual data showing that marrow stimulation may not offer any improvement over debridement alone and that, in fact, MF results in significant destruction to the subchondral bone. PMID- 25744323 TI - Arthroscopic microfracture may not be superior to arthroscopic debridement, but abrasion arthroplasty results are good, although not great. AB - Microfracture is nonanatomic because microfracture destroys the gross structure and the complex microscopic infrastructure of the subchondral plate, and may promote subchondral cyst formation. In consideration of the destruction of subchondral anatomy, it may be time to abandon the arthroscopic microfracture procedure. However, arthroscopic abrasion arthroplasty results in a positive outcome in 66% of patients, and may still merit consideration as a salvage procedure. PMID- 25744324 TI - The structure and function of the anterolateral ligament of the knee: a systematic review. AB - PURPOSE: The purpose of this systematic review was to evaluate the anatomic structure and function of the anterolateral ligament (ALL) of the knee. METHODS: The Medline, Embase, and Cochrane databases were screened for all studies related to the ALL of the knee. Two reviewers independently reviewed all eligible articles and the references of these articles. Inclusion and exclusion criteria were applied to all searched studies. Quality assessment was completed for the included studies. RESULTS: Nineteen studies were identified for final analysis. Pooled analysis identified the ALL in 430 of 449 knees (96%) examined. The ligament was found to originate from the region of the lateral femoral epicondyle and insert on the proximal tibia midway between the Gerdy tubercle and the fibular head. The ALL was found to be 34.1 to 41.5 mm in length, 5.1 to 8.3 mm in width above the lateral meniscus, and 8.9 to 11.2 mm in width below the lateral meniscus. By use of magnetic resonance imaging, the ALL was identified in 93% of knees examined (clinical, 64 of 70; cadaveric, 16 of 16). In one case study the ligament was clearly visualized by ultrasound examination. Histologic analysis across 3 studies showed characteristics consistent with ligamentous tissue. Though not shown in biomechanical studies, it is hypothesized that the ALL provides anterolateral stability to the knee, preventing anterolateral subluxation of the proximal tibia on the femur. One study identified a network of peripheral nerves, suggesting a proprioceptive function of the ALL. CONCLUSIONS: This systematic review shows the ALL to be a distinct structure with a consistent origin and insertion sites. The ALL is an extra-articular structure with a clear course from the lateral femoral epicondyle region, running anteroinferiorly, to the proximal tibia at a site midway between the Gerdy tubercle and the head of the fibula. The function of this ligament is theorized to provide anterolateral knee stability. LEVEL OF EVIDENCE: Level IV, systematic review of cadaveric and imaging studies. PMID- 25744325 TI - Mindfulness-based cognitive therapy vs. psycho-education for patients with major depression who did not achieve remission following antidepressant treatment. AB - Mindfulness-based cognitive therapy (MBCT) showed efficacy for currently depressed patients. However, most of the available studies suffer from important methodological shortcomings, including the lack of adequate control groups. The present study aims to compare MBCT with a psycho-educational control group designed to be structurally equivalent to the MBCT program but excluding the main putative "active ingredient" of MBCT (i.e., mindfulness meditation practice) for the treatment of patients with major depression (MD) who did not achieve remission following at least 8 weeks of antidepressant treatment. Out of 106 screened subjects, 43 were randomized to receive MBCT or psycho-education and were prospectively followed for 26 weeks. MD severity was assessed with the Hamilton Rating Scale for Depression (HAM-D) and the Beck Depression Inventory-II (BDI-II). Measures of anxiety, mindfulness, and quality of life were also included. All assessments were performed at baseline, 4, 8, 17 and 26-weeks. Both HAM-D and BDI scores, as well as quality of life and mindfulness scores, showed higher improvements, which were particularly evident over the long-term period, in the MBCT group than in the psycho-education group. Although limited by a small sample size, the results of this study suggest the superiority of MBCT over psycho-education for non-remitted MD subjects. PMID- 25744326 TI - Twist and shout during an acute coronary syndrome: Can dynamic changes in ECG predict OCT's findings? PMID- 25744327 TI - ST deviations and serial changes after reperfusion therapy in patients with inferior STEMIs: Relationship between inferior leads, medial chest leads and lateral leads. PMID- 25744328 TI - Tissue reaction after intrastromal corneal ring implantation in an experimental animal model. AB - PURPOSE: To evaluate corneal wound healing in the hen animal model after additive surgery with an intracorneal ring segment (ICRS). METHODS: We implanted one ICRS in each eye of 76 hens. In control group 1 (n = 22 hens), the stromal channel was prepared but no ICRS was inserted. In control group 2 (n = 2 hens), no surgery was performed. Animals were randomly separated into groups and euthanized after clinical follow-up of 4 and 12 hours, 1, 2, 3, and 7 days, and 1, 2, 3, 4, and 6 months. Corneas were stained with hematoxylin-eosin. Apoptosis was measured by terminal uridine nick end-labeling assays. Cell proliferation and myofibroblast like differentiation were assayed by BrdU and alpha-smooth muscle actin immunofluorescence microscopy. Stromal matrix changes were documented by electron microscopy. RESULTS: Epithelial and stromal cell apoptosis around the ICRS implanted and control group 1 eyes peaked at 12 hours, but continued for 72 hours. In ICRS-implanted eyes, epithelial and stromal proliferation was present at 12 and 24 hours, respectively, and peaked at 7 days and 72 hours, respectively. Some proliferation in the ICRS-implanted group continued through the 6-month follow-up, and myofibroblast-like cells differentiated one to three months after ICRS implantation. The segments rotated within the stroma as the limbal inferior angle approached the epithelium. CONCLUSIONS: Wound healing after ICRS implantation in hen corneas was similar to that of other corneal surgical wounds in stages. However, there were some specific features related to the small size of the epithelial wound and the device permanently implanted inside the cornea. PMID- 25744329 TI - Magnetic resonance imaging in congenital Brown syndrome. AB - AIMS: Our aim was to elucidate the etiology of Brown syndrome by evaluating the trochlea position, morphologic characteristics of the extraocular muscles including superior oblique muscle/tendon complex, and the presence of the cranial nerves (CN) III, IV, and VI using magnetic resonance imaging (MRI) in eight patients with unilateral congenital Brown syndrome and one patient with bilateral congenital Brown syndrome. METHODS: Nine consecutive patients diagnosed with congenital Brown syndrome had a comprehensive ocular examination and MRI for the CN III, CN VI, and the extraocular muscles. Five of the nine patients underwent additional high resolution MRI for CN IV. The distance from the annulus of Zinn to the trochlea was measured. RESULTS: Normal sized CN III, IV, and VI, as well as all extraocular muscles, could be identified bilaterally in all patients with available MRI. The distance from the annulus of Zinn to the trochlea was the same in both eyes. CONCLUSIONS: The findings for our patients, particularly in those who underwent additional high resolution MRI, did not provide evidence of a lack of CN IV as a cause of Brown syndrome. PMID- 25744330 TI - Macular pigment optical density measurements by one-wavelength reflection photometry--influence of cataract surgery on the measurement results. PMID- 25744331 TI - Plasma levels of amyloid beta and other proinflammatory mediators in patients with age-related macular degeneration. AB - PURPOSE: To investigate the plasma levels of amyloid beta (Abeta) and select inflammatory mediators in patients with various stages of AMD compared to that of age-matched controls, and discern a relationship to disease severity. METHODS: Plasma samples were obtained from AMD subjects at various stages of disease-early (drusen only), geographic atrophy (GA), neovascular AMD (CNV)-and from controls of similar age without AMD. Samples were analyzed using a commercially available ELISA kit (sixteen cytokines) or LC/MS/MS (Abeta isotypes). Descriptive statistics were compiled on all analytes. Analysis of covariance (ANCOVA) was conducted to compare each analyte across AMD groups while adjusting for sex and age of the patients, and in comparison to the control group. Receiver operating characteristics plots were generated for the strongest predictor variables. RESULTS: Levels of alternative spliced CC3 proteins were significantly different between controls and CNV groups (p < 0.05), with median levels almost twice higher in CNV than in controls. There was an increasing trend for plasma levels of Alphabeta isotypes across AMD progressive stages (p values ranged from 0.052 to 0.0012) (ANCOVA). When adjusted for multiple comparisons analysis, plasma Abeta 1-42 levels, and its ratio with Abeta 1-40 were the most significantly associated with late AMD stages. Consistently with the ANCOVA results for Alphabeta isotypes, the ROC curve showed a moderate prediction (AUC = - ~ 0.78) of AMD vs control using the Abeta 1-42 isotype. CONCLUSION: Plasma Abeta 1-42 may have utility as a systemic biomarker for AMD. PMID- 25744332 TI - Corneal regeneration after femtosecond laser small-incision lenticule extraction: a prospective study. AB - PURPOSE: To evaluate the morphologic changes of corneal after small incision lenticule extraction (SMILE) using the Heidelberg Retina Tomograph III (HRT III)/Rostock Cornea Module confocal microscope and three-dimensional optical coherence tomography (3D-OCT). METHODS: Thirty eyes of 30 patients who underwent SMILE for the correction of myopia and myopic astigmatism in this study. Morphologic modifications of corneal architecture and the density of corneal subbasal nerve were evaluated prior to SMILE and 7 days, 1, 3, and 6 months after SMILE by in-vivo confocal microscopy (IVCM) and 3D-OCT. RESULTS: The corneal epithelium morphology showed no particular changes during the entire 6-month examination period. Subbasal nerve density recovered to preoperative levels within 3 months after SMILE (P > 0.05). On the interface layer, intense keratocyte activity was noted in all eyes after SMILE. The corneal fibrotic tissues on the interface layer diminished with time, but the persistence of brightly reflective particles still existed. No particular change between preoperative and postoperative corneal endothelium. The incision margin of SMILE had the appearance of a less clearly identified fibrotic scar with epithelial plug. CONCLUSIONS: IVCM and 3D-OCT analysis showed that there is a low-level corneal wound-healing response after SMILE procedure in the early postoperative period. Subbasal nerve regeneration is recovered at the third month, but the reflective particles elevated up to the sixth month. PMID- 25744333 TI - Retinal sensitivity is a valuable complementary measurement to visual acuity--a microperimetry study in patients with maculopathies. AB - PURPOSE: To evaluate changes in macular sensitivity, as measured with microperimetry, among patients with maculopathy and stable visual acuity (VA). METHODS: Macular sensitivity was assessed using the Spectral OCT/SLOTM microperimetry (OCT/SLO, Optos Plc., Dunfermline, UK) in 25 eyes (16 patients) with maculopathy and stable VA (<5 letters change in ETDRS score) at two consecutive clinic visits. To take the limits of the test-retest repeatability of the OCT/SLO into account, coefficient of repeatability (CoR) was employed to estimate the probability of the sensitivity changes being secondary to measurement noise. RESULTS: The point sensitivity changes were statistically significant (Wilcoxon signed-rank test, P < 0.001). Seventy-seven points (11 %) out of a total of 700 sensitivity points had a genuine sensitivity change, with a mean increase of 8.6 +/- 2.6 dB in 35 points and a mean decrease of 7.9 +/- 2.2 dB in 42 points. CONCLUSIONS: Point-to-point change in macular sensitivity can be used as a biomarker of changes in disease activity in patients with maculopathy, and can be more accurate than either mean sensitivity or BCVA in detection of changes in macular function. The measurement variability should be considered when observing the local sensitivity changes. PMID- 25744334 TI - Multimodal assessment of choroideremia patients defines pre-treatment characteristics. AB - PURPOSE: Choroideremia (CHM) is a X-chromosomal disorder leading to blindness by progressive degeneration of choroid, retinal pigment epithelium (RPE), and retinal neurons. A current clinical gene therapy trial (NCT01461213) showed promising safety and efficacy data in a carefully selected patient population. The present study was performed to shed light on pre-treatment characteristics of a larger cohort of CHM patients using a high resolution multi-modal approach. METHODS: In a retrospective cross-sectional study, data from 58 eyes of 29 patients with clinically confirmed CHM were analysed including best-corrected visual acuity (BCVA), refractive error, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), perimetry, and tonometry. Residual retinal volume, area of residual RPE, and foveal thickness were quantified to further define natural disease progression and assess symmetry. RESULTS: We evaluated 98 data points of BCVA [0.34 +/- 0.06 (logMAR); mean +/- 95 % confidence interval], 80 of IOP (14.6 +/- 0.6 mmHg), and 98 of refraction ( 2.16 +/- 1.08 spherical equivalent). Visual fields (n = 76) demonstrated variable degrees of concentric constriction (54 % <10 degrees , 25 % 10-30 degrees , 21 % >30 degrees ). Mean residual RPE area on FAF (n = 64) measured 8.47 +/- 1.91 mm(2) (range 0.30-38.5 mm(2)), while mean neuroretinal volume (n = 42) was found to be 1.76 +/- 0.12 mm(3). Age at examination was exponentially associated with BCVA, while logarithmic functions best described progressive loss of retinal area and volume. A high degree of left to right symmetry was found in all modalities with structural markers showing the best correlation (r (2) area = 0.83; r (2) volume = 0.75). CONCLUSION: Analysis of these widely available clinical data defines the natural disease characteristics of a relevant patient population eligible for gene therapeutic intervention. In the wake of preliminary reports on safety and efficacy of CHM gene therapy (NCT01461213), this multi modal assessment of a cohort of CHM patients provides important evidence of the natural rate of disease progression and degree of symmetry between eyes. PMID- 25744335 TI - Pigment epithelial tears after ranibizumab injection in polypoidal choroidal vasculopathy and typical age-related macular degeneration. AB - PURPOSE: The purpose of the study was to compare the rates and characteristics of retinal pigment epithelial (RPE) tears between typical exudative age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV) after injection of intravitreal ranibizumab (IVR). METHODS: In total, 836 eyes from 784 patients with exudative AMD treated with IVR were analyzed. The presence, type, size, and height of pigment epithelial detachment (PED) in OCT before injection were evaluated, and the occurrence rate of RPE tears within three months of injection between tAMD and PCV was compared. RESULTS: In total, 515 eyes (61.6 %) had tAMD and 321 eyes (38.4 %) were diagnosed as PCV. RPE tears developed in 18 eyes (3.5 %) in the tAMD group, while only two eyes (0.62 %) were associated with PCV (p = 0.009, Chi-square test). Eleven of the eighteen eyes with RPE tears in tAMD had fibrovascular PED with contractile neovascular tissue under the surface of the RPE and a cleft at baseline. Two eyes with RPE tears in PCV showed large hemorrhagic PED before presenting with an RPE tear. CONCLUSIONS: RPE tears after IVR were significantly less common in PCV than in tAMD. The different characteristics of RPE tears between the two disease entities suggest differences in the pathogenesis underlying the event. PMID- 25744336 TI - Chronic Chagas disease with advanced cardiac complications in Japan: Case report and literature review. AB - Due to the unprecedented recent increases in global migration, Chagas disease has become a global health threat and its epidemiology has drastically changed. Here we describe the first case in Japan of benznidazole treatment for chronic Chagas disease characterized by advanced cardiac complications. A 55-year-old Japanese Brazilian woman who had previously presented with chronic heart failure was diagnosed as having Chagas disease and treated with benznidazole to prevent aggravation of her cardiac complications. However, benznidazole administration was stopped on day 56 due to severe drug-induced peripheral neuritis. Sixteen months later, her serologic test for Trypanosoma cruzi is still positive and she is being followed regularly by cardiology. Despite an estimated prevalence of over 4000 cases in Japan, only a few cases of Chagas disease have been reported. A Medline search revealed only 7 cases identified between 1995 and 2014 in Japan: in 6 cases, complications of chronic Chagas disease were apparent at the time of presentation, and sudden death occurred in 2 of these cases due to cardiac complications. This clinical case and literature review re-emphasize the urgent need to establish a surveillance network and improve the diagnostic methods and treatment framework for Chagas disease in Japan. PMID- 25744337 TI - Immune-modulating activities of polysaccharides extracted from brown algae Hizikia fusiforme. AB - The immuno-modulating activities of seaweed (Hizikia fusiforme) extracts on murine macrophage and splenocyte were studied in vitro. Polysaccharide (HFP) exhibited the potential macrophage stimulating effects than water extract (HFW) such as NO production and enhanced pro-inflammatory cytokines on the Raw 264.7 cells and splenocytes. From the mono-sugar composition, HFP-associated fucose based on HFP of H. fusiforme acts as immune modulator. PMID- 25744338 TI - Necrotizing mycosis due to Verruconis gallopava in an immunocompetent patient. AB - Verruconis gallopava is a dematiaceous mould usually causing saprophytic infection in immunosuppressed host. Only a few cases have been published even in immunocompromised states. We present a rare case of pulmonary involvement in an immunocompetent patient with recurrent disease. The mid-aged woman had no evidence of any disease causing impaired immune response. Recurrent disease shows pulmonary infiltrates and symptoms of allergic bronchopulmonary mycosis. We describe an emerging pathogen that has been found in an immunocompetent host. Eradication was not possible despite the use of several different antifungal drugs. Further recurrence of infection in the described patient is probable. PMID- 25744339 TI - Symptoms, prevalence, and risk factors of overactive bladder in women in south India. PMID- 25744340 TI - Flow collision in early aortic ejection: an additional source of kinetic energy loss in patients with mitral prosthetic valves. PMID- 25744342 TI - EACVI/HFA Cardiac Oncology Toxicity Registry in breast cancer patients: rationale, study design, and methodology (EACVI/HFA COT Registry)- EURObservational Research Program of the European Society of Cardiology. AB - The goal of adjuvant anti-cancer therapies is cure with limited or no side effects, in particular long-term side effects with negative impact on quality of life. In the palliative setting disease control, quality of life and overall survival are important end points. Partly due to improvements in treatment, the population of cancer survivors is large and growing. However, anti-cancer drug related cardiotoxicity (ADRC) is the leading cause of treatment-associated mortality in cancer survivors. It is one of the most common post-treatment problems among 5- to 10-year survivors of adult cancer. This is particularly true for breast cancer, the most common cancer in women. The EACVI/HFA COT registry is designed for comprehensive data collection and evaluation of the current European practice in terms of diagnosis and management of ADRC in breast cancer patients. The COT registry will be carried out in two continuing phases, the pilot study phase involving 13 countries followed by the long-term registry in which all the 56 ESC countries will be invited to participate. With the COT registry, several critical information will be obtained: on predisposing factors for the development of ADRC, the rate of subclinical LV dysfunction and its transition to overt heart failure, the clinical impact and outcome of ADRC. PMID- 25744341 TI - Coronary dominance and prognosis in patients undergoing coronary computed tomographic angiography: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry. AB - AIMS: Coronary computed tomographic angiography (CCTA) has become an important tool for non-invasive diagnosis of coronary artery disease (CAD). Coronary dominance can be assessed by CCTA; however, the predictive value of coronary dominance is controversially discussed. The aim of this study was to evaluate the prevalence and prognosis of coronary dominance in a large prospective, international multicentre cohort of patients undergoing CCTA. METHODS AND RESULTS: The study population consisted of 6382 patients with or without CAD (47% females, 53% males, mean age 56.9 +/- 12.3 years) who underwent CCTA and were followed over a period of 60 months. Right or left coronary dominance was determined. Right dominance was present in 91% (n = 5817) and left in 9% (n = 565) of the study population. At the end of follow-up, outcome in patients with obstructive CAD (>50% luminal stenosis) and right dominance was similar compared with patients with left dominance [hazard ratio (HR) 0.46, 95% CI 0.16-1.32, P = 0.15]. Furthermore, no differences were observed for the type of coronary dominance in patients with non-obstructive CAD (HR 0.95, 95% CI 0.41-2.21, P = 0.8962) or normal coronary arteries (HR 1.04, 95% CI 0.68-1.59, P = 0.9). Subgroup analysis in patients with left main disease revealed an elevated hazard of the combined endpoint for left dominance (HR 6.45, 95% CI 1.66-25.0, P = 0.007), but not for right dominance. CONCLUSION: In our study population, survival after 5 years of follow-up did not differ significantly between patients with left or right coronary dominance. Thus, assessment of coronary vessel dominance by CCTA may not enhance risk stratification in patients with normal coronary arteries or obstructive CAD, but may add prognostic information for specific subpopulations. PMID- 25744343 TI - When motor congruency modulates immediate memory for objects. AB - In line with the embodied cognition view, some researchers have suggested that our capacity to retain information relies on the perceptual and motor systems used to interact with our environment (Barsalou, 1999; Glenberg, 1997). For instance, the language production architecture would be responsible for the retention of verbal materials such as a list of words (Acheson & MacDonald, 2009). However, evidence for the role of the motor system in object memory is still limited. In the present experiments, participants were asked to retain lists of objects in memory. During encoding, participants had to pantomime an action to grasp (Experiments 1A & 1B) or to use the objects (Experiment 2) that was either congruent or incongruent with the objects to be retained. The results showed that performing an incongruent action impaired memory performance compared to a congruent action. This suggests that motor affordances play a role during object retention. The results are discussed in light of the embodied cognition view. PMID- 25744344 TI - High-intensity double-pulse X-ray free-electron laser. AB - The X-ray free-electron laser has opened a new era for photon science, improving the X-ray brightness by ten orders of magnitude over previously available sources. Similar to an optical laser, the spectral and temporal structure of the radiation pulses can be tailored to the specific needs of many experiments by accurately manipulating the lasing medium, that is, the electron beam. Here we report the generation of mJ-level two-colour hard X-ray pulses of few femtoseconds duration with an XFEL driven by twin electron bunches at the Linac Coherent Light Source. This performance represents an improvement of over an order of magnitude in peak power over state-of-the-art two-colour XFELs. The unprecedented intensity and temporal coherence of this new two-colour X-ray free electron laser enable an entirely new set of scientific applications, ranging from X-ray pump/X-ray probe experiments to the imaging of complex biological samples with multiple wavelength anomalous dispersion. PMID- 25744345 TI - Angiotensin-converting enzymes modulate aphid-plant interactions. AB - Angiotensin-converting enzymes (ACEs) are key components of the renin-angiotensin system in mammals. However, the function of ACE homologs in insect saliva is unclear. Aphids presumably deliver effector proteins via saliva into plant cells to maintain a compatible insect-plant interaction. In this study, we showed that ACE modulates aphid-plant interactions by affecting feeding behavior and survival of aphids on host plants. Three ACE genes were identified from the pea aphid Acyrthosiphon pisum genome. ACE1 and ACE2 were highly expressed in the salivary glands and are predicted to function as secretory proteins. The ACE2 transcript level decreased in aphids fed on artificial diet compared with aphids fed on Vicia faba. The knockdown of the expression of each ACE by RNAi failed to affect aphid survival. When ACE1 and ACE2 were simultaneously knocked down, aphid feeding was enhanced. Aphids required less time to find the phloem sap and showed longer passive ingestion. However, the simultaneous knockdown of ACE1 and ACE2 resulted in a higher mortality rate than the control group when aphids were fed on plants. These results indicated that ACE1 and ACE2 function together to modulate A. pisum feeding and survival on plants. PMID- 25744346 TI - Intraoperative functional mapping and monitoring during glioma surgery. AB - Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient's neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery. PMID- 25744348 TI - Pathology and genetics of diffuse gliomas in adults. AB - The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a presumable developmental tree of CNS. A four-tiered WHO grading scheme has been successfully applied to a spectrum of diffusely infiltrative astrocytomas, but it is not fully applicable to other gliomas, including oligodendrogliomas and ependymomas. Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion. These genetic alterations are clinically significant in terms of the response to treatment(s) and/or the prognosis. It is, thus, rational that future classification of gliomas should be based on genotypes, rather than phenotypes, although the genetic features of each tumor are not sufficiently understood at present to draw a complete map of the gliomas, and genetic testing is not yet available worldwide, particularly in Asian and African countries. This review summarizes the current concepts of the WHO classification, as well as the current understanding of the major genetic alterations in glioma and the potential use of these alterations as diagnostic criteria. PMID- 25744347 TI - Pathology and molecular genetics of meningioma: recent advances. AB - Meningiomas are the most common intracranial primary neoplasm in adults. Although the spectrum of clinical and molecular genetic issues regarding meningiomas remains undefined, novel genetic alterations that are associated with tumor morphology, malignancy, or location have recently been discovered. This review focuses on recent advances in understanding of the heterogenous pathology of meningiomas, particularly on associations between the clinical, histological, etiological, epidemiological, and molecular genetical aspects of the neoplasm. PMID- 25744349 TI - Dose-dense temozolomide: is it still promising? AB - Glioblastoma (GBM) has proven to be incurable despite recent progress on its standard of care using temozolomide (TMZ) as the main trunk of initial therapy for newly diagnosed GBM. One of the main reasons accounting for the dismal prognosis is attributed to lack of active therapeutic regimens at recurrence. Since TMZ is the most active cytotoxic agent against GBM, and the standard dosing of TMZ has shown favorable safety profile in clinical trials, re-challenge with TMZ in increased dose density schedules for recurrent tumors that have evaded from prior standard TMZ therapy appears to be a rational approach and has been intensively exploited. A number of phase II clinical trials using different alternating scheduling of dose-dense TMZ (ddTMZ) have shown superior efficacy over the standard TMZ or historical controls with other alkylating agents including nitrosoureas and procarbazine. One ddTMZ schedule, consisting of a 21 days on/7-days off regimen was applied to newly-diagnosed GBM as the adjuvant monotherapy after completion of combined radiation and TMZ and failed to demonstrate survival benefit in a large phase III trial (RTOG 0525). Thus its role in TMZ-pretreated, recurrent GBM should be carefully pursuit in randomized trials, e.g., planned JCOG 1308 trial comparing a 7-days on/7-days off ddTMZ regimen used upfront at the first relapse followed by bevacizumab on progression versus bevacizumab alone, investigating whether insertion of ddTMZ prior to bevacizumab could bestow better outcome in the recurrent setting. In this article, mode of action, past trials, and future directions of ddTMZ therapy are discussed. PMID- 25744350 TI - Pathophysiology, diagnosis, and treatment of radiation necrosis in the brain. AB - New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient's quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain. PMID- 25744351 TI - Elevated cell invasion in a tumor sphere culture of RSV-M mouse glioma cells. AB - Cancer stem cells (CSCs) are the sole population possessing high self-renewal activity in tumors, with their existence affecting tumor recurrence. However, the invasive activity of CSCs has yet to be fully understood. In this article, we established a tumor sphere culture of RSV-M mouse glioma cells (RSV-M-TS) and evaluated their migration and invasion activities. Histological analysis of a tumor formed by cranial injection of the RSV-M-TS cells showed highly invasive properties and similarities with human malignant glioma tissues. When the migration activity of both RSV-M and RSV-M-TS cells were compared by intracranial injection, rapid migration of RSV-M-TS cells was observed. To confirm the invasive capabilities of RSV-M-TS cells, a three-dimensional collagen invasion assay was performed in vitro using RSV-M, RSV-M-TS, and RSV-M-TS cells cultured with medium containing serum. RSV-M and RSV-M-TS cultured with medium containing serum for 8 days indicated low migration activity, while moderate invasion activity was observed in RSV-M-TS cells. This activity was further enhanced by incubation with medium containing serum overnight. To identify the genes involved in this invasion activity, we performed quantitative polymerase chain reaction (PCR) array analysis of RSV-M and RSV-M-TS cells. Of 84 cancer metastasis-related genes, up-regulation was observed in 24 genes, while 4 genes appeared to be down regulated in RSV-M-TS cells. These results suggest that the enhanced invasive activity of glioma sphere cells correlates with a number of tumor metastasis related genes and plays a role in the dissemination and invasion of glioma cells. PMID- 25744352 TI - The vidian canal: radiological features in Japanese population and clinical implications. AB - The vidian canal (VC), a bony tunnel in which the vidian artery and nerve pass, has been widely known as an important landmark to identify the anterior genu of the petrous carotid artery (AGPCA) especially during lateral extended endoscopic endonasal approachs (LEEEAs). The objectives of this study in the Japanese population are to describe the radiological anatomic features and relationships between VC and its surrounding structures, and discuss the clinical implications. We studied 231 high-resolution computed tomography (CT) scans with a slice thickness of 0.5 mm. All the patients had known sellar or parasellar pathologies but without any involvement of VC. The following VC-related parameters were examined: its length, relationship to AGPCA, course from the pterygopalatine fossa to the carotid canal, its position relative to the medial pterygoid plate and pneumatization pattern of the sphenoid sinus. Mean length of VC is 14.6 mm. There is more tendency of straight-running VC compared to other populations. VC locates infero-lateral to AGPCA in all the cases. The protrusion of VC and the paraclival carotid artery to the sphenoid sinus, as well as well-pneumatization of the sinus is also observed more frequently in almost a half of the population. Surgeons who perform LEEEAs in Japanese patients must know these anatomical features. The characteristics particular to Japanese populations may facilitate better identification of VC and exposure to AGPCA intraoperatively. PMID- 25744353 TI - Evaluation of neuronal protective effects of xanthine oxidoreductase inhibitors on severe whole-brain ischemia in mouse model and analysis of xanthine oxidoreductase activity in the mouse brain. AB - Global cerebral ischemia and reperfusion (I/R) often result in high mortality. Free radicals play an important role in global cerebral I/R. Xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, have been reported to protect tissues from damage caused by reactive oxygen species (ROS) by inhibiting its production through XOR inhibition. The recently introduced XOR inhibitor febuxostat, which is a more potent inhibitor than allopurinol, is expected to decrease free radical production more effectively. Here, we analyzed the effects of allopurinol and febuxostat in decreasing global severe cerebral I/R damage in mice. Mice were divided into three groups: a placebo group, an allopurinol group, and a febuxostat group. Pathological examinations, which were performed in each group in the CA1 and CA2 regions of the hippocampus 4 days after I/R surgery, revealed that there was a decrease in the number of neuronal cells in the 14-min occlusion model in both regions and that drugs that were administered to prevent this damage were not effective. The enzymatic activity was extremely low in the mouse brain, and XOR could not be detected in the nonischemic and ischemic mice brains with western blot analyses. Thus, one of the reasons for the decreased effectiveness of XOR inhibitors in controlling severe whole-brain ischemia in a mouse model was the low levels of expression of XOR in the mouse brain. PMID- 25744355 TI - Nitrogenated holey two-dimensional structures. AB - Recent graphene research has triggered enormous interest in new two-dimensional ordered crystals constructed by the inclusion of elements other than carbon for bandgap opening. The design of new multifunctional two-dimensional materials with proper bandgap has become an important challenge. Here we report a layered two dimensional network structure that possesses evenly distributed holes and nitrogen atoms and a C2N stoichiometry in its basal plane. The two-dimensional structure can be efficiently synthesized via a simple wet-chemical reaction and confirmed with various characterization techniques, including scanning tunnelling microscopy. Furthermore, a field-effect transistor device fabricated using the material exhibits an on/off ratio of 10(7), with calculated and experimental bandgaps of approximately 1.70 and 1.96 eV, respectively. In view of the simplicity of the production method and the advantages of the solution processability, the C2N-h2D crystal has potential for use in practical applications. PMID- 25744356 TI - Managing hyperglycemia and diabetes in patients receiving enteral feedings: A health system approach. AB - Evidence of poor outcomes in hospitalized patients with hyperglycemia has led to new and revised guidelines for inpatient management of diabetes. As providers become more aware of the need for better blood glucose control, they are finding limited guidance in the management of patients receiving enteral nutrition. To address the lack of guidelines in this population, Duke University Health System has developed a consistent practice for managing such patients. Here, we present our practice strategies for insulin use in patients receiving enteral nutrition. Essential factors include assessing the patients' history of diabetes, hyperglycemia, or hypoglycemia and timing and type of feedings. Insulin practices are then designed to address these issues keeping in mind patient safety in the event of abrupt cessation of nutrition. The outcome of the process is a consistent and safe method for glucose control with enteral nutrition. PMID- 25744357 TI - "The Keepers of Stories": Personal Growth and Wisdom Among Oncology Nurses. AB - This study examined whether oncology nurses experience personal growth and wisdom as a result of caring for patients. Using a grounded theory approach, 30 nurses were interviewed regarding their experiences caring for cancer patients. Every nurse in this sample cited at least one example of growth and wisdom. Subthemes of personal growth were largely consistent with the documented domains of posttraumatic growth and included appreciation of life, new perspective on life, relating to others, spiritual/religious growth, and personal strength. Subthemes of wisdom were more varied, reflecting the diversity of this construct in the context of nursing. Benevolence arose as a unifying theme between personal growth and wisdom, with subthemes centering on altruistic attitudes and behavior toward patients and the greater community. Findings suggest that nurses develop personal growth, wisdom, and benevolence as a result of the emotional connections formed with patients and the subsequent struggle to cope with their loss. This process accords well with findings in other populations experiencing trauma and adversity directly. PMID- 25744358 TI - Signaling mechanisms in pattern-triggered immunity (PTI). AB - In nature, plants constantly have to face pathogen attacks. However, plant disease rarely occurs due to efficient immune systems possessed by the host plants. Pathogens are perceived by two different recognition systems that initiate the so-called pattern-triggered immunity (PTI) and effector-triggered immunity (ETI), both of which are accompanied by a set of induced defenses that usually repel pathogen attacks. Here we discuss the complex network of signaling pathways occurring during PTI, focusing on the involvement of mitogen-activated protein kinases. PMID- 25744360 TI - Casein Kinase 2 Negatively Regulates Abscisic Acid-Activated SnRK2s in the Core Abscisic Acid-Signaling Module. AB - SnRK2 kinases, PP2C phosphatases and the PYR/PYL/RCAR receptors constitute the core abscisic acid (ABA) signaling module that is thought to contain all of the intrinsic properties to self-regulate the hormone signal output. Here we identify Casein Kinase (CK)2 as a novel negative regulator of SnRK2. CK2 phosphorylates a cluster of conserved serines at the ABA box of SnRK2, increasing its binding to PP2C and triggering protein degradation. Consequently, CK2 action has implications on SnRK2 protein levels, as well as kinase activity and its response to abiotic stimuli. PMID- 25744361 TI - Development of radioiodine-labeled 4-hydroxyphenylcysteamine for specific diagnosis of malignant melanoma. AB - INTRODUCTION: A specific diagnosis for melanoma is strongly desired because malignant melanoma has poor prognosis. In a previous study, although radioiodine 125-labeled 4-hydroxyphenyl-L-cysteine ((125)I-L-PC) was found to have good substrate affinity for tyrosinase enzyme in the melanin metabolic pathway, (123/131)I-L-PC had insufficient substrate affinity for tyrosinase to diagnose melanoma. In this study, we synthesized 4-hydroxyphenylcysteamine (4-PCA) and developed a novel radioiodine-125-labeled 4-hydroxyphenylcysteamine ((125)I-PCA) to increase affinity for the melanin biosynthesis pathway. METHODS: 4-PCA was separated with 2-hydroxyphenylcysteamine (2-PCA), which is an isomer of 4-PCA, and was examined using melting point, proton nuclear magnetic resonance, mass spectrometry and elemental analysis. (125)I-PCA was prepared using the chloramine T method under no-carrier added conditions. We performed biodistribution experiments using B16 melanoma-bearing mice using (125)I-PCA, (125)I-L-PC, (125)I alpha-methyl-L-tyrosine, (123)I-m-iodobenzylguanidine and (67)Ga-citrate. In vitro assay was performed with B16 melanoma cells, and affinity for tyrosinase, DNA polymerase and amino acid transport was evaluated using phenylthiourea, thymidine, ouabine and L-tyrosine inhibitor. In addition, partition coefficients of (125)I-PCA were evaluated. RESULTS: In the synthesis of 4-PCA, analysis values did not differ between calculated and reported values, and 4-PCA was separated from 2-PCA at high purity. In biodistribution experiments, (125)I-PCA was accumulated and retained in B16 melanoma cells when compared with (125)I-L-PC. (125)I-PCA showed the highest values at 60 min after radiotracer injection in melanoma-to-muscle ratios, melanoma-to-blood ratios and melanoma-to-skin ratios. Accumulation of (125)I-PCA was significantly inhibited by phenylthiourea and thymidine. Partition coefficients of (125)I-PCA were lower than those of N isopropyl-p-[(123)I]iodoamphetamine and were not significantly different from (125)I-L-PC. CONCLUSIONS: (125)I-PCA is a better substrate for tyrosinase and DNA polymerase and has higher uptake and longer retention in B16 melanoma cells when compared with (125)I-L-PC. Therefore, (123/131)I-PCA has good potential for diagnosis for malignant melanoma. ADVANCE IN KNOWLEDGE: (125)I-PCA will be a specific diagnosis tool for malignant melanoma. IMPLICATIONS FOR PATIENT CARE: (123/131)I-PCA has good potential for the diagnosis of malignant melanoma when compared with other SPECT tracers, as well as anti-melanoma chemotherapeutic drugs. PMID- 25744362 TI - Chewing xylitol gum improves self-rated and objective indicators of oral health status under conditions interrupting regular oral hygiene. AB - Chewing xylitol gum provides oral health benefits including inhibiting Streptococcus mutans plaque. It is thought to be especially effective in conditions where it is difficult to perform daily oral cleaning. Our study aim was to determine the effects of chewing xylitol gum on self-rated and objective oral health status under a condition interfering with oral hygiene maintenance. A randomized controlled intervention trial was conducted on 55 healthy >= 20-year old men recruited from the Japan Ground Self Defense Force who were undergoing field training. Participants were randomly assigned to a test group (chewing gum; n = 27) or a control group (no gum; n = 28) and the researchers were blinded to the group assignments. The Visual Analog Scale (VAS) scores of oral conditions subjectively evaluated oral health, and the stimulated salivary bacteria quantity objectively evaluated oral health 1 day before field training (baseline) and 4 days after the beginning of field training (follow-up). VAS scores of all three oral conditions significantly increased in the control group (malodor: p < 0.001; discomfort: p < 0.001; dryness: p < 0.001), but only two VAS scores increased in the test group (malodor: p = 0.021; discomfort: p = 0.002). The number of salivary total bacteria significantly increased in the control group (p < 0.01), while no significant change was observed in the test group (p = 0.668). Chewing xylitol gum positively affects self-rated and objective oral health status by controlling oral hygiene under conditions that interfere with oral hygiene maintenance. PMID- 25744359 TI - Focusing on the focus: what else beyond the master switches for polar cell growth? AB - Cell polarity, often associated with polarized cell expansion/growth in plants, describes the uneven distribution of cellular components, such as proteins, nucleic acids, signaling molecules, vesicles, cytoskeletal elements, and organelles, which may ultimately modulate cell shape, structure, and function. Pollen tubes and root hairs are model cell systems for studying the molecular mechanisms underlying sustained tip growth. The formation of intercalated epidermal pavement cells requires excitatory and inhibitory pathways to coordinate cell expansion within single cells and between cells in contact. Strictly controlled cell expansion is linked to asymmetric cell division in zygotes and stomatal lineages, which require integrated processes of pre-mitotic cellular polarization and division asymmetry. While small GTPase ROPs are recognized as fundamental signaling switches for cell polarity in various cellular and developmental processes in plants, the broader molecular machinery underpinning polarity establishment required for asymmetric division remains largely unknown. Here, we review the widely used ROP signaling pathways in cell polar growth and the recently discovered feedback loops with auxin signaling and PIN effluxers. We discuss the conserved phosphorylation and phospholipid signaling mechanisms for regulating uneven distribution of proteins, as well as the potential roles of novel proteins and MAPKs in the polarity establishment related to asymmetric cell division in plants. PMID- 25744363 TI - Myelodysplastic syndrome precedes the onset of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. AB - Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical synovitis predominantly involving the wrists, and is associated with marked pitting edema of the dorsum of the hands. Although the etiology of RS3PE syndrome is still unknown, several putative associations with malignancies and hematological disorders have been reported. Myelodysplastic syndrome (MDS) is characterized by infective hematopoiesis with possible transformation to leukemia; however, an association between RS3PE syndrome and MDS has been rarely reported. Here, we describe a 67-year-old man with MDS with refractory anemia who developed RS3PE syndrome 3 months after the diagnosis of MDS. The patient presented with polyarthritis with pitting edema at the dorsum of the hands, the elevated serum levels of C-reactive protein and a proinflammatory cytokine, interleukin-6, and the elevated plasma levels of vascular endothelial growth factor (VEGF). VEGF has been shown to be involved in the pathogenesis of RS3PE syndrome. Treatment with low doses of corticosteroids resulted in the regression of polyarthritis and pitting edema of the dorsum of the hands, as well as a reduction in the elevated levels of plasma VEGF. Partial resolution of refractory anemia was also observed with steroid therapy. In summary, RS3PE syndrome developed shortly after MDS was identified in this patient. The sequence of clinical events suggests that MDS-mediated immunological abnormalities including inflammatory cytokine induction may be responsible for the association between MDS and RS3PE syndrome. Patients with RS3PE syndrome should be screened for hematological disorders that promote proinflammatory mediators. PMID- 25744364 TI - Cost-effective organization of an institutional human cancer biobank in a clinical setting: CRO-Biobank experience toward harmonization. AB - This report describes the organization of the Biobank of the CRO Aviano National Cancer Institute, Aviano (CRO- Biobank), Italy, implemented as a structured facility dedicated to collecting human biological samples. It describes a particular disease-specific biobank and the integration of a research biobank in a clinical setting. The CRO-Biobank's mission is rooted in supporting and implementing cancer research, with its main focus on optimizing technical and quality processes, while also investigating ethical, legal and IT topics.The CRO Biobank has implemented processes aimed at guaranteeing the safety of the providers, protecting patient privacy and ensuring both the traceability and quality of its samples. Our 8 years of experience allow us to offer insights and useful suggestions that may solve theoretical and practical issues that can arise when starting up new biobanks or developing existing biobanks further. PMID- 25744365 TI - Single nucleotide polymorphisms in VTI1A gene contribute to the susceptibility of Chinese population to non-small cell lung cancer. AB - BACKGROUND: Genome-wide association studies (GWAS) have determined a new single nucleotide polymorphism (SNP) called VTI1A (rs7086803) that induces lung cancer susceptibility in nonsmoking women in Asia. This study aimed to evaluate the association between the VTI1A gene and the susceptibility of Chinese patients to lung cancer; it was also conducted to investigate the relationship between VTI1A SNP and adiponectin receptor 1 expression. METHODS: A total of 887 subjects were enrolled in this study. VTI1A (rs7086803) genotypes were determined by genotyping. Overall survival (OS) was evaluated using Kaplan-Meier analysis with a log-rank test. RESULTS: Multivariate regression analysis results indicated that the AA genotype of VTI1A (rs7086803) polymorphism was associated with an increased risk of developing non-small cell lung carcinoma (NSCLC) compared with the GG genotype (AA vs. GG: odds ratio [OR] = 2.020; 95% confidence interval [95% CI], 1.033-3.949, p = 0.037). The AA genotype of VTI1A (rs7086803) in smokers predicted significantly shorter OS (median survival time [MST]: AA 9.8 months, AG 19.3 months, GG 12.2 months, p = 0.017). Adiponectin receptor 1 expression in tumor tissues with the AA genotype was significantly lower than that for other genotypes (mean rank: AA 18.55, AG 25, GG 45.76, p = 0.001). CONCLUSIONS: The presence of the allele A of VTI1A (rs7086803) may be the allele contributing to the risk of lung cancer susceptibility in Chinese population. Smoking lung cancer patients with the AA genotype of VTI1A gene (rs7086803) had a poor survival rate. Adiponectin receptor 1 expression may be correlated with the susceptibility of the allele A of VTI1A. PMID- 25744366 TI - Right Ventricular Outflow Tract Velocity Time Integral Determination in 570 Healthy Children and in 52 Pediatric Atrial Septal Defect Patients. AB - Determination of the right ventricular outflow tract velocity time integral (RVOT VTI) is an important part of the noninvasive investigation of pulmonary blood flow in adults; however, age-related pediatric reference data are lacking. We examined growth-related changes of RVOT VTI values in children and the predictive value of RVOT VTI values in identifying enhanced pulmonary blood flow in children with secundum type atrial septal defect (ASD). A prospective study was conducted in a group of 570 healthy children and 52 children with a moderate-sized to large ASD. We determined the effects of age, body length (BL), body weight (BW), and body surface area (BSA) on RVOT VTI values. The predictive value of normal values stratified for age, BW, BL, and BSA was tested in our 52 ASD children. RVOT VTI values ranged from mean 9.7 +/- 1.2 cm in neonates to 23.3 +/- 2.7 cm in children with 18 years of age and showed a positive correlation with age, BL, BSA, and BW. In our population, RVOT VTI z-scores showed a high specificity for detecting ASD patients (>97 %) with sensitivity up to 71 %. We provide normal ranges and calculated z-scores of pediatric RVOT VTI values. Normal RVOT VTI z-scores might be additional predictors in identifying increased pulmonary blood flow in patients with ASD. PMID- 25744367 TI - [Plastic reconstructive surgery and prefabrication of tissue in interdisciplinary complication management]. PMID- 25744368 TI - Vitamin D: Immuno-modulation and tuberculosis treatment. AB - Tuberculosis (TB) is a major global health problem and often coincides with vitamin D deficiency. High doses of vitamin D were widely used to treat TB during the pre-antibiotic era. Vitamin D exerts its action through vitamin D receptor (VDR), and VDR gene polymorphisms are associated with susceptibility or resistance to tuberculosis as well as sputum smear and culture conversion during anti-TB treatment. In-vitro studies have revealed that 1,25-dihydroxyvitamin D3 enhances innate immunity by increased expression of various antimicrobial peptides, including cathelicidin, and induction of autophagy of the infected cells thus restricts the intracellular growth of Mycobacterium tuberculosis in macrophages. On the other hand, vitamin D has been shown to suppress the pro inflammatory cytokine response and enhance the anti-inflammatory response. Supplementation with vitamin D in concert with treatment for TB may be beneficial with respect to minimizing the excessive tissue damage that occurs during the active stage of tuberculosis disease. Several clinical trials have evaluated vitamin D supplementation as an adjunct therapy in the treatment for tuberculosis. However, results are conflicting, owing to variations in dose regimens and outcomes. Further investigations are needed to find the optimal concentration of vitamin D for supplementation with standard anti-TB drugs to optimize treatment, which could help to effectively manage both drug-sensitive and drug-resistant tuberculosis. PMID- 25744369 TI - 3D pharmacophoric similarity improves multi adverse drug event identification in pharmacovigilance. AB - Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining. PMID- 25744371 TI - Single live cell TGF-beta signalling imaging: breast cancer cell motility and migration is driven by sub-populations of cells with dynamic TGF-beta-Smad3 activity. AB - BACKGROUND: Metastasis is a process where only a small subset of cells is capable of successfully migrating to and propagating at secondary sites. TGF-beta signalling is widely known for its role in cancer metastasis and is associated with cell migration in whole cell populations. FINDINGS: We extend these findings by investigating the role of TGF-beta signalling in promoting migration and motility by imaging the signalling activity in live, individual MDA-MB-231 cancer cells utilizing a novel Smad3 Td-Tomato reporter adenovirus. Here we find that not all MDA-MB-231 cancer cells have similar TGF-beta mediated Smad3 transcription activity and display at least two distinct migratory populations. Importantly, Smad3 activity was significantly higher within migratory cells compared to non-migrated cells in wound healing and transwell assays. Furthermore, time-lapse experiments showed that MDA-MB-231 cells displaying Smad3 activity moved faster and a greater distance compared to cells not displaying Smad3 reporter activity. Interestingly, despite being more motile than cells with undetectable levels of Smad3 activity, high Smad3 activity was detrimental to cell motility compared to low and medium level of Smad3 activity. CONCLUSIONS: We have developed a method enabling real-time visualization of TGF-beta signalling in single live cells. Breast cancer cell motility and migration is driven by sub populations of cells with dynamic TGF-beta-Smad3 activity. Those sub-populations may be responsible for tumor invasion and metastasis. PMID- 25744372 TI - Silodosin causes impaired ejaculation and enlargement of seminal vesicles in sexually active men treated for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. AB - OBJECTIVE: To evaluate the sexual side effects including ejaculation after silodosin treatment in potent men with regular sexual activity, as well as possible alterations in seminal vesicle volume. METHODS: Sexually active patients aged >= 40 years with moderate to severe lower urinary tract symptoms were enrolled prospectively. International Prostate Symptom Score (IPSS) and Quality of Life (QoL), International Index of Erectile Function (IIEF) questionnaire, ejaculation frequency, and seminal vesicle volumes measured by transrectal ultrasonography were determined at study entry, and silodosin 8 mg/d was prescribed for 4 weeks. Alterations in IPSS-QoL, all domains of IIEF, ejaculation frequency, seminal vesicle volumes, and patient-reported side effects were evaluated after silodosin treatment. RESULTS: Thirty patients were included, and mean age was 56.7 +/- 6.9 years (44-70 years). IPSS-total, IPSS-storage, and IPSS voiding subscores and QoL were significantly improved after treatment. Despite a slight decrease in erectile function domain of IIEF (26.7 +/- 1.9 vs 22.9 +/- 7.5; P <.05), no significant change was determined for orgasmic functions, sexual desire, intercourse satisfaction, and overall satisfaction. Ninety percent of patients (27 of 30) had impaired ejaculation, and seminal vesicles were significantly enlarged at the end of treatment (8.1 +/- 6.4 vs 16.4 +/- 8.2 cc; P <.001). CONCLUSION: Impaired ejaculation is a common problem for sexually active men treated with silodosin, and this may result in the slight decrease in erectile functions. Enlargement of seminal vesicles may represent for the loss of seminal emission and accumulation of seminal vesicle secretion. Further studies are required for better clarifying the effects of silodosin on sexual functions including ejaculatory functions. PMID- 25744373 TI - Endothelial nitric oxide synthase gene polymorphism relationship with semen parameters and oxidative stress in infertile oligoasthenoteratozoospermic men. AB - OBJECTIVE: To assess endothelial nitric oxide synthase (eNOS) gene polymorphism relationship with semen parameters and oxidative stress in infertile oligoasthenoteratozoospermic (OAT) men. MATERIALS AND METHODS: Three hundred subjects were divided into healthy fertile men (n = 80) and infertile OAT men (n = 220). They were subjected to history taking, clinical examination, and semen analysis in addition to malondialdehyde and glutathione peroxidase estimation in seminal plasma. Polymorphisms of eNOS G894T and T786C genotypes in peripheral blood were identified by the polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Comparing infertile OAT men with fertile controls, eNOS genotype G894T demonstrated prevalence of 36.8% vs 50% for wild type (GG), 35.0% vs 47.5% for heterozygous type (GT), and 28.2% vs 2.5% for mutant homozygous type (TT). Compared with GG homozygotes, carriers with A allele exhibited >1.716-fold increased risk of OAT occurrence. Comparing infertile OAT men with fertile controls, eNOS genotype T786C demonstrated prevalence of 37.3% vs 51.3% for wild type (TT), 32.7% vs 45% for heterozygous type (TC), and 30% vs 3.7% for mutant type (CC) with significant differences. Compared with TT homozygotes, carriers with C allele exhibited >1.769-fold increased risk of OAT occurrence. G894T and T786C genotypes demonstrated significant negative correlation with sperm count, total sperm motility, sperm normal forms, and seminal glutathione peroxidase, and significant positive correlation with seminal malondialdehyde. G894T genotype demonstrated significant positive correlation with T786C genotype. CONCLUSION: There is a significant relationship between eNOS genotypes T786C, G894T polymorphisms with decreased sperm parameters and increased seminal oxidative stress. PMID- 25744374 TI - University of Toronto is criticised for study of homeopathy in ADHD. PMID- 25744370 TI - Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1. AB - BACKGROUND: No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction. METHODS: We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry. RESULTS: Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 * 10(-5)): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 * 10(-5)). Meta-analysis across all case-control cohorts resulted in p = 4.3 * 10(-8): the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971 A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 * 10(-6) for rs1799971-A/rs3778150-C and p = .79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 * 10( 8) for rs3823010). CONCLUSIONS: Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction. PMID- 25744379 TI - Aqueous phase nitric oxide detection by an amine-decorated metal-organic framework. AB - Selective and sensitive aqueous phase nitric oxide (NO) detection has been demonstrated by implementing an unsophisticated approach of ligand modulation in a porous, robust metal-organic framework (MOF). The detection is achieved through deamination by NO in an amine-decorated luminescent MOF. This is the first report of employing a physiologically stable, functionalized MOF as a NO sensor. PMID- 25744380 TI - Monoclonal antibody against Saint Louis encephalitis prM viral protein. AB - Saint Louis encephalitis virus belongs to Flavivirus genus; Flaviviridae family jointly with other medically important flaviviruses including dengue virus and West Nile virus. The biological properties and functions of prM flavivirus protein are under investigation due to its importance in the generation of infectious virion and host interactions. Monoclonal antibodies have become powerful tools in this approach. Also the use of monoclonal antibodies has been successfully applied for antigenic analysis, clinical diagnosis and treatments. Here, using an immunofluorescence assay we describe a monoclonal antibody (mAb 3D2) that uniquely recognizes native prM Saint Louis encephalitis virus protein expressed in either C6/36-HT or Vero cells. In conclusion, mAb3D2 has significant potential for use in (a) the diagnosis of infections caused by this virus and (b) therapeutic use to treat patients infected by this virus and fundamental research to understand the role of the prM in the Saint Louis encephalitis virus infectious process. PMID- 25744381 TI - Race/Ethnicity and the prevalence of thyrotoxicosis in young Americans. AB - BACKGROUND: Race/ethnicity may be a newly recognized risk factor for Graves' disease. OBJECTIVE: The aim of this study was to examine the prevalence of thyrotoxicosis by race/ethnicity in Americans aged 12-49 years using three National Health and Nutritional Examination Surveys (NHANES). METHODS: Data were analyzed from 17,939 participants in NHANES III (1988-1994), NHANES 1999-2002, and NHANES 2007-2010 with available thyroid function test results. Thyrotoxicosis was defined as a serum thyrotropin (TSH) of <=0.1 mIU/L or subjects taking methimazole or propylthiouracil, and overt thyrotoxicosis was defined as high serum thyroxine and a serum TSH of <=0.1 mIU/L. Logistic regression was performed accounting for the complex sampling design of NHANES, and the results from all three NHANES surveys were combined using a random-effects model. RESULTS: There were 75 study participants with point prevalent thyrotoxicosis, representing a pooled prevalence of 0.4% for Americans aged 12-49 years. Prevalent thyrotoxicosis was nearly three times more likely in non-Hispanic black subjects compared with non-Hispanic whites (OR=2.9 [CI 1.5-5.7]), while there was no difference between the prevalence of thyrotoxicosis in Mexican Americans compared to non-Hispanic whites (OR=1.2 [CI 0.6-2.4]; I2 for heterogeneity=0% for both). Among 27 patients with overt thyrotoxicosis, the odds ratio was 8.7 [CI 0.7 112.6] for non-Hispanic blacks and 4.6 [CI 0.4-59.3] for Mexican Americans compared with non-Hispanic whites. CONCLUSIONS: The results suggest there are race/ethnicity differences in the prevalence of thyrotoxicosis. Future studies should address whether these differences are due to heritable factors, environmental exposures, or a combination of both. PMID- 25744382 TI - The Burwell roadmap. AB - In January 2015 the current Secretary of the Department of Health and Human Services (HHS) outlined a bold initiative to shape the delivery of healthcare through a set of strategies aimed at improving the quality of care and reducing the growth of healthcare costs. The strategies include increasing payment incentives tied to higher value care, increasing care coordination and integration, and increasing access to information to guide patients and clinicians. Significantly, the proposal includes specific goals for alternative payment models and value-based payments for the first time in the history of the Medicare program. PMID- 25744383 TI - Circulating mesenchymal stem cells in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: This study examines the mobilization of mesenchymal stem cells (MSCs) in patients with hypertrophic cardiomyopathy (HCM) compared to healthy individuals. The pathogenesis of myocardial hypertrophy in HCM is not fully understood. MSCs are involved in the process of neovascularization, fibrosis, and ventricular wall remodeling. METHODS AND RESULTS: We included 40 patients with HCM and 23 healthy individuals. Using flow cytometry, we measured MSCs in peripheral blood, as a population of CD45-/CD34-/CD90+ cells and also as a population of CD45-/CD34-/CD105+ cells. The resulting MSC counts were expressed as percentages of the total cells. Patients with HCM were found to have a greater percentage of circulating CD45-/CD34-CD34-/CD90+ cells compared to controls (0.0041+/-0.005% vs. 0.0007+/-0.001%, respectively, P<.001). No significant difference in circulating CD45-/CD34-/CD105+ cells in the peripheral blood was found between HCM patients and controls (0.016+/-0.018% vs. 0.012+/-0.014%, respectively, P=.4). Notably, circulating CD45-/CD34-/CD90+ cells were positively correlated with left ventricular mass index (r=0.54, P<.001). CONCLUSIONS: Patients with HCM reveal an increased mobilization of MSCs compared to healthy individuals. Although further research is needed to reveal the clinical significance of our findings, our data open a new dimension in the pathophysiology of the disease and may indicate new future therapeutic possibilities. PMID- 25744384 TI - A lower pH value benefits regeneration of Trichosanthes kirilowii by somatic embryogenesis, involving rhizoid tubers (RTBs), a novel structure. AB - A new approach was established for the regeneration of Trichosanthes kirilowii from root, stem, and leaf explants by somatic embryogenesis (SE), involving a previously unreported SE structure, rhizoid tubers (RTBs). During SE, special rhizoids were first induced from root, stem, and leaf explants with average rhizoid numbers of 62.33, 40.17, and 11.53 per explant, respectively, on Murashige and Skoog (MS) medium (pH 4.0) supplemented with 1.0 mg/L 1 naphthaleneacetic acid (NAA) under dark conditions. Further, one RTB was formed from each of the rhizoids on MS medium (pH 4.0) supplemented with 20 mg/L thidiazuron (TDZ) under light conditions. In the suitable range (pH 4.0-9.0), a lower pH value increased the induction of rhizoids and RTBs. Approximately 37.77, 33.47, and 31.07% of in vivo RTBs from root, stem, and leaf explants, respectively, spontaneously developed into multiple plantlets on the same MS medium (supplemented with 20 mg/L TDZ) for induction of RTBs, whereas >95.00% of in vitro RTBs from each kind of explant developed into multiple plantlets on MS medium supplemented with 5.0 mg/L 6-benzylaminopurine (BAP). Morphological and histological analyses revealed that RTB is a novel type of SE structure that develops from the cortex cells of rhizoids. PMID- 25744385 TI - USP8/UBPy-regulated sorting and the development of sperm acrosome: the recruitment of MET. AB - The acrosome is a peculiar vacuole that at fertilization undergoes the acrosome reaction (AR), an event unique in the sperm life. Contents released promote sperm penetration through oocyte's investments; membranous components are involved in sperm-egg interaction/fusion. Therefore, both constituents play a role in fertilization. The biogenesis of this vacuole, however, has not been clarified yet; recently, it has been proposed as a novel lysosome-related organelle (LRO). Our research focuses on the involvement of the endosomal pathway in acrosomogenesis starting from the early phases. The trafficking sorted by USP8/UBPy, an endosomal regulator recently described as a compelling candidate for male fertility gene, was investigated in comparison to that of SP56, a marker of the biosynthetic pathway. Mouse spermatids were double/triple immunolabeled and examined by confocal microscopy. The contribution of the vesicular traffic assisted by the cortical microtubule array was also evaluated in nocodazole treated spermatids. USP8/UBPy-sorted cargo contributes early to acrosomogenesis and its trafficking is microtubule mediated. It was identified, through co immunoprecipitation/co-immunolocalization assays, that the membrane receptor MET, described herein for the first time in spermatids, as an USP8/UBPy-target substrate is delivered to the acrosome. MET and USP8/UBPy still colocalize in epididymal spermatozoa. Following the AR, MET and USP8/UBPy show a distinct fate. MET, in particular, translocates at the PAS, the post acrosomal segment known to harbor sperm-borne factors involved in oocyte activation. Overall, our results support the concept of the acrosome as a LRO and provide evidence for the identification of MET as a tyrosine kinase receptor that may play a role in fertilization. PMID- 25744386 TI - Real-time monitoring of enzyme-free strand displacement cascades by colorimetric assays. AB - The enzyme-free toehold-mediated strand displacement reaction has shown potential for building programmable DNA circuits, biosensors, molecular machines and chemical reaction networks. Here we report a simple colorimetric method using gold nanoparticles as signal generators for the real-time detection of the product of the strand displacement cascade. During the process the assembled gold nanoparticles can be separated, resulting in a color change of the solution. This assay can also be applied in complex mixtures, fetal bovine serum, and to detect single-base mismatches. These results suggest that this method could be of general utility to monitor more complex enzyme-free strand displacement reaction based programmable systems or for further low-cost diagnostic applications. PMID- 25744387 TI - Red-light-dependent interaction of phyB with SPA1 promotes COP1-SPA1 dissociation and photomorphogenic development in Arabidopsis. AB - Arabidopsis phytochromes (phyA-phyE) are photoreceptors dedicated to sensing red/far-red light. Phytochromes promote photomorphogenic developments upon light irradiation via a signaling pathway that involves rapid degradation of PIFs (PHYTOCHROME INTERACTING FACTORS) and suppression of COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1) nuclear accumulation, through physical interactions with PIFs and COP1, respectively. Both phyA and phyB, the two best characterized phytochromes, regulate plant photomorphogenesis predominantly under far-red light and red light, respectively. It has been demonstrated that SPA1 (SUPPRESSOR OF PHYTOCHROME A 1) associates with COP1 to promote COP1 activity and suppress photomorphogenesis. Here, we report that the mechanism underlying phyB-promoted photomorphogenesis in red light involves direct physical and functional interactions between red-light-activated phyB and SPA1. We found that SPA1 acts genetically downstream of PHYB to repress photomorphogenesis in red light. Protein interaction studies in both yeast and Arabidopsis demonstrated that the photoactivated phyB represses the association of SPA1 with COP1, which is mediated, at least in part, through red-light-dependent interaction of phyB with SPA1. Moreover, we show that phyA physically interacts with SPA1 in a Pfr-form dependent manner, and that SPA1 acts downstream of PHYA to regulate photomorphogenesis in far-red light. This study provides a genetic and biochemical model of how photoactivated phyB represses the activity of COP1-SPA1 complex through direct interaction with SPA1 to promote photomorphogenesis in red light. PMID- 25744388 TI - Seasonal changes in the content of dehydrins in mesophyll cells of common pine needles. AB - The appearance of dehydrins (DHNs) in cells is required for the development of cold resistance. DHNs are therefore considered specific markers of cold resistance by some authors. DHNs accumulate in plants concomitantly with a reduction of intracellular water content, and presumably protect membranes and proteins from damage caused by moisture loss. DHN content in pine needles increases in spring and autumn when moisture availability and temperatures are most unfavorable. The present work is focused on seasonal changes in DHN content in various mesophyll-cell compartments of pine (Pinus sylvestris L.) needles in association with changes in environmental factors. In spring, the number of thylakoid membranes per granum was lower than in summer and autumn. An increase in needle content of DHNs with approximate masses of 76, 73, 72, 35, and 17 kD in spring and autumn, associated with needle dehydration during this period, is shown here. The largest increase in DHN content was observed in spring, with the highest amount of DHNs presented in chloroplast membrane system including grana thylakoids, stromal thylakoids, and the two chloroplast envelope membranes and in cell walls. In the autumn, most DHNs were localized in chloroplasts and mitochondria. PMID- 25744389 TI - Carotenoid-chlorophyll coupling and fluorescence quenching in aggregated minor PSII proteins CP24 and CP29. AB - It is known that aggregation of isolated light-harvesting complex II (LHCII) in solution results in high fluorescence quenching, reduced chlorophyll fluorescence lifetime, and increased electronic coupling of carotenoid (Car) S1 and chlorophyll (Chl) Qy states, as determined by two-photon studies. It has been suggested that this behavior of aggregated LHCII mimics aspects of non photochemical quenching processes of higher plants and algae. However, several studies proposed that the minor photosystem II proteins CP24 and CP29 also play a significant role in regulation of photosynthesis. Therefore, we use a simple protocol that allows gradual aggregation also of CP24 and CP29. Similarly, as observed for LHCII, aggregation of CP24 and CP29 also leads to increasing fluorescence quenching and increasing electronic Car S1-Chl Qy coupling. Furthermore, a direct comparison of the three proteins revealed a significant higher electronic coupling in the two minor proteins already in the absence of any aggregation. These differences become even more prominent upon aggregation. A red-shift of the Qy absorption band known from LHCII aggregation was also observed for CP29 but not for CP24. We discuss possible implications of these results for the role of CP24 and CP29 as potential valves for excess excitation energy in the regulation of photosynthetic light harvesting. PMID- 25744390 TI - Fe3O4@ZnO core-shell nanocomposites for efficient and repetitive removal of low density lipoprotein in plasma and on blood vessel. AB - Low density lipoprotein (LDL)-apheresis therapy, which directly removes LDL from plasma by LDL-adsorbents in vitro is found to be clinically effective and safe to lower the LDL content in blood to prevent cardiovascular disease. Thus, developing excellent LDL adsorbents are becoming more and more attractive. Herein, functional Fe3O4@ZnO core-shell nanocomposites have been synthesized by a facile and eco-friendly two-step method. Not only do they possess high LDL adsorption (in PBS/plasma as well as on blood vessels) and favorable magnetic targeting ability but they can also be reused conveniently, which offer the Fe3O4@ZnO core-shell nanocomposites significant potential in the removal of LDL in vitro and in vivo. PMID- 25744391 TI - Highlights from the scientific and educational abstracts presented at the ASER 2014 Annual Scientific Meeting and Postgraduate Course. AB - The American Society of Emergency Radiology (ASER) 2014 Annual Scientific Meeting and Postgraduate Course offered dedicated learning sessions, oral presentations, and digital exhibits on a broad spectrum of topics in emergency radiology, including traumatic and nontraumatic emergencies, quality, communication, education, and technology. This article highlights the scientific and educational abstracts presented at the meeting (Emerg Radiol 21:431-471, 2014). PMID- 25744392 TI - The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts. AB - AIMS: Acute rejection of cardiac allografts is a major risk factor limiting survival of heart transplant recipients. Rejection is triggered by dendritic cell (DC) mediated activation of host T cells, amongst others CD4(+) T helper (TH)1- and TH17 cells. The cannabinoid receptor 2 (CB2) is an important modulator of cellular immune responses. However, its role in cardiac allograft rejection has not been studied so far. MAIN METHODS: Here, we examined the effect of CB2 on cytokine release by mature DCs and its impact on CD4(+) T cell differentiation by utilizing in vitro generated bone marrow-derived DCs (BM-DCs) and CD4(+) T cells from CB2 knockout (Cnr2(-/-)) mice. We further assessed the functional role of CB2 in acute allograft rejection using Cnr2(-/-) mice in a fully major histocompatibility complex-mismatched mouse cardiac transplantation model. KEY FINDINGS: Cardiac allograft rejection was accelerated in Cnr2(-/-) mice compared to wild type recipients. In vitro stimulation of BM-DCs showed enhanced secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF) and the immunomodulatory cytokine TGF-beta. Furthermore, secretion of the TH1/TH17 promoting cytokines IL-12 and IL-23 was increased in Cnr2(-/-) BM DCs. In addition, Cnr2(-/-) CD4(+) T cells showed an enhanced capacity to differentiate into interferon (IFN)-gamma- or IL-17-producing effector cells. SIGNIFICANCE: These results demonstrate that CB2 modulates in vitro cytokine responses via DCs and directly via its influence on TH1/TH17 differentiation. These findings and the fact that allograft rejection is enhanced in Cnr2(-/-) mice suggest that CB2 may be a promising therapeutic target in organ transplantation. PMID- 25744393 TI - Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6 OHDA and treated with L-DOPA. AB - OBJECTIVE: Evaluate the effects caused by L-DOPA on cardiovascular and autonomic parameters in an animal model of Parkinsonism induced by 6-hydroxydopamine (6 OHDA). METHODS: Adult male Wistar rats were subjected to bilateral microinfusion of 6-OHDA or saline (sham group) in the substantia nigra, and treated by gavage with L-DOPA or water for 7 days after surgery. On the 6th day the rats were subjected to femoral artery catheterization for cardiovascular recording. Mean arterial pressure (MAP) and heart rate (HR) were evaluated at baseline and during head up tilt (HUT) protocol. Spectral analysis of cardiovascular variability was performed using the V2.4 CardioSeries software v2.4. The lesion was quantified by dopamine levels in the striatum. RESULTS: Dopamine levels in the striatum were decreased in 6-OHDA rats (sham: 4.79 +/- 0.49 ng/mg; 6-OHDA: 1.99 +/- 0.68 ng/mg) and were not recovered by Prolopa treatment. Baseline values of MAP and HR were not different between groups. HUT induced an increase in MAP and HR (DeltaMAP: 17 +/- 1 mm Hg, DeltaHR: 39 +/- 4 bpm) that were attenuated in 6-OHDA and in Prolopa treated animals. At baseline, the systolic arterial pressure (SAP) variance was lower in the 6-OHDA AND sham prolopa groups. Spontaneous baroreflex sensitivity was higher at baseline in the 6-OHDA group as compared to all studied groups. CONCLUSIONS: Our data suggest that treatment with Prolopa did not interfere with cardiovascular variables at baseline. However, during HUT, the 6-OHDA and Prolopa control animals presented a lower cardiovascular compensation, suggesting a possible autonomic impairment in Parkinsonism induced by 6-OHDA. PMID- 25744394 TI - Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia. AB - AIMS: There is no effective medication to date for herpes simplex virus encephalitis (HSE). In this study, we investigated the anti-inflammatory effect of chlorogenic acid (CGA) on herpes simplex virus (HSV)-1-induced responses in BV2 microglia. MAIN METHODS: The cellular model was established with BV2 cells stimulated by HSV-1 and then treated with CGA at different concentrations. Cell viability was assayed by the MTT assay. The mRNA expression of Toll-like receptor (TLR)-2, TLR9 and myeloid differentiation factor88 (Myd88) was assayed by real time quantitative PCR, and the protein expression was assayed by flow cytometry or Western blotting. Tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL) 6 were measured by ELISA as well as real-time quantitative PCR. Nuclear NF-kappaB p65 protein was assayed by Western blotting. KEY FINDINGS: The cell survival rate was significantly improved after CGA treatment, and CGA prevented increases in TLR2, TLR9 and Myd88 following HSV-1 challenge in BV2 cells both at the mRNA and protein levels. Moreover, CGA could attenuate HSV-induced TNF-alpha and IL-6 release into the supernatant. The mRNA levels of TNF-alpha and IL-6 were also significantly inhibited by CGA. The expression of NF-kappaB p65 increased significantly in the nucleus in HSV-1-stimulated microglia but could be reduced by CGA. SIGNIFICANCE: CGA inhibits the inflammatory reaction in HSE via the suppression of TLR2/TLR9-Myd88 signaling pathways. CGA may serve as an anti inflammatory agent and provide a new strategy for treating HSE. PMID- 25744395 TI - The influence of equol on the hypothalamic-pituitary-thyroid axis and hepatic lipid metabolic parameters in adult male rats. AB - AIMS: Equol, the principal active metabolite of soy-derived phytoestrogen daidzein, has well-known estrogenic actions. Results of several studies indicate that equol may also have anti-androgenic activities. However, mechanisms of action of equol on hypothalamic-pituitary-thyroid axis (HPTA) and hepatic lipid metabolism in adult male rats have not been determined yet. MAIN METHODS: Equol at two doses of 100 and 250mg/kgbodyweight(BW)/day was orally gavaged for 5days to groups of 4-month-old male rats. As a positive anti-androgenic control group, animals received 100mg of pure anti-androgenic drug flutamide/kgBW/day. Circulating concentrations of thyroid hormones and lipids, and expression levels of genes underlying HPTA function were determined by radioimmunoassay and TaqMan(r) real-time reverse transcription polymerase chain reaction, respectively. KEY FINDINGS: Flutamide significantly decreased relative prostate weight, whereas equol did not. Both equol and flutamide caused a significant increase in relative liver weights, and decreases in plasma levels of total tetraiodothyronine (T4) and triiodothyronine (T3), whereas free T4 and T3 concentrations were not reduced. Equol caused the marked down-regulation of hypothalamic thyrotropin-releasing hormone mRNA expression, whereas flutamide did not. Equol as well as flutamide significantly down-regulated the expression levels of pituitary thyrotropin beta-subunit mRNA, without altering thyrotropin secretion. Equol caused reductions in plasma levels of total cholesterol, high- and low-density lipoproteins and triglycerides, whereas flutamide exerted opposite effects. SIGNIFICANCE: This is the first study to reveal that in male rats equol did not affect HPTA function and liver lipid metabolism through the anti-androgenic pathway, however, the intrinsic estrogenic actions of equol were observed. PMID- 25744396 TI - A comprehensive review on vernal keratoconjunctivitis with emphasis on proteomics. AB - Allergic conjunctivitis presents as a spectrum of different clinical entities, such as perennial allergic conjunctivitis, seasonal allergic conjunctivitis, atopic keratoconjunctivitis and vernal keratoconjunctivitis. Vernal keratoconjunctivitis (VKC) is a disorder that is often associated with allergens and is seen during the spring season. Herein, we focused on vernal keratoconjunctivitis (VKC) and reviewed its epidemiology, clinical presentations, ocular associations, available treatment options, and the progressive understanding of its histopathological features; we have also systematically elaborated on the various studies on proteomics. Initial theories of a solely IgE mediated mechanism have been replaced by those considering IgE and non-IgE mechanisms. Developments in basic and clinical research will open novel diagnostic approaches for the early detection and cure of the disease. PMID- 25744397 TI - Multidrug resistance-associated protein 2 is involved in the efflux of Aconitum alkaloids determined by MRP2-MDCKII cells. AB - AIMS: Aconitum alkaloids mainly contain highly toxic aconitine (AC), mesaconitine (MA), and hypaconitine (HA) and less toxic benzoylaconine (BAC), benzoylmesaconine (BMA), benzoylhypaconine (BHA), aconine, mesaconine, and hypaconine. The efflux transporters including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) can efflux toxicants to prevent poisoning. Our previous publication has proved that P-gp and BCRP contributed to the efflux of AC, MA and HA, which is demonstrated in the human colonic adenocarcinoma cell lines (Caco-2 cells), Mardin-Darby canine kidney cell lines transfected with MDR1 or BCRP (MDR1-MDCKII and BCRP-MDCKII cells). However, the role of MRP2 remains uncertain. MAIN METHODS: The MRP2-MDCKII cells were used to determine the efflux ratios (Er) and intracellular amounts of Aconitum alkaloids. In addition, the importance of MRP2 was further investigated with or without the MRP2 inhibitor, LTC4. KEY FINDINGS: The Er values of AC, MA, HA, BAC, BMA and BHA in MRP2-MDCKII cells (6.4 +/- 0.3, 5.9 +/- 0.5, 2.2 +/- 0.2, 1.6 +/- 0.3, 1.7 +/- 0.2 and 1.9 +/- 0.2 respectively) were significantly higher than those in MDCKII cells, which were close to 1. In the presence of LTC4, the Er values of AC, MA, HA, BAC, BMA and BHA were reduced to approximately 1 and their intracellular amounts were also significantly increased in MRP2-MDCKII cells. SIGNIFICANCE: MRP2 was involved in the efflux of AC, MA, HA, BAC, BMA and BHA, which would be useful for the safe application of these components or their herbs. PMID- 25744398 TI - Combining detection of Notch1 and tumor necrosis factor-alpha converting enzyme is a reliable biomarker for the diagnosis of abdominal aortic aneurysms. AB - AIMS: Although many markers were associated with abdominal aortic aneurysm (AAA), there is no clear consensus on which marker is of the most value. Studies have implicated the role of Notch signaling in the pathogenesis of AAA. We investigate the value of plasma Jagged1, Notch receptors and tumor necrosis factor-alpha converting enzyme (TACE) in identifying AAA. MAIN METHODS: 42 patients with AAA and 36 controls were enrolled in our study. The concentrations of plasma Jagged1, Notch receptors and TACE were measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic value of plasma Notch1 and TACE was assessed by logistic regression and receiver operator characteristic (ROC) curve. Double immunofluorescence staining was used to investigate the distribution of Notch1 and TACE in AAA tissue specimens. KEY FINDINGS: The concentrations of plasma Notch1 and TACE were significantly higher in AAA than in the controls, respectively (Notch1: P < 0.001; TACE: P = 0.0001). The area under the curve (AUC) from ROC curve of plasma Notch1 and TACE in determining the presence of AAA was 0.878 and 0.804, respectively. Combining detection of plasma Notch1 and TACE could improve the accuracy in detecting AAA (AUC 0.984, P < 0.0001). The predicted probability cutoff of 0.70 gave a sensitivity of 90.5% and a specificity of 100% for combining detection of plasma Notch1 and TACE in predicting AAA. SIGNIFICANCE: This is the first report revealing that plasma Notch1 and TACE are highly expressed in AAA. Combining detection of plasma Notch1 and TACE may be reliable for identifying the presence of AAA. PMID- 25744399 TI - Effect of exercise training on liver antioxidant enzymes in STZ-diabetic rats. PMID- 25744400 TI - Blockade of phosphodiesterase 4 reverses morphine-induced ventilatory disturbance without loss of analgesia. AB - AIMS: Ventilatory disturbance is a fatal side-effect of opioid analgesics. Separation of analgesia from ventilatory depression is important for therapeutic use of opioids. It has been suggested that opioid-induced ventilatory depression results from a decrease in adenosine 3',5'-cyclic monophosphate content in the respiratory-related neurons. Therefore, we examined the effects of caffeine, a methylxanthine non-selective phosphodiesterase (PDE) inhibitor with adenosine antagonistic activity, and rolipram, a racetam selective PDE4 inhibitor, on ventilatory depression induced by morphine. MAIN METHODS: Spontaneous ventilation and paw withdrawal responses to nociceptive thermal stimulation were measured in anesthetized rats simultaneously. The efferent discharge of the phrenic nerve was recorded in anesthetized, vagotomized, paralyzed and artificially ventilated rats. KEY FINDINGS: Rolipram (0.1 and 0.3 mg/kg, i.v.) and caffeine (3.0 and 10.0 mg/kg, i.v.) relieved morphine (1.0 mg/kg, i.v.)-induced ventilatory depression but had no discernible effect on its analgesic action. Rolipram (0.3 and 1.0 mg/kg, i.v.) and caffeine (10.0 and 20.0 mg/kg, i.v.) recovered morphine (3.0 mg/kg, i.v.)-induced prolongation and flattening of inspiratory discharge in the phrenic nerve. SIGNIFICANCE: Inhibition of PDE4 may be a possible approach for overcoming morphine-induced ventilatory depression without loss of analgesia. PMID- 25744401 TI - Age differences in the role of the cannabinoid type 1 receptor on glutamatergic neurons in habituation and spatial memory acquisition. PMID- 25744402 TI - Angiogenesis in the pathophysiology of schizophrenia - a comprehensive review and a conceptual hypothesis. PMID- 25744403 TI - Activation of AMPK by metformin inhibits TGF-beta-induced collagen production in mouse renal fibroblasts. AB - AIMS: To clarify whether activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin inhibits transforming growth factor beta (TGF-beta) induced collagen production in primary cultured mouse renal fibroblasts and further to address the molecular mechanisms. MAIN METHODS: Primary cultured mouse renal fibroblasts were stimulated with TGF-beta1 and the sequence specific siRNA of Smad3 or connective tissue growth factor (CTGF) was applied to investigate the involvement of these molecular mediators in TGF-beta1-induced collagen type I production. Cells were pre-incubated with AMPK agonist metformin or co-incubated with AMPK agonist metformin and AMPK inhibitor Compound C before TGF-beta1 stimulation to clarify whether activation of AMPK inhibition of TGF-beta1-induced renal fibroblast collagen type I expression. KEY FINDINGS: Our results demonstrate that TGF-beta1 time- and dose-dependently induced renal fibroblast collagen type I production; TGF-beta1 also stimulated Smad3-dependent CTGF expression and caused collagen type I generation; this effect was blocked by knockdown of Smad3 or CTGF. Activation of AMPK by metformin reduced TGF-beta1 induced collagen type I production by suppression of Smad3-driven CTGF expression. SIGNIFICANCE: This study suggests that activation of AMPK might be a novel strategy for the treatment of chronic kidney disease (CKD) partially by inhibition of renal interstitial fibrosis (RIF). PMID- 25744404 TI - Increased alpha1-adrenoreceptor activity is required to sustain blood pressure in female rats under food restriction. AB - AIMS: We evaluated the effect of food restriction (FR) on the various reflexes involved in short term cardiovascular regulation; we also evaluated the contribution of the sympathetic nervous systemand of the plasmatic nitric oxide (NO) in the development of the counterregulatory cardiovascular changes triggered by FR. MAIN METHODS: Female rats were subjected to FR for 14 days, and after this period biochemical measurements of biochemical parameters were performed. For physiological tests, animals were anaesthetised, and a catheter was inserted into the femoral artery and vein for the acquisition of blood pressure and heart hate, and drug infusion, respectively.We then tested the Bezold-Jarisch reflex, the baroreflex and chemoreflex and the effect of the infusion of adrenergic receptor antagonists in control and food restricted animals. KEY FINDINGS: The rats subjected to severe FR presented biochemical changes characteristic of malnutrition with a great catabolic state. FR also led to hypotension and bradycardia besides reducing the plasmatic concentration of NO. Moreover, activation of the Bezold-Jarisch reflex induced a more pronounced hypotensive response in animals subjected to FR. Intravenous infusion of a alpha1 adrenoreceptor antagonist induced a greater hypotensive response and a more pronounced tachycardic response in animals under food restriction,while the infusion of beta-adrenoreceptor antagonist induced lower increases in blood pressure in these animals. SIGNIFICANCE: Our results suggest that an increased alpha1-adrenoreceptor activity in the resistance arteries coupled with a reduction of plasmatic NO contributes in a complementary manner to maintain the blood pressure levels in animals under FR. PMID- 25744405 TI - Spinal p38 activity and analgesic effect after low- and high-intensity electroacupuncture stimulation in a plantar incision rat model. AB - AIMS: Postoperative pain is a major problem. Electroacupuncture (EA) has been accepted as a useful and low-risk complementary therapy for post-operative pain. Animal studies indicate that surgical incision activates p38 MAPK in the spinal microglia, which critically contributes to post-incisional nociceptive development. How EA affects incision-induced p38 activation is important but yet to be fully elucidated. METHODS: Male adult rats received plantar incision (PI) at the right hind paw followed by 30-min EA of 4-Hz, one of two intensities (3 and 10mA), and at right ST36 (Zusanli) acupoint immediately after PI and for 3 successive days. EA analgesia was evaluated by von Frey fibers and Hargreaves' tests. Spinal p38 activation was examined by immunostaining. In separate groups, SB203580, a p38 inhibitor, was intrathecally injected alone or with EA to test the combining effect on nociception and spinal phospho-p38. KEY FINDINGS: EA of 10-mA significantly ameliorated mechanical allodynia, but 3-mA did not. None of them altered thermal hyperalgesia. Repeated EA could not inhibit phospho-p38 in the PI rats, contrarily, EA per se significantly induced phospho-p38 in the normal rats. Intrathecal SB203580 injection dose-dependently prevented PI-induced allodynia. Combination of low-dose SB203580 and 3-mA EA, which were ineffective individually, profoundly reduce post-PI allodynia. SIGNIFICANCE: We demonstrated that 10-mA EA exerts a significant inhibition against post-PI mechanical hypersensitivity via a p38-independent pathway. Importantly, co-treatment with low-dose p38 inhibitor and 3-mA EA can counteract spinal phospho-p38 to exert strong analgesic effect. Our finding suggests a novel strategy to improve EA analgesic quality. PMID- 25744406 TI - Inhibition of microglial activation by elderberry extracts and its phenolic components. AB - AIMS: Elderberry (Sambucus spp.) is one of the oldest medicinal plants noted for its cardiovascular, anti-inflammatory, and immune-stimulatory properties. In this study, we investigated the anti-inflammatory and anti-oxidant effects of the American elderberry (Sambucus nigra subsp. canadensis) pomace as well as some of the anthocyanins (cyanidin chloride and cyanidin 3-O-glucoside) and flavonols (quercetin and rutin) in bv-2 mouse microglial cells. MAIN METHODS: The bv-2 cells were pretreated with elderberry pomace (extracted with ethanol or ethyl acetate) or its anthocyanins and flavonols and stimulated by either lipopolysaccharide (LPS) or interferon-gamma (IFNgamma). Reactive oxygen species (ROS) and nitric oxide (NO) production (indicating oxidative stress and inflammatory response) were measured using the ROS detection reagent DCF-DA and the Griess reaction, respectively. KEY FINDINGS: Analysis of total monomeric anthocyanin (as cyanidin 3-O-glucoside equivalents) indicated five-fold higher amount in the freeze-dried ethanol extract as compared to that of the oven-dried extract; anthocyanin was not detected in the ethyl acetate extracts. Elderberry ethanol extracts (freeze-dried or oven-dried) showed higher anti-oxidant activities and better ability to inhibit LPS or IFNgamma-induced NO production as compared with the ethyl acetate extracts. The phenolic compounds strongly inhibited LPS or IFNgamma-induced ROS production, but except for quercetin, they were relatively poor in inhibiting NO production. SIGNIFICANCE: These results demonstrated differences in anti-oxidative and anti-inflammatory effects of elderberry extracts depending on solvents used. Results further identified quercetin as the most active component in suppressing oxidative stress and inflammatory responses on microglial cells. PMID- 25744407 TI - Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB. AB - AIMS: The present study addresses the issue of enhanced apoptotic response to AZT following co-treatment with an NF-kB inhibitor. MAIN METHODS: To investigate this issue, different cell lines were assayed for susceptibility to AZT-mediated apoptosis without or with the addition of the NF-kB inhibitor Bay-11-7085. For further investigation, U937 cells were selected as good-responder cells to the combination treatment with 32 or 128 MUM AZT, and 1 MUM Bay-11-7085. Inhibition of NF-kB activation by Bay-11-7085 in cells treated with AZT was assayed through Western blot analysis of p65 expression and by EMSA. Involvement of the mitochondrial pathway of apoptosis in mechanisms underlying the improved effect of AZT following Bay-11-7085 co-treatment, was evaluated by assaying the cytochrome c release and the mitochondrial membrane potential (MMP) status using the JC-1 dye. Moreover, the transcriptional activity of both anti- and pro apoptotic genes in U937 cells after combination treatment was quantitatively evaluated through real-time PCR. KEY FINDINGS: We found that the combined treatment induced high levels of cytochrome c release and of MMP collapse in association with evident changes in the expression of both anti- and pro apoptotic genes of the Bcl-2 family. Overexpression of Bcl-2 significantly suppressed the sensitization of U937 cells to an enhanced apoptotic response to AZT following co-treatment with the NF-kB inhibitor. SIGNIFICANCE: The new findings suggest that a combination regimen based on AZT plus an NF-kB inhibitor could represent a new chemotherapeutic tool for retrovirus-related pathologies. PMID- 25744408 TI - Effects of different inspired oxygen fractions on sildenafil-induced pulmonary anti-hypertensive effects in a sheep model of acute pulmonary embolism. AB - AIMS: Sildenafil is a pulmonary anti-hypertensive agent whose action could be modified by different fractions of inspired oxygen (FiO2). We compared the effects of pure oxygen (FiO2 > 90%) or room air (21% FiO2) on the cardiopulmonary actions of sildenafil in sheep with acute pulmonary embolism (APE). MAIN METHODS: Thirty-two anesthetized, mechanically ventilated sheep (34.9 +/- 5.4 kg), were randomly distributed into four groups (n = 8 per group): FiO2 > 90% without intervention; APE induced by microspheres with FiO2 > 90%, followed 30 min later by placebo (Emb90); or APE followed 30 min later by intravenous sildenafil (0.7 mg/kg over 30 min) with FiO2 > 90% (Emb + Sild90) or 21% FiO2 (Emb + Sild21) [Corrected]. Variables were recorded until 30 min after the end of treatment administration. KEY FINDINGS: Microsphere injection increased (P < 0.05) mean pulmonary artery pressure (MPAP) in all embolized groups (111-140% higher than that of baseline). Compared with values recorded 30 min after induction of APE (E30), sildenafil induced greater decreases in MPAP in the Emb + Sil90 group than in the Emb + Sil21 group (23% and 14% lower than E30, respectively). Hypotension (mean arterial pressure < 60 mm Hg) was precipitated by sildenafil due to systemic vasodilation in the Emb + Sil21 group. Embolization lowered the PaO2/FiO2 ratio and increased venous admixture, but sildenafil did not alter the oxygenation impairment induced by APE. SIGNIFICANCE: Sildenafil induces a more consistent pulmonary anti-hypertensive effect and causes less interference with the systemic circulation with the concomitant use of pure oxygen than that with room air in the APE setting. PMID- 25744409 TI - ARHGAP21 prevents abnormal insulin release through actin rearrangement in pancreatic islets from neonatal mice. AB - AIMS: ARHGAP21 is a Rho GTPase-activating protein (RhoGAP) that associates with many proteins and modulates several cellular functions, including actin cytoskeleton rearrangement in different tissues. However, it is unknown whether ARHGAP21 is expressed in pancreatic beta cells and its function in these cells. Herein, we assess the participation of ARHGAP21 in insulin secretion. MAIN METHODS: Neonatal mice were treated with anti-sense oligonucleotide against ARHG AP21 (AS) for 2 days, resulting in a reduction of the protein's expression of about 60% in the islets. F-actin depolimerization, insulin secretion,mRNA level of genes involved in insulin secretion, maturation and proliferation were evaluated in islets from both control and AS-treated mice. KEY FINDINGS: ARHGAP21 co-localized with actin inMIN6 beta cells and with insulin in neonatal pancreatic islets. F-actin was reduced in AS-islets, as judged by lower phalloidin intensity. Insulin secretion was increased in islets from AS-treated mice, however no differences were observed in the GSIS (glucose-stimulated insulin secretion). In these islets, the pERK1/2 was increased, as well as the gene expressions of VAMP2 and SNAP25, proteins that are present in the secretory machinery. Maturation and cell proliferation were not affected in islets from AS treated mice. SIGNIFICANCE: In conclusion, our data show, for the first time, that ARHGAP21 is expressed and participates in the secretory process of pancreatic beta cells. Its effect is probably via pERK1/2, which modulates the rearrangement of the cytoskeleton. ARHGAP21 also controls the expression of genes that encodes proteins of the secretory machinery. PMID- 25744410 TI - Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats. AB - AIMS: Second-generation antipsychotic drugs (SGAs) have a high risk for serious metabolic side-effects including dyslipidemia. This study aimed to investigate the acute effects of oral olanzapine treatment on the expression of genes for fatty acid and cholesterol biosynthesis in rats. MAIN METHODS: Female Sprague Dawley rats were treated orally with olanzapine (1mg/kg, equivalent to a human clinical dose of 10mg) via self-administration aimed to measure pharmacokinetics. Based on the pharmacokinetic analysis, the acute effects of olanzapine on sterol regulatory element binding protein (SREBP)-related fatty acid/cholesterol metabolism genes were investigated in the liver and perirenal white adipose tissue (WAT) by Real-time quantitative PCR. KEY FINDINGS: A pharmacokinetic analysis demonstrated that the maximum concentration of olanzapine in plasma (Cmax) occurred at 6h with a peak concentration of 276.5ng/ml after a single oral treatment and with a plasma elimination half-life of 3.5h after peak. The mRNA expression of SREBP-2 and target genes for cholesterol synthesis and transport was increased 1.9 8.8 fold compared with the control at 6h after olanzapine administration but returned to basal level at 12h post-treatment, while the increased mRNA expression of SREBP-1c and its targeted fatty acid-related genes appeared at both 6h and 12h post-treatment. SIGNIFICANCE: The present study provided evidence that olanzapine at a clinically-relevant dose caused abnormal expression of genes involved in lipid metabolism in the liver and WAT. These results suggest that olanzapine may cause dyslipidemia side-effects through direct effects on lipid biosynthesis and efflux genes associated with SREBP stimulated transcriptional changes. PMID- 25744411 TI - The antioxidant machinery of the endoplasmic reticulum: Protection and signaling. AB - Cellular metabolism is inherently linked to the production of oxidizing by products, including reactive oxygen species (ROS) hydrogen peroxide (H2O2). When present in excess, H2O2 can damage cellular biomolecules, but when produced in coordinated fashion, it typically serves as a mobile signaling messenger. It is therefore not surprising that cell health critically relies on both low-molecular weight and enzymatic antioxidant components, which protect from ROS-mediated damage and shape the propagation and duration of ROS signals. This review focuses on H2O2-antioxidant cross talk in the endoplasmic reticulum (ER), which is intimately linked to the process of oxidative protein folding. ER-resident or ER regulated sources of H2O2 and other ROS, which are subgrouped into constitutive and stimulated sources, are discussed and set into context with the diverse antioxidant mechanisms in the organelle. These include two types of peroxide reducing enzymes, a high concentration of glutathione derived from the cytosol, and feedback-regulated thiol-disulfide switches, which negatively control the major ER oxidase ER oxidoreductin-1. Finally, new evidence highlighting emerging principles of H2O2-based cues at the ER will likely set a basis for establishing ER redox processes as a major line of future signaling research. A fundamental problem that remains to be solved is the specific, quantitative, time resolved, and targeted detection of H2O2 in the ER and in specialized ER subdomains. PMID- 25744412 TI - Proteostasis and "redoxtasis" in the secretory pathway: Tales of tails from ERp44 and immunoglobulins. AB - In multicellular organisms, some cells are given the task of secreting huge quantities of proteins. To comply with their duty, they generally equip themselves with a highly developed endoplasmic reticulum (ER) and downstream organelles in the secretory pathway. These professional secretors face paramount proteostatic challenges in that they need to couple efficiency and fidelity in their secretory processes. On one hand, stringent quality control (QC) mechanisms operate from the ER onward to check the integrity of the secretome. On the other, the pressure to secrete can be overwhelming, as for instance on antibody producing cells during infection. Maintaining homeostasis is particularly hard when the products to be released contain disulfide bonds, because oxidative folding entails production of reactive oxygen species. How are redox homeostasis ("redoxtasis") and proteostasis maintained despite the massive fluxes of cargo proteins traversing the pathway? Here we describe recent findings on how ERp44, a multifunctional chaperone of the secretory pathway, can modulate these processes integrating protein QC, redoxtasis, and calcium signaling. PMID- 25744413 TI - Overproduction of nitric oxide by endothelial cells and macrophages contributes to mitochondrial oxidative stress in adrenocortical cells and adrenal insufficiency during endotoxemia. AB - We have recently demonstrated that lipopolysaccharide (LPS) causes mitochondrial oxidative stress and dysfunction in adrenal glands, thereby leading to adrenocortical insufficiency. Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) leads to mitochondrial damage in various tissues, the present study aims to investigate whether NO contributes to mitochondrial oxidative stress in adrenal cortex and adrenocortical insufficiency during endotoxemia. Systemic administration of LPS increased iNOS expression and NO production in adrenal glands of mice. The specific iNOS inhibitor 1400 W significantly attenuated the LPS-induced mitochondrial superoxide production and dysfunction in adrenal glands, and reversed the LPS-induced adrenocortical hyporesponsiveness to adrenocorticotropic hormone (ACTH). In contrast, administration of the NO donor sodium nitroprusside (SNP) led to mitochondrial oxidative stress and dysfunction in adrenal glands, which resulted in a blunted corticosterone response to ACTH. Using double immunofluorescence staining for iNOS with the vascular endothelial cell marker CD31 or the macrophage marker CD68, we found that increased iNOS expression was found in vascular endothelial cells and macrophages, but not adrenocortical cells in the adrenal gland during endotoxemia. Administration of the hydrogen sulfide (H2S) donor GYY4137 inhibited NO production and reversed LPS-induced adrenocortical hyporesponsiveness. Our data suggest that overproduction of NO, which is mainly generated by endothelial cells and macrophages during endotoxemia, contributes to mitochondrial oxidative stress in adrenocortical cells and subsequently leads to adrenal insufficiency. PMID- 25744414 TI - Dietary polyunsaturated fatty acids and heme iron induce oxidative stress biomarkers and a cancer promoting environment in the colon of rats. AB - The end products of polyunsaturated fatty acid (PUFA) peroxidation, such as malondialdehyde (MDA), 4-hydroxynonenal (HNE), and isoprostanes (8-iso PGF2alpha), are widely used as systemic lipid oxidation/oxidative stress biomarkers. However, some of these compounds have also a dietary origin. Thus, replacing dietary saturated fat by PUFAs would improve health but could also increase the formation of such compounds, especially in the case of a pro oxidant/antioxidant imbalanced diet. Hence, the possible impact of dietary fatty acids and pro-oxidant compounds was studied in rats given diets allowing comparison of the effects of heme iron vs. ferric citrate and of omega-6- vs. omega-3-rich oil on the level of lipid peroxidation/oxidative stress biomarkers. Rats given a heme iron-rich diet without PUFA were used as controls. The results obtained have shown that MDA and the major urinary metabolite of HNE (the mercapturic acid of dihydroxynonane, DHN-MA) were highly dependent on the dietary factors tested, while 8-iso-PGF2alpha was modestly but significantly affected. Intestinal inflammation and tissue fatty acid composition were checked in parallel and could only explain the differences we observed to a limited extent. Thus, the differences in biomarkers were attributed to the formation of lipid oxidation compounds in food or during digestion, their intestinal absorption, and their excretion into urine. Moreover, fecal extracts from the rats fed the heme iron or fish oil diets were highly toxic for immortalized mouse colon cells. Such toxicity can eventually lead to promotion of colorectal carcinogenesis, supporting the epidemiological findings between red meat intake and colorectal cancer risk. Therefore, the analysis of these biomarkers of lipid peroxidation/oxidative stress in urine should be used with caution when dietary factors are not well controlled, while control of their possible dietary intake is needed also because of their pro-inflammatory, toxic, and even cocarcinogenic effects. PMID- 25744416 TI - Ultra-high-density 3D DNA arrays within nanoporous biocompatible membranes for single-molecule-level detection and purification of circulating nucleic acids. AB - Extracellular nucleic acids freely circulating in blood and other physiologic fluids are important biomarkers for non-invasive diagnostics and early detection of cancer and other diseases, yet difficult to detect because they exist in very low concentrations and large volumes. Here we demonstrate a new broad-range sensor platform for ultrasensitive and selective detection of circulating DNA down to the single-molecule level. The biosensor is based on a chemically functionalized nanoporous diamond-like carbon (DLC) coated alumina membrane. The few nanometer-thick, yet perfect and continuous DLC-coating confers the chemical stability and biocompatibility of the sensor, allowing its direct application in biological conditions. The selective detection is based on complementary hybridization of a fluorescently-tagged circulating cancer oncomarker (a 21-mer nucleic acid) with covalently immobilized DNA on the surface of the membrane. The captured DNAs are detected in the nanoporous structure of the sensor using confocal scanning laser microscopy. The flow-through membrane sensor demonstrates broad-range sensitivity, spanning from 10(15) molecules per cm(2) down to single molecules, which is several orders of magnitude improvement compared to the flat DNA microarrays. Our study suggests that these flow-through type nanoporous sensors represent a new powerful platform for large volume sampling and ultrasensitive detection of different chemical biomarkers. PMID- 25744415 TI - Redox-dependent induction of antioxidant defenses by phenolic diterpenes confers stress tolerance in normal human skin fibroblasts: Insights on replicative senescence. AB - Mild stress-induced hormesis represents a promising strategy for targeting the age-related accumulation of molecular damage and, therefore, for preventing diseases and achieving healthy aging. Fruits, vegetables, and spices contain a wide variety of hormetic phytochemicals, which may explain the beneficial health effects associated with the consumption of these dietary components. In the present study, the induction of cellular antioxidant defenses by the phenolic diterpenes carnosic acid (CA) and carnosol (CS) were studied in normal human skin fibroblasts, and insights into the aging process at the cellular level investigated. We observed that CA and CS induced several cytoprotective enzymes and antioxidant defenses in human fibroblasts, whose induction was dependent on the cellular redox state for CS and associated with Nrf2 signaling for both compounds. The stress response elicited by preincubation with CS conferred a cytoprotective action against a following oxidant challenge with tert-butyl hydroperoxide, confirming its hormetic effect. Preincubation of normal fibroblasts with CS also protected against hydrogen peroxide-induced premature senescence. Furthermore, cultivation of middle passage normal human skin fibroblasts in the presence of CS ameliorated the physiological state of cells during replicative senescence. Our results support the view that mild stress induced antioxidant defenses by CS can confer stress tolerance in normal cells and may have important implications in the promotion of healthy aging. PMID- 25744417 TI - Conferred resistance to Botrytis cinerea in Lilium by overexpression of the RCH10 chitinase gene. AB - KEY MESSAGE: Transgenic Lilium lines have been generated by Agrobacterium mediated transformation that have enhanced resistance to Botrytis cinerea as a consequence of ectopic expression of a rice chitinase gene. The production of ornamentals is an important global industry, with Lilium being one of the six major bulb crops in the world. The international trade in ornamentals is in the order of L60-75 billion and is expected to increase worldwide by 2-4% per annum. The continued success of the floriculture industry depends on the introduction of new species/cultivars with major alterations in key agronomic characteristics, such as resistance to pathogens. Fungal diseases are the cause of reduced yields and marketable quality of cultivated plants, including ornamental species. The fungal pathogen Botrytis causes extreme economic losses to a wide range of crop species, including ornamentals such as Lilium. Agrobacterium-mediated transformation was used to develop Lilium oriental cv. 'Star Gazer' plants that ectopically overexpress the Rice Chitinase 10 gene (RCH10), under control of the CaMV35S promoter. Levels of conferred resistance linked to chitinase expression were evaluated by infection with Botrytis cinerea; sporulation was reduced in an in vitro assay and the relative expression of the RCH10 gene was determined by quantitative reverse transcriptase-PCR. The extent of resistance to Botrytis, compared to that of the wild type plants, showed a direct correlation with the level of chitinase gene expression. Transgenic plants grown to flowering showed no detrimental phenotypic effects associated with transgene expression. This is the first report of Lilium plants with resistance to Botrytis cinerea generated by a transgenic approach. PMID- 25744418 TI - A randomized intervention trial of 24-wk dairy consumption on waist circumference, blood pressure, and fasting blood sugar and lipids in Japanese men with metabolic syndrome. AB - Dairy foods are postulated to have beneficial effects on blood pressure, body fat, serum lipids, and the incidence of type 2 diabetes. To evaluate the effects of the consumption of milk and dairy products, we performed a randomized dietary intervention trial for 24 wk in Japanese men, aged 20 to 60 y, with 2 or more components of the metabolic syndrome ( CLINICAL TRIAL REGISTRATION: UMIN000006353). Subjects were randomized to a control group (n=98) that received dietary intervention focused on weight control supervised by registered dietitians, and a dairy-consumption group (n=102) that received both dietary intervention and regular home dairy delivery of 400 g/d for 24 wk. Co-primary endpoints included waist circumference, blood pressure, fasting blood sugar (FBS), and serum lipids. The dietary intervention decreased energy intake from 2,150 to 1,850 kcal/d in both groups (p<0.01). Mean rates of compliance with the dairy-consumption intervention were over 90%, resulting in increased calcium intake in the dairy-consumption group from 329 to 667 mg/d (p<0.01). Co-primary endpoints improved in both groups, but the degree of improvement was smaller in the dairy-consumption group (one-sided p=0.99). Subgroup analyses specified in the study protocol identified weight and leisure-time physical activity (LTPA) as significant effect modifiers. Differences in changes in systolic blood pressure compared with the control group were 28.0 mmHg (95% CI, 214.0 to 21.9, interaction; p<0.01) in the normal weight group and 25.8 mmHg (211.4 to 20.2, interaction; p=0.02) in the moderate-to-high LTPA group, indicating lower systolic blood pressure in the dairy-consumption group among participants in these subgroups. In conclusion, although effects on the co-primary endpoints of dairy consumption were not shown, dairy consumption lowered systolic blood pressure in the subgroups with normal weight and moderate-to-high LTPA and lowered FBS in the subgroup with normal weight. PMID- 25744420 TI - Thyroid and glucocorticoid hormones induce expression of lactase-phlorizin hydrolase gene in CDX-2/HNF-1alpha co-transfected IEC-6 cells. AB - Thyroid and glucocorticoid hormones and several transcriptional factors such as caudal type homeobox (CDX)-2 and hepatocyte nuclear factor (HNF)-1alpha are important for the differentiation of small intestinal absorptive cells and the consequent expression of genes related to the digestion/absorption of carbohydrates. In this study, we investigated whether thyroid and glucocorticoid hormones enhanced the expression of lactase-phlorizin hydrolase (LPH) gene, an intestine-specific gene that encodes an enzyme for lactose digestion, in small intestinal stem-like IEC-6 cells co-transfected with CDX-2 and HNF-1alpha using a retrovirus system. Changes in expression of intestine-specific genes caused by treatment with thyroid and/or glucocorticoid hormones were monitored in empty vector-transfected cells and in CDX-2/HNF-1alpha co-transfected cells by qRT-PCR. Stable co-transfection with CDX-2 and HNF-1alpha evoked the expression of the LPH gene in IEC-6 cells. Furthermore, treatment with a thyroid hormone, triiodothyronine, and a glucocorticoid receptor agonist, dexamethasone, significantly enhanced expression of the LPH, CDX-2 and HNF-1alpha genes in CDX 2/HNF-1alpha co-transfected IEC-6 cells. These results suggest that thyroid and glucocorticoid hormones synergistically enhance expression of the LPH gene in CDX 2/HNF-1alpha co-transfected IEC-6 cells. PMID- 25744421 TI - A study of an aroma extraction method and evaluation of the aroma extract contribution to the palatability and reinforcement effect of dried bonito using mice. AB - Japanese cuisine has provided satisfying meals by fully utilizing the characteristic aroma and taste of katsuodashi (dried bonito broth), though it is not rich in sugars or fats. Katsuodashi is a very basic and indispensable element in Japanese cuisine, and is a hot water extract of katsuobushi (dried bonito). It has been reported that a dextrin solution containing natural dried bonito broth has a significant reinforcement effect, and has been suggested that the olfactory stimulation is important for the reinforcement effect. We examined various source materials for broth and identified an optimal method of aroma extraction by two bottle choice and conditioned place preference tests in mice. By two-bottle choice tests, a solution containing arabushi (a type of katsuobushi) aroma extract obtained by a supercritical CO2 extraction method showed a significantly high preference. The conditioned place preference test showed the dashi-taste solution with arabushi supercritical CO2 extract had a reinforcement effect. Our results suggest that the arabushi extract obtained by supercritical CO2 extraction contains components responsible for preference and reinforcement effects in mice; it could become conducive to making Japanese cuisine more satisfying and palatable. PMID- 25744422 TI - Large amounts of picolinic acid are lethal but small amounts increase the conversion of tryptophan-nicotinamide in rats. AB - Picolinic acid (PiA) is an endogenous metabolite of tryptophan that has been reported to possess a wide range of physiological actions. We investigated the effects of dietary PiA on the metabolism of tryptophan to nicotinamide in growing rats. Feeding an ordinary diet containing 1% PiA to growing rats (6 wk) caused death within a few days. Toxicity of PiA was higher than that of analogs such as nicotinic acid and quinolinic acid. Feeding an ordinary diet containing 0.05% and 0.1% PiA did not elicit decreased intake of food or loss in body weight. PiA did not affect the in vitro liver activities of quinolinic acid phosphoribosyltransferase or alpha-amino-beta-carboxymuconate-epsilon semialdehyde decarboxylase (ACMSDase, a Zn-dependent enzyme). Concentrations of NAD and NADP in the liver and blood were not affected by PiA. PiA administration did not affect tryptophan metabolites such as anthranilic acid, kynurenic acid, and xanthurenic acid. However, quinolinic acid and subsequent metabolites such as nicotinamide and its catabolites were increased by administration of a diet containing 0.05% PiA but not by a 0.1% PiA diet. These results suggest that the in vivo activity of ACMSDase is controlled by the Zn level. Therefore, a small amount of PiA has a beneficial effect for conversion of tryptophan to nicotinamide, but an excessive amount of PiA can be very toxic. PMID- 25744423 TI - Comparison of the effects of three persimmon cultivars on lipid and glucose metabolism in high-fat diet-fed mice. AB - We compared the effects of three persimmon cultivars, one nonastringent-type fruit (Fuyu) and two astringent-type fruits (Hiratanenashi and Hachiya), on the lipid and glucose metabolism of high-fat diet-fed mice. Persimmon samples prepared from young fruits of the three cultivars contained around 80% dietary fiber and differed in their bile acid-binding abilities and tannin contents. C57BL/6J mice were fed a modified AIN76 high-fat diet supplemented with 2% of each persimmon sample instead of cellulose for 10 wk. All cultivars significantly accelerated fecal bile acid secretion, depending on the bile acid-binding ability of the cultivars. Hiratanenashi and Hachiya, the cultivars with a strong bile acid-binding ability, prevented any increase in fasting blood glucose and plasma nonesterified fatty acid levels. Hachiya, the cultivar with the highest tannin content, also tended to prevent an increase in plasma non-high-density lipoprotein cholesterol levels. However, Fuyu, the cultivar with the lowest bile acid-binding ability and tannin content, had no effect on lipid or glucose metabolism. These effects linked to expression of the genes related to lipid and energy metabolism, including the cytochrome P450 7A1 gene in the liver and the uncoupling protein 3 gene in the brown adipose tissue. These results indicate that the beneficial effects of these cultivars on lipid and glucose metabolism are closely related to their bile acid-binding ability and tannin content. PMID- 25744424 TI - Effect of Active Hexose Correlated Compound (AHCC) in alcohol-induced liver enzyme elevation. AB - To investigate the effects of Active Hexose Correlated Compound (AHCC) supplementation and the mechanism action of AHCC in patients with alcohol-induced mildly elevated liver enzyme levels, participants were randomly allocated to the placebo, 1 g AHCC, or 3 g AHCC group and took the supplement for 12 wk. Subjects visited the hospital for clinical and biochemical measurements, for examination of adverse events, to return unused supplements, and to obtain their next supplements. Biochemical tests including liver enzymes, a questionnaire survey, and anthropometric measurements were collected at baseline and every 4 wk thereafter. Adherence and adverse events were evaluated. After 12 wk of supplementation, the percentage change in alanine aminotransferase (ALT) level was significantly different between the placebo (4.02+/-59.07%) and both AHCC groups (1 g AHCC: 223.89+/-20.59%, 3 g AHCC: 224.09+/-30.73%) (p=0.04). Serum levels of tumor necrosis factor-alpha (p<0.05) and interleukin-1beta (p<0.01) were significantly lower, while those of adiponectin were higher in both AHCC groups than in the placebo group (p<0.01). AHCC supplementation for 12 wk may improve the levels of liver enzymes and circulating pro-inflammatory and anti inflammatory cytokines in patients with alcohol-induced liver enzyme elevation with mildly elevated liver enzyme levels. PMID- 25744425 TI - Combination of bevacizumab and acyclic retinoid inhibits the growth of hepatocellular carcinoma xenografts. AB - The prognosis of patients with hepatocellular carcinoma (HCC) is poor and the development of effective treatments for this malignancy, including combination chemotherapy, is required. This study examined the possible combined inhibitory effects of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, and acyclic retinoid (ACR), which can prevent the development of HCC, on the growth of Huh7 human HCC cells. Xenograft tumors were produced by subcutaneously injecting Huh7 cells into nude mice. Starting 1 wk after the tumor cell injection, the mice were treated with bevacizumab alone (5 mg/kg body weight, subcutaneous injection, twice a week), ACR alone (given in a diet containing 0.03%), or their combination for 6 wk, and the effects of these regimens on xenograft growth were examined. Combined treatment with bevacizumab plus ACR significantly suppressed the growth of Huh7 xenografts. The combination of these agents significantly inhibited the phosphorylation of the Akt protein in tumor tissues. With combination therapy, the population of Ki-67-positive cells in xenografts decreased, while that of TUNEL-positive cells increased. The combination of bevacizumab and ACR exerts growth-suppressing effects on HCC cells by inhibiting cell proliferation and inducing apoptosis. This combination might be an effective regimen for the treatment of HCC. PMID- 25744426 TI - Development of oral immunotherapy model using B10.A mice and egg white lysozyme. AB - Oral immunotherapy for food allergy has been the focus of a lot of attention recently. The patients have to eat allergenic food instead of eliminating it in this therapy and there is no established standard method yet. To promote clear understanding and improvement of oral immunotherapy, the present study using B10.A mice investigated the effect of multiple oral administration of a model antigen, egg-white lysozyme, on both the antibody response and the anaphylactic reaction induced by subsequent administration of lysozyme. Various doses of egg white lysozyme (0-100 mg/mouse) were administered to mice intragastrically for 6 d; then additional lysozyme was administered via the intraperitoneal route in all groups. Lysozyme-specific antibody responses were promptly induced by the first oral administration and enhanced by intraperitoneal administration. An anaphylactic reaction was further induced in these sensitized mice by intragastric administration of lysozyme, and the symptoms of shock were compared in order to evaluate the effects of pretreatment. Interestingly, the decrease in rectal temperature which is one of the common anaphylactic symptoms in mice was suppressed in all of the oral pre-administration groups, and the effects were highest in the group that received 20 mg. Consequently, this study using B10.A mice has shown that sensitization can be induced by intragastric administration of lysozyme instead of oral tolerance; however, anaphylactic shock induced by subsequent intragastric administration of lysozyme is suppressed. This mouse model would be useful for assessing the method of oral immunotherapy. PMID- 25744428 TI - Synchronous mucinous colonic adenocarcinoma and multiple small intestinal adenocarcinomas: report of a case and review of literature. AB - With the wide use of diagnostic imaging modalities, multiple primary malignancies frequently occur; different associations of malignancies have been reported. We describe the case of a primary mucinous adenocarcinoma of large bowel synchronous with three primary poorly differentiated adenocarcinomas of ileum. This type of association has not been described yet; since computed tomography increasingly is proving to be highly accurate in detection of colon cancer, this technique is recommended in such patients. PMID- 25744427 TI - Structural and functional cardiac analyses using modern and sensitive myocardial techniques in adult Pompe disease. AB - The purpose of this study was to analyze comprehensively the heart using modern and sensitive myocardial techniques in order to determine if structural or functional cardiac alterations are present in adult Pompe disease. Twelve patients with adult Pompe disease and a control group of 187 healthy subjects of similar age and gender were included. Structural and functional cardiac characteristics were analyzed by conventional and 2D speckle-tracking echocardiography. In addition, in a subgroup of adult Pompe patients, we analyzed the myocardial and musculoskeletal features by means of cardiac and whole-body muscle magnetic resonance imaging. Patients with Pompe disease had significant structural and functional musculoskeletal alterations such as atrophy with fatty replacement and weakness in trunk and extremities. In contrast, Pompe patients had similar structural and functional myocardial features to healthy subjects (LV strain -20.7 +/- 1.9 vs. -21.3 +/- 2.1%; RV strain -24.2 +/- 5.3 vs. -24.8 +/- 3.8%; LA strain 41.5 +/- 10.3 vs. 44.8 +/- 11.0%; P > 0.05; and no evidence of LV and RV hypertrophy or LA enlargement). In addition, there was no evidence of valvular cardiac alterations, electrocardiographic abnormalities, or myocardial fibrosis in Pompe patients. In the current study analyzing the heart with modern and sensitive myocardial techniques, we evidenced that functional and structural cardiac alterations are not present when Pompe disease begins in adulthood. Therefore, these findings suggest that adult Pompe disease should not be taken into consideration in the differential diagnostic of structural or functional cardiac disorders. PMID- 25744429 TI - Family characteristics and health behaviour as antecedents of school nurses' concerns about adolescents' health and development: a path model approach. AB - BACKGROUND: Family socio-economic factors and parents' health behaviours have been shown to have an impact on the health and well-being of children and adolescents. Family characteristics have also been associated with school nurses' concerns, which arose during health examinations, about children's and adolescents' physical health and psychosocial development. Parental smoking has also been associated with smoking in adolescents. OBJECTIVES: The aim of this study was to determine to what extent school nurses' concerns about adolescents' physical health and psychosocial development related to family characteristics are mediated through parents' and adolescents' own health behaviours (smoking). DESIGN: A path model approach using cross-sectional data was used. SETTINGS: In 2008-2009, information about health and well-being of adolescents was gathered at health examinations of the Children's Health Monitoring Study. PARTICIPANTS: Altogether 1006 eighth and ninth grade pupils in Finland participated in the study. METHODS: The associations between family characteristics, smoking among parents and adolescents and school nurses' concerns about adolescents' physical health and psychosocial development were examined using a structural equation model. RESULTS: Paternal education had a direct, and, through fathers' and boys' smoking, an indirect association with school nurses' concerns about the physical health of boys. Paternal labour market status and family income were only indirectly associated with concerns about the physical health of boys by having an effect on boys' smoking through paternal smoking, and a further indirect effect on concerns about boys' health. In girls, only having a single mother was strongly associated with school nurses' concerns about psychosocial development through maternal and adolescent girl smoking. CONCLUSIONS: Socio-economic family characteristics and parental smoking influence adolescent smoking and are associated with school nurses' concerns about adolescents' physical health and psychosocial development. The findings underline the importance of comprehensively taking into account adolescents' and parents' health behaviours and the family situation in health-care contacts when providing health counselling. PMID- 25744430 TI - Development and validation of an iodine-specific FFQ to estimate iodine intake in Australian pregnant women. AB - Adequate iodine is important during pregnancy to ensure optimal growth and development of the offspring. We validated an iodine-specific FFQ (I-FFQ) for use in Australian pregnant women. A forty-four-item I-FFQ was developed to assess iodine intake from food and was administered to 122 pregnant women at 28 weeks gestation. Iodine supplement use was captured separately at 28 weeks gestation. Correlation between iodine intake from food estimated using the I-FFQ and a 4 d weighed food record as well as correlation between total iodine intake and 24 h urinary iodine excretion (UIE), 24 h urinary iodine concentration (UIC), spot UIC and thyroid function were assessed at 28 weeks gestation. A moderate correlation between the two dietary methods was shown (r 0.349, P< 0.001), and it was strengthened with the addition of iodine supplements (r 0.876, P<0.001). There was a fair agreement (k= 0.28, P<0.001) between the two dietary measures in the classification of women as receiving adequate (>=160 MUg/d) or inadequate (<160 MUg/d) iodine intake from food, but the limits of agreement from the Bland-Altman plot were large. Total iodine intake was associated with 24 h UIE (beta = 0.488, P<0.001) but not with spot UIC. Iodine intake from food using the I-FFQ was assessed at study entry (<20 weeks gestation) in addition to 28 weeks gestation, and there was a strong correlation in iodine intake at the two time points (r 0.622, P<0.001), which indicated good reproducibility. In conclusion, the I-FFQ provides a valid tool for estimating iodine intake in pregnant women and can be used to screen women who are at risk of inadequate intake. PMID- 25744431 TI - Short communication: study on veterinarian communication skills preferred and perceived by dairy farmers. AB - Effective communication in dairy farms improves management and herd health, and it is also pivotal for public health in a "from farm to fork" perspective. This paper reports the results of a descriptive study on dairy farmers' perception of veterinarian and other consultants' communication skills. Perceived communication skills showed to be significantly lower than desired ones for all the professional figures considered. Despite these unsatisfactory results, veterinarian were the most appreciated and skilled consultants. The observed farmers' dissatisfaction increases farmers' difficulties in identifying proper targets and proper consultant. An increase in the skill of veterinarian to deliver effective and tailored messages could help to overcome the problem. PMID- 25744432 TI - Virulence attenuation of a Mycobacterium avium subspecies paratuberculosis S-type strain prepared from intestinal mucosa after bacterial culture. Evaluation in an experimental ovine model. AB - The differences in pathogenicity between an inoculum derived directly from an intestinal tissue homogenate from a paratuberculosis affected sheep and the S type Mycobacterium avium subsp. partuberculosis (Map) strain isolated in laboratory media from the mentioned homogenate were assessed in two experiments in lambs. Specific peripheral immune responses were significantly lower in animals inoculated with the cultured organisms that showed only granulomatous lesions in the intestinal lymphoid tissue. However, in the homogenate group, more abundant granulomata also occurred in the lamina propria. Map was isolated only in lambs infected with the culture strain. Map DNA was demonstrated by nested-PCR in all the lambs but in a lower proportion (57.1% vs 100%) in those from the culture group. Under these particular experimental conditions, the results suggest that an attenuation of Map virulence has occurred in the cultured strain compared to the initial tissue homogenate, even after a low number of passages. PMID- 25744433 TI - Absorption and disposition of florfenicol after intravenous, intramuscular and subcutaneous dosing in alpacas. AB - The objectives of this study were to define disposition and systemic availability of florfenicol in alpacas. Administration of 20 mg/kg doses to 8 male alpacas by i.v., i.m. and s.c. routes was performed by randomized, 3-way crossover design. Clearance and steady state volumes (Vdss) after i.v. injection were 5 ml/min/kg and 775 ml/kg respectively. Mean residence time (MRT) and terminal phase half life (T1/2lambdaz) were 2.8 h and 2 h respectively. Maximum serum concentrations (Cmax) after i.m. were higher than s.c. administration (p = 0.034). After s.c. dosing, T1/2lambdaz and MRT were greater than after i.m. injection (p < 0.001; p = 0.006 respectively). Mean absorption time (MAT) after s.c. dosing was also prolonged (p = 0.006). Fractional absorption of florfenicol after i.m. and s.c. was not different (p > 0.05). Serum florfenicol concentrations remained >1.0 ug/ml for 20 h after i.m. dosing. Differences in rate and extent of florfenicol absorption after extravascular dosing could influence therapeutic outcomes. PMID- 25744434 TI - The effect of mitochondrial ATP-sensitive potassium channels on apoptosis of chick embryo cecal cells by Eimeria tenella. AB - The objective of this study was to investigate the effect of mitochondrial ATP sensitive potassium (mitoKATP) channels on apoptosis induced by Eimeria tenella. At 24, 48, 72, 96 and 120 h after Eimeria tenella infection, TUNEL assays and translation of phosphatidyl serines to the host cell plasma membrane surface showed that diazoxide-treated chick embryo cecal cells underwent less apoptosis (P <0.05), while light microscopy showed that infection rates of treated cells were higher (P <0.01) than untreated cells. Caspase 9 and caspase 3 of infected cells were activated less (P <0.01) in diazoxide-treated cells than untreated cells. These results indicate that opening mitoKATP channels can protect chick embryo cecal cells from mitochondria-dependent apoptosis induced by Eimeria tenella by inhibiting activations of caspase 9 and caspase 3. PMID- 25744435 TI - Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models. AB - Histiocytic sarcoma (HS) in dogs exhibits aggressive clinical and biological behavior. Currently, no effective treatments are available for dogs with HS. Survivin, a member of a family of apoptosis protein inhibitors, could serve as a potential therapeutic target in several canine cancers. Sepantronium bromide (YM155) has recently been established as a novel survivin-targeting agent. The aim of this study was to use YM155 as a tool for evaluating survivin-targeted therapies against dogs with HS, and to investigate how YM155 treatment affects antitumor and chemotherapeutic efficacies in murine xenograft models using canine HS cells. The results showed that in HS cells with lomustine (CCNU) resistance, YM155 treatment suppressed both the cell-growth potential and cell resistance to CCNU, which essentially increases the chemotherapy efficacy in the murine models. The evidence presented here supports the favorable preclinical evaluation that survivin-targeted therapies might be effective against HS in dogs. PMID- 25744436 TI - Introduction. PMID- 25744437 TI - BRAF V600E mutation-specific antibody: A review. AB - The significance of BRAF mutations in neoplasia was first recognized in 2002 when mutations were discovered in a broad range of cancers. Numerous subsequent studies expanded our understanding of BRAF V600E as a critical diagnostic, prognostic, and predictive biomarker in many cancers. Additionally, the advent of small-molecule inhibitors of BRAF V600E rendered assessment of BRAF mutation status essential in tumors such as melanoma. In clinical practice, evaluation of BRAF mutation status has routinely been performed by DNA-based assays utilizing polymerase chain reaction (PCR). However, molecular testing is not available at many hospitals since it is time-consuming, expensive, and requires expertise in molecular techniques. The first BRAF V600E-specific antibody was reported in 2011 (clone VE1). A purified version of this antibody as well as a second monoclonal antibody targeted to BRAF V600E is now commercially available. In this review, clinicopathologic characteristics associated with BRAF-mutant tumors will be highlighted, and the prognostic and predictive implications of a BRAF V600E mutation will be discussed with a focus on melanoma, thyroid carcinoma and colorectal carcinoma. Additionally, we will review the correlation between immunohistochemistry and molecular results and deliberate how BRAF immunohistochemistry might be utilized in the evaluation of these tumors. PMID- 25744438 TI - Fine Needle Aspiration Cytology: A Tool to Study NHERF1 Expression as a Potential Marker of Aggressiveness in Lung Cancer. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide and cytology is often the only diagnostic approach. Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) is a protein implicated in various cancers. However, the function of NHERF1 in lung cancer has not been described. The aim of this study was to evaluate the biological role of NHERF1 in lung tumors using fine needle aspirates cytology (FNAC) and to verify the utility and reliability of FNACs. We assessed NHERF1 expression by immunohistochemistry on 26 advanced NSCLC FNAC and on 18 surgical NSCLC samples. The relationship of its expression with clinicopathological features including stage and histotype was analyzed. In FNACs, cytoplasmic and nuclear NHERF1 expression was significantly higher than membranous expression. In surgical samples, cytoplasmic NHERF1 was significantly higher than both membranous and nuclear NHERF1 expression. In these tumors, a higher cytoplasmic and lower nuclear NHERF1 expression was observed compared to advanced NSCLCs (p < 0.0001, p < 0.05, respectively). In all 44 NSCLCs, a significant correlation was found between cytoplasmic NHERF1 expression and stage (p = 0.001), and between nuclear NHERF1 expression and histotype (p = 0.015). To our knowledge, this is the first study analyzing the immunohistochemical expression of NHERF1 in lung cancer using FNAC samples. We conclude that FNACs provide useful material for detection of NHERF1 localization and expression, and that high nuclear NHERF1 expression may be a potential marker of aggressiveness in NSCLC. PMID- 25744439 TI - IgG Aggregation Mechanism for CHO Cell Lines Expressing Excess Heavy Chains. AB - Aggregates in protein therapeutics like IgG monoclonal antibodies (mAb) are detrimental to product safety and efficacy. It has been reported that aggregates form in Chinese hamster ovary (CHO) cell lines expressing greater amount of heavy chain (HC) than light chain (LC). In this study, we observed that aggregates could form within the cells with excess HC and were partially secreted into the supernatant. The aggregates in the supernatant consisted of mainly HC and were partially dissociated under either reducing or denaturing conditions. Mutation of a predicted free cysteine on HC to prevent disulfide bonding did not reduce aggregation. Re-transfecting CHO cells with excess HC with more BiP, an important IgG molecular chaperone, partially reduced unwanted aggregates and fragments possibly by helping retain more incomplete products within the cell for either proper assembly or degradation. A second transfection of LC into CHO cells with excess HC to increase the LC expression to a level greater than the HC expression successfully removed all aggregates and fragments. mAb product aggregation in CHO cells with excess HC occur due to a combination of limited chaperones and LC:HC ratio. These results provide added insights to aggregate formation and would be useful for development of mAb cell lines with reduced aggregates. PMID- 25744440 TI - Quality of sleep in young onset Parkinson's disease: Any difference from older onset Parkinson's disease. AB - BACKGROUND: Sleep disorders occur commonly in Parkinson's disease and are often under-recognized and under treated in clinical practice. OBJECTIVES: To determine the quality of sleep in patients with Young onset Parkinson's disease (YOPD) and to note whether there is any difference in quality of sleep from those patients with older onset Parkinson's disease (OOPD). METHODS: One hundred and fifty six patients with Parkinson's disease (YOPD-51, OOPD-105) were clinically examined and quality of sleep was determined using Pittsburgh sleep quality index (PSQI), Parkinson's disease Sleep Scale (PDSS) and Epworth Sleep Scale (ESS). Other scales included Unified Parkinson's Disease Rating Scale -part III (UPDRS-III), Hoehn & Yahr Stage, Mini Mental Status Examination, Hamilton anxiety rating scale and Hamilton depression rating scale. RESULTS: The frequency of insomnia was higher in OOPD (55.2%) as compared to YOPD (27.5%) group (p = 0.001). The frequency of nightmares was lower in YOPD (7.8%) when compared to OOPD (24.8%) group (p = 0.012). The mean hours of actual sleep per night were higher in YOPD patients. Global PSQI score was better in YOPD indicating good overall sleep quality in YOPD patients. The total ESS score was significantly lower in YOPD (p = 0.019). The total PDSS score was significantly better in YOPD patients (p = 0.018). CONCLUSIONS: Patients with YOPD had an overall better quality of sleep with lesser incidence of insomnia, nightmares, daytime sleepiness and restlessness during sleep. PMID- 25744441 TI - En face OCT angiography demonstrates flow in early type 3 neovascularization (retinal angiomatous proliferation). AB - INTRODUCTION: The characteristics of type 3 neovascularization (NV), also known as retinal angiomatous proliferation, have been well described clinically, as well as with fluorescein angiography (FA), indocyanine green angiography, and optical coherence tomography (OCT). OCT angiography (OCT-A) is a novel and non invasive technique for imaging retinal microvasculature by detecting changes, with respect to time, in reflectivity related to blood flow. METHOD: In this case series, we describe two patients who presented with type 3 NV and underwent clinical examination and multimodal imaging, including OCT-A. RESULTS: In the first patient, OCT-A demonstrated flow within two separate lesions in the same eye, one of which was only weakly detected by FA. In the second patient, sequential OCT-A demonstrated a reduction in intralesional flow following intravitreal therapy. CONCLUSIONS: OCT-A may have a role in the early diagnosis of type 3 NV and in assessing the response to treatment. Further studies are needed to determine sensitivity and specificity. PMID- 25744442 TI - Implantation of refractive multifocal intraocular lens with a surface-embedded near section for cataract eyes complicated with a coexisting ocular pathology. AB - PURPOSE: To evaluate the postoperative outcomes of cataract eyes complicated with coexisting ocular pathologies that underwent implantation of a refractive multifocal intraocular lens (MIOL) with a surface-embedded near section. METHODS: LENTIS MPlus (Oculentis GmbH) refractive MIOLs were implanted in 15 eyes with ocular pathologies other than cataract (ie, six high-myopia eyes with an axial length longer than 28 mm, two fundus albipunctatus eyes, two branch retinal-vein occlusion eyes, four glaucoma eyes (one with high myopia), and two keratoconus eyes). Uncorrected or corrected distance and near visual acuity (VA) (UDVA, UNVA, CDVA, and CNVA), contrast sensitivity, and defocus curve were measured at 1 day and 6 months postoperatively, and each patient completed a 6-month postoperative questionnaire regarding vision quality and eyeglass use. RESULTS: Thirteen eyes (87%) registered 0 or better in CDVA and 12 eyes (73%) registered better than 0 in CNVA. Contrast sensitivity in the eyes of all patients was comparable to that of normal healthy subjects. No patient required eyeglasses for distance vision, but three patients (20%) required them for near vision. No patient reported poor or very poor vision quality. CONCLUSION: With careful case selection, sectorial refractive MIOL implantation is effective for treating cataract eyes complicated with ocular pathologies. PMID- 25744443 TI - Botulinum toxin injection for the treatment of epiphora in lacrimal outflow obstruction. AB - PURPOSE: To describe our experience with the use of botulinum toxin (BoNTA) for the symptomatic treatment of lacrimal outflow obstruction. METHODS: We retrospectively reviewed the case notes of patients with epiphora due to lacrimal outflow obstruction who chose to have injections of botulinum toxin into the palpebral lobe of the lacrimal gland instead of surgery between 2009 and 2014. Epiphora was graded subjectively with Munk scores obtained before and after treatment as well as qualitative degree of improvement reported by the patients. Severity and duration of side effects were also noted. RESULTS: Seventeen patients (22 eyes, mean age 70.3, 4 males and 13 females) were identified. A mean of 3.5 (range; 1-10) injections of BoNTA (Botox, Allergan; 1.25-7.5 units) were given per eye. The mean interval between injections was 3.9 months (range 3-6). The mean Munk score (3.4, range 2-4) improved significantly after treatment to 1.6 (range: 0-3, P=0.0001 paired two-tailed t-test). Epiphora completely resolved in a fifth, improved by up to 60-90% in a half and only 'a little better' in a further fifth. Temporary bruising and diplopia (lasting 2 weeks) was reported in 12% (2/17). CONCLUSION: We report our outcomes for BoNTA to the palpebral lobe of the lacrimal gland in patients with lacrimal outflow obstruction epiphora seeking alternatives to surgery. This data provide further evidence for informed consent and for commissioning organisations considering the funding of this treatment. PMID- 25744444 TI - Retinal artery lesions and long-term outcome in Chinese patients with acute coronary syndrome. AB - OBJECTIVE: To investigate the relationship between staging of retinal artery lesions and the prognosis of acute coronary syndrome (ACS) in a Chinese population. METHODS: A total of 436 Chinese patients with ACS underwent coronary angiography and the eyes fundus examinations. All the patients were divided into three groups: group 1, no retinal artery lesions (n=111); group 2, retinal artery lesions of =Stage 2 (Stage 2-the changes similar to those in Stage 1, but more prominent, Stage 3-the arteries have a 'copper wire' appearance and this is much more arteriovenous compression, and Stage 4-the arteries have a 'silver wire' appearance and the arteriovenous crossing changes are more severe; n=190). The endpoints were main adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, myocardial infarction (MI), and stroke after 3-6 years of follow-up. RESULTS: There was no significant differences of the baseline data among the three groups. After 3-6 years of follow-up, we found that patients of group 3 had more MACCE and death than those of the group 1 or group 2. Cox regression analysis found that factors related to the prognosis of ACS was staging of retinal artery lesions (P<0.05) in addition to traditional risk factors such as age, gender, diabetes, hypertension, and hypercholesterolemia. CONCLUSION: Staging of retinal artery lesions plays an important role in the long term outcome of patients with ACS. PMID- 25744445 TI - Myopic foveoschisis: a clinical review. AB - To review the literature on epidemiology, clinical features, diagnostic imaging, natural history, management, therapeutic approaches, and prognosis of myopic foveoschisis. A systematic Pubmed search was conducted using search terms: myopia, myopic, staphyloma, foveoschisis, and myopic foveoschisis. The evidence base for each section was organised and reviewed. Where possible an authors' interpretation or conclusion is provided for each section. The term myopic foveoschisis was first coined in 1999. It is associated with posterior staphyloma in high myopia, and is often asymptomatic initially but progresses slowly, leading to loss of central vision from foveal detachment or macular hole formation. Optical coherence tomography is used to diagnose the splitting of the neural retina into a thicker inner layer and a thinner outer layer, but compound variants of the splits have been identified. Vitrectomy with an internal limiting membrane peel and gas tamponade is the preferred approach for eyes with vision decline. There has been a surge of new information on myopic foveoschisis. Advances in optical coherence tomography will continually improve our understanding of the pathogenesis of retinal splitting, and the mechanisms that lead to macular damage and visual loss. Currently, there is a good level of consensus that surgical intervention should be considered when there is progressive visual decline from myopic foveoschisis. PMID- 25744446 TI - A diagnostic study of thoracic myelopathy due to ossification of ligamentum flavum. AB - PURPOSE: We set out to establish a magnetic resonance imaging (MRI) and computed tomography (CT)-based diagnostic method for determining the responsible segments in thoracic myelopathy due to ossification of the ligamentum flavum (OLF). METHODS: Forty-four patients who underwent surgery for treatment of myelopathy due to OLF between June 2005 and May 2013 were enrolled in this study as the myelopathy group. Forty-four patients who were identified through CT and MRI scans to have OLF but had no definite neurologic deficits prior to the examination were included as the control group. MRI and CT examination were reviewed, and the degree of spinal canal compromise was graded on axial T2 weighted MRI. Anteroposterior spinal canal diameter was measured at the maximally stenosed level on axial and sagittal CT. The canal grade and the cross-section area-occupying ratio were measured and calculated on the CT scans. The diagnostic coincidence rates for the indices were then compared. RESULTS: Cases of Grade IV were all in the myelopathy group while cases of Grade II were all in the control group. The canal grade (paramedian) was the most relevant continuous variable with the largest JOA score (r = 0.685, P < 0.005). A canal grade (paramedian) of <60% can be used as a critical value for determining OLF-induced myelopathy (sensitivity and specificity, 95.5%). CONCLUSION: Spinal canal compromise is relevant to spinal cord deficits in patients with OLF, and a canal grade (paramedian) can be used to quantify spinal cord deficits. Additionally, a canal grade (paramedian) of <60% on axial CT scan can serve as a critical value for diagnosing OLF-induced myelopathy, especially for Grade III compression on T2 weighted MRI. PMID- 25744448 TI - Synthesis of Z-scheme g-C3N4-Ti(3+)/TiO2 material: an efficient visible light photoelectrocatalyst for degradation of phenol. AB - In this study, a photocatalytic material g-C3N4-Ti(3+)/TiO2 nanotube arrays was prepared by a facile and viable approach involving a heat treatment followed by an electrochemical reduction step, and it was characterized using instrumental techniques such as X-ray diffraction pattern, Fourier transform-infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy and UV-vis diffuse reflectance spectra. The photocatalytic efficiency of the as prepared samples towards treating aqueous solution contaminated with phenol was systematically evaluated by a photoelectrocatalytic method and found to be highly dependent on the content of the g-C3N4. At the optimal content of g-C3N4, the apparent photocurrent density of g-C3N4-Ti(3+)/TiO2 was four times higher than that of the pristine TiO2 under visible-light illumination. The enhanced photoelectrocatalytic behavior observed for g-C3N4-Ti(3+)/TiO2 was ascribed to a cumulative impact of both g-C3N4 and Ti(3+), which enhances the photoresponsive behavior of the material into the visible region and facilitates the effective charge separation of photoinduced charge carriers. PMID- 25744447 TI - Bcl-2 phosphorylation triggers autophagy switch and reduces mitochondrial damage in limb remote ischemic conditioned rats after ischemic stroke. AB - Autophagy, an important intracellular degradation pathway, has been reported to clear impaired mitochondria and reduce mitochondria-mediated injury in ischemic disease. Our study and other recent investigations have shown that AKT-dependent autophagy contributes to the neuroprotection afforded by limb remote ischemic conditioning (RIC) in experimental stroke. However, how AKT triggers RIC-based autophagy and whether RIC-afforded autophagy is beneficial for mitochondrial function after cerebral ischemia remains unclear. The disruption of the Bcl 2/Beclin1 complex has been reported to trigger autophagy formation in the condition of Bcl-2 phosphorylation at Ser70. We investigated whether Bcl-2 phosphorylation triggers RIC-based autophagy and thereby confers RIC-induced neuroprotection against mitochondrial injury, using a transient cerebral ischemic rat model. We demonstrated that rats undergoing RIC treatment 30 min after the onset of ischemia (I-30) and at reperfusion (R-0) significantly upregulated Bcl-2 phosphorylation. Immunoprecipitation revealed that RIC increased dissociation of the Bcl-2/Beclin1 complex, leading to a higher level of autophagy than in ischemia/reperfusion rats. Furthermore, AKT activation was shown to play a critical role in regulating Bcl-2-mediated autophagy, as an AKT inhibitor (LY294002, AKTi) administered 30 min prior to ischemia significantly suppressed Bcl-2 phosphorylation and Bcl-2/Beclin1 complex dissociation, thereby reducing autophagy in RIC rats. Blocking Bcl-2 phosphorylation-dependent autophagy with AKTi suppressed RIC-afforded protection on mitochondrial potential and mitochondrial-dependent cell death effector pathway. These findings indicate that Bcl-2 phosphorylation and thereby Bcl-2/Beclin1 complex disruption play a crucial role in triggering autophagy and reducing mitochondrial damage in RIC rats after cerebral ischemia and require the involvement of the AKT activation. PMID- 25744449 TI - Exome sequencing to detect rare variants associated with general cognitive ability: a pilot study. AB - Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile. PMID- 25744450 TI - Imposed identities and limited opportunities: Advocacy agency staff perspectives on the construction of their clients with intellectual disabilities. AB - Intellectual disability is commonly conceptualised as stigmatised identity; however, within the literature, the notion of a damaged identity is contested. The aim of this research was to explore the social construction of intellectual disability from the perspective of staff who work closely with people with intellectual disabilities. Informed by a contextualist perspective, this research was based on interviews with five staff members of an advocacy agency in a regional area of Australia. Causal layered analysis was used to deconstruct the interview data. Analysis of the interactions that emerged across the causal layers revealed a complex dynamic of world views, which served to dehumanise people with intellectual disabilities and blame them for their own fate (victim blaming). For transformative change to occur, understandings of the 'problems' of intellectual disability must be reformulated and those social structures and processes that support the relationship between the powerful and the powerless must be challenged. PMID- 25744451 TI - Antiviral activity of Paulownia tomentosa against enterovirus 71 of hand, foot, and mouth disease. AB - The bark, leaves, and flowers of Paulownia trees have been used in traditional Chinese medicine to treat infectious and inflammatory diseases. We investigated the antiviral effects of Paulownia tomentosa flowers, an herbal medicine used in some provinces of P. R. China for the treatment of skin rashes and blisters. Dried flowers of P. tomentosa were extracted with methanol and tested for antiviral activity against enterovirus 71 (EV71) and coxsackievirus A16 (CAV16), the predominant etiologic agents of hand, foot, and mouth disease in P. R. China. The extract inhibited EV71 infection, although no effect was detected against CAV16 infection. Bioactivity-guided fractionation was performed to identify apigenin as an active component of the flowers. The EC50 value for apigenin to block EV71 infection was 11.0 uM, with a selectivity index of approximately 9.3. Although it is a common dietary flavonoid, only apigenin, and not similar compounds like naringenin and quercetin, were active against EV71 infection. As an RNA virus, the genome of EV71 has an internal ribosome entry site that interacts with heterogeneous nuclear ribonucleoproteins (hnRNPs) and regulates viral translation. Cross-linking followed by immunoprecipitation and reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that EV71 RNA was associated with hnRNPs A1 and A2. Apigenin treatment disrupted this association, indicating that apigenin suppressed EV71 replication through a novel mechanism by targeting the trans-acting factors. This study therefore validates the effects of Paulownia against EV71 infection. It also yielded mechanistic insights on apigenin as an active compound for the antiviral activity of P. tomentosa against EV71 infection. PMID- 25744452 TI - Nitric oxide is an important regulator of heme oxygenase-1 expression in the lipopolysaccharide and interferon-gamma-treated murine macrophage-like cell line J774.1/JA-4. AB - Heme oxygenase-1 (HO-1) catabolizes the degradation of heme into bilirubin, carbon monoxide, and iron ions. The HO-1 products provide antioxidant cytoprotection in addition to having potent antiinflammatory and immunomodulatory functions. HO-1 is induced by its substrate heme and environmental factors including oxidative and heat stresses. Although previous studies reported that lipopolysaccharide (LPS) induced the expression of both the HO-1 gene and its protein in macrophages, the major regulators of HO-1 expression remain unknown. To identify these regulators, we used two types of cell, the murine macrophage like cell line J774.1/JA-4 and its LPS-resistant mutant, LPS1916. Based on a comparison of the results obtained with these cells, we found that nitric oxide (NO) was closely linked to the induction of HO-1. Real-time polymerase chain reaction (PCR) showed that the time course for inducible HO-1 mRNA by LPS or LPS+interferon (IFN)-gamma was similar to that for inducible NO synthase (iNOS) mRNA. Furthermore, the expression of iNOS mRNA and protein increased earlier than that of HO-1 mRNA and protein. N-Nitro-L-arginine methyl ester, an NO synthase inhibitor, reduced both HO-1 expression and NO production in LPS+IFN-gamma treated JA-4 cells. Furthermore, NOC-12, an NO donor, significantly induced HO-1 expression not only in JA-4 but also in LPS1916 cells. Reactive oxygen species (ROS) scavengers, such as superoxide dismutase and catalase, did not affect HO-1 protein expression in LPS+IFN-gamma-treated JA-4 cells. These results suggest that, among ROS, NO plays an important role in HO-1 induction in activated macrophages treated with LPS+IFN-gamma. PMID- 25744453 TI - Combination effect of physical and gustatory taste masking for propiverine hydrochloride orally disintegrating tablets on palatability. AB - Orally disintegrating tablets (ODTs) containing propiverine hydrochloride (which is extremely bitter and leaves a feeling of numbness in the mouth) were prepared with a combined use of physical and organoleptic taste masking. Propiverine loaded masking particles (PLMPs) were prepared with different amounts of gastric soluble coatings as physical masking. ODTs without organoleptic masking were prepared by mixing each group of PLMPs with Ludiflash(r), crospovidone, and magnesium stearate. ODTs with organoleptic masking were also prepared by addition of L-menthol, aspartame, thaumatin, and cinnamon. Fifteen-minute dissolution of propiverine in solutions with pH 1.2 was >= 85% for all ODTs, whereas that in pH 6.8 solutions was <= 85% and increased with physical masking. A single blind randomized crossover trial was conducted. Ten healthy volunteers were asked to quantify the bitterness, numbness, and overall palatability using a 100-mm visual analog scale (VAS) at the period of disintegration as well as 1 and 5 min later. VAS scores of bitterness, numbness, and overall palatability improved along with increasing amounts of physical masking, and the effects persisted for 5 min. VAS scores for numbness increased over time regardless of the amount of physical masking. Bitterness, numbness, and overall palatability were significantly improved by organoleptic masking if the amount of physical masking was small. Combined use of physical and organoleptic masking is useful for improving palatability of ODTs containing propiverine. PMID- 25744454 TI - Splenic gene delivery system using self-assembling nano-complex with phosphatidylserine analog. AB - The recognition of phosphatidylserine on the erythrocyte membrane mediates erythrophagocytosis by resident spleen macrophages. The application of phosphatidylserine to a gene vector may be a novel approach for splenic drug delivery. Therefore, we chose 1,2-dioleoyl-sn-glycero-3-phospho-L-serin (DOPS) as an analogue of phosphatidylserine for splenic gene delivery of plasmid DNA (pDNA). In the present study, we successfully prepared a stable pDNA ternary complex using DOPS and polyethyleneimine (PEI) and evaluated its efficacy and safety. The pDNA/PEI complex had a positive charge and showed high transgene efficacy, although it caused cytotoxicity and agglutination. The addition of DOPS changed the zeta-potential of the pDNA/PEI complex to negative. It is known that anionic complexes are not taken up well by cells. Surprisingly, however, the pDNA/PEI/DOPS complex showed relatively high transgene efficacy in vitro. Fluorescence microscope observation revealed that the pDNA/PEI/DOPS complex internalized the cells while maintaining the complex formation. The injection of the pDNA/PEI complex killed most mice within 24 h at high doses, although all mice in the pDNA/PEI/DOPS complex group survived. The ternary complex with DOPS showed markedly better safety compared with the pDNA/PEI complex. The pDNA/PEI/DOPS complex showed high gene expression selectively in the spleen after intravenous injection into mice. Thus the ternary complex with DOPS can be used to deliver pDNA to the spleen, in which immune cells are abundant. It appears to have an excellent safety level, although further study to determine the mechanism of action is necessary. PMID- 25744455 TI - siRNA delivery into tumor cells by cationic cholesterol derivative-based nanoparticles and liposomes. AB - Previously, we reported that cationic nanoparticles (NP) composed of diamine-type cholesteryl-3-carboxamide (OH-Chol, N-(2-(2-hydroxyethylamino)ethyl)cholesteryl-3 carboxamide) and Tween 80 could deliver small interfering RNA (siRNA) with high transfection efficiency into tumor cells. In this study, we synthesized new diamine-type cationic cholesteryl carbamate (OH-C-Chol, cholesteryl (2-((2 hydroxyethyl)amino)ethyl)carbamate) and triamine-type carbamate (OH-NC-Chol, cholesteryl (2-((2-((2-hydroxyethyl)amino)ethyl)amino)ethyl)carbamate), and prepared cationic nanoparticles composed of OH-C-Chol or OH-NC-Chol with Tween 80 (NP-C and NP-NC, respectively), as well as cationic liposomes composed of OH-C Chol or OH-NC-Chol with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (LP C and LP-NC, respectively) for evaluation of their possible use as siRNA delivery vectors. LP-C and LP-NC/siRNA complexes (lipoplexes) exhibited larger gene silencing effects than NP-C and NP-NC/siRNA complexes (nanoplexes), respectively, in human breast tumor MCF-7 cells, although the NP-C nanoplex showed high association with the cells. In particular, LP-NC lipoplex could induce strong gene suppression, even at a concentration of 5 nM siRNA. From these results, cationic liposomes composed of OH-NC-Chol and DOPE may have potential as gene vectors for siRNA transfection to tumor cells. PMID- 25744456 TI - Cardenolide aglycones inhibit tumor necrosis factor alpha-induced expression of intercellular adhesion molecule-1 at the translation step by blocking Na+/K+ ATPase. AB - Cardiac glycosides, which are inhibitors of Na(+)/K(+)-ATPase, are classified into cardenolides and bufadienolides. We have recently shown that two cardenolide glycosides, ouabain and odoroside A, inhibit Na(+)/K(+)-ATPase, thereby preventing nuclear factor kappaB-inducible protein expression by blocking Na(+) dependent amino acid transport. In this study, we investigated the mechanism of action of cardenolide aglycones in tumor necrosis factor alpha (TNF-alpha) induced gene expression. Ouabagenin, digitoxigenin, and digoxigenin were found to inhibit the TNF-alpha-induced cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) in human lung carcinoma A549 cells. Those cardenolide aglycones did not inhibit the TNF-alpha-induced expression of ICAM-1 mRNA, but strongly inhibited the TNF-alpha-induced expression of ICAM-1 as translation product. The inhibition of the TNF-alpha-induced ICAM-1 expression by ouabagenin, digitoxigenin, and digoxigenin was significantly reversed by the ectopic expression of ouabain-resistant rat Na(+)/K(+)-ATPase alpha1 isoform. Moreover, knockdown of Na(+)/K(+)-ATPase alpha1 isoform augmented the inhibition of the TNF alpha-induced ICAM-1 expression by ouabagenin or ouabain. These results clearly indicate that cardenolide aglycones inhibit the TNF-alpha-induced ICAM-1 expression at the translation step by blocking Na(+)/K(+)-ATPase. PMID- 25744457 TI - Regulatory effect of bee venom on methamphetamine-induced cellular activities in prefrontal cortex and nucleus accumbens in mice. AB - Our previous studies demonstrated that subcutaneous injection of bee venom (BV) into the Zusanli (ST36) acupuncture point, namely BV acupuncture, dose dependently prevents conditioned place preference (CPP) induced by repeated injection of methamphetamine (METH) in mice. To expand on our observations, the present study was designed to determine the suppressive mechanisms of BV acupuncture in the development of METH-induced CPP by evaluating the changes in expression of DeltaFosB, phosphorylated extracellular signal-regulated kinase 1/2 (pERK), and phosphorylated calcium/calmodulin-dependent protein kinase type II (pCaMKII) in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in mice. Pre emptive treatment with BV at 30 min before repeated METH injection completely suppressed acquisition of CPP at the day 7 test session. METH-induced upregulation of DeltaFosB and pERK in PFC and NAc was significantly reduced by BV pretreatment. Expression of pCaMKII was significantly elevated by METH in NAc and reduced in PFC. BV pretreatment reversed the changes of pCaMKII expression in PFC and NAc. These findings suggest that BV acupuncture may exert a suppressive effect on METH-induced addiction via regulation of signaling cascades of DeltaFosB, ERK, and CaMKII in PFC and NAc. PMID- 25744458 TI - The accuracy of Japanese claims data in identifying breast cancer cases. AB - In use of a claims database for a study, an inaccurate diagnosis of breast cancer based on claims data may lead to invalid study results. The aim of this study was to assess the accuracy of definitions for identifying breast cancer cases from the Japanese claims database. The study cohort consisted of women with no prior cancer-related history, from the claims data at a single institution between January 1 and December 31, 2011. We developed 14 definitions for identifying breast cancer based on claims data, using a combination of diagnosis codes and treatment procedure codes. We calculated the sensitivity, specificity, and positive predictive value (PPV) of each definition, compared to cases identified from the standardized hospital-based cancer registry as a standard reference. A total of 50056 women were included in the study cohort from the claims database. We identified 633 breast cancer cases from the cancer registry. Of 14 definitions, 12 exhibited higher sensitivity than 90%, while the others exhibited lower sensitivity than 40%. The specificities of all definitions were high (>= 99%), and the PPVs were between 65.8 and 90.7%. We selected the most optimal definition obtained from combinations of diagnosis and cancer treatment codes (surgery, chemotherapy, medication, radiation procedure), which had high values for sensitivity (90.4%), specificity (99.8%), and PPV (87.3%). Definitions obtained via combinations of the diagnosis codes and procedure codes could be used to accurately identify breast cancer cases from the claims database. Further studies in a multi-institutional setting are planned to confirm our results. PMID- 25744459 TI - Contribution of CYP3A isoforms to dealkylation of PDE5 inhibitors: a comparison between sildenafil N-demethylation and tadalafil demethylenation. AB - The aim of this study was to characterize the kinetics of metabolite formation of the phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil by CYP3A4, CYP3A5, and CYP3A7 isoforms. The formations of N-desmethyl sildenafil and desmethylene tadalafil were examined using CYP3A supersomes co-expressing human P450 oxidoreductase and cytochrome b5. Both sildenafil N-demethylation and tadalafil demethylenation were catalyzed by CYP3A4, CYP3A5, and to a lesser extent by CYP3A7. The kinetics of desalkyl metabolite formation of the two drugs were well fitted to the Hill equation; however, the Hill coefficients (n) suggested CYP3A-mediated negative cooperativity. Next, we analyzed the kinetics with a two binding sites model assuming two reaction steps: reaction 1 with high affinity and low-capacity metabolism and reaction 2 with low-affinity and high capacity metabolism. The kinetics of desalkyl metabolite formation were also fitted to the two binding sites model. The intrinsic clearance (CLint) values of reactions 1 and 2 for sildenafil N-demethylation were 0.733 and 0.033 uL/min/pmol P450 for CYP3A4, 0.788 and 0.019 uL/min/pmol P450 for CYP3A5, and 0.079 and 0.004 uL/min/pmol P450 for CYP3A7, respectively. The CLint values of reactions 1 and 2 for tadalafil demethylenation were 0.187 and 0.014 uL/min/pmol P450 for CYP3A4, 0.050 and <0.001 uL/min/pmol P450 for CYP3A5, and 0.004 and <0.001 uL/min/pmol P450 for CYP3A7, respectively. These results may provide the basis not only for understanding the metabolic properties of the two PDE5 inhibitors, but also for one possible explanation of the mechanisms of CYP3A-mediated negative cooperativity. PMID- 25744460 TI - Purslane suppresses osteoclast differentiation and bone resorbing activity via inhibition of Akt/GSK3beta-c-Fos-NFATc1 signaling in vitro and prevents lipopolysaccharide-induced bone loss in vivo. AB - Purslane (Portulaca oleracea L.) is popular as a potherb in many areas of Europe, Asia, and the Mediterranean region and is widely distributed around the globe. It has a wide range of pharmacological effects, such as antibacterial, anti-aging, anti-inflammatory, and anti-oxidative properties. Although the extract of purslane has numerous beneficial pharmacological effects, its effect on osteoclasts remains unknown. We aimed to investigate the anti-osteoclastogenic activity in vitro and in vivo and to elucidate the underlying mechanism. The effect of purslane on the differentiation and function of bone marrow-derived macrophages (BMMs) into osteoclasts was examined using a phenotype assay such as tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and pit assay and followed by confirmation by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. To address the effect of purslane in vivo, the inflammatory, lipopolysaccharide (LPS)-induced osteolysis mouse model was chosen. Bone volume and bone microarchitecture were evaluated by microcomputed tomography and histologic analysis. Purslane inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-stimulated osteoclast differentiation accompanied by inhibition of Akt/glycogen synthase kinase 3beta (GSK3beta) signaling, which could underlie purslane-induced downregulation of c Fos and nuclear factor of activated T cells 1 (NFATc1) expression levels, transcription factors that regulate osteoclast-specific genes, as well as osteoclast fusion and resorption-related molecules. Moreover, in vivo studies further verified the bone protection activity of purslane in the LPS-induced osteolysis animal model. Purslane could exhibit its anti-osteoclastogenic activity by inhibiting Akt/GSK3beta-c-Fos-NFATc1 signaling cascades. Therefore, purslane is a potential natural medicine for the treatment of osteoclast-related diseases. PMID- 25744461 TI - Effect of genotype and environment on five bioactive components of cultivated licorice (Glycyrrhiza uralensis) populations in northern China. AB - Methods to improve the bioactive component content of cultivated licorice have become the bottleneck of industrial licorice extraction for pharmaceutical use. To evaluate the effects of genotype, environment and their interaction on major bioactive components, we analyzed the five bioactive components: liquiritin (LQ), liquiritigenin (LQG), glycyrrhizin (GL), isoliquiritin (ILQ) and isoliquiritigenin (ILQG) of four diverse licorice varieties grown in four distinct environments in northern China during 2010-11. Analysis of variance showed that environmental and genotypic effects were significant (p<0.01) for all five bioactive components. Additionally, their interaction was significant (p<0.05) for GL in the 2-year study period. LQ and ILQ were mainly affected by genetic factors and have great potential for genetic improvement, whereas LQG and ILQG were mainly affected by environmental factors. GL was similarly affected by environmental and genetic factors. Biplot of the principal component analysis showed that for quality breeding, G2 (WNT-1) and G3 (JX-1) are two relatively preferable genotypes, and E2 (Chifeng) location is suitable for accumulation of the bioactive components of these two genotypes. Stepwise regression analysis showed that sunshine and rainfall are the dominant environmental factors for licorice bioactive component accumulation; increased duration of sunshine is advantageous to GL accumulation whereas declining rainfall is conducive to LQG and ILQG accumulation. These results provide a theoretical basis for initiating licorice breeding programs with increased bioactive components and improved quality. PMID- 25744462 TI - Development and evaluation of a loop-mediated isothermal amplification assay combined with enrichment culture for rapid detection of very low numbers of Vibrio parahaemolyticus in seafood samples. AB - The aim of this study was to develop and evaluate a rapid and effective method to detect Vibrio parahaemolyticus, a leading pathogen causing seafood-borne gastroenteritis. A newly designed loop-mediated isothermal amplification (LAMP) assay including a short enrichment period was optimized. This assay correctly detected all the target strains (n=61) but none of the non-target strains (n=34). Very low numbers of V. parahaemolyticus (2 colony forming unit (CFU) per gram of seafood) could be detected within 3 h and the minimum time of the whole assay was only 5 h. Comparative screening of various seafood samples (n=70) indicated that the LAMP assay is superior to polymerase chain reaction (PCR) and conventional culture methods because it is more rapid and less complex. This highly sensitive LAMP assay can be applicable as the method of choice in large-scale and rapid screening of seafood and environmental samples to detect V. parahaemolyticus strains. PMID- 25744463 TI - Five-year experience with risedronate therapy for patients with increased fracture risk: a practice-based observational study. AB - The purpose of this practice-based observational study was to examine the effects of long-term treatment with risedronate in patients with an increased fracture risk. Seventy patients (4 men and 66 postmenopausal women; mean age, 68.0 years) with osteoporosis or osteopenia and clinical risk factors for fractures were treated with risedronate at either 2.5 mg/d or 17.5 mg/week for 5 years. The bone mineral density (BMD) of the lumbar spine and proximal femur, and the structural geometric parameters of the proximal femur were evaluated by dual-energy X-ray absorptiometry with advanced hip assessment software at baseline and after each year of treatment. The lumbar spine BMD rapidly increased during the first year of the treatment and steadily increased throughout the 5-year treatment period. The BMD of the femoral neck and total hip also significantly increased during the first 3 and 2 years of treatment, respectively, then gradually declined and reached the baseline level after 5 years of treatment. The cross-sectional moment of inertia, cross-sectional area, and mean width of the femoral neck region of interest significantly increased during the first 2 years, and these increases were maintained throughout the 5-year treatment period. The femur strength index and section modulus also significantly increased following time courses similar to those of the above three parameters. These results suggest that risedronate produced both a sustained increase in the lumbar spine BMD and improvement in the femoral structural geometric parameters for 5 years of treatment. PMID- 25744464 TI - Crystal structure of IMP-2 metallo-beta-lactamase from Acinetobacter spp.: comparison of active-site loop structures between IMP-1 and IMP-2. AB - IMP-2, a subclass B1 metallo-beta-lactamase (MBL), is a Zn(II)-containing hydrolase. This hydrolase, involved in antibiotic resistance, catalyzes the hydrolysis of the C-N bond of the beta-lactam ring in beta-lactam antibiotics such as benzylpenicillin and imipenem. The crystal structure of IMP-2 MBL from Acinetobacter spp. was determined at 2.3 A resolution. This structure is analogous to that of subclass B1 MBLs such as IMP-1 and VIM-2. Comparison of the structures of IMP-1 and IMP-2, which have an 85% amino acid identity, suggests that the amino acid substitution at position 68 on a beta-strand (beta3) (Pro in IMP-1 versus Ser in IMP-2) may be a staple factor affecting the flexibility of loop 1 (comprising residues at positions 60-66; EVNGWGV). In the IMP-1 structure, loop 1 adopts an open, disordered conformation. On the other hand, loop 1 of IMP 2 forms a closed conformation in which the side chain of Trp64, involved in substrate binding, is oriented so as to cover the active site, even though there is an acetate ion in the active site of both IMP-1 and IMP-2. Loop 1 of IMP-2 has a more flexible structure in comparison to IMP-1 due to having a Ser residue instead of the Pro residue at position 68, indicating that this difference in sequence may be a trigger to induce a more flexible conformation in loop 1. PMID- 25744465 TI - Stereoisomer-specific anticancer activities of ginsenoside Rg3 and Rh2 in HepG2 cells: disparity in cytotoxicity and autophagy-inducing effects due to 20(S) epimers. AB - Autophagy has been an emerging field in the treatment of hepatic carcinoma since anticancer therapies were shown to ignite autophagy in vitro and in vivo. Here we report that ginsenoside Rg3 and Rh2, major components of red ginseng, induce apoptotic cell death in a stereoisomer-specific fashion. The 20(S)-forms of Rg3 and Rh2, but not their respective 20(R)-forms, promoted cell death in a dose dependent manner accompanied by downregulation of Bcl2 and upregulation of Fas, resulting in apoptosis of HepG2 cells with poly ADP ribose polymerase cleavage. The LD50 value [45 uM for Rg3(S), less than 10 uM for Rh2(S)] and gross morphological electron microscopic observation revealed more severe cellular damage in cells treated with Rh2(S) than in those treated with Rg3(S). Both Rg3(S) and Rh2(S) also induced autophagy when undergoing induced apoptosis. Inhibition of autophagy with lysosomotrophic agents significantly potentiated the cellular damage, implying a favorable switch of the cell fate to tumor cell death. Blocking intracellular calcium with 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) restored the cell death induced by both Rg3(S) and Rh2(S). Our results suggest that the 20(S) forms of Rg3 and Rh2 in red ginseng possess more potent antitumor activity with autophagy than their 20(R)-forms via calcium-dependent apoptosis. PMID- 25744466 TI - Anti-inflammatory effect of cinnamaldehyde in Helicobacter pylori induced gastric inflammation. AB - Cinnamomum cassia is widely employed for gastrointestinal complaints such as dyspepsia, flatulence, diarrhea, and vomiting. Studies report cinnamaldehyde (CM) as a major active constituent of cinnamon. The aim of this study was to evaluate the anti-inflammatory mechanism of CM on Helicobacter (H.) pylori-infected gastric epithelial cells in order to validate cinnamon traditional use in gastrointestinal (GI)-related disorders. AGS/MKN-45 cells and H. pylori (193C) were employed for co-culture experiments. Anti-H. pylori cytotoxic and anti adhesion activity of CM were determined. Enzyme linked immunosorbent assay, real time polymerase chain reaction analysis and immunoblotting were used to measure the effect on interleukin-8 (IL-8) secretion/expression. The effect on activation of nuclear factor kappa B (NF-kappaB) was determined by immunoblot analysis. The non-cytotoxic CM (<=125 uM) was also non-bactericidal at the given time, suggesting the effect in H. pylori/cell co-culture system was not due to alteration in H. pylori viability or the toxicity to the cells. Also, CM did not show any anti-adhesion effect against H. pylori/cell co-culture. However, pre incubation of the cells with CM significantly inhibited the IL-8 secretion/expression from H. pylori-infected cells (p<0.01). In addition, CM suppressed H. pylori-induced NF-kappaB activation and prevented degradation of inhibitor (I)-kappaB This study provides evidence that the anti-inflammatory effect of C. cassia on H. pylori-infected gastric cells is due to blockage of the NF-kappaB pathway by cinnamaldehyde. This agent can be considered as a potential candidate for in vivo and clinical studies against various H. pylori related gastric pathogenic processes. PMID- 25744467 TI - Nucleolin is a receptor for maleylated-bovine serum albumin on macrophages. AB - Scavenger receptors have a broad range of functions that include pathogen clearance, and identification of the scavenger receptor family has been of great benefit to the field of physiology. The shuttling-protein nucleolin has recently been shown to possess scavenger receptor-like activity. We therefore investigated whether or not nucleolin is a receptor for maleylated-bovine serum albumin (maleylated-BSA), which is a common ligand for scavenger receptors. Binding and phagocytosis of native control-BSA by thioglycollate-elicited mouse peritoneal macrophages was weak, but that of maleylated-BSA was strong. Surface plasmon resonance analysis revealed that nucleolin strongly associated with maleylated BSA but not control-BSA or maleic anhydride. Further, co-treatment of macrophages with anti-nucleolin antibody, but not control-immunoglobulin G, inhibited binding of maleylated-BSA. In addition, antineoplastic guanine rich oligonucleotide (AGRO), a nucleolin-specific oligonucleotide aptamer, inhibited binding of maleylated-BSA. Further, binding of maleylated-BSA to nucleolin-transfected HEK293 cells was higher than that by control HEK cells. These results indicate that nucleolin is a receptor that enables macrophages to recognize maleylated BSA. PMID- 25744468 TI - Generation of rat induced pluripotent stem cells using a plasmid vector and possible application of a keratan sulfate glycan recognizing antibody in discriminating teratoma formation phenotypes. AB - Induced pluripotent stem cells (iPSCs) offer an invaluable tool for biological research and regenerative medicine. We report establishment of rat iPSCs (riPSCs) using a plasmid vector encoding four transcription factors, Oct3/4, Sox2, c-Myc and Klf4. Although all riPSC clones were generated and cultured under the same conditions, expressed hallmark pluripotency markers and differentiated successfully in vitro, the expression of a keratan sulfate glycan epitope with unique properties defined by R-10G antibody varied in the riPSC clones. In contrast, tumor rejection antigen (TRA)-1-81 epitope expression was comparable. A clone highly reactive to R-10G antibody formed teratomas in vivo consisting of cells from all three germ layers. However, clones expressing a lower level of the epitope defined by R-10G resulted in tumors with rapid growth consisting of undifferentiated cells. Additionally, riPSCs could be successfully differentiated into a neuronal lineage including glutamate neurons that responded to agonist stimulation. These observations demonstrate a glycophenotypic difference that may potentially serve as a useful probe for riPSC evaluation and to study the role of glycans in pluripotency and carcinogenesis in these cells. PMID- 25744469 TI - Effect of long-term treatment of L-ornithine on visual function and retinal histology in the rats. AB - L-Ornithine is a non-proteinogenic amino acid, abundant in freshwater clams and commercially available as an oral nutritional supplement. L-Ornithine is metabolized by ornithine-delta-aminotransferase. Deficiency of this enzyme causes gyrate atrophy of the choroid and retina, an autosomal recessive hereditary disease characterized by the triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy, with hyperornithinemia. However, it is unknown whether long-term L-ornithine supplementation affects visual function and retinal histology. The aim of the present study is to determine the effect of long-term supplementation of excess amounts of L-ornithine on visual function and retinal histology in rats. Male Brown Norway rats at six weeks of age were allowed free access to chow containing 4% (w/w) L-ornithine (the high ornithine diet) or that containing 4% (w/w) casein (the control diet) for 49 weeks. The dose of L-ornithine calculated from the food intake was approximately 0.8 g/d/animal, which was 100 times higher than the recommended dose for healthy humans. The amplitude of the a-wave of the scotopic rod-cone electroretinogram and the number of cells in the ganglion cell layer in the L-ornithine-treated group were larger than those in the control group 49 weeks after initiating the test diet. No functional or histological damage to the retina was seen up to 49 weeks after the start of the high-ornithine diet. The present study demonstrated that long-term supplementation of very high doses of L ornithine for at least 49 weeks did not induce retinal damage. PMID- 25744470 TI - Safety of the cell-penetrating peptide penetratin as an oral absorption enhancer. AB - Novel delivery technology using cell-penetrating peptides (CPPs) have recently shown their potential and are emerging as promising candidates for an oral protein and peptide delivery systems. As with for the development of any absorption enhancer that is meant to function across an epithelial layer covering a surface highly exposed to pathogens such as the intestines, concern arises about the safety of such enhancers. The purpose of this study was to investigate the effect of 7 d of consecutive oral administrations of CPPs and a typical enterotoxin, lipopolysaccharide (LPS) to mice to determine the degree, if any, of damage caused to the hepatic tissue. Following the 7-d dosing regimen, we could not detect significantly increased levels of the liver enzymes alanine aminotransferase and aspartate aminotransferase in plasma of mice treated with CPP and LPS compared to the controls, whereas heightened levels were observed in animals receiving the bile salt. In conclusion, the repeated use of CPPs as an oral absorption enhancer for macromolecules was found to be a safe strategy. PMID- 25744471 TI - Pharmacological discrimination of plasmalemmal and mitochondrial sodium-calcium exchanger in cardiomyocyte-derived H9c2 cells. AB - We examined the effects of SEA0400 and CGP-37157 on the plasmalemmal Na(+)-Ca(2+) exchanger (NCX) and mitochondrial NCX using H9c2 cardiomyocytes loaded with Ca(2+)-sensitive fluorescent probes. The plasmalemmal NCX activity, which was measured as the increase in cytoplasmic Ca(2+) concentration after application of low Na(+) extracellular solution, was inhibited by SEA0400 but not by CGP-37157. The mitochondrial NCX activity, which was measured in permeabilized H9c2 cells as the decrease in mitochondrial Ca(2+) concentration after application of Ca(2+) free extramitochondrial solution, was inhibited by CGP-37157 but not by SEA0400. These results indicate that SEA0400 and CGP-37157 act as selective inhibitors towards plasmalemmal and mitochondrial NCX, respectively, and provide pharmacological evidence that the plasmalemmal and mitochondrial NCX are distinct molecular entities. PMID- 25744472 TI - Milnacipran inhibits oxaliplatin-induced mechanical allodynia through spinal action in mice. AB - We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, would have therapeutic effect on oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin (3 mg/kg) induced mechanical allodynia, which peaked on day 10 after injection and almost completely subsided by day 20. Ten days post-oxaliplatin injection, the intraperitoneal administration of milnacipran (3-30 mg/kg) significantly and dose dependently inhibited the established mechanical allodynia. Intrathecal injections of milnacipran (2.1-21 ug/site) also significantly and dose dependently inhibited mechanical allodynia, but intracisternal and intracereboventricular injections at the same doses did not. The present results suggest that milnacipran is effective against oxaliplatin-induced mechanical allodynia and that the antiallodynic effect is mainly mediated by actions on the spinal cord. PMID- 25744473 TI - Greatest effect of HPV vaccination from school-based programmes. PMID- 25744475 TI - Sugar should make up less than 5% of total energy consumption, says WHO. PMID- 25744474 TI - Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis. AB - BACKGROUND: Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. METHODS: We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and chi(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure. FINDINGS: We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post vaccination periods by 68% (RR 0.32, 95% CI 0.19-0.52) and anogenital warts decreased significantly by 61% (0.39, 0.22-0.71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0.72, 95% CI 0.54-0.96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0.66 [95% CI 0.47-0.91]) and in women 20-39 years of age (0.68 [95% CI 0.51-0.89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0.50, 95% CI 0.34-0.74]) and in anogenital warts (0.86 [95% CI 0.79-0.94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. INTERPRETATION: Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. FUNDING: The Canadian Institutes of Health Research. PMID- 25744476 TI - Real-time measurement of biomagnetic vector fields in functional syncytium using amorphous metal. AB - Magnetic field detection of biological electric activities would provide a non invasive and aseptic estimate of the functional state of cellular organization, namely a syncytium constructed with cell-to-cell electric coupling. In this study, we investigated the properties of biomagnetic waves which occur spontaneously in gut musculature as a typical functional syncytium, by applying an amorphous metal-based gradio-magneto sensor operated at ambient temperature without a magnetic shield. The performance of differentiation was improved by using a single amorphous wire with a pair of transducer coils. Biomagnetic waves of up to several nT were recorded ~1 mm below the sample in a real-time manner. Tetraethyl ammonium (TEA) facilitated magnetic waves reflected electric activity in smooth muscle. The direction of magnetic waves altered depending on the relative angle of the muscle layer and magneto sensor, indicating the existence of propagating intercellular currents. The magnitude of magnetic waves rapidly decreased to ~30% by the initial and subsequent 1 mm separations between sample and sensor. The large distance effect was attributed to the feature of bioelectric circuits constructed by two reverse currents separated by a small distance. This study provides a method for detecting characteristic features of biomagnetic fields arising from a syncytial current. PMID- 25744478 TI - Clinical application and histological properties of autologous tissue-engineered skin equivalents using an acellular dermal matrix. AB - We developed a transplantable tissue-engineered skin equivalent composed of autologous cultured keratinocytes, fibroblasts, and a decellularized allogeneic dermis (acellular allogeneic dermal matrix; ADM) obtained from cadavers. In a process taking 3 weeks, cultured autologous keratinocytes from burn patients were expanded and then grown on ADMs. The tissue-engineered autologous skin equivalents (TESEs) were then transplanted in a one-stage procedure to the debrided third-degree burn wounds of 4 patients. The mean graft survival rate was 96%. Delayed graft loss and graft fragility were not observed. Histological and immunohistological findings indicated that the transplanted TESE had similar characteristics to normal human split-thickness skin grafts. These results suggest that the TESE using ADM can be used for permanent repair of full thickness skin defects. PMID- 25744477 TI - Preoperative three-dimensional virtual simulation for safe liver surgery. PMID- 25744479 TI - Serum KL-6 elevation and possible pulmonary involvement in patients with rheumatoid arthritis treated with biological agents. AB - BACKGROUNDS: Interstitial lung disease (ILD) is associated with rheumatoid arthritis (RA) itself and is also induced by biological and non-biological disease-modifying antirheumatic drugs. The glycoprotein Krebs von den Lungen-6 (KL-6) is reported to be a marker for the activity of ILD. OBJECTIVES: To elucidate the relationship between serum KL-6 levels in patients with RA treated with biological agents and pulmonary involvement on computed tomography of the chest. METHODS: The subjects were 307 patients with RA treated with infliximab, etanercept, adalimumab, or tocilizumab. Medical records were reviewed to investigate serum KL-6 levels, disease activity, and pulmonary imaging findings. RESULTS: Levels of KL-6 were abnormally elevated in 25 patients (8.1%): 15 patients (11.2%) treated with infliximab, 6 patients (4.4%) treated with etanercept, and 4 patients (22.2%) treated with adalimumab, but in no patients treated with tocilizumab. However, no clinical pulmonary events developed. Computed tomography of the chest showed the start or progression of interstitial fibrotic change in 5 of 25 (20%) patients with abnormal KL-6 values. The changes in disease activity did not differ significantly between patients who showed elevated KL-6 values and those who did not. CONCLUSIONS: Serum KL-6 levels were elevated in 8.1% of patients with RA treated with biological agents. Careful observation is necessary for these patients regarding lung fibrosis. PMID- 25744480 TI - Rate of metastasis in examined lymph nodes as a predictor of extracapsular extension in patients with axillary node-positive breast cancer. AB - BACKGROUND: The status of the axillary lymph nodes is an important factor in the prognosis and treatment of breast cancer. Extracapsular extension (ECE) is the spread of lymphatic tumor cells beyond the capsule of an axillary lymph node. Recent studies have demonstrated that ECE is a strongly unfavorable prognostic factor. OBJECTIVE: In the present study, we investigated whether the rate of metastasis among examined lymph nodes can be used to predict ECE in patients with axillary node-positive breast cancer. METHODS: The subjects were 95 women with axillary node-positive breast cancer. The numbers of lymph nodes removed (examined) and lymph nodes involved were recorded. The cut-off values, area under the curve, sensitivity, and specificity were calculated with the receiver operating characteristic curve technique for ability of the rate of metastasis to examined lymph nodes to predict ECE. RESULTS: The rate of metastasis to examined lymph nodes was significantly greater in patients with ECE than in patients without ECE [0.57 (0.03-1.00) vs. 0.22 (0.04-1.00), respectively, p: 0.001]. Similarly, the presence of vascular infiltration was significantly higher in patients with ECE than in those without ECE [30 (73.2%) vs. 25 (47.2%) respectively, p: 0.010]. On the other hand, other variables did not differ between the groups (p>0.05). When the cut-off value was >=0.23, the sensitivity and specificity of the rate of metastasis to examined lymph nodes were 80.49% and 55.56%, respectively. The area under the curve was 0.697 (95% confidence interval: 0.594-0.787, p: 0.004). CONCLUSION: Our results suggest that rate of metastasis among examined lymph nodes is a predictor of ECE in patients with axillary node-positive breast cancer. PMID- 25744481 TI - A freshman orientation program to provide an overview of the medical learning roadmap. AB - International accreditation of medical education was introduced in Japan in 2013 and is planning to be applied in late 2014 or 2015. Students will need to cope with the resulting changes and to recognize by what route they will learn medicine. Therefore, a freshman orientation course, which was based on problem based learning (PBL) and had been held for first-year students, was modified as an awareness reform program in which students would learn "how to learn medicine." We investigated whether this program has led to useful changes in students' recognition of the way of learning in medical school and their directions as learners. The program was held for 114 first-year medical school students in 2013 and consisted of PBL tutorials, large-classroom lectures, simulation learning using role-play with simulated patients, and team-based learning (TBL), presented in this order. Learning modules that is made with an integration of the clinical sciences with the basic biomedical and the behavioral and social sciences were provided. A nonanonymous questionnaire survey asking" what learning methods are effective for you?" was conducted before and after completion of the course. Furthermore, group answers obtained in TBL were investigated. The score for the question" To what extent can you imagine your route of learning during your 6 years?" significantly increased from 3.1+/-0.99 (mean+/-SD) before the course to 3.5+/-0.88 (p<0.01) after the course. The score for the question" To what extent is the small-group learning, such as PBL, useful for you?" significantly increased from 3.9+/-0.73 to 4.2+/-0.71 (p<0.05). Group responses in TBL sessions indicated that students desired classes that presented tasks and regarded" emphasis on reflection" and" observation of senior physicians as role models" as the most important methods for learning interview skills. We believe students should acquire active learning attitudes as adults early in their 6 years of medical school. The level of understanding of" how to learn as adults" was 3.7 and indicated a moderate result. This course employed many educational strategies, and we believe it helped students understand what they learn and how to learn during their 6 years of medical and to get an overview of the learning roadmap. PMID- 25744482 TI - Use of 3-dimensional computed tomography to detect a barium-masked fish bone causing esophageal perforation. AB - Computed tomography (CT) is useful for evaluating esophageal foreign bodies and detecting perforation. However, when evaluation is difficult owing to the previous use of barium as a contrast medium, 3-dimensional CT may facilitate accurate diagnosis. A 49-year-old man was transferred to our hospital with the diagnosis of esophageal perforation. Because barium had been used as a contrast medium for an esophagram performed at a previous hospital, horizontal CT and esophageal endoscopy could not be able to identify the foreign body or characterize the lesion. However, 3-dimensional CT clearly revealed an L-shaped foreign body and its anatomical relationships in the mediastinum. Accordingly, we removed the foreign body using an upper gastrointestinal endoscope. The foreign body was the premaxillary bone of a sea bream. The patient was discharged without complications. PMID- 25744483 TI - Response of gallstone ileus to conservative therapy. AB - We report a case of cholelithiasis followed by gallstone ileus, documented with serial computed tomography (CT) scans, that responded to conservative therapy. An 80-year-old woman was admitted because of abdominal pain and vomiting. Six months previously, she had presented with abdominal pain and nausea of sudden onset. A CT scan showed thickening of the gallbladder wall and a gallbladder stone. She refused cholecystectomy, and the abdominal pain gradually improved in response to conservative treatment. On admission, plain abdominal radiographs showed obstruction of the proximal small bowel. A CT scan revealed disappearance of the gallbladder stone, fluid-filled bowel loops, and the presence in the small bowel of an impacted stone (major axis, 45 mm; minor axis, 23 mm). We diagnosed gallstone ileus. Because the gallstone was not large, we inserted a stomach tube and administered conservative treatment. One day after admission, CT showed that the impacted stone had migrated to the transverse colon. Four days after admission the impacted stone was not seen on plain abdominal radiography. Five days after admission, follow-up CT revealed pneumobilia but no impacted stone. Because the symptoms had improved the patient resumed oral intake of liquids The patient was discharged 14 days after admission and is doing well. PMID- 25744484 TI - Successful treatment of gastroparesis with the antidepressant mirtazapine: a case report. AB - Treatments for gastroparesis have been unsatisfactory. We describe a patient with gastroparesis who did not respond to a series of conventional prokinetic treatments. Finally, an antidepressant, mirtazapine, was administered, and the patient's symptoms and gastric emptying showed surprisingly rapid improvement. Therefore, we recommend mirtazapine as a treatment for gastroparesis refractory to conventional treatments. PMID- 25744485 TI - Discovery of the primary site of esophageal squamous cell carcinoma based on axillary lymph nodes metastasis detected with fluorodeoxyglucose positron emission tomography: report of a case. AB - A 60-year-old Japanese man with no chief complaints underwent 18F fluorodeoxyglucose positron-emission tomography (FDG-PET) during a medical check up. FDG-PET revealed high tracer uptake in the left supraclavicular and axillary regions but no significant uptake in the esophageal region. However, upper gastrointestinal endoscopy revealed an ulcerative tumor in the middle third of the esophagus. Endoscopic biopsy revealed moderately differentiated squamous cell carcinoma. The patient underwent chemoradiotherapy. Follow-up FDG-PET and computed tomography after therapy revealed a complete response in the lymph nodes. The patient underwent subtotal esophagectomy with gastric tube reconstruction through the posterior mediastinum. However, metastasis to the axillary lymph nodes was detected 16 months after surgery, and lymph node dissection was performed. To our knowledge, this is the first reported case in which the primary site of esophageal squamous cell carcinoma was discovered on the basis of axillary lymph node metastasis detected with FDG-PET. PMID- 25744486 TI - A case of carcinosarcoma of the esophagus detected on fluorodeoxyglucose positron emission tomography. AB - A 56-year-old woman who received surgery for left breast cancer 10 years previously underwent 18F-fluorodeoxyglucose positron-emission tomography (FDG PET) for postoperative follow-up. FDG-PET revealed high uptake of tracer in the esophagogastric junction. A slightly elevated, lobular lesion was found in the lower third of the esophagus on upper gastrointestinal endoscopy. An endoscopic biopsy revealed squamous cell carcinoma. We performed thoracoscopic subtotal esophagectomy. Histopathological examination showed a polypoid spindle cell tumor arising from superficial squamous cell carcinoma. Immunohistochemically, the spindle cells were immunopositive for vimentin and AE1/AE3, and a carcinosarcoma of the esophagus was diagnosed. MIB-1 labeling indexes estimated by Ki-67 immunostaining showed that the proliferative rate of the sarcomatous component was markedly higher than that of the carcinomatous component. This is the rare reported case of esophageal carcinosarcoma that showed increased accumulation of tracer on FDG-PET. PMID- 25744487 TI - Minilaparoscopy combined with natural orifice surgery: benefits can be beyond the cosmesis. PMID- 25744488 TI - Reference values of IGF1, IGFBP3 and IGF1/IGFBP3 ratio in adult population in the Czech Republic. AB - BACKGROUND: IGF1 is responsible for regulation of growth, metabolism and differentiation of human cells. IGFBP3 is the most abundant of the carrier proteins for IGF1 in the blood. IGF1/IGFBP3 molar ratio is an indicator of IGF1 bioavailability. We decided to create a file of reference ranges of IGF1, IGFBP3 and IGF1/IGFBPP3 ratio for the adult Czech population across the age spectrum. METHODS: We selected a group of 1022 subjects, 467 males and 555 females (ages 20 98 years), from several regions in the Czech Republic. The group consisted of blood donors and patients undergoing regular preventive examinations. Serum levels of IGF1 and IGFBP3 were measured using the following radioimmunoassay kits: IRMA IGF1 (Immunotech, Marseille, France) and IRMA IGFBP3 (Immunotech, Prague, Czech Republic). The IGF1/IGFBP3 ratio was also calculated. The following groups of patients were excluded: patients with diabetes, high blood glucose, high insulin levels, post-surgery patients, polymorbid patients, and subjects with oncological diseases. Subjects were divided into seven age-groups. Changes in the levels of observed analytes in each decade across the age spectrum were evaluated. All statistical analyses were performed by SAS 9.3 (Statistical Analysis Software release 9.3; SAS Institute Inc., Cary, NC, USA). RESULTS: All three parameters IGF1, IGFBP3 and IGF1/IGFBP3 decreased in parallel with decrease in age: p<0.0001, r=-0.64, -0.35 and -0.54, respectively. The dynamics of the decline was different between males and females. Linear regression models with age as independent variable fitted by gender are displayed in Fig. 1. Non parametric reference interval curves (medians and 2.5th-97.5th percentiles) for IGF1, IGFBP3 and IGF1/IGFBP3 ratio as function of age by gender are displayed in Fig. 2(a,b,c). All medians and 2.5th-97.5th percentiles were plotted by cubic spline. For males, linear regression models were as follows: IGF1=291.34619 2.41211 * age, IGFBP3=2931.62778-6.11659 * age, IGF1/IGFBP3=0.02897-0.00021213 * age. For females, we plotted the following: IGF1=241.67406-1.98466 * age, IGFBP3=3688.60561-16.39560 * age, IGF1/IGFBP3=0.02029-0.00013233 * age. IGF1 was statistically significantly higher in males with p<0.0001 (Wilcoxon test) but decreased faster (p=0.0121). IGFBP3 was statistically significantly higher in females with p=0.0004 (Wilcoxon test) but decreased faster (p<0.0001). IGF1/IGFBP3 was statistically significantly higher in males with p<0.0001 (Wilcoxon test) but decreased faster (p<0.0001). CONCLUSION: Authors recommend using of a linear regression model based reference ranges for IGF1, IGFBP3 and IGF1/IGFBP3 ratio and using different reference ranges for genders. PMID- 25744489 TI - Serum ferritin concentration is affected by ferroportin Q248H mutation in Africans. AB - BACKGROUND: Ferroportin Q248H mutation is common in populations with African ancestry. Studies have reported that the mutation does not alter the ferroportin hepcidin axis, but there is evidence suggesting that the mutation may lead to hyperferritinemia. We report on the relationship of ferroportin Q248H mutation on serum ferritin (SF) in health adults. SUBJECTS AND METHODS: A total of 174 apparently healthy adults from Botswana were studied. SF was measured using an enzyme immunoassay and ferroportin Q248H mutation was identified by polymerase chain reaction and restriction enzyme digestion. Independent sample Mann-Whitney U test was used to correlate the presence of the mutation with SF. RESULTS: Ferroportin Q248H mutation was identified in 30 individuals (17.2%) (one homozygote, 29 heterozygotes) and was absent in 144 individuals (82.8%), with Q248H allele frequency of 8.9%. In males, SF was significantly higher in ferroportin Q248H heterozygotes compared to wild types, p=0.029, but the relationship between ferroportin Q248H mutation and iron stores was blunted in females. CONCLUSION: Our study of healthy adults provides further evidence that ferroportin Q248H mutation affects SF concentration in Africans. PMID- 25744490 TI - HAP1 helps to regulate actin-based transport of insulin-containing granules in pancreatic beta cells. AB - Huntingtin-associated protein 1 (HAP1) is enriched in neurons and binds to polyglutamine-expanded huntingtin. It consists of two alternatively spliced isoforms, HAP1A and HAP1B, which differ only in their short C-terminal sequences. Both HAP1A and HAP1B have been also detected in pancreatic beta cells, where the loss of HAP1 impairs glucose-stimulated insulin secretion. Here, we use time lapse laser scanning confocal microscopy to provide direct evidence that HAP1A, but not HAP1B, co-localizes and co-migrates with insulin-containing vesicles and actin-based myosin Va motor protein in the INS-1 pancreatic beta cell line. Knocking down HAP1 expression using small interfering RNA significantly inhibited actin-based transport of insulin vesicles following glucose stimulation. Co immunoprecipitation experiments demonstrated interaction between HAP1A, myosin Va, and phogrin, a transmembrane protein in insulin-containing vesicles. Stimulating INS-1 cells with glucose increased the association of HAP1A with myosin Va, while silencing HAP1 expression reduced the association of myosin Va with phogrin after glucose stimulation, without affecting levels of myosin Va or actin. Our results provide real-time evidence in living cells that HAP1 may help regulate transport of insulin-containing secretory granules along cortical actin filaments. This also raises the possibility that HAP1 may play an important role in actin-based secretory vesicle trafficking in neurons. PMID- 25744492 TI - Photocatalytic synthesis of anilides from nitrobenzenes under visible light irradiation: 2 in 1 reaction. AB - An efficient method has been developed for the synthesis of a series of anilides via a two in one reaction of nitrobenzenes with anhydride in the presence of TiO2 as a nanocatalyst and photocatalyst under sunlight or blue LED irradiation. In this method simultaneously, nitrobenzenes convert to the corresponding anilines via photocatalytic reduction on the TiO2 surface, and a condensation of aniline with the anhydride performed on the Lewis acid site of the TiO2 surface. Interestingly amidation step leads to the promotion of better reaction and good selectivity in reduction of nitrocompounds. This method is simple, rapid, high yield, and green. PMID- 25744491 TI - The Histochemistry and Cell Biology pandect: the year 2014 in review. AB - This review encompasses a brief synopsis of the articles published in 2014 in Histochemistry and Cell Biology. Out of the total of 12 issues published in 2014, two special issues were devoted to "Single-Molecule Super-Resolution Microscopy." The present review is divided into 11 categories, providing an easy format for readers to quickly peruse topics of particular interest to them. PMID- 25744493 TI - Behavior problems in children with cochlear implants. AB - OBJECTIVES: (1) To examine behavior problems in Mandarin-speaking children with cochlear implants (CIs); (2) to investigate the associated factors of problem behaviors; (3) to understand the relationships between behavior problems and parenting stress. METHODS AND MATERIALS: Sixty patients (25 boys, 35 girls) aged 6-18 years (mean=12.2+/-3.2) who used CIs for a mean duration of eight years participated in the study. Behavior problems were assessed by Achenbach's child behavior checklist (CBCL). Categorical auditory performance (CAP) and speech intelligibility rating (SIR) scales were utilized to investigate auditory performance and speech production intelligibility. Parenting stress index (PSI) was filled out by parents to measure parenting stress level. RESULTS: Significantly more CI subjects had problems with 'Withdrawn/Depressed' (p=0.010), 'Social Problems' (p<0.001), 'Thought Problems' (p<0.001), 'Attention Problems' (p<0.001), 'Aggressive Behavior' (p=0.010) and 'Overall Behavior' (p=0.001) than the normative sample did. 'Social Problems' was the most common problem and could be independently associated with gender, socioeconomic status and CAP (R(2)=0.361). CAP score was also associated with Overall Behaviors (R(2)=0.081). The results of PSI had a significant positive correlation with almost all CBCL subscales (p<0.05). CONCLUSION: The CI subjects still exhibit social and attention problems, which may in turn increase parenting stress. Good family support as well as aural-verbal rehabilitation are of particular importance in determining behavioral outcomes in CI children. PMID- 25744494 TI - Acute chest syndrome following adenotonsillectomy in a pediatric patient with Hemoglobin SC disease. AB - Hemoglobinopathies involving Hemoglobin S, like Hemoglobin SC disease, are characterized by anemia and vaso-occlusive crises. Vaso-occlusive crises can range in severity from localized pain to acute chest syndrome and myocardial infarction. These crises are usually brought on by stressors that induce hypothermia, hypoxia or acidosis, such as surgery [1]. Here we report a case of acute chest syndrome in a child with Hemoglobin SC disease following adenotonsillectomy and review of the literature regarding acute chest syndrome following adenotonsillectomy. PMID- 25744495 TI - Dietary methionine restriction in mice elicits an adaptive cardiovascular response to hyperhomocysteinemia. AB - Dietary methionine restriction (MR) in rodents increased lifespan despite higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia, which are symptoms associated with increased risk for cardiovascular disease. We investigated this paradoxical effect of MR on cardiac function using young, old, and apolipoprotein E-deficient (ApoE-KO) mice. Indeed, MR animals exhibited higher heart-to-body weight ratio (w/w) and hyperhomocysteinemia with a molecular pattern consistent with cardiac stress while maintaining the integrity of cardiac structure. Baseline cardiac function, which was measured by non-invasive electrocardiography (ECG), showed that young MR mice had prolonged QRS intervals compared with control-fed (CF) mice, whereas old and ApoE-KO mice showed similar results for both groups. Following beta-adrenergic challenge, responses of MR mice were either similar or attenuated compared with CF mice. Cardiac contractility, which was measured by isolated heart retrograde perfusion, was similar in both groups of old mice. Finally, the MR diet induced secretion of cardioprotective hormones, adiponectin and fibroblast growth factor 21 (FGF21), in MR mice with concomitant alterations in cardiac metabolic molecular signatures. Our findings demonstrate that MR diet does not alter cardiac function in mice despite the presence of hyperhomocysteinemia because of the adaptive responses of increased adiponectin and FGF21 levels. PMID- 25744496 TI - Characterization of patients with angioedema without wheals: the importance of F12 gene screening. AB - Sporadic and familiar forms of non-histaminergic angioedema and normal C1 inhibitor encompass a group of disorders possibly caused by bradikinin. We aimed to study the subgroups of hereditary angioedema with FXII mutation (FXII-HAE), unknown genetic defect (U-HAE) and idiopathic non-histaminergic acquired angioedema (InH-AAE). We screened the F12 locus in our cohort and delineated the clinical, laboratory and genetic features. Four families carried the p.Thr309Lys mutation in F12 gene. Haplotyping confirmed the hypothesis of a common founder. Six families were affected by U-HAE and 13 patients by sporadic InH-AAE. C4 levels were significantly lower in FXII-HAE than in InH-AAE. In the FXII-HAE group, none had attacks exclusively in high estrogenic states; acute attacks were treated with icatibant. Prophylaxis with tranexamic acid reduced the attack frequency in most patients. Our study provides new data on the diagnosis, clinical features and treatment of non-histaminergic angioedema, underlying the role of the screening for F12 mutations. PMID- 25744497 TI - Editorial commentary: Ancestry-based differences in norovirus susceptibility: implications for understanding global infection patterns. PMID- 25744498 TI - Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population. AB - BACKGROUND: Norovirus is a leading cause of acute gastroenteritis (AGE). Noroviruses bind to gut histo-blood group antigens (HBGAs), but only 70%-80% of individuals have a functional copy of the FUT2 ("secretor") gene required for gut HBGA expression; these individuals are known as "secretors." Susceptibility to some noroviruses depends on FUT2 secretor status, but the population impact of this association is not established. METHODS: From December 2011 to November 2012, active AGE surveillance was performed at 6 geographically diverse pediatric sites in the United States. Case patients aged <5 years were recruited from emergency departments and inpatient units; age-matched healthy controls were recruited at well-child visits. Salivary DNA was collected to determine secretor status and genetic ancestry. Stool was tested for norovirus by real-time reverse transcription polymerase chain reaction. Norovirus genotype was then determined by sequencing. RESULTS: Norovirus was detected in 302 of 1465 (21%) AGE cases and 52 of 826 (6%) healthy controls. Norovirus AGE cases were 2.8-fold more likely than norovirus-negative controls to be secretors (P < .001) in a logistic regression model adjusted for ancestry, age, site, and health insurance. Secretors comprised all 155 cases and 21 asymptomatic infections with the most prevalent norovirus, GII.4. Control children of Meso-American ancestry were more likely than children of European or African ancestry to be secretors (96% vs 74%; P < .001). CONCLUSIONS: FUT2 status is associated with norovirus infection and varies by ancestry. GII.4 norovirus exclusively infected secretors. These findings are important to norovirus vaccine trials and design of agents that may block norovirus-HBGA binding. PMID- 25744500 TI - The Impact of Accelerated HF-rTMS on the Subgenual Anterior Cingulate Cortex in Refractory Unipolar Major Depression: Insights From 18FDG PET Brain Imaging. AB - BACKGROUND: Although one of the most frequent diagnosed mental illnesses worldwide, it appears to be challenging to successfully treat major depressive disorder (MDD). Although the phenomenon of treatment-resistant depression (TRD) still remains unclear, the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible neurobiological marker to evaluate clinical effects of a variety of antidepressant treatments, including repetitive transcranial magnetic stimulation (rTMS). Accelerated high-frequency (HF)-rTMS may have the potential to rapidly result in beneficial clinical outcomes in TRD. No studies yet examined the clinical effects of such accelerated stimulation treatment paradigms on sgACC regional glucose metabolism (CMRglc), nor the predictive value of the latter for clinical outcome. OBJECTIVE: First, we investigated the predictive value of baseline sgACC metabolic activity for clinical outcome. Second, we hypothesized that in clinical responders only accelerated HF-rTMS treatment would result in significant metabolic decreases. METHODS: We recruited right-handed antidepressant-free unipolar melancholic TRD patients to participate in a two-week randomized sham-controlled crossover HF-rTMS treatment study. Stimulation was applied to the left dorsolateral prefrontal cortex (DLPFC). Fifteen patients underwent 18FDG PET (CMRglc) at baseline (T0), after the first week (T1) of accelerated HF-rTMS and at the end of the treatment after the second week (T2). RESULTS: Higher baseline sgACC metabolic activity may indicate beneficial clinical outcome to this kind of accelerated HF-rTMS treatment. Moreover, clinical response resulted in a significant decrease in sgACC CMRglc. Non-response did not affect sgACC CMRglc. CONCLUSIONS: Our results add to the sgACC as a specific neurobiological marker for anti-depressive response in accelerated HF-rTMS treatment paradigms. Such protocols may not only have the ability to result in fast clinical responses but they may also have potential to acutely modulate a dysfunctional sgACC. PMID- 25744501 TI - Management of Neuropathic Pain Associated with Spinal Cord Injury. AB - Spinal cord injury (SCI) is an injury to the spinal cord that leads to varying degrees of motor and/or sensory deficits and paralysis. Chronic pain of both neuropathic and nociceptive type is common and contributes to reduced quality of life. The aim of the review is to provide current clinical understanding as well as discuss and evaluate efficacy of pharmacological interventions demonstrated in the clinical studies. The review was based on literature search in PubMed and Medline with words "neuropathic pain" and "spinal cord injury". The review included clinical studies and not experimental data nor case reports. A limited number of randomized and placebo-controlled studies concerning treatment options of neuropathic pain after SCI were identified. Amitriptyline, a tricyclic antidepressant and the antiepileptic drugs, gabapentin and pregabalin, are most studied with demonstrated efficacy, and considered to be the primary choice. Opioids have demonstrated conflicting results in the clinical studies. In addition, administration route used in the studies as well as reported side effects restrict everyday use of opioids as well as ketamine and lidocaine. Topical applications of capsaicin or lidocaine as well as intradermal injections of Botulinum toxin are new treatment modalities that are so far not studied on SCI population and need further studies. Non-pharmacological approaches may have additional effect on neuropathic pain. Management of pain should always be preceded by thorough clinical assessment of the type of pain. Patients need a follow-up to evaluate individual effect of applied measures. However, the applied management does not necessarily achieve satisfactory pain reduction. Further clinical studies are needed to evaluate the effect of both established and novel management options. PMID- 25744502 TI - Iron chelation with deferasirox in a patient with de-novo ferroportin mutation. AB - Ferroportin disease is a rare type of autosomal dominantly inherited hemochromatosis caused with mutations in the ferroportin gene (SLC40A1). The patients characteristically have hyperferritinemia but normal transferin saturations. Herein, we present a 15-year-old female whose chief complaint was persistent nausea for the last one year. Extensive work-up including brain imaging revealed nothing to explain the etiology of nausea. The serum ferritin level of 1474ng/mL was suggestive for hemochromatosis syndromes and the molecular testing revealed de-novo c.485_487delTTG (P.Val162del) ferroportin gene mutation. Mild hepatic iron loading, in addition to the cumbersome nausea were accepted as indications for chelation treatment in this particular patient and deferasirox was initiated (10mg/kg/day) since family did not consent for phlebotomy. Deferasirox was stopped by the 9th month of initiation, since nausea subsided and hepatic iron content was normalized, in order to prevent over chelation. There are no well-established guidelines for the chelation of patients with hereditary hemochromatosis syndromes. However, lifelong monitorization for iron loading and re-initiation of chelation when necessary was planned in our patient. PMID- 25744503 TI - The impact of acute lung injury, ECMO and transfusion on oxidative stress and plasma selenium levels in an ovine model. AB - The purpose of this study was to determine the effects of smoke induced acute lung injury (S-ALI), extracorporeal membrane oxygenation (ECMO) and transfusion on oxidative stress and plasma selenium levels. Forty ewes were divided into (i) healthy control (n=4), (ii) S-ALI control (n=7), (iii) ECMO control (n=7), (iv) S ALI+ECMO (n=8) and (v) S-ALI+ECMO+packed red blood cell (PRBC) transfusion (n=14). Plasma thiobarbituric acid reactive substances (TBARS), selenium and glutathione peroxidase (GPx) activity were analysed at baseline, after smoke injury (or sham) and 0.25, 1, 2, 6, 7, 12 and 24h after initiation of ECMO. Peak TBARS levels were similar across all groups. Plasma selenium decreased by 54% in S-ALI sheep (1.36+/-0.20 to 0.63+/-0.27MUmol/L, p<0.0001), and 72% in sheep with S-ALI+ECMO at 24h (1.36+/-0.20 to 0.38+/-0.19, p<0.0001). PRBC transfusion had no effect on TBARS, selenium levels or glutathione peroxidase activity in plasma. While ECMO independently increased TBARS in healthy sheep to levels which were similar to the S-ALI control, the addition of ECMO after S-ALI caused a negligible increase in TBARS. This suggests that the initial lung injury was the predominant feature in the TBARS response. In contrast, the addition of ECMO in S ALI sheep exacerbated reductions in plasma selenium beyond that of S-ALI or ECMO alone. Clinical studies are needed to confirm the extent and duration of selenium loss associated with ECMO. PMID- 25744504 TI - Correlation of serum toll like receptor 9 and trace elements with lipid peroxidation in the patients of breast diseases. AB - Toll-like receptors are recognized as redox sensitive receptor proteins and have been implicated in cellular response to oxidative stress. Altered pro-oxidant antioxidant balance leads to an increased oxidative damage and consequently play an important role in breast diseases. The study was designed to access the oxidative stress status by quantification of byproducts generated during lipid peroxidation and inadequate trace elements during oxidative damage and its effects on the toll like receptor (TLR) activity in patients of breast diseases. Decreased levels of selenium, copper, zinc, magnesium and iron with elevated levels of malondialdehyde (marker of lipid peroxidation) were accompanied by decreased TLR activity in patients of benign breast diseases as well as breast carcinoma. A similar pattern was observed with the advancement of disease and its subsequent progression in breast carcinoma patients. Results of multinomial regression analysis suggest benign breast disease patients are at higher risk of developing breast cancer with high odds ratio of lipid damage. PMID- 25744506 TI - A pilot study of synbiotic supplementation on breast milk mineral concentrations and growth of exclusively breast fed infants. AB - Despite the crucial role of breast milk mineral contents for health and growth of the infants, they decrease with the duration of lactation. So, this pilot study aimed to determine the effects of synbiotic supplementation on breast milk mineral composition and infants' growth. In this pilot, randomized, double-blind, placebo-controlled trial, 57 lactating mothers were randomly divided into two groups to receive a daily supplement of synbiotic (n=30) or a placebo (n=27) for 30 days. Breast milk zinc, copper, Iron, magnesium and, calcium concentrations were determined by flame atomic absorption spectrometry. Weight for age Z-score (WAZ) and height for age Z-score (HAZ) were assessed for infants. Dietary intake was collected from lactating women using the 24-h recall method. Data analyses were carried out using nutritionist IV, Epi Info and SPSS soft wares. Synbiotic supplementation led to an insignificant increase of the mean breast milk levels of zinc (from 2.44+/-0.65 to 2.55+/-0.55mgL(-1)), copper (from 0.35+/-0.24 to 0.40+/-0.26mgL(-1)), iron (from 0.28+/-0.42 to 0.31+/-0.38mgL(-1)), magnesium (from 17.14+/-1.35 to 17.17+/-1.09mgL(-1)), and calcium (from 189+/-25.3 to 189.9+/-21.7mgL(-1)); whilst in the placebo group, these variables decreased significantly (P=0.001). The observed changes between two groups were statistically significant (P<0.05). Although WAZ and HAZ of infants increased slightly in the supplemented group (from 1.19+/-0.79 to 1.20+/-0.69 and 0.36+/ 0.86 to 0.37+/-0.85 respectively), these two parameters decreased in the placebo group which was significant only for WAZ (P=0.01). Moreover, no significant association was found between mineral intake and breast milk mineral contents. It seems, synbiotic supplementation may have positive effects on breast milk mineral contents. PMID- 25744505 TI - Umbilical cord blood and placental mercury, selenium and selenoprotein expression in relation to maternal fish consumption. AB - Seafood is an important source of nutrients for fetal neurodevelopment. Most individuals are exposed to the toxic element mercury through seafood. Due to the neurotoxic effects of mercury, United States government agencies recommend no more than 340g (12oz) per week of seafood consumption during pregnancy. However, recent studies have shown that selenium, also abundant in seafood, can have protective effects against mercury toxicity. In this study, we analyzed mercury and selenium levels and selenoprotein mRNA, protein, and activity in placenta of a cohort of women in Hawaii in relation to maternal seafood consumption assessed with dietary surveys. Fish consumption resulted in differences in mercury levels in placenta and cord blood. When taken as a group, those who consumed no fish exhibited the lowest mercury levels in placenta and cord blood. However, there were numerous individuals who either had higher mercury with no fish consumption or lower mercury with high fish consumption, indicating a lack of correlation. Placental expression of selenoprotein mRNAs, proteins and enzyme activity was not statistically different in any region among the different dietary groups. While the absence of seafood consumption correlates with lower average placental and cord blood mercury levels, no strong correlations were seen between seafood consumption or its absence and the levels of either selenoproteins or selenoenzyme activity. PMID- 25744507 TI - Impact of high dietary zinc on zinc accumulation, enzyme activity and proteomic profiles in the pancreas of piglets. AB - The exocrine pancreas plays an important role in zinc homeostasis. Feeding very high (2000-3000mgzinc/kg diet) levels of zinc oxide to piglets for short periods is a common practice in the swine industry to improve performance and prevent diseases. The impact on pancreatic function and possible side effects during long term feeding of high dietary zinc levels are still poorly understood. A total of 54 weaned piglets were either fed with low (57mg/kg, LZn), normal (164mg/kg, NZn) or high (2425mg/kg, HZn) zinc concentration in the diets. After 4 weeks of feeding, ten piglets per treatment were euthanized and pancreas samples were taken. Tissue zinc concentration and metallothionein abundance was greater with HZn compared with NZn and LZn (P<0.05). Similarly, activity of alpha-amylase, lipase, trypsin and chymotrypsin was higher with HZn as compared with NZn and LZn diets (P<0.05), whereas elastase activity was unchanged. Total trolox equivalent antioxidative capacity of pancreas tissue was higher with HZn diets compared with the other treatments (P<0.05). Pancreatic protein profiles of NZn and HZn fed piglets were obtained by 2D-DIGE technique and revealed 15 differentially expressed proteins out of 2100 detected spots (P<0.05). The differentially expressed proteins aldose reductase, eukaryotic elongation factor II and peroxiredoxin III were confirmed by immunoblotting. Identified proteins include zinc finger-containing transcription factors and proteins mainly associated with oxidative stress response and signal transduction in HZn compared with NZn pigs. Histologic examination however showed no morphologic changes. The results suggest that long-term supply of very high dietary zinc increases zinc and metallothionein concentration, and digestive enzyme activity, but also triggers oxidative stress reactions in the pancreas of young pigs. The data provide new insights into pancreatic function under outbalanced zinc homeostasis. PMID- 25744508 TI - Development of magnetic separation and quantum dots labeled immunoassay for the detection of mercury in biological samples. AB - A rapid and sensitive immunoassays of mercury (Hg) in biological samples was developed using quantum dots (QDs) and magnetic beads (MBs) as fluorescent and separated probes, respectively. A monoclonal antibody (mAb) that recognizes an Hg detection antigen (BSA-DTPA-Hg) complex was produced by the injection of BALB/c mice with an Hg immunizing antigen (KLH-DTPA-Hg). Then the ascites monoclonal antibodies were purified. The Hg monoclonal antibody (Hg-mAb) is conjugated with MBs to separate Hg from biological samples, and the other antibody, which is associated with QDs, is used to detect the fluorescence. The Hg in biological samples can be quantified using the relationship between the QDs fluorescence intensity and the concentration of Hg in biological samples following magnetic separation. In this method, the detection linear range is 1-1000ng/mL, and the minimum detection limit is 1ng/mL. The standard addition recovery rate was 94.70 101.18%. The relative standard deviation values were 2.76-7.56%. Furthermore, the Hg concentration can be detected in less than 30min, the significant interference of other heavy metals can be avoided, and the simultaneous testing of 96 samples can be performed. These results indicate that the method could be used for rapid monitoring Hg in the body. PMID- 25744510 TI - Phosphorylation controls the functioning of Staphylococcus aureus isocitrate dehydrogenase--favours biofilm formation. AB - Isocitrate dehydrogenase (IDH) gene from Staphylococcus aureus ATCC12600 was cloned, sequenced and characterized (HM067707). PknB site was observed in the active site of IDH; thus, it was predicted as IDH may be regulated by phosphorylation. Therefore, in this study, PknB, alkaline phosphatase III (SAOV 2675) and IDH genes (JN695616, JN645811 and HM067707) of S. aureus ATCC12600 were over expressed from clones PV 1, UVPALP-3 and UVIDH 1. On passing the cytosloic fractions through nickel metal chelate column, pure enzymes were obtained. Phosphorylation of pure IDH by PknB resulted in the complete loss of activity and was restored upon dephosphorylation with SAOV 2675 which indicated that phosphorylation and dephosphorylation regulate IDH activity in S. aureus. Further, when S. aureus ATCC12600 was grown in BHI broth, decreased IDH activity and increased biofilm units were observed; therefore, this regulation of IDH alters redox status in this pathogen favouring biofilm formation. PMID- 25744512 TI - Production of collagen micro- and nanofibers for potential drug-carrier systems. AB - Two different nano- and micro-collagen fiber production methods are introduced and discussed. First one is the electrospinning method, that is very common technique to produce nanofibers from different polymeric solutions and recently collagen solutions are employed to produce nanofibers for different biomedical applications. This technique is extremely versatile method to produce nanofibers in a relatively short time, easy to control the fiber diameter and orientation with small pore sizes and a high surface area. The second method is self-assembly of collagen micro-fibers by co-extrusion method. The collagen fibers are obtained without any cross-linker, by using mainly ionic interactions. We demonstrated that self-assembled collagen fibers have well preserved their native structure (0.90 PP-II fraction), when compared with electrospun collagen fibers (0.38 PP-II fraction). However, it was only possible to produce collagen fibers with nanodimensions by using electrospinning method. PMID- 25744509 TI - Resistant starch does not affect zinc homeostasis in rural Malawian children. AB - OBJECTIVE: This study tested the hypothesis that Malawian children at risk for zinc deficiency will have reduced endogenous fecal zinc (EFZ) and increased net absorbed zinc (NAZ) following the addition of high amylose maize resistant starch (RS) to their diet. METHODS: This was a small controlled clinical trial to determine the effects of added dietary RS on zinc homeostasis among 17 stunted children, aged 3-5 years consuming a plant-based diet and at risk for perturbed zinc homeostasis. Dual zinc stable isotope studies were performed before and after 28 d of intervention with RS, so that each child served as their own control. The RS was incorporated into fried wheat flour dough and given under direct observation twice daily for 28 d. Changes in zinc homeostatic measures were compared using paired Student's t-tests and linear regression analysis. RESULTS: Children had a mean height-for-age Z-score of -3.3, and consumed animal source foods <=twice per month. Their habitual diet contained a phytate:zinc molar ratio of 34:1. Children avidly consumed the RS without complaints. EFZ was 0.8+/-0.4mg/d (mean+/-SD) both before and after the intervention. Fractional absorption of zinc was 0.38+/-0.08 and 0.35+/-0.06 before and after the RS intervention respectively. NAZ was 1.1+/-0.5 and 0.6+/-0.7 before and after the RS intervention. This reduction of NAZ corresponded with diminished dietary zinc intake on the study day following intervention with RS. Regression analysis indicated no change in zinc absorption relative to dietary intake as a result of the RS intervention. CONCLUSION: Consumption of RS did not improve zinc homeostasis in rural African children without zinc deficiency. RS was well tolerated in this setting. PMID- 25744511 TI - Synthesis of 3,4-dihydroxypyrrolidine-2,5-dione and 3,5-dihydroxybenzoic acid derivatives and evaluation of the carbonic anhydrase I and II inhibition. AB - The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with some 3,4-dihydroxypyrrolidine-2,5-dione and 3,5 dihydroxybenzoic acid derivatives, were investigated by using the esterase assay, with 4-nitrophenyl acetate (4-NPA) as substrate. Compounds 10-13 showed KI values in the range of 112.7-441.5 MUM for hCA I and of 3.5-10.76 MUM against hCA II, respectively. These hydroxyl group containing compounds generally were competitive inhibitors. Some hydroxyl group containing compounds investigated here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide acetazolamide, and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents. PMID- 25744513 TI - Inhibition of carbonic anhydrase isoforms I, II, IX and XII with Schiff's bases incorporating iminoureido moieties. AB - A series of new Schiff's bases was obtained from the sulfanilamide semicarbazone (4-aminosulfonylphenyl semicarbazide) and aromatic/heterocyclic aldehydes. The new compounds were designed to incorporate moieties known to induce effective inhibitory activity against carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in crucial physiologic or pathologic processes such as the cytosolic CA I and II or the transmembrane, tumor-associated CA IX and XII: the compounds were medium potency - weak CA I inhibitors, highly effective, low nanomolar CA II inhibitors, but few of them inhibited effectively CA IX and XII. This may probably due to the long spacer between the sulfamoylphenyl and imine fragments of the molecules, which probably induces a highly flexible conformation of the inhibitor bound to the active site of the enzyme, with destabilizing effects for the adduct. The detailed structure activity relationship for this class of inhibitors is discussed. PMID- 25744514 TI - Response to letter regarding article, "Residual high-grade stenosis after recanalization of extracranial carotid occlusion in acute ischemic stroke". PMID- 25744515 TI - Stroke literature synopses: basic science. PMID- 25744516 TI - Additional diagnostic value of computed tomography perfusion for detection of acute ischemic stroke in the posterior circulation. AB - BACKGROUND AND PURPOSE: Detection of acute infarction in the posterior circulation is challenging. We aimed to determine the additional value of tomograpy (CT) perfusion to noncontrast CT and CT angiography source images for infarct detection and localization in patients suspected of acute ischemic posterior circulation stroke. METHODS: Patients with suspected acute ischemic posterior circulation stroke were selected from the Dutch acute Stroke Trial (DUST) study. Patients underwent noncontrast CT, CT angiography, and CT perfusion within 9 hours after stroke onset and CT or MRI on follow-up. Images were evaluated for signs and location of ischemia. Discrimination of 3 hierarchical logistic regression models (noncontrast CT [A], added CT angiography source images [B], and CT perfusion [C]) was compared with C-statistics. RESULTS: Of 88 patients, 76 (86%) had a clinical diagnosis of ischemic stroke on discharge and 42 patients (48%) showed a posterior circulation infarct on follow-up imaging. Model C (area under the curve from the receiver operating characteristic curve=0.86; 95% confidence interval, 0.77-0.94) predicted an infarct in the posterior circulation territory better than models A (area under the curve from the receiver operating characteristic curve=0.64; 95% confidence interval, 0.53 0.76; P(C versus A)<0.001) and B (area under the curve from the receiver operating characteristic curve=0.68; 95% confidence interval, 0.56-0.79; P(C versus B)<0.001). CONCLUSIONS: CT perfusion has significant additional diagnostic values to noncontrast CT and CT angiography source images for detecting ischemic changes in patients suspected of acute posterior circulation stroke. PMID- 25744517 TI - Letter by Zhou et al regarding article, "Residual high-grade stenosis after recanalization of extracranial carotid occlusion in acute ischemic stroke". PMID- 25744518 TI - Letter by Saver et al regarding article, "Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". PMID- 25744519 TI - Response to letter regarding article, "Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". PMID- 25744520 TI - Validity of shape as a predictive biomarker of final infarct volume in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: This study examines whether lesion shape documented on magnetic resonance diffusion-weighted imaging during acute stroke improves the prediction of the final infarct volume compared with lesion volume only. METHODS: Diffusion-weighted imaging data and clinical information were retrospectively reviewed in 110 consecutive patients who underwent (n=67) or not (n=43) thrombolytic therapy for acute ischemic stroke. Three-dimensional shape analysis was performed on admission diffusion-weighted imaging data and 5 shape descriptors were developed. Final infarct volume was measured on T2-fluid attenuated inversion recovery imaging data performed 30 days after stroke. RESULTS: Shape analysis of acute ischemic lesion and more specifically the ratio of the bounding box volume to the lesion volume before thrombolytic treatment improved the prediction of the final infarct for patients undergoing thrombolysis (R(2)=0.86 in model with volume; R(2)=0.98 in model with volume and shape). CONCLUSIONS: Our findings suggest that lesion shape contains important predictive information and reflects important environmental factors that might determine the progression of ischemia from the core. PMID- 25744521 TI - Progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. AB - BACKGROUND AND PURPOSE: In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia. METHODS: Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed >6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts. RESULTS: After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories (P=0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions (P<0.05). After recurrent infarcts, the object recognition test showed significant recognition memory deficits (P<0.001) and the Morris water maze test demonstrated persisting spatial learning and memory deficits (P<0.05). Histological analyses revealed remote astrogliosis in the hippocampus. CONCLUSIONS: Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies. PMID- 25744522 TI - Quantitative assessment of changes in cerebral arteriovenous malformation hemodynamics after embolization. AB - BACKGROUND AND PURPOSE: Embolization reduces flow in arteriovenous malformations (AVMs) before surgical resection, but achievement of this goal is determined subjectively from angiograms. Here, we quantify effects of embolization on AVM flow. METHODS: Records of patients who underwent AVM embolization at our institution between 2007 and 2013 and had flow rates obtained pre- and postembolization using quantitative magnetic resonance angiography were retrospectively reviewed. Total flow was estimated as aggregate flow within primary arterial feeders or flow in single draining veins. RESULTS: Twenty-one patients were included (mean age 35 years, 24% hemorrhagic presentation) with Spetzler-Martin grades 1 to 4. Fifty-four total embolization sessions were performed. The mean AVM flow was 403.4+/-262.4 mL/min at baseline, 285.3+/-246.4 mL/min after single session (29% drop, P<0.001), and 102.0+/-103.3 mL/min after all sessions of embolization (75% drop, P<0.001). Total number of pedicles embolized (P<0.001) and embolization of an intranidal fistula during any session (P=0.002) were significantly associated with total decreased flow postembolization. On multivariate analysis, total pedicles embolized was predictive of total flow drop (P<0.001). However, pedicles embolized per session did not correlate with flow drop related to that session (P=0.44). CONCLUSIONS: AVM flow changes after embolization can be measured using quantitative magnetic resonance angiography. The total number of pedicles embolized after multiple embolization sessions was predictive of final flow, indicating this parameter is the best angiographic marker of a hemodynamically successful intervention. The number of pedicles embolized per session, however, did not correlate with flow drop in that session, likely because of flow redistribution after partial embolization. PMID- 25744523 TI - The elephant in the room: Advertising science as a driver of economic growth is a long-term losing strategy. PMID- 25744524 TI - Attacking the system: Next-generation auto-immune therapies target pathways rather than symptoms. PMID- 25744525 TI - Nature, nurture and exposure: Connecting biobank data with geographic data could yield public and individual health benefits, but risks to human rights need to be assessed. PMID- 25744526 TI - Ytterbium (III) Luminescence in m-Methylbenzoic Acid-Containing Compounds. AB - Complex compounds of ytterbium(III) with m-methylbenzoic acid and nitrogen containing ligands luminescent in near infrared range have been synthesized. Spectral luminescence characteristics of heteroligand compounds of ytterbium(III) have been investigated. It has been established that ytterbium (III) m methylbenzoate with 1,10-phenanthroline is characterized by the highest luminescence intensity. PMID- 25744528 TI - Luminescent Properties of Cerium Doped Potassium Iodide Single Crystals in Response to gamma-irradiation. AB - Potassium iodide doped with cerium ions were prepared by Bridgemann Stockbarger technique and investigated by optical absorption, Photoluminescence(PL), Thermoluminescence(TL), Photostimulated Luminescence(PSL) and TL emission. The optical absorption measurement indicates that F and V centers are formed in the crystals during the gamma-ray irradiation process. Optical absorption and Photoluminescence studies confirm the presence of cerium ions in the trivalent state. Spectral distribution under the Thermoluminescence Emission(TLE) and Optically Stimulated Luminescence(OSL) support the idea that the defect annihilation process to be due to thermal release of F-electron in KI:Ce(3+) crystals. Both Ce(3+) and Ce(2+) emissions were observed in the Thermoluminescence emission of the crystals. Thermoluminescence(TL) has been identified to be due to thermal release of electron produced during colouration process. PMID- 25744527 TI - Fluorescence Behaviour of an Aluminium Octacarboxy Phthalocyanine--NaYGdF4:Yb/Er Nanoparticle Conjugate. AB - Using a methanol assisted thermal decomposition approach, sphere shaped NaYGdF4:Yb/Er upconversion nanoparticles (UCNPs) were successfully synthesized. The chemical, spectroscopic and fluorescence properties of the UCNPs were fully characterized. Characteristic upconversion fluorescence emissions were produced by the NPs in the green, red and NIR regions and the NPs were also shown to possess paramagnetic properties. The influence of the UCNPs on the spectroscopic and fluorescence properties of an aluminium octacarboxy phthalocyanine AlOCPc was investigated. Covalent conjugation to an AlOCPc resulted in a large blue shift of the phthalocyanine's Q band, which was accompanied by a decrease in the Pc's fluorescence lifetime in DMSO. By combining the phthalocyanine and upconversion nanoparticle, we present a system capable of multimodal imaging, using both the upconversion nanoparticle's and phthalocyanine's emission, and magnetic resonance imaging (as a result of doping the upconversion nanoparticles with Gd(3+) ions). PMID- 25744529 TI - Comfort with motherhood in late pregnancy facilitates maternal role attainment in early postpartum. AB - Quality of life, comfort, and wellbeing during pregnancy are essential for every country in the world. Pregnancy is considered a preparation period for becoming a mother. Maternal role development, including confidence and satisfaction as a mother, is important in the transition to motherhood. Negative psychosocial affect, such as increased anxiety and distress, during pregnancy adversely influences the childbirth experience and childcare, which contributes to postpartum depression. However, the impact of positive feelings on the maternal role development remains unclear. Therefore, the study purpose was to clarify the relationship between comfort in late pregnancy and maternal role attainment and childcare during early postpartum. We designed a descriptive, longitudinal, correlational study by using the Prenatal Comfort Scale, the Postpartum Maternal Role Confidence Scale, and the Postpartum Maternal Satisfaction Scale. Among 339 participants who had received care at a university hospital located in Sendai city in Japan, 215 subjects completed the longitudinal study by answering a questionnaire for the respective Scale late in their pregnancy or during early postpartum. The subjects consisted of 114 primipara (32.0 +/- 5.4 years) and 101 multipara (33.4 +/- 4.9 years). In primipara, comfort with motherhood was significantly correlated with maternal confidence regarding knowledge and childcare skills and maternal satisfaction. In multipara, comfort in late pregnancy was related to maternal confidence and satisfaction. Positive affect was related to maternal confidence and maternal satisfaction in early postpartum. Therefore, a prenatal nursing intervention helps women become more comfortable with impending motherhood, thereby promoting maternal role attainment after delivery. PMID- 25744530 TI - [Primary human demodicosis. A disease sui generis]. AB - Human Demodex mites (Demodex folliculorum and Demodex brevis) are unique in that they are an obligate human ectoparasite that can inhabit the pilosebaceous unit lifelong without causing obvious host immune response in most cases. The mode of symbiosis between humans and human Demodex mites is unclear, while the pathogenicity of human Demodex mites in many inflammatory skin diseases is now better understood. Primary human demodicosis is a skin disease sui generis not associated with local or systemic immunosuppression. Diagnosis is often underestimated and differentiation from folliculitis, papulopustular rosacea and perioral dermatitis is not always straightforward. Dependent on the morphology and degree of inflammation, the clinical manifestations can be classified into spinulate, papulopustular, nodulocystic, crustic and fulminant demodicosis. Therapy success can be achieved only with acaricides/arachidicides. The effective doses, optimal regimen and antimicrobial resistance remain to be determined. PMID- 25744531 TI - [Basic moisturizing therapy for the prevention of atopic dermatitis in the first few months of life]. PMID- 25744532 TI - Development of fluorescent lead II sensor based on an anthracene derived chalcone. AB - A simple anthracene based chalcone as a fluorescent chemosensor 1, capable of detecting Pb(2+) in aqueous media, has been synthesized by the reaction between pyridine 2-carboxaldehyde and 9-acetyl anthracene. The Pb(2+) recognition processes follows a photo induced electron transfer (PET) mechanism and are scarcely influenced by other coexisting metal ions. In addition, determination of lead in a variety of samples was also determined. PMID- 25744533 TI - BMA opposes plan to allow patients to refer themselves for cancer tests. PMID- 25744534 TI - Performance of and methanogenic communities involved in an innovative anaerobic process for the treatment of food wastewater in a pilot plant. AB - In this study, dual-cylindrical anaerobic digesters were designed and built on the pilot plant scale for the improvement of anaerobic digestion efficiency. The removal efficiency of organics, biogas productivity, yield, and microbial communities was evaluated as performance parameters of the digester. During the stable operational period in the continuous mode, the removal efficiencies of chemical oxygen demand and total solids were 74.1 and 65.1%, respectively. Biogas productivities of 63.9 m(3)/m(3)-FWW and 1.3 m(3)/kg-VSremoved were measured. The hydrogenotrophic methanogen orders, Methanomicrobiales and Methanobacteriales, were predominant over the aceticlastic methanogen order, Methanosarcinaceae, probably due to the tolerance of the hydrogenotrophs to environmental perturbation in the field and their faster growth rate compared with that of the aceticlastics. PMID- 25744535 TI - Structure-function analysis of USP1: insights into the role of Ser313 phosphorylation site and the effect of cancer-associated mutations on autocleavage. AB - BACKGROUND: In complex with its cofactor UAF1, the USP1 deubiquitinase plays an important role in cellular processes related to cancer, including the response to DNA damage. The USP1/UAF1 complex is emerging as a novel target in cancer therapy, but several aspects of its function and regulation remain to be further clarified. These include the role of the serine 313 phosphorylation site, the relative contribution of different USP1 sequence motifs to UAF1 binding, and the potential effect of cancer-associated mutations on USP1 regulation by autocleavage. METHODS: We have generated a large set of USP1 structural variants, including a catalytically inactive form (C90S), non-phosphorylatable (S313A) and phosphomimetic (S313D) mutants, deletion mutants lacking potential UAF1 binding sites, a mutant (GG/AA) unable to undergo autocleavage at the well-characterized G670/G671 diglycine motif, and four USP1 mutants identified in tumor samples that cluster around this cleavage site (G667A, L669P, K673T and A676T). Using cell based assays, we have determined the ability of these mutants to bind UAF1, to reverse DNA damage-induced monoubiquitination of PCNA, and to undergo autocleavage. RESULTS: A non-phosphorylatable S313A mutant of USP1 retained the ability to bind UAF1 and to reverse PCNA ubiquitination in cell-based assays. Regardless of the presence of a phosphomimetic S313D mutation, deletion of USP1 fragment 420-520 disrupted UAF1 binding, as determined using a nuclear relocation assay. The UAF1 binding site in a second UAF1-interacting DUB, USP46, was mapped to a region homologous to USP1(420-520). Regarding USP1 autocleavage, co expression of the C90S and GG/AA mutants did not result in cleavage, while the cancer-associated mutation L669P was found to reduce cleavage efficiency. CONCLUSIONS: USP1 phosphorylation at S313 is not critical for PCNA deubiquitination, neither for binding to UAF1 in a cellular environment. In this context, USP1 amino acid motif 420-520 is necessary and sufficient for UAF1 binding. This motif, and a homologous amino acid segment that mediates USP46 binding to UAF1, map to the Fingers sub-domain of these DUBs. On the other hand, our results support the view that USP1 autocleavage may occur in cis, and can be altered by a cancer-associated mutation. PMID- 25744537 TI - US ophthalmologists plead with drug regulator not to restrict access to Avastin. PMID- 25744536 TI - A Meta-analysis of universal mental health prevention programs for higher education students. AB - This meta-analysis investigated the effectiveness of universal mental health prevention programs for higher education students on a range of adjustment outcomes. A systematic literature search identified 103 controlled published and unpublished interventions involving college, graduate, or professional students. As hypothesized, skill-training programs that included a supervised practice component were significantly more effective overall (mean effect size = 0.45, confidence interval (CI) = 0.39 to 0.52) compared to skill-training programs without supervised practice (0.11, CI = -0.01 to 0.22) and psychoeducational (information-only) programs (0.13, CI = 0.06 to 0.21). When comparisons on specific outcomes were possible, skill-training programs including supervised practice were significantly more effective than the other two groups of programs in reducing symptoms of depression, anxiety, stress, and general psychological distress, and in improving social-emotional skills, self-perceptions, and academic behaviors and performance. The magnitude of effects achieved in several outcome areas is comparable to or higher than that reported in other reviews of universal programs, suggesting that skill-training programs for higher education students that incorporate supervised practice now join the ranks of other effective preventive mental health interventions. This review offers several recommendations to improve the experimental rigor of future research. PMID- 25744538 TI - Clinical use of diodes and micro-chambers to obtain accurate small field output factor measurements. AB - There have been substantial advances in small field dosimetry techniques and technologies, over the last decade, which have dramatically improved the achievable accuracy of small field dose measurements. This educational note aims to help radiation oncology medical physicists to apply some of these advances in clinical practice. The evaluation of a set of small field output factors (total scatter factors) is used to exemplify a detailed measurement and simulation procedure and as a basis for discussing the possible effects of simplifying that procedure. Field output factors were measured with an unshielded diode and a micro-ionisation chamber, at the centre of a set of square fields defined by a micro-multileaf collimator. Nominal field sizes investigated ranged from 6 * 6 to 98 * 98 mm(2). Diode measurements in fields smaller than 30 mm across were corrected using response factors calculated using Monte Carlo simulations of the diode geometry and daisy-chained to match micro-chamber measurements at intermediate field sizes. Diode measurements in fields smaller than 15 mm across were repeated twelve times over three separate measurement sessions, to evaluate the reproducibility of the radiation field size and its correspondence with the nominal field size. The five readings that contributed to each measurement on each day varied by up to 0.26 %, for the "very small" fields smaller than 15 mm, and 0.18 % for the fields larger than 15 mm. The diode response factors calculated for the unshielded diode agreed with previously published results, within uncertainties. The measured dimensions of the very small fields differed by up to 0.3 mm, across the different measurement sessions, contributing an uncertainty of up to 1.2 % to the very small field output factors. The overall uncertainties in the field output factors were 1.8 % for the very small fields and 1.1 % for the fields larger than 15 mm across. Recommended steps for acquiring small field output factor measurements for use in radiotherapy treatment planning system beam configuration data are provided. PMID- 25744539 TI - Shooting the messenger: the erosion of trust in science and what to do about it. PMID- 25744540 TI - CK1delta restrains lipin-1 induction, lipid droplet formation and cell proliferation under hypoxia by reducing HIF-1alpha/ARNT complex formation. AB - Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF 1alpha, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1delta phosphorylates HIF-1alpha in its N-terminus and reduces its affinity for its heterodimerization partner ARNT. To investigate the importance of this mechanism for cell proliferation under hypoxia, we visually monitored HIF 1alpha interactions within the cell nucleus using the in situ proximity ligation assay (PLA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1delta-dependent modification of HIF-1alpha impairs the formation of a chromatin binding HIF-1 complex. This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation. Inhibition of CK1delta increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1alpha- and lipin-1-dependent manner. These data reveal a novel role for CK1delta in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions. PMID- 25744541 TI - Growth factor treatment to overcome Alzheimer's dysfunctional signaling. AB - The number of people suffering from Alzheimer's disease (AD) will increase as the world population ages, creating a huge socio-economic burden. The three pathophysiological hallmarks of AD are the cholinergic system dysfunction, the beta-amyloid peptide deposition and the Tau protein hyperphosphorylation. Current treatments have only transient effects and each tends to concentrate on a single pathophysiological aspect of AD. This review first provides an overall view of AD in terms of its pathophysiological symptoms and signaling dysfunction. We then examine the therapeutic potential of growth factors (GFs) by showing how they can overcome the dysfunctional cell signaling that occurs in AD. Finally, we discuss new alternatives to GFs that help overcome the problem of brain uptake, such as small peptides, with evidence from some of our unpublished data on human neuronal cell line. PMID- 25744543 TI - Gender identity and autism spectrum disorders. AB - In this review, we briefly summarize much of the existing literature on gender related concerns and autism spectrum disorders (ASD), drawing attention to critical shortcomings in our current understanding and potential clinical implications. Some authors have concluded that gender identity disorder (GID), or gender dysphoria (GD), is more common in individuals with ASD, providing a range of potential explanations. However, existing literature is quantitatively limited, and our capacity to draw conclusions is further complicated by conceptual challenges regarding how gender identity is best understood. Discourses that emphasize gender as a component of identity formation are gaining prominence and seem particularly salient when applied to ASD. Individuals with ASD should enjoy equal rights with regard to treatment for gender dysphoria. Clinicians may be able to assist individuals in understanding this aspect of their identity by broadening the social frame and facilitating an exploration of gender roles. PMID- 25744544 TI - RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells. AB - BACKGROUND: Expression of the small calcium-binding protein S100A4 is associated with poor prognosis in patients with thyroid cancer (TC). The authors have previously shown that S100A4 is a target for relaxin and insulin-like peptide 3 signaling in TC cells and that S100A4 is secreted from human TC cells. Although the pro-migratory role of intracellular S100A4 in binding to non-muscle myosin is well known, this study investigated here whether extracellular S100A4 contributes to TC migration. METHODS: Human cell lines of follicular, papillary, and undifferentiated thyroid cancer, primary patient TC cells, and TC tissues were utilized to discover the presence of the receptor of advanced glycation end products (RAGE) in TC cells and TC tissues. Fluorescence imaging, protein pull down assays, Western blot, siRNA protein silencing, small GTPase inhibitors, cell proliferation, and cell migration assays were used to investigate the interaction of extracellular S100A4 with RAGE in promoting a TC migratory response. RESULTS: It was demonstrated that RAGE served as receptor for extracellular S100A4 mediating cell migration in TC cells. The RAGE-mediated increase in cell migration was dependent on the intracellular RAGE signaling partner diaphanous-1 (Dia-1) and involved the activation of the small GTPases Cdc42 and RhoA. Although extracellular S100A4 consistently activated ERK signaling in TC cells, it was shown that ERK signaling was not mediated by RAGE and not essential for the migratory response in TC cells. CONCLUSION: The data have identified the RAGE/Dia 1 signaling system as a mediator for the pro-migratory response of extracellular S100A4 in human TC. Thus, therapeutic targeting of the RAGE/Dia-1/small GTPases signaling may successfully reduce local invasion and metastasis in TC. PMID- 25744542 TI - The future of EPAC-targeted therapies: agonism versus antagonism. AB - Pharmaceutical manipulation of cAMP levels exerts beneficial effects through the regulation of the exchange protein activated by cAMP (EPAC) and protein kinase A (PKA) signalling routes. Recent attention has turned to the specific regulation of EPAC isoforms (EPAC1 and EPAC2) as a more targeted approach to cAMP-based therapies. For example, EPAC2-selective agonists could promote insulin secretion from pancreatic beta cells, whereas EPAC1-selective agonists may be useful in the treatment of vascular inflammation. By contrast, EPAC1 and EPAC2 antagonists could both be useful in the treatment of heart failure. Here we discuss whether the best way forward is to design EPAC-selective agonists or antagonists and the current strategies being used to develop isoform-selective, small-molecule regulators of EPAC1 and EPAC2 activity. PMID- 25744545 TI - Body mass indexes should be stratified clearly in order to determine increased arterial stiffness in subjects with impaired fasting glucose. PMID- 25744546 TI - Plasma osteoprotegerin concentrations in type 1 diabetic patients with albuminuria. AB - BACKGROUND: Osteoprotegerin (OPG) is a recently identified inhibitor of bone resorption. Recent studies indicate that OPG is also associated with endothelial dysfunction in diabetes. AIM: To investigate the relationship between plasma OPG levels and urinary albumin excretion (UAE) in type 1 diabetes. METHODS: A total of 80 type 1 diabetic subjects and 40 control subjects were enrolled. Diabetic subjects were divided into a normoalbuminuric group and a microalbuminuric group according to urinary albumin excretion rate (UAER). Plasma OPG level was measured by enzyme-linked immunoassay. RESULTS: The plasma OPG levels were significantly elevated in patients with microalbuminuria (176.39+/-25.05pg/ml) compared with patients with normoalbuminuria (154.73+/-16.66pg/ml) and control subjects (44.76+/-8.7pg/ml). The plasma OPG level had a positive correlation with patients' age, duration of disease, HbA1C and UAER. CONCLUSIONS: Plasma OPG levels are significantly associated with UAE in patients with type 1 diabetes. These findings may support the concept that elevated plasma OPG may be associated with diabetic angiopathy. PMID- 25744547 TI - Methodology for optimally sized centrifugal partition chromatography columns. AB - Centrifugal Partition Chromatography (CPC) is a separation process based on the partitioning of solutes between two partially miscible liquid phases. There is no solid support for the stationary phase. The centrifugal acceleration is responsible for both stationary phase retention and mobile phase dispersion. CPC is thus a process based on liquid-liquid mass transfer. The separation efficiency is mainly influenced by the hydrodynamics of the phases in each cell of the column. Thanks to a visualization system, called "Visual CPC", it was observed that the mobile phase can flow through the stationary phase as a sheet, or a spray. Hydrodynamics, which directly governs the instrument efficiency, is directly affected during scale changes, and non-linear phenomena prevent the successful achievement of mastered geometrical scale changes. In this work, a methodology for CPC column sizing is proposed, based on the characterization of the efficiency of advanced cell shapes, taking into account the hydrodynamics. Knowledge about relationship between stationary phase volume, cell efficiency and separation resolution in CPC allowed calculating the optimum cell number for laboratory and industrial scale CPC application. The methodology is highlighted with results on five different geometries from 25 to 5000 mL, for two applications: the separation of alkylbenzene by partitioning with heptane/methanol/water biphasic system; and the separation of peptides by partitioning with n-butanol/acetic acid/water (4/1/5) biphasic system. With this approach, it is possible to predict the optimal CPC column length leading to highest productivity. PMID- 25744548 TI - Investigation of photochemical reactions of saccharides during direct ultraviolet absorbance detection in capillary electrophoresis. AB - Direct UV detection of saccharides in capillary electrophoresis is possible due to a base-catalyzed conversion into UV absorbing substances initiated by the light of the UV detector lamp. In the present study the compounds formed during this reaction were investigated with capillary electrophoresis using an additional UV lamp for online irradiation at a certain distance before the detector resulting in a separation of the conversion products. It was found that for all investigated saccharides (glucose, ribose and sucrose) the major portion of the UV absorption in direct UV detection resulted from one and the same substance. By CE-UV, CE-MS as well as HPLC-MS measurements this substance was demonstrated to be malondialdehyde, present as its conjugate base malonenolate under alkaline conditions. Additional experiments revealed that the conversion reaction is highly sensitive to the residence time under the UV light as malondialdehyde can further degrade into non-UV absorbing products. NMR measurements showed that under alkaline conditions this degradation proceeds slowly even without UV irradiation. PMID- 25744549 TI - Microcalorimetric study of adsorption and disassembling of virus-like particles on anion exchange chromatography media. AB - Chromatographic purification of virus-like particles (VLPs) is important to the development of modern vaccines. However, disassembly of the VLPs on the solid liquid interface during chromatography process could be a serious problem. In this study, isothermal titration calorimetric (ITC) measurements, together with chromatography experiments, were performed on the adsorption and disassembling of multi-subunits hepatitis B virus surface antigen virus-like particles (HB-VLPs). Two gigaporous ion-exchange chromatography (IEC) media, DEAE-AP-280 nm and DEAE POROS, were used. The application of gigaporous media with high ligand density led to significantly increased irreversible disassembling of HB-VLPs and consequently low antigen activity recovery during IEC process. To elucidate the thermodynamic mechanism of the effect of ligand density on the adsorption and conformational change of VLPs, a thermodynamic model was proposed. With this model, one can obtain the intrinsic molar enthalpy changes related to the binding of VLPs and the accompanying conformational change on the liquid-solid interface during its adsorption. This model assumes that, when intact HB-VLPs interact with the IEC media, the total adsorbed proteins contain two states, the intact formation and the disassembled formation; accordingly, the apparent adsorption enthalpy, DeltaappH, which can be directly measured from ITC experiments, presents the sum of three terms: (1) the intrinsic molar enthalpy change associated to the binding of intact HB-VLPs (DeltabindHintact), (2) the intrinsic molar enthalpy change associated to the binding of HB-VLPs disassembled formation (DeltabindHdis), and (3) the enthalpy change accompanying the disassembling of HB VLPs (DeltaconfHdis). The intrinsic binding of intact HB-VLPs and the disassembled HB-VLPs to both kinds of gigaporous media (each of which has three different ligand densities), were all observed to be entropically driven as indicated by positive values of DeltabindHintact and DeltabindHdis; while the nagative DeltaconfHdis values suggested a spontenous enthalpy-driven process for the forming of HB-VLPs disassembled formation at all conditions studied. As ligand density increases, DeltaconfHdis became more negative, which was in agreement with the findings from chromatography experiments, that higher ligand density leads to more serious disassembling of HB-VLPs. Results from thermodynamic studies provided us insight understanding on the mechanism of adsorption and conformational change of VLPs, as well as the effect of ligand densities on the structural stability of VLPs during IEC process. PMID- 25744550 TI - Genetic factors are "substantial" in aetiology of autism, study of UK twins finds. PMID- 25744552 TI - An economic analysis of autologous hematopoietic stem cell transplantation (AHSCT) in the treatment of new onset type 1 diabetes. AB - AIMS: Autologous hematopoietic stem cell transplantation (AHSCT) is an emerging treatment option in new onset type 1 diabetes (T1DM), leading to a remission of the T1DM for a longer time period in up to 50 % of patients. The aim of the study was to analyze the cost-effectiveness of this treatment option compared with standard insulin therapy. METHODS: The medical records of patients who had undergone immunoablation with AHSCT for new onset T1DM were analyzed for the cost effectiveness of the treatment using the IMS CORE Diabetes Model. RESULTS: The expected survival of patients with T1DM treated solely with insulin (without transplantation) was estimated to be 34.4 years, and their quality-adjusted survival was 13.8 QALY, whereas the expected survival of the patients treated with AHSCT was 34.9 years when the HbA1c benefit over standard treated patients lasted for 2, 35.4 years with 8-year benefit and even up to 40.3 years with the lifelong benefit scenario. Values under the threshold of ICER were reached after 8 years of sustained benefit in terms of HbA1c concentration. If discounting was not applied, the threshold values were reached after 3 years of HbA1c benefit over the standard group, independent of insulin use after transplantation. CONCLUSIONS: The results of our study show that hematopoietic stem cell transplantation could be cost-effective in treating new onset T1DM, providing that the benefits of the transplantation lasted over 3-8 years, depending on application of discounting. PMID- 25744551 TI - Conserved and divergent aspects of human T-cell development and migration in humanized mice. AB - Humanized mice represent an important model to study the development and function of the human immune system. While it is known that mouse thymic stromal cells can support human T-cell development, the extent of interspecies cross-talk and the degree to which these systems recapitulate normal human T-cell development remain unclear. To address these questions, we compared conventional and non conventional T-cell development in a neonatal chimera humanized mouse model with that seen in human fetal and neonatal thymus samples, and also examined the impact of a human HLA-A2 transgene expressed by the mouse stroma. Given that dynamic migration and cell-cell interactions are essential for T-cell differentiation, we also studied the intrathymic migration pattern of human thymocytes developing in a murine thymic environment. We found that both conventional T-cell development and intra-thymic migration patterns in humanized mice closely resemble human thymopoiesis. Additionally, we show that developing human thymocytes engage in short, serial interactions with other human hematopoietic-derived cells. However, non-conventional T-cell differentiation in humanized mice differed from both fetal and neonatal human thymopoiesis, including a marked deficiency of Foxp3(+) T-cell development. These data suggest that although the murine thymic microenvironment can support a number of aspects of human T-cell development, important differences remain, and additional human specific factors may be required. PMID- 25744553 TI - A large family of filled skutterudites stabilized by electron count. AB - The Zintl concept is important in solid-state chemistry to explain how some compounds that combine electropositive and main group elements can be stable at formulas that at their simplest level do not make any sense. The electronegative elements in such compounds form a polyatomic electron-accepting molecule inside the solid, a 'polyanion', that fills its available energy states with electrons from the electropositive elements to obey fundamental electron-counting rules. Here we use this concept to discover a large family of filled skutterudites based on the group 9 transition metals Co, Rh, and Ir, the alkali, alkaline-earth, and rare-earth elements, and Sb4 polyanions. Forty-three new filled skutterudites are reported, with 63 compositional variations--results that can be extended to the synthesis of hundreds of additional new compounds. Many interesting electronic and magnetic properties can be expected in future studies of these new compounds. PMID- 25744554 TI - Commentary to 'Environmental, parental and gestational factors that influence the occurrence of hypospadias in male patients'. PMID- 25744555 TI - Design and optimization of self-nanoemulsifying formulations for lipophilic drugs. AB - The purpose of the current study was to develop and optimize novel self nanoemulsifying drug delivery systems (SNEDDS) with a high proportion of essential oil as carriers for lipophilic drugs. Solubility and droplet size as a function of the composition were investigated, and a ternary phase diagram was constructed in order to identify the self-emulsification regions. The optimized SNEDDS formulation consisted of lemon essential oil (oil), Cremophor RH40 (surfactant) and Transcutol HP (co-surfactant) in the ratio 50:30:20 (v/v). Ibuprofen was chosen as the model drug. The droplet size, zeta-potential and stability of the drug-loaded optimized formulations were determined. The stability of SNEDDS was proved after triple freezing/thawing cycles and storage at 4 degrees C and 25 degrees C for 3 months. In vitro drug release studies of optimized SNEDDS revealed a significant increase of the drug release and release rate in comparison to the Ibuprofen suspension (80% versus approximately 40% in 2 h). The results indicated that these SNEDDS formulations could be used to improve the bioavailability of lipophilic drugs. PMID- 25744556 TI - Germany, the G7, and global health. PMID- 25744557 TI - Caregiver-identified needs and barriers to care in Parkinson's disease. AB - Perceptions of service needs and barriers to care among caregivers of individuals with Parkinson's disease have not been well explored. The purpose of this study was to assess caregiver perceptions of their own and patients' medical and supportive service needs. An online and paper survey was disseminated to a sample of caregivers (n = 66) of individuals with Parkinson's disease. Although caregivers reported positive quality of life and adjustment to caregiving, nearly half of the sample endorsed feeling stressed about caregiving. Caregivers reported that services for symptom management, coping with changes in lifestyle, future planning, relationships, and cognition, and wellness strategies were most needed. Reported barriers to patients accessing care included limited service availability and a lack of insurance coverage for services. These findings suggest a need to improve access to services for patients and increased efforts to promote caregiver wellness at movement disorder specialty clinics. PMID- 25744558 TI - Caregiver tele-support group for Parkinson's disease: A pilot study. AB - BACKGROUND: Parkinson's disease (PD) is a disabling neurodegenerative disease that typically affects the geriatric population and requires a caregiver. Although caregiver burden reduces quality of life of the caregiver, support groups for caregivers have not been studied. Offering a tele-support group to PD caregivers would be an innovative approach to extending a novel resource. METHODS: A single-center pilot study was conducted, enrolling caregivers in an 8 week tele-support group program. Mood state and caregiver burden were assessed at baseline and conclusion of the program using self-report questionnaires. Qualitative feedback was obtained at the conclusion of the program. RESULTS: Seven female spouse caregivers enrolled; 86% completed the program. Although no statistically significant changes in questionnaire scores were found, the mean Geriatric Depression Scale decreased from 4.2 to 3 and qualitative feedback was universally positive. CONCLUSIONS: The use of tele-support groups for PD caregivers is a feasible and innovative resource to address caregiver burden. PMID- 25744560 TI - Reconstruction after pancreatic trauma by pancreaticogastrostomy. AB - INTRODUCTION: Pancreatic lesions are very infrequent after closed abdominal trauma (5% of cases) with a complication rate that affects 30-40% of patients, and a mortality rate that can reach 39%. In our experience, closed abdominal traumatisms occurring at typical popular horse-riding festivals in our region constitute a high risk of pancreatic trauma. The purpose of the present paper is to raise awareness about our experience in the diagnosis and treatment of pancreatic lesions secondary to closed abdominal traumatism. PRESENTATION OF CASE: We present the clinical cases of two young patients who, after suffering blunt abdominal trauma secondary to the impact of a horse during the celebration of typical horse-riding festival, were diagnosed with pancreatic trauma type III. The treatment was surgical in both cases and consisted in performing a pancreaticogastric anastomosis with preservation of the distal pancreas and spleen. The postoperative period was uneventful and, at present, both patients are asymptomatic. DISCUSSION: Signs and symptoms caused by pancreatic lesion are unspecific and difficult to objectify. With some limitations CT is the imaging test of choice for diagnosis and staging in the acute phase. The Wirsung section is indication for surgical treatment. The most extended surgical procedure in these cases is the resection of pancreatic body, tail, and spleen. CONCLUSION: The identification of a pancreatic injury after closed abdominal trauma requires a high suspicion based on the injury mechanism. A safer option may be the distal pancreatic preservation with pancreaticogastric anastomosis in grade III lesions with healthy pancreatic tissue. PMID- 25744559 TI - Visualizing real-time influenza virus infection, transmission and protection in ferrets. AB - Influenza transmission efficiency in ferrets is vital for risk-assessment studies. However, the inability to monitor viral infection and transmission dynamics in real time only provides a glimpse into transmissibility. Here we exploit a replication-competent influenza reporter virus to investigate dynamics of infection/transmission in ferrets. Bioluminescent imaging of ferrets infected with A/California/04/2009 H1N1 virus (CA/09) encoding NanoLuc (NLuc) luciferase provides the first real-time snapshot of influenza infection/transmission. Luminescence in the respiratory tract and in less well-characterized extra pulmonary sites is observed, and imaging identifies infections in animals that would have otherwise been missed by traditional methods. Finally, the reporter virus significantly increases the speed and sensitivity of virological and serological assays. Thus, bioluminescent imaging of influenza infections rapidly determines intra-host dissemination, inter-host transmission and viral load, revealing infection dynamics and pandemic potential of the virus. These results have important implications for antiviral drug susceptibility, vaccine efficacy, transmissibility and pathogenicity studies. PMID- 25744561 TI - Giant mucocele of the appendix in pregnancy: A case report and review of literature. AB - INTRODUCTION: Mucocoele of the appendix is an obstructive dilatation of the appendix by intraluminal accumulation of mucoid material. Mucocoeles may develop by one of four processes: Retention cysts, Mucosal hyperplasia, Cystadenomas, and Cystadenocarcinomas. The clinical presentation of a mucocele is nonspecific and often an incidental finding at operation for acute appendicitis. If mucocoele is allowed to rupture either spontaneously or during surgery, the escape of mucin and epithelial cells into the peritoneal cavity - Pseudomyxoma Peritonei - may occur. PRESENTATION OF CASE: We present the case of a 35 years old pregnant woman, who was admitted to the accident and emergency department with history and ultrasound findings suggestive of acute appendicitis. The ultrasound scan also confirmed a viable fetus at about 23week's gestational age. She had an open appendectomy. The intra-operative findings were an enlarged, tense, cystic retro caecal appendix which was about 14cm*5cm*3cm in dimensions. Histopathological examination confirmed mucocoele of the appendix. She had normal vaginal delivery at term and postoperative follow up for 1 year was uneventful. DISCUSSION: Mucocele of the appendix is an uncommon disorder with nonspecific presentation ranging from asymptomatic disease diagnosed incidentally to clinical features of appendicitis. The treatment is surgery. CONCLUSION: Appendiceal mucocoele is difficult to diagnose preoperatively, and a giant size of the simple mucocoele may be connected to hormonal influence of pregnancy. In the index case, as in majority of cases, the definitive diagnosis is made at surgery. PMID- 25744562 TI - Sinus node dysfunction requiring permanent pacemaker implantation in a young adult with Klinefelter syndrome. AB - BACKGROUND: Klinefelter syndrome is the most common genetic cause of male infertility and affects approximately 1 in 500 live births. Although accompanying cardiac disorder is not a specific feature of Klinefelter syndrome, rarely associated anomalies such as mitral valve prolapse, atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus, and hypertrophic obstructive cardiomyopathy have been reported. A clear association between Klinefelter syndrome and arrhythmic disorders has not yet been demonstrated. CASE REPORT: We report a case of a sinus node dysfunction that required permanent pacemaker implantation in a young adult with Klinefelter syndrome. The patient was consulted to cardiology clinic due to bradycardia. On physical examination, no cardiac abnormality was detected except for bradycardia. Holter results showed sinus arrhythmia with a minimum heart rate of 33 bpm and maximum of 154 Bpm. There were 3612 ventricular premature beats, 30 ventricular pairs, 804 supraventricular premature beats, 7 supraventricular pairs, and 4 supraventricular runs, the longest of which was 5 beats. The patient had defined dizziness and nausea during Holter monitoring. Electrophysiological study (EPS) was planned because existing findings indicated risk of cardiac syncope. Findings of EPS were interpreted as sinus node dysfunction. A permanent pacemaker implantation was performed and the patient has been free of symptoms since. CONCLUSIONS: This concomitance should be kept in mind when examining patients with Klinefelter syndrome with bradycardia and/or syncope. It is easily mistaken for epilepsy, which is a commonly encountered abnormality in Klinefelter syndrome. PMID- 25744563 TI - Contributing factors for a late spontaneous peripherally inserted central catheter migration: a case report and review of literature. AB - PURPOSE: Peripherally inserted central catheters (PICCs) are associated with some adverse events, the most frequent are thrombosis, tip catheter malposition and spontaneous late migration. However, the cause of spontaneous late migration in most cases remains unknown. We carried out this study to add data to the literature on PICCs late spontaneous migration. METHODS: We conducted a systematic review of all manuscripts describing PICC spontaneous late migration in adult populations and we also described two cases of late PICCs migration. RESULTS: We identified five studies for a total of 58 cases of PICC late migration. In our two cases, patients' activity is an important contributing factor for late spontaneous PICC migration. CONCLUSIONS: To avoid late catheter misplacement, initial malposition should be immediately identified and promptly corrected and a detailed patients training should be carried out. PMID- 25744564 TI - Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis. AB - Bacterial meningitis is a life-threatening infection associated with cognitive impairment in many survivors. The pathogen invades the central nervous system (CNS) by penetrating through the luminal side of the cerebral endothelium, which is an integral part of the blood-brain barrier. The replication of bacteria within the subarachnoid space occurs concomitantly with the release of their compounds that are highly immunogenic. These compounds known as pathogen associated molecular patterns (PAMPs) may lead to both an increase in the inflammatory response in the host and also microglial activation. Microglia are the resident macrophages of the CNS which, when activated, can trigger a host of immunological pathways. Classical activation increases the production of pro inflammatory cytokines, chemokines, and reactive oxygen species, while alternative activation is implicated in the inhibition of inflammation and restoration of homeostasis. The inflammatory response from classical microglial activation can facilitate the elimination of invasive microorganisms; however, excessive or extended microglial activation can result in neuronal damage and eventually cell death. This review aims to discuss the role of microglia in the pathophysiology of bacterial meningitis as well as the process of microglial activation by PAMPs and by endogenous constituents that are normally released from damaged cells known as danger-associated molecular patterns (DAMPs). PMID- 25744565 TI - Alcoholic Extract of Ashwagandha Leaves Protects Against Amnesia by Regulation of Arc Function. AB - Our earlier report on scopolamine-induced amnesia and its improvement by pre treatment with i-Extract (alcoholic extract of Ashwagandha leaf) suggested that the i-Extract mediated nootropic effect may involve neuronal immediate early gene, Arc. With a hypothesis that the i-Extract induced expression of Arc protein may cause augmentation in Arc function, we examined the effect of i-extract on a major function of Arc protein, i.e. F-actin expansion, using Arc antisense oligodeoxynucleotides (ODN). Stereotaxic infusion of Arc antisense ODN in the CA1 region of hippocampus decreased the level of Arc protein as demonstrated by immunoblotting. However, this decrease was attenuated when treated with i-Extract prior to infusion of Arc antisense ODN. We noted a significant decrease in the polymerization of F-actin during scopolamine-induced amnesia as well as Arc antisense ODN infusion that was restored rather enhanced when pre-treated with i Extract in both the cases. We also compared the corresponding changes between CA1 (the infusion site) and CA3 (neighbouring site of infusion) regions of hippocampus, and found more pronounced effects in CA1 than in the CA3 region. The extent of F-actin polymerization, as revealed by changes in the dendritic spine architecture through Golgi staining, showed that both scopolamine as well as Arc antisense ODN disrupted the spine density and mushroom-shaped morphology that was again regained if pre-treated with i-Extract. In conclusion, the findings reveal that the Arc helps in polymerization of F-actin and subsequent changes in the morphology of dendritic spines after pre-treatment with i-Extract in scopolamine induced amnesic mice, suggesting an important role of Arc in scopolamine-induced amnesia and its recovery by i-Extract. PMID- 25744566 TI - The Natural Flavonoid Pinocembrin: Molecular Targets and Potential Therapeutic Applications. AB - Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications. PMID- 25744567 TI - Altered Expression Pattern of Acid-Sensing Ion Channel Isoforms in Piriform Cortex After Seizures. AB - The piriform cortex (PC) is highly susceptible to chemical and electrical seizure induction. Epileptiform activity is associated with an acid shift in extracellular pH, suggesting that acid-sensing ion channels (ASICs) expressed by PC neurons may contribute to this enhanced epileptogenic potential. In epileptic rats and surgical samples from patients with medial temporal lobe epilepsy (TLE), PC layer II ASIC1a-immunopositive neurons appeared swollen with dendritic elongation, and there was loss of ASIC1a-positive neurons in layer III, consistent with enhanced vulnerability to TLE-induced plasticity and cell death. In rats, pilocarpine-induced seizures led to transient downregulation of ASIC1a and concomitant upregulation of ASIC2a in the first few days post-seizure. These changes in expression may be due to seizure-induced oxidative stress as a similar reciprocal change in ASIC1a, and ASIC2a expression was observed in PC12 cells following H2O2 application. The proportion of ASIC1a/ASIC2a heteromers was reduced in the acute phase following status epilepticus (SE) but increased during the latent phase when rats developed spontaneous seizures. Knockdown of ASIC2a by RNAi reduced dendritic length and spine density in primary neurons, suggesting that seizure-induced upregulation of ASIC2a contributes to dendritic lengthening in PC layer II in rats. Administration of the ASIC inhibitor amiloride before pilocarpine reduced the proportion of rats reaching Racine level IV seizures, protected layer II and III neurons, and prolonged survival in the acute phase following SE. Our findings suggest that ASICs may enhance susceptibility to epileptogenesis in the PC. Inhibition of ASICs, particularly ASIC2a, may suppress seizures originating in the PC. PMID- 25744568 TI - Intracerebroventricular Streptozotocin Injections as a Model of Alzheimer's Disease: in Search of a Relevant Mechanism. AB - Streptozotocin (STZ), a glucosamine-nitrosourea compound derived from soil bacteria and originally developed as an anticancer agent, in 1963 has been found to induce diabetes in experimental animals. Since then, systemic application of STZ became the most frequently studied experimental model of insulin-dependent (type 1) diabetes. The compound is selectively toxic toward insulin-producing pancreatic beta cells, which is explained as the result of its cellular uptake by the low-affinity glucose transporter 2 (GLUT2) protein located in their cell membranes. STZ cytotoxicity is mainly due to DNA alkylation which results in cellular necrosis. Besides pancreatic beta cells, STZ applied systemically damages also other organs expressing GLUT2, such as kidney and liver, whereas brain is not affected directly because blood-brain barrier lacks this transporter protein. However, single or double intracerebroventricular (icv) STZ injection(s) chronically decrease cerebral glucose uptake and produce multiple other effects that resemble molecular, pathological, and behavioral features of Alzheimer's disease (AD). Taking into consideration that glucose hypometabolism is an early and persistent sign of AD and that Alzheimer's brains present features of impaired insulin signaling, icv STZ injections are exploited by some investigators as a non-transgenic model of this disease and used for preclinical testing of pharmacological therapies for AD. While it has been assumed that icv STZ produces cerebral glucose hypometabolism and other effects directly through desensitizing brain insulin receptors, the evidence for such mechanism is poor. On the other hand, early data on insulin immunoreactivity showed intense insulin expression in the rodent brain, and the possibility of local production of insulin in the mammalian brain has never been conclusively excluded. Also, there are GLUT2-expressing cells in the brain, in particular in the circumventricular organs and hypothalamus; some of these cells may be involved in glucose sensing. Thus, icv STZ may damage brain glucose insulin producing cells and/or brain glucose sensors. Mechanistic explanation of the mode of action of icv STZ, which is currently lacking, would provide a valuable contribution to the field of animal models of Alzheimer's disease. PMID- 25744569 TI - Serum Uric Acid Levels and Outcomes After Acute Ischemic Stroke. AB - Previous studies assessing the association between serum uric acid levels and neurological outcome after acute ischemic stroke reported conflicting results. A systematic review and meta-analysis were conducted to assess the impact of serum uric acid levels on outcome after acute ischemic stroke. Pubmed, Embase, Web of Science, and Google scholar were searched through September 26, 2014 to identify eligible published or unpublished studies on the association between serum uric acid levels and outcome after acute ischemic stroke. Hazard ratio (HR) for poor outcome or mean differences of serum uric acid levels with 95% confidence intervals (95% CIs) were pooled using meta-analysis. The primary outcome was occurrence of poor outcomes, while the secondary outcome was the mean differences of serum uric acid levels in patients with good or poor outcomes. Ten eligible studies with a total of 8131 acute ischemic stroke patients were included into the meta-analysis. Compared with low serum uric acid level, high serum uric acid level was associated better outcome after acute ischemic stroke (HR = 0.77, 95% CI 0.68-0.88, P = 0.0001). Sensitivity analysis further identified the prognostic role of serum uric acid levels on outcome after acute ischemic stroke. Patients with good outcomes had a higher serum uric acid level compared with those with poor outcome (mean difference = 30.61 MUmol/L, 95% CI 20.13-41.08, P < 0.00001). There was no obvious risk of publication bias in the meta-analysis. This meta analysis supports that serum uric acid level has a protective effect on neurological outcome after acute ischemic stroke. High uric acid level at the onset is a biomarker of better prognosis in patients with acute ischemic stroke. PMID- 25744570 TI - Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success. AB - BACKGROUND: In the meantime, catheter ablation is widely used for the treatment of persistent atrial fibrillation (AF). There is a paucity of data about long term outcomes. This study evaluates (1) 5-year single and multiple procedure success and (2) prognostic factors for arrhythmia recurrences after catheter ablation of persistent AF using the stepwise approach aiming at AF termination. METHODS AND RESULTS: A total of 549 patients with persistent AF underwent de novo catheter ablation using the stepwise approach (2007-2009). A total of 493 patients were included (Holter ECGs >= every 6 months). Mean follow-up was 59 +/- 16 months with 2.1 +/- 1.1 procedures per patient. Single and multiple procedure success rates were 20.1% and 55.9%, respectively (80% off antiarrhythmic drug). Antiarrhythmic drug-free multiple procedure success was 46%. Long-term recurrences (n=171) were paroxysmal AF in 48 patients (28%) and persistent AF/atrial tachycardia in 123 patients (72%). Multivariable recurrent event analysis revealed the following factors favoring arrhythmia recurrence: failure to terminate AF during index procedure (hazard ratio [HR], 1.279; 95% confidence interval [CI], 1.093-1.497; P = 0.002), number of procedures (HR, 1.154; 95% CI, 1.051-1.267; P = 0.003), female sex (HR, 1.263; 95% CI, 1.027-1.553; P = 0.027), and the presence of structural heart disease (HR, 1.236; 95% CI, 1.003-1.524; P = 0.047). AF termination was correlated with a higher rate of consecutive procedures because of atrial tachycardia recurrences (P = 0.003; HR, 1.71; 95% CI, 1.20-2.43). CONCLUSIONS: Catheter ablation of persistent AF using the stepwise approach provides limited long-term freedom of arrhythmias often requiring multiple procedures. AF termination, the number of procedures, sex, and the presence of structural heart disease correlate with outcome success. AF termination is associated with consecutive atrial tachycardia procedures. PMID- 25744571 TI - Ultrasound of the joints and entheses in healthy children. AB - BACKGROUND: Tendon insertion pathologies such as enthesitis and apophysitis in children can result from trauma, overuse syndrome and arthritis. Knowledge of the US appearance of normal joints by age might aid diagnosis of pathologies. OBJECTIVE: We describe the age-related sonographic features of the elbows, knees and feet in healthy children, providing a reference for the normal appearance of tendon insertions, apophyseal cartilage and bursae. MATERIALS AND METHODS: This is a prospective cross-sectional study of 30 healthy children. Children were grouped according to age: group 1 (4-9 years, n = 11), group 2 (10-13 years, n = 9) and group 3 (14-18 years, n = 10). Children completed pain and function questionnaires and underwent a standardized joint examination by a pediatric rheumatologist. The common extensor, common flexor, quadriceps, patellar and Achilles tendons and plantar fascia insertions were evaluated with gray-scale and power Doppler ultrasound. The anterior elbow, suprapatellar and retrocalcaneal bursae were evaluated for fluid. We measured the apophyseal cartilage thickness at the enthesis. Correlation analyses examined associations between age and tendon thickness. We used ANOVA, with location as a repeated measure, to test for gender differences in cartilage thickness. RESULTS: Children had a median age of 12.4 years and 55% were boys. All 360 entheses appeared normal on gray-scale imaging. There was a strong linear relationship between tendon thickness and age. Tendon vascularity was only present in young children (group 1), in 7/22 (32%) quadriceps tendons. Peri-tendinous power Doppler signal was seen at seven sites: two patellar, four quadriceps and one common flexor tendon, and all these children were in group 2. Suprapatellar bursal fluid <3 mm was detected in 9/60 (15%) knees. Of the children in group 1, boys had thicker apophyseal cartilage than girls at the medial epicondyle, patellar poles and os calcis (P < 0.05). CONCLUSION: Tendon vascularity may be a normal finding in young children, and mild peri-tendinous vascularity is not uncommon in children 10-13 years of age. Tendon thickness has a linear relationship with age; however cartilage thickness varies across sites and also differs as a function of gender. PMID- 25744572 TI - Attachment based treatments for adolescents: the secure cycle as a framework for assessment, treatment and evaluation. AB - The emergence of attachment-based treatments (ABTs) for adolescents highlights the need to more clearly define and evaluate these treatments in the context of other attachment based treatments for young children and adults. We propose a general framework for defining and evaluating ABTs that describes the cyclical processes that are required to maintain a secure attachment bond. This secure cycle incorporates three components: (1) the child or adult's IWM of the caregiver; (2) emotionally attuned communication; and (3) the caregiver's IWM of the child or adult. We briefly review Bowlby, Ainsworth, and Main's contributions to defining the components of the secure cycle and discuss how this framework can be adapted for understanding the process of change in ABTs. For clinicians working with adolescents, our model can be used to identify how deviations from the secure cycle (attachment injuries, empathic failures and mistuned communication) contribute to family distress and psychopathology. The secure cycle also provides a way of describing the ABT elements that have been used to revise IWMs or improve emotionally attuned communication. For researchers, our model provides a guide for conceptualizing and measuring change in attachment constructs and how change in one component of the interpersonal cycle should generalize to other components. PMID- 25744573 TI - Stereoselective synthesis of a highly oxygenated decahydrocyclopenta[g]chromene derivative: the common tricyclic framework of leucosceptrine and leucosesterterpenone. AB - Stereoselective construction of the highly oxygenated decahydrocyclopenta[g]chromene skeleton, which is the tricyclic core of leucosceptrine, which possesses prolylendopeptidase inhibitory activity, and leucosesterterpenone, which exhibits anti-angiogenic activity, from Leucosceptrum canum, was achieved. PMID- 25744574 TI - Development and evaluation of a culture-independent method for source determination of fecal wastes in surface and storm waters using reverse transcriptase-PCR detection of FRNA coliphage genogroup gene sequences. AB - A method, incorporating recently improved reverse transcriptase-PCR primer/probe assays and including controls for detecting interferences in RNA recovery and analysis, was developed for the direct, culture-independent detection of genetic markers from FRNA coliphage genogroups I, II & IV in water samples. Results were obtained from an initial evaluation of the performance of this method in analyses of waste water, ambient surface water and stormwater drain and outfall samples from predominantly urban locations. The evaluation also included a comparison of the occurrence of the FRNA genetic markers with genetic markers from general and human-related bacterial fecal indicators determined by current or pending EPA validated qPCR methods. Strong associations were observed between the occurrence of the putatively human related FRNA genogroup II marker and the densities of the bacterial markers in the stormwater drain and outfall samples. However fewer samples were positive for FRNA coliphage compared to either the general bacterial fecal indicator or the human-related bacterial fecal indicator markers particularly for ambient water samples. Together, these methods show promise as complementary tools for the identification of contaminated storm water drainage systems as well as the determination of human and non-human sources of contamination. PMID- 25744575 TI - [CRISPR-Cas9 technology: a decisive tool for achieving personalized therapies?]. PMID- 25744577 TI - Expression of Cytoplasmic Gelsolin in Rat Brain After Experimental Subarachnoid Hemorrhage. AB - Convincing evidence indicates that apoptosis contributes to the unfavorable prognosis of subarachnoid hemorrhage (SAH), a significant cause of morbidity and case fatality throughout the world. Gelsolin (GSN) is a Ca(2+)-dependent actin filament severing, capping, and nucleating protein, as well as multifunctional regulator of cell structure and metabolism, including apoptosis. In the present study, we intended to investigate the expression pattern and cell distribution of GSN in rat brain after experimental SAH. GSN expression was examined in sham group and at 3, 6, 12 h, day 1 (1 day), 2, 3, 5, and 7 days after SAH by Western blot analysis as well as real-time polymerase chain reaction. Immunohistochemistry and immunofluorescence were performed to detect the localization of GSN. The level of GSN protein expression was significantly decreased in SAH group and reached a bottoming point on 1 day after SAH. GSN mRNA level was significantly decreased in SAH groups in comparison with the sham group, and reached a minimum value at 12 h after SAH. Immunohistochemistry showed that GSN was constitutively and obviously expressed in the cortex of the normal rat brain and significantly decreased in the rat cortex after SAH. In addition, immunofluorescence results revealed that GSN expression could be found in both neurons and microglias, as well as in glialfibrillary acidic protein-positive astrocytes. The decreased expression of GSN could mainly be found in neurons and astrocytes as well, and GSN-positive microglias showed different cell morphological characteristics. Interestingly, the protein and gene levels of GSN seemed to be constant in the rat hippocampus of sham and SAH groups. These findings suggested a potential role of GSN in the pathophysiology of the brain at the early stage of SAH. PMID- 25744576 TI - Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-based chemotherapy for patients with HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma patients: a retrospective study. AB - BACKGROUND: Trastuzumab with 5-fluorouracil (5-FU) and cisplatin offers prolonged survival in patients with HER2-overexpressing advanced gastric cancer (AGC) and advanced gastro-oesophageal junction cancer (AGOJ). Oxaliplatin in combination with intravenous 5-FU plus leucovorin (LV; modified [m]FOLFOX6) or capecitabine (XELOX) improves tolerability compared with 5-FU/cisplatin regimen. There are few data available on the efficacy and safety of trastuzumab-oxaliplatin-based chemotherapy in previously untreated HER2-positive AGC and AGOJ patients. METHODS: Clinical data were retrospectively analysed in patients receiving trastuzumab plus mFOLFOX6 or XELOX as first-line therapy between July 2009 and December 2012. Eligible patients had histologically proven AGC or AGOJ, HER2 overexpression, and no prior chemotherapy for metastatic disease. RESULTS: Thirty four patients met the eligibility criteria. Median age was 63 years, 79% of patients had ECOG PS score of 0-1, and all had metastatic disease. Median duration of treatment was 7.5 months. Overall response rate was 41% (95% CI: 25 56). Median progression-free survival and overall survival were 9.0 months (95% CI: 5.6-12) and 17.3 months (95% CI: 13.5-32.3), respectively. Tolerability was acceptable. The most frequent grade 3-4 toxicities were neutropenia (8.8%) and neuropathy (17.6%). CONCLUSION: mFOLFOX6-trastuzumab combination is an efficient regimen with an acceptable safety profile for AGC and AGOJ patients. These results warrant further prospective study. PMID- 25744578 TI - Urinary iodine excretion and serum thyroid function in adults after iodinated contrast administration. AB - BACKGROUND: Iodinated contrast media (ICM) is a source of excess iodine that may induce thyroid dysfunction. A prospective cohort study was conducted to assess the effects of ICM on urinary iodine clearance and serum thyroid function tests (TFTs) in adults. METHODS: In this prospective cohort study of 54 adults undergoing elective computed tomography (CT) scans at an academic medical center, serial urinary iodine concentrations (UIC) and serum TFTs were obtained until UIC normalized following ICM administration. Thyroid volume/nodularity were assessed by ultrasound. Associations between covariates and peak UIC, duration for UIC to peak and normalize, and thyroid dysfunction risk were assessed. RESULTS: The mean+/-standard deviation (SD) iodine administered was 34.6+/-6.0 g. Baseline median (range) UIC was 105.1 (17.0-866.1) MUg/L, and serum thyrotropin (TSH) concentration was 1.26 (0.5-11.2) mIU/L. The mean+/-SD times to achieve peak UIC (median [range]: 3519 [233-157,500] MUg/L] and normalized UIC were 1.1+/-0.5 and 5.2+/-4.0 weeks, respectively. Four subjects had elevated baseline TSH, and one had missing baseline TSH values. Of the remaining 49 subjects, 11 (22%) developed an abnormal TSH within one to four weeks (six elevated and five decreased). Administered iodine amount correlated with peak UIC following ICM administration (p<0.001). Increasing age and administered iodine amount predicted peak UIC (p=0.024 and p<0.001, respectively). Age, sex, race/ethnicity, smoking status, family history of thyroid disease, personal or family history of thyroid autoimmunity, thyroid volume, presence of thyroid nodules >=1 cm, iodine dose, baseline UIC, and baseline TFTs were not predictive of durations to achieve peak or normalized UIC. CONCLUSION: Peak UIC occurred at 1.1 weeks and normalized by 5.2 weeks following ICM administration for outpatient CT scans. Because thyroid dysfunction developed in 22% of individuals following a single ICM dose, monitoring of thyroid function should be considered in at-risk patients. PMID- 25744579 TI - How do Japanese gynecologists view hormone replacement therapy for survivors of endometrial cancer? Japanese Gynecologic Oncology Group (JGOG) survey. AB - BACKGROUND: This survey sought to determine Japanese gynecologists' attitudes concerning administering hormone replacement therapy (HRT) for patients after surgery for endometrial cancer (EC). METHODS: Eight hundred and eighty-eight members of the Japanese Gynecologic Oncology Group (JGOG) were asked to respond to an anonymous questionnaire on the JGOG website. The survey asked whether or not HRT was to be administered when surgery was performed (including a hysterectomy and bilateral oophorectomy) to treat EC before or after menopause. If HRT was not to be administered, respondents were asked the reason why. Respondents were presented with the same hypothetical patients that were featured in a previous survey in Germany, and differences in the mindsets of Japanese and German physicians were compared. RESULTS: Responses from 363 individuals (response rate 40.9 %) were analyzed. Seventy-eight percent of physicians considered HRT for patients undergoing surgery before menopause. The most prevalent reason of refusal to prescribe HRT was the risk of EC recurrence. Forty eight percent of physicians considered HRT for patients undergoing surgery after menopause. The most prevalent reasons of refusal of HRT were its limited benefit and the availability of alternative therapies. Sixty-five percent of Japanese physicians responded that they would administer HRT to patients with low risk of recurrence vs. 46 % of physicians in Germany (P < 0.0002). Forty-nine percent of Japanese physicians approved of prescribing HRT for patients with high risk of recurrence vs. 25 % of physicians in Germany (P < 0.0001). CONCLUSION: Many Japanese gynecologists have a favorable attitude toward prescribing HRT after treatment of EC. PMID- 25744580 TI - Loss of ARID1A expression is associated with poor prognosis in patients with stage I/II clear cell carcinoma of the ovary. AB - BACKGROUND: Recent studies have shown that somatic mutations in the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) are the most common genetic changes in clear cell carcinoma of the ovary (CCC). A gene mutation of ARID1A was found in approximately half of CCC cases, and led to absence of the encoded protein and inactivation of the putative tumor suppressor. Here, we investigated whether ARID1A could be a prognostic biomarker for this disease. METHODS: We analyzed the protein expression of ARID1A in CCC from 112 patients by immunohistochemical staining, and evaluated the association of these molecular parameters with clinical outcome. RESULTS: The loss of ARID1A expression was found in 39 % (44/112) of CCC, and was not associated with patient age, FIGO stage, and status of residual tumor. The 5-year survival rate for FIGO stage I or II patients with negative tumor expression of ARID1A was lower than those with positive tumor expression of ARID1A (74 % vs 91 %), but this difference was not observed in FIGO stage III or IV patients. Multivariable analysis revealed that ARID1A expression was an independent prognostic factor in FIGO stage I or II CCC patients. CONCLUSION: ARID1A may be a biomarker that is predictive of the outcome of FIGO stage I and II CCC. PMID- 25744581 TI - Jatrophihabitans soli sp. nov., isolated from soil. AB - One bacterial strain, designated KIS75-12T, isolated from a soil sample collected from Wonsando island located in Boryeong city, Republic of Korea, was characterized as aerobic, Gram-stain-positive, non-flagellated and a short rod. It grew between temperatures of 15-37 degrees C, pH 4-9 and 0-3.0 % (w/v) NaCl. The 16S rRNA gene analysis showed the strain was moderately related to Jatrophihabitans endophyticus S9-650T (97.7 %) and revealed low sequence similarity (<=94.7 %) with all the other species with validly published names. Its major fatty acid was iso-C16 : 0. The predominant menaquinone of strain KIS75 12T was MK-9(H4). The polar lipids consisted of diphosphatidylglycerol and several small amounts of phosphatidylinositol, aminolipids and glycolipid. The peptidoglycan contained meso-A2pm as diagnostic diamino acid and the peptidoglycan type is A4gamma. The genomic DNA G+C content of the type strain was 72.1 mol%. The combined phenotypic, chemotaxonomic and phylogenetic data showed that strain KIS75-12T could be clearly distinguished from the only member of the genus Jatrophihabitans,J. endophyticus. Therefore, the results of this study indicate the existence of a representative of a novel species of the genus Jatrophihabitans, for which we propose the name Jatrophihabitans soli sp. nov., with strain KIS75-12T ( = KACC 17298T = DSM 45908T = NBRC 109658T) as the type strain. An emended description of the genus Jatrophihabitans is also given. PMID- 25744584 TI - Amycolatopsis rhabdoformis sp. nov., an actinomycete isolated from a tropical forest soil. AB - Strain SB026T was isolated from Brazilian rainforest soil and its taxonomic position established using data from a polyphasic study. The organism showed a combination of chemotaxonomic and morphological features consistent with its classification in the genus Amycolatopsis and formed a branch in the Amycolatopsis 16S rRNA gene tree together with Amycolatopsis bullii NRRL B 24847T, Amycolatopsis plumensis NRRL B-24324T, Amycolatopsis tolypomycina DSM 44544T and Amycolatopsis vancoresmycina NRRL B-24208T. It was related most closely to A. bullii NRRL B-24847T (99.0 % 16S rRNA gene sequence similarity), but was distinguished from this strain by a low level of DNA-DNA relatedness (~46 %) and discriminatory phenotypic properties. Based on the combined genotypic and phenotypic data, it is proposed that the isolate should be classified in the genus Amycolatopsis as representing a novel species, Amycolatopsis rhabdoformis sp. nov. The type strain is SB026T ( = CBMAI 1694T = CMAA 1285T = NCIMB 14900T). PMID- 25744582 TI - Sinosporangium fuscum sp. nov., isolated from soil. AB - A novel actinomycete, A-T 8343T was isolated from a moist evergreen forest soil sample collected in the Trat Province, Thailand. Based on 16S rRNA gene sequence analysis, strain A-T 8343T belonged to the genus Sinosporangium and was closely related to Sinosporangium siamense A-T 1946T (98.81 %) and Sinosporangium album 6014T (98.54 %). The DNA-DNA relatedness values were 21.8-27 % with S. siamense A T 1946T and 31.1-31.9 % with S. album 6014T, which were significantly below 70 %. The result differentiated A-T 8343T from the closest species. The organism developed spherical sporangia containing non-motile spores on aerial mycelia. The cell-wall peptidoglycan contained meso-diaminopimelic acid. The whole-cell sugars contained rhamnose, ribose, madurose and glucose. The predominant menaquinones were MK-9(H2) and MK-9(H4). The diagnostic phospholipids were phosphatidylmethylethanolamine, phosphatidylethanolamine, hydroxyl phosphatidylethanolamine, diphosphatidylglycerol, lyso-phosphatidylethanolamine, N-acetylglucosamine-containing phospholipids, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol-mannosides, aminophosphoglycolipid and one unknown phospholipid. The major cellular fatty acids were saturated C16 : 0, iso C16 : 0, unsaturated C16 : 1 and C18 : 1. Following an evaluation of phenotypic, chemotaxonomic and genotypic characteristics, the new isolate is proposed as a representative novel species of the genus Sinosporangium to be named Sinosporangiumfuscum sp. nov. The type strain is A-T 8343T ( = BCC 52770T = NBRC 109516T). PMID- 25744585 TI - Microbacterium proteolyticum sp. nov. isolated from roots of Halimione portulacoides. AB - An endophytic actinobacterial strain RZ36T, isolated from roots of the salt-marsh plant Halimione portulacoides, was subjected to a polyphasic taxonomic characterization. 16S rRNA gene sequence analysis revealed that this strain belonged to the genus Microbacterium. The closest phylogenetic relative was Microbacterium hominis DSM 12509T, with a pairwise 16S rRNA gene sequence similarity of 98.8 %. The DNA-DNA hybridization value between strain RZ36T and M. hominis DSM 12509T was 16 %. The affiliation to the genus Microbacterium was corroborated by phenotypic and chemotaxonomic characteristics. The cell-wall peptidoglycan type was B2beta and the diagnostic diamino acid was ornithine. Whole-cell sugars detected were galactose, glucose, rhamnose, ribose and xylose. The major fatty acids were anteiso-C15 : 0 and iso-C16 : 0 and the major menaquinone was MK-11 (64 %). Main polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and two unknown glycolipids. The genomic DNA G+C content was 69.7 mol%. Thus, on the basis of phenotypic, genotypic and chemotaxonomic data, strain RZ36T is considered to represent a novel species of the genus Microbacterium, for which the name Microbacterium proteolyticum sp. nov. (type strain RZ36T = DSM 27100T = CECT 8356T) is proposed. PMID- 25744586 TI - Halorubrum persicum sp. nov., an extremely halophilic archaeon isolated from sediment of a hypersaline lake. AB - An extremely halophilic archaeon belonging to the genus Halorubrum, strain C49T, was isolated from sediment of the hypersaline lake Aran-Bidgol in Iran. Phylogenetic analysis based on 16S rRNA gene sequence similarities showed that strain C49T was closely related to Halorubrum saccharovorum JCM 8865T (99.5 %) and other species of the genus Halorubrum. Studies based on multilocus sequence analysis revealed that strain C49T is placed among the species of Halorubrum; the strain constituted a defined branch in comparison with the type strains of species of Halorubrum, while the 16S rRNA gene sequence divergence could not define the status of the newly isolated strain. For optimum growth, strain C49T required 20 % (w/v) salts at pH 7.0 and 37 degrees C under aerobic conditions. Mg2+ was not required. The cells were pleomorphic rods, motile and stained Gram variable. Colonies of the strain were pink. Hypotonic treatment with <12 % NaCl provoked cell lysis. The polar lipid pattern of strain C49T consisted of phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester derived from both C20C20 and C20C25 archaeol, phosphatidylglycerol sulfate and sulfated mannosyl glucosyl diether. The DNA G+C content was 64.2 mol%. DNA-DNA hybridization studies and average nucleotide identity confirmed that strain C49T constitutes a distinct genospecies. Data obtained in this study show that strain C49T represents a novel species, for which the name Halorubrum persicum sp. nov. is proposed. The type strain is C49T ( = IBRC-M 10232T = JCM 30541T). PMID- 25744587 TI - Peripheral substitution: an easy way to tuning the magnetic behavior of tetrakis(phthalocyaninato) dysprosium(III) SMMs. AB - Two tetrakis(phthalocyaninato) dysprosium(III)-cadmium(II) single-molecule magnets (SMMs) with different extent of phthalocyanine peripheral substitution and therefore different coordination geometry for the Dy ions were revealed to exhibit different SMM behavior, providing an easy way to tuning and controlling the molecular structure and in turn the magnetic properties of tetrakis(tetrapyrrole) lanthanide SMMs through simple tetrapyrrole peripheral substitution. PMID- 25744588 TI - One-pot total synthesis of streptindole, arsindoline B and their congeners through tandem decarboxylative deaminative dual-coupling reaction of amino acids with indoles. AB - This paper described a decarboxylative deaminative dual-coupling reaction of amino acids with indoles to afford BIM scaffolds and its further application to the one-pot total synthesis of natural products. This method featured a stimulating example of activating amino acids in one pot as multi-carbon building blocks for transformation into final targets which are equipped with amino acid side chain backbones. PMID- 25744589 TI - Discrete Li-occupation versus pseudo-continuous Na-occupation and their relationship with structural change behaviors in Fe2(MoO4)3. AB - The key factors governing the single-phase or multi-phase structural change behaviors during the intercalation/deintercalation of guest ions have not been well studied and understood yet. Through systematic studies of orthorhombic Fe2(MoO4)3 electrode, two distinct guest ion occupation paths, namely discrete one for Li and pseudo-continuous one for Na, as well as their relationship with single-phase and two-phase modes for Na(+) and Li(+), respectively during the intercalation/deintercalation process have been demonstrated. For the first time, the direct atomic-scale observation of biphasic domains (discrete occupation) in partially lithiated Fe2(MoO4)3 and the one by one Na occupation (pseudo continuous occupation) at 8d sites in partially sodiated Fe2(MoO4)3 are obtained during the discharge processes of Li/Fe2(MoO4)3 and Na/Fe2(MoO4)3 cells respectively. Our combined experimental and theoretical studies bring the new insights for the research and development of intercalation compounds as electrode materials for secondary batteries. PMID- 25744590 TI - New clinical trials in acute and recurrent pericarditis. AB - Clinical trials in the last decade have improved the quality of evidence to support preventive medical strategies to reduce the risk of recurrences after pericarditis. There are essentially three main strategies: (1) to use full anti inflammatory doses for the treatment of each attack of pericarditis till symptoms resolution and normalization of markers of inflammation (i.e., C-reactive protein); (2) to limit the use of corticosteroids and, if used, to use low to moderate doses (i.e., prednisone 0.2 to 0.5 mg/kg/day or equivalent) followed by slow tapering; and (3) to add colchicine to improve the response to conventional anti-inflammatory therapies and reduce the risk of recurrences. Recommended regimens include weight-adjusted doses (i.e., 0.5-0.6 mg twice daily for patients weighing >70 kg or 0.5-0.6 mg once daily for patients weighing <=70 kg for 3 months for acute pericarditis and 6 months for recurrences) without a loading dose to improve patients' compliance. Using these doses and appropriate selection of patients (e.g. to avoid severe renal impairment or adjust doses according to comorbid conditions and concomitant therapies), the drug is well tolerated, may cause reversible gastrointestinal intolerance (mainly diarrhea) in about 8 to 10% of cases but has no severe side effects. PMID- 25744591 TI - Reply: Essential need for research in hepatitis C. PMID- 25744592 TI - The ordinary work environment increases symptoms from eyes and airways in mild steel welders. AB - PURPOSE: We aimed to follow diary-registered symptoms from eyes and airways in mild steel welders and relate them to different exposure measures. Furthermore, we would clarify the influence of possible effect modifiers. METHODS: Non-smoking welders with (N = 74) and without (N = 32) work-related symptoms the last month were enroled. Symptoms and work tasks each day for three two-week periods during 1 year were obtained. Respirable dust (RD) was measured 1 day each period for each worker. The personal daily exposure was assessed as: (1) days at work, (2) welding time and (3) estimates of RD from welding and grinding, calculated from diary entries and measurements. RESULTS: Only 9.2 % of the particle measurements exceed the Swedish occupational exposure limit (OEL; 5 mg/m(3)). Days at work increased the risk of symptoms studied: eyes: 1.79 (1.46-2.19), nasal: 2.16 (1.81 2.58), dry cough: 1.50 (1.23-1.82) and wheezing and/or dyspnoea: 1.27 (1.03-1.56; odds ratio, 95 % confidence interval). No clear dose-response relationships were found for the other exposure estimates. Eye symptoms increased by number of years welding. Nasal symptoms and dry cough increased having forced expiratory volume in first second below median at baseline. Wheezing and/or dyspnoea increased in winter, by number of years welding, having a negative standard skin-prick test and having a vital capacity above median at baseline. CONCLUSION: The current Swedish OEL may not protect welders against eye and airway symptoms. The results add to the evidence that welders should be offered regular medical surveillance from early in the career. PMID- 25744594 TI - From rational numbers to algebra: separable contributions of decimal magnitude and relational understanding of fractions. AB - To understand the development of mathematical cognition and to improve instructional practices, it is critical to identify early predictors of difficulty in learning complex mathematical topics such as algebra. Recent work has shown that performance with fractions on a number line estimation task predicts algebra performance, whereas performance with whole numbers on similar estimation tasks does not. We sought to distinguish more specific precursors to algebra by measuring multiple aspects of knowledge about rational numbers. Because fractions are the first numbers that are relational expressions to which students are exposed, we investigated how understanding the relational bipartite format (a/b) of fractions might connect to later algebra performance. We presented middle school students with a battery of tests designed to measure relational understanding of fractions, procedural knowledge of fractions, and placement of fractions, decimals, and whole numbers onto number lines as well as algebra performance. Multiple regression analyses revealed that the best predictors of algebra performance were measures of relational fraction knowledge and ability to place decimals (not fractions or whole numbers) onto number lines. These findings suggest that at least two specific components of knowledge about rational numbers--relational understanding (best captured by fractions) and grasp of unidimensional magnitude (best captured by decimals)--can be linked to early success with algebraic expressions. PMID- 25744595 TI - Side by side treadmill walking reduces gait asymmetry induced by unilateral ankle weight. AB - Asymmetric gait is a hallmark of many neurological and musculoskeletal conditions. This behavior is often the result of a decrease in the stability of interlimb coordination, and synchronization to external signals such as auditory cuing or another walking individual may be helpful for altering abnormal movement patterns. The purpose of this study was to investigate the interaction between interlimb coordination and unintentional, interpersonal synchronization of gait in healthy individuals in response to unilateral ankle loading. Fifty participants completed four trials while walking on a motorized treadmill: (1) by themselves, (2) with a partner on an adjacent treadmill, (3) by themselves with additional weight applied unilaterally to their right ankle, and (4) with both a partner and unilateral weight. As expected, the addition of unilateral weight increased asymmetry according to several spatiotemporal measures of gait, but the presence of a partner on an adjacent treadmill significantly reduced this effect. Further, the amount of unintentional, interpersonal synchronization among pairings was relatively unaffected by the addition of ankle weight to one of the partners. All pairings realized a beneficial effect on asymmetrical gait but this effect was greater for pairings that consistently synchronized unintentionally. These results suggest that side by side walking might be an effective approach for influencing bilateral coordination of gait and may hold insight for understanding gait asymmetry and interlimb movement variability. PMID- 25744593 TI - Occupational exposure to polycyclic aromatic hydrocarbons: relations between atmospheric mixtures, urinary metabolites and sampling times. AB - PURPOSE: Occupational exposure to polycyclic aromatic hydrocarbons (PAHs) can be assessed by either air monitoring or biomonitoring using urinary 1-hydroxypyrene (1-OHP) or 3-hydroxybenzo(a)pyrene (3-OHBaP). The aim of this study was to understand the links between atmospheric PAHs and urinary metabolites, in order to improve the biomonitoring strategy for assessing carcinogenic risk. METHODS: Personal air sampling for pyrene and BaP measurements, and urines for 1-OHP and 3 OHBaP analyses of seven workers from electrode production plant were collected every day of the working week. RESULTS: High variability of atmospheric levels between activities and between days was observed, especially for gaseous pyrene. No correlation was found between urinary metabolites: 1-OHP maximum levels occurred for "electrode extrusion" activity; those of 3-OHBaP occurred for "raw materials dispatcher." Sixty percentage of 3-OHBaP maximum levels were observed in urines collected at the beginning of shift the last workday. Those of 1-OHP occurred at different sampling times, depending on the gaseous pyrene levels (not stopped by P3 respirators). Dermal absorption of PAHs was confirmed by significant effect of particulate pyrene on 1-OHP in the samples collected the morning of the following day (p < 0.02, n = 25). CONCLUSIONS: Lack of correlation between metabolites concentrations emphasizes the non-relevance of 1-OHP, from a non-carcinogenic gaseous and particulate compound, and the great interest of 3 OHBaP, from carcinogenic BaP. Its slower urinary elimination prevents the risk of exposure underestimation, and urinary analysis should be performed at the beginning of shift the end of working week, especially in case of high exposure variability. PMID- 25744596 TI - Postural stability deficits during the transition from double-leg stance to single-leg stance in anterior cruciate ligament reconstructed subjects. AB - The goal of this study was to evaluate postural stability during the transition from double-leg stance (DLS) to single-leg stance (SLS) in anterior cruciate ligament reconstructed (ACLR) (n=20) and non-injured control subjects (n=20). All ACLR subjects had fully returned to their pre-injury sport participation. Both groups were similar for age, gender, height, weight, body mass index and activity level. Spatiotemporal center of pressure outcomes of both legs of each subject were measured during the transition from DLS to SLS in eyes open and eyes closed conditions. Movement speed was standardized. The center of pressure displacement after a new stability point was reached during the SLS phase was significantly increased in the ACLR group compared to the control group in the eyes closed condition (P=.001). No significant different postural stability outcomes were found between the operated and non-operated legs. In conclusion, the ACLR group showed postural stability deficits, indicating that these persons may have a decreased ability to stabilize their body after the internal postural perturbation created by the transition from DLS to SLS. The non-operated leg may not be the best reference when evaluating postural stability of the operated leg after ACLR, as no differences were found between legs. PMID- 25744597 TI - Response to Letter to the Editor: The addition of cervical Unilateral Posterior Anterior Mobilization (UPA) in the treatment of patients with shoulder impingement syndrome: A randomized clinical trial. PMID- 25744598 TI - Oxidative stress triggers cytokinesis failure in hepatocytes upon isolation. AB - Primary hepatocytes are highly differentiated cells and proliferatively quiescent. However, the stress produced during liver digestion seems to activate cell cycle entry by proliferative/dedifferentiation programs that still remain unclear. The aim of this work was to assess whether the oxidative stress associated with hepatocyte isolation affects cell cycle and particularly cytokinesis, the final step of mitosis. Hepatocytes were isolated from C57BL/6 mice by collagenase perfusion in the absence and presence of N-acetyl cysteine (NAC). Polyploidy, cell cycle, and reactive oxygen species (ROS) were studied by flow cytometry (DNA, phospho-histone 3, and CellROX((r)) Deep Red) and Western blotting (cyclins B1 and D1, and proliferating cell nuclear antigen). mRNA expression of cyclins A1, B1, B2, D1, and F by reverse transcription (RT)-PCR was also assessed. Glutathione levels were measured by mass spectrometry. Here we show that hepatocyte isolation enhanced cell cycle entry, increased hepatocyte binucleation, and caused marked glutathione oxidation. Addition of 5 mM NAC to the hepatocyte isolation media prevented glutathione depletion, partially blocked ROS production and cell cycle entry of hepatocytes, and avoided the blockade of mitosis progression, abrogating defective cytokinesis and diminishing the formation of binucleated hepatocytes during isolation. Therefore, addition of NAC to the isolation media decreased the generation of polyploid hepatocytes confirming that oxidative stress occurs during hepatocyte isolation and it is responsible, at least in part, for cytokinesis failure and hepatocyte binucleation. PMID- 25744599 TI - Recent progress in atomistic simulation of electrical current DNA sequencing. AB - We review recent advances in the DNA sequencing method based on measurements of transverse electrical currents. Device configurations proposed in the literature are classified according to whether the molecular fingerprints appear as the major (Mode I) or perturbing (Mode II) current signals. Scanning tunneling microscope and tunneling electrode gap configurations belong to the former category, while the nanochannels with or without an embedded nanopore belong to the latter. The molecular sensing mechanisms of Modes I and II roughly correspond to the electron tunneling and electrochemical gating, respectively. Special emphasis will be given on the computer simulation studies, which have been playing a critical role in the initiation and development of the field. We also highlight low-dimensional nanomaterials such as carbon nanotubes, graphene, and graphene nanoribbons that allow the novel Mode II approach. Finally, several issues in previous computational studies are discussed, which points to future research directions toward more reliable simulation of electrical current DNA sequencing devices. PMID- 25744600 TI - Continuous power generation from glucose with two different miniature flow through enzymatic biofuel cells. AB - Enzymatic biofuel cells (EBFCs) can generate energy from metabolites present in physiological fluids. They represent an attractive alternative to lithium batteries to power implantable devices, as they work at body temperature, are light and easy-to-miniaturise. To be implantable in blood vessels, EBFCs should not only be made of non-toxic and biocompatible compounds but should also be able to operate in continuous flow-through mode. The EBFC devices reported so far, however, implement carbon-based materials of questionable toxicity and stability, such as carbon nanotubes, and rely on the use of external redox mediators for the electrical connection between the enzyme and the electrode. With this study, we demonstrate for the first time continuous power generation by flow through miniature enzymatic biofuel cells fed with an aerated solution of glucose and no redox mediators. Non-toxic highly porous gold was used as the electrode material and the immobilisation of the enzymes onto the electrodes surface was performed via cost-effective and easy-to-reproduce methodologies. The results presented here are a significant step towards the development of revolutionary implantable medical devices that extract the power they require from metabolites in the body. PMID- 25744601 TI - Oral administration of paeoniflorin attenuates allergic contact dermatitis by inhibiting dendritic cell migration and Th1 and Th17 differentiation in a mouse model. AB - Allergic contact dermatitis (ACD) is a hapten-specific CD4(+) T-cells mediated inflammatory response of the skin. Its pathomechanism involves 2 phases, an induction phase and an elicitation phase. Langerhans cells (LCs) and dendritic cells (DCs) in the skin play key roles in presenting low molecular weight chemicals (haptens) to the lymph nodes. Therefore, inhibition of the migration of LCs or DCs and T-cell proliferation is each expected to control ACD disease. To explore the effectiveness of paeoniflorin (PF) on the migration of LCs and T-cell proliferation in vivo, we establish a murine model of ACD, promoted by repeated exposure to an allergen (specifically 1-Chloro-2,4-dinitrobenzene (DNCB)). Administration of PF inhibits DC migration in this DNCB-induced model in the induction phase. As a result, epidermal LC density in the elicitation phase increased in PF-treated mice when compared to PF-untreated mice. At the same time, PF reduced IFN-gamma(+)CD4(+) and IL-17(+)CD4(+) T cells proliferation (but not IL-4(+)CD4(+) T cells proliferation), leading to an attenuated cutaneous inflammatory response. Consistent with this T-cell proliferation profile, secretions of IFN-gamma and IL-17 were reduced and IL-10 secretion increased in PF-treated mice, but production of IL-4 and IL-5 remained unchanged in the skin and blood samples. These results suggest that oral administration of PF can treat and prevent ACD effectively through inhibition of DC migration, and thus decrease the capacity of DCs to stimulate Th1 and Th17 cell differentiation and cytokine production. PMID- 25744602 TI - Tanshinone IIA attenuates renal fibrosis and inflammation via altering expression of TGF-beta/Smad and NF-kappaB signaling pathway in 5/6 nephrectomized rats. AB - PURPOSE: In traditional Chinese medicine, Tanshinone IIA is used to treat chronic kidney disease (CKD). However, its biological activity and mechanism of action in renal fibrosis and inflammation are not fully identified. The current study was conducted to determine the effects of Tanshinone IIA treatment on CKD by assessing potential modulation of the TGF-beta/Smad and NF-kappaB signaling pathway. METHODS: CKD was produced in rats by 5/6 nephrectomy. They were then divided into the following groups: control (sham operation); CKD (5/6 nephrectomy); 5/6 nephrectomy+Tanshinone IIA (10mg/kg in average, once a day for 16 weeks). Serum and urine samples were obtained from animals in each group, and serum creatinine (Scr), blood urea nitrogen (BUN) levels and 24h urinary protein excretion were measured. Tissue samples from the kidney were used for morphometric studies (Masson's trichrome). The expression of fibronectin protein and collagen types I, III, IV, and TGF-beta, TNF-alpha, CXCL-1, MCP-1, RANTES mRNA were evaluated using immunohistochemistry and RT-PCR analysis; the TGF beta/Smad and NF-kappaB signaling pathway was detected by immunohistochemistry and Western blot analysis. RESULTS: The following effects were observed in CKD rats treated with Tanshinone IIA: (1) marked improvements in Scr, and 24h urine protein excretion; (2) significant reductions in protein and mRNA levels of fibronectin, collagen III, and collagen IV and TNF-alpha, MCP-1, and CXCL-1; (3) significantly inhibited the TGF-beta/Smad and NF-kappaB signaling activation. CONCLUSIONS: These results suggest that Tanshinone IIA suppresses renal fibrosis and inflammation via altering expression of TGF-beta/Smad and NF-kappaB pathway in the remnant kidney, thus supporting the potential of Tanshinone IIA as a new therapeutic agent for slowing the progression of CKD. PMID- 25744604 TI - Tp17 membrane protein of Treponema pallidum activates endothelial cells in vitro. AB - Tp17, a membrane immunogen of Treponema pallidum subsp. pallidum, was initially recognized as an inflammatory mediator of syphilis. Because the histopathology of syphilis is characterized by endothelial cell abnormalities, we investigated the effects of recombinant Tp17 (rTp17) on endothelial cell activation in vitro. Using real-time reverse transcription-PCR and whole-cell ELISA, we found that rTp17 activated endothelial cells, as demonstrated by the up-regulated expression and increased gene transcription of intercellular adhesion molecule 1 (ICAM-1), E selectin, and monocyte chemoattractant protein-1 (MCP-1). rTp17 also enhanced the migration and subsequent adhesion of monocytes to endothelial cells as well as increased transendothelial migration of monocytes. These data suggest that the ability of Tp17 to activate endothelial cells may play an important role in the immunopathogenesis of syphilis. PMID- 25744603 TI - Paroxetine differentially modulates LPS-induced TNFalpha and IL-6 production in mouse macrophages. AB - Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is clinically used for the treatment of depression in human patients. Because of recent reports on the role of serotonin in modulating inflammation and the link between inflammation and depression, we sought to test the effect of paroxetine directly on macrophage response to an inflammatory stimulus. Lipopolysaccharide (LPS) treatment of mouse macrophages significantly enhanced TNFalpha and IL-6 production. Paroxetine treatment of macrophages, however, significantly inhibited LPS-induced IL-6 production. In contrast, paroxetine enhanced LPS-induced TNFalpha production in macrophages. These effects of paroxetine were mimicked by fluoxetine, another SSRI. To determine if the effects of paroxetine are mediated via modulation of the 5-HT system, we treated macrophages with 5-HT or 5-HT receptor antagonist (LY215840) in the presence of LPS and/or paroxetine. 5-HT treatment by itself did not affect LPS-induced cytokine production. LY215840, however, reversed paroxetine's effect on LPS-induced TNFalpha production but not IL-6. To understand the signaling mechanisms, we examined paroxetine's effect on MAPK and NFkappaB pathways. While paroxetine inhibited LPS-induced IkappaBalpha phosphorylation, MAPK pathways were mostly unaffected. Together these data demonstrate that paroxetine has critical but differential effects on IL-6 and TNFalpha production in macrophages and that it likely regulates these cytokines via distinct mechanisms. PMID- 25744605 TI - Non-viable immunobiotic Lactobacillus rhamnosus CRL1505 and its peptidoglycan improve systemic and respiratory innate immune response during recovery of immunocompromised-malnourished mice. AB - The effect of non-viable Lactobacillus rhamnosus CRL1505 and its cell wall and peptidoglycan on respiratory immunity in malnourished mice was studied. Weaned mice were malnourished with a protein-free diet for 21d and received BCD during 7d (BCD) or BCD with nasal non-viable L. rhamnosus CRL1505 (BCD+UV) or its cell wall (BCD+CW) or peptidoglycan (BCD+PG) supplementation during last 2d of the treatment. Malnourished mice without treatment (MNC) and well-nourished mice (WNC) were used as controls. Mice were infected nasally with Streptococcus pneumoniae after treatments. Resistance against pneumococci was reduced in MNC mice. Repletion with BCD reduced lung and blood bacterial cell counts when compared to MNC mice but the counts did not reach the levels of the WNC group. However, when malnourished mice received BCD+UV, BCD+CW or BCD+PG, pneumococci was not detected in lung or blood samples. Pneumococcal infection increased the levels of TNF-alpha, IL-1beta, IL-6, and IL-10 in the respiratory tract, however the values were lower in MNC than in WNC mice. BCD+UV and BCD+PG groups showed values of phagocytes, IL-1beta and IL-6 that were similar to WNC mice, while TNF alpha was significantly higher in those groups when compared to WNC mice. Moreover, BCD+UV and BCD+PG treatments improved levels of respiratory IL-10, reaching values that were superior to those observed in WNC mice. The work demonstrates for the first time that non-viable probiotic bacteria or their cellular fractions could be an interesting alternative as mucosal immunomodulators, especially in immunocompromised hosts in which the use of live bacteria might be dangerous. PMID- 25744606 TI - Analysis of a mathematical model for tumor therapy with a fusogenic oncolytic virus. AB - Oncolytic virotherapy is a tumor treatment which uses viruses to selectively target and destroy cancer cells. Fusogenic viruses, capable of causing cell-to cell fusion upon infection of a tumor cell, have shown promise in experimental studies. Fusion causes the formation of large, multinucleated syncytia which eventually leads to cell death. We formulate a partial differential equations model with a moving boundary to describe the treatment of a spherical tumor with a fusogenic oncolytic virus. Fusion, lysis, and budding are incorporated as mechanisms of viral spread, resulting in nonlocal integral terms. A proof is presented for existence and uniqueness of global solutions to the nonlinear hyperbolic-parabolic system. Numerical simulations demonstrate convergence to spatially homogeneous solutions and exponential growth or decay of the tumor radius depending on viral burst size and rate of fusion. Long-term tumor radius is shown to decrease with increasing values of viral burst size while the effect of the rate of fusion on tumor growth is demonstrated to be nonmonotonic. PMID- 25744607 TI - Some analytical and numerical approaches to understanding trap counts resulting from pest insect immigration. AB - Monitoring of pest insects is an important part of the integrated pest management. It aims to provide information about pest insect abundance at a given location. This includes data collection, usually using traps, and their subsequent analysis and/or interpretation. However, interpretation of trap count (number of insects caught over a fixed time) remains a challenging problem. First, an increase in either the population density or insects activity can result in a similar increase in the number of insects trapped (the so called "activity-density" problem). Second, a genuine increase of the local population density can be attributed to qualitatively different ecological mechanisms such as multiplication or immigration. Identification of the true factor causing an increase in trap count is important as different mechanisms require different control strategies. In this paper, we consider a mean-field mathematical model of insect trapping based on the diffusion equation. Although the diffusion equation is a well-studied model, its analytical solution in closed form is actually available only for a few special cases, whilst in a more general case the problem has to be solved numerically. We choose finite differences as the baseline numerical method and show that numerical solution of the problem, especially in the realistic 2D case, is not at all straightforward as it requires a sufficiently accurate approximation of the diffusion fluxes. Once the numerical method is justified and tested, we apply it to the corresponding boundary problem where different types of boundary forcing describe different scenarios of pest insect immigration and reveal the corresponding patterns in the trap count growth. PMID- 25744608 TI - [Classification of normal labral variants and labral injuries]. AB - The glenoid labrum is an important stabilizer of the glenohumeral joint. Labral injuries affect the stability of the shoulder joint to varying degrees depending on the localization, the extension and the structures involved. Because of the complex anatomy and the high variability of the glenoid labrum, in-depth knowledge concerning normal variations and labral injury patterns is required as well as high-resolution imaging with intra-articular contrast in order to discriminate anatomical variants from pathological findings. Therefore, magnetic resonance (MR) and alternatively computed tomography (CT) arthrography have become established as the imaging methods of choice. In this review MR arthrographic findings of normal labral variants and different labral injury patterns are portrayed. PMID- 25744609 TI - Kinetics and anthelmintic efficacy of topical eprinomectin when given orally to goats. AB - Preliminary data suggest that topical eprinomectin in goat shows an individual variation in anthelmintic efficacy when used off-license at a dose rate of 0.5 or 1.0mg/kg BW. As a result, the use of oral administration of topical formulation of eprinomectin tends to develop in dairy goat farms in France. The plasma levels and milk excretion as well as the anthelmintic efficacy of eprinomectin were determined in goats following oral administration of a topical formulation of the drug at dose rates of 0.5 and 1mg/kg BW. The area under the concentration-time curve (AUC) values were 17.62 +/- 9.68 ng day/ml and 6.56 +/- 4.00 ng day/ml for plasma and milk respectively after the administration of 0.5mg/kg BW and 45.32 +/ 13.90 ng day/ml and 13.88 +/- 1.77 ng day/ml for plasma and milk, respectively after the administration of 1mg/kg BW. The milk-to-plasma ratio ranged from 0.33 to 0.36 and the amount of drug recovered in the milk was 0.4% of the total administered dose. The maximum concentrations of eprinomectin residues determined in milk after oral treatment were < 20 MUg/kg (Maximum Residue Limit in goat milk). The anthelmintic efficacy of the oral administration of topical eprinomectin was 100% through Faecal Egg Count Reduction Test in natural infection and >= 99.8% through Controlled Test in experimental infection (Haemonchus contortus and Trichostrongylus colubriformis). Additional information is needed about the fate of the vehicles used for topical formulation when given by oral route concerning food safety. PMID- 25744610 TI - Effects of isolated positive maternal thyroglobulin antibodies on brain development of offspring in an experimental autoimmune thyroiditis model. AB - BACKGROUND: Autoimmune thyroiditis (AIT) is a very common endocrine disorder in pregnancy. However, the effect of maternal positive thyroglobulin antibodies (TgAb) on brain development of offspring remains unclear. This study used an experimental autoimmune thyroiditis model in CBA/J mice and determined whether isolated positive maternal TgAb directly affected learning and memory abilities of offspring. METHODS: An experimental autoimmune thyroiditis model was established in CBA/J mice through immunization with murine thyroglobulin (mTg). Measuring thyroid function and serum TgAb titer confirmed the presence of isolated positive maternal TgAb. Offspring serum TgAb titer, MCT8, Reelin, RC3, and BNDF mRNA expression in the brain, and brain histology were measured on postnatal days 0, 10, and 40 (PND0, PND10, PND40), and nerve cell migration (BrdU labeling) at PND40. Morris water maze, long-term potentiation (LTP), and LTP related factor ERK1/2 levels were measured at PND40 to determine offspring spatial learning and memory development. RESULTS: Maternal serum TgAb titers increased and remained elevated through pregnancy compared to controls. Thyrotropin and thyroid hormone levels were normal. The T group offspring (Tg immunized) had higher TgAb titers than the control (C) group. However, antibody titers time-dependently decreased. MCT8, Reelin, RC3, and BDNF mRNA expression in the whole brain were similar in the T and C groups on PND0, PND10, and PND40. Neuronal distribution and BrdU from the cerebral cortex and hippocampus were similar in the T and C group offspring. Morris water maze tests, excitatory postsynaptic field potentials, and ERK1/2 levels were also similar between the T and C groups. CONCLUSIONS: Isolated positive maternal TgAb did not clearly influence the learning ability and memory of offspring, or nerve cell migration, despite a transient increase in TgAb in immunized mice. PMID- 25744611 TI - Oesophageal GIST-A rare breed case report and review of the literature. AB - INTRODUCTION: Gastrointestinal stromal tumours (GIST) account for only one percent of all gastrointestinal malignancies. PRESENTATION OF CASE: A 53 year old lady presented to the gastroenterology clinic with iron deficiency anaemia. Oesophagogastroduodenoscopy (OGD) and computed tomography (CT) demonstrated a non obstructing 7cm submucosal oesophageal lesion. An oesophagectomy was performed and subsequent histology sections showed a well-circumscribed spindle cell tumour without any cellular atypia. Immunohistochemistry on the tumour was negative for S100 and positive for smooth muscle actin and desmin. C-kit (CD117) showed focal positivity in some of the tumour cells and the overall features were of a gastro intestinal stromal tumour (GIST). The patient has been fully compliant with the follow-up arrangements and is disease-free six years after her original operation. DISCUSSION: GISTs are mesenchymal tumours of the gastrointestinal (GI) tract that express the KIT protein. The incidence rate for GIST is 15 cases to one million in the USA. GISTs in the oesophagus are rare (5%) and their management is surrounded by some debate. Once the diagnosis has been secured the patient should be evaluated for suitability for surgical resection. Optimal surgical therapy should aim to achieve complete resection, if possible, without injury to the pseudocapsule surrounding the tumour. Meticulous atraumatic surgical technique is necessary and preoperative biopsies are best to be avoided as they might propagate seeding. CONCLUSIONS: Oesophagectomy with clear resection margins should be the preferred method for surgical treatment combined with the use of novel TKI strategies. PMID- 25744612 TI - The first batteryless, solar-powered cardiac pacemaker. AB - BACKGROUND: Contemporary pacemakers (PMs) are powered by primary batteries with a limited energy-storing capacity. PM replacements because of battery depletion are common and unpleasant and bear the risk of complications. Batteryless PMs that harvest energy inside the body may overcome these limitations. OBJECTIVE: The goal of this study was to develop a batteryless PM powered by a solar module that converts transcutaneous light into electrical energy. METHODS: Ex vivo measurements were performed with solar modules placed under pig skin flaps exposed to different irradiation scenarios (direct sunlight, shade outdoors, and indoors). Subsequently, 2 sunlight-powered PMs featuring a 4.6-cm(2) solar module were implanted in vivo in a pig. One prototype, equipped with an energy buffer, was run in darkness for several weeks to simulate a worst-case scenario. RESULTS: Ex vivo, median output power of the solar module was 1963 MUW/cm(2) (interquartile range [IQR] 1940-2107 MUW/cm(2)) under direct sunlight exposure outdoors, 206 MUW/cm(2) (IQR 194-233 MUW/cm(2)) in shade outdoors, and 4 MUW/cm(2) (IQR 3.6-4.3 MUW/cm(2)) indoors (current PMs use approximately 10-20 MUW). Median skin flap thickness was 4.8 mm. In vivo, prolonged SOO pacing was performed even with short irradiation periods. Our PM was able to pace continuously at a rate of 125 bpm (3.7 V at 0.6 ms) for 11/2 months in darkness. CONCLUSION: Tomorrow's PMs might be batteryless and powered by sunlight. Because of the good skin penetrance of infrared light, a significant amount of energy can be harvested by a subcutaneous solar module even indoors. The use of an energy buffer allows periods of darkness to be overcome. PMID- 25744613 TI - Comparison of radionuclide angiographic synchrony analysis to echocardiography and magnetic resonance imaging for the diagnosis of arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable arrhythmia syndrome entailing a high risk of sudden cardiac death. Discernment from benign arrhythmia disorders, particularly right ventricular outflow tract ventricular tachycardia (RVOT VT), may be challenging, providing an impetus to explore alternative modalities that may facilitate evaluation of patients with suspected ARVC. OBJECTIVE: We evaluated the role of equilibrium radionuclide angiography (ERNA) as a diagnostic tool for ARVC. METHODS: ERNA measures of ventricular synchrony-synchrony (S) and entropy (E)-were examined in patients with ARVC (n = 16), those with RVOT VT (n = 13), and healthy controls (n = 49). The sensitivity and specificity of ERNA parameters for ARVC diagnosis were compared with those of echocardiography (ECHO) and cardiovascular magnetic resonance (CMR). RESULTS: ERNA right ventricular synchrony parameters in patients with ARVC (S = 0.91 +/- 0.07; E = 0.61 +/- 0.1) differed significantly from those in patients with RVOT VT (S = 0.99 +/- 0.01 [P = .0015]; E = 0.46 +/- 0.05 [P < .001]) and healthy controls (S = 0.97 +/- 0.02 [P = .003]; E = 0.48 +/- 0.07 [P = .001]). The sensitivity of ERNA synchrony parameters for ARVC diagnosis (81%) was higher than that for ECHO (38%; P = .033) and similar to that for CMR (69%; P = .162), while specificity was lower for ERNA (89%) than that for ECHO and CMR (both 100%; P = .008). CONCLUSION: ERNA right ventricular synchrony parameters can distinguish patients with ARVC from controls with structurally normal hearts, and its performance is comparable to that of ECHO and CMR for ARVC diagnosis. These findings suggest that ERNA may serve as a valuable imaging tool in the diagnostic evaluation of patients with suspected ARVC. PMID- 25744614 TI - Where does heterogeneity exist in ventricular tachyarrhythmias? PMID- 25744615 TI - Implications for women of Louisiana's law requiring abortion providers to have hospital admitting privileges. AB - BACKGROUND: In 2014, Louisiana passed a law requiring abortion providers to have hospital admitting privileges. This law is temporarily on hold while a court case challenging it continues. We aimed to describe the population who would be affected if the law goes into effect and how closures of between three and five Louisiana abortion facilities would affect the distance Louisiana women would need to travel for an abortion. STUDY DESIGN: We abstracted patient data from three of the five Louisiana abortion care facilities in the year before the law was scheduled to take effect. We then estimated distance traveled and distances women would need to travel if clinics close. FINDINGS: Half (53%) of women who had an abortion had no education beyond high school, most were black (62%) or white (30%), three fourths (73%) had a previous live birth, and most (89%) were having a first-trimester abortion. Seventy-nine percent resided in Louisiana and 15% in Texas. The parishes in which abortion patients resided had lower median income and higher percentage poverty than the Louisiana average. Abortion patients residing in Louisiana traveled a mean distance of 58 miles each way for an abortion. If all Louisiana facilities close, the mean distance women would need to travel would more than triple to 208 miles, and the proportion of Louisiana women of reproductive age who live more than 150 miles from an abortion facility would increase from 1% to 72%. CONCLUSION: The admitting privileges law will likely significantly increase the distance Louisiana women need to travel for an abortion. This burden is likely to disproportionately affect Louisiana's more vulnerable residents. IMPLICATIONS: If all Louisiana abortion facilities close due to Louisiana's hospital admitting privileges law, the mean distance women would need to travel for an abortion would more than triple from 58 to 208 miles. Louisiana's law would thus present a considerable burden on many Louisiana women, particularly those who are more vulnerable. PMID- 25744616 TI - Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy individuals. AB - CD20(+)CD27(+)CD43(+) B (CD43(+) B) cells have been newly defined among PBMCs and proposed to be human B1 cells. However, it is controversial as to whether they are orthologs of murine B1 cells and how they are related to other B-cell populations, particularly CD20(+)CD27(+)CD43(-) memory B cells and CD20(low)CD27(high)CD43(high) plasmablasts. Our objective is to identify phenotypically the position of CD43(+) B cells among peripheral B-lineage cell compartments in healthy donors, with reference to B-cell subsets from patients with systemic lupus erythematosus (SLE). We found that CD43(+) B cells among PBMCs from healthy subjects were indistinguishable phenotypically from memory B cells in terms of surface markers, and spontaneous in vitro Ig and IL-10 secretion capability, but quite different from plasmablasts. However, a moderate correlation was found in the frequency of CD43(+) B cells with that of plasmablasts in healthy donors but not in SLE patients. An in vitro differentiation experiment indicated that CD43(+) B cells give rise to plasmablasts more efficiently than do memory B cells, suggesting that they are more closely related to plasmablasts developmentally than are memory B cells, which is also supported by quantitative PCR analysis of mRNA expression of B-cell and plasma cell signature genes. Thus, we conclude that, in healthy individuals, CD43(+) B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally, although the developmental origin of CD43(+) B cells is not necessarily the same as that of plasmablasts. PMID- 25744617 TI - Long-term survival with growth hormone replacement after liver transplantation of pediatric nonalcoholic steatohepatitis complicating acquired hypopituitarism. AB - Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease (NAFLD). In adult patients, liver transplantation (LT) is the treatment of choice for end-stage liver disease secondary to NASH. However, little information is available regarding outcomes of LT in pediatric patients with NASH. We describe here a pediatric patient with NASH associated with hypopituitarism who underwent living donor liver transplantation (LDLT). An 11 year-old boy was diagnosed with a pituitary tumor, which was removed by trans interhemispheric approach following bifrontal craniotomy. Histopathological examination revealed a mature teratoma. Eighteen months later, magnetic resonance imaging showed recurrence of the pituitary tumor, which was found to be a germinoma. He underwent 3 months of chemoradiotherapy, with a complete response. He gradually became obese, with elevated transaminase levels. At age 15 years, he developed fatigue and dyspnea and was found to have liver cirrhosis secondary to NASH with severe hepatopulmonary syndrome. He underwent LDLT using a right liver graft from his mother. Twelve months later, abdominal computed tomography showed recurrence of NAFLD. Five years after the LDLT, transaminases were slightly elevated. Growth hormone replacement therapy was started, reducing transaminase levels to their normal ranges. Ten years after LDLT, fatty liver remains stable, although his body mass index has not been reduced. Growth hormone replacement therapy may be effective in graft maintenance. This is the first case report of a patient with maintained stable liver function 10 years after LDLT for pediatric NASH. PMID- 25744618 TI - Psychedelics not linked to mental health problems or suicidal behavior: a population study. AB - A recent large population study of 130,000 adults in the United States failed to find evidence for a link between psychedelic use (lysergic acid diethylamide, psilocybin or mescaline) and mental health problems. Using a new data set consisting of 135,095 randomly selected United States adults, including 19,299 psychedelic users, we examine the associations between psychedelic use and mental health. After adjusting for sociodemographics, other drug use and childhood depression, we found no significant associations between lifetime use of psychedelics and increased likelihood of past year serious psychological distress, mental health treatment, suicidal thoughts, suicidal plans and suicide attempt, depression and anxiety. We failed to find evidence that psychedelic use is an independent risk factor for mental health problems. Psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use; serious adverse events involving psychedelics are extremely rare. Overall, it is difficult to see how prohibition of psychedelics can be justified as a public health measure. PMID- 25744619 TI - Corrigendum. AB - Corrigendum for 'GENETIC DIFFERENCES IN CYTOCHROME P450 ENZYMES AND ANTIDEPRESSANT TREATMENT RESPONSE' by: Karen Hodgson, Katherine Tansey, Mojca Zvezdana Dernovsek, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Rebecca Smith, Ian W Craig, Anne E Farmer, Katherine J Aitchison, Sarah Belsey, Oliver SP Davis, Rudolf Uher, and Peter McGuffin. Journal of Psychopharmacology 28: 133-141. DOI: 10.1177/0269881113512041. The following author name Sarah Belsey was erroneously misspelled as Sarah Belsy. PMID- 25744620 TI - Antidepressants and the adolescent brain. AB - Major unipolar depression is a significant global health problem, with the highest incident risk being during adolescence. A depressive illness during this period is associated with negative long-term consequences including suicide, additional psychiatric comorbidity, interpersonal relationship problems, poor educational performance and poor employment attainment well into adult life. Despite previous safety concerns, selective serotonin reuptake inhibitors (SSRIs) remain a key component of the treatment of moderate to severe depression episodes in adolescents. The impact of SSRIs on the developing adolescent brain, however, remains unclear. In this review we first consider what is currently known about the developing brain during adolescence and how these development processes may be affected by a depressive illness. We then review our understanding of the action of SSRIs, their effects on the brain and how these may differ between adults and adolescents. We conclude that there is currently little evidence to indicate that the human adolescent brain is at developmental risk from SSRIs. Furthermore, there is no clear-cut evidence to support the concerns of marked suicidal adverse side effects accruing in depressed adolescents being treated with SSRIs. Neither, however, is there irrefutable evidence to dismiss all such concerns. This makes SSRI prescribing a matter of medical judgement, ensuring the benefits outweigh the risks for the individual patients, as with so much in therapeutics. Overall, SSRIs show clinical benefits that we judge to outweigh the risks to neurodevelopment and are an important therapeutic choice in the treatment of moderate to severe adolescent depression. PMID- 25744621 TI - Further evidence for the association of the NPSR1 gene A/T polymorphism (Asn107Ile) with impulsivity and hyperactivity. AB - Administration of neuropeptide S (NPS) elicits anxiolysis, arousal and higher activity in rodents. In humans, the NPS receptor (NPSR1) gene rs324981 A/T (Asn(107)Ile) polymorphism is associated with fear responses and anxiety. We have recently revealed an association of NPSR1 with impulsivity-related traits and psychopathology. In the present study the association of the NPSR1 genotype with impulsivity and attention-deficit/hyperactivity disorder (ADHD)-related symptoms was re-examined in two independent non-clinical cohorts. We used self-reports of two population-derived samples of the Estonian Psychobiological Study of Traffic Behaviour (EPSTB): a community car driving sample (n=491, MAge=37) and a driving school student sample (n=773, MAge=24). Impulsivity was measured with the Adaptive and Maladaptive Impulsivity Scale (AMIS) in both samples, and with the Barratt Impulsivity Scale (BIS) in driving schools only. For the latter sample, also measurement of ADHD symptoms was carried out with the Adult ADHD Self-Report Scale (ASRS). NPSR1 T-allele carriers had higher scores of impulsivity, motor restlessness and total ADHD scores. The effect on impulsivity originated from male participants but for ADHD symptoms the association was independent of sex. Thus we have confirmed in two additional population-derived samples that the T allele of the NPSR1 rs324981 polymorphism is associated with increased impulsivity and ADHD-related traits. PMID- 25744622 TI - Radial diffusion and penetration of gas molecules and aerosol particles through laminar flow reactors, denuders, and sampling tubes. AB - Flow reactors, denuders, and sampling tubes are essential tools for many applications in analytical and physical chemistry and engineering. We derive a new method for determining radial diffusion effects and the penetration or transmission of gas molecules and aerosol particles through cylindrical tubes under laminar flow conditions using explicit analytical equations. In contrast to the traditional Brown method [Brown, R. L. J. Res. Natl. Bur. Stand. (U. S.) 1978, 83, 1-8] and CKD method (Cooney, D. O.; Kim, S. S.; Davis, E. J. Chem. Eng. Sci. 1974, 29, 1731-1738), the new approximation developed in this study (known as the KPS method) does not require interpolation or numerical techniques. The KPS method agrees well with the CKD method under all experimental conditions and also with the Brown method at low Sherwood numbers. At high Sherwood numbers corresponding to high uptake on the wall, flow entry effects become relevant and are considered in the KPS and CKD methods but not in the Brown method. The practical applicability of the KPS method is demonstrated by analysis of measurement data from experimental studies of rapid OH, intermediate NO3, and slow O3 uptake on various organic substrates. The KPS method also allows determination of the penetration of aerosol particles through a tube, using a single equation to cover both the limiting cases of high and low deposition described by Gormley and Kennedy (Proc. R. Ir. Acad., Sect. A. 1949, 52A, 163 169). We demonstrate that the treatment of gas and particle diffusion converges in the KPS method, thus facilitating prediction of diffusional loss and penetration of gases and particles, analysis of chemical kinetics data, and design of fluid reactors, denuders, and sampling lines. PMID- 25744623 TI - High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. AB - Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous disorder, characterized by the accumulation of iron in regions such as the basal ganglia. We enrolled 28 patients with childhood intellectual disability and young-onset parkinsonism (<=40 years at onset) and 4 patients with infantile neuroaxonal dystrophy. All had been clinically diagnosed, and the prevalence of genetic mutations linked to NBIA (PANK2 [exons 1-7], PLA2G6 [exons 2-17], C19orf12 [exons 1-3], WDR45 [exons 2-11], COASY [exons 1-9], FA2H [exons 1 7], and RAB39B [exons 1, 2]) was evaluated. We detected 7 female patients (25.0%, 7 of 28) with de novo heterozygote WDR45 mutations, which are known to be pathogenic for beta-propeller protein-associated neurodegeneration. All 7 patients had common clinical features. Pathogenic mutations in other NBIA genes were not found. We also screened 98 patients with early-onset parkinsonism without intellectual disability and 110 normal controls of Japanese origin for WDR45 mutations. None had WDR45 mutations. Our data suggest a high frequency of beta-propeller protein-associated neurodegeneration mutations in the Japanese population. PMID- 25744624 TI - The effect of percutaneous ultrasound-guided subacromial bursography using microbubbles in the assessment of subacromial impingement syndrome: initial experience. AB - OBJECTIVE: The purpose of this study was to determine the feasibility and the value of percutaneous ultrasound-guided subacromial bursography (PUSB) with contrast-enhanced ultrasound (CEUS) for assessment of rotator cuff tears. METHODS: Between January 2012 and September 2014, 2-D US and PUSB were prospectively performed in 135 patients with suspected rotator cuff tears from among 2,169 patients with clinically diagnosed subacromial impingement syndrome. Sixty-three patients who had undergone arthroscopy were included. The PUSB findings were compared with those from 2-D US using the McNemar test, with arthroscopy as a standard. RESULTS: Of a total of 19 full-thickness tears (FTTs), 2-D US correctly diagnosed 12 and PUSB correctly diagnosed 18 (P = 0.031). With regard to partial-thickness tears, 2-D US correctly diagnosed 31 and PUSB 35 of a total of 41 tears (P = 0.375).Accuracy in diagnosing FTTs was 81.0 % for 2-D US and 98.4 % for PUSB. 2-D US and PUSB yielded sensitivity of 63.2 % and 94.7 %, respectively, for full-thickness tears, with specificity of 88.6 % and 100.0 %, respectively. CONCLUSIONS: PUSB is a safe and feasible procedure, with greater sensitivity and specificity than 2D US in diagnosing FTTs As such, PUSB improves the value of ultrasound for assessing rotator cuff pathology. KEY POINTS: * PUSB allows new application of CEUS and offers a new form of bursography. * PUSB appears to facilitate diagnosis of full -thickness rotator cuff tears. * PUSB outlines the rotator cuff tears more clearly than 2-D US. PMID- 25744626 TI - The Circulation Journal in the world. PMID- 25744627 TI - Coronary flow reserve estimated by positron emission tomography to diagnose significant coronary artery disease and predict cardiac events. AB - Coronary artery disease (CAD) is a major cause of death in Japan. Coronary angiography is useful to assess the atherosclerotic burden in CAD patients, but its ability to predict whether patients will respond favorably to optimal medical therapy and revascularization is limited. The measurement of the fractional flow reserve with angiography is a well-validated method for identifying ischemic vessels. However, neither an anatomical assessment nor a functional assessment can delineate microvasculature or estimate its function. The quantitative coronary flow reserve (CFR) estimated from sequential myocardial perfusion images obtained by positron emission tomography (PET) during stress provides an accurate index of hyperemic reactivity to vasodilatory agents in the myocardium. In fact, there is growing evidence that the CFR reflects disease activity in the entire coronary circulation, including epicardial coronary artery stenosis, diffuse atherosclerosis, and microvascular dilatory function. Importantly, reduced CFR is observed even in patients without flow-limiting coronary stenosis, and its evaluation can improve the risk stratification of patients at any stage of CAD. This review focuses on the application of CFR estimated by cardiac PET for the diagnosis and risk stratification of patients with CAD. PMID- 25744625 TI - Optimization of brain perfusion image quality by cortical surface-based projection of arterial spin labeling maps in early-onset Alzheimer's disease patients. AB - OBJECTIVES: Arterial spin labelling (ASL) is a promising MRI sequence that allows noninvasive detection of cortical perfusion alterations in neurodegenerative disorders, but its interpretation remains difficult at an individual level. In this work, a cortical surface-based projection of ASL maps was applied in patients with early-onset Alzheimer's disease (EOAD) to improve the image quality and visual representation of perfusion data. METHODS: Eighteen patients referred from the reference centre for EOAD were assessed by MRI with ASL sequences. Data processing was applied on each examination including correction of partial volume effects and cortical projection of preprocessed ASL data. Cortical segmentation and perfusion display were qualitatively analyzed according to a three-point scale. RESULTS: All examinations were suitable for complete data processing. Quality of segmentation and of cortical surface-based perfusion maps was scored as optimal in 72 % in both cases. Cortical surface-based ASL maps provided a more global view than single slices and an accurate approach of brain perfusion in EOAD patients. CONCLUSION: Cortical surface-based analysis of ASL maps is technically feasible with a good image quality and may enable significant improvement in the detection of focal perfusion alterations in neurodegenerative disorders in the real-life clinical setting. KEY POINTS: * Arterial spin labelling is a promising sequence for assessing Alzheimer's disease. * Optimization of ASL brain perfusion image quality is crucial for image interpretation. * Cortical surface-based analysis may improve detection of perfusion alterations in a real-life clinical setting. PMID- 25744628 TI - Clinical utility and significance of intravascular ultrasound and optical coherence tomography in guiding percutaneous coronary interventions. AB - Both intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can provide critical information that facilitates pre-interventional lesion assessment and post-interventional stent assessment and both have the potential to influence treatment strategy. Meta-analyses of randomized trials and observational studies comparing IVUS-guided percutaneous coronary intervention (PCI) with angiography-guided PCI revealed that IVUS-guided procedures reduce the incidence of target vessel revascularization, stent thrombosis, and myocardial infarction. Several IVUS criteria have been proposed to optimize stent implantation. Whether these criteria can be directly used to facilitate OCT guided stent implantation needs to be clarified. Recent studies revealed several IVUS- and OCT-derived predictors of adverse events during PCI. Attenuated coronary plaque on IVUS might be related to deterioration of coronary flow after PCI, whereas tissue characterization on IVUS radiofrequency signal analysis can also detect coronary plaques at high risk for distal embolization. Thin-cap fibroatheroma on OCT has been proposed as a useful characteristic for predicting the no-reflow phenomenon. Furthermore, ostial plaque distribution as assessed by IVUS is reported to be a useful predictor of side-branch occlusion after PCI, whereas the severity of calcified lesions may be better assessed by OCT. Although IVUS and OCT each have inherent strengths and weaknesses, these techniques can complement each other, and selective utilization in appropriate patient subgroups or combined usage is expected to be beneficial during PCI procedures. PMID- 25744629 TI - Characterization of patients with angioscopically-detected in-stent mural thrombi - genetics of clopidogrel responsiveness and generations of drug-eluting stents. AB - BACKGROUND: The loss-of-function genotype of cytochrome P450 2C19 (CYP2C19) has been proposed as a risk factor for stent thrombosis in patients with drug-eluting stent implantation. The aim of this study was to clarify the clinical features of patients with angioscopically-detected in-stent mural thrombi (ISMT). METHODS AND RESULTS: Enrolled were 100 stented segments in 55 patients with stable angina (20 bare-metal stents; 39 Cypher sirolimus-eluting stents [SES]; 26 Endeavor zotarolimus-eluting stents [ZES]; 13 Xience V everolimus-eluting stents; and 2 Nobori biolimus-eluting stents). Dual antiplatelet therapy (100 mg aspirin+75 mg clopidogrel once daily) had been continued since stenting. A poor metabolizer (PM) of clopidogrel was defined as a homozygote of CYP2C19 loss-of-function alleles. Coronary angioscopy revealed ISMT in 6 patients (5 SES, 1 ZES). Between the ISMT group and control group (n=49), there were no significant differences with regards to the VerifyNow P2Y12platelet function assay or in-stent endothelial coverage grade. Exact logistic regression analyses with stepwise forward selection at a significance level of 0.10 were performed to reveal predictive variables for ISMT (respectively: odds ratio, 95% confidence interval, P value: CYP2C19 PM genotype (3.28, 0.88-24.80, 0.09), SES implantation (3.37, 0.90-28.09, 0.08), and presence of yellow plaque (3.69, 1.14-25.70, 0.02). CONCLUSIONS: Patients with ISMT were characterized by SES implantation, poor clopidogrel metabolism, and in-stent yellow plaque. PMID- 25744630 TI - Corrigendum: new insights for low dosing with the new P2Y12 inhibitors - lesson from the East. PMID- 25744631 TI - Lysosomal protein turnover contributes to the acquisition of TGFbeta-1 induced invasive properties of mammary cancer cells. AB - BACKGROUND: Normal epithelial cells and carcinoma cells can acquire invasiveness by epithelial-to-mesenchymal transition (EMT), a process of considerable cellular remodeling. The endosomal/lysosomal compartment is a principal site of intracellular protein degradation. Lysosomal cathepsin proteases are secreted during cancer progression. The established pro-metastatic role of specific cysteine cathepsins has until now been ascribed to their contribution to extracellular matrix remodeling. We hypothesized that cysteine cathepsins affect transforming growth factor beta-1 (TGFbeta-1)-induced EMT of normal and malignant mammary epithelial cells. METHODS: The role of lysosomal proteolysis in TGFbeta-1 induced EMT and invasion was investigated in a normal and a novel malignant murine mammary epithelial cell line. The contribution of cysteine cathepsins was determined by addition of the general cysteine cathepsin inhibitor E64d. Hallmarks of EMT were analyzed by molecular- and cell-biologic analyses including real-time cell migration/invasion assays. A quantitative proteome comparison using stable isotopic labeling with amino acids in culture (SILAC) showed the effect of E64d on TGFbeta-1 induced proteome changes. Lysosomal patterning and junctional adhesion molecule A (Jam-a) localization and abundance were analyzed by immunofluorescence. RESULTS: We found increased lysosome activity during EMT of malignant mammary epithelial cells. Cysteine cathepsin inhibition had no effect on the induction of the TGFbeta-1-induced EMT program on transcriptional level. Protease inhibition did not affect invasion of TGFbeta-1 treated normal mammary epithelial cells, but reduced the invasion of murine breast cancer cells. Remarkably, reduced invasion was also evident if E64d was removed 24 h before the invasion assay in order to allow for recovery of cathepsin activity. Proteome analyses revealed a high abundance of lysosomal enzymes and lysosome-associated proteins in cancer cells treated with TGFbeta-1 and E64d. An accumulation of those proteins and of lysosomal vesicles was further confirmed by independent methods. Interestingly, E64d caused lysosomal accumulation of Jam-a, a tight junction component facilitating epithelial cell-cell adhesion. CONCLUSION: Our results demonstrate an important role of lysosomal proteolysis in cellular remodeling during EMT and a pivotal contribution of lysosomal cysteine cathepsins to TGFbeta-1 induced acquisition of breast cancer cell invasiveness. These findings provide an additional rationale to use cathepsin inhibitors to stall tumor metastasis. PMID- 25744633 TI - Morphometrics and molecular analysis of Ozolaimus linstowi n. sp. (Oxyuroidea: Pharyngodonidae) from the green lizard Iguana iguana. AB - Ozolaimus linstowi n. sp. is described from the large intestine of Iguana iguana Linnaeus, 1758 from Mexico. The present species can be easily distinguished from O. megatyphlon and O. cirratus by the presence of a long and slender pharynx not divided into sections, more similar to the remaining two species, O. monhystera and O. ctenosauri. Ozolaimus linstowi n. sp. can be differentiated from O. monhystera by the shorter spicule length and smaller body size of both males and females. Males of O. linstowi n. sp. are morphologically close to those of O. ctenosauri, but females possess a markedly smaller body size and differ in the organization of the oral cuticular armature. Adult males of O. linstowi n. sp. bear some characteristic features of the J3 juvenile morphology in terms of the cuticular organization of the oral and buccal capsule. Phylogenetic analysis of O. linstowi n. sp. using partial small subunit (SSU) and D2-D3 large subunit (LSU) rDNA shows relationships with several Oxyuridae genera. PMID- 25744632 TI - Claustrophobic tendencies and continuous positive airway pressure therapy non adherence in adults with obstructive sleep apnea. AB - OBJECTIVES: (1) Determine claustrophobia frequency in adults with obstructive sleep apnea (OSA) after first CPAP night; (2) determine if claustrophobia influences CPAP non-adherence. BACKGROUND: Claustrophobia is common among CPAP treated OSA adults yet few studies have examined the problem. METHODS: Secondary analysis of prospective, longitudinal study of OSA adults (n = 97). CPAP-Adapted Fear and Avoidance Scale (CPAP-FAAS) collected immediately after CPAP titration polysomnogram. PRIMARY OUTCOME: objective CPAP use at 1 week and 1 month. RESULTS: Sixty-three percent had claustrophobic tendencies. Females had higher CPAP-FAAS scores than males. FAAS >= 25, positive score for claustrophobic tendencies, was influential on CPAP non-adherence at 1 week (aOR = 5.53, 95% CI 1.04, 29.24, p = 0.04) and less CPAP use at 1month (aOR = 5.06, 95% CI 1.48, 17.37, p = 0.01) when adjusted for body mass index and CPAP mask style. CONCLUSION: Claustrophobia is prevalent among CPAP-treated OSA adults and influences short-term and longer-term CPAP non-adherence. Interventions are needed to address this treatment-related barrier. PMID- 25744634 TI - [Mordillo: Mordillo in the Krems caricature museum (8 March 2015 - 22 November 2015)]. PMID- 25744635 TI - [Report by the president]. PMID- 25744636 TI - Surgical and endoscopic management of high grade dysplasia and early oesophageal adenocarcinoma. AB - BACKGROUND: The introduction of endoscopic techniques has led to debate about optimal management of early oesophageal adenocarcinoma. The aim was to evaluate patient selection and outcomes for endoscopic or surgical treatment at a tertiary referral centre. METHODS: A prospectively collected database of consecutive patients staged with high-grade dysplasia (HGD) or T1 oesophageal adenocarcinoma treated with curative intent between 2005 and 2013 was undertaken. All patients were discussed at the multidisciplinary team meeting. Surgical treatment was by thoracoscopic assisted or standard/laparoscopic assisted Ivor Lewis oesophagectomy. Endoscopic treatment was a structured programme of endoscopic mucosal resection (EMR) and/or radiofrequency ablation (RFA). Outcomes included treatment variables, recurrence and complications. RESULTS: 83 patients treated; 50 with endoscopic therapy (EMR only-4, EMR then RFA-22, RFA only-24) and 38 by surgery (33 straight to surgery and 5 following EMR). Median age (67) and mean follow-up (21 months) were similar. HGD was more common in the endoscopic group (32/50, 64%, vs.3/33, 9%, p = 0.0001). Significant complications were more common following surgery (13/38, 34%, vs. 1/50, 2%, p = 0.0001). There were two in hospital deaths following oesophagectomy (1 open, 1 thoracoscopic). Endoscopic treatment beyond 12 months for persisting HGD/intramucosal disease was required in 2 patients. Recurrence of HGD/invasive cancer was diagnosed in 2/36 (5.6%, T1a recurrence) of endoscopic and 1/38 (2.6%, T2N0 - subsequent hepatic metastases) surgical patients. CONCLUSION: A management algorithm including both endoscopic treatment and oesophagectomy provides optimal outcome for these patients. Due to additional morbidity of surgery, endoscopic treatment is appropriate first-line treatment. PMID- 25744638 TI - [Cellular senescence and chronic inflammation]. AB - It has recently become apparent that obesity is associated with chronic inflammation and several common types of cancer development. Although several events were proposed to be involved in these pathologies, the precise mechanisms underlying obesity-associated inflammation and cancer largely remain unclear. Here, we show that senescence-associated secretory phenotype (SASP) plays crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of a bacterial metabolite that cause DNA damage. The enterohepatic circulation of the bacterial metabolites provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn, secretes various inflammatory and tumour promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Importantly, reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the induction of SASP by the gut bacterial metabolite in HSCs plays key roles in obesity-associated HCC development. Interestingly, moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis (NASH), implying that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer. PMID- 25744639 TI - [Microbiota and autoimmunity]. AB - The microbiota plays a fundamental role in the development and the maintenance of the host immune system. Since microbiota is important in the induction and the expansion of Th17 cells and regulatory T cells, growing evidence supports that microbiome affect the induction and the disease course of autoimmune disorders. In this review, we describe the recent studies on the involvement of microbes in animal models of autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) using germ-free conditions, antibiotics treatment and gnotobiotic mice. Furthermore, we introduce the studies on analysis of microbiota in human autoimmune diseases including RA and MS. PMID- 25744640 TI - [Gut microbiota, host defense and immunity: analysis with integrative omics approach]. AB - Complex host-gut microbiota interaction is involved in the formation of a unique ecosystem in our body, the "gut ecosystem". In order to understand the complex gut ecosystem, we propose integrated multi-omics approach, where multiple layers of unbiased cyclopedic analyses such as genomics, transcriptomics and metabolomics are combined. Applying this approach, we have revealed the mechanism that gut microbiota-derived acetate, a short-chain fatty acid, protects mice from enterohemorrhagic Escherichia coli O157-infectious death. We have also shown that butyrate produced by gut microbiota such as order Clostridiales promotes differentiation of regulatory T cells from naive T cells in colonic lamina propria, through epigenetic modification. Epigenetic modification by butyrate also acts on colonic macrophages to confer anti-inflammatory phenotype by rendering them hyporesponsive to Toll-like receptor signaling. Short-chain fatty acids also signal via their G protein-coupled receptors. For example, it has been suggested that gut microbiota-derived short-chain fatty acids absorbed in the blood play a role in regulation of systemic inflammation by inducing apoptosis of neutrophils as well as chemotaxis of regulatory T cells. PMID- 25744641 TI - [Advanced technologies for the human gut microbiome analysis]. AB - Analysis of the human gut microbiome, collective genomes of over 100 trillion cells of intestinal microbes which form the complex bacterial community, has recently become more practical due to remarkable advances in next-generation sequencing technologies (NGS). Several studies using NGS-based metagenomic approaches have been conducted to comprehensively analyze genes/functions and species composition in the human gut microbiome. These NGS-based approaches have demonstrated that their ecological and biological features that have been rather difficult to pursue can now be characterized with relative ease and high throughput. There have also been several analytical developments and improvements to accurately evaluate the microbiome data from viewpoint of biology and ecology. In addition to the impact of external factors such as diet, these NGS-based studies have strongly suggested that the human gut microbiome has profound influences on various host physiologies including disease, of which the gut microbiome exhibited ecologically and functionally aberrant structure as compared with that of healthy control. On the other hand, the detailed assessment of the effect of experimental protocols including sample storage and delivery, DNA preparation, and sequencers used on the gut microbiome structure is also necessary. I herein present the NGS-based methodology for the human gut microbiome analysis. PMID- 25744642 TI - [Immunity against mycobacterium tuberculosis and risk of biological anti rheumatic agents]. AB - A third of world's population is invaded with Mycobacterium tuberculosis, about 9.0 million people developed tuberculosis (TB) illness and 1.3 million people died from the disease every year. Acquired immunity (cytotoxic CD8(+) T cell, Th1 CD4(+) helper T cell) and macrophage play important role for TB infection. Recently, natural immunity also play a very attractive role for the development TB immunity, with several cytokines, microbicidal proteins and Toll-like receptors. The introduction and uptake of biological disease-modifying anti rheumatic drugs has dramatically advanced and improved the standard care and the prognosis of patients with rheumatoid arthritis (RA). However, as clinical experience with these drugs has grown, risk of granulomatous infections - especially disseminated tuberculosis in adult RA - and reactivation of hepatitis B virus (HBV) are focused. This year marks the tenth anniversary of the approvals of the first tumor necrosis factor (TNF)-alpha antagonist for the treatment of rheumatoid arthritis in Japan. Our understanding of this subject and the knowledge of basic immunology has also advanced during ten years. This review especially focuses on the pathologic action of the TNF blockers in the development of secondary (disseminated) tuberculosis. PMID- 25744643 TI - [Clinical significance of antiphospholipid antibody measured by EliA anticardiolipin antibodies and anti-beta2Glycoprotein I antibodies in antiphospholipid syndrome]. AB - Anticardiolipin antibodies (aCL-IgG/IgM) and anti-beta2-glycoprotein I antibodies (abeta2GPI-IgG/IgM) are laboratory tests included in the current classification criteria for definite antiphospholipid syndrome (APS). However, not all of these assays have been commercially available in Japan. We investigated the efficacy of aCL-IgG/IgM and abeta2GPI-IgG/IgM assays using fluorescence enzyme immunoassay (Phadia:EliA(TM)) for the diagnosis of APS in Japan. This study comprised 229 sera from patients (100 with APS and 129 without APS). The diagnosis of APS was made according to Sydney revised Sapporo criteria. EliA(TM)Cardiolipin and EliA(TM)beta2-Glycoprotein (Phadia AB. Uppsala Sweden) were used to detect aCL IgG/M and abeta2GPI IgG/M, respectively. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were as follows; aCL-IgG (45%, 94%, 0.80), aCL-IgM (20%, 94%, 0.54), abeta2GPI-IgG (33%, 98%, 0.88) and abeta2GPI-IgM (16%, 99%, 0.64) respectively. aCL-IgM, abeta2GPI-IgG or abeta2GPI IgM were detected in 10 patients (18%) with aCL-IgG negative. The use of Phadia:EliA(TM)antiphospholipid antibodies assays improve the diagnostic yield of thrombotic risk in APS patients. PMID- 25744644 TI - A strategy for removal of foreign body in mandible with navigation system. AB - Navigation surgery in the mandible has rarely been reported because of the complexities of navigating a mobile structure. In this article, we present a simple and novel strategy for removal of a foreign body in the mandible using a navigation system. A female diagnosed with a foreign body in the left mandible underwent navigation surgery using a BrainLAB system. We used a special open splint fabricated with acrylic resin to successfully perform the mandibular navigation. This strategy may be appropriate for many types of mandibular navigation surgery. PMID- 25744646 TI - Dewaterability of sludge conditioned with surfactant DDBAC pretreatment by acid/alkali. AB - The potential benefits of surfactant-conditioned sludge dewatering treatment with acid/alkali pretreatment were investigated in this study. The water content of dewatered sludge (W C) and specific resistance of filtration (SRF) were used to evaluate sludge dewaterability. Extracellular polymeric substance (EPS) content, bound water content, zeta potential, and rheological properties were measured to explain the change of dewaterability observed in the conditioning process. By introducing dodecyl dimethyl benzyl ammonium chloride (DDBAC), the EPS content of the sludge supernatant changed, and bound water content, charge strength, and apparent viscosity decreased simultaneously. Although DDBAC-conditioned sludge in strong alkaline had low bound water content, W C and SRF increased rapidly because of the dramatically increasing of EPS in sludge supernatant. Remarkable decrement was observed in bound water content and W C in DDBAC-conditioned sludge which was in weak acid environment for comparison. The results indicated that 75 mg/g of DDBAC at pH 4.84 was the optimum under which W C and SRF were at their lowest point in sludge, 58.22 % and 0.521 * 10(13) m/kg, respectively. PMID- 25744645 TI - Association of PSMA4 polymorphisms with lung cancer susceptibility and response to cisplatin-based chemotherapy in a Chinese Han population. AB - PURPOSE: Genetic factors play an important role in our predisposition to cancer. Genome-wide association studies have linked the chromosome 15q25.1 locus to lung cancer susceptibility and implicated proteasome subunit alpha type-4 (PSMA4) as a candidate gene. In this case-control study, pathologically confirmed lung cancer patients and controls from the Chinese Han population were investigated to determine the effect of variant genotypes within the PSMA4 locus on susceptibility to lung cancer and sensitivity to cisplatin-based chemotherapy. METHODS: We identified validated tagged single nucleotide polymorphisms (tSNPs) with minor allele frequency >5 % in the HapMap Chinese Han Beijing population and genotyped seven SNPs within the PSMA4 locus. Their correlation with lung cancer risks and treatment response were examined using chi (2) test and haplotype analysis. Multivariate logistic regression analysis tested the association between the polymorphisms and chemotherapy response. RESULTS: rs12901682 is associated with lung cancer risks (OR = 1.45, 95 % CI, 1.04-2.02; P = 0.029). Using SNPStats software, we found rs12901682 (OR = 6.30, 95 % CI, 1.31-30.26; P = 0.0073) associated with lung cancer risks in the recessive model. Haplotype analysis showed that "CAGAATC" conferred an increased risk of lung cancer (OR = 1.50, 95 % CI, 1.07-2.11; P = 0.019). After adjustment for age, this association was pronounced in the male gender (OR = 6.30, 95 % CI, 1.31-30.26; P = 0.0073). PSMA4 polymorphisms did not affect the tumor sensitivity to cisplatin combination chemotherapy. CONCLUSIONS: Our study suggests a potential association between PSMA4 variants and lung cancer risk in Chinese Han population. PMID- 25744647 TI - Evaluation of the probiotic properties of new Lactobacillus and Bifidobacterium strains and their in vitro effect. AB - Probiotic ingestion is recommended as a preventive approach to maintain the balance of the intestinal microbiota and to enhance the human well-being. During the whole life of each individual, the gut microbiota composition could be altered by lifestyle, diet, antibiotic therapies and other stress conditions, which may lead to acute and chronic disorders. Hence, probiotics can be administered for the prevention or treatment of some disorders, including lactose malabsorption, acute diarrhoea, irritable bowel syndrome, necrotizing enterocolitis and mild forms of inflammatory bowel disease. The probiotic mediated effect is an important issue that needs to be addressed in relation to strain-specific probiotic properties. In this work, the probiotic properties of new Lactobacillus and Bifidobacterium strains were screened, and their effects in vitro were evaluated. They were screened for probiotic properties by determining their tolerance to low pH and to bile salts, antibiotic sensitivity, antimicrobial activity and vitamin B8, B9 and B12 production, and by considering their ability to increase the antioxidant potential and to modulate the inflammatory status of systemic-miming cell lines in vitro. Three out of the examined strains presenting the most performant probiotic properties, as Lactobacillus plantarum PBS067, Lactobacillus rhamnosus PBS070 and Bifidobacterium animalis subsp. lactis PBSO75, were evaluated for their effects also on human intestinal HT-29 cell line. The obtained results support the possibility to move to another level of study, that is, the oral administration of these probiotical strains to patients with acute and chronic gut disorders, by in vivo experiments. PMID- 25744649 TI - Targeted production of secondary metabolites by coexpression of non-ribosomal peptide synthetase and prenyltransferase genes in Aspergillus. AB - Prenylated tryptophan-containing cyclic dipeptides are found in different fungi and serve as precursors for the biosynthesis of diverse biologically active secondary metabolites. They show distinct and usually higher biological and pharmacological activities than the respective non-prenylated dipeptides. Successful production of such compounds were achieved by a new approach based on the coexpression of ftmPS, a non-ribosomal peptide synthetase from Neosartorya fischeri, with three cyclic dipeptide prenyltransferase genes from different biosynthetic gene clusters in Aspergillus nidulans. The genes are expressed under the control of constitutive gpdA promoter and trpC terminator. Expression of ftmPS alone resulted in the formation of the expected cyclic dipeptide brevianamide F with a yield of up to 36.9 mg l(-1). Introducing the reverse C2 prenyltransferase gene cdpC2PT as well as the reverse C3-prenyltransferase gene cdpNPT into a ftmPS mutant yielded reversely C2- and C3-prenylated derivatives, respectively. Coexpression of ftmPS with the reverse C3-prenyltransferase gene cdpC3PT resulted in the formation of N1-regularly, C2-, and C3-reversely prenylated derivatives. The prenyl transfer reactions catalyzed by CdpC2PT, CdpNPT, and CdpC3PT observed in this study correspond well to those detected with purified proteins. The yields of the detected prenylated products were found to be up to 12.2 mg l(-1). The results presented in this study show the potential of synthetic biology for production of prenylated compounds. PMID- 25744651 TI - Latent class analysis of alcohol treatment utilization patterns and 3-year alcohol related outcomes. AB - People who obtain treatment for alcohol use problems often utilize multiple sources of help. While prior studies have classified treatment use patterns for alcohol use, an empirical classification of these patterns is lacking. For the current study, we created an empirically derived classification of treatment use and described how these classifications were prospectively associated with alcohol-related outcomes. Our sample included 257 participants of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) who first received alcohol treatment in the 3-year period prior to their baseline interview. We used latent class analysis to identify classes of treatment users based on their patterns of treatment use of 13 types of alcohol treatment. Regression models examined how classes of treatment use at baseline were associated with alcohol-related outcomes assessed at a 3-year follow-up interview. Outcomes included a continuous measure of the quantity and frequency of alcohol use and DSM-IV alcohol use disorder status. Four classes of treatment users were identified: (1) multiservice users (8.7%), (2) private professional service users (32.8%), (3) alcoholics anonymous (AA) paired with specialty addiction service users (22.0%), and (4) users of AA alone (36.5%). Those who utilized AA paired with specialty addiction services had better outcomes compared to those who used AA alone. In addition to elucidating the most common treatment utilization patterns executed by people seeking help for their alcohol problems, the results from this study suggest that increased efforts may be needed to refer individuals across sectors of care to improve treatment outcomes. PMID- 25744650 TI - Diversion of methadone and buprenorphine from opioid substitution treatment: the importance of patients' attitudes and norms. AB - AIMS: Methadone and buprenorphine diversion by patients in opioid substitution treatment (OST) is a poorly understood phenomenon. We study the norms and attitudes on diversion among OST patients, including the role these norms and attitudes play as diversion risk factors. We also study whether perceived quality of care, social bonds to treatment staff, and deterrence can be associated with diversion. METHODS: Structured interviews were conducted with 411 patients from eleven OST programs. In total, 280 interviews were done on site by the researchers, while 131 interviews were conducted through peer interviewing by specially trained patients. The data was analyzed through frequency- and averages calculations, cross-tabulations, and logistic regression analysis. RESULTS: Most patients consider diversion as mostly positive (83.7%), morally right (76.8%), and without any significant risk of detection (66.9%). Individual differences in norms and risk perceptions may play a role in explaining variations in diversion; patients who consider it right to share medication with friends report higher treatment-episode diversion than other patients (OR 1.455, p = 0.016). Patients who perceive control measures as effective report lower diversion than other patients (OR = 0.655, p = 0.013). Furthermore, data indicate that patients who are satisfied with the care and service are less prone to engage in diversion. Social bonds with treatment staff seem to be less importance. CONCLUSIONS: The norm system described by patients resemble Bourgois' 'moral economy of sharing' concept-not sharing drugs with friends in withdrawal is considered unethical. Efforts to decrease diversion may focus on lifestyle-changing interventions, and reducing black market demand for illicit medications by expanding access to treatment. PMID- 25744652 TI - Perioperative goal directed therapy: evidence and compliance are two sides of the same coin. PMID- 25744653 TI - p21-Activated kinase 4 predicts early recurrence and poor survival in patients with nonmetastatic clear cell renal cell carcinoma. AB - BACKGROUND: p21-Activated kinase 4 (PAK4), a serine/threonine kinase implicated in the cytoskeleton organization to orchestrate cell morphology, adhesion, and motility, is associated with angiogenesis and vessel branching, which are important events in the progression of clear cell renal cell carcinoma (ccRCC). We investigated the effect of PAK4 expression on recurrence and survival among patients with nonmetastatic ccRCC following surgery. METHODS: PAK4 expression was assessed, using immunohistochemistry, in 376 patients with nonmetastatic ccRCC after nephrectomy, where data of 187 patients were obtained from 2013 to 2014 and of 189 patients were obtained from 2008. Kaplan-Meier and Cox regression analyses were used to associate PAK4 expression with overall survival and recurrence-free survival. RESULTS: Overall, 41.2% and 36.5% of specimens exhibited high PAK4 expression in 2 cohorts. Patients with high PAK4 expression were prone to possess high Fuhrman grade and tumor necrosis. Moreover, high PAK4 intensity was significantly associated with poor overall survival and recurrence-free survival. PAK4 expression remained an independent adverse prognosticator after adjusting for other well-established factors. Furthermore, in subgroups stratified by Fuhrman grade or T category, patients with high PAK4 intensity had an increased risk of recurrence and death. After adjusting for age, high PAK4 expression was an adverse prognostic marker in subgroup of low Fuhrman grade and in subgroup of early T category. CONCLUSION: PAK4 expression is an independent adverse prognostic biomarker for recurrence and survival among patients with low-risk ccRCC after nephrectomy. PMID- 25744654 TI - Urethral recurrence in women with orthotopic bladder substitutes: A multi institutional study. AB - OBJECTIVES: To evaluate risk factors for urethral recurrence (UR) in women with neobladder. MATERIAL AND METHODS: From 1994 to 2011, 297 women (median age = 54 y; interquartile range: 47-57) underwent radical cystectomy with ileal neobladder for bladder cancer in 4 centers. None of the patients had bladder neck involvement at preoperative assessment. Univariable and multivariable analyses were used to estimate recurrence-free survival and overall survival. The median follow-up was 64 months (interquartile range: 25-116). RESULTS: Of the 297 patients, 81 developed recurrence (27%). The 10- and 15-year recurrence-free survival rates were 66% and 66%, respectively. The 10- and 15-year overall survival rates were 57% and 55%, respectively. UR occurred in 2 patients (0.6%) with solitary urethral, 4 (1.2%) with concomitant urethral and distant recurrence, and 1 with concomitant urethral and local recurrence (0.3%). Bladder tumors were located at the trigone in 27 patients (9.1%). None of these patients developed UR. Lymph node tumor involvement was present in 60 patients (20.2%). On univariable and multivariable analyses, pathologic tumor and nodal stage were independent predictors for the overall risk of recurrence. UR was associated with a positive final urethral margin status (P<0.001) whereas no significant associations were found for carcinoma in situ, pathologic tumor and nodal stage, and bladder trigone involvement. CONCLUSIONS: In this series, only 0.6% of women developed solitary UR. A positive final urethral margin was associated with an increased risk of UR. Women with involvement of the bladder trigone were not at higher risk of UR. PMID- 25744648 TI - pH regulates ammonia-oxidizing bacteria and archaea in paddy soils in Southern China. AB - Ammonia-oxidizing archaea (AOA) and bacteria (AOB) play important roles in nitrogen cycling. However, the effects of environmental factors on the activity, abundance, and diversity of AOA and AOB and the relative contributions of these two groups to nitrification in paddy soils are not well explained. In this study, potential nitrification activity (PNA), abundance, and diversity of amoA genes from 12 paddy soils in Southern China were determined by potential nitrification assay, quantitative PCR, and cloning. The results showed that PNA was highly variable between paddy soils, ranging from 4.05 +/- 0.21 to 9.81 +/- 1.09 mg NOx N kg(-1) dry soil day(-1), and no significant correlation with soil parameters was found. The abundance of AOA was predominant over AOB, indicating that AOA may be the major members in aerobic ammonia oxidation in these paddy soils. Community compositions of AOA and AOB were highly variable among samples, but the variations were best explained by pH. AOA sequences were affiliated to the Nitrosopumilus cluster and Nitrososphaera cluster, and AOB were classified into the lineages of Nitrosospira and Nitrosomonas, with Nitrosospira being predominant over Nitrosomonas, accounting for 83.6 % of the AOB community. Moreover, the majority of Nitrosomonas was determined in neutral soils. Canonical correspondence analysis (CCA) analysis further demonstrated that AOA and AOB community structures were significantly affected by pH, soil total organic carbon, total nitrogen, and C/N ratio, suggesting that these factors exert strong effects on the distribution of AOB and AOA in paddy soils in Southern China. In conclusion, our results imply that soil pH was a key explanatory variable for both AOA and AOB community structure and nitrification activity. PMID- 25744655 TI - Haemonchotolerance in West African Dwarf goats: contribution to sustainable, anthelmintics-free helminth control in traditionally managed Nigerian dwarf goats. AB - West African Dwarf (WAD) goats are extremely important in the rural village economy of West Africa, but still little is known about their biology, ecology and capacity to cope with gastrointestinal nematode (GIN) infections. Here, we summarise the history of this breed and explain its economic importance in rural West Africa. We review recent work showing that Nigerian WAD goats are highly trypanotolerant and resist infections with Haemonchus contortus more effectively than other breeds of domestic goat (haemonchotolerance). We believe that haemonchotolerance is largely responsible for the generally low level GIN infections and absence of clinical haemonchosis in WADs under field conditions, and has contributed to the relatively successful and sustainable, anthelmintics free, small-scale system of goat husbandry in Nigeria's humid zone, and is immunologically based and genetically controlled. If haemonchotolerance can be shown to be genetically controlled, it should be possible to exploit the underlying genes to improve GIN resistance among productive fibre and milk producing breeds of goats, most of which are highly susceptible to nematode infections. Genetic resistance to GIN and trypanosome infections would obviate the need for expensive chemotherapy, mostly unaffordable to small-holder farmers in Africa, and a significant cost of goat husbandry in more developed countries. Either introgression of resistance alleles into susceptible breeds by conventional breeding, or transgenesis could be used to develop novel parasite resistant, but highly productive breeds, or to improve the resistance of existing breeds, benefitting the local West African rural economy as well as global caprine livestock agriculture. PMID- 25744656 TI - Generation of specific monoclonal antibodies against the extracellular loops of human claudin-3 by immunizing mice with target-expressing cells. AB - Human claudin-3 (CLDN3) is a tetraspanin transmembrane protein of tight junction structures and is known to be over-expressed in some malignant tumors. Although a specific monoclonal antibody (MAb) against the extracellular domains of CLDN3 would be a valuable tool, generation of such MAbs has been regarded as difficult using traditional hybridoma techniques, because of the conserved sequence homology of CLDN3s among various species. In addition, high sequence similarity is shared among claudin family members, and potential cross-reactivity of MAb should be evaluated carefully. To overcome these difficulties, we generated CLDN3 expressing Chinese hamster ovary and Sf9 cells to use an immunogens and performed cell-based screening to eliminate cross-reactive antibodies. As a result, we generated MAbs that recognized the extracellular loops of CLDN3 but not those of CLDN4, 5, 6, or 9. Further in vitro studies suggested that the isolated MAbs possessed the desired binding properties for the detection or targeting of CLDN3. PMID- 25744657 TI - Clinicopathological features of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. AB - PURPOSE: The incidence of hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD) is increasing. However, the clinicopathological features of HCC in these patients are little known. Thus, we investigated the differences in the clinical and pathological characteristics of HCC between NAFLD patients and hepatitis-C virus (HCV) patients. METHODS: Data from 21 HCC patients with NAFLD and 645 HCC patients with HCV who underwent curative hepatectomy were collected and analyzed. To overcome bias due to differences in the distribution of covariates between the two groups, propensity score matching was performed, and clinicopathological features and outcomes were compared. RESULTS: In propensity score analysis, the rate of microscopic vascular invasion was significantly higher in the NAFLD group than in the HCV group (65 vs. 30%; P = 0.027). However, overall survival and disease-free survival did not differ between the two matched groups. CONCLUSIONS: NAFLD may have permissive microenvironment for HCC progression. PMID- 25744658 TI - Mental Health and Online, Land-Based and Mixed Gamblers. AB - Although high rates of problem gambling have been identified among Internet gamblers, most studies have failed to identify the relative contribution of multiple forms of gambling as opposed to the exclusive participation in online forms. The aim of this study was to investigate differences in mental health status in exclusive online, exclusive land-based, and mixed Internet and land based samples of gamblers drawn from the general population. A sample of 4594 respondents completing an online survey were categorised as exclusive online, land-based and mixed form gamblers. Participants completed a questionnaire eliciting demographic details, participation on all forms of gambling, use of alcohol, tobacco and drugs, help-seeking, and personal problems experienced due to gambling, as well as measures of problem gambling and psychological distress. Findings indicated that mixed gamblers exhibited higher problem gambling scores, level of gambling involvement, and consumption of alcohol during gambling than exclusive online gamblers. Land-based gamblers experienced higher levels of psychological distress, self-acknowledged need for treatment, and help-seeking behaviour. These findings suggest that exclusive online gamblers represent a different subpopulation at lower risk of harm compared to gamblers engaging in multiple forms. Understanding the characteristics of different problem gambling subpopulations may inform the development of more effective targeted interventions. PMID- 25744661 TI - Type VIII Si based clathrates: prospects for a giant thermoelectric power factor. AB - Although clathrate materials are known for their small thermal conductivity, they have not shown a large thermoelectric power factor so far. We present the band structures of type VIII Si, Ge, and Sn clathrates as well as the alkali and alkaline-earth intercalated type VIII Si clathrates. Our calculations revealed that this group of materials has potentially large power factors due to the existence of a large number of carrier pockets near their band edges. In particular, we calculated the charge carrier transport properties of Si46-VIII both for n-type and p-type materials. The exceptionally high multi-valley band structure of Si46-VIII near the Fermi energy due to the high crystallographic symmetry resulted in a giant power factor in this material. It was shown that the intercalation of Si46-VIII with alkali and alkaline-earth guest atoms shifts the Fermi energy close to the conduction band edge and, except for Be8Si46 and Mg8Si46, they weakly influence the band structure of Si46. Among these clathrate systems, Ca8Si46, Sr8Si46, and Ba8Si46 showed negative formation energy, which should facilitate their synthesis. Our results imply that the intercalation affects the conduction band of Si46-VIII more than its valence band. Also, interestingly, the type VIII clathrates of Si46 and its derivatives (except Be8Si46 and Mg8Si46), Sn46, and Ge46 all have 26 carrier pockets near their valence band edge. Among the different derivatives of Si46-VIII, Rb8Si46 and Ba8Si46 have the highest number of electron pockets near their band edges. The thermoelectric power factor was predicted using a multiband Boltzmann transport equation linked with parameters extracted from density functional calculations. It was shown that both the increment of charge mobility and the existence of multiple band extrema contribute to the enhancement of the thermoelectric power factor considerably. Such a large power factor along with their inherently low thermal conductivity can make this group of clathrates promising thermoelectric materials. PMID- 25744659 TI - Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis. AB - Ubiquinone (UQ) is implicated in mitochondrial electron transport, superoxide generation and as a membrane antioxidant. Here we present a mouse model in which UQ biosynthesis can be interrupted and partially restored at will. Global loss of UQ leads to gradual loss of mitochondrial function, gradual development of disease phenotypes and shortened lifespan. However, we find that UQ does not act as antioxidant in vivo and that its requirement for electron transport is much lower than anticipated, even in vital mitochondria-rich organs. In fact, severely depressed mitochondrial function due to UQ depletion in the heart does not acutely impair organ function. In addition, we demonstrate that severe disease phenotypes and shortened lifespan are reversible upon partial restoration of UQ levels and mitochondrial function. This observation strongly suggests that the irreversible degenerative phenotypes that characterize ageing are not secondarily caused by the gradual mitochondrial dysfunction that is observed in aged animals. PMID- 25744660 TI - Long-term parental satisfaction with adenotonsillectomy: a population study. AB - OBJECTIVE: This study reports the presence of sleep-disordered breathing (SDB) symptoms among first graders. We evaluated the severity of symptoms and parental satisfaction in children who had undergone adenotonsillectomy (T&A) compared to children who never had T&A. METHODS: A population-based, cross-sectional study was conducted. Parent-reported questionnaire data including age, weight, height, BMI, history of T&A, and SDB symptoms (snoring intensity, observed dyspneas, mouth breathing during sleep) were analyzed. RESULTS: Of 3580 eligible children, 2504 (69.9 %) returned questionnaires. Two hundred fifty-nine (10.3 %) children had a history of T&A. Within this group, 76 % of parents were still satisfied with their child's outcome after surgery. The satisfaction rate decreased from 88.9 % in those who had surgery within 1 year to 71.3 % in those who had surgery >=3 years prior. The mean values of intensity for all analyzed SDB symptoms on a five-point scale were significantly higher for children who had ever undergone T&A when compared to those who never underwent surgery [e.g., snoring (2.11 vs 1.87; P = 0.0004), dyspneas (1.64 vs 1.22; P < 0.0001), and mouth breathing during sleep (2.95 vs 2.58; P < 0.0001)]. For those who had undergone T&A, 24 % of caregivers were not satisfied with the surgical outcome and the symptom intensity was highest (snoring = 3.16, dyspneas = 2.20, and mouth breathing = 4.23) for these children. CONCLUSIONS: The mean SDB symptom intensity was significantly higher in children who had undergone T&A when compared to those who had not. The elevated symptom intensity in those children whose caregivers were not satisfied after T&A suggests possible SDB recurrence and need for further evaluation. PMID- 25744662 TI - Audio profiles in mitochondrial deafness m.1555A>G and m.3243A>G show distinct differences. AB - BACKGROUND: Hearing loss is one of the most common symptoms of mitochondrial disorders. However, audiological phenotypes associated with different molecular defects in mtDNA are not yet well characterized. MATERIAL AND METHODS: A large cohort of 1499 nonconsanguineous patients aged 5-40 years with hearing loss of unknown etiology was screened for mutations in mtDNA. For further analysis, patients harboring m.1555A>G and m.3243A>G were selected. Hearing status of the patients was assessed by pure tone audiometry. Patterns of audiograms (hearing threshold levels at each examined frequency) were statistically compared among the carriers of the m.1555A>G and the m.3243A>G mutations. RESULTS: We identified 20 patients positive for m.1555A>G mutation and 16 patients positive for m.3243A>G change. The frequency of the above transitions was calculated in our cohort as 1.33% and 1.06%, respectively. Seventeen affected family members carrying the mutations were included into the study. Typical shape of the audiograms in patients with m.1555A>G mutation presented a ski-slope pattern, whereas the audiometric curves among the m.3243A>G individuals had a pantonal shape (a flat curve) with slight downward sloping at the higher frequencies. The differences were statistically significant. The onset of hearing loss was noted earlier among m.1555A>G than m.3243A>G patients (12.5 and 26 years, respectively). Aminoglycoside administration was declared in both groups in 11 and 4 cases respectively, and caused abrupt hearing deterioration in all cases. CONCLUSIONS: A pattern of audiogram in patients with mitochondrial deafness may suggest a localization of mtDNA mutation. The pathogenesis of the audiometric differences needs further study. PMID- 25744663 TI - Crimped braided sleeves for soft, actuating arm in robotic abdominal surgery. AB - BACKGROUND: This paper investigates different types of crimped, braided sleeve used for a soft arm for robotic abdominal surgery, with the sleeve required to contain balloon expansion in the pneumatically actuating arm while it follows the required bending, elongation and diameter reduction of the arm. MATERIAL AND METHODS: Three types of crimped, braided sleeves from PET (BraidPET) or nylon (BraidGreyNylon and BraidNylon, with different monofilament diameters) were fabricated and tested including geometrical and microstructural characterisation of the crimp and braid, mechanical tests and medical scratching tests for organ damage of domestic pigs. RESULTS: BraidPET caused some organ damage, sliding under normal force of 2-5 N; this was attributed to the high roughness of the braid pattern, the higher friction coefficient of polyethylene terephthalate (PET) compared to nylon, and the high frequency of the crimp peaks for this sleeve. No organ damage was observed for the BraidNylon, attributed to both the lower roughness of the braid pattern and the low friction coefficient of nylon. BraidNylon also required the lowest tensile force during its elongation to similar maximum strain as that of BraidPET, translating to low power requirements. CONCLUSION: BraidNylon is recommended for the crimped sleeve of the arm designed for robotic abdominal surgery. PMID- 25744665 TI - Robust design of adenovirus purification by two-column, simulated moving-bed, size-exclusion chromatography. AB - A simple, yet efficient, two-column simulated moving-bed (2CSMB) process for purifying adenovirus serotype 5 (Ad5) by size-exclusion chromatography (SEC) is presented and validated experimentally, and a general procedure for its robust design under parameter uncertainty is described. The pilot-scale run yielded a virus recovery of 86 percent and DNA and HCP clearances of 90 and 89 percent, respectively, without any fine tuning of the operating parameters. This performance compares very favorably against that of single-column batch chromatography for the same volume of size-exclusion resin. To improve the robustness of the 2CSMB-SEC process the best set of operating parameters is selected only among candidate solutions that are robust feasible, that is, remain feasible for all parameter perturbations within their uncertainty intervals. This robust approach to optimal design replaces the nominal problem by a worst case problem. Computational tractability is ensured by formulating the robust design problem with only the vertices of the uncertainty region that have the worst effect on the product purity and recovery. The robust design is exemplified on the case where the column volume and interparticle porosity are subject to uncertainty. As expected, to increase the robustness of the 2CSMB-SEC process it is necessary to reduce its productivity and increase its solvent consumption. Nevertheless, the design solution given by our robust approach is the least detrimental of all feasible operating conditions for the 2CSMB-SEC process. PMID- 25744664 TI - High-yield production of a functional bacteriophage lysin with antipneumococcal activity using a plant virus-based expression system. AB - Streptococcus pneumoniae is the causative agent of several serious infectious diseases. It is becoming increasingly antibiotic resistant worldwide, and thus new antimicrobials are needed. One alternative to antibiotics may be the use of peptidoglycan hydrolases, the bacteriophage lytic enzymes. In this study, we demonstrated high level expression of the S. pneumoniae bacteriophage lysin Pal in Nicotiana benthamiana - TMV (Tobacco Mosaic Virus) transient expression system. The protein was purified to homogeneity and tested for streptococci killing activity in vitro and in vivo. In vitro, Pal was able to lyse three tested S. pneumoniae strains: NCTC12695, NCTC12977 and NCTC11888. The treatment of BALB/c mice with 100 MUg, 200 MUg and 400 MUg of Pal 1h post-challenge with double lethal dose of S. pneumoniae NCTC12695 strain showed a clear dose response and protected from lethal sepsis 30%, 40% and 50% of mice, respectively. The improved mice survival correlated with decreased blood bacterial titers. In conclusion, these results suggest that plant-expressed bacteriophage lysins may have potential use as antimicrobial agents. PMID- 25744666 TI - Direct output of electrical signals from LSPR sensors on the basis of plasmon induced charge separation. AB - Potentiometric and conductometric sensors based on localized surface plasmon resonance were developed. The sensors can be applied to coloured and turbid samples because light need not pass through the sample solution. PMID- 25744667 TI - Recent trends in type-specific HPV infection rates in the United States. AB - SUMMARY This study examined recent trends in type-specific HPV infection rates in women referred for HPV typing as part of cervical cancer screening in the United States. HPV analyses were performed from March 2004 to March 2011. Women were aged 21-65 years at testing. The 18 most prevalent HPV types were analysed. Type specific HPV infection rates were estimated in 3-month blocks. Lowess smoothing was used to examine time trends in infection rates for each HPV type, both combined, and separated by age group (younger women 21-30 years, older women 31 64 years). A total of 220914 women were included in the final analysis. The number of HPV tests performed on the younger age group increased, with the number of HPV infections and multiple type HPV infections decreasing. When separated by HPV type-specific analysis, the majority of HPV infection rates decreased; however, HPV types 61 and 83 increased. When analysing the older age group, there was a marked increase of the number of HPV tests. Overall, the rates of any HPV infection, as well as multiple type infections, were lower compared to the younger age group. The change in type-specific HPV rates in the older age group was minimal, with many rates remaining the same. In this population of women, overall rates of HPV infection decreased, while the number of HPV tests increased. Younger women had a more marked decrease in HPV infection rates, while for older women type-specific HPV infection rates appear consistent. PMID- 25744668 TI - An introduction to pain pathways and pain "targets". AB - The purpose of this chapter is to provide a brief introduction to the anatomy and physiology of pain pathways from peripheral nociceptors to central nervous system areas involved in the perception and modulation of pain. This chapter also provides a short introduction to major types of persistent pain: neuropathic and inflammatory persistent pain, and gives an overview of some important molecular targets that are thought to mediate these types of pain. These targets, which include ion channels, receptors, and some neurotransmitters, are further discussed in the context of their relevance as potential drug targets for the better treatment of pain in patients with persistent pain. Finally, this chapter introduces several important concepts in pain research that will be primary topics for chapters that come later in the book. PMID- 25744669 TI - Peripheral scaffolding and signaling pathways in inflammatory pain. AB - Peripheral injury precipitates the release and accumulation of extracellular molecules at the site of injury. Although these molecules exist in various forms, they activate specific receptor classes expressed on primary afferent neurons to mediate cellular and behavioral responses to both nonpainful and painful stimuli. These inflammatory mediators and subsequent receptor-mediated effects exist to warn an organism of future injury, thereby resulting in protection and rehabilitation of the wounded tissue. In this chapter, inflammatory mediators, their target receptor classes, and downstream signaling pathways are identified and discussed within the context of inflammatory hyperalgesia. Furthermore, scaffolding mechanisms that exist to support inflammatory signaling in peripheral afferent neuronal tissues specifically are identified and discussed. Together, the mediators, pathways, and scaffolding mechanisms involved in inflammatory hyperalgesia provide a unique knowledge point from which new therapeutic targets can be understood. PMID- 25744670 TI - Contribution of mechanosensitive ion channels to somatosensation. AB - Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal, is a central mechanism to several physiological functions in mammals. It relies on the function of mechanosensitive ion channels (MSCs). Although the first single-channel recording from MSCs dates back to 30 years ago, the identity of the genes encoding MSCs has remained largely elusive. Because these channels have an important role in the development of mechanical hypersensitivity, a better understanding of their function may lead to the identification of selective inhibitors and generate novel therapeutic pathways in the treatment of chronic pain. Here, I will describe our current understanding of the role MSCs may play in somatosensation and the potential candidate genes proposed to encode them. PMID- 25744672 TI - The contribution of mitochondria to sensory processing and pain. AB - Mitochondria have a variety of essential functions within neurons including oxygen consumption, ATP generation, calcium buffering, and reactive oxygen species (ROS) generation. Despite extensive research into the contribution of mitochondrial function in other neurological disorders such as Parkinson's disease, the role of mitochondrial function in sensory processing and pain has been relatively unexplored until recent years. As this area of pain research is in its infancy, this review will be a descriptive summary-rather than a critical review-of data that suggests mitochondrial function/dysfunction as a causal or contributory mechanism of normal sensory processing and chronic pain. Evidence for mitochondrial dysfunction from both chronic pain patients and animal models of chronic pain will be described. Such evidence involves different aspects of mitochondria and their function including mitochondrial ultrastructure, distribution, oxygen consumption, oxidative phosphorylation, calcium buffering, ROS, and ATP levels. Most recently, substantial amounts of data have demonstrated mitochondrial involvement in painful peripheral neuropathies evoked by chemotherapy, diabetes, and HIV and these topics will be particularly highlighted in this review. PMID- 25744673 TI - Regulation of gene expression and pain states by epigenetic mechanisms. AB - The induction of inflammatory or neuropathic pain states is known to involve molecular activity in the spinal superficial dorsal horn and dorsal root ganglia, including intracellular signaling events which lead to changes in gene expression. These changes ultimately cause alterations in macromolecular synthesis, synaptic transmission, and structural architecture which support central sensitization, a process required for the establishment of long-term pain states. Epigenetic mechanisms are essential for long-term synaptic plasticity and modulation of gene expression. This is because epigenetic modifications are known to regulate gene transcription by aiding the physical relaxation or condensation of chromatin. These processes are therefore potential regulators of the molecular changes underlying permanent pain states. A handful of studies have emerged in the field of pain epigenetics; however, the field is still very much in its infancy. This chapter draws upon other specialities which have extensively investigated epigenetic mechanisms, such as learning and memory and oncology. After defining epigenetics as well as the recent field of "neuroepigenetics" and the main molecular mechanisms involved, this chapter describes the role of these mechanisms in the synaptic plasticity seen in learning and memory, and address those epigenetic mechanisms that have been linked with the development of acute and prolonged pain states. Finally, the idea that long-lasting epigenetic modifications could contribute to the transition from acute to chronic pain states by supporting maladaptive molecular changes is discussed. PMID- 25744674 TI - Translational control of chronic pain. AB - Pain is a crucial physiological response to injury and pathologies. The development and maintenance of pain requires the expression of novel genes. The expression of such genes occurs in highly regulated and orchestrated manner where protein translation provides an exquisite temporal and spatial fidelity within the axons and dendrites of neurons. Signaling pathways that regulate local translation are activated by cytokines, neurotrophic factors, or neurotransmitters, which are released either due to tissue damage or neuronal activity. In recent years, the ERK and mTOR pathways have been demonstrated to be central in regulating local translation in neurons of both the peripheral and central nervous systems in diverse models of chronic pain. The ERK and mTOR pathways converge onto the cap-dependent translational machinery that regulates genes essential for the development of nociceptive sensitization. Moreover, inhibition of these pathways has proved to be effective in normalizing the biochemical changes and the associated pain in various preclinical models. PMID- 25744671 TI - Sensory TRP channels: the key transducers of nociception and pain. AB - Peripheral detection of nociceptive and painful stimuli by sensory neurons involves a complex repertoire of molecular detectors and/or transducers on distinct subsets of nerve fibers. The majority of such molecular detectors/transducers belong to the transient receptor potential (TRP) family of cation channels, which comprise both specific receptors for distinct nociceptive stimuli, as well as for multiple stimuli. This chapter discusses the classification, distribution, and functional properties of individual TRP channel types that have been implicated in various nociceptive and/or painful conditions. PMID- 25744675 TI - MicroRNA biology and pain. AB - Endogenously expressed small noncoding microRNAs (miRNAs) play an important role in posttranscriptionally regulating gene expression by binding to mRNAs with complementary sequences. miRNA-mRNA interactions allow for cellular flexibility to fine-tune gene expression by controlling translation in response to a multitude of signaling events. Disease states or perturbations in cellular homeostasis can lead to aberrant miRNA expression. The discovery of stable miRNAs in circulation generated enormous interest in exploring their utility as potential noninvasive biomarkers. Additionally, selectively inhibiting or supplementing an miRNA contributing to pathogenesis is being pursued as a therapeutic strategy for a variety of disorders. Studies from rodent models of pain and patients have now implicated a role for miRNAs in mediating various aspects of pain processing. These noncoding RNAs can provide mechanistic insights into the pathways modulated and could serve as therapeutic targets. Here, we discuss the challenges associated with miRNA research and the promises ahead in this vastly unexplored avenue in pain biology. PMID- 25744676 TI - Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain. AB - Damage-associated molecular pattern molecules (DAMPs) are endogenous molecules that are constitutively expressed and released upon tissue damage, resulting in activation of the immune system. In the absence of injury or infection, DAMPs play important intracellular roles. However, once released subsequent to cell damage or cell stress, DAMPs promote activation of innate immune cells and recruitment and activation of antigen-presenting cells engaged in host defense and tissue repair. This process involves pattern recognition receptors, such as the Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE). Several of the TLRs and RAGE have been implicated to play key roles not only in the detection of injury but also in pain signaling. Pain-like behavior is reduced in TLR2- and TLR4-deficient mice, and after injection of TLR2-, TLR4-, and RAGE antagonists in experimental models of nerve injury, arthritis, and bone cancer pain. This suggests that the pathological processes in these models are associated with release of endogenous TLR and RAGE ligands, and further that DAMPs play an important role in persistent pain. There is now a rapidly growing list of DAMPs in the literature and here we give an overview of DAMPs that have been associated with nociceptive signaling. PMID- 25744677 TI - mGluRs head to toe in pain. AB - Metabotropic glutamate receptors (mGluRs) and their role in modulating pain throughout the peripheral and central nervous system are the focus of this chapter. Because these receptors are so prolifically involved in pain signaling throughout the neuraxis, we will use them as a vehicle to explore the totality of the neuraxis. These diverse receptors can increase or decrease pain depending on the subtype of receptor involved and anatomical location of activity. We will cover the basic molecular structure and function of mGluRs and then evaluate the role of different mGluRs at each level of the pain neuraxis. Similar to the functional anatomy involved in the processing of exogenous noxious stimuli, we will start from the peripheral nociceptive terminal and end in higher brain centers that are involved in the cognitive and emotional components of pain. We will conclude by examining the cutting-edge technology involved in the development of mGluR agents for the treatment of pain. PMID- 25744678 TI - Nonneuronal central mechanisms of pain: glia and immune response. AB - The role of central glial cells in the mechanisms underlying pain has been intensively studied in the last two decades. Most studies on glia and pain focused on the potential detrimental role of glial cells following noxious stimulus/insults manifested as an "activation" or a "reactive" state (increase in glial marker expression and production of proinflammatory/nociceptive molecules). Therefore, "activated" or "reactive" glial cells became a target for the future generation of drugs to treat chronic pain. Several glial modulators that reduce the activation of glial cells have shown great efficacy in multiple animal (rodents mostly) models of pain (acute, subacute, chronic, inflammatory, neuropathic, surgical, etc.). These encouraging findings inspired clinical trials that have been completed in the last 5 years. Unfortunately, all clinical trials with these glial modulators have failed to demonstrate efficacy for the treatment of pain. New lines of investigation and elegant experimental designs are shedding light on alternative glial functions, which demonstrate that "glial reactivity" is not necessarily deleterious in some pathological conditions. New strategies to validate findings through our current animal models are necessary to enhance the translational value of our preclinical studies. Also, more studies using human subjects would enhance our understanding of glial cells in the context of pain. This chapter explores the available literature to objectively ponder the potential role of glial cells in human pain conditions. PMID- 25744679 TI - Synaptic inhibition and disinhibition in the spinal dorsal horn. AB - Nociceptive signals originating in the periphery must be transmitted to the brain to evoke pain. Rather than being conveyed unchanged, those signals undergo extensive processing in the spinal dorsal horn. Synaptic inhibition plays a crucial role in that processing. On the one hand, neuropathy and inflammation are associated with reduced spinal inhibition; on the other hand, the hypersensitivity associated with inflammatory and neuropathic pain can be reproduced by blocking inhibition at the spinal level. To understand the consequences of disinhibition and how to therapeutically reverse it, one must understand how synaptic inhibition normally operates. To that end, this chapter will discuss the structure and function of GABAA and glycine receptors together with the role of associated molecules involved in transmitter handling and chloride regulation. Mechanisms by which inhibition modulates cellular excitability will be described. The chapter will end with discussion of how inhibition goes awry under pathological conditions and what the implications are for the treatment of resulting pain. PMID- 25744680 TI - Dendritic spine dysgenesis in neuropathic pain. AB - The failure of neuropathic pain to abate even years after trauma suggests that adverse changes to synaptic function must exist in a chronic pathological state in nociceptive pathways. The chronicity of neuropathic pain therefore underscores the importance of understanding the contribution of dendritic spines--micron sized postsynaptic structures that represent modifiable sites of synaptic contact. Historically, dendritic spines have been of great interest to the learning and memory field. More recent evidence points to the exciting implication that abnormal dendritic spine structure following disease or injury may represent a "molecular memory" for maintaining chronic pain. Dendritic spine dysgenesis in dorsal horn neurons contributes to nociceptive hyperexcitability associated with neuropathic pain, as demonstrated in multiple pain models, i.e., spinal cord injury, peripheral nerve injury, diabetic neuropathy, and thermal burn injury. Because of the relationship between dendritic spine structure and neuronal function, a thorough investigation of dendritic spine behavior in the spinal cord is a unique opportunity to better understand the mechanisms of sensory dysfunction after injury or disease. At a conceptual level, a spinal memory mechanism that engages dendritic spine remodeling would also contribute to a broad range of intractable neurological conditions. Molecules involved in regulating dendritic spine plasticity may offer novel targets for the development of effective and durable therapies for neurological disease. PMID- 25744682 TI - Dietary influence on pain via the immune system. AB - Obesity rates are approaching epidemic proportions and are a significant factor in annual health care costs. In addition to cardiovascular comorbidities, the presence of diabetes and/or chronic pain is extremely high in this population of individuals. It is now well accepted that the cells of the innate (and adaptive) immune system mediate both acute and chronic pain through release of cytokines into the system. In this chapter, we outline the ways in which poor food choices and elevated adipose tissue (body fat) are likely to activate the immune system and increase inflammation and pain. In addition, we explore the ways in which a variety of foods (e.g., broccoli, ginger, grapes, and fish oils) may have anti inflammatory effects via their direct action on cells in the immune system and on the subsequent release of inflammatory cytokines. Some foods (green tea, ginger, and broccoli) have been found to antagonize specific cell surface receptors, whereas others (grapes, soy proteins, tomatoes and ginseng) appear to reduce nuclear translocation of the major transcription factor NFkappaB, thereby reducing production of inflammatory cytokines. Together, we provide data in support of the use of diet interventions to reduce pain and inflammation in patients suffering from chronic pain or other inflammation-mediated disorders. PMID- 25744683 TI - Chemotherapy-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is common in patients receiving anticancer treatment and can affect survivability and long-term quality of life of the patient following treatment. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, thermal information, and pain. There is currently a paucity of pharmacological agents to prevent or treat CIPN. The lack of efficacious therapeutics is due, at least in part, to an incomplete understanding of the mechanisms by which chemotherapies alter the sensitivity of sensory neurons. Although the clinical presentation of CIPN can be similar with the various classes of chemotherapeutic agents, there are subtle differences, suggesting that each class of drugs might induce neuropathy via different mechanisms. Multiple mechanisms have been proposed to underlie the development and maintenance of neuropathy; however, most pharmacological agents generated from preclinical experiments have failed to alleviate the symptoms of CIPN in the clinic. Further research is necessary to identify the specific mechanisms by which each class of chemotherapeutics induces neuropathy. PMID- 25744681 TI - Commonalities between pain and memory mechanisms and their meaning for understanding chronic pain. AB - Pain sensing neurons in the periphery (called nociceptors) and the central neurons that receive their projections show remarkable plasticity following injury. This plasticity results in amplification of pain signaling that is now understood to be crucial for the recovery and survival of organisms following injury. These same plasticity mechanisms may drive a transition to a nonadaptive chronic pain state if they fail to resolve following the termination of the healing process. Remarkable advances have been achieved in the past two decades in understanding the molecular mechanisms that underlie pain plasticity following injury. The mechanisms bear a striking resemblance to molecular mechanisms involved in learning and memory processes in other brain regions, including the hippocampus and cerebral cortex. Here those mechanisms, their commonalities and subtle differences, will be highlighted and their role in causing chronic pain will be discussed. Arising from these data is the striking argument that chronic pain is a disease of the nervous system, which distinguishes this phenomena from acute pain that is frequently a symptom alerting the organism to injury. This argument has important implications for the development of disease modifying therapeutics. PMID- 25744684 TI - Stress and chronic pelvic pain. AB - Chronic pelvic pain is the number one reason that patients suffering from irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, vulvodynia, or chronic prostatitis/chronic pelvic pain syndrome seek medical attention. These syndromes generally have no associated pathology or identified underlying etiology, although dysfunction within the immune system, central nervous system, and peripheral nervous system has been identified. Due to the lack of pathology, chronic pelvic pain syndromes are often diagnosed by exclusion, and the high degree of comorbid symptomology among these and other functional pain disorders complicate identifying appropriate treatment strategies. Chronic stress exposure early in life has been shown to increase the likelihood of pelvic pain later in life, and acute stress exposure can induce or increase symptom severity. In this chapter, we describe the individual chronic pelvic pain syndromes and how stress influences the likelihood of diagnosis and the severity of symptoms experienced by patients. PMID- 25744685 TI - Meningeal afferent signaling and the pathophysiology of migraine. AB - Migraine is the most common neurological disorder. Attacks are complex and consist of multiple phases but are most commonly characterized by intense, unilateral, throbbing headache. The pathophysiology contributing to migraine is poorly understood and the disorder is not well managed with currently available therapeutics, often rendering patients disabled during attacks. The mechanisms most likely to contribute to the pain phase of migraine require activation of trigeminal afferent signaling from the cranial meninges and subsequent relay of nociceptive information into the central nervous system in a region of the dorsal brainstem known as the trigeminal nucleus caudalis. Events leading to activation of meningeal afferents are unclear, but nerve endings within this tissue are mechanosensitive and also express a variety of ion channels including acid sensing ion channels and transient receptor-potential channels. These properties may provide clues into the pathophysiology of migraine by suggesting that decreased extracellular pH and environmental irritant exposure in the meninges contributes to headache. Neuroplasticity is also likely to play a role in migraine given that attacks are triggered by routine events that are typically nonnoxious in healthy patients and clear evidence of sensitization occurs during an attack. Where and how plasticity develops is also not clear but may include events directly on the afferents and/or within the TNC. Among the mediators potentially contributing to plasticity, calcitonin gene-related peptide has received the most attention within the migraine field but other mechanisms may also contribute. Ultimately, greater understanding of the molecules and mechanisms contributing to migraine will undoubtedly lead to better therapeutics and relief for the large number of patients across the globe who suffer from this highly disabling neurological disorder. PMID- 25744686 TI - Chronic pain syndromes, mechanisms, and current treatments. AB - Although acute pain is a physiological response warning the human body of possible harm, chronic pain can be a pathological state associated with various diseases or a disease in itself. In the United States alone, around one-third of the population has experienced a chronic pain condition and annual cost to the society is in the range of 500-600 billion dollars.(1) It should be noted that if at all this is a very modest estimate, it surpasses the costs associated with cancer, heart disease, and diabetes combined.(1) Unfortunately, despite these humongous costs, the treatment of chronic pain is inadequate.(1) Chronic pain affects individuals in a variety of forms, and below we highlight some of the most common chronic pain conditions seen in a pain clinic. Most of these disorders are difficult to treat and typically require multimodal therapy including pharmacotherapy, behavioral modification, and targeted interventions. We have summarized the scope of each disorder, clinical features, proposed mechanisms, and current therapies for them (Table 1). PMID- 25744687 TI - This volume is not meant to be comprehensive, not by any stretch of the imagination, but it is meant to be exciting and new. Preface. PMID- 25744688 TI - Efficacy of biofeedback plus transanal stimulation in the management of pelvic floor dyssynergia: a randomized trial. AB - BACKGROUND: The therapy of pelvic floor dyssynergia is mostly conservative and is based on a high-fiber diet, physical activity and biofeedback training. Our aim was to compare the outcome of biofeedback (manometric-assisted pelvic relaxation and simulated defecation training) plus transanal electrostimulation with standard therapy (diet, exercise, laxatives). METHODS: Clinical, physiologic and quality of life [patient assessment of constipation quality of life (PAC-QOL)] measures, anorectal manometry and balloon expulsion test results were collected prospectively at baseline, at the end of the treatment and 6 months after treatment. Primary outcome was the modification of the Wexner score for defecation (WS) and the obstructed defecation score (ODS). Secondary outcomes were the modifications of anorectal manometry pattern and quality of life after treatment. RESULTS: The mean WS and ODS decreased significantly in the EMG biofeedback group: The WS decreased from 16.7 +/- 4 to 10 +/- 3.5 p < 0.0102, and the ODS decreased from 18.3 +/- 5.5 to 5.7 +/- 1.8, p < 0.0001. Besides, WS and ODS did not change significantly in the control group. The PAC-QOL score improved significantly from 61 +/- 8.6 to 23 +/- 4.8 (p < 0.0001) in the EMG biofeedback group; otherwise, the PAC-QOL score did not change significantly in the control group. CONCLUSIONS: Biofeedback therapy plus transanal electrostimulation provided sustained improvement in bowel symptoms and anorectal function in constipated subjects with dyssynergic defecation, whereas standard therapy was largely ineffective. PMID- 25744689 TI - Effect of HSA coated iron oxide labeling on human umbilical cord derived mesenchymal stem cells. AB - Human umbilical cord derived mesenchymal stem cells (hUC-MSCs) are known for self renewal and differentiation into cells of various lineages like bone, cartilage and fat. They have been used in biomedical applications to treat degenerative disorders. However, to exploit the therapeutic potential of stem cells, there is a requirement of sensitive non-invasive imaging techniques which will offer the ability to track transplanted cells, bio-distribution, proliferation and differentiation. In this study, we have analyzed the efficacy of human serum albumin coated iron oxide nanoparticles (HSA-IONPs) on the differentiation of hUC MSCs. The colloidal stability of the HSA-IONPs was tested over a long period of time (>=20 months) and the optimized concentration of HSA-IONPs for labeling the stem cells was 60 MUg ml(-1). Detailed in vitro assays have been performed to ascertain the effect of the nanoparticles (NPs) on stem cells. Lactate dehydrogenase (LDH) assay showed minimum release of LDH depicting the least disruptions in cellular membrane. At the same time, mitochondrial impairment of the cells was also not observed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Flow cytometry analysis revealed lesser generation of reactive oxygen species in HSA-IONPs labeled hUC-MSCs in comparison to bare and commercial IONPs. Transmission electron microscopy showed endocytic engulfment of the NPs by the hUC-MSCs. During the process, the gross morphologies of the actin cytoskeleton were found to be intact as shown by immunofluorescence microscopy. Also, the engulfment of the HSA-IONPs did not show any detrimental effect on the differentiation potential of the stem cells into adipocytes, osteocytes and chondrocytes, thereby confirming that the inherent properties of stem cells were maintained. PMID- 25744691 TI - A novel mechanism for small heat shock proteins to function as molecular chaperones. AB - Small heat shock proteins (sHSPs) are molecular chaperones ubiquitously present in all forms of life, but their function mechanisms remain controversial. Here we show by cryo-electron microscopy and single particle 3D reconstruction that, at the low temperatures (4-25 degrees C), CeHSP17 (a sHSP from Caenorhabditis elegans) exists as a 24-subunit spherical oligomer with tetrahedral symmetry. Our studies demonstrate that CeHSP17 forms large sheet-like super-molecular assemblies (SMAs) at the high temperatures (45-60 degrees C), and such SMAs are apparently the form that exhibits chaperone-like activity. Our findings suggest a novel molecular mechanism for sHSPs to function as molecular chaperones. PMID- 25744692 TI - How motivated are patients with type 2 diabetes to change their lifestyle? A survey among patients and healthcare professionals. AB - AIM: It is unknown to what extend patients with type 2 diabetes mellitus (T2DM) in primary care are motivated to change their lifestyle. We assessed the level of motivation to change lifestyle and the agreement for that level between patients and healthcare professionals. METHODS: Patients with T2DM (150) filled in a questionnaire to assess the level of motivation to change their lifestyle, using a single question with three answer options. We investigated the agreement for this level between these patients and their healthcare professionals (12 professionals). In addition, we investigated and compared the level of physical activity as indicated by the patients and the healthcare professionals. RESULTS: A large part of the patients reported to have a deficient physical activity level (35% according to patients, 47% according to healthcare professionals, kappa 0.32) and were not motivated to change their lifestyle level (29% according to patients, 43% according to healthcare professionals, kappa 0.13). Patients tended to overestimate their physical activity and their motivation to change in comparison with their healthcare professionals. CONCLUSIONS: Patients with T2DM in primary care should increase their physical activity level. Healthcare professionals often do not know whether patients are motivated to change their lifestyle, and should therefore assess motivation regularly to optimize lifestyle management. PMID- 25744690 TI - Teaching the fundamentals of electron transfer reactions in mitochondria and the production and detection of reactive oxygen species. AB - Mitochondria fulfill a number of biological functions which inherently depend on ATP and O2(-*)/H2O2 production. Both ATP and O2(-*)/H2O2 are generated by electron transfer reactions. ATP is the product of oxidative phosphorylation whereas O2(-*) is generated by singlet electron reduction of di-oxygen (O2). O2( *) is then rapidly dismutated by superoxide dismutase (SOD) producing H2O2. O2( *)/H2O2 were once viewed as unfortunately by-products of aerobic respiration. This characterization is fitting considering over production of O2(-*)/H2O2 by mitochondria is associated with range of pathological conditions and aging. However, O2(-*)/H2O2 are only dangerous in large quantities. If produced in a controlled fashion and maintained at a low concentration, cells can benefit greatly from the redox properties of O2(-*)/H2O2. Indeed, low rates of O2( *)/H2O2 production are required for intrinsic mitochondrial signaling (e.g. modulation of mitochondrial processes) and communication with the rest of the cell. O2(-*)/H2O2 levels are kept in check by anti-oxidant defense systems that sequester O2(-*)/H2O2 with extreme efficiency. Given the importance of O2( *)/H2O2 in cellular function, it is imperative to consider how mitochondria produce O2(-*)/H2O2 and how O2(-*)/H2O2 genesis is regulated in conjunction with fluctuations in nutritional and redox states. Here, I discuss the fundamentals of electron transfer reactions in mitochondria and emerging knowledge on the 11 potential sources of mitochondrial O2(-*)/H2O2 in tandem with their significance in contributing to overall O2(-*)/H2O2 emission in health and disease. The potential for classifying these different sites in isopotential groups, which is essentially defined by the redox properties of electron donator involved in O2( *)/H2O2 production, as originally suggested by Brand and colleagues is also surveyed in detail. In addition, redox signaling mechanisms that control O2( *)/H2O2 genesis from these sites are discussed. Finally, the current methodologies utilized for measuring O2(-*)/H2O2 in isolated mitochondria, cell culture and in vivo are reviewed. PMID- 25744693 TI - Corrigendum: Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott-Aldrich syndrome-like platelet defect. PMID- 25744694 TI - Three-dimensional Aerographite-GaN hybrid networks: single step fabrication of porous and mechanically flexible materials for multifunctional applications. AB - Three dimensional (3D) elastic hybrid networks built from interconnected nano- and microstructure building units, in the form of semiconducting-carbonaceous materials, are potential candidates for advanced technological applications. However, fabrication of these 3D hybrid networks by simple and versatile methods is a challenging task due to the involvement of complex and multiple synthesis processes. In this paper, we demonstrate the growth of Aerographite-GaN 3D hybrid networks using ultralight and extremely porous carbon based Aerographite material as templates by a single step hydride vapor phase epitaxy process. The GaN nano- and microstructures grow on the surface of Aerographite tubes and follow the network architecture of the Aerographite template without agglomeration. The synthesized 3D networks are integrated with the properties from both, i.e., nanoscale GaN structures and Aerographite in the form of flexible and semiconducting composites which could be exploited as next generation materials for electronic, photonic, and sensors applications. PMID- 25744695 TI - Investigating the requirement for calcium during lactococcal phage infection. AB - Calcium is widely used in the study and successful propagation of virulent bacteriophages infecting lactic acid bacteria; however, it has not been assessed if and why this divalent cation is required for the infection process. Lactococcal phages are a persistent problem in the calcium-rich dairy environment and therefore were used as the model for this study. Using representative members of nine of the currently recognized ten lactococcal phage groups, encompassing phages of the Podoviridae and Siphoviridae families, we present data to suggest that calcium is not an explicit requirement for many of these phages. However, calcium expedited the pace of the lytic cycle for certain phages. Additionally, for calcium-dependent phages belonging to the 936 siphogroup, we could substitute this cation with magnesium or manganese, indicating that these phages are more adaptable than lactococcal phages of other groups. We postulate that the ability of phages to adapt to their environment and to harness the available mineral content may ultimately decide the success of a given phage infection. This may explain, in part, why 936 phages are one of the most frequently isolated phages in the dairy industry. PMID- 25744696 TI - Hygiene and health risks associated with the consumption of edible lamellibranch molluscs. AB - Edible lamellibranch molluscs are frequently the cause of very serious outbreaks of food poisoning. Microbiological suitability for human consumption, according to EC Reg. n. 1441/2007, is only based on two faecal bacteriological contamination parameters (Escherichia coli and Salmonella) and does not consider other microorganisms which are naturally present within the marine environment and are potentially pathogenic such as those belonging to the genus Vibrio. In this study, a total of 540 samples of edible lamellibranch molluscs (mussels, clams and oysters) bred in Sardinia were analyzed for E. coli and Salmonella, according to EC Reg n. 1441/2005, and for the presence of Vibrios of major public health interest. Environmental parameters (seawater temperature and salinity) were also recorded. The 40% (n=216) of samples were positive for Vibrio while the levels of E. coli were above the legal European limit only in 6.4% of samples. A correlation between the presence of micro-organisms of faecal origin and potentially harmful Vibrios to human health was not observed. Vibrio alginolyticus was the most common in 68% of isolated species, followed by Vibrio parahaemolyticus in 22.6%, Vibrio cholerae in 6% and Vibrio vulnificus in 1.1%. Virulence gene (trh sequence) was present in 1.6% of the V. parahaemolyticus positive samples. The V. cholerae, V. vulnificus and V. alginolyticus strains detected were non toxigenic. The absence of genes encoding major virulence factors in the studied strains does not exclude the possibility of exposure to pathogenic strains. This study indicates the potential health risk associated with the presence of pathogenic Vibrios in edible lamellibranch molluscs bred in Sardinia, where shellfish production is very important to the local economy. PMID- 25744697 TI - Validation of the ICD-9-CM code for systemic sclerosis using updated ACR/EULAR classification criteria. PMID- 25744698 TI - Validation of the Korean version of the Connor-Davidson Resilience Scale-2 in firefighters and rescue workers. AB - OBJECTIVE: Resilience has been considered as a protective factor against stress. Evaluating resilience in firefighters and rescue workers, who are frequently exposed to traumatic events, is important and relevant. This study examined the psychometric properties of the Korean version of the Connor-Davidson Resilience Scale-2 (CD-RISC2). METHODS: Two-hundred twenty-two current professional firefighters and rescue workers were assessed by standardized, semi-structured clinical interviews and self-report questionnaires. Internal consistency, correlation with the CD-RISC, convergent validity, divergent validity, and predictive validity of posttraumatic stress disorder (PTSD) symptom severity were analyzed. RESULTS: The CD-RISC2 demonstrated good internal consistency (alpha=0.75), item-total correlation (r=0.89-0.90), and convergent and divergent validity. The total score of the CD-RISC2 showed significant correlations with the subtotal of the remaining 23 CD-RISC items (r=0.77, p<0.001) and with the score of each CD-RISC item (r=0.15-0.66, all p<0.05). The magnitude of the relationship between the number of traumatic experiences and PTSD symptom severity was greater in the low resilience group than in the high resilience group (p for interaction=0.002). The likelihood-ratio test confirmed that the model predicting PTSD symptom severity based on the CD-RISC2 total score was not improved by the inclusion of subtotal scores of the remaining 23 CD-RISC items (chi(2)=0.31, p=0.58). CONCLUSIONS: These results suggest that the CD-RISC2 would be a valuable tool in evaluating resilience quickly and efficiently in firefighters and rescue workers. PMID- 25744699 TI - Feasibility and Preliminary Responses to a Screening and Brief Intervention Program for Maternal Mental Disorders Within the Context of Primary Care. AB - There is little evidence of the feasibility and acceptability of integrating screening, brief intervention and referral to treatment services that address depression and alcohol, tobacco and other drug (ATOD) use into antenatal care in South Africa. Data were extracted from program records on the number of eligible women screened and number meeting criteria for depression and self-reported ATOD use. 70 women completed a questionnaire examining their preliminary responses and five MOU personnel were interviewed to identify potential barriers to implementation. Of the 3407 eligible women, 1468 (43 %) women were screened for depression or ATOD use, of whom 302 (21.4 %) screened at risk for depression, 388 (26.4 %) disclosed smoking tobacco, and 29 (2 %) disclosed alcohol or other drugs (AOD). Seventy participants completed the three month follow-up interview. Depression scores decreased significantly following the intervention (t (69) = 8.51, p < 0.001) as did self-reported tobacco use (t (73) = 3.45, p < 0.001), however self-reported AOD use remained unchanged. PMID- 25744701 TI - Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact? AB - With the discovery that vitamin K-dependent matrix Gla-protein (MGP) is a strong and modifiable factor in the prevention of arterial calcification, vitamin K was put forward as novel treatment option in cardiovascular disease. The vasculoprotective properties of vitamin K are in part based on the ability to improve gamma-glutamylcarboxylation of MGP, which is a prerequisite for MGP as a calcification inhibitor. Data from experimental animal models reveal that high intake of vitamin K can prevent and even reverse vascular calcifications. In addition, clinical data demonstrate that prescription of vitamin K antagonists for long-term oral anticoagulant therapy accelerates vascular calcification. However, controlled data from randomized prospective vitamin K interventional trials are lacking, thereby weakening a general recommendation for supplementation. The present article summarizes our current knowledge on the association between vitamin K and cardiovascular health. Additionally, we focus on an outlook on important ongoing prospective vitamin K intervention studies. These studies address the issues whether vitamin K substitution helps modifying relevant cardiovascular surrogates such as vascular calcification and whether non vitamin K oral anticoagulants provide an alternative to support cardiovascular health benefits. So research about cardiovascular protection by vitamin K is an evolving field in which we expect a boost of novel and relevant evidence shortly. PMID- 25744700 TI - P-selectin and subclinical and clinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: P-selectin is a cellular adhesion molecule that has been shown to be crucial in development of coronary heart disease (CHD). We sought to determine the role of P-selectin on the risk of atherosclerosis in a large multi-ethnic population. METHODS: Data from the Multi-Ethnic Study of Atherosclerosis (MESA), including 1628 African, 702 Chinese, 2393 non-Hispanic white, and 1302 Hispanic Americans, were used to investigate the association of plasma P-selectin with CHD risk factors, coronary artery calcium (CAC), intima-media thickness, and CHD. Regression models were used to investigate the association between P-selectin and risk factors, Tobit model for CAC, and Cox regression for CHD events. RESULTS: Mean levels of P-selectin differed by ethnicity and were higher in men (P<0.001). For all ethnic groups, P-selectin was positively associated with measures of adiposity, blood pressure, current smoking, LDL, and triglycerides and inversely with HDL. A significant ethnic interaction was observed for the association of P selectin and prevalent diabetes; however, P-selectin was positively associated with HbA1c in all groups. Higher P-selectin levels were associated with greater prevalence of CAC. Over 10.1 years of follow-up, there were 335 incident CHD events. There was a positive linear association between P-selectin levels and rate of incident CHD after adjustment for traditional risk factors. However, association was only significant in non-Hispanic white Americans (HR: 1.81, 95% CI 1.07 to 3.07, P=0.027). CONCLUSION: We observed ethnic heterogeneity in the association of P-selectin and risk of CHD. PMID- 25744704 TI - Lovastatin-producing endophytic fungus isolated from a medicinal plant Solanum xanthocarpum. AB - Lovastatin is a potent drug for lowering blood cholesterol. An endophytic fungus Phomopsis vexans was isolated from the healthy leaf tissues of Solanum xanthocarpum, a medicinal plant, and screened for lovastatin production. The fungus was identified by their characteristic cultural morphology and molecular analysis. The strain had a component with the same TLC Rf value and HPLC retention time as authentic lovastatin. The presence of lovastatin was further confirmed by FT-IR, UV, (1)H, (13)C NMR and LC-MS analyses. The amount of lovastatin produced by this endophytic fungus was quantified to be 550 mg/L, and thus the fungus can serve as a potential material to improve the production of lovastatin. PMID- 25744702 TI - Serum soluble RAGE levels and carotid atherosclerosis: the Northern Manhattan Study (NOMAS). AB - BACKGROUND: Recent cohort studies suggested that serum levels of soluble Receptor for Advanced Glycation End-products (sRAGE) are associated with the risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical atherosclerosis in a racially and ethnically diverse population. METHODS AND RESULTS: 828 stroke-free participants from the Northern Manhattan Study (mean age 71.1+/-8.7yrs; 64% Hispanic, 19% black, and 17% white) underwent high-resolution carotid B-mode ultrasound to measure carotid plaque (present in 62% of subjects) and intima-media thickness (IMT) (mean Total=0.96+/-0.10 mm). Serum sRAGE was measured by ELISA and associations tested between sRAGE with IMT and plaque presence. Soluble RAGE levels were not associated with plaque presence or IMT after adjusting for sociodemographic, vascular risk factors and medication use. Stratification by race-ethnicity did not reveal any associations with carotid IMT or plaque. CONCLUSION: In the present study, sRAGE levels were not associated with carotid atherosclerosis. PMID- 25744703 TI - Bone imaging and fracture risk assessment in kidney disease. AB - Fractures are more common and are associated with greater morbidity and morality in patients with kidney disease than in members of the general population. Thus, it is troubling that in chronic kidney disease (CKD) patients there has been a paradoxical increase in fracture rates over the past 20 years compared to the general population. Increased fracture incidence in CKD patients may be driven in part by the lack of screening for fracture risk. In the general population, dual energy X-ray absorptiometry (DXA) is the clinical standard to stratify fracture risk, and its use has contributed to decreases in fracture incidence. In contrast, in CKD, fracture risk screening with DXA has been uncommon due to its unclear efficacy in predicting fracture and its inability to predict type of renal osteodystrophy. Recently, several prospective studies conducted in patients across the spectrum of kidney disease have demonstrated that bone mineral density measured by DXA predicts future fracture risk and that clinically relevant information regarding fracture risk is provided by application of the World Health Organization cutoffs for osteopenia and osteoporosis to DXA measures. Furthermore, novel high-resolution imaging tools, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have been used to elucidate the effects of kidney disease on cortical and trabecular microarchitecture and bone strength and to identify potential targets for strategies that protect against fractures. This review will discuss the updated epidemiology of fractures in CKD, fracture risk screening by DXA, and the utility of state-of-the art imaging methods to uncover the effects of kidney disease on the skeleton. PMID- 25744705 TI - [Surgical treatment of rectourinary fistulas: review of the literature]. AB - BACKGROUND: A rectourethral fistula (RUF) is an uncommon complication resulting from surgery, radiation, or trauma. Retrospective studies and case reports have highlighted different approaches for surgical repair. OBJECTIVE: The aim of this study was to review our experience with surgical management of RUF. DATA SOURCES: MEDLINE (PubMed, Ovid) and the Cochrane Library were searched by using the terms RUFs urethrorectal fistulas, and prostatourethral-rectal fistulas. STUDY SELECTION: All studies were retrospective and in English. Of the records identified, 31 series were included. RESULTS: Four hundred sixty-five patients were identified. Most patients underwent one of four categories of repair: transanal (4.7%), transabdominal (14.1%), transsphincteric (26.6%), and transperineal (57.6%). Tissue interposition flaps, predominantly gracilis muscle, were used in 56% of repairs. The fistula was successfully closed in 93.9% of patients. CONCLUSIONS: Regardless of complexity, RUFs have an initial closure rate of 93.9%. PMID- 25744706 TI - [Clinical practice and adherence to the diagnosis and treatment of NMIBC guidelines: a report of a recognition based clinical cases study]. AB - For non-muscle invasive bladder cancer, a disease with a considerable epidemiological and socio-economic impact, the introduction of the Guidelines has always evoked as a tool for the resolution of long-standing disputes in terms of diagnosis and therapy. Check the degree of routine clinical practice adherence to the Recommendations is for this disease, more than for other uro-oncology pathology, an urgent need felt by the urological community. To assess the level of Guidelines adherence's, and study issues related to the paths of diagnosis and treatment of non-muscle invasive bladder cancer, and identifying the processes actually implemented in daily clinical practice, a series of case studies has submitted to a group of experts. The acknowledgement study allowed testing the impact of the current Evidence Based Medicine Recommendations in the everyday clinical practice identifying strengths and weaknesses. Questions Responses Analysis' of 5 clinical cases (Ta low grade, T1 low grade, T1 high grade, T1 high grade + CIS, Ta low-grade multiple recurrence) showed a moderate amendment to the European Association of Urology (EAU)-Guidelines. On the other hand, it was emphasized that there are clear discrepancies between what should be done, in accordance with the Evidence Based Medicine Recommendations, and what is actually do in everyday clinical practice. The most common reason for the low Recommendations adherences are structural and organizational practical limitations. PMID- 25744707 TI - Clinical efficacy and safety of Vitaros(c)/Virirec(c) (Alprostadil cream) for the treatment of erectile dysfunction. AB - Erectile dysfunction (ED) is a very common disorder with a deep impact on patients and their partners. Several options are now available for treating ED; oral pharmacotherapy with phosphodiesterase-5 (PDE5) inhibitors currently represents the first-line option for many ED patients. Vitaros(c)/Virirec(c) is new topical, non-invasive treatment for ED that offers the combination of an active drug (alprostadil, a synthetic PGE1) with a skin enhancer that improves its local absorption directly at the site of action. Vitaros(c)/Virirec(c) has a favorable pharmacodynamic profile and is poorly absorbed in systemic circulation. This makes it suitable in any circumstances and results in a reduced risk of adverse events (AEs), being systemic AEs reported in only 3% of the treated population. Its clinical efficacy has been demonstrated in both phase II and III trials, showing a global efficacy up to 83% with the 300 MUg dose in patients with severe ED significantly better than placebo. Its fast onset of action together with its favorable toxicity profile and lack of interactions with other drugs makes Vitaros(c)/Virirec(c) a first-line therapeutic option for patients with ED, particularly for individuals who are reluctant to take systemic treatments or with AEs. It may also have an important role in patients not responding to PDE5 inhibitors, particularly those with ED after radical prostatectomy. PMID- 25744708 TI - [Current role of training in robot-assisted urological procedures]. AB - The rapid introduction of robotic procedures necessitates new training methods. Currently, we can estimate that in a considerable proportion of the hospitals in Europe, the criteria for the surgeon's competence before starting with robotic surgery are insufficient. Therefore, the development of structured robotic training programs should be considered as one of the priorities that the urologic community must take into account in the near future. PMID- 25744709 TI - Female genital mutilations: genito-urinary complications and ethical-legal aspects. AB - Many women in the world are still undergoing female genital mutilations (FGMs) even if in almost all the countries, the practice of FGM is illegal. The increase of immigration, particularly from African Countries, to Europe, and Italy too, led to consider this phenomenon with particular attention and skill. All the operators in health services need to know the different types of FGMs and the related complications and the psychological and sexual sequels. Urological complications, in particular, are not rare and the changing anatomy of the external genital apparatus can also make the catheter insertion sometimes difficult. This review analyzes the epidemiology of FGMs, the reasons why the practice is still made, the complications, the ethical, and the principal legal aspects of this practise that must be hopefully early banned. PMID- 25744710 TI - Pd-catalyzed asymmetric allylic amination using easily accessible metallocenyl P,N-ligands. AB - Compared to their C1-symmetric counterparts, planar chiral C2-symmetric metallocenyl P,N-ligands are efficient chiral ligands for Pd-catalyzed asymmetric allylic aminations, providing a number of amination products with high enantioselectivities. A non-C2-symmetric ferrocenyl P,N-ligand (a by-product obtained during the synthesis of the above C2-symmetric species) was also found to be an efficient ligand for asymmetric allylic aminations. A mixed ligand system consisting of both C2- and non-C2-symmetric ferrocene complexes was examined and showed high catalytic activity with the amination products being obtained with excellent enantioselectivities. PMID- 25744711 TI - Which prosthesis is more resistant to vascular graft infection: polytetrafluoroethylene or Omniflow II biosynthetic grafts? AB - PURPOSE: The aim of this study was to determine whether polytetrafluoroethylene grafts or Omniflow II biosynthetic grafts are more resistant to infection caused by Staphylococcus aureus. METHODS: Sixty rats were divided into six groups. In Groups 1A, 1B and 1C, a polytetrafluoroethylene graft was implanted in each rat, and, in Groups 2A, 2B and 2C, a biosynthetic graft was implanted in each rat. Staphylococcus aureus was inoculated into Groups 1B, 1C, 2B and 2C, and the rats in Groups 1C and 2C were treated with teicoplanin. One week later, the rats were euthanized, the grafts were removed and a microbiological count was performed. A histopathological examination was subsequently carried out, and the C-reactive protein, prealbumin and leukocyte levels were investigated. RESULTS: There were no significant differences in the C-reactive protein, prealbumin and leukocyte levels. The differences in the results of the microbiological evaluations between the groups were significant. The quantitative culture results showed no bacterial growth in Groups 1A, 1C and 2A. The number of bacteria in Group 1B was statistically lower than that in Group 2B. When the groups receiving treatment were compared, Group 2C had bacterial growth, whereas Group 1C did not. The histopathological examinations showed similar results. CONCLUSIONS: Omniflow II grafts are more susceptible to infection than polytetrafluoroethylene grafts. PMID- 25744712 TI - The prevalence, correlates and reasons for using electronic cigarettes among New Zealand adults. AB - INTRODUCTION: There is strong interest in the use of electronic cigarettes (e cigarettes) globally. This paper is the first to report population-based data on ever-use and current use of e-cigarettes among New Zealand adults. The paper also extends previous international studies by exploring the reasons for trying e cigarettes, ever users' recall of brand(s) they have ever tried, and current users' recall of their current brand. METHODS: The Health and Lifestyles Survey (HLS) is a biennial face-to-face in-house survey of New Zealand adults aged 15 years or over. In 2014, 2594 participants completed the survey. RESULTS: Ever-use and current use of e-cigarettes were 13.1% and 0.8% respectively. Tobacco smoking status predicted the use of e-cigarettes, with current smokers reporting the highest rate of use (50% ever-use and 4% current use). Among current smokers who had tried an e-cigarette, curiosity (49%) and desire to quit smoking (37%) were the most common reasons for trying. About half of the ever-users could not name any of the brand(s) they had ever tried, and one-fifth of current users could not name their current brand. CONCLUSIONS: Compared with other countries, New Zealand has a high rate of ever-use. Among current smokers, one in two had tried an e cigarette. However, progression to regular use appears to be rare. The finding that 18% of current e-cigarette users could not name their current brand highlights the importance of investigating users' knowledge of e-cigarettes in general and assessing the factors that influence brand choice such as advertising, price, and accessibility. PMID- 25744713 TI - Young adults who mix alcohol with energy drinks: typology of risk-taking behaviour. AB - INTRODUCTION: Contrary to predictions, several studies have shown that people who consume alcohol mixed with energy drinks (AmED) display low odds of risk-taking during AmED versus alcohol drinking sessions. However, these results are based on treating AmED consumers as a homogeneous group. The aim of the present study was to determine typologies of AmED risk-taking behaviour amongst consumers, as well as identifying correlates of AmED risk-taking class membership. METHODS: AmED consumers (N=403) completed an online survey where they reported whether they had engaged in risk behaviours in the preceding six months during AmED and alcohol drinking sessions. Latent class models were estimated based on AmED risk-taking data; univariate multinomial logistic regression was conducted to determine correlates of class membership. RESULTS: A 3-class model was selected based on fit and parsimony, identifying: 1) Low risk-taking consumers (38%): low probability of any AmED risk behaviours; 2) disinhibited intake consumers (48%): high probability of drinking and spending more than intended; and 3) high risk taking consumers (14%): high probability of most AmED risk behaviours assessed. The latter two groups had significantly higher odds of being male and reporting hazardous alcohol use, more frequent AmED use, greater alcohol and ED intake in AmED sessions, and higher trait impulsivity scores. The latter two groups also reported significantly greater odds of risk-taking behaviours regardless of whether consuming alcohol only or AmED. CONCLUSIONS: AmED consumers are not a homogeneous group in regard to their risk-taking behaviours post-consumption. High likelihood of risk-taking behaviour in AmED sessions, as well as elevated risk-taking in alcohol drinking sessions, highlights the need for targeted harm minimisation policies and programmes for a significant minority of consumers. PMID- 25744714 TI - Donepezil attenuates Abeta-associated mitochondrial dysfunction and reduces mitochondrial Abeta accumulation in vivo and in vitro. AB - The main purpose of the present study is to investigate the influence of donepezil, a well-known acetylcholinesterase (AChE) inhibitor, on amyloid-beta (Abeta)-associated mitochondrial dysfunction, in order to gain a better understanding of the neuroprotective effects of this clinically used anti Alzheimer's disease (AD) drug. First, our study verifies the ameliorative effects of donepezil on behavioral deficits in both working memory and anxiety in APP/PS1 double transgenic mice, at a time point that AChE is not inhibited. Meanwhile, we demonstrate that donepezil enhances the resistance of brain mitochondria of APP/PS1 mice to the induction of mitochondrial permeability transition (MPT) by calcium ions. Moreover, the level of mitochondrial Abeta in the brain of donepezil-treated APP/PS1 transgenic mice is significantly lower than that of vehicle-treated APP/PS1 mice. Our in vitro study using isolated mitochondria from rat brains, which is expected as an AChE-free subcellular system, further confirms the ameliorative effects of donepezil on oligomeric Abeta1-42 induced mitochondrial swelling and ATP reduction. In addition, donepezil treatment also significantly blocks the Abeta accumulation in the isolated mitochondria. Our study reported for the first time that the protective effects of donepezil against Abeta-associated mitochondrial dysfunction are closely associated with the reduction of Abeta accumulation in the mitochondria. Above observation led us to assume that, besides potent AChE inhibitory effect, other non-cholinergic mechanisms may be involved in the neuroprotective profiles of donepezil. PMID- 25744715 TI - Exploring the potential of algae/bacteria interactions. AB - Algae are primary producers in aquatic ecosystems, where heterotrophic bacteria grow on organics produced by algae and recycle nutrients. Ecological studies have identified the co-occurrence of particular species of algae and bacteria, suggesting the presence of their specific interactions. Algae/bacteria interactions are categorized into nutrient exchange, signal transduction and gene transfer. Studies have examined how these interactions shape aquatic communities and influence geochemical cycles in the natural environment. In parallel, efforts have been made to exploit algae for biotechnology processes, such as water treatment and bioenergy production, where bacteria influence algal activities in various ways. We suggest that better understanding of mechanisms underlying algae/bacteria interactions will facilitate the development of more efficient and/or as-yet-unexploited biotechnology processes. PMID- 25744716 TI - Chaperone Hsp47 Drives Malignant Growth and Invasion by Modulating an ECM Gene Network. AB - The extracellular matrix (ECM) is a determining factor in the tumor microenvironment that restrains or promotes malignant growth. In this report, we show how the molecular chaperone protein Hsp47 functions as a nodal hub in regulating an ECM gene transcription network. A transcription network analysis showed that Hsp47 expression was activated during breast cancer development and progression. Hsp47 silencing reprogrammed human breast cancer cells to form growth-arrested and/or noninvasive structures in 3D cultures, and to limit tumor growth in xenograft assays by reducing deposition of collagen and fibronectin. Coexpression network analysis also showed that levels of microRNA(miR)-29b and 29c were inversely correlated with expression of Hsp47 and ECM network genes in human breast cancer tissues. We found that miR-29 repressed expression of Hsp47 along with multiple ECM network genes. Ectopic expression of miR-29b suppressed malignant phenotypes of breast cancer cells in 3D culture. Clinically, increased expression of Hsp47 and reduced levels of miR-29b and -29c were associated with poor survival outcomes in breast cancer patients. Our results show that Hsp47 is regulated by miR-29 during breast cancer development and progression, and that increased Hsp47 expression promotes cancer progression in part by enhancing deposition of ECM proteins. PMID- 25744717 TI - CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival. AB - CEACAM1 is a widely expressed multifunctional cell-cell adhesion protein reported to serve as a poor prognosis marker in melanoma patients. In this study, we examine the functional and clinical contributions of the four splice isoforms of CEACAM1. Specifically, we present in vitro and in vivo evidence that they affect melanoma progression and immune surveillance in a negative or positive manner that is isoform specific in action. In contrast with isoforms CEACAM1-4S and CEACAM1-4L, expression of isoforms CEACAM1-3S and CEACAM1-3L is induced during disease progression shown to correlate with clinical stage. Unexpectedly, overall survival was prolonged in patients with advanced melanomas expressing CEACAM1-3S. The favorable effects of CEACAM1-3S related to enhanced immunogenicity, which was mediated by cell surface upregulation of NKG2D receptor ligands, thereby sensitizing melanoma cells to lysis by natural killer cells. Conversely, CEACAM1 4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character. Overall, our results define the splice isoform-specific immunomodulatory and cell biologic functions of CEACAM1 in melanoma pathogenesis. PMID- 25744718 TI - CDK4/6 Inhibitor PD 0332991 Sensitizes Acute Myeloid Leukemia to Cytarabine Mediated Cytotoxicity. AB - Cyclin-dependent kinase (CDK)4 and CDK6 are frequently overexpressed or hyperactivated in human cancers. Targeting CDK4/CDK6 in combination with cytotoxic killing therefore represents a rational approach to cancer therapy. By selective inhibition of CDK4/CDK6 with PD 0332991, which leads to early G1 arrest and synchronous S-phase entry upon release of the G1 block, we have developed a novel strategy to prime acute myeloid leukemia (AML) cells for cytotoxic killing by cytarabine (Ara-C). This sensitization is achieved in part through enrichment of S-phase cells, which maximizes the AML populations for Ara-C incorporation into replicating DNA to elicit DNA damage. Moreover, PD 0332991 triggered apoptosis of AML cells through inhibition of the homeobox (HOX)A9 oncogene expression, reducing the transcription of its target PIM1. Reduced PIM1 synthesis attenuates PIM1-mediated phosphorylation of the proapoptotic BAD and activates BAD-dependent apoptosis. In vivo, timely inhibition of CDK4/CDK6 by PD 0332991 and release profoundly suppresses tumor growth in response to reduced doses of Ara-C in a xenograft AML model. Collectively, these data suggest selective and reversible inhibition of CDK4/CDK6 as an effective means to enhance Ara-C killing of AML cells at reduced doses, which has implications for the treatment of elderly AML patients who are unable to tolerate high-dose Ara-C therapy. PMID- 25744719 TI - MDSC and TGFbeta Are Required for Facilitation of Tumor Growth in the Lungs of Mice Exposed to Carbon Nanotubes. AB - During the last decades, changes have been observed in the frequency of different histologic subtypes of lung cancer, one of the most common causes of morbidity and mortality, with a declining proportion of squamous cell carcinomas and an increasing proportion of adenocarcinomas, particularly in developed countries. This suggests the emergence of new etiologic factors and mechanisms, including those defining the lung microenvironment, promoting tumor growth. Assuming that the lung is the main portal of entry for broadly used nanomaterials and their established proinflammatory propensities, we hypothesized that nanomaterials may contribute to changes facilitating tumor growth. Here, we report that an acute exposure to single-walled carbon nanotubes (SWCNT) induces recruitment and accumulation of lung-associated myeloid-derived suppressor cells (MDSC) and MDSC derived production of TGFbeta, resulting in upregulated tumor burden in the lung. The production of TGFbeta by MDSC requires their interaction with both SWCNT and tumor cells. We conclude that pulmonary exposure to SWCNT favors the formation of a niche that supports ingrowth of lung carcinoma in vivo via activation of TGFbeta production by SWCNT-attracted and -presensitized MDSC. PMID- 25744720 TI - Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling. AB - GPRC5A is a G-protein-coupled receptor expressed in lung tissue but repressed in most human lung cancers. Studies in Gprc5a(-/-) mice have established its role as a tumor-suppressor function in this setting, but the basis for its role has been obscure. Here, we report that GPRC5A functions as a negative modulator of EGFR signaling. Mouse tracheal epithelial cells (MTEC) from Gprc5a(-/-) mice exhibited a relative increase in EGFR and downstream STAT3 signaling, whereas GPRC5A expression inhibited EGFR and STAT3 signaling. GPRC5A physically interacted with EGFR through its transmembrane domain, which was required for its EGFR inhibitory activity. Gprc5a(-/-) MTEC were much more susceptible to EGFR inhibitors than wild-type MTEC, suggesting their dependence on EGFR signaling for proliferation and survival. Dysregulated EGFR and STAT3 were identified in the normal epithelia of small and terminal bronchioles as well as tumors of Gprc5a(-/-) mouse lungs. Moreover, in these lungs EGFR inhibitor treatment inhibited EGFR and STAT3 activation along with cell proliferation. Finally, overexpression of ectopic GPRC5A in human non-small cell lung carcinoma cells inhibited both EGF-induced and constitutively activated EGFR signaling. Taken together, our results show how GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling and lung tumorigenesis. Cancer Res; 75(9); 1801-14. (c)2015 AACR. PMID- 25744721 TI - IKKbeta Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis. AB - Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKbeta) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKbeta, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAi mediated silencing of LIN28B or pharmacologic inhibition of IKKbeta was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers. PMID- 25744722 TI - Notch suppresses angiogenesis and progression of hepatic metastases. AB - The Notch pathway plays multiple key roles in tumorigenesis, and its signaling components have therefore aroused great interest as targets for emerging therapies. Here, we show that inhibition of Notch, using a soluble receptor Notch1 decoy, unexpectedly caused a remarkable increase in liver metastases from neuroblastoma and breast cancer cells. Increased liver metastases were also seen after treatment with the gamma-secretase inhibitor PF-03084014. Transgenic mice with heterozygous loss of Notch1 demonstrated a marked increase in hepatic metastases, indicating that Notch1 signaling acts as metastatic suppressor in the liver microenvironment. Inhibition of DLL1/4 with ligand-specific Notch1 decoys increased sprouting of sinusoidal endothelial cells into micrometastases, thereby supporting early metastatic angiogenic growth. Inhibition of tumor-derived JAG1 signaling activated hepatic stellate cells, increasing their recruitment to vasculature of micrometastases, thereby supporting progression to macrometastases. These results demonstrate that inhibition of Notch causes pathologic activation of liver stromal cells, promoting angiogenesis and growth of hepatic metastases. Our findings have potentially serious implications for Notch inhibition therapy. PMID- 25744723 TI - Molecular portraits of epithelial, mesenchymal, and hybrid States in lung adenocarcinoma and their relevance to survival. AB - Epithelial-to-mesenchymal transition (EMT) is a key process associated with tumor progression and metastasis. To define molecular features associated with EMT states, we undertook an integrative approach combining mRNA, miRNA, DNA methylation, and proteomic profiles of 38 cell populations representative of the genomic heterogeneity in lung adenocarcinoma. The resulting data were integrated with functional profiles consisting of cell invasiveness, adhesion, and motility. A subset of cell lines that were readily defined as epithelial or mesenchymal based on their morphology and E-cadherin and vimentin expression elicited distinctive molecular signatures. Other cell populations displayed intermediate/hybrid states of EMT, with mixed epithelial and mesenchymal characteristics. A dominant proteomic feature of aggressive hybrid cell lines was upregulation of cytoskeletal and actin-binding proteins, a signature shared with mesenchymal cell lines. Cytoskeletal reorganization preceded loss of E-cadherin in epithelial cells in which EMT was induced by TGFbeta. A set of transcripts corresponding to the mesenchymal protein signature enriched in cytoskeletal proteins was found to be predictive of survival in independent datasets of lung adenocarcinomas. Our findings point to an association between cytoskeletal and actin-binding proteins, a mesenchymal or hybrid EMT phenotype and invasive properties of lung adenocarcinomas. PMID- 25744724 TI - Claudin-10 is required for relay of left-right patterning cues from Hensen's node to the lateral plate mesoderm. AB - Species-specific symmetry-breaking events at the left-right organizer (LRO) drive an evolutionarily-conserved cascade of gene expression in the lateral plate mesoderm that is required for the asymmetric positioning of organs within the body cavity. The mechanisms underlying the transfer of the left and right laterality information from the LRO to the lateral plate mesoderm are poorly understood. Here, we investigate the role of Claudin-10, a tight junction protein, in facilitating the transfer of left-right identity from the LRO to the lateral plate mesoderm. Claudin-10 is asymmetrically expressed on the right side of the chick LRO, Hensen's node. Gain- and loss-of-function studies demonstrated that right-sided expression of Claudin-10 is essential for normal rightward heart tube looping, the first morphological asymmetry during organogenesis. Manipulation of Claudin-10 expression did not perturb asymmetric gene expression at Hensen's node, but did disrupt asymmetric gene expression in the lateral plate mesoderm. Bilateral expression of Claudin-10 at Hensen's node prevented expression of Nodal, Lefty-2 and Pitx2c in the left lateral plate mesoderm, while morpholino knockdown of Claudin-10 inhibited expression of Snail1 in the right lateral plate mesoderm. We also determined that amino acids that are predicted to affect ion selectivity and protein interactions that bridge Claudin-10 to the actin cytoskeleton were essential for its left-right patterning function. Collectively, our data demonstrate a novel role for Claudin-10 during the transmission of laterality information from Hensen's node to both the left and right sides of the embryo and demonstrate that tight junctions have a critical role during the relay of left-right patterning cues from Hensen's node to the lateral plate mesoderm. PMID- 25744725 TI - More similar than you think: Frog metamorphosis as a model of human perinatal endocrinology. AB - Hormonal control of development during the human perinatal period is critically important and complex with multiple hormones regulating fetal growth, brain development, and organ maturation in preparation for birth. Genetic and environmental perturbations of such hormonal control may cause irreversible morphological and physiological impairments and may also predispose individuals to diseases of adulthood, including diabetes and cardiovascular disease. Endocrine and molecular mechanisms that regulate perinatal development and that underlie the connections between early life events and adult diseases are not well elucidated. Such mechanisms are difficult to study in uterus-enclosed mammalian embryos because of confounding maternal effects. To elucidate mechanisms of developmental endocrinology in the perinatal period, Xenopus laevis the African clawed frog is a valuable vertebrate model. Frogs and humans have identical hormones which peak at birth and metamorphosis, have conserved hormone receptors and mechanisms of gene regulation, and have comparable roles for hormones in many target organs. Study of molecular and endocrine mechanisms of hormone-dependent development in frogs is advantageous because an extended free living larval period followed by metamorphosis (1) is independent of maternal endocrine influence, (2) exhibits dramatic yet conserved developmental effects induced by thyroid and glucocorticoid hormones, and (3) begins at a developmental stage with naturally undetectable hormone levels, thereby facilitating endocrine manipulation and interpretation of results. This review highlights the utility of frog metamorphosis to elucidate molecular and endocrine actions, hormone interactions, and endocrine disruption, especially with respect to thyroid hormone. Knowledge from the frog model is expected to provide fundamental insights to aid medical understanding of endocrine disease, stress, and endocrine disruption affecting the perinatal period in humans. PMID- 25744726 TI - Application of a medial buttress plate may prevent many treatment failures seen after fixation of vertical femoral neck fractures in young adults. AB - Femoral neck fractures in young adults with normal bone are mostly vertically oriented and may have variable amounts of comminution, which result from shearing forces during high-energy trauma. These factors play a role in the high rate of complications after this injury, including nonunion, malunion, failure of fixation, and avascular necrosis. These problems often occur together and inter relate, for example, nonunion or malunion frequently result from fixation failure and varus collapse of the femoral head after reconstruction. The orthopaedic surgeon's goals of obtaining and maintaining anatomic reduction until bony union have been addressed by a number of surgical approaches and fixation constructs, however, complications are still common and no consensus exists on how these problematic fractures may be best treated. For optimal treatment of vertical femoral neck fractures, anatomic reduction must be achieved and fixation must be able to resist the high shear forces across the fracture with hip motion, weight bearing, and muscle tone. Buttress plate fixation is a common method for stabilizing fractures that require resistance to shear forces and stands as one of the basic principles of fracture care. This technique has not been widely applied to this injury pattern. We propose that the concepts of modern fracture care should be applied together for vertical femoral neck fractures in young adults. Specifically, we propose that anatomic reduction and fixation of vertically oriented femoral neck fractures with the addition of a medial buttress plate to resist shearing forces will improve on the historically high rate of complications after these difficult injuries. PMID- 25744727 TI - Prolonged-acting, multi-targeting gallium nanoparticles potently inhibit growth of both HIV and mycobacteria in co-infected human macrophages. AB - Human immunodeficiency virus (HIV) infection and Mycobacterium tuberculosis (TB) are responsible for two of the major global human infectious diseases that result in significant morbidity, mortality and socioeconomic impact. Furthermore, severity and disease prevention of both infections is enhanced by co-infection. Parallel limitations also exist in access to effective drug therapy and the emergence of resistance. Furthermore, drug-drug interactions have proven problematic during treatment of co-incident HIV and TB infections. Thus, improvements in drug access and simplified treatment regimens are needed immediately. One of the key host cells infected by both HIV and TB is the mononuclear phagocyte (MP; monocyte, macrophage and dendritic cell). Therefore, we hypothesized that one way this can be achieved is through drug-targeting by a nanoformulated drug that ideally would be active against both HIV and TB. Accordingly, we validated macrophage targeted long acting (sustained drug release) gallium (Ga) nanoformulation against HIV-mycobacterium co-infection. The multi-targeted Ga nanoparticle agent inhibited growth of both HIV and TB in the macrophage. The Ga nanoparticles reduced the growth of mycobacterium and HIV for up to 15 days following single drug loading. These results provide a potential new approach to treat HIV-TB co-infection that could eventually lead to improved clinical outcomes. PMID- 25744728 TI - Tyrosine kinase-2 gene polymorphisms are associated with ulcerative colitis and Crohn's disease in Turkish Population. AB - BACKGROUND AND OBJECTIVE: Inflammatory bowel disease is a group of chronic inflammatory conditions affecting gastrointestinal tract. Lots of genes have been identified resulting in susceptibility to inflammatory bowel disease. Any polymorphism leading to functional modifications in tyrosine kinase-2 may precipitate excessive immune response in the intestinal mucosa. The aim of our study is to investigate the involvement of tyrosine kinase-2 polymorphisms in the patients with inflammatory bowel disease in Turkish population. METHODS: Four single nucleotide polymorphisms in tyrosine kinase-2 (rs280523, rs2304256, rs280519 and rs280496) were genotyped in 60 Crohn's disease, 151 ulcerative colitis patients and 89 unrelated healthy controls. These polymorphisms were detected by real-time polymerase chain reaction. RESULTS: The presence of genotype (CC) in rs2304256 and (AA) in rs280519 were found to increase the susceptibility to ulcerative colitis (P=0.024, 0.025, respectively). rs2304256 (CA) and rs280519 (AG) have provided protection against ulcerative colitis (P=0.021, 0.012, respectively). rs280519 (AG) was protective against Crohn's disease (P=0.045). rs2304256 (CC) increased the susceptibility to inflammatory Crohn's disease (P=0.014). The presence of rs2304256 (A) increased the susceptibility to perianal Crohn's disease (P=0.03). Both rs280519 and rs2304256 polymorphisms were associated with the requirement of corticosteroid and immunosuppressive therapy in ulcerative colitis. CONCLUSION: This study is the first demonstration of the single marker association of tyrosine kinase-2 polymorphisms with ulcerative colitis and Crohn's disease in Turkish population. They may be effective in the etiology of inflammatory bowel disease in our population. Disparity between our study and others may be related to ethnic differences. PMID- 25744729 TI - Validation of p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs in patient-derived breast tumor xenografts. AB - Blockade of mammalian target of rapamycin (mTOR) is a promising area in breast cancer therapy. However, in clinical trials, objective response rate with mTOR inhibitor monotherapy in breast cancer was modest. Biomarker studies designed to identify the responders of rapalogs are of increasing interest. We validated p27KIP1 expression levels as a candidate predictive biomarker of response to rapalogs. We also analyzed the correlation between rapamycin activity and p27KIP1 expression in the primary breast cancer cells and the patient-derived breast tumor xenograft models. The cells isolated from the breast tumor tissues expressing high levels of p27KIP1 were sensitive to rapamycin, whereas the cells from the tissues expressing low levels of p27KIP1 exhibited resistance to rapamycin. The correlation between p27KIP1 expression and rapamycin antitumor activity was also observed in the patient-derived breast tumor xenograft models. Moreover, we also found rapamycin significantly decreased phosphorylated p70S6K1 and phosphorylated 4EBP1 in both samples. It seemed that the different sensitivity of tumor cells to rapamycin did not owe to its different potency against mTOR activity. We further propose p27KIP1 expression level may be also a candidate predictive biomarker of rapalogs for breast cancer therapy, which requires additional clinical validation. PMID- 25744730 TI - T-box transcription factor Brachyury in lung cancer cells inhibits macrophage infiltration by suppressing CCL2 and CCL4 chemokines. AB - Both intra-tumor macrophage and T-box transcription factor Brachyury (T) have been proved to play important roles in tumor progression and metastasis. However, it is still unknown whether T could regulate the infiltration of macrophages. Here, we report that the Brachyury expression in human lung tumors was inversely correlated with the infiltration of macrophages. Brachyury suppressed the capability of human lung cancer cells to attract macrophages. Using PCR array, we found that Brachyury inhibited expression of several chemokines, including CCL2, CCL4, and CXCL10. Accordingly, knockdown of CCL2 and CCL4 in lung cancer cells suppressed macrophage invasion under coculture conditions. Furthermore, we found that Brachyury expression was inversely correlated with CCL2 and CCL4 expression in human lung tumors. Taken together, our findings shed light on the novel role of Brachyury in regulation of macrophage infiltration. PMID- 25744731 TI - Role of miR-155 in drug resistance of breast cancer. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expressions at posttranscriptional level. Growing evidence points to their significant role in the acquisition of drug resistance in cancers. Studies show that miRNAs are often aberrantly expressed in human cancer cells which are associated with tumorigenesis, metastasis, invasiveness, and drug resistance. Breast cancer is the leading cause of cancer-induced death in women. Over the last decades, increasing attention has been paid to the effects of miRNAs on the development of breast cancer drug resistance. Among them, miR-155 takes part in a sequence of bioprocesses that contribute to the development of such drug resistance, including repression of FOXO3a, enhancement of epithelial-to-mesenchymal transition (EMT) and mitogen-activated protein kinase (MAPK) signaling, reduction of RhoA, and affecting the length of telomeres. In this review, we discuss the role of miR-155 in the acquisition of breast cancer drug resistance. This will provide a new way in antiresistance treatment of drug-resistant breast cancer. PMID- 25744732 TI - Downregulation of telomerase activity by diclofenac and curcumin is associated with cell cycle arrest and induction of apoptosis in colon cancer. AB - Uncontrolled cell proliferation is the hallmark of cancer, and cancer cells have typically acquired damage to genes that directly regulate their cell cycles. The synthesis of DNA onto the end of chromosome during the replicative phase of cell cycle by telomerase may be necessary for unlimited proliferation of cells. Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. We studied the regulation of telomerase and telomerase reverse transcriptase catalytic subunit (TERT) by diclofenac and curcumin, alone and also in combination, in 1, 2-dimethylhydrazine dihydrochloride-induced colorectal cancer in rats. The relationship of telomerase activity with tumors suppressor proteins (p51, Rb, p21), cell cycle machinery, and apoptosis was also studied. Telomerase is highly expressed in DMH group and its high activity is associated with increased TERT expression. However, telomerase is absent or is present at lower levels in normal tissue. CDK4, CDK2, cyclin D1, and cyclin E are highly expressed in DMH as assessed by RT-PCR, qRT PCR, Western blot, and immunofluorescence analysis. Diclofenac and curcumin overcome these carcinogenic effects by downregulating telomerase activity, diminishing the expression of TERT, CDK4, CDK2, cyclin D1, and cyclin E. The anticarcinogenic effects shown after the inhibition of telomerase activity by diclofenac and curcumin may be associated with upregulation of tumor suppressor proteins p51, Rb, and p21, whose activation induces the cells cycle arrest and apoptosis. PMID- 25744733 TI - [Inappropriateness rate for colonoscopy indications in an open access unit]. AB - INTRODUCTION AND OBJECTIVE: The suitability of indications for colonoscopy is important to optimize the available resources. The aim of this study was to assess the appropriateness of colonoscopy indications in an open access endoscopy unit using the EPAGE II criteria. METHODS: Colonoscopies performed between October 1 and November 30, 2011 were retrospectively included. The appropriateness of the colonoscopy was established according to the EPAGE II criteria. Demographics, medical applicants, indications and relevant findings from these examinations were recorded. RESULTS: We included 440 colonoscopies (60.8 +/- 016.3 years, 54% women). The indication was appropriate in 75.4% (CI, 71-79.3%), uncertain in 13.1% (CI, 10.2-16.6%) and inappropriate in 11.4% (CI, 8.7-14.8%). In the univariate analysis, the relevant findings in the colonoscopy were associated with age, sex, colonoscopy indications and EPAGE II. In the logistic regression analysis, factors independently associated with the presence of relevant findings were age (>= 50 years) (OR, 1.84), male sex (OR, 2.7) and two indications, inflammatory bowel disease and post-polypectomy surveillance (P < .03). The diagnostic yield of EPAGE II criteria was 37.3% for appropriate colonoscopies and 28.3% for inappropriate colonoscopies (P = .09). CONCLUSIONS: The rate of unnecessary colonoscopy is high, especially in young patients (<50 years) and some colonoscopy indications. Age (>= 50 years) and male sex are independently associated with the presence of relevant findings in colonoscopy. The diagnostic yield of EPAGE II criteria does not differ between appropriate and inappropriate examinations. PMID- 25744734 TI - The effect of low-frequency mechanical vibration on retention in an orthodontic relapse model. AB - OBJECTIVE: To investigate the effect of low-frequency mechanical vibration (LFMV) on the prevention of relapse after active orthodontic tooth movement, bone volume fraction (BVF), tissue density, and the integrity of periodontal ligament. MATERIALS AND METHODS: Thirty male CD1, 12-week-old mice were used for the study. Mice were randomly divided into three groups: 1. control group, 2. relapse group, and 3. relapse + 30 Hz vibration group. In the control group, first molar was moved mesially for 7 days using nickel-titanium coil spring delivering 10g of force, whereas in relapse and relapse + 30 Hz groups, first molar was moved mesially for 7 days and then orthodontic force was removed and molar was allowed to relapse for 7 days. In relapse + 30 Hz group, LFMVs were applied at 30 Hz. Micro-focus computed tomography (micro-CT) was used for tooth movement measurements (relapse), BVF, and tissue density. Additionally, immunostaining for sclerostin, tartrate-resistant acid phosphatase staining, and picro-sirius red staining were performed on histological sections. RESULTS: LFMV at 30 Hz showed a tendency to decrease relapse but was not statistically significant. Micro-CT analysis showed a trend towards increase in BVF and tissue density with application of LFMV. Sclerostin expression was decreased with 30 Hz vibration. Additionally, the picro-sirius staining showed that LFMV at 30 Hz helped in maintaining the thickness and integrity of collagen fibres in periodontal ligament. LIMITATIONS: This is an animal study and extrapolation of the current findings to the clinical situation must be done with caution, as there is no osteonal remodelling (secondary remodelling) in mice when compared to humans. CONCLUSION: There was no statistically significant difference in the amount of relapse between the relapse-only and relapse + 30 Hz groups. However, there was a trend of decrease in relapse with 30 Hz mechanical vibration. PMID- 25744736 TI - Current evidence of the efficacy of cell-based therapies in heart failure. AB - Heart failure (HF) is the major cause of mortality worldwide. For more than a decade, cell-based therapies have been developed as treatment for heart disease as an alternative to current therapies. Trials and systematic reviews have assessed the safety and efficacy of cell therapies in a diverse number of participants and clinical settings. The present study collated and synthesized evidence from all systematic reviews related to cell-based therapies and HF. A total of 11 systematic reviews were identified through searches of electronic databases up to June 2014. We set out to answer 2 key questions on the efficacy of cell therapies in HF: (1) What is the overall effect of cell therapies on primary outcomes such as left ventricular ejection fraction (LVEF) and mortality? (2) How important is it to define the clinical setting and length of follow-up when assessing cell therapies and HF? There seems to be enough evidence to suggest that cell therapies have a moderate, long-lasting effect on LVEF, but the reduction on the risk of mortality observed by some systematic reviews needs to be confirmed in larger, statistically powered clinical trials. Additionally, and in order to strengthen conclusions, it is important to assess clinical evidence for defined clinical settings and to standardize the length of follow-up when comparing outcome data across several trials and systematic reviews. PMID- 25744737 TI - Devices in heart failure--the new revolution. AB - Heart failure is a growing epidemic, with more patients living longer and suffering from this disease. There is a growing segment of patients who have persistent symptoms despite pharmacologic therapy. In an era when transplants are rare, the need for devices and interventions that can assist ventricular function is paramount. This review goes through the devices used in heart failure, including left ventricular reconstruction, aortic counterpulsation, short-term mechanical circulatory support, long-term mechanical circulatory support, and right heart interventions. PMID- 25744738 TI - Direct reprogramming of fibroblasts into cardiomyocytes for cardiac regenerative medicine. AB - Cardiac fibroblasts play critical roles in maintaining normal cardiac function and in cardiac remodeling during pathological conditions such as myocardial infarction (MI). Adult cardiomyocytes (CMs) have little to no regenerative capacity; damaged CMs in the heart after MI are replaced by cardiac fibroblasts that become activated and transform into myofibroblasts, which preserves the structural integrity. Unfortunately, this process typically causes fibrosis and reduces cardiac function. Directly reprogramming adult cardiac fibroblasts into induced CM-like cells (iCMs) holds great promise for restoring heart function. Direct cardiac reprogramming also provides a new research model to investigate which transcription factors and microRNAs control the molecular network that guides cardiac cell fate. We review the approaches and characterization of in vitro and in vivo reprogrammed iCMs from different laboratories, and outline the future directions needed to translate this new approach into a practical therapy for damaged hearts. PMID- 25744739 TI - Dual antiplatelet therapy for coronary artery disease. AB - Platelets initiate the formation of a thrombus at the site of an arterial injury, and the clotting cascade is activated as the thrombus matures. After coronary stent placement, dual antiplatelet therapy (DAPT) with aspirin and ticlopidine dramatically reduces the risk of stent thrombosis, compared with anticoagulation therapy, and has become the standard of care for prevention of stent thrombosis. Clopidogrel is a second-generation thienopyridine that eliminates the serious side effects of ticlopidine, and new P2Y12 receptor blockers have emerged to overcome the limitations of clopidogrel. Current guidelines recommend DAPT with aspirin and clopidogrel for 1 month after implantation of bare-metal stents, and for 6-12 months after implantation of drug-eluting stents (DES). In patients with acute coronary syndrome (ACS), DAPT administration for 12 months was shown to be superior to aspirin alone for the prevention of recurrent events. Treatment with aspirin and new P2Y12 receptor blockers has further reduced the rate of cardiovascular death, myocardial infarction or stroke after ACS compared with aspirin and clopidogrel. Nonetheless, long-term DAPT increases the risk of major bleeding, requiring a delicate balance between anti-ischemic benefit and bleeding risk. In summary, DAPT should be maintained for at least 6-12 months after implantation of DES, and for at least 12 months after ACS, unless contraindicated. PMID- 25744740 TI - ST-segment elevation myocardial infarction - ideal scenario for bioresorbable vascular scaffold implantation? AB - Bioresorbable vascular scaffolds (BVS) represent a breakthrough technology for percutaneous coronary intervention (PCI). In this context, because of the unique properties of bioresorbable devices, ST-segment elevation myocardial infarction (STEMI) may represent the ideal scenario for BVS implantation. Consistently, 57% of physicians declare they currently use BVS in this group of patients. However, continuous and growing evidence on the good performance of these devices has been actually shown only in small studies with short- and mid-term follow-up. For these reasons, we need data from sufficiently large observational studies, with long-term follow-up, to confirm that BVS can deliver the same results as 2nd generation drug-eluting stents when using an appropriate implantation technique. In this review, we discuss the potential advantages of BVS implantation in STEMI patients, together with the most recent evidence from clinical studies, highlighting safety and procedural concerns. PMID- 25744741 TI - Cardiological aspects of stroke prevention. AB - Many cardiac disorders and their treatment are associated with an increased risk for ischemic or hemorrhagic stroke, so it is important for cardiologists to be aware of recent advances in the field of stroke prevention. Atrial fibrillation (AF) is the most common cardiac disorder associated with a substantial risk for ischemic stroke (IS). The availability of implantable cardiac monitoring devices has substantially increased the detection rate of occult AF after IS. The 4 new oral anticoagulants have advantages when compared with warfarin, the standard therapy in AF to prevent IS, demonstrating a reduced risk for IS or intracerebral hemorrhage. Patients with cardiomyopathy, cardiac valve replacement, recent myocardial infarction, larger aortic arch atheroma and patent foramen ovale all have some level of increased risk for IS. The best approach for IS prevention in these disorders remains unsettled and varying approaches are recommended. PMID- 25744742 TI - MicroRNA-33a/b in lipid metabolism - novel "thrifty" models. AB - MicroRNAs (miRNAs; miRs) are small non-protein-coding RNAs that negatively regulate gene expression. They bind to the 3' UTR of specific mRNAs and either inhibit translation or promote mRNA degradation. There is emerging evidence linking miR-33a/b to lipid homoeostasis, targeting ABCA1,SREBF1, etc and it would appear that they have acted as "thrifty genes" during evolution to maintain cholesterol levels both at the cellular and whole body level. As we are now living in a period of "satiation", miR-33a/b no longer seem to be useful and could be potential therapeutic targets for lipid disorders and/or atherosclerosis. In this review, we describe the current understanding of the function of miR-33a/b in lipid homeostasis, focusing on the "thrifty" aspect. PMID- 25744743 TI - Reliability of detecting high-risk patients with fatal ventricular arrhythmias via methods using cardiac electrical signals. PMID- 25744744 TI - How can we bridge the results of global clinical trials and region/country specific clinical practice by region/country specific registry data? PMID- 25744745 TI - Measuring and reversing the effect of non-vitamin K antagonist oral anticoagulants (NOACs). PMID- 25744746 TI - Oral anticoagulation in Japanese patients with atrial fibrillation - insight to the use of non-vitamin K antagonist oral anticoagulants. PMID- 25744747 TI - Renal angioplasty for atherosclerotic renal artery stenosis revisited - efficacy and safety of renal artery stenting in the J-RAS study. PMID- 25744748 TI - Prophylactic implantation of implantable cardioverter-defibrillator for Japanese patients with heart failure - problem of "underuse". PMID- 25744749 TI - Computed tomography-based fractional flow reserve (FFR-CT) - an attractive concept, but still lacking proof of clinical utility. PMID- 25744750 TI - Plasma microRNA-100 as a biomarker of coronary plaque vulnerability - a new generation of biomarker for developing acute coronary syndrome. PMID- 25744751 TI - Perspectives on catheter ablation of atrial fibrillation. PMID- 25744752 TI - Is anticoagulant therapy unnecessary for lower-risk Japanese patients with atrial fibrillation? Lessons from the SAMURAI-NVAF and BAT studies. PMID- 25744753 TI - Clinical assessment of hypoperfusion in acute heart failure - evergreen or antique? AB - BACKGROUND: Cold hemodynamic profile assessed on physical examination predicts survival, although it has low specificity and low reproducibility. We herein propose a new cold profile definition (Cold Modified 2014), including renal and hepatic damage. The aim of the study was to evaluate the additional prognostic value of clinical and laboratory identification of hypoperfusion over hypotension in the setting of advanced acute heart failure (AHF). METHODS AND RESULTS: After preliminary analysis on derivation cohort, we studied 223 consecutive NYHA III-IV patients admitted with AHF requiring intensive care. Cold Modified 2014 definition included non-invasive hemodynamic assessment, renal and hepatic injury. Primary endpoint was a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 6 months. In the validation cohort (age, 60.5 +/- 12.8 years; ejection fraction 25.6 +/- 8.2%, systolic blood pressure [SBP] 104.3 +/- 26.1 mmHg) 77 reached the composite endpoint. Among SBP, ADHERE model, cold profile at admission and INTERMACS profile at 48 h, cold profile had the best diagnostic accuracy. On multivariate analysis only cold profile and INTERMACS predicted events, while SBP <115 mmHg and high risk on ADHERE did not. Cold Modified 2014 was more accurate than the old definition. Net reclassification improvement for Cold Modified 2014 over the old definition was 25.8%. CONCLUSIONS: This prospective study demonstrated the additional prognostic role of hypoperfusion assessment over hypotension in patients with AHF. Cold Modified 2014 improved risk stratification in advanced AHF patients. PMID- 25744754 TI - Myocardial blood flow in patients with transposition of the great arteries - risk factor for dysfunction of the morphologic systemic right ventricle late after atrial repair. AB - BACKGROUND: Dysfunction of the morphologic systemic right ventricle (RV) is a sequela in long-term survivors with transposition of the great arteries (TGA) after atrial switch operation (AtSO). Impairment of myocardial blood flow (MBF) and coronary flow reserve (CFR) are hypothesized as predisposing factors. METHODS AND RESULTS: The study group comprised 20 patients after AtSO (22.7 +/- 5.03 years) and 15 individuals with congenitally corrected transposition (ccTGA) (30.6 +/- 19.4 years). MBF was quantified by positron emission tomography; controls for coronary flow were 11 healthy volunteers (26.2 +/- 5.1 years). Exercise capacity, ventricular mass, function and end-diastolic volume assessed by coronary magnetic resonance (CMR), hemodynamic parameters assessed by cardiac catheterization and echocardiography, and B-type natriuretic peptide levels correlated with MBF. At rest, MBF did not differ between patients and healthy volunteers (MBFrestml.100 g(-1).min(-1); ccTGA: 75 +/- 14 vs. AtSO: 73 +/- 16 vs. controls: 77 +/- 15; NS). After vasodilatation, MBF increased significantly, but was significantly lower in ccTGA and AtSO groups compared with controls (MBFstressml.100 g(-1).min(-1); ccTGA: 198 +/- 38 vs. AtSO: 167 +/- 46 vs. controls 310 +/- 74; P<0.001). In ccTGA, CFR correlated significantly with clinical, CMR, echocardiographic and hemodynamic parameters, but for AtSO patients no significant correlation could be calculated. CONCLUSIONS: In patients with ccTGA, maximal coronary blood flow is attenuated and significantly correlated with ventricular function, whereas dysfunction of the morphologic systemic RV after AtSO is a multifactorial problem. PMID- 25744755 TI - Catheter ablation of atrial fibrillation and thromboembolic risk. PMID- 25744756 TI - Catheter ablation of atrial fibrillation and thromboembolic risk - reply. PMID- 25744760 TI - Autonomous surveillance for biosecurity. AB - The global movement of people and goods has increased the risk of biosecurity threats and their potential to incur large economic, social, and environmental costs. Conventional manual biosecurity surveillance methods are limited by their scalability in space and time. This article focuses on autonomous surveillance systems, comprising sensor networks, robots, and intelligent algorithms, and their applicability to biosecurity threats. We discuss the spatial and temporal attributes of autonomous surveillance technologies and map them to three broad categories of biosecurity threat: (i) vector-borne diseases; (ii) plant pests; and (iii) aquatic pests. Our discussion reveals a broad range of opportunities to serve biosecurity needs through autonomous surveillance. PMID- 25744759 TI - Initial treatment patterns in younger adult patients with differentiated thyroid cancer in California. AB - BACKGROUND: Differentiated thyroid cancer (DTC) is among the most common malignancies in the adolescent and young adult (age 15-39 years) population, and its incidence is rising. Younger age (<45 years) is an important prognostic indicator and is incorporated into the TNM classification system. This study hypothesized that this would result in distinct treatment patterns for younger and older patients. METHODS: Using the California Cancer Registry, 24,362 patients with DTC from 2004 to 2011 were identified, and they were divided into younger (<45 years) and older (>=45 years) cohorts. Demographic and clinical variables were tabulated and then compared using chi-square tests. Treatment variables included total or near total thyroidectomy, other types of thyroid surgery, and the administration of radioiodine as part of the initial treatment. Multivariable logistic regression was used to identify independent predictors of treatment administered. RESULTS: Younger patients were more likely to be Hispanic (32.5% vs. 21.2%) and female (82.7% vs. 74.7%), and to have papillary carcinoma (92.9% vs. 90.9%) and lymph node involvement (32.8% vs. 19.7%; p<0.0001). On multivariable analysis, younger patients (OR 1.20 [CI 1.11-1.30]), higher T-stage tumors, higher socioeconomic status (SES), and papillary carcinoma were predictors of undergoing total thyroidectomy versus less than total thyroid surgery. After adjustment, predictors of radioiodine administration included younger age (OR 1.12 [CI 1.05-1.18]), higher SES, total thyroidectomy, higher T stage, and lymph node positivity. CONCLUSIONS: Younger patients with DTC in California are more likely to be female and Hispanic with papillary histology. After adjustment for disease and demographic characteristics, younger patients are more likely to undergo total thyroidectomy as their initial surgery and are more likely to receive radioiodine. Given their excellent prognosis and the potential for adverse sequelae from initial treatment for DTC, these findings warrant consideration when managing younger patients with DTC. PMID- 25744761 TI - Toxicology of wear particles of cobalt-chromium alloy metal-on-metal hip implants Part I: physicochemical properties in patient and simulator studies. AB - The objective of Part I of this analysis was to identify the relevant physicochemical characteristics of wear particles from cobalt-chromium alloy (CoCr) metal-on-metal (MoM) hip implant patients and simulator systems. For well functioning MoM hip implants, the volumetric wear rate is low (<1mm(3) per million cycles or per year) and the majority of the wear debris is composed of oxidized Cr nanoparticles (<100nm) with minimal or no Co content. For implants with surgical malpositioning, the volumetric wear rate is as high as 100mm(3) per million cycles or per year and the size distribution of wear debris can be skewed to larger sizes (up to 1000nm) and contain higher concentrations of Co. In order to obtain data suitable for a risk assessment of wear debris in MoM hip implant patients, future studies need to focus on particle characteristics relevant to those generated in patients or in properly conducted simulator studies. FROM THE CLINICAL EDITOR: Metallic implants are very common in the field of orthopedics. Nonetheless, concerns have been raised about the implications of nano-sized particles generated from the wear of these implants. In this two-part review, the authors first attempted to identify and critically evaluate the relevant physicochemical characteristics of CoCr wear particles from hip implant patients and simulator systems. Then they evaluated in vitro and animal toxicology studies with respect to the physicochemistry and dose-relevance to metal-on-metal implant patients. PMID- 25744762 TI - Impact of an Integrated Pharmacy Transitions of Care Pilot Program in an Urban Hospital. AB - PURPOSE: To evaluate the effectiveness of an integrated Pharmacy Transitions of Care (PTC) pilot program on reducing hospital readmissions and improving patient satisfaction. METHODS: This prospective observational cohort study compares patients who participated in the PTC program to a control of usual hospital discharged patients during January through April 2014. The PTC program provided discharge medication review, medication counseling, delivery of medications to bedside, clinic scheduling, and follow-up phone calls. The primary outcome measure was 30-day readmissions. Secondary outcomes included emergency department (ED) visits, pharmacist interventions, and patient satisfaction. RESULTS: Seventy patients participated in the PTC program. Compared to the control (n = 725), the study group had decreased 30-day all-cause readmissions (5.7% vs 13.8%, P = .08), 30-day readmissions for the same diagnosis (2.9% vs 8.1%, P = .18), and ED visits (18.6% vs 25%, P = .82). Twenty-five interventions during discharge medication review included discontinuation of unnecessary medications and correction of medication dose or frequency. The majority of patients were satisfied with the medication education provided (94%) and the timely delivery of prescriptions to bedside (96%). CONCLUSION: There was no significant difference in 30-day readmission rates. However, pharmacists were able to make a positive impact on patient satisfaction and improve understanding of medications during discharge. PMID- 25744763 TI - Temporal trends in revascularization strategy and outcomes in left main coronary artery stenosis: data from the ASAN Medical Center-Left MAIN Revascularization registry. AB - BACKGROUND: Changes over time in revascularization strategies and outcomes among patients with unprotected left main coronary artery stenosis remain largely unknown. METHODS AND RESULTS: A total of 2618 consecutive patients with unprotected left main coronary artery stenosis who underwent revascularization were identified from the ASAN Medical Center-Left MAIN Revascularization registry and classified by time periods: bare metal stent (wave 1, 1995-1998), early drug eluting stents (wave 2, 2003-2006), and late drug-eluting stents (wave 3, 2007 2010). Primary end point was major adverse cerebrocardiovascular events (the composite of death, myocardial infarction, repeat revascularization, and stroke). During the study period, 1124 patients underwent percutaneous coronary intervention (PCI) and 1494 patients underwent coronary artery bypass grafting. The proportion of PCI significantly increased from 35% to 52% between waves 1 and 3. In patients receiving PCI, the risk-adjusted incidence rate of major adverse cerebro-cardiovascular events decreased from 20.18 cases per 100 person-years in wave 1 to 6.77 cases per 100 person-years in wave 3 (P<0.001 for trend). Death, the composite of death, myocardial infarction, stroke, and repeat revascularization were also significantly decreased by 40%, 35%, and 46%, respectively. The risk-adjusted incidence rate of major adverse cerebrocardiovascular events did not change in patients receiving coronary artery bypass grafting. The difference major adverse cerebrocardiovascular events risk between PCI and coronary artery bypass grafting progressively reduced (adjusted hazard ratio [95% confidence interval], 0.33 [0.23-0.47]; 0.53 [0.35-0.80]; and 1.01 [0.68-1.49] from wave 1 to wave 3. CONCLUSIONS: The outcomes of unprotected left main coronary artery PCI have significantly improved over time. In addition, more patients received PCI for unprotected left main coronary artery stenosis in recent years. PMID- 25744764 TI - Transfemoral tricuspid valve-in-ring implantation using the edwards Sapien XT valve: one-year follow-up. PMID- 25744765 TI - Left main revascularization: reality versus the real world. PMID- 25744766 TI - [Underestimated trivial injuries after a fall. Sometimes it is more serious]. AB - In ophthalmological emergencies, patients often present with injuries after falling on their face in particular involving the periocular region. Often these are only trivial injuries of the conjunctiva, eyelids or periocular skin, which require no further treatment. Small dehiscences can be treated with sutures, fibrin glue or Steri-Strips; however, sometimes injuries that are more serious can be mistaken as being trivial but only represent the tip of the iceberg of the actual injury and, therefore, further diagnostics and therapy are required. PMID- 25744767 TI - Morphological imaging of the hippocampus in epilepsy. AB - The hippocampus is a structure frequently involved in epilepsy, especially in partial drug-resistant forms. In addition, some hippocampal pathologies are associated with specific types of epilepsy presenting specific clinical courses and requiring specific treatments. Considering these major implications for treatment, morphological investigations of the hippocampus are crucial for epileptic patients. Indeed, discovery of hippocampal sclerosis may (depending on the clinical and electrophysiological findings) lead to the diagnosis of mesial temporal lobe epilepsy (MTLE). If the diagnosis of MTLE is retained in a case of drug-resistance, surgery may be proposed without invasive phase II investigations such as stereoelectroencephalograpy. In other instances, hippocampal abnormalities may be associated with epilepsy, but without the same value for localizing the ictal onset zone. Hippocampal dysgenesis is a strong argument for non-temporo-mesial ictal onset ipsilateral to the malformation. We describe here the specific MRI modalities adapted for hippocampal investigations and the radiological signs of hippocampal pathologies associated with epilepsy (especially hippocampal sclerosis and hippocamal dysgenesis). Hippocampus morphological investigations in epilepsy require specific MRI modalities and appropriate knowledge of the specific signs of each pathology. Careful analysis is crucial since the results may have a major impact on the therapeutic management of epileptic patients. PMID- 25744768 TI - Temporal lobe epilepsy in infants and children. AB - Clinical expression of temporal lobe seizures is different with a more diverse and more extensive etiology in infants and children than it is in adults. It is dominated by cortical dysplasia, low-grade tumors and perinatal damage. Hippocampal sclerosis, although less frequent, exists in children usually as a dual pathology associated with ipsilateral neocortical lesions. The clinical semiology of temporal seizures is more varied, and sometimes misleading. Motor features including tonic, clonic or myoclonic behaviors, and infantile spasms predominate in infants. Classical complex partial seizures with behavioral arrest and automatisms, as well as lateralizing signs are rare and occur mostly with onset after the age of two years. Interestingly, aura, emotional, and autonomic signs seem to be independent on the brain maturation process. Moreover, the neuropsychological profile varies according to age of onset and duration, lateralization of the focus and etiology. Quality of care benefits from individual cognitive assessment for memory and emotional processes. PMID- 25744769 TI - E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma. AB - Melanomas are highly proliferative and invasive, and are most frequently metastatic. Despite many advances in cancer treatment over the last several decades, the prognosis for patients with advanced melanoma remains poor. New treatment methods and strategies are necessary. The main hallmark of cancer is uncontrolled cellular proliferation with alterations in the expression of proteins. Ubiquitin and ubiquitin-related proteins posttranslationally modify proteins and thereby alter their functions. The ubiquitination process is involved in various physiological responses, including cell growth, cell death, and DNA damage repair. E3 ligases, the most specific enzymes of ubiquitination system, participate in the turnover of many key regulatory proteins and in the development of cancer. E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others) are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas. PMID- 25744770 TI - Peripheral blood Th9 cells and eosinophil apoptosis in asthma patients. AB - BACKGROUND AND OBJECTIVE: Th9 cells producing interleukin (IL) 9 are novel subset of CD4+ T helper cells, which might contribute to airway inflammation in asthma. Moreover, the effect of IL-9 on eosinophils is still not fully understood. Study aim was to evaluate peripheral blood Th9 cells and eosinophil apoptosis in allergic asthma patients. MATERIALS AND METHODS: Eighteen patients with allergic asthma and fourteen patients with allergic rhinitis were examined. Control group included sixteen healthy subjects. Allergic asthma and rhinitis patients did not use corticosteroids and antihistamines at least for 1 week. Peripheral blood eosinophils and CD4(+) cells were isolated by high density gradient centrifugation and magnetic separation. Th9 cells and apoptotic eosinophils were estimated by flow cytometer. Serum IL-9 and IL-5 concentration were determined by ELISA. RESULTS: Peripheral blood Th9 cells percentage was increased in allergic asthma group compared with allergic rhinitis and control group (0.74%+/-0.32% vs. 0.19%+/-0.10% and 0.15%+/-0.08%, respectively, P<0.05). The same tendency was observed for IL-9 (P<0.01). Percentage of peripheral blood apoptotic eosinophils was decreased in allergic asthma and allergic rhinitis groups compared with control group (P<0.05). IL-9 concentration correlated with percentage of Th9 cells (r=0.64, P<0.05) and negatively with percentage of apoptotic eosinophils in allergic asthma group (r=-0.58, P<0.05). Negative correlation was found between apoptotic eosinophils count and IL-5 concentration in allergic asthma group (r= 0.76, P<0.05). CONCLUSIONS: Patients with allergic asthma demonstrate increased peripheral blood Th9 cells count and serum IL-9, while eosinophil apoptosis is inversely related to IL-9 concentration. PMID- 25744771 TI - Use of exploratory factor analysis to ascertain the correlation between the activities of rheumatoid arthritis and infection by human parvovirus B19. AB - BACKGROUND AND OBJECTIVE: We evaluated a possible correlation between the clinical activities of rheumatoid arthritis (RA) and human parvovirus B19 (B19) infection using exploratory factor analysis (EFA). MATERIALS AND METHODS: RA patients were organized into two groups: 100 patients in the main group and 97 in the RA(DAS28) group. Four subgroups were defined from the main group according to the presence or absence of certain infection-specific markers: group I comprised 43 patients who had IgG antibodies against B19; group II, 25 patients with active B19 infection (B19-specific IgM antibodies and/or plasma viremia); group III, 19 patients with latent/persistent B19 infection (virus-specific sequences in peripheral blood leukocytes' DNA with or without B19-specific IgG antibodies), and group IV, 13 patients without infection markers. The RA(DAS28) group was divided into four subgroups similarly to the main group: group I, 35; group II, 31; group III, 19; and group IV, 12 patients. Disease-specific clinical values in both groups were analyzed employing EFA, and the RA(DAS28) group was additionally assessed using Disease Activity Score (DAS)28. RESULTS: RA activity was higher in patients who had markers of B19 infection. The highest activity of RA in both study groups was in patients with latent/persistent infection. In the RA(DAS28) group, according to DAS28, the highest activity of RA was in patients with active B19 infection. CONCLUSIONS: Using EFA and DAS28, a correlation between the clinical activity of RA and B19 infection was confirmed. These data suggest that EFA is applicable for medico-biological studies. PMID- 25744772 TI - Predictors of mortality in patients with rheumatoid arthritis in Lithuania: Data from a cohort study over 10 years. AB - BACKGROUND AND OBJECTIVE: Increased mortality and shorter survival among rheumatoid arthritis (RA) patients are recognized but not fully explained. This cohort study aimed to identify predictors of mortality among RA patients at a tertiary clinical setting. MATERIALS AND METHODS: Patients with RA were recruited during 1998-2003 and followed up until April 1, 2012, or death whichever happened first. Baseline variables included sociodemographic and disease characteristics, and comorbidities. Cox regression and hazard risk (HR) were computed to estimate risks for mortality. RESULTS: One hundred ninety-one patients were included into the study, 186 patients were eligible for the analysis and of these 131 patients (70.4%) completed the entire period of followed-up while 55 patients (29.6%) died. The average follow up period was equivalent to 9.24 year per person. A Cox regression model identified four major factors having an impact on survival. History of a stroke at baseline was identified as a major factor (HR=5.33; 95% CI, 2.13-13.32). Statistically significant risk factors were also age over 50 years (HR=4.59; 95% CI, 2.04-10.30); education less than 11 years (HR=3.3; 95% CI, 1.72-6.33) and angina pectoris (HR=1.98; 95% CI, 1.03-3.80). CONCLUSIONS: Higher age, lower education and cardiovascular comorbidities were identified as predictors of mortality in this prospective cohort study while disease-related variables were not independent predictors of mortality. PMID- 25744773 TI - Short-term results of quality of life for curatively treated colorectal cancer patients in Lithuania. AB - BACKGROUND AND OBJECTIVE: Treatment options for colorectal cancer patients create the need to assess the quality of life (QoL) of colorectal cancer patients in the early postoperative period when changes are potentially greatest. The aim of the current study was to assess the QoL of colorectal cancer patients following open and laparoscopic colorectal surgery. MATERIALS AND METHODS: A total of 82 consecutive patients requiring elective open or laparoscopic colorectal surgery were recruited to the study for 3 months in the three colorectal surgery centers of Lithuania. Patients completed the EORTC QLQ-C30 (version 3.0) questionnaire before surgery, 2 and 5 days, 1 and 3 months after operation. The EORTC QLQ-CR29 questionnaire was completed before surgery and at 1 and 3 months after operation. Analysis was done according to the manual for each instrument. RESULTS: EORTC QLQ C30 reflected the postoperative recovery of QoL. The global health status, cognitive and emotional functioning came back to the preoperative level in one month after operation. Physical and role functioning for laparoscopic group was significantly improved in 1 month after operation and in 3 months for open surgery group respectively. Colorectal module EORTC-QLQ-CR29 found that future perspective increased significantly in laparoscopic group 1 month after operation. CONCLUSIONS: The present study showed that majority of functional scale scores came back to the preoperative level during the first 3 months after colorectal cancer surgery. Differences in QoL according to surgical approach are mostly expressed on this period. PMID- 25744774 TI - Impact of hypertension on postreperfusion left ventricular recovery in patients with ST-segment elevation myocardial infarction and multivessel coronary artery disease. AB - OBJECTIVE: The aim of this study was to investigate the impact of admission systolic blood pressure (ASBP) and left ventricular (LV) mass on the postreperfusion LV recovery in patients with ST-segment elevation myocardial infarction (STEMI) and concomitant coronary multivessel disease (MVD). MATERIALS AND METHODS: A retrospective analysis of 12-month postreperfusion LV recovery was performed in 104 patients after primary percutaneous coronary intervention (PPCI). Patients with elevated ASBP (>140mmHg) were assigned to the first group (n=58); with normal ASBP (<140mmHg), to the second group (n=46); with increased myocardial mass index (MMI) (>100g/m(2)), to the third group (n=70); and with normal MMI (<100g/m(2)), to the fourth group (n=34). Severity of MVD was evaluated by the Syntax score. The LV recovery was assessed by evolution of quantitative characteristics of electrocardiography (QRS score, ST score, ECG STEMI stage) and echocardiography (LV ejection fraction, volume and mass indices) registered before and after PPCI, at discharge, and after 1, 6, and 12 months. RESULTS: There were no significant differences in the baseline QRS and ST scores, ECG STEMI stage, LVEF, MMI, and Syntax score comparing all the patients' groups. The serial ECG criteria showed only a very small impact of ASBP on postreperfusion LV recovery. Only ECG STEMI stage progression was slower in the patients with elevated ASBP. In patients with different MMI, the QRS and ST scores were higher and ECG STEMI stage was lower in patients with increased MMI. LVEF after 1 year was significantly lower in the third group as compared to the fourth group (42.58%+/-8.25% vs. 46.8%+/-7.13%, P=0.018). CONCLUSION: Postreperfusion LV recovery was more related not to ASBP but to the increased LV mass assessed by echocardiography in patients with STEMI and MVD. PMID- 25744775 TI - Do hemophiliacs have a higher risk for dental caries than the general population? AB - OBJECTIVE: The aim of this study was to examine if patients with hemophilia were at increased risk for dental decay as compared to the general population. MATERIALS AND METHODS: Census sampling was used in this case-control study to recruit cases (patients with hemophilia) and a control group individuals recruited randomly from the general population, which were matched with cases based on gender, age and place of residence. Clinical examinations included dental health and salivary assessments (flow rate, buffer capacity, caries associated bacteria) and a structured questionnaire which inquired about socioeconomic status and dental health-related behaviors. RESULTS: In the deciduous dentition, the overall caries experience (dmf) differed statistically significantly (P=0.003) between the hemophiliacs (2.6+/-2.6) and their matched healthy controls (6.1+/-2.5). Bivariate analyses did not reveal significant differences between cases and controls regarding salivary functions, except that higher bacteriological counts were found in healthy controls in deciduous dentitions than in patients with hemophilia (P=0.019). Children without hemophilia were from higher socioeconomic status families than hemophiliacs (P=0.004), but such differences were not found for adults (P=0.090). When compared to healthy adults, adult hemophiliacs had more gum bleeding at rest (P<0.001) as well as during their tooth brushing (P=0.007) and they also consumed more soft drinks than controls (P=0.025). CONCLUSIONS: Better dental health was observed in children with hemophilia as compared to children without it. There were no differences in dental health between adult hemophiliacs and healthy controls from the general population. None of the linear multiple regression models confirmed hemophilia to be an additional caries risk when it was controlled for other caries determinants. PMID- 25744776 TI - Self-reported consequences and healthcare costs of falls among elderly women. AB - BACKGROUND AND OBJECTIVE: Although the falls in elderly people lead to serious health consequences, the economic burden is underestimated. The aim of this study was to calculate the medical costs of fall consequences in elderly women. MATERIALS AND METHODS: Women aged 65 years and older were interviewed by phone recording the consequences and healthcare procedures related to every fall sustained during the previous 12 months. The healthcare costs were estimated by calculating the sum of costs for all self-reported contacts with medical care providers: ambulance, emergency department, visits to family doctor and other specialists, hospitalisations, and rehabilitation. RESULTS: The study population consisted of 878 community-dwelling women (mean age 72.2+/-4.8 years). Falls were reported by 310 (35.3%) women; one in three of them had fallen twice or more. Of all women who fell, 280 (90.3%) reported their fall resulted in an injury, and 77 (15.3%) falls led to bone fractures. Fear of falling was reported by 72.9% of women. Fall-related medical care was provided to 135 women (43.5% of those fallen), and 18 (5.8%) subjects were hospitalised, mostly for the fracture. The mean estimated healthcare cost was 254 EUR per patient receiving fall-related medical care, and 116 EUR per women fallen. The highest mean cost (1289 EUR) was estimated in falls resulted in hip fracture; the lowest (135 EUR), in nonfracture injury. CONCLUSION: The data on the self-reported consequences of falls in elderly women showed a significant number of fall-related injuries and a high cost of healthcare. PMID- 25744777 TI - The cost of newly diagnosed breast cancer in Lithuania, 2011. AB - BACKGROUND AND OBJECTIVE: Although the cost of treating women with breast cancer (BC) is an important component for cost saving and effectiveness in relation to the benefits of BC treatment interventions, there is limited information on the direct cost reported for BC in Lithuania. Therefore the aim of this study was to evaluate annual direct medical cost for newly diagnosed BC in Lithuania in the year 2011. MATERIALS AND METHODS: The retrospective incidence-based top-down direct cost analysis was used. From January 1 to December 31, 2011 incident cases of BC (N=1142) registered by the National Health Insurance Fund, the stage determined by Lithuanian Cancer Registry were included in the study. RESULTS: The total average direct cost of BC amounted per patient was 2580 (95% CI 2444 2752)EUR in 2011. The main cost driver per BC patients was the inpatient hospital stay, respectively 1655 (95% CI 1478-2334)EUR. The average outpatient cost for one BC patient was 564 (95% CI 547-898)EUR. The dominant proportion of inpatient expenditures was assigned to BC surgery and chemotherapy treatment. The BC direct medical cost increased according to the diagnosed stage of diseases from 2409 (95% CI 2196-2621)EUR in stage 1 to 3688 (95% CI 2703-4672)EUR in stage 4. The direct medical cost was inversely proportional to age. CONCLUSIONS: The direct BC medical cost estimates provided by this analysis can be used to determine priorities for the future research on BC treatment interventions. PMID- 25744778 TI - Characterization, real-time quantification and in silico modeling of arsenate reductase (arsC) genes in arsenic-resistant Herbaspirillum sp. GW103. AB - This study investigated the mechanism of arsenic resistance in the diazotrophic bacterium Herbaspirillum sp. GW103 isolated from rhizosphere soil of Phragmites austrails. The isolate Herbaspirillum sp. GW103 exhibited maximum tolerance to arsenic (550 mg/L). Four different arsenate reductase (arsC) genes (arsC1, arsC2, arsC3 and arsC4) were located in the genome of the isolate Herbaspirillum sp. GW103. The expression pattern of the arsC1 differed from other genes. All four types of arsC genes had different protein secondary structures and stereochemical properties. Molecular modeling and structural analysis of arsC genes revealed close structural homology with arsC family proteins from Escherichia coli (PDB ID: 1I9D) and Pseudomonas aeruginosa (PDB ID: 1RW1). PMID- 25744779 TI - From saprophytic to toxigenic clostridia, a complex evolution based on multiple diverse genetic transfers and/or rearrangements. PMID- 25744780 TI - About Eating: an online program with evidence of increased food resource management skills for low-income women. AB - OBJECTIVE: Produce and evaluate About Eating (AE), an online program for low income women aligned with the Satter eating competence model, congruent with best practices for nutrition education of low-income audiences. METHODS: Responses from iterative cognitive interviews and online surveys with diverse samples of low-income women informed lesson revisions. The researchers conducted a randomized controlled trial of AE with low-income women to determine its impact on dietary behavior and food security. RESULTS: In all, 284 women reviewed at least 1 AE lesson and endorsed it. After AE, women (n = 288) increased in use of food resource management skills (eg, using a budget [P = .008] and planning meals to include all food groups [P = .002]). About Eating participants who were food secure had more confidence in managing money for food (P = .002) and keeping track of food-related purchases (P = .02) than food-insecure persons. CONCLUSIONS AND IMPLICATIONS: Mixed-methods research with life stage and geodiverse samples confirmed the usefulness of AE. Food security assessment may enhance interpretation of intervention effectiveness. PMID- 25744781 TI - Radiofrequency thermotherapy in the treatment of tongue base lymphoid hyperplasia: case report. AB - OBJECTIVE: This paper describes a case where a patient diagnosed with tongue base lymphoid hyperplasia was successfully treated with radiofrequency excision and interstitial radiofrequency-induced thermotherapy. CASE REPORT: A 53-year-old female presented with globus sensation, mild dysphagia, nocturnal breathing problems and 'hot potato voice' dysphonia. On flexible nasendoscopy, a visible tongue mass was seen to obstruct the posterior oropharynx. On magnetic resonance imaging scans, this mass looked suspicious of lymphoma, but on histology was confirmed to be benign reactive lymphoid hyperplasia. Sleep study findings indicated moderate obstructive sleep apnoea, with an apnoea-hypopnoea index of 18.1 events per hour. She was treated with radiofrequency-induced thermotherapy on three separate occasions. RESULTS: A post-operative sleep study showed a dramatic improvement in the patient's apnoea-hypopnoea index (3.8 events per hour). This correlated well with the improvement in her sleep quality and reduction of snoring. Over the follow-up period, there has been sustained resolution of dyspnoea, with almost total restoration of voice quality. PMID- 25744782 TI - The long non-coding RNA PCGEM1 is regulated by androgen receptor activity in vivo. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) can orchestrate oncogenic or tumor suppressive functions in cancer biology. Accordingly, PCGEM1 and PRNCR1 were implicated in progression of prostate cancer (PCa) as transcriptional co regulators of the androgen receptor (AR). However, these findings were recently refuted asserting that neither gene physically binds to the AR. Despite evidence for differing AR transcriptional programs in vivo and in vitro, studies investigating AR-regulation of these genes hitherto have only been conducted in vitro. Here, we further examine the relevance of PCGEM1 and PRNCR1 in PCa, and their relationship with AR signaling, using patient-derived xenograft models. FINDINGS: RNA sequencing of two distinct androgen-dependent models shows PCGEM1 to be considerably expressed, while PRNCR1 showed scant basal expression. PCGEM1 was sharply down-regulated following castration and up-regulated upon AR activation in vivo. However, we found no parallel evidence following AR stimulation in vitro. A PCGEM1-associated gene expression signature (PES) was significantly repressed in response to androgen ablation therapy and in hormone refractory versus hormone-naive PCa patients. Furthermore, we found PCGEM1 was uniformly distributed in PCa cell nucleus and cytoplasm which remained unaltered upon AR transcriptional activation. PCGEM1 was up-regulated in primary PCa but not in metastasized PCa. Accordingly, the PES was significantly down-regulated in advanced and higher grade PCa patients from multiple independent studies. CONCLUSION: Our results demonstrate PCGEM1 as an in vivo androgen-regulated transcript with potential nuclear and/or cytoplasmic function(s). Importantly, the clinical expression profile of PCGEM1 implicates it in the early stages of PCa warranting further research in this direction. PMID- 25744783 TI - Anti-inflammatory and immune-modulatory therapies for preventing atherosclerotic cardiovascular disease. AB - Atherosclerosis is believed to be a chronic inflammation of the arterial wall and various immune cells of innate and adaptive immunity involves in the pathogenesis of atherosclerosis. Based on this notion, several anti-inflammatory strategies for prevention of atherosclerosis have been examined mainly using animal models. Vaccination or mucosal immunization with athero-antigens comes under candidate therapeutic methods for antigen-specific prevention of atherosclerosis. Immune suppression mediated by regulatory T cells (Tregs) could be another method to regulate pathogenic chronic inflammation in atherogenesis. Inducible Tregs are reported to differentiate peripherally in the intestine and we have been interested in the oral tolerance, in which not only Tregs but also tolerogenic dendritic cells play crucial roles. We demonstrated that modulation of the intestinal immunity including oral tolerance could be a novel therapy against atherosclerosis. Further, downregulation of effector T cell response and/or Treg predominant condition was shown to induce atherosclerosis regression and inhibit the progression of aneurysm. In clinical situations, none of the approaches to specifically and directly treat inflammation to prevent cardiovascular events or reduce atherosclerosis in human individuals were successful, although high sensitive C-reactive protein is shown to have a strong relationship with recurrent events of cardiovascular diseases in several randomized clinical trials. Now two randomized placebo-controlled clinical trials evaluating anti inflammatory agents are being conducted in the USA and Canada to clarify whether targeting the inflammation itself will reduce cardiovascular events and risks. In this review, we present the current understanding of anti-inflammatory and immune modulation therapies against atherosclerosis and discuss the future perspectives. PMID- 25744784 TI - Remote ischemic conditioning: Current clinical perspectives. AB - Remote ischemic conditioning (RIC) constitutes a promising method in which a tissue or organ is exposed to intermittent ischemia/reperfusion periods enabling it to provide protection to a distant target organ. RIC has been tested in various clinical settings through its simple application by means of intermittent inflation of a blood pressure cuff placed on a limb, primarily evaluating its potential abilities to decrease myocardial injury biomarkers. Its use on other organs, such as the kidneys or brain, has recently been a topic of research. To date, no study has yet been powerful enough to reach a conclusion on the potential benefit of RIC on clinical outcomes. The future role of RIC in the clinical arena could be clarified by the large phase III trials currently underway targeting major outcomes as primary endpoints. PMID- 25744785 TI - Erdheim-Chester disease: a systematic review. AB - Erdheim-Chester disease (ECD) is a rare form of non-Langerhans-cell histiocytosis, associated in more than 50% of cases to BRAF(V600E) mutations in early multipotent myelomonocytic precursors or in tissue-resident histiocytes. It encompasses a spectrum of disorders ranging from asymptomatic bone lesions to multisystemic, life-threatening variants. We reviewed all published reports of histologically-confirmed ECD and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 448 patients, including a unique patient from our Department. To find a clinically relevant signature defining differentiated prognostic profiles, the patients' disease features were compared in relation to their CNS involvement that occurred in 56% of the entire population. Diabetes insipidus, visual disturbances, pyramidal and extra pyramidal syndromes were the most recurrent neurological signs, whereas concomitant pituitary involvement, retro-orbital masses and axial lesions in the presence of symmetric bilateral osteosclerosis of long bones depicted the typical ECD clinical picture. Patients with CNS infiltration showed a lower occurrence of heart involvement and a higher incidence of bone, skin, retro-peritoneal, lung, aortic and renal infiltration. No difference in the therapeutic algorithm was found after stratification for CNS involvement. A better understanding of the disease pathogenesis, including BRAF deregulation, in keeping with improved prognostic criteria, will provide novel suggestions for the management of ECD. PMID- 25744786 TI - Thoracoscopic resection of pulmonary metastasis: current practice and results. AB - Video-assisted thoracoscopic surgery (VATS) is currently a routinely performed procedure for the management of early non small cell lung cancer. The oncological results of VATS in terms of local recurrence and overall survival are equivalent or superior to those of conventional thoracotomy with lower morbidity and hospital stay. In the field of pulmonary metastasectomy, current guidelines support a thoracotomy approach in order to properly palpate the lung and detect nodules too small to be identified on standard radiological examinations (typically less than 5mm in diameter). However, the oncological and clinical significance of these millimetric nodules is not known. This has led some thoracic surgeons to rethink the approach of solitary pulmonary metastasectomy: because of improvements in thin slice helical CT-scans, some support a VATS approach for solitary pulmonary nodules without formal bimanual palpation and suggest this allows equivalent oncological results and decreased surgical morbidity. PMID- 25744787 TI - [Preface]. PMID- 25744788 TI - [WHO Framework Convention on Tobacco Control (FCTC) Article 8: protection from exposure to tobacco smoke]. AB - It is necessary to implement 100% smoke-free environments in all indoor workplaces and indoor public places in order to protect people from exposure to second-hand tobacco smoke (SHS). Forty-four countries have already implemented comprehensive smoke-free legislations according to the Framework Convention on Tobacco Control (FCTC) Guidelines on protection from exposure to tobacco smoke. The Occupational Safety and Health Law (OSHL) was partially revised to strengthen the countermeasures against SHS in Japan in 2014. However, the revision was only minimal. Firstly, it is necessary to make efforts to implement countermeasures against SHS (their implementations are not obligatory, as required in Article 8). Secondly, the revised OSHL allowed the implementation of designated smoking rooms inside workplaces (Article 8 requires 100% smoke-free environments). Thirdly, revised OSHL does not effectively cover the small-scale entertainment industry so that workers in restaurants and pubs will not be protected from occupational SHS. We explain the importance of implementation of 100% smoke-free environments by law, using the data on leakage of smoke from designated smoking rooms, and occupational exposure to SHS among service industry workers. The decrease in the incidence of smoking-related diseases in people where a comprehensive smoke-free law is implemented is also introduced. These data and information should be widely disseminated to policy makers, media, owners of service industries, and Japanese people. PMID- 25744789 TI - [The need for tobacco control in Japan based on Articles 9 and 10 of the World Health Organization Framework Convention on Tobacco Control (WHO FCTC), regulation of the contents of tobacco products, and regulation of tobacco product disclosures]. AB - In Japan, ultralow-nicotine cigarette brands with ventilation holes on the cigarette filters have been widely marketed to smokers. The use of these cigarette brands leads to compensation smoking. Menthol cigarette brands that have a cooling and numbing effect are also sold. In 2013, smokeless tobacco products similar to the Swedish snus, which is banned for sale in the European Union except in Sweden, were released in Japanese markets. These tobacco products have "toxicity," have a "ventilation filter," are "attractive," and promote "dependence." Tobacco smoke and smokeless tobacco are classified into "Group 1: Carcinogenic to humans" by the International Agency for Research on Cancer (IARC). The purpose of Articles 9 and 10 of the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) is to regulate the contents of tobacco products as well as to regulate tobacco product disclosures. The implementation of some other articles has gradually advanced in Japan. However, that of Articles 9 and 10 is late. Japanese governmental authorities are being urged to immediately implement Articles 9 and 10. PMID- 25744790 TI - [WHO Framework Convention on Tobacco Control (FCTC) Article 11: packaging and labelling of tobacco products]. AB - The World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) requires member countries to implement measures aimed at reducing the demand for tobacco products. FCTC article 11 describes the important forms of health communication and packaging regulations. And this article recommends on large pictorial health warnings and encourages more effective forms of disclosure on constituents and emissions. Furthermore, article 11 recognizes the importance of the package as a promotional vehicle for tobacco companies and requires the removal of potentially misleading packaging information, including the terms "light" and "mild." The Conference of the Parties (COP) adopted guidelines for implementation of article 11 on "Packaging and labelling of Tobacco Products". Some countries, such as Canada, the U.S.A., Australia, EU countries etc. positively promoted tobacco control by implementing countermeasures such as the graphic health warning labels and plain packages. These countermeasures showed the significant effects of decreasing smoking rate and preventing smoking initiation in young people. Furthermore, these warning labels were effective for the literally challenged. However, the Japanese government has not implemented these countermeasures, and only limited texts are shown on Japanese tobacco packaging. Therefore, Japan should emulate approaches taken by other countries, and promote the tobacco control policy in accordance with FCTC. PMID- 25744791 TI - [Study on empowerment factors for career continuity of hospital nurses]. AB - OBJECTIVES: The resignation rate of nurses working in hospitals is extremely high. This study aims to identify both the factors related to the resignation of nurses and the empowerment factors supporting their job retention. METHODS: In 2011 we conducted a Web-based questionnaire survey of nurses with less than 10 years of working experience. There were 25 survey items including the following reasons for choosing the current employment position, intention of continuing work, sense of fulfillment and the presence or absence of problems in the current workplace. In addition, nurses who previously had resigned were asked why they left their last workplace. RESULTS: The reasons why they chose the current workplace were markedly different between the not-resigned (A group) and previously resigned (B group) nurses. As a result of cluster analysis, the reasons for resignation were classified into six clusters; "overwork", "burnout", "bad atmosphere", "work life balance factors", "working conditions" and "marriage". CONCLUSIONS: In this study, it is shown that there is a positive correlation between the sense of fulfillment at work and the intention to do research work. It is suggested that encouragement of nurses to undertake research work is one of the empowerment factors supporting their job retention. PMID- 25744792 TI - [Examination of diagnosis procedure combination survey data that influence function evaluation coefficient II]. AB - OBJECTIVES: On the basis of Diagnosis Procedure Combination (DPC) survey data, the factors that increase the value of function evaluation coefficient II were considered. METHODS: A total of 1,505 hospitals were divided into groups I, II, and III, and the following items were considered. 1. Significant differences in function evaluation coefficient II and DPC survey data. 2. Examination of using the Mahalanobis-Taguchi (MT) method. 3. Correlation between function evaluation coefficient II and each DPC survey data item. RESULTS: 1. Function evaluation coefficient II was highest in group II. Group I hospitals showed the highest bed capacity, and numbers of hospitalization days, operations, chemotherapies, radiotherapies and general anesthesia procedures. 2. Using the MT method, we found that the number of ambulance conveyances was effective factor in group I hospitals, the number of general anesthesia procedures was effective factor in group II hospitals, and the bed capacity was effective factor in group III hospitals. 3. In group I hospitals, function evaluation coefficient II significantly correlated to the numbers of ambulance conveyances and chemotherapies. In group II hospitals, function evaluation coefficient II significantly correlated to bed capacity, the numbers of ambulance conveyances, hospitalization days, operations, general anesthesia procedures, and mean hospitalization days. In group III hospitals, function evaluation coefficient II significantly correlated to all items. CONCLUSIONS: The factors that improve the value of function evaluation coefficient II were the increases in the numbers of ambulance conveyances, chemotherapies and radiotherapies in group I hospitals, increases in the numbers of hospitalization days, operations, ambulance conveyances and general anesthesia procedures in group II hospitals, and increases in the numbers of hospitalization days, operations and ambulance conveyances. These results indicate that the profit of a hospital will increase, which will lead to medical services of good quality. PMID- 25744793 TI - [Prevalence of eating disorders assessed using eating attitudes test-26 and their relevant factors in Japanese working women]. AB - OBJECTIVE: The purpose of the present study was to investigate the prevalence of eating disorders and their relevant factors in Japanese women. METHODS: Anonymous self-administered questionnaire surveys of 3023 working women aged 20-39 were conducted during health checkups in Tokyo, Nagoya, Osaka, and Fukuoka in 2012. Eating disorders were assessed using Eating Attitudes Test-26 (EAT-26). The factors related to EAT-26 scores >=20 were analyzed by multiple logistic regression. RESULTS: The prevalences of eating disorders among the participants with EAT-26 scores >=20 were 2.4% [95% confidence interval (95% CI): 1.8-2.9%] of all the participating women aged 20-39, 3.4% (95% CI: 2.5%-4.3%) of women in their 20s, and 1.2% (95% CI: 0.6%-1.8%) of women in their 30s. Logistic regression analysis showed that EAT-26 scores of >=20 were associated with the following variables: perceived ideal BMI <=17.5 kg/m(2) (OR: 4.55, 95% CI: 2.08 9.93), change in body weight in the previous six months (OR: 2.83, 95% CI: 1.61 4.95), being 20-29 years of age (OR: 2.64, 95% CI: 1.42-4.89), and the perception of being fat (OR=2.54, 95% CI: 1.24-5.18). CONCLUSIONS: The prevalence of eating disorders with EAT-26 scores >=20 was 2.4% (95% CI: 1.8%-2.9%) among Japanese working women aged 20-39. EAT-26 scores >=20 were most closely associated with a perceived ideal BMI of <=17.5 kg/m(2). Eating disorders may be more prevalent among women who want to lose weight to achieve a BMI of <=17.5 kg/m(2), and these women should be carefully monitored. PMID- 25744794 TI - [Prediction of upper limb recovery in the acute phase of cerebrovascular disease: study design and socio-demographic profiles, medical profiles,and acute symptoms of participants at baseline]. AB - OBJECTIVES: In this study, we aim to predict the recovery of upper limb function in patients in the acute phase of cerebrovascular disease. Here, we describe the study design and patients' characteristics at baseline. METHODS: Subjects were admitted to Takeda General Hospital with cerebrovascular disease, and were prescribed to undergo rehabilitation. The assessment was conducted between June 2010 and March 2011. The baseline survey assessed the following factors: socio demographic profiles (age, sex, number of family members, key person, occupation, and activities in daily life), medical profiles (types of cerebrovascular disease, location of brain damage, and history of diseases), and acute symptoms (Japan Coma Scale score, the Barre arm sign, the Brunnstrom recovery stage, tendon reflex, sensation, pain, ataxia, range of motion, muscle tone, grip strength, agnosia, apraxia, aphasia, dysarthria, the Hasegawa Dementia Scale Revised score, and the Barthel index). RESULTS: A total of 357 patients with cerebrovascular disease were analyzed on the basis of diagnosis [cerebral infarction (CI; 77.6%), cerebral hemorrhage (CH; 20.2%), subarachnoid hemorrhage (SAH; 2.2%)]. There was a significant difference in the average age between the types of cerebrovascular disease. In acute symptoms, sensation, grip strength, cognitive function, and activities of daily living were statistically significantly different between the types of cerebrovascular disease. CONCLUSIONS: In this report, we described the study design and characteristics of patients with cerebrovascular disease at baseline. In the future, this study could be used for predicting the recovery of upper limb function in these patients. PMID- 25744795 TI - [Comprehensive study on the prevention of food poisoning through the investigation of an affected hospital food service facility]. AB - OBJECTIVES: In Japan, more than 20,000 people suffer from various types of food poisoning annually. In this paper, we discuss the prevention of food poisoning in hospital food service facilities from the perspective of hygiene management and organizational behavior. METHODS: We inspected the kitchen environment and the meal preparation process in a hospital food service facility in Japan that had been the site of a food poisoning incident. To clarify the present state of hygiene management, interviews were conducted with both the head of the nutrition and food service section and the administrative manager. In addition, questionnaires were distributed to the food service staff to assess their level of satisfaction with the working environment. RESULTS: The facility had been built about 10 years previously and was well maintained. Meal preparations were performed according to the operation manual, and education and training for the food service staff were carried out daily. No problems were evident regarding hygiene management. However, concerning organizational behavior, the satisfaction level of the staff was found to be relatively low, which may have led to a reduction in their organizational commitment and a decrease in their performance. CONCLUSIONS: To aid in the prevention of food poisoning incidents in hospital food service facilities, it is essential not only to conduct standard hygiene management and training, but also to consider the organizational behavior of the food service staff. PMID- 25744796 TI - [Study on health support strategies by analyzing the diet, alcohol intake, and smoking behavior of university students: examination of non-communicable disease risk factors according to their sex, age and living arrangement]. AB - OBJECTIVES: The purpose of this study was to understand the diet, drinking, and smoking behaviors of university students and to analyze the health behaviors that could be a risk factor for non-communicable diseases (NCDs) in order to contribute to the promotion of NCD prevention in youth. METHODS: The survey was carried out using a questionnaire with closed questions including items about health behaviors. The subjects surveyed were students of 10 universities on the main island of Japan (1,196 valid responders). RESULTS: The score for the nutritional balance was significantly low in the group living alone for both students in their teens and 20s. For the frequency of not eating breakfast, results suggest that living alone and increase in age are related to the lack of breakfast for both males and females. Teenage males living alone tended to lack in consideration for the intake of animal fat than those not living alone. The females showed a higher tendency to eat sweets and snacks during the day than the males. For the males who living alone, results suggest that they tended to have a higher or equal alcohol intake to females in their 20s and males in their 20s not living alone even when they are underage. Males in their 20s tended to have a higher amount and frequency of smoking than other groups regardless of their living arrangement. CONCLUSIONS: Accumulation of health behavior that could be a risk for NCDs was found in some of the groups, such as males living alone. PMID- 25744798 TI - [Editor's Note]. PMID- 25744799 TI - The effects on ruminal pH and serum haptoglobin after feeding a grain-based supplement to grazing dairy cows as a partial mixed ration or during milking. AB - Ruminal pH and serum concentrations of haptoglobin (Hp) were measured in order to assess the risk of subacute ruminal acidosis (SARA) in grazing cows offered rolled wheat grain twice daily in the dairy at milking (Control group; n= 64), or as a partial mixed ration (PMR group; n= 64) on a feedpad. Cows were allocated various levels of the supplement (8, 10, 12 or 14 kg dry matter/day). Ruminal pH was measured in 16 rumen-fistulated cows (eight PMR and eight Control group cows), using indwelling pH meters, recording every 10 min for 14 days. Serum Hp was analysed in samples collected from 125 cows. No differences in ruminal pH or serum Hp concentration were found between treatment groups, or levels of feeding. It was concluded that, using ruminal pH patterns and Hp as markers of SARA at the feeding levels used in this study, there were no differences between grazing cows fed the supplement either as grain in the dairy or as a PMR fed on a feedpad. PMID- 25744800 TI - Ovine congenital myotonia associated with a mutation in the muscle chloride channel gene. AB - Congenital myotonia (CM) is characterised by a delay in muscular relaxation after sudden contractions. In a recent outbreak of ovine CM affecting 1% of new-born lambs in a Spanish flock of Rasa Aragonesa sheep, a comparative pathology approach was taken: because a mutation in the muscle chloride channel gene (CLCN1) was identified as responsible for CM in goats, the same gene was sequenced in the affected lambs. A non-synonymous single nucleotide variation (SNV) in the second exon of CLCN1 was associated with this pathology. Rams carrying this SNV heterozygously were thereafter identified and replaced by wild type homozygous young males. No additional CM cases were detected in subsequent lambing seasons. PMID- 25744801 TI - Influence of experimental protocol on response rate and repeatability of mechanical threshold testing in dogs. AB - Mechanical threshold (MT) testing is widely used to measure nociceptive thresholds. However, there has been little research into factors that contribute to the response rate and repeatability (collectively termed 'efficacy') of MT testing protocols. The aim of this study was to investigate whether the efficacy of a protocol using a hand-held algometer to measure MTs (N) in healthy dogs (n = 12) was affected by varying (1) the area over which force was applied (tip diameter), (2) rate of force application, (3) position of dog during testing, and (4) anatomical site of testing. The effect of these factors on MT and the impact of individual dog effects on both efficacy and MT were also investigated. Overall, 3175/3888 tests (82%) resulted in a measurable response. The response rate was reduced by using wider tip diameters, testing at the tibia, and testing when the dog was lying down (compared to sitting upright). Wider tips were associated with higher, more variable MTs (mean +/- standard deviation) with values of 4.18 +/- 2.55 N for 2 mm diameter tips, 5.54 +/- 3.33 for those of 4 mm, and 7.59 +/- 4.73 for 8 mm tips. Individual dog effects had the most significant impact on efficacy and MT. The findings indicate that tip diameter, dog position, and anatomical site may affect both protocol efficacy and MTs, and should be taken into account when comparing different studies and in designing protocols to measure MTs in dogs. The predominant effect of the individual dog over other factors indicates that between-subject differences should always be accounted for in future studies. PMID- 25744802 TI - Serum thymidine kinase activity in clinically healthy and diseased horses: a potential marker for lymphoma. AB - Serum thymidine kinase (sTK) activity is a tumour marker used as a prognostic indicator for lymphoma in humans, dogs and cats. The aim of this study was to evaluate the clinical utility of sTK as a biomarker for lymphoma in horses. Serum samples were collected from clinically normal horses (n = 37), horses with lymphoma (n = 23), horses with non-haematopoietic neoplasia (n = 9) and horses with inflammatory disease (n = 14). sTK was measured using a radioenzyme assay. A reference cut-off value of <2.7 U/L (mean + 2 standard deviations, SDs) was established using data from clinically normal horses. sTK activity (mean +/- SD) was 26.3 +/- 91.5 U/L (range 0.8-443 U/L) for horses with lymphoma, 2.3 +/- 1.4 U/L (range 0.6-5.7 U/L) for horses with non-haematopoietic neoplasia and 1.5 +/- 0.6 U/L (range 0.6-2.8 U/L) for horses with inflammatory disease. Horses with lymphoma had significantly higher sTK activity than horses without clinical signs of disease (P <0.01), horses with inflammatory disease (P <0.01) and horses with non-haematopoietic neoplasia (P <0.05). sTK activity is a potentially useful biomarker for equine lymphoma. PMID- 25744803 TI - Comparison of a new metamizole formulation and carprofen for extended post operative analgesia in dogs undergoing ovariohysterectomy. AB - A newly developed slow-release tablet formulation of metamizole was compared with carprofen for post-operative analgesia in dogs undergoing ovariohysterectomy. Twenty-three dogs were randomly assigned to one of two groups, and administered 50 mg/kg metamizole PO (Group M) or 4 mg/kg carprofen PO (Group C) 1 h before anaesthetic induction and 24 and 48 h later. Anaesthesia was induced with propofol and maintained with isoflurane and fentanyl, after premedication with 0.005 mg/kg medetomidine and 0.3 mg/kg methadone IM. A blinded observer assessed post-operative sedation, and analgesia using a visual analogue scale, a dynamic interactive visual analogue scale, the Glasgow composite pain scale (GCPS), and a mechanical nociceptive threshold device (T = 0.5, 1, 2, 4, 8, 12, 18, 21, 24, 36, 45, 60 and 70 h after surgery). Rescue methadone was administered if the GCPS was >6/24 in ambulatory dogs, or >5/20 in non-ambulatory dogs. Plasma concentrations of test drugs were quantified. The dose range for metamizole was 39-56 mg/kg. At T = 0.5 h sedation scores were significantly higher in Group C and GCPS scores were significantly higher in Group M. Three dogs required rescue methadone (Group M, n = 1; Group C, n = 2). Vomiting occurred post-operatively in 45% of dogs in Group M. Carprofen and metamizole were both well absorbed; peak concentrations occurred within 4-24 h, and 4-16 h for carprofen and metamizole, respectively. Both drugs provided adequate analgesia of similar duration. No side effects were observed with carprofen while vomiting was frequent following administration of metamizole. PMID- 25744804 TI - Cancer stem cells: current status and future directions. PMID- 25744805 TI - The effect of inter-laboratory variability on the protein:creatinine (UPC) ratio in canine urine. AB - Quantification of proteinuria is a fundamental step in staging dogs with chronic kidney disease and in monitoring the course of disease or the efficacy of anti proteinuric treatments. Analytical precision and accuracy of the proteinuria assessment could be affected by several factors such as biological variability, different operators and quality control materials. The aim of this study was to assess whether inter-laboratory variability could affect the urinary protein to creatinine (UPC) ratio and whether this variability may affect patient classification according to the International Renal Interest Society (IRIS) sub staging system. The same urine samples were analysed in three different laboratories using different instruments and different reagent brands. The results of the three laboratories were highly correlated to each other although urinary protein (UP), urinary creatinine (UC) and the UPC ratio of one laboratory were found to be significantly higher than those of the other two. No significant differences between the other two laboratories were recorded. The concordance in classifying dogs according to the IRIS guidelines was good if all three proteinuria categories were analysed separately or if borderline proteinuric (BP) dogs were included in the proteinuric group, and very good if BP dogs were merged into the non-proteinuric group. The inter-laboratory variability in UPC ratio measurement was not so great as to impede the identification of proteinuric dogs, but may influence the estimation of the magnitude of proteinuria. PMID- 25744806 TI - Small molecule kinase inhibitors in veterinary oncology. PMID- 25744807 TI - Pre-analytical stability of adrenocorticotrophic hormone from healthy horses in whole blood, plasma and frozen plasma samples. AB - The stability of equine adrenocorticotrophic hormone (ACTH) in blood samples is not fully known. The study objectives were to determine ACTH stability (1) in whole blood and plasma over 72 h at either 4 or 21 degrees C, and (2) in plasma frozen at either -20 or -80 degrees C over 30 days. Nine horses were sampled and ACTH concentration were measured after storage as whole blood or plasma, at 4, 21, -20 and -80 degrees C for up to 30 days. The ACTH concentration was significantly reduced at 24 h but remained stable when plasma was frozen at -20 and -80 degrees C for 30 days. Beyond 24 h, samples stored at 21 degrees C showed a greater reduction in ACTH concentrations than those stored at 4 degrees C. Therefore, samples can be stored for 8 h without centrifugation, or frozen for 30 days without appreciable reductions in ACTH concentrations. PMID- 25744808 TI - Advances in the understanding of the clinically relevant genetic pathways and molecular aspects of canine mammary tumours: part 1. Proliferation, apoptosis and DNA repair. AB - There have been significant recent advances in the understanding of the molecular events and critical pathways associated with and driving cancer of the mammary gland in humans and dogs. The study of canine mammary tumour biology, particularly of the molecular events associated with proliferation, cell survival, invasion and metastasis, is crucial for the development of effective therapeutic agents and strategies. In this first part of a two-part review, recent advances in the understanding of the clinically relevant genetic and molecular pathways driving cell proliferation, apoptosis and DNA repair in canine mammary gland tumours are described. PMID- 25744809 TI - Ex vivo pharmacokinetic and pharmacodynamic analysis of valnemulin against Mycoplasma gallisepticum S6 in Mycoplasma gallisepticum and Escherichia coli co infected chickens. AB - Pharmacokinetic and pharmacodynamic (PK/PD) indices against Mycoplasma gallisepticum (MG) S6 were investigated in an ex vivo PK/PD model following oral administration of valnemulin to chickens co-infected with M. gallisepticum and Escherichia coli. The minimum inhibitory concentrations (MICs) for valnemulin against MG S6 in artificial medium and chicken serum were determined. In vitro time-killing curves were established according to a series of multiples of the MIC value in an artificial medium, and ex vivo time-killing curves were established in serum samples obtained from infected chickens at different time points after oral administration with an initial titer of 1 * 10(6) color change units (CCU)/mL MG S6. The sigmoid Emax model was used to provide 24 h area under concentration-time curve/minimum inhibitory concentration ratios (AUC0-24h/MIC) for mycoplasmastasis, mycoplasmacidal activity and mycoplasmal elimination, respectively. The inoculum size and micro or macro methods exhibited little effect on MIC determination of MG, whereas matrix had a large effect. The rapid killing activity observed in in vitro time-killing curves seems to indicate that valnemulin was mycoplasmacidal and concentration dependent against MG. The AUC0 24h/MIC ratio for mycoplasmacidal activity and mycoplasmal elimination was 1321 h and 1960 h, respectively. A dosage regimen of 12.4 mg/kg/day and 18.3 mg/kg/day valnemulin was calculated for mycoplasmacidal activity and mycoplasmal elimination against MG S6, respectively. PMID- 25744810 TI - Dairy herd mastitis and reproduction: using simulation to aid interpretation of results from discrete time survival analysis. AB - Probabilistic sensitivity analysis (PSA) is a simulation-based technique for evaluating the relative importance of different inputs to a complex process model. It is commonly employed in decision analysis and for evaluation of the potential impact of uncertainty in research findings on clinical practice, but has a wide variety of other possible applications. In this example, it was used to evaluate the association between herd-level udder health and reproductive performance in dairy herds. Although several recent studies have found relatively large associations between mastitis and fertility at the level of individual inseminations or lactations, the current study demonstrated that herd-level intramammary infection status is highly unlikely to have a clinically significant impact on the overall reproductive performance of a dairy herd under typical conditions. For example, a large increase in incidence rate of clinical mastitis (from 92 to 131 cases per 100 cows per year) would be expected to increase a herd's modified FERTEX score (a cost-based measure of overall reproductive performance) by just L4.50(1) per cow per year. The herd's background level of submission rate (proportion of eligible cows served every 21 days) and pregnancy risk (proportion of inseminations leading to a pregnancy) correlated strongly with overall reproductive performance and explained a large proportion of the between-herd variation in performance. PSA proved to be a highly useful technique to aid understanding of results from a complex statistical model, and has great potential for a wide variety of applications within the field of veterinary science. PMID- 25744811 TI - Imaging of ceramic liner fractures in total hip arthroplasty: the value of CT. AB - Fracture of a ceramic liner of a total hip arthroplasty is rare and is radiographically occult if not displaced. We report on two patients in whom ceramic liner fracture was radiographically occult but was diagnosed on subsequent CT scan through appropriate windowing. PMID- 25744812 TI - Is there a role for diffusion-weighted MRI (DWI) in the diagnosis of central cartilage tumors? AB - OBJECTIVE: To assess if diffusion-weighted MRI (DWI) can differentiate between central enchondromas and chondrosarcomas (CS) and if DWI can distinguish low grade chondroid lesions from high-grade CS. MATERIALS AND METHODS: Fifty-two patients with central cartilage tumors were included. Patients underwent conventional MRI and DWI with ADC mapping. The slice on MRI with the most aggressive imaging feature was identified. The corresponding mean and minimum ADC maps of the tumor at this position were measured. RESULTS: There were 24 enchondromas, five atypical cartilaginous lesions, 15 grade 1, three grade 2, two grade 3, and three dedifferentiated CS. Mean ADC values (*10(-6) mm2/s) for enchondromas, atypical cartilaginous tumors, grade 1 CS, grade 2, CS, grade 3 CS and dedifferentiated CS were 1,896, 2,048, 2,152, 2,170, 2,076, and 1,261, respectively. Minimum ADC values (*10(-6) mm2/s) for enchondromas, atypical cartilaginous tumors, grade 1 CS, grade 2, CS, grade 3 CS and dedifferentiated CS were 1,820, 1,752, 2,010, 1,829, 1,752, and 767, respectively. ANOVA test demonstrated a statistically significant difference in mean and minimum ADC values in all groups. Post hoc analysis revealed this was due to difference in mean and minimum ADC values in dedifferentiated CS. The mean ADC value in low grade chondroid lesions was 2,001, while the ADC value for high-grade CS were 2,132. The minimum ADC value for low-grade chondroid lesions was 1,896, while the minimum ADC for high-grade CS was 1,837. The difference in minimum and mean ADC values was not statistically significant. CONCLUSIONS: DWI cannot differentiate between enchondromas and CS and DWI does not aid in the distinction of low-grade chondroid tumors from high-grade CS. PMID- 25744813 TI - Avoiding perioperative dexamethasone may improve the outcome of patients with rectal cancer. AB - BACKGROUND: Perioperative administration of dexamethasone may augment recurrence and mortality after tumor resection possibly by immunosuppression, which, unfortunately, has never been noted. We therefore carried out a retrospective study in rectal cancer to validate the hypothesis. METHODS: Five hundreds and fifteen patients with stage I to III rectal cancers who underwent a curative resection from June 2007 and June 2011 were enrolled in the current study. Patients who had been given intravenous (IV) dexamethasone (4-10 mg) postoperatively and/or intraoperatively were assigned to dexamethasone group. The outcome of dexamethasone group and non-dexamethasone group were compared. The primary outcome was disease-free survival (DFS) and overall survival (OS). RESULTS: dexamethasone group had significant lower three-year DFS (62.3% vs 71.8%, P = 0.026) and OS (74.1% vs 82.9%, P = 0.031) rate in comparison to non dexamethasone group, the hazard ratios (HRs) of which were 1.59 (95% CI 1.05 2.39, P = 0.028) and 1.77 (95% CI 1.05-3.01, P = 0.034), respectively. Multivariate analysis revealed that administration of systemic dexamethasone were independently associated with DFS [adjusted HR 1.60 (95% CI 1.03-2.49, p = 0.039)], but for OS, dexamethasone didn't remain significant in this model. In the analyses of a subgroup of 428 patients (55/428 in dexamethasone group) without perioperative blood transfusion, dexamethasone had independently impact on both DFS and OS. CONCLUSION: Patients not given dexamethasone had better three year survival outcomes compared with patients given dexamethasone perioperatively. Our results indicate that rectal cancer patients treated with curative surgery may get survival benefit from avoiding low-dose perioperative dexamethasone. PMID- 25744814 TI - Slow Photoelectron Velocity-Map Imaging Spectroscopy of the ortho Hydroxyphenoxide Anion. AB - We report high-resolution photodetachment spectra of cryogenically cooled ortho hydroxyphenoxide anions (o-HOC6H4O(-)) using slow photoelectron velocity-map imaging spectroscopy (cryo-SEVI). We observe transitions to the three lowest lying electronic states of the ortho-hydroxyphenoxy radical, and resolve detailed vibrational features. Comparison to Franck-Condon simulations allows for clear assignment of vibronic structure. We find an electron affinity of 2.3292(4) eV for the neutral X(2)A" ground state, improving upon the accuracy of previous experiments. We measure term energies of 1.4574(7) eV and 1.5922(48) eV for the A(2)A' and B(2)A" excited states respectively, representing their first resolution and clear assignment. Photodetachment threshold effects are considered to explain the structure of these bands. PMID- 25744815 TI - Community Health Workers as Agents of Health Promotion: Analyzing Thailand's Village Health Volunteer Program. AB - The village health volunteers (VHVs) have been a regular part of Thailand's health system since the 1960s. Despite widespread recognition, little research has been conducted to describe VHV activities, the settings in which VHVs provide help, how the program is administered, and how changing politics and health problems in Thailand have influenced the program. In order to understand the roles and practices of the VHVs, we conducted in-depth semi-structured interviews and focus groups with VHVs, community leaders and members, and public health officials in three semi-urban communities in central Thailand. Using the Social Ecological Framework, we mapped factors that influenced how the VHVs provided support, including governmental oversight, collaboration with public health officials, and community trust. These influences are discussed as "points of consideration," which help to identify the strengths and tensions within the VHV program and best practices in supporting and assessing community health worker efforts. PMID- 25744816 TI - Spatial extent of a Landauer residual-resistivity dipole in graphene quantified by scanning tunnelling potentiometry. AB - Electronic transport on a macroscopic scale is described by spatially averaged electric fields and scattering processes summarized in a reduced electron mobility. That this does not capture electronic transport on the atomic scale was realized by Landauer long ago. Local and non-local scattering processes need to be considered separately, the former leading to a voltage drop localized at a defect, the so-called Landauer residual-resistivity dipole. Lacking precise experimental data on the atomic scale, the spatial extent of the voltage drop remained an open question. Here, we provide an experimental study showing that the voltage drop at a monolayer-bilayer boundary in graphene clearly extends spatially up to a few nanometres into the bilayer and hence is not located strictly at the structural defect. Moreover, different scattering mechanisms can be disentangled. The matching of wave functions at either side of the junction is identified as the dominant process, a situation similar to that encountered when a molecule bridges two contacts. PMID- 25744817 TI - Arsenic, heavy metals, phthalates, pesticides, hydrocarbons and polyfluorinated compounds but not parabens or phenols are associated with adult remembering condition: US NHANES, 2011-2012. AB - Links between environmental chemicals and human health have emerged, but the effects on cognition were less studied. Therefore, it was aimed to study the relationships of different sets of environmental chemicals and the remembering condition in a national and population-based study in recent years. Data was retrieved from the US National Health and Nutrition Examination Surveys, 2011 2012, including demographics, blood pressure readings, serum measurements, lifestyle factors, self-reported remembering condition and urinary environmental chemical concentrations. Analyses included Chi-square test, t test and survey weighted logistic and multi-nominal regression models. Among the elderly aged 60 80 (n = 1791), 320 (17.9%) had difficulties in thinking or remembering. People who had difficulties in thinking or remembering had higher levels of urinary heavy metals, phthalates, pesticides and hydrocarbon concentrations but lower levels of urinary arsenic and polyfluorinated compound concentrations. During the recent past week, 146 people (8.2%) had trouble remembering for more than three times while 619 people (35.2%) had that for one to three times. These people had higher levels of urinary heavy metals, phthalates, pesticides and hydrocarbon concentrations but lower levels of urinary polyfluorinated compound concentrations. There were no associations with urinary bisphenols, parabens, perchlorate, nitrate or thiocyanate concentrations. This is the first time observing statistically significant risk associations of urinary heavy metals, phthalates, pesticides and hydrocarbon concentrations and the remembering condition specifically in the elderly, although the causality cannot be established. Elimination of such environmental chemicals in humans might need to be considered in future health policy and intervention programs. PMID- 25744818 TI - Fulvic acid mediates chromium (Cr) tolerance in wheat (Triticum aestivum L.) through lowering of Cr uptake and improved antioxidant defense system. AB - Chromium (Cr) stress is one of the most adverse environmental factors that affect plant growth and food chain contamination. Fulvic acid (FA) is known to enhance the growth and production of crops, but the studies are scare regarding the application of FA on metal tolerance in plants. The effects of FA application on alleviating Cr phytotoxicity in wheat plants were investigated in a pot experiment conducted in sand- and soil-grown plants. Three Cr (0, 0.25, and 0.50 mM) treatments in the form of K2Cr2O7 were applied in both soils with or without foliar application of 1.5 mg L(-1) FA. Plants were harvested after 4 months of treatments, and data regarding growth characteristics, biomass, photosynthetic pigments, and antioxidant enzymes were recorded. FA application increased plant biomass, photosynthetic pigments, and antioxidant enzymes while it decreased Cr uptake and accumulation in plants as compared with Cr treatments alone. We conclude that FA application contributes to decreased Cr concentrations in wheat grains and could be used as an amendment when aiming for decreased metal concentration in plants. PMID- 25744819 TI - Gibberellic acid in combination with pressmud enhances the growth of sunflower and stabilizes chromium(VI)-contaminated soil. AB - The present study was conducted to assess the impact of gibberellic acid on growth and yield of sunflower in hexavalent chromium [Cr(VI)]-contaminated soil in the presence as well as absence of pressmud. Seeds of sunflower were sown in potted soil amended with pressmud as an organic amendment and contaminated with different levels of Cr(VI) (12, 18, and 24 mg kg(-1)) by using K2Cr2O7 salt. Gibberellic acid (10(-4) M) was applied at time of seedling emergence in the rhizosphere. The results showed that Cr(VI) stress significantly reduced the growth and yield of sunflower. However, application of gibberellic acid and pressmud reversed the toxic effects of Cr(VI) and improved the growth and yield of sunflower. Combined application of gibberellic acid and pressmud further improved growth and yield compared to their separate application in Cr(VI) stress. Moreover, gibberellic acid and pressmud decreased the uptake of Cr and stabilized it in the soil. PMID- 25744820 TI - Riparian buffer zones as pesticide filters of no-till crops. AB - Several studies have pointed to the potential benefits of riparian vegetation as buffer zones for agricultural and industrial pollutants harmful to aquatic ecosystems. However, other studies have called into question its use as an ecological filter, questioning the widths and conditions for which they are effective as a filter. In this work, we have investigated the buffering capacity of the riparian one to retain pesticides in the water-saturated zone, on 27 sites composed by riparian buffer zones with different vegetation structure (woody, shrubs, or grass vegetation) and width (12, 36, and 60 m). Five pesticides were analyzed. The effectiveness of the filtering was largely influenced by the width and vegetation type of the buffer zone. In general, decreasing pesticide removal followed in this order wood > shrubs > grass. The 60 m woody buffer zone was the most effective in the removal of all the pesticides. Only atrazine was detected in this case (0.3 MUg L(-1)). Furthermore, a linear correlation (R (2) > 0.97) was observed in their removal for all compounds and buffer zones studied. Thus, preserving the woody vegetation in the riparian zone is important for watershed management and groundwater quality in the no-tillage system in temperate climate. PMID- 25744821 TI - Sperm-egg penetration assay assessment of the contraceptive effects of glycerol and egg yolk in rooster sperm diluents. AB - Glycerol (GLY) and egg yolk (EY) are good cryoprotectants of avian and mammalian sperm, but in birds, they strongly inhibit the eventual fertilization of ova. Using the sperm penetration (SP-holes) assay and fertility trials, the present study investigates (1) the possible mechanism by which this contraceptive effect occurs in chickens and (2) the maximum concentrations of GLY and EY tolerated by fresh rooster sperm. Seventy Black-Barred Andaluza hens (five per treatment) were inseminated four times (twice per week) with 0.1 mL of fresh semen from roosters of the same breed diluted 1:1 (v:v) with Lake and Ravie medium containing different concentrations of GLY or EY. No adverse effects on acrosome integrity, sperm motility, or viability were seen with any concentration of GLY or EY. The number of SP-holes on perivitelline layer samples taken from above the germinal disc became progressively lower at GLY concentrations of 1.5% or greater (P > 0.05). No holes caused by sperms were seen in unfertilized eggs. The corresponding fertility results showed similar reductions when the GLY concentration was 1.5% or greater. No changes in the number of SP-holes were seen with increasing EY concentrations (0%-7.5%), nor were any differences in fertility observed, except for a reduction when 15% EY was used. The results therefore reveal that GLY affects the transit of sperms through the oviduct in their attempt to reach the infundibulum area, limiting their access to the ovum perivitelline layer. Egg yolk had no such effect, nor did it influence acrosome reaction capacity; its mechanism of contraceptive action therefore remains unknown. The maximum GLY and EY concentrations tolerated by the rooster sperm were 0.75% and 7.5%, respectively. PMID- 25744822 TI - Designing of an artificial neural network model to evaluate the association of three combined Y-specific microsatellite loci on the actual and predicted postthaw motility in crossbred bull semen. AB - The freezing of bull semen significantly hamper the motility of sperm which reduces the conception rate in dairy cattle. The prediction of postthaw motility (PTM) before freezing will be useful to take the decision on discarding or freezing of the germplasm. The artificial neural network (ANN) methodology found to be useful in prediction and classification problems related to animal science, and hence, the present study was undertaken to compare the efficiency of ANN in prediction of PTM on the basis of the number of ejaculates, volume, and concentration of sperms. The combined effect of Y-specific microsatellite alleles on the actual and predicted PTM was also studied. The results revealed that the prediction accuracy of PTM based on the semen quality parameters was comparatively lower because of higher variability in the data set. The ANN gave better prediction accuracy (34.88%) than the multiple regression analysis models (32.04%). The root mean square error was lower for ANN (8.4353) than that in the multiple regression analysis (8.6168). The haplotype or combined effect of microsatellite alleles on actual and predicted PTM was found to be highly significant (P < 0.01). On the basis of results, it was concluded that the ANN methodology can be used for prediction of PTM in crossbred bulls. PMID- 25744823 TI - Evaluation of an aspiration-type semiautomatic cutting biopsy needle. AB - PURPOSE: The purpose of this study was to evaluate an aspiration-type semiautomatic cutting biopsy needle for biopsy of bovine tissue. MATERIAL AND METHODS: Aspiration-type semiautomatic cutting biopsy needles (18 gauge * 160 mm) with aspiration (Group A), aspiration-type semiautomatic biopsy needles without aspiration (Group Wo), or normal-type semiautomatic biopsy needles (18 gauge * 150 mm) (Group N) were used in 10 biopsies each of bovine liver or lung. The specimens were weighed with an electronic balance. RESULTS: Mean (standard deviation) weights for bovine liver specimens in Groups A, Wo, and N were 6.80 (0.615) mg, 5.62 (0.843) mg, and 4.19 (0.140) mg, respectively. Mean weights of bovine lung specimens from Groups A, Wo, and N were 2.98 (0.828) mg, 2.67 (0.832) mg, and 1.94 (0.864) mg, respectively. A significant difference was seen between the 3 groups for bovine liver. However, a significant difference was only seen between Groups A and N for bovine lung. CONCLUSION: Bovine liver and lung specimens obtained using the aspiration-type semiautomatic cutting biopsy needle were heavier than those obtained using the normal-type semiautomatic biopsy needle. PMID- 25744824 TI - A red-shifted photochromic sulfonylurea for the remote control of pancreatic beta cell function. AB - Azobenzene photoresponsive elements can be installed on sulfonylureas, yielding optical control over pancreatic beta cell function and insulin release. An obstacle to such photopharmacological approaches remains the use of ultraviolet blue illumination. Herein, we synthesize and test a novel yellow light-activated sulfonylurea based on a heterocyclic azobenzene bearing a push-pull system. PMID- 25744825 TI - Radio frequency responsive nano-biomaterials for cancer therapy. AB - Radiofrequency (RF)-assisted cancer therapy is well-known in the medical field as it is non-hazardous and can penetrate tissues, enabling a deeply rooted cancer treatment. However, the current treatment regimen is non-specific and invasive, making it difficult for patients to undergo the RF ablation procedure. Recently, there has been tremendous attention given on replacing RF probes (through which the RF current passes into the tumors) with metallic nanoparticles (NPs) such as gold and iron oxide. These metallic NPs can be combined with stimuli responsive polymers to have a simultaneous drug delivery to tumors and better thermal ablation. This review will give a brief overview on the various nanobiomaterials based on metals and polymers and their composites in RF-assisted cancer therapy. Special attention has been given on RF responsive composite nanomaterials. Besides these, the importance of RF-assisted drug delivery using the nanobiomaterials for cancer therapy, as well as the advantages and future perspectives of these materials are discussed in detail. PMID- 25744826 TI - Oil and drug control the release rate from lyotropic liquid crystals. AB - The control of the diffusion coefficient by the dimensionality d of the structure appears as a most promising lever to efficiently tune the release rate from lyotropic liquid crystalline (LLC) phases and dispersed particles towards sustained, controlled and targeted release. By using phosphatidylcholine (PC)- and monolinoleine (MLO)-based mesophases with various apolar structural modifiers and water-soluble drugs, we present a comprehensive study of the dimensional structural control of hydrophilic drug release, including 3-d bicontinuous cubic, 2-d lamellar, 1-d hexagonal and 0-d micellar cubic phases in excess water. We investigate how the surfactant, the oil properties and the drug hydrophilicity mitigate or even cancel the effect of structure variation on the drug release rate. Unexpectedly, the observed behavior cannot be fully explained by the thermodynamic partition of the drug into the lipid matrix, which points out to previously overlooked kinetic effects. We therefore interpret our results by discussing the mechanism of structural control of the diffusion rate in terms of drug permeation through the lipid membrane, which includes exchange kinetics. A wide range of implications follow regarding formulation and future developments, both for dispersed LLC delivery systems and topical applications in bulk phase. PMID- 25744828 TI - [Erythromycin inhibits elastin peptides-induced differentiation of CD4+T cells into Th17 cells]. AB - OBJECTIVE: To investigate the effect of erythromycin on differentiation into T helper 17 (Th17) cells from CD4+T cells exposed to elastin peptides. METHODS: The CD4+T cells from spleen of male BALB/c mice by magnetic bead sorting were randomly divided into the control group (group A), the elastin peptides group (group B) and erythromycin group(group C). The cells in group B and C were cultured in serum-free medium supplemented with 30 MUg/mL elastin peptides. The cells in group C were additionally administrated with erythromycin at a dose of 100 MUg/mL. All of the CD4+T cells were cultured in serum-free culture solution for 24 hours. The number of the Th17 cells was detected by flow cytometry and the expression of retinoic acid related orphan nuclear receptor gammat (RORgammat) mRNA was measured by fluorescence quantitative PCR in each group. The expressions of NF-kappaB(p65) and signal transducer and activator of transcription 3 (STAT3) were analyzed by Western blotting. RESULTS: The Th17 cells in group B [(11.32 +/- 2.34)%] increased as compared with that in group A [(5.21 +/- 1.36)%], and the expression of RORgammat mRNA in group B was higher than that in group A. Furthermore, the expressions of NF-kappaB(p65) and STAT3 proteins in group B increased significantly as compared with those in group A. However, compared with group B, group C presented with the significantly decreased expressions of Th17 cells, RORgammat mRNA, NF-kappaB(p65) and STAT3 proteins. CONCLUSION: Erythromycin can suppress the differentiation into Th17 cells from CD4+T cells exposed to elastin peptides. PMID- 25744829 TI - [CXCL12alpha and CXCL12beta stimulate the migration of cultured LX-2 hepatic stellate cells]. AB - OBJECTIVE: To investigate the influence of chemokine (C-X-C motif) ligand 12alpha (CXCL12alpha) and CXCL12beta on migration of hepatic stellate cells (HSCs). METHODS: The cultured human LX-2 HSCs in vitro were divided into control group, platelet-derived growth factor-BB (PDGF-BB) group (10 ng/mL), CXCL12alpha group (50, 100, 200 ng/mL) and CXCL12beta group (50, 100, 200 ng/mL). TranswellTM assay was used to observe the effect of CXCL12alpha and CXCL12beta on migration of LX-2 cells. Expression of chemokine (C-X-C motif) receptor 4 (CXCR4) in LX-2 cells after treated with or without recombinant human CXCL12 was examined by Western blotting. RESULTS: The number of migration cells in each group were as follows, control group (66.33 +/- 11.43), PDGF-BB group (127.47 +/- 31.68), 50, 100, 200 ng/mL CXCL12alpha group (106.13 +/- 12.94, 125.87 +/- 17.00, 137.07 +/- 21.03), 50, 100, 200 ng/mL CXCL12beta group (103.80 +/- 11.26, 122.33 +/- 19.46, 124.40 +/- 15.16). Both CXCL12alpha and CXCL12beta induced the migration of LX-2 cells, and migratory response increased in a dose-dependent manner. Western blotting demonstrated that CXCR4 was expressed in LX-2 cells and expression level of CXCR4 protein was not altered after stimulation with exogenous CXCL12. CONCLUSION: Both CXCL12alpha and CXCL12beta could induce the migration of HSCs. PMID- 25744827 TI - Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin containing hydrogel nanoparticle. AB - Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limit its clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key characteristic for exploiting this effect, and to that end we have developed long-circulating, PEGylated, polymeric hydrogels using the Particle Replication In Non-wetting Templates (PRINT(r)) platform and complexed cisplatin into the particles (PRINT-Platin). Sustained release was demonstrated, and drug loading correlated to surface PEG density. A PEG Mushroom conformation showed the best compromise between particle pharmacokinetic (PK) parameters and drug loading (16wt.%). While the PK profile of PEG Brush was superior, the loading was poor (2wt.%). Conversely, the drug loading in non-PEGylated particles was better (20wt.%), but the PK was not desirable. We also showed comparable cytotoxicity to cisplatin in several cancer cell lines (non-small cell lung, A549; ovarian, SKOV-3; breast, MDA-MB-468) and a higher MTD in mice (10mg/kg versus 5mg/kg). The pharmacokinetic profiles of drug in plasma, tumor, and kidney indicate improved exposure in the blood and tumor accumulation, with concurrent renal protection, when cisplatin was formulated in a nanoparticle. PK parameters were markedly improved: a 16.4-times higher area-under-the-curve (AUC), a reduction in clearance (CL) by a factor of 11.2, and a 4.20-times increase in the volume of distribution (Vd). Additionally, non-small cell lung and ovarian tumor AUC was at least twice that of cisplatin in both models. These findings suggest the potential for PRINT-Platin to improve efficacy and reduce toxicity compared to current cisplatin therapies. PMID- 25744830 TI - [Tanreqing injection promotes the immune function of mice with Lewis lung carcinoma after chemotherapy]. AB - OBJECTIVE: To investigate the effect of Tanreqing injection on immune function of mice with Lewis lung carcinoma treated by chemotherapy and discuss the immunoregulatory function of this herb. METHODS: All mouse models with Lewis lung carcinoma were randomly divided to four groups: model control group, Tanreqing injection group, chemotherapy group and chemotherapy combined with Tanreqing injection group (8 rats in each group). Other 8 normal mice served as a normal control group. After treatment, peripheral blood was collected from the mice of all groups before they were sacrificed. Tumor tissue, femur, thymus and spleen were obtained to perform the following experiments. Tumor mass and volume were first observed. The apoptosis levels of tumor cells and the ratios of CD3+T lymphocyte and CD3-NK1.1+ cells in the infiltrating lymphocytes in the tumor tissues were analyzed by flow cytometry. Thymus indexes (TI) were counted, and the structure of thymus was observed using HE staining. Cytotoxicity of spleen cytotoxic T cells (CTL) were investigated by MTT assay. The number of lymphocytes in the periphery blood and the nucleated cells in femur were also detected, and the expression levels of interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) mRNA in the tumor tissues were studied by reverse transcription PCR. RESULTS: After chemotherapy, TI, the number of the nucleated cells in femur and lymphocytes in peripheral blood of chemotherapy combined with Tanreqing injection group were obviously higher than those in the chemotherapy group. The ratios of CD3+T lymphocytes and CD3-NK1.1+ cells in the infiltrating lymphocytes in the tumor tissues of chemotherapy combined with Tanreqing injection group were also significantly higher than those in the chemotherapy group. Besides, compared with chemotherapy group, cytotoxicity of CTL in chemotherapy combined with Tanreqing injection group was improved notably. Meanwhile, the expression levels of IFN-gamma and TNF-alpha mRNA in tumor tissues of chemotherapy combined with Tanreqing injection group were dramatically higher than those in chemotherapy group. CONCLUSION: Tanreqing injection has certain protective effects on damaged immune function of body with lung carcinoma induced by chemotherapy, and also improves the anti-tumor immune function of the body. PMID- 25744831 TI - [Inhibitory effect of wogonin on the proliferation and invasion of glioblastoma U87 cells and related mechanism]. AB - OBJECTIVE: To explore the effect of wogonin on the proliferation and invasion of glioblastoma U87 cells and its related mechanism. METHODS: Glioblastoma U87 cells were cultured in vitro in RPMI1640 medium added with 100 mL/L fetal bovine serum. After cell adherence, the cells were inoculated with 20 MUL culture solution (control group), 20 MUL wogonin solutions (0, 50 and 100) MUmol/L for 48 hours, respectively. The 0 MUmol/L wogonin group used 20 MUL PBS instead. Cell proliferation was analyzed by MTT assay. The cell invasion ability was detected using TranswellTM invasion assay. The expressions of ezrin mRNA was examined through real-time quantitative PCR. The expressions of ezrin, Bcl-2 and Bax proteins as well as phosphorylated ezrin protein level were measured by Western blotting. Apoptosis index (AI) was determined through terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. RESULTS: The inhibitory rate of cell proliferation significantly increased in 50 and 100 MUmol/L wogonin groups as compared with 0 MUmol/L wogonin group and control group. Moreover, that was higher in 100 MUmol/L wogonin group than 50 MUmol/L wogonin group. In comparison with control and 0 MUmol/L wogonin groups, the mean cell numbers of permeated membrane, levels of ezrin mRNA, ezrin protein and Bcl-2 protein, and phosphorylated ezrin protein level gradually decreased but the level of Bax protein and AI were gradually elevated with the increase of wogonin concentrations; however, there was no significant difference in these indicators between 0 MUmol/L wogonin group and control group. CONCLUSION: Wogonin could attenuate the proliferation and invasion of wogonin U87 cells, which may be associated with the inhibition of ezrin protein expression and phosphorylation activity and the induction of cell apoptosis. PMID- 25744832 TI - [IL-8 inhibits the apoptosis of MCF-7 human breast cancer cells by up-regulating Bcl-2 and down-regulating caspase-3]. AB - OBJECTIVE: To investigate the effect of interleukin-8 (IL-8) on the apoptosis of MCF-7 human breast cancer cells and the molecular mechanism. METHODS: The expressions of IL-8 receptors (CXCR1, CXCR2) in MCF-7 cells were detected by Western blotting. The effects of 0, 20, 40, 80, 160 ng/mL IL-8 on the expressions of apoptosis-related genes Bcl-2 and caspase-3 in MCF-7 cells were observed by reverse transcription PCR(RT-PCR) and Western blotting. Cell proliferation was determined by CCK-8 assay after 0, 40, 80 ng/mL IL-8 treatment. Phase contrast microscope was used to examine cell morphology of MCF-7 cells after 80 ng/mL IL-8 treatment. The effects of 80 ng/mL IL-8 combined with PD980590 (10 MUmol/L), LY294002 (10 MUmol/L) or AG490 (50 MUmol/L) [mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal pathway inhibitors, respectively], on the expression of Bcl-2 were detected by Western blotting. The effects of 0, 20, 40, 80, 160 ng/mL IL-8 on the expression of p-AKT in MCF-7 cells were observed by Western blotting. The effects of 80 ng/mL IL-8 combined with 10 MUmol/L LY294002 on the apoptosis of MCF-7 cells, the expressions of Bcl 2 and caspase-3 were determined by flow cytometry, RT-PCR and Western blotting, respectively. RESULTS: Both CXCR1 and CXCR2 were expressed in MCF-7 cells. IL-8 markedly up-regulated the anti-apoptotic gene Bcl-2, down-regulated the pro apoptotic gene caspase-3, and significantly inhibited the apoptosis of MCF-7 cells. However, these effects were blocked by phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), signal pathway inhibitor LY294002. As predicted, IL-8 markedly increased the expression of p-AKT in MCF-7 cells. CONCLUSION: IL-8 might significantly inhibit the apoptosis of MCF-7 cells. This effect may be achieved by up-regulating Bcl-2 and down-regulating caspase-3 via PI3K/AKT signal pathway. PMID- 25744833 TI - [Cigarette smoke extract down-regulates expression of histone deacetylase 2 and increases inflammatory cytokines releasing from murine C2C12 skeletal muscle myocytes]. AB - OBJECTIVE: To observe changes of inflammatory mediators, histone deacetylase 2 (HDAC2) and nuclear factor kappaB (NF-kappaB) in murine C2C12 skeletal muscle myocytes after exposed to cigarette smoke. METHODS: Murine C2C12 skeletal muscle myocytes were cultured and treated with cigarette smoke extract (CSE). MTT assay was used to detect the effect of CSE on cell proliferation to determine appropriate concentration of CSE. The C2C12 cells cultured for 6-7 days were planted in six-well plates, and divided into control group, (6.25, 12.50, 25.0) mL/L CSE groups. The cells were cultured for 24 hours. The levels of interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) in the supernatant were measured by ELISA. The mRNA level of HDAC2 was determined by real-time quantitative PCR. The protein level of HDAC2 was detected by Western blotting. HDAC2/NF-kappaB compound was determined by the method of co-immunoprecipitation. RESULTS: MTT assay showed that CSE at the concentration of 50 mL/L inhibited proliferation of C2C12 cells. After 24-hour treatment with CSE, IL-8 and TNF alpha releasing from C2C12 cells increased and the level of HDAC2 mRNA and protein were reduced, which were CSE dose-dependent. Co-immunoprecipitation confirmed that HDAC2/NF-kappaB compound existed in the CSE-exposed C2C12 cells. CONCLUSION: CSE can down-regulate the expression of HDAC2 and increase inflammatory cytokines releasing from C2C12 cells. PMID- 25744834 TI - [Protective effect of hydrogen sulfide on rats with myocardial ischemia/reperfusion injury and its mechanism]. AB - OBJECTIVE: To explore the protective effect of hydrogen sulfide (H2S) on rats with myocardial ischemia/reperfusion injury (MIRI) and its related mechanism. METHODS: Thirty male SD rats were randomly divided into 3 groups: control group, model group and H2S-treated group (n=10 in each). The MIRI model was established by ligating left anterior descending coronary artery for 40 minutes followed by reperfusion for 2 hours. Rats in H2S-treated group were injected with 14 MUmol/kg sodium hydrosulfide (NaHS) intraperitoneally before ischemia and reperfusion, respectively. After 24 hours of reperfusion, blood was collected from abdominal aorta and serum was separated. Then, the heart was removed. The myocardial histopathological changes were observed using HE staining. Serum levels of creatine kinase MB isozyme (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI), as well as the activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione-peroxidase (GSH-Px) and catalase (CAT) in the homogenate of myocardium were examined using the kits. Myocardial interleukin (IL)-1beta, IL-6, IL-18 and tumor necrosis factor-alpha (TNF-alpha) contents were detected by ELISA. The levels of intracytoplasm Keap 1 and intranuclear nuclear factor-erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappaB (NF-kappaB) p65 in myocardium were measured using Western blotting. RESULTS: H2S administration markedly relieved the pathological injury of myocardium. In comparison with control group, serum CK-MB, LDH and cTnI levels, myocardial MDA activities, nuclear factor erythroid 2-related factor 2 (Nrf2) and NF-kappaB p65 levels in the nucleus, and myocardial contents of IL-1beta, IL-6, IL-18 and TNF alpha were significantly elevated, whereas myocardial SOD, GSH-Px and CAT activities as well as Keap 1 level in the cytoplasm were significantly reduced in model group. After H2S treatment, serum CK-MB, LDH and cTnI levels, myocardial MDA activities, Keap 1 level in the cytoplasm, myocardial contents of IL-1beta , IL-6, IL-18 and TNF-alpha, and NF-kappaB p65 levels in the nucleus decreased, but myocardial SOD, GSH-Px and CAT activities, and Keap 1 level in the cytoplasm increased as compared with model group. CONCLUSION: Exogenous H2S could confer protection against MIRI in mice. The mechanism might be related to the enhancement of antioxidative ability and the decrease of inflammatory factor release. PMID- 25744835 TI - [Twist gene promotes the formation and migration of mammospheres of BT-549 breast cancer cells]. AB - OBJECTIVE: To investigate the effect of Twist gene deficiency on the enrichment and migration of breast cancer stem-like cells (CSCs). METHODS: Twist gene in the BT-549 cell line was knocked down by shRNA interference technology, and the cell line BT-549-shVec was used as the negative control group. Interference efficiency was determined by real-time quantitative RT-PCR (qRT-PCR) and Western blotting. Mammospheres with the characteristics of stem-like cells were collected by long term serum-free suspension cultivation. The migration ability of mammospheres was analyzed by Transwell(TM) assay. RESULTS: The BT-549-shTwist breast cancer cells were successfully established by shRNA interference technology. The enrichment and migration abilities of CSCs from the BT-549-shTwist cell line decreased significantly. CONCLUSION: Twist gene promotes the enrichment and migration of CSCs from the BT-549 cell line. PMID- 25744836 TI - [Enhanced expressions of Wnt5a/JNK signaling pathway-related molecules in the lung tissues of asthmatic rats]. AB - OBJECTIVE: To observe the expression of Wnt5a/c-Jun N-terminal kinase (JNK) signaling pathway in the lung of asthmatic rats. METHODS: The experimental rats were randomly divided into two groups, the model group and the control group. After the rat models of asthma were established, airway pathological changes were observed by HE staining; the expression of Wnt5a mRNA in the lung tissues and peripheral blood cells was examined by real-time quantitative PCR; and the levels of phospho-c-Jun (p-c-Jun) and phospho-c-Jun N-terminal kinase (p-JNK) proteins in the lung tissues were measured by Western blotting. RESULTS: Compared with the control group, asthmatic rats presented with thickened bronchial mucosa with more obvious chrysanthemum fold, narrower airway, and more inflammatory cells infiltrated around trachea and pulmonary vessels. The inner airway wall and smooth muscle layer were much thicker in rats of asthma group than those of control group. The levels of Wnt5a mRNA, p-c-Jun and p-JNK proteins in the lung and blood of asthmatic rats increased as compared with the control group. CONCLUSION: The expressions of Wnt5a mRNA, p-JNK and p-c-Jun proteins were elevated in asthmatic rats. PMID- 25744837 TI - [Establishment and biological characterization of 5-fluorouracil-resistant human colon cancer HT-29/5-FU cell line]. AB - OBJECTIVE: To establish 5-fluorouracil (5-FU)-resistant human colon cancer HT-29 cell line (HT-29/5-FU) in vitro and observe its biological properties. METHODS: The HT-29/5-FU cell line was established by continuously exposing the HT-29 cells to ascending doses of 5-FU. The morphology and colony formation rate were detected. The growth curve and the chemosensitivity of HT-29/5-FU cell line were determined by MTT assay. Western blotting was used to analyze the expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). Cell cycle and apoptosis were measured by flow cytometry. RESULTS: The resistance of HT-29/5 FU cells to 5-FU was 3.59-fold greater than that of HT-29 cells. The morphology of HT-29/5-FU cells differed from that of HT-29 cells. Compared with HT-29 cells, HT-29/5-FU cells showed remarkable reduction of cell proliferation and colony formation, higher expressions of TS and DPD, higher percentage of cells in the S phase, and stronger ability of resistance to apoptosis induced by 5-FU. CONCLUSION: The biological characters of HT-29/5-FU cell line may play an important role in 5-FU-resistant mechanisms, which may also contribute to elucidate the potential mechanisms of tumor drug resistance as well as resistance reversal. PMID- 25744838 TI - [Human amniotic mesenchymal stem cells inhibit allogeneic lymphocyte proliferation and reduce the secretion of interferon gamma]. AB - OBJECTIVE: To investigate the effects of human amniotic mesenchymal stem cells (hAMSCs) on the function of lymphocytes in vitro. METHODS: Enzymatic digestion method was used to isolate and culture hAMSCs. Fluorophore-labeled mouse anti human monoclonal antibodies were used to identify cell surface antigens with flow cytometry. The expressions of vimentin and stage specific embryonic antigen-4 (SSEA-4) were detected by immunofluorescence staining. Isolated lymphocytes were stimulated by concanavalin (ConA), and then 1 * 104, 5 * 104, 1 * 105 hAMSCs were co-cultured with the ConA-treated lymphocytes. Lymphocyte proliferation was measured by CCK-8 assay and the supernatant level of IFN-gamma was determined by ELISA. RESULTS: ConA (5 MUg/mL) could cause lymphocyte proliferation. hAMSCs inhibited lymphocyte proliferation induced by ConA in co-culture conditions, and with the increasing number of hAMSCs, the suppressing effect was more obvious. When the cells were cultured for 72 hours, CCK-8 assay showed that the number of lymphocytes treated with ConA alone was significantly higher than that of ConA treated lymphocytes co-cultured with hAMSCs. The best inhibitory group 1 * 10(6) lymphocytes co-cultured with 1 * 105 hAMSCs was selected to measure supernatant IFN-gamma secretion by ELISA after 72 hours. The level of IFN-gamma was significantly lower than that in the simple ConA-stimulated group. CONCLUSION: HAMSCs could inhibit lymphocyte proliferation and reduce IFN-gamma secretion induced by ConA in vitro. PMID- 25744839 TI - [Intermittent hypoxia promotes the expressions of rat hippocampal neuronal hypoxia-inducible factor-1 and survivin]. AB - OBJECTIVE: To establish an intermittent hypoxia (IH) animal model by simulating the features of obstructive sleep apnea-hypopnea syndrome and observe the expressions of hypoxia-inducible factor-1 (HIF-1) and survivin and the occurrence of apoptosis in the hippocampal CA1 neuron of rats with early IH. METHODS: Male Wistar rats (n=72) were randomly divided into control group and IH group. In control group, rats were given compressed air and in IH group, rats were exposed to 50 mL/L IH for 7 hours a day, lasting 3, 7, 14 and 21 days, respectively. The expressions of HIF-1 and survivin in hippocampal CA1 were detected by immunohistochemistry and the neuronal apoptosis index was calculated by TUNEL. RESULTS: Compared with control group, apoptosis index in the third day of 5% IH group had no significant difference, while apoptosis index in IH 7-, 14- and 21 day groups were significantly higher than that in control group, and on the 21st day it reached a peak. The expressions of HIF-1 and survivin protein in 5% IH group significantly increased as compared with control group at each time point, and they peaked on the 14th day, then decreased gradually. There was a positive relationship between the expressions of HIF-1 and survivin. CONCLUSION: Early IH can induce HIF-1 and survivin protein expressions in rat hippocampal CA1, and their expressions may play an important role in the regulation of neuronal apoptosis. PMID- 25744840 TI - [Inhibitory effect of baicalein on the proliferation and invasion of osteosarcoma cells and mechanism]. AB - OBJECTIVE: To explore the effect of baicalein on the proliferation and invasion of osteosarcoma cells and its related mechanism. METHODS: Osteosarcoma MG-63 cells that were cultured in vitro were respectively treated with 20 MUL culture medium (control group), dehydrated alcohol (0 MUmol/L baicalein group), 100 and 200 MUmol/L baicalein solution for 48 hours. Cell proliferation was analyzed by MTT assay. The cell invasion ability was detected using Transwell(TM) invasion assay. The expression of ezrin mRNA was examined by real-time quantitative PCR. The expressions of ezrin protein and p-ezrin protein were measured using Western blotting. Apoptosis index (AI) was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RESULTS: The inhibitory rates of cell proliferation significantly increased in 100 and 200 MUmol/L baicalein groups as compared with 0 MUmol/L baicalein group. Moreover, that was higher in 200 MUmol/L baicalein group than in 100 MUmol/L baicalein group. In comparison with control and 0 MUmol/L baicalein groups, the mean cell numbers of permeated membrane and levels of ezrin mRNA, ezrin protein and p-ezrin protein gradually decreased, but AI was gradually elevated with the increase of baicalein concentrations, whereas there was no significant difference in these indicators between 0 MUmol/L baicalein group and control group. CONCLUSION: Baicalein can inhibit the proliferation and invasion of osteosarcoma MG-63 cells. The mechanism may be associated with the inhibited expression and activity of ezrin protein and the promoted tumor cell apoptosis. PMID- 25744841 TI - [In vitro generation of insulin-producing cells from the neonatal rat bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To observe the differentiation of the neonatal rat bone marrow mesenchymal stem cells (MSCs) into insulin-producing cells and detect the expressions of insulin, pancreatic duodenal homebox-1 (PDX-1) and nestin. METHODS: MSCs were isolated from the neonatal rats and cultured in the modified medium composed of 10 MUg/L human epidermal growth factor (EGF), 10 MUg/L basic fibroblast growth factor (bFGF), 10 MUg/L hepatocyte growth factor (HGF), 10 MUg/L human B cell regulin, 20 mmol/L nicotinamide and 20 g/L B27. After the induction, the mRNA expressions of insulin, PDX-1 and nestin were examined by reverse transcription-PCR, and the insulin, PDX-1 and nestin protein levels were detected by immunocytochemistry. RESULTS: The insulin and PDX-1 mRNA expressions increased and the nestin mRNA expression decreased in the differentiation of the neonatal rat MSCs into insulin-producing cells. The nestin, PDX-1 and insulin proteins were co-expressed in insulin-producing cells. CONCLUSION: MSCs can be induced to differentiate into insulin-producing cells. PMID- 25744842 TI - [Inhibitory effect of emodin on the growth of cervical cancer in tumor transplanted mice and underlying mechanism]. AB - OBJECTIVE: To observe the effect of emodin on the growth of transplanted U14 cervical cancer cells in mice, and explore its mechanism of anti-tumor. METHODS: The 615-strain mice with U14 cervical cancer cells were randomly divided into 4 groups: control group (DMSO), low-dose emodin group (20 mg/kg), high-dose emodin group (40 mg/kg) and cisplatin group (3 mg/kg). Each group included 10 mice. After drug intervention, all mice were sacrificed on day 26 posttransplantation. The volumes and mass of tumors were detected, and tumor inhibition rate was calculated. Microvessel density (MVD) was determined by immunohistochemistry. The mRNA and protein levels of hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelia growth factor (VEGF) and macrophage migration inhibitory factor (MIF) in tumor tissues were analyzed by real-time quantitative PCR and Western blotting, respectively. Apoptosis index (AI) of tumor tissues was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the Bcl-2 and Bax protein contents were detected by Western blotting. RESULTS: The tumor inhibition rates were 15.83%, 46.92% and 51.22% in low-dose emodin group, high-dose emodin group and cisplatin group, respectively. The tumor inhibition rates were higher in the latter two groups than that in low-dose emodin group. In comparison with control group and low-dose emodin group, the volumes and mass of tumor, MVD as well as the level of HIF-1alpha, VEGF, MIF and Bcl-2 significantly decreased, while the level of AI and Bax significantly increased in high-dose emodin group and cisplatin group. Low-dose emodin had no effects on the above parameters. CONCLUSION: Emodin might suppress the growth of cervical cancer in mice by reducing tumor neovascularization, decreasing MIF expression and promoting tumor cell apoptosis. PMID- 25744843 TI - [The expression of fibroblast activation protein-alpha in primary breast cancer is associated with poor prognosis]. AB - OBJECTIVE: To evaluate the prognostic value of fibroblast activation protein alpha (FAP-alpha) expression in primary lesions of breast cancer patients and the relationship with the clinicopathologic features. METHODS: Paraffin sections and clinical data were retrospectively collected from 130 stage I-III breast cancer patients who had underwent surgery at the Chinese PLA General Hospital from January 1st, 2000 to December 31st, 2002. Immunohistochemistry was used to assess FAP-alpha expression in primary lesions of breast cancer to evaluate the associations of FAP-alpha expression with transforming growth factor-beta1 (TGF beta1) expression in breast cancer and patients' clinicopathologic characteristics and prognosis. RESULTS: FAP-alpha was seen in cytoplasm of tumor cells and interstitial fibroblasts. Density of interstitial FAP-alpha-positive fibroblasts was positively correlated with the staining density of interstitial TGF-beta-positive cells. Intensity of CTLA-4 expression in tumor cells was positively correlated with TGF-beta1 expression in tumor cells. In patients whose lesions were negative for both estrogen and progesterone receptors, density of interstitial FAP-alpha-positive fibroblasts was an independent adverse prognostic factor for disease-free survival (DFS) and overall survival (OS); intensity of CTLA-4 expression in tumor cells was an independent adverse prognostic factor for DFS and OS. CONCLUSION: High expression of FAP-alpha in primary breast tumors is associated with a bad prognosis in patients whose lesions are negative for both estrogen and progesterone receptors. Expression of TGF-beta1 is positively related with FAP-alpha expression in primary breast tumors. PMID- 25744844 TI - [Proportion and significance of CD1d(hi)CD5+CD19+ regulatory B cell in peripheral blood of patients with neuromyelitis optica]. AB - OBJECTIVE: To detect the proportion of CD1d(hi)CD5+CD19+ regulatory B cells (Bregs) in peripheral blood of the patients with neuromyelitis optica (NMO), and explore whether CD1d(hi)CD5+CD19+ Bregs can play a role as a biomarker in the diagnosis of NMO versus multiple sclerosis (MS). METHODS: Flow cytometry was performed to detect the proportion of CD1d(hi)CD5+CD19+ Bregs in peripheral blood from 44 cases of NMO, 38 cases of MS, and 30 healthy controls. The serum level of aquaporin-4 antibody (AQP4-Ab) of patients with NMO was detected by indirect immunofluorescence assay. RESULTS: The proportion of CD1d(hi)CD5+CD19+ Bregs in CD19+ B cells and lymphocytes was significantly lower in NMO group than in MS and control groups; however, there was no significant difference between MS group and control group. The proportion of CD1d(hi)CD5+CD19+ Bregs in CD19+ B cells and lymphocytes was lower in AQP4-Ab-positive NMO patients than in AQP4-Ab-negative NMO patients, and the difference was statistically significant. CONCLUSION: CD1d(hi)CD5+CD19+ Bregs may be a biomarker in the differential diagnosis of NMO versus MS. PMID- 25744845 TI - [Combination of cytosine arabinoside and cisplatin enhances inhibition of cell proliferation and promotes apoptosis of resistant nasopharyngeal carcinoma cells]. AB - OBJECTIVE: To investigate the synergistic cytotoxicity of cisplatin and cytosine arabinoside (Ara-C) on nasopharyngeal carcinoma (NPC) cell lines TW03 and cisplatin-resistant TW03/DDP which is cisplatin-induced drug-resistant cell line. METHODS: The TW03/DDP cells was established by gradually increasing the dose of cisplatin, and then examined by real-time quantitative PCR (qRT-PCR) and semi quantitative Western blotting for the expression level of lung resistance-related protein (LRP). Effects of DDP and Ara-C combined treatment or alone on proliferation and apoptosis of TW03/DDP cells and TW03 cells were detected by CCK 8 assay and flow cytometry, respectively. RESULTS: Compared with TW03 cells, TW03/DDP cells expressed higher level of LRP. After treatments for 24 hours, both cisplatin and Ara-C inhibited proliferation and caused apoptosis of TW03/DDP and TW03 cells, and DDP showed minor effect on the proliferation of TW03/DDP cells. Compared with Ara-C or DDP treatment alone, combination of Ara-C and DDP showed a more remarkable inhibition of proliferation and promotion of apoptosis in both TW03 and TW03/DDP cells. CONCLUSION: Ara-C and DDP have a synergistic killing effect on NPC cell lines with and without DDP-caused drug resistance, and show better effects on proliferation inhibition and apoptosis promotion than Ara-C or DDP treatment alone, which provides a novel and prospective strategy for NPC chemotherapy. PMID- 25744846 TI - [Elevated levels of dendritic cell-correlated miRNAs in ascites and sera of patients with ovarian cancer]. AB - OBJECTIVE: To investigate the relationship between the clinical characteristics of ovarian cancer and the levels of miRNAs which could regulate the differentiation of dendritic cells, and assess its value in estimating the immune state and prognosis of ovarian cancer patients. METHODS: Real-time quantitative PCR was used to determine the levels of miRNAs in ascites and sera of 39 cases of ovarian cancer and in the sera of 20 healthy women. RESULTS: The levels of miR 21, miR-222 and miR-142-3p in sera of ovarian cancer patients were significantly higher than those of the healthy. The expression of miR-21 was higher in the advanced stages (III and IV) than in the earlier stages (I and II ), whereas the level of serum miR-142-3p was lower in high pathological grade than in low grade. The levels of miR-21 and miR-222 in the ascites were higher than those in the peripheral blood. CONCLUSION: The increased expressions of miR-21, miR-222 and miR-142-3p in the ascites and sera of ovarian cancer patients might be correlated with the clinical pathological grading of the patients. PMID- 25744847 TI - [Preparation and identification of monoclonal antibody against repression and activation protein 1]. AB - OBJECTIVE: To prepare and identify monoclonal antibody (mAb) against human telomere-associated repression and activation protein 1 (Rap1). METHODS: BALB/c mice were immunized with recombinant Rap1 protein. The spleen cells of the immunized mice were fused with Sp2/0 cells. The positive clones were confirmed and selected by indirect ELISA for titer determination and specificity identification. RESULTS: One hybridoma cell strain secreting specific mAb against Rap1 was obtained, namely 6F11. ELISA showed that the titer of the ascites was 1:10 000. Western blotting, immunoprecipitation and immunofluorescence experiments demonstrated that the mAb could specifically recognize and bind Rap1. CONCLUSION: We have prepared mAb against human telomere-associated protein Rap1. The Rap1 mAb has a good binding ability and specificity. PMID- 25744848 TI - [Preparation and application of a polyclonal antibody against the peptides of beta2glycoprotein 1]. AB - OBJECTIVE: To prepare a polyclonal antibody against human and murine beta2 glycoprotein 1 (beta2GP1) antigen with chemically synthesized beta2GP1 peptides, and identify its specificity and pathogenicity. METHODS: The peptides from the NH2-terminal 35th-51th amino acids of beta2GP1 were synthesized by standard Fmoc assay, and then used to immunize New Zealand white rabbits after coupling with keyhole limpet hemocyanin (KLH). The polyclonal antibody in the rabbit sera was purified by protein G column. The titer and specificity of the polyclonal antibody were determined by ELISA and Western blot analysis. The total RNA was extracted and the protein lysates were collected from C3H/HeN mouse peritoneal macrophages treated with the above anti-beta2GP1 peptides antibody/beta2GP1 complexes in vitro. And the tissue factor (TF) mRNA and protein expression in the peritoneal macrophages were detected by real-time quantitative PCR and Western blotting. The activation of p38 and NF-kappaB p65 induced by anti-beta2GP1 peptides antibody/beta2GP1 complexes was determined by Western blotting using phosphor-specific antibodies. Experimental antiphospholipid antibody syndrome (EAPS) mouse model was established in C3H/HeN mice by intraperitoneal injection of anti-beta2GP1 peptides antibody in vivo. The titers of anti-beta2GP1 antibodies in the mouse peripheral blood and the activated partial thromboplastin time (APTT) were detected. RESULTS: The purity of chemically synthesized beta2GP1 peptides was 94%, which met the immunogen standard. The titer of antiserum of the rabbit immunized with beta2GP1 peptide coupling with KLH was over 1:32 000. Western blotting showed that the anti-beta2GP1 peptides antibody could specifically recognize both human and mouse beta2GP1. Furthermore, ELISA showed that the antibody could specifically bind to beta2GP1 cryptic epitope. In vitro experiments demonstrated that the anti-beta2GP1 peptides antibody/beta2GP1 co mplexes could enhance p38 and NF-kappaB p65 phosphorylation in mouse peritoneal macrophages and induce TF mRNA and protein expression. Moreover, EAPS mouse model induced by anti-beta2GP1 peptide antibody was successfully established, in which the titers of anti-beta2GP1 antibody in mouse peripheral blood were greater than 1:3200 and APTT was significantly shorter that that of control group. CONCLUSION: The anti-beta2GP1 peptide antibody we prepared could specifically recognize both human and mouse beta2GP1 and specifically bind to beta2GP1 cryptic epitope. It was also proved to have the pathogenic effect. PMID- 25744851 TI - The Pad Test for urinary incontinence in women. PMID- 25744850 TI - Measurement of real pulsatile blood flow using X-ray PIV technique with CO2 microbubbles. AB - Synchrotron X-ray imaging technique has been used to investigate biofluid flows in a non-destructive manner. This study aims to investigate the feasibility of the X-ray PIV technique with CO2 microbubbles as flow tracer for measurement of pulsatile blood flows under in vivo conditions. The traceability of CO2 microbubbles in a pulsatile flow was demonstrated through in vitro experiment. A rat extracorporeal bypass loop was used by connecting a tube between the abdominal aorta and jugular vein of a rat to obtain hemodynamic information of actual pulsatile blood flows without changing the hemorheological properties. The decrease in image contrast of the surrounding tissue was also investigated for in vivo applications of the proposed technique. This technique could be used to accurately measure whole velocity field information of real pulsatile blood flows and has strong potential for hemodynamic diagnosis of cardiovascular diseases. PMID- 25744849 TI - Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. AB - Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF-alpha converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways, and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD. PMID- 25744852 TI - Efficacy of the addition of positive airway pressure to conventional chest physiotherapy in resolution of pleural effusion after drainage: protocol for a randomised controlled trial. AB - INTRODUCTION: Chest drainage for pleural effusion can cause pain and changes in respiratory function. It can also increase the risk of pulmonary complications and impair functional ability, which may increase length of hospital stay and the associated costs. For these reasons, surgical and clinical strategies have been adopted to reduce the duration of chest drainage. OBJECTIVES: To evaluate the efficacy of the addition of intermittent positive airway pressure applied by the Muller reanimator via a rubber facial mask versus conventional physiotherapy on the duration of chest drainage (primary objective), and its effect on the recovery of respiratory function, length of hospital stay and incidence of pulmonary complications (secondary objectives). DESIGN: Randomised, controlled trial. PARTICIPANTS AND SETTING: Inpatients with pleural effusion, aged over 18 years, who have had chest drainage in situ for < 24hours will be recruited from two university hospitals. Patients will be excluded if they have any contraindication for the use of non-invasive positive airway pressure. INTERVENTION AND CONTROL GROUPS: After initial assessments of lung function, 156 patients will be randomised into a positive airway pressure group (positive airway pressure at 15 cmH2O plus conventional chest physiotherapy), a conventional chest physiotherapy group (conventional chest physiotherapy plus non therapeutic positive airway pressure at 4 cmH2O) or a control group (non therapeutic positive airway pressure at 4 cmH2O). All groups will receive treatment three times per day for 7 consecutive days. MEASUREMENTS: A blinded assessor will conduct all assessments. Peripheral oxygenation and chest drainage output will be measured over 7 consecutive days. Lung function will be re assessed on Day 4 and Day 8. The criteria for removal of the chest drain will be a transudate output <= 200ml over 24hours and full lung expansion on chest radiography, as assessed by a blinded physician. Duration of chest drainage, length of hospital stay, and any pulmonary complications diagnosed during hospitalisation will be recorded. ANALYSIS: Intention to treat using: survival analysis for duration of chest drainage, and length of hospital stay; analysis of variance for chest-tube output, lung function and peripheral oxygen saturation; and chi-square tests for comparing the incidence of pulmonary complications between groups. DISCUSSION: Conventional chest physiotherapy and intermittent positive airway pressure breathing are widely indicated for people with pleural effusion and chest drains; however, no studies have evaluated the real benefit of this type of treatment. Our hypothesis is that optimised lung expansion achieved through the application of intermittent positive airway pressure will accelerate the reabsorption of pleural effusion, decrease the duration of chest drainage and respiratory system impairment, reduce the length of hospital stay, and reduce the incidence of pulmonary complications. PMID- 25744853 TI - Thermal conductance of metal-diamond interfaces at high pressure. AB - The thermal conductance of interfaces between metals and diamond, which has a comparatively high Debye temperature, is often greater than can be accounted for by two-phonon processes. The high pressures achievable in a diamond anvil cell (DAC) can significantly extend the metal phonon density of states to higher frequencies, and can also suppress extrinsic effects by greatly stiffening interface bonding. Here we report time-domain thermoreflectance measurements of metal-diamond interface thermal conductance up to 50 GPa in the DAC for Pb, Au0.95Pd0.05, Pt and Al films deposited on type 1A natural [100] and type 2A synthetic [110] diamond anvils. In all cases, the thermal conductances increase weakly or saturate to similar values at high pressure. Our results suggest that anharmonic conductance at metal-diamond interfaces is controlled by partial transmission processes, where a diamond phonon that inelastically scatters at the interface absorbs or emits a metal phonon. PMID- 25744854 TI - Platelet counts as a biomarker in ANCA-associated vasculitis. AB - OBJECTIVES: To determine whether platelet (PLT) counts might serve as a biomarker to distinguish between active anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) and remission and also between active disease and systemic infection. METHOD: PLTs were analysed before treatment in patients with AAV in the active state and in remission. PLTs were also analysed in AAV patients with acute infections. The results were correlated with clinical manifestations, the Birmingham Vasculitis Activity Score version 3 [BVAS(v.3)], and other laboratory findings [i.e. C-reactive protein (CRP), leucocytes, differential count, procalcitonin (PCT)]. Diagnostic accuracy was calculated with a receiver operating characteristic (ROC) curve. RESULTS: PLT counts were significantly increased in 98 patients with AAV during the active disease state [median: 405 PLTs/nL; interquartile range (IQR) 288-504] compared to patients in remission (246 PLT/nL; IQR 214-289) (p < 0.001). We found a correlation of PLT counts in active disease with the BVAS(v.3) (r = 0.582, p < 0.001). In AAV patients with systemic infections (n = 37), PLT counts exhibited significantly lower values (226 PLT/nL; IQR 163-273) compared to patients with active disease (p < 0.001). In the ROC curve analysis, the area under the curve (AUC) of PLTs was significantly larger when distinguishing active disease from systemic infection (AUC 0.868) compared to leucocytes (AUC 0.590), CRP (AUC 0.522), or procalcitonin (AUC 0.515) (p < 0.001). CONCLUSIONS: PLT counts were found to correlate with disease activity in AAV and thus may be used to represent immunological activity. In addition, PLT counts serve as a marker that can distinguish acute infection from active disease. PMID- 25744855 TI - Lead sorptive removal using magnetic and nonmagnetic fast pyrolysis energy cane biochars. AB - Energy cane biochar (ECBC) was prepared in a 72 s fast pyrolysis at 425 degrees C in an auger-fed reactor and ground into 250-600 MUm diameter particles. This biochar was magnetized by fusing an iron oxide phase to the particles by mixing aqueous biochar suspensions with aqueous Fe(3+)/Fe(2+) solutions, followed by NaOH treatment (MECBC). These biochars were characterized by Raman, FT-IR, X-ray, SEM, SEM-EDX, TEM, EDXRF, pHzpc, elemental analyses, S(BET), and magnetic moment determinations. The S(BET) of energy cane biochar was negligible and increased to 37.13 m(2)/g after Fe(3+)/Fe(2+)/NaOH magnetization. The dry biochar contains 18.4% oxygen. This allows swelling in water and permits sorption inside the solid as well as on its pore surfaces, leading to high capacities at low surface areas. Maximum lead removal occurred at pH 4-5. Sorption isotherms exhibited increasing lead removal (Q(0), mg/g) as temperature increased for nonmagnetic [Q(0)(25 degrees C)=45.70; Q(0)(35 degrees C)=52.01 and Q(0)(45 degrees C)=69.37] and magnetic [Q(0)(25 degrees C)=40.56; Q(0)(35 degrees C)=51.17 and Q(0)(45 degrees C)=51.75] biochars. Second order kinetics best fit the lead removal data. Furthermore, magnetic energy cane biochar was easily manipulated by low external magnetic field, thereby, allowing its easy recovery for further recycling and replacement from water. ECBC and MECBC were also successfully applied for Pb(2+) removal from contaminated ground water. Therefore, both chars can be used as potential green low cost sorbents for lead remediation to replace commercial activated carbon. PMID- 25744856 TI - Structure-interfacial properties relationship and quantification of the amphiphilicity of well-defined ionic and non-ionic surfactants using the PIT slope method. AB - The Phase Inversion Temperature of a reference C10E4/n-Octane/Water system exhibits a quasi-linear variation versus the mole fraction of a second surfactant S2 added in the mixture. This variation was recently proposed as a classification tool to quantify the Hydrophilic-Lipophilic Balance (HLB) of commercial surfactants. The feasibility of the so-called PIT-slope method for a wide range of well-defined non-ionic and ionic surfactants is investigated. The comparison of various surfactants having the same dodecyl chain tail allows to rank the polar head hydrophilicity as: SO3Na?SO4Na?NMe3Br>E2SO3Na~CO2Na?E1SO3Na?PhSO3Na>Isosorbide(exo)SO4Na?Isosorbidee doSO4Na?E8?NMe2O>E7>E6?Glucosyl>E5?Diglyceryl?E4>E3>E2~Isosorbide(exo)>Glyceryl>I osorbide(endo). The influence on the surfactant HLB of other structural parameters, i.e. hydrophobic chain length, unsaturation, replacement of Na(+) by K(+) counterion, and isomerism is also investigated. Finally, the method is successfully used to predict the optimal formulation of a new bio-based surfactant, 1-O-dodecyldiglycerol, when performing an oil scan at 25 degrees C. PMID- 25744857 TI - The correlation between fibronectin adsorption and attachment of vascular cells on heparinized polycaprolactone membrane. AB - The heparin-immobilized polycaprolactone (PCL) membrane was developed to investigate the effect of heparin on the adsorption behaviors of serum proteins, in particular fibronectin (Fn), and the attachment of different types of vascular cells. The heparin was covalently immobilized onto aminolyzed PCL membrane by amidation reaction. The grafting amount of heparin increased from 0.35 MUg/cm(2) to 1.31 MUg/cm(2) when the aminolysis time was prolonged from 10 min to 60 min. The adhesion of endothelial cells (ECs) and smooth muscle cells (SMCs) on the heparinized PCL surface was significantly enhanced and reduced, respectively. The adsorption of Fn was strongly improved on the heparinized PCL surface than on the pristine PCL, and showed a positive correlation with the heparin density. Therefore, the adsorbed Fn takes a decisive role on the selective adhesion of ECs and the suppression of SMCs attachment. PMID- 25744858 TI - Palladium nanoparticles decorated on activated fullerene modified screen printed carbon electrode for enhanced electrochemical sensing of dopamine. AB - In the present work, an enhanced electrochemical sensor for dopamine (DA) was developed based on palladium nanoparticles decorated activated fullerene-C60 (AC60/PdNPs) composite modified screen printed carbon electrode (SPCE). The scanning electron microscopy and elemental analysis confirmed the formation of PdNPs on AC60. The fabricated AC60/PdNPs composite modified electrode exhibited an enhanced electrochemical response to DA with a lower oxidation potential than that of SPCE modified with PdNPs and C60, indicating the excellent electrooxidation behavior of the AC60/PdNPs composite modified electrode. The electrochemical studies confirmed that the electrooxidation of DA at the composite electrode is a diffusion controlled electrochemical process. The differential pulse voltammetry was employed for the determination of DA; under optimum conditions, the electrochemical oxidation signal of DA increased linearly at the AC60/PdNPs composite from 0.35 to 133.35 MUM. The limit of detection was found as 0.056 MUM with a sensitivity of 4.23 MUA MUM(-1) cm(-2). The good recovery of DA in the DA injection samples further revealed the good practicality of AC60/PdNPs modified electrode. PMID- 25744859 TI - Detection of DNA utilizing a fluorescent reversible change of a biosensor based on the electron transfer from quantum dots to polymyxin B sulfate. AB - A fluorescent "turn off-on" pattern for the detection of herring sperm DNA (hsDNA) had been designed through utilizing the interaction between polymyxin B sulfate (PMBS) and hsDNA as an inherent performance and the fluorescent transformation of glutathione (GSH)-capped CdTe quantum dots (QDs) as an external manifestation. Due to the occurrence of the photoinduced electron transfer from the QDs to PMBS, the fluorescence of GSH-capped CdTe QDs could be effectively quenched by PMBS, causing the system into "off" state. With the addition of hsDNA, the quenched fluorescence of GSH-capped CdTe QDs could be restored for the reason that PMBS embedded into hsDNA double helix structure to form new complex and peeled off from the surface of GSH-capped CdTe QDs, leading the system into "on" condition. Corresponding experimental results illustrated that the relative recovered fluorescence intensity of GSH-capped CdTe QDs-PMBS system was near proportional to the concentration of hsDNA within the range of 0.059-15.0 MUg mL( 1). This proposed method demonstrated a good linear correlation coefficient of 0.9937 and a detection limit (3 sigma/K) of 0.018 MUg mL(-1) for hsDNA. This dual directional fluorescent biosensor overcame the selectivity problem commonly existed in the traditional mono-directional fluorescence detection mode and owned perfect analysis applications in biochemical DNA monitoring. PMID- 25744860 TI - Comparison of the enhanced gas sensing properties of tin dioxide samples doped with different catalytic transition elements. AB - In this work, non-doped SnO2 samples, and SnO2 samples doped with Zn(II), Cu(II), or Mn(II), having hierarchical microstructures, were prepared using an otherwise identical hydrothermal process, followed by annealing. The morphological and structural characteristics of the samples were systematically characterized by X ray powder diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET) measurements, and X-ray photoelectron spectroscopy (XPS). Ten gas sensors were constructed from each material, and compared as to detection of gas-phase ethanol, acetone, glacial acetic acid, methanol, and ammonia. The results indicated, for example, that SnO2 containing 2.91% Mn dopant exhibited a 2.5-fold higher gas detection response toward ethanol at 100 ppm than that of the non doped material. The fastest response time for 100 ppm ethanol was found for Cu(II)-doped SnO2 (9.7 s), compared with 12.4 s for non-doped SnO2. Graphs of sensor response versus operating temperature for SnO2 containing different types and quantities of dopant exhibited quite different morphologies. The gas-sensing mechanism appears to involve reactions between the detected gases and the various oxygenous ions, such as O, O2(-), and O(2-), present at the surface of the sensor. PMID- 25744861 TI - Microfluidic generation of uniform water droplets using gas as the continuous phase. AB - Microfluidic schemes for forming uniform aqueous microdroplets usually rely on contacting the aqueous liquid (dispersed phase) with an immiscible oil (continuous phase). Here, we demonstrate that the oil can be substituted with gas (nitrogen or air) while still retaining the ability to generate discrete and uniform aqueous droplets. Our device is a capillary co-flow system, with the inner flow of water getting periodically dispersed into droplets by the external flow of gas. The droplet size and different formation modes can be tuned by varying the liquid and gas flow rates. Importantly, we identify the range of conditions that correspond to the "dripping mode", i.e., where discrete droplets are consistently generated with no satellites. We believe this is a significant development that will be beneficial for chemical and biological applications requiring clean and contaminant-free droplets, including DNA amplification, drug encapsulation, and microfluidic cell culture. PMID- 25744862 TI - Vonoprazan: first global approval. AB - Vonoprazan (Takecab((r))) is an orally bioavailable potassium-competitive acid blocker (P-CAB) being developed by Takeda for the treatment and prevention of acid-related diseases. The drug is approved in Japan for the treatment of acid related diseases, including erosive oesophagitis, gastric ulcer, duodenal ulcer, peptic ulcer, gastro-oesophageal reflux, reflux oesophagitis and Helicobacter pylori eradication. Phase III development is underway for the prevention of recurrence of duodenal and gastric ulcer in patients receiving aspirin or NSAID therapy. Phase I development was conducted in the UK for gastro-oesophageal reflux; however, no further development has been reported. This article summarizes the milestones in the development of vonoprazan leading to this first approval for acid-related diseases. PMID- 25744863 TI - Role of occlusive devices to prevent thromboembolism among persons with a patent foramen ovale and prior stroke. AB - OPINION STATEMENT: Patent foramen ovale (PFO) has been linked to stroke, presumably through the mechanism of paradoxical embolism; however, data is confusing regarding the causal relationship between PFO and embolic stroke. What has come to light in the past decade of research is that PFO closure with devices that achieve a high rate of closure may reduce the risk of recurrent stroke compared with medical therapy, but this benefit has not been shown in the general population with a PFO and cryptogenic stroke. The important question now is which patient will benefit from PFO closure for stroke risk reduction. A validated risk prediction tool is needed to help physicians determine those patients who will derive benefit from closure of PFO to prevent recurrent stroke. It is clear that even in studies with a small number of individuals and a very small number of events, there is some benefit to closure. Furthermore, improvements in closure devices and techniques have made percutaneous device closure both safe and efficacious. As such, it is not necessary to wait for a patient to have two strokes prior to serious consideration of PFO closure. We would advocate that the decision to close a PFO in the setting of a cryptogenic stroke be made at an individual level, on a case-by-case basis. Patients with high-risk features may be more likely to benefit, though who exactly comprises this population is still being elucidated. The most difficult aspect of managing this disease is the substantial number of individuals with incidental PFOs, as well as the prevalence of stroke due to other etiologies. When treating this disease, the physician must be able to weigh the likelihood of benefit versus the risk of the procedure, as well as patient preference. PMID- 25744864 TI - Secondary breast angiosarcoma and paclitaxel-dependent prolonged disease control: report of two cases and review of the literature. AB - Secondary breast angiosarcomas are a well-known entity generally characterized by a poor outcome, especially in patients with advanced disease. Among the drugs with demonstrated activity, taxane derivatives are one of the most effective histology-driven treatments against angiosarcomas. We report two cases of secondary breast angiosarcoma, both characterized by a very peculiar behavior towards paclitaxel. Both patients showed local recurrence of angiosarcoma after primary surgery, and they achieved complete remission following treatment with weekly paclitaxel. When a locoregional recurrence was observed as a result of a brief treatment interruption or a treatment delay, a new complete remission was rapidly achieved with the resumption of the drug, without evidence of any significant adverse effects. PMID- 25744865 TI - Urinary bladder preservation for muscle-invasive bladder cancer: a survey among radiation oncologists of Lombardy, Italy. AB - AIMS AND BACKGROUND: Bladder preservation is a treatment option in muscle invasive bladder carcinoma. The most investigated approach is a trimodality schedule including maximum transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy. Our aim was to evaluate the use of bladder preservation by radiation oncologists of the Lombardy region in Italy. METHODS AND STUDY DESIGN: A survey with 13 items regarding data of 2012 was sent to all 32 radiotherapy centers within the collaboration between the Lombardy Oncological Network and the Lombardy Section of the Italian Society of Oncological Radiotherapy. RESULTS: Thirteen centers (41%) answered the survey; the presented data come from 11 active centers. In these centers, 11,748 patients were treated with external-beam radiotherapy in 2012, 100 of whom having bladder cancer (0.9%). 74/100 patients received radiotherapy as palliative treatment for T, N or M lesions. A further 9 and 5 patients received radiotherapy for oligometastatic disease (ablative doses to small volumes) and postoperatively, respectively. Bladder preservation was performed in 12 cases and included trimodality and other strategies (mainly TURBT followed by radiotherapy). A multidisciplinary urology tumor board met regularly in 5 of 11 centers. All responders declared their interest in the Lombardy multicenter collaboration on bladder preservation. CONCLUSIONS: Our survey showed that bladder preservation is rarely used in Lombardy despite the availability of the latest radiotherapy technologies and the presence of an urology tumor board in half of the centers. The initiative of multicenter and multidisciplinary collaboration was undertaken to prepare the platform for bladder preservation as a treatment option in selected patients. PMID- 25744866 TI - Neoadjuvant crizotinib in advanced inflammatory myofibroblastic tumour with ALK gene rearrangement. AB - BACKGROUND: Inflammatory myofibroblastic tumours (IMTs) are rare sarcomas that were first described in the lung. They are composed of myofibroblastic mesenchymal spindle cells accompanied by an inflammatory infiltrate of plasma cells. Complete resection is the treatment of choice. There is currently no standard treatment for inoperable or recurrent disease. Expression of ALK protein triggered by ALK gene rearrangement at chromosome 2p23 has been found in 36%-60% of IMTs. CASE REPORT: We report a rapid early response to crizotinib as neoadjuvant therapy, enabling surgical excision of a large ALK-translocated IMT, which resulted in complete disease clearance. To the best of our knowledge, this is the first case in the literature of a patient with IMT in whom crizotinib was used successfully in the neoadjuvant or curative setting. PMID- 25744867 TI - Repetitive transcranial magnetic stimulation over the left parietal cortex facilitates visual search for a letter among its mirror images. AB - Interference by task irrelevant information is seen in visual search paradigms using letters. Thus, it is harder to find the letter 'N' among its mirror reversals 'I' than vice versa. This observation, termed the reversed letter effect, involves both a linguistic association and an interference of task irrelevant information-the shape of 'N' or 'I' is irrelevant, the search requires merely distinguishing the tilts of oblique bars. We adapted the repetitive transcranial magnetic stimulation (rTMS) methods that we previously used, and conducted three rTMS experiments using healthy subjects. The first experiment investigated the effects of rTMS on the left and right posterior parietal cortex (PPC) on the search performance. The second experiment focused on the role of the left PPC. The third experiment explored whether another left posterior region, known to be involved in word reading (ventral occipito-temporal cortex, vOTC), plays a role. We found that rTMS on right PPC and left VOTC had no effect on the speed and accuracy of the visual search regardless of whether the target is 'N' or its mirror reversal. In contrast, rTMS on the left PPC speeded up the search on finding target 'N' among its mirror images. We suggest that left PPC is involved in letter recognition, and that rTMS on left PPC facilitated our visual search task by reducing task interference triggered by task irrelevant letter recognition. PMID- 25744869 TI - Emotion-inducing approaching sounds shape the boundaries of multisensory peripersonal space. AB - In order to survive in a complex environment, inhabited by potentially threatening and noxious objects or living beings, we need to constantly monitor our surrounding space, especially in the vicinity of our body. Such a space has been commonly referred to as one's 'peripersonal space' (PPS). In this study we investigated whether emotion-inducing approaching sound sources impact the boundaries of PPS. Previous studies have indeed showed that the boundaries of PPS are not fixed but modulate according to properties of stimuli in the surrounding environment. In Experiment 1, participants performed a simple tactile detection task of targets presented to their right hand. Concurrently, they were presented with intensity-changing task-irrelevant artificial sound sources perceived as approaching toward their body. The physical properties of the sound elicited emotional responses of either neutral or negative valence. Results showed larger PPS when the approaching stimulus had negative as compared to neutral emotional valence. In Experiment 2, we used ecological sounds which content (i.e., psychological associations to the sound producing source), rather than physical properties, elicited emotional responses of negative, positive or neutral valence. In agreement with results from experiment 1, we found larger PPS when the approaching stimuli had negative emotional valence as compared to both neutral and positive ones. Results are discussed within the theoretical framework that conceives PPS as a safety zone around one's body. PMID- 25744868 TI - Facial emotion recognition impairments are associated with brain volume abnormalities in individuals with HIV. AB - Impaired facial emotion recognition abilities in HIV+ patients are well documented, but little is known about the neural etiology of these difficulties. We examined the relation of facial emotion recognition abilities to regional brain volumes in 44 HIV-positive (HIV+) and 44 HIV-negative control (HC) adults. Volumes of structures implicated in HIV-associated neuropathology and emotion recognition were measured on MRI using an automated segmentation tool. Relative to HC, HIV+ patients demonstrated emotion recognition impairments for fearful expressions, reduced anterior cingulate cortex (ACC) volumes, and increased amygdala volumes. In the HIV+ group, fear recognition impairments correlated significantly with ACC, but not amygdala volumes. ACC reductions were also associated with lower nadir CD4 levels (i.e., greater HIV-disease severity). These findings extend our understanding of the neurobiological substrates underlying an essential social function, facial emotion recognition, in HIV+ individuals and implicate HIV-related ACC atrophy in the impairment of these abilities. PMID- 25744870 TI - Subliminal galvanic-vestibular stimulation recalibrates the distorted visual and tactile subjective vertical in right-sided stroke. AB - Stroke of the right cerebral hemisphere often causes deficits in the judgement of the subjective visual vertical (SVV) and subjective tactile vertical (STV) which are related to central vestibular functioning. Clinically, deficits in the SVV/STV are linked to balance problems and poor functional outcome. Galvanic Vestibular Stimulation (GVS) is a non-invasive, save stimulation technique that induces polarity-specific changes in the cortical vestibular systems. Subliminal GVS induces imperceptible vestibular stimulation without unpleasant side effects. Here, we applied bipolar subliminal GVS over the mastoids (mean intensity: 0.7 mA, 20 min duration per session) to investigate its online-influence on constant errors, difference thresholds and range values in the SVV and STV. 24 patients with subacute, single, unilateral right hemisphere stroke were studied and assigned to two patient groups (impaired vs. normal in the SVV and STV) on the basis of cut-off scores from healthy controls. Both groups performed these tasks under three experimental conditions on three different days: a) sham GVS where electric current was applied only for 30s and then turned off, b) left-cathodal GVS and c) right-cathodal GVS, for a period of 20 min per session. Left-cathodal GVS, but not right-cathodal GVS significantly reduced all parameters in the SVV. Concerning STV GVS also reduced constant error and range numerically, though not significantly. These effects occurred selectively in the impaired patient group. In conclusion, we found that GVS rapidly influences poststroke verticality deficits in the visual and tactile modality, thus highlighting the importance of the vestibular system in the multimodal elaboration of the subjective vertical. PMID- 25744871 TI - The plasticity of the mirror system: how reward learning modulates cortical motor simulation of others. AB - Cortical motor simulation supports the understanding of others' actions and intentions. This mechanism is thought to rely on the mirror neuron system (MNS), a brain network that is active both during action execution and observation. Indirect evidence suggests that (alpha/beta) mu suppression, an electroencephalographic (EEG) index of MNS activity, is modulated by reward. In this study we aimed to test the plasticity of the MNS by directly investigating the link between (alpha/beta) mu suppression and reward. 40 individuals from a general population sample took part in an evaluative conditioning experiment, where different neutral faces were associated with high or low reward values. In the test phase, EEG was recorded while participants viewed videoclips of happy expressions made by the conditioned faces. Alpha/beta mu suppression (identified using event-related desynchronisation of specific independent components) in response to rewarding faces was found to be greater than for non-rewarding faces. This result provides a mechanistic insight into the plasticity of the MNS and, more generally, into the role of reward in modulating physiological responses linked to empathy. PMID- 25744872 TI - Synthetic biology advances for pharmaceutical production. AB - Synthetic biology enables a new generation of microbial engineering for the biotechnological production of pharmaceuticals and other high-value chemicals. This review presents an overview of recent advances in the field, describing new computational and experimental tools for the discovery, optimization and production of bioactive molecules, and outlining progress towards the application of these tools to pharmaceutical production systems. PMID- 25744873 TI - Comparisons of three nicotine dependence scales in a multiethnic sample of young adult menthol and non-menthol smokers. AB - BACKGROUND: Few studies have compared nicotine dependence among menthol and non menthol cigarette smokers in a multiethnic sample of young adult daily cigarette smokers. This study examines differences in nicotine dependence among menthol and non-menthol daily smokers and the associations of nicotine dependence with quitting behaviors among Native Hawaiian, Filipino, and White cigarette smokers aged 18-35. METHODS: Craigslist.org, newspaper advertisements, and peer-to-peer referrals were used to recruit daily smokers (n = 186) into a lab-based study. Nicotine dependence was assessed using the Fagerstrom Test of Nicotine Dependence (FTND), the Nicotine Dependence Syndrome Scale (NDSS), and the brief Wisconsin Inventory for Smoking Dependence Motives (WISDM). Multiple regression analyses were used to examine differences in nicotine dependence between menthol and non menthol smokers and the relationship between each nicotine dependence scale with self-efficacy to quit, quit attempt in the past 12 months, and number of attempts. RESULTS: Menthol smokers were more likely to report difficulty refraining from smoking in places where forbidden (p = .04) and had higher scores on social/environmental goads subscale of the WISDM (p = .0005). Two-way interaction models of the FTND and menthol status showed that menthol smokers with higher levels of dependence were more likely to have tried to quit smoking in the past 12 months (p = .02), but were less likely to have had multiple quit attempts (p = .01). CONCLUSIONS: Components of the FTND and WISDM distinguish levels of dependence between menthol and non-menthol smokers. Higher FTND scores were associated with having a quit attempt, but fewer quit attempts among menthol smokers. PMID- 25744874 TI - Impaired Arousal in Older Adults Is Associated With Prolonged Hospital Stay and Discharge to Skilled Nursing Facility. AB - BACKGROUND: Poor cognitive function is associated with negative consequences across settings of care, but research instruments are arduous for routine clinical implementation. This study examined the association between impaired arousal, as measured using an ultra-brief screen, and risk of 2 adverse clinical outcomes: hospital length of stay and discharge to a skilled nursing facility (SNF). DESIGN, SETTING, AND PARTICIPANTS: A secondary data analysis was conducted using 2 separate groups of medical ward patients: a Veterans Affairs medical center in the northeast (N = 1487, between 2010 and 2012) 60 years and older and a large tertiary care, university-based medical center (N = 669, between 2007 and 2013) 65 years and older in the southeastern United States. MEASUREMENTS: The impact of impaired arousal, defined by the Richmond Agitation Sedation Scale as anything other than "awake and alert," was determined using Cox Proportional Hazard Regression for time to hospital discharge and logistic regression for discharge to a SNF. Hazard ratios (HRs) and odds ratios (OR) with their 95% confidence intervals (CI) are reported, respectively. Both models were adjusted age, sex, and dementia. RESULTS: The 2156 total patients included in these groups had a mean age of 76 years, of whom 16.4% in group 1 and 28.5% in group 2 had impaired arousal. In the first group, patients with normal arousal spent an average of 5.9 days (standard deviation 6.2) in the hospital, while those with impaired arousal spent 8.5 days (9.2). On any given day, patients with impaired arousal had 27% lower chance of being discharged (adjusted HR 0.73 (95% CI 0.63 0.84). In the second group, individuals with normal arousal spent 3.8 (4.1) days in the hospital compared with 4.7 (4.6) for those with impaired arousal; indicating a 21% lower chance of being discharged [adjusted HR 0.79 (95% CI 0.66 0.95). With regard to risk of discharge to SNF, those with impaired arousal in group 1 had a 65% higher risk than those without impaired arousal [adjusted OR 1.65 (95% CI 1.21-2.25)], and those in group 2 had a nonsignificant 27% higher risk [adjusted OR 1.27 (0.80-2.03)]. Because of the quality improvement nature, this analysis did not control for comorbidities, which is a significant limitation. CONCLUSIONS: In this study of over 2000 older hospitalized patients, the simple observation of an abnormal arousal level may be an independent predictor of a longer hospital stay and discharge to SNF. PMID- 25744876 TI - Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas. AB - Multiple osteochondromas (MO) is an autosomal-dominant skeletal disorder caused by mutations in the exostosin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we report the analysis of the mutational status of the EXT2 gene in tumor samples derived from a patient affected by hereditary MO, documenting the somatic loss of the germline mutation in a giant chondrosarcoma and in a rapidly growing osteochondroma. The sequencing of all exons and exon-intron junctions of the EXT1 and EXT2 genes from blood DNA of the proband did not reveal any mutation in the EXT1 gene but did demonstrate the presence of the transition point mutation c.67C > T in the EXT2 gene, determining the introduction of a stop codon in the coding sequence (p.Arg23*). A mutational analysis of other members of the family and the presence of osteochondromas in the metaphysis of long bones confirmed the diagnosis of hereditary multiple osteochondromas. Direct sequencing from DNA extracted from different sites of two tumor samples (a small rapidly growing osteochondroma and a giant peripheral secondary chondrosarcoma, each located at different chondrocostal junctions) revealed the loss of the germline EXT2 mutation. Analysis of microsatellite polymorphic markers in the 11p region harboring the EXT2 gene did not reveal any loss of heterozygosity. This observation supports a recent model of sarcomagenesis in which osteochondroma cells bear EXT homozygous inactivation, whereas chondrosarcoma-initiating cells are EXT-expressing cells. PMID- 25744875 TI - Pharmacologic targeting of sirtuin and PPAR signaling improves longevity and mitochondrial physiology in respiratory chain complex I mutant Caenorhabditis elegans. AB - Mitochondrial respiratory chain (RC) diseases are highly morbid multi-systemic conditions for which few effective therapies exist. Given the essential role of sirtuin and PPAR signaling in mediating both mitochondrial physiology and the cellular response to metabolic stress in RC complex I (CI) disease, we postulated that drugs that alter these signaling pathways either directly (resveratrol for sirtuin, rosiglitazone for PPARgamma, fenofibrate for PPARalpha), or indirectly by increasing NAD(+) availability (nicotinic acid), might offer effective treatment strategies for primary RC disease. Integrated effects of targeting these cellular signaling pathways on animal lifespan and multi-dimensional in vivo parameters were studied in gas-1(fc21) relative to wild-type (N2 Bristol) worms. Specifically, animal lifespan, transcriptome profiles, mitochondrial oxidant burden, mitochondrial membrane potential, mitochondrial content, amino acid profiles, stable isotope-based intermediary metabolic flux, and total nematode NADH and NAD(+) concentrations were compared. Shortened gas-1(fc21) mutant lifespan was rescued with either resveratrol or nicotinic acid, regardless of whether treatments were begun at the early larval stage or in young adulthood. Rosiglitazone administration beginning in young adult stage animals also rescued lifespan. All drug treatments reversed the most significant transcriptome alterations at the biochemical pathway level relative to untreated gas-1(fc21) animals. Interestingly, increased mitochondrial oxidant burden in gas-1(fc21) was reduced with nicotinic acid but exacerbated significantly by resveratrol and modestly by fenofibrate, with little change by rosiglitazone treatment. In contrast, the reduced mitochondrial membrane potential of mutant worms was further decreased by nicotinic acid but restored by either resveratrol, rosiglitazone, or fenofibrate. Using a novel HPLC assay, we discovered that gas 1(fc21) worms have significant deficiencies of NAD(+) and NADH. Whereas resveratrol restored concentrations of both metabolites, nicotinic acid only restored NADH. Characteristic branched chain amino acid elevations in gas-1(fc21) animals were normalized completely by nicotinic acid and largely by resveratrol, but not by either rosiglitazone or fenofibrate. We developed a visualization system to enable objective integration of these multi-faceted physiologic endpoints, an approach that will likely be useful to apply in future drug treatment studies in human patients with mitochondrial disease. Overall, these data demonstrate that direct or indirect pharmacologic restoration of altered sirtuin and PPAR signaling can yield significant health and longevity benefits, although by divergent bioenergetic mechanism(s), in a nematode model of mitochondrial RC complex I disease. Thus, these animal model studies introduce important, integrated insights that may ultimately yield rational treatment strategies for human RC disease. PMID- 25744877 TI - Temporal frequency of events rather than speed dilates perceived duration of moving objects. AB - In everyday life moving objects often follow irregular or repetitive trajectories for which distinctive events are potentially noticeable. It is known that the perceived duration of moving objects is distorted, but whether the distortion is due to the temporal frequency of the events or to the speed of the objects remains unclear. Disentangling the contribution of these factors to perceived duration distortions is ecologically relevant: if perceived duration were dependent on speed, it should contract with the distance from the observer to the moving objects. Here, we asked observers to estimate the perceived duration of an object rotating at different speeds and radii and found that perceived duration dilated with temporal frequency of rotations, rather than speed (or perceived speed, which we also measured). We also found that the dilation was larger for two than for one object, but the increase was not large enough to make perceived duration independent of the number of objects when expressed as a function of the local frequency (the number of times an object crossed a given location per time unit). These results suggest that perceived duration of natural stimuli containing distinctive events doesn't depend on the distance of the events to the observer. PMID- 25744878 TI - Reprint of: Highthroughtput analysis of behavior for drug discovery. AB - Drug testing with traditional behavioral assays constitutes a major bottleneck in the development of novel therapies. PsychoGenics developed three comprehensive highthroughtput systems, SmartCube((r)), NeuroCube((r)) and PhenoCube((r)) systems, to increase the efficiency of the drug screening and phenotyping in rodents. These three systems capture different domains of behavior, namely, cognitive, motor, circadian, social, anxiety-like, gait and others, using custom built computer vision software and machine learning algorithms for analysis. This review exemplifies the use of the three systems and explains how they can advance drug screening with their applications to phenotyping of disease models, drug screening, selection of lead candidates, behavior-driven lead optimization, and drug repurposing. PMID- 25744879 TI - Chronic agmatine treatment prevents behavioral manifestations of nicotine withdrawal in mice. AB - Smoking cessation exhibits an aversive withdrawal syndrome characterized by both increases in somatic signs and affective behaviors including anxiety and depression. In present study, abrupt withdrawal of daily nicotine injections (2mg/kg, s.c., four times daily, for 10 days) significantly increased somatic signs viz. rearing, grooming, jumping, genital licking, leg licking, head shakes with associated depression (increased immobility in forced swim test) as well as anxiety (decreased the number of entries and time spent in open arm in elevated plus maze) in nicotine dependent animals. The peak effect was observed at 24h time point of nicotine withdrawal. Repeated administration of agmatine (40 80ug/mouse, i.c.v.) before the first daily dose of nicotine from day 5 to 10 attenuated the elevated scores of somatic signs and abolished the depression and anxiety like behavior induced by nicotine withdrawal in dependent animals. However, in separate groups, its acute administration 30min before behavior analysis of nicotine withdrawal was ineffective. This result clearly shows the role of agmatine in development of nicotine dependence and its withdrawal. In extension to behavioral experiments, brain agmatine analyses, carried out at 24h time point of nicotine withdrawal demonstrated marked decrease in basal brain agmatine concentration as compared to control animals. Taken together, these data support the role of agmatine as common biological substrate for somatic signs and affective symptoms of nicotine withdrawal. This data may project therapies based on agmatine in anxiety, depression and mood changes associated with tobacco withdrawal. PMID- 25744880 TI - Descending projections from the nucleus accumbens shell excite activity of taste responsive neurons in the nucleus of the solitary tract in the hamster. AB - The nucleus of the solitary tract (NST) and the parabrachial nuclei (PbN) are the first and second relays in the rodent central taste pathway. A series of electrophysiological experiments revealed that spontaneous and taste-evoked activities of brain stem gustatory neurons are altered by descending input from multiple forebrain nuclei in the central taste pathway. The nucleus accumbens shell (NAcSh) is a key neural substrate of reward circuitry, but it has not been verified as a classical gustatory nucleus. A recent in vivo electrophysiological study demonstrated that the NAcSh modulates the spontaneous and gustatory activities of hamster pontine taste neurons. In the present study, we investigated whether activation of the NAcSh modulates gustatory responses of the NST neurons. Extracellular single-unit activity was recorded from medullary neurons in urethane-anesthetized hamsters. After taste response was confirmed by delivery of sucrose, NaCl, citric acid, and quinine hydrochloride to the anterior tongue, the NAcSh was stimulated bilaterally with concentric bipolar stimulating electrodes. Stimulation of the ipsilateral and contralateral NAcSh induced firings from 54 and 37 of 90 medullary taste neurons, respectively. Thirty cells were affected bilaterally. No inhibitory responses or antidromic invasion was observed after NAcSh activation. In the subset of taste cells tested, high frequency electrical stimulation of the NAcSh during taste delivery enhanced taste-evoked neuronal firing. These results demonstrate that two-thirds of the medullary gustatory neurons are under excitatory descending influence from the NAcSh, which is a strong indication of communication between the gustatory pathway and the mesolimbic reward pathway. PMID- 25744881 TI - Microcircuitry of agranular frontal cortex: contrasting laminar connectivity between occipital and frontal areas. AB - Neocortex is striking in its laminar architecture. Tracer studies have uncovered anatomical connectivity among laminae, but the functional connectivity between laminar compartments is still largely unknown. Such functional connectivity can be discerned through spontaneous neural correlations during rest. Previous work demonstrated a robust pattern of mesoscopic resting-state connectivity in macaque primary visual cortex (V1) through interlaminar cross-frequency coupling. Here we investigated whether this pattern generalizes to other cortical areas by comparing resting-state laminar connectivity between V1 and the supplementary eye field (SEF), a frontal area lacking a granular layer 4 (L4). Local field potentials (LFPs) were recorded with linear microelectrode arrays from all laminae of granular V1 and agranular SEF while monkeys rested in darkness. We found substantial differences in the relationship between the amplitude of gamma band (>30 Hz) LFP and the phase of alpha-band (7-14 Hz) LFP between these areas. In V1, gamma amplitudes in L2/3 and L5 were coupled with alpha-band LFP phase in L5, as previously described. In contrast, in SEF phase-amplitude coupling was prominent within L3 and much weaker across layers. These results suggest that laminar interactions in agranular SEF are unlike those in granular V1. Thus the intrinsic functional connectivity of the cortical microcircuit does not seem to generalize across cortical areas. PMID- 25744882 TI - Multiple timescales in the adaptation of the rotational VOR. AB - Goal-directed movements, such as pointing and saccades, have been shown to share similar neural architectures, in spite of the different neuromuscular systems producing them. Such structure involve an inverse model of the actuator being controlled, which produces the commands innervating the muscles, and a forward model of the actuator, which predicts the sensory consequences of such commands and allows online movement corrections. Recent studies have shown that goal directed movements also share similar motor-learning and motor-memory mechanisms, which are based on multiple timescales. The hypothesis that also the rotational vestibulo-ocular reflex (rVOR) may be based on a similar architecture has been presented recently. We hypothesize that multiple timescales are the brain's solution to the plasticity-stability dilemma, allowing adaptation to temporary and sudden changes while keeping stable motor-control abilities. If that were the case, then we would also expect the adaptation of reflex movements to follow the same principles. Thus we studied rVOR gain adaptation in eight healthy human subjects using a custom paradigm aimed at investigating the existence of spontaneous recovery, which we considered as the hallmark of multiple timescales in motor learning. Our experimental results show that spontaneous recovery occurred in six of eight subjects. Thus we developed a mathematical model of rVOR adaptation based on two hidden-states processes, which adapts the cerebellar forward model of the ocular motor plant, and show that it accurately simulates our experimental data on rVOR gain adaptation, whereas a single timescale learning process fails to do so. PMID- 25744883 TI - Kinematics of unconstrained tactile texture exploration. AB - A hallmark of tactile texture exploration is that it involves movement between skin and surface. When we scan a surface, small texture-specific vibrations are produced in the skin, and specialized cutaneous mechanoreceptors convert these vibrations into highly repeatable, precise, and informative temporal spiking patterns in tactile afferents. Both texture-elicited vibrations and afferent responses are highly dependent on exploratory kinematics, however; indeed, these dilate or contract systematically with decreases or increases in scanning speed, respectively. These profound changes in the peripheral response that accompany changes in scanning speed and other parameters of texture scanning raise the question as to whether exploratory behaviors change depending on what surface is explored or what information is sought about that surface. To address this question, we measure and analyze the kinematics as subjects explore textured surfaces to evaluate different types of texture information, namely the textures' roughness, hardness, and slipperiness. We find that the exploratory movements are dependent both on the perceptual task, as has been previously shown, but also on the texture that is scanned. We discuss the implications of our findings regarding the neural coding and perception of texture. PMID- 25744884 TI - Decoding the future from past experience: learning shapes predictions in early visual cortex. AB - Learning the structure of the environment is critical for interpreting the current scene and predicting upcoming events. However, the brain mechanisms that support our ability to translate knowledge about scene statistics to sensory predictions remain largely unknown. Here we provide evidence that learning of temporal regularities shapes representations in early visual cortex that relate to our ability to predict sensory events. We tested the participants' ability to predict the orientation of a test stimulus after exposure to sequences of leftward- or rightward-oriented gratings. Using fMRI decoding, we identified brain patterns related to the observers' visual predictions rather than stimulus driven activity. Decoding of predicted orientations following structured sequences was enhanced after training, while decoding of cued orientations following exposure to random sequences did not change. These predictive representations appear to be driven by the same large-scale neural populations that encode actual stimulus orientation and to be specific to the learned sequence structure. Thus our findings provide evidence that learning temporal structures supports our ability to predict future events by reactivating selective sensory representations as early as in primary visual cortex. PMID- 25744885 TI - Dynamic representation of spectral edges in guinea pig primary auditory cortex. AB - The central representation of a given acoustic motif is thought to be strongly context dependent, i.e., to rely on the spectrotemporal past and present of the acoustic mixture in which it is embedded. The present study investigated the cortical representation of spectral edges (i.e., where stimulus energy changes abruptly over frequency) and its dependence on stimulus duration and depth of the spectral contrast in guinea pig. We devised a stimulus ensemble composed of random tone pips with or without an attenuated frequency band (AFB) of variable depth. Additionally, the multitone ensemble with AFB was interleaved with periods of silence or with multitone ensembles without AFB. We have shown that the representation of the frequencies near but outside the AFB is greatly enhanced, whereas the representation of frequencies near and inside the AFB is strongly suppressed. These cortical changes depend on the depth of the AFB: although they are maximal for the largest depth of the AFB, they are also statistically significant for depths as small as 10 dB. Finally, the cortical changes are quick, occurring within a few seconds of stimulus ensemble presentation with AFB, and are very labile, disappearing within a few seconds after the presentation without AFB. Overall, this study demonstrates that the representation of spectral edges is dynamically enhanced in the auditory centers. These central changes may have important functional implications, particularly in noisy environments where they could contribute to preserving the central representation of spectral edges. PMID- 25744886 TI - Multisensory decisions provide support for probabilistic number representations. AB - A large body of evidence suggests that an approximate number sense allows humans to estimate numerosity in sensory scenes. This ability is widely observed in humans, including those without formal mathematical training. Despite this, many outstanding questions remain about the nature of the numerosity representation in the brain. Specifically, it is not known whether approximate numbers are represented as scalar estimates of numerosity or, alternatively, as probability distributions over numerosity. In the present study, we used a multisensory decision task to distinguish these possibilities. We trained human subjects to decide whether a test stimulus had a larger or smaller numerosity compared with a fixed reference. Depending on the trial, the numerosity was presented as either a sequence of visual flashes or a sequence of auditory tones, or both. To test for a probabilistic representation, we varied the reliability of the stimulus by adding noise to the visual stimuli. In accordance with a probabilistic representation, we observed a significant improvement in multisensory compared with unisensory trials. Furthermore, a trial-by-trial analysis revealed that although individual subjects showed strategic differences in how they leveraged auditory and visual information, all subjects exploited the reliability of unisensory cues. An alternative, nonprobabilistic model, in which subjects combined cues without regard for reliability, was not able to account for these trial-by-trial choices. These findings provide evidence that the brain relies on a probabilistic representation for numerosity decisions. PMID- 25744887 TI - The speed of object recognition from a haptic glance: event-related potential evidence. AB - Recognition of an object usually involves a wide range of sensory inputs. Accumulating evidence shows that first brain responses associated with the visual discrimination of objects emerge around 150 ms, but fewer studies have been devoted to measure the first neural signature of haptic recognition. To investigate the speed of haptic processing, we recorded event-related potentials (ERPs) during a shape discrimination task without visual information. After a restricted exploratory procedure, participants (n = 27) were instructed to judge whether the touched object corresponded to an expected object whose name had been previously presented in a screen. We encountered that any incongruence between the presented word and the shape of the object evoked a frontocentral negativity starting at ~175 ms. With the use of source analysis and L2 minimum-norm estimation, the neural sources of this differential activity were located in higher level somatosensory areas and prefrontal regions involved in error monitoring and cognitive control. Our findings reveal that the somatosensory system is able to complete an amount of haptic processing substantial enough to trigger conflict-related responses in medial and prefrontal cortices in <200 ms. The present results show that our haptic system is a fast recognition device closely interlinked with error- and conflict-monitoring processes. PMID- 25744888 TI - SPIKY: a graphical user interface for monitoring spike train synchrony. AB - Techniques for recording large-scale neuronal spiking activity are developing very fast. This leads to an increasing demand for algorithms capable of analyzing large amounts of experimental spike train data. One of the most crucial and demanding tasks is the identification of similarity patterns with a very high temporal resolution and across different spatial scales. To address this task, in recent years three time-resolved measures of spike train synchrony have been proposed, the ISI-distance, the SPIKE-distance, and event synchronization. The Matlab source codes for calculating and visualizing these measures have been made publicly available. However, due to the many different possible representations of the results the use of these codes is rather complicated and their application requires some basic knowledge of Matlab. Thus it became desirable to provide a more user-friendly and interactive interface. Here we address this need and present SPIKY, a graphical user interface that facilitates the application of time-resolved measures of spike train synchrony to both simulated and real data. SPIKY includes implementations of the ISI-distance, the SPIKE-distance, and the SPIKE-synchronization (an improved and simplified extension of event synchronization) that have been optimized with respect to computation speed and memory demand. It also comprises a spike train generator and an event detector that makes it capable of analyzing continuous data. Finally, the SPIKY package includes additional complementary programs aimed at the analysis of large numbers of datasets and the estimation of significance levels. PMID- 25744889 TI - Training voluntary motor suppression with real-time feedback of motor evoked potentials. AB - Training people to suppress motor representations voluntarily could improve response control. We evaluated a novel training procedure of real-time feedback of motor evoked potentials (MEPs) generated by transcranial magnetic stimulation (TMS) over motor cortex. On each trial, a cue instructed participants to use a mental strategy to suppress a particular finger representation without overt movement. A single pulse of TMS was delivered over motor cortex, and an MEP derived measure of hand motor excitability was delivered visually to the participant within 500 ms. In experiment 1, we showed that participants learned to reduce the excitability of a particular finger beneath baseline (selective motor suppression) within 30 min of practice. In experiment 2, we performed a double-blind study with 2 training groups (1 with veridical feedback and 1 with matched sham feedback) to show that selective motor suppression depends on the veridical feedback itself. Experiment 3 further demonstrated the importance of veridical feedback by showing that selective motor suppression did not arise from mere mental imagery, even when incentivized with reward. Thus participants can use real-time feedback of TMS-induced MEPs to discover an effective mental strategy for selective motor suppression. This high-temporal-resolution, trial-by trial-feedback training method could be used to help people better control response tendencies and may serve as a potential therapy for motor disorders such as Tourette's and dystonia. PMID- 25744890 TI - Cerebellar control of saccade dynamics: contribution of the fastigial oculomotor region. AB - The fastigial oculomotor region is the output by which the medioposterior cerebellum influences the generation of saccades. Recent inactivation studies reported observations suggesting an involvement in their dynamics (velocity and duration). In this work, we tested this hypothesis in the head-restrained monkey with the electrical microstimulation technique. More specifically, we studied the influence of duration, frequency, and current on the saccades elicited by fastigial stimulation and starting from a central (straight ahead) position. The results show ipsilateral or contralateral saccades whose amplitude and dynamics depend on the stimulation parameters. The duration and amplitude of their horizontal component increase with the duration of stimulation up to a maximum amplitude. Varying the stimulation frequency mostly changes their latency and the peak velocity (for contralateral saccades). Current also influences the metrics and dynamics of saccades: the horizontal amplitude and peak velocity increase with the intensity, whereas the latency decreases. The changes in peak velocity and in latency observed in contralateral saccades are not correlated. Finally, we discovered that contralateral saccades can be evoked at sites eliciting ipsilateral saccades when the stimulation frequency is reduced. However, their onset is timed not with the onset but with the offset of stimulation. These results corroborate the hypothesis that the fastigial projections toward the pontomedullary reticular formation (PMRF) participate in steering the saccade, whereas the fastigiocollicular projections contribute to the bilateral control of visual fixation. We propose that the cerebellar influence on saccade generation involves recruiting neurons and controlling the size of the active population in the PMRF. PMID- 25744891 TI - Transformation of spatial sensitivity along the ascending auditory pathway. AB - Locations of sounds are computed in the central auditory pathway based primarily on differences in sound level and timing at the two ears. In rats, the results of that computation appear in the primary auditory cortex (A1) as exclusively contralateral hemifield spatial sensitivity, with strong responses to sounds contralateral to the recording site, sharp cutoffs across the midline, and weak, sound-level-tolerant responses to ipsilateral sounds. We surveyed the auditory pathway in anesthetized rats to identify the brain level(s) at which level tolerant spatial sensitivity arises. Noise-burst stimuli were varied in horizontal sound location and in sound level. Neurons in the central nucleus of the inferior colliculus (ICc) displayed contralateral tuning at low sound levels, but tuning was degraded at successively higher sound levels. In contrast, neurons in the nucleus of the brachium of the inferior colliculus (BIN) showed sharp, level-tolerant spatial sensitivity. The ventral division of the medial geniculate body (MGBv) contained two discrete neural populations, one showing broad sensitivity like the ICc and one showing sharp sensitivity like A1. Dorsal, medial, and shell regions of the MGB showed fairly sharp spatial sensitivity, likely reflecting inputs from A1 and/or the BIN. The results demonstrate two parallel brainstem pathways for spatial hearing. The tectal pathway, in which sharp, level-tolerant spatial sensitivity arises between ICc and BIN, projects to the superior colliculus and could support reflexive orientation to sounds. The lemniscal pathway, in which such sensitivity arises between ICc and the MGBv, projects to the forebrain to support perception of sound location. PMID- 25744892 TI - Distinct modulating effects of TipE-homologs 2-4 on Drosophila sodium channel splice variants. AB - The Drosophila melanogaster TipE protein is thought to be an insect sodium channel auxiliary subunit functionally analogous to the beta subunits of mammalian sodium channels. Besides TipE, four TipE-homologous proteins (TEH1-4) have been identified. It has been reported that TipE and TEH1 have both common and distinct effects on the gating properties of splice variants of the Drosophila sodium channel, DmNav. However, limited information is available on the effects of TEH2, TEH3 and TEH4 on the function of DmNav channel variants. In this study, we found that TEH2 increased the amplitude of peak current, but did not alter the gating properties of three examined DmNav splice variants expressed in Xenopus oocytes. In contrast, TEH4 had no effect on peak current, yet altered the gating properties of all three channel variants. Furthermore, TEH4 enhanced persistent current and slowed sodium current decay. The effects of TEH3 on DmNav variants are similar to those of TEH4, but the data were collected from a small portion of oocytes because co-expression of TEH3 with DmNav variants generated a large leak current in the majority of oocytes examined. In addition, TEH3 and TEH4 enhanced the expression of endogenous currents in oocytes. Taken together, our results reveal distinct roles of TEH proteins in modulating the function of sodium channels and suggest that TEH proteins might provide an important layer of regulation of membrane excitability in vivo. Our results also raise an intriguing possibility of TEH3/TEH4 as auxiliary subunits of other voltage-gated ion channels besides sodium channels. PMID- 25744893 TI - Effects of extrinsic proteins on the protein conformation of the oxygen-evolving center in cyanobacterial photosystem II as revealed by Fourier transform infrared spectroscopy. AB - Extrinsic proteins of photosystem II (PSII) play an important role in optimizing oxygen-evolving reactions in all oxyphototrophs. The currently available crystal structures of cyanobacterial PSII core complexes show the binding structures of the extrinsic proteins, PsbO, PsbV, and PsbU; however, how the individual extrinsic proteins affect the structure and the function of the oxygen-evolving center (OEC) in cyanobacterial PSII remains unknown. In this study, we have investigated the effects of the binding of the extrinsic proteins on the protein conformation of the OEC in PSII core complexes from the thermophilic cyanobacterium Thermosynechococcus elongatus, using light-induced Fourier transform infrared (FTIR) difference spectroscopy. Upon removal of the three extrinsic proteins, an S2-minus-S1 FTIR difference spectrum measured in the presence of a high CaCl2 concentration showed a drastic change in amide I bands, reflecting perturbation of the secondary structures of polypeptides, whereas the overall spectral intensity was lost at a low CaCl2 concentration, indicative of inactivation of the Mn4CaO5 cluster. The amide I features as well as the overall intensity were recovered mainly by binding of PsbO, while complete amide I recovery was achieved by further binding of PsbV and PsbU. We thus concluded that PsbO, together with smaller contributions of PsbV and PsbU, plays a role in the maintenance of the proper protein conformation of the OEC in cyanobacterial PSII, which provides the stability of the Mn4CaO5 cluster via the enhanced retention capability of Ca2+ and Cl- ions. PMID- 25744895 TI - Expanding role of controlled allergen challenge facilities in allergic rhinitis research. PMID- 25744894 TI - miR-663 attenuates tumor growth and invasiveness by targeting eEF1A2 in pancreatic cancer. AB - BACKGROUND: miR-663 is associated with many important biologic processes, such as the evolution, development, viral infection, inflammatory response, and carcinogenesis among vertebrates. However, the molecular function and mechanism of miR-663 in pancreatic cancer growth and invasion is still unclear. METHODS: Western blot and real-time PCR were used to study the expression level of eEF1A2 protein and miR-663 in pancreatic cancer tissues and cell lines. The Pearson chi (2) test was used to determine the correlation between miR-663 expression and clinicopathologic features of patients. Patients' survival was analyzed using the Kaplan-Meier method, using the log-rank test for comparison. The biological function of miR-663 was examined by measuring cell growth, cell invasion and apoptosis analysis in vitro and in vivo. miR-663 target gene and signaling pathway was identified by luciferase activity assay and western blot. RESULTS: We found that, in pancreatic cancer, eEF1A2 was significantly upregulated but miR 663 was significantly downregulated. Further results showed that the expression level of eEF1A2 and miR-663 was strongly associated with TNM stage and node metastasis status of the patients. miR-663 and eEF1A2 were inversely correlated with each other, and the changes in the expression levels of each can also predict the survival of patients with pancreatic cancer. We identified miR-663 as a tumor attenuate molecular that attenuated the proliferation and invasion of pancreatic cancer cells both in vitro and in vivo. Finally, we confirmed that the expression of eEF1A2 can partially restore the pro-apoptotic and anti-invasion functions of miR-663. CONCLUSIONS: miR-663 attenuated the proliferation and invasion of pancreatic cells both in vitro and in vivo by directly targeting eEF1A2. miR-663 and eEF1A2 might be potential targets for the treatment of pancreatic cancer in the future. PMID- 25744896 TI - A new method for air sampling with real-world results. PMID- 25744897 TI - Year in review: basic science. PMID- 25744898 TI - Year in review: urticaria and angioedema. PMID- 25744899 TI - Year in review: upper respiratory diseases. PMID- 25744900 TI - Year in review: asthma. PMID- 25744901 TI - Year in review: allergen immunotherapy. PMID- 25744902 TI - Year in review: pediatric allergy and asthma, excluding food allergy. PMID- 25744903 TI - National standards for asthma self-management education. AB - BACKGROUND: Asthma education reimbursement continues to be an issue in the United States. Among the greatest barriers is the lack of a standardized curriculum for asthma self-management education recognized by a physician society, non-physician health care professional society or association, or other appropriate source. The applicable Current Procedural Terminology codes for self-management education and training are 98960 through 98962, stating that "if a practitioner has created a training curriculum for educating patients on management of their medical condition, he or she may employ a non-physician health care professional to provide education using a standardized curriculum for patients with that disease." Without a standardized curriculum, reimbursement from payers is beyond reach. OBJECTIVE: Representatives from the Joint Council of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; American Academy of Allergy, Asthma, and Immunology; American Lung Association; American Thoracic Society; National Asthma Educator Certification Board; American College of Chest Physicians; and Association of Asthma Educators gathered to write a standardized curriculum as a guideline for payer reimbursement. METHODS: The Task Force began with a review of the American Lung Association and American Thoracic Society's Operational Standards for Asthma Education. Board members of the National Asthma Educator Certification Board incorporated comments, rationale, and references into the document. RESULTS: This document is the result of final reviews of the standards completed by the Task Force and national health care professional organizations in September 2014. CONCLUSION: This document meets the requirements of Current Procedural Terminology codes 98960 through 98962 and establishes the minimum standard for asthma self-management education when teaching patients or caregivers how to effectively manage asthma in conjunction with the professional health care team. PMID- 25744904 TI - Cannabis sativa: the unconventional "weed" allergen. PMID- 25744905 TI - Early-life mold and tree sensitivity is associated with allergic eosinophilic rhinitis at 4 years of age. AB - BACKGROUND: Nasal eosinophils are a biomarker for allergic rhinitis (AR) and are associated with increased symptom severity. OBJECTIVE: To identify predictors of allergic eosinophilic rhinitis (AER) in early childhood in children at higher risk for chronic allergic respiratory disorders. METHODS: In the Cincinnati Childhood Allergy and Air Pollution Study, infants born to aeroallergen sensitized and symptomatic parents were examined and underwent skin prick testing (SPT) annually to 15 aeroallergens from 1 to 4 years of age. Wheal circumferences were traced and scanned and areas were determined by computer planimetry. At 4 years, AER was defined as (1) at least 1 positive aeroallergen SPT result, (2) presence of sneezing and runny nose without a cold or influenza, and (3) nasal eosinophilia of at least 5%. Wheal areas at 1 to 3 years were analyzed for an association with AER compared with children without AR. RESULTS: At 4 years, 487 children completed rhinitis health histories, SPT, and nasal sampling. Ninety nine children (22.8%) had AR. Thirty-eight children had AER (8.8% of total sample and 38.4% of AR sample, respectively). At 3 years, for every 1-mm(2) increase in Penicillium species (adjusted odds ratio 1.18, 95% confidence interval 1.06-1.32, P = .002) and maple (adjusted odds ratio 1.07, 95% confidence interval 1.01-1.13, P = .02), wheal area significantly increased the risk of AER at 4 years of age. CONCLUSION: Allergic eosinophilic rhinitis was identified in 8.8% of children at 4 years of age. Age 3 years was the earliest that aeroallergen SPT wheal areas were predictive of AER. Skin testing at 3 years identifies children at risk for an AR phenotype with nasal eosinophilia. PMID- 25744906 TI - Local allergic rhinitis in elderly patients. AB - BACKGROUND: Local allergic rhinitis (LAR) is characterized by the production of specific IgE in the nasal mucosa and a positive response to a nasal provocation test in the absence of atopy by conventional measurements. There is no information about LAR in elderly people, just as there is little information about allergic rhinitis (AR) in this age group. OBJECTIVE: To investigate the prevalence of LAR, AR, and non-AR in elderly patients with rhinitis. METHODS: In 219 patients with a mean (SD) age of 65.81 (5.88), skin prick tests, serum total specific IgE, and nasal provocation tests against common aeroallergens were performed. In addition, nasal specific IgE was measured in the nasal lavage at baseline and after provocation. For monitoring nasal symptoms, a visual analog scale was used. RESULTS: Of the 219 patients, 46 (21.0%) had LAR, 88 (40.2%) had AR, and 85 (38.8%) were diagnosed as having non-AR. Dermatophagoides pteronyssinus was the main sensitizing aeroallergen in patients with LAR (29 patients [63.0%]) and with AR (48 patients [56.4%]). No significant differences were found between the visual analog scale score and the type of AR (local or nonlocal) and the types of allergens. Clinical responses during the nasal provocation test were associated with significant increases in nasal IgE (Spearman correlation test, R = 0.89, P < .05). Polysensitization was more predominant in patients with AR than in those with LAR (P < .05). CONCLUSION: The results indicate that LAR and AR are common in elderly patients. However, in this age group, these conditions are often underdiagnosed. PMID- 25744908 TI - Prevalence of blueberry allergy in a Turkish population. PMID- 25744907 TI - Specific IgE recognition of pollen allergens from subtropic grasses in patients from the subtropics. AB - BACKGROUND: Pollens of subtropical grasses, Bahia (Paspalum notatum), Johnson (Sorghum halepense), and Bermuda (Cynodon dactylon), are common causes of respiratory allergies in subtropical regions worldwide. OBJECTIVE: To evaluate IgE cross-reactivity of grass pollen (GP) found in subtropical and temperate areas. METHODS: Case and control serum samples from 83 individuals from the subtropical region of Queensland were tested for IgE reactivity with GP extracts by enzyme-linked immunosorbent assay. A randomly sampled subset of 21 serum samples from patients with subtropical GP allergy were examined by ImmunoCAP and cross-inhibition assays. RESULTS: Fifty-four patients with allergic rhinitis and GP allergy had higher IgE reactivity with P notatum and C dactylon than with a mixture of 5 temperate GPs. For 90% of 21 GP allergic serum samples, P notatum, S halepense, or C dactylon specific IgE concentrations were higher than temperate GP specific IgE, and GP specific IgE had higher correlations of subtropical GP (r = 0.771-0.950) than temperate GP (r = 0.317-0.677). In most patients (71%-100%), IgE with P notatum, S halepense, or C dactylon GPs was inhibited better by subtropical GP than temperate GP. When the temperate GP mixture achieved 50% inhibition of IgE with subtropical GP, there was a 39- to 67-fold difference in concentrations giving 50% inhibition and significant differences in maximum inhibition for S halepense and P notatum GP relative to temperate GP. CONCLUSION: Patients living in a subtropical region had species specific IgE recognition of subtropical GP. Most GP allergic patients in Queensland would benefit from allergen specific immunotherapy with a standardized content of subtropical GP allergens. PMID- 25744909 TI - Allergen of the month--narrowleaf goosefoot. PMID- 25744910 TI - Evaluation of the DSM-5 severity indicator for bulimia nervosa. AB - This study examined the DSM-5 severity criterion for bulimia nervosa (BN) based on the frequency of inappropriate weight compensatory behaviors. 199 community volunteers classified with BN were categorized using DSM-5 severity levels and compared on demographic and clinical variables. 77 (39%) participants were categorized as mild, 68 (34%) as moderate, 32 (16%) as severe, and 22 (11%) as extreme. The severity groups did not differ significantly in demographic variables or body mass index. Shape and Weight concerns did not differ significantly across severity groups. Binge eating differed with the extreme group having significantly higher frequency than the severe, moderate, and mild groups, which did not differ from each other. Restraint differed with the extreme group having significantly higher levels than the mild group. Eating concerns differed with the extreme group having significantly higher levels than moderate and mild groups. Depression differed with the extreme group having significantly higher levels than severe, moderate, and mild groups, which did not differ from each other. Findings from this non-clinical group provide new, albeit modest, support for DSM-5 severity rating for BN based on frequency of inappropriate weight compensatory behaviors. Statistical findings indicate that differences in collateral clinical variables associated with the DSM-5 severity ratings reflect small effect sizes. Further research is needed with treatment-seeking patient groups with BN to establish the validity of the DSM-5 severity specifier and should include broader clinical and functional validators. PMID- 25744911 TI - Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs? AB - Genome-wide association studies (GWASs) provide an unprecedented opportunity to examine, on a large scale, the association of common genetic variants with complex diseases like type 2 diabetes (T2D) and cardiovascular disease (CVD), thus allowing the identification of new potential disease loci. Using this approach, numerous studies have associated SNPs on chromosome 9p21.3 situated near the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) locus with the risk for coronary artery disease (CAD) and T2D. However, identifying the function of the nearby gene products (CDKN2A/B and ANRIL) in the pathophysiology of these conditions requires functional genomic studies. We review the current knowledge, from studies using human and mouse models, describing the function of CDKN2A/B gene products, which may mechanistically link the 9p21.3 risk locus with CVD and diabetes. PMID- 25744912 TI - Sex differences in immunohistochemical expression and capillary density in pancreatic solid pseudopapillary neoplasm. AB - Solid pseudopapillary neoplasm (SPN) is a rare and low-grade malignant pancreatic neoplasm. Solid pseudopapillary neoplasm is rare in men, and most SPN cases are in young women. This study aimed to investigate sex differences in SPN clinical histopathology including capillary density and expression of immunochemical markers, including glypican 3. A total of 22 resected tumors from pancreatic SPN patients, including 16 women (73%) and 6 men (27%), were analyzed histopathologically and immunohistochemically for synaptophysin, beta-catenin, estrogen receptor, progesterone receptor, Ki-67, CD10, CD31, and glypican 3. The median age was 52.5 years in men and 24 years in women (P = .046). The median tumor size was 22.5 mm in men and 40 mm in women (P = .337). In 11 of the 16 women (69%), but in none of the men, tumors showed complete or incomplete fibrous cap'sules (P = .006). Cholesterol clefts were observed in tumors from 10 women (63%) but in none from the men (P = .012). No significant sex differences were noted in tumor characteristics, including size, macroscopic cystic degeneration, necrosis, lymphovascular involvement, and perineural invasion. The SPNs were weakly positive for glypican 3, although there was no significant difference between sexes. Capillary density tended to be lower in tumors from men than in those from women, but not significantly. Thus, except for the fibrous capsule and cholesterol clefts often found in tumors and the younger age of the women, there were no significant sex differences in histopathologic or immunohistochemical features of SPN, despite its markedly higher occurrence in women. PMID- 25744913 TI - Bioaccumulation of nickel and its biochemical and genotoxic effects on juveniles of the neotropical fish Prochilodus lineatus. AB - Juveniles of the freshwater fish Prochilodus lineatus were exposed to three concentrations of nickel (Ni): 25, 250 and 2500 ug L(-1) or water only for periods of 24 and 96 h to test for Ni bioaccumulation, its effects on antioxidant defenses and metallothioneins, and the occurrence of DNA damage. After exposure, the fish were sampled and tissue removed from the gills, liver, kidney and muscle to test for Ni accumulation and conduct biochemical (gills and liver) and genotoxic (blood cells and gills) analyses. The results showed that Ni accumulates in the organs in different proportions (kidney>liver>gills>muscle) and accumulation varied according to exposure time. Metallothionein (MT) levels increased in the liver and gills after exposure to Ni, implying that the presence of Ni in these tissues could induce MT synthesis. We also observed that Ni exposure affected antioxidant defenses, increasing lipid peroxidation in the liver of fish exposed to Ni for 96 h at the highest concentration tested. DNA damage increased in both blood cells and gills of fish exposed to all Ni concentrations, indicating the genotoxic potential of Ni on fish. We therefore concluded that Ni accumulates in various tissues and results in oxidative and DNA damage in P. lineatus, and that the maximum permitted Ni concentration set in Brazilian legislation (25 ug L(-1)) for freshwaters is not safe for this species. PMID- 25744914 TI - WITHDRAWN: Patient Complaints in the Emergency Department. PMID- 25744915 TI - [Reminiscence of the 100(th) annual general meeting of the Japanese Society of Gastroenterology and its commemorative project]. PMID- 25744916 TI - [Elucidating the molecular mechanism of hepatocarcinogenesis: perspectives on its clinical application]. PMID- 25744917 TI - [Recent advances in the treatment of hepatocellular carcinoma]. PMID- 25744918 TI - [Advanced liver resection for hepatocellular carcinoma]. PMID- 25744919 TI - [Liver transplantation for hepatocellular carcinoma]. PMID- 25744920 TI - [Current opinion and future perception of treatment for hepatocellular carcinoma]. PMID- 25744921 TI - [A case report of chronic intestinal pseudo-obstruction with autoimmune autonomic ganglionopathy suspected from seropositive results for anti-ganglionic acetylcholine receptor antibody]. AB - A 37-year-old woman who had previously been diagnosed with idiopathic chronic intestinal pseudo-obstruction (CIPO) at another hospital was admitted to our institution with severe abdominal pain. She had a history of several abdominal surgeries to treat ileus at the previous hospital, and contrast-enhanced computed tomography on admission revealed subileus without any apparent causes of obstruction. Total parenteral nutrition, a gastrointestinal prokinetic agent, and opiates reduced persistent pain;however, breakthrough pain continued. A neurologist at our hospital suggested autoimmune autonomic ganglionopathy (AAG) as a potential cause of CIPO. The patient was diagnosed with suspected AAG on the basis of seropositive results for anti-ganglionic acetylcholine receptor antibody. Intravenous immunoglobulin administration and plasma exchange were performed in combination with immunosuppressive drugs;however, her symptoms barely improved. Although percutaneous endoscopic gastrostomy and enterostomy were subsequently performed to reduce internal intestinal pressure, her pain relief was insufficient. PMID- 25744922 TI - [A case of jejunal ectopic pancreatic cancer: the diagnostic usefulness of MRI]. AB - A 70-year-old man was referred to our hospital because of elevated CA19-9. Magnetic resonance imaging revealed a jejunal tumor having duct and retention cyst-like structures, which suggested ectopic pancreatic cancer. We resected that part of the jejunum and the lymph nodes around the tumor. Pathological examination revealed an adenocarcinoma originating from a Heinrich type I ectopic pancreas in the jejunum. Adjuvant chemotherapy with gemcitabine was performed for half a year. After 8 months, CA19-9 remained elevated, and liver metastasis occurred. We began treatment with tegafur/gimeracil/oteracil potassium (S-1) and particle beam therapy. After 7 months, CA19-9 was normal, and the patient has remained in partial remission with S-1 treatment. Ectopic pancreas tissues typically occur in the stomach and duodenum and rarely become cancerous. Here, we report the features of a rare and illustrative case of jejunal ectopic pancreatic cancer. PMID- 25744923 TI - [Perioperative primary thrombosis prophylaxis for colorectal cancer in an asymptomatic antiphospholipid antibody carrier -a case report and literature review-]. AB - An 82-year-old woman presented with hematochezia and was diagnosed with resectable colon cancer. Laboratory analysis revealed prolonged activated partial thromboplastin time and false-positive reactions in serological tests for syphilis; results that were subsequently found to be caused by the presence of antiphospholipid antibody. Because she had no history of thrombotic events or pregnancy morbidity, she was considered to be an asymptomatic antiphospholipid antibody carrier (aaPL carrier). Throughout the perioperative period, anticoagulation was performed without complications, including thrombosis. aaPL carriers are not uncommon in clinical practice, and the attending gastroenterologist should assess the risk of future thrombotic events and the most effective means of preventing thrombosis. However, there are few evidence based recommendations for primary thrombosis prevention in aaPL carriers over the long-term and in high-risk periods, such as the perioperative period. Here, we discuss aaPL carrier management with a focus on the perioperative period together with a review of the literature. PMID- 25744924 TI - [A case of pancreatic neuroendocrine tumor presenting with main pancreatic duct invasion]. AB - A 52-year-old male visited a local clinic with a subjective complaint of pain in the left side of his abdomen. Abdominal CT revealed the presence of a pancreatic body tumor. On EUS, the tumor presented hypoechoic signals with an obscure boundary, which continued from the pancreatic parenchyma to the inside of the main pancreatic duct. Abdominal contrast CT revealed a hypervascular tumor with densely stained pancreatic parenchyma. ERP findings revealed that main pancreatic duct invasion was suspected based on partial radiolucency in the duct. Distal pancreatectomy was performed, and a definitive diagnosis of pancreatic neuroendocrine tumor (WHO class G1) was made histopathologically. PMID- 25744925 TI - [A case of chronic hepatitis B with liver failure due to untreated Basedow disease]. AB - A 45-year-old female who complained of high fever and jaundice was admitted to our hospital for severe liver failure. She had a history of treatment for chronic hepatitis B, which had not been observed for a long time. She was diagnosed with liver failure due to severe hyperthyroidism due to untreated Basedow disease and not due to acute exacerbation of chronic hepatitis B. She was successfully treated with artificial liver adjuvant therapy and total thyroidectomy. Hyperthyroidism should, therefore, be considered as one of the possible causes of acute-on-chronic liver failure. PMID- 25744927 TI - [Drug-induced liver injury caused by a dietary supplement (Kin-toki Shoga((r))) made from ginger]. AB - A 70-year-old woman who took a dietary supplement, Kin-toki Shoga((r)) made from ginger for peripheral psychroesthesia and numbness, experienced an epigastric sense of incongruity and appetite loss and passed brown urine for 2 months. Although she had stopped taking the supplement, her symptoms had not improved. She was admitted to our hospital because of jaundice and liver dysfunction. After an investigation of causes, she was diagnosed with drug-induced liver injury caused by Kin-toki Shoga((r)). Liver dysfunction gradually improved with conservative treatment. She was discharged on the 25th day of illness. Liver biopsy findings were compatible with drug-induced liver injury. PMID- 25744926 TI - [A case of ruptured giant splenic artery aneurysm]. AB - A 68-year-old woman presented with general malaise. Her vital signs were unstable, and abdominal computed tomography revealed giant (10 cm) splenic artery aneurysm with evidence of rupture. We first occluded the root of the splenic artery using a balloon catheter. Next, we resected the distal pancreas and spleen because of the aneurysm size and destruction of the related vasculature. After surgery, the patient's condition improved, and she was discharged from the hospital on postoperative day 18. Because ruptured giant splenic artery aneurysms are very rare, we report this case with a review of the literature. PMID- 25744928 TI - [A case of methotrexate-associated lymphoproliferative disorder diagnosed by liver biopsy]. AB - In 1998, a 68-year-old woman was diagnosed with rheumatoid arthritis. She was treated with prednisolone, nonsteroidal anti-inflammatory drugs, methotrexate (MTX), and biological drugs. Retroperitoneal lymph node swelling and hepatosplenomegaly appeared but spontaneously disappeared after drug withdrawal. Anorexia and general fatigue occurred in March 2012. She was admitted to our hospital with retroperitoneal, periaortic, and mediastinal lymph node swelling and was found to have multiple liver tumors. Based on the results of aspiration biopsy of a liver tumor, she was diagnosed with malignant lymphoma (Hodgkin lymphoma). She died from liver failure and disseminated intravascular coagulation before chemotherapy. We present this case of MTX-associated lymphoproliferative disorder, which caused formation of a liver tumor. PMID- 25744929 TI - The Effect of Hinge Position on Posterior Tibial Slope in Medial Open-Wedge High Tibial Osteotomy. AB - PURPOSE: To evaluate whether hinge position affects the change in posterior tibial slope in medial open-wedge high tibial osteotomy (HTO). METHODS: We retrospectively evaluated 19 knees from 17 patients who underwent medial open wedge HTO by 3-dimensional computed tomography scan before and after surgery. A 3 dimensional image model was constructed by applying reverse-engineering software to the computed tomography DICOM (Digital Imaging and Communications in Medicine) files. The hinge axis (i.e., the position of the hinge compared with the anteroposterior axis on an axial view), posterior tibial slope, medial-proximal tibial angle, and gap ratio (i.e., the ratio of anterior gap to posterior gap in the opened wedge) were measured. RESULTS: The mean hinge axis was 4.92 degrees +/- 3.86 degrees . Posterior tibial slope increased from 7.29 degrees +/- 2.56 degrees preoperatively to 10.48 degrees +/- 3.01 degrees postoperatively (P = .001). The mean medial-proximal tibial angle was 85.96 degrees +/- 1.97 degrees preoperatively and 93.13 degrees +/- 3.17 degrees postoperatively (P = .001). The mean gap ratio was 62.48% +/- 7.26%. Linear regression analysis determined that the hinge axis (P = .0001) was a significant factor changing posterior tibial slope. CONCLUSIONS: Hinge position affected the change in posterior tibial slope in medial open-wedge HTO; in particular, a posterolateral hinge position led to an increase in posterior tibial slope. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25744930 TI - Evaluation of 3 Needleless Grasping Suture Techniques for Soft-Tissue Graft Fixation: A Porcine Biomechanical Study. AB - PURPOSE: The purpose of this study was to evaluate the tendon graft holding strength of 3 needleless grasping suture techniques, namely the modified Prusik knot, Wittstein suture loop, and modified rolling hitch. METHODS: Thirty fresh frozen porcine flexor profundus tendons were used and randomly divided into 3 groups of 10 specimens. The experimental procedure was designed to assess elongation of the suture-tendon construct across 3 different needleless tendon grasping techniques. All suture configurations were completed with a multistranded nonabsorbable suture. Each tendon was pre-tensioned to 100 N for 3 cycles, cyclically loaded to 200 N for 200 cycles, and then finally loaded to failure. Elongation, load to failure, and mode of failure for each suture-tendon construct were measured. RESULTS: During cyclic loading, there were no significant differences in elongation for any of the tested suture-tendon constructs (modified rolling hitch, 21.2% +/- 9.6%; modified Prusik knot, 21.4% +/- 9.9%; and Wittstein suture loop, 26.2% +/- 4.5%). Similarly, the failure load and cross-sectional area were not significantly different across all tested suture groups. CONCLUSIONS: The modified Prusik knot, Wittstein suture loop, and modified rolling-hitch techniques had equal elongation after cyclic loading, as well as load to failure, in this in vitro biomechanical evaluation. CLINICAL RELEVANCE: These needleless grasping suture techniques may be an attractive alternative to the commonly used whipstitch techniques for tendon graft fixation in ligament reconstruction. PMID- 25744931 TI - Magnetization transfer ratio does not correlate to myelin content in the brain in the MOG-EAE mouse model. AB - Magnetization transfer ratio (MTR) is a magnetic resonance imaging (MRI) method which may detect demyelination not detected by conventional MRI in the central nervous system of patients with multiple sclerosis (MS). A decrease in MTR value has previously been shown to correlate to myelin loss in the mouse cuprizone model for demyelination. In this study, we investigated the sensitivity of MTR for demyelination in the myelin oligodendrocyte (MOG) 1-125 induced experimental autoimmune encephalomyelitis (EAE) mouse model. A total of 24 female c57Bl/6 mice were randomized to a control group (N = 6) or EAE (N = 18). MTR images were obtained at a preclinical 7 Tesla Bruker MR-scanner before EAE induction (baseline), 17-19 days (midpoint) and 31-32 days (endpoint) after EAE induction. Mean MTR values were calculated in five regions of the brain and compared to weight, EAE severity score and myelin content assessed by immunostaining for proteolipid protein and luxol fast blue, lymphocyte and monocyte infiltration and iron deposition. Contrary to what was expected, MTR values in the EAE mice were higher than in the control mice at the midpoint and endpoint. No significant difference in myelin content was found according to histo- or immunohistochemistry. Changes in MTR values did not correlate to myelin content, iron content, lymphocyte or monocyte infiltration, weight or EAE severity scores. This suggest that MTR measures of brain tissue can give significant differences between control mice and EAE mice not caused by demyelination, inflammation or iron deposition, and may not be useful surrogate markers for demyelination in the MOG1-125 mouse model. PMID- 25744932 TI - Phonon hydrodynamics in two-dimensional materials. AB - The conduction of heat in two dimensions displays a wealth of fascinating phenomena of key relevance to the scientific understanding and technological applications of graphene and related materials. Here, we use density-functional perturbation theory and an exact, variational solution of the Boltzmann transport equation to study fully from first-principles phonon transport and heat conductivity in graphene, boron nitride, molybdenum disulphide and the functionalized derivatives graphane and fluorographene. In all these materials, and at variance with typical three-dimensional solids, normal processes keep dominating over Umklapp scattering well-above cryogenic conditions, extending to room temperature and more. As a result, novel regimes emerge, with Poiseuille and Ziman hydrodynamics, hitherto typically confined to ultra-low temperatures, characterizing transport at ordinary conditions. Most remarkably, several of these two-dimensional materials admit wave-like heat diffusion, with second sound present at room temperature and above in graphene, boron nitride and graphane. PMID- 25744934 TI - The complete mitochondrial genomes of Umalia orientalis and Lyreidus brevifrons: The phylogenetic position of the family Raninidae within Brachyuran crabs. AB - The complete mitochondrial genome (mitogenome) sequences of two primitive crabs, Umalia orientalis and Lyreidus brevifrons (Decapoda: Brachyura: Raninidae) were determined. The mitogenomes of the two species are 15,466 and 16,112bp in length with AT content of 68.0% and 70.6%, respectively. Each genome contains 13 protein coding genes (PCGs), two rRNA genes, and 22 tRNA genes. The gene arrangement of U. orientalis is the same with those reported for most brachyuran species. Nevertheless, the gene arrangement of L. brevifrons differs from that of U. orientalis in having an additional non-coding region. The newly found non-coding region is located between nad3 and trnA with 641bp in length. Its nucleotide composition and secondary structure are similar to the typical control region. In L. brevifrons, the secondary structures of trnS-AGN and trnI are significantly different from those in U. orientalis and other brachyuran species. The start codon for cox1 is ATG in all reported Eubrachyura mitogenomes, while a common start codon ACG is found in the Podotremata. Phylogenetic analyses for crustacean decapods based on the nucleotide and amino acid of 13 PCGs indicate that Homolidae is more primitive in Brachyura, and Raninidae is a sister group to Eubrachyura. This implies that Raninidae is closer to Eubrachyura than to Homolidae, and Podotremata may be a paraphyletic assemblage. The results also indicate that the subfamily Lyreidinae is closer to Notopodinae than to Ranininae within Raninidae. The novel mitogenome data provides useful information for refining the phylogenetic relationships within Brachyura. PMID- 25744933 TI - Evaluation of polycaprolactone scaffold with basic fibroblast growth factor and fibroblasts in an athymic rat model for anterior cruciate ligament reconstruction. AB - Anterior cruciate ligament (ACL) rupture is a common ligamentous injury often necessitating surgery. Current surgical treatment options include ligament reconstruction with autograft or allograft, which have their inherent limitations. Thus, there is interest in a tissue-engineered substitute for use in ACL regeneration. However, there have been relatively few in vivo studies to date. In this study, an athymic rat model of ACL reconstruction was used to evaluate electrospun polycaprolactone (PCL) grafts, with and without the addition of basic fibroblast growth factor (bFGF) and human foreskin fibroblasts. We examined the regenerative potential of tissue-engineered ACL grafts using histology, immunohistochemistry, and mechanical testing up to 16 weeks postoperatively. Histology showed infiltration of the grafts with cells, and immunohistochemistry demonstrated aligned collagen deposition with minimal inflammatory reaction. Mechanical testing of the grafts demonstrated significantly higher mechanical properties than immediately postimplantation. Acellular grafts loaded with bFGF achieved 58.8% of the stiffness and 40.7% of the peak load of healthy native ACL. Grafts without bFGF achieved 31.3% of the stiffness and 28.2% of the peak load of healthy native ACL. In this in vivo rodent model study for ACL reconstruction, the histological and mechanical evaluation demonstrated excellent healing and regenerative potential of our electrospun PCL ligament graft. PMID- 25744936 TI - Strain-dependent effects on acquisition and reversal of visual and spatial tasks in a rat touchscreen battery of cognition. AB - AIM: The use of touch-screen equipped operant boxes is an increasingly popular method for modeling human cognition in the rodent. A concern of this approach is that the dependence upon vision may limit the strains of rats that can be tested in the apparatus. This is of particular concern because of the increased availability of genetically modified rats that are disproportionately on an albino background and may have compromised vision. Here we test pigmented and albino strains of rats on three touch-screen tasks of learning and memory that may require different levels of visual ability. In tests where albino animals have similar levels of performance as the pigmented rats we also tested common pharmacological models of cognitive impairment to determine the generalizability of these challenges across strains. By doing this work we hope to determine the robustness of common models of pharmacological impairment in albino rats. METHODS: We tested four strains of rats (albino: Wistar and Sprague Dawley, pigmented: Long Evans and Lister Hooded) in three touchscreen-based tasks of cognition with differing visual requirements: visual discrimination (VD) acquisition and reversal learning, and the more spatial and less visually demanding, automated spatial search task (AST). Furthermore, we tested the effects of the muscarinic antagonist scopolamine and the non-competitive NMDAR antagonist MK801 on performance of the four strains in AST. Finally, visual acuity was also assessed via a movement detection test. RESULTS: The rate of acquisition (% correct) in albino rats was significantly slower than in pigmented rats. Wistar rats were significantly slower to acquire the task, and showed differences in reversal learning when compared to the pigmented strains. Moreover, SD rats performed so badly during the acquisition phase of the VD that they failed to reach inclusion criteria (80% correct responses over 3-sessions) for the reversal phase. In contrast, no effect of strain was found in AST. Some of these differences can likely be attributed to differences in visual acuity as albino animals appeared to have reduced visual acuity when compared to the pigmented animals as previously reported in the literature. Pharmacological challenge with scopolamine or MK801 induced dissociable effects between compounds, but generally comparable impairments in all four strains. CONCLUSIONS: Albino animals showed a clear impairment on tasks that are dependent upon intact vision, while no impairment was observed in the visually less demanding spatial task. Despite a published report to the contrary, these results demonstrate that albino strains may not be appropriate for use in touchscreen tasks that are dependent upon a visual discrimination. Furthermore, the spatial search task showed distinct impairment profiles as a result of treatment with either MK-801 or scopolamine. While an interaction did exist between strain and treatment, the dissociation between MK-801 and scopolamine was consistent across 3 of 4 strains. These results highlight the importance of selecting the appropriate strain for use in tasks of visual learning and memory and also demonstrate the potential robustness of pharmacological models of cognitive impairment across strains. PMID- 25744935 TI - Corn oil, but not cocaine, is a more effective reinforcer in obese than in lean Zucker rats. AB - Obesity is associated with abnormal brain reactivity in response to palatable food consumption, a factor that may contribute to non-homeostatic eating. However, little is known about how obesity interacts with the reinforcing effects of highly palatable constituents of food (e.g., fat), and if altered reinforcement processes associated with obesity generalize to non-food reinforcers. The current study compared the reinforcing effects of a fat (corn oil) and a drug of abuse (cocaine) in obese and lean Zucker rats. Specifically, obese and lean Zucker rats self-administered corn oil or intravenous cocaine in a behavioral economic demand procedure. For corn oil, maximum demand was higher and demand elasticity was lower in the obese rats compared to their lean counterparts. However, there were no differences in demand for cocaine between the obese and lean rats. These results demonstrate that a fat in the form of corn oil is a more effective reinforcer in obese Zucker rats. However, the fact that demand for cocaine was not different between the obese and lean rats suggests that differences in reward mechanisms may be reinforcer-specific and do not necessarily generalize to non-food reinforcers. PMID- 25744937 TI - Mesenteric panniculitis: more research is needed. PMID- 25744939 TI - Autosomal recessive transmission of TRAPS in a family with a novel TNFRSF1A mutation. PMID- 25744938 TI - A potential interaction between COMT and MTHFR genetic variants in Han Chinese patients with bipolar II disorder. AB - Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype (P = 0.039) for the protective effect on the odds of developing BP-II. Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II. PMID- 25744940 TI - Translation and factor analysis of structural models of Edinburgh Postnatal Depression Scale in Serbian pregnant and postpartum women - Web-based study. AB - BACKGROUND: The Edinburgh Postnatal Depression Scale (EPDS) is well accepted for detecting symptoms of postnatal depression. The aim of this study was to examine psychometric properties and to evaluate structural models of the Serbian translation of EPDS in pregnant and postpartum women. METHODS: The original English version of the EPDS was translated into Serbian, and checked by means of back-translation. Data were collected via an anonymous online questionnaire posted on a Serbian website devoted to pregnancy topics. The study sample included 201 women (76 pregnant, 125 postpartum). The internal consistency of the scale was measured by Cronbach's alpha coefficient. Principal component analysis was used to determine scale dimensions while confirmatory factor analysis was used to evaluate model fit. FINDINGS: Cronbach alpha coefficient was 0.84 and 0.83 in pregnant and postpartum women, respectively, which indicated good internal consistency of the Serbian EPDS. Three dimensions of the scale were revealed in both groups of women. Goodness of fit indices described good and excellent model in pregnant and postpartum women, respectively. High level of depression symptoms (score >=13) was recorded in 27.6% and 24.8% (p>0.05) of pregnant and postpartum women, respectively. Moderate level of depression symptoms (score 10-12) was recorded in 21.1% and 16.8% (p>0.05) of pregnant and postpartum women, respectively. CONCLUSION: The Serbian translation of the EPDS showed good consistency and good model characteristics in pregnant and postpartum women. However, cut-off values, sensitivity and specificity of the scale should be determined in the further studies with more representative samples of women. PMID- 25744942 TI - Three-dimensional computer-assisted surgical simulation and intraoperative navigation in orthognathic surgery: a literature review. AB - By incorporating three-dimensional (3D) imaging and computer-aided design and manufacturing techniques, 3D computer-assisted technology has been applied widely to provide accurate guidance for assessment and treatment planning in clinical practice. This technology has recently been used in orthognathic surgery to improve surgical planning and outcome. The modality will gradually become popular. This study reviewed the literature concerning the use of computer assisted techniques in orthognathic surgery including surgical planning, simulation, intraoperative translation of the virtual surgery, and postoperative evaluation. A Medline, PubMed, ProQuest, and ScienceDirect search was performed to find relevant articles with regard to 3D computer-assisted orthognathic surgery in the past 10 years. A total of 460 articles were revealed, out of which 174 were publications addressed the topic of this study. The purpose of this article is to present an overview of the state-of-art methods for 3D computer assisted technology in orthognathic surgery. From the review we can conclude that the use of computer-assisted technique in orthognathic surgery provides the benefit of optimal functional and aesthetic results, patient satisfaction, precise translation of the treatment plan, and facilitating intraoperative manipulation. PMID- 25744941 TI - From static to dynamic: the need for structural ensembles and a predictive model of RNA folding and function. AB - To understand RNA, it is necessary to move beyond a descriptive categorization towards quantitative predictions of its molecular conformations and functional behavior. An incisive approach to understanding the function and folding of biological RNA systems involves characterizing small, simple components that are largely responsible for the behavior of complex systems including helix-junction helix elements and tertiary motifs. State-of-the-art methods have permitted unprecedented insight into the conformational ensembles of these elements revealing, for example, that conformations of helix-junction-helix elements are confined to a small region of the ensemble, that this region is highly dependent on the junction's topology, and that the correct alignment of tertiary motifs may be a rare conformation on the overall folding landscape. Further characterization of RNA components and continued development of experimental and computational methods with the goal of quantitatively predicting RNA folding and functional behavior will be critical to understanding biological RNA systems. PMID- 25744943 TI - Motion estimation-based image enhancement in ultrasound imaging. AB - High resolution medical ultrasound (US) imaging is an ongoing challenge in many diagnosis applications and can be achieved either by instrumentation or by post processing. Though many works have considered the issue of resolution enhancement in optical imaging, very few works have investigated this issue in US imaging. In optics, several algorithms have been proposed to achieve super-resolution (SR) image reconstruction, which consists of merging several low resolution images to create a higher resolution image. However, the straightforward implementation of such techniques for US imaging is unsuccessful, due to the interaction of ultrasound with tissue and speckle. We show how to overcome the limit of SR in this framework by refining the registration part of common multiframe techniques. For this purpose, we investigate motion estimation methods adapted to US imaging. Performance of the proposed technique is evaluated on both realistic simulated US images (providing an estimated best-case performance) and real US sequences of phantom and in-vivo thyroid images. Compared to classical SR methods, our technique brings both quantitative and qualitative improvements. Resolution gain was found to be 1.41 for the phantom sequence and 1.12 for the thyroid sequence and a quantitative study using the phantom further confirmed the spatial resolution enhancement. Furthermore, the contrast-to-noise ratio was increased by 27% and 13% for simulated and experimental US images, respectively. PMID- 25744944 TI - Environmental factors in multiple sclerosis. AB - Although multiple sclerosis (MS) is recognized as a disorder involving the immune system, the interplay of environmental factors and individual genetic susceptibility seems to influence MS onset and clinical expression, as well as therapeutic responsiveness. Multiple human epidemiological and animal model studies have evaluated the effect of different environmental factors, such as viral infections, vitamin intake, sun exposure, or still dietary and life habits on MS prevalence. Previous Epstein-Barr virus infection, especially if this infection occurs in late childhood, and lack of vitamin D (VitD) currently appear to be the most robust environmental factors for the risk of MS, at least from an epidemiological standpoint. Ultraviolet radiation (UVR) activates VitD production but there are also some elements supporting the fact that insufficient UVR exposure during childhood may represent a VitD-independent risk factor of MS development, as well as negative effect on the clinical and radiological course of MS. Recently, there has been a growing interest in the gut-brain axis, a bidirectional neuro-hormonal communication system between the intestinal microbiota and the central nervous system (CNS). Indeed, components of the intestinal microbiota may be pro-inflammatory, promote the migration of immune cells into the CNS, and thus be a key parameter for the development of autoimmune disorders such as MS. Interestingly most environmental factors seem to play a role during childhood. Thus, if childhood is the most fragile period to develop MS later in life, preventive measures should be applied early in life. For example, adopting a diet enriched in VitD, playing outdoor and avoiding passive smoking would be extremely simple measures of primary prevention for public health strategies. However, these hypotheses need to be confirmed by prospective evaluations, which are obviously difficult to conduct. In addition, it remains to be determined whether and how VitD supplementation in adult life would be useful in alleviating the course of MS, once this disease has already started. A better knowledge of the influence of various environmental stimuli on MS risk and course would certainly allow the development of add-on therapies or measures in parallel to the immunotherapies currently used in MS. PMID- 25744945 TI - [Erythema ab igne: 2 new cases]. PMID- 25744946 TI - Treatment of multiple sclerosis in children and its challenges. AB - Though pediatric-onset multiple sclerosis (MS) is a rare disease, providers must be aware of the diagnosis, and of symptoms that herald demyelination, in order to initiate prompt workup and treatment in the appropriate clinical scenarios. Though children with MS do not have significant physical disability at onset, at least a third of patients have cognitive deficits at the time of diagnosis and demonstrate worsening cognitive functioning over time. Pediatric MS patients tend to have high relapse rates and high lesion volumes early in their disease course and warrant early initiation of disease modifying therapy. This review discusses the different treatment options available for pediatric patients with MS, emerging medications, and some of the challenges associated with treating this patient population. PMID- 25744947 TI - [Cauda equina syndrome after Neisseria meningitidis type C meningitis]. PMID- 25744948 TI - [Postoperative non-opioid analgesics management]. AB - Morphine, which is known as the reference analgesic, has shown its limits. Reducing morphine consumption and multimodal analgesia are integral parts of a modern management of postoperative pain. Combination of several analgesics aims for improving pain control and the ratio between the analgesic effect and the side effects. Nefopam, paracetamol, non-steroids anti-inflammatory drugs and steroids are the most frequently prescribed non-opioid analgesics in France. They can be administered alone or in combination with or without morphine in the postoperative setting. The analgesic benefit of each of these agents and their associations is variable and described in details in this manuscript. PMID- 25744949 TI - [If I had a stroke in 2015]. AB - The management of stroke is now recognized as a real medical emergency as well as myocardial infarct, because we have now an efficacious treatment in cerebral infarct, intravenous fibrinolysis that decreases the risk of death and motor and cognitive handicap. The second characteristic is its very important frequency, and its risk that increases in young people. This medical emergency enforces the care systems because it needs a speedy network for the patient, his family and the care professionals, useful for intravenous fibrinolysis before 3 hours after 80 years and before 4 hours and a half before 80 years. It is necessary to start treatment as soon as possible because it is most effective when given early. The consequences to avoid the lost of chance, need several actions: inform the public about the interest of FAST score to identify the first signs (facial palsy, palsy of arm, aphasia and time of stroke onset); call 15; translate the patient towards an appropriate medical center; use tele-stroke when the hospital has no neurologist; and manage the patient in a stroke unit, to introduce in a second time secondary prevention thanks to therapeutical education. Therefore, stroke care is a real multiprofessional emergency around the neurologist. PMID- 25744950 TI - [Case report of cardiac tamponade resulting from jugular venous catheterization using ultrasound guidance]. PMID- 25744952 TI - Assessing the Temporal Stability of a Cigarette Purchase Task After an Excise Tax Increase for Factory-Made and Roll-Your-Own Smokers. AB - INTRODUCTION: Cigarette purchase tasks (CPTs) are used increasingly to measure simulated demand curves for tobacco. However, there is currently limited information about the temporal stability of demand curves obtained from these tasks. METHOD: We interviewed a sample (N = 210) of smokers in New Zealand both before and after a 10% increase in the tobacco excise tax that took effect on January 1, 2013. Participants were interviewed in November-December 2012 (wave 1) and February-March 2013 (wave 2). At each interview, participants completed a high-resolution CPT with 64 prices ranging from NZ $0.00 to NZ $5.00/cigarette, and questionnaires regarding their smoking habit. RESULTS: Roll-your-own smokers had higher levels of nicotine dependence and tobacco demand based on CPT responses than factory-made smokers. Although demand curves for waves 1 and 2 were similar, intentions to purchase cigarettes were significantly less at wave 2 for three prices (NZ $0.85, NZ $0.90, and NZ $0.95) that were just higher than the actual price after the tax increase, for both roll-your-own and factory-made smokers. Measures of elasticity (alpha) derived from Hursh and Silberberg's model were significantly greater at wave 2 than wave 1, and there was a significant reduction in smoking habit as measured by cigarettes/day and the Fagerstrom Test for Nicotine Dependence at wave 2. CONCLUSIONS: Purchase tasks can discriminate between smokers based on their tobacco preference, and although results are relatively stable over time, they depend on contextual factors such as the current real price for tobacco. PMID- 25744951 TI - Renal progenitors derived from human iPSCs engraft and restore function in a mouse model of acute kidney injury. AB - Acute kidney injury (AKI) is one of the most relevant health issues, leading to millions of deaths. The magnitude of the phenomenon remarks the urgent need for innovative and effective therapeutic approaches. Cell-based therapy with renal progenitor cells (RPCs) has been proposed as a possible strategy. Studies have shown the feasibility of directing embryonic stem cells or induced Pluripotent Stem Cells (iPSCs) towards nephrogenic intermediate mesoderm and metanephric mesenchyme (MM). However, the functional activity of iPSC-derived RPCs has not been tested in animal models of kidney disease. Here, through an efficient inductive protocol, we directed human iPSCs towards RPCs that robustly engrafted into damaged tubuli and restored renal function and structure in cisplatin-mice with AKI. These results demonstrate that iPSCs are a valuable source of engraftable cells with regenerative activity for kidney disease and create the basis for future applications in stem cell-based therapy. PMID- 25744953 TI - Past Year Quit Attempts and Use of Cessation Resources Among Cigarette-Only Smokers and Cigarette Smokers Who Use Other Tobacco Products. AB - INTRODUCTION: It is unclear how use of other tobacco products impacts cigarette smoking cessation. We assessed differences in past year cigarette smoking quit attempts and use of counseling and medication among current cigarette-only users, cigarette and cigar users, and cigarette and smokeless tobacco (SLT) users. METHODS: Data came from 24 448 current cigarette-only, 1064 cigarette and cigar only, and 508 cigarette and SLT only users who responded to the 2010-2011 Tobacco Use Supplement to the Current Population Survey. Demographic, smoking, and cessation characteristics were computed by group. Bivariate and multivariable logistic regression models assessed the relationship of tobacco use group to making a past year quit attempt, and use of counseling or medication during the last quit attempt. RESULTS: Dual users of cigarettes and cigars or SLT had similar interest in quitting and prevalence of reported past year quit attempts compared to cigarette-only users. In unadjusted analyses, cigarette and SLT users had higher odds of trying to quit in the past year compared to cigarette-only users (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.05, 1.64); no differences were found for cigarette and cigar users. However, adjusting for demographic and cigarette smoking variables, both groups of dual users had similar odds as cigarette-only users for having made a past year cigarette smoking quit attempt, and to have used counseling or medication during the last quit attempt. CONCLUSION: Dual tobacco use was not associated with decreased attempts to quit smoking cigarettes; however, use of evidence-based treatment was sub-optimal among cigarette-only and dual users, and should be increased. PMID- 25744954 TI - An Adaptation of Motivational Interviewing Increases Quit Attempts in Smokers With Serious Mental Illness. AB - INTRODUCTION: Smokers with serious mental illness (SMI) have a high smoking prevalence and a low quit rate. Motivational interviewing (MI) is an empirically supported approach for addressing substance use disorders and may motivate smokers with SMI to quit. METHODS: We randomized smokers (N = 98) with SMI to receive a single 45-minute session of (1) MI with personalized feedback or (2) interactive education. We hypothesized that participants receiving the MI intervention would be more likely to follow-up on a referral for tobacco dependence treatment, to make a quit attempt, and to quit smoking than those receiving the interactive educational intervention. RESULTS: Smokers receiving an MI intervention were significantly more likely to make a quit attempt by the 1 month follow-up (34.7% vs. 14.3%; OR = 4.39 [95% CI = 1.44 to 13.34], P = .009); however, these quit attempts did not translate into abstinence. In addition, 32.7% of those receiving MI followed-up on a referral for tobacco dependence treatment (vs. 20.4% receiving interactive education; OR = 2.02 [95% CI = 0.76 to 3.55], P = .157). MI Treatment Integrity Code ratings indicated that the interventions were easily distinguishable from each other and that MI was delivered with proficiency. Despite the intervention's brevity, participants reported high levels of therapeutic alliance with their therapist. CONCLUSIONS: A brief adaptation of MI with personalized feedback appears to be a promising approach for increasing quit attempts in smokers with SMI, but future research is required to determine how to best help smokers with SMI to attain sustained abstinence. PMID- 25744955 TI - The Reliability and Stability of Puff Topography Variables in Non-Daily Smokers Assessed in the Laboratory. AB - INTRODUCTION: Puff topography variables, often measured using the Clinical Research Support System device, have traditionally been studied in regular, daily smokers and have been shown to be highly stable. However, more recent research has focused on non-daily smokers as a population of interest. As such, the aim of this article was to examine puff topography stability (cross-cigarette agreement over time) and reliability (within-cigarette consistency) in non-daily smokers across six laboratory sessions. METHODS: One hundred seven non-daily smokers attended six laboratory sessions over the course of 3 months. At each session, they smoked one cigarette through the Clinical Research Support System pocket, in addition to completing questionnaires about their smoking history and dependence. RESULTS: Puff topography measurements were highly reliable (alpha values ranged from 0.87-0.95) and puff behavior was highly stable across sessions (r values ranged from 0.38-0.84). Adding sessions substantially improved reliability estimates. Aspects of puffing behavior observed in session, including puff volume, puff duration, time of puff peak, and total cigarette volume were related to level of smoke exposure, measured by expired carbon monoxide. Instability in puffing behavior was not predicted by recent or long-term smoking patterns. CONCLUSIONS: Puff topography appears to be a stable and routinized aspect of smoking in non-daily smokers. The feasibility of assessing puff topography in this population is supported by the high reliabilities observed, though it should be noted that reliability greatly improved by having more than one session. PMID- 25744956 TI - Young Adult Smokers' and Prior-Smokers' Evaluations of Novel Tobacco Warning Images. AB - INTRODUCTION: On-pack warning labels represent a very cost-effective means of communicating with smokers, who potentially see warnings each time they retrieve a cigarette. Warning labels have traditionally depicted graphic health consequences of smoking but emerging evidence suggests the distal consequences shown may prove less effective in prompting cessation among young adults. We used a novel micro-survey approach to compare novel and traditional warnings, and provide an empirical foundation for a larger study. METHODS: We recruited 4649 male and 2993 female participants aged 18-34 from Google Consumer Survey's Australian panel of Android mobile phone users. A screening question resulted in a sample comprising 3183 daily, non-daily, and former smokers. Twenty images corresponding to social and health risks, tobacco industry denormalization, and secondhand smoke (SHS) were tested in paired comparisons where respondents selected the image they thought most likely to prompt cessation. RESULTS: Irrespective of smoking status, respondents rated messages featuring harm to children as most effective and industry denormalization messages and adult SHS warnings as least effective. Within smoker groups, daily smokers rated social concerns more highly; non-daily smokers were more responsive to SHS messages, and former smokers saw intimacy and cosmetic effects warnings as more effective than other groups. CONCLUSIONS: While preliminary, the findings support emerging evidence that more diverse warning images may be required to promote cessation among all smoker sub-groups. Warnings depicting harm to vulnerable others appear to hold high potential and merit further investigation. PMID- 25744957 TI - Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice. AB - INTRODUCTION: Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. METHODS: This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open field test. RESULTS: Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal. CONCLUSIONS: Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. PMID- 25744959 TI - Is There a Relationship Between the Concentration of Same-Sex Couples and Tobacco Retailer Density? AB - BACKGROUND: Tobacco use is markedly higher among lesbian, gay, and bisexual populations than heterosexuals. Higher density of tobacco retailers is found in neighborhoods with lower income and more racial/ethnic minorities. Same-sex couples tend to live in similar neighborhoods, but the association of this demographic with tobacco retailer density has not been examined. METHODS: For a national sample of 97 US counties, we calculated the number of tobacco retailers per 1000 persons and rates of same-sex couples per 1000 households in each census tract (n = 17 941). Using spatial regression, we examined the association of these variables in sex-stratified models, including neighborhood demographics and other environmental characteristics to examine confounding. RESULTS: Results from spatial regression show that higher rates of both female and male same-sex couples were associated with a higher density of tobacco retailers. However the magnitude of this association was small. For female couples, the association was not significant after controlling for area-level characteristics, such as percent black, percent Hispanic, median household income, the presence of interstate highways, and urbanicity, which are neighborhood correlates of higher tobacco retailer density. For male couples, the association persisted after control for these characteristics. CONCLUSION: Same-sex couples reside in areas with higher tobacco retailer density, and for men, this association was not explained by neighborhood confounders, such as racial/ethnic composition and income. While lesbian, gay, and bisexual disparities in tobacco use may be influenced by neighborhood environment, the magnitude of the association suggests other explanations of these disparities remain important areas of research. PMID- 25744958 TI - Withdrawal: Expanding a Key Addiction Construct. AB - Withdrawal is an essential component of classical addiction theory; it is a vital manifestation of dependence and motivates relapse. However, the traditional conceptualization of withdrawal as a cohesive collection of symptoms that emerge during drug deprivation and decline with either the passage of time or reinstatement of drug use, may be inadequate to explain scientific findings or fit with modern theories of addiction. This article expands the current understanding of tobacco withdrawal by examining: (1) withdrawal variability; (2) underlying causes of withdrawal variability, including biological and person factors, environmental influences, and the influence of highly routinized behavioral patterns; (3) new withdrawal symptoms that allow for enhanced characterization of the withdrawal experience; and (4) withdrawal-related cognitive processes. These topics provide guidance regarding the optimal assessment of withdrawal and illustrate the potential impact modern withdrawal conceptualization and assessment could have on identifying treatment targets. PMID- 25744960 TI - Nicotine Attenuates Disruption of Blood-Brain Barrier Induced by Saturated-Fat Feeding in Wild-Type Mice. AB - INTRODUCTION: Emerging evidence suggests that integrity of blood-brain barrier (BBB) is pivotal to pathology and pathogenesis of vascular-based neurodegenerative disorders. We have recently reported BBB protective effects of nutraceutical agents with anti-inflammatory properties in an established dietary induced BBB dysfunction model. Studies also reported that nicotine exhibits anti oxidative/-inflammatory effects and improve cognitive impairment in Alzheimer's disease. However there has been no studies reporting the effect of nicotine on high-fat-induced BBB dysfunction. METHODS: In the present study, we investigated the effect of nicotine on BBB integrity and neuro-inflammation in an established mouse model of BBB disruption induced by a diet enriched in saturated fatty acids (SFA). RESULTS: Wild-type C57BL/6J mice were fed chow enriched in SFA (23% w/w) with/without nicotine for 10 weeks. Compared to mice maintained on SFA-free and low-fat (LF) chow (4% w/w), capillary permeability indicated by the parenchymal extravasation of plasma derived IgG, was significantly greater in the SFA treatment group. Nicotine provided concomitantly with the SFA diet significantly attenuated IgG extravasation, however it remained significantly greater than LF controls. Markers of neurovascular inflammation glial fibrillary acidic protein, cyclooxygenase-2, and glucose regulated protein 78 remained exaggerated in SFA+nicotine treated mice compared to LF-controls. Nicotine did however modestly, but not significantly, improve plasma total anti-oxidative status in SFA fed mice. CONCLUSION: Nicotine moderately attenuated BBB disruption induced by chronic ingestion of high-SFA diet, but had no significant effect on neuroinflammation per se. PMID- 25744961 TI - Cigarette Smoking Trajectories From Sixth to Twelfth Grade: Associated Substance Use and High School Dropout. AB - INTRODUCTION: The purpose of this longitudinal study was to identify distinct trajectories of cigarette smoking from sixth to twelfth grade and to characterize these trajectories by use of other drugs and high school dropout. METHODS: The diverse sample for this analysis consisted of a cohort of 611 students from Northeast Georgia who participated in the Healthy Teens Longitudinal Study (2003 2009). Students completed seven yearly assessments from sixth through twelfth grade. We used semi-parametric, group-based modeling to identify groups of students whose smoking behavior followed a similar progression over time. RESULTS: Current smoking (past 30 day) increased from 6.9% among sixth graders to 28.8% among twelfth graders. Four developmental trajectories of cigarette smoking were identified: Abstainers/Sporadic Users (71.5% of the sample), Late Starters (11.3%), Experimenters (9.0%), and Continuous Users (8.2%). The Abstainer/Sporadic User trajectory was composed of two distinct groups: those who never reported any tobacco use (True Abstainers) and those who reported sporadic, low-level use (Sporadic Users). The True Abstainers reported significantly less use of alcohol and other drugs and lower dropout rates than students in all other trajectories, and Sporadic Users had worse outcomes than True Abstainers. Experimenters and Continuous Users reported the highest drug use. Over one-third of Late Starters (35.8%) and almost half of Continuous Users (44.4%) dropped out of high school. CONCLUSIONS: Cigarette smoking was associated with behavioral and academic problems. Results support early and continuous interventions to reduce use of tobacco and other drugs and prevent high school dropout. PMID- 25744962 TI - Randomized Controlled Trial of a Healthy Lifestyle Intervention Among Smokers With Psychotic Disorders. AB - INTRODUCTION: People with severe mental disorders typically experience a range of health problems; consequently, interventions addressing multiple health behaviors may provide an efficient way to tackle this major public health issue. This two arm randomized controlled trial among people with psychotic disorders examined the efficacy of nicotine replacement therapy (NRT) plus either a face-to-face or predominantly telephone delivered intervention for smoking cessation and cardiovascular disease (CVD) risk reduction. METHODS: Following baseline assessment and completion of a common, individually delivered 90-minute face-to face intervention, participants (n = 235) were randomized to receive NRT plus: (1) a "Healthy Lifestyles" intervention for smoking cessation and CVD risk behaviors or (2) a predominantly telephone-based intervention (designed to control for NRT provision, session frequency, and other monitoring activities). Research assistants blind to treatment allocation performed assessments at 15 weeks (mid-intervention) and 12 months after baseline. RESULTS: There were no significant differences between intervention conditions in CVD risk or smoking outcomes at 15 weeks or 12 months, with improvements in both conditions (eg, 12 months: 6.4% confirmed point prevalence abstinence rate; 17% experiencing a 50% or greater smoking reduction; mean reduction of 8.6 cigarettes per day; mean improvement in functioning of 9.8 points). CONCLUSIONS: The health disparity experienced by people with psychotic disorders is high. Face-to-face Healthy Lifestyle interventions appear to be feasible and somewhat effective. However, given the accessibility of telephone delivered interventions, potentially combined with lower cost, further studies are needed to evaluate telephone delivered smoking cessation and lifestyle interventions for people with psychotic disorders. PMID- 25744963 TI - CYP2A6 Longitudinal Effects in Young Smokers. AB - INTRODUCTION: The present study sought to identify time-dependent within participant effects of CYP2A6 genotypes on smoking frequency and nicotine dependence in young smokers. METHODS: Predicted nicotine metabolic rate based on CYP2A6 diplotypes (CYP2A6 diplotype predicted rate [CDPR]) was partitioned into Normal, Intermediate, and Slow categories using a metabolism metric. Growth-curve models characterized baseline and longitudinal CDPR effects with data from eight longitudinal assessments during a 6-year period (from approximately age 16-22) in young smokers of European descent (N = 296, 57% female) who had smoked less than 100 cigarettes lifetime at baseline and more than that amount by Year 6. Phenotypes were number of days smoked during the previous 30 days and a youth version of the Nicotine Dependence Syndrome Scale (NDSS). A zero-inflated Poisson growth-curve model was used to account for the preponderance of zero days smoked. RESULTS: At baseline, Intermediate CDPR was a risk factor relative to both Normal and Slow CDPR for smoking frequency and the NDSS. Slow CDPR was associated with the highest probability of smoking discontinuation at baseline. However, due to CDPR time trend differences, by young adulthood these baseline effects had been reordered such that the greatest risks for smoking frequency and the NDSS were associated with Normal CDPR. CONCLUSIONS: Reduced metabolism CYP2A6 genotypes are associated with both risk and protective effects in novice smokers. However, differences in the time-by-CDPR effects result in a reordering of genotype effects such that normal metabolism becomes the risk variant by young adulthood, as has been reliably reported in older smokers. PMID- 25744964 TI - The Impact of a City-Wide Indoor Smoking Ban on Smoking and Drinking Behaviors Across Emerging Adulthood. AB - INTRODUCTION: Almost one-third of college students report recent cigarette use, primarily as "social smoking," and often in conjunction with alcohol use. While city-wide indoor smoking bans effectively reduce the number of social opportunities to smoke (eg, bars and music clubs), little is known about how these bans may impact the smoking behaviors of college students. Furthermore, nothing is known about how indoor smoking bans may impact students' drinking behaviors. The current study aims to determine the impact of a city-wide comprehensive indoor smoking ban on smoking and alcohol behaviors among a longitudinal sample of emerging adults. METHODS: Data are from a 6-year longitudinal study (10 waves of data collection) that began the summer before college enrollment. Participants (N = 2244; 60% female) reported on their past 3 month smoking and drinking behaviors using Internet-based surveys at each wave. Piecewise linear growth modeling was used to determine how a city-wide comprehensive indoor smoking ban (implemented in the Fall of 2005 between Waves 4 and 5) impacted smoking frequency, cigarette quantity, drinking frequency, and number of binge drinking episodes. RESULTS: Smoking and alcohol use increased from the summer before college through the semester before implementation of the city-wide smoking ban. While smoking frequency (P < .001) and cigarette quantity (P < .05) declined after the ban, drinking frequency increased (P < .001) and the number of binge drinking episodes remained stable. CONCLUSIONS: Current findings suggest that comprehensive indoor smoking bans can influence the smoking behaviors of emerging adults, whereas trajectories of drinking are relatively unchanged. PMID- 25744965 TI - Effect of Alcohol and Tobacco Smoke on Long-Term Memory and Cell Proliferation in the Hippocampus of Rats. AB - INTRODUCTION: Alcohol is frequently used in combination with tobacco and few studies explore interactions between these two drugs of abuse. Here, we evaluated the effect of chronic alcohol administration and concomitant exposure to tobacco smoke on long-term memory and on cell proliferation in the hippocampus of rats. METHODS: Forty male Wistar rats were assigned to four groups and treated with alcohol (2g/kg by gavage) and/or exposed to tobacco smoke (from six cigarettes, by inhalation) twice a day (at 9:00 AM and 2:00 PM) for 30 days. Long-term memory was evaluated in the inhibitory avoidance test and hippocampal cell proliferation was analyzed for bromodeoxyuridine immunohistochemistry. RESULTS: Our results showed that alcohol, tobacco smoke, or their combination improved the long-term memory evaluated by the memory index in rats. Moreover, alcohol and tobacco coadministration decreased bromodeoxyuridine-labeled cells by 60% when compared to the control group, while alcohol treatment decreased labeled cells by 40%. The tobacco group showed a nonsignificant 26% decrease in labeled cells compared to the control group. CONCLUSIONS: Chronic alcohol and tobacco coadministration improves the long-term memory in rats in the inhibitory avoidance test. However, coadministration decreases the cell proliferation in the hippocampus of rats, suggesting a deleterious effect by the combined use of these drugs of abuse. PMID- 25744966 TI - Factors Associated With Electronic Cigarette Users' Device Preferences and Transition From First Generation to Advanced Generation Devices. AB - INTRODUCTION: Electronic cigarettes (e-cigs) are becoming increasingly popular but little is known about how e-cig users' transition between the different device types and what device characteristics and preferences may influence the transition. METHODS: Four thousand four hundred twenty-one experienced e-cig users completed an online survey about their e-cig use, devices, and preferences. Participants included in analysis were ever cigarette smokers who used an e-cig at least 30 days in their lifetime and who reported the type of their first and current e-cig device and the nicotine concentration of their liquid. Analyses focused on transitions between "first generation" devices (same size as a cigarette with no button) and "advanced generation" devices (larger than a cigarette with a manual button) and differences between current users of each device type. RESULTS: Most e-cig users (n = 2603, 58.9%) began use with a first generation device, and of these users, 63.7% subsequently transitioned to current use of an advanced generation device. Among users who began use with an advanced generation device (n = 1818, 41.1%), only 5.7% transitioned to a first generation device. Seventy-seven percent of current advanced generation e-cig users switched to their current device in order to obtain a "more satisfying hit." Battery capabilities and liquid flavor choices also influenced device choice. CONCLUSION: E-cig users commonly begin use with a device shaped like a cigarette and transition to a larger device with a more powerful battery, a button for manual activation and a wider choice of liquid flavors. PMID- 25744968 TI - Relationships Between Craving Beliefs and Abstinence Self-Efficacy are Mediated by Smoking Motives and Moderated by Nicotine Dependence. AB - INTRODUCTION: Decreased abstinence self-efficacy is linked to increased craving and negative affect, as well as poorer smoking outcomes, such as lapse, relapse, and withdrawal symptom severity. Research suggests that beliefs and cognitions concerning ourselves and the world orient us toward specific goals and thus impact our judgments and behavior. This study serves to investigate whether motives for smoking mediate the relationship between beliefs about craving and abstinence self-efficacy judgments and whether this may differ by nicotine dependence. METHODS: In a sample of 198 smokers (M age = 34.96, 51.8% female, 81.8% Caucasian), self-report measures of craving beliefs, situational abstinence self-efficacy, and smoking motives were measured. We examined the effect of beliefs on abstinence self-efficacy in both craving and negative affect situations, with craving and negative reinforcement smoking motives as mediators, and nicotine dependence as a moderator. RESULTS: Results indicate that craving beliefs predict lower abstinence self-efficacy judgments in craving situations indirectly through increased craving motives. However, this relationship was only significant for less dependent smokers. Additionally, regardless of nicotine dependence, craving beliefs predicted lower abstinence self-efficacy in negative affect situations via increased negative reinforcement smoking motives. CONCLUSIONS: These findings suggest that beliefs concerning the specific nature of craving correlate with smoking motives (ie, smoking goals) and thus abstinence self-efficacy judgments. Furthermore, these associations are stronger for less dependent smokers. Such findings suggest the importance of addressing craving beliefs during smoking cessation treatment, especially for less dependent smokers whose craving beliefs are associated with abstinence self-efficacy across multiple situations. PMID- 25744967 TI - Single Cigarette Sales: State Differences in FDA Advertising and Labeling Violations, 2014, United States. AB - IMPORTANCE: Single cigarettes, which are sold without warning labels and often evade taxes, can serve as a gateway for youth smoking. The Family Smoking Prevention and Tobacco Control Act of 2009 gives the US Food and Drug Administration (FDA) authority to regulate the manufacture, distribution, and marketing of tobacco products, including prohibiting the sale of single cigarettes. To enforce these regulations, the FDA conducted over 335,661 inspections between 2010 and September 30, 2014, and allocated over $115 million toward state inspections contracts. OBJECTIVE: To examine differences in single cigarette violations across states and determine if likely correlates of single cigarette sales predict single cigarette violations at the state level. DESIGN: Cross-sectional study of publicly available FDA warning letters from January 1 to July 31, 2014. SETTING: All 50 states and the District of Columbia. PARTICIPANTS: Tobacco retailer inspections conducted by FDA (n = 33 543). EXPOSURES FOR OBSERVATIONAL STUDIES: State cigarette tax, youth smoking prevalence, poverty, and tobacco production. MAIN OUTCOMES AND MEASURES: State proportion of FDA warning letters issued for single cigarette violations. RESULTS: There are striking differences in the number of single cigarette violations found by state, with 38 states producing no warning letters for selling single cigarettes even as state policymakers developed legislation to address retailer sales of single cigarettes. The state proportion of warning letters issued for single cigarettes is not predicted by state cigarette tax, youth smoking, poverty, or tobacco production, P = .12. CONCLUSIONS AND RELEVANCE: Substantial, unexplained variation exists in violations of single cigarette sales among states. These data suggest the possibility of differences in implementation of FDA inspections and the need for stronger quality monitoring processes across states implementing FDA inspections. PMID- 25744969 TI - The Missing=Smoking Assumption: A Fallacy in Internet-Based Smoking Cessation Trials? AB - INTRODUCTION: In this study, penalized imputation (PI), a common approach to handle missing smoking status data and sometimes referred to as "missing=smoking," is compared with other missing data approaches using data from internet-based smoking cessation trials. Two hypotheses were tested: (1) PI leads to more conservative effect estimates than complete observations analysis; and (2) PI and multiple imputation (MI) lead to similar effect estimates under balanced (equal missingness proportions among the trial arms) and unbalanced missingness. METHODS: First, the outcomes of 22 trials included in a recent Cochrane review on internet-based smoking cessation interventions were reanalyzed using only the complete observations, and after applying PI. Second, in a simulation study outcomes under PI, complete observations analysis, and two types of MI were compared. For this purpose, individual patient data from one of the Cochrane review trials were used. Results of the missing data approaches were compared with reference data without missing observations, upon which balanced and unbalanced missingness scenarios were imposed. RESULTS: In the reanalysis of 22 trials, relative risks (RR = 1.15 [1.00; 1.33]) after PI were nearly identical to those under complete observations analysis (RR = 1.14 [0.98; 1.32]). In the simulation study, PI was the only approach that led to deviations from the reference data beyond its 95% confidence interval. CONCLUSIONS: Analyses after PI led to pooled results equivalent to complete observations analyses. PI also led to significant deviations from the reference in the simulation studies. PI biases the reported effects of interventions, favoring the condition with the lowest proportion of missingness. Therefore, more sophisticated missing data approaches than PI should be applied. PMID- 25744970 TI - Does the Magnitude of Reduction in Cigarettes Per Day Predict Smoking Cessation? A Qualitative Review. AB - INTRODUCTION: Reduction in cigarettes per day (CPD) aided by nicotine replacement therapy (NRT) increases cessation in smokers; however, it is unclear whether this is due to use of NRT or reduction per se. If the latter, a greater magnitude of reduction in CPD should increase the odds of cessation. METHODS: The authors searched PubMed, Cochrane, PsychINFO, http://clinicaltrials.gov and their personal libraries for studies on smoking reduction. Seven of the 76 (9%) identified intervention trials and four of 28 naturalistic studies (14%) reported on the magnitude of reduction in relation to the odds of cessation. RESULTS: Five of the seven intervention trials and three of the four naturalistic observational (cohort) studies found that increased reduction in CPD was associated with increased cessation. The intervention trials that reported effect sizes found that every 1% decrease in CPD or carbon monoxide was associated with a 3% to 4% increase in the odds of cessation. The naturalistic studies found that ordinal (eg, quartile) increases in participants' magnitude of reduction in CPD were associated with 50% to 290% increases in the odds of cessation. All of the naturalistic studies and four of the intervention trials included covariates; however, reduction's association with cessation could still be due to its association with NRT use or motivation. CONCLUSION: Although prospective prediction does not necessarily indicate causality, our findings suggest reduction in CPD is a mechanism of increased cessation in prior NRT-aided reduction studies. PMID- 25744971 TI - Predictors of Changes in Smoking From Third Trimester to 9 Months Postpartum. AB - INTRODUCTION: While much has been written about postpartum smoking relapse prevention, few have examined changes in smoking behavior from pregnancy (third trimester) through 9 months postpartum among pregnant smokers, particularly for the large number of women who decrease tobacco consumption during pregnancy but do not quit altogether. METHODS: Data were obtained from 168 women who smoked during their pregnancy. Women were followed longitudinally from their first prenatal appointment through 9 months postpartum. Maternal substance use was assessed using the Timeline Followback and verified by maternal salivary analyses. Breastfeeding, other substance use, and partner smoking were assessed through maternal interviews at each time point and were considered as potential predictors of change in smoking. RESULTS: Women returned to more than half of their levels of preconception tobacco consumption by 9 months postpartum. There was one significant predictor of changes in smoking patterns pregnancy to postpartum. Women who breastfed their infants for at least 90 days smoked far less postpartum than women who breastfed for a short time or did not breastfeed at all. CONCLUSIONS: As noted in previous research of pregnant quitters, postpartum relapse prevention or harm reduction interventions should ideally be timed early in the postpartum period. Additionally, promoting breastfeeding among pregnant smokers and supporting women through at least 3 months of breastfeeding may be beneficial to such interventions. PMID- 25744972 TI - Six cases of silicosis: implications for health surveillance of stonemasons. AB - BACKGROUND: Silicosis is one of the oldest occupational lung diseases, but it continues to cause significant morbidity and mortality worldwide. AIMS: To report cases of silicosis presenting to two specialist respiratory clinics. METHODS: A retrospective analysis of prospectively collected data of cases of silicosis in workers referred to specialist respiratory clinics. RESULTS: Over the course of 6 years, six cases were identified. The patients were all male with an age range between 24 and 39 years. The duration of silica exposure ranged between 7 and 20 years (mean 13 years). Four cases were entirely asymptomatic at presentation, and two cases described minimal shortness of breath on exertion. Pulmonary function tests were normal in three cases, and a mild restrictive ventilatory defect was documented in the other cases. All had a low apparent predicted probability of pneumoconiosis based on health questionnaires, spirometry and duration of silica exposure. The initial chest X-ray was abnormal in all six cases with radiological evidence of silicosis (International Labour Office profusion category >=1/1) on imaging, and all had evidence of silicosis on high-resolution computed tomography (HRCT). Three patients had already progressed to progressive massive fibrosis on HRCT scanning at the time of referral to specialist respiratory services. CONCLUSIONS: The appearances of these six cases of silicosis in young, asymptomatic construction workers emphasizes the importance of enforcing effective exposure control and comprehensive surveillance programmes. Our observations highlight the importance of having a low threshold for early radiological screening to promote early and effective detection of this disease. PMID- 25744973 TI - Some challenges of studies aiming to relate the Exposome to human health. PMID- 25744974 TI - Cardiac-Gated En Face Doppler Measurement of Retinal Blood Flow Using Swept Source Optical Coherence Tomography at 100,000 Axial Scans per Second. AB - PURPOSE: To develop and demonstrate a cardiac gating method for repeatable in vivo measurement of total retinal blood flow (TRBF) in humans using en face Doppler optical coherence tomography (OCT) at commercially available imaging speeds. METHODS: A prototype swept-source OCT system operating at 100-kHz axial scan rate was developed and interfaced with a pulse oximeter. Using the plethysmogram measured from the earlobe, Doppler OCT imaging of a 1.5- * 2-mm area at the optic disc at 1.8 volumes/s was synchronized to cardiac cycle to improve sampling of pulsatile blood flow. Postprocessing algorithms were developed to achieve fully automatic calculation of TRBF. We evaluated the repeatability of en face Doppler OCT measurement of TRBF in 10 healthy young subjects using three methods: measurement at 100 kHz with asynchronous acquisition, measurement at 100 kHz with cardiac-gated acquisition, and a control measurement using a 400-kHz instrument with asynchronous acquisition. RESULTS: The median intrasubject coefficients of variation (COV) of the three methods were 8.0%, 4.9%, and 6.1%, respectively. All three methods correlated well, without a significant bias. Mean TRBF measured at 100 kHz with cardiac-gated acquisition was 40.5 +/- 8.2 MUL/min, and the range was from 26.6 to 55.8 MUL/min. CONCLUSIONS: Cardiac-gated en face Doppler OCT can achieve smaller measurement variability than previously reported methods. Although further validation in older subjects and diseased subjects is required, precise measurement of TRBF using cardiac-gated en face Doppler OCT at commercially available imaging speeds should be feasible. PMID- 25744976 TI - Association of Retinal Artery and Other Inner Retinal Structures With Distribution of Tapetal-like Reflex in Oguchi's Disease. AB - PURPOSE: To report novel ophthalmoscopic features of patients with Oguchi's disease, and to describe how they may be related to the unusual tapetal-like fundus appearance. METHODS: Twenty-one eyes of 11 patients who were diagnosed with Oguchi's disease were investigated. Genetic screening of seven cases showed homozygous mutations in the SAG gene (c.926delA). The retinal appearance was retrospectively assessed in the fundus photographs, and the optical coherence tomographic (OCT) and fundus autofluorescence (AF) images. RESULTS: In 11 eyes of 7 patients, clearly demarcated dark regions without tapetal-like reflex were observed in the midperipheral retinal regions. In the dark regions, OCT showed lower reflectances in the photoreceptor layer but the AF images had normal reflectances. In nine eyes of six patients, the dark regions were partially demarcated by retinal arteries but not by veins. In nine eyes of five patients, the extent of the dark regions either increased or decreased during the course of the disease process, and these changes were not due to the state of adaptation or a posterior vitreous detachment. In all eyes, the peripheral retinal arteries but not veins had either high or low reflective regions along one side. CONCLUSIONS: Although the alterations of the outer retinal layers are believed to be most responsible for the abnormal tapetal-like reflex in patients with Oguchi's disease, these ophthalmoscopic features cannot be explained solely by the abnormality of the outer retina. Our findings suggest that the appearance of tapetal-like reflex is strongly affected by alterations of structures in the inner retinal layers. PMID- 25744975 TI - Biogeographic Ancestry in the African Descent and Glaucoma Evaluation Study (ADAGES): Association With Corneal and Optic Nerve Structure. AB - PURPOSE: We determined if quantitative measurements of biogeographic ancestry (BGA) correlate with variations in optic disc area, corneal thickness (CCT), and retinal nerve fiber layer (RNFL) thickness. METHODS: Data were obtained from 656 participants in the African Descent and Glaucoma Evaluation Study (ADAGES) cohort who consented to BGA testing. Data for CCT, optic disc area, and RNFL thickness were obtained from subjects in the ADAGES study who also had participated in the current substudy. A total of 31 ancestry informative markers (AIMs) with large allele frequencies differences between populations was used to calculate admixture proportion (implemented in STRUCTURE). Correlations with BGA adjusted for diagnosis, age, and sex for CCT and optic disc area using the whole group and RNFL thickness adjusted for age and sex for the normal study participants were determined. RESULTS: The mean percentage of African admixture was 79.6% in the self-described African Descent (AD) group and 3.5% in the European Descent (ED) group. Percent African ancestry was significantly correlated with CCT (rho = 0.27, P < 0.0001) and disc area (rho = 0.15, P < 0.0001), but only marginally associated with RNFL thickness (rho = 0.20, P = 0.092) in adjusted models. CONCLUSIONS: The BGA correlates with variation in ocular features that significantly differ across racial groups and that have been associated with the development of glaucoma. While BGA can provide an objective measurement of the biologic component of self-described race for ocular research, for most nongenetic epidemiologic studies, self-described race may adequately describe the associations with these ocular characteristics. (ClinicalTrials.gov number, NCT00221923.). PMID- 25744977 TI - Daily Injection But Not Continuous Infusion of Apomorphine Inhibits Form Deprivation Myopia in Mice. AB - PURPOSE: To compare the effects of daily injection versus continuous infusion of a nonspecific dopamine agonist, apomorphine (APO), on refraction and ocular growth in normal postnatal mice and mice with form-deprivation myopia (FDM). METHODS: The C57BL/6 mice were subjected (or not) to monocular FD by covering the left eye with a frosted goggle and leaving the right (fellow) eye uncovered. During postnatal days 28 to 56, both groups received APO (5 mg/kg/d) or vehicle either as daily intraperitoneal injection or by continuous subcutaneous infusion with mini-pumps. After these treatments, binocular refractions were measured by photoretinoscopy and binocular ocular dimensions were measured by optical coherence tomography. Monocular photopic flash electroretinograms were recorded from non-FD mice. RESULTS: In normal mice, daily injection or continuous infusion of APO did not affect normal postnatal development of refraction. However, in the FD group, daily APO-injection attenuated ocular growth and also myopia development, as reflected in the interocular differences for APO-injected mice compared with vehicle-injected mice: (1) refraction, -1.04 +/- 0.37 diopter (D) (APO-injection) compared with -4.14 +/- 0.77 D (vehicle-injection) (P < 0.05); (2) vitreous chamber depth: -0.002 +/- 0.005 mm compared with 0.032 +/- 0.009 mm (P < 0.05); and (3) axial length: 0.000 +/- 0.005 mm compared with 0.057 +/- 0.007 mm (P < 0.05). By contrast, continuous APO-infusion failed to affect these biometric parameters. Furthermore, daily APO-injection decreased the ERG a- and b wave amplitudes, whereas continuous APO-infusion increased these responses. CONCLUSIONS: In monocularly FD mice, daily APO-injection, but not continuous infusion, attenuated myopia development. Therefore, evaluating different dopamine agonist administration paradigms is important for identifying effective dopamine based treatment for myopia. PMID- 25744978 TI - Evaluation of Choroidal Thickness, Intraocular Pressure, and Serum Osmolality After the Water Drinking Test in Eyes With Primary Angle Closure. AB - PURPOSE: We evaluated changes in choroidal thickness (ChT), IOP, ocular biometry, and serum osmolality after the water drinking test (WDT) in subjects with previous acute primary angle closure (APAC) and primary angle closure glaucoma (PACG). METHODS: We evaluated 38 subjects, including 21 with APAC and 17 with PACG. Each subject underwent IOP measurement, A-scan biometry, spectral domain optical coherence tomography (SDOCT), anterior segment-optical coherence tomography (ASOCT), and osmolality measurements at baseline, 30, and 60 minutes after consuming at least 10 mL/kg of water. The ChT at the macula was measured from SDOCT images using the 7-line scan protocol. The fellow-eyes of APAC (FE APAC) were compared to eyes with PACG. RESULTS: The mean age +/- SD of the study subjects was 62.8 +/- 8.6 years and 21 (55.3%) were females. At baseline, serum osmolality was significantly lower (P < 0.001) in the FE-APAC group, whereas ChT was similar in both groups (P = 0.56). At 30 minutes after WDT, both groups demonstrated a significant increase in IOP (FE-APAC, 3.0 [95% confidence interval {CI}, 1.52, 4.48] mm Hg; PACG, 5.06 [95% CI, 3.68, 6.26] mm Hg; P < 0.001 for both) and decrease in serum osmolality (P < 0.001 for both), but no significant change in ChT. The magnitude of change in IOP was significantly greater in PACG eyes (P = 0.04). After multivariate analysis, a lower mean baseline serum osmolality (beta = -0.44, P = 0.003) was associated with a greater change in ChT at 30 minutes after WDT. CONCLUSIONS: The increase in IOP after WDT was higher in PACG eyes compared to FE-APAC; however, the latter had lower serum osmolality at baseline. Change in mean ChT following WDT was associated with a lower baseline serum osmolality. PMID- 25744979 TI - Changes in Mitochondrial Morphology and Bioenergetics in Human Lymphoblastoid Cells With Four Novel OPA1 Mutations. AB - PURPOSE: Mutations in the optic atrophy 1 gene (OPA1) have been reported in patients with autosomal dominant optic atrophy (ADOA). OPA1 plays important roles in mitochondrial dynamics and cell apoptosis. The link between OPA1 mutations and changes in bioenergetics is still not fully resolved. The aim of this study was to investigate the effects of OPA1 mutations on the mitochondrial tubular network and bioenergetics. METHODS: We established lymphoblastoid cell lines from four ADOA families harboring different OPA1 mutations, unaffected relatives (internal control cell lines), and unrelated normal controls (normal control cell lines). OPA1 splice variants and mRNA were analyzed by reverse transcription-PCR and quantitative real-time PCR. Protein isoforms were examined by Western blotting. The mitochondrial network was visualized by confocal microscopy. Mitochondrial bioenergetics were assessed using a Seahorse XF24 flux analyzer. Mitochondrial membrane potential and oxidative damage were analyzed by flow cytometry. RESULTS: OPA1 mutant cell lines showed significant decreases in OPA1 mRNA and protein expression, mitochondrial membrane potential, and ATP synthesis. A marked deficiency of the long isoform of OPA1 was observed in cells with OPA1 mutations in the middle domain and GTPase effector domain. Confocal microscopy revealed increased mitochondrial fragmentation in OPA1 mutant cells. OPA1 mutant cells also displayed reduced oxygen consumption and underwent glycolysis to produce ATP. Moreover, OPA1 mutations caused the accumulation of oxidative damage. CONCLUSIONS: Our experiments demonstrated that OPA1 mutations induced mitochondrial fragmentation, uncoupled mitochondrial respiration, and elicited dysfunctional bioenergetics. However, there were no significant differences among the various OPA1 mutations. PMID- 25744980 TI - Development of a new fully automated kinetic algorithm (program k) for detection of glaucomatous visual field loss. AB - PURPOSE: In Program K, a new automated kinetic algorithm that we developed, the frequency distributions of the number of patients' response points were obtained for external angles to distinguish normal and abnormal isopters. We also assessed the agreement between the results of Program K and Goldmann manual kinetic perimetry (MKP). METHODS: Program K detected abnormalities in isopters by using the external angles of patients' response points. In experiment 1, a normal external angle range and endpoint for the algorithm were determined by using visual field (VF) results of 100 data sets. In experiment 2, the results of Program K and Goldmann MKP were compared in 63 virtual patients. Visual field loss was assessed by using stimuli of V/4e, III/4e, I/4e, I/3e, I/2e, and I/1e at a speed of 3 deg/s. The isopters by Program K and Goldmann MKP were overlapped and the area of intersection was expressed as a percentage of the union area. The intersection percentages and test durations were evaluated. RESULTS: A normal external angle range between 150 degrees and 240 degrees and phase 3 as the appropriate endpoint for the algorithm were determined. The intersection percentages for the six isopters were 84% (V/4e), 83% (III/4e), 78% (I/4e), 71% (I/3e), 60% (I/2e), and 50% (I/1e) (average, 71%). The average examination duration for Program K was 16.0 +/- 3.2 minutes. The results of Program K and Goldmann MKP were comparable. CONCLUSIONS: Program K is clinically efficient and useful for detection and evaluation of abnormalities in a kinetic VF. PMID- 25744981 TI - Corneoscleral limbus in glaucoma patients: in vivo confocal microscopy and immunocytological study. AB - PURPOSE: To investigate morphologic changes of the corneoscleral limbus in glaucoma patients using laser scanning confocal microscopy (LSCM) and impression cytology (IC). METHODS: Eighty patients with glaucoma and 20 with dry eye were enrolled; 20 healthy subjects served as controls. Patients underwent the Ocular Surface Disease Index (OSDI) questionnaire, tear film break-up time, corneal staining, Schirmer test I, and LSCM of the limbus. Laser scanning confocal microscopy evaluated the limbal transition epithelium (LTE) regularity, dendritic cell (DC) density, and palisades of Vogt (POV). Impression cytology was performed and samples stained with HLA-DR and IL6. RESULTS: Glaucomatous patients were divided into three groups: Group 1 (40 eyes): one drug; Group 2 (20): two drugs; and Group 3 (20): three or more drugs. Limbal transition epithelium regularity was worse, and DC density higher in Groups 2, 3, and dry eyes compared with Group 1 and controls (P < 0.01). Preserved drugs worsened LTE regularity and induced higher DC density compared with preservative-free (PF) drugs (P = 0.041; P = 0.004). Despite typical POV architecture was preserved, signs of inflammation were found in glaucoma groups. HLA-DR and IL-6 positivity were higher in Groups 2, 3, and dry eye compared with controls (P < 0.001), and in preserved versus PF drugs (P < 0.05; P < 0.001). Dendritic cell density and LTE regularity correlated with HLA-DR, IL-6, and OSDI score in glaucoma groups and dry eyes (P < 0.001). CONCLUSIONS: Laser scanning confocal microscopy and IC documented antiglaucoma therapy induced morphologic alterations of limbus, which may play a role in the glaucoma-related ocular surface disease. Further studies are required to determine if limbal changes affect stem cell viability. PMID- 25744982 TI - Developmental Trajectory of McGurk Effect Susceptibility in Children and Adults With Amblyopia. AB - PURPOSE: The McGurk effect is an audiovisual illusion that involves the concurrent presentation of a phoneme (auditory syllable) and an incongruent viseme (visual syllable). Adults with amblyopia show less susceptibility to this illusion than visually normal controls, even when viewing binocularly. The present study investigated the developmental trajectory of McGurk effect susceptibility in adults, older children (10-17 years), and younger children (4-9 years) with amblyopia. METHODS: A total of 62 participants with amblyopia (22 adults, 12 older children, 28 younger children) and 66 visually normal controls (25 adults, 17 older children, 24 younger children) viewed videos that combined phonemes and visemes, and were asked to report what they heard. Videos with congruent (auditory and visual matching) and incongruent (auditory and visual not matching) stimuli were presented. Incorrect responses on incongruent trials correspond to high McGurk effect susceptibility, indicating that the viseme influenced the phoneme. RESULTS: Participants with amblyopia (28.0% +/- 3.3%) demonstrated a less consistent McGurk effect than visually normal controls (15.2% +/- 2.3%) across all age groups (P = 0.0024). Effect susceptibility increased with age (P = 0.0003) for amblyopic participants and controls. Both groups showed a similar response pattern to different speakers and syllables, but amblyopic participants invariably demonstrated a less consistent effect. CONCLUSIONS: Amblyopia is associated with reduced McGurk effect susceptibility in children and adults. Our findings indicate that the differences do not simply indicate delayed development in children with amblyopia; rather, they represent permanent alterations that persist into adulthood. PMID- 25744983 TI - Event-Related Potentials Allow for Optotype-Based Objective Acuity Estimation. AB - PURPOSE: The event-related potential P300 has been proposed for objective acuity estimation. In contrast to the acuity VEP, which relies on grating or checkerboard stimuli, the P300 can be recorded to small stimulus differences, making it suitable to use optotype stimuli. This may result in a better agreement with subjective measures of acuity than that found with VEP-based estimates. We tested the feasibility of using Landolt C optotypes with a P300 acuity paradigm and assessed the relationship between subjective and objective acuity estimates for both optotype and grating stimuli. METHODS: Dioptric blur (+1, +2, and +4 diopters) was used to degrade vision. Separate oddball sequences with Landolt Cs and with gratings, respectively, were used to record the P300. Thresholds were estimated by fitting a sigmoid curve to P300 amplitudes as a function of Landolt C size or grating coarseness, respectively. Psychophysical thresholds were also obtained for both stimulus types. RESULTS: There was a sizable discrepancy in psychophysical acuity estimates between Landolt C and grating stimuli, probably due to spurious resolution with gratings. With both stimulus types, reliable P300 acuity estimates were obtained. These reflected the psychophysical discrepancy. Conversion factors (Landolt C, 2.3; grating, 1.5) allowed for translating P300 based acuity to psychophysical acuity. CONCLUSIONS: We demonstrate, to our knowledge for the first time, that objective acuity estimation with Landolt C optotypes is feasible. Both psychophysical and P300-based estimates share the same stimulus-type dependence. P300-based acuity estimation with optotypes may thus be particularly useful with visual impairments that differentially affect grating and optotype acuity. PMID- 25744984 TI - Draft Genome Sequence of the Terrestrial Cyanobacterium Scytonema millei VB511283, Isolated from Eastern India. AB - We report here the draft genome sequence of Scytonema millei VB511283, a cyanobacterium isolated from biofilms on the exterior of stone monuments in Santiniketan, eastern India. The draft genome is 11,627,246 bp long (11.63 Mb), with 118 scaffolds. About 9,011 protein-coding genes, 117 tRNAs, and 12 rRNAs are predicted from this assembly. PMID- 25744985 TI - Draft Genome Sequence of a New Delhi Metallo-beta-Lactamase-5 (NDM-5)-Producing Multidrug-Resistant Escherichia coli Isolate. AB - A multidrug-resistant Escherichia coli isolate from an abdominal lesion displayed resistance to all beta-lactams tested, including carbapenems, in addition to macrolides, fluoroquinolones, and tetracycline. Sequence analyses demonstrated the presence of blaNDM-5 in addition to at least 13 genes and 6 efflux pumps associated with antibiotic resistance. PMID- 25744986 TI - Genome Sequences of the Lignin-Degrading Pseudomonas sp. Strain YS-1p and Rhizobium sp. Strain YS-1r Isolated from Decaying Wood. AB - Pseudomonas sp. strain YS-1p and Rhizobium sp. strain YS-1r were isolated from a lignin-degrading enrichment culture. The isolates degraded lignin-derived monomers, dimers, alkali lignin, and, to a smaller extent (3% to 5%), lignin in switch grass and alfalfa. Genome analysis revealed the presence of a variety of lignin-degrading genes. PMID- 25744987 TI - Draft Genome Sequences of Acinetobacter harbinensis Strain HITLi 7T, Isolated from River Water. AB - Acinetobacter harbinensis HITLi strain 7(T), isolated from river water, has the ability to remove ammonium and organic chemicals at 2 degrees C. The genome sequences might be useful for investigating the low-temperature adaptability and nitrogen or organic chemical metabolism. PMID- 25744988 TI - Draft genome sequence of a taxonomically unique acinetobacter clinical strain with proteolytic and hemolytic activities. AB - Acinetobacter sp. strain A47, which has been recovered from several soft tissue samples from a patient undergoing reconstructive surgery due to a traumatic amputation, was categorized as a taxonomically unique bacterial strain. The molecular analysis based on three housekeeping protein-coding genes (16S rRNA, rpoB, and gyrB) showed that strain A47 does not belong to any of the hitherto known taxa and may represent a previously undescribed Acinetobacter species. PMID- 25744989 TI - Genome Sequence of Clostridium acetobutylicum GXAS18-1, a Novel Biobutanol Production Strain. AB - Clostridium acetobutylicum is an organism involved in the production of acetone and butanol by traditional acetone-butanol-ethanol fermentation (ABE). We report the draft genome sequence of C. acetobutylicum strain GXAS18-1, which can produce ABE directly from cassava flour. PMID- 25744990 TI - Whole-Genome Sequences of Chlamydia psittaci Strain HJ, Isolated from Meat Pigeons with Severe Respiratory Distress and High Mortality. AB - The obligate intracellular Gram-negative bacterium Chlamydia psittaci causes systemic disease in psittacine birds, domestic poultry, and wild fowl. Importantly, C. psittaci may cause pneumonia, encephalitis, endocarditis, and even death in humans. The potential of pigeons as a source of human psittacosis is supported worldwide by relatively high seroconversion rates in the birds. This study reports the whole-genome sequencing of C. psittaci strain HJ, isolated from meat pigeons suffering from severe pneumonia and high mortality in 2013 in Hebei, China. PMID- 25744991 TI - Genome Sequence of Pseudomonas azelaica Strain Aramco J. AB - We report here the draft genome sequence of Pseudomonas azelaica strain Aramco J (7.3 Mbp; GC content, 61.9%), one of the few bacteria that can completely mineralize different hydroxybiphenyls, e.g., 2-hydroxybiphenyl, 2,2' dihydroxybiphenyl, and 3-hydroxybiphenyl. The findings obtained from its genome annotation suggest that this strain becomes a useful biocatalyst for aromatic bioconversions. PMID- 25744992 TI - Complete Genome of Geobacter pickeringii G13T, a Metal-Reducing Isolate from Sedimentary Kaolin Deposits. AB - We used PacBio sequencing to assemble the genome of the pristine freshwater isolate Geobacter pickeringii G13(T) into a single 3,618,700-bp circular chromosome polished to 99.999% accuracy (quality value [QV], 50). This isolate shares several features with other Geobacter spp., including genes for degradation of aromatics and an abundance of multiheme c-type cytochromes. PMID- 25744993 TI - Draft Genome Sequences of Thalassobacter Strains 1CONIMAR09 and 16PALIMAR09, Two Members of the Roseobacter Lineage Isolated from Coastal Areas of the Mediterranean Sea around Mallorca Island. AB - We report the draft genome sequence of two new members of the Roseobacter lineage, Thalassobacter strains 1CONIMAR09 and 16PALIMAR09, which were isolated from the seawater coast of Mallorca Island. Each genome harbored putative genes for obtaining energy by chemolithotrophy and making aerobic anoxygenic photosynthesis. PMID- 25744994 TI - Draft Genome Sequence of "Terrisporobacter othiniensis" Isolated from a Blood Culture from a Human Patient. AB - "Terrisporobacter othiniensis" (proposed species) was isolated from a blood culture. Genomic DNA was sequenced using a MiSeq benchtop sequencer (Illumina) and assembled using the SPAdes genome assembler. This resulted in a draft genome sequence comprising 3,980,019 bp in 167 contigs containing 3,449 coding sequences, 7 rRNAs, and 58 tRNAs. PMID- 25744995 TI - Whole-Genome Sequence of Listeria monocytogenes Serovar 4b Strain IZSAM_Lm_hs2008, Isolated from a Human Infection in Italy. AB - Listeria monocytogenes is one of the most important foodborne pathogens. In this report, we present the complete and annotated genome of L. monocytogenes sequence type 06 (ST06) serovar 4b strain IZSAM_Lm_hs2008, isolated from an adult immunocompetent patient who developed the disease and died. PMID- 25744996 TI - Burkholderia cenocepacia Strain CEIB S5-1, a Rhizosphere-Inhabiting Bacterium with Potential in Bioremediation. AB - Burkholderia cenocepacia is considered an opportunistic pathogen from humans and may cause disease in plants. A bioprospection from a plaguicide-contaminated agricultural field in Mexico identified several methyl parathion-degrading bacteria. Here, we report the draft genome sequence of B. cenocepacia strain CEIB S5-1, which gave us clues into ecological biodiversity. PMID- 25744997 TI - Draft Genome Sequence of Exopolysaccharide-Producing Cyanobacterium Aphanocapsa montana BDHKU 210001. AB - We report for the first time the draft genome sequence of Aphanocapsa montana BDHKU 210001, a halotolerant cyanobacterium isolated from India. This is a marine exopolysaccharide (EPS)-producing cyanobacterium. The genome of this species is assembled into 11.50 million bases, with 296 scaffolds carrying approximately 7,296 protein-coding genes. PMID- 25744998 TI - Complete Genome Sequence of the Opitutaceae Bacterium Strain TAV5, a Potential Facultative Methylotroph of the Wood-Feeding Termite Reticulitermes flavipes. AB - The Opitutaceae bacterium strain TAV5, a member of the phylum Verrucomicrobia, was isolated from the wood-feeding termite hindgut. We report here its complete genome sequence, which contains a chromosome and a plasmid of 7,317,842 bp and 99,831 bp, respectively. The genomic analysis reveals genes for methylotrophy, lignocellulose degradation, and ammonia and sulfate assimilation. PMID- 25744999 TI - Complete genome sequences of one human respiratory syncytial antigenic group a virus from china and its four mouse-adapted isolates. AB - In this study, one human respiratory syncytial antigenic group A virus (HRSV-A GZ08-0) and its four BALB/c mouse-adapted isolates were sequenced and elucidated. Nineteen nucleotides were mutated between HRSV-A-GZ08-0 and the four mouse adapted isolates. PMID- 25745001 TI - Draft Genome Sequence of Cyanobacterium Hassallia byssoidea Strain VB512170, Isolated from Monuments in India. AB - The draft genome assembly of Hassallia byssoidea strain VB512170 with a genome size of ~13 Mb and 10,183 protein-coding genes in 62 scaffolds is reported here for the first time. This is a terrestrial hydrophobic cyanobacterium isolated from monuments in India. We report several copies of luciferase and antibiotic genes in this organism. PMID- 25745000 TI - Whole-Genome Analysis of Quorum-Sensing Burkholderia sp. Strain A9. AB - Burkholderia spp. rely on N-acyl homoserine lactone as quorum-sensing signal molecules which coordinate their phenotype at the population level. In this work, we present the whole genome of Burkholderia sp. strain A9, which enables the discovery of its N-acyl homoserine lactone synthase gene. PMID- 25745002 TI - Draft Genome Sequence of "Candidatus Methylacidiphilum kamchatkense" Strain Kam1, a Thermoacidophilic Methanotrophic Verrucomicrobium. AB - "Candidatus Methylacidiphilum kamchatkense" strain Kam1 is an aerobic methane oxidizing thermoacidophilic bacterium belonging to the Verrucomicrobia phylum. It was recovered from an acidic geothermal site in Uzon Caldera, Kamchatka, Russian Federation. Its genome possesses three complete pmoCAB gene clusters encoding particulate methane monooxygenase enzymes and a complete Calvin-Benson-Bassham cycle for carbon assimilation. PMID- 25745003 TI - Draft Genome Sequence of Filamentous Marine Cyanobacterium Lyngbya confervoides Strain BDU141951. AB - Lyngbya confervoides strain BDU141951 is a fast-growing, unicellular, marine, nonheterocystous cyanobacterium forming long unbranched filaments inside sheaths. Here, we report the draft genome assembly of Lyngbya confervoides BDU141951 for the first time. The genome size is 8,799,693 bp and has 6,093 putative protein coding genes assembled into 298 scaffolds. PMID- 25745004 TI - Complete Genome Sequence of the Urethral Catheter Isolate Myroides sp. A21. AB - Myroides sp. A21, isolated from a urethral catheterized patient without symptoms of a urinary tract infection in Germany, proved to be extensively drug resistant. Here, we report the 4.16-Mb complete genome sequence of strain A21, carrying unusual pathogenicity islands and explaining the features of multidrug resistance. PMID- 25745005 TI - Genome Sequences of Five Disinfectant-Resistant Listeria monocytogenes Strains from Two Iberian Pork-Processing Plants. AB - We announce the draft genome sequences of five Listeria monocytogenes strains from two Iberian pork-processing plants located in Spain that were distinguished by their resistance to benzalkonium chloride. These strains seem highly adapted to the meat-processing environment according to their persistence and transmission capabilities. PMID- 25745006 TI - Draft Genome Sequence of Aeromonas caviae Strain L12, a Quorum-Sensing Strain Isolated from a Freshwater Lake in Malaysia. AB - Here, we present the draft genome sequence of Aeromonas caviae strain L12, which shows quorum-sensing activity. The availability of this genome sequence is important to the research of the quorum-sensing regulatory system in this isolate. PMID- 25745007 TI - Draft Genome Sequence of Streptococcus equinus (Streptococcus bovis) HC5, a Lantibiotic Producer from the Bovine Rumen. AB - Streptococcus equinus (Streptococcus bovis) HC5 is a bacteriocinogenic lactic acid bacterium with simple growth requirements. The draft genome sequence of S. equinus HC5 consists of 1,846,241 bp, with a G+C content of 37.04%. In silico analysis indicated that S. equinus HC5 might be useful to control bacteria that are detrimental to livestock animals. PMID- 25745008 TI - Genome Sequences of Serotype A6 Mannheimia haemolytica Isolates D174 and D38 Recovered from Bovine Pneumonia. AB - Here, we report two genomes, one complete and one draft, from virulent bovine strains of Mannheimia haemolytica serotype A6 recovered prior to the field usage of modern antimicrobial drugs. PMID- 25745009 TI - Complete Sequence of Probiotic Symbioflor 2 Escherichia coli Strain G3/10 and Draft Sequences of Symbioflor 2 E. coli Strains G1/2, G4/9, G5, G6/7, and G8. AB - The complete genome of probiotic Escherichia coli strain G3/10 is presented here. In addition, the probiotic E. coli strains G1/2, G4/9, G5, G6/7, and G8 are presented in draft form. These six strains together comprise the probiotic product Symbioflor 2 (DSM 17252). PMID- 25745010 TI - Draft Genome Sequence of Methyloferula stellata AR4, an Obligate Methanotroph Possessing Only a Soluble Methane Monooxygenase. AB - Methyloferula stellata AR4 is an aerobic acidophilic methanotroph, which, in contrast to most known methanotrophs but similar to Methylocella spp., possesses only a soluble methane monooxygenase. However, it differs from Methylocella spp. by its inability to grow on multicarbon substrates. Here, we report the draft genome sequence of this bacterium. PMID- 25745012 TI - Breast irradiation therapy innovations forgo permanent marks, minimize treatment. PMID- 25745011 TI - Draft Genome Sequences of Six Actinobacillus pleuropneumoniae Serotype 8 Brazilian Clinical Isolates: Insight into New Applications. AB - Actinobacillus pleuropneumoniae is the causative agent of swine pleuropneumonia, a highly contagious disease associated with pigs of all ages that results in severe economic losses to the industry. Here, we report for the first time six genome sequences of A. pleuropneumoniae clinical isolates of serotype 8, found worldwide. PMID- 25745013 TI - Cediranib aims for a comeback. PMID- 25745014 TI - Checkpoint blockade immunotherapy for cancer comes of age. PMID- 25745015 TI - Electronic cigarettes may lead to nicotine addiction. PMID- 25745019 TI - Correction. PMID- 25745018 TI - Landscape of insertion polymorphisms in the human genome. AB - Nucleotide substitutions, small (<50 bp) insertions or deletions (indels), and large (>50 bp) deletions are well-known causes of genetic variation within the human genome. We recently reported a previously unrecognized form of polymorphic insertions, termed templated sequence insertion polymorphism (TSIP), in which the inserted sequence was templated from a distant genomic region, and was inserted in the genome through reverse transcription of an RNA intermediate. TSIPs can be grouped into two classes based on nucleotide sequence features at the insertion junctions; class 1 TSIPs show target site duplication, polyadenylation, and preference for insertion at a 5'-TTTT/A-3' sequence, suggesting a LINE-1 based insertion mechanism, whereas class 2 TSIPs show features consistent with repair of a DNA double strand break by nonhomologous end joining. To gain a more complete picture of TSIPs throughout the human population, we evaluated whole genome sequence from 52 individuals, and identified 171 TSIPs. Most individuals had 25-30 TSIPs, and common (present in >20% of individuals) TSIPs were found in individuals throughout the world, whereas rare TSIPs tended to cluster in specific geographic regions. The number of rare TSIPs was greater than the number of common TSIPs, suggesting that TSIP generation is an ongoing process. Intriguingly, mitochondrial sequences were a frequent template for class 2 insertions, used more commonly than any nuclear chromosome. Similar to single nucleotide polymorphisms and indels, we suspect that these TSIPs may be important for the generation of human diversity and genetic diseases, and can be useful in tracking historical migration of populations. PMID- 25745020 TI - The contributions of breast density and common genetic variation to breast cancer risk. AB - We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population. PMID- 25745021 TI - Marketing of personalized cancer care on the web: an analysis of Internet websites. AB - Internet marketing may accelerate the use of care based on genomic or tumor derived data. However, online marketing may be detrimental if it endorses products of unproven benefit. We conducted an analysis of Internet websites to identify personalized cancer medicine (PCM) products and claims. A Delphi Panel categorized PCM as standard or nonstandard based on evidence of clinical utility. Fifty-five websites, sponsored by commercial entities, academic institutions, physicians, research institutes, and organizations, that marketed PCM included somatic (58%) and germline (20%) analysis, interpretive services (15%), and physicians/institutions offering personalized care (44%). Of 32 sites offering somatic analysis, 56% included specific test information (range 1-152 tests). All statistical tests were two-sided, and comparisons of website content were conducted using McNemar's test. More websites contained information about the benefits than limitations of PCM (85% vs 27%, P < .001). Websites specifying somatic analysis were statistically significantly more likely to market one or more nonstandard tests as compared with standard tests (88% vs 44%, P = .04). PMID- 25745022 TI - Association between newborn birth weight and the risk of postpartum maternal venous thromboembolism: a population-based case-control study. AB - BACKGROUND: Postpartum venous thromboembolism (VTE) is a potentially fatal and preventable event leading to substantial short- and long-term morbidity. We sought to evaluate whether the delivery of term newborns of low or high birth weight was associated with greater risks of VTE. METHODS AND RESULTS: In a population-based case-control study conducted in Washington State from 1987 through 2011, cases of hospitalized VTE within 3 months of delivery were identified by using selected International Classification of Diseases, Ninth Revision, Clinical Modification codes. Controls were randomly selected postpartum women without VTE, matched on birth year. Birth weight and other maternal and pregnancy characteristics were extracted from birth certificate data. Among term live singleton deliveries, we compared the risk of VTE for mothers of newborns of low and high birth weights (<2500 g and >4000 g, respectively) versus mothers of newborns of normal birth weight (2500-4000 g). Logistic regression models were adjusted for maternal age, race, education, body mass index, parity, delivery methods, gestational length, smoking, gestational diabetes mellitus, and preeclampsia. Patients with VTE (n=547) were older, had a higher body mass index, and experienced more pregnancy-related complications than controls (n=9482). In comparison with mothers of newborns with normal birth weight, mothers of newborns with low birth weight had a 3-fold increased risk of VTE, which persisted after multivariable adjustment (odds ratio, 2.98; 95% confidence interval, 1.80-4.93). Mothers of newborns with high birth weight had only a slightly increased risk of VTE, which was attenuated after multivariable adjustment (odds ratio, 1.26; 95% confidence interval, 0.99-1.61). CONCLUSIONS: The delivery of a newborn with low birth weight is associated with a 3-fold increased risk of maternal postpartum VTE. This should be considered when assessing VTE risk at delivery. PMID- 25745023 TI - Avoiding the ends: internal epitope tagging of proteins using transposon Tn7. AB - Peptide tags fused to proteins are used in a variety of applications, including as affinity tags for purification, epitope tags for immunodetection, or fluorescent protein tags for visualization. However, the peptide tags can disrupt the target protein function. When function is disrupted by fusing a peptide to either the N or C terminus of the protein of interest, identifying alternative ways to create functional tagged fusion proteins can be difficult. Here, we describe a method to introduce protein tags internal to the coding sequence of a target protein. The method employs in vitro Tn7-transposon mutagenesis of plasmids for random introduction of the tag, followed by subsequent Gateway cloning steps to isolate alleles with mutations in the coding sequence of the target gene. The Tn7-epitope cassette is designed such that essentially all of the transposon is removed through restriction enzyme digestion, leaving only the protein tag at diverse sites internal to the ORF. We describe the use of this system to generate a panel of internally epitope-tagged versions of the Saccharomyces cerevisiae GPI-linked membrane protein Dcw1 and the Candida glabrata transcriptional regulator Sir3. This internal protein tagging system is, in principle, adaptable to tag proteins in any organism for which Gateway-adapted expression vectors exist. PMID- 25745024 TI - A powerful nonparametric statistical framework for family-based association analyses. AB - Family-based study design is commonly used in genetic research. It has many ideal features, including being robust to population stratification (PS). With the advance of high-throughput technologies and ever-decreasing genotyping cost, it has become common for family studies to examine a large number of variants for their associations with disease phenotypes. The yield from the analysis of these family-based genetic data can be enhanced by adopting computationally efficient and powerful statistical methods. We propose a general framework of a family based U-statistic, referred to as family-U, for family-based association studies. Unlike existing parametric-based methods, the proposed method makes no assumption of the underlying disease models and can be applied to various phenotypes (e.g., binary and quantitative phenotypes) and pedigree structures (e.g., nuclear families and extended pedigrees). By using only within-family information, it can offer robust protection against PS. In the absence of PS, it can also utilize additional information (i.e., between-family information) for power improvement. Through simulations, we demonstrated that family-U attained higher power over a commonly used method, family-based association tests, under various disease scenarios. We further illustrated the new method with an application to large scale family data from the Framingham Heart Study. By utilizing additional information (i.e., between-family information), family-U confirmed a previous association of CHRNA5 with nicotine dependence. PMID- 25745025 TI - A Novel Analytic Technique to Measure Associations Between Circulating Biomarkers and Physical Performance Across the Adult Life Span. AB - Understanding associations between circulating biomarkers and physical performance across the adult life span could aid in better describing mechanistic pathways leading to disability. We hypothesized that high concentrations of circulating biomarkers would be associated with lower functioning across study populations representing the adult life span. The data were from four intervention and two observational studies with ages ranging 22-89 years. Biomarkers assayed included inflammatory, coagulation, and endothelial function markers. Physical performance was measured either by VO2peak (studies of young and middle-aged adults) or usual gait speed (studies of older adults). Partialled (by age, body mass index, race, and sex) and weighted common correlations were calculated between biomarkers and physical performance. Homogeneity of the associations was also assessed. Interleukin-6 (weighted r = -.22), tumor necrosis factor receptor 2 (weighted r = -.19), D-dimer (weighted r = -.16), tumor necrosis factor receptor 1 (weighted r = -.15), granulocyte colony-stimulating factor (weighted r = -.14), and tumor necrosis factor alpha (weighted r = -.10) were all significantly inversely correlated with physical performance (p < .05). All significant correlations were homogeneous across studies. In summary, we observed consistent inverse associations between six circulating biomarkers and objective measures of physical performance. These results suggest that these serum biomarkers may be broadly applicable for detection, trajectory, and treatment monitoring of physical function across the life span or possibly for midlife predictors of functionally deleterious conditions. PMID- 25745026 TI - Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells. AB - Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-MUm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk. PMID- 25745027 TI - Dialysis Modalities and HDL Composition and Function. AB - Lipid abnormalities may have an effect on clinical outcomes of patients on dialysis. Recent studies have indicated that HDL dysfunction is a hallmark of ESRD. In this study, we compared HDL composition and metrics of HDL functionality in patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) with those in healthy controls. We detected a marked suppression of several metrics of HDL functionality in patients on HD or PD. Compositional analysis revealed that HDL from both dialysis groups shifted toward a more proinflammatory phenotype with profound alterations in the lipid moiety and protein composition. With regard to function, cholesterol efflux and anti-inflammatory and antiapoptotic functions seemed to be more severely suppressed in patients on HD, whereas HDL-associated paraoxonase activity was lowest in patients on PD. Quantification of enzyme activities involved in HDL metabolism suggested that HDL particle maturation and remodeling are altered in patients on HD or PD. In summary, our study provides mechanistic insights into the formation of dysfunctional HDL in patients with ESRD who are on HD or PD. PMID- 25745028 TI - 15N Tracing Studies on In Vitro Reactions of Ferredoxin-Dependent Nitrite Reductase and Glutamate Synthase Using Reconstituted Electron Donation Systems. AB - It is known that plants contain ferredoxin (Fd)-dependent nitrite reductase (NiR) and glutamate synthase (GOGAT). The Fd-NiR reaction produces ammonia from nitrite, and the activity is usually measured by nitrite disappearance. The Fd GOGAT reaction forms two glutamates of different origin, from glutamine and 2 oxoglutarate, and the activity is measured by the oxidation of reductant (NADPH) or by formation of total glutamate. Here, a quantitative probe of the products and efficiency of the process was conducted using (15)N tracing techniques on these reactions in vitro. We quantified the reduction of (15)N-labeled [Formula: see text] to [Formula: see text] and the formation of [(15)N]glutamate and [(14)N]glutamate from [5-(15)N-amide]glutamine plus 2-oxoglutarate by NiR and GOGAT, respectively, with the reductant-Fd-NADP(+) oxidoreductase (FNR)-Fd system as the sequential electron donors. The supply of dithionite or NADPH to recombinant cyanobacterial NiR led to electron donation system-dependent formation of [(15)N]ammonium from [(15)N]nitrite. Addition of 20 mM NaCl and 20 mM Na-ascorbate accelerated nitrite reduction under high concentrations of NADPH. A sufficient supply of NADPH to recombinant Zea mays Fd-GOGAT generated complete GOGAT activity (transferring the [5-(15)N]amide of glutamine to 2-oxoglutarate to form [(15)N]glutamate), whereas a shortage of NADPH resulted in glutaminase activity only, which removed the amide from glutamine and released ammonia and [(14)N]glutamate. We conclude that although the recombinant Fd-GOGAT enzyme has two forms of glutamate synthesis, the first by glutaminase (ammonia release by glutamine amidotransferase) and the second by glutamate synthase (coupling of the ammonia and exogenously applied 2-oxoglutarate), the first works without NADPH, while the second is strictly dependent on NADPH availability. PMID- 25745029 TI - Understanding circadian regulation of carbohydrate metabolism in Arabidopsis using mathematical models. AB - C3 plants assimilate carbon by photosynthesis only during the day, but carbon resources are also required for growth and maintenance at night. To avoid carbon starvation, many plants store a part of photosynthetic carbon in starch during the day, and degrade it to supply sugars for growth at night. In Arabidopsis, starch accumulation in the day and degradation at night occur almost linearly, with the shape of this diel starch profile adaptively changing to allow continuous supply of sugar even in long-night conditions. The anticipation of dawn required to ensure linear consumption of starch to almost zero at dawn presumably requires the circadian clock. We review the links between carbon metabolism and the circadian clock, and mathematical models aimed at explaining the diel starch profile. These models can be considered in two classes, those that assume the level of available starch is sensed and the system ensures linearity of starch availability, and those in which sugar sensing is assumed, yielding linearity of starch availability as an emergent property of sucrose homeostasis. In the second class of model the feedback from starch metabolism to the circadian clock is considered to be essential for adaptive response to diverse photoperiods, consistent with recent empirical data demonstrating entrainment of the circadian clock by photosynthesis. Knowledge concerning the mechanisms regulating the dynamics of starch metabolism and sugar homeostasis in plants is required to develop new theories about the limitations of growth and biomass accumulation. PMID- 25745030 TI - Developmental- and Tissue-Specific Expression of NbCMT3-2 Encoding a Chromomethylase in Nicotiana benthamiana. AB - The chromomethylase (CMT) protein family is unique to plants and controls non-CpG methylation. Here, we investigated the developmental expression of CMT3-2 in Nicotiana benthamiana (NbCMT3-2) and its significance by analyzing plants with silenced NbCMT3-2 and leaf tissues transiently expressing the N-terminal polypeptide. Alignment of the NbCMT3-2 amino acid sequence with that of other plant CMT3s showed a specific N-terminal extension required for nuclear localization. Transient expression of the N-terminal polypeptide in N. benthamiana resulted in chlorotic lesions. NbCMT3-2 was expressed mainly in proliferating tissues such as the shoot apex and developing leaves. We generated transgenic N. benthamiana harboring a fusion reporter construct linking the NbCMT3-2 promoter region and the beta-glucuronidase (GUS) reporter (pNbCMT3 2::GUS) to analyze the tissue-specific expression of NbCMT3-2. NbCMT3-2 was expressed in the shoot and root apical meristem and leaf primordia in young seedlings and highly expressed in developing leaves and ovary as well as lateral buds in mature plants. Virus-induced gene silencing used to knock down the expression of NbCMT3 or NbCMT3-2 or both led to partial loss of genomic DNA methylation. Plants with suppressed NbCMT3 expression grew and developed normally, whereas leaves with NbCMT3-2 knockdown showed mild curling as compared with controls. Silencing NbCMT3/3-2 severely interfered with leaf development and directly or indirectly affected the expression of genes involved in jasmonate homeostasis. The differential roles of NbCMT3 and NbCMT3-2 were investigated and compared. We reveal the expression patterns of NbCMT3-2 in proliferating tissues. NbCMT3-2 may play an essential role in leaf development by modulating jasmonate pathways. PMID- 25745031 TI - Coherent X-Ray Diffraction Imaging of Chloroplasts from Cyanidioschyzon merolae by Using X-Ray Free Electron Laser. AB - Coherent X-ray diffraction imaging (CXDI) is a lens-less technique for visualizing the structures of non-crystalline particles with the dimensions of submicrometer to micrometer at a resolution of several tens of nanometers. We conducted cryogenic CXDI experiments at 66 K to visualize the internal structures of frozen-hydrated chloroplasts of Cyanidioschyzon merolae using X-ray free electron laser (XFEL) as a coherent X-ray source. Chloroplast dispersed specimen disks at a number density of 7/(10*10 um(2)) were flash-cooled with liquid ethane without staining, sectioning or chemical labeling. Chloroplasts are destroyed at atomic level immediately after the diffraction by XFEL pulses. Thus, diffraction patterns with a good signal-to-noise ratio from single chloroplasts were selected from many diffraction patterns collected through scanning specimen disks to provide fresh specimens into the irradiation area. The electron density maps of single chloroplasts projected along the direction of the incident X-ray beam were reconstructed by using the iterative phase-retrieval method and multivariate analyses. The electron density map at a resolution of 70 nm appeared as a C shape. In addition, the fluorescence image of proteins stained with FlamingoTM dye also appeared as a C-shape as did the autofluorescence from Chl. The similar images suggest that the thylakoid membranes with an abundance of proteins distribute along the outer membranes of chloroplasts. To confirm the present results statistically, a number of projection structures must be accumulated through high-throughput data collection in the near future. Based on the results, we discuss the feasibility of XFEL-CXDI experiments in the structural analyses of cellular organelles. PMID- 25745032 TI - Phosphorylation and Interaction with the 14-3-3 Protein of the Plasma Membrane H+ ATPase are Involved in the Regulation of Magnesium-Mediated Increases in Aluminum Induced Citrate Exudation in Broad Bean (Vicia faba. L). AB - Several studies have shown that external application of micromolar magnesium (Mg) can increase the resistance of legumes to aluminum (Al) stress by enhancing Al induced citrate exudation. However, the exact mechanism underlying this regulation remains unknown. In this study, the physiological and molecular mechanisms by which Mg enhances Al-induced citrate exudation to alleviate Al toxicity were investigated in broad bean. Micromolar concentrations of Mg that alleviated Al toxicity paralleled the stimulation of Al-induced citrate exudation and increased the activity of the plasma membrane (PM) H(+)-ATPase. Northern blot analysis shows that a putative MATE-like gene (multidrug and toxic compound extrusion) was induced after treatment with Al for 4, 8 and 12 h, whereas the mRNA abundance of the MATE-like gene showed no significant difference between Al plus Mg and Al-only treatments during the entire treatment period. Real-time reverse transcription-PCR (RT-PCR) and Western blot analyses suggest that the transcription and translation of the PM H(+)-ATPase were induced by Al but not by Mg. In contrast, immunoprecipitation suggests that Mg enhanced the phosphorylation levels of VHA2 and its interaction with the vf14-3-3b protein under Al stress. Taken together, our results suggest that micromolar concentrations of Mg can alleviate the Al rhizotoxicity by increasing PM H(+) ATPase activity and Al-induced citrate exudation in YD roots. This enhancement is likely to be attributable to Al-induced increases in the expression of the MATE like gene and vha2 and Mg-induced changes in the phosphorylation levels of VHA2, thus changing its interaction with the vf14-3-3b protein. PMID- 25745033 TI - Lack of Evidence for Regional Brain Volume or Cortical Thickness Abnormalities in Youths at Clinical High Risk for Psychosis: Findings From the Longitudinal Youth at Risk Study. AB - There is cumulative evidence that young people in an "at-risk mental state" (ARMS) for psychosis show structural brain abnormalities in frontolimbic areas, comparable to, but less extensive than those reported in established schizophrenia. However, most available data come from ARMS samples from Australia, Europe, and North America while large studies from other populations are missing. We conducted a structural brain magnetic resonance imaging study from a relatively large sample of 69 ARMS individuals and 32 matched healthy controls (HC) recruited from Singapore as part of the Longitudinal Youth At-Risk Study (LYRIKS). We used 2 complementary approaches: a voxel-based morphometry and a surface-based morphometry analysis to extract regional gray and white matter volumes (GMV and WMV) and cortical thickness (CT). At the whole-brain level, we did not find any statistically significant difference between ARMS and HC groups concerning total GMV and WMV or regional GMV, WMV, and CT. The additional comparison of 2 regions of interest, hippocampal, and ventricular volumes, did not return any significant difference either. Several characteristics of the LYRIKS sample like Asian origins or the absence of current illicit drug use could explain, alone or in conjunction, the negative findings and suggest that there may be no dramatic volumetric or CT abnormalities in ARMS. PMID- 25745035 TI - Expression of Hedgehog Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and Its Inhibition Exerts Antileukemic Effects. AB - PURPOSE: The Hedgehog pathway plays an important role in stem-cell biology and malignant transformation. Therefore, we investigated the expression and prognostic impact of Hedgehog pathway members in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Pretreatment samples from 104 newly diagnosed AML patients (AMLSG 07-04 trial) were analyzed by qPCR, and expression of Hedgehog family members was correlated with clinical outcome. Inhibition of GLI by GANT61 or shRNA was investigated in AML cells in vitro and in vivo. RESULTS: Expression of receptors Smoothened and Patched-1 and their downstream mediators, GLI1, GLI2, and GLI3, was found in AML patients in contrast to Hedgehog ligands. GLI2 expression had a significant negative influence on event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS; P = 0.037, 0.026, and 0.013, respectively) and was correlated with FLT3 mutational status (P < 0.001). Analysis of a second, independent patient cohort confirmed the negative impact of GLI2 on EFS and OS (P = 0.007 and 0.003, respectively; n = 290). Within this cohort, GLI1 had a negative prognostic impact (P < 0.001 for both EFS and OS). Although AML cells did not express Hedgehog ligands by qPCR, AML patients had significantly increased Desert Hedgehog (DHH) plasma levels compared with healthy subjects (P = 0.002), in whom DHH was presumably provided by bone marrow niche cells. Moreover, the GLI inhibitor GANT61 or knockdown of GLI1/2 by shRNA caused antileukemic effects, including induction of apoptosis, reduced proliferation, and colony formation in AML cells, and a survival benefit in mice. CONCLUSIONS: GLI expression is a negative prognostic factor and might represent a novel druggable target in AML. PMID- 25745034 TI - A Systematic Review of the Effect of Early Interventions for Psychosis on the Usage of Inpatient Services. AB - OBJECTIVES: To review and synthesize the currently available research on whether early intervention for psychosis programs reduce the use of inpatient services. METHODS: A systematic review was conducted using keywords searches on PubMed, Embase (Ovid), PsycINFO (ProQuest), Scopus, CINAHL (EBSCO), Social Work Abstracts (EBSCO), Social Science Citations Index (Web of Science), Sociological Abstracts (ProQuest), and Child Development & Adolescent Studies (EBSCO). To be included, studies had to be peer-reviewed publications in English, examining early intervention programs using a variant of assertive community treatment, with a control/comparison group, and reporting inpatient service use outcomes. The primary outcome extracted number hospitalized and total N. Secondary outcome extracted means and standard deviations. Data were pooled using random effects models. Primary outcome was the occurrence of any hospitalization during treatment. A secondary outcome was the average bed-days used during treatment period. RESULTS: Fifteen projects were identified and included in the study. Results of meta-analysis supported the occurrence of a positive effect for intervention for both outcome measures (any hospitalization OR: 0.33; 95% CI 0.18 0.63, bed-days usage SMD: -0.38, 95% CI -0.53 to -0.24). There was significant heterogeneity of effect across the studies. This heterogeneity is due to a handful of studies with unusually positive responses. CONCLUSION: These results suggest that early intervention programs are superior to standard of care, with respect to reducing inpatient service usage. Wider use of these programs may prevent the occurrence of admission for patients experiencing the onset of psychotic symptoms. PMID- 25745036 TI - The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation. AB - PURPOSE: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. EXPERIMENTAL DESIGN: We performed a phase I dose-escalation study according to the standard 3+3 design. RESULTS: Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ 3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active. CONCLUSIONS: Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605. PMID- 25745037 TI - Are Members of Long-Lived Families Healthier Than Their Equally Long-Lived Peers? Evidence From the Long Life Family Study. AB - BACKGROUND: The Long Life Family Study (LLFS) is a multicenter longitudinal study of exceptional survival among members of long-lived sibships (probands), their offspring, and spouses of either group. For these four "roles", we asked: Does membership in a long-lived family protect against disease? METHODS: We used 2008 2010 Beneficiary Annual Summary Files from the Centers for Medicare & Medicaid Services (CMS) to compare prevalences of 17 conditions among 781 LLFS participants in Medicare with those of 3,227 non-LLFS matches from the general Medicare population. Analyses accounted for nesting within LLFS families. RESULTS: Seven conditions were significantly less common among LLFS probands than their matches: Alzheimer's, hip fracture, diabetes, depression, prostate cancer, heart failure, and chronic kidney disease. Four diseases not strongly linked to mortality (arthritis, cataract, osteoporosis, glaucoma) were significantly more common for LLFS probands. Despite fewer people and less disease in those roles, LLFS offspring and LLFS spouses of either generation also had significantly lower risk for Alzheimer's, diabetes, and heart failure. CONCLUSIONS: Common, severe mortality-associated diseases are less prevalent among LLFS probands and their offspring than in the general population of aging Americans. Quality-of-life limiting diseases such as arthritis and cataract are more prevalent, potentially through more diagnosing of milder forms in otherwise healthy and active individuals. LLFS spouses are also relatively healthy. As the younger cohorts age into Medicare and develop more conditions, it will be important to see whether these tentative findings strengthen. PMID- 25745038 TI - Leptin signalling system as a target for pulmonary arterial hypertension therapy. AB - Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH. In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages <=5), we demonstrate that pulmonary endothelial cells (P ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia induced PH. We demonstrate here that Ob/ObR-b axis may represent anti proliferative and anti-inflammatory targets in PAH. PMID- 25745039 TI - Inhibition of Pim1 kinase reduces viral replication in primary bronchial epithelial cells. PMID- 25745040 TI - Dual gas techniques for peripheral airway function: diffusing the issues. PMID- 25745042 TI - Monitoring asthma in children. AB - The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence. PMID- 25745044 TI - Quadriceps muscle fibre dysfunction in patients with pulmonary arterial hypertension. PMID- 25745043 TI - Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-beta are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials. PMID- 25745046 TI - Increased expression of granzymes A and B in fatal asthma. PMID- 25745047 TI - Obstructive respiratory events and premature atrial contractions after cardioversion. AB - Recurrence of atrial fibrillation (AF) after electrical cardioversion (ECV) is increased in patients with obstructive sleep apnoea (OSA). In patients with persistent AF, with (n=40) and without (n=32) obstructive respiratory events (OREs) during sedation for ECV, we determined the occurrence of premature atrial contractions (PACs) before and after insertion of a nasopharyngeal tube. The influence of acute obstructive respiratory events on atrial electrophysiology after termination of AF was studied in pigs. Incidence of PACs directly after ECV was higher in patients with OREs compared to those without OREs (7+/-2 versus 1+/ 1 per 10 s, respectively; p<0.01). Occurrence of PACs could be reduced by 79% by insertion of a nasopharyngeal tube. In a subsequent sleeping study, patients with OREs had higher apnoea-hypopnoea indices and more PACs during night. 16 patient with and four patients without OREs had a relapse of AF during 1 week after ECV (p<0.01). In pigs, acute OREs after 30 min of AF increased occurrence of PACs and vulnerability for reinduction of AF, which could be attenuated by atropine, beta blockers and renal denervation. OREs are associated with increased occurrence of PACs and more early relapse of AF. OREs increase occurrence of PACs and vulnerability for reinduction of AF by sympathovagal imbalance. PMID- 25745048 TI - The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2-3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF. PMID- 25745045 TI - No impact of passive smoke on the somatic profile of lung cancers in never smokers. AB - EGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in never-smokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is still debate surrounding whether never-smokers exposed to passive smoke exhibit a "smoker-like" somatic profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive smoking. No significant difference was observed between mutation frequency and passive smoke exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%; ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We observed a nonsignificant trend for a negative association between EGFR mutation and cumulative duration of passive smoke exposure. No association was found for other biomarkers. There is no clear association between passive smoke exposure and somatic profile in lifelong, never smoker lung cancer. PMID- 25745049 TI - Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition. AB - In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction. Surgical lung tissue and primary broncho-epithelial cultures (in air-liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-beta1. The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-beta1 during ALI differentiation prevented vimentin induction and fibronectin release. In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF beta1-driven epithelial reprogramming. PMID- 25745051 TI - Discrepant elevation of sIL-2R levels in sarcoidosis patients with renal insufficiency. PMID- 25745050 TI - Venous thromboembolism in patients immobilised at home. PMID- 25745052 TI - Effective anti-tuberculosis therapy correlates with plasma small RNA. PMID- 25745053 TI - alphavbeta6 integrin may be a potential prognostic biomarker in interstitial lung disease. AB - Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.43 paraffin-embedded, formalin-fixed lung tissue sections were immunostained for five molecules implicated in the pathogenesis of the fibrosis: alpha-smooth muscle actin (alphaSMA), alphavbeta6 integrin, pro-surfactant protein C (SP-C), hepatocyte growth factor (HGF) and tenascin-C (TenC). Levels of immunostaining and numbers of fibroblastic foci were quantified using operator-dependent and -independent methods. The relationship of all these markers to overall survival was analysed.Staining revealed high levels of alphaSMA, alphavbeta6 integrin, pro-SP C, HGF and TenC, and fibroblastic foci. Immunostaining varied across samples for all molecules but only the extent of alphavbeta6 integrin immunostaining was associated with increased mortality. There was no association with the other markers measured.Our data suggest high levels of alphavbeta6 integrin may identify a specific endotype of progressive fibrotic lung disease. PMID- 25745054 TI - Challenges of efficacy assessments in pseudomyxoma peritonea. PMID- 25745055 TI - In reply. PMID- 25745056 TI - Nonalcoholic fatty liver disease and vascular function: cross-sectional analysis in the Framingham heart study. AB - OBJECTIVE: Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk of cardiovascular disease; however, it is not known whether NAFLD contributes to cardiovascular disease independent of established risk factors. We examined the association between NAFLD and vascular function. APPROACH AND RESULTS: We conducted a cross-sectional study of 2284 Framingham Heart Study participants without overt cardiovascular disease who had liver fat attenuation measured on computed tomography and who had measurements of vascular function and covariates. We evaluated the association between NAFLD and vascular function using multivariable partial correlations adjusting for age, sex, cohort, smoking, diabetes mellitus, hyperlipidemia, hypertension, body mass index, and visceral adipose tissue. The prevalence of NAFLD in our sample (mean age, 52+/-12 years; 51.4% women) was 15.3%. In age-, sex-, and cohort-adjusted analyses, greater liver fat was modestly associated with lower flow-mediated dilation (r=-0.05; P=0.02), lower peripheral arterial tonometry ratio (r=-0.20; P<0.0001), higher carotid-femoral pulse wave velocity (r=0.13; P<0.0001), and higher mean arterial pressure (r=0.11; P<0.0001). In multivariable-adjusted models, NAFLD remained associated with higher mean arterial pressure (r=0.06; P=0.005) and lower peripheral arterial tonometry ratio (r=-0.12; P<0.0001). The association between NAFLD and peripheral arterial tonometry ratio persisted after further adjustment for body mass index and visceral adipose tissue. CONCLUSIONS: For multiple measures of vascular function, the relationship with NAFLD appeared largely determined by shared cardiometabolic risk factors. The persistent relationship with reduced peripheral arterial tonometry response beyond established risk factors suggests that NAFLD may contribute to microvascular dysfunction. PMID- 25745057 TI - Cell Adhesion Mediated by VCAM-ITGalpha9 Interactions Enables Lymphatic Development. AB - OBJECTIVE: Adhesive ligand-receptor interactions play key roles in blood vessel angiogenesis but remain poorly characterized during lymphatic vessel growth. In this study, we use genetic approaches in both fish and mice to address the roles of cell surface integrin ligand vascular cell adhesion molecule (VCAM) and its 2 receptors, integrins alpha9 and alpha4, during lymphatic vascular development. APPROACH AND RESULTS: Conditional deletion of the Vcam gene was used to test VCAM function in lymphatic growth in midgestation mice. Morpholino knockdown and cRNA rescue of the 2 zebrafish vcam alleles, as well as integrins alpha9 and 4, were used to test the role of these ligands and receptors during lymphatic growth in the developing fish. We show that VCAM is essential for lymphatic development in the zebrafish embryo and that integrin alpha9 (Itgalpha9) rather than Itgalpha4 is the required VCAM receptor in the developing fish. VCAM is expressed along lines of lymphatic migration in the mouse intestine, but its loss only retards lymphatic growth. CONCLUSIONS: These studies reveal an unexpected role for cell cell adhesion mediated by Itgalpha9-VCAM interactions during lymphatic development in the fish but not in the mouse. We propose that the relative importance of cellular adhesive ligands is magnified under conditions of rapid tissue growth when the cell number increases faster than cell matrix, such as in the early zebrafish embryo. PMID- 25745058 TI - Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension. AB - OBJECTIVE: Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. APPROACH AND RESULTS: Patients with PAH exhibit enhanced expression and phosphorylation of beta PDGF receptor (betaPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCgamma at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of betaPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated betaPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCgamma (betaPDGFR(F3/F3)). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in betaPDGFR(F3/F3) pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in betaPDGFR(F3/F3) mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. CONCLUSIONS: By means of a genetic approach, our data provide definite evidence that the activated betaPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3 kinase and PLCgamma activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH. PMID- 25745059 TI - Genetic and genomic approaches to understanding macrophage identity and function. AB - A major goal of our laboratory is to understand the molecular mechanisms that underlie the development and functions of diverse macrophage phenotypes in health and disease. Recent studies using genetic and genomic approaches suggest a relatively simple model of collaborative and hierarchical interactions between lineage-determining and signal-dependent transcription factors that enable selection and activation of transcriptional enhancers that specify macrophage identity and function. In addition, we have found that it is possible to use natural genetic variation as a powerful tool for advancing our understanding of how the macrophage deciphers the information encoded by the genome to attain specific phenotypes in a context-dependent manner. Here, I will describe our recent efforts to extend genetic and genomic approaches to investigate the roles of distinct tissue environments in determining the phenotypes of different resident populations of macrophages. PMID- 25745060 TI - Relationship of cigarette smoking with inflammation and subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: We sought to assess the impact of smoking status, cumulative pack years, and time since cessation (the latter in former smokers only) on 3 important domains of cardiovascular disease: inflammation, vascular dynamics and function, and subclinical atherosclerosis. APPROACH AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort enrolled 6814 adults without prior cardiovascular disease. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and (1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6, and fibrinogen); (2) vascular dynamics and function (brachial flow-mediated dilation and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and (3) subclinical atherosclerosis (coronary artery calcification, carotid intima-media thickness, and ankle-brachial index). We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or flow mediated dilation outcomes. However, compared with never smokers, the adjusted association between current smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former smoking (eg, odds ratio for hsCRP>2 mg/L of 1.7 [95% confidence interval, 1.5-2.1] versus 1.2 [1.1-1.4], odds ratio for coronary artery calcification>0 of 1.8 [1.5-2.1] versus 1.4 [1.2-1.6], respectively). Similar associations were seen for interleukin-6, fibrinogen, carotid intima-media thickness, and ankle-brachial index. A monotonic association was also found between higher pack-year quartiles and increasing inflammatory markers. Furthermore, current smokers with hsCRP>2 mg/L were more likely to have increased carotid intima-media thickness, abnormal ankle-brachial index, and coronary artery calcification>75th percentile for age, sex, and race (relative to smokers with hsCRP<2 mg/L, interaction P<0.05 for all 3 outcomes). In contrast, time since quitting in former smokers was independently associated with lower inflammation and atherosclerosis (eg, odds ratio for hsCRP>2 mg/L of 0.91 [0.88-0.95] and odds ratio for coronary artery calcification>0 of 0.94 [0.90-0.97] for every 5-year cessation interval). CONCLUSIONS: These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation. PMID- 25745061 TI - Genetic ancestry is associated with measures of subclinical atherosclerosis in African Americans: the Jackson Heart Study. AB - OBJECTIVE: To determine whether genetic ancestry was associated with subclinical atherosclerosis measures after adjustment for traditional cardiovascular disease risk factors, inflammatory marker, socioeconomic status, and psychosocial factors in a large admixed African American population. APPROACH AND RESULTS: Participants were drawn from the Jackson Heart Study. Participant's percent of European ancestry (PEA) was estimated based on 1747 genetic markers using HAPMIX. Association of PEA with peripheral arterial disease and common carotid intima media thickness were investigated among 2168 participants and with coronary artery calcification >0 and abdominal aortic calcification >0 among 1139 participants. The associations were evaluated using multivariable regression models. Our results showed that a 1 SD increase in PEA was associated with a lower peripheral arterial disease prevalence after adjusting for age and sex (prevalence ratio=0.90 [95% CI, 0.82-0.99]; P=0.036). Adjustments for traditional cardiovascular disease risk factors, socioeconomic status, and psychosocial factors attenuated this association (prevalence ratio=0.91 [0.82-1.00]; P=0.046). There was also a nonlinear association between PEA and coronary artery calcification and abdominal aortic calcification. The lowest PEA was associated with a lower coronary artery calcification (prevalence ratio=0.75 [0.58-0.96]; P=0.022) and a lower abdominal aortic calcification [prevalence ratio=0.80 [0.67 0.96]; P=0.016) compared with the reference group (10th-90th percentile) after adjusting for traditional cardiovascular disease risk factors, inflammatory marker, socioeconomic status, and psychosocial factors. However, we found no significant association between PEA and common carotid intima-media thickness. CONCLUSIONS: Overall, our findings indicate that genetic ancestry was associated with subclinical atherosclerosis, suggesting unmeasured risk factors and interactions with genetic factors might contribute to the distribution of subclinical atherosclerosis among African Americans. PMID- 25745062 TI - Aneurysm development in patients with a bicuspid aortic valve is not associated with transforming growth factor-beta activation. AB - OBJECTIVE: Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysms. Transforming growth factor-beta (TGFbeta) is a crucial factor of vascular remodeling, the impaired signaling of which can alter the structure and composition of the extracellular matrix. In this study, we analyzed the activity of TGFbeta in aneurysmal and nonaneurysmal ascending aorta from BAV patients, using tricuspid aortic valve (TAV) patients as a reference group. APPROACH AND RESULTS: The response to exogenous TGFbeta was analyzed with regard to gene expression in primary aortic smooth muscle cells that were isolated from 7 BAV and 5 TAV patients and in valve fibroblasts from 7 BAV and 8 TAV patients. The set of genes that were significantly changed by TGFbeta (217 genes) was compared with gene expression profiles of the ascending aorta from BAV and TAV patients (139 arrays). By principle component analysis, based on the 217 genes, gene expression differed significantly in the intima/media region between aneurysmal BAV and TAV aortas, driven by the response in TAV patients. During aneurysm development the levels of phosphorylated SMADs and the availability of free TGFbeta were lower in BAV patients compared with TAV. Confocal microscopy analysis showed a higher colocalization of latency associated peptide and latent TGFbeta binding protein 3 in BAV aortas. CONCLUSIONS: Our findings suggest that TGFbeta activation during aneurysm formation is muted in patients with BAV, possibly as a result of an increased TGFbeta sequestration in the extracellular space. PMID- 25745064 TI - Mass spectrometry imaging with laser-induced postionization. AB - Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can simultaneously record the lateral distribution of numerous biomolecules in tissue slices, but its sensitivity is restricted by limited ionization. We used a wavelength-tunable postionization laser to initiate secondary MALDI-like ionization processes in the gas phase. In this way, we could increase the ion yields for numerous lipid classes, liposoluble vitamins, and saccharides, imaged in animal and plant tissue with a 5-micrometer-wide laser spot, by up to two orders of magnitude. Critical parameters for initiation of the secondary ionization processes are pressure of the cooling gas in the ion source, laser wavelength, pulse energy, and delay between the two laser pulses. The technology could enable sensitive MALDI-MS imaging with a lateral resolution in the low micrometer range. PMID- 25745063 TI - Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE-/- Mice From Angiotensin II-Induced Abdominal Aortic Aneurysm Formation. AB - OBJECTIVE: Rupture of abdominal aortic aneurysm (AAA), a major cause of death in the aged population, is characterized by vascular inflammation and matrix degradation. Serum amyloid A (SAA), an acute-phase reactant linked to inflammation and matrix metalloproteinase induction, correlates with aortic dimensions before aneurysm formation in humans. We investigated whether SAA deficiency in mice affects AAA formation during angiotensin II (Ang II) infusion. APPROACH AND RESULTS: Plasma SAA increased ~60-fold in apoE(-/-) mice 24 hours after intraperitoneal Ang II injection (100 MUg/kg; n=4) and ~15-fold after chronic 28-day Ang II infusion (1000 ng/kg per minute; n=9). AAA incidence and severity after 28-day Ang II infusion was significantly reduced in apoE(-/-) mice lacking both acute-phase SAA isoforms (SAAKO; n=20) compared with apoE(-/-) mice (SAAWT; n=20) as assessed by in vivo ultrasound and ex vivo morphometric analyses, despite a significant increase in systolic blood pressure in SAAKO mice compared with SAAWT mice after Ang II infusion. Atherosclerotic lesion area of the aortic arch was similar in SAAKO and SAAWT mice after 28-day Ang II infusion. Immunostaining detected SAA in AAA tissues of Ang II-infused SAAWT mice that colocalized with macrophages, elastin breaks, and enhanced matrix metalloproteinase activity. Matrix metalloproteinase-2 activity was significantly lower in aortas of SAAKO mice compared with SAAWT mice after 10-day Ang II infusion. CONCLUSIONS: Lack of endogenous acute-phase SAA protects against experimental AAA through a mechanism that may involve reduced matrix metalloproteinase-2 activity. PMID- 25745065 TI - Strong water isotopic anomalies in the martian atmosphere: probing current and ancient reservoirs. AB - We measured maps of atmospheric water (H2O) and its deuterated form (HDO) across the martian globe, showing strong isotopic anomalies and a significant high deuterium/hydrogen (D/H) enrichment indicative of great water loss. The maps sample the evolution of sublimation from the north polar cap, revealing that the released water has a representative D/H value enriched by a factor of about 7 relative to Earth's ocean [Vienna standard mean ocean water (VSMOW)]. Certain basins and orographic depressions show even higher enrichment, whereas high altitude regions show much lower values (1 to 3 VSMOW). Our atmospheric maps indicate that water ice in the polar reservoirs is enriched in deuterium to at least 8 VSMOW, which would mean that early Mars (4.5 billion years ago) had a global equivalent water layer at least 137 meters deep. PMID- 25745066 TI - Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. AB - Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D-activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, a shed form of MULT1, a high-affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are always inhibitory and suggest a new approach for cancer immunotherapy. PMID- 25745067 TI - Methane cycling. Nonequilibrium clumped isotope signals in microbial methane. AB - Methane is a key component in the global carbon cycle, with a wide range of anthropogenic and natural sources. Although isotopic compositions of methane have traditionally aided source identification, the abundance of its multiply substituted "clumped" isotopologues (for example, (13)CH3D) has recently emerged as a proxy for determining methane-formation temperatures. However, the effect of biological processes on methane's clumped isotopologue signature is poorly constrained. We show that methanogenesis proceeding at relatively high rates in cattle, surface environments, and laboratory cultures exerts kinetic control on (13)CH3D abundances and results in anomalously elevated formation-temperature estimates. We demonstrate quantitatively that H2 availability accounts for this effect. Clumped methane thermometry can therefore provide constraints on the generation of methane in diverse settings, including continental serpentinization sites and ancient, deep groundwaters. PMID- 25745068 TI - Increased hepatic Fatty Acid uptake and esterification contribute to tetracycline induced steatosis in mice. AB - Tetracycline induces microvesicular steatosis, which has a poor long-term prognosis and a higher risk of steatohepatitis development compared with macrovesicular steatosis. Recent gene expression studies indicated that tetracycline treatment affects the expression of many genes associated with fatty acid transport and esterification. In this study, we investigated the role of fatty acid transport and esterification in tetracycline-induced steatosis. Intracellular lipid accumulation and the protein expression of fatty acid translocase (FAT or CD36) and diacylglycerol acyltransferase (DGAT) 2 were increased in both mouse liver and HepG2 cells treated with tetracycline at 50 mg/kg (intraperitoneal injection, i.p.) and 100 MUM, respectively. Tetracycline increased the cellular uptake of boron-dipyrromethene-labeled C16 fatty acid, which was abolished by CD36 RNA interference. Oleate-induced cellular lipid accumulation was further enhanced by co-incubation with tetracycline. Tetracycline downregulated extracellular signal-regulated kinase (ERK) phosphorylation, which negatively regulated DGAT2 expression. U0126, a specific ERK inhibitor, also increased DGAT2 expression and cellular lipid accumulation. DGAT1 and 2 knock-down with specific small interfering (si)-RNA completely abrogated the steatogenic effect of tetracycline in HepG2 cells. Taken together, our data showed that tetracycline induces lipid accumulation by facilitating fatty acid transport and triglyceride esterification by upregulating CD36 and DGAT2, respectively. PMID- 25745069 TI - Xenopus laevis Oocytes as a Model System for Studying the Interaction Between Asbestos Fibres and Cell Membranes. AB - The mode of interaction of asbestos fibres with cell membranes is still debatable. One reason is the lack of a suitable and convenient cellular model to investigate the causes of asbestos toxicity. We studied the interaction of asbestos fibres with Xenopus laevis oocytes, using electrophysiological and morphological methods. Oocytes are large single cells, with a limited ability to endocytose molecular ligands; we therefore considered these cells to be a good model for investigating the nature of asbestos/membrane interactions. Electrophysiological recordings were performed to compare the passive electrical membrane properties, and those induced by applying positive or negative voltage steps, in untreated oocytes and those exposed to asbestos fibre suspensions. Ultrastructural analysis visualized in detail, any morphological changes of the surface membrane caused by the fibre treatment. Our results demonstrate that Amosite and Crocidolite-type asbestos fibres significantly modify the properties of the membrane, starting soon after exposure. Cells were routinely depolarized, their input resistance decreased, and the slow outward currents evoked by step depolarizations were dramatically enhanced. Reducing the availability of surface iron contained in the structure of the fibres with cation chelators, abolished these effects. Ultrastructural analysis of the fibre-exposed oocytes showed no evidence of phagocytic events. Our results demonstrate that asbestos fibres modify the oocyte membrane, and we propose that these cells represent a viable model for studying the asbestos/cell membrane interaction. Our findings also open the possibly for finding specific competitors capable of hindering the asbestos cell membrane interaction as a means of tackling the long-standing asbestos toxicity problem. PMID- 25745070 TI - Comment on the article by Trolese T et al. PMID- 25745071 TI - Cardiac resynchronization therapy improves psycho-cognitive performance in patients with heart failure. AB - BACKGROUND: Reduced cognitive performance and high prevalence of depression have been reported in patients with congestive heart failure (CHF) and severe left ventricular dysfunction. However, effects of contemporary device therapy on cognitive performance and depression symptoms have not been studied thoroughly. METHODS: Seventy-four consecutive CHF patients-45 receiving a biventricular defibrillator (CRT-D) and 29 receiving an implantable single or dual-chamber defibrillator (ICD) as a control group-were enrolled in this investigator initiated, prospective, controlled, and investigator-blinded study. A set of neuropsychological tests (mini-mental state examination, DemTect, age concentration test, and Beck depression inventory) was performed before, at 3 and at 6 months after device implantation. RESULTS: DemTect-score improved significantly (F = 7.8; P = 0.007) after CRT-D-implantation compared with ICD. Age-concentration test revealed better concentration ability after CRT-D implantation (F = 8.3; P = 0.005) compared with ICD. Under CRT-D mini-mental state examination showed a significant improvement (F = 4.2; P = 0.043). CRT with defibrillator therapy also improved depression revealed by beck depression inventory (F = 14.7; P< 0.001) compared with ICD. CONCLUSION: This prospective study is the first to demonstrate psycho-cognitive improvement by resynchronization therapy in CHF patients with severe left ventricular dysfunction. In contrast to ICD therapy, the beneficial effect of CRT-D on psycho cognitive performance might be attributed to improved cardiac function and haemodynamics. PMID- 25745072 TI - In vivo contact force measurements and correlation with left atrial anatomy during catheter ablation of atrial fibrillation. AB - AIMS: Lesion formation during catheter ablation crucially depends on catheter tissue contact. We sought to evaluate the impact of anatomical characteristics of the left atrium (LA) and the pulmonary veins (PVs) on contact force (CF) measurements. METHODS AND RESULTS: An anatomical map of the LA was obtained in 25 patients prior to catheter ablation of atrial fibrillation. Contact force (operator blinded) and local bipolar electrogram amplitudes (EGM) were measured in eight pre-defined segments around the PVs. After unblinding, points with low CF (<=5 g) were corrected to CF >5 g, and the distance between points was measured. In a pre-procedural computed tomography of the heart, LA volume as well as sizes and circumferences of the PV ostia were measured and correlated to CF measurements. Four hundred and twenty-six points in eight pre-defined LA locations were assessed. Low CF (<5 g) was found in 25.0% (43.5%) of points superior, 33.3% (66.7%) anterior, 32.1% (44.4%) inferior, and 15.5% (15.9%) posterior to the right (left) PVs. The mean distance after correction was 5.8 +/- 3.4 mm. Local bipolar electrogram amplitudes between low- and high-CF points did not differ (1.21 +/- 1.54 vs. 1.13 +/- 1.3 mV, P = ns). The mean CF at the left PVs was significantly lower than at the right PVs (7.91 +/- 3.74 vs. 13.95 +/- 6.34 g, P < 0.001), with the lowest CF anterior to the left PVs (5.2 +/- 3.6 g). Contact force measurements did not correlate to LA volume, size, and circumference of the PVs. CONCLUSION: Contact force during LA mapping significantly differs according to the location within the LA. These differences are independent of LA volume and anatomy of the PV ostia. PMID- 25745073 TI - Optimal pacing sites for cardiac resynchronization therapy for patients with a systemic right ventricle with or without a rudimentary left ventricle. AB - AIMS: This study aims to assess the impact of pacing sites on the effectiveness of cardiac resynchronization therapy (CRT) in systemic right ventricle (sRV) patients with/without a rudimentary left ventricle (rLV). METHODS AND RESULTS: We evaluated 13 procedures in 11 sRV patients with a wide QRS (>150 ms). Based on the digitalization results of ventriculography, long-axis dyssynchrony (LD) was defined as extremely delayed right ventricular (RV) outflow tract movement: >=100 ms delay from the RV apical contraction, and short-axis dyssynchrony (SD) was defined as a paradoxical contraction between the rLV and sRV caused by a conduction delay between the two ventricles. During the follow-up period (2.1 +/- 1.9 years), the response rates were 71% (5/7) and 33% (2/6) in the sRV patients with and without an rLV, respectively (P = ns). Following the CRT, the QRS duration remained similar between the responders and nonresponders. Among five responders with an rLV, the leads were placed in the longitudinal RV direction in two with LD, longitudinal RV direction with fusion of the intrinsic QRS in two with LD + SD, and laterally on opposite sides of both ventricles in one with SD. Among two responders without an rLV, the leads were placed in the longitudinal RV direction in those two with LD. CONCLUSIONS: In sRV patients with LD with/without an rLV, the leads should be placed at furthest sites in the longitudinal RV direction. In patients with an rLV and SD, the leads should be placed laterally on opposite sides of both ventricles. PMID- 25745074 TI - Author's reply: To PMID 24895019. PMID- 25745076 TI - Erratum. Involvement of RhoA/Rho-Associated Kinase Signal Transduction Pathway in Dexamethasone-Induced Alterations in Aqueous Outflow. PMID- 25745075 TI - Time-dependent risk reduction of ventricular tachyarrhythmias in cardiac resynchronization therapy patients: a MADIT-RIT sub-study. AB - AIMS: Data on the time-dependent benefit of cardiac resynchronization therapy with defibrillator (CRT-D) compared with a dual-chamber implantable cardioverter defibrillator (ICD) to reduce death or ventricular tachycardia (VT) or ventricular fibrillation (VF) are limited. We aimed to evaluate the time-related risk of death or sustained VT or VF in patients receiving CRT-D vs. ICD in the MADIT-RIT trial. METHODS AND RESULTS: Kaplan-Meier survival analyses and multivariate Cox regression models were utilized to compare the incidence and the risk of death or sustained VT/VF in the CRT-D and ICD subgroups by the elapsed time after device implantation (6 months). Of the ICD (n = 742) and CRT-D (n = 757) patients enrolled, the risk of death was lower in CRT-D vs. in ICD early after device implantation [hazard ratio (HR) = 0.42, 95% confidence interval (CI): 0.17-1.03, P = 0.058] and beyond 6 months of follow-up (HR = 0.39, 95% CI: 0.21-0.73, P = 0.004), with the 6-month interaction P = 0.899. The overall risk of sustained VT/VF was reduced in CRT-D vs. ICD patients (HR = 0.73, 95% CI: 0.52 1.03, P = 0.07). However, the risk was similar in the first 6 months (HR = 1.00, 95% CI: 0.62-1.62, P = 0.988), and a lower risk emerged 6 months after CRT-D implantation (HR = 0.58, 95% CI: 0.38-0.88, P = 0.011), with the 6-month interaction P = 0.059. CONCLUSION: The reduced mortality risk of CRT-D compared with an ICD alone began early after device implantation and was sustained during long-term follow-up; the reduced risk for ventricular tachyarrhythmias did not emerge until 6 months after device implantation. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00947310. PMID- 25745077 TI - More to stable tears than thickness of the tear film lipid layer. PMID- 25745078 TI - Author response: more to stable tears than thickness of the lipid layer. PMID- 25745079 TI - Effect of photocoagulation of ischemic areas to prevent recurrence of diabetic macular edema. PMID- 25745080 TI - Author response: effect of photocoagulation of ischemic areas to prevent recurrence of diabetic macular edema. PMID- 25745081 TI - Glutathione peroxidase 4, a unique antioxidant enzyme, plays a role in protecting ocular surface mucosal epithelia. PMID- 25745082 TI - Regional differences in cardiovascular mortality in Kazakhstan: further evidence for the 'Russian mortality paradox'? AB - BACKGROUND: The role of alcohol consumption in patterns of CVD mortality in Central Asia is still largely unexplored. Previous research in Kazakhstan and Kyrgyzstan has found that ethnic Russians have higher adult mortality rates than native ethnic groups, despite their higher socio-economic status. This has been termed the 'Russian mortality paradox'. METHODS: We calculated age-standardized CVD mortality data by gender and region of Kazakhstan, based on mortality data obtained from the Ministry of Health and population data from the State Agency for Statistics. We analysed data on self-reported alcohol consumption from the nationally representative 5th National Behavior Study. RESULTS: We found substantial differences in CVD mortality rates across regions, as well as between males and females. With the exception of Almaty and Astana cities, mortality rates are highest in the country's North-Eastern regions and lowest in South Western regions, despite the fact that North-Eastern regions have higher income levels. Patterns of self-reported alcohol consumption and alcohol sales follow a similar pattern. One explanation could be related to higher self-reported drinking prevalence among ethnic Russians who live predominantly in the country's North-Eastern regions. CONCLUSIONS: Hazardous alcohol consumption seems to be highest in Kazakhstan's North-Eastern regions, which might be related to different patterns of alcohol consumption among different ethnic groups. However, more detailed analyses are required to corroborate these assumptions. The high overall rates suggest the need for population-based measures, such as increasing taxes on alcohol, in particular spirits such as vodka, and strengthening the capacity of primary health care. PMID- 25745083 TI - Morbidity and disease management in pet rats: a study of 375 cases. AB - Typical diseases are well described in pet rats, but their prevalence and management are largely unknown. During a six-month period, standardised records were obtained for 375 rats presenting in three French centres to determine the diagnoses made and the treatments prescribed. Rhinitis, healthy animal and mammary gland tumours accounted for the majority of diagnoses. The 10 most common diagnoses accounted for 66.9 per cent of all cases. Inappropriate environment was a risk factor for respiratory disease (P<0.001). Mean age of presentation of rats with respiratory disease was lower for rats living in non-appropriate environment (P=0.049). Twenty-two per cent of animals underwent surgery, with a significant difference according to sex because of the higher rate of mammary gland tumours in females (P=0.006). Tumourectomy, ovariohysterectomy or castration accounted for 70 per cent of all procedures. Training veterinarians on 10 clinical situations, 3 surgical procedures and 3 therapeutic classes would improve the management of most of the pet rats. An early visit to provide owners with all recommendations and information on appropriate maintenance, and one visit around 15 months of age to detect any mass at an early stage, could help to reduce respiratory disease and improve clinical outcomes. PMID- 25745084 TI - Cervical intervertebral foraminal disc extrusion in dogs: clinical presentation, MRI characteristics and outcome after medical management. AB - The aim of the present study was to retrospectively evaluate the clinical signs, MRI characteristics, interobserver agreement and outcome after medical treatment in dogs affected by cervical intervertebral foraminal disc extrusion (CIFDE). The medical records of three referral institutions were searched for dogs diagnosed with CIFDE between 2010 and 2012. Thirteen dogs were identified with CIFDE; affected dogs often had a normal neurological examination, with cervical hyperaesthesia and lameness as the most common clinical signs. On MRI, sagittal images showed no evidence of compression of the spinal cord; CIFDE could be identified only on transverse sections in all cases. An excellent interobserver agreement was found in the localisation of the affected intervertebral disc space, and a substantial agreement was found on the detection of CIFDE versus foraminal stenosis caused by overgrowing articular processes. All but two dogs recovered completely, and they were considered free of clinical signs without analgesia within a median of 7.5 weeks (range: 2-20) after medical management was started. The remaining two dogs were surgically treated followed by complete recovery. In view of our findings, the importance of a thorough MRI investigation in dogs presenting with cervical hyperaesthesia as the sole clinical sign should be highlighted. PMID- 25745085 TI - Mesenchymal stem cell-mediated, tumor stroma-targeted radioiodine therapy of metastatic colon cancer using the sodium iodide symporter as theranostic gene. AB - The tumor-homing property of mesenchymal stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter (NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. We have previously shown that linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease. METHODS: To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. RANTES-NIS-MSCs were injected intravenously, followed by (123)I scintigraphy, (124)I PET imaging, and (131)I therapy. RESULTS: Results show robust MSC recruitment with RANTES/CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of (131)I in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved overall survival. CONCLUSION: This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery. PMID- 25745086 TI - Comparative studies of three 68Ga-labeled [Des-Arg10]kallidin derivatives for imaging bradykinin B1 receptor expression with PET. AB - Bradykinin B1 receptor (B1R) is a G-protein-coupled receptor that is overexpressed in a variety of cancers. B1R is not expressed in healthy tissues, making it an attractive cancer imaging marker. Previously, we reported selective uptake of (68)Ga-P03034 ((68)Ga-DOTA-dPEG2-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu) in B1R-positive (B1R+) HEK293T::hB1R tumor xenografts in mice. In this study, we compare (68)Ga-P03034 with (68)Ga-labeled P04158 ((68)Ga-DOTA-dPEG2-Lys-Lys-Arg Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic) and Z02090 ((68)Ga-DOTA-dPEG2-Lys-Lys-Arg-Pro-Hyp Gly-Cpg-Ser-D-Tic-Cpg) derived from 2 potent B1R antagonists, B9858 and B9958, respectively, for imaging B1R expression with PET. METHODS: Peptide sequences were assembled on solid-phase. Cold standards were prepared by incubating DOTA conjugated peptides with GaCl3. Binding affinity was measured via competition binding assays using hB1R-expressing Chinese hamster ovary-K1 cell membranes. (68)Ga labeling was performed in N-(2-hydroxyethyl)piperazine-N'-(2 ethanesulfonic acid) buffer with microwave heating and purified by high performance liquid chromatography. Imaging/biodistribution studies were performed in mice bearing wild-type HEK293T (B1R-) and B1R+ HEK293T::hB1R tumors. RESULTS: P03034, P04158, and Z02090 bound B1R with high affinity, with Ki values at 16.0 +/- 2.9, 1.5 +/- 1.9, and 1.1 +/- 0.8 nM, respectively. (68)Ga-labeled P03034, P04159, and Z02090 were obtained in greater than 50% decay-corrected radiochemical yields with more than 99% radiochemical purity. Biodistribution studies showed that all three (68)Ga-labeled tracers cleared rapidly from the blood and normal tissues, with excretion mainly via the renal pathway. At 1 h after injection, only the kidneys, bladders, and B1R+ HEK293T::hB1R tumors were clearly visualized in PET images. Uptake values of (68)Ga-labeled P03034, P04158, and Z02090 in B1R+ tumors were 2.17 +/- 0.49, 19.6 +/- 4.50, and 14.4 +/- 1.63 percentage injected dose per gram, respectively. Uptake ratios of B1R+ to B1R- tumor, blood, and muscle were 6.23 +/- 1.69, 5.72 +/- 2.20, and 25.5 +/- 13.1 for (68)Ga-P03034; 34.5 +/- 10.5, 19.2 +/- 8.21, and 66.1 +/- 17.0 for (68)Ga-P04158; and 29.3 +/- 9.68, 29.9 +/- 5.58, and 124 +/- 28.1 for (68)Ga-Z02090, respectively. CONCLUSION: All three (68)Ga-labeled B1R-targeting peptides generated specific and high-contrasted images of B1R+ tumors xenografted in mice. With significantly higher tumor uptake and target-to-nontarget ratios, (68)Ga labeled P04158 and Z02090 are superior to P03034 for imaging B1R expression with PET. PMID- 25745087 TI - Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding. PMID- 25745088 TI - American College of Radiology and Society of Nuclear Medicine and Molecular Imaging Joint Credentialing Statement for PET/MR Imaging: Brain. PMID- 25745089 TI - Radiation dose and prognosis of ultra-low-dose stress-first myocardial perfusion SPECT in patients with chest pain using a high-efficiency camera. AB - Although SPECT myocardial perfusion imaging (MPI) provides valuable information about patients with chest pain, there is growing concern regarding its radiation burden and lengthy duration. New high-efficiency (HE) cameras and stress-first protocols both offer the potential to markedly reduce radiation. No previous study has assessed outcomes and radiation doses of patients undergoing MPI on an HE-SPECT camera using an ultra-low-dose stress-first protocol. METHODS: One hundred patients presenting to the emergency department with chest pain who were candidates for stress-first MPI underwent injection of approximately 185 MBq (5 mCi) of (99m)Tc-tetrofosmin at peak stress, followed by supine and prone imaging on an HE-SPECT camera. Same-day rest imaging was performed on patients with any abnormality on imaging after stress. Radiation effective dose was calculated from administered and residual activities. Patients were contacted 3 mo after discharge, and electronic records were accessed to evaluate the need for reevaluation for chest pain, additional imaging, or cardiac events. RESULTS: Stress-only imaging was performed in 69 patients, for whom radiation effective dose averaged 0.99 mSv and study duration, 117 min. Radiation dose averaged 2.22 mSv over all patients. At 3 mo, 96 patients were free of major adverse cardiac events, repeat hospital chest pain evaluation, and repeat imaging or stress testing. One year after MPI and hospital discharge, all patients were living and without acute coronary syndrome. CONCLUSION: HE-SPECT stress-only imaging can be performed in more than two thirds of chest pain patients without a high pretest probability of a stress perfusion defect, with excellent prognosis, a radiation dose averaging 1 mSv, and a test duration of less than 2 h. PMID- 25745090 TI - Impact of time-of-flight PET on quantification errors in MR imaging-based attenuation correction. AB - Time-of-flight (TOF) PET/MR imaging is an emerging imaging technology with great capabilities offered by TOF to improve image quality and lesion detectability. We assessed, for the first time, the impact of TOF image reconstruction on PET quantification errors induced by MR imaging-based attenuation correction (MRAC) using simulation and clinical PET/CT studies. METHODS: Standard 4-class attenuation maps were derived by segmentation of CT images of 27 patients undergoing PET/CT examinations into background air, lung, soft-tissue, and fat tissue classes, followed by the assignment of predefined attenuation coefficients to each class. For each patient, 4 PET images were reconstructed: non-TOF and TOF both corrected for attenuation using reference CT-based attenuation correction and the resulting 4-class MRAC maps. The relative errors between non-TOF and TOF MRAC reconstructions were compared with their reference CT-based attenuation correction reconstructions. The bias was locally and globally evaluated using volumes of interest (VOIs) defined on lesions and normal tissues and CT-derived tissue classes containing all voxels in a given tissue, respectively. The impact of TOF on reducing the errors induced by metal-susceptibility and respiratory phase mismatch artifacts was also evaluated using clinical and simulation studies. RESULTS: Our results show that TOF PET can remarkably reduce attenuation correction artifacts and quantification errors in the lungs and bone tissues. Using classwise analysis, it was found that the non-TOF MRAC method results in an error of -3.4% +/- 11.5% in the lungs and -21.8% +/- 2.9% in bones, whereas its TOF counterpart reduced the errors to -2.9% +/- 7.1% and -15.3% +/- 2.3%, respectively. The VOI-based analysis revealed that the non-TOF and TOF methods resulted in an average overestimation of 7.5% and 3.9% in or near lung lesions (n = 23) and underestimation of less than 5% for soft tissue and in or near bone lesions (n = 91). Simulation results showed that as TOF resolution improves, artifacts and quantification errors are substantially reduced. CONCLUSION: TOF PET substantially reduces artifacts and improves significantly the quantitative accuracy of standard MRAC methods. Therefore, MRAC should be less of a concern on future TOF PET/MR scanners with improved timing resolution. PMID- 25745092 TI - Establishing age-associated normative ranges of the cerebral 18F-FDG uptake ratio in children. AB - In this study, we reported age-associated ranges of the regional cerebral (18)F FDG uptake ratio in pediatric patients as a surrogate to normative data from healthy children. METHODS: (18)F-FDG PET scans of 132 children and adolescents (age, 1-20 y) with non-central nervous system-related diseases and normal appearing tracer distributions in the brain were retrospectively analyzed. PET images of individual patients were warped to a 3-dimensional reference template. Uptake ratio was calculated for 63 anatomic regions by normalizing the regional count per voxel with the average count per voxel in all regions. Models of regional uptake ratio as a function of age and sex were developed to calculate the 95% prediction interval. RESULTS: The paracentral lobule and cuneus had the highest resting metabolic state among all gray matter regions, whereas the brain stem, uncus, and hippocampus had the lowest uptake. A large left-right asymmetry was present in the angular gyrus and inferior occipital gyrus. Quantitative data of the regression, 95% confidence interval, and 95% prediction interval for each age were summarized for the 63 regions. In 52 of 63 regions, the (18)F-FDG uptake ratio had a significant age effect. The linear model was optimal for 12 regions, whereas the spline model with 1 age knot was a better fit for 40 regions. In children younger than 5 y, frontal and temporal lobes had a lower uptake than parietal and occipital lobes in general. However, uptake in the frontal lobe continued to increase with age but it decreased in the parietal and occipital lobes. CONCLUSION: Anatomic regions of the brain in children and adolescents exhibited uniquely different (18)F-FDG uptake trends with age. Our results may be useful for studying childhood development and possibly regional metabolic defects in children with traumatic brain injury or central nervous system disorders or children receiving cancer treatment. PMID- 25745091 TI - Improved power for characterizing longitudinal amyloid-beta PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region. AB - In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-beta (Abeta) PET changes and evaluating Abeta modifying treatments. METHODS: Our aims were to compare the power of template based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Abeta-modifying treatments in Abeta-positive (Abeta+) and Abeta-negative (Abeta-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow up (~24 mo) florbetapir PET scans from 332 Abeta+ and Abeta- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Abeta increases in Abeta+ and Abeta- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Abeta accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Abeta increases to clinical declines. RESULTS: As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24 mo fibrillar Abeta increases and evaluate Abeta-modifying treatment effects in Abeta+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24 mo Abeta increases and clinical declines. CONCLUSION: A cerebral white matter reference region may improve the power to track longitudinal fibrillar Abeta increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Abeta-modifying treatments in randomized clinical trials. PMID- 25745093 TI - Pharmacokinetic and pharmacodynamic modifiers of EF5 uptake and binding. PMID- 25745094 TI - Improving patient selection for 18F-FDG PET scanning in the staging of gastric cancer. AB - Standard pretreatment staging for gastric cancer includes CT of the chest, abdomen, and pelvis; gastroscopy; and laparoscopy. Although (18)F-PET combined with CT has proven to be a useful staging tool in many cancers, some gastric cancers are not (18)F-FDG-avid and its clinical value is still debatable. METHODS: Gastric cancer patients who underwent staging (18)F-FDG PET scans from 2002 to 2013 at the Peter MacCallum Cancer Center were retrospectively analyzed, and a systematic review was also conducted using PubMed between 2000 to March 2014 to investigate clinicopathologic parameters associated with (18)F-FDG avidity. A pretreatment PET scoring system was developed from predictors of (18)F FDG avidity. RESULTS: Both the retrospective analysis of the patients and the systematic literature review showed similar significant predictors of (18)F-FDG avidity, including large tumor size, non-signet ring cell carcinoma type, and glucose transporter 1-positive expression on immunohistochemistry. A PET scoring system was developed from these clinicopathologic parameters that allowed (18)F FDG-avid tumors to be detected with a sensitivity of 85% and a specificity of 71%. CONCLUSION: A pretreatment PET scoring system can assist in the selection of patients with gastric adenocarcinoma when staging (18)F-FDG PET is being considered. PMID- 25745095 TI - Measurement of longitudinal beta-amyloid change with 18F-florbetapir PET and standardized uptake value ratios. AB - The accurate measurement of beta-amyloid (Abeta) change using amyloid PET imaging is important for Alzheimer disease research and clinical trials but poses several unique challenges. In particular, reference region measurement instability may lead to spurious changes in cortical regions of interest. To optimize our ability to measure (18)F-florbetapir longitudinal change, we evaluated several candidate regions of interest and their influence on cortical florbetapir change over a 2-y period in participants from the Alzheimer Disease Neuroimaging Initiative (ADNI). METHODS: We examined the agreement in cortical florbetapir change detected using 6 candidate reference regions (cerebellar gray matter, whole cerebellum, brain stem/pons, eroded subcortical white matter [WM], and 2 additional combinations of these regions) in 520 ADNI subjects. We used concurrent cerebrospinal fluid Abeta1-42 measurements to identify subgroups of ADNI subjects expected to remain stable over follow-up (stable Abeta group; n = 14) and subjects expected to increase (increasing Abeta group; n = 91). We then evaluated reference regions according to whether cortical change was minimal in the stable Abeta group and cortical retention increased in the increasing Abeta group. RESULTS: There was poor agreement across reference regions in the amount of cortical change observed across all 520 ADNI subjects. Within the stable Abeta group, however, cortical florbetapir change was 1%-2% across all reference regions, indicating high consistency. In the increasing Abeta group, cortical increases were significant with all reference regions. Reference regions containing WM (as opposed to cerebellum or pons) enabled detection of cortical change that was more physiologically plausible and more likely to increase over time. CONCLUSION: Reference region selection has an important influence on the detection of florbetapir change. Compared with cerebellum or pons alone, reference regions that included subcortical WM resulted in change measurements that are more accurate. In addition, because use of WM-containing reference regions involves dividing out cortical signal contained in the reference region (via partial volume effects), use of these WM-containing regions may result in more conservative estimates of actual change. Future analyses using different tracers, tracer-kinetic models, pipelines, and comparisons with other biomarkers will further optimize our ability to accurately measure Abeta changes over time. PMID- 25745096 TI - Influence of natural inshore and offshore thermal regimes on egg development and time of hatch in American lobsters, Homarus americanus. AB - Some egg-bearing (ovigerous) American lobsters (Homarus americanus) make seasonal inshore-to-offshore movements, subjecting their eggs to different thermal regimes than those of eggs carried by lobsters that do not make these movements. Our goal was to determine if differences in thermal regimes influence the rate of egg development and the subsequent time of hatch. We subjected ovigerous lobsters to typical inshore or offshore water temperatures from September to August in the laboratory (n=8 inshore and 8 offshore, each year) and in the field (n=8 each, inshore and offshore), over 2 successive years. Although the rate of egg development did not differ significantly between treatments in the fall (P~0.570), eggs exposed to inshore thermal regimes developed faster in the spring (P<0.001). "Inshore" eggs hatched about 30 days earlier (mean=26 June) than "offshore" eggs (mean=27 July), and their time of development from the onset of eyespot to hatch was significantly shorter (inshore=287+/-11 days vs. offshore: 311.5+/-7.5 days, P=0.034). Associated growing degree-days (GDD) did not differ significantly between inshore and offshore thermal treatments (P=0.061). However, eggs retained by lobsters exposed to offshore thermal regimes accumulated more GDD in the winter than did eggs carried by inshore lobsters, while eggs exposed to inshore temperatures acquired them more rapidly in the spring. Results suggest that seasonal movements of ovigerous lobsters influence the time and location of hatching, and thus the transport and recruitment of larvae to coastal and offshore locations. PMID- 25745097 TI - Hybrids between the Florida amphioxus (Branchiostoma floridae) and the Bahamas lancelet (Asymmetron lucayanum): developmental morphology and chromosome counts. AB - The cephalochordate genera Branchiostoma and Asymmetron diverged during the Mesozoic Era. In spite of the long separation of the parental clades, eggs of the Florida amphioxus, B. floridae, when fertilized with sperm of the Bahamas lancelet, A. lucayanum (and vice versa), develop through embryonic and larval stages. The larvae reach the chordate phylotypic stage (i.e., the pharyngula), characterized by a dorsal nerve cord, notochord, perforate pharynx, and segmented trunk musculature. After about 2 weeks of larval development, the hybrids die, as do the A. lucayanum purebreds, although all were eating the same algal diet that sustains B. floridae purebreds through adulthood in the laboratory; it is thus unclear whether death of the hybrids results from incompatible parental genomes or an inadequate diet. The diploid chromosome count in A. lucayanum and B. floridae purebreds is, respectively, 34 and 38, whereas it is 36 in hybrids in either direction. The hybrid larvae exhibit several morphological characters intermediate between those of the parents, including the size of the preoral ciliated pit and the angles of deflection of the gill slits and anus from the ventral midline. Based on the time since the two parent clades diverged (120 or 160 million years, respectively, by nuclear and mitochondrial gene analysis), the cross between Branchiostoma and Asymmetron is the most extreme example of hybridization that has ever been unequivocally demonstrated among multicellular animals. PMID- 25745098 TI - Development and larval feeding in the capitellid annelid Notomastus cf. tenuis. AB - Making inferences about the evolution of larval nutritional mode and feeding mechanisms in annelids requires data on the form and function of the larvae, but such data are lacking for many taxa. Though some capitellid annelids are known or suspected to have planktotrophic larvae, these larvae have not previously been described in sufficient detail to understand how they feed. Here we describe embryos and larvae of the capitellid Notomastus cf. tenuis from San Juan Island, Washington State. Fertilized oocytes average about 58 MUm in equivalent spherical diameter. Early embryos undergo spiral cleavage and develop into larvae that feed for about 5 weeks before metamorphosis. Larvae of N. cf. tenuis capture food particles between prototrochal and metatrochal ciliary bands and transport them to the mouth in an intermediate food groove; this arrangement is typical of "opposed band" larval feeding systems. Surprisingly, however, larvae of N. cf. tenuis appeared to have only simple cilia in the prototrochal ciliary band; among planktotrophic larvae of annelids, simple cilia in the prototroch were previously known only from members of Oweniidae. The anteriormost tier of prototrochal cilia in N. cf. tenuis appears to be non-motile; its role in swimming or particle capture is unclear. Like some planktotrophic larvae in the closely related Echiuridae and Opheliidae, larvae of N. cf. tenuis can capture relatively large particles (up to at least 45 MUm in diameter), suggesting that they may use an alternative particle capture mechanism in addition to opposed bands of cilia. PMID- 25745099 TI - Within-site variation of growth rates and terminal sizes in Mytilus californianus along wave exposure and tidal gradients. AB - Mytilus californianus is a foundation species of rocky shores of western North America. Its dominance depends on rapid growth to large sizes, which confers an advantage in size-dependent species interactions. Initial rates of growth and final (terminal) sizes of the mussels depend on environmental factors. Prior comparisons of growth made over large spatial scales (tens of meters to hundreds of kilometers) indicate that temperature, submergence time, and wave exposure affect growth. However, there are few studies quantifying variation in temperature, wave force, and mussel growth parameters at small scales within local populations-that is, meter-level increments. Such measures are necessary to better understand the consequences of the complex spatial mosaic of physical factors in the intertidal zone. We measured variation in temperature, wave force, size-specific shell growth, and terminal size at 3-4-m intervals along horizontal contours within two mussel beds separated by 15 ds of latitude. Both mussel beds showed the same general trends: growth rates attenuated along gradual clines from low and wave-exposed to high shore and sheltered. For example, young adults from low and wave-exposed microhabitats grew 9- and 6-fold higher than those from high shore-wave-sheltered points. While higher flow may promote growth by enhancing feeding, it also appears to exert a positive effect by moderating energetically costly temperature stress. Consistent with the growth rate findings, cumulative degree-hours explained 83% and 69% of the variation of terminal sizes in regressions for the two locations. PMID- 25745101 TI - Foraging and ingestive behaviors of whale sharks, Rhincodon typus, in response to chemical stimulus cues. AB - Whale sharks, Rhincodon typus, display a number of behaviors that suggest these animals can locate food from afar, as well as identify and discriminate between food items. However, their intractably large size and relative rarity in the field has so far prevented direct studies of their behavior and sensory capability. A small population of aquarium-held whale sharks facilitated direct studies of behavior in response to chemical stimulus plumes. Whale sharks were exposed to plumes composed of either homogenized krill or simple aqueous solutions of dimethyl sulfide (DMS), which is associated with krill aggregations and is used by several pelagic species as a food-finding stimulus. Whale sharks exhibited pronounced ingestive and search behaviors when exposed to both types of stimuli, compared to control trials. Ingestive behaviors included open mouth swimming and active surface feeding (gulping). These behaviors were stronger and more prevalent in response to krill homogenate plumes than to DMS plumes. Both chemical stimuli also increased visitation rate, and krill homogenate plumes additionally affected swimming speed. Whale sharks use chemosensory cues of multiple types to locate and identify palatable food, suggesting that chemical stimuli can help direct long-range movements and allow discrimination of different food items. There appears to be a hierarchy of responses: krill metabolites directly associated with food produced more frequent and intense feeding responses relative to DMS, which is indirectly associated with krill. DMS is used to find food by a number of pelagic species and may be an important signaling molecule in pelagic food webs. PMID- 25745102 TI - Calcium: amplitude, duration, or location? AB - Calcium plays a role in long-term plasticity by triggering postsynaptic signaling pathways for both the strengthening (LTP) and weakening (LTD) of synapses. Since these are opposing processes, several hypotheses have been developed to explain how calcium can trigger LTP in some situations and LTD in others. These hypotheses fall broadly into three categories, based on the amplitude of calcium concentration, the duration of the calcium elevation, and the location of the calcium influx. Here we review the experimental evidence for and against each of these hypotheses and the recent computational models utilizing each. We argue that with new experimental techniques for the precise visualization of calcium and new computational techniques for the modeling of calcium diffusion, it is time to take a new look at the location hypothesis. PMID- 25745103 TI - Challenges to accurate susceptibility testing and interpretation of quinolone resistance in Enterobacteriaceae: results of a Spanish multicentre study. AB - OBJECTIVES: The objective of this study was to evaluate the proficiency of Spanish laboratories with respect to accurate susceptibility testing and the detection and interpretation of quinolone resistance phenotypes in Enterobacteriaceae. METHODS: Thirteen strains of Enterobacteriaceae were sent to 62 participating centres throughout Spain; strains harboured GyrA/ParC modifications, reduced permeability and/or plasmid-mediated quinolone resistance genes. The centres were requested to evaluate nalidixic acid and five quinolones, provide raw/interpreted clinical categories and to detect/infer resistance mechanisms. Consensus results from reference centres were used to assign minor, major and very major errors (mEs, MEs and VMEs, respectively). RESULTS: Susceptibility testing in the participating centres was frequently performed using the MicroScan WalkAway, Vitek 2 and Wider systems (48%, 30% and 8%, respectively). CLSI/EUCAST breakpoints were used in 71%/29% of the determinations. The percentage of VMEs for all quinolones was well below 2%. Only ofloxacin and moxifloxacin showed higher values for raw VMEs (6.6%), which decreased to 0% and 2.9%, respectively, in the interpreted VMEs. These errors were particularly associated with the CC-03 strain [qnrS2 + aac(6')-Ib-cr]. For MEs, percentages were always <10%, except in the case of ofloxacin and nalidixic acid. There was a significantly higher percentage of all types of errors for strains whose MICs were at the border of clinical breakpoints. CONCLUSIONS: The use of different breakpoints and methods, the complexity of mutation-driven and transferable resistance mechanisms and the absence of specific tests for detecting low-level resistance lead to high variability and represent a challenge to accuracy in susceptibility testing, particularly in strains with MICs on the border of clinical breakpoints. PMID- 25745104 TI - Effect of tailored antibiotic stewardship programmes on the appropriateness of antibiotic prescribing in nursing homes. AB - OBJECTIVES: To evaluate the effect of tailored interventions on the appropriateness of decisions to prescribe or withhold antibiotics, antibiotic use and guideline-adherent antibiotic selection in nursing homes (NHs). METHODS: We conducted a quasi-experimental study in 10 NHs in the Netherlands. A participatory action research (PAR) approach was applied, with local stakeholders in charge of selecting tailored interventions based on opportunities for improved antibiotic prescribing that they derived from provided baseline data. An algorithm was used to evaluate the appropriateness of prescribing decisions, based on infections recorded by physicians. Effects of the interventions on the appropriateness of prescribing decisions were analysed with a multilevel logistic regression model. Pharmacy data were used to calculate differences in antibiotic use and recorded infections were used to calculate differences in guideline adherent antibiotic selection. RESULTS: The appropriateness of 1059 prescribing decisions was assessed. Adjusting for pre-test differences in the proportion of appropriate prescribing decisions (intervention, 82%; control, 70%), post-test appropriateness did not differ between groups (crude: P = 0.26; adjusted for covariates: P = 0.35). We observed more appropriate prescribing decisions at the start of data collection and before receiving feedback on prescribing behaviour. No changes in antibiotic use or guideline-adherent antibiotic selection were observed in intervention NHs. CONCLUSIONS: The PAR approach, or the way PAR was applied in the study, was not effective in improving antibiotic prescribing behaviour. The study findings suggest that drawing prescribers' attention to prescribing behaviour and monitoring activities, and increasing use of diagnostic resources may be promising interventions to improve antibiotic prescribing in NHs. PMID- 25745100 TI - Biogeography of Phallusia nigra: is it really black and white? AB - Ascidians (Chordata, Tunicata) are an important group for the study of invasive species biology due to rapid generation times, potential for biofouling, and role as filter feeders in an ecosystem. Phallusia nigra is a putative cosmopolitan ascidian that has been described as introduced or invasive in a number of regions in the Indo-Pacific Ocean (India, Japan, and Hawaii) and in the Mediterranean. The taxonomic description of P. nigra includes a striking smooth, black tunic and large size. However, there are at least two similar Phallusia species-P. philippinensis and P. fumigata-which also have dark black tunics and can be difficult to discern from P. nigra. The distribution of P. nigra broadly overlaps with P. philippinensis in the Indo-Pacific and P. fumigata in the Mediterranean. A morphological comparison of P. nigra from Japan, the Caribbean coast of Panama, and Brazil found that Atlantic and Pacific samples were different species and led us to investigate the range of P. nigra using morphological and molecular analyses. We sequenced 18S rDNA and cytochrome oxidase B of individual ascidians from the Red Sea, Greece, Singapore, Japan, Caribbean Panama, Florida, and Brazil. Our results show that identification of the disparate darkly pigmented species has been difficult, and that several reports of P. nigra are likely either P. fumigata or P. philippinensis. Here we include detailed taxonomic descriptions of the distinguishing features of these three species and sequences for molecular barcoding in an effort to have ranges and potential invasions corrected in the ascidian literature. PMID- 25745105 TI - Smoked cannabis' psychomotor and neurocognitive effects in occasional and frequent smokers. AB - Delta9-Tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis, impairs psychomotor performance, cognition and driving ability; thus, driving under the influence of cannabis is a public safety concern. We documented cannabis' psychomotor, neurocognitive, subjective and physiological effects in occasional and frequent smokers to investigate potential differences between these smokers. Fourteen frequent (>=4x/week) and 11 occasional (<2x/week) cannabis smokers entered a secure research unit ~19 h prior to smoking one 6.8% THC cigarette. Cognitive and psychomotor performance was evaluated with the critical tracking (CTT), divided attention (DAT), n-back (working memory) and Balloon Analog Risk (BART) (risk-taking) tasks at -1.75, 1.5, 3.5, 5.5 and 22.5 h after starting smoking. GLM (General Linear Model) repeated measures ANOVA was utilized to compare scores. Occasional smokers had significantly more difficulty compensating for CTT tracking error compared with frequent smokers 1.5 h after smoking. Divided attention performance declined significantly especially in occasional smokers, with session * group effects for tracking error, hits, false alarms and reaction time. Cannabis smoking did not elicit session * group effects on the n-back or BART. Controlled cannabis smoking impaired psychomotor function, more so in occasional smokers, suggesting some tolerance to psychomotor impairment in frequent users. These data have implications for cannabis associated impairment in driving under the influence of cannabis cases. PMID- 25745106 TI - Coordinated gene regulation in the initial phase of salt stress adaptation. AB - Stress triggers complex transcriptional responses, which include both gene activation and repression. We used time-resolved reporter assays in living yeast cells to gain insights into the coordination of positive and negative control of gene expression upon salt stress. We found that the repression of "housekeeping" genes coincides with the transient activation of defense genes and that the timing of this expression pattern depends on the severity of the stress. Moreover, we identified mutants that caused an alteration in the kinetics of this transcriptional control. Loss of function of the vacuolar H(+)-ATPase (vma1) or a defect in the biosynthesis of the osmolyte glycerol (gpd1) caused a prolonged repression of housekeeping genes and a delay in gene activation at inducible loci. Both mutants have a defect in the relocation of RNA polymerase II complexes at stress defense genes. Accordingly salt-activated transcription is delayed and less efficient upon partially respiratory growth conditions in which glycerol production is significantly reduced. Furthermore, the loss of Hog1 MAP kinase function aggravates the loss of RNA polymerase II from housekeeping loci, which apparently do not accumulate at inducible genes. Additionally the Def1 RNA polymerase II degradation factor, but not a high pool of nuclear polymerase II complexes, is needed for efficient stress-induced gene activation. The data presented here indicate that the finely tuned transcriptional control upon salt stress is dependent on physiological functions of the cell, such as the intracellular ion balance, the protective accumulation of osmolyte molecules, and the RNA polymerase II turnover. PMID- 25745107 TI - Ae4 (Slc4a9) Anion Exchanger Drives Cl- Uptake-dependent Fluid Secretion by Mouse Submandibular Gland Acinar Cells. AB - Transcellular Cl(-) movement across acinar cells is the rate-limiting step for salivary gland fluid secretion. Basolateral Nkcc1 Na(+)-K(+)-2Cl(-) cotransporters play a critical role in fluid secretion by promoting the intracellular accumulation of Cl(-) above its equilibrium potential. However, salivation is only partially abolished in the absence of Nkcc1 cotransporter activity, suggesting that another Cl(-) uptake pathway concentrates Cl(-) ions in acinar cells. To identify alternative molecular mechanisms, we studied mice lacking Ae2 and Ae4 Cl(-)/HCO3 (-) exchangers. We found that salivation stimulated by muscarinic and beta-adrenergic receptor agonists was normal in the submandibular glands of Ae2(-/-) mice. In contrast, saliva secretion was reduced by 35% in Ae4(-/-) mice. The decrease in salivation was not related to loss of Na(+)-K(+)-2Cl(-) cotransporter or Na(+)/H(+) exchanger activity in Ae4(-/-) mice but correlated with reduced Cl(-) uptake during beta-adrenergic receptor activation of cAMP signaling. Direct measurements of Cl(-)/HCO3 (-) exchanger activity revealed that HCO3 (-)-dependent Cl(-) uptake was reduced in the acinar cells of Ae2(-/-) and Ae4(-/-) mice. Moreover, Cl(-)/HCO3 (-) exchanger activity was nearly abolished in double Ae4/Ae2 knock-out mice, suggesting that most of the Cl(-)/HCO3 (-) exchanger activity in submandibular acinar cells depends on Ae2 and Ae4 expression. In conclusion, both Ae2 and Ae4 anion exchangers are functionally expressed in submandibular acinar cells; however, only Ae4 expression appears to be important for cAMP-dependent regulation of fluid secretion. PMID- 25745108 TI - Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae. AB - Toxicity of selenomethionine, an organic derivative of selenium widely used as supplement in human diets, was studied in the model organism Saccharomyces cerevisiae. Several DNA repair-deficient strains hypersensitive to selenide displayed wild-type growth rate properties in the presence of selenomethionine indicating that selenide and selenomethionine exert their toxicity via distinct mechanisms. Cytotoxicity of selenomethionine decreased when the extracellular concentration of methionine or S-adenosylmethionine was increased. This protection resulted from competition between the S- and Se-compounds along the downstream metabolic pathways inside the cell. By comparing the sensitivity to selenomethionine of mutants impaired in the sulfur amino acid pathway, we excluded a toxic effect of Se-adenosylmethionine, Se-adenosylhomocysteine, or of any compound in the methionine salvage pathway. Instead, we found that selenomethionine toxicity is mediated by the trans-sulfuration pathway amino acids selenohomocysteine and/or selenocysteine. Involvement of superoxide radicals in selenomethionine toxicity in vivo is suggested by the hypersensitivity of a Deltasod1 mutant strain, increased resistance afforded by the superoxide scavenger manganese, and inactivation of aconitase. In parallel, we showed that, in vitro, the complete oxidation of the selenol function of selenocysteine or selenohomocysteine by dioxygen is achieved within a few minutes at neutral pH and produces superoxide radicals. These results establish a link between superoxide production and trans-sulfuration pathway seleno-amino acids and emphasize the importance of the selenol function in the mechanism of organic selenium toxicity. PMID- 25745115 TI - ARVs: the next generation. Going boldly together to new frontiers of HIV treatment. PMID- 25745109 TI - Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2. AB - The RAG endonuclease consists of RAG1, which contains the active site for DNA cleavage, and RAG2, an accessory factor whose interaction with RAG1 is critical for catalytic function. How RAG2 activates RAG1 is not understood. Here, we used biolayer interferometry and pulldown assays to identify regions of RAG1 necessary for interaction with RAG2 and to measure the RAG1-RAG2 binding affinity (KD ~0.4 MUM) (where RAG1 and RAG2 are recombination activating genes 1 or 2). Using the Hermes transposase as a guide, we constructed a 36-kDa "mini" RAG1 capable of interacting robustly with RAG2. Mini-RAG1 consists primarily of the catalytic center and the residues N-terminal to it, but it lacks a zinc finger region in RAG1 previously implicated in binding RAG2. The ability of Mini-RAG1 to interact with RAG2 depends on a predicted alpha-helix (amino acids 997-1008) near the RAG1 C terminus and a region of RAG1 from amino acids 479 to 559. Two adjacent acidic amino acids in this region (Asp-546 and Glu-547) are important for both the RAG1 RAG2 interaction and recombination activity, with Asp-546 of particular importance. Structural modeling of Mini-RAG1 suggests that Asp-546/Glu-547 lie near the predicted 997-1008 alpha-helix and components of the active site, raising the possibility that RAG2 binding alters the structure of the RAG1 active site. Quantitative Western blotting allowed us to estimate that mouse thymocytes contain on average ~1,800 monomers of RAG1 and ~15,000 molecules of RAG2, implying that nuclear concentrations of RAG1 and RAG2 are below the KD value for their interaction, which could help limit off-target RAG activity. PMID- 25745110 TI - Identification of Subunit Binding Positions on a Model Fork and Displacements That Occur during Sequential Assembly of the Escherichia coli Primosome. AB - When replication stalls and forks disassemble, the restart primosome is required to reload the replicative helicase so that chromosomal replication can be reinitiated. We have taken a photo-cross-linking approach, using model replication forks containing a phenyl diazirine placed at single locations, to determine the positions of primosomal protein binding and changes in interactions that occur during the assembly reaction. This approach revealed a novel mode for single-stranded DNA-binding protein (SSB)-DNA binding, in which SSB interacts with both the leading and lagging single-strand segments and the parental duplex of the fork. Cross-linking to a novel region within SSB is observed only when it is bound to forked structures. This binding mode is also followed by PriB. PriA binds to the fork, excluding SSB and PriB, interacting with the primer terminus, single-stranded leading and lagging strands and duplex in immediate proximity of the fork. SSB binds to flanking single-stranded segments distal to the fork in the presence of PriA. The addition of PriB or DnaT to a PriA-SSB-fork complex does not lead to cross-linking or displacement, suggesting that their association is through protein-protein interactions at early stages of the reaction. Upon addition of DnaC and the DnaB helicase in the presence of ATPgammaS, helicase is assembled, leading to contacts within the duplex region on the tracking (lagging) strand and strong contacts with the displaced leading single strand near the fork. PriA is displaced from DNA upon helicase assembly. PMID- 25745116 TI - Stunning popularity of LARCs with good access and quality: a major opportunity to meet family planning needs. PMID- 25745117 TI - Delivering high-quality family planning services in crisis-affected settings I: program implementation. AB - In 2012, about 43 million women of reproductive age experienced the effects of conflict. Provision of basic sexual and reproductive health services, including family planning, is a recognized right and need of refugees and internally displaced people, but funding and services for family planning have been inadequate. This article describes lessons learned during the first 2.5 years of implementing the ongoing Supporting Access to Family Planning and Post-Abortion Care in Emergencies (SAFPAC) initiative, led by CARE, which supports government health systems to deliver family planning services in 5 crisis-affected settings (Chad, Democratic Republic of the Congo, Djibouti, Mali, and Pakistan). SAFPAC's strategy focuses on 4 broad interventions drawn from public health best practices in more stable settings: competency-based training for providers, improved supply chain management, regular supervision, and community mobilization to influence attitudes and norms related to family planning. Between July 2011 and December 2013, the initiative reached 52,616 new users of modern contraceptive methods across the 5 countries (catchment population of 698,053 women of reproductive age), 61% of whom chose long-acting methods of implants or intrauterine devices. Prudent use of data to inform decision making has been an underpinning to the project's approach. A key approach to ensuring sustained ability to train and supervise new providers has been to build capacity in clinical skills training and supervision by establishing in-country training centers. In addition, monthly supervision using simple checklists has improved program and service quality, particularly with infection prevention procedures and stock management. We have generally instituted a "pull" system to manage commodities and other supplies, whereby health facilities place resupply orders as needed based on actual consumption patterns and stock-alert thresholds. Finally, reaching the community with mobilization efforts appropriate to the cultural context has been integral to meeting unmet family planning needs rapidly in these crisis-affected settings. Despite the constraints in crisis-affected countries, such as travel difficulties due to security issues, in our experience, we have been able to extend access to a range of contraceptive methods, including long-acting reversible contraceptives, in such settings using best practice approaches established in more stable environments. PMID- 25745118 TI - Delivering high-quality family planning services in crisis-affected settings II: results. AB - An estimated 43 million women of reproductive age experienced the effects of conflict in 2012. Already vulnerable from the insecurity of the emergency, women must also face the continuing risk of unwanted pregnancy but often are unable to obtain family planning services. The ongoing Supporting Access to Family Planning and Post-Abortion Care (SAFPAC) initiative, led by CARE, has provided contraceptives, including long-acting reversible contraceptives (LARCs), to refugees, internally displaced persons, and conflict-affected resident populations in Chad, the Democratic Republic of the Congo (DRC), Djibouti, Mali, and Pakistan. The project works through the Ministry of Health in 4 key areas: (1) competency-based training, (2) supply chain management, (3) systematic supervision, and (4) community mobilization to raise awareness and shift norms related to family planning. This article presents data on program results from July 2011 to December 2013 from the 5 countries. Project staff summarized monthly data from client registers using hard-copy forms and recorded the data electronically in Microsoft Excel for compilation and analysis. The initiative reached 52,616 new users of modern contraceptive methods across the 5 countries, ranging from 575 in Djibouti to 21,191 in Chad. LARCs have predominated overall, representing 61% of new modern method users. The percentage of new users choosing LARCs varied by country: 78% in the DRC, 72% in Chad, and 51% in Mali, but only 29% in Pakistan. In Djibouti, those methods were not offered in the country through SAFPAC during the period discussed here. In Chad, the DRC, and Mali, implants have been the most popular LARC method, while in Pakistan the IUD has been more popular. Use of IUDs, however, has comprised a larger share of the method mix over time in all 4 of these countries. These results to date suggest that it is feasible to work with the public sector in fragile, crisis-affected states to deliver a wide range of quality family planning services, to do so rapidly, and to see a dramatic increase in the percentage of users choosing long acting reversible methods. PMID- 25745119 TI - Trends in the contraceptive method mix in low- and middle-income countries: analysis using a new "average deviation" measure. AB - The method mix of contraceptive use is severely unbalanced in many countries, with over half of all use provided by just 1 or 2 methods. That tends to limit the range of user options and constrains the total prevalence of use, leading to unplanned pregnancies and births or abortions. Previous analyses of method mix distortions focused on countries where a single method accounted for more than half of all use (the 50% rule). We introduce a new measure that uses the average deviation (AD) of method shares around their own mean and apply that to a secondary analysis of method mix data for 8 contraceptive methods from 666 national surveys in 123 countries. A high AD value indicates a skewed method mix while a low AD value indicates a more uniform pattern across methods; the values can range from 0 to 21.9. Most AD values ranged from 6 to 19, with an interquartile range of 8.6 to 12.2. Using the AD measure, we identified 15 countries where the method mix has evolved from a distorted one to a better balanced one, with AD values declining, on average, by 35% over time. Countries show disparate paths in method gains and losses toward a balanced mix, but 4 patterns are suggested: (1) rise of one method partially offset by changes in other methods, (2) replacement of traditional with modern methods, (3) continued but declining domination by a single method, and (4) declines in dominant methods with increases in other methods toward a balanced mix. Regions differ markedly in their method mix profiles and preferences, raising the question of whether programmatic resources are best devoted to better provision of the well-accepted methods or to deploying neglected or new ones, or to a combination of both approaches. PMID- 25745120 TI - A resource planning analysis of district hospital surgical services in the Democratic Republic of the Congo. AB - BACKGROUND: The impact of surgical conditions on global health, particularly on vulnerable populations, is gaining recognition. However, only 3.5% of the 234.2 million cases per year of major surgery are performed in countries where the world's poorest third reside, such as the Democratic Republic of the Congo (DRC). METHODS: Data on the availability of anesthesia and surgical services were gathered from 12 DRC district hospitals using the World Health Organization's (WHO's) Emergency and Essential Surgical Care Situation Analysis Tool. We complemented these data with an analysis of the costs of surgical services in a Congolese norms-based district hospital as well as in 2 of the 12 hospitals in which we conducted the situational analysis (Demba and Kabare District Hospitals). For the cost analysis, we used WHO's integrated Healthcare Technology Package tool. RESULTS: Of the 32 surgical interventions surveyed, only 2 of the 12 hospitals provided all essential services. The deficits in procedures varied from no deficits to 17 services that could not be provided, with an average of 7 essential procedures unavailable. Many of the hospitals did not have basic infrastructure such as running water and electricity; 9 of 12 had no or interrupted water and 7 of 12 had no or interrupted electricity. On average, 21% of lifesaving surgical interventions were absent from the facilities, compared with the model normative hospital. According to the normative hospital, all surgical services would cost US$2.17 per inhabitant per year, representing 33.3% of the total patient caseload but only 18.3% of the total district hospital operating budget. At Demba Hospital, the operating budget required for surgical interventions was US$0.08 per inhabitant per year, and at Kabare Hospital, US$0.69 per inhabitant per year. CONCLUSION: A significant portion of the health problems addressed at Congolese district hospitals is surgical in nature, but there is a current inability to meet this surgical need. The deficient services and substandard capacity in the surveyed district hospitals are systemic in nature, representing infrastructure, supply, equipment, and human resource constraints. Yet surgical services are affordable and represent a minor portion of the total operating budget. Greater emphasis should be made to appropriately fund district hospitals to meet the need for lifesaving surgical services. PMID- 25745121 TI - Successful proof of concept of family planning and immunization integration in Liberia. AB - Globally, unmet need for postpartum family planning remains high, while immunization services are among the most wide-reaching and equitable interventions. Given overlapping time frames, integrating these services provides an opportunity to leverage existing health visits to offer women more comprehensive services. From March through November 2012, Liberia's government, with support from the Maternal and Child Health Integrated Program (MCHIP), piloted an integrated family planning and immunization model at 10 health facilities in Bong and Lofa counties. Vaccinators provided mothers bringing infants for routine immunization with targeted family planning and immunization messages and same-day referrals to co-located family planning services. In February 2013, we compared service statistics for family planning and immunization during the pilot against the previous year's statistics. We also conducted in-depth interviews with service providers and other personnel and focus group discussions with clients. Results showed that referral acceptance across the facilities varied from 10% to 45% per month, on average. Over 80% of referral acceptors completed the family planning visit that day, of whom over 90% accepted a contraceptive method that day. The total number of new contraceptive users at participating facilities increased by 73% in Bong and by 90% in Lofa. Women referred from immunization who accepted family planning that day accounted for 44% and 34% of total new contraceptive users in Bong and Lofa, respectively. In Lofa, pilot sites administered 35% more Penta 1 and 21% more Penta 3 doses during the pilot period compared with the same period of the previous year, while Penta 1 and Penta 3 administration decreased in non-pilot facilities. In Bong, there was little difference in the number of Penta 1 and Penta 3 doses administered between pilot and non-pilot facilities. In both counties, Penta 1 to Penta 3 dropout rates increased at pilot sites but not in non-pilot facilities, possibly due to higher than average background dropout rates at pilot sites prior to the intervention in Lofa and the disproportionate effect of data from 1 large facility in Bong. The project provided considerable basic support to assess this proof of concept. However, results suggest that introducing a simple model that is minimally disruptive to existing immunization service delivery can facilitate integration. The model is currently being scaled-up to other counties in Liberia, which could potentially contribute to increased postpartum contraceptive uptake, leading to longer birth intervals and improved health outcomes for children and mothers. PMID- 25745122 TI - Predictors of workforce retention among Malawian nurse graduates of a scholarship program: a mixed-methods study. AB - BACKGROUND: Malawi faces critical health care worker shortages of both physicians and nurses. The Global AIDS Interfaith Alliance (GAIA) began a nursing scholarship program in Malawi that requires graduates to work in the public sector for 4-5 years following graduation. The main objective of this study was to identify job satisfaction and retention factors of scholarship recipients after graduation. METHODS: We conducted a mixed-methods study consisting of 30 individual qualitative interviews and 56 quantitative surveys that evaluated job satisfaction, factors associated with retention, and impact of the GAIA Nursing Scholarship Program. Participants included GAIA scholarship recipients who had graduated. We used thematic analysis to analyze qualitative interviews. Kruskal Wallis, Spearman correlation, and chi-squared tests were used to analyze survey data. RESULTS: The majority of survey and interview participants indicated it was unlikely that they would leave the public sector (70% and 90%, respectively). Most interview and survey participants cited a lack of supplies, inadequate human resources, and high workload as major challenges to their work. Poor working relationships with management or coworkers was significantly correlated with consideration of changing jobs in the next 6 months (correlation coefficient 0.28, P < .05 and -0.36, P < .01, respectively). Low salaries, high workload, poor accommodations, and a lack of appreciation were the most common reasons given for considering leaving the public sector while job security, desire to pursue further education, and public service agreement were primary motivations for continuing to work in the public system. Participants felt supported by GAIA staff and expressed a desire to serve their communities in return by working in government-supported health facilities. CONCLUSIONS: Despite the many challenges faced by public-sector nurses, low-income countries such as Malawi can employ non remuneration strategies to retain nurses in the public sector, including adequate housing, availability of supplies, advancement opportunities, and positive work environments. Scholarship programs with close follow-up of graduates may also help increase retention. PMID- 25745123 TI - Female health workers at the doorstep: a pilot of community-based maternal, newborn, and child health service delivery in northern Nigeria. AB - INTRODUCTION: Nigeria has one of the highest maternal mortality ratios in the world. Poor health outcomes are linked to weak health infrastructure, barriers to service access, and consequent low rates of service utilization. In the northern state of Jigawa, a pilot study was conducted to explore the feasibility of deploying resident female Community Health Extension Workers (CHEWs) to rural areas to provide essential maternal, newborn, and child health services. METHODS: Between February and August 2011, a quasi-experimental design compared service utilization in the pilot community of Kadawawa, which deployed female resident CHEWs to provide health post services, 24/7 emergency access, and home visits, with the control community of Kafin Baka. In addition, we analyzed data from the preceding year in Kadawawa, and also compared service utilization data in Kadawawa from 2008-2010 (before introduction of the pilot) with data from 2011 2013 (during and after the pilot) to gauge sustainability of the model. RESULTS: Following deployment of female CHEWs to Kadawawa in 2011, there was more than a 500% increase in rates of health post visits compared with 2010, from about 1.5 monthly visits per 100 population to about 8 monthly visits per 100. Health post visit rates were between 1.4 and 5.5 times higher in the intervention community than in the control community. Monthly antenatal care coverage in Kadawawa during the pilot period ranged from 11.9% to 21.3%, up from 0.9% to 5.8% in the preceding year. Coverage in Kafin Baka ranged from 0% to 3%. Facility-based deliveries by a skilled birth attendant more than doubled in Kadawawa compared with the preceding year (105 vs. 43 deliveries total, respectively). There was evidence of sustainability of these changes over the 2 subsequent years. CONCLUSION: Community-based service delivery through a resident female community health worker can increase health service utilization in rural, hard-to-reach areas. PMID- 25745124 TI - Barriers to health care in rural Mozambique: a rapid ethnographic assessment of planned mobile health clinics for ART. AB - BACKGROUND: In Mozambique, 1.6 million people are living with HIV, and over 60% of the population lives in rural areas lacking access to health services. Mobile health clinics, implemented in 2013 in 2 provinces, are beginning to offer antiretroviral therapy (ART) and basic primary care services. Prior to introduction of the mobile health clinics in the communities, we performed a rapid ethnographic assessment to understand barriers to accessing HIV care and treatment services and acceptability and potential use of the mobile health clinics as an alternative means of service delivery. METHODS: We conducted assessments in Gaza province in January 2013 and in Zambezia Province in April May 2013 in districts where mobile health clinic implementation was planned. Community leaders served as key informants, and chain-referral sampling was used to recruit participants. Interviews were conducted with community leaders, health care providers, traditional healers, national health system patients, and traditional healer patients. Interviewees were asked about barriers to health services and about mobile health clinic acceptance. RESULTS: In-depth interviews were conducted with 117 participants (Gaza province, n = 57; Zambezia Province, n = 60). Barriers to accessing health services included transportation and distance related issues (reliability, cost, and travel time). Participants reported concurrent use of traditional and national health systems. The decision to use a particular health system depended on illness type, service distance, and lack of confidence in the national health system. Overall, participants were receptive to using mobile health clinics for their health care and ability to increase access to ART. Hesitations concerning mobile health clinics included potentially long wait times due to high patient loads. Participants emphasized the importance of regular and published visit schedules and inclusion of community members in planning mobile health clinic services. CONCLUSION: Mobile health clinics can address many barriers to uptake of HIV services, particularly related to transportation issues. Involvement of community leaders, providers, traditional healers, and patients, as well as regularly scheduled mobile clinic visits, are critical to successful service delivery implementation in rural areas. PMID- 25745125 TI - Engaging communities with a simple tool to help increase immunization coverage. AB - The level of vaccination coverage in a given community depends on both service factors and the degree to which the public understands and trusts the immunization process. This article describes an approach that aims to raise awareness and boost demand. Developed in India, the "My Village Is My Home" (MVMH) tool, known as Uma Imunizasaun (UI) in Timor-Leste, is a poster-sized material used by volunteers and health workers to record the births and vaccination dates of every infant in a community. Introduction of the tool in 5 districts of India (April 2012 to March 2013) and in 7 initial villages in Timor Leste (beginning in January 2012) allowed community leaders, volunteers, and health workers to monitor the vaccination status of every young child and guided reminder and motivational visits. In 3 districts of India, we analyzed data on vaccination coverage and timeliness before and during use of the tool; in 2 other districts, analysis was based only on data for new births during use of the tool. In Timor-Leste, we compared UI data from the 3 villages with the most complete data with data for the same villages from the vaccination registers from the previous year. In both countries, we also obtained qualitative data about perceptions of the tool through interviews with health workers and community members. Assessments in both countries found evidence suggesting improved vaccination timeliness and coverage. In India, pilot communities had 80% or higher coverage of identified and eligible children for all vaccines. In comparison, overall coverage in the respective districts during the same time period was much lower, at 49% to 69%. In Timor-Leste, both the number of infants identified and immunized rose substantially with use of the tool compared with the previous year (236 vs. 155, respectively, identified as targets; 185 vs. 147, respectively, received Penta 3). Although data challenges limit firm conclusions, the experiences in both countries suggest that "My Village Is My Home" is a promising tool that has the potential to broaden program coverage by marshalling both community residents and health workers to track individual children's vaccinations. Three states in India have adopted the tool, and Timor-Leste had also planned to scale-up the initiative. PMID- 25745126 TI - Patient flow analysis in resource-limited settings: a practical tutorial and case study. PMID- 25745127 TI - Biometric fingerprint system to enable rapid and accurate identification of beneficiaries. PMID- 25745128 TI - A false dichotomy: RCTs and their contributions to evidence-based public health. PMID- 25745129 TI - Response to "A false dichotomy: RCTs and their contributions to evidence-based public health". PMID- 25745130 TI - Tightening up the nomenclature for non-physician clinicians: why not call all of them physician assistants? PMID- 25745131 TI - Classification of eating disorders: comparison of relative prevalence rates using DSM-IV and DSM-5 criteria. AB - DSM-5 contains substantial changes to eating disorder diagnoses. We examined relative prevalence rates of DSM-IV and DSM-5 eating disorder diagnoses using Eating Disorder Examination-Questionnaire diagnostic algorithms in 117 community out-patients. DSM-5 criteria produced a reduction in combined 'other specified feeding or eating disorder' and 'unspecified feeding or eating disorder' from 46% to 29%, an increase in anorexia nervosa diagnoses from 35% to 47%, the same number of bulimia nervosa diagnoses and a 5% rate of binge eating disorder diagnoses. PMID- 25745132 TI - Response to clozapine in a clinically identifiable subtype of schizophrenia. AB - BACKGROUND: Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples. AIMS: To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia. METHOD: We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group). RESULTS: Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine. CONCLUSIONS: Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia. PMID- 25745133 TI - Allelic variation in 5-HTTLPR and the effects of citalopram on the emotional neural network. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), such as citalopram, which selectively block serotonin transporter (5-HTT) activity, are widely used in the treatment of depression and anxiety disorders. Numerous neuroimaging studies have examined the effects of SSRIs on emotional processes. However, there are considerable inter-individual differences in SSRI effect, and a recent meta analysis further revealed discrepant effects of acute SSRI administration on neural responses to negative emotions in healthy adults. AIMS: We examined how a variant of the serotonin-transporter polymorphism (5-HTTLPR), which affects the expression and function of 5-HTT, influenced the acute effects of an SSRI (citalopram) on emotion-related brain activity in healthy adults. METHOD: Combining genetic neuroimaging, pharmacological technique and a psychological paradigm of emotion recognition, we scanned the short/short (s/s) and long/long (l/l) variants of 5-HTTLPR during perception of fearful, happy and neutral facial expressions after the acute administration of an SSRI (i.e. 30 mg citalopram administered orally) or placebo administration. RESULTS: We found that 5-HTTLPR modulated the acute effects of citalopram on neural responses to negative emotions. Specifically, relative to placebo, citalopram increased amygdala and insula activity in l/l but not s/s homozygotes during perception of fearful faces. Similar analyses of brain activity in response to happy faces did not show any significant effects. CONCLUSIONS: Our combined pharmacogenetic and functional imaging results provide a neurogenetic mechanism for discrepant acute effects of SSRIs. PMID- 25745135 TI - It starts with a poster. PMID- 25745137 TI - Atmospheric physics. A pristine Amazon's last stand. PMID- 25745134 TI - Modulatory effects of brain-derived neurotrophic factor Val66Met polymorphism on prefrontal regions in major depressive disorder. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to the development of depression (major depressive disorder, MDD), but it is unclear whether neural effects observed in healthy individuals are sustained in MDD. AIMS: To investigate BDNF Val66Met effects on key regions in MDD neurocircuitry: amygdala, anterior cingulate, middle frontal and orbitofrontal regions. METHOD: Magnetic resonance imaging scans were acquired in 79 persons with MDD (mean age 49 years) and 74 healthy volunteers (mean age 50 years). Effects on surface area and cortical thickness were examined with multiple comparison correction. RESULTS: People who were Met allele carriers showed reduced caudal middle frontal thickness in both study groups. Significant interaction effects were found in the anterior cingulate and rostral middle frontal regions, in which participants in the MDD group who were Met carriers showed the greatest reduction in surface area. CONCLUSIONS: Modulatory effects of the BDNF Val66Met polymorphism on distinct subregions in the prefrontal cortex in MDD support the neurotrophin model of depression. PMID- 25745138 TI - Nuclear disaster. Muons probe Fukushima's ruins. PMID- 25745139 TI - Education. Why many U.S. biology teachers are 'wishy-washy'. PMID- 25745140 TI - Infectious diseases. Doubts dispelled about HIV prevention. PMID- 25745141 TI - Drug flushes out hidden AIDS virus. PMID- 25745142 TI - Paleoanthropology. Deep roots for the genus Homo. PMID- 25745143 TI - Cleanup crew. PMID- 25745144 TI - Infectious disease. A sustainable model for antibiotics. PMID- 25745145 TI - Infectious disease. A return to the pre-antimicrobial era? PMID- 25745146 TI - Gene expression. Statistics requantitates the central dogma. PMID- 25745147 TI - Anthropology. New World monkey origins. PMID- 25745148 TI - RNA interference. Drugging RNAi. PMID- 25745149 TI - Structural biology. Viral chemokine mimicry. PMID- 25745150 TI - Physics. Single proteins under a diamond spotlight. PMID- 25745151 TI - Quantum mechanics. Look but don't touch the metals. PMID- 25745152 TI - Environmental science. Being smart about SMART environmental targets. PMID- 25745153 TI - A better way forward for Brazil's fisheries. PMID- 25745154 TI - Complex ecology of China's seawall. PMID- 25745155 TI - Complex ecology of China's seawall-response. PMID- 25745156 TI - Exoplanet detection. Comment on "Stellar activity masquerading as planets in the habitable zone of the M dwarf Gliese 581". AB - Robertson et al. (Reports, 25 July 2014, p. 440) claimed that activity-induced variability is responsible for the Doppler signal of the proposed planet candidate GJ 581d. We point out that their analysis using periodograms of residual data is inappropriate and promotes inadequate tools. Because the claim challenges the viability of the method to detect exo-Earths, we encourage reanalysis and a deliberation on what the field-standard methods should be. PMID- 25745157 TI - Exoplanet detection. Response to Comment on "Stellar activity masquerading as planets in the habitable zone of the M dwarf Gliese 581". AB - Anglada-Escude and Tuomi question the statistical rigor of our analysis while ignoring the stellar activity aspects that we present. Although we agree that improvements in multiparametric radial velocity (RV) modeling are necessary for the detection of Earth-mass planets, the key physical points we raised were not challenged. We maintain that activity on Gliese 581 induces RV shifts that were interpreted as exoplanets. PMID- 25745159 TI - To catch a wave. PMID- 25745158 TI - General relativity. Einstein's vision. Introduction. PMID- 25745160 TI - Einstein's milestones. PMID- 25745161 TI - The dark lab. PMID- 25745163 TI - Drop test. PMID- 25745162 TI - General Relativity: the comic book. PMID- 25745164 TI - The dark side of cosmology: dark matter and dark energy. AB - A simple model with only six parameters (the age of the universe, the density of atoms, the density of matter, the amplitude of the initial fluctuations, the scale dependence of this amplitude, and the epoch of first star formation) fits all of our cosmological data . Although simple, this standard model is strange. The model implies that most of the matter in our Galaxy is in the form of "dark matter," a new type of particle not yet detected in the laboratory, and most of the energy in the universe is in the form of "dark energy," energy associated with empty space. Both dark matter and dark energy require extensions to our current understanding of particle physics or point toward a breakdown of general relativity on cosmological scales. PMID- 25745165 TI - A century of general relativity: astrophysics and cosmology. AB - One hundred years after its birth, general relativity has become a highly successful physical theory in the sense that it has passed a large number of experimental and observational tests and finds extensive application to a wide variety of cosmic phenomena. It remains an active area of research as new tests are on the way, epitomized by the exciting prospect of detecting gravitational waves from merging black holes. General relativity is the essential foundation of the standard model of cosmology and underlies our description of the black holes and neutron stars that are ultimately responsible for the most powerful and dramatic cosmic sources. Its interface with physics on the smallest and largest scales will continue to provide fertile areas of investigation in its next century. PMID- 25745166 TI - Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor. AB - Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor's inactive state. PMID- 25745167 TI - Astrophysics. Multiple images of a highly magnified supernova formed by an early type cluster galaxy lens. AB - In 1964, Refsdal hypothesized that a supernova whose light traversed multiple paths around a strong gravitational lens could be used to measure the rate of cosmic expansion. We report the discovery of such a system. In Hubble Space Telescope imaging, we have found four images of a single supernova forming an Einstein cross configuration around a redshift z = 0.54 elliptical galaxy in the MACS J1149.6+2223 cluster. The cluster's gravitational potential also creates multiple images of the z = 1.49 spiral supernova host galaxy, and a future appearance of the supernova elsewhere in the cluster field is expected. The magnifications and staggered arrivals of the supernova images probe the cosmic expansion rate, as well as the distribution of matter in the galaxy and cluster lenses. PMID- 25745168 TI - Stellar dynamics. The fastest unbound star in our Galaxy ejected by a thermonuclear supernova. AB - Hypervelocity stars (HVSs) travel with velocities so high that they exceed the escape velocity of the Galaxy. Several acceleration mechanisms have been discussed. Only one HVS (US 708, HVS 2) is a compact helium star. Here we present a spectroscopic and kinematic analysis of US 708. Traveling with a velocity of ~1200 kilometers per second, it is the fastest unbound star in our Galaxy. In reconstructing its trajectory, the Galactic center becomes very unlikely as an origin, which is hardly consistent with the most favored ejection mechanism for the other HVSs. Furthermore, we detected that US 708 is a fast rotator. According to our binary evolution model, it was spun-up by tidal interaction in a close binary and is likely to be the ejected donor remnant of a thermonuclear supernova. PMID- 25745169 TI - Repellent materials. Robust self-cleaning surfaces that function when exposed to either air or oil. AB - Superhydrophobic self-cleaning surfaces are based on the surface micro/nanomorphologies; however, such surfaces are mechanically weak and stop functioning when exposed to oil. We have created an ethanolic suspension of perfluorosilane-coated titanium dioxide nanoparticles that forms a paint that can be sprayed, dipped, or extruded onto both hard and soft materials to create a self-cleaning surface that functions even upon emersion in oil. Commercial adhesives were used to bond the paint to various substrates and promote robustness. These surfaces maintained their water repellency after finger-wipe, knife-scratch, and even 40 abrasion cycles with sandpaper. The formulations developed can be used on clothes, paper, glass, and steel for a myriad of self cleaning applications. PMID- 25745170 TI - Protein imaging. Single-protein spin resonance spectroscopy under ambient conditions. AB - Magnetic resonance is essential in revealing the structure and dynamics of biomolecules. However, measuring the magnetic resonance spectrum of single biomolecules has remained an elusive goal. We demonstrate the detection of the electron spin resonance signal from a single spin-labeled protein under ambient conditions. As a sensor, we use a single nitrogen vacancy center in bulk diamond in close proximity to the protein. We measure the orientation of the spin label at the protein and detect the impact of protein motion on the spin label dynamics. In addition, we coherently drive the spin at the protein, which is a prerequisite for studies involving polarization of nuclear spins of the protein or detailed structure analysis of the protein itself. PMID- 25745171 TI - Freshwater ecology. Experimental nutrient additions accelerate terrestrial carbon loss from stream ecosystems. AB - Nutrient pollution of freshwater ecosystems results in predictable increases in carbon (C) sequestration by algae. Tests of nutrient enrichment on the fates of terrestrial organic C, which supports riverine food webs and is a source of CO2, are lacking. Using whole-stream nitrogen (N) and phosphorus (P) additions spanning the equivalent of 27 years, we found that average terrestrial organic C residence time was reduced by ~50% as compared to reference conditions as a result of nutrient pollution. Annual inputs of terrestrial organic C were rapidly depleted via release of detrital food webs from N and P co-limitation. This magnitude of terrestrial C loss can potentially exceed predicted algal C gains with nutrient enrichment across large parts of river networks, diminishing associated ecosystem services. PMID- 25745172 TI - Political economy. On the endogeneity of political preferences: evidence from individual experience with democracy. AB - Democracies depend on the support of the general population, but little is known about the determinants of this support. We investigated whether support for democracy increases with the length of time spent under the system and whether preferences are thus affected by the political system. Relying on 380,000 individual-level observations from 104 countries over the years 1994 to 2013, and exploiting individual-level variation within a country and a given year in the length of time spent under democracy, we find evidence that political preferences are endogenous. For new democracies, our findings imply that popular support needs time to develop. For example, the effect of around 8.5 more years of democratic experience corresponds to the difference in support for democracy between primary and secondary education. PMID- 25745173 TI - Nuclear pores. Architecture of the nuclear pore complex coat. AB - The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. Despite half a century of structural characterization, the architecture of the NPC remains unknown. Here we present the crystal structure of a reconstituted ~400-kilodalton coat nucleoporin complex (CNC) from Saccharomyces cerevisiae at a 7.4 angstrom resolution. The crystal structure revealed a curved Y-shaped architecture and the molecular details of the coat nucleoporin interactions forming the central "triskelion" of the Y. A structural comparison of the yeast CNC with an electron microscopy reconstruction of its human counterpart suggested the evolutionary conservation of the elucidated architecture. Moreover, 32 copies of the CNC crystal structure docked readily into a cryoelectron tomographic reconstruction of the fully assembled human NPC, thereby accounting for ~16 megadalton of its mass. PMID- 25745174 TI - Protein targeting. Structure of the Get3 targeting factor in complex with its membrane protein cargo. AB - Tail-anchored (TA) proteins are a physiologically important class of membrane proteins targeted to the endoplasmic reticulum by the conserved guided-entry of TA proteins (GET) pathway. During transit, their hydrophobic transmembrane domains (TMDs) are chaperoned by the cytosolic targeting factor Get3, but the molecular nature of the functional Get3-TA protein targeting complex remains unknown. We reconstituted the physiologic assembly pathway for a functional targeting complex and showed that it comprises a TA protein bound to a Get3 homodimer. Crystal structures of Get3 bound to different TA proteins showed an alpha-helical TMD occupying a hydrophobic groove that spans the Get3 homodimer. Our data elucidate the mechanism of TA protein recognition and shielding by Get3 and suggest general principles of hydrophobic domain chaperoning by cellular targeting factors. PMID- 25745175 TI - Evolutionary genomics. Evolutionary changes in promoter and enhancer activity during human corticogenesis. AB - Human higher cognition is attributed to the evolutionary expansion and elaboration of the human cerebral cortex. However, the genetic mechanisms contributing to these developmental changes are poorly understood. We used comparative epigenetic profiling of human, rhesus macaque, and mouse corticogenesis to identify promoters and enhancers that have gained activity in humans. These gains are significantly enriched in modules of coexpressed genes in the cortex that function in neuronal proliferation, migration, and cortical-map organization. Gain-enriched modules also showed correlated gene expression patterns and similar transcription factor binding site enrichments in promoters and enhancers, suggesting that they are connected by common regulatory mechanisms. Our results reveal coordinated patterns of potential regulatory changes associated with conserved developmental processes during corticogenesis, providing insight into human cortical evolution. PMID- 25745176 TI - Oh the humanities! PMID- 25745178 TI - A natural choice for hemophilia B. AB - In this issue of Blood, Crudele et al describe a novel study of adeno-associated virus (AAV) vector-mediated gene therapy that induced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX inhibitor antibodies (IAs). PMID- 25745179 TI - Multilevel BCR signals toward CLL. AB - In this issue of Blood, Iacovelli et al provide the first in vivo experimental evidence on the proleukemogenic relevance of autonomous (exo-antigen-independent) B-cell receptor (BCR) stimulation in conjunction with ligand (autoantigen)- mediated BCR signaling in chronic lymphocytic leukemia (CLL). PMID- 25745177 TI - Immunogenetics. Dynamic profiling of the protein life cycle in response to pathogens. AB - Protein expression is regulated by the production and degradation of messenger RNAs (mRNAs) and proteins, but their specific relationships remain unknown. We combine measurements of protein production and degradation and mRNA dynamics so as to build a quantitative genomic model of the differential regulation of gene expression in lipopolysaccharide-stimulated mouse dendritic cells. Changes in mRNA abundance play a dominant role in determining most dynamic fold changes in protein levels. Conversely, the preexisting proteome of proteins performing basic cellular functions is remodeled primarily through changes in protein production or degradation, accounting for more than half of the absolute change in protein molecules in the cell. Thus, the proteome is regulated by transcriptional induction for newly activated cellular functions and by protein life-cycle changes for remodeling of preexisting functions. PMID- 25745180 TI - HIV-1 Nef drives macrophages into hiding. AB - In this issue of Blood, Verollet et al show that expression of the HIV-1-derived protein Nef alters the migratory mode adopted by macrophages, enhancing macrophage tissue infiltration and explaining the observed accumulation of tissue resident macrophages in some HIV-infected patients. PMID- 25745181 TI - ITP and TTP: interpreting evidence in light of patient values. AB - In this issue of Blood, data presented by Zhou et al and Lim et al on the use of rituximab (RTX) to treat immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP), respectively, illuminate the importance of considering patient values and preferences in the interpretation of clinical evidence. PMID- 25745182 TI - Defective platelet autocrine signaling in HPS. AB - In this issue of Blood, Meng et al and Sharda et al use the Hermansky-Pudlak syndrome (HPS) as a model to show that adenosine 5'-diphosphate (ADP) released by dense granules serves as an autocrine signal to potentiate platelet release of alpha-granule and lysosome cargo and protein disulfide isomerase (PDI), all of which serve to stabilize thrombus formation. PMID- 25745183 TI - Anemia and ischemia: how low can you go? AB - In this issue of Blood, Bernaudin et al have identified the rate of acute anemic events (AAEs) and extracranial internal carotid artery (ICA) stenosis as risk factors for silent cerebral infarcts (SCIs) in children with sickle cell anemia (SCA). PMID- 25745184 TI - Early HSCT corrects the skeleton in MPS. AB - In this issue of Blood, Pievani et al have identified a potential solution to the remaining barrier to the success of hematopoietic stem cell transplantation (HSCT) in children with severe phenotype Hurler syndrome (mucopolysaccharidosis type I [MPS I]). PMID- 25745185 TI - Response: Additional data needed for a better understanding of the potential relationship between atrial fibrillation and ibrutinib. PMID- 25745186 TI - Hypomorphic mutation in TTC7A causes combined immunodeficiency with mild structural intestinal defects. PMID- 25745187 TI - The efficacy of ibrutinib in the treatment of Richter syndrome. PMID- 25745189 TI - An analysis of the thromboembolic outcomes of 2472 splenectomized individuals. PMID- 25745188 TI - The JAK-STAT signaling pathway is differentially activated in CALR-positive compared with JAK2V617F-positive ET patients. PMID- 25745190 TI - The advantage of objects over images in discrimination and reversal learning by kea, Nestor notabilis. AB - Studies investigating the same paradigm but employing different methods are often directly compared in the literature. One such paradigm used to assess behavioural flexibility in animals is reversal learning. Commonly, these studies require individuals to learn the reward contingency of either solid objects presented on the ground or images presented on a touchscreen. Once learned, these contingencies are swapped. Researchers often refer to trials required to reach learning criteria from different studies, to compare the flexibility of different species, but rarely take methodological differences into account. A direct evaluation of the validity of such comparisons is lacking. To address this latent question, we confronted kea, an alpine parrot species of New Zealand and known for its behavioural flexibility, with a standard reversal learning paradigm on the touchscreen and a standard reversal learning paradigm with solid objects. The kea required significantly more trials to reach criterion in the acquisition and the reversal on the touchscreen. Also, the absolute increase in the number of trials required for the reversal was significantly greater on the touchscreen. This indicates that it is not valid to compare learning speed across studies that do not correspond in the addressed methodology. Taking into account the kea's ecology and explorative nature we discuss stimulus abstraction (limited depth cues and tactile stimulus feedback) and the spatial relation between reward and stimulus on the touchscreen as possible causes for decreased inhibition in this condition. Contrary to the absolute increase in number of trials required for the reversal, the increase in relation to the acquisition was greater with solid objects. This highlights the need for further research on the mechanisms involved causing methodology-dependent differences, some of which we discuss, in order to increase the validity of interpretations across studies and in respect to the subject's ecology. PMID- 25745191 TI - Innovations in air sampling to detect plant pathogens. AB - Many innovations in the development and use of air sampling devices have occurred in plant pathology since the first description of the Hirst spore trap. These include improvements in capture efficiency at relatively high air-volume collection rates, methods to enhance the ease of sample processing with downstream diagnostic methods and even full automation of sampling, diagnosis and wireless reporting of results. Other innovations have been to mount air samplers on mobile platforms such as UAVs and ground vehicles to allow sampling at different altitudes and locations in a short space of time to identify potential sources and population structure. Geographical Information Systems and the application to a network of samplers can allow a greater prediction of airborne inoculum and dispersal dynamics. This field of technology is now developing quickly as novel diagnostic methods allow increasingly rapid and accurate quantifications of airborne species and genetic traits. Sampling and interpretation of results, particularly action-thresholds, is improved by understanding components of air dispersal and dilution processes and can add greater precision in the application of crop protection products as part of integrated pest and disease management decisions. The applications of air samplers are likely to increase, with much greater adoption by growers or industry support workers to aid in crop protection decisions. The same devices are likely to improve information available for detection of allergens causing hay fever and asthma or provide valuable metadata for regional plant disease dynamics. PMID- 25745192 TI - Livelihood Diversification through Migration among a Pastoral People: Contrasting Case Studies of Maasai in Northern Tanzania. AB - This paper brings together over two decades of research concerning the patterns and processes of livelihood diversification through migration among Maasai pastoralists and agro-pastoralists of northern Tanzania. Two case studies, one from the Ngorongoro Conservation Area and the other from the Simanjiro plains, jointly demonstrate the complexity of migration within a single ethnic group. We analyze the relationship between wealth and migration and examine some of the consequences of migration for building herds, expanding cultivation, and influencing political leadership. We further argue that migration in Maasai communities is becoming a cultural norm and not only a response to economic conditions. PMID- 25745193 TI - Preliminary investigations of toxicity in the Georges Bay catchment, Tasmania, Australia. AB - North-eastern Tasmania, Australia has been an area of major production for Pacific oysters (Crassostrea gigas) for over 25 years. Since the mid-1990s, increased oyster mortality has been observed. The purpose of the present study was to identify the agent causing aquatic toxicity and to investigate whether there is a chemical and/or toxicological link between river foam and monoculture timber plantation forests of exotic eucalypts (Eucalyptus nitens) present in the catchment area. Foam samples from the George River catchment demonstrated high toxicity to a freshwater cladoceran and larvae of a marine blue mussel species. After filtration to remove most particulates, foam samples also demonstrated a marked reduction in toxicity to blue mussels, which suggested that the toxicity is particle associated. Foam and leaf extracts of E. nitens were then fractionated using HPLC and size exclusion chromatography and the resulting fractions were screened for cladoceran and blue mussel toxicity. Toxicity was detected in fractions common to both the foam and the leaf extracts. This study suggests that there may be a chemical and toxicological relationship between foam and E. nitens leaf components. PMID- 25745194 TI - Botanicals as eco friendly biorational alternatives of synthetic pesticides against Callosobruchus spp. (Coleoptera: Bruchidae)-a review. AB - The article presents the potential of botanicals in the management of Callosobruchus spp., the primary insect pest causing deterioration to a variety of stored legume grains. Different botanical formulations have been reported time to time showing pronounced insecticidal activity, repellence to pest, oviposition deterrency, adult emergence inhibition, ovicidal, larvicidal, pupaecidal activity and feeding deterrency based on their contact toxicity and fumigation effects. Some of the botanicals have also been practically proved efficacious to protect the stored food commodities from the bruchids during storage conditions. Such botanical formulations have shown their promise in integrated management of the pest as semiochemicals by showing behaviour altering efficacy against the bruchids, thereby, reducing the induced pest resistance problem which is frequently reported with synthetic pesticides. Hence, they may be recommended in food security programmes as eco-friendly and biorational alternatives of synthetic pesticides providing integrated management of the losses of stored food commodities due to infestation of bruchids. PMID- 25745196 TI - Application and stability of natural antioxidants in edible oils in order to substitute synthetic additives. AB - Antioxidants are components which prevent auto-oxidation of oils and fats by giving their hydrogen to free radicals formed in the initiation and propagation stages of autoxidation. During the past two decades, a lot of researches using natural plants extract in edible oils have been carried out due to the trend to minimize or avoid the use of synthetic food additives. According to the most studies, there are various natural antioxidants which can be extracted from low cost resources, such as most parts of olive plant, green tea, sesame, medicinal plants, etc. One of the most important requirements for a suitable antioxidant in oils and fats is the thermal stability during heat processing. It has been shown that most of natural additives have more antioxidants activity and thermal stability than synthetic ones in different edible oils. In this review, recent advances in the application of natural antioxidants in the food industry will be covered. PMID- 25745195 TI - Red pepper (Capsicum annuum) carotenoids as a source of natural food colors: analysis and stability-a review. AB - Carotenoids are increasingly drawing the attention of researchers as a major natural food color due to their inherent nutritional characteristics and the implicated possible role in prevention and protection against degenerative diseases. In this report, we review the role of red pepper as a source for natural carotenoids. The composition of the carotenoids in red pepper and the application of different methodologies for their analysis were discussed in this report. The stability of red pepper carotenoids during post-harvest processing and storage is also reviewed. This review highlights the potential of red pepper carotenoids as a source of natural food colors and also discusses the need for a standardized approach for the analysis and reporting of composition of carotenoids in plant products and designing model systems for stability studies. PMID- 25745197 TI - Processing and storage of restructured surimi stew product in retortable pouches. AB - Restructured surimi gel product was prepared using short nosed white tripod (Triacanthus brevirosterus) with egg white as additive at 1 %. Heat setting was done initially at 45 degrees C for 30 min followed by heat processing 90 degrees C for 45 min. Restructured surimi gel in stew was standardized using four most popular recipes available in local cuisine based on the sensory acceptance and the Kerala fish stew was considered best. Restructured surimi gel in Kerala fish stew was then heat processed in 4 ply laminated retort pouch of dimension 150* 200 mm, at 15 psi gauge pressure for varying time duration and the Fo values ranged from 13.10 to 22.58 min. Products examined of their organoleptic and microbial qualities showed those processed with Fo value of 13.10 min was acceptable with excellent eating quality with no fishy flavour and was microbial sterile until the storage period of 6 months. PMID- 25745199 TI - The effect of process parameters and microstructural changes on a new convenience food - quick-frozen paste-coated mushrooms (Agaricus bisporus). AB - The technology of quick-freezing paste-coated mushrooms (Agaricus bisporus) was studied and optimized. The best microwave pretreatment condition for 1 cm slices, regarding color protection, was 5.4 W/g, for 55, 55-60 and 60 s for mushrooms with 3, 4 and 5 cm diameter caps respectively. For a batch of paste (668.2-1034.6 g), the process parameters considered were oil content (46.6-63.4 g), water content (381-562.6 g) and flour content (166-334 g) with a constant additional content of 30 g starch, 9 g baking powder, 2.6 g carrageenan, 30 g salt and 3 g pepper. These parameters were investigated using response surface methodology (RSM) with a central composite design. The optimal levels of the major paste components were 300 g flour, 432.5 g water and 50 g oil. The freezing time and sensory acceptability for paste-coated Agaricus bisporus(PCAB) under the optimized conditions were 7.49 min and 6.2 respectively. The freezing curves of PCAB were established at different temperatures and the freezing rates were calculated to find the freezing characteristics. In addition, the cell structure of PCAB, frozen at -75 degrees C, the lowest freezing temperature, and studied using transmission electron microscopy, was similar in quality to that of fresh Agaricus bisporus. The results suggested that Agaricus bisporus can be quick frozen with a paste coating to produce an acceptable and nutritious convenience food. PMID- 25745198 TI - Development of chicken meat caruncles on the basis of sensory attributes: process optimization using response surface methodology. AB - A three factor Box-Behnken design of response surface methodology was employed to optimize spent hen meat level (600-700 g kg(-1)), oil level (25-75 g kg(-1)) and cooking time (3-5 min) for development of ready-to-eat chicken meat caruncles on the basis of sensory attributes - colour/appearance, flavour, crispiness, after taste, meat flavour intensity and overall acceptability. The analysis of variance showed that meat and cooking time interaction showed significant effect (p < 0.01; p < 0.05; p < 0.1) on colour/appearance and crispiness of chicken meat caruncles. Quadratically meat level showed significantly higher effect (p < 0.01; p < 0.05; p < 0.1) on crispiness; and oil level and cooking time (p < 0.05; p < 0.1) on after-taste of chicken meat caruncles. Linearly meat level showed significantly higher (p < 0.05; p < 0.1) effect on colour/appearance, after taste, meat flavour intensity and overall acceptability of chicken meat caruncles. The optimized conditions were: 650 g kg(-1) meat level, 50 g kg(-1) oil level and cooking time as 4 min. Among all sensory parameters, crispiness is one of the most important sensory parameters for meat snacks, which was highest (6.68) at the optimized conditions in the final product. The other sensory parameters ranged from 6.33 to 6.68 on an eight point scale. Box-Behnken design of RSM performed well in the optimization process of development of chicken meat caruncles to produce product with very high degree of acceptability. 650 g kg(-1) of spent hen meat level produced the most acceptable product in terms of sensory profile. PMID- 25745200 TI - Assessment of banana fruit maturity by image processing technique. AB - Maturity stage of fresh banana fruit is an important factor that affects the fruit quality during ripening and marketability after ripening. The ability to identify maturity of fresh banana fruit will be a great support for farmers to optimize harvesting phase which helps to avoid harvesting either under-matured or over-matured banana. This study attempted to use image processing technique to detect the maturity stage of fresh banana fruit by its color and size value of their images precisely. A total of 120 images comprising 40 images from each stage such as under-mature, mature and over-mature were used for developing algorithm and accuracy prediction. The mean color intensity from histogram; area, perimeter, major axis length and minor axis length from the size values, were extracted from the calibration images. Analysis of variance between each maturity stage on these features indicated that the mean color intensity and area features were more significant in predicting the maturity of banana fruit. Hence, two classifier algorithms namely, mean color intensity algorithm and area algorithm were developed and their accuracy on maturity detection was assessed. The mean color intensity algorithm showed 99.1 % accuracy in classifying the banana fruit maturity. The area algorithm classified the under-mature fruit at 85 % accuracy. Hence the maturity assessment technique proposed in this paper could be used commercially to develop a field based complete automatic detection system to take decision on the right time of harvest by the banana growers. PMID- 25745201 TI - Kinetic modeling, production and characterization of an acidic lipase produced by Enterococcus durans NCIM5427 from fish waste. AB - Enterococcus durans NCIM5427 (ED-27), capable of producing an intracellular acid stable lipase, was isolated from fish processing waste. Its growth and subsequent lipase production was optimized by Box Behneken design (optimized conditions: 5 % v/v fish waste oil (FWO), 0.10 mg/ml fish waste protein hydrolysates (FWPH) at 48 h of fermentation time). Under optimized conditions, ED-27 showed a 3.0 fold increase (207.6 U/ml to 612.53 U/ml) in lipase production, as compared to un optimized conditions. Cell growth and lipase production was modeled using Logistic and Luedeking-Piret model, respectively; and lipase production by ED-27 was found to be growth-associated. Lipase produced by ED-27 showed stability at low pH ranges from 2 to 5 with its optimal activity at 30 degrees C , pH 4.6; showed metal ion dependent activity wherein its catalytic activity was activated by barium, sodium, lithium and potassium (10 mM); reduced by calcium and magnesium (10 mM). However, iron and mercury (5 mM) completely inactivated the enzyme. In addition, modifying agents like SDS, DTT, beta-ME (1%v/v) increased activity of lipase of ED-27; while, PMSF, DEPC and ascorbic acid resulted in a marked decrease. ED-27 had maximum cell growth of 9.90309 log CFU/ml under optimized conditions as compared to 13 log CFU/ml in MRS. The lipase produced has potential application in poultry and slaughterhouse waste management. PMID- 25745203 TI - Steeping preservation of cauliflower with hurdle concept. AB - Cauliflower is a rich source of proteins, carbohydrates, vitamins and minerals and also a very important vegetable having maximum availability in tropical climate from November to February which causes glut in the market and consequently producers do not get remunerative prices. The partially blanched cauliflower pieces of 3-4 cm long having stalk upto 2 cm in length are steeped in different levels of sodium chloride (NaCl, 2-6 %) and acetic acid (1-2 %) along with 350 ppm sulphur dioxide (SO2) using modified response surface methodology (RSM). The cauliflower samples steeped in 4 % NaCl, 1 % acetic acid and 350 ppm SO2 were rated best with maximum mean overall acceptability (OAA) score (6.90) and minimum mean preference (6.25) to the experimental run consisting of 6 % NaCl, 2 % acetic acid and 350 ppm SO2 was noted after 120 days of storage. There has been sharp decrease in pH values after 15 days of storage in all the experimental run of preserved cauliflower samples. The maximum mean decrease in hardness values (15.20-0.55 g.cm) was obtained in steeped cauliflower samples consisting of 6 % NaCl, 2 % acetic acid and 350 ppm SO2 during storage for 120 days at room temperature. The decrease in extent of browning, ascorbic acid and total carotenoids content in cauliflower samples was reported in all the experimental runs during 120 days of storage at room temperature. The optimum concentration for maximum desirability in the preservation of cauliflower consisted of 3.5 % sodium chloride and 1.1 % acetic acid and 350 ppm SO2. PMID- 25745202 TI - Preliminary nutritional and biological potential of Artocarpus heterophyllus L. shell powder. AB - Artocarpus heterophyllus shell powder was investigated in terms of its nutritional and biological potential. A thorough examination of shell powder demonstrated its potential as a source of minerals, beta carotene and dietary fiber, which were assessed gravimetrically & spectrophotometrically. This showed 3.05 +/- 0.19 g 100 g(-1) DW of alkaloids followed by saponins and tannins. Three different extracts; acetone, methanol, & mix solvent were used to evaluate phenolic & flavonoid content, antioxidant & antimicrobial activity, GC/MS screening and quantitative analysis of polyphenols. Among all, the methanol extract showed highest antioxidant activity evaluated by DPPH, FRAP & ABTS assays and was significantly correlated with phenolic and flavonoid contents. Phenolic & flavonoid content was found to be 158 +/- 0.34 mg (GAE) and 10.0 +/- 0.64 mg (CE) respectively. The results of antimicrobial activity showed that L. monocytogenes was more susceptible to all extracts followed by other microorganisms. Catechin, ascorbic & chlorogenic acids were identified as major polyphenols analyzed by LC MS/MS. GC/MS analysis showed that it contains a variety of compounds with different therapeutic activities. The study revealed that A. heterophyllus shell is a good source of natural antioxidants & other bioactive compounds and can be used in cosmetics, medicines and functional food application. PMID- 25745204 TI - Influence of hydrothermal processing on functional properties and grain morphology of finger millet. AB - Finger millet was hydrothermally processed followed by decortication. Changes in color, diameter, density, sphericity, thermal and textural characteristics and also some of the functional properties of the millet along with the grain morphology of the kernels after hydrothermal processing and decortication were studied. It was observed that, the millet turned dark after hydrothermal processing and color improved over native millet after decortication. A slight decrease in grain diameter was observed but sphericity of the grains increased on decortication. The soft and fragile endosperm turned into a hard texture and grain hardness increased by about 6 fold. Hydrothermal processing increased solubility and swelling power of the millet at ambient temperature. Pasting profile indicated that, peak viscosity decreased significantly on hydrothermal processing and both hydrothermally processed and decorticated millet exhibited zero breakdown viscosity. Enthalpy was negative for hydrothermally processed millet and positive for decorticated grains. Microscopic studies revealed that the orderly structure of endosperm changed to a coherent mass after hydrothermal processing and the different layers of seed coat get fused with the endosperm. PMID- 25745205 TI - Effects of storage time on compositional, micro-structural, rheological and sensory properties of low fat Iranian UF-Feta cheese fortified with fish oil or fish oil powder. AB - The fish oil (FO), and fish oil powder (FOP) at 10 % of recommended daily intake (RDI) were used to make two types of fortified feta cheeses. The physicochemical, rheological and sensory properties of ripened samples at 0, 30, and 60th days of cold store (5 degrees C) showed that the FO samples had a faster pH reduction, higher MSNF (milk solid non-fat) increase (p < 0.05) and more pores formation. Storage (G') and loss (G") moduli for both samples decreased until the 30th day of cold storage and then increased until the end of the storage time but both of them were higher for FOP samples. The index of secondary lipid oxidation or thiobarbituric acid reactive substances (TBARS) of FO was lower than FOP samples. Although the polyunsaturated fatty acids of both samples were much higher than common feta cheese, their degradation in FO was less than FOP samples after storage. The sensory scores of FO were significantly higher than FOP sample (P < 0.05), and it obtained up to 70 % of overall acceptability after 30 and 60 days storage for its better hardness, texture and flavor. PMID- 25745206 TI - Investigation into solar drying of potato: effect of sample geometry on drying kinetics and CO2 emissions mitigation. AB - Drying experiments have been performed with potato cylinders and slices using a laboratory scale designed natural convection mixed-mode solar dryer. The drying data were fitted to eight different mathematical models to predict the drying kinetics, and the validity of these models were evaluated statistically through coefficient of determination (R(2)), root mean square error (RMSE) and reduced chi-square (chi (2)). The present investigation showed that amongst all the mathematical models studied, the Modified Page model was in good agreement with the experimental drying data for both potato cylinders and slices. A mathematical framework has been proposed to estimate the performance of the food dryer in terms of net CO2 emissions mitigation potential along with unit cost of CO2 mitigation arising because of replacement of different fossil fuels by renewable solar energy. For each fossil fuel replaced, the gross annual amount of CO2 as well as net amount of annual CO2 emissions mitigation potential considering CO2 emissions embodied in the manufacture of mixed-mode solar dryer has been estimated. The CO2 mitigation potential and amount of fossil fuels saved while drying potato samples were found to be the maximum for coal followed by light diesel oil and natural gas. It was inferred from the present study that by the year 2020, 23 % of CO2 emissions can be mitigated by the use of mixed-mode solar dryer for drying of agricultural products. PMID- 25745207 TI - Optimization of a process for high fibre and high protein biscuit. AB - Biscuits are popular and convenient food products due to their ready to eat nature. Biscuits were prepared from sorghum and whole wheat flour with the addition of spirulina (Spirulina platensis) powder to produce high fibre and high protein biscuit. Levels of ingredients in biscuits such as spirulina powder, sorghum flour and guar gum were optimized using response surface methodology (RSM) for its sensory, textural and antioxidant attributes. Sensory attributes as colour intensity (R2 = 0.89, P < 0.0001), flavor (R2 = 0.98, P < 0.0001), sweetness (R2 = 0.97, P < 0.0001), graininess (R2 = 0.99, P < 0.0001), and crispiness (R2 = 0.94, P < 0.0001), textural attributes as hardness (R2 = 0.95, P < 0.0001) and fracturability (R2 = 0.96, P < 0.0001), antioxidant activity as DPPH inhibition (R2 = 0.87, P < 0.0001) and antioxidant activity as ABTS inhibition (R2 = 0.98, P < 0.0001) were significantly related to processing parameters of biscuit. Rheological characteristics (TPA and extensograph) of biscuit dough were measured. Studies indicated that amongst all the processing parameters, the composition of spirulina powder and sorghum flour was found to have significant effect on the responses. PMID- 25745208 TI - A study on noodle dough rheology and product quality characteristics of fresh and dried noodles as influenced by low glycemic index ingredient. AB - Low Glycemic Index (LGI) foods help to maintain blood glucose level in diabetic individuals. Pea flour (PF) is known to be one of LGI ingredients used in the food industry. To assess the influence of PF in noodle processing, thermally processed pea flour was incorporated at 20 % and 40 % in the preparation of noodles using Lab scale Noodle Making Machine. Evaluation for Physico-chemical, rheological and noodle making characteristics, in vitro starch digestibility (IVSD) and microstructure of noodles were carried out. Cooking quality did not show any significant difference among the samples, with solid leach out ranging from 6.7 to 7.2 % against control (6.5 %). Colour measurement showed the presence of greenish colour in PF incorporated samples. Texture was firmer in fresh noodles (FN) (5.52 Newton (N), 6.00 N) and dried noodles (DN) (7.60 N, 7.86 N) compared to control (4.38 N-FN, 6.88 N-DN). Sensory analysis of noodles revealed that the samples (FN, DN) were acceptable at 20 % and 40 % levels with overall quality score (>8.5). In vitro analysis revealed that with increase in PF content there was a significant decrease in the availability of glucose in DN followed by FN compared to control. Overall RDS was reduced and SDS was increased in 40 % PF incorporated FN. Scanning-electron microscopy revealed the presence of fiber matrix around the starch granules. PMID- 25745209 TI - Characterization of Indian beers: chemical composition and antioxidant potential. AB - Chemical composition, antioxidant potential and corresponding lipid preoxidation of Indian commercial beers were evaluated. The presence of polyphenolic compounds such as tannic acid, gallic acid, catechol, vanillin, caffeic acid, quercetin, p coumaric acid and rutin was quantified using LC-MS while the organic acids including tartaric, malic, acetic, citric and succinic acids were analysed using HPLC. Beer sample B8 had the greatest concentration of phenolic and flavonoid components (0.620 +/- 0.084 mg/mL and 0.379 +/- 0.020 mg/mL respectively) among the beer samples studied. The DPPH radical scavenging activity was observed in the range of 68.34 +/- 0.85 % to 89.90 +/- 0.71 % and ABTS radical cation scavenging activity was in the range of 59.75 +/- 0.20 % to 76.22 +/- 0.50 %. Percent protection in lipid peroxidation was quantified to be maximum (54.45 +/- 3.39 %) in sample B5. Total phenolic content positively correlates with antioxidant assays, DPPH and ABTS (r = 0.35 and r = 0.58 respectively) with p < 0.001 and also with lipid peroxidation (r = 0.04) with p < 0.001. Negative correlation was observed between total flavonoid content with ABTS and lipid peroxidation (r = -0.1 and r = -0.05) respectively. The process of brewing warrants additional research to determine how the concentration of selected phenolic compounds can be increased. PMID- 25745210 TI - Microbiological and shelf life characteristics of eviscerated and vacuum packed freshwater catfish (Ompok pabda) during chill storage. AB - The effect of vacuum packaging technique on the shelflife of eviscerated pabda catfish (Ompok pabda) during chill storage at 4 +/- 2 degrees C was studied. The shelflife of pabda fish was predicted based on the cumulative observations of biochemical, microbiological and sensory parameters. There was no significant difference in the lipid quality parameters studied between the samples during the chill storage period, whereas, vacuum packaging significantly improved the sensory and microbiological quality. Based on microbiological parameters such as Total Viable Count, Enterobacteriaceae, Escherichia coli, Salmonella Spp, total Vibrios, Listeria monocytogenes, Staphylococcus aureus, faecal Streptococcus and anaerobic sulphite reducers, the shelflife of chilled gutted pabda catfish was estimated to be 14-16 and 18-20 days for air packed and vacuum packed samples, respectively. The sensory parameters showed extended shelflife by four more days for both the samples. PMID- 25745211 TI - Protective effect of Monascus fermented rice against STZ-induced diabetic oxidative stress in kidney of rats. AB - In the present study, anti-diabetic activity and nephroprotective effect of MMFR was evaluated by using STZ-induced diabetic rats. Administration of MMFR at 100 and 200 mg/kg bw showed significant (P < 0.01) anti-hyperglycemic activity by lowering blood glucose level, HbA1C and increasing body weight. Altered lipid profiles in diabetic rats were restored to normal level on treatment with MMFR and showed significant (P < 0.01) decrease in the elevated levels of biochemical parameters. MMFR produced significant (P < 0.01) improvement in antioxidant levels in kidney. Food safety of MFR produced by using mutant Monascus purpureus 254 (MMFR) was evaluated for genotoxicity and oral acute toxicity. In Ames mutagenicity assay MMFR doesn't showed any toxicity to the test strain S. typhimurium till 5 mg/plate. Acute toxicity study also recorded no toxicity till the dose of 5,000 mg/kg bw. The study concluded that MMFR, not only possess anti diabetic activity but also prevents nephropathy and hypercholesterolemia due to diabetes. PMID- 25745212 TI - Effect of frying on the rheological and chemical properties of palm oil and its blends. AB - The aim of this research was to determine the changes in the physicochemical properties of palm oil and its blends by FTIR and rheological measurements. Application of heat produces some chemical compounds as impurities and even toxic compounds in oils and fats that give absorbance at different region. FTIR spectra of pure palm olein shows an absorbance at 3002 cm(-1) whereas other pure oils show maximum absorption at around 3007 cm(-1) due to C-H stretching vibration of cis-double bond (=C-H). By blending of high unsaturated oils with palm olein, a clear shift of 3007 cm(-1) band to 3005 cm(-1) occurs. Viscosity of palm olein was found higher among all oils while it subsequently and substantially reduced by blending with other oils. Since it is a function of temperature, viscosity of pure oils and their blends decreases with the increase of temperature. The loss modulus (G''), for all oil blends before and after frying, in rheological experiment was found higher for all oils than the storage modulus (G'), therefore, the viscous property was found higher than elastic property of oils and blends. However, the critical stress for all oil blends was found higher than that of pure oils. PMID- 25745213 TI - Microwave heating enhances antioxidant and emulsifying activities of ovalbumin glycated with glucose in solid-state. AB - The aim of this study was to characterize the properties of ovalbumin (OVA) after glycated with glucose under microwave heating. For this purpose, microwave at 480 and 640 W power levels were used for heating the OVA-glucose system in solid state for 0, 5, 10, 15, 20 and 25 min, respectively. The results indicated that the protein molecular weight was increased after glycated with glucose under microwave treatment, the pH of the system was decreased with the increase of microwave treatment power and time, while the UV absorbance, browning intensity, antioxidant activities as well as the emulsifying activity and emulsion stability of the Maillard reaction products (MRPs) were increased in according with the raise of microwave treatment power and time. The reaction time of microwave treatment is much shorter than those using traditional methods, suggesting that microwave irradiation is a novel and efficient approach to promote Maillard reaction (MR) in dry state and improve protein antioxidant and functional properties. PMID- 25745214 TI - Determination of the olive maturity index of intact fruits using image analysis. AB - In this work, the maturity index of different samples of olives was objectively assessed by image analysis obtained through machine vision, in which algorithms of color-based segmentation and operators to detect edges were used. This method allows a fast, automatic and objective prediction of olive maturity index. This prediction value was compared to maturity index (MI), generally used by olive oil industry, based on the subjective visual determination of color of fruit skin and flesh. Machine vision was also applied to the automatic estimation of size and weight of olive fruits. The proposed system was tested to obtain a good performance in the classification of the fruit in batches. When applied to several olive samples, the maturity index predicted by machine vision was in close agreement with the maturity index of fruits visually estimated, values that are currently used as standards. The evaluation of weight of fruit also provided good results (R(2) = 0.91). These results obtained by image analysis can be used as a useful method for the classification of olives at the reception in olive mill, allowing a better quality control of the production process. PMID- 25745215 TI - Physio-mechanical properties of an active chitosan film incorporated with montmorillonite and natural antioxidants extracted from pomegranate rind. AB - An active film was prepared from chitosan incorporated with montmorillonite (MMT) and pomegranate rind powder extract (PRP). The effect of MMT (1 %, 3 %, and 5 % w/w chitosan) and PRP (1 %, 1.5 %, and 2 % w/v chitosan) on the physical, mechanical and antioxidant properties of the chitosan-based films was studied. Fourier transform infrared (FTIR) spectra revealed that good interactions occurred between functional groups of chitosan with MMT or with PRP. The results showed that the water vapor barrier property of the films was significantly improved by incorporation of MMT and PRP (p < 0.05). When compared to pure chitosan film, the WVP of M3P2 film (Chitosan/3 % MMT/2 % PRP) decreased by 25.2 %. Tensile strength of the films was affected by the addition of MMT and PRP. However, percent elongation at break was not significantly changed by addition of PRP. The film incorporated with 3 % MMT and 2 % PRP that contained the highest amount of total phenolic (15.2 mg GAE/g DW), was found to be the most active radical scavenger. These results suggest that chitosan films containing MMT and PRP can be used for development of active food packaging materials. PMID- 25745216 TI - Application of simplex-centroid mixture design to optimize stabilizer combinations for ice cream manufacture. AB - This study aimed to obtain the optimum formulation for stabilizers in ice cream that could contest with blends presented nowadays. Thus, different mixtures of three stabilizers, i.e. basil seed gum, carboxymethyl cellulose, and guar gum, at two concentrations (0.15 % & 0.35 %) were studied using mixture design methodology. The influence of these mixtures on some properties of ice cream and the regression models for them were also determined. Generally, high ratios of basil seed gum in mixture developed the apparent viscosity of ice cream mixes and decreased the melting rate. Increasing proportion of this stabilizer as well as guar gum in the mixtures at concentration of 0.15 % enhanced the overrun of samples. Based on the optimization criteria, the most excellent combination was 84.43 % basil seed gum and 15.57 % guar gum at concentration of 0.15 %. This research proved the capability of basil seed gum as a novel stabilizer in ice cream stabilization. PMID- 25745217 TI - Phenolics of pomegranate peels: extraction optimization by central composite design and alpha glucosidase inhibition potentials. AB - Optimum water extraction conditions for phenolics of pomegranate peels were investigated by fractional factorial and face-centered central composite designs. Five potential factors were selected for the fractional factorial design: extraction technique, extraction temperature, extraction time, particle size and solvent to solid ratio. After eliminating statistically unimportant factors, a face-centered central composite design was set up with two controllable factors and with two responses: total phenolics and alpha-glucosidase inhibition activity. Optimum conditions were found as 100 degrees C for extraction temperature and 1 min for extraction time. There were no statistically significant differences (p > 0.05) between water extracts at optimized conditions and classical methanol extracts. Total phenolic content by HPLC was192.0 mg/g of pomegranate peels on dry matter basis. Phenolics of pomegranate peels showed alpha-glucosidase inhibition activity with an IC50 (concentration of phenolics required to inhibit 50 % of the enzyme activity) value of 5.56 +/- 2.23 MUg/ml. Pomegranate peel phenolics with its antioxidant and alpha-glucosidase inhibition properties might be a suitable ingredient for functional food applications. PMID- 25745218 TI - Screw pressing performance of whole and dehulled flaxseed and some physico chemical characteristics of flaxseed oil. AB - Screw pressing performance of whole and dehulled flaxseed at different seed moisture (6.4 to 11.1 % d.b.) and press head temperature (80-120 degrees C) was investigated. Oil recovery, residual oil, press rate and sediment content and some important physico-chemical characteristics were determined at six different levels (50, 60, 70, 80, 90 and 100 %) of dehulled flaxseed. Oil recovery decreased with increasing moisture content as well as press head temperature. Press rate was found maximum for 100 % dehulled flaxseed while minimum for 50 % dehulled flaxseed at 6.4 % moisture content. Colour of oil samples was found affected both with the level of dehulled flaxseed and press head temperature. Free fatty acids content of oil ranged from 1.07 % to 2.70 % and lower at 80 degrees C press head temperature. Oil and cake temperatures ranged from 53.10 degrees C to 65.95 degrees C and 69.15 to 103.75 degrees C, respectively. The alpha-linolenic acid content of different oil samples obtained at 80 degrees C was in the range of 53.34 +/- 0.95 to 54.21 +/- 1.04 %. In view of maximum oil recovery (82.9 % d.b.), lower FFA content, and oil and cake temperature, 7:3 ratio of dehulled and whole flaxseed having 6.4 % d.b. moisture content and 80 degrees C press head temperature may be considered for screw pressing of flaxseed. PMID- 25745219 TI - Physicochemical properties and sensory characteristics of sausage formulated with surimi powder. AB - The objectives of this study were to determine the physicochemical properties and sensory characteristics of fish sausage made with 100 % threadfin bream (Nemipterus japonicus) surimi powder (SP100), a mix of 50 % surimi powder and 50 % frozen surimi (SP50), and a control (100 % frozen surimi). No significant differences in protein content and folding test results (P > 0.05) were detected among the SP100 and SP50 samples and the control. Gel strength of SP100 was lower (P > 0.05) than that of the control. The texture profile analysis (TPA) values (hardness, cohesiveness, springiness, and chewiness) of SP100 were significantly lower (P < 0.05) than those of the control. However, the TPA values of SP100 and SP50 were still within the textural range of Malaysian commercial fish sausages. The water holding capacity, and emulsion stability of SP100 were significantly lower (P < 0.05) than those of SP50 and the control. Of the cooking properties measured, SP100 had lower (P < 0.05) cooking yield, moisture retention, and fat retention than the control. Quantitative descriptive analysis (QDA) performed by 12 trained panelists showed that sensory characteristic (hardness, cohesiveness, springiness, and chewiness) scores of SP100 were lower than those of SP50 and the control. The use of surimi powder in fish sausage did not differ with that of control in the term of color, odor, or oiliness scored by panelists. The drying process impacted the texture properties of surimi when it was used in fish sausage. However, the use of surimi powder in fish sausage formulation is still accepted since the TPA values of SP100 and SP50 were still within the textural range of Malaysian commercial fish sausages. PMID- 25745221 TI - Changes in physicochemical characteristics of ozone-treated raw white rice. AB - Ozone dose from 0.1 to 0.4 ppm has been proven to be effective in lowering Bacillus cereus count in uncooked and cooked rice. However, it induces physicochemical changes in raw white rice. Physicochemical tests were done to see the effect of ozone treatment towards moisture content, pH, color, hardness of uncooked rice, adhesiveness and hardness of cooked rice, cooking quality and total solids. Results have shown that moisture content, adhesiveness and hardness of cooked rice and uncooked rice have not undergone any significant changes (P > 0.05) in comparison with controlled rice sample. Meanwhile, color (L* and b* value), pH, total solids and cooking quality results have shown significant changes (P < 0.05). These analyses proved that limitations should be applied to ozone concentration and exposure time to minimize any detrimental effects on the physicochemical characteristics of rice. PMID- 25745220 TI - Influence of the addition of natural antioxidant from mate leaves (Ilex paraguariensis St. Hill) on the chemical, microbiological and sensory characteristics of different formulations of Prato cheese. AB - The objective of this work is to evaluate the effects of the addition of dried extract from mate leaves and mesophilic cultures (Lactococcus lactis ssp. lactis and cremoris) on the chemical, microbiological and sensory characteristics of Prato cheese. The Prato cheese presented high moisture contents (49 to 53 %) and mean pH values of 5.15 for all tested formulations. The addition of mate leaves extract in the product did not influence the growth of the microbial cultures. During the maturation time, all formulations with the addition of adjunct cultures and mate leaves extract presented lower levels of lipid and protein oxidation compared to the control, proving the antioxidant effect of mate extract. The formulation of Prato cheese added of 0.1 wt.% of extract presented acceptability of about 80 % after 30 days of maturation. The sensory evaluation showed that only the formulation added by adjunct culture and 0.2 wt.% of mate extract presented lower values for the attributes global acceptance, texture and flavor, compared to the control. The formulations added of mate leaves extract presented residual bitter flavor after 45 days of storage. PMID- 25745222 TI - Optimization of subcritical water extraction parameters of antioxidant polyphenols from sea buckthorn (Hippophae rhamnoides L.) seed residue. AB - Polyphenols was extracted with subcritical water from the sea buckthorn seed residue (after oil recovery), and the extraction parameters were optimized using response surface methodology (RSM). The independent processing variables were extraction temperature, extraction time and the ratio of water to solid. The optimal extraction parameters for the extracts with highest ABTS radical scavenging activity were 120 degrees C, 36 min and the water to solid ratio of 20, and the maximize antioxidant capacity value was 32.42 mmol Trolox equivalent (TE)/100 g. Under the optimal conditions, the yield of total phenolics, total flavonoids and proanthocyanidins was 36.62 mg gallic acid equivalents (GAE)/g, 19.98 mg rutin equivalent (RE)/g and 10.76 mg catechin equivalents (CE)/g, respectively. PMID- 25745223 TI - Improvement of efficiency of oil extraction from wild apricot kernels by using enzymes. AB - An experiment was conducted to evaluate and standardize the protocol for enhancing recovery of oil and quality from cold pressed wild apricot kernels by using various enzymes. Wild apricot kernels were ground into powder in a grinder. Different lots of 3 kg powdered kernel were prepared and treated with different concentrations of enzyme solutions viz. Pectazyme (Pectinase), Mashzyme (Cellulase) and Pectazyme + Mashzyme. Kernel powder mixed with enzyme solutions were kept for 2 h at 50(+/-2) degrees C temperature for enzymatic treatment before its use for oil extraction through oil expeller. Results indicate that use of enzymes resulted in enhancement of oil recovery by 9.00-14.22 %. Maximum oil recovery was observed at 0.3-0.4 % enzyme concentration for both the enzymes individually, as well as in combination. All the three enzymatic treatments resulted in increasing oil yield. However, with 0.3 % (Pectazyme + Mashzyme) combination, maximum oil recovery of 47.33 % could be observed against were 33.11 % in control. The oil content left (wasted) in the cake and residue were reduced from 11.67 and 11.60 % to 7.31 and 2.72 % respectively, thus showing a high increase in efficiency of oil recovery from wild apricot kernels. Quality characteristics indicate that the oil quality was not adversely affected by enzymatic treatment. It was concluded treatment of powdered wild apricot kernels with 0.3 % (Pectazyme + Mashzyme) combination was highly effective in increasing oil recovery by 14.22 % without adversely affecting the quality and thus may be commercially used by the industry for reducing wastage of highly precious oil in the cake. PMID- 25745224 TI - Effect of thermal processing on protein solubility of green gram (Phaseolus aureus) legume cultivars. AB - Green gram legume cultivars were analyzed for their protein solubility profile by fractionation in the raw form and also after heat processing. The results indicated that globulin fractions, which are present in major amounts that ranged from 79.5 to 85.4 % significantly decreased after the heat treatment. This decrease was accompanied by a significant increase in the glutelin-3 fractions. The prolamine contents did not vary considerably after processing. The protein and non-protein nitrogen contents ranged from 22.6 to 26.2 % and 2.3 to 2.7 % in the legume cultivars, respectively. The antinutritional factors like total polyphenol and phytic phosphorous were also determined. The accumulation of polyphenols was in the seed coat portion of the legume where as that of phytic phosphorus was in the cotyledons. SDS - PAGE profiles of all the three green gram cultivars had five major polypeptides (molecular weight 15, 18, 20, 45 and 60 kDa) in the total protein composition. Wide variation in electrophoresis pattern was observed after heat processing. Thermal treatment increased the insoluble protein fractions and eliminated the minor polypeptide bands below 14.3 kDa in the green gram cultivars. PMID- 25745225 TI - Effect of acidulants on the recovery of milk constituents and quality of Mozzarella processed cheese. AB - The investigation was undertaken to study the effect of acidulants on the recovery of milk constituents and composition of Mozzarella pre-cheese and physical, chemical and sensory characteristics and texture profile analysis (TPA) of processed cheese prepared there from. The pre-cheese was made by direct acidification technique using citric, acetic and lactic acid and processed with 1 % tri-sodium citrate. The acidulants significantly (p < 0.05) affected the fat and protein recoveries and chemical composition of pre-cheese. These also had a significant (p < 0.05) effect on chemical constituents (moisture, protein, fat on dry basis and moisture in non-fat substances), sensory characteristics, physical properties (expressible serum, fat leakage and meltability) and TPA (hardness, fracturability, adhesiveness, elasticity, gumminess and chewiness) of processed cheese. PMID- 25745226 TI - Effect of processing method on physico-chemical and functional properties of two fonio (Digitaria exilis) landraces. AB - In West Africa, landraces or local varieties of fonio are processed into many products by women using small processing units and marketed locally as well as exported to Europe and the United States. The objective of this study was to evaluate the effect of processing methods, namely parboiling, precooking and roasting on the physico-chemical and functional properties of two mainly preferred fonio landraces (Iporhouwan and Namba) by consumers. Results showed that the physico-chemical characteristics and most functional properties were significantly (P < 0.0001) affected by the processing methods. The lowest brightness (L*) values were obtained for parboiled fonio for the two landraces. However, parboiled fonio presented the best biochemical composition as compared to the dehusked, milled, precooked and roasted fonio samples. The protein contents of parboiled fonio samples were 6.06 % and 7.24 % for Iporhouwan and Namba landraces respectively. The values of peak viscosity, trough viscosity, breakdown, final viscosity and setback, were significantly higher for dehusked and milled fonio than for precooked, parboiled and roasted fonio with respect to both landraces. The milled fonio showed highest peak viscosity (2,668.5 cP) which was similar for the both tested landraces. PMID- 25745227 TI - Thermal stability of kudzu root (Pueraria Radix) isoflavones as additives to beef patties. AB - Kudzu root, Pueraria radix, extracts are a rich source of isoflavones. This study investigates the thermal stability of Pueraria radix extracts as a natural nutraceutical supplement in beef patties. The extract contained puerarin, diadzin, genistin, ononin, daidzein, glycitein, calycosin, genistein, formononetin and biochanin A; however, puerarin, daidzein and glycitein were the main components. The isoflavones concentrations in the spiked beef patties with kudzu root extracts were unaffected by cooking. PMID- 25745228 TI - Microbiological evolution of gilthead sea bream (Sparus aurata) in Canary Islands during ice storage. AB - This study analyses the microbiological changes with traditional methods for total mesophilic aerobic, psychrotrophic, Aeromonas sp., Pseudomonas sp., Shewanella putrefaciens, Enterobacteriaceae, sulfide-reducing Clostridium and Photobacterium phosphoreum in muscle, skin and gills of whole ungutted gilthead sea bream (Sparus aurata) stored in ice during 18 days. The muscle tissue showed the minor grade of contamination, followed by the skin and the gills, with statistic significance (p < 0.001). The most prominent microorganisms in the different tissues and at the end of the storage were Pseudomonas sp. (7.76, 10.11 and 10.40 log CFU/g), Aeromonas sp. (7.49, 8.24 and 9.02 log CFU/g) and S. putrefaciens (8.05, 7.49 and 8.05 log CFU/g) in sea bream harvested in the temperate water of the Canary Islands. The results obtained from this study can contribute to the improvement of microbiological knowledge of gilthead sea bream (Sparus aurata) by determining the evolution of microorganisms responsible for spoilage and their counts in different tissues such as muscle, skin, and gills during iced storage. PMID- 25745229 TI - Pasting, textural and thermal properties of resistant starch prepared from potato (Solanum tuberosum) starch using pullulanase enzyme. AB - Pullulanase enzyme (40 U/g, 10 h) was used for enzymatic hydrolysis of potato starch which was autoclaved (121 degrees C/30 min), stored under refrigeration (4 degrees C/24 h) and lyophilized. Comparison of morphological, pasting, textural and thermal properties among native hydrolysed starch (V2) and gelatinized hydrolysed starch (V3) prepared using pullulanase enzyme on potato starch (V1) were studied. The round, elliptical, irregular and oval shape with smooth surface of V1 was replaced with amorphous mass of cohesive structure leading to loss of granular appearance in V2 and V3. The percentage of amylose and resistant starch content of V2 (27.16 %) and (24.16 %); V3 (51.44 %) and (29.35 %) was higher when compared to V1 (22.17 %) and (3.62 %). The swelling power of V1 observed at 60 degrees C (0.85 %) and 95 degrees C (8.64 %) were significantly different from V2 at 60 degrees C (4.97 %) and 95 degrees C (7.66 %) and that of V3 at 60 degrees C (5.82 %) and 95 degrees C (7.5 %). Significance difference in water solubility (7.62 %) and absorption capacity (6.11 %) was noted in V3 when compared with V1 and V2 owing to amylose/amylopectin content. Increase in water solubility and absorption capacity along with decrease in swelling power of V2 and V3 was noted due to hydrolytic and thermal process. RS obtained from hydrolysis showed a reduction in viscosity, indicating the rupture of starch molecules. The viscosity was found to be inversely proportional to the RS content in the sample. The thermal properties of RS increased due to the retrogradation and recrystallization (P < 0.05). PMID- 25745230 TI - Cooked rice texture and rice flour pasting properties; impacted by rice temperature during milling. AB - Rice milling plays a key factor in determining rice quality and value. Therefore accurate quality assessments are critical to the rice industry. This study was undertaken to assess the effect of exposing rice to elevated temperatures during milling, on cooked rice texture and rice flour pasting properties. Two long (Cybonnett and Francis) and one medium (Jupiter) rice (oryzae sativa L.) cultivars were milled using McGill laboratory mill for 30 and 40 s after warmed up the mill before milling. Four different milling temperatures per milling duration were achieved. Cooked rice texture properties were assessed using a uniaxial compression test and rice flour pasting properties measured using a TA 2000 rheometer. Results of this study showed that exposure of rice to high temperatures during milling significantly decreased cooked rice firmness. An increase in milled rice temperature after milling from 10.0 to 13.3 degrees C resulted in a 5.4 and 8.1 N decrease in cooked rice firmness. Although not always significant, the increase in milled rice temperature during milling resulted in an increase in cooked rice stickiness. The increase in milling temperature also showed significant increase in rice flour pasting properties. Changes in rice functional characteristics were attributed to the changes occurring to rice chemical constituents due to temperature exposure as indicated by the increase in rice protein hydrophobicity. Proteins are known to affect rice starch water holding capacity and other starch gelatinization properties. PMID- 25745231 TI - Technological, physico-chemical and sensory properties of raw and cooked meat batter incorporated with various levels of cold milled flaxseed powder. AB - Flaxseed has been proven for its multidimensional health benefits and can be used for development of emulsion type functional meat products. In view of this the incorporation of cold milled flaxseed powder (FSP) in meat batter at level 1-5 % was investigated. The results revealed that incorporation significantly (P < 0.05) decreased the total fluid release (TFR), fat release (FR) and water release (WR) of raw meat batter. The surface and internal color values were differed significantly (P < 0.05) among treatments at initial as well as during refrigerated storage period. Texture values especially hardness and chewiness values were found less (P < 0.05) in FSP treated samples and textural properties in FSP treated samples were not deteriorated during storage as compared to control samples. Thus incorporation of FSP had some beneficial effects on physico chemical properties and textural properties which were also stable during storage period. However the redness values and sensory scores were observed less in FSP treated samples. PMID- 25745232 TI - Effect of blend ratio and pH on the physical properties of edible composite films prepared from silver carp surimi and skin gelatin. AB - The effect of blend ratio and pH on the physical properties of surimi-gelatin composite films was investigated. Tensile strength (TS), film water solubility and soluble proteins of composite films increased with the increasing proportion of gelatin, while elongation at break (EAB) decreased. The TS of neutral films with the same ratio of surimi and gelatin were lowest, while increased at acidic or alkaline conditions. Similar tendency was also found in protein solubility and surface hydrophobicity of the film-forming solutions. On the other hand, the film water solubility and soluble proteins of neutral composite films were higher than those of acidic and alkaline films. Furthermore, it was revealed that the dissolved surimi and gelatin proteins could form strong composite films, which were insoluble in water. These results suggested that dissolved proteins were mainly involved in the formation of surimi-gelatin composite films. PMID- 25745233 TI - Utilization of gum tragacanth as bind enhancing agent in extended restructured mutton chops. AB - Use of extenders in meat products is not only health promoting but can also increase the economic worth of the products. Extension of the meat product is generally associated with poor binding and texture. Thus, the present study was envisaged to solve this problem by the incorporation of gum tragacanth (GT) as bind enhancing agent, used at three different levels viz., 0.1, 0.15 and 0.2 % in a pre standardized formulation of extended restructured mutton chops (ERMC), by replacing the lean meat. The products were subjected to analysis for physico chemical, sensory and textural properties. There was no significant difference (P > 0.05) in any of the physicochemical property parameters of product incorporated with different levels of GT except fat percent and shear force value. Mean scores for binding, texture and overall acceptability of ERMC incorporated with 0.1 % GT recorded significantly higher value (P < 0.05) than control and other treatment products. On the basis of sensory scores and physico-chemical properties, the optimum incorporation level of GT was adjudged as 0.1 %. Hardness and adhesiveness values were significantly higher (P < 0.05) in product with 0.1 % GT level. The product with optimum level of GT was also assessed for water activity (aw) and microbiological characteristics. It was found that treatment as well as control products were quite acceptable up to 15th day of storage period without any marked differences in sensory quality. PMID- 25745234 TI - Milks pigmentation with astaxanthin and determination of colour stability during short period cold storage. AB - Astaxanthin has been used as a colorant and antioxidant with excellent results, its application and stability in food matrices to human consumption has been little studied. The aim of this work was the incorporation of astaxanthin oleoresin to milks with different fat content, simulating the red-orange color that can impart apricot fruit. For astaxanthin determination by HPLC, a methodology was implemented for its extraction from the food matrix, followed by saponification with KOH. Milk samples were stored (5 +/- 2 degrees C) and stability of color and astaxanthin content were determined by colorimetry and high performance liquid chromatography each 24 h for a week. Pigment degradation followed first-order kinetic with a constant degradation of 0.259 day(-1) and 0.104 day(-1), in whole and semi-skimmed milk, respectively. Chromaticity coordinates L*, a*, b* for different types of milk showed a low dispersion of their values during the storage time, indicating high stability of astaxanthin within the matrix. PMID- 25745235 TI - In vitro starch digestibility, pasting and textural properties of mung bean: effect of different processing methods. AB - Mung bean was subjected to different processing conditions (soaking, germination, cooking and autoclaving) and their textural, pasting and in vitro starch digestibility characteristics were studied. A significant reduction in textural properties (hardness, cohesiveness, gumminess and chewiness) after cooking and autoclaving treatment of mung bean was observed. Flours made from differently processed mung bean showed significant differences (P < 0.05) in their pastin g characteristics. Peak and final viscosity were the highest for flour from germinated mung bean whereas those made from autoclaved mung bean showed the lowest value. in vitro starch digestibility of mung bean flours was assessed enzymatically using modified Englyst method and the parameters studied were readily digestible starch (RDS), slowly digestible starch (SDS), resistant starch (RS) and total starch (TS) content. Various processing treatments increased the RDS contents of mung bean, while the SDS content was found to be the highest for soaked and the lowest for the autoclaved sample. Germinated sample showed higher amount of digestible starch (RDS + SDS) as compared to raw and soaked samples. Flours from raw and soaked samples showed significantly low starch hydrolysis rate at all the temperatures with total hydrolysis of 29.9 and 31.2 %, respectively at 180 min whereas cooked and autoclaved samples showed high hydrolysis rates with 50.2 and 53.8 % of these hydrolyzing within 30 min of hydrolysis. PMID- 25745236 TI - Determination of fat, protein and moisture in ricotta cheese by near infrared spectroscopy and multivariate calibration. AB - Near-infrared reflectance spectroscopy (NIRS) with partial least squares regression (PLSR) was used to determine levels of fat, protein and moisture in ricotta cheese without complex sample preparation. Spectra of 19 conventional and low-fat ricotta samples from different manufacturers were collected in duplicate, with 33 of the 38 spectra used as a calibration set and the remaining 5 spectra used as an external validation set. The best results were obtained by processing the spectral region between 1,100 and 2,500 nm. Multivariate models with six latent variables (LVs) showed good prediction capability for fat and protein determinations, with average relative errors (Er) of 6.37 % and 5.95 %, respectively. For moisture, a more robust model was obtained with 4 LVs, showing better prevision capacity and Er of 1.91 %. PMID- 25745237 TI - Fatty acid composition differences between adipose depot sites in dairy and beef steer breeds. AB - The objective of the study was to compare fatty acid composition of longissimus dorsi (LD) and kidney fat (KF) in Holstein steers (HS), Simmental steers (SS) and Chinese LongDong Yellow Cattle steers (CLD). All steers received the same nutrition and management but in different locations. Cattle were harvested at approximately 550 kg and fatty acid composition of longissimus dorsi and kidney fat was analyzed in samples taken after 3 days of aging. There was evidence (P < 0.05) that C18:3n6 was greater in KF than LD in CLD cattle but not in HS or SS cattle. Percentage C18:1n9, C18:2n6, C18:3n3, and n6 fatty acids were greater in LD than KF for all breeds (P < 0.05), but the difference between fat sources for n6 in CLD cattle was smaller than the other two breeds. The LD had greater percentage of polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFA), and a greater ratio of n6:n3 PUFAs compared to the KF in each breed (P < 0.05). The ?(9)-desaturase catalytic activity index was greater in LD than in KF in each breed group (P < 0.05). Percentage cis-9, trans-11 CLA was greater in KF than LD in HS (P < 0.05) but not SS or CLD cattle. These results indicate fatty acid percentages generally differed between longissimus dorsi fat and kidney fat. Further, there was some indication that some of these differences between fatty acid deposition sites were not consistent across breed group. PMID- 25745238 TI - Moisture sorption curves of fruit and nut cereal bar prepared with sugar and sugar substitutes. AB - Low sugar, low fat, dry fruit and nut cereal bars without sugar were prepared using cereals, nuts, and sugar substitutes. The sorption characteristics of the bars prepared with sugar substitutes in comparison with that of sugar were studied by keeping the bars at water activity (aw) from 0.1 to 0.9. The sorption isotherms of low sugar bars were practically identical below aw of 0.5 but above aw of 0.5, a clear differentiation in the isotherms could be observed compared to that of sugar counterpart. A sharp increase in moisture content was observed in the bars prepared with alternative sweeteners, above aw 0.6, whereas a gradual increase in aw was observed in the case of bar prepared with sugar. The ERH (Equilibrium relative humidity) value for bar with sugar was 50 %, and for bars prepared with alternative sweeteners, it was about 60 %. Low sugar cereal bar prepared with sorbitol + maltitol (SM) syrup scored higher sensory quality compared to other product prepared with sorbitol + nutriose (SN) as the former retained softness and chewiness on storage. Thus, it was observed that bars with alternative sweeteners will be more stable as their ERH is closer to normal ambient conditions compared to that prepared with sugar. PMID- 25745239 TI - Effect of extrusion variables (temperature, moisture) on the antinutrient components of cereal brans. AB - The study was carried out, to explore the potentiality of extrusion technology for elimination of antinutritional components of cereal brans. Extrusion variables were moisture content (14, 17 and 20 %) and temperatures (115 degrees C, 140 degrees C, 165 degrees C). Phytic acid, polyphenols, oxalates, trypsin inhibitor, bulk density and color of brans after extrusion were analyzed. All four raw bran samples had high concentration of phytic acid, polyphenols, oxalates and trypsin inhibitors. Extrusion cooking was found effective in reduction of these antinutritients. Extrusion processing reduced the phytic acid by 54.51 %, polyphenol by 73.38 %, oxalates by 36.84 %, and trypsin inhibitor by 72.39 %. The heat treatment caused the highest reduction in polyphenols followed by trypsin inhibitors, phytic acid and oxalates. The highest reduction in antinutrients was observed at 140 degrees C and 20 % moisture content. Bulk density increased significantly compared to raw brans and increase in redness and decrease in yellowness of brans was observed after extrusion treatment. PMID- 25745240 TI - Response surface modeling of acid activation of raw diatomite using in sunflower oil bleaching by: Box-Behnken experimental design. AB - The optimum conditions for acid activation of diatomite for maximizing bleaching efficiency of the diatomite in sun flower oil treatment were studied. Box-Behnken experimental design combining with response surface modeling (RSM) and quadratic programming (QP) was employed to obtain the optimum conditions of three independent variables (acid concentration, activation time and solid to liquid) for acid activation of diatomite. The significance of independent variables and their interactions were tested by means of the analysis of variance (ANOVA) with 95 % confidence limits (alpha = 0.05). The optimum values of the selected variables were obtained by solving the quadratic regression model, as well as by analyzing the response surface contour plots. The experimental conditions at this global point were determined to be acid concentration = 8.963 N, activation time = 11.9878 h, and solid to liquid ratio = 221.2113 g/l, the corresponding bleaching efficiency was found to be about 99 %. PMID- 25745241 TI - Optimization of demineralization on Cyprinus carpio haematopterus scale by response surface methodology. AB - Fish scale, separated during fish mechanical processing, can serve as an additional source of proteins, especially of collagen proteins. To obtain high purity native collagen, it is required to carry out deproteinization and demineralization of fish scales. Therefore, the aim of this study was to determine the optimal conditions for demineralization of Cyprinus carpio haematopterus scale without loss of collagen content in HCl solution. Here, the demineralization of Cyprinus carpio haematopterus scale was optimized by response surface methodology. The optimum conditions were as follows: extraction time of 95 min, concentration of HCl of 1.0 M, and ratio of material to solution of 1:11. Under these conditions, the experimental yield of demineralization of scales was 92.7 +/- 1.32 %, which was well consistent with the value predicted by the model. PMID- 25745242 TI - Stability of vitamin C in fresh and freeze-dried capsicum stored at different temperatures. AB - The objective of this study was to determine vitamin C stability in fresh and freeze-dried capsicum during storage at different temperatures. Fresh capsicum stored at 20 degrees C showed an initial decrease in vitamin C with a minimum peak after 2 days and then increased to a maximum peak after 13 days followed by a gradual decay. In general a gradual decrease of vitamin C was observed in the cases of fresh (i.e. stored at 5, -20, -40 degrees C) and freeze-dried capsicum stored at all temperatures (i.e. 60 to -40 degrees C). The degradation kinetics of vitamin C was modeled by zero and first order reaction and rate constants were estimated. The rate constant increased with the increase in storage temperature, while it was decreased with the decrease of moisture content. At storage temperature 5 degrees C, first order rate constants were observed as 7.1 * 10( 2), 7.7 * 10(-2), and 4.3 * 10(-3) day(-1) in the cases of samples containing moisture contents 94, 15 and 5 g/100 g sample, respectively. PMID- 25745243 TI - Qualitative test for the detection of extraneous thiocyanate in milk. AB - Thiocyanate is one of the three components of lactoperoxidase system for preserving the milk under the conditions where chilling facilities do not exist due to economic and technical reasons. In 1988, International Dairy Federation (IDF) has recommended the levels and the code of practices for the application of LP-system. As the excessive use of thiocyanates beyond the recommended limits can lead to human health hazards, its rapid detection in milk at the reception dock of dairy, where milk is tested for quality before its acceptance or rejection, is necessary. For simple and rapid detection of added thiocyanates in milk, two types of qualitative tests have been developed in this study, of which one is applicable directly to milk and the other is applicable to TCA filtrate of milk. The results of the test reveal that as low as 0.6 ppm of added thiocyanate (equivalent to 1 ppm of potassium thiocyanate) can be detected. The orange to orange-red color obtained in the test solution can be considered the basis of rejecting milk assuming that it has added levels of thiocyanate. PMID- 25745244 TI - Effect of radiation and/or traditional processings on antinutrients and HCl extractability of calcium, phosphorus and iron of sorghum cultivars. AB - Whole flours of sorghum cultivars Dabar, WadAhmed and Karamaka were irradiated and then fermented and/or cooked. Tannin and phytic acid contents were assayed for all treatments. Traditional processings (fermentation and cooking) were significantly (P >= 0.05) decreased tannin and phytate of the cultivars and further reduction was observed when the flour was irradiated before processing for all cultivars. Radiation process alone had no great effect on tannin and phytate contents but when followed by traditional processing the reduction level was significant (P >= 0.05) for all cultivars. Radiation alone had no significant (P >= 0.05) effect in increment of total and extractable calcium (Ca). However, radiation followed by fermentation and/or cooking significantly (P >= 0.05) increased both total and extractable Ca. Total phosphorus (P) was not significantly (P >= 0.05) increased at all levels of radiation and/or processing but the extractable P was increased. Total iron (Fe) was not affected by radiation and/or processings but the extractable Fe was increased significantly (P >= 0.05) with the radiation dose for all cultivars. PMID- 25745245 TI - Quality of granola prepared with dried caju-do-cerrado (Anacardium othonianum Rizz) and baru almonds (Dipteryx alata Vog). AB - The use of Brazilian Cerrado fruits and research into their nutritional potential are important for socioeconomic development and the sustainable preservation of the environment. The use of these fruits in products such as granola encourages the inclusion of healthier and more-natural foods in the diet. This study was undertaken to evaluate acceptability, microbiological, physical and nutritional characteristics and the stability of granola made from dried caju-do-cerrado and baru almonds. Granola containing Cerrado fruits had high levels of protein content (117.4 g/kg), dietary fiber (115.3 g/kg) and iron (32.1 mg/kg) and had lower moisture (57.0 g/kg), water activity (0.3), sodium (577.7 mg/kg), lipids (150.2 g/kg) and energy value (3952.2 kcal/kg) than did the control. After storage for 100 days, the granola presented adequate microbiological conditions, with acceptability scores higher than 7 assigned by 85.5 % to 95.2 % of the judges and a crunchy texture. The high nutritional potential of granola containing Cerrado fruits, coupled with its stability over 100 days of storage, may contribute to the appreciation and consumption of these fruits and meet the growing demand for healthier, more natural foods. PMID- 25745246 TI - Enzymo-chemical preparation, physico-chemical characterization and hypolipidemic activity of granular corn bran dietary fibre. AB - Corn bran dietary fibre (CF) was paid more attention for its anticancer and hypolipidemic activities. In this paper, corn bran was firstly decomposed to the threadlike fibre (CF1) by multiple enzymes and then further modified to the granular fibre (CF2) by alkali under high pressure and high temperature (APT). The two types of fibres were characterized by scanning electron microscope (SEM) and near-infrared spectrophotometer (IR), and investigated by hydration measurements and nitrite adsorption assays. The results showed that CF2 had more much specific surface area, and displayed 4.7, 6.3 and 30-fold increases in water retention (WR), swelling capacity (SC) and nitrite absorption (NA), compared with CF1, respectively. The rat feeding trials showed that the granular fibre could decrease total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDLC) by 41.4 %, 20.7 % and 56.5 %, respectively. These excellent physiological activities indicate that CF2 will be a potentially available dietary ingredient in functional food industries, and meanwile imply that the enzymochemical method is a desired strategy for CF processing. PMID- 25745248 TI - Development and evaluation of honey based mango nectar. AB - Honey enriched mango nectar was prepared by using honey as sweetening agent because of its high fructose and glucose content and medicinal properties. The nectar having 20 % pulp, 15 degrees B TSS and 0.30 % acidity was prepared, filled in pre-sterilized glass bottles, heat processed and stored up to 6 months under ambient (13.3-26.3 degrees C and 44.5-81.0 % RH) and refrigerated (4-7 degrees C and 73 % RH) conditions. The honey enriched mango nectar could be stored for 6 months at ambient temperature and low temperature storage conditions and only little changes in the quality parameters viz., TSS, titratable acidity, ascorbic acid, total and reducing sugars, carotenoids and hydroxymethylfurfural (HMF) were recorded as compared to sugar based nectar. These changes were more under ambient conditions than refrigerated and no microbial growth was found in nectars at fresh stage and during storage up to 6 months. The hydroxymethylfurfural (HMF) content in the mango nectars increased with prolonged storage period. The mustard honey based mango nectar had the higher carotenoids content but this decreased (725.60-689.20 mg/100 ml) during storage up to 6 months under ambient storage conditions, whereas the decrease was less under refrigerated storage conditions. Organoleptic quality score was higher in mustard honey based mango nectar (6.8) as compared to sugar based mango nectar under refrigerated conditions after 6 months storage. The results indicated that the mustard honey based mango nectar stored at low temperature was acceptable with respect to colour, taste and overall acceptability without any microbial spoilage and could be marketed as health drink. PMID- 25745247 TI - Effective production of S-allyl-L-cysteine through a homogeneous reaction with activated endogenous gamma-glutamyltranspeptidase in garlic (Allium Sativum). AB - S-allyl-L-cysteine (SAC) is a bioactive compound in garlic (Allium sativum). A novel process including soaking and homogeneous reaction was applied for the effective production of SAC with endogenous gamma-glutamyltranspeptidase (gamma GTP, EC 2.3.2.2) in garlic. The effects of temperature and CaCl2 concentration on gamma-GTP activity in soaking, and the relationship of SAC production with gamma GTP activity in homogeneous reaction were investigated, using fresh garlic as raw material. The experimental results showed that the gamma-GTP in fresh garlic was activated by soaking. The yield rate and the final content of SAC increased linearly with increasing initial gamma-GTP activity in the homogeneous reaction at 37 degrees C. The final SAC content reached 606.3 MUg/g (i.e. 32 times higher than that in fresh garlic) after soaking for 72 h in a 10-mM CaCl2 solution at 10 degrees C, and the homogeneous reaction for 8 h at 37 degrees C. SAC was produced effectively through the homogeneous reaction with activated endogenous gamma-GTP in garlic. PMID- 25745249 TI - Effect of coagulants on the quality of chhana and rasogolla obtained from admixture of buffalo milk and butter milk. AB - A study was carried out to investigate the effect of different coagulant (lactic acid, citric acid and calcium lactate) on yield, sensory and textural characteristics of chhana and rasogolla made from admixture of buffalo milk and sweet cream butter milk (SCBM). The highest yield of chhana was observed with calcium lactate whereas the minimum yield was found with citric acid. There was no significant difference found with respect to flavour and colour and appearances scores, however, significant (p < 0.01) difference found in body and texture of chhana samples prepared with different coagulant. In addition to that, significant (p < 0.05) difference observed with respect to body and texture, flavour and porosity of rasogolla, but no significant difference was observed in colour and appearance as well as sweetness of rasogolla prepared with chhana obtained from varying coagulants. Among different coagulants, citric acid was found best suitable for chhana as well as rasogolla making. PMID- 25745250 TI - Effect of slaughter methods on the quality of Chilean jack mackerel (Trachurus murphyi) during refrigerated storage. AB - The main objective of this study was to assess the influence of slaughter methods on the quality of Chilean jack mackerel (Trachurus murphyi) during refrigerated storage on board. Fishes were slaughtered by asphyxia in air (AA), asphyxia in ice water (AI) or stunning fish heads (SH), and the rigor mortis, pH, total volatile basic nitrogen (TVB-N), trimethylamine (TMA), 2-thiobarbituric acid reactive substances (TBARS) and sensory properties for the fishes were analyzed. On day 0, Chilean jack mackerel samples of AI group displayed higher pH values than those of AA and SH groups. TVB-N, TMA and TBARS values of all samples increased with the storage time, and these values of AI had a lower increase than AA and SH. Moreover, samples of AI had a better sensory score than AA and SH during storage. It can be concluded that slaughter method of asphyxia in ice water for Chilean jack mackerel exhibit the better efficiency on maintaining the fish quality during refrigerated storage on board. PMID- 25745251 TI - Effect of ultrasound pre-treatment of hemp (Cannabis sativa L.) seed on supercritical CO2 extraction of oil. AB - Ultrasound pre-treatment of intact hemp seeds without any solvent assistance was carried out for 10, 20 and 40 min prior to SCCO2 extraction at 40 degrees C, 300 bar and 45 kg CO2/kg feed. Sonication time effect on SC-CO2 extraction was investigated by the extraction kinetics. The maximum extraction yield was estimated to be 24.03 (% w/w) after 10 min of ultrasonic pre-treatment. The fatty acid compositions of the oils extracted by SC-CO2 without and with ultrasound pre treatments was analyzed using gas chromatography. It was shown that the content of linoleic, alpha-linolenic and oleic acids (the most abundant unsaturated fatty acids) of the hemp seed oils were not affected significantly by the application of ultrasound. UV spectroscopy indices (K232 and K268) and antiradical capacity were used to follow the quality of oils. Significant were the changes in their antiradical capacity due to ultrasound treatment. A comparison with the oil extracted by Soxhlet was also given. PMID- 25745252 TI - Effect of amurca on olive oil quality during storage. AB - Total phenolic compounds (TPC), antioxidant activity (AA), lipid peroxidation inhibition (percent) (LPOIP), free fatty acid and peroxide values were measured in olive oil samples over the period of 12 months in comparison with oil samples extracted from amurca (olive oil lees) and olive oil samples taken from the bottom of the canister (near amurca) after 12 months of storage. Olive oil samples taken over the period of 12 months possessed decreasing amounts of TPC, AA and LPOIP, which led to increased peroxide and free fatty acid values. In contrast, oil extracted from amurca and olive oil samples taken from the bottom of the container after 12 months of storage possessed significantly higher TPC, AA, LPOIP and consequently lower free fatty acid and peroxide values. These results show that the presence of naturally occurring amurca (sediment) in stored olive oil stabilizes olive oil quality during storage. PMID- 25745253 TI - Anti-oxidative effect of turmeric on frying characteristics of soybean oil. AB - Curcumin, the active principle of turmeric, is known to act as an anti-oxidant, anti-mutagen and anti-carcinogen. This study aimed to find out the thermal and oxidative stability of soybean oil when potatoes marinated with turmeric were deep fried in the oil. Two sets of experiment were carried out. In one set, 1 L of oil was heated for 24 h (8 h daily for 3 consecutive days) and 200 g of potato chips without any marination were fried each time twice daily. Foods were fried in batches to replicate the commercial practice of the food industries. The temperature maintained during the whole experiment was at 180-190 degrees C i.e. at the frying temperature. About 50 ml of the oil sample was collected after every 4 h. In the second set, another 1 L of soybean oil was heated for 24 h in the similar manner and potato chips marinated with turmeric was fried twice daily. Oil samples were collected as before and comparative studies were done. The chemical parameters like acid value, peroxide value, content of 4-hydroxy-2 trans-nonenal (HNE) and fatty acid composition for all the oil samples of each set were determined. The comparative studies on peroxide value and content of HNE revealed that the antioxidant property of curcumin in turmeric helped in reducing the oxidation of the oil initially, but with increase in duration of time, the antioxidant potency got gradually reduced. The loss of unsaturated fatty acids were calculated from the fatty acid composition and it was found that loss of unsaturation in soybean oil where turmeric marinated potatoes were fried was 6.37 % while the controlled one showed 7.76 % loss after 24 h of heating. These results indicated higher thermal and oxidative stability of the soybean oil in presence of turmeric. However, the antioxidant effect gradually decreased with increase in duration of heating. PMID- 25745254 TI - Quality changes in fish burger from Catla (Catla Catla) during refrigerated storage. AB - Fish burgers from catla (Catla catla) were assessed for proximate, chemical, microbiological and sensory quality changes over 17 days of refrigerated storage at 4 (+/-1) degrees C. The changes in proximate analysis of fish burgers were found to be significant at P < 0.01. The values of peroxide value, free fatty acid, thiobarbutric acid and total volatile base nitrogen at the end of storage increased significantly at P < 0.01 were determined as 4.98 (+/-0.22) meqO2/kg of fat, 0.94 (+/-0.01)% of oleic acid, 0.58 (+/- 0.02) mg MA/kg of sample and 4.78 (+/-0.02) mg/100 g of sample respectively. Total plate count and psychrophilic bacterial counts increased significantly (P < 0.01) during refrigerated storage. Staphylococcus aureus, Faecal streptococci, Escherichia coli, Salmonella, Vibrio, yeast and molds were found absent. According to sensory scores, the fish burgers have a shelf life of 15 days. A negative correlation was observed between storage period and overall acceptability scores. PMID- 25745255 TI - Effects of citric acid, cucumis powder and pressure cooking on quality attributes of goat meat curry. AB - In the present study, comparative effects of marination in citric acid (1 %), spray of cucumis powder (2 %) and pressure cooking (at 15 psi) were observed on quality attributes of goat meat curry. Significant difference (p < 0.05) was observed in pH of citric acid treated samples compared to other samples. Significant difference (p < 0.05) was observed in protein and soluble collagen content of meat curry treated with pressure as compared to other treated samples including control. Cooking yield was significantly (p < 0.05) higher in control samples. The significant difference was observed in chewiness and gumminess at (p < 0.05) level and hardness at (p < 0.01) level within and between the various treatment groups. However, overall values were higher in control samples. Similarly, shear force value was significantly (p < 0.05) higher for control compared to treated samples. The significant difference (p < 0.05) was observed in various sensory attributes of goat meat curry and pressure treated cooked meat curry was highly preferred followed by cucumis powder, citric acid and control samples. PMID- 25745256 TI - Selection of process parameters for producing high quality defatted sesame flour at pilot scale. AB - The present work was undertaken to study the effect of pearling duration, soaking time, steaming duration and drying temperature on the quality of sesame seeds and mechanically extracted partially defatted sesame cake. On the basis of quality attributes i.e. high protein, low crude fibre, low residual oil and low oxalic acid, the optimum process parameters were selected. The combination of 20 min of pearling duration, 15 min of soaking, 15 min of steaming at 100 kPa pressure and drying at 50 degrees C yielded high quality partially defatted protein rich sesame flour as compared to untreated defatted sesame flour. The developed high quality partially defatted protein rich sesame flour may be used in various food applications as a vital ingredient to increase the nutritional significance of the prepared foodstuffs. PMID- 25745257 TI - Nucleic acid from beans extracted by ethanediamine magnetic particles. AB - Ethanediamine magnetite nanoparticles (EDAMPs) were used as adsorbents to isolate genomic DNA from various bean-species. A "single-pot" preparation of EDAMPs was described. Further characterization, including transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), thermo-gravimetric analysis (TGA), X ray powder diffraction (XRD) and Fourier Transform Infrared Spectrophotometer (FT IR) were used to demonstrate the efficiency of this simple and general identification method. The EDAMPs provided excellent yields of genomic DNA. The isolated DNA was suitable for use in further applications by the Polymerase Chain Reaction (PCR) for the detection of Genetically Modified (GM) food and non-GM food. The EDAMPs are effective for bioseparation applications. PMID- 25745258 TI - Effect of Xylopia aethiopica aqueous extract on antioxidant properties of refrigerated Roma tomato variety packaged in low density polyethylene bags. AB - Effects of Xylopia aethiopica (Dunal) A. Richard aqueous extract on the antioxidants of matured tomato fruits at red stage were investigated at 13 +/- 2 degrees C and 80 +/- 5 % relative humidity. A sample treated with sodium bicarbonate and untreated samples were included. Samples packaged in low density polyethylene (30 MUm thickness) bags were analysed at intervals of 5 days. The treatments revealed statistically significant differences in ascorbic acid content of stored tomato fruits. Fruits treated with 5 % X. aethiopica on day 5 of storage had 21.0 mg/100 g which was significantly (p < 0.05) higher than 18.2 mg/100 g in untreated control samples. At 15th day of storage, ascorbic acid was 10.0 and 14.2 mg/100 g in tomato fruits treated with sodium bicarbonate and 5 % X. aethiopica respectively. The carotenoid and lycopene contents were lower in sodium bicarbonate-treated and the untreated control samples than in X. aethiopica-treated sample. The total phenolic contents were better retained in X. aethiopica-treated tomato than in control. Treatment of tomato fruits with X. aethiopica at 4 & 5 % levels significantly retained the qualities evaluated. PMID- 25745259 TI - Incidence and enterotoxigenic profile of Bacillus cereus in meat and meat products of Uttarakhand, India. AB - The present investigation was undertaken to study the incidence and enterotoxigenicity of Bacillus cereus in raw meat and meat products. B. cereus was isolated from 29 (30.9 %) of the 94 samples analyzed. Recorded incidences of B. cereus from raw meat and meat products samples were 27.8 and 35 %, respectively. A high level of organism was found in cooked-meat (35 %) than raw meat samples (27.78 %) from 40 cooked-meat products and 54 raw meat samples analyzed. Screening of isolates by multiplex polymerase chain reaction revealed the overall distribution of various enterotoxin genes hblDAC complex, nheABC complex, cytK and entFM as 55.2, 89.7, 41.4 and 93 %, respectively. The level of contamination with B. cereus was moderately higher in some samples but did not exceed the level which is sufficient to induce food poisoning. A relatively higher incidence of B. cereus in meat products, with the majority of isolates harboring all the enterotoxin genes can pose a potential public health threat. PMID- 25745260 TI - Microbiological contamination of dried and lyophilized garlic as a potential source of food spoilage. AB - Garlic is valued more for its flavoring and used in a wide variety of foods. In food technology, fresh garlic is not used, but instead its processed forms, most often dried and lyophilized, are utilized. The quality and safety of the final product largely depends on their microbiological quality. This research has provided information about effect of garlic fixation methods and provided information about effect of microbiological contamination of garlic used as a spice for quality of garlic mayonnaise sauce. The authors decided to undertake studies following a report from one of the manufacturers of garlic sauces on product defects which originated in dried garlic used in the production process. Samples of garlic (n = 26) were examinated using standard cultural methods (counts of fungi, lactic acid bacteria-LAB, spore-producing Bacillus sp. and the presence of anaerobic saccharolytic and proteolytic clostridia), automated system TEMPO (total viable count, Enterobacteriaceae), immunoenzymatic method using VIDAS tests (occurrence of Salmonella sp. and Listeria monocytogenes). The number of total viable count was ranged from 3.51 to 6.85 log CFU/g. Enterobacteriaceae were detected only in one sample. Comparably low values were recorded for fungi (1.30 to 3.47 log CFU/g). The number of LAB was ranged from 2.34 to 5.49 log CFU/g. Clostridium sp. were detected in 22 samples. Salmonella sp. and Listeria monocytogenes were not detected. It was found that garlic, regardless of th preservation procedure, might be a source of contamination of garlic mayonnaise sauce especially with lactic acid bacteria and Clostridium sp. spores. PMID- 25745261 TI - Betalains rich Rivina humilis L. berry extract as natural colorant in product (fruit spread and RTS beverage) development. AB - Rivina humilis L. (Phytolaccaceae) or pigeon berry accumulates betalains in its berries. It is reported that the berries are safe to consume, rich in nutrient content and exhibit efficient biological activity. In this report, Rivina berry extract was used as natural colorant in fruit spread and beverage to evaluate its effect on physicochemical properties and acceptability of the product. Results showed that 68 % color retained in Rivina banana spread after 6 months of storage at 5 degrees C, though there was reduction in L, a and chroma values. Rivina banana beverage lost redness completely during processing. Microbial analysis of the products indicated that they were safe for consumption. The spread had good overall sensorial quality and was liked by consumers indicating that addition of Rivina berry extract did not alter product quality. PMID- 25745262 TI - Study of phenolic compound and antioxidant activity of date fruit as a function of ripening stages and drying process. AB - Edible parts of two varieties of date palm (Mazfati and Kalute varieties) (Phoenix dactylifera) fruits (DPF) from Iran were analyzed to determine their phenolic compound and antioxidant activities (AA). Antioxidant activity evaluated using typical methods such as 2, 2-diphenyl-1-picrylhydrazyl (DPPH), reducing power and total antioxidant method. The total phenolic content (TPC) of the DPF was measured using Folin-Ciocalteau method. The samples used in this study included samples were gathered at three stages of khalaal, rutab, tamr and dried date from Bam and Jiroft date. The TPC ranged from 2.89 to 4.82, 1074 to 856.4 and 782.8 mg gallic acid equivalents (GAE/100 gdw sample) for khalal, rutab and tamr stage of Mozafati variety, respectively. This work demonstrates the potential of Iranian dates as good sources of antioxidant which can be used as functional food ingredients. The influence of sun drying process and oven drying at temperature ranged 50-80 degrees C on phenolic compounds and AA of date palm fruits were investigated. Result of drying process showed that TPC and AA varied with temperature and decreased by increase of drying temperature (from 667.3 to 610.5 mg galic acid in sun dried dates of Mozafati and Kaluteh respectively to 314.2 and 210.4 in dried dates (80 degrees C) of Mozafati and Kaluteh respectively). PMID- 25745263 TI - Effect of pH on turbidity, size, viscosity and the shape of sodium caseinate aggregates with light scattering and rheometry. AB - The characterization of sodium caseinate solutions as a function of pH was determined using titration with HCL through turbidimetry in different concentrations (0.03 wt.%, 0.045 wt.%, 0.06 wt.%, 0.09 wt.%, 0.2 wt.%, and 0.3 wt.%). Additionally, the coupling of slow in situ acidification of the solution and rheometry was utilized to gain deeper insights into pH-induced structural transitions during the self assembly process and particle size distribution analysis have been used to determine the behavior of sodium caseinate solutions in different pHs. The formation of aggregates during the acidification process was clearly visualized using microscopy. Surprisingly the viscosity of sodium caseinate solution at pH 4.64 was maximum and decreased by lowering pH. Particle size analysis confirmed the onset of big aggregates on decreasing pH but further acidification led to formation of smaller aggregates. A small concentration effect on pI was seen where at sodium caseinate levels of 0.03 wt.% the pI occurred at 4.29, where at sodium caseinate levels of 0.30 wt.% pI value was 4.64. PMID- 25745264 TI - Effect of modified atmospheric packaging on chemical and microbial changes in dietetic rabri during storage. AB - Rabri is a dairy based sweet popular in the Indian subcontinent. The high sugar and fat content impose restrictions on its consumption due to health reasons. Dietetic rabri was prepared by the replacement of sugar with aspartame. Inulin was added to partially replace the milk fat and to improve the consistency of rabri. The rabri samples were packed in the polyethylene bags filled with different gaseous compositions (Air, 50 % CO2:50 % N2 and 100 % N2) and stored at 10 degrees C. The shelf life was evaluated on the basis of changes in the chemical quality parameters such as HMF, TBA and FFA and microbial content such as total plate count, yeast and molds and coliform counts. The chemical parameters and microbial spoilage increased in all the samples with the progression of storage period. The samples packed with air showed significantly higher chemical deterioration and microbial spoilage as compared to the other two combinations. The samples packed with 100 % N2 were more shelf stable than with air and 50 % CO2:50 % N2 combinations. PMID- 25745265 TI - Effect of feed composition, moisture content and extrusion temperature on extrudate characteristics of yam-corn-rice based snack food. AB - Blends of yam, rice and corn flour were processed in a twin-screw extruder. Effects of yam flour (10-40 %), feed moisture content (12-24 %) and extruder barrel temperature (100-140 degrees C) on the characteristics of the dried extrudates was investigated using a statistical technique response surface methodology (RSM). Radial expansion ratio differed significantly (p <= 0.05) with change in all the independent variables. Highest expansion (3.97) was found at lowest moisture content (12 %) and highest barrel temperature (140 degrees C). Increased yam flour level decreased the expansion ratio significantly. Water absorption index (WAI) increased significantly with increase of all variables. However, water solubility index (WSI) did not change with change in yam flour percent. Hardness of extrudates that varied from 3.86 to 6.94 N was positively correlated with yam flour level and feed moisture content, however it decreased significantly (p <= 0.001) with increase of barrel temperature. Yam percent of 15.75 with feed moisture and barrel temperature at 12.00 % and 140 degrees C respectively gave an optimized product of high desirability (> 0.90) with optimum responses of 3.29 expansion ratio, 5.64 g/g dry solid water absorption index, 30.39 % water solubility index and 3.86 N hardness. The predicted values registered non-significant (p < 0.10) differences from the experimental results. Further study would include the sensory properties enhancement of extruded snacks and little emphasis on the chemistry of interaction between different components. PMID- 25745266 TI - Characterization and in vitro biological activities of Thai traditional fermented shrimp pastes. AB - In this work, chemical and biological characteristics of two types of Thai fermented shrimp paste, Kapi Ta Dam and Kapi Ta Deang, at different fermentation periods and their raw materials were investigated. Kapi had low water activity and high proteins with high glutamic acid and lysine. Both Kapis, which had different sources, showed similar characteristics. The number of lactic acid bacteria in the products increased during the early stages of fermentation. Free alpha-amino acid contents in the products increased with the fermentation time. The water extracts from Kapi products showed strong antioxidative activities against ABTS(+) radical, and ACE inhibitory activity but they did not exhibit antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Escherichia coli and Salmonella Typhimurium. Biological activities in Kapi could be developed by fermentation process, enzymatic hydrolysis of proteins and non enzymatic browning reactions. Kapi could, thus, serve as a potential source of natural bioactive substances. PMID- 25745267 TI - Compositional analysis of developed whey based fructooligosaccharides supplemented low- calorie drink. AB - Array of evidences have indicated that the supplementation of diet with functional and nutritional components to provide numerous health benefits. In this context, fortification with novel constituents as prebiotics i.e. fructooligosaccharides (FOS) is an encouraging trend all over the world. In the current exploration, FOS was used as a prebiotic in whey based functional drinks. For drink formulation, four samples were prepared i.e. whey based drink (T1) and FOS supplemented whey drinks @ 0.5, 1.0 and 1.5 % referred as T2, T3 and T4, respectively. The formulated drinks were evaluated for compositional analysis with special reference to amino acids and mineral profiles. The functional drinks showed momentous impact on total solids (TS) whilst, pH, acidity, crude protein and fat were affected non-significantly. However, pH, TS, fat and protein contents of prepared drinks were decreased substantially (p < 0.05) during storage period. However, prepared drinks showed non-significant variations in essential and non-essential amino acids. PMID- 25745268 TI - An integrative study of Necremnus Thomson (Hymenoptera: Eulophidae) associated with invasive pests in Europe and North America: taxonomic and ecological implications. AB - The species of Necremnus attacking two invasive pests of tomato and canola in Europe and North America, respectively, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) and Ceutorhynchus obstrictus (Marsham) (Coleoptera: Curculionidae), have been revised using an integrative taxonomy approach. Molecular data from the mitochondrial cytochrome oxidase c subunit I and the nuclear D2 expansion region of the 28S ribosomal subunit and internal transcribed spacer 2, the discovery of new morphological features, and study of type material resulted in the delineation of three species groups, the Necremnus artynes, Necremnus cosconius, and Necremnus tidius groups, the discovery of four new species, and the resurrection of three taxa from synonymy. Lectotypes have been designated for 13 species originally described in Eulophus by Walker. Although Necremnus has not been revised, an illustrated key is given to differentiate 23 recognized European species. The key, type images, and treatments of the three species groups will enable more accurate identification of the valid species of Necremnus in the future. They will also benefit biological control practitioners of pest species. The ecological consequences of the new taxonomic concepts are discussed. PMID- 25745269 TI - Hydrogen Bonding: HOC=O. . .H-N vs. HOC=O. . .H-C. AB - A chloroform-soluble dipyrrinone, 8,9-bis-(5-carboxypentyl)-2,3-bis-(2 methoxyethoxy)-10H-dipyrrin-1-one, with solubilizing 2-methoxyethoxy beta substituents on the lactam ring and two hexanoic acid groups (one at C(9), the other at C(8) of the pyrrole ring) was synthesized for its ability to form intramolecular hydrogen bonds to the lactam unit from either carboxylic acid, whether in the syn-(Z) or anti-(Z) conformation. In the syn-(Z) conformation, such intramolecular hydrogen bonds can also include the pyrrole N-H. In the anti (Z), intramolecular hydrogen bonds can include the pyrrole C(7)-H. Evidence for both monomer conformations in equilibrium is provided by 1H NMR analyses, which indicate that the syn-(Z) is favored over the anti-(Z) and predict an interconversion barrier of approximately 40 kJ mol-1. PMID- 25745270 TI - Under What Conditions Does Caseworker-Caregiver Racial/Ethnic Similarity Matter for Housing Service Provision? An Application of Representative Bureaucracy Theory. AB - In this article, we examine child welfare caseworkers' housing-related service strategies when they serve culturally similar versus culturally dissimilar clients. Testing hypotheses drawn from representative bureaucracy theory and using data from the second cohort of the National Survey of Child and Adolescent Well-Being, we find that when non-Caucasian caseworkers share the same racial/ethnic background as caregivers, caseworkers use more active strategies to connect caregivers to needed housing services. The relationship between racial/ethnic matching and frontline workers' repertoire of service strategies is most pronounced when the need for housing has been registered formally via referrals and case plans and thus legitimated institutionally. These results reinforce basic tenets of representative bureaucracy theory and provide evidence of the benefits of racial and ethnic diversity in the human service workforce. Our findings also highlight the need for research identifying institutional and frontline organizational factors that enhance the quality of service provision. PMID- 25745271 TI - Subsecond pore-scale displacement processes and relaxation dynamics in multiphase flow. AB - With recent advances at X-ray microcomputed tomography (MUCT) synchrotron beam lines, it is now possible to study pore-scale flow in porous rock under dynamic flow conditions. The collection of four-dimensional data allows for the direct 3 D visualization of fluid-fluid displacement in porous rock as a function of time. However, even state-of-the-art fast-MUCT scans require between one and a few seconds to complete and the much faster fluid movement occurring during that time interval is manifested as imaging artifacts in the reconstructed 3-D volume. We present an approach to analyze the 2-D radiograph data collected during fast-MUCT to study the pore-scale displacement dynamics on the time scale of 40 ms which is near the intrinsic time scale of individual Haines jumps. We present a methodology to identify the time intervals at which pore-scale displacement events in the observed field of view occur and hence, how reconstruction intervals can be chosen to avoid fluid-movement-induced reconstruction artifacts. We further quantify the size, order, frequency, and location of fluid-fluid displacement at the millisecond time scale. We observe that after a displacement event, the pore-scale fluid distribution relaxes to (quasi-) equilibrium in cascades of pore-scale fluid rearrangements with an average relaxation time for the whole cascade between 0.5 and 2.0 s. These findings help to identify the flow regimes and intrinsic time and length scales relevant to fractional flow. While the focus of the work is in the context of multiphase flow, the approach could be applied to many different MUCT applications where morphological changes occur at a time scale less than that required for collecting a MUCT scan. PMID- 25745272 TI - Model selection on solid ground: Rigorous comparison of nine ways to evaluate Bayesian model evidence. AB - Bayesian model selection or averaging objectively ranks a number of plausible, competing conceptual models based on Bayes' theorem. It implicitly performs an optimal trade-off between performance in fitting available data and minimum model complexity. The procedure requires determining Bayesian model evidence (BME), which is the likelihood of the observed data integrated over each model's parameter space. The computation of this integral is highly challenging because it is as high-dimensional as the number of model parameters. Three classes of techniques to compute BME are available, each with its own challenges and limitations: (1) Exact and fast analytical solutions are limited by strong assumptions. (2) Numerical evaluation quickly becomes unfeasible for expensive models. (3) Approximations known as information criteria (ICs) such as the AIC, BIC, or KIC (Akaike, Bayesian, or Kashyap information criterion, respectively) yield contradicting results with regard to model ranking. Our study features a theory-based intercomparison of these techniques. We further assess their accuracy in a simplistic synthetic example where for some scenarios an exact analytical solution exists. In more challenging scenarios, we use a brute-force Monte Carlo integration method as reference. We continue this analysis with a real-world application of hydrological model selection. This is a first-time benchmarking of the various methods for BME evaluation against true solutions. Results show that BME values from ICs are often heavily biased and that the choice of approximation method substantially influences the accuracy of model ranking. For reliable model selection, bias-free numerical methods should be preferred over ICs whenever computationally feasible. PMID- 25745273 TI - Incorporating spatial dependence in regional frequency analysis. AB - The efficiency of regional frequency analysis (RFA) is undermined by intersite dependence, which is usually ignored in parameter estimation. We propose a spatial index flood model where marginal generalized extreme value distributions are joined by an extreme-value copula characterized by a max-stable process for the spatial dependence. The parameters are estimated with a pairwise likelihood constructed from bivariate marginal generalized extreme value distributions. The estimators of model parameters and return levels can be more efficient than those from the traditional index flood model when the max-stable process fits the intersite dependence well. Through simulation, we compared the pairwise likelihood method with an L-moment method and an independence likelihood method under various spatial dependence models and dependence levels. The pairwise likelihood method was found to be the most efficient in mean squared error if the dependence model was correctly specified. When the dependence model was misspecified within the max-stable models, the pairwise likelihood method was still competitive relative to the other two methods. When the dependence model was not a max-stable model, the pairwise likelihood method led to serious bias in estimating the shape parameter and return levels, especially when the dependence was strong. In an illustration with annual maximum precipitation data from Switzerland, the pairwise likelihood method yielded remarkable reduction in the standard errors of return level estimates in comparison to the L-moment method. PMID- 25745274 TI - Equivariant minimax dominators of the MLE in the array normal model. AB - Inference about dependencies in a multiway data array can be made using the array normal model, which corresponds to the class of multivariate normal distributions with separable covariance matrices. Maximum likelihood and Bayesian methods for inference in the array normal model have appeared in the literature, but there have not been any results concerning the optimality properties of such estimators. In this article, we obtain results for the array normal model that are analogous to some classical results concerning covariance estimation for the multivariate normal model. We show that under a lower triangular product group, a uniformly minimum risk equivariant estimator (UMREE) can be obtained via a generalized Bayes procedure. Although this UMREE is minimax and dominates the MLE, it can be improved upon via an orthogonally equivariant modification. Numerical comparisons of the risks of these estimators show that the equivariant estimators can have substantially lower risks than the MLE. PMID- 25745275 TI - Disability Estimates between Same- and Different-Sex Couples: Microdata from the American Community Survey (2009-2011). AB - Disability and sexual orientation have been used by some to unjustly discriminate against differently-abled and differently-oriented minority groups. Because little is known about the disability rates of individuals in same-sex unions, this technical report presents disability rates by separating couples into: same sex-female; same-sex-male; different-sex-married; and different-sex-unmarried couples. Data from the American Community Survey (ACS) Public Use Microdata Sample (PUMS) 2009-2011 3-year file is utilized to produce estimates (and their standard errors) for the following six disability items: independent living; ambulatory; self-care; cognitive; hearing; and vision. Estimates of disability by selected geographies-i.e., Public Use Microdata Areas (PUMAs)-are also presented as is a figure showing a PUMA polygon. Qualitative comparisons seem to indicate that: same-sex-female couples have higher rates of disability compared to the other three groups; that in general, disability estimates for individuals in same sex couples have a greater degree of uncertainty; and that disability-item allocations are most prevalent in same-sex couples. Because societal marginalization may increase through cumulative processes, public health professionals should continue to seek out ways to identify underserved populations. PMID- 25745276 TI - Research Note: The consequences of different methods for handling missing network data in Stochastic Actor Based Models. AB - Although stochastic actor based models (e.g., as implemented in the SIENA software program) are growing in popularity as a technique for estimating longitudinal network data, a relatively understudied issue is the consequence of missing network data for longitudinal analysis. We explore this issue in our research note by utilizing data from four schools in an existing dataset (the AddHealth dataset) over three time points, assessing the substantive consequences of using four different strategies for addressing missing network data. The results indicate that whereas some measures in such models are estimated relatively robustly regardless of the strategy chosen for addressing missing network data, some of the substantive conclusions will differ based on the missing data strategy chosen. These results have important implications for this burgeoning applied research area, implying that researchers should more carefully consider how they address missing data when estimating such models. PMID- 25745277 TI - Hepatic polybrominated diphenyl ether (PBDE) levels in Wisconsin river otters (Lontra canadensis) and Michigan bald eagles (Haliaeetus leucocephalus). AB - Polybrominated diphenyl ethers (PBDEs) are persistent and toxic flame-retardant chemicals widespread in the Great Lakes ecosystem. These chemicals are now being regulated and phased-out of the region; therefore it remains important to understand the extent of contamination in order to track the efficacy of recent actions. Here, Sigma4PBDE congeners (PBDE-47, 99, 100, 153;wetweight basis unless indicated)were determined in liver tissues from Wisconsin river otters (Lontra canadensis; n = 35; 2009-2010) and Michigan bald eagles (Haliaeetus leucocephalus; n = 33; 2009-2011). In otters, Sigma4PBDE ranged from0.5 to 72.9 ng/g, with a mean (+/-SD) and median (25th-75th percentile inter-quartile range) of 16.3 +/- 16.4 ng/g and 11.3 (5.6-18.9) ng/g, respectively. The mean lipid adjusted Sigma4PBDE was 1377 +/- 1485 ng/g. In eagles, Sigma4PBDE ranged from 0 to 1,538.8 ng/g, with a mean and median of 74.3 +/- 266.7 ng/g and 21.2 (5.7 28.9) ng/g, respectively. The mean lipid-adjusted Sigma4PBDE was 5274.5 +/- 19,896.1 ng/g. In both species, PBDE-47 accounted for >50% of the Sigma4PBDE, followed by PBDE-99 and PBDE-100 (each ~17-19% of the total). The PBDE levels reported here in otters are similar to mammalian wildlife elsewhere, though the levels in eagles are among the highest worldwide across studied birds. The findings indicate that apex Great Lakes wildlife remain exposed to appreciable levels of PBDEs and more work is needed to understand whether such exposures are associated with adverse health outcomes. PMID- 25745278 TI - Building on Past Successes: Designing, Evaluating, and Providing Effective Treatments for Persons for Whom Typical Instruction Is Not Effective. AB - This article provides an overview of my experiences in special education as a teacher and subsequently as an intervention researcher providing background on where we were in providing instruction to individuals with disabilities 40 years ago (prior to legal protections and supports) compared with the present. This article acknowledges the progress that has been made in providing opportunities for students with disabilities to participate in the educational system including greater access to the general education classroom for increasing numbers of students with disabilities. However, stakeholders including special educators have inadequately targeted academic and behavioral improvements as their goals for individuals with disabilities. This is largely because the research base for students with disabilities with intensive academic and behavior needs is underdeveloped. Several recommendations are provided including increased funding for research on individuals with persistent learning and behavior problems that addresses how to acquire a more complete knowledge base about effective intensive interventions for these students. PMID- 25745279 TI - Stress and Immune Function during Pregnancy: An Emerging Focus in Mind-Body Medicine. AB - Maternal psychosocial stress during pregnancy is associated with risks to maternal health, birth outcomes, as well as adverse health and behavioral outcomes in offspring. Maternal immune dysregulation, particularly disruption of inflammatory processes, is also implicated in adverse perinatal health outcomes, with the greatest evidence in relation to preterm birth. Increasingly, the extent to which psychosocial stress induces dysregulation of inflammatory processes during pregnancy is being considered. In this article, I describe studies linking stress to immune function during pregnancy, with an emphasis on studies from our group on inflammation. As will be reviewed, research utilizing psychoneuroimmunology models in pregnancy is a rapidly developing area with abundant opportunities to address questions of clinical relevance for both maternal and child health. PMID- 25745280 TI - Category Learning Stretches Neural Representations in Visual Cortex. AB - We review recent work that shows how learning to categorize objects changes how those objects are represented in the mind and the brain. After category learning, visual perception of objects is enhanced along perceptual dimensions that were relevant to the learned categories, an effect we call dimensional modulation (DM). DM stretches object representations along category-relevant dimensions and shrinks them along category-irrelevant dimensions. The perceptual advantage for category-relevant dimensions extends beyond categorization and can be observed during visual discrimination and other tasks that do not depend on the learned categories. fMRI shows that category learning causes ventral stream neural populations in visual cortex representing objects along a category-relevant dimension to become more distinct. These results are consistent with a view that specific aspects of cognitive tasks associated with objects can account for how our visual system responds to objects. PMID- 25745281 TI - Integrated cervical smear screening using liquid based cytology and bioimpedance analysis. AB - OBJECTIVE: To minimize the false negativity in cervical cancer screening with Papanicolaou (Pap) test, there is a need to explore novel cytological technique and identification of unique and important cellular features from the perspectives of morphological as well as biophysical properties. MATERIALS AND METHODS: The present study explores the feasibility of low-cost cervical monolayer techniques in extracting cyto-pathological features to classify normal and abnormal conditions. The cervical cells were also analyzed in respect to their electrical bioimpedance. RESULT: The results show that newly developed monolayer technique for cervical smears is cost effective, capable of cyto pathological evaluation. Electrical bioimpedance study evidenced distinction between abnormal and normal cell population at more than two order of magnitude difference. CONCLUSION: The integration of bioimpedance observation along with the proposed low-cost monolayer technology could increase the efficiency of the cervical screening to a greater extent thereby reducing the rates of faulty diagnosis. PMID- 25745282 TI - Role of rapid on-site evaluation with cyto-histopathological correlation in diagnosis of lung lesion. AB - AIM: This study was conducted to assess the role of cytology in the diagnosis of lung lesions and to compare it with histopathology. It was also intended to evaluate the role of rapid on site evaluation (ROSE) as an adjunct to cytological diagnosis of lung lesions. MATERIALS AND METHODS: The study included all the cases of lung lesions, which were diagnosed on cytology followed by histopathology over a period of 21/2 years along with ROSE, wherever possible. RESULTS: Cytology was done in total 782 cases of various lung lesions and of this cyto-histopathological correlation was available in 215 cases. ROSE was done in 93.4% of total cases and smears were considered on the site adequate in the first pass in 68.1% cases and in second pass adequacy increased to 93.4%. The diagnostic accuracy of cytology was 75.3%, and that of histology was 86.9% in the diagnosis of lung lesions. The diagnostic accuracy of cytology for squamous cell carcinoma (94.4%) and adenocarcinoma (96.5%) was higher than that of histology. CONCLUSION: Cytology is comparable to histology in the diagnosis of lung lesions and may even outperform biopsy in lung tumor diagnosis. The advantages of cytology may be further added by better sampling and preanalytical assessment for adequate diagnostic material and ROSE has proved to be an important, easy and cost effective adjunct in this regard. A multidisciplinary approach involving pulmonologist, radiologist and cytopathologist with ROSE, followed by vigilant morphological examination may increase diagnostic utility of cytology for lung lesions. PMID- 25745283 TI - Crystalloids in salivary gland lesions. PMID- 25745284 TI - Schwannoma of the parotid gland: Diagnosis by fine-needle aspiration cytology. AB - In this brief report, we have described a rare case of schwannoma of the parotid gland in a young female who presented to us with a 3 cm diameter parotid swelling. The fine-needle aspiration cytology showed small fascicles, clusters and discrete spindle-shaped cells with long wavy nuclei. The cytological diagnosis of schwannoma of the parotid gland was offered and later confirmed by excision and histopathology. PMID- 25745285 TI - Fine-needle aspiration cytology of recurrent epithelioid sarcoma of the foot: Role of immonocytochemistry in definitive diagnosis. AB - Fine-needle aspirations (FNA) have played a crucial role in the diagnosis and follow-up of malignancies including sarcomas. However, relatively low specificity in the classification of sarcoma is the main limitation of FNA. Epithelioid sarcoma is a rare tumor of soft tissues. Very few individual case reports describing cytological features of epithelioid sarcoma have been documented in the literature. Here, we describe cytological features of epithelioid sarcoma with immunocytohistological correlation. PMID- 25745286 TI - Axillary node metastasis from primary ovarian carcinoma. AB - Metastasization and distinction from mammary carcinoma is of great clinical importance because of different treatment modalities. Here, we discuss a case of stage IIIC ovarian serous carcinoma, presenting with bilateral axillary nodes metastasis after 25 months interval of its initial presentation. Increased serum CA-125 level caused clinical suspicion. Computed tomography scan of abdomen and pelvis showed no residual disease or any abdominal lymphadenopathy. Mammography of both breast were normal. Bilateral axillary nodes were noted. Guided fine needle aspiration cytology (FNAC) and biopsy of ovarian carcinoma to axillary node is a rare event. Its recogn done. Cytomorphology revealed poorly differentiated carcinoma, compatible to that of primary ovarian tumor. Thus, metastatic carcinoma to axillary node from ovary was confirmed. This case illustrates a rare metastatic presentation of ovarian carcinoma and unequivocal role of FNAC to provide rapid diagnosis and preferred to be first line diagnostic procedure. PMID- 25745287 TI - Fine needle aspiration of Histiocytic sarcoma. AB - Histiocytic sarcoma is derived from histiocytes and is among the rarest of the tumors affecting the lymphoid tissue. We report a case of a histiocytic sarcoma arising from the lymph node in a 35-year-old male who came for a fine needle aspiration cytology and a subsequent biopsy was conducted and the tissue subjected to hematoxylin and eosin and immunohistochemistry staining. PMID- 25745288 TI - Cytodiagnosis of epithelioid malignant melanoma (amelanotic) and diagnostic dilemmas. AB - Melanoma is an aggressive neoplasm, and early diagnosis can reduce mortality in such patients. Diagnosis may be delayed in amelanotic tumors. We present one such case, a 35-year-old lady with a rapidly growing mass over the right angle of mandible. Fine-needle aspiration cytology was done, and smears showed discretely arranged large epithelioid cells with high N:C ratio, prominent single to multiple nucleoli. Occasional binucleated and multinucleated tumor giant cells were also noted. Poorly differentiated carcinoma, high-grade non-Hodgkin lymphoma, amelanotic melanoma, and pleomorphic sarcoma were included as differential diagnoses. Immunocytochemistry (ICC) revealed Melan-A/MART-1 positivity in some cells and S-100 positivity in most tumor cells. Desmin, pancytokeratin, and leukocyte common antigen were negative. Based on cytomorphological features and ICC findings, a diagnosis of epithelioid variant of amelanotic melanoma was rendered. Later on, true cut biopsy and histologic examination of excised specimen and adjunct immunohistochemistry with positive Melan-A and S-100 confirmed the diagnosis. PMID- 25745289 TI - Fine-needle aspiration cytology of metastatic squamous cell carcinoma thyroid: A rare entity. AB - Metastasis to the thyroid gland is rare with majority of cases discovered during an autopsy. Clinical presentation with a palpable thyroid or functional disturbances in thyroid is uncommon. We report isolated metastasis of laryngeal squamous cell carcinoma (SCC) to the thyroid gland diagnosed on fine-needle aspiration cytology which is minimally invasive and a preferred preliminary diagnostic modality in palpable thyroid swellings. A diagnosis of extra thyroidal SCC is a diagnosis of exclusion when there is no evidence of a coexistent recognizable primary thyroid cancer and/or molecular signatures suggestive of thyroidal origin. PMID- 25745290 TI - Fine needle aspiration cytology of dermal cylindroma. AB - In this paper, we have described fine needle aspiration cytology (FNAC) of a rare case of dermal cylindroma. A 40-year-old female presented with a lateral mid cervical swelling fixed to the skin. FNAC smears showed multiple clusters of small, round to oval cells with hyperchromatic nuclei, inconspicuous nucleoli and scant cytoplasm. In addition, the background showed deposits of basement membrane type material. This was dark magenta colored pinkish globular material. The globules were occasionally surrounded by the basal type of cells. Occasional cells with elongated nuclei were also noted. Cytological diagnosis of skin adnexal tumor possibly cylindroma was offered. Subsequent histopathology of the swelling showed sheets and clusters of cells in a jigsaw puzzle-like fashion. Deposition of abundant basement membrane-like material was noted in between the tumor cells. A diagnosis of cylindorma was offered. FNAC along with the subcutaneous location of the tumor and absence of primary salivary gland tumor may help to diagnose such rare case. PMID- 25745291 TI - Rosette forming glioneuronal tumor of the fourth ventricle in squash cytology smear. AB - Rosette forming glioneuronal tumor (RGNT) is a recently recognized and extremely rare glioneuronal tumor occurring in the fourth ventricle. It is crucial for the cytopathologist to be aware of this entity as it can be easily mistaken for more common neoplasms occurring at this site. We present here the cytology of such a rare case of RGNT that was misdiagnosed as ependymoma. The varying cytological features of this entity, as well as the common diagnostic difficulties encountered in cytology, are highlighted in this report. PMID- 25745292 TI - Primary thyroid lymphoma: A rare disease. AB - Primary thyroid lymphomas are rare neoplasms comprising of 1-5% of thyroid malignancies. These are predominantly B-cell in origin. Here, we report a case of 60 years lady, a known case of lymphocytic thyroiditis, diagnosed as thyroid lymphoma (diffuse large B-cell) on fine needle aspiration and confirmed histopathogically and immunohistochemically. She presented with a sudden increase in thyroid swelling. Fine needle aspiration performed showed highly cellular smears comprising predominantly of the monomorphic population of medium to large sized lymphoid cells with high nuclear/cytoplasmic ratio and scant cytoplasm. A possibility of thyroid lymphoma possibly diffuse large B-cell lymphoma was suggested which was later confirmed on biopsy. Fine needle aspiration provides an easy mode for diagnosing large cell lymphoma like diffuse large B-cell. Hence, an early diagnosis is possible for a timely intervention. Also, cases of lymphocytic thyroiditis should be regularly followed for the development of lymphoma. PMID- 25745293 TI - Oncocytic papillary cystadenoma of major salivary glands: Three rare cases with diverse cytologic features. AB - Oncocytic papillary cystadenoma (OPC) in the major salivary glands is extremely rare. We report three cases of these cystadenomas arising in major salivary glands, with varied cytologic features. Case 1: A 38-year-old man presented with a right parotid gland mass that showed papillary clusters of oncocytic cells on cytologic examination. Case 2: An 84-year-old man presented with a left parotid gland mass. Cytology revealed an acellular smear. Case 3: A 57-year-old man presented with a mass in the right submandibular gland. Cytology revealed irregular sheets of epithelial cells. Histologic diagnoses of OPC were made for all three cases. PMID- 25745294 TI - Tenosynovial giant cell tumor presenting as a parotid gland mass: Expanding the differential diagnosis of giant cell-rich lesions in salivary glands. AB - Tenosynovial giant cell tumors (TGCT) are rare benign soft tissue tumors affecting mostly young adults. The most common affected sites include the knee, ankle, elbow, shoulder, and fingers. The temporomandibular joint is occasionally affected. Herein, we report a case of a 31-year-old Caucasian male who presented clinically with a parotid gland mass. The initial clinical and radiological work up failed to reveal any involvement of the adjacent temporomandibular joint. Fine needle aspiration revealed a cellular tumor composed of mononuclear and multinucleated giant cells with fibrosis and hemosiderin deposition. This was subsequently found to be a TGCT arising from the temporomandibular joint. Giant cell-rich lesions are uncommon in salivary glands. Herein, we describe the cytomorphology and clinico-radiographic features of this tumor with emphasis on the differential diagnosis of giant cell-rich lesions presenting in salivary glands. Despite its rare occurrence, this entity should be considered when giant cells are prominent in specimens acquired from this location. PMID- 25745295 TI - An unusual presentation of Langerhans cell histiocytosis. AB - Langerhans cell histiocytosis (LCH) is a relatively rare and unique disease. An incidence of 7.9% in the jaws is reported. We report a case of 9-year-old male child referred to us from dental outpatient department, who presented with a firm swelling in right lower jaw along with bilateral submandibular lymphadenopathy for 1-month. Fine-needle aspiration was done from lytic lesion in the body of mandible and multiple smears were prepared. On the basis of the clinical and cytomorphological findings, a diagnosis of LCH was suggested. The diagnosis was confirmed on histology. Thus, a high possibility of LCH should be considered in children presenting with lytic lesions in head and neck region. PMID- 25745296 TI - Isolated cutaneous cryptococcosis in clinically unsuspected idiopathic CD4 lymphocytopenia. AB - Idiopathic CD4 lymphocytopenia first defined in 1992 by the U.S. Centers for Disease Control and Prevention, as the repeated presence of a CD4(+) T-lymphocyte count of fewer than 300 cells/cumm or of <20% of total T-cells with no evidence of human immunodeficiency virus (HIV) infection and therapy that might cause depressed CD4 T-cells. Most of the cases present with systemic opportunistic infections. We report a case without risk factors or laboratory evidence of HIV infection, presenting with cutaneous cryptococcal infection, diagnosed on cytology. PMID- 25745297 TI - Fine needle aspiration cytology of chondroblastoma of the fibula. AB - Chondroblastoma is a rare benign cartilaginous tumor typically seen in long bones, especially femur, tibia and proximal humerus. Extracortical soft tissue invasion or metastasis is rarely seen. We report here a unique case of chondroblastoma of the fibula with extracortical soft tissue invasion. Differential diagnosis on cytology is discussed. PMID- 25745298 TI - A focal nodular Hurthle cell hyperplasia in Hashimoto's thyroiditis: A diagnostic dilemma on fine needle aspiration. AB - Hurthle cells are seen in a variety of nonneoplastic and neoplastic thyroid gland lesions. Number and morphology of Hurthle cell vary in thyroid aspirate. Occasionally, thyroid aspirate in focal nodular Hurthle cell hyperplasia in Hashimoto's thyroiditis exclusively comprise of Hurthle cells and mimics Hurthle cell neoplasm. Fine needle aspiration (FNA) diagnosis in such cases is challenging. A 60-year-old female presented with goiter and clinical features of hyperthyroidism. FNA smears showed Hurthle cells arranged in flat sheets and lying singly with occasional lymphocytes in Hurthle cell sheets. Repeat aspiration from other site showed lymphocytes, infiltrating the thyroid follicular cells. We conclude that a careful search of lymphocytes in Hurthle cell sheets in cytology smears, multiple aspirates, associated clinical findings and ancillary techniques reduce the diagnostic pitfall and avoid unnecessary surgery. PMID- 25745299 TI - Cytology of secondary hemophagocytic lymphohistiocytosis masquerading as lymphoma in a nonimmunocompromised adult. AB - Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal immune disorder which is uncommon in a nonimmunocompromised adult. A 27-year-old female who presented with fever, hematuria, generalized lymphadenopathy was clinically suspected to have lymphoma was subjected to fine needle aspiration of cervical lymph nodes. Cytology of lymph node had numerous histiocytes with phagocytosed lymphocytes, red blood cells and nuclear debris. A diagnosis of secondary HLH was made based on cytological findings, clinical manifestations, and laboratory results. She was treated with steroids and recovered completely. A high degree of clinical suspicion coupled with comprehensive cytology with fine needle aspiration cytology is fruitful in the diagnosis of HLH, a potentially fatal disease and help in the delineation of therapeutic regimen. PMID- 25745300 TI - Anaplastic large cell lymphoma masquerading as rhabdomyosarcoma in fine needle aspiration cytology. PMID- 25745301 TI - Management of REM sleep behavior disorder: An evidence based review. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dream enactment behavior resulting from a loss of REM skeletal muscle atonia. The neurobiology of REM sleep and the characteristic features of REM atonia have an important basis for understanding the aggravating etiologies the proposed pharmacological interventions in its management. This review outlines the evidence for behavioral and therapeutic measures along with evidence-based guidelines for their implementation, impact on falls, and effect on polysomnography (PSG) while highlighting the non-motor, autonomic, and cognitive impact of this entity. PubMed databases were reviewed upto May 2013 in peer reviewed scientific literature regarding the pathophysiology and management of RBD in adults. The literature was graded according to the Oxford centre of evidence-based Medicine Levels. An early intervention that helps prevent consequences such as falls and provides a base for intervention with neuroprotective mechanisms and allocates a unique platform that RBD portrays with its high risk of disease conversion with a sufficiently long latency. RBD provides a unique platform with its high risk of disease conversion with a sufficiently long latency, providing an opportunity for early intervention both to prevent consequences such as falls and provide a base for intervention with neuroprotective mechanisms. PMID- 25745302 TI - The neuropsychiatric ailment of Vincent Van Gogh. AB - Vincent Van Gogh is one of the most celebrated creative artists of all time. All his life, he was afflicted by some kind of neurological or psychiatric disorder, which remains a mystery even today. Many historians and his personal physicians believe that he suffered from epilepsy while others felt that he was affected by Meniere's disease. Features such as hypergraphia, atypical sexuality, and viscosity of thinking suggest the possibility of Gastaut-Geschwind phenomenon, a known complication of complex partial seizure. On the contrary, some historians feel that he was forced to sever his right ear in order to get relief from troublesome tinnitus, a complication of Meniere's disease. He was addicted to the liquor absinthe, which is known to lead to xanthopsia, and many authorities argue that this was the reason for his penchant for the deep and bright yellow color in many of his paintings. Others have suggested the possibility of bipolar disorder, sunstroke, acute intermittent porphyria, and digitalis toxicity as well. PMID- 25745303 TI - Quantitative EEG and medial temporal lobe atrophy in Alzheimer's dementia: Preliminary study. AB - BACKGROUNDS: The electroencephalogram (EEG) abnormalities in Alzheimer's disease (AD) have been widely reported, and medial temporal lobe atrophy (MTLA) is one of the hallmarks in early stage of AD. We aimed to assess the relationship between EEG abnormalities and MTLA and its clinical validity. MATERIALS AND METHODS: A total of 18 patients with AD were recruited (the mean age: 77.83 years). Baseline EEGs were analyzed with quantitative spectral analysis. MTLA was assessed by a T1 axial visual rating scale (VRS). RESULTS: In relative power spectrum analysis according to the right MTLA severity, the power of theta waves in C4, T4, F4, F8, and T5 increased significantly and the power of beta waves in T6, C4, T4, F8, T5, P3, T3, and F7 decreased significantly in severe atrophy group. In relative power spectrum analysis according to the left MTLA severity, the power of theta waves in T3 increased significantly and that of beta waves in P4, T6, C4, F4, F8, T5, P3, C3, T3, F3, and F7 decreased significantly in severe atrophy group. CONCLUSION: The severe MTLA group, regardless of laterality, showed more severe quantitative EEG alterations. These results suggest that quantitative EEG abnormalities are correlated with the MTLA, which may play an important role in AD process. PMID- 25745304 TI - Plasmapheresis in neurological disorders: Experience from a tertiary care hospital in South India. AB - BACKGROUND: Therapeutic plasma exchange (PE) or plasmapheresis is the treatment of choice in many neurological disorders. Even though it is safe in experienced hands, there is a major concern about its safety among physicians. OBJECTIVES: To analyze our experience with 230 patients who underwent PE for various neurological disorders. MATERIALS AND METHODS: Retrospective review of PE procedures done during a period of 48 months, from July 2007 to June 2011 in a tertiary care teaching hospital in South India. Indications, clinical results and technical factors are discussed. RESULTS: The main indication for PE was GBS (203 patients; 88.3%). Age of patients ranged from 14-65 (mean = 42.3 years). The most common complications were paraesthesias and/or cramps (36.1%) and hypotension (32.2%). Four pregnant patients who underwent PE had good recovery with one intrauterine death. There was no mortality. CONCLUSION: The analysis of 240 cases of PE done in our department shows that the procedure is safe, with only minimal procedure related complications and no mortality. PMID- 25745305 TI - Pattern and risk factors of stroke in the young among stroke patients admitted in medical college hospital, Thiruvananthapuram. AB - BACKGROUND: Stroke in the young is particularly tragic because of its potential to create a long-term burden on the victims, their families, and the community. There had been relatively few studies on young stroke in Kerala's socio-economic setup, that too encapsulating the mentioned apparently relevant dimensions of stroke in the young. OBJECTIVE: To study the prevalence, patterns and risk factors of young stroke. SETTINGS AND DESIGN: A cross-sectional study with case control comparison at Government Medical College Hospital, Thiruvananthapuram, Kerala, India. MATERIALS AND AND METHODS: Total 100 stroke patients were identified over a period of 2 months, and data were collected on the basis of questionnaire developed for the purpose. RESULTS: Of 100 stroke patients, 15 had stroke in the young, among which 9 (60%) had ishaemic stroke. Hypertension was the most common risk factor. Smoking, alcohol, atrial fibrillation, and hyperlipidemia were found to be more common in cases (young stroke) when compared with controls. Alcohol use and atrial fibrillation were significantly higher among young stroke patients. Physical inactivity was significantly lesser in those with stroke in the young than elderly. Atrial fibrillation emerged as an independent risk factor of stroke in the young with adjusted odds ratio of 6.18 (1.31-29.21). CONCLUSION: In all, 15% of total stroke occurred in young adults <50 years. The proportion of hemorrhagic stroke in young adults is higher than in elderly. Atrial fibrillation is identified as an independent risk factor of stroke in the young. Compared with stroke in elderly alcohol use, smoking, hyperlipidemia, and cardiac diseases, which are known risk factors, are higher in young stroke. PMID- 25745306 TI - Pediatric Guillain-Barre syndrome: Indicators for a severe course. AB - OBJECTIVES: This study aims to retrospectively evaluate pediatric Guillain-Barre syndrome cases in a tertiary center in Istanbul, Turkey. MATERIALS AND METHODS: The data of 40 patients with Guillain-Barre syndrome who had been admitted to the Department of Pediatrics at the Istanbul University Medical Faculty between 2005 and 2011 were collected. Mann-Whitney U, Kruskal-Wallis, chi-square, and Fisher's exact tests were used for statistical analysis. RESULTS: Mean patient age was 5.4 +/- 3.0 years; 20 out of 40 patients (50%) were female and 20 (50%) were male. Preceding infection was detected in 32 cases (80%). Six patients had speech impairment. Out of eight patients with respiratory distress (20%), five required respiratory support (12.5%) of which three of them had speech impairment as well. According to nerve conduction studies, 21 patients (52.5%) had acute inflammatory demyelinating polyradiculoneuropathy, 14 (35%) had acute motor axonal neuropathy, and five (12.5%) had acute motor-sensory axonal neuropathy. Thirty-three patients (82.5%) received intravenous immunglobulin, 3 (7.5%) underwent plasmapheresis and 4 (10%) received both. Time until recovery (P = 0.022) and time until aided (P = 0.036) and unaided (P = 0.027) walking were longer in patients with acute gastrointestinal infection than in those with upper respiratory tract infection (P < 0.05). Time until response to treatment (P = 0.001), time until aided (P = 0.001) and unaided (P = 0.002) walking, and time until complete recovery (P = 0.002) were longer in acute motor axonal neuropathy cases as compared to acute inflammatory demyelinating polyradiculoneuropathy cases. CONCLUSION: Recovery was longer with acute gastrointestinal infection and acute motor axonal neuropathy. Speech impairment could be a clinical clue for the need of mechanical ventilation. PMID- 25745307 TI - Adaptation and validation of stroke-aphasia quality of life (SAQOL-39) scale to Hindi. AB - BACKGROUND: Stroke is a major detriment to the quality of life (QOL) in its victims. Several functional limitations following stroke contribute to the denigrated QOL in this population. Aphasia, a disturbance in the comprehension, processing, and/or expression of language, is a common consequence of stroke. Yet, in most Indian languages, including the national language (Hindi), there are no published tools to measure the QOL of persons with stroke-aphasia. OBJECTIVE: The current study was carried out to adapt and validate a well-known tool to measure the QOL (i.e., Stroke-Aphasia Quality of Life-39; SAQOL-39) to Hindi. MATERIALS AND METHODS: We presented the original (English) version of the SAQOL 39 to a group of six Hindi-speaking Speech Language Pathologists hailing from the central and northern regions of India to examine the sociocultural suitability of items and indicate modifications, if any. The linguistic adaptation was performed through a forward-backward translation scheme. The socioculturally and linguistically adapted (to Hindi) version was then administered on a group of 84 Hindi-speaking persons with aphasia to examine the acceptability, test-retest reliability as well as the internal consistency of the instrument. RESULTS: The SAQOL-39 in Hindi exhibited high test-retest reliability (ICC = 0.9) as well as acceptability with minimal missing data. This instrument exhibited high internal consistency (Chronbach's ? = 0.98) as well as the both item-to-total and inter domain correlations. CONCLUSIONS: The socioculturally and linguistically adapted Hindi version of SAQOL-39 is a robust tool to measure the QOL of persons with stroke-aphasia. It may serve as an essential tool to measure the QOL in this population for both clinical and research purposes. PMID- 25745308 TI - Neuropsychiatric co-morbidities in non-demented Parkinson's disease. AB - OBJECTIVE: To evaluate neuropsychiatric co-morbidities (depression, psychosis and anxiety) in non-demented patients with Parkinson's disease (PD). BACKGROUND: Non motor symptoms like neuropsychiatric co-morbidities are common in Parkinson's disease and may predate motor symptoms. Currently there is scarcity of data regarding neuropsychiatry manifestations in Indian patients with PD. METHODS: In this cross-sectional study consecutive 126 non-demented patients with PD (MMSE >=25) were enrolled. They were assessed using Unified Parkinson's disease rating scale (UPDRS), Hoehn & Yahr (H&Y) stage, Schwab and England (S&E) scale of activity of daily life. Mini-international neuropsychiatric interview (MINI) was used for diagnosis of depression, psychosis and anxiety. Beck's depression inventory (BDI), Brief psychiatric rating scale (BSRS) and Hamilton rating scale for anxiety (HAM-A) scales were used for assessment of severity of depression, psychosis and anxiety respectively. RESULTS: Mean age and duration of disease was 57.9 +/- 10.9 years and 7.3 +/- 3.6 years respectively. At least one of the neuropsychiatric co-morbidity was present in 64% patients. Depression, suicidal risk, psychosis and anxiety were present in 43.7%, 31%, 23.8% and 35.7% respectively. Visual hallucinations (20.6%) were most frequent, followed by tactile (13.5%), auditory (7.2%) and olfactory hallucinations (1.6%). Patients with depression had higher motor disability (UPDRS-motor score 33.1 +/- 14.0 vs 27.3 +/- 13.3; and UPDRS-total 50.7 +/- 21.8 vs 41.0 +/- 20.3, all p values <0.05). Patients with psychosis were older (63.6 +/- 8.0 years vs 56.1 +/- 11.1 years, p < 0.05) and had longer duration of illness (8.6 +/- 3.4 years vs 6.9 +/- 3.5, p < 0.05). CONCLUSIONS: About two third patients with Parkinson's disease have associated neuropsychiatric co-morbidities. Depression was more frequent in patients with higher disability and psychosis with longer duration of disease and older age. These co-morbidities need to be addressed during management of patients with PD. PMID- 25745309 TI - Seizures in patients with cerebral hemiatrophy: A prognostic evaluation. AB - PURPOSE: Cerebral hemiatrophy is a common childhood disease. It clinically manifests with seizures, hemiparesis and mental retardation. MATERIALS AND METHODS: In this prospective study, previously untreated patients with seizures and cerebral hemiatrophy were recruited. Cerebral hemiatrophy was diagnosed on the basis of hemispheric ratio. Patients with acquired hemiconvulsion, hemiplegia, and epilepsy (HHE) syndrome were included in group A. Group B included patients with congenital HHE syndrome. Patients were followed up for 6 months for seizure recurrence. RESULTS: Out of 42 patients 26 were in group A and 16 were in group B. After 6 months, there was significant reduction in seizure frequency (P < 0.0001) in both the groups. At least 50% reduction in seizure frequency was noted in all the patients. Complete seizure freedom was observed in 15 (35.7%) patients. Seizure recurrences were significantly higher (P = 0.008) in group A. On univariate analysis, predictors of seizure recurrences were history of febrile seizures (P = 0.013), hippocampal sclerosis (P = 0.001), thalamic atrophy (P = 0.001), basal ganglia atrophy (P = 0.001), cerebellar atrophy (P = 0.01), ventricular dilatation (P = 0.001), epileptiform discharges at presentation (P = 0.023), complex partial seizures (P = 0.006) and status epilepticus (P = 0.02). On multivariate analysis, hemispheric ratio was the only significant factor for seizure recurrence. CONCLUSION: Patients with congenital hemiatrophy had better seizure control than that in patients with HHE syndrome. PMID- 25745310 TI - Comparison of Levetiracetam and sodium Valproate in migraine prophylaxis: A randomized placebo-controlled study. AB - BACKGROUND: Migraine is a chronic and disabling disorder. Treatment of migraine often comprises of symptomatic (abortive) and preventive (prophylactic) treatment. The current drugs used in migraine prophylaxis include antidepressant drugs (Serotonin Reuptake Inhibitors, Tricyclic antidepressants), and anti epileptic drugs (valproate, gabapentin, etc). OBJECTIVE: The objective of our study was to assess the efficacy and tolerability of levetiracetam in adult migraine prophylaxis, compared to valproate and placebo. MATERIALS AND METHODS: We conducted a prospective, randomized, placebo-controlled study. A total of 85 patients were randomized to receive levetiracetam 500 mg/d (n = 27), valproate 500 mg/d (n = 32) or placebo (n = 26). The patients were evaluated for treatment efficacy after 6 months. Efficacy was assessed as a more than 50% decrease in headache frequency. RESULTS: In levetiracetam group, 17 (63.0%) patients experienced a more than 50% decrease in headache frequency, while this efficacy number was 21 (65.6%) for valproate group and 4 (15.4%) for placebo group. The difference was not statistically significant between levetiracetam and valproate, while it was significant when comparing either levetiracetam or valproate to placebo. CONCLUSION: Compared to placebo, levetiracetam offers improvement in headache frequency in patients with migraine. The efficacy of levetiracetam in migraine prophylaxis is comparable to currently used drugs such as valproate. PMID- 25745311 TI - Impulse control disorders and related behaviours (ICD-RBs) in Parkinson's disease patients: Assessment using "Questionnaire for impulsive-compulsive disorders in Parkinson's disease" (QUIP). AB - BACKGROUND: There is limited data on the prevalence of impulse control disorder and related behaviors (ICD-RBs) in Indian patients with Parkinson's Disease (PD). In the context of potential genetic and environmental factors affecting the expression of ICD-RBs, studying other multiethnic populations may bring in-sights into the mechanisms of these disorders. OBJECTIVES: To ascertain point prevalence estimate of ICD-RBs in Indian PD patients, using the validated "Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP)" and to examine their association with Dopamine replacement therapy (DRT). MATERIALS AND METHODS: This was a hospital based observational cross-sectional study. After taking informed consent, patients and their informants (spouse, or primary caregiver) were made to complete the QUIP, and were instructed to answer questions based on behaviors that occurred anytime during PD that lasted at least four consecutive weeks. RESULTS: Total of 299 patients participated in the study. At least one ICD RB was present in 128 (42.8%), at least one Impulse control disorder (ICD) was present in 74 (24.75%) and at least one Impulse control related compulsive behaviour (ICRB) was present in 93 (31.1%) patients. Punding was the most frequent (12.4%) followed by hyper sexuality (11.04%), compulsive hobbyism (9.4%), compulsive shopping (8.4%), compulsive medication use (7.7%), compulsive eating (5.35%), walkabout (4%) and pathological gambling (3.3%). >= 2 ICD-RBs were observed in 15.7% of patients. After multivariate analysis, younger age of onset, being unmarried were specifically associated with presence of ICD. Longer disease duration was specifically associated with presence of ICRB. Whereas smoking and higher dopamine levodopa equivalent daily doses (DA LEDD) were associated with both presence of ICD and ICRB. Higher LD LEDD was specifically associated with presence of ICD-RB. CONCLUSIONS: Our study revealed a relatively higher frequency of ICD-RBs, probably because of the use of screening instrument and because we combined both ICDs and ICRBs. Also high proportion of DA use (81.6%) among our patients might be responsible. The role of genetic factors that might increase the risk of developing ICD-RBs in this population needs further exploration. PMID- 25745312 TI - Test-retest reliability of transcarpal sensory NCV method for diagnosis of carpal tunnel syndrome. AB - BACKGROUND: Carpal Tunnel Syndrome (CTS) is the most frequent entrapment neuropathy affecting the upper extremity. There are a variety of electrodiagnostic methods available for documenting median neuropathy in CTS. In some studies, determining the sensory NCV across the palm-wrist segment has been introduced as the most sensitive diagnostic procedure for CTS. The aim of this study was to investigate the test-retest reliability of transcarpal median sensory NCV method for the diagnosis of CTS. MATERIALS AND METHODS: Twenty-three patients with clinical symptoms of CTS were tested two times by two different practitioners in one session and again by the first practitioner after one week. Stimulation of the median nerve was performed in the wrist and palm, with a conduction distance maximum of 7 cm, reliabilities of median nerves sensory nerve action potential latencies with stimulation at wrist and palm (W-SNAP, P-SNAP) and its transcarpal NCV were assessed with intraclass correlation coefficient (ICC). RESULTS: Comparison of the obtained values, which were done by two practitioners in one session showed ICC of W-SNAP latency, P-SNAP latency and transcarpal NCV of 0.93, 0.88 and 0.87, respectively and values that were done by one practitioner in two sessions with one-week interval showed ICC of 0.60, 0.50 and 0.47, respectively. CONCLUSION: Our findings suggest excellent interpractitioner test-retest reliability of transcarpal median sensory NCV method for diagnosing CTS. PMID- 25745313 TI - Hypertension and diabetes as risk factors for dementia: A secondary post-hoc analysis from north-west India. AB - INTRODUCTION: A relation between midlife risk factors (hypertension and diabetes) and dementia has been studied in past and an association has been documented, in spite of some studies pointing to the contrary. MATERIALS AND METHODS: The study was based on post-hoc analysis of data obtained from a study conducted on an elderly population (60 years and above) from selected geographical areas (migrant, urban, rural and tribal) of the Himachal Pradesh state in North-West India. RESULTS: Analysis of variance revealed an effect of risk factors on cognitive scores; however, post hoc Tukey's honest significant difference (HSD) test revealed that only hypertensives' demonstrated higher chances of scoring lower on cognitive measures. DISCUSSION: The possibility that hypertension and diabetes affect dementia needs further evaluation, more so in Indian context. PMID- 25745314 TI - Challenges in understanding the epidemiology of acquired brain injury in India. AB - An acquired brain injury (ABI) is an injury to the brain, which is not hereditary, congenital, degenerative, or induced by birth trauma. In India, rapid urbanization, economic growth and changes in lifestyle have led to a tremendous increase in the incidence of ABI, so much so that it is being referred to as a 'silent epidemic'. Unlike developed countries, there is no well-established system for collecting and managing information on various diseases in India. Thus it is a daunting task to obtain reliable information about acquired brain injury. In the course of conducting a systematic review on the epidemiology of ABI in India, we recognized several challenges which hampered our effort. Inadequate case definition, lack of centralized reporting mechanisms, lack of population based studies, absence of standardized survey protocols and inadequate mortality statistics are some of the major obstacles. Following a standard case definition, linking multiple hospital-based registries, initiating a state or nationwide population-based registry, conducting population-based studies that are methodologically robust and introducing centralized, standard reporting mechanisms for ABI, are some of the strategies that could help facilitate a thorough investigation into the epidemiology and understanding of ABI. This may help improve policies on prevention and management of acquired brain injury in India. PMID- 25745315 TI - Group B streptococcal meningitis in children beyond the neonatal period in sub Himalayan India. AB - OBJECTIVES: To evaluate clinicolaboratory profile and the outcomes in children (1 to 59 months) diagnosed with Group B streptococcus (GBS) meningitis over a period of 1 year. MATERIALS AND METHODS: Cerebrospinal fluid (CSF) samples of 250 pediatric patients (1 to 59 months) admitted with suspected acute bacterial meningitis(ABM)were subjected to cell count, biochemical profile, culture, latex particle agglutination (LPA) and polymerase chain reaction (PCR). They were also evaluated for complications and were followed-up till 6 months after discharge. RESULTS: Forty patients (25 boys and 15 girls), 16% of total suspected cases of ABM were diagnosed with GBS by LPA method and 30 (75%) out of these were above 3 months of age. The median duration of hospital stay was 7 days (range 1 to 72 days). State of coma was observed in two (5%) and one (2.5%) died, while 20 (50%) patients recovered completely. CONCLUSION: GBS should be considered as an important cause of ABM in Indian children beyond the neonatal period and further studies are warranted to determine the actual problem of the disease in our country. PMID- 25745316 TI - Hypertrophic multiple cranial neuropathies: An unusual presentation of primary CNS lymphoma. PMID- 25745317 TI - "Dot sign" in dengue encephalitis. AB - Neuro radiological findings in Dengue encephalitis are non specific. Here we report a case of Dengue encephalitis with transient splenial hyperintensity appearing as dot sign on magnetic resonance imaging of brain. PMID- 25745318 TI - Bright splenium of a psychotic mind. AB - A twenty-one-year old primigravida presented two weeks postpartum with new onset of behavioral alteration and irrelevant talking without fever, headache, or seizures. Magnetic resonance imaging (MRI) of brain showed a lesion with diffusion restriction in splenium of corpus callosum. A possibility of postpartum psychosis was considered after ruling out various etiologies for splenium hyperintense lesion. Near complete resolution of symptoms was noted after initiation of antipsychotic medications. Literature has described multiple etiologies for lesions involving splenium of corpus callosum on brain imaging. We present this case as a unique clinical presentation of splenial pathology in the form of postpartum psychosis. PMID- 25745319 TI - Central pontine myelinolysis presenting as isolated sixth nerve palsy in third trimester of pregnancy. AB - A 30-year-old primigravida presented with isolated left sixth nerve palsy at 38 weeks gestation. Her MRI showed a lesion consistent with central pontine myelinolysis (CPM). Extensive investigations did not reveal any secondary cause for the CPM. She recovered spontaneously in 2 weeks with complete resolution of her MRI changes. To our knowledge, this is the first report of CPM occurring in third trimester in the absence of identifiable secondary causes and of CPM presenting as an isolated sixth nerve palsy. We discuss the reported causes of CPM in pregnancy, possible pathophysiologic mechanisms involved and the anatomic basis of the unique clinical presentation of sixth nerve palsy in our case. PMID- 25745320 TI - Fazio Londe syndrome: A treatable disorder. AB - Fazio Londe Syndrome is a rare neurological disorder presenting with progressive bulbar palsy with respiratory failure. Initially considered to have an unrelenting course, is now found to be due to mutations in the SLC52A3 gene which encodes the intestinal (hRFT2) riboflavin transporter in some children. We report an 11-year-old child with features of Fazio Londe syndrome who presented to our Institute with respiratory failure. PMID- 25745321 TI - Becker's nevus with neurofibromatosis type 1. AB - Neurofibromatosis type 1 is an autosomal dominant disorder which primarily affects the growth and development of neural cell tissues. It presents as multiple tumor-like growths over the skin that arises from the nerves and is associated with other abnormalities like pigmentation over the skin and bone deformities. Becker's nevus or hairy pigmented epidermal nevus is a benign cutaneous hamartoma which is characterized by hyperpigmented macule with hypertrichosis. It is rarely associated with neurofibromatosis. We report a 22 years-old male with coexistent Becker's nevus and type 1 neurofibromatosis. PMID- 25745322 TI - Spinocerebellar ataxia-10 with paranoid schizophrenia. AB - Spino-cerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder that is characterized by cerebellar ataxia, seizures and nystagmus with a fragmented pursuit. Schizophrenia has been reported with SCAs 1 and 2 yet in SCA 10, psychiatric manifestations are uncommon. We report a Hispanic family involving a father and his four children with SCA10 genetic mutation. Two of his children, a 20-year-old female and a 23-year-old male, presented with gradually progressive spino-cerebellar ataxia and paranoid schizophrenia. Neurological examination revealed ocular dysmetria, dysdiadokinesia, impaired finger-to-nose exam, gait ataxia and hyperreflexia in both the cases. Additionally, they had a history of psychosis with destructive behavior, depression and paranoid delusions with auditory hallucinations. Serology and CSF studies were unremarkable and MRI brain revealed cerebellar volume loss. Ultimately, a test for ATAXIN-10 mutation was positive thus confirming the diagnosis of SCA10 in father and his four children. We now endeavor to investigate the association between schizophrenia and SCA10. PMID- 25745323 TI - Subacute sclerosing panencephalitis in a child with human immunodeficiency virus (HIV) infection on antiretroviral therapy. AB - Subacute Sclerosing Panencephalitis (SSPE) in HIV-infected children is a scarcely reported entity with previous reports describing fulminant course. The impact of highly active antiretroviral therapy (HAART) in altering its course remains unknown. We describe a child with HIV infection, who developed measles at 5 months of age and later developed SSPE at 14 years of age, remaining stable at 7 month follow-up, while on HAART for WHO (World Health Organisation) stage IV disease. The dynamics of HIV-related immunosuppression has an impact on the clinical course of SSPE. Contrary to reported cases of fulminant progression, a classic presentation with slow progression can be expected in children on HAART. We reemphasize the recommendation of "early measles vaccination" to prevent measles infection and subsequent SSPE in these children with an increasingly good life expectancy in the era of HAART. PMID- 25745324 TI - Alien hand and leg as the presenting feature of probable sporadic Creutzfeldt Jakob disease: A rare presentation of a rare disease. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) can have varied clinical presentation depending upon the genotype at codon 129. The common presenting clinical features of sCJD are rapid onset cognitive impairment, ataxia, psychosis and visual signs (field defects, distortion, cortical blindness). Alien limb sign was first described in patients with corpus callosal tumors and later with other neurodegenerative conditions like corticobasal degeneration. Alien hand complaints as the presenting feature of sCJD has been described in literature, but simultaneous alien hand and leg has been rarely described as presenting feature of sCJD. We describe here a case of a 55-year-old man who presented with progressive left alien hand and leg as the sole clinical manifestation of probable sCJD. PMID- 25745326 TI - Generalized chorea due to delayed encephalopathy after acute carbon monoxide intoxication. AB - Movement disorder due to delayed encephalopathy after carbon monoxide (CO) intoxication is uncommon. Generalized chorea, presenting as an initial symptom of delayed encephalopathy, is extremely rare. We describe a 60-year-old woman, who had completely recovered from acute CO poisoning, developed mental and behavioral changes, urinary incontinence and generalized chorea 2 weeks thereafter. T2 weighted brain magnetic resonance imaging showed extensive hyperintensity of the bilateral periventricular and subcortical white matter and the globus pallidus. Brain single-photon emission computed tomography (SPECT) with technetium-99 ethylene cysteine dimer showed inhomogeneous perfusion in the cerebral cortex, with decreased uptake in bilateral frontal regions. Delayed encephalopathy after acute CO intoxication was diagnosed, and the symptoms gradually improved after hyperbaric oxygen therapy (HBOT). This case report demonstrates that generalized chorea may be one of the initial presenting symptoms of delayed encephalopathy after acute CO intoxication. We hypothesize that the generalized chorea in our patient may have been caused by the subcortical white matter lesions, which most likely interrupted the basal ganglia-thalamocortical circuits and that HBOT may be the treatment of choice for such patients. PMID- 25745325 TI - Ictal Generalized EEG Attenuation (IGEA) and hypopnea in a child with occipital type 1 cortical dysplasia - Is it a biomarker for SUDEP? AB - An interesting association of ictal hypopnea and ictal generalized EEG attenuation (IGEA) as possible marker of sudden unexpected death in epilepsy (SUDEP) is reported. We describe a 5-years-old girl with left focal seizures with secondary generalization due to right occipital cortical dysplasia presenting with ictal hypopnea and IGEA. She had repeated episodes of the ictal apnoea in the past requiring ventilator support and intensive care unit (ICU) admission during episodes of status epilepticus. The IGEA lasted for 0.26-4.68 seconds coinciding with the ictal hypopnea during which both clinical seizure and electrical epileptic activity stopped. Review of literature showed correlation between post-ictal apnoea and post ictal generalized EEG suppression and increased risk for SUDEP. The report adds to the growing body of literature on peri-ictal apnea, about its association with IGEA might be considered as a marker for SUDEP. She is seizure free for 4 months following surgery. PMID- 25745327 TI - Episodic neurological dysfunction in hereditary peripheral neuropathy. AB - Episodic transient neurological symptoms are an important set of problems presenting to a neurologist in his routine practice. Occasionally, detailed clinical history including past and family history supplemented with focused examination can bring out a rare cause for such symptoms. We describe in this report in a young male presenting with episodic focal neurological dysfunction, with family history of similar episodes in mother and brother. Examination showed features of pes cavus and peripheral neuropathy for which patient was asymptomatic. Mother and brother were established cases of hereditary neuropathy. Imaging on multiple occasions showed reversible white matter abnormalities. Clinical suspicion of X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) was confirmed with detection of mutation in Gap Junction B1 (GJB1) gene, which codes for connexin 32 protein (c.425G>A; p.R142Q hemizygous mutation). Though this mutation has been already reported in CMTX patients, it has not been associated with transient neurological dysfunctions. This is probably the first reported case of CMTX patient with transient neurological dysfunction from India, whose family members had similar episodes. PMID- 25745328 TI - Unilateral rubral tremors in Wilson's disease treated with dimercaprol. AB - Tremors are reported as the most frequent neurological manifestation of Wilson's disease (WD) in some series. Postural tremors, rest tremors, action tremors and wing-beating (rubral) tremors are the different types of tremors seen in WD. We report a patient of WD with unilateral rubral tremors refractory to 1-year therapy with Penicillamine and anti-tremor medications. The tremors decreased considerably after adding chelation therapy with dimercaprol. Combination of Penicillamine and dimercaprol is an effective decoppering measure in rubral tremors of WD. PMID- 25745329 TI - Atypical lytic lesions of skull: Clinical and radiological correlation. AB - Imaging alone cannot differentiate various isolated atypical lytic lesions involving the skull. Clinical and radiological correlation is mandatory in reaching to a diagnosis. Histopathology remains the gold standard. We describe few atypical cases presenting as isolated lytic lesions of skull with characteristic imaging findings and a brief clinical approach to reach towards the diagnosis. PMID- 25745330 TI - Cerebrospinal fluid cytokines, matrix metalloproteinases, HIV, and tuberculous meningitis. PMID- 25745331 TI - Neuropsychiatric profiles in patients with Alzheimer's disease and vascular dementia. PMID- 25745332 TI - Cerebral venous sinus thrombosis: Role of extra cranial collateral circulation. PMID- 25745333 TI - Pseudo-dementia: A neuropsychological review. PMID- 25745334 TI - Safe and successful intravenous thrombolysis for acute stroke in a menstruating woman. PMID- 25745335 TI - Tacrolimus associated thrombotic thrombocytopenic purpura (TTP) and stroke in the young. PMID- 25745336 TI - Rare case of congenital absence of left internal carotid artery. PMID- 25745337 TI - Tuberculous meningitis on directly observed thrice a week regime. PMID- 25745338 TI - SEPARATION AND PURIFICATION OF TWO MINOR COMPOUNDS FROM RADIX ISATIDIS BY INTEGRATIVE MPLC AND HSCCC WITH PREPARATIVE HPLC. AB - Radix isatidis has been widely used as a Chinese traditional medicine for its anti-virus and anticancer activities where the minor components may contribute to these beneficial pharmaceutical effects. In order to enrich the target minor compounds effectively and rapidly, extraction, medium-pressure liquid chromatography (MPLC), high-speed countercurrent chromatography (HSCCC) and preparative high-performance liquid chromatography (pre-HPLC) were integratively used for separation and purification of two target minor compounds indole-3 acetonitrile-6-O-beta-D-glucopyranoside (target 1) and clemastanin B (target 2) in the present study. Radix isatidis was dried, pulverized and extracted with 50% methanol at room temperature, then concentrated and subjected to pretreatment with D-101 macroporous resin chromatography and extraction by MPLC. The first target compound was separated by MPLC at the purity raised to 70-80%, but without the second minor compounds which were irreversibly adsorbed by C18 solid support. Therefore, the second target compound in the crude extract was directly separated by HSCCC at purity of 80-90%. Finally these refined samples were further separated by pre-HPLC to obtain a high purity at 98-99%. The chemical structure identification of each target compound was carried out by IR, ESI-MS and 1H NMR. PMID- 25745339 TI - Image-guided percutaneous bone biopsy with a simulated van sonnenberg removable hub system. AB - OBJECTIVE: To retrospectively examine the success and complication rates associated with image-guided percutaneous bone biopsy with a simulated Van Sonnenberg removable hub system. MATERIALS AND METHODS: During a 3.5-year period, 27 bone lesions at different anatomic locations with an indication for biopsy based on plain film, computed tomography (CT) and/or magnetic resonance imaging (MRI) findings were determined, and a total of 28 image-guided (fluoroscopy or CT) percutaneous biopsies were performed using a simulated Van Sonnenberg removable hub system. This technique entailed the use of a cut-out Chiba needle hub that performed as a guide for the insertion of a larger needle. Either core and aspiration biopsy or core biopsy alone was utilized. RESULTS: The procedure yielded diagnostic material 89% of the cases (48% infection, 22% benign lesions, and 19% malignant lesions). Combined use of core and aspiration biopsy resulted in a higher diagnostic accuracy as compared to core biopsy alone. No false positive or false negative diagnoses were observed. No serious complications such as neurological deficits, bleeding, or organ injury were observed. CONCLUSION: The simulated Van Sonnenberg removable hub system provides a useful technique for percutaneous bone biopsies and is particulary suitable for deep seated (such as vertebral) lesions with its ability to facilitate the accessibility of the lesion with its built-in guidance needle. The procedure is safe in light of the literature data. PMID- 25745340 TI - Evaluation of Premature Infants Hospitalized in Neonatal Intensive Care Unit between 2010-2012. AB - OBJECTIVE: With continuing developments in the field of neonatology, survival rates of low birth weight and small for gestational age infants have increased, which in turn has brought important prematurity-related problems. The aim of this study was to evaluate retrospectively the prematurity problems that are the significant causes of morbidity and mortality. MATERIALS AND METHODS: 613 premature infants hospitalized in the neonatal intensive care unit of Ataturk University Medical Faculty Hospital between January 2010 and January 2012 were included in this study. Infants were divided into groups according to their birth weight and gestational age. RESULTS: 323 infants were male (52.6%) and 290 were female (47.4%). 63.9% of infants weighed >=1500 grams, and 58.5% had a gestational age of >=33 weeks. Respiratory distress syndrome (RDS) was detected in 249 (40.6%), bronchopulmonary dysplasia (BPD) in 124 (20.2%), necrotizing enterocolitis (NEC) in 41 (6.6%), retinopathy of prematurity (ROP) in 202 (32.9%), and intracranial hemorrhage (ICH) in 15 (2.4%). RDS, BPD, NEC, ROP, and ICH rates were inversely proportional to decreases in gestational age and birth weight, and were found to be statistically significant. CONCLUSION: Mortality and morbidity rates were similar to the other data published from our country, but the rates were above those reported in developed countries. We believe that our morbidity and mortality rates can reach levels comparable to those of developed countries with improved antenatal care, regular follow-up of pregnancy and increased numbers of physicians and health care personnel per patient. PMID- 25745341 TI - Significant Association between Serum Levels of Von Willebrand Factor (vWF) Antigen with Stages of Cirrhosis. AB - OBJECTIVE: Von Willebrand factor (vWF) is a mediator that increases endotoxemic medium like in cirrhosis. In this study we evaluated the association of serum VWF antigen (Ag) level with the stage of cirrhosis (according to Child-Pugh classification). MATERIALS AND METHODS: We included 82 cirrhotic patients (Female/Male (F/M): 26/56) and 86 healthy subjects (F/M: 44/42) in the study. Ages of the both groups of patients were not different (P= 0.095). We excluded possible other reasons that may cause VWF level increase. Diagnosis of cirrhosis was made on the basis of biopsy in 7 patients and with clinical and laboratory parameters in 75 patients. VWF Ag level was determined by immunoturbidimetric test. The stage of cirrhosis was defined with Child-Pugh classification. Data were analysed by using Statistical Package for the Social Sciences (SPSS) 10.0 software program. RESULTS: VWF Ag level was significantly higher in cirrhotic patients compared to control group (220+/-90 and 87+/-38, P<0.001, respectively). We observed significant increase of VWF Ag level with the increasing stages of cirrhosis according to Child-Pugh score (VWF Ag level for Child A-B-C 156.4+/ 54/215+/-45/284.8+/-93, respectively; P values for Child A-B/A-C/B-C; <0.001/<0.001/0.006, respectively). CONCLUSION: Serum VWF Ag level increases in cirrhotic patients and this is more pronounced with higher stages of cirrhosis. PMID- 25745342 TI - Third Year Medical School Students' Experiences of Revealing Patients' Stories through Role Playing. AB - OBJECTIVE: Studying medicine is hard and it takes longer time compared to other majors. In addition, medical students find medical education boring. It is now necessary to turn medical education into an enjoyable and interesting way. The aim of this study is to evaluate the impact of an educational program related to how to learn taking medical history and how an effective patient-doctor interview should be. The program is structured in various scenarios, on the students learning skills, by the "role playing" method. MATERIALS AND METHODS: A scenario prepared by the lecturer was employed in this study. While one of the students acted in a doctor role, the other one played in the role of patient's relative. The lecturer always played in the role of patient. After performing the role playing, students' written and oral feedbacks were gathered. Data were analysed by using SPSS 20.0 program. RESULTS: A total of 470 feedbacks (51.3% were given by the female students) were taken from the students. Thirty-three volunteer students, nineteen of them were male, took part in the role playing. In the patient-doctor interview, the field that students were best were greeting the patients and dealing only with patients during the examination. The mean scores were 3.81+/-0.95 and 3.79+/-0.94 respectively. The ability to "summarize" and to "address the patient with his/her name" had the lowest scores; the mean scores of the students in these areas were 2.94+/-1.11 and 2.70+/-1.31, respectively. CONCLUSION: Medical education is a long and tough process. Therefore, it should be interesting, attention getting and cheerful. Role playing can be effective in meeting that need. PMID- 25745343 TI - Investigation of antiulcer and antioxidant activity of moclobemide in rats. AB - OBJECTIVE: Even though there are many drugs for the treatment of gastric ulcers, these drugs sometimes cannot succeed. Since the 1950s, antidepressant drugs have been used for several non-psychiatric indications. Many antidepressant drugs have been shown experimentally to produce antiulcer activity in various ulcer models. Moclobemide is an antidepressant drug which inhibits monoamine oxidase-A (MAO) enzyme selectively. When it is compared to the classic antidepressants drugs, moclobemide is the first choice in depression treatment because of its effectiveness and less side effects. This study aimed to investigate the antiulcer effects of moclobemide and to determine its relationship with antioxidant mechanisms in rat gastric tissue. MATERIALS AND METHODS: The antiulcer activities of 10, 20, 40, 80, 150 mg/kg moclobemide and 20 mg/kg famotidine have been investigated on indomethacin-induced ulcers in rats, and the results have been compared with that of the control group. RESULTS: Moclobemide decreased the indomethacin-induced ulcers significantly at all doses used. While used doses of moclobemide increased the glutathione (GSH), nitric oxide (NO) level and superoxide dismutase (SOD) activity, it decreased the malondialdehyde (MDA) level and myeloperoxidase (MPO) activity in stomach tissue when compared to the control group. CONCLUSION: It is determined that an antidepressant drug, moclobemide is a potent anti-ulcer agent. Inhibition of toxic oxidant radicals and activation of antioxidant mechanisms play a role in its anti-ulcer effect mechanisms. PMID- 25745344 TI - The success of surgery in the first 24 hours in patients with esophageal perforation. AB - OBJECTIVE: Esophageal perforation (EP) is a critical and potentially life threatening condition with considerable rates of morbidity and mortality. Despite many advances in thoracic surgery, the management of patients with EP is still controversial. MATERIALS AND METHODS: We retrospectively reviewed 34 patients treated for EP, 62% male, mean age 53.9 years. Sixty-two percent of the EPs were iatrogenic. Spontaneous and traumatic EP rates were 26% and 6%, respectively. Three patients had EP in the cervical esophagus and 31 in the thoracic esophagus. RESULTS: Mean time to initial treatment was 34.2 hours. Twenty patients comprised the early group <24 h) and 14 patients the late group (>24 h). Management of the EP included primary closure in 30 patients, non-surgical treatment in two, stent in one and resection in one. Mortality occurred in nine of the 34 patients (26%). Mortality was EP-related in four patients. Three of the nine patients that died were in the early group (p<0.05). Mean hospital stay was 13.4 days. CONCLUSION: EP remains a potentially fatal condition and requires early diagnosis and accurate treatment to prevent the morbidity and mortality. PMID- 25745345 TI - Changing trends in the incidence of ovarian neoplasia and its relationship with the risk factors: a report of 311 cases from north-eastern anatolia region. AB - OBJECTIVE: Ovarian cancer is one of the most common and lethal gynecologic malignancy. In Turkey, the 8(th) most commonly seen neoplasm is ovarian cancer. The risk factors of ovarian cancer are menstrual reproductive events including gravida, menarche and menopause status, and life style habits such as cigarette smoking and habitat. In this study we aimed to determine the risk factors leading to ovarian cancer in Turkish women population and show the tumor markers in this population. MATERIALS AND METHODS: This study included 311 ovarian neoplasia cases diagnosed at the Pathology Department of Ataturk University in Erzurum over last seven years extending from 2005 to 2013. This study is a retrospective analysis basing on the pathology reports and accesible patient files. Serum tumor markers of the patients were retrospectively reported from their records. Conventional stained preparations existing in our archive examined by two pathologists as well independent of each other, and histopathologic diagnosis and the distribution of the sub-group was revised. RESULTS: A total of 311 patients were included in this study in which patients were diagnosed at the Pathology Department of Ataturk University in Erzurum. Serous cystadenoma is the most common ovarian tumor followed by mucinous cystadenoma, germ cell tumors, and dysgerminoma. All of the tumor markers were significantly normal. CONCLUSION: Upto our knowledge this was the first epidemiological study in Turkey. Analysis of each country's statistical information reflecting its own profile is also important. The relationship between the profiles of patients and types of ovarian neoplasia may give an idea about the risk factors of the disease in its region. Additionally, distribution of tumor markers might be considered for the discriminating of the benign or malign characters of the ovarian neoplasia. PMID- 25745346 TI - Turkish Validation and Adaptation of Children's Chronotype Questionnaire (CCTQ). AB - OBJECTIVE: Chronotype refers to the time of the day that a person's physical and cognitive functions are active. Simply this is a circadian phase preference of a person. While some of the people are morning active (so called larks) others are more active at nights (The owls). The study of circadian rhythms, known as chronobiology, is all about the metabolic and psychiatric differences between people who have different chronotypes. A few tests are used to determine chronotypes. The CCTQ (Children's Chronotype Questionnaire) is a parent-report, 27-item mixed format questionnaire measuring chronotype of children in multiple domains : the midsleep point on free days (MSF), a morningness/eveningness scale(M/E) score, and a five-point chronotype (CT) score. The aim of this study is adapting Children's Chronotype Questionnaire (CCTQ) into Turkish language and validating the instrument in Turkish population. MATERIALS AND METHODS: 101 children aged nine through eighteen constitude the sample of the study. The sample was composed of clinical (n=51) and community groups (n=50). CCTQ and Morningness Eveningness Scale for Children (MESC) questionnaires were applied to children and parents, then the CCTQ and MESC scores were compared to examine the validity of CCTQ. RESULTS: The internal consistency and external validity of the Turkish CCTQ was sufficient to compare MESC-Turkish. As a result of this research carried out in accordance with methodological research principles, correlation between the M/E scores of CCTQ and MESC was significant. CONCLUSION: The Turkish version of CCTQ has been found to be valid and reliable in Turkish children. PMID- 25745347 TI - Growth hormone therapy in children with chronic renal failure. AB - Growth is impaired in a chronic renal failure. Anemia, acidosis, reduced intake of calories and protein, decreased synthesis of vitamin D and increased parathyroid hormone levels, hyperphosphatemia, renal osteodystrophy and changes in growth hormone-insulin-like growth factor and the gonadotropin-gonadal axis are implicated in this study. Growth is adversely affected by immunosuppressives and corticosteroids after kidney transplantation. Treating metabolic disorders using the recombinant human growth hormone is an effective option for patients with inadequate growth rates. PMID- 25745348 TI - Angiofibroma from the tail of the inferior turbinate. AB - Nasopharyngeal angiofibromas are benign and vascular neoplasms, which originate characteristically in the posterior lateral wall of the nasopharynx. They account for less than 0.5% of all head and neck tumours. Although angiofibromas extend beyond the nasopharynx usually, they rarely originate outside the nasopharynx. Reports of primary extranasopharyngeal angiofibromas have appeared sporadically in the literature. The maxillary sinus is the most common site involved, while the inferior turbinate represents an extremely rare localization. We report a case of angiofibroma which arising from the tail of the inferior turbinate in the right nasal cavity. PMID- 25745349 TI - Traumatic fronto-ethmoidal encephalocele: a rare case. AB - Encephalocele is defined as herniation of the brain tissue from a bone defect in the cranium. It may be congenital, traumatic, tumoural or develop spontaneously. Traumatic fronto-ethmoidal encephalocele is rare and should be kept in mind for patients who have suffered trauma. Early diagnosis is important in terms of preventing life-threatening complications such as meningitis. Encephalocele and cerebrospinal fluid (CSF) leakage can be easily determined with basic radiological imaging methods and clinical findings. The computed tomography (CT) and magnetic resonance imaging (MRI) findings are here presented of a case with traumatic encephalocele. PMID- 25745350 TI - Life-threatening complication of percutaneous transthoracic fine-needle aspiration biopsy: systemic arterial air embolism. AB - Computed tomography-guided percutaneous transthoracic fine-needle aspiration biopsy of lung lesions is a well known diagnostic technique. Nevertheless, it has some complications; such as pneumothorax, intraparenchymal hemorrhage and hemoptysis, which are not rare. Air embolism is one of the rare but potentially fetal complications of this procedure. Herein, we report the case of a 69-year old male, in which case of systemic air embolism developed after the performance of lung biopsy. Early diagnosis and prompt oxygen therapy is crucial for patient's survival so careful reviewing of the obtained computed tomography images during the biopsy may prevent a missing systemic air embolism and provide an adequate therapy. PMID- 25745351 TI - Sigmoid volvulus complicating pregnancy: a case report. AB - Sigmoid volvulus during pregnancy is a rare complication, and as of 2012, fewer than 100 cases had been reported. In this report, we present a 30 year-old pregnant woman with sigmoid volvulus, and we discuss this rare entity. PMID- 25745352 TI - Spontaneous buccal hematoma secondary to enoxaparin treatment in a patient with acute coronary syndrome. PMID- 25745353 TI - Epidermal inclusion cyst of thyroid gland. PMID- 25745354 TI - Modeling Population Exposures to Silver Nanoparticles Present in Consumer Products. AB - Exposures of the general population to manufactured nanoparticles (MNPs) are expected to keep rising due to increasing use of MNPs in common consumer products (PEN 2014). The present study focuses on characterizing ambient and indoor population exposures to silver MNPs (nAg). For situations where detailed, case specific exposure-related data are not available, as in the present study, a novel tiered modeling system, Prioritization/Ranking of Toxic Exposures with GIS (Geographic Information System) Extension (PRoTEGE), has been developed: it employs a product Life Cycle Analysis (LCA) approach coupled with basic human Life Stage Analysis (LSA) to characterize potential exposures to chemicals of current and emerging concern. The PRoTEGE system has been implemented for ambient and indoor environments, utilizing available MNP production, usage, and properties databases, along with laboratory measurements of potential personal exposures from consumer spray products containing nAg. Modeling of environmental and microenvironmental levels of MNPs employs Probabilistic Material Flow Analysis combined with product LCA to account for releases during manufacturing, transport, usage, disposal, etc. Human exposure and dose characterization further employs screening Microenvironmental Modeling and Intake Fraction methods combined with LSA for potentially exposed populations, to assess differences associated with gender, age, and demographics. Population distributions of intakes, estimated using the PRoTEGE framework, are consistent with published individual-based intake estimates, demonstrating that PRoTEGE is capable of capturing realistic exposure scenarios for the US population. Distributions of intakes are also used to calculate biologically-relevant population distributions of uptakes and target tissue doses through human airway dosimetry modeling that takes into account product MNP size distributions and age-relevant physiological parameters. PMID- 25745355 TI - Origin stories from a regional placenta tissue collection. AB - Twenty-three years ago when women and their children were recruited to a longitudinal genetic epidemiological study during pregnancy, placentas were collected at birth. This paper explores the history of a regional placenta biobank and contemporary understandings of its value for the constitution of a research population. We draw on interviews with some of the mothers and those responsible for the establishment and curation of the placenta collection in order to explore the significance and meaning of the collection for them. Given its capacity to stand in for the study cohort of mothers and children, we argue that the material significance of the placenta biobank as a research tool seems far less important than the work it does in constituting a population. The stories about this collection may be understood within the wider context of developments in biobanking and the bioeconomy. PMID- 25745356 TI - Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-D-aspartate receptors. AB - BACKGROUND: Morphine-induced hyperalgesia and tolerance significantly limits its clinical use in relieving acute and chronic pain. Melatonin, a pineal gland neurohormone, has been shown to participate in certain neuropsychopharmacological actions. The present study investigated the effect of melatonin on morphine induced hyperalgesia and tolerance and possible involvement of protein kinase C (PKC)/N-methyl-D-aspartate (NMDA) pathway in melatonin-mediated. METHODS: Experiments were performed on adult, male Sprague-Dawley rats. Melatonin (10 mg/kg, intraperitoneal, i.p.) or saline was administrated 10 min after morphine injection (10 mg/kg, subcutaneous, s.c.) each day for consecutive 14 days. Withdrawal threshold of the hindpaw to mechanical and thermal stimulation was measured before any drug administration and one hour after melatonin or saline on each designated test day. On the 15(th) day, thermal withdrawal was measured after s.c. morphine (20 mg/kg), but not melatonin, and morphine tolerance was measured and expressed by MPAE% (percent of maximal possible anti-nociceptive effect) of morphine. Levels of expression of protein kinase C gamma (PKCgamma) and NMDA receptor subtype NR1 in spinal cord were detected by Western blotting. RESULTS: The mechanical withdrawal threshold and thermal withdrawal latency decreased and shortened significantly (i.e., threshold decreased) in rats that received morphine treatment for two weeks compared with that in rats receiving saline. This morphine-induced mechanical and thermal hyperalgesia were greatly attenuated by co-administration of morphine with melatonin. The MPAE% representing morphine analgesic effect was reduced approximately 60% in rats that received morphine treatment. However, following the treatment of morphine with melatonin, the MPAE% was reduced only about 30%, comparing with those that received saline treatment as control. Administration of morphine alone resulted in significantly increased expression of PKCgamma and NR1 proteins in the spinal cord. These increased levels of expression of PKCgamma and NR1 were significantly inhibited by co-administration of morphine with melatonin. CONCLUSIONS: Our findings demonstrate that melatonin have potential to attenuate repetitive morphine-induced hyperalgesia and tolerance, possibly by inhibiting PKCgamma and NR1 activities in the spinal cord. PMID- 25745357 TI - Increased cardiac index attenuates septic acute kidney injury: a prospective observational study. AB - BACKGROUND: The relationship between cardiac output and septic acute kidney injury (AKI) remains unclear. The purpose of this study was to assess the association between the cardiac index (CI) and the renal outcomes in patients with septic shock. METHODS: A one-year prospective cohort study was performed in the surgical and medical ICU of a teaching hospital in Nanjing, China. Twenty nine septic shock patients who required early goal-directed fluid resuscitation were consecutively included. Pulse indicator continuous cardiac output (PiCCO) device was used to measure hemodynamic parameters before and after early goal directed therapy (EGDT). Based on CI changes after EGDT, patients were assign to the CI increased group or the CI constant group, respectively. The incidence of poor renal outcome, which was defined as AKI on admission without recovery in following three days or new onset AKI within 28 days, was recorded. We investigated whether an increased CI was associated with a better renal outcome. RESULTS: After EGDT, there were 16 patients in the CI increased group and 13 patients in the CI constant group. The incidence of poor renal outcome was lower in CI increased group than in the CI constant group (6% vs. 62%; P = 0.003) with a relative risk of 0.10. The logistic regression showed that the CI percent change was associated with renal outcome, with an odd ratio of 0.003 (P = 0.056) after adjustment of possible confounding factors. The CI percent change would predict a good renal outcome (AU ROC 0.739, P = 0.012) with moderate accuracy (sensitivity 75% and specificity 89%) when using a 10% cut-off value from Youden index. The CI percent change was also positively correlated with creatinine clearance (CCr) after EGDT (rho = 0.548; P = 0.002). CONCLUSIONS: The increased CI after EGDT was a protective factor for kidney in patients with septic shock. A CI increased above 10% could be potentially used to predict development and reversibility of AKI in septic shock patients. TRIAL REGISTRATION: Clinicaltrials.gov:NCT01862588 (May 13, 2013). PMID- 25745358 TI - SOD2 immunoexpression predicts lymph node metastasis in penile cancer. AB - BACKGROUND: Superoxide dismutase-2 (SOD2) is considered one of the most important antioxidant enzymes that regulate cellular redox state in normal and tumorigenic cells. Overexpression of this enzyme in lung, gastric, colorectal, breast cancer and cervical cancer malignant tumors has been observed. Its relationship with inguinal lymph node metastasis in penile cancer is unknown. METHODS: SOD2 protein expression levels were determined by immunohistochemistry in 125 usual type squamous cell carcinomas of the penis from a Brazilian cancer center. The casuistic has been characterized by means of descriptive statistics. An exploratory logistic regression has been proposed to evaluate the independent predictive factors of lymph node metastasis. RESULTS: SOD2 expression in more than 50% of cells was observed in 44.8% of primary penile carcinomas of the usual type. This expression pattern was associated with lymph node metastasis both in the uni and multivariate analysis. CONCLUSIONS: Our results indicate that SOD2 expression predicts regional lymph node metastasis. The potential clinical implication of this observation warrants further studies. PMID- 25745359 TI - Psoriasin (S100A7) is a novel biomarker for lung squamous cell carcinoma in humans. AB - OBJECTIVE: Psoriasin (S100A7) plays a role in the malignant potential of several epithelial cancers, and could candidate diagnostic marker or therapeutic target. Nuclear factor kappa B (NF-kappaB) regulates cancer cell growth and is modulated by phospholipase activity in many cancer cells. In the present study, we first evaluate the involvement of S100A7 in lung squamous cell carcinoma and its clinical usefulness for diagnosis. We then study whether knockdown of S100A7 in lung squamous cell carcinoma cells would reduce cell proliferation and NF-kappaB activity in vitro and attenuate tumor growth in vivo. METHODS: We examined S100A7 expression in lung squamous cell carcinoma tissues by immunohistology. The human lung squamous cell carcinoma cell line NCI-H520 were transduced with short hairpin RNA targeting S100A7. Quantitative reverse transcriptase-polymerase chain reaction and immunoblotting confirmed knockdown of S100A7 messenger RNA and protein, respectively. Cell proliferation was evaluated by the MTT assay. NF kappaB phosphorylation was assayed by western blot. 1 * 10(6) of NCI-H520/S100A7 knockdown cells were injected into the left flanks of nude mice (aged 6 to 8 weeks). Tumors were followed for 35 days, then removed and stained with hematoxylin and eosin, stained with Ki-67, and analyzed for S100A7 protein expression. RESULTS: S100A7 protein levels were significantly higher in carcinoma specimens than in nonneoplastic tissues. S100A7 might be a useful marker for diagnosis of lung squamous cell carcinoma. In vitro data showed that inhibition of S100A7 decreased proliferation of NCI-H520 cells. S100A7 knockdown reduced NF kappaB phosphorylation and tumor growth in vivo and vivo. Explanted knockdown tumors maintained lower S100A7 levels compared with wild-type, confirmed by immunohistology. Ki-67 staining was more prominent throughout the wild-type tumors compared with knockdown tumors. CONCLUSIONS: Our present results suggest that S100A7 level is a promising tool for diagnosis of lung squamous cell carcinoma. Knockdown of S100A7 suppresses lung cancer growth in part by attenuating NF-kappaB activity. S100A7 may be a promising therapeutic target for lung squamous cell carcinoma. PMID- 25745360 TI - Human urothelial carcinoma cell response to Sunitinib malate therapy in vitro. AB - OBJECTIVES: Bladder transitional cell carcinoma (TCC) is one of the most common solid malignancies in China. This study examined the antitumor effect and underlying mechanism of action of sunitinib malate in human bladder TCC in vitro. METHODS: Bladder TCC cell lines 5637 and BIU87 were maintained in 1640 medium and T24 cell lines in DMEM/F12 medium. All 3 cell lines were then exposed to graded concentrations (0.625-20 MUmol/L) of sunitinib malate, sorafenib and cisplatin for 24-96 hours to determine the sensitivities to each drug. Cell viability was measured by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] assay, and apoptosis was analyzed by flow cytometry. Cell apoptotic morphology was observed by a fluorescence microscope after DAPI (4',6-diamidino-2-phenylindole) staining. Protein concentrations were measured by western blot. RESULTS: Sunitinib malate showed a concentration-dependent inhibitory effect on the 5637, T24 and BIU87 cell lines with IC50's of 1.74 MUmol/L, 4.22 MUmol/L, and 3.65 MUmol/L, respectively. Cisplatin also exhibited good antitumor activity, but whereas sorafenib suppressed proliferation of the cells at concentrations of 10 MUmol/L or higher, there was practically no response at lower concentrations. Sunitinib malate treatment resulted in an accumulation of cells in the sub-G1 phase, especially with the T24 and BIU87 cell lines, which induced apoptosis of the cells. CONCLUSIONS: Sunitinib malate exerted marked inhibitory activity against bladder cancer cells. The cell growth inhibitory effect of the drug was related to induction of apoptosis. These results suggest that clinical application of sunitinib-based therapy for advanced bladder cancer is possible. PMID- 25745361 TI - PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation. AB - PDZ binding-kinase (PBK) (also named T-lymphokine-activated killer cell originated protein kinase (TOPK)), a serine/threonine kinase, is tightly controlled in normal tissues but elevated in many tumors, and functions in tumorigenesis and metastasis. However, the signaling that regulates expression of PBK in cancer cells remains elusive. Here we show that atorvastatin (Lipitor), an inhibitor of hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase that is a rate limiting enzyme of mevalonate pathway, down-regulates expression of PBK by impairing protein geranylgeranylation. The shRNA knockdown demonstrated that Yes associated protein (YAP) mediates geranylgeranylation-regulated expression of PBK. Importantly, atorvastatin or the geranylgeranyltransferase I inhibitor GGTI 298 inhibited breast cancer cell proliferation through inactivation of YAP signaling and down-regulation of PBK. These findings have defined a new signaling pathway that regulated expression of PBK and identified PBK as a downstream target of the Hippo-YAP signaling, uncoverd a mechanism underlying the anti cancer effect by inhibition of mevalonate pathway and geranylgeranylation, and provided a potential target for breast cancer targeted therapy. PMID- 25745362 TI - Thanking our 2014 reviewers. AB - The Editor-in- Chief would like to thank all the reviewers who contributed to the journal in 2014. PMID- 25745363 TI - Abdominal vs. overall obesity among women in a nutrition transition context: geographic and socio-economic patterns of abdominal-only obesity in Tunisia. AB - BACKGROUND: Most assessments of the burden of obesity in nutrition transition contexts rely on body mass index (BMI) only, even though abdominal adiposity might be specifically predictive of adverse health outcomes. In Tunisia, a typical country of the Middle East and North Africa (MENA) region, where the burden of obesity is especially high among women, we compared female abdominal vs. overall obesity and its geographic and socio-economic cofactors, both at population and within-subject levels. METHODS: The cross-sectional study used a stratified, three-level, clustered sample of 35- to 70-year-old women (n = 2,964). Overall obesity was BMI = weight/height(2) >= 30 kg/m(2) and abdominal obesity waist circumference >= 88 cm. We quantified the burden of obesity for overall and abdominal obesity separately and their association with place of residence (urban/rural, the seven regions that compose Tunisia), plus physiological and socio-economic cofactors by logistic regression. We studied the within-subject concordance of the two obesities and estimated the prevalence of subject-level "abdominal-only" obesity (AO) and "overall-only" obesity (OO) and assessed relationships with the cofactors by multinomial logistic regression. RESULTS: Abdominal obesity was much more prevalent (60.4% [57.7-63.0]) than overall obesity (37.0% [34.5-39.6]), due to a high proportion of AO status (25.0% [22.8-27.1]), while the proportion of OO was small (1.6% [1.1-2.2]). We found mostly similar associations between abdominal and overall obesity and all the cofactors except that the regional variability of abdominal obesity was much larger than that of overall obesity. There were no adjusted associations of AO status with urban/rural area of residence (P = 0.21), education (P = 0.97) or household welfare level (P = 0.94) and only non-menopausal women (P = 0.093), lower parity women (P = 0.061) or worker/employees (P = 0.038) were somewhat less likely to be AO. However, there was a large residual adjusted regional variability of AO status (from 16.6% to 34.1%, adjusted P < 0.0001), possibly of genetic, epigenetic, or developmental origins. CONCLUSION: Measures of abdominal adiposity need to be included in population-level appraisals of the burden of obesity, especially among women in the MENA region. The causes of the highly prevalent abdominal-only obesity status among women require further investigation. PMID- 25745364 TI - Paternal Depression in the Postnatal Period and Early Father-Infant Interactions. AB - Objective. Paternal depressive disorder is associated with adverse effects on child development. One possible mechanism for this is through the effects of the disorder on parenting capacities. The link between paternal depression and father infant interactions was investigated at three-months postpartum. Design. Major depressive disorder was assessed in N = 192 fathers using a structured clinical interview (SCID). Altogether, 54 fathers met criteria for depression, and 99 fathers were categorized as non-depressed. Observational assessments of face-to face father-infant interactions were conducted in an infant-seat setting and a floor-mat setting. Associations between paternal depression and father-infant interactions were analyzed. Results. Paternal depression is associated with more withdrawn parental behavior in interactions on the floor-mat. There were few other differences in observed interaction between depressed and non-depressed fathers. Conclusions. Fathers with depression may be more withdrawn, displaying less verbal and behavioral stimulation during interactions with their young infants. They may initiate a pattern of parenting that remains compromised, potentially affecting their children's development. PMID- 25745365 TI - Attitudes and Training Needs of New England HIV Care and Addiction Treatment Providers: Opportunities for Better Integration of HIV and Alcohol Treatment Services. AB - OBJECTIVES: Unhealthy alcohol use is common among HIV-infected patients and contributes to co-morbidities, cognitive decline, unprotected sex, and poor medication adherence. Studies consistently show missed opportunities to address unhealthy alcohol use as part of care. Although treatment of other drug use has been integrated into HIV care in some settings, more information is needed regarding provider attitudes regarding the need for integration of alcohol treatment and HIV care. METHODS: We surveyed 119 HIV and 159 addiction providers regarding the following domains: existing knowledge, desire for new knowledge (with subdomains relative advantage, compatibility, and complexity of integrating knowledge), and individual and program development needs. Scale scores for each domain were correlated with demographics to identify factors associated with training need. RESULTS: Both HIV and addiction providers reported agreement with statements of existing knowledge and the need for additional skills. The priority attributed to training, however, was low for both groups. Knowledge and perceived prevalence of HIV and unhealthy alcohol use increased with years of experience. Perceived prevalence correlated with compatibility but not the relative advantage of training. CONCLUSIONS: Though addressing alcohol use and HIV was acknowledged to be important, the priority of this was low, particularly early career providers. These providers may be important targets for training focusing on motivating coordination of care and skills related to assessment and counseling. PMID- 25745366 TI - Being a Female Veteran: A Grounded Theory of Coping With Transitions. AB - Female veterans, the fastest growing segment in the military, have unique pre military histories and military experiences that are associated with post military physical and mental health service needs. Successful treatment is contingent on a clearer understanding of the processes underlying these experiences. Data from 20 female veterans who served post-Gulf War were analyzed to generate a substantive theory of the process of women who entered, served in, and transitioned out of the military. Coping with transitions emerged as the basic psychosocial process used by female veterans. The Coping with transitions process is comprised of seven categories: Choosing the Military, Adapting to the Military, Being in the Military, Being a Female in the Military, Departing the Military, Experiencing Stressors of Being a Civilian, and Making Meaning of Being a Veteran-Civilian. The results of this study provide a theoretical description of the process female veterans experience when transitioning from a civilian identity, through military life stressors and adaptations, toward gaining a dual identity of being a veteran-civilian. PMID- 25745367 TI - Technical tips to perform safe and effective ultrasound guided steroid joint injections in children. AB - BACKGROUND: The aim of this article is to describe the technique used to perform ultrasound guided steroid joint injections in children in a group of joints that can be injected using ultrasound as the only image guidance modality. FINDINGS: The technique is described and didactic figures are provided to illustrate key technical concepts. CONCLUSION: It is very important to be familiar with the sonographic appearance of the pediatric joints and the developing bone when performing ultrasound-guided joint injections in children. PMID- 25745369 TI - Letter from the editors. PMID- 25745368 TI - Prediction of methotrexate intolerance in juvenile idiopathic arthritis: a prospective, observational cohort study. AB - BACKGROUND: Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance. METHODS: In a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping. RESULTS: The prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0-17). At a cut-off of >=6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%. CONCLUSIONS: This clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance. TRIAL REGISTRATION: ISRCTN register, www.isrctn.com, ISRCTN13524271. PMID- 25745370 TI - The use of stem cells to study autism spectrum disorder. AB - Autism spectrum disorder (ASD) affects as many as 1 in 68 children and is said to be the fastest-growing serious developmental disability in the United States. There is currently no medical cure or diagnostic test for ASD. Furthermore, the U.S. Food and Drug Administration has yet to approve a single drug for the treatment of autism's core symptoms. Despite numerous genome studies and the identification of hundreds of genes that may cause or predispose children to ASD, the pathways underlying the pathogenesis of idiopathic ASD still remain elusive. Post-mortem brain samples, apart from being difficult to obtain, offer little insight into a disorder that arises through the course of development. Furthermore, ASD is a disorder of highly complex, human-specific behaviors, making it difficult to model in animals. Stem cell models of ASD can be generated by performing skin biopsies of ASD patients and then dedifferentiating these fibroblasts into human-induced pluripotent stem cells (hiPSCs). iPSCs closely resemble embryonic stem cells and retain the unique genetic signature of the ASD patient from whom they were originally derived. Differentiation of these iPSCs into neurons essentially recapitulates the ASD patient's neuronal development in a dish, allowing for a patient-specific model of ASD. Here we review our current understanding of the underlying neurobiology of ASD and how the use of stem cells can advance this understanding, possibly leading to new therapeutic avenues. PMID- 25745371 TI - Interactive social neuroscience to study autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative "interactive social neuroscience" methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD. PMID- 25745373 TI - Toward optimal outcome following pivotal response treatment: a case series. AB - There is a growing literature on children with autism spectrum disorder (ASD) who respond favorably to behavioral treatment, which is often termed "optimal outcome." Rates and definitions of optimal outcome vary widely. The current case series describes an empirically validated behavioral treatment approach called Pivotal Response Treatment (PRT). We present two preschool-aged children who received an intensive course of PRT and seem to be on a trajectory toward potential optimal outcome. Understanding response to treatment and predictors of response is crucial, not necessarily to predict who may succeed, but to individualize medicine and match children with customized treatment programs that will be best tailored to their unique and varied needs. PMID- 25745372 TI - Prospective MEG biomarkers in ASD: pre-clinical evidence and clinical promise of electrophysiological signatures. AB - Autism spectrum disorders (ASD) are characterized by social impairments and restricted/stereotyped behaviors and currently affect an estimated 1 in 68 children aged 8 years old. While there has been substantial recent focus on ASD in research, both the biological pathology and, perhaps consequently, a fully effective treatment have yet to be realized. What has remained throughout is the hypothesis that ASD has neurobiological underpinnings and the observation that both the phenotypic expression and likely the underlying etiology is highly heterogeneous. Given the neurodevelopmental basis of ASD, a biologically based marker (biomarker) could prove useful not only for diagnostic and prognostic purposes, but also for stratification and response indices for pharmaceutical development. In this review, we examine the current state of the field for MEG related biomarkers in ASD. We describe several potential biomarkers (middle latency delays [M50/M100], mismatch negativity latency, gamma-band oscillatory activity), and investigate their relation to symptomology, core domains of dysfunction (e.g., language impairment), and putative biological underpinnings. PMID- 25745375 TI - Sensory features as diagnostic criteria for autism: sensory features in autism. AB - In this study, we examined the frequency of sensory-related issues as reported by parents in a large sample of school-age adolescents and adults with autism/autism spectrum disorder (ASD) [1] as compared to a group of individuals receiving similar clinical evaluations for developmental/behavioral difficulties but whose final diagnoses were not on the autism spectrum. In no comparison were the features examined predictive of autism or autism spectrum in comparison to the non-ASD sample. Only failure to respond to noises had sensitivity above .75 in the comparison of the broader autism spectrum group, but specificity was poor. While sensory issues are relatively common in autism/ASD, they are also frequent in other disorders. These results question the rationale for including sensory items as a diagnostic criterion for autism. PMID- 25745374 TI - A comprehensive survey of current and former college students with autism spectrum disorders. AB - BACKGROUND: There is a paucity of research concerning individuals with autism spectrum disorders (ASD) pursuing higher education. METHOD: This study sought to augment this gap in the literature by surveying individuals with ASD who are currently college students or who have previously attended college. RESULTS: Thirty-five individuals completed an online survey. These individuals reported receiving extensive academic supports that enabled their academic success. Their reported difficulties in the social and emotional domains received less support. In addition, not all areas of campus life were supportive, as study abroad and career service offices were reported to not understand individuals with ASD. CONCLUSIONS: Overall, the results of this survey indicate the importance of self advocacy and the need for institutions of higher education to provide comprehensive supports for individuals with ASD in the academic, social, and emotional domains in order to effectively integrate this group into the campus environment. PMID- 25745376 TI - Toward innovative, cost-effective, and systemic solutions to improve outcomes and well-being of military families affected by autism spectrum disorder. AB - The burdens faced by military families who have a child with autism are unique. The usual challenges of securing diagnostic, treatment, and educational services are compounded by life circumstances that include the anxieties of war, frequent relocation and separation, and a demand structure that emphasizes mission readiness and service. Recently established military autism-specific health care benefits set the stage for community-viable and cost-effective solutions that can achieve better outcomes for children and greater well-being for families. Here we argue for implementation of evidence-based solutions focused on reducing age of diagnosis and improving access to early intervention, as well as establishment of a tiered menu of services, individualized to the child and family, that fit with the military ethos and system of health care. Absence of this new model of care could compromise the utility and sustainability of the autism-specific benefit. PMID- 25745377 TI - Advanced age and disease predict lack of symptomatic improvement after endovascular iliac treatment in male veterans. AB - BACKGROUND: Endovascular angioplasty and stent placement is currently the most frequent treatment for iliac artery occlusive disease. However, despite a successful endovascular procedure, some patients do not experience symptomatic improvement and satisfaction with their care. This study seeks to identify patient-related factors associated with lack of symptomatic improvement after endovascular iliac artery treatment in male veterans. METHODS: Retrospective review of patients treated with endovascular methods for iliac artery occlusive disease between January 2008 and July 2012 at VA Connecticut Healthcare System. Symptomatic improvement on the first post-operative visit was evaluated, with bilateral treatments counted separately. RESULTS: Sixty-two patients had 91 iliac arteries treated with angioplasty and stent placement. Forty-seven (52 percent) legs had critical limb ischemia, and 77 (85 percent) had at least two-vessel distal runoff. Angiographic success was 100 percent. Patient-reported symptomatic improvement at the first post-operative visit was 55 percent (50/91). Lack of symptomatic improvement correlated with older age (OR 1.09 [1.03-1.17], p = 0.008), presence of critical limb ischemia (OR 3.03 [1.09-8.65], p = 0.034), and need for additional surgical intervention (OR 5.61 [1.65-17.36], p = 0.006). Survival, primary and secondary patency, and freedom from restenosis were comparable between patients who reported symptomatic improvement and those who did not. CONCLUSIONS: Despite angiographically successful revascularization, patients who are older or have critical limb ischemia who are treated with isolated endovascular iliac artery intervention are more likely to require additional interventions and less likely to experience symptomatic improvement. These patients may need more extensive infra-inguinal revascularization than isolated iliac angioplasty and stent placement, despite a preserved ankle brachial index. Quality of life needs to be measured with formal instruments after iliac artery endovascular treatment, especially to determine long term outcomes. PMID- 25745378 TI - Blunt traumatic aortic injury of right aortic arch in a patient with an aberrant left subclavian artery. AB - Right-sided aortic arch (RAA) is a rare congenital developmental variant present in about 0.1 percent of the population. This anatomical anomaly is commonly associated with congenital heart disease and complications from compression of mediastinal structures. However, it is unknown if patients are at a higher risk of blunt thoracic aortic injury (BTAI). We report a case of a 20-year-old man admitted to the hospital after being hit by an automobile. Computed tomographic scan revealed an RAA with an aberrant left subclavian artery originating from a Kommerell's diverticulum. A pseudo-aneurysm was also seen along the aortic arch. A diagnosis of blunt traumatic aortic injury was made. The patient was successfully treated with a 26mm Vascutek hybrid stentgraft using the frozen elephant trunk technique. A literature review of the pathophysiology of BTAI was performed to investigate if patients with right-sided aortic arch are at a higher risk of suffering from BTAI. Results from the review suggest that although theoretically there may be a higher risk of BTAI in RAA patients, the rarity of this condition has prevented large studies to be conducted. Previously reported cases of BTAI in RAA have highlighted the possibility that the aortic isthmus may be anatomically weak and therefore prone to injury. We have explored this possibility by reviewing current literature of the embryological origins of the aortic arch and descending aorta. PMID- 25745379 TI - Long-run Relations between Childhood Shocks and Health in Late Adulthood-Evidence from the Survey of Health, Ageing, and Retirement in Europe. AB - In this article, we address the long-run associations between childhood shocks and health in late adulthood. Applying a life-course approach and data from SHARE, we estimate direct and indirect relations of shocks like relocation, dispossession, or hunger and health outcomes after 50 years of age. Having lived in a children's home, in a foster family, or having suffered a period of hunger turn out to be the most detrimental. Using a finite mixture model, which allows to classify the correlations between shocks and later health into a priori unknown groups, we show that some adverse shocks show opposite relations for specific groups. (JEL codes: J1, I12, J13). PMID- 25745380 TI - Tobacco retail availability and smoking behaviours among patients seeking treatment at a nicotine dependence treatment clinic. AB - BACKGROUND: Availability of tobacco may be associated with increased smoking. Little is known about how proximity to a retail outlet is associated with smoking behaviours among smokers seeking treatment. METHODS: A cross sectional study was conducted using chart data was extracted for 734 new clients of a nicotine dependence clinic in Toronto, Canada who visited during the period April 2008 to June 2010. Using a tobacco retail licensing list, clients were coded as to whether there were 0, 1, or more than 1 retail outlet located 250 m from their postal code address. Conditional fixed effects regression analyses were used to assess the association between proximity and quit status, number of previous quit attempts, number of cigarettes per day, and time to first cigarette, controlling for demographic characteristics and neighbourhood. RESULTS: 72% of patients lived within 250 m of a retail outlet. Those who had more than one outlet with 250 m of their address were less likely to be abstinent at the initial assessment (OR = 0.45; 95% CI: 0.23, 0.87; p = 0.014) and less likely to have a longer time to first cigarette (OR = 0.60; 95% CI: 0.45, 0.79), both before and after adjustment for covariates. Smokers who had at least one outlet within 250 m of their address smoked 3.4 cigarettes more per day than smokers without an outlet after controlling for neighbourhood and covariates. There was no significant association between proximity and lifetime number of quit attempts. CONCLUSIONS: Proximity to a tobacco retail outlet was associated with smoking behaviours among a heavily addicted, treatment seeking population. Environmental factors may have a substantial impact on the ability of smokers to quit smoking. PMID- 25745381 TI - Mental health screening and increased risk for anxiety and depression among treatment-seeking smokers. AB - BACKGROUND: The aim of this study was to compare the risk for mental health disorders between smokers and non-smokers and to assess the risk for depression and anxiety according to addiction severity. METHODS: This cross-sectional study assesses the mental health status and relationship with the severity of nicotine addiction in a sample of smokers admitted to Pamukkale University Hospital Smoking Cessation Clinic (n = 101) from 1 June 2012 to 31 August 2012 compared to a group of non-smokers from the general population (n = 101). We conducted semi structured face-to-face interviews to collect sociodemographic data; we assessed the participants' mental health status with the General Health Questionnaire-12 (GHQ-12) and the Hospital Anxiety and Depression Scale (HADS), and we measured nicotine addiction severity with the Fagerstrom Test. RESULTS: The risk for mental illness reported by smokers based on the GHQ-12 was significantly higher than that for non-smokers (p = 0.001). The anxiety and depression scores according to HADS were higher among smokers (16.8% and 22.8%, respectively) than non-smokers (4.0% and 5.0%, respectively) (p = 0.006 and p = 0.001, respectively). The nicotine addiction severity was higher in smokers with higher anxiety and depression scores (p = 0.008). CONCLUSIONS: We found high scores for mental illness in treatment-seeking smokers compared with non-smokers. The risk for anxiety and depression was higher among smokers. Increased nicotine addiction severity was associated with increased risk for mental illness and increased scores of anxiety and depression. PMID- 25745382 TI - Electronic cigarettes: patterns of use, health effects, use in smoking cessation and regulatory issues. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are battery-powered devices that vaporize a liquid solution to deliver a dose of inhaled nicotine to the user. There is ongoing debate regarding their regulation. OBJECTIVES: This comprehensive narrative review aimed to discuss key issues including usage patterns, health effects, efficacy in smoking cessation and regulatory concerns with a view to informing future regulation and research agendas. METHODS: PubMed, Scopus and Web of Science databases were searched using the terms (electronic cigarettes OR e-cigarettes) for articles in English, relevant to humans and published during January 2009-January 2014. RESULTS: The literature search revealed 37 relevant articles. Findings suggest that e-cigarettes are mostly used by middle-aged current smokers, particularly males, to help them for quitting or for recreation. E-cigarettes contain very low levels of multiple toxic substances such as formaldehyde and acrolein, but these levels are many times lower than those found in cigarettes. They were found to have effectiveness in aiding smoking cessation to a limited degree. Debate continues regarding regulating their use for cessation versus heavy restrictions to control recreational use on the basis that it perpetuates nicotine addiction. CONCLUSIONS: The cytotoxicity and long term health effects of e-cigarettes are unknown. Nevertheless the e cigarette market continues to expand, largely driven by middle-aged smokers who claim to be using e-cigarettes in an attempt to reduce or quit smoking. E cigarettes may have some potential as smoking cessation aids and, in the researchers' view, should therefore be subject to further research and regulation similar to other nicotine replacement therapies. PMID- 25745383 TI - Statistical inferences under the Null hypothesis: common mistakes and pitfalls in neuroimaging studies. AB - Published studies using functional and structural MRI include many errors in the way data are analyzed and conclusions reported. This was observed when working on a comprehensive review of the neural bases of synesthesia, but these errors are probably endemic to neuroimaging studies. All studies reviewed had based their conclusions using Null Hypothesis Significance Tests (NHST). NHST have yet been criticized since their inception because they are more appropriate for taking decisions related to a Null hypothesis (like in manufacturing) than for making inferences about behavioral and neuronal processes. Here I focus on a few key problems of NHST related to brain imaging techniques, and explain why or when we should not rely on "significance" tests. I also observed that, often, the ill posed logic of NHST was even not correctly applied, and describe what I identified as common mistakes or at least problematic practices in published papers, in light of what could be considered as the very basics of statistical inference. MRI statistics also involve much more complex issues than standard statistical inference. Analysis pipelines vary a lot between studies, even for those using the same software, and there is no consensus which pipeline is the best. I propose a synthetic view of the logic behind the possible methodological choices, and warn against the usage and interpretation of two statistical methods popular in brain imaging studies, the false discovery rate (FDR) procedure and permutation tests. I suggest that current models for the analysis of brain imaging data suffer from serious limitations and call for a revision taking into account the "new statistics" (confidence intervals) logic. PMID- 25745384 TI - Evaluating the reliability of different preprocessing steps to estimate graph theoretical measures in resting state fMRI data. AB - With resting-state functional MRI (rs-fMRI) there are a variety of post processing methods that can be used to quantify the human brain connectome. However, there is also a choice of which preprocessing steps will be used prior to calculating the functional connectivity of the brain. In this manuscript, we have tested seven different preprocessing schemes and assessed the reliability between and reproducibility within the various strategies by means of graph theoretical measures. Different preprocessing schemes were tested on a publicly available dataset, which includes rs-fMRI data of healthy controls. The brain was parcellated into 190 nodes and four graph theoretical (GT) measures were calculated; global efficiency (GEFF), characteristic path length (CPL), average clustering coefficient (ACC), and average local efficiency (ALE). Our findings indicate that results can significantly differ based on which preprocessing steps are selected. We also found dependence between motion and GT measurements in most preprocessing strategies. We conclude that by using censoring based on outliers within the functional time-series as a processing, results indicate an increase in reliability of GT measurements with a reduction of the dependency of head motion. PMID- 25745386 TI - Dual role of microglia in health and disease: pushing the balance toward repair. PMID- 25745385 TI - Cortical reorganization in recent-onset tinnitus patients by the Heidelberg Model of Music Therapy. AB - Pathophysiology and treatment of tinnitus still are fields of intensive research. The neuroscientifically motivated Heidelberg Model of Music Therapy, previously developed by the German Center for Music Therapy Research, Heidelberg, Germany, was applied to explore its effects on individual distress and on brain structures. This therapy is a compact and fast application of nine consecutive 50 min sessions of individualized therapy implemented over 1 week. Clinical improvement and long-term effects over several years have previously been published. However, the underlying neural basis of the therapy's success has not yet been explored. In the current study, the therapy was applied to acute tinnitus patients (TG) and healthy active controls (AC). Non-treated patients were also included as passive controls (PTC). As predicted, the therapeutic intervention led to a significant decrease of tinnitus-related distress in TG compared to PTC. Before and after the study week, high-resolution MRT scans were obtained for each subject. Assessment by repeated measures design for several groups (Two-Way ANOVA) revealed structural gray matter (GM) increase in TG compared to PTC, comprising clusters in precuneus, medial superior frontal areas, and in the auditory cortex. This pattern was further applied as mask for general GM changes as induced by the therapy week. The therapy-like procedure in AC also elicited similar GM increases in precuneus and frontal regions. Comparison between structural effects in TG vs. AC was calculated within the mask for general GM changes to obtain specific effects in tinnitus patients, yielding GM increase in right Heschl's gyrus, right Rolandic operculum, and medial superior frontal regions. In line with recent findings on the crucial role of the auditory cortex in maintaining tinnitus-related distress, a causative relation between the therapy-related GM alterations in auditory areas and the long-lasting therapy effects can be assumed. PMID- 25745387 TI - Identification of age- and disease-related alterations in circulating miRNAs in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by the progressive decline of memory and cognition. Histopathologically, two main hallmarks have been identified in AD: amyloid-beta peptide extracellular neuritic plaques and neurofibrillary tangles formed by posttranslational modified tau protein. A definitive diagnosis can only be achieved after the post mortem verification of the histological mentioned alterations. Therefore, the development of biomarkers that allow an early diagnosis and/or predict disease progression is imperative. The prospect of a blood-based biomarker is possible with the finding of circulating microRNAs (miRNAs), a class of small non-coding RNAs of 22-25 nucleotides length that regulate mRNA translation rate. miRNAs travel through blood and recent studies performed in potential AD cases suggest the possibility of finding pathology-associated differences in circulating miRNA levels that may serve to assist in early diagnosis of the disease. However, these studies analyzed samples at a single time-point, limiting the use of miRNAs as biomarkers in AD progression. In this study we evaluated miRNA levels in plasma samples at different time-points of the evolution of an AD-like pathology in a transgenic mouse model of the disease (3xTg-AD). We performed multiplex qRT-PCR and compared the plasmatic levels of 84 miRNAs previously associated to central nervous system development and disease. No significant differences were detected between WT and transgenic young mice. However, age-related significant changes in miRNA abundance were observed for both WT and transgenic mice, and some of these were specific for the 3xTg-AD. In agreement, variations in the levels of particular miRNAs were identified between WT and transgenic old mice thus suggesting that the age-dependent evolution of the AD-like pathology, rather than the presence and expression of the transgenes, modifies the circulating miRNA levels in the 3xTg-AD mice. PMID- 25745388 TI - Identifying the integrated neural networks involved in capsaicin-induced pain using fMRI in awake TRPV1 knockout and wild-type rats. AB - In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild type vs. knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain. PMID- 25745390 TI - Emotional modulation of synapses, circuits and memory. PMID- 25745389 TI - Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances contextual extinction learning without affecting renewal. AB - Renewal in extinction learning describes the recovery of an extinguished response if the extinction context differs from the context present during acquisition and recall. Attention may have a role in contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we investigated the role of the noradrenergic system for behavioral and brain activation correlates of contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During extinction of previously acquired cue-outcome associations, cues were presented in a novel context (ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo (PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover, ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC. Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with recall performance, suggesting high relevance of these regions for processing the renewal effect. In summary, the noradrenergic system appears to be involved in the modification of established associations during extinction learning and thus has a role in behavioral flexibility. The assignment of an association to a context and the subsequent decision on an adequate response, however, presumably operate largely independently of noradrenergic mechanisms. PMID- 25745391 TI - A robot hand testbed designed for enhancing embodiment and functional neurorehabilitation of body schema in subjects with upper limb impairment or loss. AB - Many upper limb amputees experience an incessant, post-amputation "phantom limb pain" and report that their missing limbs feel paralyzed in an uncomfortable posture. One hypothesis is that efferent commands no longer generate expected afferent signals, such as proprioceptive feedback from changes in limb configuration, and that the mismatch of motor commands and visual feedback is interpreted as pain. Non-invasive therapeutic techniques for treating phantom limb pain, such as mirror visual feedback (MVF), rely on visualizations of postural changes. Advances in neural interfaces for artificial sensory feedback now make it possible to combine MVF with a high-tech "rubber hand" illusion, in which subjects develop a sense of embodiment with a fake hand when subjected to congruent visual and somatosensory feedback. We discuss clinical benefits that could arise from the confluence of known concepts such as MVF and the rubber hand illusion, and new technologies such as neural interfaces for sensory feedback and highly sensorized robot hand testbeds, such as the "BairClaw" presented here. Our multi-articulating, anthropomorphic robot testbed can be used to study proprioceptive and tactile sensory stimuli during physical finger-object interactions. Conceived for artificial grasp, manipulation, and haptic exploration, the BairClaw could also be used for future studies on the neurorehabilitation of somatosensory disorders due to upper limb impairment or loss. A remote actuation system enables the modular control of tendon-driven hands. The artificial proprioception system enables direct measurement of joint angles and tendon tensions while temperature, vibration, and skin deformation are provided by a multimodal tactile sensor. The provision of multimodal sensory feedback that is spatiotemporally consistent with commanded actions could lead to benefits such as reduced phantom limb pain, and increased prosthesis use due to improved functionality and reduced cognitive burden. PMID- 25745392 TI - Combining time-frequency and spatial information for the detection of sleep spindles. AB - EEG sleep spindles are short (0.5-2.0 s) bursts of activity in the 11-16 Hz band occurring during non-rapid eye movement (NREM) sleep. This sporadic activity is thought to play a role in memory consolidation, brain plasticity, and protection of sleep integrity. Many automatic detectors have been proposed to assist or replace experts for sleep spindle scoring. However, these algorithms usually detect too many events making it difficult to achieve a good tradeoff between sensitivity (Se) and false detection rate (FDr). In this work, we propose a semi automatic detector comprising a sensitivity phase based on well-established criteria followed by a specificity phase using spatial and spectral criteria. In the sensitivity phase, selected events are those which amplitude in the 10-16 Hz band and spectral ratio characteristics both reject a null hypothesis (p < 0.1) stating that the considered event is not a spindle. This null hypothesis is constructed from events occurring during rapid eye movement (REM) sleep epochs. In the specificity phase, a hierarchical clustering of the selected candidates is done based on events' frequency and spatial position along the anterior-posterior axis. Only events from the classes grouping most (at least 80%) spindles scored by an expert are kept. We obtain Se = 93.2% and FDr = 93.0% in the first phase and Se = 85.4% and FDr = 86.2% in the second phase. For these two phases, Matthew's correlation coefficients are respectively 0.228 and 0.324. Results suggest that spindles are defined by specific spatio-spectral properties and that automatic detection methods can be improved by considering these features. PMID- 25745393 TI - Attachment classification, psychophysiology and frontal EEG asymmetry across the lifespan: a review. AB - In recent years research on physiological response and frontal electroencephalographic (EEG) asymmetry in different patterns of infant and adult attachment has increased. We review research findings regarding associations between attachment classifications and frontal EEG asymmetry, the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenocortical axis (HPA). Studies indicate that insecure attachment is related to a heightened adrenocortical activity, heart rate and skin conductance in response to stress, which is consistent with the hypothesis that attachment insecurity leads to impaired emotion regulation. Research on frontal EEG asymmetry also shows a clear difference in the emotional arousal between the attachment groups evidenced by specific frontal asymmetry changes. Furthermore, we discuss neurophysiological evidence of attachment organization and present up-to-date findings of EEG research with adults. Based on the overall patterns of results presented in this article we identify some major areas of interest and directions for future research. PMID- 25745394 TI - Directionality of large-scale resting-state brain networks during eyes open and eyes closed conditions. AB - The present study examined directional connections in the brain among resting state networks (RSNs) when the participant had their eyes open (EO) or had their eyes closed (EC). The resting-state fMRI data were collected from 20 healthy participants (9 males, 20.17 +/- 2.74 years) under the EO and EC states. Independent component analysis (ICA) was applied to identify the separated RSNs (i.e., the primary/high-level visual, primary sensory-motor, ventral motor, salience/dorsal attention, and anterior/posterior default-mode networks), and the Gaussian Bayesian network (BN) learning approach was then used to explore the conditional dependencies among these RSNs. The network-to-network directional connections related to EO and EC were depicted, and a support vector machine (SVM) was further employed to identify the directional connection patterns that could effectively discriminate between the two states. The results indicated that the connections among RSNs are directionally connected within a BN during the EO and EC states. The directional connections from the salience network (SN) to the anterior/posterior default-mode networks and the high-level to primary-level visual network were the obvious characteristics of both the EO and EC resting state BNs. Of the directional connections in BN, the directional connections of the salience and dorsal attention network (DAN) were observed to be discriminative between the EO and EC states. In particular, we noted that the properties of the salience and DANs were in opposite directions. Overall, the present study described the directional connections of RSNs using a BN learning approach during the EO and EC states, and the results suggested that the directionality of the attention systems (i.e., mainly for the salience and the DAN) in resting state might have important roles in switching between the EO and EC conditions. PMID- 25745395 TI - Brain activity during divided and selective attention to auditory and visual sentence comprehension tasks. AB - Using functional magnetic resonance imaging (fMRI), we measured brain activity of human participants while they performed a sentence congruence judgment task in either the visual or auditory modality separately, or in both modalities simultaneously. Significant performance decrements were observed when attention was divided between the two modalities compared with when one modality was selectively attended. Compared with selective attention (i.e., single tasking), divided attention (i.e., dual-tasking) did not recruit additional cortical regions, but resulted in increased activity in medial and lateral frontal regions which were also activated by the component tasks when performed separately. Areas involved in semantic language processing were revealed predominantly in the left lateral prefrontal cortex by contrasting incongruent with congruent sentences. These areas also showed significant activity increases during divided attention in relation to selective attention. In the sensory cortices, no crossmodal inhibition was observed during divided attention when compared with selective attention to one modality. Our results suggest that the observed performance decrements during dual-tasking are due to interference of the two tasks because they utilize the same part of the cortex. Moreover, semantic dual-tasking did not appear to recruit additional brain areas in comparison with single tasking, and no crossmodal inhibition was observed during intermodal divided attention. PMID- 25745396 TI - A Neurocomputational account of the role of contour facilitation in brightness perception. AB - A new filling-in model is proposed in order to account for challenging brightness illusions, where inducing background elements are spatially separated from the gray target such as dungeon, cube and grating illusions, bullseye display and ring patterns. This model implements the simple idea that neural response to low contrast contour is enhanced (facilitated) by the presence of collinear or parallel high-contrast contours in its wider neighborhood. Contour facilitation is achieved via dendritic inhibition, which enables the computation of maximum function among inputs to the node. Recurrent application of maximum function leads to the propagation of the neural signal along collinear or parallel contour segments. When a strong global-contour signal is accompanied with a weak local contour signal at the same location, conditions are met to produce brightness assimilation within the Filling-in Layer. Computer simulations showed that the model correctly predicts brightness appearance in all of the aforementioned illusions as well as in White's effect, Benary's cross, Todorovic's illusion, checkerboard contrast, contrast-contrast illusion and various variations of the White's effect. The proposed model offers new insights on how geometric factors (contour colinearity or parallelism), together with contrast magnitude contribute to the brightness perception. PMID- 25745397 TI - Numerical characterization of intraoperative and chronic electrodes in deep brain stimulation. AB - An intraoperative electrode (microelectrode) is used in the deep brain stimulation (DBS) technique to pinpoint the brain target and to choose the best parameters for the electrical stimulus. However, when the intraoperative electrode is replaced with the chronic one (macroelectrode), the observed effects do not always coincide with predictions. To investigate the causes of such discrepancies, a 3D model of the basal ganglia has been considered and realistic models of both intraoperative and chronic electrodes have been developed and numerically solved. Results of simulations of the electric potential (V) and the activating function (AF) along neuronal fibers show that the different geometries and sizes of the two electrodes do not change the distributions and polarities of these functions, but rather the amplitudes. This effect is similar to the one produced by the presence of different tissue layers (edema or glial tissue) in the peri-electrode space. Conversely, an inaccurate positioning of the chronic electrode with respect to the intraoperative one (electric centers not coincident) may induce a completely different electric stimulation in some groups of fibers. PMID- 25745398 TI - The Muller-Lyer illusion as seen by an artificial neural network. PMID- 25745400 TI - Differences in functional brain connectivity alterations associated with cerebral amyloid deposition in amnestic mild cognitive impairment. AB - Despite potential implications for the early detection of impending Alzheimer's disease (AD), very little is known about the differences of large-scale brain networks between amnestic mild cognitive impairment (aMCI) with high cerebral amyloid-beta protein (Abeta) deposition (i.e., aMCI+) and aMCI with no or very little Abeta deposition (i.e., aMCI-). We first aimed to extend the current literature on altering intrinsic functional connectivity (FC) of the default mode network (DMN) and salience network (SN) from cognitively normal (CN) to AD dementia. Second, we further examined the differences of the DMN and the SN between aMCI-, aMCI+, and CN. Forty-three older adult (12 CN, 10 aMCI+, 10 aMCI-, and 11 AD dementia) subjects were included. All participants received comprehensive clinical and neuropsychological assessment, resting-state functional magnetic resonance imaging, structural MRI, and Pittsburgh compound-B PET scans. FC data were preprocessed using multivariate exploratory linear optimized decomposition into independent components of FMRIB's Software Library. Group comparisons were carried out using the "dual-regression" approach. In addition, to verify presence of gray matter volume changes with intrinsic functional network alterations, voxel-based morphometry was performed on the acquired T1-weighted data. As expected, AD dementia participants exhibited decreased FC in the DMN compared to CN (particularly in the precuneus and cingulate gyrus). The degree of alteration in the DMN in aMCI+ compared to CN was intermediate to that of AD. In contrast, aMCI- exhibited increased FC in the DMN compared to CN (primarily in the precuneus) as well as aMCI+. In terms of the SN, aMCI- exhibited decreased FC compared to both CN and aMCI+ particularly in the inferior frontal gyrus. FC within the SN in aMCI+ and AD did not differ from CN. Compared to CN, aMCI- showed atrophy in bilateral superior temporal gyri whereas aMCI+ showed atrophy in right precuneus. The results indicate that despite the similarity in cross-sectional cognitive features, aMCI- has quite different functional brain connectivity compared to aMCI+. PMID- 25745399 TI - Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors. AB - Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1alpha inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2alpha exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1alpha mutant behaviors. Using patch-clamp recordings in Nrxn2alpha knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2alpha and Nrxn2beta. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2alpha, indicating that the beta-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2alpha and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders. PMID- 25745401 TI - Defining the microbial effluxome in the content of the host-microbiome interaction. PMID- 25745403 TI - Acute alcohol consumption and secondary psychopathic traits increase ratings of the attractiveness and health of ethnic ingroup faces but not outgroup faces. AB - Studies have consistently shown that both consumption of acute amounts of alcohol and elevated antisocial psychopathic traits are associated with an impaired ability for prepotent response inhibition. This may manifest as a reduced ability to inhibit prepotent race biased responses. Here, we tested the effects of acute alcohol consumption, and elevated antisocial psychopathic traits, on judgments of the attractiveness and health of ethnic ingroup and outgroup faces. In the first study, we show that following acute alcohol consumption, at a dose that is sufficient to result in impaired performance on tests of executive function, Caucasian participants judged White faces to be more attractive and healthier compared to when sober. However, this effect did not extend to Black faces. A similar effect was found in a second study involving sober Caucasian participants where secondary psychopathic traits were related to an intergroup bias in the ratings of attractiveness for White versus Black faces. These results are discussed in terms of a model which postulates that poor prefrontal functioning leads to increases in ingroup liking as a result of impaired abilities for prepotent response inhibition. PMID- 25745402 TI - SR calcium handling dysfunction, stress-response signaling pathways, and atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia. It is associated with a markedly increased risk of premature death due to embolic stroke and also complicates co-existing cardiovascular diseases such as heart failure. The prevalence of AF increases dramatically with age, and aging has been shown to be an independent risk of AF. Due to an aging population in the world, a growing body of AF patients are suffering a diminished quality of life and causing an associated economic burden. However, effective pharmacologic treatments and prevention strategies are lacking due to a poor understanding of the molecular and electrophysiologic mechanisms of AF in the failing and/or aged heart. Recent studies suggest that altered atrial calcium handling contributes to the onset and maintenance of AF. Here we review the role of stress-response kinases and calcium handling dysfunction in AF genesis in the aged and failing heart. PMID- 25745405 TI - The emergence of scalar meanings. AB - This paper analyzes the emergence of scalar additive meanings. We show that in Basque the same particle ere can obtain both the "simple additive" reading (akin to English too) and the "scalar additive" reading (akin to English even) but we argue that we do not have to distinguish two types of ere. We provide evidence, by means of a production and a perception experiment, that the reading is disambiguated by means of prosody (the placement of nuclear stress), which is a correlate of focus. We argue that the scalarity effect is generated by the combination of two presuppositions (a focus-induced one and a lexical one) and the assertion of the sentence. PMID- 25745404 TI - Feature saliency and feedback information interactively impact visual category learning. AB - Visual category learning (VCL) involves detecting which features are most relevant for categorization. VCL relies on attentional learning, which enables effectively redirecting attention to object's features most relevant for categorization, while 'filtering out' irrelevant features. When features relevant for categorization are not salient, VCL relies also on perceptual learning, which enables becoming more sensitive to subtle yet important differences between objects. Little is known about how attentional learning and perceptual learning interact when VCL relies on both processes at the same time. Here we tested this interaction. Participants performed VCL tasks in which they learned to categorize novel stimuli by detecting the feature dimension relevant for categorization. Tasks varied both in feature saliency (low-saliency tasks that required perceptual learning vs. high-saliency tasks), and in feedback information (tasks with mid-information, moderately ambiguous feedback that increased attentional load, vs. tasks with high-information non-ambiguous feedback). We found that mid information and high-information feedback were similarly effective for VCL in high-saliency tasks. This suggests that an increased attentional load, associated with the processing of moderately ambiguous feedback, has little effect on VCL when features are salient. In low-saliency tasks, VCL relied on slower perceptual learning; but when the feedback was highly informative participants were able to ultimately attain the same performance as during the high-saliency VCL tasks. However, VCL was significantly compromised in the low-saliency mid-information feedback task. We suggest that such low-saliency mid-information learning scenarios are characterized by a 'cognitive loop paradox' where two interdependent learning processes have to take place simultaneously. PMID- 25745406 TI - Degree of handedness and priming: further evidence for a distinction between production and identification priming mechanisms. AB - The distinction between implicit and explicit forms of memory retrieval is long standing, and important to the extent it reveals how different neural architecture supports different aspects of memory function. Similarly, distinctions have been made between kinds of repetition priming, a form of implicit memory retrieval. This study focuses on the production-identification (ID) priming distinction, which delineates priming tasks involving verification of stimulus features as compared to priming tasks that require use of a cue to guide response retrieval. Studies investigating this dissociation in dementia or similar patient populations indicate that these forms of priming may differ in their neural bases. The current study looks at degree of handedness as a way of investigating inferred neural architecture supporting these two forms of priming. A growing body of research indicates that degree of handedness (consistent, or CH, versus inconsistent, or ICH) is associated with greater interhemispheric interaction and functional access to right hemisphere processing in ICH, with superior performance seen in ICH on memory tasks reliant on this processing. Arguments about the theoretical mechanisms underlying ID and production forms of perceptual priming tasks suggest that performance on these tasks will differ as a function of degree of handedness. We tested this question in a group of CH and ICH young adults, who were asked to study lists of words prior to performing a production priming task (word stem completion, WSC), a perceptual word ID task, and a word stem cued recall task. While both handedness groups exhibited reliable priming across tasks, WSC priming was greater in ICH than CH participants, with ID priming not differing between groups. This dissociation supports the argument that production and ID forms of priming have different underlying neural bases. PMID- 25745407 TI - Are high-level aftereffects perceptual? PMID- 25745408 TI - Learning simple and complex artificial grammars in the presence of a semantic reference field: effects on performance and awareness. AB - This study investigated whether the negative effect of complexity on artificial grammar learning could be compensated by adding semantics. Participants were exposed to exemplars from a simple or a complex finite state grammar presented with or without a semantic reference field. As expected, performance on a grammaticality judgment test was higher for the simple grammar than for the complex grammar. For the simple grammar, the results also showed that participants presented with a reference field and instructed to decode the meaning of each exemplar (decoding condition) did better than participants who memorized the exemplars without semantic referents (memorize condition). Contrary to expectations, however, there was no significant difference between the decoding condition and the memorize condition for the complex grammar. These findings indicated that the negative effect of complexity remained, despite the addition of semantics. To clarify how the presence of a reference field influenced the learning process, its effects on the acquisition of two types of knowledge (first- and second-order dependencies) and on participants' awareness of their knowledge were examined. The results tentatively suggested that the reference field enhanced the learning of second-order dependencies. In addition, participants in the decoding condition realized when they had knowledge relevant to making a grammaticality judgment, whereas participants in the memorize condition demonstrated some knowledge of which they were unaware. These results are in line with the view that the reference field enhanced structure learning by making certain dependencies more salient. Moreover, our findings stress the influence of complexity on artificial grammar learning. PMID- 25745409 TI - Effects of working memory load on uncertain decision-making: evidence from the Iowa Gambling Task. AB - The Iowa Gambling Task (IGT) simulates uncertain gains and losses in real life situations and thus is a good measure of uncertain decision-making. The role of working memory (WM) in IGT performance still remains unclear. The present study aimed to examine the effect of WM on IGT performance. Three groups of participants matched on gender ratio were randomly assigned to no WM load, low WM load, and high WM load conditions. Initially the three groups did not show significant difference in WM capacity. They finished a modified version of IGT and then their implicit learning effect and explicit cognition on IGT were assessed. Results indicated a linear increasing trend of IGT performance among high WM load, low WM load and no WM load groups; participants in the no WM load and low WM load groups revealed implicit learning effect, while participants in the high WM load group did not; all participants showed explicit cognition on IGT to the same level. These results suggested that participants in the high WM load group showed good explicit cognition to IGT but showed poor performance. This pattern is similar to frontal patients. Further studies should be conducted to explore this issue. PMID- 25745410 TI - Hearing loss impacts neural alpha oscillations under adverse listening conditions. AB - Degradations in external, acoustic stimulation have long been suspected to increase the load on working memory (WM). One neural signature of WM load is enhanced power of alpha oscillations (6-12 Hz). However, it is unknown to what extent common internal, auditory degradation, that is, hearing impairment, affects the neural mechanisms of WM when audibility has been ensured via amplification. Using an adapted auditory Sternberg paradigm, we varied the orthogonal factors memory load and background noise level, while the electroencephalogram was recorded. In each trial, participants were presented with 2, 4, or 6 spoken digits embedded in one of three different levels of background noise. After a stimulus-free delay interval, participants indicated whether a probe digit had appeared in the sequence of digits. Participants were healthy older adults (62-86 years), with normal to moderately impaired hearing. Importantly, the background noise levels were individually adjusted and participants were wearing hearing aids to equalize audibility across participants. Irrespective of hearing loss (HL), behavioral performance improved with lower memory load and also with lower levels of background noise. Interestingly, the alpha power in the stimulus-free delay interval was dependent on the interplay between task demands (memory load and noise level) and HL; while alpha power increased with HL during low and intermediate levels of memory load and background noise, it dropped for participants with the relatively most severe HL under the highest memory load and background noise level. These findings suggest that adaptive neural mechanisms for coping with adverse listening conditions break down for higher degrees of HL, even when adequate hearing aid amplification is in place. PMID- 25745411 TI - Experience a conflict-either consciously or not (commentary on Desender, Van Opstal, and Van den Bussche, 2014). PMID- 25745412 TI - How experimental trial context affects perceptual categorization. AB - To understand object categorization, participants are tested in experiments often quite different from how people experience object categories in the real world. Learning and knowledge of categories is measured in discrete experimental trials, those trials may or may not provide feedback, trials appear one after another, after some fixed inter-trial interval, with hundreds of trials in a row, within experimental blocks with some structure dictated by the experimental design. In the real world, outside of certain educational and vocational contexts, opportunities to learn and use categories are intermixed over time with a whole multitude of intervening experiences. It is clear from any elementary understanding of human cognition that sequential effects matter, yet this understanding is often ignored, and categorization trials are often instead treated as independent events, immune to local trial context. In this perspective, we use some of our work to illustrate some of the consequences of the fact that categorization experiments have a particular trial structure. Experimental trial context can affect performance in category learning and categorization experiments in ways that can profoundly affect theoretical conclusions. PMID- 25745413 TI - Alleviating the concerns with the SDT approach to reasoning: reply to Singmann and Kellen (2014). PMID- 25745414 TI - The importance of structural anisotropy in computational models of traumatic brain injury. AB - Understanding the mechanisms of injury might prove useful in assisting the development of methods for the management and mitigation of traumatic brain injury (TBI). Computational head models can provide valuable insight into the multi-length-scale complexity associated with the primary nature of diffuse axonal injury. It involves understanding how the trauma to the head (at the centimeter length scale) translates to the white-matter tissue (at the millimeter length scale), and even further down to the axonal-length scale, where physical injury to axons (e.g., axon separation) may occur. However, to accurately represent the development of TBI, the biofidelity of these computational models is of utmost importance. There has been a focused effort to improve the biofidelity of computational models by including more sophisticated material definitions and implementing physiologically relevant measures of injury. This paper summarizes recent computational studies that have incorporated structural anisotropy in both the material definition of the white matter and the injury criterion as a means to improve the predictive capabilities of computational models for TBI. We discuss the role of structural anisotropy on both the mechanical response of the brain tissue and on the development of injury. We also outline future directions in the computational modeling of TBI. PMID- 25745415 TI - Oxygen deprivation and the cellular response to hypoxia in adipocytes - perspectives on white and brown adipose tissues in obesity. AB - Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction. We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells - particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the "browning" of white fat depots through recruitment of UCP1 and the development of brite adipocytes. PMID- 25745416 TI - Out of the dark: transitional subsurface-to-surface microbial diversity in a terrestrial serpentinizing seep (Manleluag, Pangasinan, the Philippines). AB - In the Zambales ophiolite range, terrestrial serpentinizing fluid seeps host diverse microbial assemblages. The fluids fall within the profile of Ca(2+)-OH(-) type waters, indicative of active serpentinization, and are low in dissolved inorganic carbon (DIC) (<0.5 ppm). Influx of atmospheric carbon dioxide (CO2) affects the solubility of calcium carbonate as distance from the source increases, triggering the formation of meter-scale travertine terraces. Samples were collected at the source and along the outflow channel to determine subsurface microbial community response to surface exposure. DNA was extracted and submitted for high-throughput 16S rRNA gene sequencing on the Illumina MiSeq platform. Taxonomic assignment of the sequence data indicates that 8.1% of the total sequence reads at the source of the seep affiliate with the genus Methanobacterium. Other major classes detected at the source include anaerobic taxa such as Bacteroidetes (40.7% of total sequence reads) and Firmicutes (19.1% of total reads). Hydrogenophaga spp. increase in relative abundance as redox potential increases. At the carbonate terrace, 45% of sequence reads affiliate with Meiothermus spp. Taxonomic observations and geochemical data suggest that several putative metabolisms may be favorable, including hydrogen oxidation, H2 associated sulfur cycling, methanogenesis, methanotrophy, nitrogen fixation, ammonia oxidation, denitrification, nitrate respiration, methylotrophy, carbon monoxide respiration, and ferrous iron oxidation, based on capabilities of nearest known neighbors. Scanning electron microscopy and energy dispersive X-ray spectroscopy suggest that microbial activity produces chemical and physical traces in the precipitated carbonates forming downstream of the seep's source. These data provide context for future serpentinizing seep ecosystem studies, particularly with regards to tropical biomes. PMID- 25745417 TI - Advancing the science of microbial symbiosis to support invasive species management: a case study on Phragmites in the Great Lakes. AB - A growing body of literature supports microbial symbiosis as a foundational principle for the competitive success of invasive plant species. Further exploration of the relationships between invasive species and their associated microbiomes, as well as the interactions with the microbiomes of native species, can lead to key new insights into invasive success and potentially new and effective control approaches. In this manuscript, we review microbial relationships with plants, outline steps necessary to develop invasive species control strategies that are based on those relationships, and use the invasive plant species Phragmites australis (common reed) as an example of how development of microbial-based control strategies can be enhanced using a collective impact approach. The proposed science agenda, developed by the Collaborative for Microbial Symbiosis and Phragmites Management, contains a foundation of sequential steps and mutually-reinforcing tasks to guide the development of microbial-based control strategies for Phragmites and other invasive species. Just as the science of plant-microbial symbiosis can be transferred for use in other invasive species, so too can the model of collective impact be applied to other avenues of research and management. PMID- 25745418 TI - Sequencing and characterizing the genome of Estrella lausannensis as an undergraduate project: training students and biological insights. AB - With the widespread availability of high-throughput sequencing technologies, sequencing projects have become pervasive in the molecular life sciences. The huge bulk of data generated daily must be analyzed further by biologists with skills in bioinformatics and by "embedded bioinformaticians," i.e., bioinformaticians integrated in wet lab research groups. Thus, students interested in molecular life sciences must be trained in the main steps of genomics: sequencing, assembly, annotation and analysis. To reach that goal, a practical course has been set up for master students at the University of Lausanne: the "Sequence a genome" class. At the beginning of the academic year, a few bacterial species whose genome is unknown are provided to the students, who sequence and assemble the genome(s) and perform manual annotation. Here, we report the progress of the first class from September 2010 to June 2011 and the results obtained by seven master students who specifically assembled and annotated the genome of Estrella lausannensis, an obligate intracellular bacterium related to Chlamydia. The draft genome of Estrella is composed of 29 scaffolds encompassing 2,819,825 bp that encode for 2233 putative proteins. Estrella also possesses a 9136 bp plasmid that encodes for 14 genes, among which we found an integrase and a toxin/antitoxin module. Like all other members of the Chlamydiales order, Estrella possesses a highly conserved type III secretion system, considered as a key virulence factor. The annotation of the Estrella genome also allowed the characterization of the metabolic abilities of this strictly intracellular bacterium. Altogether, the students provided the scientific community with the Estrella genome sequence and a preliminary understanding of the biology of this recently-discovered bacterial genus, while learning to use cutting-edge technologies for sequencing and to perform bioinformatics analyses. PMID- 25745419 TI - Recent advances in the genome-wide study of DNA replication origins in yeast. AB - DNA replication, one of the central events in the cell cycle, is the basis of biological inheritance. In order to be duplicated, a DNA double helix must be opened at defined sites, which are called DNA replication origins (ORIs). Unlike in bacteria, where replication initiates from a single replication origin, multiple origins are utilized in the eukaryotic genomes. Among them, the ORIs in budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe have been best characterized. In recent years, advances in DNA microarray and next-generation sequencing technologies have increased the number of yeast species involved in ORIs research dramatically. The ORIs in some non-conventional yeast species such as Kluyveromyces lactis and Pichia pastoris have also been genome-widely identified. Relevant databases of replication origins in yeast were constructed, then the comparative genomic analysis can be carried out. Here, we review several experimental approaches that have been used to map replication origins in yeast and some of the available web resources related to yeast ORIs. We also discuss the sequence characteristics and chromosome structures of ORIs in the four yeast species, which can be utilized to improve yeast replication origins prediction. PMID- 25745420 TI - xCT, not just an amino-acid transporter: a multi-functional regulator of microbial infection and associated diseases. AB - Expression of xCT, a component of the xc (-) amino-acid transporter, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and maintenance of the intracellular redox balance. Therefore, xCT plays an important role not only in the survival of somatic and immune cells, but also in other aspects of tumorigenesis, including the growth and malignant progression of cancer cells, resistance to anticancer drugs, and protection of normal cells against oxidative damage induced by carcinogens. xCT also functions as a factor required for infection by Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS) and other lymphoproliferative diseases associated with HIV/AIDS. In spite of these advances, our understanding of the role of xCT in the pathogenesis of infectious diseases is still limited. Therefore, this review will summarize recent findings about the functions of xCT in diseases associated with microbial (bacterial or viral) infections, in particular KSHV-associated malignancies. We will also discuss the remaining questions, future directions, as well as evidence that supports the potential benefits of exploring system xc (-) as a target for prevention and clinical management of microbial diseases and cancer. PMID- 25745421 TI - Characterization of Vibrio parahaemolyticus clinical strains from Maryland (2012 2013) and comparisons to a locally and globally diverse V. parahaemolyticus strains by whole-genome sequence analysis. AB - Vibrio parahaemolyticus is the leading cause of foodborne illnesses in the US associated with the consumption of raw shellfish. Previous population studies of V. parahaemolyticus have used Multi-Locus Sequence Typing (MLST) or Pulsed Field Gel Electrophoresis (PFGE). Whole genome sequencing (WGS) provides a much higher level of resolution, but has been used to characterize only a few United States (US) clinical isolates. Here we report the WGS characterization of 34 genomes of V. parahaemolyticus strains that were isolated from clinical cases in the state of Maryland (MD) during 2 years (2012-2013). These 2 years saw an increase of V. parahaemolyticus cases compared to previous years. Among these MD isolates, 28% were negative for tdh and trh, 8% were tdh positive only, 11% were trh positive only, and 53% contained both genes. We compared this set of V. parahaemolyticus genomes to those of a collection of 17 archival strains from the US (10 previously sequenced strains and 7 from NCBI, collected between 1988 and 2004) and 15 international strains, isolated from geographically-diverse environmental and clinical sources (collected between 1980 and 2010). A WGS phylogenetic analysis of these strains revealed the regional outbreak strains from MD are highly diverse and yet genetically distinct from the international strains. Some MD strains caused outbreaks 2 years in a row, indicating a local source of contamination (e.g., ST631). Advances in WGS will enable this type of analysis to become routine, providing an excellent tool for improved surveillance. Databases built with phylogenetic data will help pinpoint sources of contamination in future outbreaks and contribute to faster outbreak control. PMID- 25745422 TI - Snapshot of methanogen sensitivity to temperature in Zoige wetland from Tibetan plateau. AB - Zoige wetland in Tibetan plateau represents a cold environment at high altitude where significant methane emission has been observed. However, it remains unknown how the production and emission of CH4 from Zoige wetland will respond to a warming climate. Here we investigated the temperature sensitivity of methanogen community in a Zoige wetland soil under the laboratory incubation conditions. One soil sample was collected and the temperature sensitivity of the methanogenic activity, the structure of methanogen community and the methanogenic pathways were determined. We found that the response of methanogenesis to temperature could be separated into two phases, a high sensitivity in the low temperature range and a modest sensitivity under mesophilic conditions, respectively. The aceticlastic methanogens Methanosarcinaceae were the main methanogens at low temperatures, while hydrogenotrophic Methanobacteriales, Methanomicrobiales, and Methanocellales were more abundant at higher temperatures. The total abundance of mcrA genes increased with temperature indicating that the growth of methanogens was stimulated. The growth of hydrogenotrophic methanogens, however, was faster than aceticlastic ones resulting in the shift of methanogen community. Determination of carbon isotopic signatures indicated that methanogenic pathway was also shifted from mainly aceticlastic methanogenesis to a mixture of hydrogenotrophic and aceticlastic methanogenesis with the increase of temperature. Collectively, the shift of temperature responses of methanogenesis was in accordance with the changes in methanogen composition and methanogenic pathway in this wetland sample. It appears that the aceticlastic methanogenesis dominating at low temperatures is more sensitive than the hydrogenotrophic one at higher temperatures. PMID- 25745423 TI - In silico analysis suggests interaction between Ebola virus and the extracellular matrix. AB - The worst Ebola virus (EV) outbreak in history has hit Liberia, Sierra Leone and Guinea hardest and the trend lines in this crisis are grave, and now represents a global public health threat concern. Limited therapeutic and/or prophylactic options are available for people suffering from Ebola virus disease (EVD) and further complicate the situation. Previous studies suggested that the EV glycoprotein (GP) is the main determinant causing structural damage of endothelial cells that triggers the hemorrhagic diathesis, but molecular mechanisms underlying this phenomenon remains elusive. Using the informational spectrum method (ISM), a virtual spectroscopy method for analysis of the protein protein interactions, the interaction of GP with endothelial extracellular matrix (ECM) was investigated. Presented results of this in silico study suggest that Elastin Microfibril Interface Located Proteins (EMILINs) are involved in interaction between GP and ECM. This finding could contribute to a better understanding of EV/endothelium interaction and its role in pathogenesis, prevention and therapy of EVD. PMID- 25745424 TI - A common origin for immunity and digestion. AB - Historically, the digestive and immune systems were viewed and studied as separate entities. However, there are remarkable similarities and shared functions in both nutrient acquisition and host defense. Here, I propose a common origin for both systems. This association provides a new prism for viewing the emergence and evolution of host defense mechanisms. PMID- 25745425 TI - 5' tRNA Halves: The Next Generation of Immune Signaling Molecules. PMID- 25745426 TI - Localization of causal locus in the genome of the brown macroalga Ectocarpus: NGS based mapping and positional cloning approaches. AB - Mutagenesis is the only process by which unpredicted biological gene function can be identified. Despite that several macroalgal developmental mutants have been generated, their causal mutation was never identified, because experimental conditions were not gathered at that time. Today, progresses in macroalgal genomics and judicious choices of suitable genetic models make mutated gene identification possible. This article presents a comparative study of two methods aiming at identifying a genetic locus in the brown alga Ectocarpus siliculosus: positional cloning and Next-Generation Sequencing (NGS)-based mapping. Once necessary preliminary experimental tools were gathered, we tested both analyses on an Ectocarpus morphogenetic mutant. We show how a narrower localization results from the combination of the two methods. Advantages and drawbacks of these two approaches as well as potential transfer to other macroalgae are discussed. PMID- 25745427 TI - The green seaweed Ulva: a model system to study morphogenesis. AB - Green macroalgae, mostly represented by the Ulvophyceae, the main multicellular branch of the Chlorophyceae, constitute important primary producers of marine and brackish coastal ecosystems. Ulva or sea lettuce species are some of the most abundant representatives, being ubiquitous in coastal benthic communities around the world. Nonetheless the genus also remains largely understudied. This review highlights Ulva as an exciting novel model organism for studies of algal growth, development and morphogenesis as well as mutualistic interactions. The key reasons that Ulva is potentially such a good model system are: (i) patterns of Ulva development can drive ecologically important events, such as the increasing number of green tides observed worldwide as a result of eutrophication of coastal waters, (ii) Ulva growth is symbiotic, with proper development requiring close association with bacterial epiphytes, (iii) Ulva is extremely developmentally plastic, which can shed light on the transition from simple to complex multicellularity and (iv) Ulva will provide additional information about the evolution of the green lineage. PMID- 25745429 TI - Formation and excretion of autophagic plastids (plastolysomes) in Brassica napus embryogenic microspores. AB - The change in developmental fate of microspores reprogrammed toward embryogenesis is a complex but fascinating experimental system where microspores undergo dramatic changes derived from the developmental switch. After 40 years of study of the ultrastructural changes undergone by the induced microspores, many questions are still open. In this work, we analyzed the architecture of DNA containing organelles such as plastids and mitochondria in samples of B. napus isolated microspore cultures covering the different stages before, during, and after the developmental switch. Mitochondria presented a conventional oval or sausage-like morphology for all cell types studied, similar to that found in vivo in other cell types from vegetative parts. Similarly, plastids of microspores before induction and of non-induced cells showed conventional architectures. However, approximately 40% of the plastids of embryogenic microspores presented atypical features such as curved profiles, protrusions, and internal compartments filled with cytoplasm. Three-dimensional reconstructions confirmed that these plastids actually engulf cytoplasm regions, isolating them from the rest of the cell. Acid phosphatase activity was found in them, confirming the lytic activity of these organelles. In addition, digested plastid-like structures were found excreted to the apoplast. All these phenomena seemed transient, since microspore derived embryos (MDEs) showed conventional plastids. Together, these results strongly suggested that under special circumstances, such as those of the androgenic switch, plastids of embryogenic microspores behave as autophagic plastids (plastolysomes), engulfing cytoplasm for digestion, and then are excreted out of the cytoplasm as part of a cleaning program necessary for microspores to become embryos. PMID- 25745430 TI - Three Medicago MtFUL genes have distinct and overlapping expression patterns during vegetative and reproductive development and 35S:MtFULb accelerates flowering and causes a terminal flower phenotype in Arabidopsis. AB - The timing of the transition to flowering is carefully controlled by plants in order to optimize sexual reproduction and the ensuing production of seeds, grains, and fruits. The genetic networks that regulate floral induction are best characterized in the temperate eudicot Arabidopsis in which the florigen gene FT plays a major role in promoting the transition to flowering. Legumes are an important plant group, but less is known about the regulation of their flowering time. In the model legume Medicago truncatula (Medicago), a temperate annual plant like Arabidopsis, flowering is induced by prolonged cold (vernalization) followed by long day lengths (LD). Recent molecular-genetic experiments have revealed that a FT-like gene, MtFTa1, is a central regulator of flowering time in Medicago. Here, we characterize the three Medicago FRUITFULL (FUL) MADS transcription factors, MtFULa, MtFULb, and MtFULc using phylogenetic analyses, gene expression profiling through developmental time courses, and functional analyses in transgenic plants. MtFULa and MtFULb have similarity in sequence and expression profiles under inductive environmental conditions during both vegetative and reproductive development while MtFULc is only up regulated in the apex after flowering in LD conditions. Sustained up regulation of MtFULs requires functional MtFTa1 but their transcript levels are not affected during cold treatment. Overexpression of MtFULa and MtFULb promotes flowering in transgenic Arabidopsis plants with an additional terminal flower phenotype on some 35S:MtFULb plants. An increase in transcript levels of the MtFULs was also observed in Medicago plants overexpressing MtFTa1. Our results suggest that the MtFULs are targets of MtFTa1. Overall, this work highlights the conserved functions of FUL-like genes in promoting flowering and other roles in plant development and thus contributes to our understanding of the genetic control of the flowering process in Medicago. PMID- 25745431 TI - Stem cell genetic fidelity. PMID- 25745428 TI - Structural basis and functions of abscisic acid receptors PYLs. AB - Abscisic acid (ABA) plays a key role in many developmental processes and responses to adaptive stresses in plants. Recently, a new family of nucleocytoplasmic PYR/PYL/RCAR (PYLs) has been identified as bona fide ABA receptors. PYLs together with protein phosphatases type-2C (PP2Cs), Snf1 (Sucrose non-fermentation 1)-related kinases subfamily 2 (SnRK2s) and downstream substrates constitute the core ABA signaling network. Generally, PP2Cs inactivate SnRK2s kinases by physical interaction and direct dephosphorylation. Upon ABA binding, PYLs change their conformations and then contact and inhibit PP2Cs, thus activating SnRK2s. Here, we reviewed the recent progress in research regarding the structures of the core signaling pathways of ABA, including the (+)-ABA, (-) ABA and ABA analogs pyrabactin as well as 6AS perception by PYLs, SnRK2s mimicking PYLs in binding PP2Cs. PYLs inhibited PP2Cs in both the presence and absence of ABA and activated SnRK2s. The present review elucidates multiple ABA signal perception and transduction by PYLs, which might shed light on how to design small chemical compounds for improving plant performance in the future. PMID- 25745432 TI - Dorsal root ganglion progenitors differentiate to gamma-aminobutyric acid- and choline acetyltransferase-positive neurons. AB - This study examined the isolation and differentiation of dorsal root ganglion progenitor cells for therapeutic use in neurodegenerative diseases. Rat embryonic dorsal root ganglia progenitors were isolated and purified using the differential adhesion method combined with cytosine arabinoside treatment. After culture in serum-free medium supplemented with B27, basic fibroblast growth factor and epidermal growth factor, these cells remained viable and survived for more than 18 months in vitro. Most cells differentiated to neurons that were immunoreactive for gamma-aminobutyric acid and choline acetyltransferase as detected by immunohistochemical staining. In addition, nerve growth factor and neurotrophic tyrosine kinase receptor expression were also observed in dorsal root ganglion progenitors and differentiated cells. K252a, an inhibitor that blocks nerve growth factor-induced signaling, inhibited cell survival, suggesting the possible existence of a nerve growth factor autocrine loop in these proliferating cells. PMID- 25745433 TI - The gap junction blocker carbenoxolone enhances propofol and sevoflurane-induced loss of consciousness. AB - General anesthetics induce loss of consciousness by inhibiting ascending arousal pathways, and they interfere with gap junction electrical coupling. The present study aimed to determine whether inhibition of gap junction-mediated signaling could influence general anesthetic-induced loss of consciousness. The general anesthetics sevoflurane and propofol were used. Intracerebroventricular administration of carbenoxolone, a gap junction blocker, significantly decreased the time to loss of the righting reflex (P < 0.05), but prolonged the time to recovery of the reflex (P < 0.05). Moreover, intracerebroventricular administration of carbenoxolone increased the sensitivity to sevoflurane, with a leftward shift of the loss of righting reflex dose-response curve, and decreased the 50% effective concentration of sevoflurane. These results suggest that the gap junction blocker carbenoxolone enhances propofol and sevoflurane-mediated general anesthesia. PMID- 25745434 TI - Effect of Rho-kinase pathway on neurite outgrowth of rat hippocampal neurons under atomic force microscopy. AB - Hippocampal neurons of neonatal rats were cultured in serum-free culture medium for 5 days in vitro, and treated with the Rho-kinase inducer lysophosphatidic acid. Atomic force microscopy revealed that the numbers of level-1, -2 and -3 neurites protruding from rat hippocampal neurons was significantly reduced. After treatment with the Rho kinase inhibitor Y27632, a significant increase in the numbers of these neurites was observed. Our experimental findings indicate that the Rho-kinase pathway is closely associated with the neurites of hippocampal neurons. PMID- 25745435 TI - Activation of brain areas following ankle dorsiflexion versus plantar flexion: Functional magnetic resonance imaging verification. AB - Changes in activated areas of the brain during ankle active dorsiflexion and ankle active plantar flexion were observed in six healthy subjects using functional magnetic resonance imaging. Excited areas of ankle active dorsiflexion involved the bilateral primary motor area and the primary somatosensory area, as well as the bilateral supplementary sensory area, the primary visual area, the right second visual area, and the vermis of cerebellum. Excited areas of ankle active plantar flexion included the ipsilateral supplementary motor area, the limbic system, and the contralateral corpus striatum. Fine movements of the cerebral cortex control the function of the ankle dorsiflexion to a larger extent than ankle plate flexion, and the function of ankle plate flexion is more controlled by the subcortical area. PMID- 25745436 TI - Differentiation of fetal pancreatic stem cells into neuron-like and islet-like cells in vitro. AB - Pancreatic stem cells were isolated and cultured from aborted human fetal pancreases of gestational age 14-20 weeks. They were seeded at a density of 1 * 10(4) in serum-free media for differentiation into neuron-like cells, expressing beta-tubulin III and glial fibrillary acidic protein. These neuron-like cells displayed a synapse-like morphology and appeared to form a neuronal network. Pancreatic stem cells were also seeded at a density of 1 * 10(5) for differentiation into islet-like cells, expressing insulin and glucagon, with an islet-like morphology. These cells had glucose-stimulated secretion of human insulin and C-peptide. Results suggest that pancreatic stem cells can be differentiated into neuron-like and islet-like cells. PMID- 25745437 TI - Directional induction of dopaminergic neurons from neural stem cells using substantia nigra homogenates and basic fibroblast growth factor. AB - To date, complex components of available reagents have been used for directional induction of neural stem cells into dopaminergic neurons, resulting in a poor ability to repeat experiments. This study sought to investigate whether a homogenate of the substantia nigra of adult rats and/or basic fibroblast growth factor could directionally induce neural stem cells derived from the subventricular zone of embryonic rats to differentiate into dopaminergic neurons. Tyrosine hydroxylase-positive cells were observed exclusively after induction with the homogenate supernatant of the substantia nigra from adult rats and basic fibroblast growth factor for 48 hours in vitro. However, in the groups treated with homogenate supernatant or basic fibroblast growth factor alone, tyrosine hydroxylase expression was not observed. Moreover, the content of dopamine in the culture medium of subventricular zone neurons was significantly increased at 48 hours after induction with the homogenate supernatant of the substantia nigra from adult rats and basic fibroblast growth factor. Experimental findings indicate that the homogenate supernatant of the substantia nigra from adult rats and basic fibroblast growth factor could directionally induce neural stem cells derived from the subventricular zone of embryonic rats to differentiate into dopaminergic neurons in the substantia nigra with the ability to secrete dopamine. PMID- 25745438 TI - Expression of acetylated histone 3 in the spinal cord and the effect of morphine on inflammatory pain in rats. AB - In this study, a rat model of inflammatory pain was produced by injecting complete Freund's adjuvant into the hind paw, and the expression of acetylated histone 3 in the spinal cord dorsal horn was examined using immunohistochemical staining. One day following injection, there was a dramatic decrease in acetylated histone 3 expression in spinal cord dorsal horn neurons. However, on day 7, expression recovered in adjuvant-injected rats. While acetylated histone 3 labeling was present in dorsal horn neurons, it was more abundant in astrocytes and microglial cells. The recovery of acetylated histone 3 expression was associated with a shift in expression of the protein from neurons to glial cells. Morphine injection significantly upregulated the expression of acetylated histone 3 in spinal cord dorsal horn neurons and glial cells 1 day after injection, especially in astrocytes, preventing the transient downregulation. Our results indicate that inflammatory pain induces a transient downregulation of acetylated histone 3 in the spinal cord dorsal horn at an early stage following adjuvant injection, and that this effect can be reversed by morphine. Thus, the downregulation of acetylated histone 3 may be involved in the development of inflammatory pain. PMID- 25745439 TI - Kappa opioid receptor antagonist and N-methyl-D-aspartate receptor antagonist affect dynorphin-induced spinal cord electrophysiologic impairment. AB - The latencies of motor- and somatosensory-evoked potentials were prolonged to different degrees, and wave amplitude was obviously decreased, after injection of dynorphin into the rat subarachnoid cavity. The wave amplitude and latencies of motor- and somatosensory-evoked potentials were significantly recovered at 7 and 14 days after combined injection of dynorphin and either the kappa opioid receptor antagonist nor-binaltorphimine or the N-methyl-D-aspartate receptor antagonist MK-801. The wave amplitude and latency were similar in rats after combined injection of dynorphin and nor-binaltorphimine or MK-801. These results suggest that intrathecal injection of dynorphin causes damage to spinal cord function. Prevention of N-methyl-D-aspartate receptor or kappa receptor activation lessened the injury to spinal cord function induced by dynorphin. PMID- 25745440 TI - Genetic relationship between serum pregnancy-associated plasma protein-A gene polymorphism and ischemic cerebrovascular disease in a Northern Han Chinese population. AB - The present study recruited 193 patients with ischemic cerebrovascular disease from Inpatient and Outpatient Departments at the Affiliated Hospital of Qingdao University Medical College, China from August 2008 to May 2010, as well as 120 healthy volunteers from the Medical Examination Center at the Affiliated Hospital of Qingdao University Medical College, China, who served as controls for this study. Patients and control subjects were from the Han population in northern China. Enzyme- linked immunosorbent assay analysis revealed increased levels of serum pregnancy-associated plasma protein-A (PAPP-A) in ischemic cerebrovascular disease patients compared with healthy controls. In addition, the patients exhibited greater frequency of genotype CC and C alleles in a missense A/C (Tyr/Ser) polymorphism (dbSNP: rs7020782) of exon 14 in the PAPP-A gene. Multiple factor logistic regression analysis on correction of age, gender, history of smoking, hypertension, diabetes mellitus, hypercholesteremia, and ischemic stroke family history showed that the risk for ischemic cerebrovascular disease in the population without the A allele at the A/C genetic locus in exon 14 of the PAPP-A was 2-folds greater than the population expressing the A allele. These experimental findings suggested that ischemic cerebrovascular disease correlated with the C allele in exon 14 of PAPP-A. In addition, the A allele is likely a protective gene; individuals carrying the A allele were less prone to ischemic cerebrovascular disease compared with individuals without the A allele. PMID- 25745441 TI - Functional outcomes after home-based rehabilitation for heroin-induced spongiform leukoencephalopathy. AB - A 22-year-old man with a 2-year history of heroin vapor inhalation developed spongiform leukoencephalopathy and underwent clinical and home-based rehabilitative treatments. Activities of daily living were measured using the Functional Independence Measure at discharge and at 6, 12, and 24 months after discharge. His neurological symptoms gradually disappeared with rehabilitative treatment, and the functional scale scores increased from 55 on admission to 105 at 24 months after discharge. These results suggest that home-based rehabilitation was effective in ameliorating the pathology and improving activities of daily living in this patient with heroin-induced spongiform leukoencephalopathy. PMID- 25745442 TI - Long-term prognosis and prognostic determinants of patients with first attack of mild and moderate ischemia at Beijing community hospitals. AB - A total of 710 patients with first-ever ischemic stroke were consecutively recruited between January 2003 and December 2004 from five community hospitals/stations in five districts of Beijing, China. As of December 31, 2008, a total of 2 477 person-years were followed-up. During the five-year follow-ups, 117 adverse events occurred, including all-cause death and acute cardiovascular events (recurrent stroke, acute myocardial infarction, and sudden death). The five-year cumulative mortality rate was 2.18/100 person-years (54 cases), with 3.88/100 person-years (96 cases) of acute cardiovascular events and 3.02/100 person-years (75 cases) of recurrent stroke. Multiple factor analyses using the Cox proportional hazards ratio models showed that age, diabetes, and dependence of activities of daily living were independent predictors for death, acute cardiovascular disease events, or recurrent stroke. The results demonstrated that recurrent stroke was a major vascular disease that affected the prognosis of mild or moderate stroke patients. Secondary prevention of stroke patients should include active management of vascular risk factors and rehabilitation. PMID- 25745443 TI - Relationship between the -455G/A and -148C/T polymorphisms in the beta-fibrinogen gene and cerebral infarction in the Xinjiang Uygur and Han Chinese populations. AB - We sought to investigate the correlation between the -455G/A and -148C/T polymorphisms of the beta-fibrinogen gene and plasma fibrinogen levels in patients with cerebral infarction and in healthy subjects among the Xinjiang Uygur and Han Chinese populations, by using polymerase chain reaction-restriction enzyme digestion analysis. Results showed that there were no statistically significant differences in the distributions of the -455G/A genotype and allele frequency between the Uygurs and the Han. Plasma fibrinogen levels in cerebral infarction patients among the Uygurs and the Han were higher than those among healthy subjects. In particular, the frequencies of the -455G/A AA and -148C/T TT genotypes were significantly higher than in healthy subjects. Individuals carrying the A or T allele had a higher incidence of cerebral infarction compared with those carrying the G or C allele. Our experimental findings indicate that the -148C/T and -455G/A polymorphisms are associated with cerebral infarction in Xinjiang Uygur and Han Chinese subjects. The susceptibility- conferring alleles are -148T and -455A, and the susceptibility-conferring genotype is -455G/A + AA. PMID- 25745445 TI - 8-hydroxy-dipropylaminotetralin promotes neural plasticity in epileptic rats with depression. AB - Rats with chronic pilocarpine-induced temporal lobe epilepsy complicated with depression were studied. Anti-5-bromodeoxyuridine immunofluorescence staining and Timms staining showed that neurogenesis within the hippocampal dentate gyrus and mossy fiber sprouting were increased in model rats. Neurogenesis within the hippocampal dentate gyrus was further enhanced, while mossy fiber sprouting was decreased in model rats administered carbamazepine alone or in combination with the 5-hydroxytryptamine 1A receptor agonist, 8-hydroxy-dipropylaminotetralin (0.1 and 1 mg/kg). Among the groups, the effect was the most significant in rats receiving carbamazepine in conjunction with 1 mg/kg 8-hydroxy dipropylaminotetralin. Thus, high dose 8-hydroxy-dipropylaminotetralin can improve neural plasticity in epileptic rats with depression. PMID- 25745444 TI - Neurogenesis within the adult hippocampus under physiological conditions and in depression. AB - Adult neurogenesis can only be observed in some specific brain regions. One of these areas is the dentate gyrus of the hippocampal formation. The progenitor cells located in the subgranular layer of the dentate gyrus proliferate, differentiate, and give rise to young neurons that can become integrated into existing neuronal circuits. Under physiological conditions, hippocampal neurogenesis is linked to hippocampal-dependent learning, whereas deficits in adult hippocampal neurogenesis have been shown to correlate with disturbances in spatial learning and memory. This review summarizes the phenomenon of adult hippocampal neurogenesis and the use of suitable markers for the investigation of adult hippocampal neurogenesis. In addition, we focused on the disturbances in neurogenesis that can be seen in depression. Interestingly, several antidepressants have been found to be capable of increasing the rate of hippocampal neurogenesis. Based on that, it can be speculated that factors, which directly or indirectly increase the rate of hippocampal neurogenesis, may be helpful in the treatment of depression. PMID- 25745446 TI - Application of approximate entropy on dynamic characteristics of epileptic absence seizure. AB - Electroencephalogram signals are time-varying complex electrophysiological signals. Existing studies show that approximate entropy, which is a nonlinear dynamics index, is not an ideal method for electroencephalogram analysis. Clinical electroencephalogram measurements usually contain electrical interference signals, creating additional challenges in terms of maintaining robustness of the analytic methods. There is an urgent need for a novel method of nonlinear dynamical analysis of the electroencephalogram that can characterize seizure-related changes in cerebral dynamics. The aim of this paper was to study the fluctuations of approximate entropy in preictal, ictal, and postictal electroencephalogram signals from a patient with absence seizures, and to improve the algorithm used to calculate the approximate entropy. The approximate entropy algorithm, especially our modified version, could accurately describe the dynamical changes of the brain during absence seizures. We could also demonstrate that the complexity of the brain was greater in the normal state than in the ictal state. The fluctuations of the approximate entropy before epileptic seizures observed in this study can form a good basis for further study on the prediction of seizures with nonlinear dynamics. PMID- 25745447 TI - Recombinant human erythropoietin increases cerebral cortical width index and neurogenesis following ischemic stroke. AB - The cerebral cortical expansion index refers to the ratio between left and right cortex width and is recognized as an indicator for cortical hyperplasia. Cerebral ischemia was established in CB-17 mice in the present study, and the mice were subsequently treated with recombinant human erythropoietin via subcutaneous injection. Results demonstrated that cerebral cortical width index significantly increased. Immunofluorescence detection showed that the number of nuclear antigen antibody/5-bromodeoxyuridine-positive cells at the infarction edge significantly increased. Correlation analysis revealed a negative correlation between neurological scores and cortical width indices in rats following ischemic stroke. These experimental findings suggested that recombinant human erythropoietin promoted cerebral cortical hyperplasia, increased cortical neurogenesis, and enhanced functional recovery following ischemic stroke. PMID- 25745448 TI - Protective effects of remote ischemic preconditioning in rat hindlimb on ischemia reperfusion injury. AB - Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries (10 minutes) prior to 10 minutes of reperfusion were given once a day for 3 days before the animal received middle artery occlusion and reperfusion surgery. The results showed that brain infarct volume was significantly reduced after remote ischemic pre-conditioning. Scores in the forelimb placing test and the postural reflex test were significantly lower in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. Thus, neurological function was better in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. These results indicate that remote ischemic pre-conditioning in rat hindlimb exerts protective effects in ischemia-reperfusion injury. PMID- 25745450 TI - Effects of minocycline on apoptosis and angiogenesis-related protein expression in a rat model of intracerebral hemorrhage. AB - In the present study, a rat model of non-traumatic intracerebral hemorrhage was established by type IV collagenase injection into the right globus pallidus. Bax and Bcl-2 expression in tissues surrounding hematomas was significantly increased within 14 days after injury, and it then gradually decreased. Vascular endothelial growth factor, Flk-1 and Flt-1 mRNA expression gradually increased over time. After intraperitoneal injection with minocycline, Bax expression was decreased 1 day after intracerebral hemorrhage. Flk-1 and Flt-1 mRNA expression was decreased after minocycline injection, but Bcl-2 expression was increased, and vascular endothelial growth factor mRNA expression was decreased between 4-14 days. These results indicated that protective effects of minocycline on nerve tissues were associated with increased Bcl-2 expression and decreased Bax expression in the early stage after intracerebral hemorrhage. In the late stage, minocycline downregulated vascular endothelial growth factor and its receptor expression to inhibit brain tissue self-repair. PMID- 25745449 TI - Association between p75 neurotrophin receptor gene expression and cell apoptosis in tissues surrounding hematomas in rat models of intracerebral hemorrhage. AB - Animal models of intracerebral hemorrhage were established by injection of autologous blood into the caudate nucleus in rats. Cell apoptosis was measured by flow cytometry and immunohistochemical staining of the p75 neurotrophin receptor. p75 neurotrophin receptor protein was detected by immunohistochemistry. p75 neurotrophin receptor mRNA was examined by quantitative real-time polymerase chain reactions. At 24 hours after modeling, cellular apoptosis occured around hematoma with upregulation of p75 neurotrophin receptor protein and mRNA was observed, which directly correlated to apoptosis. This observation indicated that p75 neurotrophin receptor upregulation was associated with cell apoptosis around hematomas after intracerebral hemorrhage. PMID- 25745451 TI - Establishment of primary cultures of craniopharyngioma cells. AB - Craniopharynigoma samples were collected from 36 patients. Out of the 36 samples, 29 achieved successful sub-culturing, with a success rate of 80.6%. Immunohistochemistry staining showed that cytokeratin-7 was positively expressed in the cytomembrane and cytoplasm of craniopharyngioma cells at 6-8 passages, confirming that all cultured cells were squamous epithelial cells. The doubling time of craniopharyngioma cells was 3 days, as confirmed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In this study, craniopharyngioma cells cultured in vitro were established; however, establishment of immortalized craniopharyngioma cell lines requires further research. PMID- 25745452 TI - Role of 5-hydroxytryptamine expression in cerebellar Purkinje cells in obstructive sleep apnea syndrome. AB - In the present study, electrical stimulation to the rat insular cortex induced apnea or respiratory disturbance, reduced amplitude of genioglossal electromyogram, and decreased electromyogram integrals. In addition, arterial blood gas analysis showed arterial blood acidosis, reduced pH values, increased alkali reserve negative values, decreased peripheral blood 5-hydroxytryptamine content, and increased 5-hydroxytryptamine expression in cerebellar Purkinje cells. Following lidocaine injection to block the habenular nucleus, abnormalities in breath, genioglossal electromyogram, and blood gas values disappeared, and peripheral blood 5-hydroxytryptamine content returned to levels prior to electric stimulation. However, 5-hydroxytryptamine expression in cerebellar Purkinje cells remained high. The results suggested that 5 hydroxytryptamine expression in Purkinje cells did not correlate with ventilation function involving insular cortex and habenular nucleus. PMID- 25745453 TI - Magnetic resonance imaging markers for early diagnosis of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called "prodromal", where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging (MRI) and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD. PMID- 25745454 TI - Neurofilament proteins in axonal regeneration and neurodegenerative diseases. AB - Neurofilament protein is a component of the mature neuronal cytoskeleton, and it interacts with the zygosome, which is mediated by neurofilament-related proteins. Neurofilament protein regulates enzyme function and the structure of linker proteins. In addition, neurofilament gene expression plays an important role in nervous system development. Previous studies have shown that neurofilament gene transcriptional regulation is crucial for neurofilament protein expression, especially in axonal regeneration and degenerative diseases. Post-transcriptional regulation increased neurofilament protein gene transcription during axonal regeneration, ultimately resulting in a pattern of neurofilament protein expression. An expression imbalance of post-transcriptional regulatory proteins and other disorders could lead to amyotrophic lateral sclerosis or other neurodegenerative diseases. These findings indicated that after transcription, neurofilament protein regulated expression of related proteins and promoted regeneration of damaged axons, suggesting that regulation disorders could lead to neurodegenerative diseases. PMID- 25745455 TI - Clinical application of repetitive transcranial magnetic stimulation in stroke rehabilitation. AB - Proper stimulation to affected cerebral hemisphere would promote the functional recovery of patients with stroke. Effects of repetitive transcranial magnetic stimulation on cortical excitability can be can be altered by the stimulation frequency, intensity and duration. There has been no consistent recognition regarding the best stimulation frequency and intensity. This study reviews the intervention effects of repetitive transcranial stimulation on motor impairment, dysphagia, visuospatial neglect and aphasia, and summarizes the stimulation frequency, intensity and area for repetitive transcranial magnetic stimulation to yield the best therapeutic effects. PMID- 25745456 TI - Psycho-cognitive behavioral problems in sleep disordered children. AB - Sleep disturbances are common in childhood and adolescence. Sleep problems in early infants tend to be persistent and prominent in preschool and school-aged children. Chronic sleep disorders, especially in young children may lead to neurobehavioral problems and psycho-cognitive impairment. Sleep difficulties may be the result of underlying medical conditions, (breathing disorders) or psychological problems. Research studies have shown the association between sleep disorders and day time cognitive impairment, behavioral problems, poor school performance and inattention in children. Appropriate diagnosis and early management of sleep disorders in children lead to improvement of neurocognitive function and behavioral problems in these children. PMID- 25745457 TI - Effect of Lycium barbarum Polysaccharides on the expression of endothelin-1 and its receptors in an ocular hypertension model of rat glaucoma. AB - Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells (RGCs) in a rat chronic ocular hypertension (COH) model. Here, we investigated the expression of endothelin-1 (ET-1), a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis. Elevated intraocular pressure (IOP) was induced in the right eye of SD rats using argon laser photocoagulation. (1) The expression of ET-1, ETA and ETB in normal and COH retinas was studied. (2) Some COH rats were fed daily with Lycium barbarum Polysaccharides (LBP) using 1 mg/kg or phosphate-buffered saline (PBS) for 3 weeks (started 1 week before photocoagulation). The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated. A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET 1, ETA and ETB in retinal vasculature. We found that (1) Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity. (2) After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs. (3) By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB. In summary, ET-1 expression was up-regulated in the retina in COH model. LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH. The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature. PMID- 25745458 TI - Schisandrin B protects PC12 cells by decreasing the expression of amyloid precursor protein and vacuolar protein sorting 35. AB - PC12 cell injury was induced using 20 MUM amyloid beta-protein 25-35 to establish a model of Alzheimer's disease. The cells were then treated with 5, 10, and 25 MUM Schisandrin B. Methylthiazolyldiphenyl-tetrazolium bromide assays and Hoechst 33342 staining results showed that with increasing Schisandrin B concentration, the survival rate of PC12 cells injured by amyloid beta-protein 25-35 gradually increased and the rate of apoptosis gradually decreased. Reverse transcription PCR, immunocytochemical staining and western blot results showed that with increasing Schisandrin B concentration, the mRNA and protein expression of vacuolar protein sorting 35 and amyloid precursor protein were gradually decreased. Vacuolar protein sorting 35 and amyloid precursor protein showed a consistent trend for change. These findings suggest that 5, 10, and 25 MUM Schisandrin B antagonizes the cellular injury induced by amyloid beta-protein 25 35 in a dose-dependent manner. This may be caused by decreasing the expression of vacuolar protein sorting 35 and amyloid precursor protein. PMID- 25745459 TI - Compound Danshen tablets downregulate amyloid protein precursor mRNA expression in a transgenic cell model of Alzheimer's disease: Effects and a comparison with donepezil. AB - After gene mutation, the pcDNA3.1/APP595/596 plasmid was transfected into HEK293 cells to establish a cell model of Alzheimer's disease. The cell model was treated with donepezil or compound Danshen tablets after culture for 72 hours. Reverse transcription-PCR showed that the mRNA expression of amyloid protein precursor decreased in all groups following culture for 24 hours, and that there was no significant difference in the amount of decrease between donepezil and compound Danshen tablets. Our results suggest that compound Danshen tablets can reduce expression of the mRNA for amyloid protein precursor in a transgenic cell model of Alzheimer's disease, with similar effects to donepezil. PMID- 25745460 TI - Buyuan Congnao decoction decreases hippocampal beta-amyloid expression in a rat model of Alzheimer's disease. AB - A mixture of ibotenic acid and beta-amyloid 1-42 was injected into the hippocampus of a rat model of Alzheimer's disease, followed by intragastric administration of a traditional Chinese medicine Buyuan Congnao decoction (main components included radix astragali, radix polygoni multiflori preparata, rhizoma acori talarinowii, radix polygalae, fructus alpiniae oxyphyllae, and radix glycyrrhizae preparata) and a piracetam suspension. Following treatment with traditional Chinese medicine or western medicine, beta-amyloid expression decreased and neuronal morphology was normal in the rat hippocampal CA1 region, in addition to significantly shortened average latency in the Morris water navigation task. These findings suggested that compound prescription of Buyuan Congnao decoction, similar to the curative effects of piracetam, decreased hippocampal beta-amyloid expression in a rat model of Alzheimer's disease, as well as improved learning and memory. PMID- 25745461 TI - Puerarin antagonizes peroxyntrite-induced injury in retinal pigment epithelial cells. AB - A rat model of diabetes mellitus was established by intraperitoneal injection of streptozotocin. Three days later, the rats were intraperitoneally administered 140 mg puerarin/kg daily, for a total of 60 successive days. DNA ladder results showed increased apoptosis over time in retinal pigment epithelial cells from rats with streptozotocin-induced diabetes mellitus. Western blot analysis, Reverse transcription-PCR, immunohistochemistry, and flow cytometry results showed increased expression of 3-nitrotyrosine, a peroxyntrite marker, as well as inducible nitric synthase and Fas/FasL, in retinal pigment epithelial cells. Puerarin reversed these changes, and results demonstrated that puerarin inhibited Fas/FasL expression and alleviated peroxyntrite injury to retinal pigment epithelial cells. These results suggested that puerarin inhibited production of inducible nitric oxide synthase and directly antagonized peroxyntrite injury in retinal pigment epithelial cells. PMID- 25745462 TI - Immune reactions and nerve repair in mice with sciatic nerve injury 14 days after intraperitoneal injection of Brazil. AB - BALB/c mice were intraperitoneally injected with 10, 5 or 2.5 mg/kg Brazil for 14 days after sciatic nerve injury. Results demonstrate that the spleen T/B lymphocyte stimulation index and serum circulating immune complex concentration were significantly reduced, and the morphology of the soleus muscle was restored in mice with sciatic nerve injury. These effects of Brazil were dose-dependent. Our experimental findings indicate that Brazil can regulate immune responses after nerve injury and promote sciatic nerve repair. PMID- 25745463 TI - Infrared thermography and meridian-effect evidence and explanation in Bell's palsy patients treated by moxibustion at the Hegu (LI4) acupoint: Overall regulation or a specific target? AB - Subjects with Bell's palsy and healthy individuals were treated with moxibustion thermal stimulation on the Hegu (LI4) acupoint; an infrared thermal imaging system was used to observe facial-temperature changes. Bell's palsy patients developed low or high temperatures at the affected side, with poor symmetry. Healthy people showed high temperatures on the forehead, medial angle of the eye, nasal ala and around the lips, but low temperatures on bilateral cheeks, thus forming a "T-type hot area" in the face, with good temperature symmetry. Moxibustion treatment for 11 minutes significantly improved high asymmetry in temperature in the faces of Bell's palsy patients. This evidence indicates that moxibustion treatment on Hegu enables increases in facial temperatures in healthy people and Bell's palsy patients, especially around the lips. Moxibustion stimulation at the Hegu not only improves the global circulation but also has specific effects on the lips in Bell's palsy patients, but the underlying mechanism needs further investigation. PMID- 25745464 TI - Magnetic resonance diffusion tensor imaging-based evaluation of optic-radiation shape and position in meningioma. AB - Employing magnetic resonance diffusion tensor imaging, three-dimensional white matter imaging and conventional magnetic resonance imaging can demonstrate the tumor parenchyma, peritumoral edema and compression on surrounding brain tissue. A color-coded tensor map and three-dimensional tracer diagram were applied to clearly display the optic-radiation location, course and damage. Results showed that the altered anisotropy values of meningioma patients corresponded with optic radiation shape, size and position on both sides. Experimental findings indicate that the magnetic resonance diffusion tensor imaging technique is a means of tracing and clearly visualizing the optic radiation. PMID- 25745465 TI - Functional magnetic resonance imaging evaluation of visual cortex activation in patients with anterior visual pathway lesions. AB - The aim of this study was to examine the secondary visual cortex functional disorder in patients with glaucoma and large pituitary adenoma by functional magnetic resonance imaging, and to determine the correlation between visual field defect and primary visual cortex activation. Results showed that single eye stimulation resulted in bilateral visual cortex activation in patients with glaucoma or large pituitary adenoma. Compared with the normal control group, the extent and intensity of visual cortex activation was decreased after left and right eye stimulation, and functional magnetic resonance imaging revealed a correlation between visual field defects and visual cortex activation in patients with glaucoma and large pituitary adenoma. These functional magnetic resonance imaging data suggest that anterior optic pathway lesions can cause secondary functional disorder of the visual cortex, and that visual defects are correlated with visual cortex activation. PMID- 25745466 TI - Information entropy-based fitting of the disease trajectory of brain ischemia induced vascular cognitive impairment. AB - The present study investigated the disease trajectory of vascular cognitive impairment using the entropy of information in a neural network mathematical simulation based on the free radical and excitatory amino acids theories. Glutamate, malondialdehyde, and inducible nitric oxide synthase content was significantly elevated, but acetylcholine, catalase, superoxide dismutase, glutathione peroxidase and constitutive nitric oxide synthase content was significantly decreased in our vascular cognitive impairment model. The fitting curves for each factor were obtained using Matlab software. Nineteen, 30 and 49 days post ischemia were the main output time frames of the influence of these seven factors. Our results demonstrated that vascular cognitive impairment involves multiple factors. These factors include excitatory amino acid toxicity and nitric oxide toxicity. These toxicities disrupt the dynamic equilibrium of the production and removal of oxygen free radicals after cerebral ischemia, reducing the ability to clear oxygen free radicals and worsening brain injury. PMID- 25745468 TI - Recombinant adeno-associated virus delivered human thioredoxin-PR39 prevents hypoxia-induced apoptosis of ECV304 cells. AB - Human thioredoxin and antibacterial peptide, PR39, have been shown to have potent antioxidant effects that may prolong survival of cells during hypoxia. The pSSCMV/human thioredoxin-PR39 vector was successfully constructed in this study and used to infect ECV304 cells. Transfected ECV304 cells were incubated at 1%, 5% hypoxic, and normal oxygen conditions. We found that the number of apoptotic cells after transfection with recombinant adeno-associated virus-human thioredoxin -PR39 was significantly lower than controls, suggesting a protective effect of the recombinant human thioredoxin-PR39 protein on hypoxic cells. PMID- 25745467 TI - Anatomical feasibility of vagus nerve esophageal branch transfer to the phrenic nerve. AB - This study measured the vagus and phrenic nerves from 12 adult cadavers. We found that the width and thickness of the vagus and phrenic nerves were different in the chest. The distance from the point of the vagus nerve and phrenic nerve on the plane of the inferior border of portal pulmonary arteries (T point) was approximately 7 cm to the diaphragm and was approximately 10 cm to the clavicle level. The number of motor fibers in the vagus nerves was 1 716 +/- 362, and the number of nerve fibers was 4 473 +/- 653. The number of motor fibers in the phrenic nerves ranged from 3 078 +/- 684 to 4 794 +/- 638, and the number of nerve fibers ranged from 3 437 +/- 642 to 5 071 +/- 723. No significant difference was found in the total number of nerve fibers. The results suggest that width, thickness, and total number of nerve fibers are similar between the vagus and phrenic nerves, but the number of motor fibers is different between them. PMID- 25745469 TI - Ephrin A2 protein expression in the regeneration and plasticity of cochlear hair cells in chicken following kanamycin ototoxicity. AB - The results from this study showed that the thresholds of brainstem auditory evoked potentials peak following 10 successive days of intramuscular injection of Roman chickens with kanamycin, starting 3 days after birth. Fluorescence immunohistochemistry analysis revealed few ganglion cells positively labeled for Ephrin A2 in the cochlea of experimental chickens from 2 days before until 7 days after the last kanamycin injection. The number of Ephrin A2-positive ganglion cell bodies was increased at 15 days after the last injection and was similar to that in normal chickens at 30 days following the cessation of kanamycin treatment. These experimental findings indicate that Ephrin A2 protein expression in the acoustic ganglia is synchronized with the connection damage and regeneration of cochlear hair cells after kanamycin exposure. Ephrin A2 may play an important role in the regeneration and plasticity of cochlear hair cells in the chick cochlea following kanamycin ototoxicity. PMID- 25745470 TI - Induced pluripotent stem cells are induced pluripotent stem cell-like cells. PMID- 25745473 TI - Optimal programming management of ventricular tachycardia storm in ICD patients. AB - Ventricular tachycardia storm (VTS) is defined as a life-threatening syndrome of three or more separate episodes of ventricular tachycardia (VT) leading to implantable cardioverter defibrillator (ICD) therapy within 24 hours. Patients with VTS have poor outcomes and require immediate medical attention. ICD shocks have been shown to be associated with increased mortality in several studies. Optimal programming in minimization of ICD shocks may decrease mortality. Large controlled trials showed that long detection time and high heart rate detection threshold reduced ICD shock burden without an increase in syncope or death. As a fundamental therapy of ICD, antitachycardia pacing (ATP) can terminate most slow VT with a low risk of acceleration. For fast VT, burst pacing is more effective and less likely to result in acceleration than ramp pacing. One algorithm of optimal programming management during a VTS is presented in the review. PMID- 25745471 TI - Myocardin in biology and disease. AB - Myocardin (MYOCD) is a potent transcriptional coactivator that functions primarily in cardiac muscle and smooth muscle through direct contacts with serum response factor (SRF) over cis elements known as CArG boxes found near a number of genes encoding for contractile, ion channel, cytoskeletal, and calcium handling proteins. Since its discovery more than 10 years ago, new insights have been obtained regarding the diverse isoforms of MYOCD expressed in cells as well as the regulation of MYOCD expression and activity through transcriptional, post transcriptional, and post-translational processes. Curiously, there are a number of functions associated with MYOCD that appear to be independent of contractile gene expression and the CArG-SRF nucleoprotein complex. Further, perturbations in MYOCD gene expression are associated with an increasing number of diseases including heart failure, cancer, acute vessel disease, and diabetes. This review summarizes the various biological and pathological processes associated with MYOCD and offers perspectives to several challenges and future directions for further study of this formidable transcriptional coactivator. PMID- 25745474 TI - Trigger elimination of polymorphic ventricular tachycardia and ventricular fibrillation by catheter ablation: trigger and substrate modification. AB - Ventricular fibrillation (VF) is a malignant arrhythmia, usually initiated by a ventricular premature contraction (VPC) during the vulnerable period of cardiac repolarization. Ablation therapy for VF has been described and increasingly reported. Targets for VF triggers are VPCs preceded by Purkinje potentials or from the right ventricular outflow tract (RVOT) in structurally normal hearts, and VPC triggers preceded by Purkinje potentials in ischemic cardiomyopathy. During the session, mapping should be focused on the earliest activation and determining the earliest potential is the key to a successful ablation. However, suppression of VF can be achieved by not only the elimination of triggering VPCs, but also by substrate modification of possible reentry circuits in the Purkinje network, or between the PA and RVOT. The most important issue before the ablation session is the recording of the 12-lead ECG of the triggering event, which can prove invaluable in regionalizing the origin of the triggering VPC for more detailed mapping. In cases where the VPC is not spontaneous or inducible, ablation may be performed by pace mapping. Further studies are needed to evaluate the precise mechanisms of this arrhythmia. PMID- 25745472 TI - Optimal antiarrhythmic drug therapy for electrical storm. AB - Electrical storm, defined as 3 or more separate episodes of ventricular tachycardia or ventricular fibrillation within 24 hours, carries significant morbidity and mortality. These unstable ventricular arrhythmias have been described with a variety of conditions including ischemic heart disease, structural heart disease, and genetic conditions. While implantable cardioverter defibrillator implantation and ablation may be indicated and required, antiarrhythmic medication remains an important adjunctive therapy for these persons. PMID- 25745475 TI - Ventricular tachycardia ablation and substrate modification in ICD patients with electrical storm. AB - The electrical storm (ES) is defined as a state of electrical instability with three or more sustained ventricular arrhythmias (VAs) occurring within twenty four hours, which needs intravenous antiarrhythmic medications and frequent defibrillation. Recently, radiofrequency catheter ablation evolved as a sole therapy to terminate ES in patients with ICD, and the survival has been reported to be improved with successful ablation during follow-up. In this review, we briefly summarize substrate mapping and substrate ablation strategy in patients with ES, and discuss the reason of recurrence after ablation. PMID- 25745476 TI - Neuraxial modulation for treatment of VT storm. AB - In the hyperadrenergic state of VT storm where shocks are psychologically and physiologically traumatizing, suppression of sympathetic outflow from the organ level of the heart up to higher braincenters plays a significant role in reducing the propensity for VT recurrence. The autonomic nervous system continuously receives input from the heart (afferent signaling), integrates them, and sends efferent signals to modify or maintain cardiac function and arrhythmogenesis. Spinal anesthesia with thoracic epidural infusion of bupivicaine and surgical removal of the sympathetic chain including the stellate ganglion has been shown to decrease recurrences of VT. Excess sympathetic outflow with catecholamine release can be modified with catheter-based renal denervation. The insights provided from animal experiments and in patients that are refractory to conventional therapy have significantly improved our working understanding of the heart as an end organ in the autonomic nervous system. PMID- 25745477 TI - Prevalence of enteric pathogen-associated community gastroenteritis among kindergarten children in Gaza. AB - Gastroenteritis is considered as one of the leading causes of illness and death in children under 5 years age, especially in developing countries. It is one of the major public health problems among childhood in Gaza strip, Palestine. This study was conducted to determine the prevalence of enteric pathogen-associated community gastroenteritis among kindergarten children in Gaza. A total of 150 stool samples were collected and investigated for parasitic, viral and bacterial pathogens at Al Azhar microbiology laboratories by using standard microbiological and serological procedures. Out of the 150 study samples, the overall percentage of positive stool samples with a known enteric pathogen was 60.6%. The prevalence of different enteric pathogens causing community gastroenteritis among symptomatic cases (88.5%) was significantly higher than the prevalence in asymptomatic carriage (11.1%). The most prevalent isolated enteric pathogens were Entamoeba histolytica (28.0%) and Giardia lamblia (26.7%). Rotavirus was found in 3.1% of symptomatic cases but not detected in asymptomatic carriage. However, adenovirus type 40 and 41 were not detected in any of the study samples. The bacterial enteric pathogens Shigella and Enterohemorrhagic Escherichia coli O157:H7 (EHEC) have comparable occurrence as rotavirus (3.1%), meanwhile, Salmonella was not isolated. Mixed infection with more than 1 pathogen was found (11.4%) only among symptomatic cases. Children aged 3-year-old showed the highest prevalence of community gastroenteritis. This study demonstrates a high prevalence of parasitic enteropathogens and a relatively low prevalence of bacterial and viral enteropathogens among kindergarten children living in Gaza city, moreover, children aged 3 years old showed the highest prevalence of isolated enteropathogens. PMID- 25745478 TI - Portal vein arterialization promotes liver regeneration after extended partial hepatectomy in a rat model. AB - In the current study, we sought to establish a novel rat model of portal vein arterialization (PVA) and evaluate its impact on liver regeneration after extended partial hepatectomy (PH). A total of 105 Sprague-Dawley rats were randomly assigned to three groups: 68% hepatectomy (the PH group), portal arterialization after 68% hepatectomy (the PVA group), and right nephrectomy only (the control group). Liver regeneration rate (LRR), 5-bromo-2-deoxyuridine (BrdU) labeling index, and liver functions were assessed on postoperative day 2, 7, 14 and 28. The 28-day survival rates were compared among the three groups. The 28 day survival rates were similar in all groups (P = 0.331), and the anastomotic patency was 100%. The LRR in the PVA group was significantly higher than that of the PH group within postoperative 14 days (P < 0.05). The PVA and PH group had increased serum alanine aminotransferase levels (232 +/- 61 U/L and 212 +/- 53 U/L, respectively) compared with the control group (101 +/- 13 U/L) on postoperative day 2, whereas from postoperative day 7 to day 28 there were no differences among the three groups. Serum albumin values were higher after the PVA procedure within postoperative day 14, which gradually became comparable on postoperative day 28 among the three groups. The peaks of BrdU labeling index appeared on postoperative day 2 in all rats, and the PVA procedure was associated with increased BrdU labeling index from postoperative day 7 to 28. The 28-day survival of the PVA rats was comparable. Our findings demonstrate that the PVA procedure utilizing portal vein trunk-renal artery microvascular reconstruction promotes remnant liver regeneration and confers beneficial effects on maintaining and even optimizing liver function after extended partial hepatectomy in rats. PMID- 25745479 TI - Surgical outcomes of mini-open Wiltse approach and conventional open approach in patients with single-segment thoracolumbar fractures without neurologic injury. AB - This study aimed to introduce a novel mini-open pedicle screw fixation technique via Wiltse approach, and compared it with the traditional posterior open method. A total of 72 cases of single-segment thoracolumbar fractures without neurologic injury underwent pedicle screw fixation via two different approaches. Among them, 37 patients were treated using posterior open surgery, and 35 patients received mini-open operation via Wiltse approach. Crew placement accuracy rate, operative time, blood loss, postoperative drainage, postoperative hospitalization time, radiation exposure time, postoperative improvement in R value, Cobb's angle and visual analog scale (VAS) scores of the two methods were compared. There were no significant differences in the accuracy rate of pedicle screw placement, radiation exposure and postoperative R value and Cobb's angle improvement between the two groups. However, the mini-open method had obvious advantages over the conventional open method in operative time, blood loss, postoperative drainage, postoperative hospitalization time, and postoperative improvement in VAS. The mini-open pedicle screw technique could be applied in treatment of single-segment thoracolumbar fracture without neurologic injury and had advantages of less tissue trauma, short operative and rehabilitative time on the premise of guaranteed accuracy rate and no increased radiation exposure. PMID- 25745480 TI - Unruptured pregnancy in a noncommunicating rudimentary horn at 37 weeks with a live fetus: a case report. AB - We report an extremely rare case of an unruptured non-communicating rudimentary horn full-term pregnancy. A woman who had a uterine malformation was misdiagnosed as uterus didelphys and gave birth to a live, healthy fetus. The correct diagnosis was not made until cesarean section at 37 4/7 weeks. The case suggests that women who are pregnant in a rudimentary horn could obtain a full-term delivery and give birth to a live and healthy baby. PMID- 25745481 TI - HLA antigens and anti-sperm antibody production in Iranian vasectomized men. PMID- 25745482 TI - Invasive thyroid angiosarcoma with a favorable outcome. AB - INTRODUCTION: Thyroid angiosarcoma is a malignant neoplasm, which usually shows local aggressive behavior and associated with a high recurrence rate. It was originally described in the Alpine region and extremely rare in other parts of the world. CASE PRESENTATION: An asymptomatic 61-year-old woman presented with a right lobe thyroid nodule with fine needle aspiration cytology indicating "suspicious for malignancy" was reported in our study. Histological examination revealed a vascular 35mm neoplasm with areas of necrosis. Immunohistochemistry staining had negative results for MNF, CAM5.2, CD34, thyroglobulin, and positive for CD31. The findings described were compatible with angiosarcoma diagnosis. Besides, a 4mm papillary microcarcinoma was found in the left lobe. Computerized tomography (CT) scan performed about two months after the operation, showed a right neck nodular lesion, conditioning tracheal deviation. At our institution, the study performed was consistent with local recurrence (angiosarcoma). Tumor excision was performed and invasion to larynx, trachea and esophagus was detected intraoperatively. Histopathologic examination confirmed tumor recurrence and the patient was submitted to radiotherapy (60 Gy), completed four years ago. There is not, so far, any evidence of tumor recurrence. CONCLUSIONS: We described a rare case of a usually aggressive thyroid angiosarcoma in a patient living in a non Alpine region, with an unusual favorable outcome after the operation and radiotherapy. PMID- 25745483 TI - Desmopressin lyophilisate for the treatment of central diabetes insipidus: first experience in very young infants. AB - INTRODUCTION: In neonates and small infants, early diagnosis of central diabetes insipidus (CDI) and treatment with desmopressin in low doses (avoiding severe hypo- or hypernatremia) are important to prevent associated high morbidity and mortality in this particular age group. CASE PRESENTATION: We described pharmacokinetic and pharmacodynamic results of the use of recently launched oral desmopressin lyophilisate (Minirin Melt(r)) in two infants with CDI, diagnosed at the age of 12 and 62 days, respectively. We observed that a starting dose of 60 MUg of Minirin Melt(r) in the first case resulted in a pharmacokinetic profile largely exceeding the reference frame observed in children with nocturnal enuresis, while a dose of 15 MUg in the second case resulted in acceptable concentrations. After initial dose adjustments, administration of sublingual lyophilisate resulted in rather stable serum sodium concentrations. CONCLUSIONS: Using Minirin Melt(r) in infants with CDI appears to be effective, easy to use and well tolerated. PMID- 25745484 TI - Impact of Plasma Glucose Level at the Time of Fluorodeoxyglucose Administration on the Accuracy of FDG-PET/CT in the Diagnosis of Pancreatic Lesions. AB - BACKGROUND: High fasting plasma glucose (FPG) levels before fluorodeoxyglucose (FDG) administration for positron emission tomography/computed tomography (PET/CT) might affect the accuracy of 18-fluoro-deoxy-glucose-positron emission tomography-computed tomography (FDG-PET/CT) in diagnosis of pancreatic lesions. Current guidelines require FPG levels of < 200 mg/dL before FDG administration; however, the literature on the effect of FPG levels of < 200 mg/dL on the accuracy of FDG-PET/CT is scarce. OBJECTIVES: The aim of this study was to evaluate the effect of FPG levels of < 200 mg/dL on the accuracy of FDG-PET/CT in diagnosis of pancreatic lesions. PATIENTS AND METHODS: In this retrospective study, 161 patients who had FDG-PET/CT for initial diagnosis of pancreatic lesions were included. Fasting plasma glucose levels before FDG administration were recorded. Accuracy of FDG-PET/CT in diagnosis of pancreatic lesions was compared between patients who were non diabetic (FPG < 126 mg/dL) and hyperglycemic (126 <= FPG < 200 mg/dL). RESULTS: Thirty-four patients were hyperglycemic and 127 non diabetic. Sensitivity, specificity, positive predictive value and negative predictive value of FDG-PET/CT were 90%, 88%, 87% and 91% in non diabetic and 82%, 92%, 95% and 73% in hyperglycemic patients, respectively. Overall, the accuracy was higher in non diabetic than hyperglycemic patients (89% vs. 85%). CONCLUSIONS: Accuracy of FDG-PET/CT for primary diagnosis of pancreatic lesions is higher in patients with FPG levels < 126 mg/dL than in patients with FPG levels between 126 and 200 mg/dL. PMID- 25745485 TI - Anti-hyperglycemic and insulin sensitizer effects of turmeric and its principle constituent curcumin. AB - CONTEXT: Turmeric is obtained from the plant Curcuma longa L; its major constituent, curcumin, is a polyphenol with multiple effects which can modulate some signaling pathways. EVIDENCE ACQUISITION: Insulin resistance is a major risk factor for chronic diseases such as type 2 diabetes, atherosclerotic, metabolic syndrome and cardiovascular disease. In addition, Insulin resistance in peripheral tissue is one of the most important reasons of hyperglycemia which can cause global or systemic effects. The present study reviewed studies published in PubMed from 1998 to 2013, indicating the role of curcumin in attenuation of many pathophysiological processes involved in development and progression of hyperglycemia and insulin resistance. RESULTS: Curcumin can reduce blood glucose level by reducing the hepatic glucose production, suppression of hyperglycemia induced inflammatory state, stimulation of glucose uptake by up-regulation of GLUT4, GLUT2 and GLUT3 genes expressions, activation of AMP kinase, promoting the PPAR ligand-binding activity, stimulation of insulin secretion from pancreatic tissues, improvement in pancreatic cell function, and reduction of insulin resistance. CONCLUSIONS: Curcumin has antihyperglycemic and insulin sensitizer effects. Thereby, more studies evaluating the effects of curcumin on hyperglycemic state and insulin resistance in related disorders such as diabetes are recommended. PMID- 25745486 TI - Association of mean platelet volume with androgens and insulin resistance in nonobese patients with polycystic ovary syndrome. AB - BACKGROUND: Mean platelet volume (MPV) is generally accepted as a new marker of cardiovascular disease risk in several studies. OBJECTIVES: This study aimed to determine the association of MPV with androgen hormones and insulin resistance (IR) in nonobese patients with polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: A total of 136 patients with newly diagnosed reproductive-age PCOS (regarding the criteria of new PCOS phenotypes, based on the Rotterdam criteria) who were nonobese with the mean age of 25 years (25.39 +/- 5.51) and mean body mass index (BMI) of 21 kg/m(2) (22.07 +/- 2.13) were included. In addition, 59 healthy subjects with mean age of 26 years (22.07 +/- 2.13) and mean BMI of 22 kg/m(2) (21.52 +/- 3.84) were recruited as control. Total blood count (including MPV), total testosterone, free testosterone, dehydroepiandrosterone-sulfate (DHEAS), and androstenedione levels were recorded. IR was calculated from blood chemistry measurements of fasting insulin and glucose according to updated homeostasis model assessment. RESULTS: No differences were observed in mean MPV values between patients and control group (9.02 fL (8.5-10.1) and 8.9 fL (7.7 9.1), respectively; P = 0.777). MPV values were similar among nonobese patients with and without IR and control subjects (P > 0.05). We detected significantly lower values of MPV in patients with hyperandrogenemia in comparison to patients with normal androgen levels (8.7 and 9.5 fL, P = 0.012). There was a negative correlation between total testosterone, DHEAS, and MPV (P = 0.016, r = -0.229; and P = 0.006, r = -0.261, respectively). Multiple logistic regression analyses confirmed the independence of these associations. CONCLUSIONS: Our study revealed that nonobese women with and without PCOS have similar MPV values. While IR does not have any effect on MPV, elevated androgen levels are associated with a low MPV in nonobese patients with PCOS. PMID- 25745487 TI - Association of marital status and marital transition with metabolic syndrome: tehran lipid and glucose study. AB - BACKGROUND: Most existing reports indicate that body weight gradually increases following marital status and thereby enhances health status and decreases mortality; however, the association between marital status and the metabolic syndrome (MetS) has not been thoroughly investigated in a longitudinal study. OBJECTIVES: The aim of this study was to investigate the potential effects of marital status and marital transition on MetS during a 9.6-year follow-up in Tehran Lipid and Glucose Study. PATIENTS AND METHODS: For this study, 5221 participants (2060 males and 3161 females), aged 15 to 90 years at baseline, were followed for a median of 9.6 years. Marital status was categorized as consistent marital status and marital transition. We measured MetS risk z score and its components and calculated their changes. Then the effects of marital status and marital transition on MetS risk z score and its components were assessed using multivariable linear regression. RESULTS: In comparison to participants who were married, no significant changes in MetS risk z score was found in single participants. Employed females in the transition to married group had significant increase in MetS risk z score than single employed females. No significant changes in MetS risk z score were observed between widowed/divorced subjects and compared to consistently married subjects. CONCLUSIONS: Marital status may affect MetS risk z score differently in both genders. PMID- 25745488 TI - Thyroid function in pregnancy and its influences on maternal and fetal outcomes. AB - BACKGROUND: Maternal thyroid function alters during pregnancy. Inadequate adaptation to these changes results in thyroid dysfunction and pregnancy complications. OBJECTIVES: This prospective study aimed to evaluate the prevalence of thyroid diseases in pregnancy and its outcomes in south of Iran. MATERIALS AND METHODS: This prospective study was conducted on 600 healthy singleton pregnant women who aged 18 to 35 years old at 15 to 28 weeks of gestation. We investigated the prevalence of thyroid dysfunctions in women. Multivariate analysis was performed to determine the effect thyroid dysfunction on obstetric and neonatal outcome. RESULTS: Thyroid stimulating hormone (TSH) levels of 0.51, 1.18, 1.68, 2.4, and 4.9 mIU/L were at 2.5th, 25th, 50th, 75th, and 97.5th percentile in our population. The prevalence of clinical hypothyroidism, subclinical hypothyroidism, overt hyperthyroidism, and subclinical hyperthyroidism in all pregnant women was 2.4%, 11.3%, 1.2%, and 0.3%, respectively. In addition, 1.4% of patients had isolated hypothyroxinemia. Clinical hypothyroidism was associated with increased risk of preterm delivery (P = 0.045). Subclinical hypothyroidism had a significant association with intrauterine growth restriction (IUGR) (P = 0.028) as well as low Apgar score at first minute (P = 0.022). Maternal hyperthyroidism was associated with IUGR (P = 0.048). CONCLUSIONS: We revealed that thyroid dysfunction during pregnancy was associated with IUGR and low Apgar score even in subclinical forms. Further studies are required to determine whether early diagnosis and treatment of thyroid diseases, even in subclinical form, can prevent their adverse effect on fetus. PMID- 25745489 TI - Early detection and optimized management of thyroid disease in pregnancy. PMID- 25745490 TI - Anti-thyroid drugs-related myopathy: is carbimazole the real culprit? AB - INTRODUCTION: Anti-thyroid drugs (ATDs)-related myopathy is rarely reported in literature, but once developed, it can cause significant morbidity to patient. CASE PRESENTATION: A 28-year old Chinese female was treated with carbimazole (CMZ) for Graves' disease with hyperthyroidism. Two weeks later, she developed myalgia and proximal muscle weakness. Investigations showed evidence of myopathy. CMZ was stopped and rapid improvement of clinical condition and biochemical parameters ensued. CONCLUSIONS: Rapid decrement of thyroid hormone level is recognized as an important association for anti-thyroid drugs (ATDs)-related myopathy; however, the drug effects on muscle tissue cannot be excluded. Further elucidation of pathophysiology and identification of risk factors are needed. After commencing ATDs, early recognition of this rare condition and close monitoring are the essence of management. Different treatment strategies: dose reduction of ATDs, switching to alternative ATDs, with or without addition of thyroid hormone supplement can be applied depending on clinical situation. PMID- 25745492 TI - A case report of thyroid carcinoma confined to ovary and concurrently occult in the thyroid: is conservative treatment always advised? AB - INTRODUCTION: Struma ovarii is an ovarian teratoma, represented in more than 50% by thyroid tissue. Five percent of struma ovarii cases have been proven to be malignant and, as in the thyroid gland, papillary thyroid carcinoma is the most common histotype arising in struma ovarii. Because of the unusual occurrence of this tumor, its management and follow-up after pelvic surgery is still controversial. Usually, total thyroidectomy followed by radioiodine treatment is the choice treatment in metastatic malignant struma ovarii, while these procedures are still controversial in non-metastatic thyroid cancer arising in struma ovarii. CASE PRESENTATION: We report a female with follicular variant of papillary thyroid carcinoma arising in struma ovarii. After pelvic surgery, thyroid morphofunctional examinations were performed and a single nodular lesion in the left lobe was discovered. The patient underwent total thyroidectomy and histological examination showed a papillary carcinoma. Radioiodine-ablation of residual thyroid tissue was performed and levothyroxine mildly-suppressive treatment was started. CONCLUSIONS: A more aggressive treatment should not be denied for malignant struma ovarii without any evidence, even when apparently confined into the ovary. However, in selected cases, aggressive treatment may be advisable to decrease the risk of recurrence and to allow an accurate follow-up. PMID- 25745491 TI - The effect of ghrelin and estradiol on mean concentration of thyroid hormones. AB - BACKGROUND: Ghrelin is a novel peptide hormone that has GH releasing activity and also other endocrine and metabolic functions. It can also increase food intake and decrease T3 and T4 concentrations. Several parameters of hypothalamic pituitary-thyroid (HPT) axis function are modulated by 17beta-estradiol (E2). OBJECTIVES: The purpose of this study was to investigate the effect of interactions between ghrelin and estradiol (injected via ICV route) on plasma T3 and T4 concentrations in female rats. MATERIALS AND METHODS: Eighteen Wistar female rats (bodyweight, 200-250 g) were randomly divided into three groups. Group 1 received estradiol, Group 2 received ghrelin and Group 3 received ghrelin and estradiol. Plasma samples were used to assess T3 and T4 concentration by RIA. RESULTS: The results indicated that ghrelin significantly decreased thyroid hormone concentrations, whereas estradiol increased these concentrations. The simultaneous injection of ghrelin and estradiol significantly decreased the inhibitory effect of ghrelin on thyroid hormone concentrations (P < 0.05). CONCLUSIONS: According to the results of this study, both ghrelin and estradiol affect the concentration of thyroid hormone but in opposite directions. This difference might be due to different underlying hormonal mechanisms such as HPA and/or HPT axis melanocyte stimulating hormone (MSH) systems could be suggested. PMID- 25745493 TI - Effect of mobile phone short text messages on glycemic control in type 2 diabetes. AB - BACKGROUND: Mobile phone text messaging has rapidly become a socially popular form of communication. Several studies showed that mobile phone might offer a useful means of providing information between clinic visits and might increase adherence to diabetes therapy regimens. OBJECTIVES: We conducted a study to evaluate the effect of mobile phone short message service (SMS) on glycemic control in Saudi patients with type 2 diabetes. PATIENTS AND METHODS: One hundred patients (mean age, 41 +/- 9.5 years) were selected at the Security Forces Hospital, Riyadh, Saudi Arabia, and provided with daily educational, reminding SMS messages for four months. Glycosylated hemoglobin (HbA1c) level, frequency of hypoglycemic and hyperglycemic attacks, and compliance with blood glucose monitoring were recorded before and after the trial. RESULTS: In addition to significant improvement in patients' knowledge, mean fasting blood glucose level improved from 8.60 +/- 3.16 to 7.77 +/- 3.11 mmol/L and mean HbA1c decreased from 9.9% +/- 1.8% to 9.5% +/- 1.7%. CONCLUSIONS: Mobile phone text messaging increased adherence to diabetes therapy and improved the clinical outcome in Saudi patients with type 2 diabetes. PMID- 25745494 TI - Antimullerian hormone and its receptor gene expression in prenatally androgenized female rats. AB - BACKGROUND: Anti-mullerian hormone (AMH) levels reflect the number of small antral follicles in ovaries and expression changes of AMH and its receptor are suspected to be involved in the pathogenesis of polycystic ovary syndrome (PCOS). OBJECTIVES: The aim of this study was to evaluate gene expression of AMH and its receptor in immature and adult rats prenatally exposed to androgen excess. MATERIALS AND METHODS: Six pregnant Wistar rats in the experimental group were treated by subcutaneous injection of 5 mg free testosterone on day 20 of pregnancy, while controls (n = 6) received only 500 mL of solvent. Female pups of each mother were randomly divided into three groups as day 0 (newborn), 10-day old and days 75-85 (adult). RNAs were extracted from ovarian tissues and relative expression levels for AMH and its receptor genes were measured using TaqMan Real Time PCR. Serum AMH and testosterone levels were measured using ELISA method. RESULTS: Relative AMH expression decreased in newborns, 10-day olds and adults (0.806, 0.443 and 0.809 fold, respectively). AMHR expression was higher in newborns and adults (1.432 and 1.057 fold, respectively), while it decreased by 0.263 fold in 10-day olds, although none of them were significant (P > 0.05). In addition, AMH levels were consistent with the results of gene expression. Testosterone hormone levels from 10 day-olds to adults were significantly increased in both study groups (P = 0.016). CONCLUSIONS: While AMH receptor expression was higher in experimental rats, their serum concentrations of AMH were decreased. Further researches with greater sample sizes and measurement of bioactive forms of hormones are recommended to confirm the findings of this study. PMID- 25745495 TI - The effects of vitamin d on insulin release from isolated islets of rats. AB - BACKGROUND: Vitamin D (vit D) affects glucose metabolism. Receptors of vitamin D have been identified in beta cells and studies show that vitamin D deficiency reduces glucose-stimulated insulin secretion (GSIS). OBJECTIVES: The aim of this study was to examine the effect of vitamin D on insulin release from isolated islets of rats. MATERIALS AND METHODS: Islets were isolated from male Wistar rats, weighing 200-250 grams, using the collagenase digestion method. Insulin release was assessed following 24 and 48 hours coincubation of islets with vitamin D (0.1, 1 and 10 nM) and glucose (5.6, 11.1 and 16.7 mM). In addition, islets were preincubated with vitamin D for 24 and 48 hours and GSIS was assessed for one hour in the presence of 5.6 and 16.7 mM glucose. RESULTS: Coincubation of islets with vitamin D (10 nM) and 11.1 mM glucose increased islet insulin release (37.27 +/- 3.75 vs. 24.64 +/- 2.83 ng/islet/24 hours; P < 0.05), while vitamin D (1 and 10 nM) decreased insulin release in the presence of 16.7 mM glucose (21.14 +/- 3.58 and 18.65 +/- 3.84 vs. 37.71 +/- 4.63 ng/ islet/24 hours; P < 0.05). Islets preincubation with vitamin D (1 and 10 nM) increased GSIS in the presence of 16.7 mM glucose (4.39 +/- 0.73 and 4.39 +/- 0.63 vs. 2.07 +/- 0.43 ng/islet/1 hour; P < 0.05). CONCLUSIONS: Preincubation of islets with vitamin D increased GSIS but decreased insulin release in coincubation with high levels of glucose. Insulin secretion from beta cells in the presence of glucose seems to be related to the dosage of vitamin D and duration of preincubation. PMID- 25745496 TI - Effect of camel milk on blood sugar and lipid profile of patients with type 2 diabetes: a pilot clinical trial. AB - BACKGROUND: It has been shown that camel milk consumption has a definite decreasing effect on the prevalence of diabetes. However, most of these studies were conducted on patients with type 1 diabetes, whereas studies on patients with type 2 diabetes mellitus (T2DM) are limited. In vitro experiments have shown that camel milk was able to decrease blood glucose concentration. OBJECTIVES: The purpose of this study was to investigate effects of camel and cow milk on blood sugar, lipid profile, and blood pressure of patients with T2DM. PATIENTS AND METHODS: In a randomized single-blinded controlled clinical trial, 20 patients with T2DM were randomly allocated into two groups. Participants consumed 500 mL of either camel milk (intervention group) or cow milk (control group) daily for two months. RESULTS: Mean of insulin concentration was significantly increased from 64.59 to 84.03 pmol/L in the camel milk group during the study (P < 0.05). No significant differences were shown in fasting blood sugar, lipid profile, and blood pressure between the two groups at the end of study. There was significant increase in homeostasis model assessment of insulin resistance (HOMA-IR) during the study in both groups, but no significant difference was seen between the two groups. CONCLUSIONS: Camel milk increased insulin level in patients with T2DM and might contribute to glycemic control in T2DM. PMID- 25745497 TI - Effect of Vitamin D Supplementation on Glucose Control and Inflammatory Response in Type II Diabetes: A Double Blind, Randomized Clinical Trial. AB - BACKGROUND: Diabetes mellitus (DM) and vitamin D deficiency are major health concerns around the world. Evidence suggests a possible role of vitamin D in improvement of insulin secretion and sensitivity. OBJECTIVES: We assessed whether vitamin D supplementation could be used in vitamin D deficient-type II diabetes to improve glucose metabolism, components of metabolic syndrome (MetS) and specific inflammatory biomarkers. PATIENTS AND METHODS: A double blind, randomized clinical trial was conducted in King Khalid University Hospital, Saudi Arabia to evaluate the effect of cholecalciferol supplementation on glycemic control, MetS components and specific inflammatory biomarkers including tumor necrosis factor-alpha (TNF-alpha), Interleukin (IL-6), leptin, adiponectin and vascular cell adhesion molecule-1 (VCAM-1). Twenty-two patients with type II diabetes with insulin resistance, glycated hemoglobin (HbA1c) >= 6 (42 mmol/mol) and serum 25(OH)D < 50 nmol/L were randomized using a computer program to receive either supplementation with cholecalciferol (5000 IU/day) or placebo for 12 weeks. The primary outcome was change in HbA1c levels from baseline. RESULTS: Median [IQR] 25(OH)D levels increased significantly in the vitamin D group as 58.1 [48, 67.3] nmol/L (P = 0.002). There was no significant difference in the change of HbA1c between the groups (P = 0.5) with a decrease of -0.1% [-1, 0.5] in the vitamin D group and an increase of 0.15% [0.1, 0.2] in the placebo group. A significant improvement was observed in the homeostasis model of assessment of beta-cell activity (HOMA-%B) (P = 0.03) with vitamin D supplementation compared to baseline. CONCLUSIONS: Vitamin D repletion for 12 weeks increased serum vitamin D concentrations and improved beta-cell activity in vitamin D-deficient type II diabetes with no significant changes in HbA1c or insulin sensitivity. PMID- 25745498 TI - Acute tubular nephropathy in a patient with acute HIV infection: review of the literature. AB - We report a 57-year old man with diabetes mellitus and hypertension who presented with acute HIV infection. Routine blood tests showed an elevated blood urea nitrogen and creatinine. Renal biopsy showed acute tubular nephropathy, which has not been reported to occur during acute HIV infection, in the absence of rhabdomyolysis or multiple organ system failure. Antiretroviral therapy was initiated. His renal failure gradually resolved without further intervention. At one year of follow-up his HIV RNA was undetectable, and his renal function was normal. The case illustrates a rare manifestation of acute HIV infection - acute renal failure - in an older man with diabetes and hypertension. In this setting acute kidney injury might mistakenly have been attributed to his chronic comorbidities, and this case supports early HIV-1 testing in the setting of a high index of suspicion. PMID- 25745500 TI - Successful use of extracorporeal membrane oxygenation in a human immunodeficiency virus infected patient with severe acute respiratory distress syndrome. AB - INTRODUCTION: We report a case of an adult patient with human immunodeficiency virus (HIV), acute respiratory distress syndrome (ARDS) and ventilator associated pneumonia (VAP) caused by multidrug resistant (MDR) bacteria that was successfully managed with veno-venous extracorporeal membrane oxygenation (ECMO). CASE REPORT: A 25 year old male with no significant past medical history had been admitted to a local hospital due to dyspnea and fever. His pulmonary function subsequently failed necessitating mechanical ventilation (MV) and introduction of ECMO support. The patient was transported for 300 km by road on ECMO to a tertiary medical center. The diagnosis of ARDS, HIV infection and MDR bacterial and fungal VAP was made. Patient was successfully treated with antiretroviral therapy (ART), anti-infective agents and 58 days of veno-venous ECMO support, with complete resolution of the respiratory symptoms. CONCLUSION: HIV infected patients with ARDS and MDR bacterial VAP whose HIV replication is controlled by ART could be successfully managed with ECMO. PMID- 25745499 TI - A consensus statement on the renal monitoring of Australian patients receiving tenofovir based antiviral therapy for HIV/HBV infection. AB - A number of antiviral agents used against Human Immunodeficiency Virus (HIV) infection and hepatitis B virus (HBV) mono or co-infection have been associated with real nephrotoxicity (including tenofovir disoproxil fumarate (TDF), atazanavir, indinavir and lopinavir) or apparent changes in renal function (e.g. cobicistat, ritonavir, rilpivirine and dolutegravir). Patients with HIV are at higher risk of acute and chronic renal dysfunction, so baseline assessment and ongoing monitoring of renal function is an important part of routine management of patients with HIV. Given the paucity of evidence in this area, we sought to establish a consensus view on how routine monitoring could be performed in Australian patients on ART regimens, especially those involving TDF. A group of nephrologists and prescribers (an HIV physician and a hepatologist) were assembled by Gilead to discuss practical and reasonable renal management strategies for patients particularly those on TDF-based combination regimens (in the case of those with HIV-infection) or on TDF-monotherapy (in the case of HBV mono infection). The group considered which investigations should be performed as part of routine practice, their frequency, and when specialist renal referral is warranted. The algorithm presented suggests testing for serum creatinine along with plasma phosphate and an assessment of urinary protein (rather than albumin) and glucose. Here we advocate baseline tests of renal function at initiation of therapy. If creatinine excretion inhibitors (e.g. cobicistat or rilpivirine) are used as part of the ART regimen, we suggest creatinine is rechecked at 4 weeks and this value used as the new baseline. Repeat testing is suggested at 3-monthly intervals for a year and then at least yearly thereafter if no abnormalities are detected. In patients with abnormal baseline results, renal function assessment should be performed at least 6 monthly. In HBV mono-infected patients advocate that a similar testing protocol may be logical. PMID- 25745501 TI - An assessment of adverse drug reactions among HIV positive patients receiving antiretroviral treatment in South Africa. AB - BACKGROUND: Antiretroviral treatment (ART) has been effective in reducing HIV/AIDS related morbidity and mortality. However, the use and uptake of ART has resulted in adverse reactions, due mainly to the medicine's toxicity and interactions with other medicines. The timing of adverse drug reactions (ADRs) among these patients is a critical public health issue for antiretroviral (ARV) treatment adherence and retention. Reliable monitoring of HIV patients on ART is through a structured pharmacovigilance surveillance system. However, recurrent nature of these data pose challenges in their analyses. This study aimed at modelling the timing of ADR events in HIV patients on ART using correlated time to-event models. METHODS: The data concern 590 HIV patients registered onto the Medunsa National ARV Pharmacovigilance Surveillance System within 6 months of ART initiation between February 2007 and July 2011. Recurrent times of ADRs and baseline characteristics: patient gender, and age, ART regimen, clinic and initiation period were extracted from the data. The recurrent ADR events data were modelled using both shared frailty and marginal models on the five patients' characteristics as covariates. RESULTS: Out of 590 patients, 67% were female, 68% started on regimen: Stavudine, Lamivudine and Efavirenz; 37% had experienced at least one ADR and 67% started ART in 2009-2011. Age (p-value = 0.0210), clinic (p value < 0.0001) and period of ART initiation (p-value = 0.0002) were significantly associated with timing of first ADR. There was a significantly higher rates of ADR recurrences in patients aged 38-44 years [HR = 2.45; 95% CI = (1.47; 4.10)] vs. 30 years and less, patients taking regimen: Zidovudine, Lamivudine and Nevarapine) vs. regimen: Stavudine, Lamivudine and Efavirenz [HR = 2.09; 95% CI = (1.35; 3.22)], while the rate was lower among those who started ART in 2009-2011 vs. those who initiated in 2007-2008 [HR = 0.55; 95% CI = (0.40; 0.76)]. CONCLUSION: More realistic time-to-event models for recurrent events data have been used to analyse timing of ADR events in HIV patients taking ARV treatment. Age, antiretroviral regimen type and period of initiation of ART were associated with the timing of HIV/AIDS drug related adverse reactions regardless of the analysis model used. This study has public health policy implications in addressing the added morbidity among HIV patients taking ARV treatment in the context of universal scaling up of ARV treatment. PMID- 25745502 TI - Pulmonary artery intimal sarcoma diagnosed using endobronchial ultrasound-guided transbronchial needle aspiration. AB - Intimal sarcoma of the pulmonary artery is a rare intraluminal malignant neoplasm that has an aggressive biological behavior, and early diagnosis may improve patient outcome. We describe a case of pulmonary artery intimal sarcoma diagnosed on cytologic material obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy with rapid on-site evaluation (ROSE). The aspirate showed loosely cohesive clusters of pleomorphic malignant spindled and epithelioid cells. An immunostain panel did not demonstrate any definitive mesenchymal or epithelial differentiation. The tumor's intraluminal origin was supported by radiographic imaging studies. Subsequently, the patient received preoperative chemotherapy and underwent tumor resection with reconstruction. This report describes the cytomorphologic features of this rare intravascular tumor and demonstrates how EBUS-TBNA with ROSE was instrumental in obtaining optimal cytologic sampling for ancillary studies, thus expediting the management. PMID- 25745503 TI - Frequency and characterization of celiac ganglia diagnosed on fine-needle aspiration. AB - INTRODUCTION: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is frequently used to sample intra-abdominal lesions and lymph nodes. Celiac ganglia normally located near the celiac artery may be sampled during these procedures. The aim of this study was to determine the frequency of detection and cytologic findings of celiac ganglia diagnosed on FNA. MATERIALS AND METHODS: A 14-year retrospective review of radiologic and endoscopic FNA cases involving the celiac region was performed. Cases in which ganglia were reported were further analyzed and slides reviewed. RESULTS: A total of 354 patients underwent FNA of a suspected celiac lymph node (334 patients) or celiac mass (20 cases). In 9 of these patients (2.5%), ganglion cells were identified. These were identified in cases only after 2008 via EUS-guided FNA. Aspirates were hypocellular and bloody. Large ganglion cells were either sparsely dispersed or present in clusters. Ganglion cells had a low N: C ratio, granular cytoplasm with neuromelanin, and eccentric small round nucleus with a prominent nucleolus. One specimen had concomitant pancreatic adenocarcinoma. None of these cases had a false positive on-site adequacy assessment or final misdiagnosis. CONCLUSIONS: These data show that celiac ganglia may be infrequently encountered, especially with intra abdominal EUS-guided FNA targeting nodes or masses near the celiac region. Therefore, cytologists should be aware of the possibility of finding ganglionic cells in EUS-guided FNA samples. PMID- 25745504 TI - The individualistic fallacy, ecological studies and instrumental variables: a causal interpretation. AB - The validity of ecological studies in epidemiology for inferring causal relationships has been widely challenged as observed associations could be biased by the Ecological Fallacy. We reconsider the important design components of ecological studies, and discuss the conditions that may lead to spurious associations. Ecological associations are useful and valid when the ecological exposures can be interpreted as Instrumental Variables. A suitable example may be a time series analysis of environmental pollution (e.g. particulate matter with an aerodynamic diameter of <10 micrometres; PM10) and health outcomes (e.g. hospital admissions for acute myocardial infarction) as environmental pollution levels are a cause of individual exposure levels and not just an aggregate measurement. Ecological exposures may also be employed in situations (perhaps rare) where individual exposures are known but their associations with health outcomes are confounded by unknown or unquantifiable factors. Ecological associations have a notorious reputation in epidemiology and individualistic associations are considered superior to ecological associations because of the "ecological fallacy". We have argued that this is incorrect in situations in which ecological or aggregate exposures can serve as an instrumental variable and associations between individual exposure and outcome are likely to be confounded by unmeasured variables. PMID- 25745505 TI - The flavonoid, naringenin, decreases adipose tissue mass and attenuates ovariectomy-associated metabolic disturbances in mice. AB - OBJECTIVE: Adverse metabolic changes associated with loss of ovarian function increase the risk of developing metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) in postmenopausal women. Naringenin improves metabolic disturbances in vitro and in vivo. In the present study, we tested the effects of naringenin on metabolic disturbances resulting from estrogen deficiency in ovariectomized mice. MATERIALS/METHODS: Ovariectomized C57BL/6 J female mice were fed a control diet (10% calories from fat) for 11 weeks. Mice either continued on the control diet (n = 9) or were switched to the control diet supplemented with 3% naringenin (n = 10) for the next 11 weeks. Energy expenditure was measured by indirect calorimetry and activity was monitored by infrared beam breaks. Intra abdominal and subcutaneous adiposity was evaluated by magnetic resonance imaging (MRI). Blood biochemical measures of metabolic response included glucose, insulin, adipokines, and lipids. Lipid content in liver and muscle and expression of relevant genes in adipose tissue, liver, and muscle were quantified. RESULTS: Ovariectomized mice fed naringenin exhibited lower fasting glucose and insulin levels compared to controls, with over 50% reduction of intra-abdominal and subcutaneous adiposity. Plasma leptin and leptin mRNA in adipose depots were also decreased in mice fed a naringenin diet. Monocyte chemoattractant protein-1 (MCP1/Ccl2) and interleukin 6 (IL-6/Il6) mRNA expression levels were significantly lower in perigonadal adipose tissue of naringenin-supplemented mice. We also observed that mice fed a naringenin diet had less hepatic lipid accumulation with corresponding alterations of hepatic gene expression associated with de novo lipogenesis, fatty acid oxidation, and gluconeogenesis. CONCLUSION: Dietary naringenin attenuates many of the metabolic disturbances associated with ovariectomy in female mice. PMID- 25745506 TI - Sex-specific determinants of serum 25-hydroxyvitamin D3 concentrations in an elderly German cohort: a cross-sectional study. AB - BACKGROUND: Considering the suggested link between vitamin D insufficiency and several chronic diseases, attention should be given to approaches for improving vitamin D status. Elderly subjects are regarded as a high-risk group for developing an insufficient vitamin D status. Socioeconomic, dietary, lifestyle and environmental factors are considered as influencing factors, whereupon sex differences in predictors of vitamin D status are rarely investigated. The purpose of this study is to identify the main predictors of serum 25 hydroxyvitamin D3 [25(OH)D3] concentrations in elderly subjects by taking into account potential sex differences. METHODS: This is a cross-sectional study in 162 independently living German elderly aged 66 to 96 years. Serum 25(OH)D3 concentrations were assessed by an electrochemiluminescence immunoassay. Multiple regression analyses were performed to identify predictors of 25(OH)D3 concentrations stratified by sex. RESULTS: Median 25(OH)D3 concentration was 64 nmol/L and none of the subjects had 25(OH)D3 concentrations < 25 nmol/L. In women, intact parathyroid hormone (iPTH) (beta = -0.323), % total body fat (beta = -0.208), time spent outdoors (beta = 0.328), month of blood sampling (beta = 0.229) and intake of vitamin D supplements (beta = 0.172) were the predominant predictors of 25(OH)D3, whereas in men, iPTH (beta = -0.254), smoking (beta = 0.282), physical activity (beta = 0.336) and monthly household net income (beta = 0.302) predicted 25(OH)D3 concentrations. The final regression models accounted for 30% and 32% of the variance in 25(OH)D3 concentrations in women and men, respectively. CONCLUSION: The findings indicate that 25(OH)D3 concentrations are influenced by body composition, month of blood sampling, economic factors, lifestyle, supplement intake and iPTH, but may not be associated with age, sex, dietary factors, kidney function and presence of selected chronic diseases in community-dwelling elderly. Furthermore, our results provide evidence for sex specific determinants of the vitamin D status, which ought to be considered for preventive strategies. PMID- 25745507 TI - Association of alcohol consumption and components of metabolic syndrome among people in rural China. AB - BACKGROUND: Accumulative evidence in the literature suggests alcohol consumption is a protective factor of the metabolic syndrome (MS). However, few studies investigated the relationship between alcohol consumption and components of MS. We examined association of several types of alcoholic beverage with components of MS among people in rural China. METHODS: In the Nantong Metabolic Syndrome Study (NMSS), a cross-sectional study, a total of 20,502 participants, including 13,505 women and 6,997 men aged 18-74 years, were recruited between 2007 and 2008 in Nantong, China. Socio-economic status, dietary intake, physical exercise, alcoholic beverage consumption, and smoking status information were obtained, and triglycerides (TG), high-density lipoprtein cholesterol (HDL-c), blood pressure (BP) and blood glucose level were examined for all participants. Logistic regression model and the restricted cubic spline approach were used to analyze the associations between alcoholic beverage consumption and MS components. RESULTS: The MS prevalence was 21.1% in the whole population, which was significantly low among drinkers (20.6%), compared with non-drinkers (23.6%) in women, and was comparable in men (16.4% versus 17.1%). High HDL-c level was observed among drinkers, compared with non-drinkers in both men and women. Low TG level and Systolic BP (SBP) were found only among rice wine drinkers in women, and high waist circumference, high TG and BP were found among beer and liquor drinkers in men. Furthermore, we found that the highest quartile of rice wine drink in women may decrease 24% risk of high TG, 30% risk of low HDL-c and 43% risk of high glucose among MS components cases respectively, compared with non drinkers (p for trend <0.01 for those three components). While compared non drinkers among men, the highest quartile of liquor drink may increase 32% risk of high SBP, 55% risk of high Diastolic BP (DBP) and 34% risk of abdominal obesity among MS components cases respectively, but decrease 45% risk of low HDL-c (p for trend <0.05 for those four components). CONCLUSION: Our data suggested that all alcoholic beverages increased HDL-c level. Rice wine decreased both TG level and blood glucose in women only and it could be one of healthy alcoholic beverages in MS prevention in Chinese women. While excessive liquor consumption increased BP and waist circumference level and it may lead to hypertension and central obesity in Chinese men. PMID- 25745508 TI - A multidimensional approach to measuring well-being in students: Application of the PERMA framework. AB - Seligman recently introduced the PERMA model with five core elements of psychological well-being: positive emotions, engagement, relationships, meaning, and accomplishment. We empirically tested this multidimensional theory with 516 Australian male students (age 13-18). From an extensive well-being assessment, we selected a subset of items theoretically relevant to PERMA. Factor analyses recovered four of the five PERMA elements, and two ill-being factors (depression and anxiety). We then explored the nomological net surrounding each factor by examining cross-sectional associations with life satisfaction, hope, gratitude, school engagement, growth mindset, spirituality, physical vitality, physical activity, somatic symptoms, and stressful life events. Factors differentially related to these correlates, offering support for the multidimensional approach to measuring well-being. Directly assessing subjective well-being across multiple domains offers the potential for schools to more systematically understand and promote well-being. PMID- 25745510 TI - Improved methodology for assaying brassinosteroids in plant tissues using magnetic hydrophilic material for both extraction and derivatization. AB - BACKGROUND: Brassinosteriods (BRs) are a group of important phytohormones that have major effects on plant growth and development. To fully elucidate the function of BRs, a sensitive BR assay is required. However, most of the previously reported methods are tedious and time-consuming due to multiple pretreatment steps. Therefore, it is of great significance to develop a method to increase the throughput and detection sensitivity of BR analysis. RESULTS: We established a novel analytical method of BRs based on magnetic solid phase extraction (MSPE) combined with in situ derivatization (ISD). TiO2-coated magnetic hollow mesoporous silica spere(TiO2/MHMSS) was served as a double identity- a microextraction sorbent and "microreactor" for the capture and derivatization of BRs in sequence. BRs were first extracted onto TiO2/MHMSS through hydrophilic interaction. The BR-adsorbed TiO2/MHMSS was then employed as a "microreactor" for the derivatization of BRs with 4-(N,N dimethyamino)phenylboronic acid (DMAPBA). The MSPE-ISD method was simple and fast, which could be accomplished within 10 min. Furthermore, the derivatives of BRs showed better MS response because they were incorporated with tertiary amino groups. Uniquely, endogenous BRs were detected in only 100 mg fresh weight plant tissue. CONCLUSION: Our proposed MSPE-ISD method for the determination of endogenous BRs is rapid and sensitive. It can be applied to the analysis of endogenous BRs in 100 mg fresh plant tissue (Brassica napus L. (B. napus L)). The proposed strategy for plant sample preparation may be extended to develop analytical methods for determination of a wide range of analytes with poor MS response in other complex sample matrices. PMID- 25745509 TI - Development of a self-management intervention for employees with complaints of the arm, neck and/or shoulder (CANS): a focus group study with experts. AB - BACKGROUND: Many people suffer from complaints of the arm, neck and/or shoulder (CANS). The complaints are persistent and there is a need for intervention programs for those with longstanding CANS. Studies suggest that a behavioural change is needed in employees with CANS. A self-management program with an add-on eHealth module might be an effective option to achieve the behavioural change needed to manage the complaints in employees with CANS. The aim of this study was to determine the content and strategies of the intervention and to gain insight into possible barriers and facilitators for implementation. Therefore, we examined the views of experts on the problems and characteristics associated with employees with CANS as well as their opinion on a self-management program consisting of self-management sessions and an eHealth module. METHODS: A qualitative study was performed consisting of three focus groups involving a total of 17 experts (with experience with CANS, self-management and/or eHealth interventions). Experts were asked their opinion about the content and requirements of a self-management program for employees with CANS, including an eHealth module. Data were analysed using qualitative data analysis. After coding, the emergent themes were used to organise the data into main categories, expressing the ideas and opinions of experts on CANS, self-management and/or eHealth interventions. RESULTS: The experts pointed out that the intervention should focus on increasing employees' self-efficacy and empowerment, and address topics related to the possible risk factors for CANS, symptoms, work environment, social environment and personal factors. The eHealth module should be self explanatory and attractive, and the information provided should be brief, clear and concise. CONCLUSIONS: Experts appeared to see a role for a self-management program for employees with CANS. They indicated that the combination of group sessions and eHealth can work well. Experts provided valuable information with regard to the content of the self-management intervention and the design of the eHealth module. PMID- 25745511 TI - Anger tendency may be associated with duration of illness in panic disorder. AB - BACKGROUND: Several studies have reported an increased tendency towards anger in patients with panic disorder (PD). If this propensity for anger arises from the pathological process of PD, it may be associated with the duration of the illness. The present study therefore examined the relationship between duration of PD and the personality tendency to experience anger in PD patients. METHODS: Participants were 413 patients (132 men and 281 women; age = 38.7 years) with PD. Diagnoses were confirmed using the Mini-International Neuropsychiatric Interview. Illness duration ranged from less than a year to 51 years. After participants completed the Revised NEO Personality Inventory, we examined the association between illness duration and the Angry Hostility and Impulsiveness subscale scores. In the analysis, participants were divided into two groups by duration of illness (long group, n = 186 and short group, n = 200) using the median value (9 years) as a cut-off because of the skewed distribution of the duration. Patients with an illness duration of 9 years (n = 27) were excluded from the comparison. RESULTS: The duration of illness was significantly correlated with the Angry Hostility score (p = 0.002) after controlling for age. Scores were significantly higher in the long group than in the short group (p = 0.04). No significant association was observed between Impulsiveness scores and duration of illness. CONCLUSION: The present study suggests that longer PD duration is related to a stronger tendency to experience anger. PMID- 25745512 TI - Detection of rabbit IgG by using functional magnetic particles and an enzyme conjugated antibody with a homemade magnetic microplate. AB - BACKGROUND: The enzyme-linked immunosorbent assay (ELISA) has been used for diagnosing medical and plant pathologies. In addition, it is used for quality control evaluations in various industries. The ELISA is the simplest method for obtaining excellent results; however, it is time consuming because the immunoreagents interact only on the contact surfaces. Antibody-labeled magnetic particles can be dispersed in a solution to yield a pseudohomogeneous reaction with antigens which improved the efficiency of immunoreaction, and can be easily separated from the unreactive substances by applying a magnetic force. We used a homemade magnetic microplate, functional magnetic particles (MPs) and enzyme labeled secondary antibody to perform the sandwich ELISA successfully. RESULTS: Using antibody-labeled MPs enabled reducing the analysis time to one-third of that required in using a conventional ELISA. The secondary antibody conjugated with horseradish peroxidase (HRP) was affinity-bound to the analyte (IgG in this study). The calibration curve was established according to the measured absorbance of the 3, 3', 5, 5'-tetramethybezidine-HRP reaction products versus the concentrations of standard IgG. The linear range of IgG detection was 114 ng/mL-3.5 ng/mL. The limit of detection (LOD) of IgG was 3.4 ng/mL. The recovery and coefficient of variation were 100% (+/-7%) and 116% (+/-4%) for the spiked concentrations of 56.8 ng/mL and 14.2 ng/mL, respectively. CONCLUSION: Pseudohomogeneous reactions can be performed using functional MPs and a magnetic microplate. Using antibody-labeled MPs, the analysis time can be reduced to one third of that required in using a conventional ELISA. The substrate-enzyme reaction products can be easily transferred to another microplate, and their absorbance can be measured without interference by light scattering caused by magnetic microbeads. This method demonstrates great potential for detecting other biomarkers and in biochemical applications. Graphical AbstractA magnetic ELISA with convenient magnetic microplate. PMID- 25745513 TI - Scapula fractures in complex shoulder injuries and floating shoulders: a classification based on displacement and instability. AB - BACKGROUND: Scapula fractures with injuries of the Superior Shoulder Suspensory Complex are often referred to as floating shoulders. However, present studies do not allow comparative evidence on indication for surgical treatment mostly due to the lack of precise definitions and comparable classifications. The aim of this study was to retrospectively analyze common types of complex shoulder injuries and develop a feasible classification allowing a therapeutic algorithm. METHODS: The study group consisted of 107 patients with scapula fractures combined with ipsilateral injuries of the shoulder girdle treated in a single trauma center between 2003 and 2010. Three-dimensional computed tomography was analyzed for dislocation and instability and assigned to subgroups of a defined classification system. Clinical data was acquired from a previously established database of all patients treated for the diagnosis of a scapula fracture. RESULTS: Fifty-seven of 107 (53.3%) complex scapula fractures were non-displaced and stable representing Type A fractures. Depending on the fracture pattern, three subgroups were defined. Treatment of Type A injuries should be non-operative. Displaced fractures of the scapula with a stable shoulder girdle were considered Type B injuries and represented 18.7% of all fractures. Thirty fractures (28%) with an unstable shoulder girdle were classified as Type C injuries. Again, subgroups with common injury patterns were identified. For both groups, operative treatment is recommended. CONCLUSIONS: The described classification system is a proposal able to categorize complex shoulder injuries and allows a comparison of injury patterns in further studies. PMID- 25745514 TI - Mental disorders and criminal re-referrals in juveniles who sexually offended. AB - OBJECTIVE: To investigate the prevalence of mental disorders in (subgroups of) juvenile suspects who sexually offended (JSOs), and its relation with criminal re referrals five to eight years later. METHODS: A sample of 106 JSOs (mean age 15.0 +/- 1.5 years) referred to the Dutch Child Protection Board between May 2003 and December 2006 was classified into JSOs with child victims (N = 19), solo JSOs with adolescents and/or adults victims (N = 29), and group JSOs with adolescents and/or adults victims (N = 58). Mental disorders were assessed at baseline by means of a semi-structured interview (K-SADS-PL), the level of functioning by means of the Children's Global Assessment Scale (CGAS) and re-referrals was ascertained from official judicial registration systems. RESULTS: Three quarters of JSOs met criteria for at least one mental disorder. Comorbidity was found in more than half of the subjects and almost two thirds of the JSOs were functionally impaired. As compared to the other subgroups, JSOs with child victims showed higher rates of affective disorders and had a lower overall level of functioning. Furthermore, JSOs re-referred for another sexual offense were more often diagnosed with an affective disorder, were more often sexually abused and had a lower level of global functioning than JSOs who were not re-referred for another sex offense. CONCLUSIONS: JSOs should receive mental assistance, as more than two thirds are functionally impaired due to mental problems. This may not only be important to safeguard the development of the juvenile offender but might also reduce repeated sexual offending. PMID- 25745515 TI - TGF-beta1 conjugated chitosan collagen hydrogels induce chondrogenic differentiation of human synovium-derived stem cells. AB - BACKGROUND: Unlike bone tissue, articular cartilage regeneration has not been very successful and has many challenges ahead. We have previously developed injectable hydrogels using photopolymerizable chitosan (MeGC) that supported growth of chondrocytes. In this study, we demonstrate a biofunctional hydrogel for specific use in cartilage regeneration by conjugating transforming growth factor-beta1 (TGF-beta1), a well-documented chondrogenic factor, to MeGC hydrogels impregnating type II collagen (Col II), one of the major cartilaginous extracellular matrix (ECM) components. RESULTS: TGF-beta1 was delivered from MeGC hydrogels in a controlled manner with reduced burst release by chemically conjugating the protein to MeGC. The hydrogel system did not compromise viability of encapsulated human synovium-derived mesenchymal stem cells (hSMSCs). Col II impregnation and TGF-beta1 delivery significantly enhanced cellular aggregation and deposition of cartilaginous ECM by the encapsulated cells, compared with pure MeGC hydrogels. CONCLUSIONS: This study demonstrates successful engineering of a biofunctional hydrogel with a specific microenvironment tailored to promote chondrogenesis. This hydrogel system can provide promising efficacious therapeutics in the treatment of cartilage defects. PMID- 25745516 TI - Molecular cloning using polymerase chain reaction, an educational guide for cellular engineering. AB - BACKGROUND: Over the last decades, molecular cloning has transformed biological sciences. Having profoundly impacted various areas such as basic science, clinical, pharmaceutical, and environmental fields, the use of recombinant DNA has successfully started to enter the field of cellular engineering. Here, the polymerase chain reaction (PCR) represents one of the most essential tools. Due to the emergence of novel and efficient PCR reagents, cloning kits, and software, there is a need for a concise and comprehensive protocol that explains all steps of PCR cloning starting from the primer design, performing PCR, sequencing PCR products, analysis of the sequencing data, and finally the assessment of gene expression. It is the aim of this methodology paper to provide a comprehensive protocol with a viable example for applying PCR in gene cloning. RESULTS: Exemplarily the sequence of the tdTomato fluorescent gene was amplified with PCR primers wherein proper restriction enzyme sites were embedded. Practical criteria for the selection of restriction enzymes and the design of PCR primers are explained. Efficient cloning of PCR products into a plasmid for sequencing and free web-based software for the consecutive analysis of sequencing data is introduced. Finally, confirmation of successful cloning is explained using a fluorescent gene of interest and murine target cells. CONCLUSIONS: Using a practical example, comprehensive PCR-based protocol with important tips was introduced. This methodology paper can serve as a roadmap for researchers who want to quickly exploit the power of PCR-cloning but have their main focus on functional in vitro and in vivo aspects of cellular engineering. PMID- 25745517 TI - Combining functional genomics strategies identifies modular heterogeneity of breast cancer intrinsic subtypes. AB - BACKGROUND: The discovery of breast cancer subtypes and subsequent development of treatments aimed at them has allowed for a great reduction in the mortality of breast cancer. But despite this progress, tumors with similar characteristics that belong to the same subtype continue to respond differently to the same treatment. Five subtypes of breast cancer, namely intrinsic subtypes, have been characterized to date based on their gene expression profiles. Among other characteristics, subtypes vary in their degree of intra-subtype heterogeneity. It is not clear, however, whether this heterogeneity is shared across all tumor traits. It is also unclear whether individual traits can be highly heterogeneous among a majority of homogeneous traits. RESULTS: We employ network theory to uncover gene modules and accordingly consider them as tumor traits, which capture shared biological processes among the subtypes. We then use the beta-diversity metric from ecology to quantify the heterogeneity in these gene modules. In doing so, we show that breast cancer heterogeneity is contained in gene modules and that this modular heterogeneity increases monotonically across the subtypes. We identify a core of two modules that are shared among all subtypes which contain nucleosome assembly and mammary morphogenesis genes, and a number of modules that are specific to subtypes. This modular heterogeneity, which increases with global heterogeneity, relates to tumor aggressiveness. Indeed, we observe that Luminal A, the most treatable of subtypes, has the lowest modular heterogeneity whereas the Basal-like subtype, which is among the hardest to treat, has the highest. Furthermore, our analysis shows that a higher degree of global heterogeneity does not imply higher heterogeneity for all modules, as Luminal B shows the highest heterogeneity for core modules. CONCLUSIONS: Overall, modular heterogeneity provides a framework with which to dissect cancer heterogeneity and better understand its underpinnings, thereby ultimately advancing our knowledge towards a more effective personalized cancer therapy. PMID- 25745518 TI - Promoters and barriers to work: a comparative study of refugees versus immigrants in the United States. AB - BACKGROUND: Immigrants in general and refugees in specific are at risk for unemployment with detrimental effects on health and social well-being. Prior work has identified a series of barriers preventing employment among immigrants and refugees. However, these studies either fail to have a comparison group, or it is improper. The objective of this study is to compare unemployment determinants among culturally comparable Iraqi immigrants and refugees. METHOD: A convenience sample of Iraqis residing in Michigan, who came to US after 2003, were surveyed covering socio-demographic aspects, prior and current job history, perceived barriers and facilitators to get a job, discrimination, and health. RESULTS: results show that refugees were twice as likely to be unemployed. Lack of language skills was a bigger barrier among refugees. The results indicate that immigrants are more successful than refugees in securing a job, even after taking their pre-migration and professional experiences into consideration. CONCLUSION: This comparative study showed that refugees were more likely to have a difficult time in successfully finding a job. More attention is needed to help minimize the barriers that refugees face in the employment process. PMID- 25745519 TI - Evidence that Osteoblasts are Specialized Citrate-producing Cells that Provide the Citrate for Incorporation into the Structure of Bone. AB - Citrate is a major component of bone in all vertebrates, but its implications in bone have remained largely unknown. Recent studies identified that citrate is incorporated into the structure of the hydroxyapatite nanocrystal/collagen complex; and is essential for the important biomechanical properties of bone. This raises the important question, "What is the source of citrate for incorporation into bone?"; A question that heretofore had remained unresolved. Studies in this report were designed to determine the plausibility of our concept that the osteoblasts are specialized citrate-producing cells, which provide the citrate that is incorporated into the structure of bone; and that osteogenic differentiation of mesenchyme cells leads to the development of the citrate producing osteoblasts. The results demonstrated that primary human osteoblasts exhibit the capability of citrate-production. Undifferentiated mesenchyme cells do not exhibit the capability of citrate production; and osteogenic differentiation results in citrate-producing osteoblasts. The up-regulation of zinc uptake transporter ZIP1 is essential for the manifestation of the citrate producing capability of the osteoblasts. We determined that osteoblast transport of citrate from plasma is not a likely source of citrate in bone. Thus, this study establishes for the first time that the osteoblasts are specialized citrate producing cells that provide the citrate for incorporation into the structure of bone; and that mesenchyme cell osteogenesis leads to differentiated citrate producing osteoblasts. This is a new understanding; which must include the osteogenic development of citrate-producing osteoblasts, and the process of "citration" in concert with mineralization during bone formation. It also provides a new understanding of the role of bone in the homeostatic maintenance of plasma citrate concentration. PMID- 25745520 TI - Brain magnetic resonance imaging and magnetic resonance spectroscopy findings of children with kernicterus. AB - BACKGROUND: The term kernicterus, or bilirubin encephalopathy, is used to describe pathological bilirubin staining of the basal ganglia, brain stem, and cerebellum, and is associated with hyperbilirubinemia. Kernicterus generally occurs in untreated hyperbilirubinemia or cases where treatment is delayed. Magnetic resonance imaging (MRI)-based studies have shown characteristic findings in kernicterus. The objective of our study was to describe the role of (1)H magnetic resonance spectroscopy (MRS) in demonstrating these metabolic changes and to review conventional MRI findings of kernicterus. MATERIAL/METHODS: Forty eight pediatric cases with kernicterus were included in this study. MRI and MRS examinations were performed on variable dates (10-29 days after birth). NAA, Cr, Cho, NAA/Cr, NAA/Cho, and Cho/Cr values were evaluated visually and by computer analysis. RESULTS: There was no statistically significant difference between the NAA and Cho levels in the acute kernicterus patients and the control group (healthy patients), whereas both were significantly elevated in the chronic kernicterus patients. Both the mean NAA/Cr and Cho/Cr ratio values were significantly higher in the acute and chronic cases compared to the control group. The NAA/Cho ratio value was statistically lower in the acute cases than in the control group while it was similar in the chronic cases. CONCLUSIONS: Conventional MR imaging and (1)H-MRS are important complementary tools in the diagnostics of neonatal bilirubin encephalopathy. This study provided important information for applying these MR modalities in the evaluation of neonates with bilirubin encephalopathy. PMID- 25745521 TI - Bone involvement by adenocarcinoma of the uterine cervix: a rare entity. AB - BACKGROUND: Adenocarcinoma is the second most frequent cancer of the uterine cervix after squamous carcinoma, and the most frequent histotype is the mucinous one. Endo-cervical adenocarcinoma accounts for about 10-30% of all cervical cancers and clinically the lesion can be asymptomatic or, more frequently, presenting with anomalous bleeding and/or vaginal discharge. CASE REPORT: A 41 year-old woman with a diagnosis of adenocarcinoma of the uterine cervix was subjected to chemotherapy after radical surgery. During the follow-up, the patient underwent a Positron Emission Tomography integrated with Computed Tomography and pelvic Magnetic Resonance, which showed rapid and diffuse disease progression from the site of the lesion to the pelvic bones. CONCLUSIONS: Bone involvement in patients with cervical cancer, being a rare event, is significant since it greatly reduces life expectancy. The majority of metastatic bone lesions in cervical cancer seem to be of osteolytic nature. In our patient, Positron Emission Tomography integrated with Computed Tomography and Magnetic Resonance were the imaging methods used during the follow-up and both techniques clearly showed diffuse and rapid tumour spread to the bones. PMID- 25745522 TI - Pseudoaneurysm Arising from Mitral Aortic Intervalvular Fibrosa (P-MAIVF) Communicating with Left Atrium (LA): Multiple Detector Computed Tomography (MDCT) Evaluation. AB - BACKGROUND: The entity pseudoaneurysm arising from the mitral aortic intervalvular fibrosa (P-MAIVF) is a rare cardiac finding caused by multiple factors. This entity is usually diagnosed with echocardiography and confirmed with cardiac computed tomography (CT). CASE REPORT: We presented a case of congenital P-MAIVF communicating with the left atrium (LA) and an aberrant right subclavian artery, misdiagnosed as primary mitral regurgitation (MR) in transthoracic echocardiogram (TTE) due to relative contraindications to transesophageal echocardiogram (TEE), revealed in a hemophilic patient, and diagnosed with cardiac CT. CONCLUSIONS: In conclusion, cardiac CT plays a definitive role not only in anatomical assessment and confirmation of the lesion but also in primary diagnostics in patients suspected of MAIVF - especially those with relative and absolute contraindications to TEE. PMID- 25745523 TI - Thoracic splenosis after a gunshot: diffusion-weighted MRI findings. AB - BACKGROUND: Intrathoracic splenosis is a rare condition resulting from concomitant rupture of the spleen and left hemidiaphragm after a traumatic event involving the spleen and the diaphragma and is defined as autotransplantation of splenic tissue in thorax. CASE REPORT: The aim of this study was to present a case report of a combined intrathoracic and subcutaneous splenosis in a patient 19 years after penetrating trauma. She has left dorsal side pain and routine chest roentgenogram shows pleural nodular masses. The patient was referred to us for radiologic work up. CONCLUSIONS: The MRI scans revealed the intrathoracic and subcutan masses as mainly hypointense on T1-weighted images and hyperintense on T2-weighted images and significant restriction in diffusion-weighted images. Scintigraphy revealed abnormal hot spots in subcutaneous tissue and diaphragmatic pleura of the left hemithorax. PMID- 25745524 TI - Artifacts in magnetic resonance imaging. AB - Artifacts in magnetic resonance imaging and foreign bodies within the patient's body may be confused with a pathology or may reduce the quality of examinations. Radiologists are frequently not informed about the medical history of patients and face postoperative/other images they are not familiar with. A gallery of such images was presented in this manuscript. A truncation artifact in the spinal cord could be misinterpreted as a syrinx. Motion artifacts caused by breathing, cardiac movement, CSF pulsation/blood flow create a ghost artifact which can be reduced by patient immobilization, or cardiac/respiratory gating. Aliasing artifacts can be eliminated by increasing the field of view. An artificially hyperintense signal on FLAIR images can result from magnetic susceptibility artifacts, CSF/vascular pulsation, motion, but can also be found in patients undergoing MRI examinations while receiving supplemental oxygen. Metallic and other foreign bodies which may be found on and in patients' bodies are the main group of artifacts and these are the focus of this study: e.g. make-up, tattoos, hairbands, clothes, endovascular embolization, prostheses, surgical clips, intraorbital and other medical implants, etc. Knowledge of different types of artifacts and their origin, and of possible foreign bodies is necessary to eliminate them or to reduce their negative influence on MR images by adjusting acquisition parameters. It is also necessary to take them into consideration when interpreting the images. Some proposals of reducing artifacts have been mentioned. Describing in detail the procedures to avoid or limit the artifacts would go beyond the scope of this paper but technical ways to reduce them can be found in the cited literature. PMID- 25745525 TI - Pre-Practicum Training in Professional Psychology to Close the Research-Practice Gap: Changing Attitudes Towards Evidence-Based Practice. AB - Despite the rapid proliferation of mental health interventions with proven benefit for youth, empirically supported interventions (ESIs) are underutilized in most service settings. Treatment outcome studies in these community-based settings suggest that the majority of youth do not show improvement, underscoring the importance of addressing the gap between research and practice. Clinician attitudes toward evidence-based practice (EBP) may limit the use of ESIs, and efforts to address these attitudes with post-graduate training pose significant challenges. Pre-practicum training in EBP may address these challenges by familiarizing students with the framework of EBP as well as with the current youth treatment evidence base and the theories and strategies of well-supported interventions. We describe a required EBP course within a professional psychology doctoral program. Forty-two students in two class cohorts completed a measure of attitudes toward EBP prior to the first class and after the final class lecture. Students were predominantly Caucasian women with bachelor's degrees. As expected, over the course of the class, student attitudes became significantly more favorable toward EBP. Students who had previously received a master's degree had more favorable attitudes prior to the class, and students with a prior bachelor's degree showed the greatest change in attitude. The results support the use of pre practicum training in EBP to improve attitudes toward EBP, which may lead to use of effective practices with clients following training. PMID- 25745526 TI - Association of tuberculous thyroiditis and papillary carcinoma of the thyroid: a rare coincidence. AB - We report the case of a 25 year-old patient with no medical history, admitted to our unit for nodular goiter of the right lobe without clinical or laboratory signs of hyperthyroidism. We carried out a right lobo-isthmectomy revealing the association of tuberculosis and thyroid papillary carcinoma. A left lobectomy has, therefore, been performed in a second stage. The patient underwent a six month antituberculosis treatment with a good clinical outcome. We discuss this rare association and its best diagnostic and therapeutic support, with a review of the literature. PMID- 25745527 TI - Risks, precipitants and clinical presentation of gastro-oesophageal reflux disease at the Kilimanjaro Christian medical centre in Tanzania [corrected]. AB - INTRODUCTION: Risk factors and precipitants of gastro-oesophageal disease (GERD) differ widely in communities. We conducted an observational study to describe these risks, precipitants and clinical presentation of GERD patients at Kilimanjaro Christian Medical Centre (KCMC) in Tanzania. METHODS: We consecutively recruited 92 GERD patients who were referred for endoscopy at KCMC from March to November 2008. Using structured questionnaire risk factors, precipitants and symptoms of GERD were enquired. Their upper gastrointestinal endoscopic findings were as well documented. RESULTS: The mean (+/-SD) age of the study population was 47.32 (+/-17) years. Reported symptoms included water brash (37%), dyspepsia (6%), chronic cough (11%) and hemoptysis (5%). More than half (56%) of the patients surveyed identified food precipitants for their GERD symptoms. Triggers of GERD symptoms were boiled beans 19%, spicy food 11%, sour/fermented meals 10%, roasted tomato 9%, silver cyprinid fish (dagaa)5%,beans with cooked green banana (matoke) 2% and fermented milk 1%. Most of the studied patients had normal body mass index (52%), and 25% admitted to be consuming alcohol though they didn't associate it with their GERD symptoms. The most common endoscopy finding was 'loose lower oesophageal sphincter (85%). CONCLUSION: Most GERD patients referred for endoscopy at KCMC were found to have water brash and 'loose lower oesophageal sphincters' as described by endoscopists to denote mechanical abnormality of the lower oesophageal sphincter. GERD symptoms were precipitated by common locally available food and spices [corrected]. PMID- 25745528 TI - [Unilateral neuroretinitis: a rare manifestation of post streptococcal syndrome]. PMID- 25745529 TI - A review of the surveillance systems of influenza in selected countries in the tropical region. AB - Influenza viruses cause annual epidemics of respiratory tract disease that affect all age groups. Many developing countries do not have an influenza surveillance system or adequate laboratory capacity for virus detection. The objective of this study was to describe the influenza surveillance systems in the different countries in the tropics and to identify outstanding research needs. A questionnaire was designed and sent to 52 NICs and MoHs in the different countries in tropical Asia and Africa to gather information on the surveillance systems, sentinel sites, specimen and data collection, and laboratory testing. Replies were received from 32 NICs and MoHs (61.5% response)--17 were located in tropical Asia and 15 in Africa. There are 20 WHO recognized NICs in tropical Asia and 14 in tropical Africa, all with virus isolation and polymerase chain reaction (PCR) testing capacity. Of the Asian countries, only Hong Kong and Singapore reported that the patient population from the sites represents the broader community. In tropical Africa, only Senegal has sentinel sites distributed all over the country contributing to the geographic representativeness of the surveillance system. The rest of the countries in Africa have just established their influenza surveillance system in the past decade and are working toward geographic expansion of the ILI and SARI sites. Limited laboratory capacity or infrastructure to perform influenza surveillance makes difficult to justify the importance of influenza vaccine or other influenza control measures as a strategy for improving population health in the tropical region. PMID- 25745530 TI - [Pneumonia tuberculosis: a new series of 27 cases]. PMID- 25745531 TI - Monostotic fibrous dysplasia involving occipital bone: a case report and review of literature. AB - Fibrous dysplasia (FD) is a progressive systemic bone tumour of young and it can be seen on cranial bones. FD is divided into three types according to radiological features. The second most common subtype is polyostotic subtype. With this article, we aimed to review and present clinical features, radiological examination, differential diagnosis and treatment management of a case of solitary monostotic fibrous dysplasia of occipital bone. 15 years old female patient admitted to our hospital for a bump and in the back of his head that she noticed 1 month ago. Her physical and neurological examination was normal. On cranial CT examination we detected a bony defect. Her gadolinium enhanced cranial MRI revealed bony defect along with massive gadolinium enhancement in adjacent tissue. On histopathologic examination; PANCK, CD68, CD1a were found negative and CD45, S-100, Vimentine were found positive. Ki-67 was 4,8%. In conclusion, fibrous dysplasia is a progressive bone disease of the young patients. Despite its resemblance to a benign lesion by not being symptomatic it can progress and cause severe bony defects and skin lesions. Total surgical resection is necessary and sufficient for total treatment. PMID- 25745532 TI - Retropharyngeal abscess revealing a migrant foreign body complicated by mediastinitis: a case report. AB - Pharyngeal foreign bodies are quite common. Their diagnosis is usually easy. The risk of complications including retropharyngeal abscess and mediastinitis is rare and it depends mainly on the nature of the foreign body and the period of the therapeutic management. The occurrence of these complications darkens the prognosis of this affection usually benign. We report a 21 years old patient, without any significant history, admitted to the emergency for a high painful dysphagia and impaired general condition with fever 20 days after trauma in the posterior pharyngeal wall following a meal. The radiological assessment including cervico-thoracic CT scan had objectified the presence of a metallic foreign body in the retropharyngeal space associated with a retropharyngeal abscess and aggravated by a mediastinitis following the migration of the foreign body to the chest. Biological markers of infection were very increased. The therapeutic management consisted of a surgical drainage of the collections by a cervicotomy with removal of the foreign body. The outcome was favorable clinically and biologically. Pharyngeal foreign bodies are common and favorable when the diagnosis and extraction are made on time. The occurrence of complications, especially retropharyngeal abscess and mediastinitis is rare and burdened with a high morbidity and mortality. PMID- 25745533 TI - [Acute coronary syndromes in Dakar: therapeutic, clinical and evolutionary aspects]. PMID- 25745534 TI - [Do smokers know the harmful effects of tobacco?]. PMID- 25745535 TI - Respiratory syncytial virus genotypes circulating in urban Ghana: February to November 2006. AB - INTRODUCTION: Respiratory syncytial virus (RSV) is the major cause of acute lower respiratory tract infection (ALRI) in young children. RSV strains have been divided into 2 major antigenic groups (A and B), which are further divided into several genotypes, but very little is known about its circulating genotypes in Ghana. This study characterized RSV genotypes detected in children with ALRI in Accra between February and November 2006. METHODS: Nasopharyngeal aspirates (NPA) were obtained from children diagnosed with ALRI between February and November 2006. The NPA were screened for RSV using a nested multiplex reverse transcriptase polymerase chain reaction (RT-PCR) method for genotyping RSV. Viral RNA was extracted from the NPA using guanidinium isothiocyanate method and purified with an RNAID commercial kit. Care-givers gave their consent prior to specimen collection. Administered questionnaires captured information on patient demographic and clinical history. RESULTS: A total of 53 children were enrolled in the study with a male to female ratio of 3:1. Of the 53 NPA analyzed, 60.4% (32/53) were positive for RSV. Subsequent genotypic analysis showed that 72% (23/32) of the 60.4% RSV infections were RSV B only and 28% (9/32) were co infections of both RSV A and B. Children between the ages of 2 - 12 months were the most affected age group per an RSV infection rate of 37.5% (12/32). No significant difference was detected in the recovery rate of ALRI (98.1%) and RSV (96.9%) positive patients from the infection. One patient died resulting in a mortality rate of 3.1%. Bronchopneumonia (20 out of 32 cases) was the major diagnosis on admission. RSV infection was seasonal dependent, described by 2 peaks in October and April-May. CONCLUSION: Both RSV A and RSV B genotypes co circulated during the study period with RSV B predominating. RSV may possibly be the main pathogen of lower respiratory tract illness during epidemics in the wet seasons. Genotyping by the multiplex RT-PCR is one of the first attempts at molecular diagnosis of RSV infection in Ghana. PMID- 25745536 TI - [Contact dermatitis from ultrasound gel: about a case]. PMID- 25745538 TI - Multiple systems for motor skill learning. AB - Motor learning is a ubiquitous feature of human competence. This review focuses on two particular classes of model tasks for studying skill acquisition. The serial reaction time (SRT) task is used to probe how people learn sequences of actions, while adaptation in the context of visuomotor or force field perturbations serves to illustrate how preexisting movements are recalibrated in novel environments. These tasks highlight important issues regarding the representational changes that occur during the course of motor learning. One important theme is that distinct mechanisms vary in their information processing costs during learning and performance. Fast learning processes may require few trials to produce large changes in performance but impose demands on cognitive resources. Slower processes are limited in their ability to integrate complex information but minimally demanding in terms of attention or processing resources. The representations derived from fast systems may be accessible to conscious processing and provide a relatively greater measure of flexibility, while the representations derived from slower systems are more inflexible and automatic in their behavior. In exploring these issues, we focus on how multiple neural systems may interact and compete during the acquisition and consolidation of new behaviors. Copyright (c) 2010 John Wiley & Sons, Ltd. This article is categorized under: Psychology > Motor Skill and Performance. PMID- 25745539 TI - An Integrated X-Ray/Optical Tomography System for Pre-clinical Radiation Research. AB - The current Small Animal Radiation Research Platform (SARRP) is poor for localizing small soft tissue targets for irradiation or tumor models growing in a soft tissue environment. Therefore, an imaging method complementary to x-ray CT is required to localize the soft tissue target's Center of Mass (CoM) to within 1 mm. In this paper, we report the development of an integrated x ray/bioluminescence imaging/tomography (BLI/BLT) system to provide a pre clinical, high resolution irradiation system. This system can be used to study radiation effects in small animals under the conebeam computed tomography (CBCT) imaging guidance by adding the bioluminescence imaging (BLI) system as a standalone system which can also be docked onto the SARRP. The proposed system integrates two robotic rotating stages and an x-ray source rated at maximum 130 kVp and having a small variable focal spot. A high performance and low noise CCD camera mounted in a light-tight housing along with an optical filter assembly is used for multi-wavelength BL tomography. A three-mirror arrangement is implemented to eliminate the need of rotating the CCD camera for acquiring multiple views. The mirror system is attached to a motorized stage to capture images in angles between 0-90 degrees (for the standalone system). Camera and CBCT calibration are accomplished. PMID- 25745537 TI - Melanoma: Molecular Pathogenesis and Therapeutic Management. AB - Malignant melanoma remains one of the fastest growing cancers worldwide. Although the primary cutaneous melanoma can be managed by surgery, the advanced metastatic melanoma cannot be managed by surgery alone and thus, requires better therapeutic approaches. In view of high mortality rates due to metastatic melanoma, better understanding of the molecular pathogenesis of malignant melanoma is urgently needed. Such information is expected to prove very valuable in early detection of potential metastatic lesions and developing newer therapeutic approaches in order to better manage this malignancy. This article reviews the available information on the molecular changes associated with malignant melanoma and discusses the potential of such information in facilitating the development of newer anti melanoma therapeutics. Current state of knowledge and the future of traditional and newly approved anti-melanoma therapeutics are also discussed. PMID- 25745540 TI - Factors influencing adherence to imatinib in Indian chronic myeloid leukemia patients: a cross-sectional study. AB - Adherence to imatinib(IM) is of utmost importance in patients with chronic myeloid leukemia (CML) to maximise treatment effectiveness. The main objective is to measure adherence to IM by evaluating individual patient characteristics, personal behaviour and, treatment related psychological factors influencing adherence behaviour. Hundred patients receiving IM were analysed for adherence behaviour using 9 item Morisky Medication Adherence Scale (9-MMAS). Various factors were assessed for their impact on adherence behaviour. These factors were age, gender, duration of treatment, frequency and dosing of treatment, use of tobacco and alcohol, educational qualification, employment status, monthly income, side effects, financial assistance in treatment, social support, knowledge about medicine and disease, concomitant drug burden, polypharmacy, physician patient interaction, patient educational sessions and prevalence of depression. Seventy five percent of patients were found to be adherent. On univariate analysis, prevalence of depression (p<0.000001), moderate severe depression (p<0.000001), concomitant drug burden (p=0.036) and monthly income (p=0.015) were found to be significantly influencing adherence. The final multivariate model retained prevalence of depression with OR= 10.367 (95% CI, 3.112-34.538) as independent predictor of adherence to therapy. This study suggests that identification and treatment of depression among CML patients may further enhance adherence to IM therapy. PMID- 25745541 TI - Drug Therapy in the Progressed CML Patient with multi-TKI Failure. AB - The aim of this paper is to outline pharmacotherapy of the 'third-line management of CML' (progressive disease course after sequential TKI drugs). Current management of CML with multi-TKI failure is reviewed. TKI (bosutinib, ponatinib, dasatinib, nilotinib) and non-TKI (omacetaxine mepussecinate, IFN or PEG-IFN) drugs are available. The literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions, as well as international recommendations. Progressing CML disease with multi-TKI failure should be treated with alloSCT based on the availability of the donor and EBMT transplant risk scores. The TKI and non-TKI drugs shall be used to get best promising (hematological, cytogenetic, molecular) response. During the CP-CML phase of multi-TKI failure, 2nd generation TKIs (nilotinib or dasatinib) should be tried if not previously utilized. Bosutinib and ponatinib (3rd-generation TKIs) should be administered in double- or triple-TKI (imatinib and nilotinib and dasatinib) resistant patients. The presence of T315I mutation at any phase requires ponatinib or omacetaxine mepussecinate therapy before allografting. During the AP/BC-CML phase of multi-TKI failure, the most powerful TKI available (ponatinib or dasatinib if not previously used) together with chemotherapy should be given before alloSCT. Monitoring of CML disease and drug off-target risks (particularly vascular thrombotic events) are vital. PMID- 25745543 TI - Liver Iron Concentration and Liver Impairment in Relation to Serum IGF-1 Levels in Thalassaemia Major Patients: A Retrospective Study. PMID- 25745542 TI - Current role of autologous and allogeneic stem cell transplantation for relapsed and refractory hodgkin lymphoma. AB - Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States. First-line chemo-radiotherapy leads to cure rates approaching 80% in patients with advanced-stage disease. However, 25 to 30% of these patients are not cured with chemotherapy alone (i.e., the ABVD regimen) and show either primary refractoriness to chemotherapy, early disease relapse or late disease relapse. Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) have an established role in the management of refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients. However, due to the poor responses to second-line salvage chemotherapy and dismal long-term disease control of primary refractory and early relapsed patients, their treatment represents an unmet medical need. Allogeneic SCT represents, by far, the only strategy with a curative potential for these patients; however, as discussed in this review, it's role in cHL remains controversial. Despite a general consensus that early relapsed and primary refractory patients represent a clinical challenge requiring effective treatments to achieve long-term disease control, there has been no consensus on the optimal therapy that should be offered to these patients. This review will briefly discuss the clinical results and the main issues regarding autologous SCT as well as the current role of allogeneic SCT. PMID- 25745544 TI - Osteolytic Bone Lesions - A Rare Presentation of AML M6. AB - Acute myeloid leukemia (AML) M6 is a rare form of AML accounting for < 5 % of all AML. Extramedullary involvement is very rarely seen in this entity. Skeletal lesion has not been described in AML M6 before. We discuss the case of a 17 year old boy with AML M6, who presented with osteolytic lesion of right humerus. He was treated with induction and consolidation chemotherapy. The present case is the first report in literature of AML M6 presenting with skeletal lesions. PMID- 25745545 TI - Refractory thrombocytopenia and neutropenia: a diagnostic challenge. AB - The 2008 WHO classification identified refractory cytopenia with unilineage dysplasia (RCUD) as a composite entity encompassing refractory anemia, refractory thrombocytopenia (RT), and refractory neutropenia (RN), characterized by 10% or more dysplastic cells in the bone marrow respective lineage. The diagnosis of RT and RN is complicated by several factors. Diagnosing RT first requires exclusion of familial thrombocytopenia, chronic auto-immune thrombocytopenia, concomitant medications, viral infections, or hypersplenism. Diagnosis of RN should also be made after ruling out differential diagnoses such as ethnic or familial neutropenia, as well as acquired, drug-induced, infection-related or malignancy related neutropenia. An accurate quantification of dysplasia should be performed in order to distinguish RT or RN from the provisional entity named idiopathic cytopenia of unknown significance (ICUS). Cytogenetic analysis, and possibly in the future somatic mutation analysis (of genes most frequently mutated in MDS), and flow cytometry analysis aberrant antigen expression on myeloid cells may help in this differential diagnosis. Importantly, we and others found that, while isolated neutropenia and thrombocytopenia are not rare in MDS, those patients can generally be classified (according to WHO 2008 classification) as refractory cytopenia with multilineage dysplasia or refractory anemia with excess blasts, while RT and RN (according to WHO 2008) are quite rare. These results suggest in particular that identification of RT and RN as distinct entities could be reconsidered in future WHO classification updates. PMID- 25745546 TI - Study of serum haptoglobin level and its relation to erythropoietic activity in Beta thalassemia children. AB - BACKGROUND: Serum haptoglobin (Hp) is a reliable marker for hemolysis regardless the inflammatory state. OBJECTIVE: We investigated the possible relation between Hp depletion and hemolysis severity, hepatitis C virus (HCV) infection and iron load in beta-thalassemia children. METHODS: Twenty two beta-thalassemia major (TM),20 beta-thalassemia intermedia (TI) children with 20 age and sex matched healthy controls were involved. Pre-transfusion hemoglobin level was considered. Serum ferritin, Hp and transferrin receptor levels (sTfR) (by ELISA ), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (by colorimetric method) were assayed. Markers of hepatitis C virus (HCV) were done by PCR. RESULTS: The mean Hp levels among the studied groups were as follows; 8.02 +/- 0.93 (mg/dl), 8.6 +/-0.72 (mg/dl) and 122 +/- 18.5(mg/dl) for TM, TI and the controls respectively. Both patient groups had significantly lower Hp level compared to the controls (P<0.0001) with significant lower level in TM compared to TI children ( P= 0.034). Significant inverse correlations were found between serum Hp and sTfR levels ( reflecting the erythropoietic activity) in thalassemia children combined and in each group (TM and TI) as well as among HCV infected children. STfR was the only significant independent predictor for serum Hp level (t= -5.585, P<0.0001). Among HCV infected patients, no significant correlation was found between serum Hp and serum transaminases. CONCLUSION: Serum Hp depletion in thalassemia had significant relation to disease severity and correlated well with their erythropoietic activity, as assessed by the measurement of sTfR without significant relation to HCV infection. Extensive multicenter studies are recommended. PMID- 25745547 TI - Successful Management of Pregnancy and Hepatic Toxicity in a CML Female Patient Treated with Nilotinib: a Case Report and a Review. AB - We report a case of a young patient with chronic viral hepatitis HBV infection, diagnosed with CML in March 2006 and treated with imatinib 400mg/die as first line therapy with concomitant Lamivudine. Patient obtained a complete hematologic response (CHR) in 2 months, complete cytogenetic response (CCyR) in six months and major molecular response (MMR) at 24 months. After three years of treatment, she became imatinib intolerant and resistant. In November 2009 patient started nilotinib 400mg/BID. Patient tolerated well the new molecule never experiencing hepatic impairment. After switching to nilotinib, she reached in 12 months transcript reduction more than 3 log (MMR). Even if patient had been informed of the need of continuous therapy and to use effective methods of contraception during tyrosine kinase inhibitor (TKI) treatment, in 2012 she decided to plan a pregnancy. In August 2012 a MR4 was documented, and treatment discontinued before starting pregnancy. She was placed on interferon and observed throughout her pregnancy. The disease remained stable achieving an undetectable transcript level; she delivered a healthy boy in September 2013. Treatment with nilotinib was re-started three months after delivery, and she is still in molecular remission (MR5). A complete discussion of the case and the available literature is presented. PMID- 25745548 TI - Clinicopathological profile of salmonella typhi and paratyphi infections presenting as Fever of unknown origin in a tropical country. AB - BACKGROUND: Enteric fever, a common infection in the tropics and endemic to India, often manifests as an acute febrile illness. However, presentation as fever of unknown origin (FUO) is not uncommon in tropical countries. METHODS: We aim to describe the clinical, laboratory and pathological features of patients hospitalized with fever of unknown origin and diagnosed as enteric fever. All culture proven cases of enteric fever were analyzed retrospectively over a period of three years from January 2011 to December 2013. RESULTS: Seven of 88 (8%) cases with enteric fever presented as FUO. Abdominal pain was the most common symptom besides fever. Relative bradycardia and splenomegaly were uncommon. Thrombocytopenia was the most common haematological abnormality while leucopenia was rare. Transaminase elevation was almost universal. S. Typhi and S. Paratyphi A were isolated from six cases and one case respectively. Yield of organisms from blood culture was superior to that of bone marrow aspirate. Multiple granulomas were identified in 4 out of 6 (67%) of the bone marrows studied, including that due to S. Paratyphi A and histiocytic hemophagocytosis was noted in two cases. CONCLUSION: FUO is a relatively common manifestation of enteric fever in the tropics. Clinical and laboratory features may be atypical in such cases, including absence of relative bradycardia, leucopenia, and presence of thrombocytopenia, bicytopenia or pancytopenia. In addition, in endemic countries, enteric fever should be considered as a differential diagnosis, next to tuberculosis, in the evaluation of bone marrow granulomas in cases with FUO and culture correlation should be mandatory. PMID- 25745549 TI - Reliability of Different RBC Indices and Formulas in Discriminating between beta Thalassemia Minor and other Microcytic Hypochromic Cases. AB - OBJECTIVE: Different indices and formulas of CBC parameters have been suggested as indicators of early stage screenings to detect couples with beta-thalassemia minor (BTMi). In this study, we evaluated the accuracy of five previous published formulas and compared them to our new formula (?80-MCV?*?27-MCH?) in screening of beta-thalassemia. METHODS: All couples in the premarital beta-thalassemia screening program of Roodbar, Iran, for whom molecular analysis had been done, were selected during two years. The red blood cell parameters were applied to each formula, and a ROC curve was plotted for each one to check its discriminative effectiveness in beta-thalassemia detection. RESULT: None of the studied indices and formulas demonstrated 100% precision. However, we found that the Shine-Lal formula and our formula had the highest sensitivity in identifying BTMi individuals. The highest specificity belonged to our formula and Sirdah formula. CONCLUSION: Previous studies reported different sensitivities and specificities for the formulas. This can be attributed to different kinds of HBB gene mutations in various populations. Undoubtedly, physicians in different areas should evaluate the accuracy of published formulas for their own populations in the discrimination of BTMi from other causes of microcytic hypochromic anemia. PMID- 25745550 TI - The Role of the Carotid Doppler Examination in the Evaluation of Atherosclerotic Changes in beta-Thalassemia Patients. AB - BACKGROUND: Iron overload in patients with beta-thalassemia major (BTM) lead to alterations in the arterial structures and the thickness of the carotid arteries. Doppler ultrasound scanning of extra-cranial internal carotid arteries is non invasive and relatively quick to perform and may identify children at increased risk of stroke that would otherwise be missed. Increased carotid artery intima media thickness (CIMT) is a structural marker for early atherosclerosis and correlates with the vascular risk factors and to the severity and extent of coronary artery disease. OBJECTIVE: To evaluate the role of carotid Doppler examination and CIMT measurement as a predictor of atherosclerotic changes in BTM children with iron overload. PATIENTS AND METHODS: Sixty two children with BTM and, thirty age and sex matched normal controls were included. Complete blood count, ferritin, serum cholesterol were done, as well as carotid Doppler ultrasonography to measure the CIMT in both patients and controls. RESULTS: CIMT of thalassemic patients was significantly increased compared to controls (p=0.001). There was a significant positive correlation between CIMT and patient's age, the duration from first blood transfusion, serum cholesterol and, iron overload parameters as serum ferritin, frequency of blood transfusion, iron chelation. The length of the transfusion period was the highest risk factor, and an inadequate iron chelation was a further risk factor. Significant negative correlation was found between CIMT and hematocrit value while no significant correlation was found between CIMT and weight, height, BMI centiles and Hb level. CONCLUSION: Carotid Doppler is very useful in measurement of CIMT that increased in thalassemic patients that shows a strong relationship with features of iron overload. Routine Doppler measurement of CIMT in these patients is recommended to predict early atherosclerotic changes as well as in follow-up. PMID- 25745551 TI - Acquired hemophilia a successfully treated with rituximab. AB - Acquired hemophilia A (AHA) is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in obtaining a long-term suppression of inhibitors of AHA, besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with a normalization of clotting parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm., but after stopping rituximab, an initial worsening of coagulation parameters induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days. This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs) remains to be established and warrants further investigation. PMID- 25745552 TI - Clinical reversible myelopathy in T-cell lymphoblastic lymphoma treated with nelarabine and radiotherapy: report of a case and review of literature of an increasing complication. AB - Eleven cases of neurological defects in T-ALL patients treated with nelarabine have been described in the last 4 years, seven of these after stem cell transplantation (SCT) for T Lymphoblastic Lymphoma (T-LBL). Most of these patients had an unfavorable outcome or irreversible neurological damage. We now report the case of a 41-year-old woman suffering from T-LBL who presented with severe, but reversible myelopathy after receiving nelarabine-based treatment and mediastinal radiotherapy, and we provide a review of the literature on the topic. PMID- 25745553 TI - Genetic variant rs17225178 in the ARNT2 gene is associated with Asperger Syndrome. AB - BACKGROUND: Autism Spectrum Conditions (ASC) are neurodevelopmental conditions characterized by difficulties in communication and social interaction, alongside unusually repetitive behaviours and narrow interests. Asperger Syndrome (AS) is one subgroup of ASC and differs from classic autism in that in AS there is no language or general cognitive delay. Genetic, epigenetic and environmental factors are implicated in ASC and genes involved in neural connectivity and neurodevelopment are good candidates for studying the susceptibility to ASC. The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) gene encodes a transcription factor involved in neurodevelopmental processes, neuronal connectivity and cellular responses to hypoxia. A mutation in this gene has been identified in individuals with ASC and single nucleotide polymorphisms (SNPs) have been nominally associated with AS and autistic traits in previous studies. METHODS: In this study, we tested 34 SNPs in ARNT2 for association with AS in 118 cases and 412 controls of Caucasian origin. P values were adjusted for multiple comparisons, and linkage disequilibrium (LD) among the SNPs analysed was calculated in our sample. Finally, SNP annotation allowed functional and structural analyses of the genetic variants in ARNT2. We tested the replicability of our result using the genome-wide association studies (GWAS) database of the Psychiatric Genomics Consortium (PGC). RESULTS: We report statistically significant association of rs17225178 with AS. This SNP modifies transcription factor binding sites and regions that regulate the chromatin state in neural cell lines. It is also included in a LD block in our sample, alongside other genetic variants that alter chromatin regulatory regions in neural cells. CONCLUSIONS: These findings demonstrate that rs17225178 in the ARNT2 gene is associated with AS and support previous studies that pointed out an involvement of this gene in the predisposition to ASC. PMID- 25745554 TI - Early androgen exposure and human gender development. AB - During early development, testosterone plays an important role in sexual differentiation of the mammalian brain and has enduring influences on behavior. Testosterone exerts these influences at times when the testes are active, as evidenced by higher concentrations of testosterone in developing male than in developing female animals. This article critically reviews the available evidence regarding influences of testosterone on human gender-related development. In humans, testosterone is elevated in males from about weeks 8 to 24 of gestation and then again during early postnatal development. Individuals exposed to atypical concentrations of testosterone or other androgenic hormones prenatally, for example, because of genetic conditions or because their mothers were prescribed hormones during pregnancy, have been consistently found to show increased male-typical juvenile play behavior, alterations in sexual orientation and gender identity (the sense of self as male or female), and increased tendencies to engage in physically aggressive behavior. Studies of other behavioral outcomes following dramatic androgen abnormality prenatally are either too small in their numbers or too inconsistent in their results, to provide similarly conclusive evidence. Studies relating normal variability in testosterone prenatally to subsequent gender-related behavior have produced largely inconsistent results or have yet to be independently replicated. For studies of prenatal exposures in typically developing individuals, testosterone has been measured in single samples of maternal blood or amniotic fluid. These techniques may not be sufficiently powerful to consistently detect influences of testosterone on behavior, particularly in the relatively small samples that have generally been studied. The postnatal surge in testosterone in male infants, sometimes called mini-puberty, may provide a more accessible opportunity for measuring early androgen exposure during typical development. This approach has recently begun to be used, with some promising results relating testosterone during the first few months of postnatal life to later gender-typical play behavior. In replicating and extending these findings, it may be important to assess testosterone when it is maximal (months 1 to 2 postnatal) and to take advantage of the increased reliability afforded by repeated sampling. PMID- 25745555 TI - Variations in genome-wide RNAi screens: lessons from influenza research. AB - Genome-wide RNA interference (RNAi) screening is an emerging and powerful technique for genetic screens, which can be divided into arrayed RNAi screen and pooled RNAi screen/selection based on different screening strategies. To date, several genome-wide RNAi screens have been successfully performed to identify host factors essential for influenza virus replication. However, the host factors identified by different research groups are not always consistent. Taking influenza virus screens as an example, we found that a number of screening parameters may directly or indirectly influence the primary hits identified by the screens. This review highlights the differences among the published genome wide screening approaches and offers recommendations for performing a good pooled shRNA screen/selection. PMID- 25745557 TI - Bacterial species isolated from cats with lower urinary tract infection and their susceptibilities to cefovecin. AB - BACKGROUND: The aim of this study was to determine the bacterial species recovered from 61 cats with lower urinary tract infection (LUTI), and their susceptibility to cefovecin in vitro. RESULTS: The clinical signs and final clinical diagnosis for cats with confirmed LUTI were also reported. After physical examination of the cats, urine samples including >=5-6 leucocytes in microscopic evaluation were cultured using bacteriological techniques. The isolates were identified by conventional microbiological methods and tested for in vitro susceptibility using the Kirby-Bauer disc diffusion method recommended by the Clinical Laboratory Standards Institute. Bacterial growth was observed in 16 of 61 urine samples. Antimicrobial susceptibility tests showed that 13 of 16 (81%) isolates were susceptible to cefovecin. The most frequently isolated bacterium from cats with signs of lower urinary tract infection, was Escherichia coli. CONCLUSION: Cefovecin was found to be effective in cats with LUTI. Because cefovecin is a new antimicrobial agent in veterinary medicine, there are only few studies about urine culture of cats with LUTI. It is the first study on in vitro activity of cefovecin against bacterial isolates from cats with lower urinary infections in Istanbul, Turkey. PMID- 25745556 TI - The quest for a better insight into physiology of fluids and barriers of the brain: the exemplary career of Joseph D. Fenstermacher. AB - In June 2014 Dr. Joseph D. Fenstermacher celebrated his 80th birthday, which was honored by the symposium held in New London, NH, USA. This review discusses Fenstermacher's contribution to the field of fluids and barriers of the CNS. Specifically, his fundamental work on diffusion of molecules within the brain extracellular space and the research on properties of the blood-brain barrier in health and disease are described. Fenstermacher's early research on cerebrospinal fluid dynamics and the regulation of cerebral blood flow is also reviewed, followed by the discussion of his more recent work involving the use of magnetic resonance imaging. PMID- 25745559 TI - Change in prevalence of restrictive lung impairment in the U.S. population and associated risk factors: the National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 2007-2010. AB - BACKGROUND: Data for the U.S adult population from the National Health and Nutrition Examination Survey (NHANES) were used to evaluate risk factors for a restrictive pattern on spirometry and estimate the change in its prevalence from the 1988-1994 to 2007-2010 sampling periods. Several previous epidemiologic studies used the Global Initiative for Chronic Obstructive Lung Disease fixed forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) > 0.70 criteria for classifying restrictive pattern rather than the age-defined American Thoracic Society (ATS)/European Respiratory Society (ERS) lower limit of normal (LLN) criteria, which may lead to misclassification. METHODS: Spirometry measurements from NHANES data for the 1988-1994 and 2007-2010 periods were analyzed to estimate the age-standardized prevalence of a restrictive pattern on spirometry and the change in prevalence over time for adults aged 20-79. A restrictive pattern was defined based on ATS/ERS LLN criteria as FEV1/FVC > LLN and FVC < LLN, and a moderate to more severe restrictive pattern was further evaluated using FEV1 < 70% predicted. The associations between demographic and other individual risk factors for restrictive lung impairment were examined using multivariable logistic regression models for the two consecutive time periods. RESULTS: The overall age-standardized prevalence of restrictive pattern decreased significantly from 7.2% (1988-1994) to 5.4% (2007-2010) (p = 0.0013). The prevalence of moderate to more severe restrictive pattern also decreased significantly from 2.0% to 1.4% (p = 0.023). Factors positively associated with restrictive pattern on spirometry included age, female sex, white race, lower education, former and current smoking, and comorbidities including doctor diagnosed cardiovascular disease, doctor-diagnosed diabetes, and abdominal obesity. CONCLUSIONS: The overall prevalence of restrictive pattern and moderate to more severe restrictive pattern decreased between the 1988-1994 and 2007-2010 survey periods despite a population increase in the proportion of comorbidities associated with restrictive pattern (i.e. diabetes and abdominal obesity). This suggests a decline in individual risk factors for restrictive pattern and a need for future research. PMID- 25745558 TI - Epitope topography controls bioactivity in supramolecular nanofibers. AB - Incorporating bioactivity into artificial scaffolds using peptide epitopes present in the extracellular matrix (ECM) is a well-known approach. A common strategy has involved epitopes that provide cells with attachment points and external cues through interaction with integrin receptors. Although a variety of bioactive sequences have been identified so far, less is known about their optimal display in a scaffold. We report here on the use of self-assembled peptide amphiphile (PA) nanofiber matrices to investigate the impact of spatial presentation of the fibronectin derived epitope RGDS on cell response. Using one, three, or five glycine residues, RGDS epitopes were systematically spaced out from the surface of the rigid nanofibers. We found that cell morphology was strongly affected by the separation of the epitope from the nanofiber surface, with the longest distance yielding the most cell-spreading, bundling of actin filaments, and a round-to-polygonal transformation of cell shape. Cell response to this type of epitope display was also accompanied with activated integrin mediated signaling and formation of stronger adhesions between cells and substrate. Interestingly, unlike length, changing the molecular flexibility of the linker had minimal influence on cell behavior on the substrate for reasons that remain poorly understood. The use in this study of high persistence length nanofibers rather than common flexible polymers allows us to conclude that epitope topography at the nanoscale structure of a scaffold influences its bioactive properties independent of epitope density and mechanical properties. PMID- 25745561 TI - Urogenital tuberculosis: definition and classification. AB - OBJECTIVES: To improve the approach to the diagnosis and management of urogenital tuberculosis (UGTB), we need clear and unique classification. UGTB remains an important problem, especially in developing countries, but it is often an overlooked disease. As with any other infection, UGTB should be cured by antibacterial therapy, but because of late diagnosis it may often require surgery. METHODS: Scientific literature dedicated to this problem was critically analyzed and juxtaposed with the author's own more than 30 years' experience in tuberculosis urology. RESULTS: The conception, terms and definition were consolidated into one system; classification stage by stage as well as complications are presented. Classification of any disease includes dispersion on forms and stages and exact definitions for each stage. Clinical features and symptoms significantly vary between different forms and stages of UGTB. A simple diagnostic algorithm was constructed. CONCLUSIONS: UGTB is multivariant disease and a standard unified approach to it is impossible. Clear definition as well as unique classification are necessary for real estimation of epidemiology and the optimization of therapy. The term 'UGTB' has insufficient information in order to estimate therapy, surgery and prognosis, or to evaluate the epidemiology. PMID- 25745560 TI - Management of invasive candidiasis in nonneutropenic ICU patients. AB - Invasive candidiasis (IC) is a leading cause of morbidity and mortality among nonneutropenic ICU patients and these life-threatening nosocomial infections require early diagnosis and prompt treatment. However, none of the predictive tools are sufficiently accurate to identify high-risk patients and the potential interest of IC prophylactic, empirical and preemptive treatment in the nonneutropenic ICU population has not yet been demonstrated. In the case of nosocomial severe sepsis after necrotizing pancreatitis or upper digestive anastomotic leakage, early probabilistic antifungals are probably indicated. In the remaining ICU surgical and medical patients, prophylactic and empirical strategies are highly debated because they may promote antifungal selective pressure through an overuse of these molecules. In this context, non-culture based methods such as mannan or beta-D glucan or polymerase chain reaction tests are promising. However, none of these tests used alone in ICU patients is sufficiently accurate to avoid overuse of empirical/preemptive treatment. The interest of strategies associating predictive clinical scores and non-culture based methods still needs to be demonstrated by well-conducted randomized, controlled trials. While awaiting these studies, we consider that probabilist treatment should be stopped earlier if IC is not proven. PMID- 25745562 TI - The status of citrate in the hydroxyapatite/collagen complex of bone; and Its role in bone formation. AB - BACKGROUND: It has been known for more than 70 years that citrate is a major component of bone; comprising 1-2% weight of bone, and a concentration that is ~5 25-fold greater than the citrate concentration of most other tissues. This relationship exists in humans and in all vertebrates; which reveals that it is an indispensible and essential structural/functional component of bone. However, its implications relating to the structure and properties of bone, to the process of bone formation and regeneration, to bone disorders, and other issues have remained largely unknown and unaddressed. Recent studies have identified citrate as a structural component of the apatite nanocrystal/collagen complex, which is essential for imparting the bone properties of stability, strength, and resistance to fracture. This raises the issues of the status of citrate, and its source in normal bone formation. METHODS: The present report investigated the association of citrate with the hydroxyapatite (mineral) component and with the collagen component of human cortical bone preparations. The bone preparations were subjected to demineralization procedures to extract the mineral component; followed by extraction of the collagen component in the residual demineralized bone. The extracts were assayed for citrate, calcium, and collagen. RESULTS: The results reveal, for the first time, the existence of two major pools of citrate in bone. One pool comprising ~65-80% of the total citrate is associated with the hydroxyapatite component; and another pool comprising ~20-35% of the total citrate is tightly bound to the collagen component of the apatite nanocrystal/collagen complex. CONCLUSIONS: Citrate is an indispensible chemical and structural component of the apatite nanocrystal/collagen complex; and is required for manifestation of the biomechanical properties of bone. These results lead to a new concept of bone formation in which citrate incorporation ("citration") in concert with mineralization must be included in the process of bone formation. Along with this relationship, osteoblast citrate production has recently been identified as the likely source of citrate. It is now evident that the role of citrate in normal bone formation and its implications in bone disorders and defects, and in bone repair and regeneration, now requires renewed attention and support for much needed research. PMID- 25745563 TI - Pretreatment of garden biomass using Fenton's reagent: influence of Fe(2+) and H2O2 concentrations on lignocellulose degradation. AB - Garden biomass (GB) is defined as low density and heterogeneous waste fraction of garden rubbish like grass clippings, pruning, flowers, branches, weeds; roots. GB is generally different from other types of biomass. GB is mostly generated through maintenance of green areas. GB can be processed for bio energy production as it contains considerably good amount of cellulose and hemicellulose. However, pretreatment is necessary to delignify and facilitate disruption of cellulosic moiety. The aim of the present investigation was to pretreat GB using Fenton's reagent and to study the influence of Fe(2+) and H2O2 concentrations on degradation of lignin and cellulose. The data were statistically analyzed using ANOVA and numerical point prediction tool of MINITAB RELEASE 14 to optimize different process variables such as temperature, concentration of Fe(2+) and H2O2. The results of the present investigation showed that Fenton's reagent was effective on GB, however, concentration of Fe(2+) and H2O2 play crucial role in determining the efficiency of pretreatment. An increase in H2O2 concentration in Fenton's reagent significantly increased the rate of cellulose and lignin degradation in contrast to increasing concentration of Fe(2+) ion which led to a decrease in lignocellulosic degradation. PMID- 25745564 TI - Probability of Regenerating a Normal Limb After Bite Injury in the Mexican Axolotl (Ambystoma mexicanum). AB - Multiple factors are thought to cause limb abnormalities in amphibian populations by altering processes of limb development and regeneration. We examined adult and juvenile axolotls (Ambystoma mexicanum) in the Ambystoma Genetic Stock Center (AGSC) for limb and digit abnormalities to investigate the probability of normal regeneration after bite injury. We observed that 80% of larval salamanders show evidence of bite injury at the time of transition from group housing to solitary housing. Among 717 adult axolotls that were surveyed, which included solitary housed males and group-housed females, approximately half presented abnormalities, including examples of extra or missing digits and limbs, fused digits, and digits growing from atypical anatomical positions. Bite injury likely explains these limb defects, and not abnormal development, because limbs with normal anatomy regenerated after performing rostral amputations. We infer that only 43% of AGSC larvae will present four anatomically normal looking adult limbs after incurring a bite injury. Our results show regeneration of normal limb anatomy to be less than perfect after bite injury. PMID- 25745565 TI - Validity of a PCI Bleeding Risk Score in patient subsets stratified for body mass index. AB - OBJECTIVE: An accurate tool with good discriminative for bleeding would be useful to clinicians for improved management of all their patients. Bleeding risk models have been published but not externally validated in independent clinical data set. We chose the National Cardiovascular Data Registry (NCDR) percutaneous coronary intervention (PCI) score to validate within a large, multisite community data set. The aim of the study was validation of this Bleeding Risk Score (BRS) tool among a subgroup of patients based on body mass index. METHODS: This is a large-scale retrospective analysis of a current registry utilising data from a 37 hospital health system. The central repository of patients with coronary heart disease undergoing PCI between 1 June 2009 and 30 June 2012 was utilised to validate the NCDR PCI BRS among 4693 patients. The primary end point was major bleeding. Validation analysis calculating the receiver operating characteristic curve was performed. RESULTS: There were 143 (3%) major bleeds. Mean BRS was 14.7 (range 3-42). Incidence of bleeding by risk category: low (0.5%), intermediate (1.7%) and high risk (7.6%). Tool accuracy was poor to fair (area-under-the curve (AUC) 0.78 heparin, 0.65 bivalirudin). Overall accuracy was 0.71 (CI 0.66 to 0.76). Accuracy did not improve when confined to just the intermediate risk group (AUC 0.58; CI 0.55 to 0.67). Tool accuracy was the lowest among the low BMI group (AUC 0.62) though they are at increased risk of bleeding following PCI. CONCLUSIONS: Bleeding risk tools have low predictive value even among subgroups of patients at higher risk. Adjustment for anticoagulation use resulted in poor discrimination because bivalirudin differentially biases outcomes toward no bleeding. The current state of bleeding risk tools provide little support for diagnostic utility in regards to major bleeding and therefore have limited clinical applicability. PMID- 25745566 TI - A systematic review of ICD complications in randomised controlled trials versus registries: is our 'real-world' data an underestimation? AB - Implantable cardioverter defibrillator (ICD) implantation carries a significant risk of complications, however published estimates appear inconsistent. We aimed to present a contemporary systematic review using meta-analysis methods of ICD complications in randomised controlled trials (RCTs) and compare it to recent data from the largest international ICD registry, the US National Cardiovascular Data Registry (NCDR). PubMed was searched for any RCTs involving ICD implantation published 1999-2013; 18 were identified for analysis including 6433 patients, mean follow-up 3 months-5.6 years. Exclusion criteria were studies of children, hypertrophic cardiomyopathy, congenital heart disease, resynchronisation therapy and generator changes. Total pooled complication rate from the RCTs (excluding inappropriate shocks) was 9.1%, including displacement 3.1%, pneumothorax 1.1% and haematoma 1.2%. Infection rate was 1.5%.There were no predictors of complications but longer follow-up showed a trend to higher complication rates (p=0.07). In contrast, data from the NCDR ICD, reporting on 356 515 implants (2006-2010) showed a statistically significant threefold lower total major complication rate of 3.08% with lead displacement 1.02%, haematoma 0.86% and pneumothorax 0.44%. The overall ICD complication rate in our meta-analysis is 9.1% over 16 months. The ICD complication reported in the NCDR ICD registry is significantly lower despite a similar population. This may reflect under reporting of complications in registries. Reporting of ICD complications in RCTs and registries is very variable and there is a need to standardise classification of complications internationally. PMID- 25745567 TI - Adherence to process of care quality indicators after percutaneous coronary intervention in Ontario, Canada: a retrospective observational cohort study. AB - BACKGROUND: Public reporting of percutaneous coronary intervention (PCI) outcomes has been established in many jurisdictions to ensure optimal delivery of care. The majority of PCI report cards examine in-hospital mortality, but relatively little is known regarding the adherence to processes of care. METHODS: A modified Delphi panel comprising cardiovascular experts was assembled to develop a set of PCI quality indicators. Indicators such as prescription of aspirin, dual antiplatelet therapy, statins and smoking cessation counselling were identified to represent high-quality PCI care. Chart abstraction was performed at 13 PCI hospitals in Ontario, Canada from 2009 to 2010 with at least 200 PCI patients randomly selected from each hospital. RESULTS: Our study sample included 3041 patients, of whom 18% had stable coronary artery disease (CAD) and 82% had an acute coronary syndrome (ACS). Their mean age was 63+/-12.4 years and 29% of patients were female. Prior to PCI, 89% were prescribed aspirin, and after PCI 98.7% were prescribed aspirin, 95.1% were prescribed dual antiplatelet therapy for 12 months after drug-eluting stents, and 94.9% were prescribed statins. The lowest performing quality indicator was smoking cessation counselling, observed in only 42% of current and past smokers (18% in patients with stable CAD and 47% in ACS). CONCLUSIONS: Our study demonstrates high levels of adherence to most quality indicators for patients undergoing PCI procedures in Ontario. In conclusion, smoking cessation counselling was not consistently performed across hospitals and represents an opportunity for future quality improvement efforts. PMID- 25745568 TI - Debating Elective Single Embryo Transfer after in vitro Fertilization: A Plea for a Context-Sensitive Approach. AB - The number of embryos transferred after in vitro fertilization (IVF) have been a topic of debate for over a decade now. Due to the risk associated with multiple pregnancy, there has been a global effort at reducing the multiple pregnancy rates to a minimum while maintaining an acceptable level of successful IVF pregnancy rate. Elective single embryo transfer (eSET) is advocated in most European countries. In Belgium and Sweden, eSET is mandatory for couples with a good prognosis. However, despite clinical recommendations and policy statements, patients in clinical practice frequently do request for the transfer of multiple embryos in order to have twins. Such requests conflict with policy guidelines and create an ethical dilemma for physicians: Should the physician do as the couple requests, and there with respect the autonomy of patients, or adhere to medical policy that takes the health of the mother and children at heart? This article provides an exploration of the arguments found in the literature that plays a role in the discussion on this topic and eventually argues that what a physician should do depends on the specificities of the context in which patients and physicians are implicated. These contextual issues can be taken into account in a shared decision-making procedure, which allows reflections and the responsibilities of both patients and physicians to be attended in decision about assisted reproduction. PMID- 25745569 TI - Evaluation of analytical errors in a clinical chemistry laboratory: a 3 year experience. AB - BACKGROUND: Proficient laboratory service is the cornerstone of modern healthcare systems and has an impact on over 70% of medical decisions on admission, discharge, and medications. In recent years, there is an increasing awareness of the importance of errors in laboratory practice and their possible negative impact on patient outcomes. AIM: We retrospectively analyzed data spanning a period of 3 years on analytical errors observed in our laboratory. The data covered errors over the whole testing cycle including pre-, intra-, and post analytical phases and discussed strategies pertinent to our settings to minimize their occurrence. MATERIALS AND METHODS: We described the occurrence of pre analytical, analytical and post-analytical errors observed at the Komfo Anokye Teaching Hospital clinical biochemistry laboratory during a 3-year period from January, 2010 to December, 2012. Data were analyzed with Graph Pad Prism 5(GraphPad Software Inc. CA USA). RESULTS: A total of 589,510 tests was performed on 188,503 outpatients and hospitalized patients. The overall error rate for the 3 years was 4.7% (27,520/58,950). Pre-analytical, analytical and post-analytical errors contributed 3.7% (2210/58,950), 0.1% (108/58,950), and 0.9% (512/58,950), respectively. The number of tests reduced significantly over the 3-year period, but this did not correspond with a reduction in the overall error rate (P = 0.90) along with the years. CONCLUSION: Analytical errors are embedded within our total process setup especially pre-analytical and post-analytical phases. Strategic measures including quality assessment programs for staff involved in pre analytical processes should be intensified. PMID- 25745570 TI - Knowledge, attitudes, and practice of medical students regarding occupational risks of hepatitis B virus in college of medicine, aljouf university. AB - BACKGROUND: Medical students represent a population that is at high-risk group for acquiring and spreading hepatitis B infection (HBV). AIM: This study was designed to evaluate the knowledge and attitudes among male student regarding occupational risks of HBV infection. SUBJECTS AND METHODS: During March 2013, a descriptive cross-sectional study was conducted on medical students of AlJouf University College of Medicine. Structured questionnaires of 16 different statements concerning knowledge base of HBV, attitudes as well as practices toward occupational risks of hepatitis B were distributed to 120 students. RESULTS: Response rate of 76.7% (92/120) yielded 92 questionnaires for analysis. Majority of the students surveyed 62.0% (57/92) perceived that they are at high risk of contracting and spreading HBV. The rate of this perception among students who had a history of training on universal precautions was more than that found among those who did not have (70.8% vs. 58.8%; P < 0.01). Most of the students surveyed 63.0% (58/92) considered vaccine is safe and more than half 52.2% (48/92) were vaccinated against HBV. There were a very strong agreement about needlestick 92.4% (85/92) and blood 87.0% (80/92) as efficient modes of HBV transmission. Seventy-two percent of the participants did not have any knowledge about post-exposure prophylaxis for hepatitis B. A significant relationship was found between students who had a history of training on universal precautions and knowledge about post needlestick injury (P < 0.01). CONCLUSION: Infectious occupational risk of hepatitis B remains a challenge for medical students and the foundations of the medical institutes. Students must complete an infection control training before they start their clinical education. PMID- 25745571 TI - Poor availability of skilled birth attendants in Nigeria: a case study of enugu state primary health care system. AB - BACKGROUND: The Government of Enugu State plans to offer free perinatal services at the primary health care (PHC) centers in order to improve perinatal outcomes in the state, but it was not clear whether there are skilled birth attendants (SBAs) at the PHC level to implement the program. AIMS: To determine whether there are sufficient numbers of SBAs in the public PHC system in Enugu State of Nigeria. SUBJECTS AND METHODS: This cross-sectional survey involved enumeration of health workers who worked at each public PHC facility in Enugu State and included verification of the qualifications and trainings of each health worker. Data analysis was performed with the help of Stata statistical package version 13 and results were presented in tables and as simple proportions. RESULTS: There were 55 nurses and no midwife or doctor in the 152 PHC clinics studied. This number represents 0.36 nurses per health facility or about 9% (i.e., 55/608) of a minimum of 608 SBAs required for 24-h perinatal services at the 152 PHC clinics. There were 1233 junior community health extension worker/community health extension workers (JCHEW/CHEWs), averaging 8.1 JCHEW/CHEWs per PHC clinic. CONCLUSIONS: Enugu State has an acute shortage of SBAs. We recommend employment of qualified SBAs and in-service training of the JCHEW/CHEW and nurses to upgrade their midwifery skills. Incorporation of competency-based midwifery training into the pre-service training curricula of nurses and JCHEW/CHEW would provide a more sustainable supply of SBAs in Enugu state. PMID- 25745572 TI - Reported Sexual Violence among Women and Children Seen at the Gynecological Emergency Unit of a Rural Tertiary Health Facility, Northwest Nigeria. AB - BACKGROUND: Various forms of sexual violence including: Coerced marriage or wife inheritance, female genital mutilation, forced exposure to pornography, rape by intimate partner or strangers, unwanted sexual advances, and sexual abuse occurs, especially in vulnerable groups. However, most of these cases are not reported. AIM: The aim was to review reported cases in the facility, determine the prevalence and pattern of presentation. SUBJECTS AND METHODS: This was a prospective longitudinal study undertaken at the Gynecological Emergency Unit of a Tertiary Health Facility in a rural setting Northwest Nigeria. A study of survivors of alleged sexual violence who presented to the hospital from the September 1, 2011 to August 31, 2013. RESULTS: During the study period, there were 24 cases of sexual violence (22 were alleged rape and 2 were others) of 973 gynecological consultations at the emergency unit, giving a prevalence of 3% (24/973) for sexual violence and 2.3% (22/973) for alleged rape. Majority 91.7% (22/24) of the cases were children < 16 years; 45.8% (11/24) had no formal education while 33.3% (8/24) hawked homemade drinks and snacks. The assailants were known in 83.3% (20/24) of the cases; of which 45.8% (11/24) were neighbors, 29.2% (7/24) were buyers of snacks and drinks while 8.3% (2/24) were family members. CONCLUSION: The prevalence of reported sexual violence in this facility was low with the majority of the survivors being children and nonstranger assailants', mostly neighbors. PMID- 25745573 TI - Use of oral mucoperiosteal and pterygo-masseteric muscle flaps as interposition material in surgery of temporomandibular joint ankylosis: a comparative study. AB - BACKGROUND: The most common complication of surgery for the release of temporomandibular joint (TMJ) ankylosis is relapse of the ankylosis. To prevent re-ankylosis, a variety of interpositional materials have been used. AIM: The aim was to compare the surgical outcome of oral mucoperiosteal flap, not hitherto used as interpositional material, with pterygo-masseteric muscles flap after surgical release of TMJ ankylosis. SUBJECTS AND METHODS: This was a prospective randomized study of all consecutive patients treated for the release of complete TMJ bony ankylosis, from January 2003 to December 2012, at the Oral and Maxillofacial unit of our institution. The patients were randomized into two groups: The pterygo-masseteric group comprises 22 patients while the oral mucoperiosteal group had 23 patients. Information on demographics, clinical characteristics, and postoperative complications over a 5 year follow-up period were obtained, and analyzed using the statistical package for social sciences (Statistical Package for the Social Sciences version 13, Chicago, IL, USA). A P < 0.05 was considered significant. RESULTS: The age of the patients ranged from 15 to 28 mean 20.3 (3.35) years while the duration of ankylosis ranged from 2 to 16 mean 5.1 (3.4) years. The baseline demographic (gender; P = 0.92; side; P = 0.58) and clinical characteristics in terms of etiology (P = 0.60) and age (P = 0.52) were comparable in both treatment groups. All the patients presented with complete bony TMJ ankylosis with a preoperative inter-incisal distance of <0.5 cm. The intraoperative mouth opening achieved ranged from 4 cm to 5 cm, mean 4.6 (0.27) cm and this was not different for either group (P = 0.51). The patients were followed up postoperatively for a period ranging from 3 to 5 years, mean 3.4 (0.62) years. The mouth opening decreased, over the period of postoperative review, from the initial range of 4-5 cm to 2.9-3.6 cm, and this was not different in both groups (P = 0.18). CONCLUSION: This study suggests that oral mucoperiosteal flap could be an option in the choice of interpositional materials in surgery of TMJ ankylosis. PMID- 25745574 TI - Hematocrit, anemia, and arm preference for blood sample collection: a cross sectional study of pregnant women in enugu, South-eastern, Nigeria. AB - BACKGROUND: Anemia in pregnancy is a common cause of maternal morbidity and mortality in developing countries. Regular review of hematocrit (HCT) and anemia patterns in pregnancy is necessary in our environment. AIM: The aim was to determine the average HCT, prevalence, and pattern of anemia, as well the arm preferences for blood sample collection among pregnant women in Enugu, South East Nigeria. SUBJECTS AND METHODS: HCT was determined using venous blood of 200 antenatal women at the University of Nigeria Teaching Hospital (UNTH) Enugu, Nigeria. Questionnaires were used to assess participants' arm preference for blood sample collection for clinical investigations. Data analysis was descriptive and inferential at 95% confidence level. RESULTS: Participants' mean HCT was 33.3 (3.7%). The average HCT in second trimester 33.3% (3.76%) was significantly lower than that of third trimester (34.6 [3.4%], P = 0.01,). Prevalence of anemia was 28.0% (56/200), and a majority (94.6%, 53/56) of anemic women belong to the mild category. Only parity groups had a significant association with anemia in pregnancy (P = 0.04). None of the participants reported being asked about her arm preference during blood collection for routine antenatal investigations. One hundred and five (52.5%) women expressed preference for either left (34.5%, 69/200) or right arm (18.0%, 36/200) for blood sample collection. CONCLUSION: The average HCT among pregnant women at the UNTH, Enugu Nigeria was within normal range and the prevalence of anemia was relatively low. The majority of women expressed a preference for either right or left arm for blood sample collection for clinical investigations and would wish their choices sought for and respected. PMID- 25745575 TI - Laser guided automated calibrating system for accurate bracket placement. AB - BACKGROUND: The basic premise of preadjusted bracket system is accurate bracket positioning. It is widely recognized that accurate bracket placement is of critical importance in the efficient application of biomechanics and in realizing the full potential of a preadjusted edgewise appliance. AIM: The purpose of this study was to design a calibrating system to accurately detect a point on a plane as well as to determine the accuracy of the Laser Guided Automated Calibrating (LGAC) System. MATERIALS AND METHODS: To the lowest order of approximation a plane having two parallel lines is used to verify the accuracy of the system. On prescribing the distance of a point from the line, images of the plane are analyzed from controlled angles, calibrated and the point is identified with a laser marker. RESULTS: The image was captured and analyzed using MATLAB ver. 7 software (The MathWorks Inc.). Each pixel in the image corresponded to a distance of 1cm/413 (10 mm/413) = 0.0242 mm (L/P). This implies any variations in distance above 0.024 mm can be measured and acted upon, and sets the highest possible accuracy for this system. CONCLUSION: A new automated system is introduced having an accuracy of 0.024 mm for accurate bracket placement. PMID- 25745576 TI - Prevalence and determinants of hypertension in an agrarian rural community in southeast Nigeria. AB - BACKGROUND: Hypertension is a cardiovascular disease of increasing global burden with prevalence in Nigeria ranging from 8% to 46.4%. AIM: To determine the prevalence and determinants of hypertension in Igbeagu, a rural community in South-Eastern Nigeria. SUBJECTS AND METHODS: Consenting residents aged 18 years and above participated in this survey. A structured questionnaire was administered on the participants in their native dialect. Blood pressure (BP) and anthropometric parameters of the participants were measured using standard techniques. Hypertension was defined as systolic BP >= 140 mmHg and diastolic BP of >= 90 mmHg. RESULTS: Two hundred and sixty-seven participants had their BP and data completed satisfactorily. Sixty-two persons were hypertensive, giving a prevalence rate of 23.2% (62/267). Age, consumption of red meat, body mass index (BMI), and the number of children in the family were associated with hypertension. Regression analysis showed that only BMI and age were independent risk factors for hypertension. CONCLUSION: Although the prevalence of hypertension in this study and their associated risk factors were in agreement with studies done previously in Nigeria, the association between number of children in the family and hypertension is yet to be understood. Efforts are needed to curb the high prevalence of hypertension in this community. PMID- 25745577 TI - Demographic analysis of benign paroxysmal positional vertigo as a common public health problem. AB - BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular problem. However, demographic analysis is few. AIM: The aim of this study was to document the demographic data of patients with BPPV regarding distribution of gender, age, associated problems, most common form, symptom duration, severity of nystagmus and cure rate. SUBJECTS AND METHODS: A total of 263 patients with video-nystagmography confirmed BPPV were enrolled in this retrospective study (2009-2013). The data were collected in Anadolu Medical Center. Distribution of gender, age and affected side were reviewed. Associated problems were noted. Patients were analyzed according to the canal involvement, age, duration of symptoms, duration of nystagmus and recurrence. Mean values and standard deviations were calculated. One-way ANOVA test was used for the analysis of the data (Statistical Package for the Social Sciences 17.0 version, IBM, Chicago, III, USA). Statistical significance was set at P < 0.05. RESULTS: Women were affected more frequently than men (1:1.5). Comparative analysis of average age between the two gender groups was not statistically significant (P = 0.84). BPPV was common at middle age group. The incidence of affected side was not significant (P = 0.74). Posterior canal-BPPV (PC-BPPV) was the most leading one (129/263; 49%) followed by lateral canal (LC)-canalolithiasis (60/263; 22.8%), LC cupulolithiasis (38/263; 14.5%) and superior canal-BPPV (9/263; 3.4%). 55.1% of patients were defined as idiopathic (145/263). Associated problems were migraine (31/263; 11.8%), trauma (19/263; 7.2%), inner ear disorders (18/263; 6.8%) and other systemic problems (50/263; 19.1%). 72.6% of patients had symptoms <2 months (191/263). 23,6% of patients had intensive nystagmus lasting more than a minute regardless of canal involvement (62/263). 33% of patients required two or more maneuvers for the relief of symptoms (87/263). CONCLUSION: Symptoms are prone to recur in those of traumatic origin, associated inner ear problems and systemic disorders. As the prognostic factors are illuminated, preventive measures will be more effective and more patients will be cured properly. PMID- 25745578 TI - An overview of the predictors of symptomatic urinary tract infection among nursing students. AB - BACKGROUND: Urinary tract infection (UTI) is the most common infection experienced by humans after respiratory and gastro-intestinal infections, and also the most common cause of nosocomial infections for patients admitted to hospitals indeed UTIs are the most frequent bacterial infection in women. AIM: The aim was to determine the prevalence of UTI and to identify factors associated with an increased risk of UTI among nursing students. SUBJECTS AND METHODS: The cross-sectional study involved 177 unmarried nursing students aged 18-30 years studying in the SRMSIMS, Nursing College Bareilly. A structured questionnaire was used, and study subjects were asked regarding the symptoms of UTI in the previous 3 months. Chi-square test and Univariate Logistic Regression was used to analyze the data. RESULTS: The overall prevalence of UTI was found to be 19.8% (35/177). Rural background, inadequate water intake, and unsatisfactory toilet habits were found to be strong predictors of UTI. CONCLUSIONS: There is an urgent need to sensitize the nursing students regarding the growing need of the issue so that they themselves become aware in addition to raising the awareness of other high risk groups. PMID- 25745579 TI - Self-care activities among patients with diabetes attending a tertiary care hospital in mangalore karnataka, India. AB - BACKGROUND: Increasing prevalence of diabetes in India is resulting in an epidemiological transition. The care of the people with diabetes is traditionally seen as doctor centered, but the concept of self-care of people with diabetes is a new domain and is proven beneficial. AIM: The aim was to determine the practice of self-care activities among people with diabetes attending a tertiary care hospital in Mangalore. SUBJECTS AND METHODS: A facility-based cross-sectional study was conducted in Government Wenlock Hospital, Mangalore during September October 2012. A total of 290 patients with >1-year duration of diabetes mellitus (DM) were asked to respond to summary diabetes self-care activities questionnaire after obtaining the consent from them. The statistical analysis was performed in terms of descriptive statistics and association between the variables was tested using Mann-Whitney U-test. RESULTS: A healthy eating plan on a daily basis was followed by 45.9% (133/290) of the participants, daily exercises for 30 min were followed by 43.4% (126/290), and regular blood sugar monitoring was done by 76.6% (222/290). Regarding the adherence to oral hypoglycemic agents and insulin, daily adherence to medication was seen among 60.5% (155/256) and 66.9% (138/206) were found to be adherent to insulin injections on a daily basis. CONCLUSIONS: Self care practices were found to be unsatisfactory in almost all aspects except for blood sugar monitoring and treatment adherence. As these practices are essential for prevention of complications and better quality-of -life, more efforts should be put to educate the people with diabetes. PMID- 25745580 TI - The pattern of pediatric respiratory illnesses admitted in ebonyi state university teaching hospital South-East Nigeria. AB - BACKGROUND: Reports from the developed nations reveal respiratory tract infections as the leading cause of childhood hospital admissions. Children may be admitted for a variety of respiratory illnesses. Data on the spectrum of pediatric respiratory illnesses admitted in the hospital is scarce. AIM: To determine the pattern of pediatrics respiratory illness admissions, seasonal frequency, underlying risk factors and outcome. SUBJECTS AND METHODS: A retrospective assessment of respiratory cases admitted in the pediatric ward from 2005 to 2010 was conducted using case notes. Parameters considered included month of presentation, age, sex, immunization and nutritional status, tools of diagnosis and patient outcome. Results were analyzed using the Statistical Package for the Social Sciences with the level of significance P <= 0.05. RESULTS: Of the 239 cases admitted, there were more males than females (1.4:1). The commonest case was Bronchopneumonia, 71.6% (171/239 out of which 161 were uncomplicated, 5 had effusions and 6 were associated with measles). Other cases were Pulmonary Tuberculosis, 10.9% (26/239), Lobar pneumonia 8.8% (21/239), Bronchiolitis, 5% (12/239), Aspiration pneumonitis 2.1% (5/239) and Bronchial asthma, 0.8% (2/239). Mortality was 7.5% (18/239) mostly from Bronchopneumonia amongst the 1-5 years old. Mortality was significantly associated with malnutrition (P < 0.001) and poor immunization status (P < 0.01). CONCLUSION: Bronchopneumonia was found to be the commonest illness with significant mortality and peak occurrence in the rainy season. More emphasis must be laid on anticipatory guidance and prevention by encouraging the immunization, good nutrition and increased attention on children even after 1 year of age. PMID- 25745581 TI - Modifiable Risk factors of Hypertension and Socio-demographic Profile in Oghara, Delta State; Prevalence and Correlates. AB - BACKGROUND: Factors associated with the development of hypertension can be categorized into modifiable and non-modifiable risk factors. The modifiable risk factors include obesity, physical inactivity, high salt diet, smoking alcohol consumption and others. AIM: This study was aimed to determine the prevalence of modifiable risk factors of hypertension in a rural community; Oghara and to ascertain if any association exists with these risk factors and socio-demographic variables. SUBJECTS AND METHODS: Descriptive cross-sectional study design was utilized for the study and it was carried out over a period of 6 months (Feburary 2012 to August 2012). Cluster sampling was utilized to select a total of 272 respondents for the study. An interviewer administered questionnaire was used to collect data and data analysis was performed by SPSS version 16.0 (Chicago II, USA). RESULTS: The prevalence of hypertension is 21.0% (57/272), while the prevalence of modifiable risk factors of hypertension such as smoking, alcohol consumption and obesity are 15.8% (43/272), 43.4% (118/272) and 18.8% (51/272) respectively. There is a statistical significant association between hypertension and smoking (P < 0.001), as well as hypertension and alcohol. (P < 0.001), on the other hand socio-demographic variables were significantly associated with smoking (P < 0.001). CONCLUSION: The study showed high prevalence of modifiable risk factors of hypertension. This underscores the need for preventive efforts to encourage changes in life style pattern in order to reverse the impending epidemic of hypertension and other non-communicable diseases. PMID- 25745582 TI - Family process and content: comparing families of suicide attempters, human immunodeficiency virus positive patients and general population in southern iran, 2012. AB - BACKGROUND: Family is considered as the smallest social unit, which is the basis of forming a society and one of the effective factors for individual behaviors. When family pattern is useful, the family will be productive and otherwise it becomes nonproductive. AIM: This study aimed to investigate family process and content among families of suicide attempters, human immunodeficiency virus (HIV) positive patients, and general population in Shiraz, Southern Iran. SUBJECTS AND METHODS: This was a causal-comparative study. Our study population included three groups of single men, including suicide attempters, HIV positive patients and general population in Southern Iran. Our sample size was 180 male individuals including 60 suicide attempters referring to one of hospitals in Shiraz, 60 HIV positive patients referring to Behavioral Health Consultation Center, and 60 individuals from the general population who were selected using simple sampling method and were being investigated by Samani's family process and family content questionnaires. Data were being analyzed by ANCOVA and MANCOVA. RESULTS: The two clinical groups had a poorer situation than the general population (P < 0.001) in some dimensions of family process including decision-making and coping (P < 0.001), mutual respect, and communication (P = 0.02) when compared with the general population. HIV positive patients had significantly lower scores than suicide attempters in some dimensions of family content including financial resources, social position (P < 0.001), and place of residence (P = 0.04). The two clinical groups had a poor situation in most of the dimensions when compared with the general population (P < 0.001). CONCLUSIONS: The results of this study indicate the importance of education in the field of communication, decision making and coping skills. PMID- 25745583 TI - Complete utero vaginal prolapse in a woman with prolapsed submucous fibroid. AB - BACKGROUND: Uterine fibroids are benign tumors of the uterus and those located beneath the uterine mucosa may present as prolapsed fibroid in the vagina. Prolapsed submucous fibroid associated with complete uterovaginal prolapse is however uncommon. CASE: A case of irreducible complete utero-vaginal and infected sub-mucous fibroid prolapse, in a 45-year-old grandmultiparous woman, is reported. Bed rest and antibiotics failed to relief edema and infection of the vault. Vaginal myomectomy, followed by interval vaginal hysterectomy, and pelvic floor repair a week later resulted in a satisfactory outcome. PMID- 25745584 TI - Plastic surgery: tackling misconceptions. PMID- 25745585 TI - De-crystallization of Uric Acid Crystals in Synovial Fluid Using Gold Colloids and Microwave Heating. AB - In this study, we demonstrated a unique application of our Metal-Assisted and Microwave-Accelerated Evaporative Crystallization (MA-MAEC) technique for the de crystallization of uric acid crystals, which causes gout in humans when monosodium urate crystals accumulate in the synovial fluid found in the joints of bones. Given the shortcomings of the existing treatments for gout, we investigated whether the MA-MAEC technique can offer an alternative solution to the treatment of gout. Our technique is based on the use of metal nanoparticles (i.e., gold colloids) with low microwave heating to accelerate the de crystallization process. In this regard, we employed a two-step process; (i) crystallization of uric acid on glass slides, which act as a solid platform to mimic a bone, (ii) de-crystallization of uric acid crystals on glass slides with the addition of gold colloids and low power microwave heating, which act as "nano bullets" when microwave heated in a solution. We observed that the size and number of the uric acid crystals were reduced by >60% within 10 minutes of low power microwave heating. In addition, the use of gold colloids without microwave heating (i.e. control experiment) did not result in the de-crystallization of the uric acid crystals, which proves the utility of our MA-MAEC technique in the de crystallization of uric acid. PMID- 25745586 TI - Management of posterior fossa arteriovenous malformations. AB - BACKGROUND: Posterior fossa arteriovenous malformations (AVMs) are rare vascular lesions, representing 7-15% of all intracranial AVMs. Although less frequent than supratentorial AVMs, they present higher rupture, morbidity, and mortality rates. Microsurgery, radiosurgery, and endovascular neurosurgery are treatment options for obliteration of those lesions. In this paper, we present a critical review of the literature about the management of posterior fossa AVM. METHODS: A MEDLINE based search of articles published between January 1960 and January 2014 was performed. The search terms: "Posterior fossa arteriovenous malformation," "microsurgery," "radiosurgery," and "endovascular" were used to identify the articles. RESULTS: Current data supports the role of microsurgery as the gold standard treatment for cerebellar AVMs. Brainstem AVMs are usually managed with radiotherapy and endovascular therapy; microsurgery is considered in cases of pial brainstem AVMs. CONCLUSIONS: Succsseful treatment of posterior fossa AVMs depend on an integrated work of neurosurgeons, radiosurgeons, and endovascular neurosurgery. Although the development of radiosurgery and endovascular techniques is remarkable, microsurgery remains as the gold standard treatment for most of those lesions. PMID- 25745587 TI - Sources of delayed provision of neurosurgical care in a rural kenyan setting. AB - BACKGROUND: Delay to neurosurgical care can result in significant morbidity and mortality. In this study, we aim to identify and quantify the sources of delay to neurosurgical consultation and care at a rural setting in Kenya. METHODS: A mixed methods, cross-sectional analysis of all patients admitted to the neurosurgical department at Kijabe Hospital (KH) was conducted: A retrospective analysis of admissions from October 1 to December 31, 2013 and a prospective analysis from June 2 to June 20, 2014. Sources of delay were categorized and quantified. The Kruskal-Wallis test was used to identify an overall significant difference among diagnoses. The Mann-Whitney U test was used for pairwise comparisons within groups; the Bonferroni correction was applied to the alpha level of significance (0.05) according to the number of comparisons conducted. IBM SPSS version 22.0 (SPSS, Chicago, IL) was used for statistical analyses. RESULTS: A total of 332 admissions were reviewed (237 retrospective, 95 prospective). The majority was pediatric admissions (median age: 3 months). Hydrocephalus (35%) and neural tube defects (NTDs; 27%) were most common. At least one source of delay was identified in 192 cases (58%); 39 (12%) were affected by multiple sources. Delay in primary care (PCPs), in isolation or combined with other sources, comprised 137 of total (71%); misdiagnosis or incorrect management comprised 46 (34%) of these. Finances contributed to delays in 25 of 95 prospective cases. At a median delay of 49 and 200.5 days, the diagnoses of hydrocephalus and tumors were associated with a significantly longer delay compared with NTDs (P < 0.001). CONCLUSION: A substantial proportion of patients experienced delays in procuring pediatric neurosurgical care. Improvement in PCP knowledge base, implementation of a triage and referral process, and development of community-based funding strategies can potentially reduce these delays. PMID- 25745589 TI - Absence of the superior petrosal veins and sinus: Surgical considerations. AB - BACKGROUND: The superior petrosal vein, one of the most constant and largest drainage pathways in the posterior fossa, may result in complications if occluded. This study calls attention to a unique variant in which the superior petrosal veins and sinus were absent unilaterally, and the venous drainage was through the galenic and tentorial drainage groups. METHODS: This study examines one venogram and another anatomic specimen in which the superior petrosal vein and sinus were absent. RESULTS: The superior petrosal veins, described as 1-3 bridging veins, emptying into the superior petrosal sinus, are the major drainage pathways of the petrosal group of posterior fossa veins. In the cases presented, the superior petrosal vein and sinus were absent and venous drainage was through the galenic and tentorial groups, including the lateral mesencephalic or bridging vein on the tentorial cerebellar surface. CONCLUSIONS: In cases in which the superior petrosal sinus and veins are absent, care should be directed to preserving the collateral drainage through the galenic and tentorial tributaries. Although surgical strategies for intraoperative management and preservation of venous structures are still controversial, knowledge of the possible anatomical variations is considered to be essential to improve surgical outcomes. PMID- 25745590 TI - Statistical Significance of Geographic Heterogeneity Measures In Spatial Epidemiologic Studies. AB - Assessing geographic variations in health events is one of the major tasks in spatial epidemiologic studies. Geographic variation in a health event can be estimated using the neighborhood-level variance that is derived from a generalized mixed linear model or a Bayesian spatial hierarchical model. Two novel heterogeneity measures, including median odds ratio and interquartile odds ratio, have been developed to quantify the magnitude of geographic variations and facilitate the data interpretation. However, the statistical significance of geographic heterogeneity measures was inaccurately estimated in previous epidemiologic studies that reported two-sided 95% confidence intervals based on standard error of the variance or 95% credible intervals with a range from 2.5th to 97.5th percentiles of the Bayesian posterior distribution. Given the mathematical algorithms of heterogeneity measures, the statistical significance of geographic variation should be evaluated using a one-tailed P value. Therefore, previous studies using two-tailed 95% confidence intervals based on a standard error of the variance may have underestimated the geographic variation in events of their interest and those using 95% Bayesian credible intervals may need to re-evaluate the geographic variation of their study outcomes. PMID- 25745588 TI - Simulation and resident education in spinal neurosurgery. AB - BACKGROUND: A host of factors have contributed to the increasing use of simulation in neurosurgical resident education. Although the number of simulation related publications has increased exponentially over the past two decades, no studies have specifically examined the role of simulation in resident education in spinal neurosurgery. METHODS: We performed a structured search of several databases to identify articles detailing the use of simulation in spinal neurosurgery education in an attempt to catalogue potential applications for its use. RESULTS: A brief history of simulation in medicine is given, followed by current trends of spinal simulation utilization in residency programs. General themes from the literature are identified that are integral for implementing simulation into neurosurgical residency curriculum. Finally, various applications are reported. CONCLUSION: The use of simulation in spinal neurosurgery education is not as ubiquitous in comparison to other neurosurgical subspecialties, but many promising methods of simulation are available for augmenting resident education. PMID- 25745591 TI - Selective inhibitors of nuclear export (SINE) in hematological malignancies. AB - Regulated nucleo-cytoplasmic transport plays a major role in maintaining cellular homeostasis. CRM1 (chromosome region maintenance 1 or exportin 1 or XPO 1) is responsible for the nucleo-cytoplasmic transport of more than 200 proteins, including most of the tumor suppressor proteins (TSP). CRM1 is overexpressed in pancreatic cancer, osteosarcoma, glioma, cervical and hematological malignancies. This inspired the development of novel agents that selectively inhibit nuclear exportins (SINEs). In this review we focus on the significance of CRM1 in carcinogenesis and review the new development of SINE inhibitiors in hematological malignancies. Selinexor (KPT-330) as the first-in-human SINE agent represents this novel class of anti-cancer agents. PMID- 25745592 TI - Neurobiology of Pediatric Anxiety Disorders. AB - While the fear-based anxiety disorders (i.e., generalized anxiety disorder, social phobia and separation anxiety disorder) are among the most common psychiatric conditions in children and adolescents, only recently has an integrated understanding of the neurobiology of these disorders developed. In this regard, both structural and functional neuroimaging studies have demonstrated neuroanatomic and functional abnormalities within the amygdala and prefrontal cortex in youth with fear-based anxiety disorders, and have also suggested altered functional connectivity among components of the anterior limbic network (ALN), as well as alterations in neurochemistry within the anterior cingulate cortex. Additionally, several prefrontal structures and regions (e.g., medial prefrontal cortex) appear to be dysregulated in youth who are at risk of developing anxiety disorders (e.g., youth with inhibited temperament, behavioral inhibition, etc.). Finally, emerging data raise the possibility that functional activity within these amygdala-prefrontal networks may be affected by successful psychopharmacologic and psychotherapeutic treatment and may predict outcome. PMID- 25745593 TI - Spirituality moderates the relationship of psychosocial stress to metabolic risk factors among Afro-Caribbean immigrants in the US Virgin Islands. AB - OBJECTIVE: Spirituality may contribute to the health advantage of foreign-born blacks compared to United States (US)-born blacks. The objective of this study was to test the hypothesis that spirituality attenuates the association of psychosocial stress to stress-associated metabolic risk factors among foreign born Caribbean blacks living in a US jurisdiction. METHODS: Data on demographic factors, anthropometric measurements (height, weight and waist), fasting glucose and insulin, lifestyle behaviors (smoking and alcohol use), psychosocial stress and spirituality were collected from a population-based sample of 319 Afro Caribbean immigrants, ages 20 and older, who were recruited between 1995 and 2000 in the Virgin Islands of the United States (USVI). Glucose and insulin measurements were used to estimate insulin resistance by the homeostasis model assessment (HOMA-IR) method. Participants were classified into three levels of spirituality, "low", "medium" and "high" based on the distribution of spirituality scores. Stepwise regression analyses were used to identify the significant predictors of waist circumference and HOMA-IR within each level of spirituality. RESULTS: The predictors of waist circumference and HOMA-IR varied across the levels of spirituality. Psychosocial stress was an independent predictor of waist and HOMA-IR only among participants with a low level of spirituality. CONCLUSION: Spirituality appears to attenuate the association of psychosocial stress to waist circumference and insulin resistance among Afro Caribbean immigrants in the USVI. PMID- 25745594 TI - Overcoming transport barriers for interstitial-, lymphatic-, and lymph node targeted drug delivery. AB - Despite drug formulation improving circulation times and targeting, efficacy is stymied by inadequate penetration into and retention within target tissues. This review highlights the barriers restricting delivery to the connective tissue interstitium, lymphatics, and lymph nodes as well as advances in engineering drug carriers to overcome these delivery challenges. Three-dimensional tissue physiology is discussed in the context of providing material design principles for delivery to these tissues; in particular the influence of interstitial and lymphatic flows as well as differential permeabilities of the blood and lymphatic capillaries. Key examples of materials with different characteristics developed to overcome these transport barriers are discussed as well as potential areas for further development. PMID- 25745595 TI - Gossypiboma diagnosed fifteen years after a cesarean section: A case report. AB - Gossypiboma, a retained surgical sponge, is a rare complication following any surgical procedure and is primarily a result of human error. Such patients often have vague clinical presentations and the diagnosis often comes as a surprise. We present the case of a 40-year-old woman who had a long-standing history of lower abdominal discomfort. She was diagnosed with a gossypiboma fifteen years after a cesarean section. All general physicians, surgeons and radiologists must be aware of this rare but clinically significant entity. PMID- 25745596 TI - Prevention of type II diabetes mellitus in Qatar: Who is at risk? AB - BACKGROUND: Type II diabetes mellitus (DM) is one of the leading chronic diseases in Qatar as well as worldwide. However, the risk factors for DM in Qatar and their prevalence are not well understood. We conducted a case-control study with the specific aim of estimating, based on data from outpatients with DM in Qatar (cases) and outpatient/inpatient controls, the association between demographic/lifestyle factors and DM. METHODS: A total of 459 patients with DM from Hamad General Hospital (HGH) outpatient adult diabetes clinics, and 342 control patients from various outpatient clinics and inpatient departments within Hamad Medical Corporation (HMC) (years 2006-2008), were recruited. The association between risk factors and DM was evaluated using bivariate and multivariable logistic regression analyses. In addition to odds ratios (OR) and 95% confidence intervals (95% CI), we estimated the population attributable risk fractions for the DM demographic/lifestyle risk factors. RESULTS: Qatari nationality was the strongest risk factor for DM (adjusted OR = 5.5; 95% CI = 3.5 8.6; p < 0.0001), followed by higher monthly income (defined as >= 3000 Qatari Riyals, adjusted OR = 5.1; 95% CI = 3.0-8.7; p < 0.0001), age >65 years (adjusted OR = 3.3; 95% CI = 0.9-11.4; p = 0.06), male gender (adjusted OR = 2.9; 95% CI = 1.8-4.8; p < 0.0001), obesity (BMI >= 30, adjusted OR = 2.2; 95% CI = 1.5-3.2; p < 0.0001), no college education (adjusted OR = 1.7; 95% CI = 1.2-2.6; p = 0.009), and no daily vigorous/moderate activity (adjusted OR = 1.5; 95% CI = 0.9-2.3; p = 0.12). Among Qatari nationals, obesity was found to be the main risk factor for DM (unadjusted OR = 3.0; 95% CI = 1.6-5.6; p < 0.0001), followed by no college education (unadjusted OR = 2.7; 95% CI = 1.5-5.1; p = 0.001), while consanguinity did not appear to play a major role in predicting DM (unadjusted OR = 1.5; 95% CI = 0.8-2.8; p = 0.21). Our findings further suggested that eliminating obesity and improving access to education may reduce DM cases by up to one third for the population at large (31.7% and 26.8%, respectively) and up to half (46.9% and 49.3%, respectively) for Qatari nationals. Promoting physical activity may reduce the burden of DM by up to 9.4% for the population at large and up to 17.3% for Qatari nationals. CONCLUSIONS: Demographic/lifestyle factors appear to be the main risk factors for the high DM levels observed in Qatar, with a contribution that outweighs that of genetic risk factors. While further evaluation of DM risk factors among the Qatari population (as opposed to the resident population) is important and of interest, these findings highlight the need to focus short-term DM interventions on addressing demographic/lifestyle risk factors to achieve substantial and timely declines in DM levels. PMID- 25745597 TI - Relation between childhood experiences and adults' self-esteem: A sample from Baghdad. AB - BACKGROUND: Adverse childhood experiences are associated with significant functional impairments and loss of life in adolescence and adulthood. Literature documents the conversion of traumatic emotional experiences in childhood into psychological disorders later in life. The family is one of the most critical risks and resilient factors for mental health in adolescence and emerging adulthood. OBJECTIVE: To estimate the effect of childhood experiences on self esteem during adulthood in a sample from Baghdad city. METHODS: This cross sectional study was conducted in Baghdad city during the period from January 2013 through to January 2014. Multistage sampling techniques were used to choose 13 primary healthcare centers and eight colleges from three universities in Baghdad. Childhood experiences were measured by applying a modified standardized Adverse Childhood Experiences International Questionnaire (ACE-IQ) form. RESULTS: A total of 1040 subjects were surveyed and 1000 responded giving a response rate of 96.2%. The results revealed that 82.7% of the participants were confident within themselves, 14.9% (149) reported to feel a failure, while 28.3% of subjects expressed feeling useless at times. The score for family bonding is expected to significantly increase the score for self-esteem by a mean of 21.48. University, diploma and higher education are expected to significantly decrease the self esteem score by a mean of - 6.31 compared to those with less than secondary school education. Parents education show statistically insignificant association with the mean score for self-esteem. CONCLUSION: The findings of this study give an insight into the essential role of childhood experiences in building self esteem and adaptation later in their life. National health programs are suggested for intervention targeting early adverse childhood experiences and their consequences. PMID- 25745598 TI - Life threatening angioedema in a patient on ACE inhibitor (ACEI) confined to the upper airway. AB - INTRODUCTION: ACE inhibitors accounts for 8% of all cases of angioneurotic edema and the overall incidence is 0.1 to 0.7% of patients on ACE inhibitors. It is a leading cause (20-40%) of emergency room visits in the US with angioedema. We report a case of angioedema caused by ACE inhibitors confined to the upper airway after four years on treatment with Lisinopril which persisted for three weeks and required endotracheal intubation and subsequent tracheostomy due to delayed resolution. This case is one of the rare cases presented as upper airway edema which persisted for a long time. PRESENTATION: A 60-year-old Sudanese male patient with osteoarthritis in both knees underwent bilateral total knee replacement under single-shot epidural anesthesia. He had significant past medical history of type II diabetes, bipolar affective disorder and hypertension managed with Lisinopril for the past four years. Postoperatively after 10 hours the patient desaturated and developed airway obstruction requiring intubation. Laryngoscopy revealed an edematous tongue and upper airway and vocal cords were not visualized. In view of this clinical picture a provisional diagnosis of angioedema secondary to Lisinopril was made and it was discontinued. CT scan of the neck and soft tissues revealed severe airway edema with snugly fitting endotracheal tube with no peritubal air. A repeat CT neck on the tenth postoperative day showed no signs of resolution and an elective tracheostomy was performed on the eleventh postoperative day. C1 inhibitor protein and C4 levels were assayed to exclude hereditary angioedema and were found to be within normal range. Decannulation of tracheostomy was done after airway edema resolved on the twenty-fourth postoperative day as confirmed by CT scan. Subsequently he was transferred to the ward and discharged home. CONCLUSION: ACEI induced angioedema is a well-recognized condition. Early diagnosis based on a high index of suspicion, immediate withdrawal of the offending drug followed by supportive therapy is the cornerstone of management. PMID- 25745599 TI - Determinants of non-urgent Emergency Department attendance among females in Qatar. AB - BACKGROUND: The use of emergency department (ED) services for non-urgent conditions is well-studied in many Western countries but much less so in the Middle East and Gulf region. While the consequences are universal-a drain on ED resources and poor patient outcomes-the causes and solutions are likely to be region and country specific. Unique social and economic circumstances also create gender-specific motivations for patient attendance. Alleviating demand on ED services requires understanding these circumstances, as past studies have shown. We undertook this study to understand why female patients with low-acuity conditions choose the emergency department in Qatar over other healthcare options. SETTING AND DESIGN: Prospective study at Hamad General Hospital's (HGH) emergency department female "see-and-treat" unit that treats low-acuity cases. One hundred female patients were purposively recruited to participate in the study. Three trained physicians conducted semi-structured interviews with patients over a three-month period after they had been treated and given informed consent. RESULTS: The study found that motivations for ED attendance were systematically influenced by employment status as an expatriate worker. Forty percent of the sample had been directed to the ED by their employers, and the vast majority (89%) of this group cited employer preference as the primary reason for choosing the ED. The interviews revealed that a major obstacle to workers using alternative facilities was the lack of a government-issued health card, which is available to all citizens and residents at a nominal rate. CONCLUSION: Reducing the number of low-acuity cases in the emergency department at HGH will require interventions aimed at encouraging patients with non-urgent conditions to use alternative healthcare facilities. Potential interventions include policy changes that require employers to either provide workers with a health card or compel employees to acquire one for themselves. PMID- 25745600 TI - Elevated HbA1c levels in individuals not diagnosed with type 2 diabetes in Qatar: a pilot study. AB - BACKGROUND: The prevalence of type 2 diabetes (T2D) in Qatar and the Middle East is one of the highest in the world. It is estimated that about one quarter of the individuals with tbl2D are undiagnosed. Elevated HbA1c levels are an indicator of tbl2D or a pre-diabetic state. In this study we set out to examine which factors, such as anthropometric and socio-demographic risk factors, are associated with elevated HbA1c levels in a population without tbl2D. METHODS: We examined 191 subjects with no record of tbl2D. Anthropometrics and HbA1c were measured. Socio demographic (age, gender, ethnicity and educational level) and health information were assessed through questionnaires. Elevated HbA1c levels were defined as >6.0% (>42 mmol/mol). Individual risk factors were examined in relationship to having elevated HbA1c levels using logistic regression. RESULTS: Thirty-eight (20%) study participants had elevated HbA1c levels. Participants from South Asian and Filipino descent were more likely to present with elevated HbA1c levels than Arab participants (adjusted odds ratios (OR): 13.30 (95% confidence interval (CI): 4.24, 41.79), p < 0.001 for South Asian and 4.54 (95% CI: 1.04, 19.83), p = 0.04 for Filipinos). A body mass index of above 30 kg/m(2) was associated with elevated HbA1c levels (adjusted OR: 2.90 (95% CI: 1.29, 6.51), p = 0.01). Neither gender nor educational level was associated with elevated HbA1c levels. CONCLUSIONS: Elevated HbA1c levels in individuals not diagnosed with diabetes were most frequently found in the South Asian and Filipino immigrant population. Special attention should therefore be given to the early identification of tbl2D in these subjects. PMID- 25745601 TI - Oculo-ectodermal syndrome: A case report and further delineation of the syndrome. AB - Oculo-ectodermal syndrome (OES - OMIM 600628), also known as Toriello Lacassie Droste syndrome, is a very rare condition, first described by Toriello et al., in 1993. OES has been proposed to be a mild variant of encephalocraniocutaneous lipomatosis (ECCL). It is characterized by aplasia cutis congenita (ACC), epibulbar dermoids, coarctation of the aorta, arachnoid cysts in the brain, seizure disorder, hyperpigmented nevi, non-ossifying fibromas and a predisposition to develop giant cell tumors of the jaw. There are few reported cases of OES worldwide but with no definite diagnostic criteria yet. We present a case in a child with unilateral hyperpigmented nevi and ACC on the scalp, ocular lesions (lipodermoid cysts and coloboma), temporal arachnoid cyst, spinal lipomatosis and aortic coarctation with the aim of enhancing the foundation to establish diagnostic criteria for this condition. It additionally serves as a teaching point to emphasize the importance of pursuing a definite diagnosis when faced with such a multisystem illness, to counsel patients and their parents regarding long term morbidity and overall prognosis. PMID- 25745602 TI - Normalized real-time PCR for diagnosis of H. pylori infection. AB - OBJECTIVES: There is increasing interest in the use of quantitative PCR (q-PCR) for diagnosis of H. pylori infection. However, the assay remains largely unstandardized, making comparison between studies unreliable. The objective of this study was to assess accuracy of a normalized q-PCR assay for diagnosis of the infection. SUBJECTS AND METHODS: Seventy-six fresh gastric biopsy specimens were collected from patients undergoing upper gastrointestinal tract endoscopy and examined by rapid urease test (RUT), culture, and a commercial TaqMan q-PCR assay targeting the ureA gene. Counts obtained from the latter assay were normalized to the human ACTB gene. A subject was considered to be infected if two or more assays were positive. RESULTS: The detection rates were 42.1%, 52.6%, and 78.9% by culture, RUT and q-PCR, respectively. Bacterial density ranged 0.005 to 4800 bacteria per 100 human cells. Because q-PCR showed low initial specificity (45.7%), the cutoff value for the assay was recalculated as 1 bacterium per 100 human cells, using ROC curve analysis. Accordingly, the sensitivities and specificities were 79.5% and 97.3%, respectively, for culture; 94.9% and 91.9%, respectively, for RUT; and 94.9% and 94.6%, respectively, for q-PCR. By gold standard, 39 of the dyspeptic patients (51.3%) were found to be infected. CONCLUSIONS: With the identified cutoff value, the q-PCR assay diagnosed H. pylori infection with an accuracy slightly superior to that of RUT. However, the possibility that low counts detected only by q-PCR represent true infections warrants further investigation. Normalization of bacterial counts for standardization of q-PCR H. pylori assays is recommended. PMID- 25745603 TI - Validation of Arabic versions of three sleep surveys. AB - BACKGROUND: Research on sleep health is lacking in developing countries, particularly among the Sudanese population. This contributes to a number of social and safety risks such as workplace injury, daytime sleepiness, automobile accidents, and more. The current study aims to validate three Arabic questionnaires related to sleep health, namely the Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and Restless Legs Syndrome (RLS). METHODS: A random sample of 83 Sudanese participants was surveyed for the purpose of testing the reliability and validity of the Arabic version of the ESS, ISI, and RLS. The present study used exploratory factor analysis (EFA) of item scores to examine a potential single-factor structure of the ESS, ISI, and RLS. Reliability and validity of the instruments were assessed by internal consistency and construct validity, respectively. RESULTS: The internal consistency within the ESS, ISI, and RLS subscales was high, with Cronbach's alpha of 0.84, 0.87, and 0.94, respectively. EFA results showed the RLS and ISI scales were dominated by a single-factor structure that explained at least 84.2% and 65.70% respectively of the total variance. The ESS required a two-factor solution that explained 64.5% of the total variance, so the single-factor structure does not appear to be a good measure of the Arabic version of the ESS. CONCLUSION: The Arabic versions of the ESS, ISI, and RLS are valid and reliable tools. The RLS and ISI seem to have better psychometric properties than the ESS. PMID- 25745604 TI - The cervix cancer research network: increasing access to cancer clinical trials in low- and middle-income countries. AB - INTRODUCTION: The burden of cervical cancer is large and growing in developing countries, due in large part to limited access to screening services and lack of human papillomavirus (HPV) vaccination. In spite of modern advances in diagnostic and therapeutic modalities, outcomes from cervical cancer have not markedly improved in recent years. Novel clinical trials are urgently needed to improve outcomes from cervical cancer worldwide. METHODS: The Cervix Cancer Research Network (CCRN), a subsidiary of the Gynecologic Cancer InterGroup, is a multi national, multi-institutional consortium of physicians and scientists focused on improving cervical cancer outcomes worldwide by making cancer clinical trials available in low-, middle-, and high-income countries. Standard operating procedures for participation in CCRN include a pre-qualifying questionnaire to evaluate clinical activities and research infrastructure, followed by a site visit. Once a site is approved, they may choose to participate in one of four currently accruing clinical trials. RESULTS: To date, 13 different CCRN site visits have been performed. Of these 13 sites visited, 10 have been approved as CCRN sites including Tata Memorial Hospital, India; Bangalore, India; Trivandrum, India; Ramathibodi, Thailand; Siriaj, Thailand; Pramongkutklao, Thailand; Ho Chi Minh, Vietnam; Blokhin Russian Cancer Research Center; the Hertzen Moscow Cancer Research Institute; and the Russian Scientific Center of Roentgenoradiology. The four currently accruing clinical trials are TACO, OUTBACK, INTERLACE, and SHAPE. DISCUSSION: The CCRN has successfully enrolled eight sites in developing countries to participate in four randomized clinical trials. The primary objectives are to provide novel therapeutics to regions with the greatest need and to improve the validity and generalizability of clinical trial results by enrolling a diverse sample of patients. PMID- 25745605 TI - (18)F-FDG PET-CT for Surveillance of Brazilian Patients with Li-Fraumeni Syndrome. AB - PURPOSE: To evaluate the effectiveness of (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) for detecting early cancer in carriers of germline TP53 mutation, the genetic defect underlying Li Fraumeni and related syndromes, which predisposes to many forms of cancer throughout life. PATIENTS AND METHODS: A total of 30 adult patients from six families with germline TP53 mutations were recruited. These patients did not have a diagnosis of cancer in the 24 months preceding the study. Anomalous concentrations from whole-body (18)F-FDG-PET/CT were assessed by two independent experts. Suspicious lesions were excised and subjected to pathological examination. RESULTS: A total of 6/30 patients showed abnormal (18)F-FDG concentration. Confirmation studies revealed three cases of cancer, including one lung cancer, one ovarian cancer, and one disseminated breast cancer. Three patients had non-malignant lesions (one Bartholin's cyst and two cases of reactive lymph nodes). CONCLUSION: (18)F-FDG-PET/CT is effective in detecting cancer in subjects who are asymptomatic according to current screening guidelines. These results further suggest that (18)F-FDG-PET/CT is an appropriate method for surveillance of cancer risk in TP53 mutation carriers. PMID- 25745606 TI - Common Mutations of the Methylenetetrahydrofolate Reductase (MTHFR) Gene in Non Syndromic Cleft Lips and Palates Children in North-West of Iran. AB - INTRODUCTION: Cleft lips and cleft palates are common congenital abnormalities in children. Various chromosomal loci have been suggested to be responsible the development of these abnormalities. The present study was carried out to investigate the association between the suspected genes (methylenetetrahydrofolate reductase [MTHFR] A1298C and C677T) that might contribute into the etiology of these disorders through application of molecular methods. MATERIALS AND METHODS: This cross-sectional and explanatory study was carried out on a study population of 65 affected children, 130 respective parents and 50 healthy individuals between 2009 and 2012 at Tabriz University of Medical Sciences, IR Iran. After DNA extraction, amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and restriction fragment length polymorphism (RFLP)-PCR were used respectively to investigate the C677T and A1298C mutations for the MTHFR gene. RESULTS: There was a significant difference in the rates of the C677T mutation when affected patients and their fathers were compared with the control group (odds ratio [OR]=0.44) (OR=0.64). However, there was no significant difference observed in the rate of this mutation between the patients' mothers and the control group (OR=1.35). In addition, the abnormality rate was higher in patients with the A1298C mutation and their parents, when compared with the control group. This abnormality rate was higher for the affected children and their fathers in comparison with their mothers (Fathers, OR=0.26; Mothers, OR=0.65; Children, OR=0.55). No significant difference was seen in the rate of the polymorphism C677T in its CC, when the affected children and their parents were compared with the control group. However, there was a significant difference in the A1298C mutation. CONCLUSION: An association was seen between the A1298C mutation and cleft lip and cleft palate abnormalities in Iran. However, there seems to be a stronger relationship between the C67TT mutation and these abnormalities in other countries, which could be explained by racial differences. Moreover, this association was more notable between the affected children and their fathers than their mothers. The findings in this study may be helpful in future studies and screening programs. PMID- 25745607 TI - Corrosive injury of the upper gastrointestinal tract: review of surgical management and outcome in 14 adult cases. AB - INTRODUCTION: Caustic ingestion is responsible for a spectrum of upper gastrointestinal tract injury from self-limited to perforation. This study conducted to evaluate clinical characteristics as well as surgical outcomes in patients with caustic ingestion. MATERIALS AND METHODS: Between Nov1993 to march 2011, 14 adults with a clinical evidence of corrosive ingestion were admitted into our institutions (Omid and Ghaem hospitals). Patients evaluated for etiology of erosion, location, type of surgery, morbidity and mortality after surgery. RESULTS: 14 patients (10men and 4 women) with a age range between18-53 years were evaluated. In 6 patients, the injury was accidental and in 8 patients ingestion was a suicide attempt. Ingested agent included nitric acid in 4 patients, hydrochloric acid in 7 patients, sulfuric acid in 2 patients and strong alkali in one patient. The location and extent of lesion varied included esophagus in 13 cases, stomach in 7 cases and the pharynx in 3 cases. Acute abdomen was developed In 2 patients and a procedure of total gasterectomy and blunt esophagectomy was performed. In the remaining patients, substernal esophageal bypass in 2 patients, esophageal resection and replacement surgery in 9 patients and gastroenterostomy in one patient performed to relieve esophageal stricture. Two patients died of mediastinitis after esophageal replacement surgery. Postoperative strictures were developed in 2 survived patients with hypopharyngeal reconstruction that was managed by per oral bougienage in one patient and KTP Laser and stenting in the other patient. CONCLUSION: Esophageal resection with replacement was safe and good technique for severe corrosive esophageal stricture with low mortality and morbidity. PMID- 25745608 TI - Mastoid cavity obliteration with combined palva flapand bone pate. AB - INTRODUCTION: This study was designed to evaluate the usefulness of mastoid cavity obliteration with combined bone pate and Palva flap in the prevention of problematic mastoid cavities after canal wall down mastoidectomy. MATERIALS AND METHODS: In a prospective longitudinal study with a mean follow-up of 28 months conducted between 2008-2012, a series of 56 ears in 48 patients with chronic otitis media due to a cholesteatoma underwent canal wall down mastoidectomy that their mastoid cavity obliterated with combined bone pate and Palva flap. Seventeen (30%) ears were managed via revision surgery, with the reminder via primary surgery. Data included mastoid cavity status, results at second-look surgery with ossiculoplasty, and postoperative complications. RESULTS: All patients underwent second-look surgery. Forty-six (82%) ears maintained a very small, dry and healthy mastoid cavity. Seven (13%) ears had occasional otorrhea, and three (5%) ears had small granulation tissue. Seven (12.5%) ears had residual cholesteatoma pearl in the middle ear at second-look surgery. Four (7%) ears exhibited wound infection. CONCLUSION: Canal wall down mastoidectomy and mastoid cavity obliteration with combined bone pate and Palva flap is a effective option for the complete removal of cholesteatoma and prevention of postoperative mastoid cavity problems. PMID- 25745609 TI - Surgical Outcomes of Cerebellopontine angle Tumors in 50 Cases. AB - INTRODUCTION: To report our experience with a large series of surgical procedures for removal of cerebellopontine angle (CPA) tumors using different approaches. MATERIALS AND METHODS: This was a retrospective analysis of 50 patients (mean age, 49 years) with CPA tumors (predominantly acoustic neuroma) who underwent surgical removal using appropriate techniques (principally a translabyrinthine approach) during a 4-year period. RESULTS: One death occurred during this study. There were nine cases (18%) of cerebrospinal fluid leak, and five patients (10%) were diagnosed as having bacterial meningitis. Complete gross tumor removal was not achieved in four patients (8%). Facial nerve function as measured by the House Brackmann system was recorded in all patients 1 year following surgery: 32% had a score of 1 or 2; 26% had a score of 3 or 4; and 8% had a score of 5 or 6. Other complications included four cases of wound infection. CONCLUSION: The translabyrinthine approach was predominantly used in our series of CPA tumors, and complication rates were comparable with other large case series. PMID- 25745611 TI - Oral manifestations of human immunodeficiency virus-infected patients. AB - INTRODUCTION: Oral lesions are among the earliest clinical manifestations of human immunodeficiency (HIV) infection and are important in early diagnosis and for monitoring the progression to acquired immunodeficiency syndrome (AIDS). The purpose of this study was to determine the prevalence of oral lesions and their relationship with a number of factors in HIV/AIDS patients attending an HIV center. MATERIALS AND METHODS: A total of 110 HIV-positive patients were examined to investigate the prevalence of oral lesions according to the criteria established by the European Community Clearing House on Oral Problems Related to HIV Infection. An independent T-test was used for correlation of oral lesions with CD4+ count and a chi2 test was used for analysis of the relationship of co infection with hepatitis B virus (HBV), sexual contact, route of transmission, history of drug abuse, and history of incarceration. RESULTS: Most of the cases were male patients (82.7%). The mean age across all participants was 36.2+/-8.1 years. Rampant carries, severe periodontitis and oral candidiasis were the most notable oral lesions. Oral lesions were more prevalent in patients between 26-35 years of age. There was a significant difference between patients with and without pseudomembranous candidiasis and angular cheilitis according to mean level of CD4+. CONCLUSION: The most common oral presentations were severe periodontitis, pseudomembranous candidiasis and xerostomia. PMID- 25745610 TI - Cleft lip and Palate: A 30-year Epidemiologic Study in North-East of Iran. AB - INTRODUCTION: Cleft lip and palate are among the most common congenital anomalies worldwide. This study was conducted in order to explore the incidence and related factors of cleft lip and/or palate (CL/P) among live births in Mashhad, North Eastern Iran. MATERIALS AND METHODS: In this cross-sectional study, records of 28,519 infants born between March 1982 and March 2011 at three major hospitals in Mashhad were screened for oral clefts. Clinical and demographic factors relating to diagnosed cases, including birth date, gender, birth weight, maternal age, number of pregnancies, type and side of cleft and presence of other congenital anomalies were recorded for analysis. RESULTS: The overall incidence of CL/P was 1.9 per 1,000 live births. Cleft lip associated with cleft palate (CLP) was the most prevalent type of cleft (50%), followed by isolated cleft lip (35.2%) and isolated cleft palate (14.8%). A total of 92.6% of oral clefts were bilateral and 5.5% were located on the right side. In addition, clefts were found to be more common in male than female births (male/female ratio=2.3). The rate of associated congenital anomalies in CL/P newborns was 37%. No significant differences were observed in the incidence of oral clefts across three decades of study; except for CLP which was significantly more prevalent between 2002-2011 (P=0.027). There were no significant differences with regard to season of birth, associated anomalies or maternal age of affected newborns in the three time periods of the study. Furthermore, maternal age and number of pregnancies were not significantly different among the three types of cleft (P=0.43 and P=0.91, respectively). Although the mean birth weight of patients affected with isolated cleft palate was considerably lower than that of the other two types of cleft, the difference was not statistically significant (P=0.05). CONCLUSION: This study indicates a frequency of CL/P close to the findings in East Asian countries and higher than some previous reports from Iran, European and American countries. Ethnicity related genetic factors may have a role in the conflicting results obtained from different populations. PMID- 25745613 TI - Sleep Apnea Syndrome after Posterior Fossa Surgery: A Case of Acquired Ondine's Curse. AB - INTRODUCTION: Ondine's Curse is a catastrophic but rare condition in adults. It is referred to as a congenital or acquired condition, in which the patient cannot breathe automatically while asleep. Acquired causes of this disease can be any cause affecting the ventrolateral part of the medulla, which is considered to be the breathing center in humans. CASE REPORT: A 51-year-old woman, with ataxia and the symptoms and signs of rising Intra-Cranial Pressure, who underwent ventriculoperitoneal shunting and removal of tumour, developed episodic apnea during sleep after surgery and hypercapnia when awake. In her post-operative CT scan, some fine spots of hypodensity in the left lateral part of the medulla were observed. She was managed pharmacologically and underwent tracheotomy. After 50 days, she was discharged from the hospital when she was able to breathe normally. CONCLUSION: Having experience with this condition after resection of a fourth ventricle tumor, it was found that Ondine's Curse can be considered as one of the complications of posterior fossa surgery and is curable by proper management. PMID- 25745612 TI - A new clinical scoring system for adenoid hypertrophy in children. AB - INTRODUCTION: Chronic nasal obstruction due to adenoid hypertrophy is a very common disorder. Although the clinical assessment of adenoid hypertrophy is essential, its real value in young children is difficult to evaluate. The purpose of this prospective study was to validate a simple clinical score to predict the severity of adenoid obstruction and to evaluate the relationship between this method of clinical scoring with radiography and nasopharyngeal endoscopy. MATERIALS AND METHODS: Ninety symptomatic children were enrolled into this study. The clinical score included difficulty of breathing during sleep, apnea, and snoring. We investigated the relationship between clinical scoring, nasal endoscopy, and radiographic findings. RESULTS: The clinical score correlated very well with endoscopic findings (P<0.000), but the correlation between the clinical score and radiologic findings (P>0.05) and endoscopic findings and imaging (P>0.05) was weak. CONCLUSION: Clinical findings could be used to select children for adenoidectomy, especially when endoscopic examination is not available or cannot be performed. PMID- 25745614 TI - Coexistence of granular cell tumor with squamous cell carcinoma on the tongue: a case report. AB - INTRODUCTION: Granular cell tumors (GCTs) are rare and mostly benign soft tissue tumors. Though they have been reported in all parts of body, they are generally located in the head and neck region, especially on the tongue. Some malign forms exist, but these have been rarely reported. Granular cell tumors have a neural origin and, in immunohistochemical evaluations, they express S-100 and neuron specific enolase (NSE). The treatment of these tumors is bulky surgical excision. CASE REPORT: In this case, a cauliflower shaped lesion with a 1 cm diameter was excised from the midline tongue of a 65 year old woman. The histopathological evaluation indicated that it was squamous cell carcinoma (SCC) covering GCT. Herein, the coexistence of GCT and SCC we describe on the same region of the tongue, in accordance with literature review, since this is a very rare condition. CONCLUSION: Pseudoepitheliomatous hyperplasia may accompany GCTs on the tongue and this condition may mimic well-differentiated SCC. For this reason, with the help of Ki-67 and p63 expression, in addition to immunohistochemical markers, well-differentiated SCC should be differentiated from pseudoepitheliomatous hyperplasia through careful investigation. PMID- 25745615 TI - Subjective visual vertical and horizontal abnormalities in a patient with lateral medullary syndrome-a case report. AB - INTRODUCTION: Evaluation of persistent vertigo in post infarct patients is very important as the management depends on whether the cause is purely of central origin or due to associated vestibular affliction. CASE REPORT: A patient with left sided dorsolateral medullary syndrome and persistent vestibular symptoms was evaluated. Vestibular test battery showed abnormal smooth pursuit, bilateral hyperactive caloric responses, and abnormal dynamic subjective visual vertical and dynamic subjective visual horizontal tests. CONCLUSION: Dorsolateral medullary infarctions (Wallenberg's syndrome) typically cause a central vestibular tonus imbalance in the roll plane with ipsilateral deviations of perceived vertical orientation. The SVV and SVH tests may have a role in localizing the pathology in a patient with lateral medullary syndrome. PMID- 25745617 TI - Does BRAF Mutation and Extracellular Signal Regulated Kinase Expression in Patients With Colorectal Cancer Have Any Prognostic Significance? PMID- 25745616 TI - Imaging Amyloidopathy in Parkinson Disease and Parkinsonian Dementia Syndromes. AB - Dementia arising in patients with Parkinson disease or parkinsonian neurodegeneration comprises a heterogeneous neuropathology. Clinical labeling of patients with both dementia and Parkinson disease is dichotomous, depending on the temporal development of cognitive impairment and motor parkinsonism. Patients with dementia arising first (or within the first year of PD) are classified as dementia with Lewy bodies; patients with PD for more than one year before cognitive decline are classified as Parkinson disease with dementia. Despite this differential clinical classification, autopsy studies demonstrate variable admixtures of cortical synuicleinopathy, Abeta-amyloidopathy and tau neurofibrillary tangle deposition. There are no routine clinical diagnostic measures that accurately distinguish the underlying neuropathologies in individual patients. In the present paper, we review the published literature describing characteristics of fibrillary Abeta-amyloid deposition on the basis of PET radiotracer imaging in patients with Parkinson disease and in parkinsonian dementia syndromes. Although individual reports often include only small-to modest subject numbers, there is overall suggestion that PD patients have a lower incidence of Abeta-amyloid deposition than seen amongst elderly normal subjects, and that Parkinson disease with dementia patients have a lower incidence of Abeta amyloid deposition than do patients with dementia with Lewy bodies. These apparent features contrast the findings of Abeta-amyloid-PET imaging in normal aging and the development of Alzheimer disease, where Abeta-amyloid deposition arises asymptomatically and apparently many years before development of signs or symptoms of dementia. It is proposed that focused, prospective studies are needed to further address and understand the complex role(s) of Abeta-amyloid pathology in Parkinson disease, and that this understanding will be critical to the development of targeted disease-modifying therapy for dementia in PD. PMID- 25745618 TI - Reduced port laparoscopic surgery for rectal cancer. PMID- 25745619 TI - Can the timing of ileostomy reversal influence functional outcome? PMID- 25745620 TI - Effect of a purse-string approximation following stoma takedown on wound infection and satisfaction. PMID- 25745621 TI - Clinicopathologic Significance of BRAF Mutation and Extracellular Signal Regulated Kinase 1/2 Expression in Patients With a Colorectal Adenocarcinoma. AB - PURPOSE: BRAF mutation and expression of extracellular signal regulated kinase (ERK) are linked with colorectal carcinogenesis through the serrated pathway. BRAF and ERK1/2 play important roles in the activation of mitogen-activated protein (MAP) kinase signaling pathways. The present study investigated the clinicopathologic outcomes of BRAF mutation and ERK1/2 expression in patients with colorectal cancer (CRC) and the possibility of using them as prognostic indicators. METHODS: Dual-priming oligonucleotide-based multiplex polymerase chain reaction for BRAF (V600E) mutation and immunohistochemical analysis of ERK1/2 were performed using 65 formalin-fixed, paraffin-embedded samples from patients with CRC. We analyzed the dependences of the clinicopathologic features on BRAF mutation and ERK1/2 expression. RESULTS: Out of 65 samples from CRC patients, BRAF mutation was detected in 3 (4.6%). The 3 patients with BRAF mutation presented with T3 CRC with lymph node metastasis (stage III) showing moderately or poorly differentiated histology. ERK1 and ERK2 were positively detected in 73.8% and 15.4% of the patients with CRC, respectively. ERK1 expression was significantly correlated with lymph node metastasis (P = 0.049). ERK2 expression was significantly correlated with tumor emboli (P < 0.05), tumor invasion (P = 0.035), lymph node metastasis (P = 0.017), and stage (P = 0.02). CONCLUSION: BRAF mutation and ERK1/2 expression may be associated with advanced or more aggressive CRC. These molecular markers might play prognostic roles in CRC developed through the serrated pathway. PMID- 25745622 TI - Reduced-port laparoscopic surgery for a tumor-specific mesorectal excision in patients with colorectal cancer: initial experience with 20 consecutive cases. AB - PURPOSE: Single-port plus one-port, reduced-port laparoscopic surgery (RPLS) may decrease collisions between laparoscopic instruments and the camera in a narrow, bony, pelvic cavity while maintaining the cosmetic advantages of single-incision laparoscopic surgery. The aim of this study is to describe our initial experience with and to assess the feasibility and safety of RPLS for tumor-specific mesorectal excisions (TSMEs) in patients with colorectal cancer. METHODS: Between May 2010 and August 2012, RPLS for TSME was performed in 20 patients with colorectal cancer. A single port with four channels through an umbilical incision and an additional port in the right lower quadrant were used for RPLS. RESULTS: The median operation time was 231 minutes (range, 160-347 minutes), and the estimated blood loss was 100 mL (range, 50-500 mL). We transected the rectum with one laparoscopic stapler in 17 cases (85%). The median time to soft diet was 4 days (range, 3-6 days), and the length of hospital stay was 7 days (range, 5-45 days). The median total number of lymph nodes harvested was 16 (range, 7-36), and circumferential resection margin involvement was found in 1 case (5%). Seven patients (35%) developed postoperative complications, and no mortalities occurred within 30 days. During the median follow-up period of 20 months (range, 12-40 months), liver metastasis occurred in 1 patient 10 months after surgery, and local recurrence was nonexistent. CONCLUSION: RPLS for TSME in patients with colorectal cancer is technically feasible and safe without compromising oncologic safety. However, further studies comparing RPLS with a conventional, laparoscopic low-anterior resection are needed to prove the advantages of the RPLS procedure. PMID- 25745623 TI - Predictors of fecal incontinence and related quality of life after a total mesorectal excision with primary anastomosis for patients with rectal cancer. AB - PURPOSE: After total mesorectal excision (TME) with primary anastomosis for patients with rectal cancer, the quality of life (QoL) may be decreased due to fecal incontinence. This study aimed to identify predictors of fecal incontinence and related QoL. METHODS: Patients who underwent TME with primary anastomosis for rectal cancer between December 2008 and June 2012 completed the fecal incontinence quality of life scale (FIQoL) and Wexner incontinence score. Factors associated with these scores were identified using a linear regression analysis. RESULTS: A total of 80 patients were included. Multivariate analysis identified a diverting ileostomy (n = 58) as an independent predictor of an unfavorable outcome on the FIQoL subscale coping/behavior (P = 0.041). Ileostomy closure within and after 3 months resulted in median Wexner scores of 5.0 (interquartile range [IQR], 2.5-8.0) and 10.5 (IQR, 6.0-13.8), respectively (P < 0.001). The median FIQoL score was 15.0 (IQR, 13.1-16.0) for stoma closure within 3 months versus 12.0 (IQR, 10.5-13.9) for closure after 3 months (P = 0.001). CONCLUSION: A diverting ileostomy is a predictor for an impaired FIQoL after a TME for rectal cancer. Stoma reversal within 3 months showed better outcomes than reversal after 3 months. Patients with a diverting ileostomy should be informed about the impaired QoL, even after stoma closure. PMID- 25745624 TI - Clinical trial on the incidence of wound infection and patient satisfaction after stoma closure: comparison of two skin closure techniques. AB - PURPOSE: Surgical site infection (SSI) is one of the most common complications that can occur after stoma closure. Reports have described differences in the incidence of wound infection depending on the skin closure technique, but there is no consensus on the ideal closure technique for a stoma wound. The aim of this study was to compare the incidence of SSI and the patient satisfaction between a circumferential purse-string approximation (CPA) and a primary linear closure (PC) of a stoma wound. METHODS: This prospective nonrandomized trial enrolled 48 patients who underwent a stoma closure from February 2010 to October 2013. Patients were divided into two groups according to the stoma closing technique: the CPA group (n = 34) and the PC group (n = 14). The incidences of SSI for the two groups were compared, and the patients' satisfaction with the stoma closure was determined by using a questionnaire. RESULTS: SSI occurred in 3 of 48 patients (6.3%) and was more frequent in the PC group than in the CPA group (3/14 [21.4%] vs. 0/34 [0%], P = 0.021). Time to complete healing after stoma closure in the CPA group was 32 days (range, 14-61 days). Patients in the CPA group were more satisfied with the resulting wound scar (P = 0.043). CONCLUSION: After stoma closure, CPA was associated with a significantly lower incidence of wound infection and greater patient satisfaction compared to PC. However, with the CPA technique, the time to heal is longer than it is with PC. PMID- 25745625 TI - Late presentation of anal canal duplication in adults: a series of four rare cases. AB - Anal canal duplication (ACD) is a very rare condition, especially in adults. Four cases in adults are reported. In three cases, the orifice of duplication was located behind the native anus, and in one case, it was located anteriorly. In all cases, no communication between the anal canal and the tract of duplication was noted. Complete removals of the duplications were done through a perineal approach. Histology showed fibro-muscular tissue lined with a squamous epithelium. The postoperative courses were uneventful. PMID- 25745626 TI - Epidermoid cyst of the cecum. AB - An epidermoid cyst of the cecum is extremely rare; only eight cases have been reported in the literature. A 63-year-old woman was admitted to Kyung Hee University Medical Center with a colonic mass that had been discovered incidentally during a regular health check-up. The radiographic impression was that this mass was a gastrointestinal stromal tumor. During surgery, an exophytic mass in the cecal wall was resected by using an ileocecectomy. Based on the macroscopic and the microscopic findings, this case was identified as an epidermoid cyst of the cecal wall. We report this case to discuss the origin of this entity and the unusual nature of our case. PMID- 25745627 TI - Respiratory Variability during NAVA Ventilation in Children: Authors' Reply. PMID- 25745628 TI - Prevention and management of depression and suicidal behavior in men with prostate cancer. PMID- 25745630 TI - Cell autofluorescence and lipofuscin. PMID- 25745629 TI - Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain. AB - Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface "Cx-2D" allows for the display of significant correlations of individual regions-of interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex-changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic studies. PMID- 25745631 TI - Efficiency of the lausanne clinical pathway for proximal femoral fractures. AB - Purpose/Introduction: The number of hip fractures is rising, due to increases in life expectancy. In such cases, patients are at risk from post-operative complications and subsequently the average length of hospitalization may be extended. In 2011, we established a clinical pathway (CP), a specific model of care for patient-care management, to improve the clinical and economic outcomes of proximal femoral fracture management in elderly patients. The goal was to evaluate the CP using clinical, process, and financial indicators. METHODS: We included all surgical patients aged 65 and over, admitted to the emergency department with a fracture of the proximal femur following a fall. Assessment parameters included three performance indicators: clinical, process, and financial. The clinical indicators were the presence or absence of acute delirium on the third post-operative day, diagnosis of nosocomial pneumonia, and the number of patients fulfilling at least 75% of their nutritional requirements at the end of the hospitalization period. The process indicator was the time interval between arrival at the emergency department and surgery. The financial indicator was based on the number of days spent in hospital. RESULTS: From 2011 to 2013, 669 patients were included in the CP. We observed that the average length of stay in hospital decreased as soon as the CP was implemented and stabilized afterwards. The goal of 90% of patients undergoing surgery within 48 h of arrival in the emergency department was surpassed in 2013 (93.1%). Furthermore, we observed an improvement in the clinical indicators. CONCLUSION: The application of a CP allowed an improvement in the qualitative and quantitative efficiency of proximal femoral fracture management in elderly patients, in terms of clinical, process, and financial factors. PMID- 25745632 TI - Dynamic information processing states revealed through neurocognitive models of object semantics. AB - Recognising objects relies on highly dynamic, interactive brain networks to process multiple aspects of object information. To fully understand how different forms of information about objects are represented and processed in the brain requires a neurocognitive account of visual object recognition that combines a detailed cognitive model of semantic knowledge with a neurobiological model of visual object processing. Here we ask how specific cognitive factors are instantiated in our mental processes and how they dynamically evolve over time. We suggest that coarse semantic information, based on generic shared semantic knowledge, is rapidly extracted from visual inputs and is sufficient to drive rapid category decisions. Subsequent recurrent neural activity between the anterior temporal lobe and posterior fusiform supports the formation of object specific semantic representations - a conjunctive process primarily driven by the perirhinal cortex. These object-specific representations require the integration of shared and distinguishing object properties and support the unique recognition of objects. We conclude that a valuable way of understanding the cognitive activity of the brain is though testing the relationship between specific cognitive measures and dynamic neural activity. This kind of approach allows us to move towards uncovering the information processing states of the brain and how they evolve over time. PMID- 25745633 TI - Developing and Selecting Auditory Warnings for a Real-Time Behavioral Intervention. AB - Real-time sensing and computing technologies are increasingly used in the delivery of real-time health behavior interventions. Auditory signals play a critical role in many of these interventions, impacting not only behavioral response but also treatment adherence and participant retention. Yet, few behavioral interventions that employ auditory feedback report the characteristics of sounds used and even fewer design signals specifically for their intervention. This paper describes a four-step process used in developing and selecting auditory warnings for a behavioral trial designed to reduce indoor secondhand smoke exposure. In step one, relevant information was gathered from ergonomic and behavioral science literature to assist a panel of research assistants in developing criteria for intervention-specific auditory feedback. In step two, multiple sounds were identified through internet searches and modified in accordance with the developed criteria, and two sounds were selected that best met those criteria. In step three, a survey was conducted among 64 persons from the primary sampling frame of the larger behavioral trial to compare the relative aversiveness of sounds, determine respondents' reported behavioral reactions to those signals, and assess participant's preference between sounds. In the final step, survey results were used to select the appropriate sound for auditory warnings. Ultimately, a single-tone pulse, 500 milliseconds (ms) in length that repeats every 270 ms for 3 cycles was chosen for the behavioral trial. The methods described herein represent one example of steps that can be followed to develop and select auditory feedback tailored for a given behavioral intervention. PMID- 25745634 TI - Standardized test for anti-Tr/DNER in patients with paraneoplastic cerebellar degeneration. AB - OBJECTIVE: To determine sensitivity and specificity of a standardized recombinant cell-based indirect immunofluorescence assay (RC-IFA) for anti-Tr antibodies in comparison to a reference procedure. METHODS: Delta/Notch-like epidermal growth factor-related receptor (DNER) was expressed in HEK293 and used as a substrate for RC-IFA. HEK293 control cells expressing CDR2/Yo and CDR2L as well as mock transfected HEK293 cells were used as controls. Serum samples from 38 patients with anti-Tr antibodies (33 with paraneoplastic cerebellar degeneration [PCD] and Hodgkin lymphoma), 66 patients with anti-Tr-negative PCD, 53 patients with Hodgkin lymphoma without neurologic symptoms, 40 patients with rheumatic diseases, and 42 healthy blood donors were tested for anti-DNER reactivity in the RC-IFA. In addition, RC-IFA results were compared to those from a commercial tissue-based IFA using monkey cerebellum. RESULTS: Using the RC-IFA, anti-DNER was detected in all anti-Tr-positive patients but in none of the controls (sensitivity 100%, 95% confidence interval [CI] 92.8%-100%; specificity 100%, 95% CI 98.7%-100%). In comparison, anti-Tr was not detected in 4 samples with low titer autoantibodies using the commercial tissue-based assay. Preadsorption of sera with either recombinant full-length DNER or its extracellular domain selectively abolished anti-Tr reactivity. CONCLUSION: Anti-Tr antibodies bind to the extracellular domain of DNER and can be detected by RC-IFA using HEK293 cells expressing the recombinant receptor. The new method performs better than a frequently used commercial tissue-based indirect immunofluorescence assay (IFA) in samples with low-titer antibodies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RC-IFA accurately detects anti-Tr as compared to conventional IFA. PMID- 25745635 TI - Characterization of B cells in muscle-specific kinase antibody myasthenia gravis. AB - OBJECTIVE: To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). METHODS: In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell-activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures. RESULTS: As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naive, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease. CONCLUSIONS: We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody-positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG. PMID- 25745636 TI - Complete remission of critical neurohistiocytosis by vemurafenib. AB - OBJECTIVE: To describe a patient with life-threatening brainstem neurohistiocytosis who recovered completely upon targeted treatment with the V600E mutation-specific BRAF inhibitor vemurafenib. METHODS: We report clinical, histiologic, genetic, and sequential imaging findings, including fluorodeoxyglucose (FDG)-PET, over a follow-up period of 11 months. RESULTS: The patient presented with central hyperventilation, skeletal and perirenal Erdheim Chester disease, and cutaneous Langerhans cell histiocytosis. A BRAF V600E hotspot mutation was detected in all afflicted tissues. Therapy with vemurafenib led to complete and stable clinical remission of CNS lesions and systemic disease that could be demonstrated by brain MRI and whole-body FDG-PET. CONCLUSIONS: Neurologic involvement in Erdheim-Chester disease usually confers a poor prognosis. In this patient, vemurafenib was well-tolerated and highly efficacious for severe brainstem involvement in Erdheim-Chester disease with overlapping Langerhans cell histiocytosis. This case illustrates the heterogeneous phenotypic spectrum of neurohistiocytosis and underscores the importance of genetic testing. CLASSIFICATION OF EVIDENCE: This article provides Class IV evidence. This is a single observational study without controls. PMID- 25745637 TI - Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally. AB - OBJECTIVE: We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment. METHODS: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 * 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2-3 months. RESULTS: The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3-6 month period. CONCLUSIONS: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes. PMID- 25745639 TI - Current Themes in Understanding Children's Emotion Regulation as Developing from within the Parent-Child Relationship. AB - A large existing literature has established that children's emotion regulation (ER) behaviors and capacities emerge from within the parent-child relationship. This review identified very recently published studies that exemplify contemporary themes in this area of research. Specifically, new research suggests that the influence of fathers, above and beyond that of mothers, becomes more pronounced across development. Further, culture influences how parents socialize emotion and how specific parenting behaviors relate to children's developing ER. Lastly, studies find child-elicited effects, such that children's ER predicts parents' emotion socialization and other relevant behaviors. We suggest several future directions, including understanding the nature of situations that elicit ER patterns, as well as both expanding upon and integrating the areas highlighted in the review. PMID- 25745638 TI - Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells. AB - TGF-beta/Smads signaling plays a significant role in the regulation of growth of normal and prostate cancer cells. Smad proteins function as important mediators of intracellular signal transduction of transforming growth factor-beta (TGF beta). TGF-beta signaling pathway is known to regulate cell proliferation, differentiation, apoptosis and play a major role in some human diseases and cancers. Following their phosphorylation by TGF-beta receptor-I, Receptor regulated Smads (including Smad2 and Smad3 proteins) form a heteromeric complex with co-Smad (Smad4) and then translocate into the nucleus where they bind and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in majority of prostate cancers. Over-expression of full length or truncated ERG proteins have been shown to associate with a higher rate of recurrent and unfavorable prognosis of prostate cancer. In order to understand how ERG oncoprotein regulates TGF-beta/Smads signaling pathway, we have studied the effect of ERG on TGF-beta/Smad3 signaling pathway. In this study, we demonstrate that ERG oncoprotein physically interacts with Smad3 protein and stabilizes phospho-Smad3 protein and thereby enhance TGF-beta/Smad3 signaling pathway in prostate cells. Thus, ERG oncoprotein plays an important role in prostate tumorigenesis by using a novel mechanism to activate TGF beta/Smad3 signaling pathway. PMID- 25745641 TI - The Ontology-Epistemology Divide: A Case Study in Medical Terminology. AB - Medical terminology collects and organizes the many different kinds of terms employed in the biomedical domain both by practitioners and also in the course of biomedical research. In addition to serving as labels for biomedical classes, these names reflect the organizational principles of biomedical vocabularies and ontologies. Some names represent invariant features (classes, universals) of biomedical reality (i.e., they are a matter for ontology). Other names, however, convey also how this reality is perceived, measured, and understood by health professionals (i.e., they belong to the domain of epistemology). We analyze terms from several biomedical vocabularies in order to throw light on the interactions between ontological and epistemological components of these terminologies. We identify four cases: 1) terms containing classification criteria, 2) terms reflecting detectability, modality, uncertainty, and vagueness, 3) terms created in order to obtain a complete partition of a given domain, and 4) terms reflecting mere fiat boundaries. We show that epistemology-loaded terms are pervasive in biomedical vocabularies, that the "classes" they name often do not comply with sound classification principles, and that they are therefore likely to cause problems in the evolution and alignment of terminologies and associated ontologies. PMID- 25745642 TI - Rigid Registration of Echoplanar and Conventional Magnetic Resonance Images by Minimizing the Kullback-Leibler Distance. AB - Functional Magnetic Resonance Imaging (fMRI) studies are derived from a time series of Echo-Planar images (EPIs). Compared to conventional Magnetic Resonance Images (MRIs), EPIs are of relatively poor quality for discerning anatomic features and are often registered with corresponding MRIs to map brain activity to neuroanatomy. In this paper we demonstrate the utility of a technique to register an EPI-MRI pair by minimizing the discrepancy between its joint intensity probability mass function (PMF) and a previously learned one for a properly registered EPI-MRI pair, using the Kullback-Leibler Distance (KLD). In probing experiments Joint Entropy (JE) and Mutual Information showed significant bias relative to KLD along the axial direction and JE along a rotation axis. A comparison of searches using random starting poses showed KLD to have lower final pose errors than JE. Results of variation on parameters of the KLD based EPI-MRI registration technique are also presented. PMID- 25745640 TI - The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging. AB - Mitochondrial dysfunction is an important factor in the pathogenesis of age related diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane - 40 kD (TOMM40) is associated with risk and age-of onset of late-onset AD, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction. In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer's (AD) and Parkinson's (PD) diseases. All but 36 of the >~1,500 mitochondrial proteins are encoded by the nucleus and are synthesized on cytoplasmic ribosomes, and most of these are imported into mitochondria through the TOM complex, of which TOM40 is the central pore, mediating communication between the cytoplasm and the mitochondrial interior. APP enters and obstructs the TOM40 pore, inhibiting import of OXPHOS-related proteins and disrupting the mitochondrial redox balance. Other pathogenic proteins, such as Abeta and alpha-synuclein, readily pass through the pore and cause toxic effects by directly inhibiting mitochondrial enzymes. Healthy mitochondria normally import and degrade the PD-related protein Pink1, but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin-mediated mitophagy. Under normal circumstances, this process helps clear dysfunctional mitochondria and contributes to cellular health, but PINK1 mutations associated with PD exit mitochondria with intact membrane potentials, disrupting mitochondrial dynamics, leading to pathology. Thus, TOM40 plays a central role in the mitochondrial dysfunction that underlies age-related neurodegenerative diseases. Learning about the factors that control TOM40 levels and activity, and how TOM40, specifically, and the TOM complex, generally, interacts with potentially pathogenic proteins, will provide deeper insights to AD and PD pathogenesis, and possibly new targets for preventative and/or therapeutic treatments. PMID- 25745643 TI - Trends in weighted vital signs and the clinical course of 44,531 acutely ill medical patients while in hospital. AB - BACKGROUND: little is known about the changes and trends of individual vital signs during the course of acute illness in hospital. METHODS: the weighted points of the VitalPAC Early Warning Score (ViEWS) were assigned to each vital sign value measured on 44,531 acutely ill medical patients while they were hospitalized in the Thunder Bay Regional Health Sciences Centre, Ontario, Canada. These ViEWS weighted vital signs were averaged for every 24 hour period for five days after admission and five days before death or discharge and then combined to obtain an approximation of the trajectory of each vital sign while in hospital. RESULTS: compared with the other vital signs, the ViEWS weighted points for respiratory rate increase the most in patients who died in hospital and decrease the most in survivors. Combining respiratory rate with the weighted points for any of the other vital signs reduced rather than increased their monitoring performance. CONCLUSION: trends in respiratory rate, measured by observation at the bedside and given a ViEWS weighting is the best predictor of clinical outcome; minor changes predicted clinical outcome several days in advance. PMID- 25745644 TI - Are hospital admissions reduced by Acute Medicine consultant telephone triage of medical referrals? AB - The NHS in England is facing well-documented pressures related to increasing acute hospital admissions at a time when the acute medical bed-base is shrinking, doctors working patterns are increasingly fragmented and many acute hospital trusts are operating a financial deficit. Novel strategies are required to reduce pressure on the acute medical take. We conducted a prospective cohort study to assess the impact of acute medicine consultant triage of referrals to the acute medical take on the number of acute hospital admissions as compared to a historical control cohort. The introduction of an acute medicine consultant telephone triage service was associated with a 21% reduction in acute medical admissions during whole the study period. True admission avoidance was achieved for 28.5% of referrals triaged by an acute medicine consultant. The greatest benefit was seen for consultant-triage of GP referrals; 43% of all GP referrals resulted in a decision not to admit and in 25% the referral was avoided by giving advice alone. Consultant telephone triage of referrals to the acute medical take substantially reduces the number of acute medical admissions as compared to triage by a trained band 6 or higher nurse coordinator. Our service is cost effective and can be job-planned using 6 full-time equivalent acute medicine consultants. The telephone triage service also provides additional benefits to admission numbers beyond its hours of operation and the general management of the acute medical take. PMID- 25745645 TI - What is an acute medicine registrar? A qualitative investigation into trainee self-perception and identity. AB - OBJECTIVES: This paper explores the experiences and attitudes of acute medicine trainees regarding their own identity and function within hospital medicine, with a view to developing a coherent theoretical framework describing the identity of the acute medicine registrar. METHODS: Three focus groups involving 17 acute medicine registrars were carried out. Video recordings of the discussions were analysed for the purpose of thematic analysis. RESULTS: Qualitative analysis revealed 5 key aspects to the identity of acute medicine trainees. Novel findings were of trainees' perceptions of being poorly understood by other specialties, and of being the lead decision maker, particularly out-of-hours. CONCLUSIONS: By gaining insight into the identity and core beliefs of AIM trainees, we are better equipped to make decisions regarding the future of acute medicine. PMID- 25745646 TI - Ovarian hyperstimulation syndrome on the acute medical unit: a problem-based review. AB - Ovarian Hyperstimulation Syndrome (OHSS) is a spectrum of clinical features typically resulting from assisted conception techniques. With 2.35% of all live births in the UK resulting from in-vitro fertilisation (IVF), OHSS is on the rise. Moreover, there has been an increase in the presentation of its complications to GP surgeries and unscheduled acute care services nationwide. This review will discuss signs and symptoms of the increasingly common and potentially fatal complications of OHSS, namely pleural effusion, ascites and thromboembolic events. With such propensity toward critical, life-threatening events it is not only prudent to recognise the population at risk, but also to be aware of the signs, symptoms and complications to expedite treatment and ensure optimum outcome. PMID- 25745647 TI - Pulmonary embolism in a patient with "isolated syncope", a diagnostic challenge. AB - Syncope is a recognized presenting symptom in patients with pulmonary embolism (PE), and is more common in older patients and following a large embolus. Isolated syncope, in the absence of dyspnea or tachycardia, is uncommon in this setting, and may be misdiagnosed as cardiac in origin, leading to a delay in appropriate treatment. We present a case which illustrates the importance of consideration of pulmonary embolism in the differential diagnosis of patients presenting with syncope, and the value of echocardiography in its diagnosis. PMID- 25745648 TI - An unusual presentation of Lyme neuroborreliosis. AB - Back pain is a common symptom among patients presenting to the acute medical unit. We describe the case of a 55-year-old man with a brief history of fatigue and severe back pain, unresponsive to escalating doses of opiate analgesia. Blood tests and imaging studies were unremarkable and a functional diagnosis was considered. Several weeks into his admission he developed a lower motor neurone facial nerve palsy. He was treated with antibiotics for an incidental finding of a hospital-acquired pneumonia on imaging, which remarkably led to the resolution of his facial palsy and allowed a dramatic reduction in analgesia. This triggered further investigations; identifying Lyme neuroborreliosis as the cause of his symptoms. PMID- 25745649 TI - Ultrasound in Rheumatology: two decades of rapid development and evolving implementation. PMID- 25745651 TI - Anatomical variation of the liver with elongated left lobe may be a trap for the ultrasound detection of focal liver lesion. AB - AIMS: The aim of this study was to evaluate the impact of anatomical variations of the elongated left lobe of the liver on the ultrasound detection of focal liver lesions. MATERIALS AND METHODS: We evaluated, by ultrasonography (US), 296 patients with elongated left lobe of the liver and 30 patients with focal lesions in the normal length left lobe of the liver. Those patients had undergone prior computed tomography (CT) evaluation. RESULTS: Of the 296 patients evaluated, 34 patients had focal lesions (the size range 11- 20 mm) in the distal region of the elongated left lobe of the liver, and none of the lesions was visualized at US examination (p<0.001). All the focal lesions in the normal length left lobe of the liver of the 30 patients were visualized by US without significant difference between the dimensions established by CT and US (p=0.136). CONCLUSION: Focal lesions in the distal region of elongated left lobe of the liver are difficult to be detected by conventional US examination and the main reason is the impact of anatomical localization on the examination protocol. PMID- 25745650 TI - Value of hepatic elastography and Doppler indexes for predictions of esophageal varices in liver cirrhosis. AB - AIMS: Non-invasive methods are required to diagnose presence and grading of esophageal varices in patients with hepatic cirrhosis and in this respect we have evaluated the role of transient elastography and abdominal ultrasound parameters. MATERIAL AND METHODS: Cirrhotic patients were prospectively evaluated by transient elastography and Doppler ultrasound for diagnosis of presence and grading of esophageal varices, the results being compared with the findings of the esophagogastroduodenoscopy. RESULTS: Sixty patients with hepatic cirrhosis were analysed. The parameters that reached statistical significance for diagnosis of esophageal varices were: liver stiffness (LSM) > 15 kPa, hemodynamic liver index (PVr1) >/= 0.66, portal vascular resistance (PVR) > 17.66 and splenoportal index (SPI) > 4.77. The only parameter that reached statistical power for the diagnosis of large esophageal varices was LSM at a cut-off value of 28.8 kPa. CONCLUSIONS: Assessment of LSM in patients with liver cirrhosis can predict both the presence of esophageal varices and of large esophageal varices. The PVr1, PVR and SPI Doppler indexes can be used to diagnose the presence of esophageal varices but have no role in the prediction of large esophageal varices. Further studies are required to confirm these results and offer a stronger clinical significance. PMID- 25745652 TI - The value of contrast-enhanced ultrasound in the characterization of vascular pattern of solid pancreatic lesions. AB - The AIM of our study was to evaluate the accuracy of CEUS in the characterization of pancreatic solid lesions, considering cross sectional imaging techniques (CE CT/MRI) as the "gold standard" methods. MATERIAL AND METHODS: We performed a retrospective, monocentric study that included 91 solid pancreatic lesions which were evaluated by CEUS and by a second-line contrast imaging technique (CT or MRI), considered as the reference method. RESULTS: The rate of a conclusive diagnosis based on a typical enhancement pattern was 94% (78/83 cases). In 72 cases out of 83 (86.7%) there was a perfect concordance between CEUS and the "gold-standard" imaging method (CE-CT/MRI). In our study, 88% (73/83) of the pancreatic lesions were categorized as malignant due to their typical wash-out aspect in the late phase. The overall accuracy of CEUS for the differential diagnosis of solid pancreatic tumors was approximately 81%. The accuracy of CEUS for the diagnosis of hypoenhancing pancreatic tumors was approximately 89.1%; while for the diagnosis of hyperenhancing pancreatic tumors it was approximately 72.8%. CONCLUSION: CEUS allows the differentiation between hypo- vs. hyperenhancing pancreatic solid lesions, with a considerable diagnostic accuracy, a fundamental step in the precise diagnosis of pancreatic tumors. PMID- 25745653 TI - A comparison between gastroesophagheal ultrasonography vs. barium swallow in determining the pattern of gastroesophageal reflux in a pediatric population. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal pathology in infants and young children. Ultrasonography (US) has been considered to be a reliable diagnostic tool for GERD but the severity of GERD and the clinical implications based on imaging findings has not been evaluated. AIMS: To compare the diagnostic value of lower esophageal US with that of barium swallow in demonstrating the severity of GERD. MATERIALS AND METHODS: Fifty one pediatric patients, age between 1 month to 12 years, 34 male and 17 female with clinical suspicion of GERD were included. The patients were initially submitted to barium swallow (BS) and subsequently to transabdominal US. During BS, the number of gastroesophageal reflux episodes was documented in a 5-minute period. Transabdominal US documented the number and duration of reflux episodes during a 5-minute period, the angle of His, mucosal thickness, and intraabdominal esophageal length (IAEL). RESULTS: Duration and number of reflux episodes in US were significantly higher in patients that had severe gastroesophageal refluxes at BS. At US the cutoff point of 9.5 seconds (sensitivity 80%, specificity 60%) for reflux duration and more than 2 episodes in 5 minute ultrasound study (sensitivity 75%, specificity 58%) were defined to correlate with severe gastroesophageal reflux at BS.The angle of His, the esophageal wall mucosal thickness, and the IAEL did not correlate with the severity of GERD detected in BS. CONCLUSION: US can predict the severity of GERD. Therefore, except in the case of specific patients in whom mechanical causes are suspected to be responsible for GERD, BS can be replaced by US. PMID- 25745654 TI - The use of ultrasonography in infantile hypertrophic pyloric stenosis: does the patient's age and weight affect pyloric size and pyloric ratio? AB - AIMS: We aimed to obtain pyloric measurements of our patients with infantile hypertrophic pyloric stenosis (IHPS) using ultrasonography (US) and to evaluate the correlations between age, weight and pyloric size, pyloric ratio (PR). MATERIAL AND METHODS: We designed a retrospective study including 20 term infants with surgically proven IHPS and studied the ultrasonographically obtained pyloric muscle thickness (PMT), pyloric diameter (width) (PD), pyloric length (PL) and PR (PMT/PD) to determine if there were statistically significant associations between patient age/weight and pyloric measurements. RESULTS: The mean age of the infants was 38.7+/-17.3 days (range, 9-76 days) and their mean weight was 3688.5+/-772.7 g (range, 2810-6000 g), at referral. Mean PMT was 4.98+/-1.04 mm (range, 3.5-6.8 mm). Mean PD was 14.04+/-2.39 mm (range, 10-18 mm). Mean PL was 22.16+/-4.02 mm (range, 16-31.5 mm) and mean PR was 0.35+/-0.04 (range, 0.29 0.42). The correlation between age and PMT (r=0.654, p<0.05) and the correlation between age and PD (r=0.747, p <0.05) were significant. Age and weight were not significantly correlated with PR (p>0.05). CONCLUSIONS: The PMT and PD are age dependent parameters. The PR is age and weight independent and therefore, when combined with PMT, PD and PL, it can be useful in the diagnosis of IHPS in infants with early onset disease and/or in those with a lower weight. PMID- 25745655 TI - The utility of 40 MHz periodontal ultrasonography in the assessment of gingival inflammation evolution following professional teeth cleaning. AB - The AIM of this study was to evaluate the usefulness of 40 MHz periodontal ultrasonography in the assessment of gingival inflammation, following professional teeth cleaning. MATERIAL AND METHODS: The study was performed on 18 teeth without restorations having subgingival calculus (upper and lower premolars and frontal teeth). After the clinical exam the Gingival Index and the Sulcus Bleeding Index were calculated. Then a 40MHz transducer (ULTRASONIX SonoTouch device) was used to obtain longitudinal sections in the frontal plane. Three measurements were performed: alveolar crest - cementum-enamel junction distance (ACJ), gingival height (GH), and gingival width (GW). Professional cleaning was performed by ultrasound scaling (SatelecP5 booster, France) and airflow (NSK, Japan). Two and seven days after the first evaluation, ultrasonographic and clinical examinations were repeated. RESULTS: Two days after the treatment the median value of the ACJ, was 2.70 (2.38; 2.95) mm, whereas 7 days after treatment it was 2.55 (2.45; 3.01) mm. The intraclass correlation coefficient for ACJ measurement was 98.8 (p<0.001).The values obtained measuring GH [3.84(3.44; 4.27) mm vs. 3.52 (3.00; 3.76) mm] and GW [(1.81 (1.65; 1.95) mm vs.1.62 (1.40; 1.95) mm) had statistically significant differences between the 2nd and 7th day. CONCLUSIONS: Periodontal ultrasonography is a highly precise and reproducible imagistic method, with which bone resorption, gingival inflammation as well as the presence or absence of subgingival calculus can be assessed. PMID- 25745656 TI - Radiologic findings of idiopathic granulomatous mastitis. AB - AIM: To describe the radiological findings of idiopathic granulomatous mastitis (IGM). MATERIAL AND METHODS: Radiologic findings of 30 women with histopathological diagnosis of IGM were retrospectively evaluated. All had breast feeding history. All the patients had ultrasonography (US), with 12 of them having additional Doppler US. Of 30 patients, 11 had mammography (MG) and 5 MRI. RESULTS: US showed multiple irregular hypoechoic masses and collection areas with tubular connections in 25 of 30. The collection area with low-level internal echoes but without tubular connections, suggesting an abscess were seen in 2 of 30 (6.6%); a hypoechoic mass with an indistinct border in 2 of 30 (6.6%); multiple milimetric hypoechoic nodular masses in 1 of 30 (3.3%). On MG, normal findings were noted in 5 (45.4%); focal asymmetric density in 4 (36.4%), parenchymal distortion in 1 (9%) and diffuse asymmetric opacity with trabecular thickening in 1 (9%) of 30 patients. On MRI, segmental T2 hyperintensity with contrast-enhancement on T1 were seen in 4 of 5 (80%). An enhancing T2 hypointense mass with irregular margin was present in 1 of 5 (20%). Time-signal intensity curve of lesions showed slow enhancement in 1 and moderate in 4 of 5 patients. CONCLUSIONS: In IGM, MG findings were nonspecific. In US, multiple irregular hypoechoic masses and collections with tubular connections with fingerlike aspects, and fistulae formation to the skin in patients with breastfeeding history suggested IGM rather than carcinoma. Due to the limited number of patients, no conclusion was reached regarding MRI of IGM. PMID- 25745657 TI - The evaluation of the retrobulbar orbital fat tissue and optic nerve with strain ratio elastography. AB - AIM: The aim of this study was to evaluate the diagnostic performance of strain ratio elastography in the assessment of retrobulbar orbital fat tissue. MATERIALS AND METHODS: The retrobulbar fat tissue of 14 eyes in 14 participants was scanned by sonoelastography. All the participants had permanent vision loss secondary to glaucoma in at least one eye. The elasticity scores were determined and the strain ratio was based on the comparison of the average strain measured in the retrobulbar fat tissue around the optic nerve at the same depth. RESULTS: The mean strain values for the optic nerve (B) and the retrobulbar fat tissue (A) were 0.78+/-0.61 and 1.43+/-0.99, respectively (p=0.005). The mean strain ratio (B/A) was 0.56+/-0.24. CONCLUSION: This preliminary study showed that by providing strain values and ratios of different orbital tissues sonoelastography may have a potential use in the diagnosis and follow-up of orbital inflammatory and infiltrative diseases. PMID- 25745658 TI - Acoustic Radiation Force Impulse (ARFI) elastography quantification of muscle stiffness over a course of gradual isometric contractions: a preliminary study. AB - AIMS: To evaluate the feasibility of quantitative analysis of muscle stiffness by Acoustic Radiation Forced Impulse (ARFI) elastography over a course of graduate isometric voluntary contractions. MATERIAL AND METHODS: The stiffness of the bilateral biceps muscle of 13 healthy volunteers was measured in real time by ARFI elastography, while the forearm was in neutral-extended position, 90 degree self-flexed positions and 90 degree self-flexed position, with altered weights ranging from 1 to 8 kg placed on flattened palmar surfaces consecutively. The determined increases in biceps muscle stiffness were measured for both arms and correlated with the loadings weights adopted at progressive trial stages. RESULTS: The mean shear wave velocity (SWV) values of biceps muscles in a neutral position, in 90 degree flex position and 90 degree flex position with 1 to 8 kg weights on palmar surfaces were 2.162+/-0.302 m/sec, 3.382+/-0.581 m/sec, and 3.897+/-0.585 to 5.562+/-0.587 m/sec, respectively. Significant correlations between the muscle SWV values and related palmar weights and between the SWV values of right and left sides at different trial stages were identified (r=0.951 and r=0.954, respectively). A mutual propagation path of deep regions to entire areas was described to account for the distribution of increase in stiffness with increases in palmar weights. The confidence of method regarding inter-observer difference was confirmed by the correlation analyses of the results (r=0.998). CONCLUSIONS: ARFI elastography is a feasible imaging modality for quantifying the stiffness of isometrically voluntarily contracting muscles. PMID- 25745659 TI - Sonoelastographic assessment of the age-related changes of the Achilles tendon. AB - AIMS: Tendons are crucial for optimal muscle force transfer and subject to changes with aging which may impair functional ability of elderly individuals. Achilles is the largest and the strongest tendon in the body; therefore it is an excellent site for the radiologic investigation of aging of tendons. Sonoelastography (SE) is a new ultrasound-based imaging technique that provides information on elastic properties and stiffness of tissues. The aim of our study was to investigate the age-related alterations in Achilles tendons using SE. MATERIAL AND METHODS: Forty five geriatric (age >= 65 years) and 42 young (age 18 40 years) healthy consecutive subjects were enrolled. Subjects with known history of metabolic or endocrine diseases, sports or traumatic injuries, peripheral vascular disorders were excluded. Both Achilles tendons were scanned with a real time SE probe at a frequency of 6-15 MHz. Strains of Achilles tendons' proximal, middle and distal parts were assessed semi-quantitatively with comparing a reference tissue. RESULTS: Both SE methods -color coded evaluation and strain measurement- showed a remarkably stiffer tendon in the elderly subjects compared to young subjects in all thirds of Achilles tendons. In young subjects 84.9 % tendon thirds were blue, and 15.1% were green whereas, in elders 93.7% were blue and 6.3% were green (p=0.024). There was a significant correlation between age and stiffness of tendons assessed with strain indices. CONCLUSION: Our result showed increased tendon stiffness in elderly subjects which might be responsible for the high prevalence of Achilles tendinopathies observed in elderly subjects. PMID- 25745660 TI - Oral and I.V. contrast enhanced ultrasonography of the digestive tract--a useful completion of the B-mode examination: a literature review and an exhaustive illustration through images. AB - Contrast enhanced ultrasonography, using i.v. and/or oral/rectal contrast agents, represents a technical development of the US method, which has proved its applicability in the qualitative and quantitative assessment of the normal and pathological circulatory bed, as well as of the digestive lumen. The use of microbubbles and harmonics opens a new horizon in the detection and characterization of the inflammatory and tumoral conditions of the digestive tract. The interpretation of the data requires corroboration with the grey scale aspect of the examined lesion/area, as well as with the clinical context of the case and the results of other diagnosis techniques. The purpose of this paper is to review the main applications of CEUS in digestive tract pathology by analyzing the significant literature and guidelines in the light of our personal experience and demonstrating it through suggestive images. PMID- 25745661 TI - Ultrasound elastography in thyroid disease. AB - Thyroid elastography has become, lately, one of the main focuses in thyroid imaging. With more than one hundred papers published on this subject, the core of accumulated knowledge justifies the need for a comprehensive review on the topic. The paper presents the various elastographic techniques used for thyroid assessment. Both strain and shear wave elastography, with all their variants, are discussed. Thereafter the paper proceeds to a detailed description of the technical peculiarities, diagnostic value, limitations and pitfalls for each technique. Although the main accent is placed on thyroid nodules, the applications of elastography in other thyroid disease, diffuse or focal, are also presented. The results of the available metaanalyses are reviewed and the proven value of the technique is highlighted. Still unanswered questions and directions for future research are emphasized, whenever appropriate. PMID- 25745662 TI - Is ultrasound changing the way we understand rheumatology? Including ultrasound examination in the classification criteria of polymyalgia rheumatica and gout. AB - Ultrasonography (US) is widely used in the diagnosis of rheumatic conditions, and its value for the classification criteria of rheumatic diseases has been recently suggested. According to the EULAR/ACR provisional criteria for polymyalgia rheumatica, adding US to the clinical and serological features will significantly improve the sensitivity of proposed criteria. The ability of high resolution US to detect crystalline deposits of monosodium urate in joints and soft tissues is well recognized. For the first time, the new 2014 ACR/EULAR set of proposed criteria for gout includes advanced imaging techniques for the detection of disease: US and dual-energy computed tomography. Due to low costs and affordability, use of US evaluation for patients with suspected gout will increase both specificity and sensibility of classification criteria. The recent inclusion of US in the classification criteria of various rheumatic diseases, such as PMR and gout, implies that this imaging technique is not only useful as a valued diagnostic tool for individual cases, but also on a larger scale, it will improve doctors' ability to classify diseases. Its use is thus changing our understanding of rheumatic diseases allowing further advances in research and clinical practice. PMID- 25745663 TI - Ultrasonographic anatomy of head and neck--a pictorial for the ENT specialist. AB - An increased pressure on ENT departments has evolved as head and neck pathology is showing a higher incidence and prevalence. Therefore, the ENT specialist should develop good skills in ultrasonographic examination of patients with head and neck masses. The aim of this paper is to enable the ENT specialist to identify anatomical landmarks on ultrasonographic images in order to expedite the diagnosis with a higher degree of certainty. We describe the steps for a proper ultrasound examination of the patient. We illustrate the following anatomical areas: submandibular gland, thyroid gland, parathyroid glands, oropharinx, larynx, parotid glands, etc. Moreover we emphasize the differential diagnosis that should be taken into account when examining pathology in these regions. Ultrasonographic examination of head and neck pathology is cost efficient, non irradiating and permits fast follow up with serial examination of the lesions. Furthermore one can perform an initial TNM staging of the case prior to other expensive imaging studies such as CT and MRI. We hope to raise the awareness of fellow ENT specialists in performing ultrasonography as future developments such as elastography and CEUS will increase the specificity and sensitivity of this diagnostic method. PMID- 25745664 TI - Assessment of fetal malformations in the first trimester of pregnancy by three dimensional ultrasonography in the rendering mode. Pictorial essay. AB - We present our experience in the contribution of three-dimensional ultrasonography, using the rendering mode, to the prenatal diagnosis of congenital anomalies including neurological defects (acrania/anencephaly, encephalocele, holoprosencephaly), facial anomalies (cyclopia and facial clefts), abdominal wall defects (omphalocele and gastroschisis) and defects of extremities (fetal muscle-skeletal dysplasias). Three-dimensional ultrasonography may contribute to improve the prenatal diagnosis with further revision of the fetal images, allowing a better prenatal counsel to the parents. PMID- 25745665 TI - Prenatal diagnosis of congenital high airway obstruction syndrome (CHAOS). Five case report. AB - Congenital high airway obstruction syndrome (CHAOS) is an extremely rare life threatening condition. Laryngeal atresia appears to be the most frequent cause. Generally the diagnosis is made with severely enlarged and highly echogenic lungs and additional ultrasound findings. The prognosis of the affected infants is often poor. Five cases are reported here that were diagnosed in a tertiary center between 2008 and 2014. PMID- 25745666 TI - Ultrasound and CT imaging features in a patient with salivary duct carcinoma of the parotid gland: a case report with literature review. AB - The aim of this paper was to present the ultrasound (US) and computed tomography (CT) appearance of a patient with salivary duct carcinoma of the parotid gland. US showed a voluminous mass of the parotid gland, with multiple calcifications. Furthermore, it revealed regional multiple lymph nodes with malignant characters. Sonoelastography of the lesion and lymph nodes detected increased rigidity. Contrast enhanced CT scan of the neck completed the data description regarding the mass expansion and invasion of surrounding tissues. US and CT imaging features played a key role in establishing the malignant character of the mass and lymph nodes. PMID- 25745667 TI - Cardiac amyloidosis with gastrointestinal involvement: a case report. AB - Familial amyloidosis is a rare type of amyloidosis, difficult to diagnose. We present the case of a woman with chronic heart failure. Low ejection fraction and concentric left ventricle hypertrophy with granular sparkling were seen by echocardiography and cardiac magnetic resonance imaging. Based on myocardial biopsy and genetic tests, the diagnosis of transthyretin familial amyloidosis, secondary to the Glu54Gln gene mutation, was made. The presentation contains the diagnostic algorithm used in the case of our patient, including clinical, biochemical, imaging, histological and genetic examinations, for the purpose of a complete diagnosis. PMID- 25745668 TI - Cystic schwannoma of the axillary region: imaging findings of a rare disease. Case report. AB - Schwannomas are well capsulated, benign, and slowly growing tumors which originate from Schwann cells of peripheral nerve sheath. The incidence of schwannomanas in the axillary region is not common. This rarity causes misdiagnosis at the radiological evaluation. In this case we present the imaging and histopathological findings of a cystic schwannoma located in the axillary fossa of a 47-year-old female patient mimicking complex cyst, lymphadenopathy or hydatid cyst in radiological evaluation. Although lymphadenopathy, lymphatic malformation, lipoma, cyst, hidradenitis suppurativa or dermatofibroma are the most frequent lesions to be considered, peripheral nerve sheath should also be kept in mind in the differential diagnosis of axillary masses. PMID- 25745669 TI - Intraductal papillary mucinous neoplasia--a challenging diagnosis in a patient with paraneoplastic rheumatoid arthritis. Case report. AB - Intraductal papillary mucinous neoplasias (IPMNs) of the pancreas are potentially malignant tumors, and associated also with extrapancreatic carcinomas. We present the case of a 80 year old man with IPMN and late onset of rheumatoid arthritis. The particularity of this case is the discordance between the clinical picture and the imaging worrisome features, together with the surgery-requiring mixed type of IPMN, despite the late possible paraneoplastic onset of rheumatoid arthritis. PMID- 25745670 TI - Real-world carbon nanoparticle exposures induce brain and gonadal alterations in zebrafish (Danio rerio) as determined by biospectroscopy techniques. AB - Carbon-based nanoparticles (CNPs) have emerged as novel man-made materials with diverse applications, which may present significant risks to organisms. To bridge the gap in our knowledge of nanotoxicology, a number of in vitro or in vivo studies have been carried out. However, toxicity data remains limited. Herein, we employed a biospectroscopy approach to assess CNP-induced effects in zebrafish (Danio rerio). Zebrafish were exposed to Fullerene (C60), long or short multi walled carbon nanotubes (MWCNTs), or single-walled carbon nanotubes (SWCNTs) for 21 days at two concentrations: 0.1 mg L(-1) or 0.001 mg L(-1). Following exposure, the brain, gills, gonads and liver from zebrafish were interrogated by attenuated total reflection Fourier-transform infrared (ATR-FTIR) or Raman spectroscopy. Computational analysis was then applied to the acquired infrared (IR) spectra, and distinct biochemical segregations between the exposed tissues vs. control were observed with spectral biomarkers of alterations identified. In addition, lipid-to-protein ratios in all four tissues were calculated by the IR spectra; unsaturated lipid levels in brain and gonad were assessed by Raman spectroscopy. Marked lipid alterations were observed. These findings show that biospectroscopy approaches have the potential to detect CNP-induced biochemical alterations in zebrafish. PMID- 25745671 TI - Exploring Mn-O bonding in the context of an electronically flexible secondary coordination sphere: synthesis of a Mn(III)-oxo. AB - Complexes containing manganese-oxygen bonds have been implicated in a variety of biological and synthetic processes. Herein, we describe the synthesis of a family of stable, high-spin trigonal bipyramidal manganese complexes of the electronically flexible ligand tris(5-cyclohexylimino-pyrrol-2-ylmethyl)amine [H3N(pi(Cy))3] featuring apical water, hydroxyl, and oxo ligands. Terminal Mn(III)-O complexes are rare and the formation of this species was achieved from a variety of reagents including O2, PhIO and NO2(-). Described herein is the preparation, structural and electronic properties of these manganese complexes. PMID- 25745672 TI - An orthogonal C-H borylation--cross-coupling strategy for the preparation of tetrasubstituted "A2B2"-chrysene derivatives with tuneable photophysical properties. AB - The regioselective, orthogonal functionalisation of 4,10-dichlorochrysene enables the synthesis of a variety of 2,8,4,10-"A2B2"-tetrasubstituted chrysenes. Such compounds exhibit broadened UV-vis absorption spectra, decreased band gap and higher HOMO levels compared to the parent chrysene. PMID- 25745673 TI - Computational investigations of the thermodynamic properties of size-selected water and Ar-water clusters: high-pressure transitions. AB - Classical parallel-tempering Monte Carlo simulations in the isothermal-isobaric ensemble were carried out for the (H2O)20 and Ar(H2O)20 clusters, over a wide range of temperatures (30-1000 K) and pressures (3 kPa-10 GPa) in order to study their thermodynamic properties and structural changes. The TIP4P/ice water model is employed for the water-water interactions, while both semiempirical and ab initio-based potentials are used to model the interaction between the rare-gas atoms and the water molecules. Temperature-pressure phase diagrams for these cluster systems were constructed by employing a two-dimensional multiple histogram method. Structural changes were detected by analyzing the heat capacity landscape and the Pearson correlation coefficient profile for the interaction energy and volume. Those at high pressure correspond to solid-to-solid transitions and are found to be related to clathrate-like cages around the Ar atom. It is also shown that the formation and thermodynamic stability of such structures are determined by the intermolecular interaction between the rare-gas atoms and the host water molecules. PMID- 25745674 TI - Kinetics of aggregation in liquids with dispersed nanoparticles. AB - The process of attaching molecules of liquid media by dispersed nanoparticles is modeled and numerically studied. The growth rate of the resulting nanoparticle induced aggregates is determined by assuming the preferential attachment rule according to which the effectiveness of the connection of a new molecular unit to aggregates is determined by their size. It is shown that, depending on a specific functional form of the growth rate, the size distribution of aggregates can display very different shapes, including various multimodal structures. This can explain experimentally obtained complex size distributions of inhomogeneous aggregates appearing as a consequence of the adsorption of molecules by nanoparticles or as a consequence of the self-assembling of active dispersants on surfaces of nanoparticles. The time evolution and the stationarity of the size distribution are also analyzed, gaining an insight into the long-time behavior of systems with dispersed nanoparticles. PMID- 25745675 TI - Facile preparation and enhanced microwave absorption properties of core-shell composite spheres composited of Ni cores and TiO2 shells. AB - Core-shell microspheres with Ni cores and two phases of TiO2 (anatase, rutile) shells have been successfully synthesized. The crystal structure, morphology and microwave absorption properties of the as-prepared composites were analyzed by X ray diffraction, field-emission scanning electron microscopy, energy dispersive X ray spectroscopy, transmission electron microscopy, and vector network analysis. The core-shell rutile TiO2-coated Ni exhibits better antioxidation ability than that of pure Ni due to the presence of the rutile TiO2 shell, which is confirmed by the thermal gravimetric analysis (TGA). In comparison with bare Ni, these two composites show better microwave absorption properties. The minimum reflection loss (RL) is -38.0 dB at 11.1 GHz with a thickness of only 1.8 mm for the Ni@TiO2 (rutile) composite. The enhanced absorption capability arises from the efficient complementarities between the magnetic loss and dielectric loss, multiple interfacial polarization, high thermal conductivity of rutile TiO2 and microwave attenuation constant. These results show that the thin high-efficiency rutile TiO2-coated Ni composite is a great potential microwave absorbing material for practical applications. PMID- 25745676 TI - Information is not knowledge and certainly not wisdom. PMID- 25745677 TI - Soil-transmitted helminthiases: number of children treated in 2013. PMID- 25745678 TI - Ebola virus disease (EVD) in West Africa: an extraordinary epidemic. PMID- 25745679 TI - Author's reply: To PMID 24411550. PMID- 25745680 TI - Author's reply: To PMID 24304982. PMID- 25745681 TI - A history of the Distinguished Service Foundation of Optometry. AB - The Distinguished Service Foundation of Optometry was an organization which sought to encourage research and education to facilitate the conservation of vision through publications and the awarding of medals. It existed from 1927 to 1979, but was most active in the 1930s and 1940s. Its leaders and activities are discussed. PMID- 25745683 TI - Guyton educator of the Year Award. PMID- 25745682 TI - Robert Bannon (1910-1996), optometric practitioner, researcher, and writer. PMID- 25745684 TI - What does peer review need? PMID- 25745685 TI - Success in research at an undergraduate institution. PMID- 25745686 TI - The 2014 APS Intersociety Meeting: comparative approaches to grand challenges in physiology. San Diego, California, October 5-8, 2014. PMID- 25745687 TI - APS updates guiding principles. PMID- 25745688 TI - APS advises NIH on sex as a biologicaI variable. PMID- 25745689 TI - Obituary: Stanley G. Schultz (1931-2014). PMID- 25745690 TI - Interview with David Pollock. PMID- 25745691 TI - Letter to Lois Jane Heller. PMID- 25745692 TI - Christmas and the New Year. 1914. PMID- 25745693 TI - The value of establishing baselines. PMID- 25745694 TI - Health care professionals: opportunities to address social determinants of health. PMID- 25745695 TI - The incidence and demographics of shoulder repair in Wisconsin, 2002-2010. AB - IMPORTANCE: Recent evidence has demonstrated a profound increase in the incidence of shoulder surgery. Superior labral anterior and posterior (SLAP) repair is a common procedure that has been noted in other studies to be increasing. OBJECTIVE: The purpose of this study is to report the incidence and demographics of a single shoulder surgery code in the state of Wisconsin in order to evaluate whether it is being performed in increasing numbers relative to population. METHODS: In a retrospective review of the Wisconsin Hospital Association statewide database for the years 2002-2010, we queried one ICD-9 procedure code: 81.83, other repair of shoulder (not replacement or repair of recurrent dislocation). This code was selected because it would include SLAP repair and exclude most other common shoulder surgeries. The data retrieved includes ICD-9 diagnosis codes, county of surgery, patient age, and gender. RESULTS: The number of surgeries performed in Wisconsin over the course of the study increased by 91.4% between 2002 and 2010, starting at 5649 in 2002 and rising to 10,812 by 2010. The incidence of surgeries increased 83.1% over this time period: from 103.8 per 100,000 in 2002 to 190.1 per 100,000 in 2010. The ratio of male to female surgeries remained nearly constant at 3:2 throughout the length of the study. The mean patient age at time of surgery increased 2.6 years, from 48.3 in 2002 to 50.9 in 2010. CONCLUSIONS: The increase in number of shoulder surgeries is well beyond expectations based on population growth. The relatively high percentage of females does not correspond with reported gender ratios in other studies of similar shoulder procedures. The high mean age of patients and the large number of surgeries in older patients also is concerning. More educational effort needs to be given regarding the diagnosis and treatment of common shoulder conditions. PMID- 25745696 TI - Promoting routine use of developmental and autism-specific screening tools by pediatric primary care clinicians. AB - INTRODUCTION: In 2006, the American Academy of Pediatrics published a policy statement recommending routine developmental screening for all children. Most clinicians at that time were using informal methods to monitor child development. METHODS: Outreach to Wisconsin primary care clinicians designed to promote use of validated developmental screening tools began in 2006. A survey of 157 Wisconsin primary care clinicians was conducted in late 2012 to assess routine use of developmental and autism-specific tools. RESULTS: As compared with a similar survey conducted in 2007, where only 25% of clinicians reported use of a validated developmental screening tool, over 55% of clinicians in this survey reported routine use of validated developmental and autism-specific screening tools within well-child care. CONCLUSION: Outreach to clinicians and their care teams, in conjunction with policy statements from national professional organizations and supporting evidence, can contribute to quality improvement in well-child care delivery. PMID- 25745697 TI - Overall prescription medication use among adults: findings from the Survey of the Health of Wisconsin. AB - PURPOSE: To analyze overall prescription medication use patterns among study participants in a representative statewide sample of Wisconsin adults. METHODS: We analyzed data on 1572 participants from the 2008-2010 cycles of the Survey of the Health of Wisconsin (SHOW). SHOW is a statewide population-based survey that collects health information, including prescription medications, from 21 to 74 year olds. Prescription medication use was examined according to demographic and socioeconomic characteristics. RESULT: Almost 55% of participants reported using at least 1 medication in the past month and 14% reported using at least 5 medications. The top 5 medications reported were lisinopril, hydrochlorothiazide, simvastatin, levothyroxine, and metoprolol. Overall prescription medication use increased significantly with age. Medication use was greater among females, former smokers, adults with body mass index (BMI) >= 30, or with low family income, and non-hispanic blacks. Adults having health insurance, drug coverage, or a regular source of care were more likely to report medication use. CONCLUSION: The prevalence of prescription medication use in a general population sample in Wisconsin was high. Age, gender, race, BMI, family income, smoking history, health insurance, prescription drug coverage, and having a regular source of health care were associated with prescription medication use. PMID- 25745698 TI - Large epidermal inclusion cyst presenting as a pelvic mass. AB - INTRODUCTION: Epidermal inclusion cysts are common discrete nodules often formed in areas of previous trauma or surgery. A literature review indicated that large epidermal inclusion cysts of the pelvis are extremely rare. Accordingly, we present a case of a woman with a large pelvic epidermal inclusion cyst of the vaginal cuff, along with imaging studies and a review of the literature. CASE PRESENTATION: A 49-year-old woman, 13 years after vaginal hysterectomy, was found to have a 7-cm soft tissue pelvic mass, discovered on a computed tomography (CT) scan performed for abdominal pain. The transvaginal ultrasound showed typical findings of an unruptured epidermal inclusion cyst with a hypoechoic background with diffuse small variable echodensities (some intense echogenic reflectors), a thin wall, and no internal Doppler flow. A 7-cm epidermal inclusion cyst was removed laparoscopically from her vaginal cuff without complication. DISCUSSION: Epidermal inclusion cysts of clinical significance are rarely formed at the vaginal cuff or elsewhere in the pelvis. Increased utilization of abdominal/pelvic CT imaging is increasing the frequency in which benign pelvic cysts are encountered. The trauma of surgery may sequester portions of vaginal epithelium, which may form epidermal inclusion cysts. As the cyst increases in size, the cyst may be viewed as an incidental pelvic mass requiring clinical decision making. PMID- 25745699 TI - Mirtazapine and mefloquine therapy for non-AIDS-related progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the human nervous system caused by the JC virus. We report what is, to the best of our knowledge, the second reported case using a combination of mefloquine and mirtazapine in a patient with non-AIDS-related PML with a good clinical outcome. Conversely, the recent trial of mefloquine in 21 patients with AIDS and 3 without AIDS failed to show a reduction of JC viral DNA levels in the cerebral spinal fluid. However, the positive clinical response seen in our patient after the initiation of this combination therapy suggests that further studies in the form of randomized controlled trials for the treatment of non-AIDS-related PML are warranted. PMID- 25745700 TI - Mastocytosis as an unusual cause of hip fracture in an elderly woman. AB - Mastocytosis is a type of myeloproliferative neoplasm characterized by accumulation and proliferation of morphologically and immunophenotypically abnormal mast cells in 1 or more organ systems. Clinical manifestations vary depending upon the organ involved and chemical mediators released by mast cells along with constitutional symptoms and musculoskeletal complaints. We report a case of isolated bone marrow mastocytosis in an 87-year-old woman who presented with a fall resulting in proximal femur fracture. Bone marrow biopsy revealed mastocytosis, and no evidence of systemic involvement or peripheral mastocytosis was found. Physicians should be aware of this entity, especially in patients with osteoporosis. PMID- 25745701 TI - Discovery, education and community engagement--foundations for improving public health. PMID- 25745702 TI - Opening the door to growth. PMID- 25745703 TI - Fixed functional therapy with an anterior bite plane. AB - This clinical case report describes the treatment of Class II tendency in a patient using fixed functional appliance therapy. The appliance used was the fixed flat bite plane, consisting of an incisal acrylic located palatal to the maxillary anteriors that connected to maxillary first molar bands via heavy-gauge wires. The case reviewed involves a white male, age twelve, four months at the beginning of treatment. The patient exhibited a Class II end on molar relationship skeletal pattern with an ANB of 3 degrees and corresponding incisal overjet of 2mm, with 90% overbite. At the conclusion of treatment, fixed functional bite plane therapy resulted in improved overbite, molar canine class I relationship. The results of this case suggest use of the fixed appliance can be successful in improving function, esthetics and increased stability of post treatment both dentally and skeletally in the Class II tendency patient with severe overbite with minimal patient compliance. PMID- 25745704 TI - Penta - V Helix: a modified Quad helix for correction of bilateral dentoalveolar cross bite. AB - Standard Quad helix can be used to correct unilateral and bilateral dento alveolar posterior cross bite till first permanent molar. Correcting the second molar cross bite with quad helix is very difficult which requires fixed orthodontic attachment. To overcome this problem we have designed a Penta-V helix a modified quad helix in correcting bilateral dentoalveolar posterior cross bite up to second molar. PMID- 25745705 TI - Customized orthodontics: The Insignia System. AB - Customized treatment systems offer both patient and clinician numerous advantages, first and foremost the possibility of viewing a computerized rendering of the dentition in three dimensions. This allows the orthodontist to perform accurate measurements, analyses and simulations, and for both to be able to view the end result on screen. Thus, computerized technology consents optimization of not only the diagnostic phase, by means of extremely accurate three-dimensional imaging systems, but also the operative phase, by supplying individualized appliances with little or no correction while the treatment is in progress. In this article we present a customized orthodontic system called Insignia and how it works through two different clinical cases. PMID- 25745706 TI - Dento-skeletal effects of the Pendulum Hygienic Distalizer. AB - OBJECTIVES: To evaluate dento-skeletal effects of the Pendulum Hygienic Distalizer (P.H.D), utilized on expansion of the maxillary arch and distalizing of maxillary first molars. MATERIAL AND METHODS: Ten patients were selected from the outpatient clinic of Department of Orthodontics, Faculty of Dentistry, Mansoura University having: (1) Skeletal Class I with moderate maxillary crowding; (2) Angle Class II molars relation; (3) Constricted maxillary arch (posterior crossbite); (4) Ages ranged from 11 to 14 years with an average age of 12 years and 2 months. The changes that, brought by the appliance were evaluated from the lateral cephalometric, postero-anterior radiographs and study cast model taken before and after appliance application by means of a paired t-test. RESULTS: Significant amounts of maxillary expansion, molar distalization, molar distal tipping and anchorage loss were observed. The amount of maxillary expansion was 4.35 +/- 072 mm. The mean maxillary first molar distal movement was 2.27 +/- 0.52 mm with a distal tipping of 1.71 +/- 0.74 degrees in 3.19 +/- 0.53 months. The rate ofdistal movement was 0.70 mm per month. Reciprocal mesial movement of the first premolars was 1.73 +/- 0.92 mm with a mesial tipping of 2.60 +/- 1.02 degrees. Maxillary incisors moved 1.80 +/- 0.85 mm and tipped 2.02 +/- 1.43 degrees mesially. CONCLUSIONS: It was concluded that the Pendulum Hygienic Distalizer works well with the treatment philosophy of Class II malocclusion with posterior cross-bite by expansion the maxillary arch and distalizing of maxillary molars. PMID- 25745707 TI - Collaborative management of a young patient with generalized aggressive periodontitis. AB - What are the orthodontic treatment possibilities, limitations and risks inherent in patients with periodontal disorders, particularly active periodontal disease? This case report describes the interface between orthodontics, periodontics and restorative dentistry in the management of a 25-year-old young man with generalized aggressive periodontitis. PMID- 25745708 TI - The development and benefits of vertical dimension primary molar buildup crowns. AB - This article describes the technique and advantages of vertical dimension-primary molar buildups (VD-PMB's). These primary molar buildups help correct the vertical dimension on overclosed children from 3 to 12 years old. The advantages of these VD-PMB's are enormous, with very little or no disadvantages when placed correctly. This is a very important procedure for the orthodontist because opening the bite on these children has many beneficial results. It changes the resting tongue position, changes the slope of the anterior border of the glenoid fossa from steep to normal on Class 2 div 2 patients, corrects overclosure and otitus media with effusion (ear infections). It is important for the orthodontist since it is very simple and an easy way to correct overclosure on class 2 patients, which is often not done in the correction of overclosed patients. PMID- 25745709 TI - A camouflage treatment of Class II division 1 malocclusion complicated by missing lateral incisor. AB - This case report describes the treatment of a male patient, aged 16 years and 5 months, with a Class II division 1 malocclusion, who showed severe anterior protrusion and lower anterior crowding along with missing upper left lateral incisor. Treatment plan consisted of extraction of upper right first premolar and lower second premolars. No extraction was performed on the upper left quadrant instead canine was substituted as lateral incisor and premolar as canine to establish a good occlusion. Power arms were used for intrusion and retraction of the anterior teeth. After active treatment period of 21 months, the appliances were removed after establishing ideal overjet, overbite and other occlusal relationships. PMID- 25745710 TI - Preventive orthodontic management of tooth transposition. AB - The contemporary orthodontics should highlight the periodical control of growth and dental development in order to intercept possible disorders in facial growth and tooth eruption. This may allow avoidance or simplification of corrective orthodontic treatment, making it faster and less aggressive. Tooth transposition, a genetically determined eruptive disturbance, presents a relatively low prevalence in the world population and primarily affects maxillary canines and premolars. This paper presents an option for interceptive treatment of bilateral transposition of maxillary canine and premolar diagnosed early in a young individual. Longitudinal follow-up of RME performed in adequate timing to redirect the eruption pathway of permanent maxillary canines is presented. PMID- 25745711 TI - Correction of severe class II skeletal discrepancy with fixed twin block and high pull headgear--a case report. AB - This case report describes the management of a girl with a severe Class II skeletal discrepancy, Class II molar and canine relationship, a large overjet, an impinging overbite and a steep mandibular plane angle. Seemingly a surgical case, but as the patient was in CVMI stage 4, the treatment was initiated with a fixed twin block extending up to the maxillary second molars along with high pull headgear for the vertical control. This promoted the growth of the mandible, restrained maxilla in anteroposterior and vertical directions, combined with the fixed appliances for the aligning and levelling of the dentition improved the soft tissue profile. Thus severe skeletal Class II discrepancy with noncompensatory dental occlusion was successfully managed non-surgically with the combination of dentofacial orthopaedics along with comprehensive orthodontic mechanism without any extraction resulting in acceptable soft tissue changes. PMID- 25745712 TI - Effects of Twin-Block and Faramand-LL appliances on soft tissue profile in the treatment of Class II division 1 malocclusion. AB - Individuals with class II division I malocclusion suffer from increased over jet and unpleasant facial profile which induce poor self-image and low self-esteem. Mechanisms of different orthopedic appliances correcting class II malocclusion are investigated in numerous studies. Most of these researches focused on only the dentofacial changes and ignored the alterations of soft tissue profile. Evaluation of soft tissue alterations in patients treated with Faramand-II and Tween-Block appliances were the purposes of this study. PMID- 25745713 TI - Redefining treatment of gummy smile with Botox--a report of three cases. AB - Excessive contraction of upper lip elevator muscles is one of the many ascribed reasons of gummy smiles for which patients seek treatment. Myriad numbers of invasive surgical procedures have been employed for the improvement of the condition, but increased cost and involved risks act as major deterrent. Botulinum toxin type A (BTX-A) has been widely used in the management of several conditions associated with excessive muscular contraction and pain. This article aims to highlight the efficacy of BTX-A in treatment of gummy smiles. Three adult patients with gummy smiles due to hyperfunctional upper lip muscles were injected with BTX-A injections under electromyographic guidance. This minimally invasive treatment modality produced esthetically pleasing smiles in these patients, lasting up to 3-5 months. BTX-A injections at preselected hyperactive muscle sites provides novel and cosmetically viable alternative for management of gummy smiles caused by hypefunctional upper lip musculature. PMID- 25745714 TI - Orthognathic surgery: the definitive answer? PMID- 25745715 TI - Treatment of an impacted lower permanent cuspid: clinical and mechanical considerations. PMID- 25745716 TI - Is it almost done?. PMID- 25745717 TI - Can we move traumatized teeth? AB - Dental traumas affect primarily the upper central incisors. The risk is particularly high in cases with protrusive maxillary teeth. Often the trauma will happen in a young patient when the root is not completely formed. With all the complications that can occur on a short-term and also on a long-term, it is legitimate to ask the question of feasibility of orthodontic treatment following a dental trauma. In this article, presenting a clinical case, we will demonstrate that not only is it possible but also that there is a need for orthodontics to minimize the risk of another dental trauma at a later time. PMID- 25745718 TI - Rondeau Seminars amalgamated mid-sagittal (lateral) cephalometric analysis. AB - The author presents a comprehensive International Association for Orthodontics- Rondeau Seminars Amalgamated Mid-sagittal (Lateral) Cephalometric Analysis. Norms on the Cephalometric Data Sheet are age and gender specific for the Caucasian population and the postings are color coded for visual attraction. If the patient is ofa different ethnic group, the Norms should be adjusted accordingly. This Cephalometric Analysis is comprised often Sections, in alphabetical order and twenty nine Factors. The author expanded Rondeau Seminars Cephalometric Analysis by only six Factors, thus fulfilling the requirement for the case presentation for the Fellow of the IAO and the Diplomate ofthe IBO. PMID- 25745719 TI - An adjustment in NiTi closed coil spring for an extended range of activation. AB - The Nickel Titanium (NiTi) closed coil springs serve as an efficient force delivery system in orthodontic space closure mechanics. The closed coil springs with the eyelets come in various lengths to broaden its force characteristics for an expedient space closure. However, at a certain point of time of progressive space closure, the coil spring can be expanded no further for an adequate force delivery. In such situations, the clinician prefers to replace the existing spring with another short length spring. The present article describes a simple conservative technique for progressively re-activating the same NiTi closed coil spring for complete space closure. PMID- 25745720 TI - The Loudon Chateau repositioning appliance. AB - The LCR Appliance if fabricated and used properly, has many advantages over the Herbst and Twin Block appliances in solving tongue thrust, mandibular deficiency and repositioning with proper mandibular advancement and mandibular growth results. The regular Chateau appliance was named in 1904 after Dr. Chateau in Franc. It was originally used in Europe but was an uncomfortable removable appliance with wires used in the mandibular anterior lingual area to reposition the mandible. PMID- 25745722 TI - Maximum CI II therapy with minimum appliances. PMID- 25745721 TI - A simple technique for correction of relapsed overjet. AB - Class III malocclusions are usually growth related discrepancies, which often become more severe when growth is completed Orthognathic surgery can be a part of the treatment plan, although a good number of cases can be treated non-surgically by camouflage treatment. The purpose of this report is to review the relapse tendency in patients treated non-surgically. A simple technique is described to combat one such post-treatment relapse condition in an adult patient who had undergone orthodontic treatment by extraction of a single lower incisor. PMID- 25745723 TI - Assessment of safe zone in maxillary molar region for miniscrew placement in the mixed dentition period--a digital volumetric tomographic (DVT) study. AB - Assessment of bone thickness in maxillary frst molar region for miniscrew placement during the mixed dentition period with reference to the following variables a) mesio-distal bone width b) buccal cortical plate thickness c) palatal cortical plate thickness d) bucco-palatal bone depth. DVT images of fifteen healthy patients aged 8-10 years with early exfoliated maxillary second deciduous molar were obtained using the Kodak 9000 extra-oral imaging system. The scanned images were analyzed using Kodak dental imaging software [3DmoduleV2.2] and the bone thickness measurements were obtained at six mm and eight mm apical to the cemento-enamel junction. The mean and standard deviation for the measurements was calculated and data was statistically analysed using paired 't' test. The Method error calculations were performed using the Dahlberg formula. The mean values for the mesiodistal width, buccopalatal depth, buccal and palatal cortical bone thickness were found to be sufficient for miniscrew placement up to 1.2mm diameter and 10mm length. The bone thickness measurement and assessment of safe zone in maxillary posterior region from the present study showed potential for miniscrew placement in pediatric age group. Miniscrews can be considered as a promising aid in pediatric space management; so also, they can be used for molar distalization and space regaining in early mixed dentition period. PMID- 25745724 TI - Treatment planning considerations for molar uprighting. AB - Molar uprighting cases require individualized treatment planning depending upon condition of ridge, growth pattern of patient, periodontal condition, lower facial height, position of third molar and anchorage. Uprighting of molar was done in two cases--effectively using simple tip back spring in one case and implant in another. PMID- 25745725 TI - Total recall: an update on orthodontic wires. AB - Orthodontic therapy is a force management procedure largely based on use of arch wires for storing and distributing biologically tolerable forces by means of which position of teeth is altered. Advances in material science and technology has resulted in an array of newer arch wire materials, opening new vistas, in orthodontic treatment. Materials with widely diverging properties are in the market today and their usage has profound implications on appliance mechanics, and are very much different from stainless steel which is popular even today. The dentists who practise orthodontics have to therefore clearly outline the phases of treatment and select the arch wire most suited for attaining specific treatment goals. PMID- 25745726 TI - Difficulties achieving orthodontic stability? The answer may be blowing in the wind. PMID- 25745727 TI - Orthodontic exposure of multiple lmpactions: a case report. AB - There are rare cases of impacted permanent central incisors with dilacerations, a dental deformity characterized by pronounced angulations of the longitudinal tooth axis. Impaction of maxillary canines is an orthodontic anomaly that causes facial and dentoalveolar system problems, both functional and esthetic. A combination of surgery and orthodontics is important in bringing impacted teeth to their ideal position in the dental arch. This is a case report of a 10-year old patient with impacted and dilacerated right central incisor and impacted left maxillary canine, following surgical exposure and appropriate orthodontic traction, the impacted teeth were surgically exposed and aligned into the dental arch. PMID- 25745728 TI - Gaining space and creating a Class I molar relationship. PMID- 25745729 TI - Hawai'i hospital-based emergency department (ED) visits. PMID- 25745730 TI - Considering dating a patient? PMID- 25745731 TI - Is this harassment? PMID- 25745732 TI - Making a good impression? PMID- 25745733 TI - Do I have to encrypt my email? PMID- 25745734 TI - Is "marketing" a dirty word? PMID- 25745735 TI - Gun Violence, mental health, and Connecticut physicians. AB - While there is a public perception that gun violence is associated with mental illness we present evidence that it is a complex public health problem which defies simple characterizations and solutions. Only a small percentage of individuals with mental illness are at risk for extreme violence and they account for only a small percentage of gun-related homicides. Individuals who are at risk for gun violence are difficult to identify and successfully treat. The incidence, and perhaps the demographics, of gun violence vary substantially from state to state. We make a case for Connecticut physicians to study gun violence at the state level. We recommend that Connecticut physicians promote and expand upon the American Academy of Pediatrics' recommendation for creating a "safe home environment. "We suggest that guns be secured in all homes in which there are children. In addition we suggest that guns be voluntarily removed from homes in which there are individuals with a history of violence, threats of violence, depression, drug and/or alcohol abuse, and individuals with major mental illnesses who are not cooperating with therapy. PMID- 25745736 TI - Stem cell collection considerations for AL amyloidosis. AB - Amyloidosis is a progressive disease that traditionally is associated with poor clinical outcomes. Recent advances in amyloidosis treatment may allow for more patients tobe considered for autologous stem cell transplantation. In this report, we review a case of autologous peripheral blood stem cell transplantation in a patient with systemic amyloidosis and review special considerations in peripheral blood stem cell collection in such patients. We conclude that it may be reasonable to consider substituting heparin for some of the citrate used in peripheral blood stem cell collection procedures performed on patients with cardiac amyloidosis, so long as there are no contraindications to heparin exposure. PMID- 25745737 TI - Tumefactive multiple sclerosis: a case report and review of the literature. AB - Tumefactive multiple sclerosis (TMS) is a rare subset of inflammatory demyelinating disorders that can present with MS symptoms or the clinical or radiographic findings of a space-occupying intracranial lesion. Classically, TMS presents on computed tomography (CT) or magnetic resonance imaging (MRI) with an intracranial mass greater than 2.0 cm with a variable amount of mass effect, edema, and ring or rim enhancement with gadolinium contrast. Unfamiliarity with this condition may lead health care providers to perform unnecessary biopsies or delay proper treatment. We present the case of a patient who came to the emergency room with bilateral internuclear ophthalmoplegia who was later diagnosed as TMS. PMID- 25745738 TI - Drug development: current challenges and federal initiatives. PMID- 25745739 TI - Hospitals must notify patients of facility fees--why it matters. PMID- 25745740 TI - Are physicians obligated to treat patients with Ebola? PMID- 25745742 TI - A dynamic organization. PMID- 25745741 TI - Shared purpose. PMID- 25745743 TI - Moving forward. PMID- 25745744 TI - Ultrasound evaluation of the postpartum endometrial cavity. AB - OBJECTIVE: To establish normal ultrasonographic findings for the postpartum uterus. STUDY DESIGN: We performed a prospective cohort study on women delivering during the study period. Ultrasounds were performed abdominally within 48 hours of delivery. Measurements of the endometrial cavity and remarkable findings such as echogenic debris or uterine abnormalities were documented. Additionally, we followed patients during their hospital course for bleeding complications and the need for medical or surgical treatment of such complications. RESULTS: Of the 114 patients enrolled during our study period, 79 (69%) delivered vaginally and 35 (31%) delivered by cesarean; 39 (34%) were primiparous and 75 (66%) were multiparous. The mean endometrial cavity measurement was 1.15 +/- 0.3 cm. There was no difference in endometrial cavity when evaluating parity (p = 0.26) or vaginal versus cesarean delivery (p = 0.8). Echogenic material in the endometrial cavity was noted in 22 (19%) of the 114 patients. The presence of echogenic material was significantly higher following vaginal delivery (p = 0.008). None of the patients had a complication in the postpartum period. CONCLUSION: Air endometrial cavity measurement of < 1.2 cm after a vaginal or cesarean delivery should be considered normal. Presence of echogenic material in the endometrial cavity appears to be a normal variant. PMID- 25745745 TI - Further evidence supporting the Diff-Quik stain for sperm chromatin integrity testing. AB - OBJECTIVE: To correlate intracytoplasmic sperm injection (ICSI) fertilization with chromatin status assessed by the Diff-Quik procedure modified with a one minute soak step, and to determine the association of chromatin status with in vitro fertilization (IVF) pregnancy. STUDY DESIGN: This was a retrospective study of 81 IVF patients. Gradient-centrifuge washed sperm remaining after ICSI were fixed, stained by Diff-Quik, immersed in water for 1 minute, and analyzed under oil immersion light microscopy. Sperm nuclear coloration (types A-D), strict morphology, fertilization, and pregnancy status were determined. RESULTS: Sperm with light purple staining (type A) were correlated (R = 0.48, p < 0.05) with ICSI fertilization. The intraassay and interassay coefficients of variation were 5.9% and 4.1%, respectively. Sperm strict normal morphology was correlated neither with ICSI fertilization (R = 0.24, p > 0.05) nor with type A sperm (R = 0.35, p > 0.05). Sperm incubated in Fenton reagent that damaged DNA showed a time dependent decrease in percent type A sperm. However, there was no correlation with IVF pregnancy status. CONCLUSION: This retrospective study showed that the inclusion of a one-minute soak step post-Diff-Quik staining enhanced the detection of sperm chromatin abnormalities related to ICSI fertilization. Fenton reagent-treated sperm suggested that the staining patterns correlated with DNA damage. A large prospective trial should be undertaken to confirm these findings. PMID- 25745746 TI - B152 anti-hyperglycosylated human chorionic gonadotropin free beta-Subunit. A new, possible treatment for cancer. AB - OBJECTIVE: To investigate the ability of B152 to block cancer growth in cell lines in vivo and in nude mice in vitro. STUDY DESIGN: We examined JAR, JEG-3, and NTERA trophoblastic cancer cell lines and KLE, Hec-1A, SCaBER, and T24 nontrophoblastic cancer cell lines. JEG-3 cells were transplanted into 8 nude mice. Four nude mice were administered B152 antibody, and 4 were administered control non-specific IgG. Two studies were completed: first with antibody treatment started 2 weeks after cancer transplantation, and second with antibody treatment started at the time of transplantation. RESULTS: In 3 trophoblastic cancer lines and 4 non-trophoblastic cancer cell lines, B152 suppressed the growth of cancer cells, forcing cells into a state of regression. When B152 was administered to nude mice with tumor xenographs, the antibody blocked cancer cell growth and invoked oncostasis. When B152 was administered to nude mice starting at time of xenograph transplantation, the antibody prevented tumor growth completely. CONCLUSION: B152 suppresses tumor growth by seemingly blocking hyperglycosylated human chorionic gonadotropin (hCG) free beta-subunit effects. Thus, highly specific antibodies against hCG such as B152 may form part of a novel adjuvant treatment regimen against hCG-producing tumors in humans. This may form a new treatment for humans. PMID- 25745748 TI - Fertility outcome in laparoscopic single tube reanastomosis. AB - OBJECTIVE: To evaluate the fertility outcome in laparoscopic unilateral tubal reanastomosis. STUDY DESIGN: This was a retrospective observational study. The medical records of all patients who underwent laparoscopic unilateral tubal reanastomosis from October 2003 to October 2010 at the Center for Advanced Endoscopy and Infertility Treatment, Paul's Hospital, Cochin, Kerala, India, were analyzed. RESULTS: A total of 71 patients out of 81 could be followed up. Of those 71 women 39 (54.9%) conceived, and most of them within 1 year (36/39). Overall intra-uterine pregnancy rate was 52.11%. Thirty delivered a live infant (delivery rate 42.25%), 7 had abortions, 1 ectopic pregnancy was noted in the operated tube and 1 in the contralateral tube. Final tubal length of >= 5 cm showed statistically significant association with pregnancy rate (p = 0.0056). There was no significant difference in mean age, duration between sterilization and reanastomosis, or type of sterilization between the 2 groups. CONCLUSION: Though bilateral tubal reanastomosis is an ideal procedure, unilateral laparoscopic tubal reanastomosis gives an acceptable pregnancy rate. Unilateral laparoscopic reanastomosis is feasible in most of the cases, as most of the time only 1 tube is suitable for reanastomosis. Also, the surgical team can perform the unilateral procedure more efficiently, and the patient receives less anesthesia since the duration of surgery is shorter when compared to the bilateral procedure. Bilateral anastomosis is better when both tubes are accessible, especially in older women. PMID- 25745747 TI - Distributions of heavy metals in maternal and cord blood and the association with infant birth weight in China. AB - OBJECTIVE: To measure serum levels of heavy metals in Chinese pregnant women and their newborns, and to evaluate the association of these metals with infant birth weight. STUDY DESIGN: We measured serum concentrations of lead (Pb), thallium (Tl), cadmium (Cd), selenium (Se), arsenic (As), nickle (Ni), vanadium (V), cobalt (Co), and mercury (Hg) in 81 mother-infant pairs using an inductively coupled plasma mass spectrometry method. Multiple linear regression analyses were used to evaluate the associations of these heavy metals with infant birth weight. RESULTS: Se, Pb, As, and Cd showed the highest detection rates (98.8%) in both the maternal and cord blood, followed by Tl, which was detected in 79.0% and 71.6% of the maternal and cord blood samples, respectively. Pb had the highest concentrations in both the maternal and cord blood samples of all toxic metals detected, with concentrations of 23.1 ng/g and 22.0 ng/g, respectively. No significant associations were observed between any heavy metals and birth weight. However, Tl in the maternal and cord blood was most notably inversely associated with birth weight. CONCLUSION: Se intake was low in Chinese women and their newborns, whereas Pb had the highest concentrations in both the maternal and cord blood samples of all toxic metals detected. Tl was a unique pollution source in this population, and Tl levels were shown to have the largest effect on decreasing infant birth weight in this pilot study. Further research incorporating larger sample sizes is needed to investigate the effects of prenatal exposure to heavy metals--especially Tl and Pb--on birth outcome in Chinese infants. PMID- 25745749 TI - Comparison of the perinatal outcome of twins conceived after assisted reproductive technologies versus those conceived naturally. AB - OBJECTIVE: To analyze whether twin pregnancies resulting from assisted reproductive technologies (ARTs) had an increased risk of obstetric complications or adverse neonatal outcomes. STUDY DESIGN: The obstetric and neonatal outcomes of 252 cases of twin pregnancies, including 108 cases conceived by ART and 144 cases of natural conception, delivered at our hospital between January 1, 2009, and December 31, 2011, were compared retrospectively. RESULTS: Mean maternal age in the ART group was significantly older than that of the control group (31.04 +/ 3.63 vs. 28.81 +/- 4.75, t = 2.88, p < 0.05). Among the gravidas (< 35 years old) the incidence of premature rupture in the ART group and the control group was statistically significant (22.09% vs. 10.48%, chi2 = 5.30, p < 0.05). The incidence of mild asphyxia of the second twin in the ART group and the control group was also statistically significant (23.53% vs. 12.20%, chi2 = 4.61, p < 0.05). However, there was no statistical difference in other maternal or neonatal complications of twins between the ART group and the control group. CONCLUSION: In this study, except for a higher incidence of morbidity, premature rupture of membranes, and mild asphyxia of the second twin, the obstetric complications or adverse neonatal outcome in the ART group were similar, which indicated that ART conceived twin pregnancies were not at higher risk for obstetric complications or adverse neonatal outcome than were naturally conceived twin pregnancies. PMID- 25745750 TI - Vaginoscopy compared to traditional hysteroscopy for hysteroscopic sterilization. A randomized trial. AB - OBJECTIVE: To compare vaginoscopic hysteroscopic sterilization with traditional hysteroscopic approach for differences in pain, bilateral microinsert placement rates, and procedure time. STUDY DESIGN: We performed a prospective, randomized, single-blinded study of hysteroscopic sterilization using the Essure System. The study setting was an inner city ObGyn clinic. Ninety patients were randomized to either vaginoscopy or traditional approach. The traditional approach was speculum insertion, paracervical analgesia, and tenaculum. All procedures were done with a 5 mm, 30 degree rigid hysteroscope. Main outcome measures were pain scores (10 point visual analog scale), bilateral placement rates, and procedure times. RESULTS: Vaginoscopy was successful in 42/45 patients (93%). There was no statistically significant difference in pain-scores for microinsert placement between the groups (p = 0.71). First attempt, bilateral microinsert placement rate was 95% (40/42) with vaginoscopy and 95% (43/45) with traditional (p = 0.89). Time for treatment completion was 16 minutes (mean) (range, 13-21) in the traditional group versus vaginoscopy time of 9 minutes (mean) (range, 7-11) (p = 0.03). CONCLUSION: Hysteroscopic sterilization via vaginoscopy is feasible with bilateral microinsert rates comparable to those of traditional hysteroscopy. Vaginoscopy is associated with less overall discomfort and is faster to perform. PMID- 25745751 TI - Cabergoline for reducing ovarian hyperstimulation syndrome in assisted reproductive technology treatment cycles. A prospective randomized controlled trial. AB - OBJECTIVE: To investigate whether cabergoline (Cb2), a dopamine agonist, reduces ovarian hyperstimulation syndrome (OHSS) in high-risk women undergoing assisted reproductive technology (ART), and to analyze whether cabergoline affects the outcome of ART. STUDY DESIGN: Forty infertile women at risk of developing OHSS were enrolled in the trial. The inclusion criteria were as follows: infertile women undergoing IVF with serum estradiol concentration > 4,000 pg/mL or with > 20 follicles > 12 mm on the day of human chorionic gonadotropin (hCG) administration, and 18-40 years of age. They were randomized into 2 groups: the Cb2 group (n = 20) received 0.5 mg oral Cb2 per day for 8 consecutive days beginning on the day of hCG, and the control group (n = 20) received no medication. RESULTS: Ascites was significantly lower (p = 0.008) in the Cb2 group as compared with the control group. The incidence of moderate OHSS was also significantly lower (p = 0.04) in the Cb2 as compared to the control group. There was no evidence of statistically significant differences regarding the parameters of ART outcome. CONCLUSION: Our data supports the use of Cb2 in the management of high-risk women undergoing ART and, consequently, achieving lowered risk of OHSS, with no deleterious impact on ART outcomes. PMID- 25745752 TI - Basal transethmoidal encephalocele and malignant hypertension in a parturient with a seizure disorder. A case report. AB - BACKGROUND: Nasal encephaloceles are uncommon in North America and may be diagnosed only as incidental findings. The presence of an encephalocele and malignant hypertension in the parturient requires complex coordination of care. CASE: We present a case of severe chronic hypertension in a pregnant patient with a seizure disorder and new finding of a basal transethmoidal encephalocele. She required 5 antihypertensive agents and cesarean delivery at 34 weeks' gestation under general anesthesia. The obstetric and anesthetic management of encephalocele are reviewed. CONCLUSION: Nasal encephaloceles are rarely reported in pregnancy and present additional peripartum obstetric and anesthetic considerations that require multidisciplinary planning for optimization of maternal and fetal outcomes. PMID- 25745753 TI - Robotic-assisted laparoscopic resection of cornual ectopic pregnancy. A case report. AB - BACKGROUND: Interstitial or cornual ectopic pregnancy is an uncommon variant of ectopic pregnancy. Herein we describe the first robotic-assisted laparoscopic resection of a cornual ectopic pregnancy and review the relevant peer-reviewed English literature involving minimally invasive surgery for this condition. CASE: A 37-year-old woman, G3, P2, presented to the emergency room with an 8.5-week, 4.5-cm cornual ectopic pregnancy and underwent a successful robotic-assisted surgical excision and repair without complications. The technical description of the robotic-assisted laparoscopic cornual resection and uterine repair is presented. Thirteen peer-reviewed literature citations involving 183 cases of laparoscopic management of cornual ectopic pregnancy were identified from the year 1988 to the present, and are discussed heiein. CONCLUSION: Robotic-assisted laparoscopic resection of cornual pregnancy was feasible and was associated with minimal blood loss, aided with the use of an endoscopic vascular clamp and intramural vasopressin. PMID- 25745754 TI - Airway pressure release ventilation and respiratory failure during pregnancy. A report of three cases. AB - BACKGROUND: Acute respiratory distress syndrome is a rare complication during pregnancy but remains dificult to manage, with a high incidence of maternal mortality. CASES: We present 3 cases of respiratory failure and severe pulmonary disease managed with airway pressure release ventilation, among other ventilatory modes, with improved ventilation. CONCLUSION: Airway pressure release ventilation may be an important option as a ventilatory mode for management of maternal respiratory failure during pregnancy. PMID- 25745755 TI - Imperforate hymen presenting with fecal frequency and use of stay sutures at time of hymenectomy. A case report. AB - BACKGROUND: Imperforate hymen is a rare gynecological disorder that can lead to a number of short-term and even long-term complications. CASE: A 14-year-old girl presented complaining of fecal frequency and urgency for over 1 year. On examination she was found to have an imperforate hymen. CONCLUSION: Although often diagnosed in association with cyclic monthly pelvic pain, we present a case in which imperforate hymen presented with fecal frequency and urgency. Surgical management is the mainstay of treatment. In our experience we found the addition of stay sutures to be quite valuable in facilitating appropriate excision of tissue and feel that they should be considered as an adjunct to the classically described hymenectomy. PMID- 25745756 TI - Delayed presentation of a paracytic myoma fragment after laparoscopic supracervical hysterectomy requiring small bowel resection. A case report. AB - BACKROUND: Uterine myomas are commonly treated with laparoscopic myomectomy or hysterectomy. Morcellation is often required to evacuate tissue through the laparoscopic incisions using a designated morcellator or through extension of a port site with self-retaining retractor and a cold scalpel. Both techniques carry a risk of inadvertently leaving tissue fragments behind. CASE: We present a case of a parasitic fragment of morcellated uterus that became adherent to the small bowel, resulting in severe abdominal pain and requiring exploratory laparotomy and small bowel resection 5 months later. CONCLUSION: Gynecologic surgeons should be aware of possible delayed postoperative complications that can result from parasitic myoma fragments inadvertently left behind followinig morcellation. PMID- 25745757 TI - Single-dose intramuscular methotrexate treatment of cervical ectopic pregnancy. A case report. AB - BACKGROUND: Cervical ectopic pregnancies (CEPs) are increasingly being managed conservatively. However, the efficacy of specific conservative approaches such as the single-dose intramuscular (IM) methotrexate (MTX) therapy has not been evaluated. We reportthe successful management of 2 consecutive CEPs in the same patient with single-dose IM MTX therapy, and review published cases of CEPs treated with a similar regimen, to determine the efficacy of this approach. CASE: In our case, both CEPs resolved with single-dose IM MTX, and the patient subsequently had a successful term delivery. A Medline/OVID English language search, covering the period 1982-2012, identified 38 additional cases of CEPs treated with single-dose IM MTX. Of the total 40 cases analyzed, including our 2 cases, 30 (75%) were successfully treated, with complete remission. Of the 27 cases with no embryonic cardiac activity, 25 (93%) were successfully treated with single-dose IM MTX. CONCLUSION: Appropriately selected cases of CEPs can be successfully managed with single-dose IM MTX with very low complication rates and preservation of future fertility potential. PMID- 25745758 TI - Third trimester tubal pregnancy. A case report. AB - BACKGROUND: A viable tubal pregnancy is an extremely rare occurrence with an increased risk of fetal as well as maternal morbidity and mortality. We report a third trimester tubal pregnancy occurring after an interval tubal ligation. CASE: A 43-year-old woman, gravida 2 para 1, presented at 29 weeks' gestation with an asymptomatic extrauterine pregnancy and was managed expectantly in the antepartum unit. At 33 weeks the fetus was delivered for worsening umbilical artery velocimetry. Despite aggressive resuscitative efforts, the neonate did not survive. CONCLUSION: In managing an advanced extrauterine pregnancy, imaging with MRI may help diagnose and confirm suspicion raised by ultrasonography and may aid in presurgical planning and management. This case illustrates the diagnostic challenge and high neonatal mortality of an advanced tubal pregnancy. PMID- 25745759 TI - Retropharyngeal abscess complicated by Prevotella buccae sepsis during pregnancy. A case report. AB - BACKGROUND: Retropharyngeal abscess is extremely uncommon in adults and rare in pregnancy. A MEDLINE search yielded only 1 reported case during pregnancy. Likewise, sepsis caused by prevotella buccae, a bacteria associated with more benign conditions such as bacterial vaginosis or dental infections, is also rare, with no reported cases during pregnancy. CASE: We report a case of retropharyngeal abscess complicated by Prevotella buccae septicemia during pregnancy. CONCLUSION: Retropharyngeal abscess should be suspected in a pregnant patient who presents with sore throat, dyspnea, and dysphagia, especially when preceded by dental treatment or symptoms. If confirmed, antibiotic treatment should cover the usual pathogens associated with retropharyngeal abscess, including Pre- votella species. PMID- 25745760 TI - Bleeding after laparoscopic supracervical hysterectomy managed with cervical artery embolization. A case report. AB - BACKGROUND: Postoperative bleeding is a known complication after laparoscopic supracervical hysterectomy (LASH), and trachelectomy is the traditional management of significant bleeding. CASE: We present the case of a patient with significant postoperative bleeding 1 month after LASH, resulting in symptomatic anemia requiring blood transfusion. Gelfoam embolization of the bilateral cervical arteries was successful in stopping the bleeding. The patient had no further bleeding and had resolution of anemia at 6 months postprocedure. CONCLUSION: Our case demonstrates a successful multidisciplinary and minimally invasive approach to management of postoperative bleeding with bilateral cervical artery embolization and should be considered as a potential treatment option. PMID- 25745761 TI - Lysophosphatidylcholine and lysophosphatidylinosiol--novel promissing signaling molecules and their possible therapeutic activity. AB - For many years the role of lysophospholipids (LPLs) was associated only with structural and storage components of the cell without any informational function. Today, based on many research projects performed during the last decades, it is clear that some of the LPLs act as hormone-like signaling molecules and thus are very important inter- and intracellular lipid mediators. They can activate specific membrane receptors and/or nuclear receptors regulating many crucial physiological and pathophysiological processes. The LPLs were iden- tified as involved in a majority of cellular processes, including modulation of disease related mechanisms observed, for instance, in case of diabetes, obesity, atherosclerosis and cancer. Among LPLs, lysophosphatidylcholine (LPC) and lysophosphatidylinositol (LPI) are becoming attractive research topics. Their recently revealed activities as novel ligands of orphan G protein-coupled receptors (i.e., GPR55 and GPR119) involved in modulation of tumor physiology and insulin secretion seem to be one of the most interesting aspects of these compounds. Moreover, the most recent scientific reports emphasize the significance of the acyl chain structure bound to the glycerol basis of LPL, as it entails different biological properties and activities of the compounds. PMID- 25745762 TI - AMD--the retinal disease with an unprecised etiopathogenesis: in search of effective therapeutics. AB - AMD (age-related macular degeneration) is a progressive vision-threatening ocular disease, affecting central region of the retina--the macula--and manifesting in the elderly. AMD is a degenerative disease, and the degeneration affects primarily the retinal pigment epithelial (RPE) cells and secondarily the photoreceptors, leading consequently to disturbances or partial loss of central vision and legal blindness. Clinically, the disease is classified as: atrophic- dry AMD (in majority of cases), and neovascular--wet AMD (with choroidal neovascularization--CNV: 10-15% of all AMD cases). Pathogenesis of AMD is complex, multifactorial and only poorly recognized. Main risk factors include: advanced age, genetic predispositions, environmental determinants, history of exposure to intensive light and smoking. At least four molecular processes contribute to the development of AMD pathology: lipofuscinogenesis, drusogenesis, inflammation and choroidal neovascularization (in wet AMD). Since vascular endothelial growth factor (VEGF) is a predominant proangiogenic factor in CNV. the wet AMD can be treated with intravitreous application of "anti-VEGF" agents (Avastin, Lucentis, Eylea). Till now, there is no approved therapy for dry AMD, although several agents/treatments are currently in clinical trials. This paper briefly describes major molecular and cellular events leading to AMD, and presents currently used and new experimental therapeutic strategies against AMD. PMID- 25745763 TI - Effect of valproic acid on the proliferation and apoptosis of the human melanoma G-361 cell line. AB - Melanoma malignant is characterized by a high malignancy and low susceptibility to treatment. Due to these properties, there is a growing interest in compounds that would have the ability to inhibit proliferation, induce differentiation of tumor cells and initiate the apoptotic pathway. In vitro and in vivo research indicate that valproic acid (a histone deacetylase inhibitor) may have anti cancer properties. In our study, the role of VPA on proliferation and apoptosis in G-361 human melanoma cell line was examined. Obtained results indicated that administration of VPA at concentrations above >= 1 mM led to significant inhibition of cell growth. Simultaneously, it was observed that VPA at higher concentrations (5 and 10 mM) caused an increase in caspase-3 activity. PMID- 25745764 TI - TLC--densitometric method for qualitative analysis of betamethasone and its related compounds in pharmacautical preparations. AB - A new simple and rapid TLC-densitometric procedure for the separation and identification of betamethasone and its related substances, betamethasone-17,21 dipropionate, betamethasone-17-valerate, betamethasone-21-valerate and also betamethasone disodium phosphate was developed. One of the chromatographic systems proposed in this study, which has been satisfactory applied in separation of four pairs of examined compounds was silica gel 60F254 (E. Merck, Art. 1.05554) and a mixture containing chloroform-methanol-acetic acid (99.5%) in volume composition 28:5:0.5. Densitometric measurements were done using densitometer TLC Scanner 3 at 246 nm. The proposed method was checked in terms of its specificity for the determination of betamethasone-17,21-dipropionate and betamethasone disodium phosphate in commercially available products containing both compounds, separately, as active ingredients. The results showed that the method is suitable for qualitative analysis of betamethasone derivatives in simple and combined pharmaceuticals in various dosage forms e.g., lotion and injection solution. It also can be applied in quality control of pharmaceutical formulations of betamethasone and its related compounds in form of salts and esters. PMID- 25745765 TI - Comparison of ultraviolet detection and charged aerosol detection methods for liquid-chromatographic determination of protoescigenin. AB - Escin, a complex mixture of pentacyclic triterpene saponins obtained from horse chestnut seeds extract (HCSE; Aesculus hippocastanum L.), constitutes a traditional herbal active substance of preparations (drugs) used for a treatment of chronic venous insufficiency and capillary blood vessel leakage. A new approach to exploitation of pharmacological potential of this saponin complex has been recently proposed, in which the beta-escin mixture is perceived as a source of a hitherto unavailable raw material, pentacyclic triterpene aglycone protoescigenin. Although many liquid chromatography methods are described in the literature for saponins determination, analysis of protoescigenin is barely mentioned. In this work, a new ultra-high performance liquid chromatography (UHPLC) method developed for protoescigenin quantification has been described. CAD (charged aerosol detection), as a relatively new detection method based on aerosol charging, has been applied in this method as an alternative to ultraviolet (UV) detection. The influence of individual parameters on CAD response and sensitivity was studied. The detection was performed using CAD and UV (200 nm) simultaneously and the results were compared with reference to linearity, accuracy, precision and limit of detection. PMID- 25745766 TI - Preliminary studies on application of library of artificial receptors for differentiation of metabolites in urine of healthy and cancer bearing mice. AB - A library of artificial receptors formed by the self-organization of N-lipidated peptides attached to the cellulose via m-aminophenylamino-1,3,5-triazine was used for differentiation of metabolites in urine of healthy and cancer bearing mice. The interactions of urine metabolites with the receptors were visualized by using competitive adsorption-desorption of an appropriate reporter dye. Analysis of the binding pattern (fingerprint) of urine metabolites from healthy and from cancer suffering mice showed that there were several structures among 120-elements molecular receptors which were able to differentiate bonded ligands depending on the healthy state. For all three tested types of cancers two structures: Lipid Pro-Ala-NH-C6H4-NH-DMT-cellulose and Lipid-Arg-Pro-NH-C6H4-NH-DMT-cellulose were selected as diagnostic. PMID- 25745767 TI - Effect of GLY-HIS-LYS and its copper complex on TGF-beta secretion in normal human dermal fibroblasts. AB - Transforming growth factor beta (TGF-beta) is a cytokine involved in a wide variety of biological process- es such as cell growth, differentiation and proliferation, apoptosis and regulation of the immune response. It has an important role in wound healing process, fibrosis and scar tissue formation. Similarly to TGF-beta1, insulin growth factor (IGF) family is expressed locally in response to tissue injury. Treatment of dermal fibroblasts with IGF-1 caused a substantial induction of TGF-beta1 mRNA. Not a great deal of research so far has focused on IGF-2. Much attention has been focused on the tripeptides such as Gly His-Lys (GHK) and their copper complexes, which have a high activity and good skin tolerance. Recent data suggest that their physiological role has been related to the process of wound healing, tissue repair and skin inflammation. In the present study, the influence of 1 nM solutions of GHK, GHK-Cu and CuCl2, on IGF-2-dependent TGF-beta1 secretion in normal human dermal fibroblasts cells was investigated. Fibroblasts were cultured in 24-well plates. Total TGF-beta1 pro- tein was evaluated using the ELISA kit. The Bradford reagent was used to determine the total quantity of cel- lular protein. Treatment of fibroblasts with 100 ng/mL IGF-2 resulted in a significant increase in TGF-beta1 secretion. GHK and its copper complex and free copper ions decreased IGF-2-dependent TGF-beta1 secretion. Our observations provide some new information on the potential use of that peptide contained in cosmetics to treat and prevent the formation of hypertrophic scars. PMID- 25745768 TI - Synthesis of protoescigenin glycoconjugates with O-28 triazole linker. AB - New triazole linked conjugates were obtained from protoescigenin monopropargyl ethers and sugar azides, under Cu(II) salt promotion in good yield, without losing isopropylidene protection. PMID- 25745769 TI - Influence of cyclosporin A on expression pattern of genes associated with dna repair in human dermal fibroblasts. AB - Cyclosporin A (CsA) is a cyclic nonribosomal peptide with immunosuppressive activity. Chronic immunosuppressive medication is associated with time distant side effects and is the cause of the different secondary diseases, including cancers (especially skin cancers). Anomalies in the functioning of DNA repair mechanisms are closely related to the processes of neoplastic transformation. The object of this study was to assess the impact of CsA exposure (8 h, early cell response) on expression of genes associated with DNA repair in normal human dermal fibroblasts (NHDF). NHDF from CC-2511 cell line were routinely maintained in FBM medium. Transcriptional activity of genes associated with DNA repair in NHDF after 8 h of cells exposition to CsA (C = 100 ng/mL) in relation to control cells was compared using Affymetrix HG-U133A 2.0 oligonucleotide microarray technique. GeneSpring GX fluorescence signals analysis of 1514 probes, which represented the expression of 875 genes selected from the NetAffx Analysis Center database for "DNA repair" query, demonstrated the inhibited expression of 32 probes (p-value < 0.05; Fold Change > 2.0), including: BRCA1, RAD51, TOP2A, EXO1, RRM2, CDK1 and POLE2. The obtained results suggest that CsA can have a silencing effect on DNA repair genes. Therefore, the risk of skin cancer development during CsA therapy can result not only from immunosuppressive effects of the drug, but is also likely to arise from inhibition of DNA repair pathways. PMID- 25745770 TI - Evaluation of genistein ability to modulate CTGF mRNA/protein expression, genes expression of TGFbeta isoforms and expression of selected genes regulating cell cycle in keloid fibroblasts in vitro. AB - Keloids are characterized by overgrowth of connective tissue in the skin that arises as a consequence of abnormal wound healing. Normal wound healing is regulated by a complex set of interactions within a network of profibrotic and antifibrotic cytokines that regulate new extracellular matrix (ECM) synthesis and remodeling. These proteins include transforming growth factor beta (TGFbeta) isoforms and connective tissue growth factor (CTGF). TGFbeta1 stimulates fibroblasts to synthesize and contract ECM and acts as a central mediator of profibrotic response. CTGF is induced by TGFbeta1 and is considered a downstream mediator of TGFbeta1action in fibroblasts. CTGF plays a crucial role in keloid pathogenesis by promoting prolonged collagen synthesis and deposition and as a consequence sustained fibrotic response. During keloids formation, besides imbalanced ECM synthesis and degradation, fibroblast proliferation and it's resistance to apoptosis is observed. Key genes that may play a role in keloid formation and growth involve: suppressor gene p53.,cyclin-depend- ent kinase inhibitor CDKN1A (p21) and BCL2 family genes: antiapoptotic BCL-2 and proapoptotic BAX. Genistein (4',5,7-trihydroxyisoflavone) exhibits multidirectional biological action. The concentration of genistein is relatively high in soybean. Genistein has been shown as effective antioxidant and chemopreventive agent. Genistein can bind to estrogen receptors (ERs) and modulate estrogen action due to its structure similarity to human estrogens. Genistein also inhibits transcription factors NFkappaB. Akt and AP-l signaling pathways, that are important for cytokines expression and cell proliferation, differentiation, survival and apoptosis. The aim of the study was to investigate genistein as a potential inhibitor of CTGF and TGFbeta1, beta2 and beta3 isoforms expression and a potential regulator of p53. CDKN1A(p21), BAX and BCL-2 expression in normal fibroblasts and fibroblasts derived from keloids cultured in vitro. Real time RT-QPCR was used to estimate transcription level of selected genes in normal and keloid fibroblasts treated with genistein. Secreted/cell associated CTGF protein was evaluated in cell growth's medium by ELISA. Total protein quantification was evaluated by fluorimetric assay in cells llsates (Quant-iT TM Protein Assay Kit). It was found that TGFbeta1, beta2 and beta3 genes expression are decreased by genistein. Genistein suppresses the expression of CTGF mRNA and CTGF protein in a concentration dependent manner, p53 and p21 genes expression are modulated by genistein in concentration dependent manner. The agent also modulates BAX/BCL-2 ratio in examined cells in vitro. PMID- 25745771 TI - Influence of inositol hexaphosphate on the expression of selected proliferation markers in IL-1beta-stimulated intestinal epithelial cells. AB - The aim of the present study was to examine the influence of IP6, a naturally occurring phytochem- ical, on the expression of genes coding for proliferation markers, i.e., cyclin D1 (CCND1) and histone H3 in IL-1beta-stimulated intestinal cancer cell line Caco-2. Quantification of genes expression was carried out using real time RT-QPCR technique in Caco-2 cells after treatment with IL-1beta, 1 and 2.5 mM of IP6 for 3, 6 and 12 h. In separate cultures, cells were incubated with IL-1beta for the indicated times. The untreated Caco-2 cells were used as the control. In a time course experiment, stimulation of cells with IL-1beta only resulted in an overex- pression of both CCND1 and histone H3 mRNAs as compared with control. IP6 had no influence on IL-1beta-stimulated CCND1 expression for 3 and 6 h. After 12 h, statistically significant decrease in CCND1 mRNA was observed in cells exposed to IL-1beta and IP6 (1 and 2.5 mM) in relation to cells treated with IL-1beta only. The levels of H3 mRNA in IL-1beta-stimulated cells and cells treated with IL-1beta and IP6 revealed no statistically significant differences after 3 h. IP6 at 1 and 2.5 mM enhanced IL1beta-stimulated transcription of H3 gene after 6 h. Subsequently (12 h), the combination of IP6 and IL-1beta decreased H3 mRNA level compared to IL1beta-treated cells. In conclusion, pro-inflammatory cytokine IL-1beta up-regulates CCND1 and histone H3 mRNAs expression in Caco-2 cells. These results suggest that the ability of IP6 to inhibit colon cancer cells proliferation may be mediated through downregulation of genes encoding cyclin D1 and histone H3 at the mRNA level. PMID- 25745772 TI - Synthesis of chiral triazine coupling reagents based on esters of N-alkylproline and their application in the enantioselective incorporation of D or L amino acid residue directly from racemic substrate. AB - Esters of N-methylproline and N-allylproline were prepared and used as component for synthesis of chiral triazine based coupling reagents. N-Triazinylammonium tetrafluoroborate obtained from methylester of L-N-methylproline, 2-chloro-4,6 dimethozxy-1,3,5-triazine and tetrafluoroboric acid in the coupling of rac-Z- A1a OH with glycine methylester preferred formation of D-Z-AlaGly-OMe with L/D ratio 21/79. Coupling reagent prepared from D enantiomer of N-methylproline gave L-Z AlaGly-OMe with L/D ratio 75/25. PMID- 25745773 TI - Determination of organic volatile impurities in nepafenac by GC method. AB - The methods for controlling volatile impurities, including reagent and starting material, in Nepafenac active pharmaceutical ingredient, are reported. The proposed methods were developed using gas chromatography (GC) and gas chromatography with headspace injection (GC-HS) and validated according to the requirements of the ICH (International Conference of Harmonization) validation guidelines Q2R1 and the guideline for residual solvents Q3C. PMID- 25745774 TI - Bioresorbable copolymer of L-lactide and epsilon-caprolactone for controlled paclitaxel delivery. AB - Bioresorbable, aliphatic polyesters are known in medicine where serve as orthopedic devices (e.g., rods, pins and screws) or sutures and staples in wound closure. Moreover, such materials are extensively stud- ied as scaffolds--three dimensional structures for tissue engineering but also drug delivery systems (DDS). The aim of this study was to determine the release profile of paclitaxel, one of the anti-inflammatory, antiprolifera- tive and anti-restenotic agent, from biocompatible copolymer of L-lactide and epsilon-caprolactone that seems to be very attractive especially for minimally invasive surgery due to its potential shape-memory property. The influ- ence of drug on copolymer hydrolytic degradation was also analyzed. Three types of matrices (3%, 5% of PTX and without drug) were prepared by solvent-casting method and degraded in vitro. The physicochemical changes of copolymer were analyzed by means of nuclear magnetic resonance spectroscopy (NMR), gel per- meation chromatography (GPC) and differential scanning calorimetry (DSC). The amount of drug released into media was monitored with the use of high-pressure liquid chromatography (HPLC). Similar drug release pro- files were obtained for matrices with paclitaxel. The drug containing matrices degraded slightly slower than drug free matrices, regardless PTX content. Results of this work may be helpful in designing new bioresorbable paclitaxel delivery system applied in anti-cancer therapy or drug-eluting stents technology. PMID- 25745775 TI - Sensitive single quadrupole LC/MS method for determination of lapatinib in human plasma. AB - A sensitive liquid chromatographic-single quadrupole mass spectrometric method was developed and validated for the determination of lapatinib in human plasma. Following a liquid-liquid extraction with methyl t-butyl ether, lapatinib and isotope labelled lapatinib, used as an internal standard (IS), were separated from the endogenous compounds on a Zorbax SB-C18 (150 x 3 mm, 3.5 MUm) column. An isocratic elution with the mobile phase consisting of formic buffer and the mixture of acetonitrile, methanol and formic acid was used. Mass spectrometry with positive electrospray ionization in a single ion monitoring mode was applied. The proposed method provides the satisfactory recovery of lapatinib from human plasma and a sensitivity comparable to numerous tandem mass spectrometric methods, with a lower limit of quantification of 5 ng/mL. The validated method may be applied to pharmacokinetic studies in humans following a single 250 mg oral dose. PMID- 25745776 TI - Absorption and metabolism of biologically active genistein derivatives in colon carcinoma cell line (Caco-2). AB - Several genistein derivatives comprising an isoflavonoid skeleton substituted with an alkyl chain and a sugar moiety show ability to inhibit proliferation of cancer cells in vitro at the concentration several-fold lower than genistein. In our previous studies we shown that these compounds influenced the mitotic spindle, blocked the cell cycle and induced apoptosis. The purpose of this study was to determine the relationship between structural modifications of genistein molecule and the intestinal disposition of its derivatives. Transport and metabolism of these compounds were studied in the human intestinal Caco-2 model. The results of our study indicate that transport and metabolism of genistein derivatives depend both, on the structure of the carbonyl linker and position of genistein molecule substitution. All new compounds showed higher permeability coefficient in comparison to genistein. Moreover, genistein derivatives described in this work were transformed in Caco-2 cells into glucuronide and sulfate metabolites. PMID- 25745777 TI - Synthesis of new piroxicam derivatives and their influence on lipid bilayers. AB - A novel series of potentially biologically active 1,2-benzothiazine 1,1-dioxides- analogs of piroxicam (a recognized non-steroidal anti-inflammatory drug) were synthesized from commercially available saccharin. All of the synthesized compounds were subjected to preliminary evaluation for their ability to interact with lipid bilayers. The influence of the new derivatives of piroxicam on liposomes made of EYPC was investigated by fluorescence spectroscopy with two fluorescent probes--Laurdan and Prodan. All the studied compounds showed an interaction with model membranes. PMID- 25745779 TI - Antiproliferative effect of valproic acid and 5,7-dimethoxycoumarin against A2058 human melanoma cells. AB - Melanoma is one of the most malignant tumors of a dangerous high incidence and high metastatic potential. It grows quickly and in an advanced stage is resistant to radio-, chemo- and immunotherapy, which makes it difficult to cure. Therefore, research efforts are focused on the development of new therapeutics or chemopreventive strategies. The aim of the study was to investigate whether the valproic acid and 5,7-dimethoxycoumarin have an antiproliferative activity against A2058 human melanoma cell line. Investigated compounds inhibited the proliferation of cells, however, no synergistic effect of their co-administration was observed. PMID- 25745778 TI - In vitro evaluation of antiproliferative and cytotoxic properties of pterostilbene against human colon cancer cells. AB - Colon cancer has been remaining the second leading cause of cancer mortality in Poland in the last years. Epidemiological, preclinical and clinical studies reveal that dietary phytochemicals may exert chemopreventive and therapeutic effect against colorectal cancer. There is a growing interest in identifying new biologically active agents from dietary sources in this respect. Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a naturally occurring stilbene, that has been found to have antioxidative, anti-inflammatory and antipro- liferative properties. Compared to other stilbenes, pterostilbene has greater bioavailability, and so, a greater potential for clinical applications. Recent studies showed that pterostilbene exhibits the hallmark characteristics of an anticancer agent. The aim of this study was to analyze antiproliferative and cytotoxic effects of pterostilbene on human colon cancer Caco-2 cells. They were cultured using standard techniques and exposed to increasing doses of pterostilbene (5-100 MUM) for 48 and 72 h. Cell proliferation was determined by sulforhodamine B assay. The growth of treated cells was expressed as a percentage of that of untreated control cells. Pterostilbene decreased proliferation rate of Caco-2 cells in a dose- and time-dependent manner. Its concentrations = 25 MUM did not affect cell growth after 48 h treatment period. Significant growth inhibition was observed in cultures incubated with higher concentrations of pterostilbene (40-100 MUM). Pterostilbene at all concentrations used (5-100 MUM) caused significant inhibition of cell proliferation when the experimental time period was elongated to 72 h. The maximum growth reduction was observed at 100 mM pterostilbene. The cytotoxicity of pterostilbene was evaluated in 48 h cultures based on lactate dehydrogenase (LDH) leakage into the culture medium and showed dose-related pattern. The findings of this study showed significant dose dependent antiproliferative and cytotoxic effects of pterostilbene against human colon cancer cells in vitro. PMID- 25745780 TI - Polyunsaturated fatty acids potentiate cytotoxicity of cisplatin in A549 cells. AB - In normal and tumor cells, polyunsaturated fatty acids (PUFAs) act as intracellular second messengers, which play a role in signaling, proliferation and cell death. PUFAs have selective tumoricidal action and may alter sensitivity of tumor cells to cisplatin (CDDP), a commonly used anticancer agent. The aim of this study was to evaluate the influence of arachidonic acid (AA, 20:4 n-6), eicosapentaenoic acid (EPA, 20:5 n-3), docosahexaenoic acid (DHA, 22:6 n-3) and CDDP on autophagy and apoptosis in A549 human lung adenocarcinoma cells. Viability of A549 cells treated with CDDP and PUFAs was measured using the XTT tetrazolium salt based assay. Caspase-3/7 activity was estimated using ApoTox-Glo kit (Promega). Autophagic vac- uoles were detected by Cyto-ID Autophagy Detection Kit (Enzo). The results were compared to control cultures maintained in the absence of CDDP and PUFAs. PUFAs, in particular EPA and DHA, added to the cultivation medium, increased the antitumor activity of CDDP in A549 cells in a concentration dependent manner. In case of AA this effect was observed at the highest of the concentrations tested only (100 MUM). Both, EPA and DHA, but not AA, significantly increased the amount of autophagic vacuoles and induced caspase 3/7 activity. The obtained results suggest that the antiproliferative effect of CDDP in A549 cells can be enhanced by AA and in particular by EPA and DHA through their influence on autophagic and apoptotic cell death. It is likely that BPA and DHA incorporated to the tumor cells may improve outcomes in lung cancer patients. PMID- 25745781 TI - EPR studies of free radicals in A-2058 human melanoma cells treated by valproic acid and 5,7-dimethoxycoumarin. AB - Free radicals in A-2058 human melanoma cells were studied by the use of electron paramagnetic resonance (EPR) spectroscopy. The aim of this work was to determine the changes in relative free radical concentrations in tumor A-2058 cells after treatment by valproic acid (VPA) and 5,7-dimethoxycoumarin (DMC). The influences of VPA and DMC on free radicals in A-2058 cells were compared with those for human melanoma malignum A-375 and G-361 cells, which were tested by us earlier. Human malignant melanoma A-2058 cells were exposed to interactions with VPA, DMC, and both VPA and DMC. The tumor cells A-2058 were purchased from LGC Standards (Lomianki, Poland), and they were grown in the standard conditions: at 37 degrees C and in an atmosphere containing 95% air and 5% CO2, in the Minimum Essential Medium Eagle (MEM, Sigma-Aldrich). The A-2058 cells were incubated with VPA (1 mM) and DMC (10 MUM) for 4 days. The first-derivative EPR spectra of the control A-2058 cells, and the cells treated with VPA, DMC, and both VPA and DMC, were measured by the electron paramagnetic resonance spectrometer of Radiopan (Poznan, Poland) with microwaves from an X-band (9.3 GHz). The parameters of the EPR lines: amplitudes (A), integral intensities (I), line widths (DeltaBpp), and g factors, were analyzed. The changes of amplitudes and line widths with microwave power increasing from 2.2 to 70 mW were drawn evaluated, o-Semiquinone free radicals of melanin biopolymer are mainly responsible for the EPR lines of A-2058 melanoma malignum cells. The amounts of free radicals in A-2058 cells treated with VPA, and both VPA and DMC, were lower than in the untreated control cells. Application of the tested substances (VPA, and both VPA and DMC) as the antitumor compounds was discussed. DMC without VPA did not decrease free radicals concentration in A-2058 cells. The studies con-firmed that EPR spectroscopy may be used to examine interactions of free radicals with antitumor compounds. PMID- 25745782 TI - Fullerenes as the carriers of compounds with amide bond. PMID- 25745783 TI - Application of new data processing method for the photodiode array detector in the drug substance analysis. PMID- 25745784 TI - Synthesis of fucosylated uridine conjugates as potential glycosyltransferase inhibitors. PMID- 25745785 TI - Determination of the viscosity and density of veterinary vaccines. PMID- 25745786 TI - Transcripional activity of genes encoding MMPs and TIMPs in breast cancer cells treated by genistein and in normal cancer-associated fibroblasts--in vitro studies. PMID- 25745787 TI - CYP2C9 gene polymorphism in the pharmacological treatment of long QT patients. PMID- 25745788 TI - Development and validation of the GC method for the quantitative determination of semi-volatile solvents in the pharmaceutical substance bosentan. PMID- 25745789 TI - Measurement of the radioactivity of 137Cs in materials of plant origin with potential radioactive contamination. PMID- 25745790 TI - Secondary paroxysmal kinesigenic dyskinesia associated with CLCN2 gene mutation. PMID- 25745791 TI - Assessment and clinical factors associated with pain in patients undergoing transrectal prostate biopsy. AB - OBJECTIVES: To quantify the degree of pain experienced by patients who undergo ultrasound-guided transrectal prostate biopsy in standard clinical practice and assess the clinical factors associated with increased pain. MATERIAL AND METHODS: Analysis of a multicenter series of patients with prostate biopsy according to standard clinical practice. The biopsy was performed transrectally with a protocol of local anesthesia on the posterolateral nerve bundle. The pain was assessed at 20minutes into the procedure using the visual analog scale (0-10). The degree of pain was analyzed, and the association was studied using a univariate/multivariate analysis of selected clinical variables and the degree of pain. RESULTS: A total of 1188 patients with a median age of 64 years were analyzed. Thirty percent of the biopsies were diagnosed with a tumor. The median pain score was 2, with 65% of the patients reporting a pain score <=2. The multivariate analysis showed that the prostate volume (RR, 1.34; 95% CI 1.01 1.77; P=.04), having a previous biopsy (RR, 2.25; 95% CI 1.44-3.52; P<.01), age (RR, .63; 95% CI .47-.85; P<.01) and feel palpation (RR, 1.95; 95% CI 1.28-2.96; P<.01) were factors independently associated with greater pain during the procedure. CONCLUSIONS: Transrectal biopsy with local anesthesia is a relatively painless technique. Factors such as age, a previous biopsy, pain on being touched and prostate volume were associated with the presence of greater pain during the procedure. PMID- 25745792 TI - Laser transurethral resection of the prostate: Safety study of a novel system of photoselective vaporization with high power diode laser in prostates larger than 80mL. AB - OBJECTIVE: To present the feasibility of photoselective vaporization of the prostate (PVP) with of a new diode laser-resection system. Surgical treatment of benign prostatic hyperplasia (BPH) is constantly evolving. Laser techniques are increasingly used in prostates of large size. METHODS: A prospective study was performed to evaluate operative data and patient outcomes with PVP using high power diode laser (HPD) and a novel quartz-head fiber with shovel shape in patients with prostate>80mL. Demographic data, operative time, hemoglobin loss, operative results (IPSS, quality of life (QoL), Qmax, post void residue (PVR), IIEF-5 and micturition diary) and complications following Clavien-Dindo classification are described. RESULTS: Thirty-one patients were included in the study. Sixteen (51.6%) were on active antiplatelet treatment and 12 (38.7%) had received anticoagulants before surgery. All cases were followed at least 6mo. No intraoperative or postoperative major complications occurred. Three patients (9.7%) had minor complications according to Clavien-Dindo classification. Twenty seven (87.1%) were discharged on postoperative day one without catheter. There were significant improvements in IPSS, QoL, Qmax and PVR, both at 3 and 6mo (P<.0001), but sexual function according to IIEF-5 showed no differences. Urgency (any grade) increased at 3mo (48.4%; P=.002) and considerably decreased at 6mo (9.7%; P<.0001). CONCLUSION: This pilot experience with shovel shape fiber and HPD is encouraging. It shows that laser-resection is a safe procedure, achieving excellent results in terms of IPSS, QoL and Qmax in large prostates even in high risk patients. Longer follow-up, comparative and randomized controlled studies are needed to widespread these results. PMID- 25745793 TI - New insights into the molecular profile of lung adenocarcinoma and implications for therapy. AB - Lung cancer is a molecularly heterogeneous disease. The advent of next-generation sequencing techniques has significantly advanced our understanding of the complex molecular underpinnings of lung cancer. Furthermore, the development of targeted therapies has significantly altered the landscape of lung cancer therapy over the past decade. There is hence an increasing interest in developing a classification system that guides clinical management and also incorporates relevant genomic information. Here, we highlight the molecular features of lung adenocarcinoma as highlighted by several independent groups, and more recently The Cancer Genome Atlas and discuss their potential clinical significance. PMID- 25745794 TI - Evaluation of the pulmonary embolism rule-out criteria in a retrospective cohort at an urban academic hospital. AB - BACKGROUND: The pulmonary embolism rule-out criteria (PERC) is an 8-variable clinical decision rule that identifies patients at low risk for pulmonary embolism (PE) to prevent unnecessary diagnostic testing in the evaluation of suspected PE in the emergency department (ED). The objective of this study was to determine PERC's safety and diagnostic use in our institution's ED population. METHODS: We performed a retrospective analysis on consecutive adult patients evaluated with computed tomographic angiography (CTA) for suspicion of PE at our ED during the dates January 1, 2011, to December 31, 2011. Patients negative for all 8 PERC criteria (ie, "PERC [-]") were considered to be at low risk for PE. All data were analyzed using SPSS-20 (SPSS Inc, Chicago, IL) to calculate the variables of interest and their respective 95% confidence intervals (95% CIs). RESULTS: During the 12-month study period, 729 subjects were evaluated with CTA for suspicion of PE. Ten subjects were excluded because of nondiagnostic imaging studies. After exclusion, 719 subjects were available for analysis. Prevalence of PE was 4.5%. PERC (-) had a sensitivity of 96.9% (95% CI, 84.3%-99.4%), a negative predictive value of 98.8% (95% CI, 93.5%-99.8%), and a negative likelihood ratio of 0.26 (95% CI, 0.04-1.82) when used as an independent diagnostic test to exclude PE. CONCLUSIONS: Use of PERC could have safely avoided 11.5% of CTAs, reducing potential patient harm, health care costs, and unnecessary diagnostic testing. Consistent with prior studies, PERC can be safely used to identify low-risk patients for whom further testing can be deferred. PMID- 25745795 TI - The relationship between vascular inflammation and target organ damage in hypertensive crises. AB - OBJECTIVE: Hypertensive crises, divided depending on the presence of target organ damage (TOD), are associated with increased cardiovascular mortality and morbidity. Monocyte chemoattractant protein-1 (MCP-1) is responsible for the recruitment of monocytes to sites of vascular inflammation. The aim of this study was to evaluate the role of vascular inflammation in development of TOD. METHOD: The patients were categorized according to the presence of TOD. Thirty-three patients (15 female; mean age, 68 +/- 12 y) with TOD and 30 patients (14 female; mean age, 64 +/- 12 y) without TOD were included to the study. In addition to routine laboratory parameters, neutrophil-lymphocyte ratio, uric acid, C-reactive protein (CRP), high sensitive CRP, and plasma MCP-1 levels were evaluated. RESULTS: Neutrophil counts, white blood cells, high sensitive CRP, and uric acid levels were higher in patients with hypertensive crises. More importantly, CRP (7.2 mg/dL [2-37.8 mg/dL] vs 4.6 mg/dL [1.5-14 mg/dL] vs 2.7 mg/dL [1-8.1 mg/dL], P < .01) and MCP-1 levels (546 pg/mL [236-1350 pg/mL] vs 407 pg/mL [78-942 pg/mL] vs 264 pg/mL [34-579 pg/mL], P < .01) were higher in the group with TOD compared with other groups. CONCLUSION: In conclusion, plasma MCP-1 levels were significantly higher in patients with TOD. According to our results, we suggest that increased vascular inflammation and MCP-1 levels might be associated with the development of TOD in hypertensive crisis. PMID- 25745796 TI - Assessment of the electronic medical record in documenting trauma resuscitations in the pediatric ED. PMID- 25745797 TI - Successful treatment of metoprolol-induced cardiac arrest with high-dose insulin, lipid emulsion, and ECMO. AB - beta-Adrenergic antagonist toxicity causes cardiovascular collapse often refractory to standard therapy. Alternative therapies include high-dose insulin, lipid emulsion, and venoarterial extracorporeal membrane oxygenation (VA-ECMO). A 47-year-old man ingested 10 g of metoprolol tartrate in a suicide attempt. Upon emergency department presentation, he was comatose, bradycardic, and hypotensive. Glucagon (14 mg IV) and vasopressor/inotropic support (epinephrine 0.1 MUg/[kg min], dobutamine 10 MUg/[kg min]) were administered. Despite these therapies, he developed cardiac arrest for 55 minutes, requiring epinephrine (5 mg IV) and vasopressin (40 U IV) with multiple episodes of return of spontaneous circulation. Additional vasopressor administration (vasopressin 0.04 U/min, norepinephrine 0.5 MUg/[kg min]) did not improve his hemodynamics. High-dose insulin (250 U IV) and 20% lipid emulsion (100 mL bolus with 200 mL/30 min infusion) were administered, and VA-ECMO was initiated with hemodynamic improvement. His postarrest neurologic examination demonstrated lack of brainstem reflexes and cortical motor response. He awoke 11.5 hours after time of ingestion. Venoarterial extracorporeal membrane oxygenation was discontinued at hospital day 3, and the patient was discharged on hospital day 10 with excellent neurologic recovery. A serum metoprolol level measured 25,000 ng/mL (therapeutic 20-340 ng/mL). High-dose insulin has been shown to be beneficial in beta adrenergic antagonist cardiotoxicity. Lipid emulsion is thought to act as a lipid extractor, lowering serum and tissue levels. Venoarterial extracorporeal membrane oxygenation was used with the above therapies, restoring organ perfusion and allowing intrinsic drug metabolism and elimination. High-dose insulin, lipid emulsion, and VA-ECMO should be considered for refractory cardiac arrest secondary to beta-adrenergic antagonist toxicity such as metoprolol. PMID- 25745798 TI - Clinical predictors for delirium tremens in patients with alcohol withdrawal seizures. AB - BACKGROUND: Delirium tremens (DT) is the severest form of alcohol withdrawal syndrome, frequently after alcohol withdrawal seizures. Delirium tremens occurs in a small proportion of patients with alcohol withdrawal seizures; nevertheless, early identification of high-risk patients is important for intensive preventive management of unexpected episodes due to agitation and its associated increased mortality. However, there are limited studies on clinical predictors of the development of DT in patients with alcohol withdrawal seizures. METHODS: Patients who visited the emergency department with acute seizures were included in the study when alcohol withdrawal was the only or the strongest precipitating factor for seizures. All patients were carefully observed for at least 48 hours in the intensive care unit after the initial assessment to closely monitor vital signs and development of DT. Clinical and laboratory findings were analyzed for predicting the development of DT. RESULTS: Of the 97 patients (82 males; mean age, 48.6 +/- 13.3 years) with alcohol withdrawal seizures, 34 (35.1%) developed DT. Low platelet count, high blood level of homocysteine, and low blood level of pyridoxine were associated with the subsequent development of DT. Low platelet count and high blood level of homocysteine were independent risk factors with high diagnostic sensitivity and specificity for the development of DT. CONCLUSIONS: The study indicated that some easily determined parameters are potential clinical predictors for the development of DT in patients with alcohol withdrawal seizures. These findings would be helpful in clinical identification and management patients at high risk for DT. PMID- 25745799 TI - Preprocedure change in arterial occlusion in acute ischemic stroke patients undergoing endovascular treatment by computed tomographic angiography. AB - BACKGROUND: The American Heart Association/American Stroke Association guidelines strongly recommend a noninvasive intracranial vascular study such as computed tomographic (CT) angiogram in acute stroke patient if endovascular treatment is contemplated. OBJECTIVE: The objective was to determine the frequency of change in occlusion site between CT angiogram and cerebral angiogram in acute ischemic stroke patients undergoing endovascular treatment. METHODS: All acute ischemic stroke patients who underwent a CT angiogram and subsequently underwent endovascular treatment were included. The CT and cerebral angiographic images were reviewed independently to determine presence and location of arterial occlusion. Severity of occlusion was classified by a previously described grading scheme. Clinical outcome at discharge was determined using modified Rankin scale. RESULTS: Computed tomographic angiogram was performed in 150 patients (mean age +/- SD, 64.7 +/- 16 years) before endovascular treatment. The mean interval (+/ SD) between CT angiogram and cerebral angiogram was 193 +/- 164 minutes, and 65 (43.3%) of 150 patients received intravenous recombinant tissue plasminogen activator before cerebral angiography. Recanalization between CT angiogram and cerebral angiography was seen in 28 (18.7%) patients, whereas worsening of occlusion was seen in 31 (20.7%) patients. We noticed a trend towards higher rates of improvement (60.7% vs 42.0%, P = .07) and favorable outcome at discharge (42.9% vs 28.7%, P = .1) among patients who experienced preprocedure recanalization. After adjusting for age and initial National Institutes of Health Stroke Scale score strata, preprocedure recanalization was not associated with significantly higher rate of favorable outcome (modified Rankin scale, 0-2) at discharge (odds ratio, 2.1; 95% confidence interval, 0.8-5.5). After adjusting for age and National Institutes of Health Stroke Scale score strata, preprocedure worsening was not associated with significantly lower rates of favorable outcomes at discharge (odds ratio,0.4; 95% confidence interval, 0.1-1.4). CONCLUSIONS: A relatively high proportion of patients have preprocedure recanalization or worsening between CT angiogram and cerebral angiogram in acute ischemic stroke patients selected for endovascular treatment. PMID- 25745800 TI - Knowledge, attitudes, and practices regarding infection prevention among emergency medical services providers. PMID- 25745801 TI - A Multi-Step Algorithm for Measuring Airway Luminal Diameter and Wall Thickness in Lung CT Images. AB - Accurate measurements of airway diameter and wall thickness are important parameters in understanding numerous pulmonary diseases. Here, we describe an automated method of measuring small airway luminal diameter and wall thickness over numerous contiguous computed tomography (CT) images. Using CT lung images from 22 patients and an airway phantom, a seeded region-growing algorithm was first applied to identify the lumen of the airway. The result was applied as an initial region for boundary determination using the level set method. Once found, subsequent algorithmic expansion of the luminal border was used to calculate airway wall thickness. This algorithm automatically evaluates neighboring slices of the airway and measures the airway luminal diameter and wall thickness. This approach also detects airway bifurcations. Our new procedure provides rapid, automated, accurate, and clinically important lung airway measurements that would be useful to radiologists who use CT images for pulmonary disease assessment. PMID- 25745802 TI - A morphological algorithm for measuring angle of airway branches in lung CT images. AB - Accurate measurement of human airway lumen bifurcation angle in the bronchial tree may be an important parameter for evidence of pulmonary diseases. Here, we describe a new method for recognizing and following airway bifurcation over numerous contiguous CT images. Based on morphological properties of airways and specific changes to airway properties while digitally navigating through the bifurcation, our method is able to track airways through several levels of bifurcation. Then, based on the center of the lumen area, determined by the level set segmentation algorithm, we estimate the centerline of each branch and calculate the angle between two bifurcating branches. By applying this method to an airway imaging phantom, we obtained accurate results in a short computational time. This new approach provides a rapid, automated, and accurate lung airway angle measurement and may prove useful to radiologists who use CT images for pulmonary disease assessment. PMID- 25745803 TI - A mathematical framework for minimally invasive tumor ablation therapies. AB - Minimally invasive tumor ablations (MITAs) are an increasingly important tool in the treatment of solid tumors across multiple organs. The problems experienced in modeling different types of MITAs are very similar, but the development of mathematical models is mostly performed in isolation according to modality. Fundamental research into the modeling of specific types of MITAs is indeed required, but to choose the optimal treatment for an individual the primary clinical requirement is to have reliable predictions for a range of MITAs. In this review of the mathematical modeling of MITAs 4 modalities are considered: radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation. The similarities in the mathematical modeling of these treatments are highlighted, and the analysis of the models within a general framework is discussed. This will aid in developing a deeper understanding of the sensitivity of MITA models to physiological parameters and the impact of uncertainty on predictions of the ablation zone. Through robust validation and analysis of the models it will be possible to choose the best model for a given application. This is important because many different models exist with no objective comparison of their performance. The collection of relevant in vivo experimental data is also critical to parameterize such models accurately. This approach will be necessary to translate the field into clinical practice. PMID- 25745804 TI - Understanding the retina: a review of computational models of the retina from the single cell to the network level. AB - The vertebrate retina is a clearly organized signal-processing system. It contains more than 60 different types of neurons, arranged in three distinct neural layers. Each cell type is believed to serve unique role(s) in encoding visual information. While we now have a relatively good understanding of the constituent cell types in the retina and some general ideas of their connectivity, with few exceptions, how the retinal circuitry performs computation remains poorly understood. Computational modeling has been commonly used to study the retina from the single cell to the network level. In this article, we begin by reviewing retinal modeling strategies and existing models. We then discuss in detail the significance and limitations of these models, and finally, we provide suggestions for the future development of retinal neural modeling. PMID- 25745805 TI - Bibliometric mapping: eight decades of analytical chemistry, with special focus on the use of mass spectrometry. AB - In this Feature we use automatic bibliometric mapping tools to visualize the history of analytical chemistry from the 1920s until the present. In particular, we have focused on the application of mass spectrometry in different fields. The analysis shows major shifts in research focus and use of mass spectrometry. We conclude by discussing the application of bibliometric mapping and visualization tools in analytical chemists' research. PMID- 25745806 TI - Immune signaling pathways activated in response to different pathogenic micro organisms in Bombyx mori. AB - The JAK/STAT, Toll, Imd, and RNAi pathways are the major signaling pathways associated with insect innate immunity. To explore the different immune signaling pathways triggered in response to pathogenic micro-organism infections in the silkworm, Bombyx mori, the expression levels of the signal transducer and activator of transcription (BmSTAT), spatzle-1 (Bmspz-1), peptidoglycan recognition protein LB (BmPGRP-LB), peptidoglycan-recognition protein LE (BmPGRP LE), argonaute 2 (Bmago2), and dicer-2 (Bmdcr2) genes after challenge with Escherichia coli (E. coli), Serratiamarcescens (Sm), Bacillus bombyseptieus (Bab), Beauveriabassiana (Beb), nucleopolyhedrovirus (BmNPV), cypovirus (BmCPV), bidensovirus (BmBDV), or Nosemabombycis (Nb) were determined using real-time PCR. We found that the JAK/STAT pathway could be activated by challenge with BmNPV and BmBDV, the Toll pathway could be most robustly induced by challenge with Beb, the Imd pathway was mainly activated in response to infection by E. coli and Sm, and the RNAi pathway was not activated by viral infection, but could be triggered by some bacterial infections. These findings yield insights into the immune signaling pathways activated in response to different pathogenic micro-organisms in the silkworm. PMID- 25745807 TI - MASP-1 of the complement system promotes clotting via prothrombin activation. AB - Mannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity, and it has been shown to activate coagulation factors. Here we studied the effects of MASP-1 on clot formation in whole blood (WB) and platelet-poor plasma (PPP) by thrombelastography and further elucidated the underlying mechanism. Cleavage of prothrombin by MASP-1 was investigated by SDS PAGE and N-terminal sequencing of cleavage products. Addition of MASP-1 or thrombin to WB and PPP shortened the clotting time and clot formation time significantly compared to recalcified-only samples. The combination of MASP-1 and thrombin had additive effects. In a purified system, MASP-1 was able to induce clotting only in presence of prothrombin. Analysis of MASP-1-digested prothrombin confirmed that MASP-1 cleaves prothrombin at three cleavage sites. In conclusion, we have shown that MASP-1 is able to induce and promote clot formation measured in a global setting using the technique of thrombelastography. We further confirmed that MASP-1-induced clotting is dependent on prothrombin. Finally, we have demonstrated that MASP-1 cleaves prothrombin and identified its cleavage sites, suggesting that MASP-1 gives rise to an alternative active form of thrombin by cleaving at the cleavage site R393. PMID- 25745808 TI - Subcellular localization and activation of ADAM proteases in the context of FasL shedding in T lymphocytes. AB - The "A Disintegrin And Metalloproteinases" (ADAMs) form a subgroup of the metzincin endopeptidases. Proteolytically active members of this protein family act as sheddases and govern key processes in development and inflammation by regulating cell surface expression and release of cytokines, growth factors, adhesion molecules and their receptors. In T lymphocytes, ADAM10 sheds the death factor Fas Ligand (FasL) and thereby regulates T cell activation, death and effector function. Although FasL shedding by ADAM10 was confirmed in several studies, its regulation is still poorly defined. We recently reported that ADAM10 is highly abundant on T cells whereas its close relative ADAM17 is expressed at low levels and transiently appears at the cell surface upon stimulation. Since FasL is also stored intracellularly and brought to the plasma membrane upon stimulation, we addressed where the death factor gets exposed to ADAM proteases. We report for the first time that both ADAM10 and ADAM17 are associated with FasL containing secretory lysosomes. Moreover, we demonstrate that TCR/CD3/CD28 stimulation induces a partial positioning of both proteases and FasL to lipid rafts and only the activation-induced raft-positioning results in FasL processing. TCR/CD3/CD28-induced FasL proteolysis is markedly affected by reducing both ADAM10 and ADAM17 protein levels, indicating that in human T cells also ADAM17 is implicated in FasL processing. Since FasL shedding is affected by cholesterol depletion and by inhibition of Src kinases or palmitoylation, we conclude that it requires mobilization and co-positioning of ADAM proteases in lipid raft-like platforms associated with an activation of raft-associated Src family kinases. PMID- 25745809 TI - Oxidative dimerization of 2-oxindoles promoted by KO(t)Bu-I2: total synthesis of (+/-)-folicanthine. AB - A 'transition-metal-free' oxidative coupling of 2-oxindoles has been demonstrated in the presence of 1.2 equiv each of potassium tert-butoxide and iodine. The method yields a diverse range of structurally different homo- and heterodimerized 2-oxindoles bearing vicinal all-carbon quaternary centers of great synthetic importance. A radical-driven pathway has been tentatively proposed. PMID- 25745810 TI - Ethanol production by engineered thermophiles. AB - We compare a number of different strategies that have been pursued to engineer thermophilic microorganisms for increased ethanol production. Ethanol production from pyruvate can proceed via one of four pathways, which are named by the key pyruvate dissimilating enzyme: pyruvate decarboxylase (PDC), pyruvate dehydrogenase (PDH), pyruvate formate lyase (PFL), and pyruvate ferredoxin oxidoreductase (PFOR). For each of these pathways except PFL, we see examples where ethanol production has been engineered with a yield of >90% of the theoretical maximum. In each of these cases, this engineering was achieved mainly by modulating expression of native genes. We have not found an example where a thermophilic ethanol production pathway has been transferred to a non-ethanol producing organism to produce ethanol at high yield. A key reason for the lack of transferability of ethanol production pathways is the current lack of understanding of the enzymes involved. PMID- 25745811 TI - Health Benefits of Anthocyanins and Their Encapsulation for Potential Use in Food Systems: A Review. AB - Anthocyanins are one of the six subgroups of large and widespread group of plant constituents known as flavonoids. These are responsible for the bright and attractive orange, red, purple, and blue colors of most fruits, vegetables, flowers and some cereal grains. More than 600 structurally distinct anthocyanins have been identified in nature. Earlier, anthocyanins were only known for their coloring properties but now interest in anthocyanin pigments has intensified because of their possible health benefits as dietary antioxidants, which help to prevent neuronal diseases, cardiovascular illnesses, cancer, diabetes, inflammation, and many such others diseases. Ability of anthocyanins to counter oxidants makes them atherosclerosis fighters. Therefore, anthocyanin-rich foods may help to boost overall health by offering an array of nutrients. However, the incorporation of anthocyanins into food and medical products is a challenging task due to their low stability toward environmental conditions during processing and storage. Encapsulation seems to be an efficient way to introduce such compounds into these products. Encapsulating agents act as a protector coat against ambient adverse conditions such as light, humidity, and oxygen. Encapsulated bioactive compounds are easier to handle and offer improved stability. The main objective of this review is to explore health benefits of anthocyanins and their extraction, characterization, encapsulation, and delivery. PMID- 25745812 TI - Elevated plasma leptin levels of fasted rainbow trout decrease rapidly in response to feed intake. AB - Leptin has an anorexigenic effect in fish, indicating a role in regulation of growth and energy homeostasis. The study aimed to further clarify the physiological role of leptin in rainbow trout, specifically its short-term response to feed intake after a period of fasting. Utilizing a salmonid leptin radioimmunoassay, the study demonstrates differences in plasma leptin levels in fishes with different nutritional status and at the onset of feeding. Some of the fasted fish were clearly in a state of anorexia, and did not initiate feeding during the 72h refeeding period. For those fish that did initiate feeding, both previously fed and fasted, plasma leptin levels rapidly decreased during the first 24h in correlation with increased amount of food reaching the gastrointestinal tract, while non-feeding individuals retained a high plasma leptin levels. The data indicate that the leptin-induced anorexic state is broken after onset of feeding and that the regulatory mechanisms leading to decreased plasma leptin levels are linked to nutrient levels. PMID- 25745813 TI - Histomorphology of the bottlenose dolphin (Tursiops truncatus) pancreas and association of increasing islet beta-cell size with chronic hypercholesterolemia. AB - Bottlenose dolphins (Tursiops truncatus) can develop metabolic states mimicking prediabetes, including hyperinsulinemia, hyperlipidemia, elevated glucose, and fatty liver disease. Little is known, however, about dolphin pancreatic histomorphology. Distribution and area of islets, alpha, beta, and delta cells were evaluated in pancreatic tissue from 22 dolphins (mean age 25.7years, range 0 51). Associations of these measurements were evaluated by sex, age, percent high glucose and lipids during the last year of life, and presence or absence of fatty liver disease and islet cell vacuolation. The most common pancreatic lesions identified were exocrine pancreas fibrosis (63.6%) and mild islet cell vacuolation (47.4%); there was no evidence of insulitis or amyloid deposition, changes commonly associated with type 2 diabetes. Dolphin islet architecture appears to be most similar to the pig, where alpha and beta cells are localized to the central or periphery of the islet, respectively, or are well dispersed throughout the islet. Unlike pigs, large islets (greater than 10,000MUm(2)) were common in dolphins, similar to that found in humans. A positive linear association was identified between dolphin age and islet area average, supporting a compensatory response similar to other species. The strongest finding in this study was a positive linear association between islet size, specifically beta cells, and percent blood samples with high cholesterol (greater than 280mg/dl, R(2)=0.57). This study is the most comprehensive assessment of the dolphin pancreas to date and may help direct future studies, including associations between chronic hypercholesterolemia and beta-cell size. PMID- 25745814 TI - High temperature-induced sterility in the female Nile tilapia, Oreochromis niloticus. AB - High temperature treatments induce germ cell loss in gonads of vertebrate animals, including fish. It could be a reliable source for induction of sterility if the treatments led to a permanent loss of germ cells. Here we report that heat treatment at 37 degrees C for 45-60 days caused a complete loss of germ cells in female Nile tilapia, Oreochromis niloticus, and that sterility was achieved in fish at all stages of their life cycle. Unlike previous observations, germ cells did not repopulate even after returning them to the water at control conditions suggesting permanent depletion of germ cells. Gonadal somatic cells immunopositive for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were clustered at one end of the germ cell depleted gonads close to the blood vessel. Serum level of testosterone, 11-ketotestosterone, and 17beta-estradiol was significantly decreased in sterile fish compared to control. Body weight of sterile fish was higher than control fish at the end of experiment. Our observations of increased growth and permanent sterilization in the high temperature-treated fish suggest that this method could be an appropriate and eco friendly tool for inducing sterility in fish with a higher thermal tolerance. PMID- 25745815 TI - Development of neuroendocrine components of the thyroid axis in the direct developing frog Eleutherodactylus coqui: formation of the median eminence and onset of pituitary TSH production. AB - Direct-developing frogs lack, wholly or in part, a wide range of larval features found in metamorphosing species and form adult-specific features precociously, during embryogenesis. Most information on thyroid regulation of direct development relies on hormone manipulations; the ontogeny of many thyroid axis components has not been fully described. This analysis examines differentiation of the median eminence of the hypothalamus and production of thyroid-stimulating hormone (TSH) by the pituitary of the direct-developing frog Eleutherodactylus coqui. The median eminence is established two-thirds of the way through embryogenesis. Cells immunoreactive to human TSHbeta antibodies are first detected during embryogenesis and quantitative changes in TSHbeta-IR cells resemble those in metamorphosing amphibians. Formation of the median eminence of the hypothalamus and TSHbeta production by the pituitary precede or coincide with morphological changes during embryogenesis that occur during metamorphosis in biphasic anurans. Thus, while the onset of neuroendocrine regulation has changed during the evolution of direct development, it is likely that these thyroid axis components still mediate the formation of adult features. PMID- 25745816 TI - Expression of thyroid hormone transporters and deiodinases at the brain barriers in the embryonic chicken: Insights into the regulation of thyroid hormone availability during neurodevelopment. AB - Thyroid hormones (THs) are key regulators in the development of the vertebrate brain. Therefore, TH access to the developing brain needs to be strictly regulated. The brain barriers separate the central nervous system from the rest of the body and impose specific transport mechanisms on the exchange of molecules between the general circulation and the nervous system. As such they form ideal structures for regulating TH exchange between the blood and the brain. To investigate the mechanism by which the developing brain regulates TH availability, we investigated the ontogenetic expression profiles of TH transporters, deiodinases and the TH distributor protein transthyretin (TTR) at the brain barriers during embryonic and early postnatal development using the chicken as a model. In situ hybridisation revealed expression of the TH transporters monocarboxylate transporter 8 (MCT8) and 10 (MCT10), organic anion transporting polypeptide 1C1 (OATP1C1) and L-type amino acid transporter 1 (LAT1) and the inactivating type 3 deiodinase (D3) in the choroid plexus which forms the blood-cerebrospinal fluid barrier. This was confirmed by quantitative PCR which additionally indicated strongly increasing expression of TTR as well as detectable expression of the activating type 2 deiodinase (D2) and the (in)activating type 1 deiodinase (D1). In the brain capillaries forming the blood brain barrier in situ hybridisation showed exclusive expression of LAT1 and D2. The combined presence of LAT1 and D2 in brain capillaries suggests that the blood brain barrier forms the main route for receptor-active T3 uptake into the embryonic chicken brain. Expression of multiple transporters, deiodinases and TTR in the choroid plexus indicates that the blood-cerebrospinal fluid barrier is also important in regulating early TH availability. The impact of these barrier systems can be deduced from the clear difference in T3 and T4 levels as well as the T3/T4 ratio between the developing brain and the general circulation. We conclude that the tight regulation of TH exchange at the brain barriers from early embryonic stages is one of the factors needed to allow the brain to develop within a relative microenvironment. PMID- 25745817 TI - Puff and bite: the relationship between the glucocorticoid stress response and anti-predator performance in checkered puffer (Sphoeroides testudineus). AB - Individual variation in the endocrine stress response has been linked to survival and performance in a variety of species. Here, we evaluate the relationship between the endocrine stress response and anti-predator behaviors in wild checkered puffers (Sphoeroides testudineus) captured at Eleuthera Island, Bahamas. The checkered puffer has a unique and easily measurable predator avoidance strategy, which is to inflate or 'puff' to deter potential predators. In this study, we measured baseline and stress-induced circulating glucocorticoid levels, as well as bite force, a performance measure that is relevant to both feeding and predator defence, and 'puff' performance. We found that puff performance and bite force were consistent within individuals, but generally decreased following a standardized stressor. Larger puffers were able to generate a higher bite force, and larger puffers were able to maintain a more robust puff performance following a standardized stressor relative to smaller puffers. In terms of the relationship between the glucocorticoid stress response and performance metrics, we found no relationship between post-stress glucocorticoid levels and either puff performance or bite force. However, we did find that baseline glucocorticoid levels predicted the ability of a puffer to maintain a robust puff response following a repeated stressor, and this relationship was more pronounced in larger individuals. Our work provides a novel example of how baseline glucocorticoids can predict a fitness-related anti-predator behavior. PMID- 25745818 TI - Identification, expression and regulation of amphioxus G6Pase gene with an emphasis on origin of liver. AB - Vertebrate glucose-6-phosphatase (G6Pase) consists of three isozymes: G6Pase-I, G6Pase-II and G6Pase-III. Despite extensive study on G6Pases in vertebrates, information regarding expression and regulation of G6Pase genes is rather limited in invertebrates. Here we report the identification of G6Pase gene in amphioxus Branchiostoma japonicum, which is abundantly expressed in the digestive diverticulum and ovary in a tissue-specific manner. The phylogenetic and genomic structure analyses reveal that amphioxus G6Pase bears close resemblance to vertebrate G6Pase-III and represents the archetype of vertebrate G6Pase from which the vertebrate G6Pase isoforms may be originated by 2 rounds of genome duplication during vertebrate evolution. We also demonstrate that GH treatment induces a closely similar expression pattern and trend of g6pases in both zebrafish and amphioxus, and that G6Pase activity in amphioxus digestive diverticulum is subjected to regulation of feeding and fasting as observed in vertebrates. Collectively, all these provide functional evidences supporting the notion that the digestive diverticulum is the liver homologue playing a key role in maintaining the glucose homeostasis in amphioxus. PMID- 25745819 TI - The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians. AB - The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part i of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i)be inducers only in high doses; (ii)frequently combine with inhibitory properties; and (iii)take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i)sexual hormones, (ii) vitamin D, (iii)thyroid hormones, (iv)lipid metabolism, and (v)folic acid. PMID- 25745820 TI - Comorbidity of bipolar disorder and eating disorders. AB - INTRODUCTION: The comorbidity of bipolar disorder and eating disorders has not been studied in depth. In addition, clinical implications involved in the appearance of both disorders are very important. MATERIAL AND METHODS: A systematic literature review of MEDLINE published up to September 2013 was performed, analyzing all the articles that studied the comorbidity of both conditions (bipolar disorder and eating disorders) and others research that studied the efficacy of pharmacological treatment and psychotherapy to improve these illnesses. RESULTS: In this review we found a high comorbidity of bipolar disorder and eating disorders, especially of bulimia nervosa and binge eating disorder. Studies show that lithium and topiramate are 2 of the more effective pharmacological agents in the treatment of both disorders. CONCLUSION: There are a lot of studies that show evidence of comorbidity of bipolar disorder and eating disorders. However, further research is needed on assessment and treatment when these conditions co-exist, as well as study into the biopsychological aspects to determine the comorbid aetiology. PMID- 25745821 TI - Bone marrow iron distribution, hepcidin, and ferroportin expression in renal anemia. AB - OBJECTIVES: The hepcidin-ferroportin system is involved in both conditions associated with iron-restricted erythropoiesis in renal anemia: iron deficiency and anemia of chronic disorders. As serum hepcidin could aid diagnosis, we investigated its relationships with bone marrow iron distribution, hepcidin ferroportin expression in bone marrow cells, and peripheral iron indices in non dialysis chronic kidney disease (CKD) patients. METHODS: Fifty-four epoetin and iron naive CKD patients entered this prospective, observational study. According to bone marrow iron distribution (iliac crest biopsy, Perls' stain), 26 had iron deficiency anemia, 21 anemia of chronic disorders and 7 had normal iron stores. Medullar hepcidin and ferroportin expression (immunofluorescence (IF), semiquantitative scales) and serum hepcidin (Hep25 - ELISA) were the main studied parameters. RESULTS: Low hepcidin and high ferroportin expression by erythroblast and macrophage were seen in iron deficiency anemia, while the opposites were true in anemia of chronic disorders. In regression analysis, higher Hep25 and ferritin predicted hepcidin expression (R(2)=0.48; P < 0.0001), while lower ferritin and Hep25 - predicted ferroportin expression (R(2) = 0.29; P = 0.003) by erythroblast; inflammation had no contribution. In ROC analysis, serum hepcidin and ferritin had similar moderate utility in differentiating iron deficiency anemia from anemia of chronic disorders (AUC 0.63 95% CI 0.47-0.79 and 0.76 95% CI 0.61-0.90, respectively). CONCLUSIONS: Thus, in anemic epoetin naive non dialysis CKD patients, hepcidin and ferroportin expression by erythroblast and macrophage are closely related to bone marrow iron distribution. Although the hepcidin-ferroportin system seems regulated by ferritin-driven Hep25, serum hepcidin and peripheral iron indices are of little help in describing bone marrow iron status. PMID- 25745822 TI - Improving Concordance of MRI and PET/CT Interpretations With Retrospectively Coregistered MRI and PET/CT Data Sets. AB - This study evaluates if retrospective software-fused magnetic resonance imaging/positron emission tomography (MRI/PET) images can improve concordance of MRI and PET/computed tomography (CT) findings in the pelvis and improve overall lesion detection and characterization, as compared with independent side-by-side interpretation of MRI and PET data sets. Institutional review board approval was obtained for this retrospective study. Our institution's electronic medical record system was examined for pelvic MRI scans and whole-body (18)F fluorodeoxyglucose-PET/CT scans performed within a 2-month interval between January 2007 and June 2011. PET and MRI data sets for which there were discordant findings on original clinical reports were fused using software (Siemens TrueD, Erlangen, Germany). The fused MRI/PET data sets were reviewed by 2 radiologists for any evidence of metastatic disease in the pelvis. Interpretations were compared with original PET/CT and MRI reports (interpreted side by side), with pathology and imaging follow-up as the reference standard. Overall, 250 pairs of PET/CT and MRI scans were identified in 228 patients. A total of 57 discordant lesions were identified in 31 pairs of scans (12%) in 31 patients (14%). Software fusion resolved the discordance at 3 sites (5%) among 3 patients (10%), including 2 bone sites and a single nodal site. Software-fused MRI/PET is easy to perform and can increase the concordance rate of PET and MRI findings compared with side by-side interpretation, thereby improving confidence in lesion characterization. PMID- 25745823 TI - Placental expression of adenosine A(2A) receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system. AB - Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) promote angiogenesis and vascularisation. We investigated the temporal expression placental adenosine A2AR receptor and HIF-1alpha in early pregnancy and at delivery in normotensive (NT) and pre-eclamptic (PE) women. Results were compared to our previously reported angiotensin receptor data. Expression of A2AR and HIF-1alpha was highest at <=10 weeks, positively correlated through pregnancy and was higher in PE than NT at delivery. The A2AR associated with the AT4R only in early pregnancy. We suggest adenosine and RAS may interact to promote placentation with a potential adaptation to poor placental perfusion in PE. PMID- 25745824 TI - Dose effect of gestational ethanol exposure on placentation and fetal growth. AB - INTRODUCTION: Prenatal ethanol exposure compromises fetal growth by impairing placentation. Invasive trophoblastic cells, which mediate placentation, express the insulin-IGF regulated gene, aspartyl-asparaginyl beta-hydroxylase (ASPH), which has a critical role in cell motility and invasion. The aims of this study were to characterize effects of ethanol on trophoblastic cell motility, and assess ethanol dose-dependent impairments in placentation and fetal development. METHODS: Pregnant Long Evans dams were fed with isocaloric liquid diets containing 0%, 8%, 18% or 37% ethanol (caloric content) from gestation day (GD) 6 to GD18. Fetal development, placental morphology, density of invasive trophoblasts at the mesometrial triangle, as well as placental and mesometrial ASPH and Notch-1 protein expression were evaluated. Directional motility of control and ethanol-exposed HTR-8/SVneo cells was assessed by ATP Luminescence Based assay. RESULTS: Severity of fetal growth impairment correlated with increasing doses of ethanol. Ethanol exposure produced dose-dependent alterations in branching morphogenesis at the labyrinthine zone, and inhibited physiological transformation of maternal arteries. ASPH and Notch-1 protein expression levels were reduced, corresponding with impairments in placentation. DISCUSSION: Prenatal ethanol exposure compromises fetal growth and placentation in a dose responsive manner. Ethanol's adverse effects on placental development are mediated by: (1) altered branching morphogenesis in labyrinthine zone; (2) suppression of invasive trophoblastic precursor cells; and (3) inhibition of trophoblastic cell adhesion and motility, corresponding with reduced ASPH and Notch-1 protein expression. PMID- 25745825 TI - Multicenter Observational Study on Factors and Outcomes Associated with Various Methicillin-Resistant Staphylococcus aureus Types in Children with Cystic Fibrosis. AB - RATIONALE: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type. OBJECTIVES: We hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health care-associated" (SCCmec II) versus "community-associated" (SCCmec IV) MRSA strains. METHODS: To determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from patients not more than 18 years old at seven CF centers were typed and the association of potential risk factors and subsequent clinical course was assessed, using data provided by the CF Patient Registry. MEASUREMENTS AND MAIN RESULTS: Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%) had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IV PVL(+) strains. SCCmec IV, compared with SCCmec II, increased during the study period, 1996-2010 (P = 0.03). SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95% confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics were prescribed more frequently in those with SCCmec II strains and increased hospitalizations occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(+) strains (adjusted difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior. CONCLUSIONS: Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA detection regardless of SCCmec type. PMID- 25745826 TI - Effect of scapular dyskinesis on supraspinatus repair healing in a rat model. AB - BACKGROUND: Rotator cuff tears are common conditions that often require surgical repair to improve function and to relieve pain. Unfortunately, repair failure remains a common problem after rotator cuff repair surgery. Several factors may contribute to repair failure, including age, tear size, and time from injury. However, the mechanical mechanisms resulting in repair failure are not well understood, making clinical management difficult. Specifically, altered scapular motion (termed scapular dyskinesis) may be one important and modifiable factor contributing to the risk of repair failure. Therefore, the objective of this study was to determine the effect of scapular dyskinesis on supraspinatus tendon healing after repair. METHODS: A rat model of scapular dyskinesis was used. Seventy adult male Sprague-Dawley rats (400-450 g) were randomized into 2 groups: nerve transection of the accessory and long thoracic nerves (SD) or sham nerve transection (Sham control). After this procedure, all rats underwent unilateral detachment and repair of the supraspinatus tendon. All rats were sacrificed at 2, 4, and 8 weeks after surgery. Shoulder function, passive joint mechanics, and tendon properties (mechanical, histologic, organizational, and compositional) were evaluated. RESULTS: Scapular dyskinesis alters joint function and may lead to compromised supraspinatus tendon properties. Specifically, diminished mechanical properties, altered histology, and decreased tendon organization were observed for some parameters. CONCLUSION: This study identifies scapular dyskinesis as one underlying mechanism leading to compromise of supraspinatus healing after repair. Identifying modifiable factors that lead to compromised tendon healing will help improve clinical outcomes after repair. PMID- 25745827 TI - Total elbow arthroplasty in bleeding disorders: an additional series of 8 cases. AB - BACKGROUND: Total elbow arthroplasty (TEA) is a surgical option for an arthropathy secondary to a bleeding disorder. The literature consists of small case series. Our series provides further understanding into the outcomes of TEA in this population of patients. METHODS: Five patients underwent 8 primary TEAs for a bleeding disorder. Average age at time of surgery was 47 years. Four patients had hemophilia type A and 1 had von Willebrand disease. Clinical outcomes were evaluated with the Mayo Elbow Performance Score (MEPS) and the visual analog scale (VAS) for pain. Follow-up radiographs were evaluated for signs of loosening and infection. RESULTS: Revision surgery was performed in 3 TEAs. Two revisions were performed for aseptic loosening (104 and 118 months postoperatively). The third elbow underwent an excision arthroplasty for a deep infection 44 months postoperatively. Mean follow-up for the primary TEAs still in situ (5 elbows) was 114 months. The mean VAS score improved from 8 to 0 and MEPS from 35 to 95. The mean flexion arc improved from 70 degrees to 100 degrees , and rotation improved from 60 degrees to 160 degrees . Mean follow-up for the revised TEAs (3 elbows) was 94 months. The mean VAS score improved from 7 to 0 and the MEPS from 40 to 85. The mean flexion arc improved from 60 degrees to 95 degrees , and rotation improved from 70 degrees to 160 degrees . CONCLUSIONS: Excellent clinical outcomes and an acceptable survival rate for TEAs, comparable with the nonhemorrhagic population, can be achieved in patients with bleeding disorders. Revision arthroplasty in this group of patients yields good clinical outcomes at medium-term follow-up. PMID- 25745828 TI - Quantification of B2 glenoid morphology in total shoulder arthroplasty. AB - BACKGROUND: B2 glenoid morphology is challenging to address with shoulder reconstruction. Deformity often renders current techniques inadequate, necessitating compromises that limit long-term implant durability. The purpose of this study was to perform in vivo measurements of glenoid deformity to better appreciate the orientation of the B2 biconcavity demarcation and erosion that surgeons face intraoperatively. MATERIALS AND METHODS: A consecutive 106 total shoulder arthroplasty cases for primary glenohumeral osteoarthritis were studied. We classified glenoids by direct visualization and noted lines of biconcavity demarcation and erosion in B2s. We then calculated the "angle of erosion" as that between the back side of the unsupported, smooth-backed glenoid sizer disk and the neoglenoid. We obtained depth measurements throughout the reaming process and monitored subchondral bone. RESULTS: We classified 43 of 106 glenoids (41%) as B2. A biconcavity demarcation line between the paleoglenoid and the neoglenoid was present, on average, from the 1-o'clock to the 7-o'clock position for a left shoulder. Mean depth of erosion was 4.4 mm, occurring at 114 degrees on a Cartesian coordinate system for a left shoulder. The mean angle of erosion was 18 degrees (range, 8 degrees -43 degrees ). Despite reaming, 20 of 43 B2 glenoids (47%) had incompletely supported components at final seating. CONCLUSIONS: Arthritic B2 glenoids are common, and their maximal erosion is usually posteroinferior. Use of standard glenoid components to reconstruct them may require significant subchondral bone removal to achieve complete bone support. Alternatively, as a compromise, maintenance of subchondral bone in these cases requires implanting components with incomplete bony support. PMID- 25745829 TI - An introduction to basic quality metrics for practicing radiologists. PMID- 25745831 TI - Health-related physical fitness in patients with bipolar disorder vs. healthy controls: an exploratory study. AB - BACKGROUND: Low physical fitness has been recognized as a prominent behavioral risk factor for cardiovascular diseases and an independent risk factor for all cause mortality. To date, no studies have systematically assessed physical fitness in patients with bipolar disorder. The aim of the current study was to assess and compare the physical fitness in patients with bipolar disorder against healthy controls. METHODS: Thirty patients with bipolar disorder (16?, 40.8+/ 11.6 years) and 30 age-, gender- and body mass index (BMI)-matched healthy controls were included. All participants performed the Eurofit test battery and the International Physical Activity Questionnaire. Patients were screened for psychiatric symptoms using the Quick Inventory of Depressive Symptomatology and Hypomania Checklist-32. RESULTS: Patients with bipolar disorder had a reduced speed of limb movement (15.8+/-5.7 vs. 11.8+/-2.2s; p<0.001), explosive leg muscle strength (134.9+/-49.0 vs. 167.6+/-32.3cm; p=0.003) and abdominal muscular endurance (11.5+/-7.8 vs. 18.3+/-7.6; p<0.001). Backward regression analyses demonstrated that longer illness duration, higher body mass index, higher levels of depression and a lower physical activity level explained the variance in physical fitness. LIMITATIONS: Our data are cross-sectional and cannot establish cause and effect. CONCLUSIONS: The current findings suggest that a lower physical fitness is emerging as an eminent modifiable risk factor for somatic co-morbidity in people with bipolar disorder. In particular less physically active persons, those with a longer illness duration and those with higher levels of depression might benefit from specific rehabilitation interventions aimed at increasing physical fitness. PMID- 25745830 TI - Intradermal vaccination using the novel microneedle device MicronJet600: Past, present, and future. AB - Intradermal immunization has become a forefront of vaccine improvement, both scientifically and commercially. Newer technologies are being developed to address the need to reduce the dose required for vaccination and to improve the reliability and ease of injection, which have been major hurdles in expanding the number of approved vaccines using this route of administration. In this review, 7 y of clinical experience with a novel intradermal delivery device, the MicronJet600, which is a registered hollow microneedle that simplifies the delivery of liquid vaccines, are summarized. This device has demonstrated both significant dose-sparing and superior immunogenicity in various vaccine categories, as well as in diverse subject populations and age groups. These studies have shown that intradermal delivery using this device is safe, effective, and preferred by the subjects. Comparison with other intradermal devices and potential new applications for intradermal delivery that could be pursued in the future are also discussed. PMID- 25745832 TI - Suicidal ideation and mental health disorders in young school children across Europe. AB - INTRODUCTION: The aim of this study is to measure the prevalence of suicidal ideation and thoughts of death in elementary school children in a European survey and to determine the associated socio-demographic and clinical factors. METHODS: Data refer to children aged 6-12 (N=7062) from Italy, Turkey, Romania, Bulgaria, Lithuania, Germany, and the Netherlands randomly selected in primary schools. Suicidal thoughts and death ideation were measured using a computerized pictorial diagnostic tool from the Dominic Interactive (DI) completed by the children. The Strengths and Difficulties Questionnaire (SDQ) was administrated to teachers and parents along with a socio-demographic questionnaire. RESULTS: Suicidal ideation was present in 16.96% of the sample (from 9.9 in Italy to 26.84 in Germany), death thoughts by 21.93% (from 7.71% in Italy to 32.78 in Germany). SI and DT were more frequent in single-parent families and large families. Externalizing disorders were strongly correlated with SI and DT after controlling for other factors and this was true for internalizing disorders only when reported by the children. CONCLUSION: Recognizing suicidal ideation in young children may be recommended as part of preventive strategies such as screening in the context of the presence of any mental health problems whether externalizing or internalizing. PMID- 25745833 TI - The epidemiological characteristics of depressive symptoms in the left-behind children and adolescents of Chongqing in China. AB - OBJECTIVE: To assess the prevalence rate of depressive symptoms in left-behind participants aged 7-17 years and to explore the associated socio-demographic and communication factors. METHODS: Participants were 4857 left-behind children and adolescents in Chongqing. They were screened for depressive symptoms using a 27 item Children's Depression Inventory (CDI) and social-demographic variables were evaluated with a structured scale. Uncorrected Pearson chi-square test and logistic regression were applied to analyzing the data. RESULTS: The total prevalence rate of depressive symptoms was 24.8%. Significant difference was found in the prevalence rate of depressive symptoms among groups of different income, grade, age, left-behind subtypes, and different frequency, ways and topics of parent-child communication. We found that the risk factors for depression were absence of parents, low frequency of parent-child communication, and communication by letter or about sensitive topics. The grade group 2-3 and age group 16-17 were at a higher risk of depression than all other grade and age subgroups. The protective factors for depression were high-income, high frequency of parent-child communication, communication by telephone or about such topic as learning experience, school life, and feelings. LIMITATIONS: Self-report bias and cross-sectional nature of the sampling are major limitations of this study. CONCLUSIONS: The prevalence rate of depressive symptoms among left-behind children and adolescents in Chongqing is much higher than previously reported prevalence in other regions of China. The risk and protective factors for depression among left-behind children and adolescents are worthy of public attention. PMID- 25745835 TI - An examination of myth: a favorable cardiovascular risk-benefit analysis of high dose thyroid for affective disorders. AB - INTRODUCTION: High dose thyroid (HDT) is included in major treatment guidelines for the treatment of bipolar disorders. Yet it is seldom used partly based on perceived cardiovascular risks. The cardiovascular risks of HDT are examined. METHODS: A literature search was conducted for the cardiovascular risks of HDT and for comparisons sake psychiatric medications. Case reports of atrial fibrillation (afib) associated with HDT are reported. RESULTS: While hyperthyroidism is a significant cardiovascular risk factor causing a 20% premature death rate, HDT treatment does not appear to be of significant cardiovascular risk. HDT differs from hyperthyroidism in significant ways. The sequela of hyperthyroidism are increasingly tied to autoimmune complications which are absent with HDT. Equating hyperthyroidism with HDT is incorrect. The five case reports of HDT treatment associated with afib were potentially caused by other factors. If HDT increases the risks of afib, monitoring for afib would minimizes the risk. Even in overt hyperthyroidism the risk of other arrhythmias are minimal. When compared to many psychiatric medications HDT is as safe or safer. LIMITATIONS: There are no direct studies of cardiovascular risks of HDT for affective patients. High tolerance of a medication does not necessarily imply lack of risk. The five case reports were spontaneous, other cases may not have been reported. CONCLUSION: The cardiovascular risks of HDT appear to be low. HDT is at least as safe as or safer than many psychiatric medications. It is effective and well tolerated. PMID- 25745834 TI - Why are suicidal thoughts less prevalent in older age groups? Age differences in the correlates of suicidal thoughts in the English Adult Psychiatric Morbidity Survey 2007. AB - BACKGROUND: Suicidal ideation is more strongly associated with suicidal intent in later life, so risk factors may also differ by age. We investigated whether the relationship between suicidal ideation and established correlates varied by age in a representative population. METHODS: We used data from the 2007 Adult Psychiatric Morbidity Survey of England to assess the relationship between age and suicidal thoughts across 20-year age bands, using logistic regression, adjusted for survey weights. We used mediation analyses to assess the extent to which other factors mediate the relationship between suicidal thoughts and age. RESULTS: Reports of previous-year suicidal thoughts decreased with age. This was partly explained by (1) lower rates of reported child abuse (in those aged 75+), of depression, and of anxiety symptoms (in those aged 55+), factors all strongly associated with suicidal thoughts, and (2) higher rates of protective factors in people aged 35+, specifically homeownership and cohabitation. Rates of phobias, irritability and compulsions also decreased with age, and the association of these symptoms with suicidal thoughts was particularly strong in the youngest (16 34) age group. People who reported experiencing childhood abuse in all age groups reported more suicidal thoughts, suggesting abuse has lifelong negative effects on suicidal ideation. LIMITATIONS: The response rate was 57%. Older people may be less likely to recall childhood abuse. CONCLUSIONS: Sexual and physical abuse in childhood are associated with suicidal ideas throughout the lifespan, so screening for suicidal ideas in younger and older people should be routine and vigorous, and cover experiences in early life: management may require appropriate psychological interventions. PMID- 25745836 TI - The Bipolarity Index: a clinician-rated measure of diagnostic confidence. AB - BACKGROUND: The Bipolarity Index is a clinician-rated scale that rates cardinal features of the disorder across five domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. We tested the Index in routine clinical practice to identify the optimal cut-off for distinguishing bipolar from non-bipolar disorders. METHOD: Sequential patients in a private practice were rated with the Bipolarity Index (n=1903) at intake. Diagnoses were made with the MINI-6.0.0 International Neuropsychiatric Interview according to DSM-IV-TR criteria, except that cases of antidepressant-induced mania and hypomania were included in the bipolar group. A subset completed the self-rated Mood Disorder Questionnaire (MDQ) (n=1620) or Bipolar Spectrum Diagnostic Scale (BSDS) (n=1179). The primary analysis compared Bipolarity Index scores for bipolar vs. non-bipolar patients using receiver operator curves (ROC) to determine the optimal cut-off score. Secondary outcomes repeated this analysis with the MDQ, MDQ-7 (using only the symptomatic items of the MDQ) and BSDS. RESULTS: At a cut-off of >=50, the Bipolarity Index had a high sensitivity (0.91) and specificity (0.90). Optimal cut-offs for self-rated scales were: MDQ: >=7 (sensitivity 0.74, specificity 0.71); MDQ-7: >=6 (sensitivity 0.77, specificity 0.77); BSDS: >=12 (sensitivity 0.71, specificity 0.77). LIMITATIONS: The study utilized one rater at a single practice site; the rater was not blinded to the results of the MINI. CONCLUSION: The Bipolarity Index can enhance the clinical assessment of mood disorders and, at a score >=50 has good sensitivity and specificity for identifying bipolar disorders. PMID- 25745837 TI - Mental health interventions and future major depression among primary care patients with subthreshold depression. AB - BACKGROUND: Subthreshold depression is prevalent in primary care and is associated with poorer quality of life, higher health care use and increased risk of major depressive disorder (MDD). Currently, it is unclear how subthreshold depression should be managed in primary care and no studies have investigated the relationship between current models of care and the development of MDD. This study aimed to describe usual care over a six month follow-up for primary care patients with subthreshold depression and to investigate the relationship between usual care and the development of MDD. METHODS: Data were derived from 250 participants with subthreshold depression from the diamond study, a longitudinal cohort study of primary care patients. Participants completed questionnaires at three and six months on their health care use, the interventions they received and their depression status. Interventions were categorised according to the NICE guidelines for the management of depression in adults. Generalised estimating equation (GEE) models and logistic regression were used to estimate the association between receiving an intervention and MDD over six months. RESULTS: Four fifths (80.8%) of participants received a mental health intervention. Therapeutic listening, reassurance, pharmacotherapy and advice to exercise were most common. Subsequent MDD was predicted by history of depression, baseline depressive symptom severity and receiving a mental health intervention. LIMITATIONS: Usual care was assessed via patient self-report. CONCLUSIONS: Primary care physicians deliver mental health interventions to most subthreshold patients. However, it appears that current interventions are not averting MDD. Further research to identify effective interventions which are feasible in primary care is needed. PMID- 25745838 TI - A new concept of maternity blues: Is there a subgroup of women with rapid cycling mood symptoms? AB - BACKGROUND: Rapid cycling mood symptoms during the first postpartum week are an important aspect of maternity blues. The aim of this study is to identify women with these rapid cycling mood symptoms in the general population and to investigate possible risk factors of these symptoms. METHODS: The Maternity Blues Scale (MBS) was validated in The Netherlands in 949 women at one week postpartum. Personal and family history of mood disorders and obstetric demographics were collected and the Edinburgh Postnatal Depression Scale (EPDS) was completed. A 16 item three-factor MBS solution was found: depression, negative and positive affect. The latter two were used to define a rapid cycling mood symptoms group. RESULTS: Using the 75th percentile cut-off, 20 (2%) women reported high negative/high positive affect (rapid cycling mood group) and 65 (7%) women were depressed (EPDS>=11). A previous episode of depression, major life events and instrumental delivery were independently related to depression (OR 3.5, 2.5 and 2.3, respectively) while only a history of depression in first-degree relatives was independently related to rapid cycling mood (OR 3.4, 95% CI 1.2-9.8). Limitations First, no syndromal diagnoses were obtained for depression and rapid cycling mood disorder. Second, history of depression was self-reported (not based on structural psychiatric interviews). Third, our study was not designed to study the longitudinal follow-up of women with rapid cycling mood symptoms. Conclusion the 16-item MBS could be useful in screening programs in detecting postpartum women at risk for (severe) mood disorders. Postpartum women with 'rapid cycling mood symptoms' can be identified with a possible more familiar form of mood disorder. PMID- 25745839 TI - Is suicide under the influence of alcohol a deliberate self-harm syndrome? An autopsy study of lethality. AB - BACKGROUND: Alcohol is a risk factor for suicide and is often involved in violent actions. The aim of the study was to assess the involvement of alcohol in suicides and its relationship with the lethality of suicide methods. METHODS: In a retrospective study on autopsy reports, we compared suicide and non-suicide victims, suicides with positive and negative blood alcohol concentration (BAC), and studied the lethality of suicide methods using a multivariate analysis. RESULTS: Suicide victims (n=88) were not different to non-suicide victims (n=270) for positive BAC and narcotics, but were more often positive for prescription medications (59.1 vs. 35.6%, p=0.003) and medications in blood (72.7 vs. 54.8%, p=0.004). Whereas non-suicidal victims died mainly of traumas (60%, p<0.001), two populations of suicides emerged with regard to BAC, self-poisoning predominating with positive BAC (38.9%, p=0.039) and asphyxiation with negative BAC (41.4%, p=0.025). Positive BAC appeared as the unique and strong independent predictive factor, increasing the risk of self-poisoning suicide by 4.36 [1.29-14.76], and decreasing the risk of suicidal asphyxiation by 84% (OR=0.16 [0.03-0.83]). Positive blood narcotics tended to behave in the similar way to alcohol. LIMITATIONS: Recruitment bias (victims declared by the Forensic authorities) and incomplete autopsy reports are the two main limitations. CONCLUSIONS: Characteristics of suicide victims with positive BAC are suggestive of Deliberate Self-Harm Syndrome (low lethality methods, substance misuse). These being at high risk of repeated suicide attempts, previous self-harm involving alcohol may represent a warning sign and access to medication should be limited to prevent recidivism. PMID- 25745840 TI - Effects of prebiotic supplementation on the expression of proteins regulating iron absorption in anaemic growing rats. AB - Prebiotics may increase intestinal Fe absorption in anaemic growing rats. The present study evaluated the effects of high-performance (HP) inulin and oligofructose on factors that regulate Fe absorption in anaemic rats during the growth phase. Male Wistar rats aged 21 d of age were fed AIN-93G ration without Fe for 2 weeks to induce Fe-deficiency anaemia. The rats were fed on day 35 a control diet, or a diet with 10 % HP inulin, or a diet with 10 % oligofructose, without Fe supplementation. The animals were euthanised after 2 weeks, and segments of the duodenum, caecum, colon and liver were removed. The expression levels of proteins in the intestinal segments were assessed using Western blotting. The levels of serum, urine and liver hepcidin and the concentrations of IL-10, IL-6 and TNF-alpha in the caecum, colon and liver were measured using the ELISA test. HP inulin increased the expression of the divalent metal transporter 1 protein in the caecum by 162 % (P= 0.04), and the expression of duodenal cytochrome b reductase in the colon by 136 % (P= 0.02). Oligofructose decreased the expression of the protein ferroportin in the duodenum (P= 0.02), the concentrations of IL-10 (P= 0.044), IL-6 (P= 0.036) and TNF-alpha (P= 0.004) in the caecum, as well as the level of urinary hepcidin (P< 0.001). These results indicate that prebiotics may interfere with the expression of various intestinal proteins and systemic factors involved in the regulation of intestinal Fe absorption in anaemic rats during the growth phase. PMID- 25745841 TI - Barriers and facilitators to accessing skilled birth attendants in Afar region, Ethiopia. AB - OBJECTIVE: to explore barriers and facilitators that enable women to access skilled birth attendance in Afar Region, Ethiopia. DESIGN: researchers used a Key Informant Research approach (KIR), whereby Health Extension Workers participated in an intensive training workshop and conducted interviews with Afar women in their communities. Data was also collected from health-care workers through questionnaires, interviews and focus groups. PARTICIPANTS: fourteen health extension workers were key informants and interviewers; 33 women and eight other health-care workers with a range of experience in caring for Afar childbearing women provided data as individuals and in focus groups. FINDINGS: participants identified friendly service, female skilled birth attendants (SBA) and the introduction of the ambulance service as facilitators to SBA. There are many barriers to accessing SBA, including women's low status and restricted opportunities for decision making, lack of confidence in health-care facilities, long distances, cost, domestic workload, and traditional practices which include a preference for birthing at home with a traditional birth attendant. KEY CONCLUSIONS: many Afar men and women expressed a lack of confidence in the services provided at health-care facilities which impacts on skilled birth attendance utilisation. IMPLICATIONS FOR PRACTICE: ambulance services that are free of charge to women are effective as a means to transfer women to a hospital for emergency care if required and expansion of ambulance services would be a powerful facilitator to increasing institutional birth. Skilled birth attendants working in institutions need to ensure their practice is culturally, physically and emotionally safe if more Afar women are to accept their midwifery care. Adequate equipping and staffing of institutions providing emergency obstetric and newborn care will assist in improving community perceptions of these services. Most importantly, mutual respect and collaboration between traditional birth attendants (Afar women's preferred caregiver), health extension workers and skilled birth attendants will help ensure timely consultation and referral and reduce delay for women if they require emergency maternity care. PMID- 25745842 TI - Impact of gelation period on modified locust bean-alginate interpenetrating beads for oral glipizide delivery. AB - In this work, the effect of hydrogelation period in the design of glipizide loaded biopolymer-based interpenetrating network (IPN) beads was investigated. Carboxymethyl locust bean gum and sodium alginate IPN beads were prepared by ionic crosslinking method using aqueous aluminium chloride salt solution as gelation medium. The longer exposure of the IPN beads in the gelation medium caused a considerable loss of the drug (~ 8%), and also affected their surface morphology and drug release performance. Spherical shape of the IPN beads was observed under scanning electron microscope (SEM). The diameter of IPN beads increased with increasing gelation time. The IPNs cured for 0.5h exhibited slower drug release kinetics in HCl (pH 1.2) and phosphate buffer (pH 7.4) solution than those incubated for 1-2h. The drug release occurred at a faster rate in phosphate buffer solution and continued for a minimum period of 8h. The IPNs cured for the lowest period obeyed polymer chain-relaxation phenomenon as dominating mechanism for drug release. However, all the IPNs followed anomalous mechanism of drug transport. The drug release corroborated well with pH-dependent swelling behaviors of the IPNs. Thus, IPN beads cured for 0.5h were found most suitable for controlled delivery of BCS class II anti-diabetic drug glipizide. PMID- 25745843 TI - Effect of the competition of Cu(II) and Ni(II) on the kinetic and thermodynamic stabilities of Cr(III)-organic ligand complexes using competitive ligand exchange (EDTA). AB - The effect of competition of Cu(II) and Ni(II) on the kinetic stability of Cr(III) complexed with natural organic matter (NOM) was characterized using EDTA exchange with single-stage tangential-flow ultrafiltration. For a water sample from Serra de Itabaiana, 3% of spiked Cr(III) was exchanged, while for a sample from the Itapanhau River, 7, 10, 10, and 21% was exchanged in experiments using Cr(III) alone and in combination with Cu(II), Ni(II), or Cu(II) + Ni(II), respectively. Times required to reach exchange equilibrium with EDTA were less than 360 min. The influence of competition from Ni(II) and Cu(II) on the availability of complexed Cr(III) was low, demonstrating preference of the ligand sites for Cr(III). This was correlated with sample humification, as confirmed by EPR and (13)C NMR analyses. Exchange efficiency was in the order Cu > Ni > Cr, and the process could be readily described by first order kinetics, with average rate constants of 0.35-0.37 h(-1). PMID- 25745844 TI - A comparative review of environmental concern prioritization: LEED vs other major certification systems. AB - The matter of environmental concern prioritization integrated into globally used green building rating systems is a fundamental issue since it determines how the performance of a structure or development is reflected. Certain nationally developed certification systems are used globally without being subjected to adjustments with respect to local geographical, cultural, economic and social parameters. This may lead to a situation where the results of an evaluation may not reflect the reality of the region and/or the site of construction. The main objective of this paper is to examine and underline the problems regarding the issue of weighting environmental concerns in the Leadership in Energy and Environmental Design (LEED) certification system, which is a US-originated but globally used assessment tool. The methodology of this study consists of; (i) an analysis of the approach of LEED in the New Construction and Major Renovations scheme in version 3 (LEED NC, v.3) and the Building Design and Construction scheme in version 4 (LEED BD + C, v.4), (ii) case studies in which regional priority credits (RPCs) set by LEED for four countries (Canada, Turkey, China and Egypt) are criticized with respect to countries' own local conditions, and, (iii) an analysis of the approaches of major environmental assessment tools, namely; BREEAM, SBTool, CASBEE and Green Star, in comparison to the approach in LEED, regarding the main issue of this paper. This work shows that, even in its latest version (v.4) LEED still displays some inadequacies and inconsistencies from the aspect of environmental concern prioritization and has not yet managed to incorporate a system which is more sensitive to this issue. This paper further outlines the differences and similarities between the approaches of the aforementioned major environmental assessment tools with respect to the issue of concern and the factors that should be integrated into future versions of LEED. PMID- 25745845 TI - Relative contributions of set-asides and tree retention to the long-term availability of key forest biodiversity structures at the landscape scale. AB - Over previous decades new environmental measures have been implemented in forestry. In Fennoscandia, forest management practices were modified to set aside conservation areas and to retain trees at final felling. In this study we simulated the long-term effects of set-aside establishment and tree retention practices on the future availability of large trees and dead wood, two forest structures of documented importance to biodiversity conservation. Using a forest decision support system (Heureka), we projected the amounts of these structures over 200 years in two managed north Swedish landscapes, under management scenarios with and without set-asides and tree retention. In line with common best practice, we simulated set-asides covering 5% of the productive area with priority to older stands, as well as ~5% green-tree retention (solitary trees and forest patches) including high-stump creation at final felling. We found that only tree retention contributed to substantial increases in the future density of large (DBH >=35 cm) deciduous trees, while both measures made significant contributions to the availability of large conifers. It took more than half a century to observe stronger increases in the densities of large deciduous trees as an effect of tree retention. The mean landscape-scale volumes of hard dead wood fluctuated widely, but the conservation measures yielded values which were, on average over the entire simulation period, about 2.5 times as high as for scenarios without these measures. While the density of large conifers increased with time in the landscape initially dominated by younger forest, best practice conservation measures did not avert a long-term decrease in large conifer density in the landscape initially comprised of more old forest. Our results highlight the needs to adopt a long temporal perspective and to consider initial landscape conditions when evaluating the large-scale effects of conservation measures on forest biodiversity. PMID- 25745846 TI - Cholesterol-lowering activity of sesamin is associated with down-regulation on genes of sterol transporters involved in cholesterol absorption. AB - Sesame seed is rich in sesamin. The present study was to (i) investigate the plasma cholesterol-lowering activity of dietary sesamin and (ii) examine the interaction of dietary sesamin with the gene expression of sterol transporters, enzymes, receptors, and proteins involved in cholesterol metabolism. Thirty hamsters were divided into three groups fed the control diet (CON) or one of two experimental diets containing 0.2% (SL) and 0.5% (SH) sesamin, respectively, for 6 weeks. Plasma total cholesterol (TC) levels in hamsters given the CON, SL, and SH diets were 6.62 +/- 0.40, 5.32 +/- 0.40, and 5.00 +/- 0.44 mmol/L, respectively, indicating dietary sesamin could reduce plasma TC in a dose dependent manner. Similarly, the excretion of total fecal neutral sterols was dose-dependently increased with the amounts of sesamin in diets (CON, 2.65 +/- 0.57; SL, 4.30 +/- 0.65; and SH, 5.84 +/- 1.27 MUmol/day). Addition of sesamin into diets was associated with down-regulation of mRNA of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP-binding cassette transporters subfamily G members 5 and 8 (ABCG5 and ABCG8). Results also showed that dietary sesamin could up-regulate hepatic cholesterol-7alpha-hydroxylase (CYP7A1), whereas it down-regulated hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase and liver X receptor alpha (LXRalpha). It was concluded that the cholesterol-lowering activity of sesamin was mediated by promoting the fecal excretion of sterols and modulating the genes involved in cholesterol absorption and metabolism. PMID- 25745848 TI - Challenges in lung transplantation in Japan. PMID- 25745847 TI - Mesenchymal Stem Cell Therapy Alleviates Interstitial Cystitis by Activating Wnt Signaling Pathway. AB - Interstitial cystitis (IC) is a syndrome characterized by urinary urgency, frequency, pelvic pain, and nocturia in the absence of bacterial infection or identifiable pathology. IC is a devastating disease that certainly decreases quality of life. However, the causes of IC remain unknown and no effective treatments or cures have been developed. This study evaluated the therapeutic potency of using human umbilical cord-blood-derived mesenchymal stem cells (UCB MSCs) to treat IC in a rat model and to investigate its responsible molecular mechanism. IC was induced in 10-week-old female Sprague-Dawley rats via the instillation of 0.1 M HCl or phosphate-buffered saline (PBS; sham). After 1 week, human UCB-MSC (IC+MSC) or PBS (IC) was directly injected into the submucosal layer of the bladder. A single injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. Accordingly, denudation of the epithelium and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. The injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues and activated Wnt signaling cascade. Interference with Wnt and epidermal growth factor receptor activity by small molecules abrogated the benefits of MSC therapy. This is the first report that provides an experimental evidence of the therapeutic effects and molecular mechanisms of MSC therapy to IC using an orthodox rat animal model. Our findings not only provide the basis for clinical trials of MSC therapy to IC but also advance our understanding of IC pathophysiology. PMID- 25745849 TI - A prospective survey of idiopathic interstitial pneumonias in a web registry in Japan. AB - BACKGROUND: There have been no prospective large-scale multicenter epidemiological studies on the clinical course and treatment from the time of diagnosis of idiopathic interstitial pneumonias (IIPs) in Japan. The purpose of this study was to clarify the current clinical situation of IIP in Japan. METHODS: This study was supported by a grant from the Ministry of Health, Labour and Welfare to the Diffuse Lung Diseases Research Group. Data including clinical findings, course, and treatment of IIP from a web database created by a collaborative effort of medical institutions across Japan that specialize in the care of interstitial pneumonias were collected and analyzed. RESULTS: A total of 436 IIP patients from 19 institutions were newly registered during a 5-year period. Idiopathic pulmonary fibrosis (IPF) was the most frequently encountered IIP, and 28% of the IPF cases were initially diagnosed by abnormal chest X-ray or CT in asymptomatic patients. Until the 2008 fiscal year, no treatment was given for most cases of IPF. After the end of 2008, when pirfenidone was approved for manufacture, the number of patients for whom no treatment was recommended declined, and pirfenidone therapy was initiated in 32.9% of cases in 2009. The median survival times for IPF from the onset symptoms and from the initial visit were 105 months and 69 months, respectively. CONCLUSIONS: This study should provide valuable information for understanding the current state of IIP in Japan. PMID- 25745850 TI - Heritability of pulmonary function estimated from genome-wide SNPs in healthy Japanese adults. AB - BACKGROUND: Pulmonary function is a heritable trait, and recent genome-wide association studies (GWASs) have identified a number of loci influencing the trait. Genome-wide Complex Trait Analysis (GCTA) is a novel method provided by a software package that estimates the total additive genetic influence caused by common single nucleotide polymorphisms (SNPs) on whole-genome arrays. We conducted a GWAS and assessed the heritability of pulmonary function in an adult Japanese population using this approach. METHODS: We initially conducted a GWAS on %forced vital capacity (FVC), %forced expiratory volume (FEV1) and FEV1/FVC in healthy Japanese adults (N=967). We then examined the heritability of these traits using GCTA with a total of 480,026 SNPs. We also estimated the genetic impact of the 24 genes identified as susceptibility genes to FEV1/FVC in six previous GWASs on the heritability of FEV1/FVC in the Japanese population. RESULTS: The heritabilities for %FVC, %FEV1, and FEV1/FVC were 71.2%, 51.9% and 41.6%, respectively. These results corresponded to previous heritability estimates for pulmonary function obtained by GCTA or by twin studies. The 24 previously reported pulmonary function genes accounted for 4.3-12.0% of the entire estimated heritability of FEV1/FVC. CONCLUSIONS: This study demonstrated that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs in healthy Japanese adults. The pulmonary function genes reported in previous GWASs of non-Japanese populations showed a definite impact of the genes on FEV1/FVC, thus indicating the presence of common pathways related to this trait beyond ethnicity. PMID- 25745851 TI - Disease flare after gefitinib discontinuation. AB - INTRODUCTION: A recent retrospective analysis found that 23% of non-small cell lung cancer patients who acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) demonstrated "disease flare" after discontinuation of EGFR-TKIs. However, limitations of this study present the need for further investigation to elucidate this phenomenon in more detail. METHODS: We reviewed the clinical records of EGFR mutated patients with advanced lung adenocarcinoma who were treated with gefitinib monotherapy in our hospital between January 2007 and December 2010. Disease flare was defined as unexpected interventions (e.g. radiation therapy or pleural drainage), hospitalization, or death attributable to disease progression after gefitinib discontinuation. RESULTS: Among 52 eligible patients, only two experienced disease flare (4%; 95% confidence interval: 1-13%). In both cases, interval time from gefitinib discontinuation to disease flare was 11 days, and the brain was the site of flare. Survival time after gefitinib was significantly shorter in the flare patients (78 and 97 days, respectively) compared with the no-flare patients (median 388 days). CONCLUSIONS: Our analysis demonstrated a lower incidence rate of disease flare after gefitinib discontinuation compared with the previous report, but the prognosis was similarly poor. PMID- 25745852 TI - Serum level of periostin can predict long-term outcome of idiopathic pulmonary fibrosis. AB - BACKGROUND: KL-6 and surfactant proteins A and D are the only established serum biomarkers of idiopathic pulmonary fibrosis (IPF). We have previously shown that serum levels of periostin, a unique matricellular protein, are elevated and correlated with pulmonary function in patients with IPF. We sought to determine whether the serum periostin levels correlate with overall survival (OS) and time to-event (TTE), as a parameter reflecting long-term outcome, and with the extent of abnormality on chest high-resolution computed tomography (HRCT) scores in patients with IPF. METHODS: Twenty-nine patients with IPF were analyzed retrospectively. The mean observation period was 1035.2 +/- 663.1 days (range, 112-1800 days). High-resolution computed tomography (HRCT) scores were calculated based on the extent of abnormality evidenced by HRCT. We evaluated if there were any correlations between the serum periostin levels and clinical parameters, including HRCT score, using Spearman's rank correlation coefficients and analyzed predictors of OS and TTE using the log-rank tests. RESULTS: We showed that the serum periostin levels significantly correlated with the increase of honeycombing score on HRCT during a 6-month period. Log-rank tests showed that a higher serum periostin level was a predictor of a shortened OS and TTE. Greater extents of fibrotic lesions on HRCT scan were predictors of shortened OS and TTE. CONCLUSIONS: In IPF patients, the serum periostin level may be a good predictive biomarker for an increase in the radiological fibrotic area and long-term outcome. PMID- 25745853 TI - Stratifying the risk of COPD exacerbation using the modified Medical Research Council scale: a multicenter cross-sectional CAP study. PMID- 25745855 TI - Overestimation of free light chain antigen excess rate. AB - BACKGROUND: Free light chains (FLC) are useful biomarkers for diagnosis and follow-up of plasma cell disorders. FLC quantification is encumbered by non linearity and antigen excess (>4-fold difference between results obtained at the 2000- and 100-fold dilution). METHODS: FLC concentration was measured with Freelite(r) reagents on the BNII, using 100- and 2000-fold dilutions in 3645 samples. Samples displaying antigen excess were re-measured at the 2000- and/or 400-fold dilution. Carryover was evaluated by tracing samples to cuvettes and by measuring a normal sample in cuvettes that previously contained samples with a high FLC concentration. RESULTS: Antigen excess occurred in 0.93% of samples for kappa and in 0.55% of samples for lambda. In 81.5% of the cases, it could not be confirmed by a re-analysis of a 2000-fold and/or a 400-fold diluted sample. Real antigen excess was documented in 0.25% and 0.03% of the samples for kappa and lambda FLC, respectively. In the low concentration range (2000-fold dilution), imprecision was high. False antigen excess was reduced by batch analysis, introducing cleaning and rinsing procedures and using the 400-fold dilution. No antigen excess was detected in samples with normal FLC concentrations. CONCLUSION: Falsely high results occur by imprecision in the low concentration range and/or by carryover in cuvettes. PMID- 25745854 TI - Outcome of patients with carbon monoxide poisoning at a far-east poison center. AB - INTRODUCTION: Many cases of carbon monoxide poisoning in Taiwan are due to burning charcoal. Nevertheless, few reports have analyzed the mortality rate of these patients who survive to reach a hospital and die despite intensive treatment. Therefore, this study examined the clinical features, physiological markers, and outcomes after carbon monoxide poisoning and the associations between these findings. METHODS: We analyzed the records of 261 patients who were referred for management of carbon monoxide intoxication between 2000 and 2010. Patients were grouped according to status at discharge as alive (survivor, n = 242) or dead (non-survivor, n = 19). Demographic, clinical, laboratory, and mortality data were obtained for analysis. RESULTS: Approximately half of the cases (49.4%) attempted suicide by burning charcoal. Most of the patients were middle-aged adults (33+/-19 years), and were referred to our hospital in a relatively short period of time (6+/-10 hours). Carbon monoxide produced many serious complications after exposure: fever (26.1%), hypothermia (9.6%), respiratory failure (34.1%), shock (8.4%), myocardial infarction (8.0%), gastrointestinal upset (34.9%), hepatitis (18.4%), renal failure (25.3%), coma (18.0%) and rhabdomyolysis (21.8%). Furthermore, the non-survivors suffered greater incidences of hypothermia (P<0.001), respiratory failure (P<0.001), shock (P<0.001), hepatitis ((P=0.016), renal failure (P=0.003), coma (P<0.001) than survivors. All patients were treated with high concentration of oxygen therapy using non-rebreather mask. However, hyperbaric oxygen therapy was only used in 18.8% of the patients. In a multivariate-Cox-regression model, it was revealed that shock status was a significant predictor for mortality after carbon monoxide poisoning (OR 8.696, 95% CI 2.053-37.370, P=0.003). Finally, Kaplan-Meier analysis confirmed that patients with shock suffered greater cumulative mortality than without shock (Log-rank test, Chi-square 147.404, P<0.001). CONCLUSION: The mortality rate for medically treated carbon monoxide-poisoned patients at our center was 7.3%. Furthermore, the analysis indicates that shock was most strongly associated with higher risk of mortality. PMID- 25745856 TI - Phytochemistry of the genus Skimmia (Rutaceae). AB - The genus Skimmia is a rich source of interesting secondary metabolites, including 20 alkaloids derived from anthranilic acid, 45 coumarins, 21 limonoids, four cholestane derivatives, six pentacyclic triterpenes, six flavonoids, and two unusual fatty acid derivatives. Skimmia is employed in folk medicine e.g. against fever, inflammations, and rheumatism. Skimmia extracts, Skimmia essential oils and pure compounds isolated from Skimmia extracts have been experimentally shown to have various bioactivities such as antioxidant, anti-inflammatory, antimicrobial, and insecticidal. In this review we discuss the exact structures of compounds isolated from members of the genus Skimmia, bioactivities of Skimmia extracts and pure compounds derived from them, and systematic implications of the patterns of occurrence of these compounds. Moreover, research gaps and interesting avenues for future research are discussed briefly. PMID- 25745857 TI - Towards a taxonomy of pain modulations. AB - The subjective experience of pain is affected by various modulating factors, such as the sufferer's level of anxiety or distraction. A recent study sheds light on the neural underpinnings of pain modulation and illustrates how we can advance towards an integrated psychological, neurobiological and clinical taxonomy of pain modulations. PMID- 25745858 TI - Vascular smooth muscle cell stiffness and adhesion to collagen I modified by vasoactive agonists. AB - In vascular smooth muscle cells (VSMCs) integrin-mediated adhesion to extracellular matrix (ECM) proteins play important roles in sustaining vascular tone and resistance. The main goal of this study was to determine whether VSMCs adhesion to type I collagen (COL-I) was altered in parallel with the changes in the VSMCs contractile state induced by vasoconstrictors and vasodilators. VSMCs were isolated from rat cremaster skeletal muscle arterioles and maintained in primary culture without passage. Cell adhesion and cell E-modulus were assessed using atomic force microscopy (AFM) by repetitive nano-indentation of the AFM probe on the cell surface at 0.1 Hz sampling frequency and 3200 nm Z-piezo travelling distance (approach and retraction). AFM probes were tipped with a 5 MUm diameter microbead functionalized with COL-I (1 mg?ml). Results showed that the vasoconstrictor angiotensin II (ANG-II; 10-6) significantly increased (p<0.05) VSMC E-modulus and adhesion probability to COL-I by approximately 35% and 33%, respectively. In contrast, the vasodilator adenosine (ADO; 10-4) significantly decreased (p<0.05) VSMC E-modulus and adhesion probability by approximately -33% and -17%, respectively. Similarly, the NO donor (PANOate, 10-6 M), a potent vasodilator, also significantly decreased (p<0.05) the VSMC E modulus and COL-I adhesion probability by -38% and -35%, respectively. These observations support the hypothesis that integrin-mediated VSMC adhesion to the ECM protein COL-I is dynamically regulated in parallel with VSMC contractile activation. These data suggest that the signal transduction pathways modulating VSMC contractile activation and relaxation, in addition to ECM adhesion, interact during regulation of contractile state. PMID- 25745859 TI - L-NIO as a novel mechanism for inducing focal cerebral ischemia in the adult rat brain. AB - BACKGROUND: Ischemic stroke is the most frequent cause of persistent neurological disability in Western societies. New treatment strategies are required and effective in vivo models are crucial to their development. NEW METHOD: The current study establishes a novel in vivo rat model of focal striatal ischemia using the vasoconstrictive agent N5-(1-iminoethyl)-L-ornithine (L-NIO). Adult male Sprague Dawley rats received a unilateral intrastriatal infusion of L-NIO in combination with jugular vein occlusion. RESULTS: L-NIO infusion was associated with zero mortality, low surgical complexity and a reproducible infarct, providing advantages over established models of focal ischemia. The mean infarct volume of 8.5+/-5.3% of the volume of the contralateral striatum resulted in blood-brain barrier dysfunction, neuronal hypoxia and ongoing neurodegeneration. Further characteristics of ischemic stroke were exhibited, including robust microglia/macrophage and astroglial responses lasting at least 35 days post ischemia, in addition to chronic motor function impairment. COMPARISON WITH EXISTING METHODS: When compared to other models such as the MCAo models, the consistency in regions affected, high success rate, zero mortality, reduced surgical complexity and minimal welfare requirements of the L-NIO model make it ideal for initial high-throughput investigations into preclinical efficacy and proof of principle studies of acute ischemic stroke interventions. CONCLUSION: We propose that the L-NIO rat model of focal striatal ischemia does not replace the use of other ischemic stroke models. Rather it provides a new, complementary tool for initial preclinical investigations into the treatment of ischemic stroke. PMID- 25745860 TI - Quantitative 3-D analysis of GFAP labeled astrocytes from fluorescence confocal images. AB - BACKGROUND: There is a need for effective computational methods for quantifying the three-dimensional (3-D) spatial distribution, cellular arbor morphologies, and the morphological diversity of brain astrocytes to support quantitative studies of astrocytes in health, injury, and disease. NEW METHOD: Confocal fluorescence microscopy of multiplex-labeled (GFAP, DAPI) brain tissue is used to perform imaging of astrocytes in their tissue context. The proposed computational method identifies the astrocyte cell nuclei, and reconstructs their arbors using a local priority based parallel (LPP) tracing algorithm. Quantitative arbor measurements are extracted using Scorcioni's L-measure, and profiled by unsupervised harmonic co-clustering to reveal the morphological diversity. RESULTS: The proposed method identifies astrocyte nuclei, generates 3-D reconstructions of their arbors, and extracts quantitative arbor measurements, enabling a morphological grouping of the cell population. COMPARISON WITH EXISTING METHODS: Our method enables comprehensive spatial and morphological profiling of astrocyte populations in brain tissue for the first time, and overcomes limitations of prior methods. Visual proofreading of the results indicate a >95% accuracy in identifying astrocyte nuclei. The arbor reconstructions exhibited 3.2% fewer erroneous jumps in tracing, and 17.7% fewer false segments compared to the widely used fast-marching method that resulted in 9% jumps and 20.8% false segments. CONCLUSIONS: The proposed method can be used for large-scale quantitative studies of brain astrocyte distribution and morphology. PMID- 25745861 TI - High resolution time-intensity recording with synchronized solution delivery system for the human dynamic taste perception. AB - BACKGROUND: Time-intensity sensory evaluation of human taste perception is useful to know the feedback of a taste stimulus from tongue. However, it has not been profiled together with reaction time under the constant stimulating tongue in high time resolution. NEW METHOD: We first made intra-oral device to deliver taste solution to anterior, lateral and posterior tongue in standardized condition. Second, we developed a time-intensity sensory evaluation meter linked to synchronized taste solution delivery system. Time-intensity profiles were recorded in higher temporal resolution than our past study. Third, we analyzed the corrected taste quality reaction time from raw sensory perception data, and following sensory evaluation profile. RESULTS: The new method acquired taste sensory evaluation data with 1 ms temporal resolution and found the reaction timing was 908 ms, the corrected taste quality reaction time was 712 ms, maximum intensity was 3.47, and corrected time to reach maximum intensity was 1312 ms. The coefficient of variation ranged from 0.007 to 0.236 indicating low variance. COMPARISON WITH EXISTING METHODS: Time-intensity sensory evaluation in this study did not sacrifice the feature of raw data. The relative comparison of time intensity sensory profile among subjects will be available in this system in future study, while it was still difficult to define the absolute value of reaction time. CONCLUSIONS: Our method could gather real-time feedback for the time-intensity sensory evaluation of a taste stimulus under the standardized stimulating tongue. This could be useful for establishing database of time intensity sensory profiles for comparison of delicate taste perceptions. PMID- 25745862 TI - Correction: Characterization of a prawn OA/TA receptor in Xenopus oocytes suggests functional selectivity between octopamine and tyramine. PMID- 25745863 TI - Recombinant NAD-dependent SIR-2 protein of Leishmania donovani: immunobiochemical characterization as a potential vaccine against visceral leishmaniasis. AB - BACKGROUND: The development of a vaccine conferring long-lasting immunity remains a challenge against visceral leishmaniasis (VL). Immunoproteomic characterization of Leishmania donovani proteins led to the identification of a novel protein NAD+ dependent Silent Information regulatory-2 (SIR2 family or sirtuin) protein (LdSir2RP) as one of the potent immunostimulatory proteins. Proteins of the SIR2 family are characterized by a conserved catalytic domain that exerts unique NAD dependent deacetylase activity. In the present study, an immunobiochemical characterization of LdSir2RP and further evaluation of its immunogenicity and prophylactic potential was done to assess for its possible involvement as a vaccine candidate against leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: LdSir2RP was successfully cloned, expressed and purified. The gene was present as a monomeric protein of ~45 kDa and further established by the crosslinking experiment. rLdSir2RP shown cytosolic localization in L. donovani and demonstrating NAD+-dependent deacetylase activity. Bioinformatic analysis also confirmed that LdSir2RP protein has NAD binding domain. The rLdSir2RP was further assessed for its cellular response by lymphoproliferative assay and cytokine ELISA in cured Leishmania patients and hamsters (Mesocricetus auratus) in comparison to soluble Leishmania antigen and it was observed to stimulate the production of IFN-gamma, IL-12 and TNF-alpha significantly but not the IL-4 and IL-10. The naive hamsters when vaccinated with rLdSir2RP alongwith BCG resisted the L. donovani challenge to the tune of ~75% and generated strong IL-12 and IFN gamma mediated Th1 type immune response thereof. The efficacy was further supported by remarkable increase in IgG2 antibody level which is indicative of Th1 type of protective response. Further, with a possible implication in vaccine design against VL, identification of potential T-cell epitopes of rLdSir2RP was done using computational approach. CONCLUSION/SIGNIFICANCE: The immunobiochemical characterization strongly suggest the potential of rLdSir2RP as vaccine candidate against VL and supports the concept of its being effective T-cell stimulatory antigen. PMID- 25745865 TI - The longevity of the antimicrobial response in rainbow trout (Oncorhynchus mykiss) fed a peptidoglycan (PG) supplemented diet. AB - This study builds upon previous work studying antimicrobial peptide (AMP) gene expression in rainbow trout (Oncorhynchus mykiss) fed a peptidoglycan (PG) enriched diet. The aims here were 1) to evaluate how long AMP expression is elevated in skin with continuous feeding of fish with the PG enriched diet for 21 or 28 days, and 2) to assess the impact of stopping PG feeding at day 14 when sampled at day 21 or 28. The rainbow trout were divided into 6 groups, with two fed a control commercial diet for the duration of the experiment and the other four given the same diet enriched with 10 mg PG/Kg for 14 days (PG 1-14) or continuously (PG continuous), the former reverting back to the commercial diet at day 14. No mortalities occurred during the study and there were no significant differences in growth among the fish in the different diet groups. The expression of six AMP genes was studied by real-time PCR in the skin, since these genes were shown to be induced in response to the PG enriched diets in a previous experiment. We show that continuous PG treatment for 21 or 28 days maintained high levels of AMP expression, although in general the levels decreased with time on the diets. Withdrawal of the PG diets at day 14 resulted in a fall in expression level especially apparent with omCATH-1, omCATH-2 and omLEAP-2a, but with omDB-3 and omDB-4 remaining at elevated levels (x10) in comparison to fish given a control diet. These results confirm that orally administered PG clearly enhances the trout innate immune system and could be used as a means to boost fish defences. Future studies should be conducted to verify the impact on survival after pathogen challenge in trout fed PG enriched diets under these regimes. PMID- 25745864 TI - Genome-wide analysis of homeobox gene family in legumes: identification, gene duplication and expression profiling. AB - Homeobox genes encode transcription factors that are known to play a major role in different aspects of plant growth and development. In the present study, we identified homeobox genes belonging to 14 different classes in five legume species, including chickpea, soybean, Medicago, Lotus and pigeonpea. The characteristic differences within homeodomain sequences among various classes of homeobox gene family were quite evident. Genome-wide expression analysis using publicly available datasets (RNA-seq and microarray) indicated that homeobox genes are differentially expressed in various tissues/developmental stages and under stress conditions in different legumes. We validated the differential expression of selected chickpea homeobox genes via quantitative reverse transcription polymerase chain reaction. Genome duplication analysis in soybean indicated that segmental duplication has significantly contributed in the expansion of homeobox gene family. The Ka/Ks ratio of duplicated homeobox genes in soybean showed that several members of this family have undergone purifying selection. Moreover, expression profiling indicated that duplicated genes might have been retained due to sub-functionalization. The genome-wide identification and comprehensive gene expression profiling of homeobox gene family members in legumes will provide opportunities for functional analysis to unravel their exact role in plant growth and development. PMID- 25745866 TI - Purification and partial characterization of alpha1-proteinase inhibitor in the common marmoset (Callithrix jacchus). AB - Fecal alpha1-proteinase inhibitor (alpha1-PI) concentration has been to diagnose enteric protein loss in dogs and cats. Chronic lymphocytic enteritis is commonly seen in the marmoset (Callithrix jaccus) and is characterized by hypoalbuminemia. As a prelude to immunoassay development for detecting enteric protein loss, marmoset serum alpha1-PI was purified using immunoaffinity chromatography and ceramic hydroxyapatite chromatography. Partial characterization was performed by reducing gel electrophoresis and enzyme inhibitory assays. Protein identity was confirmed with peptide mass fingerprinting and N-terminal amino acid sequencing. Molecular mass, relative molecular mass, and isoelectric point for marmoset alpha1-PI were 54 kDa, 51,677, and 4.8-5.4, respectively. Trypsin, chymotrypsin, and elastase inhibitory activity were observed. N-terminal amino acid sequence for marmoset alpha1-PI was EDPQGDAAQKMDTSHH. In conclusion, marmoset alpha1-PI was successfully purified from serum with an overall yield of 12% using a rapid and efficient method. Purified marmoset alpha1-PI has characteristics similar to those of alpha1-PI reported for other species. PMID- 25745867 TI - Trolox and ascorbic acid reduce direct and indirect oxidative stress in the IPEC J2 cells, an in vitro model for the porcine gastrointestinal tract. AB - Oxidative stress in the small intestinal epithelium is a major cause of barrier malfunction and failure to regenerate. This study presents a functional in vitro model using the porcine small intestinal epithelial cell line IPEC-J2 to examine the effects of oxidative stress and to estimate the antioxidant and regenerative potential of Trolox, ascorbic acid and glutathione monoethyl ester. Hydrogen peroxide and diethyl maleate affected the tight junction (zona occludens-1) distribution, significantly increased intracellular oxidative stress (CM-H2DCFDA) and decreased the monolayer integrity (transepithelial electrical resistance and FD-4 permeability), viability (neutral red) and wound healing capacity (scratch assay). Trolox (2 mM) and 1 mM ascorbic acid pre-treatment significantly reduced intracellular oxidative stress, increased wound healing capacity and reduced FD-4 permeability in oxidatively stressed IPEC-J2 cell monolayers. All antioxidant pre treatments increased transepithelial electrical resistance and viability only in diethyl maleate-treated cells. Glutathione monoethyl ester (10 mM) pre-treatment significantly decreased intracellular oxidative stress and monolayer permeability only in diethyl maleate-treated cells. These data demonstrate that the IPEC-J2 oxidative stress model is a valuable tool to screen antioxidants before validation in piglets. PMID- 25745868 TI - Effects of chlortetracycline and copper supplementation on the prevalence, distribution, and quantity of antimicrobial resistance genes in the fecal metagenome of weaned pigs. AB - Use of in-feed antibiotics such as chlortetracycline (CTC) in food animals is fiercely debated as a cause of antimicrobial resistance in human pathogens; as a result, alternatives to antibiotics such as heavy metals have been proposed. We used a total community DNA approach to experimentally investigate the effects of CTC and copper supplementation on the presence and quantity of antimicrobial resistance elements in the gut microbial ecology of pigs. Total community DNA was extracted from 569 fecal samples collected weekly over a 6-week period from groups of 5 pigs housed in 32 pens that were randomized to receive either control, CTC, copper, or copper plus CTC regimens. Qualitative and quantitative PCR were used to detect the presence of 14 tetracycline resistance (tet) genes and to quantify gene copies of tetA, tetB, blaCMY-2 (a 3rd generation cephalosporin resistance gene), and pcoD (a copper resistance gene), respectively. The detection of tetA and tetB decreased over the subsequent sampling periods, whereas the prevalence of tetC and tetP increased. CTC and copper plus CTC supplementation increased both the prevalence and gene copy numbers of tetA, while decreasing both the prevalence and gene copies of tetB. In summary, tet gene presence was initially very diverse in the gut bacterial community of weaned pigs; thereafter, copper and CTC supplementation differentially impacted the prevalence and quantity of the various tetracycline, ceftiofur and copper resistance genes resulting in a less diverse gene population. PMID- 25745869 TI - Molecular epidemiology study of swine influenza virus revealing a reassorted virus H1N1 in swine farms in Cuba. AB - In this report, we describe the emergence of reassorted H1N1 swine influenza virus, originated from a reassortment event between the H1N1 pandemic influenza virus (H1N1p/2009) and endemic swine influenza virus in Cuban swine population. In November 2010, a clinical respiratory outbreak was reported on a pig fattening farm in Cuba. Phylogenetic analysis showed that all the genes of one of the isolate obtained, with the exception of neuraminidase, belonged to the H1N1p/2009 cluster. This finding suggests that H1N1pdm has been established in swine and has become a reservoir of reassortment that may produce new viruses with both animal and public health risks. PMID- 25745870 TI - Impulsive aggression, delay discounting, and adolescent suicide attempts: effects of current psychotropic medication use and family history of suicidal behavior. AB - OBJECTIVE: Impulsive-aggressive behaviors have been consistently implicated in the phenomenology, neurobiology, and familial aggregation of suicidal behavior. The purpose of this study was to extend previous work by examining laboratory behavioral measures of delayed reward impulsivity and impulsive aggression in adolescent suicide attempters and never-suicidal comparison subjects. METHODS: Using the Point Subtraction Aggression Paradigm (PSAP) and the Delay Discounting Task (DDQ), the authors examined delay discounting and impulsive aggression in 40 adolescent suicide attempters, ages 13-18, and 40 never-suicidal, demographically matched psychiatric comparison subjects. RESULTS: Overall, suicide attempters and comparison subjects performed similarly on the PSAP and DDQ. There was a significant group by current psychotropic medication use interaction (p=0.013) for mean aggressive responses on the PSAP. Group comparisons revealed that attempters emitted more aggressive responses per provocation than comparison subjects, only in those not on psychotropic medication (p=0.049), whereas for those currently treated with psychotropic medication, there were no group differences (p>0.05). This interaction effect was specific to current antidepressant use. Among all subjects, family history of suicidal behavior (suicide or suicide attempt) in first degree relatives was significantly correlated with both delay discounting (r=-0.22, p=0.049), and aggressive responding (r=0.27, p=0.015). Family history of suicidal behavior was associated with delay discounting, but not with aggressive responding on the PSAP, after controlling for relevant covariates. CONCLUSIONS: In this study, impulsive aggressive responding was associated with suicide attempt only in those not being treated with antidepressants. Future work to replicate and extend these findings could have important therapeutic implications for the treatment of depressed suicide attempters, many of whom are affected by impulsive aggression. PMID- 25745871 TI - Victor Eisenmenger (1864-1932): The man behind the syndrome. AB - Although much has been written about the cardiovascular abnormalities present in Eisenmenger's syndrome, little has been recorded previously in the medical literature about Victor Eisenmenger, the Austrian doctor whose name is attached eponymously to this disorder. Archival material together with information provided by his descendants and relatives has been gathered to make available further details of his life, family, schooling, medical training and accomplishments. An examination of Eisenmenger's book about his observations and experiences while serving from 1895 to 1914 as personal physician to Archduke Francis Ferdinand, the heir presumptive to the Austro-Hungarian throne, also sheds light on Eisenmenger's personality, abilities and interests. PMID- 25745872 TI - Spatially regularized mixture model for lesion segmentation with application to stroke patients. AB - In medical imaging, lesion segmentation (differentiation between lesioned and non lesioned tissue) is a crucial and difficult task. Automated segmentation algorithms based on intensity analysis have been already proposed and recent developments have shown that integrating spatial information enhances automatic image segmentation. However, spatial modeling is often limited to short-range spatial interactions that deal only with noise or small artifacts. Previous tissue alterations (e.g. white matter disease (WMD)) similar in intensity with the lesion of interest require a broader-scale approach to be corrected. On the other hand, imaging techniques offer now a multiparametric voxel characterization that may help differentiating lesioned from non-lesioned voxels. We developed an unsupervised multivariate segmentation algorithm based on finite mixture modeling that incorporates spatial information. We extended the usual spatial Potts model to the regional scale using a 'multi-order' neighborhood potential, with internal adjustment of the regional scale according to the lesion size. We validate the ability of this new algorithm to deal with noise and artifacts (linear and spherical) using artificial data. We then assess its performance on real magnetic resonance imaging brain scans of stroke patients with history of WMD and show that regional regularization was able to remove large-scale WMD artifacts. PMID- 25745873 TI - Greater involvement and diversity of Internet gambling as a risk factor for problem gambling. AB - BACKGROUND: Concerns that Internet gambling has elevated the prevalence of problem gambling have not been substantiated; however, evidence suggests a subgroup of Internet gamblers do experience higher rates of gambling harms. Greater overall involvement in gambling appears to be predictive of harms. The purpose of this study was to examine differences between Internet gamblers with a single or multiple online gambling accounts, including their gambling behaviours, factors influencing their online gambling and risk of experiencing gambling problems. METHODS: Internet gamblers (3178) responding to an online survey that assessed their gambling behaviour, and use of single or multiple online gambling accounts. RESULTS: Results revealed that multiple account holders were more involved gamblers, gambling on more activities and more frequently, and had higher rates of gambling problems than single account holders. Multiple account holders selected gambling sites based on price, betting options, payout rates and game experience, whereas single account holders prioritized legality and consumer protection features. CONCLUSION: Results suggest two different types of Internet gamblers: one motivated to move between sites to optimize preferred experiences with a tendency to gamble in a more volatile manner; and a smaller, but more stable group less influenced by promotions and experiences, and seeking a reputable and safe gambling experience. As the majority of Internet gamblers use multiple accounts, more universal responsible gambling strategies are needed to assist gamblers to track and control their expenditure to reduce risks of harm. PMID- 25745874 TI - Aggregate Effects of Intraocular Pressure and Cup-to-Disc Ratio Genetic Variants on Glaucoma in a Multiethnic Asian Population. AB - PURPOSE: High intraocular pressure (IOP) and large vertical cup-to-disc ratio (VCDR) are important risk factors of glaucoma. Recent genome-wide association studies have discovered several genetic variants associated with IOP and VCDR. In this study, we examined the aggregate effects of these IOP-, VCDR-associated variants on glaucoma. DESIGN: Case-control genetic association study. PARTICIPANTS: A total of 6881 participants, including 194 glaucoma and 158 primary open-angle glaucoma (POAG) cases in the Singapore Epidemiology of Eye Diseases Study. METHODS: We first identified IOP and VCDR risk single nucleotide polymorphisms (SNPs) that were located in previously discovered IOP, VCDR genetic loci and showed strongest associations with IOP and VCDR in our study. We then constructed multi-locus IOP-, VCDR-specific genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on glaucoma. Associations between tertiles of IOP- and VCDR-specific GRSs with glaucoma and POAG were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Odds ratios on glaucoma. RESULTS: Participants in the top tertile of IOP-specific GRS were 2.00 (95% CI, 1.32-3.03, P = 1.1*10(-3)) and 2.50 times (95% CI, 1.54 4.02, P = 2.0*10(-4)) likely to have glaucoma and POAG, respectively, compared with those in the bottom. Participants in the top tertile of VCDR-specific GRS were 2.09 (95% CI, 1.43-3.07, P = 1.6*10(-4)) and 2.31 times (95% CI, 1.50-3.55, P = 1.4*10(-4)) likely to have glaucoma and POAG, respectively. Participants with both GRSs in the top tertile were 5.54 (95% CI, 2.57-11.93, P = 1.1*10(-5)) and 7.77 times (95% CI, 3.03-19.93, P = 2.0*10(-5)) likely to have glaucoma and POAG, respectively, compared with participants with both GRSs in bottom tertiles. The GRSs improved AUC for glaucoma modestly when added to traditional factors (AUC difference = 0.03, P = 0.06). CONCLUSIONS: Higher IOP-, VCDR-specific GRSs were associated with greater risk of glaucoma. Participants with both GRSs in the top tertiles had a 5.5-fold increased risk of glaucoma compared with those in the bottom tertiles. These findings may provide insights into the genetic pathogenesis of glaucoma. PMID- 25745875 TI - Intravitreal Aflibercept Injection in Patients with Myopic Choroidal Neovascularization: The MYRROR Study. AB - PURPOSE: To evaluate intravitreal aflibercept 2 mg in patients with myopic choroidal neovascularization (CNV). DESIGN: An international, phase III, multicenter, randomized, double-masked, sham-controlled study. PARTICIPANTS: Patients aged >= 18 years with high myopia (<=-6.0 diopters or axial length of >= 26.5 mm), active myopic CNV, and best-corrected visual acuity (BCVA) of 73-35 Early Treatment Diabetic Retinopathy Study letters in the study eye were included. METHODS: Patients were randomized 3:1 to intravitreal aflibercept or sham. In the intravitreal aflibercept arm, patients received 1 injection at baseline. Additional injections were performed in case of CNV persistence or recurrence at monthly visits through week 44. In the sham arm, patients received sham injections through week 20. At week 24, after assessment of the primary efficacy end point, sham patients received a mandatory intravitreal aflibercept injection followed by intravitreal aflibercept (if disease persisted/recurred) or sham injection every 4 weeks. MAIN OUTCOME MEASURES: Mean change in BCVA from baseline to week 24. RESULTS: A total of 122 patients were randomized to intravitreal aflibercept (n = 91) or sham (n = 31). Baseline demographics were similar across groups. At week 24, patients in the intravitreal aflibercept and sham groups gained 12.1 and lost 2 letters, respectively (P < 0.0001). By week 48, patients in the intravitreal aflibercept and sham/intravitreal aflibercept groups gained 13.5 and 3.9 letters. Patients in the intravitreal aflibercept group received 2 injections (median) in the first study quarter (week 0-8). Median number of injections in quarters 2 to 4 was 0. Patients in the "sham/intravitreal aflibercept" group received 2 and 1 (median) intravitreal aflibercept injections in quarters 3 and 4. Central retinal thickness improved in parallel with visual gains. Incidence of ocular adverse events was similar in both groups through week 48 (37.4% vs. 38.7); most were assessed by investigators as mild. No deaths occurred. CONCLUSIONS: Intravitreal aflibercept 2 mg was effective for treatment of myopic CNV with clinically important visual and anatomic benefits achieved with a limited number of injections given in the first 8 weeks of treatment. No new safety concerns occurred with treatment. Intravitreal aflibercept should be considered as a treatment option for myopic CNV. PMID- 25745876 TI - Long-term Outcomes of Rituximab Therapy in Ocular Granulomatosis with Polyangiitis: Impact on Localized and Nonlocalized Disease. AB - PURPOSE: To evaluate the long-term outcomes of rituximab (RTX) treatment in patients with ocular granulomatosis with polyangiitis (GPA) with localized or generalized disease. DESIGN: Retrospective cohort. PARTICIPANTS: Thirty-seven patients with ocular GPA receiving RTX in a multidisciplinary vasculitis clinic between 2004 and 2013. METHODS: A total of 100 patients who received a course of RTX were identified, and notes were reviewed. Baseline demographic details, clinical characteristics (including organ involvement), drugs used, and outcome measures were recorded. MAIN OUTCOME MEASURES: The percentage in remission (inactive disease with prednisolone <=7.5 mg with or without maintenance treatment) at 6 months, time to remission, percentage relapsing, side effects, B cell count, antineutrophil cytoplasm antibody titers, induction, and maintenance regimens. RESULTS: The median follow-up time after the first RTX course was 36.5 months. Twenty patients had scleritis, and 17 patients had orbital disease; 86% achieved remission at 6 months. The percentage in remission versus partial remission was not statistically significant between patients with scleritis and patients with orbital disease (85% vs. 15% with scleritis and 82% vs. 18% with orbital disease; P = 1.00). The percentage relapsing was not statistically significant (P = 0.33) between scleritis (60%) and orbital disease (41%). Localized disease (ocular +/- ear-nose-throat/lung) was observed in 57%, and generalized disease (ocular plus other organs) was observed in 43%, the former having a median duration of disease of 40 months. There was no statistically significant difference (P = 0.37) in the percentage in remission between localized and generalized ocular disease. Relapses occurred in 51%, with localized disease being a significant risk factor for relapse. Fifty percent of patients with generalized disease versus none with localized disease received cyclophosphamide (CYP) as part of the induction regimen. Patients who received CYP during induction had significantly (P = 0.027) lower ratios of baseline 12 month proteinase 3 titers than patients who did not have CYP. Infections were observed in 16% of patients, with 8% requiring hospital admission. CONCLUSIONS: Our long-term data suggest that RTX is effective for inducing disease remission in localized and generalized ocular GPA. Localized disease is a significant risk factor for relapse, which may be related to less use of CYP in the induction regimen. PMID- 25745878 TI - Inhibition of adhesion of Clostridium difficile to human intestinal cells after treatment with serum and intestinal fluid isolated from mice immunized with nontoxigenic C. difficile membrane fraction. AB - Diarrhea and pseudomembrane colitis caused by Clostridium difficile infection is a global health concern because of the high recurrence rate after standard antibiotic therapy. Vaccination presents a powerful countermeasure against disease recurrence. In this study, mice vaccinated with the nontoxigenic C. difficile membrane fraction generated a marked immune response to the antigen, as demonstrated by the serum IgG and intestinal fluid IgA levels. Significantly, pretreatment with harvested IgG- and IgA-containing fluids was sufficient to prevent in vitro adhesion of C. difficile to human Caco-2 intestinal cells. These results highlight the potential of nontoxigenic C. difficile membrane fraction as a vaccine candidate for C. difficile infection. PMID- 25745877 TI - Intact long-type DupA protein in Helicobacter pylori is an ATPase involved in multifunctional biological activities. AB - The function of intact long-type DupA protein in Helicobacter pylori was analyzed using immunoblotting and molecular biology techniques in the study. After cloning, expression and purification, ATPase activity of DupA protein was detected. Antibody was produced for localization and interaction proteins analysis. The dupA-deleted mutant was generated for adhesion and CagA protein translocation assay, susceptibility to different pH, IL-8 secretion assay, cytotoxicity to MKN-45 cells and proteins-involved apoptosis analysis. DupA protein exhibited an ATPase activity (129.5+/-17.8 U/mgprot) and located in bacterial membrane, while it did not involve the adhesion and CagA protein delivery of H. pylori. DupA protein involved the urease secretion as the interaction proteins. The wild type strain had a stronger growth in low pH than the dupA-deleted mutant (p < 0.001). IL-8 productions from GES-1 cells infected with the wild type strain were significantly higher than from those with the mutant (p < 0.001). The amounts of vital MKN-45 cells were decreased and the numbers of apoptotic cells were increased with the wild type strain, compared to those with the mutant after 12 h (p < 0.05). The increase of cleaved Caspase-3 and Bax was significantly higher and the decrease of Bcl-2 was more obvious in MKN-45 cells exposed to the wild type strain than that exposed to the mutant after 6 h. We demonstrate that intact long-type DupA protein located in membrane as ATPase is a true virulence factor associated with duodenal ulcer development involving the IL-8 induction and urease secretion, while it inhibits gastric cancer cell growth in vitro by activating the mitochondria-mediated apoptotic pathway. PMID- 25745879 TI - Application of a Novel Liquid Nitrogen Control Technique for Heat Stress and Fire Prevention in Underground Mines. AB - With the continually increasing mining depths, heat stress and spontaneous combustion hazards in high-temperature mines are becoming increasingly severe. Mining production risks from natural hazards and exposures to hot and humid environments can cause occupational diseases and other work-related injuries. Liquid nitrogen injection, an engineering control developed to reduce heat stress and spontaneous combustion hazards in mines, was successfully utilized for environmental cooling and combustion prevention in an underground mining site named "Y120205 Working Face" (Y120205 mine) of Yangchangwan colliery. Both localized humidities and temperatures within the Y120205 mine decreased significantly with liquid nitrogen injection. The maximum percentage drop in temperature and humidity of the Y120205 mine were 21.9% and 10.8%, respectively. The liquid nitrogen injection system has the advantages of economical price, process simplicity, energy savings and emission reduction. The optimized heat exchanger used in the liquid nitrogen injection process achieved superior air cooling results, resulting in considerable economic benefits. PMID- 25745880 TI - Increased pulmonary vascular resistance in early stage systemic hypertension: a resting and exercise stress echocardiography study. AB - BACKGROUND: In early stage uncomplicated systemic hypertension (HT), increased pulmonary vascular resistance (PVR) has been reported at rest, but more rarely during exercise. Recently, limits of normal for stress echocardiography in the evaluation of the pulmonary circulation have been better defined. We therefore used this approach to assess the pulmonary circulation in early HT. METHODS: One hundred thirteen patients with mild to moderate untreated, uncomplicated HT (blood pressure, 152 +/- 19/89 +/- 11 mm Hg, heart rate, 70 +/- 13 beats per minute) and 345 age- and sex-matched healthy control subjects underwent resting Doppler echocardiography with estimation of mean pulmonary arterial pressure (mPAP), left atrial pressure (LAP), and cardiac output (CO). Measurements were repeated at exercise stress test in 25 patients from each group. RESULTS: At rest, hypertensive patients had normal right and left ventricular structure and function, higher systemic vascular resistance, mPAP (16 +/- 5 vs 14 +/- 5 mm Hg; P < 0.0001), and PVR (1.3 +/- 1.1 vs 1.0 +/- 1.2 Wood units; P = 0.006) than control participants, but similar LAP. During exercise, hypertensive patients showed a lower maximum workload and CO and higher peak mPAP than control subjects, but a similar increase in LAP. PVR determined according to multipoint mPAP-CO relationships was also higher in hypertensive patients than in control subjects (2.5 +/- 1.1 vs 1.5 +/- 0.7 mm Hg/L/min; P < 0.05), with no changes in pulmonary resistive vessel distensibility coefficient alpha (0.012 +/- 0.007 vs 0.012 +/- 0.010% change in diameter for each mm Hg increase in mPAP). CONCLUSIONS: Resting and exercise PVR are increased in uncomplicated HT, without this being related to increased pulmonary venous pressure or resistive vessel stiffness, suggesting an early increase in pulmonary vascular tone. PMID- 25745881 TI - Cor triatriatum: a reversible cause of severe pulmonary hypertension. AB - Cor triatriatum sinister is a congenital heart disorder that can lead to progressive dyspnea, pulmonary hypertension, and ultimately right ventricular (RV) failure. We report a case in which symptoms of progressive pulmonary hypertension were initially attributed to asthma, leading to a delayed diagnosis that resulted in suprasystemic pulmonary pressures and RV dysfunction. Rapid symptomatic and hemodynamic improvement was observed after surgical repair, with normalization of pulmonary artery pressures and RV function. PMID- 25745882 TI - Optimizing inter-professional communications in surgery: protocol for a mixed methods exploratory study. AB - BACKGROUND: Effective nurse-physician communication is critical to delivering high quality patient care. Interprofessional communication between surgical nurses and surgeons, often through the use of pagers, is currently characterized by information gaps and interprofessional tensions, both sources of workflow interruption, potential medical error, impaired educational experience, and job satisfaction. OBJECTIVE: This study aims to define current patterns of, and understand enablers and barriers to interprofessional communication in general surgery, in order to optimize the use of communication technologies, teamwork, provider satisfaction, and quality and safety of patient care. METHODS: We will use a mixed-methods multiphasic approach. In phase 1, a quantitative and content analysis of alpha-numeric pages (ANP) received by general surgery residents will be conducted to develop a paging taxonomy. Frequency, timing (on-call vs regular duty hours), and interval between pages will be described using a 4-week sample of pages. Results will be compared between pages sent to junior and senior residents. Finally, using an inductive analysis, two independent assessors will classify ANP thematically. In Phase 2, a qualitative constructivist approach will explore stakeholders' experiences with interprofessional communication, including paging, through interviews and shadowing of 40 residents and 40 nurses at two institutions. Finally, a survey will be developed, tested, and administered to all general surgery nurses and residents at the same two institutions, to evaluate their attitudes about the effectiveness and quality of interprofessional communication, and assess their satisfaction. RESULTS: Describing the profile of current pages is the first step towards identifying areas and root causes of IPC inefficiency. This study will identify key contextual barriers to surgical nurse house staff communication, and existing interprofessional knowledge and practice gaps. CONCLUSIONS: Our findings will inform the design of a guideline and tailored intervention to improve IPC in order to ensure high quality patient care, optimal educational experience, and provider satisfaction. PMID- 25745883 TI - Bone muscle interactions and vitamin D. AB - Beyond the established roles of vitamin D in bone and mineral homeostasis, we are becoming increasingly aware of its diverse effects in skeletal muscle. Subjects with severe vitamin D deficiency or mutations of the vitamin D receptor develop generalized atrophy of muscle and bone, suggesting coordinated effects of vitamin D in musculoskeletal physiology. At a mechanistic level, vitamin D exerts wide ranging effects in muscle and bone calcium handling, differentiation and development. Vitamin D also modulates muscle and bone-derived hormones, facilitating cross-talk between these tissues. In this review, we discuss emerging evidence that vitamin D regulates bone and muscle in a direct, integrated fashion, positioning the vitamin D pathway as a potential therapeutic target for musculoskeletal diseases. This article is part of a Special Issue entitled "Muscle Bone Interactions". PMID- 25745884 TI - Inhibitory avoidance learning in CD1 mice: Effects of chronic social defeat stress. AB - Chronic social defeat stress (CSDS) is an animal model widely used to determine the neurobiological mechanisms of stress and its associated pathologies. In this study, the effects of CSDS on inhibitory avoidance (IA) were evaluated in post pubertal and adult male CD1 mice, instead of the C57BL/6J strain used in the CSDS standard protocol. CSDS consisted of daily 5-min (experiments 1 and 2) or 10-min (experiment 3) agonistic encounters on 21 consecutive days. Twenty four hours after the last session of CSDS, all the mice were tested for IA. They were also evaluated in an elevated plus-maze, obtaining complementary measures of locomotor activity and emotionality. In experiments 1 and 2, IA learning was confirmed in both non-stressed and stressed groups, showing stressed post-pubertal mice higher test latencies than controls. In experiment 3, IA was confirmed in the non stressed but not in the stressed group. In conclusion, a moderate degree of CSDS (5-min encounters) enhances memory in post-pubertal but not in adult mice, while a high degree (10-min encounters) prevents the memory formation of IA in mice. These effects of CSDS on memory are not secondary to motor or emotional effects of stress. Furthermore, CD1 has been shown to be a valid strain for the stressed mice in the CSDS model. PMID- 25745885 TI - Cubosomes and other potential ocular drug delivery vehicles for macromolecular therapeutics. AB - INTRODUCTION: Many macromolecular therapeutics designed to treat posterior segment eye diseases (PSEDs) are administered through frequent ocular injection, which can further deteriorate eye health. Due to the high frequency of injection and the high cost of the therapeutics, there is a need to develop new ways in which to deliver these therapeutics: ways which are both safer and more cost effective. AREAS COVERED: Using the most common PSED, age-related macular degeneration, as an example of a debilitating ocular disease, this review examines the key barriers limiting the delivery of macromolecular therapeutics to the posterior segment of the eye and defines the key requirements placed on particulate drug delivery vehicles (DDVs) to be suitable for this application. Recent developments in macromolecular drug delivery to treat this disease as well as the remaining shortcomings in its treatment are surveyed. Lastly, an emerging class of DDVs potentially suited to this application, called cubosomes, is introduced. EXPERT OPINION: Based on their excellent colloidal stability and high internal surface area, cubosomes hold great potential for the sustained release of therapeutics. Novel production methods and a better understanding of the mechanisms through which drug release from these particles can be controlled are two major recent developments toward successful application. PMID- 25745886 TI - Diverging roles of bacterial siderophores during infection. AB - Siderophores are low molecular weight, high affinity iron chelating molecules that are essential virulence factors in many Gram-negative bacterial pathogens. Whereas the chemical structure of siderophores is extremely variable, the function of siderophores has been narrowly defined as the chelation and delivery of iron to bacteria for proliferation. The discovery of the host protein Lipocalin 2, capable of specifically sequestering the siderophore Enterobactin but not its glycosylated-derivative Salmochelin, indicated that diversity in structure could be an immune evasion mechanism that provides functional redundancy during infection. However, there is growing evidence that siderophores are specialized in their iron-acquisition functions, can perturb iron homeostasis in their hosts, and even bind non-iron metals to promote bacterial fitness. The combination of siderophores produced by a pathogen can enable inter-bacterial competition, modulate host cellular pathways, and determine the bacterial "replicative niche" during infection. This review will examine both classical and novel functions of siderophores to address the concept that siderophores are non redundant virulence factors used to enhance bacterial pathogenesis. PMID- 25745887 TI - Paper as a platform for sensing applications and other devices: a review. AB - Paper is a ubiquitous material that has various applications in day to day life. A sheet of paper is produced by pressing moist wood cellulose fibers together. Paper offers unique properties: paper allows passive liquid transport, it is compatible with many chemical and biochemical moieties, it exhibits piezoelectricity, and it is biodegradable. Hence, paper is an attractive low-cost functional material for sensing devices. In recent years, researchers in the field of science and engineering have witnessed an exponential growth in the number of research contributions that focus on the development of cost-effective and scalable fabrication methods and new applications of paper-based devices. In this review article, we highlight recent advances in the development of paper based sensing devices in the areas of electronics, energy storage, strain sensing, microfluidic devices, and biosensing, including piezoelectric paper. Additionally, this review includes current limitations of paper-based sensing devices and points out issues that have limited the commercialization of some of the paper-based sensing devices. PMID- 25745888 TI - Deep comparative genomics among Chlamydia trachomatis lymphogranuloma venereum isolates highlights genes potentially involved in pathoadaptation. AB - Lymphogranuloma venereum (LGV) is a human sexually transmitted disease caused by the obligate intracellular bacterium Chlamydia trachomatis (serovars L1-L3). LGV clinical manifestations range from severe ulcerative proctitis (anorectal syndrome), primarily caused by the epidemic L2b strains, to painful inguinal lymphadenopathy (the typical LGV bubonic form). Besides potential host-related factors, the differential disease severity and tissue tropism among LGV strains is likely a function of the genetic backbone of the strains. We aimed to characterize the genetic variability among LGV strains as strain- or serovar specific mutations may underlie phenotypic signatures, and to investigate the mutational events that occurred throughout the pathoadaptation of the epidemic L2b lineage. By analyzing 20 previously published genomes from L1, L2, L2b and L3 strains and two new genomes from L2b strains, we detected 1497 variant sites and about 100 indels, affecting 453 genes and 144 intergenic regions, with 34 genes displaying a clear overrepresentation of nonsynonymous mutations. Effectors and/or type III secretion substrates (almost all of those described in the literature) and inclusion membrane proteins showed amino acid changes that were about fivefold more frequent than silent changes. More than 120 variant sites occurred in plasmid-regulated virulence genes, and 66% yielded amino acid changes. The identified serovar-specific variant sites revealed that the L2b specific mutations are likely associated with higher fitness and pointed out potential targets for future highly discriminatory diagnostic/typing tests. By evaluating the evolutionary pathway beyond the L2b clonal radiation, we observed that 90.2% of the intra-L2b variant sites occurring in coding regions involve nonsynonymous mutations, where CT456/tarp has been the main target. Considering the progress on C. trachomatis genetic manipulation, this study may constitute an important contribution for prioritizing study targets for functional genomics aiming to dissect the impact of the identified intra-LGV polymorphisms on virulence or tropism dissimilarities among LGV strains. PMID- 25745889 TI - Identifying the pattern of molecular evolution for Zaire ebolavirus in the 2014 outbreak in West Africa. AB - The current Ebola virus disease (EVD) epidemic has killed more than all previous Ebola outbreaks combined and, even as efforts appear to be bringing the outbreak under control, the threat of reemergence remains. The availability of new whole genome sequences from West Africa in 2014 outbreak, together with those from the earlier outbreaks, provide an opportunity to investigate the genetic characteristics, the epidemiological dynamics and the evolutionary history for Zaire ebolavirus (ZEBOV). To investigate the evolutionary properties of ZEBOV in this outbreak, we examined amino acid mutations, positive selection, and evolutionary rates on the basis of 123 ZEBOV genome sequences. The estimated phylogenetic relationships within ZEBOV revealed that viral sequences from the same period or location formed a distinct cluster. The West Africa viruses probably derived from Middle Africa, consistent with results from previous studies. Analysis of the seven protein regions of ZEBOV revealed evidence of positive selection acting on the GP and L genes. Interestingly, all putatively positive-selected sites identified in the GP are located within the mucin-like domain of the solved structure of the protein, suggesting a possible role in the immune evasion properties of ZEBOV. Compared with earlier outbreaks, the evolutionary rate of GP gene was estimated to significantly accelerate in the 2014 outbreak, suggesting that more ZEBOV variants are generated for human to human transmission during this sweeping epidemic. However, a more balanced sample set and next generation sequencing datasets would help achieve a clearer understanding at the genetic level of how the virus is evolving and adapting to new conditions. PMID- 25745890 TI - Difficult conversations in orthopaedics. AB - There is an overall lack of training in the communication skills needed by physicians to effectively navigate challenging patient encounters. So-called difficult patients have specific obstructive behaviors that make it challenging to establish a successful doctor-patient partnership and can elicit strong negative emotions in the physician. Instead of labeling the patient as difficult, it is more useful to consider encounters as difficult events and rely on diagnostic and interventional techniques similar to those used in solving any other clinical problem. In difficult interactions, patients may have the perception that the physician is less technically skilled, they were allotted inadequate time, received poor explanations, and were overall dissatisfied with the visit. Physicians who experience difficult encounters may find it difficult to communicate with patients. The physician is often not attuned to the psychosocial aspects of patient care and is frustrated and uneasy with patients. To improve patient and physician satisfaction and healthcare outcomes, it is helpful to review the skills and strategies for delivering bad news, managing angry patients, addressing financial concerns, and dealing with drug-seeking patients. PMID- 25745891 TI - The effects of obesity in orthopaedic care. AB - Obesity is a costly, difficult, and increasingly prevalent challenge facing orthopaedic care. It adds complexity to caring for patients throughout all types and stages of treatment in all orthopaedic subspecialties. There are medical complications to mitigate, anesthetic challenges to meet, and surgical complexities to overcome. The financial implications of treating patients who are obese will continue to challenge surgeons, especially as new payment models are encountered. Research continues to provide more evidence of the unfavorable effects of obesity on outcomes after various orthopaedic procedures. An increasing awareness of the effects of obesity on patients undergoing orthopaedic procedures and educating orthopaedic providers on methods of countering the challenges associated with obesity should ultimately benefit both the provider and the patient. PMID- 25745892 TI - A comprehensive overview of osteoporotic fracture treatment. AB - Osteoporosis is a worldwide epidemic, affecting more than 75 million people in the United States, Europe, and Japan. At a consensus conference in 1990, European and American leaders defined osteoporosis as a disease characterized by low bone mass, microarchitectural deterioration of bone tissue, and a resulting increase in fracture risk. In 2000, the National Institutes of Health modified this definition, describing osteoporosis as a skeletal disorder characterized by compromised bone strength and a predisposition for increased fracture risk. It was emphasized that bone strength, which is a more comprehensive concept than bone mass, integrates the concepts of both bone density and bone quality. As orthopaedic surgeons, recognizing osteoporosis and its healthcare implications is critical to optimize the musculoskeletal health of patients of all ages and both sexes. PMID- 25745893 TI - Advances in the understanding and treatment of musculoskeletal infections. AB - Musculoskeletal infections are a challenging treatment problem for orthopaedic surgeons. Despite advances in aseptic techniques and improved chemotherapeutic options, there has not been a substantial decrease in the incidence of musculoskeletal infections for the past quarter century. Understanding how microbes gain a foothold in tissue and bone and establish a chronic infectious state is imperative to the successful treatment of bone and soft-tissue infections. The methodic establishment of microbes in a sessile state in a mature biofilm represents the basis for instituting a chronic microbial defense system and sustainability in a host. To properly eradicate such infections requires a stepwise treatment algorithm of meticulous and thorough debridement, dead-space management, and soft-tissue and bone reconstruction. A comprehensive understanding of the reconstruction ladder combined with a detailed treatment plan from the initial staging of an infection through final reconstruction can cure an infection and achieve good functional results for patients. PMID- 25745894 TI - Periprosthetic joint infection: the algorithmic approach and emerging evidence. AB - Periprosthetic joint infections (PJIs) continue to affect patients, result in accelerated mortality, and consume approximately $1 billion of annual healthcare resources. The future of otherwise successful total joint arthroplasties can be jeopardized by PJI. In recent years, the issue of hospital-acquired infections has gained increasing attention in the United States and the rest of the world, and numerous efforts are being made to address this problem. The orthopaedic community continues to partner with societies, professional organizations, and industry to address this challenge. Recently, an international group of more than 300 surgical experts produced a 350-page document that outlines some of the best practices and identifies the evidence gap related to the management of PJIs. The document, using an algorithmic approach, outlines effective strategies for the prevention, diagnosis, and surgical management of PJIs. It is anticipated that the application of this algorithmic approach will lead to a reduction in the incidence of PJIs, will allow clinicians to diagnose PJI effectively and expeditiously, and will improve the outcome of patients affected by PJIs. PMID- 25745895 TI - MRI of the knee in adults. AB - MRI of the knee is a crucial component for evaluating symptomatic patients. An awareness of normal and abnormal appearances assists in clinical decision making. Chronic degenerative changes and focal traumatic injuries can sometimes be confused with one another, so differentiation is crucial. As technology continues to evolve, identifying early disease and preventing disease progression will become an integral part of MRI interpretation. PMID- 25745896 TI - MRI of the shoulder in adults. AB - MRI can be used to assist in distinguishing pathology and anatomic disruptions adjacent to shoulder articulations and is a crucial tool in evaluating the symptomatic shoulder. The differentiation of traumatic and degenerative etiologies is important for patient management. A review of common adult degenerative and posttraumatic conditions can help familiarize general orthopaedic surgeons and sports medicine care providers to the perspective of shoulder specialists and musculoskeletal radiologists. PMID- 25745897 TI - The need for structural allograft biomechanical guidelines. AB - Because of their osteoconductive properties, structural bone allografts retain a theoretic advantage in biologic performance compared with artificial interbody fusion devices and endoprostheses. Current regulations have addressed the risks of disease transmission and tissue contamination, but comparatively few guidelines exist regarding donor eligibility and bone processing issues with a potential effect on the mechanical integrity of structural allograft bone. The lack of guidelines appears to have led to variation among allograft providers in terms of processing and donor screening regarding issues with recognized mechanical effects. Given the relative lack of data on which to base reasonable screening standards, a basic biomechanical evaluation was performed on one source of structural bone allograft, the femoral ring. Of the tested parameters, the minimum and maximum cortical wall thicknesses of femoral ring allograft were most strongly correlated with the axial compressive load to failure of the graft, suggesting that cortical wall thickness may be a useful screening tool for compressive resistance expected from fresh cortical bone allograft. Development of further biomechanical and clinical data to direct standard development appears warranted. PMID- 25745898 TI - Diagnosis and Management of Soft-tissue Masses. AB - Soft-tissue masses of the extremities are common entities encountered by nearly all providers of musculoskeletal patient care. Proper management of these lesions requires a specific process of evaluation. A detailed history and physical examination must be performed. Appropriate imaging studies must be obtained based on clinical indications. MRI is the imaging modality of choice for diagnosis of soft-tissue masses, with CT and ultrasonography used as secondary options. These modalities aid the clinician in developing an appropriate differential diagnosis and treatment plan. When the initial evaluation is inconclusive, biopsy must be performed. A diagnosis must be established before definitive treatment with surgical excision or, in rare cases, radiation therapy is performed. Clinicians without substantial experience in treating soft-tissue masses should consider referral to a musculoskeletal oncologist for specialized care when a definitive diagnosis of a benign lesion cannot be made. Several studies have shown that multidisciplinary care in specialized referral centers optimizes outcomes and diminishes comorbid complications. PMID- 25745899 TI - Extremity amputations: principles, techniques, and recent advances. AB - It is estimated that approximately 1.7 million Americans are living with the loss of a limb, and this number is expected to nearly double by 2050. The most common reasons for amputation include vascular compromise, trauma, cancer, and congenital deformities. Orthopaedic surgeons are often called on to manage patients requiring an amputation or those with amputation-related conditions. It is helpful to review the principles and techniques for performing lower and upper limb amputations, with a focus on common complications and how to avoid them and to be familiar with recent advances in prosthetic design and management of a residual limb. PMID- 25745900 TI - Complex trauma to the shoulder girdle, including the proximal humerus, the clavicle, and the scapula: current concepts in diagnosis and treatment. AB - Fractures to the shoulder girdle are common injuries in an aging population. Many techniques and theories lie behind the treatment of such injuries. Knowledge and understanding of current concepts for diagnosing and treating proximal humeral, clavicular, and scapular fractures and the theory behind them will help surgeons make informed decisions with regard to patient care. PMID- 25745901 TI - Current management of posterior wall fractures of the acetabulum. AB - The general goals for treating an acetabular fracture are to restore congruity and stability of the hip joint. These goals are no different from those for the subset of fractures of the posterior wall. Nevertheless, posterior wall fractures present unique problems compared with other types of acetabular fractures. Successful treatment of these fractures depends on a multitude of factors. The physician must understand their distinctive radiologic features, in conjunction with patient factors, to determine the appropriate treatment. By knowing the important points of posterior surgical approaches to the hip, particularly the posterior wall, specific techniques can be used for fracture reduction and fixation in these often challenging fractures. In addition, it is important to develop a complete grasp of potential complications and their treatment. The evaluation and treatment protocols initially developed by Letournel and Judet continue to be important; however, the surgeon also should be aware of new information published and presented in the past decade. PMID- 25745902 TI - The treatment of periprosthetic fractures. AB - The management of periprosthetic fractures is an issue of increasing importance for orthopaedic surgeons. Because of the expanding indications for total joint arthroplasty (TJA) and an aging population with increasingly active lifestyles, the incidence of primary and revision TJA is increasing, and there is a corresponding increase in the prevalence of periprosthetic fractures about a TJA. The management of these fractures is often complex because of issues with obtaining fixation around implants, dealing with osteopenic bone or compromised bone stock, and the potential need for revising loose TJA components. In addition, these injuries frequently occur in frail, elderly patients, and the literature has demonstrated that both morbidity and mortality in these patients is similar to that of the geriatric hip fracture population. As such, the early restoration of function and ambulation is critical in patients with these injuries, and effective surgical strategies to achieve these goals are essential. PMID- 25745903 TI - Controversies in the intramedullary nailing of proximal and distal tibia fractures. AB - Management of tibia fractures by internal fixation, particularly intramedullary nails, has become the standard for diaphyseal fractures. However, for metaphyseal fractures or those at the metaphyseal-diaphyseal junction, the choice of fixation device and technique is controversial. For distal tibia fractures, nailing and plating techniques may be used, the primary goal for each being to achieve acceptable alignment with minimal complications. Different techniques for reduction of these fractures are available and can be applied with either fixation device. Overall outcomes appear to be nearly equivalent, with minor differences in complications. Proximal tibia fractures can be fixed using nailing, which is associated with deformity of the proximal short segment. A newer technique--suprapatellar nailing--may minimize these problems, and use of this method has been increasing in trauma centers. However, most data are still largely based on case series. PMID- 25745904 TI - External fixation of tibial fractures. AB - External fixation for definitive or initial management of tibial fractures has a long history, with pin-to-bar external fixation being the standard of care for definitive management. However, the use of this method has lessened because of the increased popularity of intramedullary nailing and drawbacks associated with external fixation. This method is still commonly used in the military environment and can be used for temporary stabilization of tibial fractures, especially in the setting of periarticular injuries. These fixators also may be useful for salvage of open and/or infected fractures that are unsuitable for internal fixation. PMID- 25745905 TI - Shoulder prosthetic arthroplasty options in 2014: what to do and when to do it. AB - The number of shoulder arthroplasty procedures performed in the United States is steadily increasing as a result of an expansion in implant options, clinical indications, and surgical experience. Available options include stemmed implants, short-stemmed or stemless prostheses, fracture-specific designs, resurfacing implants, partial surface replacement, metal-backed or polyethylene glenoid components designed for cementation or bone ingrowth, and reverse total shoulder arthroplasty. Efforts to re-create anatomy, improve outcomes, and avoid complications have resulted in many changes in prosthesis design. Despite these changes, failures still occur, and revision surgery is sometimes necessary. A thorough knowledge of current arthroplasty options, indications, and the principles of implantation is necessary to optimize outcomes after shoulder arthroplasty. PMID- 25745906 TI - Proximal humeral fractures: pin, plate, or replace. AB - Proximal humeral fractures are becoming increasingly common in individuals older than 60 years, with only fractures of the hip and distal radius occurring with a higher frequency. Most proximal humeral fractures can be managed without surgery; however, if a fracture is displaced or angulated, surgical treatment may be required. There are four main options for the surgical management of proximal humeral fractures: minimally invasive percutaneous reduction and fixation, open reduction and periarticular plating, hemiarthroplasty, and reverse total shoulder arthroplasty. PMID- 25745907 TI - Elbow arthroscopy: indications, techniques, outcomes, and complications. AB - Elbow arthroscopy is a tool useful for the treatment of a variety of pathologies about the elbow. The major indications for elbow arthroscopy include debridement for septic elbow arthritis, synovectomy for inflammatory arthritis, debridement for osteoarthritis, loose body extraction, contracture release, treatment of osteochondral defects and selected fractures or instability, and tennis elbow release. To achieve favorable outcomes after elbow arthroscopy, the surgeon should be aware of contraindications, technical considerations, anatomic principles, and the need for proper patient positioning and portal selection. Elbow arthroscopy is an effective procedure for the treatment of inflammatory arthritis, osteoarthritis, and lateral epicondylitis. PMID- 25745908 TI - Arthroscopic tennis elbow release. AB - Lateral epicondylitis, originally referred to as tennis elbow, affects between 1% and 3% of the population and is usually found in patients aged 35 to 50 years. Although it was initially thought that lateral epicondylitis was caused by an inflammatory process, most microscopic studies of excised tissue demonstrate a failure of reparative response in the extensor carpi radialis brevis tendon and in any of the associated structures. Most cases of lateral epicondylitis respond to appropriate nonsurgical treatment protocols, which include medication, bracing, physical therapy, corticosteroid injections, shock wave therapy, platelet-rich plasma, and low-dose thermal or ultrasound ablation devices. However, when these protocols are unsuccessful, surgical measures may be appropriate and have a high rate of success. The results of arthroscopic surgical procedures have documented satisfactory results, with improvement rates reported between 91% and 97.7%. Recent advances in arthroscopic repair and plication of these lesions, along with recognizing the presence and repair of coexisting lesions, have allowed arthroscopic techniques to provide excellent results. PMID- 25745909 TI - Unlinked total elbow arthroplasty. AB - For more than 60 years, total elbow arthroplasty (TEA) has been successfully used to treat a variety of elbow conditions. Although first designed to treat older patients with rheumatoid arthritis, the indications have expanded to include younger, higher-demand patients with a broad range of elbow pathology. Two groups of TEA currently exist. The first group includes linked or semiconstrained elbows with a mechanical connection between the humeral and ulnar components that prevents disassociation. These implants do not rely on muscular or ligamentous tissues for stability. The second group includes unlinked implants that have no physical connection between the humeral and ulnar components. They rely on bearing surface architecture as well as soft-tissue integrity for elbow stability. Critical to the success of unlinked implants is a thorough preoperative evaluation of elbow stability, including bone stock, collateral ligament integrity, and periarticular muscle function. Unlinked implants should apply less strain to the bone-cement-implant interfaces, which may theoretically decrease rates of bearing wear and aseptic loosening. For this reason, some surgeons prefer unlinked implants for younger, higher-demand patients. To date, unlinked implants have not been clinically shown to improve survivorship compared with linked devices. No prospective randomized trials comparing linked and unlinked TEAs are currently available. Historically, unlinked implants have had higher revision rates, mostly caused by instability and early design flaws. More recent series have shown no significant differences in outcomes compared with linked devices. Unlinked TEA provides reliable pain relief and improved range of motion for patients with a variety of elbow disorders. Diligent patient selection and careful surgical technique are of utmost importance when considering an unlinked TEA as a treatment option. The recent development of convertible implants now allows surgeons to make intraoperative decisions regarding elbow stability and convert to a linked implant without revising the stems. PMID- 25745910 TI - Repair and reconstruction of the lateral ulnar collateral ligament. AB - Lateral ulnar collateral ligament repair and reconstruction are techniques used to treat posterolateral rotatory instability of the elbow. The choice to perform repair versus reconstruction is typically dependent on the chronicity of the injury and the quality of tissue available at the time of surgery. PMID- 25745911 TI - Wide-awake Hand and Wrist Surgery: A New Horizon in Outpatient Surgery. AB - There has been increased interest in and experience with performing several surgical procedures on the hand and the wrist utilizing local anesthesia in an unsedated patient. These surgical procedures can be safely performed on an outpatient basis. Experience has shown that the strategic use of local anesthesia with epinephrine is safe and, in procedures such as tendon repair or transfer, permits intraoperative control of overall motion and function. PMID- 25745912 TI - Dorsal proximal interphalangeal joint fracture-dislocations: evaluation and treatment. AB - Proximal interphalangeal joint injuries are common and often can be treated nonsurgically. Some dorsal fracture-dislocations, however, require special attention or surgical management to optimize outcomes. Treatment options for dorsal proximal interphalangeal fracture-dislocations include splinting, percutaneous pinning, fracture fixation, external fixation devices, volar plate arthroplasty, and hemihamate arthroplasty. PMID- 25745913 TI - Treatment recommendations for carpal tunnel syndrome and peripheral nerve repair. AB - Although open and endoscopic techniques for carpal tunnel release can provide excellent results, neither technique has demonstrated clinical superiority. A permanent nerve injury remains the most devastating complication regardless of the technique used. Symptoms in carpal tunnel syndrome recur in up to 30% of patients, usually secondary to scarring of the median nerve. Repeated nerve decompression alone does not always provide satisfactory results in patients with recalcitrant carpal tunnel syndrome. Supplementary techniques with either biologic or synthetic adhesion barriers can be used to cover the nerve, improving functional recovery and preventing recurrent scarring. Direct end-to-end repair without tension remains the gold standard treatment of peripheral nerve lacerations. When primary repair is not possible, biologic or synthetic nerve conduits and nerve allografts are an alternative to autografts. Future advances in bioengineering and better understanding of nerve biology combined with randomized, multicenter, larger studies may lead to the optimal method of peripheral nerve reconstruction. PMID- 25745914 TI - Arthritis of the thumb and digits: current concepts. AB - Osteoarthritis of the hand continues to be a problem in an aging population and affects the proximal and distal interphalangeal, metacarpophalangeal, and carpometacarpal joints in the hands. Heberden nodes develop in the distal interphalangeal joints and typically present as a deformed and enlarged joint and can cause pain. Surgery rarely is necessary because functional difficulties are uncommon; however, there may be problems if the metacarpophalangeal and proximal interphalangeal joints are involved because cartilage destruction generates pain and causes weakness and motion loss. Implant arthroplasty typically can improve pain but does not reliably improve range of motion, and complication and revision rates are substantial. Arthrodesis continues as a treatment for digital osteoarthritis, but the surgeon must balance the risks of complications with the benefits of improved patient outcomes. The opposable thumb, which is critical for hand dexterity and strength, can be severely disabled by basal joint arthritis. The complex architecture of the basal joint continues to be defined by its relationship to the surrounding bony and ligamentous anatomy and its effect on the trapeziometacarpal joint. Nonsurgical treatment may be beneficial, but surgical options, including arthroscopy, osteotomy, and arthroplasty, should be considered if nonsurgical management fails. Prosthetic arthroplasty has a historically poor record; therefore, trapeziectomy remains the hallmark of current reconstructive techniques. Ligament reconstruction and tendon interposition arthroplasty are the most commonly performed surgical procedures, but hematoma distraction arthroplasty and various methods of suspensionplasty also are currently used. PMID- 25745915 TI - Avoiding complications and treating failures of arthroscopic femoroacetabular impingement correction. AB - Complications and failures after hip arthroscopy are reported to be relatively uncommon. Because there are no recent comprehensive, prospective studies observing complications and failures after hip arthroscopy, the current rates are unclear. As the number of surgeons performing hip arthroscopy and the number of procedures performed continue to increase, there is the need for an increased awareness of potential adverse events. PMID- 25745916 TI - How do I get out of this jam? Overcoming common intraoperative problems in primary total hip arthroplasty. AB - Prompt attention is typically required in managing intraoperative problems associated with total hip arthroplasty. There is often limited time for consultation or a review of the literature. The treating surgeon should be familiar with treatment options, favored treatment methods, and should be able to implement the most appropriate and optimal treatment for his or her patient. Common intraoperative complications associated with primary total hip arthroplasty include difficulty gaining sufficient exposure, problems with cup fixation, challenges with implant anteversion, intraoperative fracture of the femur, and difficulties with intraoperative limb length and hip instability. PMID- 25745917 TI - How do I get out of this jam? Early postoperative problems of primary total hip arthroplasty. AB - Acute postoperative problems associated with total hip arthroplasty typically require prompt attention. Because the circumstances surrounding these problems provide limited time for consultation or literature review, effective management depends on the surgeon being aware of treatment options and favored treatment methods and executing the best treatments. Surgeons should be aware of management strategies for the most common and difficult early postoperative complications after primary total hip arthroplasty, including wound problems, periprosthetic femur fractures, nerve dysfunction, and venous thromboembolism. State-of-the-art knowledge will help the treating surgeon successfully manage complications. PMID- 25745918 TI - Early postoperative complications after total hip arthroplasty: current strategies for prevention and treatment. AB - Total hip arthroplasty is a highly successful treatment for end-stage arthritis that substantially improves patients' symptoms and function. Unfortunately, complications in the early postoperative period are inevitable, even in procedures performed by experienced surgeons using careful surgical techniques. Current strategies to prevent and effectively manage the most common early complications after total hip arthroplasty, including periprosthetic joint infection, instability, leg-length inequality, and periprosthetic femoral fracture, are discussed. PMID- 25745919 TI - The Role of Dual-mobility Cups in Total Hip Arthroplasty. AB - It is often challenging to address instability risks when dealing with complex primary total hip arthroplasty and revision hip surgery. The implant-related options available to surgeons to deal with the risks of instability include femoral head size, femoral neck length/offset, component orientation, and the use of constrained articulations. Dual-mobility articulations have long been used in Europe in the setting of a potential or proven unstable hip; this type of articulation is now available in North America after regulatory approval. However, a dual-mobility articulation has its own unique advantages and disadvantages. Before choosing this implant option, the arthroplasty surgeon needs to be fully informed of the design concept, the surgical technique, the advantages, the disadvantages, and the literature surrounding the use of a dual mobility articulation. PMID- 25745920 TI - Tapered, fluted titanium stems in revision total hip arthroplasty: role and results in contemporary practice. AB - The burden of revision total hip arthroplasty (THA) is rising. As increasingly younger patients are treated with THA procedures, it is likely that this trend will continue. The results of revision THA are greatly influenced by the quantity and the quality of available femoral bone stock available for reconstruction. Modular and nonmodular tapered fluted titanium stems are increasingly used in revision THA. It is helpful to be familiar with the use of these components in revision THA. PMID- 25745921 TI - Ensuring a Winner: The ABCs of Primary Total Knee Arthroplasty. AB - Total knee arthroplasty is a common and immensely successful surgical procedure that reliably relieves pain and improves function. However, early revision rates and patient dissatisfaction are high suggesting that there is need for improvement through careful patient selection and education as well as attention to surgical technique. After ensuring that a patient is an appropriate candidate for the procedure, patient education is critical to ensure appropriate expectations. Careful preoperative planning and achieving appropriate alignment, sizing, and ligament balance are critical for optimal knee function. Careful attention to the cement technique is important for long-term implant fixation. With appropriate patient selection and careful surgical techniques, optimal patient outcomes will be achieved. PMID- 25745922 TI - Diagnosis and Management of Extra-articular Causes of Pain After Total Knee Arthroplasty. AB - Postoperative pain, which has been attributed to poor outcomes after total knee arthroplasty (TKA), remains problematic for many patients. Although the source of TKA pain can often be delineated, establishing a precise diagnosis can be challenging. It is often classified as intra-articular or extra-articular pain, depending on etiology. After intra-articular causes, such as instability, aseptic loosening, infection, or osteolysis, have been ruled out, extra-articular sources of pain should be considered. Physical examination of the other joints may reveal sources of localized knee pain, including diseases of the spine, hip, foot, and ankle. Additional extra-articular pathologies that have potential to instigate pain after TKA include vascular pathologies, tendinitis, bursitis, and iliotibial band friction syndrome. Patients with medical comorbidities, such as metabolic bone disease and psychological illness, may also experience prolonged postoperative pain. By better understanding the diagnosis and treatment options for extra-articular causes of pain after TKA, orthopaedic surgeons may better treat patients with this potentially debilitating complication. PMID- 25745923 TI - Diagnosis and Management of Intra-articular Causes of Pain After Total Knee Arthroplasty. AB - Total knee arthroplasty (TKA) is an effective procedure for decreasing pain, improving functional capability, and increasing the overall quality of life for thousands of people with chronic knee osteoarthritis. Although patient outcomes and satisfaction remain high, a substantial percentage of patients report residual pain after TKA. Sources of postoperative pain include intra- and extra articular etiologies as well as factors unrelated to the implants themselves. A patient-centered approach to the painful TKA may aid clinicians in diagnosing and treating patients with intra-articular causes of pain after TKA. A thorough understanding of the mechanisms involved may lead to improved preoperative planning and patient selection, ultimately decreasing the number of patients with less than optimal postoperative outcomes. PMID- 25745924 TI - Diagnosis, treatment, and complications of adult lumbar disk herniation: evidence based data for the healthcare professional. AB - Lumbar disk herniation is a commonly seen disorder that requires care by spinal surgeons and healthcare professionals. Although there has been substantial research on the diagnosis, treatment, complications, and outcomes of lumbar disk herniation, patient management varies. A review and evaluation of the literature (with special regard for high-quality randomized studies) and familiarity with best practices guidelines for the evaluation, management, and treatment of adult lumbar disk herniation will enhance the optimal delivery of health care to affected patients. PMID- 25745925 TI - Advances in the understanding of cervical spine deformity. AB - Cervical spine deformities pose substantial challenges for spine surgeons. The anatomy and biomechanics of the cervical spine play an important role in the decision-making process regarding treatment. The etiology of cervical deformities can be congenital, developmental, iatrogenic, degenerative, or inflammatory. Dropped head syndrome has been recently described but is poorly understood. Patients have variable presentations ranging from neck pain to an inability to maintain head position and neural compromise. Radiographic angles are important to monitor the deformity and plan the surgical correction. Treatment is focused on relieving pain, preventing and improving neurologic compromise, and improving overall spinal alignment and balance. The surgical approach and the level of fusion should be individualized on a case-by-case basis. The surgeon can greatly improve a patient's quality of life by understanding the nature of the patient's deformity and fully considering all treatment options. PMID- 25745926 TI - Management of idiopathic and nonidiopathic flatfoot. AB - Flatfoot in a child may be normal before development of the arch, but the prevalence decreases with age. Treatment is indicated only in the presence of pain and should begin with nonsurgical management options such as stretching of the Achilles tendon and the use of soft shoe orthotics. If pain persists, a modified Evans procedure, together with additional procedures to address forefoot supination, can be successful in correcting deformity and addressing pain. A thorough understanding of the pathology and correction desired will help minimize complications and recurrence. If neuromuscular pathology is present, treatment principles are altered and greatly depend on the severity of the deformity, the association of tibialis posterior spasticity, and ambulatory status. In mild to moderate pathology in walking patients with cerebral palsy, osteotomies can be successful. Various forms of arthrodesis can decrease recurrence when the deformity is severe in a nonambulatory patient with cerebral palsy and a symptomatic valgus foot deformity. In cases of collagen disorders, where soft tissue laxity complicates management, deformity correction may be of higher importance. Overall alignment always should be evaluated and corrected when necessary to optimize the outcome in patients with valgus foot deformities. The successful treatment of flexible or rigid flatfoot deformity must take into account underlying pathology to optimize outcomes. PMID- 25745927 TI - Posterior tibial tendon dysfunction in the adult: current concepts. AB - The management of posterior tibial tendon dysfunction in adults has evolved substantially, and controversy persists regarding a specific recommended algorithm for treatment. The current focus is on early diagnosis and treatment of this disorder with joint-sparing surgeries, such as corrective osteotomies and tendon transfers, when nonsurgical modalities have been exhausted. It is helpful to be familiar with the pertinent pathophysiology and diagnostic pearls associated with posterior tibial tendon dysfunction, its treatment options, pertinent literature, and technique tips for the procedures currently being used. PMID- 25745928 TI - Pediatric femoral shaft fractures: a system for decision making. AB - Pediatric femoral shaft fractures are one of the most common major pediatric injuries treated by orthopaedic surgeons. Historically, casting, with or without traction, was the standard of care for almost all pediatric femoral fractures. However, during the past 15 years, there has been a trend toward surgical fixation and rapid mobilization. This evolution has given orthopaedic surgeons many treatment methods in which they must consider patient age and size, fracture pattern, and the surgeon's own skills and experience. The evolution away from casting, with or without traction, has led to seven treatment options: (1) a Pavlik harness with or without a splint, (2) a walking spica cast, (3) a standard spica cast with or without traction, (4) elastic intramedullary nailing, (5) submuscular plating, (6) external fixation, or (7) trochanteric-entry intramedullary nailing. To determine which treatment option is best for a specific fracture type in a specific patient, pediatric femoral shaft fractures can be divided into five classes: (1) fractures that will heal with limited intervention; (2) fractures that should be treated without surgery, but must be watched closely; (3) fractures that benefit from surgical intervention with load sharing implants; (4) fractures that may benefit from surgical intervention with rigid fixation; and (5) fractures in a patient with a limb at risk and associated injuries that require initial treatment precedence. PMID- 25745929 TI - Complications of pediatric femoral shaft and distal physeal fractures. AB - Fractures of the femoral shaft comprise about 1.6% of all bony injuries in children and are the most common pediatric orthopaedic injury that requires hospitalization. The treatment of femoral fractures in children is largely dependent on the child's age and size and takes into account multiple considerations: the child's weight, associated injuries, the fracture pattern, the mechanism of injury, institutional or surgeons' preferences, and economic and social concerns. In addition, during the past two decades, there has been a dramatic change favoring surgical fixation rather than casting because of the many advantages of fixation, including more rapid mobilization. The goal of treatment should be to ultimately obtain a healed fracture and avoid associated complications, such as nonunion or delayed union, angular or rotational deformity, unequal limb lengths, infection, neurovascular injury, disruption of the growth plate, muscle weakness, and/or compartment syndrome. PMID- 25745930 TI - Complications of tibial eminence and diaphyseal fractures in children: prevention and treatment. AB - Fractures of the tibial eminence and the diaphyseal tibia are common pediatric orthopaedic injuries. Although most tibial fractures can be treated nonsurgically, those that require surgical intervention may encounter specific complications. Surgical treatment of fractures of the tibial eminence may be complicated by failed fixation, knee joint stiffness, and arthrofibrosis of the knee, a complication rarely seen in children but occurring most frequently after tibial eminence injuries. Complications of healing after tibial fractures in pediatric patients are uncommon, although some tibial shaft fractures exhibit delayed union or nonunion, infection, and soft-tissue complications. PMID- 25745931 TI - Complications of pediatric supracondylar humeral fractures. AB - Supracondylar humeral fractures are common in the pediatric population and can result in complications caused by both the injury itself and surgical or nonsurgical treatment. Neurologic complications are frequent, with the anterior interosseous nerve being the most common nerve affected. Vascular injuries, although less common, can result in long-term sequelae and should be recognized and treated promptly. Loss of reduction can occur with both surgical and nonsurgical treatment. Compartment syndrome and infection, although rare, require rapid recognition and treatment. It is important to be familiar with the potential complications surrounding the treatment of pediatric supracondylar humeral fractures to maximize outcomes and know when a referral may be warranted. PMID- 25745932 TI - Complications of pediatric elbow dislocations and monteggia fracture dislocations. AB - Pediatric elbow dislocations and Monteggia lesions are prone to acute and chronic complications. A pediatric patient's cartilaginous and unossified distal humerus contributes to the risks of inaccurate diagnoses resulting from the misinterpretation of findings on plain radiographs. The debate continues regarding the amount of acceptable displacement for medial epicondyle fractures. In contrast, the radial head should always point directly to the capitellum. Chronic complications include instability and arthritis. Instability, which can be subtle and difficult to diagnose, can occur in the medial or the posterolateral direction, depending on the injured stabilizer. Restoration of stability remains the mainstay of treatment. Pediatric traumatic arthritis is extremely difficult to manage with surgery because of the limited number of reliable treatment options. PMID- 25745933 TI - Complications of pediatric distal radius and forearm fractures. AB - Distal radius and forearm fractures represent a large percentage of pediatric fractures. The most common mechanism of injury is a fall onto an outstretched arm, which can lead to substantial rotational displacement. If this rotational displacement is not adequately addressed, there will be resultant loss of forearm motion and subsequent limitations in performing the activities of daily living. Good initial reductions and proper casting techniques are necessary when treating distal radius and forearm fractures nonsurgically; however, maintaining an acceptable reduction is not always possible. Atraumatic reduction of a displaced physeal fracture should occur within 7 days of the injury. If an impending malunion presents at 2 weeks or later after injury, observation is warranted because of concerns about physeal arrest with repeated attempts at manipulation, and it should be followed by a later assessment of functional limitations. Pediatric patients and their parents have higher expectations for recovery, which has contributed to an increase in the surgical management of pediatric distal radius and forearm fractures. In addition, surgical interventions, such as intramedullary nailing, have their own associated complications. PMID- 25745934 TI - The management of meniscal pathology: from partial meniscectomy to transplantation. AB - The management of meniscal pathology continues to evolve as researchers gain a better understanding of the role of the meniscus in normal knee kinematics. Evidence now supports retention or transplantation of meniscal tissue to maintain homeostatic knee mechanisms because the removal of meniscal tissue changes the contact stresses and leads to structural and biomechanical changes in the articular cartilage and the subchondral plate that predisposes the knee to the development of degenerative arthritis. Advances in repair techniques, biologic adjuvants, and progressive tissue-engineering strategies are rapidly adding to the surgeon's armamentarium when dealing with meniscal injury and insufficiency. Early clinical data support many of these advanced techniques. It is helpful to explore meniscal function, pathology, and current treatment modalities, with a focus on meniscal repair and transplantation as well as adjuvants to biologic healing and future directions in this field. PMID- 25745935 TI - Acute Management and Surgical Timing of the Multiligament-injured Knee. AB - Multiligament knee injuries are relatively rare, but the outcomes can be disastrous if they are not identified and treated appropriately. Recent trends in the literature are showing more focus on early identification and subspecialist management as important ways to achieve the best possible outcomes for these injuries. Early identification and the appropriate treatment of associated injury patterns are the keys to improving outcomes. These injuries are usually associated with high-energy trauma, but low-energy injuries also cause these severe injuries in patients with other comorbidities, such as those with high body mass indices. Familiarity with an evidence-based approach is helpful for managing these complex injuries. PMID- 25745936 TI - Repair and Reconstruction of Medial- and Lateral-sided Knee Injuries. AB - Surgical treatment of medial and lateral knee injuries using repair and/or reconstruction techniques is often necessary to restore knee ligament stability and optimize function. Successful execution of these repairs and reconstructions requires a sound understanding of basic anatomy and biomechanics. Against this backdrop, numerous repair and reconstruction techniques have been developed. Although medial knee injuries are often amenable to healing, posterolateral knee injuries often do not heal after a complete tear. Posterolateral corner repair should be attempted only in acute lateral knee injuries and never for midsubstance tears. Postoperative rehabilitation follows a period approach, with an emphasis on early range-of-motion exercises and protection of the surgical repair or reconstruction. By following these approaches to medial and lateral knee repairs and reconstructions, it is possible to restore stability to an injured knee and expedite return to desired levels of activity. PMID- 25745937 TI - Advances in posterior cruciate ligament reconstruction. AB - Current advances in posterior cruciate ligament reconstruction have led to excellent clinical and functional outcomes. It is helpful to review anatomy, cadaver sectioning studies, biomechanical studies, clinical outcome data, and novel surgical techniques for posterior cruciate ligament reconstruction, including all-inside reconstructions. Surgeons also should be aware of current controversies regarding transtibial versus inlay, autograft versus allograft, and single-bundle versus double-bundle reconstructions. PMID- 25745938 TI - High tibial osteotomy: indications, techniques, and postoperative management. AB - High tibial osteotomy is a safe and effective treatment for medial compartment arthrosis of the knee accompanied by varus alignment. This procedure has seen increasing use as an adjunct to cartilage restoration procedures, such as autologous chondrocyte and meniscal allograft transplantation, when angular deformity exists. The overall goals of high tibial osteotomy can be accomplished by several different techniques. The main indications for high tibial osteotomy are as a primary treatment for varus gonarthrosis and in conjunction with cartilage restoration procedures, such as autologous chondrocyte implantation or microfracture, where success rates are enhanced by correcting the varus deformity. PMID- 25745939 TI - Disorders of the long head of the biceps tendon. AB - The functional importance of the long head of the biceps tendon is a source of debate. Despite the controversy concerning its functional role, the long head of the biceps tendon is a recognized pain generator in the shoulder. Because long head of the biceps tendinopathy is commonly associated with other shoulder pathologies, a thorough assessment and examination are critical to making the correct diagnosis and choosing a management plan. If nonsurgical treatment has failed, biceps tenotomy and biceps tenodesis can provide pain relief. Biceps tenodesis is reserved for young, higher demand patients; requires more rehabilitation time; and has a higher cost. All-arthroscopic proximal tenodesis and distal open subpectoral tenodesis have advantages and disadvantages. Although recent midterm reports suggest slightly better revision and complication rates with subpectoral tenodesis, more studies are needed to verify these findings. Persistent shoulder symptoms after biceps tenodesis commonly occur secondary to missed or untreated associated shoulder pathologies but also may result from mechanical failure of the tenodesis. PMID- 25745940 TI - Laparoscopic repair of obturator nerve transection during pelvic lymphadenectomy. PMID- 25745941 TI - [The Annales: a sustained growth]. PMID- 25745942 TI - [Tetraspanins: a new target for antiangiogenic therapy?]. AB - Inhibition of the vascular endothelial growth factor A or inhibition of its receptors are currently used for the treatment of cancer. However, the results are still modest, especially because of the multitude and redundancy of angiogenic factors. It can be hypothesized that therapies targeting directly endothelial cells themselves could be more effective. The tetraspanins are transmembrane molecules, which are devoid of intrinsic enzymatic activity but can associate with each other and with other molecules such as integrins or proteins of the immunoglobulin superfamily to form a network. The tetraspanins are present on the surface of endothelial cells and in vitro, inhibition of these molecules by antibodies or small interfering RNA suggests that tetraspanins play a role in angiogenesis. These preliminary data have been confirmed by the study of cancer xenografts in tetraspanin-deficient mice, which have a significant decrease in tumor size and tumor angiogenesis. In vivo, it has been shown that intravenous administration of a monoclonal antibody (ALB6) directed against CD9 decreases the tumor growth and angiogenesis and that intravitreal injection of a small interfering RNA decreasing CD9 significantly inhibits choroidal neovascularization induced by laser. Finally, anti-angiogenic effects and potent anti-tumor activity are observed by the intraperitoneal administration of GS 168AT2, a peptide derived from CD9-Partner 1, a molecule belonging to the immunoglobulin superfamily, which interacts strongly with the CD9 and CD81. These data suggest that the pharmacological modulation of the tetraspanin web could play a new promising anti-angiogenic strategy. PMID- 25745943 TI - [Feedback on the evaluation of clinical pharmacy activities developed in surgery]. AB - INTRODUCTION: Our current development strategy integrates clinical pharmacy activities prioritized in surgical services. Patients in these services are typically risk patients: transfers, multiple prescribers, frequent medication change, pharmacotherapeutic risk classes. PATIENTS AND METHODS: Three clinical pharmacy activities (admission reconciliation, pharmaceutical analysis, participation doctors round) have been developed in orthopaedic surgery and neurosurgery. Pharmacists prospectively recorded data describing their activities: number of reconciliations and analyzed requirements and time required to achieve them. Data on pharmaceutical interventions were recorded on the basis ActIP(r). The clinical significance of interventions was retrospectively rated by a team of two pharmacists and two physicians on the scale adapted Hatoum et al. RESULTS: Four thousand five hundred pharmaceutical analysis and 248 reconciliations were conducted. One hundred and fifty-six pharmaceutical interventions were issued. The average acceptance rate was 80%. A total of 5.8% of pharmaceutical interventions have been listed with a very significant clinical importance and 48.1% with at least significant clinical importance. The activities and documentation required pharmaceutical average daily time (senior pharmacist, resident and external pharmacist) about 6 hours. DISCUSSION AND CONCLUSION: Other studies, including comparative and medico-economic, must be conducted to support these results. Nevertheless, the indicators obtained attend a better readability of the clinical importance of the activities performed by clinical pharmacists and this particularly in surgical services, both by prescribers and authorities. PMID- 25745944 TI - [Responsibility due to medication errors in France: a study based on SHAM insurance data]. AB - PURPOSE: The safe medication practices at the hospital constitute a major public health problem. Drug supply chain is a complex process, potentially source of errors and damages for the patient. SHAM insurances are the biggest French provider of medical liability insurances and a relevant source of data on the health care complications. METHODS: The main objective of the study was to analyze the type and cause of medication errors declared to SHAM and having led to a conviction by a court. We did a retrospective study on insurance claims provided by SHAM insurances with a medication error and leading to a condemnation over a 6-year period (between 2005 and 2010). RESULTS: Thirty-one cases were analysed, 21 for scheduled activity and 10 for emergency activity. Consequences of claims were mostly serious (12 deaths, 14 serious complications, 5 simple complications). The types of medication errors were a drug monitoring error (11 cases), an administration error (5 cases), an overdose (6 cases), an allergy (4 cases), a contraindication (3 cases) and an omission (2 cases). Intravenous route of administration was involved in 19 of 31 cases (61%). The causes identified by the court expert were an error related to service organization (11), an error related to medical practice (11) or nursing practice (13). Only one claim was due to the hospital pharmacy. CONCLUSION: The claim related to drug supply chain is infrequent but potentially serious. These data should help strengthen quality approach in risk management. PMID- 25745945 TI - [Aseptic process validation and stability study of an injectable preparation of fructose (5%)-glycerol (10%) as part of a hospital clinical research program on endoscopic curative treatment for early epithelial neoplastic lesions of the gastrointestinal tract]. AB - INTRODUCTION: As part of a hospital clinical research program on endoscopic curative treatment for early epithelial neoplastic lesions of the gastrointestinal tract, a new hospital sterile and non-pyrogenic preparation of fructose (5%)-glycerol (10%) was realized. Under pharmaceutical legislation, the provision of this hospital preparation involves of aseptic process validation and achieve a stability study. MATERIALS AND METHODS: After the aseptic process validation with Mediafill Test, the preparation was made under aseptic conditions associated with a sterilizing filtration according to the good practices preparation. Prepared flexible bags (100mL of solution) were stored for one year in a climatic chamber (25+/-2 degrees C). To assess stability, the physicochemical controls (fructose concentration, glycerol concentration, hydroxy methyl-5 furfural [5-HMF] concentration, sodium concentration, pH measure, osmolality and sub-visible particles count) and microbiological (bioburden, bacterial endotoxin and sterility) were performed at regular intervals for one year. RESULTS: Neither significant decrease of fructose concentration, glycerol concentration and sodium concentration nor pH, 5-HMF, osmolality variations out of specifications were observed for one year. The sub-visible particles count, the bacterial endotoxin and sterility were in accordance with the European pharmacopoeia attesting limpidity, apyrogenicity and sterility of this injectable preparation. DISCUSSION AND CONCLUSION: The hospital preparation was stable over one year at 25+/-2 degrees C, ensuring safe administration in humans within the framework of this clinical research. PMID- 25745946 TI - [Advantages and special features of hospital preparations of parenteral nutrition in neonatalogy]. AB - INTRODUCTION: The care of premature infants requires specific, suitable parenteral nutrition, in which the dosage must be frequently adjusted. METHOD: A comparative analysis of four industrial standard parenteral nutrition formulations NP 100(r), Pediaven AP-HP Nouveau-ne 1(r), Pediaven AP-HP Nouveau-ne 2(r) and Numetah G13% E(r) and of two hospital preparations made specifically in hospital pharmacies produced by two separate university hospitals (Nutrine(r) HCL and Formule standardisee debut de nutrition) was conducted. The comparison between the formulations focused on electrolytic compositions and protein/energy ratio. RESULTS: Formule standardisee debut de nutrition and Pediaven AP-HP Nouveau-ne 1(r) are free from (i) sodium and potassium, (ii) potassium respectively. Almost equivalent sodium concentration (19-27 mM) and more variable potassium concentration (~9-26 mM) characterize the other formulations. Protein/energy ratio of Numetah G13% E(r), Nutrine(r) HCL and Formule standardisee debut de nutrition is 58% higher than that of NP 100(r), Pediaven AP HP Nouveau-ne 1(r) and Pediaven AP-HP Nouveau-ne 2(r). DISCUSSION: Formule standardisee debut de nutrition and Pediaven AP-HP Nouveau-ne 1(r) are in accordance with the recommendations about hydro-electrolytic supplies during transition phase. Nutrine(r) HCL complies best to the recommendations about hydro electrolytic account during stabilization phase. CONCLUSION: Hydro-electrolytic composition and protein/energy ratio of standard hospital parenteral nutrition formulations comply best to nutritional needs of premature infants. PMID- 25745947 TI - H3 receptor renal expression in normal and diabetic rats. AB - INTRODUCTION: To extend our previous observation of H4R upregulation in the kidney of diabetic rats, we evaluated in the same specimens the presence of the H3R. MATERIALS AND METHODS: Kidney specimens from 24 8-week-old male Wistar rats (12 non-diabetic and 12 diabetic animals) were processed for both immunohistochemical and immunofluorescence analyses. RESULTS AND CONCLUSION: H3R is expressed in the apical membrane by collecting duct cells in the kidney of rats and it is significantly increased in diabetic animals. These data support the hypothesis that H3R could also mediate non-neuronal histamine effects, suggesting its involvement in fluid homeostasis. PMID- 25745948 TI - Neurosurgery Education and Development program to treat hydrocephalus and to develop neurosurgery in Africa using mobile neuroendoscopic training. AB - OBJECT A shortage of neurosurgeons and a lack of knowledge of neuroendoscopic management of hydrocephalus limits modern care in sub-Saharan Africa. Hence, a mobile teaching project for endoscopic third ventriculostomy (ETV) procedures and a subsequent program to develop neurosurgery as a permanent specialty in Kenya and Zanzibar were created and sponsored by the Neurosurgery Education and Development (NED) Foundation and the Foundation for International Education in Neurological Surgery. The objective of this work was to evaluate the results of surgical training and medical care in both projects from 2006 to 2013. METHODS Two portable neuroendoscopy systems were purchased and a total of 38 ETV workshops were organized in 21 hospitals in 7 different countries. Additionally, 49 medical expeditions were dispatched to the Coast General Hospital in Mombasa, Kenya, and to the Mnazi Moja Hospital in Zanzibar. RESULTS From the first project, a total of 376 infants with hydrocephalus received surgery. Six-month follow-up was achieved in 22%. In those who received follow-up, ETV efficacy was 51%. The best success rates were achieved with patients 1 year of age or older with aqueductal stenosis (73%). The main causes of hydrocephalus were infection (56%) and spina bifida (23%). The mobile education program interacted with 72 local surgeons and 122 nurses who were trained in ETV procedures. The second project involved 49 volunteer neurosurgeons who performed a total of 360 nonhydrocephalus neurosurgical operations since 2009. Furthermore, an agreement with the local government was signed to create the Mnazi Mmoja NED Institute in Zanzibar. CONCLUSIONS Mobile endoscopic treatment of hydrocephalus in East Africa results in reasonable success rates and has also led to major developments in medicine, particularly in the development of neurosurgery specialty care sites. PMID- 25745949 TI - Predictors of postconcussion syndrome after sports-related concussion in young athletes: a matched case-control study. AB - OBJECT Sport-related concussion (SRC) is a major public health problem. Approximately 90% of SRCs in high school athletes are transient; symptoms recover to baseline within 1 week. However, a small percentage of patients remain symptomatic several months after injury, with a condition known as postconcussion syndrome (PCS). The authors aimed to identify risk factors for PCS development in a cohort of exclusively young athletes (9-18 years of age) who sustained SRCs while playing a sport. METHODS The authors conducted a retrospective case-control study by using the Vanderbilt Sports Concussion Clinic database. They identified 40 patients with PCS and matched them by age at injury and sex to SRC control patients (1 PCS to 2 control). PCS patients were those experiencing persistent symptoms at 3 months after an SRC. Control patients were those with documented resolution of symptoms within 3 weeks of an SRC. Data were collected in 4 categories: 1) demographic variables; 2) key medical, psychiatric, and family history; 3) acute-phase postinjury symptoms (at 0-24 hours); and 4) subacute phase postinjury features (at 0-3 weeks). The chi-square Fisher exact test was used to assess categorical variables, and the Mann-Whitney U-test was used to evaluate continuous variables. Forward stepwise regression models (Pin = 0.05, Pout = 0.10) were used to identify variables associated with PCS. RESULTS PCS patients were more likely than control patients to have a concussion history (p = 0.010), premorbid mood disorders (p = 0.002), other psychiatric illness (p = 0.039), or significant life stressors (p = 0.036). Other factors that increased the likelihood of PCS development were a family history of mood disorders, other psychiatric illness, and migraine. Development of PCS was not predicted by race, insurance status, body mass index, sport, helmet use, medication use, and type of symptom endorsement. A final logistic regression analysis of candidate variables showed PCS to be predicted by a history of concussion (OR 1.8, 95% CI 1.1-2.8, p = 0.016), preinjury mood disorders (OR 17.9, 95% CI 2.9-113.0, p = 0.002), family history of mood disorders (OR 3.1, 95% CI 1.1-8.5, p = 0.026), and delayed symptom onset (OR 20.7, 95% CI 3.2-132.0, p < 0.001). CONCLUSIONS In this age- and sex-matched case-control study of risk factors for PCS among youth with SRC, risk for development of PCS was higher in those with a personal and/or family history of mood disorders, other psychiatric illness, and migraine. These findings highlight the unique nature of SRC in youth. For this population, providers must recognize the value of establishing the baseline health and psychiatric status of children and their primary caregivers with regard to symptom reporting and recovery expectations. In addition, delayed symptom onset was an unexpected but strong risk factor for PCS in this cohort. Delayed symptoms could potentially result in late removal from play, rest, and care by qualified health care professionals. Taken together, these results may help practitioners identify young athletes with concussion who are at a greater danger for PCS and inform larger prospective studies for validation of risk factors from this cohort. PMID- 25745950 TI - Rapid ventricular pacing for a basilar artery pseudoaneurysm in a pediatric patient: case report. AB - Large cerebral aneurysms of the basilar apex are difficult to treat. Recently, endovascular treatment has mitigated much of the morbidity associated with treating these lesions. However, the morphology of aneurysms of the vertebrobasilar system can preclude endovascular treatment. Rapid ventricular pacing (RVP) facilitates open surgical treatment of cerebral aneurysms. It can assist in reducing the pressure of the neck of the aneurysm, allowing safe application of a clip. The authors present a case of a pediatric patient who developed a basilar artery pseudoaneurysm that required surgery. Given the large size of the aneurysm, RVP was performed, allowing the surgeons to dissect the dome of the aneurysm from the surrounding tissue and pontine perforating branches away from the lesion to safely clip the lesion. The patient had an uneventful recovery. To the authors' knowledge, this represents the first known case of RVP to aid in basilar artery clip occlusion in a pediatric patient. PMID- 25745951 TI - A membranous structure separating the adenohypophysis and neurohypophysis: an anatomical study and its clinical application for craniopharyngioma. AB - OBJECT This study aimed to identify the membranous septation between the adeno- and neurohypophysis. The clinical impact of this septation in the surgical removal of infradiaphragmatic craniopharyngioma (Id-CP) is also clarified. METHODS The sellar regions from 8 fetal and 6 adult cadavers were dissected. After staining first with H & E and then with picro-Sirius red, the membranous structures were observed and measured under normal light and polarization microscopy. The pre- and postsurgical images and intraoperative procedures in 28 cases of childhood Id-CP were reviewed and analyzed. RESULTS There is a significant membranous septation (termed the adenoneurohypophysis septation [ANHS]) lying behind the intermediate lobe to separate the adeno- and neurohypophysis. The average thicknesses are 21.9 +/- 16.9 MUm and 79.1 +/- 43.2 MUm in fetal and adult heads, respectively. The median segment of the septation is significantly thicker than the upper and lower segments. The ANHS extends from the suprasellar pars tuberalis to the sellar floor, where it is fused with the pituitary capsule. During Id-CP surgery performed via a transcranial approach, the ANHS can be identified to reserve the neurohypophysis. Moreover, by understanding the anatomy of this membrane, the pituitary stalk was preserved in 3 patients (10.7%). CONCLUSIONS There is a significant membrane separating the anterior and posterior lobes of the pituitary gland, which lies behind the intermediate lobe. Understanding the anatomy of this septation is important for identifying and preserving the neurohypophysis and pituitary stalk during Id-CP surgery. PMID- 25745952 TI - Risk factors for traumatic blunt cerebrovascular injury diagnosed by computed tomography angiography in the pediatric population: a retrospective cohort study. AB - OBJECT Computed tomography angiography (CTA) is frequently used to examine patients for blunt cerebrovascular injury (BCVI) after cranial trauma, but the pediatric population at risk for BCVI is poorly defined. Although CTA is effective for BCVI screening in adults, the increased lifetime risk for malignant tumors associated with this screening modality warrants efforts to reduce its use in children. The authors' objective was to evaluate the incidence of BCVI diagnosed by CTA in a pediatric patient cohort and to create a prediction model to identify children at high risk for BCVI. METHODS Demographic, clinical, and radiographic data were collected retrospectively for pediatric patients who underwent CTA during examination for traumatic cranial injury from 2003 through 2013. The primary outcome was injury to the carotid or vertebral artery diagnosed by CTA. RESULTS The authors identified 234 patients (mean age 8.3 years, range 0.04-17 years, 150 [64%] boys) who underwent CTA screening for BCVI. Of these, 24 (10.3%) had a focal neurological deficit, and 153 (65.4%) had intracranial hemorrhage on a head CTA. Thirty-seven BCVIs were observed in 36 patients (15.4%), and 16 patients (6.8%) died. Multivariate regression analysis identified fracture through the carotid canal, petrous temporal bone fracture, Glasgow Coma Scale (GCS) score of < 8, focal neurological deficit, and stroke on initial CT scan as independent risk factors for BCVI. A prediction model for identifying children at high risk for BCVI was created. A score of <= 2 yielded a 7.9% probability of BCVI and a score of >= 3 a risk of 39.3% for BCVI. CONCLUSIONS For cranial trauma in children, fracture of the petrous temporal bone or through the carotid canal, focal neurological deficit, stroke, and a GCS score of < 8 are independent risk factors for BCVI. PMID- 25745953 TI - The accuracy of linear indices of ventricular volume in pediatric hydrocephalus: technical note. AB - Assessment of ventricular size is essential in clinical management of hydrocephalus and other neurological disorders. At present, ventricular size is assessed using indices derived from the dimensions of the ventricles rather than the actual volumes. In a population of 22 children with congenital hydrocephalus and 22 controls, the authors evaluated the relationship between ventricular volume and linear indices in common use, such as the frontooccipital horn ratio, Evans' index, and the bicaudate index. Ventricular volume was measured on high resolution anatomical MR images. The frontooccipital horn ratio was found to have a stronger correlation with both absolute and relative ventricular volume than other indices. Further analysis of the brain volumes found that congenital hydrocephalus produced a negligible decrease in the volume of the brain parenchyma. PMID- 25745954 TI - HPA-axis reactivity interacts with stage of pubertal development to predict the onset of depression. AB - Both elevated and blunted levels of cortisol secretion during childhood and adolescence have been linked to the subsequent onset of major depressive disorder (MDD). These mixed findings may be due to developmental changes in HPA-axis functioning, which have not been previously assessed in the context of risk. In the present study, therefore, we examined whether pubertal development moderated the influence of cortisol secretion on the subsequent development of MDD. Eighty nine never-disordered girls ages 9-15 years, many of whom were at high risk for depression by virtue of having a maternal history of the disorder, completed a laboratory stress task. To index cortisol reactivity, salivary cortisol samples were collected at baseline and 15 min following the onset of the stressor. Girls' levels of pubertal development were measured using Tanner staging. All participants were followed through age 18 in order to assess the subsequent development of MDD. Pubertal stage moderated the effects of cortisol stress reactivity on the development of MDD. Specifically, the onset of MDD was predicted by cortisol hyporeactivity in girls who were earlier in pubertal development (Tanner stage <= 2), but by cortisol hyperreactivity in girls who were later in pubertal development (Tanner stage >= 3.5). CONCLUSIONS: These findings demonstrate that girls' cortisol stress reactivity predicts the subsequent onset of MDD, and further, that the nature of this effect depends on the girls' level of pubertal development. Results are discussed in the context of clarifying previous findings, and directions for future research are offered. PMID- 25745955 TI - Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients. AB - Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity. PMID- 25745957 TI - Development of a TaqMan MGB RT-PCR for the rapid detection of H3 subtype avian influenza virus circulating in China. AB - Previous studies demonstrated that the H3 avian influenza virus (AIV) in China is isolated most frequently from wild birds and live poultry markets. However, there is no subtype-specific real-time polymerase chain reaction (RT-PCR) available for the rapid and highly sensitive identification of H3 AIV. In this study, a TaqMan minor groove binder (MGB) probe and a pair of primers were designed based on a conserved region in the hemagglutinin gene of H3 AIV. These were used to generate an H3-MGB RT-PCR assay that recognizes only H3 AIV. The detection limit of the H3 MGB RT-PCR was 10 copies of DNA per reaction when 10-fold serial dilutions of T H3HA plasmid were used as the template. This was 1000-times more sensitive than conventional RT-PCR. In experimental samples obtained from oropharyngeal swabs or cloacal swabs, the virus was detected in all ducks using H3-MGB RT-PCR, whereas only one duck tested positive for the virus in oropharyngeal swabs tested using conventional RT-PCR. The H3-MGB RT-PCR assay developed in this study is a sensitive and rapid tool for screening H3 AIV in China. PMID- 25745956 TI - Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells. AB - Dysregulation of androgen-binding protein (ABP) is associated with a number of endocrine and andrology diseases. However, the ABP metabolism in Sertoli cells is largely unknown. We report that autophagy degrades ABP in rat Sertoli cells, and the autophagic clearance of ABP is regulated by testosterone, which prolongs the ABP biological half-life by inhibiting autophagy. Further studies identified that the autophagic clearance of ABP might be selectively regulated by testosterone, independent of stress (hypoxia)-induced autophagic degradation. These data demonstrate that testosterone up-regulates ABP expression at least partially by suppressing the autophagic degradation. We report a novel finding with respect to the mechanisms by which ABP is cleared, and by which the process is regulated in Sertoli cells. PMID- 25745958 TI - Recombinant nucleocapsid protein-based enzyme-linked immunosorbent assay for detection of antibody to turkey coronavirus. AB - Nucleocapsid (N) protein gene of turkey coronavirus (TCoV) was expressed in a prokaryotic system and used to develop an enzyme-linked immunosorbent assay (ELISA) for detection of antibody to TCoV. Anti-TCoV hyperimmune turkey serum and normal turkey serum were used as positive or negative controls for optimization of the ELISA. Goat anti-turkey IgG (H+L) conjugated with horseradish peroxidase was used as detector antibody. Three hundred and twenty two turkey sera from the field were used to evaluate the performance of ELISA and determine the cut-off point of ELISA. The established ELISA was also examined with serum samples obtained from turkeys experimentally infected with TCoV. Those serum samples were collected at various time intervals from 1 to 63 days post-infection. The optimum conditions for differentiation between anti-TCoV hyperimmune serum and normal turkey serum were recombinant TCoV N protein concentration at 20 MUg/ml, serum dilution at 1:800, and conjugate dilution at 1:10,000. Of the 322 sera from the field, 101 were positive for TCoV by immunofluorescent antibody assay (IFA). The sensitivity and specificity of the ELISA relative to IFA test were 86.0% and 96.8%, respectively, using the optimum cut-off point of 0.2 as determined by logistic regression method. Reactivity of anti-rotavirus, anti-reovirus, anti adenovirus, or anti-enterovirus antibodies with the recombinant N protein coated on the ELISA plates was not detected. These results indicated that the established antibody-capture ELISA in conjunction with recombinant TCoV N protein as the coating protein can be utilized for detection of antibodies to TCoV in turkey flocks. PMID- 25745959 TI - [Picture in clinical hematology no. 79]. PMID- 25745960 TI - [Severe fever with thrombocytopenia syndrome, an emerging infectious disease for hematologists]. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by tick-borne SFTS virus infection that was first described in rural areas of China in 2011. Since then, SFTS has also been found in the western part of Japan in 2013. The clinical pictures of SFTS are characterized by abrupt onset of fever and gastrointestinal symptoms, followed by a progressive decline in platelet and white blood cell counts. Disseminated intravascular coagulation and hemophagocytic lymphohistiocytosis are also frequently observed in the patients with advanced phase of SFTS. No specific treatment of SFTS is available, and avoiding tick bites is an important way to prevent the infection of SFTS virus. Standard precautions should be applied to SFTS patients to prevent human to-human transmission of SFTS virus. Since ticks bearing SFTS virus are found in all area of Japan including Hokkaido, this disease has become a substantial risk to public health in all parts of Japan. PMID- 25745961 TI - [Cardiac and breast diffuse large B-cell lymphoma with pericardial effusion and AV-block]. AB - Primary cardiac lymphoma is extremely rare and is associated with a poor prognosis. In most cases, cardiac involvement occurs as a late symptom and the diagnosis is thus delayed. We herein report a 35-year-old woman with cardiac diffuse large B-cell lymphoma (DLBCL) with breast infiltration. The patient was admitted to our hospital based on an initial presentation with dyspnea on exertion, chest pain, and a hard mass of the left breast. Echocardiography revealed a mass in the right atrium wall and interatrial septum, and massive pericardial effusion. ECG showed atrioventoricular block. We promptly performed a needle biopsy of the breast mass, which showed CD5-positive DLBCL, non-GCB type. The serum HIV reaction was negative. We thus diagnosed this patient as having cardiac and breast CD5-positive DLBCL, stage IVA, based on the massive pericardial effusion. The patient's prognosis was apparently poor. Therefore, she received 3 cycles of R-CHOP chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT), resulting in a complete response. In general, cardiac lymphoma is associated with high mortality and has a poor prognosis. This case demonstrates that rapid and appropriate diagnosis, and immediate intensive chemotherapy followed by PBSCT might be necessary for the treatment of extranodal lymphoma indicative of a poor prognosis. PMID- 25745962 TI - [Diagnosis of disseminated bone marrow carcinomatosis from gastric carcinoma initially presenting as asymptomatic anemia]. AB - A 75-year-old man who had undergone subtotal gastrectomy for advanced gastric cancer 18 years previously with no signs of recurrence visited our hospital because of anemia detected by medical examination. Although no clinical abnormalities were evident, treatment with iron and vitamin B12 was started. However, because serum ALP was elevated, metastatic bone cancer was suspected. Subsequently, upper gastrointestinal endoscopy revealed findings suggestive of residual gastric cancer, and examination of a biopsy specimen demonstrated signet ring cell carcinoma. Furthermore, cells in a bone marrow biopsy sample showed morphology similar to that of cells obtained by stomach biopsy. FDG-PET demonstrated FDG accumulation only in the bone and residual stomach. The final diagnosis was bone metastasis from residual gastric cancer, and disseminated carcinomatosis of the bone marrow. Thereafter, pancytopenia progressed rapidly, and the patient died due to disseminated intravascular coagulation. When serum ALP is elevated in patients with a history of gastric cancer, bone marrow carcinomatosis should be suspected irrespective of symptoms, and imaging studies and bone marrow examination should be performed. PMID- 25745963 TI - [Acute renal tubular damage caused by disseminated Trichosporon infection in primary myelofibrosis]. AB - A 70-year-old man received a course of therapy that consisted of prednisolone, cyclosporine, and etoposide due to hemophagocytic syndrome which had developed during primary myelofibrosis. He also received micafungin (MCFG) as prophylaxis against a potential fungal infection. We diagnosed febrile neutropenia due to the hemophagocytic syndrome therapy and candidemia because Candida species were detected in blood cultures. He received liposomal amphotericin B (L-AMB) for the candidemia but did not respond to this treatment. Oliguria was diagnosed and renal failure progressed rapidly. We suspected that his renal failure had been induced by the antibiotics. We thus changed the antibiotic regimen but he died of progressive renal failure. We performed renal necropsy and diagnosed acute interstitial tubular nephritis, due to a yeast-like fungus that generally invades the renal tubules. The yeast-like fungus was later identified as Trichosporon asahii, rather than candida, by blood cultures. An immunocompromised host receiving MCFG for acute progressive renal failure requires an appropriate antifungal drug considering the possibility of disseminated Trichosporon. PMID- 25745964 TI - [Myelofibrosis ameliorated after treatment for nontuberculous mycobacterial infection]. AB - A 42-year-old female was admitted to our hospital because of continuous fever, anemia, and immature myeloid cells in peripheral blood. Bone marrow biopsy revealed severe myelofibrosis (MF). We performed computed tomography and identified several swollen mediastinal lymph nodes and nodules in the right upper lung. Lymph node biopsy showed an infection with Mycobacterium intracellulare (M. intracellulare), a nontuberculous mycobacterium (NTM). Antituberculosis drugs led to remission of the NTM infection. Bone marrow biopsy revealed marked improvement in MF and red blood cell infusion was not required after therapy. No prior cases of concomitant NTM with M. intracellulare and MF have been reported. This is thus the first reported case showing improvement of myelofibrosis after NTM treatment. This case report offers valuable insights into the pathology of MF. PMID- 25745965 TI - [Acute painful crisis in a female Nigerian patient with sickle cell disease]. AB - We report a 38-year-old Nigerian woman with sickle cell disease. Sickle cell disease had been diagnosed when she experienced her first sickle cell crisis episode at age 8 years. Thereafter, she had infrequent minor episodes. She visited a hospital presenting with fever, anemia, jaundice, and systemic pain, and was then transferred to our hospital. Together with rehydration and red blood cell transfusion, analgesics and antibiotics were prescribed, and produced gradual improvement of all symptoms and signs. The patient was discharged on day 9 of hospitalization. Sickle cell crisis is an acute painful episode caused by occlusion of arterioles. The degree of pain and accompanying symptoms, as well as the frequencies of crises, are variable. Moreover, one third of individuals with sickle cell disease never experience a crisis. As our society becomes increasingly globalized, the probabilities of encountering sickle cell disease patients will be higher. PMID- 25745966 TI - [Successful treatment with azacitidine for myelodysplastic syndrome with large vessel vasculitis]. AB - Paraneoplastic inflammation of the large vessels is a rare complication of myelodysplastic syndrome (MDS), and patients with MDS and systemic vasculitis have a poor prognosis. We present a 66-year-old male with MDS and large vessel vasculitis treated with azacitidine. Azacitidine administration improved his clinical symptoms, high fever and thickening of the arterial wall, and he achieved a complete bone marrow remission. However, 1 year later he showed progression of MDS. For MDS with vasculitis, intensive therapy, the same as that given to the high-risk group, should be considered and azacitidine administration may represent an efficacious treatment. PMID- 25745967 TI - [Thalidomide-associated hypothyroidism in a patient with multiple myeloma]. AB - Thalidomide is highly effective against multiple myeloma, but some patients must discontinue this medication due to adverse effects. We present herein an instructive case report on thalidomide-associated hypothyroidism in a patient with multiple myeloma. Thyroid hormone replacement therapy allowed us to restart administration of thalidomide, a potentially life-saving therapy. Known adverse effects of thalidomide, such as lethargy, constipation, and bradycardia, are potential symptoms of hypothyroidism, but we tend to overlook drug-associated hypothyroidism. Our case highlights the importance of routinely testing thyroid function in patients receiving thalidomide therapy. PMID- 25745968 TI - [Primary pulmonary Hodgkin lymphoma diagnosed by CT-guided percutaneous biopsy]. AB - A 36-year-old woman with a left lung tumor was referred to our hospital since a pathological diagnosis had not been obtained at a previous medical institution. We carried out CT-guided percutaneous lung biopsy with an 18-gauge needle and obtained four samples. Immunological staining revealed the specimens to be CD30- and PAX5-positive, with large dysplastic lymphocytes negative for Bob-1 and Oct-2 with a background of small lymphocytes and eosinophils. Primary pulmonary Hodgkin lymphoma (PPHL) was diagnosed. Although PPHL is very rare, it should be included in the differential diagnosis of lung tumors and immunological staining with CD15 and CD30 is recommended. Furthermore, carefully planned CT-guided lung biopsy is useful for diagnosing PPHL. PMID- 25745970 TI - [Light chain escape followed by leukemic transformation in a patient with IgD myeloma]. AB - A 63-year-old male with multiple myeloma (IgD-lambda) received autologous peripheral blood stem cell transplantation (PBSCT) after induction of VAD in March 2008, and obtained a very good partial response. However, he required BOR/DEX and a second PBSCT for relapse, and in August 2012, treatment with LEN/DEX was started. After 4 cycles of LEN/DEX, IgD decreased but FLC-lambda increased paradoxically, indicating a clonal change. In January 2013, an LCD regimen was started and after 4 cycles, IgD showed normalization, but his condition worsened as FLC-lambda increased. This case showed a fulminant clinical course with light chain escape in this era of treating multiple myeloma with novel agents. PMID- 25745969 TI - [Bortezomib-associated acute congestive heart failure in a patient with multiple myeloma]. AB - We report an 81-year-old woman with multiple myeloma who developed acute cardiac injury after receiving bortezomib. The patient received weekly intravenous bortezomib. She developed shortness of breath and bilateral pedal edema on day 19. Electrocardiography showed no ST-T changes but the cardio-thoracic ratio was increased, the ejection fraction was decreased, the ventricular septum showed hypokinesis and mitral regurgitation was noted. We stopped bortezomib and started acute congestive heart failure treatment. ST-T changes were detected after the patient's condition improved. There was no evidence of coronary stenosis on CT angiography. Acute cardiac injury is rare during bortezomib administration, but patients should be monitored carefully during treatment. PMID- 25745974 TI - [Clinical hematology research in Japan - meeting experts]. PMID- 25745975 TI - Postictal MRI abnormalities and seizure-induced brain injury: notions to be challenged. AB - OBJECTIVE: This was a bibliographic search to address the quality of evidence in clinical reports supporting the assertion that brain MRI signal abnormalities are a direct consequence of seizures. METHODS: The search on PubMed was performed by applying the following inclusion criteria: a) original case reports, b) in humans, c) as single case reports or series of patients, d) of visually detected acute MRI signal abnormalities, e) attributable directly to seizures, and f) published in English. Bibliographic references of initially selected publications were reviewed for additional articles. Full texts of selected publications were read for information regarding clinical, EEG, and MRI features. Moreover, claimed evidence supporting seizure-induced excitotoxicity was assessed. RESULTS: The search resulted in 91 publications corresponding to 413 cases. There was a wide range of clinical features and EEG and MRI abnormalities. Premorbid or comorbid conditions were present in many cases, and some of them are potential causes of MRI changes. Claimed evidence for MRI signal abnormalities as a direct consequence of ictal activity was mostly based on the similarity with previous reports, animal models, reversibility, congruent EEG, MRI changes not respecting vascular territories, and ruling out other etiologies. CONCLUSIONS: Evidence supporting the notion of seizure-induced excitotoxicity is questionable in the studied reports of postictal MRI abnormalities. PMID- 25745976 TI - Constipation enhances the propensity to seizure in pentylenetetrazole-induced seizure models of mice. AB - Epilepsy is characterized by spontaneous recurrent seizures and represents one of the most frequent neurological diseases, affecting about 60 million people worldwide. The cellular and neurocircuit bases of epilepsy are poorly understood. Constipation is a common gastrointestinal disorder characterized by symptoms such as straining, hard stool, and infrequent defecation. Population-based studies have shown that the prevalence of constipation is up to 30% of the population in developed countries. The causal link between seizure and constipation is a common belief among patients and physicians, but there are no scientific data to support this association. The current investigation evaluated the effects of constipation induced by loperamide (a peripheral MU-opioid receptor agonist without effect on central nervous system receptors) and clidinium (a quaternary amine antimuscarinic agent with reduced central nervous system effects) on two different seizure models of mice: (1) myoclonic, clonic, and generalized tonic seizures and death induced by intraperitoneal administration of pentylenetetrazole and (2) clonic seizure threshold induced by intravenous infusion of pentylenetetrazole. We demonstrated that the measured intestinal transit (%intestinal transit) decreased after loperamide or clidinium treatment for 3days. Constipation in mice which was induced by loperamide or clonidine caused a decrease in threshold to clonic seizure in the intravenous pentylenetetrazole seizure model. Moreover loperamide- or clidinium-induced constipation decreased latencies to, clonic, and tonic seizures and death in the intraperitoneal pentylenetetrazole model of mice. Serum ammonia levels were slightly elevated in both loperamide- and clidinium-treated mice. In conclusion, loperamide- or clidinium-induced constipated mice are more prone to seizure which might confirm the belief of patients and physicians about constipation as a trigger of seizure. PMID- 25745977 TI - Reduced event-related low frequency EEG activity in patients with early onset schizophrenia and their unaffected siblings. AB - Low-frequency oscillations in the electroencephalogram (EEG) have been found to be abnormal in patients with schizophrenia. It is unclear, however, whether these abnormalities are related to severity of illness or are a marker for risk. This study investigated total and evoked theta and delta activity in schizophrenia patients, unaffected siblings, and healthy controls (HCs). EEG data were recorded whilst 24 individuals with schizophrenia, 26 unaffected siblings of individuals with schizophrenia and 26 healthy control participants completed a Go/No-Go task. Event-related total activity and evoked theta and delta activity were calculated for correct hits (CH), failed inhibitions (FI) and correct inhibitions (CI) trials. Patients displayed significantly less total delta, evoked delta, total theta and evoked theta activity when compared with healthy controls. Unaffected siblings displayed abnormalities of evoked delta, but other measures were similar to those in control participants. The findings of this study add to evidence that abnormal low-frequency EEG oscillations contribute to impairments in information processing seen in schizophrenia. These findings also suggest abnormal evoked delta oscillations are associated with an increased familial risk of developing the disorder. PMID- 25745978 TI - Efficient screening strategy for Lynch syndrome in Japanese endometrial cancer. AB - Lynch syndrome (LS) is an inherited disorder caused by a germline mutation in the DNA mismatch repair (MMR) genes and is associated with increased risk of various cancers, particularly colorectal cancer and endometrial cancer (EC). It is significant to identify LS in EC patients for prediction and prevention of the succeeding other associated cancers. However, useful LS screening guidelines for EC have not been established. The purpose of our study is to devise an efficient and practical screening strategy for LS in EC. We designed original criteria, named "APF criteria," with lenient terms (Age of onset < 50, or Personal or Family history of associated cancers) and applied it to unselected EC patients. We performed immunohistochemistry (IHC) and the methylation assay of MutL homolog 1 (MLH1) gene promoter using the tumors of patients who met our criteria, and thus selected "suspected LS" as the candidates for genetic analyses. Of 360 EC patients, 187 (51.9%) met the APF criteria, and the tumor specimens were available from 182 out of the 187 patients. IHC revealed that expression of at least one MMR protein was absent in cell nuclei of 54 (29.6%) tumors. Of 20 tumors lacking MLH1 protein expression, 14 cases were judged sporadic EC because of the hypermethylated MLH1 promoter. We thus selected 40 (11.1%) of 360 EC patients as "suspected LS." Our strategy that consists of clinical triage and the molecular analyses is expected to improve the screening efficiency and reduce the cost of LS identification in EC. PMID- 25745979 TI - Environment friendly biomass gasifier cookstove for community cooking. AB - Traditional community cookstoves have a low level of efficiency due to their poor heat transfer efficiency and incomplete combustion. The low efficiency results in a high consumption of fuel wood, thereby creating a need of more fuel wood. This paper deals with the development of a biomass cookstove suitable for community cooking. The stove exhibits approximately 36.38% thermal efficiency and has a thermal power rating of 5 kW. The maximum flame temperature recorded was 712 degrees C. The data indicate that the developed cookstove can save approximately 7155 kg of CO2 per annum. PMID- 25745980 TI - Sodium valproate induces mitochondrial respiration dysfunction in HepG2 in vitro cell model. AB - Sodium valproate (VPA) is a potentially hepatotoxic antiepileptic drug. Risk of VPA-induced hepatotoxicity is increased in patients with mitochondrial diseases and especially in patients with POLG1 gene mutations. We used a HepG2 cell in vitro model to investigate the effect of VPA on mitochondrial activity. Cells were incubated in glucose medium and mitochondrial respiration-inducing medium supplemented with galactose and pyruvate. VPA treatments were carried out at concentrations of 0-2.0mM for 24-72 h. In both media, VPA caused decrease in oxygen consumption rates and mitochondrial membrane potential. VPA exposure led to depleted ATP levels in HepG2 cells incubated in galactose medium suggesting dysfunction in mitochondrial ATP production. In addition, VPA exposure for 72 h increased levels of mitochondrial reactive oxygen species (ROS), but adversely decreased protein levels of mitochondrial superoxide dismutase SOD2, suggesting oxidative stress caused by impaired elimination of mitochondrial ROS and a novel pathomechanism related to VPA toxicity. Increased cell death and decrease in cell number was detected under both metabolic conditions. However, immunoblotting did not show any changes in the protein levels of the catalytic subunit A of mitochondrial DNA polymerase gamma, the mitochondrial respiratory chain complexes I, II and IV, ATP synthase, E3 subunit dihydrolipoyl dehydrogenase of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and glutathione peroxidase. Our results show that VPA inhibits mitochondrial respiration and leads to mitochondrial dysfunction, oxidative stress and increased cell death, thus suggesting an essential role of mitochondria in VPA-induced hepatotoxicity. PMID- 25745982 TI - Double cardiac myxomas in the left atrium and ventricle. PMID- 25745983 TI - Localized constrictive pericarditis mimicking a cardiac apex diverticulum. PMID- 25745981 TI - Cardiac tissue inhibitor of matrix metalloprotease 4 dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes: Road to therapy. AB - BACKGROUND: TIMP4 (Tissue Inhibitors of Matrix Metalloprotease 4), goes down in failing hearts and mice lacking TIMP4 show poor regeneration capacity after myocardial infarction (MI). This study is based on our previous observation that administration of cardiac inhibitor of metalloproteinase (~TIMP4) attenuates oxidative stress and remodeling in failing hearts. Therefore, we hypothesize that TIMP4 helps in cardiac regeneration by augmenting contractility and inducing the differentiation of cardiac progenitor cells into cardiomyocytes. METHODS: To validate this hypothesis, we transfected mouse cardiomyocytes with TIMP4 and TIMP4-siRNA and performed contractility studies in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. We evaluated the calcium channel gene serca2a (sarcoplasmic reticulum calcium ATPase2a) and mir122a which tightly regulates serca2a to explain the changes in contractility. We treated mouse embryonic stem cells with cardiac extract and cardiac extract minus TIMP4 (using TIMP4 monoclonal antibody) to examine the effect of TIMP4 on differentiation of cardiac progenitor cells. RESULTS: Contractility was augmented in the TIMP4 transfected cardiomyocytes as compared to siRNA-TIMP4 transfected cardiomyocytes. There was elevated expression of serca2a in the TIMP4 transformed myocytes and down regulation of mir122a. The cells treated with cardiac extract containing TIMP4 showed cardiac phenotype in terms of Ckit+, GATA4+ and Nkx2.5 expression. CONCLUSION: This is a novel report suggesting that TIMP4 augments contractility and induces differentiation of progenitor cells into cardiac phenotype. In view of the failure of MMP9 inhibitors for cardiac therapy, TIMP4 provides an alternative approach, being an indigenous molecule and a natural inhibitor of MMP9. PMID- 25745984 TI - An extremely rare presentation of supraventricular tachycardia: Burping. PMID- 25745985 TI - Management of juvenile stroke from noncompaction with muscular dystrophy. PMID- 25745987 TI - The double burden of overweight and thinness among children and adolescents in Shandong China. PMID- 25745986 TI - Characterization of metabolic syndrome among diverse Hispanics/Latinos living in the United States: Latent class analysis from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - BACKGROUND/OBJECTIVES: Empirical investigation of the adequacy of metabolic syndrome (MetS) diagnostic criteria, and whether meaningful subtypes of MetS exist, is needed among Hispanics/Latinos. METHODS: In 15,825 US Hispanics/Latinos from HCHS/SOL, latent class analysis of MetS components (waist circumference, systolic and diastolic blood pressure, HDL cholesterol, triglycerides, glucose, and antihypertensive, lipid- and glucose-lowering medication use) was used to investigate (1) whether distinct subtypes of MetS could be identified, and how component levels differed between them, and (2) how identified subtypes related to covariates and cardiovascular disease (CVD) prevalence. RESULTS: Two latent clusters emerged in both men (n=6317) and women (n=9508): one characterized by relatively healthy mean levels (Non-MetS cluster, 77.1% of men and 67.1% of women) and the other by clinically elevated mean levels (MetS cluster, 22.9% of men and 32.9% of women) across most MetS components. These clusters showed expected associations with covariates and CVD prevalence. Notable results suggest that (1) HDL cholesterol may poorly differentiate between US Hispanics/Latinos with and without MetS (mean=45.4 vs. 44.6 mg/dL for men and 51.3 vs. 52.0 mg/dL for women in the MetS vs. Non-MetS clusters, respectively) and (2) the NCEP-ATP III 88 cm waist circumference cutoff for US females may not optimize diagnosis among Hispanic/Latino women (MetS cluster mean waist circumference=102.5 cm). CONCLUSIONS: Beyond classification into having MetS or not, additional subtypes of MetS do not clearly emerge in US Hispanics/Latinos. Current diagnostic cutoffs for some components may not optimize MetS identification among this population. PMID- 25745988 TI - What is the role of left bundle branch block in atrial fibrillation-induced cardiomyopathy? PMID- 25745989 TI - Prevalence of ideal cardiovascular health in southeast Chinese adults. PMID- 25745990 TI - Rationale and design of RETAIN study: Rosuvastatin Effect on Telomere-telomerase system in Acute coronary syndrome patients undergoing percutaneous coronary Intervention. PMID- 25745991 TI - Hypertrophic cardiomyopathy with apical aneurysm. PMID- 25745992 TI - Systematic discovery of molecular probes targeting multiple non-orthosteric and spatially distinct sites in the botulinum neurotoxin subtype A (BoNT/A). AB - The development of molecular probes targeting proteins has traditionally relied on labeling compounds already known to bind to the protein of interest. These known ligands bind to orthosteric or allosteric sites in their target protein as a way to control their activity. Binding pockets other than known orthosteric or allosteric sites may exist that are large enough to accommodate a ligand without significantly disrupting protein activity. Such sites may provide opportunities to discriminate between subtypes or other closely related proteins, since they are under less evolutionary pressure to be conserved. The Protein Scanning with Virtual Ligand Screening (PSVLS) approach was previously used to identify a novel inhibitor and a fluorescent probe against the catalytic site of the botulinum neurotoxin subtype A (BoNT/A). PSVLS screens compound databases against multiple sites within a target protein, and the results for all the sites probed against BoNT/A, not only the catalytic site, are available online. Here, we analyze the PSVLS data for multiple sites in order to identify molecular probes with affinity for binding pockets other than the catalytic site of BoNT/A. BoNT/A is a large protein with a light (LC) and a heavy (HC) chain that can be assayed separately. We used scintillation proximity assay (SPA) to test experimentally 5 probe candidates predicted computationally to have affinity for different non orthosteric binding regions within the HC and LC, and one compound predicted not to have affinity for either domain. The binding profiles obtained experimentally confirmed the targeting of multiple and spatially distinct pockets within BoNT/A. Moreover, inhibition assay results indicate that some of these probes do not significantly interfere with the catalytic activity of BoNT/A. PMID- 25745993 TI - Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. AB - The poor efficacy of the in vivo anti-tumor immune response has been partially attributed to ineffective T-cell responses mounted against the tumor. Fas-FasL dependent activation-induced cell death (AICD) of T cells is believed to be a major contributor to compromised anti-tumor immunity. The molecular mechanisms of AICD are well-investigated, yet the possibility of regulating AICD for cancer therapy remains to be explored. In this study, we show that histone deacetylase inhibitors (HDACIs) can inhibit apoptosis of CD4(+) T cells within the tumor, thereby enhancing anti-tumor immune responses and suppressing melanoma growth. This inhibitory effect is specific for AICD through suppressing NFAT1-regulated FasL expression on activated CD4(+) T cells. In gld/gld mice with mutation in FasL, the beneficial effect of HDACIs on AICD of infiltrating CD4(+) T cells is not seen, confirming the critical role of FasL regulation in the anti-tumor effect of HDACIs. Importantly, we found that the co-administration of HDACIs and anti-CTLA4 could further enhance the infiltration of CD4(+) T cells and achieve a synergistic therapeutic effect on tumor. Therefore, our study demonstrates that the modulation of AICD of tumor-infiltrating CD4(+) T cells using HDACIs can enhance anti-tumor immune responses, uncovering a novel mechanism underlying the anti-tumor effect of HDACIs. PMID- 25745994 TI - Repression of Hox genes by LMP1 in nasopharyngeal carcinoma and modulation of glycolytic pathway genes by HoxC8. AB - Epstein-Barr virus (EBV) causes human lymphoid malignancies, and the EBV product latent membrane protein 1 (LMP1) has been identified as an oncogene in epithelial carcinomas such as nasopharyngeal carcinoma (NPC). EBV can epigenetically reprogram lymphocyte-specific processes and induce cell immortalization. However, the interplay between LMP1 and the NPC host cell remains largely unknown. Here, we report that LMP1 is important to establish the Hox gene expression signature in NPC cell lines and tumor biopsies. LMP1 induces repression of several Hox genes in part via stalling of RNA polymerase II (RNA Pol II). Pol II stalling can be overcome by irradiation involving the epigenetic regulator TET3. Furthermore, we report that HoxC8, one of the genes silenced by LMP1, has a role in tumor growth. Ectopic expression of HoxC8 inhibits NPC cell growth in vitro and in vivo, modulates glycolysis and regulates the expression of tricarboxylic acid (TCA) cycle-related genes. We propose that viral latency products may repress via stalling key mediators that in turn modulate glycolysis. PMID- 25745995 TI - Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1alpha to promote the metastasis of hepatocellular carcinoma. AB - Hypoxic microenvironment is a powerful driving force for the invasion and metastasis of hepatocellular carcinoma (HCC). Hypoxia-inducible factor 1alpha (HIF-1alpha), as a crucial regulator of transcriptional responses to hypoxia, induces the expression of multiple target genes involved in different steps of HCC metastatic process. It is critical to find target genes associated with metastasis under hypoxia for shedding new light on molecular mechanism of HCC metastasis. In this study, we uncovered that hypoxia could induce the upregulation of Rab11-family interacting protein 4 (Rab11-FIP4) and activation of Rab11-FIP4 promoter by HIF-1alpha. The overexpression of Rab11-FIP4 significantly enhanced the mobility and invasiveness of HCC cells in vitro, also contributed to distant lung metastasis in vivo, whereas silencing of Rab11-FIP4 decreased the ability of migration and invasion in HCC cells in vitro and suppressed lung metastasis in vivo. Rab11-FIP4 facilitated HCC metastasis through the phosphorylation of PRAS40, which was regulated by mTOR. Furthermore, the expression level of Rab11-FIP4 was significantly increased in HCC tissues and high expression of Rab11-FIP4 was closely correlated with vascular invasion and poor prognosis in HCC patients. A markedly positive correlation between the expression of Rab11-FIP4 and HIF-1alpha was observed in HCC tissues and combination of Rab11-FIP4 and HIF-1alpha was a more valuable predictor of poor prognosis for HCC patients. In conclusion, Rab11-FIP4 is a target gene of HIF 1alpha and has a pro-metastatic role in HCC, suggesting that Rab11-FIP4 may be a promising candidate target for HCC treatment. PMID- 25745996 TI - Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer. AB - The retinoblastoma gene (Rb) is mutated at significant frequency in various human epithelial tumors, including colorectal cancer, and is strongly associated with metastatic disease. However, sole inactivation of Rb in the mouse has so far failed to yield epithelial cancers. Here, we specifically inactivate Rb and/or p53 in the urogenital epithelium and the intestine. We find that the loss of both tumor suppressors is unable to yield tumors in the transitional epithelium lining the bladder, kidneys and ureters. Instead, these mice develop highly metastatic tumors of neuroendocrine, not epithelial, origin within the urogenital tract to give prostate cancer in the males and vaginal tumors in the females. Additionally, we discovered that the sole inactivation of Rb in the intestine was sufficient to induce formation of metastatic colorectal adenocarcinomas. These tumors closely mirror the human disease in regard to the age of onset, histological appearance, invasiveness and metastatic potential. Like most human colorectal carcinomas, our murine Rb-deficient tumors demonstrate genomic instability and they show activation of beta-catenin. Deregulation of the Wnt/beta-catenin pathway is specific to the intestinal tumors, as genomic instability but not activation of beta-catenin was observed in the neuroendocrine tumors. To date, attempts to generate genetically engineered mouse models of colorectal cancer tumors have yielded mostly cancer of the small intestine, which rarely occurs in humans. Our system provides the opportunity to accurately model and study colorectal cancer in the mouse via a single gene mutation. PMID- 25745998 TI - The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis. AB - Increased abundance of proto-oncogene AKT and reduced expression of tumor suppressor Forkhead box O3 (FOXO3a), the downstream target of AKT, is frequent in carcinogenesis. Mechanistic insights of AKT gene regulation are limited. DEAD box RNA helicase p68 is overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including beta catenin. Here, we report a novel mechanism of p68-mediated transcriptional activation of AKT, and its ensuing effect on FOXO3a, in colon carcinogenesis. Interestingly, we found that the expression of p68 and AKT exhibits strong positive correlation in normal and colon carcinoma patient samples. In addition, p68 increased both AKT messenger RNA (mRNA) and protein, enhanced AKT promoter activity in multiple colon cancer cell lines. Conversely, p68 knockdown led to reduced AKT mRNA and protein, diminished AKT promoter activity. Here, we demonstrated that p68 occupies AKT promoter with beta-catenin as well as nuclear factor-kappaB (NF-kappaB)and cooperates with these in potentiating AKT transcription. Furthermore, p68 and FOXO3a expression followed inverse correlation in the same set of colon carcinoma samples. We observed that p68 significantly reduced FOXO3a protein level in an AKT-dependent manner. Studies in primary tumors and metastatic lung nodules generated in mice colorectal allograft model, using syngeneic cells stably expressing p68, corroborated our in vitro findings. Hence, a new mechanism of oncogenesis is attributed to p68 by upregulation of AKT and consequent nuclear exclusion and degradation of tumor suppressor FOXO3a. PMID- 25745997 TI - Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. AB - We previously identified CLEC14A as a tumour endothelial marker. Here we show that CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a human umbilical vein endothelial cell spheroid-sprouting assay, we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a(+/+) and clec14a(-/-) mice revealed defects in sprouting angiogenesis in CLEC14A-deficient animals. Tumour growth was retarded and vascularity reduced in clec14a(-/-) mice. Pull-down and co-immunoprecipitation experiments confirmed that MMRN2 binds to the extracellular region of CLEC14A. The CLEC14A-MMRN2 interaction was interrogated using mouse monoclonal antibodies. Monoclonal antibodies were screened for their ability to block this interaction. Clone C4, but not C2, blocked CLEC14A-MMRN2 binding. C4 antibody perturbed tube formation and endothelial sprouting in vitro and in vivo, with a similar phenotype to loss of CLEC14A. Significantly, tumour growth was impaired in C4-treated animals and vascular density was also reduced in the C4-treated group. We conclude that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumour growth, which has the potential to be manipulated in future antiangiogenic therapy design. PMID- 25745999 TI - Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity. AB - Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and the glycocalyx, thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of the dual functions of HPSE to malignant melanoma in vitro, as well as in different mouse melanoma models based on the intradermal or intravenous injection of melanoma cells. Consistent with its extracellular action, an HPSE deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of vascular endothelial growth factor, affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-alpha and most prominently, MMP-9, upon HPSE knockdown. In vivo, an HPSE deficiency was related to increased lymph node metastasis. Since the inhibition of its extracellular function with heparin was unable to block the gene regulatory impact of HPSE, we proposed an intracellular mechanism. Immunostaining revealed a counter-staining of HPSE and NF-kappaB in the nucleus, suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual function for HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor-suppressive nuclear action. The identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells could provide new therapeutic options. PMID- 25746000 TI - MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription. AB - Malignant tumors are exemplified by excessive proliferation and aggressive migration/invasion contributing to increased mortality of cancer patients. Matrix metalloproteinase 9 (MMP9) expression is positively correlated with lung cancer malignancy. The mechanism underlying an elevated MMP9 expression is not clearly defined. We demonstrate here that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) was activated by hypoxia and transforming growth factor (TGF beta), two prominent pro-malignancy factors, in cultured lung cancer cells. MKL1 levels were also increased in more invasive types of lung cancer in humans. Depletion of MKL1 in lung cancer cells attenuated migration and invasion both in vitro and in vivo. Overexpression of MKL1 potentiated the induction of MMP9 transcription by hypoxia and TGF-beta, whereas MKL1 silencing diminished MMP9 expression. Of interest, MKL1 knockdown eliminated histone H3K4 methylation surrounding the MMP9 promoter. Further analyses revealed that MKL1 recruited ASH2, a component of the H3K4 methyltransferase complex, to activate MMP9 transcription. Depletion of ASH2 ameliorated cancer cell migration and invasion in an MMP9-dependent manner. Together our data indicate that MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription. PMID- 25746001 TI - ECM1 regulates tumor metastasis and CSC-like property through stabilization of beta-catenin. AB - Extracellular Matrix Protein 1 (ECM1) is a marker for tumorigenesis and is correlated with invasiveness and poor prognosis in various types of cancer. However, the functional role of ECM1 in cancer metastasis is unclear. Here, we detected high ECM1 level in breast cancer patient sera that was associated with recurrence of tumor. The modulation of ECM1 expression affected not only cell migration and invasion, but also sphere-forming ability and drug resistance in breast cancer cell lines. In addition, ECM1 regulated the gene expression associated with the epithelial to mesenchymal transition (EMT) progression and cancer stem cell (CSC) maintenance. Interestingly, ECM1 increased beta-catenin expression at the post-translational level through induction of MUC1, which was physically associated with beta-catenin. Indeed, the association between beta catenin and the MUC1 cytoplasmic tail was increased by ECM1. Furthermore, forced expression of beta-catenin altered the gene expression that potentiated EMT progression and CSC phenotype maintenance in the cells. These data provide evidence that ECM1 has an important role in cancer metastasis through beta catenin stabilization. PMID- 25746002 TI - An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis. AB - Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival, and its overactivation drives cancer development. One important branch of EGFR signaling is through activation of GTPase Rac1, which further promotes cell proliferation, survival and cancer metastasis. Here, we show that EGFR activates Rac1 via inducing the accumulation of its specific guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (Tiam1) in non-small cell lung cancer and colon cancer cells. Conversely, elevated Tiam1 is required for EGFR-induced tumorigenesis. In human lung adenocarcinoma and colon cancer specimens, Tiam1 expression strongly correlates with EGFR expression. We further reveal that AKT, a key downstream protein kinase of EGFR, phosphorylates Tiam1 at several consensus sites, facilitates the interaction of Tiam1 with scaffold proteins 14-3-3 and leads to an increase of Tiam1 stability. Subsequently, Tiam1 is dephosporylated and destabilized by PP2A. Together, our study identifies a bidirectional (phosphorylation and dephosphorylation) regulatory mechanism controlling Tiam1 stability and provides new insights on how EGFR signaling triggers Rac1 activation and cancer development. PMID- 25746003 TI - PKCdelta maintains phenotypes of tumor initiating cells through cytokine-mediated autocrine loop with positive feedback. AB - The existence of tumor initiating cells (TICs) has been emerged as a good therapeutic target for treatment of glioblastoma that is the most aggressive brain tumor with poor prognosis. However, the molecular mechanisms that regulate the phenotypes of TICs still remain obscure. In this study, we found that PKCdelta, among PKC isoforms, is preferentially activated in TICs and acts as a critical regulator for the maintenance of TICs in glioblastoma. By modulating the expression levels or activity of PKCdelta, we demonstrated that PKCdelta promotes self-renewal and tumorigenic potentials of TICs. Importantly, we found that the activation of PKCdelta persists in TICs through an autocrine loop with positive feedback that was driven by PKCdelta/STAT3/IL-23/JAK signaling axis. Moreover, for phenotypes of TICs, we showed that PKCdelta activates AKT signaling component by phosphorylation specifically on Ser473. Taken together, we proposed that TICs regulate their own population in glioblastoma through an autocrine loop with positive feedback that is driven by PKCdelta-dependent secretion of cytokines. PMID- 25746004 TI - Tumor-specific signaling to p53 is mimicked by Mdm2 inactivation in zebrafish: insights from mdm2 and mdm4 mutant zebrafish. AB - In mice, the deletion of either Mdm2 or Mdm4 results in a p53-dependent embryonic lethality. We used zinc-finger nucleases to construct mutations in the mdm2 and mdm4 genes of zebrafish. Although the loss of mdm2 results in a p53-dependent early embryonic lethality, mdm4 mutant fish are viable and grow to adulthood. We also found that an in-frame five-amino acid deletion in mdm2 creates a novel hypomorphic allele. The lethal phenotype observed in the mdm2 mutant fish could be partially rescued by injecting mRNA encoding functional Mdm2, and this required the E3 ligase activity of the protein. Complete rescue was obtained by crossing the mdm2 mutant fish onto a p53M214K mutant background. Although p53 mutant fish on a wild-type mdm2 background were shown to accumulate high levels of p53 protein specifically in tumor tissues, we detected extensive staining of p53 in many normal tissues of the mdm2-p53M214K double-mutant fish. Our results are suggestive of the hypothesis that p53 protein accumulates during tumor formation as a result of tumor-specific inactivation of the Mdm2 pathway. PMID- 25746005 TI - Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential. AB - Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of known EMT regulators, miR-200 family of microRNAs in controlling the epithelial state, stem-like properties and therapeutic response in an in vivo primary, syngeneic p53(null) claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. miR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion and motility. Accordingly, induced miR200c expression significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53(null) claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity and metastatic potential in vivo. PMID- 25746007 TI - Trends in the adsorption and reactivity of hydrogen on magnesium silicate nanoclusters. AB - We study nanoclusters of Mg-rich olivine and pyroxene (having (MgO)6(SiO2)3 and (MgO)4(SiO2)4 compositions) with respect to their reactivity towards hydrogen atoms, using density functional calculations. Ultrasmall silicate particles are fundamental intermediates in cosmic dust grain formation and processing, and are thought to make up a significant mass fraction of the grain population. Due to their nanoscale dimensions and high surface area to bulk ratios, they are likely to also have a disproportionately large influence on surface chemistry in the interstellar medium. This work investigates the potential role of silicate nanoclusters in vital interstellar hydrogen-based chemistry by studying atomic H adsorption and H2 formation. Our extensive set of calculations confirm the generality of a Bronsted-Evans-Polanyi (BEP) relation between the H2 reaction barrier and the 2Hchem binding energy, suggesting it to be independent of silicate dust grain shape, size, crystallinity and composition. Our results also suggest that amorphous/porous grains with forsteritic composition would tend to dissociate H2, but relatively Mg-poor silicate grains (e.g. enstatite composition) and/or more crystalline/compact silicate grains would tend to catalyse H2 formation. The high structural thermostability of silicate nanoclusters with respect to the heat released during exothermic H2 formation reactions is also verified. PMID- 25746006 TI - DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2. AB - Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth. PMID- 25746008 TI - Encapsulation of haloalkane 1-(3-chlorophenyl)-4-(3-chloropropyl)-piperazinium in symmetrical alpha,alpha',delta,delta'-tetramethyl-cucurbit[6]uril. AB - Complexation of haloalkane 1-(3-chlorophenyl)-4-(3-chloropropyl)-piperazinium (PZ(+)) dihydrochloride with symmetrical alpha,alpha',delta,delta'-tetramethyl cucurbit[6]uril (TMeQ[6]) has been investigated using NMR spectroscopy, MALDI-TOF mass spectrometry, isothermal titration calorimetry (ITC), and X-ray crystallography. Our data indicate that the chloropropyl group of PZ(+) resides within the cavity of TMeQ[6] in both aqueous solution and the solid state, generating a highly stable inclusion complex PZ(+)@TMeQ[6]. In aqueous solution, the formation of the inclusion complex PZ(+)@TMeQ[6] benefits from the ion-dipole interactions between the guest PZ(+) and the host TMeQ[6]. While in the solid state, hydrogen-bonding interactions also play an important role in stabilizing the inclusion complex PZ(+)@TMeQ[6]. PMID- 25746009 TI - Biatrial neuroablation attenuates atrial remodeling and vulnerability to atrial fibrillation in canine chronic rapid atrial pacing. AB - AIMS: We investigated the proposition that an intact cardiac nervous system may contribute to electrophysiological remodeling and increased vulnerability to atrial fibrillation (AF) following chronic rapid atrial pacing (RAP). METHODS AND RESULTS: Baseline study was conducted prior to ablating right and left ganglionated plexuses (RAGP, LAGP) in 11 anesthetized canines (Neuroablation group) and in 11 canines without neuroablation (Intact GP). After being subjected to RAP (400 beats/min) for 6 weeks, animals were reanesthetized for terminal study. The ERP shortening typical of chronic RAP was significantly more pronounced in the Intact GP (baseline: 112 +/- 12 to terminal: 80 +/- 11 ms) than in the Neuroablation group (113 +/- 18 to 102 +/- 21 ms, p < .001), and AF inducibility (extrastimulus protocol) showed significantly greater increment in the Intact GP (baseline: 23 +/- 19% to terminal: 60 +/- 17% of trials) than in the Neuroablation group (18 +/- 15% to 27 +/- 17%, p = 0.029). Negative chronotropic responses to right vagus nerve stimulation were markedly reduced immediately after the neuroablation procedure but had recovered at terminal study. Vagally-evoked repolarization changes (from 191 unipolar electrograms) occurred in a majority of Intact GP animals in the superior, middle and inferior RA free wall, and in the LA appendage. In the Neuroablation group, repolarization changes were restricted to the superior RA free wall but none occurred in the inferior RA and only infrequently in the LA appendage, yielding significantly smaller affected areas in Neuroablation than in Intact GP animals. CONCLUSION: Persistent functional denervation in LA and RA regions other than RA pacemaker areas may contribute to prevent the development of a tachycardia-dependent AF substrate. PMID- 25746010 TI - A Dual-reporter system for real-time monitoring and high-throughput CRISPR/Cas9 library screening of the hepatitis C virus. AB - The hepatitis C virus (HCV) is one of the leading causes of chronic hepatitis, liver cirrhosis and hepatocellular carcinomas and infects approximately 170 million people worldwide. Although several reporter systems have been developed, many shortcomings limit their use in the assessment of HCV infections. Here, we report a real-time live-cell reporter, termed the NIrD (NS3-4A Inducible rtTA mediated Dual-reporter) system, which provides an on-off switch specifically in response to an HCV infection. Using the NIrD system and a focused CRISPR/Cas9 library, we identified CLDN1, OCLN and CD81 as essential genes for both the cell free entry and the cell-to-cell transmission of HCV. The combination of this ultra-sensitive reporter system and the CRISPR knockout screening provides a powerful and high-throughput strategy for the identification of critical host components for HCV infections. PMID- 25746012 TI - c-Flip KO fibroblasts display lipid accumulation associated with endoplasmic reticulum stress. AB - c-Flip proteins are well-known apoptosis modulators. They generally contribute to tissue homeostasis maintenance by inhibiting death-receptor-mediated cell death. In the present manuscript, we show that c-Flip knock-out (KO) mouse embryonic fibroblasts (MEFs) kept in culture under starvation conditions gradually modify their phenotype and accumulate vacuoles, becoming progressively larger according to the duration of starvation. Large vacuoles are present in KO MEFs though not in WT MEFs, and are Oil Red-O positive, which indicates that they represent lipid droplets. Western blot experiments reveal that, unlike WT MEFs, KO MEFs express high levels of the lipogenic transcription factor PPAR-gamma. Lipid droplet accumulation was found to be associated with endoplasmic reticulum (ER) stress activation and autophagic modulation valuated by means of BIP increase, LC3 lipidation and AMP-activated protein kinase (AMPK) phosphorylation, and p62 accumulation. Interestingly, XBP-1, an ER stress-induced lipogenic transcription factor, was found to preferentially localize in the nucleus rather than in the cytoplasm of KO MEFs. These data demonstrate that, upon starvation, c-Flip affects lipid accumulation, ER stress and autophagy, thereby pointing to an important role of c-Flip in the adaptive response and ER stress response programs under both normal and pathological conditions. PMID- 25746011 TI - Sulphate in pregnancy. AB - Sulphate is an obligate nutrient for healthy growth and development. Sulphate conjugation (sulphonation) of proteoglycans maintains the structure and function of tissues. Sulphonation also regulates the bioactivity of steroids, thyroid hormone, bile acids, catecholamines and cholecystokinin, and detoxifies certain xenobiotics and pharmacological drugs. In adults and children, sulphate is obtained from the diet and from the intracellular metabolism of sulphur containing amino acids. Dietary sulphate intake can vary greatly and is dependent on the type of food consumed and source of drinking water. Once ingested, sulphate is absorbed into circulation where its level is maintained at approximately 300 MUmol/L, making sulphate the fourth most abundant anion in plasma. In pregnant women, circulating sulphate concentrations increase by twofold with levels peaking in late gestation. This increased sulphataemia, which is mediated by up-regulation of sulphate reabsorption in the maternal kidneys, provides a reservoir of sulphate to meet the gestational needs of the developing foetus. The foetus has negligible capacity to generate sulphate and thereby, is completely reliant on sulphate supply from the maternal circulation. Maternal hyposulphataemia leads to foetal sulphate deficiency and late gestational foetal death in mice. In humans, reduced sulphonation capacity has been linked to skeletal dysplasias, ranging from the mildest form, multiple epiphyseal dysplasia, to achondrogenesis Type IB, which results in severe skeletal underdevelopment and death in utero or shortly after birth. Despite being essential for numerous cellular and metabolic functions, the nutrient sulphate is largely unappreciated in clinical settings. This article will review the physiological roles and regulation of sulphate during pregnancy, with a particular focus on animal models of disturbed sulphate homeostasis and links to human pathophysiology. PMID- 25746013 TI - Abstracts of the 29th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC). PMID- 25746014 TI - Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model. AB - Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the 'blood tumor barrier' (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg(-1). This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823 +/- 600, 1817 +/- 732 and 2432 +/- 448 ng g(-1)) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P < 0.05, P < 0.01, and P < 0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222 +/- 784, 3687 +/- 796 and 5658 +/- 821 ng g(-1)) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (P < 0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ?2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used. PMID- 25746015 TI - Rejoinder to Dennis Gorman's critique of: "Preventing alcohol harm: Early results from a cluster randomised, controlled trial in Victoria, Australia of comprehensive harm minimisation school drug education". PMID- 25746016 TI - Bioresorbable vascular scaffolds: a new revolution in percutaneous coronary intervention? PMID- 25746017 TI - Weekend warriors: can early invasive management of stable non-ST-elevation acute coronary syndromes save health care dollars? PMID- 25746018 TI - Transcatheter reduction of paravalvular leaks: a systematic review and meta analysis. AB - BACKGROUND: Significant paravalvular leak (PVL) after surgical valve replacement can result in intractable congestive heart failure and hemolytic anemia. Because repeat surgery is performed in only few patients, transcatheter reduction of PVL is emerging as an alternative option, but its safety and efficacy remain uncertain. In this study we sought to assess whether a successful transcatheter PVL reduction is associated with an improvement in clinical outcomes. METHODS: We identified 12 clinical studies that compared successful and failed transcatheter PVL reductions in a total of 362 patients. A Bayesian hierarchical meta-analysis was performed using cardiac mortality as a primary end point. The combined occurrence of improvement in New York Heart Association functional class or hemolytic anemia and the need for repeat surgery, were used as secondary end points. RESULTS: A successful transcatheter PVL reduction was associated with a lower cardiac mortality rate (odds ratio [OR], 0.08; 95% credible interval [CrI], 0.01-0.90) and with a superior improvement in functional class or hemolytic anemia, compared with a failed intervention (OR, 9.95; 95% CrI, 2.10-66.73). Fewer repeat surgeries were also observed after successful procedures (OR, 0.08; 95% CrI, 0.01-0.40). CONCLUSIONS: A successful transcatheter PVL reduction is associated with reduced all-cause mortality and improved functional class in patients deemed unsuitable for surgical correction. PMID- 25746019 TI - A systematic review and meta-analysis of the association between implantable cardioverter-defibrillator shocks and long-term mortality. AB - BACKGROUND: It is unknown whether implantable cardioverter-defibrillator (ICD) discharges actively contribute to a worse prognosis independent of the underlying arrhythmia. There is considerable variability in the reported risk of mortality after appropriate and inappropriate ICD shocks. The aim of our systematic review was to provide a reliable effect size of the association between ICD shock and mortality for both types of therapies. METHODS: On the basis of a systematic literature search, 10 studies were considered eligible for inclusion in the analysis, and data on the hazard ratio (HR) of mortality after ICD shock were extracted from each study. RESULTS: On pooled analysis, a substantial difference was detected in the risk for subsequent mortality between appropriate and inappropriate shocks. Among patients receiving an appropriate ICD shock, the HR for cardiac death was 2.95 (95% confidence interval [CI], 2.12-4.11; P < 0.001) compared with an HR of 1.71 (95% CI, 1.45-2.02) for those receiving an inappropriate shock. Clinical variables like ejection fraction, New York Heart Association class, and length of follow-up did not affect the HRs in our meta regression models. CONCLUSIONS: Our analysis showed a significant association between appropriate and inappropriate ICD shocks and mortality, with a stronger association for appropriate shocks. Previous trials of ICD therapy reduction programming have shown a significant reduction of inappropriate shocks. The management of appropriate shocks is more challenging and may be optimized by the assessment and treatment of the underlying ventricular arrhythmias. The role of therapies aimed at modifying the arrhythmic substrate and the potential impact on ICD shocks and mortality requires further investigation. PMID- 25746020 TI - Association of inflammatory and hemostatic markers with stroke and thromboembolic events in atrial fibrillation: a systematic review and meta-analysis. AB - BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke and thromboembolic events. Recently, biomarkers have been proposed as a practical tool to predict adverse outcomes in patients with AF. The prognostic value of inflammatory and hemostatic markers in AF has been widely studied; however, the results of previous studies have been inconclusive. METHODS: We conducted a systematic review and meta-analysis to evaluate the association of inflammatory and hemostatic markers with stroke and thromboembolic events in patients with AF. RESULTS: A total of 27 studies including 22,176 participants met our inclusion criteria for the systematic review. Our meta-analysis determined that elevated circulating plasminogen activator inhibitor-1 (PAI-1) and thrombin-antithrombin (TAT) were significantly associated with increased risk of stroke in patients with AF (standardized mean difference [SMD], 0.89; 95% confidence interval [CI], 0.20-1.59 and 1.43; 95% CI, 0.40-2.47, respectively). Higher levels of D-dimer were associated with increased subsequent thromboembolic event risk with a pooled hazard ratio of 2.90 (95% CI, 1.22-6.90) for cohort studies and an SMD of 0.93 (95% CI, 0.36-1.50) for case-control studies. There was also very limited evidence indicating that other biomarkers-such as interleukin-6, von Willebrand factor, P-selectin, and mean platelet volume-could predict adverse outcomes in AF. CONCLUSIONS: In conclusion, increased circulating PAI-1 and TAT levels were significantly associated with subsequent stroke in patients with AF, and high levels of D-dimer were associated with thromboembolic events in AF. Further epidemiologic studies are needed to accumulate more evidence on the prognostic role of inflammatory and hemostatic markers in AF. PMID- 25746021 TI - Troponin rise in hospitalized patients with nonacute coronary syndrome: retrospective assessment of outcomes and predictors. AB - BACKGROUND: Cardiac troponin is elevated in several clinical settings apart from thrombotic acute coronary syndrome (ACS) and is associated with increased adverse events. It is not clear whether troponin elevation in type II myocardial infarction (MI) is associated with increased cardiovascular events. Our objectives were to identify the cause of mortality in type II MI and to attempt to establish the threshold range of cardiac troponin-I (cTnI) elevation as well as clinical factors associated with adverse outcomes in type II MI. METHODS: This retrospective cohort study included 245 patients presenting with a noncardiac primary diagnosis associated with cTnI elevation at a single centre from January 2003 to December 2011. Primary outcome was a composite of cardiovascular and noncardiovascular mortality. Secondary outcomes included subsequent stroke, ACS, and heart failure (HF). RESULTS: At 1 year, ACS occurred in 13 patients (5.3%), stroke was seen in 10 (4.1%) patients, and HF occurred in 19 (7.8%) patients. Overall 1-year mortality included 102 events (41.6%), with 10 cardiovascular deaths (9.8%), 65 noncardiovascular deaths (63.7%), and 27 (26.5%) deaths from unknown causes. In multivariable analysis, factors independently associated with increased overall 1-year mortality included cTnI elevation >= 4.63 MUg/L (odds ratio [OR], 3.37; 95% confidence interval [CI], 1.55-7.34; P = 0.002), age >= 70 years (OR, 2.44; 95% CI, 1.40-4.29; P = 0.002), and estimated glomerular filtration rate < 30 mL/min/1.73m(2) (OR, 2.40; 95% CI 1.31-4.40; P = 0.005). CONCLUSIONS: Unlike the published literature, our study includes a variety of both operative and nonoperative clinical settings associated with troponin elevation. We illustrate that although overall mortality is high after type II MI, the majority of mortality is caused by noncardiovascular events. PMID- 25746022 TI - Cost implication of an early invasive strategy on weekdays and weekends in patients with acute coronary syndromes. AB - BACKGROUND: Early invasive intervention is associated with shorter length of stay (LOS) and similar outcomes in a delayed strategy in lower-risk patients with non ST segment elevation acute coronary syndromes (NSTEACS), but is superior in higher-risk patients. However, early invasive intervention might be constrained by the need to mobilize the on-call team on weekends. We evaluated costs associated with an early vs delayed invasive intervention strategy, including patients who present on weekends. METHODS: Health care utilization was extracted from the Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial for Canadian patients from case report forms. Only direct costs were considered and only hospitalization events were included. Canadian unit costs were applied to health care resources consumed for all patients. Sensitivity and subgroup analyses were performed. RESULTS: Early invasive intervention reduced LOS costs by $2808 (95% confidence interval [CI], $4,629-$987). Total costs per Canadian patient for early invasive intervention were $16,579 (95% CI, $14,949-$18,209) compared with $19,517 (95% CI, $17,897-$21,136) for the delayed invasive approach. This resulted in a savings of $2938 (95% CI, $5236-$640). Findings were confirmed using bootstrap simulation. Sensitivity analyses confirmed savings regardless of proportion of cases done on weekends. All subgroup costs favoured early intervention. CONCLUSIONS: Early invasive strategy was cost-saving, even on weekends, for Canadian NSTEACS patients because of significant LOS savings. Because many high-risk NSTEACS patients receive delayed intervention because of weekend catheterization laboratory status, these findings support opening catheterization laboratories on weekends to facilitate the use of early invasive intervention. PMID- 25746023 TI - Heart block and temporary pacing during rotational atherectomy. AB - BACKGROUND: Rotational atherectomy (RA) performed during percutaneous coronary intervention is commonly associated with distal embolization of calcific particles resulting in conduction abnormalities. As a result, temporary pacing is often used during these procedures. It is unknown whether temporary pacing should be routinely used. METHODS: We performed an analysis of 134 consecutive patients who underwent RA at our institution between January 2011 and September 2013 for the presence of intraprocedural heart block or pacemaker activation. RESULTS: A temporary pacemaker was inserted in 50% of cases. Forty-two (31%) patients experienced either heart block (n = 16) or pacemaker activation (n = 26). There was no difference in baseline characteristics between those who experienced heart block or required temporary pacing, and those who did not. Interventional characteristics including burr size, maximum rotations per minute used, and maximum run duration were also similar among the groups. Only target RA vessel was associated with the presence of heart block or temporary pacing in multivariate analysis (P < 0.0001). Heart block or temporary pacing occurred in 28 (53%) of RA to the right coronary artery, 2 (5%) of the left anterior descending artery, 8 (62%) of the left-dominant circumflex artery, and 2 (18%) with RA to the circumflex artery with right-dominant circulation. Asystole occurred only in patients who underwent RA to the right coronary artery. CONCLUSIONS: Heart block or temporary pacing was more commonly associated with right coronary artery and left-dominant circumflex lesions. Prophylactic pacemaker insertion might be avoided with RA to other vessels. PMID- 25746024 TI - Longitudinal assessment of inflammation in recipients of continuous-flow left ventricular assist devices. AB - BACKGROUND: The long-term effects of continuous-flow left ventricular assist device (CF-LVAD) support on trends of inflammatory markers over time are unknown. We examined the hypothesis that the levels of inflammatory markers in CF-LVAD recipients are higher than in healthy controls and that these levels increase over time with long-term CF-LVAD support. METHODS: We examined the levels of inflammatory markers longitudinally at baseline before CF-LVAD implantation and at 3, 6, and 9 months after implantation. We then compared the levels of inflammatory markers to those in a healthy control group. RESULTS: Compared with baseline values before CF-LVAD implantation, left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd) decreased significantly at 3, 6, and 9 months after CF-LVAD implantation. Brain natriuretic peptide (BNP) levels dropped significantly after CF-LVAD implantation but did not normalize. Improvements in ejection fraction at 3, 6, and 9 months after CF-LVAD implantation did not reach significance. Monocyte chemoattractant protein-1, interferon gamma-induced protein, and C-reactive protein levels were higher in the CF-LVAD recipients at each of the time points (baseline before CF-LVAD implantation and 3, 6, and 9 months after implantation) compared with levels in healthy controls. In CF-LVAD recipients, serum interleukin-8, tumour necrosis factor-alpha, and macrophage inflammatory protein-beta increased significantly at 9 months, and macrophage-derived chemokine increased at 6 months after CF-LVAD implantation compared with baseline. CONCLUSIONS: Despite improvements in LV dimensions and BNP levels, markers of inflammation remained higher in CF-LVAD recipients. High levels of inflammation in CF-LVAD recipients may result from heart failure preconditioning or the long-term device support, or both. Because inflammation may be detrimental to CF-LVAD recipients, future studies should determine whether inflammatory pathways are reversible. PMID- 25746025 TI - Ceramide is upregulated and associated with mortality in patients with chronic heart failure. AB - BACKGROUND: Ceramide is involved in apoptosis, inflammation, and stress responses, which are among the pathogenic components of chronic heart failure (CHF). However, no one has documented the levels of ceramide itself in CHF or determined its potential prognostic value. METHODS: In this study we recruited patients with heart failure consecutively from the hospital, of whom 423 stable patients were eventually selected to participate in this study after an observation period of at least 3 months after hospital discharge. All patents were followed up for all-cause death to December 31, 2013. RESULTS: Plasma ceramide levels were increased stepwise with New York Heart Association functional class (I, 5.32 +/- 1.98; II, 5.81 +/- 1.63; III, 6.14 +/- 2.14; IV, 6.66 +/- 2.61 ng/mL). During a mean follow-up of 4.4 years (interquartile range: 3.5-5.3 years), a total of 200 CHF patients died. The optimal threshold value of ceramide was 6.05 ng/mL. Ceramide levels as continuous and as dichotomous variables are risk factors for mortality in CHF (adjusted hazard ratio, 1.31; 95% confidence interval, 1.16-1.47; P < 0.001 and adjusted hazard ratio, 2.07, 95% confidence interval, 1.53-2.81; P < 0.001, respectively). When ceramide levels were combined with conventional CHF risk factors, the area under the curve increased from 0.68 (0.63-0.72) to 0.72 (0.68-0.76); P = 0.047. The continuous net reclassification index and integrated discrimination improvement index were 17.2% (5.0-29.9%; P = 0.027) and 0.04 (0.01-0.08; P = 0.020), respectively. CONCLUSIONS: Plasma ceramide levels were increased and correlated with the severity of CHF, and were an independent risk factor of mortality in patients with CHF and reduced left ventricular systolic function. Ceramide levels might provide additional predictive value after conventional risk assessment. PMID- 25746026 TI - Multimodality imaging for assessment of coronary embolus. AB - Caseous mitral annulus calcification involving aortomitral curtain is a rare occurrence. We report a case of a 64-year-old woman with end-stage renal failure and a candidate for renal transplant who presented with late ST-elevation myocardial infarction. Intracoronary imaging, computed tomography cardiac imaging, and histopathology confirmed coronary embolus into the left main stem artery from an extensive caseous mitral annulus calcification. PMID- 25746027 TI - Reply to letter from DeVon et al. - Time to standardize and broaden the criteria of acute coronary syndrome symptom presentations in women. PMID- 25746028 TI - Comment on Kuyper et al.--Atenolol vs nonatenolol beta-blockers for the treatment of hypertension: a meta-analysis. PMID- 25746029 TI - Reply to letter from Li et al.--Atenolol vs nonatenolol beta-blockers for the treatment of hypertension: a meta-analysis. PMID- 25746030 TI - Feasibility of smaller arterial cannulas in venoarterial extracorporeal membrane oxygenation. AB - OBJECTIVES: To facilitate venoarterial extracorporeal membrane oxygenation (ECMO) insertion for cardiogenic shock, we recently adopted a strategy of using a 15F arterial cannula in all patients, rather than 1 designed to maximize flow. We aimed to compare the clinical outcomes of these 2 strategies. METHODS: In this retrospective study, 101 consecutive patients supported with ECMO via femoral cannulation between March 2007 and March 2013 were divided into 2 groups: Group L (17F-24F arterial cannula to accommodate full flow [ie, cardiac index of 2.5 L/m(2)/min]; n = 51) and Group S (15F arterial cannula; n = 50). The primary outcomes of interest were patients' overall status at 24 hours of support and cannulation-related adverse events. RESULTS: There were no significant differences in patient demographics, etiology of cardiogenic shock, or severity of illness before ECMO initiation between the 2 groups. Group L had significantly higher ECMO flow than Group S (flow index at 24 hours: 2.2 +/- 0.7 vs 1.7 +/- 0.3 L/m(2)/min; P < .001). However, there was no significant difference in use of vasoactive medication/hemodynamic parameters/laboratory parameters. Group L had higher incidence of cannulation-related adverse events (35% vs 22% in Group S [P = .14]), particularly in cannulation site bleeding (28% vs 10% [P = .03]). Thirty day survival was 55% in Group L versus 52% in Group S (P = .77). Bleeding complication occurred in 53% in Group L versus 32% in Group S (P = .03). CONCLUSIONS: Compared with the use of larger cannulas, ECMO with a 15F arterial cannula appears to provide comparable clinical support with reduced bleeding complications. PMID- 25746031 TI - Topical antibiotics help to reduce sternal infections. PMID- 25746032 TI - The butterfly takes flight. PMID- 25746033 TI - [Psychosocial risk's factors in primary health care: a comparative study between job position]. PMID- 25746034 TI - [Physical activity in adult working population: results from the European National Health Survey for Spain (2009)]. AB - OBJECTIVES: 1) To describe physical activity in the Spanish adult working population aged 16-70 years in 2009, and 2) to describe the prevalence of physical activity according to socio-demographic features, self-perceived health status, co-morbidity, and lifestyle habits. DESIGN: An epidemiological population based descriptive study was conducted using individual data taken from the European Health Survey for Spain. SETTING: Community. PARTICIPANTS: The number of subjects aged 16-70 years included in the study was 10,928 (5,628 women and 5,300 men). INTERVENTIONS: None. MAIN VARIABLES: Physical activity and intensity were assessed from questions included in the interview-survey. An analysis was performed on the socio-demographic characteristics and self-rated physical and mental health, using multivariate logistic regression models. RESULTS: Not having a partner (OR 1.44; P<.001), have university studies (OR 1.62; P<.001), non smoker (OR 1.50; P<.001), and taking medications (OR 1.22; P<.5) were a predictor of intense physical activity in men. The first 3 factors are equal for intense activity in women. In contrast, obesity (OR 0.58; P<.001), and 36-50 years (OR 0.68; P<.001) were factors related to low activity in men. Aged between 36-50 years (OR 1.26; P<.01), suffering>=2 co-morbid conditions (OR 1.30; P<.001), and non-smoker (OR 1.17; P<.5) were also associated with higher probability of reporting moderate physical activity in women. The positive mental health was significant for physical activity in both sexes (OR 1.01; P<.5). CONCLUSIONS: This study identified several factors that appear to influence physical activity in the Spanish adult working population, with potential implications for healthcare providers. PMID- 25746035 TI - Four out of ten Spanish GPs declare to prescribe high-doses of beta-lactams in suspected streptococcal pharyngitis. PMID- 25746036 TI - TERT promoter mutations in sinonasal malignant melanoma: a study of 49 cases. AB - Sinonasal malignant melanoma (SNMM) comprises less than 1% of all melanomas and is located in the nasal cavity and the paranasal sinuses. The majority of SNMMs have unknown underlying oncogenic driver mutations. The recent identification of a high frequency of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in cutaneous melanoma led us to investigate whether these mutations also occur in SNMM. Our aim was to determine the TERT promoter mutation frequencies in primary SNMMs. Laser capture microdissection and manual dissection were used to isolate tumour cells from 49 formalin-fixed paraffin embedded tissues. The tumours were screened for TERT promoter mutations by direct Sanger sequencing. Information on NRAS, BRAF and KIT mutation was available from an earlier study. Overall, 8% (4/49) of SNMMs harboured TERT promoter mutations. One of these mutated tumours had a coexistent NRAS mutation and one had a BRAF mutation. Our findings show that TERT promoter mutations are present in a moderate proportion of SNMM. No conclusion can be drawn on their potential influence on the clinical outcome or tumour progression. PMID- 25746037 TI - Induction vemurafenib followed by consolidative radiation therapy for surgically incurable melanoma. AB - Approximately half of melanomas are driven by a point mutation in the BRAF kinase gene, targetable with vemurafenib. However, the chief limitation of continuous BRAF inhibition is that the majority of patients develop resistance within 8 months, including those with surgically unresectable stage III melanoma. Researchers retrospectively reviewed medical records of all patients at our institution with surgically incurable BRAF V600E mutated stage III or limited stage IV melanoma treated with induction vemurafenib, stopped electively during ongoing response, followed by consolidative radiation therapy with or without intervening surgery to debulk nodal metastases. In our six-patient cohort, the median duration of vemurafenib was 5.8 months and the median radiation dose was 57 Gy using conventional fractionation. This algorithm produced 100% locoregional control at 29+ months following radiation and a median progression-free survival of 32.5+ months. Three of six patients remained progression free, and three relapsed in a single organ and achieved ongoing complete response to subsequent therapy. Outcomes greatly exceeding those reported with either BRAF inhibition or radiation alone suggest unanticipated synergies with this therapeutic sequence for both in-field and distant melanoma control, which may be mediated by radiosensitization and immune activation, respectively. In patients with surgically incurable melanoma encompassed within a radiation field, induction vemurafenib and consolidative radiation therapy, rather than continuing vemurafenib until progression, also limit the duration of vemurafenib toxicity and preserve sensitivity to future BRAF inhibition. PMID- 25746038 TI - High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients. AB - Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is- BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1 mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease. PMID- 25746039 TI - Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study. AB - The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2+/-13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents. PMID- 25746040 TI - Dynamics of non-cohabiting sex partnering in sub-Saharan Africa: a modelling study with implications for HIV transmission. AB - OBJECTIVE: To develop an analytical understanding of non-cohabiting sex partnering in sub-Saharan Africa (SSA) using nationally representative sexual behaviour data. METHOD: A non-homogenous Poisson stochastic process model was used to describe the dynamics of non-cohabiting sex. The model was applied to 25 countries in SSA and was fitted to Demographic and Health Survey data. The country-specific mean values and variances of the distributions of number of non cohabiting partners were estimated. RESULTS: The model yielded overall robust fits to the empirical distributions stratified by marital status and sex. The median across all country-specific mean values was highest for unmarried men at 0.574 non-cohabiting partners over the last 12 months, followed by that of unmarried women at 0.337, married men at 0.192 and married women at 0.038. The median of variances was highest for unmarried men at 0.127, followed by married men at 0.057, unmarried women at 0.003 and married women at 0.000. The largest variability in mean values across countries was for unmarried men (0.103-1.206), and the largest variability in variances was among unmarried women (0.000-1.994). CONCLUSIONS: Non-cohabiting sex appears to be a random 'opportunistic' phenomenon linked to situations that may facilitate it. The mean values and variances of number of partners in SSA show wide variation by country, marital status and sex. Unmarried individuals have larger mean values than their married counterparts, and men have larger mean values than women. Unmarried individuals appear to play a disproportionate role in driving heterogeneity in sexual networks and possibly epidemiology of sexually transmitted infections. PMID- 25746041 TI - Human papillomavirus genotype distribution among Cameroonian women with invasive cervical cancer: a retrospective study. AB - OBJECTIVES: We determined the human papillomavirus (HPV) types present in invasive cervical cancer (ICC) of women in Cameroon in order to estimate the potential efficacies of HPV prophylactic vaccines. METHODS: This is a retrospective study using 181 formalin-fixed paraffin-embedded cervical tissue samples of ICC collected from the Institute of Pathology, Gyneco-Obstetric and Pediatric Hospital, Yaounde, Cameroon. HPV was detected by PCR using modified GP5+/GP6+ (MGP) primers. Genotyping was performed by reverse-blot hybridisation, which allowed the detection of 9 of the 14 high-risk HPV types. RESULTS: Of the 181 samples, 91.7% were squamous cell carcinomas and 6.6% were adenocarcinomas. Counting all the single and multiple infections, the three most common high-risk types in descending order were HPV16 (88%), HPV45 (32%) and HPV18 (14.8%). 54.9% of cases were infected with a single HPV type and 45.1% had two or more HPV infections. CONCLUSIONS: The frequencies of HPV16, HPV45 and multiple infections are all higher than previously reported. These observations have significant implications on the consideration of vaccination strategies because each vaccine has different duration and efficacies in cross-protection of different HPV types. The method used proved to be sensitive and cost-efficient for retrospective studies where fresh materials are not available. PMID- 25746042 TI - High-resolution multilocus sequence typing reveals novel urogenital Chlamydia trachomatis strains in women in Mopani district, South Africa. AB - OBJECTIVES: Recently, we reported a high prevalence (16%) of urogenital Chlamydia trachomatis infections among women in a rural setting in South Africa. Molecular epidemiological studies on C. trachomatis infections could provide insights into the characteristics of this epidemic, yet such data are not available. The objective of this study was therefore to assess the distribution of C. trachomatis strains among women from a South African rural community, the Mopani district, and to compare it with strains from Amsterdam, the Netherlands. METHODS: High-resolution multilocus sequence typing (hr-MLST) was used to study urogenital C. trachomatis infections in women visiting primary healthcare facilities across rural Mopani District in Limpopo Province, South Africa. Sequence types (STs) were compared with 100 strains from women visiting the sexually transmitted infection clinic in Amsterdam, the Netherlands. RESULTS: Full hr-MLST data were obtained for C. trachomatis infection in 43 women from Mopani district. Using the complete hr-MLST profile of all 43 women from Mopani district, 26 STs could be identified, of which 18 (69%) were novel to the hr-MLST database. The remaining STs clustered together with strains from Amsterdam. CONCLUSIONS: Hr-MLST data revealed a diverse molecular epidemiology with novel STs and a specific cluster for the Mopani district. Also C. trachomatis types that occur worldwide were detected. PMID- 25746043 TI - Striving to maintain a dignified life for the patient in transition: next of kin's experiences during the transition process of an older person in transition from hospital to home. AB - Next of kin represent significant resources in the care for older patients. The aim of this study was to describe and illuminate the meaning of the next of kin's experiences during the transition of an older person with continuing care needs from hospital to home. The study has a phenomenological hermeneutic design. Individual, narrative interviews were conducted, and the data analysis was conducted in accordance with Lindseth and Norberg's phenomenological hermeneutic method. Two themes and four subthemes were identified and formulated. The first theme: "Balancing vulnerability and strength," encompassed the subthemes "enduring emotional stress" and "striving to maintain security and continuity." The second theme: "Coping with an altered everyday life," encompassed "dealing with changes" and "being in readiness." Our findings suggest that the next of kin in striving to maintain continuity and safety in the older person's transition process are both vulnerable individuals and significant agents. Thus, it is urgent that health care providers accommodate both their vulnerability and their abilities to act, and thereby make them feel valued as respected agents and human beings in the transition process. PMID- 25746044 TI - The adhesion- and degranulation-promoting adaptor protein and its role in the modulation of experimental autoimmune encephalomyelitis. AB - Adaptor proteins mediate protein-protein interactions in signal transduction cascades. These signaling molecules are organized in multimolecular complexes that translate information from cell surface receptors into cellular responses. The cytosolic adhesion- and degranulation-promoting adaptor protein (ADAP) is expressed in T cells, natural killer cells, myeloid cells, and platelets. Here we summarize the data about the function of ADAP in these cells with respect to their contribution to the pathogenesis of experimental autoimmune encephalomyelitis. We discuss possible mechanisms of strongly attenuated experimental autoimmune encephalomyelitis in ADAP-deficient mice. PMID- 25746045 TI - The ezrin-radixin-moesin family of proteins in the regulation of B-cell immune response. AB - Dynamic reorganization of the cortical cytoskeleton is essential for numerous cellular processes, including B- and T-cell activation and migration. The ezrin radixin-moesin (ERM) family of proteins plays structural and regulatory roles in the rearrangement of plasma membrane flexibility and protrusions through its members' reversible interaction with cortical actin filaments and the plasma membrane. Recent studies demonstrated that ERM proteins not only are involved in cytoskeletal organization but also offer a platform for the transmission of signals in response to a variety of extracellular stimuli through their ability to cross-link transmembrane receptors with downstream signaling components. In this review, we summarize present knowledge relating to ERMs and recent progress made toward elucidating a novel role for them in the regulation of B-cell function in health and disease. PMID- 25746046 TI - Orchestration of invariant natural killer T cell development by E and Id proteins. AB - Natural killer T (NKT) cells are alphabeta T cells that express a semi-invariant T-cell receptor (TCR) along with natural killer (NK) cell markers and have an innate cell-like ability to produce a myriad of cytokines very quickly upon antigen exposure and subsequent activation. These cells are diverted from conventional single positive (SP) T-cell fate at the double positive (DP) stage, where TCR-mediated recognition of a lipid antigen presented on a CD1d molecule promotes their selection into the NKT lineage. Although many key regulatory molecules have been shown to play important roles in the development of NKT cells, the mechanism of lineage specification and acquisition of effector functions in these cells still remain to be fully addressed. In this review, we specifically discuss the role of a family of class-I helix-loop-helix proteins known as E proteins, and their antagonists Id proteins in NKT celldevelopment. Recent work has shown that these proteins play key roles in invariant NKT (iNKT) development, from the invariant TCR rearrangement to terminal differentiation and maturation. Elucidating these roles provides an opportunity to uncover the transcriptional network that separates NKT cells from concurrently developed conventional alphabeta T cells. PMID- 25746047 TI - Interleukin 35-Producing B Cells (i35-Breg): A New Mediator of Regulatory B-Cell Functions in CNS Autoimmune Diseases. AB - Neuroinflammation contributes to neuronal deficits in neurodegenerative CNS (central nervous system) autoimmune diseases, such as multiple sclerosis and uveitis. The major goal of most treatment modalities for CNS autoimmune diseases is to limit inflammatory responses in the CNS; immune-suppressive drugs are the therapy of choice. However, lifelong immunosuppression increases the occurrence of infections, nephrotoxicity, malignancies, cataractogenesis, and glaucoma, which can greatly impair quality of life for the patient. Biologics that target pathogenic T cells is an alternative approach that is gaining wide acceptance as indicated by the popularity of a variety of Food and Drug Administration (FDA) approved anti-inflammatory compounds and humanized antibodies such as Zenapax, Etanercept, Remicade, anti-ICAM, rapamycin, or tacrolimus. B cells are also potential therapeutic targets because they provide costimulatory signals that activate pathogenic T cells and secrete cytokines that promote autoimmune pathology. B cells also produce autoreactive antibodies implicated in several organ-specific and systemic autoimmune diseases including lupus erythematosus, Graves' disease, and Hashimoto's thyroiditis. On the other hand, recent studies have led to the discovery of several regulatory B-cell (Breg) populations that suppress immune responses and autoimmune diseases. In this review, we present a brief overview of Breg phenotypes and in particular, the newly discovered IL35 producing regulatory B cell (i35-Breg). We discuss the critical roles played by i35-Bregs in regulating autoimmune diseases and the potential use of adoptive Breg therapy in CNS autoimmune diseases. PMID- 25746048 TI - CD28-CD80/86 and CD40-CD40L Interactions Promote Thymic Tolerance by Regulating Medullary Epithelial Cell and Thymocyte Development. AB - Development and central tolerance of T lymphocytes in the thymus requires both TCR signals and collaboration with signals generated through costimulatory molecule interactions. In this review, we discuss the importance of CD28-CD80/86 and CD40-CD40L costimulatory interactions in promoting normal thymic development. This discussion includes roles in the generation of a normal thymic medulla, in the development of specific T-cells subsets, including iNKT and T regulatory cells, and in the generation of a tolerant mature T-cell repertoire. We discuss recent contributions to the understanding of CD28-CD80/86 and CD40-CD40L costimulatory interactions in thymic development, and we highlight the ways in which the many important roles mediated by these interactions collaborate to promote normal thymic development. PMID- 25746050 TI - Introduction to the special section. PMID- 25746051 TI - Practical strategies for effective lectures. AB - Lecturing is an essential teaching skill for scientists and health care professionals in pulmonary, critical care, and sleep medicine. However, few medical or scientific educators have received training in contemporary techniques or technology for large audience presentation. Interactive lecturing outperforms traditional, passive-style lecturing in educational outcomes, and is being increasingly incorporated into large group presentations. Evidence-based techniques range from the very simple, such as inserting pauses for audience discussion, to more technologically advanced approaches such as electronic audience response systems. Alternative software platforms such as Prezi can overcome some of the visual limits that the ubiquitous PowerPoint imposes on complex scientific narratives, and newer technology formats can help foster the interactive learning environment. Regardless of the technology, adherence to good principles of instructional design, multimedia learning, visualization of quantitative data, and informational public speaking can improve any lecture. The storyline must be clear, logical, and simplified compared with how it might be prepared for scientific publication. Succinct outline and summary slides can provide a roadmap for the audience. Changes of pace, and summaries or other cognitive breaks inserted every 15-20 minutes can renew attention. Graphics that emphasize clear, digestible data graphs or images over tables, and simple, focused tables over text slides, are more readily absorbed. Text slides should minimize words, using simple fonts in colors that contrast to a plain background. Adherence to these well-established principles and addition of some new approaches and technologies will yield an engaging lecture worth attending. PMID- 25746052 TI - Therapeutic Effect of Cereal Grains: A Review. AB - Over the last few decades, life style changes have resulted in drastic increase in the incidence of diabetes all over the world, especially in the developing countries. Oral hypoglycemic agents and insulin form the main stay in controlling diabetes but they have prominent side effects and fail to significantly alter the course of diabetic complications. Appropriate diet and exercise programs that form a part of lifestyle modifications have proven to be greatly effective in the management of this disease. Dietary therapy is showing a bright future in the prevention and treatment of diabetes. Cereal grains which form the staple diet for humans in most of the countries are increasingly being used to treat diabetes and other associated disorders in view of their anti-diabetic and anti-lipidemic potential. Given this background, this paper reviews the possible mechanisms of lowering blood sugar and cholesterol levels possessed by various commonly consumed cereal grains. It is concluded that cereal grains are not only the potential sources of energy but also possess the therapeutic role in preventing metabolic disorders and decreasing the risk factors for cardiovascular and renal diseases. PMID- 25746049 TI - Maternal PUFA status and offspring allergic diseases up to the age of 18 months. AB - Studies have suggested that maternal PUFA status during pregnancy may influence early childhood allergic diseases, although findings are inconsistent. We examined the relationship between maternal PUFA status and risk of allergic diseases in early childhood in an Asian cohort. Maternal plasma samples from the Growing Up in Singapore Towards Healthy Outcomes mother-offspring cohort were assayed at 26-28 weeks of gestation for relative abundance of PUFA. Offspring (n 960) were followed up from 3 weeks to 18 months of age, and clinical outcomes of potential allergic diseases (rhinitis, eczema and wheezing) were assessed by repeated questionnaires. Skin prick testing (SPT) was also performed at the age of 18 months. Any allergic disease with positive SPT was defined as having any one of the clinical outcomes plus a positive SPT. The prevalence of a positive SPT, rhinitis, eczema, wheezing and any allergic disease with positive SPT was 14.1 % (103/728), 26.5 % (214/808), 17.6 % (147/833), 10.9 % (94/859) and 9.4 % (62/657), respectively. After adjustment for confounders, maternal total n-3, n-6 PUFA status and the n-6:n-3 PUFA ratio were not significantly associated with offspring rhinitis, eczema, wheezing, a positive SPT and having any allergic disease with positive SPT in the offspring (P>0.01 for all). A weak trend of higher maternal n-3 PUFA being associated with higher risk of allergic diseases with positive SPT in offspring was observed. These findings do not support the hypothesis that the risk of early childhood allergic diseases is modified by variation in maternal n-3 and n-6 PUFA status during pregnancy in an Asian population. PMID- 25746053 TI - Letter to the Editor on: The RV144 vaccine regimen was not associated with enhancement of infection. PMID- 25746054 TI - Pyrazinamide: the importance of uncovering the mechanisms of action in mycobacteria. AB - Pyrazinamide (PZA) is still one of the key drugs used in current therapeutic regimens for tuberculosis (TB). Despite its importance for TB therapy, the mode of action of PZA remains unknown. PZA has to be converted to its active form pyrazinoic acid (POA) by the nicotinamidase PncA and is then excreted by an unknown efflux pump. At acidic conditions, POA is protonated to HPOA and is reabsorbed into the cell where it causes cellular damage. For a long time, it has been thought that PZA/POA has no defined target of action, but recent studies have shown that both PZA and POA have several different targets interfering with diverse biochemical pathways, especially in the NAD(+) and energy metabolism. PZA resistance seems to depend not only on a defective pyrazinamidase but is also rather a result of the interplay of many different enzyme targets and transport mechanisms. PMID- 25746055 TI - Topiramate for weight loss in two young adult women with autism spectrum disorder. PMID- 25746056 TI - Continuous Noninvasive Hemoglobin Monitoring: A Measured Response to a Critical Review. PMID- 25746057 TI - The effect of sevoflurane on interventions for blood loss during dilation and evacuation procedures at 18-24 weeks of gestation: a randomized controlled trial. AB - OBJECTIVE: The objective was to evaluate whether the use of sevoflurane during general anesthesia for dilation and evacuation (D&E) procedures increases the frequency of interventions to treat excess bleeding. STUDY DESIGN: A randomized, double-blinded, placebo-controlled trial of a standardized general anesthesia protocol with or without inhaled sevoflurane for D&Es between 18 and 24 weeks' gestation was performed. The primary outcome was need for any intervention to treat blood loss. Secondary outcomes included measured blood loss, procedure time, complications, side effects, patient satisfaction and provider ease of procedure. RESULTS: One hundred sixty subjects were randomized. Those in the sevoflurane group were slightly more likely to have interventions for bleeding as compared to those subjects who did not receive sevoflurane (25% versus 16.3%, p=.17) or a measured blood loss above 300 mL (15% versus 7.5%, p=.13); however, these differences could have arisen by chance. Most cases of excess bleeding required only minor interventions, including uterine massage and/or uterotonic agents. Procedure time, complications, side effects, satisfaction and ease of procedure were similar between groups. CONCLUSION: Addition of sevoflurane to general anesthesia during a D&E between 18 and 24 weeks' gestation did not increase the risk of intervention for bleeding; however, this study was underpowered to detect clinically important differences. IMPLICATIONS: In this randomized, double-blinded, placebo-controlled trial, sevoflurane did not significantly increase the risk of intervention for bleeding during D&Es. However, this agent should be used with caution as an anesthetic for surgical abortions. PMID- 25746058 TI - Towards the development of a longer-acting injectable contraceptive: past research and current trends. AB - OBJECTIVES: A longer-acting injectable contraceptive that lasts for 6 months would be a valuable addition to the contraceptive method mix and ideal for women who are interested in spacing births and/or uncertain about their future reproductive plans. Here we review past applications of drug delivery technologies to injectable contraceptives as well as recent advancements in sustained drug delivery technologies that hold promise for the development of a new longer-acting injectable contraceptive product. STUDY DESIGN: A global landscape analysis was conducted, promising sustained drug delivery technologies, and research opportunities and partnerships were established with experts in the fields of contraception and drug delivery to identify new approaches in developing a longer-acting injectable contraceptive product. RESULTS: The landscape analysis confirmed that a number of existing polymer systems, such as poly-lactic-co-glycolic acid and poly(epsilon-caprolactone), remain promising candidates for application to a longer-acting injectable product. Novel polymers and materials also hold promise for achieving longer release profiles and/or having other advantages over existing polymer systems, but products using these materials could potentially have longer roads to regulatory approval. Additionally, recent advancements in the manufacturing process of microspheres may benefit the development of a longer-acting injectable contraceptive. CONCLUSION: The design of any new injectable product must take into account the limitations of current injectable contraceptives and address concerns that women may have for a longer-acting product. FHI 360 is supporting several research collaborations for proof of concept of various drug delivery approaches for achieving longer-acting product that fits an established target product profile. PMID- 25746059 TI - Massive glutamine cyclization to pyroglutamic acid in human serum discovered using NMR spectroscopy. AB - Glutamine is one of the most abundant metabolites in blood and is a precursor as well as end product central to numerous important metabolic pathways. A number of surprising and unexpected roles for glutamine, including cancer cell glutamine addiction discovered recently, stress the importance of accurate analysis of glutamine concentrations for understanding its role in health and numerous diseases. Utilizing a recently developed NMR approach that offers access to an unprecedented number of quantifiable blood metabolites, we have identified a surprising glutamine cyclization to pyroglutamic acid that occurs during protein removal. Intact, ultrafiltered and protein precipitated samples from the same pool of human serum were comprehensively investigated using (1)H NMR spectroscopy at 800 MHz to detect and quantitatively evaluate the phenomenon. Interestingly, although glutamine cyclization occurs in both ultrafiltered and protein precipitated serum, the cyclization was not detected in intact serum. Strikingly, due to cyclization, the apparent serum glutamine level drops by up to 75% and, concomitantly, the pyroglutamic acid level increases proportionately. Further, virtually under identical conditions, the magnitude of cyclization is vastly different for different portions of samples from the same pool of human serum. However, the sum of glutamine and pyroglutamic acid concentrations in each sample remains the same for all portions. These unexpected findings indicate the importance of considering the sum of apparent glutamine and pyroglutamic acid levels, obtained from the contemporary analytical methods, as the actual blood glutamine level for biomarker discovery and biological interpretations. PMID- 25746060 TI - Exo-selective reductive macrocyclization of ynals. AB - A general protocol for the highly exo-selective macrocyclization of ynals using a nickel/N-heterocyclic carbene catalyst system has been developed. A series of 10- to 21-membered macrocycles bearing an exomethylene substituent was synthesized in good yields with excellent regioselectivity (exo/endo >95:5). Very high levels of long-range diastereocontrol can also be achieved for some classes of macrocycles. Complementary to previously reported endo-selective macrocyclizations, this method provides accesses to exoalkylidene macrocycles from simple ynals in high selectivity. PMID- 25746061 TI - Chemical composition of defatted strawberry and raspberry seeds and the effect of these dietary ingredients on polyphenol metabolites, intestinal function, and selected serum parameters in rats. AB - Strawberry and raspberry seeds were chemically analyzed and added as dietary ingredients to investigate the physiological response of rats. In both cases the main component was dietary fiber and the main polyphenols were ellagitannins (ET). The strawberry ET were mainly constituted by monomers and a dimer, agrimoniin, whereas raspberry ET were mainly constituted by a dimer, sanguiin-H 6, and a trimer, lambertianin-C. The lower content and the less polymerized structure of strawberry ET resulted in a higher cecal metabolites concentration (mainly nasutin and urolithin-A) in comparison to rats fed diet containing raspberry seeds. Dietary raspberry seeds, a source of dietary fiber, despite being richer in polyphenol compounds, were better utilized in fermentation processes, resulting in enhanced production of short-chain fatty acids. As opposed to strawberry seeds, the treatment with raspberry seeds beneficially improved the atherogenic index of a diet, mainly due to reduced triacylglycerol concentration in the serum. PMID- 25746063 TI - Spontaneous Decisions and Free Will: Empirical Results and Philosophical Considerations. AB - Spontaneous actions are preceded by brain signals that may sometimes be detected hundreds of milliseconds in advance of a subject's conscious intention to act. These signals have been claimed to reflect prior unconscious decisions, raising doubts about the causal role of conscious will. Murakami et al. (2014. Nat Neurosci 17: 1574-1582) have recently argued for a different interpretation. During a task in which rats spontaneously decided when to abort waiting, the authors recorded neurons in the secondary motor cortex. The neural activity and relationship to action timing was parsimoniously explained using an integration to-bound model, similar to those widely used to account for evidence-based decisions. In this model, the brain accumulates spontaneously occurring inputs voting for or against an action, but only commits to act once a certain threshold is crossed. The model explains how spontaneous decisions can be forecast (partially predicted) by neurons that reflect either the input or output of the integrator. It therefore presents an explicit hypothesis capable of rejecting the claim that such predictive signals imply unconscious decisions. We suggest that these results can inform the current debate on free will but must be considered with caution. PMID- 25746064 TI - Characterization of Airborne Nanoparticle Loss in Sampling Tubing. AB - Airborne nanoparticle release has been studied extensively lately using a variety of instruments and nanoparticle loss data for the instrument sampling tubes were required. This study used real-time measurements to characterize particle losses. Particle concentrations were measured by Fast Mobility Particle Sizer (FMPS). Electrically conductive and Tygon sampling tubes 7.7 mm I.D. and 2.0, 4.9, 7.0, and 8.4 m long, were used to analyze particle losses. Two different sources of nearly steady-state particles-atmospheric nanoparticles (maximum concentration of 4,000-6,000 particle/cm(3)) and nebulizer-generated salt aerosols (maximum concentration of 14,000-16,000 particle/cm(3))-were utilized. For all test conditions, a reduction in particle number concentration was observed and found to be proportional to tube length for particle diameter (dp) less than 40 nm. A maximum loss up to 30% was found for the longest tube length (8.4 m) at particle size of approximately 8 nm. For particles from 40 to 400 nm, the losses were less than 3%. Measured particle losses were greater than predicted by theory for the smallest particles. The two types of tubing showed similar particle losses for both test aerosols. Particle losses were low for dp greater than 40 nm, and for all particle sizes when the tube length was less than 2 m. PMID- 25746062 TI - Cognitive Skills Needed for Social Hierarchies. AB - Dominance hierarchies are ubiquitous in social species that require social cognition to maintain. Status may be established initially through physical conflict but is maintained by social signals between individuals that depend critically on the relative social status of those interacting. How do individuals collect information they need to modulate their behavior? Using a particularly suitable fish model system living in a complex social environment, we describe how the social context of behavior shapes the brain and, in turn, alters the behavior of animals as they interact. These fish observe social interactions carefully to gather information vicariously that guides future behavior. Social opportunities produce rapid changes in gene expression in key brain nuclei, and both social success and failure produce changes in neuronal cell size and connectivity in reproductive centers of the brain. It remains unknown how social information is transduced into cellular and molecular changes. Understanding the cellular and molecular changes underlying animal cognition will yield unique insights into how the brain works. PMID- 25746066 TI - Raspberrylike SiO2@reduced graphene oxide@AgNP composite microspheres with high aqueous dispersity and excellent catalytic activity. AB - The hybridizations of functional microspheres with graphene or graphene oxide (GO) sheets often suffer from severe agglomeration behaviors, leading to poor water dispersity of the resultant composite materials. Here, we first demonstrate that the sonication-assisted self-assembly of tiny GO sheets (whose lateral size less than 200 nm) on microspheric substrates like cationic polyelectrolyte modified SiO2 microspheres could effectively overcome such a common drawback. On the basis of this facile strategy, we further developed reduced graphene oxide/silver nanoparticle composite film wrapped SiO2 microspheres, which not only possessed unique raspberrylike structure and high aqueous dispersity but also exhibited exceptional catalytic activity toward the reduction of 4 nitrophenol. PMID- 25746065 TI - Risk-benefit considerations when prescribing phosphodiesterase-5 inhibitors in children. AB - INTRODUCTION: Sildenafil (Revatio(r)) and tadalafil (Adcirca(r)) are specific inhibitors of the phosphodiesterase-5 enzyme and produce pulmonary vasodilation by inhibiting the breakdown of cyclic guanosine monophosphate (cGMP) in the walls of pulmonary arterioles. AREAS COVERED: We focus on the efficacy and safety of sildenafil and tadalafil in the treatment of pulmonary hypertension (PH) in children through a PubMed literature search. EXPERT OPINION: Although used since 1999 in the treatment of PH in children, it is only in the past few years that robust evidence for the use of sildenafil has emerged principally in the pivotal STARTS-1 study. The open-label extension of this study, STARTS-2, has revealed safety concerns substantiated by FDA post marketing surveillance leading to recommendations to use lower doses. More recently, tadalafil has been introduced allowing once daily dosing with apparently similar efficacy to sildenafil in children. Recently there have been suggestions that sildenafil and tadalafil may have a place in treating muscular dystrophy. PMID- 25746067 TI - Palladium nanoparticle-based surface acoustic wave hydrogen sensor. AB - Palladium (Pd) nanoparticles (5-20 nm) are used as the sensing layer on surface acoustic wave (SAW) devices for detecting H2. The interaction with hydrogen modifies the conductivity of the Pd nanoparticle film, producing measurable changes in acoustic wave propagation, which allows for the detection of this explosive gas. The nanoparticle-based SAW sensor responds rapidly and reversibly at room temperature. PMID- 25746068 TI - Odds ratio vs risk ratio in randomized controlled trials. AB - OBJECTIVE: Use of odds ratio (OR) in randomized controlled trials (RCTs) has been criticized because it overestimates the effect size, if incorrectly interpreted as risk ratio (RR). To what extent does this make a difference in the context of clinical research is unclear. We, therefore, aimed to address this issue considering its importance in evidence-based practice of medicine. METHODS: We reviewed 580 RCTs published in the New England Journal of Medicine between January 2004 and June 2014 and identified 107 RCTs that reported unadjusted RR (n = 76) or OR (n = 31) for the primary outcome. For studies reporting ORs, we calculated RRs, and vice versa, using Stata software. The percentage of divergence between the reported and calculated effect size estimates was analyzed. RESULTS: None of the RCTs showed a statistically significant result becoming insignificant or vice versa depending on the effect size estimate. OR exaggerated the RR in 62% of the RCTs. The percentage of overestimation was > 50% in 28 RCTs and > 100% in 13 RCTs. The degree of overestimation was positively correlated with the prevalence of outcomes (spearman's rho = 0.84 and 0.66, p < 0.001). CONCLUSION: Use of OR instead of RR in RCTs does not change the qualitative inference of results. However, the use of OR can markedly exaggerate the effect size in RCTs if misinterpreted as RR and, hence, has the potential to mislead clinicians. PMID- 25746069 TI - [A case of cryptococcal ventriculitis with slowly progressive gait disturbance and memory impairment as initial symptoms]. AB - A 54-year-old man was admitted due to progressive gait disturbance and cognitive impairment. On MRI, a hyperintense region was observed in the periventricular white matter on FLAIR imaging, with Gd-enhancement in the choroid plexus and periventricular wall. Cerebrospinal fluid (CSF) examination showed marked abnormalities including a high white blood cell count (WBC, 360 cells/mm(3). 83% lymphocytes), an elevated protein level (1,416 mg/dl), a low glucose level (12 mg/dl), and elevated cryptococcal antigen with positive Indian ink staining. Cryptococcal ventriculitis was diagnosed. The patient was initially treated with liposomal amphotericin B, fluconazole, voriconazole, and flucytosine for 38 weeks, followed by administration of itraconazole and fluconazole with some improvement. The brain MRI after one month showed septum formation in the posterior horn, which was suggestive of ventriculitis. Although ventriculitis is rare, we should pay attention to the presence of ventriculitis due to cryptococcal infection in the central nervous system. PMID- 25746070 TI - [A case of left hemifacial metamorphopsia by a right retrosplenial infarction]. AB - We report a 70-year-old women with left hemifacial metamorphopsia due to an infarction in the right retrosplenial region. She firstly noticed that the left half of her face reflected in the mirror was distorted. She complained of the same kind of distortion when she looked at the face of humans. Neurological examination on admission showed no other symptoms. Her visual acuity and visual field were normal. Diffusion weighted images of the brain revealed a high intense lesion in the right retrosplenial region, which was considered to account for her symptom. This case contributes to clarify the pathogenesis of hemifacial metamorphopsia. PMID- 25746071 TI - [A case of neurologic muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome with a novel mitochondrial mutation m.8729 G>A]. AB - We report a patient having classical clinical feature of neurologic muscle weakness, ataxia, and retinitis pigmentosa (NARP) and a novel mutation, m.8729 G>A in mitochondria DNA. The patient was referred to our hospital because of progressive ataxia in her limbs and trunk. She had a history of incapability of running long distances from childhood. Neurological examination revealed cerebellar ataxia, distal dominant muscle weakness in the limbs, hyporeflexia, hypoesthesia, myoclonus, sensorineural deafness, and retinitis pigmentosa. Magnetic resonance imaging (MRI) showed atrophy of brain stem and cerebellum as well as calcification of basal ganglia. In both serum and cerebrospinal fluid, lactate and pyruvate levels were elevated. Histological examination of biopsied muscle revealed chronic neurogenic changes without ragged red fibers. Genetic analysis of mitochondrial DNA (mtDNA) of the muscle revealed a heteroplasmic mutation, m.8729 G>A. Chemical analysis of the respiratory chain complexes in her muscle specimen demonstrated lower activities of complexes I and V. In our case, novel mutation of m.8729 G>A in mtDNA was indicated as the cause of NARP syndrome. PMID- 25746072 TI - [A case of an anti-Ma2 antibody-positive patient presenting with variable CNS symptoms mimicking multiple system atrophy with a partial response to immunotherapy]. AB - A 70-year-old man with a 5-month history of progressive bradykinesia of the bilateral lower extremities was admitted to our hospital. At the age of 64, he underwent proximal gastrectomy for gastric cancer. He also had a history of subacute combined degeneration of the spinal cord since the age of 67, which was successfully treated with vitamin B12 therapy. Four weeks before admission to our hospital, he admitted himself to his former hospital complaining of walking difficulty. Two weeks later, however, his symptoms progressed rapidly; he was immobilized for two weeks and did not respond to the vitamin therapy. On admission to our hospital, he showed moderate paralysis of the lower extremities, cog-wheel rigidity of the four extremities, and dystonic posture of his left hand. He also showed orthostatic hypotension and vesicorectal disorders. Blood examination and cerebrospinal fluid analysis revealed no remarkable abnormalities. Electroencephalography showed frontal dominant, high voltage, sharp waves. His brain and spinal MRI revealed no notable abnormalities. We suspected autoimmune disease and commenced one course of intravenous methylprednisolone therapy, resulting in improvement of the parkinsonism and orthostatic hypotension. Based on these results, we investigated possible neural antigens and detected anti-Ma2 antibody. In addition to limbic encephalitis, anti Ma2 antibody-positive neural disorders are characterized by rapid eye movement sleep behavior disorders or parkinsonism. Here, we report an anti-Ma2 antibody positive patient presenting variable CNS symptoms mimicking multiple system atrophy, who responded to immunotherapy. PMID- 25746073 TI - [A case of intravascular large B-cell lymphoma that presented with recurrent multiple cerebral infarctions and followed an indolent course]. AB - A 66-year-old woman presented with vertigo and deafness. Diffusion-weighted magnetic resonance imaging of the head showed multiple cerebral infarctions involving several blood vessel regions. A diagnosis of cardiogenic embolism was made, and anticoagulation therapy was begun. The woman had no additional symptoms until suddenly developing left hemiparesis one year later. She was again found to have multiple cerebral infarctions. The hemiparesis gradually improved, but ataxic gait and apraxia appeared and progressed over two weeks. Holter ECG, carotid ultrasound, and transthoracic/transesophageal echocardiography revealed no evidence of cardiogenic embolism. However, serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL2R) levels were elevated (LDH, 782 IU/l; sIL2R, 1,396 IU/ml), which suggested malignant lymphoma. Contrast chest/abdominal CT scan and gallium-67 scintigraphy revealed no evident lesions; however, random skin biopsy and open brain biopsy showed that blood vessels were infiltrated by CD20-positive atypical lymphocytes. These findings were consistent with intravascular large B-cell lymphoma. This type of lymphoma is known as a rapidly progressive disease with poor prognosis, but this case followed an indolent course, with a one-year interruption in disease progression. PMID- 25746074 TI - [Medial longitudinal fasciculus (MLF) syndrome in a patient with giant cell arteritis]. AB - A 76-year-old female was referred to our department because of diplopia for two months and intermittent claudication for five months. She showed medial longitudinal fasciculus (MLF) syndrome. Brain MRI (T2WI) showed multiple infarctions in the right pontine tegmentum and left paramedian midbrain. A biopsy of superficial temporal artery showed the characteristic findings of glanulomatous inflammation indicative of giant cell arteritis. We thought the mechanism of this cerebral infarction as artery to artery embolization or intracranial arteritis. Treatment with oral prednisolone (1 mg/kg/day) improved her limb claudication and normalized serum C-reactive protein level. PMID- 25746075 TI - [A case of progressive encephalomyelitis with rigidity and myoclonus associated with anti-GAD, anti-glycine receptor and anti-GM1 antibodies]. AB - A 62-year-old woman with one-year history of type 1 diabetes mellitus was admitted to our hospital with progressive weakness in the lower extremities and urinary dysfunction following high fever. On admission, she had rigidity and myoclonus in the upper extremities with sensory ataxia. Cerebrospinal fluid examination revealed mild pleocytosis and oligoclonal band. Glutamic acid decarboxylase (GAD) antibodies were detected at high titer in serum, but antibodies to glycine receptor (GlyR), thyroid peroxidase, mitochondrial M2, and GM1 were also detected. She was diagnosed with progressive encephalomyelitis with rigidity and myoclonus (PERM), which probably developed on the basis of polyglandular autoimmune syndromes. The clinical symptoms began to improve after initiation of intravenous high-dose methylprednisolone. Muscle weakness might be related to GM1 antibodies. This is the first report of PERM, in which GM1 antibodies were detected with GAD and GlyR antibodies. PMID- 25746076 TI - [A case of acute progressive myelopathy due to intravascular large B cell lymphoma diagnosed with only random skin biopsy]. AB - A 64-year old woman was admitted to our hospital with subacute onset paraparesis and sensory disturbance at a level below Th10. Spinal MRI showed a T2 weighted high-signal intensity lesion at a level from Th5 to Th12, and an abdominal CT showed a mass in the left kidney. Her paraparesis deteriorated rapidly, and administration of high dose methyl prednisolone followed by oral steroid therapy was started before obtaining of a definitive diagnosis. However her symptoms did not improve after the beginning of treatment. At the same time, a bone marrow puncture, and biopsies from kidney and spinal cord were performed. These biopsies demonstrated no clues, diagnostically. Therefore a random skin biopsy was performed at the five sites on the 17th day after the steroid dosage end. From this, pathological evidence of intravascular large B cell lymphoma (IVLBCL) was shown. For rapid diagnosis of acute myelopathy with mass lesion of another organ due to IVLBCL, a biopsy is taken not only from spinal cord or mass lesions, but is also taken of multiple sites in skin randomly. This must be performed without a delay before a sudden deterioration of neurologic symptoms can occur from ischemic events not responsive to steroid therapy. PMID- 25746077 TI - [Pneumococcal meningitis with accompanying severe hearing loss: 3D-FLAIR imaging of the inner ear and treatment]. AB - A 66-year-old man was admitted to our hospital because of unconsciousness. He was diagnosed with pneumococcal meningitis and treated with a combination of antibiotics (meropenem hydrate), dexamethasone, and intravenous immunoglobulin. Although he gradually regained consciousness, he started showing signs of hearing disturbance. Measurement of auditory brainstem response revealed severe sensorineural hearing loss. The patient then underwent three-dimensional fluid attenuated inversion recovery magnetic resonance imaging, which revealed increased signals in the cochlea and the vestibuum, and their enhancement after gadolinium administration. This enhancement was still observed on images of the inner ear acquired on the 52nd hospital day. These findings suggested that the change of content in the lymph and the damage to the blood-labyrinth barrier was caused and aggravated by an immune response. Recent studies have shown that an MyD88-dependent immune response contributes to hearing loss in an experimental mouse model of pneumococcal meningitis. The patient was administered steroid pulse and hyperbaric oxygen therapies for improving the hearing deficit, but these therapies were discontinued because of the aggravation of hepatitis B and diabetes mellitus, which he had developed previously. PMID- 25746078 TI - [A case of tuberculous meningitis complicated with multiple drug hypersensitivity to antituberculosis agents]. AB - Multiple drug hypersensitivity (MDH) is an allergy to two or more chemically unrelated drugs. We present a case of MDH caused by antituberculosis agents during the treatment of tuberculous meningitis (TBM). A 64-year-old man without a history of drug allergy developed fever and severe headache. Examination of cerebrospinal fluid showed lymphocytosis, a low glucose level, and a high ADA activity, suggestive of TBM. The patient was treated with isoniazid, rifampicin, pyrazinamide, and ethambutol, and his symptoms resolved quickly. However, 20 days after the initiation of therapy, he developed remittent fever without mucocutaneous lesions. A drug-induced lymphocyte stimulation test was positive for isoniazid, rifampicin, and pyrazinamide, which was consistent with a diagnosis of MDH. All the antituberculosis drugs were replaced with levofloxacin and ethionamide, both of which have excellent cerebrospinal fluid penetration, and the fever subsided. The patient made a full recovery from TBM. Because standard antituberculosis regimens include three or four antituberculosis drugs, it is difficult to determine the culprit drug when hypersensitivity occurs. Moreover, there can be multiple causative drugs as illustrated by the present case. During a time-consuming desensitization therapy, TBM could flare up, leading to permanent neurological damage. Thus, treatment with suitable alternative drugs should be started immediately. PMID- 25746085 TI - Comparison of hematite-facilitated anaerobic digestion of acetate and beef extract. AB - The effect of hematite with different specific surface areas (SSA) on anaerobic methanogenic process was investigated in this study using two different carbon sources (acetate or beef extract). Comparative analyses showed that methane generation rate, microbial growth and the starting-up duration were all significantly enhanced by hematite. The reduction rate of high SSA hematite was 2.5-3.5 times greater than that of low SSA hematite. This work indicated that low SSA hematite was superior to high SSA hematite in facilitating methanogenesis which was partially attributed to the lower affinity for the iron-reduction bacteria. PMID- 25746084 TI - Treatment with anti-interleukin-6 receptor antibody ameliorates intestinal polyposis in Apc(Min/+) mice under high-fat diet conditions. AB - The prevalence of colorectal malignancies is increasing in the world. The parallel increase of metabolic syndrome gives a speculation between these two conditions, although the precise mechanism is still unclear. Interleukin-6 (IL-6) is a cytokine known to correlate with obesity and serve as a proinflammatory adipokine. In the present study, we investigated the effect of IL-6 signaling blockade on intestinal polyp formation in obesity using a mouse model of adenomatous polyposis coli (Apc). Male C57BL/6J-Apc(Min/+) mice were fed a high fat diet from 5 weeks of age, and the overweight mice thus obtained were given a weekly intraperitoneal injection of anti-mouse IL-6 receptor antibody (MR16-1) from 6 to 15 weeks of age, while control mice received IgG or phosphate-buffered saline (PBS). The total number of intestinal polyps was significantly decreased in the MR16-1-injected group (53.1 +/- 6.8) relative to the control groups (PBS injected, 81.3 +/- 6.1; rat IgG-injected, 74.7 +/- 4.8, p = 0.01), and in particular the number of polyps larger than 2 mm in diameter was markedly decreased. In addition, the mean diameter of polyps in the MR16-1-injected group was significantly smaller than that in the control groups. On the other hand, no significant differences in body weight, epididymal fat pad mass, or the plasma levels of glucose, insulin and triglyceride were observed among the three groups. Thus, treatment with anti-IL-6 receptor antibody suppressed polyp growth in obese Apc(Min/+) mice fed the high-fat diet. We suggest that IL-6 signaling may be responsible for the obesity-associated colorectal tumorigenesis. PMID- 25746086 TI - Training in self-needling and performing it as part of a clinical trial: the practitioner and patient experience. AB - OBJECTIVE: To explore the experience of training and performing self-needling from both the practitioners' and patients' perspective. METHODS: A qualitative study was conducted using focus groups and interviews, nested within our multi site randomised controlled trial, Acupuncture for Cancer-Related Fatigue in Patients with Breast Cancer. Patients allocated to self-needling across two UK study sites and all therapists who were involved in the trial were invited to participate. The interviews/focus groups were then transcribed verbatim and analysed thematically by the process of content analysis. RESULTS: Of the 67 eligible patients, 8 (12%) contributed to the focus groups and 15 practitioners (100%), contributed to the study by either attending a focus group or being interviewed. Themes identified for patients included: the allocation to self needling, teaching techniques and practical considerations and whether they would self-needle again. Themes identified for practitioners included: views on self needling, teaching self-needling and future implications of self-needling. CONCLUSIONS: Self-needling was found to be acceptable to, and manageable by, patients, and enthusiastically adopted by most practitioners. Methods of teaching self-needling need to be developed and evaluated with guidelines recommended for best practice. PMID- 25746087 TI - Knowledge, attitude and practice among Chinese acupuncturists receiving sham and/or placebo acupuncture: a cross-sectional survey. AB - BACKGROUND: Placebo and sham acupuncture are common control strategies in acupuncture studies. However, the perception and practice of these approaches in acupuncturists are poorly documented. OBJECTIVE: To investigate knowledge of, attitude towards and practice of sham and/or placebo acupuncture among Chinese acupuncturists. METHOD: A cross-sectional survey conducted in six different tertiary care hospitals of traditional Chinese medicine in Beijing, China. A total of 92 licensed acupuncturists were asked to complete a predesigned and structured questionnaire on-site. RESULTS: A response rate of 92.4% (n=85) was achieved. Almost all participants (99%, n=84) had moderate knowledge about sham and/or placebo acupuncture, but only a minority (27%, n=23) reported an excellent understanding. The general attitude towards sham and/or placebo acupuncture was positive. Most respondents (99%, n=84) thought such controls were necessary and the majority (81%, n=69) believed they were feasible in acupuncture research. More than two-thirds of participants (71%, n=60) had applied sham and/or placebo acupuncture, but only a few (8%, 5/60) used it as the most common control strategy in clinical trials. CONCLUSIONS: The result of our survey suggests that Chinese acupuncturists have a moderate knowledge of, and a positive attitude towards, sham and/or placebo acupuncture. Research into sham and/or placebo acupuncture is limited in comparison with other control strategies. Therefore, an in-service education programme for acupuncturists and standardisation of sham and/or placebo acupuncture need to be developed. PMID- 25746088 TI - Setting the stage: local delivery of cytoreductive agents for the treatment of glioblastoma. PMID- 25746089 TI - Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. AB - Gene therapy offers a multidimensional set of approaches intended to treat and cure glioblastoma (GBM), in combination with the existing standard-of-care treatment (surgery and chemoradiotherapy), by capitalizing on the ability to deliver genes directly to the site of neoplasia to yield antitumoral effects. Four types of gene therapy are currently being investigated for their potential use in treating GBM: (i) suicide gene therapy, which induces the localized generation of cytotoxic compounds; (ii) immunomodulatory gene therapy, which induces or augments an enhanced antitumoral immune response; (iii) tumor suppressor gene therapy, which induces apoptosis in cancer cells; and (iv) oncolytic virotherapy, which causes the lysis of tumor cells. The delivery of genes to the tumor site is made possible by means of viral and nonviral vectors for direct delivery of therapeutic gene(s), tumor-tropic cell carriers expressing therapeutic gene(s), and "intelligent" carriers designed to increase delivery, specificity, and tumoral toxicity against GBM. These vehicles are used to carry genetic material to the site of pathology, with the expectation that they can provide specific tropism to the desired site while limiting interaction with noncancerous tissue. Encouraging preclinical results using gene therapies for GBM have led to a series of human clinical trials. Although there is limited evidence of a therapeutic benefit to date, a number of clinical trials have convincingly established that different types of gene therapies delivered by various methods appear to be safe. Due to the flexibility of specialized carriers and genetic material, the technology for generating new and more effective therapies already exists. PMID- 25746090 TI - Convection-enhanced delivery for the treatment of glioblastoma. AB - Effective treatment of glioblastoma (GBM) remains a formidable challenge. Survival rates remain poor despite decades of clinical trials of conventional and novel, biologically targeted therapeutics. There is considerable evidence that most of these therapeutics do not reach their targets in the brain when administered via conventional routes (intravenous or oral). Hence, direct delivery of therapeutics to the brain and to brain tumors is an active area of investigation. One of these techniques, convection-enhanced delivery (CED), involves the implantation of catheters through which conventional and novel therapeutic formulations can be delivered using continuous, low-positive-pressure bulk flow. Investigation in preclinical and clinical settings has demonstrated that CED can produce effective delivery of therapeutics to substantial volumes of brain and brain tumor. However, limitations in catheter technology and imaging of delivery have prevented this technique from being reliable and reproducible, and the only completed phase III study in GBM did not show a survival benefit for patients treated with an investigational therapeutic delivered via CED. Further development of CED is ongoing, with novel catheter designs and imaging approaches that may allow CED to become a more effective therapeutic delivery technique. PMID- 25746092 TI - Human computer interactions in next-generation of aircraft smart navigation management systems: task analysis and architecture under an agent-oriented methodological approach. AB - The limited efficiency of current air traffic systems will require a next generation of Smart Air Traffic System (SATS) that relies on current technological advances. This challenge means a transition toward a new navigation and air-traffic procedures paradigm, where pilots and air traffic controllers perform and coordinate their activities according to new roles and technological supports. The design of new Human-Computer Interactions (HCI) for performing these activities is a key element of SATS. However efforts for developing such tools need to be inspired on a parallel characterization of hypothetical air traffic scenarios compatible with current ones. This paper is focused on airborne HCI into SATS where cockpit inputs came from aircraft navigation systems, surrounding traffic situation, controllers' indications, etc. So the HCI is intended to enhance situation awareness and decision-making through pilot cockpit. This work approach considers SATS as a system distributed on a large scale with uncertainty in a dynamic environment. Therefore, a multi-agent systems based approach is well suited for modeling such an environment. We demonstrate that current methodologies for designing multi-agent systems are a useful tool to characterize HCI. We specifically illustrate how the selected methodological approach provides enough guidelines to obtain a cockpit HCI design that complies with future SATS specifications. PMID- 25746091 TI - Polymeric drug delivery for the treatment of glioblastoma. AB - Glioblastoma (GBM) remains an almost universally fatal diagnosis. The current therapeutic mainstay consists of maximal safe surgical resection followed by radiation therapy (RT) with concomitant temozolomide (TMZ), followed by monthly TMZ (the "Stupp regimen"). Several chemotherapeutic agents have been shown to have modest efficacy in the treatment of high-grade glioma (HGG), but blood-brain barrier impermeability remains a major delivery obstacle. Polymeric drug-delivery systems, developed to allow controlled local release of biologically active substances for a variety of conditions, can achieve high local concentrations of active agents while limiting systemic toxicities. Polymerically delivered carmustine (BCNU) wafers, placed on the surface of the tumor-resection cavity, can potentially provide immediate chemotherapy to residual tumor cells during the standard delay between surgery and chemoradiotherapy. BCNU wafer implantation as monochemotherapy (with RT) in newly diagnosed HGG has been investigated in 2 phase III studies that reported significant increases in median overall survival. A number of studies have investigated the tumoricidal synergies of combination chemotherapy with BCNU wafers in newly diagnosed or recurrent HGG, and a primary research focus has been the integration of BCNU wafers into multimodality therapy with the standard Stupp regimen. Overall, the results of these studies have been encouraging in terms of safety and efficacy. However, the data must be qualified by the nature of the studies conducted. Currently, there are no phase III studies of BCNU wafers with the standard Stupp regimen. We review the rationale, biochemistry, pharmacokinetics, and research history (including toxicity profile) of this modality. PMID- 25746093 TI - Dynamic reconfiguration of security policies in wireless sensor networks. AB - Providing security and privacy to wireless sensor nodes (WSNs) is very challenging, due to the heterogeneity of sensor nodes and their limited capabilities in terms of energy, processing power and memory. The applications for these systems run in a myriad of sensors with different low-level programming abstractions, limited capabilities and different routing protocols. This means that applications for WSNs need mechanisms for self-adaptation and for self protection based on the dynamic adaptation of the algorithms used to provide security. Dynamic software product lines (DSPLs) allow managing both variability and dynamic software adaptation, so they can be considered a key technology in successfully developing self-protected WSN applications. In this paper, we propose a self-protection solution for WSNs based on the combination of the INTER TRUST security framework (a solution for the dynamic negotiation and deployment of security policies) and the FamiWare middleware (a DSPL approach to automatically configure and reconfigure instances of a middleware for WSNs).We evaluate our approach using a case study from the intelligent transportation system domain. PMID- 25746094 TI - A highly sensitive ELISA and immunochromatographic strip for the detection of Salmonella typhimurium in milk samples. AB - Murine monoclonal antibodies to target Salmonella typhimurium flagellin and lipopolysaccharide (LPS) were prepared and characterized. For the immunological detection of S. typhimurium, different pairs of monoclonal antibodies (MAbs) were tested in a sandwich enzyme linked immunosorbent assay (ELISA) format. After comparison, a sandwich ELISA and immunochromatographic strip based on LPS MAbs was established to detect S. typhimurium. The determination limits of the immunochromatographic strip in phosphate-buffered saline (PBS) containing 0.1% Tween 20 (PBST) and pure milk sample were found to be 1.25 * 10(5) colony-forming units (cfu)/mL and 1.25 * 10(6) cfu/mL S. typhimurium, respectively. Results can be obtained with the naked eye in 10 min. Cross-reactivity was observed with Salmonella paratyphi B, but not S. paratyphi A or Salmonella enteritidis. The LPS MAbs based immunochromatographic strip is rapid and convenient to detect S. typhimurium in milk samples. PMID- 25746095 TI - Magnetometer-augmented IMU simulator: in-depth elaboration. AB - The location of objects is a growing research topic due, for instance, to the expansion of civil drones or intelligent vehicles. This expansion was made possible through the development of microelectromechanical systems (MEMS), inexpensive and miniaturized inertial sensors. In this context, this article describes the development of a new simulator which generates sensor measurements, giving a specific input trajectory. This will allow the comparison of pose estimation algorithms. To develop this simulator, the measurement equations of every type of sensor have to be analytically determined. To achieve this objective, classical kinematic equations are used for the more common sensors, i.e., accelerometers and rate gyroscopes. As nowadays, the MEMS inertial measurement units (IMUs) are generally magnetometer-augmented, an absolute world magnetic model is implemented. After the determination of the perfect measurement (through the error-free sensor models), realistic error models are developed to simulate real IMU behavior. Finally, the developed simulator is subjected to different validation tests. PMID- 25746096 TI - Fast fingerprint database maintenance for indoor positioning based on UGV SLAM. AB - Indoor positioning technology has become more and more important in the last two decades. Utilizing Received Signal Strength Indicator (RSSI) fingerprints of Signals of OPportunity (SOP) is a promising alternative navigation solution. However, as the RSSIs vary during operation due to their physical nature and are easily affected by the environmental change, one challenge of the indoor fingerprinting method is maintaining the RSSI fingerprint database in a timely and effective manner. In this paper, a solution for rapidly updating the fingerprint database is presented, based on a self-developed Unmanned Ground Vehicles (UGV) platform NAVIS. Several SOP sensors were installed on NAVIS for collecting indoor fingerprint information, including a digital compass collecting magnetic field intensity, a light sensor collecting light intensity, and a smartphone which collects the access point number and RSSIs of the pre-installed WiFi network. The NAVIS platform generates a map of the indoor environment and collects the SOPs during processing of the mapping, and then the SOP fingerprint database is interpolated and updated in real time. Field tests were carried out to evaluate the effectiveness and efficiency of the proposed method. The results showed that the fingerprint databases can be quickly created and updated with a higher sampling frequency (5Hz) and denser reference points compared with traditional methods, and the indoor map can be generated without prior information. Moreover, environmental changes could also be detected quickly for fingerprint indoor positioning. PMID- 25746097 TI - Hydrodynamic voltammetry as a rapid and simple method for evaluating soil enzyme activities. AB - Soil enzymes play essential roles in catalyzing reactions necessary for nutrient cycling in the biosphere. They are also sensitive indicators of ecosystem stress, therefore their evaluation is very important in assessing soil health and quality. The standard soil enzyme assay method based on spectroscopic detection is a complicated operation that requires the removal of soil particles. The purpose of this study was to develop a new soil enzyme assay based on hydrodynamic electrochemical detection using a rotating disk electrode in a microliter droplet. The activities of enzymes were determined by measuring the electrochemical oxidation of p-aminophenol (PAP), following the enzymatic conversion of substrate-conjugated PAP. The calibration curves of beta galactosidase (beta-gal), beta-glucosidase (beta-glu) and acid phosphatase (AcP) showed good linear correlation after being spiked in soils using chronoamperometry. We also performed electrochemical detection using real soils. Hydrodynamic chronoamperometry can be used to assess the AcP in soils, with a detection time of only 90 s. Linear sweep voltammetry was used to measure the amount of PAP released from beta-gal and beta-glu by enzymatic reaction after 60 min. For the assessment of soil enzymes, the results of hydrodynamic voltammetry assay compared favorably to those using a standard assay procedure, but this new procedure is more user-friendly, rapid and simple. PMID- 25746098 TI - The use of a generalized reconstruction by inversion of coupled systems (GRICS) approach for generic respiratory motion correction in PET/MR imaging. AB - Respiratory motion is a source of artifacts in multimodality imaging such as PET/MR. Solutions include retrospective or prospective gating. They have however found limited use in clinical practice, since their increased overall acquisition duration to maintain overall image quality. More elaborate methods consist of using 4D MR datasets to extract spatial deformations in order to correct for the respiratory motion in PET. The main drawbacks of such approaches is the relatively long acquisition times associated with 4D MR imaging which is often incompatible with clinical PET/MR protocols. The objective of this work was to overcome these limitations by exploiting a generalized reconstruction by inversion of coupled systems (GRICS) approach. The methodology is based on a joint estimation of motion during the MR image reconstruction process, providing internal structure motion and associated deformation matrices for retrospective use in PET respiratory motion correction. This method was first validated on four MR volunteers and two PET/MR patient datasets by comparing GRICS generated MR images to 4D MR series obtained by retrospective gating. In a second step 4D PET datasets corresponding to acquired 4D MR images were simulated using the GATE Monte Carlo simulation platform. GRICS generated deformation matrices were subsequently used to correct respiratory motion in comparison to the 4D MR image based deformations both for the simulated and the two 4D PET/MR patient datasets. Results confirm that GRICS synchronized MR images correlate well with the acquired 4D MR series. Similarly, the use of GRICS for respiratory motion correction allows an equivalent percentage improvement on lesion contrast, position and size, considering the PET simulated tumors as well as PET real tumors. This work demonstrates the potential interest of using GRICS for PET respiratory motion correction in combined PET/MR using shorter duration acquisitions without the need for 4D MRI and associated specific MR sequences. PMID- 25746099 TI - Vitamin D Status in South Asian Populations - Risks and Opportunities. AB - Human body acquires a significant amount of vitamin D by cutaneous synthesis under the action of sunlight and less is supplied through nutritional sources. Diversified sociocultural and economic determinants have been identified that limit the dietary intake of vitamin D and enough distribution of sunlight to maintain optimal levels of 25-hydroxyvitamin D (25(OH)D). Consequently, the world has witnessed a high prevalence of hypovitaminosis D in resource-limited South Asian countries. The purpose of this review is to provide a South Asian perspective of vitamin D status, critically examining India, Pakistan, Bangladesh, and Sri Lanka, and to shed light on potential determinants (latitude and season, sunshine exposure habits, age, gender, and genetic factors) leading to hypovitaminosis D among a variety of population groups. Literature search was carried out using bibliographic databases "PubMed," "Google Scholar," and "ScienceDirect.com." Serum 25(OH)D level, 20-50 nmol/L, was mainly taken as vitamin D deficiency, and determinants of low serum 25(OH)D concentration of the population under study were also considered. The review concludes that vitamin D deficiency is highly prevalent among South Asian populations and global efforts are needed to overcome hypovitaminosis in the region. In addition, dietary diversification, supplementation and fortification of foods with vitamin D, adequate exposure to sunlight, and consumption of animal foods were suggested as viable approaches to maintain 25(OH)D levels for optimal health. PMID- 25746100 TI - Discussion of difficult assessment cases: psychodynamic perspectives. AB - I discuss the papers of Kleiger (this issue), Husain (this issue), and Bram (this issue), each of whom described their personality assessment of a very challenging case. Each case illustrates the way in which experienced personality assessors integrate psychoanalytic theory with clinical reasoning, multi-method assessment, and an understanding of the patient-examiner relationship when evaluating patients with serious psychiatric needs. The discussion elaborates particular aspects of each case and integrates the different estuaries through which personality assessors use psychoanalytic theory to develop diagnostic and treatment inferences. PMID- 25746101 TI - Deacetylation of chromatin and gene expression regulation: a new target for epigenetic therapy. AB - Besides the genetic information thath is encoded by DNA, heritable information can also be passed on without relying on changes in the nucleotide sequence of DNA, a phenomenon known as epigenetics. Gene expression in eukaryotes is partly regulated by epigenetic mechanisms both at the DNA and histone protein levels. Chromatin structure can be influenced by various modifications, including the reversible posttranslational processes of acetylation and deacetylation of DNA binding proteins. Histone acetyl transferase (HAT) is referred to as the writer of this process, whereas histone deacetylase (HDAC) is the eraser of this lysine modification. Dysregulation of gene expression and changes in the HDAC expression profile have been associated with carcinogenesis, and HDAC inhibitors are already approved for the treatment of cutaneous T-cell lymphoma and peripheral T-cell lymphoma. These inhibitors are able to influence epigenetic processes by targeting HDAC activity, increasing nuclear histone acetylation status, and contributing to chromatin remodeling, thereby affecting gene expression. In addition, HDACs also act on a plethora of cytosolic proteins with many cellular functions, including angiogenesis, immune responses, and autophagy. In this review, we will give an overview of histone deacetylase and how it can regulate gene expression at the chromatin level. PMID- 25746102 TI - Altered expression of histone deacetylases in cancer. AB - Epigenetic mechanisms, including histone deacetylation, are commonly deregulated in cancer. Histone deacetylases (HDACs) play an important role in tumorigenesis and their value as therapeutic targets has been under intense investigation in recent years. In addition to classical HDACs (HDAC classes I, II, and IV), sirtuins (class III HDACs) are currently in the spotlight of cancer research showing promise as cancer biomarkers and therapeutic targets. Translating research knowledge into the clinical setting is, however, a challenging and demanding task. This review describes the association between HDAC deregulation and cancer promotion and highlights recent advances in the use of HDAC inhibitors in the management of neoplastic diseases, with emphasis on urological tumors. Sirtuins' bivalent role in tumor development and therapeutic agents targeting these molecules will be also addressed. PMID- 25746104 TI - Multifaceted Modulation of SIRT1 in Cancer and Inflammation. AB - SIRT1 is a highly conserved NAD+-dependent protein deacetylase that is involved in diverse cellular processes. SIRT1 can deacetylate not only histones, but also a growing number of nonhistone substrates involved in multiple signaling pathways. Accumulating evidence has indicated that SIRT1 is a key regulator of life span extension, DNA damage, metabolism stress, inflammation, and cancer. In inflammation, SIRT1 deacetylates several transcription factors and regulates the immune cell responses. In cancer, recent discoveries revealed opposite effects of SIRT1 as an oncoprotein or a tumor suppressor under different conditions. In the tumor microenvironment, both infiltrated immune cells and cancer cells can be affected by SIRT1. Understanding the proper cancer-related functions of SIRT1 in both systems may provide potential evidence for SIRT1-based therapies. Here, we discuss the current understanding of SIRT1 in regulating immune responses and tumorigenesis. PMID- 25746103 TI - Histone deacetylases and mechanisms of regulation of gene expression. AB - In recent years it has become widely recognized that histone modification plays a pivotal role in controlling gene expression and is involved in a wide spectrum of disease regulation. Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate lysines of histone proteins, resulting in the relaxation of chromatin structure, and they also facilitate gene activation. Conversely, HDACs remove acetyl groups from hyperacetylated histones and suppress general gene transcription. In addition to histones, numerous nonhistone proteins can be acetylated and deacetylated, and they also are involved in the regulation of a wide range of diseases. To date there are 18 HDACs in mammals classified into 4 classes based on homology to yeast HDACs. Accumulating evidence has revealed that HDACs play crucial roles in a variety of biological processes including inflammation, cell proliferation, apoptosis, and carcinogenesis. In this review we summarize the current state of knowledge of HDACs in carcinogenesis and describe the involvement of HDACs in cancer-associated molecular processes. It is hoped than an understanding of the role of HDACs in cancer will lead to the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease. PMID- 25746105 TI - HDAC6-Dependent Functions in Tumor Cells: Crossroad with the MAPK Pathways. AB - Histone deacetylase 6 (HDAC6) is emerging as a novel therapeutic target in cancer treatment. HDAC6 plays an important role in cell migration, cell transformation, and DNA damage response. Our and others' studies have linked HDAC6's functions and HDAC6's regulation to the mitogen-activated protein kinase (MAPK) pathways. In particular, HDAC6's activity has been found to be regulated by EGF-EGFR-Ras Raf-MEK-ERK signaling. Inversely, HDAC6 has been reported to modulate the functions of EGFR and Ras. In this review, we summarize the literature on HDAC6 and MAPK pathways, and emphasize the interaction between HDAC6 and the ERK-MAPK signaling cascade. PMID- 25746106 TI - Drug Combinations with HDAC Inhibitors in Antitumor Therapy. AB - The treatment of tumor cells with HDAC inhibitors (HDACi) induces a range of effects including apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune response, and altered angiogenesis. The single-agent activities of several HDACi have been tested in preclinical and clinical studies and are currently the subject of ongoing clinical trials. Although HDACi have been shown to be effective as a single agent against a defined subset of hematological tumors, less convincing results have been found in the treatment of solid tumors. Since current clinical trials of single-agent HDACi showed limited efficacy, in this review we focus on drug combinations including HDACi with conventional chemotherapeutic agents and novel targeted agents. Particular emphasis has been devoted to combinations effective in solid tumors and to combinations between HDACi and immunotherapies. An outline of novel combination strategies, including a new generation of more potent and specific HDACi (e.g., compounds with adamantine and noradamantane as scaffolds) as well as chemical hybrid molecules, has been provided. The paradoxical role of HDACs as tumor suppressors in developing tumors and as therapeutic targets in established neoplasms has also been considered. PMID- 25746107 TI - Histone deacetylases and cancer-associated angiogenesis: current understanding of the biology and clinical perspectives. AB - Histone deacetylase enzymes (HDACs) have been shown to be important to the development and progression of human cancers. Angiogenesis is a vital process that facilitates tumor growth and survival. More than a dozen of different activators and inhibitors are involved in at least as many diverse mechanisms to control angiogenesis. HDACs directly or indirectly control many of these regulators. In the current review, we give a brief overview of molecular mechanisms of HDAC actions and link these to the current knowledge concerning HDAC-mediated regulation of tumor-associated angiogenesis. HDAC specific knockdown studies and the use of pan-HDAC inhibitors (HDACi) contributed to the identification of: (i) HDACs that are key to angiogenesis and (ii) their multiple protein targets essential for angiogenic process. The clinical development of HDACi is an active area of investigation. In the scope of this review, we highlight several preclinical studies that examine the anti-angiogenic role of HDACi. Certainly, there is still much to be learned about the use of HDACi to inhibit tumoral angiogenesis. Recent efforts in the clinics aiming to combine broad HDACi (mainly vorinostat, which is FDA approved for T-cell lymphoma) with other anti-angiogenic therapies could, however, bring the proof that the lack of specificity of pan-HDACi may not be a major issue as compared with (long-time idealized) selective inhibitors targeting one particular HDAC. PMID- 25746108 TI - Modulation of immune responses by histone deacetylase inhibitors. AB - Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases. PMID- 25746109 TI - Mediterranean diet and other lifestyle factors in relation to 20-year all-cause mortality: a cohort study in an Italian population. AB - The aim of the present analysis was to evaluate the association of the Mediterranean diet (MeDi), smoking habits and physical activity with all-cause mortality in an Italian population during a 20-year follow-up study. A total of 1693 subjects aged 40-74 who enrolled in the study in 1991-5 were asked about dietary and other lifestyle information at baseline. Adherence to the MeDi was evaluated by the Mediterranean dietary score (MedDietScore). A healthy lifestyle score was computed by assigning 1 point each for a medium or high adherence to the MedDietScore, non-smoking and physical activity. Cox models were used to assess the associations between lifestyle factors and healthy lifestyle scores and all-cause mortality, adjusting for potential confounders. The final sample included 974 subjects with complete data and without chronic disease at baseline. During a median of 17.4 years of follow-up, 193 people died. Subjects with high adherence to the MedDietScore (hazard ratio (HR) 0.62, 95 % CI 0.43, 0.89)), non smokers (HR 0.71, 95 % CI 0.51, 0.98) and physically active subjects (HR 0.55, 95 % CI 0.36, 0.82) were at low risk of death. Each point increase in the MedDietScore was associated with a significant 5 % reduction of death risk. Subjects with 1, 2 or 3 healthy lifestyle behaviours had a significantly 39, 56, and 73 % reduced risk of death, respectively. A high adherence to MeDi, non smoking and physical activity were strongly associated with a reduced risk of all cause mortality in healthy subjects after long-term follow-up. This reduction was even stronger when the healthy lifestyle behaviours were combined. PMID- 25746110 TI - A universal infant rotavirus vaccine program in two delivery models: Effectiveness and adverse events following immunization. AB - Rotavirus is the most common cause of diarrhea leading to hospitalization in young children. Rotavirus vaccines are available in Canada but have not been introduced in all provinces. In a controlled trial, 2 study sites (Prince Edward Island and the Capital District Health Authority (District 9, Nova Scotia) introduced universal rotavirus vaccine programs for infants at 2 and 4 months of age beginning 1 December 2010, using public health nurse or general practitioner delivery models, respectively. A third site (Saint John, NB) served as the non intervention control setting. Vaccine coverage, rotavirus hospitalizations, intussusception and all-cause diarrhea were monitored. A universal rotavirus vaccine program with >90% coverage was associated with reductions in rotavirus associated hospitalizations (from a peak of 52.8 hospitalizations/100,000 population to 0 hospitalizations) in infants < 12 months and 1 to < 2 y of age 12 months after program implementation. No apparent reduction occurred in the site with vaccine coverage of < 40%, or in the non-intervention control site. No cases of intussusception were associated with vaccine receipt, and no increase in all cause diarrhea was observed. A universal infant rotavirus vaccine program with high coverage was associated with reductions in rotavirus and no safety signals; no reduction was observed in settings with low vaccine coverage. PMID- 25746111 TI - The accuracy of computed tomography to predict completeness of pulmonary fissures. A prospective study. AB - RATIONALE: Endobronchial valves are a potential alternative to lung volume reduction surgery for advanced emphysema. The greatest improvements in pulmonary function are seen in patients with complete pulmonary fissures, as determined by computed tomography (CT). However, the accuracy of CT to predict completeness of pulmonary fissures has not been compared with the reference standard of direct observation during thoracic surgery. OBJECTIVES: To determine the accuracy of CT scans to predict completeness of pulmonary fissures. METHODS: We conducted a double-blind, prospective trial in which completeness of pulmonary fissures was evaluated by direct observation during thoracic surgery. Preoperative CT scans were independently reviewed by two dedicated thoracic radiologists and completeness of the fissures was recorded and compared with intraoperative findings. MEASUREMENTS AND MAIN RESULTS: The fissures of 46 patients were evaluated. The positive predictive value of CT scan to detect a complete fissure was 100% for the right major fissure and 75% for the left fissure, but only 33% for the right minor fissure. CT scans had a negative predictive value of 29% in evaluation of the right major fissure. CONCLUSIONS: CT scans overestimate completeness of the right minor fissure and underestimate completeness of the right major fissure. These findings may have implications for the use of CT scans to select patients for endobronchial valve insertion. PMID- 25746112 TI - Diagnosis of Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) virus is the most extensive tick-borne virus, it causes a severe infection, which occurs widely in Africa, Eastern Europe and Asia. In recent years, the dramatic increase in the global distribution of CCHF, with the high mortality rates, highlights the importance of improving diagnostic capacity. Clinical and epidemiological data play a crucial role for early recognition of CCHF. However, CCHF is clinically difficult to diagnose and to distinguish, a rapid and reliable laboratory confirmation is necessary. Confirmation of infection in the acute phase of the disease can be made by detection of viral nucleic acid using reverse transcription-PCR, by demonstration of viral antigen or by virus isolation. In the convalescent phase of the disease, the diagnosis is confirmed by demonstration of an antibody response. The consideration of viral replication kinetics and antiviral humoral immune responses facilitates the selection of appropriate laboratory tests and accurate interpretation of laboratory findings. PMID- 25746113 TI - Change of the guards. PMID- 25746114 TI - Identifying adolescents at highly elevated risk for suicidal behavior in the emergency department. AB - OBJECTIVE: The feasibility and concurrent validity of adolescent suicide risk screening in medical emergency departments (EDs) has been documented. The objectives of this short-term prospective study of adolescents who screened positive for suicide risk in the ED were: 1) to examine adolescents' rate of suicidal behavior during the 2 months following their ED visits and compare it with reported rates for psychiatric samples; and 2) to identify possible predictors of acute risk for suicidal behavior in this at-risk sample. METHOD: Participants were 81 adolescents, ages 14-19 years, seeking services for psychiatric and nonpsychiatric chief complaints, who screened positive for suicide risk because of recent suicidal ideation, a suicide attempt, and/or depression plus alcohol or substance misuse. A comprehensive assessment of suicidal behavior, using the Columbia-Suicide Severity Rating Scale, was conducted at baseline and 2 month follow-up. RESULTS: Six adolescents (7.4%) reported a suicide attempt and 15 (18.5%) engaged in some type of suicidal behavior (actual, aborted, or interrupted suicide attempt; preparatory behavior) during the 2 months following their ED visit. These rates suggest that this screen identified a high-risk sample. Furthermore, adolescents who screened positive for suicidal ideation and/or attempt plus depression and alcohol/substance misuse were most likely to engage in future suicidal behavior (38.9%). CONCLUSIONS: In this study, use of a higher screen threshold (multiple suicide risk factors) showed promise for identifying highly elevated acute risk for suicidal behavior. PMID- 25746115 TI - Predictors of intramedullary lesion expansion rate on MR images of patients with subaxial spinal cord injury. AB - OBJECT Studies of preclinical spinal cord injury (SCI) in rodents indicate that expansion of intramedullary lesions (IMLs) seen on MR images may be amenable to neuroprotection. In patients with subaxial SCI and motor-complete American Spinal Injury Association (ASIA) Impairment Scale (AIS) Grade A or B, IML expansion has been shown to be approximately 900 MUm/hour. In this study, the authors investigated IML expansion in a cohort of patients with subaxial SCI and AIS Grade A, B, C, or D. METHODS Seventy-eight patients who had at least 2 MRI scans within 6 days of SCI were enrolled. Data were analyzed by regression analysis. RESULTS In this cohort, the mean age was 45.3 years (SD 18.3 years), 73 patients were injured in a motor vehicle crash, from a fall, or in sport activities, and 77% of them were men. The mean Injury Severity Score (ISS) was 26.7 (SD 16.7), and the AIS grade was A in 23 patients, B in 7, C in 7, and D in 41. The mechanism of injury was distraction in 26 patients, compression in 22, disc/osteophyte complex in 29, and Chance fracture in 1. The mean time between injury onset and the first MRI scan (Interval 1) was 10 hours (SD 8.7 hours), and the mean time to the second MRI scan (Interval 2) was 60 hours (SD 29.6 hours). The mean IML lengths of the first and second MR images were 38.8 mm (SD 20.4 mm) and 51 mm (SD 36.5 mm), respectively. The mean time from the first to the second MRI scan (Interval 3) was 49.9 hours (SD 28.4 hours), and the difference in IML lengths was 12.6 mm (SD 20.7 mm), reflecting an expansion rate of 366 MUm/ hour (SD 710 MUm/hour). IML expansion in patients with AIS Grades A and B was 918 MUm/hour (SD 828 MUm/hour), and for those with AIS Grades C and D, it was 21 MUm/hour (SD 304 MUm/hour). Univariate analysis indicated that AIS Grade A or B versus Grades C or D (p < 0.0001), traction (p= 0.0005), injury morphology (p < 0.005), the surgical approach (p= 0.009), vertebral artery injury (p= 0.02), age (p < 0.05), ISS (p < 0.05), ASIA motor score (p < 0.05), and time to decompression (p < 0.05) were all predictors of lesion expansion. In multiple regression analysis, however, the sole determinant of IML expansion was AIS grade (p < 0.005). CONCLUSIONS After traumatic subaxial cervical spine or spinal cord injury, patients with motor-complete injury (AIS Grade A or B) had a significantly higher rate of IML expansion than those with motor-incomplete injury (AIS Grade C or D). PMID- 25746116 TI - Correlation between degree of subvoxel spinal cord compression measured with super-resolution tract density imaging and neurological impairment in cervical spondylotic myelopathy. AB - OBJECT The purpose of this study was to explore the use of super-resolution tract density images derived from probabilistic diffusion tensor imaging (DTI) tractography of the spinal cord as an imaging surrogate for microstructural integrity and functional impairment in patients with cervical spondylosis. METHODS Structural MRI and DTI images were collected for 27 patients with cervical spondylosis with (n= 21) and without (n= 6) functional impairment as defined by the modified Japanese Orthopaedic Association Scale (mJOA). DTI was performed axially through the site of compression in a total of 20 directions with 10 averages. Probabilistic tractography was performed at 0.5-mm isotropic spatial resolution using the streamline technique combined with constrained spherical deconvolution. The following measurements were calculated for each patient: maximum tract density at the site of compression, average tract density in rostral normal-appearing spinal cord, and the ratio of maximum density to normal density. RESULTS Compared with normal tissue, the site of compression exhibited elevated fiber tract density in all patients, and a higher fiber tract density was also noted in focal areas at the site of compression in patients with functional impairment. There was a strong negative correlation between maximum tract density and mJOA score (R(2)= 0.6324, p < 0.0001) and the ratio of maximum tract density to normal tract density (R(2)= 0.6647, p < 0.0001). When grouped according to severity of neurological impairment (asymptomatic, mJOA score of 18; mild, mJOA score of 15-17; moderate, mJOA score of 11-14; and severe, mJOA score < 11), the results showed a significant difference in the ratio between severe and both no impairment (p= 0.0009) and any impairment (p= 0.036). A ratio of maximum fiber tract density at the site of compression to fiber tract density at C-2 greater than 1.45 had 82% sensitivity and 70% specificity for identifying patients with moderate to severe impairment (ROC AUC= 0.8882, p= 0.0009). CONCLUSIONS These results support the use of DTI as a surrogate for determining spinal cord integrity in patients with cervical spondylosis. Probabilistic tractography provides spinal cord microstructural information that can help discern clinical status in cervical spondylosis patients with varying degrees of neurological impairment. PMID- 25746117 TI - Microsurgical anatomy of the arterial basket of the conus medullaris. AB - OBJECT The arterial basket of the conus medullaris (ABCM) consists of 1 or 2 arteries arising from the anterior spinal artery (ASA) and circumferentially connecting the ASA and the posterior spinal arteries (PSAs). The arterial basket can be involved in arteriovenous fistulas and arteriovenous malformations of the conus. In this article, the authors describe the microsurgical anatomy of the ABCM with emphasis on its morphometric parameters and important role in the intrinsic blood supply of the conus medullaris. METHODS The authors performed microsurgical dissections on 16 formalin-fixed human spinal cords harvested within 24 hours of death. The course, diameter, and branching angles of the arteries comprising the ABCM were then identified and measured. In addition, histological sections were obtained to identify perforating vessels arising from the ABCM. RESULTS The ASA tapers as it nears the conus medullaris (mean preconus diameter 0.7 +/- 0.12 mm vs mean conus diameter 0.38 +/- 0.08 mm). The ASA forms an anastomotic basket with the posterior spinal artery (PSA) via anastomotic branches. In most of the specimens (n= 13, 81.3%), bilateral arteries formed connections between the ASA and PSA. However, in the remaining specimens (n= 3, 18.7%), a unilateral right-sided anastomotic artery was identified. The mean diameter of the right ABCM branch was 0.49 +/- 0.13 mm, and the mean diameter of the left branch was 0.53 +/- 0.14 mm. The mean branching angles of the arteries forming the anastomotic basket were 95.9 degrees +/- 36.6 degrees and 90 degrees +/- 34.3 degrees for the right- and left-sided arteries, respectively. In cases of bilateral arterial anastomoses between the ASA and PSA, the mean distance between the origins of the arteries was 4.5 +/- 3.3 mm. Histological analysis revealed numerous perforating vessels supplying tissue of the conus medullaris. CONCLUSIONS The ABCM is a critical anastomotic connection between the ASA and PSA, which play an important role in the intrinsic blood supply of the conus medullaris. The ABCM provides an important compensatory function in the blood supply of the spinal cord. Its involvement in conus medullaris vascular malformations makes it a critical anatomical structure. PMID- 25746118 TI - Failure analysis of C-5 after total disc replacement with ProDisc-C at 1 and 2 levels and in combination with a fusion cage: finite-element and biomechanical models. AB - OBJECT The purpose of this study was to evaluate the failure risk of cervical vertebrae after total disc replacement with a keel-design prosthesis (ProDisc-C), taking into consideration the effects of vertebral body height, multilevel replacement, and the association with an adjacent fusion cage. Although promising clinical results have been reported for the ProDisc-C, some clinical studies have reported vertebral body-splitting fractures at single- and multilevel arthroplasty sites. This implant has central keels to provide solid initial stability, and some authors associate the potential risk of vertebral body failure with the keel design, especially in patients with small vertebral body height or when the implant is used at multiple levels. METHODS The study was performed using a specimen-specific C4-6 cervical-segment finite-element model to assess the compressive strains on the C-5 vertebral body for each cervical segment configuration, and synthetic polyurethane models to experimentally predict the compressive load at failure for 3 vertebral body heights. RESULTS The use of a keeled ProDisc-C prosthesis at multiple levels or in combination with a fusion cage increases by a factor of 2-3 the compressive strains at the C-5 vertebral body relative to single-level arthroplasty. All implanted segment configurations tested demonstrated a continuum of the load at failure and the vertebral body height, but no significant differences were found between the 3 vertebral body heights in each segment configuration. CONCLUSIONS The use of a keeled ProDisc-C prosthesis at 2 adjacent levels or combined with a fusion cage presented the lowest load-at-failure values, 2 times higher on average than the ones occurring during physiological tasks. This fact indicates an identical and limited risk of vertebral body failure for these 2 segment configurations, whereas vertebral body height appears to slightly affect this risk. However, for some tasks that place higher physical demands on the neck, beyond what was represented by our models, there may also be risk of microdamage initiation, which is not present in the single-level arthroplasty. PMID- 25746119 TI - Multimodal evaluation of CSF dynamics following extradural decompression for Chiari malformation Type I. AB - OBJECT Extradural decompression is a minimally invasive technique for treating Chiari malformation Type I (CM-I) that avoids the complications of dural opening. While there is no agreement on which surgical method is optimal, mounting evidence demonstrates that extradural decompression effectively treats clinical symptoms, with a minimal reoperation rate. Neurological symptoms such as headache may be related to obstructed flow of CSF, and one aspect of successful extradural decompression is improved CSF dynamics. In this series, the authors report on their use of phase-contrast cine flow MRI to assess CSF flow as well as satisfactory decompression. METHODS The authors describe their first surgical series of 18 patients with CM-I undergoing extradural decompression and correlate clinical improvement with radiological changes. Patients were categorized as having complete, partial, or no resolution of their symptoms. Posterior fossa area, cisterna magna area, and tonsillar herniation were assessed on T2-weighted MRI, whereas improvement of CSF flow was evaluated with phase-contrast cine flow MRI. All patients received standard pre- and postoperative MRI studies; 8 (44.4%) patients had pre- and postoperative phase-contrast cine, while the rest underwent cine studies only postoperatively. RESULTS All 18 patients presented with symptomatic CM-I, with imaging studies demonstrating tonsillar herniation >= 5 mm, and 2 patients had associated syringomelia. All patients underwent suboccipital decompression and C-1 laminectomy with splitting of the dura. Patients with complete resolution of their symptoms had a greater relative increase in cisterna magna area compared with those with only partial improvement (p = 0.022). In addition, in those with complete improvement the preoperative cisterna magna area was smaller than in those who had either partial (0.020) or no (0.025) improvement. Ten (91%) of the 11 patients with improved flow also had improvement in their symptoms. There was 1 postoperative complication of dysphagia and dysphonia. None of the patients have required a second operation. CONCLUSIONS Extradural decompression has the potential to be the first-line treatment for CM-I but has been lacking an objective measure by which to assess surgical success as well as the need for reoperation. An increase in the CSF spaces and improved CSF dynamics may be associated with resolution of clinical symptoms. Including cine imaging as part of routine pre- and postoperative evaluation can help identify which patients are most likely to benefit from surgery. PMID- 25746120 TI - Epidemiology and prognostic factors in severe sepsis/septic shock. Evolution over six years. AB - OBJECTIVE: To determine the clinical characteristics and prognostic factors of patients with severe sepsis/septic shock admitted to the Intensive Care Unit of Donostia University Hospital (Guipuzcoa, Spain). DESIGN: A prospective, observational study was carried out during a consecutive 6-year period (1st February 2008-31st December 2013). SETTING: The Intensive Care Unit of Donostia University Hospital, the only third level hospital in the province of Guipuzcoa, with a recruitment population of 700,000 inhabitants. RESULTS: Number of patients with severe sepsis/septic shock has progressively increased over the last years to reach 1,136 patients, yet significant changes in age, sex, Acute Physiology and Chronic Health Evaluation II, procalcitonin and lactate values could not be observed. In the last years, admission rate from Emergency Department has increased in comparison to admissions from hospitalization ward, with a higher incidence of urological sepsis. Hemodynamic and renal dysfunctions have been the most prevalent disorders, respiratory involvement and thrombocytopenia have gone down while coagulopathy has increased significantly. Mortality has decreased significantly. We have performed a multivariate analysis of the early prognostic factors. Type, origin, sepsis etiology, lactate and the presence of organ dysfunction -except for hyperbilirubinemia and hypotension- were the most important mortality factors. CONCLUSIONS: Severe sepsis and septic shock result in growing ICU admissions. Although clinical features have barely changed over the last years, we have observed a decrease in mortality. We find important knowing these early prognostic factors to improve the management of these patients. PMID- 25746121 TI - [Traumatic brain injury. Intracraneal foreign body]. PMID- 25746122 TI - Amphiphilic polyelectrolyte/prodrug nanoparticles constructed by synergetic electrostatic and hydrophobic interactions with cooperative pH-sensitivity for controlled doxorubicin delivery. AB - To achieve higher therapeutic efficiency with catabatic side effects, desirable nanocarriers should be designed to retain the loaded drug tightly during the systemic circulation, but release the drug rapidly and efficiently upon endocytosis by tumor cells. Herein, to achieve "off-on" controlled delivery of DOX, novel amphiphilic polyelectrolyte/prodrug nanoparticles (NPs) with cooperative pH-sensitivity were constructed via synergistic electrostatic and hydrophobic interactions between slightly positively charged methoxy polyethylene glycol-b-(poly(2-(diisopropylamino) ethyl methacrylate-co-aminopropyl methacrylamide) (PEDPA) copolymer and negatively charged cis-aconityl-doxorubicin (CAD) prodrug (termed as PEDPA/CAD NPs). With polymer-prodrug synergistic noncovalent interactions, the drug loading content of PEDPA/CAD NPs could be improved up to 12.6% with favorable serum stability, and significantly lowered the drug leakage to 2.5% within 24 h at pH 7.4. However, nearly 80% of encapsulated drug could be released at pH 5.0 within 12 h, due to the cooperative effects of the protonation of PDPA blocks resulting in quick disassembly of NPs and the rapid hydrolysis of cis-aconityl linkage leading to charge-reverse of CAD. Moreover, the results of fluorescent microscopy imaging and flow cytometry measurements exhibited that DOX could be recovered and released rapidly from PEDPA/CAD NPs upon endocytosis and then exert therapeutic action in the cell nucleus. Importantly, the PEDPA/CAD NPs exhibited significantly higher antitumor efficiency in vivo with reduced nonspecific toxicity to normal tissues in comparation with free DOX. In summary, the NPs designed in this work, constructed by synergistic electrostatic and hydrophobic interactions with cooperative pH sensitivity, which potentially resolved the dilemma between systemic stability and rapid intracellular drug release, would provide a promising nanomedicine platform for cancer therapy. PMID- 25746124 TI - The future can shape memory for the present. AB - A recent study demonstrates that memory for ostensibly irrelevant events can be enhanced when new information reveals that those events are important. These findings emphasize that memories are malleable, such that new information can update the priority and content of existing memory traces. PMID- 25746123 TI - Motor skill learning between selection and execution. AB - Learning motor skills evolves from the effortful selection of single movement elements to their combined fast and accurate production. We review recent trends in the study of skill learning which suggest a hierarchical organization of the representations that underlie such expert performance, with premotor areas encoding short sequential movement elements (chunks) or particular component features (timing/spatial organization). This hierarchical representation allows the system to utilize elements of well-learned skills in a flexible manner. One neural correlate of skill development is the emergence of specialized neural circuits that can produce the required elements in a stable and invariant fashion. We discuss the challenges in detecting these changes with fMRI. PMID- 25746126 TI - [RhCp*Cl2]2-catalyzed directed N-Boc amidation of arenes "on water". AB - Rhodium(III) catalysis "on water" is effective for directed C-H amidation of arenes. The catalytic process is promoted by OH groups present on the hydrophobic water surface and is inefficient in all (most) common organic solvents investigated so far. In the presence of easily prepared tert-butyl 2,4 dinitrophenoxycarbamate, a new and stable nitrene source, the "on water" reaction can efficiently provide the desired N-Boc-aminated products with good functional group tolerance. PMID- 25746127 TI - Exploring the relationships between participatory decision-making, visit duration, and general practitioners' provision of argumentation to support their medical advice: results from a content analysis. AB - OBJECTIVE: General practitioners' medical recommendations are not always accepted by their patients. As patients bring their own beliefs, knowledge, and preferences to the medical encounter, their opinions concerning diagnosis and treatment may deviate from their doctors'. Aiming to convince their patients of the acceptability of their advice, doctors can advance arguments. Few quantitative studies have been conducted focusing on general practitioners' provision of argumentation and little is known about the relationship between the use of argumentation and characteristics of the medical visit, such as (participatory) decision-making and visit duration. This study seeks to explore these relationships. METHODS: An observational study of seventy, randomly drawn videos of general practice consultations was conducted. A theory-based codebook was developed. Two independent coders analyzed doctors' provision of argumentation, their decision-making style, and the duration of each visit. RESULTS: General practitioners' provision of argumentation was found to be associated with lengthier visits and a more participatory decision-making style. In addition, visit duration and participatory decision-making appeared associated. CONCLUSION: These results suggest that the use of argumentation may contribute toward achieving patient-centered care through communication. PRACTICE IMPLICATIONS: As a result, the findings underscore the potential relevance of developing courses focusing on doctors' argumentation skills. PMID- 25746128 TI - Application of the health belief model to improve the understanding of antihypertensive medication adherence among Chinese patients. AB - OBJECTIVES: We aimed to gain insight into antihypertensive medication adherence on the basis of a well-developed behavior theory. METHODS: A cross-sectional study of Chinese hypertensive patients was conducted using the health belief model as a theoretical framework. RESULTS: The HBM explained 48.8% of the variance in antihypertensive medication adherence with an overall prediction accuracy was 82.8%. After adjusting for controlling factors, the HBM explained 50.5% of the variance in antihypertensive medication adherence with an overall prediction accuracy of 86.2%. Higher levels of perceived susceptibility (p = 0.017), cues to action (p=0.034), and self-efficacy (p = 0.002) and a lower level of perceived barriers (p < 0.001) were significantly associated with better antihypertensive medication adherence. The risk factors of older age (p = 0.037), longer duration of HTN (p = 0.003), longer duration of drug use (p = 0.001), and taking a combination of antiplatelet agents (p < 0.001) were significantly associated with better antihypertensive medication adherence and influenced different HBM constructs. CONCLUSION: The HBM is reliable in predicting medication adherence among Chinese hypertensive patients. Intervention programs in clinical practice could be guided by the relationship between risk factors and HBM constructs and antihypertensive medication adherence. PRACTICE IMPLICATIONS: This study provides a structured understanding of the relationships between risk factors and HBM constructs and antihypertensive medication adherence. PMID- 25746129 TI - Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer. AB - INTRODUCTION: Signal transducer and activator of transcription 3 (STAT3) mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in several cellular processes such as cell growth and apoptosis. Deregulation of the STAT3 activity has been shown in many malignancies, including breast, head and neck, prostate, pancreas, ovarian and brain cancers and melanoma. Thus, STAT3 may represent an ideal target for cancer therapy. AREAS COVERED: The authors review recent data on the role of STAT3 in tumor initiation and progression, as well as the ongoing clinical trials in cancer patients. The content includes information derived from trial databases, regulatory authorities and scientific literature. EXPERT OPINION: Targeting STAT3 activation leads to the inhibition of tumor growth and metastasis both in vitro and in vivo without affecting normal cells; this suggests that STAT3 could be a valid molecular target for cancer therapy. Extensive clinical research is trying to find anti STAT3 agents with high single-agent activity. The identification and development of novel drugs that can target deregulated STAT3 activation effectively is both a scientific and clinical challenge that needs to be addressed in the near future. PMID- 25746130 TI - Laser-driven isomerization of HCN -> HNC: the importance of rotational excitation. AB - We report a time-dependent quantum wave packet theory, which is employed to interpret the isomerization dynamics of HCN molecules induced by an intense picosecond infrared laser field. Considering the molecular rotational degrees of the freedom, the wave functions are expanded in terms of molecular rotational bases. Our full-dimensional quantum model includes the full Coriolis coupling in the molecular kinetic energy Hamiltonian and dipole approximation in interaction terms. The numerical results show that the field-induced molecule rotational excitation plays an important role in the isomerization dynamical process. Some phenomena appear such as two-step two-photon absorption and highly oscillatory structure in rotational state distributions. The centrifugal sudden (CS) approximation calculation is also carried out and compared in this work; it is shown that the Coriolis couplings may lead to a significant decrease in the isomerization rate but highly enhanced molecular rotational excitation. PMID- 25746131 TI - Surfactant-aided precipitation/on-pellet-digestion (SOD) procedure provides robust and rapid sample preparation for reproducible, accurate and sensitive LC/MS quantification of therapeutic protein in plasma and tissues. AB - For targeted protein quantification by liquid chromatography mass spectrometry (LC/MS), an optimal approach for efficient, robust and hi-throughput sample preparation is critical, but often remains elusive. Here we describe a straightforward surfactant-aided-precipitation/on-pellet-digestion (SOD) strategy that provides effective sample cleanup and enables high and constant peptide yields in various matrices, allowing reproducible, accurate and sensitive protein quantification. This strategy was developed using quantification of monocolnocal antibody in tissues and plasma as the model system. Surfactant treatment before precipitation substantially increased peptide recovery and reproducibility from plasma/tissue, likely because surfactant permits extensive denaturation/reduction/alkylation of proteins and inactivation of endogenous protease inhibitors, and facilitates removal of matrix components. The subsequent precipitation procedure effectively eliminates the surfactant and nonprotein matrix components, and the thorough denaturation by both surfactant and precipitation enabled very rapid on-pellet-digestion (45 min at 37 degrees C) with high peptide recovery. The performance of SOD was systematically compared against in-solution-digestion, in-gel-digestion and filter-aided-sample preparation (FASP) in plasma/tissues, and then examined in a full pharmacokinetic study in rats. SOD achieved the best peptide recovery (~21.0-700% higher than the other three methods across various matrices), reproducibility (3.75-10.9%) and sensitivity (28-30 ng/g across plasma and tissue matrices), and its performance was independent of matrix types. Finally, in validation and pharmacokinetic studies in rats, SOD outperformed other methods and provided highly accurate and precise quantification in all plasma samples without using stable isotope labeled (SIL)-protein internal standard (I.S.). In summary, the SOD method has proven to be highly robust, efficient and rapid, making it readily adaptable to large-scale clinical and pharmaceutical quantification of biomarkers or biotherapeutics. PMID- 25746132 TI - Development and validation of an on-line multidimensional SPE-LC-MS/MS method for the quantitation of Tetrandrine in blood samples. AB - On-line solid-phase extraction (SPE) is becoming an increasingly widespread technique in the clean-up of complex matrices such as body fluids, prior to chromatographic analysis. The use of small SPE columns instead of disposable SPE cartridges allows multiple injections and complete automation. In addition, it decreases the cost of consumables and improves the quality of the overall analysis. Coupling of SPE with HPLC combines sample preparation and separation in one system. In this paper a validated on-line multidimensional (MD) SPE-LC-MS/MS method is described for the determination of Tetrandrine (model drug) in human blood samples. The developed method showed the applicability of direct injection of plasma samples to an on-line MD-SPE-LC-MS/MS system to determine small molecules i.e. drugs. The experimental design is unique. Quantification was through tandem mass spectrometry with positive electrospray ionization (ESI) and multiple reactions monitoring (MRM). The limit of detection was calculated as 31.98 ng/mL. The linear range of the method was between 40.0 and 800.0 ng/mL. Pharmacokinetic parameters are usually determined by analysis of drug concentrations in plasma rather than whole blood. Parameters determined using plasma data may be misleading if concentrations of drug differ between plasma and red blood cells. We successfully applied the developed method for the determination of the distribution coefficient of the model drug Tetrandrine between human red blood cells and blood plasma proteins. The determination of distribution coefficient study results demonstrated that the developed method can provide direct and accurate measurement of RBC partitioning in a model drug and could be applied for screening of other compounds for potential high RBC partition, predicting potential drug toxicity and investigating mechanisms associated with RBC partitions. PMID- 25746133 TI - Application of a FLAP-consensus docking mixed strategy for the identification of new fatty acid amide hydrolase inhibitors. AB - Fatty acid amide hydrolase (FAAH) is the principal responsible for the termination of anandamide signaling, a major actor of the endocannabinoid system. The indirect stimulation of endocannabinoid responses achieved through FAAH inhibition can represent a valid pharmacological strategy for the treatment of neurodegenerative and neuroinflammatory diseases such as multiple sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases, as well as rheumatoid arthritis, gastrointestinal inflammatory states, anxiety, and other pathologies. With the aim of identifying new noncovalent FAAH inhibitors and also experimentally validating the reliability of the recently reported consensus docking approach, we filtered a commercial database of about 1 million compounds by using a mixed FLAP (fingerprints for ligands and proteins) consensus docking approach. Enzymatic assays showed FAAH inhibitory activity and selectivity versus MAGL for 8 out of the 10 top ranked compounds, with IC50 values in the low micromolar range for the two most active compounds. These results demonstrate the reliability of the virtual screening strategy and constitute an experimental validation of the consensus docking approach. Moreover, the two most active compounds described could represent promising leads for the development of high potent noncovalent FAAH inhibitors. PMID- 25746134 TI - Solubilization of single-walled carbon nanotubes using a peptide aptamer in water below the critical micelle concentration. AB - The solubilizing ability of single-walled carbon nanotubes (SWCNTs) in water with several dispersants was investigated. Among the dispersants, including low molecular-weight surfactants, peptides, DNA, and a water-soluble polymer, the peptide aptamer, A2 (IFRLSWGTYFS), exhibited the highest dispersion capability below the critical micelle concentration at a concentration of 0.02 w/v%. The dispersion of supernatant aqueous solution of SWCNTs containing aptamer A2 was essentially unchanged for several months after high-speed ultracentrifugation and gave rise to an efficient and stable dispersion of the SWCNTs in water. From the results of isothermal titration calorimetry and molecular dynamics simulations, the effective binding capability of A2 was due to pi-pi interaction between aromatic groups in the peptide aptamer and the side walls of SWCNTs. Interestingly, the peptide aptamer showed the possibility of diameter separation of semiconducting SWCNTs using a uniform density gradient ultracentrifuge. These phenomena are encouraging results toward an effective approach to the dispersion and separation of SWCNTs. PMID- 25746135 TI - Management of atrial fibrillation: What is new in the 2014 ACC/AHA/HRS guideline? AB - Recently, the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society published an updated guideline on the management of atrial fibrillation (AF). This document is a complete revision of the 2006 guideline. Prominent changes in the 2014 guideline include the use of the CHA2DS2 VASc score for risk stratification of stroke, recommendations on when and how to use newer oral anticoagulants for thromboprophylaxis, downgrading of the use of aspirin for thromboprophylaxis of moderate-risk patients, and the use of catheter ablation in selected patients as first-line therapy for paroxysmal AF. In regard to rate control, the 2014 guideline reverts back to a previous recommendation for stricter targets for mean and maximum heart rate on therapy. The current guideline incorporates many recent trials in updating existing recommendations from the 2006 guideline. The 2014 guideline will be a vital tool in guiding physicians in the management of AF. PMID- 25746136 TI - Low cost whole-organism screening of compounds for anthelmintic activity. AB - Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-alpha]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47 MUM. Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships. PMID- 25746137 TI - Combinative treatment of transarterial chemoembolization, celecoxib and lanreotide in unresectable hepatocellular carcinoma. PMID- 25746138 TI - Renal proximal tubular dysfunction due to tenofovir in a patient with chronic hepatitis B monoinfection. PMID- 25746139 TI - MicroRNAs as biomarkers for hepatocellular carcinoma diagnosis and prognosis. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and it is the second leading cause of cancer-related deaths. Despite improvements in HCC therapy, the overall survival rate is still very low because of the late detection of the tumors. Thus, early detection of HCC offers the best chance of survival for patients. MicroRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs involved in the regulation of gene expression and protein translation. Many studies have shown that they played a very important role in cancer progresses and outcomes. The aberrant expression of miRNAs is common in various human malignancies and it modulates cancer-associated genomic regions or fragile sites. As for the relationship between miRNAs and HCC, several studies have demonstrated that the aberrant expression of specific miRNAs can be detected in HCC patients' serum and plasma or HCC cells and tissues, and miRNAs have shown great promise as diagnostic and prognostic markers for HCC. In the present review, we discussed the applications of miRNAs as biomarkers for HCC diagnosis and prognosis, and the association between miRNAs polymorphisms and the risk of HCC as well. PMID- 25746140 TI - Elucidation of two giants: challenges to thick-shell synthesis in CdSe/ZnSe and ZnSe/CdS core/shell quantum dots. AB - Core/thick-shell giant quantum dots (gQDs) possessing type II electronic structures exhibit suppressed blinking and diminished nonradiative Auger recombination. We investigate CdSe/ZnSe and ZnSe/CdS as potential new gQDs. We show theoretically and experimentally that both can exhibit partial or complete spatial separation of an excited-state electron-hole pair (i.e., type II behavior). However, we reveal that thick-shell growth is challenged by competing processes: alloying and cation exchange. We demonstrate that these can be largely avoided by choice of shelling conditions (e.g., time, temperature, and QD core identity). The resulting CdSe/ZnSe gQDs exhibit unusual single-QD properties, principally emitting from dim gray states but having high two-exciton (biexciton) emission efficiencies, whereas ZnSe/CdS gQDs show characteristic gQD blinking suppression, though only if shelling is accompanied by partial cation exchange. PMID- 25746141 TI - Visualization of the wrist ganglion capsule by methylene blue staining as an aid for complete resection in children. AB - PURPOSE: To evaluate the effectiveness of methylene blue staining during ganglion resection in children, to assess ganglion resection and minimize recurrence. METHODS: From August 2007 to March 2011, 36 children with dorsal or volar wrist ganglions with an average size of 2 cm (range, 1-4 cm), including 5 recurrent cases, underwent resection performed with intraoperative methylene blue marking of the cyst wall. RESULTS: We found recurrence in one patient after 2 years; no obvious complications were observed in any patient. CONCLUSIONS: Methylene blue staining of the ganglion during resection may be helpful for achieving complete resection. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 25746142 TI - Health literacy in hand surgery patients: a cross-sectional survey. AB - PURPOSE: To determine the prevalence of and factors associated with limited health literacy among outpatients presenting to an urban academic hospital-based hand surgeon. METHODS: A cohort of 200 English- and Spanish-speaking patients completed the Newest Vital Sign (NVS) health literacy assessment tool, a sociodemographic survey, and 2 Patient-Reported Outcomes Measurement Information System-based computerized adaptive testing questionnaires: Patient-Reported Outcomes Measurement Information System Pain Interference and Upper-Extremity Function. The NVS scores were divided into limited (0-3) and adequate (4-6) health literacy. Multivariable regression modeling was used to identify independent predictors of limited health literacy. RESULTS: A total of 86 patients (43%) had limited health literacy (English-speaking: 33%; Spanish speaking: 100%). Factors associated with limited health literacy were advanced age, lower income, and being publicly insured or uninsured. Increasing years of education was a protective factor. Primary language was not included in the logistic regression model because all Spanish-speaking patients had limited health literacy. When evaluating health literacy on a continuum, primary language was the factor that most influenced the NVS scores, accounting for 14% of the variability. CONCLUSIONS: Limited health literacy was commonplace among patients seeing a hand surgeon, more so in elderly and disadvantaged individuals. We hope our study raises awareness of this issue among hand surgeons and encourages providers to simplify messages and improve communication strategies. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25746143 TI - Idiopathic carpal tunnel syndrome in children and adolescents. AB - PURPOSE: A retrospective review of a single institution's experience with idiopathic carpal tunnel syndrome (CTS) in children and adolescents was performed to evaluate management and outcomes in an effort to establish a treatment protocol. METHODS: All patients diagnosed with idiopathic CTS from ages 1 to 16 years of age between 1983 and 2013 were reviewed. The results of diagnostic testing and efficacy of therapeutic interventions were analyzed. The Boston Carpal Tunnel Questionnaire was sent to all patients following medical or surgical management. RESULTS: A total of 20 patients with 31 involved wrists met criteria for entrance into the study. The mean age at diagnosis was 14.4 years. Orthosis fabrication was used as the initial treatment in 30 of 31 wrists and was successful in completely alleviating symptoms in 9 of 30 wrists. A steroid injection was performed in 11 of 31 wrists, completely relieving symptoms in 5 of 11 wrists. Carpal tunnel release was performed in 10 of 31 wrists. Following surgery, patients had complete relief of symptoms in 5 of 10 wrists and partial relief of symptoms in 5 of 10 wrists. Questionnaire response incidence was 55% (11 of 20), with an average long-term follow-up of 17.6 years. Eight questionnaire respondents continued to have mild to moderate symptoms while performing activities of daily living. CONCLUSIONS: Once metabolic, anatomical, and hereditary causes of pediatric CTS are ruled out, a reasonable treatment course should follow that of adults with orthosis fabrication, followed by injection, and then surgery for those that are refractory to nonsurgical treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 25746144 TI - Hypothenar hammer syndrome: long-term results of vascular reconstruction. AB - PURPOSE: To evaluate long-term patency rates and related outcomes after vascular reconstruction of hypothenar hammer syndrome and identify patient- or treatment related factors that may contribute to differences in outcome. METHODS: We used color flow ultrasound to determine the patency of 18 vein graft reconstructions of the ulnar artery at the wrist in 16 patients. Validated questionnaires evaluated patients' functional disability with the Disabilities of the Arm, Shoulder, and Hand score, pain with the visual analog scale, and cold intolerance with the Cold Intolerance Symptom Severity survey. Patient demographics, clinical data, and surgical factors were analyzed for association with graft failure. Patients were asked to grade the result of treatment on a scale of 0 to 10. RESULTS: Of 18 grafts, 14 (78%) were occluded at a mean of 118 months postoperatively. Patients with patent grafts had significantly less disability related to cold intolerance according to the Cold Intolerance Symptom Severity survey in addition to significantly less pain on the visual analog scale. There was no statistical difference in Disabilities of the Arm, Shoulder, and Hand scores between patients with patent or occluded grafts. Patients graded the result significantly higher in patent reconstructions. CONCLUSIONS: We noted a higher incidence of graft occlusion than previously reported at a mean follow-up of 9.8 years, which represents a long-duration follow-up study of surgical treatment of hypothenar hammer syndrome. Despite a high percentage of occlusion, overall, patients remained satisfied with low functional disability and all would recommend surgical reconstruction. This study suggests that improved outcomes may result from patent grafts in the long term. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 25746145 TI - Rerouting extensor pollicis longus tendon transfer. AB - Following radial nerve palsy, loss of the extensor pollicis longus (EPL), abductor pollicis longus and extensor pollicis brevis tendons results in loss of thumb extension and radial abduction. Multiple tendon transfers are described to address the loss of thumb extension following radial palsy utilizing the palmaris longus or flexor digitorum sublimis transferred to the EPL tendon. Owing to its ulnar vector of pull, the EPL tendon is a secondary adductor of the thumb, and in order to mitigate the tendency for thumb adduction, the EPL tendon is divided at the wrist and brought subcutaneously to the radial side of the wrist for repair to the donor tendon to improve the line of pull for the donor tendon. We describe the use of a technique to reroute the EPL tendon through the first compartment in a retrograde fashion prior to repair with the donor tendon on the radial side of the wrist. The use of the first dorsal compartment provides a pulley to maintain the position of the transfer and to prevent potential bowstringing of the tendon as wrist flexion and thumb extension are attempted. because the repair is performed proximal to the extensor retinaculum, the donor tendon length is not compromised. Because the tendon is redirected through the first dorsal compartment and inserts into the distal phalanx, a single transfer attempts to restores both thumb extension and radial abduction. PMID- 25746146 TI - Delayed and suspended replantation for complete amputation of digits and hands. AB - PURPOSE: To analyze the clinical outcome for delayed or suspended replantation of complete amputations of digits or hands, or both. METHODS: We analyzed 20 cases involving 28 digital and 4 hand amputations that underwent delayed or suspended replantation. In 15 cases of single-digit amputation, patients underwent delayed replantation the morning following amputation. With amputation of multiple digits, bilateral digits, or the hand, the important digits or dominant hand underwent immediate replantation, and we suspended the surgeries for the residual digits or non-dominant hand, or both, until the next morning. We then evaluated the mean warm and cold ischemic time for the operations, graft survival rates, and clinical outcomes. The mean follow-up period was 26 months. We evaluated the clinical results using the criteria of Chen. RESULTS: The mean warm and cold ischemic times in 15 cases of delayed replantation were 2 hours 4 minutes and 7 hours 21 minutes, respectively. In 8 cases of suspended replantation, the mean warm and cold ischemic times in the first operation were 5 hours 54 minutes and 2 hours 36 minutes, respectively. In the second operation, the cold ischemic time averaged 15 hours 48 minutes. In this series, 24 of 28 digits and all 4 hands survived. Total survival incidence in both delayed and suspended replantation was 88%, not statistically different from the overall survival incidence in 711 cases of immediate replantation during the same period (84%). In delayed replantation, we observed an excellent result with 6 digits and a good result with another 6 digits. In suspended cases, we observed a good result with one multiple-digit and one hand procedure and we obtained a fair result in 3 multiple-digit and 2 hand replantation procedures. CONCLUSIONS: Delayed and suspended replantations demonstrate results comparable to immediate replantation regarding graft survival and clinical outcome. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25746148 TI - EDTA-mediated inhibition of DNases protects circulating cell-free DNA from ex vivo degradation in blood samples. AB - OBJETIVES: The extracellular DNA occurring in plasma-EDTA and serum is a biomarker of growing interest, especially in prenatal diagnosis and oncology. The objectives of the present study were to compare the DNase activity in these specimens and to investigate its ex-vivo impact over the circulating cell-free DNA yield (ccfDNA), using the circulating cell-free fetal DNA (ccffDNA) as a tool. DESIGN AND METHODS: EDTA-plasma and serum from women bearing male fetus were submitted to an endogenous DNase activity assay based on qPCR hydrolysis probe degradation, they were treated with DNAse I to investigate the action of an exogenous nuclease and also submitted to different temperature conditions to investigate the temperature-dependent degradation of the ccffDNA. In all instances, all male ccffDNA were quantified by qPCR targeting the Y chromosome specific sequence DYS-14. Moreover, a serial dilution of EDTA was added to nonanticoagulated plasma and serum before the endogenous DNAse activity assay, to investigate the EDTA-mediated inhibition of the blood's DNase. RESULTS: The endogenous nuclease activity was 14.9-fold higher in serum compared to EDTA plasma. The DNAse I treatment did not alter the ccffDNA yields in EDTA-plasma, but completely degraded it in serum. The addition of increasing doses of EDTA to nonanticoagulated plasma and serum resulted in a stepwise inhibition of their nucleases activity. Finally, we observed a much more pronounced temperature mediated decrease on the ccffDNA amount in serum compared to EDTA-plasma. CONCLUSION: The exogenous and endogenous DNases are more active in serum, the anticoagulant EDTA indirectly inhibits blood DNases, and consequently ccfDNA is protected from the blood's DNase preanalytical impact in EDTA-plasma. PMID- 25746147 TI - Regionally diverse mitochondrial calcium signaling regulates spontaneous pacing in developing cardiomyocytes. AB - The quintessential property of developing cardiomyocytes is their ability to beat spontaneously. The mechanisms underlying spontaneous beating in developing cardiomyocytes are thought to resemble those of adult heart, but have not been directly tested. Contributions of sarcoplasmic and mitochondrial Ca(2+)-signaling vs. If-channel in initiating spontaneous beating were tested in human induced Pluripotent Stem cell-derived cardiomyocytes (hiPS-CM) and rat Neonatal cardiomyocytes (rN-CM). Whole-cell and perforated-patch voltage-clamping and 2-D confocal imaging showed: (1) both cell types beat spontaneously (60-140/min, at 24 degrees C); (2) holding potentials between -70 and 0mV had no significant effects on spontaneous pacing, but suppressed action potential formation; (3) spontaneous pacing at -50mV activated cytosolic Ca(2+)-transients, accompanied by in-phase inward current oscillations that were suppressed by Na(+)-Ca(2+) exchanger (NCX)- and ryanodine receptor (RyR2)-blockers, but not by Ca(2+)- and If-channels blockers; (4) spreading fluorescence images of cytosolic Ca(2+) transients emanated repeatedly from preferred central cellular locations during spontaneous beating; (5) mitochondrial un-coupler, FCCP at non-depolarizing concentrations (~50nM), reversibly suppressed spontaneous pacing; (6) genetically encoded mitochondrial Ca(2+)-biosensor (mitycam-E31Q) detected regionally diverse, and FCCP-sensitive mitochondrial Ca(2+)-uptake and release signals activating during INCX oscillations; (7) If-channel was absent in rN-CM, but activated only negative to -80mV in hiPS-CM; nevertheless blockers of If-channel failed to alter spontaneous pacing. PMID- 25746149 TI - Increased urinary cystatin C level is associated with interstitial fibrosis and tubular atrophy in kidney allograft recipients. AB - AIM: The objective of this study was to investigate the correlation between the urinary excretion of cystatin C (CysC) and the presence of interstitial fibrosis/tubular atrophy (IF/TA) in renal transplant (RT) recipients. METHODS: This prospective study included 21 adult patients who had undergone renal biopsy and RT >=6 months prior. According to the renal biopsy reports, the patients were divided into groups with (n=12) or without (n=9) IF/TA. Analytical parameters included the following: serum and urinary levels of CysC, creatinine (Cr) and sodium (Na), total urinary protein, urinary CysC/creatinine ratio [u(CysC/Cr)], fractional excretion of sodium (FENa) and estimated glomerular filtration rate (eGFR) based on the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The values of uCysC, u(CysC/Cr), proteinuria, and FENa were significantly higher in patients with IF/TA than in patients without IF/TA. The values of eGFR were statistically lower in patients with IF/TA (p=0.001). Values of uCysC significantly correlated with those of serum Cr, FENa, and eGFR (p<0.001). Among the patients with IF/TA, 67% presented with glomerulosclerosis (segmental/global). CONCLUSION: Elevated levels of urinary CysC are associated with interstitial fibrosis and tubular atrophy in RT recipients and may become a useful tool for monitoring kidney allografts. PMID- 25746150 TI - A systematic approach to selecting task relevant neurons. AB - BACKGROUND: Since task related neurons cannot be specifically targeted during surgery, a critical decision to make is to select which neurons are task-related when performing data analysis. Including neurons unrelated to the task degrade decoding accuracy and confound neurophysiological results. Traditionally, task related neurons are selected as those with significant changes in firing rate when a stimulus is applied. However, this assumes that neurons' encoding of stimuli are dominated by their firing rate with little regard to temporal dynamics. NEW METHOD: This paper proposes a systematic approach for neuron selection, which uses a likelihood ratio test to capture the contribution of stimulus to spiking activity while taking into account task-irrelevant intrinsic dynamics that affect firing rates. This approach is denoted as the model deterioration excluding stimulus (MDES) test. RESULTS: MDES is compared to firing rate selection in four case studies: a simulation, a decoding example, and two neurophysiology examples. COMPARISON WITH EXISTING METHODS: The MDES rankings in the simulation match closely with ideal rankings, while firing rate rankings are skewed by task-irrelevant parameters. For decoding, 95% accuracy is achieved using the top 8 MDES-ranked neurons, while the top 12 firing-rate ranked neurons are needed. In the neurophysiological examples, MDES matches published results when firing rates do encode salient stimulus information, and uncovers oscillatory modulations in task-related neurons that are not captured when neurons are selected using firing rates. CONCLUSIONS: These case studies illustrate the importance of accounting for intrinsic dynamics when selecting task-related neurons and following the MDES approach accomplishes that. MDES selects neurons that encode task-related information irrespective of these intrinsic dynamics which can bias firing rate based selection. PMID- 25746151 TI - Economic evaluation of neutral-pH, low-glucose degradation product peritoneal dialysis solutions compared with standard solutions: a secondary analysis of the balANZ Trial. AB - BACKGROUND: Biocompatible solutions may lower peritonitis rates, but are more costly than conventional solutions. The aim of the present study was to assess the additional costs and health outcomes of biocompatible over conventional solutions in incident peritoneal dialysis patients to guide practice decisions. STUDY DESIGN: Secondary economic evaluation of a randomized controlled trial. SETTING & POPULATION: 185 participants in the balANZ trial. MODEL, PERSPECTIVE, & TIMEFRAME: Cost-effectiveness of biocompatible compared to standard solution over the 2 years using an Australian health care funder perspective. INTERVENTION: Intervention group received biocompatible solutions and control group received standard solutions over 2 years. OUTCOMES: Costs included dialysis charges, costs of treating peritonitis, non-peritonitis-related hospital stays, and medication. Peritonitis was the health outcome of interest; incremental cost-effectiveness ratios were reported in terms of the additional cost per additional patient avoiding peritonitis at 2 years. RESULTS: Mean total per-patient costs were A$57,451 and A$53,930 for the biocompatible and standard-solution groups, respectively. The base-case analysis indicated an incremental cost of A$17,804 per additional patient avoiding peritonitis at 2 years for biocompatible compared to standard solution. In a sensitivity analysis excluding extreme outliers for non-peritonitis-related hospitalizations, mean per-patient costs were A$49,159 and A$52,009 for the biocompatible and standard-solution groups, respectively. Consequently, the incremental cost-effectiveness ratio also was reduced significantly: biocompatible solution became both less costly and more effective than standard solution and, in economic terms, was dominant over standard solution. LIMITATIONS: Peritonitis was a secondary outcome of the balANZ trial. Health outcomes measured only in terms of patients avoiding peritonitis over 2 years may underestimate the longer term benefits (eg, prolonged technique survival). CONCLUSIONS: Biocompatible dialysis solutions may offer a cost effective alternative to standard solutions for peritoneal dialysis patients. Reductions in peritonitis-related hospital costs may offset the higher costs of biocompatible solution. PMID- 25746152 TI - Scleral lenses in the treatment of post-LASIK ectasia and superficial neovascularization of intrastromal corneal ring segments. AB - OBJECTIVE: This case report aims to explore the use of scleral lenses for the treatment of ocular and visual complications in an adult patient presenting with post-LASIK (Laser-Assisted in situ Keratomileusis) ectasia in both eyes with cross-linking in the right eye and intrastromal corneal ring segments (ICRS; Intacs, Addition Technology, Fremont, CA) in the left eye. METHODS: Following a comprehensive eye exam and specific testing for contact lens fitting, scleral lenses were fitted with success in both eyes and dispensed. Due to progressive fibrosis and neovascularization of the inferior ICRS in the left eye, the inferior ICRS was removed and scleral lenses were refit with success. RESULTS: Prescribed scleral lenses helped the patient achieve optimal visual correction (20/20) as well as ocular protection of the cornea. CONCLUSION: Post-LASIK ectasia is a common finding among contact lens specialists today. When ICRS surgery is involved, the fitting of contact lenses may become more challenging. Scleral lenses offer a unique way of addressing many issues raised in this case report including corneal neovascularization and ectasia. This lens modality may be considered for any other case involving irregular corneal curvature following surgery resulting in reduced visual acuity. PMID- 25746153 TI - Self-Consistent MUSIC: An approach to the localization of true brain interactions from EEG/MEG data. AB - MUltiple SIgnal Classification (MUSIC) is a standard localization method which is based on the idea of dividing the vector space of the data into two subspaces: signal subspace and noise subspace. The brain, divided into several grid points, is scanned entirely and the grid point with the maximum consistency with the signal subspace is considered as the source location. In one of the MUSIC variants called Recursively Applied and Projected MUSIC (RAP-MUSIC), multiple iterations are proposed in order to decrease the location estimation uncertainties introduced by subspace estimation errors. In this paper, we suggest a new method called Self-Consistent MUSIC (SC-MUSIC) which extends RAP-MUSIC to a self-consistent algorithm. This method, SC-MUSIC, is based on the idea that the presence of several sources has a bias on the localization of each source. This bias can be reduced by projecting out all other sources mutually rather than iteratively. While the new method is applicable in all situations when MUSIC is applicable we will study here the localization of interacting sources using the imaginary part of the cross-spectrum due to the robustness of this measure to the artifacts of volume conduction. For an odd number of sources this matrix is rank deficient similar to covariance matrices of fully correlated sources. In such cases MUSIC and RAP-MUSIC fail completely while the new method accurately localizes all sources. We present results of the method using simulations of odd and even number of interacting sources in the presence of different noise levels. We compare the method with three other source localization methods: RAP-MUSIC, dipole fit and MOCA (combined with minimum norm estimate) through simulations. SC MUSIC shows substantial improvement in the localization accuracy compared to these methods. We also show results for real MEG data of a single subject in the resting state. Four sources are localized in the sensorimotor area at f=11Hz which is the expected region for the idle rhythm. PMID- 25746154 TI - Simultaneous detection of five notifiable viral diseases of cattle by single-tube multiplex real-time RT-PCR. AB - Multiplexed real-time PCR (qPCR) assays enable the detection of several target genes in a single reaction, which is applicable for simultaneous testing for the most important viral diseases in samples obtained from ruminants with unspecific clinical symptoms. Here, reverse transcription qPCR (RT-qPCR) systems for the detection of bovine viral diarrhoea virus (BVDV) and bluetongue virus (BTV) were combined with an internal control system based on the beta-actin gene. Additionally, a background screening for three further major pathogens of cloven hoofed animals reportable to the World Organisation for Animal Health, namely foot-and-mouth disease virus, epizootic haemorrhagic disease virus, and Rift Valley fever virus, was integrated using the identical fluorophore for the respective RT-qPCR assays. Every pathogen-specific assay had an analytical sensitivity of at least 100 genome copies per reaction within the multiplex approach, and a series of reference samples and clinical specimens obtained from cattle, but also from small ruminants, were detected reliably. The qPCR systems integrated in the background screening were even not influenced by the simultaneous amplification of very high BVDV and BTV genome copy numbers. The newly developed multiplex qPCR allows the specific and sensitive detection of five of the most important diseases of ruminants and could be used in the context of monitoring programs or for differential diagnostics. PMID- 25746155 TI - Painting a picture of trans-Tasman mortality. AB - OBJECTIVES: The determinants of health and mortality inequalities in New Zealand and Australia have been subjected to research, with the influence of a range of socio-economic and demographic influences (deprivation, social class, ethnicity) receiving notable attention. Both countries are considered privileged, positioned amongst the world leaders in rankings of mortality and life expectancy. This paper reports on observed rates of mortality and views how the countries have fared over time with respect to one another. STUDY DESIGN, OBSERVATIONAL, METHODS: This study derives comparable rates of mortality for both New Zealand and Australia, disaggregated by age and sex for the time period 1948-2008. The age-standardised rates are visualised using the Lexis mapping software program, showing the relative differences between the countries over time whilst simultaneously highlighting age, period and cohort effects. RESULTS: Relative to Australia, New Zealand had advantageous rates of mortality across almost all age groups between the years 1948 and 1980 (approximately). For both sexes, a dramatic reversal of fortunes in New Zealand has followed relative to Australia. For example, for younger males in New Zealand, the reversal is startling. Over the time period observed, males aged 10-20 years in New Zealand have moved from an advantageous position of having a mortality rate 20% lower than Australia to a relative position of 50% higher. CONCLUSIONS: The social and economic forces in both New Zealand and Australia which may have driven the divergence require further scrutiny. It is argued here, that the changing fortunes of the populations are linked to the process of selective migration and the large-scale population movements between the countries facilitated by the Trans-Tasman Travel Arrangement. These findings have important implications for policy formation and service planning, if the inequality in mortality between the areas of study is to be addressed. PMID- 25746156 TI - Risk factors of overweight and obesity in childhood and adolescence in South Asian countries: a systematic review of the evidence. AB - OBJECTIVE: To assess and synthesize the published evidence on risk factors of overweight and obesity in childhood and adolescence in South Asia. STUDY DESIGN: A systematically conducted narrative review. METHODS: A systematic review was conducted of all primary studies published between January 1990 and June 2013 from India, Pakistan, Nepal, Bangladesh, Sri Lanka, Bhutan, and Maldives located through the following data bases: PubMed, PubMed central, EMBASE, MEDLINE, BioMed central, Directory of Open Access Journals (DOAJ) and electronic libraries of the authors' institutions. Data extraction and quality appraisal of included studies was done independently by two authors and findings were synthesized in a narrative manner as meta-analysis was found to be inappropriate due to heterogeneity of the included studies. RESULTS: Eleven primary studies were included in the final review, all of which were conducted in school settings in India, Pakistan and Bangladesh. Prevalence of overweight and obesity showed wide variations in the included studies. The key individual risk factors with statistically significant associations to overweight and obesity included: lack of physical activities reported in six studies; prolonged TV watching/playing computer games reported in four studies; frequent consumption of fast food/junk food reported in four studies; and frequent consumption of calorie dense food items reported in two studies. Family level risk factors included higher socioeconomic status reported in four studies and family history of obesity reported in three studies. CONCLUSION: This review provides evidence of key contributors to the increasing burden of obesity and overweight among children and adolescents in South Asia, and demonstrates the nutritional transition that characterizes other developing countries and regions around the world. The findings have implications for policy, practice and the development of interventions at various levels to promote healthy eating and physical activity among children and adolescents in the region as well as more globally. PMID- 25746157 TI - Vascular calcification on plain radiographs is related with the severity of lesions detected by coronary angiography in dialysis patients. AB - Coronary artery disease (CAD) is a primary cause of mortality and morbidity in dialysis patients. However, it is difficult to select the proper point for coronary angiographic procedure, because dialysis patients frequently do not display typical symptoms. Vascular calcification (VC) scores of artery or aorta on plain radiographs are associated with CAD events and may be predictive of CAD in dialysis patients. Therefore, we evaluated whether high or meaningful VC scores on plain radiographs are related with the severity of lesions detected by coronary angiography (CAG) in dialysis patients. We retrospectively enrolled dialysis patients who underwent CAG and checked several plain radiographs within one year before or after CAG. Significant VC is defined as high or meaningful VC scores, such as long abdominal aortic calcification and medial artery calcification on feet. Of all 55 patients, 41 patients (74.5%) exhibited significant VC on plain radiographs and 23 patients (41.8%) underwent stent insertion. Among the 23 patients, longer stents were used in 18 patients with significant VC (34.1 +/- 19.5 mm vs. 16.6 +/- 15.2 mm, P = 0.029). Patients with significant VC showed higher prevalence rate of severe coronary artery calcification (P = 0.007) and diffuse/tubular stenosis (P = 0.012), detected by CAG, than those without significant VC. Thus, high or meaningful VC scores on plain radiographs were associated with the degree of calcification or stenosis detected by CAG. In conclusion, VC scores on plain radiographs may be predictive of calcification or stenosis of coronary artery before CAG in dialysis patients. PMID- 25746158 TI - Recommendations for preventing stillbirth: a regional population-based study in Japan during 2007-2011. AB - The perinatal mortality rate in Japan has recently been at the lowest level in the world. However, the perinatal mortality rate of Shiga prefecture has been continuously higher than the Japanese average. The reason for this has not yet been explained. The perinatal mortality rate comprises both stillbirths and neonatal deaths. As stillbirths were almost double neonatal deaths, we focused on the stillbirths to determine how they might be prevented. All of the stillbirth certificates in Shiga Prefecture during 2007-2011 were inspected. On the basis of that information, we designed the original questionnaire and sent it to each obstetrician submitting a death certificate to obtain further information associated with the stillbirth. Reviewing retrospectively returned questionnaires by a peer-review team, we evaluated the possibility of preventing stillbirth along with recommendations for prevention. There were 252 stillbirths among 66,682 deliveries in Shiga during this period. We were able to analyze 188 stillbirths (75%). The audit conference judged that 47 cases of them (25%) were determined to have had some possibility of prevention with seven cases (4%) having strong possibility. We identified major causes of preventable stillbirths, including substandard obstetrical management, delayed referral of high-risk women from primary obstetrical clinics to higher perinatal centers, and delayed visits of pregnant women with decreased fetal movements to clinics or hospitals. Based on the results of this study, we conclude that education for pregnant women is required as well as the necessity of improving obstetric care to prevent stillbirths. PMID- 25746159 TI - Impact of incarceration on rates of methadone use in a community recruited cohort of injection drug users. AB - BACKGROUND: Despite barriers to its use in many settings, opioid agonist therapy with methadone has become the standard of care for treating opioid (e.g. heroin) use disorder. Since people with opioid use disorders have an increased incidence of incarceration, we undertook the present study to evaluate the association between incarceration and methadone maintenance therapy among a cohort of injection drug users in a Canadian setting. METHODS: A cohort of people who inject drugs was prospectively followed between May 1996 and May 2013 in Vancouver, Canada. We investigated the relationship between recent incarceration and methadone use using multivariate generalized estimating equation (GEE) logistic regression analysis. RESULTS: Overall, 2758 individuals were recruited during the study period and followed for a median of 64 (interquartile range: 23 106) months. After adjusting for various potential confounders in the multivariate GEE model, being incarcerated remained independently associated with a lower likelihood of having received methadone treatment (Adjusted Odds Ratio: 0.87, 95% confidence interval: 0.81-0.93). CONCLUSIONS: Our study demonstrates that incarceration was independently associated with a significantly lower likelihood of being on methadone. Given the role of methadone in reducing the harms of heroin use, including drug acquisitive crime and recidivism, these data suggest a need to scale-up methadone provision for incarcerated injection drug users. PMID- 25746160 TI - Measuring alcohol-related consequences and motives among students attending Historically Black Colleges and Universities. AB - INTRODUCTION: College student drinkers have the propensity to engage in heavy alcohol consumption. These consumption patterns can be problematic given the well established relationship between heavy drinking and negative consequences of alcohol consumption. Though the research on college student drinking is abundant, much of the work conducted has been with Caucasian samples and less so with African American samples or at Historically Black Colleges and Universities (HBCUs). METHODS: The current paper assessed the internal reliability and concurrent validity of two popular measures of alcohol related negative consequences (CAPS-r and YAACQ) and a measure of drinking motives (DMQ-R) within a HBCU sample. RESULTS: Total scores for the CAPS-r and YAACQ and all five subscales of the DMQ-R were internally reliable as determined by Cronbach's alpha. Correlations and regressions established concurrent validity for both measures of negative consequences as well as the subscales for the DMQ-R. CONCLUSIONS: Findings support the use of these measures in the assessment of negative consequences and motivations for alcohol consumption within a HBCU population. PMID- 25746161 TI - Membrane transporter engineering in industrial biotechnology and whole cell biocatalysis. AB - Because they mainly do not involve chemical changes, membrane transporters have been a Cinderella subject in the biotechnology of small molecule production, but this is a serious oversight. Influx transporters contribute significantly to the flux towards product, and efflux transporters ensure the accumulation of product in the much greater extracellular space of fermentors. Programmes for improving biotechnological processes might therefore give greater consideration to transporters than may have been commonplace. Strategies for identifying important transporters include expression profiling, genome-wide knockout studies, stress based selection, and the use of inhibitors. In addition, modern methods of directed evolution and synthetic biology, especially those effecting changes in energy coupling, offer huge opportunities for increasing the flux towards extracellular product formation by transporter engineering. PMID- 25746162 TI - Source-separated urine opens golden opportunities for microbial electrochemical technologies. AB - The food security of a booming global population demands a continuous and sustainable supply of fertilisers. Their current once-through use [especially of the macronutrients nitrogen (N), phosphorus (P), and potassium (K)] requires a paradigm shift towards recovery and reuse. In the case of source-separated urine, efficient recovery could supply 20% of current macronutrient usage and remove 50 80% of nutrients present in wastewater. However, suitable technology options are needed to allow nutrients to be separated from urine close to the source. Thus far none of the proposed solutions has been widely implemented due to intrinsic limitations. Microbial electrochemical technologies (METs) have proved to be technically and economically viable for N recovery from urine, opening the path for novel decentralised systems focused on nutrient recovery and reuse. PMID- 25746163 TI - [Anesthesiologist: the patient's perception]. AB - BACKGROUND AND OBJECTIVES: Anesthesia is still a major concern for patients, although the anesthetic complications have decreased significantly. Additionally, the role assigned to the anesthesiologist remains inaccurate. The aim of this study was to evaluate the concerns with anesthesia and assess the patient's knowledge about the anesthesiologist's duties. METHODS: Prospective study conducted over three months with patients in the preoperative anesthetic visit in a university hospital. Demographic information about the level of education and prior anesthesia was obtained. The knowledge of patients regarding the anesthesiologists' education was evaluated. Patients' concerns and anesthesiologist and surgeon responsibilities were classified with a 5-point scale. The analysis was performed with SPSS 21, and p<0.05 was considered statistically significant. RESULTS: We included 204 patients, and 135 (66.2%) recognized the anesthesiologist as a specialist physician. Not waking up after surgery and postoperative infection were the main concerns compared to all others (p<0.05). Women expressed more concern than men about not waking up after surgery, nausea and postoperative vomiting, medical problems, and waking up during surgery (p<0.05). Ensure that patients do not wake up during surgery was the anesthesiologist task most recognized, compared to all other (p<0.05). The surgeon was more recognized (p<0.05) than the anesthesiologist in post-operative, antibiotics administration, and blood transfusions pain management. CONCLUSIONS: Patients need to be informed about the current safety of anesthesia and the anesthesiologist's functions. The patient involvement will demystify some fears and reassure the confidence in the health system. PMID- 25746164 TI - [Effectiveness of combined regional-general anesthesia for reducing mortality in coronary artery bypass: meta-analysis]. AB - BACKGROUND AND OBJECTIVES: Neuraxial anesthesia (NA) has been used in association with general anesthesia (GA) for coronary artery bypass; however, anticoagulation during surgery makes us question the viability of benefits by the risk of epidural hematoma. The aim of this study was to perform a meta-analyzes examining the efficacy of NA associated with GA compared to GA alone for coronary artery bypass on mortality reduction. METHODS: Mortality, arrhythmias, cerebrovascular accident (CVA), myocardial infarction (MI), length of hospital stay (LHS), length of ICU stay (ICUS), reoperations, blood transfusion (BT), quality of life, satisfaction degree, and postoperative cognitive dysfunction were analyzed. The weighted mean difference (MD) was estimated for continuous variables, and relative risk (RR) and risk difference (RD) for categorical variables. RESULTS: 17 original articles analyzed. Meta-analysis of mortality (RD=-0.01, 95% CI=-0.03 to 0.01), CVA (RR=0.79, 95% CI=0.32 to 1.95), MI (RR=0.96, 95% CI=0.52 to 1.79) and LHS (MD=-1.94, 95% CI=-3.99 to 0.12) were not statistically significant. Arrhythmia was less frequent with NA (RR=0.68, 95% CI=0.50 to 0.93). ICUS was lower in NA (MD=-2.09, 95% CI=-2.92 to -1.26). CONCLUSION: There was no significant difference in mortality. Combined NA and GA showed lower incidence of arrhythmias and lower ICUS. PMID- 25746165 TI - Genetic characterization of a novel astrovirus in Pekin ducks. AB - Three divergent groups of duck astroviruses (DAstVs), namely DAstV-1, DAstV-2 (formerly duck hepatitis virus type 3) and DAstV-3 (isolate CPH), and other avastroviruses are known to infect domestic ducks. To provide more data regarding the molecular epidemiology of astroviruses in domestic ducks, we examined the prevalence of astroviruses in 136 domestic duck samples collected from four different provinces of China. Nineteen goose samples were also included. Using an astrovirus-specific reverse transcription-PCR assay, two groups of astroviruses were detected from our samples. A group of astroviruses detected from Pekin ducks, Shaoxing ducks and Landes geese were highly similar to the newly discovered DAstV-3. More interestingly, a novel group of avastroviruses, which we named DAstV-4, was detected in Pekin ducks. Following full-length sequencing and sequence analysis, the variation between DAstV-4 and other avastroviruses in terms of lengths of genome and internal component was highlighted. Sequence identity and phylogenetic analyses based on the amino acid sequences of the three open reading frames (ORFs) clearly demonstrated that DAstV-4 was highly divergent from all other avastroviruses. Further analyses showed that DAstV-4 shared low levels of genome identities (50-58%) and high levels of mean amino acid genetic distances in the ORF2 sequences (0.520-0.801) with other avastroviruses, suggesting DAstV-4 may represent an additional avastrovirus species although the taxonomic relationship of DAstV-4 to DAstV-3 remains to be resolved. The present works contribute to the understanding of epidemiology, ecology and taxonomy of astroviruses in ducks. PMID- 25746166 TI - Prospective safety performance evaluation on construction sites. AB - This paper presents a systematic Structural Equation Modeling (SEM) based approach for Prospective Safety Performance Evaluation (PSPE) on construction sites, with causal relationships and interactions between enablers and the goals of PSPE taken into account. According to a sample of 450 valid questionnaire surveys from 30 Chinese construction enterprises, a SEM model with 26 items included for PSPE in the context of Chinese construction industry is established and then verified through the goodness-of-fit test. Three typical types of construction enterprises, namely the state-owned enterprise, private enterprise and Sino-foreign joint venture, are selected as samples to measure the level of safety performance given the enterprise scale, ownership and business strategy are different. Results provide a full understanding of safety performance practice in the construction industry, and indicate that the level of overall safety performance situation on working sites is rated at least a level of III (Fair) or above. This phenomenon can be explained that the construction industry has gradually matured with the norms, and construction enterprises should improve the level of safety performance as not to be eliminated from the government-led construction industry. The differences existing in the safety performance practice regarding different construction enterprise categories are compared and analyzed according to evaluation results. This research provides insights into cause-effect relationships among safety performance factors and goals, which, in turn, can facilitate the improvement of high safety performance in the construction industry. PMID- 25746167 TI - Mobile phone use while driving: a hybrid modeling approach. AB - The analysis of the effects that mobile phone use produces while driving is a topic of great interest for the scientific community. There is consensus that using a mobile phone while driving increases the risk of exposure to traffic accidents. The purpose of this research is to evaluate the drivers' behavior when they decide whether or not to use a mobile phone while driving. For that, a hybrid modeling approach that integrates a choice model with the latent variable "risk perception" was used. It was found that workers and individuals with the highest education level are more prone to use a mobile phone while driving than others. Also, "risk perception" is higher among individuals who have been previously fined and people who have been in an accident or almost been in an accident. It was also found that the tendency to use mobile phones while driving increases when the traffic speed reduces, but it decreases when the fine increases. Even though the urgency of the phone call is the most important explanatory variable in the choice model, the cost of the fine is an important attribute in order to control mobile phone use while driving. PMID- 25746168 TI - Serum concentrations of L-arginine and L-homoarginine in male patients with intermittent claudication: a cross-sectional and prospective investigation in the CAVASIC Study. AB - BACKGROUND: High serum concentrations of l-arginine and l-homoarginine increase nitric oxide (NO) availability and thereby improve endothelial function. Information about the association of these markers with peripheral arterial disease (PAD) and related outcomes is sparse. METHODS: l-arginine, its metabolites and l-homoarginine were analyzed in the CAVASIC Study including 232 male patients diagnosed with intermittent claudication and 246 age- and diabetes matched controls. After the baseline investigation PAD patients were prospectively followed (median 7 years). The association of these markers with symptomatic PAD at baseline, incident cardiovascular events and all-cause mortality was assessed. RESULTS: At baseline each increase of ln-l-homoarginine and l-arginine by one standard deviation was associated with symptomatic PAD: OR=0.75, 95%CI 0.59-0.96, P=0.02 and OR=1.36, 95%CI 1.07-1.73, P=0.01, respectively (both models adjusted for ln-CRP, GFR, HDL cholesterol, and current smoking). Only l-arginine remained significant after additional adjustment for ln NT-proBNP and hs-cTnT: OR=1.49, P=0.002. In the Cox regression analysis elevated ln-l-homoarginine significantly reduced the risk to die (n=38) even independent from ln-NT-proBNP and hs-cTnT: HR=0.59, 95%CI 0.41-0.84, P=0.004. l-arginine was significantly predicting incident cardiovascular events (n=65): HR=1.68, 95%CI 1.35-2.10, P < 0.001. CONCLUSIONS: This study in male patients with intermittent claudication and age- and diabetes-matched controls showed an association of l homoarginine and l-arginine with PAD. During follow-up, l-arginine was associated with incident cardiovascular events probably due to its primary role in NO metabolism and impact on endothelial integrity. l-homoarginine was related to all cause mortality implying a broader role in metabolic processes besides endothelial function. PMID- 25746169 TI - Risk factors for the progression of carotid intima-media thickness over a 16-year follow-up period: the Malmo Diet and Cancer Study. AB - OBJECTIVE: To evaluate the progression of carotid intima-media thickness (IMT) in the common carotid artery (CCA) and the bifurcation over a mean follow-up of 16 years in relation to cardiovascular risk factors. METHODS: The study population included 3426 middle-aged Swedish men and women participating in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the cardiovascular cohort of the Malmo Diet and Cancer Study (MDCS). RESULTS: There were differences in risk factor patterns in arterial segments in that diabetes and male sex were associated with the progression of IMT in the bifurcation, but not in the CCA, and high-density lipoprotein cholesterol (HDL) was associated with the progression of IMT in the CCA, but not in the bifurcation. Favourable changes in systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL) and HDL during follow-up decreased the IMT progression rate in the CCA. There was a cumulative relationship between traditional cardiovascular risk factors (i.e., regular smoking, LDL/HDL-ratio >= 3, hypertension) and IMT progression rates. The odds ratio (OR) of high IMT CCA progression rate (>75th percentile) was 1.0 (reference), 1.4 (95% CI: 1.1, 1.7), 1.7 (95% CI: 1.3, 2.2) and 2.1 (95% CI: 1.4, 3.1), respectively, for individuals with none, one, two, and three risk factors. CONCLUSION: There were differences in the associations between risk factors and progression rate in different arterial segments. Favourable changes in SBP and lipids during the follow-up period were associated with reduced IMT progression rates in the CCA. PMID- 25746170 TI - Association of adoptive child's thought disorders and schizophrenia spectrum disorders with their genetic liability for schizophrenia spectrum disorders, season of birth and parental Communication Deviance. AB - Joint effects of genotype and the environment have turned out to be significant in the development of psychotic disorders. The purpose of the present study was to assess the association of an adoptive child's thought and schizophrenia spectrum disorders with genetic and environmental risk indicators and their interactions. A subgroup of the total sample used in the Finnish Adoptive Family Study was considered in the present study. The subjects were 125 adoptees at a high (n=53) or low (n=72) genetic risk of schizophrenia spectrum disorders and their adoptive parents. The risk factors evaluated were the adoptive child's genetic risk for schizophrenia spectrum disorders, winter or spring birth and parental Communication Deviance (CD). Thought disorders in the adoptees were assessed using the Thought Disorder Index and diagnoses were made according to DSM-III-R criteria. The adoptive child's Thought Disorder Index was only associated with parental Communication Deviance. The adoptive child's heightened genetic risk or winter or spring birth or parental CD or their interactions did not predict the adoptee's schizophrenia spectrum disorder. The results suggest that studies taking several risk indicators and their interactions into account may change views on the mutual significance of well-known risk factors. PMID- 25746171 TI - Psychotic experiences as indicators of suicidal ideation in a non-clinical college sample. AB - Suicide is a leading cause of preventable death. Epidemiological studies have shown strong associations between sub-threshold psychotic experiences and risk for suicidal ideation and behavior. Screens designed to assess psychotic experiences may have clinical utility in improving suicide prevention efforts. In the current study, we hypothesized that the Prodromal Questionnaire-Brief (PQ-B) would reliably distinguish levels of suicidal ideation within a sample of college students (n=376). As predicted, PQ-B scores varied significantly across levels of suicidal ideation, both when treated as a raw count of sub-threshold psychotic experiences and when taking into account subjective distress associated with those symptoms. In addition, we explored the feasibility of developing a short screen based on the most discriminating items, finding that a six-item version of the PQ-B yielded higher accuracy for detecting elevated suicidal ideation over the full measure. The PQ-B has the potential for clinical utility in detecting groups that might be at increased risk for suicidal ideation. PMID- 25746172 TI - Childhood body mass index trajectories predicting cardiovascular risk in adolescence. AB - PURPOSE: The present study compared growth parameters of girls' and boys' body mass index (BMI) trajectories from infancy to middle childhood and evaluated these parameters as predictors of cardiovascular disease (CVD) risk in adolescence. METHODS: Using 657 children from the NICHD Study of Early Child Care and Youth Development, quadratic growth curve analyses were conducted to establish growth parameters (intercept, slope, and quadratic term) for girls and boys from age 15 months to 10.5 years. Parameters were compared across gender and evaluated as predictors of a CVD risk index at the age of 15 years, controlling for characteristics of the adiposity rebound (AR) including age at which it occurred and children's BMI at the rebound. RESULTS: Boys had more extreme trajectories of growth than girls with higher initial BMI at age 15 months (intercept), more rapid declines in BMI before the AR (slope), and sharper rebound growth in BMI after the rebound (quadratic term). For boys and girls, higher intercept, slope, and quadratic term values predicted higher CVD risk at the age of 15 years, controlling for characteristics of the AR. CONCLUSIONS: Findings suggest that individuals at risk for developing CVD later in life may be identified before the AR by elevated BMI at 15 months and slow BMI declines. Because of the importance of early intervention in altering lifelong health trajectories, consistent BMI monitoring is essential in identifying high-risk children. PMID- 25746174 TI - The proper reload selection during laparoscopic sleeve gastrectomy. PMID- 25746175 TI - Mitochondrial transfer from Wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function. AB - Adult mesenchymal stem cell (MSC)-conducted mitochondrial transfer has been recently shown to rescue cellular bioenergetics and prevent cell death caused by mitochondrial dysfunction. Wharton's jelly-derived MSCs (WJMSCs) harvested from postpartum umbilical cords are an accessible and abundant source of stem cells. This study aimed to determine the capability of WJMSCs to transfer their own mitochondria and rescue impaired oxidative phosphorylation (OXPHOS) and bioenergetics caused by mitochondrial DNA defects. To do this, WJMSCs were co cultured with mitochondrial DNA (mtDNA)-depleted rho(0) cells and the recapture of mitochondrial function was evaluated. WJMSCs were shown to be capable of transferring their own mitochondria into rho(0) cells and underwent interorganellar mixture within these cells. Permissive culture media (BrdU containing and pyruvate- and uridine-free) sieved out a survival cell population from the co-cultured WJMSCs (BrdU-sensitive) and rho(0) cells (pyruvate/uridine free). The survival cells had mtDNA identical to that of WJMSCs, whereas they expressed cellular markers identical to that of rho(0) cells. Importantly, these rho(0)-plus -WJMSC-mtDNA (rho(+W)) cells recovered the expression of mtDNA encoded proteins and exhibited functional oxygen consumption and respiratory control, as well as the activity of electron transport chain (ETC) complexes I, II, III and IV. In addition, ETC complex V-inhibitor-sensitive ATP production and metabolic shifting were also recovered. Furthermore, cellular behaviors including attachment-free proliferation, aerobic viability and OXPHOS-reliant cellular motility were also regained after mitochondrial transfer by WJMSCs. The therapeutic effect of WJMSCs-derived mitochondrial transfer was able to stably sustain for at least 45 passages. In conclusion, this study suggests that WJMSCs may serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction through the donation of healthy mitochondria to cells with genetic mitochondrial defects. PMID- 25746176 TI - Shear strength characteristics of mechanically biologically treated municipal solid waste (MBT-MSW) from Bangalore. AB - Strength and stiffness properties of municipal solid waste (MSW) are important in landfill design. This paper presents the results of comprehensive testing of shear strength properties of mechanically biologically treated municipal solid waste (MBT-MSW) in laboratory. Changes in shear strength of MSW as a function of unit weight and particle size were investigated by performing laboratory studies on the MSW collected from Mavallipura landfill site in Bangalore. Direct shear tests, small scale and large scale consolidated undrained and drained triaxial tests were conducted on reconstituted compost reject MSW samples. The triaxial test results showed that the MSW samples exhibited a strain-hardening behaviour and the strength of MSW increased with increase in unit weight. Consolidated drained tests showed that the mobilized shear strength of the MSW increased by 40% for a unit weight increase from 7.3kN/m(3) to 10.3kN/m(3) at 20% strain levels. The mobilized cohesion and friction angle ranged from 5 to 9kPa and 8 degrees to 33 degrees corresponding to a strain level of 20%. The consolidated undrained tests exhibited reduced friction angle values compared to the consolidated drained tests. The friction angle increased with increase in the unit weight from 8 degrees to 55 degrees in the consolidated undrained tests. Minor variations were found in the cohesion values. Relationships for strength and stiffness of MSW in terms of strength and stiffness ratios are developed and discussed. The stiffness ratio and the strength ratio of MSW were found to be 10 and 0.43. PMID- 25746173 TI - The use of nonhuman primates in research on seasonal, pandemic and avian influenza, 1893-2014. AB - Attempts to reproduce the features of human influenza in laboratory animals date from the early 1890s, when Richard Pfeiffer inoculated apes with bacteria recovered from influenza patients and produced a mild respiratory illness. Numerous studies employing nonhuman primates (NHPs) were performed during the 1918 pandemic and the following decade. Most used bacterial preparations to infect animals, but some sought a filterable agent for the disease. Since the viral etiology of influenza was established in the early 1930s, studies in NHPs have been supplemented by a much larger number of experiments in mice, ferrets and human volunteers. However, the emergence of a novel swine-origin H1N1 influenza virus in 1976 and the highly pathogenic H5N1 avian influenza virus in 1997 stimulated an increase in NHP research, because these agents are difficult to study in naturally infected patients and cannot be administered to human volunteers. In this paper, we review the published literature on the use of NHPs in influenza research from 1893 through the end of 2014. The first section summarizes observational studies of naturally occurring influenza-like syndromes in wild and captive primates, including serologic investigations. The second provides a chronological account of experimental infections of NHPs, beginning with Pfeiffer's study and covering all published research on seasonal and pandemic influenza viruses, including vaccine and antiviral drug testing. The third section reviews experimental infections of NHPs with avian influenza viruses that have caused disease in humans since 1997. The paper concludes with suggestions for further studies to more clearly define and optimize the role of NHPs as experimental animals for influenza research. PMID- 25746177 TI - Numerical and experimental studies on effects of moisture content on combustion characteristics of simulated municipal solid wastes in a fixed bed. AB - In order to reveal the features of the combustion process in the porous bed of a waste incinerator, a two-dimensional unsteady state model and experimental study were employed to investigate the combustion process in a fixed bed of municipal solid waste (MSW) on the combustion process in a fixed bed reactor. Conservation equations of the waste bed were implemented to describe the incineration process. The gas phase turbulence was modeled using the k-epsilon turbulent model and the particle phase was modeled using the kinetic theory of granular flow. The rate of moisture evaporation, devolatilization rate, and char burnout was calculated according to the waste property characters. The simulation results were then compared with experimental data for different moisture content of MSW, which shows that the incineration process of waste in the fixed bed is reasonably simulated. The simulation results of solid temperature, gas species and process rate in the bed are accordant with experimental data. Due to the high moisture content of fuel, moisture evaporation consumes a vast amount of heat, and the evaporation takes up most of the combustion time (about 2/3 of the whole combustion process). The whole bed combustion process reduces greatly as MSW moisture content increases. The experimental and simulation results provide direction for design and optimization of the fixed bed of MSW. PMID- 25746178 TI - Hazardous waste status of discarded electronic cigarettes. AB - The potential for disposable electronic cigarettes (e-cigarettes) to be classified as hazardous waste was investigated. The Toxicity Characteristic Leaching Procedure (TCLP) was performed on 23 disposable e-cigarettes in a preliminary survey of metal leaching. Based on these results, four e-cigarette products were selected for replicate analysis by TCLP and the California Waste Extraction Test (WET). Lead was measured in leachate as high as 50mg/L by WET and 40mg/L by TCLP. Regulatory thresholds were exceeded by two of 15 products tested in total. Therefore, some e-cigarettes would be toxicity characteristic (TC) hazardous waste but a majority would not. When disposed in the unused form, e cigarettes containing nicotine juice would be commercial chemical products (CCP) and would, in the United States (US), be considered a listed hazardous waste (P075). While household waste is exempt from hazardous waste regulation, there are many instances in which such waste would be subject to regulation. Manufactures and retailers with unused or expired e-cigarettes or nicotine juice solution would be required to manage these as hazardous waste upon disposal. Current regulations and policies regarding the availability of nicotine containing e-cigarettes worldwide were reviewed. Despite their small size, disposable e-cigarettes are consumed and discarded much more quickly than typical electronics, which may become a growing concern for waste managers. PMID- 25746179 TI - Efficacy of methuselah gene mutation toward tolerance of dichlorvos exposure in Drosophila melanogaster. AB - Adverse reports on the exposure of organisms to dichlorvos (DDVP; an organophosphate insecticide) necessitate studies of organismal resistance/tolerance by way of pharmacological or genetic means. In the context of genetic modulation, a mutation in methuselah (mth; encodes a class II G protein-coupled receptor (GPCR)) is reported to extend (~35%) the life span of Drosophila melanogaster and enhance their resistance to oxidative stress induced by paraquat exposure (short term, high level). A lack of studies on organismal tolerance of DDVP by genetic modulation prompted us to examine the protective efficacy of mth mutation in exposed Drosophila. Flies were exposed to 1.5 and 15.0 ng/ml DDVP for 12-48 h to examine oxidative stress endpoints and chemical resistance. After prolonged exposure of flies to DDVP, antioxidant enzyme activities, oxidative stress, glutathione content, and locomotor performance were assayed at various days (0, 10, 20, 30, 40, 50) of age. Flies with the mth mutation (mth(1)) showed improved chemical resistance and rescued redox impairment after acute DDVP exposure. Exposed mth(1) flies exhibited improved life span along with enhanced antioxidant enzyme activities and rescued oxidative perturbations and locomotor insufficiency up to middle age (~20 days) over similarly exposed w(1118) flies. However, at late (>=30 days) age, these benefits were undermined. Further, similarly exposed mth-knockdown flies showed effects similar to those observed in mth(1) flies. This study provides evidence of tolerance in organisms carrying a mth mutation against prolonged DDVP exposure and further warrants examination of similar class II GPCR signaling facets toward better organismal health. PMID- 25746181 TI - Buckling of particle-laden interfaces. AB - In this paper, we investigate the buckling of an oil-water interface populated by micron-sized latex particles using a Langmuir trough. In this work, we extend results of buckling of particle-laden interfaces from the millimeter down to the submicron range while investigating the effect of a different capillary length on the resulting wavelength. The experimental data is compared to the existing theoretical framework. An unexpected deviation from the prediction of theory of the dominant wavelength of buckling is observed for particles smaller than one micron. Those observations suggest that there is a transition to a new buckling regime involving the formation of trilayers below one micron. For the first time in particle rafts, cascading of the dominant wavelength similar to that observed in thin polymer films is reported. In addition a series of transitions between wavelengths not observed in thin films is observed within the same particle raft. Lastly, the effect of compression history on the macroscopic arrangement of particles is investigated, along with its effect on the buckling wavelength. PMID- 25746180 TI - Concentration-driven phase control for low temperature synthesis of phase-pure anatase and rutile titanium oxide. AB - It is highly desirable to develop controlled synthetic methods at low temperature (<100 degrees C) for defined phases of titanium oxide nanoparticle. We present here a simple low temperature approach which is based on the peroxide route. This approach allows the preparation of phase-pure rutile and anatase without the use of any additives or surfactants or external acids. The formation of crystalline phases is found to be dependent on reaction temperature and highly dependent on concentration. Phase-pure rutile is obtained in two concentration zones while phase-pure anatase is obtained in one concentration zone. The relationship between phases and reaction conditions (concentration and temperature) fits well with the nucleation diffusion rate model. PMID- 25746182 TI - Separation of dielectric Janus particles based on polarizability-dependent induced-charge electroosmotic flow. AB - A new method of sorting dielectric Janus particle is proposed and studied numerically in this paper. The Janus particles are composed of two hemispheres of two different dielectric materials. When the particle is placed in a microchannel under uniform DC electric field along the channel, vortices are induced near the particle. The strengths of the four vortices are determined by the dielectric permittivity of the particle surface, the size of the particle, the external electric field and the orientation of the Janus particle in the electric field. The numerical simulation results show that the dividing line of the Janus particle will align with the channel walls in the uniform electric field. The equilibrium distance between the wall and a particle is determined by the relative polarizability ratio and the size of the Janus particle. Thus Janus particles of the same polarizability ratio and the same size will follow the same streamline; Janus particles of different polarizability ratio and different sizes will have different trajectories. Consequently, by inducing different streamlines into different branch channels, Janus particles can be separated and collected by their polarizability ratios and their sizes. PMID- 25746183 TI - Influence of the electrostatic interactions in a Pickering emulsion polymerization for the synthesis of silica-polystyrene hybrid nanoparticles. AB - HYPOTHESIS: Silica-polystyrene hybrid nanoparticles were synthesized by Pickering emulsion polymerization. The coupling effect of initiator type and silica surface charge was studied to exhibit the predominant role of electrostatic interactions in the synthesis mechanisms. EXPERIMENTS: Non-ionic hydrophobic initiator (2,2' azobis(2-methylpropionitrile), AIBN) or anionic hydrophilic initiator (sodium persulfate, NaPS), and positively or negatively charged silica were used as reactants with styrene for Pickering emulsion polymerization. Their interactions were evaluated by Zeta potential measurements. The droplet size and the stability of the Pickering emulsions, and the hybrid particle morphology, surface coverage, size and agglomeration were evaluated by laser granulometry and microscopy. FINDINGS: Similar surface charge between negatively charged silica particles and an anionic initiator led to strong repulsions and thus to non-covered polystyrene nanoparticles. With positively charged silica, a high decoration was obtained due to attractive interactions between the inorganic and the organic phases, but a strong agglomeration was also observed. The use of a non-ionic initiator led to a homogeneous coverage with negatively charged silica. With positively charged silica micronic sizes were formed by following two different mechanisms. These data, by enriching the existing literature, led to a more complete and robust description of the emulsion polymerization synthesis for hybrid nanostructures. PMID- 25746184 TI - Enhancing performance of P3HT:TiO2 solar cells using doped and surface modified TiO2 nanorods. AB - Here we demonstrated an approach to increase performance of P3HT:TiO2 solar cell either by electron deficient boron or electron rich bismuth doping into TiO2 nanorods. The B doping increases the absorption, crystallinity and electron mobility of TiO2 nanorods. The Bi-doped TiO2 has higher J(sc) as compared with B doped TiO2, mainly due to the improvement of electron density and increased absorption of TiO2 nanorods. The devices were fabricated from TiO2 nanorods being surface modified by organic dye W-4. The dye facilitates the bandgap alignment and compatibility between TiO2 and P3HT. The power conversion efficiency of solar cell has been increased by 1.33 times and 1.30 times for Bi-doped TiO2 and B doped TiO2, respectively, as compared with that of as-synthesized TiO2. The results suggest the optical and electronic properties of TiO2 can be tuned by various dopants to enhance the device performance. PMID- 25746185 TI - Synthesis, characterization and DFT-modeling of novel agents for the protection and restoration of historical calcareous stone substrates. AB - The ammonium salts of oxamate (AmOxam) and monomethyloxalate (AmMeox), structurally related to ammonium oxalate (AmOx), were synthesized and characterized as protecting agents/filler for calcareous stone substrates. Both compounds featured an improved solubility in water and alcoholic-water mixtures with respect to AmOx. While AmOxam is stable in aqueous solution and reacts with calcite to afford the corresponding insoluble calcium oxamate (CaOxam), AmMeox spontaneously undergoes hydrolysis to give ammonium monohydrogen oxalate hemihydrate (AmBiox) and calcium oxalate (CaOx). Both compounds have been tested for the restoration of naturally weathered marble and biomicritic limestone. The formation of a superficial layer of CaOxam and CaOx was observed on stone samples treated with AmOxam and AmMeox, respectively, depending on the solvent mixture. A quantum-mechanical study was carried out at DFT level in order to investigate the nature of the interactions occurring between the lithic substrate (calcite) and the passivating agents, showing how the structural modifications on oxalic acid derivatives can be exploited to fine-tune their interaction with the calcite surface. PMID- 25746186 TI - Effects of pH, dissolved oxygen, and aqueous ferrous iron on the adsorption of arsenic to lepidocrocite. AB - The adsorption of arsenic to iron oxyhydroxides strongly depends on water chemistry. Iron(III) oxyhydroxides can also participate in the oxidation of As(III) to As(V), which changes arsenic's toxicity and adsorption behavior. As(III) and As(V) adsorption to lepidocrocite (gamma-FeOOH) were examined in batch experiments that explored the effects of lepidocrocite dose, pH, availability of dissolved oxygen, and the presence of aqueous Fe(II) on adsorption. Lepidocrocite is an iron oxyhydroxide found in soils, and it is one of the major products of iron electrocoagulation for water treatment. A surface complexation model was able to describe the adsorption of both As(III) and As(V) to lepidocrocite over a broad range of conditions. The concentration and oxidation states of arsenic in solution were measured over the course of the reactions. At both oxic and anoxic conditions, As(III) was oxidized to As(V) in systems that contained lepidocrocite together with Fe(II); this oxidation led to overall enhanced arsenic adsorption at near neutral pH. With oxygen the pH dependent generation of oxidants from the Fenton reaction drove the As(III) oxidation. In the absence of oxygen the As(III) was probably oxidized by Fe(III) in lepidocrocite that had become more reactive upon reaction with Fe(II). PMID- 25746187 TI - Interaction of Moringa oleifera seed protein with a mineral surface and the influence of surfactants. AB - The paper describes the adsorption of purified protein from seeds of Moringa oleifera to a sapphire interface and the effects of addition of the anionic surfactant sodium dodecylsulfate (SDS) and the cationic surfactant hexadecyltrimethylammonium bromide (CTAB). Neutron reflection was used to determine the structure and composition of interfacial layers adsorbed at the solid/solution interface. The maximum surface excess of protein was found to be about 5.3 mg m(-2). The protein does not desorb from the solid/liquid interface when rinsed with water. Addition of SDS increases the reflectivity indicating co adsorption. It was observed that CTAB is able to remove the protein from the interface. The distinct differences to the behavior observed previously for the protein at the silica/water interface are identified. The adsorption of the protein to alumina in addition to other surfaces has shown why it is an effective flocculating agent for the range of impurities found in water supplies. The ability to tailor different surface layers in combination with various surfactants also offers the potential for adsorbed protein to be used in separation technologies. PMID- 25746188 TI - Competitive adsorption of heavy metal ions on carbon nanotubes and the desorption in simulated biofluids. AB - Carbon nanotubes (CNTs) had meaningful adsorption capacities for Pb(2+), Cu(2+), Zn(2+) and Cd(2+), while Pb(2+) showed the highest adsorption in the competitive adsorption evaluations. The desorption behaviors of heavy metal ions were completely different in various biofluids, where the desorption was significantly influenced by pH and the presence of proteins/other cations. The desorption was most effective in simulated stomach juice, and much less effective in other simulated biofluids. More Pb(2+) stuck to CNTs than others, resulting in less desorption. Interestingly, the competitive desorption behaviors of four ions were largely changed comparing to the individual desorption behaviors. The implications to the biosafety evaluations and synergistic effects of CNT are discussed. PMID- 25746189 TI - Dependence of capillary forces on relative humidity and the surface properties of femtosecond laser micromachined titanium. AB - Capillary forces were measured with colloidal atomic force microscopy at different levels of relative humidity on femtosecond laser micromachined titanium surfaces. After laser machining at different intensity levels, the titanium surfaces show a nanoscale ripple topology or microscopic bumpy structures. Different machining environments were chosen to influence the surface chemistry in addition to topology: while machining in pure oxygen and water resulted in surfaces consisting of TiO2, a composite surface of TiO2 and TiN was obtained after machining in pure nitrogen. All samples were subsequently exposed to pure oxygen, carbon dioxide or water, and showed different levels of wettability and capillary force. We have introduced the concept of humidity sensitivity as the relative increase of the capillary force with respect to the measured force at 0% humidity. We report that samples with a nanoscale ripple topology machined in pure oxygen exhibit the lowest level of capillary force and the lowest sensitivity towards humidity in the environment. Surfaces with low sensitivity towards changes of the relative humidity are good candidates for technical applications, where capillary forces have to be controlled. This study contributes to the development of such surfaces, to a better understanding of how capillary bridges are formed on rough surfaces and ultimately to the exploration of the relationship between surface wettability and capillary forces. PMID- 25746190 TI - Self-assembly and template-free synthesis of ZnO hierarchical nanostructures and their photocatalytic properties. AB - Despite significant progress in the field of semiconductor photocatalysis has been made, it is still a great challenge to prepare low-cost photocatalysts with high activities. In our work, three dimensional (3D) flower-like ZnO hierarchical nanostructures assembled with numerous nanosheets were fabricated by a simple, template-free and one-step hydrothermal route. The products were characterized by XRD, UV-Vis, PL, SEM, TEM, HRTEM techniques. In the process, NH4F played a crucial role for the formation of ZnO hierarchical nanostructures, which was acted both as the alkali source and morphology director. Furthermore, the growth of ZnO involved a phase transformation from intermediate compound ZnF(OH) to ZnO. To further improve the photocatalytic activity, Ag-doped ZnO photocatalyst was also prepared. The photocatalytic results indicated that the Ag/ZnO exhibited higher photocatalytic activity than the pure ZnO. The great enhancement was mainly ascribed to their unique hierarchical nanostructures as well as the modification of Ag nanoparticles. Additionally, both ZnO and Ag/ZnO microspheres showed good recycling stabilities over several separation cycles in photodegradation. PMID- 25746191 TI - Ferrocene-containing thixotropic molecular gels: creation and a novel strategy for water purification. AB - Low-molecular-mass gelators and relevant molecular gels have been employed for water purification owing to their convenience and efficiency, but the process is time consuming due to low extraction efficiency originated from limited contact of the two phases. In this work, two novel di-cholesterol-based gelators, 1 and 2, with a ferrocenyl unit were synthesized and the gels based on 2 possess a smart thixotropic property. In particular, 2/heptane gel, the shear force induced phase transition is fast (within seconds) and fully reversible without the need of heating-cooling cycle. Based upon the thixotropic molecular gel, a novel separation strategy, which combines the great efficiency of liquid-liquid extraction and the convenience of liquid-solid separation, has been successfully conducted for removing iodine from wastewater. It was demonstrated that iodine was removed within several minutes and the extraction efficiency (72%) was the same with the one using corresponding liquid. Furthermore, 2/heptane gel is also responsive to chemical oxidation and variation in temperature. FTIR, NMR, CD and XRD studies revealed that helical fibers were formed via intermolecular hydrogen bonding and van der Waals interaction. It is believed that the results presented in this work are of importance for extending real-life applications of molecular gels. PMID- 25746192 TI - Studies of heavy metal ion adsorption on chitosan/sulfydryl-functionalized graphene oxide composites. AB - Chitosan/Sulfydryl-functionalized graphene oxide composite (CS/GO-SH) was successfully synthesized via covalent modification and electrostatic self assembly. A facile diazonium chemical process was developed to fabricate sulfydryl-functionalized graphene oxide (GO-SH) by introducing sulfydryl compounds to the graphene oxide sheets (GO), and the GO-SH was used to self assemble with chitosan via an electrostatic interaction. The chemical structure and morphology of the CS/GO-SH composite were characterized by Fourier transformed infrared, Raman spectroscopy, scanning electron microscopy, X-ray powder diffraction and thermogravimetric examination. The results indicated that the CS/GO-SH was a new type of with multifunctional groups such as -OH, -COOH, SH and -NH2. Simultaneously, the self-assembly of chitosan with GO-SH sheets changed the blocky structure of the CS to the loosely packed structure which is analogous to graphene oxide sheets. The resulting CS/GO-SH was used as an adsorbent material for removal of Cu (II), Pb (II) and Cd (II) in single- and multi-metal ions systems. It was found that the CS/GO-SH has potential applications in fields of adsorptive materials due to its superiority of the chemical characteristic and the specific surface area. PMID- 25746193 TI - Design, synthesis, and physico-chemical interactions of bile acid derived dimeric phospholipid amphiphiles with model membranes. AB - Understanding of amphiphile-membrane interactions is crucial in design and development of novel amphiphiles for drug delivery, gene therapy, and biomedical applications. Structure and physico-chemical properties of amphiphiles determine their interactions with biomembranes thereby influencing their drug delivery efficacies. Here, we unravel the interactions of bile acid derived dimeric phospholipid amphiphiles with model membranes using Laurdan-based hydration, DPH based membrane fluidity, and differential scanning calorimetry studies. We synthesized three dimeric bile acid amphiphiles where lithocholic acid, deoxycholic acid, and cholic acid are conjugated to cholic acid phospholipid using click chemistry. Interactions of these dimeric amphiphiles with model membranes showed that these amphiphiles form different structural assemblies and molecular packing in model membranes depending on the number and position of free hydroxyl groups on bile acids. We discovered that cholic acid-cholic acid dimeric phospholipid form self-assembled aggregates in model membranes without changing membrane fluidity; whereas cholic acid-deoxycholic acid derived amphiphile induces membranes fluidity and hydration of model membranes. PMID- 25746194 TI - Preparation of AgI sensitized amorphous TiO2 as novel high-performance photocatalyst for environmental applications. AB - A novel visible-light-active material was prepared by dispersion of AgI on amorphous TiO2 through simple one-pot process (AgI/Am-TiO2-S). For comparison, AgI sensitized TiO2 (amorphous, anatase and P25) were also prepared via traditional deposition-precipitation method. The samples were characterized by XRD, XPS, TGA-DSC, UV-Vis-DRS, BET, and etc. Larger specific surface area, negative shift of flat band potential, as well as greatly reduced charge transfer resistance were observed for AgI/Am-TiO2-S comparing to other samples. Moreover, with the same molar of initial Ti and Ag, the weight of AgI/Am-TiO2-S obtained was the heaviest, due to large amount of surface titania hydrate. The photocatalytic activity of the as-prepared AgI/titania samples were evaluated by the reduction of Cr(VI) in the absence or presence of organic pollutants (dyes, phenol). AgI/Am-TiO2-S always presented the highest photocatalytic activity. The estimated k(Cr(VI)) on AgI/Am-TiO2-S was about 2 times that on AgI/P25-TiO2 in the absence/presence of RhB. Superior stability was also observed in the cyclic runs indicating that the as-prepared AgI/Am-TiO2-S is highly desirable for the remediation of Cr(VI)-organic co-contaminated wastewaters. PMID- 25746195 TI - New insight into the promoting role of process on the CeO2-WO3/TiO2 catalyst for NO reduction with NH3 at low-temperature. AB - This study aimed at investigating the reason of high catalytic activity for CeO2 WO3/TiO2 catalyst from the aspects of WO3 interaction with other species and the NO oxidation process. Analysis by X-ray diffractometry, photoluminescence spectra, diffuse reflectance UV-visible, X-ray photoelectron spectroscopy, density functional theory calculations, electron paramagnetic resonance spectroscopy, temperature-programmed-desorption of NO and in situ diffuse reflectance infrared transform spectroscopy showed that WO3 could interact with CeO2 to improve the electron gaining capability of CeO2 species. In addition, WO3 species acted as electron donating groups to transfer the electrons to CeO2 species. The two aspects enhanced the formation of reduced CeO2 species to improve the formation of superoxide ions. Furthermore, the Ce species were the active sites for the NO adsorption and the superoxide ions over the catalyst needed oxidizing the adsorbed NO to improve the NO oxidation. This process was responsible for the high catalytic activity of CeO2-WO3/TiO2 catalyst. PMID- 25746196 TI - Patients' impression of change following treatment for chronic pain: global, specific, a single dimension, or many? AB - The Patient Global Impression of Change (PGIC) measure has frequently been used as an indicator of meaningful change in treatments for chronic pain. However, limited research has examined the validity of PGIC items despite their wide adoption in clinical trials for pain. Additionally, research has not yet examined predictors of PGIC ratings following psychologically based treatment for pain. The purpose of the present study was to examine the validity, factor structure, and predictors of PGIC ratings following an interdisciplinary psychologically based treatment for chronic pain. Patients with chronic pain (N = 476) completed standard assessments of pain, daily functioning, and depression before and after a 4-week treatment program based on the principles of acceptance and commitment therapy. Following the program, patients rated 1 item assessing their impression of change overall and several items assessing their impression of more specific changes: physical and social functioning, work-related activities, mood, and pain. Results indicated that the global and specific impression of change items represent a single component. In the context of the acceptance and commitment therapy-based treatment studied here, overall PGIC ratings appeared to be influenced to a greater degree by patients' experienced improvements in physical activities and mood than by improvements in pain. The findings suggest that in addition to a single overall PGIC rating, domain-specific items may be relevant for some treatment trials. PERSPECTIVE: This article reports on the validity and predictors of patients' impression of change ratings following interdisciplinary psychologically based treatment for pain. In addition to a single overall PGIC rating, domain-specific items may be important for clinicians and researchers to consider depending on the focus of treatment. PMID- 25746197 TI - Development and initial validation of a brief self-report measure of cognitive dysfunction in fibromyalgia. AB - Pain is often the focus of research and clinical care in fibromyalgia (FM); however, cognitive dysfunction is also a common, distressing, and disabling symptom in FM. Current efforts to address this problem are limited by the lack of a comprehensive, valid measure of subjective cognitive dysfunction in FM that is easily interpretable, accessible, and brief. The purpose of this study was to leverage cognitive functioning item banks that were developed as part of the Patient Reported Outcomes Measurement Information System (PROMIS) to devise a 10 item short form measure of cognitive functioning for use in FM. In study 1, a nationwide (U.S.) sample of 1,035 adults with FM (age range = 18-82, 95.2% female) completed 2 cognitive item pools. Factor analyses and item response theory analyses were used to identify dimensionality and optimally performing items. A recommended 10-item measure, called the Multidimensional Inventory of Subjective Cognitive Impairment (MISCI) was created. In study 2, 232 adults with FM completed the MISCI and a legacy measure of cognitive functioning that is used in FM clinical trials, the Multiple Ability Self-Report Questionnaire (MASQ). The MISCI showed excellent internal reliability, low ceiling/floor effects, and good convergent validity with the MASQ (r = -.82). PERSPECTIVE: This paper presents the MISCI, a 10-item measure of cognitive dysfunction in FM, developed through classical test theory and item response theory. This brief but comprehensive measure shows evidence of excellent construct validity through large correlations with a lengthy legacy measure of cognitive functioning. PMID- 25746198 TI - Biodegradation of dispersed Macondo oil in seawater at low temperature and different oil droplet sizes. AB - During the Deepwater Horizon (DWH) accident in 2010 a dispersant (Corexit 9500) was applied at the wellhead to disperse the Macondo oil and reduce the formation of surface slicks. A subsurface plume of small oil droplets was generated near the leaking well at 900-1300 m depth. A novel laboratory system was established to investigate biodegradation of small droplet oil dispersions (10 MUm or 30 MUm droplet sizes) of the Macondo oil premixed with Corexit 9500, using coastal Norwegian seawater at a temperature similar to the DWH plume (4-5 degrees C). Biotransformation of volatile and semivolatile hydrocarbons and oil compound groups was generally faster in the 10 MUm than in the 30 MUm dispersions, showing the importance of oil droplet size for biodegradation. These data therefore indicated that dispersant treatment to reduce the oil droplet size may increase the biodegradation rates of oil compounds in the deepwater oil droplets. PMID- 25746199 TI - Intersex related gene expression profiles in clams Scrobicularia plana: Molecular markers and environmental application. AB - Intersex, the appearance of female characteristics in male gonads, has been identified in several aquatic species. It is a widespread phenomenon in populations of the bivalve, Scrobicularia plana, from the southwest coast of the U.K. Genes previously identified as differentially expressed (ferritin, testicular haploid expressed gene, THEG, proliferating cell nuclear antigen, PCNA; receptor activated protein kinase C, RACK; cytochrome B, CYB; and cytochrome c oxidase 1, COX1) in intersex clams relative to normal male clams, were selected for characterisation and an environmental survey of the Channel region. Transcripts were significantly differentially expressed at sites with varying intersex incidence and contaminant burdens. Significant correlations between specific gene expressions, key contaminants and sampling locations have been identified, though no single gene was associated with intersex incidence. The results highlight the difficulty in understanding the intersex phenomenon in molluscs where there is still a lack of knowledge on the control of normal reproduction. PMID- 25746200 TI - Response to Svejkovsky et al. PMID- 25746202 TI - Why vertically pi-expanded imidazo[1,2-a]pyridines are weak fluorescence emitters: experimental and computational studies. AB - Photophysics of pi-expanded analogs of imidazo[1,2-a]pyridine, a well-known heterocyclic compound, has been experimentally and theoretically studied. Two regioisomeric systems differing only in the arrangement of the benzene ring have shown different optical properties (electronic transition energies, fluorescence quantum yields and decay times). DFT calculations have been in agreement with experimental results. Low fluorescence quantum yields have been attributed to the S1-> T2 intersystem crossing channel. Additional computations predict architectures which should possess higher fluorescence quantum yields. PMID- 25746201 TI - Vector optimization and needle-free intradermal application of a broadly protective polyvalent influenza A DNA vaccine for pigs and humans. AB - The threat posed by the 2009 pandemic H1N1 virus emphasized the need for new influenza A virus vaccines inducing a broad cross-protective immune response for use in both humans and pigs. An effective and broad influenza vaccine for pigs would greatly benefit the pork industry and contribute to public health by diminishing the risk of emerging highly pathogenic reassortants. Current inactivated protein vaccines against swine influenza produce only short-lived immunity and have no efficacy against heterologous strains. DNA vaccines are a potential alternative with advantages such as the induction of cellular and humoral immunity, inherent safety and rapid production time. We have previously developed a DNA vaccine encoding selected influenza proteins of pandemic origin and demonstrated broad protective immune responses in ferrets and pigs. In this study, we evaluated our DNA vaccine expressed by next-generation vectors. These new vectors can improve gene expression, but they are also efficiently produced on large scales and comply with regulatory guidelines by avoiding antibiotic resistance genes. In addition, a new needle-free delivery of the vaccine, convenient for mass vaccinations, was compared with intradermal needle injection followed by electroporation. We report that when our DNA vaccine is expressed by the new vectors and delivered to the skin with the needle-free device in the rabbit model, it can elicit an antibody response with the same titers as a conventional vector with intradermal electroporation. The needle-free delivery is already in use for traditional protein vaccines in pigs but should be considered as a practical alternative for the mass administration of broadly protective influenza DNA vaccines. PMID- 25746203 TI - Super-heavy element research. AB - A review of the discovery and investigation of the 'island of stability' of super heavy nuclei at the separator DGFRS (FLNR, JINR) in the fusion reactions of (48)Ca projectiles with target nuclei (238)U-(249)Cf is presented. The synthesis of the heaviest nuclei, their decay properties, and methods of identification are discussed. The role of shell effects in the stability of super-heavy nuclei is demonstrated by comparison of the experimental data and results of theoretical calculations. The radioactive properties of the new nuclei, the isotopes of elements 112-118 as well as of their decay products, give evidence of the significant increase of the stability of the heavy nuclei with rise of their neutron number and approaching magic number N = 184. PMID- 25746205 TI - Top-Down and Bottom-Up Approaches in 3D Printing Technologies for Drug Delivery Challenges. AB - 3-Dimensional printing (3DP) constitutes a raft of technologies, based on different physical mechanisms, that generate a 3-dimensional physical object from a digital model. Because of its rapid fabrication and precise geometry, 3DP has gained a prominent focus in biomedical and nanobiomaterials research. Despite advancements in targeted, controlled, and pulsatile drug delivery, the achievement of site-specific and disease-responsive drug release and stringent control over in vivo biodistribution, are still some of the important, challenging areas for pharmaceutical research and development and existing drug delivery techniques. Microelectronic industries are capable of generating nano /microdrug delivery devices at high throughputs with a highly precise control over design. Successful miniaturizations of micro-pumps with multireservoir architectures for delivery of pharmaceuticals developed by micro electromechanical systems technology were more acceptable than implantable devices. Inkjet printing technologies, which dispense a precise amount of polymer ink solutions, find applications in controlled drug delivery. Bioelectronic products have revolutionized drug delivery technologies. Designing nanoparticles by nanoimprint lithography showed a controlled drug release pattern, biodistribution, and in vivo transport. This review highlights the "top-down" and "bottom-up" approaches of the most promising 3DP technologies and their broader applications in biomedical and therapeutic drug delivery, with critical assessment of its merits, demerits, and intellectual property rights challenges. PMID- 25746206 TI - [Teaching infectious diseases in the Medical Degree within the European higher education area]. AB - During their medical studies, students must acquire basic competencies in different areas of knowledge, one of which is infectious diseases. Training in infectious diseases is essential for general medical practice and for academic or professional expertise in many areas of medicine, both medical and surgical. The vast amount of knowledge that is continuously generated about infectious diseases requires a well-structured undergraduate medical education program and framed in a setting dominated by globalization. The incorporation of Spain to the European higher education area has forced medical schools to adapt their curriculum and to establish the content and learning objectives of all courses of study. In this paper, we discuss the implications of the integration of the Spanish university system in the European higher education area ("Bologna Process") in the teaching of infectious diseases in the Degree of Medicine, and describe the learning program in infectious diseases of the University Miguel Hernandez of Elche (Alicante, Spain) based on learning outcomes and competencies. PMID- 25746207 TI - The effects of ROS in prostatic stromal cells under hypoxic environment. AB - OBJECTIVE: The objective of this study is to explore the effects of reactive oxygen species (ROS) under hypoxic environment in prostatic stromal cells (PSC). METHODS AND MATERIALS: To detect the expression of ROS in PSC and the tissues of benign prostatic hyperplasia (BPH) by flow cytometry; under hypoxic conditions, to observe the changes of cells growth and ROS in PSC; quantitative PCR was used to detect hypoxia inducible factor-1alpha (HIF-1alpha), androgen receptors (AR), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) in PSC; After edaravone intervening, to examine the changes of cells growth, ROS, HIF-1alpha, AR, VEGF, and IL-8 under hypoxic conditions. RESULTS: The expression of ROS in tissues and cells which under hypoxic condition was significantly increased. 3% O2 promoted the proliferation. The HIF-1alpha, AR, VEGF, and IL-8 were upregulated under 3% O2. After edaravone intervening, ROS significantly decreased, HIF-1alpha and VEGF were downregulated, and cell proliferation declined. CONCLUSIONS: Hypoxia stimulates the generation of ROS, and the ROS may play a key role in BPH. PMID- 25746208 TI - Poor levels of agreement between serum and saliva testosterone measurement following exercise training in aging men. AB - Testosterone (T) is a biologically important androgen that demonstrates a widely known natural decline with advancing age. The use of salivary T (sal-T), as a determinant of systemic T, has shown promising results in recent years. However, the strength of the salivary-serum T relationship may be affected by measurement method and binding capacity with salivary proteins. The potential influence exercise may impact on this relationship is unstudied in aging men. Therefore, the aim of the present investigation was to examine the relationship of the delta change (Delta) in sal-T with Deltaserum T following six weeks exercise training. Fifteen sedentary (SED) males (aged 60.4 +/- 5.0 years of age) and 20 lifelong exercising (LE) males (60.4 +/- 4.7 years of age) were participated. Pearson's correlation coefficient revealed sal-T did not correlate with total testosterone (TT), sex hormone binding globulin (SHBG), bioactive T (bio-T), or free T (free T) at week 0 or week 6. Deltasal-T did not correlate with DeltaTT, DeltaSHBG, Deltabio-T or Deltafree-T (r = 0.271, p = 0.180; r = 0.197, p = 0.335; r = 0.258, p = 0.205; and r = 0.257, p = 0.205, respectively). In conclusion, poor levels of agreement existed between saliva and serum measurements of T in response to exercise amongst aging men. PMID- 25746209 TI - The effects of androgen deprivation therapy with weight management on serum aP2 and adiponectin levels in prostate cancer patients. AB - Androgen deprivation therapy (ADT) for the treatment of prostate cancer (PCa) causes an increase in total body fat, leading to a net gain in body weight. Moreover, the use of the luteinizing hormone-releasing hormone agonists in ADT causes a decrease in serum androgen levels, leading to the development of metabolic syndrome (MetS). Androgen blockade significantly increases plasma adiponectin levels, which has some efficacy against MetS, whereas ADT increases fasting plasma insulin and decreases insulin sensitivity, suggesting that there are other mechanisms involved in the onset of MetS besides adiponectin activation. We investigated the effects of ADT on serum aP2 and adiponectin in PCa patients. Six months post-ADT, serum aP2 and adiponectin levels were significantly increased, although there were no changes in patient body weight and no correlation between the changes in serum aP2 and total adiponectin levels. The serum adiponectin and aP2 levels have independent implications in ADT for PCa; therefore, their combined measurement will clarify the impact on the development of obesity-related diseases during ADT. Contrary to adiponectin, high serum aP2 levels were correlated with the late development of MetS. Further studies are needed to investigate the future occurrence of metabolic diseases post-ADT. PMID- 25746210 TI - Macrolide-resistant Streptococcus pyogenes: prevalence and treatment strategies. AB - Although penicillin remains the first-choice treatment for Streptococcus pyogenes infection, macrolides are important alternatives for allergic patients and lincosamides are recommended together with beta-lactams in invasive infections. S. pyogenes may exhibit macrolide resistance because of active efflux (mef genes) or target modification (erm genes), the latter conferring cross resistance to lincosamides and streptogramin B. Worldwide, resistance is restricted to a limited number of genetic lineages, despite resistance genes being encoded on mobile genetic elements. For reasons that are not completely clear, resistance and the associated phenotypes are highly variable across countries. Although resistance remains high in several countries, particularly in Asia, an overall decreasing trend of resistance has been noted in recent years, mostly in Europe. This decrease is not always accompanied by declines in macrolide consumption, suggesting significant roles of other factors in determining the dynamics of macrolide-resistant clones. Continued surveillance is needed to obtain further insights into the forces governing macrolide resistance in S. pyogenes. PMID- 25746211 TI - Modelling energy deposition in nanoscintillators to predict the efficiency of the X-ray-induced photodynamic effect. AB - Scintillating nanoparticles (NPs) in combination with X-ray or gamma-radiation have a great potential for deep-tissue cancer therapy because they can be used to locally activate photosensitizers and generate singlet oxygen in tumours by means of the photodynamic effect. To understand the complex spatial distribution of energy deposition in a macroscopic volume of water loaded with nanoscintillators, we have developed a GEANT4-based Monte Carlo program. We thus obtain estimates of the maximum expected efficiency of singlet oxygen production for various materials coupled to PS, X-ray energies, NP concentrations and NP sizes. A new parameter, etanano, is introduced to quantify the fraction of energy that is deposited in the NPs themselves, which is crucial for the efficiency of singlet oxygen production but has not been taken into account adequately so far. We furthermore emphasise the substantial contribution of primary interactions taking place in water, particularly under irradiation with high energy photons. The interplay of all these contributions to the photodynamic effect has to be taken into account in order to optimize nanoscintillators for therapeutic applications. PMID- 25746204 TI - Nanostructured platforms for the sustained and local delivery of antibiotics in the treatment of osteomyelitis. AB - This article provides a critical view of the current state of the development of nanoparticulate and other solid-state carriers for the local delivery of antibiotics in the treatment of osteomyelitis. Mentioned are the downsides of traditional means for treating bone infection, which involve systemic administration of antibiotics and surgical debridement, along with the rather imperfect local delivery options currently available in the clinic. Envisaged are more sophisticated carriers for the local and sustained delivery of antimicrobials, including bioresorbable polymeric, collagenous, liquid crystalline, and bioglass- and nanotube-based carriers, as well as those composed of calcium phosphate, the mineral component of bone and teeth. A special emphasis is placed on composite multifunctional antibiotic carriers of a nanoparticulate nature and on their ability to induce osteogenesis of hard tissues demineralized due to disease. An ideal carrier of this type would prevent the long-term, repetitive, and systemic administration of antibiotics and either minimize or completely eliminate the need for surgical debridement of necrotic tissue. Potential problems faced by even hypothetically "perfect" antibiotic delivery vehicles are mentioned too, including (i) intracellular bacterial colonies involved in recurrent, chronic osteomyelitis; (ii) the need for mechanical and release properties to be adjusted to the area of surgical placement; (iii) different environments in which in vitro and in vivo testings are carried out; (iv) unpredictable synergies between drug delivery system components; and (v) experimental sensitivity issues entailing the increasing subtlety of the design of nanoplatforms for the controlled delivery of therapeutics. PMID- 25746212 TI - Distribution patterns of mucosally applied particles and characterization of the antigen presenting cells. AB - Mucosal application is the most common route of vaccination to prevent outbreaks of infectious diseases like Newcastle disease virus (NDV). To gain more knowledge about distribution and uptake of a vaccine after mucosal vaccination, we studied the distribution pattern of antigens after different mucosal routes of administration. Chickens were intranasally (i.n.), intratracheally (i.t.) or intraocularly (i.o.) inoculated with fluorescent beads and presence of beads in nasal-associated lymphoid tissue (NALT), Harderian gland (HG), conjunctiva associated lymphoid tissue (CALT), trachea, lungs, air sacs, oesophagus and blood was characterized. The distribution patterns differed significantly between the three inoculation routes. After i.t. inoculation, the beads were mainly retrieved from trachea, NALT and lung. I.n. inoculation resulted in beads found mainly in NALT but detectable in all organs sampled. Finally, after i.o. inoculation, the beads were detected in NALT, CALT, HG and trachea. The highest number of beads was retrieved after i.n. inoculation. Development of novel vaccines requires a comprehensive knowledge of the mucosal immune system in birds in order to target vaccines appropriately and to provide efficient adjuvants. The NALT is likely important for the induction of mucosal immune responses. We therefore studied the phenotype of antigen-presenting cells isolated from NALT after i.n. inoculation with uncoated beads or with NDV-coated beads. Both types of beads were efficiently taken up and low numbers of bead+ cells were detected in all organs sampled. Inoculation with NDV-coated beads resulted in a preferential uptake by NALT antigen-presenting cells as indicated by high percentages of KUL01+-, MHC II+ and CD40+ bead+ cells. PMID- 25746213 TI - Muta-mycosynthesis of naphthalene analogs. AB - A mutasynthetic strategy is introduced for the mycosynthesis of naphthalene-based molecules (mutadalesols A-F) with directed substitution patterns and new frameworks by generating and using the DeltapksTL mutant strain of Daldinia eschscholzii. (+/-)-Mutadalesol A and its (+)-enantiomer are cytotoxic, and its ( )-enantiomer inhibits Toll-like receptor 5 (TLR5). The in-culture reactability of fungal oligoketide intermediates with 5-aminonaphthalen-1-ol (ANL) is demonstrated, shedding light on bioorthogonal accesses to unnatural molecule libraries valuable in drug discovery pipelines. PMID- 25746214 TI - [Effect of co-payments on the adherence to prescribed medications]. PMID- 25746215 TI - TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study. AB - The mechanism of the TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole was studied by a combination of theoretical and experimental techniques. The energy profile of plausible reaction paths was evaluated by DFT calculations, and various reaction intermediates were isolated or observed in solution by NMR spectroscopy. Theoretical and experimental results indicate that the reaction proceeds in three steps, all promoted by titanium: (1) formation of the enolate ion of methyl acetoacetate, (2) Knoevenagel condensation of the enolate ion and aldehyde, and (3) Michael addition of indole to the Knoevenagel adduct. The study sheds light on the role of titanium in the reaction, providing a mechanistic model for analogous reactions. PMID- 25746216 TI - Using Xenopus tissue cultures for the study of myasthenia gravis pathogenesis. AB - Myasthenia gravis (MG), the most common autoimmune disease of neuromuscular junction (NMJ), is heterogeneous in terms of pathophysiology, which is determined by the pathogenic antigen of autoantibodies targeting to synaptic proteins at the NMJs. Currently, patients suspected with MG are routinely screened for the presence of autoantibodies against acetylcholine receptor (AChR) or muscle specific kinase (MuSK) using a cell-based assay (CBA) that involves the expression of target synaptic membrane protein in heterologous cell lines. However, some autoantibodies may only show reactivity for binding to densely clustered AChR in the physiological conformation, while AChR clustering is known to involve signaling events orchestrated by over a dozen of postsynaptic proteins. To improve the existing serological diagnosis of MG, this study explored the possibility of using the well-established Xenopus primary culture system as a novel CBA for MG. Here, by examining the pathogenic effects of four MG human plasma samples, we found that the samples from both seropositive and seronegative MG patients effectively induced the disassembly of aneural AChR clusters in cultured Xenopus muscle cells, as well as the nerve-induced AChR clusters in the nerve-muscle co-cultures. Importantly, the disassembly of AChR clusters was spatio-temporally correlated to the disappearance of actin depolymerizing factor (ADF)/cofilin, an actin regulator involved in AChR trafficking and clustering. Taken together, this study develops a reliable CBA using Xenopus primary cultures for screening the pathogenicity of human MG plasma samples, and providing a platform for investigating the pathogenic mechanisms underlying the endocytic trafficking and degradation of AChRs at NMJs in MG patients. PMID- 25746217 TI - HSV-1 gM and the gK/pUL20 complex are important for the localization of gD and gH/L to viral assembly sites. AB - Herpes simplex virus-1 (HSV-1), like all herpesviruses, is a large complex DNA virus containing up to 16 different viral membrane proteins in its envelope. The assembly of HSV-1 particles occurs by budding/wrapping at intracellular membranes producing infectious virions contained within the lumen of cytoplasmic membrane bound compartments that are then released by secretion. To ensure incorporation of all viral membrane proteins into the envelope, they need to be localized to the appropriate intracellular membranes either via the endocytic pathway or by direct targeting to assembly sites from the biosynthetic secretory pathway. Many HSV-1 envelope proteins encode targeting motifs that direct their endocytosis and targeting, while others do not, including the essential entry proteins gD and the gH/gL complex, and so it has been unclear how these envelope proteins reach the appropriate assembly compartments. We now show that efficient endocytosis of gD and gH/gL and their incorporation into mature virions relies upon the presence of the HSV-1 envelope proteins gM and the gK/pUL20 complex. Our data demonstrate both redundant and synergistic roles for gM and gK/pUL20 in controlling the targeting of gD and gH/L to the appropriate intracellular virus assembly compartments. PMID- 25746219 TI - Inulin Potential for Enzymatic Obtaining of Prebiotic Oligosaccharides. AB - Oligosaccharides have been marketed since the 80s as low-calorie agents and recently have gained interest in the pharmaceutical and food industry as functional sweeteners and prebiotic enriching population of Bifidobacteria. Currently, they have an approximated value of $200 per kg and recently, inulin has been proposed as a feedstock for production of oligosaccharides through selective hydrolysis by action of endoinulinase. High optimum temperature (60 degrees C) and thermostability are two important criteria that determine suitability of this enzyme for industrial applications as well as enzyme cost, a major limiting factor. Significant reduction in cost can be achieved by employing low-value and abundant inulin-rich plants as Jerusalem artichoke, dahlia, yacon, garlic, and onion, among others. In general, the early harvested tubers of these plants contain a greater amount of highly polymerized sugar fractions, which offer more industrial value than late-harvested tubers or those after storage. Also, development of recombinant microorganisms could be useful to reduce the cost of enzyme technology for large-scale production of oligosaccharides. In the case of fungal inulinases, several studies of cloning and modification have been made to achieve greater efficiency. The present paper reviews inulin from vegetable sources as feedstock for oligosaccharides production through the action of inulinases, the impact of polymerization degree of inulin and its availability, and some strategies to increase oligosaccharide production. PMID- 25746218 TI - Differential expression of HERV-K (HML-2) proviruses in cells and virions of the teratocarcinoma cell line Tera-1. AB - Human endogenous retrovirus (HERV-K (HML-2)) proviruses are among the few endogenous retroviral elements in the human genome that retain coding sequence. HML-2 expression has been widely associated with human disease states, including different types of cancers as well as with HIV-1 infection. Understanding of the potential impact of this expression requires that it be annotated at the proviral level. Here, we utilized the high throughput capabilities of next-generation sequencing to profile HML-2 expression at the level of individual proviruses and secreted virions in the teratocarcinoma cell line Tera-1. We identified well defined expression patterns, with transcripts emanating primarily from two proviruses located on chromosome 22, only one of which was efficiently packaged. Interestingly, there was a preference for transcripts of recently integrated proviruses, over those from other highly expressed but older elements, to be packaged into virions. We also assessed the promoter competence of the 5' long terminal repeats (LTRs) of expressed proviruses via a luciferase assay following transfection of Tera-1 cells. Consistent with the RNASeq results, we found that the activity of most LTRs corresponded to their transcript levels. PMID- 25746221 TI - Analysis of subsequent publication of scientific orally presented abstracts of the French National Congress of Radiology. Part II: Focus on the French abstracts. AB - AIM: To evaluate the publication rate of scientific abstracts that were presented orally at the 2008, 2009, and 2010 annual meetings of the French Society of Radiology by French radiologists, and to perform a French regional analysis. MATERIAL AND METHODS: Orally presented abstracts were identified by examining online abstract books of the 2008, 2009, and 2010 annual meetings of the French Society of Radiology, and cross-checked by reviewing the paper version of abstracts for the same period. Only abstracts from French teams were selected. The administrative region of submission was noted for each abstract and for each region the total population, the number of active radiologists, the number of active members of the French Society of Radiology and the number of academic radiologists were noted. Imaging subspecialties were also noted. RESULTS: 625 abstracts were identified resulting in 268 publications (publication rate: 43%). The median number of presentations and publications per region was 18 (range: 1 255) and 7 (range: 0-101), respectively. The ratio per million inhabitants was 7.5 and 3 respectively. The median number of presentations and publications per 100 active radiologists (respectively members of the FSR) was 7 and 3 (respectively 10 and 4). The median number of presentations and publications per academic radiologist were 2.6, and 1.2, respectively. The regional variations for each indicator were high (40-180%). Three subspecialties had a publication rate of more than 50%: thoracic imaging (58%), abdominal imaging (52%), and genitourinary imaging (51%). CONCLUSION: The publication rate of orally presented French scientific abstracts was high, with important variations according to the regions of origin and imaging subspecialties. PMID- 25746220 TI - Ethanol withdrawal is required to produce persisting N-methyl-D-aspartate receptor-dependent hippocampal cytotoxicity during chronic intermittent ethanol exposure. AB - Chronic intermittent ethanol consumption is associated with neurodegeneration and cognitive deficits in preclinical laboratory animals and in the clinical population. While previous work suggests a role for neuroadaptations in the N methyl-d-aspartate (NMDA) receptor in the development of ethanol dependence and manifestation of withdrawal, the relative roles of ethanol exposure and ethanol withdrawal in producing these effects have not been fully characterized. To examine underlying cytotoxic mechanisms associated with chronic intermittent ethanol (CIE) exposure, organotypic hippocampal slices were exposed to 1-3 cycles of ethanol (50 mM) in cell culture medium for 5 days, followed by 24 h of ethanol withdrawal, in which a portion of slices were exposed to competitive NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV; 40 MUM). Cytotoxicity was assessed using immunohistochemical labeling of neuron-specific nuclear protein (NeuN; Fox-3), a marker of mature neurons, and thionine (2%) staining of Nissl bodies. Multiple cycles of CIE produced neurotoxicity, as reflected in persisting losses of neuron NeuN immunoreactivity and thionine staining in each of the primary cell layers of the hippocampal formation. Hippocampi aged in vitro were significantly more sensitive to the toxic effects of multiple cycles of CIE than were non-aged hippocampi. This effect was not demonstrated in slices exposed to continuous ethanol, in the absence of withdrawal, or to a single exposure/withdrawal regimen. Exposure to APV significantly attenuated the cytotoxicity observed in the primary cell layers of the hippocampus. The present findings suggest that ethanol withdrawal is required to produce NMDA receptor-dependent hippocampal cytotoxicity, particularly in the aging hippocampus in vitro. PMID- 25746222 TI - Analysis of subsequent publication of scientific orally presented abstracts of the French national congress of radiology. Part I: General characteristics. AB - PURPOSE: To evaluate the publication rate of scientific abstracts orally presented at the annual meeting of the French Society of Radiology (FSR), and to identify factors associated with publication. MATERIAL AND METHODS: Abstracts were selected from the books of abstracts of the 2008-2010 annual meetings of the FSR. For each abstract, country of origin, diagnostic/interventional radiology, imaging techniques (plain radiography, angiography, ultrasound [US], computed tomography [CT], magnetic resonance imaging [MRI]), human/experimental study, retrospective/prospective design, number of subjects, oncologic study or not were noted. Publications were searched in Medline-indexed journals and factors associated analyzed by multivariate analysis. RESULTS: Seven hundred and forty four abstracts lead to 298 publications (publication rate 40%). Most abstracts reported retrospective studies (61%), in humans (94%), diagnostic imaging (85%), from European authors (90%), and oncology (27%). Median number of subject was 39 (19-87). Main imaging techniques were MRI, CT, US (46%, 29%, 21%). Publications were mostly in English (89%), in radiological journals (72%), with a mean 3.5+/ 3.7 impact factor. Publication was associated with a prospective design (OR=1.80), a submission from Europe (OR=1.71), angiography (OR=2.44), and oncology (OR=1.81). CONCLUSION: The annual meeting of the FSR is in French, but the rate of publication of presented abstracts is high, mostly in English in reputable journals. PMID- 25746223 TI - Eosinophilic fasciitis: typical abnormalities, variants and differential diagnosis of fasciae abnormalities using MR imaging. AB - Eosinophilic fasciitis is a rare condition. It is generally limited to the distal parts of the arms and legs. MRI is the ideal imaging modality for diagnosing and monitoring this condition. MRI findings typically evidence only fascial involvement but on a less regular basis signal abnormalities may be observed in neighboring muscle tissue and hypodermic fat. Differential diagnosis of eosinophilic fasciitis by MRI requires the exclusion of several other superficial and deep soft tissue disorders. PMID- 25746224 TI - Recursive Random Forests Enable Better Predictive Performance and Model Interpretation than Variable Selection by LASSO. AB - Variable selection is of crucial significance in QSAR modeling since it increases the model predictive ability and reduces noise. The selection of the right variables is far more complicated than the development of predictive models. In this study, eight continuous and categorical data sets were employed to explore the applicability of two distinct variable selection methods random forests (RF) and least absolute shrinkage and selection operator (LASSO). Variable selection was performed: (1) by using recursive random forests to rule out a quarter of the least important descriptors at each iteration and (2) by using LASSO modeling with 10-fold inner cross-validation to tune its penalty lambda for each data set. Along with regular statistical parameters of model performance, we proposed the highest pairwise correlation rate, average pairwise Pearson's correlation coefficient, and Tanimoto coefficient to evaluate the optimal by RF and LASSO in an extensive way. Results showed that variable selection could allow a tremendous reduction of noisy descriptors (at most 96% with RF method in this study) and apparently enhance model's predictive performance as well. Furthermore, random forests showed property of gathering important predictors without restricting their pairwise correlation, which is contrary to LASSO. The mutual exclusion of highly correlated variables in LASSO modeling tends to skip important variables that are highly related to response endpoints and thus undermine the model's predictive performance. The optimal variables selected by RF share low similarity with those by LASSO (e.g., the Tanimoto coefficients were smaller than 0.20 in seven out of eight data sets). We found that the differences between RF and LASSO predictive performances mainly resulted from the variables selected by different strategies rather than the learning algorithms. Our study showed that the right selection of variables is more important than the learning algorithm for modeling. We hope that a standard procedure could be developed based on these proposed statistical metrics to select the truly important variables for model interpretation, as well as for further use to facilitate drug discovery and environmental toxicity assessment. PMID- 25746225 TI - Interferon-alpha competing endogenous RNA network antagonizes microRNA-1270. AB - A new form of circuitry for gene regulation has been identified in which RNAs can crosstalk by competing for shared microRNAs (miRNAs). Such competing endogenous RNAs (ceRNAs) form a network via shared miRNA response elements (MREs) to antagonize miRNA function. We previously reported natural antisense RNA (AS) as an important modulator of interferon-alpha1 (IFN-alpha1) mRNA levels by promoting IFN-alpha1 mRNA stability. We show that IFN-alpha1 AS forms a ceRNA network with specific IFN-alpha AS (IFN-alpha7/-alpha8/-alpha10/-alpha14) and mRNA (IFN alpha8/-alpha10/-alpha14/-alpha17) subtypes from the IFN-alpha gene (IFNA) family to antagonize miRNA-1270 (miR-1270), thereby modulating IFN-alpha1 mRNA levels. Bioinformatic analysis demonstrated that IFN-alpha1 AS harbors multiple miR-1270 MREs (MRE-1270s), whose presence was substantiated by miR-1270 overexpression and transfection of antimiR-1270. The antimiR-1270, complementary to the miR-1270 seed region, revealed that IFN-alpha1 AS likely shares the MRE-1270 with IFN alpha1 mRNA and specific IFN-alpha AS and mRNA subtypes. Subsequent bioinformatic analysis for MRE-1270s showed that IFN-alpha1 AS and other RNA subtypes shared the 6-mer MRE-1270 site. Further MRE-mapping demonstrated that the total number of MRE-1270s in IFN-alpha1 AS accounted for approximately 30 % of the miR-1270 population. AntimiR-1270 transfection also caused specific de-repression of five cellular mRNAs, including that of CAPRIN1. These results suggest that IFN-alpha1 AS, together with specific IFN-alpha AS and mRNA subtypes, as well as the five cellular mRNAs, participate as competing molecules in the ceRNA network against miR-1270. This coordinated regulatory architecture suggests a vital function for the innate immune system in maintaining precise physiological type I IFN levels via post-transcriptional regulatory mechanisms. PMID- 25746226 TI - The HERC1 E3 Ubiquitin Ligase is essential for normal development and for neurotransmission at the mouse neuromuscular junction. AB - The ubiquitin-proteasome system (UPS) plays a fundamental role in protein degradation in neurons, and there is strong evidence that it fulfills a key role in synaptic transmission. The aim of the present work was to study the implication of one component of the UPS, the HERC1 E3 Ubiquitin Ligase, in motor function and neuromuscular transmission. The tambaleante (tbl) mutant mouse carries a spontaneous mutation in HERC1 E3 Ubiquitin Ligase, provoking an ataxic phenotype that develops in the second month of life. Our results show that motor performance in mutant mice is altered at postnatal day 30, before the cerebellar neurodegeneration takes place. This defect is associated with by: (a) a reduction of the motor end-plate area, (b) less efficient neuromuscular activity in vivo, and (c) an impaired evoked neurotransmitter release. Together, these data suggest that the HERC1 E3 Ubiquitin Ligase is fundamental for normal muscle function and that it is essential for neurotransmitter release at the mouse neuromuscular junction. PMID- 25746228 TI - The molecular structure of aqueous Hg(II)-EDTA as determined by X-ray absorption spectroscopy. AB - The widespread presence and persistence of ethylenediaminetetraacetic acid (EDTA) in aquatic environments can lead to the formation of metal-EDTA complexes that influence metal bioavailability and mobility. Recently, the Hg(II)-EDTA complex was observed to slightly promote the biouptake of Hg(II) to the bacterium Escherichia coli and to undergo a relatively quick ligand exchange reaction with thiols at the bacterial cell membrane. The reactivity of a metal complex depends on its molecular structure; however, the molecular structure of aqueous Hg(II) EDTA has yet to be reported. Here, we use X-ray absorption spectroscopy to determine the molecular structure of aqueous Hg(II)-EDTA. Our results suggest that aqueous Hg(II)-EDTA displays distorted octahedral geometry with one water molecule in the coordination sphere. PMID- 25746227 TI - Properties of a newly identified esterase from Bacillus sp. K91 and its novel function in diisobutyl phthalate degradation. AB - The widely used plasticizer phthalate esters (PAEs) have become a public concern because of their effects on environmental contamination and toxicity on mammals. However, the biodegradation of PAEs, especially diisobutyl phthalate (DiBP), remains poorly understood. In particular, genes involved in the hydrolysis of these compounds were not conclusively identified. In this study, the CarEW gene, which encodes an enzyme that is capable of hydrolyzing rho-nitrophenyl esters of fatty acids, was cloned from a thermophilic bacterium Bacillus sp. K91 and heterologously expressed in Escherichia coli BL21 using the pEASY-E2 expression system. The enzyme showed a monomeric structure with a molecular mass of approximately 53.76 kDa and pI of 4.88. The enzyme exhibited maximal activity at pH 7.5 and 45 degrees C, with rho-NP butyrate as the best substrate. The enzyme was fairly stable within the pH range from 7.0 to 8.5. High-pressure liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS) were employed to detect the catabolic pathway of DiBP. Two intermediate products were identified, and a potential biodegradation pathway was proposed. Altogether, our findings present a novel DiBP degradation enzyme and indicate that the purified enzyme may be a promising candidate for DiBP detoxification and for environmental protection. PMID- 25746229 TI - Perianal Crohn's disease: a review. AB - Perianal involvement in Crohn's disease (CD), which encompasses fistulas, ulcers, abscesses, strictures and cancer, can lead to significant impairment in quality of life. The objective of this article is to review the major perianal complications of CD and the current medical and surgical modalities used to treat them. Antibiotics are commonly used despite a lack of controlled trials to validate their use and should be used as a bridge to maintenance therapy. The anti-metabolites azathioprine and 6-MP have shown a positive response in terms of fistula closure, although these data are mostly from trials looking at this as a secondary endpoint. Infliximab is an effective agent for induction and maintenance of treatment of fistulizing CD. Further studies to evaluate the use of subcutaneous anti-tumor necrosis factors are needed to convincingly prove their efficacy for perianal fistulizing disease. In CD, clinicians should avoid surgery as a first-line approach for skin tags, hemorrhoids or fissures in the setting of proctitis. Surgery, particularly lateral internal sphincterotomy, in combination with medical therapy is associated with higher fissure healing rates in the absence of proctitis. Fistulotomy is curative for most simple low perianal fistulae, but complex fistulas often require sphincter-sparing surgical procedures. Less invasive approaches such as a chemical sphincterotomy should be used first, with therapy escalated only if this fails. PMID- 25746230 TI - P38/MAPK contributes to endothelial barrier dysfunction via MAP4 phosphorylation dependent microtubule disassembly in inflammation-induced acute lung injury. AB - Excessive activation of inflammation and the accompanying lung vascular endothelial barrier disruption are primary pathogenic features of acute lung injury (ALI). Microtubule-associated protein 4 (MAP4), a tubulin assembly promoting protein, is important for maintaining the microtubule (MT) cytoskeleton and cell-cell junctional structures. However, both the involvement and exact mechanism of MAP4 in the development of endothelial barrier disruption in ALI remains unknown. In this study, lipopolysaccharide (LPS) and tumour necrosis factor-alpha (TNF-alpha) were applied to human pulmonary microvascular endothelial cells (HPMECs) to mimic the endothelial damage during inflammation in vitro. We demonstrated that the MAP4 (Ser696 and Ser787) phosphorylation increased concomitantly with the p38/MAPK pathway activation by the LPS and TNF alpha stimulation of HPMECs, which induced MT disassembly followed by hyperpermeability. Moreover, the application of taxol, the overexpression of a MAP4 (Ala) mutant, or the application of the p38/MAPK inhibitor SB203580 inhibited the MT disruption and the intracellular junction dysfunction. In contrast, MKK6 (Glu), which constitutively activated p38/MAPK, resulted in microtubule depolymerisation and, subsequently, hyperpermeability. Our findings reveal a novel role of MAP4 in endothelial barrier dysfunction. PMID- 25746231 TI - Drosha, Dicer-1 and Argonaute-1 in the desert locust: phylogenetic analyses, transcript profiling and regulation during phase transition and feeding. AB - In this article, we identify and characterise the miRNA machinery components Drosha, Dicer-1 and Argonaute-1 of the desert locust. By means of phylogenetic analyses, we reveal important insights in the evolutionary context of these components. Our data illustrate that insect Argonaute-1 proteins form a monophyletic group with ALG-1 and ALG-2 of Caenorhabditis elegans and with the four (non-Piwi) Argonaute proteins present in humans. On the other hand, humans apparently lack clear homologues of the insect Argonaute-2 proteins. In addition, we demonstrate that drosha, dicer-1 and argonaute-1 display wide transcript tissue-distribution in adult desert locusts, and that during locust phase transition and feeding of starved locusts the expression levels of the miRNA pathway are regulated at the transcript level. PMID- 25746233 TI - Size-dependent electrocatalytic reduction of CO2 over Pd nanoparticles. AB - Size effect has been regularly utilized to tune the catalytic activity and selectivity of metal nanoparticles (NPs). Yet, there is a lack of understanding of the size effect in the electrocatalytic reduction of CO2, an important reaction that couples with intermittent renewable energy storage and carbon cycle utilization. We report here a prominent size-dependent activity/selectivity in the electrocatalytic reduction of CO2 over differently sized Pd NPs, ranging from 2.4 to 10.3 nm. The Faradaic efficiency for CO production varies from 5.8% at 0.89 V (vs reversible hydrogen electrode) over 10.3 nm NPs to 91.2% over 3.7 nm NPs, along with an 18.4-fold increase in current density. Based on the Gibbs free energy diagrams from density functional theory calculations, the adsorption of CO2 and the formation of key reaction intermediate COOH* are much easier on edge and corner sites than on terrace sites of Pd NPs. In contrast, the formation of H* for competitive hydrogen evolution reaction is similar on all three sites. A volcano-like curve of the turnover frequency for CO production within the size range suggests that CO2 adsorption, COOH* formation, and CO* removal during CO2 reduction can be tuned by varying the size of Pd NPs due to the changing ratio of corner, edge, and terrace sites. PMID- 25746232 TI - Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. AB - The Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) blocking loop 2 (BL2) structure differs significantly from that of SARS CoV PLpro, where it has been proven to play a crucial role in SARS-CoV PLpro inhibitor binding. Four SARS-CoV PLpro lead inhibitors were tested against MERS CoV PLpro, none of which were effective against MERS-CoV PLpro. Structure and sequence alignments revealed that two residues, Y269 and Q270, responsible for inhibitor binding to SARS-CoV PLpro, were replaced by T274 and A275 in MERS-CoV PLpro, making critical binding interactions difficult to form for similar types of inhibitors. High-throughput screening (HTS) of 25 000 compounds against both PLpro enzymes identified a small fragment-like noncovalent dual inhibitor. Mode of inhibition studies by enzyme kinetics and competition surface plasmon resonance (SPR) analyses suggested that this compound acts as a competitive inhibitor with an IC50 of 6 MUM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC50 of 11 MUM. These results raised the possibility that inhibitor recognition specificity of MERS-CoV PLpro may differ from that of SARS-CoV PLpro. In addition, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3). PMID- 25746234 TI - Cannabis problem experiences among users of the tobacco-cannabis combination known as blunts. AB - BACKGROUND: In most of the world, cannabis smokers mix loose tobacco inside a joint, pipe, spliff, or cone. More recently, a 'blunt' formulation combines these two drugs by inserting cannabis into a hollowed-out cigar. Epidemiological research linking simultaneous use of these two drugs and the development of cannabis use disorders (CUD) remains unclear. This study estimates associations linking blunt smoking with levels and subtypes of cannabis problems. METHODS: Cross-sectional data on 27,767 past-year cannabis users were analyzed from the US National Survey on Drug Use and Health (NSDUH) conducted from 2009 to 2012. Ten self-reported items of DSM-IV CUD features elicited a single latent trait of cannabis problem (CP) severity, which was then regressed on past-year blunt smoking and past-month blunt frequency measures within the context of a conceptual model. Differential item functioning (DIF) analysis evaluated potential bias in CP feature response by blunt smoking history. RESULTS: Past year blunt smoking was associated with higher CP severity compared to cannabis users who did not smoke blunts. Days of blunt smoking in the past month also predicted higher CP severity than less frequent blunt use. Those smoking blunts experienced more subjectively felt tolerance and having spent more time obtaining or using cannabis, but were less likely to experience other problems, even at the same level of CP severity. CONCLUSIONS: These findings suggest smoking blunts might promote the development of problematic cannabis use. Responses to cannabis problems differed by history of blunt smoking, possibly implicating an influence of tobacco on measurement of cannabis use disorders. PMID- 25746235 TI - Female smokers have the highest alcohol craving in a residential alcoholism treatment cohort. AB - BACKGROUND: Cigarette smoking among female and male alcoholics has not been extensively studied as a factor related to intensity of alcohol craving during residential treatment and corresponding sobriety length. METHODS: This retrospective cohort study assessed self-reported sobriety outcomes in patients with alcohol dependence at 3-month intervals over 12 months after completion of a 30-day residential treatment program. Demographic and clinical variables were collected including smoking status, alcohol craving utilizing the Penn Alcohol Craving Scale (PACS), and alcohol relapse. Statistical analyses included Chi square, ANOVA, Tukey's test, Kaplan-Meier plots and Cox proportional hazards models as appropriate. RESULTS: Of the 761 alcohol-dependent study subjects, 355 (47%) were current smokers. Alcohol craving intensity was higher in smoking females compared to nonsmoking females (p=0.0096), smoking males (p<0.0001), and nonsmoking males (p<0.0001). Smoking status-by-sex interaction was not associated with post-treatment relapse. After controlling for other variables, higher PACS scores at admission were associated with higher probability of relapse (p=0.0003). CONCLUSIONS: In this study, female alcoholic smokers experienced the highest level of alcohol craving in an alcohol treatment setting. Interestingly, this did not translate into higher rates of post-treatment relapse. Further research is warranted to explore the neurobiological basis for sex differences in this highly prevalent comorbidity. PMID- 25746236 TI - Abrupt decline in oxycodone-caused mortality after implementation of Florida's Prescription Drug Monitoring Program. AB - BACKGROUND: In Florida, oxycodone-caused deaths declined substantially in 2012. Multiple important law enforcement, pharmaceutical, policy, and public health actions occurred concurrently, including implementation of a statewide Prescription Drug Monitoring Program (PDMP). The effects of the PDMP on oxycodone caused mortality in Florida were evaluated. METHODS: A time-series, quasi experimental research design with autoregressive integrated moving average (ARIMA) statistical models, including internal and external covariates. Data included 120 repeated monthly observations. Monthly counts of oxycodone-caused deaths, obtained from the Florida Medical Examiners Commission (MEC) was the outcome variable. Models included market-entry of tamper-resistant oxycodone HC1 controlled release tablets (OxyContin((r))), enforcement crackdowns (Operation Pill Nation), and regulation by FL House Bill 7095, measured by the monthly count of Florida pain management clinics closed. Two approaches were used to test the PDMP's hypothesized effect: (1) a binary indicator variable (0=pre implementation, 1=post-implementation), and (2) a continuous indicator consisting of the number of PDMP queries by health care providers. RESULTS: Oxycodone-caused mortality abruptly declined 25% the month after implementation of Florida's PDMP (p=0.008). The effect remained after integrating other related historical events into the model. Results indicate that for a system-wide increase of one PDMP query per health care provider, oxycodone-caused deaths declined by 0.229 persons per month (p=0.002). CONCLUSIONS: This is the first study to demonstrate that the PDMP had a significant effect in reducing oxycodone-caused mortality in Florida. Results have implications for national efforts to address the prescription drug epidemic. PMID- 25746237 TI - Mobile lipid bilayers on gold surfaces through structure-induced lipid vesicle rupture. AB - Forming fluid supported lipid bilayers (SLBs) on a gold surface can enable various lipid-membrane-associated biomolecular interactions to be investigated by several surface sensing techniques, such as surface plasmon resonance and scanning tunneling microscopy. However, forming fluid SLBs on a gold surface through lipid vesicle deposition continues to pose a challenge. In this study, we constructed nanograting structures on a gold surface to induce lipid vesicle rupture for forming a mobile layer of SLBs. Observations based on fluorescence recovery after photobleaching showed that SLBs on the prepared grating supports had some fluidity, while SLBs on the planar support had no fluidity. The anisotropic fluorescence intensity recovery shape changes observed in the SLBs on the grating support suggested that a second layer of SLBs partially formed on top of the first layer in contact with the gold surface and extended along the grating structure. Comparisons of the relative amounts of second bilayer and the fluorescence recovery fractions on supports with various grating edge densities suggested that the second layer formed at the edge regions and that the coverage ratio was directly proportional to the grating edge density. All of these results showed that the grating edges could serve as vesicle-rupture-inducing sites for the formation of a mobile second SLB on a gold surface. The formation of the second layer of SLBs at the edge regions but not in the flat regions enabled us to determine the second layer locations and provided us with an opportunity to pattern mobile lipid bilayers on gold surfaces by controlling the edge locations. PMID- 25746238 TI - New antimicrobial contact catalyst killing antibiotic resistant clinical and waterborne pathogens. AB - Microbial growth on medical and technical devices is a big health issue, particularly when microorganisms aggregate to form biofilms. Moreover, the occurrence of antibiotic-resistant bacteria in the clinical environment is dramatically growing, making treatment of bacterial infections very challenging. In search of an alternative, we studied a novel antimicrobial surface coating based on micro galvanic elements formed by silver and ruthenium with surface catalytic properties. The antimicrobial coating efficiently inhibited the growth of the nosocomial pathogens Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium as demonstrated by the growth inhibition on agar surface and in biofilms of antibiotic resistant clinical E. faecalis, E. faecium, and S. aureus isolates. It also strongly reduced the growth of Legionella in a drinking water pipeline and of Escherichia coli in urine. We postulate a mode of action of the antimicrobial material, which is independent of the release of silver ions. Thus, the novel antimicrobial coating could represent an alternative to combat microbial growth avoiding the toxic side effects of high levels of silver ions on eukaryotic cells. PMID- 25746239 TI - Design and fabrication of biomimetic multiphased scaffolds for ligament-to-bone fixation. AB - Conventional ligament grafts with single material composition cannot effectively integrate with the host bones due to mismatched properties and eventually affect their long-term function in vivo. Here we presented a multi-material strategy to design and fabricate composite scaffolds including ligament, interface and bone multiphased regions. The interface region consists of triphasic layers with varying material composition and porous structure to mimic native ligament-to bone interface while the bone region contains polycaprolactone (PCL) anchor and microchanneled ceramic scaffolds to potentially provide combined mechanical and biological implant-bone fixation. Finite element analysis (FEA) demonstrated that the multiphased scaffolds with interference value smaller than 0.5 mm could avoid the fracture of ceramic scaffold during the implantation process, which was validated by in-vitro implanting the multiphased scaffolds into porcine joint bones. Pull-out experiment showed that the initial fixation between the multiphased scaffolds with 0.47 mm interference and the host bones could withstand the maximum force of 360.31+/-97.51 N, which can be improved by reinforcing the ceramic scaffolds with biopolymers. It is envisioned that the multiphased scaffold could potentially induce the regeneration of a new bone as well as interfacial tissue with the gradual degradation of the scaffold and subsequently realize long-term biological fixation of the implant with the host bone. PMID- 25746240 TI - An in vivo swine study for xeno-grafts of calcium sulfate-based bone grafts with human dental pulp stem cells (hDPSCs). AB - The purpose of this in vivo study was to evaluate the effect of human dental pulp stem cells (hDPSCs) on various resorbable calcium sulfate/calcium phosphate bone grafts in bone regeneration. Granular particles of calcium sulfate dehydrate (CSD), alpha-calcium sulfate hemihydrate/amorphous calcium phosphate (alpha CSH/ACP), and CSD/beta-tricalcium phosphates (beta-TCP) were prepared for in vitro dissolution and implantation test. The chemical compositions of specimen residues after dissolution test were characterized by XRD. The ratios of new bone formation for implanted grafts/hDPSCs were evaluated using mandible bony defect model of Lanyu pig. All the graft systems exhibited a similar two-stage dissolution behavior and phase transformation of poor crystalline HAp. Eight weeks post-operation, the addition of hDPSCs to various graft systems showed statistically significant increasing in the ratio of new bone formation (p<0.05). Null hypothesis of hDPSCs showing no scaffold dependence in bone regeneration was rejected. The results suggest that the addition of hDPSCs to calcium sulfate based xenografts could enhance the bone regeneration in the bony defect. PMID- 25746241 TI - Evaluating the effects of hydroxyapatite coating on the corrosion behavior of severely deformed 316Ti SS for surgical implants. AB - The present work investigates the effects of severe plastic deformation by cold rolling on the microstructure, the mechanical properties and the corrosion behavior of austenitic stainless steel (SS) 316Ti. Hydroxyapatite coating (HA) was applied on the deformed material to improve their corrosion resistance. The martensitic transformation due to cold rolling was recorded by X-ray diffraction spectra. The effects of cold rolling on the corrosion behavior were studied using potentiodynamic polarization. The electrochemical tests were carried out in Ringer's solution at 37+/-1 degrees C. Cold rolling markedly enhanced the mechanical properties while the electrochemical tests referred to a lower corrosion resistance of the deformed material. The best combination of both high strength and good corrosion resistance was achieved after applying hydroxyapatite coating. PMID- 25746242 TI - Facile and green synthesis of silver nanoparticles using oxidized pectin. AB - In the current work, an alternative route for facile synthesis of nanosilver is reported. Oxidized pectin has been used as the reducing agent as well as the stabilizing agent, resulting in the formation of oxidized pectin-nanosilver (OP NS) core sheath nanohydrogels. The effect of reaction parameters on the synthesized nanoparticles is investigated. The structural and morphological features have been analyzed using X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM) respectively. The crystal size of the synthesized nanosilver was calculated to be 28.76 nm. While the average size of the core sheath structure varied from 289 nm to 540 nm, the size of the silver nanoparticle entities at the core varied from 100 nm to 180 nm, with variation in reaction time. From the morphological examination, it could be seen that flower like nanostructures are formed with nanosilver in the core surrounded by a polymeric halo. PMID- 25746243 TI - Surface modification of Ni-Ti alloys for stent application after magnetoelectropolishing. AB - The constant demand for new implant materials and the multidisciplinary design approaches for stent applications have expanded vastly over the past decade. The biocompatibility of these implant materials is a function of their surface characteristics such as morphology, surface chemistry, roughness, surface charge and wettability. These surface characteristics can directly influence the material's corrosion resistance and biological processes such as endothelialization. Surface morphology affects the thermodynamic stability of passivating oxides, which renders corrosion resistance to passivating alloys. Magnetoelectropolishing (MEP) is known to alter the morphology and composition of surface films, which assist in improving corrosion resistance of Nitinol alloys. This work aims at analyzing the surface characteristics of MEP Nitinol alloys by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The wettability of the alloys was determined by contact angle measurements and the mechanical properties were assessed by Nanoindentation. Improved mechanical properties were observed with the addition of alloying elements. Cyclic potentiodynamic polarization tests were performed to determine the corrosion susceptibility. Further, the alloys were tested for their cytotoxicity and cellular growth with endothelial cells. Improved corrosion resistance and cellular viability were observed with MEP surface treated alloys. PMID- 25746244 TI - Development of nanosilica bonded monetite cement from egg shells. AB - This work represents further effort from our group in developing monetite based calcium phosphate cements (CPC). These cements start with a calcium phosphate powder (MW-CPC) that is manufactured using microwave irradiation. Due to the robustness of the cement production process, we report that the starting materials can be derived from egg shells, a waste product from the poultry industry. The CPC were prepared with MW-CPC and aqueous setting solution. Results showed that the CPC hardened after mixing powdered cement with water for about 12.5+/-1 min. The compressive strength after 24h of incubation was approximately 8.45+/-1.29 MPa. In addition, adding colloidal nanosilica to CPC can accelerate the cement hardening (10+/-1 min) process by about 2.5 min and improve compressive strength (20.16+/-4.39 MPa), which is more than double the original strength. The interaction between nanosilica and CPC was monitored using an environmental scanning electron microscope (ESEM). While hardening, nanosilica can bond to the CPC crystal network for stabilization. The physical and biological studies performed on both cements suggest that they can potentially be used in orthopedics. PMID- 25746245 TI - First principles theoretical investigations of low Young's modulus beta Ti-Nb and Ti-Nb-Zr alloys compositions for biomedical applications. AB - High alloyed beta-phase stabilized titanium alloys are known to provide comparable Young's modulus as that to the human bones (~30 GPa) but is marred by its high density. In the present study the low titanium alloyed compositions of binary Ti-Nb and ternary Ti-Nb-Zr alloy systems, having stable beta-phase with low Young's modulus are identified using first principles density functional framework. The theoretical results suggest that the addition of Nb in Ti and Zr in Ti-Nb increases the stability of the beta-phase. The beta-phase in binary Ti Nb alloys is found to be fully stabilized from 22 at.% of Nb onwards. The calculated Young's moduli of binary beta-Ti-Nb alloy system are found to be lower than that of pure titanium (116 GPa). For Ti-25(at.%)Nb composition the calculated Young's modulus comes out to be ~80 GPa. In ternary Ti-Nb-Zr alloy system, the Young's modulus of Ti-25(at.%)Nb-6.25(at.%)Zr composition is calculated to be ~50 GPa. Furthermore, the directional Young's moduli of these two selected binary (Ti-25(at.%)Nb) and ternary alloy (Ti-25(at.%)Nb 6.25(at.%)Zr) compositions are found to be nearly isotropic in all crystallographic directions. PMID- 25746246 TI - Study of photo-oxidative reactivity of sunscreening agents based on photo oxidation of uric acid by kinetic Monte Carlo simulation. AB - In the present study, the mechanism of free radical production by light reflective agents in sunscreens (TiO2, ZnO and ZrO2) was obtained by applying kinetic Monte Carlo simulation. The values of the rate constants for each step of the suggested mechanism have been obtained by simulation. The effect of the initial concentration of mineral oxides and uric acid on the rate of uric acid photo-oxidation by irradiation of some sun care agents has been studied. The kinetic Monte Carlo simulation results agree qualitatively with the existing experimental data for the production of free radicals by sun care agents. PMID- 25746247 TI - Biodegradation-tunable mesoporous silica nanorods for controlled drug delivery. AB - Mesoporous silica in the forms of micro- or nanoparticles showed great potentials in the field of controlled drug delivery. However, for precision control of drug release from mesoporous silica-based delivery systems, it is critical to control the rate of biodegradation. Thus, in this study, we demonstrate a simple and robust method to fabricate "biodegradation-tunable" mesoporous silica nanorods based on capillary wetting of anodic aluminum oxide (AAO) template with an aqueous alkoxide precursor solution. The porosity and nanostructure of silica nanorods were conveniently controlled by adjusting the water/alkoxide molar ratio of precursor solutions, heat-treatment temperature, and Na addition. The porosity and biodegradation kinetics of the fabricated mesoporous nanorods were analyzed using N2 adsorption/desorption isotherm, TGA, DTA, and XRD. Finally, the performance of the mesoporous silica nanorods as drug delivery carrier was demonstrated with initial burst and subsequent "zero-order" release of anti cancer drug, doxorubicin. PMID- 25746248 TI - Polybiguanide (PHMB) loaded in PLA scaffolds displaying high hydrophobic, biocompatibility and antibacterial properties. AB - Polyhexamethylenebiguanide hydrochloride (PHMB), a low molecular weight polymer related to chlorohexidine (CHX), is a well-known antibacterial agent. In this study, polylactide (PLA) nanofibers loaded with PHMB were produced by electrospinning to obtain 3D biodegradable scaffolds with antibacterial properties. PLA fibers loaded with CHX were used as control. The electrospun fibers were studied and analyzed by SEM, FTIR, DSC and contact angle measurements. PHMB and CHX release from loaded scaffolds was evaluated, as well as their antibacterial activity and biocompatibility. The results showed that the nanofibers became smoother and their diameter smaller with increasing the amount of loaded PHMB. This feature led to an increase of both surface roughness and hydrophobicity of the scaffold. PHMB release was highly dependent on the hydrophilicity of the medium and differed from that determined for CHX. Lastly, PHMB-loaded PLA scaffolds showed antibacterial properties since they inhibited adhesion and bacterial growth, and exhibited biocompatible characteristics for the adhesion and proliferation of both fibroblast and epithelial cell lines. PMID- 25746249 TI - Finite element analysis of stress distributions in mono- and bi-cortical dental implants. AB - The finite element analysis (FEA) of the stress distribution in the mono- and bicortically fixed implants subjected to 3-axial loading was performed and verified experimentally on a model mandible to evaluate the benefits of each type of fixation from the viewpoint of the compressive stress reduction in the cortical part of atrophied mandible. The analysis revealed that the highest compressive stresses in the cortical bone are generated at the edge of the cortical bone where the highest torque from the implant is acting. The most effective way to reduce the maximum level of compressive stresses in the cortical bone and in the implant is the recession of the implant thread slightly below the surface of the cortical bone. Shortening of the intraosseal length of the implant and/or thinning of the upper cortical bone result in a substantial increase of the maximum compressive stresses. The comparison of FEA and model experiments suggests that bicortical fixation is the most efficient in the fresh implants and the advantage of bicortical fixation compared to monocortical fixation decreases with time due to osteointegration, possibly as a result of gradual suppression of sliding between the bone and implant during loading. PMID- 25746250 TI - Study of the chain microstructure effects on the resulting thermal properties of poly(L-lactide)/poly(N-isopropylacrylamide) biomedical materials. AB - The development of thermally-sensitive poly(N-isopropylacrylamide) (PNIPAAm) and biocompatible/biodegradable poly(L-lactide) (PLLA) blends offers us an efficient strategy in order to obtain materials with improved functional properties to be used in the emerging field of biomedicine. In this sense, thermal properties of PLLA and PNIPAAm have been investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and wide angle X-ray diffraction (WAXD) were conducted to shed more light on the obtained results. For a better understanding of PLLA/PNIPAAm system, both low and high molecular weight PLLA and PNIPAAm have been synthesized by ring opening polymerization and aqueous redox polymerization respectively. Obtained results are interpreted from the viewpoint of chain microstructure of each homopolymer and the ratio between two constituent materials. DSC, SEM and WAXD results show a phase separation over the entire composition range irrespectively of the molecular weight of both homopolymers. Additionally, it was found a nucleating agent behavior of low molecular weight PNIPAAm, while high molecular weight PNIPAAm hinders the crystallization of PLLA. FTIR results suggest that the strong autoassociation present in PNIPAAm plays a key role impairing the miscibility of the whole system. Thermogravimetric analysis reveals that thermodegradation process of PLLA could be continuously delayed with the addition of PNIPAAm due to the increased thermal stability of N-isopropylacrylamide in regard to L-lactide sequences. PMID- 25746251 TI - Magnetically responsive siliceous frustules for efficient chemotherapy. AB - In the present investigation, curcumin loaded magnetically active frustules have been reported. The diatoms were cultured and frustules were obtained by chemical and thermal processes. The frustules were rendered magnetically active by incorporation of iron oxide nanoparticle using two different methods involving ferrofluid (CMDM-F) and in situ synthesis (CMDM-I) of iron oxide nanoparticle. These CMDM prepared by two techniques were characterized using FT-IR and vibrating sample magnetometer (VSM) analyses. Particle size and potential were measured using the Malvern Zetasizer. Scanning electron microscopy (SEM) was utilized for studying the surface morphology of CMDM, and in addition to this elemental analysis was also performed for confirming the presence of iron. The cell viability assay was carried out using the HeLa cell line. SEM images showed a change in surface morphology of diatoms before and after rendering magnetic activity. Cell viability assay revealed that CMDM-F had reasonably high cytotoxicity (60.2%) compared to Curcumin (42.1%), DM (1.9%), CDM (44.8%), and CMDM-I (59.9). Both, CMDM-F and CMDM-I showed improved cytotoxicity when compared with pure curcumin. The overall study suggests that the developed CMDM could be utilized as a potential carrier to deliver cargo for efficient chemotherapy. PMID- 25746252 TI - Synthesis and characterization of nanocrystalline forsterite coated poly(L lactide-co-beta-malic acid) scaffolds for bone tissue engineering applications. AB - In this research, after synthesizing poly(L-lactide-co-beta-malic acid) (PLMA) copolymer, hybrid particles of ice and nanocrystalline forsterite (NF) as coating carriers were used to prepare NF-coated PLMA scaffolds. The porous NF-coated scaffolds were directly fabricated by a combined technique using porogen leaching and freeze-drying methods. The obtained results indicate that the scaffolds were structurally porous with NF particles on their surfaces. When compared to the uncoated scaffolds, the NF coating improved both mechanical properties as well as enhanced bioactivity of the scaffolds. In addition, in vitro biological response of the rat bone marrow stromal cells indicated that NF significantly increased the biocompatibility of NF-coated scaffolds compared with PLMA. PMID- 25746253 TI - Nano-level monitoring of Mn(2+) ion by fabrication of coated pyrolytic graphite electrode based on isonicotinohydrazide derivatives. AB - The two ionophores N'(N',N'''E,N',N'''E)-N',N'''-((((oxybis(ethane-2,1 diyl))bis(oxy)) bis(2,1-phenylene))bis(methanylylidene))di(isonicotinohydrazide) (I1) and (N',N'''E,N',N'''E)-N',N'''-(((propane-1,3-diylbis(oxy))bis(2,1 phenylene))bis(methanylylidene))di(isonicotinohydrazide) (I2) were synthesised and investigated as neutral carrier in the fabrication of Mn(2+) ion selective sensor. Several membranes were prepared by incorporating different plasticizers and anionic excluders and their effect on potentiometric response was studied. The best analytical performance was obtained with the electrode having a membrane of composition of I2: PVC: o-NPOE: NaTPB in the ratio of 6:34:58:2 (w/w, mg). Comparative studies of coated graphite electrode (CGE) and coated pyrolytic graphite electrode (CPGE) based on I2 reveal the superiority of CPGE. The CPGE exhibits wide working concentration range of 1.23*10(-8)-1.0*10(-1) mol L(-1) and a detection limit down to 4.78*10(-9) mol L(-1) with a Nernstian slope of 29.5+/ 0.4 mV decade(-1) of activity. The sensor performs satisfactorily over a wide pH range (3.5-9.0) and exhibited a quick response time (9s). The sensor can work satisfactorily in water-acetonitrile and water-methanol mixtures. It can tolerate 30% acetonitrile and 20% methanol content in the mixtures. The sensor could be used for a period of four months without any significant divergence in performance. The sensor reflects its utility in the quantification of Mn(2+) ion in real samples and has been successfully employed as an indicator electrode in the potentiometric titration of Mn(2+) ion with ethylenediaminetetraacetic acid (EDTA). PMID- 25746254 TI - Creation of a functional graded nanobiomembrane using a new electrospinning system for drug release control and an in vitro validation of drug release behavior of the coating membrane. AB - Functional graded nanobiomembranes (FGMs) with multiple layers were created by a single process using a novel electrospinning system equipped with a generator and a PCI type motion board as a controller in order to control the drug release rate. By varying physical apparatus-related parameters such as nozzle-to collector distance via a robot and the collector moving velocity the FGMs were formed. For the membrane base layer, poly-(epsilon-caprolactone) (PCL) with paclitaxel (PTX) was dissolved in a solvent (dichloromethane, N,N dimethylformamide) and electrospun. For the top layers, the PCL solution was electrospun according to the distance and FGM system parameters, which can move the collector location at a constant ratio. It was observed that pore size, porosity, and permeability were higher when the membrane was spun at the far distance. The top surface of FGM is more porous, rougher, more permeable, and more hydrophilic so as to be active to the surrounding tissue cells. Meanwhile, the porous inside membrane was as low as the membrane spun at a close distance. Thus it induced a slow drug release due to the internal structure of FGM, which is considered to be very effective for slow drug release as well as bioactivity and bioconductivity. PMID- 25746255 TI - Letter to the Editor regarding "Depletion of water molecules during ethanol wet bonding with etch and rinse dental adhesives". AB - I would like to comment on the above titled paper that recently published in Materials Science and Engineering C 33:21-27 (2013). I mentioned potential deficiencies in the study design. Then, I argued some statements made in the paper about interactions between bounded water around collagen molecules and resin infiltration, hence longevity of resin bonding. It is important to highlight these concerns regarding this paper so that readers are provided with another view of the ethanol wet-bonding concept. PMID- 25746256 TI - Evaluation of hemocompatibility and in vitro immersion on microwave-assisted hydroxyapatite-alumina nanocomposites. AB - This study reports the microwave-assisted synthesis and characterization of nHAp (nano-hydroxyapatite)-alumina composites. The crystalline phase and interaction of alumina with nHAp was analyzed using X-ray diffraction (XRD) and Raman microscopy analysis, respectively. High resolution transmission electron microscopy (HRTEM) micrographs exhibit morphological changes of nHAp composites with increasing alumina concentrations. Microhardness studies reveal the enhanced mechanical strength of nHAp10 and nHAp20 nanocomposites than pure nHAp. In vitro bioactivity of the nanocomposites was studied by immersing samples in simulated body fluid (Hank's solution) for 21 days. The surface of biomineralized samples were analyzed using field emission scanning electron microscopy (FESEM) and energy dispersive X-ray spectroscopy (EDX). Hemolytic assay revealed acceptable compatibility for varying concentrations of all the samples. Cell proliferation assay was systematically investigated for 1 day and 3 days on Saos-2 osteoblast like cell lines and it was found that nHAp nanocomposites improved the proliferation. PMID- 25746257 TI - Cerium fluoride nanoparticles protect cells against oxidative stress. AB - A novel facile method of non-doped and fluorescent terbium-doped cerium fluoride stable aqueous sols synthesis is proposed. Intense green luminescence of CeF3:Tb nanoparticles can be used to visualize these nanoparticles' accumulation in cells using confocal laser scanning microscopy. Cerium fluoride nanoparticles are shown for the first time to protect both organic molecules and living cells from the oxidative action of hydrogen peroxide. Both non-doped and terbium-doped CeF3 nanoparticles are shown to provide noteworthy protection to cells against the vesicular stomatitis virus. PMID- 25746258 TI - Chondrogenesis of human bone marrow mesenchymal stromal cells in highly porous alginate-foams supplemented with chondroitin sulfate. AB - To overcome the limited intrinsic cartilage repair, autologous chondrocyte or bone-marrow-derived mesenchymal stromal cell (BM-MSC) was implanted into cartilage defects. For this purpose suitable biocompatible scaffolds are needed to provide cell retention, chondrogenesis and initial mechanical stability. The present study should indicate whether a recently developed highly porous alginate (Alg) foam scaffold supplemented with chondroitin sulfate (CS) allows the attachment, survival and chondrogenesis of BM-MSCs and articular chondrocytes. The foams were prepared using a freeze-drying method; some of them were supplemented with CS and subsequently characterized for porosity, biodegradation and mechanical profile. BM-MSCs were cultured for 1-2 weeks on the scaffold either under chondrogenic or maintenance conditions. Cell vitality assays, histology, glycosaminoglycan (sGAG) assay, and type II and I collagen immunolabelings were performed to monitor cell growth and extracellular matrix (ECM) synthesis in the scaffolds. Scaffolds had a high porosity ~93-95% with a mean pore sizes of 237+/-48 MUm (Alg) and 197+/-61 MUm (Alg/CS). Incorporation of CS increased mechanical strength of the foams providing gradually CS release over 7 days. Most of the cells survived in the scaffolds. BM-MSCs and articular chondrocytes formed rounded clusters within the scaffold pores. The BM-MSCs, irrespective of whether cultured under non/chondrogenic conditions and chondrocytes produced an ECM containing sGAGs, and types II and I collagen. Total collagen and sGAG contents were higher in differentiated BM-MSC cultures supplemented with CS than in CS-free foams after 14 days. The cell cluster formation induced by the scaffolds might stimulate chondrogenesis via initial intense cell-cell contacts. PMID- 25746259 TI - Autonomous patterning of cells on microstructured fine particles. AB - Regularly patterned cells can clarify cellular function and are required in some biochip applications. This study examines cell patterning along microstructures and the effect of microstructural geometry on selective cellular adhesion. Particles can be autonomously assembled on a soda-lime glass substrate that is chemically patterned by immersion in a suspension of fine particles. By adopting various sizes of fine particles, we can control the geometry of the microstructure. Cells adhere more readily to microstructured fine particles than to flat glass substrate. Silica particles hexagonally packed in 5-40 MUm line and space microstructures provide an effective cell scaffold on the glass substrate. Cultured cells tend to attach and proliferate along the microstructured region while avoiding the flat region. The difference in cell adhesion is attributed to their geometries, as both of the silica particles and soda-lime glass are hydrophilic related with cell adhesiveness. After cell seeding, cells adhered to the flat region migrated toward the microstructured region. For most of the cells to assemble on the scaffold, the scaffolding microstructures must be spaced by at most 65 MUm. PMID- 25746260 TI - Superelasticity, corrosion resistance and biocompatibility of the Ti-19Zr-10Nb 1Fe alloy. AB - Microstructure, mechanical properties, superelasticity and biocompatibility of a Ti-19Zr-10Nb-1Fe alloy are investigated. X-ray diffraction spectroscopy and transmission electron microscopy observations show that the as-cast Ti-19Zr-10Nb 1Fe alloy is composed of alpha' and beta phases, but only the beta phase exists in the as-rolled and as-quenched alloys. The tensile stress-strain tests indicate that the as-quenched alloy exhibits a good combination of mechanical properties with a large elongation of 25%, a low Young's modulus of 59 GPa and a high ultimate tensile stress of 723 MPa. Superelastic recovery behavior is found in the as-quenched alloy during tensile tests, and the corresponding maximum of superelastic strain is 4.7% at the pre-strain of 6%. A superelastic recovery of 4% with high stability is achieved after 10 cyclic loading-unloading training processes. Potentiodynamic polarization and ion release measurements indicate that the as-quenched alloy shows a lower corrosion rate in Hank's solution and a much less ion release rate in 0.9% NaCl solution than those of the NiTi alloys. Cell culture results indicate that the osteoblasts' adhesion and proliferation are similar on both the Ti-19Zr-10Nb-1Fe and NiTi alloys. A better hemocompatibility is confirmed for the as-quenched Ti-19Zr-10Nb-1Fe alloy, attributed to more stable platelet adhesion and small activation degree, and a much lower hemolysis rate compared with the NiTi alloy. PMID- 25746261 TI - Silver(I) complexes of N-methylbenzothiazole-2-thione: synthesis, structures and antibacterial activity. AB - Three silver(I) complexes containing N-methylbenzothiazole-2-thione (mbtt) have been prepared and structurally characterized by X-ray single-crystal analysis. Silver(I) nitrate, and silver(I) triflate react with mbtt to give homoleptic complexes of formula [(mbtt)2Ag(MU-mbtt)2Ag(mbtt)2](NO3)2 (1) and [Ag(mbtt)3](CF3SO3) (2) respectively, while silver(I) chloride gives the binuclear halide-bridged [(mbtt)2Ag(MU2-Cl)2Ag(mbtt)2] (3). In the binuclear complex 1 the two metal ions, separated by 3.73 A from each other, are doubly bridged by the exocyclic S-atoms of two mbtt ligands, with the tetrahedral environment around each silver ion being completed by the S-atoms of two terminally bonded mbtt units. Compound 2 is mononuclear with the metal ion surrounded by the exocyclic S-atoms of three mbtt ligands in a nearly ideal trigonal planar arrangement. The new complexes showed significant in vitro antibacterial activity against certain Gram-positive and Gram-negative bacterial strains. PMID- 25746262 TI - Solution combustion synthesis of calcium phosphate particles for controlled release of bovine serum albumin. AB - Four different phase compositions of calcium phosphate (CaP) particles were prepared via a solution combustion method. X-ray diffraction (XRD) and Rietveld analysis results revealed that the variations in the nominal Ca/P (molar) ratios were found to provide a favorable control in the different proportions of CaP materials. Bovine serum albumin (BSA) was used as a model protein to study the loading and release behavior. The release profile indicated that the BSA release rates depended on the phase compositions of the CaP particles, and showed an order of TCP-BSA>BCP-1-BSA>BCP-2-BSA>HA-BSA. The results suggested that the BSA protein release rate can be controlled by varying the phase compositions of CaP carriers. Moreover, the release process involved two stages: firstly surface diffusion via ion exchange and secondly intraparticle diffusion. PMID- 25746263 TI - Hydrophilic PCU scaffolds prepared by grafting PEGMA and immobilizing gelatin to enhance cell adhesion and proliferation. AB - Gelatin contains many functional motifs which can modulate cell specific adhesion, so we modified polycarbonate urethane (PCU) scaffold surface by immobilization of gelatin. PCU-g-gelatin scaffolds were prepared by direct immobilizing gelatins onto the surface of aminated PCU scaffolds. To increase the immobilization amount of gelatin, poly(ethylene glycol) methacrylate (PEGMA) was grafted onto PCU scaffolds by surface initiated atom transfer radical polymerization. Then, following amination and immobilization, PCU-g-PEGMA-g gelatin scaffolds were obtained. Both modified scaffolds were characterized by chemical and biological methods. After immobilization of gelatin, the microfiber surface became rough, but the original morphology of scaffolds was maintained successfully. PCU-g-PEGMA-g-gelatin scaffolds were more hydrophilic than PCU-g gelatin scaffolds. Because hydrophilic PEGMA and gelatin were grafted and immobilized onto the surface, the PCU-g-PEGMA-g-gelatin scaffolds showed low platelet adhesion, perfect anti-hemolytic activity and excellent cell growth and proliferation capacity. It could be envisioned that PCU-g-PEGMA-g-gelatin scaffolds might have potential applications in tissue engineering artificial scaffolds. PMID- 25746264 TI - Chitosan-aluminum monostearate composite sponge dressing containing asiaticoside for wound healing and angiogenesis promotion in chronic wound. AB - There are many factors that delay healing in chronic wounds including lowering level of growth factors and increasing exudate level comprising high amount of tissue destructive enzymes. Asiaticoside possesses interesting wound healing and angiogenic activities that are employed to stimulate tissue regeneration in wound healing application. This study attempted to develop chitosan-aluminum monostearate (Alst) composite sponge containing asiaticoside for use as an absorbent medical dressing in chronic wound. N-methyl-2-pyrrolidone (NMP) was used to enhance homogeneity of asiaticoside in the polymer composite matrix. The sponge dressings were prepared by lyophilization and dehydrothermal treatment (DHT). Functional group interaction, crystallinity, and morphology of the prepared sponges were investigated using FT-IR, PXRD, and SEM, respectively. Physicochemical properties, porosity, hydrophilic/hydrophobic properties and mechanical property, were evaluated. Wound dressing properties, water vapor transmission rate (WVTR), fluid absorbency, oxygen permeation (OP), and bio adhesive property, were investigated. In vitro asiaticoside release study was conducted using immersion method. Cytotoxicity was studied in normal human dermal fibroblast (NHDF) and normal human epidermal keratinocyte (NHEK). Angiogenic activity of asiaticoside was evaluated using chick-chorioallantoic membrane (CAM) assay. FT-IR and PXRD results revealed the amidation after DHT to enhance the crystallinity of the prepared sponges. The prepared sponges had high porosity comprising high Alst-loaded amount that exhibited more compact structure. Alst enhanced hydrophobicity therefore it reduced the fluid absorption and WVTR together with bio-adhesion of the prepared sponge dressings. Porosity of all sponges was more than 85% therefore resulting in their high OP. Enhancing hydrophobicity of the material by Alst and more homogeneity caused by NMP eventually retarded the asiaticoside release for 7 days. The sponge extractions were non-toxic to the cells moreover they promoted NHDF and NHEK cell proliferation. Asiaticoside and asiaticoside-contained dressings exhibited dose dependent angiogenic activity in CAM model. PMID- 25746265 TI - Controlling silk fibroin microspheres via molecular weight distribution. AB - Silk fibroin (SF) microspheres were produced by salting out SF solution via the addition of potassium phosphate buffer solution (K2HPO4-KH2PO4). The morphology, size and polydispersity of SF microspheres were adjusted by changing the molecular weight (MW) distribution and concentration of SF, as well as the ionic strength and pH of the buffer solution. Changing the conditions under which the SF fiber dissolved in the Lithium Boride (LiBr) solution resulted in altering the MW distribution of SF solution. Under optimal salting-out conditions (ionic strength>0.7 M and pH>7) and using a smaller and narrower SF MW distribution, SF microspheres with smoother shapes and more uniform sizes were produced. Meanwhile, the size and polydispersity of the microspheres increased when the SF concentration was increased from 0.25 mg/mL to 20 mg/mL. The improved SF microspheres, obtained by altering the distribution of molecular weight, have potential in drug and gene delivery applications. PMID- 25746266 TI - Application of response surface methodology in optimization of electrospinning process to fabricate (ferrofluid/polyvinyl alcohol) magnetic nanofibers. AB - Magnetic nanofibers are composed of good dispersion of magnetic nanoparticles along an organic material. Magnetic nanofibers are potentially useful for composite reinforcement, bio-medical and tissue engineering. Nanofibers with the thinner diameter have to result in higher rigidity and tensile strength due to better alignments of lamellae along the fiber axis. In this study, the performance of electrospinning process was explained using response surface methodology (RSM) during fabrication of magnetic nanofibers using polyvinyl alcohol (PVA) as a shelter for (gamma-Fe2O3) nanoparticles where the parameters investigated were flow rate, applied voltage, distance between needle and collector and collector rotating speed. The response variable was diameter distribution. The two parameters flow rate and applied voltage in primary evaluation were distinguished as significant factors. Central composite design was applied to optimize the variable of diameter distribution. Quadratic estimated model developed for diameter distribution indicated the optimum conditions to be flow rate of 0.25 ml/h at voltage of 45 kV while the distance and rotating speed are at 8 cm and 1500 rps respectively. The obtained model was verified successfully by the confirmation experiments. PMID- 25746267 TI - Characterization of supramolecular gels based on beta-cyclodextrin and polyethyleneglycol and their potential use for topical drug delivery. AB - Novel gels were prepared by blending beta-cyclodextrin and polyethyleneglycol (PEG) in the presence of K2CO3. The objective of this study was thus to characterize the gels using rheology, modulated temperature differential scanning calorimetry (MTDSC), turbidity measurements, and hot stage microscopy, and then investigate the potential use of the gel for topical drug delivery. Two types of supramolecular gels, GelL and GelH were prepared at a low temperature (below 50 degrees C) and at a high temperature (above 70 degrees C), respectively. Both gels were thermo-reversible. Upon heating, GelL could turn to GelH. Nevertheless, upon cooling, GelH that was more stable than GelL precipitated and GelL could not be reformed. GelL may form through simple complexation of polyethyleneglycol (PEG) with beta-cyclodextrin in the presence of K2CO3. However, GelH may form a specific complex or a pseudopolyrotaxane gel. For pharmaceutical application, GelL was investigated instead of GelH because the forming temperature of this gel was close to the human body temperature. The interactions among diclofenac sodium (DS), a model drug, and the components of the gel were examined using FTIR. These interactions may include ionic attraction and hydrogen bonds between the carboxylate groups of DS and the hydroxyl groups of PEG or beta-cyclodextrin and probably also the inclusion of the aromatic ring of DS into the cavity of beta cyclodextrin. Furthermore, the release and permeation of diclofenac from GelL were significantly greater than those from a commercial gel. Therefore, GelL may be useful for the topical delivery of drugs. PMID- 25746268 TI - Boronate affinity nanoparticles for RNA isolation. AB - In this presented paper, boronic acid incorporated poly(HEMA) based nanoparticles were synthesized for RNA adsorption. For this purpose, poly(HEMA) nanoparticles were synthesized by using the surfactant free emulsion polymerization technique. Then, nanoparticles were modified with 3-(2-imidazoline-1 yl)propyl(triethoxysilane) (IMEO) and functionalized with phenylboronic acid (PBA). Prepared nanoparticles were characterized with SEM, FTIR and zeta-size. Optimum RNA adsorption conditions were investigated with different pHs, temperatures and initial RNA concentrations in order to determine the maximum RNA adsorption onto poly(HEMA)-IMEO-PBA nanoparticles. It was also studied that, synthesized nanoparticles could be used for 5 successive reuses and adsorption capacity of the nanoparticles decreased only about 5% at the end of the 5 cycles. PMID- 25746269 TI - In vitro degradation and cell response of calcium carbonate composite ceramic in comparison with other synthetic bone substitute materials. AB - The robust calcium carbonate composite ceramics (CC/PG) can be acquired by fast sintering calcium carbonate at a low temperature (650 degrees C) using a biocompatible, degradable phosphate-based glass (PG) as sintering agent. In the present study, the in vitro degradation and cell response of CC/PG were assessed and compared with 4 synthetic bone substitute materials, calcium carbonate ceramic (CC), PG, hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) ceramics. The degradation rates in decreasing order were as follows: PG, CC, CC/PG, beta-TCP, and HA. The proliferation of rat bone mesenchymal stem cells (rMSCs) cultured on the CC/PG was comparable with that on CC and PG, but inferior to HA and beta-TCP. The alkaline phosphatase (ALP) activity of rMSCs on CC/PG was lower than PG, comparable with beta-TCP, but higher than HA. The rMSCs on CC/PG and PG had enhanced gene expression in specific osteogenic markers, respectively. Compared to HA and beta-TCP, the rMSCs on the CC/PG expressed relatively lower level of collagen I and runt-related transcription factor 2, but showed more considerable expression of osteopontin. Although CC, PG, HA, and beta-TCP possessed impressive performances in some specific aspects, they faced extant intrinsic drawbacks in either degradation rate or mechanical strength. Based on considerable compressive strength, moderate degradation rate, good cell response, and being free of obvious shortcoming, the CC/PG is promising as another choice for bone substitute materials. PMID- 25746270 TI - Investigation on the physical-mechanical properties of dental resin composites reinforced with novel bimodal silica nanostructures. AB - The aim of this study was to investigate the influence of bimodal silica nanostructures comprising of SiO2 nanoparticles (SiO2 NPs, ~70 nm) and SiO2 nanoclusters (SiO2 NCs, 0.07-2.70 MUm) on physical-mechanical properties of resin based composites (RBCs). SiO2 NPs and SiO2 NCs were prepared with the Stober method and the coupling reaction, respectively, then silanized and employed as fillers to construct RBCs using a mixture of bisphenol A glycerolate dimethacrylate (Bis-GMA) and tri(ethylene glycol) dimethacrylate (TEGDMA) as the organic matrix. Results showed that the properties of RBCs were influenced by the filler ratios of bimodal silica nanostructures, and the appropriate amount of SiO2 NPs could effectively increase the activating light efficiency and filler packing density of RBCs. Among all experimental RBCs, RBC 50-20 (SiO2 NPs:SiO2 NCs=50:20, wt/wt) presented the highest degree of conversion (71.6+/-1.1%), the lowest polymerization shrinkage (2.6+/-0.1%), and the enhanced flexural strength (104.8+/-4.4 MPa), flexural modulus (6.2+/-0.3 GPa), and compressive strength (205.8+/-14.3 MPa), which were improved by 44%, 19%, 28%, 48%, and 42% in comparison with those of RBC 0-60 (SiO2 NPs:SiO2 NCs=0:60, wt/wt), respectively. Besides, in vitro cytotoxicity evaluation of RBC 50-20 indicated its acceptable cytotoxicity. Although the best performance was achieved by commercial Z350 XT, the introduction of bimodal silica nanostructures might provide the enhanced physical-mechanical properties of RBCs, compared with those of RBC 0-60 reinforced with unimodal SiO2 NCs. PMID- 25746271 TI - T-style keratoprosthesis based on surface-modified poly (2-hydroxyethyl methacrylate) hydrogel for cornea repairs. AB - Corneal disease is a common cause of blindness, and keratoplasty is considered as an effective treatment method. However, there is a severe shortage of donor corneas worldwide. This paper presents a novel T-style design of a keratoprosthesis and its preparation methods, in which a mechanically and structurally effective artificial cornea is made based on a poly(2-hydroxyethyl methacrylate) hydrogel. The porous skirt was modified with hyaluronic acid and cationized gelatin, and the bottom of the optical column was coated with poly(ethylene glycol). The physical properties of the T-style Kpro were analyzed using ultraviolet and visible spectrophotometry and electron scanning microscopy. The surface chemical properties were characterized using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The surface modification in the spongy skirt promoted cell adhesion and produced a firm bond between the corneal tissue and the implant device, while the surface modification in the optic column resisted cell adhesion and prevented retroprosthetic membrane formation. Through improved surgical techniques, the novel T-style keratoprosthesis provides enough mechanical stability to facilitate long-term biointegration with the host environment. In vivo implantation experiments showed that the T-style keratoprosthesis is a promising cornea alternative for patients with severe limbal stem cell deficiency and corneal opacity. PMID- 25746272 TI - Simulated effect on the compressive and shear mechanical properties of bionic integrated honeycomb plates. AB - Honeycomb plates can be applied in many fields, including furniture manufacturing, mechanical engineering, civil engineering, transportation and aerospace. In the present study, we discuss the simulated effect on the mechanical properties of bionic integrated honeycomb plates by investigating the compressive and shear failure modes and the mechanical properties of trabeculae reinforced by long or short fibers. The results indicate that the simulated effect represents approximately 80% and 70% of the compressive and shear strengths, respectively. Compared with existing bionic samples, the mass-specific strength was significantly improved. Therefore, this integrated honeycomb technology remains the most effective method for the trial manufacturing of bionic integrated honeycomb plates. The simulated effect of the compressive rigidity is approximately 85%. The short-fiber trabeculae have an advantage over the long-fiber trabeculae in terms of shear rigidity, which provides new evidence for the application of integrated bionic honeycomb plates. PMID- 25746273 TI - MWNT-hybrided supramolecular hydrogel for hydrophobic camptothecin delivery. AB - To encapsulate the hydrophobic camptothecin (CPT) into hydrogel matrix with a high loading amount, a supramolecular hydrogel hybrided with multi-walled carbon nanotubes (MWNTs) was developed by the host-guest interactions and used for loading and delivering CPT. Firstly, carboxylated MWNTs were modified by polyethylene glycol monomethyl ether (MPEG), which resulted in the water dispersed MPEG-MWNTs. Then alpha-cyclodextrin (alpha-CD) was mixed with MPEG MWNTs and the hybrid supramolecular hydrogel was fabricated by the inclusion interactions between alpha-CD and MPEG. The used MPEG not only dispersed MWNTs in aqueous solution, but also functioned as hydrogel matrix by interacting with alpha-CD. The gelation time for the sol-gel transition and rheological properties of the resultant hydrogels were studied. Due to the excellent application of MWNTs in drug delivery, hydrophobic CPT could be loaded into the hydrogel matrix by a higher amount compared with micelles. By in vitro release and cell viability tests, it was found that the encapsulated CPT could exhibit a controlled and sustained release behavior as well as sustained antitumor efficacy. PMID- 25746274 TI - Ocular biocompatibility evaluation of hydroxyl-functionalized graphene. AB - We have presented our recent efforts on genotoxicity and intraocular biocompatibility of hydroxylated graphene (G-OH) prepared by ball milling. We have previously demonstrated that the as-synthesized G-OH could be considered as an excellent alternative for graphene oxide which had been applied widely. Following our last report on G-OH, we carried out detailed studies on genotoxicity and in vivo biocompatibility of G-OH in this work. Less than 5% enhanced caspase-3 level was observed for cells exposed to more than 50 MUg/mL G OH over 72 h, suggesting G-OH caused cell apoptosis was slight. The G-OH induced DNA damage was also found to be mild since expression of p53 and ROS regeneration level was quite low even at high concentration of G-OH over a long time. Cell viability was found to be higher than 90% with 50 MUg/mL G-OH and 80% with 100 MUg/mL G-OH using flow cytometry. Comet results suggested that less than 5% tail could be found with 100 MUg/mL G-OH. TEM results confirmed that G-OH could penetrate into and out of the cytoplasm by means of endocytosis and exocytosis without causing damage on cell membranes. In vivo biocompatibility of G-OH was studied by intravitreal injection of G-OH into rabbits. The ocular fundus photography results showed that G-OH could be diffused in the vitreous body gradually without any damage caused. Injection of G-OH had caused few damages on eyesight related functions such as intraocular pressure, electroretinogram and histological structures of the retina. PMID- 25746275 TI - Improvement of cytocompatibility of polylactide by filling with marine algae powder. AB - This work evaluated the cytocompatibility, thermal and mechanical properties of composites of polylactide (PLA) and marine algae powder (MAP). To improve the thermal and mechanical properties of PLA-MAP composites, glycidyl methacrylate (GMA) was used as the compatibilizer for the blending of PLA and MAP. The PLA-g GMA/MAP composites exhibited superior mechanical properties, attributing to higher compatibility between the polymer and MAP, comparing to PLA/MAP composites. The dispersion of MAP in the PLA-g-GMA matrix was highly homogeneous as a result of etherification. The lower melt torque of the PLA-g-GMA/MAP composites also made them more processable than PLA/MAP. To assess the cytocompatibility, normal human foreskin fibroblasts (FBs) were seeded onto each type of the composites. Results of FB proliferation, collagen production, and cytotoxicity assays indicated greater cytocompatibility for the PLA/MAP composites than for the PLA-g-GMA/MAP composites. Furthermore, both PLA/MAP and PLA-g-GMA/MAP composites were more cytocompatible than pure PLA. PMID- 25746276 TI - In vitro apatite formation and drug loading/release of porous TiO2 microspheres prepared by sol-gel processing with different SiO2 nanoparticle contents. AB - Bioactive titania (TiO2) microparticles can be used as drug-releasing cement fillers for the chemotherapeutic treatment of metastatic bone tumors. Porous anatase-type TiO2 microspheres around 15 MUm in diameter were obtained through a sol-gel process involving a water-in-oil emulsion with 30:70 SiO2/H2O weight ratio and subsequent NaOH solution treatment. The water phase consisted of methanol, titanium tetraisopropoxide, diethanolamine, SiO2 nanoparticles, and H2O, while the oil phase consisted of kerosene, Span 80, and Span 60. The resulting microspheres had a high specific surface area of 111.7 m(2).g(-1). Apatite with a network-like surface structure formed on the surface of the microspheres within 8 days in simulated body fluid. The good apatite-forming ability of the microspheres is attributed to their porous structure and the negative zeta potential of TiO2. The release of rhodamine B, a model for a hydrophilic drug, was rapid for the first 6 h of soaking, but diffusion controlled thereafter. The burst release in the first 6h is problematic for clinical applications; nonetheless, the present results highlight the potential of porous TiO2 microspheres as drug-releasing cement fillers able to form apatite. PMID- 25746277 TI - Microstructure and properties of the Ti/Al2O3/NiCr composites fabricated by explosive compaction/cladding. AB - Titanium/aluminum oxide/nickel chromium (Ti/Al2O3/NiCr) composite bar prepared by explosive compaction/cladding technique represents a new kind of sandwich structural composites for medical application. Formation of the interfaces of Ti/Al2O3 and Al2O3/NiCr govern the properties of the composite material. The electrical resistivity and microstructure of the intermediate layer and the interfaces of the Ti/Al2O3/NiCr explosive compaction/cladding bar are investigated by means of four-point probe analysis, optical microscopy, scanning electron microscopy, electron microprobe analysis, and X-ray diffraction. The Ti/Al2O3/NiCr composite bar is characterized by the consolidated ceramic intermediate layer and the metallurgical bonding interfaces. The intermediate ceramic layer plays a role of insulation and thermal conductance in this composite. The average shear strength of the composite bar is about 9.36 MPa. The heat affected zone characterized by relatively larger sizes of grains is distinguished from the other part of the Ti tube. The intermetallics AlTi3 and Al0.9Ni4.22 are generated at the intermediate ceramic layer. Formation mechanism of the interfaces of the explosive compaction/cladding bar are described. PMID- 25746278 TI - Silver nanoparticle based antibacterial methacrylate hydrogels potential for bone graft applications. AB - Infections are frequent and very undesired occurrences after orthopedic procedures; furthermore, the growing concern caused by the rise in antibiotic resistance is progressively dwindling the efficacy of such drugs. Artificial bone graft materials could solve some of the problems associated with the gold standard use of natural bone graft such as limited bone material, pain at the donor site and rejections if donor tissue is used. We have previously described new acrylate base nanocomposite hydrogels as bone graft materials. In the present paper, we describe the integration of silver nanoparticles in the polymeric mineralized biomaterial to provide non-antibiotic antibacterial activity against Staphylococcus epidermidis and Methicillin-resistant Staphylococcus aureus. Two different crosslinking degrees were tested and the silver nanoparticles were integrated into the composite matrix by means of three different methods: entrapment in the polymeric hydrogel before the mineralization; diffusion during the process of calcium phosphate crystallization and adsorption post mineralization. The latter being generally the most effective method of encapsulation; however, the adsorption of silver nanoparticles inside the pores of the biomaterial led to a decreasing antibacterial activity for adsorption time longer than 2 days. PMID- 25746279 TI - Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery. AB - In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid "burst" release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)-doxorubicin (PEG-DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG-DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal /m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH functionalized PEG and PEG-DOX prodrug were confirmed by (1)H NMR analysis. The PEG-DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG-DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy. PMID- 25746280 TI - Upon synthesis of a polymeric matrix with pH and temperature responsiveness and antioxidant bioactivity based on poly(maleic anhydride-co-3,9-divinyl-2,4,8,10 tetraoxaspiro [5.5] undecane) derivatives. AB - Poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane), acquired through radical polymerization, was synthesized with the aim to prepare an alternant copolymer with precise placement of functional groups along the polymer backbones. The new structure owing to the suitable and specific functionalities is anticipated to be used as reactive polymer to link bioactive compounds via maleic anhydride moiety. The copolymer was improved in its functionality by maleic anhydride ring opening with different amounts of erythritol in order to confer antioxidant characteristics to the polymeric structure. The chemical structure of the new prepared polymers was confirmed by FTIR and (1)H NMR spectra, and the polymers were also characterized from the viewpoint of their thermal stability. The dual sensitivity of the polymeric structure, at temperature and pH, was evaluated by determining the hydrodynamic radius and zeta potential in interdependence with the environment conditions. The polymer morphology was investigated by SEM. The antioxidant character was evaluated measuring the scavenger properties of the functionalized copolymer with erythritol against the 2,2-diphenyl-1-picrylhydrazyl radicals. The acute toxicity investigation, realized in vivo for the copolymer and the derivatives, allows the inclusion of the compounds into the group of moderately toxic accordingly to Hodge and Sterner toxicity scale owing to the lethal dose 50 determined values. PMID- 25746281 TI - Study on the interactions of trans-resveratrol and curcumin with bovine alpha lactalbumin by spectroscopic analysis and molecular docking. AB - The ability of bovine alpha-lactalbumin (BLA) as a whey protein to carry curcumin and trans-resveratrol as two natural polyphenolic compounds was investigated by fluorescence quenching measurements and docking studies. Curcumin is the bioactive component of turmeric and trans-resveratrol is abundant in different types of fruits and vegetables. The binding parameters such as binding constants and the number of substantive binding sites have been estimated from the analysis of fluorescence quenching measurements. The differences in affinities of curcumin and trans-resveratrol for BLA were compared. The short Forster's distance (r) between donor (BLA) and acceptor (curcumin and trans-resveratrol) and also the binding constant values demonstrated the strong interaction between these two polyphenolic compounds and BLA. The thermodynamic parameters were obtained from the fluorescence quenching measurements in different temperatures. It can be concluded from the sign and magnitude of ?H and ?S that the final ligand-protein complexes were stabilized by hydrogen bonds. The considerable change in microregion of the Trp residues in BLA is observed upon the binding of the trans resveratrol to BLA by synchronous fluorescence while this conformation alteration was not observed upon interaction with curcumin. It was indicated by docking studies that curcumin come closer to the Trp-118 than to other tryptophans and trans-resveratrol binds in the vicinity of Trp-60 and Trp-104. Docking studies indicated that these two compounds bind to BLA by two hydrogen bonds. The calculated distances between bound ligands and tryptophans obtained by docking studies were in agreement with fluorescence resonance energy transfer results. Therefore, the strong interaction of curcumin and trans-resveratrol with BLA was confirmed by theoretical and experimental studies. These achieved results may be applicable in the milk industry and drug formulation. PMID- 25746282 TI - Surface characterizations of laser modified biomedical grade NiTi shape memory alloys. AB - Laser processing of shape memory alloys (SMAs) promises to enable the multifunctional capabilities needed for medical device applications. Prior to clinical implementation, the surface characterisation of laser processed SMA is essential in order to understand any adverse biological interaction that may occur. The current study systematically investigated two Ni-49.8 at.% Ti SMA laser processed surface finishes, including as-processed and polished, while comparing them to a chemically etched parent material. Spectrographic characterisation of the surface included; X-ray photoelectron spectroscopy (XPS), auger electron spectroscopy (AES), and Raman spectroscopy. Corrosion performance and Ni ion release were also assessed using potentiodynamic cyclic polarization testing and inductively coupled plasma optical emission spectroscopy (ICP-OES), respectively. Results showed that surface defects, including increased roughness, crystallinity and presence of volatile oxide species, overshadowed any possible performance improvements from an increased Ti/Ni ratio or inclusion dissolution imparted by laser processing. However, post-laser process mechanical polishing was shown to remove these defects and restore the performance, making it comparable to chemically etched NiTi material. PMID- 25746283 TI - Reversible adsorption of catalase onto Fe(3+) chelated poly(AAm-GMA)-IDA cryogels. AB - In this presented study, poly(acrylamide-glycidyl methacrylate) [poly(AAm-GMA)] cryogels were synthesized by cryopolymerization technique at sub-zero temperature. Prepared cryogels were then functionalized with iminodiacetic acid (IDA) and chelated with Fe(3+) ions in order produce the metal chelate affinity matrix. Synthesized cryogels were characterized with FTIR, ESEM and EDX analysis, and it was found that the cryogel had sponge like structure with interconnected pores and their pore diameter was about 200 MUm. Fe(3+) chelated poly(AAm-GMA) IDA cryogels were used for the adsorption of catalase and optimum adsorption conditions were determined by varying the medium pH, initial catalase concentration, temperature and ionic strength. Maximum catalase adsorption onto Fe(3+) chelated poly(AAm-GMA)-IDA cryogel was found to be 12.99 mg/g cryogel at 25 degrees C, by using pH 5.0 acetate buffer. Adsorbed catalase was removed from the cryogel by using 1.0M of NaCl solution and desorption yield was found to be 96%. Additionally, reusability profile of the Fe(3+) chelated poly(AAm-GMA)-IDA cryogel was also investigated and it was found that, adsorption capacity of the cryogels didn't decrease significantly at the end of the 40 reuses. Catalase activity studies were also tested and it was demonstrated that desorbed catalase retained 70% of its initial activity. PMID- 25746284 TI - Immobilization of alpha-amylase onto poly(glycidyl methacrylate) grafted electrospun fibers by ATRP. AB - In this study, novel alpha-amylase immobilized poly(vinyl alcohol) (PVA) nanofibers were prepared. The PVA nanofiber surfaces were functionalized with 2 bromoisobutyryl bromide (BiBBr) and followed by surface initiated atom transfer radical polymerization (SI-ATRP) of glycidyl methacrylate (GMA). The morphology of the poly(glycidyl methacrylate) (PGMA) grafted PVA nanofibers was characterized by scanning electron microscopy (SEM). Also PGMA brushes were confirmed by X-ray photo electron microscopy (XPS). alpha-Amylase was immobilized in a one step process onto the PGMA grafted PVA nanofiber. The characteristic properties of the immobilized and free enzymes were examined. The thermal stability of the enzyme was improved and showed maximum activity at 37 degrees C by immobilization. pH values of the maximum activity of the free and immobilized enzymes were also found at 6.0 and 6.5, respectively. Free enzyme lost its activity completely within 15 days. The immobilized enzyme lost only 23.8% of its activity within 30 days. PMID- 25746285 TI - Electrochemical behavior and effect of heat treatment on morphology, crystalline structure of self-organized TiO2 nanotube arrays on Ti-6Al-7Nb for biomedical applications. AB - In the present work, we investigate the formation of self-organized titanium oxide nanotube layers by anodic oxidation on titanium alloy Ti-6Al-7Nb in electrolyte solution containing sulfuric acid and hydrofluoric acid. The anodized surface was characterized by micro-Raman, X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and energy-dispersive X-ray spectroscopy (EDS). The corrosion behavior of the treated and untreated samples was investigated through electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization studies in simulated body fluid (Hanks' solution). The investigations show that the native oxide on the sample is replaced by self assembled nanoarray by anodization. FESEM of samples annealed at 450 to 800 degrees C show tubular morphology whereas those annealed at 850 degrees C show collapse of nanotubes. Electrochemical impedance data of the substrate and 10 V anodized samples were fitted with a two-time constant equivalent circuit and that of anodized samples (20, 30 V) with a three-time constant equivalent circuit. PMID- 25746286 TI - Heat shock protein 22 (Hsp22) regulates oxidative phosphorylation upon its mitochondrial translocation with the inducible nitric oxide synthase in mammalian heart. AB - OBJECTIVES: Stress-inducible heat shock protein 22 (Hsp22) confers protection against ischemia through induction of the inducible isoform of nitric oxide synthase (iNOS). Hsp22 overexpression in vivo stimulates cardiac mitochondrial respiration, whereas Hsp22 deletion in vivo significantly reduces respiration. We hypothesized that Hsp22-mediated regulation of mitochondrial function is dependent upon its mitochondrial translocation together with iNOS. METHODS AND RESULTS: Adenoviruses harboring either the full coding sequence of Hsp22 (Ad-WT Hsp22) or a mutant lacking a N-terminal 20 amino acid putative mitochondrial localization sequence (Ad-N20-Hsp22) were generated, and infected in rat neonatal cardiomyocytes. Compared to beta-Gal control, WT-Hsp22 accumulated in mitochondria by 2.5 fold (P<0.05) and increased oxygen consumption rates by 2 fold (P<0.01). This latter effect was abolished upon addition of the selective iNOS inhibitor, 1400 W. Ad-WT-Hsp22 significantly increased global iNOS expression by about 2.5-fold (P<0.01), and also increased iNOS mitochondrial localization by 4.5 fold vs. beta-gal (P<0.05). Upon comparable overexpression, the N20-Hsp22 mutant did not show significant mitochondrial translocation or stimulation of mitochondrial respiration. Moreover, although N20-Hsp22 did increase global iNOS expression by 4.6-fold, it did not promote iNOS mitochondrial translocation. CONCLUSION: Translocation of both Hsp22 and iNOS to the mitochondria is necessary for Hsp22-mediated stimulation of oxidative phosphorylation. PMID- 25746287 TI - Homogeneous electrochemical strategy for human telomerase activity assay at single-cell level based on T7 exonuclease-aided target recycling amplification. AB - As an important biomarker for early cancer diagnostics and a valuable therapeutic target, telomerase has attracted extensive attention concerning its detection and monitoring. Herein, a homogeneous electrochemical strategy based on T7 exonuclease-aided target recycling amplification is proposed for a simple, rapid, and highly sensitive assay of human telomerase activity from crude cancer cell extracts. In this strategy, a 5' methylene blue (MB)-labeled hairpin (HP) probe is designed, which can hybridize with the telomerase reaction products to initiate the subsequent digestion by T7 exonuclease, and a large amount of MB labeled mononucleotides are released to result in the significantly amplified electrochemical signal. By taking advantage of the high amplification efficiency of T7-aided target recycling, the present assay enables the detection of telomerase activity at the single-cell level, which is superior or comparable to that of the reported literature. Furthermore, the assay was carried out in a homogeneous solution without complex modification or immobilization procedures, which has the merits of simplicity, rapid response, and improved recognition efficiency compared with heterogeneous biosensors. With the ability of fast detection, outstanding sensitivity, and excellent selectivity, this strategy offers a convenient and specific method for telomerase activity detection, which exhibits great potential in the practical application in telomerase-based early stage cancer diagnosis. PMID- 25746288 TI - Risk Prediction Tool for Medical Appointment Attendance Among HIV-Infected Persons with Unsuppressed Viremia. AB - Successful treatment of HIV infection requires regular clinical follow-up. A previously published risk-prediction tool (RPT) utilizing data from the electronic health record (EHR) including medication adherence, previous appointment attendance, substance abuse, recent CD4+ count, prior antiretroviral therapy (ART) exposure, prior treatment failure, and recent HIV-1 viral load (VL) has been shown to predict virologic failure at 1 year. If this same tool could be used to predict the more immediate event of appointment attendance, high-risk patients could be identified and interventions could be targeted to improve this outcome. We conducted an observational cohort study at the Vanderbilt Comprehensive Care Clinic from August 2013 through March 2014. Patients with routine medical appointments and most recent HIV-1 VL >200 copies/mL were included. Risk scores for a modified RPT were calculated based on data from the EHR. Odds ratios (OR) for missing the next appointment were estimated using multivariable logistic regression. Among 510 persons included, median age was 39 years, 74% were male, 55% were black, median CD4+ count was 327 cells/mm(3) [Interquartile Range (IQR): 142-560], and median HIV-1 VL was 21,818 copies/mL (IQR: 2,030-69,597). Medium [OR 3.95, 95% confidence interval (CI) 2.08-7.50, p value<0.01] and high (OR 9.55, 95% CI 4.31-21.16, p-value<0.01) vs. low RPT risk scores were independently associated with missing the next appointment. RPT scores, constructed using readily available data, allow for risk-stratification of HIV medical appointment non-attendance and could support targeting limited resources to improve appointment adherence in groups most at-risk of poor HIV outcomes. PMID- 25746290 TI - Chest pain and arrhythmia in a 64-year-old man. PMID- 25746289 TI - Exercise heart rates in patients with hypertrophic cardiomyopathy. AB - The exercise heart rate (HR) profile and its relation to cardiac function and arrhythmias were investigated in patients with hypertrophic cardiomyopathy (HC). Chronotropic response (CR) and heart rate recovery (HRR) were computed during and after treadmill exercise testing in 273 patients with HC and 95 age-matched healthy controls. Patients with HC had higher prevalence of chronotropic incompetence and lower HRR1-5min compared with controls. Exercise capacity, diastolic function (assessed by E/e') and left atrial volume index were associated with HRR1min and CR in HC. Septal myectomy was associated with reduction in chronotropic incompetence but did not affect HRR1min. In conclusion, impaired CR and HRR1min are associated with advanced disease and do not appear to be independent clinical markers indicating high-risk status in HC. Improving CR by titrating doses of negative chronotropic agents, myectomy, and atrial pacing may be useful to increase exercise capacity in patients with HC. PMID- 25746291 TI - Specific microRNAs regulate heat stress responses in Caenorhabditis elegans. AB - The ability of animals to sense and respond to elevated temperature is essential for survival. Transcriptional control of the heat stress response has been much studied, whereas its posttranscriptional regulation by microRNAs (miRNAs) is not well understood. Here we analyzed the miRNA response to heat stress in Caenorhabditis elegans and show that a discrete subset of miRNAs is thermoregulated. Using in-depth phenotypic analyses of miRNA deletion mutant strains we reveal multiple developmental and post-developmental survival and behavioral functions for specific miRNAs during heat stress. We have identified additional functions for already known players (mir-71 and mir-239) as well as identifying mir-80 and the mir-229 mir-64-66 cluster as important regulators of the heat stress response in C. elegans. These findings uncover an additional layer of complexity to the regulation of stress signaling that enables animals to robustly respond to the changing environment. PMID- 25746292 TI - The problematic construction of 'Palaeolithic Man': The Old Stone Age and the difficulties of the comparative method, 1859-1914. AB - The growth of a prehistoric timescale was one of the most dramatic developments in nineteenth-century ideas of humanity, massively extending the assumed course of human development and placing it within the deep chronologies of geological time. A dominant motif linking prehistory with wider studies of humanity and notions of historical change was the 'comparative method'-the idea that modern 'savages' were analogous to prehistoric Europeans, and that the two sets of peoples could explain one another. The importance of this mode of reasoning has been well-studied, and shown to have had great significance for concepts of progress and social evolution. What has been less investigated are cases when the comparative method broke down, and where 'modern savages' and 'prehistoric man' seemed to be dissimilar and analogies hard to make. This paper examines how a series of authors engaged with problems in the comparative method when they attempted to place human development within this deep prehistoric past. In doing so, it highlights the changing interactions between the Victorian deep time sciences and the 'sciences of man,' and how notions of European prehistory and modern 'primitives' often rested on a notion of variability in the 'savage' condition. PMID- 25746293 TI - Conceptualizing risk and effectiveness: a qualitative study of women's and providers' perceptions of nonsurgical female permanent contraception. AB - OBJECTIVE: Novel approaches to nonsurgical permanent contraception (NSPC) for women that are low cost and require no incision or hysteroscope/surgical equipment could improve access to, and the acceptability of, permanent contraception (PC). To better understand opportunities and limitations for NSPC approaches, we examined women's and obstetrician-gynecologist (OB/GYN) providers' perceptions of NSPC in Portland, OR. STUDY DESIGN: Semistructured, qualitative interviews were conducted with 40 women recruited from outpatient clinics with purposive sampling, and a focus group was conducted with 9 OB/GYNs in academic and community practice. Transcripts were coded and inductively analyzed with a grounded theory approach. RESULTS: The majority of women identified as white (67%) or Latina (25%). They had a median age of 31.5 years, and median number of children was one. Perspectives on NSPC were closely aligned with women's general attitudes towards PC; over half were considering PC for themselves or partners in the future. Most respondents valued multiple aspects of a nonsurgical approach, with themes of minimizing recovery time, invasiveness and risk and avoiding hormonal contraception. Many assumed that NSPC would be less effective than surgery, however, and felt that a confirmation test would be necessary regardless of the failure rate. Providers welcomed efforts to expand contraceptive choice with NSPC, but would require long-term safety and efficacy data before recommending, and voiced concerns that NSPC's potential relative ease of administration could undermine the inherent seriousness of choosing PC. CONCLUSIONS: Women's and providers' perceptions of NSPC hinged on the ways in which they conceptualized risk and effectiveness. While perceptions were generally favorable, confirmation of safety and effectiveness would be required for a new approach to be accepted. IMPLICATIONS: This hypothesis-generating study elucidates women's and provider's perspectives on new methods of NSPC and contributes to understanding their perceptions of various types of risk. A technique to verify tubal occlusion would be needed for women and providers to accept NSPC. PMID- 25746294 TI - Ovulatory effects of three oral contraceptive regimens: a randomized, open-label, descriptive trial. AB - OBJECTIVE: This study describes ovarian activity suppression of a 21/7-active low dose combined oral contraceptive (COC) regimen that included only ethinyl estradiol (EE) during the traditional hormone-free interval (HFI) and two commercially available 28-day regimens, a 24/4 and a 21/7 regimen. STUDY DESIGN: The randomized, open-label, parallel-group descriptive study was conducted at two US sites. Healthy, reproductive-aged women (n=146) were randomized to one of three groups for three consecutive 28-day cycles, as follows: treatment 1 (n=39 completed): 21/7-active COC [21 days of 150 mcg desogestrel (DSG)/20 mcg EE, followed by 7 days of 10 mcg EE (DSG/EE+7 days EE)], treatment 2 (n=39 completed): 24 days of 3mg drospirenone (DRSP)/20 mcg EE, followed by 4 placebo (PBO)-pill days (DRSP/EE+4 days PBO) and treatment 3 (n=42 completed): 21 days of 100 mcg levonorgestrel (LNG)/20 mcg EE, followed by 7 PBO-pill days (LNG/EE+7 days PBO). The primary outcome was ovarian activity suppression assessed by transvaginal ultrasound and serum hormone concentrations and classified using the Hoogland and Skouby (H/S) method. RESULTS: Ovarian activity rate (H/S grade 4 or 5) was low for all three treatments: 0% [95% confidence interval (CI) 0-2.8] for DSG/EE+7 days EE, 1% (95% CI 0.2-5.2) for DRSP/EE+4days PBO and 1% (95% CI 0-3.9) for LNG/EE+7 days PBO. All three treatments showed similar suppression of serum progesterone, 17beta-estradiol, follicle-stimulating hormone and luteinizing hormone levels. CONCLUSIONS: The 21/7-active low-dose COC regimen (DSG/EE+7 days EE) showed ovarian activity suppression that was similar to the 24/4 (DRSP/EE+4 days PBO) and 21/7 (LNG/EE+7days PBO) regimens. IMPLICATIONS: The 21/7-active low dose COC regimen (DSG/EE+7 days EE) that included only EE during the traditional HFI showed suppression of ovarian follicular activity that was similar to the 24/4 (DRSP/EE+4days PBO) and the 21/7 (LNG/EE+7 days PBO) comparator regimens. PMID- 25746295 TI - The experiences and adaptations of abortion providers practicing under a new TRAP law: a qualitative study. AB - OBJECTIVE: Abortion laws are proliferating in the United States, but little is known about their impact on abortion providers. In 2011, North Carolina instituted the Woman's Right to Know (WRTK) Act, which mandates a 24-h waiting period and counseling with state-prescribed information prior to abortion. We performed a qualitative study to explore the experiences of abortion providers practicing under this law. STUDY DESIGN: We conducted semistructured interviews with 31 abortion providers (17 physicians, 9 nurses, 1 physician assistant, 1 counselor and 3 clinic administrators) in North Carolina. Interviews were audio recorded and transcribed. Interview transcripts were analyzed using a grounded theory approach. We identified emergent themes, coded all transcripts and developed a thematic framework. RESULTS: Two major themes define provider experiences with the WRTK law: provider objections/challenges and provider adaptations. Most providers described the law in negative terms, though providers varied in the extent to which they were affected. Many providers described extensive alterations in clinic practices to balance compliance with minimization of burdens for patients. Providers indicated that biased language and inappropriate content in counseling can negatively impact the patient-physician relationship by interfering with trust and rapport. Most providers developed verbal strategies to mitigate the emotional impacts for patients. CONCLUSIONS: Abortion providers in North Carolina perceive WRTK to have a negative impact on their clinical practice. Compliance is burdensome, and providers perceive potential harm to patients. The overall impact of WRTK is shaped by interaction between the requirements of the law and the adaptations providers make in order to comply with the law while continuing to provide comprehensive abortion care. IMPLICATIONS: Laws like WRTK are burdensome for providers. Providers adapt their clinical practices not only to comply with laws but also to minimize the emotional and practical impacts on patients. The effects on providers, frequently not a central consideration, should be considered in ongoing debates regarding abortion regulation. PMID- 25746296 TI - Development and host compatibility of plasmids for two important ruminant pathogens, Mycoplasma bovis and Mycoplasma agalactiae. AB - Mycoplasma bovis is a cause of pneumonia, mastitis, arthritis and otitis media in cattle throughout the world. However, despite its clinical significance, there is a paucity of tools to genetically manipulate it, impeding our capacity to further explore the molecular basis of its virulence. To address this limitation, we developed a series of homologous and heterologous replicable plasmids from M. bovis and M. agalactiae. The shortest replicable oriC plasmid based on the region downstream of dnaA in M. bovis was 247 bp and contained two DnaA boxes, while oriC plasmids based on the region downstream of dnaA in M. agalactiae strains 5632 and PG2 were 219 bp and 217 bp in length, respectively, and contained only a single DnaA box. The efficiency of transformation in M. bovis and M. agalactiae was inversely correlated with the size of the oriC region in the construct, and, in general, homologous oriC plasmids had a higher transformation efficiency than heterologous oriC plasmids. The larger pWholeoriC45 and pMM21-7 plasmids integrated into the genomic oriC region of M. bovis, while the smaller oriC plasmids remained extrachromosomal for up to 20 serial passages in selective media. Although specific gene disruptions were not be achieved in M. bovis in this study, the oriC plasmids developed here could still be useful as tools in complementation studies and for expression of exogenous genes in both M. bovis and M. agalactiae. PMID- 25746297 TI - Correction: Hatching time and alevin growth prior to the onset of exogenous feeding in farmed, wild and hybrid Norwegian Atlantic salmon. PMID- 25746298 TI - A pilot study on the feasibility of European harmonized human biomonitoring: Strategies towards a common approach, challenges and opportunities. AB - In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main objective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother-child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).(1) Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy. PMID- 25746299 TI - Anaerobic digestion of lipid-extracted Auxenochlorella protothecoides biomass for methane generation and nutrient recovery. AB - This study evaluated methane production and nutrient recovery from industrially produced, lipid extracted algal biomass (LEA) of Auxenochlorella protothecoides using semi-continuous anaerobic digestion (AD) at different organic loading rates (OLRs) and hydraulic retention times (HRTs). It was shown, that AD can improve biofuel production efficiency and sustainability, especially for scaled processes, through up to 30% increase in energy generation (up to 0.25 L of methane per g of LEA volatile solids) and partial nutrient recovery and recycling. The nutrient recycling with the AD effluent may reduce the cost of the supplied fertilizers by up to 45%. However, methane production was limited to nearly 50% of theoretical maxima potentially due to biomass recalcitrance and inhibition effects from the residual solvent in the LEA. Therefore, further AD optimization is required to maximize methane yield and nutrient recovery as well as investigation and elimination of inhibition from solvent residues. PMID- 25746300 TI - Ozonolysis pretreatment of maize stover: the interactive effect of sample particle size and moisture on ozonolysis process. AB - Maize stover was ozonolyzed to improve the enzymatic digestibility. The interactive effect of sample particle size and moisture content on ozonolysis was studied. After ozonolysis, both lignin and xylan decreased while cellulose was only slightly affected in all experiments. It was also found that the smaller particle size is better for ozonolysis. The similar water activity of the different optimum moisture contents for ozonolysis reveals that the free and bound water ratio is a key factor of ozonolysis. The best result of ozonolysis was obtained at the mesh of -300 and the moisture of 60%, where up to 75% lignin was removed. The glucose yield after enzymatic hydrolysis increased from 18.5% to 80%. Water washing had low impact on glucose yield (less than 10% increases), but significantly reduced xylose yield (up to 42% decreases). The result indicates that ozonolysis leads to xylan solubilization. PMID- 25746301 TI - Lignin extraction distinctively enhances biomass enzymatic saccharification in hemicelluloses-rich Miscanthus species under various alkali and acid pretreatments. AB - In this study, one- and two-step pretreatments with alkali and acid were performed in the three Miscanthus species that exhibit distinct hemicelluloses levels. As a result, one-step with 4% NaOH or two-step with 2% NaOH and 1% H2SO4 was examined to be optimal for high biomass saccharification, indicating that alkali was the main effecter of pretreatments. Notably, both one- and two-step pretreatments largely enhanced biomass digestibility distinctive in hemicelluloses-rich samples by effectively co-extracting hemicelluloses and lignin. However, correlation analysis further indicated that the effective lignin extraction, other than the hemicelluloses removals, predominately determined biomass saccharification under various alkali and acid pretreatments, leading to a significant alteration of cellulose crystallinity. Hence, this study has suggested the potential approaches in bioenergy crop breeding and biomass process technology. PMID- 25746302 TI - Breast lipofilling: A new treatment of Becker nevus syndrome. AB - INTRODUCTION: The association of Becker's nevus with other cutaneous, musculoskeletal or maxillofacial anomalies is called Becker nevus syndrome. Ipsilateral breast hypoplasia is the main reason for female patients to seek medical advice. We present two clinical cases of Becker nevus syndrome with thoracic nevus and ipsilateral breast hypoplasia treated with lipofilling alone (fat grafting). MATERIAL AND METHODS: For the two consecutive cases of Becker nevus syndrome treated by fat grafts, we present the surgical technique and the outcome at one year follow-up. Fat was harvested with cannula after infiltration. The adipose tissue was prepared with a short centrifugation. Fat grafting was realized as backward injections. RESULTS: We have noticed a concomitant improvement of the thoracic nevus color with a stable result after one-year follow-up. The aesthetic result after lipofilling was evaluated as very satisfying by the patient. The breast symmetry was improved. CONCLUSIONS: We believe that the lipofilling technique is a natural and valuable treatment option for thoracic anomalies in Becker nevus syndrome with a major impact on patient's quality of life. PMID- 25746303 TI - Frequency and allele burden of CALR mutations in Chinese with essential thrombocythemia and primary myelofibrosis without JAK2(V617F) or MPL mutations. AB - CALR mutations are detected in about 50% of persons of predominately European descent with essential thrombocythemia (ET) or primary myelofibrosis (PMF) with wild-type alleles of JAK2 and MPL. We studied 1088 Chinese with diverse myeloproliferative neoplasms including ET (N=234) and PMF (N=50) without JAK2(V617F) or MPL exon 10 mutations. CALR mutation was detected in 53% (95% CI, 46-60%) of subjects with ET and 56% (95% CI, 41-70%) of subjects with PMF. 152 CALR mutations were identified clustering into 15 types including deletions (N=8), insertions (N=3) and complex indels (N=4). We also identified 9 new mutations. Mean (+/-SD) mutant allele burden was 31+/-12% (range, 0.5-69%). Persons with PMF had higher CALR mutant allele burdens than those with ET (38+/ 8% vs. 29+/-12%; P<0.001). Amongst persons with CALR mutations, those with PMF had different clinical features from those with ET. These data may be useful for diagnosing ET and PMF in Chinese who are about 40% of all persons with ET and PMF and for monitoring therapy-response. They also highlight similarities and differences in CALR mutations between Chinese and persons of predominately European descent with these diseases. PMID- 25746304 TI - Stem cell transplantation enhances endogenous brain repair after experimental stroke. AB - Stem cell transplantation for stroke treatment has been a promising therapy in small and large animal models, and many clinical trials are ongoing to establish this strategy in a clinical setting. However, the mechanism underlying functional recovery after stem cell transplantation has not been fully established and there is still a need to determine the ideal subset of stem cells for such therapy. We herein reviewed the recent evidences showing the underlying mechanism of functional recovery after cell transplantation, focusing on endogenous brain repair. First, angiogenesis/neovascularization is promoted by trophic factors including vascular endothelial growth factor secreted from stem cells, and stem cells migrated to the lesion along with the vessels. Second, axonal sprouting, dendritic branching, and synaptogenesis were enhanced altogether in the both ipsilateral and contralateral hemisphere remapping the pyramidal tract across the board. Finally, endogenous neurogenesis was also enhanced although little is known how much these neurogenesis contribute to the functional recovery. Taken together, it is clear that stem cell transplantation provides functional recovery via endogenous repair enhancement from multiple ways. This is important to maximize the effect of stem cell therapy after stroke, although it is still undetermined which repair mechanism is mostly contributed. PMID- 25746306 TI - Selecting an appropriate surgical treatment instead of carotid artery stenting alone according to the patient's risk factors contributes to reduced perioperative complications in patients with internal carotid stenosis: a single institutional retrospective analysis. AB - This retrospective study was aimed to compare the perioperative complications for internal carotid artery stenosis (ICS) in a Japanese single institute between the use of carotid artery stenting (CAS) alone or the use of an appropriate individualized treatment method allowing either carotid endarterectomy (CEA) or CAS based on patient risk factors. Based on the policy at our hospital, only CAS was performed on patients (n = 33) between January 2005 and November 2009. From December 2009 to December 2012, either CEA or CAS (tailored treatment) was selected for patients (n = 61) based on individual patient risk factors. CEA was considered the first-line treatment in all cases. In high-risk CEA cases, CAS was performed instead (n = 11), whereas in low-risk CEA cases, CEA was performed (n = 19). Further, in moderate-risk CEA cases based on own criteria, CAS was considered first, whereas for high-risk CAS cases, CEA was performed (n = 17). For low-risk CAS cases, CAS was performed (n = 9). Perioperative clinical complications (any stroke, myocardial infarction, or death within 30 days) were compared between both periods. Significantly reduced perioperative complications were observed during the tailored period (4/61 sites, 6.6%) as compared with the CAS period (8/33 sites, 24.2%) [Fisher's exact test p = 0.022; odds ratio, 4.56 (CAS/tailored); 95% confidence interval, 1.26-16.5]. Selecting an appropriate individualized treatment method according to patient risk factors, as opposed to adhering to a single treatment approach such as CAS, may contribute to improved overall outcomes in patients with ICS. PMID- 25746305 TI - Regenerative medicine for Parkinson's disease. AB - Regenerative medicine for Parkinson's disease (PD) is expected to develop dramatically with the advancement of biotechnology as represented by induced pluripotent stem cells. Existing therapeutic strategy for PD consists of medication using L-DOPA, surgery such as deep brain stimulation and rehabilitation. Current treatment cannot stop the progression of the disease, although there is definite therapeutic effect. True neurorestoration is strongly desired by regenerative medicine. This review article describes the historical development of regenerative medicine for PD, with a focus on fetal nigral cell transplantation and glial cell line-derived neurotrophic factor infusion. Subsequently, the current status of regenerative medicine for PD in terms of cell therapy and gene therapy are reviewed. In the end, the future direction to realize regenerative medicine for PD is discussed. PMID- 25746307 TI - Reappraisal of primary balloon angioplasty without stenting for patients with symptomatic middle cerebral artery stenosis. AB - There is a controversy regarding the safety and efficacy of intracranial stenting. We describe our experience with primary balloon angioplasty without stenting for symptomatic middle cerebral artery (MCA) stenosis. All patients who underwent balloon angioplasty without stenting for MCA stenosis between 1996 and 2010 were retrospectively reviewed. We evaluated technical success rates, degrees of stenosis, and stroke or death within 30 days. Among patients who were followed up for > 1 year we evaluated latest functional outcomes, stroke recurrence at 1 year, and restenosis. In total 45/47 patients (95.7%) were successfully treated. Average pre- and postprocedure stenosis rates were 79.9% and 39.5%, respectively. Three neurological complications occurred within 30 days: one thromboembolism during the procedure; one lacunar infarction; and one fatal intraparenchymal hemorrhage after the procedure. Stroke or death rate within 30 days was 6.4%. Thirty-three patients were available for follow-up analysis with a mean period of 51.5 months. The combined rate of stroke or death within 30 days and ipsilateral ischemic stroke of the followed-up patients within 1 year beyond 30 days was 9.4%. Restenosis was observed in 26.9% of patients and all remained asymptomatic. In our retrospective series, balloon angioplasty without stenting was a safe, effective modality for symptomatic MCA stenosis. For patients refractory to medical therapy, primary balloon angioplasty may offer a better supplemental treatment option. PMID- 25746308 TI - Does preoperative measurement of cerebral blood flow with acetazolamide challenge in addition to preoperative measurement of cerebral blood flow at the resting state increase the predictive accuracy of development of cerebral hyperperfusion after carotid endarterectomy? Results from 500 cases with brain perfusion single photon emission computed tomography study. AB - The purpose of the present study was to determine whether preoperative measurement of cerebral blood flow (CBF) with acetazolamide in addition to preoperative measurement of CBF at the resting state increases the predictive accuracy of development of cerebral hyperperfusion after carotid endarterectomy (CEA). CBF at the resting state and cerebrovascular reactivity (CVR) to acetazolamide were quantitatively assessed using N-isopropyl-p-[(123)I] iodoamphetamine (IMP)-autoradiography method with single-photon emission computed tomography (SPECT) before CEA in 500 patients with ipsilateral internal carotid artery stenosis (>= 70%). CBF measurement using (123)I-IMP SPECT was also performed immediately and 3 days after CEA. A region of interest (ROI) was automatically placed in the middle cerebral artery territory in the affected cerebral hemisphere using a three-dimensional stereotactic ROI template. Preoperative decreases in CBF at the resting state [95% confidence intervals (CIs), 0.855 to 0.967; P = 0.0023] and preoperative decreases in CVR to acetazolamide (95% CIs, 0.844 to 0.912; P < 0.0001) were significant independent predictors of post-CEA hyperperfusion. The area under the receiver operating characteristic curve for prediction of the development of post-CEA hyperperfusion was significantly greater for CVR to acetazolamide than for CBF at the resting state (difference between areas, 0.173; P < 0.0001). Sensitivity, specificity, and positive- and negative-predictive values for the prediction of the development of post-CEA hyperperfusion were significantly greater for CVR to acetazolamide than for CBF at the resting state (P < 0.05, respectively). The present study demonstrated that preoperative measurement of CBF with acetazolamide in addition to preoperative measurement of CBF at the resting state increases the predictive accuracy of the development of post-CEA hyperperfusion. PMID- 25746310 TI - Results and current trends of multimodality treatment for infectious intracranial aneurysms. AB - The authors retrospectively reviewed their cases of infectious intracranial aneurysms and discuss results and trends of current treatment modalities including medical, neurosurgical, and endovascular. Twenty patients (10 males and 10 females; mean age 46 years) with 23 infectious aneurysms were treated by various treatment modalities during a 15-year period. Fifteen cases (75.0%) were caused by infective endocarditis. Eleven aneurysms (47.8%) were ruptured. Two aneurysms (8.7%) presented a mass effect and 7 (30.4%) were unruptured and asymptomatic. The average aneurysm size was 6.5 +/- 4.8 mm (range 1-22 mm). The aneurysms were located in proximal cerebral circulation in 7 (30.4%) and distal in 16 (69.6%). Six (26.1%) aneurysms were treated surgically (5: trapping, 1: neck clipping), 10 (43.5%) endovascularly (7: trapping, 2: proximal occlusion, 1: saccular coiling), and the remaining 7 (30.4%) medically. Endovascular treatment was gradually increased with time. Medical and surgical treatments were continuously performed during the study period. Surgery was preferred for the patient with intraparenchymal hematoma or treated by bypass surgery. Three periprocedural minor complications occurred in endovascular treatment. There was one postoperative infarction with permanent deficit developed from surgical treatment. During the follow-up period (mean 28.8 months), none of the aneurysms presented a recurrence or rebleeding. Thirteen patients (65.0%) had favorable clinical outcomes (modified Rankin Scale: 0-2), although four (20.0%) had poor outcomes (modified Rankin Score: 5-6). A multimodal approach for the management of infectious aneurysms achieved satisfactory results. Endovascular intervention is a feasible and efficacious treatment option and surgical intervention is still an indispensable procedure. PMID- 25746309 TI - Evaluation and management of plaque protrusion or thrombus following carotid artery stenting. AB - Carotid artery stenting (CAS) has become a common treatment for carotid artery stenosis. However, complications, such as an ischemic event, can occur with CAS during intra- and post-operative periods. Among these ischemic complications, plaque protrusion into the stent and thrombus on the stent have occurred after CAS. We retrospectively evaluated the temporal profile and treatment options for these complications in 32 consecutive cases who underwent CAS at our hospital between April 2009 and December 2011. The cases were evaluated pre-operatively for risk factors, as well as the plaque morphology and characteristics using computed tomographic angiography (CTA), ultrasound (US), and magnetic resonance imaging (MRI). Post-operatively, lesions were examined by CTA and/or US within 1 week of CAS. As a result, among the 32 cases, 8 experienced plaque protrusions or thrombus, which were treated with medication (anti-platelet and/or anti coagulation reinforcement). In 7 of these 8 cases, the plaque protrusion or thrombus was stabilized with medication alone. However, the remaining case showed growth and migration of the plaque protrusion or thrombus when treated with medication alone, and therefore, required further endovascular treatment. We identified that a history of symptomatic cerebral infarction and plaques with ulceration were risk factors for plaque protrusion or thrombus formation after CAS, and pre dilatation can decrease the risk of these complications. Medication was effective in most cases of plaque protrusion or thrombus; however, further endovascular treatment was required when medication alone was unsuccessful. PMID- 25746311 TI - Efficacy and limitations of transarterial acrylic glue embolization for intracranial dural arteriovenous fistulas. AB - The efficacy and limitations of transarterial acrylic glue embolization for the treatment of intracranial dural arteriovenous fistulas (DAVFs) were investigated. Thirty-four DAVFs treated by transarterial embolization using n-butyl cyanoacrylate were retrospectively reviewed. The locations of DAVFs were the transverse-sigmoid sinus in 11, tentorium in 10, cranial vault in 9, and superior sagittal sinus, jugular bulb, foramen magnum, and middle cranial fossa in 1 each. Borden classification was type I in 7, type II in 3, and type III in 24. Eight patients had undergone prior transvenous coil embolization. Complete obliteration rate was 56% immediately after embolization, 71% at follow-up angiography, and 85% after additional treatments (1 transvenous embolization and 4 direct surgery). Complications occurred in three patients, consisting of asymptomatic vessel perforations during cannulation in two patients and leakage of contrast medium resulting in medullary infarction in one patient. Transarterial glue embolization is highly effective for Borden type III DAVF with direct cortical venous drainage, but has limitations for Borden type I and II DAVFs in which the affected sinus is part of the normal venous circulation. Onyx is a new liquid embolic material and is becoming the treatment of choice for DAVF. The benefits of glue embolization compared to Onyx embolization are high thrombogenicity, and relatively low risks of cranial nerve palsies and of excessive migration into the draining veins of high flow fistula. Transarterial glue embolization continues to be useful for selected patients, and complete cure can be expected in most patients with fewer complications if combined with transvenous embolization or direct surgery. PMID- 25746312 TI - Magnetic resonance imaging findings predict the recurrence of chronic subdural hematoma. AB - The exact predictive factors for postoperative recurrence of chronic subdural hematoma (CSDH) are still unknown. Based on the preoperative magnetic resonance imaging (MRI), low recurrence rate of T1-hyperintensity hematoma was previously reported. We investigated the other types of radiological findings which are related to the recurrence rate of CSDH in large number of patients analyzed by multivariate logistic regression model. Preoperative MRI and postoperative computed tomography (CT) were performed and the influence of the preoperative use of antiplatelet or anticoagulant drugs was also studied. The overall recurrence rate was 9.3% (47 of 505 hematomas). The MRI T1-iso/hypointensity group showed a significantly higher recurrence rate (18.2%, 29 of 159) compared to the other groups (5.2%, 18 of 346; p < 0.001). Multivariate logistic regression analysis showed T1 classification was the solo significant prognostic predictor among various factors such as bilateral hematoma, antiplatelet or anticoagulant drug usage, residual hematoma on postoperative CT, and MRI classification (p < 0.001): adjusted odds ratio for the recurrence in T1-iso/hypointensity group relative to the T1-hyperintensity group was 5.58 [95% confidence interval (CI), 2.09-14.86] (p = 0.001). Postoperative residual hematoma and antiplatelet or anticoagulant drug usage did not increase the recurrence risk. The preoperative MRI findings, especially T1WI findings, have predictive value for postoperative recurrence of CSDH and the T1-iso/hypointensity group can be assumed to be a high recurrence risk group. PMID- 25746313 TI - Posttraumatic cerebellar infarction after repeated sport-related minor head injuries in a young adult: a case report. AB - A healthy 23-year-old man suffered helmet-to-helmet collisions with an opponent during American football game twice within 3 days. He then experienced continuous vomiting and dizziness. Magnetic resonance imaging revealed acute infarction in the right cerebellar hemisphere, and magnetic resonance angiography revealed transient stenosis of the right superior cerebellar artery. Although minor head injury is not usually accompanied by complications, posttraumatic ischemic stroke has been reported on rare occasions. We report a case of cerebellar infarction after repeated sports-related minor head injuries in a young adult and discuss the etiology. PMID- 25746315 TI - Approaches to improve development methods for therapeutic cancer vaccines. AB - Therapeutic cancer vaccines are an immunotherapy that amplify or induce an active immune response against tumors. Notably, limitations in the methodology for existing anti-cancer drugs may subsist while applying them to cancer vaccine therapy. A retrospective analysis was performed using information obtained from ClinicalTrials.gov, PubMed, and published articles. Our research evaluated the optimal methodologies for therapeutic cancer vaccines based on (1) patient populations, (2) immune monitoring, (3) tumor response evaluation, and (4) supplementary therapies. Failure to optimize these methodologies at an early phase may impact development at later stages; thus, we have proposed some points to be considered during the early phase. Moreover, we compared our proposal with the guidance for industry issued by the US Food and Drug Administration in October 2011 entitled "Clinical Considerations for Therapeutic Cancer Vaccines". Consequently, while our research was aligned with the guidance, we hope it provides further insights in order to predict the risks and benefits and facilitate decisions for a new technology. We identified the following points for consideration: (1) include in the selection criteria the immunological stage with a prognostic value, which is as important as the tumor stage; (2) select immunological assays such as phenotype analysis of lymphocytes, based on their features and standardize assay methods; (3) utilize optimal response criteria for immunotherapy in therapeutic cancer vaccine trials; and (4) consider supplementary therapies, including immune checkpoint inhibitors, for future therapeutic cancer vaccines. PMID- 25746316 TI - Incidence of headache as a presenting complaint in over 1000 patients with sellar lesions and factors predicting postoperative improvement. AB - INTRODUCTION: Due to the high incidence of headaches and pituitary tumors, neurosurgeons often evaluate patients with benign-appearing sellar lesions and headaches without insight into whether the headache is attributable to the lesion. We sought to evaluate the incidence of headache as a presenting complaint in patients undergoing transsphenoidal surgery for various pathologies and to identify factors predicting postoperative improvement. METHODS: We conducted a 5 year retrospective review of our first 1015 transsphenoidal surgeries since establishing a dedicated pituitary center. RESULTS: Of 1015 patients, 329 (32%) presented with headache. Of these 329 patients, 241 (73)% had headache as their chief complaint. Headache was most common in patients with apoplexy (84%), followed by Rathke's cleft cysts (RCCs) (60%). Multivariate analyses revealed diagnosis (P = 0.001), younger age (P = 0.001), and female gender (P = 0.006) to be associated with headache. Of patients presenting with headaches, 11% reported improvement at 6-week follow-up and 53% improved at 6-month follow-up. Multivariate analyses revealed gross total resection (GTR; P = 0.04) and decreased duration of headache (P = 0.04) to be associated with improvement, while diagnosis, age, gender, lesion size, whether headache was a chief complaint, and location of headache were not associated with improvement (P > 0.05). CONCLUSION: In analyzing over 1000 consecutive patients undergoing transsphenoidal surgery, younger patients, females, and patients with RCCs and apoplexy were more likely to present with headache. Patients who underwent GTR and had shorter duration of headache were more likely to experience headache improvement. This information can be used to counsel patients preoperatively. PMID- 25746317 TI - The endoscopic endonasal approach for cerebrospinal fluid leak repair in the elderly. AB - INTRODUCTION: Cerebrospinal fluid (CSF) rhinorrhea can lead to CNS infections, carrying significant morbidity and mortality, especially in the elderly. Endoscopic endonasal surgery is a validated technique in the repair of anterior skull base CSF leaks. The aim of this study is to assess diagnostic management, surgical technique and clinical outcome in a consecutive series of elderly patients. METHODS: Patients older than 65 years treated for anterior skull base CSF leaks through endoscopic endonasal surgery between 2003 and 2014 were retrospectively reviewed. All patients underwent preoperative nasal endoscopy, laboratory and radiological assessment. In doubtful cases endoscopic exploration was performed after intrathecal fluorescein (IF) injection. Patients were discharged between 3 and 4 days after surgery, and the endoscopic follow-up ranged from 3 to 24 months. RESULTS: 20 patients (age range 65-92) presented with 10 spontaneous and 10 traumatic/iatrogenic CSF leaks. In 40% of patients formal rhinoscopy and radiological assessment did not localize the CSF leak and IF injection was performed. IF enabled the identification of the skull base defect in all cases, with no adverse effects. In 11 cases the dura was repaired with fascia lata graft. All patients had successful endoscopic repair of the CSF fistula with no complications nor recurrences during follow-up. CONCLUSION: Endoscopic endonasal surgery is a minimally invasive procedure for CSF leak treatment. In our experience, IF injection proved safe and efficient in detecting skull base defects not identified by preoperative imaging. Endoscopic endonasal surgery proved effective and reliable also in elderly patients, with short hospitalization times and no morbidity. PMID- 25746318 TI - Does CT wand guidance improve shunt placement in patients with hydrocephalus? AB - OBJECT: To evaluate the effectiveness of stereotactic navigation in enhancing the accuracy of ventricular shunt placement in patients with hydrocephalus. METHODS: A retrospective cohort study at a single institution by a single surgeon was performed. Consecutive patients who underwent implantation of a ventricular shunt for the management of hydrocephalus between July 2001 and December 2011 were included in the study, totaling 535 patients. Patients were classified as either having optimal or sub-optimal placement of the shunt into the ventricle. Multiple logistic regression analysis was used. RESULTS: Overall, 93.8% of patients were found to have optimal shunt placement. On multivariate analysis, navigation use was not significantly associated with improved accuracy of shunt placement (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.19-1.54; p = 0.25). Pseudotumor cerebri diagnosis was significantly associated with increased odds of sub-optimal shunt placement (OR = 6.41; 95% CI = 1.90-21.59; p=0.003). CONCLUSIONS: CT guided navigation did not significantly improve the accuracy of ventricular shunt placement in adults with hydrocephalus for an experienced surgeon. Further studies are required to assess the utility of CT guided navigation for less experienced surgeons and patients with small or dysmorphic ventricles. PMID- 25746319 TI - Recovery of neurological function after stereotactic radiosurgery for skull base tumors. PMID- 25746320 TI - Apparent diffusion coefficients distinguish amyotrophic lateral sclerosis from cervical spondylotic myelopathy. AB - OBJECTIVE: Fifty percent of patients with amyotrophic lateral sclerosis (ALS) have cervical spondylotic myelopathy (CSM) as a complication. Because patients with ALS do not develop bulbar signs and symptoms at onset, differentiating them from patients with CSM is sometimes difficult. We aimed to determine whether the apparent diffusion coefficients (ADCs) of intracranial corticospinal tracts can be used to distinguish between patients with ALS and those with CSM. METHODS: We evaluated 19 consecutive patients with ALS who did not have CSM by cervical MRI, 16 patients with CSM, and 11 healthy controls. We examined the mean ADCs in the precentral gyrus, the corona radiata, the posterior limbs of the internal capsule (PLIC), and the cerebral peduncle by 3T magnetic resonance imaging (MRI). The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM. RESULTS: The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM (p<0.05). Additionally, the mean ADCs in the precentral gyrus, the PLIC, and the cerebral peduncle in the patients with ALS, including the patients who were initially diagnosed as having clinically possible ALS on the basis of the revised El Escorial criteria and did not develop bulbar symptoms at onset, were also higher than those in patients with CSM (p<0.05). CONCLUSIONS: Elevated ADCs in the intracranial corticospinal tracts might be useful for distinguishing ALS from CSM in the early stage of the disease. PMID- 25746321 TI - Human history and deep time in nineteenth-century British sciences: An introduction. AB - The historicisation of humans was a major endeavour in nineteenth-century Britain, and one that led to wide-ranging debates involving a variety of disciplinary approaches, new and old. Within the context of science and medicine these discussions centred on the issues of human origins and evolution. Did the various races living throughout the world develop from a single location, or were their physical and social differences evidence for their separate genesis? Which disciplinary tradition offered the best method for tracing human development? Was it even possible to trace that development, or had too much time passed since the dawn of humans? Furthermore, who had the authority to speak about these matters? This special issue will examine these core questions and introduce some of the ways that researchers attempted to historicise humans within the context of nineteenth-century British sciences. PMID- 25746322 TI - Brief report: symmetricity of radiographic and MRI-detected structural joint damage in persons with knee pain--the Joints on Glucosamine (JOG) Study. AB - OBJECTIVE: Most MRI-based osteoarthritis (OA) studies have focused on a single knee per person and thus, data on bilaterality is sparse. Study aim was to describe symmetricity of MRI-detected OA features in a cohort of subjects with knee pain. DESIGN: Participants were 169 subjects with chronic knee pain who had 3 T MRI of both knees using the same protocol as in the Osteoarthritis Initiative. Knees were read for cartilage damage, bone marrow lesions (BMLs), and meniscal damage according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Chi(2) tests were used to compare the proportion of knees with unilateral tissue pathology to the proportion what would be expected if both knees were independent. We further used percent agreement and linear weighted kappa statistics to describe agreement of cartilage damage and BMLs in the same articular plates. RESULTS: 51.2% of participants were men, mean age was 52.1 (+/ 6.2), mean BMI was 29.0 kg/m(2) (+/-4.1). All plates showed a significant higher degree of symmetricity for cartilage damage as evidenced by weighted kappas ranging from 0.32 to 0.59. For BMLs the degree of symmetricity was higher for the patella, trochlea, medial tibia, lateral femur, and medial femur; for meniscal damage the degree of unilaterality was lower for all medial meniscal subregions but not all lateral. Kappas ranged between 0.52 and 0.68 for cartilage and 0.30 and 0.55 for BMLs for the four subregions with highest agreement. CONCLUSION: A higher degree of symmetricity of tissue damage than expected by chance was observed in this cohort of subjects with knee pain. PMID- 25746323 TI - Histone acetyltransferase p300 promotes MRTF-A-mediates transactivation of VE cadherin gene in human umbilical vein endothelial cells. AB - Vascular endothelial cadherin (VE-cadherin) is the major determinant of endothelial cell contact integrity and is required in vascular development and angiogenesis. Serum response factor (SRF) plays essential roles in postnatal retinal angiogenesis and adult neovascularization. It is unclear whether transcription of VE-cadherin is mediated by a SRF co-activator, myocardin-related transcription factor-A (MRTF-A). Here we have demonstrated that MRTF-A is a key regulatory factor to activate the transcription of VE-cadherin in human umbilical vein endothelial cells (HUVECs). siRNA-mediated knockdown of MRTF-A decreased the level of VE-cadherin in HUVECs. Vascular endothelial growth factor (VEGF) induced MRTF-A binding to the SRF-binding site (CArG box) within VE-cadherin promoter. Histone acetyltransferase p300 and MRTF-A could synergistically augment the expression of VE-cadherin by enhancing acetylation of histone3K9 (H3K9Ac), histone3K14 (H3K14Ac) and histone4 at the SRF-binding site within VE-cadherin promoter. Taken together, these data identified a detailed regulatory mechanism of VE-cadherin gene expression. PMID- 25746324 TI - DLEC1 is not silenced solely by promoter methylation in head and neck squamous cell carcinoma. AB - Different types of genetic and epigenetic changes are associated with HNSCC. The molecular mechanisms of HNSCC carcinogenesis are still undergoing intensive investigation. The Deleted in lung and esophageal cancer 1 (DLEC1) gene is frequently silenced by methylation in various kinds of cancer. However, there is no data in the literature investigating the DLEC1 gene in the HNSCC. Tumor tissues from 97 patients were analyzed by real-time quantitative RT-PCR and DLEC1 expression levels were correlated with the methylation of the DLEC1 gene promoter. A statistically significant down-regulation was observed in tumors compared to non-cancerous tissue samples (p = 0.00). However, this down regulation was not directly associated with hypermethylation of the promoter (p >= 0.05). Our results indicate that the DLEC1 gene may play an important role in the development of HNSCC. However, its down-regulation is not associated with the clinicopathological parameters and is not solely under the control of promoter methylation. PMID- 25746325 TI - Genetic association and gene-smoking interaction study of carotid intima-media thickness at five GWAS-indicated genes: the Bogalusa Heart Study. AB - OBJECTIVES: To examine the associations of five GWAS-identified genes with carotid intima-media thickness (IMT) in a biracial sample from the Bogalusa Heart Study, and evaluate their participation in gene-smoking interactions. METHODS: Far wall IMTs of common carotid arteries were measured using high-resolution B mode ultrasound. Both the gene-smoking interactions and single-marker associations were evaluated by linear models of carotid IMT levels, while the gene-based analyses were assessed through the truncated product method. A Bonferroni multiple testing correction was applied. RESULTS: Marker rs7840785 (PINX1) was significantly associated with right carotid IMT (p=0.0003) using all participants; mean levels for the CC, TC, and TT genotypes were 0.74 (0.73 to 0.75), 0.76 (0.75 to 0.78), and 0.78 (0.75, 0.81), respectively. Similar trends were observed in blacks (p=0.0031) and whites (p=0.0118). Marker rs7844465 (ZHX2) was significantly associated with left carotid IMT in whites (p=0.0005); mean IMT levels for the GG, TG, and TT genotypes were 0.73 (0.71 to 0.74), 0.75 (0.74 to 0.77) and 0.78 (0.75 to 0.81), respectively. Marker rs6841473 (EDNRA) modified the association between smoking and left carotid IMT in blacks (p=2.79*10(-5)). In addition, gene-based analysis demonstrated that EDNRA and ZHX2 were associated with left carotid IMT in the white and overall participants, respectively, while PINX1 was associated with right carotid IMT in both blacks and whites. CONCLUSION: We identified two novel markers that were associated with IMT in both blacks and whites. One gene-smoking interaction was identified in blacks only. Three genes showed gene-based associations with IMT levels. However, genetic markers with small effects may have been missed due to the limited number of black participants. PMID- 25746326 TI - The association of folate pathway and DNA repair polymorphisms with susceptibility to childhood acute lymphoblastic leukemia. AB - Genetic factors may play an important role in susceptibility to childhood acute lymphoblastic leukemia (ALL). The aim of our study was to evaluate the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. In total, 121 children with ALL and 184 unrelated healthy controls of Slovenian origin were genotyped for 14 polymorphisms in seven genes of folate pathway, base excision repair and homologous recombination repair (TYMS, MTHFR, OGG1, XRCC1, NBN, RAD51, and XRCC3). In addition, the exon 6 of NBN was screened for the presence of mutations using denaturing high performance liquid chromatography. Twelve polymorphisms were in Hardy-Weinberg equilibrium in controls and their genotype frequencies were in agreement with those reported in other Caucasian populations. Among the investigated polymorphisms and mutations, NBN Glu185Gln significantly decreased susceptibility to B-cell ALL (p=0.037), while TYMS 3R allele decreased susceptibility to T-cell ALL (p=0.011). Moreover, significantly decreased susceptibility to ALL was observed for MTHFR TA (p=0.030) and RAD51 GTT haplotypes (p=0.016). Susceptibility to ALL increased with the increasing number of risk alleles (ptrend=0.007). We also observed significant influence of hOGG-RAD51 and NBN-RAD51 interactions on susceptibility to ALL. Our results suggest that combination of several polymorphisms in DNA repair and folate pathways may significantly affect susceptibility to childhood ALL. PMID- 25746327 TI - The role of hematologists in a changing United States health care system. AB - Major and ongoing changes in health care financing and delivery in the United States have altered opportunities and incentives for new physicians to specialize in nonmalignant hematology. At the same time, effective clinical tools and strategies continue to rapidly emerge. Consequently, there is an imperative to foster workforce innovation to ensure sustainable professional roles for hematologists, reliable patient access to optimal hematology expertise, and optimal patient outcomes. The American Society of Hematology is building a collection of case studies to guide the creation of institutionally supported systems-based clinical hematologist positions that predominantly focus on nonmalignant hematology. These roles offer a mix of guidance regarding patient management and the appropriate use and stewardship of clinical resources, as well as development of new testing procedures and protocols. PMID- 25746328 TI - Enhanced cellular uptake and intracellular drug controlled release of VESylated gemcitabine prodrug nanocapsules. AB - Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N4-amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N4-amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of -33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5+cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC 3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity. PMID- 25746329 TI - Global longitudinal strain is not impaired in type 1 diabetes patients without albuminuria: the Thousand & 1 study. AB - OBJECTIVES: The purpose of this study was to investigate if systolic myocardial function is reduced in all patients with type 1 diabetes (T1DM) or only in patients with albuminuria. BACKGROUND: Heart failure is a common cause of mortality in T1DM, and a specific diabetic cardiomyopathy has been suggested. It is not known whether myocardial dysfunction is a feature of T1DM per se or primarily associated with diabetes with albuminuria. METHODS: This cross sectional study compared 1,065 T1DM patients without known heart disease from the outpatient clinic at the Steno Diabetes Center with 198 healthy control subjects. Conventional echocardiography and global longitudinal strain (GLS) by 2 dimensional speckle-tracking echocardiography was performed and analyzed in relation to normoalbuminuria (n = 739), microalbuminuria (n = 223), and macroalbuminuria (n = 103). Data were analyzed in univariable and multivariable linear regression models adjusted for confounding factors including conventional risk factors, medication, and systolic and diastolic dysfunction. Investigators were blinded to degree of albuminuria. RESULTS: Mean age was 49.5 years, 52% men, mean glycated hemoglobin 8.2% (66 mmol/mol), mean body mass index 25.5 kg/m(2), and mean diabetes duration 26.1 years. In unadjusted analyses, GLS differed significantly between T1DM patients and control subjects (p = 0.02). When stratified by degrees of albuminuria, the difference in GLS compared with control subjects was -18.8 +/- 2.5% versus -18.5 +/- 2.5% for normoalbuminuria (p = 0.28), versus -17.9 +/- 2.7% for microalbuminuria (p = 0.001), and versus -17.4 +/- 2.9% for macroalbuminuria (p < 0.001). Multivariable analyses, including clinical characteristics, diastolic and systolic dysfunction, and use of medication, did not change this relationship. CONCLUSIONS: Systolic function assessed by GLS was reduced in T1DM compared with control subjects. This difference, however, was driven solely by decreased GLS in T1DM patients with albuminuria. T1DM patients with normoalbuminuria have systolic myocardial function similar to healthy control subjects. These findings do not support the presence of specific diabetic cardiomyopathy without albuminuria. PMID- 25746330 TI - Infralimbic cortex activation and motivated arousal induce histamine release. AB - Appetitive behaviours occur in a state of behavioural and physiological activation that allows the optimal performance of these goal-directed behaviours. Here, we tested the hypothesis that histamine neurons under the command of the infralimbic cortex are important to provide behavioural activation. Extracellular histamine and serotonin were measured by microdialysis of the medial prefrontal cortex in behaving rats in parallel with a picrotoxin microinjection into the infralimbic cortex. The injection aroused the rats behaviourally, increased histamine release and decreased serotonin levels. Inhibition of the infralimbic cortex with muscimol produced the opposite effects on neurotransmitter release. The behavioural activation induced by motivating hungry rats with caged food was paralleled by an immediate histamine release, whereas awakening induced by tapping their microdialysis bowl increased serotonin, but not histamine levels. In conclusion, picrotoxin injection into the infralimbic cortex produces behavioural activation together with histamine release; in a similar manner, induction of an appetitive state produced histamine release, likely related to increased behavioural activation characteristic of an appetitive behaviour. PMID- 25746332 TI - A dark-to-bright reporter cell for classical swine fever virus infection. AB - Current methods to quantitate classical swine fever virus (CSFV) infectivity in cell culture are time-consuming and labor-intensive. This study described the generation of a dark-to-bright fluorescent reporter cells to facilitate in vitro studies of CSFV infection and replication. This assay was based on a novel reporter cell stably expressing the enhanced green fluorescent protein (EGFP) fused in-frame to a quenching peptide via a special recognition sequence of the CSFV NS3 protease. Chromophore maturation of EGFP can be prevented by quenching peptide until the quenching peptide was specifically cleaved by NS3 protease during CSFV infection, making it a dark-to-bright reporter of CSFV infection. The result demonstrated that the CSFV-infected cells were clearly distinguishable from mock-infected cells and cells infected with other viruses. There was a strong correlation between the fluorescence intensity and viral RNA replication in CSFV-infected cells. The cell enabled rapid and sensitive detection of CSFV infection and viral replication in cell culture. The best time to examine the fluorescence in CSFV-infected cells was at 48h post-inoculation. These data suggested that the cells can be used as a reporter cell in CSFV infection assays. This reporter cell provides a sensitive method for the detection and isolation of CSFV and it will be useful for the screening of antiviral drugs or neutralizing antibody assays. PMID- 25746331 TI - The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: a model of smallpox disease. AB - Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox. PMID- 25746333 TI - LiCl inhibits PRRSV infection by enhancing Wnt/beta-catenin pathway and suppressing inflammatory responses. AB - Lithium chloride (LiCl) has been used as a mood stabilizer in the manic depressive disorders treatment. Recent studies show that LiCl is also a potent inhibitor for some DNA and RNA viruses. Porcine reproductive and respiratory syndrome virus (PRRSV) is an important viral pathogen in modern pig industry. In this study, we assessed the inhibitory effect of LiCl on PRRSV infection using plaque-formation assay, Q-PCR and Western blot analysis. Our results showed that LiCl could inhibit PRRSV infection in MARC-145 and PAM-CD163 cells. Previous reports have shown that LiCl could induce the Wnt pathway in the absence of Wnt ligands. In our studies, we demonstrated that LiCl activates the Wnt pathway in PRRSV infected cells. Additionally, the knockdown of beta-catenin or the Wnt/beta catenin pathway inhibitor PNU74654 was able to reverse the antiviral effect of LiCl, which suggested that the inhibitory effect of LiCl against PRRSV replication might be associated with the activation of the Wnt/beta-catenin pathway. We also found that lower viral replication after LiCl treatment was associated with the reduced mRNA levels of pro-inflammatory IL-8, IL-6, IL-1 beta, tumor necrosis factor alpha and decreased NF-kappaB nuclear translocation. Collectively, our data demonstrated that LiCl inhibited PRRSV infection by enhancing Wnt/beta-catenin pathway and suppressing pro-inflammatory responses. PMID- 25746334 TI - [Perianesthetic refractory anaphylactic shock with cefuroxime in a patient with history of penicillin allergy on multiple antihypertensive medications]. AB - We report a case of perianesthetic refractory anaphylactic shock with cefuroxime in a patient with history of penicillin allergy on regular therapy with atenolol, losartan, prazosin and nicardipine. Severe anaphylactic shock was only transiently responsive to 10mL of (1:10000) epinephrine and needed norepinephrine and dopamine infusion. Supportive therapy with vasopressors and inotropes along with mechanical ventilation for the next 24hours resulted in complete recovery. She was successfully operated upon 2 weeks later with the same anesthetic drugs but intravenous ciprofloxacin as the alternative antibiotic for perioperative prophylaxis. PMID- 25746335 TI - [Comparison between continuous thoracic epidural and paravertebral blocks for postoperative analgesia in patients undergoing thoracotomy: meta-analysis of clinical trials]. PMID- 25746336 TI - [Maintenance of balance between airway pressure and intracranial pressure in a patient with tracheal stenosis undergoing craniotomy: a case report]. AB - BACKGROUND AND OBJECTIVES: Tracheal stenosis is a rare but a life-threatening condition and anesthesia of a patient with tracheal stenosis is challenging for anesthesiologists. Maintaining stable hemodynamics and ventilation parameters are important issues in neuroanesthesia. Any increase in airway peak pressure and ETCO2 will result in increase in intracranial pressure which must be avoided during craniotomies. Tracheal stenosis could be a reason for increased airway pressure. CASE REPORT: We described a patient undergoing craniotomy with tracheal stenosis. CONCLUSION: Detailed preparation for intubation, to stabilize airway dynamics and to make the right decision for the surgery were important points. To maintain a good balance between cerebral dynamics and airway dynamics were the pearls of this case. PMID- 25746337 TI - [Correlation of bispectral index (BIS) monitoring and end-tidal sevoflurane concentration in a patient with lobar holoprosencephaly]. AB - OBJECTIVE: The bispectral index (BIS) is a parameter derived by electroencephalography (EEG) which provides a direct measurement of the effects of sedatives and anesthetics on the brain and offers guidance on the adequacy of anesthesia. The literature lacks studies on BIS monitoring in pediatric patients with congenital brain disease undergoing general anesthesia. CLINICAL FEATURES: A 13-year-old child weighing 32kg, suffering from lobar holoprosencephaly, underwent surgery in which the bispectral index (BIS) monitoring the depth of anesthesia showed an abnormal response. Detailed analysis of the trends of BIS values in the different observation times demonstrated sudden falls and repetitive values of BIS likely related to repetitive epileptiform electrical activity caused by sevoflurane. CONCLUSION: The BIS is a very useful monitoring tool for assessing the degree of depth of anesthesia and to analyze the electroencephalographic variations of anesthetics. Particular attention should be given to patients with congenital disorders of the central nervous system in which the BIS may give abnormal responses that do not reflect an accurate assessment of the depth of anesthesia. PMID- 25746338 TI - [Total knee replacement induces peripheral blood lymphocytes apoptosis and it is not prevented by regional anesthesia - a randomized study]. AB - BACKGROUND: Among the many changes caused by a surgical insult one of the least studied is postoperative immunosuppression. This phenomenon is an important cause of infectious complications of surgery such as surgical site infection or hospital acquired pneumonia. One of the mechanisms leading to postoperative immunosuppression is the apoptosis of immunological cells. Anesthesia during surgery is intended to minimize harmful changes and maintain perioperative homeostasis. The aim of the study was evaluation the effect of the anesthetic technique used for total knee replacement on postoperative peripheral blood lymphocyte apoptosis. METHODS: 34 patients undergoing primary total knee replacement were randomly assigned to two regional anesthetic protocols: spinal anesthesia and combined spinal-epidural anesthesia. 11 patients undergoing total knee replacement under general anesthesia served as control group. Before surgery, immediately after surgery, during first postoperative day and seven days after the surgery venous blood samples were taken and the immunological status of the patient was assessed with the use of flow cysts 87 m, along with lymphocyte apoptosis using fluorescent microscopy. RESULTS: Peripheral blood lymphocyte apoptosis was seen immediately in the postoperative period and was accompanied by a decrease of the number of T cells and B cells. There were no significant differences in the number of apoptotic lymphocytes according to the anesthetic protocol. Changes in the number of T CD3/8 cells and the number of apoptotic lymphocytes were seen on the seventh day after surgery. CONCLUSION: Peripheral blood lymphocyte apoptosis is an early event in the postoperative period lasts up to seven days and is not affected by the choice of the anesthetic technique. PMID- 25746339 TI - [Anesthetic management of a patient with multiple sclerosis - case report]. AB - BACKGROUND AND OBJECTIVES: Multiple sclerosis is a demyelinating disease of the brain and spinal cord, characterized by muscle weakness, cognitive dysfunction, memory loss, and personality disorders. Factors that promote disease exacerbation are stress, physical trauma, infection, surgery, hyperthermia. The objective is to describe the anesthetic management of a case referred to urological surgery. CASE REPORT: A female patient, 44 years of age, with multiple sclerosis, diagnosed with nephrolithiasis, referred for endoscopic ureterolythotripsy. Balanced general anesthesia was chosen, with midazolam, propofol and remifentanil target-controlled infusion; sevoflurane via laryngeal mask airway; and spontaneous ventilation. Because the patient had respiratory difficulty presenting with chest wall rigidity, it was decided to discontinue the infusion of remifentanil. There was no other complication or exacerbation of disease postoperatively. CONCLUSION: The use of neuromuscular blockers (depolarizing and non-depolarizing) is a problem in these patients. As there was no need for muscle relaxation in this case, muscle relaxants were omitted. We conclude that the combination of propofol and sevoflurane was satisfactory, not resulting in hemodynamic instability or disease exacerbation. PMID- 25746340 TI - [A question about ropivacaine for unilateral spinal anesthesia: hypobaric solution]. PMID- 25746341 TI - [Cardiac complications in a metamizole-induced type I Kounis syndrome]. AB - Kounis syndrome is defined as the coincidental occurrence of allergic reaction and acute coronary syndrome secondary to vasospasm. Anti-inflammatory drugs are included as one of the multiple causes. Current data available about this syndrome come from case reports. We present the case of a patient who suffered Kounis syndrome with cardiogenic shock and asystole after intravenous infusion of Metamizole, and in which no lesions were observed in coronariography. PMID- 25746342 TI - Subjective evaluation of running footwear depends on country and assessment method: a bi-national study. AB - This study examined (1) the perception of running shoes between China (Beijing) and Singapore and (2) whether running shoe preference depended on assessment methods. One hundred (n = 50 each country) Chinese males subjectively evaluated four shoe models during running by using two assessment procedures. Procedure 1 used a visual analogue scale (VAS) to assess five perception variables. Procedure 2 was a 'head-to-head' comparison of two shoes simultaneously (e.g. left foot: A and right foot: B) to decide which model was preferred. VAS scores were consistently higher in Beijing participants (p < .001), indicating a higher degree of liking. Singapore participants used the lower end but a wider range of the 15 cm scale for shoe discrimination. Moderate agreement was seen between the VAS and 'head-to-head' procedures, with only 14 out of 100 participants matched all 6 pairwise comparisons (median = 4 matches). Footwear companies and researchers should be aware that subjective shoe preference may vary with assessment methods. Practitioner Summary: Footwear preference depends on country and assessment methods. Running shoe perception differed between Beijing and Singapore Chinese, suggesting that footwear recommendation should be country specific. Individuals' shoe preference measured by visual analogue scale when wearing complete pairs may not reflect that when directly comparing different models in left and right feet. PMID- 25746343 TI - Cost structure and clinical outcome of a stem cell transplantation program in a developing country: the experience in northeast Mexico. AB - BACKGROUND AND OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) in developing countries is cost-limited. Our primary goal was to determine the cost structure for the HSCT program model developed over the last decade at our public university hospital and to assess its clinical outcomes. MATERIALS AND METHODS: Adults and children receiving an allogeneic hematopoietic stem cell transplant from January 2010 to February 2011 at our hematology regional reference center were included. Laboratory tests, medical procedures, chemotherapy drugs, other drugs, and hospitalization costs were scrutinized to calculate the total cost for each patient and the median cost for the procedure. Data regarding clinical evolution were incorporated into the analysis. Physician fees are not charged at the institution and therefore were not included. RESULTS: Fifty patients were evaluated over a 1-year period. The total estimated cost for an allogeneic HSCT was $12,504. The two most expensive diseases to allograft were non-Hodgkin lymphoma ($11,760 +/- $2,236) for the malignant group and thalassemia ($12,915 +/ $5,170) for the nonmalignant group. Acute lymphoblastic leukemia ($11,053 +/- 2,817) and acute myeloblastic leukemia ($10,251 +/- $1,538) were the most frequent indications for HSCT, with 11 cases each. Median out-of-pocket expenses were $1,605, and 1-year follow-up costs amounted to $1,640, adding up to a total cost of $15,749 for the first year. The most expensive components were drugs and laboratory tests. CONCLUSION: Applying the cost structure described, HSCT is an affordable option for hematological patients living in a developing country. PMID- 25746344 TI - Poor awareness of risk factors for cancer in Irish adults: results of a large survey and review of the literature. AB - BACKGROUND: Knowledge of cancer risk factors is unknown in Ireland. An understanding of risk factors could help inform cancer prevention programs. AIMS AND METHODS: A 48-question online survey was designed to gather data to assess levels of public knowledge about cancer risk factors. RESULTS: There were 748 participants (648 women, 100 men). Mean age was 37 years (range: 18-74 years). For the public, 81% were concerned about developing cancer; however, 20% believed that cancer is unavoidable if a family history exists, 27% believed that >50% of cancers are inherited, and 54% believed that 10%-20% of cancers are inherited; 20% were unaware that risk increases with age. The top five risk factors listed by respondents were smoking (87%), diet (76%), genetics (47%), alcohol (42%), and obesity (33%). Only 32% of the public were aware that obesity is a risk factor, and 33% did not think the location of fat was important. Moreover, 29% and 48% believed that risk could be increased by wearing a tight bra and by a blow to the breast, respectively. In addition, 85% and 86% believed that stress and that mobile phones, respectively, "strongly" increase risk; 12% believed that luck is important in avoiding cancer; 35% thought that "detox" diets could reduce risk; and 61% believed that organic food reduces risk. The majority were aware that physical activity of 30 minutes per day can reduce risk. CONCLUSION: A sizable portion of the population is misinformed about cancer risk. Most participants were aware of classic risk factors (e.g., smoking, diet); however, many overestimated risk attributable to genetics, environment, and stress and underestimated age, obesity, and sunlight. One in seven participants believed that lifetime risk of cancer is not modifiable. PMID- 25746345 TI - The value of personalizing medicine: medical oncologists' views on gene expression profiling in breast cancer treatment. AB - OBJECTIVES: Guidelines recommend gene-expression profiling (GEP) tests to identify early-stage breast cancer patients who may benefit from chemotherapy. However, variation exists in oncologists' use of GEP. We explored medical oncologists' views of GEP tests and factors impacting its use in clinical practice. METHODS: We used a qualitative design, comprising telephone interviews with medical oncologists (n = 14; 10 academic, 4 in the community) recruited through oncology clinics, professional advertisements, and referrals. Interviews were analyzed for anticipated and emergent themes using the constant comparative method including searches for disconfirming evidence. RESULTS: Some oncologists considered GEP to be a tool that enhanced confidence in their established approach to risk assessments, whereas others described it as "critical" to resolving their uncertainty about whether to recommend chemotherapy. Some community oncologists also valued the test in interpreting what they considered variable practice and accuracy across pathology reports and testing facilities. However, concerns were also raised about GEP's cost, overuse, inappropriate use, and over-reliance on the results within the medical community. In addition, although many oncologists said it was simple to explain the test to patients, paradoxically, they remained uncertain about patients' understanding of the test results and their treatment implications. CONCLUSION: Oncologists valued the test as a treatment-decision support tool despite their concerns about its cost, over reliance, overuse, and inappropriate use by other oncologists, as well as patients' limited understanding of GEP. The results identify a need for decision aids to support patients' understanding and clinical practice guidelines to facilitate standardized use of the test. PMID- 25746346 TI - Acute phase cytokines, TAC1, and toll-like receptor4 mRNA expression and health associated with group size in veal calves. AB - Chronic stressors are a major health and well-being issue in animals. Immune status of animals under chronic stress is compromised, thus reducing disease resistance and compromising well-being of the animal. The objective of this study was to determine the influence of group size of veal calves on immune status and leukocyte mRNA expression of acute phase cytokines, toll-like receptor 4 (TLR4) and tachykinin 1 (TAC1) over a five-month finishing period. Holstein bull calves (n=168), 44+/-3 days of age were assigned to one of three treatments; 2, 4, or 8 calves/pen (pen space allowance of 1.82m(2)/calf). Jugular blood samples were collected at the day of grouping and then monthly for 4 months. The differential leukocyte counts were determined and mRNA was extracted from the leukocytes. Reverse transcription-qPCR was used to measure the gene expression of interleukin 1 (IL-1beta), IL-1 receptor antagonist (IL-1Ra), tumor necrosis factor (TNF alpha), TLR4, and TAC1 in leukocytes. Health was evaluated before grouping and monthly for 4 months. On the 1st month after grouping, veal calves that were housed in groups of 8 have greater expression of IL-1beta mRNA than calves housed in groups of 4 or 2 (treatment*month, P=0.04). Also at 1 month, groups of 8 had greater TAC1 expression (P<0.05) than calves housed in groups of 4 or 2. However, the expression of IL-1Ra, TNF-alpha, and TLR4 were not influenced by group size. In the first month of the trial, calves in groups of 8 coughed more (P<0.05) than calves in groups of 2 and coughed more than calves in groups of 4 and 2 during the 2nd month (treatment*month, P=0.03). Calves housed in groups of 8 tended to have greater neutrophil percentage (P=0.09), neutrophil to lymphocyte ratio (P=0.06), and had lower lymphocyte percentage (P=0.06) than those housed in groups of 4 or 2. In conclusion, the number of veal calves in a group, given the same space during the finishing period did not alter IL-1Ra, TNF-alpha, and TLR4 mRNA expression. However, housing of calves in groups of 8 was associated with greater expression of IL-1beta and TAC1 mRNA in peripheral blood leukocytes, and coughing during the first 2 months after grouping. Therefore, housing of veal calves in larger groups may lead to greater susceptibility to respiratory disease and stress. PMID- 25746347 TI - Polymorphisms of nucleotide-binding oligomerization domain 2 (NOD2) gene in miniature dachshunds with inflammatory colorectal polyps. AB - Inflammatory colorectal polyps (ICRPs) frequently occur in miniature dachshunds (MDs) in Japan, typically form multiple polyps with severe neutrophil infiltration. ICRPs are speculated as a novel, breed-specific canine inflammatory bowel disease. Pattern recognition receptors (PRRs) play an important role in the differentiation of pathogens from commensal bacteria and food antigens, and polymorphisms of various PRRs have been shown to be associated with human and canine IBD. We recently reported that the reactivity of nucleotide-binding oligomerization domain 2 (NOD2), toll-like receptor (TLR) 1/2, TLR2, and TLR2/6 are greater in ICRP-affected MDs than that in controls. Therefore, this study was aimed to investigate single nucleotide polymorphisms (SNPs) of PRRs associated with ICRPs in MDs. Mutational analysis of canine NOD2, TLR1, TLR2, and TLR6 genes was performed with six ICRP-affected MDs, five control MDs, and five healthy beagles. The mutational analysis identified 13 non-synonymous SNPs in NOD2, TLR1, TLR2, and TLR6 genes, of which six SNPs in NOD2 exon 3 were further analyzed in an association study using 63 ICRP-affected MDs, 82 control MDs, and 237 control dogs of various breeds. Four of the SNPs (A1532G, T1573C, C1688G, and G1880A of the NOD2 gene) were in Hardy-Weinberg equilibrium and in complete linkage disequilibrium in MDs, and their minor allele frequencies were significantly lower in ICRP-affected MDs than in control MDs (0.016 vs. 0.140, P=0.0002). The calculated inheritance model was an additive model (odds ratio=0.10, 95% confidence interval=0.02-0.45, P=0.0001), which indicates that the haplotype with minor alleles in these SNPs (A, T, C, and G in A1532G, T1573C, C1688G, and G1880A) possess a protective effect regarding the development of ICRPs. However, these SNPs were not specific for MDs, although the minor allele frequencies of these SNPs in control MDs were significantly lower than in other breed dogs. These results suggest that the identified four SNPs (A1532G, T1573C, C1688G, and G1880A in the NOD2 gene) may play a role in the pathogenesis of ICRPs in MDs. Because the majority of MDs and other breed dogs do not have the protective alleles, their absence may not be a specific cause of ICRPs in MDs but rather contribute to the development of inflammation. PMID- 25746348 TI - What is the normal tissues morbidity following Helical Intensity Modulated Radiation Treatment for cervical cancer? AB - BACKGROUND AND PURPOSE: To report on normal tissues morbidity following IMRT for cervix cancer. MATERIAL AND METHODS: The first 61 patients of a prospective series were included. 50 Gy to the PTV 1(pelvis) and 60 Gy to the PTV 2 (centro pelvic disease and GTV nodes) were delivered concomitantly in 28 fractions, followed by a brachytherapy boost. For the small bowel, 50 Gy was the maximal dose, while V45 and V40 had to be <50 cc and 200 cc, respectively. For the bladder, rectum and sigmoid structures, 60 Gy was the maximal dose, and V45 and V40 had to be <20% and <50%. Acute and late toxicity data were prospectively collected. RESULTS: The median follow-up period was 40 months (range: 23-60). 30% and 90% of acute and moderate late side effects were reported respectively. Considering the AUC data of the organs at risk (OAR) DVH, late morbidity and doses were significantly linked (p?0.03), predominantly between 10 Gy and 40 Gy, considering the small bowel and sigmoid colon. The high dose regions exhibited no significant impact. CONCLUSION: The moderate dose volumes represent the predominant cause of morbidity after IMRT. Prospective trials are thus required to investigate new ways of dose distribution within the OAR. PMID- 25746349 TI - Adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery in patients with rectal cancer: meta-analysis of all patients in 4 landmark trials. PMID- 25746351 TI - Parenchymal lung changes on computed tomography after stereotactic radiotherapy using high dose rate flattening filter free beams. AB - Flattening filter free (FFF) beams allow fast delivery of stereotactic radiotherapy. To evaluate biological effects of FFF in lung, we compared parenchymal changes after FFF and non-FFF stereotactic volumetric modulated arc therapy. Standardized multi-observer consensus evaluation of follow-up CT scans revealed no major differences between FFF and non-FFF. PMID- 25746350 TI - CT-based radiomic signature predicts distant metastasis in lung adenocarcinoma. AB - BACKGROUND AND PURPOSE: Radiomics provides opportunities to quantify the tumor phenotype non-invasively by applying a large number of quantitative imaging features. This study evaluates computed-tomography (CT) radiomic features for their capability to predict distant metastasis (DM) for lung adenocarcinoma patients. MATERIAL AND METHODS: We included two datasets: 98 patients for discovery and 84 for validation. The phenotype of the primary tumor was quantified on pre-treatment CT-scans using 635 radiomic features. Univariate and multivariate analysis was performed to evaluate radiomics performance using the concordance index (CI). RESULTS: Thirty-five radiomic features were found to be prognostic (CI>0.60, FDR<5%) for DM and twelve for survival. It is noteworthy that tumor volume was only moderately prognostic for DM (CI=0.55, p value=2.77*10(-5)) in the discovery cohort. A radiomic-signature had strong power for predicting DM in the independent validation dataset (CI=0.61, p value=1.79*10(-17)). Adding this radiomic-signature to a clinical model resulted in a significant improvement of predicting DM in the validation dataset (p value=1.56*10(-11)). CONCLUSIONS: Although only basic metrics are routinely quantified, this study shows that radiomic features capturing detailed information of the tumor phenotype can be used as a prognostic biomarker for clinically-relevant factors such as DM. Moreover, the radiomic-signature provided additional information to clinical data. PMID- 25746352 TI - The effects of radiation therapy on height and spine MRI characteristics in children with neuroblastoma. AB - PURPOSE: To investigate the effect of radiotherapy (RT) on height and spine using magnetic resonance imaging (MRI) analysis in children with neuroblastoma and to identify parameters related to patient height. METHODS AND MATERIALS: We performed a retrospective cohort study of neuroblastoma patients treated between January 1997 and December 2007. Twenty-seven children were enrolled. Whole spine MRI was completed and height percentiles were compared with national growth charts. RESULTS: The median ages were 28, 43, and 126 months at diagnosis, RT, and analysis, respectively. All of the enrolled children received local RT, and 15 patients received total body irradiation (TBI). Median growth percentiles were 67.0, 54.0, and 4.9 at diagnosis, RT, and analysis, respectively. The number of irradiated vertebrae (P=0.009) and having undergone TBI (P=0.03) were significantly associated with shorter stature. Among the MRI parameters for irradiated vertebrae, signal intensity was higher (P=0.05) and more heterogeneous (P=0.02) in T1-weighted images and roundness was lower (P=0.03) in T2-weighted images. CONCLUSIONS: Height of children with neuroblastoma was significantly affected by RT. The number of irradiated vertebrae and having undergone TBI were significantly associated with lower height. Irradiated spine showed changes in both signal and shape on MRI. PMID- 25746353 TI - Benchmark IMRT evaluation of a Co-60 MRI-guided radiation therapy system. AB - A device for MRI-guided radiation therapy (MR-IGRT) that uses cobalt-60 sources to deliver intensity modulated radiation therapy is now commercially available. We investigated the performance of the treatment planning and delivery system against the benchmark recommended by the American Association of Physicists in Medicine (AAPM) Task Group 119 for IMRT commissioning and demonstrated that the device plans and delivers IMRT treatments within recommended confidence limits and with similar accuracy as linac IMRT. PMID- 25746354 TI - Boldine, a natural aporphine alkaloid, inhibits telomerase at non-toxic concentrations. AB - In a preliminary screening study of natural alkaloids, boldine, an aporphine alkaloid, showed an interesting dose and time dependent anti-proliferative effect in several cancer cell lines. Cytotoxicity of boldine in human fibroblasts was considerably lower than the telomerase positive embryonic kidney HEK293 and breast cancer MCF-7 and MDA-MB-231 cells. Whether boldine can inhibit telomerase was investigated here using a modified quantitative real-time telomere repeat amplification protocol (q-TRAP). This test showed that boldine inhibits telomerase in cells treated with sub-cytotoxic concentrations. Telomerase inhibition occurs via down-regulation of hTERT, the catalytic subunit of the enzyme. Boldine changed the splicing variants of hTERT towards shorter non functional transcripts as well. A direct interaction of boldine with the enzyme may also be involved, though thermal FRET method did not detect any substantial interaction between boldine and synthetic telomere sequences. This study advocates boldine as a valuable candidate for telomerase-targeted cancer care. This study suggests that derivatives of boldine could be potent anti-cancer drugs. PMID- 25746355 TI - Inhibition of RNA transportation induces glioma cell apoptosis via downregulation of RanGAP1 expression. AB - The prognosis of glioblastoma remains poor, even treatment with surgery, radiation, or chemotherapy. Therefore, it is still important to develop a new strategy for treatment of glioblastoma. Previous reports demonstrated that rRNA is produced at abnormally high levels in tumor cells. Nuclear export of all non coding RNAs are known to depend on RanGTPase system. Hydrolyzation of RanGTP-RNA complex by RanGTPase activating protein 1 (RanGAP1) releases RNA from nucleus to cytoplasm. Therefore, inhibition of RNA transportation would be a useful strategy to affect cancer cell fate. In this study, 5-30 MUM of oridonin, a natural diterpenoid compound isolated from the traditional Chinese medicine, Rabdosia rubescens, induced U87MG glioma cell apoptosis and RNA accumulation in nucleus at 12h-time point. Before U87MG cell apoptosis, the RanGAP1 protein amount decreased and RanGTP accumulated in nucleus as respectively determined by immunoprecipitation and immunofluorescence, suggesting that decrease of RanGAP1 may result in nuclear entrapment of RanGTP and RNA, and then induce U87MG cell death. In contrast, over-expression of the RanGAP1 protein reversed oridonin induced U87MG cell apoptosis. Hence, we demonstrated that downregulation of the RanGAP1 protein level by oridonin may result in RNA accumulation in nucleus via nuclear entrapment of RanGTP which eventually led to the apoptosis of glioma cells. PMID- 25746356 TI - Hypothalamus metabolomic profiling to elucidate the tissue-targeted biochemical basis of febrile response in yeast-induced pyrexia rats. AB - In the previous reports regarding thermoregulation, the hypothalamus is thought to be the primary centre in the central nervous system for controlling the body temperature. However, to date, there has not been sufficient evidence to reveal its thermoregulatory mechanism. In the current study, we utilised a tissue targeted metabolomics strategy to elucidate the underlying biochemical mechanisms of thermoregulation in the fever process by analysing the global metabolic profile of the hypothalamus in yeast-induced pyrexia rats. Data acquisition was completed using the HPLC-LTQ-Orbitrap/MS in both positive and negative ion mode. Principal component analysis was used to observe the cluster characteristics between the control group and the pyrexia group. Potential biomarkers were screened using orthogonal partial least-squares-discriminant analysis. Seventeen potential biomarkers were identified in the hypothalamus samples to discriminate the control and pyrexia groups, including amino acids, nucleic acids, vitamins, carbohydrates, and phospholipids. As a result, purine metabolism was enhanced pronouncedly, and perturbation of lipid metabolism was also observed. Meanwhile, amino acid metabolism and energy metabolism were also activated significantly. In conclusion, the study indicated that hypothalamus-targeted metabolomics could provide a powerful tool to further understand the pathogenesis of febrile response. PMID- 25746357 TI - Decreased expression of heat shock proteins may lead to compromised wound healing in type 2 diabetes mellitus patients. AB - BACKGROUND: Heat shock proteins (HSPs) are inducible stress proteins expressed in cells exposed to stress. HSPs promote wound healing by recruitment of dermal fibroblasts to the site of injury and bring about protein homeostasis. Diabetic wounds are hard to heal and inadequate HSPs may be important contributors in the etiology of diabetic foot ulcers (DFU). OBJECTIVE: To analyze the differential expression of HSPs and their downstream molecules in human diabetic wounds compared to control wounds. METHODS: Expressional levels of HSP27, HSP47 and HSP70 and their downstream molecules like TLR4, p38-MAPK were seen in biopsies from 101 human diabetic wounds compared to 8 control subjects without diabetes using RT-PCR, western blot and immunohistochemistry. RESULTS: Our study suggested a significant down regulation of HSP70, HSP47 and HSP27 (p value=<0.001 for HSP70; p value=0.007 for HSP47; p value=0.007 for HSP27) in DFU along with their downstream molecules TLR4 and p38-MAPK (p value=0.006 for p38-MAPK; p value=0.02 for TLR4). HSP70 levels were significantly lower in male subjects and their levels increased significantly with the grades of wound on Wagner's scale. Infection status of the wounds was found to be significantly associated with the increased levels of HSP70 and HSP27 in infected diabetic wounds. CONCLUSIONS: Our study demonstrates that the down regulation of HSPs in diabetic wounds is associated with wound healing impairment in T2DM subjects. PMID- 25746358 TI - Quit_line treatment protocols for users of non-cigarette tobacco and nicotine containing products. AB - INTRODUCTION: Use of non-cigarette tobacco and nicotine containing products (TNCPs) is increasing in the US. Telephone tobacco quit lines (QLs) are one of the most widely disseminated tools for providing cessation services to cigarette smokers, but the range of QL treatment services offered to non-cigarette TNCP users needs to be determined. METHODS: We surveyed QLs across 50 US states, Washington D.C., and Guam for the number of treatment protocols offered, products they were intended to treat, and how telephone counselors triaged patients reporting the use of non-cigarette TNCPs. RESULTS: Thirteen organizations provided US QL interventions of which eleven agreed to be interviewed regarding their treatment services (84.6%). Seven of the eleven QL providers (63.6%) used a single intervention protocol adapted to the type of non-cigarette TNCP used. Two of the eleven QLs (18.2%) referred hookah users to another provider and one QL (9.1%) referred electronic cigarette users to third party resources for cessation support; otherwise a single intervention protocol was used for all other TNCP users. Only one QL (9.1%) had a specialized protocol for smokeless tobacco users in addition to a standard protocol for all other callers. CONCLUSIONS: QL providers do not have access to tailored protocols for non-cigarette TNCP users, and it remains uncertain whether a common tobacco protocol will be efficacious for these users. Future research should both validate potential common protocols for non-cigarette TNCP users and address the need for and the development of specialized QL interventions for TNCP users to help them quit. PMID- 25746359 TI - Gender as a moderator of the relationship between preparty motives and event level consequences. AB - OBJECTIVE: Prepartying is often associated with increased alcohol consumption and negative alcohol-related consequences among college students. General drinking motives are often only weakly related to preparty alcohol use, and few studies have examined the associations between preparty-specific drinking motives and alcohol-related consequences that occur during or after a preparty event. The current study utilizes event-level data to address this gap in the literature by examining the relationship between four types of preparty motives (prepartying to relax or loosen up, to increase control over alcohol use, to meet a dating partner, and to address concerns that alcohol may not be available later) and alcohol consequences as a function of gender. METHODS: Participants (N=952) reported on their most recent preparty event in the past month. RESULTS: After controlling for general drinking motives, all four preparty motives predicted greater event-level consequences for both males and females. Further, prepartying to increase control over alcohol consumed was associated with greater consequences for males as compared to females. CONCLUSIONS: The findings are consistent with research suggesting that preparty specific motives may further our understanding of prepartying outcomes over and above the use of general drinking motive measures. PMID- 25746360 TI - Flexible emotion-based decision-making behavior varies in current and former smokers. AB - INTRODUCTION: Suboptimal decision-making is a feature in the initiation and maintenance of substance use, often manifested in choosing for short-term benefits rather than long-term gain, and the failure to display cognitive flexibility, respectively. Studies of nicotine users typically focus on characterizing those who are already addicted; less is known about decision making in former smokers. METHODS: Non- (n=21), former daily- (n=23) and current daily smokers (n=24), completed the contingency-shifting variant Iowa Gambling Task (csIGT), in which the reward and punishment contingencies of the decks are systematically varied after 100 trials of the 'standard' IGT. Scores on the standard blocks of the csIGT provided an index of emotion-based decision-making, while the contingency-shifting blocks assessed flexible decision-making. Subjective ratings were also recorded at 20-trial intervals. RESULTS: Both current and former smokers showed significantly impaired performance relative to non-smokers when making decisions during the standard blocks of the csIGT. Both former and non-smokers' awareness of the reward/punishment contingencies was significantly higher than those of current smokers at the end of the standard IGT. Both former and non-smokers had significantly better performance on the contingency shifting blocks, relative to current smokers. CONCLUSIONS: The findings indicate that both current and former smokers display a suboptimal pattern of decision-making than non-smokers during the standard IGT. However, with respect to the ability to change behavior following reversed contingencies, former smokers are more similar to non-smokers than to current smokers. Former smokers were also more aware of the contingencies than current smokers. PMID- 25746361 TI - Validation of the reasons for gambling questionnaire (RGQ) in a British population survey. AB - INTRODUCTION: The aims of the study are to validate and further psychometrically test the five-dimensional structure of the Reasons for Gambling Questionnaire (RGQ), and to test the differences between different types of gamblers (i.e., offline gamblers who gambled in-person only vs. mixed-mode gamblers who gambled both online and offline) on the five dimensions of the RGQ. METHODS: Data from the 2010 British Gambling Prevalence Survey (BGPS) were used. The analyzed data comprised 5677 individuals (52.7% female; mean age=47.64 years; SD=17.82). Confirmatory factor analysis and independent-sample t-tests were applied. RESULTS: The five-dimensional structure of the RGQ was confirmed in the general sample and among gender and age subgroups. Furthermore, mixed-mode gamblers (MMGs) who gambled both online and offline had higher scores for enhancement, recreation and money motives than offline gamblers that gambled in-person only (IPGs). In addition among males, there was a significant difference in the scores for enhancement and recreation motives across MMGs and IPGs. Among past-year gamblers aged 16-34 years, MMGs had higher scores for enhancement, recreational and monetary motives than IPGs while among past-year gamblers aged 35-55 years, MMGs had higher scores for enhancement and recreational motives than IPGs. CONCLUSIONS: The results are consistent with a previous test of the RGQ and the findings indicate that the RGQ is a valid instrument to assess gambling motives among the general population. PMID- 25746362 TI - Complex interventions and the amalgamation of marginal gains: A way forward for understanding and researching essential nursing care? PMID- 25746363 TI - External validation of a simple non-invasive algorithm to rule out chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. AB - PURPOSE: International guidelines do not provide strong recommendations on the duration and intensity of follow-up after acute pulmonary embolism (PE), nor on screening-programs for chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to address this gab by performing an external validation of the easy "CTEPH rule-out-criteria" based on a normal NT-proBNP level and the absence of 3 ECG characteristics. METHODS: 134 patients underwent clinical follow-up 6months after PE. Predefined transthoracic echocardiographic (TTE) criteria were used to categorize patients as "PH unlikely" or "PH possible/likely". The latter patients underwent further (invasive) diagnostic procedures to confirm and classify the diagnosis of pulmonary hypertension. NT-proBNP and ECGs, both assessed at the day of echocardiography, were evaluated post-hoc. RESULTS: Sixty-three patients (47%) scored none of the "CTEPH rule-out criteria" positive, of whom 61 had normal TTE (97%). Twenty-five patients (19%) were categorized by TTE as "PH possible/likely"; of those, 6 were diagnosed with CTEPH. The sensitivity of rule out criteria for CTEPH was 100% (95%CI 56-100%; 6/6 patients identified), and for "PH possible/likely" on TTE 92% (95%CI 74-99%; 23/25 patients identified): 2 asymptomatic patients with estimated systolic pulmonary arterial pressure of 36mmHg and 38mmHg, respectively, who remained stable during further 2-year follow up, were not identified. Inter-observer agreement for the adjudication of the ECG characteristics was excellent (kappa-statistic 0.97). CONCLUSIONS: In this external validation cohort, we confirmed the diagnostic accuracy and reproducibility of the "CTEPH rule-out criteria". These results provide a solid ground for future outcome trials applying this algorithm. PMID- 25746364 TI - Preserved clot formation detected by the Thrombodynamics analyzer in patients with cirrhosis. AB - INTRODUCTION: Patients with cirrhosis have substantial alterations in their hemostatic system, which are paradoxically associated with the risk of both bleeding and thrombotic complications. However, it still remains difficult to predict those risks, because results from conventional coagulation tests, such as the prothrombin time (PT) and activated partial thromboplastin time (APTT), do not reflect the complex hemostatic changes in these patients. More sophisticated global hemostasis tests, such as thrombin generation assays, are not standardized for routine use yet. Here we examined the spatial clot growth in plasma from patients with cirrhosis using the novel Thrombodynamics assay, which uses a fundamentally new approach to test plasma hemostatic capacity. MATERIALS AND METHODS: Thrombodynamics assays were performed in plasma from thirty-one patients with cirrhosis and twenty-five healthy controls. Results were compared to results with thrombin generation testing and PT/APTT test results. RESULTS: Rates of clot growth, clot size, and clot density from the Thrombodynamics assay were comparable between patients and controls. Thrombin generation in the presence of thrombomodulin was increased in the patients, despite prolonged PT and APTT test results. There was little correlation between parameters derived from the Thrombodynamics assay and the PT, APTT, or thrombin generation data. CONCLUSIONS: The Thrombodynamics assay showed preserved clot formation in plasma from patients with cirrhosis, which is in line with the results of the thrombin generation assay in this study and previously reported by others. PMID- 25746365 TI - iTRAQ quantitative proteomics-based identification of cell adhesion as a dominant phenotypic modulation in thrombin-stimulated human aortic endothelial cells. AB - INTRODUCTION: The phenotypic changes in thrombin-stimulated endothelial cells include alterations in permeability, cell shape, vasomotor tone, leukocyte trafficking, migration, proliferation, and angiogenesis. Previous studies regarding the pleotropic effects of thrombin on the endothelium used human umbilical vein endothelial cells (HUVECs)-cells derived from fetal tissue that does not exist in adults. Only a few groups have used screening approaches such as microarrays to profile the global effects of thrombin on endothelial cells. Moreover, the proteomic changes of thrombin-stimulated human aortic endothelial cells (HAECs) have not been elucidated. MATERIALS AND METHODS: HAECs were stimulated with 2 units/mL thrombin for 5h and their proteome was investigated using isobaric tags for the relative and absolute quantification (iTRAQ) and the MetaCore(TM) software. RESULTS: A total of 627 (experiment A) and 622 proteins (experiment B) were quantified in the duplicated iTRAQ analyses. MetaCore(TM) pathway analysis identified cell adhesion as a dominant phenotype in thrombin stimulated HAECs. Replicated iTRAQ data revealed that "Cell adhesion_Chemokines and adhesion," "Cell adhesion_Histamine H1 receptor signaling in the interruption of cell barrier integrity," and "Cell adhesion_Integrin-mediated cell adhesion and migration" were among the top 10 statistically significant pathways. The cell adhesion phenotype was verified by increased THP-1 adhesion to thrombin stimulated HAECs. In addition, the expression of ICAM-1, VCAM-1, and SELE was significantly upregulated in thrombin-stimulated HAECs. CONCLUSIONS: Several regulatory pathways are altered in thrombin-stimulated HAECs, with cell adhesion being the dominant altered phenotype. Our findings show the feasibility of the iTRAQ technique for evaluating cellular responses to acute stimulation. PMID- 25746366 TI - Fc-based half-life extension of human FVIIa--a new player for hemophilia treatment? PMID- 25746367 TI - Detection of elevated INR by thromboelastometry and thromboelastography in warfarin treated patients and healthy controls. AB - INTRODUCTION: The diagnostic potential of whole blood viscoelastic tests thromboelastography (TEG(r)) and thromboelastometry (ROTEM(r)) to detect warfarin induced INR elevation remains elusive. METHODS: Viscoelastic tests were performed in 107 patients on warfarin and 89 healthy controls. Tests were activated by kaolin for TEG, and ellagic acid (INTEM) or tissue factor (EXTEM) for ROTEM. RESULTS: Viscoelastic tests revealed significant differences in clotting profiles between controls and warfarin-treated patients. Compared with healthy controls, patients treated with warfarin had prolonged EXTEM clotting and TEG reaction time (p<0.001), both of which were also increased beyond the reference range. Increased INR values correlated with EXTEM CT (Spearman rho=0.87) and TEG R-time (rho=0.73). EXTEM CT had a sensitivity and specificity of 0.89 and 1.00, respectively, to detect elevated INR above 1.2 units, with a positive and negative predictive values (PPV and NPV) of 1.00 and 0.88, respectively. Similarly, TEG R-time had a sensitivity and specificity of 0.86 and 0.87, respectively, with a PPV of 0.89 and a NPV of 0.83. The corresponding receiver operator characteristic area under the curve was 0.99 (95% confidence interval [CI], 0.99 - 1.00) for EXTEM CT and 0.94 (95% CI, 0.91 - 0.97) for TEG R-time. CONCLUSIONS: Tissue factor-activated viscoelastic testing (EXTEM) revealed individuals with warfarin-induced INR elevation accurately, while TEG - activated through the intrinsic pathway - still was of acceptable diagnostic value. Further studies are required to evaluate the diagnostic potential of viscoelastic tests in relation to standard laboratory tests in other mixed patient populations, where the PPV and NPV may be inferior. PMID- 25746368 TI - Dual antiplatelet response during PCI: VerifyNow P2Y12 predicts myocardial necrosis and thromboxane B2 generation confirms wide variation in aspirin response. AB - INTRODUCTION: There remains concern that the antiplatelet effects of aspirin and clopidogrel vary between patients and poor responders may be at increased risk of adverse events. However, the optimal method of measuring aspirin and/or clopidogrel response remains unresolved. We compared three methods of measuring clopidogrel response recommended by a recent consensus statement for the European Society of Cardiology, and investigated a novel approach to measuring aspirin response in patients established on both aspirin and clopidogrel. In addition, we investigated whether any of these assays predict peri-procedural myocardial necrosis following percutaneous coronary intervention (PCI). METHODS: A cross section of 323 patients attending for PCI was tested for clopidogrel response using VerifyNow P2Y12, VASP Platelet Reactivity Index (VASP-PRI) and whole blood impedance aggregometry (WBPA). Aspirin response was assessed by measuring the residual ability of platelets to generate thromboxane, calculated as the difference between thromboxane B2 levels in serum and plasma, [TxB2]S-P. Peri procedural myocardial necrosis was determined by a change in troponin I >0.2 MUmol/l. RESULTS: Patients demonstrated wide variation in response to both aspirin and clopidogrel. Correlation between VerifyNow P2Y12 and VASP-PRI was good (r=0.702, p<0.001). Correlation was moderate between WBPA and VerifyNow P2Y12 (r=0.639, p<0.001) and weak for WBPA and VASP-PRI (r=0.353, p<0.001). Only VerifyNow P2Y12 predicted peri-procedural myocardial necrosis. CONCLUSIONS: The three methods of measuring response to clopidogrel identify different patients as poor responders. Poor response to clopidogrel assessed by VerifyNow P2Y12 predicts myocardial necrosis. Measurement of [TxB2]S-P demonstrates a wide variation in aspirin response in patients taking dual antiplatelet therapy. PMID- 25746369 TI - Pattern recall skills of talented soccer players: Two new methods applied. AB - In this study we analyzed the pattern recall skills of talented soccer players by means of two innovative methods of analysis and gaze behavior data. Twenty-two young female soccer players watched video clips of 3 vs. 3 small-sided games and, after occlusion, had to reproduce the positions of the players. Recall performance was measured by calculating the spatial error of the recalled player positions at the moment of occlusion and at consecutive 33ms increments. We analyzed player positions relative to each other, by assessing geometric pattern features in terms of angles between players, and we transformed the data into real-world coordinates to exclude the effects of the 2D perspective in the video clips. The results showed that the participants anticipated the movements of the patterns. In real-world coordinates, the more experienced players anticipated the pattern further in advance than the less experienced players and demonstrated a higher search rate, a shorter fixation duration and a higher fixation order. The differences in recall accuracy between the defensive and offensive elements were not consistent across the methods of analysis and, therefore, we propose that perspective effects of the video clip should be taken into account in further research. PMID- 25746370 TI - Exploring the kinaesthetic sensitivity of skilled performers for implementing movement instructions. AB - The capability to effectively control or adapt a movement pattern based on instructional feedback is essential for effective motor skill learning in high level sport, as it is in other domains such as rehabilitation or music. Despite this, little is known about the capabilities of skilled athletes to use kinematic feedback to purposefully modify complex movements. This study examined the accuracy with which skilled junior tennis players could translate specific kinematic feedback into appropriate modifications of their service actions. Participants were required to either increase or decrease maximum knee flexion or shift impact position laterally by incremental amounts. Further, participants were required to execute their serve with the smallest increase and decrease in these kinematic components as they could consciously produce. Inherent variability within the desired target parameters was calculated to add context to the athlete's accuracy. Results demonstrated that while participants had considerable control over their movements, only some instructions were executed with accuracy greater the variability normally present within their movement. As the required change in knee flexion and impact position increased, absolute accuracy of implementation decreased. These findings are discussed with reference to the smallest controllable changes produced by the athletes and the variability within their actions. PMID- 25746371 TI - Anti-allergic activity of R-phycocyanin from Porphyra haitanensis in antigen sensitized mice and mast cells. AB - The prevalence of food allergy has increased in Asian countries. Marine algae have been proposed as the potential resource for anti-allergic therapeutics. The present study was aimed at isolating R-phycocyanin (RPC) from Porphyra haitanensis and determining the anti-allergy potential of RPC in antigen sensitized mice and mast cells. In animal experiments, RPC could effectively reduce tropomyosin (TM)-specific immunoglobulin E (IgE) and histamine levels, alleviate allergy symptoms and jejunum tissue inflammation in mice, and inhibit the expression and release of cytokines (interleukin-4 (IL-4) and IL-13) in peritoneal lavage fluid. In spleen lymphocyte experiments, high purity of RPC skewed the immunological function of CD4(+) T cells towards Th1 activity. A higher expression of interferon (IFN)-gamma was induced by a synergistic effect of TM and RPC. Through the Jun N-terminal kinase and Janus kinase 2 signaling pathways, IFN-gamma synthesis was induced by RPC in combination with TM. Anti allergic effect of RPC was evaluated in IgE-mediated rat mast RBL-2H3 cells. The results demonstrated that RPC inhibited allergy markers, including the release of beta-hexosaminidase, histamine and ROS in antigen-sensitized RBL-2H3 cells. RPC also suppressed the production of pro-inflammatory factors (IL-4 and tumor necrosis factor-alpha). In conclusion, RPC decreased allergic sensitization against TM by blocking Th2 cell polarization as well as suppressed the release of allergic-mediators in antigen-stimulated mast cells. It may be used as a functional food component or active pharmaceutical ingredient for allergic patients. PMID- 25746372 TI - A new score to predict recurrent cardiovascular events? PMID- 25746373 TI - Is albuminuria a myocardial infarction risk equivalent for atherothrombotic events? AB - OBJECTIVE: People with chronic kidney disease frequently experience cardiovascular events. This study sought to investigate whether the presence of albuminuria displays a vascular risk equivalent to that in patients with prior myocardial infarction. METHODS: Albuminuria was defined as a urinary albumin to creatinine ratio of 30 MUg/mg or greater in 852 consecutive patients undergoing coronary angiography. Prospectively, we recorded vascular events over 3.2+/-1.2 years. RESULTS: From our patients, 513 (60.2%) had neither albuminuria nor a history of MI, 126 (14.8%) had albuminuria without prior MI, 137 (16.1%) did not have albuminuria but had a history of MI, and 76 (8.9%) had both, albuminuria and prior MI. Compared with the incidence of the composite endpoint among normoalbuminuric patients with no prior MI (11.9%), event rates nearly doubled both in patients with albuminuria without prior MI (24.6%; p=0.003) and in normoalbuminuric patients with a history of prior MI (21.2%; p=0.004) and were highest in patients with both, albuminuria and prior MI (36.8%; p<0.001). Importantly, event rates were not significantly different between patients with albuminuria and no prior history of MI and those with normoalbuminuria but prior MI (p=0.972). Moreover, the event rate in patients with both, albuminuria and history of MI, was significantly higher (p<0.05) than in the two groups exhibiting only one of the two conditions. CONCLUSION: This is the first study demonstrating that albuminuria is a CAD risk equivalent. Thus, cardiovascular risk factors in albuminuric patients should be treated as aggressively as in patients with prior MI. PMID- 25746374 TI - Increased aldehyde-modification of collagen type IV in symptomatic plaques--a possible cause of endothelial dysfunction. AB - OBJECTIVE: Subendothelial LDL-adhesion and its subsequent oxidation are considered as key events in the development of atherosclerotic lesions. During oxidation of LDL, reactive aldehydes such as malondialdehyde (MDA) are formed, which modify apolipoprotein B100. However, the possibility that these reactive aldehydes could leak out of the LDL-particle and modify surrounding extracellular matrix proteins has been largely unexplored. We have investigated if aldehyde modification of collagen type IV, one of the major basement membrane components, in plaques is associated with cardiovascular events. METHODS: The amount of MDA modified collagen type IV and native collagen type IV were determined in homogenates from 155 carotid artery lesions, removed by endarterectomy from patients with or without previous cerebrovascular events. RESULTS: Plaque MDA collagen type IV, but not native collagen type IV, correlated with oxidized LDL (r=0.31, P<0.001) and lipoprotein-associated phospholipase A2 (r=0.44, P<0.001). MDA-collagen type IV was increased in lesions from symptomatic patients compared to lesions from asymptomatic patients. Auto-antibodies against MDA-collagen type IV in plasma correlated with the amount of MDA-collagen type IV in lesions. MDA modification of collagen type IV decreased endothelial cell attachment. In addition, culture of endothelial cells with MDA-modified collagen type IV increased vascular cell adhesion molecule expression and reduced the anti coagulant proteins thrombomodulin and endothelial protein C receptor. In the lesions native collagen type IV, but not MDA-collagen type IV, was positively associated with thrombomodulin. CONCLUSION: The present observations imply that aldehyde-modification of collagen type IV, associated with LDL oxidation, in atherosclerotic plaques may cause endothelial dysfunction and increase the risk of clinical events. PMID- 25746375 TI - Nebivolol to attenuate the effects of hyper-homocysteinaemia in rats. AB - OBJECTIVE: This study investigated the prophylactic effect of nebivolol against hyper-homocysteinaemia (hHcy) induced oxidative stress in brain, heart, liver and kidney tissues and histomorphometric changes in the thoracic aorta. METHODS: Twenty-four adult male Wistar rats were divided into a control, nebivolol, hHcy and nebivolol+hHcy group. hHcy was induced by oral administration of L-methionine (1 g/kg/day) for 28 days. 10 mg/kg/day nebivolol was administered orally for 28 days. Malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) and superoxide dismutase (SOD) activities in the tissues were determined. The total cross-sectional area (TCSA), luminal cross-sectional area (LCSA) and intima-media thickness (IMT) were measured in the thoracic aorta. RESULTS: Homocysteine (Hcy) levels were lower in the nebivolol+hHcy group than in the hHcy group. Nebivolol treatment significantly decreased high MDA levels in the brain, heart and liver tissues. The level of GSH was higher in the brain, heart and kidney tissues of the nebivolol+hHcy group (P<0.001). The activity of CAT increased only in the kidney tissue of the nebivolol+hHcy group (P<0.01), and the activity of SOD was significantly increased in all the tissues in this group. Increased TCSA and IMT in the nebivolol+hHcy group were significantly decreased after nebivolol administration. The LCSA was significantly higher in the hHcy group than the control group, probably due to outward vascular remodelling. CONCLUSION: Nebivolol treatment may be useful in different clinical scenarios where hHcy affects physiopathological pathways. PMID- 25746376 TI - Interaction effects between Paraoxonase 1 variants and cigarette smoking on risk of coronary heart disease in a Singaporean Chinese population. AB - OBJECTIVE: Paraoxonase 1 (PON1) plays an important role in reducing the risk of coronary heart disease (CHD). Smoking is known to reduce PON1 activity. We aimed to investigate the effects of interactions between PON1 variants and smoking on CHD in the Singaporean Chinese population. METHODS: In a case-control study nested within Singapore Chinese Health Study (N=1914), subjects with and without CHD were classified into never-smokers and ever-smokers (ever smoked at least one cigarette a day for 1 year or longer). Associations at four independent SNPs at the PON1 locus (rs3735590, rs3917550, rs662, rs3917481) with CHD were evaluated using logistic regression, before/after stratification on smoking status. Interactions between smoking and PON1 variants were analyzed with likelihood ratio tests, by including the SNP*smoking interaction term in regression analyses. RESULTS: The T allele at the coding SNP, rs662, was associated with higher risk of CHD in ever-smokers only (OR=1.35, 95% CI 1.08-1.68; adjusted P=0.036). At the miR-SNP, rs3735590, carrying at least one copy of minor allele T was associated with increased risk of CHD in a dominant manner in never-smokers only (OR=1.53, 95% CI 1.11-2.11; adjusted P=0.036). Significant interactions between two PON1 SNPs and smoking in relation to CHD risk were identified (adjusted P=0.012 for rs662; adjusted P=0.044 for rs3735590). These associations remained significant after adjustment for known CHD risk factors and upon correction for multiple tests. CONCLUSIONS: Two PON1 SNPs, rs662 and rs3735590, were found to significantly interact with cigarette smoking to modulate the risk of CHD in the Singaporean Chinese population. PMID- 25746377 TI - Association of computed tomography-derived left ventricular size with major cardiovascular events in the general population: the Heinz Nixdorf recall study. AB - OBJECTIVE: To investigate the relationship between LV size as determined by non contrast enhanced cardiac CT with incident cardiovascular disease in the general population free of clinical cardiovascular disease. METHODS: LV axial area was quantified from non-contrast CT in axial, end-diastolic images at a mid ventricular slice in participants from the population-based Heinz Nixdorf recall study, free of cardiovascular disease (n=3926, 59+/-8years, 53%female). LV size index (LVI) was defined as the quotient of LV area and body surface area. Major CV events (coronary events, stroke, CV death) were assessed during follow-up. Association of LVI with events was assessed using Cox regression analysis in unadjusted and multivariable adjusted models. RESULTS: During 8.0+/-1.5years of follow-up, 219 subjects developed a major CV event. Those with events had larger LVI at baseline (2258+/-352 vs. 2149+/-276 mm2/m2, p<0.0001). In univariate analysis, increase of LVI by 1 standard deviation was associated with 40% higher risk of events (HR(95%CI):1.41(1.26-1.59), p<0.0001). Associations remained statistically significant after adjustment for CV risk factors (1.24(1.10-1.40), p=0.0007) and when further adjusting for CAC (1.21(1.07-1.37), p=0.003). There was a trend towards stronger association for subjects with low CAC-score (CAC<100:1.41(1.16-1.71), p=0.0005, CAC>=100:1.24(1.06-1.44), p=0.006) in univariate analysis which persisted after multivariable adjustment (CAC<100: 1.41(1.14-1.73), p=0.001, CAC>=100: 1.12(0.96-1.31), p=0.16). CONCLUSION: CT derived LV size is associated with incident major CV events independent of traditional risk factors and CAC-score in a population-based cohort and may improve the prediction of hard events especially in subjects with low CAC-scores. PMID- 25746378 TI - In reply: "Bottle-opener" effect in bipolar hip prostheses dislocations. PMID- 25746379 TI - [Anaphylaxis in the preanesthesia evaluation]. PMID- 25746380 TI - Arabidopsis proteome responses to the smoke-derived growth regulator karrikin. AB - Karrikins are butenolide plant growth regulators in smoke from burning plant material that have proven ability to promote germination and seedling photomorphogenesis. However, the molecular mechanisms underlying these processes are unclear. Here we provide the first proteome-wide analysis of early responses to karrikin in plants (Arabidopsis seedlings). Image analysis of two dimensionally separated proteins, Rubisco-depleted proteomes and phosphoproteomes, together with LC-MS profiling, detected >1900 proteins, 113 of which responded to karrikin treatment. All the differentially abundant proteins (except HSP70-3) are novel karrikin-responders, and most are involved in photosynthesis, carbohydrate metabolism, redox homeostasis, transcription control, proteosynthesis, protein transport and processing, or protein degradation. Our data provide functionally complementary information to previous identifications of karrikin-responsive genes and evidence for a novel karrikin signalling pathway originating in chloroplasts. We present an updated model of karrikin signalling that integrates proteomic data and is supported by growth response observations. BIOLOGICAL SIGNIFICANCE: Karrikin has shown promising potential in agricultural applications, yet this process is poorly understood at the molecular level. To the best of our knowledge, this is the first survey of early global proteomic responses to karrikin in plants (Arabidopsis seedlings). The combination of label-free LC-MS profiling and 2-DE analyses provided highly sensitive snapshots of protein abundance and quantitative information on proteoform-level changes. These results present evidence of proteasome independent karrikin signalling pathways and provide novel targets for detailed mechanistic studies using, e.g., mutants and transgenic plants. PMID- 25746381 TI - Proteomic analysis of elicitation of downy mildew disease resistance in pearl millet by seed priming with beta-aminobutyric acid and Pseudomonas fluorescens. AB - Downy mildew is one of the severe diseases of pearl millet, globally affecting its commercial production. Priming of seeds of a susceptible cultivar of pearl millet with beta-aminobutyric acid (BABA) and Pseudomonas fluorescens has reduced the downy mildew disease incidence level under field studies. In the current study, proteomic approach was used to elucidate the poorly studied resistance mechanism in these elicitor primed pearl millet seeds in response to Sclerospora graminicola infection. 2DE-MS/MS based proteomic approach revealed that majority of the 63 differentially accumulated (p<=0.05) proteins associated with energy and metabolism followed by stress and defense category. Multivariate statistics disclosed that infection caused by the pathogen rather than elicitor treatment had a major influence on the dynamics of protein abundance. Mechanism of priming mediated by BABA and P. fluorescens were different from each other as evident by the protein abundance profile of hierarchical clustering analysis. Over representation of proteins pertaining to glucose metabolism suggests that seed priming ensures plant protection against disease without compromising its normal growth and development. In addition the study forms a basis for future investigation by functional analysis of these differentially accumulated proteins to further unravel the resistance mechanism of elicitor primed plant against the S. graminicola. BIOLOGICAL SIGNIFICANCE: The study is based on the comparative proteomic analysis between BABA and P. fluorescens mediated resistance in pearl millet, in response to downy mildew causing biotroph - S. graminicola. To our knowledge, this article is the first to report on seedling proteome of pearl millet whose genome is not yet sequenced. In addition, the study also provides clue for the plausible antagonistic cross-talk that might exist between jasmonic acid signaling and salicylic acid signaling in SAR and ISR mediated resistance by BABA and P. fluorescens against the downy mildew pathogen. Furthermore, pearl millet seedling proteome being perturbed by pathogen inoculation was more apparent than that caused by elicitor treatment, as revealed by multivariate statistics like PCA. Analysis by gene enrichment tools further revealed that the glucose metabolism pathway was majorly being affected in our study. This could be attributed to the essential balance that is being maintained in energy diversion towards stress and normal physiological process due to the priming effect of the elicitors against biotic stress. PMID- 25746382 TI - The utility of HepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death. AB - Drug-induced mitochondrial dysfunction has been hypothesized to be an important determining factor in the onset of drug-induced liver injury. It is essential to develop robust screens with which to identify drug-induced mitochondrial toxicity and to dissect its role in hepatotoxicity. In this study we have characterised a mechanistically refined HepG2 model, using a panel of selected hepatotoxicants and non-hepatotoxicants. We have demonstrated that acute metabolic modification, via glucose-deprivation over a 4 h period immediately prior to compound addition, is sufficient to allow the identification of drugs which induce mitochondrial dysfunction, in the absence of cell death over a short exposure (2-8 h) using a plate-based screen to measure cellular ATP content and cytotoxicity. These effects were verified by measuring changes in cellular respiration, via oxygen consumption and extracellular acidification rates. Overall, these studies demonstrate the utility of HepG2 cells for the identification of mitochondrial toxins which act directly on the electron transport chain and that the dual assessment of ATP content alongside cytotoxicity provides an enhanced mechanistic understanding of the causes of toxicity. PMID- 25746383 TI - Cytotoxicity of organic surface coating agents used for nanoparticles synthesis and stability. AB - Impact on health by nanomaterials has become a public concern with the great advances of nanomaterials for various applications. Surface coating agents are an integral part of nanoparticles, but not enough attention has been paid during toxicity tests of nanoparticles. As a result, there are inconsistent toxicity results for certain nanomaterials. In this study, we explored the cytotoxicity of eleven commonly used surface coating agents in two cell lines, human epidermal keratinocyte (HaCaT) and lung fibroblast (CRL-1490) cells, at surface coating agent concentrations of 3, 10, 30, and 100 MUM. Two exposure time points, 2 h and 24 h, were employed for the study. Six of the eleven surface coating agents are cytotoxic, especially those surfactants with long aliphatic chains, both cationic (cetyltrimethylammonium bromide, oleylamine, tetraoctylammonium bromide, and hexadecylamine) and anionic (sodium dodecylsulfate). In addition, exposure time and the use of different cell lines also affect the cytotoxicity results. Therefore, factors such as cell lines used and exposure times must be considered when conducting toxicity tests or comparing cytotoxicity results. PMID- 25746384 TI - Cytostatic and genotoxic effect of temephos in human lymphocytes and HepG2 cells. AB - Temephos is an organophosphorus pesticide that is used in control campaigns against Aedes aegypti mosquitoes, which transmit dengue. In spite of the widespread use of temephos, few studies have examined its genotoxic potential. The aim of this study was to evaluate the cytotoxic, cytostatic and genotoxic effects of temephos in human lymphocytes and hepatoma cells (HepG2). The cytotoxicity was evaluated with simultaneous staining (FDA/EtBr). The cytostatic and genotoxic effects were evaluated using comet assays and the micronucleus technique. We found that temephos was not cytotoxic in either lymphocytes or HepG2 cells. Regarding the cytostatic effect in human lymphocytes, temephos (10 MUM) caused a significant decrease in the percentage of binucleated cells and in the nuclear division index as well as an increase in the apoptotic cell frequency, which was not the case for HepG2 cells. The comet assay showed that temephos increased the DNA damage levels in human lymphocytes, but it did not increase the MN frequency. In contrast, in HepG2 cells, temephos increased the tail length, tail moment and MN frequency in HepG2 cells compared to control cells. In conclusion, temephos causes stable DNA damage in HepG2 cells but not in human lymphocytes. These findings suggest the importance of temephos biotransformation in its genotoxic effect. PMID- 25746385 TI - SEMA4B inhibits growth of non-small cell lung cancer in vitro and in vivo. AB - We have recently shown that Semaphorin 4B (SEMA4B) inhibits the invasion of non small cell lung cancer (NSCLC) through PI3K-dependent suppression of MMP9 activation. In the current study, we evaluated whether SEMA4B may also affect the growth of NSCLC. We thus used two human NSCLC lines, A549 and Calu-3, to examine our hypothesis. We found that overexpression of SEMA4B significantly decreased NSCLC cell growth, while SEMA4B inhibition significantly increased NSCLC cell growth, both in vitro and in vivo in an implanted NSCLC model. Adaptation of SEMA4B in NSCLC cells did not alter cell apoptosis, but changed the cell proliferation. Further analyses show that SEMA4B may induce FoxO1 nuclear retention through suppressing PI3K/Akt signaling pathway, which subsequently inhibited cell growth through the direct nuclear target of FoxO1, p21. Our study thus demonstrate a role of SEMA4B in suppressing NSCLC growth, besides its role in inhibiting cell metastasis, and highlights SEMA4B as a promising therapeutic target for NSCLC. PMID- 25746387 TI - Hypoxia-sensitive reporter system for high-throughput screening. AB - The induction of anti-hypoxic stress enzymes and proteins has the potential to be a potent therapeutic strategy to prevent the progression of ischemic heart, kidney or brain diseases. To realize this idea, small chemical compounds, which mimic hypoxic conditions by activating the PHD-HIF-alpha system, have been developed. However, to date, none of these compounds were identified by monitoring the transcriptional activation of hypoxia-inducible factors (HIFs). Thus, to facilitate the discovery of potent inducers of HIF-alpha, we have developed an effective high-throughput screening (HTS) system to directly monitor the output of HIF-alpha transcription. We generated a HIF-alpha-dependent reporter system that responds to hypoxic stimuli in a concentration- and time dependent manner. This system was developed through multiple optimization steps, resulting in the generation of a construct that consists of the secretion-type luciferase gene (Metridia luciferase, MLuc) under the transcriptional regulation of an enhancer containing 7 copies of 40-bp hypoxia responsive element (HRE) upstream of a mini-TATA promoter. This construct was stably integrated into the human neuroblastoma cell line, SK-N-BE(2)c, to generate a reporter system, named SKN:HRE-MLuc. To improve this system and to increase its suitability for the HTS platform, we incorporated the next generation luciferase, Nano luciferase (NLuc), whose longer half-life provides us with flexibility for the use of this reporter. We thus generated a stably transformed clone with NLuc, named SKN:HRE-NLuc, and found that it showed significantly improved reporter activity compared to SKN:HRE MLuc. In this study, we have successfully developed the SKN:HRE-NLuc screening system as an efficient platform for future HTS. PMID- 25746386 TI - Using hydroxyl radical footprinting to explore the free energy landscape of protein folding. AB - Characterisation of the conformational states adopted during protein folding, including globally unfolded/disordered structures and partially folded intermediate species, is vital to gain fundamental insights into how a protein folds. In this work we employ fast photochemical oxidation of proteins (FPOP) to map the structural changes that occur in the folding of the four-helical bacterial immunity protein, Im7. Oxidative footprinting coupled with mass spectrometry (MS) is used to probe changes in the solvent accessibility of amino acid side-chains concurrent with the folding process, by quantifying the degree of oxidation experienced by the wild-type protein relative to a kinetically trapped, three-helical folding intermediate and an unfolded variant that lacks secondary structure. Analysis of the unfolded variant by FPOP-MS shows oxidative modifications consistent with the species adopting a solution conformation with a high degree of solvent accessibility. The folding intermediate, by contrast, experiences increased levels of oxidation relative to the wild-type, native protein only in regions destabilised by the amino acid substitutions introduced. The results demonstrate the utility of FPOP-MS to characterise protein variants in different conformational states and to provide insights into protein folding mechanisms that are complementary to measurements such as hydrogen/deuterium exchange labelling and Phi-value analysis. PMID- 25746388 TI - Gas in the heart. PMID- 25746389 TI - Plasma 25-hydroxyvitamin D levels and survival of colorectal cancer patients: a meta-analysis. PMID- 25746390 TI - Prediction of clinical risks by analysis of preclinical and clinical adverse events. AB - This study examines the ability of nonclinical adverse event observations to predict human clinical adverse events observed in drug development programs. In addition it examines the relationship between nonclinical and clinical adverse event observations to drug withdrawal and proposes a model to predict drug withdrawal based on these observations. These analyses provide risk assessments useful for both planning patient safety programs, as well as a statistical framework for assessing the future success of drug programs based on nonclinical and clinical observations. Bayesian analyses were undertaken to investigate the connection between nonclinical adverse event observations and observations of that same event in clinical trial for a large set of approved drugs. We employed the same statistical methods used to evaluate the efficacy of diagnostic tests to evaluate the ability of nonclinical studies to predict adverse events in clinical studies, and adverse events in both to predict drug withdrawal. We find that some nonclinical observations suggest higher risk for observing the same adverse event in clinical studies, particularly arrhythmias, QT prolongation, and abnormal hepatic function. However the lack of these events in nonclinical studies is found to not be a good predictor of safety in humans. Some nonclinical and clinical observations appear to be associated with high risk of drug withdrawal from market, especially arrhythmia and hepatic necrosis. We use the method to estimate the overall risk of drug withdrawal from market using the product of the risks from each nonclinical and clinical observation to create a risk profile. PMID- 25746391 TI - Regular expression-based learning to extract bodyweight values from clinical notes. AB - BACKGROUND: Bodyweight related measures (weight, height, BMI, abdominal circumference) are extremely important for clinical care, research and quality improvement. These and other vitals signs data are frequently missing from structured tables of electronic health records. However they are often recorded as text within clinical notes. In this project we sought to develop and validate a learning algorithm that would extract bodyweight related measures from clinical notes in the Veterans Administration (VA) Electronic Health Record to complement the structured data used in clinical research. METHODS: We developed the Regular Expression Discovery Extractor (REDEx), a supervised learning algorithm that generates regular expressions from a training set. The regular expressions generated by REDEx were then used to extract the numerical values of interest. To train the algorithm we created a corpus of 268 outpatient primary care notes that were annotated by two annotators. This annotation served to develop the annotation process and identify terms associated with bodyweight related measures for training the supervised learning algorithm. Snippets from an additional 300 outpatient primary care notes were subsequently annotated independently by two reviewers to complete the training set. Inter-annotator agreement was calculated. REDEx was applied to a separate test set of 3561 notes to generate a dataset of weights extracted from text. We estimated the number of unique individuals who would otherwise not have bodyweight related measures recorded in the CDW and the number of additional bodyweight related measures that would be additionally captured. RESULTS: REDEx's performance was: accuracy=98.3%, precision=98.8%, recall=98.3%, F=98.5%. In the dataset of weights from 3561 notes, 7.7% of notes contained bodyweight related measures that were not available as structured data. In addition 2 additional bodyweight related measures were identified per individual per year. CONCLUSION: Bodyweight related measures are frequently stored as text in clinical notes. A supervised learning algorithm can be used to extract this data. Implications for clinical care, epidemiology, and quality improvement efforts are discussed. PMID- 25746392 TI - Carbohydrate conjugation through microwave-assisted functionalization of single walled carbon nanotubes using perfluorophenyl azides. AB - Carbohydrate-functionalized single-walled carbon nanotubes (SWNTs) were synthesized using microwave-assisted reaction of perfluorophenyl azide with the nanotubes. The results showed that microwave radiation provides a rapid and effective means to covalently attach carbohydrates to SWNTs, producing carbohydrate-SWNT conjugates for biorecognition. The carbohydrate-functionalized SWNTs were furthermore shown to interact specifically with cognate carbohydrate specific proteins (lectins), resulting in predicted recognition patterns. The carbohydrate-presenting SWNTs constitute a new platform for sensitive protein- or cell recognition, which pave the way for glycoconjugated carbon nanomaterials in biorecognition applications. PMID- 25746393 TI - Nuclear envelope regulates the circadian clock. AB - Daily rhythms of behavior and physiology arise from endogenous circadian clocks. At the molecular level, the circadian clock consists of intricate transcriptional and post-transcriptional feedback loops that drive 24h rhythms in a vast repertoire of basic cellular processes. The nuclear envelope, as a fundamental component of the cell, has been shown to function as a global transcriptional regulatory machinery. Recently we found that nuclear envelope proteins regulate the circadian clock both in the mammalian system and in fruit flies. One of these proteins, MAN1, impinges on the clock by binding to the promoter region of the core clock gene BMAL1 and enhances its transcription. Here we discuss about other potential mechanisms employed by nuclear envelope proteins to regulate the circadian clock and possible biological relevance of these modulations. PMID- 25746394 TI - NAc Shell Arc/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required. AB - BACKGROUND: Relapse into drug abuse evoked by reexposure to the drug-associated context has been a primary problem in the treatment of drug addiction. Disrupting the reconsolidation of drug-related context memory would therefore limit the relapse susceptibility. METHODS: Morphine conditioned place preference (CPP) was used to assess activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and correlative molecule expression in the Nucleus accumbens (NAc) shell during the reconsolidation of morphine CPP. U0126 and Arc/Arg3.1 antisense oligodeoxynucleotide were adapted to evaluate the role and the underlying mechanism of Arc/Arg3.1 during the reconsolidation. RESULTS: The retrieval of morphine CPP in rats specifically increased the Arc/Arg3.1 protein level in the NAc shell, accompanied simultaneously by increases in the phosphorylation of extracellular signal-regulated kinase1/2 (pERK1/2), the phosphorylation of Cyclic Adenosine monophosphate (cAMP) response element-binding (pCREB), and the up regulation of the membrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors GluR1 subunit level. Intra-NAc shell infusion U0126, an inhibitor of the Mitogen-activated protein kinase kinase (MEK), prevented the retrieval-induced up-regulation of pERK1/2, pCREB, Arc/Arg3.1, and membrane GluR1 immediately after retrieval of morphine CPP. The effect of disrupting the reconsolidation of morphine CPP by U0126 could last for at least 14 days, and could not be evoked by a priming injection of morphine. Furthermore, the specific knockdown of Arc/Arg3.1 in the NAc shell decreased the membrane GluR1 level, and impaired both the reconsolidation and the reinstatement of morphine CPP. CONCLUSIONS: Arc/Arg3.1 in the NAc shell mediates the reconsolidation of morphine associated context memory via up-regulating the level of membrane of GluR1, for which the local activation of the ERK-CREB signal pathway, as an upstream mechanism of Arc/Arg3.1, is required. PMID- 25746395 TI - Differential effects of volatile anesthetics on leukocyte integrin macrophage-1 antigen. AB - Macrophage-1 antigen (Mac-1, alphaMbeta2) is a leukocyte adhesion molecule that plays a significant role in leukocyte crawling and phagocytosis, and is homologous to its sister protein leukocyte function-associated antigen-1 (LFA-1, alphaLbeta2). The authors have previously demonstrated that volatile anesthetics isoflurane and sevoflurane bound to and inhibited LFA-1. Here, the hypothesis tested was that isoflurane and sevoflurane would inhibit Mac-1. A binding assay of Mac-1 to its ligand inter-cellular adhesion molecule-1 (ICAM-1) using V-bottom plates was established. The effect of isoflurane and sevoflurane on Mac-1 was examined using this ICAM-1 binding assay and by probing exposure of activation sensitive epitopes. The docking program Glide was used to predict anesthetic binding site(s) on Mac-1. The functional role of this predicted binding site was then assessed by introducing point mutations in this region. Lastly, the effect of anesthetic on activating mutants was evaluated. The results indicated that isoflurane inhibited binding of Mac-1 to ICAM-1, but sevoflurane did not. Isoflurane also attenuated the exposure of the activation-sensitive epitopes. The docking simulation predicted the isoflurane binding site to be at the cavity underneath the alpha7 helix of the ligand binding domain (the alphaM I domain). Point mutants at this predicted binding site contained both activating and deactivating mutants, suggesting its functional significance. The binding of activating mutants alphaM-Y267A beta2-WT and alphaM-L312A beta2-WT to ICAM-1 was not affected by isoflurane, but binding of another activating mutant alphaM-WT beta2-L132A was inhibited supporting the binding of isoflurane to this cavity. The conclusion reached from these findings was that isoflurane inhibited Mac-1 binding to ICAM-1 by binding to the cavity underneath the alpha7 helix of the alphaM I domain, but sevoflurane did not. Thus, because these common clinical volatile anesthetics demonstrated different effects on Mac-1, this implied their effects on the immune system might differ. PMID- 25746396 TI - Comparison of mitochondrial genome sequences of pangolins (Mammalia, Pholidota). AB - The complete mitochondrial genome was sequenced for three species of pangolins, Manis javanica, Phataginus tricuspis, and Smutsia temminckii, and comparisons were made with two other species, Manis pentadactyla and Phataginus tetradactyla. The genome of Manidae contains the 37 genes found in a typical mammalian genome, and the structure of the control region is highly conserved among species. In Manis, the overall base composition differs from that found in African genera. Phylogenetic analyses support the monophyly of the genera Manis, Phataginus, and Smutsia, as well as the basal division between Maninae and Smutsiinae. Comparisons with GenBank sequences reveal that the reference genomes of M. pentadactyla and P. tetradactyla (accession numbers NC_016008 and NC_004027) were sequenced from misidentified taxa, and that a new species of tree pangolin should be described in Gabon. PMID- 25746397 TI - Reciprocal protection from natural enemies in an ant-wasp association. AB - We show that in French Guiana the large carton nests of Azteca chartifex, a territorially-dominant arboreal dolichoderine ant, are protected from bird attacks when this ant lives in association with Polybia rejecta, an epiponine social wasp. Because A. chartifex colonies are well known for their ability to divert army ant raids from the base of their host tree so that they protect their associated wasps from these raids, there is a reciprocal benefit for these two partners, permitting us to call this association a mutualism. We also show that P. rejecta nests are significantly less often attacked by birds than are those of two compared epiponine social wasp species. Furthermore, experimentation using a standardized protocol demonstrated the significantly higher aggressiveness of P. rejecta compared to seven other wasp species. We conclude that the efficacious protection of its associated ant nests is likely due to the extreme aggressiveness of P. rejecta. PMID- 25746398 TI - Metastable alloy nanoparticles, metal-oxide nanocrescents and nanoshells generated by laser ablation in liquid solution: influence of the chemical environment on structure and composition. AB - Alloy nanoparticles are characterized by the combination of multiple interesting properties, which are attractive for technological and scientific purposes. A frontier topic of this field is nanoalloys with compositions not thermodynamically allowed at ordinary temperature and pressure (i.e. metastable), because they require out-of-equilibrium synthetic approaches. Recently, laser ablation synthesis in solution (LASiS) was successfully applied for the realization of metastable nanoalloys because of the fast kinetics of nanoparticle formation. However, the role played by the chemical environment on the final composition and structure of laser generated nanoalloys still has to be fully elucidated. Here, we investigated the influence of different synthetic conditions on the LASiS of metastable nanoalloys composed of Au and Fe, such as the use of water instead of ethanol, the bubbling of inert gases and the addition of a few vol% of H2O2 and H2O. The two elements showed different reactivity when LASiS was performed in water instead of ethanol, while minor effects were observed from bubbling pure gases such as N2, Ar and CO2 in the liquid solution. Moreover, the plasmonic response and the structure of the nanoalloys were sensibly modified by adding H2O2 to water. We also found that nanoparticle production is dramatically influenced just by adding 0.2% of H2O in ethanol. These results suggest that the formation of a cavitation bubble with long lifetime and large size during LASiS is useful for the preservation of the metastable alloy composition, whereas an oxidative environment hampers the formation of metastable alloy nanoparticles. Overall, by acting on the type of solvent and solutes, we were able to switch from a traditional synthetic approach for the composition of Au-Fe nanoalloys to one using a reactive environment, which gives unconventional structures such as metal@iron-oxide nanoshells and nanocrescents of oxide supported on metal nanospheres. These results expand the knowledge about the mechanism of the formation of nanoalloys using LASiS and show how to obtain multielement nanoparticles of enormous interest for nanomedicine, plasmonics, magneto plasmonics and catalysis. PMID- 25746399 TI - Exercise and cognitive function: a randomized controlled trial examining acute exercise and free-living physical activity and sedentary effects. AB - OBJECTIVE: To simultaneously examine the effects of acute exercise intensity and free-living physical activity and sedentary behavior on cognitive function in young, healthy adults. PATIENTS AND METHODS: Using a counterbalanced, crossover, randomized controlled design, 87 young adults (mean age, 21.4 years) completed various cognitive assessments with and without an acute bout of exercise preceding the assessment. Participants were randomized into 1 of 4 groups to complete a 30-minute bout of acute exercise: control (no exercise), light intensity (40%-50% of predicted maximum heart rate [HR(max)]), moderate intensity (51%-70% of predicted HR(max)), or vigorous intensity (71%-85% of predicted HR(max)). Subjectively and objectively determined (accelerometry) physical activity and sedentary behavior were assessed to examine the association between these free-living behaviors and cognitive function. The study duration was August 26, 2013, to September 11, 2014. RESULTS: Concentration-related cognition (mean +/- SD Feature Match test score) was significantly higher after a 30-minute acute bout of moderate-intensity exercise (145.1+/-26.9) compared with cognitive assessment without exercise (121.3+/-19.2; P=.004). Furthermore, questionnaire determined sedentary behavior was inversely associated with visual attention and task switching (Trail Making Test A score) (beta=-0.23; P=.04). Last, estimated cardiorespiratory fitness (volume of maximum oxygen consumption) was positively associated with reasoning-related cognitive function (Odd One Out test score) (beta=0.49; P=.05); when adding metabolic equivalent of task minutes per week to this model, the results were not significant (beta=0.47; P=.07). CONCLUSION: These findings provide some support for acute moderate-intensity exercise, sedentary behavior, and cardiorespiratory fitness being associated with executive functioning-related cognitive function in young, healthy adults. PMID- 25746400 TI - [An unusual cause of headache]. PMID- 25746401 TI - Anxiolytic Effects of Royal Sun Medicinal Mushroom, Agaricus brasiliensis (Higher Basidiomycetes) on Ischemia-Induced Anxiety in Rats. AB - We investigated the anxiolytic effects Agaricus brasiliensis extract (AbSE) on ischemia-induced anxiety using the plus-maze test and the social interaction test. The animals were treated orally with AbSE (4, 8, and 10 mg/kg/d, respectively) for 30 d, followed by middle cerebral artery occlusion-induced cerebral ischemia. Levels of noradrenaline, dopamine, and serotonin in the cerebral cortex of rats, as well as oxidative stress and plasma corticosterone levels were analyzed, respectively. The rota-rod test was carried out to exclude any false positive results in experimental procedures related to anxiety disorders, and the catalepsy test was carried out to investigate whether AbSE induces catalepsy. Our results demonstrate that oral administration of AbSE presented anxiolytic-like effects in the elevated plus-maze test and the social interaction test. Furthermore, AbSE did not induce extrapyramidal symptoms in the catalepsy test. The mechanism underlying the anxiolytic effect of AbSE might be increased brain monoamine levels and plasma corticosterone levels and decreased oxidative stress in cerebral ischemia/reperfusion rats. PMID- 25746402 TI - Effects of Selenium Presence in Mycelia of Ganoderma species (Higher Basidiomycetes) on Their Medicinal Properties. AB - This study aimed to research the antifungal, antioxidant, and cytotoxic potential of Ganoderma applanatum and Ganoderma lucidum mycelial extracts as well as the possible effect of Se enrichment on these activities. Both Se-enriched and nonenriched extracts of G. applanatum and G. lucidum showed fungi static activity, while a fungicidal effect was not noted. The extracts exhibited significant 1,1-diphenyl-2-picryl-hydrazil radical scavenging capacity, while the effect of Se on this potential was stimulatory in G. applanatum (1.3%-33.9% without Se and 3.1%-67.1% in Se enrichment) and inhibitory in G. lucidum (1.4% 71.6% and 1.3%-48.6% without and with Se, respectively). Only phenols in G. applanatum and phenols and flavonoids in G. lucidum were holders of antioxidant activity. Cytotoxic activity against both HeLa and LS174 cell lines was very low in comparison with cis-diamminedichloroplatinum. PMID- 25746403 TI - Antioxidant and Anti-Inflammatory Properties of Solid-State Fermented Products from a Medicinal Mushroom, Taiwanofungus salmoneus (Higher Basidiomycetes) from Taiwan. AB - Cooked grains of buckwheat (TSFB), oats (TSFO), embryo rice (TSFR), or wheat (TSFW) were inoculated with the medicinal fungus Taiwanofungus salmoneus (=Antrodia salmonea), and the metabolites formed were evaluated for antioxidant activity using the conjugated diene method, reducing power, scavenging ability, and chelating ability. Overall, the effectiveness was generally in the descending order of TSFB >= TSFO > TSFR >= TSFW. The correlation between effective concentration (EC50) of antioxidant property and antioxidant component content measured was established. However, flavonoid contents correlated well with antioxidant properties assayed (r = 0.707-0.933). Fermented products contained substantial amounts of adenosine (34.7-73.8 ug/g), ergosterol (1070-1212 ug/g), ergothioneine (81.0-119.8 ug/g), gamma-aminobutyric acid (100.9-170.2 ug/g), and lovastatin (3.06-5.60 ug/g). In addition, with the addition of the extracts from fermented products, lipopolysaccharide-induced nitric oxide, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 production in RAW 264.7 murine macrophage cells could be effectively suppressed. Accordingly, four types of T. salmoneus fermented products could be beneficially used as food-flavoring materials and food ingredients or as nutritional supplements. PMID- 25746404 TI - Nutritional Composition and Bioactive Constituents of Artificial Culture of Ophiocordyceps longissima (Ascomycetes). AB - In this study, the compositions of Ophiocordyceps longissima mycelia, synnemata, and fruiting bodies were first analyzed in order to clarify its chemical basis for development as a health food or medicine. We found that the contents of crude protein, polysaccharides, and macroelements were highest in mycelia, whereas effective components, including mannitol, ergosterol, adenosine, inosine, Zn, and Se, were lowest in mycelia. Polysaccharide, mannitol, and ergosterol levels in synnemata (2.33, 4.54, and 0.66 g/100 g, respectively) were similar to those in fruiting bodies, but was significantly different from those of mycelia (4.79, 1.77, and 0.43 g/100 g). Trehalose content in fruiting bodies (2.15 g/100 g) was >4 times higher than that in synnemata (0.5 g/100 g). Adenosine content in fruiting bodies (0.024 g/100 g) was 3-4 times higher than that of synnemata, whereas inosine, cytosine, guanosine, and uridine (0.093, 0.145, 0.053, and 0.073 g/100 g) were highest in synnemata. Cu and Se were lower in mycelia (3.30 * 10-4 and 3.1 * 10-5 g/100 g) than in synnemata (1.85 * 10-3 and 7.2 * 10-5 g/100 g) and fruiting bodies (1.67 * 10-3 and 4.3 * 10-5 g/100 g). As, Hg, Cd, and Pb in mycelia were under the limit of edible fungus health standard; Pb was not found, but Cd, Hg, and As were detected in fruiting bodies. These findings suggest that O. longissima could be utilized in different culture methods according to market demand and might be a possible health food or medicinal resource. PMID- 25746405 TI - Nutritional Composition of Three Domesticated Culinary-Medicinal Mushrooms: Oudemansiella sudmusida, Lentinus squarrosulus, and Tremella aurantialba. AB - The nutritional composition of three recently domesticated culinary-medicinal mushroom species (Oudemansiella sudmusida, Lentinus squarrosulus, and Tremella aurantialba) was evaluated for contents of protein, fiber, fat, total sugar content, amino acid, carbohydrate, and nucleotide components. The data indicated that fruiting bodies of these three mushroom species contained abundant nutritional substances. The protein contents of L. squarrosulus and O. submucida were 26.32% and 14.70%, which could be comparable to other commercially cultivated species. T. aurantialba contained 74.11% of carbohydrate, of which soluble polysaccharide was 40.55%. Oudemansiella sudmusida contained 15.95% of arabitol as the highest sugar alcohol in three mushrooms. These mushrooms also possessed distinct taste by their flavor component composition. Among them, L. squarrosulus contained 10.68% and 9.25% of monosodium glutamate-like and sweet amino acids, which were higher than the other two mushrooms. However, the nucleotide amounts of the three mushrooms were all lower than those of other commercially cultivated mushrooms. Among them, L. squarrosulus contained the highest amount of flavor nucleotides, which was 1.010/00. Results revealed that these three mushroom species are potentially suitable resources for commercial cultivation and healthy food. PMID- 25746406 TI - Isolation of the Entomopathogenic Fungal Strain Cod-MK1201 from a Cicada Nymph and Assessment of Its Antibacterial Activities. AB - The entomopathogenic fungus Cod-MK1201 was isolated from a dead cicada nymph. Three regions of ribosomal nuclear DNA, the internal transcribed spacers of nuclear ribosomal DNA repeats (ITS), the partial small subunit of rDNA (nrSSU) , and the partial large subunit of rDNA (nrLSU), and two protein-coding regions, the elongation factor 1alpha (EF-1alpha), and the largest subunit of the RNA polymerase II (rpb1) gene, were sequenced and used for fungal identification. The phylogenetic analysis of the ITS and the combined data set of the five genes indicated that the fungal isolate Cod-MK1201 is a new strain of Cordyceps sp. that is closely related to Cordyceps nipponica and C. kanzashiana. Crude extracts of mycelium-cultured Cod-MK1201 were obtained using distilled water and 50% (v/v) ethanol, and the antibacterial activity of each was determined. Both extracts had activity against Gram-positive and Gram-negative bacteria, but the ethanol extract was the more potent of the two. The antibacterial activity of the protein fractions of these extracts was also determined. The protein fraction from the ethanol extract was more antibacterial than the protein fraction from the aqueous extract. Three antibacterial constituents including adenosine, the total phenolic content (TPC), and the total flavonoid content (TFC) was also determined. The results showed that the adenosine content, the TPC, and the TFC of the ethanol extract were more active than those of the aqueous extract. Moreover, synergism was detected between these antibacterial constituents. In conclusion, the entomopathogenic fungal isolate Cod-MK1201 represents a natural source of antibacterial agents. PMID- 25746407 TI - Submerged Culture of Grifola gargal and G. sordulenta (Higher Basidiomycetes) from Argentina as a Source of Mycelia with Antioxidant Activity. AB - Submerged culture is an alternative mycelium source for Grifola gargal and G. sordulenta, two rare edible mushrooms related to Grifola frondosa. This work studies their mycelia as a source of antioxidants. The efficient concentrations of methanolic extracts in both radical scavenging (RS) and reducing power (RP) abilities in G. gargal and in G. sordulenta showed a high antioxidant activity. In the experimental design used, the antioxidant activity mainly depended on the culture conditions rather than on the media composition. Irrespective of the basal culture medium, mycelium methanolic extracts of G. sordulenta obtained from culture in Erlenmeyer flasks showed equivalents to ascorbic acid (EQ(AA)) RS EQ(AA) and RP-EQ(AA) contents higher than the corresponding values obtained with jar cultures. Under stationary cultivation, G. sordulenta produced approximately 50% higher content in both RS-EQ(AA) and RP-EQ(AA) than the medicinal mushroom G. frondosa. Phenolics correlated with RS-EQ(AA) and RP-EQ(AA) in G. gargal and with RP-EQ(AA) in G. sordulenta; besides, thin-layer chromatography showed these compounds to be at least in part related to the RS capacity. It is concluded that G. gargal and G. sordulenta mycelia are excellent sources of antioxidant metabolites. PMID- 25746408 TI - Shiitake Medicinal Mushroom, Lentinus edodes (Higher Basidiomycetes) Productivity and Lignocellulolytic Enzyme Profiles during Wheat Straw and Tree Leaf Bioconversion. AB - Two commercial strains of Lentinus edodes have been comparatively evaluated for their productivity and lignocellulolytic enzyme profiles in mushroom cultivation using wheat straw or tree leaves as the growth substrates. Both substrates are profitable for recycling into shiitake fruit bodies. L. edodes 3715 gave the lowest yield of mushroom during tree leaves bioconversion with the biological efficiency (BE) 74.8% while the L. edodes 3721 BE achieved 83.4%. Cultivation of shiitake on wheat straw, especially in the presence of additional nitrogen source, increased the L. edodes 3721 BE to 92-95.3% owing to the high hydrolases activity and favorable conditions. Despite the quantitative variations, each strain of L. edodes had a similar pattern for secreting enzymes into the wheat straw and tree leaves. The mushrooms laccase and MnP activities were high during substrate colonization and declined rapidly during primordia appearance and fruit body development. While oxidase activity decreased, during the same period cellulases and xylanase activity raised sharply. Both cellulase and xylanase activity peaked at the mature fruit body stage. When mushrooms again shifted to the vegetative growth, oxidase activity gradually increased, whereas the hydrolases activity dropped rapidly. The MnP, CMCase, and FP activities of L. edodes 3721 during cultivation on wheat straw were higher than those during mushroom growth on tree leaves whereas the laccase activity was rather higher in fermentation of tree leaves. Enrichment of wheat straw with an additional nitrogen source rather favored to laccase, MnP, and FPA secretion during the vegetative stage of the L. edodes 3721 growth. PMID- 25746409 TI - Enhancement of Shelf Life of Button Mushroom, Agaricus bisporus (Higher Basidiomycetes) by Fumigant Application of Lippia alba Essential Oil. AB - Eleven essential oils isolated from higher plant species were assessed against the four isolates of Verticillium fungicola found on fruiting bodies of Agaricus bisporus. Eucalyptus citriodora and Lippia alba oils were more efficacious and completely inhibited the mycelial growth of fungal isolates. L. alba oil was fungistatic and fungicidal at 10- and 20-uL concentrations against all of the isolates, respectively, and was more potent than E. citriodora oil as well as some prevalent synthetic fungicides such as benomyl, ethylene dibromide, and phosphine. Eighty microliters of L. alba oil protected 500 g of fruiting bodies of A. bisporus for up to 7 d from infection of the fungus under in vivo conditions. The findings strengthen the possibility of L. alba oil as a plant based protectant to enhance the shelf life of A. bisporus fruiting bodies. PMID- 25746410 TI - Association of older paternal age with earlier onset among co-affected schizophrenia sib-pairs. AB - BACKGROUND: Advanced paternal age is associated with increased risk of schizophrenia. This study aimed to explore whether older paternal age is associated with earlier onset among co-affected schizophrenia sib-pairs with the same familial predisposition. METHOD: A total of 1297 patients with schizophrenia from 630 families, which were ascertained to have at least two siblings affected, throughout Taiwan were interviewed using the Diagnostic Interview for Genetic Studies. Both inter-family comparisons, a hierarchical regression model allowing for familial dependence and adjusting for confounders, and within-family comparisons, examining the consistency between onset order and birth order, were performed. RESULTS: An inverted U shape was observed between paternal age and onset of schizophrenia. Affected offspring with paternal age of 20-24 years had the oldest onset. As paternal age increased over 25 years, older paternal age exhibited a linear decrease in the onset of schizophrenia. On average, the onset was lowered by 1.5 years for paternal age of 25-29 years and by 5.5 years for paternal age ?50 years (p = 0.04; trend test). The proportion of younger siblings with earlier onset (58%) was larger than that of older siblings with earlier onset (42%) (p = 0.0002). CONCLUSIONS: These findings indicate that paternal age older than 25 years and younger than 20 years were both associated with earlier onset among familial schizophrenia cases. The associations of advanced paternal age with both increased susceptibility to schizophrenia and earlier onset of schizophrenia are consistent with the rate of increases in spontaneous mutations in sperm as men age. PMID- 25746411 TI - Insights into carbon nanotube and graphene formation mechanisms from molecular simulations: a review. AB - The discovery of carbon nanotubes (CNTs) and graphene over the last two decades has heralded a new era in physics, chemistry and nanotechnology. During this time, intense efforts have been made towards understanding the atomic-scale mechanisms by which these remarkable nanostructures grow. Molecular simulations have made significant contributions in this regard; indeed, they are responsible for many of the key discoveries and advancements towards this goal. Here we review molecular simulations of CNT and graphene growth, and in doing so we highlight the many invaluable insights gained from molecular simulations into these complex nanoscale self-assembly processes. This review highlights an often overlooked aspect of CNT and graphene formation-that the two processes, although seldom discussed in the same terms, are in fact remarkably similar. Both can be viewed as a 0D -> 1D -> 2D transformation, which converts carbon atoms (0D) to polyyne chains (1D) to a complete sp(2)-carbon network (2D). The difference in the final structure (CNT or graphene) is determined only by the curvature of the catalyst and the strength of the carbon-metal interaction. We conclude our review by summarizing the present shortcomings of CNT/graphene growth simulations, and future challenges to this important area. PMID- 25746413 TI - Template engaged synthesis of hollow ceria-based composites. AB - Hollow ceria-based composites, which consist of noble metal nanoparticles or metal oxides as a secondary component, are being studied extensively for potential applications in heterogeneous catalysis. This is due to their unique features, which exhibit the advantages of a hollow structure (e.g. high surface area and low weight), and also integrate the properties of ceria and noble metals/metal oxides. More importantly, the synergistic effect between constituents in hollow ceria-based composites has been demonstrated in various catalytic reactions. In this feature article, we summarize the state-of-the-art in the synthesis of hollow ceria-based composites, including traditional hard templates and more recently, sacrificial-template engaged strategies, highlighting the key role of selected templates in the formation of hollow composites. In addition, the catalytic applications of hollow ceria-based composites are briefly surveyed. Finally, challenges and perspectives on future advances of hollow ceria-based composites are outlined. PMID- 25746414 TI - Chronic wound infections: the role of Pseudomonas aeruginosa and Staphylococcus aureus. AB - Chronic leg ulcers affect 1-2% of the general population and are related to increased morbidity and health costs. Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacteria isolated from chronic wounds. They can express virulence factors and surface proteins affecting wound healing. The co infection of S. aureus and P. aeruginosa is more virulent than single infection. In particular, S. aureus and P. aeruginosa have both intrinsic and acquired antibiotic resistance, making clinical management of infection a real challenge, particularly in patients with comorbidity. Therefore, a correct and prompt diagnosis of chronic wound infection requires a detailed knowledge of skin bacterial flora. This is a necessary prerequisite for tailored pharmacological treatment, improving symptoms, and reducing side effects and antibiotic resistance. PMID- 25746415 TI - Genetic characterization of South American infectious bursal disease virus reveals the existence of a distinct worldwide-spread genetic lineage. AB - Infectious bursal disease virus (IBDV) is one of the most concerning health problems for world poultry production. IBDVs comprise four well-defined evolutionary lineages known as classic (c), classic attenuated (ca), variant (va) and very virulent (vv) strains. Here, we characterized IBDVs from South America by the genetic analysis of both segments of the viral genome. Viruses belonging to c, ca and vv strains were unambiguously classified by the presence of molecular markers and phylogenetic analysis of the hypervariable region of the vp2 gene. Notably, the majority of the characterized viruses (9 out of 15) could not be accurately assigned to any of the previously described strains and were then denoted as distinct (d) IBDVs. These dIBDVs constitute an independent evolutionary lineage that also comprises field IBDVs from America, Europe and Asia. The hypervariable VP2 sequence of dIBDVs has a unique and conserved molecular signature (272T, 289P, 290I and 296F) that is a diagnostic character for classification. A discriminant analysis of principal components (DAPC) also identified the dIBDVs as a cluster of genetically related viruses separated from the typical strains. DAPC and genetic distance estimation indicated that the dIBDVs are one of the most genetically divergent IBDV lineages. The vp1 gene of the dIBDVs has non-vvIBDV markers and unique nucleotide and amino acid features that support their divergence in both genomic segments. The present study suggests that the dIBDVs comprise a neglected, highly divergent lineage that has been circulating in world poultry production since the early time of IBDV emergence. PMID- 25746416 TI - Highly stereoselective ruthenium(II)-catalyzed direct C2-syn-alkenylation of indoles with alkynes. AB - A carboamide-directed ruthenium-catalyzed C2-hydroindolation of alkynes has been described. This transformation provides a rapid access to free (N-H) C2-syn alkenylated indole derivatives with the assistance of copper(II) salts, in which the directing group is removed via a one-pot process. PMID- 25746417 TI - [Burden of mortality due to diabetes mellitus in Latin America 2000-2011: the case of Argentina, Chile, Colombia, and Mexico.] AB - OBJECTIVE: To analyze trends in mortality in Argentina, Chile, Colombia and Mexico, between 2000 and 2011, by sex and 5-year age groups (between 20 and 79 years of age). MATERIAL AND METHODS: Mortality vital statistics and census data or projected population estimates were used for each country. Age-specific mortality rates and the years of life lost were calculated. RESULTS: Among the countries analyzed, Mexico had the highest mortality rate and lost the most years of life due to diabetes. Between 2000 and 2011, Mexicans lost an average of 1.13 years of life, while Colombia (0.24), Argentina (0.21) and Chile (0.18) lost considerably fewer life years. In general, deaths from diabetes were higher in men than in women except in Colombia. Nearly 80% of years of life lost due to diabetes occurred between 50 and 74 years of age in the four countries. DISCUSSION: Diabetes is a huge challenge for Latin America, especially in Mexico where mortality due to diabetes is accelerating. Even though the proportion of deaths due to diabetes in Argentina, Chile and Colombia is smaller, this disease figures among the main causes of death in these countries. PMID- 25746418 TI - Toxocariasis diagnosed in international travelers at the Institute of Tropical Medicine, Antwerp, Belgium, from 2000 to 2013. AB - Although infection with Toxocara canis or T. catis (commonly referred as toxocariasis) appears to be highly prevalent in (sub)tropical countries, information on its frequency and presentation in returning travelers and migrants is scarce. In this study, we reviewed all cases of asymptomatic and symptomatic toxocariasis diagnosed during post-travel consultations at the reference travel clinic of the Institute of Tropical Medicine, Antwerp, Belgium. Toxocariasis was considered as highly probable if serum Toxocara-antibodies were detected in combination with symptoms of visceral larva migrans if present, elevated eosinophil count in blood or other relevant fluid and reasonable exclusion of alternative diagnosis, or definitive in case of documented seroconversion. From 2000 to 2013, 190 travelers showed Toxocara-antibodies, of a total of 3436 for whom the test was requested (5.5%). Toxocariasis was diagnosed in 28 cases (23 symptomatic and 5 asymptomatic) including 21 highly probable and 7 definitive. All but one patients were adults. Africa and Asia were the place of acquisition for 10 and 9 cases, respectively. Twelve patients (43%) were short-term travelers (< 1 month). Symptoms, when present, developed during travel or within 8 weeks maximum after return, and included abdominal complaints (11/23 symptomatic patients, 48%), respiratory symptoms and skin abnormalities (10 each, 43%) and fever (9, 39%), often in combination. Two patients were diagnosed with transverse myelitis. At presentation, the median blood eosinophil count was 1720/MUL [range: 510-14160] in the 21 symptomatic cases without neurological complication and 2080/MUL [range: 1100-2970] in the 5 asymptomatic individuals. All patients recovered either spontaneously or with an anti-helminthic treatment (mostly a 5 day course of albendazole), except both neurological cases who kept sequelae despite repeated treatments and prolonged corticotherapy. Toxocariasis has to be considered in travelers returning from a (sub)tropical stay with varying clinical manifestations or eosinophilia. Prognosis appears favorable with adequate treatment except in case of neurological involvement. PMID- 25746419 TI - Properties of the liquid-vapor interface of acetone-methanol mixtures, as seen from computer simulation and ITIM surface analysis. AB - Molecular dynamics simulations of the liquid-vapor interface of acetone-methanol mixtures of different compositions, including the two neat systems, have been performed on the canonical (N,V,T) ensemble at 293 K. The intrinsic liquid surface has been determined in terms of the Identification of the Truly Interfacial Molecules (ITIM) method. The results have revealed that the proximity of the interface influences the properties of only the first molecular layer of the liquid phase, while the second layer already turns out to be bulk-like in every respect. The two molecules are distributed uniformly along the macroscopic surface normal axis, as no strong preference for surface adsorption is shown by any of them. However, similarly to the bulk liquid phase, both molecules exhibit a marked tendency for self-association within the surface layer. Surface orientations are found to be composition independent; all the preferred orientations of both molecules correspond to the same alignment of the molecular dipole vector, which is nearly parallel to the macroscopic surface plane, declining only 10-20 degrees from it towards the vapor phase. The surface properties are thus primarily governed by dipolar interactions, whereas hydrogen bonding within the surface layer, which decreases steadily with an increase in the acetone mole fraction, plays only a minor role in this respect. PMID- 25746421 TI - Activation of histamine H3 receptor decreased cytoplasmic Ca(2+) imaging during electrical stimulation in the skeletal myotubes. AB - Histamine is a neurotransmitter and chemical mediator in multiple physiological processes. Histamine H3 receptor is expressed in the nervous system, heart, and gastrointestinal tract; however, little is known about H3 receptor in skeletal muscle. The aim of this study was to investigate the role of H3 receptor in skeletal myotubes. The expression of H3 receptor and myosin heavy chain (MHC), a late myogenesis marker, was assessed by real-time PCR and immunostaining in C2C12 skeletal myogenesis and adult mid-urethral skeletal muscle tissues. H3 receptor mRNA showed a significant increase upon differentiation of C2C12 into myotubes: 1 , 26-, 91-, and 182-fold at days 0, 2, 4, and 6, respectively. H3 receptor immunostaining in differentiated C2C12 cells and adult skeletal muscles was positive and correlated with that of MHC. The functional role of H3receptor in differentiated myotubes was assessed using an H3 receptor agonist, (R)-a methylhistamine ((R)-alpha-MeHA). Ca(2+) imaging, stimulated by electric pacing, was decreased by 55% after the treatment of mature C2C12 myotubes with 1MUM (R) alpha-MeHA for 10min and 20min, while treatment with 100nm (R)-alpha-MeHA for 5min caused 45% inhibition. These results suggested that H3 receptor may participate in the maintenance of the relaxed state and prevention of over contraction in mature differentiated myotubes. The elucidation of the role of H3R in skeletal myogenesis and adult skeletal muscle may open a new direction in the treatment of skeletal muscle disorders, such as muscle weakness, atrophy, and myotonia in motion systems or peri-urethral skeletal muscle tissues. PMID- 25746420 TI - Effect of dietary iron loading on recognition memory in growing rats. AB - While nutritional and neurobehavioral problems are associated with both iron deficiency during growth and overload in the elderly, the effect of iron loading in growing ages on neurobehavioral performance has not been fully explored. To characterize the role of dietary iron loading in memory function in the young, weanling rats were fed iron-loading diet (10,000 mg iron/kg diet) or iron adequate control diet (50 mg/kg) for one month, during which a battery of behavioral tests were conducted. Iron-loaded rats displayed elevated non-heme iron levels in serum and liver, indicating a condition of systemic iron overload. In the brain, non-heme iron was elevated in the prefrontal cortex of iron-loaded rats compared with controls, whereas there was no difference in iron content in other brain regions between the two diet groups. While iron loading did not alter motor coordination or anxiety-like behavior, iron-loaded rats exhibited a better recognition memory, as represented by an increased novel object recognition index (22% increase from the reference value) than control rats (12% increase; P=0.047). Western blot analysis showed an up-regulation of dopamine receptor 1 in the prefrontal cortex from iron-loaded rats (142% increase; P=0.002). Furthermore, levels of glutamate receptors (both NMDA and AMPA) and nicotinic acetylcholine receptor (nAChR) were significantly elevated in the prefrontal cortex of iron-loaded rats (62% increase in NR1; 70% increase in Glu1A; 115% increase in nAChR). Dietary iron loading also increased the expression of NMDA receptors and nAChR in the hippocampus. These results support the idea that iron is essential for learning and memory and further reveal that iron supplementation during developmental and rapidly growing periods of life improves memory performance. Our investigation also demonstrates that both cholinergic and glutamatergic neurotransmission pathways are regulated by dietary iron and provides a molecular basis for the role of iron loading in improved memory. PMID- 25746422 TI - Phloretin ameliorates arsenic trioxide induced mitochondrial dysfunction in H9c2 cardiomyoblasts mediated via alterations in membrane permeability and ETC complexes. AB - Arsenic trioxide (ATO), though a very effective drug for the treatment of acute promyelocytic leukemia, leads to cardiotoxicity. As mitochondria are the center of attention of cardiac cell's general metabolic status, it is primarily important to see the interaction of ATO with mitochondria. Studies related exclusively to the alterations in mitochondria and its associated functions caused by ATO are very limited. The present investigation aims to explore the effect of ATO on various components of electron transport chain, oxygen consumption, ATP production, mitochondrial superoxide generation, transmembrane potential, permeability pore opening, calcium homeostasis and apoptosis. Attempts were also made to see the efficacy of phloretin, a potent antioxidant flavonoid found majorly in apple peel on cardiotoxicity. The H9c2 cells exposed to ATO (5uM) exhibited increased oxidative stress with reduced innate antioxidant status, mitochondrial dysfunctions and apoptosis. It increased the intracellular calcium content, caused alterations in the activity of transcription factor Nrf2, xanthine oxidase, aconitase and caspase 3 compared to the control group. Phloretin at 2.5 and 5uM concentrations were able to protect the cells from ATO toxicity via protecting mitochondria through its antioxidant potential. The present investigation based on mitochondria reveals the probability of cardioprotective potential of phloretin for the cancer patients on ATO chemotherapy. PMID- 25746423 TI - Berberine inhibits Chlamydia pneumoniae infection-induced vascular smooth muscle cell migration through downregulating MMP3 and MMP9 via PI3K. AB - The mechanisms by which Chlamydia pneumoniae infection promote vascular smooth muscle cell (VSMC) migration required in the development of atherosclerosis have not yet been fully clarified. Matrix metalloproteinases (MMPs) have important roles in VSMC migration. However, it is still unknown whether MMPs are involved in C. pneumoniae infection-induced VSMC migration. In addition, whether berberine can exert its inhibitory effects on the infection-induced VSMC migration also remains unclear. Accordingly, we investigated the effects of berberine on C. pneumoniae infection-induced VSMC migration and explored the possible mechanisms involved in this process. Herein, we found that C. pneumoniae infection could induce VSMC migration through Matrigel-coated membrane (P<0.05), which can be significantly inhibited by the broad-spectrum MMP inhibitor GM6001 (P<0.05). Our results also showed that C. pneumoniae infection upregulated both mRNA and protein expressions of MMP3 and MMP9 (P<0.05). The specific phosphoinositide 3 kinase (PI3K) inhibitor LY294002 significantly suppressed the increases in MMP3 and MMP9 protein expressions induced by C. pneumoniae infection (P<0.05). Further experiments showed that berberine significantly attenuated C. pneumoniae infection-induced VSMC migration (P<0.05). Moreover, berberine suppressed the protein expressions of MMP3 and MMP9 caused by C. pneumoniae infection in a dose dependent manner (P<0.05). C. pneumoniae infection-induced increase in the phosphorylation level of Akt at Ser473 was inhibited by the treatment with berberine (P<0.05). Taken together, our data suggest that berberine inhibits C. pneumoniae infection-induced VSMC migration by downregulating the expressions of MMP3 and MMP9 via PI3K. PMID- 25746424 TI - Spontaneous coronary artery dissection in puerperium. AB - Spontaneous coronary artery dissection in puerperium is uncommon and most often occurs in the third trimester of pregnancy and in the early postpartum period. Two weeks after delivery, a 41-year-old woman presented with typical retrosternal chest pain and inverted T-waves in leads II, V5 and V6, and Q-waves in aVR. Her peak troponin I level was 16.39 ugcL(-1) Coronary angiography showed left main spiral dissection extending to the mid left anterior descending artery and involving the first diagonal branch. Urgent coronary artery bypass grafting was performed successfully. The mechanism and approach are discussed. PMID- 25746425 TI - A rat model of aortic arch aneurysm with excellent survival. AB - BACKGROUND: The complex mechanisms of aortic arch aneurysm have not been well studied. An animal model of aortic arch aneurysm would be beneficial to study this fatal disease. In this study, we tried to establish a rat model of aortic arch aneurysm by constricting the aortic isthmus. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into three groups. Rats with no aortic isthmus constriction were assigned to group A (control group). The aortic isthmus was constricted to 1.5 mm in group B and to 0.8 mm in group C. The blood pressure of the rats was measured at 0, 1, 3 and 6 months after the operation. The diameter and wall thickness of aortic arch were measured at 3 and 6 months after surgery. RESULTS: Compared to group A, group B showed no significant increase in blood pressure or aortic diameter after the operation. Compared to the control group, group B showed a marked increase in wall thickness at 3 and 6 months after surgery (p < 0.05). Compared to group A, group C showed significant increases in both blood pressure (p < 0.05) and aortic diameter (p < 0.05) after the operation. Group C also showed a more than 50% increase in wall thickness at 3 and 6 months after surgery (P < 0.05). CONCLUSIONS: By constricting the aortic isthmus to 0.8 mm, a rat model of aortic arch aneurysm could be induced at 3 and 6 months after surgery. PMID- 25746426 TI - A simple method for proximal anastomoses marking during CABG for future coronary angiography. AB - Evaluation of aortic proximal anastomoses in patients who have undergone coronary artery bypass surgery poses a special challenge to the interventional cardiologist during follow-up angiography procedures. We present a simple, safe, and fast technique for proximal anastomoses marking using hemostatic clips. Successful visualization of the graft marker was achieved using medium-sized hemoclips during fluoroscopy. The use of hemoclips for this procedure proved to be straightforward and required no additional surgical training. PMID- 25746427 TI - Shelf-life Assessment of Food Undergoing Oxidation-A Review. AB - Oxidation is the most common event leading to the end of shelf life of microbiologically stable foods. Thus, a reliable shelf-life assessment is crucial to verify how long the product will last before it becomes oxidized to an unacceptable level to the consumers. Shelf-life assessment strategies of foods and beverages suffering oxidation are critically discussed focusing on definition of the acceptability limit, as well as the choice of the proper oxidative indicators, and methodologies for shelf-life testing. Testing methodologies for shelf-life determination under actual and accelerated storage conditions are considered, highlighting possible uncertainties, pitfalls, and future research needs. PMID- 25746428 TI - A huge thrombosed pulmonary artery aneurysm without pulmonary hypertension in a patient with hepatosplenic schistosomiasis. AB - BACKGROUND: We herein report a case of huge pulmonary artery aneurysm in a 55 year-old male farmer from the Nile delta (Lower-Egypt), mostly due to infestation with Schistosoma mansoni, which is the parasite causing hepatosplenic schistosomiasis. CASE REPORT: This male patient was admitted with a month-long history of progressive shortness of breath, 2-month history of fever, and a cough with mucoid sputum for 10 days. On examination, he had normal temperature and blood pressure, but he had tachypnea, tachycardia, and congested neck veins. Electrocardiography showed multifocal atrial tachycardia and right bundle branch block. CONCLUSIONS: The present case is unique in that it shows the presence of a huge pulmonary artery aneurysm despite the absence of pulmonary hypertension. PMID- 25746429 TI - Increasing Child Fruit and Vegetable Intake: Findings from the US Department of Agriculture Fresh Fruit and Vegetable Program. AB - BACKGROUND: Fewer than 10% of US children and adolescents consume the recommended amounts of fruits and vegetables (F/V). The US Department of Agriculture's Fresh Fruit and Vegetable Program (FFVP) is intended to increase child F/V consumption by funding low-income schools to distribute free fresh F/V snacks outside of school mealtimes. OBJECTIVE: The evaluation assessed FFVP effects on student F/V consumption and total energy intake in and out of school. DESIGN: The evaluation employed a regression discontinuity design; that is, cross-sectional comparisons of a sample of students in schools just above and just below the FFVP funding cutoff for the program, which depended on the proportion of students eligible for free or reduced-price meals. During the 2010-2011 school year within a randomly selected sample of states, we selected schools in closest proximity to each state specific FFVP funding cutoff. Interviewers conducted 24-hour diary-assisted recall interviews to assess dietary intake among children in selected schools. PARTICIPANTS/SETTING: Participants were 4,696 students (grades 4 to 6) from 214 elementary schools in 16 randomly selected states. STATISTICAL ANALYSES PERFORMED: Analysis proceeded via multivariate regression, comparing adjusted mean student intake in schools just above and just below the funding cutoff. RESULTS: Adjusted mean daily F/V intake was one-third of a cup per day higher in FFVP-participating schools than in nonparticipating schools (0.32 cups per day; P<0.001), a difference of 15.5%. This included one-quarter cup higher daily F/V intake during school hours (0.26 cups; P<0.001) among students attending FFVP participating schools. Fresh (but not total) F/V consumption also increased outside of school. CONCLUSIONS: The FFVP increases child fresh and total F/V intake in school, and fresh F/V intake outside of school. PMID- 25746431 TI - [Gayet-Wernicke encephalopathy: A rare complication of prolonged parenteral nutrition]. PMID- 25746432 TI - Update on rehabilitation in multiple sclerosis. AB - Given that mobility impairment is a hallmark of multiple sclerosis, people with this disease are likely to benefit from rehabilitation therapy throughout the course of their illness. The review provides an update on rehabilitation focused on balance and walking impairment. Classical rehabilitation focusing on muscle rehabilitation, neurotherapeutic facilitation is effective and recommended. Other techniques did not prove their superiority: transcutaneal neurostimulation, repetitive magnetic stimulation, electromagnetic therapy, whole body vibration and robot-assisted gait rehabilitation and need more studies to conclude. Cooling therapy, hydrotherapy, orthoses and textured insoles could represent a complementary service to other techniques in specific conditions. Multidisciplinary rehabilitation program provides positive effects and high satisfaction for patients with multiple sclerosis but needs more evaluation. New technologies using serious game and telerehabilitation seem to be an interesting technique to promote physical activity, self-management and quality of life. Rehabilitation like other therapy needs regular clinical evaluation to adapt the program and propose appropriate techniques. Moreover, the objective of rehabilitation needs to be decided with the patient with realistic expectation. PMID- 25746433 TI - [Eagle's syndrome]. PMID- 25746434 TI - [Hospital innovation and organization]. PMID- 25746430 TI - Inflammation: a culprit for vascular calcification in atherosclerosis and diabetes. AB - It is today acknowledged that aging is associated with a low-grade chronic inflammatory status, and that inflammation exacerbates age-related diseases such as osteoporosis, Alzheimer's disease, atherosclerosis and type 2 diabetes mellitus (T2DM). Vascular calcification is a complication that also occurs during aging, in particular in association with atherosclerosis and T2DM. Recent studies provided compelling evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. In the present review, we propose on one hand to highlight the most important and recent findings on the cellular and molecular mechanisms of vascular inflammation in atherosclerosis and T2DM. On the other hand, we will present the effects of inflammatory mediators on the trans-differentiation of vascular smooth muscle cell and on the deposition of crystals. Since vascular calcification significantly impacts morbidity and mortality in affected individuals, a better understanding of its induction and development will pave the way to develop new therapeutic strategies. PMID- 25746435 TI - p21(WAF1/CIP1) RNA expression in highly HIV-1 exposed, uninfected individuals. AB - Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Delta32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1. PMID- 25746436 TI - Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: A case series. AB - OBJECTIVE: Obtaining a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) can decrease hepatic complications and be curative, however, extrahepatic manifestations including mixed cryoglobulinemia (MCN) may persist with interferon-based therapy. Our objective was to review our experience in treating patients with new oral antiviral agents and to assess common factors associated with MCN persistence despite SVR. METHODS: We analyzed a case series of five patients with genotype one chronic HCV complicated by MCN who had persistence of cryoglobulins despite completion of triple therapy with oral antiviral agents (boceprivir, telaprivir or sofosbuvir). RESULTS: Patients with cirrhosis appear to have a decreased ability to clear immune complexes. We observed that early viral response by week 8 of therapy and longer periods of undetectable virus on treatment correlated with eventual clearance of serum cryoglobulins in patients without cirrhosis. Two patients were treated with anti B-cell agent rituximab prior to starting therapy for HCV; this did not lead to a more effective clearance of cryoglobulins. CONCLUSIONS: We suggest that a longer treatment course than the standard 24 weeks with triple therapy could aid in the clearance of these immune complexes and cryoglobulins in cirrhotics. More studies to determine the ideal duration of treatment for chronic HCV and coincident MCN are needed, especially in light of the new all oral direct-acting antiviral regimens that are now recommended for HCV treatment. PMID- 25746437 TI - An accurate metalloprotein-specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy. AB - Metalloproteins, particularly zinc metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal-ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynamically sample and regenerate decoy poses used in each iteration step of refining the scoring function, thus dramatically improving both the effectiveness of the exploration of the binding conformational space and the sensitivity of the ranking of the native binding poses. To validate the zinc metalloprotein-specific scoring function and its special built-in docking program, denoted MpSDockZn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4Zn, and EADock DSS. The zinc metalloprotein-specific knowledge-based scoring function exhibited prominent performance in accurately describing the geometries and interactions of the coordination bonds between the zinc ions and chelating agents of the ligands. In addition, MpSDockZn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs. PMID- 25746438 TI - Relational learning in honeybees (Apis mellifera): Oddity and nonoddity discrimination. AB - Honeybee learning is surprisingly similar to vertebrate learning and one implication is that the basic associative learning principles are also similar. This research extends the work to more complex cognitive phenomena. Forager bees were trained individually to visit a laboratory window for sucrose. On each training trial for all experiments, bees found three stimuli, two identical and one different. In Experiments 1 and 2, stimuli were three-dimensional two-color patterns, and in Experiments 3 and 4, stimuli were two-color patterns displayed on a computer monitor. Training was trial-unique, that is, a different triad of stimuli was presented on each trial. In Experiments 1 and 3, choice of odd was rewarded and choice of nonodd was punished. In Experiments 2 and 4, choice of nonodd was rewarded and choice of odd was punished. On every trial, the initial choice was recorded and correction permitted. Honeybees learned to choose the odd stimulus in Experiments 1 and 3 and the nonodd stimuli in Experiments 2 and 4. The results provide compelling evidence of oddity and nonoddity learning, often interpreted as relational learning in vertebrates. Whether the mechanism of such learning in honeybees is similar to that of vertebrate species remains to be determined. PMID- 25746439 TI - Comments to the article "A systematic analysis of neonatal mouse heart regeneration after apical resection". PMID- 25746440 TI - Neutral poly-/perfluoroalkyl substances in air and snow from the Arctic. AB - Levels of neutral poly-/perfluoroalkyl substances (nPFASs) in air and snow collected from Ny-Alesund were measured and their air-snow exchange was determined to investigate whether they could re-volatilize into the atmosphere driven by means of air-snow exchange. The total concentration of 12 neutral PFASs ranged from 6.7 to 39 pg m(-3) in air and from 330 to 690 pg L(-1) in snow. A significant log-linear relationship was observed between the gas/particle partition coefficient and vapor pressure of the neutral PFASs. For fluorotelomer alcohol (FTOHs) and fluorotelomer acrylates (FTAs), the air-snow exchange fluxes were positive, indicating net evaporative from snow into air, while net deposition into snow was observed for perfluorooctane sulfonamidoethanols (Me/EtFOSEs) in winter and spring of 2012. The air-snow exchange was snow-phase controlled for FTOHs and FTAs, and controlled by the air-phase for FOSEs. Air snow exchange may significantly interfere with atmospheric concentrations of neutral PFASs in the Arctic. PMID- 25746441 TI - Double-inversion mechanisms of the X- + CH3Y [X,Y = F, Cl, Br, I] SN2 reactions. AB - The double-inversion and front-side attack transition states as well as the proton-abstraction channels of the X(-) + CH3Y [X,Y = F, Cl, Br, I] reactions are characterized by the explicitly correlated CCSD(T)-F12b/aug-cc-pVTZ(-PP) level of theory using small-core relativistic effective core potentials and the corresponding aug-cc-pVTZ-PP bases for Br and I. In the X = F case the double inversion classical(adiabatic) barrier heights are 28.7(25.6), 15.8(13.4), 13.2(11.0), and 8.6(6.6) kcal mol(-1) for Y = F, Cl, Br, and I, respectively, whereas the barrier heights are in the 40-90 kcal mol(-1) range for the other 12 reactions. The abstraction channels are always above the double-inversion saddle points. For X = F, the front-side attack classical(adiabatic) barrier heights, 45.8(44.8), 31.0(30.3), 24.7(24.2), and 19.5(19.3) kcal mol(-1) for Y = F, Cl, Br, and I, respectively, are higher than the corresponding double-inversion ones, whereas for the other systems the front-side attack saddle points are in the 35 70 kcal mol(-1) range. The double-inversion transition states have XH...CH2Y(-) structures with Cs point-group symmetry, and the front-side attack saddle points have either Cs (X = F or X = Y) or C1 symmetry with XCY angles in the 78-88 degrees range. On the basis of the previous reaction dynamics simulations and the minimum energy path computations along the inversion coordinate of selected XH...CH2Y(-) systems, we suggest that the double inversion may be a general mechanism for SN2 reactions. PMID- 25746442 TI - Palladium-catalyzed, ring-forming aromatic C-H alkylations with unactivated alkyl halides. AB - A catalytic C-H alkylation using unactivated alkyl halides and a variety of arenes and heteroarenes is described. This ring-forming process is successful with a variety of unactivated primary and secondary alkyl halides, including those with beta-hydrogens. In contrast to standard polar or radical cyclizations of aromatic systems, electronic activation of the substrate is not required. The mild, catalytic reaction conditions are highly functional group tolerant and facilitate access to a diverse range of synthetically and medicinally important carbocyclic and heterocyclic systems. PMID- 25746443 TI - Propargyl radical chemistry: renaissance instigated by metal coordination. AB - Over the last two decades, radical chemistry of propargyl systems was developed into a potent synthetic field providing access to classes of organic compounds that are otherwise hardly accessible. The levels of diastereoselection thus achieved (up to 100%) are unprecedented for free propargyl radicals, as well as for organic radicals pi-bonded to transition metals. These advances were enabled by the coordination of the triple bond to a Co2(CO)6 core that precluded an acetylene-allene rearrangement, stabilized requisite propargyl cations, created conformational constraints at the carbon-carbon bond formation site, configurationally altered the acetylenic moiety allowing for 1,3-steric induction upon the newly formed stereocenters, increased bulkiness of propargyl triads thus controlling the spatial orientation of converging radicals, and allowed for alpha to-gamma projection of the reaction site and alteration of the transiency of radical intermediates. In the course of these studies, a number of popular "beliefs" were proven to be untrue. First, cobalt-complexed propargyl cations, which have long been considered to be thermally labile species, were engaged in synthetically meaningful transformation at temperatures as high as 147 degrees C. Second, in radical dimerization reactions, higher reaction temperatures did not adversely impact the yields and levels of d,l-diastereoselectivity. Third, pi bonded organometallic radicals, deemed unruly, were effectively controlled with complementary mechanistic tools, thus achieving the highest levels of stereoselectivity (up to 100%) in inter- and intramolecular reactions. Fourth, meso stereoisomers, being thermally labile and kinetically disfavored, were discovered to be major products in intramolecular cyclizations induced by cobaltocene. Fifth, propargyl cations were synthesized in the absence of strong acids, thus increasing the functional tolerance and achieving a long sought after compatibility with acid-sensitive functionalities. A concept of sequestered propargyl radicals was introduced to explain disparity in diastereoselectivity data: heterogeneous reducing agents allegedly produce "free" radicals, while homogeneous reductants generate "sequestered" radicals associated with reductant derived oxidized species. Among mechanistic tools, a 1,3-steric induction was found to be most efficient for controlling the stereoselectivity of radical reactions (up to 100% d,l). In intramolecular reactions, a d,l-to-meso reversal of stereoselectivity was discovered with zinc being replaced with cobaltocene as a reductant. Among efficient tools for controlling the stereoselectivity in intramolecular cyclizations is a rigidity of the carbon tether that provides for an exclusive formation of d,l-diastereomers. Two novel reactions that belong to a new field of unorthodox organometallic radical chemistry were discovered: the spontaneous conversion of cobalt-complexed propargyl cations to radicals and the THF-mediated process wherein a THF molecule assumes a new role of an initiator in radical reactions. A multistep mechanism involves a THF-induced alteration of propargyl cations that facilitates a redox process between metal clusters. Novel stereoselective methods provide access to topologically and functionally diverse 3,4-diaryl and 3,4-dialkyl-1,5-alkadiynes, 3,4-disubstituted 1,5-cycloalkadiynes (C8-C12), 3,4-dialkoxy-1,5-(cyclo)alkadiynes, and 3,7-diene-1,9-alkadiynes, which can be used in targeted syntheses of organic assemblies of relevance to medicinal chemistry, materials science, and natural product syntheses. Novel mechanistic tools and methodologies for controlling stereoselectivity in radical reactions can be expanded toward new types of pi-bonded unsaturated units (dienes, arenes, diynes, and enynes) and transition metals other than cobalt (Fe, Cr, Mo, W, and Mn). PMID- 25746445 TI - BASIC: A New Biopart Assembly Standard for Idempotent Cloning Provides Accurate, Single-Tier DNA Assembly for Synthetic Biology. AB - The ability to quickly and reliably assemble DNA constructs is one of the key enabling technologies for synthetic biology. Here we define a new Biopart Assembly Standard for Idempotent Cloning (BASIC), which exploits the principle of orthogonal linker based DNA assembly to define a new physical standard for DNA parts. Further, we demonstrate a new robust method for assembly, based on type IIs restriction enzyme cleavage and ligation of oligonucleotides with single stranded overhangs that determine the assembly order. It allows for efficient, parallel assembly with great accuracy: 4 part assemblies achieved 93% accuracy with single antibiotic selection and 99.7% accuracy with double antibiotic selection, while 7 part assemblies achieved 90% accuracy with double antibiotic selection. The linkers themselves may also be used as composable parts for RBS tuning or the creation of fusion proteins. The standard has one forbidden restriction site and provides for an idempotent, single tier organization, allowing all parts and composite constructs to be maintained in the same format. This makes the BASIC standard conceptually simple at both the design and experimental levels. PMID- 25746444 TI - New poly(amino acid methacrylate) brush supports the formation of well-defined lipid membranes. AB - A novel poly(amino acid methacrylate) brush comprising zwitterionic cysteine groups (PCysMA) was utilized as a support for lipid bilayers. The polymer brush provides a 12-nm-thick cushion between the underlying hard support and the aqueous phase. At neutral pH, the zeta potential of the PCysMA brush was ~-10 mV. Cationic vesicles containing >25% DOTAP were found to form a homogeneous lipid bilayer, as determined by a combination of surface analytical techniques. The lipid mobility as measured by FRAP (fluorescence recovery after photobleaching) gave diffusion coefficients of ~1.5 MUm(2) s(-1), which are comparable to those observed for lipid bilayers on glass substrates. PMID- 25746446 TI - Bronchopulmonary neuroendocrine tumours. PMID- 25746448 TI - The Structure of Photosystem II and the Mechanism of Water Oxidation in Photosynthesis. AB - Oxygenic photosynthesis forms the basis of aerobic life on earth by converting light energy into biologically useful chemical energy and by splitting water to generate molecular oxygen. The water-splitting and oxygen-evolving reaction is catalyzed by photosystem II (PSII), a huge, multisubunit membrane-protein complex located in the thylakoid membranes of organisms ranging from cyanobacteria to higher plants. The structure of PSII has been analyzed at 1.9-A resolution by X ray crystallography, revealing a clear picture of the Mn4CaO5 cluster, the catalytic center for water oxidation. This article provides an overview of the overall structure of PSII followed by detailed descriptions of the specific structure of the Mn4CaO5 cluster and its surrounding protein environment. Based on the geometric organization of the Mn4CaO5 cluster revealed by the crystallographic analysis, in combination with the results of a vast number of experimental studies involving spectroscopic and other techniques as well as various theoretical studies, the article also discusses possible mechanisms for water splitting that are currently under consideration. PMID- 25746447 TI - 12-Month naturalistic outcomes of depressive disorders in Hong Kong's primary care. AB - BACKGROUND: In Asia, the role of primary care physicians (PCPs) in mental health delivery is not clearly defined and what happens to patients following a depressive episode remains poorly understood. OBJECTIVE: To examine the 12-month naturalistic outcomes of depression in primary care and the impact of PCP identification. METHODS: A cohort study was conducted. A total of 10179 adults were consecutively recruited from the waiting rooms of 59 PCPs across Hong Kong to complete a survey which screened for depression. Blinded doctors provided data on their diagnosis and management; 539 screened-positive and 3819 screened negative subjects consented to telephone follow-up at 3, 6 and 12 months. Study instruments included Patient Health Questionnaire-9, Centre for Epidemiologic Studies Depression Scale 20 and Short-Form Health Survey Version 2.0 (SF-12v2) and self-reported mental health and primary care service use. RESULTS: 12-month remission rate was 60.31%. PCP detection had no association with remission. Identified patients had poorer health-related quality of life (HRQOL) at baseline but a faster rate of recovery in SF-12v2 mental component scores. PCP detection was associated with greater mental health service use at 12, 26 and 52 weeks, while GP consultation rates were only increased at 12 weeks. CONCLUSIONS: Over 1 year, ~60% of depressed patients experience symptom resolution, while 40% continue to suffer a chronic or remitting course of illness. Identification of depression by a PCP does not appear to affect remission of mood symptoms at 12 months, but is associated with a faster rate of recovery of HRQOL. PCP detection raises GP consultation rates temporarily however appears to enable more patients to access mental health services over 12 months. PMID- 25746449 TI - Alternative solutions and new scenarios for translesion DNA synthesis by human PrimPol. AB - PrimPol is a recently described DNA polymerase that has the virtue of initiating DNA synthesis. In addition of being a sensu stricto DNA primase, PrimPol's polymerase activity has a large capacity to tolerate different kind of lesions. The different strategies used by PrimPol for DNA damage tolerance are based on its capacity to "read" certain lesions, to skip unreadable lesions, and as an ultimate solution, to restart DNA synthesis beyond the lesion thus acting as a TLS primase. This lesion bypass potential, revised in this article, is strengthened by the preferential use of moderate concentrations of manganese ions as the preferred metal activator. We show here that PrimPol is able to extend RNA primers with ribonucleotides, even when bypassing 8oxoG lesions, suggesting a potential new scenario for PrimPol as a TLS polymerase assisting transcription. We also show that PrimPol displays a high degree of versatility to accept or induce distortions of both primer and template strands, creating alternative alignments based on microhomology that would serve to skip unreadable lesions and to connect separate strands. In good agreement, PrimPol is highly prone to generate indels at short nucleotide repeats. Finally, an evolutionary view of the relationship between translesion synthesis and primase functions is briefly discussed. PMID- 25746450 TI - Sex-related differences in effects of progesterone following neonatal hypoxic brain injury. AB - There is no satisfactory therapeutic intervention for neonatal hypoxic-ischemic (HI) encephalopathy. Progesterone is known to be effective in treating traumatic brain injury in adult animals but its effects in neonatal brains have not been reported. Brain injuries were induced by a unilateral common carotid artery ligation plus hypoxia exposure. Progesterone was administered immediately after hypoxia and daily for 5 days at 8 mg/kg, followed by a tapered dose for two days. At six weeks post-injury, lesion size and inflammatory factors were evaluated. Progesterone-treated, HI-injured male animals, but not females, showed significant long-term tissue protection compared to vehicle, suggesting an important sex difference in neuroprotection. Progesterone-treated, HI-injured male rats had fewer activated microglia in the cortex and hippocampus compared to controls. The rats were tested for neurological reflexes, motor asymmetry, and cognitive performance at multiple time points. The injured animals exhibited few detectable motor deficits, suggesting a high level of age- and injury-related neuroplasticity. There were substantial sex differences on several behavioral tests, indicating that immature males and females should be analyzed separately. Progesterone-treated animals showed modest beneficial effects in both sexes compared to vehicle-treated injured animals. Sham animals given progesterone did not behave differently from vehicle-treated sham animals on any measures. PMID- 25746451 TI - Hippocampal increase of 5-hmC in the glucocorticoid receptor gene following acute stress. AB - 5-Hydroxymethylcytosine (5-hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, 5-hmC was functionally linked to learning and cognition and these studies revealed an accumulation of 5 hmC in the prefrontal cortex of mice undergoing fear extinction. These studies led us to hypothesize a role for 5-hmC in response to stress. To test this hypothesis, we combined immunohistochemistry, tandem mass spectrometry, and tet assisted sodium bisulfite sequencing (TAB-seq) analyses on tissue and DNA from the hippocampus of 7-week old male mice exposed to a single 30-min restraint stress. After first identifying that the broad neuronal distribution of 5-hmC is not disrupted by acute stress, we used TAB-seq to find a stress-induced increase of 5-hmC in the 3'UTR of the glucocorticoid receptor gene (Nr3c1). Nr3c1 has a well-defined role in the stress pathway and these data suggest that 5-hmC contributes to these processes. Together, these data indicate that a deeper investigation of stress-related 5-hmC levels may reveal an environmental impact on this newly discovered epigenetic mark in the brain. PMID- 25746452 TI - Prolonged androgen deprivation may influence the autoregulation of estrogen receptors in the brain and pelvic floor muscles of male rats. AB - Androgen deprivation in males has detrimental effects on various tissues and bodily functions, some of which can be restored by estradiol (E2) administration. We investigated how the duration of androgen deprivation affects the autoregulation of estrogen receptors (ERs) levels in core brain areas associated with sexual behavior and cognition, as well as in pelvic floor muscles (PFM). We also measured c-Fos levels in brain areas associated with sexual behavior shortly after the rats mated. Prolonged castration increases ERalpha levels in the preoptic area (POA) and E2 treatment reverses these effects. In the POA, c-Fos levels after mating are not affected by the duration of androgen deprivation and/or E2 treatment. ERbeta levels in the POA as well as c-Fos levels in the POA and the core area of nucleus accumbens correlate with the mounting frequency for E2-treated Short-Term castrates. Additionally, ERbeta levels in the medial amygdala are positively correlated with the mounting frequency of Long-Term castrates that received E2 treatment. In the hippocampus, ERs are downregulated only when E2 is administered early after castration, whereas downregulation of ERalpha in the prefrontal cortex only occurs with delayed E2 treatment. Early, but not delayed, E2 treatment after castration increases ERbeta levels in the bulbocavernosus and ERalpha levels in the levator ani of male rats. Our data suggest that the duration of androgen deprivation may influence the autoregulation of ERs by E2 treatment in select brain areas and pelvic floor muscles of male rats. PMID- 25746453 TI - Chronic stress effects on working memory: association with prefrontal cortical tyrosine hydroxylase. AB - Chronic stress causes deficits in cognitive function including working memory, for which transmission of such catecholamines as dopamine and noradrenaline transmission in the prefrontal cortex (PFC) are crucial. Since catecholamine synthesis depends on the rate-limiting enzyme, tyrosine hydroxylase (TH), TH is thought to play an important role in PFC function. In this study, we found that two distinct population existed in Sprague-Dawley rats in terms of working memory capacity, one with higher working memory capacity, and the other with low capacity. This distinction of working memory capacity became apparent after rats were exposed to chronic stress. In addition, such working memory capacity and alterations of working memory function by chronic stress were associated with TH expression in the PFC. PMID- 25746454 TI - Somatosensory input to non-primary motor areas is enhanced during preparation of cued contraterlateral finger sequence movements. AB - Frontal N30 somatosensory evoked potentials (SEPs) represent early somatosensory input into non-primary motor areas. Importantly, modulations of frontal N30 SEPs can provide insight into the mechanisms involved in sensory processing for movement control. Enhancements of frontal N30 SEPs have been revealed during repetitive but not during the preparation of movements that are contralateral to median nerve (MN) stimulation (i.e. contralateral movements). Importantly, these enhancements during contralateral movements may be dependent on increased activity in several neural areas such as the primary motor cortex (M1), supplementary motor area (SMA) and basal ganglia (BG). Furthermore, research has also shown that patients with prefrontal lesions have enhanced early frontal SEPs (i.e. N28) at rest supporting a role of the prefrontal cortex in inhibitory modulation of early somatosensory input. The current study evaluated whether differential modulations of frontal N30 SEPs occurred during different time periods when individuals prepared and executed contralateral (right) finger sequences to attended vibrotactile (VibT) stimuli at the left index finger. SEPs were measured to median nerve (MN) stimuli elicited at the left wrist and MN stimuli were time-locked in four different periods relative to VibT onset (during pre-stimulus, early response preparation, late movement preparation and movement execution). Results revealed that frontal N30 SEPs were significantly enhanced when MN stimulation occurred in the late preparatory and/or early movement execution period (~750 ms) after the attended VibT stimuli. This result supports that increases in frontal N30 amplitudes during contralateral movements are dependent on the complexity of preparing and executing finger sequences, which is associated with increased activity in several neural areas such as the non primary motor areas, prefrontal cortex and BG. Furthermore, enhanced N30 SEPs during contralateral movement preparation and execution may be a necessary mechanism to decrease sensory gating to facilitate somatosensory processing in non-primary motor areas when there is a 'noisy' environment. PMID- 25746456 TI - C-C chemokine receptor type 2 (CCR2) signaling protects neonatal male mice with hypoxic-ischemic hippocampal damage from developing spatial learning deficits. AB - Chemokines are a family of cytokines involved in the chemotaxis of leukocytes and other target cells by binding to specific G-protein-coupled receptors on their membranes. As such, the activation of C-C chemokine receptor type 2 (CCR2) is involved in the mobilization of "inflammatory" monocytes from bone marrow and in their recruitment to the brain under inflammatory/pathological conditions. In this study, we investigated whether CCR2 signaling could affect the progression of learning deficits and hippocampal damage in a model of neonatal hypoxic ischemic (HI) brain injury. Postnatal day 3 wild-type (WT) and CCR2 knockout (KO) mice of both sexes were subjected to the Rice-Vannucci model of neonatal hypoxia ischemia and were followed for up to 14 weeks. HI CCR2 KO male mice were the only animals to exhibit long-term spatial learning deficits in the T-water maze task, compared to their corresponding sham-operated controls. CCR2 KO mouse pups of both sexes had a lower number of circulating monocytes, although only HI CCR2 KO male mice exhibited reduced numbers of activated macrophages/microglia in the damaged hippocampus, compared to WT mice. However, no differences were observed in hippocampal atrophy between HI CCR2 KO and HI WT mice. These results suggest that CCR2 signaling can protect neonatal mice from developing spatial learning deficits after a HI insult, in a sex-specific fashion. PMID- 25746455 TI - Adrenal-dependent diurnal modulation of conditioned fear extinction learning. AB - Post traumatic stress disorder (PTSD) is associated with altered conditioned fear extinction expression and impaired circadian function including dysregulation of glucocorticoid hormone secretion. We examined in adult male rats the relationship between conditioned fear extinction learning, circadian phase, and endogenous glucocorticoids (CORT). Rats maintained on a 12h light:dark cycle were trained and tested across 3 separate daily sessions (conditioned fear acquisition and 2 extinction sessions) that were administered during either the rats' active or inactive circadian phase. In an initial experiment we found that rats at both circadian phases acquired and extinguished auditory cue conditioned fear to a similar degree in the first extinction session. However, rats trained and tested at zeitgeber time-16 (ZT16) (active phase) showed enhanced extinction memory expression during the second extinction session compared to rats trained and tested at ZT4 (inactive phase). In a follow-up experiment, adrenalectomized (ADX) or sham surgery rats were similarly trained and tested across 3 separate daily sessions at either ZT4 or ZT16. ADX had no effect on conditioned fear acquisition or conditioned fear memory. Sham ADX rats trained and tested at ZT16 exhibited better extinction learning across the two extinction sessions compared to all other groups of rats. These results indicate that conditioned fear extinction learning is modulated by time of day, and this diurnal modulation requires the presence of adrenal hormones. These results support an important role of CORT dependent circadian processes in regulating conditioned fear extinction learning, which may be capitalized upon to optimize effective treatment of PTSD. PMID- 25746457 TI - Repeated exposure of male mice to low doses of lipopolysaccharide: dose and time dependent development of behavioral sensitization and tolerance in an automated light-dark anxiety test. AB - Although lipopolysaccharide (LPS) is widely used to examine immune behavior relationships there has been little consideration of the effects of low doses and the roles of sensitization and, or tolerance. Here low doses of LPS (1.0, 5.0 and 25.0 MUg/kg) were peripherally administered to male mice on Days 1, 4, 28 and 32 after a baseline recording of anxiety-like behaviors in an automated light-dark apparatus (total time in the light chamber, number of light-dark transitions, nose pokes into the light chamber). LPS at 1.0 MUg/kg, while having no significant effects on anxiety-like behaviors in the light-dark test on Days 1 and 4, displayed sensitization with the mice exhibiting significantly enhanced anxiety-like responses on Days 28 and 32. LPS at 5.0 MUg/kg had no consistent significant effects on anxiety-like behavior on Days 1 and 4, with sensitization and enhanced anxiety-like behaviors on Day 28 followed by tolerance on Day 32. LPS at 25 MUg/kg significantly enhanced anxiety-like behaviors on Day 1, followed by tolerance on Day 4, which was not evident by Day 28 and re-emerged on Day 32. There was a similar overall pattern of sensitization and tolerance for LPS induced decreases in locomotor activity in the safe dark chamber, without, however, any significant effects on activity in the riskier light chamber. This shows that low doses of LPS induce anxiety-like behavior and these effects are subject to sensitization and tolerance in a dose, context, and time related manner. PMID- 25746459 TI - Cascade exciton-pumping engines with manipulated speed and efficiency in light harvesting porous pi-network films. AB - Light-harvesting antennae are the machinery for exciton pumping in natural photosynthesis, whereas cascade energy transfer through chlorophyll is key to long-distance, efficient energy transduction. Numerous artificial antennae have been developed. However, they are limited in their cascade energy-transfer abilities because of a lack of control over complex chromophore aggregation processes, which has impeded their advancement. Here we report a viable approach for addressing this issue by using a light-harvesting porous polymer film in which a three-dimensional pi-network serves as the antenna and micropores segregate multiple dyes to prevent aggregation. Cascade energy-transfer engines are integrated into the films; the rate and efficiency of the energy-funneling engines are precisely manipulated by tailoring the dye components and contents. The nanofilms allow accurate and versatile luminescence engineering, resulting in the production of thirty emission hues, including blue, green, red and white. This advance may open new pathways for realising photosynthesis and photoenergy conversion. PMID- 25746460 TI - Impact of simulation training on self-efficacy of outpatient health care providers to use electronic health records. AB - OBJECTIVES: To examine whether simulation training enhanced self-efficacy of physicians and nurses who work in the outpatient setting to use electronic medical records, and whether the training changed their perceptions about the importance of electronic medical records (EMRs) in helping patients and improving patients' safety. METHODS: Two-hundred and ninety-three physicians and 94 nurses participated in the study. Participants first attended two computer classroom training sessions on how to use EMRs. Subsequently, the participants attended simulation training and practiced application of EMRs while encountering standardized patients. They answered questionnaires on a seven-point Likert-type scale prior to and immediately after simulation training. The questionnaires assessed their perceptions about the importance of EMRs in helping patients and improving patients' safety and their confidence and preparedness level to use EMRs. RESULTS: The overall self-efficacy of physicians and nurses to use EMRs increased after simulation training as compared to before simulation training. The physicians' and nurses' ratings about importance of EMRs to help patients' and improve patients' safety after simulation training were relatively unchanged compared to the ratings before simulation training. Additionally, participants described simulation training as exceptional, because it was an interactive learning opportunity to use EMRs within a simulated clinical setting with a simulated patient. CONCLUSIONS: Simulation training in the current study enhanced physicians' and nurses' level of self-confidence and preparedness to use EMRs. To train health care providers how to use EMRs, simulation training should be considered as an interactive and effective method of teaching prior to implementation of EMRs in medical institutions. PMID- 25746461 TI - Evaluation of clinical rules in a standalone pharmacy based clinical decision support system for hospitalized and nursing home patients. AB - OBJECTIVES: To improve the current standalone pharmacy clinical decision support system (CDSS) by identifying and quantifying the benefits and limitations of the system. METHODS: Alerts and handling of the executed clinical rules were extracted from the CDSS from the period September 2011 to December 2011. The number of executed clinical rule alerts, number of actions on alerts, and the reason why alerts were classified as not relevant were analyzed. The alerts where considered clinically relevant when the pharmacist needed to contact the physician. RESULTS: The 4065 alerts have been separated into: 1137 (28.0%) new alerts, 2797 (68.8%) repeat alerts and 131 (3.2%) double alerts. When the alerts were analyzed, only 3.6% were considered clinically relevant. Reasons why alerts were considered as not to be relevant were: (a) the dosage was correct or already adjusted, (b) the drug was (temporarily) stopped and (c) the monitored laboratory value or drug dosage had already reverted to be within the reference limits. The reasons for no action were linked to three categorical limitations of the used system: 'algorithm alert criteria', 'CDSS optimization', and 'data delivery'. CONCLUSION: This study highlighted a number of ways in which the CDSS could be improved. These different aspects have been identified as important for developing an efficient CDSS. PMID- 25746458 TI - Ephrin-A5 regulates inter-male aggression in mice. AB - The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5(-/-)) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5(-/-) mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5(-/-) mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice. PMID- 25746462 TI - Protective effect of hispidulin on kainic acid-induced seizures and neurotoxicity in rats. AB - Hispidulin is a flavonoid compound which is an active ingredient in a number of traditional Chinese medicinal herbs, and it has been reported to inhibit glutamate release. The purpose of this study was to investigate whether hispidulin protects against seizures induced by kainic acid, a glutamate analog with excitotoxic properties. The results indicated that intraperitoneally administering hispidulin (10 or 50mg/kg) to rats 30 min before intraperitoneally injecting kainic acid (15 mg/kg) increased seizure latency and decreased seizure score. In addition, hispidulin substantially attenuated kainic acid-induced hippocampal neuronal cell death, and this protective effect was accompanied by the suppression of microglial activation and the production of proinflammatory cytokines such as interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in the hippocampus. Moreover, hispidulin reduced kainic acid-induced c-Fos expression and the activation of mitogen-activated protein kinases in the hippocampus. These data suggest that hispidulin has considerable antiepileptic, neuroprotective, and antiinflammatory effects on kainic acid-induced seizures in rats. PMID- 25746463 TI - Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus. AB - Nephrogenic diabetes insipidus is a clinical sub-type of a diversely expounded disorder, named diabetes insipidus. It is characterized by inability of the renal cells to sense and respond to the stimulus of vasopressin. Amongst its various etiologies, one of the most inevitable causes includes lithium-induced instigation. Numerous studies reported marked histological damage to the kidneys upon long-term treatment with lithium. The recent researches have hypothesized many lithium-mediated mechanisms to explain the damage and dysfunction caused in the kidneys following lithium exposure. These mechanisms, widely, intend to justify the lithium-induced electrolyte imbalance, its interference with some vital proteins and a specific steroidal hormone, obstruction caused to a certain imperative transducer pathway and the renal tubular acidification defect produced on its prolonged therapy. Thorough study of such mechanisms aids in better understanding of the role of lithium in the pathophysiology of this disorder. Hence, the ameliorated knowledge regarding disease-pathology might prove beneficial in developing therapies that aim on disrupting the various lithium mediated pathways. Hence, this may effectively lead to the demonstration of a novel treatment for nephrogenic diabetes insipidus, which is, at present, limited to the use of diuretics which block lithium reuptake into the body. PMID- 25746464 TI - Identification and characterisation of a prototype for a new class of competitive PPARgamma antagonists. AB - Understanding of the physiological role of peroxisome proliferator-activated receptor gamma (PPARgamma) offers new opportunities for the treatment of cancers, immune disorders and inflammatory diseases. In contrast to PPARgamma agonists, few PPARgamma antagonists have been studied, though they do exert immunomodulatory effects. Currently, no therapeutically useful PPARgamma antagonist is commercially available. The aim of this study was to identify and kinetically characterise a new competitive PPARgamma antagonist for therapeutic use. A PPARgamma-dependent transactivation assay was used to kinetically characterise (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4 (trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB) in kidney, T and monocytic cell lines. Cytotoxic effects were analysed and intracellular accumulation of MTTB was assessed by tandem mass spectrometry (LC-MS/MS). Potential interactions of MTTB with the PPARgamma protein were suggested by molecular docking analysis. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), MTTB exhibited competitive antagonism against rosiglitazone in HEK293T and Jurkat T cells, with IC50 values in HEK293T cells of 4.3uM and 1.6uM, using the PPARgamma ligand binding domain (PPARgamma-LBD) and the full PPARgamma protein, respectively. In all cell lines used, however, MTTB showed much higher intracellular accumulation than GW9662. MTTB alone exhibited weak partial agonistic effects and low cytotoxicity. Molecular docking of MTTB with the PPARgamma-LBD supported direct interaction with the nuclear receptor. MTTB is a promising prototype for a new class of competitive PPARgamma antagonists. It has weak partial agonistic and clear competitive antagonistic characteristics associated with rapid cellular uptake. Compared to commercially available PPARgamma modulators, this offers the possibility of dose regulation of PPARgamma and immune responses. PMID- 25746465 TI - Diagnostic utility of handheld ultrasonography as an extension of the physical examination of patients with heart failure. AB - BACKGROUND AND OBJECTIVES: Conventional echocardiography is the technique of choice for assessing left ventricular function and the presence of structural heart disease in patients with heart failure. The aim of this study was to assess the diagnostic performance of handheld ultrasonography performed by a medical internist on patients with a clinical diagnosis of heart failure. PATIENTS AND METHODS: Cross-sectional observational study of 212 patients diagnosed with heart failure in a hospital center. A medical internist with basic training in echocardiography performed an examination using handheld ultrasonography and semiquantitatively assessed several variables. The patients' left ventricular systolic function was assessed, along with the cavity dimensions, significant valvular heart disease, pericardial effusion and the diameter of the inferior vena cava. RESULTS: The examination using handheld ultrasonography was conducted in less than 6minutes. The agreement between the diagnoses of the medical internist and the expert echocardiographist was very good (k>0.81) for the diameter, hypertrophy and left ventricular systolic function, valvular regurgitation, pericardial effusion and diameter of the inferior vena cava. CONCLUSIONS: Handheld echocardiography performed by a medical internist, as an extension of the physical examination of patients with heart failure, is a valid and safe test that helps increase the diagnostic performance. PMID- 25746466 TI - Infectious spondylitis in the Balearic Islands: An analysis of 51 cases. AB - INTRODUCTION: Vertebral osteomyelitis (VO) is a rare entity, although its incidence has increased in recent years. The objective is to describe the patients with this infection in our environment and a comparison with other published series. METHODS: A retrospective review was conducted of epidemiological, clinical, microbiological, treatment, complications and evolution data of patients with VO during 10 years (2004-2014) in two hospitals of Mallorca. RESULTS: 51 cases, median age 66 (range 22-85) years, 37 (72.5%) men with a mean onset of symptoms of 80.1 +/- 125.1 days. In thirty-six (70.6%) cases the origin of infection was considered hematogenous, although previous bacteremia was documented in 23 (45%) cases, being of urinary in 10 (43.5%) cases. Clinically at the moment of diagnosis 35 (68.8%) had fever, 32 (62.7%) pain, 14 (27.5%) irradiated nerve pain and 10 (19.6%) paralysis/paresia. MRI was the most performed radiological test 46 (90.2%), being pathological in all cases. S. aureus 23 (52.3%) was the most common microbiological isolates. At the moment of the diagnosis, blood cultures were positive in 27 (65.8%) of 41 cases and 11 (50%) of 22 percutaneous puncture was positive. Paraspinal, epidural or psoas abscesses were observed in 23 (45.1%), neurological deficit in 7 (13.7%) and chronic pain in 6 (11.8%). One patient (1.9%) died in relation with infection. CONCLUSIONS: Diagnosis was delayed in most cases. Previous bacteremia being main predisposing factor and hematogenous origin the main source of infection. S. aureus was the most isolated. Percutaneous puncture together with blood cultures increase etiologic diagnosis. A high percentage of patients had complications or sequelae. PMID- 25746467 TI - Direction-controlled chemical doping for reversible G-phonon mixing in ABC trilayer graphene. AB - Not only the apparent atomic arrangement but the charge distribution also defines the crystalline symmetry that dictates the electronic and vibrational structures. In this work, we report reversible and direction-controlled chemical doping that modifies the inversion symmetry of AB-bilayer and ABC-trilayer graphene. For the "top-down" and "bottom-up" hole injection into graphene sheets, we employed molecular adsorption of electronegative I2 and annealing-induced interfacial hole doping, respectively. The chemical breakdown of the inversion symmetry led to the mixing of the G phonons, Raman active Eg and Raman-inactive Eu modes, which was manifested as the two split G peaks, G(-) and G(+). The broken inversion symmetry could be recovered by removing the hole dopants by simple rinsing or interfacial molecular replacement. Alternatively, the symmetry could be regained by double side charge injection, which eliminated G(-) and formed an additional peak, G(o), originating from the barely doped interior layer. Chemical modification of crystalline symmetry as demonstrated in the current study can be applied to other low dimensional crystals in tuning their various material properties. PMID- 25746470 TI - Correction: On the use of leaf spectral indices to assess water status and photosynthetic limitations in Olea europaea L. during water-stress and recovery. PMID- 25746468 TI - Thy1.2 YFP-16 transgenic mouse labels a subset of large-diameter sensory neurons that lack TRPV1 expression. AB - The Thy1.2 YFP-16 mouse expresses yellow fluorescent protein (YFP) in specific subsets of peripheral and central neurons. The original characterization of this model suggested that YFP was expressed in all sensory neurons, and this model has been subsequently used to study sensory nerve structure and function. Here, we have characterized the expression of YFP in the sensory ganglia (DRG, trigeminal and vagal) of the Thy1.2 YFP-16 mouse, using biochemical, functional and anatomical analyses. Despite previous reports, we found that YFP was only expressed in approximately half of DRG and trigeminal neurons and less than 10% of vagal neurons. YFP-expression was only found in medium and large-diameter neurons that expressed neurofilament but not TRPV1. YFP-expressing neurons failed to respond to selective agonists for TRPV1, P2X(2/3 and TRPM8 channels in Ca2+ imaging assays. Confocal analysis of glabrous skin, hairy skin of the back and ear and skeletal muscle indicated that YFP was expressed in some peripheral terminals with structures consistent with their presumed non-nociceptive nature. In summary, the Thy1.2 YFP-16 mouse expresses robust YFP expression in only a subset of sensory neurons. But this mouse model is not suitable for the study of nociceptive nerves or the function of such nerves in pain and neuropathies. PMID- 25746469 TI - Devising an indicator to detect mid-term abortions in dairy cattle: a first step towards syndromic surveillance of abortive diseases. AB - Bovine abortion surveillance is essential for human and animal health because it plays an important role in the early warning of several diseases. Due to the limited sensitivity of traditional surveillance systems, there is a growing interest for the development of syndromic surveillance. Our objective was to assess whether, routinely collected, artificial insemination (AI) data could be used, as part of a syndromic surveillance system, to devise an indicator of mid term abortions in dairy cattle herds in France. A mid-term abortion incidence rate (MAIR) was computed as the ratio of the number of mid-term abortions to the number of female-weeks at risk. A mid-term abortion was defined as a return-to service (i.e., a new AI) taking place 90 to 180 days after the previous AI. Weekly variations in the MAIR in heifers and parous cows were modeled with a time dependent Poisson model at the departement level (French administrative division) during the period of 2004 to 2010. The usefulness of monitoring this indicator to detect a disease-related increase in mid-term abortions was evaluated using data from the 2007-2008 episode of bluetongue serotype 8 (BT8) in France. An increase in the MAIR was identified in heifers and parous cows in 47% (n = 24) and 71% (n = 39) of the departements. On average, the weekly MAIR among heifers increased by 3.8% (min-max: 0.02-57.9%) when the mean number of BT8 cases that occurred in the previous 8 to 13 weeks increased by one. The weekly MAIR among parous cows increased by 1.4% (0.01-8.5%) when the mean number of BT8 cases occurring in the previous 6 to 12 weeks increased by one. These results underline the potential of the MAIR to identify an increase in mid-term abortions and suggest that it is a good candidate for the implementation of a syndromic surveillance system for bovine abortions. PMID- 25746471 TI - Effects of metabolic uncouplers on excess sludge reduction and microbial products of activated sludge. AB - The present study investigated the influences of three metabolic uncouplers (pCP, oCP and oNP) on excess activated sludge reduction and microbial products of extracellular polymeric substances (EPS) and intracellular storage product (polyhydroxybutyrate, PHB) in short-term tests. Results showed sludge was reduced 58.2%, 59.8% and 80.8%, respectively, at pCP, oCP and oNP concentrations of 20mg/L. The dosage of three uncouplers had no obviously influences on COD removal and sludge settleability, but had significant inhibition effect on ammonia removal, especially for oNP. Low concentration of pCP and oNP (5mg/L) dosing resulted in protein and polysaccharide content increased in EPS, however, they were decreased at high pCP and oNP concentrations (>5mg/L). To oCP, the protein content in EPS was increased linearly with oCP concentration. Furthermore, metabolic uncouplers addition stimulated the production of PHB. Among three uncouplers, oCP could be an alternative uncoupler for sludge reduction in activated sludge process. PMID- 25746472 TI - Evaluating biomethane production from anaerobic mono- and co-digestion of food waste and floatable oil (FO) skimmed from food waste. AB - Batch anaerobic digestion was employed to investigate the performance of the floatable oil (FO) skimmed from food waste (FW) and the effect of different FO concentrations (5, 10, 20, 30, 40 and 50g/L) on biomethane production and system stability. FO and FO+FW were mono-digested and co-digested. The results showed that FO and FO+FW could be well anaerobically converted to biomethane in appropriate loads. For the mono-digestions of FO, the biomethane yield, TS and VS reduction achieved 607.7-846.9mL/g, 69.7-89% and 84.5-92.8%, respectively, when FO concentration was 5-40g/L. But the mono-digestion appeared instability when FO concentration was 50g/L. For the co-digestions of FW+FO, TS and VS reductions reached 70.7-86.1% and 87.5-91.4%, respectively, when FO concentration was 5 30g/L. However, the inhibition occurred when FO concentrations increased to 40 50g/L. The maximal FO loads of 40g/L and 30g/L were hence suggested for efficient mono-digestions and co-digestions of FO and FO+FW. PMID- 25746473 TI - Role of extracellular polymeric substances in biosorption of dye wastewater using aerobic granular sludge. AB - In this study, the role of extracellular polymeric substances (EPS) in biosorption of dye wastewater was evaluated using aerobic granular sludge as biosorbent. Based on the experimental data, the removal efficiencies of methylene blue (MB) by EPS and Sludge were 9.38 and 80.72%, respectively, implying that EPS made a certain contribution for MB removal. The adsorption rates of EPS, Sludge, and total Sludge+EPS for MB were better fitted with pseudo-second order kinetic model, and the equilibrium adsorption isotherm data agreed well with Langmuir model. The interaction between EPS and MB was explored by a combined three dimensional excitation-emission matrix (3D-EEM) and synchronous fluorescence spectra. 3D-EEM indicated that protein- and humic acid-like substances were the main peaks of EPS, and gradually quenched with increased MB concentrations. According to synchronous fluorescence spectra, the main fluorescence quenching was caused by tryptophan residues, and the type belonged to a combined dynamic and static quenching. PMID- 25746474 TI - Efficient extraction of bagasse hemicelluloses and characterization of solid remainder. AB - To reduce the degradation of cellulose and obtain high molecular weight of hemicellulose from the extracts, pH pre-corrected hot water pretreatment was developed by employing sodium hydroxide (3.9mol/L). The response surface model was established to optimize the extraction process. The species composition and purity of hemicellulose extract was analyzed by High Performance Liquid Chromatography (HPLC). The obtained solid remainder was analyzed by FTIR and SEM. The results showed that the component of xylose in hemicellulose extract was similar with commercial xylan. FTIR and SEM were shown to be able to evaluate solid remainder composition and surface characterization of the bagasse. The biggest balance between solid remainder and dissolved solid was obtained. Not only the yield of dissolved solid was improved, but the structure of solid remainder was also proved, which was beneficial to pulping and papermaking. PMID- 25746475 TI - Enzymatic degradation of aliphatic nitriles by Rhodococcus rhodochrous BX2, a versatile nitrile-degrading bacterium. AB - Nitriles are common environmental pollutants, and their removal has attracted increasing attention. Microbial degradation is considered to be the most acceptable method for removal. In this work, we investigated the biodegradation of three aliphatic nitriles (acetonitrile, acrylonitrile and crotononitrile) by Rhodococcus rhodochrous BX2 and the expression of their corresponding metabolic enzymes. This organism can utilize all three aliphatic nitriles as sole carbon and nitrogen sources, resulting in the complete degradation of these compounds. The degradation kinetics were described using a first-order model. The degradation efficiency was ranked according to t1/2 as follows: acetonitrile>trans-crotononitrile>acrylonitrile>cis-crotononitrile. Only ammonia accumulated following the three nitriles degradation, while amides and carboxylic acids were transient and disappeared by the end of the assay. mRNA expression and enzyme activity indicated that the tested aliphatic nitriles were degraded via both the inducible NHase/amidase and the constitutive nitrilase pathways, with the former most likely preferred. PMID- 25746476 TI - Electro-biocatalytic production of formate from carbon dioxide using an oxygen stable whole cell biocatalyst. AB - The use of biocatalysts to convert CO2 into useful chemicals is a promising alternative to chemical conversion. In this study, the electro-biocatalytic conversion of CO2 to formate was attempted with a whole cell biocatalyst. Eight species of Methylobacteria were tested for CO2 reduction, and one of them, Methylobacterium extorquens AM1, exhibited an exceptionally higher capability to synthesize formate from CO2 by supplying electrons with electrodes, which produced formate concentrations of up to 60mM. The oxygen stability of the biocatalyst was investigated, and the results indicated that the whole cell catalyst still exhibited CO2 reduction activity even after being exposed to oxygen gas. From the results, we could demonstrate the electro-biocatalytic conversion of CO2 to formate using an obligate aerobe, M. extorquens AM1, as a whole cell biocatalyst without providing extra cofactors or hydrogen gas. This electro-biocatalytic process suggests a promising approach toward feasible way of CO2 conversion to formate. PMID- 25746477 TI - Continuous cultivation of Chlorella pyrenoidosa using anaerobic digested starch processing wastewater in the outdoors. AB - Microalgae cultivation using wastewater might be a suitable approach to support sustainable large-scale biomass production. Its compelling characteristics included the recycling of nutrients and water resources, reducing carbon emissions and harvesting available biomass. In outdoor batch and continuous cultures, Chlorella pyrenoidosa completely adapted to anaerobic digested starch processing wastewater and was the dominant microorganism in the photobioreactor. However, seasonal changes of environmental conditions significantly influenced biomass growth and lipid production. The long-term outdoor operation demonstrated that the biomass concentration and productivity in continuous operations at different hydraulic retention times (HRTs) can be successfully predicted using the kinetic growth parameters obtained from the batch culture. A moderate HRT (4days) in the summer provided the best microalgae and lipid production and achieved relatively high biomass concentrations of 1.29-1.62g/L, biomass productivities of 342.6+/-12.8mg/L/d and lipids productivities of 43.37+/ 7.43mg/L/d. PMID- 25746478 TI - Introduction: What we do and do not know regarding redox processes of thiols in signaling pathways. AB - Due to their susceptibility towards redox modification, protein thiols represent primary targets for the modulation of protein activity, conformation and oligomerization. Until fairly recently, such modifications were considered "damage" as a result of oxidative stress, before researchers recognized their physiological importance for biologic signaling. This paradigm shift, and the associated necessity to accurately characterize and quantify the various pathways of thiol redox modifications not only for specific proteins, but also within the cellular environment, has enticed researchers to take a close look at the impact of environment and molecular (protein) structure on these reactions. This Special Issue on Redox Biology of Thiols in Signaling Pathways is the result of a workshop organized at the 2013 Annual Meeting of the Society for Free Radical Biology and Medicine in San Antonio, Texas, summarizing the contributions from many of the presenters. It will provide a stimulating synopsis on what is known, and what is not known, about the reaction mechanisms which underlie the role of thiols and oxidative processes in signaling pathways. PMID- 25746479 TI - Inhibition of miR122a by Lactobacillus rhamnosus GG culture supernatant increases intestinal occludin expression and protects mice from alcoholic liver disease. AB - Alcoholic liver disease (ALD) has a high morbidity and mortality. Chronic alcohol consumption causes disruption of intestinal microflora homeostasis, intestinal tight junction barrier dysfunction, increased endotoxemia, and eventually liver steatosis/steatohepatitis. Probiotic Lactobacillus rhamnosus GG (LGG) and the bacteria-free LGG culture supernatant (LGGs) have been shown to promote intestinal epithelial integrity and protect intestinal barrier function in ALD. However, little is known about how LGGs mechanistically works to increase intestinal tight junction proteins. Here we show that chronic ethanol exposure increased intestinal miR122a expression, which decreased occludin expression leading to increased intestinal permeability. Moreover, LGGs supplementation decreased ethanol-elevated miR122a level and attenuated ethanol-induced liver injury in mice. Similar to the effect of ethanol exposure, overexpression of miR122a in Caco-2 monolayers markedly decreased occludin protein levels. In contrast, inhibition of miR122a increased occludin expression. We conclude that LGGs supplementation functions in intestinal integrity by inhibition of miR122a, leading to occludin restoration in mice exposed to chronic ethanol. PMID- 25746480 TI - Unifying principles of calcium wave propagation - Insights from a three dimensional model for atrial myocytes. AB - Atrial myocytes in a number of species lack transverse tubules. As a consequence the intracellular calcium signals occurring during each heartbeat exhibit complex spatio-temporal dynamics. These calcium patterns arise from saltatory calcium waves that propagate via successive rounds of diffusion and calcium-induced calcium release. The many parameters that impinge on calcium-induced calcium release and calcium signal propagation make it difficult to know a priori whether calcium waves will successfully travel, or be extinguished. In this study, we describe in detail a mathematical model of calcium signalling that allows the effect of such parameters to be independently assessed. A key aspect of the model is to follow the triggering and evolution of calcium signals within a realistic three-dimensional cellular volume of an atrial myocyte, but with low computational costs. This is achieved by solving the linear transport equation for calcium analytically between calcium release events and by expressing the onset of calcium liberation as a threshold process. The model makes non-intuitive predictions about calcium signal propagation. For example, our modelling illustrates that the boundary of a cell produces a wave-guiding effect that enables calcium ions to propagate further and for longer, and can subtly alter the pattern of calcium wave movement. The high spatial resolution of the modelling framework allows the study of any arrangement of calcium release sites. We demonstrate that even small variations in randomly positioned release sites cause highly heterogeneous cellular responses. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25746481 TI - [Management of sudden unexpected infant death syndrome (SUIDS) in reference centers in France in 2013]. AB - In France, nearly 500 infants still die unexpectedly every year. In 2009, the French Institute for Public Health Surveillance published a survey showing great heterogeneity in the management of sudden unexpected infant death (SUID) cases. The aim of this study was to evaluate the actual diagnostic approach to SUID in the different reference centers in France and to determine the degree to which the 2007 recommendations of the French National Authority for Health (Haute Autorite de sante [HAS]) are applied. We conducted a multicenter cross-sectional epidemiological study by email sent to the 36 SIDS reference centers with questions on examinations usually performed in SIDS cases. We also submitted six SUID test cases for death classification to the different reference physicians. Twenty-nine of 36 centers (80.5%) responded. Among the recommended tests, only blood cultures, analysis of cerebrospinal fluid, and a proposal to autopsy are done in 100% of the centers. Other investigations are not carried out systematically: skeleton radiography (65.5%), cranial CT scan (58%), eye fundus (20.7%), metabolic analysis (65.5%), and blood toxicology (62%). The main reasons for non-completion of these tests were hospital practices, lack of resources, technical difficulties, cost of tests, and difficulty in interpreting results (50% reported not knowing the postmortem biological standards). None of the institutions apply the HAS recommendations entirely. The classification of causes of-death test cases also varied between the centers, with a maximum of 62% concordance in their responses. In 2013, in France, there is still substantial heterogeneity in the diagnostic set-up of SUIDS, a non-exhaustive implementation of the recommendations of the French National Authority for Health, and an unsatisfactory SUIDS classification tool because of considerable discordance between physicians. These results explain the current difficulties in obtaining reliable epidemiological data, because many teams do not use all the investigations recommended to find the cause of death. Therefore, the establishment of a national registry would provide accurate and up-to-date epidemiological, environmental, medical, and biological data to identify the events causing death and propose appropriate means of prevention. PMID- 25746482 TI - Online marketing of personalised cancer tests discusses benefits more than limitations, study shows. PMID- 25746483 TI - Left ventricular assist device driveline infection and the frequency of dressing change in hospitalized patients. AB - OBJECTIVES: To determine if driveline infection is related to dressing change frequency in hospitalized adult patients with newly implanted left ventricular assist devices (LVAD). BACKGROUND: Guidelines do not exist for the frequency of driveline exit-site dressing change in hospitalized patients resulting in wide variation in practice. METHODS: A retrospective chart review was conducted on 68 patients implanted with a HeartMate II LVAD between August 2008 and September 2013 at an urban medical center. RESULTS: No driveline infections were found. Frequency of the driveline dressing change varied from daily, three times a week, and weekly. The daily dressing change group was younger in age compared to the weekly group (p = 0.005) and three times a week group (p = 0.001). No other differences were found. CONCLUSION: Driveline infections do not appear to be related to the frequency of dressing change in this population. Our data and other studies on this topic thus far are too limited to draw definitive conclusions about optimal frequency of dressing change for infection prevention. PMID- 25746484 TI - Depression and Outcome of Fear of Falling in a Falls Prevention Program. AB - OBJECTIVE: To examine whether depression predicts less improvement in fear of falling and falls efficacy in older adults attending a falls prevention program (FPP). METHODS: Using a prospective observational design in an academic medical center, the authors studied 69 nondemented adults aged 55 years or older (mean age: 77.8+/-8.9 years) who had experienced at least one fall in the previous year and who attended the FPP. The primary outcome variable was change in severity of fear of falling during the FPP. Secondary outcome variables were change in falls efficacy and fear-related restriction of activities during the FPP. Independent variables were baseline depressive disorders and depressive symptom severity. RESULTS: Twenty-one of 69 study participants (30.4%) had a depressive disorder at baseline. Depressive disorder and depressive symptoms were not associated with change in severity of fear of falling or restriction of activity. On the other hand, depressive disorder was associated with improvement in falls efficacy, although this finding was not significant in multivariate analysis. Among participants with a depressive disorder, improvement in falls efficacy was significantly correlated with improvement in depressive symptoms. CONCLUSION: There was no association between baseline depression and change in fear of falling in this FPP. The correlation between improvement in depressive symptoms and improvement in falls efficacy raises the question as to whether a cognitive behavioral intervention that simultaneously targets both depression and falls efficacy would be a useful component of a FPP. PMID- 25746486 TI - A Life-Course Study of Cognitive Reserve in Dementia--From Childhood to Old Age. AB - OBJECTIVE: To test a life-course model of cognitive reserve in dementia and examine if school grades around age 10 years, formal educational attainment, and lifetime occupational complexity affect the risk of dementia in old age. METHODS: 7,574 men and women from the Uppsala Birth Cohort Multigenerational Study were followed for 21 years. Information on school performance, formal education, and occupational attainment was collected prospectively from elementary school archives and population censuses. Dementia diagnosis was extracted from the two Swedish registers. Discrete-time Cox proportional hazard models were estimated. RESULTS: Dementia was diagnosed in 950 individuals (12.5%). Dementia risk was lower among individuals with higher childhood school grades (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.68 to 0.93) and was lower among individuals in data-complex occupations (HR: 0.77; 95% CI: 0.64 to 0.92). Professional/university education predicted lower risk of dementia in minimally adjusted models (HR: 0.74; 95% CI: 0.60 to 0.91), although the effect faded with adjustment for occupational complexity. Lowest risk was found in the group with both higher childhood school performance and high occupational complexity with data (HR: 0.61; 95% CI: 0.50 to 0.75). Importantly, high occupational complexity could not compensate for the effect of low childhood grades. In contrast, dementia risk was reduced in those with higher school grades, irrespective of occupational complexity. CONCLUSION: Higher childhood school performance is protective of dementia risk, particularly when preserved through complex work environments in adulthood, although it will remain protective even in the absence of later-life educational or occupational stimulation. PMID- 25746485 TI - Subjective Cognitive Complaints, Personality and Brain Amyloid-beta in Cognitively Normal Older Adults. AB - OBJECTIVE: Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-beta in cognitively normal older adults; and to explore personality factors as potential moderators of this association. DESIGN: Cross-sectional observational study. SETTING: Clinical neuroimaging research center. PARTICIPANTS: Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation. MEASUREMENTS: Subjective cognitive self-report measures included the Memory Functioning Questionnaire (MFQ), Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-beta deposition was assessed with Pittsburgh compound B (PiB)-PET imaging. RESULTS: One of three cognitive complaint measures, the MFQ, was associated with global PiB retention (standardized beta = -0.230, p = 0.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint-high amyloid-beta association. CONCLUSION: Evidence for association between subjective cognition and brain amyloid-beta deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ-amyloid-beta association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer disease. PMID- 25746487 TI - Better ways to move ahead. PMID- 25746488 TI - Seasonal patterns in acute aortic diseases: US results confirm Italian findings - The author's reply. PMID- 25746489 TI - Primary prophylactic anticoagulation is mandatory if noncompaction is associated with atrial fibrillation or heart failure. PMID- 25746490 TI - Obstructive sleep apnea and stroke risk in atrial fibrillation: Is there a correlation or not? PMID- 25746491 TI - Is neuregulin 4 a potential regulator of apolipoprotein A-V gene expression. PMID- 25746492 TI - Increased serum HMGB1 level may predict the fatal outcomes in patients with chronic heart failure. PMID- 25746493 TI - CMR to distinguish Takotsubo cardiomyopathy from myocardial infarction in acute course of ischemic stroke in a male patient. PMID- 25746494 TI - Percutaneous mitral valve repair using the MitraClip system in patients with anemia. AB - BACKGROUND: Patients with anemia show a negative outcome in percutaneous coronary intervention, transcatheter aortic valve replacement and cardiac surgery. The impact of anemia on periprocedural major adverse cardiac and cerebrovascular events (MACCE) and mortality in patients undergoing treatment of severe mitral regurgitation (MR) with percutaneous mitral valve repair using the MitraClip system is not known. OBJECTIVE: To assess whether percutaneous mitral valve repair with the MitraClip system is safe and effective in patients with anemia. METHODS AND RESULTS: 80 patients with severe and moderate-to-severe MR were included in this open-label observational single-center study. Anemia was prevalent in 51.3% of patients (n=41). MitraClip devices were successfully implanted in 97.6% (n=40) of patients with anemia and in 97.4% (n=38) of patients without anemia (p=0.971). Periprocedural MACCE occurred in 4.9% (n=2) of patients with anemia and 5.1% (n=2) of patients without anemia (p=0.959). Thirty-day mortality was 2.4% (n=1) in patients with anemia and 5.1% (n=2) in patients without anemia (p=0.611). Follow up of up to 12 months showed a significant improvement of NYHA class and quality of life evaluated by the Minnesota Living with Heart Failure Questionnaire in both groups. One-year survival was 80.5% in patients with anemia and 84.6% in patients without anemia (p=0.634). CONCLUSION: Mitral valve repair with the MitraClip system can be performed safely and efficiently in patients with anemia. Anemia does not affect clinical outcome and quality of life in patients undergoing mitral valve repair. PMID- 25746495 TI - High-sensitive troponin-T in adult congenital heart disease. AB - BACKGROUND: Adult congenital heart disease (ACHD) patients are at risk of late complications including arrhythmias, heart failure and sudden death. High sensitive troponin-T (hs-TnT) is the standard for diagnosing acute coronary syndrome, but is also associated with cardiac function and prognosis in other cardiac diseases. We aimed to describe hs-TnT level in ACHD patients, and determine its relationship with cardiac function and other biomarkers. METHODS: Consecutive ACHD patients, visiting the outpatient clinic, underwent echocardiography, exercise testing and venipuncture on the same day. RESULTS: In total 587 patients were included (median age 33 [IQR 25-41] years, 58% male, 90% NYHA class I). hs-TnT was above the detection limit of 5 ng/L in 241 patients (41%), of whom 47 (8%) had hs-TnT levels above the 99th percentile of normal of 14 ng/L. hs-TnT levels were highest in patients with a systemic RV or pulmonary hypertension. Patients with normal or non-detectable hs-TnT were younger (32 [IQR 24-40] years) than patient with elevated hs-TnT (42 [IQR 36-60] years, p<0.001). The prevalence of hs-TnT >=14 ng/L was higher in patients with NYHA >=II (36%, p<0.001), systemic systolic dysfunction (38%, p<0.001), non-sinus rhythm (43%, p<0.001) and elevated pulmonary pressures (39%, p<0.001). hs-TnT was correlated with NT-proBNP (r=0.400, p<0.001). CONCLUSIONS: hs-TnT above the 99th percentile of normal is observed in a non-trivial portion of stable ACHD patients, especially in those with a systemic RV or elevated pulmonary pressures. Since this biomarker of myocardial damage is related to NT-proBNP and ventricular function, its potential predictive value in ACHD patients seems promising and further investigation of underlying mechanisms is warranted. PMID- 25746496 TI - Trapped cardioverter-defibrillator lead after interventional closure of an iatrogenic atrial septal defect after catheter-based mitral valve repair with the MitraClip system. PMID- 25746497 TI - Avoid overtreatment in the setting of chronic total occlusions: The role of blood flow restoration in positive vascular remodeling. PMID- 25746498 TI - Influence of process conditions and water quality on the formation of mutagenic byproducts in UV/H2O2 processes. AB - UV/H2O2 processes in drinking water treatment may generate byproducts which cause an increased response in Ames fluctuation assays. As this probably involves a mixture of substances in very low concentrations, it is challenging to identify the individual byproducts. Therefore it was studied under which conditions mutagenic byproducts are formed and how this can be prevented. It was found that positive Ames fluctuation test responses only are obtained when Medium Pressure UV lamps are used, and not with Low Pressure lamps. This probably is explained by the photolysis of nitrate, which plays an important role in the formation of mutagenic byproducts. The most important parameters involved in the formation of such byproducts were demonstrated to be the nitrate concentration, the natural organic matter, the UV spectrum of the lamps, and the UV dose applied. These factors explain up to 74-87% of the Ames fluctuation test responses after UV/H2O2 drinking water treatment. By taking this into account, drinking water utilities can estimate whether UV processes applied in their case may cause the formation of mutagenic byproducts, and how to take measures to prevent it. PMID- 25746500 TI - Reply to "An analysis of whether surgeon-performed neck ultrasonography can be used as the main localizing study in primary hyperparathyroidism". PMID- 25746499 TI - A new general methodology for incorporating physico-chemical transformations into multi-phase wastewater treatment process models. AB - This paper introduces a new general methodology for incorporating physico chemical and chemical transformations into multi-phase wastewater treatment process models in a systematic and rigorous way under a Plant-Wide modelling (PWM) framework. The methodology presented in this paper requires the selection of the relevant biochemical, chemical and physico-chemical transformations taking place and the definition of the mass transport for the co-existing phases. As an example a mathematical model has been constructed to describe a system for biological COD, nitrogen and phosphorus removal, liquid-gas transfer, precipitation processes, and chemical reactions. The capability of the model has been tested by comparing simulated and experimental results for a nutrient removal system with sludge digestion. Finally, a scenario analysis has been undertaken to show the potential of the obtained mathematical model to study phosphorus recovery. PMID- 25746501 TI - Preclinical pharmacokinetic evaluation and metabolites identification of methyl salicylate-2-O-beta-d-lactoside in rats using LC-MS/MS and Q-TOF-MS methods. AB - Methyl salicylate-2-O-beta-d-lactoside (MSL) is a natural salicylate derivative from the traditional Chinese medicine of Gaultheria yunnanensis (Franch.) Rehder (G. yunnanensis). As a non-steroidal anti-inflammatory drug (NSAID), MSL exerts a significant anti-arthritis effect but hardly has any gastrointestinal toxicity. In this paper, the pharmacokinetics, distribution, excretion and identification of MSL and its metabolites are described following rat oral and intravenous administration. The biological samples were quantified by UPLC-MS/MS and the metabolites in urine and feces were identified by using Q-TOF-MS. These results will support future investigations leading to clinical development of this drug. PMID- 25746502 TI - Visualization and prediction of porosity in roller compacted ribbons with near infrared chemical imaging (NIR-CI). AB - The porosity of roller compacted ribbon is recognized as an important critical quality attribute which has a huge impact on the final product quality. The purpose of this study was to investigate the use of near-infrared chemical imaging (NIR-CI) for porosity estimation of ribbons produced at different roll pressures. Two off-line methods were utilized as reference methods. The relatively fast method (oil absorption) was comparable with the more time consuming mercury intrusion method (R(2)=0.98). Therefore, the oil method was selected as the reference off line method. It was confirmed by both reference methods that ribbons compressed at a higher pressure resulted in a lower mean porosity. Using NIR-CI in combination with multivariate data analysis it was possible to visualize and predict the porosity distribution of the ribbons. This approach is considered important for process monitoring and control of continuously operating roller compaction line. PMID- 25746503 TI - Fingerprinting of morphine using chromatographic purity profiling and multivariate data analysis. AB - Chromatographic purity profiling (CPP) is the common name of a group of analytical and chemometric applications for detection, identification and quantitative determination of related substances and other impurities in active pharmaceutical ingredients (APIs) and finished dosage forms (FDFs). CPP is used for fingerprinting and discriminating between samples, thus representing a core activity in modern drug analysis. The worldwide demand for morphine and its congeners is tremendous and depends entirely on the supply of natural opiates. The aim of this research was to develop a methodology that enables identification of a source of morphine, thus revealing falsification of the substance. The characteristic and reproducible features of impurity profiles for 28 samples of morphine (6 morphine sulfate, 9 morphine hydrochloride and 13 morphine base) were captured by a new LC/MS method for impurity profiling of morphine. The impurity profile encompasses the related substances specified in relevant Ph.Eur. monographs, as well as the other morphinane like impurities, including the naturally occurring co-extracted alkaloids. Different pattern recognition techniques (unsupervised and supervised) were used to reveal the differentiation features of the morphine fingerprints for classification and authentication purposes. The results described in this research open the possibility of using the chromatographic purity profile combined with multivariate data analysis for fingerprinting of morphine samples. PMID- 25746504 TI - Qualitative and quantitative analysis of an alkaloid fraction from Piper longum L. using ultra-high performance liquid chromatography-diode array detector electrospray ionization mass spectrometry. AB - In a previous research, an alkaloid fraction and 18 alkaloid compounds were prepared from Piper longum L. by series of purification process. In this paper, a qualitative and quantitative analysis method using ultra-high performance liquid chromatography-diode array detector-mass spectrometry (UHPLC-DAD-MS) was developed to evaluate the alkaloid fraction. Qualitative analysis of the alkaloid fraction was firstly completed by UHPLC-DAD method and 18 amide alkaloid compounds were identified. A further qualitative analysis of the alkaloid fraction was accomplished by UHPLC-MS/MS method. Another 25 amide alkaloids were identified according to their characteristic ions and neutral losses. At last, a quantitative method for the alkaloid fraction was established using four marker compounds including piperine, pipernonatine, guineensine and N-isobutyl-2E,4E octadecadienamide. After the validation of this method, the contents of above four marker compounds in the alkaloid fraction were 57.5mg/g, 65.6mg/g, 17.7mg/g and 23.9mg/g, respectively. Moreover, the relative response factors of other three compounds to piperine were calculated. A comparative study between external standard quantification and relative response factor quantification proved no remarkable difference. UHPLC-DAD-MS method was demonstrated to be a powerful tool for the characterization of the alkaloid fraction from P. longum L. and the result proved that the quality of alkaloid fraction was efficiently improved after appropriate purification. PMID- 25746505 TI - Insight into the conformational polymorph transformation of a block-buster multiple sclerosis drug fingolimod hydrochloride (FTY 720). AB - Single-crystal structures of fingolimod hydrochloride (FTY 720), a block-buster multiple sclerosis drug, were revealed for the first time in this study. Three different conformational polymorphs (designated as forms I-III) were characterized using a variety of analytical techniques, including single-crystal XRD, VT-PXRD, DSC, HSM, and VT-confocal Raman spectroscopy. A temperature dependent solid-solid transformation between different conformational polymorphs was observed to be reversible, and the transition process was studied using both VT-PXRD and VT-Raman techniques. Structural analysis revealed that the FTY 720 molecules adopt distinctive conformations in different polymorphs. Single-crystal to single-crystal transformation from form I to II was observed and was closely monitored by X-ray diffraction. PMID- 25746506 TI - Monitoring quality of care through linkage of administrative data: national trends in bloodstream infection in U.K. PICUs 2003-2012. AB - OBJECTIVES: Interventions to reduce hospital-acquired bloodstream infection have succeeded in reducing rates in U.S. PICUs, but there is a lack of evidence for the impact of similar interventions in the United Kingdom. We assessed variation in bloodstream infection rates within and between PICUs over a 10-year period, during which time infection control strategies (care bundles) were implemented. DESIGN: Observational study linking laboratory data to national audit data of pediatric intensive care admissions (Paediatric Intensive Care Audit Network). SETTING: Twenty PICUs in England and Wales, 2003-2012. PATIENTS: One hundred and two thousand nine hundred ninety-nine children less than 16 years. INTERVENTIONS: Implementation of infection control strategies in PICU captured through a survey of clinicians. MEASUREMENTS AND MAIN RESULTS: Rates of bloodstream infection per 1,000 bed-days were estimated from samples taken between 2 days after admission and up to 2 days following discharge from PICU. Two percent of children experienced at least one bloodstream infection, corresponding to 5.11 (95% CI, 4.90-5.31) per 1,000 bed-days. There was a significant difference in trends preimplementation of infection control strategies (annual decrease of 8.0%; 95% CI, 6.3-9.7%) versus postimplementation (annual decrease of 13.4%; 95% CI, 10.3 16.4%). By 24 months postimplementation, the rate of bloodstream infection had fallen 25.5% and was 15.1% lower than would have been expected if preimplementation trends had continued. CONCLUSIONS: Our population-based study of PICUs in England and Wales demonstrates a steady decline in bloodstream infection rates over time. In addition, there was a significant and incremental further decrease in rates associated with timing of implementation of infection control strategies. Assessment of bloodstream infection trends before as well as after implementation of infection control strategies can be facilitated using data linkage and is important to avoid overestimating the impact of unit-level interventions to improve infection control. Advances in collection and linkage of real-time data could further support quality improvement efforts. PMID- 25746507 TI - Lung inflammation persists after 27 hours of protective Acute Respiratory Distress Syndrome Network Strategy and is concentrated in the nondependent lung. AB - OBJECTIVE: PET with [18F]fluoro-2-deoxy-D-glucose can be used to image cellular metabolism, which during lung inflammation mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. We aimed at studying the location and evolution of inflammation by PET imaging, relating it to morphology (CT), during the first 27 hours of application of protective ventilation strategy as suggested by the Acute Respiratory Distress Syndrome Network, in a porcine experimental model of acute respiratory distress syndrome. DESIGN: Prospective laboratory investigation. SETTING: University animal research laboratory. SUBJECTS: Ten piglets submitted to an experimental model of acute respiratory distress syndrome. INTERVENTIONS: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. During 27 hours of controlled mechanical ventilation according to Acute Respiratory Distress Syndrome Network strategy, the animals were studied with dynamic PET imaging of [18F]fluoro-2-deoxy-D-glucose at two occasions with 24-hour interval between them. MEASUREMENTS AND MAIN RESULTS: [18F]fluoro-2-deoxy-D-glucose uptake rate was computed for the total lung, four horizontal regions from top to bottom (nondependent to dependent regions) and for voxels grouped by similar density using standard Hounsfield units classification. The global lung uptake was elevated at 3 and 27 hours, suggesting persisting inflammation. In both PET acquisitions, nondependent regions presented the highest uptake (p = 0.002 and p = 0.006). Furthermore, from 3 to 27 hours, there was a change in the distribution of regional uptake (p = 0.003), with more pronounced concentration of inflammation in nondependent regions. Additionally, the poorly aerated tissue presented the largest uptake concentration after 27 hours. CONCLUSIONS: Protective Acute Respiratory Distress Syndrome Network strategy did not attenuate global pulmonary inflammation during the first 27 hours after severe lung insult. The strategy led to a concentration of inflammatory activity in the upper lung regions and in the poorly aerated lung regions. The present findings suggest that the poorly aerated lung tissue is an important target of the perpetuation of the inflammatory process occurring during ventilation according to the Acute Respiratory Distress Syndrome Network strategy. PMID- 25746508 TI - Inhibition of forkhead boxO-specific transcription prevents mechanical ventilation-induced diaphragm dysfunction. AB - OBJECTIVES: Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation induced diaphragm weakness remains unknown. DESIGN: This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. SETTING: University research laboratory. SUBJECTS: Young adult female Sprague-Dawley rats. INTERVENTIONS: Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. MEASUREMENTS AND MAIN RESULTS: Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. CONCLUSIONS: Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction. PMID- 25746509 TI - Patient load effects on response time to critical arrhythmias in cardiac telemetry: a randomized trial. AB - OBJECTIVES: Remotely monitored patients may be at risk for a delayed response to critical arrhythmias if the telemetry watchers who monitor them are subject to an excessive patient load. There are no guidelines or studies regarding the appropriate number of patients that a single watcher may safely and effectively monitor. Our objective was to determine the impact of increasing the number of patients monitored on response time to simulated cardiac arrest. DESIGN: Randomized trial. SETTING: Laboratory-based experiment. SUBJECTS: Forty-two remote telemetry technicians and nurses from cardiac units. INTERVENTIONS: Number of patients monitored in a simulation of cardiac telemetry monitoring work. MEASUREMENTS AND MAIN RESULTS: We carried out a study to compare response times to ventricular fibrillation across five patient loads: 16, 24, 32, 40, and 48 patients. The simulation replicated the work of telemetry watchers using a combination of real recorded patient electrocardiogram signals and a simulated patient experiencing ventricular fibrillation. Study participants were assigned to one of the five patient loads and completed a 4-hour monitoring session, during which they performed tasks-including event documentation and phone calls to report events-similar to real monitoring work. When the simulated patient sustained ventricular fibrillation, the time required to report this arrhythmia was recorded. As patient loads increased, there was a statistically significant increase in response times to the ventricular fibrillation. In addition, frequency of failure to meet a response time goal of less than 20 seconds was significantly higher in the 48-patient condition than in all other conditions. Task performance decreased as patient load increased. CONCLUSIONS: As participants monitored more patients in a laboratory setting, their performance with respect to recognizing critical and noncritical events declined. This study has implications for the design of remote telemetry work and other patient monitoring tasks in critical and intermediate care units. PMID- 25746510 TI - Enduring attentional deficits in rats treated with a peripheral nerve injury. AB - The present study investigated the impact of a spared nerve injury (SNI) on the daily performance of rats tested in two instrumental conditioning procedures: the progressive ratio (PR) schedule of food reinforcement to study motivation for an appetitive stimulus, and the 5-choice serial reaction time task (5-CSRTT), a test of attention and reaction time. Separate groups of male, Sprague-Dawley rats of age 8-10 months were trained to asymptotic performance in either task, before undergoing either SNI or sham surgery. After a recovery period of 3-4 days the animals were run 5 days/week for 3 months in either task. Tests of responsivity to evoked tactile (Von Frey) and thermal (acetone) stimuli were also conducted over this period to check integrity of the model. Post SNI surgery, rats showed equivalent responding to sham controls for food available under a PR schedule throughout the test period, implying a similar level of motivation for a food reward. In contrast, a performance deficit emerged in SNI treated rats run in the 5-CSRTT, consistent with an attentional deficit. This deficit emerged during the second month post-surgery and was characterized by slower response speed, reduced accuracy and increased trial omissions. Both SNI groups showed equivalent hypersensitivity to evoked sensory stimuli compared to controls. Since attention based deficits have been reported in individuals with clinical forms of neuropathic pain, the present studies suggest a novel approach to study this phenomena and a means to study the effect of treatments against this cognitive endpoint. PMID- 25746511 TI - Alterations in cognitive flexibility in a rat model of post-traumatic stress disorder. AB - Exposure to stressful or traumatic events is associated with increased vulnerability to post-traumatic stress disorder (PTSD). This vulnerability may be partly mediated by effects of stress on the prefrontal cortex (PFC) and associated circuitry. The PFC mediates critical cognitive functions, including cognitive flexibility, which reflects an organism's ability to adaptively alter behavior in light of changing contingencies. Prior work suggests that chronic or acute stress exerts complex effects on different forms of cognitive flexibility, via actions on the PFC. Similarly, PFC dysfunction is reported in PTSD, as are executive function deficits. Animal models that permit study of the effects of stress/trauma on cognitive flexibility may be useful in illuminating ways in which stress-linked cognitive changes contribute to PTSD. Here, we examined the behavioral effects of a rodent model of PTSD - single prolonged stress (SPS) - on performance of two forms of cognitive flexibility: reversal learning and strategy set-shifting. SPS did not impair acquisition of either a response or visual-cue discrimination but did cause slight impairments in the retrieval of the visual cue rule. During response discrimination reversal, SPS rats made more perseverative errors. In comparison, during set-shifting from the visual-cue to response discrimination, SPS rats did not show enhanced perseveration, but did display increased never-reinforced errors, indicative of impairment in selecting a novel strategy. These data demonstrate that SPS leads to a complex and intriguing pattern of deficits in flexible responding and suggest that impairments in executive functioning associated with PTSD could, in part, be a neuro-cognitive consequence of trauma exposure. PMID- 25746512 TI - Development of the acoustic startle response in rats and its change after early acoustic trauma. AB - Even brief acoustic trauma during the critical period of development that results in no permanent hearing threshold shift may lead to altered auditory processing in adulthood. By monitoring the acoustic startle response (ASR), we examined the development of auditory function in control rats and in rats exposed to intense noise at the 14th postnatal day (P14). First ASRs appeared on P10-P11 to intense low-frequency tones. By P14, the range of sound intensities and frequencies eliciting ASRs extended considerably, the ASR reactivity being similar at all frequencies (4-32 kHz). During the subsequent two weeks, ASR amplitudes to low frequency stimuli (4-8 kHz) increased, whereas the ASRs to high-frequency tones were maintained (16 kHz) or even decreased (32 kHz). Compared to controls, noise exposure on P14 (125 dB SPL for 8, 12, or 25 min) produced transient hyper reactivity to startle stimuli, manifested by a decrease of ASR thresholds and an increase of ASR amplitudes. ASR enhancement occurred regardless of permanent hearing loss and was more pronounced at high frequencies. The hyper-reactivity of ASRs declined by P30; the ASR amplitudes in adult exposed rats were lower than in controls. The histological control did not reveal loss of hair cells in adult exposed rats, however, the number of inner hair cell ribbon synapses was significantly decreased, especially in the high-frequency part of the cochlea. The results indicate that early acoustic trauma may result in complex changes of ASRs during development. PMID- 25746513 TI - Increased latencies to initiate cocaine self-administration following laterodorsal tegmental nucleus lesions. AB - Cholinergic input to the ventral tegmental area (VTA), origin of the mesocorticolimbic dopamine system that is critical for cocaine reward, is important for both cocaine seeking and cocaine taking. The laterodorsal tegmental nucleus (LDTg) provides one of the two major sources of excitatory cholinergic input to the VTA, but little is known of the role of the LDTg in cocaine reward. LDTg cholinergic cells express urotensin-II receptors and here we used local microinjections of a conjugate of the endogenous ligand for these receptors with diphtheria toxin (Dtx::UII) to lesion the cholinergic cells of the LDTg in rats previously trained to self-administer cocaine (1mg/kg/infusion, i.v.). Lesioned rats showed long latencies to initiate cocaine self-administration after treatment with the toxin, which resulted in a reduction in cocaine intake per session. Priming injections reduced latencies to initiate responding for cocaine in lesioned rats, and once they began to respond the rats regulated their moment to-moment cocaine intake within normal limits. Thus we conclude that while LDTg cholinergic cell loss does not significantly alter the rewarding effects of cocaine, LDTg lesions can reduce the rat's responsiveness to cocaine-predictive stimuli. PMID- 25746514 TI - The impact of social stress during adolescence or adulthood and coping strategy on cognitive function of female rats. AB - The age of stressor exposure can determine its neurobehavioral impact. For example, exposure of adolescent male rats to resident-intruder stress impairs cognitive flexibility in adulthood. The current study examined the impact of this stressor in female rats. Rats were exposed to resident-intruder stress during early adolescence (EA), mid-adolescence (MA) or adulthood (Adult). They were tested in an operant strategy-shifting task for side discrimination (SD), reversal learning (REV) and strategy set-shifting (SHIFT) the following week. Performance varied with age, stress and coping style. MA and EA rats performed SD and SHIFT better than other ages, respectively. Social stress impaired performance in rats depending on their coping strategy as determined by a short (SL) or long (LL) latency to become subordinate. SL rats were impaired in SD and REV, whereas EA-LL rats were impaired in SHIFT. These impairing effects of female adolescent stress did not endure into adulthood. Strategy set-shifting performance for female adolescents was positively correlated with medial prefrontal cortex (mPFC) activation as indicated by c-fos expression suggesting that this region is engaged during task performance. This contrasts with the inverse relationship between these indices reported for male adolescent rats. Together, the results demonstrate that social stress produces cognitive impairments for female rats that depend on age and coping style but unlike males, the impairing effects of female adolescent social stress are immediate and do not endure into adulthood. Sex differences in the impact of adolescent social stress on cognition may reflect differences in mPFC engagement during the task. PMID- 25746515 TI - Time-dependent effects of rapamycin on consolidation of predator stress-induced hyperarousal. AB - Previous studies have indicated that rapamycin, a potent inhibitor of the mammalian target of rapamycin (mTOR) pathway, blocks consolidation of shock induced associative fear memories. Moreover, rapamycin's block of associative fear memories is time-dependent. It is unknown, however, if rapamycin blocks consolidation of predator stress-induced non-associative fear memories. Furthermore, the temporal pattern of mTOR activation following predator stress is unknown. Thus, the goal of the current studies was to determine if rapamycin blocks consolidation of predator stress-induced fear memories and if so, whether rapamycin's effect is time-dependent. Male rats were injected systemically with rapamycin at various time points following predator stress. Predator stress involves an acute, unprotected exposure of a rat to a cat, which causes long lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behaviour. We show that rapamycin injected immediately after predator stress blocked consolidation of stress-induced startle. However, rapamycin injected 9, 24 or 48h post predator stress potentiated stress-induced startle. Consistent with shock-induced associative fear memories, we show that mTOR signalling is essential for consolidation of predator stress-induced hyperarousal. However, unlike shock-induced fear memories, a second, persistent, late phase mTOR-dependent process following predator stress actually dampens startle. Consistent with previous findings, our data support the potential role for rapamycin in treatment of stress related disorders such as posttraumatic stress disorder. However, our data suggest timing of rapamycin administration is critical. PMID- 25746517 TI - Effect of cochlear implant electrode array design on auditory nerve and behavioral response in children. AB - AIM: To study the effect of change in the array design of cochlear implant electrode on electrophysiological, and behavioral functional measures of cochlear implant users. METHOD: A total of 33 children using cochlear implants were included in this study. Subjects were implanted with different electrode types including Slim Straight (CI422) and Freedom Contour Advance (CI24RE) electrode arrays. The electrically evoked compound action potential (ECAP) thresholds were evoked by stimulation of basal, mid, and apical electrodes. The behavioral aided responses using the implant were obtained about 6-12 months post fitting of implant. RESULTS: ECAP thresholds decreased significantly postoperatively in both electrode arrays. Slim straight electrode (CI422) had higher thresholds than Freedom Contour Advance (CI24RE) electrode at most recording sites, but the differences were only significant at basal site. This is a direct consequence of a perimodiolar electrode versus a lateral wall electrode, i.e., the neurons are further away requiring more current (higher threshold) to record the NRT. CONCLUSION: Although the curved electrode array appeared to evoke responses at lower thresholds, effect on patient performance was not obvious. PMID- 25746519 TI - Circulation Journal awards for the year 2014. PMID- 25746518 TI - The utility of heart rate and minute ventilation as predictors of whole-body metabolic rate during occupational simulations involving load carriage. AB - The utility of cardiac and ventilatory predictors of metabolic rate derived under temperate and heated laboratory conditions was evaluated during three fire fighting simulations (70-mm hose drag, Hazmat recovery, bushfire hose drag; N = 16 per simulation). The limits of agreement for cardiac (temperate: - 0.54 to 1.77; heated: - 1.39 to 0.80 l min(- 1)) and ventilatory surrogates (temperate: - 0.19 to 1.27; heated: - 0.26 to 1.16 l min(- 1)) revealed an over-estimation of oxygen consumption that exceeded the acceptable limits required by occupational physiologists (N = 25; +/- 0.24 l min(- 1)). Although ventilatory predictions offered superior precision during low-intensity work (P < 0.05), a cardiac prediction was superior during more demanding work (P < 0.05). Deriving those equations under heated conditions failed to improve precision, with the exception of the cardiac surrogate during low-intensity work (P < 0.05). These observations imply that individualised prediction curves are necessary for valid estimations of metabolic demand in the field. PMID- 25746520 TI - Ca(2+)-activated K(+) channels as therapeutic targets for myocardial and vascular protection. AB - Small- and large-conductance Ca(2+)-activated K(+)channels (SKCa and BKCa, respectively) may be important targets for therapeutic interventions in a variety of cardiac conditions. In cardiomyocytes, BKCa channels are localized to mitochondria where they beneficially modulate reactive oxygen species, mitochondrial Ca(2+), and respiration. In vascular smooth muscle cells, BKCa channels regulate vascular tone and promote vasodilation. Activation of BKCa channels has demonstrated significant cardioprotection following ischemic injury, including improved function and reduced infarct size. SKCa channels are expressed in both the membrane and mitochondria of cardiomyocytes. Modulation of cardiomyocyte SKCa channels may be beneficial for arrhythmia, heart failure, and ischemia. Mitochondrial SKCa channels may provide similar benefit to BKCa channels. In addition, activation of SKCa channels on the endothelium promotes vasodilation. This mini-review focuses on the modulation of cardiomyocyte BKCa and SKCa channels for cardioprotection and briefly address associated potential therapeutic benefits in the coronary circulation. PMID- 25746516 TI - Docosahexaenoic acid partially ameliorates deficits in social behavior and ultrasonic vocalizations caused by prenatal ethanol exposure. AB - Prenatal ethanol exposure disrupts social behavior in humans and rodents. One system particularly important for social behavior is the somatosensory system. Prenatal ethanol exposure alters the structure and function of this area. Docosahexaenoic acid (DHA), an omega 3 polyunsaturated fatty acid, is necessary for normal brain development and brains from ethanol-exposed animals are DHA deficient. Thus, we determined whether postnatal DHA supplementation ameliorated behavioral deficits induced by prenatal ethanol exposure. Timed pregnant Long Evans rats were assigned to one of three groups: ad libitum access to an ethanol containing liquid diet, pair fed an isocaloric isonutritive non-alcohol liquid diet, or ad libitum access to chow and water. Pups were assigned to one of two postnatal treatment groups; gavaged intragastrically once per day between postnatal day (P)11 and P20 with DHA (10 mg/kg in artificial rat milk) or artificial rat milk. A third group was left untreated. Isolation-induced ultrasonic vocalizations (iUSVs) were recorded on P14. Social behavior and play induced USVs were tested on P28 or P42. Somatosensory performance was tested with a gap crossing test around P33 or on P42. Anxiety was tested on elevated plus maze around P35. Animals exposed to ethanol prenatally vocalized less, play fought less, and crossed a significantly shorter gap than control-treated animals. Administration of DHA ameliorated these ethanol-induced deficits such that the ethanol-exposed animals given DHA were no longer significantly different to control-treated animals. Thus, DHA administration may have therapeutic value to reverse some of ethanol's damaging effects. PMID- 25746521 TI - Molecular variants of soluble guanylyl cyclase affecting cardiovascular risk. AB - Soluble guanylyl cyclase (sGC) is the physiological receptor for nitric oxide (NO) and NO-releasing drugs, and is a key enzyme in several cardiovascular signaling pathways. Its activation induces the synthesis of the second messenger cGMP. cGMP regulates the activity of various downstream proteins, including cGMP dependent protein kinase G, cGMP-dependent phosphodiesterases and cyclic nucleotide gated ion channels leading to vascular relaxation, inhibition of platelet aggregation, and modified neurotransmission. Diminished sGC function contributes to a number of disorders, including cardiovascular diseases. Knowledge of its regulation is a prerequisite for understanding the pathophysiology of deficient sGC signaling. In this review we consolidate the available information on sGC signaling, including the molecular biology and genetics of sGC transcription, translation and function, including the effect of rare variants, and present possible new targets for the development of personalized medicine in vascular diseases. PMID- 25746523 TI - Assessment and management of right ventricular failure in left ventricular assist device patients. AB - Mechanical circulatory support devices, including ventricular assist devices (VADs) and the total artificial heart, have evolved to become accepted therapeutic options for patients with severe congestive heart failure. Continuous flow left VADs are the most prevalent option for mechanical circulatory assistance and reliably provide years of support. However, problems related to acute and chronic right heart failure in patients with left VADs continue to cause important mortality and morbidity. This review discusses the assessment and management of right ventricular failure in left VAD patients. The goal is to summarize current knowledge and suggest new approaches to managing this problem. PMID- 25746522 TI - Diastolic dysfunction. AB - Despite the growing number of patients affected, the understanding of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) is still poor. Clinical trials, largely based on successful treatments for systolic heart failure, have been disappointing, suggesting that HFpEF has a different pathology to that of systolic dysfunction. In this review, general concepts, epidemiology, diagnosis, and treatment of diastolic dysfunction are summarized, with an emphasis on new experiments suggesting that oxidative stress plays a crucial role in the pathogenesis of at least some forms of the disease. This observation has lead to potential new diagnostics and therapeutics for diastolic dysfunction and heart failure caused by diastolic dysfunction. PMID- 25746524 TI - Myocardial T1 mapping. AB - Cardiovascular magnetic resonance is a well-established tool for the quantification of focal fibrosis. With the introduction of T1 mapping, diffuse myocardial processes can be detected and quantified. In particular, infiltration and storage disorders with large disease-related changes, and diffuse fibrosis where measurement is harder but the potential impact larger. This has added a new dimension to the understanding and assessment of various myocardial diseases. T1 mapping promises to detect early disease, quantify disease severity and provide prognostic insights into certain conditions. It also has the potential to be a robust surrogate marker in drug development trials to monitor therapeutic response and be a prognostic marker in certain diseases. T1 mapping is an evolving field and numerous factors currently preclude its standardization. In this review, we describe the current status of T1 mapping and its potential promises and pitfalls. PMID- 25746526 TI - Ultrasound of silence abdominal aortic aneurysm. PMID- 25746525 TI - Role of inflammation in atrial fibrillation pathophysiology and management. AB - Atrial fibrillation (AF) is the most common clinically relevant arrhythmia, but the methods available for treating AF and its complications (of which the most important is thrombogenesis), as well as for assessing AF risk and underlying pathophysiology, are largely limited. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF. That evidence includes elevated serum levels of inflammatory biomarkers in AF subjects, the expression of inflammatory markers in cardiac tissues of AF patients and animal models of AF, and beneficial effects of anti-inflammatory drugs in experimental AF paradigms. Inflammation is suggested to be linked to various pathological processes, such as oxidative stress, apoptosis, and fibrosis, that promote AF substrate formation. Inflammation has also been associated with endothelial dysfunction, platelet activation, and coagulation cascade activation, leading to thrombogenesis. Thus, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Here, we review the evidence for a role of inflammation and inflammatory biomarkers in the risk management and treatment of AF. We also summarize the current knowledge of inflammation-dependent cellular and molecular mechanisms in AF pathophysiology and their potential as therapeutic targets. PMID- 25746527 TI - A classical but useful predictor of future left ventricular assist device explantation. PMID- 25746528 TI - Statins beneficial for heart failure with preserved ejection fraction but not heart failure with reduced ejection fraction? PMID- 25746529 TI - Importance of neural arc for baroreflex resetting in hypertension. PMID- 25746530 TI - Expansion of the clinical application of optical coherence tomography to percutaneous coronary intervention and assessment of the instability of coronary atherosclerosis. PMID- 25746531 TI - Assessment of coronary flow reserve by dynamic single-photon emission computed tomography. PMID- 25746532 TI - Qualifying the use of common cardiovascular drugs in cardiology. PMID- 25746533 TI - Assessment and treatment of systemic right ventricular dyssynchrony. PMID- 25746534 TI - Developing improved clinical markers to detect heart failure and chronic kidney disease. PMID- 25746535 TI - Multicenter investigations of the prevalence of abdominal aortic aneurysm in elderly Japanese patients with hypertension. AB - BACKGROUND: Physical examination as an initial screening tool to diagnose abdominal aortic aneurysm (AAA) has lost favor over the past 20 years. This multicenter cohort study aimed to determine the prevalence of AAA in elderly Japanese patients with hypertension (HT) and to clarify the diagnostic accuracy of physical examination using a pocket-sized ultrasound imaging device (the "pocket-echo"). METHODS AND RESULTS: A total of 1,731 patients with HT aged >60 years from 20 collaborating institutions were enrolled in this study. Abdominal palpation was performed on physical examination, and the pocket-echo was used to confirm the diagnosis of AAA. The abdominal aorta was well visualized in 1,692 patients (98%). AAA was discovered in 69 patients (4.1%), with advanced age and male sex identified as independent risk factors. The prevalence of AAA increased according to age regardless of sex, and reached 9.2% and 5.7%, respectively, in males and females >=80 years. Overall, 33 cases of AAA were missed on abdominal palpation (sensitivity, 52%), whereas for AAAs >40 mm, the sensitivity was 75%. CONCLUSIONS: We assessed the utility of the pocket-echo and physical examination for diagnosing AAA in Japanese patients with HT aged over 60 years. Our findings highlight the importance of AAA screening programs in high-risk Japanese populations, and confirm the ability of physical examination to detect large, but not small, AAAs. PMID- 25746536 TI - Papaverine-induced polymorphic ventricular tachycardia during coronary flow reserve study of patients with moderate coronary artery disease. AB - BACKGROUND: Papaverine is useful for evaluating the functional status of a coronary artery, but it may provoke malignant ventricular arrhythmia (VA). The aim of this study was to investigate the incidence, and clinical and ECG characteristics of patients with papaverine-induced VAs. METHODS AND RESULTS: The 182 consecutive patients underwent fractional flow reserve (FFR) measurement of 277 lesions. FFR was determined after intracoronary papaverine administration by standard procedures. The clinical and ECG characteristics were compared between patients with and without ventricular tachycardia (VT: >=3 successive premature ventricular beats (PVBs), or ventricular fibrillation (VF)). After papaverine administration, the QTc interval, QTUc interval, and T-peak to U-end interval were prolonged significantly. Single PVBs on the T-wave or U-wave type developed in 29 patients (15.9%). Polymorphic VT (torsade de pointes) occurred in 5 patients (2.8%), and of those, VF developed in 3 patients (1.7%). No clinical and baseline ECG parameters were predictors for VT or VF except for sex and administration of papaverine into the left coronary artery. Excessive prolongation of QT (or QTU), T-peak to U-end intervals and giant T-U waves were found immediately prior to the ventricular tachyarrhythmias (VTAs), which were unpredictable from the baseline data. CONCLUSIONS: Intracoronary administration of papaverine induced fatal VTAs, although the incidence is rare. Excessive prolongation of the QT (and QTU) interval appeared prior to VTAs; however, they were unpredictable. PMID- 25746537 TI - Endovascular therapy for steno-occlusive subclavian and innominate artery disease. AB - BACKGROUND: This study investigated the safety and outcome of endovascular therapy for steno-occlusive subclavian or innominate artery disease at a single center over a long period of more than 2 decades. METHODS AND RESULTS: We retrospectively analyzed all endovascular procedures of stenosis or occlusion of the subclavian or innominate artery between January 1990 and October 2013. During the observation period, a total of 130 procedures were attempted in 127 mostly symptomatic patients with stenosis (n=108; 83%) or occlusion (n=22; 17%) of the subclavian (n=119; 92%) and innominate (n=11; 8%) artery. The overall technical success rate was 97.7% (n=127/130). Accounting for the type of lesion, the success rate for stenosis was 100% (n=108/108) and for total occlusion, 86% (n=19/22). The periprocedural complication rate was low and included stroke, transient ischemic attack, and access site complications of 0.8%, 1.5%, and 3.8%, respectively. During a mean follow-up of 28 months the rate of restenosis (>70%) was 12%. Due to the overall low event rate no significant lesion or procedural risk factor for the development of restenosis could be identified. CONCLUSIONS: Stenosis and occlusion of the subclavian and innominate artery can be treated safely and successfully by endovascular therapy with excellent long-term patency. PMID- 25746538 TI - Comparison of the first- and second-generation limus-eluting stents for bifurcation lesions from a Korean multicenter registry. AB - BACKGROUND: There are limited data on the relative efficacy of 1st- vs. 2nd generation limus-eluting stents in bifurcation lesions. METHODS AND RESULTS: Our analysis of a Korean multicenter registry for bifurcated coronary lesions enrolled 1,762 patients treated with 2nd-generation everolimus-eluting stent (EES, n=348) or 1st-generation sirolimus-eluting stents (SES, n=1,414). In the overall population, EES was comparable to SES regarding major adverse cardiac events (MACE: composite of cardiac death, nonfatal myocardial infarction, and target vessel revascularization (TVR)), cardiac death, and TVR rates within a 2 year follow-up. In 1:3 propensity score-matched populations, EES showed a significantly lower MACE rate compared with SES (HR [95% CI], 0.53 [0.29-0.97]; P=0.039), mainly through a reduction in repeat revascularization (HR [95% CI], 0.47 [0.24-0.92]; P=0.027). EES was superior to SES in reducing TVR in patients with left main (LM) lesions (HR [95% CI], 0.21 [0.06-0.67]; P=0.008) or in patients treated with 2-stent technique PCI (HR [95% CI], 0.28 [0.09-0.91]; P=0.035). There was no difference in clinical outcomes between 2 stents in a non LM bifurcation lesion or in patients treated with a 1-stent technique. CONCLUSIONS: At 2-year follow-up, 1st- and 2nd-generation limus-eluting stents showed comparable clinical outcomes in general bifurcation lesions. EES was superior to SES after matching by propensity score, especially in patients with LM bifurcation or in those treated by a 2-stent technique. PMID- 25746539 TI - In vivo assessment of novel stentless valve in the mitral position. AB - BACKGROUND: We conducted in vivo examinations of a newly designed stentless mitral valve (SMV), formed by suturing 2 leaflets with the "legs" serving as chorda tendinea, made from bovine pericardium, to a flexible ring. METHODS AND RESULTS: Seven pigs underwent implantation of the SMV constructed with a 23-mm (n=5) or 25-mm (n=2) Duran ring. Baseline echocardiography examinations were used to evaluate the annular anteroposterior diameter, and distance between the mitral annulus (MA) and papillary muscles (PMs) to determine SMV-leg length. After removing the native valve, the SMV-legs were fixed to the anterior and posterior PMs, followed by fixation of the ring to the native MA. Immediately after surgery, all animals presented none or trivial mitral regurgitation, with mean and peak trans-SMV pressure gradient values of 1.9+/-0.8 and 6.0+/-3.1 mmHg, respectively. The mean length of the SMV-leg was 19.4+/-3.9 mm, which correlated with the distance between anterior and posterior MA-PM (r=0.96 and 0.94, respectively, P<0.01 for both). The discrepancy between the anteroposterior diameter of the ring (outside diameter) and that of the native valve was 1.0+/ 2.9 mm, which correlated with the trans-SMV pressure gradient (r=0.81, P=0.025). CONCLUSIONS: In our preliminary study, the SMV demonstrated excellent diastolic inflow dynamics and closing function in vivo. Preoperative precise assessment of MV configuration may serve as a basis for selection of appropriate ring size and SMV-leg length. PMID- 25746540 TI - Novel scoring system using postoperative cardiopulmonary exercise testing predicts future explantation of left ventricular assist device. AB - BACKGROUND: Although cardiopulmonary exercise (CPX) testing is an established tool for predicting survival in patients with heart failure (HF), its prognostic impact on explantation of left ventricular assist device (LVAD) was unknown. METHODS AND RESULTS: We enrolled 33 patients who had undergone implantation of extracorporeal pulsatile flow LVAD and symptom-limited CPX testing at 3 months after operation, and who were followed between 2005 and 2014. Patients who received conversion to continuous flow LVAD were excluded. On Cox regression analysis, E1 (maximum load >=51W; HR, 27.55), E2 (minute ventilation/carbon dioxide output [VE/VCO2] slope <=34; HR, 16.86), and E3 (peak oxygen consumption [PVO2] >=12.8 ml.kg(-1).min(-1); HR, 18.35) significantly predicted explantation expectancy during 2 years after LVAD implantation (P<0.05 for all). Explantation score, the sum of positive E1-3, significantly stratified 2-year cumulative explantation rate into low (0 points), intermediate (1-2 points), and high (3 points) expectancy groups (0%, 29%, and 86%, respectively, P<0.001). When the scoring system was used for 45 patients with continuous flow LVAD, the 2 patients who had explantation were assigned to the high expectancy group. CONCLUSIONS: Explantation score, calculated simply from 3 postoperative symptom-limited CPX testing parameters, is a novel tool to predict explantation expectancy of LVAD and to select good candidates for the weaning test. PMID- 25746541 TI - Acute type B aortic dissection with communicating vs. non-communicating false lumen. AB - BACKGROUND: In practice, patients with acute aortic dissection (AAD) are generally divided into 2 groups according to the status of the false lumen: non communicating or communicating. The similarities and differences between the 2 groups, however, have not been fully determined in a large population. METHODS AND RESULTS: We studied 502 patients with Stanford type B AAD. Clinical background at symptom onset was compared, and similarities and differences characterized, for patients with non-communicating (NC group, n=288) vs. communicating (C group, n=214) false lumens. Time of day (00.00-06.00 hours, 06.00-12.00 hours, 12.00-18.00 hours, and 18.00-24.00 hours) and extent of physical activity (extreme exertion, slight exertion, at rest, and sleeping) at symptom onset were similar between groups. Patients in the NC group were older (mean age, 71+/-11 years vs. 64+/-14 years, P<0.01) and had lower prevalence of distally extended aortic dissection (26% vs. 8%, P<0.01) and deaths in hospital (2% vs. 7%, P=0.011) than those in the C group. CONCLUSIONS: At symptom onset, clinical circumstances and physical activity were similar between the groups, and old age and a background of DeBakey IIIa aortic dissection may be associated with determination of false lumen status. The outcome in the NC group was better than in the C group. PMID- 25746542 TI - Prognostic impact of statin use in patients with heart failure and preserved ejection fraction. AB - BACKGROUND: The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF >=50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients. CONCLUSIONS: These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death. PMID- 25746544 TI - Predominant role of neural arc in sympathetic baroreflex resetting of spontaneously hypertensive rats. AB - BACKGROUND: There is ongoing controversy over whether neural or peripheral factors are the predominant cause of hypertension. The closed-loop negative feedback operation of the arterial baroreflex hampers understanding of how arterial pressure (AP) is determined through the interaction between neural and peripheral factors. METHODS AND RESULTS: A novel analysis of an isolated open loop baroreceptor preparation to examine sympathetic nervous activity (SNA) and AP responses to changes in carotid sinus pressure (CSP) in adult spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) was conducted. In the neural arc (CSP-SNA relationship), the midpoint pressure (128.9+/-3.8 vs. 157.9+/-8.1 mmHg, P<0.001) and the response range of SNA to CSP (90.5+/-3.7 vs. 115.4+/-7.6%/mmHg, P=0.011) were higher in SHR. In the peripheral arc (SNA-AP relationship), slope and intercept did not differ. A baroreflex equilibrium diagram was obtained by depicting neural and peripheral arcs in a pressure-SNA plane with rescaled SNA (% in WKY). The operating-point AP (111.3+/-4.4 vs. 145.9+/-5.2 mmHg, P<0.001) and SNA (90.8+/-3.2 vs. 125.1+/-6.9% in WKY, P<0.001) were shifted towards a higher level in SHR. CONCLUSIONS: The shift of the neural arc towards a higher SNA range indicated a predominant contribution to baroreflex resetting in SHR. Notwithstanding the resetting, the carotid sinus baroreflex in SHR preserved an ability to reduce AP if activated with a high enough pressure. PMID- 25746543 TI - Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction. AB - BACKGROUND: Chronic kidney disease is associated with sympathetic activation and muscle abnormalities, which may contribute to decreased exercise capacity. We investigated the correlation of renal function with peak exercise oxygen consumption (VO2) in heart failure (HF) patients. METHODS AND RESULTS: We recruited 2,938 systolic HF patients who underwent clinical, laboratory, echocardiographic and cardiopulmonary exercise testing. The patients were stratified according to estimated glomerular filtration rate (eGFR). Mean follow up was 3.7 years. The primary outcome was a composite of cardiovascular death and urgent heart transplantation at 3 years. On multivariable regression, eGFR was predictor of peakVO2(P<0.0001). Other predictors were age, sex, body mass index, HF etiology, NYHA class, atrial fibrillation, resting heart rate, B-type natriuretic peptide, hemoglobin, and treatment. After adjusting for significant covariates, the hazard ratio for primary outcome associated with peakVO2<12 ml.kg(-1).min(-1)was 1.75 (95% confidence interval (CI): 1.06-2.91; P=0.0292) in patients with eGFR >=60, 1.77 (0.87-3.61; P=0.1141) in those with eGFR of 45-59, and 2.72 (1.01-7.37; P=0.0489) in those with eGFR <45 ml.min(-1).1.73 m(-2). The area under the receiver-operating characteristic curve for peakVO2<12 ml.kg( 1).min(-1)was 0.63 (95% CI: 0.54-0.71), 0.67 (0.56-0.78), and 0.57 (0.47-0.69), respectively. Testing for interaction was not significant. CONCLUSIONS: Renal dysfunction is correlated with peakVO2. A peakVO2cutoff of 12 ml.kg(-1).min( 1)offers limited prognostic information in HF patients with more severely impaired renal function. PMID- 25746545 TI - Prediction of chronic vessel enlargement by a novel intravascular ultrasound finding. AB - BACKGROUND: Coronary arterial segments distal to the severely stenotic lesion sometimes shrink as a result of decreased coronary flow. Pathological studies have shown that vessel shrinkage is accompanied by folding of the internal elastic membrane (IEM). A peri-medial high-echoic band (PHB) by intravascular ultrasound (IVUS) may represent folding of the IEM and therefore detect chronically shrunken coronary segments that have potential to enlarge subsequently. METHODS AND RESULTS: IVUS imaging of the distal reference segments was performed in 27 patients after stenting. PHB was defined as a high-echoic band observed at the luminal side of the media. Serial (baseline and 9 months) changes in minimal lumen diameter (LD) were compared between those with (PHB group) and without PHB (non-PHB group). During follow-up, LD increased significantly in PHB group (1.2+/-0.3 vs. 1.7+/-0.5 mm, P=0.001) but not in the non-PHB group (2.0+/-0.7 vs. 2.1+/-0.7 mm, P=NS). Late lumen gain (LLG) was observed in 16 of the 27 (59%) lesions. Lesions with LLG showed a trend toward smaller baseline lumen cross-sectional area and significantly higher prevalence of PHB (88% vs. 18%, P=0.007). By multivariable logistic regression analysis, PHB was the only IVUS predictor of LLG. CONCLUSIONS: Presence of PHB on IVUS predicts chronic enlargement of the coronary segments distal to the stented lesion. PMID- 25746546 TI - The Speckle Tracking Imaging for the Assessment of Cardiac Resynchronization Therapy (START) study. AB - BACKGROUND: We sought to identify the feasibility of speckle tracking echocardiography (STE) to predict cardiac resynchronization therapy (CRT) responders in a prospective multicenter study. METHODS AND RESULTS: Patients who were newly implanted with a CRT device were enrolled. Time (T) from QRS to maximum peak radial and circumferential strain (CS) in 6 segments on the left ventricular (LV) short-axis plane, and to the maximum peak of longitudinal strain in 18 segments on 3 apical LV planes was measured (Tmax). In segments with multiple peaks on the time-strain curves, time to the first peak (Tfirst) was also assessed. Difference in T between the earliest and latest segment and standard deviation (SD) of T in each strain component were assessed. CRT responders were defined as having LV end-systolic volume reduction >15% at 6 months after CRT. Clinical outcomes were assessed with a composite endpoint of death from cardiac causes or unplanned hospitalization for heart failure. Among 180 patients, 109 patients were identified as responders. Tfirst-SD of CS >116 ms was selected as the best independent predictor of CRT responders (P<0.001, hazard ratio=9.83, 95% confidence interval 3.78-25.6). In addition, Tfirst-SD of CS was associated with the clinical endpoints. CONCLUSIONS: This prospective multicenter study revealed the high feasibility of dyssynchrony assessment by STE, which may improve the ability to predict CRT responders. PMID- 25746547 TI - Prediction of left main or 3-vessel disease using myocardial perfusion reserve on dynamic thallium-201 single-photon emission computed tomography with a semiconductor gamma camera. AB - BACKGROUND: Myocardial perfusion imaging (MPI) may fail to detect balanced ischemia. We evaluated myocardial perfusion reserve (MPR) using Tl dynamic single photon emission computed tomography (SPECT) and a novel cadmium zinc telluride (CZT) camera for predicting 3-vessel or left main coronary artery disease (CAD). METHODS AND RESULTS: A total of 55 consecutive patients with suspected CAD underwent SPECT-MPI and coronary angiography. The MPR index was calculated using the standard 2-compartment kinetic model. We analyzed the utility of MPR index, other SPECT findings, and various clinical variables. On multivariate analysis, MPR index and history of previous myocardial infarction (MI) predicted left main and 3-vessel disease. The area under the receiver operating characteristic curve was 0.81 for MPR index, 0.699 for history of previous MI, and 0.86 for MPR index plus history of previous MI. MPR index <=1.5 yielded the highest diagnostic accuracy. Sensitivity, specificity, and accuracy were 86%, 78%, and 80%, respectively, for MPR index, 64%, 76%, 73% for previous MI, and 57%, 93%, and 84% for MPR index plus history of previous MI. CONCLUSIONS: Quantification of MPR using dynamic SPECT and a novel CZT camera may identify balanced ischemia in patients with left main or 3-vessel disease. PMID- 25746548 TI - Relationship between beta-blocker and angiotensin-converting enzyme inhibitor dose and clinical outcome following acute myocardial infarction. AB - BACKGROUND: Benefit of beta-blockers (BB) and angiotensin-converting-enzyme inhibitors (ACEI) on mortality following acute myocardial infarction (MI) is well demonstrated. This study assessed the impact of BB and ACEI doses administered following ST-elevation MI on mortality and outcome up to 1 year. METHODS AND RESULTS: The French prospective observational cohort "RIMA" included 1,461 MI patients. Dosing of BB and ACEI given at 24 h and at time of discharge was assessed as follows: no treatment; <50% of target dose; or >=50% of target dose. For in-hospital mortality, after MI, the use of BB in the first 24 h, but not ACEI, was associated with significantly lower event rate on multivariate analysis (OR, 5.78; 95% CI: 2.62-12.76, P<0.001). In contrast at 1 year, use of higher doses of ACEI, but not BB, was associated with significantly lower CV mortality, readmission for heart failure and the composite of CV mortality and readmission for heart failure (HR, 2.65; 95% CI: 1.32-5.31, P=0.006 for absence of ACEI at discharge). CONCLUSIONS: Prescription of BB in the first 24 h was independently associated with a lower in-hospital mortality following MI. There appeared to be a significant dose effect on outcome with regard to <50% vs. >=50% of target dose, which requires confirmation in further large-scale clinical studies. PMID- 25746549 TI - Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel prognostic biomarker in patients with ST-segment elevation acute myocardial infarction. AB - BACKGROUND: Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX 1) level is a reliable prognostic biomarker in acute coronary syndrome. However, it is unclear whether its plasma level at acute phase is related to the long-term prognosis in patients with ST-segment elevation acute myocardial infarction (STEMI). METHODS AND RESULTS: We prospectively examined the relation between plasma sLOX-1 level on admission and prognosis in 153 consecutive STEMI patients admitted within 24 h of onset. Primary percutaneous coronary intervention was performed in 144 patients. The patients were divided into 2 groups by the median value (71 pg/ml) of plasma sLOX-1 level on admission [sLOX-1 level <=71 pg/ml (n=77) and >71 pg/ml (n=76)], and were followed for median of 1,156 days. All cause mortality and the combined endpoints of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and recurrent MI were both significantly higher in patients with sLOX-1 values above median than in those below median (25.0% vs. 3.9%, P<0.001, and 19.4% vs. 6.5%, P=0.019 by log-rank test, respectively). Even after adjustment for confounders, a level of sLOX-1 above median was an independent predictor for all-cause mortality (hazard ratio (HR): 5.893; 95% confidence interval (CI): 1.665-20.854, P=0.006) and MACE (HR: 3.457; 95% CI: 1.164-10.270, P=0.030). CONCLUSIONS: Elevated plasma sLOX-1 level on admission independently predicts long-term all-cause mortality and MACE after STEMI. PMID- 25746550 TI - Cardiac resynchronization therapy for various systemic ventricular morphologies in patients with congenital heart disease. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) can result in functional improvement and reduced mortality in patients with medically refractory heart failure. Although CRT is reportedly effective in patients with congenital heart disease (CHD), it is still controversial in patients who have systemic right ventricle. METHODS AND RESULTS: Twenty CHD patients treated with CRT since 2006 were divided into 3 groups based on systemic ventricular (sysV) morphology (7 with left ventricle [sLV], 7 with right ventricle [sRV], and 6 with unbalanced 2 ventricles as a single-ventricular physiology [sBV]). The acute effects of CRT on hemodynamics and sysV function before device implantation was retrospectively evaluated and the chronic (>=6 months) effects of CRT on late outcomes was assessed. In our CHD populations, sysV volume index was reduced from 139+/-41 to 118+/-33 ml/m(2)(P=0.04) after CRT, and there was significant improvement in B type natriuretic peptide levels (from 341+/-384 to 160+/-152 pg/ml, P=0.01) and New York Heart Association (NYHA) functional class (from 2.1+/-0.6 to 1.8+/-0.7, P=0.02) on a late outcome. The sRV group did not show a late sysV volume reduction despite significant QRS shortening, and an increase of sysV peak dP/dt in the acute study differed from that of other groups. CONCLUSIONS: CRT improves late hemodynamic and functional status in sLV and sBV CHD patients with a dyssynchronized sysV. However, an acute CRT effect cannot guarantee long-term benefit in sRV patients. PMID- 25746551 TI - Multimarker approach to risk stratification for long-term mortality in patients on chronic hemodialysis. AB - BACKGROUND: We prospectively investigated the prognostic value of the combined use of cardiac troponin T (TnT), B-type natriuretic peptide (BNP), and high sensitivity C-reactive protein (CRP) for long-term mortality in hemodialysis (HD) patients. METHODS AND RESULTS: Baseline measurements of TnT, BNP, and CRP were performed in 516 patients on chronic HD. Patients were followed up for 10 years. Using the Cox multivariate model with these 3 biomarkers as variables categorized into tertiles for mortality, a simplified score was obtained by underscoring individual biomarkers based on the adjusted hazard ratio (HR). The multimarker score was defined as the sum of these points. TnT, BNP, and CRP levels were individually independent predictors for mortality (P<0.05). Among low-risk (multimarker score <4), intermediate-risk (multimarker score 4-7), and high-risk (multimarker score >=7) groups, 10-year survival rates were 83.3%, 54.3%, and 27.2% (P<0.0001), respectively. After adjusting for other confounders, the multimarker score had strong predictive power for mortality (HR: 4.26; P<0.0001 for high-risk vs. low-risk group). Furthermore, adding the multimarker score to a baseline model with established risk factors improved the C-index (P<0.01), net reclassification improvement (P<0.0001), and integrated discrimination improvement (P<0.0001) greater than that of any single biomarker or baseline model alone. CONCLUSIONS: The multimarker approach (ie, simultaneous assessment of TnT, BNP, and CRP, which individually independently predict prognosis) may improve the prediction of long-term mortality in HD patients. PMID- 25746552 TI - Predictors and prognostic impact of post-traumatic stress disorder after the great East Japan earthquake in patients with cardiovascular disease. AB - BACKGROUND: We examined the prevalence, predictors and prognostic impact of post traumatic stress disorder (PTSD) after the Great East Japan Earthquake in patients with cardiovascular disease (CVD) in the CHART-2 study. METHODS AND RESULTS: The prevalence of PTSD was 14.7% at 6 months after the Earthquake. Female sex, experiencing the Tsunami, property loss, poverty, and insomnia medication use were associated with PTSD. The patients with PTSD more frequently experienced a composite of death, acute myocardial infarction, stroke and heart failure (18.5% vs. 15.0%, P=0.035). CONCLUSIONS: PTSD was frequent in CVD patients after the Earthquake and had an adverse prognostic impact. PMID- 25746553 TI - Seasonal changes in systemic volume overload are to be considered. PMID- 25746554 TI - Seasonal changes in systemic volume overload are to be considered--reply. PMID- 25746557 TI - Effect of UV-light on the uniaxial tensile properties and structure of uncoated and TiO2 coated Bombyx mori silk fibers. AB - The effect of UV-light on the uniaxial tensile properties and the structure of uncoated and TiO2 coated silk fibers in the bave form by using sol-gel method was investigated with tensile testing and FT-IR/ATR spectroscopy methods after the silk filaments were exposed to UV-light with high intensity of 760W/m(2) for different times from 0.5h to 1day. It was clearly observed that TiO2 coating considerably increased the Young's modulus of the uncoated silk single filament by around 17% before the UV-irradiation. The yield point and the post yield region disappeared on the stress-strain curves of both uncoated and TiO2 coated silk filaments after UV-irradiation time higher than 1h. Except for the Young's modulus, most of the tensile characteristics of both uncoated and TiO2 coated silk filaments decreased remarkably with increasing UV-irradiation time, e.g., after 1h irradiation, although the Young's modulus slightly changed and ultimate tensile strength decreased by only around 18% and 23%, for the uncoated and TiO2 coated silk filaments, respectively; breaking extension decreased dramatically by 67% and 72%, respectively, for uncoated and TiO2 coated silk filaments. Only the Young's modulus of TiO2 coated silk filaments which can be considered as a more stable tensile characteristic became significantly higher than that of the uncoated silk filaments with increasing UV-irradiation time. After 1day irradiation, even though the uncoated silk filaments could not be tested and completely lost of their fiber properties, the TiO2 coated silk filaments showed a stress-strain curve in initial elastic region with Young's modulus of ~13GPa which indicates considerable protective effect of TiO2 on the silk fiber structure, especially on the beta-sheet microcrystals against UV-radiation. The FT-IR/ATR spectral results showed that significant photodegradation took place in not only crystalline but also amorphous regions which were deduced from the decrease in the absorbance ratios of the bands assigned to CH3 rocking, Calpha Cbeta, Calpha-C stretching vibrations in beta-sheet crystalline regions as well as the Amide I, II, and III bands for both crystalline and amorphous regions. Even though the ratio of crystalline to amorphous regions in uncoated silk filaments decreased significantly, the ratio in TiO2 coated silk filaments became almost constant with increasing UV-irradiation time which may indicate more stable beta-sheet microcrystals against photodegradation. PMID- 25746559 TI - Abnormal coactivation of the hypothalamus and salience network in patients with cluster headache. AB - OBJECTIVE: The purpose of this study was to investigate whether the resting-state coactivation of the hypothalamus, both ipsilateral and contralateral to the headache side, and the salience network (SN) was altered in patients with cluster headache (CH) in the headache attack remission state in the cluster period, and to reveal possible pathogenesis of CH attacks and gain further insight into the pathophysiology of CH. METHODS: Resting-state fMRI scans of 21 patients with CH were obtained (13 with right-sided headache and 8 with left-sided headache) and 21 age- and sex-matched normal controls. The resting-state fMRI data were analyzed using independent component analysis to identify the group differences of hypothalamic-SN coactivation between the patients with CH and healthy controls. RESULTS: Decreased functional coactivation was detected between the hypothalamus, both ipsilateral and contralateral to the headache side, and the SN both in patients with right-sided CH and in those with left-sided CH. CONCLUSION: Our findings suggest that the decreased hypothalamus-SN coactivation may have a role in CH attacks by the defective central pathway of pain control and autonomic nervous system dysregulation. This helps to gain additional insight into the pathophysiologic basis of CH and the nature of the brain dysfunction in CH. PMID- 25746558 TI - White and gray matter contributions to executive function recovery after traumatic brain injury. AB - OBJECTIVE: We investigated the association between regional white and gray matter volume loss and performance on executive functions (EFs) in patients with penetrating traumatic brain injury (pTBI). METHODS: We studied 164 pTBI patients and 43 healthy controls from the Vietnam Head Injury Study. We acquired CT scans for pTBI patients and divided them according to lesion localization (left and right prefrontal cortex [PFC]). We administered EF tests (Verbal Fluency, Trail Making, Twenty Questions) and used voxel-based lesion symptom mapping (VLSM) and group-based correlational and multiple regression analyses to examine the relative influence of gray and white matter lesions on EF recovery. RESULTS: The VLSM analysis revealed that white and gray white matter lesions were associated with impaired EFs. In the left PFC lesion group, damage to the PFC gray matter, anterior corona radiata, and superior longitudinal fasciculus (SLF) were most correlated with functional recovery. Verbal Fluency, which involves a broad fronto-temporo-parietal network, was best predicted by SLF lesion volume. Trail Making and Twenty Questions, which is associated with more focal left frontal damage, was better predicted by PFC lesions. CONCLUSIONS: Our results indicated that white matter volume loss can be a superior predictor of recovery and a crucial factor driving clinical outcome in functions involving a broad network such as Verbal Fluency. White matter damage may place additional burden on recovery by deteriorating signal transmission between cortical areas within a functional network. PMID- 25746560 TI - The role of cerebral disconnection in cognitive recovery after brain damage. PMID- 25746561 TI - From clinical to tissue-based dual TIA: Validation and refinement of ABCD3-I score. AB - OBJECTIVE: To investigate whether dual tissue-defined ischemic attacks, defined as multiple diffusion-weighted imaging lesions of different age and/or arterial territory (dual DWI), are an independent and stronger predictor of 90-day stroke than dual clinical TIAs (dual TIA). METHODS: Consecutive patients with clinically defined TIA were enrolled and assessed clinically and by MRI within 3 days. The predictive ability of the ABCD clinical factors, dual TIA, and dual DWI was evaluated by means of multivariate logistic regression. RESULTS: Among 658 patients who were included in the study and completed 90 days of follow-up, a total of 70 patients (10.6%) experienced subsequent stroke by 90 days. Multivariate logistic regression indicated that dual DWI was an independent predictor for subsequent stroke (odds ratio 4.64, 95% confidence interval 2.15 10.01), while dual TIA was not (odds ratio 1.18, 95% confidence interval 0.69 2.01). C statistics was higher when the item of dual TIA in ABCD3-I score was replaced by dual DWI (0.759 vs 0.729, p = 0.035). The net reclassification value for 90-day stroke risk was also improved (continuous net reclassification improvement 0.301, p = 0.017). CONCLUSION: Dual DWI independently predicted future stroke in patients with TIA. A new ABCD3-I score with dual DWI instead of dual clinical TIA may improve risk stratification for early stroke risk after TIA. PMID- 25746562 TI - Elevated pretreatment blood pressure and IV thrombolysis in stroke. AB - OBJECTIVES: We investigated whether an active blood pressure-lowering strategy is associated with more patients receiving thrombolytics compared with a conservative "watch and measure" strategy, and assessed safety and functional outcome of these 2 treatment strategies. METHODS: This is a post hoc analysis in 2 randomized controlled stroke trials, the PRACTISE (Promoting Acute Thrombolysis in Ischemic Stroke) and the PASS (Preventive Antibiotics in Stroke Study). We included all patients with elevated pretreatment blood pressure above 185/110 mm Hg at presentation but otherwise eligible for IV thrombolysis (IVT). The decision to use an active or conservative strategy was in accordance with local hospital treatment guidelines. The primary outcome was the proportion of patients treated with IVT. Secondary outcomes were (1) symptomatic intracranial hemorrhage (increased neurologic deficit with a concomitant hemorrhage on neuroimaging), (2) functional outcome at 3 months, and (3) the door-to-needle time. RESULTS: We included 224 patients, 66 (29%) received the active and 158 (71%) the conservative strategy. In the active group, 55 patients (83%) received thrombolytics vs 87 (55%) in the conservative group, an increase of 28% (95% confidence interval: 16%-40%). If only patients actually treated with IVT were considered, the rate of symptomatic intracranial hemorrhage was 7% in both groups. There was no difference in door-to-needle time. CONCLUSIONS: Active blood pressure lowering was associated with an increased proportion of patients treated with IVT compared with a conservative strategy, without a difference in symptomatic hemorrhage rate. PMID- 25746563 TI - Ictal adipokines are associated with pain severity and treatment response in episodic migraine. AB - OBJECTIVE: To evaluate ictal adipokine levels in episodic migraineurs and their association with pain severity and treatment response. METHODS: This was a double blind, placebo-controlled trial evaluating peripheral blood specimens from episodic migraineurs at acute pain onset and 30 to 120 minutes after treatment with sumatriptan/naproxen sodium vs placebo. Total adiponectin (T-ADP), ADP multimers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]), leptin, and resistin levels were evaluated by immunoassays. RESULTS: Thirty-four participants (17 responders, 17 nonresponders) were included. In all participants, pretreatment pain severity increased with every quartile increase in both the HMW:T-ADP ratio (coefficient of variation [CV] 0.51; 95% confidence interval [CI]: 0.08, 0.93; p = 0.019) and resistin levels (CV 0.58; 95% CI: 0.21, 0.96; p = 0.002), but was not associated with quartile changes in leptin levels. In responders, T-ADP (CV -0.98; 95% CI: -1.88, -0.08; p = 0.031) and resistin (CV -0.95; 95% CI: -1.83, -0.07; p = 0.034) levels decreased 120 minutes after treatment as compared with pretreatment. In addition, in responders, the HMW:T-ADP ratio (CV -0.04; 95% CI: -0.07, -0.01; p = 0.041) decreased and the LMW:T-ADP ratio (CV 0.04; 95% CI: 0.01, 0.07; p = 0.043) increased at 120 minutes after treatment. In nonresponders, the LMW:T-ADP ratio (CV -0.04; 95% CI: -0.07, -0.01; p = 0.018) decreased 120 minutes after treatment. Leptin was not associated with treatment response. CONCLUSIONS: Both pretreatment migraine pain severity and treatment response are associated with changes in adipokine levels. Adipokines represent potential novel migraine biomarkers and drug targets. PMID- 25746565 TI - Influence of surface heterogeneities on reversibility of fullerene (nC60) nanoparticle attachment in saturated porous media. AB - This study systematically investigated influence of surface roughness and surface chemical heterogeneity on attachment and detachment of nC60 nanoparticles in saturated porous media by conducting laboratory column experiments. Sand and glass beads were employed as a model collectors to represent a different surface roughness. The two collectors were treated by washing with only deionized water or by using acids to extensively remove chemical heterogeneities. Results show that both attachment and detachment were more in the acid-treated sand than those in the acid-treated glass beads. The greater attachment and detachment were attributed to the reason that sand surfaces have much more nanoscale asperities, which facilitates particle attachment atop of them at primary minima and subsequent detachment upon reduction of ionic strength. No detachment was observed if the water-washed collectors were employed, demonstrating that the couple of chemical heterogeneity with nanoscale roughness causes irreversible attachment in primary minima. Whereas existing studies frequently represented surface rough asperities as regular geometries (e.g., hemisphere, cone, pillar) for estimating influence of surface roughness on Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction energies, our theoretical calculations indicate that the assumptions could underestimate both attachment and detachment because these geometries cannot account for surface curvature effects. PMID- 25746564 TI - Nuclear actin aggregation is a hallmark of anti-synthetase syndrome-induced dysimmune myopathy. AB - OBJECTIVE: To analyze antisynthetase syndrome-associated myositis by modern myopathologic methods and to define its place in the spectrum of idiopathic inflammatory myopathies (IIMs). METHODS: Skeletal muscle biopsies from antisynthetase syndrome-associated myositis and other IIMs from different institutions worldwide were analyzed by histopathology, quantitative PCR, and electron microscopy. RESULTS: Myonuclear actin filament inclusions were identified as a unique morphologic hallmark of antisynthetase syndrome-associated myositis. Nuclear actin inclusions were never found in dermatomyositis, polymyositis, sporadic inclusion body myositis, autoimmune necrotizing myopathy associated with signal recognition particle or 3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibodies, or nonspecific myositis associated with other systemic diseases, harboring myositis-associated autoantibodies, and presenting myofiber necrosis. We show that molecules involved in actin filament formation and actin shuttling mechanisms are altered in antisynthetase syndrome, and may thus be involved in pathologic myonuclear actin aggregation. In addition, we have identified a typical topographic distribution of necrotic myofibers predominantly located at the periphery of muscle fascicles accompanied by inflammation and destruction of the perimysial connective tissue. CONCLUSION: Antisynthetase syndrome-associated myositis is characterized by distinctive myonuclear actin filament inclusions, including rod formations and a typical necrotizing perimysial myositis. This supports the hypothesis that antisynthetase syndrome-associated myositis is unique and should not be grouped among dermatomyositis, polymyositis, sporadic inclusion body myositis, necrotizing autoimmune myositis, or nonspecific myositis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with IIMs, the presence of myonuclear actin filament inclusions accurately identifies patients with antisynthetase syndrome-associated myositis (sensitivity 81%, specificity 100%). PMID- 25746566 TI - Investigation of the colloidal Cr2O3 removal possibilities from aqueous solution using the ionic polyamino acid block copolymers. AB - Disposal of the environmentally dangerous metal oxide suspensions from the waste water is an essential problem. The polymers adsorption can be one of the most effective and suitable methods. In the presented paper the ionic diblock copolymers impact on the Cr2O3 suspensions was investigated. The copolymer adsorption layers structure was determined on the basis of the adsorption and electrokinetic (surface charge density and zeta potential) tests. The polymers adsorption amount was measured using the static method from aqueous solutions. Additionally, the application of the turbidimetric method enabled determination of the interactions between the system constituents. Analysis of this data allows the estimation of the most probable stabilization (or destabilization) mechanism of the Cr2O3 suspensions in the presence of the studied macromolecular compounds. Hence, the Cr2O3 suspensions are unstable in the presence of the anionic copolymer at pH 3 and the cationic one in the alkaline medium. PMID- 25746567 TI - Burning rate of merged pool fire on the hollow square tray. AB - In order to characterize fire merging, pool fires on hollow trays with varying side lengths were burned under quasi-quiescent condition and in a wind tunnel with the wind speed ranging from 0m/s to 7.5m/s. Burning rate and flame images were recorded in the whole combustion process. The results show that even though the pool surface area was kept identical for hollow trays of different sizes, the measured burning rates and fire evolutions were found to be significantly different. Besides the five stages identified by previous studies, an extra stage, fire merging, was observed. Fire merging appeared possibly at any of the first four stages and moreover resulted in 50-100% increases of the fire burning rates and heights in the present tests. The tests in wind tunnel suggested that, as the wind speed ranges from 0 m/s to 2 m/s, the burning rates decrease. However with further increase of the wind speed from 2 m/s to 7.5 m/s, the burning rate was found to increase for smaller hollow trays while it remains almost constant for larger hollow trays. Two empirical correlations are presented to predict critical burning rate of fire merging on the hollow tray. The predictions were found to be in reasonably good agreement with the measurements. PMID- 25746568 TI - The first evidence of deinoxanthin from Deinococcus sp. Y35 with strong algicidal effect on the toxic dinoflagellate Alexandrium tamarense. AB - Harmful algal blooms (HABs) could be deemed hazardous materials in aquatic environment. Alexandrium tamarense is a toxic HAB causing alga, which causes serious economic losses and health problems. In this study, the bacterium Deinococcus xianganensis Y35 produced a new algicide, showing a high algicidal effect on A. tamarense. The algicidal compound was identified as deinoxanthin, a red pigment, based on high resolution mass spectrometry and NMR after the active compound was isolated and purified. Deinoxanthin exhibited an obvious inhibitory effect on algal growth, and showed algicidal activity against A. tamarense with an EC50 of 5.636 MUg/mL with 12h treatment time. Based on the unique structure and characteristics of deinoxanthin, the content of reactive oxygen species (ROS) increased after 0.5h exposure, the structure of organelles including chloroplasts and mitochondria were seriously damaged. All these results firstly confirmed that deinoxanthin as the efficient and eco-environmental algicidal compound has potential to be used for controlling harmful algal blooms through overproduction of ROS. PMID- 25746569 TI - Adaption of the microbial community to continuous exposures of multiple residual antibiotics in sediments from a salt-water aquacultural farm. AB - Residual antibiotics from aquacultural farming may alter microbial community structure in aquatic environments in ways that may adversely or positively impact microbially-mediated ecological functions. This study investigated 26 ponds (26 composited samples) used to produce fish, razor clam and shrimp (farming and drying) and 2 channels (10 samples) in a saltwater aquacultural farm in southern China to characterize microbial community structure (represented by phospholipid fatty acids) in surface sediments (0-10 cm) with long-term exposure to residual antibiotics. 11 out of 14 widely-used antibiotics were quantifiable at MUg kg(-1) levels in sediments but their concentrations did not statistically differ among ponds and channels, except norfloxacin in drying shrimp ponds and thiamphenicol in razor clam ponds. Concentrations of protozoan PLFAs were significantly increased in sediments from razor clam ponds while other microbial groups were similar among ponds and channels. Both canonical-correlation and stepwise multiple-regression analyses on microbial community and residual antibiotics suggested that roxithromycin residuals were significantly related to shifts in microbial community structure in sediments. This study provided field evidence that multiple residual antibiotics at low environmental levels from aquacultural farming do not produce fundamental shifts in microbial community structure. PMID- 25746570 TI - Oxidation process of dissolvable sulfide by synthesized todorokite in aqueous systems. AB - Todorokite, formed from Mn(II) in supergene environments, can affect the transformation and migration of dissolvable sulfides in soils and water. In this work, todorokite was synthesized with different degrees of crystallinity, and the redox mechanism of dissolvable sulfide and todorokite was studied in both closed and open aqueous systems. The influences of pH, temperature, crystallinity, the amount of manganese oxides, and oxygen gas on S(2-) oxidation process were investigated. It is found that S(2-) was oxidized to S(0), SO3(2-), S2O3(2-) and SO4(2-), and about 90% of S(2-) was converted into S(0) in closed systems. The participation of oxygen facilitated the further oxidation of S(0) to S2O3(2-). S(0) and S2O3(2-) were formed with the conversion rates of S(2-) about 45.3% and 38.4% after 1h of reaction, respectively, and the conversion rate for S2O3(2-) increased as reaction prolonged for a longer period. In addition, todorokite was reduced to Mn(OH)2 in the presence of nitrogen gas, and its chemical stability increased when oxygen gas was admitted into the reaction system during the process. The oxidation rate of dissolvable sulfide followed a pseudo-first-order kinetic law in the initial stage (within 10 min), and the initial oxidation rate constant of S(2-) increased with elevating temperature, increasing the quantity and decreasing crystallinity of todorokite. The initial oxidation rate of dissolvable sulfide decreased with continuous feeding of O2 into the test solution, possibly due to a decrease in active Mn(III) content in todorokite. The present work demonstrates the redox behaviors and kinetics of dissolvable sulfide and todorokite in aquatic environments. PMID- 25746571 TI - Antimicrobial behavior of biosynthesized silica-silver nanocomposite for water disinfection: a mechanistic perspective. AB - The biosynthesis of nano-silica silver nanocomposite (NSAgNC) and it is as antibacterial effect on gram-negative bacteria viz.Escherichia coli and Pseudomonas aeruginosa has been investigated for disinfection of water. The as synthesized NSAgNC exhibited antibacterial activity in a dose dependent manner and ~ 99.9% of E. coli and P. aeruginosa were killed at a concentration of 1.5 mg/mL of NSAgNC (5.1 wt% Ag) within 5h. The NSAgNC showed similar antibacterial activities both in oxic and anoxic conditions. The results further demonstrated that NSAgNC exhibited reactive oxygen species (ROS) independent "particle specific" antibacterial activity through multiple steps in absence of leached out Ag(+) ions. The initial binding of NSAgNC on the cell wall caused loss of cell membrane integrity and leakage of cytoplasmic materials. Inhibition of respiratory chain dehydrogenase by NSAgNC caused metabolic inactivation of the cells and affecting the cell viability. Genomic and proteomic studies further demonstrated the fragmentations of both plasmid and genomic DNA and down regulation of protein expression in NSAgNC treated cells, which leading to the cell death. Thus the biosynthesized NSAgNC has great potential as disinfectant for water purification while minimizing the toxic effects. PMID- 25746572 TI - The impact of seizures on pregnancy and delivery. AB - PURPOSE AND METHODS: The treatment of women with epilepsy during pregnancy is known to increase the risk of teratogenic effects. Whether seizures during pregnancy have a deleterious effect on the developing child is difficult to determine, but recent animal studies, case studies, cohort studies and population studies have provided useful insights. RESULTS AND CONCLUSION: Seizures before pregnancy are a predictor for seizures during pregnancy, and catamenial epilepsy may also predict the course of seizures during pregnancy. A first epileptic seizure may also have implications for the pregnancy, depending on the seizure aetiology. Seizures affecting maternal awareness and responsiveness may have cardiac effects on the foetus and may impact on the weight of the newborn. Status epilepticus in pregnancy is rare, but isolated cases of perinatal death and malformations after status epilepticus have been reported in women on antiepileptic drugs. Seizures during delivery occur in about 2% of pregnancies of women with epilepsy, and case studies indicate that the foetal heart may be affected. However, a diagnosis of epilepsy is not an indication per se for caesarean delivery. A well-planned pregnancy can reduce the likelihood of seizures occurring. PMID- 25746573 TI - Clinical significance of papillary thyroid cancer risk loci identified by genome wide association studies. AB - Four single nucleotide polymorphisms (SNPs) have been reported to be associated with thyroid cancer risk in two genome-wide association studies (GWASs) and were validated in a Chinese population. Because of a lack of further clinical and functional evidence, the clinical significances of these SNPs remain unknown. Four GWAS-identified SNPs of papillary thyroid cancer (PTC), rs965513, rs944289, rs966423 and rs2439302, were genotyped in a case-control study of 838 patients with PTC and 501 patients with benign thyroid tumor (BTT) from the Chinese Han population. The associations between these SNPs, clinicopathologic features, and the outcome of the PTC patients were examined. The CT and CT + TT genotypes of rs966423 were more common in PTC patients with extrathyroidal extension and more advanced T stage. The TC and TC + CC genotypes and the C allele of rs944289 were significantly less frequent in patients with multifocal disease. No correlation was observed between GWAS-identified SNPs and disease persistence of PTC after a short-term follow-up. Significantly different allele distributions between the PTC and BTT groups were observed for all four selected SNPs. Individuals with more than five risk alleles were 8.84-fold (95% CI 3.23-24.17) more likely to suffer from PTC compared with those with zero or 1 risk allele. GWAS-identified SNPs affect the individual predisposition to PTC without interacting with existing Hashimoto thyroiditis and BTT lesions. GWAS-identified SNPs were associated with certain clinicopathologic features of PTC, and may contribute to identifying PTC patients with different clinical patterns. Large prospective studies are required to further evaluate the diagnostic and prognostic power of these genetic markers. PMID- 25746574 TI - Effects of dietary supplementation with green tea polyphenols on digestion and meat quality in lambs infected with Haemonchus contortus. AB - Ujumqin sheep are susceptible to infection by the gastrointestinal nematode Haemonchus contortus, which reduces productivity and total meat yield in sheep. Thus, the effects of green tea polyphenol (GTP) supplements (0, 2, 4, or 6g of GTP/kg feed) on dietary nutrient digestibility and meat quality in lambs infected with H. contortus were examined; control lambs were not infected. H. contortus infections did not affect digestion but the apparent digestibilities of nutrients were decreased by dietary 2g of GTP/kg feed supplementation. There was an interaction between treatment and sampling time on plasma total protein, urea nitrogen, and amino acid concentrations. The antioxidant activity and meat color of INFGTP0 lambs decreased. In conclusion, H. contortus infections in lambs decreased meat quality, but appropriate levels of dietary GTP supplementation diminished these negative effects though lower dose of GTP supplement showed negative effects on digestion. PMID- 25746575 TI - The uncertainty of predicting intact anterior cruciate ligament degeneration in terms of structural properties using T(2)(*) relaxometry in a human cadaveric model. AB - The combination of healing anterior cruciate ligament (ACL) volume and the distributions of T2(*) relaxation times within it have been shown to predict the biomechanical failure properties in a porcine model. This MR-based prediction model has not yet been used to assess ligament degeneration in the aging human knee. Using a set of 15 human cadaveric knees of varying ages, we obtained in situ MR measures of volume and T2(*) of the intact ACL and then related these MR variables to biomechanical outcomes (maximum and yield loads, linear stiffness) obtained via ex vivo failure testing. Using volume in conjunction with the median T2(*) value, the multiple linear regression model did not predict maximum failure load for the intact human ACL; R(2)=0.23, p=0.200. Similar insignificant results were found for yield load and linear stiffness. Naturally restricted distributions of the intact ligament volume and T2(*) (demonstrated by the respective Z-scores) in an older cadaveric population were the likely reason for the insignificant results. These restricted distributions may negatively affect the ability to detect a correlation when one exists. Further research is necessary to understand the relationship of MRI variables and ligament degeneration. While this study failed to find a significant prediction of human biomechanical outcome using these MR variables, with further research, an MR based approach may offer a tool to longitudinally assess changes in cruciate ligament degradation. PMID- 25746576 TI - Comparative pharmacokinetics of puerarin, daidzin, baicalin, glycyrrhizic acid, liquiritin, berberine, palmatine and jateorhizine by liquid chromatography-mass spectrometry after oral administration of Gegenqinlian decoction and active components alignment (ACA) to rats. AB - An LC-MS/MS method was developed for simultaneous analysis of puerarin, daidzin, baicalin, glycyrrhizic acid, liquiritin, berberine, palmatine and jateorhizine of Gegenqinlian Decoction (GQD) and active components alignment (ACA) in rat plasma using hesperidin as the internal standard (I.S.). Chromatography was performed using a C18 column, with gradient elution with 1% acetic acid-0.001 mol/L ammonium acetate and acetonitrile at 0.2 ml/min. All analytes including I.S. were monitored under positive ionization conditions by selected reaction monitoring with an electrospray ionization source. The optimized mass transition ion-pairs (m/z) for quantitation were 471/297 for puerarin, 471/255 for daidzin, 447/271 for baicalin, 823/453 for glycyrrhizic acid, 419/257 for liquiritin, 336/320 for berberine, 352/336 for palmatine, 338/322 for jateorhizine and 611/303 for hesperidin. The calibration curves were linear over the concentration ranges from 0.15-63.0 to 6.3-6340.0 ng/mL. Intra-day and inter-day precisions (RSD%) were within 15.0%, and accuracy (RE%) ranged from -7.4 to 13.2%. The extraction recoveries were ranged from 60.4 to 93.3%. The proposed method was further applied to compare the pharmacokinetics of all analytes following a single oral administration of GQD and ACA. In conclusion, the eight analytes of GQD and ACA had partly similar pharmacokinetics, which were different from single composition (such as puerarin). PMID- 25746577 TI - Reply: To PMID 25746578. PMID- 25746578 TI - Variability in Medicare utilization and payment among urologists. AB - OBJECTIVE: To analyze variability in urologists' Medicare utilization and payment and estimate potential cost savings of standardized service utilization using information from the recently released Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File (PUF) and to highlight potential limitations of PUF analysis. MATERIALS AND METHODS: The Centers for Medicare and Medicaid Services just released the PUF with payment or utilization data for 8792 urologists participating in Medicare in 2012. Linear regression correlated total number of patient visits with total Medicare payments to each urologist. Physicians were categorized into quartiles by actual payment in excess of predicted payment modeled by this regression. Utilization variability was calculated as a relative risk for the 40 most highly reimbursed services per patient visit, comparing the highest vs lowest quartile of urologists. Potential cost savings for those 40 services were calculated if services per visit >50% above the median were eliminated. RESULTS: Medicare reimbursement was strongly predicted by the number of patient visits (R(2) = 0.70). Utilization variability of services performed per visit had a relative risk up to 3.52. The potential cost savings was $125,199,007 (9.0% of total 2012 Medicare urologist reimbursements). CONCLUSION: Overall Medicare payment to urologists was strongly predicted by number of patient visits. Substantial variability existed in utilization of services per patient visit. Standardized utilization may result in significant Medicare cost savings. However, future analyses accounting for variable patient characteristics are needed to accurately determine appropriate service utilization. PMID- 25746579 TI - Trends, utilization, and immediate perioperative complications of urethroplasty in the United States: data from the national inpatient sample 2000-2010. AB - OBJECTIVE: To determine national urethroplasty trends based on type of surgery and patient and hospital characteristics. We hypothesized that the number of complex urethroplasty procedures performed has increased over time and may be associated with increased periprocedure complications. METHODS: The National Inpatient Sample from years 2000 to 2010 was queried for patients with urethroplasty-associated International Classification of Diseases, Ninth Revision, Clinical Modification codes. We analyzed trends in urethroplasty procedures, patient demographics, comorbidities, and hospital characteristics. We evaluated the relationship between patient demographics and comorbid disease, length of hospital stay, hospital charges, and inpatient complications. RESULTS: During the study period, an estimated 13,700 men (95% confidence interval, 9507 17,894) underwent urethroplasty nationally. Excision with primary anastomosis, buccal graft, and other graft or flap urethroplasty comprised 80.3%, 14.3%, and 5.4%, respectively. Buccal mucosa graft procedures increased over time (P = .03). Only 1.6% of hospitals have >= 20 urethroplasties performed annually. Urethroplasty type and urethroplasty volume were not associated with immediate complication rates. Hypertension, diabetes, chronic pulmonary disease, and obesity were the most common comorbidities in urethroplasty patients. Complications during urethroplasty hospitalization occurred in 6.6% of men, with surgical or wound complications being the most common (5.2%). Postoperative mortality was exceedingly rare. Older patients, African Americans, and patients with increased comorbidities were more likely to have complications. CONCLUSION: An increasing number of buccal mucosa graft urethroplasties occurred over time. Urethroplasty patients have low immediate perioperative morbidity (6.6%) and mortality (0.07%). Patients who are older, African American, or have more comorbid conditions have greater risk for complications. PMID- 25746580 TI - The therapeutic effect of solifenacin succinate on the recovery from voiding dysfunction after radical prostatectomy in men with clinically localized prostate cancer: a prospective, randomized, controlled study. AB - OBJECTIVE: To evaluate whether anticholinergic medication contributes to early recovery of continence and improvement of other voiding symptoms after radical prostatectomy (RP). PATIENTS AND METHODS: A total of 78 patients with clinically localized prostate cancer who had incontinence at 1 week after RP were enrolled prospectively. The patients were allocated to one of the 2 groups: group 1 (alpha adrenergic agonist [midodrine] plus an anticholinergic [solifenacin]) or group 2 (alpha-adrenergic agonist only). A urodynamic study and the International Continence Society male Short Form questionnaire were completed preoperatively and 4 months after RP. One-hour pad test and 3-day frequency volume chart at 1 and 4 months after medication were also analyzed. RESULTS: The rate of continence, defined as being pad free, did not differ between the groups at 4 months (both 71.8%; P >.05). However, the decreased value of mean weight of daily pads worn by groups 1 and 2 were 51.5 vs 11.7 g, respectively (P = .005). The incontinence (P = .008) and quality of life (P = .044) subscale scores significantly worsened in group 2, whereas they remained unchanged in group 1. Maximal detrusor pressure and maximal urethral closure pressure significantly decreased in both groups, whereas maximal cystometric capacity increased significantly in group 1 only (290.8-332.0 cm H2O; P <.001). CONCLUSION: Anticholinergics may facilitate early recovery from incontinence and prevent worsening of quality of life, which might be attributed to increased cystometric capacity after their use. PMID- 25746581 TI - Editorial comment. PMID- 25746582 TI - Surgical treatment for mesial temporal lobe epilepsy associated with hippocampal sclerosis. AB - INTRODUCTION: Hippocampal sclerosis is the most common cause of pharmacoresistant epilepsy amenable for surgical treatment and seizure control. The aim of this article is to review and evaluate the published literature related to the outcome of the surgical treatment of mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) and to describe the future prospects in this field. STATE OF ART: Surgery of MTLE associated with HS achieves long-term seizure freedom in about 70% (62-83%) of cases. Seizure outcome is similar in the pediatric population. Mortality following temporal resection is very rare (<1%) and the rate of definitive neurological complication is low (1%). Gamma knife stereotactic radiosurgery used as a treatment for MTLE would have a slightly worse outcome to that of surgical resection, but would provide neuropsychological advantage. However, the average latency before reducing or stopping seizures is at least 9 months with radiosurgery. Regarding palliative surgery, amygdalohippocampal stimulation has been demonstrated to improve the control of epilepsy in carefully selected patients with intractable MTLE who are not candidates for resective surgery. PERSPECTIVES: Recent progress in the field of imaging and image-guidance should allow to elaborate tailored surgical strategies for each patient in order to achieve seizure freedom. Concerning therapeutics, closed-loop stimulation strategies allow early seizure detection and responsive stimulation. It may be less toxic and more effective than intermittent and continuous neurostimulation. Moreover, stereotactic radiofrequency amygdalohippocampectomy is a recent approach leading to hopeful results. Closed loop stimulation and stereotactic radiofrequency amygdalohippocampectomy may provide a new treatment option for patients with pharmacoresistant MTLE. CONCLUSIONS: Mesial temporal lobe surgery has been widely evaluated and has become the standard treatment for MTLE associated with HS. Alternative surgical procedures like gamma knife stereotactic radiosurgery and amygdalohippocampal stimulation are currently under assessment, with promising results. PMID- 25746583 TI - The use of the pulse oximetric saturation to fraction of inspired oxygen ratio in an automated acute respiratory distress syndrome screening tool. AB - PURPOSE: To determine the relationship between the pulse oximetric saturation to fraction of inspired oxygen (SF) ratio and the arterial partial pressure of oxygen to the fraction of inspired oxygen (PF) ratio, and to assess the usefulness of the SF ratio in an automated acute respiratory distress syndrome (ARDS) screening tool. MATERIAL AND METHODS: This was a retrospective cohort study using the Multiparameter Intelligent Monitoring in Intensive Care II database. The relationship was derived and validated in all patients ventilated for at least 24 hours. RESULTS: The total data set included 7544 paired measurements from 3767 intensive care unit admissions. The correlation between SF ratio and PF ratio in the whole data set was good (Spearman rho = 0.72, P < .001). An automated ARDS diagnostic tool using the derived SF cutoff had excellent agreement with the same tool using the PF ratio of 300 (kappa = 0.87). CONCLUSION: The SF ratio may be an adequate substitute for the PF ratio in an automated ARDS screening tool. PMID- 25746584 TI - Heparin dose adjustment required to maintain goal-activated partial thromboplastin time during therapeutic hypothermia. AB - PURPOSE: The impact of therapeutic hypothermia (TH) on unfractionated heparin (UFH) management is essentially unknown. The aim of this study was to evaluate the effect of TH on UFH dosing and activated partial thromboplastin (aPTT) response. MATERIALS AND METHODS: Consecutive patients treated from 2005 to 2011 who received intravenous UFH via a dosing nomogram during TH were included. First, heparin doses and aPTT responses were compared between 2 core temperature groups, less than or equal to 33 degrees C and greater than 35 degrees C. Next, the first aPTT, drawn at 6 hours for temperature less than or equal to 33 degrees C, was assessed. Lastly, a linear model was developed to predict the mean aPTT, based on temperatures and heparin doses. RESULTS: Of the 156 TH patients, 68 were included. At temperatures less than or equal to 33 degrees C, 76.3% of all aPTT levels and 81.0% of the first aPTTs were above goal range, respectively. Using a linear model, an UFH dose of 12 U/kg per hour predicts an aPTT of 134 seconds at less than or equal to 33 degrees C. CONCLUSIONS: Using guideline-recommended heparin dosing without dose adjustment for temperature changes produced excessive aPTT during the cooling phase for TH patients. Reduction in the UFH dose of 43% to 54% may be required during TH. We recommend frequent aPTT monitoring during the cooling and rewarming phases to attain a desired aPTT range. PMID- 25746585 TI - Clinical outcomes associated with high, intermediate, and low rates of failed extubation in an intensive care unit. AB - PURPOSE: Extubation failure is associated with adverse outcomes in mechanically ventilated patients, and it is believed that high rates of failed planned extubation (FPE) should be avoided. However, many believe that very low rates may also correlate with adverse outcomes if resulting from overly conservative weaning practices. We examined the relationship between the percentage of FPE (%FPE) and associated outcomes, with the aim of elucidating a favorable middle range. METHODS: A total of 1395 extubations were analyzed in mechanically ventilated subjects. Monthly %FPE values were separated into tertiles. Ventilator free days (VFDs), intensive care unit-free days (IFDs), and mortality were compared among tertiles. RESULTS: Monthly %FPE tertiles were as follows: low, less than 7%; intermediate, 7% to 15%; and high, greater than 15%. There were significant differences in VFDs and IFDs by tertile from low to high (VFDs: low, 11.8; intermediate, 12.1; high, 9.9 [P = .003]; IFDs: low, 10.5; intermediate, 10.7; high, 9.0 [P = .033]). Post hoc comparisons demonstrated significant differences between the middle and high tertiles for both VFDs and IFDs. CONCLUSIONS: Although exact rates may vary depending on setting, this suggests that a high %FPE (>15) should be avoided in the intensive care unit and that there may be an intermediate range where ventilator outcomes are optimized. PMID- 25746586 TI - Save the patient a trip. Outcome difference between conservatively treated patients with traumatic brain injury in a nonspecialized intensive care unit vs a specialized neurosurgical intensive care unit in the Sultanate of Oman. AB - Traumatic brain injury (TBI) continues to be the main cause of death among trauma patients. Accurate diagnosis and timely surgical interventions are critical steps in reducing the mortality from this disease. For patients who have no surgically reversible head injury pathology, the decision to transfer to a dedicated neurosurgical unit is usually controversial. OBJECTIVE: To compare the outcome of patients with severe TBI treated conservatively in a specialized neurosurgical intensive care unit (ICU) and those treated conservatively at a general ICU in the Sultanate of Oman. DESIGN: Retrospective cohort study. METHODS: This is a retrospective study of patients with severe TBI admitted to Khoula Hospital ICU (specialized neurosurgical ICU) and Nizwa Hospital ICU (general ICU) in Oman in 2013. Surgically treated patients were excluded. Data extracted included demographics, injury details, interventions, and outcomes. The outcome variables included mortality, length of stay, length of ICU days, and ventilated days. RESULTS: There were 100 patients with severe TBI treated conservatively at Khoula Hospital compared with 74 patients at Nizwa Hospital. Basic demographics were similar between the 2 groups. No significant difference was found in mortality, length of stay, ICU days, and ventilation days. CONCLUSION: There is no difference in outcome between patients with TBI treated conservatively in a specialized neurosurgical ICU and those treated in a general nonspecialized ICU in Oman in 2013. Therefore, unless neurosurgical intervention is warranted or expected, patients with TBI may be managed in a general ICU, saving the risk and expense of a transfer to a specialized neurosurgical ICU. PMID- 25746587 TI - Doppler-based renal resistive index for prediction of renal dysfunction reversibility: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Doppler-based renal resistive index (RI) might help in distinguishing transient from persistent acute kidney injury (AKI). The main objective of these systematic review and meta-analysis was to investigate the diagnostic performance of RI in predicting short-term reversibility of AKI. STUDY DESIGN: A systematic review of the literature was performed. Relevant studies were identified in Pubmed and Cochrane databases covering the years 1985 to 2013 and reviewed independently by 3 authors. Renal transplant recipients were excluded from this analysis. The summary estimates were computed using a random effects model based on the DerSimonian and Lair meta-analytic method. RESULTS: Among the 154 unique articles identified, 9 studies were included. Of the 176 patients in these studies with elevated RI or pulsatility index, 146 (83%) had a persistent AKI vs 44 (16%) of the 273 patients with normal values. Elevated RI or pulsatility index was associated with an increased risk of persistent AKI (odds ratio, 29.85; 95% confidence interval [CI], 8.73-102.16; P < .00001) with significant heterogeneity (I(2) = 75.0%, P < .0001). The pooled sensitivity and specificity were 0.83 (95% CI, 0.77-0.88) and 0.84 (95% CI, 0.79-0.88). The summary positive and negative likelihood ratios were 4.9 (95% CI, 2.44-9.87) and 0.21 (95% CI, 0.11-0.41). CONCLUSION: These results suggest that an elevated RI may be a predictor of persistent AKI in critically ill patients. Further studies are warranted, however, to clarify the exact test performance given the marked heterogeneity among the included studies. PMID- 25746588 TI - Osteomalacia-Inducing Tumors of the Brain: A Case Report, Review and a Hypothesis. AB - BACKGROUND: Osteomalacia-inducing tumors (OIT) are mesenchymal tumors that characteristically secrete fibroblast growth factor 23, resulting in a paraneoplastic syndrome of hypophosphatemic osteomalacia. These tumors are known to occur in soft tissues and bones in various sites. It is very unusual for OITs to occur intracranially, with only 10 reported intracranial cases since their discovery in 1959. The most common intracrainal OITs are phosphaturic mesenchymal tumors and hemangiopericytomas. We report a case of hypophosphatemic osteomalacia caused by a tumor in the right anterior cranial fossa. We also hypothesize, based on our review of the literature, that this entity is underdiagnosed. CASE DESCRIPTION: A 49-year-old woman had a history of a nonhealing ankle fracture that required repeated surgery over 3 years. She subsequently was found to have severe hypophosphatemia and evidence of osteomalacia together with multiple occult fractures. A diagnosis of tumor-induced osteomalacia was suspected. An elevated serum fibroblast growth factor 23 level confirmed the diagnosis. An octreotide scan that was performed to locate the responsible tumor revealed an area of avid uptake in the right frontal lobe. Magnetic resonance imaging showed a large right anterior fossa extra-axial mass. The patient was referred for surgical intervention and was cured clinically after surgical removal of the tumor. Pathologic examination revealed a phosphaturic mesenchymal OIT. Her phosphate levels returned to normal 3 weeks after surgery. CONCLUSIONS: The diagnosis of OIT should be considered in a case of severe hypophosphatemia and metabolic bone disease that is not explained by any other metabolic or hereditary disease. These tumors can occur intracranially and may be confused with a meningioma or a hemangiopericytoma. Taking OIT into consideration in such cases could lead to a shorter time to diagnosis and management, which in our case took 4 years. PMID- 25746589 TI - Acute coronary syndrome-associated depression: the salience of a sickness response analogy? AB - Depression emerging in conjunction with acute coronary syndrome (ACS) is thought to constitute a distinct high-risk phenotype with inflammatory determinants. This review critically examines the notion put forward in the literature that ACS associated depression constitutes a meaningful subtype that is qualitatively different from depressive syndromes observed in psychiatric patients; and evaluates the salience of an analogy to the acute sickness response to infection or injury as an explanatory model. Specific features differentiating ACS associated depression from other phenotypes are discussed, including differences in depression symptom profiles, timing of the depressive episode in relation to ACS, severity of the cardiac event, and associated immune activation. While an acute sickness response analogy offers a plausible conceptual framework, concrete evidence is lacking for inflammatory activity as the triggering mechanism. It is likely that ACS-associated depression encompasses several causative scenarios. PMID- 25746590 TI - Cosmetics for the matrix: An attractive new style for Matrix Biology. PMID- 25746591 TI - Functional expression and molecular characterization of Culex quinquefasciatus salivary alpha-glucosidase (MalI). AB - Salivary alpha-glucosidases (MalI) have been much less characterized when compared with midgut alpha-glucosidases, which have been studied in depth. Few studies have been reported on the partial characterization of MalI, but no clear function has been ascribed. The aim of this study is to purify and characterize the recombinant Culex quinquefasciatus (CQ) alpha-glucosidase expressed in Pichia pastoris. The cDNA encoding mature Cx. quinquefasciatus alpha-glucosidase gene with polyhistidine tag (rCQMalIHis) was successfully cloned into the expression vector, pPICZalphaB, designated as pPICZalphaB/CQMalIHis. The activity of recombinant rCQMalIHis expressed in P. pastoris could be detected at 3.75U/ml, under optimal culture conditions. The purified rCQMalIHis showed a single band of molecular weight of approximately 92kDa on SDS-PAGE. After Endoglycosidase H digestion, a single band at 69kDa was found on SDS-PAGE analysis, suggesting that rCQMalIHis is a glycoprotein. Additionally, tryptic digestion and LC-MALDI MS/MS analysis suggested that the 69kDa band corresponds to the Cx. quinquefasciatus alpha-glucosidase. Thus, rCQMalIHis is a glycoprotein. The rCQMalIHis exhibited optimum pH and temperature at 5.5 and 35 degrees C, respectively. The catalytic efficiency (kcat/Km) of the purified rCQMalIHis for maltotriose is higher than those for sucrose, maltotetraose, maltose and p-nitrophenyl-alpha-glucoside, indicating that the enzyme prefers maltotriose. Additionally, the rCQMalIHis is significantly inhibited by d-gluconic acid delta-lactone, but not by Mg(2+), Ca(2+) and EDTA. The rCQMalIHis is strongly inhibited by acarbose with IC50 67.8+/-5.6nM, but weakly inhibited by glucose with IC50 115.9+/-7.3mM. PMID- 25746592 TI - MicroRNA-141 is a biomarker for progression of squamous cell carcinoma and adenocarcinoma of the lung: clinical analysis of 125 patients. AB - Lung cancer is the most common malignant tumor worldwide. MicroRNA has become an ideal biomarker for cancer diagnosis, prognosis and therapy. The relationship between microRNA-141 and non-small cell lung cancer (NSCLC) is contradictory. Thus, in current study, we aimed to investigate the level of microRNA-141 in NSCLC tissues and to evaluate its potential clinical value. This study enrolled 125 NSCLC patients (75 males and 50 females) with a median age of 61 years (range, 23-90 years). NSCLC patients included 23 squamous cell carcinomas (SCCs), 101 adenocarcinomas (ADCs) and 1 large cell carcinoma. The expression level of microRNA-141 was significantly higher in NSCLC tissues than in adjacent lung tissues (P < 0.001), detected by real time RT-PCR. Receiver operating characteristic (ROC) exhibited a moderate diagnostic value of microRNA-141 for NSCLC with the area under curve of 0.707. The microRNA-141 expression increased with the larger tumor size (P = 0.002), lymph node metastasis (P = 0.018) and advanced stage (P = 0.022) in NSCLC patients. For subgroup analysis, microRNA-141 expression in SCC was correlated with tumor size (r = 0.490, P = 0.018), and in ADC, microRNA-141 level was positively associated with tumor size (r = 0.222, P = 0.026), lymph node metastasis (r = 0.242, P = 0.015) and TNM stage (r = 0.210, P = 0.035). Furthermore, univariate analysis revealed that the expression of microRNA-141 was an independent prognostic indicator of ADC. In conclusion, microRNA-141 is a potential biomarker for the molecular diagnosis and risk stratification of NSCLC. PMID- 25746593 TI - Organic carbon, influent microbial diversity and temperature strongly influence algal diversity and biomass in raceway ponds treating raw municipal wastewater. AB - Algae based wastewater treatment coupled to biofuel production has financial benefits and practical difficulties. This study evaluated the factors influencing diversity and growth of indigenous algal consortium cultivated on untreated municipal wastewater in a high rate algal pond (HRAP) for a period of 1 year using multivariate statistics. Diversity analyses revealed the presence of Chlorophyta, Cyanophyta and Bacillariophyta. Dominant microalgal genera by biovolume in various seasons were Scenedesmus sp., Microcystis sp., and Chlorella sp. Scenedesmus sp., persisted throughout the year but none of three strains co dominated with the other. The most significant factors affecting genus dominance were temperature, inflow cyanophyta and organic carbon concentration. Cyanophyta concentration affected microalgal biomass and diversity, whereas temperature impacted biomass. Preferred diversity of microalgae is not sustained in wastewater systems but is obligatory for biofuel production. This study serves as a guideline to sustain desired microalgal consortium in wastewater treatment plants for biofuel production. PMID- 25746594 TI - Anaerobic biofilm reactors for dark fermentative hydrogen production from wastewater: A review. AB - Dark fermentation is a bioprocess driven by anaerobic bacteria that can produce hydrogen (H2) from organic waste and wastewater. This review analyses a relevant number of recent studies that have investigated dark fermentative H2 production from wastewater using two different types of anaerobic biofilm reactors: anaerobic packed bed reactor (APBR) and anaerobic fluidized bed reactor (AFBR). The effect of various parameters, including temperature, pH, carrier material, inoculum pretreatment, hydraulic retention time, substrate type and concentration, on reactor performances was investigated by a critical discussion of the results published in the literature. Also, this review presents an in depth study on the influence of the main operating parameters on the metabolic pathways. The aim of this review is to provide to researchers and practitioners in the field of H2 production key elements for the best operation of the reactors. Finally, some perspectives and technical challenges to improve H2 production were proposed. PMID- 25746595 TI - Selecting an indigenous microalgal strain for lipid production in anaerobically treated piggery wastewater. AB - The aim of this study was to select a potential microalgal strain for lipid production and to examine the suitability of anaerobically treated piggery wastewater as a nutrient source for production of lipid-rich biomass with the selected microalga. Biomass and lipid productivity of three microalgal strains (Chlorella sorokiniana CY1, Chlorella vulgaris CY5 and Chlamydomonas sp. JSC-04) were compared by using different media, nitrogen sources, and nitrogen concentrations. The highest lipid content and productivity (62.5 wt%, 162 mg/L/d) were obtained with C. vulgaris with BG-11 with 62 mg N/L. Secondly, C. vulgaris was cultivated in sterilized, diluted (1-20*), anaerobically treated piggery wastewater. Biomass production decreased and lipid content increased, when wastewater was more diluted. The highest lipid content of 54.7 wt% was obtained with 20* dilution, while the highest lipid productivity of 100.7 mg/L/d with 5* dilution. Piggery wastewater is a promising resource for mass production of oleaginous microalgal biomass. PMID- 25746596 TI - Noninvasive pacing study via pacemakers and implantable cardioverter defibrillators for differentiating right from left atrial flutter. AB - BACKGROUND: Patients with atrial flutter who are implanted with a pacemaker (PM) or implantable cardioverter-defibrillator (ICD) present with the opportunity to perform a noninvasive pacing study (NIPS) using the right atrial pacing lead to differentiate right from left atrial flutter. OBJECTIVES: The purpose of this study was to study the feasibility and accuracy of NIPS to distinguish right from left atrial flutter. METHODS: We enrolled consecutive patients scheduled for an electrophysiological study or ablation procedure who were in atrial flutter and who were implanted with a PM or ICD with a functional atrial lead in the right atrial appendage. Flutter tachycardia cycle lengths (TCLs) and postpacing intervals (PPIs) were measured noninvasively via the device during the procedure. RESULTS: A total of 48 (67%) patients were studied. Right atrial flutter was present in 32 patients (of whom 29 had typical cavotricuspid isthmus-dependent flutter) and 16 (33%) patients had left atrial flutter. A PPI-TCL interval of >100 ms was 100% specific and 81% sensitive to identify left atrial flutter, with an overall accuracy of 94% and a c statistic of 0.94 (95% confidence interval 0.87-1.00). A PPI-TCL interval of <=100 ms had a positive predictive value of 86% for diagnosing typical flutter. CONCLUSION: NIPS via PMs and ICDs with a PPI-TCL interval of >100 ms can reliably identify left atrial flutter (although we have only validated this cutoff for leads implanted in the right atrial appendage). This simple maneuver may allow planning for left-sided access and may avoid an unnecessary invasive electrophysiological study if left atrial flutter ablation is not to be considered. PMID- 25746597 TI - New insights into structural determinants of prion protein folding and stability. AB - Prions are the etiological agent of fatal neurodegenerative diseases called prion diseases or transmissible spongiform encephalopathies. These maladies can be sporadic, genetic or infectious disorders. Prions are due to post-translational modifications of the cellular prion protein leading to the formation of a beta sheet enriched conformer with altered biochemical properties. The molecular events causing prion formation in sporadic prion diseases are still elusive. Recently, we published a research elucidating the contribution of major structural determinants and environmental factors in prion protein folding and stability. Our study highlighted the crucial role of octarepeats in stabilizing prion protein; the presence of a highly enthalpically stable intermediate state in prion-susceptible species; and the role of disulfide bridge in preserving native fold thus avoiding the misfolding to a beta-sheet enriched isoform. Taking advantage from these findings, in this work we present new insights into structural determinants of prion protein folding and stability. PMID- 25746598 TI - Vancomycin protects against Acinetobacter baumannii infection in a Galleria mellonella model. PMID- 25746599 TI - Clinical significance of circulating endothelial cells in patients with severe sepsis or septic shock. AB - BACKGROUND: Endothelial damage developing in severe sepsis or septic shock results in multiorgan dysfunction. An increased circulating endothelial cell (CEC) count represents a novel marker of endothelial damage, which has been reported in cases of severe sepsis or septic shock. The aim of this study was to evaluate the clinical significance of CECs in patients with severe sepsis or septic shock. METHODS: CECs were evaluated and quantified by flow cytometry using plasma collected from patients with severe sepsis or septic shock who were admitted to a medical intensive care unit from February 2011 to August 2011. RESULTS: During the study period, 77 patients were enrolled. The median CEC count was 350 cells/ml (range 0-15 984 cells/ml). There was no significant difference between cases of severe sepsis and septic shock [163 cells/ml (0-15 984 cells/ml) vs 363 cells/ml (0-7884 cells/ml), p = 0.507]. There were no correlations between the number of CECs and inflammatory markers. CEC counts were significantly increased in non-survivors compared to survivors [588.5 cells/ml (1-15 984 cells/ml) vs 292 cells/ml (0-12 882 cells/ml), p = 0.044] within 28 days. The sequential-related organ failure assessment score, CEC counts >= 500 cells/ml and blood lactate levels were significantly associated with 28 day mortality. CONCLUSIONS: CEC counts were higher in non-survivors of severe sepsis or septic shock and could be used as a biomarker to predict the prognosis in these patients. PMID- 25746600 TI - Sulbactam treatment for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex. AB - BACKGROUND: Multidrug-resistant (MDR) Acinetobacter calcoaceticus-Acinetobacter baumannii (Acb) complex has become an important cause of nosocomial pneumonia. Sulbactam is a beta-lactamase inhibitor with antimicrobial activity against MDR Acb complex. METHODS: To investigate outcomes of pneumonia involving MDR Acb complex treated with sulbactam or ampicillin/sulbactam for at least 7 days, we conducted a retrospective study of 173 adult patients over a 34 month period. RESULTS: Of 173 patients, 138 (79.8%) received combination therapy, mainly with carbapenems (119/138, 86.2%). The clinical response rate was 67.6% and the 30 day mortality rate was 31.2%. The independent predictors of clinical failure were malignancy, bilateral pneumonia and shorter duration of treatment. In patients with sulbactam-susceptible strains, there was no difference in clinical and microbiological outcome between combination therapy and monotherapy. Compared to the sulbactam-susceptible group, the sulbactam-resistant group had a lower rate of airway eradication, a longer duration of treatment and a higher rate of combination therapy with predominantly carbapenems (p < 0.05). There was no significant difference between the two groups in clinical resolution and 30 day mortality rates. CONCLUSIONS: Sulbactam could be a treatment option for pneumonia involving MDR Acb complex, and combination therapy with carbapenems could be considered for sulbactam-resistant cases. PMID- 25746602 TI - Prevalence of BK viremia in Iranian hemodialysis and peritoneal dialysis patients. AB - BACKGROUND: BK virus (BKV) is a common human polyomavirus which infects up to 90% of the general population with little clinical significance and with various epidemiological patterns of infection. Immune suppression is considered the main risk factor for BKV reactivation. Owing to their impaired cellular and humoral immunity, patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) are at high risk of infectious diseases such as BKV infection. BKV presents with different distributions in different populations. This study aimed to determine the prevalence of BKV in Iranian patients with chronic renal disease undergoing HD and PD. METHODS: Sixty-three HD patients and 33 PD cases from the main dialysis units in Tehran, Iran, were enrolled in the study. BK viremia was determined by qualitative polymerase chain reaction in all subjects. RESULTS: Sixty-three cases under HD (mean age 59.3 +/- 14.5 years) and 33 subjects on PD (mean age 53.7 +/- 13 years) were enrolled in the study. The mean duration of HD was 59.1 +/- 53.8 months and the dialysis interval was three times a week. In the PD group, the mean duration of dialysis was 38.9 +/- 35.2 months. The prevalence of BK viremia was 3.03% in PD and 0% in HD subjects. CONCLUSIONS: This study showed a low rate of BK viremia in chronic renal disease patients undergoing HD or PD. Differently from other studies in various populations, our results demonstrated low or absent BKV replication in Iranian dialysis patients, highlighting the varying epidemiological pattern of BKV distribution. PMID- 25746601 TI - Telavancin for refractory methicillin-resistant Staphylococcus aureus bacteremia and infective endocarditis. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and infective endocarditis (IE) have become increasingly difficult to treat over the past decade, with suboptimal response rates of less than 50%. Although vancomycin and daptomycin are standard therapeutic options, treatment failures with either or both agents are common. Telavancin is a lipoglycopeptide antibiotic with activity against MRSA. In vitro, telavancin displays bactericidal activity and has lower minimum inhibitory concentrations to MRSA than vancomycin. METHODS: We present a retrospective, case-series report of 14 patients treated with telavancin for refractory MRSA bacteremia with and without IE at our institution from 9 September 2010 to 2 April 2012. RESULTS: Of the 14 patients who received telavancin for refractory MRSA bacteremia and IE, eight survived their inpatient admission and were able to be followed for 30 days. The overall survival rate was 57% (n = 8). Of the eight surviving patients, five were diagnosed with MRSA IE and the remaining three were diagnosed with complicated MRSA bacteremia. All six patients who did not survive the inpatient admission were diagnosed with left sided IE involving the mitral valves. CONCLUSIONS: This retrospective case series provides clinical evidence for the use of telavancin as a treatment option for refractory MRSA bacteremia and IE. With limited effective agents in the treatment of MRSA-complicated bacteremia and IE, telavancin represents a potential treatment option. Further randomized, controlled trials are necessary to define the optimal role of telavancin in the treatment of MRSA bacteremia and IE. PMID- 25746603 TI - Prevalence of penicillin-non-susceptible Streptococcus pneumoniae in children in day-care centres subjected to an intervention to prevent dispersion. AB - BACKGROUND: The aim of this study was to evaluate the day-care interventions implemented in southern Sweden to restrict the dispersion of penicillin-non susceptible pneumococci with a minimum inhibitory concentration of penicillin G of at least 0.5 mg/l (PNSP0.5). METHODS: A retrospective epidemiological study was performed and data from 109 day-care centre interventions from 2000 to 2010 were analysed, including screening results from 7157 individuals. RESULTS: It was found that 42% of the children were carriers of pneumococci and 5% of the screened children were PNSP0.5 carriers. Very few personnel were PNSP0.5 carriers and they were carriers for only a short time. Significantly more contact cases with the same serogroup as the index case were found in the first screening and in the same department as the index case, but a substantial number of contact cases were found in adjacent departments. CONCLUSIONS: Screening of personnel is not worth the effort. Based on our results, procedures to restrict dispersion of PNSP0.5 in day-care centres could be improved. To find the majority of contact cases with PNSP0.5 an early screening including adjacent departments seems to be the best approach. PMID- 25746604 TI - Mycobacterium tuberculosis infection may provide an antigenic stimulus enabling children to mount a strong immune cell response. PMID- 25746605 TI - Absence of Streptococcus pneumoniae in pharyngeal swabs of geriatric inpatients. AB - Colonization of the pharynx by Streptococcus pneumoniae was studied in 185 in hospital geriatric patients (median age 81 years) from 29 March 2011 to 22 June 2011. Swabs were plated on blood agar plates. Colonies with a morphology suggesting S. pneumoniae were further analyzed. Surprisingly, pneumococci were not found in any of the samples. Pneumococci chronically colonizing the pharynx of elderly people may be much rarer than previously thought and probably are not the source of pneumococcal pneumonia in old age. PMID- 25746606 TI - Diagnostic potential of inflammatory markers in septic arthritis and periprosthetic joint infections: a clinical study with 719 patients. AB - BACKGROUND: The aim of this study was to investigate which markers in serum and in the synovial fluid have the highest diagnostic potential for predicting septic arthritis and periprosthetic joint infections (PJIs). The likelihood ratio assesses the diagnostic utility of a diagnostic test and the likelihood that a patient has a disease. METHODS: The levels of inflammatory markers in serum [white blood cells, C-reactive protein (CRPS)] and synovial fluid [synovial fluid white blood cell count (SFWBC), percentage of polymorphonuclear cells (%PMN), lactic acid, lactate dehydrogenase (LDH), glucose, total protein] of patients suffering from septic arthritis (n = 114), PJI (n = 67), non-infectious joint diseases (n = 495) and arthralgia after total joint arthroplasty (n = 43) were determined. The arithmetical means, cut-off values, sensitivities, specificities, positive and negative likelihood ratios (+ LR, -LR), interval likelihood ratios and receiver operating characteristic curves with corresponding area under the curve (AUC) of inflammatory markers were calculated. RESULTS: The parameters with the highest diagnostic potential for differing between septic arthritis and non infectious arthritis were the SFWBC (AUC = 0.850, cut-off value = 6.7 * 10(3)/MUl, sensitivity = 81.8%, specificity = 76.5%,+ LR = 3.41, -LR = 0.24), CRPS (AUC = 0.797), %PMN (AUC = 0.766) and synovial lactate (AUC = 0.760). The highest diagnostic potential for predicting a PJI was shown by LDH (AUC = 0.833) and the SFWBC (AUC = 0.828). CONCLUSIONS: The SFWBC, CRPS, %PMN and synovial lactate were the best inflammatory markers in predicting septic arthritis. Synovial lactate levels > 10 mmol/l or an SFWBC > 50 * 10(3)/MUl substantially increased disease probability, while SFWBC < 1.0 * 10(3)/MUl or CRPS < 0.5 mg/dl diminished the post-test probability of septic arthritis considerably. An SFWBC < 1.1 * 10(3)/MUl or a %PMN < 70% made a PJI unlikely, while SFWBC > 20 * 10(3)/MUl or %PMN > 86% increased the post-test probability of a PJI. The use of the corresponding interval likelihood ratios could help physicians to estimate the probability of septic arthritis and PJI more accurately. PMID- 25746607 TI - Epstein-Barr virus viral load in human immunodeficiency virus-positive patients with reactive hemophagocytic syndrome. AB - Because human immunodeficiency virus (HIV)-infected patients control Epstein-Barr virus (EBV) replication poorly, we hypothesized that reactive hemophagocytic syndrome (HS) in these patients may be associated with poor control of EBV. The files of 314 patients with a suspected diagnosis of HS were retrospectively reviewed. EBV viral load at the time of HS was compared between HIV-positive and negative patients. A confirmed diagnosis of HS was made in 162 patients [109 males, median age 48 (35-62) years]. Among them, 61 (38%) were HIV positive [median HIV viral load 3.2 (1.6-5.5) log/ml, median CD4 count 94 (28-190)/mm(3)]. The median EBV viral load was significantly higher in HIV-positive than in HIV negative patients [4.0 (2.9-4.6) vs 2.5 (0-4.2) log/ml, p = 0.002]. It was higher both in patients with hematological malignancy-associated HS [4.0 (2.9-4.4) vs 2.9 (0-4.9) log/ml, p = 0.03] and in patients with infection-associated HS [3.9 (0-4.9) vs 0 (0-4.1) log/ml, p = 0.14]. However, EBV viral load was not significantly higher in HIV-infected patients with confirmed HS than in HIV infected patients for whom HS was unlikely [4.0 (2.9-4.6) vs 3.9 (2.6-4.1) log/ml, p = 0.48].The high EBV viral load observed in HIV-infected patients with HS may be more likely to reflect the chronic HIV infection than to be the direct trigger of HS. PMID- 25746608 TI - [Importance of a full assessment in patients diagnosed with juvenile dermatomyositis]. PMID- 25746609 TI - The impact of steam on the electronic structure of the selective propane oxidation catalyst MoVTeNb oxide (orthorhombic M1 phase). AB - The selective propane oxidation catalyst MoVTeNb oxide M1 was investigated by microwave conductivity, synchrotron X-ray photoelectron, soft X-ray absorption and resonant photoelectron spectroscopy under reaction conditions to identify the influence of steam on the electronic bulk and surface properties. Steam significantly increases both the conversion of propane and the selectivity to the target product acrylic acid. The increased catalytic performance comes along with a decreased conductivity, a modification of the surface chemical and electronic structure with an enrichment of covalently bonded V(5+) species to the extent of Mo(6+), a decreased work function and hence polarity of the surface and a modified valence band structure. The higher degree of covalency in metal oxide bonds affects the mobility of the free charge carriers, and hence explains the decrease of the conductivity with steam. Furthermore we could prove that a subsurface space charge region depleted in electrons and thus an upward bending of the electronic band structure are induced by the reaction mixture, which is however not dependent on the steam content. PMID- 25746610 TI - [Renal denervation as treatment of resistant hypertension]. PMID- 25746611 TI - [Reply]. PMID- 25746612 TI - [Asymptomatic pigmentation on the breast of years of evolution]. PMID- 25746613 TI - [Chronic subdural hematoma]. PMID- 25746614 TI - Implementation and outcome evaluation of high-fidelity simulation scenarios to integrate cognitive and psychomotor skills for Korean nursing students. AB - OBJECTIVES: This study is involved in designing high-fidelity simulations reflecting the Korean nursing education environment. In addition, it evaluated the simulations by nursing students' learning outcomes and perceptions of the simulation design features. DESIGN: A quantitative design was used in two separate phases. SETTINGS AND PARTICIPANTS: For the first phase, five nursing experts participated in verifying the appropriateness of two simulation scenarios that reflected the intended learning objectives. For the second phase, 69 nursing students in the third year of a bachelor's degree at a nursing school participated in evaluating the simulations and were randomized according to their previous course grades. METHODS: The first phase verified the two simulation scenarios using a questionnaire. The second phase evaluated students' perceptions of the simulation design, self-confidence, and critical thinking skills using a quasi-experimental post-test design. ANCOVA was used to compare the experimental and control groups, and correlation coefficient analysis was used to determine the correlation among them. RESULTS: We created 2 simulation scenarios to integrate cognitive and psychomotor skills according to the learning objectives and clinical environment in Korea. The experimental group had significantly higher scores on self-confidence in the first scenario. The positive correlations between perceptions of the simulation design features, self-confidence, and critical thinking skill scores were statistically significant. CONCLUSIONS: Students with a more positive perception of the design features of the simulations had better learning outcomes. Based on this result, simulations need to be designed and implemented with more differentiation in order to be perceived more appropriately by students. PMID- 25746615 TI - Review on Chaga Medicinal Mushroom, Inonotus obliquus (Higher Basidiomycetes): Realm of Medicinal Applications and Approaches on Estimating its Resource Potential. AB - This paper presents a review of the realm of medicinal applications of Inonotus obliquus raw materials, sterile conks I. obliquus, based on the bibliographies of chemical studies of the fungus. The experimental part of the paper is devoted to the presentation of methods of estimating the resource potential of this fungus based on data obtained in the comfort zone of ththis species. A new form, I. obliquus f. sterilis, is formally described. PMID- 25746616 TI - Effect of Selenium-Enriched Agaricus bisporus (Higher Basidiomycetes) Extracts, Obtained by Pressurized Water Extraction, on the Expression of Cholesterol Homeostasis Related Genes by Low-Density Array. AB - Culinary-medicinal mushrooms are able to lower blood cholesterol levels in animal models by different mechanisms. They might impair the endogenous cholesterol synthesis and exogenous cholesterol absorption during digestion. Mushroom extracts, obtained using pressurized water extractions (PWE) from Agaricus bisporus basidiomes, supplemented or not supplemented with selenium, were applied to HepG2 cell cultures to study the expression of 19 genes related to cholesterol homeostasis by low-density arrays (LDA). Only the PWE fractions obtained at 25 degrees C showed 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitory activity. Besides the enzymatic inhibition, PWE extracts may downregulate some of the key genes involved in the cholesterol homeostasis, such as the squalene synthase gene (FDFT1), since its mRNA expression falls by one third of its initial value. In summary, A. bisporus extracts may also modulate biological cholesterol levels by molecular mechanisms further than the enzymatic way previously reported. PMID- 25746617 TI - Determination of Lovastatin, beta-glucan, Total Polyphenols, and Antioxidant Activity in Raw and Processed Oyster Culinary-Medicinal Mushroom, Pleurotus ostreatus (Higher Basidiomycetes). AB - The objective of this study was to quantify a number of bioactive compounds and antioxidant activity of the oyster mushroom, Pleurotus. Ostreatus, and characterize the effects of processing, such as blanching, on these outcomes. Dry matter content was 8%. Lovastatin was not detected in this study. beta-glucan content of 23.9% and total polyphenol content of 487.12 mg gallic acid equivalent/100 g of dry matter were obtained in raw P. ostreatus. Antioxidant activities as evaluated by 1,1-diphenyl-2-picrylhydrazyl, Trolox equivalent antioxidant capacity, and ferric reducing antioxidant power assays in raw P. ostreatus were 14.46, 16.51, and 11.21 umol/g, respectively. Blanching did not significantly affect beta-glucan content but caused significant decrease in dry matter content, polyphenol content, and antioxidant activities. Mushroom rolls produced from blanched mushrooms and blanching water contained significantly higher amounts of beta-glucan, total polyphenol content, and FRAP antioxidant activity compared to blanched mushrooms. In conclusion, P. ostreatus is a good source for beta-glucan, dietary polyphenols, and antioxidants. Although the blanching process could affect these properties, re-addition of the blanching water during the production process of mushroom rolls could potentially recover these properties and is therefore recommended. PMID- 25746618 TI - Antidiabetic and antioxidant activities of eight medicinal mushroom species from China. AB - The objective of the current study was to verify antidiabetic effects of different types of mushrooms as folk medicines in treating diabetes. The antidiabetic effects were evaluated by in vitro alpha-glycosidase and aldose reductase (AR) inhibitory assays and antioxidant activity assay. Ganoderma lucidum extract exhibited the best dose-dependent inhibitory activity against alpha-glycosidase with IC50 at 4.88 mg/mL, and also exhibited aldose reductase inhibitory potential with IC50 value of 9.87 mg/mL. Tremella fuciformis demonstrated the highest AR inhibitory activity (IC50=8.39 mg/mL). Antioxidant activities of selected mushrooms were evaluated based on the total phenolic content (TPC), total flavonoids content (TFC), and DPPH free radical scavenging activity. The result showed that G. lucidum contained the highest TPC (39.3 mg GAE/g sample extract), TFC (15.1 mg CE/g sample extract), and the strongest DPPH free radical scavenging activity (IC50=3.66 mg/mL) among the mushroom samples. PMID- 25746619 TI - Biological Activities of the Polysaccharides Produced from Different Sources of Xylaria nigripes (Ascomycetes), a Chinese Medicinal Fungus. AB - Xylaria nigripes, a local rare medicinal fungus, has multi-antioxidant activities owing to its water extraction as shown by previous research. However, the main indicator causing the antioxidant effect was not clear, so this research focused on the antioxidant activities from different sources of X. nigripes such as fruiting body polysaccharides, mycelium intracellular polysaccharides, mycelium extracellular polysaccharides, and their deproteinization products. The mycelium intracellular polysaccharide (XnIPS-1) from X. nigripes showed the highest reducing power of antioxidant activity, since it revealed the lowest IC50 values in all the assayed methodologies. The IC50 values of chelating ferrous ion ability, ABTS radical scavenging activity, and DPPH free radical scavenging were 1412, 174.25, and 351.56 ug/mL, respectively. In addition to these results, this research also explored the mechanism between polysaccharides and antioxidants compared by FT-IR analysis. The spectrum shows that the X. nigripes polysaccharide structure changed after the proteins were removed. PMID- 25746620 TI - Immunomodulatory Activities on RAW 264.7 Macrophages of a Polysaccharide from Veiled Lady Mushroom, Dictyophora indusiata (Higher Basidiomycetes). AB - A water-soluble polysaccharide named DI was extracted from the fruiting bodies of gastroid mushroom Dictyophora indusiata with boiling water. The chemical and physical characteristics of DI were investigated by a combination of chemical and instrumental analysis methods. The immunomodulatory activities on RAW 264.7 macrophage of DI in vitro were also studied. The results showed that DI is a beta (1->3)-glucan with side branches of beta-(1->6)-glucosyl units, and it has triple helical structure. DI has no toxic effect on cells, but can promote macrophage multiplication. DI significantly affects the immune function by promoting the production of nitric oxide and cytokines, such as tumor necrosis factor-alpha, interleukin-1, -6, and -12, showing an obvious dose-effect relationship. This work extends the application scope of the polysaccharide from D. indusiata in the biomedical field. PMID- 25746621 TI - Armillaridin, a Honey Medicinal Mushroom, Armillaria mellea (Higher Basidiomycetes) Component, Inhibits Differentiation and Activation of Human Macrophages. AB - Armillaridin (AM) is an aromatic ester compound isolated from honey medicinal mushroom, Armillaria mellea, which has anti-cancer potential. This study was designed to examine the effects of AM on differentiation and activation macrophages, the major ontogeny of innate immunity. Macrophages were derived from CD14+ monocytes which were sorted from human peripheral blood mononuclear cells. Cell viability was assessed by trypan blue exclusion test. Cells were stained with Liu's dye for observation of morphology. Expression of surface antigens was examined by flow cytometric analysis. Phagocytosis and generation of reactive oxygen species (ROS), as functional assays, were evaluated by counting engulfed yeasts and DCFH-DA reaction. The viability of macrophages was not significantly reduced by AM. AM at nontoxic concentrations markedly increased cytoplasmic vacuoles. The expression of surface CD14, CD16, CD36, and HLA-DR was suppressed. The phagocytosis function, but not ROS production, of macrophages was inhibited by AM. Armillaridin could inhibit the differentiation and activation of human macrophages. It may have potential to be developed as a biological response modifier for inflammatory diseases. PMID- 25746622 TI - Oyster Culinary-Medicinal Mushroom, Pleurotus ostreatus (Higher Basidiomycetes), Growth in Grain-Based Diet Improves Broiler Chicken Production. AB - Many alternative compounds have been tested to improve poultry performance but few of them have previously used mycelial-colonized substrate to partially replace standard diet in broiler chickens. The objective of this study was to evaluate broiler chicken production, health, and meat sensory characteristics, with partial replacement of the standard diet by Pleurotus ostreatus-colonized substrate. One hundred fifty 1-day-old male Cobb chicks were given standard diet partially replaced by 0, 5, 10, 100, or 200 g.kg-1 of P. ostreatus-colonized substrate and randomly distributed into five treatments. Each treatment had three replicates, with 10 birds per replicate, totaling 30 birds. The replacement of the standard diet by 10 g.kg-1 of colonized substrate increased (P<=0.05) chicken body mass up to 57% at 21 days, and up to 28% at 42 days. In general, partial replacement of standard diet by colonized substrate increased hematocrits and typical lymphocytes, and reduced low density lipoproteins. Also, it reduced chicken production period up to 21% and there is no meat taste alteration. The use of P. ostreatus-colonized substrate in chicken feeding is an alternative method to improve broiler chicken production. PMID- 25746624 TI - Functional nutraceutical profiling of wild edible and medicinal mushrooms consumed by ethnic tribes in India. AB - Wild edible mushrooms occupy an important place in the traditional food habits of the ethnic tribes of India. Specimens collected from the forests and local markets of Meghalaya, India were affiliated to ten different species. The mushroom extracts were analyzed for nutrient and mineral compositions along with phenolics, flavonoids, ascorbic acid, beta-carotene, and lycopene. These extracts were also investigated for antioxidant, anti-inflammatory, and antimicrobial activities. Fungal extracts were found to be rich in nutrients and minerals, and exhibited potent antioxidant, anti-inflammatory, and antimicrobial activities under assay conditions. The nutrient profiles generated for each of these ten species revealed them to be rich sources of functional nutraceuticals. PMID- 25746623 TI - Effect of Carbon Source on Properties and Antioxidant Potential of Exopolysaccharides Produced by Trametes robiniophila (Higher Basidiomycetes). AB - The effects of carbon source on properties and antioxidant potential of exopolysaccharides (EPS) produced by Trametes robiniophila were investigated in this study. The results indicated that the EPS production varied with five different carbon sources. The predominant carbohydrate compositions in EPSs identified were glucose and mannose. Then, FT-IR spectral analysis revealed prominent characteristic groups in the EPSs. Furthermore, thermogravimetric analysis (TGA) indicated the EPS with lactose as the carbon source showed different degradation behavior as compared to the other four EPSs, probably due to larger ribose content as one of major monosaccharides in the EPS. The variation also affects the antioxidant activities investigated by using hydroxyl and DPPH radical scavenging assay. Sucrose was the best carbon source from the viewpoint of antioxidant activity due to the relatively high xylose content in the EPS. PMID- 25746625 TI - Notes on a New Productive Strain of King Oyster Mushroom, Pleurotus eryngii (Higher Basidiomycetes), a Prized Italian Culinary-Medicinal Mushroom. AB - In this paper, the authors provide data on a culinary-medicinal, host-specific variety of P. eryngii species-complex that is known in Italy as "cardoncello". A species description, the techniques of isolation of a new strain (C-142-c), and the preparation of the substratum are illustrated. Data on the productivity of substratum inoculated with C-142-c strain and the nutritional value of cultivated "cardoncello" mushrooms are also provided. PMID- 25746626 TI - A usage-based approach to early-discourse pragmatic functions of the Japanese subject markers wa and ga. AB - This study investigates the emergence and development of the discourse-pragmatic functions of the Japanese subject markers wa and ga from a usage-based perspective (Tomasello, 2000). The use of each marker in longitudinal speech data for four Japanese children from 1;0 to 3;1 and their parents available in the CHILDES database (MacWhinney, 2000) was coded and analyzed. Findings showed that the four children initially used wa as a wh-question marker. They then gradually shifted its use to convey the proposition of given information. In contrast, the use of ga varied among the children. One child used ga with dynamic verbs in the past tense to report events he witnessed/experienced, while the other three children used it with a particular stative predicate in the present tense, expressing their subjective feeling toward referents. Findings were explained by the frequency of input to which the children had been exposed. PMID- 25746627 TI - Characterization of a thermostable glucose dehydrogenase with strict substrate specificity from a hyperthermophilic archaeon Thermoproteus sp. GDH-1. AB - A hyperthermophilic archaeon was isolated from a terrestrial hot spring on Kodakara Island, Japan and designated as Thermoproteus sp. glucose dehydrogenase (GDH-1). Cell extracts from cells grown in medium supplemented with glucose exhibited NAD(P)-dependent glucose dehydrogenase activity. The enzyme (TgGDH) was purified and found to display a strict preference for D-glucose. The gene was cloned and expressed in Escherichia coli, resulting in the production of a soluble and active protein. Recombinant TgGDH displayed extremely high thermostability and an optimal temperature higher than 85 degrees C, in addition to its strict specificity for D-glucose. Despite its thermophilic nature, TgGDH still exhibited activity at 25 degrees C. We confirmed that the enzyme could be applied for glucose measurements at ambient temperatures, suggesting a potential of the enzyme for use in measurements in blood samples. PMID- 25746629 TI - Dendriform pulmonary ossification visualised by scanning acoustic microscope. PMID- 25746630 TI - Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. AB - BACKGROUND: Steroid-insensitive endotypes of asthma are an important clinical problem and effective therapies are required. They are associated with bacterial infection and non-eosinophilic inflammatory responses in the asthmatic lung. Macrolide therapy is effective in steroid-insensitive endotypes, such as non eosinophilic asthma. However, whether the effects of macrolides are due to antimicrobial or anti-inflammatory mechanisms is not known. OBJECTIVE: To determine and assess the efficacy of macrolide (ie, clarithromycin) and non macrolide (ie, amoxicillin) antibiotic treatments in experimental models of infection-induced, severe, steroid-insensitive neutrophilic allergic airways disease (SSIAAD), compared with steroid-sensitive AAD and to delineate the antimicrobial and anti-inflammatory effects of macrolide therapy. METHODS: We developed and used novel mouse models of Chlamydia and Haemophilus lung infection induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. RESULTS: Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor alpha and interleukin 17 responses that induce SSIAAD. CONCLUSIONS: Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD. PMID- 25746631 TI - Bronchoscopic transparenchymal nodule access (BTPNA): first in human trial of a novel procedure for sampling solitary pulmonary nodules. AB - INTRODUCTION: The promise of benefits from lung cancer screening is tempered by the false positive rate and the need to perform diagnostic procedures to determine the aetiology of the solitary pulmonary nodules (SPN) identified. We have developed a novel procedure which allows sampling of SPNs via a transparenchymal approach, and report the results from this as a first in human trial. METHODS: This study was a prospective single-arm interventional study. We recruited patients with a SPN detected on CT imaging, which was suspicious for lung cancer, who were suitable for surgical resection. Using the subject's CT, an optimal airway wall point of entry (POE), and an avascular path through lung tissue from the POE to the SPN was calculated. A tunnel tract was created from the POE to the nodule using a set of catheter-based tools under fused fluoroscopy guidance. The patients proceeded to surgical resection immediately after the biopsy. The participants were followed-up for 6 months after the procedure. The primary endpoint of the study was to evaluate the feasibility to access and biopsy the nodule. RESULTS: Twelve patients were recruited, and a tunnel pathway created in 10 patients. There were no adverse events during the procedures. Adequate biopsies were obtained from 10 patients (83%), which correlated with the histological findings from the surgical resection. Inspection of the resected lobes did not raise any safety concerns and indicated appropriately tunnelled pathways to the nodule. CONCLUSIONS: This first in human study demonstrates that bronchoscopic transparenchymal access of SPNs is feasible. TRIAL REGISTRATION NUMBER: NCT02130115. PMID- 25746632 TI - Treatment options for community-acquired pneumonia in the elderly people. AB - Community-acquired pneumonia (CAP) represents one of the most common reasons for hospitalization in elderly people. Because older persons are the fastest growing segment of the population, a further increase of the incidence of CAP is expected in the next few years. Due to the high frequency, the different epidemiology, the atypical clinical presentation and the age-related modifications in drug metabolism that complicate the treatment, infections in the elderly people represent a major challenge for physicians. Despite the peculiarity of the management of CAP in the elderly people, no specific recommendations for antimicrobial treatment are provided in the international guidelines. The aim of this review is to give an update of the current antibiotic options for CAP in the elderly people reporting available data on the CAP etiology and risk factors, and tolerability, toxicity and pharmacokinetics/pharmacodynamic of antimicrobial agents used for elderly patients. PMID- 25746633 TI - One-Year Postapproval Clinical Experience with Radium-223 Dichloride in Patients with Metastatic Castrate-Resistant Prostate Cancer. AB - OBJECTIVES: We report our 1-year postapproval clinical experience with Radium-223 dichloride for treatment of castrate-resistant prostate cancer with bone metastases. METHODS: The clinical courses of the first 25 patients treated were reviewed retrospectively. Incidence of hematologic, gastrointestinal, and other adverse events were identified, including those events that led to cessation or delay in treatment. Alterations in bone pain and serum alkaline phosphatase and prostate-specific antigen (PSA) levels were evaluated. RESULTS: Six patients received all 6 scheduled doses of Radium-223 dichloride, 2 completed 5 doses, 6 received 4 doses, 2 completed 3 doses, 6 patients had 2 doses, and 3 patients received one dose, for a total of 91 doses administered. Nine patients discontinued treatment after receiving at least one dose due to progressive disease, 5 required blood transfusions, 5 developed gastrointestinal symptoms, 4 reported worsening bone pain, and 1 developed dermatitis. Downward trends in serum alkaline phosphatase and PSA were seen in 11 and 5 patients, respectively. CONCLUSIONS: About one-quarter of cohort completed the entire six-dose treatment. Advancing soft tissue disease was the primary reason for cessation of therapy. The adverse events were mild and manageable. A decline in serum alkaline phosphatase was more common than a decline in PSA. PMID- 25746634 TI - Biosynthesis of the anti-infective marformycins featuring pre-NRPS assembly line N-formylation and O-methylation and post-assembly line C-hydroxylation chemistries. AB - The biosynthetic gene cluster governing production of anti-infective marformycins was identified from deep sea-derived Streptomyces drozdowiczii SCSIO 10141. The putative mfn gene cluster (45 kb, 20 orfs) was found to encode six NRPSs and related proteins for cyclodepsipeptide core construction (mfnCDEFKL), a methionyl tRNA formyltransferase (mfnA), a SAM-dependent methyltransferase (mfnG), and a cytochrome P450 monooxygenase for piperazic acid moiety hydroxylation (mfnN); notably, only MfnN uses an intact cyclodepsipeptide intermediate as its substrate. PMID- 25746635 TI - Editorial: Full-scale investigations in water and wastewater treatment. PMID- 25746636 TI - A review on full-scale decentralized wastewater treatment systems: techno economical approach. AB - As a solution to the shortcomings of centralized systems, over the last two decades large numbers of decentralized wastewater treatment plants of different technology types have been installed all over the world. This paper aims at deriving lessons learned from existing decentralized wastewater treatment plants that are relevant for smaller towns (and peri-urban areas) as well as rural communities in developing countries, such as India. Only full-scale implemented decentralized wastewater treatment systems are reviewed in terms of performance, land area requirement, capital cost, and operation and maintenance costs. The results are presented in tables comparing different technology types with respect to those parameters. PMID- 25746637 TI - Circular economy in drinking water treatment: reuse of ground pellets as seeding material in the pellet softening process. AB - Calcium carbonate pellets are produced as a by-product in the pellet softening process. In the Netherlands, these pellets are applied as a raw material in several industrial and agricultural processes. The sand grain inside the pellet hinders the application in some high-potential market segments such as paper and glass. Substitution of the sand grain with a calcite grain (100% calcium carbonate) is in principle possible, and could significantly improve the pellet quality. In this study, the grinding and sieving of pellets, and the subsequent reuse as seeding material in pellet softening were tested with two pilot reactors in parallel. In one reactor, garnet sand was used as seeding material, in the other ground calcite. Garnet sand and ground calcite performed equally well. An economic comparison and a life-cycle assessment were made as well. The results show that the reuse of ground calcite as seeding material in pellet softening is technologically possible, reduces the operational costs by ?38,000 (1%) and reduces the environmental impact by 5%. Therefore, at the drinking water facility, Weesperkarspel of Waternet, the transition from garnet sand to ground calcite will be made at full scale, based on this pilot plant research. PMID- 25746638 TI - Full-scale phosphorus recovery from digested waste water sludge in Belgium - part I: technical achievements and challenges. AB - To date, phosphorus recovery as struvite in wastewater treatment plants has been mainly implemented on water phases resulting from dewatering processes of the sludge line. However, it is possible to recover struvite directly from sludge phases. Besides minimising the return loads of phosphorus from the sludge line to the water line, placing such a process within the sludge line is claimed to offer advantages such as a higher recovery potential, enhanced dewaterability of the treated sludge, and reduced speed of scaling in pipes and dewatering devices. In the wastewater treatment plant at Leuven (Belgium), a full-scale struvite recovery process from digested sludge has been tested for 1 year. Several monitoring campaigns and experiments provided indications of the efficiency of the process for recovery. The load of phosphorus from the sludge line returning to the water line as centrate accounted for 15% of the P-load of the plant in the reference situation. Data indicated that the process divides this phosphorus load by two. An improved dewaterability of 1.5% of dry solids content was achieved, provided a proper tuning of the installation. Quality analyses showed that the formed struvite was quite pure. PMID- 25746639 TI - Full-scale phosphorus recovery from digested wastewater sludge in Belgium - part II: economic opportunities and risks. AB - One of the options to recycle phosphorus (P) in the wastewater sector is to recover it as struvite crystals from digested sludge. Measurements on a full scale demonstration plant in Leuven, Belgium, yielded a first indication of the profitability of struvite recovery, in function of different variables such as incoming PO(4)(3-) concentration, MgCl2dosing, improved dewaterability, etc. An uncertainty and sensitivity analysis was carried out. Although possible improvement in sludge dewaterability when recovering struvite from digested sludge has a positive economic amortization effect, it is at the same time the largest source of financial risk. A theoretical exercise showed that for struvite recovery from centrate, uncertainty would be lower, and the largest sensitivity would be attributed to ingoing PO(4)(3-) concentration. Although struvite recovery from digested sludge is riskier, it is an investment with potentially a higher return than investment in struvite recovery from centrate. The article provides information for possible financial incentive schemes to support P recovery. PMID- 25746640 TI - Start-up and maturation phases of a full-scale, high-rate anaerobic pond bioreactor((r)) plus improved facultative ponds to treat municipal wastewater. AB - Results of the start-up and maturation phases of a full-scale, high-rate anaerobic pond bioreactor (HRAPB)((r)) plus improved facultative ponds (IFPs) to treat municipal wastewater are presented (CODt: 759 mg L-1, CODf: 219 mg L-1, S SO(4)(2-): 102 mg L-1, and Cr+: 1,500 MUgL-1). The start-up of the HRAPB((r)) comprised, first, the application of a selective pressure increasing up-flow velocity rates. Second, batch stages between successive rates were allowed until 70% of the initial CODf was removed. The IFPs were left in batch and ended when in-pond Chlorophyll-a concentration reached 800 MUgL-1. Subsequently, the system underwent gradual maturation and reached effluent concentrations of CODt: 223 mg L-1, CODf: 50 mg L-1, and Cr+: 60 MUgL-1. The actual efficiency of the system compared with the expected design efficiency was lower given the characteristics of the influent wastewater biochemical oxygen demand/chemical oxygen demand ratios < 0.4, presence of Cr+ >1,000 MUgL-1, and variations in both conductivity (500-4,500 MUScm-1) and pH (6.5-10.5 units). Nonetheless, the system exhibited an adaptation state in less than 1.5 months and yielded an ST/SV ratio of 0.46, and specific methanogenic activity of 0.43 g-CH4-CODg-1SV-1d-1 for HRAPB((r)); the in pond Chlorophyll-a was on average 1,200 MUgL-1 in the IFPs, which demonstrated the robustness of these eco-technologies in tropical conditions. PMID- 25746641 TI - Water quantity and quality assessment on a tertiary treatment wetland in a tropical climate. AB - This study aimed to assess the quantity and quality of water in a surface flow constructed wetland in Australia's far north Queensland. Owing to tropical climate in the region, the wetland provided dual functions: retention of a treated wastewater for zero discharge during the dry season and tertiary treatment prior to discharge during the wet season. Rainfall data, permeability of wetland soil, evaporation, inflow and outflow were analysed in a water balance analysis; the results showed that based on a 72-year-average rainfall pattern, daily wastewater inflow of 85 m(3)/d is the maximum this wetland can cope with without breaching its discharge certificate. In water quality analysis, the K-C* model was used to predict changes of biochemical oxygen demand (BOD, suspended solids (SS), total nitrogen (TN), total phosphorus (TP) and faecal coliforms (FC) in the wetland. Model predictions were compared with field sampling results. It was found that the wetland was effective in removing FC (>99.9%), TN (70.7%) and TP (68.2%), for which the predictions by the K-C* model were consistent with field testing results. However, significant disparities between the predictions and testing results were found for BOD and SS. A revised K-C* equation was proposed to account for the internal generation of organics in constructed wetlands with a long retention time. PMID- 25746642 TI - Protection of biomass from snail overgrazing in a trickling filter using sponge media as a biomass carrier: down-flow hanging sponge system. AB - This study investigated down-flow hanging sponge (DHS) technology as a promising trickling filter (TF) using sponge media as a biomass carrier with an emphasis on protection of the biomass against macrofauna overgrazing. A pilot-scale DHS reactor fed with low-strength municipal sewage was operated under ambient temperature conditions for 1 year at a sewage treatment plant in Bangkok, Thailand. The results showed that snails (macrofauna) were present on the surface of the sponge media, but could not enter into it, because the sponge media with smaller pores physically protected the biomass from the snails. As a result, the sponge media maintained a dense biomass, with an average value of 22.3 gVSS/L sponge (58.1 gTSS/L sponge) on day 370. The snails could graze biomass on the surface of the sponge media. The DHS reactor process performance was also successful. The DHS reactor requires neither chemical treatments nor specific operations such as flooding for snail control. Overall, the results of this study indicate that the DHS reactor is able to protect biomass from snail overgrazing. PMID- 25746643 TI - A comparative study of clonal selection algorithm for effluent removal forecasting in septic sludge treatment plant. AB - The development of effluent removal prediction is crucial in providing a planning tool necessary for the future development and the construction of a septic sludge treatment plant (SSTP), especially in the developing countries. In order to investigate the expected functionality of the required standard, the prediction of the effluent quality, namely biological oxygen demand, chemical oxygen demand and total suspended solid of an SSTP was modelled using an artificial intelligence approach. In this paper, we adopt the clonal selection algorithm (CSA) to set up a prediction model, with a well-established method - namely the least-square support vector machine (LS-SVM) as a baseline model. The test results of the case study showed that the prediction of the CSA-based SSTP model worked well and provided model performance as satisfactory as the LS-SVM model. The CSA approach shows that fewer control and training parameters are required for model simulation as compared with the LS-SVM approach. The ability of a CSA approach in resolving limited data samples, non-linear sample function and multidimensional pattern recognition makes it a powerful tool in modelling the prediction of effluent removals in an SSTP. PMID- 25746644 TI - Developing a demand model integrating end uses of water (DMEUW): structure and process of integration. AB - The process of developing an integrated water demand model integrating end uses of water has been presented. The model estimates and forecasts average daily water demand based on the end-use pattern and trend of residential water consumption, daily rainfall and temperature, water restrictions and water conservation programmes. The end-use model uses the latest end-use data set collected from Yarra Valley Water, Australia. A computer interface has also been developed using hypertext markup language and hypertext pre-processor. The developed model can be used by water authorities and water resource planners in forecasting water demand and by household owners in determining household water consumption. PMID- 25746645 TI - Changes in water biostability levels in water treatment trials. AB - This article presents the results of studies of changes in water biostability levels in water treatment systems. In order to evaluate the potential of microorganism regrowth, both the organic and non-organic nutrient substrate content was taken into account. Pre-treatment in the analyzed water treatment plants ensured high phosphate ion removal effectiveness but a significantly worse effectiveness in removing biodegradable dissolved organic carbon (BDOC). Lowering nutrient substrate content during the main treatment stage was only possible in water treatment systems that incorporated biological processes. Conversely, final water treatment processes only influenced BDOC content in the treated water. Irrespective of the water type and unit treatment process, the limiting factors for microorganism regrowth in the distribution system were the phosphate ion content and BDOC content. However, none of the analyzed treatment systems ensured a reduction in non-organic nitrogen content that would ensure biological stability of the water. PMID- 25746646 TI - Practical experience with full-scale structured sheet media (SSM) integrated fixed-film activated sludge (IFAS) systems for nitrification. AB - Many wastewater treatment plants in the USA, which were originally designed as secondary treatment systems with no or partial nitrification requirements, are facing increased flows, loads, and more stringent ammonia discharge limits. Plant expansion is often not cost-effective due to either high construction costs or lack of land. Under these circumstances, integrated fixed-film activated sludge (IFAS) systems using both suspended growth and biofilms that grow attached to a fixed plastic structured sheet media are found to be a viable solution for solving the challenges. Multiple plants have been retrofitted with such IFAS systems in the past few years. The system has proven to be efficient and reliable in achieving not only consistent nitrification, but also enhanced bio-chemical oxygen demand removal and sludge settling characteristics. This paper presents long-term practical experiences with the IFAS system design, operation and maintenance, and performance for three full-scale plants with distinct processes; that is, a trickling filter/solids contact process, a conventional plug flow activated sludge process and an extended aeration process. PMID- 25746647 TI - Start-up of a full-scale deammonification SBR-treating effluent from digested sludge dewatering. AB - This study shows the start-up and operation of a full-scale sequencing batch reactor (SBR) with a volume of 550 m3 for deammonification of reject water from sludge dewatering over the first 650 days of operation. The SBR was operated with discontinuous aeration and achieved an optimum of around 85% of ammonium removal at a load of 0.17 kg m-3 d-1. The application of batch tests for the activity measurement of aerobic ammonium and nitrite oxidizing bacteria and anaerobic ammonium oxidizing bacteria were proven to support the identification of setbacks in reactor operation. Furthermore, the calculation of the oxygen uptake rates from online oxygen measurements helped to explain the overall reactor performance. The aeration regime is a key parameter for stable operation of such an SBR for deammonification. At aeration/non-aeration time ranges from 6-9 min, the best results with respect to turnover rates and low nitrate production were achieved. Compared with the nitrification/denitrification SBR operated in parallel with methanol as the carbon source, a significant reduction in costs for energy and chemicals was achieved. The costs for maintenance slightly increased. PMID- 25746648 TI - A full-scale plug-flow reactor for biological sludge ozonation. AB - The reduction of biological excess sludge production using ozone is a well-known technology and is applied in several full-scale plants around the world. Nevertheless, optimisation of the process is not yet adequately documented in the literature. Operational parameters are usually chosen by assuming a direct proportionality between ozone dose and excess sludge reduction. This paper investigates the role of ozone concentration on process efficiency and demonstrates the (non-linear) inverse relationship between ozone dose and specific particulate chemical oxygen demand solubilisation in plug-flow contact reactors. The influence of total suspended solids concentration is also studied and described. No short-term lethal effects on heterotrophic biomass have been observed. PMID- 25746649 TI - The practical influence of rapid mixing on coagulation in a full-scale water treatment plant. AB - This study focuses on the effect of rapid mixing on the coagulation efficiency in a full-scale drinking-water treatment plant and discusses the mechanisms involved in the floc-formation process. The results refer to three periods of operation of the waterworks when no mechanical mixing was provided in the tanks for coagulant dosing due to mechanical failure of the rapid mixers. Although a certain deterioration of the subsequent flocculation process was observed, as assessed using the data for suspended solids, turbidity, and chemical oxygen demand, the overall water treatment performance was not affected. This suggests an insignificant role for intense rapid mixing in sweep flocculation during full scale water treatment and reveals the potential to reduce the required energy costs for mechanical mixers. PMID- 25746650 TI - Diagnosis of the anaerobic reject water effects on WWTP operational characteristics as a precursor of bulking and foaming. AB - This study investigates the effects observed on operational parameters in a large and full-scale wastewater treatment plant subjected to anaerobic reject water (ARW) diversion off the main line for a 3-month period and further monitoring for a 2-year period. The plant's secondary unit consists of a two-stage plug-flow modified Bardenpho process receiving wastewater from both municipal and industrial origins. As a result, ARW was found to have a direct effect on bulking in secondary clarifiers and foaming in anaerobic digesters (AD) despite its relatively small flow rate. During the cut-off period a highly stable sludge volume index at 80 mL g(-1) level was obtained in the secondary clarifiers, effluent suspended solids concentration was reduced and continuous feeding to AD was recovered. Sludge density increased in the thickeners during hot season. Secondary clarifiers showed good and stable settleability despite low dissolved oxygen, food/microorganism ratio and high sludge retention time and ammonium levels in the biological unit. The bulking and foaming effect was presented on the plant's internal flow balance. ARW needs serious consideration for elimination by appropriate technologies because of its high potential as a multi dimensional pollutant source, not only as a carrier of nutrients but also as a possible carrier of filamentous bacteria, which might promote chronic seeding and retention in the system. PMID- 25746651 TI - Comparison of reverse osmosis membrane fouling characteristics in full-scale leachate treatment systems with chemical coagulation and microfiltration pre treatments. AB - Fouling characteristics of reverse osmosis (RO) membrane with chemical coagulation and microfiltration (MF) pre-treatment were investigated at full scale leachate treatment systems. In chemical coagulation pre-treatment, solid separation from stabilized leachate was performed by ferric chloride coagulation followed by sand filtration. Meanwhile, MF pre-treatment and the RO system utilized direct filtration using a 0.03 um membrane without chemical addition. MF pre-treatment yielded better pollutant removals in terms of organics and nitrogen. The study on effect of pre-treatment on RO membrane fouling revealed that accumulated foulant on the RO membrane in MF pre-treatment was significantly lower than that of chemical coagulation. Nevertheless, NaOH cleaning of the fouled RO membrane after chemical coagulation pre-treatment could better recover its permeate flux, thus suggesting that the formation of a loose-structure cake layer by chemical coagulation pre-treatment could allow effective penetration of chemical cleaning and detachment of foulant layer from the membrane surface. PMID- 25746652 TI - High-strength wastewater treatment in a pure oxygen thermophilic process: 11-year operation and monitoring of different plant configurations. AB - This research was carried out on a full-scale pure oxygen thermophilic plant, operated and monitored throughout a period of 11 years. The plant treats 60,000 t y-1 (year 2013) of high-strength industrial wastewaters deriving mainly from pharmaceuticals and detergents production and landfill leachate. Three different plant configurations were consecutively adopted: (1) biological reactor + final clarifier and sludge recirculation (2002-2005); (2) biological reactor + ultrafiltration: membrane biological reactor (MBR) (2006); and (3) MBR + nanofiltration (since 2007). Progressive plant upgrading yielded a performance improvement chemical oxygen demand (COD) removal efficiency was enhanced by 17% and 12% after the first and second plant modification, respectively. Moreover, COD abatement efficiency exhibited a greater stability, notwithstanding high variability of the influent load. In addition, the following relevant outcomes appeared from the plant monitoring (present configuration): up to 96% removal of nitrate and nitrite, due to denitrification; low-specific biomass production (0.092 kgVSS kgCODremoved-1), and biological treatability of residual COD under mesophilic conditions (BOD5/COD ratio = 0.25-0.50), thus showing the complementarity of the two biological processes. PMID- 25746653 TI - Methodological approach for the optimization of drinking water treatment plants' operation: a case study. AB - Critical barriers to safe and secure drinking water may include sources (e.g. groundwater contamination), treatments (e.g. treatment plants not properly operating) and/or contamination within the distribution system (infrastructure not properly maintained). The performance assessment of these systems, based on monitoring, process parameter control and experimental tests, is a viable tool for the process optimization and water quality control. The aim of this study was to define a procedure for evaluating the performance of full-scale drinking water treatment plants (DWTPs) and for defining optimal solutions for plant upgrading in order to optimize operation. The protocol is composed of four main phases (routine and intensive monitoring programmes - Phases 1 and 2; experimental studies - Phase 3; plant upgrade and optimization - Phase 4). The protocol suggested in this study was tested in a full-scale DWTP placed in the North of Italy (Mortara, Pavia). The results outline some critical aspects of the plant operation and permit the identification of feasible solutions for the DWTP upgrading in order to optimize water treatment operation. PMID- 25746654 TI - Performance of upflow gravel filtration in multi-stage filtration plants. AB - This paper presents the results of a study of four full-scale upflow gravel filters that are part of full-scale multi-stage filtration. The study explored the design criteria, the operation and maintenance (O&M) practices, and the performance of the systems. Findings showed that most design criteria and O&M procedures are following the recommendations as presented in the literature but several diversions were also identified. Performance data showed that removal efficiencies were on the low side when compared to the literature, possibly because of the good influent quality water that was treated. Cleaning efficiency was analyzed and the overall conclusion is that an adjustment of the design criteria and O&M procedures is needed to enhance system performance. This includes drainage system design, surface cleaning by weir, and filter bed cleaning to allow a reduction in cleaning cycles and an improvement in operation control. PMID- 25746655 TI - Particle counter as a tool to control pre-hydrolyzed coagulant dosing and rapid filtration efficiency in a conventional treatment system. AB - Filtration efficiency in a conventional water treatment system was analyzed in the context of pre-hydrolyzed coagulant overdosing. Two commercial coagulants of different aluminum speciation were tested. A study was carried out at a water treatment plant supplied with raw water of variable quality. The lack of stability of water quality caused many problems with maintaining the optimal coagulant dose. The achieved results show that the type of coagulant had a very strong influence on the effectiveness of filtration resulting from the application of an improper coagulant dose. The overdosing of high basicity coagulant (PAC85) caused a significant increase of fine particles in the outflow from the sedimentation tanks, which could not be retained in the filter bed due to high surface charge and the small size of hydrolysis products. When using a coagulant of lower basicity (PAC70), it was much easier to control the dose of coagulant and to adjust it to the changing water quality. PMID- 25746656 TI - Arsenic and antimony removal from drinking water by adsorption on granular ferric oxide. AB - Arsenic and antimony occur in drinking water due to natural weathering or anthropogenic activities. There has been growing concern about their impact on health. The aim of this study was to assess the efficiency of a granular ferric oxide adsorbent medium to remove arsenic and antimony from drinking water via rapid small-scale column tests (RSSCTs). Three different water matrices - deionized, raw water treated with a reverse osmosis domestic device and raw water - were spiked with arsenic and/or antimony to a concentration of 100 MUg L-1. Both elements were successfully adsorbed onto the medium. The loadings until the guideline value was exceeded in the effluent were found to be 0.35-1.63 mg g-1 for arsenic and 0.12-2.11 mg g-1 for antimony, depending on the water matrix. Adsorption of one element was not substantially affected by the presence of the other. Aeration did not affect significantly the adsorption capacity. Granular ferric oxide could be employed for the simultaneous removal of arsenic and antimony from drinking water, whereas full-scale systems should be assessed via laboratory tests before their implementation. PMID- 25746657 TI - Anaerobic/aerobic treatment of greywater via UASB and MBR for unrestricted reuse. AB - The aim of the present study was to investigate the efficiency of integrated up flow anaerobic sludge blanket (UASB) as anaerobic system followed by membrane bioreactor (MBR) as aerobic system for the treatment of greywater for unrestricted reuse. Pilot-scale UASB and MBR units were installed and operated in the NRC, Egypt. Real raw greywater was subjected to UASB and the effluent was further treated with microfiltration MBR. The necessary trans-membrane pressure difference is applied by the water head above the membrane (gravity flow) without any energy input. The average characteristics of the raw greywater were 95, 392, 298, 10.45, 0.4, 118.5 and 28 mg/L for total suspended solids (TSS), chemical oxygen demand (COD), biochemical oxygen demand (BOD), total phosphates, nitrates, oil and grease, and total Kjeldahl nitrogen (TKN), respectively. The pH was 6.71. The UASB treatment efficiency reached 19.3, 57.8, 67.5 and 83.7% for TSS, COD, BOD5 and oil and grease, respectively. When the UASB effluent was further treated with MBR, the overall removal rate achieved 97.7, 97.8, 97.4 and 95.8% for the same parameters successively. The characteristics of the final effluent reached 2.5, 8.5, 6.1, 0.95, 4.6 and 2.3 mg/L for TSS, COD, BOD, phosphates, oil and grease and TKN, respectively. This final treated effluent could cope with the unrestricted water reuse of local Egyptian guidelines. PMID- 25746658 TI - Selection of the surface water treatment technology - a full-scale technological investigation. AB - A technological investigation was carried out over a period of 2 years to evaluate surface water treatment technology. The study was performed in Poland, in three stages. From November 2011 to July 2012, for the first stage, flow tests with a capacity of 0.1-1.5 m3/h were performed simultaneously in three types of technical installations differing by coagulation modules. The outcome of the first stage was the choice of the technology for further investigation. The second stage was performed between September 2012 and March 2013 on a full-scale water treatment plant. Three large technical installations, operated in parallel, were analysed: coagulation with sludge flotation, micro-sand ballasted coagulation with sedimentation, coagulation with sedimentation and sludge recirculation. The capacity of the installations ranged from 10 to 40 m3/h. The third stage was also performed in a full-scale water treatment plant and was aimed at optimising the selected technology. This article presents the results of the second stage of the full-scale investigation. The critical treatment process, for the analysed water, was the coagulation in an acidic environment (6.5 < pH < 7.0) carried out in a system with rapid mixing, a flocculation chamber, preliminary separation of coagulation products, and removal of residual suspended solids through filtration. PMID- 25746659 TI - Removal of organic matter from surface water during coagulation with sludge flotation and rapid filtration - a full-scale technological investigation. AB - Coagulation with sludge flotation and rapid filtration was selected as a surface water treatment technology to be optimised with a full-scale investigation, which was carried out in Poland between August and October 2013. The river water treated was characterized by low alkalinity, high-temperature variability and a high organic matter content. In the course of technological studies, the processes of coagulation with sludge flotation and rapid filtration were analysed. The studies were performed in the most adverse conditions for the applied technology i.e. during the period of algal bloom and subsequent decomposition of dead plankton. Throughout the study, the river water contained mainly dissolved organic matter, with occasional increases in the concentration of the undissolved fraction during algal bloom. The undissolved total organic carbon (TOC) fraction was effectively removed through coagulation while small doses of ClO2added prior to coagulation enhanced the process. The process of coagulation using high-coagulant doses at pH = 6.5 did not provide a reduction in the TOC value below the level of 4 mg C/L required for treated water. The effect was achieved by adding powdered activated carbon (PAC) before the filters. The coagulation products were characterised by low-hydraulic resistance which should be taken into account at the stage of water delivery to the filters, after flotation. PMID- 25746660 TI - [Basal cell carcinoma with matrical differentiation]. AB - Basal cell carcinoma with matrical differentiation is a very rare variant of basal cell carcinoma. To our knowledge, less than 30 cases have been reported. This tumor is composed of basaloid lobules showing a differentiation toward the pilar matrix cells. Recently, it has been demonstrated that beta-catenin would interfer with physiopathogenesis of matrical tumors, in particular pilomatricomas, but also basal cell carcinomas with matrical differentiation. This is a new case, with immunohistochemical and molecular analysis of beta catenin, in order to explain its histogenesis. PMID- 25746661 TI - Deregulation of DNMT1, DNMT3B and miR-29s in Burkitt lymphoma suggests novel contribution for disease pathogenesis. AB - Methylation of CpG islands in promoter gene regions is frequently observed in lymphomas. DNA methylation is established by DNA methyltransferases (DNMTs). DNMT1 maintains methylation patterns, while DNMT3A and DNMT3B are critical for de novo DNA methylation. Little is known about the expression of DNMTs in lymphomas. DNMT3A and 3B genes can be regulated post-transcriptionally by miR-29 family. Here, we demonstrated for the first time the overexpression of DNMT1 and DNMT3B in Burkitt lymphoma (BL) tumor samples (69% and 86%, respectively). Specifically, the treatment of two BL cell lines with the DNMT inhibitor 5-aza-dC decreased DNMT1 and DNMT3B protein levels and inhibited cell growth. Additionally, miR-29a, miR-29b and miR-29c levels were significantly decreased in the BL tumor samples. Besides, the ectopic expression of miR-29a, miR-29b and miR-29c reduced the DNMT3B expression and miR-29a and miR-29b lead to increase of p16(INK4a) mRNA expression. Altogether, our data suggest that deregulation of DNMT1, DNMT3B and miR29 may be involved in BL pathogenesis. PMID- 25746662 TI - High-mobility group box-1 gene, a potent proinflammatory mediators, is upregulated in more degenerated human discs in vivo and its receptor upregulated by TNF-alpha exposure in vitro. AB - Mechanisms which control and enhance proinflammatory cytokine expression during human disc degeneration are still poorly understood. The high-mobility group box 1 gene (HMGB1) produces a protein which can itself act as a cytokine, or can function as a potent proinflammatory mediator. Little is known about expression of HMGB1 in the human disc. Since proinflammatory cytokines increase significantly during human disc degeneration, in this work we hypothesized that HMGB1 may show upregulation with advancing stages of degeneration, and upregulation in cells exposed to TNF-alpha. Immunohistochemistry was performed to confirm the presence of HMGB1 in the human disc, and human annulus cells were cultured and challenged with 10(3)pM TNF-alpha for 14days in 3D culture. Cells with positive HMGB1 immunolocalization were abundant in the outer annulus. Molecular analysis of cultured cells showed an 8-fold significant increase in HMGB1 expression in more degenerated Thompson grade V discs compared to healthier grade I/II discs (p=0.033). Human disc tissue was assessed in molecular studies. Herniated specimens showed a 6.3-fold significantly greater expression level than that seen in control specimens (p=0.001). In culture experiments, expression of the receptor to HMGB1, toll-like receptor 2, showed a 24-fold upregulation in vitro in cells exposed to TNF-alpha vs. controls (p=0.0003). PMID- 25746664 TI - Current perspectives of mi-RNA in oesophageal adenocarcinoma: Roles in predicting carcinogenesis, progression and values in clinical management. AB - Aberrant expressions of micro-ribonucleic acids (miRs) are closely associated with the pathogenesis in many human cancers. In oesophageal adenocarcinomas, altered expressions of different sets of miRs are noted to be associated with the development of adenocarcinoma from Barrett's oesophagus. In different studies, miRs such as miR-192, miR-196 and miR-21 were frequently noted to up-regulated whereas miR-203, miR-205 and miR-let-7 were commonly down-regulated during the development of Barrett's oesophagus to oesophageal adenocarcinoma. In addition, changes in the expression of miRs are associated with the predication of metastasis, prognosis and response to chemo-radiation in the patients with oesophageal adenocarcinoma. Experimental studies in manipulating the miRs in cancer cell lines could provide hints for therapeutics for the cancer. However, the number of studies reported on these aspects of oesophageal adenocarcinoma was limited and the miRs noted needed to be confirmed by additional studies. Overall, the mechanisms of involvements of miRs in pathogenesis and progression of oesophageal adenocarcinoma are complex. Although miRs have the potential to act as prognostic and clinical biomarkers for cancer therapy in oesophageal adenocarcinoma, more works in larger populations and clinical trials are needed to validate these clinical implications. PMID- 25746663 TI - A multiplex allele-specific real-time PCR assay for screening of ESR1 mutations in metastatic breast cancer. AB - BACKGROUND: Acquired resistance to endocrine-based therapies occurs in virtually all estrogen receptor-alpha (ERalpha, encoded by ESR1) positive breast cancer patients. The underlying molecular mechanism is attributed to the activating mutations in ESR1. These mutations provide an exciting opportunity for the development of new antagonists that specifically inhibit the mutant proteins. Therefore, accurate detection of ESR1 mutations is of critical importance in clinical practice. MATERIALS AND METHODS: We carried out a single tube, multiplex allele-specific real-time PCR assay for the detection of four ESR1 mutations (Y537S, Y537C, Y537N, and D538G). RESULTS: The assay was found to be highly specific and sensitive. With this assay, as low as 1% mutant DNA template in wild type DNA could be detected. Fifteen DNA samples were prepared from archived formalin-fixed paraffin-embedded metastatic breast cancer biopsies. They were further screened with this assay, and three samples were identified as ESR1 mutant. The results were validated with pyrosequencing and complete concordance was observed between the two assays. CONCLUSION: The multiplex allele-specific real-time PCR assay provides a rapid and reliable diagnostic tool for accurate detection of ESR1 mutations. This procedure may be used in the clinical treatment of breast cancer. PMID- 25746665 TI - Hydrogen-rich saline ameliorates lung injury associated with cecal ligation and puncture-induced sepsis in rats. AB - AIMS: Although hydrogen has been proved to be a novel therapeutic medical gas in several lung injury animal models, to our knowledge, it has not been tested yet in acute lung injury (ALI) induced by cecal ligation and puncture (CLP). This study was to investigate the hypothesis that hydrogen could ameliorate CLP induced lung injury in rats. METHODS AND RESULTS: Our experiments exhibited that gas exchange dysfunction and lung tissue inflammation were observed in animals exposed to CLP. Hydrogen-rich saline treatment significantly attenuated lung injury as indicated by significantly improved gas exchange and histological changes in the lung and significantly reduced lung water content (LWC) and neutrophil infiltration 8h after CLP. Lipid peroxidation and DNA oxidation in the lung tissue were significantly reduced along with a decreased nitrotyrosine content and maintained superoxide dismutase activity in the presence of hydrogen, demonstrating antioxidant role of hydrogen in CLP-induced ALI. Importantly, hydrogen-rich saline treatment significantly inhibited the activation of p-p38 and NF-kappaB while suppressing the production of several proinflammatory mediators. CONCLUSIONS: This observation indicated that hydrogen-rich saline peritoneal injection improves histological and functional assessment in rat model of CLP-induced ALI. The therapeutic effects of hydrogen-rich saline may be related to antioxidant and anti-inflammatory actions. PMID- 25746666 TI - Complexes between insulin-like growth factor binding proteins and alpha-2 macroglobulin in patients with tumor. AB - The intention of this work was to systematically study the presence of insulin like growth factor-binding protein 1 and 2 (IGFBP-1 and IGFBP-2) complexes with alpha-2-macroglobulin (alpha2M) in the circulation of patients with various types of cancer. Serum samples were collected from patients diagnosed with cancer and divided into eight groups according to the tumor type: liver, pancreas, colon, lung, prostate, breast, cervix and ovary. Results obtained for each cancer group were compared with results obtained for the age and gender-matched controls. Electrophoretic separation and densitometric evaluation of immunoreactive protein bands were performed. According to our results, IGFBP-1/alpha2M and IGFBP 2/alpha2M complexes did not exhibit the same presence in different tumors and were also not uniformly related to the amount of monomer forms. Variations in relative quantities of IGFBP-1 monomers and complexes in different tumor types were much more pronounced than those of IGFBP-2. The amount of IGFBP-2 monomer increased in sera from all studied patients compared to controls, whereas the amount of IGFBP-2/alpha2M complexes most often decreased, being significantly reduced in patients with pancreas, colon, breast or ovary tumor. Although there is still no confirmation of the physiological role of IGFBP-2/alpha2M complexes, their decreased concentration in the circulation provides greater amount of free IGFBP-2. PMID- 25746667 TI - Polaron stability in molecular semiconductors: theoretical insight into the impact of the temperature, electric field and the system dimensionality. AB - A semi-empirical Holstein-Peierls model is used to study the temperature effects on the polaron stability in organic semiconductors at a molecular scale. The approach takes into account both intra- and inter-molecular electron-lattice interactions and is aimed at describing charge transport in the system. Particularly, we present a systematic numerical investigation to characterize the influence of both temperature and electric field on the stability as well as mobility of the polaron. It is found that the parameter space for which the polaron is dynamically stable is quite limited and the variations in some of these parameters strongly depend on the temperature. The electric field can play a role in further localizing the charge causing a compression of the lattice distortions associated with the polaron, increasing thereby its stability, up to a field strength of approximately 2.0 mV A(-1). Considering field strengths higher than this critical value, the polaron is annihilated spreading charge through the lattice. Furthermore, we have studied the polaron mobility as a function of the anisotropy of the system, going from a one-dimensional system via a highly anisotropic two-dimensional system to a uniform two-dimensional system. There is a clearly observed mobility edge for the polaron; it exhibits a high mobility in the one-dimensional system but as the coupling in the second dimension is turned on the polaron slows down and becomes immobile in the uniform system. The results provided by this transport mechanism are in good agreement with experimental observations and may provide guidance to improve the charge transport in organic optoelectronic devices. PMID- 25746668 TI - Effects of prenatal Leydig cell function on the ratio of the second to fourth digit lengths in school-aged children. AB - Prenatal sex hormones can induce abnormalities in the reproductive system and adversely impact on genital development. We investigated whether sex hormones in cord blood influenced the ratio of the second to fourth digit lengths (2D/4D) in school-aged children. Of the 514 children who participated in a prospective cohort study on birth in Sapporo between 2002 and 2005, the following sex hormone levels were measured in 294 stored cord blood samples (135 boys and 159 girls); testosterone (T), estradiol (E), progesterone, LH, FSH, inhibin B, and insulin like factor 3 (INSL3). A total of 350 children, who were of school age and could be contacted for this survey, were then requested via mail to send black-and white photocopies of the palms of both the left and right hands. 2D/4D was calculated in 190 children (88 boys and 102 girls) using photocopies and derived from participants with the characteristics of older mothers, a higher annual household income, higher educational level, and fewer smokers among family members. 2D/4D was significantly lower in males than in females (p<0.01). In the 294 stored cord blood samples, T, T/E, LH, FSH, Inhibin B, and INSL3 levels were significantly higher in samples collected from males than those from females. A multivariate regression model revealed that 2D/4D negatively correlated with INSL3 in males and was significantly higher in males with <0.32 ng/mL of INSL3 (p<0.01). No correlations were observed between other hormones and 2D/4D. In conclusion, 2D/4D in school-aged children, which was significantly lower in males than in females, was affected by prenatal Leydig cell function. PMID- 25746669 TI - A retrospective study of clinical characteristics of interstitial lung disease associated with rheumatoid arthritis in Chinese patients. AB - BACKGROUND: Interstitial lung disease (ILD) in rheumatoid arthritis (RA) is associated with a poor prognosis. The purpose of this study was to assess the characteristics of ILD that are associated with RA. MATERIAL AND METHODS: This was a retrospective study of 544 Chinese patients with RA (427 women and 117 men). RA-ILD was diagnosed by high-resolution computed tomography (HRCT). Patients with RA-ILD or with RA alone were compared in terms of age, sex distribution, duration of disease, clinical and laboratory parameters, history of smoking, and medication. RESULTS: Based on HRCT imaging, 83 (15.26%) patients with RA were diagnosed with ILD. ILD was more frequent in older patients (59.60+/ 9.66 vs. 50.54+/-13.76 years, P<0.001), in those with a longer duration of disease (7.46+/-7.40 vs. 5.27+/-6.32 years, P=0.013) and in male patients (34.9% vs. 19.1%, P=0.001). RA-ILD was found to be associated with hepatitis B surface antigen (HBsAg) positivity (odds ratio [OR]=2.56, 95% confidence interval [95% CI] 1.02-6.43) and smoking (OR=3.38, 95% CI 1.65-6.95). Higher levels of C reactive protein (OR=3.59, 95% CI 1.58-8.15), anti-cyclic citrullinated peptide (CCP) (OR=2.24, 95% CI 2.09-4.13), and rheumatoid factor (OR=3.72, 95% CI 1.56 8.86) were detected in association with RA-ILD. RA-ILD was more frequently observed in patients treated with steroids (OR=1.91, 95% CI 1.18-3.09) or Tripterygium wilfordii (OR=2.56, 95% CI 1.21-5.40). Age (OR=2.20, 95% CI 1.04 4.65), age at RA onset (OR=2.55, 95% CI 1.11-5.90), anti-CCP (OR=2.47, 95% CI 1.19-5.17), and steroid use (OR=1.83, 95% CI 1.04-3.20) were independently associated with RA-ILD in multivariate analysis. CONCLUSIONS: RA-ILD was associated with age, age at RA onset, anti-CCP, and steroid use. Anti-CCP antibodies might be important biomarkers of RA-ILD. PMID- 25746670 TI - A lower viral set point but little immunological impact after early treatment during primary HIV infection. AB - The Primo-SHM trial, a multicenter randomized trial comparing no treatment with 24 or 60 weeks of combination antiretroviral therapy (cART) during primary human immunodeficiency virus (HIV) infection (PHI), recently demonstrated that temporary early cART lowered the viral set point and deferred the need for re initiation of cART during chronic HIV infection. This study examined whether the beneficial effect of early treatment was caused by preservation of immunological responses. Twenty-seven treated and 20 untreated PHI individuals participating in the Primo-SHM trial were compared at viral set point, that is, 36 weeks after baseline or after treatment interruption, respectively, for a diverse set of immunological parameters. The results show no differences between treated and untreated individuals at the level of effector T-cell formation or replication capacity of the T-cells; regulation of various T, B, natural killer, or dendritic cells; polyfunctionality of the CD8 T-cells; preservation of CD4 T-cells in the gut associated lymphoid tissue; or immune activation. There were subtle differences in the quality of the cytolytic CD4 T-cell response: 11% (median) of CD4 T-cells of the early treated individuals produced the cytolytic molecule perforin compared to 5% in untreated individuals (p=0.046), and treatment caused a modest increase in CD4 T-cells expressing both perforin and granzyme B (median 9% vs. 4% of CD4 T-cells; p=0.045). Early treatment had a modest positive effect on the quality of the CD4 T-cell response. It remains unclear, however, whether these subtle immunological differences were the cause or a result of the lower viral set point in patients who received early treatment. PMID- 25746671 TI - Evaluation of the Impact of Ruminant Trans Fatty Acids on Human Health: Important Aspects to Consider. AB - The definition and evaluation of trans fatty acids (TFA) with regard to foodstuffs and health hazard are not consistent. Based on the current situation, the term should be restricted only to TFA with isolated double bonds in trans configuration. Conjugated linoleic acids (CLA) should be separately assessed. Ideally, the origin of the consumed fat should be declared, i.e., ruminant TFA (R TFA) and industrial TFA (non-ruminant; I-TFA). In ruminant fat, more than 50% of R-TFA consists of vaccenic acid (C18:1 t11). In addition, natural CLA, i.e., c9,t11 CLA is also present. Both are elevated in products from organic farming. In contrast to elaidic acid (t9) and t10, which occur mainly in partially hydrogenated industrial fat, t11 is partially metabolized into c9,t11 CLA via Delta9-desaturation. This is the major metabolic criterion used to differentiate between t11 and other trans C18:1. t11 indicates health beneficial effects in several studies. Moreover, CLA in milk fat is associated with the prevention of allergy and asthma. An analysis of the few studies relating to R-TFA alone makes clear that no convincing adverse physiological effect can be attributed to R-TFA. Only extremely high R-TFA intakes cause negative change in blood lipids. In conclusion, in most European countries, the intake of R-TFA is assessed as being low to moderate. Restriction of R-TFA would unjustifiably represent a disadvantage for organic farming of milk. PMID- 25746672 TI - Allosteric coupling via distant disorder-to-order transitions. AB - Intrinsic disorder provides a means of maximizing allosteric coupling in proteins. However, the mechanisms by which the disorder functions in allostery remain to be elucidated. Small ligand, bio-5'-AMP, binding and dimerization of the Escherichia coli biotin repressor are allosterically coupled. Folding of a disordered loop in the allosteric effector binding site is required to realize the full coupling free energy of -4.0 +/- 0.3 kcal/mol observed in the wild-type protein. Alanine substitution of a glycine residue on the dimerization surface that does not directly contribute to the dimerization interface completely abolishes this coupling. In this work, the structure of this variant, solved by X ray crystallography, reveals a monomeric corepressor-bound protein. In the structure loops, neither of which contains the alanine substitution, on both the dimerization and effector binding surfaces that are folded in the corepressor bound wild-type protein are disordered. The structural data combined with functional measurements indicate that allosteric coupling between ligand binding and dimerization in BirA (E. coli biotin repressor/biotin protein ligase) is achieved via reciprocal communication of disorder-to-order transitions on two distant functional surfaces. PMID- 25746673 TI - [Anterior mandibular bone grafts by sub-mental approach]. AB - INTRODUCTION: Some cases of totally edentulous mandibles are associated with extreme osseous resorption which do not allow the placement of dental implants, even in the symphysis area. We present a bone graft technique performed by mean of a submental approach. TECHNICAL NOTE: The reconstruction is performed under general anesthesia by mean of calvarial bone bone grafts affixed on the superior face and occasionally on the inferior face of the mandibular symphysis, between the mental foramens. The approach is a conventional sub-mental approach that exposes the entire symphysal region. Four patients (aged 61 to 81) have been operated according to this technic. There was no postoperative complication. Mean bone increase was 9.3mm. Nineteen implants were inserted (4.75 implants per patient). No implant have been lost. The scare was inconspicuous. DISCUSSION: This technique is indicated for cases with extreme bone resorption. It allows the reconstruction of the mandibular symphysis, without an intraoral approach and thus with minimized risk of bone graft exposure. Postoperative courses are uneventful. This technique is therefore indicated for elderly patients who complain about ill-fitting dentures. PMID- 25746674 TI - A novel PAX6 deletion in a Chinese family with congenital aniridia. AB - Aniridia is a rare, congenital ocular disorder with the characteristics of incomplete formation of the iris caused by the mutations of the paired box gene-6 (PAX6). To investigate the clinical characterization and the underlying genetic defect in a Chinese family with autosomal dominant aniridia, we recruited the family members who underwent comprehensive ophthalmic examination. A novel heterozygous PAX6 deletion mutation c.796 del G (p.A266 fs) (GenBank ID: KP255960) in exon 10 was exclusively observed in all affected individuals but not in any of the unaffected family members or unrelated controls. The PAX6 mRNA level was about 50% lower in patients with aniridia than in unaffected family members, indicating that this mutation caused nonsense-mediated mRNA decay. In conclusion, we identified a novel deletion mutation in the PAX6 gene resulting in an abnormal PAX6 COOH-terminal extension in the Chinese family with aniridia. Our study further expands the mutation spectrum of PAX6. PMID- 25746675 TI - Galectin-3, a prognostic marker--and a therapeutic target? AB - The natriuretic peptides BNP and NT-proBNP are currently the most commonly used biomarkers in heart failure, but they have limitations. There is thus a need to identify new biomarkers that may prove useful, alone or in combination, for screening, diagnosis and prognosis. Galectin-3 is a protein involved in a variety of cellular signaling pathways and is found in many tissues. Its expression is low in normal hearts but elevated in fibrotic hearts. Among other effects, it promotes fibroblast proliferation and collagen synthesis, contributing to the cardiac remodeling that is central to the development and progression of heart failure. Heart failure associated with elevated galectin-3 (>17.8 ng/ml) affects 30-50% of patients with chronic heart failure, and is a marker of worse prognosis, with higher rates of short-term rehospitalization and mortality. It is thought that galectin-3 inhibition, or even genetic disruption, may reverse or delay disease progression. Galectin-3 appears to have greater prognostic value than natriuretic peptides when assessed separately, however, when combined their prognostic value is even higher. Galectin-3, associated with BNP or NT-proBNP, may help improve the diagnosis and prognosis of heart failure. PMID- 25746676 TI - Educational inequalities in diabetes mortality across Europe in the 2000s: the interaction with gender. AB - OBJECTIVES: To evaluate educational inequalities in diabetes mortality in Europe in the 2000s, and to assess whether these inequalities differ between genders. METHODS: Data were obtained from mortality registries covering 14 European countries. To determine educational inequalities in diabetes mortality, age standardised mortality rates, mortality rate ratios, and slope and relative indices of inequality were calculated. To assess whether the association between education and diabetes mortality differs between genders, diabetes mortality was regressed on gender, educational rank and 'gender * educational rank'. RESULTS: An inverse association between education and diabetes mortality exists in both genders across Europe. Absolute educational inequalities are generally larger among men than women; relative inequalities are generally more pronounced among women, the relative index of inequality being 2.8 (95 % CI 2.0-3.9) in men versus 4.8 (95 % CI 3.2-7.2) in women. Gender inequalities in diabetes mortality are more marked in the highest than the lowest educated. CONCLUSIONS: Education and diabetes mortality are inversely related in Europe in the 2000s. This association differs by gender, indicating the need to take the socioeconomic and gender dimension into account when developing public health policies. PMID- 25746678 TI - Origin of kinetic instability of fullerenes that violate the isolated pentagon rule. AB - The isolated pentagon rule (IPR) holds without exceptions for neutral fullerene molecules. Unlike those in non-IPR fullerenes, 5/5 bonds (i.e., pi-bonds shared by two pentagons) in many planar polycyclic pi-systems are kinetically rather stable with large positive bond resonance energies (BREs), where BRE is a graph theoretically defined index of kinetic stability. Geometric conditions were explored for designing planar polycyclic pi-systems with unstable 5/5 bonds. We then found that the kinetic instability of non-IPR fullerenes stems from the coexistence of pentalene substructures and nearby disjoint pentagons. Proper arrangements of fused pentagons and disjoint pentagons make the 5/5 bonds highly reactive with large negative BREs. PMID- 25746677 TI - Evaluation of iron oxide nanoparticle micelles for magnetic particle imaging (MPI) of thrombosis. AB - Magnetic particle imaging (MPI) is an emerging medical imaging modality that directly visualizes magnetic particles in a hot-spot like fashion. We recently developed an iron oxide nanoparticle-micelle (ION-Micelle) platform that allows highly sensitive MPI. The goal of this study was to assess the potential of the ION-Micelles for MPI-based detection of thrombi. To this aim, an in vivo carotid artery thrombosis mouse model was employed and ex vivo magnetic particle spectrometer (MPS) measurements of the carotid arteries were performed. In addition, we studied the effect of functionalization of the ION-Micelle nanoplatform with fibrin-binding peptides (FibPeps) with respect to nanoparticle thrombus uptake and hence thrombus detection. In vivo quantitative MR imaging pre and post-ION-Micelle injection was performed as reference for visualization of ION-micelle uptake. ION-Micelles significantly decreased T2 values in the thrombi with respect to pre-injection T2 values (p < 0.01) and significantly increased ex vivo MPS thrombus signal with respect to the noninjured, contralateral carotid (p < 0.01). Functionalization of the ION-Micelles with the FibPep peptides did not result in an increased MPS thrombus signal with respect to the non-fibrin binding ION-Micelles. The lack of a significant increased thrombus uptake for the FibPep ION-Micelles indicates that (non-fibrin-specific) entrapment of nanoparticles in the mesh-like thrombi is the key contributor to thrombus nanoparticle uptake. Therefore, (nontargeted) ION-Micelles might be of value for noninvasive MPI-based diagnosis, characterization and treatment monitoring of thrombosis. PMID- 25746679 TI - Hispanic Americans living in the United States and their risk for obesity, diabetes and kidney disease: Genetic and environmental considerations. AB - The Hispanic American, the largest minority population in the United States, is at increased risk for obesity, diabetes and end-stage renal disease. Here we review genetic and environmental factors that might account for their increased risk for these conditions. Whereas many environmental and genetic factors have important roles in driving the increased risk for obesity and kidney disease in this population, a case is made that excessive intake of sugary beverages is a contributory cause. Studies focusing on decreasing intake of sugary beverages among the Hispanic American could potentially reduce renal and cardiovascular complications in this population. PMID- 25746680 TI - Tumor cell secretion of soluble factor(s) for specific immunosuppression. AB - Studies of tumor models using syngeneic transplantation have advanced our understanding of tumor immunity, including both immune surveillance and evasion. Murine mammary carcinoma 4T1 cells secrete immunosuppressive soluble factors as demonstrated in splenocyte culture. Cultured primary splenocytes secrete IFN gamma, which was strikingly elevated when the cells were isolated from 4T1 tumor bearing mice. The secretion of IFN-gamma peaked a week after 4T1 inoculation and then declined. This reduction may be due to the relatively decreased lymphocytes and increased granulocytes in a spleen accompanied by splenomegaly with time after the 4T1 inoculation. IFN-gamma production was further suppressed with the addition of the conditioned media from 4T1 cells to the splenocyte culture. This suppressive effect was more evident in the splenocytes isolated from mice that had 4T1 tumors for a longer period of time and was not observed in the conditioned medium either from CT26 cells or with splenocytes isolated from CT26 tumor-bearing mice. These results suggest that the IFN-gamma suppression is 4T1 tumor-specific. The soluble factor(s) in the 4T1-conditioned media was a protein between 10 to 100 kDa. The cytokine tip assay demonstrated several known cytokines that negatively regulate immune responses and may be candidates for this immunosuppression activity. PMID- 25746681 TI - Whole transcriptome analysis of the monogonont rotifer Brachionus koreanus provides molecular resources for developing biomarkers of carbohydrate metabolism. AB - Rotifers (phylum Rotifera) are the most common non-arthropod animal. Species in the monogonont rotifer Brachionus are widely distributed in coastal areas and play an important role in aquatic food webs as secondary producers. Brachionus koreanus is currently being developed as a model system for ecotoxicological research. We sequenced the whole transcriptome of B. koreanus using RNA-seq technology. De novo sequence assembly by Trinity integrated with TransDecoder produced 36,918 contigs, including putative alternatively spliced variants. A total of 13,784 genes were identified based on Blast analysis. KEGG pathway analysis detected transcripts annotated as coding for enzymes involved in metabolic pathways, the immune system, translation, and signal transduction. Most identified enzymes and pathways were involved in carbohydrate metabolism, such as the tricarboxylic acid (TCA) cycle and glycolysis. We anticipate that the availability of whole transcriptome data for B. koreanus will provide insights into rotifer biology and physiology and facilitate the development of biomarkers for ecotoxicology studies. PMID- 25746682 TI - A common single-site Pt(II)-O(OH)x- species stabilized by sodium on "active" and "inert" supports catalyzes the water-gas shift reaction. AB - While it has long been known that different types of support oxides have different capabilities to anchor metals and thus tailor the catalytic behavior, it is not always clear whether the support is a mere carrier of the active metal site, itself not participating directly in the reaction pathway. We report that catalytically similar single-atom-centric Pt sites are formed by binding to sodium ions through -O ligands, the ensemble being equally effective on supports as diverse as TiO2, L-zeolites, and mesoporous silica MCM-41. Loading of 0.5 wt % Pt on all of these supports preserves the Pt in atomic dispersion as Pt(II), and the Pt-O(OH)x- species catalyzes the water-gas shift reaction from ~120 to 400 degrees C. Since the effect of the support is "indirect," these findings pave the way for the use of a variety of earth-abundant supports as carriers of atomically dispersed platinum for applications in catalytic fuel-gas processing. PMID- 25746683 TI - Structural characterisation of the virulence-associated protein VapG from the horse pathogen Rhodococcus equi. AB - Virulence and host range in Rhodococcus equi depends on the variable pathogenicity island of their virulence plasmids. Notable gene products are a family of small secreted virulence-associated proteins (Vaps) that are critical to intramacrophagic proliferation. Equine-adapted strains, which cause severe pyogranulomatous pneumonia in foals, produce a cell-associated VapA that is necessary for virulence, alongside five other secreted homologues. In the absence of biochemical insight, attention has turned to the structures of these proteins to develop a functional hypothesis. Recent studies have described crystal structures for VapD and a truncate of the VapA orthologue of porcine-adapted strains, VapB. Here, we crystallised the full-length VapG and determined its structure by molecular replacement. Electron density corresponding to the N terminal domain was not visible suggesting that it is disordered. The protein core adopted a compact elliptical, anti-parallel beta-barrel fold with beta1 beta2-beta3-beta8-beta5-beta6-beta7-beta4 topology decorated by a single peripheral alpha-helix unique to this family. The high glycine content of the protein allows close packing of secondary structural elements. Topologically, the surface has no indentations that indicate a nexus for molecular interactions. The distribution of polar and apolar groups on the surface of VapG is markedly uneven. One-third of the surface is dominated by exposed apolar side-chains, with no ionisable and only four polar side-chains exposed, giving rise to an expansive flat hydrophobic surface. Other surface regions are more polar, especially on or near the alpha-helix and a belt around the centre of the beta-barrel. Possible functional significance of these recent structures is discussed. PMID- 25746684 TI - Antiviral effect of mefloquine on feline calicivirus in vitro. AB - Feline calicivirus (FCV) is an important viral pathogen of domestic cats causing clinical signs ranging from mild to severe oral ulceration or upper respiratory tract disease through to a severe fatal systemic disease. Current therapeutic options are limited, with no direct acting antivirals available for treatment. This study screened a panel of 19 compounds for potential antiviral activity against FCV strain F9 and recent field isolates in vitro. Using a resazurin-based cytopathic effect (CPE) inhibition assay, mefloquine demonstrated a marked inhibitory effect on FCV induced CPE, albeit with a relatively low selectivity index. Orthogonal assays confirmed inhibition of CPE was associated with a significant reduction in viral replication. Mefloquine exhibited a strong inhibitory effect against a panel of seven recent FCV isolates from Australia, with calculated IC50 values for the field isolates approximately 50% lower than against the reference strain FCV F9. In vitro combination therapy with recombinant feline interferon-omega, a biological response modifier currently registered for the treatment of FCV, demonstrated additive effects with a concurrent reduction in the IC50 of mefloquine. These results are the first report of antiviral effects of mefloquine against a calicivirus and support further in vitro and in vivo evaluation of this compound as an antiviral therapeutic for FCV. PMID- 25746686 TI - Mitochondria: the cellular hub of the dynamic coordinated network. AB - Mitochondria are the powerhouses of the eukaryotic cell. After billions of years of evolution, mitochondria have adaptively integrated into the symbiont. Such integration is not only evidenced by the consolidation of genetic information, that is, the transfer of most mitochondrial genes into the nucleus, but also manifested by the functional recombination by which mitochondria participate seamlessly in various cellular processes. In the past decade, the field of mitochondria biology has been focused on the dynamic and interactive features of these semiautonomous organelles. Aspects of a complex multilayer quality control system coordinating mitochondrial function and environmental changes are being uncovered and refined. This Forum summarizes the recent progress of these critical topics, with a focus on the dynamic quality control of mitochondrial reticulum, including their biogenesis, dynamic remodeling, and degradation, as well as the homeostasis of the mitochondrial proteome. These diverse but interconnected mechanisms are found to be critical in the maintenance of a functional, efficient, and responsive mitochondrial population and could therefore become therapeutic targets in numerous mitochondrion-implicated disorders. PMID- 25746685 TI - Increased Vesicular Monoamine Transporter 2 (VMAT2; Slc18a2) Protects against Methamphetamine Toxicity. AB - The psychostimulant methamphetamine (METH) is highly addictive and neurotoxic to dopamine terminals. METH toxicity has been suggested to be due to the release and accumulation of dopamine in the cytosol of these terminals. The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is a critical mediator of dopamine handling. Mice overexpressing VMAT2 (VMAT2-HI) have an increased vesicular capacity to store dopamine, thus augmenting striatal dopamine levels and dopamine release in the striatum. Based on the altered compartmentalization of intracellular dopamine in the VMAT2-HI mice, we assessed whether enhanced vesicular function was capable of reducing METH-induced damage to the striatal dopamine system. While wildtype mice show significant losses in striatal levels of the dopamine transporter (65% loss) and tyrosine hydroxylase (46% loss) following a 4 * 10 mg/kg METH dosing regimen, VMAT2-HI mice were protected from this damage. VMAT2-HI mice were also spared from the inflammatory response that follows METH treatment, showing an increase in astroglial markers that was approximately one-third of that of wildtype animals (117% vs 36% increase in GFAP, wildtype vs VMAT2-HI). Further analysis also showed that elevated VMAT2 level does not alter the ability of METH to increase core body temperature, a mechanism integral to the toxicity of the drug. Finally, the VMAT2-HI mice showed no difference from wildtype littermates on both METH-induced conditioned place preference and in METH-induced locomotor activity (1 mg/kg METH). These results demonstrate that elevated VMAT2 protects against METH toxicity without enhancing the rewarding effects of the drug. Since the VMAT2-HI mice are protected from METH despite higher basal dopamine levels, this study suggests that METH toxicity depends more on the proper compartmentalization of synaptic dopamine than on the absolute amount of dopamine in the brain. PMID- 25746687 TI - Mean-field coarse-grained model for poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide) triblock copolymer systems. AB - The microscopic modeling of surfactant systems is of the utmost importance in understanding the mechanisms related to the micellization process because it allows for prediction and comparison with experimental data of diverse equilibrium system properties. In this work, we present a coarse-grained model for Pluronics, a trademarked type of triblock copolymer, from simulations based on a single-chain mean-field theory (SCMF). This microscopic model is used to quantify the micellization process of these nonionic surfactants at 37 degrees C and has been shown to be able to quantitatively reproduce experimental data of the critical micelle concentration (CMC) along with other equilibrium properties. In particular, these results correctly capture the experimental behavior with respect to the lengths of the hydrophobic and hydrophilic moieties of the surfactants for low and medium hydrophobicities. However, for the more highly hydrophobic systems with low CMCs, a deviation is found which has been previously attributed to nonequilibrium effects in the experimental data (Garcia Daza, F. A.; Mackie, A. D. Low Critical Micelle Concentration Discrepancy between Theory and Experiment. J. Phys. Chem. Lett. 2014, 5, 2027-2032). PMID- 25746688 TI - Paramagnetic nanoparticles as a platform for FRET-based sarcosine picomolar detection. AB - Herein, we describe an ultrasensitive specific biosensing system for detection of sarcosine as a potential biomarker of prostate carcinoma based on Forster resonance energy transfer (FRET). The FRET biosensor employs anti-sarcosine antibodies immobilized on paramagnetic nanoparticles surface for specific antigen binding. Successful binding of sarcosine leads to assembly of a sandwich construct composed of anti-sarcosine antibodies keeping the Forster distance (Ro) of FRET pair in required proximity. The detection is based on spectral overlap between gold-functionalized green fluorescent protein and antibodies@quantum dots bioconjugate (lambdaex 400 nm). The saturation curve of sarcosine based on FRET efficiency (F604/F510 ratio) was tested within linear dynamic range from 5 to 50 nM with detection limit down to 50 pM. Assembled biosensor was then successfully employed for sarcosine quantification in prostatic cell lines (PC3, 22Rv1, PNT1A), and urinary samples of prostate adenocarcinoma patients. PMID- 25746689 TI - Active control of electromagnetic radiation through an enhanced thermo-optic effect. AB - The control of electromagnetic radiation in transformation optical metamaterials brings the development of vast variety of optical devices. Of a particular importance is the possibility to control the propagation of light with light. In this work, we use a structured planar cavity to enhance the thermo-optic effect in a transformation optical waveguide. In the process, a control laser produces apparent inhomogeneous refractive index change inside the waveguides. The trajectory of a second probe laser beam is then continuously tuned in the experiment. The experimental results agree well with the developed theory. The reported method can provide a new approach toward development of transformation optical devices where active all-optical control of the impinging light can be achieved. PMID- 25746690 TI - A screening algorithm for the efficient exclusion of biliary atresia in infants with cholestatic jaundice. AB - BACKGROUND: Neonates with cholestasis may undergo many tests before biliary atresia (BA) or an alternative diagnosis is reached, and delayed intervention may worsen outcomes. An optimal diagnostic approach to reduce risk, cost, and delay has yet to be defined. The purpose of this study was to develop an algorithm that rapidly and accurately excludes BA for infants with cholestatic jaundice. METHODS: A single-center retrospective comparison of diagnostic workup was made between cholestatic infants with BA, and those without BA who underwent hepatobiliary iminodiacetic acid (HIDA) scan during admission. Patients were born between 2000 and 2010 and those older than 100days at assessment were excluded. Sensitivity and specificity analysis of predictive variables was performed and an algorithm constructed. RESULTS: There were 45 BA and 167 non-BA patients. Some variables were 100% sensitive for the exclusion of BA: conjugated bilirubin <2.5mg/dL, gamma-glutamyl transpeptidase <150U/L, excretion on HIDA, or a normal percutaneous cholangiogram. Clinical variables and ultrasound were less useful as screening tests owing to low specificity and sensitivity, respectively. Liver biopsy was 98% sensitive and 84% specific in the diagnosis of BA. An algorithm was constructed that rules out BA with a negative laparotomy rate of 3-22%. CONCLUSION: We propose a screening algorithm for infants with conjugated hyperbilirubinemia that permits efficient exclusion of BA with minimal invasive testing and with a low risk of negative laparotomy. This algorithm now requires prospective evaluation to determine its diagnostic accuracy and its ability to reduce hospital costs, patient morbidity, and time to Kasai portoenterostomy in patients with BA. PMID- 25746691 TI - Sonic hedgehog (SHH) and glioblastoma-2 (Gli-2) expressions are associated with poor jaundice-free survival in biliary atresia. AB - BACKGROUND/PURPOSE: Biliary atresia (BA) causes biliary obstruction in neonates. Although the Kasai operation can successfully treat certain BA cases, many patients exhibit recurrent jaundice and secondary biliary cirrhosis requiring liver transplantation. Consequently, studies of the prognostic factors of the Kasai operation are needed. Accordingly, sonic hedgehog (SHH) pathway expression at the extrahepatic bile duct (EHBD), an important bile duct repair mechanism, will be investigated via immunohistochemistry in patients with BA to examine the association with post-Kasai operation prognosis. METHODS: Fifty-seven EHBD specimens were obtained during Kasai operations from 1992 to 2009. The SHH, patched (PTCH), and glioblastoma-2 (Gli-2) immunohistochemical staining results were analyzed quantitatively. RESULTS: Overall, 57.9% of patients had bile flow normalization after the Kasai operation; 43.1% did not. High preoperative serum total bilirubin, direct bilirubin, and aspartate aminotransferase levels were associated with sustained jaundice post-Kasai operation, as was an age >=65days at the time of surgery (all p<0.05). High Gli-2 and SHH expression rates were significantly associated with early post-Kasai operation jaundice relapse. CONCLUSION: Strong Gli-2 and SHH expression in the EHBD might be a poor prognostic factor in Kasai operation-treated patients with BA. PMID- 25746692 TI - Usefulness and safety of endoscopic retrograde cholangiopancreatography in children with pancreaticobiliary maljunction. AB - BACKGROUND: To assess the diagnostic ability and safety of endoscopic retrograde cholangiopancreatography (ERCP) in in-depth preoperative examination of children patients with pancreaticobiliary maljunction (PBM). METHODS: In 63 patients with a definite diagnosis of PBM, the ability to visualize the bile and main pancreatic ducts was compared between ERCP, which was performed in 63 patients with a definite diagnosis of PBM, and magnetic resonance cholangiopancreatography (MRCP), which was performed before ERCP in 29 patients. For ERCP, its complications were also evaluated. RESULTS: The intrahepatic bile ducts could be visualized using ERCP in 44 patients (69.8%) and using MRCP in 18 (62.1%). The extrahepatic bile ducts could be visualized using ERCP in 59 patients (93.7%) and using MRCP in 29 (100%). The rates of the visualization of the main pancreatic duct and pancreaticobiliary ductal union were significantly higher in using ERCP than in using MRCP (96.8 vs. 41.4% and 90.5 vs. 37.9%, respectively; P<0.0001). As complications, hyperamylasemia developed in 12 patients (19%), but no other severe complications such as pancreatitis were observed. CONCLUSIONS: ERCP as part of an in-depth preoperative examination of children with PBM is useful and safe. PMID- 25746693 TI - Focal nodular hyperplasia in children: an institutional experience with review of the literature. AB - BACKGROUND: Focal nodular hyperplasia (FNH) is uncommonly diagnosed in pediatric patients and may be difficult to distinguish from a malignancy. We present a review of all children with a tissue diagnosis of FNH at our institution, describe the diagnostic modalities, and provide recommendations for diagnosis and follow-up based on our experience and review of the literature. METHODS: A retrospective review of children <18years of age diagnosed with FNH at a single institution was performed from 2000 to 2013. RESULTS: Twelve patients were identified with a tissue diagnosis of FNH. Two patients required surgical resection of their lesion owing to concern for malignancy. Ten patients were managed expectantly with imaging surveillance after biopsy confirmed a diagnosis of FNH. All patients who underwent MRI had very typical findings including hypointensity on T1 weighted sequences, hyperintensity on T2, and homogenous uptake of contrast on the arterial phase. On follow-up all patients had either a stable lesion or reduction in size. CONCLUSIONS: Focal nodular hyperplasia presents typically in children with liver disease, have undergone chemotherapy, and adolescent females. Young children, particularly <5years of age, without underlying liver disease or history of chemotherapy can pose a diagnostic dilemma. In this unique subgroup of children with FNH, MRI and/or needle biopsy should be adequate diagnostic modalities for these lesions. PMID- 25746694 TI - Congenital diaphragmatic hernia: focus on abnormal muscle formation. AB - BACKGROUND: CDH is a major birth defect, characterized by high mortality. How the initial defective mesenchymal substructures affects muscle malformation is unclear. Defects of genes involved in diaphragmatic development, such as friend of-GATA2 (Fog2), may play an important role in its pathogenesis. We investigated the expression of Fog2 and proteins of myogenesis in a series of CDH and in diaphragms at different fetal ages, in order to clarify the role of muscular components during diaphragmatic development in cases with CDH. MATERIAL AND METHODS: Specimen were obtained from seven diaphragms of CDH cases undergoing surgery, 3 entire diaphragms from non repaired CDH, 5 control diaphragms at different gestational ages (16, 17, 22, 32, and 40g.w.), and 3 biopsy samples of normal voluntary muscle. The thickness of diaphragms at the edge of the defect in CDH and in developing diaphragms was measured. All samples were processed for HE staining and immunohistochemistry. Immunohistochemical expression of MyoD, Myf4, Pax7, Mib1 and Fog2 was evaluated. RESULTS: Mean thickness at the edge of the defect was 4.14mm. Contralateral hemi-diaphragm in 3 autopsies and in controls at 32 and 40weeks measured 2.25mm; histology showed a higher density of desmin positive muscular cells at the edge of defect. CDH displayed scattered Myf4 positive cells (range 0%-10%, mean 2.4%), numerous Pax7-positive cells (range 0% 24%, mean 12.1%) and less than 1% Mib1-positive cells. Controls showed a reduction of positive cell with the progression of gestational age for Myf4 (30% at 16 weeks, 20% at 17 weeks, 5% at 22 weeks, 1% at 32 and 40 weeks), Pax7 (85% at 16 weeks and 17 weeks, 35% at 22 weeks, 11% at 32 weeks) and Mib1 (20% at 16 weeks, 8% at 17 weeks, 7% at 22weeks, 2% at 32 weeks). Fog-2 was diffusely positive in mesenchymal, mesothelial and muscular cells, in diaphragms from 16 to 22 weeks, decreasing to 20% of positive muscular cells in 32-week diaphragm. In CDH only mesothelial and mesenchymal cells were positive. Stem cell markers were negative in cases and controls. COMMENT: CDH shows a thick muscular border, with high number of mature muscle cells and significant increase of quiescent satellite cells (PAX7+, Mib1-). Abnormal architecture may affect the normal process of myogenesis and thus signaling and cell-cell interactions of myocytes. The expression of Fog2 in mesothelial and mesenchymal cells in CDH demonstrates the absence of a genetic defect involving Fog2 in our cases. Being Fog2 expressed in muscle cells at early stage supports the hypothesis that the altered diaphragmatic genesis may undermine also the muscular component instead of the only mesenchymal one. PMID- 25746695 TI - Neurodevelopmental outcome in congenital diaphragmatic hernia survivors: role of ventilatory time. AB - BACKGROUND: Neurodevelopmental impairment is one of the most significant morbidities among CDH survivors. PURPOSE: Assess correlation between ventilatory time (VT) and short-term neurodevelopmental outcome in congenital diaphragmatic hernia (CDH) survivors. METHODS: A prospective longitudinal study was conducted between 2008 and 2012. Assessment of mental and motor development was performed at 6 and 12months by Bayley Scales of Infant and Toddler Development - 3rd Edition (BSID-III). ROC curve analysis was used. RESULTS: Forty-two subjects were included in the study. There was a significant inverse correlation between neurodevelopment at 6 and 12months and VT during first admission (p<0.0001). VT predicting the risk of moderate (BSID-III <85) and severe (BSID-III <70) delay was 13 and 28days, respectively (area under the curve - delay <85: 6months mental 0.943 and motor 0.992; 12months mental 0.877 and motor 0.925; delay <70: 6months mental 0.934 and motor 0.943; 12months mental 0.906 and motor 0.975; p<0.0001). CONCLUSIONS: VT should be considered an important marker to identify subjects at risk for short-term neurodevelopmental delay in CDH survivors. Early follow-up intervention therapy should be activated in every baby with a history exceeding 13days of VT. PMID- 25746696 TI - Differences in the distribution and presentation of bronchogenic cysts between adults and children. AB - BACKGROUND: Bronchogenic cysts are rare congenital malformations that occur in adults and children, with differences in distribution and presentation. METHODS: The study population comprised 16 infants and children (aged 7 days to 18 years) and 23 adults (aged 20-78 years) who received pathological diagnoses of bronchogenic cysts over a 14-year period (1999-2012). Cyst distribution and presentation were reviewed. RESULTS: Half (8/16) of the infants and children presented with palpable masses in the neck (n=6) or on the skin (n=2), and only one (12.5%) presented with symptoms of mild stridor. Another eight pediatric patients had mediastinal (n=7) or pulmonary (n=1) bronchogenic cysts, and respiratory symptoms were present in six (75%) patients. Thirteen of 23 (56.5%) adult patients had asymptomatic cysts (neck, n=1; mediastinum, n=11; lung, n=1). Symptomatic presentations occurred in 10/23 (43.5%) patients, including 2 with palpable mass in the neck, 3 in the mediastinum, 4 in the lung, and 1 in the retroperitoneum. Among the 13 asymptomatic patients, 6 were identified during regular health screening, 5 during routine chest computed tomographic surveys for cancer, and 2 incidentally found during thyroid and parathyroid surgery. Bronchogenic cysts tended to be larger in symptomatic than in asymptomatic adults. CONCLUSION: The clinical spectra of bronchogenic cysts differ between adults and children and are closely related to cyst location and, probably, size. PMID- 25746697 TI - Tracheobronchomalacia in pediatric patients with esophageal atresia: comparison of diagnostic laryngoscopy/bronchoscopy and dynamic airway multidetector computed tomography. AB - PURPOSE: Diagnostic laryngoscopy and bronchoscopy (DLB) has been the traditional preoperative diagnostic modality for evaluating presence and severity of tracheobronchomalacia (TBM), and requires anesthesia. Alternatively, multidetector computed tomography (MDCT) is potentially a noninvasive modality that provides high-resolution, 3-dimensional (3D) imaging of the thorax providing preoperative guidance for pediatric surgeons. This study compares MDCT with intraoperative DLB in the assessment of TBM in symptomatic pediatric patients with esophageal atresia (EA). METHODS: Following IRB approval all pediatric patients (<=18 years) who had EA and who underwent an MDCT study as a preoperative evaluation of TBM prior to aortopexy were retrospectively reviewed. Patients with incomplete reports on intraoperative DLB or MDCT studies were excluded. Two pediatric radiologists independently evaluated all MDCT studies in a blinded fashion. On both DLB and MDCT studies, TBM was scored as present or absent in five anatomic segments: upper, middle, and lower trachea, as well as right and left main stem bronchi. Operative reports including DLB findings were reviewed and compared to findings from MDCT study using the chance corrected kappa (kappa) coefficient. Diagnostic accuracy of dynamic MDCT for detecting TBM was determined by sensitivity and specificity, and interobserver agreement between two radiology reviewers was measured by the kappa statistic. RESULTS: The final study population included 18 patients (8 males and 10 females) with ages ranging from 1month to 11years (median: 7 months). Their presenting clinical symptoms included apneic spells (n=15, 83%) and failure to extubate (n=3, 17%). The overall diagnostic accuracy of dynamic airway MDCT compared to DLB was 91% (82/90 possible segments for TBM) with excellent overall agreement across all 5 anatomic segments (kappa=0.82, p<0.001). The agreements for upper, mid, lower trachea, and right and left trachea were 89% (kappa=0.73, p<0.001), 94% (kappa=0.85, p<0.001), 89% (kappa=0.76, p<0.001), 94% (kappa=0.82, p<0.001), and 89% (kappa=0.61, p=0.005); respectively. Interobserver agreement between two radiologists was excellent (kappa=0.98, 95% confidence interval: 0.94-1.00, p<0.001) with only 1 disagreement between two radiologists that was found for the left main bronchus. Fifteen (83.3%) of the patients clinically improved after the aortopexy. CONCLUSION: MDCT with 3D imaging is a highly accurate and reliable preoperative noninvasive imaging modality for evaluating TBM in pediatric patients with EA providing anatomic information consistent with and complimentary to bronchoscopy. PMID- 25746698 TI - Investigation of the effects of enteral hormones on the pyloric muscle in newborn rats. AB - PURPOSE: To investigate the effects of enteral hormones on pyloric muscle in order to clarify the etiopathogenesis of hypertrophic pyloric stenosis (HPS). METHODS: Forty-two newborn Wistar-Albino rats were included. No intervention was done in the control group (CG, n=6). In the sham group (SG, n=6) 1ml saline (0.9% NaCl solution), in the Nw-nitro-l-arginine methyl ester hydrochloride (L-NAME) group (LNG, n=6) 100mg/kg/d L-NAME, in the somatostatin group (STG, n=6) 7mcg/kg/d ST, in the cholecystokinin group (CCKG, n=6) 3mcg/kg/d CCK, in the substance P group (SPG, n=6) 5ml/kg/d SP, and in the prostaglandin-E1 group (PGE1G, n=6) a cumulative dose of 360mcg/kg PGE1 was given intraperitoneally for 14days. On the 21st day, histopathological examination and muscle thickness measurements were done. Results were evaluated statistically. RESULTS: Total and circular pyloric muscle thicknesses were significantly increased in the LNG compared to the CG and SG (p<0.05). Circular pyloric muscle thickness was not increased in the STG, CCKG and SPG compared to the CG and SG (p>0.05). In the PGE1G, muscle thickness was significantly decreased in the pylorus and increased in the antrum compared to the CG and SG (p<0.05). CONCLUSION: Nitric oxide synthase (NOS) inhibition with L-NAME seems to be a causative factor in HPS by increasing pyloric muscle thickness. PGE predominantly affects antral gastric muscle and has no profound effect on pyloric muscle. PMID- 25746699 TI - Gastroscopic treatment of membranous duodenal stenosis in infants and children: report of 6 cases. AB - OBJECTIVE: To investigate the efficacy of gastroscopic treatment in the treatment of membranous duodenal stenosis. METHODS: We performed a retrospective study of 6 patients with membranous duodenal stenosis, aging from 7days to 37months, who underwent gastroscopic balloon dilatation in a children's hospital between January 2012 and December 2013. All surgical procedures of balloon dilatation were performed under direct gastroscopic vision. The balloon dilators with diameter 8mm and 10mm for neonates and children aged over one month, respectively, were placed through the foramen of the membranous stenosis. The septum in the membranous stenosis was gradually extended by increasing diameter of the balloon dilator. The residual septum was removed by gastroscopic electrocauterization. RESULTS: The membranous stenosis in duodenum of all children was successfully expanded by gastroscopic balloon dilatation, and only one case with residual septum received gastroscopic electrocauterization. No complications such as bleeding, intestinal perforation, etc., were observed. Postoperative radiography using iodine-based contrast media showed that the gastrointestinal tract was unobstructed. During a follow-up period ranging from 3 to 24months, all patients ate normally without vomiting and abdominal distension and grew normally. CONCLUSION: Gastroscopic balloon dilatation is an effective method in the treatment of membranous duodenal stenosis in children. For the patients with residual septum, they can be cured by using gastroscopic electrocauterization. PMID- 25746700 TI - The impact of children's hospital designation on outcomes in children with malrotation. AB - BACKGROUND: The benefit of Ladd's procedure for malrotation at a Children's Hospital (CH) has not previously been established. Our aim was to characterize the potential variations in management and outcomes between CH and Non-Children's Hospitals (NCH) in the treatment of malrotation with Ladd's procedure. METHODS: There were 2827 children identified with malrotation and complete information from the Kids' Inpatient Database (2003, 2006, 2009). Outcomes were compared between CH and NCH and evaluated with logistic and linear regressions. Additional propensity score matching was used to balance covariates between CH and NCH. RESULTS: There were 2261 (80.0%) children with malrotation undergoing Ladd's procedures treated at CH; 566 (20.0%) were treated at NCH. In multivariate analysis, CH was associated with a 39% lower odds of resection (p=0.004), with no differences observed for mortality, morbidity and LOS. Comparison of a propensity score matched cohort confirmed these findings, as well as demonstrated no significant differences in associated costs. CONCLUSIONS: The majority of pediatric intestinal malrotation is managed at CH. While measured outcomes of mortality, morbidity, LOS, and costs were not different at NCH, CH was less likely to perform intestinal resection during Ladd's procedure. PMID- 25746701 TI - Delayed repeat enemas are safe and cost-effective in the management of pediatric intussusception. AB - BACKGROUND/PURPOSE: The purpose of the study is to compare outcomes between delayed repeat enema (DRE) and immediate surgery (IS) in children with ileocolic intussusception who fail initial enema reduction. METHODS: Retrospective cohort study of children <6 years-of-age from 2008 to 2012 in the Pediatric Health Information System (PHIS) database. Outcomes measured were bowel resection, length of stay (LOS), and adjusted hospital costs (AHC). RESULTS: 4980 of 6889 (72.3%) children with intussusception were discharged without operation following a single successful enema. 1407 of 1909 (73.7%) remaining patients underwent IS while 502 (26.3%) had a DRE. Bowel resection was required in 372 of 1407 (26.4%) patients in IS group compared to 59 of 502 (11.8%) in the DRE group (p<0.001). The number of patients needed to treat by DRE to prevent a bowel resection was 7. In multivariable analysis, the IS patients had a 2.5 times greater likelihood of undergoing bowel resection than the DRE patients (adjusted odds ratio [OR] 2.50, 95% confidence interval [CI] 1.83-3.41, p<0.001). The DRE group had a mean LOS of 3.2 days (95% CI 2.9-3.6) and mean AHC of $9205 (95% CI $7673-$10,735). The IS group had a longer LOS (4.4days, 95% CI 4.0-4.8, p<=0.001) and higher AHC ($14,422, 95% CI $12,631-$16,214, p<0.001). CONCLUSION: Delayed repeat enemas for ileocolic intussusception increase the success of nonoperative reduction, decrease the rate of bowel resection and reduce mean hospital length of stay and costs. PMID- 25746702 TI - Infectious complications following serial transverse enteroplasty in infants and children with short bowel syndrome. AB - BACKGROUND: Serial transverse enteroplasty (STEP) lengthens and tapers dilated small bowel in patients with short bowel syndrome (SBS). Previous reports document encouraging outcomes with regard to tolerance for enteral nutrition (EN) and complications appear related to the re-operative nature of many cases and to the presence of multiple staple lines. However, infectious complications following STEP have not been examined. Since infections, especially catheter related blood stream infections (CRBSI), are considered detrimental in infants and children with SBS, we sought to define the frequency and outcomes of peri operative infections associated with STEP. METHODS: All children with SBS who underwent a STEP between 2004 and 2012 were indentified and their medical records were reviewed. Patients were considered candidates for a STEP if they had dilated small bowel and failure to advance enteral nutrition. For the purpose of this study, infections occurring within a 14-day period after STEP were considered procedure-related and were the focus of the study. RESULTS: A total of 18 patients underwent 23 STEP procedures. Primary diagnoses included intestinal atresia, gastroschisis, necrotizing enterocolitis, and midgut volvulus. After the STEP, eight patients (35%) developed CRBSI, three developed wound infections, and two had urinary tract infections. Organisms isolated from either blood, wound or urine cultures included gram-positive cocci, gram-negative rods, and yeast. Perioperative antibiotics were administered in all cases with cefoxitin (43%) and piperacillin/tazobactam (30%) being most common. Neither antibiotic appeared superior in reducing the incidence of CRBSI. In three patients with persistent bacteremia despite adequate antibiotic therapy, a 74% ethanol lock resulted in negative blood cultures in all cases. Only one central venous catheter required replacement acutely for persistent fungemia. CONCLUSION: STEP can improve enteral tolerance. In this fragile patient population, however, STEP carries a documented infectious burden. The optimal antibiotic prophylaxis and the role of ethanol locking in patients undergoing STEP require further study. PMID- 25746703 TI - Vaginal anomalies and atresia associated with imperforate anus: diagnosis and surgical management. AB - BACKGROUND: The association of vaginal atresia (or Mayer-Rokitansky-Kuster-Hauser Syndrome) with imperforate anus is rare and can present significant diagnostic and therapeutic challenges. This study describes clinical characteristics, surgical treatment and outcomes in this group of complex children. METHODS: Records of 20 patients were retrospectively analyzed from two pediatric surgical centers. RESULTS: Five patients were excluded from the long-term analysis due to inadequate information, leaving long-term follow-up in 15 patients. Mean follow up was 10 years (range 1-31.1 years). The diagnosis of vaginal atresia was made pre-operatively in 12 out of 15 patients, and in three patients it was identified during the anoplasty. The anorectal malformations were rectoperineal (N=2), rectovestibular (N=6), recto-bladder neck (N=1) and imperforate anus without fistula (N=6). Satisfactory surgical repair was performed in 13 patients, while one continues to stool through a low perineal fistula awaiting definitive surgery and another underwent a colostomy and mucous fistula. Delayed vaginal reconstruction was due to a failure to identify the problem prior to anoplasty (N=3). Long-term results demonstrated that anorectal continence was much worse than initially appreciated, and many had associated urinary incontinence. Overall stooling score was far lower than in a separate group of children with imperforate anus without vaginal atresia (Levitt and Pena, 2007). CONCLUSIONS: Vaginal atresia with imperforate anus is a rare and an extensive pre-operative workup of females with imperforate anus must include assessment of vagina patency. Vaginal reconstruction and anorectal continuity can be performed in a variety of approaches, but long-term continence is often not optimal. We propose a pathway for management of this difficult genito-anorectal disorder. PMID- 25746704 TI - Anorectal manometry with and without ketamine for evaluation of defecation disorders in children. AB - INTRODUCTION: Anorectal manometry (ARCM) provides valuable information in children with chronic constipation and fecal incontinence but may not be tolerated in the awake child. This study aimed to evaluate the effect of ketamine anesthesia on the assessment of anorectal function by manometry and to evaluate defecation dynamics and anal sphincter resting pressure in the context of pathophysiology of chronic functional (idiopathic) constipation and soiling in children. METHODS: This was a prospective study of children who were investigated for symptoms of chronic constipation and soiling between April 2001 and April 2004. We studied 52 consecutive children who had awake ARCM, biofeedback training and endosonography (awake group) and 64 children who had ketamine anesthesia for ARCM and endosonography (ketamine group). We age matched 31 children who had awake anorectal studies with 27 who had ketamine anesthesia. RESULTS: The children in awake and ketamine groups were comparable for age, duration of bowel symptoms and duration of laxative treatments. ARCM profile was comparable between the awake and the ketamine groups with regard to anal sphincter resting pressure, rectal capacity, amplitude of rectal contractions, frequency of rectal and IAS contractions and functional length of anal canal. Of 52 children who had awake ARCM, dyssynergia of the EAS muscles was observed in 22 (42%) and median squeeze pressure was 87mm Hg (range 25-134). The anal sphincter resting pressure was non obstructive and comparable to healthy normal children. Rectoanal inhibitory reflex was seen in all children excluding diagnosis of Hirschsprung disease. CONCLUSIONS: Ketamine anesthesia does not affect quantitative or qualitative measurements of autonomic anorectal function and can be used reliably in children who will not tolerate the manometry while awake. Paradoxical contraction of the EAS can only be evaluated in the awake children and should be investigated further as the underlying cause of obstructive defecation in patients with chronic functional constipation and soiling. PMID- 25746705 TI - Effectiveness of an organized bowel management program in the management of severe chronic constipation in children. AB - BACKGROUND: Chronic constipation is a common problem in children. The cause of constipation is often idiopathic, when no anatomic or physiologic etiology can be identified. In severe cases, low dose laxatives, stool softeners and small volume enemas are ineffective. The purpose of this study was to assess the effectiveness of a structured bowel management program in these children. METHODS: We retrospectively reviewed children with chronic constipation without a history of anorectal malformation, Hirschsprung's disease or other anatomical lesions seen in our pediatric colorectal center. Our bowel management program consists of an intensive week where treatment is assessed and tailored based on clinical response and daily radiographs. Once a successful treatment plan is established, children are followed longitudinally. The number of patients requiring hospital admission during the year prior to and year after initiation of bowel management was compared using Fisher's exact test. RESULTS: Forty-four children with refractory constipation have been followed in our colorectal center for greater than a year. Fifty percent had at least one hospitalization the year prior to treatment for obstructive symptoms. Children were treated with either high-dose laxatives starting at 2mg/kg of senna or enemas starting at 20ml/kg of normal saline. Treatment regimens were adjusted based on response to therapy. The admission rate one-year after enrollment was 9% including both adherent and nonadherent patients. This represents an 82% reduction in hospital admissions (p<0.001). CONCLUSIONS: Implementation of a structured bowel management program similar to that used for children with anorectal malformations, is effective and reduces hospital admissions in children with severe chronic constipation. PMID- 25746706 TI - Imaging assessment of renal injuries in children and adolescents: CT or ultrasound? AB - BACKGROUND: Since the introduction of the ALARA ("as low as reasonably achievable") concept, ultrasound (US) has been progressively advocated for paediatric diagnostic imaging. This study aimed to analyse the role and accuracy of US in paediatric renal trauma. METHODS: From 1999 to 2009, the tertiary-care hospital database was retrospectively evaluated for renal trauma with regards to aetiology, type of injury, diagnostics, management and outcome. RESULTS: Forty seven patients (29 males, 18 females; median age=14years, range 1-17 years) were identified. US was initially applied in 45 patients with correct results in 86.6%. Computed tomography (CT) was performed in 16 patients in the acute trauma setting - complementary to US in 14 cases, with a diagnostic accuracy of 93%. Most renal injuries were grade I degrees (n=30), followed by grade III degrees (n=8), IV degrees (n=5), and II degrees /V degrees (n=2 each). All patients were initially managed conservatively and followed by US. Clinical deterioration necessitated surgery in four patients (2 nephrectomies, 1 partial nephrectomy, 1 urinoma drainage). The outcome was generally favourable with a renal preservation rate of 95%. CONCLUSION: With respect to the ALARA principle, US can be safely and reliably applied as the first-line diagnostic imaging technique and for follow-up for suspected traumatic paediatric renal injuries. PMID- 25746707 TI - Laparoscopic-assisted management of traumatic abdominal wall hernias in children: case series and a review of the literature. AB - BACKGROUND: Traumatic abdominal wall hernia (TAWH) is defined as herniation through a disrupted portion of musculature/fascia without skin penetration or history of prior hernia. In children, TAWH is a rare injury. OBJECTIVE: The objectives of this study were to report our experience with different management strategies of TAWH in children and to determine the utility of laparoscopy. DESIGN/METHOD: A retrospective chart review of all children treated by pediatric surgery at our institution for TAWH in a 5year interval was performed. Data were collected on mechanism of injury, initial patient presentation, surgical management, and outcomes. RESULTS: We present 5 cases of traumatic abdominal wall hernia; 3 were managed using laparoscopic assistance. One patient was managed nonoperatively. All patients recovered without complications and were asymptomatic on follow up. CONCLUSION: Traumatic abdominal wall hernias require a high index of suspicion in the cases of blunt abdominal trauma. Laparoscopy is useful mainly as a diagnostic modality, both to evaluate the hernia and associated injuries to intraabdominal structures. Its use may facilitate repair through a smaller incision. Conservative management of TAWH may be appropriate in select cases where there is a low risk of bowel strangulation. PMID- 25746708 TI - Malignant transformation in sacrococcygeal teratoma and in presacral teratoma associated with Currarino syndrome: a comparative study. AB - BACKGROUND/PURPOSE: The risk of malignant transformation of sacrococcygeal teratoma (SCT) and of presacral teratoma in Currarino syndrome (CS) may differ despite the similar position and appearance. METHODS: Malignant transformation and teratoma recurrence were assessed in a national retrospective comparative analysis of 205 SCT and 16 CS patients treated in one of the six pediatric surgical centers in the Netherlands between January 1981 and December 2010. RESULTS: The malignancy free survival of patients with SCT was lower than for patients with a presacral teratoma associated with CS (80% and 58% after one and two years in SCT versus 100% after two years in CS, p=0.017) CONCLUSIONS: In SCT, malignancy and recurrence risk are high. Therefore, early and complete resection is mandatory. Our data show that the risk of malignant transformation of a presacral teratoma in CS is small. PMID- 25746709 TI - Optimizing working space in laparoscopy: CT measurement of the influence of small body size in a porcine model. AB - INTRODUCTION: In our continuing research into the determinants of laparoscopic working space, the influence of small body size was investigated. METHODS: In eight 6-kg pigs, the effects of intraabdominal CO2 pneumoperitoneum pressure (IAP), prestretching of the abdominal wall, and neuromuscular blockade (NMB) on laparoscopic working space volume and distances were studied. Computed tomography was used to measure working space during two stepwise abdominal insufflation-runs up to an IAP of 15mm Hg. Results were compared with data from earlier experiments in 20-kg pigs. RESULTS: Cardiorespiratory parameters were stable up to an IAP of 8-10mm Hg. In 6-kg pigs working-space dimensions were five times smaller than in 20-kg pigs. Working-space volume, anteroposterior (AP) diameter and symphysis diaphragm distance increased linearly up to an IAP of 8mm Hg. Above 8mm Hg, compliance decreased. Eighty percent of the total volume (618ml) and of AP diameter (3cm) at 15mm Hg had been achieved at an IAP of 10mm Hg. Prestretching by a first insufflation resulted in a statistically significant increase in working space volume and in AP diameter during the second insufflation. This effect was significantly larger than in 20-kg pigs. Neuromuscular blockade did not have a significant effect on working-space. CONCLUSIONS: Working space in growing individuals is very limited. Eighty percent of the working space created by an IAP of 15mm Hg was already achieved at 10mm Hg, while cardiorespiratory side effects at an IAP of 8-10mm Hg seem acceptable. Prestretching of the abdominal wall significantly increased working space, even more so than in 20-kg pigs. As in 20-kg pigs, NMB had no significant effect on laparoscopic working space. Prestretching of the abdominal wall is a promising cheap, safe and easy strategy to increase laparoscopic working space, lessening the need for prolonged high-pressure pneumoperitoneum. PMID- 25746710 TI - Inhibition of heparin precipitation, bacterial growth, and fungal growth with a combined isopropanol-ethanol locking solution for vascular access devices. AB - BACKGROUND: Clinical reports of ethanol-lock use for the prevention of catheter related bloodstream infections have been marked by the occurrence of serious catheter occlusions, particularly among children with mediports. We hypothesized that precipitate forms when ethanol mixes with heparin at the concentrations relevant for vascular access devices, but that the use of a combination of two alcohols, ethanol and isopropanol, would diminish heparin-related precipitation, while retaining anti-bacterial and anti-fungal effects. METHODS: Heparin (0 100units/mL) was incubated in ethanol-water solutions (30%-70% vol/vol) or in an aqueous solution containing equal parts (35% and 35% vol/vol) of isopropanol and ethanol. Precipitation at temperatures from 4 to 40 degrees C was measured in nephelometric turbidity units using a benchtop turbidimeter. Growth of Escherichia coli, Staphylococcus aureus, and Candida albicans colonies were measured following exposure to solutions of ethanol or isopropanol-ethanol. Groupwise comparisons were performed using analysis of variance with Bonferroni corrected, post-hoc T-testing. RESULTS: Seventy percent ethanol and heparin exhibit dose-dependent precipitation that is pronounced and significant at the concentrations typically used in mediports (p<0.05). Precipitate is significantly reduced by use of a combined 35% isopropanol-35% ethanol solution rather than 70% ethanol (p<0.05), while maintaining the solution's anti-bacterial and anti-fungal properties. On the other hand, although ethanol solutions under 70% form less precipitate with heparin, such concentrations are also less effective at bacterial colony inhibition than solutions of either 70% ethanol or 35% isopropanol-35% ethanol (p<0.05). CONCLUSIONS: A combined 35% isopropanol-35% ethanol locking solution inhibits bacterial and fungal growth similarly to 70% ethanol, but results in less precipitate than 70% ethanol when exposed to heparin. Further study of a combined isopropanol-ethanol locking solution for the prevention of catheter-related bloodstream infections should focus on the determination as to whether such a locking solution may reduce the rate of precipitation-related catheter occlusion, and whether it may be administered with low systemic toxicity. PMID- 25746711 TI - Gender-related differences of inguinal hernia and asymptomatic patent processus vaginalis in term and preterm infants. AB - INTRODUCTION: The aim of this study was to analyze the gender-related differences of inguinal hernia (IH) and patent processus vaginalis (PPV) in term and preterm infants. METHODS: Over a nine-year-period 411 infants underwent laparoscopic herniorrhaphy within the first six months of life. 246 term (191 male; 55 female) and 165 preterm (118 male; 47 female) infants were included in this retrospective study. Initial presentation of IH and intraoperative anatomical findings of PPV were reviewed. RESULTS: We found that term boys (58.6%) and girls (58.2%) predominantly presented with right-sided IH whereas preterm boys (36.4%) and girls (44.7%) mostly presented with bilateral IH. Female babies had a higher incidence of initial left-sided IH. Term and preterm girls with initial left sided hernia were found to have highest incidence of PPV. Male term babies with initial left-sided IH were found to have the lowest incidence of PPV (25.0%). The highest incidence of PPV in male was found in preterm boys with either left- or right-sided IH. CONCLUSION: Incidence and laterality of IH and PPV differ between term and preterm girls and boys. In open hernia repair decision concerning contralateral groin exploration should consider term/preterm birth as well as gender. PMID- 25746712 TI - Application of continuous incisional infusion of local anesthetic after major pediatric urological surgery: prospective randomized controlled trial. AB - PURPOSE: The aim of the study was to determine efficacy of continuous incisional infusion of local anesthetic, ON-Q(r) pain relief system (Kimberly-Clark, Georgia), in improving postoperative pain, reducing narcotic requirement, and shortening recovery time after major pediatric urological surgery. MATERIAL AND METHODS: Prospective open-labeled randomized controlled trial comparing the ON Q(r) pain relief system to standard of care pain management. Pain was assessed by nurses using the Visual Analog Scale or the Face, Legs, Activity, Cry, Consolability Scale depending on the child's age. Information regarding analgesic consumption and recovery parameters such as temperature, start of oral nutrition, and length of hospitalization were prospectively collected. RESULTS: Patient's demographic, clinical, and surgical characteristics were similar in both groups. The ON-Q(r) group experienced significantly lower scores of maximal daily pain episodes compared to the control on the day of surgery (1.9+/-1.8 vs. 4.2+/-2.2 p=0.009) and first postoperative day (2.28+/-3.2 vs. 5.47+/-2.45 p=0.004). Mean number of narcotic doses was significantly lower in treatment group compared to control [Total (2.21 vs. 4.6 p=0.02), POD0 (0.7 vs. 1.7 p=0.02) and POD1 (1.3 vs. 2.8 p=0.04)]. CONCLUSION: The ON-Q(r) system is a viable option for postoperative pain management in children undergoing urological surgeries. This technology significantly decreases the amount of maximal pain, and the need for systemic narcotic consumption. PMID- 25746714 TI - Lower esophageal banding in extremely low birth weight infants with esophageal atresia and tracheoesophageal fistula is a life saving practice followed by a successful delayed primary thoracoscopy reconstruction. AB - In extremely low birth weight (ELBW) infants, i.e. <1000g, with esophageal atresia (EA) and tracheoesophageal fistula (TEF), surgical treatment is a real challenge. High morbidity is associated with primary repair of EA on these patients. We report our recent experience with three cases of ELBW infants with EA and TEF treated by lower esophageal banding (LEB). From September 2012 to January 2013, three ELBW infants with EA/TEF were born prematurely with severe respiratory distress. One of them had VACTER association with anorectal malformation (ARM). The gestational age was between 25 and 27weeks, and the mean birth weight was 690g (500-790). All were treated by LEB and gastrostomy, followed by delayed primary thoracoscopy reconstruction. One baby died in the postoperative period because of intraventricular hemorrhage at 7days after initial surgery. Among the 2 others cases, one of them required ligation without section of the TEF with removal of LEB by thoracoscopy at 30days old and 1300g. Delayed primary thoracoscopy reconstruction and section of TEF were performed by thoracoscopy at 70 and 80days old and 2100g and 2200g respectively without early complication. The follow-up was 12months. One baby presented a stenosis requiring one dilation of lower esophagus with uneventful course. LEB is a life saving practice in ELBW babies with EA and TEF. The esophagus can tolerate the ligation even with a thread without having a long time major complication. Thoracoscopic reconstruction of the esophagus is possible in these babies. PMID- 25746713 TI - The use of polyacrylate-polyalcohol copolymer hydrogel in the endoscopic treatment of primary vesicoureteral reflux in children. AB - BACKGROUND/PURPOSE: It is still under discussion which is the best tissue augmenting substance for the endoscopic treatment of children with vesicoureteral reflux (VUR). We describe our preliminary experience (September 2009-November 2011) with polyacrylate-polyalcohol copolymer hydrogel (PPCH). METHODS: This is an observational, descriptive, prospective study which included 81 female and male patients (age 1-14 years) diagnosed with unilateral (n=45) and bilateral (n=36) primary VUR comprising a total of 117 refluxing renal units (RRU). Complex cases were excluded from the study. All patients were clinically and radiologically evaluated and those who met the inclusion criteria were treated endoscopically with a single subureteral injection of PPCH by a single surgeon. 11 patients (13.5%) had a pathological 99mTc-DMSA before treatment. The volume of injected product was measured in all cases. Results were considered successful if 6months postinjection, conventional voiding cystourethrogram (VCUG) revealed VUR was cured (Grade 0). Follow-up ranged from 7 to 32months. RESULTS: The overall resolution rate based on the number of RRUs studied was 92.3% (108/117). The mean injected volume of PPCH per patient was 0.6ml. One patient with obstructive anuria required vesicoureteral reimplantation. Other complications were persistent, self-limiting hematuria (n=2); lumbar pain (n=4) and urinary tract infection with normal VCUG (n=4). CONCLUSIONS: Our short term data show PPCH provides a high level of reflux resolution in selected patients. Long term follow up is required. PMID- 25746715 TI - Duodenal lengthening in short bowel with dilated duodenum. AB - Although duodenal dilatation occurs in children with short bowel syndrome (SBS) facilitating dismotility and bacterial overgrowth, the duodenum has been an untouchable intestinal segment for lengthening procedures owing to its close relationship with bilio-pancreatic structures and blood supply shared with the pancreas. Three children (age range, 0.5-7 years) with SBS and dilated duodenum underwent a novel surgical procedure of duodenal lengthening combined with a technical modification of serial transverse enteroplasty (STEP). Pre-STEP, jejunum length was 5, 35 and 45cm, respectively. Duodenal lengthening was performed with sequential transverse applications of an endoscopic stapler on the anterior and posterior wall of the duodenum to avoid bilio-pancreatic structure injury. Two patients underwent 3 duodenal firings (stapler of 35mm) and the third 5 firings (stapler of 45mm). Duodenal firings were 17%, 21% and 83% of the total firings. RESULTS: No surgical complications occurred. One patient developed transient episodes of D-lactic acidosis. Two patients (5 and 45cm) were weaned off parenteral nutrition at 12months post-surgery and the remaining patient's (35cm) parenteral calorie requirements have decreased by 60%. CONCLUSION: Duodenal lengthening is effective since it tailors and increases the absorptive surface of the duodenum, even in cases of extreme SBS. PMID- 25746716 TI - Reply to letter to the editor. PMID- 25746717 TI - Regarding risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy. PMID- 25746718 TI - Selective Versus Hilar Clamping During Minimally Invasive Partial Nephrectomy: A Systematic Review and Meta-Analysis. AB - PURPOSE: To compare the clinical efficacy and safety of selective vs hilar clamping during minimally invasive partial nephrectomy (PN). METHODS: Studies comparing the effect and safety of selective versus hilar clamping during PN were identified by a systematic search using MEDLINE and EMBASE from January 2000 to November 2014. Quality of the selected studies was assessed according to the Newcastle-Ottawa Scale (NOS). RESULTS: A total of seven retrospective studies were included. No significant differences were observed between the two groups in age, body mass index, tumor size, pre-estimated glomerular filtration rate (eGFR), operative time, and length of stay. The selective clamping group had greater estimated blood loss (P<0.01) but similar blood transfusion rate (P=0.78) compared with the hilar clamping group. There were no significant differences between the two groups in terms of urinary leaks, overall complication rate, and positive margin rate. Patients who underwent selective clamping had a lower change in eGFR (mean difference [MD]: 13.95; 95% CI 8.85 to 19.05; P<0.01) and a lower percent change in eGFR (MD: 18.51; 95% CI 14.18 to 22.84; P<0.01) at 1 week. Combined results from two studies showed a trend toward a lower percent change in eGFR at 3 months (MD: 5.47; 95% CI -0.28 to 11.22; P=0.06). At 6 months, two studies showed no significant differences in percent change of renal function between the two groups (MD: 16.85; 95% CI -10.47 to 44.16; P=0.23). CONCLUSIONS: Although selective clamping resulted in greater estimated blood loss, it provided comparable perioperative safety and superior short-term renal function preservation. The advantage of selective clamping in preservation of intermediate-term renal function remains to be evaluated in the future, however. There is a need for properly designed studies to confirm our founding. PMID- 25746719 TI - Special issue on iron-sulfur proteins: Structure, function, biogenesis and diseases. PMID- 25746720 TI - P21 activated kinase-1 mediates transforming growth factor beta1-induced prostate cancer cell epithelial to mesenchymal transition. AB - Transforming growth factor beta (TGFbeta) is believed to play a dual role in prostate cancer. Molecular mechanism by which TGFbeta1 suppresses early prostate tumor growth and induces epithelial-to-mesenchymal transition (EMT) in advanced stages is not known. We determined if P21-activated kinase1 (Pak1), which mediates cytoskeletal remodeling is necessary for the TGFbeta1 induced prostate cancer EMT. Effects of TGFbeta1 on control prostate cancer PC3 and DU145 cells and those with IPA 3 and siRNA mediated Pak1 inhibition were tested for prostate tumor xenograft in vivo and EMT in vitro. TGFbeta1 inhibited PC3 tumor xenograft growth via activation of P38-MAPK and caspase-3, 9. Long-term stimulation with TGFbeta1 induced PC3 and DU145 cell scattering and increased expression of EMT markers such as Snail and N-cadherin through tumor necrosis factor receptor associated factor-6 (TRAF6)-mediated activation of Rac1/Pak1 pathway. Selective inhibition of Pak1 using IPA 3 or knockdown using siRNA both significantly inhibited TGFbeta1-induced prostate cancer cell EMT and expression of mesenchymal markers. Our study demonstrated that TGFbeta1 induces apoptosis and EMT in prostate cancer cells via activation of P38-MAPK and Rac1/Pak1 respectively. Our results reveal the potential therapeutic benefits of targeting TGFbeta1-Pak1 pathway for advanced-stage prostate cancer. PMID- 25746721 TI - Ictal high-frequency oscillations and hyperexcitability in refractory epilepsy. AB - OBJECTIVE: High-frequency oscillations (HFOs, 80-500Hz) from intracranial electroencephalography (EEG) may represent a biomarker of epileptogenicity for epilepsy. We explored the relationship between ictal HFOs and hyperexcitability with a view to improving surgical outcome. METHODS: We evaluated 262 patients with refractory epilepsy. Fifteen patients underwent electrode implantation, and surgical resection was performed in 12 patients using a semi-prospective design. Ictal intracranial EEGs were examined by continuous wavelet transform (CWT). Significant ictal HFOs were denoted by normalized wavelet power above the 50th percentile across all channels. Each patient underwent functional mapping with cortical electrical stimulation. Hyperexcitability was defined as the appearance of afterdischarges or clinical seizures after electrical stimulation (50Hz, biphasic, pulse width=0.5ms, 5s, 5mA). RESULTS: Among the group of patients achieving Engel Class I/II outcome at 1+ year, the mean proportion of significant ictal HFOs among resected channels for any given patient was 69% (33.3-100%). The respective figures for conventional frequency ictal patterns (CFIPs), hyperexcitability, and radiological lesion were 68.3% (26.3-100%), 39.6% (0 100%), and 52.8% (0-100%). Statistical significance was only achieved with ictal HFOs when comparing patients with Engel Class I/II outcomes versus III/IV outcomes (12.6% vs. 4.2%, the number of channels as the denominator, p=0.005). Further analysis from all patients irrespective of the surgical outcome showed that ictal HFOs co-occurred with CFIP (p<0.001), hyperexcitability (p<0.001), and radiological lesion (p<0.001). The combination of ictal HFOs/hyperexcitability improved the sensitivity from 66.7% to 100%, and the specificity from 66.7% to 75% when compared with ictal HFOs or hyperexcitability alone. CONCLUSIONS: We confirmed the utility of ictal HFOs in determining surgical outcome. Ictal HFOs are affiliated to cortical hyperexcitability, which may represent a pathological manifestation of epileptogenicity. SIGNIFICANCE: Presurgical evaluation of refractory epilepsy may incorporate both ictal HFOs and cortical stimulation in determining epileptogenic foci. PMID- 25746722 TI - The internal architecture of dendritic spines revealed by super-resolution imaging: What did we learn so far? AB - The molecular architecture of dendritic spines defines the efficiency of signal transmission across excitatory synapses. It is therefore critical to understand the mechanisms that control the dynamic localization of the molecular constituents within spines. However, because of the small scale at which most processes within spines take place, conventional light microscopy techniques are not adequate to provide the necessary level of resolution. Recently, super resolution imaging techniques have overcome the classical barrier imposed by the diffraction of light, and can now resolve the localization and dynamic behavior of proteins within small compartments with nanometer precision, revolutionizing the study of dendritic spine architecture. Here, we highlight exciting new findings from recent super-resolution studies on neuronal spines, and discuss how these studies revealed important new insights into how protein complexes are assembled and how their dynamic behavior shapes the efficiency of synaptic transmission. PMID- 25746723 TI - Introduction to the ECR special issue on lysophospholipids in biology. PMID- 25746724 TI - RhoD is a Golgi component with a role in anterograde protein transport from the ER to the plasma membrane. AB - RhoD is a member of the Rho GTPase family and it coordinates actin dynamics and membrane trafficking. Activation of RhoD results in formation of filopodia, dissolution of stress fibers, and the subsequent formation of short actin bundles. In addition, RhoD localizes to early endosomes and recycling endosomes, and has a regulatory role in endosome trafficking. In this study, we report on a function of RhoD in the regulation of Golgi homeostasis. We show that manipulation of protein and activation levels of RhoD, as well as of its binding partner WHAMM, result in derailed localization of Golgi stacks. Moreover, vesicle trafficking from the endoplasmic reticulum to the plasma membrane via the Golgi apparatus measured by the VSV-G protein is severely hampered by manipulation of RhoD or WHAMM. In summary, our studies demonstrate a novel role for this member of the Rho GTPases in the regulation of Golgi function. PMID- 25746725 TI - Error-related brain activity in the age of RDoC: A review of the literature. AB - The ability to detect and respond to errors is critical to successful adaptation to a changing environment. The error-related negativity (ERN), an event-related potential (ERP) component, is a well-validated neural response to errors and reflects the error monitoring activity of the anterior cingulate cortex (ACC). Additionally, the ERN is implicated in several processes key to adaptive functioning. Abnormalities in error-related brain activity have been linked to multiple forms of psychopathology and individual differences. As such, the component is likely to be useful in NIMH's Research Domain Criteria (RDoC) initiative to establish biologically-meaningful dimensions of psychological dysfunction, and currently appears as a unit of measurement in three RDoC domains: Positive Valence Systems, Negative Valence Systems, and Cognitive Systems. In this review paper, we introduce the ERN and discuss evidence related to its psychometric properties, as well as important task differences. Following this, we discuss evidence linking the ERN to clinically diverse forms of psychopathology, as well as the implications of one unit of measurement appearing in multiple RDoC dimensions. And finally, we discuss important future directions, as well as research pathways by which the ERN might be leveraged to track the ways in which dysfunctions in multiple neural systems interact to influence psychological well-being. PMID- 25746726 TI - Effects of selective REM sleep deprivation on prefrontal gamma activity and executive functions. AB - Given that the dorsolateral prefrontal cortex is involved in executive functions and is deactivated and decoupled from posterior associative regions during REM sleep, that Gamma temporal coupling involved in information processing is enhanced during REM sleep, and that adult humans spend about 90 min of every 24h in REM sleep, it might be expected that REM sleep deprivation would modify Gamma temporal coupling and have a deteriorating effect on executive functions. We analyzed EEG Gamma activity and temporal coupling during implementation of a rule guided task before and after REM sleep deprivation and its effect on verbal fluency, flexible thinking and selective attention. After two nights in the laboratory for adaptation, on the third night subjects (n=18) were randomly assigned to either selective REM sleep deprivation effectuated by awakening them at each REM sleep onset or, the same number of NREM sleep awakenings as a control for unspecific effects of sleep interruptions. Implementation of abstract rules to guide behavior required greater activation and synchronization of Gamma activity in the frontopolar regions after REM sleep reduction from 20.6% at baseline to just 3.93% of total sleep time. However, contrary to our hypothesis, both groups showed an overall improvement in executive task performance and no effect on their capacity to sustain selective attention. These results suggest that after one night of selective REM sleep deprivation executive functions can be compensated by increasing frontal activation and they still require the participation of supervisory control by frontopolar regions. PMID- 25746727 TI - Effects of nutritional supplementation on fatigue, and autonomic and immune dysfunction in patients with end-stage renal disease: a randomized, double-blind, placebo-controlled, multicenter trial. AB - BACKGROUND: Fatigue is a predictor of cardiovascular events in patients with end stage renal disease (ESRD) undergoing hemodialysis treatment. We hypothesized that multinutritional support would improve quality of life, fatigue symptoms, and potential quantitative measures including endocrine, immune and autonomic functions in patients with ESRD undergoing hemodialysis. METHODS: Two hundred and two hemodialysis patients were randomly assigned to receive active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naive galacto-oligosaccharide, and zinc) or placebo after each dialysis session for 12 weeks. The patients and attending physicians were blinded to the treatment, and 172 patients (86 in each group) completed the study. Fatigue was evaluated via fatigue questionnaire at 0, 4, and 12 weeks. To assess human herpes virus (HHV) 6 and 7 reactivation, numbers of viral DNA copies were determined in saliva by polymerase chain reaction at weeks 0 and 12. Autonomic function was determined via measurement of beat-to-beat variation by using acceleration plethysmography. RESULTS: Clinical characteristics, changes in fatigue, quality of life score, endocrine functions, and laboratory data did not differ significantly between the two groups. Several parameters of heart rate variability significantly increased after nutritional treatment compared to placebo. Nutritional drink for 12 weeks significantly suppressed HHV7 DNA copy numbers. Similarly, HHV6 DNA copy numbers tended to be decreased by treatment but without reaching statistical significance. CONCLUSIONS: Nutritional supplementation may modulate immune and autonomic dysfunction in ESRD patients undergoing hemodialysis. PMID- 25746729 TI - Correction: [Pt(O,O'-acac)(gamma-acac)(DMS)] alters SH-SY5Y cell migration and invasion by the inhibition of Na+/H+ exchanger isoform 1 occurring through a PKC epsilon/ERK/mTOR pathway. PMID- 25746728 TI - Hospital expenditure at the end-of-life: what are the impacts of health status and health risks? AB - BACKGROUND: It is important for health policy and expenditure projections to understand the relationship between age, death and expenditure on health care (HC). Research has shown that older age groups incur lower hospital costs than previously anticipated and that remaining time to death (TTD) was a much stronger indicator for expenditure than age. How health behaviour or risk factors impact on HC utilisation and costs at the end of life is relatively unknown. Smoking and Body Mass Index (BMI) have featured most prominently and mixed findings exist as to the exact nature of this association. METHODS: This paper considers the relationship between TTD, age and expenditure for inpatient care in the last 12 quarters of life; and introduces measures of health status and risks. A longitudinal dataset covering 35 years is utilised, including baseline survey data linked to hospital and death records. The effect of age, TTD and health indicators on expenditure for inpatient care is estimated using a two-part model. RESULTS: As individuals approach death costs increase. This effect is highly significant (p<0.01) from the last until the 8th quarter before death and influenced by age. Statistically significant effects on costs were found for: smoking status, systolic blood pressure and lung function (FEV1). On average, smokers incurred lower quarterly costs in their last 12 quarters of life than non smokers (~7%). Participants' BMI at baseline did show a negative association with probability of HC utilisation however this effect disappeared when costs were estimated. CONCLUSIONS: Health risk measures obtained at baseline provide a good indication of individuals' probability of needing medical attention later in life and incurring costs, despite the small size of the effect. Utilising a linked dataset, where such measures are available can add substantially to our ability to explain the relationship between TTD and costs. PMID- 25746731 TI - Atrial electromechanical coupling: a complementary index for quantifying atrial cardiac electrical heterogeneity in preeclampsia. PMID- 25746732 TI - Stereotactic ablative body radiotherapy for lung cancer. AB - Lung stereotactic ablative radiotherapy (SABR) is a method of delivering high 'ablative' doses of radiotherapy to tumours in the lung. It was developed at the Karolinska Institute in the early 1990s using the methods established in cranial radiosurgery with multiple beams prescribed to an isodose and using a custom designed stereotactic body frame for immobilisation. Since then, aligned with the advances in radiotherapy technology and techniques (e.g. four-dimensional computed tomography simulation and image-guided radiotherapy), there has been a rapid increase in the use of lung SABR for both early stage lung cancer and lung metastases. For peripheral primary lung cancers less than 5 cm in diameter, high rates of local control and low levels of acute and late toxicity are consistently reported in the published literature. Compared with historical control rates of stage I lung cancers treated with conventionally fractionated radiotherapy, SABR seems to offer higher rates of local control, lower levels of acute toxicity and a better quality of life after treatment. However, the full results of randomised controlled trials of SABR versus conventionally fractionated are awaited and will provide higher-level evidence. For central lung tumours, very high SABR doses can be associated with significant toxicity. Dose-adapted fractionation schedules seem to have much lower rates of toxicity and prospective trials, including the completed RTOG 0813 study and the on-going EORTC LUNGTEC study, should provide further evidence of safety and establish organ at risk tolerances. SABR can also be used for tumours metastatic to the lung with high rates of local control and is a reasonable alternative to surgery in selected patients. Going forward, prospective trials are underway to establish the safety and efficacy of SABR in oligometastatic disease. Population-based outcomes will be crucial in supporting/establishing SABR as the treatment of choice in medically inoperable patients with peripheral stage I lung cancers. Randomised phase III trials will hopefully extend the evidence base and show the safety and the utility of SABR in early central tumours and oligometastatic disease. PMID- 25746730 TI - NuMoM2b Sleep-Disordered Breathing study: objectives and methods. AB - OBJECTIVE: The objective of the Sleep Disordered Breathing substudy of the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b) is to determine whether sleep disordered breathing during pregnancy is a risk factor for adverse pregnancy outcomes. STUDY DESIGN: NuMoM2b is a prospective cohort study of 10,037 nulliparous women with singleton gestations that was conducted across 8 sites with a central Data Coordinating and Analysis Center. The Sleep Disordered Breathing substudy recruited 3702 women from the cohort to undergo objective, overnight in-home assessments of sleep disordered breathing. A standardized level 3 home sleep test was performed between 6(0)-15(0) weeks' gestation (visit 1) and again between 22(0)-31(0) weeks' gestation (visit 3). Scoring of tests was conducted by a central Sleep Reading Center. Participants and their health care providers were notified if test results met "urgent referral" criteria that were based on threshold levels of apnea hypopnea indices, oxygen saturation levels, or electrocardiogram abnormalities but were not notified of test results otherwise. The primary pregnancy outcomes to be analyzed in relation to maternal sleep disordered breathing are preeclampsia, gestational hypertension, gestational diabetes mellitus, fetal growth restriction, and preterm birth. RESULTS: Objective data were obtained at visit 1 on 3261 women, which was 88.1% of the studies that were attempted and at visit 3 on 2511 women, which was 87.6% of the studies that were attempted. Basic characteristics of the substudy cohort are reported in this methods article. CONCLUSION: The substudy was designed to address important questions regarding the relationship of sleep disordered breathing on the risk of preeclampsia and other outcomes of relevance to maternal and child health. PMID- 25746733 TI - G6PD deficiency at Sumba in Eastern Indonesia is prevalent, diverse and severe: implications for primaquine therapy against relapsing Vivax malaria. AB - Safe treatment of Plasmodium vivax requires diagnosis of both the infection and status of erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity because hypnozoitocidal therapy against relapse requires primaquine, which causes a mild to severe acute hemolytic anemia in G6PD deficient patients. Many national malaria control programs recommend primaquine therapy without G6PD screening but with monitoring due to a broad lack of G6PD deficiency screening capacity. The degree of risk in doing so hinges upon the level of residual G6PD activity among the variants present in any given area. We conducted studies on Sumba Island in eastern Indonesia in order to assess the potential threat posed by primaquine therapy without G6PD screening. We sampled 2,033 residents of three separate districts in western Sumba for quantitative G6PD activity and 104 (5.1%) were phenotypically deficient (<4.6U/gHb; median normal 10U/gHb). The villages were in two distinct ecosystems, coastal and inland. A positive correlation occurred between the prevalence of malaria and G6PD deficiency: 5.9% coastal versus inland 0.2% for malaria (P<0.001), and 6.7% and 3.1% for G6PD deficiency (P<0.001) at coastal and inland sites, respectively. The dominant genotypes of G6PD deficiency were Vanua Lava, Viangchan, and Chatham, accounting for 98.5% of the 70 samples genotyped. Subjects expressing the dominant genotypes all had less than 10% of normal enzyme activities and were thus considered severe variants. Blind administration of anti-relapse primaquine therapy at Sumba would likely impose risk of serious harm. PMID- 25746734 TI - Texture analysis as a tool to study the kinetics of wet agglomeration processes. AB - In this work wet granulation experiments were carried out in a planetary mixer with the aim to develop a novel analytical tool based on surface texture analysis. The evolution of a simple formulation (300g of microcrystalline cellulose with a solid binders pre-dispersed in water) was monitored from the very beginning up to the end point and information on the kinetics of granulation as well as on the effect of liquid binder amount were collected. Agreement between texture analysis and granules particle size distribution obtained by sieving analysis was always found. The method proved to be robust enough to easily monitor the process and its use for more refined analyses on the different rate processes occurring during granulation is also suggested. PMID- 25746735 TI - Solid formulations by a nanocrystal approach: critical process parameters regarding scale-ability of nanocrystals for tableting applications. AB - Nanocrystallization is among the foremost drug delivery platform approaches for the commercial development of poorly soluble drugs. There exists an urge to enable a universal shift of the production of the solid nanocrystal formulations from laboratory scale to industrially feasible scale. The success of any formulation development depends on its transferability to large scale manufacture. The objectives of the study were to increase the nanocrystallization batch size and to screen and optimize parameters for industrially feasible itraconazole (ITC) and indomethacin (IND) nanocrystal composition for tablet formulation. Thus, ITC and IND were transformed into nanocrystal suspensions, using an increased batch size of a wet milling process, freeze-dried, and further developed into both direct compression (DC) and granulated (G) tableting masses. According to the investigated powder and tablet properties (true density, flowability, dose uniformity, maximum upper punch force, crushing strength, dissolution and disintegration) and stability testings, it was clear that the amount of the nanocrystals in the solid tablet formulation is critical in order to fully utilize the benefits of the nanocrystals, i.e., fast dissolution, and to produce high-quality tablets. The DC designs of both the model drugs with compositions including 40% of freeze-dried nanocrystalline drug powder outperformed the corresponding granulated tablets in all parameters after the stability surveillance. PMID- 25746736 TI - In vitro dissolution of proton-pump inhibitor products intended for paediatric and geriatric use in physiological bicarbonate buffer. AB - Proton-pump inhibitor (PPI) products based on enteric coated multiparticulates are design to meet the needs of patients who cannot swallow tablets such as children and older adults. Enteric coated PPI preparations exhibit delays in in vivo absorption and onset of antisecretory effects, which is not reflected by the rapid in vitro dissolution in compendial pH 6.8 phosphate buffer commonly used for assessment of these products. A more representative and physiological medium, pH 6.8 mHanks bicarbonate buffer, was used in this study to evaluate the in vitro dissolution of enteric coated multiparticulate-based PPI products. Commercially available omeprazole, lansoprazole and esomeprazole products were subject to dissolution tests using USP-II apparatus in pH 4.5 phosphate buffer saline for 45 min (acid stage) followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, all nine tested products displayed rapid and comparable dissolution profiles meeting the pharmacopeia requirements for delayed release preparations. In pH 6.8 mHanks buffer, drug release was delayed and failed the pharmacopeia requirements from most enteric coated preparations. Despite that the same enteric polymer, methacrylic acid-ethyl acrylate copolymer (1:1), was applied to all commercial multiparticulate-based products, marked differences were observed between dissolution profiles of these preparations. The use of pH 6.8 physiological bicarbonate (mHanks) buffer can serve as a useful tool to provide realistic and discriminative in vitro release assessment of enteric coated PPI preparations and to assist rational formulation development of these products. PMID- 25746737 TI - Quality by design approach for optimizing the formulation and physical properties of extemporaneously prepared orodispersible films. AB - The quality by design (QbD) approach was applied for optimizing the formulation of extemporaneously prepared orodispersible films (ODFs) using Design-Expert(r) Software. The starting formulation was based on earlier experiments and contained the film forming agents hypromellose and carbomer 974P and the plasticizer glycerol (Visser et al., 2015). Trometamol and disodium EDTA were added to stabilize the solution. To optimize this formulation a quality target product profile was established in which critical quality attributes (CQAs) such as mechanical properties and disintegration time were defined and quantified. As critical process parameters (CPP) that were evaluated for their effect on the CQAs the percentage of hypromellose and the percentage of glycerol as well as the drying time were chosen. Response surface methodology (RMS) was used to evaluate the effects of the CPPs on the CQAs of the final product. The main factor affecting tensile strength and Young's modulus was the percentage of glycerol. Elongation at break was mainly influenced by the drying temperature. Disintegration time was found to be sensitive to the percentage of hypromellose. From the results a design space could be created. As long as the formulation and process variables remain within this design space, a product is obtained with desired characteristics and that meets all set quality requirements. PMID- 25746738 TI - Cytotoxic T-lymphocyte antigen-4 blockade in melanoma. AB - PURPOSE: Melanoma is an aggressive malignancy that has a complex relationship with the host immune system. Immunotherapies have long been a mainstay of melanoma therapy, and advanced therapies continue to be effective in treating this disease. Immune checkpoint blockade has proven to be a novel target in melanoma, with the approval of cytotoxic T-lymphocyte antigen-4 (CTLA-4)-targeted therapy. This review evaluates the role of CTLA-4-targeted therapies in the treatment of metastatic melanoma, with a focus on mechanisms, efficacy, toxicity, and future directions of this therapy. METHODS: A search was performed in PubMed to identify relevant clinical studies that explored the clinical experience with CTLA-4-targeted therapy in melanoma. FINDINGS: Signaling through CTLA-4 causes deactivation of T cells after the initial stimulatory signals. Therapies that block CTLA-4 lead to increased T-cell function and an antitumor response in patients with metastatic melanoma. The adverse event profile of these agents is different from that seen with more traditional cancer therapies and consists of dermatitis, colitis, and other autoimmune toxicities. In addition, the pattern of response is different from that seen with traditional cytotoxic therapies, with some patients experiencing initial progression followed by response and some patients having long-term durable responses. IMPLICATIONS: Extensive clinical evidence supports the use of CTLA-4-targeted agents in the treatment of metastatic melanoma. The durability of response seen in patients receiving these agents has changed the landscape for patients with melanoma. Combination therapies and other agents with similar mechanisms warrant further exploration for the treatment of metastatic melanoma. PMID- 25746739 TI - When to drool is cool. PMID- 25746740 TI - The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues. AB - Based on a report that sulfanylphthalimides are highly potent monoamine oxidase (MAO) B selective inhibitors, the present study examines the adenosine receptor affinities and MAO-B inhibitory properties of a series of 4- and 5 sulfanylphthalimide analogues. Since adenosine antagonists (A1 and A2A subtypes) and MAO-B inhibitors are considered agents for the therapy of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, dual-target directed drugs that antagonize adenosine receptors and inhibit MAO-B may have enhanced therapeutic value. The results document that the sulfanylphthalimide analogues are selective for the adenosine A1 receptor over the A2A receptor subtype, with a number of compounds also possessing MAO-B inhibitory properties. Among the compounds evaluated, 5-[(4-methoxybenzyl)sulfanyl]phthalimide was found to possess the highest binding affinity to adenosine A1 receptors with a Ki value of 0.369 MUM. This compound is reported to also inhibit MAO-B with an IC50 value of 0.020 MUM. Such dual-target-directed compounds may act synergistic in the treatment of Parkinson's disease: antagonism of the A1 receptor may facilitate dopamine release, while MAO-B inhibition may reduce dopamine metabolism. Additionally, dual-target-directed compounds may find therapeutic value in Alzheimer's disease: antagonism of the A1 receptor may be beneficial in the treatment of cognitive dysfunction, while MAO-B inhibition may exhibit neuroprotective properties. In neurological diseases, such as Parkinson's disease and Alzheimer's disease, dual-target-directed drugs are expected to be advantageous over single-target treatments. PMID- 25746741 TI - Isolation and identification of cultivable Bifidobacterium spp. from the faeces of 5 baby common marmosets (Callithrix jacchus L.). AB - Ninety-two bifidobacterial strains were obtained from the faeces of 5 baby common marmosets, three known species Bifidobacterium aesculapii, Bifidobacterium callithricos and Bifidobacterium reuteri and 4 novel putative bifidobacterial species were retrieved. The occurrence of bifidobacteria in non-human primate babies is described for the first time. PMID- 25746742 TI - The formation, elements of success, and challenges in managing a critical care program: part II. AB - Leaders of critical care services require knowledge and skills not typically acquired during their medical education and training. Leaders possess personality characteristics and evolve and adopt behaviors and knowledge in addition to those useful in the care of patients and rounding with an ICU team. Successful leaders have impeccable integrity, possess a service mentality, are decisive, and speak the truth consistently and accurately. Effective leaders are thoughtful listeners, introspective, develop a range of relationships, and nurture others. They understand group psychology, observe, analyze assumptions, decide, and improve the system of care and the performance of their team members. A leader learns to facilely adapt to circumstance, generate new ideas, and be a catalyst of change. Those most successful further their education as a leader and learn when and where to seek mentorship. Leaders understand their organization and its operational complexities. Leaders learn to participate and knowledgeably contribute to the fiscal aspects of income, expense, budget, and contracts from an institutional and department perspective. Clinician compensation must be commensurate with expectations and be written to motivate and make clear duties that are clinical and nonclinical. A leader understands and plans to address the evolving challenges facing healthcare, especially resource constraints, the emotions and requirements of managing the end of life, the complexities of competing demands and motivations, the bureaucracy of healthcare practice, and reimbursement. Responsibilities to manage and evolve must be met with intelligence, sensitivity, and equanimity. PMID- 25746743 TI - The formation, elements of success, and challenges in managing a critical care program: Part I. AB - Leaders of critical care programs have significant responsibility to develop and maintain a system of intensive care. At inception, those clinician resources necessary to provide and be available for the expected range of patient illness and injury and throughput are determined. Simultaneously, non-ICU clinical responsibilities and other expectations, such as education of trainees and participation in hospital operations, must be understood. To meet these responsibilities, physicians must be recruited, mentored, and retained. The physician leader may have similar responsibilities for nonphysician practitioners. In concert with other critical care leaders, the service adopts a model of care and assembles an ICU team of physicians, nurses, nonphysician providers, respiratory therapists, and others to provide clinical services. Besides clinician resources, leaders must assure that services such as radiology, pharmacy, the laboratory, and information services are positioned to support the complexities of ICU care. Metrics are developed to report success in meeting process and outcomes goals. Leaders evolve the system of care by reassessing and modifying practice patterns to continually improve safety, efficacy, and efficiency. Major emphasis is placed on the importance of continuity, consistency, and communication by expecting practitioners to adopt similar practices and patterns. Services anticipate and adapt to evolving expectations and resource availability. Effective services will result when skilled practitioners support one another and ascribe to a service philosophy of care. PMID- 25746744 TI - Characterizing degree of lung injury in pediatric acute respiratory distress syndrome. AB - OBJECTIVE: Although all definitions of acute respiratory distress syndrome use some measure of hypoxemia, neither the Berlin definition nor recently proposed pediatric-specific definitions proposed by the Pediatric Acute Lung Injury Consensus Conference utilizing oxygenation index specify which PaO2/FIO2 or oxygenation index best categorizes lung injury. We aimed to identify variables associated with mortality and ventilator-free days at 28 days in a large cohort of children with acute respiratory distress syndrome. DESIGN: Prospective, observational, single-center study. SETTING: Tertiary care, university-affiliated PICU. PATIENTS: Two-hundred eighty-three invasively ventilated children with the Berlin-defined acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between July 1, 2011, and June 30, 2014, 283 children had acute respiratory distress syndrome with 37 deaths (13%) at the Children's Hospital of Philadelphia. Neither initial PaO2/FO2 nor oxygenation index at time of meeting acute respiratory distress syndrome criteria discriminated mortality. However, 24 hours after, both PaO2/FIO2 and oxygenation index discriminated mortality (area under receiver operating characteristic curve, 0.68 [0.59-0.77] and 0.66 [0.57-0.75]; p < 0.001). PaO2/FIO2 at 24 hours categorized severity of lung injury, with increasing mortality rates of 5% (PaO2/FIO2, > 300), 8% (PaO2/FIO2, 201-300), 18% (PaO2/FIO2, 101-200), and 37% (PaO2/FIO2, <= 100) across worsening Berlin categories. This trend with 24-hour PaO2/FIO2 was seen for ventilator-free days (22, 19, 14, and 0 ventilator-free days across worsening Berlin categories; p < 0.001) and duration of ventilation in survivors (6, 9, 13, and 24 d across categories; p < 0.001). Similar results were obtained with 24-hour oxygenation index. CONCLUSIONS: PaO2/FIO2 and oxygenation index 24 hours after meeting acute respiratory distress syndrome criteria accurately stratified outcomes in children. Initial values were not helpful for prognostication. Definitions of acute respiratory distress syndrome may benefit from addressing timing of oxygenation metrics to stratify disease severity. PMID- 25746745 TI - Frequency, cost, and risk factors of readmissions among severe sepsis survivors. AB - OBJECTIVE: To determine the frequency, mortality, cost, and risk factors associated with readmission after index hospitalization with severe sepsis. DESIGN: Observational cohort study of Healthcare Cost and Utilization Project data. SETTING: All nonfederal hospitals in three U.S. states. PATIENTS: Severe sepsis survivors (n = 43,452) in the first two quarters of 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured readmission rates and the associated cost and mortality of readmissions in severe sepsis survivors. We used multivariable logistic regression to identify patient and hospitalization characteristics associated with readmission. Of 43,452 sepsis survivors, 26% required readmission within 30 days and 48% within 180 days. The cumulative mortality rate of sepsis survivors attributed to readmissions was 8%, and the estimated cost was over $1.1 billion. Among survivors, 25% required multiple readmissions within 180 days and accounted for 77% of all readmissions. Age younger than 80 years (odds ratio, 1.14; 95% CI, 1.08-1.21), black race (odds ratio, 1.18; 95% CI, 1.10-1.26), and Medicare or Medicaid payor status (odds ratio, 1.21; 95% CI, 1.13-1.30; odds ratio, 1.34; 95% CI, 1.23-1.46, respectively) were associated with greater odds of 30-day readmission while female gender was associated with reduced odds (odds ratio, 0.92; 95% CI, 0.87 0.96). Comorbidities including malignancy (odds ratio, 1.34; 95% CI, 1.24-1.45), collagen vascular disease (odds ratio, 1.30; 95% CI, 1.15-1.46), chronic kidney disease (odds ratio, 1.24; 95% CI, 1.18-1.31), liver disease (odds ratio, 1.22; 95% CI, 1.11-1.34), congestive heart failure (odds ratio, 1.14; 95% CI, 1.08 1.19), lung disease (odds ratio, 1.12; 95% CI, 1.06-1.18), and diabetes (odds ratio, 1.12; 95% CI, 1.07-1.17) were associated with greater odds of 30-day readmission. Index hospitalization characteristics including longer length of stay, discharge to a care facility, higher hospital annual severe sepsis case volume, and higher hospital sepsis mortality rate were also positively associated with readmission rates. CONCLUSION: The 30-day and 180-day readmissions are common in sepsis survivors with significant resultant cost and mortality. Patient sociodemographics and comorbidities as well as index hospitalization characteristics are associated with 30-day readmission rates. PMID- 25746746 TI - Derivation and validation of the acute organ failure score to predict outcome in critically ill patients: a cohort study. AB - OBJECTIVES: Prediction models for ICU mortality rely heavily on physiologic variables that may not be available in large retrospective studies. An alternative approach when physiologic variables are absent stratifies mortality risk by acute organ failure classification. DESIGN: Retrospective cohort study. SETTING: Two large teaching hospitals in Boston, MA. SUBJECTS: Ninety-two thousand eight hundred eighty-six patients aged 18 years old or older admitted between November 3, 1997, and February 25, 2011, who received critical care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The derivation cohort consisted of 35,566 patients from Brigham and Women's Hospital, and the validation cohort comprised 57,320 patients from Massachusetts General Hospital. Acute organ failure was determined for each patient based on International Classification of Diseases, 9th Revision, Clinical Modification code combinations. The main outcome measure was 30-day mortality. A clinical prediction model was created based on a logistic regression model describing the risk of 30-day mortality as a function of age, medical versus surgical patient type, Deyo-Charlson index, sepsis, and type acute organ failure (respiratory, renal, hepatic, hematologic, metabolic, and neurologic) after ICU admission. We computed goodness-of fit statistics and c-statistics as measures of model calibration and 30-day mortality discrimination, respectively. Thirty-day mortality occurred in 5,228 of 35,566 patients (14.7%) assigned to the derivation cohort. The clinical prediction model was predictive for 30-day mortality. The c statistic for the clinical prediction model was 0.7447 (95% CI, 0.74-0.75) in the derivation cohort and 0.7356 (95% CI, 0.73-0.74) in the validation cohort. For both the derivation and validation cohorts, the Hosmer-Lemeshow chi-square p values indicated good model fit. In a smaller cohort of 444 patients with Acute Physiologic and Chronic Health Evaluation II scores determined, differences in model discrimination of 30-day mortality between the clinical prediction model and Acute Physiologic and Chronic Health Evaluation II were not significant (chi square=0.76; p=0.38). CONCLUSIONS: An acute organ failure-based clinical prediction model shows good calibration and discrimination for 30-day mortality in the critically ill. The clinical prediction model compares favorably to Acute Physiologic and Chronic Health Evaluation II score in the prediction of 30-day mortality in the critically ill. This score may be useful for severity of illness risk adjustment in observational studies where physiologic data are unavailable. PMID- 25746747 TI - Gaming hospital-level pneumonia 30-day mortality and readmission measures by legitimate changes to diagnostic coding. AB - OBJECTIVE: Risk-standardized 30-day mortality and hospital readmission rates for pneumonia are increasingly being tied to hospital reimbursement to incentivize the delivery of high-quality care. Such measures may be susceptible to gaming by recoding patients with pneumonia to a primary diagnosis of sepsis or respiratory failure. We sought to determine the degree to which hospitals can game mortality or readmission measures and change their rankings by recoding patients with pneumonia. DESIGN AND SETTING: Simulated experimental study of 2,906 U.S. acute care hospitals with at least 25 admissions for pneumonia using 2009 Medicare data. PATIENTS: Elderly (age >= 65 yr) Medicare fee-for-service beneficiaries hospitalized with pneumonia. Patients eligible for recoding to sepsis or respiratory failure were those with a principal International Classification of Diseases, 9th Edition, Clinical Modification, discharge code for pneumonia and secondary codes for respiratory failure or acute organ dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the number of hospitals that improved their pneumonia mortality or readmission rates after recoding eligible patients. When a sample of 100 hospitals with pneumonia mortality rates above the 50th percentile recoded all eligible patients to sepsis or respiratory failure, 90 hospitals (95% CI, 84-95) improved their mortality rate (mean improvement, 1.09%; 95% CI, 0.94-1.28%) and 41 hospitals dropped below the 50th percentile (95% CI, 33-52). When a sample of 100 hospitals with pneumonia readmission rates above the 50th percentile recoded all eligible patients, 66 hospitals (95% CI, 54-75) improved their readmission rate (mean improvement, 0.34%; 95% CI, 0.19-0.45%) and 15 hospitals (95% CI, 9-22) dropped below the 50th percentile. CONCLUSIONS: Hospitals can improve apparent pneumonia mortality and readmission rates by recoding pneumonia patients. Centers for Medicare and Medicaid Services should consider changes to their methods used to calculate hospital-level pneumonia outcome measures to make them less susceptible to gaming. PMID- 25746748 TI - Association of cumulative dose of haloperidol with next-day delirium in older medical ICU patients. AB - OBJECTIVES: To evaluate the association between cumulative dose of haloperidol and next-day diagnosis of delirium in a cohort of older medical ICU patients, with adjustment for its time-dependent confounding with fentanyl and intubation. DESIGN: Prospective, observational study. SETTING: Medical ICU at an urban, academic medical center. PATIENTS: Age 60 years and older admitted to the medical ICU who received at least one dose of haloperidol (n = 93). Of these, 72 patients were intubated at some point in their medical ICU stay, whereas 21 were never intubated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Detailed data were collected concerning time, dosage, route of administration of all medications, as well as for important clinical covariates, and daily status of intubation and delirium using the confusion assessment method for the ICU and a chart-based algorithm. Among nonintubated patients, and after adjustment for time-dependent confounding and important covariates, each additional cumulative milligram of haloperidol was associated with 5% higher odds of next-day delirium with odds ratio of 1.05 (credible interval [CI], 1.02-1.09). After adjustment for time dependent confounding and covariates, intubation was associated with a five-fold increase in odds of next-day delirium with odds ratio of 5.66 (CI, 2.70-12.02). Cumulative dose of haloperidol among intubated patients did not change their already high likelihood of next-day delirium. After adjustment for time-dependent confounding, the positive associations between indicators of intubation and of cognitive impairment and next-day delirium became stronger. CONCLUSIONS: These results emphasize the need for more studies regarding the efficacy of haloperidol for treatment of delirium among older medical ICU patients and demonstrate the value of assessing nonintubated patients. PMID- 25746749 TI - Percutaneous cannulation for extracorporeal membrane oxygenation by intensivists: a retrospective single-institution case series. AB - OBJECTIVE: Extracorporeal membrane oxygenation provides support for patients with severe acute cardiopulmonary failure, allowing the application of lung or myocardial rest in anticipation of organ recovery, or as a bridge to long-term support. Advances in technology have improved the safety and ease of application of extracorporeal membrane oxygenation. Percutaneous cannulation is one of these advances and is now preferred over surgical cannulation in most cases. Percutaneous cannulation is increasingly performed by intensivists, cardiologists, interventional radiologists, and related specialties. The objective of this study is to review the experience of percutaneous cannulation by intensivists at a single institution. DESIGN: A retrospective review of 100 subjects undergoing percutaneous cannulation for extracorporeal membrane oxygenation. SETTING: Adult ICUs and PICUs at a tertiary academic medical institution. PATIENTS: Critically ill neonatal, pediatric, and adult subjects with severe respiratory and/or cardiac failure undergoing percutaneous cannulation for extracorporeal membrane oxygenation. Modes of support included venoarterial, venovenous, venovenoarterial, and arteriovenous. INTERVENTIONS: Percutaneous extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Case reports submitted to the Extracorporeal Life Support Organization and hospital records of the subjects were retrospectively reviewed. Subject demographics, type of support, cannulation configuration, types of cannulas, use of imaging modalities, and complications were recorded and summarized. One hundred ninety cannulations with cannula sizes from size 12 to 31F were performed by four intensivists in 100 subjects. Twenty-three were arterial (12-16F) and 167 were venous (12-31F). Preinsertion ultrasound was performed in 93 subjects (93%), fluoroscopic guidance in 79 subjects (85% of nonarteriovenous subjects), and ultrasound-guided insertion was performed in 65 subjects (65%). Two major complications occurred, each associated with mortality. Cannulation was successful in all other subjects (98% of subjects and 99% of cannulations). There were no cases of cannula-related bloodstream infection. CONCLUSIONS: Percutaneous cannulation for extracorporeal membrane oxygenation by intensivists can be performed with a high rate of success and a low rate of complications when accompanied by imaging support. PMID- 25746750 TI - Preface: crystallography. PMID- 25746751 TI - A novel dereplication strategy for the identification of two new trace compounds in the extract of Gastrodia elata using UHPLC/Q-TOF-MS/MS. AB - An ultra performance liquid chromatography (UHPLC) coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS/MS) was used in the structural determination of natural compounds in Gastrodia elata. A total of 64 compounds were identified or tentatively characterized. The strategy used for characterization was comparing their retention time and fragmentation behaviors with those of the reference standards, or investigating their accurate mass measurements and characteristic fragmentation patterns followed by low energy collision dissociation tandem mass spectrometry (CID-MS/MS). Phenolic conjugates mainly underwent consecutive losses of gastrodin residues and combined losses of H2O and CO2 from their citric acid units under negative MS/MS conditions. According to these rules, we have successfully characterized fifteen potential novel compounds. To confirm the reliability of this strategy, two targeted unknown trace parishins were obtained from G. elata by LC/MS-guided isolation. Based on the analysis of data from NMR spectroscopy and other techniques, the two unknown parishins were identified as 2-[4-O-(beta-d glucopyranosyl)benzyl]-3-methyl-citrate (parishin J) and 1,2-di-[4-O-(beta-d glucopyranosyl)benzyl]-3-methyl-citrate (parishin K), respectively. The fully established structures were consistent with the MS-oriented structural elucidation. This study expanded our knowledge on parishins in Gastrodia species, and the proposed strategy was proven efficient and reliable in the discovery of new minor compounds from herbal extracts. PMID- 25746752 TI - Systematic profiling of indole-3-acetic acid biosynthesis in bacteria using LC MS/MS. AB - Indole-3-acetic acid (IAA) is produced from tryptophan through five synthesis pathways. A comprehensive method for the quantification of IAA and biosynthesis related intermediates in a culture medium was developed. Sample preparation was simple with protein precipitation. The analytes were separated on a superficially porous C18 silica column and detected by electrospray ionization-tandem mass spectrometry in the positive ion multiple reaction monitoring mode. The limit of detection was 0.05 MUM, and the lower limits of quantification ranged from 0.05 to 2 MUM. The intra-day and inter-day precision and accuracy were less than 13.96%. Ion suppression was observed, and the deuterated internal standards were used to compensate for the matrix effect. The method was applied to analyze changes in tryptophan catabolism in a culture medium of Pseudomonas putida. The proposed method is robust and suitable for the systematic profiling of IAA biosynthesis in culture supernatant. PMID- 25746753 TI - In vivo study on the neurotransmitters and their metabolites change in depressive disorder rat plasma by ultra high performance liquid chromatography coupled to tandem mass spectrometry. AB - A sensitive and versatile, ultra-high performance, liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method coupled to pre-column derivatization for the simultaneous determination of 5-hydroxytryptamine (5-HT), 5 hydroxyindoleacetic acid (5-HIAA), dopamine (DA), norepinephrine (NE), homovanillic acid (HVA), gamma-aminobutyric acid (GABA) and glutamic acid (Glu) was developed and validated in rat plasma. The analytes were dansylated under strong alkaline conditions after protein precipitation extraction, which were analyzed on a BEH C18 column using a gradient elution. The lower limit of quantification (LLOQ) values for 5-HT, 5-HIAA, DA, NE, HVA, GABA and Glu were 1.00, 1.00, 0.991, 0.992, 1.02, 1000, and 5030 pmol/mL, respectively. Good linearity was obtained (r > 0.99) and the intra- and inter-day precisions of the method (relative standard deviation, RSD%) were lower than 12%. The method was novel, sensitive and specific which can provide an alternative method for the quantification of neurotransmitters and their metabolites in plasma samples. PMID- 25746754 TI - "Center punch" and "whole spot" bioanalysis of apixaban in human dried blood spot samples by UHPLC-MS/MS. AB - Apixaban (EliquisTM) was developed by Bristol-Myers Squibb (BMS) and Pfizer to use as an antithrombotic/anticoagulant agent and has been recently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. A clinical study of apixaban, sponsored by BMS and Pfizer, included a pilot exploratory portion to evaluate the potential for future drug concentration monitoring using dried blood spot (DBS) sample collection. For DBS sample collection, a fixed blood volume was dispensed onto a DBS card by either regular volumetric pipette (venous blood collection) or capillary dispenser (finger prick blood collection). A 96-well semi-automated liquid-liquid extraction sample preparation procedure was developed to provide clean extracts for UHPLC-MS/MS quantitation. Assays using both partial-spot center punch and whole spot punch were developed and validated. The linear dynamic ranges for all the analyses were from 0.5 to 500 ng/mL. The coefficient of determination (r(2)) values was >0.9944 for all the validation runs. For the center punch approach, the intra-assay precision (%CV) was within 4.4% and inter-assay precision was within 2.6%. The assay accuracy, expressed as %Dev., was within +/- 5.4% of the nominal concentrations. One accuracy and precision run was performed using the whole spot approach, the intra-assay precision (%CV) was within 7.1% and the accuracy was within +/- 8.0% of the nominal concentrations. In contrast to the center punch approach, the whole spot approach eliminated the effect of hematocrit and high lipids on the analysis of apixaban in human DBS when an accurate sample blood volume was collected on DBS cards. PMID- 25746755 TI - Electrochemical generation of selegiline metabolites coupled to mass spectrometry. AB - The metabolic pathways of selegiline (a drug used for the treatment of early stage Parkinson's disease) were analyzed by electrochemical oxidation with application of the flow electrochemical cell consisting of three electrodes (ROXYTM, Antec, the Netherlands). Two types of working electrodes were applied: glassy carbon (GC) and boron-doped diamond (BDD). The potential applied at working electrode and composition of the solvent were optimized for the best conditions for oxidation and identification processes. All products were directly analyzed on-line by mass spectrometry. For further characterization of electrochemical oxidation products, the novel approach involving reversed phase chromatography linked to mass spectrometry with dielectric barrier discharge ionization (DBDI-MS) was used. In this manuscript, we report a novel technique for simulation of drug metabolism by electrochemical system (EC) connected to liquid chromatography (LC) and dielectric barrier discharge ionization (DBDI) mass spectrometry (MS) for direct on-line detection of electrochemical oxidation products. Here, we linked LC/DBDI-MS system with an electrochemical flow cell in order to study metabolic pathways via identification of drug metabolites generated electrochemically. The DBDI source has never been used before for identification of psychoactive metabolites generated in an electrochemical flow cell. Our knowledge on the biological background of xenobiotics metabolism and its influence on human body is constantly increasing, but still many mechanisms are not explained. Nowadays, metabolism of pharmaceuticals is mainly studied using liver cells prepared from animals or humans. Cytochrome P450, present in microsomes, is primarily responsible for oxidative metabolism of xenobiotics. It was also shown, that breakdown of popular medicines may be successfully simulated by electrochemistry under appropriate conditions. The presented experiments allow for comparison of these two entirely distinct techniques using selegiline as the model xenobiotic with well-described metabolic pathway in human body. The obtained results for selegiline oxidation show that it is possible to generate the most important selegiline metabolites present in human body - some of them with psychoactive properties, such as methamphetamine and amphetamine. These metabolites, serving as an evidence of the xenobiotic intake, can also be produced, among a larger group of metabolites, by incubation of selegiline with rat and human liver microsomes. The EC/LC/DBDI-MS system provides novel, promising platform for drugs screening of the phase I metabolism. The metabolites can be detected directly by MS or collected and separated by liquid chromatography. PMID- 25746756 TI - Ligand-assisted elution chromatography for separation of lanthanides. AB - Lanthanides (Ln's) are the major components of rare earth elements, which are critical components of many high-value products. The ions of adjacent Ln's have the same valence and very similar ionic radii. They cannot be separated using conventional adsorption or ion exchange processes. Current production of high purity Ln's is based on multiple sequential and parallel solvent extraction processes, which require large amounts of toxic solvents and result in serious negative impact on the environment. In this study, a ligand-assisted elution chromatography process for the separation of Ln's was developed for the first time for titania, which is a robust and inexpensive inorganic sorbent. A selective ligand for Ln's, ethylenediaminetetraacetic acid (EDTA), was found to adsorb on the sorbent. The adsorbed EDTA became strong adsorption sites for the Ln's. Desorption of Ln's was driven by reversible reactions of Ln's with EDTA in the mobile phase. The overall sorbent selectivity for the reaction and adsorption process was approximately equal to the ratio of the sorbent selectivity to the ligand selectivity. The separation mechanisms were tested and verified using rate model simulations and experimental data for the separation of praseodymium (Pr), neodymium (Nd), and samarium (Sm). Simulations based on the model were used to design efficient linear gradient elution and stepwise elution processes. The purity and yield of all three Ln's were found to be above 95% in the designed processes. Stepwise elution can be implemented in a continuous process for increasing sorbent productivity and reducing costs for large-scale separation. Ligand assisted elution processes are much simpler and more environmentally friendly than the conventional solvent extraction processes. PMID- 25746757 TI - Chromatographic isolation of the functionally active MutS protein covalently linked to deoxyribonucleic acid. AB - DNA metabolism is based on formation of different DNA-protein complexes which can adopt various conformations. To characterize functioning of such complexes, one needs a solution-based technique which allows fixing a complex in a certain transient conformation. The crosslinking approach is a popular tool for such studies. However, it is under debate if the protein components retain their natural activities in the resulting crosslinked complexes. In the present work we demonstrate the possibility of obtaining pure DNA conjugate with functionally active protein using as example MutS protein from Escherichia coli mismatch repair system. A conjugate of a chemically modified mismatch-containing DNA duplex with MutS is fixed by thiol-disulfide exchange reaction. To perform a reliable test of the protein activity in the conjugate, such conjugate must be thoroughly separated from the uncrosslinked protein and DNA prior to the test. In the present work, we employ anion exchange chromatography for this purpose for the first time and demonstrate this technique to be optimal for the conjugate purification. The activity test is a FRET-based detection of DNA unbending. We show experimentally that MutS in the conjugate retains its ability to unbend DNA in response to ATP addition and find out for the first time that the DNA unbending rate increases with increasing ATP concentration. Since the crosslinked complexes contain active MutS protein, they can be used in further experiments to investigate MutS interactions with other proteins of the mismatch repair system. PMID- 25746758 TI - Purification of monoclonal antibody against Ebola GP1 protein expressed in Nicotiana benthamiana. AB - Monoclonal antibodies (mAbs) are one of the fastest growing drug molecules targeting the treatment of diseases ranging from arthritis, immune disorders, and infectious diseases to cancer. Due to its unique application principle, antibodies are commonly produced in large quantities. Plants, such as Nicotiana benthamiana, offer a unique production platform for bio-therapeutics due to their ability to produce large amounts of biomolecules in a relatively quick manner. However, purification of a target protein from plant is an arduous task due to the presence of toxic compounds in ground plant tissue and the large quantities of plant tissues to be processed. Here, a process was developed prior to the chromatographic purification of a mAb against Ebola GP1 protein expressed in N. benthamiana. The process includes a diafiltration step and a charged polyelectrolyte precipitation. The diafiltration step significantly improved the precipitation efficiency, reducing the usage of polyelectrolyte by more than 2000 fold while improving the native plant protein removed from 60% to 80%. The mAb can then be purified to near homogeneity judging from SDS-PAGE by either Protein A affinity chromatography or a tandem of hydrophobic interaction chromatography and a hydrophobic charge induction chromatography. The purified mAbs were shown to retain their binding specificity to irradiated Ebola virus. PMID- 25746760 TI - Screening for anabolic steroids in sports: analytical strategy based on the detection of phase I and phase II intact urinary metabolites by liquid chromatography tandem mass spectrometry. AB - In order to improve the detection capabilities of anabolic androgenic steroids (AAS) in sports, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening method for the simultaneous detection of AAS phase I and phase II intact urinary metabolites (glucuronides and sulfates) was developed. A total of 36 metabolites (7 unconjugated; 19 glucuronides and 10 sulfates) corresponding to 15 of the most reported AAS were included. Analytes were extracted from urine using C18 cartridges. LC and MS conditions were studied in-depth to determine the most sensitive and selective conditions for each analyte. A selected reaction monitoring method was set up. The optimization of the experimental parameters for 13 metabolites not available as standards was performed using excretion study urines. Extraction recoveries were above 77% for all 23 validated analytes. Intra day precision was lower than 21%, and LODs were in the range 0.25-4ng/mL for 18 of the 23 analytes. Matrix effect was evaluated using post column infusion and ranged from 92 to 147%. The method was successfully applied to excretion study urines of different exogenous AAS. The suitability of the strategy was demonstrated with methyltestosterone and stanozolol excretion study urines by achieving detection times of 22 and 21 days, respectively. The method is compliant with the World Antidoping Agency requirements for most of the studied compounds. It represents a cost-effective approach that improves the detection capabilities of AAS by increasing the sensitivity for some metabolites and by including recently described phase II long-term metabolites not detectable using the current screening strategy. PMID- 25746759 TI - Simultaneous determination of a variety of endocrine disrupting compounds in carrot, lettuce and amended soil by means of focused ultrasonic solid-liquid extraction and dispersive solid-phase extraction as simplified clean-up strategy. AB - The present study is focused on the development of an analytical method based on focused ultrasonic solid-liquid extraction (FUSLE) followed by dispersive solid phase extraction (dSPE) clean-up and liquid chromatography-triple quadrupole tandem mass spectrometry (LC-MS/MS) optimised for the simultaneous analysis of certain endocrine disrupting compounds (EDCs), including alkylphenols (APs), bisphenol A (BPA), triclosan (TCS) and several hormones and sterols in vegetables (lettuce and carrot) and amended soil samples. Different variables affecting the chromatographic separation, the electrospray ionisation and mass spectrometric detection were optimised in order to improve the sensitivity of the separation and detection steps. Under the optimised extraction conditions (sonication of 5min at 33% of power with pulse times on of 0.8s and pulse times off of 0.2s in 10mL of n-hexane:acetone (30:70, v:v) mixture using an ice bath), different dSPE clean-up sorbents, such as Florisil, Envi-Carb, primary-secondary amine bonded silica (PSA) and C18, or combinations of them were evaluated for FUSLE extracts before LC-MS/MS. Apparent recoveries and precision in terms of relative standard deviation (RSDs %) of the method were determined at two different fortification levels (according to the matrix and the analyte) and values in the 70-130% and 2 27% ranges, respectively, were obtained for most of the target analytes and matrices. Matrix-matched calibration approach and the use of labelled standards as surrogates were needed for the properly quantification of most analytes and matrices. Method detection limits (MDLs), estimated with fortified samples, in the ranges of 0.1-100ng/g for carrot, 0.2-152ng/g for lettuce and 0.9-31ng/g for amended soil were obtained. The developed methodology was applied to the analysis of 11 EDCs in both real vegetable bought in a local market and in compost (from a local wastewater treatment plant, WWTP) amended soil samples. PMID- 25746761 TI - A Lamb waves based statistical approach to structural health monitoring of carbon fibre reinforced polymer composites. AB - This research investigates a Lamb-wave based structural health monitoring approach matching an out-of-phase actuation of a pair of piezoceramic transducers at low frequency. The target is a typical quasi-isotropic carbon fibre reinforced polymer aeronautical laminate subjected to artificial, via Teflon patches, and natural, via suitable low velocity drop weight impact tests, delaminations. The performance and main influencing factors of such an approach are studied through a Design of Experiment statistical method, considering both Pulse Echo and Pitch Catch configurations of PZT sensors. Results show that some factors and their interactions can effectively influence the detection of a delamination-like damage. PMID- 25746762 TI - Urachal-colonic fistula: MR imaging and MDCT features. PMID- 25746763 TI - Selective killing of G2 decatenation checkpoint defective colon cancer cells by catalytic topoisomerase II inhibitor. AB - Cancer cells with defective DNA decatenation checkpoint can be selectively targeted by the catalytic inhibitors of DNA topoisomerase IIalpha (topo IIalpha) enzyme. Upon treatment with catalytic topo IIalpha inhibitors, cells with defective decatenation checkpoint fail to arrest their cell cycle in G2 phase and enter into M phase with catenated and under-condensed chromosomes resulting into impaired mitosis and eventually cell death. In the present work we analyzed decatenation checkpoint in five different colon cancer cell lines (HCT116, HT-29, Caco2, COLO 205 and SW480) and in one non-cancerous cell line (HEK293T). Four out of the five colon cancer cell lines i.e. HCT116, HT-29, Caco2, and COLO 205 were found to be compromised for the decatenation checkpoint function at different extents, whereas SW480 and HEK293T cell lines were found to be proficient for the checkpoint function. Upon treatment with ICRF193, decatenation checkpoint defective cell lines failed to arrest the cell cycle in G2 phase and entered into M phase without proper chromosomal decatenation, resulting into the formation of tangled mass of catenated and under-condensed chromosomes. Such cells underwent mitotic catastrophe and rapid apoptosis like cell death and showed higher sensitivity for ICRF193. Our study suggests that catalytic inhibitors of topoisomerase IIalpha are promising therapeutic agents for the treatment of colon cancers with defective DNA decatenation checkpoint. PMID- 25746764 TI - IL4 receptor alpha mediates enhanced glucose and glutamine metabolism to support breast cancer growth. AB - The type II interleukin-4 receptor (IL4R) is expressed in human breast cancer, and in murine models thereof. It is activated by interleukin-4 (IL4), a cytokine produced predominantly by immune cells. Previously, we showed that expression of IL4Ralpha, a signaling component of IL4R, mediates enhanced metastatic growth through promotion of tumor cell survival and proliferation. In lymphocytes, these processes are supported by increased glucose and glutamine metabolism, and B lymphocyte survival is dependent upon IL4/IL4R-induced glucose metabolism. However, it is unknown whether IL4R-mediated metabolic reprogramming could support tumor growth. Here, we show that IL4Ralpha expression increases proliferation thus enhancing primary mammary tumor growth. In vitro, IL4-enhanced glucose consumption and lactate production in 4T1 cells was mediated by IL4Ralpha. Expression of the glucose transporter GLUT1 increased in response to IL4 in vitro, and enhanced GLUT1 expression was associated with the presence of IL4Ralpha in 4T1 mammary tumors in vivo. Although IL4 treatment did not induce changes in glucose metabolism in MDA-MB-231 human breast cancer cells, it increased expression of the main glutamine transporter, ASCT2, and enhanced glutamine consumption in both MDA-MB-231 and 4T1 cells. Pharmacologic inhibition of glutamine metabolism with compound 968 blocked IL4/IL4Ralpha-increased cell number in both cell lines. Our results demonstrate that IL4R mediates enhanced glucose and glutamine metabolism in 4T1 cancer cells, and that IL4-induced growth is supported by IL4/IL4R-enhanced glutamine metabolism in both human and murine mammary cancer cells. This highlights IL4Ralpha as a possible target for effective breast cancer therapy. PMID- 25746765 TI - Correction of Hammer Toe Deformity of Lateral Toes With Subtraction Osteotomy of the Proximal Phalanx Neck. AB - Existing techniques for surgical treatment of hammer toe commonly combine skeletal and soft tissues interventions to obtain a durable correction of the deformity, balance the musculotendinous forces of flexion and extension of the toe, and normalization of the relations between interosseous muscles and metatarsal bones. The most common surgical techniques can provide the correction of the deformity through arthroplasty with resection of the head of the proximal phalanx or arthrodesis of the proximal interphalangeal joint. In most cases, these have been associated with elongation of the extensor apparatus, capsulotomy of the metatarsophalangeal joint, and stabilization with a Kirschner wire. To experiment with a technique that respects the anatomy and joint function, we used a distal subtraction osteotomy of the proximal phalanx neck. We evaluated a series of 40 patients, aged 18 to 82 years, who underwent surgery from January 2008 to December 2010. All patients were evaluated clinically and radiographically pre- and postoperatively and underwent examination at a mean final follow-up point of 24.4 (minimal 12, maximal 36) months. For the clinical evaluation, we used the American Orthopaedic Foot and Ankle Society score. The rate of excellent and good results was >90%. Compared with other techniques, this technique led to considerable correction, restoration of the biomechanical and radiographic parameters, and an adjunctive advantage of preserving the integrity of the proximal interphalangeal joint. Thus, our results have caused us to prefer this technique. PMID- 25746766 TI - Evaluation methods used on health information systems (HISs) in Iran and the effects of HISs on Iranian healthcare: a systematic review. AB - OBJECTIVES: The most important goal of a health information system (HIS) is improvement of quality, effectiveness and efficiency of health services. To achieve this goal, health care systems should be evaluated continuously. The aim of this paper was to study the impacts of HISs in Iran and the methods used for their evaluation. METHODS: We systematically searched all English and Persian papers evaluating health information systems in Iran that were indexed in SID, Magiran, Iran medex, PubMed and Embase databases until June 2013. A data collection form was designed to extract required data such as types of systems evaluated, evaluation methods and tools. RESULTS: In this study, 53 out of 1103 retrieved articles were selected as relevant and reviewed by the authors. This study indicated that 28 studies used questionnaires to evaluate the system and in 27 studies the study instruments were distributed within a research population. In 26 papers the researchers collected the information by means of interviews, observations, heuristic evaluation and the review of documents and records. The main effects of the evaluated systems in health care settings were improving quality of services, reducing time, increasing accessibility to information, reducing costs and decreasing medical errors. CONCLUSION: Evaluation of health information systems is central to their development and enhancement, and to understanding their effect on health and health services. Despite numerous evaluation methods available, the reviewed studies used a limited number of methods to evaluate HIS. Additionally, the studies mainly discussed the positive effects of HIS on health care services. PMID- 25746767 TI - Phylogenomic analysis of Emiliania huxleyi provides evidence for haptophyte stramenopile association and a chimeric haptophyte nuclear genome. AB - Emiliania huxleyi is a haptophyte alga of uncertain phylogenetic affinity containing a secondarily derived, chlorophyll c containing plastid. We sought to characterize its relationships with other taxa by quantifying the bipartitions in which it was included from a group of single protein phylogenetic trees in a way that allowed for variation in taxonomic content and accounted for paralogous sequences. The largest number of sequences supported a phylogenetic relationship of E. huxleyi with the stramenopiles, in particular Aureococcus anophagefferens. Far fewer nuclear sequences gave strong support to the placement of this coccolithophorid with the cryptophyte, Guillardia theta. The majority of the sequences that did support this relationship did not have plastid related functions. These results suggest that the haptophytes may be more closely allied with the heterokonts than with the cryptophytes. Another small set of genes associated E. huxleyi with the Viridiplantae with high support. While these genes could have been acquired with a plastid, the lack of plastid related functions among the proteins for which they code and the lack of other organisms with chlorophyll c containing plastids within these bipartitions suggests other explanations may be possible. This study also identified several genes that may have been transferred from the haptophyte lineage to the dinoflagellates Karenia brevis and Karlodinium veneficum as a result of their haptophyte derived plastid, including some with non-photosynthetic functions. PMID- 25746768 TI - Is the internet a reliable source of information for patients seeking total ankle replacement? AB - The modern patient population relies on the Internet to provide knowledge about medical procedures. However, a gap between established medical guidelines and the information provided on the Internet exists. Because of the general poor quality of the medical information available on the Internet and the increasing popularity of total ankle replacement (TAR) with its known potential serious complications, we undertook the present study to evaluate the information on TAR available to the general public through the Internet and to determine the quality of information according to authorship type and site certification status. Three common search engines were used to identify a total of 105 websites. The TAR information quality was rated as "excellent," "high," "moderate," "low," or "unacceptable." The sites were evaluated for authorship or sponsorship, content, and other criteria. The data were analyzed as a complete set, as a comparison among authorship types (academic, private, industry, or other), and by certification status. Websites with scores of excellent or high were 35% of the sites reviewed, and 48% were ranked as poor or unacceptable. Of the authorship types, the highest quality authorship was for the industry and other sites, which rated high or excellent 46% of the time. Eight percent of the sites evaluated were certified; however, certification status was not associated with improved information quality. Our study has demonstrated a low quality of TAR information available across all website types, regardless of authorship type. We suggest a partnership between professional organizations and physicians to ensure that provider websites reflect the current indications and contraindications of TAR to enhance patient education. PMID- 25746769 TI - Subtle lisfranc subluxation: results of operative and nonoperative treatment. AB - Subtle Lisfranc instability is typically a low-energy, twisting, axial-loading injury. The present study evaluated the operative treatment of subtle Lisfranc injuries after nonoperative failure. The data from consecutive patients with subtle Lisfranc instabilities were reviewed. Those in whom initial nonoperative treatment had failed underwent surgery. The American Orthopaedic Foot and Ankle Society (AOFAS) midfoot score was obtained initially, after nonoperative treatment, and, for those in whom nonoperative treatment had failed, after operative treatment. Of 36 patients enrolled, 16 (44.44%) were successfully treated nonoperatively, and 20 (55.56%) required surgery after nonoperative treatment had failed. Of those treated operatively, 9 (45%) were stabilized with dual screws and 11 (55%) with dual suture buttons. The mean follow-up period was 36 +/- 12.2 months. The AOFAS scores significantly improved from the pre- to final post-treatment values. The overall mean pretreatment AOFAS score (62.8 +/- 8.84) was significantly lower statistically than the mean overall post-treatment AOFAS score (91.3 +/- 8.34; p < .0001). The mean AOFAS score before nonoperative treatment (61.9 +/- 9.5) improved to a mean AOFAS score of 75.3 +/- 15.8 after nonoperative treatment (p = .0029). The mean preoperative AOFAS score (63.5 +/- 8.46) improved to a postoperative AOFAS score of 92.3 +/- 8.43 (p < .0001). The mean AOFAS score before nonoperative treatment (61.9 +/- 9.5) was not significantly different statistically from the mean preoperative AOFAS score (63.5 +/- 8.46; p = .62). The mean AOFAS score after nonoperative treatment (75.3 +/- 15.8) was lower than the mean postoperative AOFAS score (92.3 +/- 8.43; p < .0001). Of the 9 feet stabilized with dual screws, 7 (77.78%) required screw removal during the observation period. Subtle Lisfranc injuries failing nonoperative treatment were successfully stabilized using either a dual screw or suture button technique. PMID- 25746770 TI - Radiation therapy for recurrent heterotopic ossification prophylaxis after partial metatarsal amputation. AB - The formation of heterotopic ossification is a relatively common, yet rarely discussed, cause of re-ulceration after previous partial metatarsal amputation. Excessive bone growth at the amputation site has the potential to create an unwanted prominence on the weightbearing surface of the foot, intuitively increasing plantar pressure and placing the neuropathic patient at greater risk of re-ulceration and limb loss. The aim of the present study was to assess the efficacy of single-dose radiation therapy in preventing recurrent heterotopic ossification. The inclusion criteria consisted of a history of clinically relevant heterotopic ossification formation after partial metatarsal amputation with subsequent partial metatarsal amputation for heterotopic ossification resection, followed by prophylactic single-dose radiation therapy. Eleven consecutive patients meeting the inclusion criteria were identified for the present study. Before the intervention, 10 (91%) patients demonstrated formation of mid- to high-grade heterotopic ossification, and 9 (82%) patients exhibited an associated neuropathic ulceration. On follow-up at least 6 weeks after intervention, 2 (18%) patients exhibited low-grade heterotopic ossification reformation that was not clinically relevant and 9 (82%) did not show signs of heterotopic recurrence. Single-dose radiation therapy can help prevent the formation of heterotopic ossification in high-risk patients, acting as an effective adjunct to surgery in minimizing the risk of re-ulceration and re amputation in the neuropathic patient. PMID- 25746771 TI - First Tarsometatarsal Arthrodesis: An Anatomic Evaluation of Dorsomedial Versus Plantar Plating. AB - Fusion of the first tarsometatarsal joint is a widely used procedure for the correction of hallux valgus deformity. Although dorsomedial H-shaped plating systems are being increasingly used, fusion can also be achieved by plantar plating. The goal of the present study was to compare these 2 operative techniques based on the anatomic considerations and show the potential pitfalls of both procedures. Six pairs of deep-frozen human lower legs were used in the present cadaveric study. In a randomized manner, either dorsomedial arthrodesis or plantar plating through a medial incision was performed. With regard to arterial injury, the plantar technique resulted in fewer lesions (plantar, 4 injuries [66.7%] to the terminal branches of the first digital branch of the medial plantar artery; dorsomedial, 3 injuries [50%] to the main trunks of the plantar metatarsal arteries and the first dorsal metatarsal artery). With respect to injury to the veins, the plantar procedure affected significantly fewer high caliber subcutaneous trunk veins. The nerves coursing through the operative field, such as the saphenous and superficial fibular nerves, were compromised more often by the dorsal approach. Neither the plantar plating nor the dorsomedial plating technique was associated with injury to the insertion of the tibialis anterior muscle. Both studied techniques are safe, well-established procedures. Arthrodesis with plantar plating, however, offers additional advantages and is a reliable tool in the foot and ankle surgeon's repertoire. PMID- 25746772 TI - Hemiarthroplasty for Hallux Rigidus: Mid-Term Results. AB - Hallux rigidus is a progressive osteoarthritic condition affecting the first metatarsophalangeal joint that causes pain and stiffness, with a marked reduction in dorsiflexion. Joint arthrodesis has previously been the standard treatment of hallux rigidus; however, new surgical techniques have evolved and first metatarsophalangeal joint hemiarthroplasty is now a viable option. The present retrospective study reviewed the data from the 11 patients (12 feet) who had undergone first metatarsophalangeal joint hemiarthroplasty with the HemiCAP((r)) prosthesis. Postoperatively, all feet were clinically and radiologically assessed and scored using the hallux metatarsophalangeal-interphalangeal scale developed by the American Orthopaedic Foot and Ankle Society and the Foot and Ankle Disability Index score. Follow-up examinations were performed at a mean of 47 (range 36 to 48) months and showed a mean postoperative American Orthopaedic Foot and Ankle Society score of 66.5 (range 22 to 92) and mean Foot and Ankle Disability Index score of 63.7 (range 26.9 to 98.1). Of the 12 feet, 5 (41.7%) were reported to be pain free at the follow-up examination, 3 (25%) had mild pain, 2 (16.7%) had moderate, and 2 (16.7%) severe pain. Furthermore, 5 feet (42%) displayed no evidence of radiologic subsidence and 7 feet (58%) displayed a mean subsidence of 2.71 (range 1 to 6) mm. Hemiarthroplasty is designed to maintain the joint range of movement and allow easy conversion to arthrodesis, if required. In the present study, most patients continued to have a limited range of movement with only reasonable levels of satisfaction. Most patients continued to experience some level of pain postoperatively. The HemiCAP((r)) prosthesis has recently been adapted to include a dorsal flange. This might improve the range of dorsiflexion not seen with the traditional model. PMID- 25746773 TI - Molecular mechanisms linking amyloid beta toxicity and Tau hyperphosphorylation in Alzheimer's disease. AB - Neurofibrillary tangles (aggregates of cytoskeletal Tau protein) and senile plaques (aggregates mainly formed by amyloid beta peptide) are two landmark lesions in Alzheimer's disease. Some researchers have proposed tangles, whereas others have proposed plaques, as primary lesions. For a long time, these were thought of as independent mechanisms. However, experimental evidence suggests that both lesions are intimately related. We review here some molecular pathways linking amyloid beta and Tau toxicities involving, among others, glycogen synthase kinase 3beta, p38, Pin1, cyclin-dependent kinase 5, and regulator of calcineurin 1. Understanding amyloid beta and Tau toxicities as part of a common pathophysiological mechanism may help to find molecular targets to prevent or even treat the disease. PMID- 25746774 TI - Pterostilbene and allopurinol reduce fructose-induced podocyte oxidative stress and inflammation via microRNA-377. AB - High dietary fructose is an important causative factor in the development of metabolic syndrome-associated glomerular podocyte oxidative stress and injury. Here, we identified microRNA-377 (miR-377) as a biomarker of oxidative stress in renal cortex of fructose-fed rats, which correlated with podocyte injury and albuminuria in metabolic syndrome. Fructose feeding increased miR-377 expression, decreased superoxide dismutase (SOD) expression and activity, and caused O2(-) and H2O2 overproduction in kidney cortex or glomeruli of rats. This reactive oxygen species induction increased p38 MAPK phosphorylation and thioredoxin interacting protein (TXNIP) expression and activated the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome to produce interleukin-1beta in kidney glomeruli of fructose-fed rats. These pathological processes were further evaluated in cultured differentiated podocytes exposed to 5mM fructose, or transfected with miR-377 mimic/inhibitor and TXNIP siRNA, or co-incubated with p38 MAPK inhibitor, demonstrating that miR-377 overexpression activates the O2( )/p38 MAPK/TXNIP/NLRP3 inflammasome pathway to promote oxidative stress and inflammation in fructose-induced podocyte injury. Antioxidants pterostilbene and allopurinol were found to ameliorate fructose-induced hyperuricemia, podocyte injury, and albuminuria in rats. More importantly, pterostilbene and allopurinol inhibited podocyte miR-377 overexpression to increase SOD1 and SOD2 levels and suppress the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway activation in vivo and in vitro, consistent with the reduction of oxidative stress and inflammation. These findings suggest that miR-377 plays an important role in glomerular podocyte oxidative stress, inflammation, and injury driven by high fructose. Inhibition of miR-377 by antioxidants may be a promising therapeutic strategy for the prevention of metabolic syndrome-associated glomerular podocyte injury. PMID- 25746776 TI - Comprehensive computational analysis of leucine-rich repeat (LRR) proteins encoded in the genome of the diatom Phaeodactylum tricornutum. AB - We have screened the genome of the marine diatom Phaeodactylum tricornutum for gene models encoding proteins exhibiting leucine-rich repeat (LRR) structures. In order to reveal the functionality of these proteins, their amino acid sequences were scanned for known domains and for homologies to other proteins. Additionally, proteins were categorized into different LRR-families according to the variable sequence part of their LRR. This approach enabled us to group proteins with potentially similar functionality and to classify also LRR proteins where no characterized homologues in other organisms exist. Most interestingly, we were able to indentify several transmembrane LRR-proteins, which are likely to function as receptor-like molecules. However, none of them carry additional domains that are typical for mammalian or plant-like receptors. Thus, the respective signal recognition pathways seem to be substantially different in diatoms. Moreover, P. tricornutum encodes a family of secreted LRR proteins likely to function as adhesion or binding proteins as part of the extracellular matrix. Additionally, intracellular LRR-only proteins were divided into proteins similar to RasGTPase activators, regulators of nuclear transport, and mitotic regulation. Our approach allowed us to draw a detailed picture of the conservation and diversification of LRR proteins in the marine diatom P. tricornutum. PMID- 25746775 TI - Knockout of the ergothioneine transporter ETT in zebrafish results in increased 8 oxoguanine levels. AB - Ergothioneine (ET) is a natural compound that humans and other vertebrates must absorb from dietary sources. In general, ET is considered an intracellular antioxidant. However, the precise physiological purpose of ET and the consequences of ET deficiency are still unclear. The ergothioneine transporter ETT (human gene symbol SLC22A4) is a highly specific transporter for the uptake of ET. Here, we sought to identify and knock out ETT from zebrafish (Danio rerio) to determine the function of ET. We cloned and assayed three related proteins from zebrafish, only one of which catalyzed the uptake of ET. RT-PCR analysis revealed that the protein is strongly expressed in the skin, brain, kidney, intestine, and eye. In ETT-knockout animals generated by retroviral insertion into exon 1, ET content was reduced by more than 1000-fold compared to the wild type. Thus, ETT is the sole transporter responsible for uptake of ET into zebrafish. ETT-knockout fish did not exhibit obvious differences in morphology or behavior. In whole-fish homogenates, an increase in 4-hydroxy-2,3-trans-nonenal and malondialdehyde was observed, but only after stress caused by incubation with Pb(2+) or Cu(2+). Comparison of unstressed fish at the level of small molecules by LC-MS difference shading revealed a 3.8-fold increase in 8-oxoguanine (8-oxo 7,8-dihydroguanine) in the skin of ETT-knockout animals. Our knockout represents a new model for examining the consequences of complete absence of ET. Based on the phenotype observed here, we hypothesize that the specific purpose of ET could be to eliminate singlet oxygen. PMID- 25746777 TI - A randomized-controlled trial of an early minimal cognitive-behavioural therapy for insomnia comorbid with cancer. AB - OBJECTIVE: This study aimed to provide preliminary evidence on the efficacy of an early minimal cognitive-behavioural therapy for acute insomnia (mCBT-I) comorbid with cancer. METHOD: Thirty-eight patients (92% female; Mage 57; all Caucasian) with various types of cancer and having insomnia symptoms for less than 6 months were randomized to a self-administered mCBT-I condition (n=20; 6 short booklets + 3 phone consultations with a psychologist, over 6 weeks) or a no-treatment condition (n=18). Measures were completed at pre-treatment and post-treatment, as well as at 3- and 6-month follow-ups. RESULTS: All sleep parameters and the average dosage of hypnotics were significantly improved from pre- to post treatment among treated participants, but not in control participants. mCBT-I was also associated with a significantly greater reduction of anxiety and depression symptoms, maladaptive sleep habits, and erroneous beliefs about sleep, as well as with a significantly greater improvement of subjective cognitive functioning. A greater proportion of mCBT-I participants than controls met the criteria for a clinical remission at post-treatment. Therapeutic gains of mCBT-I were well sustained up to 6 months after the intervention. CONCLUSIONS: This study supports the efficacy of an early minimal CBT-I to treat acute insomnia comorbid with cancer. PMID- 25746778 TI - Recent Innovations at Nicotine & Tobacco Research. PMID- 25746780 TI - New beginnings. PMID- 25746779 TI - The Relations Between False Positive and Negative Screens and Smoking Cessation and Relapse in the National Lung Screening Trial: Implications for Public Health. AB - INTRODUCTION: Lung screening is an opportunity for smoking cessation and relapse prevention, but smoking behaviors may differ across screening results. Changes in smoking were evaluated among 18 840 current and former smokers aged 55-74 scheduled to receive three annual lung screenings. METHODS: Participants were randomized to low-dose computed tomography or single-view chest radiography in the American College of Radiology/National Lung Screening Trial. Outcome measures included point and sustained (6-month) abstinence and motivation to quit among smokers; and relapse among smokers who quit during follow-up, recent quitters (quit < 6 months), and long-term former smokers (quit >= 6 months). RESULTS: During five years of follow-up, annual point prevalence quit rates ranged from 11.6%-13.4%; 48% of current smokers reported a quit attempt and 7% of long-term former smokers relapsed. Any false positive screening result was associated with subsequent increased point (multivariable hazard ratio HR = 1.23, 95% CI = 1.13, 1.35) and sustained (HR = 1.28, 95% CI = 1.15, 1.43) abstinence among smokers. Recent quitters with >=1 false positive screen were less likely to relapse (HR = 0.72, 95% CI = 0.54, 0.96). Screening result was not associated with relapse among long-term former smokers or among baseline smokers who quit during follow up. CONCLUSIONS: A false positive screen was associated with increased smoking cessation and less relapse among recent quitters. Consistently negative screens were not associated with greater relapse among long-term former smokers. Given the Affordable Care Act requires most health plans to cover smoking cessation and lung screening, the impact and cost-effectiveness of lung screening could be further enhanced with the addition of smoking cessation interventions. PMID- 25746781 TI - Trial participants' understanding of randomization, double-blinding, and placebo use in low literacy populations: findings from a study conducted within a microbicide trial in Malawi. AB - Concerns have been raised about the limits of understanding of consent by clinical trial participants in developing countries. Consequently, this empirical study was conducted in Malawi to assess microbicide trial participants' understanding of randomization, double-blinding, and placebo use. The study used a combination of quantitative and qualitative methods, including structured questionnaire interviews with a random sample of 203 individual participants, four in-depth interviews with research nurses, and two focus group discussions with 18 study participants. Most respondents earned high scores on questions related to randomization (85%) and placebo use (72%), while a greater proportion of the same respondents obtained low scores on questions related to double blinding (68%) and personal implications of the study procedures (63%). Overall, most respondents (61%; n = 124) obtained low scores on combined understanding of all the three concepts under study. PMID- 25746782 TI - Undergraduate Consent Form Reading in Relation to Conscientiousness, Procrastination, and the Point-of-Time Effect. AB - Informed consent is central to conducting ethical research with human participants. The present study investigated differences in consent form reading in relation to conscientiousness, procrastination, and the point-of-time (PT) effect among undergraduate participants at a U.S. university. As hypothesized, conscientious participants and those who signed up to participate in a research study more days in advance and for earlier sessions (PT effect) read the consent form more thoroughly. However, procrastination was not related to consent form reading. Most importantly, consent form reading in general was poor, with 80% of participants demonstrating that they had not read the consent form. Conscientious participants were more likely to self-report reading the consent form, irrespective of their measured consent form reading. The article closes with suggestions to improve the process of obtaining informed consent with undergraduate participants. PMID- 25746783 TI - Attitudes and willingness to donate biological samples for research among potential donors in the Italian Twin Register. AB - Most ethical and social research is focused on disease-oriented biobanks, while healthy donors' motivation toward population biobanking is scarcely explored. We investigated willingness to donate biological samples for research and attitudes toward donation by a mail survey among 4,894 twins enrolled in the population based Italian Twin Register. We compared responses in different socio-demographic categories and estimated, by the twin design, environmental and genetic components of this attitude. More than 80% of respondents expressed willingness to donate. A prevailing collaborative attitude to donation emerged. Attitude was mainly influenced by individual social and cultural factors. Education was important in shaping motivation and willingness to donate. Future surveys of the general population are desirable to continue investigating attitude toward donation and concerns about biobanking. PMID- 25746784 TI - Informed consent, biobank research, and locality: perceptions of breast cancer patients in three European countries. AB - Comparative studies are missing that explore how socio-cultural and institutional circumstances influence patient comprehension and expectations regarding informed consent for current and future research on their tissue and data. This study compares how breast cancer patients in three European countries (the United Kingdom, Belgium, and Germany) who have consented to participate in tumor banking assess the given consent and the accompanying local contextual factors influencing it. Our survey demonstrates that only 59% of the patients in the British survey, but about 90% in the German and Belgian surveys, correctly recalled tissue and data donation for study purposes. Of those who remembered the study participation status correctly, about 90% had altruistic motives. At the same time, approximately half of the survey participants, or even 70% of the Belgians, expected personal benefit from research participation and information on cancer risk within the family. About half of the interviewees, but only 27% of the British participants, definitively wanted to be asked for re-consent for future research. Of the local contextual factors under study, participants' appraisals of medical science and data protection were particularly pertinent. More culturally and contextually sensitive comparative research is needed to better understand patient attitudes toward research participation and tissue donation in the context of biobank research. PMID- 25746785 TI - Professionals' attitudes regarding large-scale genetic information generated through next generation sequencing in research: a pilot study. AB - Under the auspices of a multi-national European scientific project involving whole genome sequencing, GEUVADIS, we set out to investigate the attitudes of the participating scientists of having their own genome sequenced. The views of such researchers on this subject have not been fully explored before and we utilized questionnaires and discussion groups to elicit their opinions. Many said that it was the first time that they had an opportunity to discuss ethical and social issues about sequencing. The many ongoing multi-national science projects present a good opportunity for social science research involving scientists and would benefit from rigorous research methodology, taking into account any language barriers. PMID- 25746786 TI - Toward ethical research practice with deaf participants. AB - In recent years, scholars have been critical of what they consider unethical conduct by researchers whose studies focus on members of the Deaf or signing communities. This is the first empirical study that investigates ethical concerns and recommendations from the perspective of three stakeholder groups (Deaf research participants, researchers, and Deaf studies experts). We analyzed focus group discussions using strategies from grounded theory and community-based participatory research. The themes we identified highlight the need for the broader scientific research community to include linguistically and culturally sensitive research procedures that more adequately protect the rights of Deaf research participants, as well as other marginalized groups. We address the need to increase the number of Deaf scientists and reconsider collaboration practices between Deaf and hearing researchers. PMID- 25746787 TI - Human research ethics committees in technical universities. AB - Human research ethics has developed in both theory and practice mostly from experiences in medical research. Human participants, however, are used in a much broader range of research than ethics committees oversee, including both basic and applied research at technical universities. Although mandated in the United States, the United Kingdom, Canada, and Australia, non-medical research involving humans need not receive ethics review in much of Europe, Asia, Latin America, and Africa. Our survey of the top 50 technical universities in the world shows that, where not specifically mandated by law, most technical universities do not employ ethics committees to review human studies. As the domains of basic and applied sciences expand, ethics committees are increasingly needed to guide and oversee all such research regardless of legal requirements. We offer as examples, from our experience as an ethics committee in a major European technical university, ways in which such a committee provides needed services and can help ensure more ethical studies involving humans outside the standard medical context. We provide some arguments for creating such committees, and in our supplemental article, we provide specific examples of cases and concerns that may confront technical, engineering, and design research, as well as outline the general framework we have used in creating our committee. PMID- 25746788 TI - Community-engaged research: cancer survivors as community researchers. AB - The personal rewards and challenges experienced by community researchers are not well explored. Training laypersons to be engaged in some or all aspects of community-engaged research is becoming more common, highlighting the need to understand the challenges associated with this role. The complexities of this role are magnified when the layperson has multiple identities of overlap with the research participant. In this brief report, we explore the rewards and challenges reported by 8 cancer survivors and 2 cancer caregivers who conducted interviews with 32 other survivors, caregivers, and health care professionals. We report specifically on data from their exit interviews regarding the experience of being a community researcher conducting research on a subject matter that was very personal. Overall, being a community researcher was a rewarding experience that allowed them to reflect critically on their own personal path and cancer experiences. Importantly, this role provided them with insights into cancer and other disparities in their community beyond their own situation. PMID- 25746789 TI - Heterogeneity in European research integrity guidance: relying on values or norms? AB - Similar forms of misconduct are perceived differently throughout Europe. There are no extensive surveys on the guidance on research integrity in the different countries of Europe. Therefore, we performed a systematic content analysis of (biomedical) research integrity guidance documents from all the countries of the European Economic Area. We show that there is strong heterogeneity concerning research integrity guidance on crucial aspects, for example, the defining of research misconduct, at both an international and a national level. We also sought to explain why the guidance documents differ by distinguishing the approaches that underlie them. We distinguished a value-based and a norm-based approach, as well as different perspectives on trust. The current confusing situation concerning research integrity guidance hampers international research and possibly wastes research funds. We risk talking past each other, if we do not take the distinction between these underlying approaches into account. PMID- 25746791 TI - Scientific review by the ethics committee. PMID- 25746792 TI - Teenagers want schools to give them more information about sex. PMID- 25746793 TI - Mesenchyme-specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation. AB - Previous studies showed that nucleolar protein 66 (NO66), the Jumonji C-domain containing histone demethylase for methylated histone H3K4 and H3K36 (H3K36me), negatively regulates osteoblast differentiation in vitro by inhibiting the activity of transcription factor osterix (Osx). However, whether NO66 affects mammalian skeletogenesis in vivo is not yet known. Here, we generated transgenic (TG) mice overexpressing a flag-tagged NO66 transgene driven by the Prx1 (paired related homeobox 1) promoter. We found that NO66 overexpression in Prx1 expressing mesenchymal cells inhibited skeletal growth and bone formation. The inhibitory phenotype was associated with >50% decreases in chondrocyte/osteoblast proliferation and differentiation. Moreover, we found that in bones of NO66-TG mice, expression of Igf1, Igf1 receptor (Igf1r), runt-related transcription factor 2, and Osx was significantly down-regulated (P < 0.05). Consistent with these results, we observed >50% reduction in levels of phosphorylated protein kinase B (Akt) and H3K36me3 in bones of NO66-TG mice, suggesting an inverse correlation between NO66 histone demethylase and the activity of IGF1R/Akt signaling. This correlation was further confirmed by in vitro assays of C2C12 cells with NO66 overexpression. We propose that the decrease in the IGF1R/Akt signaling pathway in mice with mesenchymal overexpression of NO66 may contribute in part to the inhibition of skeletal growth and bone formation. PMID- 25746795 TI - Loss of bone strength in HLA-B27 transgenic rats is characterized by a high bone turnover and is mainly osteoclast-driven. AB - OBJECTIVE: Although osteopenia is frequent in spondyloarthritis (SpA), the underlying cellular mechanisms and association with other symptoms are poorly understood. This study aimed to characterize bone loss during disease progression, determine cellular alterations, and assess the contribution of inflammatory bowel disease (IBD) to bone loss in HLA-B27 transgenic rats. METHODS: Bones of 2-, 6-, and 12-month-old non-transgenic, disease-free HLA-B7 and disease-associated HLA-B27 transgenic rats were examined using peripheral quantitative computed tomography, MUCT, and nanoindentation. Cellular characteristics were determined by histomorphometry and ex vivo cultures. The impact of IBD was determined using [21-3 x 283-2]F1 rats, which develop arthritis and spondylitis, but not IBD. RESULTS: HLA-B27 transgenic rats continuously lost bone mass with increasing age and had impaired bone material properties, leading to a 3-fold decrease in bone strength at 12 months of age. Bone turnover was increased in HLA-B27 transgenic rats, as evidenced by a 3-fold increase in bone formation and a 6-fold increase in bone resorption parameters. Enhanced osteoclastic markers were associated with a larger number of precursors in the bone marrow and a stronger osteoclastogenic response to RANKL or TNFalpha. Further, IBD-free [21-3 x 283-2]F1 rats also displayed decreased total and trabecular bone density. CONCLUSIONS: HLA-B27 transgenic rats lose an increasing amount of bone density and strength with progressing age, which is primarily mediated via increased bone remodeling in favor of bone resorption. Moreover, IBD and bone loss seem to be independent features of SpA in HLA-B27 transgenic rats. PMID- 25746796 TI - Monitoring in vivo (re)modeling: a computational approach using 4D microCT data to quantify bone surface movements. AB - Bone undergoes continual damage repair and structural adaptation to changing external loads with the aim of maintaining skeletal integrity throughout life. The ability to monitor bone (re)modeling would allow for a better understanding in how various pathologies and interventions affect bone turnover and subsequent bone strength. To date, however, current methods to monitor bone (re)modeling over time and in space are limited. We propose a novel method to visualize and quantify bone turnover, based on in vivo microCT imaging and a 4D computational approach. By in vivo tracking of spatially correlated formation and resorption sites over time it classifies bone restructuring into (re)modeling sequences, the spatially and temporally linked sequences of formation, resorption and quiescent periods on the bone surface. The microCT based method was validated using experimental data from an in vivo mouse tibial loading model and ex vivo data of the mouse tibia. In this application, the method allows the visualization of time resolved cortical (re)modeling and the quantification of short-term and long-term modeling on the endocortical and periosteal surface at the mid-diaphysis of loaded and control mice tibiae. Both short-term and long-term modeling processes, independent formation and resorption events, could be monitored and modeling (spatially not correlated formation and resorption) and remodeling (resorption followed by new formation at the same site) could be distinguished on the bone surface. This novel method that combines in vivo microCT with a computational approach is a powerful tool to monitor bone turnover in animal models now and is waiting to be applied to human patients in the near future. PMID- 25746794 TI - An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics. AB - There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm-inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine. PMID- 25746797 TI - Plant virus replication and movement. AB - Replication and intercellular spread of viruses depend on host mechanisms supporting the formation, transport and turnover of functional complexes between viral genomes, virus-encoded products and cellular factors. To enhance these processes, viruses assemble and replicate in membrane-associated complexes that may develop into "virus factories" or "viroplasms" in which viral components and host factors required for replication are concentrated. Many plant viruses replicate in association with the cortical ER-actin network that is continuous between cells through plasmodesmata. The replication complexes can be highly organized and supported by network interactions between the viral genome and the virus-encoded proteins. Intracellular PD targeting of replication complexes links the process of movement to replication and provides specificity for transport of the viral genome by the virus-encoded movement proteins. The formation and trafficking of replication complexes and also the development and anchorage of replication factories involves important roles of the cortical cytoskeleton and associated motor proteins. PMID- 25746799 TI - A systematic approach to novel virus discovery in emerging infectious disease outbreaks. AB - The discovery of novel viruses is of great importance to human health-both in the setting of emerging infectious disease outbreaks and in disease syndromes of unknown etiology. Despite the recent proliferation of many efficient virus discovery methods, careful selection of a combination of methods is important to demonstrate a novel virus, its clinical associations, and its relevance in a timely manner. The identification of a patient or an outbreak with distinctive clinical features and negative routine microbiological workup is often the starting point for virus hunting. This review appraises the roles of culture, electron microscopy, and nucleic acid detection-based methods in optimizing virus discovery. Cell culture is generally slow but may yield viable virus. Although the choice of cell line often involves trial and error, it may be guided by the clinical syndrome. Electron microscopy is insensitive but fast, and may provide morphological clues to choice of cell line or consensus primers for nucleic acid detection. Consensus primer PCR can be used to detect viruses that are closely related to known virus families. Random primer amplification and high-throughput sequencing can catch any virus genome but cannot yield an infectious virion for testing Koch postulates. A systematic approach that incorporates carefully chosen combinations of virus detection techniques is required for successful virus discovery. PMID- 25746798 TI - Technical reproducibility of single-nucleotide and size-based DNA biomarker assessment using DNA extracted from formalin-fixed, paraffin-embedded tissues. AB - DNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissues has been used in the past to analyze genetic polymorphisms. We evaluated the technical reproducibility of different types of assays for gene polymorphisms using DNA extracted from FFPE material. By using the MassARRAY iPLEX system, we investigated polymorphisms in DPYD (rs1801159 and rs3918290), UMPS (rs1801019), ERCC1 (rs11615), ERCC1 (rs3212986), and ERCC2 (rs13181) in 56 FFPE DNA samples. By using PCR, followed by size-based gel electrophoresis, we also examined TYMS 5' untranslated region 2R/3R repeats and GSTT1 deletions in 50 FFPE DNA samples and 34 DNAs extracted from fresh-frozen tissues and cell lines. Each polymorphism was analyzed by two independent runs. We found that iPLEX biomarker assays measuring single-nucleotide polymorphisms provided consistent concordant results. However, by using FFPE DNA, size-based PCR biomarkers (GSTT1 and TYMS 5' untranslated region) were discrepant in 32.7% (16/49, with exact 95% CI, 19.9% 47.5%; exact binomial confidence limit test) and 4.2% (2/48, with exact 95% CI, 0.5%-14.3%) of cases, respectively, whereas no discrepancies were observed using intact genomic DNA. Our findings suggest that DNA from FFPE material can be used to reliably test single-nucleotide polymorphisms. However, results based on size based PCR biomarkers, and particularly GSTT1 deletions, using FFPE DNA need to be interpreted with caution. Independent repeated assays should be performed on all cases to assess potential discrepancies. PMID- 25746801 TI - Effects of densities of brominated flame retardants on the detection response for HPLC analysis with a corona-charged aerosol detector. AB - Dependence of the response of a corona-charged aerosol detector (corona CAD) on the concentration and densities of brominated flame retardants and some related substrates was studied. The calibration curves of the substrates did not show linearity and the substrate with a lower density exhibited the stronger response. Regardless of the solvents (chloroform or toluene), and the injected volume of the substrate solution, the signal intensity of the substrate observed by a corona CAD was substantially proportional to 2/3 power law of concentration and proportional to (-2/3) power law of the density of the substrates. These results suggest that the responses should be proportional to the surface area of the particles generated through the drying process in corona CAD. Contrary to the former reports that the detector response of a corona CAD was independent of chemical species, it was proved that the response varies with the density of a substrate. PMID- 25746800 TI - 2beta- and 16beta-hydroxylase activity of CYP11A1 and direct stimulatory effect of estrogens on pregnenolone formation. AB - The biosynthesis of steroid hormones in vertebrates is initiated by the cytochrome P450 CYP11A1, which performs the side-chain cleavage of cholesterol thereby producing pregnenolone. In this study, we report a direct stimulatory effect of the estrogens estradiol and estrone onto the pregnenolone formation in a reconstituted in vitro system consisting of purified CYP11A1 and its natural redox partners. We demonstrated the formation of new products from 11 deoxycorticosterone (DOC), androstenedione, testosterone and dehydroepiandrosterone (DHEA) during the in vitro reaction catalyzed by CYP11A1. In addition, we also established an Escherichia coli-based whole-cell biocatalytic system consisting of CYP11A1 and its redox partners to obtain sufficient yields of products for NMR-characterization. Our results indicate that CYP11A1, in addition to the previously described 6beta-hydroxylase activity, possesses a 2beta-hydroxylase activity towards DOC and androstenedione as well as a 16beta-hydroxylase activity towards DHEA. We also showed that CYP11A1 is able to perform the 6beta-hydroxylation of testosterone, a reaction that has been predominantly attributed to CYP3A4. Our results are the first evidence that sex hormones positively regulate the overall production of steroid hormones suggesting the need to reassess the role of CYP11A1 in steroid hormone biosynthesis and its substrate-dependent mechanistic properties. PMID- 25746802 TI - Integration of a reconstituted cell-free protein-synthesis system on a glass microchip. AB - Recently, a cell-free protein synthesis system reconstituted solely from essential elements of the Escherichia coli translation system, termed protein synthesis using recombinant elements (PURE), has been widely used in synthetic biology to analyze fundamental life systems. Here, the system was integrated on a glass microchip system to construct a simple protein synthesis system. GFP template DNAs were immobilized on Sepharose microbeads by streptavidin-biotin binding. The beads were introduced into a Y-shaped microchannel in a glass microchip with a 10-MUm height dam structure, and a PURE system reaction mixture was flowed through the microchannel. The recovered solutions had a higher fluorescent intensity than that of the reaction mixture before its introduction into the microchannel, thus verifying that GFP synthesis had been achieved. The microchip with DNA immobilized microbeads is reusable. This is advantageous over a conventional in vitro protein synthesis protocol requiring the preparation and addition of template DNA or mRNA into the reaction mixtures in aspect of simpleness and rapidness. PMID- 25746803 TI - Silicon nanowire biosensor for highly sensitive and multiplexed detection of oral squamous cell carcinoma biomarkers in saliva. AB - Silicon nanowire (SiNW) field-effect transistor (FET) biosensors have already been used as powerful sensors for the direct detection of disease-related biomarkers. However, the multiplexed detection of biomarkers in real samples is still challenging. Interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF alpha) are two typical biomarkers of oral squamous cell carcinoma (OSCC). In this study, we developed a multiplexed detection methodology for IL-8 and TNF-alpha detection in saliva using SiNW FET biosensors. We fabricated the SiNW FET sensors using a top-down lithography fabrication technique. Subsequently, we achieved the multiplexed detection of two biomarkers in saliva by specific recognition of the two biomarkers with their corresponding antibodies, which were modified on the SiNW. The established method was found to have a limit of detection as low as 10 fg/mL in 1 * PBS as well as 100 fg/mL in artificial saliva. Because of its advantages, including label-free and multiplexed detection, non-invasive analysis, highly sensitive and specific determination, the proposed method is expected to be widely used for the early diagnosis of OSCC. PMID- 25746804 TI - Rapid and direct compositional analysis of poly(3-hydroxybutyrate-co-3 hydroxyvalerate) in whole bacterial cells by thermally assisted hydrolysis and methylation-gas chromatography. AB - Thermally assisted hydrolysis and methylation-gas chromatography (THM-GC) in the presence of an organic alkali was applied to the direct analysis of copolymer composition for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-3HV)] accumulated in whole bacterial cells. Cupriavidus necator was grown on a liquid medium with different molar ratios of valeric acid (V) to glucose (G) in order to control the compositions of P(3HB-co-3HV) produced in the cells. Trace amounts (0.03 mg) of dried Cupriavidus necator cells were directly subjected to THM-GC in the presence of tetramethylammonium hydroxide (TMAH) at 400 degrees C. The obtained chromatograms clearly showed nine characteristic peaks, attributed to the THM products from 3HB and 3HV units in the polymer chains, without any appreciable interference by the bacterial matrix components. Based on these peak intensities, the copolymer compositions were determined rapidly without using any cumbersome sample pretreatment. Moreover, the compositions thus obtained were in good agreement with those obtained by the conventional technique. PMID- 25746805 TI - Simple and rapid separation of soyasaponin Bb from a soy extract. AB - A simple method to separate soyasaponin Bb from a soy extract is presented. This method is based on the difference in the solubility of soyasaponin Bb and Ba and other components into 3:7 and 1:1 (v/v) acetone-water mixed solvents. The crude soyasaponin consisting of soyasaponins Aa, Ab, Ba, and Bb at the 10 wt% level and other components was examined as the soy extract. A 10 mg quantity of the crude soyasaponin was mixed with 1 mL of the 3:7 acetone-water containing 0.1 mol/L HCl, and the supernatant was removed to obtain a precipitate, which was found to contain mainly soyasaponins Bb and Ba. The precipitate was mixed with 0.4 mL of the 1:1 acetone-water containing 0.1 mol/L HCl; the supernatant was transferred, and was mixed with 0.6 mL of water to obtain a precipitate, which was found to contain mainly soyasaponin Bb. The yield was ca. 30%, which may be much higher than that by the conventional preparative chromatographic approach. The separation method is rapid and easy to carry out, and is useful for the preparation of a soyasaponin Bb sample. PMID- 25746806 TI - Evaluation of column carryover of phosphorylated peptides and fumonisins by duplicated solvent gradient method in liquid chromatography/tandem mass spectrometry. AB - Columns made of three different materials were evaluated with regard to the carryover of phosphorylated peptides and fumonisins in liquid chromatography/tandem mass spectrometry (LC/MS/MS). In order to eliminate carryover caused by the injection operation in the autosampler, the column carryover was calculated using the duplicated solvent gradient method. A column made of a glass-lined stainless-steel tube and polyethylene frits (GL-PE column) yielded the most significant improvements in the peak shape and the carryover as compared to the other columns. The carryover of fumonisin B1 (FB1) and HLADLSpK (T19p) in the GL-PE column could be reduced; the lower limit of quantitation of T19p, and the range of the calibration curve were also improved. Since carryover peaks with the GL-PE column were symmetrical peaks of the samples, carryover in the column did not occur. The carryover calculated by the duplicated solvent gradient method corresponded to those in the flow path from the injection port to the inlet frit of the column. The carryover value of FB1 in the column with a stainless-steel tube and stainless-steel frits (S-S column) was 1.70%, and that of the flow path was 0.23%. We found that the majority of the carryover in our system occurred in the S-S column. PMID- 25746807 TI - Determination of formaldehyde in aqueous samples with a miniaturized extraction capillary coupled to high-performance liquid chromatography. AB - A novel analytical method for determining formaldehyde (FA) in aqueous samples was developed with a miniaturized extraction capillary in high-performance liquid chromatography (HPLC). The extraction capillary was prepared by packing silica gel particles in a stainless steel capillary of 0.8 mm i.d. and 1.6 mm o.d. A derivatization reagent of 2,4-dinitrophenylhydrazine (DNPH) was impregnated on the silica gel particles by pumping a solution of DNPH to the capillary. Two extraction methods; dynamic extraction and purge-and-trap (PT) methods, were investigated for derivatizing and extracting FA from water samples onto the silica gel in the extraction capillary. The extraction capillary was directly connected to a six-port valve, and then desorption of the derivative from the capillary and injection to conventional HPLC system were simultaneously achieved with a flow of acetonitrile through the capillary. In the dynamic extraction, FA was determined with a simple sample preparation procedure, and the limit of detection (LOD) was 18 MUg L(-1) at a sample volume of 20 mL, while several limitations were found in the method, such as bleeding of the derivatization reagent and the corresponding derivatized FA from the capillary during the sample load/extraction process. The sensitivity was significantly improved by introducing a PT technique, where the LOD was 6.9 MUg L(-1) at a sample volume of 20 mL with a sampling time of approximately 20 min. With the PT method, successful recoveries of FA were confirmed for spiked tap water, river water and fruit juice samples. PMID- 25746808 TI - Spectroscopic characteristics of spiral flow ICP for axially viewing ICP optical emission spectrometry. AB - Spectroscopic characteristics of a spiral flow inductively coupled plasma (ICP), which could be sustained stably at 9 L min(-1) of Ar plasma gas flow rate with 1.5 kW RF forward power, were studied for axially viewing ICPOES. The emission intensity profile, excitation temperature and plasma robustness were evaluated, and were similar to those of the standard ICP. The background and emission intensities of elements as well as the excitation behavior for both atom and ion lines were also examined and compared to those of the standard ICP. Since the spectroscopic characteristics of the spiral flow ICP were similar to those of the standard ICP, it could be used as a new low gas flow ICP in axially viewing ICPOES. PMID- 25746809 TI - Development of a mercury detection kit based on melamine-functionalized gold nanoparticles. AB - A fast and simple mercury detection kit was developed based on melamine functionalized gold nanoparticles (GNPs). The detection kit contained reagent 1 (GNPs), reagent 2 (melanine), a reaction cuvette with four separated cells, a colorimetric card and a plastic pipette. The GNPs were prepared by a citrate reduction of HAuCl4. A proper amount of melamine was applied to functionalize the GNPs. The complex reaction took place in the present of Hg(2+) in the test samples, leading to the combination of Hg(2+) with the C=N group of melamine located on the surface of the GNPs. This reaction resulted in damage to the stability of colloid gold, and the aggregation of GNPs occurred. Different color changes (from claret-red to lilac, purple and plum) were displayed with different concentrations of Hg(2+) in the test samples. It was very easy and convenient to determine the amount of mercury ion by the naked eye. The advantages of this methodology are listed as follows: a short detecting time (within 10 min), a high specificity (no significant interference was indicated upon adding a certain amount of Cu(2+), Pb(2+), Zn(2+), Mg(2+), Cd(2+) and Fe(2+)), high sensitivity with a detection limit of 0.01 mg L(-1) , easy operation and practical on-site use. PMID- 25746810 TI - A novel dispersive liquid-liquid microextraction method based on solidification of floating organic drop for preconcentration of Pd(II) by graphite furnace atomic absorption spectrometry after complexation by a thienyl substituted 1,2 ethanediamine. AB - A novel dispersive liquid-liquid microextraction method based on solidification of floating organic drop (DLLME-SFO) was developed for the preconcentration of ultratrace amounts of palladium (Pd)(II) before its determination by electrothermal atomic absorption spectrometry. Diphenyl ether (m.p. 26 degrees C) was used for the first time as a heavier than water organic solvent in the developed method. Pd was complexed by N,N'-bis(thiophen-2-ylmethylene)ethane-1,2 diamine to be extracted into the dispersed diphenyl ether phase using acetonitril as the disperser solvent. Upon cooling and centrifugation, the organic solvent was sedimented at the bottomn and the aqueous phase was easily decantated. Some factors influencing the extraction efficiency of Pd(II) and its subsequent determination, including extraction and dispersive solvent type and volume, pH of sample solution, concentration of the chelating agent and salting out effect, were studied and optimized both with univariate and multivariate methods. Under the optimized conditions, the calibration graph exhibited linearity over a range of 10 - 120 MUg L(-1). The enrichment factor was 83.3, the detection limit for Pd (3sigma) was 47 ng L(-1) and the relative standard deviation was 3.2% (n = 10, 1 ng mL(-1)). The method was successfully applied to the determination of trace amounts of Pd(II) in water samples. PMID- 25746811 TI - Improved spectrophotometric analysis of fullerenes C60 and C70 in high-solubility organic solvents. AB - Fullerenes are among a number of recently discovered carbon allotropes that exhibit unique and versatile properties. The analysis of these materials is of great importance and interest. We present previously unreported spectroscopic data for C60 and C70 fullerenes in high-solubility solvents, including error bounds, so as to allow reliable colorimetric analysis of these materials. The Beer-Lambert-Bouguer law is found to be valid at all wavelengths. The measured data were highly reproducible, and yielded high-precision molar absorbance coefficients for C60 and C70 in o-xylene and o-dichlorobenzene, which both exhibit a high solubility for these fullerenes, and offer the prospect of improved extraction efficiency. A photometric method for a C60/C70 mixture analysis was validated with standard mixtures, and subsequently improved for real samples by correcting for light scattering, using a power-law fit. The method was successfully applied to the analysis of C60/C70 mixtures extracted from fullerene soot. PMID- 25746812 TI - Streptococcus mutans sortase A inhibitory metabolites from the flowers of Sophora japonica. AB - A new maltol derivative (2) along with three known maltol derivative (1) and flavonol glycosides (3 and 4) were isolated from the dried flowers of Sophora japonica. Based upon the results of combined spectroscopic methods, the structure of new compound (2) was determined to be maltol-3-O-(4'-O-cis-p-coumaroyl-6'-O-(3 hydroxy-3-methylglutaroyl))-beta-glucopyranoside, an isomer of 1. These compounds strongly inhibited the action of sortase A (SrtA) from Streptococcus mutans, a primary etiologic agent of human dental caries. The onset and magnitude of inhibition of the saliva-induced aggregation in S. mutans treated with compound 2 (4*IC50) were comparable to the behavior of untreated srtA-deletion mutant. PMID- 25746813 TI - SAH derived potent and selective EZH2 inhibitors. AB - A series of novel enhancer of zeste homolog 2 (EZH2) inhibitors was designed based on the chemical structure of the histone methyltransferase (HMT) inhibitor SAH (S-adenosyl-l-homocysteine). These nucleoside-based EZH2 inhibitors blocked the methylation of nucleosomes at H3K27 in biochemical assays employing both WT PRC2 complex as well as a Y641N mutant PRC2 complex. The most potent compound, 27, displayed IC50's against both complexes of 270 nM and 70 nM, respectively. To our knowledge, compound 27 is the most potent SAH-derived inhibitor of the EZH2 PRC2 complex yet identified. This compound also displayed improved potency, lipophilic efficiency (LipE), and selectivity profile against other lysine methyltransferases compared with SAH. PMID- 25746814 TI - Discovery of novel S1P2 antagonists. Part 1: discovery of 1,3-bis(aryloxy)benzene derivatives. AB - The structure-activity relationships of a novel series of sphingosine-1-phosphate receptor antagonists have been examined in detail. The initial hit compound 1 was modified through synthesis to improve its S1P2 activity. The synthesis of a series of analogs revealed that 1,3-bis(aryloxy)benzene derivatives, as represented by 22, are potent and selective S1P2 antagonists. PMID- 25746815 TI - Benzofused hydroxamic acids: useful fragments for the preparation of histone deacetylase inhibitors. Part 2: 7-fluorobenzothiophenes and benzofurans. AB - In the search for a new class of histone deacetylase inhibitors, we prepared a series of very simple benzofused hydroxamic acids to find an anchoring fragment of minimal molecular weight: they showed very good ligand efficiencies. Following these findings, classical fragment growing work was performed to increase binding energy and selective cytotoxicity. In the second phase of the work, information from the SARs of the benzothiophene series and data available in literature, we explored the in vitro pharmacological properties of the 6-substituted-7-fluoro benzothiophene hydroxamates and the 5-susbtituted-benzofuran hydroxamates. PMID- 25746816 TI - Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities. AB - Several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. The new compounds were tested for their activities against one strain of the causative organism of Malaria tropica, Plasmodium falciparum K1, which is resistant against chloroquine and pyrimethamine. In addition, their cytotoxicity and their activity against the pathogen of the East African form of sleeping sickness, Trypanosoma brucei rhodesiense, were investigated. Structure-activity relationships are discussed considering data of readily prepared compounds. For the first time, a distinct in vivo activity was observed against Plasmodium berghei in a mouse model. The active compound was further investigated. PMID- 25746817 TI - Enrichment design with patient population augmentation. AB - Clinical trials can be enriched on subpopulations that may be more responsive to treatments to improve the chance of trial success. In 2012 FDA issued a draft guidance to facilitate enrichment design, where it pointed out the uncertainty on the subpopulation classification and on the treatment effect outside of the identified subpopulation. We consider a novel design strategy where the identified subpopulation (biomarker-positive) is augmented by some biomarker negative patients. Specifically, after sufficiently powering biomarker-positive subpopulation we propose to enroll biomarker-negative patients, enough to assess the overall treatment benefit. We derive a weighted statistic for this assessment, correcting for the disproportionality of biomarker-positive and biomarker-negative subpopulations under enriched trial setting. Screening information is utilized for weight determination. This statistic is an unbiased estimate of the overall treatment effect as that in all-comer trials, and is the basis to power for the overall treatment effect. For analysis, testing will be first performed on biomarker-positive subpopulation; only if treatment benefit is established in this subpopulation will overall treatment effect be tested using the weighted statistic. This design approach differs from typical enrichment design or stratified all-comer design in that the former enrolls only biomarker positive patients and the latter enrolls a regular all-comer population. It also differs from adaptive enrichment by maintaining the trial design and analysis priority on biomarker-positive subpopulation. Therefore the proposed approach not only warrants a high probability of trial success on biomarker-positive subpopulation, but also efficiently assesses the overall treatment effect in the presence of an uncertain treatment benefit among biomarker-negative patients. PMID- 25746818 TI - Rapid human immunodeficiency virus disease progression is associated with human leukocyte antigen-B homozygocity and human leukocyte antigen-B51 in a cohort from Manitoba, Canada. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection is associated with variable rates of disease progression, influenced by the quality of CD8 T lymphocyte response, which is determined by human leukocyte antigen (HLA) I alleles. Some individuals progress slowly and maintain viral control, while at the opposite end of the spectrum some individuals endure a faster progression with rapid CD4 decline. We sought to determine the role of HLA-B allele frequency on rapid HIV disease progression. It was hypothesized that rapid progression is associated with the presence of high allele frequency of HLA-B35 and HLA-B homozygocity. METHODS: This retrospective cohort study was conducted in the Manitoba HIV Program, Health Sciences Centre, a tertiary care facility in Winnipeg, Manitoba, Canada. We defined a set of new criteria to describe a subset of individuals with the most rapid HIV disease progression, and collected demographic, clinical, laboratory (CD4 count, viral load) and HLA data on a subset of 20 individuals meeting these criteria. RESULTS: Among those individuals who display extreme rapid progression, an overrepresentation of Aboriginal ethnicities, high frequencies of HLA-B35 and significantly higher rates of HLA B51, as well as a very high rate of homozygocity for HLA-B alleles, were observed. CONCLUSIONS: Individuals with the most rapid disease progression have higher rates of HLA-B homozygocity, HLA-B51 alleles and higher viral loads than those with normal progression rates. This group, at the extreme end of the spectrum of progression, should be targeted for early treatment. PMID- 25746820 TI - Poverty, inequality and a political economy of mental health. AB - The relationship between poverty and mental health is indisputable. However, to have an influence on the next set of sustainable global development goals, we need to understand the causal relationships between social determinants such as poverty, inequality, lack of education and unemployment; thereby clarifying which aspects of poverty are the key drivers of mental illness. Some of the major challenges identified by Lund (2014) in understanding the poverty-mental health relationship are discussed including: the need for appropriate poverty indicators; extending this research agenda to a broader range of mental health outcomes; the need to engage with theoretical concepts such as Amartya Sen's capability framework; and the need to integrate the concept of income/economic inequality into studies of poverty and mental health. Although income inequality is a powerful driver of poor physical and mental health outcomes, it features rarely in research and discourse on social determinants of mental health. This paper interrogates in detail the relationships between poverty, income inequality and mental health, specifically: the role of income inequality as a mediator of the poverty-mental health relationship; the relative utility of commonly used income inequality metrics; and the likely mechanisms underlying the impact of inequality on mental health, including direct stress due to the setting up of social comparisons as well as the erosion of social capital leading to social fragmentation. Finally, we need to interrogate the upstream political, social and economic causes of inequality itself, since these should also become potential targets in efforts to promote sustainable development goals and improve population (mental) health. In particular, neoliberal (market-oriented) political doctrines lead to both increased income inequality and reduced social cohesion. In conclusion, understanding the relationships between politics, poverty, inequality and mental health outcomes requires us to develop a robust, evidence based 'political economy of mental health.' PMID- 25746819 TI - The effects of regular consumption of a multiple micronutrient fortified milk beverage on the micronutrient status of school children and on their mental and physical performance. AB - Multiple micronutrient deficiencies exist in school going children in India and bridging the gap between nutrient intake and requirements is an effective way to combat the deficiencies. This study aimed to test the effect of a multi micronutrient fortified malt and cocoa based milk beverage on the micronutrient status, cognition, physical performance and nutritional deficiencies of 7-10 years old south Indian children. A randomized, double blind placebo controlled study design was used with normal healthy children from low to middle income families, aged 7-10 years randomly assigned to receive either a multi micronutrient fortified or an unfortified milk based control drink. The drinks were provided 6 days/week for 5 months. Assessments included anthropometry, blood biochemistry, physical performance and cognition at baseline and endline. The baseline characteristics of the study groups were similar. The changes in body weight and height were similar between the groups at the end of the study. Levels of vitamin B12, red cell folate and vitamin B2 significantly improved in the intervention group, while vitamin D, selenium and body iron showed no difference. The Hemoglobin (Hb) and serum ferritin levels of the control group decreased at endline, while those in the intervention group maintained their levels. The serum transferrin receptor levels increased in both the groups. The prevalence of iron deficiency and Vitamin B2 deficiency were significantly lower in the intervention group at endline. Overall improvement in cognitive and physical performance was seen in both the groups at endline, with no significant differences between the groups. The micronutrient fortified milk based drink was efficacious in improving the micronutrient status of Vitamin B2, Vitamin B12 and red cell folate and in preventing a decline in Hb level compared to an unfortified milk based drink. It also reduced anemia and the risk of deficiencies of iron, and B12, in apparently healthy children. ClinicalTrials.gov IdentifierNCT01415557. Clinical Trial RegistryIndia - REF/2012/12/004332. PMID- 25746821 TI - Longitudinal mathematics development of students with learning disabilities and students without disabilities: a comparison of linear, quadratic, and piecewise linear mixed effects models. AB - Effective instructional planning and intervening rely heavily on accurate understanding of students' growth, but relatively few researchers have examined mathematics achievement trajectories, particularly for students with special needs. We applied linear, quadratic, and piecewise linear mixed-effects models to identify the best-fitting model for mathematics development over elementary and middle school and to ascertain differences in growth trajectories of children with learning disabilities relative to their typically developing peers. The analytic sample of 2150 students was drawn from the Early Childhood Longitudinal Study - Kindergarten Cohort, a nationally representative sample of United States children who entered kindergarten in 1998. We first modeled students' mathematics growth via multiple mixed-effects models to determine the best fitting model of 9 year growth and then compared the trajectories of students with and without learning disabilities. Results indicate that the piecewise linear mixed-effects model captured best the functional form of students' mathematics trajectories. In addition, there were substantial achievement gaps between students with learning disabilities and students with no disabilities, and their trajectories differed such that students without disabilities progressed at a higher rate than their peers who had learning disabilities. The results underscore the need for further research to understand how to appropriately model students' mathematics trajectories and the need for attention to mathematics achievement gaps in policy. PMID- 25746822 TI - Self-monitoring as a viable fading option in check-in/check-out. AB - This study systematically replaced the teacher completed Daily Behavior Report Card (DBRC) and feedback component of check-in/check-out (CICO) with self monitoring for four elementary students referred for Tier 2 behavioral supports within School-Wide Positive Behavior Interventions and Supports (SWPBIS). An ABAB withdrawal design was used to test the effectiveness of CICO. Then, following the second B phase, teacher completion of the DBRC and corresponding feedback to students was replaced with self-monitoring. For all four participants, CICO was associated with increases in academic engagement and reductions in disruptive behavior. Moreover, students' behavioral gains were maintained when teacher completion of the DBRC was replaced with self-monitoring. Results are discussed in terms of CICO research and practice. PMID- 25746823 TI - Profiles of classroom behavior in high schools: associations with teacher behavior management strategies and classroom composition. AB - Although there has been considerable attention to the issue of classroom management and processes in educational reform models, there has been relatively limited research on these factors in high schools. The current study utilized observational data from 1262 classrooms in 52 high schools to examine teacher classroom management strategies and ratings of student compliance, engagement, and social disruption. Latent profile analysis (LPA) was conducted to examine specific patterns of classroom-wide student behavior in relation to teachers' use of classroom management strategies and classroom composition. The LPA revealed three distinct classroom behavioral profiles where students consistently met behavioral expectations (71%), inconsistently met expectations (23%), and were noncompliant (6%). Analyses indicated a functional association between patterns of student behavior and teachers' classroom management. In classrooms where students consistently met expectations, teachers provided more opportunities to respond and less disapproval and reactive behavioral management. Classrooms with noncompliant students had teachers who used the most disapproval and reactive behavior management. In addition, classrooms characterized as consistent had fewer males and more White students than classrooms characterized by inconsistent and noncompliant behaviors. These findings highlight the link between student patterns of behavior and teacher classroom management and have important implications for screening and professional development. PMID- 25746824 TI - A comparative analysis of massed vs. distributed practice on basic math fact fluency growth rates. AB - To best remediate academic deficiencies, educators need to not only identify empirically validated interventions but also be able to apply instructional modifications that result in more efficient student learning. The current study compared the effect of massed and distributed practice with an explicit timing intervention to evaluate the extent to which these modifications lead to increased math fact fluency on basic addition problems. Forty-eight third-grade students were placed into one of three groups with each of the groups completing four 1-min math explicit timing procedures each day across 19 days. Group one completed all four 1-min timings consecutively; group two completed two back-to back 1-min timings in the morning and two back-to-back 1-min timings in the afternoon, and group three completed one, 1-min independent timing four times distributed across the day. Growth curve modeling was used to examine the progress throughout the course of the study. Results suggested that students in the distributed practice conditions, both four times per day and two times per day, showed significantly higher fluency growth rates than those practicing only once per day in a massed format. These results indicate that combining distributed practice with explicit timing procedures is a useful modification that enhances student learning without the addition of extra instructional time when targeting math fact fluency. PMID- 25746825 TI - Size and consistency of problem-solving consultation outcomes: an empirical analysis. AB - In this study, we analyzed extant data to evaluate the variability and magnitude of students' behavior change outcomes (academic, social, and behavioral) produced by consultants through problem-solving consultation with teachers. Research questions were twofold: (a) Do consultants produce consistent and sizeable positive student outcomes across their cases as measured through direct and frequent assessment? and (b) What proportion of variability in student outcomes is attributable to consultants? Analyses of extant data collected from problem solving consultation outcome studies that used single-case, time-series AB designs with multiple participants were analyzed. Four such studies ultimately met the inclusion criteria for the extant data, comprising 124 consultants who worked with 302 school teachers regarding 453 individual students. Consultants constituted the independent variable, while the primary dependent variable was a descriptive effect size based on student behavior change as measured by (a) curriculum-based measures, (b) permanent products, or (c) direct observations. Primary analyses involved visual and statistical evaluation of effect size magnitude and variability observed within and between consultants and studies. Given the nested nature of the data, multilevel analyses were used to assess consultant effects on student outcomes. Results suggest that consultants consistently produced positive effect sizes on average across their cases, but outcomes varied between consultants. Findings also indicated that consultants, teachers, and the corresponding studies accounted for a significant proportion of variability in student outcomes. This investigation advances the use of multilevel and integrative data analyses to evaluate consultation outcomes and extends research on problem-solving consultation, consultant effects, and meta analysis of case study AB designs. Practical implications for evaluating consultation service delivery in school settings are also discussed. PMID- 25746826 TI - Septic arthritis due to methylcyllin-resistant Staphylococcus aureus in adults. AB - INTRODUCTION: Septic arthritis due to methylcyllin resistant Staphylococcus aureus (MRSA) is a serious infection that has increased in incidence in the past 10years. METHODS: We conducted a retrospective study (1984-2011) in which a description of the clinical and epidemiological characteristics of MRSA arthritis in adults was performed and then compared to native joint infections caused by MRSA vs. methylcyllin sensitive Staphylococcus aureus (MSSA). RESULTS: Fourteen MRSA infections were included (7 native joint, 5 prosthetic and 2 bursae). No case was polyarticular. There was significant comorbidity, although none was associated to rheumatoid arthritis. Seven patients had bacteremia. Four required surgical treatment. Six died. When comparing the 7 patients with native joint MRSA infection with the 17 cases caused by MSSA, no significant differences in risk factors were seen, except more malignancies in the MRSA group. The infection was polyarticular in 7 cases (41%) of the MSSA group. Bacteremia was more frequent in the MRSA group (71.4 vs 58.8%). Empirical antibiotic was useful in 28.6% of MRSA cases versus 100% of MSSA cases. There was a greater tendency to associated mortality in MRSA arthritis (57.1% vs 17.6%, P=.07). CONCLUSIONS: MRSA septic arthritis is a serious condition that occurs in the elderly and patients with high comorbidity. It is usually monoarticular, with positive blood cultures and higher mortality than MSSA arthritis. In patients at risk, vancomycin empiric antibiotic therapy is indicated. PMID- 25746827 TI - Association between biomarkers of oxidative stress, trace elements, and cell proliferation index in patients with benign and malignant breast diseases. AB - OBJECTIVES: To understand the association between biomarkers of oxidative stress, antioxidants, trace elements, and cell proliferation index in relation to the disease progression in the pathophysiology of breast diseases. DESIGN AND METHODS: Concentrations of markers of oxidative stress, antioxidants, trace elements, and cell proliferation index were evaluated in the patients with benign breast diseases, malignant breast diseases, and healthy volunteers as controls. Multinomial logistic regression analysis was used to identify the contribution of the selected indexes using odds ratio and associated confidence interval. RESULTS: The level of markers of oxidative stress (malondialdehyde [MDA]) and cell proliferation index were found to be significantly higher with significantly depleted levels of antioxidants and trace elements in breast cancer patients compared with control subjects as well as benign breast disease patients. A similar pattern of changes were observed between benign and control subjects. CONCLUSION: An inadequate amount of antioxidant enzymes and trace elements may be an important contributing factor associated with oxidative stress leading to elevated levels of MDA and cell proliferation index in relation to disease progression and clinical stage in the pathophysiology of breast diseases. PMID- 25746828 TI - The influence of gingerol treatment on aluminum toxicity in rats. AB - BACKGROUND: Ginger is widely used as a medicine in the Ayurvedic system. It contains the active compound gingerol, which scavenges free radicals. Prolonged intake of aluminum (Al) in drinking water and from other sources may lead to neurological, renal, and hepatic dysfunction. OBJECTIVE: The present study was designed to evaluate the protective effect of gingerol, an active principal of ginger against aluminum as Al (NO3)3 -induced toxicity in rats. METHODS: Al (NO3)3 at 32.5 mg/kg body weight was administered to female albino rats intraperitoneally once only, followed by treatment with gingerol at 25, 50, and 100 mg/kg p.o. for 3 consecutive days beginning 24 h after Al exposure. Animals of all of the groups were sacrificed after 48 h of the last gingerol treatment for experimental observations. RESULTS: Significant elevations were observed in serum tranaminases, cholesterol, triglyceride, creatinine, urea, and blood delta aminolevulinic acid dehydratase (ALAD) after Al exposure. In liver, kidney, and brain tissues, the thiobarbituric acid reactive substances (TBARS) level and total and esterified cholesterol were significantly increased, whereas glutathione (GSH), acetyl cholinesterase (AChE), and delta-aminolevulinic acid synthetase (ALAS) were significantly decreased. Treatment of gingerol for 3 days surprisingly reversed almost all of the biochemical variables toward control levels in a significant manner. CONCLUSION: Treatment with gingerol (50 mg/kg body weight) was most effective in coping with aluminum-induced toxicity in rats. The antioxidant activity of gingerol might be due not only to the radical scavenging activity of antioxidants but also to the affinity of these antioxidants to the substrates. PMID- 25746829 TI - Lead acetate-induced hepatoxicity in Wistar rats: possible protective role of combination therapy. AB - Experimental studies have shown that sulphur-containing antioxidants have beneficial effects against the detrimental properties of Pb. In the present study, we investigated the therapeutic potential of combined administration of N acetyl cysteine (NAC; 50 mg/kg p.o.) and selenium (Se; 0.5 mg/kg p.o.) against lead acetate intoxication (Pb; 0.2% in water ad libitum) in a male rat model for 12 wk. The exposure of rats to lead acetate produced significant (P < 0.05) alterations in cytochrome P450 (CYP) activity, microsomal lipid peroxidation, reduced glutathione, and proteins. In addition, significant elevation in liver markers transaminases, triglycerides, cholesterol, and bilirubin as well as a decline in albumin were also compared with the experimental control rats. Combined treatment of lead-exposed animals with NAC and Se showed marked improvement of the biochemical, molecular, and histopathological findings. These experimental results strongly indicate the protective effect of NAC alone with Se against toxic effects of lead on liver tissue. PMID- 25746830 TI - Higher AgNOR Expression in Metaplastic and Dysplastic Airway Epithelial Cells Predicts the Risk of Developing Lung Cancer in Women Chronically Exposed to Biomass Smoke. AB - We evaluated AgNOR expression in airway epithelial cells (AECs) as a risk factor of lung carcinogenesis in 228 nonsmoking women exposed to biomass fuel (BMF). A total of 185 age-matched women who cooked with cleaner fuel (liquefied petroleum gas [LPG]) were enrolled as study controls. Compared with controls, Papanicolaou stained sputum samples showed 4 and 8 times higher prevalence of metaplasia and dysplasia, respectively, in AECs of BMF users. AgNOR staining showed significantly larger numbers of dots and larger size and percentage of AgNOR occupied nuclear area in normal AECs of BMF users than in controls. Interestingly, AgNOR parameters increased dramatically when the cells were transformed from normalcy to metaplasia and dysplasia. Compared with LPG users, BMF users showed a marked rise in reactive oxygen species (ROS) generation and a depletion of superoxide dismutase (SOD), indicating oxidative stress. Indoor air of BMF-using households had 2-5 times more particulate pollutants (PM10 and PM2.5), 73% more nitrogen dioxide (NO2), and 4 times more particulate-laden benzo(a)pyrene [B(a)P], but no difference in sulfur dioxide was observed. A high performance liquid chromatography (HPLC) study estimated a 6-fold rise in benzene metabolite trans, trans-muconic acid (t,t-MA) in urine of BMF users. After controlling confounding factors using multivariate logistic regression, positive associations were observed between cellular changes, AgNOR parameters, and PM10, PM2.5, NO2, B(a)P, and t,t-MA levels, especially the concentration of B(a)P. In conclusion, cumulative exposure to biomass smoke causes oxidative stress and enhances AgNOR expression in precancerous metaplastic and dysplastic AECs and appears to be a risk factor for developing lung cancer. PMID- 25746831 TI - Zoledronic acid aggravates kidney damage during ischemia reperfusion injury in rat. AB - INTRODUCTION: Zoledronic acid (ZA), a bisphosphonate, increases the levels of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha), and reactive oxygen species (ROS) in subjects without cancer. Increased production of ROS, TNF-alpha, and IL-6 during ischemia and reperfusion (I/R) injury stimulates apoptosis that leads to renal injury. We aimed to investigate whether ZA treatment has a protective effect on renal tissues during I/R. MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were used in this study, and they were subdivided randomly into three groups, each containing eight rats. Infrarenal abdominal aortic cross ligation was performed on the I/R group. After 2 h of ischemia, 2 h of reperfusion was applied. A single dose of 100 ug/kg ZA was administered intraperitoneally to the ZA group. I/R was performed after 48 h. RESULTS: Whereas TNF-alpha, IL-6, and nitric oxide (NO) levels of the I/R group were higher than those of the control group, TNF-alpha, IL-6, and NO levels of the ZA group were higher than those of the I/R group [TNF-alpha (p=0.038), IL-6 (p=0.012), NO (p=0.002), and caspase-3 (p=0.037)] and the control group [TNF alpha (p<0.001), IL-6 (p<0.001), NO (p<0.001), and caspase-3 (p<0.001)]. Whereas the carbonic anhydrase II (CA-II) level of the ZA group was lower than that of the control group (p=0.040), the CA-II level of the I/R group was higher than that of the control group (p=0.020). CONCLUSION: ZA may aggravate renal injury during I/R by increasing cytokine production and apoptosis. It may also increase renal injury and metabolic acidosis during I/R by suppressing CA-II enzyme activities. PMID- 25746832 TI - Epigenetic targets of arsenic: emphasis on epigenetic modifications during carcinogenesis. AB - DNA methylation and histone modification promote opening and closure of chromatin structure, which affects gene expression without altering the DNA sequence. Epigenetic markers regulate the dynamic nature of chromatin structure at different levels: DNA, histone, noncoding RNAs, as well as the higher-order chromatin structure. Accumulating evidence strongly suggests that arsenic-induced carcinogenesis involves frequent changes in the epigenetic marker. However, progress in identifying arsenic-induced epigenetic changes has already been made using genome-wide approaches; the biological significance of these epigenetic changes remains unknown. Moreover, arsenic-induced changes in the chromatin state alter gene expression through the epigenetic mechanism. The current review provides a summary of recent literature regarding epigenetic changes caused by arsenic in carcinogenesis. We highlight the transgenerational studies needed to explicate the biological significance and toxicity of arsenic over a broad spectrum. PMID- 25746833 TI - (-)-Epigallocatechin-3-gallate inhibits osteosarcoma cell invasiveness by inhibiting the MEK/ERK signaling pathway in human osteosarcoma cells. AB - The notorious lung metastatic capability of osteosarcoma aggravates patient mortality and remains the primary challenge to be overcome. We investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on the metastasis capability of osteosarcoma cells. We performed cytotoxicity assays (MTT) to determine the appropriate concentration of EGCG for experiments. Migration, invasion, wound healing, and adhesion assays were performed to assess the effect of EGCG on the metastasis of osteosarcoma. Changes in the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway were investigated using Western blot analyses. In addition, a MEK inhibitor (U0126) was used in invasion assays to determine the effect of the MEK/ERK signaling pathway. We found that EGCG may markedly inhibit the migration and invasion capacity of osteosarcoma cells, which occurred concurrently with inhibition of the expression of phospho-MEK and phospho-ERK. Inhibitors of MEK inhibited the invasion of osteosarcoma cells, and this effect could be enhanced by EGCG. We also detected the expression of c-Jun N-terminal kinase, p38, and their respective phospho-proteins, but did not find any meaningful changes. Taken together, our results demonstrated that EGCG could inhibit the metastasis capability of osteosarcoma cells by inhibiting MEK/ERK signaling activity and may provide new therapeutic value for osteosarcoma. PMID- 25746834 TI - Regulation of circRNA biogenesis. AB - Unlike linear RNAs terminated with 5' caps and 3' tails, circular RNAs are characterized by covalently closed loop structures with neither 5' to 3' polarity nor polyadenylated tail. This intrinsic characteristic has led to the general under-estimation of the existence of circular RNAs in previous polyadenylated transcriptome analyses. With the advent of specific biochemical and computational approaches, a large number of circular RNAs from back-spliced exons (circRNAs) have been identified in various cell lines and across different species. Recent studies have uncovered that back-splicing requires canonical spliceosomal machinery and can be facilitated by both complementary sequences and specific protein factors. In this review, we highlight our current understanding of the regulation of circRNA biogenesis, including both the competition between splicing and back-splicing and the previously under-appreciated alternative circularization. PMID- 25746835 TI - Characterization of the human alpha9 integrin subunit gene: Promoter analysis and transcriptional regulation in ocular cells. AB - alpha9beta1 is the most recent addition to the integrin family of membrane receptors and consequently remains the one that is the least characterized. To better understand how transcription of the human gene encoding the alpha9 subunit is regulated, we cloned the alpha9 promoter and characterized the regulatory elements that are required to ensure its transcription. Transfection of alpha9 promoter/CAT plasmids in primary cultured human corneal epithelial cells (HCECs) and uveal melanoma cell lines demonstrated the presence of both negative and positive regulatory elements along the alpha9 promoter and positioned the basal alpha9 promoter to within 118 bp from the alpha9 mRNA start site. In vitro DNaseI footprinting and in vivo ChIP analyses demonstrated the binding of the transcription factors Sp1, c-Myb and NFI to the most upstream alpha9 negative regulatory element. The transcription factors Sp1 and NFI were found to bind the basal alpha9 promoter individually but Sp1 binding clearly predominates when both transcription factors are present in the same extract. Suppression of Sp1 expression through RNAi also caused a dramatic reduction in the expression of the alpha9 gene. Most of all, addition of tenascin-C (TNC), the ligand of alpha9beta1, to the tissue culture plates prior to seeding HCECs increased alpha9 transcription whereas it simultaneously decreased expression of the alpha5 integrin subunit gene. This dual regulatory action of TNC on the transcription of the alpha9 and alpha5 genes suggests that both these integrins must work together to appropriately regulate cell adhesion, migration and differentiation that are hallmarks of tissue wound healing. PMID- 25746836 TI - Compounds for imaging amyloid-beta deposits in an Alzheimer's brain: a patent review. AB - INTRODUCTION: beta-amyloid (Abeta) plaques in the brain are regarded as a hallmark of Alzheimer's disease (AD), and the imaging of Abeta is a critical step for early diagnosis. Extensive research has been done to develop probes for targeting Abeta with available imaging modalities. AREAS COVERED: In this review, the authors give an overview of published patents and papers about the discovery and development of compounds possessing potential utilization in imaging Abeta for the diagnosis of AD. SciFinder is the main electronic database for patent study in this review. EXPERT OPINION: Despite achievements in Abeta imaging, there is still a need to develop innovative compounds with selectivity and high affinity to Abeta. Positron emission tomography imaging agents will still be the trend in the field in the short term. Due to the low costs for single-photon emission computed tomography (SPECT) and the excellent nuclear properties of (99m)Tc, substantial research should be conducted on the development of the probes for SPECT. Refining the current imaging techniques and in the meantime developing new efficient imaging multimodality and compounds would be a promising approach to imaging Abeta. PMID- 25746837 TI - Hierarchical multi-scale simulations of adhesion at polymer-metal interfaces: dry and wet conditions. AB - We performed hierarchical multi-scale simulations to study the adhesion properties of various epoxy-aluminium interfaces in the absence and presence of water. The epoxies studied differ from each other in their hexagonal ring structures where one contains aromatic and the other aliphatic rings. As aluminium is unavoidably covered with alumina, a cross-linked epoxy structure near an alumina substrate is created and relaxed by performing coarse-grained simulations. To that purpose, we employ a recently developed parameterization method for variable bead sizes. For polymer-metal interactions, a multi-scale parameterization scheme is applied where the relative adsorption of each bead type is quantified. At the mesoscopic scale, the adhesion properties of different epoxy systems are discussed in terms of their interfacial structure and adsorption behavior. To further perform all-atom simulations, the mesoscopic structures are transformed into atomistic coordinates by applying a reverse mapping procedure. Interface internal energies are quantified and the simulation results observed at different scales are compared with each other as well as with the available experimental data. The good agreement between observations from simulations and experiments shows the usefulness of such an approach to better understand polymer-metal oxide adhesion. PMID- 25746838 TI - (+/-)-Sinensilactam A, a pair of rare hybrid metabolites with Smad3 phosphorylation inhibition from Ganoderma sinensis. AB - (+)- and (-)-Sinensilactam A (1), novel hybrid metabolites possessing a unique 2H pyrrolo[2,1-b][1,3]oxazin-6(7H)-one ring system, were isolated from the fruit bodies of Ganoderma sinensis. The structures of these substances and absolute configurations at their stereocenters were assigned using spectroscopic and computational methods along with X-ray crystallographic analysis. A plausible pathway for the biosynthesis of 1 is proposed. (-)-1 was found to be a Smad3 phosphorylation inhibitor in TGF-beta1 induced human renal proximal tubular cells. PMID- 25746841 TI - The relationship between grade of ischemia, success of reperfusion, and type of thrombolytic regimen. AB - BACKGROUND: This study was aimed to determine whether the grade of ischemia can predict the success of reperfusion in patients treated with thrombolytic therapy (TT) for ST elevation myocardial infarction (STEMI). MATERIAL AND METHODS: We enrolled 229 consecutive patients with diagnosis of STEMI and receiving TT. Patients were divided into 2 groups--grade 2 ischemia (GI2) and grade 3 ischemia (GI3)--according to initial electrocardiogram (ECG). As TT, fibrin-specific (tissue plasminogen activator (t-PA)) or non-fibrin-specific (streptokinase (SKZ)) regimens were used. Successful reperfusion was defined as >50% resolution of the maximal ST segment on 90-min ECG. We tried to evaluate whether the grade of ischemia could predict the success of reperfusion and if there were any differences in terms of successful reperfusion between different thrombolytic regimens. RESULTS: The successful reperfusion rate was significantly higher in GI2 than GI3 (82.4% vs. 64.4% respectively, p=0.002). The success rate was lowest at anterior GI3 (55.8%). Although there was no significant difference between thrombolytic regimens in all groups (p=0.77), t-Pa was superior to SKZ in anterior GI3 (63,6% vs. 30%, p=0.061). In addition, in multivariate analysis, GI and infarct localization were found as independent predictors for successful reperfusion with TT (p=0.006 and p=0.042, respectively). CONCLUSIONS: In the current study, we found that GI2 is an independent predictor for successful reperfusion in STEMI treated with TT. Fibrin specific regime should be preferred in anterior GI3. PMID- 25746840 TI - Tumor protein D52-like 2 accelerates gastric cancer cell proliferation in vitro. AB - Tumor protein D52-like 2 (TPD52L2) has been commonly described as a protein involved in tumorigenesis, according to its name. However, its pathological function remains under investigation. In the present study, TPD52L2 was found to be widely expressed in several gastric cancer cell lines. An efficient knockdown of TPD52L2 by a specific short hairpin RNA (shRNA) loaded in lentivirus resulted in a remarkable reduction in cell proliferation in both MGC80-3 and SGC-7901 cell lines with high TPD52L2 expression, but a slight or little reduction in the proliferation of MKN-28 and AGS cells with low TPD52L2 expression. Further analysis by flow cytometry revealed that the cell cycle was primarily blocked in the G0/G1 phase, especially in the sub-G1 phase by TPD52L2 silencing, implying its possible roles in cell cycle control and apoptosis. Knockdown of TPD52L2 caused a cleavage of PARP in MGC80-3 cells. Their study suggests that TPD52L2 might promote gastric carcinogenesis, and could be a promising target with respect to developing new therapeutic strategies to treat gastric cancer. PMID- 25746842 TI - Nutritional intervention and impact of polyphenol on glycohemoglobin (HbA1c) in non-diabetic and type 2 diabetic subjects: Systematic review and nmeta-analysis. AB - Polyphenols have been extensively studied for their antioxidant and anti inflammatory properties. Recently, their antiglycative actions by oxidative stress modulation have been linked to the prevention of diabetes and associated complications. This article assesses the evidence for polyphenol interventions on glycohemoglobin (HbA1c) in non-diabetic, pre-diabetic, and type 2 diabetes mellitus (T2DM) subjects. A systematic review of polyphenols' clinical trials on HbA1c in humans was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis. Thirty-six controlled randomized trials with HbA1c values were included. Polyphenols (extracts, supplements, and foods) were supplemented (28 mg to 1.5 g) for 0.7 to 12 months. Combining all subjects (n = 1954, mean baseline HbA1c = 7.03%, 53 mmol/mol), polyphenol supplementation significantly (P < 0.001) lowered HbA1c% by -0.53 +/- 0.12 units (-5.79 +/- 0.13 mmol/mol). This reduction was significant (P < 0.001) in T2DM subjects, specifically (n = 1426, mean baseline HbA1c = 7.44%, 58 mmol/mol), with HbA1c% lowered by -0.21 +/- 0.04 units (-2.29 +/- 0.4 mmol/mol). Polyphenol supplementation had no significant effect (P > 0.21) in the non-diabetic (n = 258, mean baseline HbA1c = 5.47%, 36 mmol/mol) and the pre-diabetic subjects (n = 270, mean baseline HbA1c = 6.06%, 43 mmol/mol) strata: -0.39 +/- 0.27 HbA1c% units (-4.3 +/- 0.3 mmol/mol), and -0.38 +/- 0.31 units (-4.2 +/- 0.31 mmol/mol), respectively. In conclusion, polyphenols can successfully reduce HbA1c in T2DM without any intervention at glycemia, and could contribute to the prevention of diabetes complications. PMID- 25746843 TI - Model of mucociliary clearance in cystic fibrosis lungs. AB - Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways. PMID- 25746844 TI - Neighbourhood reaction in the evolution of cooperation. AB - Combining evolutionary games with adaptive networks, an entangled model between strategy evolution and structure adaptation is researched in this paper. We consider a large population of cooperators C and defectors D placed in the networks, playing the repeated prisoner's dilemma (PD) games. Because of the conflicts between social welfare and personal rationality, both strategy and structure are allowed to change. In this paper, the dynamics of strategy originates form the partner imitation based on social learning and the dynamics of structure is driven by the active linking and neighbourhood reaction. Notably, the neighbourhood reaction is investigated considering the changes of interfaces between cooperators and defectors, where some neighbours may get away from the interface once the focal agent changes to different strategy. A rich landscape is demonstrated by changing various embedding parameters, which sheds light upon that reacting promptly to the shifted neighbour will promote the prevalence of cooperation. Our model encapsulates the dynamics of strategy, reaction and structure into the evolutionary games, which manifests some intriguing principles in the competition between two groups in natural populations, artificial systems and even human societies. PMID- 25746845 TI - Efficacy of cleaning tablets for removable orthodontic appliances: an in vivo pilot study. AB - OBJECTIVES: The purpose of this study was to test the cleaning effect of three commercially available effervescent tablet products on acrylic resin surfaces compared to water as control medium. METHODS: A total of 20 volunteers were instructed to wear a vacuum-formed maxillary splint continuously for 96 h. Each splint incorporated four resin discs in the palate area. Each of these PMMA (polymethyl methacrylate) discs was split into two specimens which were analyzed upon removing the splint after the 4-day period. One specimen per disc was analyzed uncleaned and one after cleaning, using one of the investigated tablet products according to the manufacturer's recommendations or water as control medium. The outcomes of cleaning were evaluated with the modified ortho phthaldialdehyde (OPA) method by determining the amounts of surface protein. RESULTS: Significant differences in relative (%) protein removal were noted between all three tablet products and water, and fittydent super(r) was significantly more effective in removing biofilm than Kukis(r). No significant differences were observed between fittydent super(r) and NitrAdine(r) Ortho&JuniorTM or NitrAdine(r) Ortho&JuniorTM and Kukis(r). CONCLUSION: The modified OPA method proved to be successful in examining protein-containing contaminations on the specimens, and the effervescent products tested were more effective than pure water in removing contaminants from orthodontic appliances. These results are, however, confined to soft plaque not older than 4 days. PMID- 25746846 TI - Proliferation and differentiation potential of human adipose-derived stem cells grown on chitosan hydrogel. AB - Applied tissue engineering in regenerative medicine warrants our enhanced understanding of the biomaterials and its function. The aim of this study was to evaluate the proliferation and differentiation potential of human adipose-derived stem cells (hADSCs) grown on chitosan hydrogel. The stability of this hydrogel is pH-dependent and its swelling property is pivotal in providing a favorable matrix for cell growth. The study utilized an economical method of cross linking the chitosan with 0.5% glutaraldehyde. Following the isolation of hADSCs from omentum tissue, these cells were cultured and characterized on chitosan hydrogel. Subsequent assays that were performed included JC-1 staining for the mitochondrial integrity as a surrogate marker for viability, cell proliferation and growth kinetics by MTT assay, lineage specific differentiation under two dimensional culture conditions. Confocal imaging, scanning electron microscopy (SEM), and flow cytometry were used to evaluate these assays. The study revealed that chitosan hydrogel promotes cell proliferation coupled with > 90% cell viability. Cytotoxicity assays demonstrated safety profile. Furthermore, glutaraldehyde cross linked chitosan showed < 5% cytotoxicity, thus serving as a scaffold and facilitating the expansion and differentiation of hADSCs across endoderm, ectoderm and mesoderm lineages. Additional functionalities can be added to this hydrogel, particularly those that regulate stem cell fate. PMID- 25746847 TI - [Predictors of sentinel lymph node status]. PMID- 25746848 TI - Superior broadband antireflection from buried Mie resonator arrays for high efficiency photovoltaics. AB - Establishing reliable and efficient antireflection structures is of crucial importance for realizing high-performance optoelectronic devices such as solar cells. In this study, we provide a design guideline for buried Mie resonator arrays, which is composed of silicon nanostructures atop a silicon substrate and buried by a dielectric film, to attain a superior antireflection effect over a broadband spectral range by gaining entirely new discoveries of their antireflection behaviors. We find that the buried Mie resonator arrays mainly play a role as a transparent antireflection structure and their antireflection effect is insensitive to the nanostructure height when higher than 150 nm, which are of prominent significance for photovoltaic applications in the reduction of photoexcited carrier recombination. We further optimally combine the buried Mie resonator arrays with micron-scale textures to maximize the utilization of photons, and thus have successfully achieved an independently certified efficiency of 18.47% for the nanostructured silicon solar cells on a large-size wafer (156 mm * 156 mm). PMID- 25746850 TI - Composite grafting for distal digital amputation with respect to injury type and amputation level. AB - PURPOSE: This study evaluated the composite graft survival rate in distal digital amputations with respect to injury type and amputation level. METHODS: Twenty seven patients with complete fingertip amputations (32 digits) distal to the distal interphalangeal joint who were treated by composite grafting from January 2010 to February 2012 were enrolled. Injury type was classified as clean-cut, blunt-cut, or crush-avulsion. Amputation level was classified according to Ishikawa's classification: subzones I-IV. Graft survival was categorised as complete, partial, or no survival. RESULTS: The graft was more likely to exhibit complete survival in clean-cut injuries (50%) than in blunt-cut (10%) or crush avulsion injuries (12.5%). However, when complete and partial survival were combined, there was no significant difference among injury types (clean-cut = 83.3%, blunt-cut = 70.0%; crush-avulsion = 68.8%). Composite grafting in sub-zone I provided good results (complete survival = 50%; partial survival = 50.0%; no survival = 0%). When complete and partial survival were combined, there was no significant difference with respect to amputation level except sub-zone I (II = 70.6%; III = 66.7%; IV = 60%). In sub-zone II, clean-cut injuries exhibited better graft survival than blunt-cut or crush-avulsion injuries. In sub-zones III and IV, no complete graft survival was observed. CONCLUSION: In conclusion, all types of injuries in sub-zone I and clean-cut injuries in sub-zone II are candidates for composite grafting. Blunt-cut and crush-avulsion injuries in sub zone II are marginal candidates for composite grafting. Any type of injury in sub zone III or IV is contraindicated for composite grafting and should be treated by microanastomosis. PMID- 25746849 TI - Prokinetic drugs for gastric emptying in critically ill ventilated patients: Analysis through breath testing. AB - PURPOSE: The prupose was to identify, through the BreathID automatic breath testing device, the best prokinetic therapy to enhance gastric-emptying rate (GER) in ventilated intensive care unit patients. MATERIALS AND METHODS: This was a prospective, crossover, nonrandomized study. Consecutive ventilated patients who could be fed enterally and expected to require 5 days of ventilation were included. (13)C-labeled-acetate in 100 mL Osmolite (BreathID; Exalenz Bioscience Ltd, Jerusalem, Israel) was administered intragastrically and followed by a 4 hour continuous recording of expiratory (13)CO2 by the BreathID. Prokinetics were changed daily: (1) baseline (no prokinetic), (2) intravenous (IV) metoclopramide (10 mg every 6 hours), (3) IV metoclopramide (10 mg every 6 hours) and continuous low-dose erythromycin (10 mg/h), (4) IV continuous low-dose erythromycin alone (10 mg/h), and (5) IV bolus erythromycin (200 mg every 12 hours). Gastric emptying rate was assessed by the percentage dose recovered (PDR)-change from time 0 of the recording in the ratio of (13)CO2/(12)CO2 in exhaled gases (%/h). We used PDR peak values and time to peak (minutes to reach PDR peak) to express GER. RESULTS: In the first 17 patients (group A), baseline GER measurements preceded prokinetic therapy. In the subsequent 14 patients (group B), 2 prokinetic regimens preceded baseline. No order-time effect was observed, justifying pooled analysis of all 31 patients. Combined metoclopramide-continuous low-dose erythromycin yielded significantly higher PDR peak and shorter time to peak vs baseline (P = .0001, P = .005, respectively). The PDR peak was also significantly higher from baseline during continuous low-dose administration of erythromycin alone (P = .004). Metoclopramide alone did not improve GER significantly. CONCLUSIONS: Combined metoclopramide-continuous low-dose erythromycin was found to be the best protocol in the current study to increase GER in ventilated patients. It should be tested as a first-line prokinetic therapy in ventilated patients with poor gastric emptying in further randomized controlled studies. The breath-test device presented in this study can be a user friendly and practical method to monitor GER, enabling individual tailoring of prokinetic therapy. Further studies to explore its utility are warranted. PMID- 25746851 TI - Effect of low-temperature aging on the mechanical behavior of ground Y-TZP. AB - This study evaluated the effects of low-temperature aging on the surface topography, phase transformation, biaxial flexural strength, and structural reliability of a ground Y-TZP ceramic. Disc-shaped specimens were manufactured and divided according to two factors: "grinding" - without grinding (as-sintered, Ctrl), grinding with an extra-fine diamond bur (25 um Xfine) and coarse diamond bur (181 um Coarse); and "low-temperature-aging" (absence or presence). Grinding was performed using a contra-angle handpiece under water-cooling. Aging was performed in an autoclave at 134 degrees C, under 2 bar, over a period of 20 h. Surface topography analysis showed an increase in roughness based on grit-size (Coarse>Xfine>Ctrl), and aging promoted different effects on roughness (Ctrl AgCoarse). Grinding and aging promoted an increase in the amount of m-phase, although different susceptibilities to degradation were observed. Weibull analysis showed an increase in characteristic strength after grinding (Coarse=Xfine>Ctrl); however, distinct effects were observed for aging (CtrlCoarse Ag). Weibull moduli were statistically similar. Grinding promoted an increase in characteristic strength as a result of an increase in m-phase content; when the Y TZP surface was ground by coarse diamond burs followed by aging, characteristic strength was reduced, meaning the low-temperature degradation appeared to intensify for rougher Y-TZP surfaces. PMID- 25746852 TI - Striatoids A-F, Cyathane Diterpenoids with Neurotrophic Activity from Cultures of the Fungus Cyathus striatus. AB - Six new highly oxygenated polycyclic cyathane-xylosides, named striatoids A-F (1 6), were isolated from the cultures of the basidiomycete Cyathus striatus. Their structures were established by comprehensive spectroscopic analysis including 2D NMR (HMBC, HSQC, ROESY, (1)H-(1)H-COSY) and HRESIMS experiments. Compounds 2 and 3 possess an unusual 15,4'-ether ring system. The isolated compounds dose dependently enhanced nerve growth factor (NGF)-mediated neurite outgrowth in rat pheochromocytoma (PC-12) cells. PMID- 25746853 TI - Polymorph selectivity of superconducting CuSe2 through kinetic control of solid state metathesis. AB - Rational preparation of materials by design is a major goal of inorganic, solid state, and materials chemists alike. Oftentimes, the use of nonmetallurgical reactions (e.g., chalcogenide fluxes, hydrothermal syntheses, and in this case solid-state metathesis) alters the thermodynamic driving force of the reaction and allows new, refractory, or otherwise energetically unfavorable materials to form under softer conditions. Taking this a step further, alteration of a metathesis reaction pathway can result in either the formation of the equilibrium marcasite polymorph (by stringent exclusion of air) or the kinetically controlled formation of the high-pressure pyrite polymorph of CuSe2 (by exposure to air). From analysis of the reaction coordinate with in situ synchrotron X-ray diffraction and pair distribution function analysis as well as differential scanning calorimetry, it is clear that the air-exposed reaction proceeds via slight, endothermic rearrangements of crystalline intermediates to form pyrite, which is attributed to partial solvation of the reaction from atmospheric humidity. In contrast, the air-free reaction proceeds via a significant exothermic process to form marcasite. Decoupling the formation of NaCl from the formation of CuSe2 enables kinetic control to be exercised over the resulting polymorph of these superconducting metal dichalcogenides. PMID- 25746854 TI - QuantiFERON-TB Gold In-Tube assay for screening arthritis patients for latent tuberculosis infection before starting anti-tumor necrosis factor treatment. AB - BACKGROUND: Patients undergoing anti-tumor necrosis factor (TNF) treatment are at an increased risk of reactivating a latent tuberculosis infection (LTBI). This study evaluated the effectiveness of the QuantiFERON-TB Gold In-Tube (QFT) assay for diagnosing LTBI in arthritis patients undergoing anti-TNF treatment. METHODS: We enrolled 342 consecutive patients from August 2007 to October 2013: 176 (51.5%) patients with ankylosing spondylitis and 166 (48.5%) with rheumatoid arthritis. Screening tests included tuberculin skin test (TST) and QFT assay. Positive QFT results, regardless of TST results, were considered an indicator for LTBI treatment. RESULTS: Bacillus Calmette-Guerin scars were found in 236 (69.0%) patients. Of 342 patients, TST and QFT were positive in 122 (35.7%) and 103 (30.1%) patients, respectively, and discordant in 101 (29.5%) patients. During a median follow-up duration of 41.7 months, five patients (1.5%) developed TB in a median of 20.8 months after initiation of anti-TNF treatment (428/100,000 person years). TB did not occur in 62 TST+/QFT+ patients who received LTBI treatment. Of 41 TST-/QFT+ patients who received LTBI treatment, one (2.4%) developed TB 20.5 months after starting anti-TNF treatment (705/100,000 person-years). Of 60 TST+/QFT- patients who did not receive LTBI treatment, two (3.3%) developed TB 20.8 and 22.0 months after starting anti-TNF treatment (871/100,000 person years). Of 179 TST-/QFT- patients, two (1.1%) developed TB 7.2 and 22.7 months, respectively, after initiating anti-TNF treatment (341/100,000 person-years). TB incidence rate during the follow-up period did not differ among TST-/QFT+, TST+/QFT-, and TST-/QFT- patients (P = 0.661). CONCLUSION: QFT might be used instead of TST for diagnosing LTBI in patients before starting anti-TNF therapy in countries, such as Korea, where the TB prevalence is intermediate and the BCG vaccination is mandatory at birth. In the absence of a true gold standard test for LTBI, however, there is still a risk of TB development during anti-TNF treatment. PMID- 25746855 TI - Endometrial expression of selected transcripts in postpartum of primiparous Holstein cows with clinical and subclinical endometritis. AB - Postpartum endometritis compromises milk production and fertility in high producing dairy cows. Infection of the endometrium induces an inflammatory response with secretion of cytokines that lead to polymorphonuclear cells (PMN) influx and bacterial clearance. Considering that only a portion of cows with endometritis is eligible for clinical diagnosis, there is an increasing effort for developing reliable tools and protocols for diagnosis of subclinical endometritis. Recent reports have indicated that primiparous cows are at greater risk of uterine infection and primiparous cows with subclinical endometritis produce less milk compared to healthy cows. In the present study, gene expression profiles were compared for selected cytokine and hormone endometrial transcripts in the postpartum of primiparous Holstein cows with clinical and subclinical endometritis. Cows were classified as healthy (no signs of clinical endometritis), cows with subclinical endometritis (PMN<5% in the cytological sample) and cows with clinical endometritis (PMN>5%). Although, cows with clinical endometritis had greater (P<0.05) relative amounts of mRNA for the IL1A, IL6, IL17A, TNFalpha, PGES and PGHS2 genes compared to healthy cows; no significant differences were detected between clinical and subclinical endometritis groups. Spearman correlation coefficients were positive between relative amounts of gene expression as indicated by amount of these transcripts and PMN percentages and ranged from 0.74 to 0.93 (P<0.05). Relative amounts of cytokine mRNA suggest similar inflammatory response in the endometrium of cows with subclinical and clinical endometritis. Moreover, differential relative amounts of hormone transcripts suggest dysregulation of the luteolytic mechanism and PG synthases but not ERalpha in cows with endometritis. PMID- 25746856 TI - Serotonergic Regulation of Prefrontal Cortical Circuitries Involved in Cognitive Processing: A Review of Individual 5-HT Receptor Mechanisms and Concerted Effects of 5-HT Receptors Exemplified by the Multimodal Antidepressant Vortioxetine. AB - It has been known for several decades that serotonergic neurotransmission is a key regulator of cognitive function, mood, and sleep. Yet with the relatively recent discoveries of novel serotonin (5-HT) receptor subtypes, as well as an expanding knowledge of their expression level in certain brain regions and localization on certain cell types, their involvement in cognitive processes is still emerging. Of particular interest are cognitive processes impacted in neuropsychiatric and neurodegenerative disorders. The prefrontal cortex (PFC) is critical to normal cognitive processes, including attention, impulsivity, planning, decision-making, working memory, and learning or recall of learned memories. Furthermore, serotonergic dysregulation within the PFC is implicated in many neuropsychiatric disorders associated with prominent symptoms of cognitive dysfunction. Thus, it is important to better understand the overall makeup of serotonergic receptors in the PFC and on which cell types these receptors mediate their actions. In this Review, we focus on 5-HT receptor expression patterns within the PFC and how they influence cognitive behavior and neurotransmission. We further discuss the net effects of vortioxetine, an antidepressant acting through multiple serotonergic targets given the recent findings that vortioxetine improves cognition by modulating multiple neurotransmitter systems. PMID- 25746857 TI - Even when feeding breastmilk there are no free lunches. PMID- 25746858 TI - Stretch-activated pore of the antimicrobial peptide, magainin 2. AB - Antimicrobial peptide magainin 2 forms pores in lipid membranes and induces membrane permeation of the cellular contents. Although this permeation is likely the main cause of its bactericidal activity, the mechanism of pore formation remains poorly understood. We therefore investigated in detail the interaction of magainin 2 with lipid membranes using single giant unilamellar vesicles (GUVs). The binding of magainin 2 to the lipid membrane of GUVs increased the fractional change in the area of the membrane, delta, which was proportional to the surface concentration of magainin 2, X. This indicates that the rate constant of the magainin 2-induced two-state transition from the intact state to the pore state greatly increased with an increase in delta. The tension of a lipid membrane following aspiration of a GUV also activated magainin 2-induced pore formation. To reveal the location of magainin 2, the interaction of carboxyfluorescein (CF) labeled magainin 2 (CF-magainin 2) with single GUVs containing a water-soluble fluorescent probe, AF647, was investigated using confocal microscopy. In the absence of tension due to aspiration, after the interaction of magainin 2 the fluorescence intensity of the GUV rim due to CF-magainin 2 increased rapidly to a steady value, which remained constant for a long time, and at 4-32 s before the start of leakage of AF647 the rim intensity began to increase rapidly to another steady value. In contrast, in the presence of the tension, no increase in rim intensity just before the start of leakage was observed. These results indicate that magainin 2 cannot translocate from the outer to the inner monolayer until just before pore formation. Based on these results, we conclude that a magainin 2 induced pore is a stretch-activated pore and the stretch of the inner monolayer is a main driving force of the pore formation. PMID- 25746859 TI - 19th World Muscle Society congress, Berlin 2014. A city of cranes and dinosaurs. PMID- 25746860 TI - Development of bipolar all-solid-state lithium battery based on quasi-solid-state electrolyte containing tetraglyme-LiTFSA equimolar complex. AB - The development of high energy-density lithium-ion secondary batteries as storage batteries in vehicles is attracting increasing attention. In this study, high voltage bipolar stacked batteries with a quasi-solid-state electrolyte containing a Li-Glyme complex were prepared, and the performance of the device was evaluated. Via the successful production of double-layered and triple-layered high-voltage devices, it was confirmed that these stacked batteries operated properly without any internal short-circuits of a single cell within the package: Their plateau potentials (6.7 and 10.0 V, respectively) were two and three times that (3.4 V) of the single-layered device, respectively. Further, the double layered device showed a capacity retention of 99% on the 200th cycle at 0.5 C, which is an indication of good cycling properties. These results suggest that bipolar stacked batteries with a quasi-solid-state electrolyte containing a Li Glyme complex could readily produce a high voltage of 10 V. PMID- 25746862 TI - Fresh challenges for nurses. PMID- 25746861 TI - High-temperature superconductivity in compressed solid silane. AB - Crystal structures of silane have been extensively investigated using ab initio evolutionary simulation methods at high pressures. Two metallic structures with P21/c and C2/m symmetries are found stable above 383 GPa. The superconductivities of metallic phases are fully explored under BCS theory, including the reported C2/c one. Perturbative linear-response calculations for C2/m silane at 610 GPa reveal a high superconducting critical temperature that beyond the order of 10(2) K. PMID- 25746863 TI - Law change will oblige nurses to report female genital mutilation. PMID- 25746866 TI - Correction. PMID- 25746867 TI - All-day landing sites being prepared for flying doctors in Wales. PMID- 25746868 TI - Increase in 12-hour waiting-time breaches in Northern Ireland. PMID- 25746869 TI - Keeping an eye on crime. PMID- 25746870 TI - Crowding and exit block cause rise in mortality rate. PMID- 25746871 TI - New NMC code of conduct covers 'good Samaritan' acts. PMID- 25746872 TI - Staff turn failing service into a success. PMID- 25746873 TI - Should NHS 111 take blame for emergency care pressures? PMID- 25746875 TI - Bigger picture. PMID- 25746879 TI - Board's eye view--Restorative justice. PMID- 25746887 TI - Resuscitation training for emergency nurses in Africa. AB - Equipment and training for nurses in Africa are scarce but, as this article explains, if aid were targeted at local suppliers of cheap but vital equipment, such as resuscitation manikins, nursing practice would be enhanced and patient outcomes may improve. PMID- 25746888 TI - Recognising and assessing blunt abdominal trauma. AB - Blunt abdominal trauma is common following major traumatic injury but may not be recognised quickly enough and is therefore a cause of preventable death in trauma patients. Emergency department nurses have a major role to play in reducing the incidence of unrecognised abdominal trauma by enhancing their knowledge and skills. They can do this by attending trauma-related courses, taking on more expanded roles, carrying out full and comprehensive physical assessments, and ensuring that members of the multidisciplinary team use the wide range of diagnostic adjuncts available to them. This article reviews the anatomy and physiology of the abdominal cavity, explains abdominal trauma, gives an overview of advanced abdominal assessment techniques and diagnostic adjuncts, and reviews some management strategies for uncontrolled haemorrhage that have been adopted in the UK. PMID- 25746889 TI - Accessory ossicles and sesamoid bones: recognition and treatment. AB - Accessory ossicles and sesamoid bones are normal variants of bone development. In foot and ankle X-rays these bones can appear similar to, or can obscure, fractures, which makes the X-rays difficult to interpret. This article illustrates and describes some of the more common ossicles and sesamoid bones, and provides a brief description of the management of the patients with foot or ankle pain whose X-rays are inconclusive. PMID- 25746890 TI - Use of antibiotics in the management of sore throat. AB - As the number of antibiotic-resistant strains of bacteria rises, it becomes crucial that decisions about the use of antibiotics are based on sound evidence. This article offers a case study to explore the treatment of patients with sore throat who present to minor injury settings. It describes some 'red flag' presentations, discusses the pros and cons of prescribing antibiotics for sore throat, and describes some scoring systems that can help differentiate between bacterial and viral throat infections. PMID- 25746891 TI - Unexpected change. PMID- 25746892 TI - Altered alpha brain oscillations during multistable perception in schizophrenia. AB - Schizophrenia is a complex mental disorder with impairments in integrating sensory and cognitive functions, leading to severe problems in coherent perception. This impairment might be accelerated during multistable perception. Multistable perception is a phenomenon, where a visual pattern gives rise to at least two different perceptual representations. We addressed this issue by assessing event-related alpha oscillations during continuous viewing of an ambiguous and unambiguous control stimulus. Perceptual reversals were indicated by a manual response, allowing differentiation between phases of reversion and non-reversion (that is perceptual stability) in both tasks. During the ambiguous task, patients and controls showed a comparable number of perceptual reversals. Alpha amplitudes in patients were larger in non-reversion phases, accompanied by a stronger decrease of alpha activity preceding the perceptual reversal. This group difference was pronounced for lower alpha activity and not apparent during the unambiguous task. This indicates that ambiguous perception taps into the specific deficits that patients experience in maintaining coherent perception. Given that top-down influences in generating a meaningful percept seems to be low in patients, they appear more dependent on sensory information. Similar, bottom up mechanisms might be more important in triggering perceptual reversals in patients than in controls. PMID- 25746893 TI - Identification and co-localization of perforin-like (TgPLP1) protein in Toxoplasma gondii bradyzoites. AB - For the first time, we show here that perforin-like (TgPLP1) is expressed in bradyzoites of Toxoplasma gondii. An immunofluorescence assay (IFA) and immunohistochemistry (IHC) revealed that TgPLP1 is expressed in T. gondii encysted and in vitro-induced bradyzoites, TgPLP1 is distributed in micronemes in a manner similar to its distribution in tachyzoites. To shed light on the function of TgPLP1 in bradyzoites, quantitative PCR revealed that the expression level of TgPLP1 gene decreased over time during differentiation into bradyzoites in vitro. This finding suggests that TgPLP1 may play a role in the rupture of tissue cysts or the maintenance of cyst structure, although the exact function of this gene in the bradyzoites is still unknown. PMID- 25746894 TI - Suppression of antibiotic resistance acquisition by combined use of antibiotics. AB - We analyzed the effect of combinatorial use of antibiotics with a trade-off relationship of resistance, i.e., resistance acquisition to one drug causes susceptibility to the other drug, and vice versa, on the evolution of antibiotic resistance. We demonstrated that this combinatorial use of antibiotics significantly suppressed the acquisition of resistance. PMID- 25746895 TI - Re: "localization and retrieval of an eyelid metallic foreign body with an oscillating magnet and high-resolution ultrasonography". PMID- 25746896 TI - Reply re: "localization and retrieval of an eyelid metallic foreign body with an oscillating magnet and high-resolution ultrasonography". PMID- 25746897 TI - Re: "optic nerve cyst-like formation presenting as a delayed complication of optic nerve sheath fenestration". PMID- 25746898 TI - Re: "safety of onabotulinum toxin A injection to the central upper eyelid and eyebrow regions". PMID- 25746899 TI - Re: "long-term cicatrization analysis in periocular incisions for oculoplastic surgery performed with cold blade and colorado needle". PMID- 25746900 TI - Punctal keratinizing cyst: report in a pediatric patient with fourier domain optical coherence tomography features. PMID- 25746901 TI - Impact of the spheroid model complexity on drug response. AB - Pharmaceutical investigators are searching for preclinical models closely resembling the original cancer and predicting clinical outcome. This study compares drug response of three in vitro 3D-drug screening models with different complexity. Tumor cell line spheroids were generated from the cell lines Caco-2, DLD-1, COLO 205, HT-29 and HCT-116, and treated with clinically relevant combination therapies, namely 5-FU/oxaliplatin (FO), 5-FU/irinotecan (FI) and the molecular drugs Cetuximab, Trastuzumab, Vorinostat and Everolimus. Treatment results were compared with spheroids originated from tumor cell lines (Caco-2, DLD-1) co-cultured with stromal cells (PBMCs, cancer-associated fibroblasts of colorectal origin) and spheroids directly prepared from colon cancer tissues. Different microenvironment compositions altered the tumor cell line spheroid response patterns. Adding PBMCs increased resistance to FO treatment by 10-15% in Caco-2 and DLD-1 spheroids but decreased resistance to FI by 16% in DLD-1 spheroids. Fibroblast co-cultures decreased resistance to FI in Caco-2 spheroids by 38% but had no impact on FO. Treatment of colon cancer tissue spheroids revealed three distinct response pattern subgroups not detectable in 3D cell lines models. The cancer tissue spheroid model mimics both tumor characteristics and the stromal microenvironment and therefore is an invaluable screening model for pharmaceutical drug development. PMID- 25746902 TI - Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor. AB - The feeding of a fed-batch cultivation producing recombinant protein was controlled by a soft sensor set-up. It was assumed that the control approach could be based on the cell's production of carbon dioxide and that this parameter indicates the metabolic state occurring at induced protein expression. The soft sensor used the on-line signals from a carbon dioxide analyser and a near infrared (NIR) probe for biomass to estimate the specific production rate qCO2. Control experiments were carried out with various qCO2 set-points where we observe that the feeding of nutrients to the culture could easily be controlled and resulted in a decreased variability compared to uncontrolled cultivations. We therefore suggest that this control approach could serve as an alternative to other commonly applied methods such as controlling the cell's overflow metabolism of acetate or the cell's specific growth rate. However, further studies of the internal metabolic fluxes of CO2 during protein expression would be recommended for a more precise characterization of the relationship between qCO2 and protein expression in order to fully interpret the control behaviour. PMID- 25746903 TI - Exploring continuous and integrated strategies for the up- and downstream processing of human mesenchymal stem cells. AB - The integration of up- and downstream unit operations can result in the elimination of hold steps, thus decreasing the footprint, and ultimately can create robust closed system operations. This type of design is desirable for the bioprocess of human mesenchymal stem cells (hMSC), where high numbers of pure cells, at low volumes, need to be delivered for therapy applications. This study reports a proof of concept of the integration of a continuous perfusion culture in bioreactors with a tangential flow filtration (TFF) system for the concentration and washing of hMSC. Moreover, we have also explored a continuous alternative for concentrating hMSC. Results show that expanding cells in a continuous perfusion operation mode provided a higher expansion ratio, and led to a shift in cells' metabolism. TFF operated either in continuous or discontinuous allowed to concentrate cells, with high cell recovery (>80%) and viability (>95%); furthermore, continuous TFF permitted to operate longer with higher cell concentrations. Continuous diafiltration led to higher protein clearance (98%) with lower cell death, when comparing to discontinuous diafiltration. Overall, an integrated process allowed for a shorter process time, recovering 70% of viable hMSC (>95%), with no changes in terms of morphology, immunophenotype, proliferation capacity and multipotent differentiation potential. PMID- 25746904 TI - Label-free impedimetric detection of Listeria monocytogenes based on poly-5 carboxy indole modified ssDNA probe. AB - Listeria monocytogenes is a life threatening pathogenic bacteria concerned with human health. The accurate and rapid detection of L. monocytogenes is required for preventing of listeriosis. In this study, DNA sensing probe based on conducting polymer poly-5-carboxy indole (5C Pin) was developed for the detection of L. monocytogenes hlyA gene responsible for pathogenicity. The probe sequences (24 mer ssDNA) were covalently immobilized on 5C Pin via N-(3 dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (EDC) and N hydroxysuccinimide (NHS). The probe having ssDNA was further hybridized with the target DNA sequence. Electrochemical impedance spectroscopic study was carried out to determine the extent of DNA hybridization over the probe. Significant change was observed in the impedance spectra before and after hybridization of ssDNA immobilized over the probe with the target DNA. RCT (charge transfer resistance) was estimated from the Nyquist plot (impedance plot) for target DNA (hlyA gene) in the solution. RCT vs. logarithmic concentrations of the target (genomic) DNA plot showed a linear range (1 * 10(-4) to 1 * 10(-12)M) in case hybridization was performed under optimized conditions. The method proposed, is simple, free from any label, and highly sensitive for the detection of L. monocytogenes in environmental and clinical samples. PMID- 25746905 TI - Complete genome sequence of solvent-tolerant Pseudomonas putida S12 including megaplasmid pTTS12. AB - Pseudomonas putida S12 is a solvent-tolerant gamma-proteobacterium with an extensive track record for production of industrially relevant chemicals. Here we report the annotated complete genome sequence of this organism, including the megaplasmid pTTS12 which encodes many of the unique features of the S12 strain. PMID- 25746906 TI - A pilot study to assess Fatty infiltration of the supraspinatus in patients with rotator cuff tears: comparison with magnetic resonance imaging. AB - The aim of this study was to quantitatively assess the echo intensity of the supraspinatus muscle and compare magnetic resonance imaging and ultrasound findings for 27 patients (12 women, 15 men, 65.8 +/- 11.5 y). Tear size and fatty infiltration were determined by magnetic resonance imaging; five stages were assigned based on Goutallier's classification. Gray-scale histogram analysis was used for ultrasound assessment, which was performed in both subcutaneous fat and supraspinatus muscle in three different regions; the echo intensity ratio was the ratio of echo intensity in subcutaneous fat to that in the supraspinatus muscle. Sonograms of 27 shoulders revealed 3 shoulders with a partial tear, and 4 with a small tear, 6 with a medium tear, 6 with a large tear and 4 with a massive tear; 4 shoulders had no tear. Supraspinatus muscle echo intensity and echo intensity ratio were significantly lower in the stage 0 and 1 than in stages 2-4. Our study suggests that ultrasound can quantitatively and objectively assess fatty infiltration in the rotator cuff muscle. PMID- 25746907 TI - Test-Retest Reliability of Single Transverse versus Panoramic Ultrasound Imaging for Muscle Size and Echo Intensity of the Biceps Brachii. AB - This study compared test-retest reliability and sensitivity to change for muscle size and echo intensity (EI) measurements from single transverse (EIST) versus panoramic (EIP) ultrasound (US) images of the biceps brachii. Forearm flexor muscle thickness and EIST and biceps brachii muscle cross-sectional area and EIP were quantified from single transverse and panoramic US images in 14 men (age = 21.8 +/- 2.5 y [mean +/- standard deviation]) on two separate days. The intra class correlation coefficients, coefficients of variation, and minimum differences for muscle thickness, EIST, muscle cross-sectional area and EIP ranged from 0.78 to 0.99, from 2.26% to 3.29%, and from 6.26% to 9.12%, respectively. These findings suggested that single transverse imaging and panoramic US imaging are comparable, reliable techniques for quantifying muscle size and EI of the biceps brachii. Single transverse images may be simpler to obtain; thus, future studies may choose to quantify muscle size and EI from a single transverse US image in the biceps brachii. PMID- 25746908 TI - Skin and subcutaneous tissue strain in legs with lymphedema and lipodermatosclerosis. AB - We compared skin and subcutaneous tissue strains in legs with lymphedema (LE) of varying severity and legs with lipodermatosclerosis (LDS) using real-time tissue elastography. Strain was assessed at the inner thigh and calf in 62 legs with LE (International Society of Lymphology [ISL] stage 0: 16, stage I: 5, stage II: 28, late stage II: 7, stage III: 6) and 15 legs with LDS. In thighs and calves with LE, skin strain and subcutaneous tissue strain did not significantly differ between ISL stage 0, that is, asymptomatic legs, and other stages. However, strain values in calves with LDS were lower than values in calves with stage 0, II and late II LE. These results indicate that skin and subcutaneous tissue strains were not lower in legs with symptomatic LE than in asymptomatic legs until an advanced stage. PMID- 25746909 TI - Dependence of thresholds for pulmonary capillary hemorrhage on diagnostic ultrasound frequency. AB - Pulmonary ultrasound examination has become routine for diagnosis in many clinical and point-of-care medical settings. However, the phenomenon of pulmonary capillary hemorrhage (PCH) induction during diagnostic ultrasound imaging presents a poorly understood risk factor. PCH was observed in anesthetized rats exposed to 1.5-, 4.5- and 12.0-MHz diagnostic ultrasound to investigate the frequency dependence of PCH thresholds. PCH was detected in the ultrasound images as growing comet tail artifacts and was assessed using photographs of the surface of excised lungs. Previous photographs acquired after exposure to 7.6-MHz diagnostic ultrasound were included for analysis. In addition, at each frequency we measured dosimetric parameters, including peak rarefactional pressure amplitude and spatial peak, pulse average intensity attenuated by rat chest wall samples. Peak rarefactional pressure amplitude thresholds determined at each frequency, based on the proportion of PCH in groups of five rats, were 1.03 +/- 0.02, 1.28 +/- 0.14, 1.18 +/- 0.12 and 1.36 +/- 0.15 MPa at 1.5, 4.5, 7.6 and 12.0 MHz, respectively. Although the PCH lesions decreased in size with increasing ultrasonic frequency, owing to the smaller beam widths and scan lengths, the peak rarefactional pressure amplitude thresholds remained approximately constant. This dependence was different from that of the mechanical index, which indicates a need for a specific dosimetric parameter for safety guidance in pulmonary ultrasound. PMID- 25746910 TI - Type 2 diabetic patients with Graves' disease have more frequent and severe Graves' orbitopathy. AB - BACKGROUND AND AIMS: Due to the worldwide increasing prevalence of diabetes (DM), patients with both diabetes and Graves' disease (GD) have become more frequent. Sporadic reports indicate that Graves' orbitopathy (GO), a GD complication that affects orbital soft tissues, can be severe in DM patients. The relationship between these diseases is not well understood. This study aims at evaluating the association of GD and GO with autoimmune and non-autoimmune diabetes (DM) and to assess diabetic features that influence GD and GO prevalence and severity. METHODS AND RESULTS: This retrospective study evaluated GD, GO and DM association in 1211 consecutive GD patients (447 with GO and 77 with DM). A case-control study was carried out to evaluate DM relationship with GO severity by comparing at 1:2 ratio GO patients with or without DM. A strong association was found between GD and T1DM (p = 0.01) but not T2DM. Instead, the presence of GO was strongly associated with T2DM (p = 0.01). Moreover, GO was more frequently severe in GD patients with T2DM (11/30 or 36.6%) than in those without T2DM (1/60 or 1.7%, p = 0.05). T2DM was the strongest risk factor for severe GO (OR = 34.1 vs. 4.4 p < 0.049 in cigarette smokers). DM duration, obesity and vascular complications, but not metabolic control were significant determinants of GO severity. CONCLUSIONS: GD is associated with T1DM but not with T2DM, probably because of the common autoimmune background. GO, in contrast, is more frequent and severe in T2DM, significantly associated with obesity, diabetes duration and diabetic vasculopathy but not metabolic control. PMID- 25746911 TI - Management of idiopathic granulomatous mastitis with observation. AB - BACKGROUND: Idiopathic granulomatous mastitis (IGM) is becoming more commonly recognized and reported more often. Currently, many recommend corticosteroids in its management. METHODS: A retrospective chart review was conducted from January 2002 to June 2013. Data were collected regarding sociodemographic information, clinical history, treatment, and outcomes. RESULTS: Thirty-seven patients were found with IGM. Thirty-five patients were Hispanic born outside the United States. Early in the time period reviewed, 5 patients had masses excised and 5 patients were lost to follow-up. Twenty-seven cases of IGM resolved with observation. Corticosteroids were not used in the management. The average time to resolution was 7.4 months. Three patients (11%) had recurrent episodes after resolution. CONCLUSIONS: IGM is a self-limited benign condition that will resolve spontaneously without treatment. Patience with the natural history of IGM is important, as the process often includes periods of exacerbation before resolution. PMID- 25746912 TI - Treatment of carcinomatosis using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in adolescents and young adults. AB - BACKGROUND: Among colorectal carcinoma patients, approximately 150 patients/year are age 25 years old or younger according to Surveillance, Epidemiology, and End Results Program statistics. Because of lack of screening in their age group, they are at risk to have more advanced disease and have been largely unstudied. OBJECTIVE: To determine outcome of colon cancer adolescent and young adult patients. METHODS: Patients under the age of 26 were retrospectively reviewed from a single institution. RESULTS: The 5-year overall survival rate from the time of the first surgery was .45 (95% confidence interval .17 to .70). The median overall survival for the cohort was 2.98 years. Patients aged 15 to 21 years had a poorer overall survival than patients aged 22 to 25 years (82% survival vs 100% at 2 years and zero vs 56% at 5 years). Five patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Three are alive at 82, 36, and 16 weeks after hyperthermic intraperitoneal chemotherapy. CONCLUSIONS: Patients less than 21 years with nonsyndromic colorectal carcinoma may have a poorer outcome. Novel, more aggressive therapy may be necessary in these patients. PMID- 25746913 TI - Assessing temporal modulation sensitivity using electrically evoked auditory steady state responses. AB - Temporal cues are important for cochlear implant (CI) users when listening to speech. Users with greater sensitivity to temporal modulations show better speech recognition and modifications to stimulation parameters based on modulation sensitivity have resulted in improved speech understanding. Behavioural measures of temporal sensitivity require cooperative participants and a large amount of time. These limitations have motivated the desire for an objective measure with which to appraise temporal sensitivity for CI users. Electrically evoked auditory steady state responses (EASSRs) are neural responses to periodic electrical stimulation that have been used to predict threshold (T) levels. In this study we evaluate the use of EASSRs as a tool for assessing temporal modulation sensitivity. Modulation sensitivity was assessed behaviourally using modulation detection thresholds (MDTs) for a 20 Hz rate. On the same stimulation sites, EASSRS were measured using sinusoidally amplitude modulated pulse trains at 4 and 40 Hz. Measurements were taken using a bipolar configuration on 12 electrode pairs over 5 participants. Results showed that EASSR amplitudes and signal-to noise ratios (SNRs) were significantly related to the MDTs. Larger EASSRs corresponded with sites of improved modulation sensitivity. This relation was driven by across-subject variation. This result indicates that EASSRs may be used as an objective measure of site-specific temporal sensitivity for CI users. PMID- 25746914 TI - Modulation frequency discrimination with single and multiple channels in cochlear implant users. AB - Temporal envelope cues convey important speech information for cochlear implant (CI) users. Many studies have explored CI users' single-channel temporal envelope processing. However, in clinical CI speech processors, temporal envelope information is processed by multiple channels. Previous studies have shown that amplitude modulation frequency discrimination (AMFD) thresholds are better when temporal envelopes are delivered to multiple rather than single channels. In clinical fitting, current levels on single channels must often be reduced to accommodate multi-channel loudness summation. As such, it is unclear whether the multi-channel advantage in AMFD observed in previous studies was due to coherent envelope information distributed across the cochlea or to greater loudness associated with multi-channel stimulation. In this study, single- and multi channel AMFD thresholds were measured in CI users. Multi-channel component electrodes were either widely or narrowly spaced to vary the degree of overlap between neural populations. The reference amplitude modulation (AM) frequency was 100 Hz, and coherent modulation was applied to all channels. In Experiment 1, single- and multi-channel AMFD thresholds were measured at similar loudness. In this case, current levels on component channels were higher for single-than for multi-channel AM stimuli, and the modulation depth was approximately 100% of the perceptual dynamic range (i.e., between threshold and maximum acceptable loudness). Results showed no significant difference in AMFD thresholds between similarly loud single- and multi-channel modulated stimuli. In Experiment 2, single- and multi-channel AMFD thresholds were compared at substantially different loudness. In this case, current levels on component channels were the same for single- and multi-channel stimuli ("summation-adjusted" current levels) and the same range of modulation (in dB) was applied to the component channels for both single- and multi-channel testing. With the summation-adjusted current levels, loudness was lower with single than with multiple channels and the AM depth resulted in substantial stimulation below single-channel audibility, thereby reducing the perceptual range of AM. Results showed that AMFD thresholds were significantly better with multiple channels than with any of the single component channels. There was no significant effect of the distribution of electrodes on multi-channel AMFD thresholds. The results suggest that increased loudness due to multi-channel summation may contribute to the multi-channel advantage in AMFD, and that overall loudness may matter more than the distribution of envelope information in the cochlea. PMID- 25746915 TI - The role of complement factor C3 in lipid metabolism. AB - Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low grade inflammation associated with obesity. PMID- 25746916 TI - Clinical deployment of antibodies for treatment of melanoma. AB - The concept of using immunotherapy to treat melanoma has existed for decades. The rationale comes from the knowledge that many patients with melanoma have endogenous immune responses against their tumor cells and clinically meaningful tumor regression can be achieved in a minority of patients using cytokines such as interleukin-2 and adoptive cellular therapy. In the last 5 years there has been a revolution in the clinical management of melanoma in large measure based on the development of antibodies that influence T cell regulatory pathways by overcoming checkpoint inhibition and providing co-stimulation, either of which results in significantly more effective immune-mediated tumor destruction. This review will describe the pre-clinical and clinical application of antagonistic antibodies targeting the T-cell checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), and agonistic antibodies targeting the costimulatory pathways OX40 and 4-1BB. Recent progress and opportunities for future investigation of combination antibody therapy will be described. PMID- 25746917 TI - Thermoluminescence properties of irradiated commercial color pencils for accidental retrospective dosimetry. AB - Color pencils are widely used mostly in kindergartens, in schools and could be found in all houses with families having young children. Their wide spread use in modern times as well as their chemical composition, consisting mostly of Si and Al, constitute two strong motivations towards exploiting their use as accidental retrospective thermoluminescent dosimeters. The present manuscript reports on the study of colored pencils manufactured by a commercial brand in China which is very common throughout Turkey. The preliminary results discussed in the present work illustrated encouraging characteristics, such as the presence of a trapping level giving rise to natural TL in a temperature range that is sufficiently high. Specific thermoluminescence features of this peak, such as glow peak shape and analysis, anomalous fading, thermal quenching, reproducibility, linearity and recovery ability to low attributed doses were studied. The results suggest that the color pencils could be effectively used in the framework of retrospective thermoluminescent dosimetry with extreme caution, based on multiple aliquot protocols. PMID- 25746918 TI - Thermoluminescent properties of ZnS:Mn nanocrystalline powders. AB - Thermoluminescent ZnS nanocrystals doped with Mn(2+) ions were synthesized by chemical co-precipitation method. From X-ray diffraction studies it was observed that the synthesized nanoparticles have cubic zinc blende structure with average sizes of about 40-50nm. Morphology was analyzed by TEM. Photoluminescence studies showed two transitions, one of them close to 396nm and other close to 598nm, which is enhanced with increasing dopant concentration, this behavior was also observed in the cathodoluminescence spectrum. The thermoluminescence gamma dose response has linear behavior over dose range 5-100mGy, the glow curve structure shows two glow peaks at 436K and at 518K that were taken into account to calculate the kinetic parameters using the Computerized Glow Curve Deconvolution procedure. PMID- 25746919 TI - Modification of the radial beam port of ITU TRIGA Mark II research reactor for BNCT applications. AB - This paper aims to describe the modification of the radial beam port of ITU (Istanbul Technical University) TRIGA Mark II research reactor for BNCT applications. Radial beam port is modified with Polyethylene and Cerrobend collimators. Neutron flux values are measured by neutron activation analysis (Au Cd foils). Experimental results are verified with Monte Carlo results. The results of neutron/photon spectrum, thermal/epithermal neutron flux, fast group photon fluence and change of the neutron fluxes with the beam port length are presented. PMID- 25746920 TI - Characterizing treated wastewaters of different industries using clustered fluorescence EEM-PARAFAC and FT-IR spectroscopy: implications for downstream impact and source identification. AB - The quantity and spectroscopic features of dissolved organic matter (DOM) in treated wastewaters were studied for up to 57 facilities across 12 industrial categories to evaluate the potential influences of the effluents on downstream ecosystems and the feasibility of spectroscopic techniques in discriminating pollution sources. The average dissolved organic carbon (DOC) concentration was 3.30+/-0.70-73.4+/-14.0 mg L(-1) for each category, high enough to pollute downstream waterbodies. The average specific UV absorbance at 254 nm (SUVA) for each category spanned a broad range between 0.79+/-0.24 and 5.35+/-1.41 L(mg m)( 1), suggesting a variable aromaticity of DOM. Fluorescence excitation emission matrix-parallel factor analysis (EEM-PARAFAC) identified four humic-like and two protein-like components. The EEMs were grouped into seven clusters, five of which were dominated by a single PARAFAC component in each cluster. Fourier transform infrared (FT-IR) spectroscopy revealed notable variations in relative intensities of several characteristic absorbance bands among different wastewaters. The large variability in SUVA, PARAFAC and FT-IR features indicated that the chemical composition of DOM greatly differ among industrial wastewaters, and further implied variable biogeochemical reactivity in downstream waterbodies. The results also suggested the potential of DOM features in discriminating different wastewaters, although the variations within each industrial category were also significant. PMID- 25746921 TI - The fin whale, a marine top consumer, exposes strengths and weaknesses of the use of fluoride as ecological tracer. AB - Fluoride is retained in bone tissues of animals and its availability in the environment varies between regions according to natural and anthropogenic sources. These properties suggest this element as a suitable tracer of origin, distribution or movements of animals. In marine environments, krill builds-up fluoride concentrations that are transferred to its predators. In this study we examine the ability of bone fluoride concentrations to discriminate two separate populations of a krill consumer, the fin whale. Background levels of the sampling areas (Western Iceland and North-Western Spain) were determined through the analysis of krill samples. As expected, due to the high load of volcanic-derived fluoride in Icelandic waters, krill from W Iceland showed much higher fluoride concentrations than that from NW Spain. Concentrations in whales' bone were correlated with sex and age, increasing linearly with age in females and showing significantly lower values and a different age-related pattern of accumulation in males. Fluoride concentrations in whales' bone were much higher than in krill, indicating accumulation of the element but, rather unexpectedly, the area of origin had no influence on concentrations. This apparent contradiction may be explained either by the integration in bone of food consumed in other areas, or by the activation of homeostatic responses at very high levels of fluoride exposure. It is concluded that fluoride can be a useful tracer only if age and sex data are integrated into the analysis, year-round information on diet is available and/or the investigated population is exposed to mild levels of this element. PMID- 25746922 TI - Micromanaging of tumor metastasis by extracellular vesicles. AB - Extracellular vesicles (EVs) are nanometer-sized membranous vesicles that are released by a variety of cell types into the extracellular space. In the past two decades, EVs have emerged as novel mediators of cancer biology. Many reports have demonstrated the contribution of EVs to cancer metastasis. Metastasis is a multistep process that is responsible for the majority of deaths in cancer patients. This process includes proliferation, angiogenesis, immune modulation, extravasation, intravasation, and colonization. EVs from cancer cells impact these steps through modulation of the host immune system, angiogenesis, and pre /pro-metastatic niche formation. In this review, we summarize the function of EVs in cancer metastasis. In addition, we also discuss the hurdles to be overcome for further developing this research field. PMID- 25746923 TI - Oral administration of Lactococcus lactis subsp. lactis JCM5805 enhances lung immune response resulting in protection from murine parainfluenza virus infection. AB - When activated by viral infection, plasmacytoid dendritic cells (pDCs) play a primary role in the immune response through secretion of IFN-alpha. Lactococcus lactis subsp. lactis JCM5805 (JCM5805) is a strain of lactic acid bacteria (LAB) that activates murine and human pDCs to express type I and type III interferons (IFNs). JCM5805 has also been shown to activate pDCs via a Toll-like receptor 9 (TLR9) dependent pathway. In this study, we investigated the anti-viral effects of oral administration of JCM5805 using a mouse model of murine parainfluenza virus (mPIV1) infection. JCM5805-fed mice showed a drastic improvement in survival rate, prevention of weight loss, and reduction in lung histopathology scores compared to control mice. We further examined the mechanism of anti-viral effects elicited by JCM5805 administration using naive mice. Microscopic observations showed that JCM5805 was incorporated into CD11c+ immune cells in Peyer's patches (PP) and PP pDCs were significantly activated and the expression levels of IFNs were significantly increased. Interestingly, nevertheless resident pDCs at lung were not activated and expressions levels of IFNs at whole lung tissue were not influenced, the expressions of anti-viral factors induced by IFNs, such as Isg15, Oasl2, and Viperin, at lung were up-regulated in JCM5805-fed mice compared to control mice. Therefore expressed IFNs from intestine might be delivered to lung and IFN stimulated genes might be induced. Furthermore, elevated expressions of type I IFNs from lung lymphocytes were observed in response to mPIV1 ex vivo stimulation in JCM5805-fed mice compared to control. This might be due to increased ratio of pDCs located in lung were significantly increased in JCM5805 group. Taken together, a specific LAB strain might be able to affect anti-viral immunological profile in lung via activation of intestinal pDC leading to enhanced anti-viral phenotype in vivo. PMID- 25746924 TI - Agitation down-regulates immunoglobulin binding protein EibG expression in Shiga toxin-producing Escherichia coli (STEC). AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) carrying eibG synthesize Escherichia coli immunoglobulin binding protein (EibG). EibG nonspecifically binds to immunoglobulins and tends to aggregate in multimers but is poorly expressed in wild-type strains. To study synthesis of the proteins and their regulation in the pathogens, we identified natural growth conditions that increased EibG synthesis. EibG proteins as well as corresponding mRNA were highly expressed under static growth conditions while shearing stress created by agitation during growth repressed protein synthesis. Further regulation effects were driven by reduced oxygen tension, and pH up-regulated EibG expression, but to a lesser extent than growth conditions while decreased temperature down regulated EibG. Bacteria with increased EibG expression during static growth conditions showed a distinct phenotype with chain formation and biofilm generation, which disappeared with motion. High and low EibG expression was reversible indicating a process with up- and down-regulation of the protein expression. Our findings indicate that shear stress represses EibG expression and might reduce bacterial attachments to cells and surfaces. PMID- 25746925 TI - Correction: Mechanical stress downregulates MHC class I expression on human cancer cell membrane. PMID- 25746927 TI - Breed, gender and age pattern of diagnosis for veterinary care in insured dogs in Japan during fiscal year 2010. AB - We calculated the annual prevalence of diseases of 18 diagnostic categories in the insured dog population in Japan, using data from 299,555 dogs insured between April 2010 and March 2011. The prevalence was highest for dermatological disorders (22.6% for females and 23.3% for males), followed by otic diseases (16.4% for females and 17.2% for males) and digestive system disorders (15.7% for females and 16.4% for males). The prevalence of cardiovascular, urinary, neoplasia and endocrine disorders, increased with age; infectious diseases and injuries showed a high prevalence at young ages, and the prevalence of musculoskeletal and respiratory disorders showed a bimodal peak at young and old ages. A large variation in prevalence was observed between breeds for dermatological, otic, digestive, ophthalmological and cardiovascular disorders. PMID- 25746926 TI - Exposure of Trypanosoma brucei to an N-acetylglucosamine-binding lectin induces VSG switching and glycosylation defects resulting in reduced infectivity. AB - Trypanosoma brucei variant surface glycoproteins (VSG) are glycosylated by both paucimannose and oligomannose structures which are involved in the formation of a protective barrier against the immune system. Here, we report that the stinging nettle lectin (UDA), with predominant N-acetylglucosamine-binding specificity, interacts with glycosylated VSGs and kills parasites by provoking defects in endocytosis together with impaired cytokinesis. Prolonged exposure to UDA induced parasite resistance based on a diminished capacity to bind the lectin due to an enrichment of biantennary paucimannose and a reduction of triantennary oligomannose structures. Two molecular mechanisms involved in resistance were identified: VSG switching and modifications in N-glycan composition. Glycosylation defects were correlated with the down-regulation of the TbSTT3A and/or TbSTT3B genes (coding for oligosaccharyltransferases A and B, respectively) responsible for glycan specificity. Furthermore, UDA-resistant trypanosomes exhibited severely impaired infectivity indicating that the resistant phenotype entails a substantial fitness cost. The results obtained further support the modification of surface glycan composition resulting from down-regulation of the genes coding for oligosaccharyltransferases as a general resistance mechanism in response to prolonged exposure to carbohydrate-binding agents. PMID- 25746928 TI - The prevalence and distribution of Brucella melitensis in goats in Malaysia from 2000 to 2009. AB - A study was conducted to describe the prevalence and distribution of zoonotic Brucella melitensis in goats in Peninsular Malaysia. Using serosurveillance data of the last decade (2000-2009) involving 119,799 goats and 3555 farms, the seroprevalence of brucellosis among goats was 0.91% (95% CI=0.86-0.96) and among farms was 7.09% (95% CI=6.27-7.98). The odds of brucellosis was significantly (P<0.05) higher in the later part of the decade, in larger herd size and among the states located in the peninsula as compared to eastern Malaysia. The infection was detected throughout Malaysia but at generally low seroprevalences with states like Perlis that border neighbouring countries having higher seroprevalence of brucellosis than other non-border states. PMID- 25746929 TI - Design of a detection survey for Ostreid herpesvirus-1 using hydrodynamic dispersion models to determine epidemiological units. AB - Using Ostreid herpesvirus-1 (OsHV-1) as a case study, this paper considers a survey design methodology for an aquatic animal pathogen that incorporates the concept of biologically independent epidemiological units. Hydrodynamically modelled epidemiological units are used to divide marine areas into sensible sampling units for detection surveys of waterborne diseases. In the aquatic environment it is difficult to manage disease at the animal level, hence management practices are often aimed at a group of animals sharing a similar risk. Using epidemiological units is a way to define these groups, based on a similar level of probability of exposure based on the modelled potential spread of a viral particle via coastal currents, that can help inform management decisions. PMID- 25746930 TI - Mechanical characterization of oligo(ethylene glycol)-based hydrogels by dynamic nanoindentation experiments. AB - Oligo(ethylene glycol)-based (OEG) hydrogel samples of varying cross-link densities and degrees of swelling were characterized through dynamic nanoindentation testing. Experiments were performed using a non-standard nanoindentation method, which was validated on a standard polystyrene sample. This method maximizes the capability of the instrument to measure the stiffness and damping of highly compliant, viscoelastic materials. Experiments were performed over the frequency range of 1 to 50 Hz, using a 1mm diameter flat punch indenter. A hydration method was adopted to avoid sample dehydration during testing. Values of storage modulus (E') ranged from 3.5 to 8.9 MPa for the different OEG-hydrogel samples investigated. Samples with higher OEG concentrations showed greater scatter in the modulus measurements and it is attributed to inhomogeneities in these materials. The (E') values did not show a strong variation over frequency for any of the samples. Values of loss modulus (E") were two orders of magnitude lower than the storage modulus, resulting in very low values of loss factor (E"/E'<0.1). These are characteristics of strong gels, which present negligible viscous properties. PMID- 25746931 TI - Aging of retrieved gel breast implants: a comparison between two product generations. AB - In order to get a marketing authorization, breast implants (BI) must meet a number of standard requirements. French and European standards ISO 14607 list a number of official tests to be performed before an implant can be used clinically. However, the BI material characteristics evolution over implantation time remains a research field which is unexplored. The goal of the present study is to compare the mechanical ageing of two breast implant generations and assess if the use of one generation rather than the other is advantageous in terms of durability. For that purpose, 21 explanted BI were analyzed in terms of biomechanical characteristics and compared. Twelve BI were textured anatomic specimens of 5th generation and 10 BI were round textured specimens of 4th generation. All the specimens were produced by the same manufacturer. Implantation time ranged from 3 to 130 months. Both the shell and the gel of every specimen were analyzed. Results show that the mechanical properties go down with the implantation time for all the implants. Moreover, the shell of round implants appear to be less resistant than the shell of anatomic specimens with 25% lower rupture forces. With regard to the gel, whatever the specimen, results show that the properties change with implantation time. The color changes from transparent to milky to finally become yellow, while the cohesion goes down especially for the round specimens. Globally, the study brings out that BI get degraded with implantation time and provides information which could help predicting the durability of the implant. PMID- 25746932 TI - [Physical activity reference for health promotion 2013 and the prevalence of metabolic syndrome: A cross-sectional study]. AB - OBJECTIVES: This study aimed to examine the association between meeting the reference value for physical activity (PA) defined in the "Physical activity reference for health promotion 2013" recommendations or incremental increases in PA (add 10-minute per day) and the prevalence of metabolic syndrome (MS). METHODS: A total of 906 adults aged 23-64 years participated in this cross sectional study. The amount of moderate to vigorous PA was measured with a tri axial accelerometer. The participants were classified into 2 groups-those with a PA level greater than or equal to the reference value of 23 metabolic equivalents (METs)-hours/week versus those with a PA level less than the reference value. Pre MS and MS were determined based on the diagnostic criteria used in Japan. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of pre-MS and MS by adherence with the PA reference value were analyzed using a multivariable logistic regression model. Furthermore, adjusted ORs were calculated for each 3.5 METs-hours/week increase in PA, which is comparable to 10 minute increments of PA such as walking. RESULTS: The prevalence rates of pre-MS and MS were 10.3% (n=93) and 4.4% (n=40), respectively. The adjusted OR (95% CI) for the prevalence of pre-MS/MS among the participants meeting the PA reference compared with those not meeting the reference was 0.49 (0.33-0.74). Each 3.5 METs hours/week increase in PA was associated with a lower adjusted OR for the prevalence of pre-MS/MS (OR 0.92, 95% CI 0.87-0.98). CONCLUSION: Our results suggest that meeting the reference value for PA (as defined in the "Physical activity reference for health promotion 2013" recommendations) and an increase in PA (add 10-minute) are both associated with a lower prevalence of pre-MS/MS. PMID- 25746933 TI - [Factors related to smoking and consumption of alcohol and kava in children attending the upper grades of primary schools in Vanuatu]. AB - OBJECTIVES: To identify factors related to smoking and consumption of alcohol and kava in children attending the upper grades of primary schools in Vanuatu. METHODS: We conducted a self-administered survey of 6th, 7th, and 8th grade students attending primary schools in both urban and rural areas of Vanuatu. The main survey items included questions on the personal attribute (sex, age, grade); experience of smoking and consumption of alcohol and kava; food consumption (local food/store-bought food); perceptions of local foods and store-bought foods; attitudes toward smoking and consumption of alcohol and kava; knowledge related to non-communicable diseases; attitudes toward health practices; guardians' health-related parenting attitudes; and family members' use of tobacco, alcohol, and kava.The responses for the main outcome variables (smoking and consumption of alcohol and kava) were dichotomized as 'ever' versus 'never'. Factors related to smoking and consumption of alcohol and kava were examined using logistic regression analysis. The significance level was set at P<0.05. RESULTS: A total of 415 (194 urban and 221 rural) students participated in our study that had total and valid response rates of 100% for both. Of the participants, 8%, 12.4%, and 5.8% had previously smoked, consumed alcohol, or consumed kava, respectively. Students' experience of smoking and consumption of alcohol and kava were mutually associated. Student sex and family members' smoking status were significantly associated with the participants' smoking status. Student grades, attitudes toward drinking, and perceptions of local and store-bought food were significantly associated with alcohol consumption. Lastly, attitudes toward kava and alcohol consumption and perceptions of local food were significantly associated with kava consumption. CONCLUSION: Our results indicate that the food consumption, attitudes toward smoking and consumption of alcohol and kava, and family members' smoking status were associated with the participants' smoking and consumption of alcohol and kava. In conclusion, it may be necessary to consider these factors when establishing measures to prevent smoking and consumption of alcohol and kava among primary school students. PMID- 25746934 TI - Reprint of: photostability of wool fabrics coated with pure and modified TiO2 colloids. AB - The surface of wool fabrics was coated with TiO2 and TiO2-based nanocomposite colloids and the impact of this coating on the photostability of wool was investigated. TiO2 along with TiO2/Metal and TiO2/Metal/SiO2 sols were synthesized through a low-temperature sol-gel method and applied to fabrics. Composite colloids were synthesized through integrating the silica and three noble metals of silver (Ag), gold (Au) and platinum (Pt) into the synthesis process of sols. Four different molar ratios of Metal to TiO2 (0.01%, 0.1%, 0.5% and 1%) were used to elucidate the role of metal type and amount on the obtained features. Photostability and UV protection features of fabrics were evaluated through measuring the photo-induced chemiluminescence (PICL), photoyellowing rate and ultraviolet protection factor (UPF) of fabrics. PICL and photoyellowing tests were carried out under UVA and UVC light sources, respectively. PICL profiles demonstrated that the presence of pure and modified TiO2 nanoparticles on fabrics reduced the intensity of PICL peak indicating a lower amount of polymer free radicals in coated wool, compared to that of pristine fabric. Moreover, a higher PICL peak intensity as well as photoyellowing rate was observed on fabrics coated with modified colloids in comparison with pure TiO2. The surface morphology of fabrics was further characterized using FESEM images. PMID- 25746935 TI - Substitution of sugar-sweetened beverages with other beverage alternatives: a review of long-term health outcomes. AB - BACKGROUND: Excessive consumption of sugar-sweetened beverages (SSBs) has become an intractable public health concern worldwide, making investigation of healthy beverage alternatives for SSBs imperative. AIM: To summarize the available evidence on the effects of replacing SSBs with beverage alternatives on long-term health outcomes. METHOD: We systematically retrieved studies from six electronic databases from inception to November 2013. Prospective cohort studies and randomized controlled trials (RCTs) examining the effects of substituting beverage alternatives for SSBs on long-term health outcomes in both children and adults were included. The quality of included studies was assessed using the Scottish Intercollegiate Guidelines Network 50 methodology checklists. RESULTS: Six cohort studies and four RCTs were included in the systematic review with the quality rating ranging from acceptable to high. Evidence from both cohort studies and RCTs showed substitution of SSBs by various beverage alternatives was associated with long-term lower energy intake and lower weight gain. However, evidence was insufficient to draw conclusions regarding the effect of beverage substitution on other health outcomes, and which beverage alternative is the best choice. CONCLUSIONS: Although studies on this topic are sparse, the available evidence suggests a potential beneficial effect on body weight outcomes when SSBs are replaced by water or low-calorie beverages. Further studies in this area are warranted to fully understand the long-term health implications of beverage substitutions. PMID- 25746936 TI - Ultrastructure of the replication sites of positive-strand RNA viruses. AB - Positive strand RNA viruses replicate in the cytoplasm of infected cells and induce intracellular membranous compartments harboring the sites of viral RNA synthesis. These replication factories are supposed to concentrate the components of the replicase and to shield replication intermediates from the host cell innate immune defense. Virus induced membrane alterations are often generated in coordination with host factors and can be grouped into different morphotypes. Recent advances in conventional and electron microscopy have contributed greatly to our understanding of their biogenesis, but still many questions remain how viral proteins capture membranes and subvert host factors for their need. In this review, we will discuss different representatives of positive strand RNA viruses and their ways of hijacking cellular membranes to establish replication complexes. We will further focus on host cell factors that are critically involved in formation of these membranes and how they contribute to viral replication. PMID- 25746937 TI - Is neural adaptation of the N170 category-specific? Effects of adaptor stimulus duration and interstimulus interval. AB - Neural adaptation paradigms have been used in the electrophysiological and neuroimaging literature to characterise neural populations underlying face and object perception. It was recently reported by Nemrodov and Itier (2012) that adaptation of the N170 event-related potential (ERP) component is not stimulus category-specific over rapid adapting stimulus durations (S1 durations) and interstimulus intervals (ISIs). We therefore tested the category-specificity of adaptation over a range of S1 durations and ISIs. Faces and chairs were presented at S1 (for 200, 500 or 1000 ms) and S2 (for 200 ms), over a variable ISI (200 or 500 ms). Mean amplitudes of the P1, N170 and P2 visual ERP components were measured following S1 and S2 stimuli. Faces at S1 led to the smallest (i.e., most adapted) N170 amplitudes to both faces and chairs at S2, more than chairs at S1. N170s at S2 were smallest after a 500ms S1 duration; but N170 amplitude did not vary over ISI. Effects were also seen for the two surrounding positive components, the P1 and P2. Presenting faces at S1 led to enhanced P1 amplitudes evoked by S2 chair stimuli. The P2 showed the smallest amplitudes following the shorter 200 ms ISI. These results indicate that adaptation of the N170 is not actually category-specific but instead dependent on the S1 category (regardless of S2 category), and may also be influenced by earlier effects at the P1 (i.e., not specific to the N170). This challenges the assumption that N170 category adaptation indexes effects on distinct neural populations that differ between faces and non-face objects. PMID- 25746938 TI - Infant diet, gender and the development of vagal tone stability during the first two years of life. AB - Postnatal nutrition influences neurodevelopment, but it is not known whether the development of individual differences in physiologic measures is related to variations in early postnatal diet. To address this issue we studied the stability of vagal tone (V)--an index of individual differences in parasympathetic heart rate control-by measuring resting V quarterly during infancy and again at 2 years in 146 breast-fed (BF), 143 milk formula-fed (MF), and 137 soy formula-fed (SF) infants. Stability of V across infancy was more consistently significant for BF than formula-fed infants. Stability was similar for boys and girls in BF and SF groups but was generally higher in boys than girls in the MF group. Significant stability between infancy and 2 years emerged later in SF than other groups and later in boys than girls. Stability generally peaked between 6 and 9 months-a time when postnatal vagal myelination slows and which may represent a pivotal stage in the development of V stability. These findings indicate that infant diet and gender are important modulators of the early development of autonomic state control. PMID- 25746939 TI - Head-to-head comparison of the Montreal nomogram with the detection of primary malignant circulating prostate cells to predict prostate cancer at initial biopsy in Chilean men with suspicion of prostate cancer. AB - INTRODUCTION: The limitations of total serum prostate-specific antigen (PSA) level values remain problematic. Nomograms may improve the predictive value of a positive prostate biopsy (PB) finding. We compare in a prospective study of Chilean men suspicious of having prostate cancer (PC), owing to an elevated total serum PSA or abnormal digital rectal examination finding or both, the use of the online Montreal nomogram for the detection of primary malignant circulating prostate cells (mCPCs) to predict a positive PB finding. METHODS AND PATIENTS: Consecutive men suspicious of PC underwent 12-core transrectal ultrasound PB; their age, total serum PSA levels and percent free PSA values, and Montreal nomogram scores were registered. Immediately before the PB, an 8-ml blood sample was taken to detect primary mCPCs. Mononuclear cells were obtained by differential gel centrifugation and identified using double immunomarcations with anti-PSA and anti-P504S. Biopsies were classified according to presence of cancer/no cancer. The test results for the detection of mCPC were stated as negative/positive, and the total number of cells/8 ml of blood was registered. Areas under the curve for total serum PSA level, percent free PSA value, Montreal score, and detection of mCPCs were calculated and compared. Diagnostic yields, the number of possible biopsies that could be avoided, and the number of clinically significant cancers that would be missed were calculated. RESULTS: Overall, 607 men underwent biopsy, where 197 (32.5%) had cancer. These men were significantly older, had higher total serum PSA level and Montreal score, and lower percent free PSA value. The values for area under the curve were 0.56 for total PSA level, 0.78 for percent free PSA, 0.78 for Montreal score, and 0.84 for mCPC detection; mCPC detection had a significantly superior prediction value (P = 0.018). Using cutoff values of percent free PSA < 10%, Montreal score > 50%, and >= 1 mCPC detected, mCPC detection had a higher diagnostic yield. Of the 197 cancers, 41 complied with the criteria for active surveillance; percent free PSA and the Montreal score missed a higher number of significant cancers when compared with mCPC detection. CONCLUSIONS: Primary mCPC detection outperformed the use of percent free PSA and the Montreal nomogram in predicting clinically significant PC at initial PB. PMID- 25746940 TI - Locoregional symptoms in patients with de novo metastatic prostate cancer: Morbidity, management, and disease outcome. AB - BACKGROUND: The paradigm change observed over the last few years in several solid tumors emphasizes the value of locoregional treatment in the presence of metastatic disease, currently ignored in de novo prostate cancer (CaP). We investigated the effect of the primary tumor that is left untreated on prostate cancer-specific morbidity and mortality, time to castration resistance, and overall survival (OS). METHODS: We performed a bicentric cohort study. The overall population included de novo metastatic CaP managed at the Genito-Urinary Oncology Unit of the Gustave Roussy Institute and the Urology Clinic of the University Hospital of Pointe-a-Pitre, France. Descriptive statistical and outcome analyses were performed in the overall cohort and also separately in the N+M0 and M+subgroups. RESULTS: The overall cohort included 263 patients. Approximately two-thirds of patients (64%) presented with locoregional symptoms at diagnosis, and 78% throughout the disease. Of the symptomatic patients, 59% required a locoregional procedure. Median OS of patients with locoregional symptoms at diagnosis was shorter than in those who were asymptomatic (47 vs. 86 mo, P = 0.0007); this difference was maintained in the N+M0 and M+subgroups. Median OS and time to castration resistance showed a nonsignificant trend in favor of patients undergoing a locoregional treatment at diagnosis. CONCLUSION: The presence of symptoms due to locoregional disease in de novo metastatic CaP entails significant morbidity and even mortality and requires active management. Randomized prospective trials are needed to evaluate the role of initial definite locoregional treatment in these patients. PMID- 25746941 TI - The role of the prostate cancer gene 3 urine test in addition to serum prostate specific antigen level in prostate cancer screening among breast cancer, early onset gene mutation carriers. AB - OBJECTIVE: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers. MATERIALS AND METHODS: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level >= 3.0 ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate b iopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed. RESULTS: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff >= 25; 34%) or 134 (cutoff >= 35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (>= 25; 28%) or 109 (>= 35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff >= 25) or 43 (cutoff >= 35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated. CONCLUSIONS: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels. PMID- 25746942 TI - Biomarker development in the context of urologic cancers. AB - BACKGROUND: The Food and Drug Administration (FDA) has called for the use of analytically validated biomarkers that have strong evidence of being fit for purpose to identify patients likely to respond and to evaluate the patient response to a therapy, potential toxicity, and drug resistance. This article discusses development and application of these biomarkers in the context of urologic cancers-specifically in cancers of the prostate and urinary bladder. METHODS: The FDA has defined four specific categories for contexts of biomarker use: prognostic, predictive, response-indicator, and efficacy-response (surrogate endpoints). Prognostic and predictive biomarkers include pretreatment characteristics of the patient and the tumor. Response-indicator and efficacy response biomarkers occur after treatment and show the effects of treatment on biomarkers. Efficacy response biomarkers show changes associated with clinical benefit and can be surrogates for clinical endpoints leading to drug approvals. RESULTS: Well-structured development plans are required to satisfy rigorous criteria that must be met to qualify biomarkers for specific contexts of use in drug development and patient management. A description of the extensive effort applied to the validation and qualification of circulating tumor cells in castration resistant prostate cancer is described as an example of the potential utility of biomarkers in urological cancers. CONCLUSIONS: Many potential biomarkers have been identified in prostate and urinary bladder cancers, but few have sufficient demonstration of analytical and clinical validity to meet FDA standards for use in clinical settings. Circulating tumor cell (CTC) assays are particularly promising candidates for informative new biomarkers to measure disease before and after treatment. New technologies are providing opportunities for high definition, more informative analysis. Statistical and computational methodologies to describe assay results are also rapidly evolving. These advances will lead to better diagnosis, earlier indications of treatment response and failure, and better definition of patient cohorts that will respond to a specific treatment. PMID- 25746943 TI - Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI: An updated meta-analysis of 10,350 patients from five randomized clinical trials. AB - AIMS: To evaluate the impact of bivalirudin versus heparin on efficacy and safety outcomes of ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) and to explore the impact of differential use (bailout vs. routine) of glycoprotein IIb/IIIa inhibitors (GPI). METHODS AND RESULTS: Five randomized controlled trials encompassing 10,350 patients were included. Primary efficacy and safety endpoints were all-cause death and major bleeding, respectively. All-cause death at 30 days did not significantly differ with bivalirudin compared to heparin (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.74-1.28; P=0.84). Major bleeding was significantly reduced by bivalirudin compared to heparin (OR 0.58, 95% CI 0.40 0.85; P=0.005). Bivalirudin use was associated with non-significantly different rates of 30-day definite stent thrombosis (ST) (OR 1.71, 95% CI 0.84-3.49; P=0.14), albeit with higher rates of acute ST (OR 3.55, 95% CI 1.67-7.56; P=0.001) and non-significantly different rates of subacute ST (OR 0.86, 95% CI 0.46-1.61; P=0.64). There were non-significant differences in the 30-day rates of reinfarction (OR 1.47, 95% CI 0.94-2.30; P=0.10) and cardiovascular death (OR 0.76, 95% CI 0.56-1.02; P=0.07). There were no significant interactions between bailout versus routine GPI use in the heparin arm for any of the safety or efficacy outcomes (all Pinteraction>0.10). CONCLUSIONS: Bivalirudin compared with heparin was associated with comparable 30-day rates of mortality with reduced major bleeding, at the price of an increased risk of acute ST, with non significant differences in the overall 30-day rates of ST and reinfarction. Intended use of GPI in the heparin arm did not significantly modify the treatment effects of bivalirudin. Given the important differences between trials, as well as evolution in technique and adjunct pharmacotherapy, further randomized trials are warranted to discriminate whether there are substantial safety and efficacy differences between these agents during primary PCI in STEMI. PMID- 25746944 TI - Uncommon cause of intracardiac thrombus. AB - We present a rare image documenting direct transit of a thrombus originating from the venous circulation and passing through a patent foramen ovale linked to a malpositioned cannula in the setting of temporary mechanical circulatory assistance in a young patient who underwent a peripheral extra corporeal membrane oxygenation as a circulatory support. PMID- 25746945 TI - Dissociation of anatomical and functional alterations of the default-mode network in first-episode, drug-naive schizophrenia. AB - OBJECTIVE: Anatomical and functional alterations of the default-mode network (DMN) have been implicated in the pathophysiology of schizophrenia. However, no study is engaged to explore whether structural and functional abnormalities of the DMN overlap in schizophrenia. This study was undertaken to examine whether anatomical and functional abnormalities are present in similar or different brain regions of the DMN in first-episode, drug-naive schizophrenia. METHODS: Forty nine first-episode, drug-naive schizophrenia patients and 50 age-, sex-, and education-matched healthy controls underwent structural and resting-state functional magnetic resonance imaging (fMRI) scanning. The voxel-based morphometry (VBM) and fractional amplitude of low-frequency fluctuation (fALFF) methods were used to analyze imaging data. RESULTS: The patients exhibited significantly decreased gray matter volume (GMV) in the left medial prefrontal cortex (orbital part) and increased fALFF in the left posterior cingulate cortex compared with the controls. No overlap of brain regions with anatomical and functional abnormalities was observed in the patient group. There was also no correlation between decreased GMV/increased fALFF and clinical variables in patients. CONCLUSIONS: A dissociation pattern of brain regions with anatomical and functional changes within the DMN is revealed in schizophrenia patients. SIGNIFICANCE: Our findings suggest that brain functional and anatomical abnormalities within the DMN might contribute independently to the pathophysiology of schizophrenia. PMID- 25746946 TI - Evaluation of microwave oven heating for prediction of drug-excipient compatibilities and accelerated stability studies. AB - Microwave ovens have been used extensively in organic synthesis in order to accelerate reaction rates. Here, a set up comprising a microwave oven combined with silicon carbide (SiC) plates for the controlled microwave heating of model formulations has been applied in order to investigate, if a microwave oven is applicable for accelerated drug stability testing. Chemical interactions were investigated in three selected model formulations of drug and excipients regarding the formation of ester and amide reaction products. In the accelerated stability studies, a design of experiments (DoE) approach was applied in order to be able to rank excipients regarding reactivity: Study A: cetirizine with PEG 400, sorbitol, glycerol and propylene glycol. Study B: 6-aminocaproic acid with citrate, acetate, tartrate and gluconate. Study C: atenolol with citric, tartaric, malic, glutaric, and sorbic acid. The model formulations were representative for oral solutions (co-solvents), parenteral solutions (buffer species) and solid dosage forms (organic acids applicable for solubility enhancement). The DoE studies showed overall that the same impurities were generated by microwave oven heating leading to temperatures between 150 degrees C and 180 degrees C as compared to accelerated stability studies performed at 40 degrees C and 80 degrees C using a conventional oven. Ranking of the reactivity of the excipients could be made in the DoE studies performed at 150-180 degrees C, which was representative for the ranking obtained after storage at 40 degrees C and 80 degrees C. It was possible to reduce the time needed for drug-excipient compatibility testing of the three model formulations from weeks to less than an hour in the three case studies. The microwave oven is therefore considered to be an interesting alternative to conventional thermal techniques for the investigation of drug-excipient interactions during preformulation. PMID- 25746947 TI - Surface characterization and protein interaction of a series of model poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanocarriers for drug targeting. AB - The surface properties of intravenously injected nanoparticles determine the acquired blood protein adsorption pattern and subsequently the organ distribution and cellular recognition. A series of poly[acrylonitrile-co-(N-vinyl pyrrolidone)] (PANcoNVP) model nanoparticles (133-181 nm) was synthesized, in which the surface properties were altered by changing the molar content of NVP (0 33.8 mol%) as the more hydrophilic repeating unit. The extent of achieved surface property variation was comprehensively characterized. The residual sodium dodecyl sulfate (SDS) content from the synthesis was in the range 0.3-1.6 MUgml(-1), potentially contributing to the surface properties. Surface hydrophobicity was determined by Rose Bengal dye adsorption, hydrophobic interaction chromatography (HIC) and aqueous two-phase partitioning (TPP). Particle charge was quantified by zeta potential (ZP) measurements including ZP-pH profiles. The interaction with proteins was analyzed by ZP measurements in serum and by adsorption studies with single proteins. Compared to hydrophobic polystyrene model nanoparticles, all PANcoNVP particles were very hydrophilic. Differences in surface hydrophobicity could be detected, which did not linearly correlate with the systematically altered bulk composition of the PANcoNVP nanoparticles. This proves the high importance of a thorough surface characterization applying a full spectrum of methods, complementing predictions solely based on bulk polymer composition. PMID- 25746948 TI - Comparative evaluation of polymeric and waxy microspheres for combined colon delivery of ascorbic acid and ketoprofen. AB - The goal of this work was to combine the ketoprofen anti-inflammatory effect with the ascorbic acid antioxidant properties for a more efficient treatment of colonic pathologies. With this aim, microspheres (MS) based on both waxy materials (ceresine, Precirol((r)) and Compritol((r))) or hydrophilic biopolymers (pectine, alginate and chitosan) loaded with the two drugs were developed, physicochemically characterized and compared in terms of entrapment efficiency, in vitro release profiles, potential toxicity and drug permeation properties across the Caco-2 cell line. Waxy MS revealed an high encapsulation efficiency of ketoprofen but a not detectable entrapment of ascorbic acid, while polymeric MS showed a good entrapment efficiency of both drugs. All MS need a gastro-resistant coating, to avoid any premature release of the drugs. Ketoprofen release rate from polymeric matrices was clearly higher than from the waxy ones. In contrast, the ASC release rate was higher, due to its high hydro-solubility. Cytotoxicity studies revealed the safety of all the formulations. Transport studies showed that the ketoprofen apparent permeability increased, when formulated with the different MS. In conclusion, only polymeric MS enabled an efficient double encapsulation of both the hydrophilic and lipophilic drugs, and, in addition, presented higher drug release rate and stronger enhancer properties. PMID- 25746949 TI - Benign subcutaneous emphysema: A case report with bite. AB - INTRODUCTION: Subcutaneous emphysema is the presence of air/gas within the subcutaneous tissue plane. Though there are numerous causative factors, benign subcutaneous emphysema is rare. CASE REPORT: We report a very rare case of benign subcutaneous emphysema following an insect bite on the forearm of a 48-year old man. The puncture area was erythematous and the emphysema extended to the whole arm, axilla and superior mediastinum. Despite, conservative management, the patient had residual discomfort and erythema around the puncture site. Surgical debridement resulted in resolution of symptoms. DISCUSSION: Subcutaneous emphysema affecting an isolated limb is extremely rare. It is vital to differentiate it from life-threatening soft-tissue infections secondary to a gas forming organism. Immunodeficiency states are key factors in the development and the outcomes of patients with subcutaneous emphysema. Medical management successfully resolves symptoms in the majority of cases. However, surgical debridement of the puncture site and surrounding fibrotic tissue has been advocated for those with persistent symptoms. CONCLUSION: This case highlights a rare cause of benign subcutaneous emphysema, highlighting key issues surrounding its management for a successful outcome. PMID- 25746950 TI - Unique case of sporadic multiple gastro intestinal stromal tumour. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and they derived from transformed neoplastic precursors of Cajal's interstitial cell (ICC). PRESENTATION OF THE CASE: We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient. Our patient showed anemia for the gastric GIST bleeding and only after other tumors were instrumentally and intra surgery discovered. The patient showed genetic mutation V559A/1676 T>C of the juxtamembrane domain of the exon 11 causing the replacement of Valine with Alanine in the 559 codon. DISCUSSION: GISTS estimated annual incidence is 12-14 per million. Multiple GISTs associated with familiarity or hereditary syndromes are described only in few case reports and sporadic mGISTs have not been studied yet. Literature review has been done. CONCLUSION: We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient localized trough out all the gastrointestinal tract. This is the only case of sporadic multiple GISTs reported in literature. PMID- 25746951 TI - Infraclavicular subpectoral lipoma causing thoracic outlet syndrome. AB - INTRODUCTION: Thoracic outlet syndrome (TOS) includes a group of disorders caused by extrinsic compression of neurovascular structures between the 1st rib and clavicle. It usually presents as an enlarging neck mass, with shoulder or upper limb pain, weakness, paresthesias and impalpable radial pulse (Raynaud's phenomenon). PRESENTATION OF CASE: We report a rare case of TOS caused by an infraclavicular subpectoral lipoma that, although challenging because of limited access and proximity of vital neurovascular structures, was successfully removed through a simple transaxillary incision with an excellent esthetic result. The patients is symptom-free 6 months after surgery. DISCUSSION: Multiplicity of symptoms makes causes, diagnosis, and treatment of TOS controversial. Accurate diagnosis of TOS can be a substantial challenge in practice, because of a lack of physician awareness, overlapping of clinical features, and an absence of clearly defined diagnostic criteria. TOS may be associated with the presence of a benign subpectoral mass like lipomas, that seldom have an irregular distribution that involve neurovascular structures. CONCLUSION: Although benign soft tissue tumors infraclavicular subpectoral lipomas may exert pressure on neurovascular surrounding structures during their progressive expansion and cause TOS. Therefore, a thorough preoperative study by radiological imaging such as MRI or neurophysiological test should always be performed in order to prevent unintentional lesions of the involved axillo-subclavicular plexus and plan correct surgical procedure. PMID- 25746952 TI - A rare case of a intracardiac lipoma. AB - INTRODUCTION: Primary tumors of the heart are exceedingly rare, accounting for less than 5% of all cardiac tumors; the remaining 95% of tumors are metastatic tumors to the heart. The most common primary cardiac tumors in adults are myxomas (usually occurring in the left atrium) followed by papillary fibroelastomas and lipomas with rhabdomyoma the most common in children. PRESENTATION OF CASE: We are presenting a case of a 74-years-old female who initially presents with dizziness. No other associated symptoms reported and initial labs were in normal range. Echocardiogram was done as part of the dizziness/syncope work up which demonstrated a large right atrial mass. Due to the size of the mass and patient being symptomatic the mass was surgically resected with complete resolution of her symptoms and pathology consistent with a lipoma. DISCUSSION: Cardiac lipomas are benign and may be associated with a spectrum of symptoms which depends upon the size and location of the lipoma; although most cardiac lipomas are found incidentally and are asymptomatic. The best radiologic study to identify and help differentiate cardiac lipoma is echocardiogram. Cardiac computerized tomography (CCT) and cardiac magnetic resonance imaging (CMR) also place a role in differentiating cardiac lipomas from other cardiac tumors/lesions. CONCLUSION: Cardiac lipomas are benign primary tumors which have no defined age or sex distribution and present with a wide range of symptoms. Echocardiography is first line diagnosis method with CCT/CMR for better imaging before surgical intervention. Surgical resection of the symptomatic cardiac lipomas remains the mainstream treatment. PMID- 25746953 TI - Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. AB - Sepsis is characterized by a dysregulated inflammatory response to infection. Despite studies in mice, the cellular and molecular basis of human sepsis remains unclear and effective therapies are lacking. Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. However, the response of these cells in human sepsis and their contribution to sepsis pathogenesis is poorly understood. To investigate this, we performed a transcriptomic, functional, and mechanistic analysis of blood monocytes from patients during sepsis and after recovery. Our results revealed the functional plasticity of monocytes during human sepsis, wherein they transited from a pro-inflammatory to an immunosuppressive phenotype, while enhancing protective functions like phagocytosis, anti-microbial activity, and tissue remodeling. Mechanistically, hypoxia inducible factor-1alpha (HIF1alpha) mediated this functional re programming of monocytes, revealing a potential mechanism for their therapeutic targeting to regulate human sepsis. PMID- 25746954 TI - Novel structurally similar chromene derivatives with opposing effects on p53 and apoptosis mechanisms in colorectal HCT116 cancer cells. AB - In the present work, novel chromene derivatives fused with the imidazo[1,2 a]pyridine nucleus were tested for their anticancer potential in the human colorectal cancer HCT116 cells. Compounds 2a and 2c showed significant growth inhibitory activity with GI50 of 15 MUM and 11 MUM, respectively. Compound 2c, the most potent, has a carbamate group in position 8 of the pyridine ring, and showed significant cell cycle arrest and induction of cell death by apoptosis, even at 5 MUM. Besides different potencies, chromene analogs 2a and 2c showed different mechanisms of action. Whereas the carbamate-free chromene 2a induced cell cycle arrest at G1/G0 phase, compound 2c showed to arrest cell cycle at both S and G2 phases. Chromene derivative 2a at concentrations higher than its GI50 remarkably induced caspases-dependent apoptosis in a p53-independent manner. On the other hand, compound 2c increased significantly p53 levels and induced apoptosis in a p53- and caspases-dependent manner, even at concentrations lower than its GI50. Both compounds increased the Bax/Bcl-2 ratio, induced mitochondria depolarization and activated MAP kinases. In conclusion, two novel and structurally similar chromene derivatives showed cytotoxicity to HCT16 cells through opposing effects on p53 levels and apoptosis mechanisms, which may be relevant for further development of drugs acting on distinct molecular targets useful in the treatment of cancers with different genetic profiles and for personalized medicine. PMID- 25746955 TI - In vitro skin models as a tool in optimization of drug formulation. AB - (Trans)dermal drug therapy is gaining increasing importance in the modern drug development. To fully utilize the potential of this route, it is important to optimize the delivery of active ingredient/drug into/through the skin. The optimal carrier/vehicle can enhance the desired outcome of the therapy therefore the optimization of skin formulations is often included in the early stages of the product development. A rational approach in designing and optimizing skin formulations requires well-defined skin models, able to identify and evaluate the intrinsic properties of the formulation. Most of the current optimization relies on the use of suitable ex vivo animal/human models. However, increasing restrictions in use and handling of animals and human skin stimulated the search for suitable artificial skin models. This review attempts to provide an unbiased overview of the most commonly used models, with emphasis on their limitations and advantages. The choice of the most applicable in vitro model for the particular purpose should be based on the interplay between the availability, easiness of the use, cost and the respective limitations. PMID- 25746956 TI - Ferrier rearrangement promoted by an electrochemically generated zirconium catalyst. AB - In situ generated zirconium catalyst from a sacrificial zirconium anode was successfully applied to promote Ferrier rearrangement of 3,4,5-tri-O-acetyl-D glucal and 6-deoxy-3,4-di-O-acetyl-L-glucal (3,4-di-O-acetyl-L-rhamnal) in the presence of three thiols and eleven thiophenols as nucleophiles. A simple constant current electrolysis (20 mA, 0.4 F mol(-1)) of an acetonitrile solution of lithium perchlorate (0.1 M) containing the corresponding glycal and S nucleophiles, using a zirconium anode and a platinum cathode resulted in the successful synthesis of the corresponding 2,3-unsaturated peracetylated thioglycosides (with an average anomer ratio alpha/beta=4.129 in the case of peracetylated D-glucal and 8.740 in the case of L-rhamnal). The same procedure proved to be appropriate in synthesizing dihydropyran derivatives ('C glycosides') using allyltrimethylsilane as the nucleophile (only 'alpha-anomers' were obtained). All new compounds were fully characterized by spectral data, whereas single-crystal X-ray analysis was performed for two thioglycosides. PMID- 25746957 TI - Potential mechanisms for bioregeneration of perchlorate-containing ion-exchange resin. AB - Ion-exchange (IX) is the most feasible technology for perchlorate removal from drinking water. Reuse of resins present challenges, however. Selective resins are non-regenerable, and are incinerated after one time use, while non-selective resins, when regenerable, produce a waste stream that contains high concentration of perchlorate that must be disposed of. A process to bioregenerate spent resin containing perchlorate with perchlorate-reducing bacteria (PRB) has been recently developed. In this research, potential mechanisms for bioregeneration of resin attached perchlorate (RAP) were investigated. Batch bioregeneration experiments were performed using gel-type and macroporous-type resins. Various initial chloride concentrations and various resin bead sizes were used. The results of the bioregeneration experiments suggested that chloride, i.e. the product of perchlorate biodegradation, is more likely the desorbing agent of RAP; and increasing the concentration of chloride enhances the bioregeneration process. Both film and pore diffusion were found to be relevant with respect to the rate of perchlorate mass-transfer to the bulk liquid. Bioregeneration was found to be more effective for macroporous than for gel-type resins, especially in the case of macroporous resins with relatively small bead size in the presence of higher chloride concentration. PMID- 25746958 TI - Degradation of pharmaceuticals in UV (LP)/H2O2 reactors simulated by means of kinetic modeling and computational fluid dynamics (CFD). AB - UV/H2O2 treatment is a well-established technique to degrade organic micropollutants. A CFD model in combination with an advanced kinetic model is presented to predict the degradation of organic micropollutants in UV (LP)/H2O2 reactors, accounting for the hydraulics, fluence rate, complex (photo)chemical reactions in the water matrix and the interactions between these processes. The model incorporates compound degradation by means of direct UV photolysis, OH radical and carbonate radical reactions. Measurements of pharmaceutical degradations in pilot-scale UV/H2O2 reactors are presented under different operating conditions. A comparison between measured and modeled degradation for a group of 35 pharmaceuticals resulted in good model predictions for most of the compounds. The research also shows that the degradation of organic micropollutants can be dependent on temperature, which is relevant for full-scale installations that are operated at different temperatures over the year. PMID- 25746959 TI - Entero- and parechovirus distributions in surface water and probabilities of exposure to these viruses during water recreation. AB - Numerous studies have reported quantitative data on viruses in surface waters generated using different methodologies. In the current study, the impact of the use of either cell culture-based or molecular-based methods in quantitative microbial risk assessment was assessed. Previously and newly generated data on the presence of infectious human enteroviruses (HEV) and enterovirus and parechovirus RNA were used to estimate distributions of virus concentrations in surface waters. Because techniques for the detection of infectious human parechoviruses (HPeV) in surface waters were not available, a 'Parallelogram Approach' was used to estimate their concentrations based on the ratio infectious HEV/HEV RNA. The obtained virus concentrations were then used to estimate the probability of exposure for children during recreation in such virus contaminated surface waters. Human enterovirus cell culture/PCR ratios ranged from 2.3 * 10( 3) to 0.28. This broad range of ratios indicates that care should be taken in assuming a fixed ratio for assessing the risk with PCR based virus concentrations. The probabilities of exposure to both enteroviruses and parechoviruses were calculated, using our Parallelogram Approach for the calculation of infectious parechoviruses. For both viruses it was observed that the detection method significantly influenced the probability of exposure. Based on the calculated culture data, PCR data, and the ingestion volume, it was estimated that the mean probabilities of exposure, of recreating children, to surface water containing viruses were 0.087 (infectious enteroviruses), 0.71 (enterovirus particles), 0.28 (parechovirus particles) and 0.025 (calculated infectious parechoviruses) per recreation event. The mean probabilities of exposure of children recreating in surface water from which drinking water is produced to infectious enteroviruses were estimated for nine locations and varied between 1.5 * 10(-4) - 0.09 per recreation event. In this study, the use of the rotavirus dose response relationship as a surrogate was avoided. Instead, the probabilities of exposure were derived as a function of the distributions of the calculated doses. Our 'Parallelogram Approach' was used to estimate the unavailable infectious parechovirus concentrations using Monte Carlo simulations, and the exposure assessment carried out showed that virus concentrations present in surface waters could pose a health risk for children and other vulnerable populations. PMID- 25746960 TI - Cost-effective bioregeneration of nitrate-laden ion exchange brine through deliberate bicarbonate incorporation. AB - Bioregeneration of nitrate-laden ion exchange brine is desired to minimize its environmental impacts, but faces common challenges, i.e., enriching sufficient salt-tolerant denitrifying bacteria and stabilizing brine salinity and alkalinity for stable brine biotreatment and economically removing undesired organics derived in biotreatment. Incorporation of 0.25 M bicarbonate in 0.5 M chloride brine little affected resin regeneration but created a benign alkaline condition to favor bio-based brine regeneration. The first-quarter sulfate-mainly enriched spent brine (SB) was acidified with carbon source acetic acid for using CaCl2 at an efficiency >80% to remove sulfate. Residual Ca(2+) was limited below 2 mM by re-mixing the first-quarter and remained SB to favor denitrification. Under [Formula: see text] system buffered pH condition (8.3-8.8), nitrate was removed at 0.90 gN/L/d by hematite-enriched well-settled activated sludge (SVI 8.5 ml/g) and the biogenic alkalinity was retained as bicarbonate. The biogenic alkalinity met the need of alkalinity in removing residual Ca(2+) after sulfate removal and in CaCl2-induced CaCO3 flocculation to remove 63% of soluble organic carbon (SOC) in biotreated brine. Carbon-limited denitrification was also operated after activated sludge acclimation with sulfide to cut SOC formation during denitrification. Overall, this bicarbonate-incorporation approach, stabilizing the brine salinity and alkalinity for stable denitrification and economical removal of undesired SOC, suits long-term cost-effective brine bioregeneration. PMID- 25746961 TI - UV photolysis kinetics of sulfonamides in aqueous solution based on optimized fluence quantification. AB - The ultraviolet (UV) photolysis kinetics of eight sulfonamide (SA) antibiotics was investigated in a quasi-collimated beam apparatus. By using a micro fluorescent silica detector to monitor online the dynamic irradiance fluctuation, the accuracy in fluence quantification could be increased by up to 15%. Solution pH governed the speciation of selected SAs, thus impacting significantly their molar absorption coefficients (epsilon), fluence-based photolysis rate constants (k'), and quantum yields. An increasing pH induced a hyperchromic effect and a blue shift of the UV-Vis absorption spectra of selected SAs, thus causing the anionic species to show a relatively higher specific epsilon value than the neutral species at 254 nm. On UV exposure, the photodegradation of selected SAs all followed pseudo-first order reaction kinetics. The SAs with a penta heterocycle, because of their higher electron densities, exhibited an obviously higher photodegradation rate than those with a hexa-heterocycle. The specific k' values of the neutral and anionic species were in the ranges of (0.30-14.49) * 10(-3) and (0.61-20.90) * 10(-3) cm(2) mJ(-1), respectively. With the specific k' values obtained, it is estimated that only part of SAs can be photodegraded during UV disinfection of water and wastewater, so an advanced oxidation process is necessary if a higher removal of selected SAs is to be achieved. PMID- 25746962 TI - Role of extracellular polymeric substance in determining the high aggregation ability of anammox sludge. AB - The high aggregation ability of anammox sludge has been extensively observed, but the cause for their aggregation is challenging. Here the structure and composition of extracellular polymeric substance (EPS) excreted from anammox sludge were systematically investigated to interpret the high aggregation ability. We combine results of contact angle, zeta potential and surface thermodynamics analysis as well as the following DLVO theory to address this issue. The results show that hydrophobic interaction is the main force determining the aggregation of anammox sludge. To go insight into inherent mechanism, Fourier transform infrared (FTIR) and x-ray photoelectron (XPS) spectroscopy were conducted and demonstrated there were comparatively few hydrophilic functional groups in the EPS of anammox sludge, compared to that of activated sludge, nitrifying and denitrifying sludge. Further, amino acid composition and secondary structure analyses of protein indicated that large amounts of hydrophobic amino acids and high level of protein loose structure for exposing inner hydrophobic groups of protein in EPS significantly contributed to the hydrophobic interaction and further to the high aggregation ability of anammox sludge, which is the critical finding of this work. This investigation is useful for understanding anammox bacteria and then for accelerating the application of the anammox process in wastewater treatment. PMID- 25746963 TI - Microplastics in freshwater systems: a review of the emerging threats, identification of knowledge gaps and prioritisation of research needs. AB - Plastic contamination is an increasing environmental problem in marine systems where it has spread globally to even the most remote habitats. Plastic pieces in smaller size scales, microplastics (particles <5 mm), have reached high densities (e.g., 100,000 items per m(3)) in waters and sediments, and are interacting with organisms and the environment in a variety of ways. Early investigations of freshwater systems suggest microplastic presence and interactions are equally as far reaching as are being observed in marine systems. Microplastics are being detected in freshwaters of Europe, North America, and Asia, and the first organismal studies are finding that freshwater fauna across a range of feeding guilds ingest microplastics. Drawing from the marine literature and these initial freshwater studies, we review the issue of microplastics in freshwater systems to summarise current understanding, identify knowledge gaps and suggest future research priorities. Evidence suggests that freshwater systems may share similarities to marine systems in the types of forces that transport microplastics (e.g. surface currents); the prevalence of microplastics (e.g. numerically abundant and ubiquitous); the approaches used for detection, identification and quantification (e.g. density separation, filtration, sieving and infrared spectroscopy); and the potential impacts (e.g. physical damage to organisms that ingest them, chemical transfer of toxicants). Differences between freshwater and marine systems include the closer proximity to point sources in freshwaters, the typically smaller sizes of freshwater systems, and spatial and temporal differences in the mixing/transport of particles by physical forces. These differences between marine and freshwater systems may lead to differences in the type of microplastics present. For example, rivers may show a predictable pattern in microplastic characteristics (size, shape, relative abundance) based on waste sources (e.g. household vs. industrial) adjacent to the river, and distance downstream from a point source. Given that the study of microplastics in freshwaters has only arisen in the last few years, we are still limited in our understanding of 1) their presence and distribution in the environment; 2) their transport pathways and factors that affect distributions; 3) methods for their accurate detection and quantification; 4) the extent and relevance of their impacts on aquatic life. We also do not know how microplastics might transfer from freshwater to terrestrial ecosystems, and we do not know if and how they may affect human health. This is concerning because human populations have a high dependency on freshwaters for drinking water and for food resources. Increasing the level of understanding in these areas is essential if we are to develop appropriate policy and management tools to address this emerging issue. PMID- 25746964 TI - Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome may have a hypothalamus-periaqueductal gray localization. AB - BACKGROUND: Anatomical localization of the rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome has proved elusive. Most patients had neuroimaging after cardiorespiratory collapse, revealing a range of ischemic lesions. PATIENT DESCRIPTION: A 15-year-old obese boy with an acute febrile encephalopathy had hypoventilation, autonomic dysfunction, visual hallucinations, hyperekplexia, and disordered body temperature, and saltwater regulation. These features describe the ROHHAD syndrome. Cerebrospinal fluid analysis showed pleocytosis, elevated neopterins, and oligoclonal bands, and serology for systemic and antineuronal antibodies was negative. He improved after receiving intravenous steroids, immunoglobulins, and long-term mycophenolate. Screening for neural crest tumors was negative. CONCLUSION: Magnetic resonance imaging of the brain early in his illness showed focal inflammation in the periaqueductal gray matter and hypothalamus. This unique localization explains almost all symptoms of this rare autoimmune encephalitis. PMID- 25746967 TI - Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain-containing inositol 5-phosphatase (SHIP-1). AB - BACKGROUND: Inpp5d (Src homology 2 domain-containing inositol-5-phosphatase [Ship1])-deficient mice experience spontaneous airway inflammation and have enhanced sensitivity to allergen-induced airway inflammation. OBJECTIVE: We hypothesized that lineage-specific deletion of Ship1 expression in cells known to be crucial for adaptive TH2 responses would uncover distinct roles that could either positively or negatively regulate susceptibility to allergic airway inflammation (AAI). METHODS: Ship1 expression was deleted in B cells, T cells, or dendritic cells (DCs), and the resulting Ship1(DeltaB cell), Ship1(DeltaT cell), Ship1(DeltaDC), or Ship1(F/F) (wild-type) control mice were evaluated in a model of house dust mite (HDM)-induced AAI. RESULTS: Unlike germline panhematopoietic Ship1 deletion, deletion of Ship1 selectively in either the B-cell, T-cell, or DC lineages did not result in spontaneous airway inflammation. Strikingly, although loss of Ship1 in the B-cell lineage did not affect HDM-induced AAI, loss of Ship1 in either of the T-cell or DC lineages protected mice from AAI by skewing the typical TH2 immune response toward a TH1 response. CONCLUSIONS: Although panhematopoietic deletion of Ship1 leads to spontaneous lung inflammation, selective deletion of Ship1 in T cells or DCs impairs the formation of an adaptive TH2 response and protects animals from HDM-induced AAI. PMID- 25746966 TI - Treatment responsiveness of phenotypes of symptomatic airways obstruction in adults. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous disorders encompassing different phenotypes of airflow obstruction, which might differ in their response to treatment. OBJECTIVE: The aim of this study was to determine distinct phenotypes comprising the syndromes of asthma and COPD and the treatment responsiveness of these phenotypes to inhaled beta agonist, antimuscarinic, and corticosteroid therapy. METHODS: We undertook a cross-sectional study with 3 phases. In phase 1, 1,264 participants aged 18 to 75 years with self-reported current wheeze and breathlessness were identified from a random population sample of 16,459. In phase 2, 451 participants attended for detailed assessment, including responsiveness to inhaled salbutamol and ipratropium bromide. In phase 3, 168 steroid-naive participants were enrolled in a 12-week trial of inhaled budesonide. Cluster analysis was performed in 389 participants who completed phase 2 with full data. Treatment responsiveness was compared between phenotypes. RESULTS: Cluster analysis identified 5 phenotypes: moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, obese comorbid, mild childhood-onset atopic asthma, and mild intermittent. Bronchodilation after salbutamol was equal to or greater than that after ipratropium for all phenotypes. The moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, and obese-comorbid phenotypes had greater efficacy with inhaled corticosteroid treatment than the mild intermittent group. CONCLUSION: Cluster analysis of adults with symptomatic airflow obstruction identifies 5 disease phenotypes, including asthma-COPD overlap and obese-comorbid phenotypes, and provides evidence that patients with the asthma-COPD overlap syndrome might benefit from inhaled corticosteroid therapy. PMID- 25746968 TI - Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms. AB - BACKGROUND: Asthma is a chronic inflammatory disease involving diverse cells and mediators whose interconnectivity and relationships to asthma severity are unclear. OBJECTIVE: We performed a comprehensive assessment of TH17 cells, regulatory T cells, mucosal-associated invariant T (MAIT) cells, other T-cell subsets, and granulocyte mediators in asthmatic patients. METHODS: Sixty patients with mild-to-severe asthma and 24 control subjects underwent detailed clinical assessment and provided induced sputum, endobronchial biopsy, bronchoalveolar lavage, and blood samples. Adaptive and invariant T-cell subsets, cytokines, mast cells, and basophil mediators were analyzed. RESULTS: Significant heterogeneity of T-cell phenotypes was observed, with levels of IL-13-secreting T cells and type 2 cytokines increased at some, but not all, asthma severities. TH17 cells and gammadelta-17 cells, proposed drivers of neutrophilic inflammation, were not strongly associated with asthma, even in severe neutrophilic forms. MAIT cell frequencies were strikingly reduced in both blood and lung tissue in relation to corticosteroid therapy and vitamin D levels, especially in patients with severe asthma in whom bronchoalveolar lavage regulatory T-cell numbers were also reduced. Bayesian network analysis identified complex relationships between pathobiologic and clinical parameters. Topological data analysis identified 6 novel clusters that are associated with diverse underlying disease mechanisms, with increased mast cell mediator levels in patients with severe asthma both in its atopic (type 2 cytokine-high) and nonatopic forms. CONCLUSION: The evidence for a role for TH17 cells in patients with severe asthma is limited. Severe asthma is associated with a striking deficiency of MAIT cells and high mast cell mediator levels. This study provides proof of concept for disease mechanistic networks in asthmatic patients with clusters that could inform the development of new therapies. PMID- 25746969 TI - Immunopathophysiology of food protein-induced enterocolitis syndrome. AB - There is increasing recognition of the non-IgE-mediated gastrointestinal food allergy known as food protein-induced enterocolitis syndrome (FPIES), with several recent publications summarizing the clinical experience with FPIES in the United States, the United Kingdom, Europe, and Australia. Our understanding of the mechanisms linking food exposure to typical symptoms of vomiting, hypotension, and diarrhea has lagged far behind our understanding of the immune mechanisms of IgE-mediated food allergy. The goal of this overview is to summarize and critique the current state of knowledge of the immunology of FPIES and to identify major gaps in our knowledge that need to be addressed to make significant gains in developing therapies and prevention strategies for FPIES. PMID- 25746970 TI - Pediatric severe asthma with fungal sensitization is mediated by steroid resistant IL-33. AB - BACKGROUND: The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. OBJECTIVE: We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. METHODS: Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n = 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. RESULTS: Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P = .006), higher total IgE levels (637 vs 177 IU/mL, P = .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P = .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL 33 levels, and IL-13(+) innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13(+) ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2(-/-) mice lacking a functional receptor for IL-33. CONCLUSION: Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS. PMID- 25746971 TI - In vivo allergenic activity of a hypoallergenic mutant of the major fish allergen Cyp c 1 evaluated by means of skin testing. PMID- 25746973 TI - Repellency of tsetse-refractory waterbuck (Kobus defassa) body odour to Glossina pallidipes (Diptera: Glossinidae): assessment of relative contribution of different classes and individual constituents. AB - Our earlier studies on the comparative behavioural responses of caged savanna tsetse (Glossina morsitans morsitans and Glossina pallidipes) on a preferred host (ox) and a non-host (waterbuck) suggested the presence of allomonal constituents on the latter. Follow up comparison of the compositions of odours of waterbuck with those of ox and buffalo led to the identification of a series of compounds (15) specific to waterbuck, including straight chain carboxylic acid (C5-C10), phenols (guaiacol and carvacrol), 2-alkanone homologues (C8-C12), geranylacetone and delta-octalactone. Behavioural studies in a windtunnel in the laboratory suggested that G. m. morsitans was repelled by a synthetic blend of waterbuck specific constituents. In the present study, the effects of different blends of these compounds on catches of mixed sexes of G. pallidipes in attractant-baited NG2G traps were evaluated in the field. Each multicomponent class of constituents (acids, ketones and phenols) was found to reduce fly catches, but a 14-component blend of all these compounds was more effective (reduced catches by 79-85%), indicating that each of these classes of compounds contributes incrementally to the repellency of the waterbuck odour. However, subtractive assays showed some redundancy within each class of compounds, with some even demonstrating attractive properties. Addition of (RS)-delta-octalactone to the 14-component significantly increased the repellency of the resulting blend. A 5-component blend of compounds selected on the basis of their relative performance in subtractive assays (delta-octalactone, guaiacol, geranylacetone, hexanoic and pentanoic acid) showed substantial reduction in fly catches (84%) relative to the baited control. In separate sets of experiments involving an ox tethered in the middle of an incomplete ring of electric screens in the presence or absence of 15 component or 5-component blends, comparable levels in the reduction of fed flies (94 and 96%, respectively) were obtained with the two blends. The chemo ecological significance and practical implication of these results are highlighted. PMID- 25746975 TI - MPs raise fears over unfair funding of public health services. PMID- 25746972 TI - TH9 cells are required for tissue mast cell accumulation during allergic inflammation. AB - BACKGROUND: IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, natural killer T cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined. OBJECTIVE: We sought to elucidate the role of TH9 cells in promoting mast cell accumulation in models of allergic lung inflammation. METHODS: Adoptive transfer of ovalbumin-specific TH2 and TH9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild-type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation. RESULTS: Adoptive transfer experiments demonstrated that recipients of TH9 cells had significantly higher mast cell accumulation and expression of mast cell proteases compared with control or TH2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, a cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4(+) T cells, but not natural killer T cells or innate lymphoid cells, suggesting a TH cell-dependent phenotype. Rag1(-/-) mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable with accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment. CONCLUSION: TH9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation. PMID- 25746974 TI - Occurrence of Neospora caninum and Toxoplasma gondii DNA in brain tissue from hoary foxes (Pseudalopex vetulus) in Brazil. AB - The hoary fox (Pseudalopex vetulus) is a wild canid native to Brazil and is commonly found in the semiarid northeastern area living in contact with cattle. The main purpose of this study was to investigate the presence of Neospora caninum and Toxoplasma gondii DNA in hoary foxes, in the state of Paraiba, Brazil. Brain tissue samples were collected from 49 hoary foxes. From the samples, DNA extraction and the polymerase chain reaction (PCR) were performed using specific primers for N. caninum and T. gondii. The prevalences found were 14.3% (7/49) for T. gondii and 12.2% (6/49) for N. caninum. The molecular identities of the amplified products were confirmed by means of the sequencing reaction. This study demonstrated the presence of N. caninum and T. gondii DNA in free-ranging hoary foxes in Brazil for the first time, thus confirming that this species is an intermediate host. PMID- 25746976 TI - The acute-phase protein SAA3 is present in the preterm human colostrum and breast milk. PMID- 25746977 TI - Endoscopic needle-knife stricturotomy for nipple valve stricture of continent ileostomy (with video). PMID- 25746978 TI - Endoscopes and devices to improve colon polyp detection. PMID- 25746979 TI - Underwater colorectal EMR: remodeling endoscopic mucosal resection. AB - BACKGROUND: Underwater EMR (UEMR) has been reported as a new technique for the removal of large sessile colorectal polyps without need for submucosal injection. OBJECTIVE: To evaluate (1) outcomes of UEMR, (2) whether UEMR can be easily performed by an endoscopist skilled in traditional EMR without specific dedicated training in UEMR, and (3) whether EUS is required before UEMR. DESIGN: Prospective, observational study. SETTING: Single, tertiary-care referral center. INTERVENTION: Underwater EMR. MAIN OUTCOME MEASUREMENTS: Complete resection and adverse events. RESULTS: A total of 72 consecutive patients underwent UEMR of 81 sessile colorectal polyps. EUS was performed before UEMR in 9 cases (11.1%) with a suspicious mucosal/vascular pattern. The mean polyp size was 18.7 mm (range 10 50 mm); the mean UEMR time was 11.8 minutes. Fifty-five polyps (68%) were removed en bloc, and 26 (32%) were removed with a piecemeal technique. Histopathology consisted of tubular adenomas (25.9%), tubulovillous adenomas (5%), adenomas with high-grade dysplasia (42%), serrated polyps (4.9%), carcinoma in situ (13.6%), and hyperplastic polyps (8.6%). Surveillance colonoscopy was scheduled at 3 months. Complete resection was successful in all patients. No adverse events or recurrence was recorded in any of the patients. LIMITATIONS: Limited follow-up; single-center, uncontrolled study. CONCLUSION: Interventional endoscopists skilled in conventional EMR performed UEMR without specific dedicated training. EUS may not be required for lesions with no invasive features on high-definition narrow-band imaging. UEMR appears to be an effective and safe alternative to traditional EMR and could eventually improve the way in which we can effectively and safely treat colorectal lesions. PMID- 25746980 TI - EUS-guided transgastric biliary drainage in complete situs viscerum inversus. PMID- 25746981 TI - Disseminated varicella-zoster virus involving the esophagus and stomach. PMID- 25746982 TI - Bleeding from a gastric subepithelial tumor associated with eosinophilia. PMID- 25746983 TI - Massive obscure bleeding from a jejunal diverticulum (with video). PMID- 25746984 TI - Co-ordination of Flower Development Through Epigenetic Regulation in Two Model Species: Rice and Arabidopsis. AB - Angiosperms produce flowers for reproduction. Flower development is a multistep developmental process, beginning with the initiation of the floral meristems, followed by floral meristem identity specification and maintenance, organ primordia initiation, floral organ identity specification, floral stem cell termination and finally floral organ maturation. During flower development, each of a large number of genes is expressed in a spatiotemporally regulated manner. Underlying these molecular and phenotypic events are various genetic and epigenetic pathways, consisting of diverse transcription factors, chromatin remodeling factors and signaling molecules. Over the past 30 years, genetic, biochemical and genomic assays have revealed the underlying genetic frameworks that control flower development. Here, we will review the transcriptional regulation of flower development in two model species: Arabidopsis thaliana and rice (Oryza sativa). We focus on epigenetic regulation that functions to co ordinate transcription pathways in flower development. PMID- 25746985 TI - Apple SVP Family MADS-Box Proteins and the Tomato Pedicel Abscission Zone Regulator JOINTLESS have Similar Molecular Activities. AB - Pedicel abscission occurs widely in fruit-bearing plants to detach ripe, senescent or diseased organs, and regulation of abscission plays a substantial role in regulating yield and quality in fruit crops. In tomato, development of pedicel abscission zones (AZs) requires the MADS-box genes JOINTLESS (J), MACROCALYX (MC) and SlMBP21. In other plants, however, the involvement of MADS box genes in pedicel abscission remains unclear. Here, we used genetic and biochemical methods to characterize apple J homologs in the context of the regulation of abscission in tomato. We identified three genes encoding two J homologs, MdJa and MdJb. Similarly to J, MdJa and MdJb interacted with MC and SlMBP21, but their interactions differed slightly: like J, MdJb formed a multimer (probably a tetramer) with SlMBP21; however, MdJa formed multimers to a lesser extent. Ectopic expression of MdJb in a J-deficient tomato mutant restored development of functional pedicel AZs, but ectopic expression of MdJa did not complement j mutants. Introduction of MdJb also restored expression of J dependent genes in the mutant, such as genes for polygalacturonase, cellulase and AZ-specific transcription factors. These results suggest a potentially conserved mechanism of pedicel AZ development in apple and other plants, regulated by MADS box transcription factors. PMID- 25746986 TI - A Lactobacillus plantarum esterase active on a broad range of phenolic esters. AB - Lactobacillus plantarum is the lactic acid bacterial species most frequently found in the fermentation of food products of plant origin on which phenolic compounds are abundant. L. plantarum strains showed great flexibility in their ability to adapt to different environments and growth substrates. Of 28 L. plantarum strains analyzed, only cultures from 7 strains were able to hydrolyze hydroxycinnamic esters, such as methyl ferulate or methyl caffeate. As revealed by PCR, only these seven strains possessed the est_1092 gene. When the est_1092 gene was introduced into L. plantarum WCFS1 or L. lactis MG1363, their cultures acquired the ability to degrade hydroxycinnamic esters. These results support the suggestion that Est_1092 is the enzyme responsible for the degradation of hydroxycinnamic esters on the L. plantarum strains analyzed. The Est_1092 protein was recombinantly produced and biochemically characterized. Surprisingly, Est_1092 was able to hydrolyze not only hydroxycinnamic esters, since all the phenolic esters assayed were hydrolyzed. Quantitative PCR experiments revealed that the expression of est_1092 was induced in the presence of methyl ferulate, an hydroxycinnamic ester, but was inhibited on methyl gallate, an hydroxybenzoic ester. As Est_1092 is an enzyme active on a broad range of phenolic esters, simultaneously possessing feruloyl esterase and tannase activities, its presence on some L. plantarum strains provides them with additional advantages to survive and grow on plant environments. PMID- 25746987 TI - Metabolic Profiling of Geobacter sulfurreducens during Industrial Bioprocess Scale-Up. AB - During the industrial scale-up of bioprocesses it is important to establish that the biological system has not changed significantly when moving from small laboratory-scale shake flasks or culturing bottles to an industrially relevant production level. Therefore, during upscaling of biomass production for a range of metal transformations, including the production of biogenic magnetite nanoparticles by Geobacter sulfurreducens, from 100-ml bench-scale to 5-liter fermentors, we applied Fourier transform infrared (FTIR) spectroscopy as a metabolic fingerprinting approach followed by the analysis of bacterial cell extracts by gas chromatography-mass spectrometry (GC-MS) for metabolic profiling. FTIR results clearly differentiated between the phenotypic changes associated with different growth phases as well as the two culturing conditions. Furthermore, the clustering patterns displayed by multivariate analysis were in agreement with the turbidimetric measurements, which displayed an extended lag phase for cells grown in a 5-liter bioreactor (24 h) compared to those grown in 100-ml serum bottles (6 h). GC-MS analysis of the cell extracts demonstrated an overall accumulation of fumarate during the lag phase under both culturing conditions, coinciding with the detected concentrations of oxaloacetate, pyruvate, nicotinamide, and glycerol-3-phosphate being at their lowest levels compared to other growth phases. These metabolites were overlaid onto a metabolic network of G. sulfurreducens, and taking into account the levels of these metabolites throughout the fermentation process, the limited availability of oxaloacetate and nicotinamide would seem to be the main metabolic bottleneck resulting from this scale-up process. Additional metabolite-feeding experiments were carried out to validate the above hypothesis. Nicotinamide supplementation (1 mM) did not display any significant effects on the lag phase of G. sulfurreducens cells grown in the 100-ml serum bottles. However, it significantly improved the growth behavior of cells grown in the 5-liter bioreactor by reducing the lag phase from 24 h to 6 h, while providing higher yield than in the 100-ml serum bottles. PMID- 25746988 TI - Lactococcal 949 group phages recognize a carbohydrate receptor on the host cell surface. AB - Lactococcal bacteriophages represent one of the leading causes of dairy fermentation failure and product inconsistencies. A new member of the lactococcal 949 phage group, named WRP3, was isolated from cheese whey from a Sicilian factory in 2011. The genome sequence of this phage was determined, and it constitutes the largest lactococcal phage genome currently known, at 130,008 bp. Detailed bioinformatic analysis of the genomic region encoding the presumed initiator complex and baseplate of WRP3 has aided in the functional assignment of several open reading frames (ORFs), particularly that for the receptor binding protein required for host recognition. Furthermore, we demonstrate that the 949 phages target cell wall phospho-polysaccharides as their receptors, accounting for the specificity of the interactions of these phages with their lactococcal hosts. Such information may ultimately aid in the identification of strains/strain blends that do not present the necessary saccharidic target for infection by these problematic phages. PMID- 25746989 TI - Mutational Analyses of Glucose Dehydrogenase and Glucose-6-Phosphate Dehydrogenase Genes in Pseudomonas fluorescens Reveal Their Effects on Growth and Alginate Production. AB - The biosynthesis of alginate has been studied extensively due to the importance of this polymer in medicine and industry. Alginate is synthesized from fructose-6 phosphate and thus competes with the central carbon metabolism for this metabolite. The alginate-producing bacterium Pseudomonas fluorescens relies on the Entner-Doudoroff and pentose phosphate pathways for glucose metabolism, and these pathways are also important for the metabolism of fructose and glycerol. In the present study, the impact of key carbohydrate metabolism enzymes on growth and alginate synthesis was investigated in P. fluorescens. Mutants defective in glucose-6-phosphate dehydrogenase isoenzymes (Zwf-1 and Zwf-2) or glucose dehydrogenase (Gcd) were evaluated using media containing glucose, fructose, or glycerol. Zwf-1 was shown to be the most important glucose-6-phosphate dehydrogenase for catabolism. Both Zwf enzymes preferred NADP as a coenzyme, although NAD was also accepted. Only Zwf-2 was active in the presence of 3 mM ATP, and then only with NADP as a coenzyme, indicating an anabolic role for this isoenzyme. Disruption of zwf-1 resulted in increased alginate production when glycerol was used as the carbon source, possibly due to decreased flux through the Entner-Doudoroff pathway rendering more fructose-6-phosphate available for alginate biosynthesis. In alginate-producing cells grown on glucose, disruption of gcd increased both cell numbers and alginate production levels, while this mutation had no positive effect on growth in a non-alginate-producing strain. A possible explanation is that alginate synthesis might function as a sink for surplus hexose phosphates that could otherwise be detrimental to the cell. PMID- 25746990 TI - Mortality Caused by Bath Exposure of Zebrafish (Danio rerio) Larvae to Nervous Necrosis Virus Is Limited to the Fourth Day Postfertilization. AB - Nervous necrosis virus (NNV) is a member of the Betanodavirus genus that causes fatal diseases in over 40 species of fish worldwide. Mortality among NNV-infected fish larvae is almost 100%. In order to elucidate the mechanisms responsible for the susceptibility of fish larvae to NNV, we exposed zebrafish larvae to NNV by bath immersion at 2, 4, 6, and 8 days postfertilization (dpf). Here, we demonstrate that developing zebrafish embryos are resistant to NNV at 2 dpf due to the protection afforded by the egg chorion and, to a lesser extent, by the perivitelline fluid. The zebrafish larvae succumbed to NNV infection during a narrow time window around the 4th dpf, while 6- and 8-day-old larvae were much less sensitive, with mortalities of 24% and 28%, respectively. PMID- 25746991 TI - Simple Method for Markerless Gene Deletion in Multidrug-Resistant Acinetobacter baumannii. AB - The traditional markerless gene deletion technique based on overlap extension PCR has been used for generating gene deletions in multidrug-resistant Acinetobacter baumannii. However, the method is time-consuming because it requires restriction digestion of the PCR products in DNA cloning and the construction of new vectors containing a suitable antibiotic resistance cassette for the selection of A. baumannii merodiploids. Moreover, the availability of restriction sites and the selection of recombinant bacteria harboring the desired chimeric plasmid are limited, making the construction of a chimeric plasmid more difficult. We describe a rapid and easy cloning method for markerless gene deletion in A. baumannii, which has no limitation in the availability of restriction sites and allows for easy selection of the clones carrying the desired chimeric plasmid. Notably, it is not necessary to construct new vectors in our method. This method utilizes direct cloning of blunt-end DNA fragments, in which upstream and downstream regions of the target gene are fused with an antibiotic resistance cassette via overlap extension PCR and are inserted into a blunt-end suicide vector developed for blunt-end cloning. Importantly, the antibiotic resistance cassette is placed outside the downstream region in order to enable easy selection of the recombinants carrying the desired plasmid, to eliminate the antibiotic resistance cassette via homologous recombination, and to avoid the necessity of constructing new vectors. This strategy was successfully applied to functional analysis of the genes associated with iron acquisition by A. baumannii ATCC 19606 and to ompA gene deletion in other A. baumannii strains. Consequently, the proposed method is invaluable for markerless gene deletion in multidrug resistant A. baumannii. PMID- 25746992 TI - Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms. AB - Phage therapy is a promising option for fighting against staphylococcal infections. Two lytic phages, vB_SauM_phiIPLA-RODI (phiIPLA-RODI) and vB_SepM_phiIPLA-C1C (phiIPLA-C1C), belonging to the Myoviridae family and exhibiting wide host ranges, were characterized in this study. The complete genome sequences comprised 142,348 bp and 140,961 bp and contained 213 and 203 open reading frames, respectively. The gene organization was typical of Spounavirinae members, with long direct terminal repeats (LTRs), genes grouped into modules not clearly separated from each other, and several group I introns. In addition, four genes encoding tRNAs were identified in phiIPLA-RODI. Comparative DNA sequence analysis showed high similarities with two phages, GH15 and 676Z, belonging to the Twort-like virus genus (nucleotide identities of >84%); for phiIPLA-C1C, a high similarity with phage phiIBB-SEP1 was observed (identity of 80%). Challenge assays of phages phiIPLA-RODI and phiIPLA-C1C against planktonic staphylococcal cells confirmed their lytic ability, as they were able to remove 5 log units in 8 h. Exposure of biofilms to phages phiIPLA RODI and phiIPLA-C1C reduced the amount of adhered bacteria to about 2 log units in both monospecies and dual-species biofilms, but phiIPLA-RODI turned out to be as effective as the mixture of both phages. Moreover, the frequencies of bacteriophage-insensitive mutants (BIMs) of Staphylococcus aureus and S. epidermidis with resistance to phiIPLA-RODI and phiIPLA-C1C were low, at 4.05 * 10(-7) +/- 2.34 * 10(-9) and 1.1 * 10(-7) +/- 2.08 * 10(-9), respectively. Overall, a generally reduced fitness in the absence of phages was observed for BIMs, which showed a restored phage-sensitive phenotype in a few generations. These results confirm that lytic bacteriophages can be efficient biofilm disrupting agents, supporting their potential as antimicrobials against staphylococcal infections. PMID- 25746993 TI - Accumulation of d-glucose from pentoses by metabolically engineered Escherichia coli. AB - Escherichia coli that is unable to metabolize d-glucose (with knockouts in ptsG, manZ, and glk) accumulates a small amount of d-glucose (yield of about 0.01 g/g) during growth on the pentoses d-xylose or l-arabinose as a sole carbon source. Additional knockouts in the zwf and pfkA genes, encoding, respectively, d-glucose 6-phosphate 1-dehydrogenase and 6-phosphofructokinase I (E. coli MEC143), increased accumulation to greater than 1 g/liter d-glucose and 100 mg/liter d mannose from 5 g/liter d-xylose or l-arabinose. Knockouts of other genes associated with interconversions of d-glucose-phosphates demonstrate that d glucose is formed primarily by the dephosphorylation of d-glucose-6-phosphate. Under controlled batch conditions with 20 g/liter d-xylose, MEC143 generated 4.4 g/liter d-glucose and 0.6 g/liter d-mannose. The results establish a direct link between pentoses and hexoses and provide a novel strategy to increase carbon backbone length from five to six carbons by directing flux through the pentose phosphate pathway. PMID- 25746994 TI - Novel Substrate Specificity and Temperature-Sensitive Activity of Mycosphaerella graminicola CYP51 Supported by the Native NADPH Cytochrome P450 Reductase. AB - Mycosphaerella graminicola (Zymoseptoria tritici) is an ascomycete filamentous fungus that causes Septoria leaf blotch in wheat crops. In Europe the most widely used fungicides for this major disease are demethylation inhibitors (DMIs). Their target is the essential sterol 14alpha-demethylase (CYP51), which requires cytochrome P450 reductase (CPR) as its redox partner for functional activity. The M. graminicola CPR (MgCPR) is able to catalyze the sterol 14alpha-demethylation of eburicol and lanosterol when partnered with Candida albicans CYP51 (CaCYP51) and that of eburicol only with M. graminicola CYP51 (MgCYP51). The availability of the functional in vivo redox partner enabled the in vitro catalytic activity of MgCYP51 to be demonstrated for the first time. MgCYP51 50% inhibitory concentration (IC50) studies with epoxiconazole, tebuconazole, triadimenol, and prothioconazole-desthio confirmed that MgCYP51 bound these azole inhibitors tightly. The characterization of the MgCPR/MgCYP51 redox pairing has produced a functional method to evaluate the effects of agricultural azole fungicides, has demonstrated eburicol specificity in the activity observed, and supports the conclusion that prothioconazole is a profungicide. PMID- 25746995 TI - Influence of Adhesion Force on icaA and cidA Gene Expression and Production of Matrix Components in Staphylococcus aureus Biofilms. AB - The majority of human infections are caused by biofilms. The biofilm mode of growth enhances the pathogenicity of Staphylococcus spp. considerably, because once they adhere, staphylococci embed themselves in a protective, self-produced matrix of extracellular polymeric substances (EPSs). The aim of this study was to investigate the influence of forces of staphylococcal adhesion to different biomaterials on icaA (which regulates the production of EPS matrix components) and cidA (which is associated with cell lysis and extracellular DNA [eDNA] release) gene expression in Staphylococcus aureus biofilms. Experiments were performed with S. aureus ATCC 12600 and its isogenic mutant, S. aureus ATCC 12600 Deltapbp4, deficient in peptidoglycan cross-linking. Deletion of pbp4 was associated with greater cell wall deformability, while it did not affect the planktonic growth rate, biofilm formation, cell surface hydrophobicity, or zeta potential of the strains. The adhesion forces of S. aureus ATCC 12600 were the strongest on polyethylene (4.9 +/- 0.5 nN), intermediate on polymethylmethacrylate (3.1 +/- 0.7 nN), and the weakest on stainless steel (1.3 +/- 0.2 nN). The production of poly-N-acetylglucosamine, eDNA presence, and expression of icaA genes decreased with increasing adhesion forces. However, no relation between adhesion forces and cidA expression was observed. The adhesion forces of the isogenic mutant S. aureus ATCC 12600 Deltapbp4 (deficient in peptidoglycan cross-linking) were much weaker than those of the parent strain and did not show any correlation with the production of poly-N-acetylglucosamine, eDNA presence, or expression of the icaA and cidA genes. This suggests that adhesion forces modulate the production of the matrix molecule poly-N acetylglucosamine, eDNA presence, and icaA gene expression by inducing nanoscale cell wall deformation, with cross-linked peptidoglycan layers playing a pivotal role in this adhesion force sensing. PMID- 25746996 TI - Bacillus halodurans Strain C125 Encodes and Synthesizes Enzymes from Both Known Pathways To Form dUMP Directly from Cytosine Deoxyribonucleotides. AB - Analysis of the genome of Bacillus halodurans strain C125 indicated that two pathways leading from a cytosine deoxyribonucleotide to dUMP, used for dTMP synthesis, were encoded by the genome of the bacterium. The genes that were responsible, the comEB gene and the dcdB gene, encoding dCMP deaminase and the bifunctional dCTP deaminase:dUTPase (DCD:DUT), respectively, were both shown to be expressed in B. halodurans, and both genes were subject to repression by the nucleosides thymidine and deoxycytidine. The latter nucleoside presumably exerts its repression after deamination by cytidine deaminase. Both comEB and dcdB were cloned, overexpressed in Escherichia coli, and purified to homogeneity. Both enzymes were active and displayed the expected regulatory properties: activation by dCTP for dCMP deaminase and dTTP inhibition for both enzymes. Structurally, the B. halodurans enzyme resembled the Mycobacterium tuberculosis enzyme the most. An investigation of sequenced genomes from other species of the genus Bacillus revealed that not only the genome of B. halodurans but also the genomes of Bacillus pseudofirmus, Bacillus thuringiensis, Bacillus hemicellulosilyticus, Bacillus marmarensis, Bacillus cereus, and Bacillus megaterium encode both the dCMP deaminase and the DCD:DUT enzymes. In addition, eight dcdB homologs from Bacillus species within the genus for which the whole genome has not yet been sequenced were registered in the NCBI Entrez database. PMID- 25746997 TI - Zoonotic and Potentially Host-Adapted Enterocytozoon bieneusi Genotypes in Sheep and Cattle in Northeast China and an Increasing Concern about the Zoonotic Importance of Previously Considered Ruminant-Adapted Genotypes. AB - This study investigated fecal specimens from 489 sheep and 537 cattle in multiple cities in northeast China for the prevalence and genetic characteristics of Enterocytozoon bieneusi by PCR and sequencing of the ribosomal internal transcribed spacer. Sixty-eight sheep specimens (13.9%) and 32 cattle specimens (6.0%) were positive for E. bieneusi. Sequence polymorphisms enabled the identification of 9 known genotypes (BEB4, BEB6, CM7, CS-4, EbpC, G, I, J, and OEB1) and 11 new genotypes (NESH1 to NESH6 and NECA1 to NECA5). The genotypes formed two genetic clusters in a phylogenetic analysis, with CS-4, EbpC, G, NESH1 to NESH3, and NECA1 to NECA5 distributed in zoonotic group 1 and BEB4, BEB6, CM7, EbpI, J, OEB1, and NESH4 to NESH6 distributed in potentially host-adapted group 2. Nearly 70% of cases of E. bieneusi infections in sheep were contributed by human-pathogenic genotypes BEB6, CS-4, and EbpC, and over 80% of those in cattle were by genotypes BEB4, CS-4, EbpC, I, and J. The cooccurrence of genotypes BEB4, CS-4, EbpC, I, and J in domestic ruminants and children in northeast China and the identification of BEB6 and EbpC in humans and water in central China imply the possibility of zoonotic transmission. This study also summarizes E. bieneusi genotypes obtained from ruminants worldwide and displays their host ranges, geographical distributions, and phylogenetic relationships. The data suggest a host range expansion in some group 2 genotypes (notably BEB4, BEB6, I, and J) that were previously considered to be adapted to ruminants. We should be concerned about the increasing zoonotic importance of group 2 genotypes with low host specificity. PMID- 25746998 TI - Evolutionary Engineering Improves Tolerance for Replacement Jet Fuels in Saccharomyces cerevisiae. AB - Monoterpenes are liquid hydrocarbons with applications ranging from flavor and fragrance to replacement jet fuel. Their toxicity, however, presents a major challenge for microbial synthesis. Here we evolved limonene-tolerant Saccharomyces cerevisiae strains and sequenced six strains across the 200 generation evolutionary time course. Mutations were found in the tricalbin proteins Tcb2p and Tcb3p. Genomic reconstruction in the parent strain showed that truncation of a single protein (tTcb3p(1-989)), but not its complete deletion, was sufficient to recover the evolved phenotype improving limonene fitness 9 fold. tTcb3p(1-989) increased tolerance toward two other monoterpenes (beta pinene and myrcene) 11- and 8-fold, respectively, and tolerance toward the biojet fuel blend AMJ-700t (10% cymene, 50% limonene, 40% farnesene) 4-fold. tTcb3p(1 989) is the first example of successful engineering of phase tolerance and creates opportunities for production of the highly toxic C10 alkenes in yeast. PMID- 25746999 TI - Biofilm Formation and Quorum-Sensing-Molecule Production by Clinical Isolates of Serratia liquefaciens. AB - Serratia spp. are opportunistic human pathogens responsible for an increasing number of nosocomial infections. However, little is known about the virulence factors and regulatory circuits that may enhance the establishment and long-term survival of Serratia liquefaciens in the hospital environment. In this study, two reporter strains, Chromobacterium violaceum CV026 and VIR24, and high-resolution triple-quadrupole liquid chromatography-mass spectrometry (LC-MS) were used to detect and to quantify N-acyl-homoserine lactone (AHL) quorum-sensing signals in 20 S. liquefaciens strains isolated from clinical samples. Only four of the strains produced sufficient amounts of AHLs to activate the sensors. Investigation of two of the positive strains by high-performance liquid chromatography (HPLC)-MS confirmed the presence of significant amounts of short acyl-chain AHLs (N-butyryl-l-homoserine lactone [C4-HSL] and N-hexanoyl-l homoserine lactone [C6-HSL]) in both strains, which exhibited a complex and strain-specific signal profile that included minor amounts of other short-acyl chain AHLs (N-octanoyl-l-homoserine lactone [C8-HSL] and N-3-oxohexanoyl-l homoserine lactone [OC6-HSL]) and long-acyl-chain (C10, C12, and C14) AHLs. No correlation between biofilm formation and the production of large amounts of AHLs could be established. Fimbria-like structures were observed by transmission electron microscopy, and the presence of the type 1 fimbrial adhesin gene fimH in all strains was confirmed by PCR. The ability of S. liquefaciens to adhere to abiotic surfaces and to form biofilms likely contributes to its persistence in the hospital environment, increasing the probability of causing nosocomial infections. Therefore, a better understanding of the adherence properties of this species will provide greater insights into the diseases it causes. PMID- 25747000 TI - New shuttle vector-based expression system to generate polyhistidine-tagged fusion proteins in Staphylococcus aureus and Escherichia coli. AB - Four Staphylococcus aureus-Escherichia coli shuttle vectors were constructed for gene expression and production of tagged fusion proteins. Vectors pBUS1-HC and pTSSCm have no promoter upstream of the multiple cloning site (MCS), and this allows study of genes under the control of their native promoters, and pBUS1-Pcap HC and pTSSCm-Pcap contain the strong constitutive promoter of S. aureus type 1 capsule gene 1A (Pcap) upstream of a novel MCS harboring codons for the peptide tag Arg-Gly-Ser-hexa-His (rgs-his6). All plasmids contained the backbone derived from pBUS1, including the E. coli origin ColE1, five copies of terminator rrnB T1, and tetracycline resistance marker tet(L) for S. aureus and E. coli. The minimum pAMalpha1 replicon from pBUS1 was improved through either complementation with the single-strand origin oriL from pUB110 (pBUS1-HC and pBUS1-Pcap-HC) or substitution with a pT181-family replicon (pTSSCm and pTSSCm-Pcap). The new constructs displayed increased plasmid yield and segregational stability in S. aureus. Furthermore, pBUS1-Pcap-HC and pTSSCm-Pcap offer the potential to generate C-terminal RGS-His6 translational fusions of cloned genes using simple molecular manipulation. BcgI-induced DNA excision followed by religation converts the TGA stop codon of the MCS into a TGC codon and links the rgs-his6 codons to the 3' end of the target gene. The generation of the rgs-his6 codon-fusion, gene expression, and protein purification were demonstrated in both S. aureus and E. coli using the macrolide-lincosamide-streptogramin B resistance gene erm(44) inserted downstream of Pcap. The new His tag expression system represents a helpful tool for the direct analysis of target gene function in staphylococcal cells. PMID- 25747002 TI - Integrated kinetic and probabilistic modeling of the growth potential of bacterial populations. AB - When bacteria are exposed to osmotic stress, some cells recover and grow, while others die or are unculturable. This leads to a viable count growth curve where the cell number decreases before the onset of the exponential growth phase. From such curves, it is impossible to estimate what proportion of the initial cells generates the growth because it leads to an ill-conditioned numerical problem. Here, we applied a combination of experimental and statistical methods, based on optical density measurements, to infer both the probability of growth and the maximum specific growth rate of the culture. We quantified the growth potential of a bacterial population as a quantity composed from the probability of growth and the "suitability" of the growing subpopulation to the new environment. We found that, for all three laboratory media studied, the probability of growth decreased while the "work to be done" by the growing subpopulation (defined as the negative logarithm of their suitability parameter) increased with NaCl concentration. The results suggest that the effect of medium on the probability of growth could be described by a simple shift parameter, a differential NaCl concentration that can be accounted for by the change in the medium composition. Finally, we highlighted the need for further understanding of the effect of the osmoprotectant glycine betaine on metabolism. PMID- 25747003 TI - Treatment of myasthenia gravis with dropped head: a report of 2 cases and review of the literature. AB - We report two patients with myasthenia gravis (MG) who showed dropped head as an early myasthenic manifestation. They had elevated anti-acetylcholine receptor antibody and showed improvement of the symptoms after intravenous injection of edorophonium chloride. One patient had thymoma and developed myasthenic crisis two weeks after thymectomy. The patient recovered from the crisis after a combination of immunoadsorption plasmapheresis (IAPP) and initiation of steroid and tacrolimus. The other patient without thymoma initiated treatment with steroid, tacrolimus and IAPP and showed complete recovery one month later. Dropped head in MG can recover well with immunosuppression therapy using steroid, and IAPP is helpful in getting a rapid improvement of dropped head as well as recovery from myasthenic crisis. When we consider treatment for MG with dropped head, we should take into account that MG of this type can develop myasthenic crisis and use the same treatment strategy as that for generalized MG. PMID- 25747001 TI - Novel blaROB-1-bearing plasmid conferring resistance to beta-lactams in Haemophilus parasuis isolates from healthy weaning pigs. AB - Haemophilus parasuis, the causative agent of Glasser's disease, is one of the early colonizers of the nasal mucosa of piglets. It is prevalent in swine herds, and lesions associated with disease are fibrinous polyserositis and bronchopneumonia. Antibiotics are commonly used in disease control, and resistance to several antibiotics has been described in H. parasuis. Prediction of H. parasuis virulence is currently limited by our scarce understanding of its pathogenicity. Some genes have been associated with H. parasuis virulence, such as lsgB and group 1 vtaA, while biofilm growth has been associated with nonvirulent strains. In this study, 86 H. parasuis nasal isolates from farms that had not had a case of disease for more than 10 years were obtained by sampling piglets at weaning. Isolates were studied by enterobacterial repetitive intergenic consensus PCR and determination of the presence of lsgB and group 1 vtaA, biofilm formation, inflammatory cell response, and resistance to antibiotics. As part of the diversity encountered, a novel 2,661-bp plasmid, named pJMA-1, bearing the blaROB-1 beta-lactamase was detected in eight colonizing strains. pJMA-1 was shown to share a backbone with other small plasmids described in the Pasteurellaceae, to be 100% stable, and to have a lower biological cost than the previously described plasmid pB1000. pJMA-1 was also found in nine H. parasuis nasal strains from a separate collection, but it was not detected in isolates from the lesions of animals with Glasser's disease or in nontypeable Haemophilus influenzae isolates. Altogether, we show that commensal H. parasuis isolates represent a reservoir of beta-lactam resistance genes which can be transferred to pathogens or other bacteria. PMID- 25747004 TI - Zebra body myopathy is caused by a mutation in the skeletal muscle actin gene (ACTA1). AB - We present follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame. PMID- 25747005 TI - A novel large deletion in the RYR1 gene in a Belgian family with late-onset and recessive core myopathy. AB - We report a novel and particularly unusual type of mutation, namely, large deletion in the RYR1 gene, in a Belgian family with myopathy: Patients were found to be compound heterozygous and presented a clinico-pathological phenotype characterized by late-onset and recessive myopathy with cores. We depict the clinical, electrophysiological, pathological and molecular genetic characteristics of family members. To date, large deletions in the RYR1 gene have been reported in only two cases. Both involved different mutations and, in sharp contrast to our cases, presented with a very early-onset, neonatal, and a very severe or lethal phenotype. Overview of reported clinico-pathologic phenotypes, also highlights the rarity of combined late-onset/recessive co-occurrence in this group of myopathies with cores. Finally, this report underlines the broadening spectrum in this group of myopathologic disorders and highlights the concept of 'RYR1-associated/related core myopathies'. PMID- 25747006 TI - Elucidation of the serosal cuticle machinery in the beetle Tribolium by RNA sequencing and functional analysis of Knickkopf1, Retroactive and Laccase2. AB - Insects have been extraordinary successful in colonizing terrestrial habitats and this success is partly due to a protective cuticle that mainly contains chitin and proteins. The cuticle has been well studied in larvae and adults, but little attention has been paid to the cuticle of the egg. This cuticle is secreted by the serosa, an extraembryonic epithelium that surrounds the yolk and embryo in all insect eggs, but was lost in the Schizophoran flies to which Drosophila belongs. We therefore set out to investigate serosal cuticle formation and function in a beetle (Tribolium castaneum) using RNAi-mediated knockdown of three candidate genes known to structure chitin in the adult cuticle, and we aimed to identify other serosal cuticle genes using RNA sequencing. Knockdown of Knickkopf (TcKnk-1) or Retroactive (TcRtv) affects the laminar structure of the serosal cuticle, as revealed by Transmission Electron Microscopy in knockdown eggs. In the absence of this laminar structure, significantly fewer eggs survive at low humidity compared to wild-type eggs. Survival in dry conditions is also adversely affected when cross-linking among proteins and chitin is prevented by Laccase2 (TcLac-2) RNAi. Finally, we compare the transcriptomes of wild-type eggs to serosa-less eggs and find serosa-biased expression of 21 cuticle-related genes including structural components, chitin deacetylases and chitinases. Our data indicate that the serosal cuticle utilizes the same machinery for structuring the cuticle as adults. We demonstrate that the structure of the cuticle is crucial for desiccation resistance, and we put forward the serosal cuticle of Tribolium as an excellent model to study the ecological properties of the insect cuticle. PMID- 25747007 TI - In vivo functional analysis of the Drosophila melanogaster nicotinic acetylcholine receptor Dalpha6 using the insecticide spinosad. AB - The vinegar fly, Drosophila melanogaster, has been used to identify and manipulate insecticide resistance genes. The advancement of genome engineering technology and the increasing availability of pest genome sequences has increased the predictive and diagnostic capacity of the Drosophila model. The Drosophila model can be extended to investigate the basic biology of the interaction between insecticides and the proteins they target. Recently we have developed an in vivo system that permits the expression and study of key insecticide targets, the nicotinic acetylcholine receptors (nAChRs), in controlled genetic backgrounds. Here this system is used to study the interaction between the insecticide spinosad and a nAChR subunit, Dalpha6. Reciprocal chimeric subunits were created from Dalpha6 and Dalpha7, a subunit that does not respond to spinosad. Using the in vivo system, the Dalpha6/Dalpha7 chimeric subunits were tested for their capacity to respond to spinosad. Only the subunits containing the C-terminal region of Dalpha6 were able to respond to spinosad, thus confirming the importance this region for spinosad binding. A new incompletely dominant, spinosad resistance mechanism that may evolve in pest species is also examined. First generated using chemical mutagenesis, the Dalpha6(P146S) mutation was recreated using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system, the first use of this technology to introduce a resistant mutation into a controlled genetic background. Both alleles present with the same incompletely dominant, spinosad resistance phenotype, proving the P146S replacement to be the causal mutation. The proximity of the P146S mutation to the conserved Cys-loop indicates that it may impair the gating of the receptor. The results of this study enhance the understanding of nAChR structure:function relationships. PMID- 25747008 TI - Expression of insect alpha6-like nicotinic acetylcholine receptors in Drosophila melanogaster highlights a high level of conservation of the receptor:spinosyn interaction. AB - Insecticide research has often relied on model species for elucidating the resistance mechanisms present in the targeted pests. The accuracy and applicability of extrapolations of these laboratory findings to field conditions varies but, for target site resistance, conserved mechanisms are generally the rule rather than the exception (Perry et al., 2011). The spinosyn class of insecticides appear to fit this paradigm and are a pest control option with many uses in both crop and animal protection. Resistance to spinosyns has been identified in both laboratory-selected and field-collected pest insects. Studies using the model insect, Drosophila melanogaster, have identified the nicotinic acetylcholine receptor subunit, Dalpha6 as an important target of the insecticide spinosad (Perry et al., 2007; Watson et al., 2010). Field-isolated resistant strains of several agricultural pest insects provide evidence that resistance cases are often associated with mutations in orthologues to Dalpha6 (Baxter et al., 2010; Puinean et al., 2013). The expression of these receptors is difficult in heterologous systems. In order to examine the biology of the Dalpha6 receptor subunit further, we used Drosophila as a model and developed an in vivo rescue system. This allowed us to express four different isoforms of Dalpha6 and show that each is able to rescue the response to spinosad. Regulatory sequences upstream of the Dalpha6 gene able to rescue the resistance phenotype were identified. Expression of other D. melanogaster subunits revealed that the rescue phenotype appears to be Dalpha6 specific. We also demonstrate that expression of pest insect orthologues of Dalpha6 from a variety of species are capable of rescuing the spinosad response phenotype, verifying the relevance of this receptor to resistance monitoring in the field. In the absence of a robust heterologous expression system, this study presents an in vivo model that will be useful in analysing many other aspects of these receptors and their biology. PMID- 25747009 TI - Knickkopf and retroactive proteins are required for formation of laminar serosal procuticle during embryonic development of Tribolium castaneum. AB - Chitin, a homopolymer of beta-1-4-linked N-acetylglucosamine synthesized by chitin synthase A (Chs-A), is organized in the procuticle of the postembryonic cuticle or exoskeleton, which is composed of laminae stacked parallel to the cell surface to give stability and integrity to the underlying insect epidermal and other tissues. Our previous work has revealed an important role for two proteins from Tribolium castaneum named Knickkopf (TcKnk) and Retroactive (TcRtv) in postembryonic cuticular chitin maintenance. TcKnk and TcRtv were shown to be required for protection and organization of newly synthesized procuticular chitin. To study the functions of TcKnk and TcRtv in serosal and larval cuticles produced during embryogenesis in T. castaneum, dsRNAs specific for these two genes were injected into two week-old adult females. The effects of dsRNA treatment on ovarial integrity, oviposition, egg hatching and adult survival were determined. Insects treated with dsRNA for chitin synthase-A (TcChs-A) and tryptophan oxygenase (TcVer) were used as positive and negative controls for these experiments, respectively. Like TcChs-A RNAi, injection of dsRNA for TcKnk or TcRtv into adult females exhibited no adult lethality and oviposition was normal. However, a vast majority of the embryos did not hatch. The remaining (~10%) of the embryos hatched into first instar larvae that died without molting to the second instar. Chitin content analysis following TcKnk and TcRtv parental RNAi revealed approximately 50% reduction in chitin content of eggs in comparison with control TcVer RNAi, whereas TcChs-A dsRNA-treatment led to >90% loss of chitin. Furthermore, transmission electron microscopic (TEM) analysis of serosal cuticle from TcChs-A, TcKnk and TcRtv dsRNA-treated insects revealed a complete absence of laminar organization of serosal (and larval) procuticle in comparison with TcVer dsRNA-treated controls, which exhibited normal laminar organization of procuticular chitin. The results of this study demonstrate that in addition to their essential roles in maintenance and organization of chitin in epidermal cuticle in larval and later stages of insect development, TcKnk and TcRtv also are required for egg hatch, chitin maintenance and laminar organization of both serosal and larval cuticle during embryonic development of T. castaneum. PMID- 25747010 TI - Silencing the odorant receptor co-receptor RproOrco affects the physiology and behavior of the Chagas disease vector Rhodnius prolixus. AB - Olfaction is one of the main sensory modalities that allow insects to interpret their environment. Several proteins, including odorant-binding proteins (OBPs) and odorant receptors (ORs), are involved in this process. Odorant receptors are ion channels formed by a binding unit OR and an odorant receptor co-receptor (Orco). The main goal of this study was to characterize the Orco gene of Rhodnius prolixus (RproOrco) and to infer its biological functions using gene silencing. The full-length RproOrco gene sequence was downloaded from VectorBase. This gene has 7 introns and is located in the genome SuperContig GL563069: 1,017,713 1,023,165. RproOrco encodes a protein of 473 amino acids, with predicted 7 transmembrane domains, and is highly expressed in the antennae during all R. prolixus developmental stages. The RNAi technique effectively silenced RproOrco, reducing the gene's expression by approximately 73%. Interestingly, the effect of gene silencing persisted for more than 100 days, indicating a prolonged effect of dsRNA that was maintained even after molting. The phenotypic effects of silencing involved the following: (1) loss of the ability to find a vertebrate host in a timely manner, (2) decreased ingested blood volume, (3) delayed and decreased molt rate, (4) increased mortality rate, and (5) decreased egg laying. Our data strongly suggest that dsOrco disrupts R. prolixus host-finding behavior, which is further reflected in the blood ingestion, molting, mortality, and egg laying data. This study clearly demonstrates that Orco is an excellent target for controlling triatomine populations. Thus, the data presented here open new possibilities for the control of vector-borne diseases. PMID- 25747011 TI - Neuropsychological underpinnings of the dynamics of bipolar disorder. AB - Although we have gained enormous insights into neurobiological and psychological underpinnings of bipolar disorder (BD) symptoms, our knowledge concerning pathogenic mechanisms initiating recurrent affective episodes is still fragmentary. Previous research has highlighted the role of significant life events and social rhythm in recurrent episodes of mania and depression. However, most studies share the drawback of retrospective self-report data, which are prone to recall biases and limited introspective abilities. Therefore, more objective data, such as neuropsychological and neurobiological measures are needed to further unravel the pathogenic mechanisms of the dynamics of bipolar disorder. Previous research has highlighted disturbed emotional reactivity as well as impaired emotion regulation and impulse control as major behavioural characteristics of BD and aberrancies in prefrontal-limbic-striatal networks that have been proposed to be the correlates of these behavioural alterations. However, longitudinal studies assessing these neural and behavioural alterations are rare. Future research should therefore adopt prospective study designs including behavioural and neuroimaging measures underlying cognitive, emotional and motivational deficits in bipolar disorder. Particularly, these measures should be collected continuously at multiple time points as implemented in modern ambulatory assessment tools. PMID- 25747012 TI - Hemichorea in a diabetes mellitus patient following acute ischemic stroke with changes in regional cerebral blood flow. AB - It is not unusual to observe hemichorea in patients with diabetes mellitus, with origins attributable to recent ischemia. Our patient was a 66-year-old female with diabetes mellitus who suddenly developed right hemichorea, mild muscle weakness of the right upper extremity, ideational apraxia, and acalculia. Her blood glucose was 600 mg/dL, and HbA1c was 13.3%. After the patient underwent head magnetic resonance imaging (MRI), a new cerebral infarction was observed in the left frontal lobe, and treatment was started with edaravone and cilostazol. At the same time, insulin treatment was also started for hyperglycemia. The acalculia and ideational apraxia improved approximately 1 week after treatment initiated, and the hemichorea also decreased. ECD-SPECT was performed on admission, and it was observed that blood flow was decreased in the left frontal lobe and striatum, but increased in the thalamus; two weeks later on follow-up ECD-SPECT, blood flow had increased slightly in the left forebrain and striatum, while it had decreased slightly in the thalamus. This suggests that the cause of hemichorea was related to ischemia. When the activity of the pallidum is impaired, it is presumed that the inhibitory activity towards the thalamus weakens and the thalamic cells become over-excited, causing chorea. PMID- 25747014 TI - [Dynamic system for maintenance of homeostasis of blood pressure via interaction between brain, kidney, heart, and blood vessel]. PMID- 25747015 TI - [Impairment of vasodilation and effects of perivascular adipose tissue in metabolic syndrome]. PMID- 25747013 TI - Pregnancy outcome of systemic lupus erythematosus in relation to lupus activity before and during pregnancy. AB - BACKGROUND: To analyze the pregnancy complications and pregnancy outcome relating to the disease activity of systemic lupus erythematosus before conception and during pregnancy. METHODS: Seventy-two pregnancies were collected in a single tertiary medical center within a 5-year period. Twelve pregnancies were terminated due to various causes in the first half of pregnancy. Analysis of pregnancy complications and pregnancy outcome relating to the lupus activity before conception and during pregnancy was made among the remaining 60 pregnancies with gestational length > 26 weeks. The assessment of lupus activity was based on the routine monitoring, including urine routine, white blood cell count, hemoglobin and platelet count, erythrocyte sediment rate, serum titers of C3, C4, and double-stranded DNA. Monitoring of renal function with daily urinary protein loss and clearance rate of creatinine was needed when worsened nephropathy was suspected. RESULTS: The etiologies of the terminated pregnancies were deteriorated nephropathy (6 cases), involvement of central nervous system (1 case), unwanted pregnancy due to drug exposure (3 cases), and two early intrauterine fetal deaths (both during the 23(rd) week of gestation). Pregnancy complications were related to the lupus activity before conception [odds ratio = 0.238, 95% confidence interval (CI) = 0.073, 0.778, p = 0.014] and during pregnancy (odds ratio = 0.153, 95% CI = 0.031, 0.754, p = 0.012). Meanwhile, pregnancy outcome significantly related to the lupus activity of the preconception period and during pregnancy. The gestational length was significantly longer in the pregnancies with remitted lupus activity either before conception (38.2 +/- 1.6 weeks vs. 36.3 +/- 3.4 weeks, p = 0.011 and 95% CI = -3.454, -0.478) or during pregnancy (38.2 +/- 1.6 weeks vs. 35.2 +/- 3.8 weeks, p = 0.005 and with 95% CI = -4.988, -1.005). Significant relationships were also found between newborn birth weights and lupus activity preconceptionally (2940 +/- 389 g vs. 2448 +/- 674 g, p = 0.002 and 95% CI = 792, -192) and after having conceived (2960 +/- 383 g vs. 2136 +/- 585 g, p < 0.001 and 95% CI = -1081, -568). Multivariate analysis showed that lupus remission during pregnancy was correlated with a significantly longer gestation, since pregnant women with active lupus had a three-fold greater risk of preterm deliveries (hazard ratio = 3.022, 95% CI = 1.261, 7.242) compared with pregnant women without active lupus. CONCLUSION: In order to reduce the incidence of pregnancy complication, especially preterm delivery, and to gain good pregnancy outcome, good preparation before conception and good control of the disease during pregnancy are mandatory. PMID- 25747016 TI - [Is novel adipocytokine, omentin, a therapeutic target for obesity-related hypertension?]. PMID- 25747017 TI - [Mechanisms underlying dysfunction of retinal blood vessels in diabetic rats]. PMID- 25747018 TI - [Attractive target for cancer, gap junction and its components, connexin]. PMID- 25747019 TI - [The effect of self-training in advance using an e-learning system on pharmacological practice]. PMID- 25747020 TI - [Challenge for new value creation in future medication in Osaka University]. PMID- 25747021 TI - [Pharmacological properties of simeprevir (SOVRIAD(r) capsules 100 mg), a new drug for the treatment of hepatitis C, and results of its clinical studies]. PMID- 25747022 TI - [Pharmacological and clinical profile of afatinib (Giotrif(r))]. PMID- 25747023 TI - Research innovations in cultural psychiatry and public mental health. PMID- 25747024 TI - A cultural consultation service in East London: experiences and outcomes from implementation of an innovative service. AB - This paper reports on a feasibility study and evaluation of a new type of cultural consultation service (CCS). This multi-component and systemic complex intervention was offered over 18 months to specialist mental health providers in one of the poorest regions of the UK. The service received 900 clinically related contacts and 99 in-depth consultations. Service users who were referred to the CCS had high levels of clinical needs with an average score of 15.9 on the Health of the Nation Outcomes Scale. Overall, Global Assessment of Function scores improved and there were trends for improvements in symptoms. The level of routine care (and by implication associated costs) significantly reduced after CCS intervention, due to a reduction in use of accident and emergency (A&E) services, psychiatrists and community psychiatric nurses (CPNs)/case managers. Cost analysis indicates that savings amounted to L497 per patient. The cost of intervention was no greater than usual care, and may reduce spend per patient over a 3-month follow-up and perhaps longer. More specifically, clinicians felt the cultural consultation service helped to improve the treatment plan (71%), engagement (50%), medication compliance (21%) and earlier discharge (7%). PMID- 25747025 TI - Explanations of illness experiences among community mental health patients: an argument for the use of an ethnographic interview method in routine clinical care. AB - Cultural variations in perceptions of mental distress are important issues for healthcare. They can affect communication between patients and professionals and may be a root cause for misdiagnosis, patient disengagement, and disparities in access, outcomes and overall experiences of treatment by patients. Taking into account patients' explanatory models (EMs) of mental distress is fundamental to patient-centred care, and improved outcomes. This paper reports on the outcomes from the Cultural Consultation Service, commissioned in an inner-city London borough. We used a narrative-based ethnographic method of assessment, in which community mental health patients referred for a cultural consultation were interviewed using Barts Explanatory Model Inventory and Checklist (BEMI) to assess the EMs of their mental distress. Patients mainly attributed the causes and consequences of their mental distress to emotional and psychological factors, which were inextricably linked to existing social concerns and interpersonal issues. Desired solutions mainly focused on treatment, social, and systemic interventions. We found that using BEMI could contribute to a comprehensive assessment in routine care and can be used by professionals within a short timeframe and with minimal training. Ethnographic assessment method captures patients' EMs and illness experiences, opening the way for patient-centred interventions and potentially better outcomes and experiences. PMID- 25747026 TI - Protocol: Reducing suicidal ideation among Turkish migrants in the Netherlands and in the UK: effectiveness of an online intervention. AB - BACKGROUND: The Turkish community living in Europe has an increased risk for suicidal ideation and attempted suicide. Online self-help may be an effective way of engagement with this community. This study will evaluate the effectiveness of a culturally adapted, guided, cognitive behavioural therapy-based online self help intervention targeting suicidal ideation for Turkish adults living in the Netherlands and in the UK. METHODS AND DESIGN: This study will be performed in two phases. First, the Dutch online intervention will be adapted to Turkish culture. The second phase will be a randomized controlled trial with two conditions: experimental and waiting-list control. Ethical approval has been granted for the trials in London and Amsterdam. The experimental group will obtain direct access to the intervention, which will take 6 weeks to complete. Participants in the waiting-list condition will obtain access to the modules after 6 weeks. Participants in both conditions will be assessed at baseline, post test and 3 months post-test follow-up. The primary outcome measure is reduction in frequency and intensity of suicidal thoughts. Secondary outcome measures are self-harm, attempted suicide, suicide ideation attributes, depression, hopelessness, anxiety, quality of life, worrying and satisfaction with the treatment. PMID- 25747027 TI - Role of innate immune sensors, TLRs, and NALP3 in rheumatoid arthritis and osteoarthritis. AB - Innate immune sensors, Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain-like receptors (NLRs) participate in the induction of innate inflammatory and adaptive immune responses in rheumatoid arthritis (RA) and osteoarthritis (OA). Danger signals, e.g., heat-shock proteins (HSPs) and high mobility group box-1 protein (HMGB-1), internal ligands of TLRs, have been reported in the patients with RA and OA. In RA, TLR1-9 have been implicated in the pathogenesis. Although the precise role of each receptor is still unknown, immunohistochemical analyses of RA tissues after treatment of biologic disease modifying antirheumatic drugs showed phenotypic changes of immune cell types and residual expression of some TLRs. This suggests the potential for modulation of moderate/severe local joint inflammation, composed in particular of and possibly driven by the "auto-inflammatory" TLR+ cells, still responding to internal ligands derived from destroyed tissues. In OA, systematic profiling of TLR using a histological grading system recently showed that TLR+ cells are greater in number in the surface zone of grades 3 and 4 OA, but interestingly not grade 5. NACHT, LRR, and PYD domains-containing protein (NALP) 3 and related molecules have been also demonstrated both in RA and OA. In addition, a cross talk mechanism of TLR and NALP responsible for increasing joint inflammation has been suggested. Taken together, although OA is not basically an inflammatory disease, and is different from that of RA, pattern recognition receptors-signaling pathways, TLRs and NALP3 may play a role in the pathogenesis of both these conditions, probably as driving forces of progression. Precise and intensive analyses of both receptors, signal pathways, and cross talk mechanisms may provide a new therapeutic approach as molecular targets. PMID- 25747028 TI - Joint replacement surgery and the innate immune system. AB - Total joint replacement is a highly successful, cost-effective surgical procedure that relieves pain and improves function for patients with end-stage arthritis. The most commonly used materials for modern joint replacements include metal alloys such as cobalt chrome and titanium alloys, polymers including polymethylmethacrylate and polyethylene, and ceramics. Implantation of a joint prosthesis incites an acute inflammatory reaction that is regulated by the innate immune system, a preprogrammed non-antigen specific biological response composed of cells, proteins, and other factors. This "frontline" immune mechanism was originally designed to combat invading microorganisms, but now responds to both pathogen-associated molecular patterns or PAMPS (by-products from microorganisms), and damage associated molecular patterns or DAMPS (molecular by products from cells), via pattern recognition receptors (PRRs). In this way, potentially injurious stimuli that might disrupt the normal homeostatic regulatory mechanisms of the organism are efficiently dealt with, ensuring the survival of the host. Initial surgical implantation of the joint replacement, as well as ongoing generation of wear debris and byproducts during usage of the joint, activates the innate immune system. Understanding and potentially modulating these events may lead to improved function and increased longevity of joint replacements in the future. PMID- 25747029 TI - Role of macrophages in the biological reaction to wear debris from joint replacements. AB - Normal usage of total joint replacements results in the production of wear debris and other byproducts. In particular, polyethylene particles are heavily involved in the stimulation of local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone resorption (osteolysis), and, eventually, implant loosening. As sentinels of the innate immune system, cells of the monocyte/macrophage lineage initiate the inflammatory cascade that leads to osteolysis. The biological processes involved are complex, based on the unique properties of the monocytes/macrophages, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The interaction with wear debris triggers the release of pro-inflammatory factors, such as TNF-alpha, IL-1, and others, pro osteoclastic factors such as RANKL, and chemokines, such as MCP-1 and MIP-1, all being crucial to the recruitment, migration, differentiation, and ultimately activation of bone resorbing osteoclasts. In parallel, other distinct macrophage populations inhibit inflammation and mitigate its consequences on the bone implant interface. Here, the role of the monocyte/macrophage cell lineage in the initiation and maintenance of the host inflammatory response to wear debris and subsequent periprosthetic osteolysis is presented. PMID- 25747030 TI - Macrophage polarization and activation in response to implant debris: influence by "particle disease" and "ion disease". AB - Macrophages derive from human embryonic and fetal stem cells and from human bone marrow-derived blood monocytes. They play a major homeostatic role in tissue remodeling and maintenance facilitated by apoptotic "eat me" opsonins like CRP, serum amyloid P, C1q, C3b, IgM, ficolin, and surfactant proteins. Three subsets of monocytes, classic, intermediate, and nonclassic, are mobilized and transmigrate to tissues. Implant-derived wear particles opsonized by danger signals regulate macrophage priming, polarization (M1, M2, M17, and Mreg), and activation. CD14(+) monocytes in healthy controls and CD16(+) monocytes in inflammation differentiate/polarize to foreign body giant cells/osteoclasts or inflammatory dendritic cells (infDC). These danger signal opsonins can be pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), but in aseptic loosening, usually are damage-associated molecular patterns (DAMPs). Danger signal-opsonized particles elicit "particle disease" and aseptic loosening. They provide soluble and cell membrane-bound co-stimulatory signals that can lead to cell-mediated immune reactions to metal ions. Metal-on-metal implant failure has disclosed that quite like Ni(2+), its neighbor in the periodic table Co(2+) can directly activate toll-like receptor 4 (TLR4) as a lipopolysaccharide-mimic. "Ion disease" concept needs to be incorporated into the "particle disease" concept, due to the toxic, immune, and inflammatory potential of metal ions. PMID- 25747031 TI - Innate immune reactions in septic and aseptic osteolysis around hip implants. AB - According to the long-standing definition, septic and aseptic total joint replacement loosening are two distinct conditions with little in common. Septic joint replacement loosening is driven by bacterial infection whereas aseptic loosening is caused by biomaterial wear debris released from the bearing surfaces. However, recently it has been recognized that the mechanisms that drive macrophage activation in septic and aseptic total joint replacement loosening resemble each other. In particular, accumulating evidence indicates that in addition to mediating bacterial recognition and the subsequent inflammatory reaction, toll-like receptors (TLRs) and their ligands, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS), play a key role in wear debris-induced inflammation and macrophage activation. In addition, subclinical bacterial biofilms have been identified from some cases of seemingly aseptic implant loosening. Furthermore, metal ions released from some total joint replacements can activate TLR signaling similar to bacterial derived PAMPs. Likewise, metal ions can function as haptens activating the adaptive immune system similar to bacterial derived antigens. Thus, it appears that aseptic and septic joint replacement loosening share similar underlying pathomechanisms and that this strict dichotomy to sterile aseptic and bacterial caused septic implant loosening is somewhat questionable. Indeed, rather than being two, well-defined clinical entities, peri-implant osteolysis is, in fact, a spectrum of conditions in which the specific clinical picture is determined by complex interactions of multiple local and systemic factors. PMID- 25747033 TI - Back-side wear in HexLoc cups clinico-radiological, immunohistopathological, finite element, and retrieval analysis studies. AB - The HexLoc locking system was designed to prevent back-side wear of the polyethylene liner in the modular cementless metal-backed acetabular cup, but failed. Back-side wear was analyzed using clinico-radiological data, immunohistopathology, finite element modeling (FEM, and retrieval analysis. Screw holes allowed entry of titanium oxide and exit of polyethylene particles. Birefringent polyethylene wear particles were found behind the metal cup in macrophages containing pro-inflammatory tumor necrosis factor-alpha and interleukin-1beta, whereas fibroblast-like cells stained for osteoclastogenic receptor activator of nuclear factor kappa B ligand (RANKL). Computerized tomography revealed granulomas (83% versus 17 %) and cortical destruction (50% versus 5%) better than radiographs. In FEM, a change of the abduction angle from 45 to 60 deg, and liner thickness from 4.8 mm to 2.5 mm, increased the back-side wear by 90% and 120%, respectively. Screw holes were stress concentration areas; their removal decreased wear by 40%. Modeling results were validated in retrieved implants, which demonstrated extensive back-side wear damage of liners with a high abduction angle. Combined clinico-radiological, immunohistopathological, FEM, and retrieval analysis disclosed that back-side wear in the HexLoc design is sensitive to the abduction angle, liner thickness, and presence of screw holes. PMID- 25747034 TI - Bioelectrochemical analysis of a hyperthermophilic microbial fuel cell generating electricity at temperatures above 80 degrees C. AB - We examined whether a hyperthermophilic microbial fuel cell (MFC) would be technically feasible. Two-chamber MFC reactors were inoculated with subsurface microorganisms indigenous to formation water from a petroleum reservoir and were started up at operating temperature 80 degrees C. The MFC generated a maximum current of 1.3 mA 45 h after the inoculation. Performance of the MFC improved with an increase in the operating temperature; the best performance was achieved at 95 degrees C with the maximum power density of 165 mWm(-2), which was approximately fourfold higher than that at 75 degrees C. Thus, to our knowledge, our study is the first to demonstrate generation of electricity in a hyperthermophilic MFC (operating temperature as high as 95 degrees C). Scanning electron microscopy showed that filamentous microbial cells were attached on the anode surface. The anodic microbial consortium showed limited phylogenetic diversity and primarily consisted of hyperthermophilic bacteria closely related to Caldanaerobacter subterraneus and Thermodesulfobacterium commune. PMID- 25747032 TI - Innate immunity sensors participating in pathophysiology of joint diseases: a brief overview. AB - The innate immune system consists of functionally specialized "modules" that are activated in response to a particular set of stimuli via sensors located on the surface or inside the tissue cells. These cells screen tissues for a wide range of exogenous and endogenous danger/damage-induced signals with the aim to reject or tolerate them and maintain tissue integrity. In this line of thinking, inflammation evolved as an adaptive tool for restoring tissue homeostasis. A number of diseases are mediated by a maladaptation of the innate immune response, perpetuating chronic inflammation and tissue damage. Here, we review recent evidence on the cross talk between innate immune sensors and development of rheumatoid arthritis, osteoarthritis, and aseptic loosening of total joint replacements. In relation to the latter topic, there is a growing body of evidence that aseptic loosening and periprosthetic osteolysis results from long term maladaptation of periprosthetic tissues to the presence of by-products continuously released from an artificial joint. PMID- 25747035 TI - Genetic variations of IL-28B and PD-1 are in association with the susceptibility and outcomes of HCV infection in Southeast China. AB - Programmed cell death-1 (PD-1) is an important co-inhibitory molecule involved in the progression of chronic viral infections. To investigate the associations of three single nucleotide polymorphisms (SNPs) (rs10204525, rs2227982 and rs36084323) in PD-1 and a previously well-inquired SNP rs12979860 in IL-28B with the outcomes of hepatitis C virus (HCV) infection in Southeast China, a total of 375 healthy controls, 219 spontaneous resolved HCV patients and 600 chronic HCV patients were enrolled in this study. The generation of HCV F protein and PD-1 expression on T cells was determined. Multivariate logistic regression analysis showed no association of rs12979860 CC genotype with spontaneous clearance of HCV infection in our subjects. The generation of HCV F protein was significantly related to HCV infection chronicity, but no significant relationship was found between HCV F protein and SNPs in PD-1. The rs10204525 TT genotype was associated with an increased risk of HCV infection chronicity in age ?56years subgroup (adjusted OR=0.390, P=3.8*10(-4)). The C allele of rs10204525 played protective roles in females infected with HCV (adjusted OR=0.608, P=0.008). A significant higher percentage of PD-1 expression on T cells was observed in rs10204525 TT genotype when compared to CC genotype (P=0.047). Moreover, a significant genotype genotype interaction between IL-28B rs12979860 CC and PD-1 rs10204525 TC+CC was found to be associated with higher rates of spontaneous clearance (adjusted OR=0.689, P=0.032). The combined effect of rs12979860 and rs10204525 was of great value in predicting the outcomes of HCV infection. These analyses showed the importance of IL-28B and PD-1 polymorphisms and their interactions in the outcomes of HCV infection in Chinese Han population in Southeast China. PMID- 25747036 TI - A balanced view of choroid plexus structure and function: Focus on adult humans. AB - Recently tremendous progress has been made in studying choroid plexus (CP) physiology and pathophysiology; and correcting several misconceptions about the CP. Specifically, the details of how CP, a locus of the blood-CSF barrier (BCSFB), secretes and purifies CSF, generates intracranial pressure (ICP), maintains CSF ion homeostasis, and provides micronutrients, proteins and hormones for neuronal and glial development, maintenance and function, are being understood on a molecular level. Unequivocal evidence that the CP secretory epithelium is the predominant supplier of CSF for the ventricles comes from multiple lines: uptake kinetics of tracer (22)Na and (36)Cl penetration from blood to CSF, autoradiographic mapping of rapid (22)Na and (36)Cl permeation (high permeability coefficients) into the cerebroventricles, CSF sampling from several different in vivo and in vitro CP preparations, CP hyperplasia that increases CSF formation and ICP; and in vitro analysis of CP ability to transport molecules (with expected directionality) and actively secrete fluid against an hydrostatic fluid column. Furthermore, clinical support for this CP-CSF model comes from neurosurgical procedures to remove lateral ventricle CPs in hydrocephalic children to reduce CSF formation, thereby relieving elevated ICP. In terms of micronutrient transport, ascorbic acid, folate and other essential factors are transported by specific (cloned) carriers across CP into ventricular CSF, from which they penetrate across the ependyma and pia mater deeply into the brain to support its viability and function. Without these choroidal functions, severe neurological disease and even death can occur. In terms of efflux or clearance transport, the active carriers (many of which have been cloned and expressed) in the CP basolateral and apical membranes perform regulatory removal of some metabolites (e.g. choline) and certain drugs (e.g. antibiotics like penicillin) from CSF, thus reducing agents such as penicillin to sub-therapeutic levels. Altogether, these multiple transport and secretory functions in CP support CSF homeostasis and fluid dynamics essential for brain function. PMID- 25747037 TI - The effect of focal brain injury on beta-amyloid plaque deposition, inflammation and synapses in the APP/PS1 mouse model of Alzheimer's disease. AB - Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Abeta) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Abeta plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Abeta antibody) MOAB-2 labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Abeta plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p<0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p>0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d PI (p>0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Abeta plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Abeta plaque pathology that causes synaptic degeneration. PMID- 25747039 TI - Current view of the potential roles of proteins enriched on the inactive X chromosome. AB - X chromosome inactivation (X-inactivation) is triggered by X-linked noncoding Xist RNA, which is expressed asymmetrically from one of the two X chromosomes in females and coats it in cis to induce chromosome-wide silencing. Xist RNA is thought to play a role as a platform in recruiting proteins involved in gene silencing and heterochromatinization, which mediate serial changes in epigenetic modification of the chromatin. During the last two decades, many proteins have been shown to be enriched on the inactivated X chromosome in mouse and human. Although the biological significance of most of them for X-inactivation has not been fully established, extensive studies of these proteins should provide a better understanding of the molecular basis of how X-inactivation mediated by Xist RNA is regulated. Here, we review the potential roles of some of these proteins in the stepwise process of Xist RNA-mediated chromosome silencing. PMID- 25747040 TI - Expression analysis of individual homoeologous wheat genome- and rye genome specific transcripts in a 2BS.2RL wheat-rye translocation. AB - Wheat-rye translocations are widely used in wheat breeding to confer resistance against abiotic and biotic stress. Studying gene expression in wheat-rye translocations is complicated due to the presence of homoeologous genes in hexaploid wheat and high levels of synteny between wheat and rye chromatin. To distinguish transcripts expressed from each of the three wheat genomes and those from rye chromatin, genomic probes generated from diploid progenitors of wheat and rye were synthesized on a custom array. A total of 407 transcripts showed homoeologous genome ('A', 'B' or 'D' genome)- or rye genome ('R')-specific differential expression, based on unequal values of probe hybridization. In a 2BS.2RL wheat-rye translocation, thirteen of the 407 transcripts showed preferential expressions from rye chromatin. As well as quantifying variation in homoeologous transcript in wheat-rye translocations, this study also provides a potential aid to examine the contribution of the subgenomes to complex allohexapolyploids. PMID- 25747041 TI - Green fluorescent protein fused to the C terminus of RAD51 specifically interferes with secondary DNA binding by the RAD51-ssDNA complex. AB - Green fluorescent protein (GFP), fused to the N or C terminus of a protein of interest, is widely used to monitor the localization and mobility of proteins in cells. RAD51 is an essential protein that functions in mitotic DNA repair and meiotic chromosome segregation by promoting the homologous recombination reaction. A previous genetic study with Arabidopsis thaliana revealed that GFP fused to the C terminus of RAD51 (RAD51-GFP) inhibits mitotic DNA repair, but meiotic homologous recombination remained unaffected. To determine how the C terminal GFP specifically inhibits mitotic DNA repair by RAD51, we purified rice RAD51A1-GFP and RAD51A2-GFP, and performed biochemical analyses. Interestingly, purified RAD51A1-GFP and RAD51A2-GFP are proficient in DNA binding and ATP hydrolysis. However, nucleoprotein complexes containing single-stranded DNA and RAD51A1-GFP or RAD51A2-GFP are significantly defective in binding to the second DNA molecule (secondary DNA binding), and consequently fail to catalyze homologous pairing. In contrast, RAD51A1-GFP and RAD51A2-GFP efficiently stimulated homologous pairing promoted by the meiosis-specific RAD51 isoform DMC1. These biochemical characteristics are well conserved in human RAD51-GFP. Therefore, GFP fused to the C terminus of RAD51 abolishes the homologous pairing activity of RAD51 by disrupting secondary DNA binding, but does not affect its DMC1-stimulating activity. PMID- 25747042 TI - Hyperexpansion of wheat chromosomes sorted by flow cytometry. AB - Despite remarkable recent progress in the analysis of plant genome organization and chromosome structure, there is a need for methods enabling DNA sequences to be mapped by fluorescence in situ hybridization (FISH) at high spatial resolution. We sorted mitotic metaphase chromosomes of wheat by flow cytometry and observed the occurrence of hyperexpanded chromosomes among them. However, this phenomenon was not reproducible in subsequent experiments. An investigation into the procedures of flow cytometry revealed that the hyperexpansion of chromosomes became reproducible when the concentration of formaldehyde used in sample fixation was reduced. We conducted FISH analysis with 45S rDNA, 5S rDNA and wheat centromeric repeat sequences as probes on flow-sorted chromosomes and also on chromosomes from squash preparations. We measured the length of chromosomes 1B and 6B, identified by FISH. On average, the hyperexpanded 1B and 6B chromosomes were 7.26 and 7.53 times longer, respectively, than the same chromosomes from the squash preparations. The most stretched 1B and 6B chromosomes both exceeded 100 micrometers. PMID- 25747043 TI - Polyphyletic origins of schizothoracine fish (Cyprinidae, Osteichthyes) and adaptive evolution in their mitochondrial genomes. AB - The schizothoracine fish, also called snow trout, are members of the Cyprinidae, and are the most diversified teleost fish in the Qinghai-Tibetan Plateau (QTP). Clarifying the evolutionary history of the schizothoracine fish is therefore important for better understanding the biodiversity of the QTP. Although morphological and molecular phylogenetic studies have supported the monophyly of the Schizothoracinae, a recent molecular phylogenetic study based on the mitochondrial genome questioned the monophyly of this taxon. However, the phylogenetic analysis of that study was on the basis of only three schizothoracine species, and the support values were low. In this report, we inferred the phylogenetic tree on the basis of mitochondrial genome data including 21 schizothoracine species and five closely related species, and the polyphyletic origins of the Schizothoracinae were strongly supported. The tree further suggests that the Schizothoracinae consists of two clades, namely the "morphologically specialized clade" and the "morphologically primitive clade", and that these two clades migrated independently of each other to the QTP and adapted to high altitude. We also detected in their mitochondrial genomes strong signals of positive selection, which probably represent evidence of high-altitude adaptation. In the case of the morphologically specialized clade, positive selection mainly occurred during the Late Paleocene to the Early Oligocene. Its migration also seems to have occurred in the Early Eocene, and this timing is consistent with the drastic uplifting of the QTP. On the other hand, positive selection in the morphologically primitive clade has mainly occurred since the Late Miocene. Because its members are thought to have migrated to the QTP recently, it is possible that they are now undergoing high-altitude adaptation. PMID- 25747044 TI - Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer's disease. AB - INTRODUCTION: The 37/67 kDa high-affinity laminin receptor (laminin receptor precursor/laminin receptor, LRP/LR) is a multi-faceted cellular receptor. It plays a vital role in the malignancy of various cancer types where it is seen to contribute to invasion, adhesion, apoptosis evasion and angiogenesis. Furthermore, it has been found to play an important role in facilitating the processes leading to neurotoxicity in Alzheimer's disease (AD). Various therapeutic options targeting this receptor have been patented with the outlook on application for the treatment/prevention of these diseases. AREAS COVERED: The various roles that LRP/LR plays in cancer, AD and infectious diseases caused by viruses and bacteria have been examined in detail and an overview of the current patented therapeutic strategies targeting this receptor is given. EXPERT OPINION: Molecular tools directed against LRP/LR, such as antibodies and small interfering RNA, could prove to be effective in the prevention of metastasis and angiogenesis while inducing apoptosis in cancers. Moreover, these strategies could also be applied to AD where LRP/LR is seen to facilitate the production and internalization of the neurotoxic Abeta peptide. This review provides a comprehensive overview of the mechanisms by which LRP/LR is involved in eliciting pathogenic events, while showing how the use of patented approaches targeting this receptor could be used to treat them. PMID- 25747046 TI - News from the Biological Stain Commission, no. 16. AB - In the 16(th) issue of News from the Biological Stain Commission (BSC) under the heading of Regulatory affairs, the Biological Stain Commission's International Affairs Committee presents information from the 28(th) meeting of CEN/TC 140 In vitro diagnostic medical devices held on October 23, 2013 in Berlin, Germany. Information is also presented from the 19(th) meeting of ISO/TC 212 Clinical laboratory testing and in vitro diagnostic test systems held on October 19 - 21, 2013 in Singapore. PMID- 25747045 TI - Simultaneous detection of electronic structure changes from two elements of a bifunctional catalyst using wavelength-dispersive X-ray emission spectroscopy and in situ electrochemistry. AB - Multielectron catalytic reactions, such as water oxidation, nitrogen reduction, or hydrogen production in enzymes and inorganic catalysts often involve multimetallic clusters. In these systems, the reaction takes place between metals or metals and ligands to facilitate charge transfer, bond formation/breaking, substrate binding, and release of products. In this study, we present a method to detect X-ray emission signals from multiple elements simultaneously, which allows for the study of charge transfer and the sequential chemistry occurring between elements. Kbeta X-ray emission spectroscopy (XES) probes charge and spin states of metals as well as their ligand environment. A wavelength-dispersive spectrometer based on the von Hamos geometry was used to disperse Kbeta signals of multiple elements onto a position detector, enabling an XES spectrum to be measured in a single-shot mode. This overcomes the scanning needs of the scanning spectrometers, providing data free from temporal and normalization errors and therefore ideal to follow sequential chemistry at multiple sites. We have applied this method to study MnOx-based bifunctional electrocatalysts for the oxygen evolution reaction (OER) and the oxygen reduction reaction (ORR). In particular, we investigated the effects of adding a secondary element, Ni, to form MnNiOx and its impact on the chemical states and catalytic activity, by tracking the redox characteristics of each element upon sweeping the electrode potential. The detection scheme we describe here is general and can be applied to time-resolved studies of materials consisting of multiple elements, to follow the dynamics of catalytic and electron transfer reactions. PMID- 25747047 TI - Estrogen modulates 7/4 antigen distribution within eccentrically contracted injured skeletal muscle. AB - Eccentric contractions are skeletal muscle stretches with concurrent active force production; these contractions commonly occur during dynamic sports activities and can cause acute muscle injury. Recovery from this injury depends in part on pro-inflammatory processes, such as neutrophil infiltration at the injured site, which is affected by estrogen. This estrogen effect has been examined broadly, but without distinguishing between major compartments within muscle in which neutrophil infiltration can occur. Therefore, we compared neutrophil antigen expression in two compartments of eccentrically contracted muscle of ovariectomized mice with or without estrogen. To quantify neutrophil antigen expression, serial cross sections of muscle were immunolabeled with antibodies that recognize 7/4 or Ly6C/G, then quantified using computer-assisted image analysis. At 48 h post injury, estrogen-positive (E+) mice had more 7/4-positive and Ly6C/G-positive myofibers, increased 7/4 area percentage, and more 7/4 positive cells in the connective tissue. In addition, E+ mice showed more 7/4 positive myofibers that were Ly6C/G-negative and more Ly6C/G-positive myofibers that were 7/4-negative. These data suggest that in injured muscle, estrogen increases 7/4 antigen in connective tissue and myofibers and is associated with more Ly6C/G-positive myofibers when the 7/4 antigen is absent from these myofibers. PMID- 25747049 TI - Clinical and light microscopic studies of the conjunctival tissues of dogs with bilateral keratoconjunctivitis sicca before and after treatment with topical 2% cyclosporine. AB - We determined the concentrations of goblet and immune cells in conjunctival imprints and tissues of canines with keratoconjunctivitis sicca (KCS) before and after cyclosporine A (CsA) treatment. Twelve dogs with bilateral KCS were assigned to three groups: untreated, treatment group 1, and treatment group 2. The treatment groups were treated topically with 2% ophthalmic CsA solution for 45 days; CsA treatment group 2 was followed for an additional 30 days after discontinuation of the drug. Schirmer tear test (STT) scores were recorded prior to CsA treatment and on alternate days throughout the experiment. CsA treatment improved the STT scores, restored conjunctival histology, increased goblet and epithelial cell numbers, and decreased numbers of inflammatory cells. Although the STT scores regressed slightly at day 30 after discontinuing the treatment, the scores were higher than the baseline values. Topical CsA treatment resolved clinical signs of KCS, improved STT scores and restored normal conjunctival histology. PMID- 25747050 TI - Communication: On the competition between adiabatic and nonadiabatic dynamics in vibrationally mediated ammonia photodissociation in its A band. AB - Non-adiabatic processes play an important role in photochemistry, but the mechanism for conversion of electronic energy to chemical energy is still poorly understood. To explore the possibility of vibrational control of non-adiabatic dynamics in a prototypical photoreaction, namely, the A-band photodissociation of NH3(X(1)A1), full-dimensional state-to-state quantum dynamics of symmetric or antisymmetric stretch excited NH3(X(1)A1) is investigated on recently developed coupled diabatic potential energy surfaces. The experimentally observed H atom kinetic energy distributions are reproduced. However, contrary to previous inferences, the NH2(A(2)A1)/NH2(X(2)B1) branching ratio is found to be small regardless of the initial preparation of NH3(X(1)A1), while the internal state distribution of the preeminent fragment, NH2(X(2)B1), is found to depend strongly on the initial vibrational excitation of NH3(X(1)A1). The slow H atoms in photodissociation mediated by the antisymmetric stretch fundamental state are due to energy sequestered in the internally excited NH2(X(2)B1) fragment, rather than in NH2(A(2)A1) as previously proposed. The high internal excitation of the NH2(X(2)B1) fragment is attributed to the torques exerted on the molecule as it passes through the conical intersection seam to the ground electronic state of NH3. Thus in this system, contrary to previous assertions, the control of electronic state branching by selective excitation of ground state vibrational modes is concluded to be ineffective. The juxtaposition of precise quantum mechanical results with complementary results based on quasi-classical surface hopping trajectories provides significant insights into the non-adiabatic process. PMID- 25747051 TI - Communication: The absolute shielding scales of oxygen and sulfur revisited. AB - We present an updated semi-experimental absolute shielding scale for the (17)O and (33)S nuclei. These new shielding scales are based on accurate rotational microwave data for the spin-rotation constants of H2(17)O [Puzzarini et al., J. Chem. Phys. 131, 234304 (2009)], C(17)O [Cazzoli et al., Phys. Chem. Chem. Phys. 4, 3575 (2002)], and H2(33)S [Helgaker et al., J. Chem. Phys. 139, 244308 (2013)] corrected both for vibrational and temperature effects estimated at the CCSD(T) level of theory as well as for the relativistic corrections to the relation between the spin-rotation constant and the absolute shielding constant. Our best estimate for the oxygen shielding constants of H2(17)O is 328.4(3) ppm and for C(17)O -59.05(59) ppm. The relativistic correction for the sulfur shielding of H2(33)S amounts to 3.3%, and the new sulfur shielding constant for this molecule is 742.9(4.6) ppm. PMID- 25747052 TI - Communication: Observation of dipole-bound state and high-resolution photoelectron imaging of cold acetate anions. AB - We report the observation of a dipole-bound state and a high-resolution photoelectron imaging study of cryogenically cooled acetate anions (CH3COO(-)). Both high-resolution non-resonant and resonant photoelectron spectra via the dipole-bound state of CH3COO(-) are obtained. The binding energy of the dipole bound state relative to the detachment threshold is determined to be 53 +/- 8 cm( 1). The electron affinity of the CH3COO. neutral radical is measured accurately as 26 236 +/- 8 cm(-1) (3.2528 +/- 0.0010 eV) using high-resolution photoelectron imaging. This accurate electron affinity is validated by observation of autodetachment from two vibrational levels of the dipole-bound state of CH3COO( ). Excitation spectra to the dipole-bound states yield rotational profiles, allowing the rotational temperature of the trapped CH3COO(-) anions to be evaluated. PMID- 25747053 TI - Communication: Equilibrium rate coefficients from atomistic simulations: The O((3)P) + NO((2)Pi) -> O2(X(3)Sigmag(-)) + N((4)S) reaction at temperatures relevant to the hypersonic flight regime. AB - The O((3)P) + NO((2)Pi) -> O2(X(3)Sigmag(-)) + N((4)S) reaction is among the N- and O- involving reactions that dominate the energetics of the reactive air flow around spacecraft during hypersonic atmospheric re-entry. In this regime, the temperature in the bow shock typically ranges from 1000 to 20,000 K. The forward and reverse rate coefficients for this reaction derived directly from trajectory calculations over this range of temperature are reported in this letter. Results compare well with the established equilibrium constants for the same reaction from thermodynamic quantities derived from spectroscopy in the gas phase which paves the way for large-scale in silico investigations of equilibrium rates under extreme conditions. PMID- 25747054 TI - Communication: Accurate hydration free energies at a wide range of temperatures from 3D-RISM. AB - We present a new model for computing hydration free energies by 3D reference interaction site model (3D-RISM) that uses an appropriate initial state of the system (as suggested by Sergiievskyi et al.). The new adjustment to 3D-RISM theory significantly improves hydration free energy predictions for various classes of organic molecules at both ambient and non-ambient temperatures. An extensive benchmarking against experimental data shows that the accuracy of the model is comparable to (much more computationally expensive) molecular dynamics simulations. The calculations can be readily performed with a standard 3D-RISM algorithm. In our work, we used an open source package AmberTools; a script to automate the whole procedure is available on the web (https://github.com/MTS Strathclyde/ISc). PMID- 25747055 TI - A reduced-scaling density matrix-based method for the computation of the vibrational Hessian matrix at the self-consistent field level. AB - An analytical method to calculate the molecular vibrational Hessian matrix at the self-consistent field level is presented. By analysis of the multipole expansions of the relevant derivatives of Coulomb-type two-electron integral contractions, we show that the effect of the perturbation on the electronic structure due to the displacement of nuclei decays at least as r(-2) instead of r(-1). The perturbation is asymptotically local, and the computation of the Hessian matrix can, in principle, be performed with O(N) complexity. Our implementation exhibits linear scaling in all time-determining steps, with some rapid but quadratic complexity steps remaining. Sample calculations illustrate linear or near-linear scaling in the construction of the complete nuclear Hessian matrix for sparse systems. For more demanding systems, scaling is still considerably sub-quadratic to quadratic, depending on the density of the underlying electronic structure. PMID- 25747056 TI - Exact milestoning. AB - A new theory and an exact computer algorithm for calculating kinetics and thermodynamic properties of a particle system are described. The algorithm avoids trapping in metastable states, which are typical challenges for Molecular Dynamics (MD) simulations on rough energy landscapes. It is based on the division of the full space into Voronoi cells. Prior knowledge or coarse sampling of space points provides the centers of the Voronoi cells. Short time trajectories are computed between the boundaries of the cells that we call milestones and are used to determine fluxes at the milestones. The flux function, an essential component of the new theory, provides a complete description of the statistical mechanics of the system at the resolution of the milestones. We illustrate the accuracy and efficiency of the exact Milestoning approach by comparing numerical results obtained on a model system using exact Milestoning with the results of long trajectories and with a solution of the corresponding Fokker-Planck equation. The theory uses an equation that resembles the approximate Milestoning method that was introduced in 2004 [A. K. Faradjian and R. Elber, J. Chem. Phys. 120(23), 10880-10889 (2004)]. However, the current formulation is exact and is still significantly more efficient than straightforward MD simulations on the system studied. PMID- 25747057 TI - Conduction of molecular electronic devices: qualitative insights through atom atom polarizabilities. AB - The atom-atom polarizability and the transmission probability at the Fermi level, as obtained through the source-and-sink-potential method for every possible configuration of contacts simultaneously, are compared for polycyclic aromatic compounds. This comparison leads to the conjecture that a positive atom-atom polarizability is a necessary condition for transmission to take place in alternant hydrocarbons without non-bonding orbitals and that the relative transmission probability for different configurations of the contacts can be predicted by analyzing the corresponding atom-atom polarizability. A theoretical link between the two considered properties is derived, leading to a mathematical explanation for the observed trends for transmission based on the atom-atom polarizability. PMID- 25747058 TI - Comparison of the kinetics of different Markov models for ligand binding under varying conditions. AB - We recently derived a Markov model for macromolecular ligand binding dynamics from few physical assumptions and showed that its stationary distribution is the grand canonical ensemble [J. W. R. Martini, M. Habeck, and M. Schlather, J. Math. Chem. 52, 665 (2014)]. The transition probabilities of the proposed Markov process define a particular Glauber dynamics and have some similarity to the Metropolis-Hastings algorithm. Here, we illustrate that this model is the stochastic analog of (pseudo) rate equations and the corresponding system of differential equations. Moreover, it can be viewed as a limiting case of general stochastic simulations of chemical kinetics. Thus, the model links stochastic and deterministic approaches as well as kinetics and equilibrium described by the grand canonical ensemble. We demonstrate that the family of transition matrices of our model, parameterized by temperature and ligand activity, generates ligand binding kinetics that respond to changes in these parameters in a qualitatively similar way as experimentally observed kinetics. In contrast, neither the Metropolis-Hastings algorithm nor the Glauber heat bath reflects changes in the external conditions correctly. Both converge rapidly to the stationary distribution, which is advantageous when the major interest is in the equilibrium state, but fail to describe the kinetics of ligand binding realistically. To simulate cellular processes that involve the reversible stochastic binding of multiple factors, our pseudo rate equation model should therefore be preferred to the Metropolis-Hastings algorithm and the Glauber heat bath, if the stationary distribution is not of only interest. PMID- 25747059 TI - Electron dynamics upon ionization: control of the timescale through chemical substitution and effect of nuclear motion. AB - Photoionization can generate a non-stationary electronic state, which leads to coupled electron-nuclear dynamics in molecules. In this article, we choose benzene cation as a prototype because vertical ionization of the neutral species leads to a Jahn-Teller degeneracy between ground and first excited states of the cation. Starting with equal populations of ground and first excited states, there is no electron dynamics in this case. However, if we add methyl substituents that break symmetry but do not radically alter the electronic structure, we see charge migration: oscillations in the spin density that we can correlate with particular localized electronic structures, with a period depending on the gap between the states initially populated. We have also investigated the effect of nuclear motion on electron dynamics using a complete active space self-consistent field (CASSCF) implementation of the Ehrenfest method, most previous theoretical studies of electron dynamics having been carried out with fixed nuclei. In toluene cation for instance, simulations where the nuclei are allowed to move show significant differences in the electron dynamics after 3 fs, compared to simulations with fixed nuclei. PMID- 25747060 TI - Forster resonance energy transfer, absorption and emission spectra in multichromophoric systems. I. Full cumulant expansions and system-bath entanglement. AB - We study the Forster resonant energy transfer rate, absorption and emission spectra in multichromophoric systems. The multichromophoric Forster theory (MCFT) is determined from an overlap integral of generalized matrices related to the donor's emission and acceptor's absorption spectra, which are obtained via a full 2nd-order cumulant expansion technique developed in this work. We calculate the spectra and MCFT rate for both localized and delocalized systems, and calibrate the analytical 2nd-order cumulant expansion with the exact stochastic path integral method. We present three essential findings: (i) The role of the initial entanglement between the donor and its bath is found to be crucial in both the emission spectrum and the MCFT rate. (ii) The absorption spectra obtained by the cumulant expansion method are nearly identical to the exact spectra for both localized and delocalized systems, even when the system-bath coupling is far from the perturbative regime. (iii) For the emission spectra, the cumulant expansion can give reliable results for localized systems, but fail to provide reliable spectra of the high-lying excited states of a delocalized system, when the system bath coupling is large and the thermal energy is small. This paper also provides a simple golden-rule derivation of the MCFT, reviews existing methods, and motivates further developments in the subsequent papers. PMID- 25747061 TI - Forster resonance energy transfer, absorption and emission spectra in multichromophoric systems. II. Hybrid cumulant expansion. AB - We develop a hybrid cumulant expansion method to account for the system-bath entanglement in the emission spectrum in the multi-chromophoric Forster transfer rate. In traditional perturbative treatments, the emission spectrum is usually expanded with respect to the system-bath coupling term in both real and imaginary time. This perturbative treatment gives a reliable absorption spectrum, where the bath is Gaussian and only the real-time expansion is involved. For the emission spectrum, the initial state is an entangled state of the system plus bath. Traditional perturbative methods are problematic when the excitations are delocalized and the energy gap is larger than the thermal energy, since the second-order expansion cannot predict the displacement of the bath. In the present method, the real-time dynamics is carried out by using the 2nd-order cumulant expansion method, while the displacement of the bath is treated more accurately by utilizing the exact reduced density matrix of the system. In a sense, the hybrid cumulant expansion is based on a generalized version of linear response theory with entangled initial states. PMID- 25747062 TI - Forster resonance energy transfer, absorption and emission spectra in multichromophoric systems. III. Exact stochastic path integral evaluation. AB - A numerically exact path integral treatment of the absorption and emission spectra of open quantum systems is presented that requires only the straightforward solution of a stochastic differential equation. The approach converges rapidly enabling the calculation of spectra of large excitonic systems across the complete range of system parameters and for arbitrary bath spectral densities. With the numerically exact absorption and emission operators, one can also immediately compute energy transfer rates using the multi-chromophoric Forster resonant energy transfer formalism. Benchmark calculations on the emission spectra of two level systems are presented demonstrating the efficacy of the stochastic approach. This is followed by calculations of the energy transfer rates between two weakly coupled dimer systems as a function of temperature and system-bath coupling strength. It is shown that the recently developed hybrid cumulant expansion (see Paper II) is the only perturbative method capable of generating uniformly reliable energy transfer rates and emission spectra across a broad range of system parameters. PMID- 25747063 TI - Competitive effects between stationary chemical reaction centres: a theory based on off-center monopoles. AB - The subject of this paper is competitive effects between multiple reaction sinks. A theory based on off-center monopoles is developed for the steady-state diffusion equation and for the convection-diffusion equation with a constant flow field. The dipolar approximation for the diffusion equation with two equal reaction centres is compared with the exact solution. The former turns out to be remarkably accurate, even for two touching spheres. Numerical evidence is presented to show that the same holds for larger clusters (with more than two spheres). The theory is extended to the convection-diffusion equation with a constant flow field. As one increases the convective velocity, the competitive effects between the reactive centres gradually become less significant. This is demonstrated for a number of cluster configurations. At high flow velocities, the current methodology breaks down. Fixing this problem will be the subject of future research. The current method is useful as an easy-to-use tool for the calibration of other more complicated models in mass and/or heat transfer. PMID- 25747064 TI - Accurate nonadiabatic quantum dynamics on the cheap: making the most of mean field theory with master equations. AB - In this article, we show how Ehrenfest mean field theory can be made both a more accurate and efficient method to treat nonadiabatic quantum dynamics by combining it with the generalized quantum master equation framework. The resulting mean field generalized quantum master equation (MF-GQME) approach is a non perturbative and non-Markovian theory to treat open quantum systems without any restrictions on the form of the Hamiltonian that it can be applied to. By studying relaxation dynamics in a wide range of dynamical regimes, typical of charge and energy transfer, we show that MF-GQME provides a much higher accuracy than a direct application of mean field theory. In addition, these increases in accuracy are accompanied by computational speed-ups of between one and two orders of magnitude that become larger as the system becomes more nonadiabatic. This combination of quantum-classical theory and master equation techniques thus makes it possible to obtain the accuracy of much more computationally expensive approaches at a cost lower than even mean field dynamics, providing the ability to treat the quantum dynamics of atomistic condensed phase systems for long times. PMID- 25747065 TI - Comments on the optical lineshape function: application to transient hole-burned spectra of bacterial reaction centers. AB - The vibrational spectral density is an important physical parameter needed to describe both linear and non-linear spectra of multi-chromophore systems such as photosynthetic complexes. Low-temperature techniques such as hole burning (HB) and fluorescence line narrowing are commonly used to extract the spectral density for a given electronic transition from experimental data. We report here that the lineshape function formula reported by Hayes et al. [J. Phys. Chem. 98, 7337 (1994)] in the mean-phonon approximation and frequently applied to analyzing HB data contains inconsistencies in notation, leading to essentially incorrect expressions in cases of moderate and strong electron-phonon (el-ph) coupling strengths. A corrected lineshape function L(omega) is given that retains the computational and intuitive advantages of the expression of Hayes et al. [J. Phys. Chem. 98, 7337 (1994)]. Although the corrected lineshape function could be used in modeling studies of various optical spectra, we suggest that it is better to calculate the lineshape function numerically, without introducing the mean phonon approximation. New theoretical fits of the P870 and P960 absorption bands and frequency-dependent resonant HB spectra of Rb. sphaeroides and Rps. viridis reaction centers are provided as examples to demonstrate the importance of correct lineshape expressions. Comparison with the previously determined el-ph coupling parameters [Johnson et al., J. Phys. Chem. 94, 5849 (1990); Lyle et al., ibid. 97, 6924 (1993); Reddy et al., ibid. 97, 6934 (1993)] is also provided. The new fits lead to modified el-ph coupling strengths and different frequencies of the special pair marker mode, omegasp, for Rb. sphaeroides that could be used in the future for more advanced calculations of absorption and HB spectra obtained for various bacterial reaction centers. PMID- 25747066 TI - A simple way to test for collinearity in spin symmetry broken wave functions: general theory and application to generalized Hartree Fock. AB - We introduce a necessary and sufficient condition for an arbitrary wavefunction to be collinear, i.e., its spin is quantized along some axis. It may be used to obtain a cheap and simple computational procedure to test for collinearity in electronic structure theory calculations. We adapt the procedure for Generalized Hartree Fock (GHF), and use it to study two dissociation pathways in CO2. For these dissociation processes, the GHF wave functions transform from low-spin Unrestricted Hartree Fock (UHF) type states to noncollinear GHF states and on to high-spin UHF type states, phenomena that are succinctly illustrated by the constituents of the collinearity test. This complements earlier GHF work on this molecule. PMID- 25747067 TI - The total position-spread tensor: spin partition. AB - The Total Position Spread (TPS) tensor, defined as the second moment cumulant of the position operator, is a key quantity to describe the mobility of electrons in a molecule or an extended system. In the present investigation, the partition of the TPS tensor according to spin variables is derived and discussed. It is shown that, while the spin-summed TPS gives information on charge mobility, the spin partitioned TPS tensor becomes a powerful tool that provides information about spin fluctuations. The case of the hydrogen molecule is treated, both analytically, by using a 1s Slater-type orbital, and numerically, at Full Configuration Interaction (FCI) level with a V6Z basis set. It is found that, for very large inter-nuclear distances, the partitioned tensor growths quadratically with the distance in some of the low-lying electronic states. This fact is related to the presence of entanglement in the wave function. Non-dimerized open chains described by a model Hubbard Hamiltonian and linear hydrogen chains Hn (n >= 2), composed of equally spaced atoms, are also studied at FCI level. The hydrogen systems show the presence of marked maxima for the spin-summed TPS (corresponding to a high charge mobility) when the inter-nuclear distance is about 2 bohrs. This fact can be associated to the presence of a Mott transition occurring in this region. The spin-partitioned TPS tensor, on the other hand, has a quadratical growth at long distances, a fact that corresponds to the high spin mobility in a magnetic system. PMID- 25747068 TI - Nanoplasmonics simulations at the basis set limit through completeness-optimized, local numerical basis sets. AB - We present an approach for generating local numerical basis sets of improving accuracy for first-principles nanoplasmonics simulations within time-dependent density functional theory. The method is demonstrated for copper, silver, and gold nanoparticles that are of experimental interest but computationally demanding due to the semi-core d-electrons that affect their plasmonic response. The basis sets are constructed by augmenting numerical atomic orbital basis sets by truncated Gaussian-type orbitals generated by the completeness-optimization scheme, which is applied to the photoabsorption spectra of homoatomic metal atom dimers. We obtain basis sets of improving accuracy up to the complete basis set limit and demonstrate that the performance of the basis sets transfers to simulations of larger nanoparticles and nanoalloys as well as to calculations with various exchange-correlation functionals. This work promotes the use of the local basis set approach of controllable accuracy in first-principles nanoplasmonics simulations and beyond. PMID- 25747069 TI - Finite element discretization of non-linear diffusion equations with thermal fluctuations. AB - We present a finite element discretization of a non-linear diffusion equation used in the field of critical phenomena and, more recently, in the context of dynamic density functional theory. The discretized equation preserves the structure of the continuum equation. Specifically, it conserves the total number of particles and fulfills an H-theorem as the original partial differential equation. The discretization proposed suggests a particular definition of the discrete hydrodynamic variables in microscopic terms. These variables are then used to obtain, with the theory of coarse-graining, their dynamic equations for both averages and fluctuations. The hydrodynamic variables defined in this way lead to microscopically derived hydrodynamic equations that have a natural interpretation in terms of discretization of continuum equations. Also, the theory of coarse-graining allows to discuss the introduction of thermal fluctuations in a physically sensible way. The methodology proposed for the introduction of thermal fluctuations in finite element methods is general and valid for both regular and irregular grids in arbitrary dimensions. We focus here on simulations of the Ginzburg-Landau free energy functional using both regular and irregular 1D grids. Convergence of the numerical results is obtained for the static and dynamic structure factors as the resolution of the grid is increased. PMID- 25747070 TI - Accuracy of Lagrange-sinc functions as a basis set for electronic structure calculations of atoms and molecules. AB - We developed a self-consistent field program based on Kohn-Sham density functional theory using Lagrange-sinc functions as a basis set and examined its numerical accuracy for atoms and molecules through comparison with the results of Gaussian basis sets. The result of the Kohn-Sham inversion formula from the Lagrange-sinc basis set manifests that the pseudopotential method is essential for cost-effective calculations. The Lagrange-sinc basis set shows faster convergence of the kinetic and correlation energies of benzene as its size increases than the finite difference method does, though both share the same uniform grid. Using a scaling factor smaller than or equal to 0.226 bohr and pseudopotentials with nonlinear core correction, its accuracy for the atomization energies of the G2-1 set is comparable to all-electron complete basis set limits (mean absolute deviation <=1 kcal/mol). The same basis set also shows small mean absolute deviations in the ionization energies, electron affinities, and static polarizabilities of atoms in the G2-1 set. In particular, the Lagrange-sinc basis set shows high accuracy with rapid convergence in describing density or orbital changes by an external electric field. Moreover, the Lagrange-sinc basis set can readily improve its accuracy toward a complete basis set limit by simply decreasing the scaling factor regardless of systems. PMID- 25747071 TI - GROMOS polarizable charge-on-spring models for liquid urea: COS/U and COS/U2. AB - Two one-site polarizable urea models, COS/U and COS/U2, based on the charge-on spring model are proposed. The models are parametrized against thermodynamic properties of urea-water mixtures in combination with the polarizable COS/G2 and COS/D2 models for liquid water, respectively, and have the same functional form of the inter-atomic interaction function and are based on the same parameter calibration procedure and type of experimental data as used to develop the GROMOS biomolecular force field. Thermodynamic, dielectric, and dynamic properties of urea-water mixtures simulated using the polarizable models are closer to experimental data than using the non-polarizable models. The COS/U and COS/U2 models may be used in biomolecular simulations of protein denaturation. PMID- 25747072 TI - An efficient method for energy levels calculation using full symmetry and exact kinetic energy operator: tetrahedral molecules. AB - A simultaneous use of the full molecular symmetry and of an exact kinetic energy operator (KEO) is of key importance for accurate predictions of vibrational levels at a high energy range from a potential energy surface (PES). An efficient method that permits a fast convergence of variational calculations would allow iterative optimization of the PES parameters using experimental data. In this work, we propose such a method applied to tetrahedral AB4 molecules for which a use of high symmetry is crucial for vibrational calculations. A symmetry-adapted contracted angular basis set for six redundant angles is introduced. Simple formulas using this basis set for explicit calculation of the angular matrix elements of KEO and PES are reported. The symmetric form (six redundant angles) of vibrational KEO without the sin(q)(-2) type singularity is derived. The efficient recursive algorithm based on the tensorial formalism is used for the calculation of vibrational matrix elements. A good basis set convergence for the calculations of vibrational levels of the CH4 molecule is demonstrated. PMID- 25747073 TI - The externally corrected coupled cluster approach with four- and five-body clusters from the CASSCF wave function. AB - An externally corrected CCSDt (coupled cluster with singles, doubles, and active triples) approach employing four- and five-body clusters from the complete active space self-consistent field (CASSCF) wave function (denoted as ecCCSDt-CASSCF) is presented. The quadruple and quintuple excitation amplitudes within the active space are extracted from the CASSCF wave function and then fed into the CCSDt like equations, which can be solved in an iterative way as the standard CCSDt equations. With a size-extensive CASSCF reference function, the ecCCSDt-CASSCF method is size-extensive. When the CASSCF wave function is readily available, the computational cost of the ecCCSDt-CASSCF method scales as the popular CCSD method (if the number of active orbitals is small compared to the total number of orbitals). The ecCCSDt-CASSCF approach has been applied to investigate the potential energy surface for the simultaneous dissociation of two O-H bonds in H2O, the equilibrium distances and spectroscopic constants of 4 diatomic molecules (F2(+), O2(+), Be2, and NiC), and the reaction barriers for the automerization reaction of cyclobutadiene and the Cl + O3 -> ClO + O2 reaction. In most cases, the ecCCSDt-CASSCF approach can provide better results than the CASPT2 (second order perturbation theory with a CASSCF reference function) and CCSDT methods. PMID- 25747074 TI - Population transfer HMQC for half-integer quadrupolar nuclei. AB - This work presents a detailed analysis of a recently proposed nuclear magnetic resonance method [Wang et al., Chem. Commun. 49(59), 6653-6655 (2013)] for accelerating heteronuclear coherence transfers involving half-integer spin quadrupolar nuclei by manipulating their satellite transitions. This method, called Population Transfer Heteronuclear Multiple Quantum Correlation (PT-HMQC), is investigated in details by combining theoretical analyses, numerical simulations, and experimental investigations. We find that compared to instant inversion or instant saturation, continuous saturation is the most practical strategy to accelerate coherence transfers on half-integer quadrupolar nuclei. We further demonstrate that this strategy is efficient to enhance the sensitivity of J-mediated heteronuclear correlation experiments between two half-integer quadrupolar isotopes (e.g., (27)Al-(17)O). In this case, the build-up is strongly affected by relaxation for small T2' and J coupling values, and shortening the mixing time makes a huge signal enhancement. Moreover, this concept of population transfer can also be applied to dipolar-mediated HMQC experiments. Indeed, on the AlPO4-14 sample, one still observes experimentally a 2-fold shortening of the optimum mixing time albeit with no significant signal gain in the (31)P-{(27)Al} experiments. PMID- 25747075 TI - Intersystem-crossing and phosphorescence rates in fac-Ir(III)(ppy)3: a theoretical study involving multi-reference configuration interaction wavefunctions. AB - We have employed combined density functional theory and multi-reference configuration interaction methods including spin-orbit coupling (SOC) effects to investigate the photophysics of the green phosphorescent emitter fac-tris-(2 phenylpyridine)iridium (fac-Ir(ppy)3). A critical evaluation of our quantum chemical approaches shows that a perturbational treatment of SOC is the method of choice for computing the UV/Vis spectrum of this heavy transition metal complex while multi-reference spin-orbit configuration interaction is preferable for calculating the phosphorescence rates. The particular choice of the spin-orbit interaction operator is found to be of minor importance. Intersystem crossing (ISC) rates have been determined by Fourier transformation of the time correlation function of the transition including Dushinsky rotations. In the electronic ground state, fac-Ir(ppy)3 is C3 symmetric. The calculated UV/Vis spectrum is in excellent agreement with experiment. The effect of SOC is particularly pronounced for the metal-to-ligand charge transfer (MLCT) band in the visible region of the absorption spectrum which does not only extend its spectral onset towards longer wavelengths but also experiences a blue shift of its maximum. Pseudo-Jahn-Teller interaction leads to asymmetric coordinate displacements in the lowest MLCT states. Substantial electronic SOC and a small energy gap make ISC an ultrafast process in fac-Ir(ppy)3. For the S1?T1 non radiative transition, we compute a rate constant of kISC = 6.9 * 10(12) s(-1) which exceeds the rate constant of radiative decay to the electronic ground state by more than six orders of magnitude, in agreement with the experimental observation of a subpicosecond ISC process and a triplet quantum yield close to unity. As a consequence of the geometric distortion in the T1 state, the T1 -> S0 transition densities are localized on one of the phenylpyridyl moieties. In our best quantum chemical model, we obtain phosphorescence decay times of 264 MUs, 13 MUs, and 0.9 MUs, respectively, for the T1,I, T1,II, and T1,III fine-structure levels in dichloromethane (DCM) solution. In addition to reproducing the correct orders of magnitude for the individual phosphorescence emission probabilities, our theoretical study gives insight into the underlying mechanisms. In terms of intensity borrowing from spin-allowed transitions, the low emission probability of the T1,I substate is caused by the mutual cancellation of contributions from several singlet states to the total transition dipole moment. Their contributions do not cancel but add up in case of the much faster T1,III -> S0 emission while the T1,II -> S0 emission is dominated by intensity borrowing from a single spin allowed process, i.e., the S2 -> S0 transition. PMID- 25747076 TI - Unusual solvation through both p-orbital lobes of a carbene carbon. AB - As a result of a configurational space search done to explain the experimental evidence of transient specific solvation of singlet fluorocarbene amide with tetrahydrofuran, we found that the most stable structures consist in a group in which each oxygen of two tetrahydrofuran molecules act as electron donor to its respective empty p-orbital lobe of the carbene carbon atom, located at each side of the carbene molecular plane. This kind of species, which to our knowledge has not been reported before, explains very well the particular experimental characteristics observed for the transient solvation of this system. We postulate that the simultaneous interaction to both p-orbital lobes seems to confer a special stability to the solvation complexes, because this situation moves away the systems from the proximity of the corresponding transition states for the ylide products. Additionally, we present an analysis of other solvation complexes and a study of the nature of the involved interactions. PMID- 25747077 TI - Relativistic configuration interaction calculation on the ground and excited states of iridium monoxide. AB - We present the fully relativistic multi-reference configuration interaction calculations of the ground and low-lying excited electronic states of IrO for individual spin-orbit component. The lowest-lying state is calculated for Omega = 1/2, 3/2, 5/2, and 7/2 in order to clarify the ground state of IrO. Our calculation suggests that the ground state is of Omega = 1/2, which is highly mixed with (4)Sigma(-) and (2)Pi states in Lambda - S notation. The two low-lying states 5/2 and 7/2 are nearly degenerate with the ground state and locate only 234 and 260 cm(-1) above, respectively. The equilibrium bond length 1.712 A and the harmonic vibrational frequency 903 cm(-1) of the 5/2 state are close to the experimental measurement of 1.724 A and 909 cm(-1), which suggests that the 5/2 state should be the low-lying state that contributes to the experimental spectra. Moreover, the electronic states that give rise to the observed transition bands are assigned for Omega = 5/2 and 7/2 in terms of the obtained excited energies and oscillator strengths. PMID- 25747078 TI - The effect of large amplitude motions on the vibrational intensities in hydrogen bonded complexes. AB - We have developed a model to calculate accurately the intensity of the hydrogen bonded XH-stretching vibrational transition in hydrogen bonded complexes. In the Local Mode Perturbation Theory (LMPT) model, the unperturbed system is described by a local mode (LM) model, which is perturbed by the intermolecular modes of the hydrogen bonded system that couple with the intramolecular vibrations of the donor unit through the potential energy surface. We have applied the model to three complexes containing water as the donor unit and different acceptor units, providing a series of increasing complex binding energy: H2O?N2, H2O?H2O, and H2O?NH3. Results obtained by the LMPT model are presented and compared with calculated results obtained by other vibrational models and with previous results from gas-phase and helium-droplet experiments. We find that the LMPT model reduces the oscillator strengths of the fundamental hydrogen bonded OH-stretching transition relative to the simpler LM model. PMID- 25747079 TI - Effective bond orders from two-step spin-orbit coupling approaches: the I2, At2, IO(+), and AtO(+) case studies. AB - The nature of chemical bonds in heavy main-group diatomics is discussed from the viewpoint of effective bond orders, which are computed from spin-orbit wave functions resulting from spin-orbit configuration interaction calculations. The reliability of the relativistic correlated wave functions obtained in such two step spin-orbit coupling frameworks is assessed by benchmark studies of the spectroscopic constants with respect to either experimental data, or state-of-the art fully relativistic correlated calculations. The I2, At2, IO(+), and AtO(+) species are considered, and differences and similarities between the astatine and iodine elements are highlighted. In particular, we demonstrate that spin-orbit coupling weakens the covalent character of the bond in At2 even more than electron correlation, making the consideration of spin-orbit coupling compulsory for discussing chemical bonding in heavy (6p) main group element systems. PMID- 25747080 TI - Fragmentation of doubly charged HDO, H2O, and D2O molecules induced by proton and monocharged fluorine beam impact at 3 keV. AB - Doubly charged ions HDO(2+), H2O(2+), and D2O(2+) were prepared selectively to triplet or singlet excited states in collisions with F(+) or H(+) projectiles at 3 keV. Excitation energies of dications following two-body or three-body dissociation channels were measured and compared with recent calculations using ab initio multi-reference configuration interaction method [Gervais et al., J. Chem. Phys. 131, 024302 (2009)]. For HDO(2+), preferential cleavage of O-H rather than O-D bond has been observed and the ratio between the populations of the fragmentation channels OD(+)_H(+) and OH(+)_D(+) were measured. The kinetic energy release has been measured and compared with previous experiments. PMID- 25747081 TI - Element specificity of ortho-positronium annihilation for alkali-metal loaded SiO2 glasses. AB - Momentum distributions associated with ortho-positronium (o-Ps) pick-off annihilation photon are often influenced by light elements, as, e.g., carbon, oxygen, and fluorine. This phenomenon, so-called element specificity of o-Ps pick off annihilation, has been utilized for studying the elemental environment around the open spaces. To gain an insight into the element specificity of o-Ps pick-off annihilation, the chemical shift of oxygen 1s binding energy and the momentum distributions associated with o-Ps pick-off annihilation were systematically investigated for alkali-metal loaded SiO2 glasses by means of X-ray photoelectron spectroscopy and positron-age-momentum correlation spectroscopy, respectively. Alkali metals introduced into the open spaces surrounded by oxygen atoms cause charge transfer from alkali metals to oxygen atoms, leading to the lower chemical shift for the oxygen 1s binding energy. The momentum distribution of o-Ps localized into the open spaces is found to be closely correlated with the oxygen 1s chemical shift. This correlation with the deepest 1s energy level evidences that the element specificity of o-Ps originates from pick-off annihilation with orbital electrons, i.e., dominantly with oxygen 2p valence electrons and s electrons with lower probability. PMID- 25747082 TI - Theoretical study of molecular vibrations in electron momentum spectroscopy experiments on furan: an analytical versus a molecular dynamical approach. AB - The influence of thermally induced nuclear dynamics (molecular vibrations) in the initial electronic ground state on the valence orbital momentum profiles of furan has been theoretically investigated using two different approaches. The first of these approaches employs the principles of Born-Oppenheimer molecular dynamics, whereas the so-called harmonic analytical quantum mechanical approach resorts to an analytical decomposition of contributions arising from quantized harmonic vibrational eigenstates. In spite of their intrinsic differences, the two approaches enable consistent insights into the electron momentum distributions inferred from new measurements employing electron momentum spectroscopy and an electron impact energy of 1.2 keV. Both approaches point out in particular an appreciable influence of a few specific molecular vibrations of A1 symmetry on the 9a1 momentum profile, which can be unravelled from considerations on the symmetry characteristics of orbitals and their energy spacing. PMID- 25747083 TI - A hybrid variational-perturbation calculation of the ro-vibrational spectrum of nitric acid. AB - Rotation-vibration spectra of the nitric acid molecule, HNO3, are calculated for wavenumbers up to 7000 cm(-1). Calculations are performed using a Hamiltonian expressed in internal curvilinear vibrational coordinates employing a hybrid variational-perturbation method. An initial potential energy surface (PES) and dipole moment function (DMF) are calculated ab initio at the CCSD(T)/aug-cc-pVQZ level of theory. Parameters of the PES and DMF are varied to minimize differences between the calculated and experimental transition frequencies and intensities. The average, absolute deviation between calculated and experimental values is 0.2 cm(-1) for frequencies in the fundamental bands and 0.4 cm(-1) for those in the first overtone and lowest combination bands. For the intensities, the calculated and experimental values differ by 0.3% and 40% for the fundamentals and overtones, respectively. The optimized PES and DMF are used to calculate the room temperature ro-vibrational spectrum. These calculation reproduce both the form of the absorption bands and fine details of the observed spectra, including the rotational structure of the vibrational bands and the numerous hot absorption band. Many of these hot bands are found to be missing from the compilation in HITRAN. A room temperature line list comprising 2 * 10(9) lines is computed. PMID- 25747084 TI - Ground and excited states of zinc phthalocyanine, zinc tetrabenzoporphyrin, and azaporphyrin analogs using DFT and TDDFT with Franck-Condon analysis. AB - The electronic structure of eight zinc-centered porphyrin macrocyclic molecules are investigated using density functional theory for ground-state properties, time-dependent density functional theory (TDDFT) for excited states, and Franck Condon (FC) analysis for further characterization of the UV-vis spectrum. Symmetry breaking was utilized to find the lowest energy of the excited states for many states in the spectra. To confirm the theoretical modeling, the spectroscopic result from zinc phthalocyanine (ZnPc) is used to compare to the TDDFT and FC result. After confirmation of the modeling, five more planar molecules are investigated: zinc tetrabenzoporphyrin (ZnTBP), zinc tetrabenzomonoazaporphyrin (ZnTBMAP), zinc tetrabenzocisdiazaporphyrin (ZnTBcisDAP), zinc tetrabenzotransdiazaporphyrin (ZnTBtransDAP), and zinc tetrabenzotriazaporphyrin (ZnTBTrAP). The two latter molecules are then compared to their phenylated sister molecules: zinc monophenyltetrabenzotriazaporphyrin (ZnMPTBTrAP) and zinc diphenyltetrabenzotransdiazaporphyrin (ZnDPTBtransDAP). The spectroscopic results from the synthesis of ZnMPTBTrAP and ZnDPTBtransDAP are then compared to their theoretical models and non-phenylated pairs. While the Franck-Condon results were not as illuminating for every B-band, the Q-band results were successful in all eight molecules, with a considerable amount of spectral analysis in the range of interest between 300 and 750 nm. The pi-pi(*) transitions are evident in the results for all of the Q bands, while satellite vibrations are also visible in the spectra. In particular, this investigation finds that, while ZnPc has a D4h symmetry at ground state, a C4v symmetry is predicted in the excited-state Q band region. The theoretical results for ZnPc found an excitation energy at the Q-band 0-0 transition of 1.88 eV in vacuum, which is in remarkable agreement with published gas-phase spectroscopy, as well as our own results of ZnPc in solution with Tetrahydrofuran that are provided in this paper. PMID- 25747085 TI - On the validity of the basis set superposition error and complete basis set limit extrapolations for the binding energy of the formic acid dimer. AB - We report the variation of the binding energy of the Formic Acid Dimer with the size of the basis set at the Coupled Cluster with iterative Singles, Doubles and perturbatively connected Triple replacements [CCSD(T)] level of theory, estimate the Complete Basis Set (CBS) limit, and examine the validity of the Basis Set Superposition Error (BSSE)-correction for this quantity that was previously challenged by Kalescky, Kraka, and Cremer (KKC) [J. Chem. Phys. 140, 084315 (2014)]. Our results indicate that the BSSE correction, including terms that account for the substantial geometry change of the monomers due to the formation of two strong hydrogen bonds in the dimer, is indeed valid for obtaining accurate estimates for the binding energy of this system as it exhibits the expected decrease with increasing basis set size. We attribute the discrepancy between our current results and those of KKC to their use of a valence basis set in conjunction with the correlation of all electrons (i.e., including the 1s of C and O). We further show that the use of a core-valence set in conjunction with all electron correlation converges faster to the CBS limit as the BSSE correction is less than half than the valence electron/valence basis set case. The uncorrected and BSSE-corrected binding energies were found to produce the same (within 0.1 kcal/mol) CBS limits. We obtain CCSD(T)/CBS best estimates for De = - 16.1 +/- 0.1 kcal/mol and for D0 = - 14.3 +/- 0.1 kcal/mol, the later in excellent agreement with the experimental value of -14.22 +/- 0.12 kcal/mol. PMID- 25747086 TI - Electronic spectra of DyF studied by four-component relativistic configuration interaction methods. AB - The electronic states of the DyF molecule below 3.0 eV are studied using 4 component relativistic CI methods. Spinors generated by the average-of configuration Hartree-Fock method with the Dirac-Coulomb Hamiltonian were used in CI calculations by the KRCI (Kramers-restricted configuration interaction) program. The CI reference space was generated by distributing 11 electrons among the 11 Kramers pairs composed mainly of Dy [4f], [6s], [6p] atomic spinors, and double excitations are allowed from this space to the virtual molecular spinors. The CI calculations indicate that the ground state has the dominant configuration (4f(9))(6s(2))(Omega = 7.5). Above this ground state, 4 low-lying excited states (Omega = 8.5, 7.5, 7.5, 7.5) are found with dominant configurations (4f(10))(6s). These results are consistent with the experimental studies of McCarthy et al. Above these 5 states, 2 states were observed at T0 = 2.39 eV, 2.52 eV by McCarthy et al. and were named as [19.3]8.5 and [20.3]8.5. McCarthy et al. proposed that both states have dominant configurations (4f(9))(6s)(6p), but these configurations are not consistent with the large Re's (~3.9 a.u.) estimated from the observed rotational constants. The present CI calculations provide near degenerate states of (4f(10))(6p3/2,1/2), (4f(10))(6p3/2,3/2), and (4f(9))(6s)(6p3/2,1/2) at around 3 eV. The former two states have larger Re (3.88 a.u.) than the third, so that it is reasonable to assign (4f(10))(6p3/2,1/2) to [19.3]8.5 and (4f(10))(6p3/2,3/2) to [20.3]8.5. PMID- 25747087 TI - Perturbation-facilitated detection of the first quintet-quintet band in C2. AB - The first high-spin transition in C2 (1 (5)Piu - 1 (5)Pig) is observed by perturbation-facilitated optical-optical double resonance spectroscopy. The experiment is performed by applying unfolded two-color resonant four-wave mixing. C2 radicals in the initial a (3)Piu, v = 5 state are produced by using a discharge source in a molecular beam environment. The final quintet state is excited via intermediate "gateway" states exhibiting both substantial triplet and quintet character due to a perturbation between the 1 (5)Pig, v = 0 and the d (3)Pig, v = 6 states. Fifty seven rotational transitions in the P, Q, and R branches of all spin sub-states are measured and yield accurate molecular constants of the newly found upper level 1 (5)Piu. In addition, satellite transitions (DeltaJ ? DeltaN) are observed and allow an accurate determination of the spin-orbit constant. The results are compared with high-level ab initio computations at the multi-reference configuration interaction level of theory. The high-lying quintet state is found to be predissociative and displays a shallow potential that accommodates three vibrational levels only. PMID- 25747088 TI - Nucleation and interfacial adsorption in ternary systems. AB - Nucleation is studied in incompressible ternary fluids by examining the topology of the overall landscape of the energy surface. Minimum free energy paths for nucleation (MFEPs) of a single nucleus in an infinite matrix are computed with the string method in the framework of the continuum theory of nucleation for the regular solution. Properties of the critical nucleus are compared with the predictions of the classical nucleation theory. MFEPs are found to exhibit complex nucleation pathways with non-monotonic variations of compositions in the interfacial region, specifically adsorption of a component. In the symmetric regular solution, the minority component is found to segregate at the interface during nucleation with a concomitant depletion of the nucleus core, resulting in unpredicted partition of the non-selective component. Despite increasing the gradient energy, such inhomogeneity in composition is shown to lower the nucleation barrier. PMID- 25747089 TI - The associating lattice gas in the presence of interacting solutes. AB - We have investigated the phase diagram of a statistical model for hydrogen bonding solutions for polar solutes. The structured solvent is represented by an associating lattice gas, which presents anomalous density and liquid-liquid coexistence. Polar solute particles and solvent particles interact attractively, while the solvent-solvent interaction is made directional through bonding arms, which mimic hydrogen bonds. The model behavior is obtained via Monte Carlo simulations in the grand-canonical ensemble, for different sets of parameters. For small solute chemical potential and weak attraction between solute and solvent particles, addition of solute yields a shift in the transition lines of the pure solvent. This is the scenario explored by different authors, in the pursuit of stabilizing the water liquid-liquid coexistence line. However, as we show, in the case of larger solute chemical potentials, or of stronger solute solvent attractions, new phases may arise. PMID- 25747090 TI - Transition fields in organic materials: from percolation to inverted Marcus regime. A consistent Monte Carlo simulation in disordered PPV. AB - In this article, we analyze the electric field dependence of the hole mobility in disordered poly(p-phenylene vinylene). The charge carrier mobility is obtained from Monte Carlo simulations. Depending on the field strength three regions can be identified: the percolation region, the correlation region, and the inverted region. Each region is characterized by a different conduction mechanism and thus a different functional dependence of the mobility on the electric field. Earlier studies have highlighted that Poole-Frenkel law, which appears in the correlation region, is based on the type of correlation caused by randomly distributed electric dipoles. This behavior is thus observed in a limited range of field strengths, and by studying a broader range of electric fields, a more fundamental understanding of the transport mechanism is obtained. We identify the electric fields determining the transitions between the different conduction mechanisms in the material and we explain their physical origin. In principle, this allows us to characterize the mobility field dependence for any organic material. Additionally, we study the charge carrier trapping mechanisms due to diagonal and off-diagonal disorder, respectively. PMID- 25747091 TI - Experimental triplet and quadruplet fluctuation densities and spatial distribution function integrals for liquid mixtures. AB - Kirkwood-Buff or Fluctuation Solution Theory can be used to provide experimental pair fluctuations, and/or integrals over the pair distribution functions, from experimental thermodynamic data on liquid mixtures. Here, this type of approach is used to provide triplet and quadruplet fluctuations, and the corresponding integrals over the triplet and quadruplet distribution functions, in a purely thermodynamic manner that avoids the use of structure factors. The approach is then applied to binary mixtures of water + methanol and benzene + methanol over the full composition range under ambient conditions. The observed correlations between the different species vary significantly with composition. The magnitude of the fluctuations and integrals appears to increase as the number of the most polar molecule involved in the fluctuation or integral also increases. A simple physical picture of the fluctuations is provided to help rationalize some of these variations. PMID- 25747092 TI - Transformation pathways in high-pressure solid nitrogen: from molecular N2 to polymeric cg-N. AB - The transformation pathway in high-pressure solid nitrogen from N2 molecular state to polymeric cg-N phase was investigated by means of ab initio molecular dynamics and metadynamics simulations. In our study, we observed a transformation mechanism starting from molecular Immm phase that initiated with formation of trans-cis chains. These chains further connected within layers and formed a chain planar state, which we describe as a mixture of two crystalline structures--trans cis chain phase and planar phase, both with Pnma symmetry. This mixed state appeared in molecular dynamics performed at 120 GPa and 1500 K and in the metadynamics run at 110 GPa and 1500 K, where the chains continued to reorganize further and eventually formed cg-N. During separate simulations, we also found two new phases--molecular P2(1)/c and two-three-coordinated chain-like Cm. The transformation mechanism heading towards cg-N can be characterized as a progressive polymerization process passing through several intermediate states of variously connected trans-cis chains. In the final stage of the transformation chains in the layered form rearrange collectively and develop new intraplanar as well as interplanar bonds leading to the geometry of cg-N. Chains with alternating trans and cis conformation were found to be the key entity- structural pattern governing the dynamics of the simulated molecular-polymeric transformation in compressed nitrogen. PMID- 25747093 TI - Lattice simulation method to model diffusion and NMR spectra in porous materials. AB - A coarse-grained simulation method to predict nuclear magnetic resonance (NMR) spectra of ions diffusing in porous carbons is proposed. The coarse-grained model uses input from molecular dynamics simulations such as the free-energy profile for ionic adsorption, and density-functional theory calculations are used to predict the NMR chemical shift of the diffusing ions. The approach is used to compute NMR spectra of ions in slit pores with pore widths ranging from 2 to 10 nm. As diffusion inside pores is fast, the NMR spectrum of an ion trapped in a single mesopore will be a sharp peak with a pore size dependent chemical shift. To account for the experimentally observed NMR line shapes, our simulations must model the relatively slow exchange between different pores. We show that the computed NMR line shapes depend on both the pore size distribution and the spatial arrangement of the pores. The technique presented in this work provides a tool to extract information about the spatial distribution of pore sizes from NMR spectra. Such information is difficult to obtain from other characterisation techniques. PMID- 25747094 TI - Local pressure components and interfacial tensions of a liquid film in the vicinity of a solid surface with a nanometer-scale slit pore obtained by the perturbative method. AB - A classical molecular dynamics simulation was conducted for a liquid-solid interfacial system with a nanometer-scale slit pore in order to reveal local thermodynamic states: local pressure components and interfacial tensions of a liquid film in the vicinity of the slit. The simulation also examined the transition mechanism between the two states of the liquid film: (a) liquid film on the slit and (b) liquid film in the slit, based on the local thermodynamic quantities from a molecular point of view. An instantaneous expression of the local pressure components and interfacial tensions, which is based on a volume perturbation, was presented to investigate time-dependent phenomena in molecular dynamics simulations. The interactions between the particles were described by the 12-6 Lennard-Jones potential, and effects of the fluid-solid interaction intensity on the local pressure components and interfacial tensions of the fluid in the vicinity of the slit were examined in detail by the presented perturbative method. The results revealed that the local pressure components tangential to the solid surface in the vicinity of the 1st fluid layer from the solid surface are different in a two dimensional plane, and the difference became pronounced in the vicinity of the corner of the slit, for cases where the fluid-solid interaction intensities are relatively strong. The results for the local interfacial tensions of the fluid inside the slit suggested that the local interfacial tensions in the vicinity of the 2nd and 3rd layers of the solid atoms from the entrance of the slit act as a trigger for the transition between the two states under the influence of a varying fluid-solid interaction. PMID- 25747095 TI - Influence of leaching on surface composition, microstructure, and valence band of single grain icosahedral Al-Cu-Fe quasicrystal. AB - The use of quasicrystals as precursors to catalysts for the steam reforming of methanol is potentially one of the most important applications of these new materials. To develop application as a technology requires a detailed understanding of the microscopic behavior of the catalyst. Here, we report the effect of leaching treatments on the surface microstructure, chemical composition, and valence band of the icosahedral (i-) Al-Cu-Fe quasicrystal in an attempt to prepare a model catalyst. The high symmetry fivefold surface of a single grain i-Al-Cu-Fe quasicrystal was leached with NaOH solution for varying times, and the resulting surface was characterized by x-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The leaching treatments preferentially remove Al producing a capping layer consisting of Fe and Cu oxides. The subsurface layer contains elemental Fe and Cu in addition to the oxides. The quasicrystalline bulk structure beneath remains unchanged. The subsurface gradually becomes Fe3O4 rich with increasing leaching time. The surface after leaching exhibits micron sized dodecahedral cavities due to preferential leaching along the fivefold axis. Nanoparticles of the transition metals and their oxides are precipitated on the surface after leaching. The size of the nanoparticles is estimated by high resolution transmission microscopy to be 5-20 nm, which is in agreement with the AFM results. Selected area electron diffraction (SAED) confirms the crystalline nature of the nanoparticles. SAED further reveals the formation of an interface between the high atomic density lattice planes of nanoparticles and the quasicrystal. These results provide an important insight into the preparation of model catalysts of nanoparticles for steam reforming of methanol. PMID- 25747096 TI - Theoretical investigations on the layer-anion interaction in Mg-Al layered double hydroxides: influence of the anion nature and layer composition. AB - The influence of the anion nature and layer composition on the anion-layer interaction in Mg-Al layered double hydroxides (LDHs) is investigated using density functional theory. Changes in the strength of the anion-layer interaction are assessed calculating the potential energy surface (PES) associated to the interlayer anion (OH(-)/Cl(-)) in Mg-Al-OH and Mg-Al-Cl LDHs. The layer composition is varied changing the divalent to trivalent cation proportion (R). Mg-Al-OH is thus investigated with R = 2, 3, 3.5 and Mg-Al-Cl with R = 3. It is found that the PES for OH(-) in Mg-Al-OH/R = 3 presents wider energy basins and lower energy barriers than any other of the investigated compositions. It is shown that the latter is connected to the number of hydrogen bonds formed by the anions. These results have interesting implications for understanding the enhancement of the physicochemical properties of LDHs upon changing composition. PMID- 25747097 TI - Oxygen transport in off-stoichiometric uranium dioxide mediated by defect clustering dynamics. AB - Oxygen transport is central to many properties of oxides such as stoichiometric changes, phase transformation, and ionic conductivity. In this paper, we report a mechanism for oxygen transport in uranium dioxide (UO2) in which the kinetics is mediated by defect clustering dynamics. In particular, the kinetic Monte Carlo method has been used to investigate the kinetics of oxygen transport in UO2 under the condition of creation and annihilation of oxygen vacancies and interstitials as well as oxygen interstitial clustering, with variable off-stoichiometry and temperature conditions. It is found that in hypo-stoichiometric UO(2-x), oxygen transport is well described by the vacancy diffusion mechanism while in hyper stoichiometric UO(2+x), oxygen interstitial cluster diffusion contributes significantly to oxygen transport kinetics, particularly at high temperatures and high off-stoichiometry levels. It is also found that di-interstitial clusters and single interstitials play dominant roles in oxygen diffusion while other larger clusters have negligible contributions. However, the formation, coalescence, and dissociation of these larger clusters indirectly affects the overall oxygen diffusion due to their interactions with mono and di-interstitials, thus providing an explanation of the experimental observation of saturation or even drop of oxygen diffusivity at high off-stoichiometry. PMID- 25747098 TI - Dynamic density functional theory with hydrodynamic interactions: theoretical development and application in the study of phase separation in gas-liquid systems. AB - Building on recent developments in dynamic density functional theory, we have developed a version of the theory that includes hydrodynamic interactions. This is achieved by combining the continuity and momentum equations eliminating velocity fields, so the resulting model equation contains only terms related to the fluid density and its time and spatial derivatives. The new model satisfies simultaneously continuity and momentum equations under the assumptions of constant dynamic or kinematic viscosity and small velocities and/or density gradients. We present applications of the theory to spinodal decomposition of subcritical temperatures for one-dimensional and three-dimensional density perturbations for both a van der Waals fluid and for a lattice gas model in mean field theory. In the latter case, the theory provides a hydrodynamic extension to the recently studied dynamic mean field theory. We find that the theory correctly describes the transition from diffusive phase separation at short times to hydrodynamic behaviour at long times. PMID- 25747099 TI - On the stability of the disordered molecular alloy phase of ammonia hemihydrate. AB - The disordered-molecular-alloy phase (DMA) of ammonia hydrates [J. S. Loveday and R. J. Nelmes, Phys. Rev. Lett. 83, 4329 (1999)] is unique in that it has substitutional disorder of ammonia and water over the molecular sites of a body centred cubic lattice. Whilst this structure has been observed in ammonia di- and mono-hydrate compositions, it has not been conclusively observed in the ammonia hemihydrate system. This work presents investigations of the structural behaviour of ammonia hemihydrate as a function of P and T. The indications of earlier studies [Ma et al. RSC Adv. 2, 4290 (2012)] that the DMA structure could be produced by compression of ammonia hemihydrate above 20 GPa at ambient temperature are confirmed. In addition, the DMA structure was found to form reversibly both from the melt, and on warming of ammonia hemihydrate phase-II, in the pressure range between 4 and 8 GPa. The route used to make the DMA structure from ammonia mono- and di-hydrates--compression at 170 K to 6 GPa followed by warming to ambient temperature--was found not to produce the DMA structure for ammonia hemihydrate. These results provide the first strong evidence that DMA is a thermodynamically stable form. A high-pressure phase diagram for ammonia hemihydrate is proposed which has importance for planetary modelling. PMID- 25747100 TI - Short-time transport properties of bidisperse suspensions and porous media: a Stokesian dynamics study. AB - We present a comprehensive computational study of the short-time transport properties of bidisperse hard-sphere colloidal suspensions and the corresponding porous media. Our study covers bidisperse particle size ratios up to 4 and total volume fractions up to and beyond the monodisperse hard-sphere close packing limit. The many-body hydrodynamic interactions are computed using conventional Stokesian Dynamics (SD) via a Monte-Carlo approach. We address suspension properties including the short-time translational and rotational self diffusivities, the instantaneous sedimentation velocity, the wavenumber-dependent partial hydrodynamic functions, and the high-frequency shear and bulk viscosities and porous media properties including the permeability and the translational and rotational hindered diffusivities. We carefully compare the SD computations with existing theoretical and numerical results. For suspensions, we also explore the range of validity of various approximation schemes, notably the pairwise additive approximations with the Percus-Yevick structural input. We critically assess the strengths and weaknesses of the SD algorithm for various transport properties. For very dense systems, we discuss in detail the interplay between the hydrodynamic interactions and the structures due to the presence of a second species of a different size. PMID- 25747101 TI - Phosphatidylcholine reverse micelles on the wrong track in molecular dynamics simulations of phospholipids in an organic solvent. AB - Here, we examine a well-characterized model system of phospholipids in cyclohexane via molecular dynamics simulations using a force field known for reproducing both phospholipid behavior in water and cyclohexane bulk properties to a high accuracy, CHARMM36, with the aim of evaluating the transferability of a force field parametrization from an aqueous environment to an organic solvent. We compare the resulting reverse micelles with their expected experimental shape and size, and find the model struggles with reproducing basic, experimentally known reverse micellar structural characteristics for common phosphadidylcholine lipids such as 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dioleyl-sn glycero-3-phosphatidylcholine (DOPC), and 1,2-dilinoleyl-sn-glycero-3 phosphatidylcholine (DLPC) in cyclohexane solvent. We find evidence that the deviation from the experimental behavior originates from an underestimation of the lipid tail-cyclohexane interaction in the model. We compensate for this, obtain reverse micellar structures within the experimentally expected range, and characterize these structurally in molecular detail. Our findings indicate extra caution and verification of model applicability is warranted in simulational studies employing standard biomolecular models outside the usual aqueous environment. PMID- 25747102 TI - Equilibrium gels of low-valence DNA nanostars: a colloidal model for strong glass formers. AB - Kinetic arrest in colloidal dispersions with isotropic attractive interactions usually occurs through the destabilization of the homogeneous phase and the formation of a non-equilibrium network of jammed particles. Theory and simulations predict that a different route to gelation should become available when the valence of each colloidal particle is suitably reduced. Under these conditions, gelation should be achievable through a reversible sequence of equilibrium states. Here we report the reversible dynamic arrest of a dispersion of DNA-based nanoparticles with anisotropic interactions and a coordination number equal to four. As the temperature is decreased, the relaxation time for density fluctuations slows down by about five orders of magnitude, following an Arrhenius scaling in the entire experimentally accessible temperature window. The system is in thermodynamic equilibrium at all temperatures. Gelation in our system mimics the dynamic arrest of networking atomic strong glass formers such as silica, for which it could thus provide a suitable colloidal model. PMID- 25747103 TI - Terbium doped SnO2 nanoparticles as white emitters and SnO2:5Tb/Fe3O4 magnetic luminescent nanohybrids for hyperthermia application and biocompatibility with HeLa cancer cells. AB - SnO2:5Tb (SnO2 doped with 5 at% Tb(3+)) nanoparticles were synthesised by a polyol method and their luminescence properties at different annealing temperatures were studied. Characterization of nanomaterials was done by X-ray diffraction (XRD), Fourier transformation infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and vibrating sample magnetometry (VSM). XRD studies indicate that the prepared nanoparticles were of tetragonal structures. Upon Tb(3+) ion incorporation into SnO2, Sn(4+) changes to Sn(2+) and, on annealing again at higher temperature, Sn(2+) changes to Sn(4+). The prepared nanoparticles were spherical in shape. Sn-O vibrations were found from the FTIR studies. In photoluminescence studies, the intensity of the emission peaks of Tb(3+) ions increases with the increase of annealing temperature, and emission spectra lie in the region of white emission in the CIE diagram. CCT calculations show that the SnO2:5Tb emission lies in cold white emission. Quantum yields up to 38% can be obtained for 900 degrees C annealed samples. SnO2:5Tb nanoparticles were well incorporated into the PVA polymer and such a material incorporated into the polymer can be used for display devices. The SnO2:5Tb/Fe3O4 nanohybrid was prepared and investigated for hyperthermia applications at different concentrations of the nanohybrid. This achieves a hyperthermia temperature (42 degrees C) under an AC magnetic field. The hybrid nanomaterial SnO2:5Tb/Fe3O4 was found to exhibit biocompatibility with HeLa cells (human cervical cancer cells) at concentrations up to 74% for 100 MUg L(-1). Also, this nanohybrid shows green emission and thus it will be helpful in tracing magnetic nanoparticles through optical imaging in vivo and in vitro application. PMID- 25747104 TI - Preoperative use of statins does not improve outcomes and development of acute renal failure after cardiac surgery. A propensity score analysis of ARIAM Andalucia database. AB - BACKGROUND: Statin use prior to cardiac surgery has been reported to improve outcomes in the postoperative period because of other effects apart from decreasing lipid levels. Objective of the study was to analyse mortality and acute renal failure (ARF) during the cardiac surgery postoperative period in patients treated with or without statins. METHODS: This prospective cohort study comprised adult patients who underwent cardiac surgery at 11 institutions in the Andalusian community from March 2008 to July 2012 included in the ARIAM adult cardiac surgery project. We performed a first analysis in the whole cohort and in a second analysis statin users prior to surgery were pair matched with non-users according to their propensity score based on demographics, comorbidities, medication and surgical data. We analysed differences in outcomes, ARF, need for renal replacement therapy (RRT) and a composite end point with mortality or major morbidity in both groups. RESULTS: The study included 7276 patients, of whom 3749 were treated with statins. Overall, hospital mortality was 10.1%, 10.5% developed ARF and 2.5% required RRT. In the whole non-matched cohort, statins were associated with lower hospital mortality (OR 0.79; 95% CI, 0.67-0.93) and less ARF (OR 0.79; 95% CI, 0.68-0.93). However, after propensity score analysis in the matched cohort of 3056 patients (1528 in each group), statin use was not consistently associated with less ARF (OR 0.94; 95% CI, 0.74-1.19), hospital mortality (OR 0.83; 95% CI, 0.68-1.1) or composite outcome (OR 0.857; 95% CI, 0.723-1.015). CONCLUSION: Despite better outcomes for the statin users in the whole cohort, the matched analysis showed that statin use before cardiac surgery was not associated with a lower risk of ARF. Nor was presurgery statin use associated with lower hospital mortality. PMID- 25747105 TI - Magnetic Resonance Imaging Targeted Biopsy Improves Selection of Patients Considered for Active Surveillance for Clinically Low Risk Prostate Cancer Based on Systematic Biopsies. AB - PURPOSE: Current selection criteria for active surveillance based on systematic biopsy underestimate prostate cancer volume and grade. We investigated the role of additional magnetic resonance imaging targeted biopsy in reclassifying patients eligible for active surveillance based on systematic biopsy. MATERIALS AND METHODS: We performed a study at 2 institutions in a total of 281 men with increased prostate specific antigen. All men met certain criteria, including 1) prebiopsy magnetic resonance imaging, 12-core transrectal systematic biopsy and 2 additional magnetic resonance imaging targeted biopsies of lesions suspicious for cancer during the same sequence as systematic biopsy, and 2) eligibility for active surveillance based on systematic biopsy results. Criteria for active surveillance were prostate specific antigen less than 10 ng/ml, no Gleason grade 4/5, 5 mm or less involvement of any biopsy core and 2 or fewer positive systematic biopsy cores. Patient characteristics were compared between reclassified and nonreclassified groups based on magnetic resonance imaging targeted biopsy results. RESULTS: On magnetic resonance imaging 58% of the 281 patients had suspicious lesions. Magnetic resonance imaging targeted biopsy was positive for cancer in 81 of 163 patients (50%). Of 281 patients 28 (10%) were reclassified by magnetic resonance imaging targeted biopsy as ineligible for active surveillance based on Gleason score in 8, cancer length in 20 and Gleason score plus cancer length in 9. Suspicious areas on magnetic resonance imaging were in the anterior part of the prostate in 15 of the 28 men (54%). Reclassified patients had a smaller prostate volume (37 vs 52 cc) and were older (66.5 vs 63 years) than those who were not reclassified (p < 0.05). CONCLUSIONS: Magnetic resonance imaging targeted biopsy reclassified 10% of patients who were eligible for active surveillance based on systematic biopsy. Its incorporation into the active surveillance eligibility criteria may decrease the risk of reclassification to higher stages during followup. PMID- 25747107 TI - Toward optimization of AgoshRNA molecules that use a non-canonical RNAi pathway: variations in the top and bottom base pairs. AB - Short hairpin RNAs (shRNAs) are widely used for gene knockdown by inducing the RNA interference (RNAi) mechanism. The shRNA precursor is processed by Dicer into small interfering RNAs (siRNAs) and subsequently programs the RNAi-induced silencing complex (RISC) to find a complementary target mRNA (mRNA) for post transcriptional gene silencing. Recent evidence indicates that shRNAs with a relatively short basepaired stem bypass Dicer to be processed directly by the Ago2 nuclease of the RISC complex. We named this design AgoshRNA as these molecules depend on Ago2 both for processing and subsequent silencing activity. This alternative AgoshRNA processing route yields only a single active RNA strand, an important feature to restrict off-target effects induced by the passenger strand of regular shRNAs. It is therefore important to understand this novel AgoshRNA processing route in mechanistic detail such that one can design the most effective and selective RNA reagents. We performed a systematic analysis of the optimal base pair (bp) composition at the top and bottom of AgoshRNA molecules. In this study, we document the importance of the 5' end nucleotide (nt) and a bottom mismatch. The optimized AgoshRNA design exhibits improved RNAi activity across cell types. These results have important implications for the future design of more specific RNAi therapeutics. PMID- 25747108 TI - Never too old for a change. ECG in a nonagenarian with apical hypertrophic cardiomyopathy, aneurysm, and encephalomyopathy. PMID- 25747110 TI - Social discounting: Choice between rewards for other people. AB - The purpose of the present study was to test the prediction that when two rewards, a smaller but "socially closer" one and a larger but "socially more distant" one, are moved away from the subject by the same social distance, subjective value of the socially more distant reward will increase (i.e. the rate of social discounting will be shallower). The effect was absent when the recipients were moved back 10 places, but emerged when they were moved back 20 places. In addition, the hyperbolic model was found to correctly describe choices between two socially distant rewards. The results confirm similarities between social and temporal discounting. PMID- 25747109 TI - Phages of dairy Leuconostoc mesenteroides: genomics and factors influencing their adsorption. AB - Phages infecting Leuconostoc mesenteroides strains can be overlooked during milk fermentation because they do not slowdown the acidification process. However, they can negatively impact the flavor profile of the final product. Yet, the information about these phages is still scarce. In this work, we investigated diverse factors influencing the adsorption of seven virulent Ln. mesenteroides phages, isolated from blue cheese manufacture in Argentina, to their host cells. The addition of calcium ions was generally necessary to observe complete cell lysis and plaque formation for four of the seven phages, but adsorption was very high even in the absence of this cation for all phages. The temperature barely influenced the adsorption process as it was high within the temperature range tested (0 to 50 degrees C). Moreover, the kinetics of adsorption were similar on viable and non-viable cells, revealing that phage adsorption does not depend on physiological state of the bacterial cells. The adsorption rates were also high at pH values from 4 to 9 for all Ln. mesenteroides phages. We also analyzed the complete genome sequences of two of these phages. Complete nucleotide analysis of phages Ln-8 and Ln-9 showed dsDNA genomes with sizes of 28.5 and 28.9 kb, and the presence of 45 and 48 open reading frames (ORFs), respectively. These genomes were highly similar to those of previously characterized Phi1-A4 (USA, sauerkraut, fermentation) and PhiLN25 (England, whey), both virulent Ln. mesenteroides phages. A detailed understanding of these phages will lead to better control strategies. PMID- 25747111 TI - Comparison of three-dimensional proximal isovelocity surface area to cardiac magnetic resonance imaging for quantifying mitral regurgitation. AB - The aim of our study was to evaluate 3-dimensional (3D) color Doppler proximal isovelocity surface area (PISA) as a tool for quantitative assessment of mitral regurgitation (MR) against in vitro and in vivo reference methods. A customized 3D PISA software was validated in vitro against a flowmeter MR phantom. Sixty consecutive patients, with >=mild MR of any cause, were recruited and the regurgitant volume (RVol) was measured by 2D PISA, 3D peak PISA, and 3D integrated PISA, using transthoracic (TTE) and transesophageal echocardiography (TEE). Cardiac magnetic resonance imaging (CMR) was used as reference method. Flowmeter RVol was associated with 3D integrated PISA as follows: y = 0.64x + 4.7, r(2) = 0.97, p <0.0001 for TEE and y = 0.88x + 4.07, r(2) = 0.96, p <0.0001 for TTE. The bias and limit of agreement in the Bland-Altman analysis were 6.8 ml [-3.5 to 17.1] for TEE and -0.059 ml [-6.2 to 6.1] for TTE. In vivo, TEE-derived 3D integrated PISA was the most accurate method for MR quantification compared to CMR: r(2) = 0.76, y = 0.95x - 3.95, p <0.0001; 5.1 ml (-14.7 to 26.5). It was superior to TEE 3D peak PISA (r(2) = 0.67, y = 1.00x + 6.20, p <0.0001; -6.3 ml [ 33.4 to 21.0]), TEE 2D PISA (r(2) = 0.54, y = 0.76x + 0.18, p <0.0001; 8.4 ml [ 20.4 to 37.2]), and TTE-derived measurements. It was also most accurate by receiver operating characteristic analysis (area under the curve 0.99) for the detection of severe MR, RVol cutoff = 48 ml, sensibility 100%, and specificity 96%. RVol and the cutoff to define severe MR were underestimated using the most accurate method. In conclusion, quantitative 3D color Doppler echocardiography of the PISA permits a more accurate MR assessment than conventional techniques and, consequently, should enable an optimized management of patients suffering from MR. PMID- 25747112 TI - Vibrational energy transport in molecules studied by relaxation-assisted two dimensional infrared spectroscopy. AB - This review presents an overview of the relaxation-assisted two-dimensional infrared (RA 2DIR) spectroscopy method for measuring structures and energy transport dynamics in molecules. The method strongly enhances the range of accessible distances compared to traditional 2DIR and offers new structural reporters, such as the energy transport time, cross-peak amplification factors, and connectivity patterns. The use of the method for assigning vibrational modes with various levels of delocalization is illustrated. RA 2DIR relies on vibrational energy transport in molecules; as such, the transport mechanism can be conveniently studied by the method. Applications to identify diffusive and ballistic energy transport are demonstrated. PMID- 25747114 TI - Author's reply to Comment on "A randomized clinical trial of Saccharomyces cerevisiae versus placebo in the irritable bowel syndrome" by Guillaume Pineton de Chambrun et al. [Digestive and Liver Disease 2015;47:119-24]. PMID- 25747113 TI - Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. AB - PURPOSE: Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCDelta468 mice. EXPERIMENTAL DESIGN: In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCDelta468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor associated and systemic inflammation. RESULTS: Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. CONCLUSIONS: This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer. PMID- 25747115 TI - The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis. AB - BACKGROUND: The overlap syndrome between primary biliary cirrhosis and primary sclerosing cholangitis is an extremely rare condition that has been reported in only six published cases so far. METHODS: Here we report two cases showing the clinical manifestations of both primary biliary cirrhosis and primary sclerosing cholangitis. RESULTS: In one case the overlap condition was associated with psoriatric arthritis, and the patient successfully underwent dual treatment with ursodeoxycholic acid and the anti-tumour necrosis factor-alpha agent adalimumab. In the second case, the predominant condition was, initially, an antimitochondrial antibody-negative primary biliary cirrhosis with progressive course towards end-stage liver disease; the patient then developed either antimitochondrial antibody positivity or changes in the biliary tree compatible with primary sclerosing cholangitis. CONCLUSIONS: These two cases add information on a controversial issue in the literature, and indicate the importance of recognizing a possible overlap syndrome to optimize treatment. PMID- 25747117 TI - Langerin-heparin interaction: two binding sites for small and large ligands as revealed by a combination of NMR spectroscopy and cross-linking mapping experiments. AB - Langerin is a C-type lectin present on Langerhans cells that mediates capture of pathogens in a carbohydrate-dependent manner, leading to subsequent internalization and elimination in the cellular organelles called Birbeck granules. This mechanism mediated by langerin was shown to constitute a natural barrier for HIV-1 particle transmission. Besides interacting specifically with high mannose and fucosylated neutral carbohydrate structures, langerin has the ability to bind sulfated carbohydrate ligands as 6-sulfated galactosides in the Ca(2+)-dependent binding site. Very recently langerin was demonstrated to interact with sulfated glycosaminoglycans (GAGs), in a Ca(2+)-independent way, resulting in the proposal of a new binding site for GAGs. On the basis of those results, we have conducted a structural study of the interactions of small heparin (HEP)-like oligosaccharides with langerin in solution. Heparin bead cross linking experiments, an approach specifically designed to identify HEP/heparan sulfate binding sites in proteins were first carried out and experimentally validated the previously proposed model for the interaction of langerin extracellular domain with 6 kDa HEP. High-resolution NMR studies of a set of eight synthetic HEP-like trisaccharides harboring different sulfation patterns demonstrated that all of them bound to langerin in a Ca(2+)-dependent way. The binding epitopes were determined by saturation transfer difference NMR and the bound conformations by transferred NOESY experiments. These experimental data were combined with docking and molecular dynamics and resulted in the proposal of a binding mode characterized by the coordination of calcium by the two equatorial hydroxyl groups, OH3 and OH4, at the non-reducing end. The binding also includes the carboxylate group at the adjacent iduronate residue. This epitope is shared by all eight ligands, explaining the absence of any impact on binding from differences in their substitution patterns. Finally, in contrast to the small trisaccharides, we demonstrated that a longer HEP-like hexasaccharide, bearing an additional O-sulfate group at the non-reducing end, which precludes binding to the Ca(2+) site, interacts with langerin in the previously identified Ca(2+) independent binding site. PMID- 25747118 TI - Identification of the Biosynthetic Gene Cluster for the Anti-infective Desotamides and Production of a New Analogue in a Heterologous Host. AB - The desotamides (DSAs) are potent antibacterial cyclohexapeptides produced by Streptomyces scopuliridis SCSIO ZJ46. We have identified the 39-kb dsa biosynthetic gene cluster by whole-genome scanning. Composed of 17 open reading frames, the cluster codes for four nonribosomal peptide synthetases and associated resistance, transport, regulatory, and precursor biosynthesis proteins. Heterologous expression of the dsa gene cluster in S. coelicolor M1152 afforded desotamides A and B and the new desotamide G. Cluster identification and its demonstrated amenability to heterologous expression provide the foundation for future mechanistic studies as well as the generation of new and potentially clinically significant DSA analogues. PMID- 25747116 TI - Functional Interplay between Dopaminergic and Serotonergic Neuronal Systems during Development and Adulthood. AB - The complex integration of neurotransmitter signals in the nervous system contributes to the shaping of behavioral and emotional constitutions throughout development. Imbalance among these signals may result in pathological behaviors and psychiatric illnesses. Therefore, a better understanding of the interplay between neurotransmitter systems holds potential to facilitate therapeutic development. Of particular clinical interest are the dopaminergic and serotonergic systems, as both modulate a broad array of behaviors and emotions and have been implicated in a wide range of affective disorders. Here we review evidence speaking to an interaction between the dopaminergic and serotonergic neuronal systems across development. We highlight data stemming from developmental, functional, and clinical studies, reflecting the importance of this transmonoaminergic interplay. PMID- 25747119 TI - Modern surgical management of breast cancer therapy related upper limb and breast lymphoedema. AB - Breast cancer is the commonest cancer in the UK. Advances in breast cancer treatment means that the sequelae of treatment are affecting more women and for a longer duration. Lymphoedema is one such sequela, with wide-ranging implications, from serious functional and psychological effects at the individual level to wider economic burdens to society. Breast cancer-related lymphoedema is principally managed by conservative therapy comprising compression garments and manual decongestive massage. This approach is effective for early stages of lymphoedema, but it is not curative and the effectiveness depends on patient compliance. Early surgical approaches were ablative, gave significant morbidity and hence, reserved for the most severe cases of refractory lymphoedema. However, recent non-ablative reconstructive surgical approaches have seen a revival of interest in the prevention or surgical management of breast cancer-related lymphoedema. This review examines the modern surgical techniques for the treatment of breast cancer-related lymphoedema. Liposuction reduces the volume and symptoms of lymphedema, but requires continual compressive therapy to avoid recurrence. Lymphatic reconstruction or bypass techniques including lymph node transfer (inguinal nodes are transferred to the affected limb), lymphatico lymphatic bypass (lymphatics bypass the axilla using a lymph vessel graft reconstructing lymphatic flow from arm to neck) and lymphaticovenous anastomoses (lymphatics in the arm are joined to the venous system aiding lymph drainage) show promise in reducing lymphedema significantly. Further research is required, including into the role of primary lymphaticovenous anastomoses in the prevention of lymphedema at the time of axillary dissection. PMID- 25747120 TI - Relation between Breast Cancer and High Glycemic Index or Glycemic Load: A Meta analysis of Prospective Cohort Studies. AB - Breast cancer is the commonest form of cancer in women worldwide. It has been suggested that chronic hyperinsulinemia associated with insulin resistance plays a role in breast cancer etiology. To test the hyperinsulinemia hypothesis, a dietary pattern associated with a high glycemic index and glycemic load, both proxies for chronic hyperinsulinemia, should be associated with an increased risk of breast cancer. A meta-analysis restricted to prospective cohort studies was undertaken using a random effects model with tests for statistical significance, publication bias and heterogeneity. The metric for analysis was the risk of breast cancer in the highest relative to the lowest glycemic index and glycemic load dietary pattern. A dietary pattern with a high glycemic index was associated with a summary relative risk (SRR) of 1.05 (95% CI: 1.00, 1.11), and a high glycemic load with a SRR of 1.06 (95% CI: 1.00, 1.13). Adjustments for body mass index [BMI], physical activity and other lifestyle factors did not influence the SRR, nor did menopausal status and estrogen receptor status of the tumor. In conclusion, the current evidence supports a modest association between a dietary pattern with high glycemic index or glycemic load and the risk of breast cancer. PMID- 25747121 TI - Evaporation of droplets on strongly hydrophobic substrates. AB - The manner in which the extreme modes of droplet evaporation (namely, the constant contact radius and the constant contact angle modes) become indistinguishable on strongly hydrophobic substrates is described. Simple asymptotic expressions are obtained which provide good approximations to the evolutions of the contact radius, the contact angle, and the volume of droplets evaporating in the extreme modes for a wide range of hydrophobic substrates. As a consequence, on strongly hydrophobic substrates it is appropriate to use the so called "2/3 power law" to extrapolate the lifetimes of droplets evaporating in the constant contact radius mode as well as in the constant contact angle mode. PMID- 25747122 TI - Loss of anticodon wobble uridine modifications affects tRNA(Lys) function and protein levels in Saccharomyces cerevisiae. AB - In eukaryotes, wobble uridines in the anticodons of tRNA(Lys)UUU, tRNA(Glu)UUC and tRNA(Gln)UUG are modified to 5-methoxy-carbonyl-methyl-2-thio-uridine (mcm5s2U). While mutations in subunits of the Elongator complex (Elp1-Elp6), which disable mcm5 side chain formation, or removal of components of the thiolation pathway (Ncs2/Ncs6, Urm1, Uba4) are individually tolerated, the combination of both modification defects has been reported to have lethal effects on Saccharomyces cerevisiae. Contrary to such absolute requirement of mcm5s2U for viability, we demonstrate here that in the S. cerevisiae S288C-derived background, both pathways can be simultaneously inactivated, resulting in combined loss of tRNA anticodon modifications (mcm5U and s2U) without a lethal effect. However, an elp3 disruption strain displays synthetic sick interaction and synergistic temperature sensitivity when combined with either uba4 or urm1 mutations, suggesting major translational defects in the absence of mcm5s2U modifications. Consistent with this notion, we find cellular protein levels drastically decreased in an elp3uba4 double mutant and show that this effect as well as growth phenotypes can be partially rescued by excess of tRNA(Lys)UUU. These results may indicate a global translational or protein homeostasis defect in cells simultaneously lacking mcm5 and s2 wobble uridine modification that could account for growth impairment and mainly originates from tRNA(Lys)UUU hypomodification and malfunction. PMID- 25747123 TI - CD47 deficiency protects mice from diet-induced obesity and improves whole body glucose tolerance and insulin sensitivity. AB - CD47 is a transmembrane protein with several functions including self recognition, immune cell communication, and cell signaling. Although it has been extensively studied in cancer and ischemia, CD47 function in obesity has never been explored. In this study, we utilized CD47 deficient mice in a high-fat diet induced obesity model to study for the first time whether CD47 plays a role in the development of obesity and metabolic complications. Male CD47 deficient and wild type (WT) control mice were fed with either low fat (LF) or high fat (HF) diets for 16 weeks. Interestingly, we found that CD47 deficient mice were protected from HF diet-induced obesity displaying decreased weight gain and reduced adiposity. This led to decreased MCP1/CCR2 dependent macrophage infiltration into adipose tissue and reduced inflammation, resulting in improved glucose tolerance and insulin sensitivity. In addition, CD47 deficiency stimulated the expression of UCP1 and carnitine palmitoyltransferase 1b (CPT1b) levels in brown adipose tissue, leading to increased lipid utilization and heat production. This contributes to the increased energy utilization and reduced adiposity observed in these mice. Taken together, these data revealed a novel role for CD47 in the development of obesity and its related metabolic complications. PMID- 25747124 TI - Methoxy-modified kaolinite as a novel carrier for high-capacity loading and controlled-release of the herbicide amitrole. AB - Methoxy-modified kaolinite was used as a novel carrier for loading and release of the herbicide 3-amino-1,2,4-triazole, known as amitrole (abbreviated here as AMT). The methoxy modification made the interlayer space of the kaolinite available for AMT intercalation. The AMT loading content in methoxy-modified kaolinite reached up to 20.8 mass% (twice the loading content by unmodified kaolinite). About 48% of this amount is located in the interlayer space. The release profiles of the AMT fit with the modified Korsmeyer-Peppas model. Due to the diffusional restriction of the intercalated AMT by the lamellar structure of the kaolinite and the strong electrostatic attraction between the intercalated AMT and the kaolinite, a slow release of AMT from the methoxy-modified kaolinite was achieved. These results show that the methoxy-modification is a facile method to make the interlayer space of kaolinite available for hosting other guest molecules. The methoxy-modified kaolinite is a promising candidate for high capacity loading and controlled-release of other molecules such as drugs, agrochemicals, and biochemicals. PMID- 25747125 TI - Advances in pharmacotherapy for the treatment of allergic rhinitis; MP29-02 (a novel formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) fills the gaps. AB - INTRODUCTION: Effective pharmacologic treatment exists for most patients suffering from allergic rhinitis (AR). However, both in clinical trials and in real-life studies, many patients are dissatisfied with treatment. Physicians often use multiple therapies, in an attempt to improve symptom control, often with limited evidence of success. Novel treatment options are needed and must consider unmet medical needs. AREAS COVERED: This article reviews the clinical data for a new AR treatment. MP29-02 (Dymista(r), Meda, Solna, Sweden) contains azelastine hydrochloride (AZE) and fluticasone propionate (FP), in a novel formulation and delivered in an improved device as a single nasal spray. It has shown superior efficacy in AR patients than either commercially available AZE or FP monotherapy for both nasal and ocular symptom relief, regardless of disease severity. MP29-02 also provided more effective and rapid symptom relief than either AZE or FP monotherapy delivered in the MP29-02 formulation and device. However, the effect was less than that observed versus commercial comparators, suggesting the impact of formulation and device on clinical efficacy. EXPERT OPINION: MP29-02 simplifies AR management, surpassing the efficacy of gold standard treatment, intranasal corticosteroids (INS), for the first time. It is indicated for the treatment of moderate-to-severe seasonal allergic rhinitis and perennial allergic rhinitis when monotherapy with either intranasal antihistamine or INS is NOT considered sufficient. Most patients present with moderate/severe disease, with evidence of current or previous treatment insufficiency. MP29-02 should be the treatment of choice for these patients. PMID- 25747126 TI - Genetic mechanisms leading to primary amenorrhea in balanced X-autosome translocations. AB - OBJECTIVE: To map the X-chromosome and autosome breakpoints in women with balanced X-autosome translocations and primary amenorrhea, searching candidate genomic loci for female infertility. DESIGN: Retrospective and case-control study. SETTING: University-based research laboratory. PATIENT(S): Three women with balanced X-autosome translocation and primary amenorrhea. INTERVENTION(S): Conventional cytogenetic methods, genomic array, array painting, fluorescence in situ hybridization, and quantitative reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Karyotype, copy number variation, breakpoint mapping, and gene expression levels. RESULT(S): All patients presented with breakpoints in the Xq13q21 region. In two patients, the X-chromosome breakpoint disrupted coding sequences (KIAA2022 and ZDHHC15 genes). Although both gene disruptions caused absence of transcription in peripheral blood, there is no evidence that supports the involvement of these genes with ovarian function. The ZDHHC15 gene belongs to a conserved syntenic region that encompasses the FGF16 gene, which plays a role in female germ line development. The break in the FGF16 syntenic block may have disrupted the interaction between the FGF16 promoter and its cis-regulatory element. In the third patient, although both breakpoints are intergenic, a gene that plays a role in the DAX1 pathway (FHL2 gene) flanks distally the autosome breakpoint. The FHL2 gene may be subject to position effect due to the attachment of an autosome segment in Xq21 region. CONCLUSION(S): The etiology of primary amenorrhea in balanced X-autosome translocation patients may underlie more complex mechanisms than interruption of specific X-linked candidate genes, such as position effect. The fine mapping of the rearrangement breakpoints may be a tool for identifying genetic pathogenic mechanisms for primary amenorrhea. PMID- 25747127 TI - Impairment of male reproductive function after sleep deprivation. AB - OBJECTIVE: To evaluate the influence of sleep loss on sexual behavior, hormone levels, sperm parameters, and testis-specific gene expression in male rats. DESIGN: Experimental research. SETTING: Animal laboratory. ANIMAL(S): Male adult Wistar-Hannover rats. INTERVENTION(S): Sexually experienced rats were subjected to paradoxic sleep deprivation (PSD) for 96 hours or sleep restriction (SR) for 21 days or kept in their home cage as control (CTRL). MAIN OUTCOME MEASURE(S): Sexual behavior, hormone levels, sperm parameters and expression of stress and nitric oxide-related genes were evaluated. RESULT(S): PSD significantly decreased sexual behavior compared with the CTRL group, whereas SR had no effect. The PSD group had significantly lower testosterone levels than the CTRL group. Both PSD and SR groups had lower sperm viabilities than the CTRL group. The decrease in the number of live sperm compared with the CTRL group was larger in the PSD group than in the SR group. Regarding testicular gene expression, both PSD and SR led to an increase of iNOS and hydroxysteroid 11beta-dehydrogenase 1 expressions compared with the CTRL group. These changes were more pronounced in the PSD group. A significant increase in endothelial nitric oxide synthase expression was observed in the PSD groups compared with the CTRL group. No changes were observed in dimethylarginine dimethylaminohydrolase 1 and casein kinase 2beta-polypeptide expressions. CONCLUSION(S): Sleep loss can promote marked changes in the male reproductive system of rats, particularly affecting spermatic function in part by interfering in the testicular nitric oxide pathway. PMID- 25747129 TI - Ability of Escherichia coli to produce hemolysis leads to a greater pathogenic effect on human sperm. AB - OBJECTIVE: To determine the effect on human sperm of Escherichia coli strains separated on the basis of their ability to produce hemolysis. DESIGN: Experimental study. SETTING: University-based laboratory. PATIENT(S): Semen samples from healthy donors. INTERVENTION(S): Five million sperm, selected via the swim-up method, were incubated with 3 E. coli concentrations to obtain ratios of sperm to E. coli of 1:2, 1:16, and 1:128. The E. coli strains were: a hemolytic isolated strain (H), a nonhemolytic American Type Culture Collection strain (NH-ATCC), and a nonhemolytic isolated strain (NH-I). MAIN OUTCOME MEASURE(S): Aliquots of human sperm were used to measure progressive motility using computer-aided sperm analysis, mitochondrial membrane potential (DeltaPsim) with a JC-1 (5,5',6,6' tetrachloro-1,1',3,3'-tetraethylbenzamidazolocarbocyanin iodide) and propidium iodide stain, and intracellular reactive oxygen species (iROS) with a dihydroethidium (DHE) stain. Sperm DeltaPsim and iROS were measured by flow cytometry. Sperm vitality was considered the mean of propidium iodide negative and DHE-negative cells. RESULT(S): Sperm incubated with the H strain in a 1:2 sperm to bacteria ratio demonstrated a significant decrease in motility and DeltaPsim, and an increase of iROS. The NH-ATCC strain decreased sperm motility and DeltaPsim, but in a ratio of sperm to bacteria of 1:128; it increased iROS at a ratio of 1:16. The NH-I strain did not affect the analyzed sperm functions, even at a 1:128 sperm to bacteria ratio. CONCLUSION(S): Results show a greater pathogenic effect on human sperm of E. coli strains with, versus without, hemolytic capacity. PMID- 25747128 TI - Perfluoroalkyl substances and ovarian hormone concentrations in naturally cycling women. AB - OBJECTIVE: To examine associations between environmental exposure to perfluoroalkyl substances (PFASs) and ovarian hormone concentrations in naturally cycling women. DESIGN: E2 and P were measured in saliva samples collected daily for a single menstrual cycle and concentrations of PFASs (including perfluoroctane sulfonate [PFOS] and perfluoroctanoic acid) were measured in serum samples collected during the same cycle. SETTING: Not applicable. PATIENT(S): A total of 178 healthy, naturally cycling women, aged 25-35 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mean follicular E2 (cycle days -7 to -1, where 0 is the day of ovulation); mean luteal P (cycle days +2 to 10). RESULT(S): Among nulliparous, but not parous women, PFOS concentrations were inversely associated with E2 (beta = -0.025, 95% CI -0.043, -0.007) and P (beta = -0.027, 95% CI 0.048, -0.007). Similar, but weaker results were observed for perfluorooctanesulfonic acid. No associations were observed between other PFASs (including perfluoroctanoic acid) and ovarian steroid concentrations, nor were any associations noted in parous women. CONCLUSION(S): Our results demonstrate that PFOS and perfluorooctanesulfonic acid may be associated with decreased production of E2 and P in reproductive age women. These results suggest a possible mechanism by which PFASs affect women's health, and underscore the importance of parity in research on PFASs and women's reproductive health. PMID- 25747130 TI - Freeze-all policy: fresh vs. frozen-thawed embryo transfer. AB - OBJECTIVE: To compare in vitro fertilization (IVF) outcomes between fresh embryo transfer (ET) and frozen-thawed ET (the "freeze-all" policy), with fresh ET performed only in cases without progesterone (P) elevation. DESIGN: Prospective, observational, cohort study. SETTING: Private IVF center. PATIENT(S): A total of 530 patients submitted to controlled ovarian stimulation (COS) with a gonadotropin-releasing hormone-antagonist protocol, and cleavage-stage, day-3 ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rates. RESULT(S): A total of 530 cycles were included in the analysis: 351 in the fresh ET group (when P levels were <=1.5 ng/mL on the trigger day); and 179 cycles in the freeze-all group (ET performed after endometrial priming with estradiol valerate, at 6 mg/d, taken orally). For the fresh ET group vs. the freeze-all group, respectively, the implantation rate was 19.9% and 26.5%; clinical pregnancy rate was 35.9% and 46.4%; and ongoing pregnancy rate was 31.1% and 39.7%. CONCLUSION(S): The IVF outcomes were significantly better in the group using the freeze-all policy, compared with the group using fresh ET. These results suggest that even in a select group of patients that underwent fresh ET (P levels <=1.5 ng/mL), endometrial receptivity may have been impaired by COS, and outcomes may be improved by using the freeze-all policy. PMID- 25747131 TI - Thirty-five years later, the first assisted reproductive technology program opens in Cambodia. PMID- 25747132 TI - Role of Mucin 1 and Glycodelin A in recurrent implantation failure. AB - OBJECTIVE: To evaluate and compare the levels of Mucin 1 (MUC-1) and Glycodelin A (GdA) in precisely timed endometrial biopsies and blood samples taken from women with recurrent implantation failure, and women with proven fertility, in a control group. DESIGN: Molecular studies in human blood and tissue. SETTING: University hospital. PATIENT(S): Women with recurrent implantation failure and women with proven fertility. INTERVENTION(S): Primary endometrial cells and blood samples during the implantation "window" (between day 7 and day 9 after the surge in luteinizing hormone). MAIN OUTCOME MEASURE(S): Expression of MUC-1 and GdA in the human endometrium and in blood during the implantation window were analyzed by enzyme-linked immunosorbent assay. Additionally, MUC-1 and GdA levels in tissue were analyzed by western blot during the same period. RESULT(S): Both blood and tissue measurements of MUC-1 and GdA were significantly lower in women with recurrent implantation failure than in fertile women during the implantation window. In addition, we found a highly significant correlation between blood vs. tissue measurements of both MUC-1 and GdA. CONCLUSION(S): The present study reveals that blood and tissue levels of MUC-1 and GdA are much lower in women with RIF, compared with those in fertile women. Receptivity can be evaluated with noninvasive blood sampling, rather than more-invasive endometrium sampling, as the blood and tissue measurements of MUC-1 and GdA are correlated. PMID- 25747133 TI - Cryopreserved embryo transfer is an independent risk factor for placenta accreta. AB - OBJECTIVE: To explore the association between cryopreserved embryo transfer (CET) and risk of placenta accreta among patients utilizing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). DESIGN: Case-control study. SETTING: Academic medical center. PATIENT(S): All patients using IVF and/or ICSI, with autologous or donor oocytes, undergoing fresh or cryopreserved transfer, who delivered a live-born fetus at >=24 weeks of gestation at our center, from 2005 to 2011 (n = 1,571), were reviewed for placenta accreta at delivery. INTERVENTION(S): Cases of accreta (n = 50) were matched by age and prior cesarean section to controls (1:3) without accreta. The association between CET and accreta was modeled using conditional logistic regression, controlling a priori for age and placenta previa. Receiver operating characteristic curves were used to determine thresholds of endometrial thickness and peak serum E2 levels related to accreta. MAIN OUTCOME MEASURE(S): Placenta accreta. RESULT(S): Univariate predictors of accreta were non-Caucasian race (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.25-6.47); uterine factor infertility (OR 5.80, 95% CI 2.49-13.50); prior abdominal or laparoscopic myomectomy (OR 7.24, 95% CI 1.92 27.28); and persistent or resolved placenta previa (OR 4.25, 95% CI 1.94-9.33). In multivariate analysis, we observed a significant association between CET and accreta (adjusted OR 3.20, 95% CI 1.14-9.02), which remained when analyses were restricted to cases of accreta with morbid complications (adjusted OR 3.87, 95% CI 1.08-13.81). Endometrial thickness and peak serum E2 level were each significantly lower in CET cycles and those with accreta. CONCLUSION(S): Cryopreserved ET is a strong independent risk factor for accreta among patients using IVF and/or ICSI. A threshold endometrial thickness and a "safety window" of optimal peak E2 level are proposed for external validation. PMID- 25747135 TI - Effect of sperm DNA fragmentation on the clinical outcomes for in vitro fertilization and intracytoplasmic sperm injection in women with different ovarian reserves. AB - OBJECTIVE: To investigate effect of sperm DNA fragmentation (SDF) on clinical outcomes of assisted reproductive technology in women with normal ovarian reserve (NOR) versus reduced ovarian reserve (ROR). DESIGN: Retrospective clinical study. SETTING: University-affiliated tertiary teaching hospital. PATIENT(S): A total of 2,865 consecutive couples undergoing their first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle. INTERVENTION(S): SDF assessed using sperm chromatin dispersion in sperm samples 1-2 months before treatment. MAIN OUTCOME MEASURE(S): SDF, IVF, and ICSI outcomes. RESULT(S): The grouping criteria were [1] basal follicle stimulating hormone >10 IU/L, [2] antral follicle count <6, and [3] female age >=38 years. Women fulfilling two of the three criteria were considered to have ROR, and those not meeting any criteria were considered to have NOR. The area under the receiver operating characteristic curve was 0.594 (0.539-0.648) for the ROR group and 0.510 (0.491-0.530) for the NOR group. A cutoff value for SDF to predict the clinical pregnancy rate (CPR) in the ROR group was 27.3%. When the SDF exceeded 27.3%, the live-birth and implantation rates in the ROR group were statistically significantly decreased, but the clinical pregnancy, live-birth, and implantation rates were not affected in the NOR group. The risk of early abortion increased significantly in the NOR group when the SDF exceeded 27.3%. CONCLUSION(S): Sperm DNA fragmentation has a greater impact on IVF and ICSI outcomes among women with ROR, so SDF testing may be of particular clinical significance for these couples. PMID- 25747134 TI - MicroRNAome in decidua: a new approach to assess the maintenance of pregnancy. AB - OBJECTIVE: To comparatively analyze the human microRNAomes between normal pregnant and miscarriage deciduas by an in-depth sequencing of microRNA (miRNA); and to specifically examine miRNA-199b-5p and serum/glucocorticoid regulated kinase 1 (SGK1) in vivo and in vitro for their possible roles in pregnancy maintenance. DESIGN: Samples of deciduas from 6-8-week spontaneous miscarriages and normal pregnant women were irrespectively collected and comparatively analyzed by miRNA sequencing. The miR-199b-5p and SGK1 expressions were validated in vivo and in vitro. SETTING: University research and clinical institutes. PATIENT(S): In this experimental study, samples of deciduas were obtained from October 2011 to April 2012 from 29 women with spontaneous miscarriages and 35 normal pregnant women (control group) who underwent pregnancy termination at 6-8 weeks at our university gynecology unit. INTERVENTION(S): Endometrial biopsies, cell transfection, and production of an miR-199b-5p transgenic mouse model. MAIN OUTCOME MEASURE(S): In-depth sequencing of the miRNAome on human deciduas was performed for statistically significant differences in miRNA expression. Expression levels of SGK1 were detected by quantitative polymerase chain reaction and immunoblotting (Western blot) in vitro while miR-199b-5p is overexpressed or knockdown in miR-199b-5p transgenic mice. RESULT(S): Expression of the 1,921 known miRNAs was analyzed in the study. In aborted deciduas, 0.57% of the miRNAs were expressed abundantly (>10,000 transcripts per million) and represented 86.38% of all the miRNA reads. Six miRNAs were down-regulated (let-7a-5p, let-7f 5p, let-7g-5p, let-7e-5p, let-7d-5p, and miR-98), whereas miR-199b-5p was significantly up-regulated. Overexpression or knockdown of miR-199b-5p in HEK293T and Ishikawa cells decreased or increased SGK1 expression. Furthermore, overexpression of miR-199b-5p in human endometrial stromal cells or in transgenic mouse decreased SGK1 expression at the mRNA and protein levels, respectively. CONCLUSION(S): Among the miRNAomes, the abundant expression of the let-7 members was decreased in aborted samples, whereas miR-199b-5p expression was consistently increased. A significant inverse correlation was found between miR-199b-5p and SGK1 in vivo and in vitro. PMID- 25747136 TI - Protein redox regulation in the thylakoid lumen: the importance of disulfide bonds for violaxanthin de-epoxidase. AB - When exposed to saturating light conditions photosynthetic eukaryotes activate the xanthophyll cycle where the carotenoid violaxanthin is converted into zeaxanthin by the enzyme violaxanthin de-epoxidase (VDE). VDE protein sequence includes 13 cysteine residues, 12 of which are strongly conserved in both land plants and algae. Site directed mutagenesis of Arabidopsis thaliana VDE showed that all these 12 conserved cysteines have a major role in protein function and their mutation leads to a strong reduction of activity. VDE is also shown to be active in its completely oxidized form presenting six disulfide bonds. Redox titration showed that VDE activity is sensitive to variation in redox potential, suggesting the possibility that dithiol/disulfide exchange reactions may represent a mechanism for VDE regulation. PMID- 25747137 TI - Unusual non-enzymatic flavin catalysis enhances understanding of flavoenzymes. AB - Flavin cofactors are central to many biochemical transformations and are typically tightly bound as part of a catalytically active flavoenzyme. This work indicates that naturally occurring flavins can act as stand-alone catalysts to promote the oxidation of biosynthetically inspired heterocycles in aqueous buffers. Flavin activity was compared with that of oxidases important in non ribosomal peptide synthesis, providing a rare direct comparison between the catalytic efficacy of flavins alone and in the context of a full flavoenzyme. This study suggests that such oxidases are likely to possess an active site base, as oxidase activity was greater than that of flavins alone, particularly for less acidic substrates. These findings offer perspective on the development of robust and catalytically effective, designed miniature flavoenzymes. PMID- 25747138 TI - Pseudomonas aeruginosa injects type III effector ExoS into epithelial cells through the function of type IV pili. AB - Translocation of Pseudomonas aeruginosa through epithelial tissues can cause sepsis. Here, we examined whether P. aeruginosa penetrates epithelial cell layers using type IV pili (TFP). Deletion of TFP (pilA) did not affect association with Caco-2 cells, although it decreased penetration through, and disruption of, Caco 2 cell monolayers. We found that TFP are necessary for injection of the type III effector ExoS, which impairs defense against P. aeruginosa penetration, into host cells. Deletion of pilA attenuated oral infection in silkworms. We conclude that P. aeruginosa injects ExoS into cells through the function of TFP, enabling penetration of epithelial barriers. PMID- 25747139 TI - Inter-limb coupling during diadochokinesis in Parkinson's and Huntington's disease. AB - Patients with neurodegenerative diseases often exhibit deficits in bimanual coordination. One characteristic of bimanual movements is inter-limb coupling. It is the property of motor performance harmonization between hands during a bimanual task. The objective of this study was to identify whether spatial and temporal inter-limb coupling occurred in Parkinson's disease (PD) and Huntington's disease (HD) patients. Twenty-three PD patients and 15 healthy controls were tested. Data from 12 choreic HD patients were also taken from a databank. Participants were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference between hands in mean amplitude and mean duration of cycles was computed in the unimanual and bimanual tasks for each group. Results show that healthy controls exhibited temporal and spatial inter-limb coupling during the bimanual diadochokinesis task. Conversely, PD and HD patients exhibited temporal inter-limb coupling; but failed to exhibit spatial inter-limb coupling during the bimanual diadochokinesis task. Furthermore, HD patients exhibited reduced levels of structural coupling compared to controls and PD patients. These results suggest that alterations in basal ganglia-thalamo cortical networks due to PD and HD do not affect temporal inter-limb coupling. However, common pathophysiological changes related to PD and HD may cause altered spatial inter-limb coupling during a rapid repetitive bimanual diadochokinesis task. PMID- 25747140 TI - Short and long term release mechanisms of arsenic, selenium and boron from a tunnel-excavated sedimentary rock under in situ conditions. AB - Sedimentary rocks of marine origin excavated from tunnel construction projects usually contain background levels of hazardous trace elements, but when exposed to the environment, they generate leachates with concentrations of arsenic (As), selenium (Se) and boron (B) exceeding the WHO guideline for drinking water. In this study, the leaching of As, Se and B was evaluated under in situ conditions at various flow patterns, particle size distributions and column thicknesses. The results showed that these trace elements were leached out of the rock via short and long term mechanisms. In the short term, all three elements were rapidly and simultaneously released due to the dissolution of soluble evaporite salts formed from entrapped sea water of the Cretaceous. After their rapid release, however, these trace elements behaved differently as a result of their contrasting adsorption affinities onto minerals like clays and Fe-oxyhydroxides, which were further influenced by the pH, presence of coexisting ions and speciation of the trace elements. Selenium was quickly and easily transported out of the columns because it was mostly present as the very mobile selenate ion (Se[VI]). In comparison, the migration of As and B was hindered by adsorption reactions onto mineral phases of the rock. Boron was initially the least mobile among the three because of its preferential adsorption onto clay minerals that was further enhanced by the slightly alkaline pH and high concentrations of Ca(2+) and Na(+). However, it was gradually re-mobilized in the latter part of the experiments because it was only weakly adsorbed via outer sphere complexation reactions. In the long term, the rock continued to release substantial amounts of As, Se and B via pyrite oxidation and adsorption/desorption reactions, which were regulated by the temperature and rainfall intensity/frequency on site. PMID- 25747141 TI - Trends in insomnia and excessive daytime sleepiness among U.S. adults from 2002 to 2012. AB - OBJECTIVE: Insomnia is a prevalent disorder in the United States and elsewhere. It has been associated with a range of somatic and psychiatric conditions, and adversely affects quality of life, productivity at work, and school performance. The objective of this study was to examine the trend in self-reported insomnia and excessive daytime sleepiness among US adults. METHODS: We used data of participants aged >=18 years from the National Health Interview Survey for the years 2002 (30,970 participants), 2007 (23,344 participants), and 2012 (34,509 participants). RESULTS: The unadjusted prevalence of insomnia or trouble sleeping increased from 17.5% (representing 37.5 million adults) in 2002 to 19.2% (representing 46.2 million adults) in 2012 (relative increase: +8.0%) (P trend <0.001). The age-adjusted prevalence increased from 17.4% to 18.8%. Significant increases were present among participants aged 18-24, 25-34, 55-64, and 65-74 years, men, women, whites, Hispanics, participants with diabetes, and participants with joint pain. Large relative increases occurred among participants aged 18-24 years (+30.9%) and participants with diabetes (+27.0%). The age-adjusted percentage of participants who reported regularly having excessive daytime sleepiness increased from 9.8% to 12.7% (P trend <0.001). Significant increases were present in most demographic groups. The largest relative increase was among participants aged 25-34 years (+49%). Increases were also found among participants with hypertension, chronic obstructive pulmonary disease, asthma, and joint pain. CONCLUSIONS: Given the deleterious effects of insomnia on health and performance, the increasing prevalence of insomnia and excessive daytime sleepiness among US adults is a potentially troubling development. PMID- 25747142 TI - The impact of restless legs syndrome on physical functioning in a community dwelling population of middle-aged and elderly people. AB - OBJECTIVE: To investigate whether restless legs syndrome (RLS) is associated with impaired physical functioning using subjective and objective assessments. METHODS: From 2006-2013, 5,960 participants (mean age 67.2; 57.5% females) of the prospective population-based Rotterdam Study, aged 45 years and over, were cross sectionally investigated for presence of restless legs syndrome using a questionnaire. Physical functioning was assessed subjectively with the Stanford Health Assessment Questionnaire (basic activities of daily living) and the Instrumental Activities of Daily living scale (instrumental activities of daily living). Additionally, physical functioning was assessed objectively by quantifying fine motor performance with the Purdue Pegboard Test and by quantifying gait with an electronic walkway. RESULTS: Restless legs syndrome was present in 13.7% of the participants. Persons with restless legs had more impairment in basic (difference in score 0.65, 95% CI 0.41;0.90) and instrumental activities of daily living (difference in score 0.28, 95% CI 0.09;0.48) than persons without restless legs. This association was strongest when symptoms were present two or more times a week (basic activities of daily living score difference 1.69, 95% CI 1.28;2.09). The association between restless legs syndrome and activities of daily living attenuated after adjusting for sleep quality or depressive symptoms. There was no association with the Purdue Pegboard Test score nor with gait. CONCLUSIONS: Individuals with restless legs syndrome experienced significantly more impairment in activities of daily function than persons without restless legs. This seemed to be (partly) mediated by poor sleep quality and depressive symptoms. No association was found with objectively assessed physical functioning. PMID- 25747143 TI - Dendrimer-like alpha-d-glucan nanoparticles activate dendritic cells and are effective vaccine adjuvants. AB - The use of nanoparticles for delivery of vaccine antigens and as vaccine adjuvants is appealing because their size allows efficient uptake by dendritic cells and their biological properties can be tailored to the desired function. Here, we report the effect of chemically modified phytoglycogen, a dendrimer-like alpha-d-glucan nanoparticle, on dendritic cells in vitro, and the utility of this type of nanoparticle as a vaccine adjuvant in vivo. The modified phytoglycogen nanoparticle, termed Nano-11, has a positive surface charge which enabled electrostatic adsorption of negatively charged protein antigens. The Nano-11 antigen complexes were efficiently phagocytized by dendritic cells. Nano-11 induced increased expression of costimulatory molecules and the secretion of IL 1beta and IL-12p40 by dendritic cells. Intramuscular injection of Nano-11-antigen formulations induced a significantly enhanced immune response to two different protein antigens. Examination of the injection site revealed numerous monocytes and relatively few neutrophils at one day after injection. The inflammation had nearly completely disappeared by 2 weeks after injection. These studies indicate that Nano-11 is an effective vaccine delivery vehicle that significantly enhances the immune response. This type of plant based nanoparticle is considered highly cost-effective compared with fully synthetic nanoparticles and appears to have an excellent safety profile making them an attractive adjuvant candidate for prophylactic vaccines. PMID- 25747144 TI - A functionalized, injectable hydrogel for localized drug delivery with tunable thermosensitivity: synthesis and characterization of physical and toxicological properties. AB - Thermosensitive injectable hydrogels have been used for the delivery of pharmacological and cellular therapies in a variety of soft tissue applications. A promising class of synthetic, injectable hydrogels based upon oligo(ethylene glycol) methacrylate (OEGMA) monomers has been previously reported, but these polymers lack reactive groups for covalent attachment of therapeutic molecules. In this work, thermosensitive, amine-reactive and amine-functionalized polymers were developed by incorporation of methacrylic acid N-hydroxysuccinimide ester or 2-aminoethyl methacrylate into OEGMA-based polymers. A model therapeutic peptide, bivalirudin, was conjugated to the amine-reactive hydrogel to investigate effects on the polymer thermosensitivity and gelation properties. The ability to tune the thermosensitivity of the polymer in order to compensate for peptide hydrophilicity and maintain gelation capability below physiological temperature was demonstrated. Cell encapsulation studies using an H9 T-cell line (CD4+) were conducted to evaluate feasibility of the hydrogel as a carrier for cellular therapies. Although this class of polymers is generally considered to be non toxic, it was found that concentrations required for gelation were incompatible with cell survival. Investigation into the cause of cytotoxicity revealed that a hydrolysis byproduct, diethylene glycol monomethyl ether, is likely a contributing factor. While modifications to structure or composition will be required to enable viable cell encapsulation, the functionalized injectable hydrogel has the potential for controlled delivery of a wide range of drugs. PMID- 25747145 TI - Ultrasonic delivery of silica-gold nanoshells for photothermolysis of sebaceous glands in humans: Nanotechnology from the bench to clinic. AB - Recent advances in nanotechnology have provided numerous opportunities to transform medical therapies for the treatment of diseases including cancer, atherosclerosis, and thrombosis. Here, we report, through in vitro studies and in vivo human pilot clinical studies, the use of inert, inorganic silica-gold nanoshells for the treatment of a widely prevalent and researched, yet poorly treated disease of acne. We use ~150nm silica-gold nanoshells, tuned to absorb near-IR light and near-IR laser irradiation to thermally disrupt overactive sebaceous glands in the skin which define the etiology of acne-related problems. Low-frequency ultrasound was used to facilitate deep glandular penetration of the nanoshells. Upon delivery of the nanoshells into the follicles and glands, followed by wiping of superficial nanoshells from skin surface and exposure of skin to near-infrared laser, nanoshells localized in the follicles absorb light, get heated, and induce focal thermolysis of sebaceous glands. Pilot human clinical studies confirmed the efficacy of ultrasonically-delivered silica-gold nanoshells in inducing photothermal disruption of sebaceous glands without damaging collateral skin. PMID- 25747146 TI - Faecal microbiota transplantation: Key points to consider. AB - Faecal microbiota transplantation (FMT) from a healthy donor has become the gold standard treatment for patients suffering from recurrent Clostridium difficile infection where antibiotic treatment (with vancomycin, metronidazole or fidaxomicin) has failed. FMT eradicates C. difficile and helps restore the recipient's intestinal flora, but its mechanism of action remains unclear. Since FMT's complex and highly variable composition cannot be easily characterized - nor its quality routinely assessed - FMT as a sui generis biologic drug cannot conform to existing standards for preparation. Clearly, donors must be carefully selected and the raw material prepared under close microbiological control, but FMT should also conform to manufacturing and laboratory practice standards for which international consensus can only be achieved with further experience. The objective should be to engage biomedical research to develop protocols that help elucidate the mechanism of action of FMT and support the production of safe and efficacious products. PMID- 25747147 TI - Syneilesis palmata (Thunb.) Maxim. extract attenuates inflammatory responses via the regulation of TRIF-dependent signaling and inflammasome activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Syneilesis palmata (Thunb.) Maxim. (S. palmata, Asteraceae) is a traditional Korean therapeutic herb widely used to treat pain, arthritis, and other symptoms. This study provides the scientific basis for the anti-inflammatory effects of S. palmata extract (SP) in both in vitro and in vivo experimental models. MATERIALS AND METHODS: Lipopolysaccharide (LPS)-stimulated murine macrophages were used to study the regulatory effect of SP on the inflammatory mediators in vitro. Bone marrow-derived macrophages were used to study the effects of SP on inflammasome activation. Escherichia coli-induced sepsis mouse model and LPS-induced endotoxin shock model were employed to study the effect of SP on in vivo efficacy. RESULTS: SP inhibited the LPS-stimulated release of proinflammatory mediators, such as nitric oxide and interleukin (IL)-6 in RAW 264.7 cells. SP treatment also attenuated IL-1beta secretion via the inhibition of NLRP3 inflammasome activation induced by monosodium urate, ATP, and nigericin. Further, SP ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin and E. coli-induced sepsis mouse models. Mechanistic studies revealed that inhibitory effects of SP were mediated through the regulation of TRIF-dependent signaling and inflammasome activation. CONCLUSION: This study was the first to reveal mechanistic-based evidence substantiating the traditional claims of SP in the treatment of inflammation related disorders, such as pain and arthritis. PMID- 25747148 TI - An ethnobotanical study of medicinal plants of Chungtia village, Nagaland, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicinal plant knowledge is an integral and very important part of Indigenous cultures worldwide. For many communities there is a great urgency in recording this knowledge in written form. This is the first ethnobotanical report of medicinal plant knowledge of the Nagaland Ao tribe of Chungtia village and is an important step in the preservation of this culturally and medicinally significant knowledge. AIM OF THE STUDY: The aim of the presented work was to perform an ethnobotanical study on plants of medicinal and other significance to the Chungtia villagers of Nagaland, North East India. MATERIALS AND METHODS: Ethnobotanical data were collected from traditional practitioners and Elders of Chungtia village by means of open group discussions and semi-structured interviews of groups and individuals using questionnaires. The interviews were also recorded in an audio format in the local Mongsen language. The gathered ethnobotanical knowledge was compared with reported ethnobotanical usages worldwide and reported biological properties and phytochemical studies relevant to the Chungtia villagers' applications. RESULTS: A total of 135 plant species of 69 families and 123 genera were recorded for medicinal and household maintenance applications. Those applications were grouped into 13 categories based on Chungtia villagers' classification system. The families most represented were Asteraceae, Euphorbiaceae and Solanaceae. The most reported uses were for gastrointestinal problems, followed by dermatological problems. The most commonly used plant parts were leaves, followed by fruits and stems and they were most commonly administered as a paste, decoction, infusion, juice or poultice, or taken orally with no preparation. There was strong agreement among the informants as to the usages of the plants (informant consensus factor 0.80-0.91). The use value of 6 for Cassia floribunda, Dolichos lablab, Hedyotis scandens, Phyllanthus urinaria and Rhus javanica indicated these are the most important species. Forty four of the 135 plants had a fidelity level of 100%. CONCLUSION: This study has helped to document and preserve in written format important traditional plant knowledge of 135 plants of the Chungtia villagers, assisting them in the continued preservation of their cultural values. PMID- 25747149 TI - Vanadium(V) complex with Schiff-base ligand containing a flexible amino side chain: Synthesis, structure and reactivity. AB - The Schiff-base ligand (H2salhyhNH3)Cl (1) derived from salicylaldehyde and 6 aminohexanoic acid hydrazide hydrochloride reacts with ammonium metavanadate in methanol solution to yield the dioxidovanadium(V) complex [VO2(salhyhNH3)] (2). The utilized hydrazone ligand contains a flexible and protonated amino side chain. Crystallization from methanol affords complex 2 in the monoclinic space group P21/n, whereas crystallization from a methanol/water mixture 1:1 yields crystals, containing a water molecule of crystallization per two formula units (2?1/2H2O), in the orthorhombic space group Pbcn. In both cases the protonated amino group compensates the negative charge on the dioxidovanadium moiety and is involved in an extensive hydrogen bonding network particularly including the oxido groups from neighboring vanadium complexes. The reactivity of complex 2 toward protonation in aqueous solution has been investigated by spectrophotometric titrations and is characterized by two subsequent protonation steps at the hydrazide nitrogen atom of the ligand system and an oxido group leading to the formation of an oxidohydroxidovanadium(V) species with corresponding pKa values of 3.2 and 2.9, respectively. With larger excess of acid the oxidohydroxidovanadium(V) species starts to form the corresponding anhydride. The formation of the anhydride is strongly favored in the presence of methanol. The reaction of complex 2 with hydrogen peroxide in methanol solution leads to the formation of an oxidoperoxidovanadium(V) species, whereas in aqueous solution the addition of one equivalent of acid is required. Complex 2 catalyzes the oxidation of methylphenylsulfane to the corresponding sulfoxide in methanol/dichloromethane mixture using hydrogen peroxide as oxidant at room temperature. PMID- 25747150 TI - Mimicking peroxidase activity by a polymer-supported oxidovanadium(IV) Schiff base complex derived from salicylaldehyde and 1,3-diamino-2-hydroxypropane. AB - The polymer-supported oxidovanadium(IV) complex PS-[V(IV)O(sal-dahp)] (2) (PS=chloromethylated polystyrene crosslinked with 5% divinylbenzene, and H3sal dahp=dibasic pentadentate ligand derived from salicylaldehyde and 1,3-diamino-2 hydroxypropane) was prepared from the corresponding monomeric oxidovanadium(IV) complex [V(IV)O(Hsal-dahp)(DMSO)] (1), characterized and successfully used as catalyst for the peroxidase-like oxidation of pyrogallol. The oxidation of pyrogallol to purpurogallin with PS-[V(IV)O(sal-dahp)] (2) was achieved under mild conditions at pH7 buffered solution. Plausible intermediate species formed during peroxidase mimicking experiments are proposed, by studying the model complex [V(IV)O(Hsal-dahp)(DMSO)] (1) by UV-visible and (51)V NMR spectroscopies. The high peroxidase mimicking ability of polymer-supported complex 2, its stability in a wide pH range, the easy separation from the reaction media, and the reusability without considerable decrease in activity, suggest that this heterogeneous catalyst has high potential for application in sustainable industrial catalysis. PMID- 25747152 TI - Fuelling the Fire of Life: A tribute to Professor W.K. Milsom. PMID- 25747151 TI - Investigating the role of free-ranging wild boar (Sus scrofa) in the re-emergence of enzootic pneumonia in domestic pig herds: a pathological, prevalence and risk factor study. AB - Enzootic pneumonia (EP) caused by Mycoplasma hyopneumoniae has a significant economic impact on domestic pig production. A control program carried out from 1999 to 2003 successfully reduced disease occurrence in domestic pigs in Switzerland, but recurrent outbreaks suggested a potential role of free-ranging wild boar (Sus scrofa) as a source of re-infection. Since little is known on the epidemiology of EP in wild boar populations, our aims were: (1) to estimate the prevalence of M. hyopneumoniae infections in wild boar in Switzerland; (2) to identify risk factors for infection in wild boar; and (3) to assess whether infection in wild boar is associated with the same gross and microscopic lesions typical of EP in domestic pigs. Nasal swabs, bronchial swabs and lung samples were collected from 978 wild boar from five study areas in Switzerland between October 2011 and May 2013. Swabs were analyzed by qualitative real time PCR and a histopathological study was conducted on lung tissues. Risk factor analysis was performed using multivariable logistic regression modeling. Overall prevalence in nasal swabs was 26.2% (95% CI 23.3-29.3%) but significant geographical differences were observed. Wild boar density, occurrence of EP outbreaks in domestic pigs and young age were identified as risk factors for infection. There was a significant association between infection and lesions consistent with EP in domestic pigs. We have concluded that M. hyopneumoniae is widespread in the Swiss wild boar population, that the same risk factors for infection of domestic pigs also act as risk factors for infection of wild boar, and that infected wild boar develop lesions similar to those found in domestic pigs. However, based on our data and the outbreak pattern in domestic pigs, we propose that spillover from domestic pigs to wild boar is more likely than transmission from wild boar to pigs. PMID- 25747153 TI - Biomarkers and echocardiographic predictors of myocardial dysfunction in patients with hypertension. AB - The study aimed to identify early echocardiographic and circulating biomarkers of heart failure (HF) in hypertensive patients with normal resting echocardiography. Echocardiography at rest and during exercise, and selected biomarkers were assessed in control group, dyspnea group, and HF group. On exercise dyspnea patients had lower early diastolic (E') and systolic (S') mitral annular velocity (12.8 +/- 1.0 vs 14.9 +/- 3.0 cm/sec and 9.3 +/- 2.0 vs 10.9 +/- 2.0 cm/sec, respectively), and higher E/E' ratio compared to control group (6.7 +/- 1.0 vs 5.9 +/- 1.0) (p < 0.05 for all comparisons). The level of N-terminal propeptide of procollagen type III (PIIINP) was significantly higher in dyspnea group than in controls (p = 0.01). Control and dyspnea patients had lower levels of cardiotrophin-1, cystatin C, syndecan-4, and N terminal-probrain natriuretic peptide than HF patients (all p <= 0.01). In multivariate analysis PIIINP (unadjusted odds ratio [OR] = 8.2, 95% confidence interval [Cl] 1.7-40.6; p = 0.001; adjusted OR = 8.7; 95%CI: 1.5-48.3; p = 0.001) and E/E' ratio on exercise (unadjusted OR = 1.8, 95%CI: 0.8-4.0; p = 0.033; adjusted OR = 2.0; 95%CI: 0.8 4.8; p = 0.012) were the only factors significantly associated with the presence of dyspnea. PIIINP is the first early biomarker for the HF development in patients with HA and normal resting echocardiography. Exertional echocardiography may indicate patients with incipient HF with preserved ejection fraction. PMID- 25747154 TI - Dietary intake of trace elements from highly consumed cultured fish (Labeo rohita, Pangasius pangasius and Oreochromis mossambicus) and human health risk implications in Bangladesh. AB - Concentrations of fourteen trace elements (essential and toxic) in the composite samples (collected from 30 different agro-ecological zones for the first time in Bangladesh) of three highly consumed cultured fish species (Labeo rohita, Pangasius pangasius and Oreochromis mossambicus) were measured by inductively coupled plasma mass spectrometry (ICP-MS). The estimated daily dietary intake (EDI) of all the studied elements was estimated on the basis of a calculation of the amount of fish consumed by Bangladeshi households (mean fish consumption of 49.5 g person(-1) d(-1)). The studied fish species pose no risk with respect to the EDI of Cd, Pb, Cr, Ni, Zn, Se, Cu, Mo, Mn, Sb, Ba, V, and Ag. Among the three studied fishes O. mossambicus showed higher content of dietary arsenic (1.486 mg kg(-1)). From the human health point of view, this study showed that the inhabitants in the arsenic-contaminated area, who consume arsenic-contaminated water with fish (especially for O. mossambicus), are exposed chronically to arsenic pollution with carcinogenic and non-carcinogenic risks. PMID- 25747155 TI - Alteration in the cytokine levels and histopathological damage in common carp induced by glyphosate. AB - Glyphosate is one of the most frequently used herbicides, and it has been demonstrated to generate a series of toxicological problems in animals and humans. However, relatively little is known about the effects of glyphosate on the immune system of fish. In the present study, the acute toxicity of glyphosate on common carp was first determined; then, the contents of interferon-gamma (IFN gamma), interleukin-1beta (IL-1beta), and tumor necrosis factor -alpha (TNF alpha) and histopathological alterations in the liver, kidneys, and spleen of common carp exposed to 52.08 or 104.15 mg L(-1) of glyphosate for 168 h were also determined and evaluated. The results of the acute toxicity tests showed that the 96 h LC50 of glyphosate for common carp was 520.77 mg L(-1). Moreover, sub-acute exposure of glyphosate altered the contents of IFN-gamma, IL-1beta, and TNF-alpha in fish immune organs. For example, there was a remarkable increase in the IFN gamma content in the kidneys, while there was a decrease in the liver and spleen. The IL-1beta content increased in liver and kidneys, but it decreased in the spleen, and TNF-alpha mainly increased in the fish liver, kidneys, and spleen. In addition, glyphosate-exposure also caused remarkable histopathological damage in the fish liver, kidneys, and spleen. These results suggest that glyphosate-caused cytokine alterations may result in an immune suppression or excessive activation in the treated common carp as well as may cause immune dysfunction or reduced immunity. In conclusion, glyphosate has immunotoxic effects on common carp. PMID- 25747156 TI - The HR96 activator, atrazine, reduces sensitivity of D. magna to triclosan and DHA. AB - HR96 is a CAR/PXR/VDR ortholog in invertebrates, and a promiscuous endo- and xenobiotic nuclear receptor involved in acclimation to toxicants. Daphnia HR96 is activated by chemicals such as atrazine and linoleic acid (LA) (n-6 fatty acid), and inhibited by triclosan and docosahexaenoic acid (DHA) (n-3 fatty acid). We hypothesized that inhibitors of HR96 may block the protective responses of HR96 based on previously performed luciferase assays. Therefore, we performed acute toxicity tests with two-chemical mixtures containing a HR96 inhibitor (DHA or triclosan) and a HR96 activator (LA or atrazine). Surprisingly, results demonstrate that triclosan and DHA are less toxic when co-treated with 20-80 MUM atrazine. Atrazine provides concentration-dependent protection as lower concentrations have no effect and higher concentrations cause toxicity. LA, a weaker HR96 activator, did not provide protection from triclosan or DHA. Atrazine's protective effects are presumably due to its ability to activate HR96 or other toxicologically relevant transcription factors and induce protective enzymes. Atrazine did not significantly induce glucosyltransferase, a crucial enzyme in triclosan detoxification. However, atrazine did increase antioxidant activities, crucial pathways in triclosan's toxicity, as measured through GST activity and the TROLOX equivalence assay. The increase in antioxidant capacity is consistent with atrazine providing protection from a wide range of toxicants that induce ROS, including triclosan and unsaturated fatty acids predisposed to lipid peroxidation. PMID- 25747157 TI - Can acupuncture treatment be double-blinded? An evaluation of double-blind acupuncture treatment of postoperative pain. AB - Blinding protects against bias but the success of blinding is seldom assessed and reported in clinical trials including studies of acupuncture where blinding represents a major challenge. Recently, needles with the potential for double blinding were developed, so we tested if acupuncture can be double-blinded in a randomized study of sixty-seven patients with acute pain >= 3 (0-10 scale following third molar removal) who received active acupuncture with a penetrating needle or placebo acupuncture with a non-penetrating needle. To test if acupuncture was administered double-blind, patients and acupuncturists were asked about perceived treatment allocation at the end of the study. To test if there were clues which led to identification of the treatment, deep dull pain associated with needle application and rotation (termed "de qi" in East Asian medicine), and patients' pain levels were assessed. Perceived treatment allocation depended on actual group allocation (p < 0.015) for both patients and acupuncturists, indicating that the needles were not successful in double blinding. Up to 68% of patients and 83% of acupuncturists correctly identified the treatment, but for patients the distribution was not far from 50/50. Also, there was a significant interaction between actual or perceived treatment and the experience of de qi (p = 0.027), suggesting that the experience of de qi and possible non-verbal clues contributed to correct identification of the treatment. Yet, of the patients who perceived the treatment as active or placebo, 50% and 23%, respectively, reported de qi. Patients' acute pain levels did not influence the perceived treatment. In conclusion, acupuncture treatment was not fully double-blinded which is similar to observations in pharmacological studies. Still, the non-penetrating needle is the only needle that allows some degree of practitioner blinding. The study raises questions about alternatives to double blind randomized clinical trials in the assessment of acupuncture treatment. PMID- 25747158 TI - Cancer vaccines: can they improve survival? AB - In patients with metastatic cancer, therapeutic anticancer vaccines are rarely associated with objective antitumor responses; so, many investigators have focused on progression-free survival (PFS) as a key endpoint for clinical trials. However, it is not clear that PFS is a surrogate for overall survival (OS), and OS may be a more appropriate endpoint because of the effects on long-term memory in the adaptive immune system. Recently, reported vaccine trials were reviewed to determine their primary and secondary endpoints and results. Randomized trials testing sipuleucel-T and prostvac-vf in prostate cancer and ipilimumab and eltrapuldencel-T in melanoma were associated with low objective response rates, no improvement in PFS, but statistically significant improvement in OS. Although compared with PFS, it takes longer to get a final result when OS is the primary endpoint; there is increasing evidence that if long-term memory recognition of tumor-associated antigens is the mechanism of action of an investigational product, then OS may be the only valid clinical endpoint for efficacy. PMID- 25747159 TI - Comments on "Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: a meta-analysis of randomized controlled trials". PMID- 25747160 TI - Correction: The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload. PMID- 25747161 TI - Evaluation of a new technique for preparation of endothelial grafts for descemet membrane endothelial keratoplasty. AB - PURPOSE: The purpose of this study was to compare the Muraine technique, a relatively new method for preparing endothelial grafts for Descemet membrane endothelial keratoplasty (DMEK), with the current standard submerged cornea using backgrounds away (SCUBA) peeling technique. METHODS: This study was a prospective ex vivo investigation. In a wet-lab setting, 20 donor corneas were prepared for DMEK using The Muraine technique and 20 donor corneas using the SCUBA technique. In each of the technique groups, 10 corneas were prepared by a corneal surgeon and 10 were prepared by a corneal fellow. Primary outcome measures were the time needed to prepare endothelial grafts and the number of graft tears. RESULTS: In the SCUBA technique, median time to prepare grafts was shorter for both the surgeon (301 +/- 85 seconds) and fellow (523 +/- 58 seconds) compared with the Muraine technique (surgeon, 359 +/- 83 seconds; fellow, 543 +/- 44 seconds). However, these findings were not statistically significant (surgeon, P = 0.33; fellow, P = 0.24; pooled, P = 0.46). There was a statistically significant difference between surgeon time and fellow time for each technique (SCUBA technique, P = 0.0005; Muraine technique, P = 0.002). In the Muraine technique, there were 5 graft tears (surgeon = 2, fellow = 3), and no graft tears in the SCUBA technique, which was statistically significant (P = 0.047). CONCLUSIONS: The present study demonstrates that the SCUBA technique may be a more effective technique to prepare endothelial donor grafts for DMEK. PMID- 25747162 TI - Corneal biomechanical properties in floppy eyelid syndrome. AB - PURPOSE: To determine corneal biomechanical properties in patients with floppy eyelid syndrome (FES) and to compare them with eyes of controls. METHODS: This case-control study included 208 eyes (72 eyes with FES and 136 without FES) of 107 patients (37 patients with FES and 70 without FES). Patients underwent a complete clinical eye examination that included corneal biomechanical evaluation carried out with the Reichert Ocular Response Analyzer. RESULTS: Corneal hysteresis (CH), corneal resistance factor (CRF), central corneal thickness (CCT), Goldmann-correlated intraocular pressure (IOPg), and corneal-compensated intraocular pressure (IOPcc) were evaluated. Mean CH was significantly lower in patients with FES than in those without FES (9.51 +/- 1.56 vs. 11.66 +/- 9.11; P < 0.001). These results remained statistically significant after adjusting for age and apnea-hypoapnea index (AHI) (P = 0.028). Mean CRF was 10.02 +/- 2.08 in the group of patients with FES and 11.21 +/- 5.36 in the group of patients without FES (P = 0.001). Mean IOPcc was 17.7 +/- 4.8 in patients with FES and 16.3 +/- 4.4 in those without FES (P = 0.036). After adjusting for age and AHI, these differences in CRF and IOPcc were not statistically significant (P = 0.26 and P = 0.87, respectively). No statistically significant difference was found between patients with and without FES for Goldmann-correlated intraocular pressure or CCT. CONCLUSIONS: Patients with FES had statistically lower CH values. Our findings suggest that corneal biomechanical properties could be changed in patients with FES, reflecting additional structural changes in FES. PMID- 25747163 TI - Identification of corneal neovascularization-related long noncoding RNAs through microarray analysis. AB - PURPOSE: To reveal the role of long noncoding RNAs (lncRNAs) in corneal neovascularization (CN). METHODS: We established a murine CN model and performed lncRNA expression profiling to identify differentially expressed lncRNAs between normal and vascularized corneas. Based on Pearson correlation analysis, an lncRNA/mRNA coexpression network was constructed. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of lncRNA-coexpressed mRNAs were conducted to determine the related biological modules and pathological pathways. Real-time polymerase chain reactions were carried out to detect the expression pattern of lncRNA in the clinical samples. RESULTS: A total of 154 differentially expressed lncRNAs were identified between vascularized and normal corneas, including 60 downregulated lncRNAs and 94 upregulated lncRNAs. GO enrichment analysis of lncRNA-coexpressed mRNAs indicated that the biological modules were correlated with extracellular region, DNA binding, and immune response. KEGG pathway analysis indicated that "pathways in cancer" was the most enriched signaling pathway. Moreover, the human ortholog of NR_033585 and lincRNA:chr8:129102060-129109035 reverse strand was found to be differentially expressed between vascularized and avascular corneas. CONCLUSIONS: This study provides a novel insight into CN pathogenesis. The intervention of dysregulated lncRNAs may become potential targets for the prevention and treatment of ocular vascular diseases. PMID- 25747164 TI - Bilateral ectasia after femtosecond laser-assisted small-incision lenticule extraction. AB - This case report describes clinical and topographic features of bilateral corneal ectasia after femtosecond laser-assisted small-incision lenticule extraction. The case suggests that patients with preoperative forme fruste keratoconus or early keratoconus might develop significant progression of corneal ectasia after the small-incision lenticule extraction procedure and shows that the procedure can affect the corneal biomechanics. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. PMID- 25747165 TI - Interface quality of different corneal lamellar-cut depths for femtosecond laser assisted lamellar anterior keratoplasty. AB - PURPOSE: To evaluate the interface quality of different corneal lamellar-cut depths with the femtosecond laser and determine a feasible range of depth for femtosecond laser-assisted lamellar anterior keratoplasty. SETTING: Casey Eye Institute, Portland, Oregon, USA. DESIGN: Experimental study. METHODS: Full lamellar cuts were made on 20 deepithelialized human cadaver corneas using the femtosecond laser. The cut depth was 17% to 21% (100 MUm), 31%, 35%, 38% to 40%, and 45% to 48% of the central stromal thickness. Scanning electron microscopy images of the cap and bed surfaces were subjectively graded for ridge and roughness using a scale of 1 to 5 (1 = best). The graft-host match was evaluated by photography and optical coherence tomography in a simulated procedure. RESULTS: The ridge score was correlated with the cut depth (P = .0078, R = 0.58) and better correlated with the percentage cut depth (P = .00024, R = 0.73). The shallowest cuts had the fewest ridges (score 1.25). The 31% cut depth produced significantly fewer ridges (score 2.15) than deeper cuts. The roughness score ranged from 2.19 to 3.08 for various depths. A simulated procedure using a 100 MUm host cut and a 177 MUm (31%) graft had a smooth interface and flush anterior junction using an inverted side-cut design. CONCLUSIONS: The femtosecond laser produced more ridges in deeper lamellar cuts. A depth setting of 31% stromal thickness might produce adequate surface quality for femtosecond laser-assisted lamellar anterior keratoplasty. The inverted side-cut design produced good edge apposition even when the graft was thicker than the host lamellar-cut depth. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 25747166 TI - Effect of increased vacuum and aspiration rates on phacoemulsification efficiency. AB - PURPOSE: To evaluate the effect of vacuum and aspiration rates on phacoemulsification efficiency. SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Formalin-soaked porcine lenses were divided into 2.0 mm cubes, and 0.9 mm 30-degree beveled 20-degree bent tips were used with micropulse ultrasound (US) (6 milliseconds on and 6 milliseconds off) and a peristaltic flow system. Vacuum levels were tested at 200, 300, 400, and 500 mm Hg, and aspiration rates were tested at 20, 35, and 50 mL/min. Efficiency (time to lens removal) and chatter (number of lens fragment repulsions from the tip) were determined. RESULTS: Increasing vacuum increased efficiency only when going from 200 mm Hg to higher vacuum levels. Increasing aspiration increased efficiency at all points measured (25 mL/min versus 35 mL/min, P < .0001; 35 mL/min versus 50 mL/min, P = .012; 25 mL/min versus 50 mL/min, P < .0001). Chatter was highest at 200 mm Hg and decreased when vacuum was increased from 200 mm Hg to 300 mm Hg and up. Chatter decreased with increasing flow. CONCLUSIONS: Vacuum improved efficiency only up to 300 mm Hg and was more dependent on increasing flow. Similarly, chatter correlated with 200 mm Hg vacuum only and was more correlated with flow. Limitations of this study include use of only 1 US power modulation and hard nuclear material. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25747168 TI - [A systematic review of intervention programs for frail elderly people enrolled in the Japanese social long-term care insurance system]. AB - OBJECTIVES: The aim of this study was to systematically review intervention programs for frail elderly people enrolled in the Japanese social long-term care insurance system to clarify the effects and identify any problems. METHODS: We reviewed 61 articles (7 in English and 54 in Japanese) from four databases: MEDLINE, CINAHL, PsycInfo, and "Igaku Chuo Zasshi Web" (the Japana Centra Revuo Medicina) version 5. We focused on the following three areas: age and male/female ratio of participants, study design, and intervention program. RESULTS: The results showed that (1) participants tended to be >=75 years of age and female, (2) more than half of the programs were of a before and after design, and (3) most interventions took place in local community centers and were group programs for muscle training and/or physical exercise that improved physical function. CONCLUSION: Future studies focusing on the following intervention programs are necessary: individual programs such as home visits for those who do not want to participate in group programs and programs that improve instrumental activities of daily living, nutrition, oral function, cognitive function, and depression. Additionally, while there are many studies reporting the effect of muscle training and exercise, randomized controlled studies are necessary to more accurately evaluate the effects. PMID- 25747167 TI - Electrical remodeling reflected by QRS and T vector changes following cardiac resynchronization therapy is related to survival in heart failure patients with left bundle branch block. AB - INTRODUCTION: We investigated changes in electrocardiographic spatial QRS and T vectors as markers of electrical remodeling before and after cardiac resynchronization therapy (CRT) and their association with altered outcome. METHODS AND RESULTS: In 41 patients with LBBB, ECGpost was recorded during intrinsic rhythm after interrupting CRT pacing and compared to the pre-implant ECGpre and the ECG during CRT (ECGCRT). Mean spatial angles between QRS and T vectors were determined with the Kors matrix conversion. Left ventricular ejection fraction (LVEF) was determined with nuclear isotope ventriculography before CRT implantation (LVEFpre) and at inclusion (LVEFpost). Following CRT, LVEF improved significantly from 26 +/- 10 to 36 +/- 14% (p=0.01). Duration of QRSpre (168 +/- 15 ms) was not different from QRSpost (166 +/- 15 ms). A smaller angle between QRSCRT and Tpost was related to a greater angle between Tpre and Tpost (Pearson's R -0.61 - p<0.001). During follow-up (30 +/- 2 months) 9 patients (22%) died. Univariate Cox regression revealed higher mortality in the patients with lower LVEFpost (HR 1.10, p=0.01), a larger angle QRSCRTTpost (HR 1.03, p=0.03), a smaller angle QRSpreQRSpost (HR 0.97, p=0.03) and smaller angle TpreTpost (HR 0.95, p<0.01). After adjusting for LVEFpost, only smaller angle TpreTpost was associated with mortality (HR 0.96, p=0.03). CONCLUSIONS: Electrical remodeling can be quantified by measuring the angles between spatial QRS and T vectors before, during and after CRT. In absence of QRS duration changes, more extensive electrical remodeling is associated with a significantly better survival. QRS and T vector changes deserve further investigation to better understand the individual response to CRT. PMID- 25747169 TI - [Characteristics and related factors of individuals who refuse the support of health and welfare professionals]. AB - OBJECTIVES: Health and welfare professionals experience difficulties during their casework on individuals in the community. The purpose of this study was to identify the characteristics and related factors of those in the community who refuse the support of health and welfare professionals. METHODS: Since 2006, based on a signed research agreement between researchers and local government office A, the series of psychiatric consultation services was initiated for healthcare professionals who experienced difficulties in carrying out their casework on individuals in the community. Data were acquired from local government office A and included the patient's basic attributes, family-related factors, psychiatric factors, and problematic behaviors. Additionally, information on whether individuals refused support was obtained. The data did not include private information. To investigate risk factors for refusing healthcare professional support, 372 profiles of patients who underwent consultation services from 2006 to 2012, were analyzed by logistic regression analysis. RESULTS: Among 309 persons, only 102 (33.0%) accepted support from health and welfare professionals, and 207 (67.0%) persons refused support. Logistic regression analysis revealed that individuals in the community who received welfare benefits (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.02-3.39), refused medication (OR=2.07, 95%CI=1.10-3.90), or used abusive language towards healthcare professionals (OR=1.97, 95%CI=1.09-3.55) were more likely to refuse support from health and welfare professionals. CONCLUSION: The results indicate that individuals in the community who refused support of health and welfare professionals tend to have a worsening condition and a greater need for crisis intervention than those who did not refuse support. PMID- 25747170 TI - [Cancer treatment situation in Japan with regard to the type of medical facility using medical claim data of Health Insurance Societies]. AB - OBJECTIVES: Analyzing the cancer treatment situation in Japan is an important public health issue, especially because of increasing crude cancer morbidity in a rapidly aging society. This study aimed to examine where cancer patients received treatment, with special attention to designated regional cancer hospitals, and the treatment modality they received. METHODS: Using health insurance claim data (1,064,875 subjects on December 2011) managed by the Japan Medical Data Center, we included patients that received treatments for stomach, colon, liver, lung, or breast cancer, the most common cancers in Japan, between 2005 and 2011. We divided the medical facilities where they were treated into five groups: prefectural designated regional cancer hospitals, local designated regional cancer hospitals, large/medium hospitals (>=100 beds), small hospitals (20-99 beds), and clinics (0-19 beds). We calculated the percentage of patients treated at each type of medical facility with different treatment modalities. RESULTS: The study included 2,901 patients. In total, 43.9% patients were treated at designated regional cancer hospitals (prefectural or local). This percentage was the highest for lung cancer (60.0%) and the lowest for colon cancer (31.3%). Surgeries for liver cancer (67.6%) and lung cancer (61.9%) were performed more at designated regional cancer hospitals (prefectural or local) than surgeries for stomach cancer (45.5%), colon cancer (40.1%), and breast cancer (49.8%). Some procedures were performed at small hospitals or clinics (surgery for stomach cancer [9.4%], surgery for breast cancer [9.3%], endoscopic procedures for stomach cancer [14.1%] and colon cancer [40.6%], and chemotherapy for breast cancer [11.4%]). Colon and breast cancer patients treated at prefectural designated regional cancer hospitals or clinics were younger than those treated at other types of facilities. CONCLUSION: The distribution of facilities at which cancer patients received treatment differed significantly according to cancer site, treatment modality, and patient age. PMID- 25747171 TI - Integrated development of up- and downstream processes supported by the Cherry TagTM for real-time tracking of stability and solubility of proteins. AB - Product analytics is the bottleneck of most processes in bioprocess engineering, as it is rather time-consuming. Real-time and in-line product tracing without sample pre-treatment is only possible for few products. The Cherry-TagTM (Delphi Genetics, Belgium) which can be fused to any target protein allows for straightforward product analytics by VIS absorption measurements. When the fused protein becomes unstable or insoluble, the chromophore function of the group is lost, which makes this technology an ideal screening tool for solubility and stability in up- and downstream process development. The Cherry-TagTM technology will be presented for the tagged enzyme glutathione-S-transferase (GST) from Escherichia coli in a combined up- and downstream process development study. High throughput cultivations were carried out in a 48-well format in a BioLector system (m2p-Labs, Germany). The best cultivation setup of highest product titer was scaled up to a 2.5L shake flask culture, followed by a selective affinity chromatography product capturing step. In upstream applications the tag was capable of identifying conditions where insoluble and non-native inclusion bodies were formed. In downstream applications the red-colored product was found to be bound effectively to a GST affinity column. Thus, it was identified to be a native and active protein, as the binding mechanism relies on catalytic activity of the enzyme. The Cherry-TagTM was found to be a reliable and quantitative tool for real-time tracking of stable and soluble proteins in up- and downstream processing applications. Denaturation and aggregation of the product can be detected in-line at any stage of the process. Critical stages can be identified and subsequently changed or replaced. PMID- 25747172 TI - Purification of monoclonal antibodies from clarified cell culture fluid using Protein A capture continuous countercurrent tangential chromatography. AB - Recent studies using simple model systems have demonstrated that continuous countercurrent tangential chromatography (CCTC) has the potential to overcome many of the limitations of conventional Protein A chromatography using packed columns. The objective of this work was to optimize and implement a CCTC system for monoclonal antibody purification from clarified Chinese Hamster Ovary (CHO) cell culture fluid using a commercial Protein A resin. Several improvements were introduced to the previous CCTC system including the use of retentate pumps to maintain stable resin concentrations in the flowing slurry, the elimination of a slurry holding tank to improve productivity, and the introduction of an "after binder" to the binding step to increase antibody recovery. A kinetic binding model was developed to estimate the required residence times in the multi-stage binding step to optimize yield and productivity. Data were obtained by purifying two commercial antibodies from two different manufactures, one with low titer (~ 0.67 g/L) and one with high titer (~ 6.9 g/L), demonstrating the versatility of the CCTC system. Host cell protein removal, antibody yields and purities were similar to those obtained with conventional column chromatography; however, the CCTC system showed much higher productivity. These results clearly demonstrate the capabilities of continuous countercurrent tangential chromatography for the commercial purification of monoclonal antibody products. PMID- 25747174 TI - Commentary on 'peripheral artery disease: a marked lack of awareness in Ireland'. PMID- 25747173 TI - Differential impact of bypass surgery and angioplasty on angiosome-targeted infrapopliteal revascularization. AB - OBJECTIVE: The aim of this study was to evaluate the impact of angiosome targeted revascularization according to the revascularization method. DESIGN: Retrospective observational study. MATERIALS AND METHODS: This study cohort comprised 744 consecutive patients who underwent infrapopliteal endovascular or surgical revascularization between January 2010 and July 2013. Differences in outcomes after bypass surgery and PTA were adjusted by estimating a propensity score, which was employed for one to one matching as well as adjusted analysis. RESULTS: Cox proportional hazards analysis showed that angiosome-targeted revascularization (HR 1.29, 95% CI 1.02-1.65), bypass surgery (HR 1.79, 95% CI 1.41-2.27), C-reactive protein <=10 mg/dL (HR 1.42, 95% CI 1.11-1.81), and the number of affected angiosomes (HR 0.85, 95% CI 0.74-0.98) were independent predictors of improved wound healing. When adjusted for the number of affected angiosomes and C-reactive protein <=10 mg/dL, angiosome-targeted bypass surgery was associated with a significantly higher rate of wound healing than non angiosome-targeted angioplasty (HR 2.27, 95% CI 1.61-3.20). This was confirmed in propensity score adjusted analysis (HR 1.72, 95% CI 1.35-2.16). Among patients who underwent angiosome-targeted revascularization, the propensity score adjusted analysis showed that bypass surgery was associated with a significantly better rate of wound healing (HR 154, 95% CI 1.09-2.16) but similar limb salvage rates when compared with angioplasty (HR 0.79, 95% CI 0.44-1.43). CONCLUSION: Rates of wound healing and limb salvage in patients with critical limb ischemia (CLI) were significantly better after angiosome-targeted revascularization, bypass surgery achieving significantly better wound healing than angioplasty. PMID- 25747175 TI - Treatment of postparotidectomy Frey syndrome with the interposition of temporalis fascia and sternocleidomastoid flaps. AB - OBJECTIVES: This study was performed to evaluate the effectiveness of overlapping the temporalis fascia flaps (TFFs) and the sternocleidomastoid muscle flaps (SCMFs) as physical barriers to treat established Frey syndrome and concavity after parotidectomy. STUDY DESIGN: We retrospectively reviewed 17 patients who underwent corrective procedures with simultaneous TFF and SCMF interposition for the treatment of Frey syndrome. The affected areas of the cheek skin were identified with starch-iodine tests. The facial contours of the patients were classified as bilaterally symmetric (BS), with a slightly shallow (SS) contour on the surgical side, or with a conspicuously shallow (CS) contour on the surgical side. RESULTS: The sample was followed up for a mean of 22 months. The average area of gustatory-sweating positive skin was reduced from 12.80 to 1.32 square centimeters postoperatively. The facial asymmetry secondary to parotidectomy was greatly improved. CONCLUSIONS: The authors concluded that this technique was efficacious in ameliorating Frey syndrome and facial concavity secondary to parotidectomy. PMID- 25747178 TI - Prevalence and determinants of the gender differentials risk factors of child deaths in Bangladesh: evidence from the Bangladesh demographic and health survey, 2011. AB - BACKGROUND: The number of child deaths is a potential indicator to assess the health condition of a country, and represents a major health challenge in Bangladesh. Although the country has performed exceptionally well in decreasing the mortality rate among children under five over the last few decades, mortality still remains relatively high. The main objective of this study is to identify the prevalence and determinants of the risk factors of child mortality in Bangladesh. METHODS: The data were based on a cross-sectional study collected from the Bangladesh Demographic and Health Survey (BDHS), 2011. The women participants numbered 16,025 from seven divisions of Bangladesh - Rajshahi, Dhaka, Chittagong, Barisal, Khulna, Rangpur and Sylhet. The ??2 test and logistic regression model were applied to determine the prevalence and factors associated with child deaths in Bangladesh. RESULTS: In 2011, the prevalence of child deaths in Bangladesh for boys and girls was 13.0% and 11.6%, respectively. The results showed that birth interval and birth order were the most important factors associated with child death risks; mothers' education and socioeconomic status were also significant (males and females). The results also indicated that a higher birth order (7 & more) of child (OR=21.421 & 95%CI=16.879-27.186) with a short birth interval <= 2 years was more risky for child mortality, and lower birth order with longer birth interval >2 were significantly associated with child deaths. Other risk factors that affected child deaths in Bangladesh included young mothers of less than 25 years (mothers' median age (26-36 years): OR=0.670, 95%CI=0.551-0.815), women without education compared to those with secondary and higher education (OR =0 .711 & .628, 95%CI=0.606-0.833 & 0.437 0.903), mothers who perceived their child body size to be larger than average and small size (OR= 1.525 & 1.068, 95%CI=1.221-1.905 & 0.913-1.249), and mothers who delivered their child by non-caesarean (OR= 1.687, 95%CI=1.253-2.272). CONCLUSION: Community-based educational programs or awareness programs are required to reduce the child death in Bangladesh, especially for younger women should be increase the birth interval and decrease the birth order. The government should apply the strategies to enhance the socioeconomic conditions, especially in rural areas, increase the awareness program through media and expand schooling, particularly for girls. PMID- 25747176 TI - CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: a tissue microarray study. AB - OBJECTIVE: Squamous cell carcinoma of the oral tongue (SCCOT) exhibits high risk for recurrence and regional metastasis even after surgical resection. We assessed the clinicopathologic and prognostic significance of a group of functionally related biomarkers. STUDY DESIGN: We used a tissue microarray consisting of SCCOT from 32 patients for this study. These patients were treated at the University of Texas MD Anderson Cancer Center from 1995 to 2008. Biomarker expression levels were examined by immunohistochemistry and graded semiquantitatively to determine their prognostic significance. RESULTS: CD147 and Tp63 expressions were significantly associated with a higher T stage and Ki-67 labeling index, as well as a shorter overall survival (OS) rate. Expression of Tp63 associated positively with poorly differentiated histology. There was significant association of Tp63 with the expression levels of CD147 and Glut-1. Glut-1 overexpression was marginally associated with a higher T stage. There was no prognostic significance of CD44 v6 expression in SCCOT. CONCLUSION: SCCOT with CD147 overexpression in combination with high Ki-67 labeling index had poor OS. CD147 and Ki-67 overexpression is associated with aggressive disease with poor prognosis in SCCOT. PMID- 25747177 TI - Polymorphous low-grade adenocarcinoma of the upper lip: 11 cases of an uncommon diagnosis. AB - OBJECTIVE: The aim of this case study was to describe an international case series of polymorphous low-grade adenocarcinoma (PLGA) affecting the upper lip. MATERIAL AND METHODS: Over a 30-year-period, the files of five pathology services were reviewed for PLGA affecting the upper lip. Hematoxylin and eosin-stained slides were reviewed by three oral and maxillofacial pathologists, and microscopic features were described. Clinical data were retrieved from patients' medical records. RESULTS: The review identified 11 cases of upper lip PLGAs, with a complete set of clinical data available for 5 cases. There was a male predominance (1.2:1), and the mean age was 58.7 years. Most cases presented as small asymptomatic swellings that resembled benign tumors. All patients underwent surgery, and no recurrences or metastases were reported in the 8 cases from which follow-up data were available. Microscopically, the typical polymorphic architectural arrangement of PLGA was seen in all cases, with lobular, trabecular, papillary, and cribriform patterns identified. Perineural invasion, normal gland entrapment, Indian filing, and concentric growth were frequently identified. CONCLUSION: PLGA must be included in the list of differential diagnoses of tumors affecting the upper lip because of its similar clinical presentation to benign entities. The follow-up data available from 8 of 11 cases suggest that these tumors follow a low-grade clinical course, similar to the majority of palatal cases of PLGA. PMID- 25747179 TI - A new systematic framework for crystallographic analysis of atom probe data. AB - In this article, after a brief introduction to the principles behind atom probe crystallography, we introduce methods for unambiguously determining the presence of crystal planes within atom probe datasets, as well as their characteristics: location; orientation and interplanar spacing. These methods, which we refer to as plane orientation extraction (POE) and local crystallography mapping (LCM) make use of real-space data and allow for systematic analyses. We present here application of POE and LCM to datasets of pure Al, industrial aluminium alloys and doped-silicon. Data was collected both in DC voltage mode and laser-assisted mode (in the latter of which extracting crystallographic information is known to be more difficult due to distortions). The nature of the atomic planes in both datasets was extracted and analysed. PMID- 25747180 TI - Scanning electron microscope measurement of width and shape of 10nm patterned lines using a JMONSEL-modeled library. AB - The width and shape of 10nm to 12 nm wide lithographically patterned SiO2 lines were measured in the scanning electron microscope by fitting the measured intensity vs. position to a physics-based model in which the lines' widths and shapes are parameters. The approximately 32 nm pitch sample was patterned at Intel using a state-of-the-art pitch quartering process. Their narrow widths and asymmetrical shapes are representative of near-future generation transistor gates. These pose a challenge: the narrowness because electrons landing near one edge may scatter out of the other, so that the intensity profile at each edge becomes width-dependent, and the asymmetry because the shape requires more parameters to describe and measure. Modeling was performed by JMONSEL (Java Monte Carlo Simulation of Secondary Electrons), which produces a predicted yield vs. position for a given sample shape and composition. The simulator produces a library of predicted profiles for varying sample geometry. Shape parameter values are adjusted until interpolation of the library with those values best matches the measured image. Profiles thereby determined agreed with those determined by transmission electron microscopy and critical dimension small-angle x-ray scattering to better than 1 nm. PMID- 25747181 TI - Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis of Cryptococcus humicola response to aluminum stress. AB - Cryptococcus humicola is a highly aluminum (Al) tolerant yeast strain isolated from a tea field. Here the relative changes of protein expression in C. humicola undergoing aluminum stress were analyzed to understand the genetic basis of aluminum tolerance. In this work, iTRAQ-based (isobaric tags for relative and absolute quantification) quantitative proteomic technology was used to detect statistically significant proteins associated with the response to aluminum stress. A total of 625 proteins were identified and were mainly involved in translation/ribosomal structure and biogenesis, posttranslational modification/protein turnover/chaperones, energy production and conversion, and amino acid transport and metabolism. Of these proteins, 59 exhibited differential expression during aluminum stress. Twenty-nine proteins up-regulated by aluminum were mainly involved in translation/ribosomal structure and biogenesis, posttranslational modification/protein turnover and chaperones, and lipid transport and metabolism. Thirty proteins down-regulated by aluminum were mainly associated with energy transport and metabolism, translation/ribosomal structure and biogenesis, posttranslational modification/protein turnover/chaperones, and lipid transport and metabolism. The potential functions of some proteins in aluminum tolerance are discussed. These functional changes may be beneficial for cells to protect themselves from aluminum toxic conditions. PMID- 25747183 TI - An integrated approach of bioassay and molecular docking to study the dihydroxylation mechanism of pyrene by naphthalene dioxygenase in Rhodococcus sp. ustb-1. AB - Naphthalene dioxygenase (NDO) is the initial enzyme catalyzing the biodegradation of aromatic compounds, and it plays a key role in microbial remediation of polluting sites. In this study, Rhodococcus sp. ustb-1 derived from crude oil was selected to investigate the biodegradation characters and dihydroxylation mechanism of pyrene by an integrated approach of bioassay and molecular docking. The biodegradation experiment proved that the strain ustb-1 shows high effective biodegradability to pyrene with a 70.8% degradation on the 28th day and the metabolite pyrene cis-4,5-dihydrodiol was found. The results of molecular docking indicated that the regions surrounding pyrene are defined by hydrophobic amino acids which are favorable for the binding of dioxygen molecule at C4 and C5 positions of pyrene in a side-on mode. The binding positions of dioxygen are in agreement with the mass spectral analysis of the metabolite pyrene cis-4,5 dihydrodiol. In summary, this study provides a promising explanation for the possible binding behavior between pyrene and active site of NDO. PMID- 25747185 TI - Leveraging "big data" to enhance the effectiveness of "one health" in an era of health informatics. AB - Zoonoses constitute 61% of all known infectious diseases. The major obstacles to control zoonoses include insensitive systems and unreliable data. Intelligent handling of the cost effective big data can accomplish the goals of one health to detect disease trends, outbreaks, pathogens and causes of emergence in human and animals. PMID- 25747184 TI - Recruitment of the prefrontal cortex and cerebellum in Parkinsonian rats following skilled aerobic exercise. AB - Exercise modality and complexity play a key role in determining neurorehabilitative outcome in Parkinson's disease (PD). Exercise training (ET) that incorporates both motor skill training and aerobic exercise has been proposed to synergistically improve cognitive and automatic components of motor control in PD patients. Here we introduced such a skilled aerobic ET paradigm in a rat model of dopaminergic deafferentation. Rats with bilateral, intra-striatal 6-hydroxydopamine lesions were exposed to forced ET for 4weeks, either on a simple running wheel (non-skilled aerobic exercise, NSAE) or on a complex wheel with irregularly spaced rungs (skilled aerobic exercise, SAE). Cerebral perfusion was mapped during horizontal treadmill walking or at rest using [(14)C] iodoantipyrine 1week after the completion of ET. Regional cerebral blood flow (rCBF) was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains by statistical parametric mapping. SAE compared to NSAE resulted in equal or greater recovery in motor deficits, as well as greater increases in rCBF during walking in the prelimbic area of the prefrontal cortex, broad areas of the somatosensory cortex, and the cerebellum. NSAE compared to SAE animals showed greater activation in the dorsal caudate-putamen and dorsal hippocampus. Seed correlation analysis revealed enhanced functional connectivity in SAE compared to NSAE animals between the prelimbic cortex and motor areas, as well as altered functional connectivity between midline cerebellum and sensorimotor regions. Our study provides the first evidence for functional brain reorganization following skilled aerobic exercise in Parkinsonian rats, and suggests that SAE compared to NSAE results in enhancement of prefrontal cortex- and cerebellum-mediated control of motor function. PMID- 25747186 TI - Association between worldwide dietary and lifestyle patterns with total cholesterol concentrations and DALYs for infectious and cardiovascular diseases: an ecological analysis. AB - Global dietary and lifestyle trends are primary risk factors for communicable and non-communicable diseases. An ecological analysis was conducted to examine the association of global dietary and lifestyle patterns with total cholesterol concentrations. This study also investigated whether total cholesterol modified the association between dietary and lifestyle habits with disability-adjusted life-years-lost (DALYs) for infectious and cardiovascular diseases (CVDs). Country-specific mean total cholesterol concentrations and DALYs for infectious and CVDs were obtained. Data were then matched to country-specific food and energy availability for consumption and information on obesity, physical inactivity, urbanization, gross domestic product (GDP), life expectancy and smoking. Stepwise multiple regression models were developed to identify significant predictors of total cholesterol concentrations and DALYs for infectious and CVDs. Life expectancy and egg and meat consumption were significantly associated with cholesterol concentrations. DALYs for infectious diseases were associated with smoking, life expectancy and per capita GDP. Smoking was the only predictor of DALYs for CVDs. The improvement of socio demographic conditions and economic growth is likely to reduce the burden of communicable diseases in developing countries. A concurring increase in non communicable diseases is expected, and these results have, yet again, identified smoking as a primary risk factor for CVDs. PMID- 25747187 TI - The effect of relaxing music on heart rate and heart rate variability during ECG GATED-myocardial perfusion scintigraphy. AB - BACKGROUND: The positive changes in human behavior caused by relaxing music demonstrate the psychological effect of music on human body. A meta-analytical study has shown that relaxing music affects blood pressure and heart rate in coronary heart patients and cancer patients. The aim of our study is to research whether there is a significant effect on heart rate and heart rate variability due to listening to relaxing music during ECG GATED MPS imaging under gamma camera. METHOD: The music group (n = 50 patients) could choose from 15 different musical types including folk music (no lyric). The other 50 patients were placed in a "no music group" and did not get headphones or any music. RESULTS: There was a statistically significant reduction in the heart rate of patients in the music group compared to those in the control group. CONCLUSIONS: Relaxing music provides great benefits to both patient and clinician. There is close relationship between relaxing music and health procedure, can use every area of the health noninvasiv, safe, cheap and is a method don't have side effect. PMID- 25747188 TI - A missed opportunity: tophaceous gout. PMID- 25747189 TI - WITHDRAWN: Solve it Like Sherlock: Misplaced Electrodes. AB - This article has been withdrawn at the request of the Publisher. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25747190 TI - Treacherous Travelers: Emboli. PMID- 25747192 TI - The 126th regional meeting (kinki area). PMID- 25747193 TI - The 67th regional meeting (seinan area). PMID- 25747191 TI - A subdermal source: contact dermatitis. PMID- 25747195 TI - Two-trait random regression model to estimate the genetic association of scrotal circumference with female reproductive performance in Nelore cattle. AB - In an attempt to determine when scrotal circumference (SC) could be a reasonable indicator of female reproductive performance, a series of two-trait random regression model (regression for SC on age at measurement) using Gibbs sampling was applied to field data of Nelore cattle raised in a tropical environment. The female traits evaluated were age at first calving (AFC), first calving interval (FCI), heifer pregnancy (HP), and stayability (STAY). The posterior means of heritability of female traits ranged from 0.15 for AFC to 0.46 for HP and were about 0.50 for SC. The posterior means of genetic correlations between SC and AFC, FCI, HP, STAY were up to -0.70, -0.25, 0.48, and 0.29, respectively. Genetically, SC could be a reasonable indicator of female puberty (e.g., HP) as long as it is measured at a young age (400-440 days). However, for female reproductive traits measured at an older age (e.g., STAY), SC is merely a modest or even poor indicator. The use of sire expected progeny differences for female reproductive traits will be more effective than the use of expected progeny differences for SC to improve the reproductive performance of female cattle. PMID- 25747194 TI - Positive impact of sucrose supplementation during slow freezing of cat ovarian tissues on cellular viability, follicle morphology, and DNA integrity. AB - The objectives of the study were to (1) examine and optimize the impact of sucrose during slow freezing and (2) compare the results of two freezing methods (slow freezing and vitrification) on cellular viability (germinal and stromal cells), follicle morphology, DNA integrity, and gap junction protein expression (connexin 43 [Cx 43]). Different sucrose supplementations (0, 0.1, and 0.3 M) in standard freezing medium were compared before and after slow freezing. Ovarian tissue slow frozen using 0.1- (4.0 +/- 0.4) or 0.3-M sucrose (3.9 +/- 0.5) yielded better follicular viability (number of positive follicles per 0.0625 mm(2)) than the group without sucrose (1.9 +/- 0.2; P < 0.05). Morphologically normal primordial follicles were higher in the sucrose-treated groups (0.1 M, 47.4% and 0.3 M, 43.5%) than the group without sucrose (0 M, 33.8%; P < 0.05). Moreover, less apoptotic primordial follicles were found in both sucrose groups (0.1 M, 1.2% and 0.3 M, 1.9%) than the group without sucrose (7.7%; P < 0.05). However, their Cx 43 expression showed no difference among the groups of different sucrose concentrations. In terms of the freezing methods used, vitrified ovarian tissues had fewer viable follicles (3.2 +/- 0.6) than the slow freezing method (4.6 +/- 0.6; P < 0.05). In addition, the slow freezing resulted in more postthawed morphologically normal primordial follicles (38.8% vs. 28.3%, P < 0.05) and less apoptotic primordial follicles (3.8% vs. 8.9%, P < 0.05) than vitrification. The Cx 43 expression showed no difference between slow freezing and vitrification. The present study reported the positive effects of sucrose supplementation and slow-freezing method on the follicular viability, follicular histologic appearances of follicles, and apoptosis of the follicles and stromal cells in cat ovarian tissues. PMID- 25747196 TI - On the margins of health economics: a response to 'resolving NICE'S nasty dilemma'. AB - In a 2011 article published in this journal, Baker et al. set out to resolve a nasty dilemma for NICE by reconciling two approaches for determining whether adopting a new intervention would increase total health gains produced from available resources and hence increase system efficiency. In this response we show how the proposed reconciliation, as well as the two approaches on which it is based, fail to inform decision makers about the efficiency of a new intervention. We show how this arises from the misuse of incremental costs and effects of between-intervention comparisons as measures of changes in costs and effects associated with marginal adjustments to the scale of an intervention. Ironically, incremental data represent the choices faced by decision makers and we illustrate a method for determining unambiguously whether a new intervention represents an improvement in efficiency. PMID- 25747198 TI - Sliding mode based fault detection, reconstruction and fault tolerant control scheme for motor systems. AB - The fault-tolerant control problem belongs to the domain of complex control systems in which inter-control-disciplinary information and expertise are required. This paper proposes an improved faults detection, reconstruction and fault-tolerant control (FTC) scheme for motor systems (MS) with typical faults. For this purpose, a sliding mode controller (SMC) with an integral sliding surface is adopted. This controller can make the output of system to track the desired position reference signal in finite-time and obtain a better dynamic response and anti-disturbance performance. But this controller cannot deal directly with total system failures. However an appropriate combination of the adopted SMC and sliding mode observer (SMO), later it is designed to on-line detect and reconstruct the faults and also to give a sensorless control strategy which can achieve tolerance to a wide class of total additive failures. The closed-loop stability is proved, using the Lyapunov stability theory. Simulation results in healthy and faulty conditions confirm the reliability of the suggested framework. PMID- 25747197 TI - Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study. AB - INTRODUCTION: This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer. METHODS: Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint. RESULTS: In total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss >= 8.4 versus < 8.4 mg.h/mL), respectively. CONCLUSIONS: There was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00511459. PMID- 25747199 TI - Characterization of Avt1p as a vacuolar proton/amino acid antiporter in Saccharomyces cerevisiae. AB - Several genes for vacuolar amino acid transport were reported in Saccharomyces cerevisiae, but have not well been investigated. We characterized AVT1, a member of the AVT vacuolar transporter family, which is reported to be involved in lifespan of yeast. ATP-dependent uptake of isoleucine and histidine by the vacuolar vesicles of an AVT exporter mutant was lost by introducing avt1? mutation. Uptake activity was inhibited by the V-ATPase inhibitor: concanamycin A and a protonophore. Isoleucine uptake was inhibited by various neutral amino acids and histidine, but not by gamma-aminobutyric acid, glutamate, and aspartate. V-ATPase-dependent acidification of the vesicles was declined by the addition of isoleucine or histidine, depending upon Avt1p. Taken together with the data of the amino acid contents of vacuolar fractions in cells, the results suggested that Avt1p is a proton/amino acid antiporter important for vacuolar compartmentalization of various amino acids. PMID- 25747200 TI - Can we just call everything physiotherapy? PMID- 25747201 TI - Effects of pathogenic mutations in membrane subunits of mitochondrial Complex I on redox activity and proton translocation studied by modeling in Escherichia coli. AB - Effects of Complex I mutations were studied by modeling in NuoH, NuoJ or NuoK subunits of Escherichia coli NDH-1 by simultaneous optical monitoring of deamino NADH oxidation and proton translocation and fitting to the data a model equation of transmembrane proton transport. A homolog of the ND1-E24 LHON/MELAS mutation caused 95% inhibition of d-NADH oxidation and proton translocation. The NuoJ-Y59F replacement decreased proton translocation. The NuoK-E72Q mutation lowered the enzyme activity, but proton pumping could be rescued by the double mutation NuoK E72Q/I39D. Moving the NuoK-E72/E36 pair one helix turn towards the periplasm did not affect redox activity but decreased proton pumping. PMID- 25747202 TI - Two fifths of pregnant women in India are underweight. PMID- 25747203 TI - In vitro and in vivo evaluation of anti-leishmanial and immunomodulatory activity of Neem leaf extract in Leishmania donovani infection. AB - The toxicity and emergence of resistance to available chemical drugs against visceral leishmaniasis is evoking to explore herbal treatment. One such attempt with the Neem is being reported here. The current study is primarily focused to evaluate the anti-leishmanial effects of Neem leaf extracts. Among which, ethyl acetate fraction (EAF) alone was found to exhibit leishmanicidal effect validated through cytotoxicity assay and estimated its IC50 to be 52.4 ug/ml on the promastigote stage. Propidium iodide (PI) staining of dead cells substantiated the aforementioned activity. Carboxy fluorescein-diaceate succinimidyl ester (CFSE) staining of promastigotes has affirmed its anti-proliferation activity. The characteristic features such as DNA fragmentation, reduced mitochondrial membrane potential, increased sub G0/G1 phase parasites and increased reactive oxygen species (ROS) production in EAF treated promastigotes indicate the apoptosis like death. In addition, the reduced parasite burden both in vitro (viz. ~45% in human monocytic leukemia cell line (THP-1) and ~50% in peripheral blood mononuclear cells) and in vivo (spleen and liver) provides the evidence for its anti-leishmanial activity on amastigote stage. The increase of ROS levels in THP-1 and nitric oxide (NO) production from J774.1 cell line (mouse macrophages) upon EAF treatment was evidenced for oxidative killing of intracellular amastigotes. Active immunomodulatory activity at m-RNA level (viz. upregulation of Th1 cytokines, and downregulation of Th2 cytokines) both in vitro and in vivo was also shown to be exhibited by EAF. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of EAF revealed the presence of 14 compounds. PMID- 25747205 TI - [Necessity of advance pharmaceutical education and research for upbringing of the pharmacist who can make a immediate decision in patient's problems]. PMID- 25747206 TI - [The necessity for pharmaceutical education on perioperative care -- considering the activities of operating room pharmacists in relation to types of anesthetic operations involved]. AB - In an effort better to understand the application of pharmaceutical services in the operating room (OR) we conducted a survey among OR department directors of 526 hospitals throughout Japan. A total of 202 directors responded to the survey. Pharmacists are expected to achieve better outcomes in pharmacotherapy as well as play major roles as members of diverse perioperative care teams. Besides implementing medication safety standards, pharmacists' roles include optimizing drug therapy and other clinical interventions, both in OR and wards. Presently, few pharmacists in Japan participate in perioperative care, which is one of the reasons that the majority of pharmacy schools in Japan have been providing fewer lectures or rotations related to perioperative care. Yet, developing general perioperative management as another crucial role OR pharmacists play and incorporating it into pharmaceutical education would be important. Enriching perioperative care provided by pharmacists can contribute toward improving clinical competence in these professionals. PMID- 25747207 TI - [Practice of drug monitoring based on comprehensive pharmaceutical judgment]. AB - With the revisions to the pay for performance of pharmaceutical service of inpatients in April 2012, the ward permanent time of pharmacists grew longer than previously; however, there are as yet few reports on the pharmaceutical outcome of the new medical service. To improve the pharmaceutical service requires that pharmacists collect useful medical information and extract the problems of pharmaceutical care for inpatients. Since many cases of treatment with multidrug regimens are regularly performed, pharmacists cannot contribute to medical treatment only by knowledge of a single disease. Therefore quick and comprehensive judgment of pharmacists is necessary in addition to acquisition of pharmaceutical knowledge. We especially highlight medical emergencies such as severe cases of sepsis and infection to which physicians require rapid judgment. Pharmacists alike require appropriate knowledge of drug administration to avoid medical treatment failure. Moreover, it is necessary for pharmacists to apply advanced drug monitoring in difficult cases. On the other hand, integrated team medical treatment is now advancing, although pharmacists' roles in clinical decision making are increasing, and pharmacists have a greater burden of responsibility than before. PMID- 25747208 TI - [Health assessment of local residents who made full use of symptomatology skills and test device]. AB - A strategy named "Japan is back" adopted in June 2013 specifies that pharmacies shall be regarded as community-based places where health-related information is provided, and the public shall be encouraged to use the services of pharmacies and pharmacists who can advise on health and appropriate use of over-the-counter (OTC) drugs, and promote self medication. In Japan there are approximately 55000 pharmacies and 260000 pharmacists, and community residents are recommended to use these resources. As advisors on healthcare in the community, pharmacists are required to make judgments regarding drug use in individuals performing self medication and using OTC drugs in consideration of their symptoms and level of understanding of their health conditions, and recommend that they consult a medical center if necessary. To meet these requirements pharmacists need to have the skills to monitor each individual's lifestyle, behavior, and environment as well as trends in society, and assess their health status. However, education that allows pharmacists to practice such skills remains insufficiently developed. We consider that to be able to detect diseases early among community residents and appropriately support them using pharmacotherapy, it is very important to train pharmacists to do the following at pharmacies: 1) determine individuals who should be treated early using symptomatologic skills; 2) promote public awareness of disease; and 3) perform biochemical examination (blood is collected by fingerprick promptly to obtain biochemical data) in cooperation with the Department of Clinical Pharmacotherapy, Faculty of Pharmaceutical Sciences, Hiroshima University. PMID- 25747209 TI - [Key points in clinical pharmaceutical education and research, as seen from pharmaceutical consultation clinics]. AB - Pharmaceutical education was expanded to a 6-year system in 2006, in an efforts to enhance clinical pharmaceutical research and education. Since that time, pharmacists have attempted to participate in medical all aspects of medical care, but an environment in which they can master direct pharmaceutical techniques for patients has not yet been sufficiently developed. This is because pharmaceutical education emphasizes the acquisition of knowledge and has not reached the point where it cultivates minds that can adapt to the multitude of situations that are envisaged in medical settings. By incorporating physical assessment in pharmaceutical settings, it is believed that a mind-set of treating patients can be formed in students, leading to the development of pharmacists skilled in the implementation of their area of treatment. We feel that, by shifting to clinical pharmaceutical education and research we will realize an integrated ability in pharmacists to treat patients, which will earn multifaceted appreciation from both patients themselves and medical practitioners. The pharmaceutical consultation clinic established at Mie University offers second opinions by pharmacists, but patients' opinions of pharmacists are tepid and the letter sometimes became the target of acerbic comments. This is a reflection of the current state in which pharmacists have not made their role in medicine clear. Ultimately, efforts must be made to resolve anxiety with respect to the things patients want to hear, without evading this responsibility even when under pressure. Pharmaceutical science should always be cognizant of what the pharmacists' contribution to medicine, should be, and research a means to help that individual acquire the ability to make quick though careful judgments while gathering needed findings. PMID- 25747210 TI - [Necessity of research of pharmaceutical departments in the creation of new pharmaceutical skills through technical education of physical assessment]. AB - Physical assessment skills are now being more widely accepted by pharmacists and pharmaceutical departments than in the past. This is explained by the realization that pharmacists can prevent serious adverse effects and evaluate drug efficacy for their patients through assessment, thus providing effective medical care. However, is that all physical assessment can provide to pharmacists and pharmaceutical students? These students, in turn, should recognize the "need for skill" and the "pleasure to be gained in acquiring that skill" through the physical assessment performed by doctors. They should also recognize the importance of medical devices (e.g., stethoscope, electrocardiograph and endoscope) and take responsibility for creating their own techniques for their use. Here they will consider valuable pharmaceutical skills. "Yaku-jutsu" is a pharmaceutical diagnosis to determine the time required to achieve maximum beneficial effects and effective drug administration based on that diagnosis. Pharmacists cannot gain public trust unless they relieve a patient's pain using Yaku-jutsu which has been made available to them by the research support of a pharmaceutical department. PMID- 25747211 TI - [The creation of useful analytical tools to elucidate biological phenomena]. PMID- 25747212 TI - [Chemiluminescence assay for the investigation of reactive oxygen species generator]. AB - Quinones play critical roles in biological systems, but are also regarded as a class of toxins that can cause oxidative stress in living cells, and the involvement of quinone-based reactive oxygen species in oxidative stress has been reported. In biological systems, quinones are reduced to semiquinone radicals by the enzyme NADPH:quinone reductase. Next, semiquinone radicals react with dissolved oxygen to form superoxide anion, which reacts with biological molecules to cause oxidative stress. On the other hand, chemiluminescence reagents such as luminol can emit chemiluminescence after oxidation by reactive oxygen species. Therefore, chemiluminescence reagents have been used widely to investigate reactive oxygen species. We have developed a sensitive and selective assay for quantifying quinones using luminol chemiluminescence. This chemiluminescence assay is based on the generation of reactive oxygen species through the redox reaction between quinone and dithiothreitol, a reductant, followed by detection of the generated reactive oxygen by luminol. Additionally, this assay can be used to quantify the toxic herbicide, paraquat, which produces reactive oxygen species in the same manner as quinones. This review describes the development of a sensitive and selective chemiluminescence assay for investigating quinones and paraquat by utilizing their ability to generate reactive oxygen species. PMID- 25747213 TI - [Development and application of FD-LC-MS/MS proteomics analysis revealing protein expression and biochemical events in tissues and cells]. AB - It is routine to search for and recognized genetic defects in human disorders to provide knowledge for diagnosis, treatment, and protection against diseases. It is also important to investigate and demonstrate the cause of a disease from the proteomic perspective, because intracellular signaling systems depend on protein dynamics. Demonstrating changes in protein levels enables us to understand biochemical events during the initiation and progression of a disease. To understand changes in protein levels in tissues and cells, we have developed a novel proteomics approach, FD-LC-MS/ MS. This consists of fluorogenic derivatization (FD), HPLC separation and detection/quantification of proteins in a biological sample, followed by the isolation and tryptic digestion of target proteins, and then their identification using HPLC and tandem mass spectrometry (MS/MS) with a database-searching algorithm. The method is highly sensitive (femtomole-level detection) through the use of less noisy fluorogenic rather than fluorescence derivatization, and enables precise and comprehensive relative quantitation of protein levels (between-day relative standard deviation of peak heights of ca. 20%) by combining FD with HPLC separation. In this paper, after a simple review of differential profiling using FD-LC-MS/MS, for example the analysis of stimulated vs. unstimulated samples, we introduce the development and application of the FD-LC-MS/MS method for comprehensive differential proteomics of several tissues, including mouse liver, mouse brain, and breast cancer cell lines, to reveal protein levels and biochemical events in tissues and cells. PMID- 25747214 TI - [Highly selective analysis of biogenic-related compounds utilizing fluorous chemistry]. AB - Perfluoroalkyl-containing compounds are highly fluorous, meaning that they have a remarkable affinity for one another and effectively exclude non-fluorous species. Utilizing this unique property, we have developed a fluorous derivatization with a liquid chromatographic analysis method for highly selective analysis of target analytes. Although most previous methods focused on extremely sensitive detection oriented derivatization, the fluorous derivatization method involves highly specific separation for analytes. This method includes perfluoroalkylation of analytes with a fluorous reagent, and separation of the derivatives using a perfluoroalkyl-modified stationary phase LC column. The derivatives can be selectively retained on the fluorous-phase LC column, whereas the non-fluorous derivatives are poorly retained under the same separation conditions. The combination of this method with LC-tandem mass spectrometry (MS/MS) is very useful for complex biological sample analysis, because matrix-induced suppression effects, which are a common problem in LC-MS/MS analysis arising from components of a biological endogenous matrix, have not been observed. We have successfully applied this method to precise and accurate LC-MS/MS analysis of some biogenic compounds, such as sialic acids and biogenic amines, in complex biological samples. PMID- 25747215 TI - [Development of HPLC analysis methods for therapeutic monoclonal antibodies]. AB - Therapeutic monoclonal antibody (mAb) preparations are produced from cultured cells; therefore, detailed and multidimensional analyses of their heterogeneities are required. We analyzed five commercially available mAb preparations by high temperature reversed-phase LC using a wide-pore core-shell column for pluralistic quality assessment. At a highly elevated column temperature, isopropanol with high eluotropic strength coefficients and a wide-pore core-shell type octyl column showed good peak resolution of the investigated mAbs and their related constituents. We used this method to estimate the residual rate of intact mAbs after a heat aggregation treatment and conducted fragmentation analysis by analyzing their pepsin digests. Each peak component was identified by matrix assisted laser desorption ionization-time of flight mass spectrometry. All results were compared with those of reversed-phase and size exclusion analyses. PMID- 25747216 TI - [Next generation type formulation developed using innovation to overcome trade offs between patient-oriented approach and clinical effectiveness of formulation]. PMID- 25747217 TI - [Trade-offs in the development of various dosage form (overview)]. AB - In this symposium we focused on trade-offs which might occur in the process of development of many types of formulation and corresponding dissolution methods. Firstly, we focused on a solubility-permeability trade-off in the case of micelle with surfactant or molecular complex with CyD. The micelle would be successful in increasing drug solubility, however it rather decreased permeability of model drug progesterone (Biopharmaceutics Classfication System (BCS) Class II) as an overall flux. Secondly in order to reduce bitterness of branched chain amino acid (BCAA), increasing particle sizes of each amino acid crystals involved in formulation was effective since the release rate of amino acid was restricted efficiently. Thirdly, in the case of injection of paclitaxel (BCS Class II)formulation, the drug was adsorbed to albumin. Thereby the risk of allergy was dramatically decreased compared to the case when non-ionic surfactant was used as an additive. Fourth, anticancer drug was incorporated into the internal (core) phase of an orally disintegrating tablet (ODT), this is also merit to avoid exposure of the drug to a nursing person or individual working person in manufacturing process. Fifth, the convenient syringe type kit pharmaceutical preparation for administration of total parenteral nutrition (TPN) to avoid incompatibility and its risk management effect was briefly discussed. Finally, the risk of an additive such as alcohol for a preterm infant was described. PMID- 25747218 TI - [Trade-offs in oral drug product development]. AB - Drug products are developed to meet multiple targets, thereby increasing their value. Pharmaceutical scientists encounter several trade-offs during the development of novel oral formulations. These trade-offs are generated by their desire to supply the highest possible quality products under the prevailing conditions of limited time and cost, and feasible options. When there are two incompatible factors, it is sometimes difficult to dismiss one element. This is because a quality target product profile (QTPP) is critical for each product being developed, and all elements should basically be satisfied with the criteria. Therefore, technological innovation becomes important to overcome the trade-offs. This article introduces examples of such innovations which have been successful in doing this, as well as some encountered in the oral formulation development and in the selection of proper dosage forms. Based on these examples, points to be considered in order to produce the drug product are thoroughly discussed. PMID- 25747219 TI - [Clinical functionality required for orally disintegrating tablets selected as the next generation type]. AB - Orally disintegrating tablets (ODTs) are currently widely used in drug therapy and are clinically attractive, because they are suitable for administration to patients with dysphagia and improve adherence, both of which increase the possibility of achieving the expected therapeutic effect. These properties of ODTs, which increase treatment effectiveness, are termed their "clinical functionality", and ODTs with a high clinical functionality are required to meet the increasing need for these tablets. For example, there is a need for development of a clinically effective ODT with superior disintegrating properties while maintaining high tablet strength, bioequivalence with normal tablets while masking the bitterness with a fine particle coating, and a disintegration mechanism while maintaining moisture resistance and good storage quality. Thus, next-generation ODTs that overcome these conflicting properties, "trade-offs", will be developed, using innovative formulation research technology. In this symposium, we will discuss a next-generation OD formulation known as PLETAAL OD, a high-dose antiplatelet agent, and will present the results of validation tests performed in our laboratory pertaining to high tablet strength, superior disintegration property, high wicking capacity, and storage stability with high moisture resistance. We will also introduce a second-generation antihistamine ALLELOCK OD and discuss its high clinical functionality achieved by masking the bitterness and obtaining bioequivalence with normal tablets by using granules while maintaining high tablet strength with EXLUB and SOLBLET technology. PMID- 25747220 TI - [Oral dosage forms for children: acceptability and palatability]. AB - Children generally reject taking medicine which does not have a favorable shape, taste, flavor, etc. However, if a child who needs to take a medicine, rejects taking it, he might never recover from his condition. When a child is unable to take medicine orally, it is intravenously administered, and he and his caregivers then may experience stress. Syrups and suspensions are considered as favorable types of dosage forms in which to orally administer medicine to infants and children. However, they may have disadvantages such as solubility, a bad taste, portability problems or required refrigerator storage. World Health Organization (WHO) currently favors that infants and children be treated with oral solid medicines. New oral solid tablets, such as a mini-tablet, instead of liquid medicines are proposed for this group, however, there are a few reports that mini tablets are suitable for infants and children. Palatability is one of the main elements of patient acceptability of an oral pediatric medicine. Palatability is defined as the overall appreciation of an oral medicinal product in relation to its smell, taste, aftertaste and feeling in the mouth. Design of the formulation of an oral pediatric medicine should be considered together with its palatability. PMID- 25747221 TI - [Development of a novel oral jelly formulation for elderly patients]. AB - Deterioration of the swallowing function in elderly persons and drug refusal among the behavioral abnormalities in Alzheimer's disease (AD) are commonly reported. Therefore, we developed an easy-to-swallow jelly formulation of Donepezil HCl which AD patients can take as a dessert. The development process, however, was full of trade-off problems. (1) Need for evaluating the taste of a drug product vs. Safety of human sensory evaluation of the taste. The trade-off was resolved by using a taste sensor. (2) Speed of development vs. Safety of the manufacturing process. We put priority on the safety rather than speed, and a safer antioxidant agent was found. (3) Usability of the container for AD patients with dysphagia vs. Size of the container. We put priority on its being user friendly rather than on the size and chose a stable wide-mouth cup. (4) Suitable texture of jelly for swallowing the drug product vs. Residual volume of jelly in the cup. We designed the texture so that the residual volume of jelly in the cup was reduced. (5) Easy peeling properties of aluminum seal vs. High sealing strength for sterilization. The sealing strength was adjusted so that it was adequate to sterilize the drug product. (6) One cup in a heat-sealed aluminum pillow package to prevent overdose vs. Seven cups in a pillow package. A single dose package was relatively expensive, but it was chosen to assure safety. We faced many difficult trade-off problems in the development of process. However, they were resolved using technical innovations and a people-friendly policy. Finally, we were able to launch a novel oral jelly formulation for elderly patients. PMID- 25747222 TI - [Development of injection containers for patient and medical staff]. AB - Recently, there has been a transition from glass to plastic injection containers in Japan. In our previous study, we suggested that plastic containers had less impurity contamination than glass containers. However, the use of some plasticizers has been limited because of their endocrine disrupting effects. Therefore, contamination has been a concern due to chemicals in injection solution packed with plastic containers. Indeed, in our recent study, photoinitiators were detected in an injection solution coming from plastic containers. Photoinitiators mainly exist in ink. We therefore speculated that ink originating from a photoinitiator directly printing on plastic containers had migrated into the injection solutions. In a clinical setting, plastic containers are very tractable because they are lightweight and less breakable. On the other hand, from a safety view point, these containers may be hazardous because of permeation by steam, ambient air or photoinitiators. In the present symposium, we will discuss the risk of photoinitiators leaking into injection solution packed with plastic containers, and countermeasures to avoid this risk. PMID- 25747223 TI - [The role of formulation and dosage form in vaccine]. AB - The importance of vaccination has recently been widely recognized among Japanese people with a growing interest in vaccine. On the other hand, because vaccine is administrated to healthy people, it has had a difficult history due to overreaction to adverse events. With the recent rapid increase in the rate of vaccination, however, it is essential to correct the understanding of the public as to the risk and benefit of vaccine. Life spans around the world and infectious diseases are closely related, and vaccine certainly contributes to the control of the latter. Research and Development (R&D) of novel antigens is necessary for creating a next generation vaccine, a high performance device for efficient antigen delivery, and a safe adjuvant for adequate immunological response are also a key to the future. Moreover, various initiatives involving industry, academia, and government cooperation are essential to benefit the people of Japan and appropriate vaccination could actually be viewed as national security. PMID- 25747224 TI - [What is proper drug information for patients to minimize risk? Constructing drug guide for patients]. PMID- 25747225 TI - [Present state and future tasks of "Drug Guide for Patients"]. AB - Safety information on drugs is provided through package inserts, which are the most basic tool offered by pharmaceutical companies, "Emergency Safety Information" and "Pharmaceuticals and Medical Devices Safety Information", etc. issued by the Ministry of Health, Labour and Welfare (MHLW). In addition, the Pharmaceuticals and Medical Devices Agency (PMDA) recently established an information website, and the provision of enhanced information is now being promoted not only for health care professionals but also for patients. "Drug Guide for Patients" is one of the information tools for patients. The "Drug Guide for Patients" is presented so that the patient understands the correct use of the prescribed drug and serious adverse drug reactions can be recognized at an early stage. It is expected to contribute to the prevention of such adverse reactions by early detection and rapid cure. However, the guides have a low profile and are not yet fully exploited. They are currently being prepared without the direct involvement of patients although they are prepared from a patient point of view. These issues need to be resolved by encouraging broad use, a review of the contents and the involvement of patient groups to provide truly useful information. It is hoped that with these steps the guides will aid in further increasing risk communication to patients reading them. PMID- 25747226 TI - [Drug information for patients (Package Leaflets), and user testing in EU]. AB - Patients and consumers have desired high quality drug information in their pharmacotherapy, and are entitled to receive it. It is desirable that the information should be aimed at shared decision-making between patients and healthcare professionals about medications. The quality of drug information available to patients should also be assured. With an aim to improve the quality of "Drug Guide for Patients", we investigated Patient Information Leaflets (PILs) which are approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom (UK) with regard to the criteria of development and user testing for assuring the quality of the PILs. In the European Union (EU), these are called Package Leaflets (PLs). PILs have been a legal requirement in the UK since 1999 for all medications. The user testing of PILs has been implemented as evidence since 2005 so that people can rely on the information provided in the leaflet. Execution of PILs which follow the guidance of the user testing, according to the guidance of this user testing, would reflect the views of patients. Here, we introduce the development process and implementation of user testing of PILs. In terms of readability, accessibility and understandability of drug information for patients, we need to discuss involving the public in decisions on how its quality should be assured and how it can be made easily be comprehensible for patients, in order to make effective use of "Drug Guide for Patients" in the future in Japan. PMID- 25747227 TI - [Review of drug information provided to patients from the viewpoint of hospital pharmacists]. AB - Risks for patients and consumers can be minimized depending on how they are provided appropriate drug information. Therefore, from the viewpoint of hospital pharmacists, I would like to report on how information should be provided in order to minimize patient risk. For example, there is an ongoing opinion that the provision of easy-to-understand drug information to patients and consumers "does not appear necessary". The reasons for this include the following: Because the level of understanding varies greatly among patients, it is difficult to define what "easy-to-understand" information entails; rather, it may cause misunderstanding. These problems occur repeatedly if they are resolved by individual institutions. Therefore, it is essential to standardize the drug information provided to patients, that is, to establish a system to transmit drug information to patients and consumers. Regardless of whether the development of a hospital information system is in progress or not, it can be said that the development of such information systems is gradually spreading outside of hospitals and the situation is changing. From the viewpoint of patients, medical services are not limited to those from hospitals. Patient-centered collaboration between hospitals/clinics and pharmacies (but not the collaboration between hospital pharmacists and community pharmacists (why not?)) can provide good medical services only if patient information is shared. It is essential to establish a system for providing a drug guide for patients, in order to have patients understand drug information. The preparation of Drug Information for Patients would provide health care specialists a communication tool that helps minimize patient risk. PMID- 25747228 TI - [Findings from a questionnaire survey on new guidelines for preparing Drug Guide for Patients and a perspective from a pharmaceutical company as the information provider]. AB - Draft versions of two products of based on a "Drug Guide for Patients" have been prepared the guidelines proposed in "Research on risk communication between patients and healthcare professionals regarding information on safety measures for drugs, etc." by Health and Labour Sciences Research Grants. We conducted a questionnaire survey on the draft to identify issues regarding the contents and their preparation from the viewpoint of pharmaceutical companies as authors. The questionnaire results indicated that, the segments of the contents of the "Drug Guide for Patients" based on the new guidelines are generally acceptable. In this paper, the author offers proposals to address issues regarding the preparation of easy-to-read contents for patients and strategies to promote the overall understanding recognition of Drug Guide for Patients. Drug Guide for Patients are expected to be utilized as materials providing information to be used for routine risk minimization activities of the Risk Management Plan in the future. PMID- 25747229 TI - [What is a medication guide suits patients' needs?]. AB - In order for a patient to read a medication guide and develop appropriate behavior regarding use of the medication, the guide should suit patients' needs. In medical care, the primary needs of patients are preventing/curing disease and/or relieving symptoms. Certainly, patients would like knowledge about what can be expected after taking a medication. However, current "Drug Guides for Patients" are based on drug labeling, which is essentially a medically sophisticated instruction manual for medical professionals who have existing knowledge about the medical treatment of the disease. Thus, there seems to be a gap in patients' needs and the contents of existing drug guides. Consequently, this disconnect may be part of the reason Drug Guides for Patients have been underused. If a patient treatment guide, which gives an overview of the disease and possible treatment strategies, is provided in conjunction with a drug guide, this combination may be useful for satisfying patients' needs. In addition, patients generally prefer detailed drug information. Consistently, surveys have revealed that many patients would like to get more information about prescribed medicine than what is frequently provided in medical practice. Furthermore, one survey reported that detailed information about possible side effects resulted in improved compliance. The need to provide patients with drug information can be considered from three points of view: patients' rights, best decision-making by the patient, and minimizing risks. Although in daily practice doctors and pharmacists may have some difficulty providing detailed medication information that includes all possible risks, more effective ways to communicate this information to patients have been suggested. PMID- 25747230 TI - [Development of metallomics research on environmental toxicology]. AB - Metallomics is newly coined terms and defined as a comprehensive analysis of the entirety of metal and metalloid species within a cell or tissue type. Then, metallome is defined as the entire category of metalloproteins and any other metal-containing biomolecules. Metallomics and research on metallome require analytical techniques that can provide information on the identification and quantification of metal/metalloid-containing biomolecules. This concept has been called speciation, and the acquisition of data according to the concept is performed using hyphenated techniques involving both separation and detection methods. In this review, the author intends to present several applications of complementary use of HPLC-inductively coupled plasma mass spectrometry (ICP-MS) and HPLC-electrospray ionization tandem mass spectrometry for identification of unknown selenium-containing metabolites, and also to present a newly developed technique, capillary LC-ICP-MS to be used for the analysis of metal-binding proteins. PMID- 25747231 TI - [Pharmacokinetics characteristics of dexamethasone in Crush syndrome model rats]. AB - Crush syndrome (CS) is characterized by ischemia/reperfusion-induced rhabdomyolysis and subsequent systemic inflammation and has a high mortality rate, even when treated with conventional therapy. In previous studies, we demonstrated that treatment of rats with acute lethal CS using dexamethasone (DEX) had therapeutic effects in laboratory findings and improved the clinical course of CS. However, because the application of DEX in CS therapy is unknown, evaluation of the pharmacokinetic parameters of DEX was considered essential to support its clinical use. Here, we investigated the pharmacokinetic characteristics of DEX in a rat model of CS. Anesthetized rats were subjected to bilateral hind limb compression using rubber tourniquets for 5 h, followed by reperfusion for 0 to 24 h. Rats were divided randomly into 4 groups: saline treated sham (S) and CS groups and 5.0 mg/kg DEX-treated S (S-DEX) and CS (CS DEX) groups. Blood and tissue samples were collected for HPLC analysis. In the CS DEX group, the pharmacokinetic parameters of the area under the concentration time curve, mean residence time, and distribution volume levels increased significantly compared to the S-DEX group, whereas total body clearance, elimination rate constant, and renal clearance levels decreased significantly. Moreover, decrease of muscle tissue DEX concentration and of CYP3A activity were observed in the CS-DEX group. These results show the pharmacokinetic characteristics of DEX in the rat CS model and support the potential use of DEX in disaster medical care. PMID- 25747232 TI - [Fundamental study of memory impairment and non-cognitive behavioral alterations in APPswe/PS1dE9 mice]. AB - In addition to cognitive decline, Alzheimer's disease patients also exhibit non cognitive symptoms commonly referred to as behavioral and psychological symptoms of dementia, or BPSD. These symptoms have a serious impact on the quality of life of these patients, as well as that of their caregivers, but there are currently no effective therapies. The amyloid beta-peptide (Abeta) is suspected to play a central role in the cascade leading to Alzheimer's disease, but the precise mechanisms are still incompletely known. To assess the influence of Abeta pathology on cognitive and non-cognitive behaviors, we examined locomotor activity, motor coordination, and spatial memory in male and female APPswePS1dE9 mice (Alzheimer's disease model, double transgenic mice expressing an amyloid precursor protein with Swedish mutation and a presenilin-1 with deletion of exon 9) at 5 months of age, when the mice had subtle Abeta deposits, and again at 9 months of age, when the mice had numerous Abeta deposits. Compared to wild-type mice, the male and female APPswe/PS1dE9 mice showed normal motor coordination in the rotarod test at both 5 and 9 months. In the Morris water maze test, male and female APPswe/PS1dE9 mice showed impaired spatial memory at 9 months; however, no such deficits were found at 5 months. In a locomotor activity test, male APPswe/PS1dE9 mice exhibited locomotor hyperactivity at 9 months, while females exhibited locomotor hyperactivity at both 5 and 9 months compared to the control mice. Together, these results indicate that APPswe/PS1dE9 mice developed spatial memory impairment and BPSD-like behavioral alterations resulting from Abeta accumulation. PMID- 25747233 TI - Statistical aspects of food safety sampling. AB - In food safety management, sampling is an important tool for verifying control. Sampling by nature is a stochastic process. However, uncertainty regarding results is made even greater by the uneven distribution of microorganisms in a batch of food. This article reviews statistical aspects of sampling and describes the impact of distributions on the sampling results. Five different batch contamination scenarios are illustrated: a homogeneous batch, a heterogeneous batch with high- or low-level contamination, and a batch with localized high- or low-level contamination. These batch contamination scenarios showed that sampling results have to be interpreted carefully, especially when heterogeneous and localized contamination in food products is expected. PMID- 25747234 TI - Principles and application of high pressure-based technologies in the food industry. AB - High pressure processing (HPP) has emerged as a commercially viable food manufacturing tool that satisfies consumers' demand for mildly processed, convenient, fresh-tasting foods with minimal to no preservatives. Pressure treatment, with or without heat, inactivates pathogenic and spoilage bacteria, yeast, mold, viruses, and also spores and extends shelf life. Pressure treatment at ambient or chilled temperatures has minimal impact on product chemistry. The product quality and shelf life are often influenced more by storage conditions and packaging material barrier properties than the treatment itself. Application of pressure reduces the thermal exposure of the food during processing, thereby protecting a variety of bioactive compounds. This review discusses recent scientific advances of high pressure technology for food processing and preservation applications such as pasteurization, sterilization, blanching, freezing, and thawing. We highlight the importance of in situ engineering and thermodynamic properties of food and packaging materials in process design. Current and potential future promising applications of pressure technology are summarized. PMID- 25747235 TI - Infant Breastfeeding and Kidney Function in School-Aged Children. AB - BACKGROUND: Early life factors may influence kidney growth and function throughout the life course. We examined the associations of breastfeeding duration and exclusivity and age at introduction of solid foods with kidney outcomes at school age. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: 5,043 children in the Netherlands. PREDICTORS: Infant feeding was assessed prospectively using questionnaires. OUTCOMES & MEASUREMENTS: In children at a median age of 6.0 years, we measured kidney volume with ultrasound, estimated glomerular filtration rate (eGFR) from serum creatinine level, and microalbuminuria from urinary albumin and creatinine levels. RESULTS: 92% of all children were ever breastfed, of whom 27% were breastfed for more than 6 months and 21% were breastfed exclusively for at least 4 months. Compared with ever-breastfed children, never-breastfed children had smaller combined kidney volumes (-2.69 [95% CI, -4.83 to -0.56] cm(3)) and lower eGFRs (-2.42 [95% CI, -4.56 to -0.28] mL/min/1.73 m(2)) at school age. Among breastfed children, shorter duration of breastfeeding was associated with smaller combined kidney volume and lower microalbuminuria risk (P<0.05). Compared to exclusive breastfeeding for 4 months, nonexclusive breastfeeding in the first 4 months was associated with smaller combined kidney volume and lower eGFR (both P<0.05). Associations with eGFR were explained largely by kidney volume. Age at introduction of solid foods was not associated with any kidney outcome. LIMITATIONS: Observational study, so causality cannot be established. Follow-up measurements were available for 76% of children. CONCLUSIONS: These results suggest that breastfeeding is associated with subclinical changes in kidney outcomes in childhood. Further studies are needed to explore whether early life nutrition also affects the risk of kidney disease in adulthood. PMID- 25747236 TI - Photoluminescence imaging of Zn(2+) in living systems. AB - Zn(2+) plays essential roles in various physiological processes in living systems, and the investigation of Zn(2+) related physiology and pathology has attracted considerable interest. Because photoluminescence (PL) imaging possesses distinct advantages, such as high sensitivity and non-invasiveness, and excellent temporal and spatial resolution, it has become a powerful tool for the real time monitoring of Zn(2+) distribution, uptake, and trafficking. Over the last two decades, great efforts have been devoted to PL Zn(2+) imaging in living systems, which proved the Zn(2+) fluctuations in physiological processes and the temporal spatial distribution of labile Zn(2+) as well as the localization of labile Zn(2+) pools. Advances in PL techniques, such as fluorescence microscopy, confocal fluorescence microscopy, two photon fluorescence microscopy, lifetime based techniques and luminescence optical imaging systems, have made remarkable contributions in tackling major challenges in Zn(2+) PL imaging. With the rational design and proper use of fluorescent sensors, Zn(2+) imaging in various cell lines, organelles, tissues, organs and living animals has been realized, which was shown to be crucial in elucidating the biological and physiological roles of labile Zn(2+). PMID- 25747237 TI - Phytoremediation of Heavy Metals in Contaminated Water and Soil Using Miscanthus sp. Goedae-Uksae 1. AB - The aim of this study is to characterize the heavy metal phytoremediation potential of Miscanthus sp. Goedae-Uksae 1, a hybrid, perennial, bio-energy crop developed in South Korea. Six different metals (As, Cu, Pb, Ni, Cd, and Zn) were used for the study. The hybrid grass effectively absorbed all the metals from contaminated soil. The maximum removal was observed for As (97.7%), and minimum removal was observed for Zn (42.9%). Similarly, Goedae-Uksae 1 absorbed all the metals from contaminated water except As. Cd, Pb, and Zn were completely (100%) removed from contaminated water samples. Generally, the concentration of metals in roots was several folds higher than in shoots. Initial concentration of metals highly influenced the phytoremediation rate. The results of the bioconcentration factor, translocation factor, and enrichment coefficient tests indicate that Goedae-Uksae 1 could be used for phytoremediation in a marginally contaminated ecosystem. PMID- 25747238 TI - Lithium, Vanadium and Chromium Uptake Ability of Brassica juncea from Lithium Mine Tailings. AB - The potential for phytoremediation and phytostabilization of lithium in lieu with vanadium and chromium on a formulated acidic heterogeneous growth media engineered around lithium mine tailings, was investigated in four phases: (1) overall efficiency of the removal of the three metals, (2) bioaccumulation ratios of the three metals, (3) overall relative growth rate, and (4) translocation index of the three metals in the physiology of the hyperaccumulator plant. A pot study was conducted to assess the suitability of Brassica juncea (Indian mustard) in a phytoremediation process whereby it was lingered for eighty-six days under homogeneous growth conditions and irrigated bidaily with organic fertilizer amended with LiCl. A post harvest data analysis was achieved through ashing and the implementation of cold digestion procedure in a concentrated hydrochloric acidic matrix. In physiological efficiency parameters, the hyperaccumulator plant was twice as able to phytostabilize chromium and four times was able to phytostabilize vanadium in comparison to lithium. Moreover, it was extremely efficient in translocating and accumulating lithium inside its upper physiological sites, more so than chromium and vanadium, thereby demonstrating Indian mustard, as a hyperaccumulator plant, for phytoextraction and phytostabilization in an acidic heterogeneous rhizosphere, with an extremely low relative growth rate. PMID- 25747239 TI - Effect of vegetation rehabilitation on soil carbon and its fractions in Mu Us Desert, northwest China. AB - Although vegetation rehabilitation on semi-arid and arid regions may enhance soil carbon sequestration, its effects on soil carbon fractions remain uncertain. We carried out a study after planting Artemisia ordosica (AO, 17 years), Astragalus mongolicum (AM, 5 years), and Salix psammophila (SP, 16 years) on shifting sand land (SL) in the Mu Us Desert, northwest China. We measured total soil carbon (TSC) and its components, soil inorganic carbon (SIC) and soil organic carbon (SOC), as well as the light and heavy fractions within soil organic carbon (LF SOC and HF-SOC), under the SL and shrublands at depths of 100 cm. TSC stock under SL was 27.6 Mg ha(-1), and vegetation rehabilitation remarkably elevated it by 40.6 Mgha(-1), 4.5 Mgha(-1), and 14.1 Mgha(-1) under AO, AM and SP land, respectively. Among the newly formed TSC under the three shrublands, SIC, LF-SOC and HF-SOC accounted for 75.0%, 10.7% and 13.1% for AO, respectively; they made up 37.0%, 50.7% and 10.6% for AM, respectively; they occupied 68.6%, 18.8% and 10.0% for SP, respectively. The accumulation rates of TSC within 0-100 cm reached 238.6 g m(-2) y(-1), 89.9 g m(-2) y(-1) and 87.9 g m(-2) y(-1) under AO, AM and SP land, respectively. The present study proved that the accumulation of SIC considerably contributed to soil carbon sequestration, and vegetation rehabilitation on shifting sand land has a great potential for soil carbon sequestration. PMID- 25747240 TI - The Tolerance and Accumulation of Miscanthus Sacchariflorus (maxim.) Benth., an Energy Plant Species, to Cadmium. AB - Miscanthus sacchariflorus (Maxim.) Benth. is a metallophyte suitable for the phytoremediation of mine wastes. The tolerance and accumulation of M. sacchariflorus to cadmium was studied by pot experiments. The results showed that O2.- generation rate, plasma membrane permeability and MDA content of M. sacchariflorus leaves increased with increasing Cd concentrations in soil, but significant effect was only observed when Cd concentrations were >=50 mg.kg(-1). SOD and POD activities increased initially but decreased later on, whereas CAT activity only increased significantly at higher Cd concentrations, 50-100 mg.kg( 1). The content of photosynthetic pigment and growth of M. sacchariflorus were both not significantly affected when Cd concentration was <=25 mg.kg(-1). In contrast, both parameters were significantly affected when Cd concentration was >=50 mg.kg(-1). M. sacchariflorus could accumulate much Cd, but most of the Cd assimilated was retained in the belowground part, suggesting that M. sacchariflorus has poor ability to translocate Cd to the aboveground part. Our results suggested that although M. sacchariflorus was not a hyper-accumulator, it has a strong capacity to tolerate and stabilize the Cd. Therefore, M. sacchariflorus has a certain potential in the phytostabilization of Cd contaminated soils. PMID- 25747241 TI - Ni-induced Changes in Nitrate Assimilation and Antioxidant Metabolism of Verbascum olympicum Boiss.: Could the Plant be Useful for Phytoremediation or/and Restoration Purposes? AB - Verbascum olympicum Boiss. (Scrophulariaceae) were studied as a candidate plant for remediating the Ni polluted soils. The metabolic responses, such as nitrate assimilation (nitrate reductase and glutamine synthetase activity) and antioxidant system activity [superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) activity], of this species exposed to nickel in Hoagland's nutrient medium were investigated as remediation performance parameters. The accumulation of nickel and the variations in the content of some elements (B, Cu, Fe, Mg, Mn, Mo and Zn) and some growth parameters, such as the water content, biomass production, and contents of chlorophyll and soluble protein, were also examined. The accumulation of Ni in both the roots and leaves varied depending on the exposure times and doses. Increased oxidative stress was suggested by the increases in the activities of SOD, CAT and APX. Although some element contents were inhibited by Ni treatments, these inhibitory effects was decreased depending on the time, and even these elements are accumulated in roots. These results are the novelties in the use of this species in biotechnology. PMID- 25747242 TI - Mycorrhizal limonium sinuatum (L.) mill. Enhances accumulation of lead and cadmium. AB - Heavy metals accumulation in soils poses a potential threat to ecosystems, which, in turn, threat human health through food chains. Therefore, remediating polluted sites is important to environment and humanity. In this investigation, statice (L. sinuatum) was exposed to Cd (0, 15, 30, 60 mg kg(-1) soil) or Pb (0, 100, 150, 300 mg kg(-1) soil) in a pot experiment to assess its tolerance to each metal and study its phytoaccumulation capability. The benefits of mycorrhization (mixture of Glomus mosseae and G. intraradices) were also studied simultaneously. Single exposure to Cd or Pb reduced the plant growth, but statice was still relatively tolerant to both metals. The plants accumulated both metals in their roots; little was translocated to the shoots. Total Pb and total Cd accumulated by the roots was approximately 2 and 3 times higher in mycorrhizal than non mycorrhizal plants (49 versus 147 and 595 versus 956 MUg plant(-1)) respectively; however, mycorrhization alleviated metal phytotoxicity. The results suggest that statice is a potential candidate to be used as an ornamental plant in lead and cadmium polluted sites, mainly inoculated with arbuscular mycorrhizae. Besides that, it would be useful as a Pb or Cd controlling agent by means of phytostabilization. PMID- 25747243 TI - The Optimal Root Length for Vetiveria zizanioides When Transplanted to Cd Polluted Soil. AB - In order to facilitate transportation and accelerate growth, roots of Vetiveria zizanioides must be pruned before transplanting. The present research is aimed to investigate the best root length for vetiver grown in cadmium (Cd) polluted soil. The results indicated that 6 cm root-length plant (RLP) was the best candidate in phytoremediation of Cd-contaminated soil for its stronger tolerance and better growth promoting activities. PMID- 25747244 TI - Effect of EDTA and Tannic Acid on the Removal of Cd, Ni, Pb and Cu from Artificially Contaminated Soil by Althaea rosea Cavan. AB - In this study an ornamental plant of Althaea rosea Cavan was investigated for its potential use in the removal of Cd, Ni, Pb and Cu from an artificially contaminated soil. Effect of two different chelating agents on the removal has also been studied by using EDTA (ethylenediaminetetracetic acid) and TA (tannic acid). Both EDTA and TA have led to higher heavy metal concentration in shoots and leaves compared to control plants. However EDTA is generally known as an effective agent in metal solubilisation of soil, in this study, TA was found more effective to induce metal accumulation in Althaea rosea Cavan under the studied conditions. In addition to this, EDTA is toxic to some species and restraining the growth of the plants. The higher BCF (Bio Concentration Factor) and TF (Translocation Factor) values obtained from stems and leaves by the effects of the chemical enhancers (EDTA and TA) show that Althaea rosea Cavan is a hyper accumulator for the studied metals and may be cultivated to clean the contaminated soils. PMID- 25747245 TI - Efficiency of repeated phytoextraction of cadmium and zinc from an agricultural soil contaminated with sewage sludge. AB - Long-term application of sewage sludge resulted in soil cadmium (Cd) and zinc (Zn) contamination in a pot experiment conducted to phytoextract Cd/Zn repeatedly using Sedum plumbizincicola and Apium graceolens in monoculture or intercropping mode eight times. Shoot yields and soil physicochemical properties changed markedly with increasing number of remediation crops when the two plant species were intercropped compared with the unplanted control soil and the two monoculture treatments. Changes in soil microbial indices such as average well colour development, soil enzyme activity and soil microbial counts were also significantly affected by the growth of the remediation plants, especially intercropping with S. plumbizincicola and A. graveolens. The higher yields and amounts of Cd taken up indicated that intercropping of the hyperaccumulator and the vegetable species may be suitable for simultaneous agricultural production and soil remediation, with larger crop yields and higher phytoremediation efficiencies than under monoculture conditions. PMID- 25747246 TI - A Study on Cadmium Phytoremediation Potential of Indian Mustard, Brassica juncea. AB - The objective of this study was to investigate Cd phytoremediation ability of Indian mustard, Brassica juncea. The study was conducted with 25, 50, 100, 200 and 400 mg Kg(-1) CdCl2 in laboratory for 21 days and Cd concentrations in the root, shoot and leaf tissues were estimated by atomic absorption spectroscopy. The plant showed high Cd tolerance of up to 400 mg Kg(-1) but there was a general trend of decline in the root and shoot length, tissue biomass, leaf chlorophyll and carotenoid contents. The tolerance index (TI) of plants were calculated taking both root and shoot lengths as variables. The maximum tolerance (TI shoot=87.4 % and TI root=89.6%) to Cd toxicity was observed at 25 mg Kg(-1), which progressively decreased with increase in dose. The highest shoot (10791 MUg g(-1) dry wt) and root (9602 MUg g(-1) dry wt) Cd accumulation was achieved at 200 mg kg(-1) Cd treatment and the maximum leaf Cd accumulation was 10071.6 MUg g(-1) dry wt achieved at 100 mg Kg(-1) Cd, after 21 days of treatment. The enrichment coefficient and root to shoot translocation factor were calculated, which, pointed towards the suitability of Indian mustard for removing Cd from soil. PMID- 25747247 TI - Stability of Lead Immobilized by Apatite in Lead-Containing Rhizosphere Soil of Buckwheat (Fagopyrum esculentum) and Hairy Vetch (Vicia villosa). AB - This study conducted plant growth experiments using a rhizobox system to understand the growth of buckwheat and hairy vetch as well as the stability of lead immobilized by hydroxyapatite (HAP) in the lead-containing rhizosphere soil. The shoot dry weight of buckwheat did not significantly differ between the lead containing rhizosphere soil with and without HAP, whereas that of hairy vetch with rhizosphere soil without HAP was reduced. Lead was not accumulated from the rhizosphere soil to the shoots of either plant when HAP was added. The percentage of each lead fraction in sequential extraction was approximately the same through the 3 mm of rhizosphere soils from the root surface and non-planted soil, with and without the addition of HAP. For hairy vetch, the amount of water-soluble lead in the HAP-added rhizosphere soil within 3 mm thickness from the root surface did not increase. However, for buckwheat, the amount of water-soluble lead in the HAP-added rhizosphere soil 1 mm from the root surface increased to the same level as that in the non-planted soil without HAP. Our results suggest that when applying phytostabilization combined with apatite to lead-contaminated soil, the plant that cannot re-mobilize lead should be selected. PMID- 25747248 TI - Innervation of the lower third of the sternocleidomastoid muscle by the ansa cervicalis through the C1 descendens hypoglossal branch: a previously unreported anatomical variant. AB - We describe a previously unreported anatomical variant (found during a routine neck dissection) in which the lower third of the sternocleidomastoid was innervated by the C1 branch of the ansa cervicalis (descendens hypoglossi). PMID- 25747249 TI - Doctor, here is my palate: rare occurrence of subtotal maxillary osteomyelitis. AB - Osteomyelitis of the jaws, although well documented, is rare, but osteomyelitis of the maxilla is extremely rare. We report the case of a 56-year-old Togolese man with avulsion of part of his maxilla. PMID- 25747250 TI - A 75 year history of a neck lump--is this a record for a patient referred to a one stop clinic? PMID- 25747253 TI - Friction between ring polymer brushes. AB - Friction between ring polymer brush bilayers sliding past each other at melt densities is studied using extensive coarse-grained molecular dynamics simulations and scaling arguments, and the results are compared to the friction between bilayers of linear polymer brushes. We show that for a velocity range spanning over three decades, the frictional forces measured for ring polymer brushes are half of the corresponding friction in the case of linear brushes. In the linear-force regime, the weak inter-digitation between ring brush layers as compared to linear brushes leads also to a lower number of binary collisions between the monomers from opposing brushes. At high velocities, where the thickness of the inter-digitation between bilayers is on the order of monomer size regardless of brush topology, stretched segments of ring polymers adopt the double-stranded conformation. As a result, monomers of the double-stranded segments collide on average less with the monomers of the opposing ring brush even though a similar number of monomers occupies the inter-digitation layer for ring and linear brush bilayers. The numerical data obtained from our simulations are consistent with the proposed scaling analysis. Conformation-dependent friction reduction observed in ring brushes can have important consequences in non-equilibrium bulk systems. PMID- 25747251 TI - Unexpected ancient paralogs and an evolutionary model for the COPII coat complex. AB - The coat protein complex II (COPII) is responsible for the transport of protein cargoes from the Endoplasmic Reticulum (ER) to the Golgi apparatus. COPII has been functionally characterized extensively in vivo in humans and yeast. This complex shares components with the nuclear pore complex and the Seh1-Associated (SEA) complex, inextricably linking its evolution with that of the nuclear pore and other protocoatomer domain-containing complexes. Importantly, this is one of the last coat complexes to be examined from a comparative genomic and phylogenetic perspective. We use homology searching of eight components across 74 eukaryotic genomes, followed by phylogenetic analyses, to assess both the distribution of the COPII components across eukaryote diversity and to assess its evolutionary history. We report that Sec12, but not Sed4 was present in the Last Eukaryotic Common Ancestor along with Sec16, Sar1, Sec13, Sec31, Sec23, and Sec24. We identify a previously undetected paralog of Sec23 that, at least, predates the archaeplastid clade. We also describe three Sec24 paralogs likely present in the Last Eukaryotic Common Ancestor, including one newly detected that was anciently present but lost from both opisthokonts and excavates. Altogether, we report previously undescribed complexity of the COPII coat in the ancient eukaryotic ancestor and speculate on models for the evolution, not only of the complex, but its relationship to other protocoatomer-derived complexes. PMID- 25747254 TI - Stepwise assembly of a semiconducting coordination polymer [Cd8S(SPh)14(DMF)(bpy)]n and its photodegradation of organic dyes. AB - Chalcogenolate clusters can be interlinked with organic linkers into semiconducting coordination polymers with photocatalytic properties. Here, discrete clusters of Cd8S(SPh)14(DMF)3 were interlinked with 4,4'-bipyridine into a one dimensional coordination polymer of [Cd8S(SPh)14(DMF)(bpy)]n with helical chains. A stepwise mechanism for the assembly of the coordination polymer in DMF was revealed by an ex situ dynamic light scattering study. The cluster was electrostatically neutral and showed a penta-supertetrahedral structure. During the assembly each cluster was interlinked with two 4,4'-bipyridine molecules, which replaced the two terminal DMF molecules of the clusters. In their solid state forms, the cluster and the coordination polymer were semiconductors with wide band gaps of 3.08 and 2.80 ev. They photocatalytically degraded rhodamine B and methylene blue in aqueous solutions. The moderate conditions used for the synthesis could allow for further in situ studies of the reaction-assembly of related clusters and coordination polymers. PMID- 25747252 TI - Genome-wide analysis reveals diverged patterns of codon bias, gene expression, and rates of sequence evolution in picea gene families. AB - The recent sequencing of several gymnosperm genomes has greatly facilitated studying the evolution of their genes and gene families. In this study, we examine the evidence for expression-mediated selection in the first two fully sequenced representatives of the gymnosperm plant clade (Picea abies and Picea glauca). We use genome-wide estimates of gene expression (>50,000 expressed genes) to study the relationship between gene expression, codon bias, rates of sequence divergence, protein length, and gene duplication. We found that gene expression is correlated with rates of sequence divergence and codon bias, suggesting that natural selection is acting on Picea protein-coding genes for translational efficiency. Gene expression, rates of sequence divergence, and codon bias are correlated with the size of gene families, with large multicopy gene families having, on average, a lower expression level and breadth, lower codon bias, and higher rates of sequence divergence than single-copy gene families. Tissue-specific patterns of gene expression were more common in large gene families with large gene expression divergence than in single-copy families. Recent family expansions combined with large gene expression variation in paralogs and increased rates of sequence evolution suggest that some Picea gene families are rapidly evolving to cope with biotic and abiotic stress. Our study highlights the importance of gene expression and natural selection in shaping the evolution of protein-coding genes in Picea species, and sets the ground for further studies investigating the evolution of individual gene families in gymnosperms. PMID- 25747255 TI - Integrated HPV genomes tend to integrate in gene desert areas in the CaSki, HeLa, and SiHa cervical cancer cell lines. AB - AIMS: The integration preferences of human papillomavirus (HPV) have been intensively studied and contested over recent years. To disclose the integration preferences of high-risk HPV in cervical cancer, HPV transcriptional sites and features in different cervical cancer cell lines were identified. MAIN METHODS: In this study, three cervical cancer cell lines (CaSki, HeLa, and SiHa) were subjected for HPV genome status determination by amplification of papillomavirus oncogene transcripts (APOT) assay. The numbers of viral copies in human genomes and numbers of viral-human fusion mRNAs in three HPV-integrated cervical cancer cell lines were measured and analysed. KEY FINDINGS: The results revealed that the gene desert region 8q24 of the HPV type 18 integrated HeLa cell line and the 13q21-22 region of the HPV type 16 integrated CaSki and SiHa cell lines were hotspots for HPV integration, and the numbers of viral copies in the human genomes of the three cell lines that we detected were not in accordance with those reported in previous studies. SIGNIFICANCE: Integration of the HPV genome into the host cell chromosome suggests that persistent HPV infection is vital for malignant cell transformation and carcinogenesis. This study provides information to benefit health care professionals seeking more comprehensive and accurate diagnostics for HPV-related disease"? Please check, and amend as necessary. PMID- 25747256 TI - The role of glucocorticoid receptor phosphorylation in the model of negative affective states. AB - OBJECTIVES: To develop a structural equation model of negative affectivity (NA) that involves interaction of glucocorticoid receptor (GR) signaling, personality dimensions and recent stressful life events. METHODS: Seventy participants - 35 diagnosed with major depression and 35 healthy controls, were enrolled in the study. Morning plasma cortisol levels were determined by chemiluminescent immunometric assays. Molecular parameters (total nuclear and cytoplasmatic GR, nuclear GR phosphorylated at serine 211 (pGR-211) and at serine 226 (pGR-226) and cytoplasmic FKBP51) were analysed from peripheral blood lymphocytes by Western blot. NA, personality dimensions and stressful life events were assessed by self report instruments. RESULTS: GR signalling parameters had direct independent effect on measures of NA, with pGR-226 levels showing the strongest correlation, followed by FKBP51 and pGR-211 levels. Neuroticism and extraversion also demonstrated strong independent effect on NA, while recent stressful events did not predict NA directly, but demonstrated a significant effect on personality dimensions. Cortisol, total nuclear GR and total cytoplasmatic GR levels were excluded from the model due to non-significant correlations with NA. CONCLUSIONS: Negative affectivity is a transdiagnostic factor in vulnerability to affective disorders and possible therapeutic target. Molecular signature of negative affectivity should incorporate GR phosphorylation with other known biological underpinnings. PMID- 25747257 TI - Factors affecting response, number of laser sessions and complications in nevus of Ota treated by Q-switched alexandrite laser: a retrospective study. AB - BACKGROUND: The aim of this study was to study and analyze the factors influencing the treatment response to Q-switched alexandrite laser in patients with nevus of Ota and the factors influencing the number of laser sessions. METHODS: Forty-eight patients treated with Q-switched alexandrite between 2009 and 2013 for nevus of Ota were enrolled in this retrospective, single-center study. The subjects (13 male, 35 female) were divided into three groups according to the number of treatment sessions. Patients were then called back to the hospital for a follow-up interview and examination. Single and multiple variate analyses of various factors were performed. RESULTS: The 48 patients were predominantly female (35 female, 13 male, F:M ratio = 2.7:1), mean age 17.2+/ 10.41. Twenty-five (52.1%) had lesion on the right side of the face, 22 (45.8%) on the left side, and one (2.1%) on both sides. The predominant color was brown (41.7%), followed by cyan (39.6%) and lividity (18.8%). Satisfactory result was observed in all patients, after 3 to 11 treatment sessions (mean 5.37+/-2); 19 of these (39.6%) needed three to four sessions (short treatment sessions), 22 (45.8%) needed five to seven sessions (intermediate treatment sessions), and 7 (14.6%) needed nine to eleven sessions (long treatment sessions). The clinical response and treatment sessions of the young-age group were significantly better than the adult group. Those with higher Tanino's classification needed more treatment sessions. Dark-colored lesions, which reflect deep melanosis of the lesion, needed more sessions than lighter-colored lesions. As for skin color, better response was obtained in light-skinned patients than in dark-skinned ones. Two patients showed transient hypopigmentation that lasted for less than six months, and recurrence has been seen in one child with dark-colored lesion. CONCLUSIONS: Q-switched alexandrite laser is an ideal minimally-invasive method for treating nevus of Ota. Fewer treatment sessions are needed for children and younger patients, whereas brown lesion, lower Tanino's classification and light skin patients. PMID- 25747258 TI - Dermoscopy as an adjuvant tool for the diagnosis and management of basal cell carcinoma. AB - The list of dermoscopic criteria associated with basal cell carcinoma (BCC) have been several times updated and renewed. Up to date, dermoscopy has been shown to increase diagnostic and therapeutic accuracy, since provides valuable information about histopathologic subtype, a more accurate assessment of the true extension of tumor, the presence of pigmentation not visible to the naked eye and the treatment choice for BCC. In the current review, we provide an update of the traditional and latest knowledges on the value of dermatoscopy for the diagnosis and management of BCC. PMID- 25747259 TI - Psoriasis awareness among Italian patients: results of a nationwide survey. AB - BACKGROUND: This was a prospective, multicentre study conducted in 14 Italian psoriasis referral centres (January-June 2014) with the objective of identifying factors associated with different levels of patient awareness on psoriasis. METHODS: Overall, 298 patients (119 females, mean age 49.4 years, range 20-88) with a diagnosis of psoriasis (median of 14.1 years) were enrolled. Patients were more knowledgeable about the pathogenic nature of their condition compared with the other parameters (diagnosis, clinical course, prognosis, effect on QoL). Variables associated with significantly higher awareness, included years of education (the higher the educational levels the greater awareness), internet usage, other family member with the disease, diet rich in fruit/vegetables, cigarette smoking and bone and joint involvement. RESULTS: Older age, diabetes, and alcohol abuse were inversely associated. CONCLUSIONS: Having established factors that affect awareness in our patients we can now go on to devise educational interventions to address these needs. PMID- 25747260 TI - Biosimilar infliximab: an expert view. AB - CT-P13, a biosimilar of infliximab, was the first biosimilar monoclonal antibody to be approved in both the European Union and Korea. As a monoclonal antibody, CT P13 is a large molecule with a high molecular weight, and as such it differs from other biosimilars currently in the market. The comparability exercise for CT-P13, therefore, requires special consideration, as it was the first demonstration of biosimilarity between a biosimilar monoclonal antibody and its originator. This paper summarizes current regulations on the approval of biosimilars, describes the evidence leading to the approval of CT-P13, and discusses the potential role of this molecule in the Italian scenario on the basis of the view of a group of experts. PMID- 25747261 TI - Genome-wide analysis of core promoter structures in Schizosaccharomyces pombe with DeepCAGE. AB - The core promoter, which immediately flanks the transcription start site (TSS), plays a critical role in transcriptional regulation of eukaryotes. Recent studies on higher eukaryotes have revealed an unprecedented complexity of core promoter structures that underscores diverse regulatory mechanisms of gene expression. For unicellular eukaryotes, however, the structures of core promoters have not been investigated in detail. As an important model organism, Schizosaccharomyces pombe still lacks the precise annotation for TSSs, thus hampering the analysis of core promoter structures and their relationship to higher eukaryotes. Here we used a deep sequencing-based approach (DeepCAGE) to generate 16 million uniquely mapped tags, corresponding to 93,736 positions in the S. pombe genome. The high resolution TSS landscape enabled identification of over 8,000 core promoters, characterization of 4 promoter classes and observation of widespread alternative promoters. The landscape also allowed precise determination of the representative TSSs within core promoters, thus redefining the 5' UTR for 82.8% of S. pombe genes. We further identified the consensus initiator (Inr) sequence- PyPyPuN(A/C)(C/A), the TATA-enriched region (between position -25 and -37) and an Inr immediate downstream motif--CC(T/A)(T/C)(T/C/A)(A/G)CCA(A/T/C), all of which were associated with highly expressed promoters. In conclusion, the detailed analysis of core promoters not only significantly improves the genome annotation of S. pombe, but also reveals that this unicellular eukaryote shares a highly similar organization in the core promoters with higher eukaryotes. These findings lend additional evidence for the power of this model system in delineating complex regulatory processes in multicellular organisms, despite its perceived simplicity. PMID- 25747262 TI - Rapid identification and source-tracking of Listeria monocytogenes using MALDI TOF mass spectrometry. AB - Listeria monocytogenes is an important foodborne pathogen responsible for the sometimes fatal disease listeriosis. Public health concerns and stringent regulations associated with the presence of this pathogen in food and food processing environments underline the need for rapid and reliable detection and subtyping techniques. In the current study, the application of matrix assisted laser desorption/ionisation-time-of-flight mass spectrometry (MALDI-TOF MS) as a single identification and source-tracking tool for a collection of L. monocytogenes isolates, obtained predominantly from dairy sources within Australia, was explored. The isolates were cultured on different growth media and analysed using MALDI-TOF MS at two incubation times (24 and 48 h). Whilst reliable genus-level identification was achieved from most media, identification at the species level was found to be dependent on culture conditions. Successful speciation was highest for isolates cultured on the chromogenic Agar Listeria Ottaviani Agosti agar (ALOA, 91% of isolates) and non-selective horse blood agar (HBA, 89%) for 24h. Chemometric statistical analysis of the MALDI-TOF MS data enabled source-tracking of L. monocytogenes isolates obtained from four different dairy sources. Strain-level discrimination was also observed to be influenced by culture conditions. In addition, t-test/analysis of variance (ANOVA) was used to identify potential biomarker peaks that differentiated the isolates according to their source of isolation. Source-tracking using MALDI-TOF MS was compared and correlated with the gold standard pulsed-field gel electrophoresis (PFGE) technique. The discriminatory index and the congruence between both techniques were compared using the Simpsons Diversity Index and adjusted Rand and Wallace coefficients. Overall, MALDI-TOF MS based source-tracking (using data obtained by culturing the isolates on HBA) and PFGE demonstrated good congruence with a Wallace coefficient of 0.71 and comparable discriminatory indices of 0.89 and 0.86, respectively. MALDI-TOF MS thus represents a rapid and cost-effective source-tracking technique for L. monocytogenes. PMID- 25747263 TI - A feasibility dosimetric study on prostate cancer : are we ready for a multicenter clinical trial on SBRT? AB - PURPOSE: The Italian Association of Medical Physics (AIFM) started a working group dedicated to stereotactic body radiotherapy (SBRT) treatment. In this work, we performed a multicenter planning study on patients who were candidates for SBRT in the treatment of prostate cancer with the aim of evaluating the dosimetric consistency among the different hospitals. METHODS AND MATERIALS: Fourteen centers were provided the contours of 5 patients. Plans were performed following the dose prescription and constraints for organs at risk (OARs) of a reference paper. The dose prescription was 35 Gy in five fractions for the planning target volume (PTV). Different techniques were used (3D-CRT, fixed-Field IMRT, VMAT, CyberKnife). Plans were compared in terms of dose-volume histogram (DVH) parameters. Furthermore, the median DVH was calculated and one patient was re-planned. RESULTS: A total of 70 plans were compared. The maximum dose to the body was 107.9 +/- 4.5 % (range 101.5-116.3 %). Dose at 98 % (D98 %) and mean dose to the clinical target volume (CTV) were 102.0 +/- 0.9 % (global range 101.1 102.9 %) and 105.1 +/- 0.6 % (range 98.6-124.6 %). Similar trends were found for D95 % and mean dose to the PTV. Important differences were found in terms of the homogeneity index. Doses to OARs were heterogeneous. The subgroups with the same treatment planning system showed differences comparable to the differences of the whole group. In the re-optimized plans, DVH differences among institutes were reduced and OAR sparing improved. CONCLUSION: Important dosimetric differences with possible clinical implications, in particular related to OARs, were found. Replanning allowed a reduction in the OAR dose and decreased standard deviations. Multicenter clinical trials on SBRT should require a preplanning study to standardize the optimization procedure. PMID- 25747265 TI - Correction: The influence of promoter architectures and regulatory motifs on gene expression in Escherichia coli. PMID- 25747266 TI - Dinoflagellate diversity among nudibranchs and sponges from French Polynesia: insights into associations and transfer. AB - Symbioses with the dinoflagellate Symbiodinium are widespread among marine invertebrates and protists, especially in nutritionally demanding habitats, such as tropical coral reefs, where they play a major role in ecosystem survival. Moreover, apart from corals and sea anemones, many of the Symbiodinium species and clades involved in these partnerships remain to be characterized. This study provides new insights into nudibranch and sponge associations with Symbiodinium by sequencing regions of the Symbiodinium 28S rDNA and the host mitochondrial COI oxidase. Specimens were sampled between 2011 and 2013 from locations around the islands of Moorea and Tahiti, French Polynesia. Our results revealed that some of the sponges and nudibranchs harbored typical Symbiodinium from clade B or C while others harbored new, undescribed Symbiodinium-like dinoflagellates. A detailed analysis of the different life stages of the nudibranch Phestilla lugubris and of its specific coral prey, Porites rus, suggests a prey-predator horizontal transfer of the symbiont and its vertical inheritance from the parent to the eggs. PMID- 25747264 TI - Residual deficits in quality of life one year after intensity-modulated radiotherapy for patients with locally advanced head and neck cancer: Results of a prospective study. AB - PURPOSE: Patients with locally advanced head and neck cancer (LAHNC) undergo life changing treatments that can seriously affect quality of life (QoL). This prospective study examined the key QoL domains during the first year after intensity-modulated radiotherapy (IMRT) and identified predictors of these changes in order to improve patient outcomes. PATIENTS AND METHODS: A consecutive series of patients with LAHNC completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core module (QLQ C30) and the HNC-specific QLQ-HN35 before (t0) and at the end (t1) of definitive or adjuvant IMRT, then at 6-8 weeks (t2), 6 months (t3), and 1 year (t4) after IMRT. RESULTS: Patients (n = 111) completing questionnaires at all five time points were included (baseline response rate: 99%; dropout rate between t0 and t4: 5%). QoL deteriorated in all domains during IMRT and improved slowly during the first year thereafter. Many domains recovered to baseline values after 1 year but problems with smelling and tasting, dry mouth, and sticky saliva remained issues at this time. Increases in problems with sticky saliva were greater after 1 year in patients with definitive versus adjuvant IMRT (F = 3.5, P = 0.05). CONCLUSION: QoL in patients with LAHNC receiving IMRT takes approximately 1 year to return to baseline; some domains remain compromised after 1 year. Although IMRT aims to maintain function and QoL, patients experience long-term dry mouth and sticky saliva, particularly following definitive IMRT. Patients should be counseled at the start of therapy to reduce disappointment with the pace of recovery. PMID- 25747267 TI - Impact of dual inoculation with Rhizobium and PGPR on growth and antioxidant status of Vicia faba L. under copper stress. AB - Plant-growth-promoting bacteria (PGPR) may help reduce the toxicity of heavy metals in plants in polluted environments. In this work, the effects of dual inoculation with Rhizobium and PGPR strains on the growth of Vicia faba grown under copper stress were assessed during hydroponic culture. Growth parameters, copper (Cu) accumulation and antioxidant enzyme activities were studied. Copper concentrations above 1mM damaged plant growth, but co-inoculation reduced its harmful effect. Co-inoculation of plants treated with 1mM Cu and 2mM Cu increased the dry weights as compared with Cu-treated and uninoculated plants. However, it decreased copper uptake up to 80% in the roots of 1-mM-Cu-treated plants as compared to non-inoculated control. Copper tolerance in Vicia faba is linked to the activity of antioxidant systems that are modulated by metal concentrations: both superoxide dismutase (SOD) and catalase (CAT) were higher in the presence of Cu; a lower Cu dose of 0.5mM stimulated ascorbate peroxidase (APX) and/or peroxidase (POX) activities in shoots and roots; however in nodules CAT appeared to be the main peroxidase in H2O2 scavenging. The 1mM Cu treatment enhanced SOD, CAT and APX activities in roots and only SOD and POX were activated in shoots. All enzyme activities were inhibited by inoculation of 2mM Cu. The effect of inoculation with copper-accumulating PGPRs and the status of the antioxidant enzyme system were linked to changes in the copper tolerance status of Vicia faba. Our results suggested that Vicia faba inoculation with Rhizobium and PGPR Enterobacter clocae and Pseudomonas sp. could help to alleviate copper stress under hydroponic conditions. This result should be tested under field conditions for soil fertilization and phytostabilisation purposes. PMID- 25747268 TI - High-throughput enantiopurity analysis using enantiomeric DNA-based sensors. AB - Distinguishing between the two enantiomers of a molecule is a challenging task due to their nearly identical physical properties. Time-consuming chromatography methods are typically required for this task, which greatly limits the throughput of analysis. Here we describe a fluorescence-based method for the rapid and high throughput analysis of both small-molecule enantiopurity and concentration. Our approach relies on selective molecular recognition of one enantiomer of the target molecule using a DNA aptamer, and the ability of aptamer-based biosensors to transduce the presence of a target molecule into a dose-dependent fluorescence signal. The key novel aspect of our approach is the implementation of enantiomeric DNA biosensors, which are synthesized from D- and L-DNA, but labeled with orthogonal fluorophores. According to the principle of reciprocal chiral substrate specificity, these biosensors will bind to opposite enantiomers of the target with equal affinity and selectivity, enabling simultaneous quantification of both enantiomers of the target. Using the previously reported DNA biosensor for L-tyrosinamide (L-Tym), we demonstrate the ability to rapidly and accurately measure both enantiopurity and concentration for mixtures of L- and D-Tym. We also apply our enantiomeric biosensors to the optimization of reaction conditions for the synthesis of D-Tym and provide mathematical modeling to suggest that DNA biosensors having only modest binding selectivity can also be used for fluorescence-based enantiopurity measurement. This research provides a generalizable method for high-throughput analysis of reaction mixtures, which is anticipated to significantly accelerate reaction optimization for the synthesis of high-value chiral small molecules. PMID- 25747270 TI - Walnuts (Juglans regia) Chemical Composition and Research in Human Health. AB - Walnuts are among the most widely consumed commercially grown tree nuts in the world. Many health benefits have been claimed for the consumption of these, including reduced risk of cardiovascular disease, coronary heart disease, type II diabetes treatment, and prevention and treatment of certain cancers, and the lessening of symptoms attributed to age-related and other neurological disorders. The health-promoting benefits of walnut consumption are ascribed to its fatty acid profile, which is rich in polyunsaturated fatty acids with a particularly high omega3:omega6 ratio-the highest among all the tree nuts. The content of polyphenols and other phytochemicals in walnuts, with their claimed cytotoxic properties, also make them an attractive candidate for research for the prevention of free radical-induced nucleic acid damage. Research of walnut consumption in humans and animals employing a range of data sets and statistical methods suggest that walnuts may be considered a safe potential nutraceutical or possibly pharmaceutical substance. Nevertheless, few reviews of scientific research on the proposed benefits of these nuts exist, in spite of the numerous claims attributed to them in the lay media. This brief review article attempts to disseminate much of the information surrounding walnut consumption, and human health benefits, to other scientists and the interested general reader. PMID- 25747269 TI - Pertussis post-exposure prophylaxis among household contacts: a cost-utility analysis. AB - BACKGROUND: Recent pertussis outbreaks have prompted re-examination of post exposure prophylaxis (PEP) strategies, when immunization is not immediately protective. Chemoprophylaxis is recommended to household contacts; however there are concerns of clinical failure and significant adverse events, especially with erythromycin among infants who have the highest disease burden. Newer macrolides offer fewer side effects at higher drug costs. We sought to determine the cost effectiveness of PEP strategies from the health care payer perspective. METHODS: A Markov model was constructed to examine 4 mutually exclusive strategies: erythromycin, azithromycin, clarithromycin, or no intervention, stratified by age group of contacts ("infant", "child", and "adult"). Transition probabilities, costs and quality-adjusted life years (QALYs) were derived from the literature. Chronic neurologic sequelae were modeled over a lifetime, with costs and QALYs discounted at 5%. Associated health outcomes and costs were compared, and incremental cost-effectiveness ratios (ICER) were calculated in 2012 Canadian dollars. Deterministic and probabilistic sensitivity analyses were performed to evaluate the degree of uncertainty in the results. FINDINGS: Azithromycin offered the highest QALYs in all scenarios. While this was the dominant strategy among infants, it produced an ICER of $16,963 per QALY among children and $2,415 per QALY among adults. Total QALYs with azithromycin were 19.7 for a 5-kg infant, 19.4 for a 10-year-old child, and 18.8 for a 30-year-old adult. The costs of azithromycin PEP among infants, children and adults were $1,976, $132 and $90, respectively. While results were sensitive to changes in PEP effectiveness (11% to 87%), disease transmission (variable among age groups) and hospitalization costs ($379 to $59,644), the choice of strategy remained unchanged. INTERPRETATION: Pertussis PEP is a cost-effective strategy compared with no intervention and plays an important role in contact management, potentially in outbreak situations. From a healthcare payer perspective, azithromycin is the optimal strategy among all contact groups. PMID- 25747271 TI - 25I-NBOMe related death in Australia: a case report. AB - We present a toxicologically confirmed 25I-NBOMe related death from Australia. 25I-NBOMe is a synthetic new psychoactive substance (NPS), which is a derivative of the 2C-X series of phenethylamines. NBOMe compounds have hallucinogenic and stimulant properties and are potent agonists of the human 5HT2A receptor. They have been associated with severe toxicity and fatalities. No case reports on deaths related to 25I-NBOMe toxicity from Australia have been published thus far. Very limited toxicological data is available in the current literature. The decedent in the presented case had a post mortem aortic non-preserved blood concentration of 25I-NBOMe of approximately 28 MUg/L, a concentration that appears to be much higher than those previously reported in non-fatal cases of toxicity and analytically confirmed 25I-NBOMe related fatalities. The publication of new data is essential in improving knowledge and awareness amongst the forensic community regarding emerging psychoactive substances, such as the NBOMe compounds. PMID- 25747272 TI - Single-quantum-dot tracking reveals altered membrane dynamics of an attention deficit/hyperactivity-disorder-derived dopamine transporter coding variant. AB - The presynaptic, cocaine- and amphetamine-sensitive dopamine (DA) transporter (DAT, SLC6A3) controls the intensity and duration of synaptic dopamine signals by rapid clearance of DA back into presynaptic nerve terminals. Abnormalities in DAT mediated DA clearance have been linked to a variety of neuropsychiatric disorders, including addiction, autism, and attention deficit/hyperactivity disorder (ADHD). Membrane trafficking of DAT appears to be an important, albeit incompletely understood, post-translational regulatory mechanism; its dysregulation has been recently proposed as a potential risk determinant of these disorders. In this study, we demonstrate a link between an ADHD-associated DAT mutation (Arg615Cys, R615C) and variation on DAT transporter cell surface dynamics, a combination only previously studied with ensemble biochemical and optical approaches that featured limited spatiotemporal resolution. Here, we utilize high-affinity, DAT-specific antagonist-conjugated quantum dot (QD) probes to establish the dynamic mobility of wild-type and mutant DATs at the plasma membrane of living cells. Single DAT-QD complex trajectory analysis revealed that the DAT 615C variant exhibited increased membrane mobility relative to DAT 615R, with diffusion rates comparable to those observed after lipid raft disruption. This phenomenon was accompanied by a loss of transporter mobilization triggered by amphetamine, a common component of ADHD medications. Together, our data provides the first dynamic imaging of single DAT proteins, providing new insights into the relationship between surface dynamics and trafficking of both wild-type and disease-associated transporters. Our approach should be generalizable to future studies that explore the possibilities of perturbed surface DAT dynamics that may arise as a consequence of genetic alterations, regulatory changes, and drug use that contribute to the etiology or treatment of neuropsychiatric disorders. PMID- 25747273 TI - Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. AB - BACKGROUND & AIMS: No adjuvant therapy has been shown to extend the survival of patients with hepatocellular carcinoma (HCC) receiving curative treatment. We investigated whether injections of activated cytokine-induced killer (CIK) cells (CD3+/CD56+ and CD3+/CD56- T cells and CD3-/CD56+ natural killer cells) prolongs recurrence-free survival of patients after curative therapy for HCC. METHODS: We performed a multicenter, randomized, open-label, phase 3 trial of the efficacy and safety of adjuvant immunotherapy with activated CIK cells (created by incubation of patients' peripheral blood mononuclear cells with interleukin 2 and an antibody against CD3). The study included 230 patients with HCC treated by surgical resection, radiofrequency ablation, or percutaneous ethanol injection at university-affiliated hospitals in Korea. Patients were assigned randomly to receive immunotherapy (injection of 6.4 * 10(9) autologous CIK cells, 16 times during 60 weeks) or no adjuvant therapy (controls). The primary end point was recurrence-free survival; secondary end points included overall survival, cancer specific survival, and safety. RESULTS: The median time of recurrence-free survival was 44.0 months in the immunotherapy group and 30.0 months in the control group (hazard ratio with immunotherapy, 0.63; 95% confidence interval [CI], 0.43-0.94; P = .010 by 1-sided log-rank test). Hazard ratios also were lower in the immunotherapy than in the control group for all-cause death (0.21; 95% CI, 0.06-0.75; P = .008) and cancer-related death (0.19; 95% CI, 0.04-0.87; P = .02). A significantly higher proportion of patients in the immunotherapy group than in the control group had an adverse event (62% vs 41%; P = .002), but the proportion of patients with serious adverse events did not differ significantly between groups (7.8% vs 3.5%; P = .15). CONCLUSIONS: In patients who underwent curative treatment for HCC, adjuvant immunotherapy with activated CIK cells increased recurrence-free and overall survival. ClinicalTrials.gov number: NCT00699816. PMID- 25747275 TI - Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance. AB - Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. PMID- 25747276 TI - Physiological functions at single-cell level of Lactobacillus spp. isolated from traditionally fermented cabbage in response to different pH conditions. AB - Changes in pH are significant environmental stresses that may be encountered by lactobacilli during fermentation processes or passage through the gastrointestinal tract. Here, we report the cell response of Lactobacillus spp. isolated from traditionally fermented cabbage subjected to acid/alkaline treatments at pH 2.5, 7.4 and 8.1, which represented pH conditions of the gastrointestinal tract. Among six isolates, four species of Lactobacillus plantarum and two of Lactobacillus brevis were identified by fluorescence in situ hybridization (FISH). The fluorescence-based strategy of combining carboxyfluorescein diacetate (CFDA) and propidium iodine (PI) into a dual staining assay was used together with epifluorescence microscopy (EFM) and flow cytometry (FCM) for viability assessment. The results showed that the cells maintained esterase activity and membrane integrity at pH 8.1 and 7.4. There was also no loss of culturability as shown by plate counts. In contrast, the majority of 2.5 pH-treated cells had a low extent of esterase activity, and experienced membrane perturbation. For these samples, an extensive loss of culturability was demonstrated. Comparison of the results of an in situ assessment with that of the conventional culturing method has revealed that although part of the stressed population was unable to grow on the growth media, it was deemed viable using a CFDA/PI assay. However, there was no significant change in the cell morphology among pH-treated lactobacilli populations. These analyses are expected to be useful in understanding the cell response of Lactobacillus strains to pH stress and may facilitate future investigation into functional and industrial aspects of this response. PMID- 25747277 TI - Superhydrophobic and highly luminescent polyfluorene/silica hybrid coatings deposited onto glass and cellulose-based substrates. AB - Neat poly(9,9-dioctyl-9H-fluorene) (PFO) and composites of PFO and a modified organonanosilica P(7) at weight ratios 90/10, 70/30, and 50/50 have been employed to prepare fluorescent and superhydrophobic coatings by spraying onto three different substrates: glass, Whatman paper, and a filtration membrane of mixed cellulose esters. The water repellency of the coatings and their photophysical properties are therein studied. It is found that, irrespective of the substrate and the composite composition, all coatings remain fluorescent. In some of the coatings prepared, confined morphologies are created, which fluoresce with a wavelength distribution resembling that of an ordered planar beta-phase. Among the coatings prepared in this work, those with a ratio PFO/P(7) of 50/50 are the ones with the strongest chain confinement and the highest surface roughness, being highly emissive at the beta-phase wavelengths and also superhydrophobic. Depending on the substrate these materials are also tough and flexible (cellulose based substrates) or display a remarkable light transmittance (glass). A final merit of these multifunctional materials is the simplicity of the preparation procedure, adequate for large surfaces and industrial applications. PMID- 25747274 TI - beta-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. AB - beta-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at beta-catenin. beta-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1alpha to regulate the expression of target genes. We discuss the role of beta-catenin in metabolic zonation of the adult liver. beta-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in beta-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of beta-catenin, so this molecule could be a therapeutic target. We discuss how alterations in beta-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics. PMID- 25747278 TI - Role of toll-like receptor-4 in lung ischemia-reperfusion injury. AB - BACKGROUND: Toll-like receptor-4 has been implicated in modulating ischemia reperfusion injury in cardiac, hepatic, renal, and cerebral models. However, its role in lung ischemia-reperfusion injury is unknown. We hypothesize that toll like receptor-4 has a key role in initiating the inflammatory cascade in lung ischemia-reperfusion injury. METHODS: We used toll-like receptor-4 specific short interference RNA to achieve toll-like receptor-4 knockdown in rats prior to undergoing ischemia and reperfusion. Lungs were explanted and studied for protein expression and markers of lung injury. Additional animals were evaluated for cellular uptake of toll-like receptor-4 short interference RNA. Toll-like receptor-4 short interference RNA localized to the alveolar macrophage. RESULTS: In animals pretreated with toll-like receptor-4 short interference RNA, toll-like receptor-4 expression and mitogen-activated protein kinase phosphorylation were suppressed. Markers of lung injury including permeability index, myeloperoxidase content, and bronchoalveolar lavage inflammatory cell counts were all reduced with toll-like receptor-4 knockdown. CONCLUSIONS: Toll-like receptor-4 is critical in the development of lung ischemia-reperfusion injury and its activation in the alveolar macrophage may be the initiating step. PMID- 25747279 TI - Oral administration of PF-01247324, a subtype-selective Nav1.8 blocker, reverses cerebellar deficits in a mouse model of multiple sclerosis. AB - Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS). We previously showed that sodium channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia and MS like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of disease in a mouse MS model; unfortunately A-803467 is not orally bioavailable, diminishing the potential for translation to human patients. In the present study, we assessed the effect of per os (p.o.) dosing of a new orally bioavailable Nav1.8-selective blocker, PF-01247324, in transgenic mice expressing Nav1.8 in Purkinje neurons, and in wildtype mice in the experimental autoimmune encephalomyelitis (EAE) model. PF-01247324 was administered by oral gavage at 1000 mg/kg; control groups received an equal volume of vehicle. Behavioral assays of motor coordination, grip strength, and ataxia were performed. We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. These preclinical proof-of-concept data suggest that PF-01247324, its derivatives, or other Nav1.8-selective blockers merit further study for providing symptomatic therapy for cerebellar dysfunction in MS and related disorders. PMID- 25747280 TI - Mechanisms shaping size structure and functional diversity of phytoplankton communities in the ocean. AB - The factors regulating phytoplankton community composition play a crucial role in structuring aquatic food webs. However, consensus is still lacking about the mechanisms underlying the observed biogeographical differences in cell size composition of phytoplankton communities. Here we use a trait-based model to disentangle these mechanisms in two contrasting regions of the Atlantic Ocean. In our model, the phytoplankton community can self-assemble based on a trade-off emerging from relationships between cell size and (1) nutrient uptake, (2) zooplankton grazing, and (3) phytoplankton sinking. Grazing 'pushes' the community towards larger cell sizes, whereas nutrient uptake and sinking 'pull' the community towards smaller cell sizes. We find that the stable environmental conditions of the tropics strongly balance these forces leading to persistently small cell sizes and reduced size diversity. In contrast, the seasonality of the temperate region causes the community to regularly reorganize via shifts in species composition and to exhibit, on average, bigger cell sizes and higher size diversity than in the tropics. Our results raise the importance of environmental variability as a key structuring mechanism of plankton communities in the ocean and call for a reassessment of the current understanding of phytoplankton diversity patterns across latitudinal gradients. PMID- 25747281 TI - Function and repair of dental enamel - Potential role of epithelial transport processes of ameloblasts. AB - The hardest mammalian tissue, dental enamel is produced by ameloblasts, which are electrolyte-transporting epithelial cells. Although the end product is very different, they show many similarities to transporting epithelia of the pancreas, salivary glands and kidney. Enamel is produced in a multi-step epithelial secretory process that features biomineralization which is an interplay of secreted ameloblast specific proteins and the time-specific transport of minerals, protons and bicarbonate. First, "secretory" ameloblasts form the entire thickness of the enamel layer, but with low mineral content. Then they differentiate into "maturation" ameloblasts, which remove organic matrix from the enamel and in turn further build up hydroxyapatite crystals. The protons generated by hydroxyapatite formation need to be buffered, otherwise enamel will not attain full mineralization. Buffering requires a tight pH regulation and secretion of bicarbonate by ameloblasts. The whole process has been the focus of many immunohistochemical and gene knock-out studies, but, perhaps surprisingly, no functional data existed for mineral ion transport by ameloblasts. However, recent studies including ours provided a better insight for molecular mechanism of mineral formation. The secretory regulation is not completely known as yet, but its significance is crucial. Impairing regulation retards or prevents completion of enamel mineralization and results in the development of hypomineralized enamel that easily erodes after dental eruption. Factors that impair this function are fluoride and disruption of pH regulators. Revealing these factors may eventually lead to the treatment of enamel hypomineralization related to genetic or environmentally induced malformation. PMID- 25747282 TI - Conservation, management, and restoration of coral reefs. AB - The 8th International Conference on Coelenterate Biology (ICCB 8) was held in Eilat, Israel from December 1st to 5th 2013. The conference included 15 sessions, one of which discussed the latest information on the conservation, management, and restoration of Coelenterata in different parts of the world. A total of 16 oral presentations and 5 posters were presented in this session. Of these 21 papers, 11 were related to conservation issues, 7 described management, and 3 discussed restoration. This session provided insights on the current conservation, management, and restoration of coelenterates in different parts of the world. PMID- 25747283 TI - HAADF-STEM atom counting in atom probe tomography specimens: Towards quantitative correlative microscopy. AB - The geometry of atom probe tomography tips strongly differs from standard scanning transmission electron microscopy foils. Whereas the later are rather flat and thin (<20 nm), tips display a curved surface and a significantly larger thickness. As far as a correlative approach aims at analysing the same specimen by both techniques, it is mandatory to explore the limits and advantages imposed by the particular geometry of atom probe tomography specimens. Based on simulations (electron probe propagation and image simulations), the possibility to apply quantitative high angle annular dark field scanning transmission electron microscopy to of atom probe tomography specimens has been tested. The influence of electron probe convergence and the benefice of deconvolution of electron probe point spread function electron have been established. Atom counting in atom probe tomography specimens is for the first time reported in this present work. It is demonstrated that, based on single projections of high angle annular dark field imaging, significant quantitative information can be used as additional input for refining the data obtained by correlative analysis of the specimen in APT, therefore opening new perspectives in the field of atomic scale tomography. PMID- 25747284 TI - Density functional theory for field emission from carbon nano-structures. AB - Electron field emission is understood as a quantum mechanical many-body problem in which an electronic quasi-particle of the emitter is converted into an electron in vacuum. Fundamental concepts of field emission, such as the field enhancement factor, work-function, edge barrier and emission current density, will be investigated, using carbon nanotubes and graphene as examples. A multi scale algorithm basing on density functional theory is introduced. We will argue that such a first principle approach is necessary and appropriate for field emission of nano-structures, not only for a more accurate quantitative description, but, more importantly, for deeper insight into field emission. PMID- 25747285 TI - The association between personality traits and body mass index varies with nativity among individuals of Mexican origin. AB - Personality traits have been associated consistently with health-related outcomes, but less is known about how aspects of the sociocultural environment modify these associations. This study uses a sample of participants of Mexican origin (N = 1013) to test whether exposure to the United States, indexed by nativity (Mexicans living in Mexico, foreign-born Mexican Americans, and U.S. born Mexican Americans), moderates the association between personality traits and body mass index (BMI). Higher Conscientiousness was associated with lower BMI, regardless of nativity. In contrast, the association between Neuroticism and BMI was moderated by exposure to the U.S.: Neuroticism was associated with higher BMI among U.S.-born Mexican Americans (partial r = .15) but not among Mexican participants (partial r = .00), an effect strongest and most robust for the impulsivity facet of Neuroticism. This finding suggests that with more exposure to the United States, those who are more emotionally impulsive are at greater risk for obesity. More broadly, these findings suggest that social and psychological vulnerabilities interact to contribute to health outcomes. PMID- 25747286 TI - Viewers vs. doers. The relationship between watching food television and BMI. AB - The objective of this study was to examine where nutritional gatekeepers obtain information about new foods, and whether information source is associated with Body Mass Index (BMI), as well as whether any association varied according to how often the participant cooked from scratch. A national panel survey of 501 females aged 20-35 assessed how participants obtained information on new recipes, and asked a series of questions about their cooking habits, their weight and height. Linear regressions were run to determine associations between information source, cooking from scratch, and BMI. Obtaining information from cooking shows was positively correlated with BMI (p <0.05), as was obtaining information from social media (p <0.05), whereas obtaining information from other print, online, or in-person sources was not significantly associated with BMI. A significant interaction between watching cooking shows and cooking from scratch indicated that cooking from scratch, as well as watching cooking shows was associated with higher BMI (p <0.05). Obtaining information about new foods from television cooking shows or social media - versus other sources - appears to have a unique relationship with BMI. Furthermore, watching cooking shows may have a differential effect on BMI for those who are merely TV "viewers," versus those who are "doers." Promoting healthy foods on cooking shows may be one way to positively influence the weight status of "doers" as well as "viewers." PMID- 25747287 TI - Assessing the progression of autophagy pathways in different organisms and tissues. PMID- 25747288 TI - Molecular cloning and characterization of the ABA-specific glucosyltransferase gene from bean (Phaseolus vulgaris L.). AB - Levels of the plant hormone abscisic acid (ABA) are maintained in homeostasis by a balance of its biosynthesis, catabolism and conjugation. The detailed molecular and signaling events leading to strict homeostasis are not completely understood in crop plants. In this study, we obtained cDNA of an ABA-inducible, ABA-specific UDP-glucosyltransferase (ABAGT) from the bean plant (Phaseolus vulgaris L.) involved in conjugation of a glucose residue to ABA to form inactive ABA-glucose ester (ABA-GE) to examine its role during development and abiotic stress in bean. The bacterially expressed PvABAGTase enzyme showed ABA-specific glucosylation activity in vitro. A higher level of the PvABAGT transcript was observed in mature leaves, mature flowers, roots, seed coats and embryos as well as upon rehydration following a period of dehydration. Overexpression of 35S::PvABAGT in Arabidopsis showed reduced sensitivity to ABA compared with WT. The transgenic plants showed a high level of ABA-GE without significant decrease in the level of ABA compared with the wild type (WT) during dehydration stress. Upon rehydration, the levels of ABA and phaseic acid (PA) decreased in the WT and the PvABAGT overexpressing lines with high levels of ABA-GE only in the transgenic plants. Our findings suggest that the PvABAGT gene could play a role in ABA homeostasis during development and stress responses in bean and its overexpression in Arabidopsis did not alter ABA homeostasis during dehydration stress. PMID- 25747289 TI - Expression of genes for the biosynthesis of compatible solutes during pollen development under heat stress in tomato (Solanum lycopersicum). AB - Accumulation of compatible solutes is considered a key adaptation mechanism in many plants in response to abiotic stress. The expression of four genes, involved in sucrose metabolism (SPS and SuSy), biosynthesis of galactinol (GoLS1) and proline accumulation (P5CS) was compared: at meiosis (MM), vacuolated and mature stages of pollen development in heat tolerant and heat sensitive tomato genotypes. The results showed differences in gene expression across tomato genotypes and stages of pollen development. Three genes (P5CS, SPS and SuSy) were up regulated in heat tolerant genotype CLN1621L at the mature stage and one gene (P5CS) in genotype CLN5915-93D at the MM stage. Two genes (SPS and GoLS1) were down regulated in heat sensitive genotype CA4 and one gene (GoLS1) in genotype CLN2498E at the MM stage. Additionally, the continuous exposure of tomato genotypes to temperatures of 35 degrees C/28 degrees C day/night completely impaired flower development in genotypes CA4 and CLN2498E but not in genotypes CLN1621L and CLN5915-93D. Tomato genotypes CLN1621L and CLN5915-93D produced fully developed flowers containing mixture of non viable pollens and very few viable pollens grains. Membrane permeability was affected at all stages of development under heat stress with heat tolerant genotypes CL5915-93D4, CLN2498E and CLN1621L showing varying degrees of heat acclimation. Significant increases in total chlorophyll were seen in all genotypes in response to heat stress. The expression of compatible solute genes at MM is more critical than at mature stage for the development of viable pollen grain. PMID- 25747290 TI - Biosynthesis and biotechnological production of ginsenosides. AB - Medicinal plants are essential for improving human health, and around 75% of the population in developing countries relies mainly on herb-based medicines for health care. As the king of herb plants, ginseng has been used for nearly 5,000 years in the oriental and recently in western medicines. Among the compounds studied in ginseng plants, ginsenosides have been shown to have multiple medical effects such as anti-oxidative, anti-aging, anti-cancer, adaptogenic and other health-improving activities. Ginsenosides belong to a group of triterpene saponins (also called ginseng saponins) that are found almost exclusively in Panax species and accumulated especially in the plant roots. In this review, we update the conserved and diversified pathway/enzyme biosynthesizing ginsenosides which have been presented. Particularly, we highlight recent milestone works on functional characterization of key genes dedicated to the production of ginsenosides, and their application in engineering plants and yeast cells for large-scale production of ginsenosides. PMID- 25747291 TI - Industrial applications of enzyme biocatalysis: Current status and future aspects. AB - Enzymes are the most proficient catalysts, offering much more competitive processes compared to chemical catalysts. The number of industrial applications for enzymes has exploded in recent years, mainly owing to advances in protein engineering technology and environmental and economic necessities. Herein, we review recent progress in enzyme biocatalysis, and discuss the trends and strategies that are leading to broader industrial enzyme applications. The challenges and opportunities in developing biocatalytic processes are also discussed. PMID- 25747292 TI - Children's Views on Long-Term Screening for Type 1 Diabetes. AB - There are an increasing number of medical research studies involving children, including many long-term birth cohort studies. Involving children raises many issues, and little is known about children's own views. This study explored children's views (N = 5,851) on participation in a long-term screening study for type 1 diabetes. The results show that children 10 to 13 years of age have in general a positive attitude to pediatric research and emphasized trust in researchers. The children stressed the importance to receive information and to be involved in decisions. The children also reported feeling concerned about blood sampling and disease risk. Researchers involved in long-term pediatric research need to address these issues to promote involvement and decrease worry. PMID- 25747293 TI - Latino beliefs about biomedical research participation: a qualitative study on the U.S.-Mexico border. AB - Latinos are under-represented in biomedical research conducted in the United States, impeding disease prevention and treatment efforts for this growing demographic group. We gathered perceptions of biomedical research and gauged willingness to participate through elicitation interviews and focus groups with Latinos living on the U.S.-Mexico border. Themes that emerged included a strong willingness to participate in biomedical studies and suggested that Latinos may be under-represented due to limited formal education and access to health information, not distrust. The conflation of research and clinical care was common and motivated participation. Outreach efforts and educational interventions to inform Latinos of participation opportunities and clarify harms and benefits associated with biomedical research participation will be essential to maintain trust within Latino communities. PMID- 25747294 TI - Impact of non-welfare interests on willingness to donate to biobanks: an experimental survey. AB - The ethical debate surrounding biobanks has focused on protecting donors' welfare and privacy. However, little attention has been given to the ethical significance of donor interests that go beyond privacy and welfare (non-welfare interests [NWIs]), such as their concerns about the moral or religious implications of researchers using their donated samples. Using an experimental survey design with 1,276 participants recruited via Amazon Mechanical Turk (MTurk), we studied the potential impact of eight NWI scenarios on people's attitudes toward research studies being performed on samples donated to biobanks by assessing willingness to donate, attitudes toward disclosure of NWIs, impact of timing and format of disclosure (number of NWIs disclosed on a page), and participant factors associated with willingness to donate. Baseline willingness to donate to biobanks prior to any mention of NWIs was comparable with previous studies, at 85% to 89%. Most participants wanted NWI disclosures prior to donation to biobanks, but far fewer favored specific consent. Overall pattern of responses showed that as participants receive more information about NWIs, willingness to donate decreases in a scenario dependent manner. Specifically, NWI concerns about profit seeking research and insurance risk assessment had the strongest impact, even greater than controversial issues such as reproductive research, regardless of political, religious, and most other characteristics of respondents. Based on the results, a schema of NWI types is proposed that could be used for further research and policy discussions. PMID- 25747295 TI - Why does geoprivacy matter? The scientific publication of confidential data presented on maps. AB - We examined published maps containing sensitive data, and the protection methods, if any, that were used. We investigated whether the many published warnings about disclosure risk have been effective in reducing privacy risk. During an 8-year period (2005-2012), 19 journals related to GIScience, geography, spatial crime analysis, and health geography were examined. We identified 41 articles that display actual confidential information and 16 articles where confidential information is protected by the use of a geographical mask. During the investigated time frame, the numbers of articles with unmasked confidential data increased, and in total more than 68,000 home addresses were disclosed. One of the more significant findings of this study is that efforts to instill sensitivity to location privacy and disclosure risk have been relatively unsuccessful. PMID- 25747296 TI - Assessing Institutional Ethics Committees in India Using the IRB-RAT. AB - Institutional ethics committees (IECs) are currently still in their infancy in low- to middle-income countries (LMICs), which may have important implications with regard to the oversight of the protection of human participants. Understanding how these IECs currently function is a critical first step in helping LMICs build infrastructures that support the protection of research participants and improve the scientific quality of health research worldwide. We assessed the functioning of the IECs at two medical colleges in Gujarat, India, by administering the Institutional Review Board Researcher's Assessment Tool (IRB RAT) to 42 IEC and faculty members. The IRB-RAT includes eight scales assessing various domains related to how investigators and members perceive their ethics committees. Results from t tests revealed significant differences between ideal ratings and descriptive ratings on each of the IRB-RAT scales with ideal ratings being higher than current descriptive ratings on all of the scales (<.001). These findings suggest areas that can be targeted for improvement and also provide important information about the values of Indian IECs. PMID- 25747297 TI - Developing an index to measure the voluntariness of consent to research. AB - The goals of the current study were to expand the content domain and further validate the Coercion Assessment Scale (CAS), a measure of perceived coercion for criminally involved substance abusers being recruited into research. Unlike the few existing measures of this construct, the CAS identifies specific external sources of pressure that may influence one's decision to participate. In Phase 1, we conducted focus groups with criminal justice clients and stakeholders to expand the instrument by identifying additional sources of pressure. In Phase 2, we evaluated the expanded measure (i.e., endorsement rates, reliability, validity) in an ongoing research trial. Results identified new sources of pressure and provided evidence supporting the CAS's utility and reliability over time as well as convergent and discriminative validity. PMID- 25747298 TI - Exploring determinants of surrogate decision-maker confidence: an example from the ICU. AB - This article is an exploratory data analysis of the determinants of confidence in a surrogate decision maker who has been asked to permit an intensive care unit (ICU) patient's participation in genetic research. We pursue the difference between surrogates' and patients' confidence that the surrogate can accurately represent the patient's wishes. The article also explores whether greater confidence leads to greater agreement between patients and surrogates. Our data come from a survey conducted in three hospital ICUs. We interviewed 445 surrogates and 214 patients. The only thing that influences patients' confidence in their surrogate's decision is whether they had prior discussions with him or her; however, there are more influences operating on the surrogate's self confidence. More confident surrogates are more likely to match their patients' wishes. Patients are more likely to agree to research participation than their surrogates would allow. The surrogates whose response did not match as closely were less trusting of the hospital staff, were less likely to allow patient participation if there were no direct benefits to the patient, had given less thought about the way genetic research is conducted, and were much less likely to have a person in their life who they would trust to make decisions for them if they were incapacitated. PMID- 25747299 TI - IRB Authority. PMID- 25747300 TI - Chemometric study on the electrochemical incineration of nitrilotriacetic acid using platinum and boron-doped diamond anode. AB - This study investigated the electrochemical incineration of nitrilotriacetic acid (NTA) at boron-doped diamond (BDD) and platinum (Pt) anodes. Trials were performed in the presence of sulfate electrolyte media under recirculation mode. The parameters that influence the degradation efficiency were investigated, including applied current density, flow rate, supporting electrolyte concentration and reaction time. To reduce the number of experiments, the system had been managed under chemometric technique named Doehlert matrix. As a consequence, the mineralization of NTA demonstrated similar behavior upon operating parameters on these two anodes. Further kinetic study indicated that the degradations followed pseudo-first-order reactions for both BDD and Pt anodes, and the reaction rate constant of the former was found to be higher than that of the latter. Such difference could be interpreted by results from fractal analysis. In addition, a reaction sequence for NTA mineralization considering all the detected intermediates was also proposed. PMID- 25747301 TI - Remediation of nitrate-nitrogen contaminated groundwater using a pilot-scale two layer heterotrophic-autotrophic denitrification permeable reactive barrier with spongy iron/pine bark. AB - A novel two-layer heterotrophic-autotrophic denitrification (HAD) permeable reactive barrier (PRB) was proposed for remediating nitrate-nitrogen contaminated groundwater in an oxygen rich environment, which has a packing structure of an upstream pine bark layer and a downstream spongy iron and river sand mixture layer. The HAD PRB involves biological deoxygenation, heterotrophic denitrification, hydrogenotrophic denitrification, and anaerobic Fe corrosion. Column and batch experiments were performed to: (1) investigate the NO3(-)-N removal and inorganic geochemistry; (2) explore the nitrogen transformation and removal mechanisms; (3) identify the hydrogenotrophic denitrification capacity; and (4) evaluate the HAD performance by comparison with other approaches. The results showed that the HAD PRB could maintain constant high NO3(-)-N removal efficiency (>91%) before 38 pore volumes (PVs) of operation (corresponding to 504d), form little or even negative NO2(-)-N during the 45 PVs, and produce low NH4(+)-N after 10 PVs. Aerobic heterotrophic bacteria played a dominant role in oxygen depletion via aerobic respiration, providing more CO2 for hydrogenotrophic denitrification. The HAD PRB significantly relied on heterotrophic denitrification. Hydrogenotrophic denitrification removed 10-20% of the initial NO3(-)-N. Effluent total organic carbon decreased from 403.44mgL(-1) at PV 1 to 9.34mgL(-1) at PV 45. Packing structure had a noticeable effect on its denitrification. PMID- 25747302 TI - Aluminium (Al) fractionation and speciation; getting closer to describing the factors influencing Al(3+) in water impacted by acid mine drainage. AB - Acid mine drainage (AMD) severely impacts the water chemistry of a receiving resource, changing the occurrence, speciation and toxicity of metals such as Aluminium (Al). The toxicity of Al is determined by its speciation represented by the labile monomer Al fraction or Al(3+). The purpose of the study was to combine fractionation and Visual MINTEQ speciation to calculate the effect of AMD altered water chemistry on Al speciation and Al(3+) concentration. Water in rivers impacted by AMD presented with monomeric Al (Almon) concentrations between 0.35 and 15.37mgL(-)(1) which existed almost exclusively in the toxic labile form (98%). For the reference site, Almon was less than 2% (10MUgL(-1)), suggesting significantly lower Al toxicity. Principal component analysis plots illustrated that labile Al was directly related to the total Al and iron concentrations and strongly influenced by parameters such as pH, electrical conductivity, sulphate and dissolved organic carbon. Visual MINTEQ modelling was used to determine the primary Al species distribution. The dominant form of Al in AMD impacted water was AlSO4(+), which increased proportionally with the sulphate and Al(3+) concentration. Heavily impacted areas, presented with an average of 1mgmL(-)(1) Al(3+), which poses a potential human health risk. A novel centrifugal ultrafiltration method was investigated as an alternative to determining Almon to simplify the speciation of Al. Monomeric and centrifugal ultrafiltrated (<10kD) Al fractions were significantly similar (p=0.74), suggesting that ultrafiltration may present a time, energy and cost saving alternative to organic extraction of Almon. PMID- 25747303 TI - Effect of influent COD/SO4(2-) ratios on UASB treatment of a synthetic sulfate containing wastewater. AB - The effect of the chemical oxygen demand/sulfate (COD/SO4(2-)) ratio on the anaerobic treatment of synthetic chemical wastewater containing acetate, ethanol, and sulfate, was investigated using a UASB reactor. The experimental results show that at a COD/SO4(2-) ratio of 20 and a COD loading rate of 25.2gCODL(-1)d(-1), a COD removal of as high as 87.8% was maintained. At a COD/SO4(2-) ratio of 0.5 (sulfate concentration 6000mgL(-1)), however, the COD removal was 79.2% and the methane yield was 0.20LCH4gCOD(-1). The conversion of influent COD to methane dropped from 80.5% to 54.4% as the COD/SO4(2-) ratio decreased from 20 to 0.5. At all the COD/SO4(2-) ratios applied, over 79.4% of the total electron flow was utilized by methane-producing archaea (MPA), indicating that methane fermentation was the predominant reaction. The majority of the methane was produced by acetoclastic MPA at high COD/SO4(2-) ratios and both acetoclastic and hydrogenthrophic MPA at low COD/SO4(2-) ratios. Only at low COD/SO4(2-) ratios were SRB species such as Desulfovibrio found to play a key role in ethanol degradation, whereas all the SRB species were found to be incomplete oxidizers at both high and low COD/SO4(2-) ratios. PMID- 25747304 TI - Hydrocarbon degrading microbial communities in bench scale aerobic biobarriers for gasoline contaminated groundwater treatment. AB - BTEX compounds (benzene, toluene, ethylbenzene and xylenes) and methyl tert-butyl ether (MTBE) are some of the main constituents of gasoline and can be accidentally released in the environment. In this work the effect of bioaugmentation on the microbial communities in a bench scale aerobic biobarrier for gasoline contaminated water treatment was studied by 16S rRNA gene sequencing. Catabolic genes (tmoA and xylM) were quantified by qPCR, in order to estimate the biodegradation potential, and the abundance of total bacteria was estimated by the quantification of the number of copies of the 16S rRNA gene. Hydrocarbon concentration was monitored over time and no difference in the removal efficiency for the tested conditions was observed, either with or without the microbial inoculum. In the column without the inoculum the most abundant genera were Acidovorax, Bdellovibrio, Hydrogenophaga, Pseudoxanthomonas and Serpens at the beginning of the column, while at the end of the column Thauera became dominant. In the inoculated test the microbial inoculum, composed by Rhodococcus sp. CE461, Rhodococcus sp. CT451 and Methylibium petroleiphilum LMG 22953, was outcompeted. Quantitative PCR results showed an increasing in xylM copy number, indicating that hydrocarbon degrading bacteria were selected during the treatment, although only a low increase of the total biomass was observed. However, the bioaugmentation did not lead to an increase in the degradative potential of the microbial communities. PMID- 25747305 TI - Correction: Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats. PMID- 25747306 TI - Deletion of the MC4R gene in a 9-year-old obese boy. AB - BACKGROUND: The most common monogenic form of obesity is caused by mutations in the melanocortin 4 receptor (MC4R) gene. More than 150 mutations have been reported in the MC4R gene, the majority being point mutations. Most individuals with MC4R gene mutations have early-onset obesity, hyperphagia, and increased longitudinal growth. METHODS: A 9-year-old Caucasian boy was referred to genetics for obesity, food-seeking behavior, and developmental delay. History and physical exam were not consistent with Prader Willi syndrome, but revealed several minor anomalies. Owing to significant obesity and hyperphagia, a Prader Willi syndrome methylation test and a microarray were requested. RESULTS: Methlylation testing for Prader Willi syndrome was normal. Microarray analysis revealed two changes: (1) A 2.6-Mb deletion at chromosome 18q21.31 was identified and contained several OMIM genes, including the MC4R gene, and (2) an 0.87-Mb duplication at chromosome region 16p13.3 was found and contained one gene. Parental samples revealed that the boy's father had the same deletion and duplication. This case appears to be the first with a deletion of 18q21.31 encompassing the MC4R gene presenting with features of hyperphagia and obesity. CONCLUSIONS: Haploinsufficiency of the MC4R gene either through whole gene deletion or nonsense or missense mutations is associated with a significant risk of obesity. The case emphasizes both the role of the MC4R gene in obesity as well as the importance of looking for chromosomal microdeletions/duplications as a cause of obesity in children with minor anomalies or developmental delay. PMID- 25747307 TI - The oxidative pentose phosphate pathway is the primary source of NADPH for lipid overproduction from glucose in Yarrowia lipolytica. AB - Oleaginous microbes represent an attractive means of converting a diverse range of feedstocks into oils that can be transesterified to biodiesel. However, the mechanism of lipid overproduction in these organisms is incompletely understood, hindering the development of strategies for engineering superior biocatalysts for "single-cell oil" production. In particular, it is unclear which pathways are used to generate the large quantities of NADPH required for overproduction of the highly reduced fatty acid species. While early studies implicated malic enzyme as having a key role in production of lipogenic NADPH in oleaginous fungi, several recent reports have cast doubts as to whether malic enzyme may contribute to production of lipogenic NADPH in the model oleaginous yeast Yarrowia lipolytica. To address this problem we have used (13)C-Metabolic Flux Analysis to estimate the metabolic flux distributions during lipid accumulation in two Y. lipolytica strains; a control strain and a previously published engineered strain capable of producing lipids at roughly twice the yield. We observe a dramatic rearrangement of the metabolic flux distribution in the engineered strain which supports lipid overproduction. The NADPH-producing flux through the oxidative Pentose Phosphate Pathway is approximately doubled in the engineered strain in response to the roughly two-fold increase in fatty acid biosynthesis, while the flux through malic enzyme does not differ significantly between the two strains. Moreover, the estimated rate of NADPH production in the oxidative Pentose Phosphate Pathway is in good agreement with the estimated rate of NADPH consumption in fatty acid biosynthesis in both strains. These results suggest the oxidative Pentose Phosphate Pathway is the primary source of lipogenic NADPH in Y. lipolytica. PMID- 25747308 TI - Lactation support and breastfeeding duration in jaundiced infants: a randomized controlled trial. AB - OBJECTIVES: Neonatal jaundice is the most common problem in full-term infants during the immediate post-natal period. We examined the effect of a lactation support intervention on breastfeeding duration in hospitalized jaundiced infants. STUDY DESIGN: We conducted a randomized controlled trial with a qualitative component involving mothers of hospitalized jaundiced breastfed infants <4 weeks of age. Mothers receiving the intervention met with an International Board Certified Lactation Consultant in hospital and 1-3 times post discharge. Both groups received the standard care for jaundice. The primary outcome was exclusive breastfeeding at 3 months. To the exception of research assistants enrolling participants and completing qualitative interviews, all research staff, investigators and statisticians were blinded to group assignment. Qualitative interviews elicited feedback on breastfeeding experiences for both groups. RESULTS: 99 participants were recruited, and 86 analyzed for primary outcome. There was no difference in exclusive breastfeeding at 3 months between groups (RR 0.84, 95% CI 0.56-1.24, p = 0.40) or in the secondary outcomes. 31 participants were included in the qualitative analysis. Participants in the intervention group described an increase in comfort and confidence levels with breastfeeding. Participants in the control group reported limited lactation support. CONCLUSIONS: Our hospital-based lactation support program did not result in a higher proportion of mothers exclusively breastfeeding at 3 months compared to current hospital standard care. Qualitative feedback from the intervention group suggests that mothers' confidence was increased, which is linked to breastfeeding duration. The decision to breastfeed is multifactorial and hospital-based lactation support may be only a small piece of the puzzle in hospitalized jaundiced infants. Further studies may be needed to fully elucidate the impact of an in-hospital lactation support program on successful breastfeeding for these infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00966719 https://www.clinicaltrials.gov/ct2/show/NCT00966719?term=Lactation+Support+and+Br astfeeding+Duration+in+Jaundiced+Infants%3A+a+Randomized+Controlled+Trial&rank=1. PMID- 25747309 TI - Modulating the properties of sunflower oil based novel emulgels using castor oil fatty acid ester: prospects for topical antimicrobial drug delivery. AB - The current study describes the effect of polyglycerol polyricinoleate (PGPR) on the properties of sunflower oil and span-40 based emulgels. The prepared emulgels contained PGPR in varied concentrations. The microstructure of the emulgels was characterized by bright-field microscopy. The molecular interactions amongst the components of the emulgels were studied using FTIR spectroscopy. The flow and mechanical behaviors of the emulgels were studied using cone-and-plate viscometer and static mechanical tester, respectively. The efficiency of the metronidazole loaded emulgels as antimicrobial formulations was tested in vitro. E. coli was used as the model microorganism for the antimicrobial study. The emulgels were also explored for iontophoretic delivery applications. The biocompatibility of the emulgels was tested using human keratinocytes (HaCaT). The microscopic evaluation of the emulgels indicated formation of biphasic formulations. FTIR studies suggested a decrease in the hydrogen bonding amongst the components of the emulgels as the concentration of the PGPR was increased. Viscosity studies indicated shear-thinning property of the emulgels. An increase in the PGPR concentration resulted in the reduction in the mechanical properties of the emulgels. Incorporation of PGPR resulted in the decrease in the drug released (both passive and iontophoresis) from the emulgels. The emulgels were found to be cytocompatible in the presence of keratinocytes. The drug loaded emulgels showed good antimicrobial activity against E. coli. In gist, the developed emulgels can be tried for controlled delivery of antimicrobial drugs. The physical and the release properties of the emulgels can be modulated by incorporating PGPR in varied proportions. PMID- 25747310 TI - Cysteine modified and bile salt based micelles: preparation and application as an oral delivery system for paclitaxel. AB - The aim of the present study is to construct a cysteine modified polyion complex micelles made of Pluronic F127-chitosan (PF127-CS), Pluronic F127-cysteine (PF127 cysteine) and sodium cholate (NaC) and to evaluate the potential of the micelles as an oral drug delivery system for paclitaxel. Systematic studies on physicochemical properties including size distribution, zeta-potential and morphology were conducted to validate the formation of micelle structure. Compared with Pluronic micelles, drug-loading capacity of PF127-CS/PF127 cysteine/NaC micelles was increased from 3.35% to 12.77%. Both the critical micelle concentration and the stability test confirmed that the PF127-CS/PF127 cysteine/NaC micelles were more stable in aqueous solution than sodium cholate micelles. Pharmacokinetic study demonstrated that when oral administration the area under the plasma concentration-time curve (AUC0-infinity) and the absolute bioavailability of paclitaxel-loaded micelles were five times greater than that of the paclitaxel solution. In general, PF127-CS/PF127-cysteine/NaC micelles were proven to be a potential oral drug delivery system for paclitaxel. PMID- 25747311 TI - Modulating effect of lipid bilayer-carotenoid interactions on the property of liposome encapsulation. AB - Liposomes have become an attractive alternative to encapsulate carotenoids to improve their solubility, stability and bioavailability. The interaction mechanism of carotenoid with lipid bilayer is one of the major concerns in improving the delivery efficiency of liposomes. In this study, the microstructure and carotenoid encapsulation efficiency of liposomes composed of native phospholipid (egg yolk phosphatidylcholine, EYPC) and nonionic surfactant Tween 80 were investigated by atomic force microscopy, dynamic light scattering, and Raman spectroscopy, respectively. Subsequently, the effects of carotenoid incorporation on the physical properties of liposomal membrane were performed by Raman spectroscopy, fluorescence polarization, and electron paramagnetic resonance. Results showed that the incorporation of carotenoids affected the liposomes morphology, size and size distribution to various extents. Analysis on the Raman characteristic peaks of carotenoids revealed that lutein exhibited the strongest incorporating ability into liposomes, followed by beta-carotene, lycopene, and canthaxanthin. Furthermore, it was demonstrated that carotenoids modulated the dynamics, structure and hydrophobicity of liposomal membrane, highly depending on their molecular structures and incorporated concentration. These modulations were closely correlated with the stabilization of liposomes, including mediating particle aggregation and fusion. These findings should guide the rationale designing for liposomal encapsulation technology to efficiently deliver carotenoids in pharmaceutics, nutraceuticals and functional foods. PMID- 25747312 TI - Animal-derived natural products review: focus on novel modifications and applications. AB - Bio-based natural products have attracted exploding interests, while the environmental pollutions caused by the synthetic polymers are deteriorating dramatically. In this review, we provide a comprehensive overview of the modification of animal-derived natural products with an emphasis on casein, chitosan and collagen. Furthermore, their novel applications in controlled drug delivery system, leather finishing, and pollutant adsorption are also demonstrated. Accordingly, some perspectives in the future development of animal derived natural products are further proposed. PMID- 25747314 TI - Role of anaesthetics and opioids in perioperative hyperalgesia: one step towards familiarisation. PMID- 25747313 TI - Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design. AB - The surface of enveloped viruses can be extensively glycosylated. Unlike the glycans coating pathogens such as bacteria and fungi, glycans on viruses are added and processed by the host-cell during biosynthesis. Glycoproteins are typically subjected to alpha-mannosidase processing and Golgi-mediated glycosyltransferase extension to form complex-type glycans. In envelope viruses, exceptions to this default pathway are common and lead to the presence of oligomannose-type glycan structures on the virion surface. In one extreme example, HIV-1 utilises a high density of glycans to limit host antibody recognition of protein. However, the high density limits glycan processing and the resulting oligomannose structures can be recognised by broadly neutralising antibodies isolated from HIV-1 infected patients. Here we discuss how divergence from host-cell glycosylation can be targeted for vaccine design. PMID- 25747315 TI - Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo controlled study: Retraction. AB - The authors of the 2014 article "Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: A crossover, randomised, double-blinded, placebo-controlled study" wish to retract the article as Dr Kozek Langenecker did not consent to its submission and publication. PMID- 25747316 TI - Associated ilium and femur from Koobi Fora, Kenya, and postcranial diversity in early Homo. AB - During the evolution of hominins, it is generally accepted that there was a shift in postcranial morphology between Australopithecus and the genus Homo. Given the scarcity of associated remains of early Homo, however, relatively little is known about early Homo postcranial morphology. There are hints of postcranial diversity among species, but our knowledge of the nature and extent of potential differences is limited. Here we present a new associated partial ilium and femur from Koobi Fora, Kenya, dating to 1.9 Ma (millions of years ago) that is clearly attributable to the genus Homo but documents a pattern of morphology not seen in eastern African early Homo erectus. The ilium and proximal femur share distinctive anatomy found only in Homo. However, the geometry of the femoral midshaft and contour of the pelvic inlet do not resemble that of any specimens attributed to H. erectus from eastern Africa. This new fossil confirms the presence of at least two postcranial morphotypes within early Homo, and documents diversity in postcranial morphology among early Homo species that may reflect underlying body form and/or adaptive differences. PMID- 25747317 TI - The Middle Pleistocene tunnel valley at Schoningen as a Paleolithic archive. AB - Schoningen represents one of the key sites for Lower Paleolithic archaeology in central Europe, where a Middle to Late Pleistocene sedimentary succession, locally up to 45 m thick, has been preserved in an Elsterian tunnel valley. After deglaciation, the tunnel valley remained underfilled and provided the accommodation space for Holsteinian interglacial deposition and also kept the artifact-bearing strata below base level for subsequent erosion. The Holsteinian (MIS 9) succession consists of laterally and vertically stacked lacustrine delta systems, which were controlled by repeated lake-level changes. In the face of changing climatic and environmental conditions the long-lived interglacial lake provided an attractive site for animals and early humans. Artifacts were deposited on the subaerial delta plain and became embedded during lake-level rise. Although the area was considerably affected by erosion and glacitectonic deformation during the subsequent Saalian glaciation, the artifact-bearing Holsteinian strata were preserved in the deeper part of the tunnel valley. Tunnel valleys should be regarded as potential archives for interglacial deposits, which may contain important Paleolithic sites. Tunnel valleys may provide accommodation space and also have a high preservation potential. Interglacial lakes situated within underfilled tunnel valleys represented attractive sites for animals and early human hunter-gatherers. PMID- 25747318 TI - Giant subfossil lemur graveyard discovered, submerged, in Madagascar. PMID- 25747319 TI - Pattern segmentation with activity dependent natural frequency shift and sub threshold resonance. AB - Understanding the mechanisms underlying distributed pattern formation in brain networks and its content driven dynamical segmentation is an area of intense study. We investigate a theoretical mechanism for selective activation of diverse neural populations that is based on dynamically shifting cellular resonances in functionally or structurally coupled networks. We specifically show that sub threshold neuronal depolarization from synaptic coupling or external input can shift neurons into and out of resonance with specific bands of existing extracellular oscillations, and this can act as a dynamic readout mechanism during information storage and retrieval. We find that this mechanism is robust and suggest it as a general coding strategy that can be applied to any network with oscillatory nodes. PMID- 25747320 TI - Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor dependent fashion. AB - Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (beta-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and beta-AR signaling within the amygdala, which led to the hypothesis that some stress induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making. PMID- 25747323 TI - Father of modern immunology-Robert A. Good (1922-2003). PMID- 25747322 TI - Longitudinal observation of children with enhanced total serum IgE. AB - BACKGROUND: Long-term studies on the evolution of elevated total IgE (tIgE) concentration are in demand. OBJECTIVE: To investigate the prevalence of allergic diseases and influential factors in children with high tIgE levels during a 5 year period. METHODS: Children with high tIgE levels (>100 IU/mL) were study subjects. After the 5-year follow-up, an interview with the parents, clinical examination, and evaluation of tIgE and specific IgE (sIgE) to selected food and inhalant allergens were performed. RESULTS: The mean tIgE decreased significantly after 5 years in girls and boys regardless of the place of residence. Monosymptomatic patients accounted for most cases throughout the study, with the highest tIgE level at the beginning. After follow-up, the percentage of polysymptomatic patients increased. Their mean tIgE level was significantly higher than in the other groups. After follow-up, 11.7% of participants remained asymptomatic, and another 11.7% reported relief from symptoms. Allergy symptoms persisted in most children with normal tIgE levels. The 2-allergen sensitization was the most common through the study. Only patients sensitized to 4 allergens had unchanged levels of mean tIgE after follow-up and those with the highest mean tIgE level had a newly diagnosed sensitization to at least 1 allergen. A significant decrease of sIgE level was observed for food allergens. The values of sIgE to inhalant allergens even increased after the 5-year follow-up, despite decreased tIgE levels. CONCLUSION: In children with allergy and an elevated concentration of tIgE, the increasing or stable value of tIgE could be a useful parameter for the prediction of the development of polysymptomatic allergy. PMID- 25747321 TI - Activation of physiological stress responses by a natural reward: Novel vs. repeated sucrose intake. AB - Pharmacological rewards, such as drugs of abuse, evoke physiological stress responses, including increased heart rate and blood pressure, and activation of the hypothalamic-pituitary-adrenal (HPA) axis. It is not clear to what extent the natural reward of palatable foods elicits similar physiological responses. In order to address this question, HPA axis hormones, heart rate, blood pressure and brain pCREB immunolabeling were assessed following novel and repeated sucrose exposure. Briefly, adult, male rats with ad libitum food and water were given either a single (day 1) or repeated (twice-daily for 14 days) brief (up to 30 min) exposure to a second drink bottle containing 4 ml of 30% sucrose drink vs. water (as a control for bottle presentation). Sucrose-fed rats drank more than water-fed on all days of exposure, as expected. On day 1 of exposure, heart rate, blood pressure, plasma corticosterone, and locomotion were markedly increased by presentation of the second drink bottle regardless of drink type. After repeated exposure (day 14), these responses habituated to similar extents regardless of drink type and pCREB immunolabeling in the hypothalamic paraventricular nucleus (PVN) also did not vary with drink type, whereas basolateral amygdala pCREB was increased by sucrose intake. Taken together, these data suggest that while sucrose is highly palatable, physiological stress responses were evoked principally by the drink presentation itself (e.g., an unfamiliar intervention by the investigators), as opposed to the palatability of the offered drink. PMID- 25747324 TI - Renin-angiotensin system inhibitor and statins combination therapeutics - what have we learnt? AB - Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin-angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD. PMID- 25747325 TI - Depletion of metronidazole in brook trout (Salvelinus fontinalis). AB - Metronidazole (MNZ), which is effective in the treatment of intestinal infections in fish, is also a suspected carcinogen and has been banned in numerous jurisdictions for use in any food-producing animal, including fish. Few reports have been published on the depletion of MNZ in fish. A depletion study was therefore undertaken using MNZ in feed provided to trout under controlled conditions. The water was maintained at 17.5 +/- 0.9 degrees C throughout the medication and depletion periods in the study. Following a 20-day acclimatisation period in the holding tanks, the trout (approximately 150-200 g bodyweight at the start of the study) were subjected to two separate medication and withdrawal periods: (A) 5 day medication/5 day withdrawal and (B) 5 day medication/16 day withdrawal. This simulated a potential multiple dosing in an aquaculture setting. In both medication periods, the trout were dosed with medicated feed containing 3 g MNZ kg(-1) fish. Fish were sacrificed in accordance with accepted animal care protocols and tissue samples were analysed by UPLC-MS/MS. Analyte concentrations in trout muscle ranged from a high of 27,000 +/- 10,000 ng g(-1) for MNZ and 830 +/- 570 ng g(-1) for MNZ-OH on day 1 of withdrawal period A to a low of 1.8 +/- 2.3 ng g(-1) for MNZ and < 0.4 ng g(-1) for MNZ-OH on day 16 of withdrawal period B. The results demonstrate that when using the UPLC-MS/MS method, residues of MNZ may be detected in fish treated with MNZ after 16 days of withdrawal. PMID- 25747326 TI - Restoration of firearm serial numbers with electron backscatter diffraction (EBSD). AB - Firearm serial numbers are a critical identifying mark, and restoration of destroyed serial numbers is often crucial for prosecution of a criminal case. A method is presented utilizing electron backscatter diffraction (EBSD) in the scanning electron microscope (SEM) which allows for clear visualization of die stamped imprints which have been completely polished away. Evidence of the stamp can be observed to a depth of approximately 760 MUm below the surface. With further development, the described method is capable of reconstructing an 8 character serial number in approximately 1 h. PMID- 25747327 TI - The experimental and numerical investigation of pistol bullet penetrating soft tissue simulant. AB - Gelatin, a representative simulant for soft tissue of the human body, was used to study the effects of 9 mm pistol bullet's penetration. The behavior of a bullet penetrating gelatin was quantified by the temporary cavity sizes in ballistic gelatin and the pressure values of bullet's impact. A numerical simulation model of a bullet penetrating the soft tissue simulant gelatin was built using the finite element method (FEM). The model was validated by the comparison between the numerical results and the experimental results. During a bullet penetrating ballistic gelatin, four stages were clearly observed in both the experiment and the numerical simulation: a smooth attenuation stage, a rolling stage, a full penetration stage, and a stage of expansion and contraction. The cavity evolution, equivalent stress field and the strain field in gelatin were analyzed by numerical simulation. Moreover, the effects of the bullet's impact velocities and angles of incidence on the temporary cavity in gelatin, its velocity attenuation, and its rolling angle were investigated, as well as the bullet's resistance and energy variation. The physical process and the interactive mechanism during a pistol bullet penetrating gelatin were comprehensively revealed. This may be significant for research in wound ballistics. PMID- 25747328 TI - Studies on the alkaloid composition of the Hawaiian Baby Woodrose Argyreia nervosa, a common legal high. AB - Seeds from the Hawaiian Baby Woodrose Argyreia nervosa of different origin and labelling and with allegedly high levels of ergot alkaloids were analysed using high performance liquid chromatography-high resolution mass spectrometry (HPLC HRMS/MS) technique. Lysergic acid amide (LSA), ergometrine, lysergol/elymoclavine/setoclavine, chanoclavine, lysergic acid and their respective stereoisomers were identified as well as penniclavine and lysergic acid alpha-hydroxyethylamide. In addition, methylergometrine, methysergide, and lysergylalanine were detected, some high molecular weight ergot alkaloid derivatives and hydroxyalanine derived ergopeptide fragments were detected indicating the presence of ergopeptides in the seeds. The results of the study demonstrate that the content of ergot alkaloids in Argyreia nervosa seeds depends on the quality of the material. For a consumer the quality of the seeds is unforeseeable. For the toxicological expert it is essential to investigate not only the identity of such a confiscated seed material, but also the various ergot alkaloid constituents to assess the hazardous nature and the toxic potential of the material. PMID- 25747329 TI - Drug-related death: adulterants from cocaine preparations in lung tissue and blood. AB - The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid-liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight-mass spectrometry (LC/TOF-MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether - for the determination in the cause of death - the lung should be examined in addition to heart blood, urine or brain tissue. PMID- 25747330 TI - Application of soil in forensic science: residual odor and HRD dogs. AB - Decomposing human remains alter the environment through deposition of various compounds comprised of a variety of chemical constituents. Human remains detection (HRD) dogs are trained to indicate the odor of human remains. Residual odor from previously decomposing human remains may remain in the soil and on surfaces long after the remains are gone. This study examined the ability of eight nationally certified HRD dogs (four dual purpose and four single purpose) to detect human remains odor in soil from under decomposing human remains as well as soils which no longer contained human remains, soils which had been cold water extracted and even the extraction fluid itself. The HRD dogs were able to detect the odor of human remains successfully above the level of chance for each soil ranging between 75% and 100% accurate up to 667 days post body removal from soil surface. No significant performance accuracy was found between the dual and single purpose dogs. This finding indicates that even though there may not be anything visually observable to the human eye, residual odor of human remains in soil can be very recalcitrant and therefore detectible by properly trained and credentialed HRD dogs. Further research is warranted to determine the parameters of the HRD dogs capabilities and in determining exactly what they are smelling. PMID- 25747331 TI - Sleep deficits in the High Arctic summer in relation to light exposure and behaviour: use of melatonin as a countermeasure. AB - BACKGROUND: There are conflicting reports regarding seasonal sleep difficulties in polar regions. Herein we report differences in actigraphic sleep measures between two summer trials (collected at Canadian Forces Station Alert, 82.5 degrees N, in 2012 and 2014) and evaluate exogenous melatonin for preventing/treating circadian phase delay due to nocturnal light exposure. METHODS: Subjects wore actigraphs continuously to obtain sleep data. Following seven days of actigraphic recording the subjects filled out questionnaires regarding sleep difficulty and psychosocial parameters and subsequently remained in dim light conditions for 24 hours, during which saliva was collected bihourly to measure melatonin. During Trial 2, individuals who reported difficulty sleeping were prescribed melatonin, and a second saliva collection was conducted to evaluate the effect of melatonin on the circadian system. RESULTS: Trial 1 subjects collectively had late dim light melatonin onsets and difficulty sleeping; however, the Trial 2 subjects had normally timed melatonin rhythms, and obtained a good quantity of high-quality sleep. Nocturnal light exposure was significantly different between the trials, with Trial 1 subjects exposed to significantly more light between 2200 and 0200h. Melatonin treatment during Trial 2 led to an improvement in the subjective sleep difficulty between the pre- and post-treatment surveys; however there were no significant differences in the objective measures of sleep. CONCLUSIONS: The difference in sleep and melatonin rhythms between research participants in June 2012 and June 2014 is attributed to the higher levels of nocturnal light exposure in 2012. The avoidance of nocturnal light is likely to improve sleep during the Arctic summer. PMID- 25747332 TI - Sleep quality and the menstrual cycle. AB - OBJECTIVE: This study aimed to assess the temporal relationship of subjective sleep quality to menstrual cycle phase in a community (non help-seeking) sample of adult women over six months. Previous work has produced contradictory results and often used student samples. PARTICIPANTS/METHODS: PATIENTS/METHODS: This was a cohort study, using daily electronic data collection in the Greater Toronto Area, Ontario, Canada; 76 women aged 18-42 years recruited by random digit telephone dialing, recorded mood, sleep quality, and other health variables on a daily basis for 24 weeks. RESULTS: Using linear mixed models, we assessed the relationship between subjective sleep quality and three menstrual cycle phases (menses, premenstrual and midcycle) over 395 cycles. Premenstrual sleep quality was poorer than during the rest of the cycle, with a mean difference of 1.32 between premenstrual and midcycle reference phase, on a 1-100 quality scale (higher score denotes poorer quality). This difference held when the independent variables of daily exercise and physical health were added to the model; it became non-significant when perceived stress and later, social support were also added to the model. CONCLUSIONS: Sleep quality in adult non-help seeking women is statistically poorer in the premenstruum but the size of the difference is of little clinical significance and was no longer statistically significant with inclusion of the potentially confounding variables, perceived stress and social support. PMID- 25747333 TI - Biomarkers associated with obstructive sleep apnea and morbidities: a scoping review. AB - OBJECTIVE: To map potential biomarkers of obstructive sleep apnea (OSA) associated morbidities in both adults and children, to identify gaps in current evidence, and to determine the value of conducting a full systematic review. METHODS: A scoping review was undertaken of studies in patients with OSA that evaluated the potential value of biological markers in identifying OSA-associated morbidities. Retained articles were only those studies whose main objective was to identify morbidity biomarkers in subjects with OSA, the latter being confirmed with a full overnight polysomnography (PSG) in a laboratory or at-home settings. The methodology of the selected studies was classified using an adaptation of the evidence quality criteria recommended by the American Academy of Pediatrics. Additionally the biomarkers were categorized according to their potential clinical applicability. RESULTS: 572 citations were identified of which 48 met inclusion criteria. Thirty-four studies were conducted in adults and 14 involved children. Most of the studies evaluated blood biomarkers, and presented 31 potential diagnostic biomarkers. CONCLUSION: The majority of studies that performed explored blood-based biomarkers, with most not identifying definitive morbidity biomarkers. Of the potentially promising morbidity biomarkers, plasma IL-6 and high sensitivity C-reactive protein appear to exhibit a favorable profile, and may discriminate OSA patients with and without morbidities in both adults and children. MRP 8/14 was retained in children as well as cardiovascular morbidity-associated biomarker. Urinary neurotransmitters may also provide a good tool for screening OSA cognitive morbidity in children. PMID- 25747334 TI - Sleep, memory and schizophrenia. PMID- 25747335 TI - Are NREM sleep characteristics associated to subjective sleep complaints after mild traumatic brain injury? AB - INTRODUCTION: Sleep complaints are common after mild traumatic brain injury (mTBI). While recent findings suggest that sleep macro-architecture is preserved in mTBI, features of non-rapid eye movement (NREM) sleep micro-architecture including electroencephalography (EEG) spectral power, slow waves (SW), and sleep spindles could be affected. This study aimed to compare NREM sleep in mTBI and healthy controls, and explore whether NREM sleep characteristics correlate with sleep complaints in these groups. METHODS: Thirty-four mTBI participants (mean age: 34.2 +/- 11.9 yrs; post-injury delay: 10.5 +/- 10.4 weeks) and 29 age matched controls (mean age: 32.4 +/- 8.2 yrs) were recruited for two consecutive nights of polysomnographic (PSG) recording. Spectral power was computed and SW and spindles were automatically detected in three derivations (F3, C3, O1) for the first three sleep cycles. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). RESULTS: mTBI participants reported significant poorer sleep quality than controls on the PSQI and showed significant increases in beta power during NREM sleep at the occipital derivation only. Conversely, no group differences were found in SW and spindle characteristics. Interestingly, changes in NREM sleep characteristics were not associated with mTBI estimation of sleep quality. CONCLUSIONS: Compared to controls, mTBI were found to have enhanced NREM beta power. However, these changes were not found to be associated with the subjective evaluation of sleep. While increases in beta bands during NREM sleep may be attributable to the occurrence of a brain injury, they could also be related to the presence of pain and anxiety as suggested in one prior study. PMID- 25747336 TI - Targeting PTEN using small molecule inhibitors. AB - PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. It's PI(3,4,5)P3 lipid phosphatase activity is an important counteracting mechanism in PI 3-kinase (phosphoinositide 3-kinase) signalling. Furthermore, PTEN lies upstream of Akt kinase, a key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore, PTEN has recently gained attention as a valuable drug target for the treatment of diabetes, stroke, cardiac infarct and fertility. This review summarizes the use of small molecules as PTEN inhibitors. Currently available methodologies and techniques for accessing PTEN inhibition in vitro and in cellulo will be discussed. PMID- 25747337 TI - Rmax: A systematic approach to evaluate instrument sort performance using center stream catch. AB - Sorting performance can be evaluated with regard to Purity, Yield and/or Recovery of the sorted fraction. Purity is a check on the quality of the sample and the sort decisions made by the instrument. Recovery and Yield definitions vary with some authors regarding both as how efficient the instrument is at sorting the target particles from the original sample, others distinguishing Recovery from Yield, where the former is used to describe the accuracy of the instrument's sort count. Yield and Recovery are often neglected, mostly due to difficulties in their measurement. Purity of the sort product is often cited alone but is not sufficient to evaluate sorting performance. All of these three performance metrics require re-sampling of the sorted fraction. But, unlike Purity, calculating Yield and/or Recovery calls for the absolute counting of particles in the sorted fraction, which may not be feasible, particularly when dealing with rare populations and precious samples. In addition, the counting process itself involves large errors. Here we describe a new metric for evaluating instrument sort Recovery, defined as the number of particles sorted relative to the number of original particles to be sorted. This calculation requires only measuring the ratios of target and non-target populations in the original pre-sort sample and in the waste stream or center stream catch (CSC), avoiding re-sampling the sorted fraction and absolute counting. We called this new metric Rmax, since it corresponds to the maximum expected Recovery for a particular set of instrument parameters. Rmax is ideal to evaluate and troubleshoot the optimum drop-charge delay of the sorter, or any instrument related failures that will affect sort performance. It can be used as a daily quality control check but can be particularly useful to assess instrument performance before single-cell sorting experiments. Because we do not perturb the sort fraction we can calculate Rmax during the sort process, being especially valuable to check instrument performance during rare population sorts. PMID- 25747338 TI - Parents' and peers' contribution to risky driving of male teen drivers. AB - The current study joins efforts devoted to understanding the associations of parents' personality, attitude, and behavior, and to evaluating the added contribution of peers to the driving behavior of young drivers during their solo driving. The study combines data gathered using in-vehicle data recorders from actual driving of parents and their male teen driver with data collected from self-report questionnaires completed by the young drivers. The sample consists of 121 families, who participated in the study for 12 months, beginning with the licensure of the teen driver. The current examination concentrates on the last 3 months of this first year of driving. The experimental design was based on a random control assignment into three treatment groups (with different forms of feedback) and a control group (with no feedback). Findings indicate that the parents' (especially the fathers') sensation seeking, anxiety, and aggression, as well as their risky driving events rate were positively associated with higher risky driving of the young driver. In addition, parents' involvement in the intervention, either by feedback or by training, led to lower risky driving events rate of young drivers compared to the control group. Finally, higher cohesion and adaptability mitigated parents' model for risky driving, and peers norms' of risky driving were associated with higher risk by the teen drivers. We conclude by claiming that there is an unequivocal need to look at a full and complex set of antecedents in parents' personality, attitudes, and behavior, together with the contribution of peers to the young drivers' reckless driving, and address the practical implications for road safety. PMID- 25747339 TI - The impact of childhood symptoms of conduct disorder on driver aggression in adulthood. AB - BACKGROUND: Despite limited empirical investigation, existing scientific literature suggests that individuals with a history or current diagnosis of conduct disorder (CD) may be more likely to demonstrate reckless and aggressive driving. Much of the limited research in this field examines the impact of childhood CD on driver behaviour and collision risk in young adults. Few if any, studies assess the impact of this disorder on driver behaviour beyond age 21 years. The current research is a population-based study of the impact of CD symptoms during childhood on the risk of engaging in driver aggression during adulthood. METHODS: Data are based on telephone interviews with 5230 respondents who reported having driven in the past year. Data are derived from the 2011-2013 cycles of the CAMH Monitor, an ongoing cross-sectional survey of adults in Ontario, Canada aged 18 years and older. A binary logistic regression analysis of self-reported driver aggression in the previous 12 months was conducted, consisting of measures of demographic characteristics, driving exposure, problem substance use, alcohol- and drug-impaired driving, symptoms of attention deficit hyperactivity disorder, and childhood (before age 15) symptoms of CD. RESULTS: When entered with demographic characteristics, driving exposure, and other potential confounders, childhood symptoms of CD increased the odds of reporting driver aggression more than two-fold (adjusted OR=2.12). Exploratory analyses of the interaction between childhood symptoms of CD and age was not a significant predictor of driver aggression. CONCLUSIONS: Results suggest that symptoms of CD during childhood are associated with significantly increased odds of self reported driver aggression during adulthood. Limitations and future directions of the research are discussed. PMID- 25747340 TI - Maximizing clinical cohort size using free text queries. AB - BACKGROUND: Cohort identification is important in both population health management and research. In this project we sought to assess the use of text queries for cohort identification. Specifically we sought to determine the incremental value of unstructured data queries when added to structured queries for the purpose of patient cohort identification. METHODS: Three cohort identification tasks were evaluated: identification of individuals taking gingko biloba and warfarin simultaneously (Gingko/Warfarin), individuals who were overweight, and individuals with uncontrolled diabetes (UCD). We assessed the increase in cohort size when unstructured data queries were added to structured data queries. The positive predictive value of unstructured data queries was assessed by manual chart review of a random sample of 500 patients. RESULTS: For Gingko/Warfarin, text query increased the cohort size from 9 to 28,924 over the cohort identified by query of pharmacy data only. For the weight-related tasks, text search increased the cohort by 5-29% compared to the cohort identified by query of the vitals table. For the UCD task, text query increased the cohort size by 2-43% compared to the cohort identified by query of laboratory results or ICD codes. The positive predictive values for text searches were 52% for Gingko/Warfarin, 19-94% for the weight cohort and 44% for UCD. DISCUSSION: This project demonstrates the value and limitation of free text queries in patient cohort identification from large data sets. The clinical domain and prevalence of the inclusion and exclusion criteria in the patient population influence the utility and yield of this approach. PMID- 25747341 TI - Computer-Aided Detection and diagnosis for prostate cancer based on mono and multi-parametric MRI: a review. AB - Prostate cancer is the second most diagnosed cancer of men all over the world. In the last few decades, new imaging techniques based on Magnetic Resonance Imaging (MRI) have been developed to improve diagnosis. In practise, diagnosis can be affected by multiple factors such as observer variability and visibility and complexity of the lesions. In this regard, computer-aided detection and computer aided diagnosis systems have been designed to help radiologists in their clinical practice. Research on computer-aided systems specifically focused for prostate cancer is a young technology and has been part of a dynamic field of research for the last 10 years. This survey aims to provide a comprehensive review of the state-of-the-art in this lapse of time, focusing on the different stages composing the work-flow of a computer-aided system. We also provide a comparison between studies and a discussion about the potential avenues for future research. In addition, this paper presents a new public online dataset which is made available to the research community with the aim of providing a common evaluation framework to overcome some of the current limitations identified in this survey. PMID- 25747343 TI - Inflammasomes are neuroprotective targets for sex steroids. AB - Neuroinflammation in the central nervous system is triggered by toxic stimuli or degenerative events, orchestrates the interplay of brain-intrinsic immune cells and neighboring neural cells, and sequentially allows leukocyte extravasation from the periphery into the brain parenchyma. During the inflammatory cascade, immune-competent cells become activated and secrete a plethora of cytokines and chemokines which form a local inflammatory signaling network important for warding off harmful stimuli to the host but are likewise necessary to preserve damaged brain tissue. Inflammatory responses are initiated by extra- and intra cellular pathogen and danger-associated receptors. These signals are processed by multi-protein complexes termed inflammasomes which trigger the production of biologically active interleukins-1 and 18 after the cleavage of caspase-1. Estrogens and progesterone are neuroprotective and anti-inflammatory in diverse disease models of the brain in particular under acute inflammatory conditions such as stroke and traumatic brain injury. Both steroids are able to attenuate pro-inflammatory cytokine activity. Recent literature and our own studies provide convincing evidence that the anti-inflammatory potency of these steroids result from a complex interaction with the inflammasome activation and their up-stream regulatory network of miRNAs in brain-intrinsic innate immune cells. This article examines steroid-inflammasome interactions in the brain during brain injury and illuminates the importance of regulation initial upstream events during neuroinflammation. This article is part of a Special Issue entitled 'Steroid Perspectives'. PMID- 25747342 TI - Structure constrained semi-nonnegative matrix factorization for EEG-based motor imagery classification. AB - BACKGROUND: Electroencephalogram (EEG) provides a non-invasive approach to measure the electrical activities of brain neurons and has long been employed for the development of brain-computer interface (BCI). For this purpose, various patterns/features of EEG data need to be extracted and associated with specific events like cue-paced motor imagery. However, this is a challenging task since EEG data are usually non-stationary time series with a low signal-to-noise ratio. NEW METHOD: In this study, we propose a novel method, called structure constrained semi-nonnegative matrix factorization (SCS-NMF), to extract the key patterns of EEG data in time domain by imposing the mean envelopes of event related potentials (ERPs) as constraints on the semi-NMF procedure. The proposed method is applicable to general EEG time series, and the extracted temporal features by SCS-NMF can also be combined with other features in frequency domain to improve the performance of motor imagery classification. RESULTS: Real data experiments have been performed using the SCS-NMF approach for motor imagery classification, and the results clearly suggest the superiority of the proposed method. COMPARISON WITH EXISTING METHODS: Comparison experiments have also been conducted. The compared methods include ICA, PCA, Semi-NMF, Wavelets, EMD and CSP, which further verified the effectivity of SCS-NMF. CONCLUSIONS: The SCS-NMF method could obtain better or competitive performance over the state of the art methods, which provides a novel solution for brain pattern analysis from the perspective of structure constraint. PMID- 25747344 TI - Predictors of delayed wound healing after endovascular therapy of isolated infrapopliteal lesions underlying critical limb ischemia in patients with high prevalence of diabetes mellitus and hemodialysis. AB - OBJECTIVES: Acceptable limb salvage rates underlie the widespread use of endovascular therapy (EVT) for patients with critical limb ischemia (CLI) secondary to isolated infrapopliteal lesions; however, post-EVT delayed wound healing remains a challenge. Predictors of delayed wound healing and their use in risk stratification of EVT in patients with CLI due to isolated infrapopliteal lesions are explored. METHODS: This was a retrospective multicenter study. 871 consecutive critically ischemic limbs were studied. There was tissue loss in 734 patients (age: 71 +/- 10 years old; 71% male) who had undergone EVT between April 2004 and December 2012. The wound healing rate after EVT was estimated by the Kaplan-Meier method. The association between baseline characteristics and delayed wound healing was assessed by the Cox proportional hazard model. RESULTS: Diabetes mellitus and regular dialysis were present in 75% (553/734) and 64% (476/734) of patients, respectively; 67% of limbs (585/871) had Rutherford class 5 CLI; 8% (67/871) of wounds were located in the heel only; 25% (219/871) of limbs had Rutherford 6 (involving not only the heel); and 42% (354/871) of wounds were complicated by infection. The rate of freedom from major amputation at 1 year reached 88%, whereas the wound healing rate was 67%. Median time to wound healing was 146 days. By multivariate analysis, non-ambulatory status (hazard ratio [HR], 1.58; 95% confidence interval [CI] 1.31-1.91) serum albumin <3 g/dL (HR 1.42; 95% CI 1.08-1.86), Rutherford 6 (not only heel) (HR 1.68; 95% CI 1.33 2.14), wound infection (HR 1.24; 95% CI 1.03-1.50), EVT not based on angiosome concept (HR 1.28; 95% CI 1.06-1.55), and below the ankle (BTA) 0 vessel runoff after EVT (HR 1.45; 95% CI 1.14-1.86) were independent predictors of delayed wound healing. CONCLUSIONS: Non-ambulatory status, low albumin level, Rutherford 6 (not only heel), wound infection, indirect intervention, and poor BTA runoff were independent predictors for delayed wound healing after EVT in patients with CLI secondary to infrapopliteal lesions, and their use in risk stratification allows estimation of the wound healing rate. PMID- 25747345 TI - Clinical and imaging features associated with an increased risk of early and late stroke in patients with symptomatic carotid disease. AB - OBJECTIVE: The aim of this review was to identify clinical and/or imaging parameters that are associated with an increased (decreased) risk of early/late stroke in patients with symptomatic carotid disease. IN THE FIRST 14 DAYS: Natural history studies suggest that 8-15% of patients with 50-99% stenoses will suffer a stroke within 72 hours of their index symptom. Currently, there are insufficient validated data to identify highest-risk patients for emergency carotid endarterectomy (CEA), but an increased risk of stroke appears to be predicted by (i) an ABCD(2) score of 4-7; (ii) the presence of acute cerebral injury on CT/MRI; (iii) Gray Scale Median (GSM) <15, (iv) spontaneous embolisation on Transcranial Doppler (TCD); and (v) increased fluorodeoxyglucose (FDG) uptake in the carotid plaque on positron emission tomography (PET). A future goal must be to develop predictive algorithms (based on accessible imaging strategies) for identifying acutely symptomatic patients with highly unstable plaques for emergency CEA. MEDIUM TO LONG TERM: In the randomised trials, about 70% of patients with symptomatic 70-99% stenoses were stroke-free on "best medical therapy" at 5 years. Clinical predictors of increased stroke risk include (i) male gender; (ii) age >75; (iii) hemispheric symptoms; and (iv) increasing comorbidity. Imaging features associated with increased stroke risk include (i) irregular stenoses; (ii) contralateral occlusion; (iii) increasing stenosis severity, but not subocclusion; (iv) tandem intracranial disease; (v) a failure to recruit intracranial collaterals; (vi) low GSM; (vii) MR diagnosis of intra plaque haemorrhage; (vii) spontaneous embolisation on TCD; and (viii) increased FDG uptake in the carotid plaque on PET. Clinical/imaging parameters associated with a lower risk of stroke include (i) female gender, especially those with 50 99% stenoses; (ii) ocular symptoms/lacunar stroke; (iii) smooth stenoses; and (iv) chronic subocclusion. PMID- 25747346 TI - Renal artery aneurysm at the hilum secondary to neurofibromatosis type I. PMID- 25747347 TI - Buying time. PMID- 25747348 TI - Rheumatoid arthritis: Perioperative management of biologics and DMARDs. AB - OBJECTIVE: Arthroplasty remains prevalent for patients with rheumatoid arthritis (RA), but outcomes are not equivalent to patients with osteoarthritis, and complications including infection are increased. The objective of this article is to review the current evidence supporting perioperative medication management. Challenges are discussed such as continuing potent disease-modifying therapy (DMARDs) and biologics, which may increase infection risk, versus withholding these medications, which may result in disease flares. METHODS: Published literature regarding arthroplasty in RA has been reviewed and discussed. RESULTS: Some DMARDs such as methotrexate and hydroxychloroquine appear safe in the perioperative period. Anti-TNFalpha biologics should be withheld due to increase in infection risk, while the impact of rituximab and abatacept on infection risk has not been as clearly defined. CONCLUSION: This article provides an overview of arthroplasty in RA, summarizes the evidence supporting perioperative medication management including corticosteroids, and identifies areas where further study is needed. PMID- 25747349 TI - Milestones for Internal Medicine Sub-interns. AB - BACKGROUND: As residency programs move toward measuring milestones for competency based education assessment, medical schools will need to collaborate with residencies to determine competencies for graduating students. The objective of this study is to define the educational milestones for fourth-year medical students during an Internal Medicine sub-internship. METHODS: A cross-sectional Internet-based survey (with attention to validity evidence) was developed in early 2013 and administered to Internal Medicine attendings and Internal Medicine sub-interns working on an inpatient team at 3 academic medical centers. With the purpose to determine the milestones for sub-interns, items asked respondents what responsibilities a sub-intern could be entrusted to perform without direct supervision. RESULTS: Faculty responded that behaviors sub-interns could perform with indirect supervision were mostly at the "reporter" level, including completing a history and physical examination and collecting data such as test results. Other skills such as venipuncture and some communication skills such as calling consults, providing patient counseling, responding to pages, and creating discharge instructions were examples of tasks in which the majority of faculty felt that students were progressing toward unsupervised practice. Behaviors where the majority of faculty would always supervise a medical student performance included performance on the "interpreter" level, including interpreting electrocardiograms, significant physical examination findings, and laboratory results. Medical students less commonly noted needing supervision on the majority of the items when compared with faculty. CONCLUSION: Tasks in the reporter domain such as taking a history, collecting medical records, and reporting results can be characterized as medical student milestones. PMID- 25747350 TI - Indirect purification method provides high yield and quality ssDNA sublibrary for potential aptamer selection. AB - The quality and yield of single-stranded DNA (ssDNA) play key roles in ssDNA aptamer selection. However, current methods for generating and purifying ssDNA provides either low yield due to ssDNA loss during the gel purification process or low specificity due to tertiary structural damage of ssDNA by alkaline or exonuclease treatment in removing dsDNA and by-products. This study developed an indirect purification method that provides a high yield and quality ssDNA sublibrary. Symmetric PCR was applied to generate a sufficient template, while asymmetric PCR using an excessive nonbiotinylated forward primer and an insufficient biotinylated reverse primer combined with a biotin-strepavidin system was applied to eliminate dsDNA, hence, leading to ssDNA purification. However, no alkaline or exonuclease were involved in treating dsDNA, so as to warrant the tertiary structure of ssDNA for potential aptamer SELEX selection. Agarose gel imaging indicated that no dsDNA or by-product contamination was detected in the ssDNA sublibrary generated by the indirect purification method. Purified ssDNA concentration reached 1020+/-210nM, which was much greater than previous methods. In conclusion, this novel method provided a simple and fast tool for generating and purifying a high yield and quality ssDNA sublibrary. PMID- 25747351 TI - Changes in intestinal barrier function and gut microbiota in high-fat diet-fed rats are dynamic and region dependent. AB - A causal relationship between the pathophysiological changes in the gut epithelium and altered gut microbiota with the onset of obesity have been suggested but not defined. The aim of this study was to determine the temporal relationship between impaired intestinal barrier function and microbial dysbiosis in the small and large intestine in rodent high-fat (HF) diet-induced obesity. Rats were fed HF diet (45% fat) or normal chow (C, 10% fat) for 1, 3, or 6 wk; food intake, body weight, and adiposity were measured. Barrier function ex vivo using FITC-labeled dextran (4,000 Da, FD-4) and horseradish peroxidase (HRP) probes in Ussing chambers, gene expression, and gut microbial communities was assessed. After 1 wk, there was an immediate but reversible increase in paracellular permeability, decrease in IL-10 expression, and decrease in abundance of genera within the class Clostridia in the ileum. In the large intestine, HRP flux and abundance of genera within the order Bacteroidales increased with time on the HF diet and correlated with the onset of increased body weight and adiposity. The data show immediate insults in the ileum in response to ingestion of a HF diet, which were rapidly restored and preceded increased passage of large molecules across the large intestinal epithelium. This study provides an understanding of microbiota dysbiosis and gut pathophysiology in diet-induced obesity and has identified IL-10 and Oscillospira in the ileum and transcellular flux in the large intestine as potential early impairments in the gut that might lead to obesity and metabolic disorders. PMID- 25747352 TI - Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus. AB - Myocytes are nonhemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid-onset nonhemopoietic mechanism potently triggers early ileus in a Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)-dependent manner. Moreover, synergistically with hemopoietic cells, nonhemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. We therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. TLR4(+/+), TLR4(-/-), bmTLR4(+/+)/TLR4(-/-) chimera, SM22-Cre(-/ )TLR4(flox/flox), and selective myocyte TLR4-deficient (SM22-Cre(+/ )TLR4(flox/flox)) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal, skeletal, and vascular myocytes, of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to nonhemopoietic TLR4 deficiency, deletion of myocyte TLR4 signaling prevented neither endotoxin-induced suppression of spontaneous jejunal contractility in vitro nor early ileus in vivo at 6 h. Circulating plasma colony-stimulating factor 3 was greatly elevated during endotoxemia, independent of myocyte TLR4 signaling or time. TLR4 activation of myocytes contributed significantly to an early enteric IL-6 mRNA induction and systemic IL-6 release, as well as to a late increase in circulating chemokine (C-X-C motif) ligand 1 (CXCL1) and IL-17. Consequently, inhibition of myocyte TLR4 signaling allowed functional recovery of motility by preventing inflammation-driven late ileus at 24 h. Direct TLR4 activation of myocytes is not responsible for nonhemopoietic-mediated early ileus. However, myocytes are proinflammatory cells that potently drive enteric and systemic inflammation, subsequently fueling late mediator-triggered ileus. Specifically, the myocyte TLR4-dependent inflammatory signature of elevated plasma IL-6, CXCL1, and IL-17 is strongly associated with late rodent ileus. PMID- 25747353 TI - Expression of Reg family genes in the gastrointestinal tract of mice treated with indomethacin. AB - Regenerating gene (Reg) family proteins, which are classified into four types, commonly act as trophic and/or antiapoptotic factors in gastrointestinal (GI) diseases. However, it remains unclear how these proteins coordinate their similar roles under such pathophysiological conditions. Here, we investigated the interrelationships of Reg family gene expression with mucosal cell proliferation and apoptosis in nonsteroidal anti-inflammatory drug (NSAID)-induced GI injury. GI injury was induced by subcutaneous injection of indomethacin into Reg I knockout (KO) and wild-type (WT) mice, and its severity was scored histopathologically. Temporal changes in the expression of Reg family genes, mucosal proliferation, and apoptosis were evaluated throughout the GI tract by real-time RT-PCR, Ki-67 immunoreactivity, and TUNEL assay, respectively. Reg I, Reg III family, and Reg IV were predominantly expressed in the upper, middle, and lower GI mucosa, respectively. Expression of Reg I and Reg III family genes was upregulated in specific portions of the GI tract after indomethacin treatment. Ki 67-positive epithelial cells were significantly decreased in the gastric and small-intestinal mucosa of Reg I KO mice under normal conditions. After treatment with indomethacin, the number of TUNEL-positive cells was significantly greater throughout the GI mucosa in Reg I KO mice than in WT mice. Expression of Reg I was independent of that of other Reg family genes in, not only normal GI tissues, but also indomethacin-induced GI lesions. Members of the Reg gene family show distinct profiles of expression in the GI tract, and Reg I independently plays a role in protecting the GI mucosa against NSAID-induced injury. PMID- 25747355 TI - Promoting international collaboration through the International Commission on Occupational Health. PMID- 25747356 TI - European Expert Panel on effective ways of investing in health: opinion on primary care. PMID- 25747354 TI - Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease. AB - The status of the GP130-STAT3 signaling pathway in humans with nonalcoholic fatty liver disease (NAFLD) and its relevance to disease pathogenesis are unknown. The expression of the gp130-STAT3 axis and gp130 cytokine receptors were studied in subjects with varying phenotypes of NAFLD including nonalcoholic steatohepatitis (NASH) and compared with lean and weight-matched controls without NAFLD. Gp130 and its downstream signaling element (Tyk2 and STAT3) expression were inhibited in obese controls whereas they were increased in NAFLD. IL-6 levels were increased in NASH and correlated with gp130 expression (P < 0.01). Palmitate inhibited gp130-STAT3 expression and signaling. IL-6 and palmitate inhibited hepatic insulin signaling via STAT3-dependent and independent mechanisms, respectively. STAT3 overexpression reversed palmitate-induced lipotoxicity by increasing autophagy (ATG7) and decreasing endoplasmic reticulum stress. These data demonstrate that the STAT3 pathway is activated in NAFLD and can worsen insulin resistance while protecting against other lipotoxic mechanisms of disease pathogenesis. PMID- 25747357 TI - Radiocarbon-based impact assessment of open biomass burning on regional carbonaceous aerosols in North China. AB - Samples of total suspended particulates (TSPs) and fine particulate matter (PM2.5) were collected from 29th May to 1st July, 2013 at a regional background site in Bohai Rim, North China. Mass concentrations of particulate matter and carbonaceous species showed a total of 50% and 97% of the measured TSP and PM2.5 levels exceeded the first grade national standard of China, respectively. Daily concentrations of organic carbon (OC) and elemental carbon (EC) were detected 7.3 and 2.5 MUg m(-3) in TSP and 5.2 and 2.0 MUg m(-3) in PM2.5, which accounted 5.8% and 2.0% of TSP while 5.6% and 2.2% for PM2.5, respectively. The concentrations of OC, EC, TSP and PM2.5 were observed higher in the day time than those in the night time. The observations were associated with the emission variations from anthropogenic activities. Two merged samples representing from south and north source areas were selected for radiocarbon analysis. The radiocarbon measurements showed 74% of water-insoluble OC (WINSOC) and 59% of EC in PM2.5 derived from biomass burning and biogenic sources when the air masses were from south region, and 63% and 48% for the air masses from north, respectively. Combined with backward trajectories and daily burned area, open burning of agricultural wastes was found to be predominating, which was confirmed by the potential source contribution function (PSCF). PMID- 25747358 TI - Baltic Sea sediment records: unlikely near-future declines in PCBs and HCB. AB - We present a comprehensive study on PCBs and HCB in dated sediment cores from the Baltic Sea covering the 20th century, and compare their spatiotemporal trends with those of PCDD/Fs from the same areas. PCB concentrations in coastal impacted sediment followed the temporal trend of estimated global emissions of PCBs and thus responded quickly to changes in global industrial use, whereas concentrations in offshore sediment needed 10-20 years longer to respond. Differences in spatiotemporal trends of PCDD/Fs and PCBs were smaller than expected based on documented differences in key sources and source areas. Sediment concentrations of HCB varied little over time and space, but concentrations are increasing in recent years. The steep PCB concentration reduction over time observed for the late 20th century levelled off during the last 20 years, and levels of PCBs appear to be at or near a steady-state condition. CAPSULE: PCB concentrations in Baltic Sea sediments appear to be at or near steady-state, and no significant concentration decreases are to be expected in the near future. PMID- 25747359 TI - Effects of temperature on nitrous oxide (N2O) emission from intensive aquaculture system. AB - This study examines the effects of temperature on nitrous oxide (N2O) emissions in a bench-scale intensive aquaculture system rearing Koi fish. The water temperature varied from 15 to 24 degrees C at interval of 3 degrees C. Both volumetric and specific rate for nitrification and denitrification declined as the temperature decreased. The concentrations of ammonia and nitrite, however, were lower than the inhibitory level for Koi fish regardless of temperature. The effects of temperature on N2O emissions were significant, with the emission rate and emission factor increasing from 1.11 to 1.82 mg N2O-N/d and 0.49 to 0.94 mg N2O-N/kg fish as the temperature decreased from 24 to 15 degrees C. A global map of N2O emission from aquaculture was established by using the N2O emission factor depending on temperature. This study demonstrates that N2O emission from aquaculture is strongly dependent on regional water temperatures as well as on fish production. PMID- 25747360 TI - The influence of changes in wind patterns on the areal extension of surface cyanobacterial blooms in a large shallow lake in China. AB - It has been hypothesized that climate change will induce the areal extension of cyanobacterial blooms. However, this hypothesis lacks field-based observation. In the present study both long-term historical data and short-term field measurement were used to identify the importance of changes in wind patterns on the cyanobacterial bloom in Lake Taihu (China), a large, shallow, eutrophic lake located in a subtropical zone. The cyanobacterial bloom mainly composed of Microcystis spp. recurred frequently throughout the year. The regression analysis of multi-year satellite image data extracted by the Floating Algae Index revealed that both the annual mean monthly maximum cyanobacterial bloom area (MMCBA) increased year by year from 2000 to 2011, while the contemporaneous cyanobacterial biomass showed no significant change. However, the correlation analysis shows that MMCBA was negatively correlated with wind speed. Our short term field measurements indicated that the influence of wind on surface cyanobacterial blooms is that the Chlorophyll-a (Chla) concentration is fully mixing throughout the water column when the wind speed exceed 7 m s(-1). At lower wind speeds, there was vertical stratification of Chla with high surface concentrations and an increase in bloom area. The regression analysis of wind speed indicates that the climate has changed over the last decade. Lake Taihu has become increasingly calm, with the decrease of strong wind frequency between 2000 and 2011, corresponding to the increase in the MMCBA over time. Therefore, we conclude that changes in wind patterns related to climate change have favored the increase of cyanobacterial blooms in Lake Taihu. PMID- 25747361 TI - Levels of PBDEs in plasma of juvenile starlings (Sturnus vulgaris) from British Columbia, Canada and assessment of PBDE metabolism by avian liver microsomes. AB - In this study, the levels of polybrominated diphenyl ethers (PBDEs), HO-PBDEs, and bromophenols were monitored in starling chick plasma samples collected in Delta (British Columbia, Canada) close to the Vancouver municipal landfill and in Glen Valley, a rural area in British Columbia. The in vitro formation of hydroxylated metabolites of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) was also investigated using starling chick liver microsomes. Total PBDE plasma levels were approximately 60 times higher in starling chicks from Delta than from Glen Valley, suggesting that the Delta site is a major source of PBDEs for the local population of starlings and that PBDEs previously measured in starling eggs are bioavailable to chicks. In both locations, BDE-47 and BDE-99 were the two major congeners present at similar concentrations, suggesting contamination with the Penta-BDE mixture. Among the several possible hydroxylated metabolites of PBDEs monitored in starling plasma, only 2,4,5-tribromophenol was detected and its levels did not exceed 18+/-7 pg/mL. Also, several hydroxylated metabolites of BDE-47 and BDE-99 were formed by starling chick liver microsomes, but in low amounts. Therefore, our data consistently suggest that oxidative metabolism of PBDEs in starling chicks proceeds at low rate in vivo and in vitro. In conclusion, the landfill located in Delta is a relevant source of bioavailable PBDEs for the local starling population. Because of the limited ability of starling chicks to metabolize PBDEs, these compounds are likely to bioaccumulate in starlings over time. The possible toxicological implications of PBDEs bioaccumulation in starlings are currently unknown and require further research. PMID- 25747362 TI - DNA damage in Mexican children living in high-risk contaminated scenarios. AB - The aim of this study was to evaluate the deoxyribonucleic acid (DNA) damage (as a biomarker of biological effects) in children living in areas at high risk of contamination in Mexico using the comet assay. The alkaline comet assay was performed in order to assess DNA damage levels in blood cells of 276 children living in eleven communities in four states of Mexico. Moreover, levels of arsenic and 1-hydroxypyrene (1-OHP) in urine and lead and total DDT [sum of 1,1 dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) and 1,1-bis(p-chlorophenyl)-2,2,2 trichloroethane (DDT)] in blood were quantified. We found urinary 1-OHP levels between .05). The SAF and PUI showed significantly better performances in removing mTAP from the coronal third (P < .05). CONCLUSIONS: The use of irrigation activation regimens significantly improves the removal of mTAP from root canals when compared with CI. PMID- 25747379 TI - Removing fractured endodontic instruments with a modified tube technique using a light-curing composite. AB - INTRODUCTION: The aim of this in vitro study was to assess an alternative method using light-curing composite for removing fractured endodontic instruments with a tube technique. METHODS: Two different stainless steel endodontic instruments (ISO 20: Hedstrom files, K-files; VDW, Munich, Germany) were cut at the diameter of 0.4 mm. These fragments were fixed in a vise leaving a free end of 1 or 2 mm. Cyanoacrylate (Instant Fix; Henry Schein Dental, Melville, NY), dual-curing Rebilda DC (VOCO, Cuxhaven, Germany), and light-curing SureFil SDR (Dentsply, York, PA) were placed into microtubes (N'Durance Syringe Tips; Septodont, Saint Maur, France) and shifted over the instruments (n = 20 in each group). After polymerization, pull-out tests were performed with a constant speed of 2 mm/min; failure load was measured digitally. Data were analyzed using the Kruskal-Wallis test followed by the Dunn test for pairwise comparison. RESULTS: The median failure load was up to 62.5 N for SDR, 35.8 N for Rebilda, and 14.7 N for cyanoacrylate, respectively. Both tested composites yielded significantly higher values in pull-out tests than cyanoacrylate. The disconnecting force was highest when light-cured composite SDR was used for fixation. Removing Hedstrom files resulted in higher values than removing K-files. The median force when using SDR was 79.7 N (interquartile range, 66.0-86.8 N) in Hedstrom files and 53.3 N (interquartile range, 47.1-58.5 N) in K-files. CONCLUSIONS: Within the limitations of this study, the use of light-curing composite inside of the microtube was superior compared with the use of cyanoacrylate or chemically cured composite, which are being used presently. PMID- 25747380 TI - Fatty liver, inflamed blood and calcified coronary arteries: lessons and uncertainties from the multiethnic study of atherosclerosis -commentary on the study of Al Rifai et al. PMID- 25747381 TI - Phytotoxic metabolites from Neofusicoccum parvum, a pathogen of Botryosphaeria dieback of grapevine. AB - Liquid chromatography-diode array screening of the organic extract of the cultures of 13 isolates of the fungus Neofusicoccum parvum, the main causal agent of botryosphaeria dieback of grapevine, showed similar metabolites. One strain was selected for further chemical studies and led to the isolation and characterisation of 13 metabolites. Structures were elucidated through spectroscopic analyses, including one- and two-dimensional NMR and mass spectrometry, and through comparison to literature data. The isolated compounds belong to four different chemical families: five metabolites, namely, (-) terremutin (1), (+)-terremutin hydrate (2), (+)-epi-sphaeropsidone (3) (-)-4 chloro-terremutin hydrate (4) and(+)-4-hydroxysuccinate-terremutin hydrate (5), belong to the family of dihydrotoluquinones; two metabolites, namely, (6S,7R) asperlin (6) and (6R,7S)-dia-asperlin (7), belong to the family of epoxylactones; four metabolites, namely, (R)-(-)-mellein (8), (3R,4R)-4-hydroxymellein (9), (3R,4S)-4-hydroxymellein (10) (R)(-)-3-hydroxymellein (11), belong to the family of dihydroisocoumarins; and two of the metabolites, namely, 6-methyl-salicylic acid (12) and 2-hydroxypropyl salicylic acid (13), belong to the family of hydroxybenzoic acids. We determined the phytotoxic activity of the isolated metabolites through a leaf disc assay and the expression of defence-related genes in Vitis vinifera cells cv. Chardonnay cultured with (-)-terremutin (1), the most abundant metabolite. Finally, analysis of the brown stripes of grapevine wood from plants showing botryosphaeria dieback symptoms revealed the presence of two of the isolated phytotoxins. PMID- 25747382 TI - Multiple seeds sensitivity using a single seed with threshold. AB - Spaced seeds are a fundamental tool for similarity search in biosequences. The best sensitivity/selectivity trade-offs are obtained using many seeds simultaneously: This is known as the multiple seed approach. Unfortunately, spaced seeds use a large amount of memory and the available RAM is a practical limit to the number of seeds one can use simultaneously. Inspired by some recent results on lossless seeds, we revisit the approach of using a single spaced seed and considering two regions homologous if the seed hits in at least t sufficiently close positions. We show that by choosing the locations of the don't care symbols in the seed using quadratic residues modulo a prime number, we derive single seeds that when used with a threshold t > 1 have competitive sensitivity/selectivity trade-offs, indeed close to the best multiple seeds known in the literature. In addition, the choice of the threshold t can be adjusted to modify sensitivity and selectivity a posteriori, thus enabling a more accurate search in the specific instance at issue. The seeds we propose also exhibit robustness and allow flexibility in usage. PMID- 25747383 TI - On correlated reaction sets and coupled reaction sets in metabolic networks. AB - Two reactions are in the same "correlated reaction set" (or "Co-Set") if their fluxes are linearly correlated. On the other hand, two reactions are "coupled" if nonzero flux through one reaction implies nonzero flux through the other reaction. Flux correlation analysis has been previously used in the analysis of enzyme dysregulation and enzymopathy, while flux coupling analysis has been used to predict co-expression of genes and to model network evolution. The goal of this paper is to emphasize, through a few examples, that these two concepts are inherently different. In other words, except for the case of full coupling, which implies perfect correlation between two fluxes (R(2) = 1), there are no constraints on Pearson correlation coefficients (CC) in case of any other type of (un)coupling relations. In other words, Pearson CC can take any value between 0 and 1 in other cases. Furthermore, by analyzing genome-scale metabolic networks, we confirm that there are some examples in real networks of bacteria, yeast and human, which approve that flux coupling and flux correlation cannot be used interchangeably. PMID- 25747384 TI - Respiratory calcium fluctuations in low-frequency oscillating astrocytes in the pre-Botzinger complex. AB - Astrocytes have been found to modulate neuronal activity through calcium dependent signaling in various brain regions. However, whether astrocytes of the pre-Botzinger complex (preBotC) exhibit respiratory rhythmic fluctuations is still controversial. Here we evaluated calcium-imaging experiments within preBotC in rhythmically active medullary slices from TgN(hGFAP-EGFP) mice using advanced analyses. 13.8% of EGFP-negative cells, putative neurons, showed rhythmic fluorescent changes that were highly correlated to the respiratory rhythmic fluctuation (cross-correlation coefficient>0.5 and dF/F>0.2%). In contrast, a considerable number of astrocyte somata exhibited synchronized low-frequency (<0.03Hz) calcium oscillations. After band-pass filtering, signals that irregularly preceded the calcium signal of EGFP-negative cells were observed in 10.2% of astrocytes, indicating a functional coupling between astrocytes and neurons in preBotC. A model simulation confirmed that such preinspiratory astrocytic signals can arise from coupled neuronal and astrocytic oscillators, supporting a concept that slow oscillatory changes of astrocytic functions modulate neighboring neuronal activity to add variability in respiratory rhythm. PMID- 25747385 TI - Hypoxia exaggerates inspiratory accessory muscle deoxygenation during hyperpnoea. AB - The purpose of this study was to elucidate inspiratory accessory muscle deoxygenation and myoelectric activity during isolated volitional hyperpnoea under hypoxic conditions. Subjects performed voluntary isocapnic hyperpnoea (tidal volume=30-40% of forced vital capacity, breathing frequency=60 breaths/min) in normoxia [inspired gas fraction (FIO2)=0.21] and hypoxia (FIO2). Muscle deoxyhemoglobin/myoglobin (Deoxy-Hb/Mb) and muscle oxygen saturation (SMO2) using near-infrared spectroscopy and surface electromyography were measured from sternocleidomastoid (SCM) and intercostal (IC) muscles. During hyperpnoea, increases in Deoxy-Hb/Mb and reductions of SMO2 in the SCM and IC muscles were larger (P<0.05) in hypoxia than those in normoxia. Under hypoxic conditions, the electromyogram increases from the SCM and IC muscles during hyperpnoea were greater than that under the normoxic conditions. These results suggest that inspiratory accessory muscle deoxygenation during isolated hyperpnoea is exaggerated in hypoxia compared with normoxia and that hypoxia has a significant impact on inspiratory accessory muscle activation. PMID- 25747386 TI - Identification of minimum Rpn4-responsive elements in genes related to proteasome functions. AB - The proteasome is an essential, 66-subunit protease that mediates ubiquitin dependent proteolysis. The transcription factor Rpn4 regulates concerted expression of proteasome subunits to increase the proteasome by recognizing nonamer proteasome-associated control element (PACE) elements on the promoter regions. However, the genes for proteasome assembly chaperones and some of the subunits have no PACEs. Here we identified a minimal hexamer "PACE-core" sequence that responds to Rpn4. PACE-cores are found in many genes related to proteasome function including the assembly chaperones, but cannot substitute for PACE of the subunits. Our results add a new layer of complexity in transcriptional regulation of genes involved in protein degradation. PMID- 25747387 TI - Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells. AB - To investigate TRAIL resistance mechanisms in hepatocellular carcinoma (HCC), we isolated a stable TRAIL-resistant sub-population of the HCC cell line LH86, designated LH86-TR. Differential activation of AKT was not responsible for acquisition of TRAIL resistance. Cells with both congenital and acquired resistance to TRAIL exhibited increased Msi1 expression, which conferred TRAIL resistance by activating ERK. Forced expression of Msi1 decreased the sensitivity of HCC cells to TRAIL both in vitro and in vivo. Conversely, shRNA-mediated depletion of Msi1 enhanced TRAIL efficacy. SiRNA-mediated depletion of ERK overcame TRAIL resistance. Hence, we conclude that Msi1 is a mediator of TRAIL resistance in HCC cells. PMID- 25747388 TI - Acquiring snapshots of the orientation of trans-membrane protein domains using a hybrid FRET pair. AB - One challenge in studying the function of membrane-embedded proteins is determining the orientation of key domains in the context of the changing and dynamic membrane environment. We describe a confocal microscopy setup that utilizes external electric field pulses to direct dipicrylamine (DPA) to a membrane leaflet. The detection of FRET between DPA and a fluorescent probe attributes it to the inner or outer leaflet of a membrane. By utilizing short acquisition times and confocal imaging, this attribution could be made even in changing membrane environments. Our setup adds versatility to the study of the biological activity of membrane-embedded proteins. PMID- 25747389 TI - Improved O2-tolerance in variants of a H2-evolving [NiFe]-hydrogenase from Klebsiella oxytoca HP1. AB - In this study, we investigated the mechanism of O2 tolerance of Klebsiella oxytoca HP1 H2-evolving hydrogenase 3 (KHyd3) by mutational analysis and three dimensional structure modeling. Results revealed that certain surface amino acid residues of KHyd3 large subunit, in particular those at the outer entrance of the gas channel, have a visible effect on its oxygen tolerance. Additionally, solution pH, immobilization and O2 partial pressure also affect KHyd3 O2 tolerance to some extent. We propose that the extent of KHyd3 O2-tolerance is determined by a balance between the rate of O2 access to the active center through gas channels and the deoxidation rate of the oxidized active center. Based on our findings, two higher O2-tolerant KHyd3 mutations G300E and G300M were developed. PMID- 25747390 TI - Urmylation and tRNA thiolation functions of ubiquitin-like Uba4.Urm1 systems are conserved from yeast to man. AB - The ubiquitin-like protein Urm1 from budding yeast and its E1-like activator Uba4 have dual roles in protein urmylation and tRNA thiolation pathways. To study whether these are conserved among eukaryotes, we used gene shuffles to replace the yeast proteins by their human counterparts, hURM1 and hUBA4/MOCS3. As judged from biochemical and genetical assays, hURM1 and hUBA4 are functional in yeast, albeit at reduced efficiencies. They mediate urmylation of the peroxiredoxin Ahp1, a known urmylation target in yeast, and support tRNA thiolation. Similar to hUBA4, yeast Uba4 itself is modified by Urm1 and hURM1 suggesting target overlap between eukaryal urmylation pathways. In sum, our study shows that dual-function ubiquitin-like Urm1.Uba4 systems are conserved and exchangeable between human and yeast cells. PMID- 25747391 TI - Effects of a Telehealth Care Coordination Intervention on Perceptions of Health Care by Caregivers of Children With Medical Complexity: A Randomized Controlled Trial. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of advanced practice registered nurse (APRN) telehealth care coordination for children with medical complexity (CMC) on family caregiver perceptions of health care. METHOD: Families with CMC ages 2 to 15 years (N = 148) were enrolled in a three-armed, 30 month randomized controlled trial to test the effects of adding an APRN telehealth care coordination intervention to an existing specialized medical home for CMC. Satisfaction with health care was measured using items from the Consumer Assessment of Healthcare Providers and Systems survey at baseline and after 1 and 2 years. RESULTS: The intervention was associated with higher ratings on measures of the child's provider, provider communication, overall health care, and care coordination adequacy, compared with control subjects. Higher levels of condition complexity were associated with higher ratings of overall health care in some analyses. DISCUSSION: APRN telehealth care coordination for CMC was effective in improving ratings of caregiver experiences with health care and providers. Additional research with CMC is needed to determine which children benefit most from high-intensity care coordination. PMID- 25747392 TI - Protective effects of alisol B 23-acetate from edible botanical Rhizoma alismatis against carbon tetrachloride-induced hepatotoxicity in mice. AB - Carbon tetrachloride (CCl4)-induced hepatotoxicity is a common syndrome with simultaneous severe hepatocyte death and acute cholestasis. The purpose of the present study is to investigate the hepatoprotective effect of alisol B 23 acetate (AB23A), a natural triterpenoid from edible botanical Rhizoma alismatis, on acute hepatotoxicity induced by CCl4 in mice, and further to elucidate the involvement of farnesoid X receptor (FXR), signal transducers and activators of transcription 3 (STAT3) in the hepatoprotective effect. H&E staining, BrdU immunohistochemistry and TUNEL assay were used to identify the amelioration of histopathological changes, hepatocyte proliferation and apoptosis. Real-time PCR and western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection. The results indicated that AB23A treatment in a dose-dependent manner resulted in protection against hepatotoxicity induced by CCl4via FXR activation. Through FXR activation, AB23A promoted hepatocyte proliferation via an induction in hepatic levels of FoxM1b, Cyclin D1 and Cyclin B1. AB23A also reduced hepatic bile acids through a decrease in hepatic uptake transporter Ntcp, bile acid synthetic enzymes Cyp7a1, Cyp8b1, and an increase in efflux transporter Bsep, Mrp2 expression. In addition, AB23A induced the expression of STAT3 phosphorylation, and STAT3 target genes Bcl-xl and SOCS3, resulting in decreased hepatocyte apoptosis. In conclusion, AB23A produces a protective effect against CCl4-induced hepatotoxicity, due to FXR and STAT3-mediated gene regulation. PMID- 25747394 TI - Role of angiotensin II and oxidative stress in renal inflammation by hypernatremia: benefits of atrial natriuretic peptide, losartan, and tempol. AB - The body regulates plasma sodium levels within a small physiologic range, despite large variations in daily sodium and water intake. It is known that sodium transport in the kidneys plays an important role in hypoxia, being the major determinant of renal oxygen consumption. Tubular epithelial cell hypoxia is an important contributor to the development of renal inflammation, and the damage may progress to structural injury, ending in acute renal failure. In this review, we will summarize the renal inflammatory effects of high acute plasma sodium (acute hypernatremia), and the molecular mechanisms involved. We will also discuss recent findings related to the role of oxidative stress and angiotensin II (Ang II) in the pathogenesis of renal injury. We will comment on the effects of agents used to prevent or attenuate the inflammatory response, such as the atrial natriuretic peptide, the superoxide dismutase mimetic - tempol, and losartan. PMID- 25747393 TI - Antioxidative effects of ethyl 2-(3-(benzo[d]thiazol-2-yl)ureido)acetate against amyloid beta-induced oxidative cell death via NF-kappaB, GSK-3beta and beta catenin signaling pathways in cultured cortical neurons. AB - We have previously shown that 2-(3-(benzo[d]thiazol-2-yl)ureido)acetate (KHG21834) attenuates amyloid beta(Abeta)25-35-induced apoptotic death and shows anti-inflammatory activity against Abeta25-35-induced microglial activation. However, antioxidative effects of KHG21834 against Abeta-induced oxidative stress have not yet been reported. In the present study, we investigated the antioxidative function of KHG21834 in primary cultured cortical neurons, to expand the potential therapeutic efficacy of KHG21834. Pretreatment with KHG21834 protected against Abeta-induced neuronal cell death and mitochondrial damage, and significantly restored GSH levels and the activities of catalase, superoxide dismutase, and glutathione peroxidase, and also suppressed the production of reactive oxygen species and protein oxidation. These results imply that KHG21834 may play a role in cellular defense mechanisms against Abeta-induced oxidative stress in cultured cortical neurons. Furthermore, KHG21834 significantly attenuated the effects of Abeta treatment on levels of NF-kappaB, beta-catenin, and GSK-3beta proteins in cortical neurons. Taken together, our results suggest that the antioxidant effects of KHG21834 may result at least in part from its ability to regulate the NF-kappaB, beta-catenin, and GSK-3beta signaling pathways. To our knowledge, this is the first report showing that KHG21834 significantly attenuates Abeta25-35-induced oxidative stress in primary cortical neurons, and provides novel insights into KHG21834 as a possible therapeutic agent for the treatment of Abeta-mediated neurotoxicity involving oxidative stress. PMID- 25747395 TI - 2-Phenylbenzothiazole conjugated with cyclopentadienyl tricarbonyl [CpM(CO)3] (M = Re, (99m)Tc) complexes as potential imaging probes for beta-amyloid plaques. AB - Technetium-99m-labeled cyclopentadienyl tricarbonyl complexes conjugated with the 2-phenylbenzothiazole binding motif were synthesized. The rhenium surrogates , , and were demonstrated to have moderate to high affinities for Abeta1-42 aggregates with Ki values of 142, 76, 64 and 24 nM, respectively. During the fluorescence staining of brain sections of transgenic mice and patients with Alzheimer's disease, these rhenium complexes demonstrated perfect and intense labeling of Abeta plaques. Moreover, in in vitro autoradiography, (99m)Tc-labeled complexes clearly detected beta-amyloid plaques on sections of brain tissue from transgenic mice, which confirmed the sufficient affinity of these tracers for Abeta plaques. However, these compounds did not show desirable properties in vivo, especially showing poor brain uptake (below 0.5% ID g(-1)), which will hinder the further development of these tracers as brain imaging agents. Nonetheless, it is encouraging that these (99m)Tc-labeled complexes designed by a conjugate approach displayed sufficient affinities for Abeta plaques. PMID- 25747396 TI - PIWI-Interacting RNA: Its Biogenesis and Functions. AB - PIWI-interacting RNAs (piRNAs) are a class of small RNAs that are 24-31 nucleotides in length. They associate with PIWI proteins, which constitute a germline-specific subclade of the Argonaute family, to form effector complexes known as piRNA-induced silencing complexes, which repress transposons via transcriptional or posttranscriptional mechanisms and maintain germline genome integrity. In addition to having a role in transposon silencing, piRNAs in diverse organisms function in the regulation of cellular genes. In some cases, piRNAs have shown transgenerational inheritance to pass on the memory of "self" and "nonself," suggesting a contribution to various cellular processes over generations. Many piRNA factors have been identified; however, both the molecular mechanisms leading to the production of mature piRNAs and the effector phases of gene silencing are still enigmatic. Here, we summarize the current state of our knowledge on the biogenesis of piRNA, its biological functions, and the underlying mechanisms. PMID- 25747397 TI - Structure and energy transfer in photosystems of oxygenic photosynthesis. AB - Oxygenic photosynthesis is the principal converter of sunlight into chemical energy on Earth. Cyanobacteria and plants provide the oxygen, food, fuel, fibers, and platform chemicals for life on Earth. The conversion of solar energy into chemical energy is catalyzed by two multisubunit membrane protein complexes, photosystem I (PSI) and photosystem II (PSII). Light is absorbed by the pigment cofactors, and excitation energy is transferred among the antennae pigments and converted into chemical energy at very high efficiency. Oxygenic photosynthesis has existed for more than three billion years, during which its molecular machinery was perfected to minimize wasteful reactions. Light excitation transfer and singlet trapping won over fluorescence, radiation-less decay, and triplet formation. Photosynthetic reaction centers operate in organisms ranging from bacteria to higher plants. They are all evolutionarily linked. The crystal structure determination of photosynthetic protein complexes sheds light on the various partial reactions and explains how they are protected against wasteful pathways and why their function is robust. This review discusses the efficiency of photosynthetic solar energy conversion. PMID- 25747398 TI - Transport of sugars. AB - Soluble sugars serve five main purposes in multicellular organisms: as sources of carbon skeletons, osmolytes, signals, and transient energy storage and as transport molecules. Most sugars are derived from photosynthetic organisms, particularly plants. In multicellular organisms, some cells specialize in providing sugars to other cells (e.g., intestinal and liver cells in animals, photosynthetic cells in plants), whereas others depend completely on an external supply (e.g., brain cells, roots and seeds). This cellular exchange of sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is critical for plants, animals, and humans. At present, three classes of eukaryotic sugar transporters have been characterized, namely the glucose transporters (GLUTs), sodium-glucose symporters (SGLTs), and SWEETs. This review presents the history and state of the art of sugar transporter research, covering genetics, biochemistry, and physiology-from their identification and characterization to their structure, function, and physiology. In humans, understanding sugar transport has therapeutic importance (e.g., addressing diabetes or limiting access of cancer cells to sugars), and in plants, these transporters are critical for crop yield and pathogen susceptibility. PMID- 25747399 TI - Nuclear ADP-Ribosylation and Its Role in Chromatin Plasticity, Cell Differentiation, and Epigenetics. AB - Protein ADP-ribosylation is an ancient posttranslational modification with high biochemical complexity. It alters the function of modified proteins or provides a scaffold for the recruitment of other proteins and thus regulates several cellular processes. ADP-ribosylation is governed by ADP-ribosyltransferases and a subclass of sirtuins (writers), is sensed by proteins that contain binding modules (readers) that recognize specific parts of the ADP-ribosyl posttranslational modification, and is removed by ADP-ribosylhydrolases (erasers). The large amount of experimental data generated and technical progress made in the last decade have significantly advanced our knowledge of the function of ADP-ribosylation at the molecular level. This review summarizes the current knowledge of nuclear ADP-ribosylation reactions and their role in chromatin plasticity, cell differentiation, and epigenetics and discusses current progress and future perspectives. PMID- 25747401 TI - Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. AB - Lamins are intermediate filament proteins that form a scaffold, termed nuclear lamina, at the nuclear periphery. A small fraction of lamins also localize throughout the nucleoplasm. Lamins bind to a growing number of nuclear protein complexes and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, gene regulation, genome stability, differentiation, and tissue-specific functions. The lamin-based complexes and their specific functions also provide insights into possible disease mechanisms for human laminopathies, ranging from muscular dystrophy to accelerated aging, as observed in Hutchinson-Gilford progeria and atypical Werner syndromes. PMID- 25747402 TI - Cryogenic electron microscopy and single-particle analysis. AB - About 20 years ago, the first three-dimensional (3D) reconstructions at subnanometer (<10-A) resolution of an icosahedral virus assembly were obtained by cryogenic electron microscopy (cryo-EM) and single-particle analysis. Since then, thousands of structures have been determined to resolutions ranging from 30 A to near atomic (<4 A). Almost overnight, the recent development of direct electron detectors and the attendant improvement in analysis software have advanced the technology considerably. Near-atomic-resolution reconstructions can now be obtained, not only for megadalton macromolecular complexes or highly symmetrical assemblies but also for proteins of only a few hundred kilodaltons. We discuss the developments that led to this breakthrough in high-resolution structure determination by cryo-EM and point to challenges that lie ahead. PMID- 25747400 TI - Termination of Transcription of Short Noncoding RNAs by RNA Polymerase II. AB - The RNA polymerase II transcription cycle is often divided into three major stages: initiation, elongation, and termination. Research over the last decade has blurred these divisions and emphasized the tightly regulated transitions that occur as RNA polymerase II synthesizes a transcript from start to finish. Transcription termination, the process that marks the end of transcription elongation, is regulated by proteins that interact with the polymerase, nascent transcript, and/or chromatin template. The failure to terminate transcription can cause accumulation of aberrant transcripts and interfere with transcription at downstream genes. Here, we review the mechanism, regulation, and physiological impact of a termination pathway that targets small noncoding transcripts produced by RNA polymerase II. We emphasize the Nrd1-Nab3-Sen1 pathway in yeast, in which the process has been extensively studied. The importance of understanding small RNA termination pathways is underscored by the need to control noncoding transcription in eukaryotic genomes. PMID- 25747404 TI - Evidence-based treatment of neurocognitive disorders: measured optimism about select outcomes. PMID- 25747403 TI - Periodontal Disease and Risks of Kidney Function Decline and Mortality in Older People: A Community-Based Cohort Study. AB - BACKGROUND: The association between periodontal disease and chronic kidney disease in older people is controversial, and evidence for a causal link between kidney function decline and subsequent mortality risk is limited. STUDY DESIGN: Longitudinal, observational, community-based cohort study. SETTING & PARTICIPANTS: Participants were citizens 65 years or older who received the Taipei City Government-sponsored Annual Elderly Health Examination Program during 2005 to 2010, including dental status assessment and biochemical examinations. PREDICTORS: Participants with periodontal disease defined by the World Health Organization Community Periodontal Index of Treatment Need criteria. OUTCOMES: All-cause and cardiovascular mortality and estimated glomerular filtration rate (eGFR) decline >= 30% over 2 years. RESULTS: Of 100,263 study participants, 13,749 (13.7%) had periodontal disease. In a mean follow-up of 3.8 years, all cause and cardiovascular mortality rates in those with periodontal disease (11.5% and 2.6%, respectively) were higher compared with those without periodontal disease (6.7% and 1.6%, respectively). After adjustment for demographic characteristics, comorbid conditions, and biochemistry data, adjusted HRs for all cause and cardiovascular mortality were 1.34 (95% CI, 1.26-1.42) and 1.25 (95% CI, 1.13-1.41), respectively. The frequency of eGFR decline >= 30% over 1-, 2-, and 3-years' follow-up in those with periodontal disease was 1.8%, 3.7%, and 4.0%, respectively. In a logistic regression model, adjusted ORs of the detrimental effect of periodontal disease on 30% eGFR decline in participants over 1-, 2-, or 3-years' follow-up were 1.03 (95% CI, 0.85-1.25), 1.62 (95% CI, 1.41-1.87), and 1.59 (95% CI, 1.37-1.86), respectively. In subgroup analyses according to age, sex, and comorbid conditions, risks for eGFR decline and mortality remained consistent. LIMITATIONS: Results may not be generalizable to other non-Asian ethnic populations. CONCLUSIONS: The results indicate that periodontal disease is a risk factor for all-cause and cardiovascular mortality and eGFR decline >= 30% over 2 to 3 years in older people. PMID- 25747405 TI - Donepezil treatment in ethnically diverse patients with Alzheimer disease. AB - OBJECTIVE: To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. METHODS: Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self identified their ethnicity. RESULTS: The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. CONCLUSION: Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients. PMID- 25747406 TI - Oral films: Current status and future perspectives: I - Galenical development and quality attributes. AB - Polymers are the most common excipients used in pharmaceutical dosage forms, and often new applications and innovative polymers appear aiming to overcome unmet needs in the drug formulation field. Orodispersible dosage forms based on polymeric matrices have currently demonstrated their prominence in accordance with the actual market requirements and patients' demands. The versatility of the polymeric oral films had proven their high value as suitable technological platforms for extension and adjustment to different delivery routes and promising markets. These are the main reasons for the increasing investment of several companies in this technology and their applicability in different therapeutic segments. This pharmaceutical form with a blustering beginning as a breath freshener had an emergent entrance in the Rx market proving its reliable value. This review describes and explores the oral film technology from its main component, the polymeric matrices, to the new and possible market applications, highlighting all the critical and important points of its development. PMID- 25747407 TI - Nanofiber-mediated microRNA delivery to enhance differentiation and maturation of oligodendroglial precursor cells. AB - Remyelination in the central nervous system (CNS) is critical in the treatment of many neural pathological conditions. Unfortunately, the ability to direct and enhance oligodendrocyte (OL) differentiation and maturation remains limited. It is known that microenvironmental signals, such as substrate topography and biochemical signaling, regulate cell fate commitment. Therefore, in this study, we developed a nanofiber-mediated microRNA (miR) delivery method to control oligodendroglial precursor cell (OPC) differentiation through a combination of fiber topography and gene silencing. Using poly(epsilon-caprolactone) nanofibers, efficient knockdown of OL differentiation inhibitory regulators were achieved by either nanofiber alone (20-40%, p<0.05) or the synergistic integration with miR 219 and miR-338 (up to 60%, p<0.05). As compared to two-dimensional culture, nanofiber topography enhanced OPC differentiation by inducing 2-fold increase in RIP(+) cells (p<0.01) while the presence of miRs further enhanced the result to 3 fold (p<0.001). In addition, nanofiber-mediated delivery of miR-219 and miR-338 promoted OL maturation by increasing the number of MBP(+) cells significantly (p<0.01). Taken together, the results demonstrate the efficacy of nanofibers in providing topographical cues and microRNA reverse transfection to direct OPC differentiation. Such scaffolds may find useful applications in directing oligodendrocyte differentiation and myelination for treatment of CNS pathological conditions that require remyelination. PMID- 25747409 TI - Kullar R et al (Clin Infect Dis 2014; 59:1455-61). PMID- 25747408 TI - Editorial commentary: Setting national targets for antibiotic use. PMID- 25747411 TI - Derivation of stretched exponential tap density equations of granular powders. AB - The tap density of granular powders was found to be better fitted with the stretched exponential law. In our previous work, the stretched exponential tap density equations were derived with the rate process theory and free volume concept, under the assumption that the particle packing rate during the tapping process obeys the stretched Arrhenius equation, which, however, has an empirical origin. In this article, the above assumption is eliminated and attempts are made to obtain the stretched exponential tap density equations from very fundamental bases. In a vertical tapping process, the probability of particles attaining certain energy states is assumed to obey the Boltzmann distribution and particles traveling from one site to another are assumed to follow a very common memoryless random exponential law. The stretched exponential tap density equations are thus derived and all parameters acquire clear physical meanings. The most important parameter, the stretched exponential, is demonstrated to correlate with the interparticle forces: a small value may indicate a strong adhesive or cohesive interaction. Therefore, the stretched exponential could be a better indicator for powder flowability correlated with particle interactions as well. PMID- 25747410 TI - US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. AB - BACKGROUND: Appropriate antibiotic prescribing is an essential strategy to reduce the spread of antibiotic resistance. US prescribing practices have not been thoroughly characterized. We analyzed outpatient antibiotic prescribing data to identify where appropriate antibiotic prescribing interventions could have the most impact. METHODS: Oral antibiotic prescriptions dispensed during 2011 were extracted from the IMS Health Xponent database. The number of prescriptions and census denominators were used to calculate prescribing rates. Prescription totals were calculated for each provider specialty. Regression modeling was used to examine the association between socioeconomic and population health factors and prescribing rates. RESULTS: Healthcare providers prescribed 262.5 million courses of antibiotics in 2011(842 prescriptions per 1000 persons). Penicillins and macrolides were the most common antibiotic categories prescribed. The most commonly prescribed individual antibiotic agent was azithromycin. Family practitioners prescribed the most antibiotic courses (24%). The prescribing rate was higher in the South census region (931 prescriptions per 1000 persons) than in the West (647 prescriptions per 1000 persons; P < .001); this pattern was observed among all age groups, including children <= 2 and persons >= 65 years of age. Counties with a high proportion of obese persons, infants and children <= 2 years of age, prescribers per capita, and females were more likely to be high prescribing by multivariable analysis (adjusted odds ratio, >1.0). CONCLUSIONS: Efforts to characterize antibiotic prescribing practices should focus on the South census region and family practitioners. Further understanding of the factors leading to high prescribing among key target populations will inform appropriate prescribing interventions. PMID- 25747412 TI - Evolution of calcium signalling. PMID- 25747413 TI - Bias in observational study designs: cross sectional studies. PMID- 25747414 TI - A delayed eco-epidemiological system with infected prey and predator subject to the weak Allee effect. AB - We consider a system of delay differential equations to represent predator-prey eco-epidemic dynamics with weak Allee effect in the growth of predator population. The basic aim of the paper is to observe the dynamics of such system under the influence of gestation delay of predator and Allee parameter. We analyze essential mathematical features of the proposed model such as uniform persistence, stability and Hopf-bifurcation at the interior equilibrium point of the system. Global asymptotic stability analysis of the positive equilibrium points by constructing a suitable Lyapunov function for the delayed model is carried out separately. We perform several numerical simulations to illustrate the applicability of the proposed mathematical model and our analytical findings. We observe that the system exhibits chaotic oscillation due to increase of the delay parameter tau. We also observe that there is a threshold of Allee parameter above which the predator population will be washed away from the system. PMID- 25747415 TI - Quantifying uncertainty in parameter estimates for stochastic models of collective cell spreading using approximate Bayesian computation. AB - Wound healing and tumour growth involve collective cell spreading, which is driven by individual motility and proliferation events within a population of cells. Mathematical models are often used to interpret experimental data and to estimate the parameters so that predictions can be made. Existing methods for parameter estimation typically assume that these parameters are constants and often ignore any uncertainty in the estimated values. We use approximate Bayesian computation (ABC) to estimate the cell diffusivity, D, and the cell proliferation rate, lambda, from a discrete model of collective cell spreading, and we quantify the uncertainty associated with these estimates using Bayesian inference. We use a detailed experimental data set describing the collective cell spreading of 3T3 fibroblast cells. The ABC analysis is conducted for different combinations of initial cell densities and experimental times in two separate scenarios: (i) where collective cell spreading is driven by cell motility alone, and (ii) where collective cell spreading is driven by combined cell motility and cell proliferation. We find that D can be estimated precisely, with a small coefficient of variation (CV) of 2-6%. Our results indicate that D appears to depend on the experimental time, which is a feature that has been previously overlooked. Assuming that the values of D are the same in both experimental scenarios, we use the information about D from the first experimental scenario to obtain reasonably precise estimates of lambda, with a CV between 4 and 12%. Our estimates of D and lambda are consistent with previously reported values; however, our method is based on a straightforward measurement of the position of the leading edge whereas previous approaches have involved expensive cell counting techniques. Additional insights gained using a fully Bayesian approach justify the computational cost, especially since it allows us to accommodate information from different experiments in a principled way. PMID- 25747416 TI - Men's sexual interest in children: one-year incidence and correlates in a population-based sample of Finnish male twins. AB - In a study of 1,310 Finnish adult male twins we found that sexual interest in children aged 12 or younger was reported by 0.2% of the sample. Sexual interest in children aged 15 or younger was reported by 3.3%. Participants reporting sexual interest in children aged 15 or younger were younger, reported stronger sexual desire, and had experienced more childhood sexual and nonsexual abuse. The present study is the first to give a population-based estimate of the incidence of sexual interest in children among adult men. The 12-month incidence of sexual interest in children below the age of 16 years is roughly comparable to the one year incidence of major depression or the lifetime prevalence of transvestitic fetishism. PMID- 25747417 TI - The influence of child sexual abuse on the self from adult narrative perspectives. AB - The impact of child sexual abuse on the adult self is not yet clearly understood. We explored adult perspectives through the use of narrative interviews (N = 30). Three key themes or views of self were identified in all narratives to varying degrees: the worthless self, the self as unknown, and the potential/developing self. Ambivalence and tension were present in all narratives. Individuals were challenged to integrate the sexual abuse experience in a constructive way and develop a more coherent perception of the self. The narrative method highlighted the dynamic nature of peoples' experiences at the same time recognizing that the narratives themselves are in progress. Reactions to disclosure, social support, and interpersonal connections are crucial at every turn. PMID- 25747418 TI - "From that moment on my life changed": turning points in the healing process for men recovering from child sexual abuse. AB - Recent research indicates that child sexual abuse often undermines the health of boys and men across the lifespan. However, some male survivors experience a turning point marking a positive change in their health trajectories and healing process. Although frequently discussed in reference to physical health problems or addictions, very little is known about turning points with respect to child sexual abuse for men. The purpose of this secondary qualitative analysis was to describe the different types of turning points experienced by male survivors who completed the 2010 Health and Well-Being Survey (N = 250). Using conventional content analysis, researchers identified seven types of turning points that were classified into three broad categories: influential relationships (professional and group support, personal relationships), insights and new meanings (cognitive realizations, necessity to change, spiritual transformation), and action-oriented communication (disclosure of CSA, pursuit of justice). Implications for clinical practice and future research are discussed. PMID- 25747419 TI - A case study of social cognitive treatment of PTSD in a South African rape survivor: the central role of case formulation. AB - This is a systematic case study of the psychological assessment and treatment of Zinhle (19), a Black South African student with posttraumatic stress disorder, following a rape at age 10. Treatment was based on Ehlers and Clark's (2000) cognitive therapy, a flexible formulation driven model. The study documented the secondary trauma experienced by families following child sexual abuse and showed how treatment not only needed to target the trauma memory but also the ruptured relationships within and outside the family. This was done within the framework of Tarrier and Humphreys's (2004) social cognitive model. At the end of treatment Zinhle no longer met criteria for PTSD, and the narrative supports Ehlers and Clark's model as well as the social cognitive model. PMID- 25747420 TI - Commentary: Problems with the sexual disorders sections of DSM-5. AB - There are a number of problems with the sexual disorders sections of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. These problems must be understood in a historical context, namely the evolution of criteria for psychosexual disorders from DSM-II (1968) to DSM-5 (2013). There are many inconsistencies in the DSM-5 criteria for different sexual disorders. Given these inconsistencies--and the history of diagnostic criteria for homosexuality and gender identity disorder from DSM-II to DSM-5--it is possible that, like homosexuality, DSM-5 gender dysphoria could disappear from future editions of the manual. Even if that does not happen, there are numerous problems with the DSM-5 sexual disorders that require attention. PMID- 25747421 TI - Response to Ross's "Commentary: Problems with the sexual disorders sections of DSM-5". AB - The recent commentary by Ross (2015) addresses concerns regarding the newly created Paraphilic Disorders section of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, and "inconsistencies." The author's statements reflect notable confusion regarding issues related to human sexuality and the categories thereof in the DSM-5 (e.g., gender dysphoria and pedophilic disorder). This is a response to Ross's commentary. PMID- 25747422 TI - Understanding sexual, paraphilic, and gender dysphoria disorders in DSM-5. AB - With every Diagnostic and Statistical Manual of Mental Disorders that has been published, there has been controversy within controversy; however, what appears to be lacking is the importance of truly understanding what, why, and how the changes impact the community at large. Issues such as homosexuality, the five axial diagnostic system, and transitioning from a medical model to a biopsychosocial model have been hot topics that have led clinicians to challenge the reliability and validity of the manual throughout history. As clinicians and medical professionals, it is important to objectively look at the manual and become educated on how and why these changes exist. With that being said, this commentary aims to challenge the article " COMMENTARY: Problems with the Sexual Disorders Sections of DSM-5" by Colin A. Ross (2015). The structure of this commentary purposefully mirrors the structure of the commentary that it is challenging. PMID- 25747423 TI - Rouxiella chamberiensis gen. nov., sp. nov., a member of the family Enterobacteriaceae isolated from parenteral nutrition bags. AB - Parenteral nutrition bags for newborns were found contaminated by a previously undescribed member of the family Enterobacteriaceae. The six isolates studied by rrs gene (encoding 16S rRNA) sequence analysis and multi-locus sequence analysis (MLSA) formed a discrete branch close to the genera Ewingella, Rahnella, Yersinia,Hafnia and Serratia. Phenotypically, the new taxon was distinct from these five genera. The new taxon gave positive results in Voges-Proskauer, Simmons citrate and o-nitrophenyl-beta-galactoside hydrolysis tests; fermented d glucose, d-mannitol, l-rhamnose, melibiose, l-arabinose and d-xylose; hydrolysed aesculin; and did not ferment maltose, trehalose, raffinose, d-sorbitol, sucrose or cellobiose. Tests for motility, gas production, urease, gelatinase and nitrate reduction were also negative. All isolates failed to grow at 37 degrees C. The DNA G+C content of strain 130333T was 53 mol%. On the basis of data obtained in this study, the six isolates represent a novel species of a new genus in the family Enterobacteriaceae, named Rouxiella chamberiensis gen. nov., sp. nov. The type strain of the type species is 130333T ( = CIP 110714T = DSM 28324T). PMID- 25747424 TI - Plantactinospora veratri sp. nov., an actinomycete isolated from black false hellebore root (Veratrum nigrum L.). AB - A novel actinomycete, designated strain NEAU-FHS4T, was isolated from the root of black false hellebore (Veratrum nigrum L.). Strain NEAU-FHS4T formed single spores with smooth surfaces on substrate mycelium. The novel strain contained meso-diaminopimelic as amino acid of the peptidoglycan and xylose and glucose as whole-cell sugars. The predominant menaquinones were MK-10(H6) and MK-10(H8). Mycolic acids were not detected. The diagnostic phospholipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylinositol. The predominant cellular fatty acids were iso-C16 : 0, C16 : 0, C18 : 0 and anteiso C17 : 0. Phenotypic and chemotaxonomic analysis showed that the novel isolate had characteristics typical of members of the genus Plantactinospora. 16S rRNA gene sequence analysis also indicated that strain NEAU-FHS4T belonged to the genus Plantactinospora, with highest sequence similarities to Plantactinospora mayteni YIM 61359T (98.88 %) and Plantactinospora endophytica YIM 68255T (98.85 %). The results of DNA-DNA hybridization and physiological and biochemical tests allowed genotypic and phenotypic differentiation of the novel strain from the most closely related strains. Based on morphological, chemotaxonomic and phylogenetic data, strain NEAU-FHS4T is considered to represent a novel species of the genus Plantactinospora, for which the name Plantactinospora veratri sp. nov. is proposed. The type strain is NEAU-FHS4T ( = CGMCC 4.7143T = DSM 46718T). PMID- 25747425 TI - Defluviimonas alba sp. nov., isolated from an oilfield. AB - Two Gram-stain-negative, rod-shaped bacterial strains, cai42T and b45, were isolated from oil-production water taken from Xinjiang Oilfield, China. Optimum growth was observed at 30 degrees C, at pH 8 and with 1-3% (w/v) NaCl. According to phylogenetic analyses, the two strains were members of the genus Defluviimonas, with 16S rRNA gene sequence similarities of 95.5-96.3 % with the type strains of species of the genus. The major cellular fatty acids of strains cai42T and b45 were C10 : 0 3-OH, C16 : 0 and summed feature 8 (C18 : 1omega7c/C18 : 1omega6c), and the predominant ubiquinone was Q-10, all of these data being typical for the genus Defluviimonas. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, glycolipid, phosphatidylcholine, two unidentified aminolipids, an unidentified phospholipid and two unidentified lipids. The mean genomic DNA G+C contents of strains cai42T and b45 were 60.8+/ 1.1 and 60.4+/-1.0 mol%, respectively. On the basis of phylogenetic, physiological and chemotaxonomic analyses, strains cai42T and b45 represent a novel species of the genus Defluviimonas, for which the name Defluviimonas alba sp. nov. is proposed. The type strain is cai42T ( = CGMCC 1.12518T = LMG 27406T). PMID- 25747426 TI - Modified transversal sagittal maxillary expander for correction of upper midline deviation associated with maxillary arch deficiency. AB - The transversal sagittal maxillary expander (TSME) is a fixed device designed to develop arch form in patients with constricted dental arches. The present article describes a modified TSME appliance, the activation method, the therapeutic benefits as well as clinical advantages. The appliance has two molar bands, a Hyrax-type transverse expansion screw, one 0.045-inch wire extending from the molar band to the palatal surface of the central incisor in the emiarch crossbite and an 8 mm-Hyrax-type screw attached to this wire between the molar band and the incisor. A buccal arm with a terminal loop is welded to the band in the emiarch and it is extended to the labial surface on the central incisor on the side opposite to the crossbite and the maxillary midline deviation. The modified TSME appliance described in this paper are specifically designed for anteroposterior and transverse development. It has a sagittal effect on the maxillary alveolar process and at the same time allow to restore the correct transverse maxillary diameters. PMID- 25747427 TI - Breathing pattern and head posture: changes in craniocervical angles. AB - AIM: The aim of this study was to observe the influence of oral breathing on head posture and to establish possible postural changes observing the variation of craniocervical angles NSL/OPT and NSL/CVT between oral breathing subjects and physiological breathing subjects. METHODS: A cross-sectional study was conducted. The sample included 115 subject, 56 boys and 59 girls, 5-22-year-old. Among these, 80 were classified as oral breathers and 35 as physiological breathers. The diagnosis of oral breathing was carried out thanks to characteristic signs and symptoms evaluated on clinical examination, the analysis of characteristic X ray images, ENT examination with active anterior rhinomanometric (AAR) test. The structural and postural analysis was carried out, calculating the craniofacial angles NSL/OPT and NSL/CVT. RESULTS: Both NSL/OPT and NSL/CVT appear to be significantly greater to those observed in physiological breathing patients. This means that patients who tend to breathe through the mouth rather than exclusively through the nose show a reduction of cervical lordosis and a proinclination of the head. CONCLUSION: Our study confirms that the oral breathing modifies head position. The significant increase of the craniocervical angles NSL/OPT and NSL/CVT in patients with this altered breathing pattern suggests an elevation of the head and a greater extension of the head compared with the cervical spine. So, to correct the breathing pattern early, either during childhood or during adolescence, can lead to a progressive normalization of craniofacial morphology and head posture. PMID- 25747428 TI - Profile changes following lower incisor repositioning: a comparison between patients with different growth pattern. AB - AIM: Individual growth changes might play a large role in the variability of treatment results for the soft-tissue profile. The aim of this study is to evaluate the real existence of the relationship between the repositioning of lower incisors, evaluated by Frankfort Mandibular Incisor Angle (FMIA), and the enhancement of profile, evaluated by the angle formed by its intersection with Frankfort plane (Z-angle). We finally compared this relationship in patients with different growth pattern. METHODS: A sample of 81 subjects all treated with Merrifield Directional Force System was divided in two group on the basis of INDEX value (ratio between posterior and anterior facial height): Group 1 (INDEX value <=0.65, non-favorable growth pattern) and Group 2 (INDEX value >0.65, favorable growth pattern). Differences between post-treatment and pre-treatment values of FMIA and Z-angle were calculated for each group and was named respectively ? FMIA and ? Z-angle. A ratio between ? Z-angle and ? FMIA was also calculated. RESULTS: The results of this study show a statistically significant correlation between lower incisors uprighting and profile outcome. A statistically significant difference between Group 1 and Group 2 was not found. CONCLUSION: These results underline the difficulty to quantify and separate the effects of growth and orthodontic treatment of growing patients in determining the final facial configuration. PMID- 25747429 TI - Evaluation of preformed endodontic postretention force using post-BRUSH technique. AB - AIM: In this work it has been evaluated how the use of an endocanalar brush (post brush) is able to clean the post-space macroscopically and eliminate permanently any debris, leading to the determination of an enhancement of the dentine-cement interface adhesion. The retentive power of cylindrical-grooved in two different groups of dental elements (A GROUP and B GROUP) will be compared, cementing A group according to standard protocol and B group with treatment of Post-Brush. METHODS: Forty monoradicular elements were selected to carry out this experimental work. The roots were treated endodontically. Samples were divided randomly into two groups. For each group was used a different type of cementation. These tests were performed through the use of an electronic dynamometer. The samples were subjected to tensile strength to obtain a axial traction shear-stress and a subsequent separation of sample postreconstruction from root canal, at a loading maximum value recorded by the dynamometer right after the detachment. RESULTS: B GROUP, which included cemented cylindrical rubbed posts before treatment of Post-Brush, has shown a tensile shear-stress at break performances higher than that A GROUP, in which cylindrical-rubbed posts have been cemented according to the standard protocol. CONCLUSION: Post-brush allows to obtain a better mechanical cleaning, going to remove gutta-percha residues, smear-layer and endodontic cement, which remain adhere on the canal walls otherwise they will not be removed completely by the use of the etching and the washing techniques as it tends to adhere to the canal walls. PMID- 25747430 TI - Obstructive sleep apnea syndrome: a literature review. AB - Obstructive sleep apnea syndrome (OSAS) is a complete or partial airway obstruction that can cause significant physiologic disturbance with various clinical impacts. The etiology is multifactorial and its clinical manifestations are night snoring, headache when patient wakes up, day-time sleepiness and degrease of cognitive performance. Some recent international studies suggest that the OSAS prevalence is 2-4% in men and 1-2% in women of average age. The aim of this work was presenting a literature review in Medline concerning Obstructive sleep apnea syndrome. A review of the articles ranging from 1980 to 2014 has been done. Over 2000 articles were found and those which give useful information about etiology, diagnosis, therapy and found results after the study were selected and evaluated. In literature there is no unanimous opinion on the treatment of OSAS. According to the majority of the authors it should be multidisciplinary. The choice of therapy is predicated on the etiology, severity and natural history of the increased upper airway resistance. The importance of a praecox diagnosis and orthodontic therapy in order to re-establish normal function is underlined, since OSAS is linked with high risk of hypertension, cardiovascular diseases, daytime sleepiness, home and work-related accidents, with consequent worsening of life quality. PMID- 25747431 TI - No association of TP53 codon 72 SNP with male infertility: a study in a Chinese population and a meta-analysis. AB - Genetic polymorphisms may affect human male fertility. Even though TP53 plays a role in spermatogenesis we know little about the association of the functional polymorphism at codon 72 of TP53 with respect to susceptibility to male infertility. We conducted a case-control study to investigate this association in a Chinese population and performed a meta-analysis in different populations to clarify this association. The single nucleotide polymorphism (SNP) of TP53 codon 72 (rs1042522 G>C) was genotyped by PCR-RFLP in 83 Chinese male infertility patients and 401 healthy controls. Meta-analysis was performed using the data from four currently available studies. The data from our study were overlayed using the v.9.0 STATA software package. We observed no association between the TP53 codon 72 polymorphism and male infertility (p = 0.84, OR = 1.04, 95% CI, 0.74-1.45). Meta-analysis confirmed the case-control result that there was no significant association between the codon 72 polymorphism of TP53 and male infertility (Pro vs. Arg; p = 0.31, OR = 0.86, 95% CI, 0.65-1.15; Pro/Pro vs. Arg carriers; p = 0.65, OR = 0.91, 95% CI, 0.61-1.36; Pro-carriers vs. Arg/Arg: p = 0.15, OR = 0.75, 95% CI, 0.51-1.11). The data presented in this communication supports the view that the codon 72 polymorphism of TP53 may not contribute to male infertility susceptibility in the Chinese population. PMID- 25747432 TI - DNA hypomethylation predisposes sperm to DNA damage in individuals with varicocele. AB - This study aimed to assess and compare global DNA methylation (GDM) between fertile men and infertile men with varicocele. In addition, we evaluated the correlations between DNA methylation with reactive oxygen species (ROS), protamine deficiency, and DNA integrity. Semen samples were collected from 44 men with grades II and III varicocele, and 15 fertile men for assessment of semen parameters, DNA methylation, DNA fragmentation, oxidative stress, and protamine deficiency. Samples were evaluated by the World Health Organization (WHO) criteria, immunostaining, the TUNEL assay, 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, and chromomycin A3 (CMA3) staining. Semen parameters were significantly lower in individuals with varicocele compared to fertile men. The percentage of GDM and intensity of DCFH were reduced and the percentages of DCFH, TUNEL, and CMA3 positive sperm significantly increased in individuals with varicocele compared to fertile men. Correlation analysis revealed a negative significant relation between DNA methylation and DNA fragmentation, but not with the degree of protamine deficiency and ROS production. The results have shown that individuals with varicocele show increased DNA susceptibility to damage when DNA is hypomethylated. This phenomenon appears to be independent of ROS production. PMID- 25747433 TI - Computed tomography scan versus upper gastrointestinal fluoroscopy for diagnosis of staple line leak following bariatric surgery. AB - BACKGROUND: The best radiographic modality to diagnose staple line leaks following bariatric surgery remains controversial. Two common studies used are upper gastrointestinal (UGI) fluoroscopy and computed tomography (CT). This study sought to determine the better modality in detecting clinically significant postoperative leaks. METHODS: This retrospective review was performed of patients undergoing imaging for suspected staple line leaks following bariatric surgery. These studies were reinterpreted by 2 radiologists who were blinded to the original findings. RESULTS: Six hundred nineteen radiographic "leak tests" were selectively performed following bariatric procedures at our institution between January 2005 and December 2011. CT was found to have a sensitivity of 95% (95% confidence interval [CI] 81.8 to 99.1) and a specificity of 100% (95% CI 93.1 to 100) in diagnosing postoperative leaks, while UGI demonstrated a sensitivity of 79.4% (95% CI 61.6 to 90.0) and a specificity of 95% (95% CI 85.2 to 98.7). CONCLUSION: CT is a superior modality compared with UGI for detecting staple line leaks following bariatric surgery. PMID- 25747434 TI - Quantitative structure-activity relationships for cellular uptake of surface modified nanoparticles. AB - Quantitative structure-activity relationships (QSARs) were developed, for cellular uptake of nanoparticles (NPs) of the same iron oxide core but with different surface-modifying organic molecules, based on linear and non-linear (epsilon support vector regression (epsilon-SVR)). A linear QSAR provided high prediction accuracy of R2=0.751 (coefficient of determination) using 11 descriptors selected from an initial pool of 184 descriptors calculated for the NP surfacemodifying molecules, while a epsilon-SVR based QSAR with only 6 descriptors improved prediction accuracy to R2=0.806. The linear and epsilon-SVR based QSARs both demonstrated good robustness and well spanned applicability domains. It is suggested that the approach of evaluating pertinent descriptors and their significance, via QSAR analysis, to cellular NP uptake could support planning and interpretation of toxicity studies as well as provide guidance for the tailor-design NPs with respect to targeted cellular uptake for various applications. PMID- 25747435 TI - G-Protein Coupled Receptors (GPCRs): A Comprehensive Computational Perspective. AB - GPCRs are ubiquitous in most of the organs of the human body. These receptors were found to be the important targets to attenuate inflammation, cancer, cardiac dysfunction, diabetes, etc. The advanced technologies employed on GPCRs provided an opportunity to understand the physiological process of various diseases. Recently, GPCRs were viewed as viable therapeutic targets to deliver safer and more efficacious drug. In the literature, several computational studies were reported to describe the biological mechanism, function and three-dimensional structure of GPCRs. These studies revealed the multiple conserved transmembrane domains of GPCRs which were connected by intra and extracellular loops. In this review, we provide an updated overview on the computational tools and methodologies which were conducted to explore the structural and mechanistic features of GPCRs. The study also demonstrates the most recent computer-aided drug design approaches employed on GPCRs. This review provides the information that can be exploited toward the molecular understanding of GPCRs with an aim to design the novel ligands for GPCRs. PMID- 25747436 TI - Using Online Tool (iPrior) for Modeling ToxCastTM Assays Towards Prioritization of Animal Toxicity Testing. AB - The use of long-term animal studies for human and environmental toxicity estimation is more discouraged than ever before. Alternative models for toxicity prediction, including QSAR studies, are gaining more ground. A recent approach is to combine in vitro chemical profiling and in silico chemical descriptors with the knowledge about toxicity pathways to derive a unique signature for toxicity endpoints. In this study we investigate the ToxCastTM Phase I data regarding their ability to predict long-term animal toxicity. We investigated thousands of models constructed in an effort to predict 61 toxicity endpoints using multiple descriptor packages and hundreds of in vitro assays. We investigated the use of in vitro assays and biochemical pathways on model performance. We identified 10 toxicity endpoints where biologically derived descriptors from in vitro assays or pathway perturbations improved the model prediction ability. In vivo toxicity endpoints proved generally challenging to model. Few models were possible to readily model with a balanced accuracy (BA) above 0.7. We also constructed in silico models to predict the outcome of 144 in vitro assays. This showed better statistical metrics with 79 out of 144 assays having median balanced accuracy above 0.7. This suggests that the in vitro datasets have a better modelability than in vivo animal toxicities for the given datasets. Moreover, we published an online platform (http://iprior.ochem.eu) that automates large-scale model building and analysis. PMID- 25747437 TI - Recent progress in the identification and development of anti-malarial agents using virtual screening based approaches. AB - Malaria has continued to be one of the most perplexing diseases for biological science community around the world due to its prevalent devastating nature and quick developing resistance against the frontline drugs. Artimisinin-based combination therapy (ACT) has been so far found to be among the best therapies against Plasmodium pathogens but alarming emergence of resistance in parasites against every known chemotherapy has prompted the scientific community to step up all the efforts towards development of new and affordable anti-malarial drugs. Computer-aided approaches have received enormous attention in recent years in the field of identification and design of novel drugs. In this review, we summarize recently published research concerning the identification and development of anti malarial compounds using virtual screening approaches. It would be admirable to discern the successful application of in silico studies for anti-malarial drug discovery hitherto and would certainly help in generating new avenues for pursuing integrated studies between the experimentalists and computational chemists in a systematic manner as a time and cost efficient alternative for future antimalarial drug discovery projects. PMID- 25747438 TI - In silico identification of irreversible cathepsin B inhibitors as anti- cancer agents: virtual screening, covalent docking analysis and molecular dynamics simulations. AB - Cathepsin B is a cysteine protease that belongs to the papain superfamily. Malfunctions related to cathepsin B can lead to inflammation and cancer. Via an integrated in silico approach, this study is aimed to identify novel Michael acceptors-type compounds that can irreversibly inhibit cathepsin B enzyme via covalent bond formation with the active site cysteine residue. Here, we report the first account of covalent docking approach incorporated into a hybrid ligand/structure-based virtual screening to estimate the binding affinities of various compounds from chemical databases against the cathepsin B protein. For validation, compounds with experimentally determined anti-cathepsin B activity from PubChem bioassay database were also screened and covalently docked to the enzyme target. Interestingly, four novel compounds exhibited better covalent binding affinity when compared against the experimentally determined prototypes. Molecular dynamics simulations were performed to ensure the stability of the docked complexes and to allow further analysis on the MD average structures. Perresidue interaction decomposition analysis was carried out to provide deeper insight into the interaction themes of discovered hits with the active site residues. It is found that polar and hydrophobic interactions contributed the most towards drug binding. The hybrid computational methods applied in this study should serve as a powerful tool in the drug design and development process. PMID- 25747439 TI - Is there a relationship between sweet taste and seizures? Anticonvulsant and proconvulsant effects of non-nutritive sweeteners. AB - From a virtual screening campaign, a number of artificial and natural sweeteners were predicted as potential anticonvulsant agents with protective effects in the seizure animal model Maximal Electroshock Seizure (MES) test. In all cases, the predictions were experimentally confirmed in the aforementioned preclinical seizure model. The article reviews and expands previous reports from our group on anticonvulsant activity of those non-nutritive sweeteners, illustrating the potential of virtual screening approaches to propose new medical uses of food additives. This constitutes a particular case of knowledge-based drug repositioning, which may greatly shorten the development time and investment required to introduce novel medications to the pharmaceutical market. We also briefly overview evidence on possible molecular explanations on the anticonvulsant and proconvulsant effects of different non-nutritive sweeteners. Our analysis -based on Swanson's ABC model- suggests that group I metabotropic glutamate receptors and carbonic anhydrase isoform VII (both proposed or validated molecular targets of antiepileptic drugs) might be involved in the anticonvulsant effect of artificial sweeteners. The first hypothesis is in line with recent advances on development of selective modulators of group I metabotropic glutamate receptors as potential antiepileptic agents. PMID- 25747440 TI - Systematic Comparison of the Performance of Different 2D and 3D Ligand-Based Virtual Screening Methodologies to Discover Anticonvulsant Drugs. AB - Virtual screening encompasses a wide range of computational approaches aimed at the high-throughput, cost-efficient exploration of chemical libraries or databases to discover new bioactive compounds or novel medical indications of known drugs. Here, we have performed a systematic comparison of the performance of a large number of 2D and 3D ligand-based approaches (2D and 3D similarity, QSAR models, pharmacophoric hypothesis) in a simulated virtual campaign on a chemical library containing 50 known anticonvulsant drugs and 950 decoys with no previous reports of anticonvulsant effect. To perform such comparison, we resorted to Receiver Operating Characteristic curves. We also tested the relative performance of consensus methodologies. Our results indicate that the selective combination of the individual approaches (through voting and ranking combination schemes) significantly outperforms the individual algorithms and/or models. Among the best-performing individual approaches, 2D similarity search based on circular fingerprints and 3D similarity approaches should be highlighted. Combining the results from different query molecules also led to enhanced enrichment. PMID- 25747441 TI - Comparing global and local likelihood score thresholds in multiclass laplacian modified Naive Bayes protein target prediction. AB - The increase of publicly available bioactivity data has led to the extensive development and usage of in silico bioactivity prediction algorithms. A particularly popular approach for such analyses is the multiclass Naive Bayes, whose output is commonly processed by applying empirically-derived likelihood score thresholds. In this work, we describe a systematic way for deriving score cut-offs on a per-protein target basis and compare their performance with global thresholds on a large scale using both 5-fold cross-validation (ChEMBL 14, 189k ligand-protein pairs over 477 protein targets) and external validation (WOMBAT, 63k pairs, 421 targets). The individual protein target cut-offs derived were compared to global cut-offs ranging from -10 to 40 in score bouts of 2.5. The results indicate that individual thresholds had equal or better performance in all comparisons with global thresholds, ranging from 95% of protein targets to 57.96%. It is shown that local thresholds behave differently for particular families of targets (CYPs, GPCRs, Kinases and TFs). Furthermore, we demonstrate the discrepancy in performance when we move away from the training dataset chemical space, using Tanimoto similarity as a metric (from 0 to 1 in steps of 0.2). Finally, the individual protein score cut-offs derived for the in silico bioactivity application used in this work are released, as well as the reproducible and transferable KNIME workflows used to carry out the analysis. PMID- 25747442 TI - Prediction of drug induced liver injury using molecular and biological descriptors. AB - In this paper we report quantitative structure-activity models linking in vivo Drug-Induced Liver Injury (DILI) of organic molecules with some parameters both measured experimentally in vitro and calculated theoretically from the molecular structure. At the first step, a small database containing information of DILI in humans was created and annotated by experimentally observed information concerning hepatotoxic effects. Thus, for each compound a binary annotation "yes/no" was applied to DILI and seven endpoints causing different liver pathologies in humans: Cholestasis (CH), Oxidative Stress (OS), Mitochondrial injury (MT), Cirrhosis and Steatosis (CS), Hepatitis (HS), Hepatocellular (HC), and Reactive Metabolite (RM). Different machine-learning methods were used to build classification models linking DILI with molecular structure: Support Vector Machines, Artificial Neural Networks and Random Forests. Three types of models were developed: (i) involving molecular descriptors calculated directly from chemical structure, (ii) involving selected endpoints as "biological" descriptors, and (iii) involving both types of descriptors. It has been found that the models based solely on molecular descriptors have much weaker prediction performance than those involving in vivo measured endpoints. Taking into account difficulties in obtaining of in vivo data, at the validation stage we used instead five endpoints (CH, CS, HC, MT and OS) measured in vitro in human hepatocyte cultures. The models involving either some of experimental in vitro endpoints or their combination with theoretically calculated ones correctly predict DILI for 9 out of 10 reference compounds of the external test set. This opens an interesting perspective to use for DILI predictions a combination of theoretically calculated parameters and measured in vitro biological data. PMID- 25747443 TI - Computer-aided discovery in antimicrobial research: In silico model for virtual screening of potent and safe anti-pseudomonas agents. AB - Resistance of bacteria to current antibiotics is an alarming health problem. In this sense, Pseudomonas represents a genus of Gram-negative pathogens, which has emerged as one of the most dangerous species causing nosocomial infections. Despite the effort of the scientific community, drug resistant strains of bacteria belonging to Pseudomonas spp. prevail. The high costs associated to drug discovery and the urgent need for more efficient antimicrobial chemotherapies envisage the fact that computeraided methods can rationalize several stages involved in the development of a new drug. In this work, we introduce a chemoinformatic methodology devoted to the construction of a multitasking model for quantitative-structure biological effect relationships (mtk-QSBER). The purpose of this model was to perform simultaneous predictions of anti-Pseudomonas activities and ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties of organic compounds. The mtk-QSBER model was created from a large and heterogeneous dataset (more than 54000 cases) and displayed accuracies higher than 90% in both training and prediction sets. In order to demonstrate the applicability of our mtk-QSBER model, we used the investigational antibacterial drug delafloxacin as a case of study, for which experimental results were recently reported. The predictions performed for many biological effects of this drug exhibited a remarkable convergence with the experimental assays, confirming that our model can serve as useful tool for virtual screening of potent and safer anti-Pseudomonas agents. PMID- 25747444 TI - Molecular docking to identify associations between drugs and class I human leukocyte antigens for predicting idiosyncratic drug reactions. AB - Idiosyncratic drug reactions (IDRs) are rare, somewhat dose-independent, patient specific and hard to predict. Human leukocyte antigens (HLAs) are the major histocompatibility complex (MHC) in humans, are highly polymorphic and are associated with specific IDRs. Therefore, it is important to identify potential drug-HLA associations so that individuals who would develop IDRs can be identified before drug exposure. We harvested the associations between drugs and class I HLAs from the literature. The results revealed that there are many drug HLA pairs without clinical data. For better potential interactions of the drug HLA pairs, molecular docking was used to explore the potential of associations between the drugs and HLAs. From the analysis of docking scores between the 17 drugs and 74 class I HLAs, it was observed that the known significantly associated drug-HLA pairs had statistically lower docking scores than those not reported to be significantly associated (t-test p < 0.05). This indicates that molecular docking could be utilized for screening drug-HLA interactions and predicting potential IDRs. Examining the binding modes of drugs in the docked HLAs suggested several distinct binding sites inside class I HLAs, expanding our knowledge of the underlying interaction mechanisms between drugs and HLAs. PMID- 25747445 TI - Rational drug design paradigms: the odyssey for designing better drugs. AB - Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules. PMID- 25747447 TI - Exploring structural requirements of imaging agents against Abeta plaques in Alzheimer's disease: a QSAR approach. AB - Exploring molecular imaging agents against the beta amyloid (Abeta) plaques for an early detection of Alzheimer's disease (AD) is one of the emerging research areas in medicinal chemistry. In the present in-silico study, a congeneric series of 44 imaging agents, including 17 positron emission tomography (PET) and 27 single photon emission computed tomography (SPECT) imaging agents, was utilized to understand the structural features required for having essential binding affinity against Abeta plaques. Here, 2D-quantitative structure-activity relationship (2D-QSAR) and group-based QSAR (G-QSAR) models have been developed using genetic function approximation (GFA) and validated using various statistical metrics. Both the models showed satisfactory performance signifying the reliability and robustness of the developed QSAR models. The vital information gained from both the QSAR models will be useful in developing new PET and SPECT imaging agents and also in predicting their binding affinity against Abeta plaques. The results of this study would be important in view of the widespread clinical applicability of the SPECT imaging agents, especially in the developing countries. In this study, we have also designed some imaging agents based on the information provided by the models. Some of these designed compounds were predicted to be similar to or more active than the most active imaging agents present in the original dataset. PMID- 25747446 TI - The Monte Carlo method based on eclectic data as an efficient tool for predictions of endpoints for nanomaterials - two examples of application. AB - The theoretical predictions of endpoints related to nanomaterials are attractive and more efficient alternatives for their experimental determinations. Such type of calculations for the "usual" substances (i.e. non nanomaterials) can be carried out with molecular graphs. However, in the case of nanomaterials, descriptors traditionally used for the quantitative structure--property/activity relationships (QSPRs/QSARs) do not provide reliable results since the molecular structure of nanomaterials, as a rule, cannot be expressed by the molecular graph. Innovative principles of computational prediction of endpoints related to nanomaterials extracted from available eclectic data (technological attributes, conditions of the synthesis, etc.) are suggested, applied to two different sets of data, and discussed in this work. PMID- 25747448 TI - LiSIs: An Online Scientific Workflow System for Virtual Screening. AB - Modern methods of drug discovery and development in recent years make a wide use of computational algorithms. These methods utilise Virtual Screening (VS), which is the computational counterpart of experimental screening. In this manner the in silico models and tools initial replace the wet lab methods saving time and resources. This paper presents the overall design and implementation of a web based scientific workflow system for virtual screening called, the Life Sciences Informatics (LiSIs) platform. The LiSIs platform consists of the following layers: the input layer covering the data file input; the pre-processing layer covering the descriptors calculation, and the docking preparation components; the processing layer covering the attribute filtering, compound similarity, substructure matching, docking prediction, predictive modelling and molecular clustering; post-processing layer covering the output reformatting and binary file merging components; output layer covering the storage component. The potential of LiSIs platform has been demonstrated through two case studies designed to illustrate the preparation of tools for the identification of promising chemical structures. The first case study involved the development of a Quantitative Structure Activity Relationship (QSAR) model on a literature dataset while the second case study implemented a docking-based virtual screening experiment. Our results show that VS workflows utilizing docking, predictive models and other in silico tools as implemented in the LiSIs platform can identify compounds in line with expert expectations. We anticipate that the deployment of LiSIs, as currently implemented and available for use, can enable drug discovery researchers to more easily use state of the art computational techniques in their search for promising chemical compounds. The LiSIs platform is freely accessible (i) under the GRANATUM platform at: http://www.granatum.org and (ii) directly at: http://lisis.cs.ucy.ac.cy. PMID- 25747449 TI - A ligand-based virtual screening approach to identify small molecules as HERG channel activators. AB - The hERG potassium channel is currently emerging as a potential target for the treatment of some forms of arrhythmias or to contrast an unintentional channel block caused by drugs. Despite its therapeutic relevance, so far only few compounds are described as able to enhance channel function by potentiating hERG currents. This gap is also related to the lack of hERG crystal structure which strongly limits the possibility to employ structure-based techniques in the search and design of novel activators. To overcome this limitation, in the present work, a ligand-based virtual screening was performed using as separate search queries two conformations of NS1643, the most deeply investigated and better characterized hERG activator. The library of compounds resulting from the virtual screening was then clustered based on recurring chemical features, and 5 hits were selected to be evaluated for their ability to enhance hERG current in vitro. Compound 3 showed a good activating effect, also displaying a mechanism of action similar to that of NS1643. Moreover, the most interesting compounds were further investigated by synthesizing in a parallel fashion some analogs, with the aim to get insights about structure-activity relationships. PMID- 25747451 TI - [Innovative supply mechanisms and models of networked supply]. PMID- 25747450 TI - Mechanisms on boron-induced alleviation of aluminum-toxicity in Citrus grandis seedlings at a transcriptional level revealed by cDNA-AFLP analysis. AB - The physiological and biochemical mechanisms on boron (B)-induced alleviation of aluminum (B)-toxicity in plants have been examined in some details, but our understanding of the molecular mechanisms underlying these processes is very limited. In this study, we first used the cDNA-AFLP to investigate the gene expression patterns in Citrus grandis roots responsive to B and Al interactions, and isolated 100 differentially expressed genes. Results showed that genes related to detoxification of reactive oxygen species (ROS) and aldehydes (i.e., glutathione S-transferase zeta class-like isoform X1, thioredoxin M-type 4, and 2 alkenal reductase (NADP+-dependent)-like), metabolism (i.e., carboxylesterases and lecithin-cholesterol acyltransferase-like 4-like, nicotianamine aminotransferase A-like isoform X3, thiosulfate sulfurtransferase 18-like isoform X1, and FNR, root isozyme 2), cell transport (i.e., non-specific lipid-transfer protein-like protein At2g13820-like and major facilitator superfamily protein), Ca signal and hormone (i.e., calcium-binding protein CML19-like and IAA-amino acid hydrolase ILR1-like 4-like), gene regulation (i.e., Gag-pol polyprotein) and cell wall modification (i.e., glycosyl hydrolase family 10 protein) might play a role in B-induced alleviation of Al-toxicity. Our results are useful not only for our understanding of molecular processes associated with B-induced alleviation of Al-toxicity, but also for obtaining key molecular genes to enhance Al-tolerance of plants in the future. PMID- 25747452 TI - Solid lipid nanoparticles loaded with lipoyl-memantine codrug: preparation and characterization. AB - Solid lipid nanoparticles (SLNs) are considered very attractive drug-delivery systems (DDS) able to enhance the efficacy of some therapeutic agents in several pathologies difficult to treat in a conventional way. Starting from these evidences, this study describes the preparation, physicochemical characterization, release, and in vitro cytotoxicity of stealth SLNs as innovative approach to improve solubility and absorption through the gastrointestinal tract of lipoyl-memantine (LA-MEM), a potential anti-Alzheimer codrug. Physico-chemical properties of LA-MEM loaded SLNs have been intensively investigated. Differential scanning calorimetry (DSC) was used to clarify the state and crystalline structure of the formulation. The results obtained from particles size analysis, polydispersity (PDI), and zeta potential measurements allowed the identification of the optimized formulation, which was characterized by a drug-lipid ratio 1:5, an average intensity diameter of 170nm, a PDI of 0.072, a zeta potential of -33.8mV, and an entrapment efficiency of 88%. Moreover, in vitro stability and release studies in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), and preliminary in vitro cytotoxicity studies revealed that LA-MEM loaded SLNs could represent potential candidate for an in vivo investigation as DDS for the brain since it resulted devoid of citotoxicity and able to release the free codrug. PMID- 25747453 TI - A geometric pore adsorption model for predicting the drug loading capacity of insoluble drugs in mesoporous carbon. AB - In this work, a simple and accurate geometric pore-adsorption model was established and experimentally validated for predicting the drug loading capacity in mesoporous carbon. The model was designed according to the shape of pore channels of mesoporous carbon and the arrangement of drug molecules loaded in the pores. Three different small molecule drugs (celecoxib, fenofibrate and carvedilol) were respectively loaded in mesoporous carbon with different pore sizes. In order to test the accuracy of the established model, nitrogen adsorption-desorption analysis was employed to confirm the pore structure of mesoporous carbon and to calculate the occupation volume of the adsorbed drugs. The adsorption isotherms of celecoxib were systematically investigated to describe the adsorption process. It was found that the experimental results of adsorption capacity were all in the range of the predicted values for all the tested drugs and mesoporous carbon. The occupation volumes calculated from the model also agreed well with the experimental data. These results demonstrated that the established model could accurately provide the range of drug loading capacity, which may provide a useful option for the prediction of the drug loading capacity of small molecule drugs in mesoporous materials. PMID- 25747454 TI - Intestinal behavior of the ester prodrug tenofovir DF in humans. AB - Tenofovir-disoproxil-fumarate (TDF) is a double ester prodrug which enables intestinal uptake of tenofovir (TFV) after oral administration in humans. In this study, prodrug stability was monitored in situ in the human intestine and in vitro using biorelevant media. In fasted state human intestinal fluids, the prodrug was completely degraded within 90 min, resulting in the formation of the mono-ester intermediate and TFV; in fed state intestinal fluids, the degradation rate of TDF was slightly reduced and no TFV was formed. Intestinal fluid samples aspirated after administration of TDF confirmed extensive intraluminal degradation of TDF in fasted state conditions; a relatively fast absorption of TDF partly compensated for the degradation. Although food intake reduced intestinal degradation, the systemic exposure was not proportionally increased. The lower degradation in fed state conditions may be attributed to competing esterase substrates present in food, lower chemical degradation in the slightly more acidic environment and micellar entrapment, delaying exposure to the "degrading" intestinal environment. The results of this study demonstrate premature intestinal degradation of TDF and suggest that TFV may benefit from a more stable prodrug approach; however, fast absorption may compensate for fast degradation, indicating that prodrug selection should not be limited to stability assays. PMID- 25747455 TI - Injectable nanoparticle-loaded hydrogel system for local delivery of sodium alendronate. AB - Systemic administration of bisphosphonates, e.g. sodium alendronate (Aln) is characterized by extremely low bioavailability and high toxicity. To omit aforementioned drawbacks an injectable system for the intra-bone delivery of Aln based on Aln-loaded nanoparticles (NPs-Aln) suspended in a hydrogel matrix (gellan gum, GG) was developed. Aln was encapsulated in poly(lactide-co glycolide) (PLGA 85:15) by solid-oil-water emulsification. Drug release tests showed that within 25 days all the encapsulated drug was released from NPs-Aln and the release rate was highest at the beginning and decreased with time. In contrast, by suspending NPs-Aln in a GG matrix, the release rate was significantly lower and more constant in time. The GG-NPs-Aln system was engineered to be easily injectable and was able to reassemble its structure after extrusion as shown by rheological measurements. Invitro studies showed that the GG-NPs-Aln was cytocompatible with MG-63 osteoblast-like cells and it inhibited RANKL-mediated osteoclastic differentiation of RAW 264.7 cells. The injectability, the sustained local delivery of small doses of Aln and the biological activity render the GG-NPs-Aln system promising for the local treatment of osteoporosis and other bone tissue disorders. PMID- 25747456 TI - Interfacial dominated ferromagnetism in nanograined ZnO: a MUSR and DFT study. AB - Diamagnetic oxides can, under certain conditions, become ferromagnetic at room temperature and therefore are promising candidates for future material in spintronic devices. Contrary to early predictions, doping ZnO with uniformly distributed magnetic ions is not essential to obtain ferromagnetic samples. Instead, the nanostructure seems to play the key role, as room temperature ferromagnetism was also found in nanograined, undoped ZnO. However, the origin of room temperature ferromagnetism in primarily non-magnetic oxides like ZnO is still unexplained and a controversial subject within the scientific community. Using low energy muon spin relaxation in combination with SQUID and TEM techniques, we demonstrate that the magnetic volume fraction is strongly related to the sample volume fraction occupied by grain boundaries. With molecular dynamics and density functional theory we find ferromagnetic coupled electron states in ZnO grain boundaries. Our results provide evidence and a microscopic model for room temperature ferromagnetism in oxides. PMID- 25747457 TI - Effect of ankle weight on blind navigation. AB - This study tested the hypotheses that loading the ankle with a 2.3 kg weight would modify deviation (unilateral loading) and distance (unilateral and bilateral loading) during three blind navigation tasks. Ankle loading increased the distance traveled while navigating toward a previously seen target at an 8 m distance and reduced the undetected fore-aft displacement while stepping in place for 100 steps. Unilateral ankle loading had no effect on deviation during these tasks, nor in walking back and forth on an imaginary straight line. The results suggest that somatosensory cues associated with ankle loading and the increased effort to walk and step interacted with motor and cognitive functions involved in blind navigation and influenced the control of anterior-posterior body displacement. PMID- 25747458 TI - Correction: Combined use of systematic conservation planning, species distribution modelling, and connectivity analysis reveals severe conservation gaps in a megadiverse country (Peru). PMID- 25747459 TI - Estimating effective population size from temporally spaced samples with a novel, efficient maximum-likelihood algorithm. AB - The effective population size [Formula: see text] is a key parameter in population genetics and evolutionary biology, as it quantifies the expected distribution of changes in allele frequency due to genetic drift. Several methods of estimating [Formula: see text] have been described, the most direct of which uses allele frequencies measured at two or more time points. A new likelihood based estimator [Formula: see text] for contemporary effective population size using temporal data is developed in this article. The existing likelihood methods are computationally intensive and unable to handle the case when the underlying [Formula: see text] is large. This article tries to work around this problem by using a hidden Markov algorithm and applying continuous approximations to allele frequencies and transition probabilities. Extensive simulations are run to evaluate the performance of the proposed estimator [Formula: see text], and the results show that it is more accurate and has lower variance than previous methods. The new estimator also reduces the computational time by at least 1000 fold and relaxes the upper bound of [Formula: see text] to several million, hence allowing the estimation of larger [Formula: see text]. Finally, we demonstrate how this algorithm can cope with nonconstant [Formula: see text] scenarios and be used as a likelihood-ratio test to test for the equality of [Formula: see text] throughout the sampling horizon. An R package "NB" is now available for download to implement the method described in this article. PMID- 25747461 TI - Pain now or later: an outgrowth account of pain-minimization. AB - The preference for immediate negative events contradicts the minimizing loss principle given that the value of a delayed negative event is discounted by the amount of time it is delayed. However, this preference is understandable if we assume that the value of a future outcome is not restricted to the discounted utility of the outcome per se but is complemented by an anticipated negative utility assigned to an unoffered dimension, which we termed the "outgrowth." We conducted three studies to establish the existence of the outgrowth and empirically investigated the mechanism underlying the preference for immediate negative outcomes. Study 1 used a content analysis method to examine whether the outgrowth was generated in accompaniment with the delayed negative events. The results revealed that the investigated outgrowth was composed of two elements. The first component is the anticipated negative emotions elicited by the delayed negative event, and the other is the anticipated rumination during the waiting process, in which one cannot stop thinking about the negative event. Study 2 used a follow-up investigation to examine whether people actually experienced the negative emotions they anticipated in a real situation of waiting for a delayed negative event. The results showed that the participants actually experienced a number of negative emotions when waiting for a negative event. Study 3 examined whether the existence of the outgrowth could make the minimizing loss principle work. The results showed that the difference in pain anticipation between the immediate event and the delayed event could significantly predict the timing preference of the negative event. Our findings suggest that people's preference for experiencing negative events sooner serves to minimize the overall negative utility, which is divided into two parts: the discounted utility of the outcome itself and an anticipated negative utility assigned to the outgrowth. PMID- 25747460 TI - A cis-regulatory mutation in troponin-I of Drosophila reveals the importance of proper stoichiometry of structural proteins during muscle assembly. AB - Rapid and high wing-beat frequencies achieved during insect flight are powered by the indirect flight muscles, the largest group of muscles present in the thorax. Any anomaly during the assembly and/or structural impairment of the indirect flight muscles gives rise to a flightless phenotype. Multiple mutagenesis screens in Drosophila melanogaster for defective flight behavior have led to the isolation and characterization of mutations that have been instrumental in the identification of many proteins and residues that are important for muscle assembly, function, and disease. In this article, we present a molecular-genetic characterization of a flightless mutation, flightless-H (fliH), originally designated as heldup-a (hdp-a). We show that fliH is a cis-regulatory mutation of the wings up A (wupA) gene, which codes for the troponin-I protein, one of the troponin complex proteins, involved in regulation of muscle contraction. The mutation leads to reduced levels of troponin-I transcript and protein. In addition to this, there is also coordinated reduction in transcript and protein levels of other structural protein isoforms that are part of the troponin complex. The altered transcript and protein stoichiometry ultimately culminates in unregulated acto-myosin interactions and a hypercontraction muscle phenotype. Our results shed new insights into the importance of maintaining the stoichiometry of structural proteins during muscle assembly for proper function with implications for the identification of mutations and disease phenotypes in other species, including humans. PMID- 25747462 TI - Live cell plasma membranes do not exhibit a miscibility phase transition over a wide range of temperatures. AB - Lipid/cholesterol mixtures derived from cell membranes as well as their synthetic reconstitutions exhibit well-defined miscibility phase transitions and critical phenomena near physiological temperatures. This suggests that lipid/cholesterol mediated phase separation plays a role in the organization of live cell membranes. However, macroscopic lipid-phase separation is not generally observed in cell membranes, and the degree to which properties of isolated lipid mixtures are preserved in the cell membrane remain unknown. A fundamental property of phase transitions is that the variation of tagged particle diffusion with temperature exhibits an abrupt change as the system passes through the transition, even when the two phases are distributed in a nanometer-scale emulsion. We support this using a variety of Monte Carlo and atomistic simulations on model lipid membrane systems. However, temperature-dependent fluorescence correlation spectroscopy of labeled lipids and membrane-anchored proteins in live cell membranes shows a consistently smooth increase in the diffusion coefficient as a function of temperature. We find no evidence of a discrete miscibility phase transition throughout a wide range of temperatures: 14 37 degrees C. This contrasts the behavior of giant plasma membrane vesicles (GPMVs) blebbed from the same cells, which do exhibit phase transitions and macroscopic phase separation. Fluorescence lifetime analysis of a DiI probe in both cases reveals a significant environmental difference between the live cell and the GPMV. Taken together, these data suggest the live cell membrane may avoid the miscibility phase transition inherent to its lipid constituents by actively regulating physical parameters, such as tension, in the membrane. PMID- 25747463 TI - Postharvest Processing and Benefits of Black Pepper, Coriander, Cinnamon, Fenugreek, and Turmeric Spices. AB - Spices are prime source for flavor, aroma, and taste in cuisines and play an active role as medicines due to their high antioxidant properties. As medicine or food, the importance of spices cannot be overemphasized. The medicinal values of spices are very well established in treating various ailments like cancer, fever, malaria, stomach offset, nausea, and many more. A spice may be available in several forms: fresh, whole dried, or pre-ground dried which requires further processing to be utilized in the form of value-added product. This review paper deals with the cultivation, postharvesting, chemical composition, uses, health, and medicinal benefits of the selected spice viz., black pepper, coriander, cinnamon, fenugreek, turmeric, and technological advances in processing of spices viz., super critical fluid extraction, cryogenic grinding, and microencapsulation etc. This paper also focuses on issues related to utilization of spices toward its high end-product development and characterization in pharmaceuticals and other medicinal purposes. The availability of different spices and their varietal differences and location have their pertinent characters, which are much demanding to refine postharvest and processing to assure its quality in the international market. PMID- 25747464 TI - The neurosteroid dehydroepiandrosterone sulfate, but not androsterone, enhances the antidepressant effect of cocaine examined in the forced swim test--Possible role of serotonergic neurotransmission. AB - One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use. PMID- 25747465 TI - Testosterone attenuates and the selective estrogen receptor modulator, raloxifene, potentiates amphetamine-induced locomotion in male rats. AB - Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine in adolescent males. Our previous work suggests that increasing testosterone during adolescence may bias midbrain neurons to synthesise more dopamine. We hypothesised that baseline and amphetamine-induced locomotion would differ in adult males depending on testosterone exposure during adolescence. We hypothesised that concomitant stimulation of estrogen receptor signaling, through a selective estrogen receptor modulator (SERM), raloxifene, can counter testosterone effects on locomotion. Male Sprague-Dawley rats at postnatal day 45 were gonadectomised (G) or sham-operated (S) prior to the typical adolescent testosterone increase. Gonadectomised rats were either given testosterone replacement (T) or blank implants (B) for six weeks and sham-operated (i.e. intact or endogenous testosterone group) were given blank implants. Subgroups of sham-operated, gonadectomised and gonadectomised/testosterone-replaced rats were treated with raloxifene (R, 5mg/kg) or vehicle (V), daily for the final four weeks. There were six groups (SBV, GBV, GTV, SBR, GBR, GTR). Saline and amphetamine-induced (1.25mg/kg) locomotion in the open field was measured at PND85. Gonadectomy increased amphetamine-induced locomotion compared to rats with endogenous or with exogenous testosterone. Raloxifene increased amphetamine induced locomotion in rats with either endogenous or exogenous testosterone. Amphetamine-induced locomotion was negatively correlated with testosterone and this relationship was abolished by raloxifene. Lack of testosterone during adolescence potentiates and testosterone exposure during adolescence attenuates amphetamine-induced locomotion. Treatment with raloxifene appears to potentiate amphetamine-induced locomotion and to have an opposite effect to that of testosterone in male rats. PMID- 25747466 TI - [Use of antipyretics in paediatric emergencies]. PMID- 25747467 TI - Effect of continuous and intermittent bouts of isocaloric cycling and running exercise on excess postexercise oxygen consumption. AB - OBJECTIVES: The purpose of this study was to investigate excess postexercise oxygen consumption (EPOC) induced by isocaloric bouts of continuous and intermittent running and cycling exercise. DESIGN: This was a counterbalanced randomized cross-over study. METHODS: Ten healthy men, aged 23-34yr, performed six bouts of exercise: (a) two maximal cardiopulmonary exercise tests for running and cycling to determine exercise modality-specific peak oxygen uptake (VO2peak); and (b) four isocaloric exercise bouts (two continuous bouts expending 400kcal and two intermittent bouts split into 2*200kcal) performed at 75% of the running and cycling oxygen uptake reserve. Exercise bouts were separated by 72h and performed in a randomized, counter-balanced order. The VO2 was monitored for 60 min postexercise and for 60-min during a control non-exercise day. RESULTS: The VO2 was significantly greater in all exercise conditions compared to the control session (P<0.001). The combined magnitude of the EPOC from the two intermittent bouts was significantly greater than that of the continuous cycling (mean difference=3.5L, P=0.001) and running (mean difference=6.4L, P<0.001). The exercise modality had a significant effect on net EPOC, where running elicited a higher net EPOC than cycling (mean difference=2.2L, P<0.001). CONCLUSIONS: Intermittent exercise increased the EPOC compared to a continuous exercise bout of equivalent energy expenditure. Furthermore, the magnitude of EPOC was influenced by exercise modality, with the greatest EPOC occurring with isocaloric exercise involving larger muscle mass (i.e., treadmill running vs. cycling). PMID- 25747468 TI - Equating accelerometer estimates among youth: The Rosetta Stone 2. AB - OBJECTIVES: Different accelerometer cutpoints used by different researchers often yields vastly different estimates of moderate-to-vigorous intensity physical activity (MVPA). This is recognized as cutpoint non-equivalence (CNE), which reduces the ability to accurately compare youth MVPA across studies. The objective of this research is to develop a cutpoint conversion system that standardizes minutes of MVPA for six different sets of published cutpoints. DESIGN: Secondary data analysis. METHODS: Data from the International Children's Accelerometer Database (ICAD; Spring 2014) consisting of 43,112 Actigraph accelerometer data files from 21 worldwide studies (children 3-18 years, 61.5% female) were used to develop prediction equations for six sets of published cutpoints. Linear and non-linear modeling, using a leave one out cross-validation technique, was employed to develop equations to convert MVPA from one set of cutpoints into another. Bland Altman plots illustrate the agreement between actual MVPA and predicted MVPA values. RESULTS: Across the total sample, mean MVPA ranged from 29.7MVPAmind(-1) (Puyau) to 126.1MVPAmind(-1) (Freedson 3 METs). Across conversion equations, median absolute percent error was 12.6% (range: 1.3 to 30.1) and the proportion of variance explained ranged from 66.7% to 99.8%. Mean difference for the best performing prediction equation (VC from EV) was 0.110mind(-1) (limits of agreement (LOA), -2.623 to 2.402). The mean difference for the worst performing prediction equation (FR3 from PY) was 34.76mind(-1) (LOA, -60.392 to 129.910). CONCLUSIONS: For six different sets of published cutpoints, the use of this equating system can assist individuals attempting to synthesize the growing body of literature on Actigraph, accelerometry-derived MVPA. PMID- 25747469 TI - Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. AB - The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFbeta1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFbeta1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures. PMID- 25747470 TI - Peptide ligation and RNA cleavage via an abiotic template interface. AB - We report herein DNA- and RNA-templated chemical transformation of bifacial peptide nucleic acid (bPNA) fragments directed by an abiotic triplex hybrid interface. Assembly of one bPNA strand with two unstructured oligo T/U strands enables facile insertion of DNA and RNA template sites within partially folded nucleic acids; this template topology is not easily accessed through native base pairing. Triplex hybridization of reactive bPNA fragments on DNA and RNA templates is shown to catalyze amide bond ligation and controlled bPNA chain extension. RNA-templated oxidative coupling of bPNA fragments is found to result in the emergence of ribozyme cleavage function, thus establishing a connection between engineered and native reaction sites. These data demonstrate the use of new topologies in nucleic acid-templated chemistry that could serve as chemically sensitive DNA and RNA switches. PMID- 25747471 TI - Risk factors for invasive Cryptococcus neoformans diseases: a case-control study. AB - BACKGROUND: Cryptococcus neoformans is a ubiquitous environmental fungus that can cause life-threatening meningitis and fungemia, often in the presence of acquired immunodeficiency syndrome (AIDS), liver cirrhosis, diabetes mellitus, or other medical conditions. To distinguish risk factors from comorbidities, we performed a hospital-based, density-sampled, matched case-control study. METHODS: All new onset cryptococcal meningitis cases and cryptococcemia cases at a university hospital in Taiwan from 2002-2010 were retrospectively identified from the computerized inpatient registry and were included in this study. Controls were selected from those hospitalized patients not experiencing cryptococcal meningitis or cryptococcemia. Controls and cases were matched by admission date, age, and gender. Conditional logistic regression was used to analyze the risk factors. RESULTS: A total of 101 patients with cryptococcal meningitis (266 controls) and 47 patients with cryptococcemia (188 controls), of whom 32 patients had both cryptococcal meningitis and cryptococcemia, were included in this study. Multivariate regression analysis showed that AIDS (adjusted odds ratio [aOR] = 181.4; p < 0.001), decompensated liver cirrhosis (aOR = 8.5; p = 0.008), and cell mediated immunity (CMI)-suppressive regimens without calcineurin inhibitors (CAs) (aOR = 15.9; p < 0.001) were independent risk factors for cryptococcal meningitis. Moreover, AIDS (aOR = 216.3, p < 0.001), decompensated liver cirrhosis (aOR = 23.8; p < 0.001), CMI-suppressive regimens without CAs (aOR = 7.3; p = 0.034), and autoimmune diseases (aOR = 9.3; p = 0.038) were independent risk factors for developing cryptococcemia. On the other hand, diabetes mellitus and other medical conditions were not found to be risk factors for cryptococcal meningitis or cryptococcemia. CONCLUSIONS: The findings confirm AIDS, decompensated liver cirrhosis, CMI-suppressive regimens without CAs, and autoimmune diseases are risk factors for invasive C. neoformans diseases. PMID- 25747472 TI - Investigating the role of H2S in 4-HNE scavenging. AB - 4-HNE (4-hydroxy-2-nonenal) is a highly reactive alpha,beta-unsaturated aldehyde generated from oxidation of polyunsaturated fatty acids and has been suggested to play a role in the pathogenesis of several diseases. 4-HNE can bind to amino acids, proteins, polynucleotides, and lipids and exert cytotoxicity. 4-HNE forms adducts (Michael adducts) with cysteine, lysine, as well as histidine on proteins with the thiol function as the most reactive nucleophilic moiety. Thus, detoxification strategies by 4-HNE scavenging compounds might be of interest. Recently, hydrogen sulfide (H2S) has been identified as an endogenous vascular gasotransmitter and neuromodulator. Assuming that the low-molecular thiol H2S may react with 4-HNE, methods to monitor the ability of H2S to counteract the protein modifying and cytotoxic activity of 4-HNE are described in this chapter. PMID- 25747473 TI - Inhalation exposure model of hydrogen sulfide (H2S)-induced hypometabolism in the male Sprague-Dawley rat. AB - Hydrogen sulfide (H2S) has been accepted as a physiologically relevant cell signaling molecule with both toxic and beneficial effects depending on its concentration in mammalian tissues. Notably, exposure to H2S in breathable air has been shown to decrease aerobic metabolism and induce a reversible hypometabolic-like state in laboratory rodent models. Herein, we describe an experimental exposure setup that can be used to define the reversible cardiovascular and metabolic physiology of rodents (rats) during H2S-induced hypometabolism and following recovery. PMID- 25747474 TI - Use of the "tag-switch" method for the detection of protein S-sulfhydration. AB - Protein S-sulfhydration (i.e., converting protein cysteines -SH to persulfides SSH) is a redox-based posttranslational modification. This reaction plays an important role in signaling pathways mediated by hydrogen sulfide or other reactive sulfane sulfur species. Recently, our laboratories developed a "tag switch" method which can be used to selectively label and detect protein S sulfhydrated residues. In this chapter, we provide a comprehensive summary of this method, including the design of the method, preparation of the reagents, validation on small-molecule substrates, as well as applications in protein labeling. Experimental protocols for the use of the method are described in details. PMID- 25747475 TI - Real-time assays for monitoring the influence of sulfide and sulfane sulfur species on protein thiol redox states. AB - Hydrogen sulfide (H2S) is known to induce persulfidation of protein thiols. However, the process of H2S-induced persulfidation is not fully understood as it requires an additional oxidant. There are several mechanistic possibilities and it is of interest to determine which pathway is kinetically most relevant. Here, we detail in vitro assays for the real-time monitoring of thiol redox states in two model proteins with oxidizable cysteines, PTEN, and roGFP2. These allow kinetic measurements of the response of defined protein thiols (or disulfides) to sulfide and sulfane sulfur species. The combination of these assays with cold cyanolysis reveals the role of intermediary sulfane sulfur species in H2S-induced protein thiol oxidation. PMID- 25747476 TI - Protein sulfhydration. AB - Hydrogen sulfide (H2S) is one of the gasotransmitters that modulates various biological processes and participates in multiple signaling pathways. H2S signals by a process termed sulfhydration. Sulfhydration has recently been recognized as a posttranslational modification similar to nitrosylation. Sulfhydration occurs at reactive cysteine residues in proteins and results in the conversion of an -SH group of cysteine to an -SSH or a persulfide group. Sulfhydration is highly prevalent in vivo, and aberrant sulfhydration patterns have been observed under several pathological conditions ranging from heart disease to neurodegenerative diseases such as Parkinson's disease. The biotin switch assay, originally developed to detect nitrosylation, has been modified to detect sulfhydration. In this chapter, we discuss the physiological roles of sulfhydration and the methodologies used to detect this modification. PMID- 25747478 TI - Attenuation of inflammatory responses by hydrogen sulfide (H2S) in ischemia/reperfusion injury. AB - Cellular and tissue injury induced by ischemia is often exacerbated by restoring perfusion to the affected organ system. The injury, termed ischemia-reperfusion injury, is mediated in large part by the inflammatory response generated in the setting of reperfusion. Recent research has demonstrated that the administration of hydrogen sulfide as a therapeutic agent in the setting of ischemia-reperfusion can markedly attenuate the inflammatory response with subsequent mitigation of tissue injury and improved function. This beneficial anti-inflammatory effect has been observed in multiple organ systems, subject to ischemia-reperfusion injury, the details of which are the subject of this chapter. PMID- 25747477 TI - Intravital microscopic methods to evaluate anti-inflammatory effects and signaling mechanisms evoked by hydrogen sulfide. AB - Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule with potent anti-inflammatory properties. Exogenous application of H2S donors, administered either acutely during an inflammatory response or as an antecedent preconditioning intervention that invokes the activation of anti-inflammatory cell survival programs, effectively limits leukocyte rolling, adhesion and emigration, generation of reactive oxygen species, chemokine and cell adhesion molecule expression, endothelial barrier disruption, capillary perfusion deficits, and parenchymal cell dysfunction and injury. This chapter focuses on intravital microscopic methods that can be used to assess the anti-inflammatory effects exerted by H2S, as well as to explore the cellular signaling mechanisms by which this gaseous molecule limits the aforementioned inflammatory responses. Recent advances include use of intravital multiphoton microscopy and optical biosensor technology to explore signaling mechanisms in vivo. PMID- 25747479 TI - CD47-dependent regulation of H2S biosynthesis and signaling in T cells. AB - Pharmacological concentrations of H2S donors inhibit some T cell functions by inhibiting mitochondrial function, but evidence is also emerging that H2S at physiological concentrations produced via chemical sources and endogenously is a positive physiological mediator of T cell function. Expression of the H2S biosynthetic enzymes cystathionine gamma-lyase (CSE) and cystathionine beta synthase (CBS) is induced in response to T cell receptor signaling. Inhibiting the induction of these enzymes limits T cell activation and proliferation, which can be overcome by exposure to exogenous H2S at submicromolar concentrations. Exogenous H2S at physiological concentrations increases the ability of T cells to form an immunological synapse by altering cytoskeletal actin dynamics and increasing the reorientation of the microtubule-organizing center. Downstream, H2S enhances T cell receptor-dependent induction of CD69, CD25, and Interleukin-2 (IL-2) gene expression. The T cell stimulatory activity of H2S is enhanced under hypoxic conditions that limit its oxidative metabolism by mitochondrial and nonenzymatic processes. Studies of the receptor CD47 have revealed the first endogenous inhibitory signaling pathway that regulates H2S signaling in T cells. Binding of the secreted protein thrombospondin-1 to CD47 elicits signals that block the stimulatory activity of exogenous H2S on T cell activation and limit the induction of CSE and CBS gene expression. CD47 signaling thereby inhibits T cell receptor-mediated T cell activation. PMID- 25747480 TI - Anti-inflammatory and cytoprotective properties of hydrogen sulfide. AB - Hydrogen sulfide is an endogenous gaseous mediator that plays important roles in many physiological processes in microbes, plants, and animals. This chapter focuses on the important roles of hydrogen sulfide in protecting tissues against injury, promoting the repair of damage, and downregulating the inflammatory responses. The chapter focuses largely, but not exclusively, on these roles of hydrogen sulfide in the gastrointestinal tract. Hydrogen sulfide is produced throughout the gastrointestinal tract, and it contributes to maintenance of mucosal integrity. Suppression of hydrogen sulfide synthesis renders the tissue more susceptible to injury and it impairs repair. In contrast, administration of hydrogen sulfide donors can increase resistance to injury and accelerate repair. Hydrogen sulfide synthesis is rapidly and dramatically enhanced in the gastrointestinal tract after injury is induced. These increases occur specifically at the site of tissue injury. Hydrogen sulfide also plays an important role in promoting resolution of inflammation, and restoration of normal tissue function. In recent years, these beneficial actions of hydrogen sulfide have provided the basis for development of novel hydrogen sulfide-releasing drugs. Nonsteroidal anti-inflammatory drugs that release small amounts of hydrogen sulfide are among the most advanced of the hydrogen sulfide-based drugs. Unlike the parent drugs, these modified drugs do not cause injury in the gastrointestinal tract, and do not interfere with healing of preexisting damage. Because of the increased safety profile of these drugs, they can be used in circumstances in which the toxicity of the parent drug would normally limit their use, such as in chemoprevention of cancer. PMID- 25747481 TI - H2S and substance P in inflammation. AB - Hydrogen sulfide (H2S) and substance P play a key role in inflammation. Using animal models of inflammation of different etiologies such as acute pancreatitis, sepsis, burns, and joint inflammation, studies have recently shown an important role of the proinflammatory action of H2S and substance P. Also, H2S contributes to inflammation in different conditions via substance P. This chapter reviews methods and key data that have led to our current understanding of the role of H2S and substance P in inflammation. PMID- 25747483 TI - Detection of thiol modifications by hydrogen sulfide. AB - Hydrogen sulfide (H2S) is an important gasotransmitter in both animals and plants. Many physiological events, including responses to stress, have been suggested to involve H2S, at least in part. On the other hand, numerous responses have been reported following treatment with H2S, including changes in the levels of antioxidants and the activities of transcription factors. Therefore, it is important to understand and unravel the events that are taking place downstream of H2S in signaling pathways. H2S is known to interact with other reactive signaling molecules such as reactive oxygen species (ROS) and nitric oxide (NO). One of the mechanisms by which ROS and NO have effects in a cell is the modification of thiol groups on proteins, by oxidation or S-nitrosylation, respectively. Recently, it has been reported that H2S can also modify thiols. Here we report a method for the determination of thiol modifications on proteins following the treatment with biological samples with H2S donors. Here, the nematode Caenorhabditis elegans is used as a model system but this method can be used for samples from other animals or plants. PMID- 25747484 TI - Analysis of some enzymes activities of hydrogen sulfide metabolism in plants. AB - Hydrogen sulfide (H2S) which is considered as a novel gasotransmitter after reactive oxygen species and nitric oxide in plants has dual character, that is, toxicity that inhibits cytochrome oxidase at high concentration and as signal molecule which is involved in plant growth, development, and the acquisition of tolerance to adverse environments such as extreme temperature, drought, salt, and heavy metal stress at low concentration. Therefore, H2S homeostasis is very important in plant cells. The level of H2S in plant cells is regulated by its synthetic and degradative enzymes, L-/D-cysteine desulfhydrase (L-/D-DES), sulfite reductase (SiR), and cyanoalanine synthase (CAS), which are responsible for H2S synthesis, while cysteine synthase (CS) takes charge of the degradation of H2S, but its reverse reaction also can produce H2S. Here, after crude enzyme is extracted from plant tissues, the activities of L-/D-DES, SiR, CAS, and CS are measured by spectrophotometry, the aim is to further understand homeostasis of H2S in plant cells and its potential mechanisms. PMID- 25747482 TI - Role of hydrogen sulfide in brain synaptic remodeling. AB - Synapses are the functional connection between neurons which are necessary for the transfer of electric activity or chemical activity from one cell to another. Synapses are formed by the pre- and postsynaptic membrane which communicates between pre- and postneurons while a neurochemical modulator is operated in this process. H2S has been known as a toxic gas with rotten eggs smell. However, increasing number of researches show that it regulate a variety of physiological and pathological processes in mammals. Hence, H2S is a physiologically important molecule and has been referred to as the third gaseous molecule alongside carbon monoxide and nitric oxide. The previous era has made an exponential development in the physiological and pathological significance of H2S. Specifically, in the central nervous system, H2S facilitates long-term potentiation and regulates intracellular calcium concentration in brain cells. We as well as others have also shown that H2S has antioxidant, antiapoptotic, and anti-inflammatory properties against various neurodegenerative disorders such as stroke, Alzheimer's disease, and vascular dementia. In this chapter, we highlight the current knowledge of H2S and its neuroprotective effects with a special emphasis on synaptic remodeling. PMID- 25747485 TI - Sulfide detoxification in plant mitochondria. AB - In contrast to animals, which release the signal molecule sulfide in small amounts from cysteine and its derivates, phototrophic eukaryotes generate sulfide as an essential intermediate of the sulfur assimilation pathway. Additionally, iron-sulfur cluster turnover and cyanide detoxification might contribute to the release of sulfide in mitochondria. However, sulfide is a potent inhibitor of cytochrome c oxidase in mitochondria. Thus, efficient sulfide detoxification mechanisms are required in mitochondria to ensure adequate energy production and consequently survival of the plant cell. Two enzymes have been recently described to catalyze sulfide detoxification in mitochondria of Arabidopsis thaliana, O acetylserine(thiol)lyase C (OAS-TL C), and the sulfur dioxygenase (SDO) ethylmalonic encephalopathy protein 1 (ETHE1). Biochemical characterization of sulfide producing and consuming enzymes in mitochondria of plants is fundamental to understand the regulatory network that enables mitochondrial sulfide homeostasis under nonstressed and stressed conditions. In this chapter, we provide established protocols to determine the activity of the sulfide releasing enzyme beta-cyanoalanine synthase as well as sulfide-consuming enzymes OAS-TL and SDO. Additionally, we describe a reliable and efficient method to purify OAS-TL proteins from plant material. PMID- 25747486 TI - Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. AB - Molecular hydrogen (H2) was believed to be inert and nonfunctional in mammalian cells. We overturned this concept by demonstrating that H2 reacts with highly reactive oxidants such as hydroxyl radical ((*)OH) and peroxynitrite (ONOO(-)) inside cells. H2 has several advantages exhibiting marked effects for medical applications: it is mild enough neither to disturb metabolic redox reactions nor to affect signaling by reactive oxygen species. Therefore, it should have no or little adverse effects. H2 can be monitored with an H2-specific electrode or by gas chromatography. H2 rapidly diffuses into tissues and cells to exhibit efficient effects. Thus, we proposed the potential of H2 for preventive and therapeutic applications. There are several methods to ingest or consume H2: inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline onto the eyes. Recent publications revealed that, in addition to the direct neutralization of highly reactive oxidants, H2 indirectly reduces oxidative stress by regulating the expression of various genes. Moreover, by regulating gene expression, H2 functions as an anti-inflammatory, antiallergic, and antiapoptotic molecule, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under way. Since most drugs specifically act on their specific targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has potential for clinical applications for many diseases. PMID- 25747487 TI - Methods in Enzymology. Hydrogen sulfide in redox biology, part B. Preface. PMID- 25747488 TI - Occurrence of antibodies against Toxoplasma gondii and its isolation and genotyping in donkeys, mules, and horses in Brazil. AB - The occurrence of antibodies against Toxoplasma gondii was determined in donkeys, mules, and horses from different regions of Brazil. Serum samples from 304 donkeys (67.11%), 118 horses (26.05%), and 31 mules (6.84%) were analyzed by means of the indirect fluorescent antibody test (cutoff=64). Antibodies against T. gondii were detected in 129 equids (28.47%) (82 donkeys, 32 horses, and 15 mules). Tissue samples from 19 seropositive and 50 seronegative animals were obtained in order to isolate the parasite by means of mouse bioassay, and T. gondii was isolated from a donkey. Through genotypic characterization of the isolate, by means of polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) using 11 genotypic markers, the genotype #163 (TgCkBr220), which has already been described in chickens in Brazil, was identified. PMID- 25747489 TI - Fine-scale temperature fluctuation and modulation of Dirofilaria immitis larval development in Aedes aegypti. AB - We evaluated degree-day predictions of Dirofilaria immitis development (HDU) under constant and fluctuating temperature treatments of equal average daily temperature. Aedes aegypti mosquitoes were infected with D. immitis microfilariae and parasite development was recorded at set time points in dissected mosquitoes. Time to L3 development in Malpighian tubules and detection in mosquito heads was shorter for larvae experiencing a daily regime of 19+/-9 degrees C than larvae at constant 19 degrees C; larval development rate in Malpighian tubules was slower in fluctuating regimes maintained above the 14 degrees C developmental threshold than larvae under constant temperatures. We showed that hourly temperature modeling more accurately predicted D. immitis development to infective L3 stage. Development time differed between fluctuating and constant temperature treatments spanning the 14 degrees C development threshold, implicating a physiological basis for these discrepancies. We conclude that average daily temperature models underestimate L3 development-and consequently dog heartworm transmission risk-at colder temperatures, and spatiotemporal models of D. immitis transmission risk should use hourly temperature data when analyzing high daily temperature ranges spanning 14 degrees C. PMID- 25747490 TI - Clinical and lifestyle-related risk factors for incident multimorbidity: 10-year follow-up of Finnish population-based cohorts 1982-2012. AB - BACKGROUND: Multimorbidity is a huge burden to individuals and societies and more attention should be paid on its risk factors and prevention possibilities. The aim of this study was to investigate which clinical and lifestyle characteristics predict the development of multimorbidity both among initially disease-free people and among people who have diabetes or CVD. METHODS: Data comprised 25-64 year old, randomly selected men and women (n=32,972) who participated in one of the five national FINRISK surveys between 1982 and 2002 in Finland. The surveys included anthropometric measurements, blood samples and structured questionnaire. Data on incident diagnoses of the five most common chronic diseases during 10 years were received from the national registers on mortality, hospitalizations, and reimbursement rights. RESULTS: Predisposing factors for multimorbidity among disease-free population were smoking, physical inactivity, and BMI. Among men also systolic blood pressure and low education predicted multimorbidity. Among men with DM at baseline, high blood pressure, physical inactivity, and smoking increased the likelihood of incident multimorbidity. Among women, significant predictors of multimorbidity were high BMI and smoking. Among men and women with CVD, the only baseline factor that was significantly associated with the development of multimorbidity in the multivariate prediction model was low fruit and vegetable consumption. CONCLUSION: Several modifiable clinical and lifestyle risk factors were found to predict incident multimorbidity. Better recognition and management of these risk factors could potentially have a large impact on the development of multimorbidity, and consequently, premature mortality and costs of care among the aging populations. PMID- 25747491 TI - UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions. AB - Photochemotherapy, the combination of a photosensitiser and ultraviolet (UV) or visible light, is an effective treatment for skin conditions including cancer. The high mutagenicity and non-selectivity of photochemotherapy regimes warrants the development of alternative approaches. We demonstrate that the thiopyrimidine nucleosides 5-bromo-4-thiodeoxyuridine (SBrdU) and 5-iodo-4-thiodeoxyuridine (SIdU) are incorporated into the DNA of cultured human and mouse cells where they synergistically sensitise killing by low doses of UVA radiation. The DNA halothiopyrimidine/UVA combinations induce DNA interstrand crosslinks, DNA protein crosslinks, DNA strand breaks, nucleobase damage and lesions that resemble UV-induced pyrimidine(6-4)pyrimidone photoproducts. These are potentially lethal DNA lesions and cells defective in their repair are hypersensitive to killing by SBrdU/UVA and SIdU/UVA. DNA SIdU and SBrdU generate lethal DNA photodamage by partially distinct mechanisms that reflect the different photolabilities of their C-I and C-Br bonds. Although singlet oxygen is involved in photolesion formation, DNA SBrdU and SIdU photoactivation does not detectably increase DNA 8-oxoguanine levels. The absence of significant collateral damage to normal guanine suggests that UVA activation of DNA SIdU or SBrdU might offer a strategy to target hyperproliferative skin conditions that avoids the extensive formation of a known mutagenic DNA lesion. PMID- 25747492 TI - Predicting the aggregation propensity of prion sequences. AB - The presence of prions can result in debilitating and neurodegenerative diseases in mammals and protein-based genetic elements in fungi. Prions are defined as a subclass of amyloids in which the self-aggregation process becomes self perpetuating and infectious. Like all amyloids, prions polymerize into fibres with a common core formed of beta-sheet structures oriented perpendicular to the fibril axes which form a structure known as a cross-beta structure. The intermolecular beta-sheet propensity, a characteristic of the amyloid pattern, as well as other key parameters of amyloid fibril formation can be predicted. Mathematical algorithms have been proposed to predict both amyloid and prion propensities. However, it has been shown that the presence of amyloid-prone regions in a polypeptide sequence could be insufficient for amyloid formation. It has also often been stated that the formation of amyloid fibrils does not imply that these are prions. Despite these limitations, in silico prediction of amyloid and prion propensities should help detect potential new prion sequences in mammals. In addition, the determination of amyloid-prone regions in prion sequences could be very useful in understanding the effect of sporadic mutations and polymorphisms as well as in the search for therapeutic targets. PMID- 25747493 TI - Effects of (-)-sesamin on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and dopaminergic neuronal cells of Parkinson's disease rat models. AB - The present study investigated the effects of (-)-sesamin on 6-hydroxydopamine (6 OHDA)-induced neurotoxicity using PC12 cells and dopaminergic neuronal cells of 6 OHDA-lesioned rat model of Parkinson's disease (PD). In PC12 cells, treatment with (-)-sesamin (25 uM) reduced 6-OHDA (100 uM)-induced cell death and induced transient extracellular signal-regulated kinase (ERK1/2) phosphorylation and Bad phosphorylation at Ser112 (BadSer112). In contrast, sustained ERK1/2 phosphorylation, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N terminal kinase (JNK1/2) phosphorylation, and cleaved-caspase-3 activity, all of which were induced by 6-OHDA (100 uM), were inhibited by treatment with (-) sesamin (25 uM). Furthermore, co-treatment with (-)-sesamin (30 mg/kg, p.o.) once a day for 28 days significantly increased the number of tyrosine hydroxylase immunopositive neuronal cells and the levels of dopamine, norepinephrine, 3,4 dihydroxyphenylacetic acid, and homovanillic acid in the substantia nigra striatum of 6-OHDA-lesioned rat model of PD with or without L-DOPA treatment. These results suggest that (-)-sesamin protects 6-OHDA-induced cytotoxicity via the activation of transient ERK1/2-BadSer112 system and the inhibition of sustained ERK-p38MAPK-JNK1/2-caspase-3 system in PC12 cells. (-)-Sesamin also shows protective effects on long-term L-DOPA therapy in dopaminergic neuronal cells of PD rat models. (-)-Sesamin may serve as adjuvant therapeutics in PD. PMID- 25747494 TI - Examination of placental three-dimensional power Doppler indices and perinatal outcome in pregnancies complicated by intrauterine growth restriction. AB - OBJECTIVE: To examine placental vascularization using three-dimensional power Doppler (3DPD) ultrasonography in pregnancies complicated by intrauterine growth restriction (IUGR). METHODS: The present prospective study was conducted at the University of Szeged (Szeged, Hungary) from February 2012 to March 2013. Women with a singleton pregnancy who attended the maternity outpatient ward in the second or third trimester were enrolled consecutively. Women were divided into two groups: those with a normal pregnancy and those with a pregnancy complicated by IUGR. Three 3DPD indices-vascularization index (VI), flow index (FI), and vascularization flow index (VFI)-were assessed. RESULTS: A total of 223 women were enrolled: 171 were in the control group and 52 in the IUGR group. Median VI was 3.7% (interquartile range [IQR] 3.2%-4.2%) in the IUGR group and 10.1% (IQR 8.6%-10.9%) in the control group (P=0.001). Median FI was 40.0 (IQR 39.7-42.5) in the IUGR group and 45.1 (IQR 44.1-53.1) in the control group (P=0.012). Median VFI was 2.2 (IQR 2.1-2.4) in the IUGR group and 4.8 (IQR 4.4-5.3) in the control group (P<0.001). CONCLUSION: Placental vascularization was reduced in pregnancies complicated by IUGR. PMID- 25747495 TI - Clerodane type diterpene as a novel antifungal agent from Polyalthia longifolia var. pendula. AB - Bioactivity-guided chemical examination of methanolic extract of leaves of Polyalthia longifolia var. pendula led to the isolation of the active constituent, a diterpene 1 which was identified as 16alpha-hydroxycleroda 3,13(14)Z-dien-15,16-olide on the basis of its spectral data. Among the tested strains, diterpene 1 was found to exhibit antifungal activities having MIC90 values of 50.3, 100.6 and 201.2 MUM against Candida albicans NCIM3557, Cryptococcus neoformans NCIM3542 (human pathogens) and Neurospora crassa NCIM870 (saprophyte), respectively. Initial, structure-activity-relationship (SAR) data generated by synthesizing some derivatives revealed that the double bond between C3-C4 and the free hydroxyl group at C16 are crucial for the antifungal activity of the diterpene 1. The mode of action of 1 in C. albicans is due to compromised cell membrane permeability and also probably due to disruption of cell wall structures. The red blood cell haemolysis of all the compounds (1-4) did not show any significant haemolysis and was found to be less than 15% for all the compounds when tested at highest concentration, i.e. 1200 MUM. Interestingly, all the tested compounds inhibited Y-H transition in dimorphic C. albicans NCIM3557 at much lower concentration than their MIC90 values. Determination of ROS generation by diterpene 1 using DCFH-DA and DHR123 (dihydrorhodamine) staining of C. albicans NCIM3557 indicated production of intracellular ROS as a mechanism of antifungal activity. PMID- 25747496 TI - Hexadentate 3-hydroxypyridin-4-ones with high iron(III) affinity: design, synthesis and inhibition on methicillin resistant Staphylococcus aureus and Pseudomonas strains. AB - A range of hexadentate 3-hydroxypyridin-4-ones have been synthesized. These compounds were found to possess a high affinity for iron(III), with logK1 values of about 34 and pFe values over 30. Antimicrobial assays indicated that they can inhibit the growth of three clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) and three clinical isolates of Pseudomonas, suggesting that hexadentate 3-hydroxypyridin-4-ones have potential application in the treatment of wound infections. PMID- 25747497 TI - Synthesis, characterization, and antileishmanial activities of gold(I) complexes involving quinoline functionalized N-heterocyclic carbenes. AB - A series of new mononuclear cationic or neutral gold(I) complexes containing quinoline functionalized N-heterocyclic carbene(s) (NHC(s)) were synthesized and fully characterized by spectroscopic methods. The X-ray structures of two key compounds are presented. Proligands and their corresponding gold(I) complexes together with previously described silver(I) and gold(I) bis(NHC-quinoline) and gold(I) bis(NHC-methylbipyridine) complexes were evaluated in vitro towards Leishmania infantum. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine macrophages J774A.1. All gold(I) compounds show potent antileishmanial activity against L. infantum promastigotes and three of them are also efficient against L. infantum intracellular amastigotes. Structure-activity and toxicity relationships enables to evidence a lead-compound (6) displaying both a high activity and a good selectivity index. PMID- 25747498 TI - 3D-QSAR, design, synthesis and characterization of trisubstituted harmine derivatives with in vitro antiproliferative properties. AB - Apolar trisubstituted derivatives of harmine show high antiproliferative activity on diverse cancer cell lines. However, these molecules present a poor solubility making these compounds poorly bioavailable. Here, new compounds were synthesized in order to improve solubility while retaining antiproliferative activity. First, polar substituents have shown a higher solubility but a loss of antiproliferative activity. Second, a Comparative Molecular Field Analysis (CoMFA) model was developed, guiding the design and synthesis of eight new compounds. Characterization has underlined the in vitro antiproliferative character of these compounds on five cancerous cell lines, combining with a high solubility at physiological pH, making these molecules druggable. Moreover, targeting glioma treatment, human intestinal absorption and blood brain penetration have been calculated, showing high absorption and penetration properties. PMID- 25747499 TI - Synthesis of isocryptolepine analogues and their structure-activity relationship studies as antiplasmodial and antiproliferative agents. AB - Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2 Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2 chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities. PMID- 25747500 TI - Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages. AB - This study aimed to evaluate changes in natural killer (NK) cell activity and the percentage of monocytes in women with recurrent miscarriage who received medium dose intravenous immunoglobulin (IVIg) therapy. Fourteen women with a history of six or more recurrent miscarriages of unexplained etiology received 60-g IVIg therapy (20 g daily, for three days) during early gestation. NK cell activity in the peripheral blood decreased to 12% one week after therapy compared with before therapy (median, 22%, P < 0.001) and the percentage of monocytes increased from 5.2% to 7.5% (P < 0.005). Four pregnancies ended in live births of healthy neonates, whereas the other ten pregnancies ended in miscarriages. Excluding one miscarriage with a chromosomal abnormality, the live birth rate was 30.8% (4/13). The rate of reduction of NK cell activity in the success group (-58.8%) tended to be greater than that in the failure group (-14.8%, P = 0.057). PMID- 25747501 TI - Inventory of antibiotic stewardship programs in general practice in France and abroad. AB - OBJECTIVES: The authors conducted a survey of measures implemented in France and abroad for a better use of antibiotics in general practice. METHODS: A literature review was conducted from January 2000 to July 2014. Emails were sent to every infectious diseases department, to all regional health authorities (ARS), to the health insurance offices (CPAM) with the highest and lowest antibiotic use, and to the ministry of health to make an inventory of all antibiotic stewardship programs. The ministry of health, the board of general practitioners, infectious diseases specialists, pharmacists, and the medical and pharmacy schools of the nation's capital were contacted in 17 countries of Europe and North America. RESULTS: The main measures implemented in France were training of healthcare professionals, publishing guidelines, feedback to the practitioners on their prescriptions, and availability of rapid diagnostic tests. Telephone networks were created in some regions, such as Antibiolor or Medqual, to help physicians with antibiotic prescription. Many foreign countries issued pedagogical material to physicians, for patients to explain what to do in case of viral infection or delayed prescription. In Alberta (Canada), the government introduced an optional authorization for quinolones. In Denmark, the government temporarily suspended the reimbursement of some agents to preserve them according to bacterial ecology. In the United-Kingdom, the antibiotic susceptibility test report must include less than 5 agents. CONCLUSIONS: The measures implemented in France and abroad were usually more persuasive than restrictive. But the bacterial resistance crisis should lead to implementing more restrictive measures. PMID- 25747502 TI - The effects of prenatal undernutrition and postnatal high-fat diet on hypothalamic Kiss1 mRNA and serum leptin levels. AB - Prenatal undernutrition and postnatal overnutrition increase the risk of some metabolic disorders in adulthood, and hypothalamic leptin resistance makes an important contribution to these effects. Leptin plays important roles in the maintenance of reproductive function, and its actions might be partially mediated by kisspeptin, which is a potent positive regulator of gonadotropin-releasing hormone. In this study, the effects of prenatal undernutrition and postnatal overnutrition on reproductive parameters and sexual maturation during the peripubertal period were evaluated. Rats subjected to prenatal undernutrition (IUGR) and fed a postnatal high-fat diet (HFD) (n = 7) exhibited 40% higher serum leptin levels and 30% lower hypothalamic Kiss1 (the gene encoding kisspeptin) mRNA levels than those subjected to prenatal undernutrition (IUGR) and fed a normal diet (n = 7). No such HFD-induced postnatal alterations were observed in the rats fed a normal diet during the prenatal period (control) (n = 7 per group). Although the consumption of the HFD did not affect the serum luteinizing hormone levels or body weight of the IUGR or control rats, it did promote vaginal opening in both groups (evaluated in 14 rats per group). These findings indicate that hypothalamic leptin resistance might occur in IUGR-HFD rats, but these changes do not influence downstream effectors of the reproductive endocrinological system. They also suggest that the relationships between nutritional conditions, body weight, reproductive factors, and sexual maturation are complex. PMID- 25747503 TI - A comparison of fruits, vegetables, sugar-sweetened beverages, and desserts in the packed lunches of elementary school children. AB - BACKGROUND: An estimated 40% of children bring a packed lunch to school. These lunches are not required to meet nutrition standards. The aim of this study was to compare differences in the nutritional quality of elementary packed lunches by the presence or absence of sugar-sweetened beverages (SSB), desserts, and fruits and vegetables (FVs). METHODS: Observational data for prekindergarten and kindergarten packed lunches were collected from three schools in rural Virginia for 5 consecutive school days and analyzed for macro- and micronutrients and by the presence or absence of food and beverage items. RESULTS: Of the 561 packed lunch observations collected, 41.7% contained no FV, 41.2% contained an SSB, and 61.1% contained a dessert. The nutrient profile of packed lunches with at least one fruit or vegetable had significantly higher levels of carbohydrate, fiber, sugar, vitamin A, and vitamin C. Packed lunches containing an SSB had significantly higher levels of sugar and vitamin C and significantly lower levels of protein, fiber, vitamin A, calcium, and iron. Packed lunches containing a dessert had significantly higher levels of energy, carbohydrate, fat, saturated fat, sodium, sugar, vitamin C, and iron and significantly lower levels of vitamin A. CONCLUSIONS: Additional research is needed to fully understand parent and child motivations for packing lunches and the decision processes that influence the inclusion of food items. The development of packed lunch interventions, encouragement of National School Lunch Program participation, or enactment of school policies to increase the nutritional value of packed lunches is warranted. PMID- 25747504 TI - Validation of an apicoplast genome target for the detection of Plasmodium species using polymerase chain reaction and loop mediated isothermal amplification. AB - The genome of the Plasmodium apicoplast, which has a higher copy number compared with current targets for molecular diagnosis of malaria, appears to be a suitable target for detection of submicroscopic infections that are capable of sustaining transmission. Novel primers targeting a conserved segment of the apicoplast (PFC10_AP|0010:rRNA) were designed and used in a number of different high throughput platforms such as single-step PCR (ssPCR), nested PCR (nPCR) and loop mediated isothermal amplification (LAMP) for parasite detection. Replicates of ten-fold serial dilutions of Plasmodium falciparum 3D7 DNA, with equivalent parasite density ranges of 200,000 to 0.2 parasites/MUL, were used to determine the limit of detection and repeatability of each assay. A panel of 184 archived DNA samples extracted from either EDTA whole blood or dried blood spots, from across West Africa and South East Asia was used to determine the diagnostic performance of the assays. All assays amplified the 2 parasites/MUL dilution except the ssPCR, which amplified two of the three replicates. Using an 18S rRNA PCR as reference, the sensitivity was 98% (95% CI 93-100%) for the LAMP assay, 87% (95% CI 79-93%) for ssPCR and 100% (95% CI 97-100%) for nPCR. Specificity was 91% (95% CI 83-96%) for LAMP, 82% (95% CI 72-90%) for ssPCR and 66% (95% CI 54 76%) for nPCR. The apicoplast genome-based nPCR detected more positive samples overall than the reference method. Discrepant samples were confirmed as true positives using a probe-based real-time quantitative PCR assay. The results show that the apicoplast genome is a suitable target for molecular diagnosis of malaria. PMID- 25747505 TI - UV-assisted photocatalytic synthesis of highly dispersed Ag nanoparticles supported on DNA decorated graphene for quantitative iodide analysis. AB - Herein, we report, for the first time, the synthesis of reduced graphene oxide DNA-Ag (RGO-DNA-Ag) nanohybrids by ultraviolet (UV) irradiation of aqueous solutions of GO and Ag ions in the presence of DNA. The morphology and microstructure characterizations of the resultant nanohybrids reveal that the proposed method leads to the simultaneous reduction of GO and Ag ions together with efficient dispersion of Ag nanoparticles on the surface of RGO sheets. This simple and fast synthesis route is carried out at ambient conditions without using any additional chemical reducing agents, which has the potential to provide new avenues for the green fabrication of various RGO-based nanomaterials. Additionally, the RGO-DNA-Ag nanohybrids can be utilized as a novel sensing interfacial for direct determination of iodide by simple differential pulse voltammetry (DPV), without requiring any preceding preconcentration of the analyte. Based on the RGO-DNA-Ag nanohybrids modified electrode, a wide linear range of 1MUM-1mM and a low detection limit of 0.2MUM were obtained. This sensitive and direct method of analysis can be applied successfully to the determination of iodide in real samples. PMID- 25747506 TI - Multiplex diagnosis of viral infectious diseases (AIDS, hepatitis C, and hepatitis A) based on point of care lateral flow assay using engineered proteinticles. AB - Lateral flow assay (LFA) is an attractive method for rapid, simple, and cost effective point of care diagnosis. For LFA-based multiplex diagnosis of three viral intractable diseases (acquired immune deficiency syndrome and hepatitis C and A), here we developed proteinticle-based 7 different 3D probes that display different viral antigens on their surface, which were synthesized in Escherichia coli by self-assembly of human ferritin heavy chain that was already engineered by genetically linking viral antigens to its C-terminus. Each of the three test lines on LFA strip contains the proteinticle probes to detect disease-specific anti-viral antibodies. Compared to peptide probes, the proteinticle probes were evidently more sensitive, and the proteinticle probe-based LFA successfully diagnosed all the 20 patient sera per each disease without a false negative signal, whereas the diagnostic sensitivities in the peptide probe-based LFAs were 65-90%. Duplex and triplex assays performed with randomly mixed patient sera gave only true positive signals for all the 20 serum mixtures without any false positive signals, indicating 100% sensitivity and 100% specificity. It seems that on the proteinticle surface the antigenic peptides have homogeneous orientation and conformation without inter-peptide clustering and hence lead to the enhanced diagnostic performance with solving the problems of traditional diagnostic probes. Although the multiplex diagnosis of three viral diseases above was demonstrated as proof-of-concept here, the proposed LFA system can be applied to multiplex point of care diagnosis of other intractable diseases. PMID- 25747507 TI - A water-soluble carboxylic-functionalized chemosensor for detecting Al(3+) in aqueous media and living cells: Experimental and theoretical studies. AB - A new water-soluble carboxylic-functionalized chemosensor 1 was designed and synthesized. 1 exhibited the selective fluorescence enhancement toward aluminum ions with a 1:1 complexation stoichiometry in aqueous solution. The detection limit (24nM) of 1 for Al(3+) is about two order lower than the WHO guideline (7.41MUM) for the drinking water. 1 was successfully applied to living cells and real samples for detecting Al(3+). Moreover, the sensing mechanism originated from the inhibited excited-state intramolecular proton transfer (ESIPT) process and the chelation-enhanced fluorescence (CHEF) effect, as supported by theoretical calculations. PMID- 25747508 TI - Amplified electrochemical sensing of lead ion based on DNA-mediated self-assembly catalyzed polymerization. AB - Lead ion (Pb(2+), a heavy metal ion existed every aspect of life) is one of the most important hazards for environment and human health. Herein we design an in situ amplified electronic monitoring system for sensitive determination of Pb(2+) on Pb(2+)-specific DNAzyme-modified sensing interface. The assay consists of target-triggered cleavage of Pb(2+)-specific DNAzyme, initiator strand-induced DNA hybridization chain reaction, formation of hemin/G-quadruplex -based DNAzyme and its automatically catalyzed polymerization of aniline monomer along the double-stranded DNA. Experimental results indicated that the catalytic currents of the as-produced polyaniline were linearly dependent on target Pb(2+) concentrations from 0.05 to 50nM with a detection limit (LOD) of 32pM. Such a synergistic effect of hybridization chain reaction with DNAzyme-catalyzed polymerization provided a universal platform for sensitive screening of target Pb(2+), thereby holding great promise for application in practice. PMID- 25747509 TI - An electrochemiluminescence biosensor for 8-oxo-7,8-dihydro-2'-deoxyguanosine quantification and DNA repair enzyme activity analysis using a novel bifunctional probe. AB - A new electrochemiluminescence (ECL) sensor was developed for 8-oxo-7,8-dihydro 2'-deoxyguanosine (8-oxodGuo) quantification and Escherichia coli formamidopyrimidine-DNA glycosylase (FPG) activity assay. The sensor employed a novel spermine conjugated ruthenium tris-(bipyridine) derivative (spermine-Ru) which binds specifically with 8-oxodGuo through a one-step reaction and also acts as an ECL signal reporter. In the sensor, an 8-oxodGuo-containing ds-DNA film was first immobilized on a gold electrode by self-assembly. The DNA film was then incubated with spermine-Ru under oxidative condition for 8-oxodGuo labeling. The ECL intensity was found to correlate with the amount of 8-oxodGuo on the surface and the detection limit was estimated to be about 1 lesion in 500 DNA bases. Addition of FPG resulted in some loss of the signal due to the excision of 8 oxodGuo by the enzyme. An inverse relationship between ECL intensity and FPG concentration was observed in a range from 0 to 4.0U/uL, demonstrating that this sensor could be used for FPG activity assay. A number of metal ions were screened by the sensor for their inhibition effect on FPG activity. Among them, Hg(2+) and methyl Hg(II) shown very potent inhibition, with IC50 values of 4.04uM and 4.34nM respectively. The result may suggest that interference on the DNA repair system could be another mechanism for the high toxicity of MeHg. PMID- 25747510 TI - Target-regulated proximity hybridization with three-way DNA junction for in situ enhanced electronic detection of marine biotoxin based on isothermal cycling signal amplification strategy. AB - A new signal amplification strategy based on target-regulated DNA proximity hybridization (TRPH) reaction accompanying formation of three-way DNA junction was designed for electronic detection of Microcystin-LR (MC-LR used in this case), coupling with junction-induced isothermal cycling signal amplification. Initially, a sandwiched-type immunoreaction was carried out in a low-cost PCR tube between anti-MC-LR mAb1 antibody-labeled DNA1 (mAb1-DNA1) and anti-MC-LR mAb2-labeled DNA2 (mAb2-DNA2) in the presence of target to form a three-way DNA junction. Then, the junction could undergo an unbiased strand displacement reaction on an h-like DNA nanostructure-modified electrode (labeled with methylene blue redox tag on the short DNA strand), thereby resulting in the dissociation of methylene blue-labeled signal DNA from the electrode. The newly formed double-stranded DNA could be cleaved again by exonuclease III, and the released three-way DNA junction retriggered the strand-displacement reaction with h-like DNA nanostructures for junction recycling. During the strand-displacement reaction, numerous methylene blue-labeled DNA strands were far away from the electrode, thus decreasing the detectable electrochemical signal within the applied potentials. Under optimal conditions, the TRPH-based immunosensing system exhibited good electrochemical responses for detecting target MC-LR at a concentration as low as 1.0ngkg(-1) (1.0ppt). Additionally, the precision, reproducibility, specificity and method accuracy were also investigated with acceptable results. PMID- 25747511 TI - How profitable is a voluntary deductible in health insurance for the consumer? AB - To counteract moral hazard in health insurance, insured can be offered a voluntary deductible (VD) in return for a premium rebate. In the Dutch mandatory basic health insurance however, only 11 per cent of the insured opted for a VD in 2014. Several determinants could affect the decision to opt for a VD. This paper examines one of these determinants: the financial profitability. A VD is profitable for the consumer if the out-of-pocket expenses do not exceed the offered premium rebate. The empirical analyses, based upon individual-level data on costs and characteristics of over 800,000 Dutch insured, show that a VD of ?500 on top of the mandatory deductible of ?360 would have been financially profitable for 48 per cent of the Dutch insured given the average premium rebate of ? 240 in 2014. If the whole population had a VD, most insured would obtain either the maximum loss (44 per cent) or the maximum gain (41 per cent). A VD is profitable for males, young insured, healthy insured and insured with few healthcare expenses in the past. To further reduce moral hazard, the following strategies can be used to increase the number of insured opting for a VD: provide insured with information regarding the VD and introduce a shifted deductible. PMID- 25747512 TI - Screening for cervical cancer: What are the determinants among adults with disabilities living in institutions? Findings from a National Survey in France. AB - OBJECTIVES: To explore the rate and determinants of the likelihood of cervical cancer screening participation among disabled women living in institutions in France. METHODS: The data source was the French national Health and Disability Survey-Institutions Section, 2009. Disability severity was assessed by scoring mobility and cognitive limitations. Chi-square tests revealed the significant factors associated with the screening rates; these factors were used in a multivariate logistic regression of Pap-test use within the 3 years prior to the interview (n=1052, women aged 20-65 years living in institutions for disabled adults). RESULTS: The cervical cancer screening rate was particularly low in this population. After adjusting for all other covariates, women with more severe degrees of mobility or cognitive limitations had a lower likelihood of receiving a Pap test. Our findings also showed that being socially isolated, illiterate or underweight significantly decreased screening participation. CONCLUSION: Even in institutions, disability severity remains a barrier to cancer screening. Given the increasing prevalence of disabling conditions and cancers, and the lack of previous studies on this specific topic, our findings are highly important from a policy point of view. These findings should alert health authorities to increase their efforts to provide medical care for institutionalized people with disabilities. PMID- 25747513 TI - Bacterial diversity associated with wild caught Anopheles mosquitoes from Dak Nong Province, Vietnam using culture and DNA fingerprint. AB - BACKGROUND: Microbiota of Anopheles midgut can modulate vector immunity and block Plasmodium development. Investigation on the bacterial biodiversity in Anopheles, and specifically on the identification of bacteria that might be used in malaria transmission blocking approaches, has been mainly conducted on malaria vectors of Africa. Vietnam is an endemic country for both malaria and Bancroftian filariasis whose parasitic agents can be transmitted by the same Anopheles species. No information on the microbiota of Anopheles mosquitoes in Vietnam was available previous to this study. METHOD: The culture dependent approach, using different mediums, and culture independent (16S rRNA PCR - TTGE) method were used to investigate the bacterial biodiversity in the abdomen of 5 Anopheles species collected from Dak Nong Province, central-south Vietnam. Molecular methods, sequencing and phylogenetic analysis were used to characterize the microbiota. RESULTS AND DISCUSSION: The microbiota in wild-caught Anopheles was diverse with the presence of 47 bacterial OTUs belonging to 30 genera, including bacterial genera impacting Plasmodium development. The bacteria were affiliated with 4 phyla, Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria, the latter being the dominant phylum. Four bacterial genera are newly described in Anopheles mosquitoes including Coxiella, Yersinia, Xanthomonas, and Knoellia. The bacterial diversity per specimen was low ranging from 1 to 4. The results show the importance of pairing culture and fingerprint methods to better screen the bacterial community in Anopheles mosquitoes. CONCLUSION: Sampled Anopheles species from central-south Vietnam contained a diverse bacterial microbiota that needs to be investigated further in order to develop new malaria control approaches. The combination of both culture and DNA fingerprint methods allowed a thorough and complementary screening of the bacterial community in Anopheles mosquitoes. PMID- 25747514 TI - Exploiting the oxygen inhibitory effect on UV curing in microfabrication: a modified lithography technique. AB - Rapid prototyping (RP) of microfluidic channels in liquid photopolymers using standard lithography (SL) involves multiple deposition steps and curing by ultraviolet (UV) light for the construction of a microstructure layer. In this work, the conflicting effect of oxygen diffusion and UV curing of liquid polyurethane methacrylate (PUMA) is investigated in microfabrication and utilized to reduce the deposition steps and to obtain a monolithic product. The conventional fabrication process is altered to control for the best use of the oxygen presence in polymerization. A novel and modified lithography technique is introduced in which a single step of PUMA coating and two steps of UV exposure are used to create a microchannel. The first exposure is maskless and incorporates oxygen diffusion into PUMA for inhibition of the polymerization of a thin layer from the top surface while the UV rays penetrate the photopolymer. The second exposure is for transferring the patterns of the microfluidic channels from the contact photomask onto the uncured material. The UV curing of PUMA as the main substrate in the presence of oxygen is characterized analytically and experimentally. A few typical elastomeric microstructures are manufactured. It is demonstrated that the obtained heights of the fabricated structures in PUMA are associated with the oxygen concentration and the UV dose. The proposed technique is promising for the RP of molds and microfluidic channels in terms of shorter processing time, fewer fabrication steps and creation of microstructure layers with higher integrity. PMID- 25747516 TI - Well-woman visits: guidance and monitoring are key in this turning point for women's health. PMID- 25747515 TI - Synergic chemoprevention with dietary carbohydrate restriction and supplementation of AMPK-activating phytochemicals: the role of SIRT1. AB - Calorie restriction or a low-carbohydrate diet (LCD) can increase life span in normal cells while inhibiting carcinogenesis. Various phytochemicals also have calorie restriction-mimetic anticancer properties. We investigated whether an isocaloric carbohydrate-restriction diet and AMP-activated protein kinase (AMPK) activating phytochemicals induce synergic tumor suppression. We used a mixture of AMPK-activating phytochemical extracts including curcumin, quercetin, catechins, and resveratrol. Survival analysis was carried out in a B16F10 melanoma model fed a control diet (62.14% kcal carbohydrate, 24.65% kcal protein and 13.2% kcal fat), a control diet with multiple phytochemicals (MP), LCD (16.5, 55.2, and 28.3% kcal, respectively), LCD with multiple phytochemicals (LCDmp), a moderate carbohydrate diet (MCD, 31.9, 62.4, and 5.7% kcal, respectively), or MCD with phytochemicals (MCDmp). Compared with the control group, MP, LCD, or MCD intervention did not produce survival benefit, but LCDmp (22.80+/-1.58 vs. 28.00+/-1.64 days, P=0.040) and MCDmp (23.80+/-1.08 vs. 30.13+/-2.29 days, P=0.008) increased the median survival time significantly. Suppression of the IGF 1R/PI3K/Akt/mTOR signaling, activation of the AMPK/SIRT1/LKB1pathway, and NF kappaB suppression were the critical tumor-suppression mechanisms. In addition, SIRT1 suppressed proliferation of the B16F10 and A375SM cells under a low-glucose condition. Alterations in histone methylation within Pten and FoxO3a were observed after the MCDmp intervention. In the transgenic liver cancer model developed by hydrodynamic transfection of the HrasG12V and shp53, MCDmp and LCDmp interventions induced significant cancer-prevention effects. Microarray analysis showed that PPARalpha increased with decreased IL-6 and NF-kappaB within the hepatocytes after an MCDmp intervention. In conclusion, an isocaloric carbohydrate-restriction diet and natural AMPK-activating agents induce synergistic anticancer effects. SIRT1 acts as a tumor suppressor under a low glucose condition. PMID- 25747517 TI - Why are U.S. girls getting meningococcal but not human papilloma virus vaccines? Comparison of factors associated with human papilloma virus and meningococcal vaccination among adolescent girls 2008 to 2012. AB - BACKGROUND: Human papilloma virus (HPV) vaccination rates in the United States remain low, compared with other recommended adolescent vaccines. We compared factors associated with intention to receive and receipt of HPV and meningococcal vaccines and completion of the HPV vaccine series among U.S. adolescent girls. METHODS: Secondary analysis of data from the National Immunization Survey-Teen for 2008 through 2012 was performed. Multivariable logistic modeling was used to determine factors associated with intent to receive and receipt of HPV and meningococcal vaccination, completion of the HPV vaccine series among girls who started the series, and receipt of HPV vaccination among girls who received meningococcal vaccination. FINDINGS: Provider recommendation increased the odds of receipt and intention to receive both HPV and meningococcal vaccines. Provider recommendation was also associated with a three-fold increase in HPV vaccination among girls who received meningococcal vaccination (p<.001), indicating a relationship between provider recommendation and missed vaccine opportunities. However, White girls were 10% more likely to report provider recommendation than Black or Hispanic girls (p<.01), yet did not have higher vaccination rates, implying a role for parental refusal. No factors predicted consistently the completion of the HPV vaccine series among those who started. CONCLUSION: Improving provider recommendation for co-administration of HPV and meningococcal vaccines would reduce missed opportunities for initiating the HPV vaccine series. However, different interventions may be necessary to improve series completion. PMID- 25747518 TI - Knowledge, perceptions, and decision making about human papillomavirus vaccination among Korean American women: a focus group study. AB - OBJECTIVE: As one of the fastest growing ethnic minority groups in the United States, Korean American (KA) women experience a heightened cervical cancer burden. The advent of the human papillomavirus (HPV) vaccine offers an unprecedented opportunity to eliminate cervical cancer disparities in KA women. However, the uptake of HPV vaccine among KA adolescents remains suboptimal. Hence, we set out to explore knowledge, perceptions, and decision making about HPV vaccination among KA women. METHODS: We conducted four focus groups of 26 KA women who participated in a community-based, randomized, controlled trial to promote breast and cervical cancer screening. Focus group data were analyzed using qualitative content analysis. RESULTS: Four main themes emerged from the focus groups: 1) limited awareness and knowledge of HPV vaccine, 2) perceptions and beliefs about HPV vaccination (acceptance, negative perceptions, ambivalence), 3) patterns of decision making about HPV vaccination (hierarchical, peer influenced, autonomous, and collaborative), and 4) promoting HPV education and information sharing in the Korean community. CONCLUSION: KA women are generally positive toward HPV vaccination, but lack awareness and knowledge about HPV. Culturally tailored HPV education programs based on KA women's decision making patterns and effective information sharing by trustworthy sources in comfortable environments are suggested strategies to promote HPV vaccination in the KA community. The findings point to the need for a multilevel approach to addressing linguistic, cultural, and system barriers that the recent immigrant community faces in promoting HPV vaccinations. In the development of targeted interventions for KA women, educational strategies and patterns of decision making need to be considered. PMID- 25747519 TI - "I'm not ashamed to talk on it!": African-American women's decisions about cervical cancer prevention and control in South Carolina. AB - BACKGROUND: Cervical cancer disparities persist despite cervical cancer prevention advances and declining mortality rates, particularly among African American women in the South. The purpose of this qualitative study was to explore behavior, knowledge, and attitudes as influences on health decisions and preferences for cervical cancer prevention and control among African-American women in South Carolina. METHODS: Data were collected from three focus groups conducted with 28 adult women aged 18 to 70 years in South Carolina. Purposive snowball sampling was employed. Data were coded using a content analysis approach in NVivo 10. Fleiss' kappa coefficient, a measure of interrater reliability, was 0.83. FINDINGS: Twenty-seven participants self-identified as African American. The mean age of focus group participants was 45.3 years. Knowledge of human papillomavirus (HPV) and cervical cancer risk was relatively low. Participants positively viewed cervical cancer screening and HPV vaccination. Lack of health insurance and costs were screening barriers. Providers were viewed as trusted health information sources, yet stigma and fear negatively influenced screening. Cultural identity served as a facilitator and barrier for screening. Motivated by strength, identified as a central to African-American womanhood, participants viewed cervical cancer prevention as an important responsibility. However, the "Strong Black Woman" script, which has been associated with self-care and coping strategies, was also a screening barrier owing to competing priorities. CONCLUSIONS: Study findings provide insight into cervical cancer prevention decision making and support tailored interventions. Culturally relevant interventions may better convey evidence-based messages about advances in cervical cancer prevention and control. PMID- 25747520 TI - Potential for prenatal yoga to serve as an intervention to treat depression during pregnancy. AB - BACKGROUND: When left untreated, antenatal depression can have a serious negative impact on maternal, and infant outcomes. Many affected women do not obtain treatment for depression owing to difficulties accessing care or because they do not find standard antidepressant treatments to be acceptable during pregnancy. This study examined the acceptability and feasibility of a gentle prenatal yoga intervention, as a strategy for treating depression during pregnancy. METHODS: We developed a 10-week prenatal yoga program for antenatal depression and an accompanying yoga instructors' manual, and enrolled 34 depressed pregnant women from the community into an open pilot trial. We measured change in maternal depression severity from before to after the intervention. RESULTS: Results suggested that the prenatal yoga intervention was feasible to administer and acceptable to the women enrolled. No study-related injuries or other safety issues were observed during the trial. On average, participants' depression severity decreased significantly by the end of the intervention based on both observed-rated and self-report depression assessment measures. CONCLUSION: The current study suggests that prenatal yoga may be a viable approach to addressing antenatal depression, one that may have advantages in terms of greater acceptability than standard depression treatments. Research and policy implications are discussed. PMID- 25747521 TI - A systematic review of the literature on weight in sexual minority women. AB - BACKGROUND: Over the past 20 years, a growing literature has demonstrated that sexual minority women have greater weight than heterosexual women, prompting concern that they may be at high risk for disparities in physical disorders. In 2008, Bowen et al. published a review of the existing research on sexual minority women and obesity, finding no methodologically strong studies with representative sampling procedures. METHOD: We conducted a systematic review of the literature covering the period of July 2006 to February 2014 on the relationship between sexual orientation and weight. The review includes 20 population-based and 17 nonprobability sample studies. CONCLUSIONS: The majority of these studies found that lesbian and bisexual women had significantly greater body mass index (BMI) or a higher percentage with a BMI over 30 than heterosexual women. The difference in BMI was fairly consistent across the lifespan, with the weight differences beginning in adolescence. The studies, however, did not show a higher prevalence of physical disorders thought to be associated with weight. This potentially paradoxical finding warrants further research to compare prevalence of chronic disease by BMI category and sexual orientation. PMID- 25747522 TI - Encapsulation, protection, and release of hydrophilic active components: potential and limitations of colloidal delivery systems. AB - There have been major advances in the development of edible colloidal delivery systems for hydrophobic bioactives in recent years. However, there are still many challenges associated with the development of effective delivery systems for hydrophilic bioactives. This review highlights the major challenges associated with developing colloidal delivery systems for hydrophilic bioactive components that can be utilized in foods, pharmaceuticals, and other products intended for oral ingestion. Special emphasis is given to the fundamental physicochemical phenomena associated with encapsulation, stabilization, and release of these bioactive components, such as solubility, partitioning, barriers, and mass transport processes. Delivery systems suitable for encapsulating hydrophilic bioactive components are then reviewed, including liposomes, multiple emulsions, solid fat particles, multiple emulsions, biopolymer particles, cubosomes, and biologically-derived systems. The advantages and limitations of each of these delivery systems are highlighted. This information should facilitate the rational selection of the most appropriate colloidal delivery systems for particular applications in the food and other industries. PMID- 25747523 TI - High dissolved organic carbon release by benthic cyanobacterial mats in a Caribbean reef ecosystem. AB - Benthic cyanobacterial mats (BCMs) are increasing in abundance on coral reefs worldwide. However, their impacts on biogeochemical cycling in the surrounding water and sediment are virtually unknown. By measuring chemical fluxes in benthic chambers placed over sediment covered by BCMs and sediment with BCMs removed on coral reefs in Curacao, Southern Caribbean, we found that sediment covered by BCMs released 1.4 and 3.5 mmol C m(-2) h(-1) of dissolved organic carbon (DOC) during day and night, respectively. Conversely, sediment with BCMs removed took up DOC, with day and night uptake rates of 0.9 and 0.6 mmol C m(-2) h(-1). DOC release by BCMs was higher than reported rates for benthic algae (turf and macroalgae) and was estimated to represent 79% of the total DOC released over a 24 h diel cycle at our study site. The high nocturnal release of DOC by BCMs is most likely the result of anaerobic metabolism and degradation processes, as shown by high respiration rates at the mat surface during nighttime. We conclude that BCMs are significant sources of DOC. Their increased abundance on coral reefs will lead to increased DOC release into the water column, which is likely to have negative implications for reef health. PMID- 25747524 TI - Nebivolol and valsartan as a fixed-dose combination for the treatment of hypertension. AB - INTRODUCTION: The fixed-dose combination of nebivolol and valsartan drug has been clinically evaluated and demonstrated to represent a unique combination of nebivolol, a selective beta1-adrenoceptor antagonist and a beta3-adrenoceptor agonist; beta3 receptor activation increases endothelial nitric oxide and produces vasodilation. Valsartan is highly selective angiotensin AT1 receptor blocker and exerts its major pharmacological effect by decreasing angiotensin II induced vasoconstriction and production of aldosterone. The addition of nebivolol counteracts the effects of increased angiotensin II concentrations resulting from potent AT1 blockade. This review describes a recently completed trial establishing the efficacy of the nebivolol/valsartan combination. AREAS COVERED: This review provides a literature search of pertinent pharmacological and clinical data that describes the mechanisms of both drugs individually and the results of a clinical trial comparing fixed-dose combinations of nebivolol with valsartan as compared with each drug as monotherapy. EXPERT OPINION: Fixed-dose combination drugs are intended to improve patient compliance and reduce drug costs, as well as to reduce long-term cardiovascular event rates and block counter-regulatory effects due to monotherapy. The vast majority of hypertensive patients will require at least two medications. We believe that the clinical evidence suggests that the combination of nebivolol with valsartan offers a definite clinical benefit, combining beta1-adrenoceptor and angiotensin AT1 receptor blockade with beta3 receptor activation and resultant increase in nitric oxide and vasodilation. PMID- 25747527 TI - Association study of monoamine oxidase-A gene promoter polymorphism (MAOA-uVNTR) with self-reported anxiety and other psychopathological symptoms in a community sample of early adolescents. AB - The polymorphism upstream of the gene for monoamine oxidase A (MAOA-uVNTR) is reported to be an important enzyme involved in human physiology and behavior. With a sample of 228 early-adolescents from a community sample (143 girls) and adjusting for environmental variables, we examined the influence of MAOA-uVNTR alleles on the scores obtained in the Screen for Childhood Anxiety and Related Emotional Disorders and in the Child Symptom Inventory-4. Our results showed that girls with the high-activity MAOA allele had higher scores for generalized and total anxiety than their low-activity peers, whereas boys with the low-activity allele had higher social phobia scores than boys with the high-activity allele. Results for conduct disorder symptoms did not show a significant relationship between the MAOA alleles and the presence of these symptoms. Our findings support a possible association, depending on gender, between the MAOA-uVNTR polymorphism and psychopathological disorders such as anxiety, which affects high rates of children and adolescents. PMID- 25747526 TI - Thyroid ultrasound features and risk of carcinoma: a systematic review and meta analysis of observational studies. AB - BACKGROUND: Thyroid nodules are a common finding in the general population, and their detection is increasing with the widespread use of ultrasound (US). Thyroid cancer is found in 5-15% of cases depending on sex, age, and exposure to other risk factors. Some US parameters have been associated with increased risk of malignancy. However, no characteristic seems sufficiently reliable in isolation to diagnose malignancy. The objective of this meta-analysis was to evaluate the diagnostic performance of US features for thyroid malignancy in patients with unselected thyroid nodules and nodules with indeterminate fine-needle aspiration (FNA) cytology. METHODS: Electronic databases were reviewed for studies published prior to July 2012 that evaluated US features of thyroid nodules and reported postoperative histopathologic diagnosis. A manual search of references of review and key articles, and previous meta-analyses was also performed. A separate meta analysis was performed including only nodules with indeterminate cytology. Analyzed features were solid structure, hypoechogenicity, irregular margins, absence of halo, microcalcifications, central vascularization, solitary nodule, heterogeneity, taller than wide shape, and absence of elasticity. RESULTS: Fifty two observational studies (12,786 nodules) were included. Nine studies included nodules with indeterminate cytology as a separate category, comprising 1851 nodules. In unselected nodules, all US features were significantly associated with malignancy with an odds ratio varying from 1.78 to 35.7, and microcalcifications, irregular margins, and a taller than wide shape had high specificities (Sp; 87.8%, 83.1%, 96.6%) and positive likelihood ratios (LHR; 3.26, 2.99, 8.07). Absence of elasticity was the single feature with the best diagnostic performance (sensitivity 87.9%, Sp 86.2%, and positive LHR 6.39). The presence of central vascularization was the most specific US feature in nodules with indeterminate cytology (Sp 96% and positive LHR 2.13). CONCLUSIONS: US features in isolation do not provide reliable information to select nodules that should have a FNA performed. A combination of US characteristics with higher likelihood ratios and consequently with higher post-test probabilities of malignancy-microcalcifications, or a taller than wide shape, or irregular margins, or absence of elasticity-will probably identify nodules with an increased risk for malignancy. Further studies are required to standardize elastography techniques and evaluate outcomes, especially in nodules with an indeterminate cytology. PMID- 25747528 TI - Isolation and characterization of a 17-kDa FKBP-type peptidyl-prolyl cis/trans isomerase from Vibrio anguillarum. AB - Peptidyl-prolyl cis/trans isomerase (PPIase) catalyzes the isomerization of peptide bonds to achieve conformational changes in native folded proteins. An FKBP-type PPIase with an approximate molecular weight of 17kDa was isolated from Vibrio anguillarum O1 and named VaFKBP17. To investigate its biochemical properties, the ppi gene from V. anguillarum O1 was isolated and overexpressed in Escherichia coli. A protease-coupled assay for isomerization activity, using Succinyl-Ala-Phe-Pro-Phe-p nitroanilide as substrate, indicated that the activity of VaFKBP17 was highest at low temperature (5 degrees C) and alkaline conditions (pH 10). The immunosuppressant FK506 inhibited the isomerization activity of VaFKBP17. The chaperone activity of VaFKBP17 was assessed using a citrate synthase thermal aggregation activity assay. To evaluate its ability to catalyze protein refolding, the effect of VaFKBP17 on inclusion bodies was investigated during a dilution process. In this assay, VaFKBP17 was able to assist protein refolding. These results provide evidence that VaFKBP17 possesses chaperone-like activity. The structural homology of VaFKBP17 relative to other known bacterial FKBPs was also examined. PMID- 25747529 TI - Molecular and pharmacological characterization of the Chelicerata pyrokinin receptor from the southern cattle tick, Rhipicephalus (Boophilus) microplus. AB - We identified the first pyrokinin receptor (Rhimi-PKR) in Chelicerata and analyzed structure-activity relationships of cognate ligand neuropeptides and their analogs. Based on comparative and phylogenetic analyses, this receptor, which we cloned from larvae of the cattle tick Rhipicephalus microplus (Acari: Ixodidae), is the ortholog of the insect pyrokinin (PK)/pheromone biosynthesis activating neuropeptide (PBAN)/diapause hormone (DH) neuropeptide family receptor. Rhimi-PKR functional analyses using calcium bioluminescence were performed with a developed stable recombinant CHO-K1 cell line. Rhimi-PKR was activated by four endogenous PKs from the Lyme disease vector, the tick Ixodes scapularis (EC50s range: 85.4 nM-546 nM), and weakly by another tick PRX-amide peptide, periviscerokinin (PVK) (EC50 = 24.5 MUM). PK analogs with substitutions of leucine, isoleucine or valine at the C-terminus for three tick PK peptides, Ixosc-PK1, Ixosc-PK2, and Ixosc-PK3, retained their potency on Rhimi-PKR. Therefore, Rhimi-PKR is less selective and substantially more tolerant than insect PK receptors of C-terminal substitutions of leucine to isoleucine or valine, a key structural feature that serves to distinguish insect PK from PVK/CAP2b receptors. In females, ovary and synganglion had the highest Rhimi-PKR relative transcript abundance followed by the rectal sac, salivary glands, Malpighian tubules, and midgut. This is the first pharmacological analysis of a PK/PBAN/DH-like receptor from the Chelicerata, which will now permit the discovery of the endocrinological roles of this neuropeptide family in vectors of vertebrate pathogens. PMID- 25747530 TI - Functional connectivity of parietal cortex during temporal selective attention. AB - Perception of natural experiences requires allocation of attention towards features, objects, and events that are moving and changing over time. This allocation of attention is controlled by large-scale brain networks that, when damaged, cause widespread cognitive deficits. In particular, damage to ventral parietal cortex (right lateralized TPJ, STS, supramarginal and angular gyri) is associated with failures to selectively attend to and isolate features embedded within rapidly changing visual sequences (Battelli, Pascual-Leone, & Cavanagh, 2007; Husain, Shapiro, Martin, & Kennard, 1997). In this study, we used fMRI to investigate the neural activity and functional connectivity of intact parietal cortex while typical subjects judged the relative onsets and offsets of rapidly flickering tokens (a phase discrimination task in which right parietal patients are impaired). We found two regions in parietal cortex correlated with task performance: a bilateral posterior TPJ (pTPJ) and an anterior right-lateralized TPJ (R aTPJ). Both regions were deactivated when subjects engaged in the task but showed different patterns of functional connectivity. The bilateral pTPJ was strongly connected to nodes within the default mode network (DMN) and the R aTPJ was connected to the attention network. Accurate phase discriminations were associated with increased functional correlations between sensory cortex (hMT+) and the bilateral pTPJ, whereas accuracy on a control task was associated with yoked activity in the hMT+ and the R aTPJ. We conclude that temporal selective attention is particularly sensitive for revealing information pathways between sensory and core cognitive control networks that, when damaged, can lead to nonspatial attention impairments in right parietal stroke patients. PMID- 25747531 TI - Myxoid liposarcoma with heterologous components: dedifferentiation or metaplasia? A FISH-documented and CGH-documented case report. AB - Heterologous differentiation in myxoid liposarcoma is a rare phenomenon. Few cases have been reported thus far, often without molecular assays, and the concept of "dedifferentiated" myxoid liposarcoma remains controversial. We describe a primary myxoid liposarcoma with chondroid and osseous components affecting the right thigh of a 27-year-old woman. We wondered whether these areas represented dedifferentiated components or simply metaplasia, and performed fluorescent in situ hybridization and array comparative genomic hybridization assays in the myxoid liposarcoma component and chondroid component. Fluorescent in situ hybridization analysis demonstrated a DDIT3 gene rearrangement in both components; array comparative genomic hybridization analysis did not detect any gain or loss of DNA regions in both components. Our results, demonstrating that both components have the same molecular alterations, suggest that heterologous components seen in some myxoid liposarcomas reflect a metaplastic phenomenon and not a real dedifferentiation phenomenon, challenging the concept of "dedifferentiated" myxoid liposarcoma. PMID- 25747533 TI - Breaking the barriers: New role for insulin-like growth factor 1 receptor in vascular permeability. AB - This commentary highlights the article by Liang et al that describes a critical role for insulin-like growth factor 1 receptor in the progression of chronic kidney disease. PMID- 25747532 TI - The role of viral, host, and secondary bacterial factors in influenza pathogenesis. AB - Influenza A virus infections in humans generally cause self-limited infections, but can result in severe disease, secondary bacterial pneumonias, and death. Influenza viruses can replicate in epithelial cells throughout the respiratory tree and can cause tracheitis, bronchitis, bronchiolitis, diffuse alveolar damage with pulmonary edema and hemorrhage, and interstitial and airspace inflammation. The mechanisms by which influenza infections result in enhanced disease, including development of pneumonia and acute respiratory distress, are multifactorial, involving host, viral, and bacterial factors. Host factors that enhance risk of severe influenza disease include underlying comorbidities, such as cardiac and respiratory disease, immunosuppression, and pregnancy. Viral parameters enhancing disease risk include polymerase mutations associated with host switch and adaptation, viral proteins that modulate immune and antiviral responses, and virulence factors that increase disease severity, which can be especially prominent in pandemic viruses and some zoonotic influenza viruses causing human infections. Influenza viral infections result in damage to the respiratory epithelium that facilitates secondary infection with common bacterial pneumopathogens and can lead to secondary bacterial pneumonias that greatly contribute to respiratory distress, enhanced morbidity, and death. Understanding the molecular mechanisms by which influenza and secondary bacterial infections, coupled with the role of host risk factors, contribute to enhanced morbidity and mortality is essential to develop better therapeutic strategies to treat severe influenza. PMID- 25747535 TI - Ultrasound-guided intrauterine injection of lipopolysaccharide as a novel model of preterm birth in the mouse. AB - Mouse models are used to study mechanisms that link intrauterine infection and preterm birth (PTB). To mimic intrauterine infection, lipopolysaccharide (LPS) is commonly injected into the uterus via minilaparotomy, which is invasive, and can cause PTB in control animals. We hypothesized that less-invasive ultrasound guided intrauterine LPS injection or intravaginal LPS administration could induce PTB by stimulating an inflammatory response of the uteroplacental tissues, while minimizing PTB in control animals. On day 17 of gestation mice received LPS intravaginally (10 to 240 MUg; n = 3 to 8) or into the uterus (20 MUg) under ultrasound guidance (n = 7) or via laparotomy (n = 7). Control animals received phosphate-buffered saline (PBS; n = 5 to 7). Intrauterine administration of LPS, both under ultrasound guidance and via laparotomy, induced delivery earlier than in PBS control groups (P < 0.01). Intravaginal LPS administration did not stimulate PTB. Quantitative real-time PCR and immunohistochemistry of tissues harvested 6 hours after treatment confirmed that ultrasound-guided LPS administration induced a localized inflammatory response. Ultrasound-guided intrauterine LPS injection reliably induces PTB in the mouse and mimics the local inflammatory and immune responses observed in the more-invasive laparotomy model of inflammation-induced PTB. Ultrasound-guided intrauterine LPS injection is a useful novel model of PTB for future studies and concords with the principles of reduction, replacement, and refinement. PMID- 25747534 TI - Cyclin-dependent kinase inhibitors and the treatment of gastrointestinal cancers. AB - The cell cycle is a highly conserved and tightly regulated biological system that controls cellular proliferation and differentiation. The cell cycle regulatory proteins, which include the cyclins, the cyclin-dependent kinases (CDKs), and the CDK inhibitors, are critical for the proper temporal and spatial regulation of cellular proliferation. Conversely, alterations in cell cycle regulatory proteins, leading to the loss of normal cell-cycle control, are a hallmark of many cancers, including gastrointestinal cancers. Accordingly, overexpression of CDKs and cyclins and by contrast loss of CDK inhibitors, are all linked to gastrointestinal cancers and are often associated with less favorable prognoses and outcomes. Because of the importance that the cell cycle regulatory proteins play in tumorigenesis, currently there is a broad spectrum of cell-cycle inhibitors under development that, as a group, hold promise as effective cancer treatments. In support of this approach to cancer treatment, the growing availability of molecular diagnostics techniques may help in identifying patients who have driving abnormalities in the cell-cycle machinery and are thus more likely to respond to cell-cycle inhibitors. In this review, we discuss the prevalence of cell-cycle abnormalities in patients with gastrointestinal cancers and provide a preclinical and clinical overview of new agents that target cell cycle abnormalities with a special emphasis on gastrointestinal cancers. PMID- 25747536 TI - Combination of FVIII and low-dose rFVIIa improves haemostasis in acquired haemophilia A patients: a collaborative controlled study. AB - INTRODUCTION: Acquired haemophilia A (AHA) is an autoimmune disease that potentially leads to severe bleeding and has a high rate of mortality. This collaborative study aimed to assess the efficacy of the co-administration of FVIII and low-dose rFVIIa in patients with AHA. MATERIALS AND METHODS: This study retrospectively compared the combined FVIII/low-dose rFVIIa therapy (initial dose range of 25-55MUg/Kg) with the combined FVIII/PCC therapy and low-dose rFVIIa monotherapy. Adverse drug reactions and recurrent bleeding episodes were also monitored. Crude comparisons and the exact conditional logistic regression were performed to compare the outcomes between three treatment groups. RESULTS: First bleeding episodes of 56 consecutive patients from 5 centres were analyzed, and 37 bleeding episodes (66.1%) were determined to be severe. Specifically, the rate of bleeding control was significantly higher with the FVIII/low-dose rFVIIa therapy compared to that of the low-dose rFVIIa alone therapy or the FVIII/PCC therapy (58.3% vs. 41.7% vs. 95.0%, respectively). Analyzing of total 236 bleeding episodes showed a clear positive association between the early initiation of haemostatic treatment and efficacy. No therapy-related adverse events in which thrombosis predominated were reported. CONCLUSIONS: The combination of FVIII and low-dose rFVIIa offers an ideal haemostatic cover and may be promoted as a feasible and safe therapy protocol for patients with AHA. PMID- 25747537 TI - Tranexamic acid for treatment of bleeding in hemophagocytic lymphohistiocytosis. PMID- 25747539 TI - Blisters: the enemy of the feet. PMID- 25747538 TI - Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy. AB - INTRODUCTION: Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the CYP4F2 genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats. MATERIALS AND METHODS: Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats. RESULTS: Patients with the CYP4F2 (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including VKORC1, CYP4F2, and CYP2C9 genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of CYP4F2 polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients. CONCLUSIONS: The plasma VK1 and MK-4 concentrations are significantly influenced by CYP4F2 genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The CYP4F2 polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement. PMID- 25747540 TI - Smoking increases the risk of acute mountain sickness. AB - OBJECTIVE: We aimed to ascertain risk factors for acute mountain sickness (AMS) in miners exposed to chronic intermittent high altitude conditions. METHODS: All new hires (2009-2012) for mine employment (4000 m above sea level) were followed up for 12 months after first ascent. Demographics, physiologic data, and cigarette smoking were assessed at preemployment screening. Mine site clinic care for AMS defined incident events. Cox regression analysis estimated risk of AMS associated with smoking and selected covariates. RESULTS: There were 46 AMS cases among 569 individuals during the first 12 months of employment. Adjusted for age, sex, and altitude of permanent residence, cigarettes smoked per day before hiring were prospectively associated with AMS (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.2 per 10 cigarettes smoked). This risk was higher in the subset of workers with less demanding physical work (n=336; HR, 3.3; 95% CI, 1.7 to 6.3), whereas among those with more physically demanding jobs (n=233), smoking was not associated with increased risk (HR, 0.6; 95% CI, 0.1 to 2.3). CONCLUSIONS: In workers newly hired to work at high altitude, smoking increases the likelihood of AMS, but this effect appears to be operative only among those with less physically demanding work duties. PMID- 25747541 TI - Complex alpine extrication: case report of mountain and speleological rescue cooperation. AB - Mountain sporting activities are an increasingly popular practice that exposes mountaineers to a high risk of adverse events. This report describes a unique case of recovery in an austere environment that involved explosives. In June 2012, a 52-year-old man ascended a cliff tower in the Eastern Alps, Italy. A landslide occurred, and a boulder crushed the climber against a large stone located farther down the cliff, causing compression of the lower limbs and the pelvis with consequent severe musculoskeletal trauma. The National Alpine and Cave Rescue Unit (NACRU) arrived and proceeded with stabilization of the injured climber, which took 6 hours and involved a difficult extrication supported by the Cave Rescue division of NACRU. Unfortunately, during transport to the trauma center of Borgo Trento, Verona, the patient exhibited signs of progressive traumatic shock because of crush syndrome, hypovolemia, and acidosis, which led to cardiac arrest and death. Based on an extensive literature review, this report was determined to be the only one of a mountain rescue using explosives for the extrication of a victim in the Northeast Italian Alps. This case describes how a rescue in austere environments can represent a high-risk situation, and it shows how improvisation and cooperation between rescue teams are crucial for a successful recovery. PMID- 25747542 TI - Genetic susceptibility to prosthetic joint infection following total joint arthroplasty: A systematic review. AB - BACKGROUND: Prosthetic joint infection (PJI) is the most common cause of total joint arthroplasty failure and revision surgery. Genetic polymorphisms could be determinant factors for PJI. METHODS: We performed a systematic research of Medline, Pubmed, Embase, Cochrane Library, and Google Scholar, and identified 11 studies with 34 kinds of gene polymorphisms, were included in the synthesis. RESULTS: Our data suggest that the C allele and genotype C/C for MBL-550 SNP, genotype A/A for MBL-54 SNP and G allele for MBL-221 SNP increase the risk of PJI, while G allele and genotype G/G for MBL-550 SNP decrease the risk of PJI in Caucasian populations. Several other genes reported by single-center studies also contribute to the genetic susceptibility to septic PJI. No definitive conclusions could be achieved due to the small amount of data in the included studies. CONCLUSION: Several genes contribute to the genetic susceptibility to PJI following total joint arthroplasty. Further studies will enhance the understanding of PJI, and may inform and direct early interventions. PMID- 25747543 TI - Characterization of silver nanoparticles in selected consumer products and its relevance for predicting children's potential exposures. AB - Due to their antifungal, antibacterial, antiviral, and antimicrobial properties, silver nanoparticles (AgNPs) are used in consumer products intended for use by children or in the home. Children may be especially affected by the normal use of consumer products because of their physiological functions, developmental stage, and activities and behaviors. Despite much research to date, children's potential exposures to AgNPs are not well characterized. Our objectives were to characterize selected consumer products containing AgNPs and to use the data to estimate a child's potential non-dietary ingestion exposure. We identified and cataloged 165 consumer products claiming to contain AgNPs that may be used by or near children or found in the home. Nineteen products (textile, liquid, plastic) were selected for further analysis. We developed a tiered analytical approach to determine silver content, form (particulate or ionic), size, morphology, agglomeration state, and composition. Silver was detected in all products except one sippy cup body. Among products in a given category, silver mass contributions were highly variable and not always uniformly distributed within products, highlighting the need to sample multiple areas of a product. Electron microscopy confirmed the presence of AgNPs. Using this data, a child's potential non-dietary ingestion exposure to AgNPs when drinking milk formula from a sippy cup is 1.53 MUg Ag/kg. Additional research is needed to understand the number and types of consumer products containing silver and the concentrations of silver in these products in order to more accurately predict children's potential aggregate and cumulative exposures to AgNPs. PMID- 25747544 TI - Use of ethidium monoazide and propidium monoazide to determine viral infectivity upon inactivation by heat, UV- exposure and chlorine. AB - Despite the great sensitivity of PCR in monitoring enteric viruses in an aquatic environment, PCR detects viral nucleic acids of both infectious and noninfectious viruses, limiting the conclusions regarding significance for public health. Ethidium monoazide (EMA) and propidium monoazide (PMA) are closely related membrane impermeant dyes that selectively penetrate cells with compromised membranes. Inside the cells, the dye can intercalate into nucleic acids and inhibit PCR amplification. To assess whether EMA and PMA pretreatment is a suitable approach to inhibit DNA amplification from noninfectious viruses upon heat treatment, UV exposure or chlorine treatment, viruses were measured by qPCR, EMA-qPCR, PMA-qPCR and cell culture titration. EMA/PMA-qPCR of UV- and heat treated viruses did not correlate with the results of the cell culture assay. However, the data from EMA/PMA-qPCR of chlorine-inactivated viruses was consistent with the cell culture infectivity assay. Therefore, a dye treatment approach could be a rapid and inexpensive tool to screen the efficacy of chlorine disinfection, but it is not able to distinguish between infectious and noninfectious viruses inactivated via heat treatment or UV irradiation. Indeed, different viruses may have different trends and mechanisms of inactivation; thus, the assay must be evaluated for each virus separately. PMID- 25747545 TI - Morbidity and mortality associated with mode of delivery for breech periviable deliveries. AB - OBJECTIVE: The purpose of this study was to estimate the odds of morbidity and death that are associated with cesarean delivery, compared with vaginal delivery, for breech fetuses who are delivered from 23-24 6/7 weeks' gestational age. STUDY DESIGN: We conducted a retrospective cohort study of state-level maternal and infant hospital discharge data that were linked to vital statistics for breech deliveries that occurred from 23-24 6/7 weeks' gestation in California, Missouri, and Pennsylvania from 2000-2009 (N = 1854). Analyses were stratified by gestational age (23-23 6/7 vs 24-24 6/7 weeks' gestation). RESULTS: Cesarean delivery was performed for 46% (335 fetuses) and 77% (856 fetuses) of 23- and 24 week breech fetuses. In multivariable analyses, overall survival was greater for cesarean-born neonates (adjusted odds ratio [AOR], 3.98; 95% confidence interval [CI], 2.24-7.06; AOR, 2.91; 95% CI, 1.76-4.81, respectively). When delivered for nonemergent indications, cesarean-born survivors were more than twice as likely to experience major morbidity (intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, asphyxia composite; AOR, 2.83; 95% CI, 1.37 5.84; AOR, 2.07; 95% CI, 1.11-3.86 at 23 and 24 weeks' gestation, respectively). Among intubated neonates, despite a short-term survival advantage, there was no difference in survival to >6-month corrected age (AOR, 1.77; 95% CI, 0.83-3.74; AOR, 1.50; 95% CI, 0.81-2.76, respectively). There was no difference in survival for intubated 23-week neonates who were delivered by cesarean for nonemergent indications or cesarean-born neonates who weighed <500 g. CONCLUSION: Cesarean delivery increased overall survival and major morbidity for breech periviable neonates. However, among intubated neonates, despite a short-term survival advantage, there was no difference in 6-month survival. Also, cesarean delivery did not increase survival for neonates who weighed <500 g. Patients and providers should discuss explicitly the trade-offs related to neonatal death and morbidity, maternal morbidity, and implications for future pregnancies. PMID- 25747546 TI - The multidisciplinary approach to the care of the obese parturient. AB - Maternal obesity in pregnancy is associated with increased maternal and fetal risks. Pregnancy management should include counseling, screening, and optimization of maternal health, increased fetal surveillance, and preparation for parturition. A multidisciplinary approach should be implemented including collaboration from obstetricians, nutritionists, anesthesiologists, social workers, and neonatologists to optimize perinatal outcomes. Pregnancy is an ideal window of opportunity to influence both the patient's long-term health and the health of the offspring. PMID- 25747547 TI - Reply: To PMID 24909340. PMID- 25747548 TI - Hereditary breast cancer: an update on risk assessment and genetic testing in 2015. AB - The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals. PMID- 25747549 TI - Infant mortality rate as a metric for best gestational age for delivery. PMID- 25747550 TI - Synthesis, biological evaluation and 3D QSAR study of 2,4-disubstituted quinolines as anti-tuberculosis agents. AB - The synthesis and anti-tuberculosis activity for three series of 2,4 disubstituted quinolines is reported. The synthesized compounds were evaluated for activity against M. tuberculosis H37Rv strain; most promising compounds from the series exhibited MIC99 values ranged between 3.125 and 6.25 MUg/mL. None of the compounds exhibited cytotoxicity up to the highest test concentration of 200 MUg/mL. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Atom-fit alignment provided the best model, and allowed prediction of the activity of molecules in the test sets leading to the rationalization of the relationship between structure and activity. PMID- 25747551 TI - Geographic and facility variation in inpatient stroke rehabilitation: multilevel analysis of functional status. AB - OBJECTIVE: To examine geographic and facility variation in cognitive and motor functional outcomes after postacute inpatient rehabilitation in patients with stroke. DESIGN: Retrospective cohort design using Centers for Medicare and Medicaid Services (CMS) claims files. Records from 1209 rehabilitation facilities in 298 hospital referral regions (HRRs) were examined. Patient records were analyzed using linear mixed models. Multilevel models were used to calculate the variation in outcomes attributable to facilities and geographic regions. SETTING: Inpatient rehabilitation units and facilities. PARTICIPANTS: Patients (N=145,460) with stroke discharged from inpatient rehabilitation from 2006 through 2009. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Cognitive and motor functional status at discharge measured by items in the CMS Inpatient Rehabilitation Facility-Patient Assessment Instrument. RESULTS: Variation profiles indicated that 19.1% of rehabilitation facilities were significantly below the mean functional status rating (mean +/- SD, 81.58+/-22.30), with 221 facilities (18.3%) above the mean. Total discharge functional status ratings varied by 3.57 points across regions. Across facilities, functional status values varied by 29.2 points, with a 9.1-point difference between the top and bottom deciles. Variation in discharge motor function attributable to HRR was reduced by 82% after controlling for cluster effects at the facility level. CONCLUSIONS: Our findings suggest that variation in motor and cognitive function at discharge after postacute rehabilitation in patients with stroke is accounted for more by facility than geographic location. PMID- 25747553 TI - Prevalence of class-I, class-II and class-III obesity in Australian adults between 1995 and 2011-12. AB - OBJECTIVE: To compare the prevalence of class-I, II and III obesity in Australian adults between 1995, 2007-08 and 2011-12. METHODS: Prevalence data for adults (aged 18+ years) were sourced from customised data from the nationally representative National Nutrition Survey (1995), the National Health Survey (2007 08), and the Australian Health Survey (2011-12) conducted by the Australian Bureau of Statistics. Obesity classifications were based on measured height and weight (class-I body mass index: 30.0-34.9 kg/m(2), class-II: 35.0-39.9 kg/m(2) and class-III: >= 40.0 kg/m(2)). Severe obesity was defined as class-II or class III obesity. RESULTS: Between 1995 and 2011-12, the prevalence of obesity (all classes combined) increased from 19.1% to 27.2%. During this 17 year period, relative increases in class I, II and III obesity were 1.3, 1.7 and 2.2-fold respectively. In 2011-12, the prevalence of class I, II and III obesity was 19.4, 5.9 and 2.0 per cent respectively in men, and 16.1, 6.9 and 4.2 per cent respectively in women. One in every ten people was severely obese, increasing from one in twenty in 1995, and women were disproportionally represented in this population. Obesity prevalence increased with increasing levels of area-level socioeconomic disadvantage, particularly for the more severely obese classes. Severe obesity affected 6.2% and 13.4% in the least and most disadvantaged quintiles respectively. CONCLUSION: Over the last two decades, there have been substantial increases in the prevalence of obesity, particularly the more severe levels of obesity. This study highlights high risk groups who warrant targeted weight gain prevention interventions. PMID- 25747552 TI - Functional independence after inpatient rehabilitation for traumatic brain injury among minority children and adolescents. AB - OBJECTIVE: To compare motor and cognitive functional independence scores between Hispanic, non-Hispanic black (NHB), and non-Hispanic white (NHW) children with traumatic brain injury (TBI) after discharge from inpatient rehabilitation. DESIGN: Retrospective cohort study using the Uniform Data System for Medical Rehabilitation national dataset from the years 2002 to 2012. SETTING: Inpatient rehabilitation units. PARTICIPANTS: Children (N=10,141) aged 6 months to 18 years who received inpatient rehabilitation for TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Motor and cognitive functional independence after discharge from inpatient rehabilitation, adjusting for age, sex, admission function, length of stay, insurance, and region. RESULTS: Inpatient rehabilitation therapy improved functional independence for all children. Younger age, lower admission functional independence scores, and Medicaid insurance were associated with lower functional independence at discharge. Hispanic and NHB children had lower discharge cognitive scores compared with NHW children; however, differences were small and were partially explained by insurance status and region. Children who received rehabilitation therapy at pediatric facilities had greater cognitive improvement. CONCLUSIONS: While racial/ethnic disparities are small, minority children are more likely to be younger, to have Medicaid, and to be cared for at nonpediatric facilities, factors that increase their risk for lower functional outcomes. PMID- 25747554 TI - Important details about the red cell distribution width. AB - In the recent issue of the Journal of Atherosclerosis and Thrombosis, Wang et al. assessed the relationship between the red cell distribution width (RDW) and acute myocardial infarction (AMI). However, assessing all parameters affecting the RDW, determining the optimum RDW cut-off value for predicting the prognosis of coronary artery disease (CAD), excluding metabolic comorbidities affecting the RDW values and identifying the specific range for the WBC count within the exclusion criteria would provide more reliable results and improve the credibility of the entire article in this study population. PMID- 25747555 TI - Eunethta: further steps towards European cooperation on health technology assessment. PMID- 25747556 TI - Developing the HTA core model for the online environment. AB - BACKGROUND: A framework for collaborative production and sharing of HTA information, the HTA Core Model, was originally developed within EUnetHTA in 2006 08. In this paper, we describe the further development of the Model to allow implementation and utilization of the Model online. The aim was to capture a generic HTA process that would allow effective use of the HTA Core Model and resulting HTA information while at the same time not interfering with HTA agencies' internal processes. METHODS: The work was coordinated by a development team in Finland, supported by an international expert group. Two pilot testing rounds were organized among EUnetHTA agencies and two extensive core HTA projects tested the tool in a real setting. The final work was also formally validated by a group of HTA agencies. RESULTS: The HTA Core Model Online--available at http://www.corehta.info--is a web site hosting a) a tool to allow electronic utilization of the HTA Core Model and b) a database of produced HTA information. While access to the HTA information is free to all, the production features are currently available to EUnetHTA member agencies only. A policy was crafted to steer the use of the Model and produced information. CONCLUSIONS: We have successfully enabled electronic use of the HTA Core Model and agreed on a policy for its utilization. The system is already being used in subsequent HTA projects within EUnetHTA Joint Action 2. Identified shortcomings and further needs will be addressed in subsequent development. PMID- 25747557 TI - Standardized reporting for rapid relative effectiveness assessments of pharmaceuticals. AB - OBJECTIVES: Many European countries perform rapid assessments of the relative effectiveness (RE) of pharmaceuticals as part of the reimbursement decision making process. Increased sharing of information on RE across countries may save costs and reduce duplication of work. The objective of this article is to describe the development of a tool for rapid assessment of RE of new pharmaceuticals that enter the market, the HTA Core Model(r) for Rapid Relative Effectiveness Assessment (REA) of Pharmaceuticals. METHODS: Eighteen member organisations of the European Network of Health Technology Assessment (EUnetHTA) participated in the development of the model. Different versions of the model were developed and piloted in this collaboration and adjusted accordingly based on feedback on the content and feasibility of the model. RESULTS: The final model deviates from the traditional HTA Core Model(r) used for assessing other types of technologies. This is due to the limited scope (strong focus on RE), the timing of the assessment (just after market authorisation), and strict timelines (e.g. 90 days) required for performing the assessment. The number of domains and assessment elements was limited and it was decided that the primary information sources should preferably be a submission file provided by the marketing authorisation holder and the European Public Assessment Report. CONCLUSIONS: The HTA Core Model(r) for Rapid REA (version 3.0) was developed to produce standardised transparent RE information of pharmaceuticals. Further piloting can provide input for possible improvements, such as further refining the assessment elements and new methodological guidance on relevant areas. PMID- 25747558 TI - Planned and ongoing projects (pop) database: development and results. AB - OBJECTIVES: The aim of this study was to present the development, structure and results of a database on planned and ongoing health technology assessment (HTA) projects (POP Database) in Europe. METHODS: The POP Database (POP DB) was set up in an iterative process from a basic Excel sheet to a multifunctional electronic online database. The functionalities, such as the search terminology, the procedures to fill and update the database, the access rules to enter the database, as well as the maintenance roles, were defined in a multistep participatory feedback loop with EUnetHTA Partners. RESULTS: The POP Database has become an online database that hosts not only the titles and MeSH categorizations, but also some basic information on status and contact details about the listed projects of EUnetHTA Partners. Currently, it stores more than 1,200 planned, ongoing or recently published projects of forty-three EUnetHTA Partners from twenty-four countries. Because the POP Database aims to facilitate collaboration, it also provides a matching system to assist in identifying similar projects. Overall, more than 10 percent of the projects in the database are identical both in terms of pathology (indication or disease) and technology (drug, medical device, intervention). In addition, approximately 30 percent of the projects are similar, meaning that they have at least some overlap in content. CONCLUSIONS: Although the POP DB is successful concerning regular updates of most national HTA agencies within EUnetHTA, little is known about its actual effects on collaborations in Europe. Moreover, many non-nationally nominated HTA producing agencies neither have access to the POP DB nor can share their projects. PMID- 25747559 TI - Is the planned and ongoing project (POP) database a suitable tool to reduce duplication in the process of assessing new health technologies in the European Union? Preliminary experience in the context of the EUnetHTA Joint Action Project Framework (2010-2012). AB - OBJECTIVES: The European Network for Health Technology Assessment (EUnetHTA) Joint Action Project Framework, 2010-12, Work Package 7B (WP 7B), was aimed at facilitating collaboration between HTA agencies to avoid duplication of assessment efforts. A major task of WP 7B was to collect information on planned and ongoing (POP) projects by EUnetHTA agencies and to incorporate this information in a POP Database. We analyzed whether the Database served its intended purpose. METHODS: A survey was sent to all fifty-seven EUnetHTA partners, complemented by telephone interviews with the Ludwig Boltzmann Institute of HTA in Austria (lead institution). Furthermore, detailed documentation on the activities of the POP Database was provided to the research team at CAST (University of Southern Denmark) by the lead institution. RESULTS: Forty-two of fifty-seven agencies (74 percent) responded to the survey. Eleven collaborations initiated by agencies themselves were reported. The scope of these collaborative activities was usually limited to information exchange on for example literature search protocols. A slight reduction of duplication of effort was documented. In addition, twelve collaborations at the full report level were initiated by the lead institution. CONCLUSION: While the POP Database has the potential to reduce duplication of effort, this has not been realized during the 3-year period of the EUnetHTA Joint Action Project Framework, 2010-12. Further evidence needs to be gathered to determine whether the POP Database is effective and whether the benefits outweigh the resources required to maintain it. PMID- 25747560 TI - Endpoints for relative effectiveness assessment (REA) of pharmaceuticals. AB - OBJECTIVES: Clinical endpoints are defined as valid measures of clinical benefit or harm due to treatment, that describe the impact of treatment on how a patient feels, functions, and survives. The choice of endpoints and the manner in which they are reported have a major impact on the relative effectiveness assessment (REA) of pharmaceuticals. The aim of this article is to describe the guideline development process and the key findings that set a framework for appropriate use of endpoints in REAs in Europe. METHODS: A multi-health technology assessment (HTA)-agency collaborative process in EUnetHTA JA1 was used to scope, draft, and finalize methodological guidelines for REA in Europe. RESULTS: Patient-relevant clinical endpoints can be broadly categorized into: mortality, morbidity and health-related quality of life. A clinical endpoint is a main symptom or sign of a disease that is clinically relevant, valid, reproducible and responsive to change. Preference is for long-term or final endpoints whenever possible. Surrogate endpoints may be used when there is compelling evidence of a clear and consistent correlation of treatment effects on the surrogate and final outcome of interest. CONCLUSIONS: The relevance and hierarchy of the different types of clinical endpoints depend on the research question, disease, and the treatment investigated. Not only the primary endpoint, but also other relevant endpoints are assessed in comparison to adequate comparator(s). This simultaneous assessment of all relevant endpoints is a hallmark of REA. PMID- 25747561 TI - EUnetHTA information management system: development and lessons learned. AB - OBJECTIVES: The aim of this study was to describe the techniques used in achieving consensus on common standards to be implemented in the EUnetHTA Information Management System (IMS); and to describe how interoperability between tools was explored. METHODS: Three face to face meetings were organized to identify and agree on common standards to the development of online tools. Two tools were created to demonstrate the added value of implementing interoperability standards at local levels. Developers of tools outside EUnetHTA were identified and contacted. RESULTS: Four common standards have been agreed on by consensus; and consequently all EUnetHTA tools have been modified or designed accordingly. RDF Site Summary (RSS) has demonstrated a good potential to support rapid dissemination of HTA information. Contacts outside EUnetHTA resulted in direct collaboration (HTA glossary, HTAi Vortal), evaluation of options for interoperability between tools (CRD HTA database) or a formal framework to prepare cooperation on concrete projects (INAHTA projects database). CONCLUSIONS: While being entitled a project on IT infrastructure, the work program was also about people. When having to agree on complex topics, fostering a cohesive group dynamic and hosting face to face meetings brings added value and enhances understanding between partners. The adoption of widespread standards enhanced the homogeneity of the EUnetHTA tools and should thus contribute to their wider use, therefore, to the general objective of EUnetHTA. The initiatives on interoperability of systems need to be developed further to support a general interoperable information system that could benefit the whole HTA community. PMID- 25747562 TI - Piloting international production of rapid relative effectiveness assessments of pharmaceuticals. AB - BACKGROUND: This article describes the lessons learned from an international pilot assessment using the first version of the HTA Core Model(r) and Guidelines for rapid Relative Effectiveness Assessment (REA) of pharmaceuticals based on input from three different perspectives: the assessors, the users (health technology assessment organisations) and the marketing authorisation holder. METHODS: A pilot assessment was performed of pazopanib for the treatment of advanced or metastatic renal cell carcinoma for which 54 individuals from 22 EUnetHTA member organisations from 16 European countries gave their contribution. The work was divided in eight domain teams. Subsequently, results of these domain teams were synthesised in one pilot report. Feedback on the outcomes of the pilot was gathered throughout the project and through structured surveys. RESULTS: The first version of the assessment was produced in six months and consisted of 55 question and answer pairs, 8 domain reports and a synthesis section that combined the results from the different domains. The organisation of the pilot required intense coordination. Main points of criticism on the assessment were the lengthiness of the document and overlap of information throughout the assessment. CONCLUSIONS: A reduction in the number of authoring organisations and individuals participating is necessary to avoid information overlap and increase efficiency in undertaking the assessment. Involving several organisations (e.g. five) in an in-depth review could still ensure the benefit of broad participation from various countries. The focus of a rapid REA should be on the first four domains of the Model. PMID- 25747563 TI - Comparing the hta core model with a national health technology assessment report. AB - OBJECTIVES: The HTA Core Model is a framework for producing health technology assessments (HTAs) in a structured format. The Model splits the content of a HTA into assessment elements. The objective is to explore the adaptability of these assessment elements in national report production in a pilot case study comparing a national HTA report and the HTA Core Model. METHODS: An on-going Dutch HTA report on endovascular repair of abdominal aortic aneurysm (EVAR) was chosen as a typical representative of a national report on medical interventions. The author of the EVAR report assessed the relevance and comprehensiveness of the assessment elements of the HTA Core Model for her work. Another researcher annotated the Core Model specific content in the EVAR report. Matching and missing content, as well as the distribution of information in the EVAR report were tabulated and analysed in joint deliberations. RESULTS: Forty percent of the assessment elements of the Core Model were considered relevant for the EVAR report. Some issues relevant for EVAR but missing from the Core Model were identified: they were about re-interventions, secondary prevention, subpopulations that benefit most, and the length of the hospital stay. The distribution of information differed substantially between the Code Model and the national report. CONCLUSIONS: The assessment elements of the HTA Core Model covered most relevant questions of the national report. In order to facilitate easy adaptation of information, the distribution of information should be more consistent in the national report and the Core model. PMID- 25747564 TI - Collaborative models for the joint production of core health technology assessments: negative and positive aspects for the joint work of different European agencies. AB - OBJECTIVES: The purpose of the European network for Health Technology Assessment (EUnetHTA) is to make HTA agencies collaborate sharing methods and tools thus avoiding duplication of evaluative efforts and allowing resource savings. From 2010 to 2012, the activities of the network were carried out through EUnetHTA Joint Action 1 and Work Package 4 Strand B aimed at producing two Core HTAs with two main objectives: to test the Web based Core model and the collaborative working models. Our objective in this article is to give an historical record of the Work Package activities highlighting what worked and what did not in the collaboration of researchers' groups coming from different agencies. METHODS: A retrospective description of all the steps for the joint production of the two Core HTAs is provided starting from the first step of selecting technologies of common interest. Primary researchers' views on the whole process have been collected through a semi-structured telephonic interview supported by a questionnaire. Coordinators views were gathered during internal meetings and validated. RESULTS: Majority of respondents thought topic selection procedure was not clear and well managed. About collaborative models, small groups were seen to enable more exchange, whatever the model. According to coordinators, loss of expertise and experience during the production process, different languages, and novelty of the Online Tool were main barriers. CONCLUSIONS: Lessons learned from this first experience in Joint Action 1 paved the path for the collaboration in Joint Action 2, as it allowed enhancements and changes in models of collaborations and coordination. PMID- 25747565 TI - Success factors for international HTA projects: evaluating EUnetHTA Joint Action as an exemplar. AB - OBJECTIVES: Evaluation is essential for the management of international projects or networks in health technology assessment (HTA). It extends beyond the normal process of project management by incorporating qualitative dimensions and provides information about a project's effectiveness and achievements. This article aimed to identify the factors that are important for the success of international HTA projects. The European network for Health Technology Assessment Joint Action (EUnetHTA JA) is presented as an exemplar. METHODS: METHODS for the evaluation of international HTA projects include interviews, focus groups, questionnaires, observations and documentary review, and the key points of these approaches have been summarized. The impact and effectiveness of the EUnetHTA JA was evaluated by questionnaires of project participants and external stakeholders, and by documentary review. RESULTS: The response rate for the three annual questionnaires sent to project participants ranged from 86 percent to 88 percent and for external stakeholders ranged from 65 percent to 88 percent. Key factors for project success included production of deliverables according to the workplan, achievement of objectives, added value generated, effective communication, involvement of external stakeholders, workstream management and progress from the preceding EUnetHTA 2006-2008 project. CONCLUSIONS: The experience of this project can inform the evaluation of future international HTA collaborations, such as the EUnetHTA 2nd Joint Action and HTAsiaLink. A high response rate was achieved to the self-completion questionnaires and the strategy followed is recommended for evaluation of international HTA projects. Future assessments of international HTA projects should strive to measure outcomes and impact, not just outputs and process. PMID- 25747566 TI - Big data! Big deal? PMID- 25747567 TI - Applications and limitations of the concept of 'avoidable mortality' among immigrant groups in Europe: a scoping review. AB - OBJECTIVES: Avoidable mortality is often used as a key indicator of broader health inequalities. Health inequalities refer to unfair differences in the quality of health and wellbeing, and health care across different populations. This includes differences in the presence of disease, health outcomes, or access to health care. Migrants represent a disadvantaged and growing demographic with special health risks. This study analyses the usages of the concept of avoidable mortality as applied in studies on migrants in Europe. In doing so, the study aims to identify the strengths and limitations of the concept of avoidable mortality for comparative work. STUDY DESIGN: A scoping review was conducted for the period of 1990-2011. METHODS: Publications were identified by a systematic search of PUBMED and WEB OF SCIENCE. An additional five publications were found through the search via references. A total number of 37 publications from 10 European countries were included in the analysis. RESULTS: The authors divided studies according to direct versus indirect usage of the concept. Studies with direct usage of the concept established a correlation between patterns of avoidable mortality and health care system performance. Additionally, they searched studies which indirectly used avoidable mortality to examine further evidence for the strengths and weaknesses of the concept. These studies used indicators of amenable mortality (at times alongside other mortality indicators) without making direct reference to the concept. Findings using both approaches identified a similar trend in principal causes of premature death. The difference between the two types of studies concerned the more detailed analysis of the causes of death in studies with direct usage categorising into treatable versus preventable causes of death, or health policy versus medical intervention. CONCLUSIONS: The results of this article highlight the role of health care systems in contributing to migrant health outcomes: whereas mixed outcomes across a number of indicators of avoidable mortality used indirectly do arise, the large number of studies - especially those using the concept directly - evidence a higher share of premature mortality for migrants compared to host populations. These findings can provide policy makers with important insights into targeted ways of improving the access and quality of health services for marginalised populations. However, the strength and depth of such insights stand to improve, as current research on avoidable mortality is often indirect (rather than overt and systematic), thereby limiting the potential for cross-national comparison, as well as a clearer understanding of the links between health outcomes and health care system performance for a disadvantaged group. PMID- 25747568 TI - Forecasts of health care utilization related to pandemic A(H1N1)2009 influenza in the Nord-Pas-de-Calais region, France. AB - OBJECTIVES: To describe and evaluate the forecasts of the load that pandemic A(H1N1)2009 influenza would have on the general practitioners (GP) and hospital care systems, especially during its peak, in the Nord-Pas-de-Calais (NPDC) region, France. STUDY DESIGN: Modelling study. METHODS: The epidemic curve was modelled using an assumption of normal distribution of cases. The values for the forecast parameters were estimated from a literature review of observed data from the Southern hemisphere and French Overseas Territories, where the pandemic had already occurred. Two scenarios were considered, one realistic, the other pessimistic, enabling the authors to evaluate the 'reasonable worst case'. Forecasts were then assessed by comparing them with observed data in the NPDC region--of 4 million people. RESULTS: The realistic scenarios forecasts estimated 300,000 cases, 1500 hospitalizations, 225 intensive care units (ICU) admissions for the pandemic wave; 115 hospital beds and 45 ICU beds would be required per day during the peak. The pessimistic scenario's forecasts were 2-3 times higher than the realistic scenario's forecasts. Observed data were: 235,000 cases, 1585 hospitalizations, 58 ICU admissions; and a maximum of 11.6 ICU beds per day. CONCLUSIONS: The realistic scenario correctly estimated the temporal distribution of GP and hospitalized cases but overestimated the number of cases admitted to ICU. Obtaining more robust data for parameters estimation--particularly the rate of ICU admission among the population that the authors recommend to use--may provide better forecasts. PMID- 25747569 TI - Hidden disorder propensity of the N-terminal segment of universal adapter protein 14-3-3 is manifested in its monomeric form: Novel insights into protein dimerization and multifunctionality. AB - The multiplicity of functions of 14-3-3 proteins, integrated into many cellular interactions and signaling networks, is primarily based upon their dimeric alpha helical structure that is capable of binding phosphorylated protein partners as well as displaying a "moonlighting" chaperone-like activity. The structure and functions of 14-3-3 proteins are regulated in different ways, including Ser58 phosphorylation in the interface, which shifts equilibrium towards the formation of protein monomers whose role is poorly understood. While modification of Ser58 induced only partial dissociation, the engineered triple mutation of human 14-3 3zeta located in the first alpha-helix deeply monomerized the protein, allowing for a structural analysis of the monomeric form. Dimer-incapable 14-3-3 proteins retained binding capacity and specificity towards some phosphopartners, and also demonstrated increased chaperone-like activity on various substrates. Here, we found a substantial propensity of the N-terminal segment (~40 residues) of 14-3-3 proteins to intrinsic disorder, showing remarkable conservation across different isoforms and organisms. We hypothesized that this intrinsic disorder propensity, hidden in the alpha-helical 14-3-3 dimer, can be manifested upon its dissociation and interrogated novel monomeric 14-3-3zeta carrying both monomerizing and S58E mutations (14-3-3zetamS58E). CD spectroscopy showed that, at physiological temperatures, this protein has ~10-15% reduced helicity relative to the wild type protein, corresponding to roughly 40 residues. Along with the known flexibility of C-terminus, SAXS-based modeling of the 14-3-3zetamS58E structure strongly suggested pliability of its N-terminus. The unraveled disorder propensity of the N-terminal tails of 14-3-3 proteins provides new clues for better understanding of the molecular mechanisms of dimerization and multifunctionality of these universal adapter proteins. PMID- 25747570 TI - Rats anticipate damaged rungs on the elevated ladder: Applications for rodent models of Parkinson's disease. AB - The present study examined rats' ability to anticipate undetectable wider gaps between rungs produced when they stepped on and dislodged damaged rungs while they traversed a slightly inclined elevated ladder. Rats in the first of three experiments reduced running speeds when they encountered four evenly spaced damaged rungs either always placed on the first or second half of the ladder (the break-a-way (BW) phase) but quickly recovered to their baseline (BL) levels when damaged rungs where replaced with intact rungs (the recovery phase). Rats previously exposed to damaged rungs over the first half of the ladder increased their speeds above BL on its second "safer" half during the recovery phase, a delayed "relief-like" positive contrast effect. In Experiment 2, other rats decreased their speeds more as they approached a single damaged rung at a fixed location when it occurred before than after the mid-point of the ladder. Although they quickly recovered to BL speeds on the portion of the ladder after the damaged rung or replaced intact rung, they never showed any "relief-like"/escape effects. Rats also reduced their likelihood of dislodging the damaged rung with a fore paw over extended BW training. In the third experiment rats encountered a more easily dislodged damaged rung that was signaled by a closer intact rung on half the trials. Under these conditions rats displayed a more reliable positive contrast "relief-like" effect. We discussed how traditional associative and cognitive theories of aversive conditioning account for these findings and their relationship to normal changes in dopamine production and possible effects of reduced production from the substantia nigra pars compacta (SNpc) in the Basal ganglia in rodent models of Parkinson's disease. PMID- 25747571 TI - Report predicts US physician shortage could exceed 90,000 by 2025. PMID- 25747572 TI - Prevalence and associations of erectile dysfunction in a sample of Italian males with type 2 diabetes. AB - AIM: The aim of this study was to evaluate the prevalence of erectile dysfunction (ED) in a sample of type 2 diabetic patients. As secondary endpoint, we evaluated the levels of some adipocytokines in patients with and without ED. MATERIAL AND METHODS: We enrolled 220 males affected by type 2 diabetes mellitus. We administered the IIEF (International Index of Erectile Function), SAS (self rating anxiety scale) and SDS (self-rating depression scale) questionnaires. We evaluated body mass index, glycemic control, fasting plasma insulin (FPI), homeostasis model assessment of insulin resistance index (HOMA-IR), lipid profile, sexual hormones, adiponectin (ADN), resistin, retinol binding protein-4 (RBP-4), visfatin, vaspin. RESULTS: 52.9% of patients were affected by ED. Patients with a HbA1c <7% (53 mmol/mol) in all measurements in the two previous years had a lower incidence of ED, while the prevalence of ED increased with the increasing of times HbA1c was >7% (53 mmol/mol). Patients with ED had higher levels of triglycerides, and higher levels of FPI, 9.9 MUU/ml vs 8.2 MUU/ml (p<0.05). Resistin levels were higher in patients with ED compared to those without ED (p<0.05) and free testosterone was lower in patients affected by ED. CONCLUSIONS: Almost half of type 2 diabetic patients attending our clinic were affected by ED and glycemic control seems to play a role in ED pathogenesis. PMID- 25747573 TI - Mapping the structure of perceptual and visual-motor abilities in healthy young adults. AB - The ability to quickly detect and respond to visual stimuli in the environment is critical to many human activities. While such perceptual and visual-motor skills are important in a myriad of contexts, considerable variability exists between individuals in these abilities. To better understand the sources of this variability, we assessed perceptual and visual-motor skills in a large sample of 230 healthy individuals via the Nike SPARQ Sensory Station, and compared variability in their behavioral performance to demographic, state, sleep and consumption characteristics. Dimension reduction and regression analyses indicated three underlying factors: Visual-Motor Control, Visual Sensitivity, and Eye Quickness, which accounted for roughly half of the overall population variance in performance on this battery. Inter-individual variability in Visual Motor Control was correlated with gender and circadian patters such that performance on this factor was better for males and for those who had been awake for a longer period of time before assessment. The current findings indicate that abilities involving coordinated hand movements in response to stimuli are subject to greater individual variability, while visual sensitivity and occulomotor control are largely stable across individuals. PMID- 25747574 TI - Selective deficits in episodic feeling of knowing in ageing: a novel use of the general knowledge task. AB - Failure to recall an item from memory can be accompanied by the subjective experience that the item is known but currently unavailable for report. The feeling of knowing (FOK) task allows measurement of the predictive accuracy of this reflective judgement. Young and older adults were asked to provide answers to general knowledge questions both prior to and after learning, thus measuring both semantic and episodic memory for the items. FOK judgements were made at each stage for all unrecalled responses, providing a measure of predictive accuracy for semantic and episodic knowledge. Results demonstrated a selective effect of age on episodic FOK resolution, with older adults found to have impaired episodic FOK accuracy while semantic FOK accuracy remained intact. Although recall and recognition measures of episodic memory are equivalent between the two age groups, older adults may have been unable to access contextual details on which to base their FOK judgements. The results suggest that older adults are not able to accurately predict future recognition of unrecalled episodic information, and consequently may have difficulties in monitoring recently encoded memories. PMID- 25747575 TI - The relationship between social anxiety and the perception of depth-ambiguous biological motion stimuli is mediated by inhibitory ability. AB - Orthographically projected biological motion stimuli are depth-ambiguous. Consequently, their projection when oriented towards the viewer is the same as when oriented away. Despite this, observers tend to interpret such stimuli as facing the viewer more often. Some have speculated that this facing-the-viewer bias may exist for sociobiological reasons: Mistaking another human as retreating when they are actually approaching could have more severe consequences than the opposite error. An implication of this theory is that the facing-towards percept may be perceived as more threatening than the facing-away percept. Given this, as well as the finding that anxious individuals have been found to display an attentional bias towards threatening stimuli, we reasoned that more anxious individuals might have stronger facing-the-viewer biases. Furthermore, since anxious individuals have been found to perform poorer on inhibition tasks, we hypothesized that inhibitory ability would mediate the relationship between anxiety and the facing-the-viewer bias (i.e., difficulty inhibiting the threatening percept). Exploring individual differences, we asked participants to complete anxiety questionnaires, to perform a Go/No-Go task, and then to complete a perceptual task that allowed us to assess their facing-the-viewer biases. As hypothesized, we found that both greater anxiety and weaker inhibitory ability were associated with greater facing-the-viewer biases. In addition, we found that inhibitory ability significantly mediated the relationship between anxiety and facing-the-viewer biases. Our results provide further support that the facing-the viewer bias is sensitive to the sociobiological relevance of biological motion stimuli, and that the threat bias for ambiguous visual stimuli is mediated by inhibitory ability. PMID- 25747576 TI - The illusion of nonmediation in telecommunication: voice intensity biases distance judgments to a communication partner. AB - The illusion of nonmediation is an experience in mediated communication where individuals respond as if the medium is not there. It is frequently associated with advanced media technology, such as virtual environments and teleconference systems. In this paper, we investigate whether people experience an illusion of nonmediation during interactions as simple as making a phone call. In three experiments, participants were asked to listen to someone's voice on a mobile phone (Experiment 1) or through VoIP software (Experiment 2 and 3) before guessing the location of the person and indicating this location on a map. Results consistently demonstrated that louder voices were judged to be closer, as if the technical mediation was ignored. Combining the three experiments, a small scale meta-analysis yielded an effect size estimate of d=0.37 for the 'louder-as closer' effect. Implications of the results and suggestions for future research are discussed. PMID- 25747577 TI - Therapeutic effects of human multilineage-differentiating stress enduring (MUSE) cell transplantation into infarct brain of mice. AB - OBJECTIVE: Bone marrow stromal cells (BMSCs) are heterogeneous and their therapeutic effect is pleiotropic. Multilineage-differentiating stress enduring (Muse) cells are recently identified to comprise several percentages of BMSCs, being able to differentiate into triploblastic lineages including neuronal cells and act as tissue repair cells. This study was aimed to clarify how Muse and non Muse cells in BMSCs contribute to functional recovery after ischemic stroke. METHODS: Human BMSCs were separated into stage specific embryonic antigen-3 positive Muse cells and -negative non-Muse cells. Immunodeficient mice were subjected to permanent middle cerebral artery occlusion and received transplantation of vehicle, Muse, non-Muse or BMSCs (2.5*104 cells) into the ipsilateral striatum 7 days later. RESULTS: Motor function recovery in BMSC and non-Muse groups became apparent at 21 days after transplantation, but reached the plateau thereafter. In Muse group, functional recovery was not observed for up to 28 days post-transplantation, but became apparent at 35 days post transplantation. On immunohistochemistry, only Muse cells were integrated into peri-infarct cortex and differentiate into Tuj-1- and NeuN-expressing cells, while negligible number of BMSCs and non-Muse cells remained in the peri-infarct area at 42 days post-transplantation. CONCLUSIONS: These findings strongly suggest that Muse cells and non-Muse cells may contribute differently to tissue regeneration and functional recovery. Muse cells may be more responsible for replacement of the lost neurons through their integration into the peri-infarct cortex and spontaneous differentiation into neuronal marker-positive cells. Non Muse cells do not remain in the host brain and may exhibit trophic effects rather than cell replacement. PMID- 25747579 TI - MiRNAcles in the Brain: what to wish and what to fear. PMID- 25747578 TI - The role of Misshapen NCK-related kinase (MINK), a novel Ste20 family kinase, in the IRES-mediated protein translation of human enterovirus 71. AB - Human Enterovirus 71 (EV71) commonly causes Hand, Foot and Mouth Disease in young children, and occasional occurrences of neurological complications can be fatal. In this study, a high-throughput cell-based screening on the serine/threonine kinase siRNA library was performed to identify potential antiviral agents against EV71 replication. Among the hits, Misshapen/NIKs-related kinase (MINK) was selected for detailed analysis due to its strong inhibitory profile and novelty. In the investigation of the stage at which MINK is involved in EV71 replication, virus RNA transfection in MINK siRNA-treated cells continued to cause virus inhibition despite bypassing the normal entry pathway, suggesting its involvement at the post-entry stage. We have also shown that viral RNA and protein expression level was significantly reduced upon MINK silencing, suggesting its involvement in viral protein synthesis which feeds into viral RNA replication process. Through proteomic analysis and infection inhibition assay, we found that the activation of MINK was triggered by early replication events, instead of the binding and entry of the virus. Proteomic analysis on the activation profile of p38 Mitogen-activated Protein Kinase (MAPK) indicated that the phosphorylation of p38 MAPK was stimulated by EV71 infection upon MINK activation. Luciferase reporter assay further revealed that the translation efficiency of the EV71 internal ribosomal entry site (IRES) was reduced after blocking the MINK/p38 MAPK pathway. Further investigation on the effect of MINK silencing on heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) localisation demonstrated that cytoplasmic relocalisation of hnRNP A1 upon EV71 infection may be facilitated via the MINK/p38 MAPK pathway which then positively regulates the translation of viral RNA transcripts. These novel findings hence suggest that MINK plays a functional role in the IRES-mediated translation of EV71 viral RNA and may provide a potential target for the development of specific antiviral strategies against EV71 infection. PMID- 25747580 TI - Delivery of the growth restricted preterm fetus. PMID- 25747581 TI - Boko Haram insurgency: implications for public health. PMID- 25747582 TI - 2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial. AB - BACKGROUND: No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV). METHODS: In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26-32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs >=29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499. FINDINGS: Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30.7 weeks (IQR 29.1-32.1) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0.09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 140, 95%, 95% CI 90-98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78-90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality. INTERPRETATION: Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age. FUNDING: ZonMw, The Netherlands and Dr Hans Ludwig Geisenhofer Foundation, Germany. PMID- 25747584 TI - NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients With Acute Coronary Syndromes: Genome-Wide Association Study in the PLATelet inhibition and patient Outcomes Trial (PLATO). AB - BACKGROUND: Interleukin 18 (IL-18) promotes atherosclerotic plaque formation and is increased in patients with acute coronary syndromes. However the relative contribution of genetic variants to the IL-18 levels has not been fully determined. METHODS AND RESULTS: Baseline plasma IL-18 levels were measured in 16 633 patients with acute coronary syndrome, of whom 9340 had genetic data that passed genotype quality control. A 2-stage genome-wide association study was performed, followed by combined analyses using >10 million genotyped or imputed genetic markers. Single nucleotide polymorphisms at 3 loci (IL18, NLRC4, and MROH6) were identified (P<3.15*10(-8)) in the discovery cohort (n=3777) and replicated in the remaining patients (n=5563). In the pooled data (discovery+replication cohort), 7 independent associations, in 5 chromosomal regions, were associated with IL-18 levels (minimum P=6.99*10(-72)). Six single nucleotide polymorphisms are located in predicted promoter regions of which one disrupts a transcription factor binding site. One single nucleotide polymorphism in NLRC4 is a rare missense variant, predicted to be deleterious to the protein. Altogether, the identified genetic variants explained 8% of the total variation in IL-18 levels in the cohort. CONCLUSIONS: Our results show that genetic variants play an important role in determining IL-18 levels in patients with acute coronary syndrome and we have identified genetic variants located in the IL 18 gene (IL18) or close to genes that are involved in procaspase-1 activation (NLRC4 and CARD16, CARD17, and CARD18). These associations also highlight the importance of the NLRC4 inflammasome for IL-18 production in acute coronary syndrome patients. PMID- 25747583 TI - SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest. AB - Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD 208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD 208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment. PMID- 25747586 TI - The Mommy and Me Play Program: a pilot play intervention for low-income, African American preschool families. AB - In this study the author examined the effects of a dyadic, mother-paired play intervention-The Mommy and Me Play Program-an innovative intervention program designed using a live-action modeling technique in which mothers serve as "natural helpers" to each other. By identifying natural strengths in mothers and employing opportunities for scaffolded learning, this intervention aimed to enhance mother-child play interactions and children's social and emotional competence. Fifty mother-child dyads from a single, low-income, African American, urban community were assessed in this study on measures of mother-child play interactions and children's social and emotional competency. Results from this pilot were not statistically significant, but provide important information regarding future research with this intervention program. These preliminary findings indicated that mothers with fewer play skills pre-intervention demonstrated improvement in their play skills post-intervention beyond other intervention participants; and children of those same mothers showed the greatest decrease in angry and aggressive behaviors in the classroom when compared to other participating children from pre- to post-intervention. Implications for research and practice in community-based, intervention work with low-income, ethnic-minority families are discussed. PMID- 25747587 TI - Lack of an effect of nephron-specific deletion of adenylyl cyclase 3 on renal sodium and water excretion or arterial pressure. AB - Adenylyl cyclase (AC)-stimulated cAMP plays a key role in modulating transport and channel activity along the nephron. However, the role of individual adenylyl cyclase isoforms in such regulation is largely unknown. Since adenylyl cyclase 3 (AC3) is expressed throughout nephron, we investigated its role in the physiologic regulation of renal Na(+) and water transport. Mice were generated with inducible nephron knockout of AC3 (AC3 KO) by breeding mice with loxP flanked critical exons in the Adcy3 gene with mice expressing Pax8-rtTA and LC-1 transgenes. After doxycycline treatment at 1 month of age, nephron AC3 KO mice had 100% Adcy3 gene recombination in all renal tubule segments, but not in glomeruli. Sodium intake, urinary Na(+) excretion, glomerular filtration rate, and blood pressure were similar between nephron KO mice and the controls during normal, high, and low Na(+) diets. Plasma renin concentration was not different between the two groups during varied Na(+) intake. Moreover, there were no differences in urine volume and urine osmolality between the two genotypes during normal or restricted water intake. In conclusion, these data suggested that AC3 is not involved in the physiological regulation of nephron Na(+) and water handling. PMID- 25747585 TI - Blood pressure in relation to general and central adiposity among 500 000 adult Chinese men and women. AB - BACKGROUND: Greater adiposity is associated with higher blood pressure. Substantial uncertainty remains, however, about which measures of adiposity most strongly predict blood pressure and whether these associations differ materially between populations. METHODS: We examined cross-sectional data on 500 000 adults recruited from 10 diverse localities across China during 2004-08. Multiple linear regression was used to estimate the effects on systolic blood pressure (SBP) of general adiposity [e.g. body mass index (BMI), body fat percentage, height adjusted weight] vs central adiposity [e.g. waist circumference (WC), hip circumference (HC), waist-hip ratio (WHR)], before and after adjustment for each other. The main analyses excluded those reported taking any antihypertensive medication, and were adjusted for age, region and education. RESULTS: The overall mean [standard deviation (SD)] BMI was 23.6 (3.3) kg/m(2) and mean WC was 80.0 (9.5) cm. The differences in SBP (men/women, mmHg) per 1SD higher general adiposity (height-adjusted weight: 6.6/5.6; BMI: 5.5/4.9; body fat percentage: 5.5/5.0) were greater than for central adiposity (WC: 5.0/4.3; HC: 4.8/4.1; WHR: 3.7/3.2), with a 10 kg/m(2) greater BMI being associated on average with 16 (men/women: 17/14) mmHg higher SBP. The associations of blood pressure with measures of general adiposity were not materially altered by adjusting for WC and HC, but those for central adiposity were significantly attenuated after adjusting for BMI (WC: 1.1/0.7; HC: 0.3/-0.2; WHR: 0.6/0.6). CONCLUSION: In adult Chinese, blood pressure is more strongly associated with general adiposity than with central adiposity, and the associations with BMI were about 50% stronger than those observed in Western populations. PMID- 25747588 TI - Contrasting effects of hyperoxia on GM-CSF gene transcription in alveolar epithelial cells and T cells. AB - Granulocyte/macrophage colony-stimulating factor (GM-CSF) is critically important for normal pulmonary innate immunity and for functional maturation of alveolar macrophages. Alveolar epithelial cells (AEC) are a major source of GM-CSF in the lung and express this growth factor constitutively, whereas most other cells, including T cells, express GM-CSF following inflammatory stimulation. AEC expression of GM-CSF is suppressed by oxidative stress, at least in part through induction of microRNA leading to increased mRNA turnover. In this report, we compare and contrast the effect of hyperoxia on transcriptional aspects of gene regulation of GM-CSF in lung epithelia and T cells of human and mouse origin. Similar to primary murine AEC, human H820 cells that express multiple characteristics of normal alveolar epithelial cells express GM-CSF constitutively, with decreased expression and increased mRNA turnover following exposure to hyperoxia. In contrast, hyperoxia induces augmented GM-CSF expression in human and murine activated T cells, in association with enhanced GM-CSF mRNA stability. Alveolar epithelial cells demonstrate constitutive transcription, with the proximal promoter in an open configuration in normoxia, without change in hyperoxia. Conversely, in both human and murine T cells, hyperoxia increased GM CSF gene transcription. The proximal promoter was in a closed configuration in unstimulated T cells but became accessible upon activation and still more accessible in activated T cells exposed to hyperoxia. These fundamental differences in molecular regulation of GM-CSF expression highlight the distinctive niche of alveolar epithelial cell expression of GM-CSF and offer insights into the biology of GM-CSF in the setting of acute lung injury. PMID- 25747589 TI - Concurrent chemotherapy for T4 classification nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy. AB - OBJECTIVE: To evaluate concurrent chemotherapy for T4 classification nasopharyngeal carcinoma (NPC) treated by intensity-modulated radiotherapy (IMRT). METHODS: From July 2004 to June 2011, 180 non-metastatic T4 classification NPC patients were retrospectively analyzed. Of these patients, 117 patients were treated by concurrent chemoradiotherapy (CCRT) using IMRT and 63 cases were treated by IMRT alone. RESULTS: The median follow-up time was 58.97 months (range, 2.79-114.92) months. For all the patients, the 1, 3 and 5-year local failure-free survival (LFFS) rates were 97.7%, 89.2% and 85.9%, regional failure free survival (RFFS) rates were 98.9%, 94.4% and 94.4%, distant failure free survival (DFFS) rates were 89.7%, 79.9% and 76.2%, and overall survival (OS) rates were 92.7%, 78.9% and 65.3%, respectively. No statistically significant difference was observed in LFFS, RFFS, DFFS and OS between the CCRT group and the IMRT alone group. No statistically significant difference was observed in acute toxicity except leukopenia (p = 0.000) during IMRT between the CCRT group and the IMRT alone group. CONCLUSION: IMRT alone for T4 classification NPC achieved similar treatment outcomes in terms of disease local control and overall survival as compared to concurrent chemotherapy plus IMRT. However, this is a retrospective study with a limited number of patients, such results need further investigation in a prospective randomized clinical trial. PMID- 25747590 TI - Biostructural Science Inspired by Next-Generation X-Ray Sources. AB - Next-generation synchrotron radiation sources, such as X-ray free-electron lasers, energy recovery linacs, and ultra-low-emittance storage rings, are catalyzing novel methods of biomolecular microcrystallography and solution scattering. These methods are described and future trends are predicted. Importantly, there is a growing realization that serial microcrystallography and certain cutting-edge solution scattering experiments can be performed at existing storage ring sources by utilizing new technology. In this sense, next-generation sources are serving two distinct functions, namely, provision of new capabilities that require the newer sources and inspiration of new methods that can be performed at existing sources. PMID- 25747592 TI - Contemporary NMR Studies of Protein Electrostatics. AB - Electrostatics play an important role in many aspects of protein chemistry. However, the accurate determination of side chain proton affinity in proteins by experiment and theory remains challenging. In recent years the field of nuclear magnetic resonance spectroscopy has advanced the way that protonation states are measured, allowing researchers to examine electrostatic interactions at an unprecedented level of detail and accuracy. Experiments are now in place that follow pH-dependent (13)C and (15)N chemical shifts as spatially close as possible to the sites of protonation, allowing all titratable amino acid side chains to be probed sequence specifically. The strong and telling response of carefully selected reporter nuclei allows individual titration events to be monitored. At the same time, improved frameworks allow researchers to model multiple coupled protonation equilibria and to identify the underlying pH dependent contributions to the chemical shifts. PMID- 25747591 TI - Single-Cell Physiology. AB - Single-cell techniques have a long history of unveiling fundamental paradigms in biology. Recent improvements in the throughput, resolution, and availability of microfluidics, computational power, and genetically encoded fluorescence have led to a modern renaissance in microbial physiology. This resurgence in research activity has offered new perspectives on physiological processes such as growth, cell cycle, and cell size of model organisms such as Escherichia coli. We expect these single-cell techniques, coupled with the molecular revolution of biology's recent half-century, to continue illuminating unforeseen processes and patterns in microorganisms, the bedrock of biological science. In this article we review major open questions in single-cell physiology, provide a brief introduction to the techniques for scientists of diverse backgrounds, and highlight some pervasive issues and their solutions. PMID- 25747593 TI - Mechanisms of Autophagy. AB - The formation of the autophagosome, a landmark event in autophagy, is accomplished by the concerted actions of Atg proteins. The initial step of starvation-induced autophagy in yeast is the assembly of the Atg1 complex, which, with the help of other Atg groups, recruits Atg conjugation systems and initiates the formation of the autophagosome. In this review, we describe from a structural biological point of view the structure, interaction, and molecular roles of Atg proteins, especially those in the Atg1 complex and in the Atg conjugation systems. PMID- 25747594 TI - Roles for Synonymous Codon Usage in Protein Biogenesis. AB - Owing to the degeneracy of the genetic code, a protein sequence can be encoded by many different synonymous mRNA coding sequences. Synonymous codon usage was once thought to be functionally neutral, but evidence now indicates it is shaped by evolutionary selection and affects other aspects of protein biogenesis beyond specifying the amino acid sequence of the protein. Synonymous rare codons, once thought to have only negative impacts on the speed and accuracy of translation, are now known to play an important role in diverse functions, including regulation of cotranslational folding, covalent modifications, secretion, and expression level. Mutations altering synonymous codon usage are linked to human diseases. However, much remains unknown about the molecular mechanisms connecting synonymous codon usage to efficient protein biogenesis and proper cell physiology. Here we review recent literature on the functional effects of codon usage, including bioinformatics approaches aimed at identifying general roles for synonymous codon usage. PMID- 25747595 TI - Selenopeptides and elemental selenium in Thunbergia alata after exposure to selenite: quantification method for elemental selenium. AB - Three month old Thunbergia alata were exposed for 13 days to 10 MUM selenite to determine the biotransformation of selenite in their roots. Selenium in formic acid extracts (80 +/- 3%) was present as selenopeptides with Se-S bonds and selenium-PC complexes (selenocysteinyl-2-3-dihydroxypropionyl-glutathione, seleno phytochelatin2, seleno-di-glutathione). An analytical method using HPLC-ICPMS to detect and quantify elemental selenium in roots of T. alata plants using sodium sulfite to quantitatively transform elemental selenium to selenosulfate was also developed. Elemental selenium was determined as 18 +/- 4% of the total selenium in the roots which was equivalent to the selenium not extracted using formic acid extraction. The results are in an agreement with the XAS measurements of the exposed roots which showed no occurrence of selenite or selenate but a mixture of selenocysteine and elemental selenium. PMID- 25747596 TI - Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus. AB - BACKGROUND & AIMS: The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS: A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS: The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5 aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5 ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS: Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success. PMID- 25747599 TI - Novel stilbenes from Artocarpus nanchuanensis. AB - Four new stilbene derivatives, hypargystilbenes B-E (1-4), together with seven known compounds (5-11), were isolated from the stems of Artocarpus nanchuanensis S.S. Chang. Their structures were elucidated on the basis of spectral data. Hypargystilbene B, hypargystilbene D, and hypargystilbene E exhibited protein tyrosine phosphatase 1B inhibitory effects with corresponding IC50 values of 3.23, 37.31, and 2.53 nM. PMID- 25747597 TI - gammadelta Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. AB - BACKGROUND & AIMS: Intraepithelial lymphocytes that express the gammadelta T-cell receptor (gammadelta IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether gammadelta IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection. METHODS: Salmonella typhimurium or Toxoplasma gondii were administered to knockout (KO) mice lacking either the T cell receptor delta chain (Tcrd) or CD103, or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of green fluorescent protein (GFP)-tagged gammadelta T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of gammadelta IEL migration on early pathogen invasion and chronic systemic infection. RESULTS: Morphometric analyses of intravital video microscopy data showed that gammadelta IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hour, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO gammadelta T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient gammadelta T cells, whereas invasion in CD103 KO mice, which have increased migration of gammadelta T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of gammadelta T cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient gammadelta IELs, relative to those with wild-type or CD103 KO gammadelta IELs. CONCLUSIONS: In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to gammadelta IEL surveillance and immediate host defense. gammadelta IEL occludin is required for early surveillance that limits systemic disease. PMID- 25747598 TI - The emperor's new clothes: PDE5 and the heart. AB - Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design. PMID- 25747600 TI - Associations of IL-2 and IL-4 Expression and Polymorphisms With the Risks of Mycoplasma pneumoniae Infection and Asthma in Children. AB - INTRODUCTION: Asthma is an inflammatory disorder of the airways and the symptoms of asthma could be exacerbated by Mycoplasma pneumoniae infection. Interleukin-2 and interleukin-4 have been implicated in immune and inflammatory reactions. We examined the associations of IL2 and IL4 polymorphisms and expression with the risks of asthma and M. pneumoniae infection in children. METHODS: 392 asthmatic children and 849 controls were recruited into the study. Eight polymorphisms in IL2 and IL4 were genotyped with Sequenom MassARRAY platform. M. pneumoniae infection and copy number was determined with fluorescence PCR. IL-2 and IL-4 serum expression levels were determined by using ELISA. RESULTS: We found a significant association of IL2 rs6534349 polymorphism with increased asthma risk (heterozygotes, P=.029; homozygous variants; P=.013) and of IL4 rs2227284 polymorphism with reduced asthma risk (heterozygotes, P=.026; homozygous variants; P=.001). Besides, the association of other polymorphisms, except rs2070874 polymorphism, became apparent when the asthmatic children were grouped according to GINA classification of asthma control and severity. In addition, IL 2 and IL-4 serum expression levels were significantly higher in M. pneumoniae negative (P=.038) and positive (P=.011) subjects respectively. This observation holds true among asthmatic patients (P=.016 for IL-2 and P=.042 for IL-4), but only the IL-4 observation remained correct among non-asthmatic controls (P=.032). We also observed that the rs6534349 GG genotype was significantly associated with increased odds of getting high load M. pneumoniae infection (P=.0376). CONCLUSIONS: IL2 and IL4 could be important biomarkers for estimating the risks of asthma and M. pneumoniae infection in children. PMID- 25747602 TI - Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism. AB - Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A2A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4(-/-) mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A2A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos(+) neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD. PMID- 25747601 TI - Using data-driven model-brain mappings to constrain formal models of cognition. AB - In this paper we propose a method to create data-driven mappings from components of cognitive models to brain regions. Cognitive models are notoriously hard to evaluate, especially based on behavioral measures alone. Neuroimaging data can provide additional constraints, but this requires a mapping from model components to brain regions. Although such mappings can be based on the experience of the modeler or on a reading of the literature, a formal method is preferred to prevent researcher-based biases. In this paper we used model-based fMRI analysis to create a data-driven model-brain mapping for five modules of the ACT-R cognitive architecture. We then validated this mapping by applying it to two new datasets with associated models. The new mapping was at least as powerful as an existing mapping that was based on the literature, and indicated where the models were supported by the data and where they have to be improved. We conclude that data-driven model-brain mappings can provide strong constraints on cognitive models, and that model-based fMRI is a suitable way to create such mappings. PMID- 25747603 TI - Time-dependent modulation of glutamate synapses onto 5-HT neurons by antidepressant treatment. AB - Antidepressants, including the selective serotonin reuptake inhibitors (SSRIs), are thought to exert their clinical effects by enhancing serotonin (5-HT) transmission. However, animal studies show that the full magnitude of this enhancement is reached only following prolonged treatments with SSRIs, consistent with the well-described therapeutic delay of this class of medications. Thus, the clinical efficacy of SSRIs most likely does not emerge from their acute pharmacological actions, but rather indirectly from cellular alterations that develop over the course of a sustained treatment. Here, we show that sustained administration of the SSRI citalopram leads to a homeostatic-like increase in the strength of excitatory glutamate synapses onto 5-HT neurons of the dorsal raphe nucleus that was apparent following one week of treatment. A shorter treatment with citalopram rather induced a paradoxical decrease in the strength of these synapses, which manifested itself by both pre- and postsynaptic mechanisms. As such, these results show that an SSRI treatment induced a concerted and time dependent modulation of the synaptic drive of 5-HT neurons, which are known to be critically involved in mood regulation. This regulation, and its time course, provide a mechanistic framework that may be relevant not only for explaining the therapeutic delay of antidepressants, but also for the perplexing increases in suicide risks reportedly occurring early in the course of antidepressant treatments. PMID- 25747604 TI - Reduction of inflammatory responses by L-serine treatment leads to neuroprotection in mice after traumatic brain injury. AB - This study was designed to evaluate the neuroprotective effect of l-serine and the underlying mechanisms in mice after traumatic brain injury (TBI) induced using a weight drop model. The mice were intraperitoneally injected with l-serine 3 h after TBI and then injected twice each day for 7 days or until the end of the experiment. The neurological severity score, brain water content, lesion volume, and neurone loss were determined. The levels of TNF-alpha, IL-1beta, IL-6, and IL 10 and the number of GFAP- and Iba-1-positive cells and activated caspase-3 positive neurones in the brain tissue ipsilateral to TBI were also measured. Simultaneously, the influences of l-serine on these variables were observed. In addition, the expression of glycine receptors and l-serine-induced currents were measured. We found l-serine treatment: 1) decreased the neurological deficit score, brain water content, lesion volume, and neurone loss; 2) inhibited activated caspase-3; and 3) reduced the levels of TNF-alpha, IL-1beta and IL-6 and the number of GFAP- and Iba-1-positive cells. The effects of l-serine were antagonised by the administration of strychnine, an antagonist of glycine receptors. In addition, we found that glycine receptors were expressed mainly in the cortical neurones but less in the astrocytes or microglial cells, and l serine activated these receptors and induced strychnine-sensitive currents in these neurones. In conclusion, l-serine induces the activation of glycine receptors, which alleviates neuronal excitotoxicity, a secondary brain injury process, thereby reduces the activation of astrocytes and microglial cells and secretion of proinflammatory cytokines and inhibits neuronal apoptosis. Thus, l serine treatment leads to neuroprotection of brain tissue through reducing inflammatory responses and improves recovery of the neurological functions in mice after traumatic brain injury. PMID- 25747605 TI - MAM-2201, a synthetic cannabinoid drug of abuse, suppresses the synaptic input to cerebellar Purkinje cells via activation of presynaptic CB1 receptors. AB - Herbal products containing synthetic cannabinoids-initially sold as legal alternatives to marijuana-have become major drugs of abuse. Among the synthetic cannabinoids, [1-(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) has been recently detected in herbal products and has psychoactive and intoxicating effects in humans, suggesting that MAM-2201 alters brain function. Nevertheless, the pharmacological actions of MAM-2201 on cannabinoid receptor type 1 (CB1R) and neuronal functions have not been elucidated. We found that MAM-2201 acted as an agonist of human CB1Rs expressed in AtT-20 cells. In whole-cell patch-clamp recordings made from Purkinje cells (PCs) in slice preparations of the mouse cerebellum, we also found that MAM-2201 inhibited glutamate release at parallel fiber-PC synapses via activation of presynaptic CB1Rs. MAM-2201 inhibited neurotransmitter release with an inhibitory concentration 50% of 0.36 MUM. MAM-2201 caused greater inhibition of neurotransmitter release than Delta(9)-tetrahydrocannabinol within the range of 0.1-30 MUM and JWH-018, one of the most popular and potent synthetic cannabinoids detected in the herbal products, within the range of 0.03-3 MUM. MAM-2201 caused a concentration-dependent suppression of GABA release onto PCs. Furthermore, MAM 2201 induced suppression of glutamate release at climbing fiber-PC synapses, leading to reduced dendritic Ca(2+) transients in PCs. These results suggest that MAM-2201 is likely to suppress neurotransmitter release at CB1R-expressing synapses in humans. The reduction of neurotransmitter release from CB1R containing synapses could contribute to some of the symptoms of synthetic cannabinoid intoxication including impairments in cerebellum-dependent motor coordination and motor learning. PMID- 25747606 TI - Risk factors for left atrial thrombus from transesophageal echocardiography findings in ischemic stroke patients. AB - BACKGROUND: To identify the cause of cerebral embolism, we performed transesophageal echocardiography (TEE) in patients suspected of embolic brain infarction including transient ischemic attack (TIA). We analyzed TEE findings and investigated factors associated with left atrial thrombus (LAT) detected by TEE. METHODS: We enrolled 98 consecutive patients who underwent TEE and had acute brain infarction or TIA that was possibly due to embolism. We assessed age, sex, presence of atrial fibrillation (AF), days from admission to TEE and TEE findings, including the prevalence of LAT, spontaneous echo contrast (SEC), left atrial appendage (LAA) slow flow velocity, patent foramen ovale (PFO), atrial septal aneurysm and aortic plaque (ASA). RESULTS: LAT was detected with TEE in 20 patients (20%). The factors that were significantly associated with the presence of LAT were male sex (unadjusted odds ratio (OR), 3.94; 95% confidence interval (CI), 1.07-14.58; p=0.037), presence of AF (unadjusted OR, 9.58; 95% CI, 2.58 35.50; p< 0.001), SEC (unadjusted OR, 8.48; 95% CI, 2.57-28.00; p< 0.001) and LAA slow flow velocity (unadjusted OR, 5.18; 95% CI, 1.59-16.91; p=0.005). Multivariate logistic regression analysis revealed that male sex (adjusted OR, 5.30; 95% CI, 1.09-25.71; p=0.039), presence of AF (adjusted OR, 8.97; 95% CI, 1.10-73.20; p=0.041) and SEC (adjusted OR, 10.87; 95% CI, 1.001-118.0; p=0.049) were independently associated with LAT, but LAA slow flow velocity was not. CONCLUSION: SEC is an important risk factor associated with LAT in patients suspected of embolic brain infarction that is independent of AF. PMID- 25747607 TI - The basic data for residents aged 16 years or older who received a comprehensive health check examinations in 2011-2012 as a part of the Fukushima Health Management Survey after the great East Japan earthquake. AB - AIM: To assist in the long-term health management of residents and evaluate health impacts after the Tokyo Electric Power Company's Fukushima Daiichi Nuclear Power Plant accident in Fukushima Prefecture, the Fukushima prefectural government decided to conduct the Fukushima Health Management Survey. This report describes the results for residents aged 16 years or older who received the health check examinations and evaluates the data obtained from 2011 and 2012. METHODS: The target group consisted of residents aged 16 years or older who had lived in the evacuation zone. The health check examinations were performed on receipt of an application for a health check examination from any of the residents. The examinations, including measurements of height, weight, abdominal circumference/body mass index (BMI), blood pressure, biochemical laboratory findings, and peripheral blood findings, were performed as required. RESULTS: 1) A total of 56,399 (30.9%) and 47,009 (25.4%) residents aged 16 years or older received health checks in 2011 and 2012, respectively. 2) In both years, a number of male and female residents in the 16-39 year age group were found to suffer obesity, hyperlipidemia, hyperuricemia, or liver dysfunction, and the prevalence of obesity and hyperlipidemia among residents increased with age. Furthermore, the proportion of residents with hypertension, glucose metabolic abnormalities or renal dysfunction was higher in those aged 40 years or older. 3) The frequencies of obesity, hypertension and hyperlipidemia among residents in 2012 were lower than those in 2011. However, the prevalence of liver dysfunction, hyperuricemia, glucose metabolic abnormalities and renal dysfunction among residents was higher in 2012 than in 2011. CONCLUSIONS: These results suggested the number of residents who had lived in the evacuation zone with obesity, hyperlipidemia, hyperuricemia, liver dysfunction, hypertension, glucose metabolic abnormalities, or renal dysfunction increased with age in all age groups. Therefore, we think that it is necessary to continue with health check examinations for these residents in order to ameliorate lifestyle-related disease. PMID- 25747608 TI - A case of a child with sle presenting with hps as a primary manifestation. AB - The primary manifestations of systemic lupus erythematosus (SLE) are various. One such manifestation is hemophagocytic syndrome (HPS). We here report a child with SLE presenting with HPS as a primary manifestation. In October 2010, an 11-year old Japanese boy presented with pancytopenia, elevated liver enzymes, hyperferritinemia and hemophagocytosis due to macrophages in the bone marrow, and was diagnosed with HPS. A year later, he was found to have proteinuria and hematuria. Oral aphtha and Raynaud's phenomenon were observed, and the patient showed low serum complement levels and was positive for anti-nuclear antibodies (ANAs). He was subsequently diagnosed with SLE. Moreover, low serum complement levels and ANA positivity were detected in a serum sample preserved at the onset of HPS. The HPS was considered to be a primary manifestation of SLE on the basis of these findings. Based on this case, the presence of an underlying disease, such as SLE, should be investigated in cases of HPS. PMID- 25747609 TI - A case of endocrine cell carcinoma combined with squamous cell carcinoma of the esophagus resected by endoscopic submucosal dissection. AB - A 55-year-old man with esophageal carcinoma received endoscopic submucosal dissection (ESD) in en-bloc resection. Histopathological examination revealed an admixture of squamous cell carcinoma (SCC) and endocrine cell carcinoma (ECC) with invasion of the deep submucosa. Immunohistochemically, CD 56 and chromogranin A were positive for ECC. Small-cell, medium-cell, and large-cell type ECC were partly surrounded with SCC and partly formed the duct, presenting various patterns. After ESD, he received chemotherapy including CPT-11 plus Cisplatin. He is alive and in good condition today, 55 months after ESD, with no evidence of recurrence. PMID- 25747610 TI - Prevalence of thyroid nodular lesions in children and adolescents. PMID- 25747611 TI - Fukushima radiation symposium 2014: sharing the achievement from the Fukushima Health Management Survey. PMID- 25747612 TI - Findings from thyroid examination. PMID- 25747613 TI - External radiation dose estimation by the basic survey. PMID- 25747614 TI - Mental health of children. PMID- 25747615 TI - What about the mental health of adults? AB - Mental health problems such as post-traumatic stress disorder (PTSD) and depression have surfaced and are affecting many residents in Fukushima prefecture as a result of the Great East Japan Earthquake and tsunami and the subsequent nuclear disaster. It has also been reported that such mental health problems appeared and persisted after large-scale nuclear accidents in the past, such as the Chernobyl and Three Mile Island accidents, widely affecting the disaster victims. PMID- 25747616 TI - How lifestyle affects health--changes in health status before and after the earthquake. PMID- 25747617 TI - Survey of pregnant women in fukushima prefecture and future issues. PMID- 25747618 TI - Past and future species definitions for Bacteria and Archaea. AB - Species is the basic unit of biological diversity. However, among the different microbiological disciplines there is an important degree of disagreement as to what this unit may be. In this minireview, we argue that the main point of disagreement is the definition (i.e. the way species are circumscribed by means of observable characters) rather than the concept (i.e. the idea of what a species may be as a unit of biodiversity, the meaning of the patterns of recurrence observed in nature, and the why of their existence). Taxonomists have defined species by means of genetic and expressed characters that ensure the members of the unit are monophyletic, and exhibit a large degree of genomic and phenotypic coherence. The new technologies allowing high-throughput data acquisition are expected to improve future classifications significantly and will lead to database-based taxonomy centered on portable and interactive data. Future species descriptions of Bacteria and Archaea should include a high quality genome sequence of at least the type strain as an obligatory requirement, just as today an almost full-length 16S rRNA gene sequence must be provided. Serious efforts are needed in order to re-evaluate the major guidelines for standard descriptions. PMID- 25747619 TI - A novel method for the analysis of clinical biomarkers to investigate the effect of diet on health in a rat model. AB - Experiments into the relationship between diet and health have been an area of high interest for a long time. In this study, we investigate the application of multivariate data analysis to differentiate between rat populations fed on two different diets: normal rat diet (control) and Western affluent diet (WAD). Two sets of data were acquired and analysed: one from a biochemical clinical analyser, taking measurements of blood-based biochemical markers; the other from the analysis of the volatile organic compounds (VOCs) emitted from faecal samples from the same animals using selected ion flow tube mass spectrometry (SIFT-MS). Five classes were considered: weanlings, 12 month controls, 12 month WADs, 18 month controls, and 18 month WADs. Data from the biochemical analyser, weanlings and 18 month WAD fed rats showed significant differences from the other measurement classes. This was shown in both the exploratory analysis and through multivariate classification. Classification of control diet versus WAD diets suggested there are differences between classes with 92% accuracy for the 12 month classes and 91% for the 18 month classes. Cholesterol markers, especially as low density lipoprotein-cholesterol (LDL), were the main factor in influencing WAD samples. The data from the SIFT-MS analysis also produced very good classification accuracies. Classification of control diet versus WAD diets using the H3O(+) precursor ion data suggested there are differences between classes with 71% accuracy for the 12 month classes and 100% for the 18 month classes. These findings confirm that total cholesterol and LDL-cholesterol are elevated in the 18 month WAD-fed rats. We therefore suggest that the analysis of VOCs from faecal samples in conjunction with multivariate data analysis may be a useful alternative to blood analysis for the detection of parameters of health. PMID- 25747620 TI - Foreword. PMID- 25747621 TI - Editorial. PMID- 25747622 TI - 2013 military health system research symposium supplement: issue overview. PMID- 25747623 TI - Finishing what was started: an analysis of theater research conducted from 2010 to 2012. AB - The Joint Combat Casualty Research Team (JC2RT) is part of the human research protection regulatory system implemented in 2005 to oversee the conduct of research in a deployed military combatant command. In 2010, SharePoint, a web based tool, was established to track study documents. This study conducted by JC2RT no. 13 describes characteristics of research studies under the purview of the JC2RT from 2010 through 2012. Of the 83 research studies reviewed, 34% were completed, 32% were not completed, and 34% were still in progress. Target sample sizes ranged from 12 to 70,000, with 96% of the research studying U.S. military members. The design of 61% of the studies was prospective, 20% surveys, and 14% retrospective reviews. Approximately one-half of the studies were conducted at single sites. Eighty-four percent of the studies that finished an institutional review board (IRB) were completed, whereas a large number of studies never made it to IRB approval. Even after studies have gone through the rigorous process of scientific review and IRB approval some continue to struggle for years to be completed in the theater of operations. The JC2RT is committed to helping facilitate the ethical conduct of research during war. PMID- 25747624 TI - Prehospital and en route analgesic use in the combat setting: a prospectively designed, multicenter, observational study. AB - BACKGROUND: Combat injuries result in acute, severe pain. Early use of analgesia after injury is known to be beneficial. Studies on prehospital analgesia in combat are limited and no prospectively designed study has reported the use of analgesics in the prehospital and en route care setting. Our objective was to describe the current use of prehospital analgesia in the combat setting. METHODS: This prospectively designed, multicenter, observational, prehospital combat study was undertaken at medical treatment facilities (MTF) in Afghanistan between October 2012 and September 2013. It formed part of a larger study aimed at describing the use of lifesaving interventions in combat. On arrival at the MTF, trained on-site investigators enrolled eligible patients and completed standardized data capture forms, which included the name, dose, and route of administration of all prehospital analgesics, and the type of provider who administered the drug. Physiological data were retrospectively ascribed as soon as practicable. The study was prospectively approved by the Brooke Army Medical Center institutional review board. RESULTS: Data were collected on 228 patients, with 305 analgesia administrations recorded. The predominant mechanism of injury was blast (50%), followed by penetrating (41%), and blunt (9%). The most common analgesic used was ketamine, followed by morphine. A combination of analgesics was given to 29% of patients; the most common combination was ketamine and morphine. Intravenous delivery was the most commonly used route (55%). Patients transported by the UK Medical Emergency Response Team (MERT) or U.S. Air Medical Evacuation (Dust-off) team were more likely to receive ketamine than those evacuated by U.S. Pararescue Jumpers (Pedro). Patients transported by Medical Emergency Response Team or Pedro were more likely to receive more than 1 drug. Patients who received only ketamine had a higher pulse rate (p<0.005) and lower systolic blood pressure (p=0.01) than other groups, and patients that received hydromorphone had a lower respiratory rate (p=0.04). CONCLUSIONS: In our prospectively designed, multicenter, observational, prehospital combat study, ketamine was the most commonly used analgesic drug. The most frequently observed combination of drugs was ketamine and morphine. The intravenous route was used for 55% of drug administrations. PMID- 25747625 TI - Evidence for a higher risk of hypovolemia-induced hemodynamic instability in females: implications for decision support during prehospital triage. AB - Lower body negative pressure (LBNP) simulates hemorrhage, and tolerance to LBNP (time to presyncope [TTP]) is indicative of tolerance to blood loss. The purpose of this study was to predict TTP based on demographic characteristics (sex, age, height, and body mass index) and physiological variables (heart rate [HR], systolic arterial pressure, diastolic arterial pressure [DAP], pulse pressure, stroke volume, total peripheral resistance [TPR], and baroreflex sensitivity [BRS]) at baseline, and during 2 levels of LBNP (-15, -30 mm Hg). Multiple linear regression analysis was used to create a model to predict TTP (range: 670 to 2516 seconds, n=187) based on demographic characteristics and physiological variables changes (Delta) from baseline to -30 mm Hg LBNP. The prediction model revealed that TTP (seconds)=1667.5+(5.1*Age)+(61.1*Sex)-(21.5*DeltaHR)+(55.3*DeltaDAP) (88.2*DeltaTPR)-(4.9*DeltaBRS). Most significantly, our analysis demonstrated a lesser survival trajectory for females given the same rate and magnitude of hemorrhage compared to males. Young age and female sex are predictors of low tolerance to blood loss, and should be considered for early triage in the prehospital setting. PMID- 25747626 TI - TXA in combat casualty care--does it adversely affect extremity reconstruction and flap thrombosis rates? AB - INTRODUCTION: Tranexamic acid (TXA) is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin. In recent years, the military has adapted TXA's use in combat casualties suffering severe hemorrhagic injuries. The purpose of this study is to examine the association between TXA on complications such as venous thromboembolic events (VTEs) and flap-related thrombosis in combat trauma patients undergoing tissue transfer for extremity reconstruction. METHODS: A retrospective chart review of war wounded undergoing extremity reconstructions from 2003 to 2012 at Walter Reed National Military Medical Center was completed. Data collected included patient demographics and administration of TXA. Outcomes measured included VTE rates and flap complications in TXA and non-TXA cohorts. RESULTS: From 2003 to 2012, 173 extremity flap procedures were performed (100 pedicle, 73 free flaps). TXA was used in 11% of all patients reviewed. The overall VTE rate was 23.7%; however, there were no documented VTEs in patients who received TXA. Total flap complications, 26% versus 21%, or flap failure, 5% versus 4%, (p=0.571 and 0.564, respectively) did not differ significantly between those that received TXA versus those that did not. CONCLUSION: Given the increasing use of TXA in the combat casualties, concern over its impact on VTE rates and flap complications is of interest. However, in this early review, we did not find significant differences in patients who received TXA and those that did not. Further research is indicated to better determine the significance and the effect of TXA on complex limb salvages. PMID- 25747627 TI - Nonoperative management of splenic injury in combat: 2002-2012. AB - BACKGROUND: Selective nonoperative management of combat-related blunt splenic injury (BSI) is controversial. We evaluated the impact of the November 2008 blunt abdominal trauma clinical practice guideline that permitted selective nonoperative management of some patients with radiological suggestion of hemoperitoneum on implementation of nonoperative management (NOM) of splenic injury in austere environments. METHODS: Retrospective evaluation of patients with splenic injuries from November 2002 through January 2012 in Iraq and Afghanistan was performed. International Classification of Diseases, 9th Revision, Clinical Modification procedure codes identified patients as laparotomy with splenectomy, or NOM. Delayed operative management had no operative intervention at earlier North American Treaty Organization (NATO) medical treatment facilities (MTFs), and had a definitive intervention at a latter NATO MTFs. Intra-abdominal complications and overall mortality were juxtaposed. RESULTS: A total of 433 patients had splenic injuries from 2002 to 2012. Initial NOM of BSI from 2002 to 2008 compared to 2009-2012 was 44.1% and 47.2%, respectively (p=0.75). Delayed operative management and NOM completion had intra abdominal complication and mortality rates of 38.1% and 9.1% (p<0.01), and 6.3% and 8.1% (p=0.77). CONCLUSIONS: Despite high-energy explosive injuries, NATO Role II MTFs radiological constraints and limited medical resources, hemodynamically normal patients with BSI and low abdominal abbreviated injury scores underwent NOM in austere environments. PMID- 25747628 TI - An 8-year review of operation enduring freedom and operation iraqi freedom resuscitative thoracotomies. AB - BACKGROUND: Appropriate indications for resuscitative thoracotomy (RT) in an austere environment continue to evolve; the aim of this study was to determine survival and to analyze demographics of survivors within U.S. military personnel undergoing RT. METHODS: A retrospective review was performed of all U.S. soldiers who underwent thoracotomy in theater during Operation Iraqi Freedom and Operation Enduring Freedom. After individualized review, patients in extremis or who lost pulses and had their thoracotomy performed within 10 minutes of arrival to the emergency department were included. The primary outcome was survival at final hospital discharge, and secondary outcomes included demographics associated with survival. RESULTS: Between January 2003 and May 2010, 81 U.S. military personnel met inclusion criteria for RT in theater. As low as 6.7% (3/45) of patients receiving prehospital cardiopulmonary resuscitation were alive at final hospital discharge. Survival from RT after explosive/blast injury, penetrating (gunshot wound), and blunt trauma were 16.3% (8/49), 0% (0/28), and 0% (0/4), respectively. Patients with primary explosive/blast extremity trauma undergoing RT had a survival of 27.3% (6/22). Higher initial oxygen saturations, larger volume of crystalloids and blood products infused, and higher extremity abbreviated injury score were all associated with survival. CONCLUSIONS: Combat casualties who present pulseless or in extremis who were injured as a result of an explosive/blast injury mechanism resulting in a primary extremity injury may have a survival benefit from undergoing a RT in an austere environment. PMID- 25747629 TI - Intraoperative fluorescence angiography: a review of applications and outcomes in war-related trauma. AB - AIMS: In the recent Iraq and Afghanistan conflicts, survival rates from complex battlefield injuries have continued to improve. The resulting war-related wounds are challenging, with confounding issues making assessment of tissue perfusion subjective and variable. This review discusses the utility of intraoperative fluorescence angiography, and its usefulness as an objective tool to evaluate the perfusion of tissues in the face of complex war-related injuries. METHODS: A retrospective review of all war-related traumatic and reconstructive cases employing intraoperative indocyanine green laser angiography (ICGLA) was performed. Data analyzed included indication for use, procedure success/failure rates, modifications performed, and perfusion-related complications. Anatomical regions assessed were extremity, head and neck, truncal, and intra-abdominal viscera. The endpoint of specific interest involved the decision for additional debridement of poorly perfused tissue, as based on the ICGLA findings. RESULTS: Over a 3-year period, this study examined 123 extremity soft tissue flaps, 41 extremity injuries including amputation and/or amputation revision cases, 13 craniofacial flaps, and 9 truncal/abdomen/gastrointestinal cases in which ICGLA was utilized to assess tissue perfusion and viability. A total of 35 (18.8%) of cases employing ICGLA required intraoperative modifications to address perfusion related issues. CONCLUSIONS: Intraoperative fluorescent angiography is an objective, useful tool to assess various war-related traumatic injuries. This study expands on prior cited indications for ICGLA to include (1) guiding debridement in heavily contaminated wounds, (2) providing improved assessment of avulsion soft tissue injuries, (3) allowing for rapid detection of vascular and/or microvascular compromise in soft tissue and osseous flap reconstructions, (4) reducing and preventing perfusion-related complications in trauma, amputation closures, and reconstruction procedures, (5) contributing to better outcomes in certain complex orthopedic and composite tissue injuries, and (6) enabling improved postoperative wound and reconstruction assessment in those cases of perfusion-related issues that arise within a delayed setting. PMID- 25747630 TI - Assessment of pain in less severely ill and injured aeromedical evacuation patients: a prospective field study. AB - Pain management is vitally important to injured patients being evacuated from the warzone. A prospective assessment of real-time ratings of pain acceptability, intensity, and satisfaction of a convenience sample of 114 less severely ill and injured U.S. military patients being evacuated on Aeromedical Evacuation (AE) missions from Ramstein Air Field, Germany, to Andrews Air Force Base, Maryland, was conducted. Data were collected before and during 12 AE flights in December 2012 and May 2013. Acceptable pain intensity was a median of 6/10 (range 2-9), with 76% of patients indicating an acceptable pain intensity greater than 4. During AE transport, 75% of patients reported at least one pain score>=4. Despite these high pain ratings, there was documentation of administration for only 58% of routine and 48% for as-needed analgesics/adjuvants. Over 47% of patients experienced pain that exceeded their acceptable intensity level, but of those patients with pain that was more severe than acceptable, only 10% rated their satisfaction with their pain management as poor or fair. This is the first study to provide real-time concurrent assessment of pain and pain management during en route care. The worst pain was reported for the hospital to aircraft arrival, suggesting the need for interventions to safely optimize pain management during this handoff period. PMID- 25747631 TI - Reducing secondary insults in traumatic brain injury. AB - OBJECTIVES: To determine the alterations in intracranial pressure (ICP) during U. S. Air Force Critical Care Air Transport Team transport of critically injured warriors with ICP monitoring by intraventricular catheter (IVC). METHODS: Patients with an IVC following traumatic brain injury requiring aeromedical evacuation from Bagram to Landstuhl Regional Medical Center were studied A data logger monitored both ICP and arterial blood pressure and was equipped with an integral XYZ accelerometer to monitor movement. RESULTS: Eleven patients were studied with full collection of data from takeoff to landing. The number of instances of ICP>20 mm Hg ranged from 0 to 238 and duration of instances ranged from 0 to 3,281 seconds. The number of instances of ICP+/-50% of the baseline ICP ranged from 0 to 921 and duration of instances ranged from 0 to 9,054 seconds. Five of the patients did not experience ICP>20 mm Hg throughout their flight, but 10 patients showed instances of ICP+/-50% of baseline ICP. CONCLUSION: Patient movement results in changes in ICP both from external stimuli (vibration, noise) and from acceleration and deceleration forces. During transport, Critical Care Air Transport Team crews should prioritize monitoring and correcting ICP including additional sedation and/or venting IVC. PMID- 25747632 TI - A comparison of acute respiratory distress syndrome outcomes between military and civilian burn patients. AB - BACKGROUND: The objective of this report was to compare the prevalence of acute respiratory distress syndrome (ARDS) and associated mortality between military service members with burns sustained during or in support of combat operations and civilian burn patients treated at a single burn center. METHODS: Demographic and physiologic data were collected retrospectively on mechanically ventilated military and civilian patients admitted to our burn intensive care unit between January 2003 and December 2011. Patients with ARDS were identified and categorized as mild, moderate, or severe using the Berlin criteria. Demographics and clinical outcomes were compared. After initial comparison, propensity matching was performed and mortality compared. RESULTS: A total of 891 burn patients required mechanical ventilation during the study period; 291 military and 600 civilian. The prevalence of ARDS was 34% (n=304) for the entire cohort, 33% (n=96) for military, and 35% (n=208) for civilians (p=0.55). For the entire cohort, despite more severe injury burden, military patients had a significantly lower overall mortality (17% vs. 28%; p=0.0002) as well as ARDS mortality (33 vs. 48%, p=0.02) when compared to civilians. This difference was not significant after propensity matching based on age. CONCLUSION: In a retrospective cohort study, burned military patients on mechanical ventilation had a significantly lower overall and ARDS mortality despite larger burns and more severe injury when compared to civilian burn patients. This difference appears to be largely because of age. PMID- 25747633 TI - A comparison of the incidence of cricothyrotomy in the deployed setting to the emergency department at a level 1 military trauma center: a descriptive analysis. AB - Airway management is a critical skill of emergency medicine physicians and prehospital providers. Airway compromise is the cause of 1.8% of battlefield deaths. Cricothyrotomy is a critical, lifesaving procedure. In this study, we conducted a retrospective descriptive analysis comparing the incidence of cricothyrotomies in the deployed setting versus the incidence in a military level 1 trauma center emergency department (ED) setting in San Antonio, Texas. The deployed/in-theater procedures were performed from September 2007 to July 2009. The ED procedures were performed from April 2010 to February 2012. Over these study periods, 28 cricothyrotomies were performed in the deployed setting against a backdrop of 11,492 trauma admissions compared to 4 cricothyrotomies performed during 2,741 trauma admissions in the ED setting. The per admission incidence of deployed cricothyrotomies was 0.24% versus an incidence of 0.15% in the ED (p=0.46). We conclude that this rare, lifesaving procedure is performed more often in the deployed setting than the ED, but this difference was not statistically significant. PMID- 25747634 TI - Characteristics of genitourinary injuries associated with pelvic fractures during operation Iraqi Freedom and operation Enduring Freedom. AB - OBJECTIVES: Pelvic fractures are markers of severe injury and are often associated with lower genitourinary injuries. The purpose of this study was to investigate the incidence of lower genitourinary injuries and complaints associated with pelvic fractures sustained in combat among nonsurvivors and survivors. METHODS: The Armed Forces Medical Examiner System and The Joint Theater Trauma Registry databases were searched to identify survivors and nonsurvivors who sustained a pelvic fracture in combat in 2008. Survivor and autopsy data consisted of injury mode and mechanism and associated organ and extremity injuries. Pelvic fractures were classified using the Tile system. RESULTS: The database search yielded 91 nonsurvivors and 10 survivors with pelvic fractures. Forty-one patients (40%) sustained 61 genitourinary injuries. The majority of genitourinary injuries in nonsurvivors were associated with Tile C pelvic fractures (70%). Twenty percent of survivors had genitourinary injuries, all of which were associated with Tile A fractures. CONCLUSIONS: A higher incidence of genitourinary injuries in patients with combat-related pelvic fractures (60%) was found than that of their civilian counterparts. Of the survivors, 100% of those with genitourinary injuries were being treated for erectile dysfunction at their last follow-up. Continued collaboration between orthopaedic surgeons and urologist is needed to address these concurrent injuries. PMID- 25747635 TI - Evolution of Pararescue medicine during operation Enduring Freedom. AB - This article highlights recent advances made in U.S. Air Force Pararescue Medical Operations in relation to tactical evacuation procedures. Most of these changes have been adopted and adapted from civilian medicine practice, and some have come from shared experiences with partner nations. Patient assessment includes a more comprehensive evaluation for hemorrhage and indications for hemorrhagic control. Ketamine has replaced morphine and fentanyl as the primary sedative used during rapid sequence intubation and procedural sedation. There has been an increasing use of the bougie to clear an airway or nasal cavity that becomes packed with debris. Video laryngoscopy provides advantages over direct laryngoscopy, especially in situations where there are environmental constraints such as the back of a Pave Hawk helicopter. Intraosseous access has become popular to treat and control hemorrhagic shock when peripheral intravenous access is impractical or impossible. Revisions to patient treatment cards have improved the efficacy and compliance of documentation and have made patient handoff more efficient. These improvements have only been possible because of the concerted efforts of U.S. Air Force and partner platforms operating in Afghanistan. PMID- 25747636 TI - Focused comprehensive, quantitative, functionally based echocardiographic evaluation in the critical care unit is feasible and impacts care. AB - OBJECTIVES: To determine whether comprehensive quantitative echocardiogram could be used as a resuscitation tool in critically ill surgical patients and to assess its effect on patient care. DESIGN: Prospective observational. SETTING: The Trauma and Surgical Intensive Care Units of the University of Maryland Medical Center. PATIENTS: Critically ill trauma and surgical patients. INTERVENTIONS: The Focused Rapid Echocardiographic Evaluation (FREE), an abbreviated version of a comprehensive transthoracic echocardiogram, which is under an approved protocol, was performed. MEASUREMENTS AND MAIN RESULTS: Over a 30-month period, 791 FREEs were performed on 659 patients. The mean patient age was 60 (+/-17) years. Ninety one percent were intubated and 80% were postoperative. Ejection fraction was reported for 95%, and cardiac index was reported for 89% of FREE studies. Right heart function was assessed for 94%. Measures of volume status--internal left ventricular diameter, inferior vena cava diameter, diameter change, and stroke volume variation--were reported for 88%, 79%, 75%, and 89% of patients, respectively. The FREE was judged to be useful by the consulting primary care team for 95% of patients, and altered the plan of care for 57%. The most common change was administration of a fluid bolus (43%), followed by change from an original prestudy plan to one of monitoring (24%), diuresis (23%), addition/titration of an inotropic agent (19%), and/or addition/titration of a vasoconstrictor (8%). CONCLUSIONS: The FREE is feasible and alters care in the intensive care unit by providing clinical data not otherwise available at the bedside. Further studies are warranted to assess the impact of comprehensive echocardiogram-directed resuscitation on patient outcomes. PMID- 25747637 TI - Effect of Ibuprofen dose on platelet aggregation and coagulation in blood samples from pigs. AB - INTRODUCTION: Ibuprofen is commonly used by Soldiers in the deployed environment. This study investigated its dose-effects on in vitro coagulation. METHODS: Blood samples were collected from 4 normal healthy pigs and were processed to make platelet-adjusted (100*10(3)/MUL) blood samples. Ibuprofen was added to the samples at doses of 0 MUg/mL (control), recommended oral dose (163 MUg/mL, 1*), 2*, 4*, 8*, 10*, 12*, 16*, and 20*. Arachidonic acid or collagen-stimulated platelet aggregation was assessed at 15 minutes after the addition of ibuprofen. Coagulation was assessed with measurements of prothrombin time (PT) and activated partial thromboplastin time (aPTT), and thrombelastography by Rotem. RESULTS: A robust inhibition of ibuprofen on arachidonic acid-induced platelet aggregation was observed at all doses tested. Collagen-stimulated platelet aggregation was inhibited to 71%+/-5% and 10%+/-5% of the control values at ibuprofen doses of 4* and 20*, respectively (both p<0.05). No changes were observed in PT at any dose, but aPTT was prolonged at dose of 16* and 20*. Rotem measurements of coagulation time, clot formation time, maximum clot firmness, and A10 were compromised at dose 16* and 20* (all p<0.05). CONCLUSION: Ibuprofen inhibited platelet aggregation at recommended doses, but did not compromise aPTT or coagulation profile until at 16 times the recommended doses and higher. Further effort is needed to clarify whether there are different dose-responses between human and pig blood samples in trauma situations. PMID- 25747638 TI - In vitro study of the adverse effect of nicotine and physical strain on human gingival fibroblasts as a model of the healing of wounds commonly found in the military. AB - BACKGROUND: Significant adverse effects on fibroblast growth and metabolism are observed with nicotine. We investigated the synergistic effects of nicotine and cyclical mechanical strain (CMS) on human gingival fibroblasts (HGFs) in a wound healing model. METHODS: HGFs were isolated and grown in Dulbecco's modified Eagle's medium. Three-millimeter wounds were created on a confluent cell monolayer grown in a media containing 0, 1, 2, or 4 mM nicotine, with or without CMS. The applied deformation regimen remains constant for 6 days. On days 1, 2, 4, and 6, the cells were stained with hematoxylin and eosin Y for the evaluation of wound repopulation. RESULTS: The application of CMS alone demonstrates a biphasic response, with an initial stimulatory effect on wound repopulation (days 1-2) and less repopulation during the later phase (days 4-6). The addition of nicotine clearly demonstrated a time and inverse dose-dependent relationship on wound repopulation, with no effect during the early phase and reduced wound repopulation during the later phase. CONCLUSIONS: Initial treatment of HGF wounds with CMS resulted in faster wound repopulation regardless of nicotine presence. By day 6, wound healing of HGF exposed to both nicotine and CMS is delayed. These findings suggest that CMS and nicotine may affect fibroblasts and delay wound healing at other sites in the body as well. PMID- 25747639 TI - The effectiveness of endodontic solvents to remove endodontic sealers. AB - Dental emergencies negatively affect troop readiness, especially during combat. Endodontic retreatment, when required, is especially challenging when the removal of endodontic sealer is required. In this study, we investigated the effectiveness of synthetic endodontic solvents to remove endodontic sealers. Fifty capillary tubes (2.7 mm ID*22 mm L), each filled to 15 mm with either Roth 801, AH Plus, MetaSEAL, or gutta-percha, were stored at 75% humidity for 14 days at 37 degrees C. Ten capillary tubes containing each sealer were treated with either chloroform, xylene, EndoSolv R, EndoSolv E, or no solvent, and then penetrated with D3 ProTaper Universal Retreatment file on the same day. The time for the file to penetrate the length of each sealer was recorded, and the data statistically analyzed. Roth 801 failed to set and was not tested. The file took 3.4+/-0.1, 4.8+/-0.3, 5.7+/-0.4, 4.5+/-0.2, and 10.6+/-1.0 seconds (mean+/-SD) to penetrate gutta-percha using chloroform, xylene, EndoSolv R, EndoSolv E, or no solvent, respectively, and was performed by one endodontic resident at one sitting. The time for penetration of gutta-percha with any solvent was significantly faster (p<=0.05) than for AH Plus or MetaSEAL.The time for AH Plus ranged from 23.1+/-1.0 to 81.5+/-4.5 seconds. The time for MetaSEAL ranged from 97.2+/-6.1 to >180 seconds. EndoSolv E was the most effective solvent for AH Plus. It took significantly more time to remove MetaSEAL than AH Plus, regardless of the solvent used. Our study indicated that the use of the proper endodontic solvent makes complete removal of a sealer much more effective during retreatment. PMID- 25747640 TI - Closed-loop target-controlled infusion systems: stability and performance aspects. AB - OBJECTIVE: This article addresses the design of a robust autopilot for the delivery of intravenous anesthesia drugs. METHODS: A mathematical framework that expresses the pharmacological variability of a patient population into uncertainty bounds is proposed. These bounds can be effectively used to tune the parameters of a controller to ensure its stability, a key design aspect related to the safety of the overall system. RESULTS: The proposed method is applied to the control of propofol, a powerful hypnotic agent used for sedation and anesthesia. Simulations show that the controller remains stable for all patients considered and that performance are clinically acceptable. CONCLUSION: This methodology can be an important step forward in the design and regulatory approval of such systems. PMID- 25747641 TI - Ultrasonic imaging of foreign inclusions and blood vessels through thick skull bones. AB - We report a new progress in the development of a portable ultrasonic transcranial imaging system, which is expected to significantly improve the clinical utility of transcranial diagnostic ultrasound. When conventional ultrasonic phased array and Doppler techniques are applied through thick skull bones, the ultrasound field is attenuated, deflected, and defocused, leading to image distortion. To address these deficiencies, the ultrasonic transcranial imaging system implements two alternative ultrasonic methods. The first method improves detection of small foreign objects, such as bone fragments, pieces of shrapnel, or bullets, lodged in the brain tissue. Using adaptive beamforming, the method compensates for phase aberration induced by the skull and refocuses the distorted ultrasonic field at the desired location. The second method visualizes the blood flow through intact human skull using ultrasonic speckle reflections from the blood cells, platelets, or contrast agents. By analyzing these random temporal changes, it is possible to obtain 2D or 3D blood flow images, despite the adverse influence of the skull. Both methods were implemented on an advanced open platform phased array controller driving linear and matrix array probes. They were tested on realistic skull bone and head phantoms with foreign inclusions and blood vessel models. PMID- 25747642 TI - Quantifying white matter structural integrity with high-definition fiber tracking in traumatic brain injury. AB - There is an urgent, unmet demand for definitive biological diagnosis of traumatic brain injury (TBI) to pinpoint the location and extent of damage. We have developed High-Definition Fiber Tracking, a 3 T magnetic resonance imaging-based diffusion spectrum imaging and tractography analysis protocol, to quantify axonal injury in military and civilian TBI patients. A novel analytical methodology quantified white matter integrity in patients with TBI and healthy controls. Forty-one subjects (23 TBI, 18 controls) were scanned with the High-Definition Fiber Tracking diffusion spectrum imaging protocol. After reconstruction, segmentation was used to isolate bilateral hemisphere homologues of eight major tracts. Integrity of segmented tracts was estimated by calculating homologue correlation and tract coverage. Both groups showed high correlations for all tracts. TBI patients showed reduced homologue correlation and tract spread and increased outlier count (correlations>2.32 SD below control mean). On average, 6.5% of tracts in the TBI group were outliers with substantial variability among patients. Number and summed deviation of outlying tracts correlated with initial Glasgow Coma Scale score and 6-month Glasgow Outcome Scale-Extended score. The correlation metric used here can detect heterogeneous damage affecting a low proportion of tracts, presenting a potential mechanism for advancing TBI diagnosis. PMID- 25747643 TI - A high-definition fiber tracking report for patients with traumatic brain injury and their doctors. AB - We have developed a tablet-based application, the High-Definition Fiber Tracking Report App, to enable clinicians and patients in research studies to see and understand damage from Traumatic Brain Injury (TBI) by viewing 2-dimensional and 3-dimensional images of their brain, with a focus on white matter tracts with quantitative metrics. The goal is to visualize white matter fiber tract injury like bone fractures; that is, to make the "invisible wounds of TBI" understandable for patients. Using mobile computing technology (iPad), imaging data for individual patients can be downloaded remotely within hours of a magnetic resonance imaging brain scan. Clinicians and patients can view the data in the form of images of each tract, rotating animations of the tracts, 3 dimensional models, and graphics. A growing number of tracts can be examined for asymmetry, gaps in streamline coverage, reduced arborization (branching), streamline volume, and standard quantitative metrics (e.g., Fractional Anisotropy (FA)). Novice users can learn to effectively navigate and interact with the application (explain the figures and graphs representing normal and injured brain tracts) within 15 minutes of simple orientation with high accuracy (96%). The architecture supports extensive graphics, configurable reports, provides an easy to-use, attractive interface with a smooth user experience, and allows for securely serving cases from a database. Patients and clinicians have described the application as providing dramatic benefits in understanding their TBI and improving their lives. PMID- 25747644 TI - Head stabilization measurements as a potential evaluation tool for comparison of persons with TBI and vestibular dysfunction with healthy controls. AB - A large percentage of persons with traumatic brain injury incur some type of vestibular dysfunction requiring vestibular physical therapy. These injuries may affect the natural ability to stabilize the head while walking. A simple method of utilizing motion capture equipment to measure head movement while walking was used to assess improvements in head stabilization of persons undergoing computerized vestibular physical therapy and virtual reality training for treatment of their vestibular problems. Movement data from the head and sacrum during gait were obtained over several visits and then analyzed to determine improved oscillatory head movement relative to the sacrum. The data suggest that, over time with treatment, head stabilization improves and moves toward a pattern similar to that of a healthy control population. This simple analysis of measuring head stability could be transferred to smaller, portable systems that are easily utilized to measure head stability during gait for use in gait assessment and physical therapy training. PMID- 25747645 TI - Improvements in gait speed and weight shift of persons with traumatic brain injury and vestibular dysfunction using a virtual reality computer-assisted rehabilitation environment. AB - Many people sustaining a traumatic brain injury experience vestibular pathology requiring physical therapy for treatment. This study measured improvements in gait speed and weight shift for subjects receiving vestibular physical therapy using a Computer-Assisted Rehabilitation Environment (CAREN). A 6-session CAREN, 6-session traditional vestibular therapy group was compared with a 12-session CAREN only (0 traditional sessions) therapy group. These two groups were compared to each other and with data from healthy controls performing similar tasks on the CAREN. Those participating in 12 CAREN sessions had greater improvements in gait speed (p=0.014) and weight shift scores (p<0.001) and demonstrated similar values achieved by a healthy control population. PMID- 25747646 TI - RBC mechanical fragility as a direct blood quality metric to supplement storage time. AB - INTRODUCTION: Lengthy storage times and associated storage lesion can result in reduced red blood cell (RBC) efficacy, particularly dangerous for massively transfused patients. Today's inventory management makes storage times the de facto metric of blood quality. However, RBC units' quality may vary because of time-independent factors. Mechanical fragility (MF) of RBC, reflecting sub-lethal cell damage, can potentially provide a more physiologically relevant predictor of cell's performance "in vivo." METHODS: Mechanical stress was applied using a bead mill (50 Hz) over durations varying from 0.5 to 60 minutes, or using ultrasound (40 W) with durations from 0.1 to 120 seconds. MF profiles were described in terms of percentage hemolysis following stresses of specified durations. RESULTS: RBC MF declined significantly in the presence of albumin, with albumin protecting membrane against damage from elevated temperature or from methyl-beta cyclodextrin or diamide. MF profiles allowed detection of sub-lethal membrane damage caused by elevated temperature, to a greater extent than was reflected by autohemolysis. Different types of profiles for RBC damage were associated with MF changes at different stress intensities and potentially stress types. CONCLUSIONS: These findings indicate that MF profiles can provide a powerful and versatile tool for investigation of RBC, as well as a potential metric of RBC quality. PMID- 25747647 TI - Reevaluating the selection process for the Israeli Defense Force's paramedic training program. AB - BACKGROUND: Selecting candidates for medical training programs is a complicated process aimed at identifying specific personal competencies, in an attempt to minimize attrition and produce better medical providers. The objective of this study was to evaluate the accuracy of the selection process for the Israeli Defense Force's paramedic training program and its ability to predict success measured at different end points. METHODS: Selection process test scores were crossed and measured against three different end points: attrition, national certification test scores, and training program graduation scores. RESULTS: Data were available for 146 candidates. A positive association was detected between lower formulated selection scores and attrition rates (p<0.01). Out of the 11 tests conducted that comprise the final selection score, two had shown significant association with attrition. The calculated score of these specific two tests was found to have similar association with attrition as the formulated selection score. CONCLUSIONS: The current Israeli Defense Force's paramedic formulated selection score has shown association with attrition; candidates performing poorly throughout the selection process were less likely to complete training. Similar results may be achieved by implementing a more efficient selection process based on fewer tests. Further studies are required to identify the optimal composition for selection processes. Ongoing learning and research form the ground for improvement, not only of trauma medicine but of all aspects of medicine. PMID- 25747648 TI - "Live cadavers" for practicing airway management. AB - Human cadavers have been used successfully as training models to practice airway management, but the lack of lifelike conditions reduces the utility of this model when softness of tissue and the ability to bleed are required for training scenarios. This report describes our "live cadaver" model, which combines lifelike conditions with real human anatomy. Five human cadavers were prepared as "live cadavers". This entailed cannulating the carotid and femoral arteries and the jugular and femoral veins, and then connected them to artificial blood reservoirs. An intra-aortic balloon pump was used to provide pulsating flow through the heart and major arteries. Finally, central and peripheral lines were inserted. Multiple techniques related to airway management were practiced in setting simulating the treatment of casualties with multiple trauma to include emergency cricothyroidotomy. With this model, participants were confronted with medical situations similar to those found in traumatized live patients (e.g., blood and other body fluids filling the mouth and nose, edema of the tongue and face). With the combination of lifelike conditions and real human anatomy, our experience demonstrated that the "live cadaver" increased the training value of traditionally prepared cadaver models. PMID- 25747649 TI - Reassessment of psychological distress and post-traumatic stress disorder in United States Air Force Distributed Common Ground System operators. AB - The goal of this study was to assess for the main sources of occupational stress, as well as self-reported symptoms of distress and post-traumatic stress disorder among U.S. Air Force (USAF) Distributed Common Ground System (DCGS) intelligence exploitation and support personnel. DCGS intelligence operators (n=1091) and nonintelligence personnel (n = 447) assigned to a USAF Intelligence, Surveillance, and Reconnaissance Wing responded to the web-based survey. The overall survey response rate was 31%. Study results revealed the most problematic stressors among DCGS intelligence personnel included high workload, low manning, as well as organizational leadership and shift work issues. Results also revealed 14.35% of DCGS intelligence operators' self-reported high levels of psychological distress (twice the rate of DCGS nonintelligence support personnel). Furthermore, 2.0% to 2.5% self-reported high levels of post-traumatic stress disorder symptoms, with no significant difference between groups. The implications of these findings are discussed along with recommendations for USAF medical and mental health providers, as well as operational leadership. PMID- 25747650 TI - Changes in combat task performance under increasing loads in active duty marines. AB - U.S. Marines perform mission tasks under heavy loads which may compromise performance of combat tasks. However, data supporting this performance decrement are limited. PURPOSE: The aim of this study was to determine the effects of load on performance of combat-related tasks. METHODS: Subjects (N=18) ran a modified Maneuver Under Fire ([MANUF], 300 yards [yd] total: two 25-yd sprints, 25-yd crawl, 75-yd casualty drag, 150-yd ammunition can carry, and grenade toss) portion of the U.S. Marine Corps Combat Fitness Test under 4 trial conditions: neat (no load), 15%, 30%, and 45% of body weight, with a shooting task pre- and post-trial. RESULTS: There was a significant increase in total time to completion as a function of load (p<0.0001) with a relationship between load and time (r=0.592, p<0.0001). Pre- to post-MANUF shot accuracy (p=0.005) and precision (p<0.0001) was reduced. CONCLUSION: Short aerobic performance is significantly impacted by increasing loads. Marksmanship is compromised as a function of fatigue and load. These data suggest that loads of 45% body weight increase time to cover distance and reduce the ability to precisely hit a target. PMID- 25747651 TI - Brief report: a hypothetical construct based on limited data visual system recovery after refractive surgery. AB - Laser refractive surgery, involving the computer-controlled application of a 193 nm beam of excimer laser "light," is utilized to resculpt the central cornea, thus reducing its apical thickness. On casual inspection, this simple matter of removing or excising a specific amount of central corneal avascular tissue is a smooth, seamless alteration with few apparent secondary issues or sequelae. Normal postoperative recovery is typically gauged by the recovery of high contrast visual acuity to the same (or better) degree as was previously obtained with a spectacle correction. However, although this is an acceptable means of determining operative success, it is not indicative of the complex challenges imposed upon the neurosensory system. The secondarily imposed strain upon the visual system, regarding the return to its pre-existing visual line-of-sight organization occurs only by bringing multiple adaptations into subtle and seamless play. This process is initiated and completed in a relatively short time period, such that most patients (but not all) are not even marginally aware of the challenges imposed to the visual system. This article is meant to probe those system challenges, serving to highlight this postoperative plasticity, seeking to gain a broader understanding and appreciation of the perceptual range of the visual recovery process. PMID- 25747652 TI - Prescription stimulant misuse in a military population. AB - BACKGROUND: Increased prescription drug misuse has been reported in veterans, yet there has not been a focused look at stimulant misuse in the military community or correlation with deployment injuries and illnesses. Our objective was to identify rates of stimulant misuse and any correlation with deployment in the military population. METHODS: A prospective, anonymous institutional review board approved survey in the emergency department waiting room of a military tertiary care hospital using a 12-item questionnaire created with fixed response and multiple-choice questions. Stimulant misuse was defined as taking more than prescribed, obtaining stimulants from others, and taking it for a nonprescribed reason. Proportions were assessed by Chi-square test and Fisher's exact test. RESULTS: 26/498 (5%) of respondents reported misusing stimulants in the last 5 years. Misusers were more likely to have a mental health diagnosis, and they suffered either a deployment-related injury or another injury, as compared to those who used stimulants properly (p<0.05). The stimulant misuse did not correlate with age, gender, active duty status, education, location of deployment, number of times deployed, traumatic brain injury diagnosis, or enlistment status. CONCLUSION: Stimulant drug misuse in the military community is associated with mental health conditions, deployment-related injuries, or new physical injuries. PMID- 25747653 TI - The integrated blast effects sensor suite: a rapidly developed, complex, system of systems. AB - Spurned by the increasing concern and consciousness of traumatic brain injuries in deployed U.S. service members, the U.S. Army Rapid Equipping Force sought help from the Georgia Tech Research Institute to rapidly develop and deploy a system capable of gathering relevant soldier-centric data-the Integrated Blast Effects Sensor Suite. To meet aggressive program milestones and requirements, Georgia Tech Research Institute engaged in rapid systems engineering efforts focused on leveraging iterative development and test methodologies. Ultimately, an integrated system of systems composed of vehicle systems, soldier-worn headset and torso systems, and data retrieval systems was deployed to troops in Afghanistan for an operational assessment. The Integrated Blast Effects Sensor Suite development process and parallel efforts investigating injury dosimetry methodologies have yielded unique findings and lessons learned, which should be incorporated into future evolutions of similar systems. PMID- 25747654 TI - Lessons learned from the analysis of soldier collected blast data. AB - In recent U.S. military experience, widespread exposure to improvised explosive devices has been implicated in noticeable changes in the incidence of brain injuries inversely related to reduced mortality--thought to be the unintended consequence of increase in exposure to blast wave effects--secondary to improved vital organ protection, improved personal protective equipment. Subsequently, there is a growing need for the development and fielding of fully integrated sensor systems capable of both capturing dynamic effects (i.e., "blast") on the battlefield--providing critical information for researchers, while providing value to the medical community and leaders--for development of pre-emptive measures and policies. Obtaining accurate and useful data remains a significant challenge with a need for sensors which feed systems that provide accurate interpretation of dynamic events and lend to an enhanced understanding of their significance to the individual. This article describes lessons learned from a data analysis perspective of a collaborative effort led by a team formed at Georgia Tech Research Institute to develop a "sensor agnostic" system that demonstrates full integration across variant platforms/systems. The system is designed to allow digital and analog time/frequency data synchronization and analysis, which facilitated the development of complex multimodal modeling/algorithms. PMID- 25747655 TI - Let a hundred flowers bloom: the role of context dependence in creating phenotypic diversity following targeted therapy. AB - Using a newly developed computational platform, COSPER, Litvin et al. (2015) identify context-dependent interactions between MEK and interferon signaling that underlie sensitivity and resistance to MEK inhibition in melanoma. PMID- 25747656 TI - The (phospho) needle in the (MELT) Haystack. AB - The spindle assembly checkpoint promotes chromosome bi-orientation and halts mitotic progression in the presence of improper kinetochore-microtubule attachments. Knl1, a kinetochore protein, acts as a scaffold for SAC signaling. A new study unveils remarkable complexity in the interplay of Knl1 phosphorylation and SAC function (Vleugel et al., 2015). PMID- 25747657 TI - Structural plasticity allows UCH37 to be primed by RPN13 or locked down by INO80G. AB - Two studies in this issue of Molecular Cell,VanderLinden et al. (2015) and Sahtoe et al. (2015),report crystal structures that define how deubiquitinating enzyme UCH37 is switched on or off by proteasome ubiquitin receptor RPN13 or chromatin remodeler component INO80G. PMID- 25747658 TI - A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases. AB - Mind bomb (Mib) proteins are large, multi-domain E3 ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. This ubiquitination step marks the ligand proteins for epsin-dependent endocytosis, which is critical for in vivo Notch receptor activation. We present here crystal structures of the substrate recognition domains of Mib1, both in isolation and in complex with peptides derived from Notch ligands. The structures, in combination with biochemical, cellular, and in vivo assays, show that Mib1 contains two independent substrate recognition domains that engage two distinct epitopes from the cytoplasmic tail of the ligand Jagged1, one in the intracellular membrane proximal region and the other near the C terminus. Together, these studies provide insights into the mechanism of ubiquitin transfer by Mind bomb E3 ligases, illuminate a key event in ligand-induced activation of Notch receptors, and identify a potential target for therapeutic modulation of Notch signal transduction in disease. PMID- 25747660 TI - Optimism for patients with genotype 4 HCV infection: clinical trials with direct acting antivirals finally available. PMID- 25747659 TI - Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. AB - Cells chemically isolate molecules in compartments to both facilitate and regulate their interactions. In addition to membrane-encapsulated compartments, cells can form proteinaceous and membraneless organelles, including nucleoli, Cajal and PML bodies, and stress granules. The principles that determine when and why these structures form have remained elusive. Here, we demonstrate that the disordered tails of Ddx4, a primary constituent of nuage or germ granules, form phase-separated organelles both in live cells and in vitro. These bodies are stabilized by patterned electrostatic interactions that are highly sensitive to temperature, ionic strength, arginine methylation, and splicing. Sequence determinants are used to identify proteins found in both membraneless organelles and cell adhesion. Moreover, the bodies provide an alternative solvent environment that can concentrate single-stranded DNA but largely exclude double stranded DNA. We propose that phase separation of disordered proteins containing weakly interacting blocks is a general mechanism for forming regulated, membraneless organelles. PMID- 25747661 TI - The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver. AB - Interleukin-33 (IL-33), a cytokine belonging to the IL-1 family, is crucially involved in inflammatory pathologies including liver injury and linked to various modes of cell death. However, a link between IL-33 and necroptosis or programmed necrosis in liver pathology remains elusive. We aimed to investigate the regulation of IL-33 during necroptosis-associated liver injury. The possible regulation of IL-33 during liver injury by receptor-interacting protein kinase 1 (RIPK1) and poly(ADP-ribose) polymerase 1 (PARP-1) was investigated in mice in vivo and in hepatic stellate cells in vitro. The liver immunohistopathology, flow cytometry, serum transaminase measurement, ELISA, and qPCR-based cytokine measurement were carried out. By using a chemical approach, we showed that pretreatment of mice with Necrostatin-1 (Nec-1) (inhibitor of RIPK1) and/or PJ34 (inhibitor of PARP-1) significantly protected mice against concanavalin A (ConA) liver injury (aspartate amino-transferase (AST)/alanine amino-transferase (ALT)) associated with down-regulated hepatocyte-specific IL-33 expression. In contrast, the expression level of most systemic cytokines (except for IL-6) or activation of liver immune cells was not altered by chemical inhibitors rather an increased infiltration of neutrophils in the liver. During polyinosine-polycytidylic acid (Poly(I:C))-induced acute hepatitis, liver injury and hepatocyte-specific IL-33 expression was also inhibited by PJ34 without any protective effect of PJ34 in CCl4-induced liver injury. Moreover, PJ34 down-regulated the protein expression of IL-33 in activated hepatic stellate cells by cocktail of cytokines or staurosporine in vitro. In conclusion, we evidenced that the Nec-1/PJ34 is a potent inhibitor of liver injury and Nec-1/PJ34 down-regulated hepatocyte specific IL-33 expression in the liver in vivo or in hepatic stellate cells in vitro, suggesting IL-33 as a possible readout of necroptosis-involved liver pathologies. KEY MESSAGE: Necroptosis inhibitors can protect mice against liver injury induced by ConA or Poly(I:C). IL-33 expression in liver injury in vivo is inhibited by PJ34. IL-33 expression in hepatic stellate cells in vitro is inhibited by PJ34. Hepatocyte-specific IL-33 expression is down-regulated by Nec 1/PJ34 during hepatitis. IL-33 is a new marker of necroptosis-associated liver injuries. PMID- 25747662 TI - Pocket-sized focused cardiac ultrasound: strengths and limitations. AB - Focused cardiac ultrasound (FCU) has emerged in recent years and has created new possibilities in the clinical assessment of patients both in and out of hospital. The increasing portability of echocardiographic devices, with some now only the size of a smartphone, has widened the spectrum of potential indications and users, from the senior cardiologist to the medical student. However, many issues still need to be addressed, especially the acknowledgment of the advantages and limitations of using such devices for FCU, and the extent of training required in this rapidly evolving field. In recent years, an increasing number of studies involving FCU have been published with variable results. This review outlines the evidence for the use of FCU with pocket-echo to address specific questions in daily clinical practice. PMID- 25747665 TI - Binding of pyrazine-functionalized calix[4]arene ligands with lanthanides in an ionic liquid: thermodynamics and coordination modes. AB - The complexation of representative lanthanides with three calix[4]arenes functionalized with four pyrazine pendent arms containing different substituents such as carbamoyl dioctyl (), diisopropyl phosphonate (), and diphenyl phosphoryl () was investigated in water-saturated 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BumimTf2N) by absorption spectroscopy, luminescence spectroscopy, and microcalorimetry. All three ligands form 1 : 1 ML complexes (M = Eu(3+) and L = ligand), and the stability constants (log beta) follow the order: (-1.38 +/- 0.66) ? (3.71 +/- 0.02) < (7.47 +/- 0.03), similar to the trend in the metal distribution coefficients in solvent extraction using these ligands as extractants. The enthalpy of complexation, determined by microcalorimetry, shows that the complexation of lanthanides with these bulky ligands is exothermic, and proceeds via replacement of water molecules from the primary coordination spheres. The 1 : 1 stoichiometry of the ML complexes was confirmed by electrospray ionization mass spectrometry. Results from optical absorption, luminescence and (31)P-NMR spectroscopy suggest that, out of four pendent arms on the rigid calixarene platform, only two arms coordinate with the lanthanide ion and each arm is tridentate. The influence of structural features of the ligand on the complexation of lanthanides is explained with the help of thermodynamic parameters. PMID- 25747663 TI - Towards an HIV-1 cure: measuring the latent reservoir. AB - The latent reservoir (LR) of HIV-1 in resting memory CD4(+) T cells serves as a major barrier to curing HIV-1 infection. While many PCR- and culture-based assays have been used to measure the size of the LR, correlation between results of different assays is poor and recent studies indicate that no available assay provides an accurate measurement of reservoir size. The discrepancies between assays are a hurdle to clinical trials that aim to measure the efficacy of HIV-1 eradication strategies. Here we describe the advantages and disadvantages of various approaches to measuring the LR. PMID- 25747666 TI - Revisiting resolution in hydrodynamic countercurrent chromatography: tubing bore effect. AB - A major challenge in countercurrent chromatography (CCC), the technique that works with a support-free biphasic liquid system, is to retain the liquid stationary phase inside the CCC column (Sf parameter). Two solutions are commercially available: the hydrostatic CCC columns, also called centrifugal partition chromatographs (CPC), with disks of interconnected channels and rotary seals, and the hydrodynamic CCC columns with bobbins of coiled open tube and no rotary seals. It was demonstrated that the amount of liquid stationary phase retained by a coiled tube was higher with larger bore tubing than with small bore tubes. At constant column volume, small bore tubing will be longer producing more efficiency than larger bore tube that will better retain the liquid stationary phase. Since the resolution equation in CCC is depending on both column efficiency and stationary phase retention ratio, the influence of the tubing bore should be studied. This theoretical work showed that there is an optimum tubing bore size depending on solute partition coefficient and mobile phase flow rate. The interesting result of the theoretical study is that larger tubing bores allow for dramatically reduced experiment durations for all solutes: in reversed phase CCC (polar mobile phase), hydrophobic solutes are usually highly retained. These apolar solutes can be separated by the same coil at high flow rates and reduced Sf with similar retention times as polar solutes separated at smaller flow rates and much higher Sf. PMID- 25747664 TI - The role of DNA methylation in directing the functional organization of the cancer epigenome. AB - The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes. PMID- 25747667 TI - Sensitivity enhancement in direct coupling of supported liquid membrane extractions to capillary electrophoresis by means of transient isotachophoresis and large electrokinetic injections. AB - Enhanced sensitivity for determination of basic drugs in body fluids was achieved by in-line coupling of extraction across supported liquid membrane (SLM) to large electrokinetic injection and transient isotachophoresis-capillary zone electrophoresis (tITP-CZE) in commercial CZE instrument. Twelve cm long tITP plug of 300mM ammonium acetate was formed in the separation capillary just before the electrokinetic injection of acceptor solution containing nortriptyline, haloperidol and loperamide extracted across the SLM. The tITP plug ensured efficient stacking and preconcentration of the injected basic drugs due to the tITP action of ammonium and the drugs were then separated by CZE using 5.2M acetic acid as background electrolyte. No interferences were observed from highly abundant body fluid species (NaCl and human serum albumin) due to the excellent clean-up properties of SLMs and analytical sensitivity increased up to 340 times compared to SLM extractions coupled in-line to CZE with standard hydrodynamic injections. The SLM-tITP-CZE method was characterized by good repeatability (RSDs of peak areas below 7.8%), linearity over two orders of magnitude (r(2) better than 0.994) and limits of detection (defined as 3*S/N) between 3 and 45MUg/L. Interfacing of SLM extractions to CZE instrumentation was achieved by low-cost, disposable micro-extraction devices, which can be routinely prepared in every analytical laboratory. These devices eliminated sample carry-over, minimized the need for manual sample handling and ensured fully automated determination (including extraction, injection, preconcentration and separation) of the three basic drugs in 20MUL of untreated body fluids. PMID- 25747668 TI - Serial versus parallel columns using isocratic elution: a comparison of multi column approaches in mono-dimensional liquid chromatography. AB - When a new separation problem is faced with high-performance liquid chromatography (HPLC), the analysis is addressed conventionally with a single column, trying to find out a single experimental condition aimed to resolve all compounds. However, in practice, the system selectivity may be insufficient to achieve full resolution. When a separation fails, the usual practice consists of introducing drastic changes in the chromatographic system (e.g. use of another column, solvent or pH). An alternative solution is taking benefit of the combined separation capability of two or more columns, which can be attained in multiple ways, such as diverse modalities of two-dimensional HPLC, or mono-dimensional HPLC with serial or parallel columns. In this work, the separation performance offered by the serial coupling of columns of different nature and length, operated at varying mobile phase composition in isocratic elution, is compared with the results offered by parallel columns. The resolution capability of both approaches is characterised through the limiting peak purities. It is demonstrated that serial columns of different lengths perform as new columns that increase enormously the probabilities of success. The potential of the approach is illustrated through the separation of 15 sulphonamides. In spite of the poor individual performance of the four selected columns (phenyl, cyano and two C18 columns, with nearly null resolution for the cyano column), it was found that the serial coupling of the phenyl and cyano columns of appropriate lengths succeeded in the full resolution of the 15 compounds in 20-25min, and the serial coupling of the two C18 columns yielded acceptable resolution in less than 20min. PMID- 25747669 TI - Sorption of amitriptyline and amphetamine to mixed-mode solid-phase microextraction in different test conditions. AB - A solid-phase microextraction (SPME) method based on a sampler coating that includes strong cation groups (C18/SCX) is explored as a rapid direct sampling tool to detect and quantify freely dissolved basic drugs. Sampling kinetics, sorption isotherms and competitive effects on extraction yields in mixtures were tested for amphetamine and the relatively large/hydrophobic tricyclic antidepressant amitriptyline. Both compounds are >99% ionized at pH 7.4 but their affinity for the C18/SCX fiber is markedly different with distribution coefficients (Dfw values) of 2.49+/-0.02 for amphetamine and 4.72+/-0.10 for amitriptyline. Typical changes in electrolyte homeostasis that may occur in biomedical samples were simulated by altering pH and ionic composition (Na(+) and K(+) concentrations). These changes were shown to affect C18/SCX sorption affinities of the tested drugs with less than 0.2log units. At relatively low fiber loadings (<10mmol/L coating) and at all tested exposure times, linear sorption isotherms were obtained for both compounds but at aqueous concentrations of the individual drugs corresponding to concentrations in blood that are lethal, sorption isotherms became strongly nonlinear. Competition effects within binary mixtures occurred only if combinations of aqueous concentrations resulted in total fiber loadings that were in the nonlinear range of the SPME sorption isotherm for the individual compounds. We also compared sorption to the (prototype) C18/SCX SPME coating with analogue (biocompatible) C18 coated SPME fibers. C18/SCX fibers show increased sorption affinity for cationic compounds compared to C18 fibers, as tested using amitriptyline, amphetamine and trimethoprim. Surprisingly, sorption affinity of these ionized compounds for the C18 SPME fibers were within 1log unit of the C18/SCX SPME fibers. This shows that the strong cation exchange groups within the C18/SCX coating only has a relatively small contribution to the total sorption affinity of cationic compounds. Also the role of negatively charged silanol groups in both the C18 and C18/SCX coating seems small, as anionic diclofenac species sorbed strongly to the C18 fiber. Ionized organic species seem to be substantially adsorbed to the high surface area of C18 in SPME types using porous silica based coatings. PMID- 25747670 TI - Building New Teams for Late Life Care: Lessons From LifeCourse. AB - This article details team development within a longitudinal cohort study designed to bring team-based, whole person care early in the course of serious illness. The primary innovation of this approach is the use of nonclinically trained care guides who support patients and family members by focusing care around what matters most to patients, linking to resources, collaborating with other providers, and offering continuity through care transitions. By describing the development of this team, we document the kinds of questions others may ask during the process of team creation. PMID- 25747671 TI - The Influence of Nursing Unit Characteristics on RN Vacancies in Specialized Hospice and Palliative Care. AB - The nursing shortage is projected to intensify in the United States. Organizations providing specialized hospice and palliative care will be particularly hard hit. The purpose of our study was to examine the influence of the nursing unit on registered nurse (RN) vacancies and test the moderating role of recruitment strategies in perinatal hospices. We estimated the association between the nursing unit and RN vacancies and tested the interaction effects of recruitment strategies (signing bonus and recruitment bonus). Our findings showed that increasing RN unit size and nursing leadership directly affected vacancies and that recruitment bonuses had stronger influence on reducing vacancies than signing bonuses. The findings offer critical insights for hospice administrators in attracting nurses among specialized hospice and palliative care providers. PMID- 25747672 TI - Older adults' definitions of health: A metasynthesis. AB - BACKGROUND: Despite many gerontological studies focusing on the health of older adults, little attention has been paid to their perceptions of health. Understanding older adults' health perceptions is important because their self perceptions are important predictors of and strongly related to survival and mortality. Older adults have different perceptions of health compared with younger adults because of their age-related changes, diseases, and limitations. There are also differences between older adults' and health professionals' perceptions of health. OBJECTIVES: The purpose of this systematic review was to analyze and synthesize qualitative studies that have explored older adults' perceptions of health. METHODS: Four electronic databases were searched for qualitative studies published from the earliest year to 2013, revealing 12 studies for inclusion. The systematic review employed three components of the meta-study including meta-data-analysis, meta-method, and meta-theory. RESULTS: Five health themes are identified from the included studies: ability to do something independently, absence or management of symptoms, acceptance and adjustment with optimism, connectedness with others, and feeling enough energy. CONCLUSION: Future gerontological research should use appropriate existing health theories and develop new health theories specific to older adults. Healthcare providers should evaluate and revise their health definitions according to older adults' health perceptions and provide appropriate health interventions. Policymakers should have an in-depth understanding of older adults' health perceptions to establish effective older-adult-centered health policies. PMID- 25747673 TI - Anhydrobiosis and freezing-tolerance: adaptations that facilitate the establishment of Panagrolaimus nematodes in polar habitats. AB - Anhydrobiotic animals can survive the loss of both free and bound water from their cells. While in this state they are also resistant to freezing. This physiology adapts anhydrobiotes to harsh environments and it aids their dispersal. Panagrolaimus davidi, a bacterial feeding anhydrobiotic nematode isolated from Ross Island Antarctica, can survive intracellular ice formation when fully hydrated. A capacity to survive freezing while fully hydrated has also been observed in some other Antarctic nematodes. We experimentally determined the anhydrobiotic and freezing-tolerance phenotypes of 24 Panagrolaimus strains from tropical, temperate, continental and polar habitats and we analysed their phylogenetic relationships. We found that several other Panagrolaimus isolates can also survive freezing when fully hydrated and that tissue extracts from these freezing-tolerant nematodes can inhibit the growth of ice crystals. We show that P. davidi belongs to a clade of anhydrobiotic and freezing-tolerant panagrolaimids containing strains from temperate and continental regions and that P. superbus, an early colonizer at Surtsey island, Iceland after its volcanic formation, is closely related to a species from Pennsylvania, USA. Ancestral state reconstructions show that anhydrobiosis evolved deep in the phylogeny of Panagrolaimus. The early-diverging Panagrolaimus lineages are strongly anhydrobiotic but weakly freezing-tolerant, suggesting that freezing tolerance is most likely a derived trait. The common ancestors of the davidi and the superbus clades were anhydrobiotic and also possessed robust freezing tolerance, along with a capacity to inhibit the growth and recrystallization of ice crystals. Unlike other endemic Antarctic nematodes, the life history traits of P. davidi do not show evidence of an evolved response to polar conditions. Thus we suggest that the colonization of Antarctica by P. davidi and of Surtsey by P. superbus may be examples of recent "ecological fitting" of freezing-tolerant anhydrobiotic propagules to the respective abiotic conditions in Ross Island and Surtsey. PMID- 25747675 TI - US healthcare kickback schemes come under heavy scrutiny. PMID- 25747674 TI - gammadelta T cells confer protection against murine cytomegalovirus (MCMV). AB - Cytomegalovirus (CMV) is a leading infectious cause of morbidity in immune compromised patients. gammadelta T cells have been involved in the response to CMV but their role in protection has not been firmly established and their dependency on other lymphocytes has not been addressed. Using C57BL/6 alphabeta and/or gammadelta T cell-deficient mice, we here show that gammadelta T cells are as competent as alphabeta T cells to protect mice from CMV-induced death. gammadelta T cell-mediated protection involved control of viral load and prevented organ damage. gammadelta T cell recovery by bone marrow transplant or adoptive transfer experiments rescued CD3epsilon-/- mice from CMV-induced death confirming the protective antiviral role of gammadelta T cells. As observed in humans, different gammadelta T cell subsets were induced upon CMV challenge, which differentiated into effector memory cells. This response was observed in the liver and lungs and implicated both CD27+ and CD27- gammadelta T cells. NK cells were the largely preponderant producers of IFNgamma and cytotoxic granules throughout the infection, suggesting that the protective role of gammadelta T cells did not principally rely on either of these two functions. Finally, gammadelta T cells were strikingly sufficient to fully protect Rag-/-gammac-/- mice from death, demonstrating that they can act in the absence of B and NK cells. Altogether our results uncover an autonomous protective antiviral function of gammadelta T cells, and open new perspectives for the characterization of a non classical mode of action which should foster the design of new gammadelta T cell based therapies, especially useful in alphabeta T cell compromised patients. PMID- 25747676 TI - Superior oblique extraocular muscle shape in superior oblique palsy. AB - PURPOSE: To investigate the superior oblique (SO) extraocular muscle cross section in normal controls and in SO palsy using high-resolution magnetic resonance imaging (MRI). DESIGN: Prospective observational study. METHODS: At a single academic medical center, high-resolution MRI was obtained at 312 MUm in plane resolution using surface coils in multiple, contiguous, quasi-coronal planes perpendicular to the orbital axis in 12 controls and 62 subjects with SO palsy. Previous strabismus surgery was excluded. Imaging was repeated in central gaze and infraduction. In each image plane along the SO, its cross section was outlined to compute cross-sectional area and the major and minor axes of the best fitting ellipse. Main outcome measures were SO morphology and ocular motility. RESULTS: The major and minor axes, cross-sectional area distributions, and volume of the SO belly were subnormal in orbits with SO palsy at most anteroposterior locations (P = .001), but discriminant analysis showed that palsied SO cross sections segregated distinctly into round and elongate shapes representing isotropic vs anisotropic atrophy, respectively. The major axis was relatively preserved in anisotropic atrophy (P = .0146). Cases with isotropic atrophy exhibited greater hypertropia in infraversion than central gaze, as well as greater excyclotorsion, than cases with anisotropic atrophy (P < .05 for all). CONCLUSIONS: Characteristic differences in shape of the palsied SO belly correlate with different clinical features, and may reflect both the degree of differential pathology in the medial vs lateral neuromuscular SO compartments and the basis for diversity in patterns of resulting hypertropia. PMID- 25747677 TI - Supraciliary Micro-stent Implantation for Open-Angle Glaucoma Failing Topical Therapy: 1-Year Results of a Multicenter Study. AB - PURPOSE: To evaluate the safety and efficacy of a supraciliary micro-stent (CyPass Micro-Stent; Transcend Medical, Menlo Park, California, USA) for surgical treatment of glaucoma in patients refractory to topical medications. DESIGN: Multicenter, single-arm interventional study. METHODS: Patients with open-angle glaucoma (Shaffer Grade 3 and 4) and uncontrolled medicated intraocular pressure (IOP) >21 mm Hg at baseline and candidates for conventional glaucoma surgery were enrolled. Glaucoma medications were discontinued at surgery and resumed at investigator discretion. CyPass Micro-Stent implantation was completed in all patients using a standard clear corneal approach. Adverse events, postoperative IOP changes, and need for IOP-lowering medications during the first 12 postoperative months (12M) were monitored. RESULTS: Sixty-five eyes were enrolled, and 55 were available at 12M, accounting for loss to follow-up and early termination. Baseline IOP was 24.5 +/- 2.8 mm Hg, and the mean number of medications recorded was 2.2 +/- 1.1. There were no serious intraoperative events or major adverse events (eg, retinal or choroidal detachment, persistent uveitis, persistent hyphema, hypotony maculopathy). The most common adverse events included IOP increases >30 mm Hg beyond 1 month (11%, 7/65), transient hyphema (6%, 4/65), and cataract progression (12%, 5/41 phakic eyes). Mean IOP was 16.4 +/- 5.5 mm Hg at 12 months-a 34.7% reduction (P < .0001). Mean medication usage also decreased from baseline to a mean of 1.4 +/- 1.3 medications at 12M (P = .002). In eyes originally indicated for conventional glaucoma surgery, no secondary surgery was performed in 83% (53/64). CONCLUSION: Supraciliary stenting with the CyPass Micro-Stent effectively lowers IOP as a surgical treatment for glaucoma, precluding the need for more invasive glaucoma surgery in >80% of patients at 1 year, thereby reducing postoperative glaucoma surgical complications. PMID- 25747678 TI - Immunomodulatory molecule PD-L1 is expressed on malignant plasma cells and myeloma-propagating pre-plasma cells in the bone marrow of multiple myeloma patients. PMID- 25747679 TI - Fasting blood glucose and HbA1c in children with ADHD. AB - Reports of hypocortisolism and overweight in pediatric ADHD motivate an investigation of blood glucose regulation in this group. Fasting blood glucose and HbA1c were investigated in 10 children (10-15 years) with ADHD and 22 comparisons. Fasting blood glucose was similar in both groups. HbA1c values were higher in the ADHD-group. BMI-SDS was also higher in the ADHD-group but did not predict HbA1c. The results suggest an association between ADHD and an altered blood glucose homeostasis. PMID- 25747680 TI - Short-term heart rate variability in older patients with newly diagnosed depression. AB - Dysfunction of the autonomic nervous system has been considered to be a risk factor for major depressive disorder (MDD) and cardiovascular disease (CVD). The aim of this study was to evaluate short-term heart rate variability (HRV) in elderly patients with newly diagnosed MDD. Thirty MDD patients over 60 years old newly diagnosed by a structured interview were enrolled, free from antidepressants. Socio-demographic data, blood tests, and heart rate variability (HRV) obtained from 5-min ECG were gathered. The MDD group showed significantly lower very low frequency power, low frequency power, high frequency power, and total power in frequency domain. In time domain analysis, the MDD group showed a significantly smaller standard deviation of the NN, root mean square of the differences of the successive NN, and NN50/total number of all NNs. These findings demonstrated a lower HRV in older patients who were newly diagnosed with depression without a history of CVD and antidepressants effect, compared with the control subjects. Low HRV may be an important predictor of both MDD and CVD in elderly. The use of HRV in elderly depressive patients could be a meaningful screening method for risk of CVD. PMID- 25747681 TI - The association of SNCA with hazardous alcohol use is mediated by impulsivity. PMID- 25747682 TI - From hospital admission to independent living: is prediction possible? AB - An integral component of recovery from mental illness is being able to engage in everyday activities. This ability is often restricted among people with schizophrenia. Although functional deficits are addressed during hospitalization, the ability to predict daily functioning based on information gathered during hospitalization has not been well established. This study examines whether measurements completed during hospitalization can be useful for predicting independent living within the community. Inpatients with schizophrenia (N=104) were enrolled in the study and assessed for cognitive functioning, functional capacity and symptoms. They were approached again 6 months after discharge to evaluate their functioning with respect to everyday life Instrumental Activities of Daily Living (IADL) and Activities of Daily Living (ADL). Functional capacity during hospitalization predicted 26.8% of ADL functioning and 38.8% of IADL functioning. ADL was best predicted by the severity of negative symptoms, cognitive functioning, and the number of hospitalizations (51.2%), while IADL was best predicted by functional capacity, cognition, and number of hospitalizations (60.1%). This study provides evidence that evaluations during hospitalization can be effective, and demonstrates the advantage of a holistic approach in predicting daily functioning. When a holistic approach is not practical, a functional capacity measurement may serve as an effective predictor. PMID- 25747683 TI - Maternal psychiatric history is associated with the symptom severity of ADHD in offspring. AB - Controversy exists about the role of parent psychopathology in persistence and severity of attention deficit hyperactivity disorder (ADHD) symptoms in their children. Here we aimed to analyse the potential association between the severity of ADHD symptoms in children and the presence of psychiatric and ADHD symptoms in their biological parents. Seventy-three triads of children and their parents who were in active treatment for their diagnosed ADHD were evaluated in our Child and Adolescent Mental Health Centers. The mental health of the parents was also assessed. The general psychopathology of the parents was evaluated using the Symptom Checklist-90-R (SCL-90-R), and symptoms of hyperactivity were examined using the Adult ADHD Self-Report Scale (ASRS v.1.1). The severity of symptoms in children was assessed using the ADHD Rating Scale-IV (ADHD-RS-IV). Variables that could have affected the clinical development of ADHD such as sex, evolution time, age, academic level and the presence of comorbidities were controlled. The severity of the symptoms in children with ADHD was significantly related to the psychiatric history of their mother, the younger age of the child and the presence of a comorbid conduct disorder in the child. We discussed the importance of screening for parental psychopathology in clinical practice. PMID- 25747684 TI - Human adipocytes stimulate invasion of breast cancer MCF-7 cells by secreting IGFBP-2. AB - BACKGROUND AND AIMS: A better understanding of the effects of human adipocytes on breast cancer cells may lead to the development of new treatment strategies. We explored the effects of adipocytes on the migration and invasion of breast cancer cells both in vitro and in vivo. METHODS: To study the reciprocal effects of adipocytes and cancer cells, we co-cultured human mature adipocytes and breast cancer cells in a system devoid of heterogeneous cell-cell contact. To analyze the factors that were secreted from adipocytes and that affected the invasive abilities of breast cancer cells, we detected different cytokines in various co culture media. To study the communication of mature adipocytes and breast cancer cells in vivo, we chose 10 metastatic pathologic samples and 10 non-metastatic pathologic samples to do immunostaining. RESULTS: The co-culture media of human MCF-7 breast cancer cells and human mature adipocytes increased motility of MCF-7 cells. In addition, MMP-2 was remarkably up-regulated, whereas E-cadherin was down-regulated in these MCF-7 cells. Based on our co-culture medium chip results, we chose four candidate cytokines and tested their influence on metastasis individually. We found that IGFBP-2 enhanced the invasion ability of MCF-7 cells in vitro more prominently than did the other factors. In vivo, metastatic human breast tumors had higher levels of MMP-2 than did non-metastatic tumor tissue, whereas adipocytes around metastatic breast tumors had higher levels of IGFBP-2 than did adipocytes surrounding non-metastatic breast tumors. CONCLUSIONS: IGFBP 2 secreted by mature adipocytes plays a key role in promoting the metastatic ability of MCF-7 breast cancer cells. PMID- 25747685 TI - A randomized controlled trial of an electronic informed consent process. AB - A pilot study assessed an electronic informed consent model within a randomized controlled trial (RCT). Participants who were recruited for the parent RCT project were randomly selected and randomized to either an electronic consent group (n = 32) or a simplified paper-based consent group (n = 30). Results from the electronic consent group reported significantly higher understanding of the purpose of the study, alternatives to participation, and who to contact if they had questions or concerns about the study. However, participants in the paper based control group reported higher mean scores on some survey items. This research suggests that an electronic informed consent presentation may improve participant understanding for some aspects of a research study. PMID- 25747686 TI - Privacy in confidential administrative micro data: implementing statistical disclosure control in a secure computing environment. AB - The demand for comprehensive and innovative data is constantly growing in social science. In particular, micro data from various social security agencies become more and more attractive. In contrast to survey data, administrative data offer a census with highly reliable information but are restricted in their usage. To make them accessible for researchers, data or research output either have to be anonymized or released after disclosure review procedures have been used. This article discusses the trade-off between maintaining a high capability of research potential while protecting private information, by exploiting the data disclosure portfolio and the adopted disclosure strategies of the Research Data Center of the German Federal Employment Agency. PMID- 25747687 TI - Genomic data in the electronic medical record: perspectives from a biobank community advisory board. AB - A proof of principle pharmacogenomic translational study was used as a case example to explore Biobank Community Advisory Board (CAB) member views about placing genomic information into the medical record and to establish how CAB input could affect research design. CAB members expressed enthusiasm for the potential benefit of the research discussed, yet voiced concerns regarding the recruitment and consent materials. They discussed the value of genomic research and its clinical utility; the risk of genetic discrimination; and personal ownership of genomic data. Members distinguished between indirect benefits to future generations and individual risk to research participants. Feedback was used to revise the recruitment and consent materials. Results highlight tensions reported between the public's support for genomic research and concerns with genomic information in the medical record and its use in medical decision-making. PMID- 25747688 TI - "Protecting" or "Policing": Academic Researchers' View of IRBs in an Arab Context. AB - A recent surge of research universities and human subjects research funding in the Arab world raises concerns about applied research ethics and oversight. In depth interviews conducted with 52 researchers in Lebanon and Qatar about their research conduct and the problems they face while conducting it indicate that although researchers admit to the added value of institutional review board (IRB) functions, the researchers have several complaints, such as rigid and contextually insensitive requirements, delays, and inadequate resources at IRBs, and a lack of outreach and effective communication with researchers. The study discusses these challenges pointing to the need for socioculturally adaptive regulations and forms and strengthening outreach and communication between IRBs and their users to improve ethical practices. Implications for future research are also presented. PMID- 25747689 TI - Using the Emanuel et al. framework to assess ethical issues raised by a biomedical research ethics committee in South Africa. AB - The Emanuel, Wendler, and Grady framework was designed as a universal tool for use in many settings including developing countries. However, it is not known whether the work of African health research ethics committees (RECs) is compatible with this framework. The absence of any normative or empirical weighting of the eight principles within this framework suggests that different health RECs may raise some ethical issues more frequently than others when reviewing protocols. We used the Emanuel et al. framework to assess, code, and rank the most frequent ethical issues considered by a biomedical REC during review of research protocols for the years 2008 to 2012. We extracted data from the recorded minutes of a South African biomedical REC for the years 2008 to 2012, designed the data collection sheet according to the Emanuel et al. framework, and removed all identifiers during data processing and analysis. From the 98 protocols that we assessed, the most frequent issues that emerged were the informed consent, scientific validity, fair participant selection, and ongoing respect for participants. This study represents the first known attempt to analyze REC responses/minutes using the Emanuel et al. framework, and suggests that this framework may be useful in describing and categorizing the core activities of an REC. PMID- 25747690 TI - A learning activity to introduce undergraduate students to bioethics in human clinical research: a case study. AB - We developed a pharmacology practicum assignment to introduce students to the research ethics and steps involved in a clinical trial. The assignment included literature review, critical analysis of bioethical situations, writing a study protocol and presenting it before a simulated ethics committee, a practice interview with a faculty member to obtain informed consent, and a student reflective assessment and self-evaluation. Students were assessed at various steps in the practicum; the learning efficiency of the activity was evaluated using an independent survey as well as students' reflective feedback. Most of the domains of Bloom's and Fink's taxonomies of learning were itemized and covered in the practicum. Students highly valued the translatability of theoretical concepts into practice as well as the approach to mimic professional practice. This activity was within a pharmacy program, but may be easily transferable to other medical or health sciences courses. PMID- 25747691 TI - Publication pressure and scientific misconduct in medical scientists. AB - There is increasing evidence that scientific misconduct is more common than previously thought. Strong emphasis on scientific productivity may increase the sense of publication pressure. We administered a nationwide survey to Flemish biomedical scientists on whether they had engaged in scientific misconduct and whether they had experienced publication pressure. A total of 315 scientists participated in the survey; 15% of the respondents admitted they had fabricated, falsified, plagiarized, or manipulated data in the past 3 years. Fraud was more common among younger scientists working in a university hospital. Furthermore, 72% rated publication pressure as "too high." Publication pressure was strongly and significantly associated with a composite scientific misconduct severity score. PMID- 25747692 TI - Survey of organizational research climates in three research intensive, doctoral granting universities. AB - The Survey of Organizational Research Climate (SOuRCe) is a new instrument that assesses dimensions of research integrity climate, including ethical leadership, socialization and communication processes, and policies, procedures, structures, and processes to address risks to research integrity. We present a descriptive analysis to characterize differences on the SOuRCe scales across departments, fields of study, and status categories (faculty, postdoctoral scholars, and graduate students) for 11,455 respondents from three research-intensive universities. Among the seven SOuRCe scales, variance explained by status and fields of study ranged from 7.6% (Advisor-Advisee Relations) to 16.2% (Integrity Norms). Department accounted for greater than 50% of the variance explained for each of the SOuRCe scales, ranging from 52.6% (Regulatory Quality) to 80.3% (Integrity Inhibitors). It is feasible to implement this instrument in large university settings across a broad range of fields, department types, and individual roles within academic units. Published baseline results provide initial data for institutions using the SOuRCe who wish to compare their own research integrity climates. PMID- 25747693 TI - What Is the Role of a Statistician on the IRB? PMID- 25747694 TI - Diabetic Bone Fracture Repair: A Progenitor Cell-Based Paradigm. AB - Long bone fractures in diabetics are slower to heal, have an increased risk of developing non-union and demonstrate greater potential of infection and perioperative complications compared to non-diabetics. The causative aberrant bone mineral density and insufficient bone microstructure of diabetic patients are thought to result from altered osteoblast and osteocyte function, increased bone marrow adiposity, decreased progenitor osteo- and chondral differentiation potential and increased pro-inflammatory cytokine circulation. It is therefore reasonable to hypothesize that the root cause of faulty diabetic bone homeostasis and fracture repair is a reduced population of bone marrow progenitor cells and/or their decreased osteochondral capacity complicated by their repressed neo vascular potential. The potential of transplanted mesenchymal stem cells with a scaffold to support callus formation through the creation of de novo bone in hyperglycemia has been reported. However, there are minimal supporting pre clinical and clinical investigations confirming these findings. Clinical trials have instead examined mesenchymal stem cell transplantation to slow disease progression, support .-cell viability and function and restore glucose homeostasis while the direct application of allogenic non-diabetic mesenchymal stem cells at the site of orthopaedic injury remains un-investigated. Here, the literature supporting the application of mesenchymal stem cells in diabetic fracture repair is reviewed including the process of dysfunctional diabetic fracture healing, osteoblast dysregulation and the effect of the hyperglycaemic environment on progenitor cell number and performance with a view to translating the preclinical knowledge base to the administration of mesenchymal stem cells in diabetic fracture repair. PMID- 25747695 TI - Biomaterial and Stem Cell Interactions: Histological Biocompatibility. AB - Advancements in biomaterials and stem cell technology have lead current medical technology to tissue engineering and regenerative medicine. Human engineered cartilage, bone, fascia, tendon, nerve and skin tissues have been used for the treatment of tissue injuries and degenerative diseases in combination with embryonic, fetal or adult stem and progenitor cells. Mesenchymal stem cells are one of the most extensively studied adult stem cell population and are widely utilized in cell therapies. Regeneration and 3-dimensional reconstruction of specialized connective tissues by combining differently originated micro and nanoscaled, natural or synthetic scaffolds with stem or progenitor cells are highly expected to guarantee patients to maintain acceptable life quality. In this review we discuss the important issues in biomaterial and stem cell interactions based on histological biocompatibility, updating recent basic research in this field and addressing possible future perspectives. PMID- 25747696 TI - Transmission Electron Microscopy as Key Technique for the Characterization of Telocytes. AB - It was 50 years ago when the details of cellular structure were first observed with an electron microscope (EM). Today, transmission electron microscopy (TEM) still provides the highest resolution detail of cellular ultrastructure. The existence of telocytes (TCs) has been described by Hinescu and Popescu in 2005 and up to now, many studies have been done in different tissues. EM has been fundamental in identification and recognition of TC and relationship between TC and stem cells (SCs) in recent years. We present a review on the importance of TEM to provide major advances in the knowledge of the biology of these cells. PMID- 25747697 TI - Culture and characterisation of canine mitral valve interstitial and endothelial cells. AB - Valve interstitial cells (VICs) have an important role in the aetiopathogenesis of myxomatous mitral valve disease (MMVD) in the dog. Furthermore, there is evidence that valve endothelial cells (VECs) also contribute to disease development. In addition to examining native valve tissue to understand MMVD, another strategy is to separately examine VIC and VEC biology under in vitro culture conditions. The aim of this study was to isolate and characterise canine mitral VICs and VECs from normal dog valves using a combination of morphology, immunohistochemistry and reverse transcription PCR (RT-PCR). Canine mitral VECs and VICs were isolated and cultured in vitro. The two cell populations exhibited different morphologies and growth patterns. VECs, but not VICs, expressed the endothelial markers, platelet endothelial cell adhesion molecule (PECAM-1 or CD31) and acetylated low density lipoprotein (Dil-Ac-LDL). Both VECs and VICs expressed vimentin and embryonic non-smooth muscle myosin heavy chain (SMemb), an activated mesenchymal cell marker. The myofibroblast marker, alpha smooth muscle actin (alpha-SMA), was detected at the mRNA level in both VEC and VIC cultures, but only at the protein level in VIC cultures. The morphological heterogeneity and expression of non-endothelial phenotypic markers in VEC cultures suggested that a mixture of cell types was present, which might be due to cell contamination and/or endothelial-mesenchymal transition (EndoMT). The use of a specific endothelial culture medium for primary VEC cultures enhanced the endothelial properties of the cells and reduced alpha-SMA and SMemb expression. PMID- 25747698 TI - Management of transitional cell carcinoma of the urinary bladder in dogs: a review. AB - Transitional cell carcinoma (TCC), also referred to as urothelial carcinoma, is the most common form of urinary bladder cancer in dogs, affecting tens of thousands of dogs worldwide each year. Canine TCC is usually a high grade invasive cancer. Problems associated with TCC include urinary tract obstruction, distant metastases in >50% of affected dogs, and clinical signs that are troubling both to the dogs and to their owners. Risk factors for TCC include exposure to older types of flea control products and lawn chemicals, obesity, female sex, and a very strong breed-associated risk. This knowledge is allowing pet owners to take steps to reduce the risk of TCC in their dog. The diagnosis of TCC is made by histopathology of tissue biopsies obtained by cystoscopy, surgery, or catheter. Percutaneous aspirates and biopsies should be avoided due to the risk of tumor seeding. TCC is most commonly located in the trigone region of the bladder precluding complete surgical resection. Medical treatment is the mainstay for TCC therapy in dogs. Although TCC is not usually curable in dogs, multiple drugs have activity against it. Approximately 75% of dogs respond favorably to TCC treatment and can enjoy several months to a year or more of good quality life. Many promising new therapies for TCC are emerging and with the close similarity between TCC in dogs and high grade invasive bladder cancer in humans, new treatment strategies found to be successful in canine studies are expected to help dogs and to be subsequently translated to humans. PMID- 25747699 TI - How well do vaccines for Bordetella bronchiseptica work in dogs? A critical review of the literature 1977-2014. AB - Bordetella bronchiseptica (Bb) has long been causally associated with respiratory disease in dogs. Parenteral and intranasal vaccines for this pathogen have been in common use since their development in the late 1970s and early 1980s and recently a commercial oral Bb vaccine has become available. Overall, the literature (comprising experimental infection models and field studies) documents the efficacy of these vaccines in stimulating disease-sparing mucosal and systemic immune responses that can be associated with reduced growth of Bb in vivo. However, many of the published studies are limited by flaws in experimental design, most notably a failure to consider the biological and statistical implications of the 'pen effect'. Many questions related to the longevity of vaccine induced immunity against Bb and the impact of natural exposure on herd immunity remain unanswered. PMID- 25747700 TI - Utility of socioeconomic status in predicting 30-day outcomes after heart failure hospitalization. AB - BACKGROUND: An individual's socioeconomic status (SES) is associated with health outcomes and mortality, yet it is unknown whether accounting for SES can improve risk-adjustment models for 30-day outcomes among Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure. METHODS AND RESULTS: We linked clinical data on hospitalized patients with heart failure in the Get With The Guidelines-Heart Failure database (January 2005 to December 2011) with Centers for Medicare & Medicaid Services claims and county-level SES data from the 2012 Area Health Resources Files. We compared the discriminatory capabilities of multivariable models that adjusted for SES, patient, and hospital characteristics to determine whether county-level SES data improved prediction or changed hospital rankings for 30-day all-cause mortality and rehospitalization. After adjusting for patient and hospital characteristics, median household income (per $5000 increase) was inversely associated with odds of 30-day mortality (odds ratio, 0.97; 95% confidence interval, 0.95-1.00; P=0.032) and the percentage of people with at least a high school diploma (per 5 U increase) was associated with lower odds of 30-day rehospitalization (odds ratio, 0.95; 95% confidence interval, 0.91-0.99). After adjustment for county-level SES data, relative to whites, Hispanic ethnicity (odds ratio, 0.70; 95% confidence interval, 0.58-0.83) and black race (odds ratio, 0.57; 95% confidence interval, 0.50-0.65) remained significantly associated with lower 30-day mortality, but had similar 30-day rehospitalization. County-level SES did not improve risk adjustment or change hospital rankings for 30-day mortality or rehospitalization. CONCLUSIONS: County level SES data are modestly associated with 30-day outcomes for Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure, but do not improve risk adjustment models based on patient characteristics alone. PMID- 25747701 TI - Bioactivity-guided fractionation of an antidiarrheal Chinese herb Rhodiola kirilowii (Regel) Maxim reveals (-)-epicatechin-3-gallate and (-) epigallocatechin-3-gallate as inhibitors of cystic fibrosis transmembrane conductance regulator. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is the principal apical route for transepithelial fluid transport induced by enterotoxin. Inhibition of CFTR has been confirmed as a pharmaceutical approach for the treatment of secretory diarrhea. Many traditional Chinese herbal medicines, like Rhodiola kirilowii (Regel) Maxim, have long been used for the treatment of secretory diarrhea. However, the active ingredients responsible for their therapeutic effectiveness remain unknown. The purpose of this study is to identify CFTR inhibitors from Rhodiola kirilowii (Regel) Maxim via bioactivity directed isolation strategy. We first identified fractions of Rhodiola kirilowii (Regel) Maxim that inhibited CFTR Cl- channel activity. Further bioactivity directed fractionation led to the identification of (-)-epigallocatechin-3 gallate (EGCG) as CFTR Cl- channel inhibitor. Analysis of 5 commercially available EGCG analogs including (+)-catechins (C), (-)-epicatechin (EC), (-) epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) and EGCG revealed that ECG also had CFTR inhibitory activity. EGCG dose-dependently and reversibly inhibited CFTR Cl- channel activity in transfected FRT cells with an IC50 value around 100 MUM. In ex vivo studies, EGCG and ECG inhibited CFTR-mediated short circuit currents in isolated rat colonic mucosa in a dose-dependent manner. In an intestinal closed-loop model in mice, intraluminal application of EGCG (10 MUg) and ECG (10 MUg) significantly reduced cholera toxin-induced intestinal fluid secretion. CFTR Cl- channel is a molecular target of natural compounds EGCG and ECG. CFTR inhibition may account, at least in part, for the antidiarrheal activity of Rhodiola kirilowii (Regel) Maxim. EGCG and ECG could be new lead compounds for development of CFTR-related diseases such as secretory diarrhea. PMID- 25747702 TI - The sound and the fury--bees hiss when expecting danger. AB - Honey bees are important model systems for the investigation of learning and memory and for a better understanding of the neuronal basics of brain function. Honey bees also possess a rich repertoire of tones and sounds, from queen piping and quacking to worker hissing and buzzing. In this study, we tested whether the worker bees' sounds can be used as a measure of learning. We therefore conditioned honey bees aversively to odours in a walking arena and recorded both their sound production and their movement. Bees were presented with two odours, one of which was paired with an electric shock. Initially, the bees did not produce any sound upon odour presentation, but responded to the electric shock with a strong hissing response. After learning, many bees hissed at the presentation of the learned odour, while fewer bees hissed upon presentation of another odour. We also found that hissing and movement away from the conditioned odour are independent behaviours that can co-occur but do not necessarily do so. Our data suggest that hissing can be used as a readout for learning after olfactory conditioning, but that there are large individual differences between bees concerning their hissing reaction. The basis for this variability and the possible ecological relevance of the bees' hissing remain to be investigated. PMID- 25747703 TI - Action and valence modulate choice and choice-induced preference change. AB - Choices are not only communicated via explicit actions but also passively through inaction. In this study we investigated how active or passive choice impacts upon the choice process itself as well as a preference change induced by choice. Subjects were tasked to select a preference for unfamiliar photographs by action or inaction, before and after they gave valuation ratings for all photographs. We replicate a finding that valuation increases for chosen items and decreases for unchosen items compared to a control condition in which the choice was made post re-evaluation. Whether choice was expressed actively or passively affected the dynamics of revaluation differently for positive and negatively valenced items. Additionally, the choice itself was biased towards action such that subjects tended to choose a photograph obtained by action more often than a photographed obtained through inaction. These results highlight intrinsic biases consistent with a tight coupling of action and reward and add to an emerging understanding of how the mode of action itself, and not just an associated outcome, modulates the decision making process. PMID- 25747704 TI - Studies on the epidemiology of hepatitis B and C virus infections are still needed. PMID- 25747705 TI - Inhibition of farnesoid X receptor signaling shows beneficial effects in human obesity. PMID- 25747706 TI - Towards a method for optimized extraction of soluble nutrients from fresh and composted chicken manures. AB - A preliminary method for extraction of soluble nutrients from organic materials is presented that investigates important characteristics of design for efficient extraction. The study was conducted in Polyvinyl Chloride (PVC) columns (length: 50 and 100 mm, diameter: 87.5 mm) filled with fresh and composted chicken manures, packed to densities in the range of 0.2-0.6 g cm(-3). The columns were leached with distilled water. A total of 5 cm(3) of water per cm(3) of material was applied. Leachate collection was sequentially partitioned to enable determination of soluble nutrients throughout time, including: total dissolved nitrogen (TDN), water soluble phosphorus (P) and potassium (K). Waste material state, density of packing and lengths of column all significantly (P<0.05) affected the concentration of ions in the leachate. In general, longer contact time between the percolating water and the material resulted in higher (P<0.05) concentration of ions in the leachate. Cumulative TDN and water soluble-P were greater (P<0.05) in fresh manure leachates, compared with compost leachates. Although, compost leachates provided relatively greater (P<0.05) concentration of K. Salinity ionic concentration of leachates, determined as Na and Cl, was consistently greater from fresh manure as compared to that from mature compost. Fresh manure and mature compost were determined to provide different responses to nutrient leaching because of differences in physico-chemical characteristics. Saturated hydraulic conductivity in fresh manure columns reduced rapidly with application of water to the columns. The mechanisms involved in this process are discussed with the implication for nutrient extraction and use of leachate from chicken manure waste sources. PMID- 25747707 TI - Past, present, and prospects: Reflections 40 years on from the selective impairment of semantic memory (Warrington, 1975). AB - We summarize the main findings and conclusions of Warrington's (1975) paper, The Selective Impairment of Semantic memory, a neuropsychological paper that described three cases with degenerative neurological conditions [Warrington, E. K. (1975). The selective impairment of semantic memory. The Quarterly Journal of Experimental Psychology, 27, 635-657]. We consider the developments that have followed from its publication and give a selective overview of the field in 2014. The initial impact of the paper was on neuropsychological investigations of semantic loss followed some 14 years later by the identification of Semantic Dementia (the condition shown by the original cases) as a distinctive form of degenerative disease with unique clinical and pathological characteristics. We discuss the distinction between disorders of semantic storage and refractory semantic access, the evidence for category- and modality-specific impairments of semantics, and the light that has been shed on the structure and organization of semantic memory. Finally we consider the relationship between semantic memory and the skills of reading and writing, phonological processing, and autobiographical memory. PMID- 25747708 TI - Genetic variability and phylogenetic analysis of Han population from Guanzhong region of China based on 21 non-CODIS STR loci. AB - In the present study, we presented the population genetic data and their forensic parameters of 21 non-CODIS autosomal STR loci in Chinese Guanzhong Han population. A total of 166 alleles were observed with corresponding allelic frequencies ranging from 0.0018 to 0.5564. No STR locus was observed to deviate from the Hardy-Weinberg equilibrium and linkage disequilibriums after applying Bonferroni correction. The cumulative power of discrimination and probability of exclusion of all the 21 STR loci were 0.99999999999999999993814 and 0.999998184, respectively. The results of genetic distances, phylogenetic trees and principal component analysis revealed that the Guanzhong Han population had a closer relationship with Ningxia Han, Tujia and Bai groups than other populations tested. In summary, these 21 STR loci showed a high level of genetic polymorphisms for the Guanzhong Han population and could be used for forensic applications and the studies of population genetics. PMID- 25747709 TI - Calcium sensing receptor mediated the excessive generation of beta-amyloid peptide induced by hypoxia in vivo and in vitro. AB - Hypoxia played an important role in the pathogenesis of AD. Hypoxia increased Abeta formation, then caused Alzheimer's disease. Calcium sensing receptor (CaSR) was involved in the regulation of cell growth, differentiation, hormonal secretion and other physiological function. Increasing evidence supported CaSR might play a more prominent role in susceptibility to AD, but the role of CaSR in Abeta overproduction induced by hypoxia and its mechanisms remain unclear. To investigate whether CaSR mediated the overproduction of Abeta induced by hypoxia, immunoblot and immunochemistry were employed to determine the expression of CaSR and BACE1 in hippocampal neurons and tissue and Ca(2+) image system was used to measure [Ca(2+)]i in hippocampal neurons. The content of Abeta was detected with ELISA kits. Our research found that hypoxia increased the expression of CaSR in hippocampal neurons and tissue and [Ca(2+)]i in hippocampal neurons. Calhex 231, a selective blocher of CaSR, inhibited the increase in [Ca(2+)]i induced by hypoxia. Hypoxia or GdCl3, an agonist of CaSR, increased the expression of BACE1 in hippocampal neurons and tissue, but Calhex 231 or Xesto C (a selective inhibitor of IP3 receptor) partly prevented hypoxia-induced BACE1 overexpression. Hypoxia or GdCl3 increased the content of Abeta42 and Abeta40 in hippocampal tissue, however Calhex 231 or Xesto C prevented hypoxia-induced the overproduction of Abeta42 and Abeta40 partly. Based on the above data, we suggested that hypoxia increased [Ca(2+)]i by elevated CaSR expression to promote BACE1 expression, thereby resulting in the overproduction of Abeta42 and Abeta40. PMID- 25747710 TI - Cepharanthine induces apoptosis through reactive oxygen species and mitochondrial dysfunction in human non-small-cell lung cancer cells. AB - Cepharanthine is a medicinal plant-derived natural compound which possesses potent anti-cancer properties. However, there is little report about its effects on lung cancer cells. In this study, we investigated the effects of cepharanthine on the cell viability and apoptosis in human non-small-cell lung cancer H1299 and A549 cells. It was found that cepharanthine inhibited the growth of H1299 and A549 cells in a dose-dependent manner which was associated with the generation of reactive oxygen species(ROS) and the dissipation of mitochondrial membrane potential (Deltapsim). These effects were markedly abrogated when cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, indicating that the apoptosis-inducing effect of cepharanthine in lung cancer cells was mediated by ROS. In addition, cepharanthine triggered apoptosis in non-small lung cancer cells via the upregulation of Bax, downregulation of Bcl-2 and significant activation of caspase-3 and PARP. These results provide the rationale for further research and preclinical investigation of cepharanthine's anti-tumor effect against human non-small-cell lung cancer. PMID- 25747711 TI - Micro RNA-214 contributes to proteasome independent downregulation of beta catenin in Huntington's disease knock-in striatal cell model STHdhQ111/Q111. AB - Role of beta catenin in Huntington's disease (HD) is not clear. Previous studies on HD reported varied levels of beta catenin. In the present study we showed that beta catenin is post transcriptionally down-regulated in mutant huntingtin knock in cell model STHdhQ111/Q111. This in turn leads to decreased level of wnt/beta catenin responsive genes. We observed that Gsk3beta or Gsk3beta (phospho Ser 9) is unaltered in HD and this down-regulation of beta catenin is independent of proteasomal degradation. Finally, we showed that the overexpression of miR-214 leads to the down-regulation of beta catenin at protein level only and reduces its transcriptional activity. We concluded that, miR-214 contributes to the processes that result in proteasome independent post transcriptional down regulation of beta catenin in STHdhQ111/Q111, probably through inhibition of protein synthesis from beta catenin mRNA. PMID- 25747712 TI - Polysulfide promotes neuroblastoma cell differentiation by accelerating calcium influx. AB - Polysulfides are a typical type of bound sulfur, which is physiologically stable form of sulfur species, derived from the hydrogen sulfide (H2S) that is generated endogenously in cells. We previously reported that bound sulfur protects neuronal cells from oxidative injury. In the present study, we demonstrated that polysulfides inhibited cell growth and promoted neurite outgrowth in mouse neuroblastoma Neuro2A (N2A) cells. However, Na2S showed no effect on neurite outgrowth in N2A cells. Furthermore, 2-APB and SKF96365, which are typical transient receptor potential (TRP) channel inhibitors, suppressed the neurite outgrowth induced by Na2S4. These new findings suggest that bound sulfur could induce neurite outgrowth and cell differentiation of N2A cells by accelerating calcium influx. PMID- 25747713 TI - Molecular mechanisms of resistance to human pathogenic bacteria in Caenorhabditis elegans by MEV-1 mediated oxidative stress. AB - Both mutation and knockdown in mev-1 gene render Caenorhabditis elegans susceptibility to Enterococcus faecalis infection. However, the mechanisms by which of MEV-1 defects pathogen resistance remain unclear. Here we show that mev 1RNAi causes a dramatic decrease in oxidative stress and antioxidant enzyme expressions, thereby leading to increased E. faecalis accumulation in nematode intestine. Mitochondrial superoxide change after infection induced these oxidative responses through DAF-16 activity. All together, this highlights MEV-1 as a key regulatory component for determining genetic responsiveness to oxidant/antioxidant imbalance that is associated with innate immunity. PMID- 25747714 TI - Internal dynamics of F-actin and myosin subfragment-1 studied by quasielastic neutron scattering. AB - Various biological functions related to cell motility are driven by the interaction between the partner proteins, actin and myosin. To obtain insights into how this interaction occurs, the internal dynamics of F-actin and myosin subfragment-1 (S1) were characterized by the quasielastic neutron scattering measurements on the solution samples of F-actin and S1. Contributions of the internal motions of the proteins to the scattering spectra were separated from those of the global macromolecular diffusion. Analysis of the spectra arising from the internal dynamics showed that the correlation times of the atomic motions were about two times shorter for F-actin than for S1, suggesting that F actin fluctuates more rapidly than S1. It was also shown that the fraction of the immobile atoms is larger for S1 than for F-actin. These results suggest that F actin actively facilitates the binding of myosin by utilizing the more frequent conformational fluctuations than those of S1. PMID- 25747715 TI - Cadherin-6B is required for the generation of Islet-1-expressing dorsal interneurons. AB - Cadherin-6B induces bone morphogenetic protein (BMP) signaling to promote the epithelial mesenchymal transition (EMT) in the neural crest. We have previously found that knockdown of Cadherin-6B inhibits both BMP signaling and the emigration of the early pre-migratory neural crest cells from the dorsal neural tube. In this study, we found that inhibition of BMP signaling in the neural tube, mediated by the ectopic expression of Smad-6 or Noggin, decreased the size of the Islet-1-positive dorsal cell population. Knockdown or loss of function of Cadherin-6B suppressed the generation of Islet-1-expressing cells in the dorsal neural tube, but not the Lim-1/2 positive dorsal cell population. Our results thus indicate that Cadherin-6B is necessary for the generation of Islet-1 positive dorsal interneurons, as well as the initiation of pre-migratory neural crest cell emigration. PMID- 25747716 TI - Spontaneous L-glutamate release enhancement in rat substantia gelatinosa neurons by (-)-carvone and (+)-carvone which activate different types of TRP channel. AB - Transient receptor potential (TRP) channels in the spinal dorsal horn lamina II (substantia gelatinosa; SG), which are involved in the modulation of nociceptive transmission, have not yet been fully examined in property. Activation of the TRP channels by various plant-derived chemicals results in an increase in the spontaneous release of L-glutamate onto the SG neurons. We examined the effects of a monoterpene ketone (-)-carvone (contained in spearmint) and its stereoisomer (+)-carvone (in caraway) on glutamatergic spontaneous excitatory transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. (-)-Carvone and (+)-carvone increased the frequency of spontaneous excitatory postsynaptic current (sEPSC) in a reversible and concentration dependent manner with a small increase in its amplitude. Half-maximal effective concentrations of (-)-carvone and (+)-carvone in increasing sEPSC frequency were 0.70 mM and 0.72 mM, respectively. The (-)-carvone but not (+)-carvone activity was inhibited by a TRPV1 antagonist capsazepine. On the other hand, the (+) carvone but not (-)-carvone activity was inhibited by a TRPA1 antagonist HC 030031. These results indicate that (-)-carvone and (+)-carvone activate TRPV1 and TRPA1 channels, respectively, resulting in an increase in spontaneous L glutamate release onto SG neurons, with almost the same efficacy. Such a difference in TRP activation between the stereoisomers may serve to know the properties of TRP channels in the SG. PMID- 25747717 TI - Nanoscale analysis of unstained biological specimens in water without radiation damage using high-resolution frequency transmission electric-field system based on FE-SEM. AB - Scanning electron microscopy (SEM) has been widely used to examine biological specimens of bacteria, viruses and proteins. Until now, atmospheric and/or wet biological specimens have been examined using various atmospheric holders or special equipment involving SEM. Unfortunately, they undergo heavy radiation damage by the direct electron beam. In addition, images of unstained biological samples in water yield poor contrast. We recently developed a new analytical technology involving a frequency transmission electric-field (FTE) method based on thermionic SEM. This method is suitable for high-contrast imaging of unstained biological specimens. Our aim was to optimise the method. Here we describe a high resolution FTE system based on field-emission SEM; it allows for imaging and nanoscale examination of various biological specimens in water without radiation damage. The spatial resolution is 8 nm, which is higher than 41 nm of the existing FTE system. Our new method can be easily utilised for examination of unstained biological specimens including bacteria, viruses and protein complexes. Furthermore, our high-resolution FTE system can be used for diverse liquid samples across a broad range of scientific fields, e.g. nanoparticles, nanotubes and organic and catalytic materials. PMID- 25747718 TI - MicroRNA-373 functions as an oncogene and targets YOD1 gene in cervical cancer. AB - miR-373 was reported to be elevated in several tumors; however, the role of miR 373 in cervical cancer has not been investigated. In this study we aimed to investigate the role of miR-373 in tumorigenicity of cervical cancer cells in vivo and in vitro. The expression of miR-373 was investigated using real-time reverse transcription-polymerase chain reaction assay in 45 cervical specimens and cervical cancer cell lines. The role of miR-373 in tumorigenicity of cervical cancer cells was assessed by cell proliferation, colony formation in vitro as well as tumor growth assays in vivo with the overexpression of miR-373 or gene silencing. The functional target gene of miR-373 in cervical cancer cells was identified using integrated bioinformatics analysis, gene expression arrays, and luciferase assay. We founded that the expression of miR-373 is upregulated in human cervical cancer tissues and cervical carcinoma cell lines when compared to the corresponding noncancerous tissues. Ectopic overexpression of miR-373 in human cervical cancer cells promoted cell growth in vitro and tumorigenicity in vivo, whereas silencing the expression of miR-373 decreased the rate of cell growth. YOD1 was identified as a direct and functional target of miR-373 in cervical cancer cells. Expression levels of miR-373 were inversely correlated with YOD1 levels in human cervical cancer tissues. RNAi-mediated knockdown of YOD1 phenocopied the proliferation-promoting effect of miR-373. Moreover, overexpression of YOD1 abrogated miR-373-induced proliferation of cervical cancer cells. These results demonstrate that miR-373 increases proliferation by directly targeting YOD1, a new potential therapeutic target in cervical cancer. PMID- 25747719 TI - A classroom-based physical activity intervention for urban kindergarten and first grade students: a feasibility study. AB - BACKGROUND: Urban elementary schools in minority communities with high obesity prevalence may have limited resources for physical education (PE) to achieve daily activity recommendations. Little is known whether integrating physical activity (PA) into classrooms can increase activity levels of students attending such schools. METHODS: We conducted a cluster randomized, controlled trial among kindergarten and first-grade students from four Bronx, New York, schools to determine feasibility and impact of a classroom-based intervention on students' PA levels. Students in two intervention schools received the Children's Hospital at Montefiore Joining Academics and Movement (CHAM JAM), an audio CD consisting of 10-minute, education-focused aerobic activities led by teachers three times a day. PA was objectively measured by pedometer. Each subject wore a sealed pedometer during the 6-hour school day for 5 consecutive days at baseline (Time 1) and 8 weeks postintervention (Time 2). Hierarchical linear models were fit to evaluate differences in mean number of steps between the two groups. RESULTS: A total of 988 students participated (intervention group, n=500; control group, n=488). There was no significant difference at baseline between the two groups on mean number of steps (2581 [standard deviation (SD), 1284] vs. 2476 [SD, 1180]; P=0.71). Eight weeks post-CHAM JAM, intervention group students took significantly greater mean number of steps than controls (2839 [SD, 1262] vs. 2545 [SD, 1153]; P=0.0048) after adjusting for baseline number of steps and other covariates (grade, gender, recess, and PE class). CHAM JAM was equally effective in gender, grade level, and BMI subgroups. CONCLUSIONS: CHAM JAM significantly increased school-based PA among kindergarten and first-grade students in inner city schools. This approach holds promise as a cost-effective means to integrate the physical and cognitive benefits of PA into high-risk schools. PMID- 25747722 TI - Fraction of exhaled nitric oxide measurements and asthma control: Are the numbers starting to add up? PMID- 25747720 TI - The alpha-gal story: lessons learned from connecting the dots. AB - Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal, and therefore establishing its cause is pivotal to long-term risk management. Our recent work has identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal). IgE to alpha-gal has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Results of our studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern, and central United States; Europe; Australia; and parts of Asia. Typical immune responses to carbohydrates are considered to be T-cell independent, whereas IgE antibody production is thought to involve sequential class-switching that requires input from T cells. Therefore, establishing the mechanism of the specific IgE antibody response to alpha-gal will be an important aspect to address as this area of research continues. PMID- 25747723 TI - Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells. AB - BACKGROUND: Balanced activation and inhibition of the immune system ensures pathogen clearance while avoiding hyperinflammation. Siglecs, sialic acid-binding proteins found on subsets of immune cells, often inhibit inflammation: Siglec-8 on eosinophils and Siglec-9 on neutrophils engage sialoglycan ligands on airways to diminish ongoing inflammation. The identities of human siglec ligands and their expression during inflammation are largely unknown. OBJECTIVE: The histologic distribution, expression, and molecular characteristics of siglec ligands were explored in healthy and inflamed human upper airways and in a cellular model of airway inflammation. METHODS: Normal and chronically inflamed upper airway tissues were stained for siglec ligands. The ligands were extracted from normal and inflamed tissues and from human Calu-3 cells for quantitative analysis by means of siglec blotting and isolation by means of siglec capture. RESULTS: Siglec-8 ligands were expressed on a subpopulation of submucosal gland cells of human inferior turbinate, whereas Siglec-9 ligands were expressed more broadly (submucosal glands, epithelium, and connective tissue); both were significantly upregulated in patients with chronic rhinosinusitis. Human airway (Calu-3) cells expressed Siglec-9 ligands on mucin 5B (MUC5B) under inflammatory control through the nuclear factor kappaB pathway, and MUC5B carried sialoglycan ligands of Siglec-9 on human upper airway tissue. CONCLUSION: Inflammation results in upregulation of immune-inhibitory Siglec-8 and Siglec-9 sialoglycan ligands on human airways. Siglec-9 ligands are upregulated through the nuclear factor kappaB pathway, resulting in their enhanced expression on MUC5B. Siglec sialoglycan ligand expression in inflamed cells and tissues may contribute to the control of airway inflammation. PMID- 25747724 TI - [Injectable hospital preparation of valine labeled with the carbon 13 and nitrogen 15 (5 mg/mL) for a clinical trial on the brain tumor metabolism: Pharmaceutical control of active pharmaceutical ingredient and stability study of the finished product]. AB - INTRODUCTION: The L-Valine labeled (L-[U-(13)C,(15)N] Val) is a stable isotopic tracer administered by parenteral route within the framework of a new clinical research program concerning the brain tumor metabolism. To meet regulatory requirements and have ready to use solution with an expiration date, a pharmaceutical control of active pharmaceutical ingredient followed by stability study of hospital preparation were realised. MATERIALS AND METHODS: After the pharmaceutical control of the L-[U-(13)C,(15)N] Val, the hospital preparation was prepared according to the good manufacturing preparation. Prepared bottles were stored at 5 degrees C+/-3 degrees C and 25 degrees C+/-2 degrees C for six months. The stability of the preparation was determined by physico-chemical controls (pH, osmolality, sub-visible particles, L-[U-(13)C,(15)N] Val concentration, sodium concentration, isotopic enrichment) and microbiological (bacterial endotoxin and sterility). RESULTS: Concentrations of L-[U-(13)C, (15)N] Val and sodium does not significantly decrease during the stability study. In parallel, no change in pH and osmolality were highlighted. Isotopic enrichment higher than 99.9% reflected the stability of labeling of L-valine molecule. The sub-visible particles, the bacterial endotoxin and sterility were in accordance with the European Pharmacopoeia attesting limpidity, apyrogenicity and sterility of this injectable preparation. DISCUSSION AND CONCLUSION: The stability of this hospital preparation of L-[U-(13)C, (15)N] Val has been demonstrated for six months at 5 degrees C+/-3 degrees C and 25 degrees C+/-2 degrees C, ensuring a parenteral administration as part of the clinical trial. PMID- 25747725 TI - Microsporidian parasites feminise hosts without paramyxean co-infection: support for convergent evolution of parasitic feminisation. AB - Feminisation of amphipod crustaceans is associated with the presence of at least three microsporidian parasites and one paramyxean parasite, suggesting that the ability to feminise has evolved multiple times in parasites of amphipods. Co infection by a paramyxean with one of the putative microsporidian feminisers, Dictyocoela duebenum, has inspired the alternative hypothesis that all feminisation of amphipods is caused by paramyxea and that all microsporidian associations with feminisation are due to co-infection with paramyxea (Short et al., 2012). In a population of the amphipod Gammarus duebeni, breeding experiments demonstrate that the microsporidia D. duebenum and Nosema granulosis are associated with feminisation in the absence of paramyxea. Co-infection of the two microsporidia is no more frequent than expected at random and each parasite is associated with feminisation in the absence of the other. These findings support the original hypothesis that the ability to feminise amphipods has evolved in microsporidia on multiple occasions. Additionally, the occurrence of a non-feminising strain of D. duebenum in Gammarus pulex suggests that different strains vary in their feminising ability, even within microsporidian species. The presence or absence of feminising ability in a particular microsporidian strain should not therefore be generalised to the species as a whole. PMID- 25747726 TI - Improving the gene structure annotation of the apicomplexan parasite Neospora caninum fulfils a vital requirement towards an in silico-derived vaccine. AB - Neospora caninum is an apicomplexan parasite which can cause abortion in cattle, instigating major economic burden. Vaccination has been proposed as the most cost effective control measure to alleviate this burden. Consequently the overriding aspiration for N. caninum research is the identification and subsequent evaluation of vaccine candidates in animal models. To save time, cost and effort, it is now feasible to use an in silico approach for vaccine candidate prediction. Precise protein sequences, derived from the correct open reading frame, are paramount and arguably the most important factor determining the success or failure of this approach. The challenge is that publicly available N. caninum sequences are mostly derived from gene predictions. Annotated inaccuracies can lead to erroneously predicted vaccine candidates by bioinformatics programs. This study evaluates the current N. caninum annotation for potential inaccuracies. Comparisons with annotation from a closely related pathogen, Toxoplasma gondii, are also made to distinguish patterns of inconsistency. More importantly, a mRNA sequencing (RNA-Seq) experiment is used to validate the annotation. Potential discrepancies originating from a questionable start codon context and exon boundaries were identified in 1943 protein coding sequences. We conclude, where experimental data were available, that the majority of N. caninum gene sequences were reliably predicted. Nevertheless, almost 28% of genes were identified as questionable. Given the limitations of RNA-Seq, the intention of this study was not to replace the existing annotation but to support or oppose particular aspects of it. Ideally, many studies aimed at improving the annotation are required to build a consensus. We believe this study, in providing a new resource on gene structure and annotation, is a worthy contributor to this endeavour. PMID- 25747727 TI - Unexpected magnetic semiconductor behavior in zigzag phosphorene nanoribbons driven by half-filled one dimensional band. AB - Phosphorene, as a novel two-dimensional material, has attracted a great interest due to its novel electronic structure. The pursuit of controlled magnetism in Phosphorene in particular has been persisting goal in this area. In this paper, an antiferromagnetic insulating state has been found in the zigzag phosphorene nanoribbons (ZPNRs) from the comprehensive density functional theory calculations. Comparing with other one-dimensional systems, the magnetism in ZPNRs display several surprising characteristics: (i) the magnetic moments are antiparallel arranged at each zigzag edge; (ii) the magnetism is quite stable in energy (about 29 meV/magnetic-ion) and the band gap is big (about 0.7 eV); (iii) the electronic and magnetic properties is almost independent on the width of nanoribbons; (iv) a moderate compressive strain will induce a magnetic to nonmagnetic as well as semiconductor to metal transition. All of these phenomena arise naturally due to one unique mechanism, namely the electronic instability induced by the half-filled one-dimensional bands which cross the Fermi level at around pi/2a. The unusual electronic and magnetic properties in ZPNRs endow them possible potential for the applications in nanoelectronic devices. PMID- 25747728 TI - Oxidative stress as common trait of endothelial dysfunction in chorionic arteries from fetuses with IUGR and LGA. AB - INTRODUCTION: Fetal macrosomia and intrauterine growth restriction (IUGR) associate with increased morbidity in the neonate. Placental vascular relaxation is impaired in fetal macrosomia, as well as in IUGR, and this could result from increased oxidative stress present in both conditions. We determined the role of pro- and anti-oxidants on NOS dependent relaxation in placental chorionic arteries from pregnancies with LGA babies from overweight and/or obese mothers (LOOM) and IUGR fetuses from normal BMI women. METHODS: Chorionic arteries were mounted in a wire-myograph, where responses to the NOS-dependent agent CGRP in presence or absence of the antioxidant N-acetyl cysteine (NAC), the pro-oxidant SIN-1, the SOD inhibitor DDC, and the GPx inhibitor MS were determined. Additionally the presence of pro- and antioxidant enzymes (NOX-4, SOD-1, SOD-2 and GPx-1) and eNOS in chorionic and umbilical vessels were addressed by immunohistochemistry. RESULTS: Maximal CGRP-induced relaxation was comparable to controls but presented a reduced potency in chorionic arteries from LOOM placentae, whilst in IUGR vessels both maximal response and potency were reduced. NAC increased maximal relaxation in controls, IUGR and LOOM arteries, whilst SIN 1 completely abolished the CGRP-induced relaxation only in IUGR and LOOM samples, the later effect was paralleled by SOD or GPx inhibition. These responses associated with the presence of NOX-4, SOD-1 and GPx-1 in the endothelium and vascular wall of chorionic and umbilical arteries in the different groups studied. DISCUSSION: These data suggest that NOS dependent relaxation in placental vessels from IUGR and LOOM pregnancies present a higher sensitivity to oxidative stress. PMID- 25747729 TI - Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta--a study on maternal cholestasis model. AB - INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and potential adverse fetal outcome. Farnesoid X receptor (FXR), also known as a bile acid receptor, was found to be expressed in placenta with low level. Whether activation of FXR by specific agonists could regulate the pathogenesis of ICP is still unclear. METHODS: A model of maternal cholestasis was induced by administration of 17alpha-ethynylestradiol (E2) in pregnant mice for 6 days. We explored the regulatory effect of WAY-362450 (W450), a highly selective and potent FXR agonist on placenta. RESULTS: In this study, we demonstrated that administration of E2 increased bile acid levels in mouse serum, liver and amniotic fluid. Bile acid levels were significantly decreased after W450 treatment. W450 protected against the impairment of placentas induced by E2, including severe intracellular edema and apoptosis of trophoblasts. Moreover, W450 significantly induced the expressions of FXR target bile acid transport gene ATP-binding cassette, sub-family B (MDR/TAP), member 11 (Abcb11;Bsep) in placenta. W450 could also attenuate placental oxidative stress and increase the expressions of antioxidant enzymes Prdx1 and Prdx3. DISCUSSION AND CONCLUSION: In conclusion, our data demonstrated that FXR agonist W450 modulated bile acid balance and protected against placental oxidative stress. Thus, our results support that potent FXR agonists might represent promising drugs for the treatment of ICP. PMID- 25747730 TI - The chemical ecology of the fly. AB - Not only is the sense of smell of pivotal importance to most animals but also serves as a significant model system in biological research. In recent years, great strides in our understanding of how the olfactory system is organized and operates have been made. Instrumental in these efforts has been work performed in Drosophila melanogaster. In spite of the wealth of information gathered, it remains unclear how the fly's olfactory system is used to decode the chemical environment. Here we describe recent findings on the chemical ecology of the fly and speculate on possible functions of the volatile chemicals that flies detect. We argue that for many of the fly's olfactory chemoreceptors, distinct and ecologically relevant functions can be identified. PMID- 25747732 TI - Cell therapy for liver diseases: current medicine and future promises. AB - Liver diseases are a major health problem worldwide since they usually represent the main causes of death in most countries, causing excessive costs to public health systems. Nowadays, there are no efficient current therapies for most hepatic diseases and liver transplant is infrequent due to the availability of organs, cost and risk of transplant rejection. Therefore, alternative therapies for liver diseases have been developed, including cell-based therapies. Stem cells (SCs) are characterized by their self-renewing capacity, unlimited proliferation and differentiation under certain conditions into tissue- or organ specific cells with special functions. Cell-based therapies for liver diseases have been successful in experimental models, showing anti-inflammatory, antifibrogenic and regenerative effects. Nowadays, clinical trials using SCs for liver pathologies are increasing in number, and those that have reached publication have achieved favorable effects, encouraging us to think that SCs will have a potential clinical use in a short time. PMID- 25747731 TI - Mammalian pheromones: emerging properties and mechanisms of detection. AB - The concept of mammalian pheromones was established decades before the discovery of any bioactive ligands. Therefore, their molecular identity, native sources, and the meaning of their detection has been largely speculative. There has been recent success in identifying a variety of candidate mouse pheromones and other specialized odors. These discoveries reveal that mammalian pheromones come in a variety of ligand types and they are detected by sensory neurons that are pre-set to promote an array of social and survival behaviors. Importantly, recent findings show that they activate molecularly diverse sensory neurons that differ from canonical odorant detectors. These novel sensory neurons hold future promise to unlock the mystery of how their detection is hardwired to generate behavior. PMID- 25747733 TI - Photoaddition of two guanine bases to single Ru-TAP complexes. Computational studies and ultrafast spectroscopies to elucidate the pH dependence of primary processes. AB - The covalent photoadduct (PA) between [Ru(TAP)3](2+) (TAP = 1,4,5,8 tetraazaphenanthrene) and guanosine monophosphate (GMP) opened the way to interesting photobiological applications. In this context, the PA's capability upon illumination to give rise to the addition of a second guanine base is especially interesting. The origins of these intriguing properties are for the first time thoroughly investigated by an experimental and theoretical approach. The PA's spectroscopic and redox data combined with TDDFT results corroborated with resonance Raman data show that the properties of this PA (pKa around 7) depend on the solution pH. Theoretical results indicate that the acid form PA.H(+) when excited should relax to MLCT (metal-to-ligand charge transfer) excited states, in contrast to the basic form PA whose excited state should have LLCT/ILCT (ligand-to-ligand charge transfer/intra ligand charge transfer) characteristics. Ultrafast excitation of PA.H(+) at pH 5.9 produces continuous dynamic processes in a few hundred picoseconds involving coupled proton-electron transfers responsible for luminescence quenching. Long-lived species of a few microseconds capable of reacting with GMP are produced at that pH, in agreement with the formation of covalent addition of a second GMP to PA, as shown by mass spectrometry results. In contrast, at pH 8 (mainly nonprotonated PA), other ultrafast transient species are detected and no GMP biadduct is formed in the presence of GMP. This pH dependence of photoreaction can be rationalized with the different nature of the excited states, thus at pH 8, unreactive LLCT/ILCT states and at pH 5.9 reactive MLCT states. PMID- 25747734 TI - Validation of the Childbirth Attitudes Questionnaire in Greek and psychosocial characteristics of pregnant women with fear of childbirth. AB - BACKGROUND: Fear of childbirth has been found to be a factor that influences women's decision about their choice of delivery. The investigation of psychological factors that relate to fear of childbirth as well as the validation of the Childbirth Attitudes Questionnaire (CAQ) can help identify pregnant women with high fear of childbirth. AIM: This study aimed to (a) translate and validate the Childbirth Attitude Questionnaire in Greek and (b) explore how fear of childbirth was related to childbirth self-efficacy, state anxiety, depression, neuroticism, self-esteem and optimism. METHODS: 145 nulliparous pregnant women, in late pregnancy, attending routine antenatal visit in a private maternity clinic participated. All participants completed the CAQ (fear of childbirth) and other self-report questionnaires that measured childbirth self-efficacy, self esteem, optimism, neuroticism, state anxiety and depressive symptomatology. Factor structure was investigated using principal axis factoring. Cronbach's alpha was used to measure internal consistency reliability. Pearson's correlation coefficients were calculated between all study variables, followed by multiple linear regression. FINDINGS: The factor analysis suggested the existence of one factor structure. Construct validity was confirmed by computing correlations between the CAQ and childbirth self-efficacy, self-esteem and optimism. Multivariate analysis showed that childbirth self-efficacy, self-esteem and optimism were negatively and significantly associated with fear of childbirth. CONCLUSION AND IMPLICATIONS FOR PRACTICE: The Greek version of the CAQ is a reliable and valid measure. The clinical use of CAQ may enable midwives and other health care professionals to identify pregnant women with low childbirth confidence and to provide information and support. PMID- 25747735 TI - Oxidative stress markers at birth: Analyses of a neonatal population. AB - In order to further understand neonatal stress and, thus, control it efficaciously, there is a need for more information on the manifestations of stress at the molecular level in the newborn, with particular regard to oxidants, and anti-oxidant and anti-stress mechanisms, including mitochondrial heat shock protein-chaperones such as Hsp60. We investigated patterns of anti-oxidants, biomarkers of oxidative stress, and Hsp60 levels in sera from newborns and found significant associations between glutathione (GSH) levels and gestational age, delivery modality, and lipid hydroperoxydes (LOOH) level. LOOH levels and spontaneous (vaginal) delivery were independently associated with increased GSH levels when these were above the median. Hsp60 and LOOH levels were positively correlated whereas Hsp60 and GSH levels were inversely correlated in spontaneously delivered newborns; in contrast, Hsp60 and GSH levels were positively correlated in newborns delivered by cesarea. Our results point to new directions in the search for definite patterns of GSH, LOOH, and Hsp60 in the newborn's serum that might have functional and diagnostic significance and that could help in the monitoring of newborn health during and after delivery. In addition, the data provide a starting basis for investigating the precise roles and interplay of GSH and Hsp60 in the maintenance of an optimal redox balance at birth to cope with the stress inherent to delivery, and also for investigating the predictive value of any given pattern of GSH, LOOH, and Hsp60 at birth with regard to health status and risk of disease in adult life. PMID- 25747736 TI - Wharton's jelly derived mesenchymal stromal cells: Biological properties, induction of neuronal phenotype and current applications in neurodegeneration research. AB - Multipotent mesenchymal stromal cells, also known as mesenchymal stem cells (MSC), can be isolated from bone marrow or other tissues, including fat, muscle and umbilical cord. It has been shown that MSC behave in vitro as stem cells: they self-renew and are able to differentiate into mature cells typical of several mesenchymal tissues. Moreover, the differentiation toward non-mesenchymal cell lineages (e.g. neurons) has been reported as well. The clinical relevance of these cells is mainly related to their ability to spontaneously migrate to the site of inflammation/damage, to their safety profile thanks to their low immunogenicity and to their immunomodulation capacities. To date, MSCs isolated from the post-natal bone marrow have represented the most extensively studied population of adult MSCs, in view of their possible use in various therapeutical applications. However, the bone marrow-derived MSCs exhibit a series of limitations, mainly related to their problematic isolation, culturing and use. In recent years, umbilical cord (UC) matrix (i.e. Wharton's jelly, WJ) stromal cells have therefore emerged as a more suitable alternative source of MSCs, thanks to their primitive nature and the easy isolation without relevant ethical concerns. This review seeks to provide an overview of the main biological properties of WJ derived MSCs. Moreover, the potential application of these cells for the treatment of some known dysfunctions in the central and peripheral nervous system will also be discussed. PMID- 25747737 TI - Predicting a safe screw length for volar plate fixation of distal radius fractures: lunate depth as a marker for distal radius depth. AB - PURPOSE: We hypothesized that the lunate depth as measured on plain lateral radiographs can be used to predict distal radius depth radially and ulnarly and serve as a useful reference for intraoperative screw placement in volar plate fixation of distal radius fractures. METHODS: Plain radiographs and magnetic resonance imaging (MRI) of the wrists of 30 patients were reviewed. The lunate depth and the maximal depth of the distal radius were determined from plain lateral radiographs. Depth of the distal radius, measured in quartiles, was determined from axial MRI images, and the lunate depth was obtained from sagittal MRI images. The depth of the distal radius in each quartile was then calculated related to the lunate depth. RESULTS: The mean depth of the lunate on plain radiographs and MRI was 17.5 mm and 17.4 mm, respectively. The depth of the distal radius from ulnar to radial was 18.4 mm, 20.2 mm, 19.4 mm, and 15.1 mm for the 1st through 4th quartiles, respectively. The depth of the distal radius is the least radially (4th quartile), with a mean 87% of the lunate depth, and greatest in the 2nd quartile, with a mean 116% of the lunate depth. CONCLUSIONS: The depth of the lunate as measured on plain radiographs can be used as a marker for drilling and placement of safe screw lengths during volar plate fixation of distal radius fractures. We recommend that surgeons use the lunate depth as an estimate for the length of their longest screw when fixing distal radius fractures with volar plate techniques to avoid extensor tendon irritation and rupture. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 25747738 TI - Trends in carpal tunnel surgery: an online survey of members of the American Society for Surgery of the Hand. AB - PURPOSE: To investigate the current treatment patterns of carpal tunnel surgery by members of the American Society of Surgeons of the Hand today and to assess how several elements of practice vary by surgeon location and experience. METHODS: An online survey consisting of 10 questions was sent electronically to members of the American Society of Surgeons of the Hand (N = 2,413). A brief description of the study and a link were sent to participants by the investigators. Results were anonymously uploaded to an online spreadsheet. RESULTS: 716 hand surgeons (30%) responded to the survey. Surgeons were nearly equally represented by region. A wide variation in surgeon experience was observed. A majority (65%) performed most of their surgery at an outpatient surgical center. Preoperative electrodiagnostic testing was used, at least occasionally, by 90% of surgeons. Approximately one-half did not administer preoperative antibiotics at the time of surgery. Intravenous sedation with local anesthesia was the most common practice (43%), followed by Bier block (18%). A mini-open incision was most commonly used (50%). A minority reported using an orthosis postoperatively (29%), and they rarely prescribed a course of postoperative therapy (12%). Postoperative pain management was variable, with hydrocodone and derivatives given most commonly (61%). International practitioners were much less likely to operate in an outpatient surgical center (45%) or use antibiotics (13%). Younger surgeons were more likely to use electrodiagnostic testing (96%) compared with the mean (90%). CONCLUSIONS: When compared with several previous similar studies, we noted a trend toward increased use of electrodiagnostic testing and decreased use of postoperative therapy and immobilization. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analysis V. PMID- 25747739 TI - Flexor tendon repair with a knotless, bidirectional barbed suture: an in vivo biomechanical analysis. AB - PURPOSE: To compare and analyze biomechanical properties and histological characteristics of flexor tendons either repaired by a 4-strand modified Kessler technique or using barbed suture with a knotless repair technique in an in vivo model. METHODS: A total of 25 chickens underwent surgical transection of the flexor digitorum profundus tendon followed by either a 4-strand Kessler repair or a knotless repair with barbed suture. Chickens were randomly assigned to 1 of 3 groups with various postoperative times to death. Harvested tendons were subjected to biomechanical testing or histologic analysis. RESULTS: Harvested tendons revealed failures in 25% of knotless repairs (8 of 32) and 8% of 4-strand Kessler repairs (2 of 24). Biomechanical testing revealed no significant difference in tensile strength between 4-strand Kessler and barbed repairs; however, this lack of difference may be attributed to lower statistical power. We noted a trend toward a gradual decrease in strength over time for barbed repairs, whereas we noticed the opposite for the 4-strand Kessler repairs. Mode of failure during testing differed between repair types. The barbed repairs tended toward suture breakage as opposed to 4-strand Kessler repairs, which demonstrated suture pullout. Histological analysis identified no difference in the degree of inflammation or fibrosis; however, there was a vigorous foreign body reaction around the 4-strand Kessler repair and no such response around the barbed repairs. CONCLUSIONS: In this model, knotless barbed repairs trended toward higher in vivo failure rates and biomechanical inferiority under physiologic conditions, with each repair technique differing in mode of failure and respective histologic reaction. We are unable to recommend the use of knotless barbed repair over the 4-strand modified Kessler technique. CLINICAL RELEVANCE: For the repair techniques tested, surgeons should prefer standard Kessler repairs over the described knotless technique with barbed suture. PMID- 25747740 TI - Forearm compartment syndrome as a result of eosinophilic fasciitis: case report. AB - Eosinophilic fasciitis is an uncommon scleroderma-like connective tissue disease, usually characterized by symmetrical and painful swelling and induration of the skin and thickened fascia infiltrated with lymphocytes and eosinophils. A middle aged woman with follicular lymphoma being treated with chemotherapy presented with acute onset atraumatic forearm swelling and severe pain. The history, physical examination, and pressure measurements were consistent with compartment syndrome. Intraoperative biopsy of the forearm fascia confirmed eosinophilic fasciitis. PMID- 25747741 TI - Human induced pluripotent stem cell-derived neurons improve motor asymmetry in a 6-hydroxydopamine-induced rat model of Parkinson's disease. AB - BACKGROUND AIMS: Since human embryonic stem cells and human fetal neural stem cells have immune rejection and ethical issues, recent advancements in induced pluripotent stem cells (iPS cells) provide new possibilities to study autologous cell therapy for Parkinson's disease (PD). METHODS: We isolated human skin fibroblasts from normal individuals and patients with PD; we generated iPS cells by transfecting these human skin fibroblasts with retroviral reprogramming factors of OCT4, SOX2, KLF4 and c-MYC and induced iPS cells to differentiate neural stem cells (NSCs) and then into neurons and dopamine neurons in vitro. RESULTS: We found that iPS cell-derived NSC transplant into the striatum of the 6 hydroxydopamine (OHDA)-induced PD rats improved their functional defects of rotational asymmetry at 4, 8, 12 and 16 weeks after transplantation. iPS cell derived NSCs were found to survive and integrate into the brain of transplanted PD rats and differentiated into neurons, including dopamine neurons in vivo. CONCLUSIONS: Transplantation of iPS cell-derived NSCs has therapeutic potential for PD. Our study provided experimental proof for future clinical application of iPS cells in cell-based treatment of PD. PMID- 25747742 TI - Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. AB - BACKGROUND AIMS: Natural killer (NK) cell-based immunotherapy is a promising treatment for a variety of malignancies. However, generating sufficient cell numbers for therapy remains a challenge. To achieve this, optimization of protocols is required. METHODS: Mature NK cells were expanded from peripheral blood mononuclear cells PBMCs in the presence of anti-CD3 monoclonal antibody and interleukin-2. Additionally, NK-cell progenitors were generated from CD34(+) hematopoietic stem cells or different T/NK-cell progenitor populations. Generated NK cells were extensively phenotyped, and functionality was determined by means of cytotoxicity assay. RESULTS: Addition of ascorbic acid (AA) resulted in more proliferation of NK cells without influencing NK-cell functionality. In more detail, PBMC-derived NK cells expanded 2362-fold (median, range: 90-31,351) in the presence of AA and were capable of killing tumor cells under normoxia and hypoxia. Moreover, hematopoietic stem cell-derived progenitors appeared to mature faster in the presence of AA, which was also observed in the NK-cell differentiation from early T/NK-cell progenitors. CONCLUSIONS: Mature NK cells proliferate faster in the presence of phospho-L-AA, resulting in higher cell numbers with accurate functional capacity, which is required for adoptive immunotherapy. PMID- 25747743 TI - Progenitor cells are mobilized by acute psychological stress but not beta adrenergic receptor agonist infusion. AB - OBJECTIVES: Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological beta-adrenergic (betaAR) stimulation on peripheral PC numbers in humans. METHODS: In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and betaAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the betaAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs). RESULTS: Both psychological stress and betaAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8(+) T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a betaAR-agonist did not result in a significant change in circulating PCs. CONCLUSION: PCs are rapidly mobilized by psychological stress via mechanisms independent of betaAR-stimulation, although the findings do not exclude betaAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress induced PC mobilization seems warranted. PMID- 25747745 TI - Evidence-based policy versus morality policy: the case of syringe access programs. AB - Evidence-based practice (EBP) combines proven interventions with clinical experience, ethics, and client preferences to inform treatment and services. Although EBP is integrated into most aspects of social work and public health, at times EBP is at odds with social policy. In this article the authors explore the paradox of evidence-based policy using syringe access programs (SAP) as a case example, and review methods of bridging the gap between the emphasis on EBP and lack of evidence informing SAP policy. Analysis includes the overuse of morality policy and examines historical and current theories why this paradox exists. Action steps are highlighted for creating effective policy and opportunities for public health change. Strategies on reframing the problem and shifting target population focus to garner support for evidence-based policy change are included. This interdisciplinary understanding of the way in which these factors converge is a critical first step in moving beyond morality-based policy toward evidence based policy. PMID- 25747746 TI - Goiter in paintings by Rogier van der Weyden (1399-1464). AB - Figures affected by goiter were only sparsely depicted by Peter Paul Rubens and Albrecht Durer among Flemish artists, because obvious goiter was not common in regions such as the Netherlands and Belgium. However, the recent observation of two figures with a goiter elegantly depicted by Rogier van der Weyden has raised our interest in this topic. When taking a close look at the paintings of this Flemish Renaissance painter, it is interesting to note that 16 portrayed subjects show an abnormal profile of the neck with swelling, suggestive of a presumptive medico-artistic diagnosis of goiter. Van der Weyden travelled to Italy where he soon acquired great fame and was second only to the other Flemish painter of the time, Jan Van Eyck. It is very likely that in Italy he had the opportunity to look at several female figures depicted with goiter, which may have influenced his paintings. Van der Weyden was appreciated because of his style to mix realistic details with idealized softened features to increase the beauty and appeal of his models. It is also likely that the integration of the goiter may have been part of the Renaissance tendency toward a more realistic and precise representation of subjects. The fact that in almost all cases the goiter was a low-to-moderate grade enlargement of the thyroid may confirm our speculation that perhaps the painter used the same model or the template derived from one model for subsequent paintings. PMID- 25747744 TI - How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction. AB - Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. The pathophysiology and etiology of addiction is only partially understood despite extensive research because of the gap between current preclinical models of addiction and the clinical criteria of the disorder. This review presents a brief overview, based on selected methodologies, of how behavioral models have evolved over the last 50 years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. It is hoped that these new models will increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additionally, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. PMID- 25747747 TI - A comparison of lateral fixation versus dual plating for simple bicondylar fractures. AB - BACKGROUND: The best fixation method for bicondylar tibial plateau fracture is debated. The aim of this study was to compare the effect of a lateral locking plate with that of dual plates in the treatment of tibial plateau fracture with a relatively intact medial condyle fragment. METHODS: Eighty-six patients diagnosed with a bicondylar tibial plateau fracture with a relatively intact medial condyle were assigned to groups treated with either dual buttress plates (DP group) or a lateral locking plate (LP group). Preoperative characteristics, surgical details, and postoperative complications were recorded and compared between groups. Hospital for Special Surgery Knee Scoring System score was used to evaluate clinical outcome. RESULTS: Both groups displayed satisfactory clinical and radiographic results. There were no significant differences in associated preoperative conditions between the DP and LP groups. Durations of hospital stay and operation were significantly shorter, and blood loss significantly less, in the LP group than in the DP group (P=0.045;0.038;0.031). The rate of delayed union was significantly lower in the LP group than in the DP group (P=0.023). CONCLUSION: Both dual-plate and lateral locking-plate fixation can provide satisfactory treatment of bicondylar tibial plateau fractures if properly used. When the medial tibial condyle is relatively intact, a lateral locking plate can provide stability similar to that of dual plate while decreasing operative duration and soft-tissue complications, which can assist fracture healing and shorten hospital stay. LEVEL OF EVIDENCE: I - Randomized controlled trial. PMID- 25747748 TI - Myocardial autophagic energy stress responses--macroautophagy, mitophagy, and glycophagy. AB - An understanding of the role of autophagic processes in the management of cardiac metabolic stress responses is advancing rapidly and progressing beyond a conceptualization of the autophagosome as a simple cell recycling depot. The importance of autophagy dysregulation in diabetic cardiomyopathy and in ischemic heart disease - both conditions comprising the majority of cardiac disease burden - has now become apparent. New findings have revealed that specific autophagic processes may operate in the cardiomyocyte, specialized for selective recognition and management of mitochondria and glycogen particles in addition to protein macromolecular structures. Thus mitophagy, glycophagy, and macroautophagy regulatory pathways have become the focus of intensive experimental effort, and delineating the signaling pathways involved in these processes offers potential for targeted therapeutic intervention. Chronically elevated macroautophagic activity in the diabetic myocardium is generally observed in association with structural and functional cardiomyopathy; yet there are also numerous reports of detrimental effect of autophagy suppression in diabetes. Autophagy induction has been identified as a key component of protective mechanisms that can be recruited to support the ischemic heart, but in this setting benefit may be mitigated by adverse downstream autophagic consequences. Recent report of glycophagy upregulation in diabetic cardiomyopathy opens up a novel area of investigation. Similarly, a role for glycogen management in ischemia protection through glycophagy initiation is an exciting prospect under investigation. PMID- 25747750 TI - Cathepsins in heart disease-chewing on the heartache? PMID- 25747751 TI - Renal deafferentation: target for treatment of cardiovascular diseases involving sympathetic overactivity. PMID- 25747752 TI - Exercise training prevents the deterioration in the arterial baroreflex control of sympathetic nerve activity in chronic heart failure patients. AB - Arterial baroreflex control of muscle sympathetic nerve activity (ABRMSNA) is impaired in chronic systolic heart failure (CHF). The purpose of the study was to test the hypothesis that exercise training would improve the gain and reduce the time delay of ABRMSNA in CHF patients. Twenty-six CHF patients, New York Heart Association Functional Class II-III, EF <= 40%, peak Vo2 <= 20 ml.kg(-1).min(-1) were divided into two groups: untrained (UT, n = 13, 57 +/- 3 years) and exercise trained (ET, n = 13, 49 +/- 3 years). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique. Arterial pressure was measured on a beat-to-beat basis. Time series of MSNA and systolic arterial pressure were analyzed by autoregressive spectral analysis. The gain and time delay of ABRMSNA was obtained by bivariate autoregressive analysis. Exercise training was performed on a cycle ergometer at moderate intensity, three 60-min sessions per week for 16 wk. Baseline MSNA, gain and time delay of ABRMSNA, and low frequency of MSNA (LFMSNA) to high-frequency ratio (HFMSNA) (LFMSNA/HFMSNA) were similar between groups. ET significantly decreased MSNA. MSNA was unchanged in the UT patients. The gain and time delay of ABRMSNA were unchanged in the ET patients. In contrast, the gain of ABRMSNA was significantly reduced [3.5 +/- 0.7 vs. 1.8 +/- 0.2, arbitrary units (au)/mmHg, P = 0.04] and the time delay of ABRMSNA was significantly increased (4.6 +/- 0.8 vs. 7.9 +/- 1.0 s, P = 0.05) in the UT patients. LFMSNA-to-HFMSNA ratio tended to be lower in the ET patients (P < 0.08). Exercise training prevents the deterioration of ABRMSNA in CHF patients. PMID- 25747749 TI - Chasing cardiac physiology and pathology down the CaMKII cascade. AB - Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca(2+) in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca(2+) signaling explains the subtle and critical control of important events of ECC and relaxation, such as Ca(2+) influx and SR Ca(2+) release and uptake. The multifunctional Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation but also in cell death, transcriptional activation of hypertrophy, inflammation, and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca(2+) levels. This activity can be sustained, creating molecular memory after the decline in Ca(2+) concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation, and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca(2+) regulation and dysregulation in cardiac health and disease. PMID- 25747753 TI - An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia reperfusion injury. AB - Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP 1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4 day pretreatment with alogliptin reduced the infarct size from 43.1 +/- 2.5% to 17.1 +/- 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3beta, and cAMP response element binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways. PMID- 25747755 TI - Whole grain in manufactured foods: Current use, challenges and the way forward. AB - Some countries now incorporate recommendations for increased consumption of whole grain (WG) into local dietary guidelines. Cereal and pseudo-cereal grains are good sources of complex carbohydrates, dietary fiber, proteins, phytochemicals, vitamins and minerals. However, research shows that the large majority of consumers are still falling short of WG consumption goals. To address this, we are actively involved in research to help increase the WG content of processed foods without compromising on taste and texture. In order to ensure consumer trust, the advancement of process technologies in incorporating WG to produce tasty food has to go hand in hand with well designed clinical trials that confirm the health benefits resulting from diets rich in WG. PMID- 25747756 TI - Maleimide as an efficient nucleophilic partner in the aza-Morita-Baylis-Hillman reaction: synthesis of chiral 3-substituted-3-aminooxindoles. AB - A highly enantioselective Morita-Baylis-Hillman reaction of maleimides with isatin derived ketimines has been developed to obtain enantiomerically enriched 3 substituted-3-aminooxindoles using beta-isocupreidine as an organocatalyst. Maleimide acting as a nucleophile provides products with up to 99% ee. PMID- 25747754 TI - Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice. AB - Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg.kg(-1).day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (3 v. <= 3 week) and source of detection by Surveillance (active vs. passive), were the most protective factors for relapse (OR = 0.58; CI 95%: 0.46-0.74), treatment after interruption (0.36; 0.31-0.42) treatment failure (0.24; 0.20-0.29) and clinical resistance (0.24; 0.09-0.67). CONCLUSION: Head lesions and treatment variables (e.g. therapy method and duration) could predict the occurrence of adverse post term outcomes of Cutaneous Lishmaniosis. Further longitudinal studies have to clarify cause and effect relationships. PMID- 25747780 TI - First case of NDM-1 producing Klebsiella pneumoniae in Caribbean islands. AB - OBJECTIVES: Characterize a NDM-1 producing K. pneumoniae isolate recovered from a patient hospitalized in Guadeloupe, French West Indies, after its transfer from Cuba METHODS: Antibiotic susceptibilities were determined by the disk diffusion method, and E-test. Carbapenemase production was assessed using the Carba NP test. Antibiotic resistance determinants and their surrounding structures were characterized by PCR mapping and DNA sequencing. Transfer of the beta-lactam resistance marker was attempted by liquid mating-out assays RESULTS: Here we reported the first NDM-1 producing enterobacterial isolate recovered from Caribbean islands. This K. pneumoniae isolate belongs to a new sequence type (ST1649). The blaNDM-1 gene together with the aacA4 gene were carried on a self conjugative IncR plasmid of c.a. 80kb. CONCLUSION: This study describes the first identification of a NDM-1 producer in Caribbean islands. The uncommon incompatibility group of the blaNDM-1 carrying plasmid and the uncommon ST type of the K. pneumoniae strain suggest a possible local emergence of NDM producers. PMID- 25747781 TI - Brain, memory and development: the imprint of Gabriel Horn. PMID- 25747782 TI - Human tissue kallikrein 9 in asthmatic patients. PMID- 25747783 TI - Occupational asthma and rhinoconjunctivitis by melon plant allergy. PMID- 25747784 TI - Effect of catastrophic wildfires on asthmatic outcomes in obese children: breathing fire. AB - BACKGROUND: Air pollutants from wildfires and obesity independently exacerbate asthma, yet no study has determined the combined effects of these 2 variables on asthma outcomes. OBJECTIVE: To determine the effect of 2 catastrophic wildfires affecting the Southern California region (in 2003 and 2007) on several asthma outcomes in a cohort of children. METHODS: To investigate the association between wildfire exposure and asthma outcomes, we stratified our study population by body mass index categories (underweight, normal, overweight, and obese) and zip codes (to distinguish individuals who were closer to the fires vs farther away). The primary outcome was the prevalence of physician-dispensed short-acting beta agonist (SABAs). Secondary outcomes included the rate of emergency department visits and/or hospitalizations for asthma, the frequency of oral corticosteroid use for asthma, and number of new diagnoses of asthma. RESULTS: A total of 2,195 and 3,965 asthmatic children were analyzed as part of our retrospective cohort during the 2003 and 2007 wildfires, respectively. SABA dispensing increased the most in the obese group after the 2003 wildfires (P < .05). Increased prevalence of SABA dispensing was also noted in the obese group in 2007, but this was not statistically higher than the increases seen in other body mass index groups. There was no observed increase in emergency department and/or hospitalization rates, oral corticosteroid dispensing frequency, or new asthma diagnoses after either wildfire. CONCLUSION: Catastrophic wildfires lead to worsening asthma outcomes, particularly in obese individuals. This study gives further evidence of a link between obesity and asthma severity and suggests that air pollutants released during wildfires can have substantial detrimental effects on asthma control. PMID- 25747785 TI - The utility of specific IgE testing to chlorhexidine in the investigation of perioperative adverse reactions. PMID- 25747786 TI - Association of common filaggrin null mutations with atopy but not chronic rhinosinusitis. PMID- 25747787 TI - beta2-Adrenergic receptor Gly16Arg polymorphism and impaired asthma control in corticosteroid-treated asthmatic adults. PMID- 25747788 TI - Positive response to omalizumab in patients with acquired idiopathic nonhistaminergic angioedema. PMID- 25747789 TI - Relationship between trace metal concentrations in the terrestrial moss Pseudoscleropodium purum and in bulk deposition. AB - The relationship between trace metal concentrations in Pseudoscleropodium purum (Hedw.) M. Fleish. and bulk deposition (BD) was examined at 21 sites (SS) to ascertain whether the lack of correlations reported in previous studies are due to limitations in the experimental design. Thus, we implemented some improvements to it and examined the correlations in depth. We could conclude that this relationship is determined by other variables rather than by the pollutant inputs themselves (BD). Thus, whether or not moss concentrations and bulk deposition are significantly correlated will depend on the combination of the above referred factors in a given area at a given time. Therefore, P. purum in particular, and most likely native terrestrial mosses in general, are less than ideal biomonitors for yielding absolute values of atmospheric trace metal deposition. We recommend their use as qualitative indicators and the use of classical methods to obtain absolute values. PMID- 25747790 TI - Concordance of Child and Parent Reports of Health-Related Quality of Life in Children With Mild Traumatic Brain or Non-Brain Injuries and in Uninjured Children: Longitudinal Evaluation. AB - INTRODUCTION: This study aimed to determine (a) concordance between parents' and children's perceptions of health-related quality of life (HRQoL) for children who sustained a mild traumatic brain injury or a mild non-brain injury or who were uninjured at baseline and at 1, 3, 6, and 12 months postinjury; (b) test-retest reliability of the Pediatric Quality of Life Inventory Generic Core and Cognitive Functioning Scales in the uninjured group; and (c) which, if any, variables predicted parity in child/parent dyad responses. METHODS: This longitudinal study included 103 child/parent dyads in three groups. Each child and parent completed Pediatric Quality of Life Inventory questionnaires within 24 hours of injury and at months 1, 3, 6, and 12 postinjury. RESULTS: Child/parent HRQoL concordance was generally poor. The variables for age, gender, and study group were not found to be response-parity predictors. DISCUSSION: Inclusion of child and parent perceptions provides a more comprehensive picture of the child's HRQoL, increasing provider awareness of related health care needs. PMID- 25747791 TI - A Health-Related Quality of Life Measure for Older Adolescents With Asthma: Child Health Survey for Asthma-T (Teen Version). AB - BACKGROUND: Although adolescent substance use can have direct effects on asthma symptoms and interact with medications used to treat asthma, no validated health related quality of life (HRQL) instrument exists for adolescents 17 to 19 years of age with asthma. PURPOSE: The American Academy of Pediatric's HRQL instrument, the Child Health Survey for Asthma (CHSA)-Child version, was modified with a substance use subscale to address outcomes specific to adolescents ages 17 to 19 years with asthma. METHODS: Two cohorts (N = 70) were recruited for instrument testing at pediatric primary care practices and two university clinics. A small methodological study with 24 adolescents was conducted to obtain initial support of the psychometric properties for the CHSA-Teen version at baseline, day 14, and day 16. A follow-up study included 46 teens to provide further support. RESULTS: The psychometric properties of the CHSA-Teen version were good and comparable with the CHSA-Child version for feasibility, reliability, and validity. CONCLUSIONS: Health care providers need to be aware of each adolescent's substance use to personalize counseling related to asthma medications. PMID- 25747792 TI - Evaluation of nasogastric tubes to enable differentiation between upper and lower gastrointestinal bleeding in unselected patients with melena. AB - Gastrointestinal (GI) bleeding is a common surgical problem. The aim of this study was to evaluate how insertion of the nasogastric tube may enable differentiation between upper and lower GI bleeding in patients with melena. A retrospective study involving patients admitted to our surgery division with a melena was carried out between the years 2010 and 2012. A total of 386 patients were included in the study. Of these, 279 (72.2%) patients had negative nasogastric aspirate. The sensitivity of examination of nasogastric aspirate to establish the upper GI as the source of bleeding was only 28% and the negative predictive value of a negative nasogastric aspirate was less than 1%. Most patients who initially presented with melena and were found to have upper GI bleeding had a negative nasogastric aspirate. Insertion of a nasogastric tube does not affect the clinical decision to perform upper endoscopy and should not be routinely carried out. PMID- 25747793 TI - Identification and expression analysis of an atypical chemokine receptor-2 (ACKR2)/CC chemokine binding protein-2 (CCBP2) in rainbow trout (Oncorhynchus mykiss). AB - Atypical chemokine receptors (ACKRs) have emerged as key components of the chemokine system, with an essential regulatory function in innate and adaptive immune responses and inflammation. In mammals ACKR2 is a 'scavenging' receptor for inflammatory CC chemokines and plays a central role in the resolution of in vivo inflammatory responses. An ACKR2 like gene has been identified and cloned in rainbow trout (Teleostei) in the present study, enabling the further identification of this molecule in another group of ray-finned teleost fish (Holostei), in a lobe-finned fish (Sarcopterygii-coelacanth), and in reptiles. The identity of these ACKR2 molecules is supported by their conserved structure, and by phylogenetic tree and synteny analysis. Trout ACKR2 is highly expressed in spleen and head kidney, suggesting a homeostatic role of this receptor in limiting the availability of its potential ligands. Trout ACKR2 expression can be modulated in vivo by bacterial and parasitic infections, and in vitro by PAMPs (poly I:C and peptidoglycan) and cytokines (IL-6, TNF-alpha, IFN-gamma and IL-21) in a time dependent manner. These patterns of expression and modulation suggest that trout ACKR2 is regulated in a complex way and has an important role in control of the chemokine network in fish as in mammals. PMID- 25747794 TI - Exclusion of metal oxide by an RF sputtered Ti layer in flexible perovskite solar cells: energetic interface between a Ti layer and an organic charge transporting layer. AB - In this work, the effects of a titanium (Ti) layer on the charge transport and recombination rates of flexible perovskite solar cells were studied. Ti as an efficient barrier layer was deposited directly on PET-ITO flexible substrates through RF magnetic sputtering using a Ti-source and a pressure of ~5 mTorr. A Ti coated PET-ITO was used for the fabrication of a flexible perovskite solar cell without using any metal oxide layer. The fabricated flexible perovskite solar cell was composed of a PET-ITO/Ti/perovskite (CH3NH3PbI3)/organic hole transport layer of 2,2',7,7'-tetrakis [N,N'-di-p-methoxyphenylamine]-9,9'-spirobifluorene (spiro-OMeTAD)-Li-TFSI/Ag. A high conversion efficiency of ~8.39% along with a high short circuit current (JSC) of ~15.24 mA cm(-2), an open circuit voltage (VOC) of ~0.830 V and a high fill factor (FF) of ~0.66 was accomplished by the fabricated flexible perovskite solar cell under a light illumination of ~100 mW cm(-2) (1.5 AM). Intensity-modulated photocurrent (IMPS)/photovoltage spectroscopy (IMVS) studies demonstrated that the fabricated flexible perovskite solar cell considerably reduced the recombination rate. PMID- 25747795 TI - Thalidomide (5HPP-33) suppresses microtubule dynamics and depolymerizes the microtubule network by binding at the vinblastine binding site on tubulin. AB - Thalidomides were initially thought to be broad-range drugs specifically for curing insomnia and relieving morning sickness in pregnant women. However, its use was discontinued because of a major drawback of causing teratogenicity. In this study, we found that a thalidomide derivative, 5-hydroxy-2-(2,6 diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33), inhibited the proliferation of MCF-7 with a half-maximal inhibitory concentration of 4.5 +/- 0.4 MUM. 5HPP-33 depolymerized microtubules and inhibited the reassembly of cold-depolymerized microtubules in MCF-7 cells. Using time-lapse imaging, the effect of 5HPP-33 on the dynamics of individual microtubules in live MCF-7 cells was analyzed. 5HPP-33 (5 MUM) decreased the rates of growth and shortening excursions by 34 and 33%, respectively, and increased the time microtubules spent in the pause state by 92% as compared to that of the vehicle-treated MCF-7 cells. 5HPP-33 (5 MUM) reduced the dynamicity of microtubules by 62% compared to the control. 5HPP-33 treatment reduced the distance between the two poles of a bipolar spindle, induced multipolarity in some of the treated cells, and blocked cells at mitosis. In vitro, 5HPP-33 bound to tubulin with a weak affinity. Vinblastine inhibited the binding of 5HPP-33 to tubulin, and 5HPP-33 inhibited the binding of BODIPY FL vinblastine to tubulin. Further, a molecular docking analysis suggested that 5HPP 33 shares its binding site on tubulin with vinblastine. The results provided significant insight into the antimitotic mechanism of action of 5HPP-33 and also suggest a possible mechanism for the teratogenicity of thalidomides. PMID- 25747796 TI - Health service utilization of heroin abusers: a retrospective cohort study. AB - AIMS: This study aimed to determine the patterns of medical service utilization among heroin users and to identify the factors associated with the frequency of utilization. METHODS: We conducted a retrospective/prospective cohort study of 789 heroin-using adults in a catchment area, collecting data on their usage of medical care, including inpatient care, emergency visits, and outpatient care, in a 2-year observation period. We interviewed and reviewed the medical records of 789 heroin users in a methadone clinic of a general hospital in a rural area of Taiwan. The demographic data, records of service use, diagnoses, and information on viral infection status from Jan. 1, 2007 to Dec. 31, 2008 were collected. Most patients were middle-aged and unemployed, had a basic educational level, and began their first heroin use in their twenties. RESULTS: The health service utilization of heroin users was mostly for infectious diseases, orthopedic conditions, and gastroenterological disorders mainly due to blood-borne or local infections and traumatic injury. Heroin users utilize fewer outpatient or inpatient services, but more emergency care than the general public. The major correlates of inpatient and emergency service utilization were HIV status and education level. CONCLUSIONS: Our findings suggest that integrated outpatient services may help to enhance medical service accessibility and adherence, and also imply the necessity of putting more effort into promoting health management and safe behaviors in heroin users, particularly the lower-educated addicts. PMID- 25747797 TI - Reply: To PMID 25549882. PMID- 25747799 TI - Small for gestational age children have specific food preferences. PMID- 25747798 TI - Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors. AB - BACKGROUND: Although 5-HTTLPR has been shown to influence the risk of life stress induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. METHODS: In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. RESULTS: The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5 HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (<=30) individuals. LIMITATIONS: Our study is cross sectional and applies self-report questionnaires. CONCLUSIONS: Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups. PMID- 25747800 TI - Utilization of nebulized 3% saline in infants hospitalized with bronchiolitis. AB - OBJECTIVES: To describe utilization of 3% hypertonic saline (HTS) in hospitalized infants and to evaluate the association between HTS use and length of stay (LOS) in a real-world setting. STUDY DESIGN: This multicenter retrospective cohort study included infants<=12 months hospitalized with bronchiolitis between October 2008 and September 2011 using the Pediatric Health Information System. HTS use was categorized as trial, rescue, daily, or sporadic. Differences in LOS were compared after matching daily HTS recipients and nonrecipients on propensity score. RESULTS: There were 63,337 hospitalizations for bronchiolitis. HTS was used in 24 of 42 hospitals and 2.9% of all hospitalizations. HTS use increased from 0.4% of visits in 2008 to 9.2% of visits in 2011. There was substantial variation in HTS use across hospitals (range 0.1%-32.6%). When used, HTS was given daily during 60.6% of hospitalizations, sporadically in 10.4%, as a trial in 11.3%, and as a rescue in 17.7%. The propensity score-matched analysis of daily HTS recipients (n=953) vs nonrecipients (n=953) showed no difference in mean LOS (HTS 2.3 days vs nonrecipients 2.5 days; beta-coefficient -0.04; 95% CI 0.15, 0.07; P=.5) or odds of staying longer than 1, 2, or 3 days. Daily HTS recipients had a 33% decreased odds of staying in the hospital>4 days compared with nonrecipients (OR 0.67; 95% CI 0.47, 0.97; P=.03). CONCLUSIONS: Variation in HTS use and the lack of association between HTS and mean LOS demonstrates the need for further research to standardize HTS use and better define the infants for whom HTS will be most beneficial. PMID- 25747801 TI - Role of calcium, glutamate and NMDA in major depression and therapeutic application. AB - Major depression is a common, recurrent mental illness that affects millions of people worldwide. Recently, a unique fast neuroprotective and antidepressant treatment effect has been observed by ketamine, which acts via the glutamatergic system. Hence, a steady accumulation of evidence supporting a role for the excitatory amino acid neurotransmitter (EAA) glutamate in the treatment of depression has been observed in the last years. Emerging evidence indicates that N-methyl-D-aspartate (NMDA), group 1 metabotropic glutamate receptor antagonists and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) agonists have antidepressant properties. Indeed, treatment with NMDA receptor antagonists has shown the ability to sprout new synaptic connections and reverse stress-induced neuronal changes. Based on glutamatergic signaling, a number of therapeutic drugs might gain interest in the future. Several compounds such as ketamine, memantine, amantadine, tianeptine, pioglitazone, riluzole, lamotrigine, AZD6765, magnesium, zinc, guanosine, adenosine aniracetam, traxoprodil (CP-101,606), MK-0657, GLYX 13, NRX-1047, Ro25-6981, LY392098, LY341495, D-cycloserine, D-serine, dextromethorphan, sarcosine, scopolamine, pomaglumetad methionil, LY2140023, LY404039, MGS0039, MPEP, 1-aminocyclopropanecarboxylic acid, all of which target this system, have already been brought up, some of them recently. Drugs targeting the glutamatergic system might open up a promising new territory for the development of drugs to meet the needs of patients with major depression. PMID- 25747802 TI - XRN1 stalling in the 5' UTR of Hepatitis C virus and Bovine Viral Diarrhea virus is associated with dysregulated host mRNA stability. AB - We demonstrate that both Hepatitis C virus (HCV) and Bovine Viral Diarrhea virus (BVDV) contain regions in their 5' UTRs that stall and repress the enzymatic activity of the cellular 5'-3' exoribonuclease XRN1, resulting in dramatic changes in the stability of cellular mRNAs. We used biochemical assays, virus infections, and transfection of the HCV and BVDV 5' untranslated regions in the absence of other viral gene products to directly demonstrate the existence and mechanism of this novel host-virus interaction. In the context of HCV infection, we observed globally increased stability of mRNAs resulting in significant increases in abundance of normally short-lived mRNAs encoding a variety of relevant oncogenes and angiogenesis factors. These findings suggest that non coding regions from multiple genera of the Flaviviridae interfere with XRN1 and impact post-transcriptional processes, causing global dysregulation of cellular gene expression which may promote cell growth and pathogenesis. PMID- 25747803 TI - Standard and fenestrated endograft sizing in EVAR planning: Description and validation of a semi-automated 3D software. AB - An abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta that may lead to a rupture with fatal consequences. Endovascular aneurysm repair (EVAR) is a minimally invasive surgical procedure consisting of the deployment and fixation of a stent-graft that isolates the damaged vessel wall from blood circulation. The technique requires adequate endovascular device sizing, which may be performed by vascular analysis and quantification on Computerized Tomography Angiography (CTA) scans. This paper presents a novel 3D CTA image-based software for AAA inspection and EVAR sizing, eVida Vascular, which allows fast and accurate 3D endograft sizing for standard and fenestrated endografts. We provide a description of the system and its innovations, including the underlying vascular image analysis and visualization technology, functional modules and user interaction. Furthermore, an experimental validation of the tool is described, assessing the degree of agreement with a commercial, clinically validated software, when comparing measurements obtained for standard endograft sizing in a group of 14 patients. PMID- 25747804 TI - Introduction. PMID- 25747805 TI - Fruit and vegetable consumption and risk of lung cancer: a dose-response meta analysis of prospective cohort studies. AB - OBJECTIVES: A meta-analysis was conducted to summarize evidence from prospective cohort studies about the association of fruit and vegetable consumption with the risk of lung cancer. MATERIALS AND METHODS: Pertinent studies were identified by a search of Embase and PubMed databases to October 2014. A random-effects model was used to combine study-specific relative risks and 95% confidence interval [RR (95% CI)]. Dose-response relationship was assessed by restricted cubic spline. RESULTS: The RR (95% CI) of lung cancer for highest versus lowest category of fruit and vegetable (FV) consumption was 0.87 (0.79-0.95) (8 studies including 12,942 cases among 1,571,494 subjects), and the effect was 0.84 (0.79-0.90) for fruit (16 studies including 15,421 cases among 1,791,469 subjects) and 0.90 (0.84 0.96) for vegetable (19 studies including 16,422 cases among 1,877,375 subjects). The above-mentioned associations did not differed significantly in subgroup analysis by country, age, number of covariates adjusted, quality score, sex, smoking status and histological subtypes; however, studies with follow-up duration of >=10 years and with FV assessed by interview showed a stronger association than those of <10 years and by self-administrated food frequency questionnaires, respectively. The risk of lung cancer decreased by 3% (P=0.07), 5% (P<0.01) and 3% (P=0.09) for every 1 serving/day increment in FV, fruit and vegetable consumption, respectively. There was a threshold around 2 servings/day of fruit and 2 servings/day of vegetable, respectively, after which the risk of lung cancer did not reduce further. CONCLUSIONS: Fruit and vegetable consumption are inversely associated with risk of lung cancer. PMID- 25747807 TI - New insights into lung diseases using hyperpolarized gas MRI. AB - Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRI) of the lung airspaces. HP gas MRI has become important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed. PMID- 25747808 TI - Novel reactions of homodinuclear Ni2 complexes [Ni(RNPyS4)]2 with Fe3(CO)12 to give heterotrinuclear NiFe2 and mononuclear Fe complexes relevant to [NiFe]- and [Fe]-hydrogenases. AB - The homodinuclear complexes [Ni(RNPyS4)]2 (; RNPyS4 = 2,6-bis(2 mercaptophenylthiomethyl)-4-R-pyridine; R = H, MeO, Cl, Br, i-Pr) were found to be prepared by reactions of the in situ generated Li2[Ni(1,2-S2C6H4)2] with 2,6 bis[(tosyloxy)methyl]pyridine and its substituted derivatives 2,6 bis[(tosyloxy)methyl]-4-R-pyridine. Further reactions of with Fe3(CO)12 gave both heterotrinuclear complexes NiFe2(RNPyS4)(CO)5 () and mononuclear complexes Fe(RNPyS4)(CO) (), unexpectedly. Interestingly, complexes and could be regarded as models for the active sites of [NiFe]- and [Fe]-hydrogenases, respectively. All the prepared complexes were characterized by elemental analysis, spectroscopy, and particularly for some of them, by X-ray crystallography. In addition, the electrochemical properties of and as well as the electrocatalytic H2 production catalyzed by and were investigated by CV techniques. PMID- 25747806 TI - Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib. AB - OBJECTIVES: Gefitinib is currently used as a first-line therapy in patients of advanced non-small cell lung cancer (NSCLC) with susceptible epidermal growth factor receptor (EGFR) mutations. However, treatment outcomes of these patients vary. This study was conducted to evaluate the impact of specific metastatic sites on treatment outcomes of patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving first-line gefitinib, focusing on the impact of liver metastasis. MATERIALS AND METHODS: Between October 2009 and April 2014, patients of stage IV lung adenocarcinoma harboring EGFR mutation in exon 19 or 21, who received first-line gefitinib treatment, were enrolled in two hospitals and followed until December 22, 2014. The impacts of various clinical features, including sex, age, smoking history, performance status, EGFR mutation site, metastatic sites, etc., on progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: A total of 148 patients were eligible for analysis. Patients with liver metastasis on initial diagnosis (n=19) had shorter PFS and OS than those without liver metastasis did (median of PFS, 6.7 vs. 11.2 months, p<0.0001; median of OS, 9.2 vs. 17.5 months, p<0.0001). Multivariable Cox regression analysis showed liver metastasis was an independent poor prognostic factor for PFS (HR=2.939 [95% CI: 1.729-4.997], p<0.0001) and OS (HR=3.300 [95% CI: 1.708-6.373], p=0.0004). CONCLUSION: Liver metastasis predicts poorer PFS and OS in stage IV lung adenocarcinoma patients with susceptible gene mutations receiving first-line gefitinib. Further study is warranted to elucidate the underlying mechanisms and find treatment modalities to improve prognosis of these patients. PMID- 25747809 TI - From "retailers" to health care providers: Transforming the role of community pharmacists in chronic disease management. AB - Community pharmacists are the third largest healthcare professional group in the world after physicians and nurses. Despite their considerable training, community pharmacists are the only health professionals who are not primarily rewarded for delivering health care and hence are under-utilized as public health professionals. An emerging consensus among academics, professional organizations, and policymakers is that community pharmacists, who work outside of hospital settings, should adopt an expanded role in order to contribute to the safe, effective, and efficient use of drugs-particularly when caring for people with multiple chronic conditions. Community pharmacists could help to improve health by reducing drug-related adverse events and promoting better medication adherence, which in turn may help in reducing unnecessary provider visits, hospitalizations, and readmissions while strengthening integrated primary care delivery across the health system. This paper reviews recent strategies to expand the role of community pharmacists in Australia, Canada, England, the Netherlands, Scotland, and the United States. The developments achieved or under way in these countries carry lessons for policymakers world-wide, where progress thus far in expanding the role of community pharmacists has been more limited. Future policies should focus on effectively integrating community pharmacists into primary care; developing a shared vision for different levels of pharmacist services; and devising new incentive mechanisms for improving quality and outcomes. PMID- 25747810 TI - Primary Cutaneous Polymorphic EBV-Associated Posttransplant Lymphoproliferative Disorder After a Renal Transplant and Review of the Literature. AB - IMPORTANCE: Posttransplant lymphoproliferative disorder (PTLD) is an uncommon complication after solid organ transplants and hematopoietic stem cell transplants. Extranodal involvement in PTLD can involve several organ systems, including the central nervous system, bone marrow, lungs, gastrointestinal tract, and skin. Isolated involvement of the skin without systemic involvement in PTLD is rare. Primary cutaneous PTLD is generally categorized as either cutaneous T cell lymphomas or cutaneous B-cell lymphomas, with variable Epstein-Barr virus (EBV) positivity. Herein, we describe an exceedingly uncommon case of a polymorphic variant of primary cutaneous PTLD. OBSERVATIONS: A woman in her 30s, who received an EBV+ deceased donor kidney transplant, presented with a 2-week history of 2 indurated patches over the lower abdomen. A skin biopsy revealed an atypical lymphoid proliferation with immunohistochemical stains demonstrating a mixed population of both B and T cells that stained strongly positive for EBV encoded RNA. A bone marrow biopsy and positron emission tomography/computed tomography were negative for systemic involvement. The patient was treated with immunosuppression reduction and rituximab infusions. CONCLUSIONS AND RELEVANCE: This case highlights a rare polymorphic variant of primary cutaneous EBV associated PTLD and increases awareness of this uncommon posttransplant complication. Cutaneous PTLD is reviewed, therefore dermatologists are aware of this uncommon disorder. PMID- 25747811 TI - Melanomas arising on skin with chronic sun-induced damage exhibit low degree of angiogenesis and lymphangiogenesis. AB - Differences in gene expression between melanomas arising on skin intermittently and chronically sun-exposed areas were described. Additionally, several studies have shown differences in clinical characteristics and prognosis, suggesting distinct biological pathways in the development of these tumors. We performed a retrospective investigation aimed on evaluation of the differences in angiogenesis and lymphangiogenesis between melanomas arising on skin with and without signs of chronic sun-induced damage. For that purpose, we evaluated relative blood and lymphatic vessel areas, blood and lymphatic endothelial cell proliferation fractions, separately for peritumoral and intratumoral areas. We have shown that melanomas arising on sun-exposed skin exhibit lower angiogenic and lymphangiogenic potentials and better prognosis than those arising on skin without signs of chronic sun-induced damage. PMID- 25747812 TI - Seborrheic keratosis with bowenoid transformation: the immunohistochemical features and its association with human papillomavirus infection. AB - The bowenoid transformation of seborrheic keratosis (SK) has rarely been reported. The purpose of this study is to identify their diagnostic immunohistochemical features and association with human papillomavirus (HPV) infection. Skin biopsy specimens of the phenomenon were retrieved from 2001 to 2010. Benign SK, Bowen disease, bowenoid papulosis, and squamous cell carcinoma were included as controls. All specimens were stained for hematoxylin and eosin, Ki-67, p21, p16, p53, and cyclin D1. Polymerase chain reaction-amplified HPV DNA was analyzed. Seventeen cases of SK with bowenoid transformation were identified. The immunohistochemical pattern of bowenoid transformation was similar to that of Bowen disease and bowenoid papulosis. The malignant cells exhibited increased expressions of p16, p21, and ki-67 and a decreased expression of cyclin D1 (P < 0.01). HPV DNA was detected in 5 cases of bowenoid transformation. In conclusion, a portion of the cases of SK with bowenoid transformation were associated with HPV infection. Selective immunohistochemical stains were helpful in the diagnosis of malignant change in these cases. PMID- 25747813 TI - Tuberculosis: A biosocial study of admissions to a children's sanatorium (1936 1954) in Stannington, Northumberland, England. AB - This study considers the biosocial profile of children admitted to the Philipson Children's Sanatorium at Stannington, Morpeth, Northumberland, England (1936 1954). The objective was to understand the differential impact of TB on male and female admissions at Stannington, according to a number of variables. A total of 1987 medical files were analysed. More females than males were admitted, peaks of admission at age six and 13 were documented, and the majority of children derived from poor urban areas. Over 60% (1199, 63.5%) of children had pulmonary TB, and 12% (230) had bone or joint involvement. The implementation of chemotherapy (streptomycin) at Stannington (1946), the end of the 2nd World War (1945), and the founding of the National Health Service (1948) did not have any great effect on the biosocial profile of children admitted to the sanatorium and treated (age, sex, origin, type of TB suffered, and socioeconomic status). Reasons for these finding are discussed. PMID- 25747814 TI - Trends in mortality from pulmonary tuberculosis before and after antibiotics in the Portuguese sanatorium Carlos Vasconcelos Porto (1918-1991): Archival evidence and its paleopathological relevance. AB - The comparative study of patients' profiles and outcomes from pulmonary tuberculosis (TB), before and after the discovery of antibiotic therapy, using sanatoria archives is an unexplored approach in paleopathology. Although higher mortality rates are assumed before chemotherapy, scarce information exists regarding the disease's duration in institutionalized patients and to what extent tuberculous sufferers lived enough to develop skeletal lesions. To fill this gap, 315 clinical files from the former male Sanatorium Carlos Vasconcelos Porto, located in Sao Bras de Alportel, Portugal, were studied. Two periods of hospitalization were considered: 1931-1944 (n = 128, Group 1) and 1955-1961 (n = 187, Group 2). The average duration of hospitalization (350.3 days for Group 1 and 371.8 for Group 2) and the crude mortality (18.2% and 11.2%, respectively in Groups 1 and 2) did not differ significantly between groups. However, Cox's regression revealed significant differences between survival curves, after adjusting for age at admission (14-74 years old), with pre-chemotherapy patients presenting a higher risk of dying during hospitalization (p = 0.037, hazard ratio = 1.94, IC95% = 1.03-3.63). This study also confirms poorer prognoses for pulmonary tuberculosis sufferers hospitalized in sanatoria before antibiotics and reveals that a significant number of patients survived enough time to develop bone lesions. PMID- 25747815 TI - Langerhans cell histiocytosis or tuberculosis on a medieval child (Oppidum de la Granede, Millau, France - 10th-11th centuries AD). AB - In 2008, a skeleton of a 1 - 2.5-year-old child radiocarbon dated from the 10th - 11th century AD was discovered on the oppidum of La Granede (Millau, France). It presents multiple cranial osteolytic lesions having punched-out or geographical map-like aspects associated with sequestrum and costal osteitis. A multi 3D digital approach (CT, MUCT and virtual reconstruction) enabled us to refine the description and identify the diploic origin of the lytic process. Furthermore, precise observation of the extent of the lesions and associated reorganization of the skeletal micro-structure were possible. From these convergent pieces of evidence, the differential diagnosis led to three possibilities: Langerhans cell histiocytosis, tuberculosis, or Langerhans cell histiocytosis and tuberculosis. PMID- 25747817 TI - Work-related stress and cognitive enhancement among university teachers. AB - BACKGROUND: Working conditions of academic staff have become increasingly complex and occupational exposure has risen. This study investigates whether work-related stress is associated with the use of prescription drugs for cognitive enhancement (CE). METHODS: The study was designed around three web-based surveys (n1 = 1131; n2 = 936; n3 = 906) to which university teachers at four German universities were asked to respond. It assessed past CE-drug use and the willingness to use CE drugs as factors influencing future use. Overlap among participants across the surveys allowed for analyses of stability of the results across time. RESULTS: Our study suggests a currently very low prevalence of CE-drug use as well as a low willingness to use such drugs. The results showed a strong association between perceptions of work-related stress and all measures of CE-drug use (when controlling for potential confounding factors). They also showed that past use of CE-drugs increased participants' willingness to use them again in the future, as did lower levels of social support. Two different measures showed that participants' moral qualms against the use of CE-drugs decreased their probability of using them. CONCLUSIONS: The results increase our knowledge about the prevalence of CE-drug use and our understanding of what motivates and inhibits the use of CE-drug. PMID- 25747816 TI - Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region. AB - The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21. PMID- 25747818 TI - Perinatal exposure to chlordecone, thyroid hormone status and neurodevelopment in infants: the Timoun cohort study in Guadeloupe (French West Indies). AB - BACKGROUND: Perinatal exposure to endocrine-disrupting chemicals may affect thyroid hormones homeostasis and impair brain development. Chlordecone, an organochlorine insecticide widely used in the French West Indies has known estrogenic and progestin properties, but no data is available, human or animal, on its action on thyroid hormone system. OBJECTIVES: Our aim was to evaluate the impact of perinatal exposure to chlordecone on the thyroid hormone system of a sample of infants from the Timoun mother-child cohort in Guadeloupe and their further neurodevelopment. METHODS: Chlordecone was measured in cord blood and breast milk samples. Thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), free thyroxine (FT4) were determined in child blood at 3 months (n=111). Toddlers were further assessed at 18 months using an adapted version of the Ages and Stages Questionnaire (ASQ). RESULTS: Cord chlordecone was associated with an increase in TSH in boys, whereas postnatal exposure was associated with a decrease in FT3 overall, and in FT4 among girls. Higher TSH level at 3 months was positively associated with the ASQ score of fine motor development at 18 months among boys, but TSH did not modify the association between prenatal chlordecone exposure and poorer ASQ fine motor score. CONCLUSIONS: Perinatal exposure to chlordecone may affect TSH and thyroid hormone levels at 3 months, differently according to the sex of the infant. This disruption however did not appear to intervene in the pathway between prenatal chlordecone exposure and fine motor child development. PMID- 25747819 TI - Impact of ferromanganese alloy plants on household dust manganese levels: implications for childhood exposure. AB - Adolescents living in communities with ferromanganese alloy plant activity have been shown to exhibit deficits in olfactory and fine motor function. Household dust may serve as an important manganese (Mn) exposure pathway to children, though dust Mn concentrations have not previously been measured to assess household contamination from ferromanganese alloy plant emissions. Here we determined the association between dust concentrations and surface loadings of Mn and other metals (Al, Cd, Cr, Cu, Fe, Pb, and Zn) in indoor and outdoor household dust from three Italian communities that differ by history of ferromanganese alloy plant activity: Bagnolo Mella, with an active ferromanganese alloy plant (n=178 households); Valcamonica, with historically active plants (n=166); and Garda Lake, with no history of ferromanganese plant activity (n=99). We also evaluated Mn levels in other environmental (soil, airborne particulates) and candidate biomarker (blood, hair, saliva, fingernails) samples from children within the households. Household dust Mn concentrations and surface loadings were significantly different between the three sites, with levels highest in Bagnolo Mella (outdoor median Mn concentration=4620, range 487-183,000ug/g), intermediate in Valcamonica (median=876, range 407-8240ug/g), and lowest in Garda Lake (median=407, range 258-7240ug/g). Outdoor dust Mn concentrations in Bagnolo Mella, but not the other communities, were significantly inversely related with distance from the plant (R(2)=0.6630, P<0.0001). Moreover, outdoor dust Mn concentrations and loadings were highly predictive of but significantly higher than indoor dust Mn concentrations and loadings by ~2 to ~7-fold (Mn concentrations) and ~7 to ~20-fold (Mn loadings). Finally, both indoor and outdoor dust Mn concentrations and outdoor dust Mn loading values were highly significantly correlated with both soil and air Mn concentrations, and with children's hair and fingernail Mn concentrations, but weakly or not associated with saliva or blood Mn levels. Given the evidence associating elevated Mn exposure with neurological impairments in children, these data support that dust Mn levels should be reduced in contaminated environments to protect the health of resident children. PMID- 25747820 TI - Two enzymes catalyze vitamin K 2,3-epoxide reductase activity in mouse: VKORC1 is highly expressed in exocrine tissues while VKORC1L1 is highly expressed in brain. AB - VKORC1 and VKORC1L1 are enzymes that both catalyze the reduction of vitamin K2,3 epoxide via vitamin K quinone to vitamin K hydroquinone. VKORC1 is the key enzyme of the classical vitamin K cycle by which vitamin K-dependent (VKD) proteins are gamma-carboxylated by the hepatic gamma-glutamyl carboxylase (GGCX). In contrast, the VKORC1 paralog enzyme, VKORC1L1, is chiefly responsible for antioxidative function by reduction of vitamin K to prevent damage by intracellular reactive oxygen species. To investigate tissue-specific vitamin K 2,3-epoxide reductase (VKOR) function of both enzymes, we quantified mRNA levels for VKORC1, VKORC1L1, GGCX, and NQO1 and measured VKOR enzymatic activities in 29 different mouse tissues. VKORC1 and GGCX are highly expressed in liver, lung and exocrine tissues including mammary gland, salivary gland and prostate suggesting important extrahepatic roles for the vitamin K cycle. Interestingly, VKORC1L1 showed highest transcription levels in brain. Due to the absence of detectable NQO1 transcription in liver, we assume this enzyme has no bypass function with respect to activation of VKD coagulation proteins. Our data strongly suggest diverse functions for the vitamin K cycle in extrahepatic biological pathways. PMID- 25747821 TI - Vena cava filter use in cancer patients with acute venous thromboembolism in California. AB - BACKGROUND: Few studies have evaluated the use of vena cava filters (VCF) in cancer patients with acute venous thromboembolism (VTE). METHODS: Hospital discharge records of patients who were admitted with a principal diagnosis of lower extremity deep-vein thrombosis or pulmonary embolism and cancer in California between January 1, 2005 and December 31, 2009 were analyzed. Multivariable logistic regression analysis was used to identify variables associated with VCF use. RESULTS: A VCF was placed in 2747 (19.6%) of 14,000 cancer patients. The percentage of patients treated with a VCF varied widely across hospitals, from 0% to 52% (mean=19.2%, median=17.2%), and by cancer type, ranging from 8% for lip/oral to 43% for brain. Using multivariable analysis, the strongest predictors of VCF use were a diagnosis of brain cancer (OR=4.6, CI: 3.7 -5.6), undergoing major surgery (OR=4.9, CI: 3.9 -6.1), and bleeding (OR=2.7, CI: 2.0-3.5). Other factors significantly associated with VCF insertion included hospital characteristics (larger, urban and private), and greater severity-of illness at the time of admission. Only 1083 (7.7%) of patients had an absolute contraindication to anticoagulation (bleeding or surgery). CONCLUSIONS: A VCF was deployed in approximately 20% of acute VTE patients with cancer, but use varied widely between hospitals and cancer types. The strongest risk factors were undergoing surgery, active bleeding, and having brain cancer. Only 21% of VCF treated cancer patients had a strict contraindication to anticoagulation therapy. Further research is needed to determine if VCF use is of any benefit in cancer patients with acute VTE. PMID- 25747822 TI - Nitrofurantoin-induced pulmonary toxicity: A case report and review of the literature. AB - This paper describes a case of lung injury attributed to the use of Nitrofurantoin and a review of the relevant literature. An 88-year-old woman was admitted to the floor for the evaluation of recent symptoms of dyspnea, fatigue and productive cough. She was initiated on nitrofurantoin 300 mg per day for the treatment of a urinary tract infection 3 days earlier. Upon examination, chest auscultation revealed bilateral inspiratory crackles. Chest radiograph showed bilateral airspace and interstitial infiltrates. Laboratory studies revealed an elevated white blood cell count of 13,500/MUL (reference range = 5200-12,400/MUL) and blood eosinophilia (10%, reference range: 0-7%). Using clinical judgment and the algorithm of Naranjo, it was determined that nitrofurantoin use was the probable cause of the patient's lung injury. Symptomatic improvement was observed shortly after the drug was discontinued. A review of information from several European and North American pharmacovigilance databases (through June 2014) identified several reports of suspected nitrofurantoin-induced toxicity, including reports of acute toxicity reactions, which were related in many ways to the case we are reporting here. PMID- 25747823 TI - Q fever endocarditis in Iran: A case report. AB - In this report, we describe the first chronic case of Q fever endocarditis in a 72-year-old woman in Iran. The patient developed radiation-associated heart disease status post (s/p) coronary artery bypass surgery, mitral and aortic valve replacements, and tricuspid valve repair. Endocarditis was also suspected due to a history of heart valve surgery. Blood cultures were negative, but a diagnosis of Q fever endocarditis was confirmed based on serologic titers (IgG phase I 1:32,768). The patient was treated with doxycycline and hydroxychloroquine. PMID- 25747824 TI - Devices used by automated milking systems are similarly accurate in estimating milk yield and in collecting a representative milk sample compared with devices used by farms with conventional milk recording. AB - Information on accuracy of milk-sampling devices used on farms with automated milking systems (AMS) is essential for development of milk recording protocols. The hypotheses of this study were (1) devices used by AMS units are similarly accurate in estimating milk yield and in collecting representative milk samples compared with devices used by certified milk recording providers on farms with conventional milking systems (CMS) and (2) devices used on both AMS and CMS comply with accuracy criteria described by the New Zealand Standard and by the International Committee of Animal Recording (ICAR). Milk recording data from 5 AMS farms were collected during 13 milk recording test days between December 2011 and February 2013. Milk yield was estimated by ICAR-approved milk meters on AMS units. Milk samples were collected over a 48-h period and submitted to an off site certified laboratory for milk composition analysis. Data were also collected manually from 5 to 10 cows per AMS unit; a complete milking of a cow was weighed to serve as gold standard for milk yield, and 3 milk samples per cow milking were collected and analyzed in the laboratory to serve as gold standards for milk composition. A similar procedure was used during 6 milk recording occasions with devices used during conventional milk recording at a CMS research farm. Farm type, breed, season, and region did not appear to affect accuracy of devices used on AMS units. Milk meters used by AMS units complied with ICAR limits in 12.5 and 25% of the milk recording test days for test bucket weights between 2 and 10kg and for test bucket weights >10kg, respectively. These percentages were 52 and 42%, respectively, for devices used on CMS. Analyzing all samples as one milk recording test day, 1.4% fell outside the 20% difference band for AMS compared with 1.1% of the milk samples for CMS. Devices used by AMS complied with ICAR in 73% of the milk recording test days for fat percentage, compared with 42% of the milk recording test days by devices used at the CMS farm. When analyzing all milk samples as one milk recording test day, 3.5% of the milk samples fell outside the 99% ICAR limit for AMS compared with 17.2% of the milk samples for CMS. Applying the ICAR standards for fat percentage to crude protein percentage and SCC, devices used on AMS were accurate in estimating crude protein percentage but not in estimating SCC. Thus, devices on AMS units did not comply with national nor ICAR standards with regard to milk yield and fat percentage. However, devices used on AMS were similarly or more accurate compared with devices used during conventional milk recording. It is proposed that devices used on AMS units, when calibrated regularly and when set up according to the manufacturer's instruction, have similar or improved accuracy compared with CMS devices. Because the New Zealand industry accepts data from devices currently used by certified providers for milk recording on CMS farms, results imply that the AMS devices should also be permitted to be used for milk recording. PMID- 25747825 TI - Inhibition of local blood flow control systems in the mammary glands of lactating cows affects uptakes of energy metabolites from blood. AB - To test the effect of mammary blood flow on net uptakes of milk precursors by the mammary glands, inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX) were infused into the mammary circulation of 4 lactating cows. Inhibitors were infused in a 4*4 Latin square design, where treatments were infusion for 1 h of saline, NOS inhibitor (Nomega-nitro-l-arginine methyl ester hydrochloride), COX inhibitor (indomethacin), or both NOS + COX inhibitors into one external iliac artery. Para-aminohippuric acid was also infused to allow for estimation of iliac plasma flow (IPF), of which approximately 80% flows to the mammary glands. Blood samples were collected before, during, and after inhibitor infusion from the contralateral external iliac artery and ipsilateral mammary vein. Inhibition of COX and NOS each produced a decrease in IPF, although the NOS effect was smaller and IPF continued to be depressed throughout the recovery period. The combination of COX and NOS inhibition produced a 50% depression in IPF and there was no carryover into the recovery period. Treatments that depressed IPF also increased arterial concentrations of acetate, beta-hydroxybutyrate (BHBA), and glucose. Similarly, arteriovenous differences of acetate, BHBA, and glucose were all increased during IPF depression. To correct for a potential effect of arterial concentration, arteriovenous differences were normalized to arterial concentration, producing an extraction percentage. Inhibition of COX increased glucose extraction and tended to increase acetate and BHBA extraction. Dual inhibition only increased BHBA extraction and had no effect on mammary extraction of other metabolites. These extractions did not increase because clearances of glucose and TAG decreased as IPF decreased, and clearances of acetate and BHBA tended to decrease. Net uptake of TAG was depressed by dual NOS/COX inhibition, whereas uptakes of acetate, BHBA, and glucose were not affected by any of the treatments. To separate effects of flow from effects of arterial concentration, uptakes were regressed against IPF and arterial concentration simultaneously. According to the slopes of the regressions, a 10% decrease in IPF from the mean observed during saline infusion resulted in 3.8, 7.3, and 10.4% decreases in uptakes of acetate, glucose, and triacylglycerol, respectively. These findings indicate that mammary blood flow affects milk precursor uptake, and that clearance should not be assumed constant to predict mammary uptakes of milk precursors in situations where blood flow is changing. PMID- 25747826 TI - Estrus traits derived from activity measurements are heritable and closely related to the time from calving to first insemination. AB - The aim of this study was to estimate genetic parameters for estrus-related traits that could improve selection for increased fertility due to improved ability of the cow to return to cycling and go into heat after calving. We compared the time from calving to first insemination (CFI) to 3 physical activity traits: the interval from calving to first high activity (CFHA), estrus duration (ED), and estrus strength (ES). We calculated CFI based on data from commercial Holstein herds that included the insemination dates for 11,363 cows. The CFHA, ED, and ES traits were derived from electronic activity tags for 3,533 Holstein cows. Estimates of heritability were 0.07 for CFI, 0.16 for CFHA, 0.02 for ED, and 0.05 for ES. We found a strong genetic correlation between CFI and CFHA (0.96). Genetic correlations between ED and CFI and CFHA were -0.37 and -0.68, respectively. Genetic correlations between ES and CFI and CFHA were -0.50 and 0.58, respectively. The heritability of CFHA and its strong genetic correlation with CFI suggest that including CFHA in the genetic evaluation of female cow fertility could improve the effectiveness of selection, because CFHA reflects the ability to return to cyclicity and go into heat after calving. PMID- 25747827 TI - Short communication: Comparison of estrus characteristics in Holstein heifers by 2 activity monitoring systems. AB - Two activity monitoring systems-Heatime (SCR Engineers Ltd., Netanya, Israel) and IceTag (IceRobotics Ltd., Edinburgh, UK)-were compared on their ability to detect and quantify estrus expression. Holstein heifers (n=57) were fitted with Heatime (HT) and IceTag (IT) sensors from 12 mo of age until confirmation of pregnancy. Upon detection of high activity by HT, ovaries were scanned by ultrasound, a blood sample was collected for analysis of plasma estradiol, and signs of estrus (clear vaginal mucus, uterine muscle tone, visual mounting activity, standing to be mounted, or rump showing signs of repeated acceptance of mounts) were recorded. Because only estrus episodes detected by HT (n=111) were further evaluated, only the positive predictive value was measured. Heifers were housed in groups of 24 in a freestall pen. Data were analyzed using Proc CORR and GLM of SAS (SAS Institute Inc., Cary, NC). The positive predictive value was 84.7% (94/111) for HT and 98.7% (74/75) for IT. Estrus duration was recorded by HT as 14.3+/-4.1h [mean +/- standard deviation (SD)] and by IT as 15.0+/-4.0h; duration measurements were correlated (r=0.60). The mean duration difference was 0.74+/ 3.52h. Recordings of onset and end of estrus by IT were 3.5+/-4.3h and 2.9+/-4.9h earlier than those by HT. The overlap in duration was 9h. Measurements of estrus intensity were correlated (r=0.63). Peak activity was 77.3+/-19.5 index value (approximately 7.7 SD from basal activity) on HT. The relative increase in activity measured by IT was 360+/-170% baseline value. Measurements of intensity and duration from HT were correlated (r=0.64) but those from IT were not (r=0.13). Plasma estradiol concentration (11.2+/-4.6pg/mL) was not correlated with preovulatory follicle diameter or with duration or intensity of estrus. Diameter of preovulatory follicle (15.7+/-2.6mm) had no correlation with duration of estrus and was only weakly correlated with intensity measured by either system. Baseline steps/hour was negatively correlated with intensity from both sensors (r=-0.37 and -0.70 for HT and IT). Estrus episodes accompanied by 2 or 3 of the monitored signs of estrus had greater intensity and duration on HT but not on IT. Preovulatory follicle diameter and plasma estradiol concentration did not influence occurrence of estrus signs. Results indicate that both systems identified estrus precisely, with correlated characterization and similar timing. In contrast, relationships with plasma estradiol concentration and signs of estrus require further investigation. PMID- 25747828 TI - Isolation and purification of immunoglobulin G from bovine colostrums by hydrophobic charge-induction chromatography. AB - Hydrophobic charge-induction chromatography, a novel chromatographic technique for bioseparation, was developed to isolate and purify bovine IgG with high purity. In this work, the raw IgG solution, a precipitate from bovine colostrum powder solution with 40% (wt/vol) ammonium sulfate, was dissolved in 50mM phosphate buffer and used as loading solution for investigating chromatographic conditions on a mercapto-ethyl-pyridine (MEP) HyperCel (Pall Corp., Port Washington, NY) sorbent. The initial IgG concentration had no effect on the dynamic binding capacity of MEP HyperCel resin, but the linear velocity of loading solution had an obvious effect on the dynamic IgG binding capacity and IgG recovery. The maximum linear velocity was optimized as 0.4cm/min of loading solution, and 90% recovery of IgG was achieved. Under these optimized binding conditions, the pH and ionic strength for the elution process were selected as pH 4.5 and 0.5 M NaCl, respectively. Subsequently, hydrophobic charge-induction chromatography was performed on a MEP HyperCel sorbent to isolate IgG using bovine colostrum whey as the loading solution. Under the optimized operation conditions, a remarkable process improvement in IgG purification was received, which includes a yield of 91.5%, a purity of 93.9% (wt/wt), and a purification factor of 6.8. The results indicated that MEP HyperCel chromatography offers an efficient means to purify IgG from bovine colostrums. PMID- 25747829 TI - Predicting nitrogen excretion from cattle. AB - Manure nitrogen (N) from cattle production facilities can lead to negative environmental effects, such as contribution to greenhouse gas emissions, leaching and runoff to aqueous ecosystems leading to eutrophication, and acid rain. To mitigate these effects and to improve the efficiency of N use, accurate prediction of N excretion and secretions are required. A genetic algorithm was implemented to select models to predict fecal, urinary, and total manure N excretions, and milk N secretions from 3 classes of animals: lactating dairy cows, heifers and dry cows, and steers. Two tiers of model classes were developed for each category of animals based on model input requirements. A total of 6 models for heifers and dry cows and steers and an additional 2 models for lactating dairy cattle were developed. Evaluation of the models using K-fold cross validation based on all data and using the most recent 6 yr of data showed better prediction for total manure N and fecal N compared with urinary N excretion, which was the most variable response in the database. Compared with extant models from the literature, the models developed in this study resulted in a significant improvement in prediction error for fecal and urinary N excretions from lactating cows. For total manure production by lactating cows, extant and new models were comparable in their prediction ability. Both proposed and extant models performed better than the prediction methods used by the US Environmental Protection Agency for the national inventory of greenhouse gases. Therefore, the proposed models are recommended for use in estimation of manure N from various classes of animals. PMID- 25747830 TI - Effects of Pleurotus eryngii polysaccharides on bacterial growth, texture properties, proteolytic capacity, and angiotensin-I-converting enzyme-inhibitory activities of fermented milk. AB - Pleurotus eryngii is one of the most favored oyster mushrooms and contains various beneficial bioactive compounds. Polysaccharide extracted from P. eryngii (PEPS) was added as a natural-source ingredient to milk before fermentation, and the effects of additional PEPS on fermented milk were investigated in this study. The PEPS were extracted and added to reconstituted skim milk (12%, wt/vol) at 0.5, 0.25, and 0.125% (wt/vol) and fermented by a non-exopolysaccharide-producing strain, Streptococcus thermophilus Australian Starter Culture Collection (ASCC) 1303 (ST 1303), or an exopolysaccharide-producing Strep. thermophilus ASCC 1275 (ST 1275). Bacterial growth, texture properties, microstructure, proteolytic capacity, and angiotensin-I-converting enzyme-inhibitory activities of fermented milk (FM) were determined during refrigerated storage at 4 degrees C for 21d. Viable counts of starter bacteria in FM with 0.5% PEPS added were the highest. Changes in pH were consistent with changes in titratable acidities for all samples. The FM samples with added PEPS showed denser protein aggregates containing larger serum pores in confocal micrographs compared with those without PEPS at d 0 and 21during refrigerated storage. The values for spontaneous whey separation of FM with added PEPS were significantly higher than those of FM fermented by ST 1303 or ST 1275 without PEPS. The proteolytic activities of ST 1303 of FM with added PEPS were higher than those of FM fermented by ST 1303 without PEPS. The FM with added 0.125% PEPS had similar angiotensin-I-converting enzyme-inhibitory activity to that fermented by ST 1303 without PEPS; both were higher than those of other samples during refrigerated storage. Firmness and gumminess values of FM with added PEPS were higher than those of FM fermented by ST 1303 or ST 1275 without PEPS. PMID- 25747831 TI - Effect of dextran and dextran sulfate on the structural and rheological properties of model acid milk gels. AB - Various types of polysaccharides are widely used in cultured dairy products. However, the interaction mechanisms, between milk proteins and these polysaccharides, are not entirely clear. To explore the interactions between uncharged and charged polysaccharides and the caseins, we used a model acid-milk gel system, which allowed acidification to occur separately from gelation. The effect of adding uncharged dextran (DX; molecular weight ~2.0*10(6) Da) and negatively charged dextran sulfate (DS; molecular weight ~1.4*10(6) Da) to model acid milk gels was studied. Two concentrations (0.075 and 0.5%, wt/wt) of DX or DS were added to cold milk (~0 degrees C) that had been acidified to pH values 4.4, 4.6, 4.8, or 4.9. Acidified milks containing DX or DS were then quiescently heated at the rate of 0.5 degrees C/min to 30 degrees C, which induced gelation, and gels were then held at 30 degrees C for 17 h to facilitate gel development. Dynamic small-amplitude-oscillation rheology and large-deformation (shear) tests were performed. Microstructure of gels was examined by fluorescence microscopy. Gels made with a high concentration of DX gelled at a lower temperature, but after 17 h at 30 degrees C, these gels exhibited lower storage moduli and lower yield-stress values. At pH 4.8 or 4.9 (pH values greater than the isoelectric point of caseins), addition of 0.5% DS to acidified milk resulted in lower gelation temperature. At pH 4.4 (pH values less than the isoelectric point of caseins), addition of 0.5% DS to acidified milk resulted in gels with very high stiffness values. Gels made at pH 4.8 or 4.9 with both concentrations of DS had much lower stiffness and yield-stress values than control gels. Microstructural analysis indicated that gels made at pH 4.4 with the addition of 0.5% DX exhibited large protein strands and pores, whereas gels made with 0.075% DX or the control gels had a finer protein matrix. At higher pH values (>4.4), gels made with 0.5% DX had a finer structure. At all pH values, gels made with 0.5% DS exhibited larger pores than the control gels. This study demonstrated that low concentrations of uncharged DX did not significantly affect the rheological properties of model acid milk gels; high concentrations of DX resulted in earlier gelation, possibly caused by depletion-induced attractions between casein particles, which altered the microstructure and created weaker gels. At pH values <4.6, negatively charged DS produced stiff casein gels, which might be due to attractive crosslinking by electrostatic interactions between DS and caseins at pH values below the isoelectric pH of casein (i.e., positively charged casein regions interacted with negatively charged DS molecules). PMID- 25747832 TI - Effects of day of gestation and feeding regimen in Holstein * Gyr cows: III. Placental adaptations and placentome gene expression. AB - This study investigated the influence of day of gestation (DG) and feeding regimens (FR) on the expression of genes responsible for placenta development, nutrient transfer, and angiogenic factors in Holstein * Gyr cows. Forty pregnant multiparous Holstein * Gyr cows with an average initial body weight of 482+/ 10.8kg and an initial age of 5+/-0.8 yr were allocated to 1 of 2 FR: ad libitum (AL; n=20) or maintenance level (ML; n=20). Maintenance level was considered to be 1.15% of body weight (dry matter basis) and met 100% of the net energy requirements and AL provided 190% of the total net energy requirements. Cows were slaughtered at 4 DG: 139, 199, 241, and 268d. After the cows were slaughtered, the placenta and uterus were separated and weighed. Caruncles and cotyledons were individually separated, counted, and weighed. Placenta expressed as kilograms and grams per kilogram of empty body weight (EBW) was heavier in ML- than in AL-fed cows at 268d of gestation. Placenta expressed as kilograms and grams per kilogram of EBW was the lightest at 139d of gestation, and the greatest mass was observed at 268d in ML-fed cows. However, in AL-fed cows, the heaviest placenta expressed as grams per kilogram of EBW was observed from 199d of gestation. Placentomes expressed as grams per kilogram of EBW were heavier in ML-fed cows during gestation, and the number of placentomes was greater in ML-fed cows at 268d of gestation. We observed that IGFR1 and IGFR2 were involved in placenta adaptations when ML was provided, as their expression in placentome cells was greater in ML fed cows at 268d of gestation. The genes responsible for angiogenesis were also greater in ML-fed cows: VEGFA, GUCY1B3, HIFA, FGF2, and NOS3 were altered by FR and DG interaction and they were greater in ML-fed cows at 268d of gestation. In addition, VEGFB and ANGPT2 did not show interactions between FR and DG, but they were greater in ML-fed cows. Thus, we suggest that the placenta from an ML-fed cow develops adaptations to the reduced nutrient supply by altering its structure and gene expression, thereby developing mechanisms for potential increased nutrient transfer efficiency to the fetus. PMID- 25747833 TI - Effect of variable water intake as mediated by dietary potassium carbonate supplementation on rumen dynamics in lactating dairy cows. AB - Water is a critical nutrient for dairy cows, with intake varying with environment, production, and diet. However, little work has evaluated the effects of water intake on rumen parameters. Using dietary potassium carbonate (K2CO3) as a K supplement to increase water intake, the objective of this study was to evaluate the effect of K2CO3 supplementation on water intake and on rumen parameters of lactating dairy cows. Nine ruminally cannulated, late-lactation Holstein cows (207+/-12d in milk) were randomly assigned to 1 of 3 treatments in a replicated 3*3 Latin square design with 18-d periods. Dietary treatments (on a dry matter basis) were no added K2CO3 (baseline dietary K levels of 1.67% dietary K), 0.75% added dietary K, and 1.5% added dietary K. Cows were offered treatment diets for a 14-d adaption period followed by a 4-d collection period. Ruminal total, liquid, and dry matter digesta weights were determined by total rumen evacuations conducted 2h after feeding on d 4 of the collection period. Rumen fluid samples were collected to determine pH, volatile fatty acids, and NH3 concentrations, and Co-EDTA was used to determine fractional liquid passage rate. Milk samples were collected twice daily during the collection period. Milk, milk fat, and protein yields showed quadratic responses with greatest yields for the 0.75% added dietary K treatment. Dry matter intake showed a quadratic response with 21.8kg/d for the 0.75% added dietary K treatment and 20.4 and 20.5kg/d for control and the 1.5% added dietary K treatment, respectively. Water intake increased linearly with increasing K2CO3 supplementation (102.4, 118.4, and 129.3L/d) as did ruminal fractional liquid passage rate in the earlier hours after feeding (0.118, 0.135, and 0.141 per hour). Total and wet weights of rumen contents declined linearly and dry weight tended to decline linearly as dietary K2CO3 increased, suggesting that the increasing water intake and fractional liquid passage rate with increasing K2CO3 increased the overall ruminal turnover rate. Ruminal ammonia concentrations declined linearly and pH increased linearly as K supplementation increased. As a molar percentage of total volatile fatty acids, acetate increased linearly as dietary K increased, though propionate declined. Increasing dietary K2CO3 and total K in the diets of lactating dairy cows increased water consumption and modified ruminal measures in ways suggesting that both liquid and total ruminal turnover were increased as both water and K intake increased. PMID- 25747834 TI - Short communication: Single molecule, real-time sequencing technology revealed species- and strain-specific methylation patterns of 2 Lactobacillus strains. AB - Pacific Biosciences' (Menlo Park, CA) single molecule, real-time sequencing technology was reported to have some advantages in generating finished genomes and characterizing the epigenome of bacteria. In the present study, this technology was used to sequence 2 Lactobacillus strains, Lactobacillus casei Zhang and Lactobacillus plantarum P-8. Previously, the former bacterium was sequenced by an Applied Biosystems 3730 DNA analyzer (Grand Island, NY), whereas the latter one was analyzed with Roche 454 (Indianapolis, IN) and Illumina sequencing technologies (San Diego, CA). The results showed that single molecule, real-time sequencing resulted in high-quality, finished genomes for both strains. Interestingly, epigenome analysis indicates the presence of 1 active N(6) methyladenine methyltransferase in L. casei Zhang, but none in L. plantarum P-8. Our study revealed for the first time a completely different methylation pattern in 2 Lactobacillus strains. PMID- 25747835 TI - A comparison of ruminal or reticular digesta sampling as an alternative to sampling from the omasum of lactating dairy cows. AB - The objective of this study was to develop and compare techniques for determining nutrient flow based on digesta samples collected from the reticulum or rumen of lactating dairy cows with estimates generated by the omasal sampling technique. Pre-experimental method development suggested, after comparing with the particle size distribution of feces, application of primary sieving of ruminal and reticular digesta from lactating cows through an 11.6-mm sieve, implying that digesta particles smaller than this were eligible to flow out of the rumen. For flow measurements at the different sampling sites 4 multiparous, lactating Nordic Red cows fitted with ruminal cannulas were used in a Latin square design with 4 dietary treatments, in which crimped barley was replaced with 3 incremental levels of protein supplementation of canola meal. Digesta was collected from the rumen, reticulum, and omasum to represent a 24-h feeding cycle. Nutrient flow was calculated using the reconstitution system based on Cr, Yb, and indigestible neutral detergent fiber and using (15)N as microbial marker. Large and small particles and the fluid phase were recovered from digesta collected at all sampling sites. Bacterial samples were isolated from the digesta collected from the omasum. Several differences existed for digesta composition, nutrient flows, and estimates of ruminal digestibility among the 3 different sampling sites. Sampling site * diet interactions were not significant. The estimated flows of DM, potentially digestible neutral detergent fiber, nonammonia N, and microbial N were significantly different between all sampling sites. However, the difference between DM flow based on sampling from the reticulum and the omasum was small (0.13kg/d greater in the omasum). The equality between the reticulum and the omasum as sampling sites was supported by the following regression: omasal DM flow=0.37 (+/-0.649) + 0.94 (+/-0.054) reticular DM flow (R(2)=0.96 and root mean square error=0.438kg/d). More deviating nutrient-flow estimates when sampling digesta from the rumen than the reticulum compared with the omasum suggested that sampling from the reticulum is the most promising alternative to the omasal sampling technique. To definitively promote sampling from the reticulum as an alternative to the omasal sampling technique, more research is needed to determine selection criteria of reticular digesta for accurate and precise flow estimates across a range of diets. PMID- 25747836 TI - Factors associated with the financial performance of spring-calving, pasture based dairy farms. AB - As land becomes a limiting resource for pasture-based dairy farming, the inclusion of purchased supplementary feeds to increase milk production per cow (through greater dry matter intake) and per hectare (through increased stocking rate) is often proposed as a strategy to increase profitability. Although a plausible proposition, virtually no analysis has been done on the effect of such intensification on the profitability of commercial pasture-based dairy farm businesses. The objective of this study was to characterize the average physical and financial performance of dairy systems differing in the proportion of the cow's diet coming from grazed pasture versus purchased supplementary feeds over 4 yr, while accounting for any interaction with geographic region. Physical, genetic, and financial performance data from 1,561 seasonal-calving, pasture based dairy farms in Ireland were available between the years 2008 and 2011; data from some herds were available for more than 1 yr of the 4-yr study period, providing data from 2,759 dairy farm-years. The data set was divided into geographic regions, based on latitude, rainfall, and soil characteristics that relate to drainage; these factors influence the length of the pasture growth season and the timing of turnout to pasture in spring and rehousing in autumn. Farms were also categorized by the quantity of feed purchased; farms in which cows received <10, 11-20, 21-30, or >30% of their annual feed requirements from purchased feed were considered to be categories representative of increasing levels of system intensification. Geographic region was associated with differences in grazing days, pasture harvested per hectare, milk production per cow and per hectare, and farm profitability. Farms in regions with longer grazing seasons harvested a greater amount of pasture [an additional 19kg of dry matter (DM)/ha per grazing day per hectare], and greater pasture harvested was associated with increased milk component yield per hectare (58.4kg of fat and 51.4kg of protein more per tonne of DM pasture harvested/ha) and net profit per hectare (?268/ha more per tonne of DM harvested). Milk yield and yield of milk components per cow and per hectare increased linearly with increased use of purchased feed (additional 30.6kg of milk fat and 26.7kg of milk protein per tonne of DM purchased feed per hectare), but, on average, pasture harvested/hectare and net profit/hectare declined (-0.60 t of DM/ha and ?78.2/ha, respectively) with every tonne of DM supplementary feed purchased per hectare. The results indicate an effect of purchased feeds not usually accounted for in marginal economic analyses (e.g., milk to feed price ratio): the decline in pasture harvested/hectare, with the costs of producing the unutilized pasture in addition to the cost of feed resulting in a lower profit. In conclusion, greater milk component yields per cow were associated with increased profit per hectare, and a greater use of purchased feeds was associated with an increase in the yield of milk components. However, on average, increasing yield of milk components through the supply of purchased feeds to pasture-based cows was associated with a decline in pasture harvested per hectare and profitability. The decline in pasture harvested per hectare with increased use of purchased supplements per cow is probably the primary reason for the low milk production response and the failure to capitalize on the potential benefits of purchased supplements, with the associated costs of growing the unutilized pasture, in conjunction with increased nonfeed variable and fixed costs outweighing the increased milk production and revenue from supplementation. Farmers considering intensification through use of purchased supplements to increase the stock carrying capacity of the farm (i.e., stocking rate) must ensure that they focus on management of pasture and total cost control to capture the potential benefits of supplementary feed use. PMID- 25747837 TI - Digestive development in neonatal dairy calves with either whole or ground oats in the calf starter. AB - A series of 3 trials was conducted to determine effects of whole or ground oats in starter grain on reticulorumen fermentation and digestive system development of preweaned calves. Male Holstein calves (43.1+/-2.3kg at birth; n=8, 9, and 7 for trials 1, 2, and 3, respectively) were housed in individual pens in a heated facility; bedding was covered with landscape fabric to prevent consumption of bedding by the calves. In trials 1 and 2 only, calves were fitted with rumen cannulas by wk 2 of life. In all trials, a fixed amount of starter (containing 25% oats either ground and in the pellet or whole) was offered daily; orts were fed through the cannula in trials 1 and 2. Calves were randomly assigned to an all-pelleted starter or pellets plus whole oats. Rumen contents (trials 1 and 2) were sampled weekly at -8, -4, 0, 2, 4, 8, and 12 h after grain feeding for determination of pH and volatile fatty acids. Calves were killed 3 wk (trial 1) or 4 wk (trials 2 and 3) after grain was offered; organs were harvested, emptied, rinsed, and weighed to gauge digestive organ development. Starter intake was not different between treatments. Weekly measurements of rumen digesta pH did not change and only subtle changes were observed in molar proportions of individual volatile fatty acids. Molar proportion of butyrate and pH linearly decreased with age, whereas acetate proportion increased. Reticulorumen weight and papillae length tended to be greater for calves fed pelleted starter, whereas abomasum weight was greater for calves fed pellets plus whole oats. Fecal particle size and starch content were greater for calves fed pellets plus whole oats. Under the conditions of this study, physical form of oats in starter grain did not affect rumen fermentation measurements; greater rumen weight and papillae length in calves fed pelleted starter may be the result of greater nutrient availability of ground oats. Under the conditions of this study with young calves on treatments for <4 wk, increasing particle size of the starter by feeding whole oats did not affect rumen fermentation nor did it improve digestive system development. PMID- 25747838 TI - Prediction of nutrient digestibility and energy concentrations in fresh grass using nutrient composition. AB - Improved nutrient utilization efficiency is strongly related to enhanced economic performance and reduced environmental footprint of dairy farms. Pasture-based systems are widely used for dairy production in certain areas of the world, but prediction equations of fresh grass nutritive value (nutrient digestibility and energy concentrations) are limited. Equations to predict digestible energy (DE) and metabolizable energy (ME) used for grazing cattle have been either developed with cattle fed conserved forage and concentrate diets or sheep fed previously frozen grass, and the majority of them require measurements less commonly available to producers, such as nutrient digestibility. The aim of the present study was therefore to develop prediction equations more suitable to grazing cattle for nutrient digestibility and energy concentrations, which are routinely available at farm level by using grass nutrient contents as predictors. A study with 33 nonpregnant, nonlactating cows fed solely fresh-cut grass at maintenance energy level for 50 wk was carried out over 3 consecutive grazing seasons. Freshly harvested grass of 3 cuts (primary growth and first and second regrowth), 9 fertilizer input levels, and contrasting stage of maturity (3 to 9 wk after harvest) was used, thus ensuring a wide representation of nutritional quality. As a result, a large variation existed in digestibility of dry matter (0.642-0.900) and digestible organic matter in dry matter (0.636-0.851) and in concentrations of DE (11.8-16.7 MJ/kg of dry matter) and ME (9.0-14.1 MJ/kg of dry matter). Nutrient digestibilities and DE and ME concentrations were negatively related to grass neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents but positively related to nitrogen (N), gross energy, and ether extract (EE) contents. For each predicted variable (nutrient digestibilities or energy concentrations), different combinations of predictors (grass chemical composition) were found to be significant and increase the explained variation. For example, relatively higher R(2) values were found for prediction of N digestibility using N and EE as predictors; gross-energy digestibility using EE, NDF, ADF, and ash; NDF, ADF, and organic matter digestibilities using N, water soluble carbohydrates, EE, and NDF; digestible organic matter in dry matter using water-soluble carbohydrates, EE, NDF, and ADF; DE concentration using gross energy, EE, NDF, ADF, and ash; and ME concentration using N, EE, ADF, and ash. Equations presented may allow a relatively quick and easy prediction of grass quality and, hence, better grazing utilization on commercial and research farms, where nutrient composition falls within the range assessed in the current study. PMID- 25747839 TI - Assessment and non-clinical impact of medical devices. AB - Medical devices (MDs) cover a wide variety of products. They accompany changes in medical practice in step with technology innovations. Innovations in the field of MDs can improve the conditions of use of health technology and/or modify the organisation of care beyond the strict diagnostic or therapeutic benefit for the patients. However, these non purely clinical criteria seem to be only rarely documented or taken into account in the assessment of MDs during reimbursement decisions at national level or for formulary listing by hospitals even though multidimensional models for the assessment of health technologies have been developed that take into account the views of all stakeholders in the healthcare system In this article, after summarising the background concerning the assessment of health technologies in France, a definition of non-clinical criteria for the assessment of MDs is proposed and a decision tree for the assessment of MDs is described. Future lines of approach are proposed as a conclusion. PMID- 25747840 TI - Creating conditions for the success of the French industrial advanced therapy sector. AB - Although the European Union merely followed the initiatives of the United States and Japan by introducing special regimes for orphan medicinal products, it has introduced a special status for a new category of biological medicinal products, advanced therapy medicinal products (ATMPs), adopting specific associated regulations. European Regulation (which constitutes the highest legal instrument in the hierarchy of European law texts) [EC] No. 1394/2007, published in 2007, uses this term to define somatic cell therapy medicinal products, tissue engineered products, and gene therapy medicinal products, possibly combined with medical devices. The stated objective was two-fold: both to promote their industrialization and market access, while guaranteeing a high level of health protection for patients. Since publication of the regulation, few marketing authorizations have been granted in Europe, and these have not been accompanied by commercial success. However, certain recent studies show that this is a growing sector and that France remains the leading European nation in terms of clinical trials. This round table brought together a panel of representatives of French public and private protagonists from the advanced therapy sector. The discussions focused on the conditions to ensure the success of translational research and, more generally, the French advanced therapy sector. These enabled a number of obstacles to be identified, which once lifted, by means of recommendations, would facilitate the development and success of this sector. PMID- 25747842 TI - Fourteen-year experience with the intraoperative frozen section examination of testicular lesion in a tertiary university center. AB - Most testicular tumors are germ cell neoplasias. The number of incidentally detected small-sized, nonpalpable testicular lesions is increasing with the use of high-frequency ultrasound for infertility or trauma. These lesions are benign in 80% of cases and can be treated by organ-sparing surgery on the basis of frozen section examination (FSE). We assess the reliability of FSE in testicular and paratesticular lesions and its possible impact on surgical management. We performed a retrospective review of intraoperative FSE in testicular/paratesticular lesions at Geneva University Hospital during a 14-year period. A total of 170 cases were identified, with 159 testicular and 11 paratesticular lesions. The FSE results, permanent sections, and orchiectomy slides were reviewed and compared. Frozen section examinations were reported to be benign in 9 paratesticular and in 43 testicular lesions, and malignant in 2 paratesticular and 105 testicular lesions. Comparing FSE and final diagnosis, FSE correctly identified all nontumor lesions. There was a failure rate of 3.5% to identify tumor. Specificity was 100%, sensitivity was 95%, positive predictive value was 100%, and negative predictive value was 89%. Frozen section examination is a highly sensitive and specific intraoperative procedure, which allows to differentiate between benign and malignant testicular and paratesticular lesions, with a possibility of organ-sparing surgery when they are benign. PMID- 25747841 TI - What strategy should France implement for H2020? AB - The initiation of Horizon 2020--the European Union's 8th Framework Programme for Research and Innovation, allotted a budget of 79 billion euros--provides an opportunity to review France's participation in previous Framework Programmes. Indeed, French participation does not match either its scientific importance or its financial investment. While France contributed 16.5 to 17% of the EU's 7th Framework Programme research budget, its return through the funding of coordinated projects in which French teams are participating stands at around 12.5 to 13%, a shortfall of 600 million euros. Although the situation depends on the type of activity, French participation in clinical research appears to be smaller than that of its neighbours, with fewer responses to European calls for proposals. While France has many assets, which include the assured funding of clinical research, structured thematic networks and the initiation of major national programmes, it suffers from the dilution of resources due to France's regional development policy, the lack of multidisciplinarity and the ignorance of both the medical and scientific community and the institutions to which they belong as to how Horizon 2020 actually works. We propose three types of strategy to encourage proposals for coordinated clinical research projects or projects involving French teams, and to help in the drawing up of applications: Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. Recognise the value of European actions to influence the European landscape and change mentalities. Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application. * Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. * Recognise the value of European actions to influence the European landscape and change mentalities. * Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application. PMID- 25747843 TI - Genetic Architecture of Natural Variation in Rice Chlorophyll Content Revealed by a Genome-Wide Association Study. AB - Chlorophyll content is one of the most important physiological traits as it is closely related to leaf photosynthesis and crop yield potential. So far, few genes have been reported to be involved in natural variation of chlorophyll content in rice (Oryza sativa) and the extent of variations explored is very limited. We conducted a genome-wide association study (GWAS) using a diverse worldwide collection of 529 O. sativa accessions. A total of 46 significant association loci were identified. Three F2 mapping populations with parents selected from the association panel were tested for validation of GWAS signals. We clearly demonstrated that Grain number, plant height, and heading date7 (Ghd7) was a major locus for natural variation of chlorophyll content at the heading stage by combining evidence from near-isogenic lines and transgenic plants. The enhanced expression of Ghd7 decreased the chlorophyll content, mainly through down-regulating the expression of genes involved in the biosynthesis of chlorophyll and chloroplast. In addition, Narrow leaf1 (NAL1) corresponded to one significant association region repeatedly detected over two years. We revealed a high degree of polymorphism in the 5' UTR and four non-synonymous SNPs in the coding region of NAL1, and observed diverse effects of the major haplotypes. The loci or candidate genes identified would help to fine-tune and optimize the antenna size of canopies in rice breeding. PMID- 25747844 TI - Yam Tuber Storage Protein Reduces Plant Oxidants Using the Coupled Reactions as Carbonic Anhydrase and Dehydroascorbate Reductase. PMID- 25747845 TI - Making the Bread: Insights from Newly Synthesized Allohexaploid Wheat. AB - Bread wheat (or common wheat, Triticum aestivum) is an allohexaploid (AABBDD, 2n = 6x = 42) that arose by hybridization between a cultivated tetraploid wheat T. turgidum (AABB, 2n = 4x = 28) and the wild goatgrass Aegilops tauschii (DD, 2n = 2x = 14). Polyploidization provided niches for rigorous genome modification at cytogenetic, genetic, and epigenetic levels, rendering a broader spread than its progenitors. This review summarizes the latest advances in understanding gene regulation mechanisms in newly synthesized allohexaploid wheat and possible correlation with polyploid growth vigor and adaptation. Cytogenetic studies reveal persistent association of whole-chromosome aneuploidy with nascent allopolyploids, in contrast to the genetic stability in common wheat. Transcriptome analysis of the euploid wheat shows that small RNAs are driving forces for homoeo-allele expression regulation via genetic and epigenetic mechanisms. The ensuing non-additively expressed genes and those with expression level dominance to the respective progenitor may play distinct functions in growth vigor and adaptation in nascent allohexaploid wheat. Further genetic diploidization of allohexaploid wheat is not random. Regional asymmetrical gene distribution, rather than subgenome dominance, is observed in both synthetic and natural allohexaploid wheats. The combinatorial effects of diverged genomes, subsequent selection of specific gene categories, and subgenome-specific traits are essential for the successful establishment of common wheat. PMID- 25747846 TI - Rapid Decoding of Sequence-Specific Nuclease-Induced Heterozygous and Biallelic Mutations by Direct Sequencing of PCR Products. PMID- 25747847 TI - Seed oil polyphenols: rapid and sensitive extraction method and high resolution mass spectrometry identification. AB - Phenolic content is a primary parameter for vegetables oil quality evaluation, and directly involved in the prevention of oxidation and oil preservation. Several methods have been reported in the literature for polyphenols extraction from seed oil but the approaches commonly used remain manually handled. In this work, we propose a rapid and sensitive method for seed oil polyphenols extraction and identification. For this purpose, polyphenols were extracted from Opuntia stricta Haw seed oil, using high frequency agitation, separated, and then identified using a liquid chromatography-high resolution mass spectrometry method. Our results showed good sensitivity and reproducibility of the developed methods. PMID- 25747848 TI - Routine Western blot to check autophagic flux: cautions and recommendations. AB - At present, the analysis of autophagic flux by Western blotting (WB), which measures two of the most important markers of autophagy, i.e., microtubule associated protein 1 light chain 3 (LC3) and p62, is widely accepted in the scientific community. In this study, we addressed the possible disadvantages and limitations that this method presents for a correct interpretation of the results according to the lysis buffer used for extracting proteins. Here, we tested the LC3 and p62 protein levels by WB in four cell models (mouse embryonic and human fibroblasts (MEFs and HFs, respectively), N27 rat mesencephalic dopaminergic neurons and SH-SY5Y human neuroblastoma cells). The cells were exposed to the autophagy inhibitor bafilomycin A1 (Baf. A1) in combination (or not) with nutrient deprivation to induce autophagy, and they were lysed by using four different buffers (nonyl phenoxypolyethoxylethanol (NP-40), radioimmunoprecipitation assay (RIPA), Triton X-100, and sample buffer (SB) 1*). Based on our observations, we want to highlight that this technique is not always appropriate for analyzing and monitoring autophagy. In this report, we show conflicting data that hinder the correct interpretation of the results, especially in relation to p62 protein levels, at least in the models studied in this work. PMID- 25747849 TI - Body weight status and onset of cognitive impairment among U.S. middle-aged and older adults. AB - OBJECTIVE: To examine the relationship between body weight status and onset of cognitive impairment among U.S. middle-aged and older adults. METHODS: Study sample came from 1996 to 2010 waves of the Health and Retirement Study, consisting of 6739 community-dwelling adults born between 1931 and 1941 who were free from cognitive impairment in 1996. Body mass index (BMI) was calculated from self-reported height/weight. Cognitive impairment was defined by a composite score of 11 or lower on the immediate and delayed word recall, serial 7's, and backwards counting tests. Kaplan-Meier estimator and Cox proportional hazards model were performed to examine the association between base-year body weight status and future onset of cognitive impairment. RESULTS: Compared with their normal weight counterparts, the unadjusted hazard ratio (HR) for cognitive impairment incidence was 2.03 (95% confidence interval: 1.38-3.00), 1.15 (1.02 1.29), 1.28 (1.14-1.43), and 1.59 (1.33-1.92) among underweight (BMI<18.5), overweight (25 <= BMI < 30), class I obese (30 <= BMI < 35), and class II obese or above (BMI >= 35) participants, respectively. The unadjusted relationship between obesity and cognitive impairment onset appeared stronger among females than among males. After adjusting for base-year individual sociodemographics, functional limitations and chronic conditions, the estimated associations between body weight status and cognitive impairment were attenuated but remained statistically significant for underweight participants. CONCLUSION: Underweight is a robust risk factor for onset of cognitive impairment in later life. Weight management programs targeting middle-aged and older adults should focus on achieving and maintaining optimal body weight. PMID- 25747850 TI - The enduring effect of education-socioeconomic differences in disability trajectories from age 85 years in the Newcastle 85+ Study. AB - OBJECTIVE: Little is known about disability progression in very old age despite this being vital for care planning. We investigate whether distinct trajectories of disability are evident from age 85 to 90 and their association with socio economic status (SES). METHODS: The Newcastle 85+ Study recruited people born in 1921 through participating general practices in Newcastle and North Tyneside. Participants underwent a health assessment (HA) at baseline, 18, 36 and 60 months and a GP record review (GPRR) at baseline, 36 and 60 months. Disability was measured via difficulty in 17 Activities of Daily Living. Trajectory identification was assessed by gender stratified, mortality adjusted, group-based trajectory modelling (GBTM) and the impact of life-course SES (level of education; occupational class; deprivation) on trajectory membership evaluated (adjusting for confounding variables). RESULTS: 851 participants agreed to HA and GPRR, 840 (98.7%) with complete disability data. Four distinct trajectories were evident for both sexes. A disability-free trajectory between age 85 and 90 was identified in men only (9% of the sample). The most disabled trajectories had severe disability at age 85 progressing to profound disability by age 90. After adjusting for confounders education remained significant; men and women with most education being less likely to be in the most disabled trajectory (Men: OR=0.80, 95% CI 0.65-0.98; women: OR=0.59, 95% CI 0.42-0.83). CONCLUSION: Distinct disability trajectories are evident in the very old and these are influenced by education, suggesting SES disadvantages cumulate throughout the life-course to create health and mortality inequalities later. PMID- 25747851 TI - Obesity in breast cancer--what is the risk factor? AB - Environmental factors influence breast cancer incidence and progression. High body mass index (BMI) is associated with increased risk of post-menopausal breast cancer and with poorer outcome in those with a history of breast cancer. High BMI is generally interpreted as excess adiposity (overweight or obesity) and the World Cancer Research Fund judged that the associations between BMI and incidence of breast cancer were due to body fatness. Although BMI is the most common measure used to characterise body composition, it cannot distinguish lean mass from fat mass, or characterise body fat distribution, and so individuals with the same BMI can have different body composition. In particular, the relation between BMI and lean or fat mass may differ between people with or without disease. The question therefore arises as to what aspect or aspects of body composition are causally linked to the poorer outcome of breast cancer patients with high BMI. This question is not addressed in the literature. Most studies have used BMI, without discussion of its shortcomings as a marker of body composition, leading to potentially important misinterpretation. In this article we review the different measurements used to characterise body composition in the literature, and how they relate to breast cancer risk and prognosis. Further research is required to better characterise the relation of body composition to breast cancer. PMID- 25747852 TI - Muscle gets stressed? p53 represses and protects. PMID- 25747853 TI - JunB and PTEN in prostate cancer: 'loss is nothing else than change'. PMID- 25747854 TI - Meat, beyond the plate. Data-driven hypotheses for understanding consumer willingness to adopt a more plant-based diet. AB - A shift towards reduced meat consumption and a more plant-based diet is endorsed to promote sustainability, improve public health, and minimize animal suffering. However, large segments of consumers do not seem willing to make such transition. While it may take a profound societal change to achieve significant progresses on this regard, there have been limited attempts to understand the psychosocial processes that may hinder or facilitate this shift. This study provides an in depth exploration of how consumer representations of meat, the impact of meat, and rationales for changing or not habits relate with willingness to adopt a more plant-based diet. Multiple Correspondence Analysis was employed to examine participant responses (N = 410) to a set of open-ended questions, free word association tasks and closed questions. Three clusters with two hallmarks each were identified: (1) a pattern of disgust towards meat coupled with moral internalization; (2) a pattern of low affective connection towards meat and willingness to change habits; and (3) a pattern of attachment to meat and unwillingness to change habits. The findings raise two main propositions. The first is that an affective connection towards meat relates to the perception of the impacts of meat and to willingness to change consumption habits. The second proposition is that a set of rationales resembling moral disengagement mechanisms (e.g., pro-meat justifications; self-exonerations) arise when some consumers contemplate the consequences of meat production and consumption, and the possibility of changing habits. PMID- 25747855 TI - Adult picky eating. Phenomenology, taste sensitivity, and psychological correlates. AB - OBJECTIVES: To explore psychosocial correlates of picky eating in adults, document differences in the taste sensitivity of picky and non-picky eating adults, and examine behavioral characteristics of this understudied phenomenon. METHODS: In Study One, 489 participants completed a survey on food choice and habits, including questions that asked participants to self-identify as picky eaters. Picky and non-picky eaters were compared on their rates of endorsement of a range of food selection behaviors and attitudes. In Study Two, participants who identified as either picky or non-picky responded to questionnaire measures of obsessive compulsive disorder, depression, disordered eating symptoms, disgust sensitivity, and food and general neophobia. Participants also rated the intensity of bitter and sweet solutions at three concentrations on a Labeled Magnitude Scale. RESULTS: In Study One, picky eaters were more likely to endorse a variety of anomalous eating behaviors and attitudes toward food, including rejection of foods based on sensory characteristics (taste, color, texture). Picky eaters were less likely to endorse enjoyment of eating, and more likely to report that they were unhealthy eaters. In Study Two, picky eaters had significantly higher OCD symptoms, disgust sensitivity, and food neophobia than non-picky eaters, and were more likely to score within the clinical range of depression symptoms, but did not have higher scores on measures of disordered eating or general neophobia. Picky eaters rated both bitter and sweet tastants as more intense than did non-picky eaters. DISCUSSIONS: Implications of findings for the future study of the correlates and mechanisms of Avoidant/Restrictive Food Intake Disorder are discussed. PMID- 25747856 TI - Strategies used by parents to influence their children's food preferences. AB - BACKGROUND: Food preferences are important determinants of children's food intakes. Parental feeding behaviours have a significant influence on the development of children's food preferences. The aim of the present study was to describe the ways in which parents attempt to influence their children's food preferences. METHODS: Parents of 2-5 year old children participated in semi structured qualitative interviews, which were transcribed and content analysed using a thematic coding manual. The parents described the ways in which they tried to influence the foods their child liked and disliked. Participants (N = 57) were separated into three separate groups based on an a priori study measuring food preferences and food neophobia: those who either had children with healthy food preferences (i.e. closely aligned with dietary guidelines) (N = 20), or unhealthy food preferences (i.e. not closely aligned with dietary guidelines) (N = 18), or high levels of food neophobia (N = 19). RESULTS: The parents used many, diverse behaviours to influence their child's food preferences. Some of these behaviours were likely to be effective in promoting healthy food preferences in children (e.g. parental modelling, food exposure), whilst others were likely to be ineffective (e.g. forcing consumption, restricting food access). Parents of children with healthy food preferences appeared to use more of the feeding behaviours predicted to promote healthy preferences than parents in the other two groups. Parents of children with unhealthy food preferences and those of food neophobic children appeared to rely more on ineffective behaviours. CONCLUSION: Parents used a mixture of effective and ineffective behaviours, with parents of children with unhealthy food preferences or high food neophobia using fewer behaviours known to be effective. Interventions aimed at influencing parental feeding behaviours should include those behaviours targeted at children's food preferences. PMID- 25747857 TI - Nickel sensitization and dietary nickel are a substantial cause of symptoms provocation in patients with chronic allergic-like dermatitis syndromes. AB - Data in literature seem to show that, in patients with contact allergic dermatitis, dietary nickel might be a cause of systemic dermatitis, but little information exists in literature about the role of nickel sensitization and dietary nickel in patients with allergic-like chronic dermatitis syndromes. The prevalence of nickel sensitization in patients with chronic allergic-like, non IgE-mediated skin diseases, and the possible impact of dietary nickel on symptom provocation and persistence has been assessed in the present retrospective study on a case series of 1726 patients referred to our allergy unit for chronic allergic-like skin diseases. IgE-mediated pathogenesis and other differential diagnoses excluded, patients were patch tested. Nickel-positive patients underwent an elimination diet and double-blind placebo-controlled nickel challenge (DBPCNC) test. A total of 339 (20%) tested nickel-positive. Fifty-two patients (15%) recovered by avoiding sources of nickel contact and 29 (10%) dropped out. Out of the remaining nickel-sensitized patients, 277 (80%) achieved complete or near complete recovery with low-nickel content diet, and 185 of them (89%) were positive to DBPCNC. We conclude that nickel sensitization and dietary nickel seem to be the chief trigger for provocation and persistence of symptoms in an important part (~11%) of patients with chronic allergic-like dermatitis syndromes. PMID- 25747858 TI - How can data harmonisation benefit mental health research? An example of The Cannabis Cohorts Research Consortium. PMID- 25747859 TI - Visual attention model based on statistical properties of neuron responses. AB - Visual attention is a mechanism of the visual system that can select relevant objects from a specific scene. Interactions among neurons in multiple cortical areas are considered to be involved in attentional allocation. However, the characteristics of the encoded features and neuron responses in those attention related cortices are indefinite. Therefore, further investigations carried out in this study aim at demonstrating that unusual regions arousing more attention generally cause particular neuron responses. We suppose that visual saliency is obtained on the basis of neuron responses to contexts in natural scenes. A bottom up visual attention model is proposed based on the self-information of neuron responses to test and verify the hypothesis. Four different color spaces are adopted and a novel entropy-based combination scheme is designed to make full use of color information. Valuable regions are highlighted while redundant backgrounds are suppressed in the saliency maps obtained by the proposed model. Comparative results reveal that the proposed model outperforms several state-of the-art models. This study provides insights into the neuron responses based saliency detection and may underlie the neural mechanism of early visual cortices for bottom-up visual attention. PMID- 25747861 TI - Non-tuberculous mycobacterial cochlear implant infection: An emerging pathogen. AB - OBJECTIVE AND IMPORTANCE: To report one of the first cases of a cochlear implant infected by non-tuberculous mycobacteria (NTM), an emerging otologic pathogen. CLINICAL PRESENTATION: We report the case of a 78-year-old woman who underwent uncomplicated cochlear implantation though subsequently developed wound dehiscence and device exposure. Tissue culture grew non-tuberculous mycobacterial infection with Mycobacterium abscessus. INTERVENTION: The device was explanted, the surgical bed debrided, and the patient was successfully treated with a prolonged course of oral and parenteral antibiotics. She elected not to undergo re-implantation. CONCLUSION: Non-tuberculous mycobacterial infections are being increasingly encountered and reported within the temporal bone. Although this is the first reported case of cochlear implant contamination with NTM, surgeons should be aware of this entity so that an appropriate treatment plan can be initiated. PMID- 25747860 TI - Uptake of systematic reviews and meta-analyses based on individual participant data in clinical practice guidelines: descriptive study. AB - OBJECTIVE: To establish the extent to which systematic reviews and meta-analyses of individual participant data (IPD) are being used to inform the recommendations included in published clinical guidelines. DESIGN: Descriptive study. SETTING: Database maintained by the Cochrane IPD Meta-analysis Methods Group, supplemented by records of published IPD meta-analyses held in a separate database. POPULATION: A test sample of systematic reviews of randomised controlled trials that included a meta-analysis of IPD, and a separate sample of clinical guidelines, matched to the IPD meta-analyses according to medical condition, interventions, populations, and dates of publication. DATA EXTRACTION: Descriptive information on each guideline was extracted along with evidence showing use or critical appraisal, or both, of the IPD meta-analysis within the guideline; recommendations based directly on its findings and the use of other systematic reviews in the guideline. RESULTS: Based on 33 IPD meta-analyses and 177 eligible, matched clinical guidelines there was evidence that IPD meta analyses were being under-utilised. Only 66 guidelines (37%) cited a matched IPD meta-analysis. Around a third of these (n=22, 34%) had critically appraised the IPD meta-analysis. Recommendations based directly on the matched IPD meta analyses were identified for only 18 of the 66 guidelines (27%). For the guidelines that did not cite a matched IPD meta-analysis (n=111, 63%), search dates had preceded the publication of the IPD meta-analysis in 23 cases (21%); however, for the remainder, there was no obvious reasons why the IPD meta analysis had not been cited. CONCLUSIONS: Our results indicate that systematic reviews and meta-analyses based on IPD are being under-utilised. Guideline developers should routinely seek good quality and up to date IPD meta-analyses to inform guidelines. Increased use of IPD meta-analyses could lead to improved guidelines ensuring that routine patient care is based on the most reliable evidence available. PMID- 25747862 TI - Effects of emergence time and early social rearing environment on behaviour of Atlantic salmon: consequences for juvenile fitness and smolt migration. AB - Consistent individual differences in behaviour have been well documented in a variety of animal taxa, but surprisingly little is known about the fitness and life-history consequences of such individual variation. In wild salmonids, the timing of fry emergence from gravel spawning nests has been suggested to be coupled with individual behavioural traits. Here, we further investigate the link between timing of spawning nest emergence and behaviour of Atlantic salmon (Salmo salar), test effects of social rearing environment on behavioural traits in fish with different emergence times, and assess whether behavioural traits measured in the laboratory predict growth, survival, and migration status in the wild. Atlantic salmon fry were sorted with respect to emergence time from artificial spawning nest into three groups: early, intermediate, and late. These emergence groups were hatchery-reared separately or in co-culture for four months to test effects of social rearing environment on behavioural traits. Twenty fish from each of the six treatment groups were then subjected to three individual-based behavioural tests: basal locomotor activity, boldness, and escape response. Following behavioural characterization, the fish were released into a near natural experimental stream. Results showed differences in escape behaviour between emergence groups in a net restraining test, but the social rearing environment did not affect individual behavioural expression. Emergence time and social environment had no significant effects on survival, growth, and migration status in the stream, although migration propensity was 1.4 to 1.9 times higher for early emerging individuals that were reared separately. In addition, despite individuals showing considerable variation in behaviour across treatment groups, this was not translated into differences in growth, survival, and migration status. Hence, our study adds to the view that fitness (i.e., growth and survival) and life-history predictions from laboratory measures of behaviour should be made with caution and ideally tested in nature. PMID- 25747863 TI - Curcumin, encapsulated in nano-sized PLGA, down-regulates nuclear factor kappaB (p65) and subarachnoid hemorrhage induced early brain injury in a rat model. AB - BACKGROUND: More and more evidence revealed early brain injury (EBI) may determine the final outcome in aneurismal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of nano-particle curcumin (nanocurcumin), a diarylheptanoid, on a SAH-induced EBI model. METHODS: A rodent double hemorrhage model was employed. Nanocurcumin (75/150/300MUg/kg/day) was administered via osmotic mini-pump post-SAH. CSF samples were collected to examine IL-1beta, IL-6, IL-8 and TNF-alpha (rt-PCR). Cerebral cortex was harvested for NF-kappaB (p50/p65) (western blot), caspases (rt-PCR) measurement. RESULTS: Nanocurcumin significantly reduced the bio-expression of NF-kappaB (p65), when compared with the SAH groups. The levels of IL-1beta and IL-6 were increased in animals subjected to SAH, compared with the healthy controls, but absent in the high dose nanocurcumin+SAH group. Moreover, the levels of TNF-alpha in the SAH groups were significantly elevated. Treatment with nanocurcumin (300MUg/kg) reduced the level to the healthy control. The cleaved caspase-3 and 9a was significantly reduced in 300MUg/kg nanocurcumin treatment groups (P<0.05). CONCLUSION: Treatment with nanocurcumin exerts its neuroprotective effect through the upward regulation of NF-kappaB (p65) and also reduced mitochondrion related caspase-9a expression. Besides, nanocurcumin decreased CSF levels of TNF-alpha and IL-1beta, which may contribute to the extrinsic antiapoptotic effect. This study shows promise to support curcuminin, in a nano-particle, could attenuate SAH induced EBI. PMID- 25747864 TI - Interaction between Oc-1 and Lmx1a promotes ventral midbrain dopamine neural stem cells differentiation into dopamine neurons. AB - Recent studies have shown that Onecut (Oc) transcription factors may be involved in the early development of midbrain dopaminergic neurons (mdDA). The expression profile of Oc factors matches that of Lmx1a, an important intrinsic transcription factor in the development of mDA neuron. Moreover, the Wnt1-Lmx1a pathway controls the mdDA differentiation. However, their expression dynamics and molecular mechanisms remain to be determined. To address these issues, we hypothesize that cross-talk between Oc-1 and Lmx1a regulates the mdDA specification and differentiation through the canonical Wnt-beta-catenin pathway. We found that Oc-1 and Lmx1a displayed a very similar expression profile from embryonic to adult ventral midbrain (VM) tissues. Oc-1 regulated the proliferation and differentiation of ventral midbrain neural stem cells (vmNSCs). Downregulation of Oc-1 decreased both transcript and protein level of Lmx1a. Oc-1 interacted with lmx1a in vmNSCs in vitro and in VM tissues in vivo. Knockdown of Lmx1a reduced the expression of Oc-1 and Wnt1 in vmNSCs. Inhibiting Wnt1 signaling in vmNSCs provoked similar responses. Our data suggested that Oc-1 interacts with Lmx1a to promote vmNSCs differentiation into dopamine neuron through Wnt1-Lmx1a pathway. PMID- 25747865 TI - Emotional conflict in facial expression processing during scene viewing: an ERP study. AB - Facial expressions are fundamental emotional stimuli as they convey important information in social interaction. In everyday life a face always appears in complex context. Scenes which faces are embedded in provided typical visual context. The aim of the present study was to investigate the processing of emotional conflict between facial expressions and emotional scenes by recording event-related potentials (ERPs). We found that when the scene was presented before the face-scene compound stimulus, the scene had an influence on facial expression processing. Specifically, emotionally incongruent (in conflict) face scene compound stimuli elicited larger fronto-central N2 amplitude relative to the emotionally congruent face-scene compound stimuli. The effect occurred in the post-perceptual stage of facial expression processing and reflected emotional conflict monitoring between emotional scenes and facial expressions. The present findings emphasized the importance of emotional scenes as a context factor in the study of the processing of facial expressions. PMID- 25747866 TI - Comparative proteome analysis of brown adipose tissue in obese C57BL/6J mice using iTRAQ-coupled 2D LC-MS/MS. AB - High-fat diet (HFD) leads to the development of obesity accompanied by insulin resistance, which increases the risk of type 2 diabetes mellitus and cardiovascular disease. Brown adipose tissue (BAT) plays an essential role in energy metabolism, thus it will give us promising treatment targets through elucidating underlying mechanisms of BAT in obesity. In this study, female C57BL/6J mice were fed HFD or normal diet (ND) for 22 weeks. Hyperinsulinemic euglycemic clamp was performed to evaluate insulin sensitivity, which was independently correlated with obesity. Using isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC-MS/MS, we quantitated 3048 proteins in BAT. As compared HFD with ND, we obtained 727 differentially expressed proteins. Functional analysis found that those proteins were mainly assigned to the pathway of mitochondrial function. In this pathway, carnitine O palmitoyltransferase 2 (CPT2), uncoupling protein 1 (UCP1) and apoptosis-inducing factor 1 (AIF1) were up-regulated significantly by HFD, and they were confirmed by western blotting. The results indicated that HFD might induce the apoptosis of brown adipocytes via the up-regulated AIF1. Meanwhile, HFD also stimulated fatty acid beta-oxidation and raised compensatory energy consuming through the increases of CPT2 and UCP1, respectively. However, the apoptosis of brown adipocytes might weaken the compensatory energy expenditure, and finally contribute to overweight/obesity. So, preventing the apoptosis of brown adipocytes may be the key target to treat obesity. PMID- 25747867 TI - Pulmonary toxicity of instilled silver nanoparticles: influence of size, coating and rat strain. AB - Particle size and surface chemistry are potential determinants of silver nanoparticle (AgNP) respiratory toxicity that may also depend on the lung inflammatory state. We compared the effects of intratracheally-administered AgNPs (20 nm and 110 nm; polyvinylpyrrolidone (PVP) and citrate-capped; 0.1 mg/Kg) in Brown-Norway (BN) and Sprague-Dawley (SD) rats. In BN rats, there was both a neutrophilic and eosinophilic response, while in SD rats, there was a neutrophilic response at day 1, greatest for the 20 nm citrate-capped AgNPs. Eosinophilic cationic protein was increased in bronchoalveolar lavage (BAL) in BN and SD rats on day 1. BAL protein and malondialdehyde levels were increased in BN rats at 1 and 7 days, and BAL KC, CCL11 and IL-13 levels at day 1, with increased expression of CCL11 in lung tissue. Pulmonary resistance increased and compliance decreased at day 1, with persistence at day 7. The 20 nm, but not the 110 nm, AgNPs increased bronchial hyperresponsiveness on day 1, which continued at day 7 for the citrate-capped AgNPs only. The 20 nm versus the 110 nm size were more proinflammatory in terms of neutrophil influx, but there was little difference between the citrate-capped versus the PVP-capped AgNPs. AgNPs can induce pulmonary eosinophilic and neutrophilic inflammation with bronchial hyperresponsiveness, features characteristic of asthma. PMID- 25747868 TI - Cohort Profile: The Mexican American Mano a Mano Cohort. AB - Hispanic Americans comprise the largest and fastest-growing ethnic minority in the USA. In Houston, Texas, 44% of the population is of Hispanic descent, with the majority being Mexican Americans (78%). This population is under-represented in health-related research despite their high prevalence of obesity and diabetes, which may predispose them to cancer and other chronic conditions. Recognizing the need for a greater research effort into the health risks of Hispanic Americans, the population-based Mexican American (Mano a Mano) Cohort study was launched in 2001. This is an open cohort with enrolment ongoing to 2019, and as of 30 June 2014, 23 606 adult participants from over 16 600 households were enrolled. Bilingual interviewers elicit information in person on demographics, acculturation, lifestyle, occupation, medical history, family cancer history, self-reported and measured height and weight, and other exposures. Urine, blood and saliva samples have been collected at baseline from 43%, 56% and 63% of participants, respectively. DNA samples are available for about 90% of participants. Incident cancers and other chronic diseases are ascertained through annual telephone re-contact and linkage to the Texas Cancer Registry and/or medical records. Molecular data such as genetic ancestry markers, blood telomere length and HbA1c, a marker of impaired glucose tolerance, are available for a substantial proportion of the participants. Data access is provided on request [manoamano@mdanderson.org]. For further information please visit [www.mano mano.us]. PMID- 25747869 TI - Health & Demographic Surveillance System Profile: The Rufiji Health and Demographic Surveillance System (Rufiji HDSS). AB - The Rufiji Health and Demographic Surveillance System (HDSS) was established in October 1998 to evaluate the impact on burden of disease of health system reforms based on locally generated data, prioritization, resource allocation and planning for essential health interventions. The Rufiji HDSS collects detailed information on health and survival and provides a framework for population-based health research of relevance to local and national health priorities.In December 2012 the population under surveillance was about 105,503 people, residing in 19,315 households. Monitoring of households and members within households is undertaken in regular 6-month cycles known as 'rounds'. Self reported information is collected on demographic, household, socioeconomic and geographical characteristics. Verbal autopsy is conducted using standardized questionnaires, to determine probable causes of death. In conjunction with core HDSS activities, the ongoing studies in Rufiji HDSS focus on maternal and new-born health, evaluation of safety of artemether-lumefantrine (AL) exposure in early pregnancy and the clinical safety of a fixed dose of dihydroartemisinin-piperaquine (DHA PQP) in the community. Findings of studies conducted in Rufiji HDSS can be accessed at www.ihi.or.tz/IHI-Digital-Library. PMID- 25747870 TI - Direct effects of hypoxia and nitric oxide on ecdysone secretion by insect prothoracic glands. AB - Insect molting and metamorphosis are controlled by the molt stimulating hormone ecdysone. A recent study suggests that reduced tissue oxygenation correlates with the size-sensing mechanism responsible for triggering molting. When reared in hypoxia, larvae of Manduca sexta and Drosophila melanogaster initiate molting at lower weights than do larvae reared in normoxia. Furthermore, in Drosophila, the signaling gas nitric oxide (NO) appears to be required for normal developmental timing. As observed in Drosophila, NO signaling targets the nuclear hormone receptor beta fushi tarazu transcription factor 1 (betaFTZ-F1) through activation of Drosophila hormone receptor 3 (DHR3), two key regulators of ecdysone production and metamorphic tissue progression. We set out to directly examine the effects of hypoxia and NO on ecdysone secretion using prothoracic glands from feeding fifth (last) larval stage M. sexta. Our results indicate that in vitro treatment of prothoracic glands with hypoxia (2% oxygen) or the NO donor DETA NONOate significantly inhibit ecdysone secretion. Protein markers of glandular activity were also in keeping with an initial inhibition, measured a decrease in phosphorylated ERK (extracellular signal regulated kinase) and an increase in non phosphorylated 4EBP (eukaryotic initiation factor 4E binding protein). Additionally, gene expression levels of Manduca hormone receptor 3 (mhr3), betaftz-f1, nitric oxide synthase (nos), and the PTTH receptor torso, were quantified using real-time PCR. NO treatment increased mhr3 expression and decreased nos expression. Hypoxia increased mhr3 transcription after 2 hr, but decreased transcription after 12 hr, with no effect on nos expression. Both NO and hypoxia had small effects on betaftz-f1 expression, yet strongly increased torso transcription. Our results demonstrate that, in isolated prothoracic glands, hypoxia and NO signaling directly inhibit ecdysteroid secretion, but at the same time alter aspects of prothoracic gland function that may enhance secretory response. PMID- 25747871 TI - Using mobile phone data to predict the spatial spread of cholera. AB - Effective response to infectious disease epidemics requires focused control measures in areas predicted to be at high risk of new outbreaks. We aimed to test whether mobile operator data could predict the early spatial evolution of the 2010 Haiti cholera epidemic. Daily case data were analysed for 78 study areas from October 16 to December 16, 2010. Movements of 2.9 million anonymous mobile phone SIM cards were used to create a national mobility network. Two gravity models of population mobility were implemented for comparison. Both were optimized based on the complete retrospective epidemic data, available only after the end of the epidemic spread. Risk of an area experiencing an outbreak within seven days showed strong dose-response relationship with the mobile phone-based infectious pressure estimates. The mobile phone-based model performed better (AUC 0.79) than the retrospectively optimized gravity models (AUC 0.66 and 0.74, respectively). Infectious pressure at outbreak onset was significantly correlated with reported cholera cases during the first ten days of the epidemic (p < 0.05). Mobile operator data is a highly promising data source for improving preparedness and response efforts during cholera outbreaks. Findings may be particularly important for containment efforts of emerging infectious diseases, including high mortality influenza strains. PMID- 25747872 TI - Urea Dependent (15)N NMR-Relaxation Studies on PfP2 Multimers Reveal that the C Terminal Behaves like an Independent Intrinsically Disordered Peptide. AB - Intrinsically disordered proteins or such domains in globular proteins are believed to be playing important roles in protein functions by virtue of their ability to adapt themselves to requirements of different binding partners and thereby accord high specificity to the interaction. Eukaryotic ribosomal stalk is made up of a supramolecular assembly of P0, P1 and P2 proteins. In Plasmodium falciparum, homo-oligomers of P2 are also seen which seem to be involved in many non-ribosomal functions of the protein in the parasite, and in all of these the protein interacts with different interactors. Here we show by extensive (15)N NMR relaxation studies that the C-terminal stretch of about 45 residues of the protein always remains as a flexible disordered domain, regardless of the state of association of the protein. The relaxation behaviors and the derived rotational correlation times for this portion of the protein are essentially the same in the presence of different concentrations of urea which produce different mixtures of PfP2 oligomers in rapid exchange, whereas the rest of the protein shows substantial variations with urea concentration in the relaxation behaviors. In other words, the C-terminal domain behaves as if it were an independent intrinsically disordered peptide. This would augment the notion that the C terminal domain of PfP2 would be acting as a scavenger for different interactors depending upon the different functions of the protein inside the parasite. PMID- 25747873 TI - Strong Communities for Children: Results of a multi-year community-based initiative to protect children from harm. AB - This article reports the evaluation results from Strong Communities for Children, a multi-year comprehensive community-based initiative to prevent child maltreatment and improve children's safety. The outcome study consisted of a survey of a random sample of caregivers of children under age 10 in the Strong Communities service area and a set of comparison communities matched at the block group level on demography. Survey data were collected in two waves 4 years apart. Data were collected on (a) perceptions of the neighborhood and neighbors (e.g., neighboring, collective efficacy), (b) perceptions of neighbors' parenting practices, (c) parental attitudes and beliefs (e.g., parental stress; parental efficacy), and (d) self-reported parenting practices. The survey data were supplemented by data on substantiated reported rates of child abuse and neglect per 1,000 children and ICD-9 coded child injuries suggesting child abuse and neglect per 1,000 children. Compared to the non-intervention sample across time, the Strong Communities samples showed significant changes in the expected direction for social support, collective efficacy, child safety in the home, observed parenting practices, parental stress, parental efficacy, self-reported parenting practices, rates of officially substantiated child maltreatment, and rates of ICD-9 coded child injuries suggesting child maltreatment. These promising results, obtained through multiple methods of evaluation, confirm that a community mobilization strategy can shift norms of parents' care for their children and neighbors' support for one another, so that young children are safer at home and in the community. Replications should be undertaken and evaluated in other communities under diverse auspices. PMID- 25747874 TI - Attachment in institutionalized children: a review and meta-analysis. AB - In this article we review the literature on attachment patterns in institutionalized children and then perform a meta-analysis on data from 10 attachment studies involving 399 children in institutional settings. We computed the overall attachment distribution of secure, insecure, and disorganized rates and explored the effect of a set of moderating variables (i.e., country of institutionalization, attachment assessment procedure, age at entry, and age at assessment). To overcome bias related to the small number of studies, we conducted both classical and Bayesian meta-analysis and obtained comparable results. Distribution of children's attachment patterns was: 18% secure, 28% insecure, and 54% disorganized/cannot classify. Compared to their family-reared peers, children living in an institution were found to be at greater risk for insecure and disorganized attachment, with a similar medium effect size for both distributions (d=0.77 and d=0.76, respectively). The following moderating variables were associated with insecure attachment: representational assessment procedures (d=0.63) and Eastern European countries of origin (d=1.13). Moderators for disorganized attachment were: Eastern European countries of origin (d=1.12), age at institution entry before the first birthday (d=0.93), and age at assessment under three years of age (d=0.91). Implications for child development and policies are discussed. PMID- 25747875 TI - Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury. AB - Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. BMX, a member of the TEC family of nonreceptor tyrosine kinases, is upregulated after traumatic neural injury in a rat model of mTBI. The objective of this investigation was to determine if BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between13-15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks post injury. The participant was asssigned to 'case group' if the subject's complaints of dizziness became worse at 6th week assessment; otherwise, the participant was assigned to 'control group '. A receiver operating characteristic (ROC) curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve (AUCs) for prediction of change in DHI post-injury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score and 0.66 for functional score. Specificities were between 0.69 and 0.77 for total score and emotional score, respectively. Therefore, BMX demonstrates potential as a candidate serum biomarker of exacerbating dizziness after mTBI. PMID- 25747877 TI - Prevention and management of stroke in women. AB - Stroke is the leading cause of acquired disability and the third leading cause of death in women worldwide. Sex differences in risk factors, treatment response and quality of life after stroke complicate stroke management in women. Women have an increased lifetime incidence of stroke compared to men, largely due to a sharp increase in stroke risk in older postmenopausal women. Women also have an increased lifetime prevalence of stroke risk factors, including hypertension and atrial fibrillation in postmenopausal women, as well as abdominal obesity and metabolic syndrome in middle-aged women. Controversy continues over the risks of oral contraceptives, hormone therapy and surgical intervention for carotid stenosis in women. Pregnancy and the postpartum period represent a time of increased risk, presenting challenges to stroke management. Recognition of these issues is critical to improving acute care and functional recovery after stroke in women. PMID- 25747878 TI - Lipid production in the under-characterized oleaginous yeasts, Rhodosporidium babjevae and Rhodosporidium diobovatum, from biodiesel-derived waste glycerol. AB - The growth, lipid production, and carbon use efficiency of two oleaginous yeasts, Rhodosporidium babjevae and Rhodosporidium diobovatum, were compared under nitrogen-limiting conditions with glycerol as the carbon source. Final biomass concentrations of R. babjevae and R. diobovatum were 9.4+/-0.80g/L and 12.0+/ 0.82g/L, respectively, after 120h of growth. Final lipid accumulation in for R. babjevae and R. diobovatum were 34.9+/-3.0% cell dry weight (cdw) and 63.7+/-4.5% cdw, respectively. Biomass production increased to 9.9+/-0.2g/L for R. babjevae and 14.1+/-0.2g/L for R. diobovatum in medium containing biodiesel-derived waste glycerol, but lipid accumulation decreased in both species. In a 7L bioreactor with biodiesel-derived glycerol as carbon source, R. diobovatum produced 13.6+/ 0.4g/L biomass and accumulated lipids to 50.7+/-2.2% cdw, matching flask experiments. PMID- 25747876 TI - Moderate prenatal alcohol exposure enhances GluN2B containing NMDA receptor binding and ifenprodil sensitivity in rat agranular insular cortex. AB - Prenatal exposure to alcohol affects the expression and function of glutamatergic neurotransmitter receptors in diverse brain regions. The present study was undertaken to fill a current gap in knowledge regarding the regional specificity of ethanol-related alterations in glutamatergic receptors in the frontal cortex. We quantified subregional expression and function of glutamatergic neurotransmitter receptors (AMPARs, NMDARs, GluN2B-containing NMDARs, mGluR1s, and mGluR5s) by radioligand binding in the agranular insular cortex (AID), lateral orbital area (LO), prelimbic cortex (PrL) and primary motor cortex (M1) of adult rats exposed to moderate levels of ethanol during prenatal development. Increased expression of GluN2B-containing NMDARs was observed in AID of ethanol exposed rats compared to modest reductions in other regions. We subsequently performed slice electrophysiology measurements in a whole-cell patch-clamp preparation to quantify the sensitivity of evoked NMDAR-mediated excitatory postsynaptic currents (EPSCs) in layer II/III pyramidal neurons of AID to the GluN2B negative allosteric modulator ifenprodil. Consistent with increased GluN2B expression, ifenprodil caused a greater reduction in NMDAR-mediated EPSCs from prenatal alcohol-exposed rats than saccharin-exposed control animals. No alterations in AMPAR-mediated EPSCs or the ratio of AMPARs/NMDARs were observed. Together, these data indicate that moderate prenatal alcohol exposure has a significant and lasting impact on GluN2B-containing receptors in AID, which could help to explain ethanol-related alterations in learning and behaviors that depend on this region. PMID- 25747879 TI - Efficient production of succinic acid from macroalgae hydrolysate by metabolically engineered Escherichia coli. AB - In this study, microbial production of succinic acid from macroalgae (i.e., Laminaria japonica) was investigated for the first time. The engineered Escherichia coli BS002 exhibited higher molar yield of succinic acid on mannitol (1.39+/-0.01mol/mol) than glucose (1.01+/-0.05mol/mol). After pretreatment and enzymatic hydrolysis, L. japonica hydrolysate was mainly glucose (10.31+/ 0.32g/L) and mannitol (10.12+/-0.17g/L), which was used as the substrate for succinic acid fermentation with the recombinant BS002. A final 17.44+/-0.54g/L succinic acid was obtained from the hydrolysate after 72h dual-phase fermentation. The yield was as high as 1.24+/-0.08mol/mol total sugar, which reached 73% of the maximum theoretical yield. The results demonstrate that macroalgae biomass represents a novelty and economical alternative feedstock for biochemicals production. PMID- 25747880 TI - Evolutionary patterns and coevolutionary consequences of MIRNA genes and microRNA targets triggered by multiple mechanisms of genomic duplications in soybean. AB - The evolutionary dynamics of duplicated protein-encoding genes (PEGs) is well documented. However, the evolutionary patterns and consequences of duplicated MIRNAs and the potential influence on the evolution of their PEG targets are poorly understood. Here, we demonstrate the evolution of plant MIRNAs subsequent to a recent whole-genome duplication. Overall, the retention of MIRNA duplicates was correlated to the retention of adjacent PEG duplicates, and the retained MIRNA duplicates exhibited a higher level of interspecific preservation of orthologs than singletons, suggesting that the retention of MIRNA duplicates is related to their functional constraints and local genomic stability. Nevertheless, duplication status, rather than local genic collinearity, was the primary determinant of levels of nucleotide divergence of MIRNAs. In addition, the retention of duplicated MIRNAs appears to be associated with the retention of their corresponding duplicated PEG targets. Furthermore, we characterized the evolutionary novelty of a legume-specific microRNA (miRNA) family, which resulted from rounds of genomic duplication, and consequent dynamic evolution of its NB LRR targets, an important gene family with primary roles in plant-pathogen interactions. Together, these observations depict evolutionary patterns and novelty of MIRNAs in the context of genomic duplication and evolutionary interplay between MIRNAs and their PEG targets mediated by miRNAs. PMID- 25747881 TI - ENHANCED DISEASE RESISTANCE4 associates with CLATHRIN HEAVY CHAIN2 and modulates plant immunity by regulating relocation of EDR1 in Arabidopsis. AB - Obligate biotrophs, such as the powdery mildew pathogens, deliver effectors to the host cell and obtain nutrients from the infection site. The interface between the plant host and the biotrophic pathogen thus represents a major battleground for plant-pathogen interactions. Increasing evidence shows that cellular trafficking plays an important role in plant immunity. Here, we report that Arabidopsis thaliana ENHANCED DISEASE RESISTANCE4 (EDR4) plays a negative role in resistance to powdery mildew and that the enhanced disease resistance in edr4 mutants requires salicylic acid signaling. EDR4 mainly localizes to the plasma membrane and endosomal compartments. Genetic analyses show that EDR4 and EDR1 function in the same genetic pathway. EDR1 and EDR4 accumulate at the penetration site of powdery mildew infection, and EDR4 physically interacts with EDR1, recruiting EDR1 to the fungal penetration site. In addition, EDR4 interacts with CLATHRIN HEAVY CHAIN2 (CHC2), and edr4 mutants show reduced endocytosis rates. Taken together, our data indicate that EDR4 associates with CHC2 and modulates plant immunity by regulating the relocation of EDR1 in Arabidopsis. PMID- 25747883 TI - An uncommon gallbladder location associated with polycystic liver. PMID- 25747884 TI - Histopathologic characteristics of gastric adenocarcinoma in Mexican patients: a 10-year experience at the Hospital Juarez of Mexico. AB - BACKGROUND: Gastric cancer is the second cause of death by cancer worldwide. Histologic classification may predict tumor biology, clinical behavior, and outcome. According to the Lauren classification, the disease is divided into 2 types, diffuse and intestinal, and the latter has a better prognosis. AIM: To determine the frequency of gastric adenocarcinoma and compare the histopathologic characteristics of intestinal and diffuse-type gastric adenocarcinoma in Mexican patients treated at a tertiary referral hospital. METHODOLOGY: A retrospective study evaluated the pathology reports of patients with gastric adenocarcinoma corresponding to the time frame of January 2003 to December 2012. Adenocarcinomas of the gastric cardia were excluded. Frequencies were expressed as percentages and the categorical variables were compared with the chi-square test. Statistical significance was set at a P<.05. RESULTS: A total of 417 cases of gastric adenocarcinoma were found, 230 (55.2%) of which were diffuse-type and 118 (28.2%) were intestinal-type. The mean age of the patients with diffuse type gastric cancer was 54.02+/-14.93 and 119 (51.3%) of those patients were men. The mean age of the patients with intestinal-type gastric cancer was 63.43+/-13.78, and 69 (62.2%) were men. Ninety-two of the diffuse-type patients were under the age of 50 years, compared with 22 of the patients with intestinal-type carcinoma. CONCLUSIONS: This is the first study on the Mexican population to analyze the differences in the histologic types of adenocarcinoma. Diffuse-type gastric carcinoma was the most frequent subtype in our study population and it is associated with worse outcome. PMID- 25747882 TI - Binding of SEC11 indicates its role in SNARE recycling after vesicle fusion and identifies two pathways for vesicular traffic to the plasma membrane. AB - SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins drive vesicle fusion in all eukaryotes and contribute to homeostasis, pathogen defense, cell expansion, and growth in plants. Two homologous SNAREs, SYP121 (=SYR1/PEN1) and SYP122, dominate secretory traffic to the Arabidopsis thaliana plasma membrane. Although these proteins overlap functionally, differences between SYP121 and SYP122 have surfaced, suggesting that they mark two discrete pathways for vesicular traffic. The SNAREs share primary cognate partners, which has made separating their respective control mechanisms difficult. Here, we show that the regulatory protein SEC11 (=KEULE) binds selectively with SYP121 to affect secretory traffic mediated by this SNARE. SEC11 rescued traffic block by dominant-negative (inhibitory) fragments of both SNAREs, but only in plants expressing the native SYP121. Traffic and its rescue were sensitive to mutations affecting SEC11 interaction with the N terminus of SYP121. Furthermore, the domain of SEC11 that bound the SYP121 N terminus was itself able to block secretory traffic in the wild type and syp122 but not in syp121 mutant Arabidopsis. Thus, SEC11 binds and selectively regulates secretory traffic mediated by SYP121 and is important for recycling of the SNARE and its cognate partners. PMID- 25747885 TI - The Alpha Consensus Meeting on the professional status of the clinical embryologist: proceedings of an expert meeting. AB - This proceedings report presents the outcomes from an international Workshop designed to establish consensus on the professional status of the Clinical Embryologist, and then to work towards creating international standards that can be referenced by regulators and professional societies around the world. The participants represented a total of 20 countries (Australia, Austria, Belgium, Brazil, Canada, China, Croatia, Finland, France, Germany, Ireland, Italy, the Netherlands, Russia, South Africa, Spain, Sweden, Turkey, UK and USA) and 18 national and regional societies (as presented in the list of participants). This report includes general presentations about current practice, and factors for consideration in the development of a competency-based framework for certification of Clinical Embryologists. PMID- 25747886 TI - Bilinguals at the "cocktail party": dissociable neural activity in auditory linguistic brain regions reveals neurobiological basis for nonnative listeners' speech-in-noise recognition deficits. AB - We examined a consistent deficit observed in bilinguals: poorer speech-in-noise (SIN) comprehension for their nonnative language. We recorded neuroelectric mismatch potentials in mono- and bi-lingual listeners in response to contrastive speech sounds in noise. Behaviorally, late bilinguals required ~10dB more favorable signal-to-noise ratios to match monolinguals' SIN abilities. Source analysis of cortical activity demonstrated monotonic increase in response latency with noise in superior temporal gyrus (STG) for both groups, suggesting parallel degradation of speech representations in auditory cortex. Contrastively, we found differential speech encoding between groups within inferior frontal gyrus (IFG) adjacent to Broca's area-where noise delays observed in nonnative listeners were offset in monolinguals. Notably, brain-behavior correspondences double dissociated between language groups: STG activation predicted bilinguals' SIN, whereas IFG activation predicted monolinguals' performance. We infer higher-order brain areas act compensatorily to enhance impoverished sensory representations but only when degraded speech recruits linguistic brain mechanisms downstream from initial auditory-sensory inputs. PMID- 25747887 TI - Congenital agenesis of inferior vena cava: a rare cause of unprovoked deep venous thrombosis. AB - Congenital anomalies of the inferior vena cava (IVC), although rare, are a risk factor for lower limb deep venous thrombosis (DVT). A 19-year-old male presented with a left flank and groin pain caused by iliofemoral venous thrombosis. Vascular imaging by computed tomography (CT) scanning and venography demonstrated agenesis of the IVC. Catheter-directed thrombolysis via a popliteal vein was attempted but did not alter the patency of the common femoral vein outflow collaterals into the retroperitoneal azygous venous system. The patient was anticoagulated using systemic heparin infusion and clinical symptoms resolved within 5 days. He was transitioned to oral Coumadin anticoagulation, and follow up venous duplex testing demonstrated no infrainguinal DVT and phasic venous flow with respiration in the femoral vein indicating patent collateral veins. Anomalies of the IVC are present in 0.3-0.5% of otherwise healthy individuals. Agenesis of the IVC has an incidence of 0.0005-1% in the general population but is found in almost 5% of patients <30 years of age with unprovoked lower limb DVT. In adults, IVC agenesis anomaly can cause diagnostic problems in the paravertebral area because of the tumor-like appearance of the azygous venous collaterals on noncontrast CT imaging. In young adults presenting with unprovoked lower limb DVT, the presence of an IVC anomaly should be considered and evaluated for by venous duplex testing and if necessary CT venography. PMID- 25747888 TI - Surgical management of a primary retroperitoneal venous aneurysm originating from the presacral venous plexus. AB - Venous aneurysms are rare vascular abnormalities, and primary venous aneurysm originating from sacral venous plexus is exceedingly rare. In this article, we report a 28-year-old man with a large venous aneurysm (~15 * 10 cm in size) originating from presacral venous plexus. The patient complained of 1 year of constant back pain associated with frequent defecation and urination, caused by the compression from the aneurysm. Exploratory laparotomy was performed for diagnosis, with successful aneurysmectomy to relieve the compression. The patient recovered uneventfully with complete relief of symptoms. Postoperative histopathologic examination manifested classic venous aneurysm. During follow-up 6 months after surgery, all symptoms were resolved without significant postoperative complications. PMID- 25747889 TI - Cooperative effect of Bifidobacteria lipoteichoic acid combined with 5 fluorouracil on hepatoma-22 cells growth and apoptosis. AB - AIMS: To investigate the cooperative effect of Bifidobacteria lipoteichoic acid (BLTA) combined with 5-fluorouracil on tumor cells growth and apoptosis in mice bearing H22. METHODS: Hepatoma-22 (H22) cells were cultured in RPMI1640. Establish tumor-bearing mice model of liver cancer by injecting intraperitoneally 1*10(6)/mL cells into the above-mentioned Balb/c mice. 5-FU alone, BLTA alone or BLTA in combination with 5-FU were used to treat tumor-bearing mice. The tumor size were observed and measured regularly. The growth-inhibiting rate (IR) of tumor was detected. Real-Time PCR and Western blot were used to detect Bcl-2, Bax and Caspase-3 expressions of mRNA and protein in tumor tissue of tumor-bearing mice. Detection of apoptotic cells in tumor tissue by HE staining analysis. Detection of the organ index was for evaluate the added-activity of immune organs in mouse. FCM was used to detect T subgroup ratio of spleen cells of tumor bearing mice. Expression change of mRNA and proteins of Foxp3 and TIM-3 were detected by Real-Time PCR and Western blot in tumor-bearing mice tumor tissue. RESULTS: BLTA and 5-FU significantly inhibited the proliferation of tumor and induced obvious apoptosis, the combined effects were greater than those of the individual agents (P<0.01). The underlying molecular mechanism of apoptotic process could be up-regulation of Bax and down-regulation of Bcl-2 and Caspase-3. The HE staining indicated that combined treat could both induce tissue cells necrosis and increase immune cells infiltration. Organ index showed that BLTA can enhance the proliferation of immune organs. The ratio of CD4(+)CD25(+) Treg significantly decreased and CD4(+) T cell increased in BLTA and 5-FU group (P<0.01). Compared to NS group, mRNA and proteins expression of Foxp3 and TIM-3 down regulated in BLTA and 5-FU group (P<0.01). CONCLUSIONS: These results show that combined effects of Bifidobacteria lipoteichoic acid and 5-FU on H22 cells were superior to the individual. The combination did not only increase anti-tumor effect, but also could alleviate the side effects of chemotherapy, with inhibiting TIM-3/TIM-3L pathway, cutting down immunosuppressive activity of CD4(+)CD25(+) Treg and enhancing cell-mediated immunity. PMID- 25747890 TI - Pain burden in desmoid tumor patients: a survey of the French Advocacy Group SOS Desmoid. AB - INTRODUCTION: The French Patient Advocacy Group SOS Desmoid conducted a survey to measure the pain burden of desmoid tumor patients. MATERIAL AND METHODS: We used a structured questionnaire to measure the occurrence and consequences of pain. RESULTS: The pain occurrence was approximately 63%. In one-third of the cases, the pain was permanent. This pain led to severe social and economic consequences. DISCUSSION: The occurrence of pain and its consequences are underestimated among these patients. Pain needs to be closely and precisely measured and monitored in future clinical trials to assess the efficacy of proposed treatments better. PMID- 25747891 TI - The role and nature of evidence: a systematic review of social workers' evidence based practice orientation, attitudes, and implementation. AB - Concerns have been raised over the appropriateness of adopting evidence-based practice (EBP) as a framework for practice within social work. In this systematic review the authors aim to synthesise research findings exploring social workers' EBP orientation, attitudes, adoption, knowledge, skills, and perceived EBP barriers and facilitators. Numerous challenges to EBP implementation were identified, including: time management, research accessibility, and misperceptions of the role of evidence in decision making. Colleagues, supervisors, perceived experts, organizational culture, and tailored training were important for social workers' dissemination and utilization of evidence. Social workers may prefer more conversational, face-to-face methods of research dissemination. Implications of the review findings are discussed. PMID- 25747893 TI - Associated injuries in pediatric patients with facial fractures in Portugal: Analysis of 1416 patients. AB - BACKGROUND: The authors performed a retrospective study to clarify the occurrence, causes, severity and predictors of concomitant injuries in pediatric patients with facial fractures in Portugal. METHODS: The clinical records of children and adolescents (0-18 years) with facial fractures treated by the Department of Plastic, Reconstructive, and Aesthetic Surgery and of Maxillofacial Surgery of Sao Joao Hospital, in Porto, Portugal, over a period of 20 years (1993 2012) were reviewed. RESULTS: A total of 1416 patients with facial fractures were included in this study. Concomitant injuries were observed in 1015 (71.7%) patients. No significant associations were found between sex and concomitant injury. Head and neck injuries other than facial fractures occurred in 962 patients (67.7%), lower limb injuries in 122 (8.6%), upper limb injuries in 115 (8.1%), thoracic injuries in 89 (6.3%) and abdominal injuries in 47 (3.3%). Concomitant injuries occurred more frequently after motor vehicle accidents (car accident, motorcycle accident and car-pedestrian accident) compared with other etiologies (p < 0.001). CONCLUSION: The incidence of these facial fractures and their concomitant injuries is very high in Portugal. It is necessary to continue with the implementation of control measures and educational programs for the population, so that the number and severity of accidents causing fractures and their associated injuries continue to decrease. PMID- 25747894 TI - Non-dairy Based Probiotics: A Healthy Treat for Intestine. AB - Dairy-based fermented products and yoghurts have been utilized as potential probiotic products since ancient times. However, recent upsurge in interest of consumers towards dairy alternatives has opened up new vistas for non-dairy probiotic research and development. Various matrices and substrates such as cereals, fruit juices, or mixture thereof are being utilized for delivering these beneficial microorganisms. Each matrix offers some advantages over the other. Vast knowledge available on a number of conventional fermented foods can also be utilized for future research in this area. The present review provides an insight on the recent research/developments in the field of non-dairy probiotic foods with particular reference to the foods consumed conventionally, in addition to their commercial availability and a way forward. PMID- 25747892 TI - Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system. AB - BACKGROUND: Increasing attention has focused on the prevalence and outcomes of hyperthyroidism in pregnancy, given concerns for hepatotoxicity and embryopathy associated with antithyroid drugs (ATDs). METHODS: In an integrated health care delivery system, we examined the prevalence of thyrotoxicosis and gestational ATD use (propylthiouracil [PTU] or methimazole [MMI]) in women with delivered pregnancies from 1996 to 2010. Birth outcomes were compared among all infants and those born to mothers with diagnosed thyrotoxicosis or ATD therapy during gestation, with examination of ATD-associated hepatotoxicity and congenital malformations in the latter subgroups. RESULTS: Among 453,586 mother-infant pairs (maternal age 29.7+/-6.0 years, 57.1% nonwhite), 3.77 per 1000 women had diagnosed thyrotoxicosis and 1.29 per 1000 had gestational ATD exposure (86.5% PTU, 5.1% MMI, 8.4% both). Maternal PTU-associated hepatotoxicity occurred with a frequency of 1.80 per 1000 pregnancies. Infants of mothers with diagnosed thyrotoxicosis (odds ratio [OR] 1.28, 95% confidence interval [CI 1.05-1.55]) or gestational ATD use (OR 1.31 [1.00-1.72]) had an increased risk of preterm birth compared to those born to mothers without thyrotoxicosis or ATD. The risk of neonatal intensive care unit (NICU) admission was also higher with maternal thyrotoxicosis (OR 1.30 [1.07-1.59]) and ATD exposure (OR 1.64 [CI 1.26-2.13]), adjusting for prematurity. Congenital malformation rates were low and similar among infants born to mothers with thyrotoxicosis or ATD exposure (30-44 per 1000 infants). CONCLUSIONS: Gestational ATD exposure occurred in 1.29 per 1000 mother infant pairs while a much larger number had maternal diagnosed thyrotoxicosis but no drug exposure during pregnancy. Infants of mothers with gestational ATD use or diagnosed thyrotoxicosis were more likely to be preterm and admitted to the NICU. The rates of congenital malformation were low for mothers diagnosed with thyrotoxicosis and did not differ by ATD use. Among women with gestational PTU therapy, the frequency of PTU-associated hepatotoxicity was 1.8 per 1000 delivered pregnancies. These findings from a large, population-based cohort provide generalizable estimates of maternal and infant risks associated with maternal thyrotoxicosis and related pharmacotherapy. PMID- 25747895 TI - (Pro)renin receptor is crucial for Wnt/beta-catenin-dependent genesis of pancreatic ductal adenocarcinoma. AB - Although Wnt/beta-catenin signaling is known to be aberrantly activated in PDAC, mutations of CTNNB1, APC or other pathway components are rare in this tumor type, suggesting alternative mechanisms for Wnt/beta-catenin activation. Recent studies have implicated the (pro)renin receptor ((P)RR) is related to the Wnt/beta catenin signaling pathway. We therefore investigated the possible role of (P)RR in pancreatic carcinogenesis. Plasma s(P)RR levels were significantly (P < 0.0001) higher in patients with PDAC than in healthy matched controls. We also identified aberrant expression of (P)RR in premalignant PanIN and PDAC lesions and all the PDAC cell lines examined. Inhibiting (P)RR with an siRNA attenuated activation of Wnt/beta-catenin signaling pathway and reduced the proliferative ability of PDAC cells in vitro and the growth of engrafted tumors in vivo. Loss of (P)RR induced apoptosis of human PDAC cells. This is the first demonstration that (P)RR may be profoundly involved in ductal tumorigenesis in the pancreas. PMID- 25747896 TI - Somatic cancer mutations in the DNMT2 tRNA methyltransferase alter its catalytic properties. AB - Methylation of tRNA is an important post-transcriptional modification and aberrations in tRNA modification has been implicated in cancer. The DNMT2 protein methylates C38 of tRNA-Asp and it has a role in cellular physiology and stress response and its expression levels are altered in cancer tissues. Here we studied whether DNMT2 somatic mutations found in cancer tissues affect the activity of the enzyme. We have generated 13 DNMT2 variants and purified the corresponding proteins. All proteins were properly folded as determined by circular dichroism spectroscopy. We tested their RNA methylation activity using in vitro generated tRNA-Asp. One of the mutations (E63K) caused a twofold increase in activity, while two of them led to a strong (over fourfold) decrease in activity (G155S and L257V). Two additional mutant proteins were almost inactive (R371H and G155V). The strong effect of some of the somatic cancer mutations on DNMT2 activity suggests that these mutations have a functional role in tumorigenesis. PMID- 25747898 TI - Reductive cleavage of P4 by iron(I) centres: synthesis and structural characterisation of Fe2(P2)2 complexes with two bridging P2(2-) ligands. AB - The selective transformation of white phosphorus with a beta-diketiminato iron(I) toluene complex under mild reaction conditions is reported which furnishes a new dinuclear iron(III) Fe2(P2)2 complex with two bridging P2(2-) ligands. Its reduction with potassium results in the formation of the first delocalised mixed valent bis-diphosphido iron(II,III) complex which is isostructural with the neutral Fe2P4 precursor. PMID- 25747897 TI - Relationships between the pulmonary densitometry values obtained by CT and the forced oscillation technique parameters in patients with silicosis. AB - OBJECTIVE: To evaluate the correlations between pulmonary densitometry values and forced oscillation technique (FOT) parameters in patients with silicosis. METHODS: This cross-sectional study comprised 36 non-smoker patients with silicosis and 20 matched control subjects who were submitted to FOT and multidetector CT (MDCT). RESULTS: Compared with the control subjects, the MDCT evaluation demonstrated that patients with silicosis exhibited greater total lung mass. These patients also had larger non-aerated and poorly aerated compartments, which included nodules and scarring. Compared with the control subjects, FOT evaluation demonstrated that patients with silicosis exhibited changes in both reactive and resistive properties of the respiratory system. In these patients, there was a greater heterogeneity of the respiratory system and increased work of breathing. Significant correlations between non-aerated compartment size and FOT parameters that reflect the non-homogeneity of the respiratory system were observed. The dynamic compliance of the respiratory system was negatively correlated with non-aerated compartment size, while the impedance at 4 Hz was positively correlated with non-aerated compartment size. CONCLUSION: Patients with silicosis have heavier lungs. In these patients, a larger non-aerated compartment is associated with a worsening of lung function. A more significant pulmonary involvement is associated with a loss of homogeneity and increased mechanical load of the respiratory system. Advances in knowledge The findings provided by both pulmonary densitometry and FOT may add valuable information to the subjective analysis of silicosis; however, more studies are necessary to evaluate the potential use of these methods for assessing disease progression. PMID- 25747899 TI - Nurse-Led School-Based Child Obesity Prevention. AB - School-based childhood obesity prevention programs have grown in response to reductions in child physical activity (PA), increased sedentariness, poor diet, and soaring child obesity rates. Multiple systematic reviews indicate school based obesity prevention/treatment interventions are effective, yet few studies have examined the school nurse role in obesity interventions. Building on a previous study, this study examines a refined health messaging (Let's Go 5-2-1-0) program delivered to fourth and fifth graders (n = 72) by a school nurse with reinforcement on-site health coaching by senior nursing students. Two nursing schools and two elementary schools participated. Measures of PA, body mass index percentile, and self-reported health habits were collected at baseline (School A, September 2009 and School B, January 2010) and end of year (April 2010 for both schools). Findings included statistically significant increases in PA levels and improvements in child-reported health habits. School nurses can influence obesity prevention. Further research on adoption of school nurse-led obesity interventions is warranted. PMID- 25747900 TI - Rationales for Support That African American Grandmothers Provide to Their Children Who Are Parenting Adolescents. AB - African American grandmothers are known to be a major source of support for their children who are parenting adolescents, but little is known about why they provide support. The purpose of this study was to describe the kinds of support provided by African American maternal and paternal grandmothers to their parenting adolescents and the reasons for giving support. In all, 10 maternal and 10 paternal grandmothers were recruited from one low-income African American community to participate in this cross-sectional, qualitative, descriptive study. Grandmothers provided support due to love and concern for their adolescent parenting children and their grandchildren. Grandmothers were influenced by their own past experiences and by the adolescent's personality and behavior. School nurses and school health clinic personnel are tactically positioned within the lives of families with parenting adolescents and can help facilitate the provision of support that allows adolescent parents to successfully transition to adulthood and assume adult roles. PMID- 25747901 TI - Advances in myocardial perfusion imaging. PMID- 25747902 TI - Stabilized naked sub-nanometric Cu clusters within a polymeric film catalyze C-N, C-C, C-O, C-S, and C-P bond-forming reactions. AB - Sub-nanometric Cu clusters formed by endogenous reduction of Cu salts and Cu nanoparticles are active and selective catalysts for C-N, C-C, C-O, C-S, and C-P bond-forming reactions. Sub-nanometric Cu clusters have also been generated within a polymeric film and stored with full stability for months. In this way, they are ready to be used on demand and maintain high activity (TONs up to 10(4)) and selectivity for the above reactions. A potential mechanism for the formation of the sub-nanometric clusters and their electronic nature is presented. PMID- 25747903 TI - Bifurcation study of blood flow control in the kidney. AB - Renal blood flow is maintained within a narrow window by a set of intrinsic autoregulatory mechanisms. Here, a mathematical model of renal hemodynamics control in the rat kidney is used to understand the interactions between two major renal autoregulatory mechanisms: the myogenic response and tubuloglomerular feedback. A bifurcation analysis of the model equations is performed to assess the effects of the delay and sensitivity of the feedback system and the time constants governing the response of vessel diameter and smooth muscle tone. The results of the bifurcation analysis are verified using numerical simulations of the full nonlinear model. Both the analytical and numerical results predict the generation of limit cycle oscillations under certain physiologically relevant conditions, as observed in vivo. PMID- 25747905 TI - Interplay between receptor tyrosine kinases and hypoxia signaling in cancer. AB - Deregulated signaling via receptor tyrosine kinase (RTK) pathways is prevalent in numerous types of human cancers and is commonly correlated with worst prognosis, resistance to various treatment modalities and increased mortality. Likewise, hypoxic tumors are often manifested by aggressive mode of growth and progression following an adaptive genetic reprogramming with consequent transcriptional activation of genes encoding proteins, which support tumor survival under low oxygen-related conditions. Consequently, both the hypoxia-inducible factor (HIF) system, which is the major mediator of hypoxia-related signaling, and numerous RTK systems are considered critical molecular targets in current cancer therapy. It is now evident that there is an intricate molecular crosstalk between RTKs and hypoxia-related signaling in the sense that hypoxia can activate expression of particular RTKs and/or their corresponding ligands, while some RTK systems have been shown to trigger activation of the HIF machinery. Moreover, signaling regulation of some RTK systems under hypoxic conditions has also been documented to take place in a HIF-independent manner. With this review we aim at overviewing the most current observations on that topic and highlight the importance of the potential co-drugging the HIF system along with particular relevant RTKs for better tumor growth control. PMID- 25747904 TI - Role of discoidin domain receptor 1 in dysregulation of collagen remodeling by cyclosporin A. AB - The anti-transplant rejection drug cyclosporin A (CsA) causes loss of collagen homeostasis in rapidly remodeling connective tissues, such as human gingiva. As a result of CsA treatment, collagen degradation by fibroblasts is inhibited, which leads to a net increase of tissue collagen and gingival overgrowth. Since fibrillar collagen is the primary ligand for the discoidin domain receptor 1 (DDR1), we hypothesized that CsA perturbs DDR1-associated functions that affect collagen homeostasis. For these experiments, human fibroblasts obtained from gingival explants or mouse 3T3 fibroblasts (wild type, over-expressing DDR1 or DDR1 knockdown) or mouse GD25 cells (expressing DDR1 but null for beta1 integrin), were treated with vehicle (dimethyl sulfoxide) or with CsA. The effect of CsA on cell binding to collagen was examined by flow cytometry; cell-mediated collagen remodeling was analyzed with contraction, compaction and migration assays. We found that CsA inhibited cell binding to collagen, internalization of collagen, contraction of collagen gels and cell migration over collagen in a DDR1 dependent manner. CsA also enhanced collagen compaction around cell extensions. Treatment with CsA strongly reduced surface levels of beta1 integrins in wild type and DDR1 over-expressing 3T3 cells but did not affect beta1 integrin activation or focal adhesion formation. We conclude that CsA inhibition of collagen remodeling is mediated through its effects on both DDR1 and cell surface levels of the beta1 integrin. PMID- 25747906 TI - Herman N. Eisen, M.D. (1918-2014): Scholar, Gentleman, and AAI President (1968 1969). PMID- 25747907 TI - Interfering with immunity: detrimental role of type I IFNs during infection. AB - Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation. PMID- 25747908 TI - [Revising the nosology of bradykinin-mediated angioedema]. PMID- 25747909 TI - Editorial comment. PMID- 25747910 TI - Use of the ultrasonic bone aspirator for lateral osteotomies in rhinoplasty. PMID- 25747911 TI - Reply: Preemptive analgesia with bupivacaine in reduction mammaplasty: a prospective, randomized, double-blind, placebo-controlled trial. PMID- 25747912 TI - Reply: use of the ultrasonic bone aspirator for lateral osteotomies in rhinoplasty. PMID- 25747913 TI - Discussion: Financial conflicts of interest in plastic surgery: background, potential for bias, disclosure, and transparency. PMID- 25747914 TI - Competition between rhythmic and linguistic organization in a sentence-rhythm Stroop task. AB - We provide a test of Patel's [( 2003 ). Language, music, syntax and the brain. Nature Neuroscience, 6, 674-681] shared syntactic integration resources hypothesis by investigating the competition between determinants of rhythmic parsing and linguistic parsing using a sentence-rhythm Stroop task. We played five-note rhythm patterns in which each note is replaced with a spoken word of a five-word sentence and asked participants to indicate the starting point of the rhythm while they disregarded which word would normally be heard as the first word of the sentence. In Study 1, listeners completed the task in their native language. In Study 2, we investigated whether this competition is weakened if the sentences were in a listener's non-native language. In Study 3, we investigated how much language mastery is necessary to obtain the effects seen in Studies 1 and 2. We demonstrate that processing resources for rhythmic parsing and linguistic parsing overlap with one another, particularly when the task is demanding. We also show that the tendency for language to bias processing does not require deep knowledge of the language. PMID- 25747915 TI - Intervendor variability of two-dimensional strain using vendor-specific and vendor-independent software. AB - BACKGROUND: Although two-dimensional (2D) strain is widely used to assess left ventricular mechanics, the strain values derived from vendor-specific 2D speckle tracking software are different even for the same subjects and are therefore not interchangeable. The aim of this study was to test the hypothesis that vendor independent software would produce lower intervendor variability between 2D strain measurements and overcome this limitation. METHODS: Two sets of three apical images were acquired using two of three types of ultrasound machines (GE, Philips, and Toshiba) in 81 healthy volunteers (GE vs Philips in 26 subjects, Philips vs Toshiba in 31 subjects, and GE vs Toshiba in 24 subjects). Two dimensional global longitudinal strain (GLS) was measured using vendor-specific software and two vendor-independent software packages (TomTec and Epsilon) in each set of apical images, and GLS values were directly compared with one another. RESULTS: The upgrades of vendor-specific software yielded different values of GLS compared with the previous versions of the software. The correlations between the GLS values determined using vendor-specific software exhibited a wide range of r values (r = 0.23, r = 0.42, and r = 0.72), with significant bias, with the exception of one comparison. The vendor-independent software provided modest degrees of correlation (TomTec: r = 0.65, r = 0.65, and r = 0.77; Epsilon: r = 0.65, r = 0.74, and r = 0.77), with limits of agreement (range, +/-3% to +/-4.5%) that were not negligible. CONCLUSIONS: Although the vendor-independent 2D strain software provided moderate correlations between the GLS values of the ultrasound images obtained from the same subjects using different vendors, relatively large limits of agreement remain a relevant problem. These results suggest that the same ultrasound machine and the same 2D speckle-tracking software should be used for longitudinal analysis of strain values in the same subjects and for cross-sectional studies. PMID- 25747916 TI - A kurtosis-based wavelet algorithm for motion artifact correction of fNIRS data. AB - Movements are a major source of artifacts in functional Near-Infrared Spectroscopy (fNIRS). Several algorithms have been developed for motion artifact correction of fNIRS data, including Principal Component Analysis (PCA), targeted Principal Component Analysis (tPCA), Spline Interpolation (SI), and Wavelet Filtering (WF). WF is based on removing wavelets with coefficients deemed to be outliers based on their standardized scores, and it has proven to be effective on both synthetized and real data. However, when the SNR is high, it can lead to a reduction of signal amplitude. This may occur because standardized scores inherently adapt to the noise level, independently of the shape of the distribution of the wavelet coefficients. Higher-order moments of the wavelet coefficient distribution may provide a more diagnostic index of wavelet distribution abnormality than its variance. Here we introduce a new procedure that relies on eliminating wavelets that contribute to generate a large fourth moment (i.e., kurtosis) of the coefficient distribution to define "outliers" wavelets (kurtosis-based Wavelet Filtering, kbWF). We tested kbWF by comparing it with other existing procedures, using simulated functional hemodynamic responses added to real resting-state fNIRS recordings. These simulations show that kbWF is highly effective in eliminating transient noise, yielding results with higher SNR than other existing methods over a wide range of signal and noise amplitudes. This is because: (1) the procedure is iterative; and (2) kurtosis is more diagnostic than variance in identifying outliers. However, kbWF does not eliminate slow components of artifacts whose duration is comparable to the total recording time. PMID- 25747918 TI - Bistability breaks-off deterministic responses to intracortical stimulation during non-REM sleep. AB - During non-rapid eye movement (NREM) sleep (stage N3), when consciousness fades, cortico-cortical interactions are impaired while neurons are still active and reactive. Why is this? We compared cortico-cortical evoked-potentials recorded during wakefulness and NREM by means of time-frequency analysis and phase-locking measures in 8 epileptic patients undergoing intra-cerebral stimulations/recordings for clinical evaluation. We observed that, while during wakefulness electrical stimulation triggers a chain of deterministic phase-locked activations in its cortical targets, during NREM the same input induces a slow wave associated with an OFF-period (suppression of power>20Hz), possibly reflecting a neuronal down-state. Crucially, after the OFF-period, cortical activity resumes to wakefulness-like levels, but the deterministic effects of the initial input are lost, as indicated by a sharp drop of phase-locked activity. These findings suggest that the intrinsic tendency of cortical neurons to fall into a down-state after a transient activation (i.e. bistability) prevents the emergence of stable patterns of causal interactions among cortical areas during NREM. Besides sleep, the same basic neurophysiological dynamics may play a role in pathological conditions in which thalamo-cortical information integration and consciousness are impaired in spite of preserved neuronal activity. PMID- 25747919 TI - Harvard Review of Psychiatry. Introduction. PMID- 25747917 TI - Heritability of fractional anisotropy in human white matter: a comparison of Human Connectome Project and ENIGMA-DTI data. AB - The degree to which genetic factors influence brain connectivity is beginning to be understood. Large-scale efforts are underway to map the profile of genetic effects in various brain regions. The NIH-funded Human Connectome Project (HCP) is providing data valuable for analyzing the degree of genetic influence underlying brain connectivity revealed by state-of-the-art neuroimaging methods. We calculated the heritability of the fractional anisotropy (FA) measure derived from diffusion tensor imaging (DTI) reconstruction in 481 HCP subjects (194/287 M/F) consisting of 57/60 pairs of mono- and dizygotic twins, and 246 siblings. FA measurements were derived using (Enhancing NeuroImaging Genetics through Meta Analysis) ENIGMA DTI protocols and heritability estimates were calculated using the SOLAR-Eclipse imaging genetic analysis package. We compared heritability estimates derived from HCP data to those publicly available through the ENIGMA DTI consortium, which were pooled together from five-family based studies across the US, Europe, and Australia. FA measurements from the HCP cohort for eleven major white matter tracts were highly heritable (h(2)=0.53-0.90, p<10(-5)), and were significantly correlated with the joint-analytical estimates from the ENIGMA cohort on the tract and voxel-wise levels. The similarity in regional heritability suggests that the additive genetic contribution to white matter microstructure is consistent across populations and imaging acquisition parameters. It also suggests that the overarching genetic influence provides an opportunity to define a common genetic search space for future gene-discovery studies. Uniquely, the measurements of additive genetic contribution performed in this study can be repeated using online genetic analysis tools provided by the HCP ConnectomeDB web application. PMID- 25747920 TI - Medication-assisted treatment of opioid use disorder: review of the evidence and future directions. AB - Medication-assisted treatment of opioid use disorder with physiological dependence at least doubles rates of opioid-abstinence outcomes in randomized, controlled trials comparing psychosocial treatment of opioid use disorder with medication versus with placebo or no medication. This article reviews the current evidence for medication-assisted treatment of opioid use disorder and also presents clinical practice imperatives for preventing opioid overdose and the transmission of infectious disease. The evidence strongly supports the use of agonist therapies to reduce opioid use and to retain patients in treatment, with methadone maintenance remaining the gold standard of care. Combined buprenorphine/naloxone, however, also demonstrates significant efficacy and favorable safety and tolerability in multiple populations, including youth and prescription opioid-dependent individuals, as does buprenorphine monotherapy in pregnant women. The evidence for antagonist therapies is weak. Oral naltrexone demonstrates poor adherence and increased mortality rates, although the early evidence looks more favorable for extended-release naltrexone, which has the advantages that it is not subject to misuse or diversion and that it does not present a risk of overdose on its own. Two perspectives-individualized treatment and population management-are presented for selecting among the three available Food and Drug Administration-approved maintenance therapies for opioid use disorder. The currently unmet challenges in treating opioid use disorder are discussed, as are the directions for future research. PMID- 25747921 TI - Long-term course of opioid addiction. AB - Opioid addiction is associated with excess mortality, morbidities, and other adverse conditions. Guided by a life-course framework, we review the literature on the long-term course of opioid addiction in terms of use trajectories, transitions, and turning points, as well as other factors that facilitate recovery from addiction. Most long-term follow-up studies are based on heroin addicts recruited from treatment settings (mostly methadone maintenance treatment), many of whom are referred by the criminal justice system. Cumulative evidence indicates that opioid addiction is a chronic disorder with frequent relapses. Longer treatment retention is associated with a greater likelihood of abstinence, whereas incarceration is negatively related to subsequent abstinence. Over the long term, the mortality rate of opioid addicts (overdose being the most common cause) is about 6 to 20 times greater than that of the general population; among those who remain alive, the prevalence of stable abstinence from opioid use is low (less than 30% after 10-30 years of observation), and many continue to use alcohol and other drugs after ceasing to use opioids. Histories of sexual or physical abuse and comorbid mental disorders are associated with the persistence of opioid use, whereas family and social support, as well as employment, facilitates recovery. Maintaining opioid abstinence for at least five years substantially increases the likelihood of future stable abstinence. Recent advances in pharmacological treatment options (buprenorphine and naltrexone) include depot formulations offering longer duration of medication; their impact on the long-term course of opioid addiction remains to be assessed. PMID- 25747922 TI - Treatment of tobacco use disorders in smokers with serious mental illness: toward clinical best practices. AB - Addiction to tobacco-derived nicotine remains highly prevalent in the United States, with 18% using daily, and 53% of those with serious mental illness using daily. While smokers with serious mental illness have been excluded from most large nicotine-dependence treatment studies, a growing evidence base is available to guide clinicians in assisting their patients with psychiatric illness to quit smoking. The aim of this review is to present the evidence on safety and efficacy of smoking cessation interventions for those with serious mental illness. Smokers with schizophrenia spectrum disorders should receive varenicline or bupropion with or without nicotine replacement therapy in combination with behavioral treatment. Although more research is needed, preliminary evidence suggests that varenicline in combination with behavioral support is efficacious and well tolerated for smoking cessation for those with bipolar disorder and major depressive disorder. Controlled trials have found no evidence that in patients with serious mental illness, the use of pharmacotherapeutic cessation aids worsens psychiatric symptoms or increases the rate of psychiatric adverse events. Converging evidence indicates that a majority of smokers with serious mental illness want to quit smoking and that available pharmacotherapeutic cessation aids combined with behavioral support are both effective for, and well tolerated by, these smokers. PMID- 25747923 TI - Treatment of co-occurring anxiety disorders and substance use disorders. AB - Anxiety disorders commonly co-occur with substance use disorders both in the general population and in treatment-seeking samples. This co-occurrence is associated with greater symptom severity, higher levels of disability, and poorer course of illness relative to either disorder alone. Little research has been conducted, however, on the treatment of these co-occurring disorders. This gap may not only leave anxiety untreated or undertreated but also increase the risk for relapse and poor substance use outcomes. The aim of this article is to review the current state of the literature on treating co-occurring anxiety and substance use disorders. In addition to presenting a brief overview of the epidemiology of this co-occurrence, the article discusses the challenges in assessing anxiety in the context of a substance use disorder, the evidence for various treatment approaches, and recent advances and future directions in this understudied area. Also highlighted is the need for future research to identify optimal behavioral and pharmacologic treatments for co-occurring anxiety and substance use disorders. PMID- 25747924 TI - Alcohol use disorders in pregnancy. AB - Alcohol use disorders (AUDs) are less prevalent in pregnant women than in nonpregnant women, but these disorders can create a host of clinical challenges when encountered. Unfortunately, little evidence is available to guide clinical decision making in this population. Drinking alcohol during pregnancy can have negative consequences on both fetus and mother, but it remains controversial as to the volume of alcohol consumption that correlates with these consequences. Likewise, little evidence is available to support the use of particular pharmacologic interventions for AUDs during pregnancy or to guide the management of alcohol detoxification in pregnant women. The use of benzodiazepines (the mainstay of most alcohol detoxification protocols) in pregnant women is controversial. Nevertheless, despite the lack of robust data to guide management of AUDs in pregnancy, clinicians need to make management decisions when confronted with these challenging situations. In that context, this article reviews the epidemiology of AUDs in pregnancy and the pharmacologic management of both AUDs and alcohol withdrawal in pregnant women, with the goal of informing clinicians about what is known about managing these co-occurring conditions. PMID- 25747925 TI - Pharmacotherapy for alcohol use disorder: current and emerging therapies. AB - Alcohol use disorder is a heterogeneous illness with a complex biology that is controlled by many genes and gene-by-environment interactions. Several efficacious, evidence-based treatments currently exist for treating and managing alcohol use disorder, including a number of pharmacotherapies that target specific aspects of biology that initiate and maintain dangerous alcohol misuse. This article reviews the neurobiological and neurobehavioral foundation of alcohol use disorder, the mechanisms of action and evidence for the efficacy of currently approved medications for treatment, and the literature on other emerging pharmacotherapies. PMID- 25747927 TI - The globalization of addiction research: capacity-building mechanisms and selected examples. AB - Over the past decade, the amount and variety of addiction research around the world has increased substantially. Researchers in Australia, Canada, United Kingdom, United States, and western Europe have significantly contributed to knowledge about addiction and its treatment. However, the nature and context of substance use disorders and the populations using drugs are far more diverse than is reflected in studies done in Western cultures. To stimulate new research from a diverse set of cultural perspectives, the National Institute on Drug Abuse (NIDA) has promoted the development of addiction research capacity and skills around the world for over 25 years. This review will describe the programs NIDA has developed to sponsor international research and research fellows and will provide some examples of the work NIDA has supported. NIDA fellowships have allowed 496 individuals from 96 countries to be trained in addiction research. The United Arab Emirates and Saudi Arabia have recently developed funding to support addiction research to study, with advice from NIDA, the substance use disorder problems that affect their societies. Examples from Malaysia, Tanzania, Brazil, Russian Federation, Ukraine, Republic of Georgia, Iceland, China, and Vietnam are used to illustrate research being conducted with NIDA support. Health services research, collaboratively funded by the U.S. National Institutes of Health and Department of State, addresses a range of addiction service development questions in low- and middle-income countries. Findings have expanded the understanding of addiction and its treatment, and are enhancing the ability of practitioners and policy makers to address substance use disorders. PMID- 25747928 TI - Challenges in managing acute on chronic pain in a pregnant woman at high risk for opioid use disorder in the general hospital setting. PMID- 25747926 TI - Gambling disorder and other behavioral addictions: recognition and treatment. AB - Addiction professionals and the public are recognizing that certain nonsubstance behaviors--such as gambling, Internet use, video-game playing, sex, eating, and shopping--bear resemblance to alcohol and drug dependence. Growing evidence suggests that these behaviors warrant consideration as nonsubstance or "behavioral" addictions and has led to the newly introduced diagnostic category "Substance-Related and Addictive Disorders" in DSM-5. At present, only gambling disorder has been placed in this category, with insufficient data for other proposed behavioral addictions to justify their inclusion. This review summarizes recent advances in our understanding of behavioral addictions, describes treatment considerations, and addresses future directions. Current evidence points to overlaps between behavioral and substance-related addictions in phenomenology, epidemiology, comorbidity, neurobiological mechanisms, genetic contributions, responses to treatments, and prevention efforts. Differences also exist. Recognizing behavioral addictions and developing appropriate diagnostic criteria are important in order to increase awareness of these disorders and to further prevention and treatment strategies. PMID- 25747929 TI - A stable phosphanyl phosphaketene and its reactivity. AB - Sodium phosphaethynolate, Na(OCP), reacts with the bulky P-chloro-diazaphosphole yielding a phosphanyl phosphaketene, which is stable for weeks under an inert atmosphere in the solid state. This compound is best described as a tight ion pair with a remarkably long P-P bond distance (2.44 A). In solution, this phosphaketene dimerizes under loss of CO to give 1,2,3-triphosphabicyclobutane identified by an X-ray diffraction study. As an intermediate, a five-membered heterocyclic diphosphene was trapped in a Diels-Alder reaction with 2,3 dimethylbutadiene. The formation of this intermediate in a hetero-Cope rearrangement as well as dimerization/CO loss were computed with various DFT methods which allowed us to understand the reaction mechanisms. PMID- 25747930 TI - Effects of infusing nitric oxide donors and inhibitors on plasma metabolites, muscle lactate production and meat quality in lambs fed a high quality roughage based diet. AB - As nitric oxide (NO) is postulated to be a mediator of the effects of pre slaughter stress on meat quality the aims of this experiment were to investigate the effects of modulating NO pharmacologically on meat quality of sedentary lambs. As pharmacological NO donors are prohibitively expensive to use in the lamb model L-Arginine, the substrate for NO synthase (NOS) was infused into lambs and increased NO production by ~30%. In a 2 * 2 factorial design we infused either L-Arginine (500 mg/kg) or the NOS inhibitor L-N(G) nitroarginine methyl ester hydrochloride (L-NAME, 30 mg/kg) 190 min pre-slaughter and investigated meat quality in the Longissimus thoracis lumborum (LTL) or Semimembranosus (SM). The principal outcome of the experiment was that L-NAME inhibited proteolysis and reduced tenderness in the SM. These data indicate that events pre-slaughter that affect NO synthesis can influence meat tenderness, potentially via altered muscle metabolism or modulation of proteolytic enzymes. PMID- 25747931 TI - Effect of a screen with flaps and straw on behaviour, stress response, productive performance and meat quality in indoor feedlot lambs. AB - We analysed the effect of a modified pen using a wooden screen with flaps and cereal straw as forage and bedding, on behaviour, stress response, performance and meat quality variables of lambs housed in feedlots. Sixty male lambs were placed in enriched (ESF) or conventional (CO) pens (3 pens/treatment, 10 lambs/pen). The CO environment was barren. The ESF lambs showed a great preference for the provided items, which encouraged more natural and richer behaviour, reducing stereotypies and lamb aggressions, and increasing affiliations (P <= 0.05), which improves group cohesion. However, ESF lambs also developed a more natural coping style to the handling, evidenced by the higher cortisol levels (65.4 vs. 43.8 nmol/L) and a higher eye temperature as response to the reactivity test (38.1 vs. 37.8 degrees C). The ESF lambs had a higher (P <= 0.05) slaughter weight (27.2 vs. 26.3 kg), conformation score (7.38 vs. 6.07) and pH 24 (5.63 vs. 5.56) but lower cooking losses (12.9 vs. 14.9%) than CO lambs. PMID- 25747932 TI - Living in an urban environment and non-communicable disease risk in Thailand: Does timing matter? AB - BACKGROUND: This paper uses a life-course approach to explore whether the timing and/or duration of urban (vs rural) exposure was associated with risk factors for NCDs. METHODS: A cross-sectional survey was conducted among health care workers in two hospitals in Thailand. Two measures of urbanicity were considered: early life urban exposure and the proportion of urban life years. We explored four behavioral NCD risk factors, two physiological risk factors and four biological risk factors. RESULTS: Both measures of urbanicity were each independently associated with increases in all behavioral and physiological risk factors. For some biological risk factors, people spending their early life in an urban area may be more susceptible to the effect of increasing proportion of urban life years than those growing up in rural areas. CONCLUSION: Urbanicity was associated with increases in behavioral and physiological risk factors. However, these associations may not translate directly into increases in biological risk factors. It is likely that these biological risk factors were results of a complex interaction between both long term accumulation of exposure and early life exposures. PMID- 25747933 TI - Survival After Out-of-Hospital Cardiac Arrest in Relation to Age and Early Identification of Patients With Minimal Chance of Long-Term Survival. AB - BACKGROUND: Survival after out-of-hospital cardiac arrest has increased during the last decade in Denmark. We aimed to study the impact of age on changes in survival and whether it was possible to identify patients with minimal chance of 30-day survival. METHODS AND RESULTS: Using data from the nationwide Danish Cardiac Arrest Registry (2001?2011), we identified 21 480 patients >=18 years old with a presumed cardiac-caused out-of-hospital cardiac arrest for which resuscitation was attempted. Patients were divided into 3 preselected age-groups: working-age patients 18 to 65 years of age (33.7%), early senior patients 66 to 80 years of age (41.5%), and late senior patients >80 years of age (24.8%). Characteristics in working-age patients, early senior patients, and late senior patients were as follows: witnessed arrest in 53.8%, 51.1%, and 52.1%; bystander cardiopulmonary resuscitation in 44.7%, 30.3%, and 23.4%; and prehospital shock from a defibrillator in 54.7%, 45.0%, and 33.8% (all P<0.05). Between 2001 and 2011, return of spontaneous circulation on hospital arrival increased: working age patients, from 12.1% to 34.6%; early senior patients, from 6.4% to 21.5%; and late senior patients, from 4.0% to 15.0% (all P<0.001). Furthermore, 30-day survival increased: working-age patients, 5.8% to 22.0% (P<0.001); and early senior patients, 2.7% to 8.4% (P<0.001), whereas late senior patients experienced only a minor increase (1.5% to 2.0%; P=0.01). Overall, 3 of 9499 patients achieved 30-day survival if they met 2 criteria: had not achieved return of spontaneous circulation on hospital arrival and had not received a prehospital shock from a defibrillator. CONCLUSIONS: All age groups experienced a large temporal increase in survival on hospital arrival, but the increase in 30-day survival was most prominent in the young. With the use of only 2 criteria, it was possible to identify patients with a minimal chance of 30-day survival. PMID- 25747935 TI - Comparison of self-reported and Medicare claims-identified acute myocardial infarction. AB - BACKGROUND: Cardiovascular disease is often studied through patient self-report and administrative data. However, these 2 sources provide different information, and few studies have compared them. METHODS AND RESULTS: We compared data from a longitudinal, nationally representative survey of older Americans with matched Medicare claims. Self-reported heart attack in the previous 2 years was compared with claims-identified acute myocardial infarction (AMI) and acute coronary syndrome. Among the 3.1% of respondents with self-reported heart attack, 32.8% had claims-identified AMI, 16.5% had non-AMI acute coronary syndrome, and 25.8% had other cardiac claims; 17.3% had no inpatient visits in the previous 2.5 years. Claims-identified AMIs were found in 1.4% of respondents; of these, 67.8% reported a heart attack. Self-reports were less likely among respondents >75 years of age (62.7% versus 74.6%; P=0.006), with less than high school education (61.6% versus 71.4%; P=0.015), with at least 1 limitation in activities of daily living (59.6% versus 74.7%; P=0.001), or below the 25th percentile of a word recall memory test (60.7% versus 71.3%; P=0.019). Both self-reported and claims identified cardiac events were associated with increased mortality; the highest mortality was observed among those with claims-identified AMI who did not self report (odds ratio, 2.8; 95% confidence interval, 1.5-5.1) and among those with self-reported heart attack and claims-identified AMI (odds ratio, 2.5; 95% confidence interval, 1.7-3.6) or non-AMI acute coronary syndrome (odds ratio, 2.7; 95% confidence interval, 1.8-4.1). CONCLUSIONS: There is considerable disagreement between self-reported and claims-identified events. Although self reported heart attack may be inaccurate, it indicates increased risk of death, regardless of whether the self-report is confirmed by Medicare claims. PMID- 25747934 TI - Pentraxin 3 Induces Vascular Endothelial Dysfunction Through a P-selectin/Matrix Metalloproteinase-1 Pathway. AB - BACKGROUND: Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function. METHODS AND RESULTS: Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin-deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensive patients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21). CONCLUSIONS: Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensive patients. PMID- 25747936 TI - Effect of cervical sympathetic block on optic nerve sheath diameter measured by ultrasonography. AB - Optic nerve sheath diameter (ONSD) measurement using ocular ultrasonography was introduced as a non-invasive technique to assess intracranial pressure. We investigated changes in ONSD after cervical sympathetic block (CSB). Ultrasound guided CSB was performed with a lateral approach at the C6 level in 35 patients. ONSD was measured before CSB and after checking for Horner's syndrome 15 minutes after CSB. The mean ONSD was significantly higher after CSB than before (5.15 +/- 0.38 mm vs. 4.75 +/- 0.32 mm, p < 0.001). A comparison of ONSDs between the blocked and non-blocked sides revealed that these values did not differ significantly between sides at baseline and after CSB. On the basis of these preliminary data, CSB caused an increase in ONSD in patients without intracranial pathology or neurologic disorders. Further larger and controlled studies of the effect of CSB on intracranial pressure in humans are needed to confirm our findings. PMID- 25747938 TI - Do not forget to calculate the mean shear wave speed as assessed by acoustic radiation force impulse elastography as a harmonic mean, not an arithmetical mean. PMID- 25747937 TI - Efficacy of contrast-enhanced ultrasound washout rate in predicting hepatocellular carcinoma differentiation. AB - The aim of this retrospective study was to evaluate the efficacy of contrast enhanced ultrasound (CEUS) washout rate in predicting hepatocellular carcinoma (HCC) differentiation. Two hundred seventy-one patients underwent liver resection for HCC between April 2008 and December 2012 after being examined by CEUS using the contrast agent SonoVue with a low mechanical index (<0.1) in a routine procedure. Contrast agent washout rates obtained from video images were divided into four categories from slow to fast: WR1 = no washout in all phases (slowest); WR2 = washout after 120 s from contrast injection (late-phase washout); WR3 = washout between 41 and 120 s from contrast injection (portal venous washout); WR4 = washout before 40 s from contrast injection (fastest washout rate). HCC nodules were graded as well, moderately and poorly differentiated. Spearman rank correlation and chi(2)-tests were used to assess group relationships and differences. Receiver operating characteristic curve analysis was used to determine the diagnostic predictive value of CEUS. Among the 271 patients, 18 (6.6%) had well differentiated, 150 (55.4%) had moderately differentiated and 103 (38.0%) had poorly differentiated HCC. Statistical tests indicated that washout rate was significantly correlated with tumor differentiation (p < 0.05), and the poorly differentiated HCCs had earlier washout. At the cutoff point of WR4, CEUS based on washout rate performed poorly in distinguishing poorly differentiated from moderately and well-differentiated HCCs, with a sensitivity, specificity and accuracy (area under the curve) of 24%, 97% and 0.68, respectively. However, at the cutoff point of WR2, the sensitivity, specificity and accuracy of CEUS in differentiating well-differentiated HCC from other HCCs were significantly better: 98%, 78% and 0.96, respectively. Thus, CEUS washout rate may have a role in identifying patients with well-differentiated HCC. PMID- 25747939 TI - Abnormal left ventricular contraction sequence in hypertrophic cardiomyopathy patients: first description of hypersynchrony and invert synchrony. AB - The aim of this study was to compare left ventricular contraction sequence in patients with hypertrophic cardiomyopathy (HCM) and healthy controls. Normal left ventricular contraction sequence in healthy controls exhibits an apex-to-base delay (ABD) contributing to efficient cardiac mechanics (physiologic asynchrony). Echocardiographic data from 20 controls and 40 HCM patients were prospectively analyzed. Endocardial longitudinal and circumferential strains and ABD were measured using custom-built software. HCM patients had increased circumferential (-36.4 +/- 6.0 vs. -32.9 +/- 5.0, p < 0.01) and decreased longitudinal (-19.3 +/- 6.4 vs. -23.4 +/- 5.7, p < 0.01) strains. In controls, physiologic ABD was observed (35.7 +/- 18.1 ms). This delay was reduced in HCM patients (5.5 +/- 22.7 ms, p < 0.01 vs. controls). There was no interaction between ABD and common clinical or echocardiographic parameters in the HCM population. Left ventricular contraction sequence can be modified in HCM patients, with the loss of the physiologic ABD. This phenomenon is independent from commonly measured parameters. PMID- 25747940 TI - IL-33/ST2 axis controls Th2/IL-31 and Th17 immune response in allergic airway diseases. AB - IL-33 targeting ST2 receptor (T1/ST2), expressed on Th2 cell surface, regulates the production of cytokines like IL-17A and IL-31. We studied the role of IL 33/ST2 axis in IL-31 and IL-17A production in patients with allergic rhinitis (AR) and with concomitant allergic asthma and rhinitis (AAR). 20 healthy control subjects (HC), 14 AR and 17 AAR subjects were recruited and blood samples collected. IL-33, soluble ST2 (sST2), IL-17A and IL-31 plasma concentrations were measured by ELISA method. T1/ST2, IL-31 and IL-17A cellular expression were studied in peripheral blood mononuclear cells (PBMC) from HC, AR and AAR (n=6 for each group) by flow-cytometry. In vitro, we also evaluated the effect of beclomethasone dipropionate (BDP) on T1/ST2, IL-31 and IL-17A expression in CD3(+)T-cells from PBMC of AAR (n=6). Plasma levels of IL-33, IL-31 and IL-17A were significantly higher and sST2 was lower in patients with AR and AAR than in HC. IL-31 and IL-17A intracellular levels significantly increased, whereas T1/ST2 expression was significantly lower, in CD3(+)T-cells from AR and AAR compared to HC. Positive correlations were observed between plasmatic components of IL-33/ST2 axis and IL-31 in both AR and AAR and IL-17A in AAR. In vitro IL-31 and IL-17A intracellular levels decreased after BDP treatment, whereas T1/ST2 expression increased in cultured CD3(+)T-cells obtained from AAR. IL-33/ST2 axis is involved in Th2/IL-31 and Th17 immune response during the progression of allergic airway disease. In vitro BDP is able to control Th2/IL-31 and Th17 immune response in PBMC from allergic patients. PMID- 25747941 TI - Characterization of phosphate sequestration by a lanthanum modified bentonite clay: a solid-state NMR, EXAFS, and PXRD study. AB - Phosphate (Pi) sequestration by a lanthanum (La) exchanged clay mineral (La Bentonite), which is extensively used in chemical lake restoration, was investigated on the molecular level using a combination of (31)P and (139)La solid state NMR spectroscopy (SSNMR), extended X-ray absorption spectroscopy (EXAFS), powder X-ray diffraction (PXRD) and sorption studies. (31)P SSNMR show that all Pi was immobilized as rhabdophane (LaPO4.n H2O, n <= 3), which was further supported by (139)La SSNMR and EXAFS. However, PXRD results were ambiguous with respect to rhabdophane and monazite (LaPO4). Adsorption studies showed that at dissolved organic carbon (DOC) concentration above ca. 250 MUM the binding capacity was only 50% of the theoretical value or even less. No other La or Pi phases were detected by SSNMR and EXAFS indicating the effect of DOC is kinetic. Moreover, (31)P SSNMR showed that rhabdophane formed upon Pi sequestration is in close proximity to the clay matrix. PMID- 25747943 TI - [Current aspects of medullary nailing: approaches and locking techniques]. PMID- 25747942 TI - Suppression of RNAi by dsRNA-degrading RNaseIII enzymes of viruses in animals and plants. AB - Certain RNA and DNA viruses that infect plants, insects, fish or poikilothermic animals encode Class 1 RNaseIII endoribonuclease-like proteins. dsRNA-specific endoribonuclease activity of the RNaseIII of rock bream iridovirus infecting fish and Sweet potato chlorotic stunt crinivirus (SPCSV) infecting plants has been shown. Suppression of the host antiviral RNA interference (RNAi) pathway has been documented with the RNaseIII of SPCSV and Heliothis virescens ascovirus infecting insects. Suppression of RNAi by the viral RNaseIIIs in non-host organisms of different kingdoms is not known. Here we expressed PPR3, the RNaseIII of Pike perch iridovirus, in the non-hosts Nicotiana benthamiana (plant) and Caenorhabditis elegans (nematode) and found that it cleaves double-stranded small interfering RNA (ds-siRNA) molecules that are pivotal in the host RNA interference (RNAi) pathway and thereby suppresses RNAi in non-host tissues. In N. benthamiana, PPR3 enhanced accumulation of Tobacco rattle tobravirus RNA1 replicon lacking the 16K RNAi suppressor. Furthermore, PPR3 suppressed single stranded RNA (ssRNA)--mediated RNAi and rescued replication of Flock House virus RNA1 replicon lacking the B2 RNAi suppressor in C. elegans. Suppression of RNAi was debilitated with the catalytically compromised mutant PPR3-Ala. However, the RNaseIII (CSR3) produced by SPCSV, which cleaves ds-siRNA and counteracts antiviral RNAi in plants, failed to suppress ssRNA-mediated RNAi in C. elegans. In leaves of N. benthamiana, PPR3 suppressed RNAi induced by ssRNA and dsRNA and reversed silencing; CSR3, however, suppressed only RNAi induced by ssRNA and was unable to reverse silencing. Neither PPR3 nor CSR3 suppressed antisense-mediated RNAi in Drosophila melanogaster. These results show that the RNaseIII enzymes of RNA and DNA viruses suppress RNAi, which requires catalytic activities of RNaseIII. In contrast to other viral silencing suppression proteins, the RNaseIII enzymes are homologous in unrelated RNA and DNA viruses and can be detected in viral genomes using gene modeling and protein structure prediction programs. PMID- 25747944 TI - [Penetrating injury of two body cavities with a 20 cm long dagger-like sliver after falling into a glass door]. AB - In Germany the numbers of penetrating thoracic injuries are rare compared to Anglo-American countries; however, the number of cases has increased in recent years due to an increase in violent incidents. This article reports the case of a patient who suffered such a penetrating thoracic injury after a domestic accident. Operative treatment was performed according to the well-established standard treatment algorithms. Contrary to the initial assessment of the emergency doctor, substantially more severe injuries were found. PMID- 25747945 TI - Complexity of parental prenatal attachment during pregnancy at risk for preterm delivery. AB - OBJECTIVE: To clarify the links between parents' prenatal attachment and psychosocial perinatal factors such as maternal depression, anxiety and social support. METHODS: Cross-sectional study including 43 couples with high-risk pregnancy (RP) and 37 with physiologic pregnancy (PP). Self-report measures (depression, anxiety, social support and prenatal attachment) are completed by mothers, prenatal attachment questionnaire by fathers. RESULTS: Depression (p < 0.001) and state anxiety (p < 0.001) are higher in RP. Both, maternal and paternal antenatal attachment is significantly lower in RP (p < 0.001; p < 0.005) but not related to depression or anxiety. Paternal antenatal attachment is strictly related to the maternal attachment scale in both groups (PP: r < 0.034; RP: r < 0.004) and paternal antenatal scores in RP have a negative significant correlation with mothers' depression (r < 0.095). CONCLUSION: Hospitalized expecting parents at risk of preterm delivery develop less attachment to the fetus and higher levels of anxiety and depression compared to the physiologic pregnancy group. Maternal antenatal attachment is an independent variable related to the diagnosis of a possible preterm delivery. The promotion of prenatal psychological well-being and attachment for future mothers and fathers may serve to improve maternal health practices, perinatal health and neonatal outcome. PMID- 25747946 TI - Gastroesophageal reflux related to respiratory inhibition after crying and feeding hypoxemia in infants. AB - OBJECTIVE: To determine the relationships between gastroesophageal reflux (GER) and both respiratory inhibition after crying (RIAC) and feeding hypoxemia in infants. METHODS: We screened for RIAC and feeding hypoxemia among infants with a gestational age of 36 weeks or greater using pulse oximetry. We investigated the infants who showed hypoxemia with a decrease in SpO2 to less than 70% and bradycardia with a heart rate of less than 100 beats per minute caused by GER. We then evaluated the relationships between these events and both RIAC and feeding hypoxemia. RESULTS: We examined 250 infants in the present study. RIAC and feeding hypoxemia were observed in 35 (14.0%), and 30 (12.0%) infants, respectively. Ten infants showed hypoxemia and bradycardia caused by GER. These events were correlated with RIAC (p = 0.006) and feeding hypoxemia (p = 0.031). CONCLUSIONS: In the infants with RIAC and feeding hypoxemia, some show severe hypoxemia and bradycardia caused by GER. Medical staff caring for infants should note the presence of RIAC and feeding hypoxemia. PMID- 25747947 TI - Tocolysis in women with advanced preterm labor: a secondary analysis of a randomized clinical trial. AB - OBJECTIVE: To compare the efficacy of tocolytic treatment with indomethacin (I), magnesium sulfate (M) and nifedipine (N) for acute tocolysis in women with advanced cervical dilation (4-6 cm). METHODS: A single center, randomized trial was carried out involving patients in preterm labor (cervix 1-6 cm). Secondary analysis of women with advanced cervical dilation (cervix 4-6 cm) at 24-32 weeks' gestation who received intravenous M, oral N or I suppositories comprised this study population. RESULTS: Over 38 months, 92 women with advanced cervical dilation were randomized to one tocoloytic type. Days gained in utero (11.7) and percent remaining undelivered at 48 h (60.8%), 72 h (53.1%) and >7 days (38.3%) were similar regardless of tocolytic employed (p = 0.923, 0.968, 0.791, 0.802, respectively). Likewise, gestational age at delivery (30.7 +/- 3.2) was similar between groups (p = 0.771). Finally, neonatal statistics were not different when stratified by tocolytic treatment. CONCLUSION: There were no statistical differences between tocolytics in treating women with advanced cervical dilation. All offered significant days gained in utero after therapy, a high percentage remaining undelivered after 48 or 72 h and after 7 days. It would appear from data that there may be advantages to tocolytic treatment even in women with advanced cervical dilation. PMID- 25747949 TI - Crack abuse during pregnancy: maternal, fetal and neonatal complication. AB - OBJECTIVE: The aim of this study was to assess the effects of crack on pregnancy outcomes. METHODS: We studied 88 crack user pregnant women in this study. These women were matched to a drug-free group (n = 90) chosen from the population of the same hospital. Maternal outcomes including preeclampsia, placenta abruption, gestational diabetes and preterm labor, and neonatal complication including low birth weight and low Apgar score in 5 min were compared in crack using and drug free groups. Data were analyzed by SPSS software. Chi-square test and Student's t test and Relative Risks (RRs) were used in this study. RESULTS: The results of our study showed that crack abuse during pregnancy was associated with higher rate of preeclampsia p = 0.003 (RR, 1.731; 95% CI, 1.777-2.545), placental abruption p = 0.001 (RR, 2.439; 95% CI, 1.369-4.343), preterm labor p < 0.000 (RR, 3.249; 95% CI, 2.053-5.141) and low birth weight p < 0.000 (RR, 2.179; 95% CI, 1.462-3.247). CONCLUSIONS: Crack abuse had significant influence on pregnancy outcomes. Crack appears to influence the prevalence of low birth weight, preterm labor, preeclampsia and placental abruption. PMID- 25747948 TI - Fetal loss following second trimester amniocentesis. Who is at greater risk? How to counsel pregnant women? AB - OBJECTIVE: The purpose of this retrospective observational cohort study was to determine the impact of certain risk factors on fetal loss, after mid-trimester amniocentesis. MATERIAL AND METHODS: Six thousand seven-hundred and fifty-two (6752) consecutive amniocenteses with known pregnancy outcome performed during a 7-year period (2004-2010) were included in this study. Different maternal-, fetal and procedure-related factors were evaluated in this study. RESULTS: During this 7-year period, 6752 cases who underwent amniocentesis, with complete data available were evaluated for the outcome and risk factors mentioned. Total fetal loss rate (FLR) up to the 24th week was 1.19%. Risk factors associated with increased risk of fetal loss after amniocentesis were maternal age (OR:2.0), vaginal spotting (OR:2.2) and serious bleeding (OR:3.5) during pregnancy, history of 2nd trimester termination of pregnancy (OR:4.0), history of more than three spontaneous (OR:3.0) or surgical first trimester abortions (OR:2.1), fibromas (OR:3.0) and stained amniotic fluid (OR:6.1). CONCLUSIONS: Amniocentesis is a safe-invasive procedure for prenatal diagnosis with total FLR of 1.19% in our institution during the study period. The present study has emphasized the significance of certain risk factors for adverse outcome and therefore the need to individualize the risk. PMID- 25747950 TI - Does the antenatal detection of fetal growth restriction (FGR) have a prognostic value for mortality and short-term morbidity for very preterm infants? Results from the MOSAIC cohort. AB - OBJECTIVE: We investigated the impact of antenatal diagnosis of fetal growth restriction (FGR) on the risks of mortality and morbidity for very preterm infants given actual birthweight percentiles. METHODS: Data on 4608 live born infants 24-31 weeks of gestational age (GA) in 10 European regions in 2003 were used to compare in-hospital mortality, bronchopulmonary dysplasia (BPD) and severe neurological morbidity by birthweight percentiles and antenatal diagnosis of FGR. Other covariates were GA, sex, multiplicity, maternal complications, antenatal corticosteroids, birth in a level III center and region. RESULTS: Sixteen percent (n = 728) of all infants and 72%, 30% and 6%, respectively, of those with birthweight percentiles <10th, 10th-24th and >=25th had an antenatal diagnosis of FGR. After adjustment for clinical factors, antenatal diagnosis of FGR was not associated with mortality for infants with a birthweight >=10th percentile (OR [95% CI]: 0.9 [0.5-1.9] and 1.0 [0.6-1.8] for birthweights between the 10th-24th percentile and >=25th percentile, respectively), but infants with a birthweight <10th percentile had higher mortality (OR [95% CI]: 2.4 [1.0-5.8]). No association was observed at any birthweight percentile with BPD or severe neurological morbidity. CONCLUSION: Antenatal diagnosis of FGR did not influence risks of mortality or morbidity when birthweight was >=10th percentile; however, mortality risk was higher in antenatally detected infants with birthweight below the <10th percentile. PMID- 25747951 TI - Clinical features and outcome of pregnancy with SLE-associated thrombocytopenia. AB - OBJECTIVE: To analyze the course of maternal diseases and compare pregnancy outcomes in patients with systemic lupus erythematosus (SLE)-associated thrombocytopenia to patients without. METHODS: Medical charts of 77 pregnancies in 73 SLE patients were systematically reviewed. Patients were divided into two groups according to the presence or absence of thrombocytopenia. Patients who are new onset SLE during pregnancy were also been studied. RESULT: Thrombocytopenia was found in 18 (23.3%) of the pregnancies. SLE patients with thrombocytopenia during pregnancy had higher percentage of disease flaring (11/18 versus 14/59, p = 0.003) and SLE-Pregnancy Disease Activity Index (7.89 +/- 6.192 versus 2.41 +/- 3.3.89, p = 0.001) compared to patients without. Also, patients with thrombocytopenia had a higher percentage of pulmonary, cardiac and multiple organ system involvement. There was a statistically significant difference in preeclampsia and early onset hypertensive disorder induced before 34 weeks as well as the rate of live birth less than 34 weeks (33.3% versus 6.8%, p = 0.003 & 38.9% versus 13.6%, p = 0.018 & 16.7% versus 1.7%, p = 0.038). Patients with thrombocytopenia suffered from higher rate of pregnancy loss (22.2% versus 3.4%, p = 0.024) and neonatal death (33.3% versus 1.7%, p = 0.000). In our study there were 17 patients with new-onset of SLE during pregnancy. The hematological system manifestation occurred in all of them and there was a significant increase in the incidence of thrombocytopenia (n = 12, 70.6%). CONCLUSION: Thrombocytopenia in SLE during pregnancy indicates higher disease activity, severe organ damage, early onset preeclampsia and higher pregnancy loss. PMID- 25747952 TI - The role of extracellular inducer of matrix metalloproteinases in premature rupture of membranes. AB - OBJECTIVE: To investigate the role of matrix metalloproteinases (MMP-2, MMP-9) and their inducer (CD147) in premature rupture of membranes (PROM) at term labor. METHODS: In a cross-sectional study, 24 women aged 19-39, with 37-40-week pregnancy, and no clinical and histological signs of chorioamnionitis, were divided into two groups with and without PROM. The histological and immunohistochemical study of the fetal membranes was performed with polyclonal rabbit antibodies to MMP-2/MMP-9 and monoclonal rabbit antibodies to CD147. RESULTS: The analysis of MMP revealed the increase of MMP-9 expression in the amniotic epithelium during premature membrane rupture both in rupture area, and beyond it, and increased MMR-2 expression in the mesodermal cells. We also found high level of CD147 in the amniotic epithelium in PROM group. The above-mentioned changes were found in all areas of fetal membranes, regardless of the rupture localization. CONCLUSIONS: The study results demonstrate the increased expression of MMR-2 and MMR-9, which regulate the catabolism of fetal membrane extracellular matrix proteins, in amniotic membranes of women with PROM at term labor. The increased expression of CD147 may be one of the mechanisms triggering PROM in the absence of infection. PMID- 25747953 TI - Postnatal outcomes of infants with gastroschisis: a 5-year follow-up in a tertiary referral center in Brazil. AB - OBJECTIVE: The aim of this study was to evaluate postnatal outcomes in fetuses with gastroschisis. METHODS: This is a retrospective study (2009-2013) of patients with gastroschisis at the Hospital Sao Paulo (Federal University of Sao Paulo, Brazil). RESULTS: A total of 44 infants with gastroschisis were examined. The mean maternal age was 21.1 years and mean gestational age at delivery was 36.1 weeks. Delivery occurred before 34 weeks in 13.6%, between 34 and 36 weeks and 6 d in 40.9%, and after 37 weeks in 45.5%. The mean birth weight was 2349 g, with 37.2% small-for-gestational age infants. The mean umbilical cord blood pH was 7.32. Bowel resection and delayed fascial closure was performed in 14.6% and 19.5%, respectively. The mean hospitalization time in the neonatal intensive care unit was 52.7 d. Neonatal infection was detected in 52.4%, with a positive blood culture; 77.3% of those cases were coagulase negative staphylococci. The overall rate of mortality was 25%; 18.2% before birth, 45.4% during the neonatal period, and 36.4% in infants. The main cause of postnatal death was septicemia (55.5%). CONCLUSIONS: Despite advances in perinatal care and surgical techniques, infants with gastroschisis still present high rates of complications and death. PMID- 25747954 TI - Pregnancy outcome after electrosurgical cervical cone biopsy using Fischer cone biopsy excisor. AB - OBJECTIVE: To evaluate the pregnancy outcomes of all patients who underwent electrosurgical cone biopsy of the cervix between January 2000 and December 2011 and subsequently became pregnant. STUDY DESIGN: Retrospective cohort study. SETTINGS: District General Hospital in the North East of England. METHODS: Patients were identified from the local colposcopy electronic data, Hospital Episode Statistics and Maternity electronic data. Data were collected on a pro forma with two sections: (1) treatment section and (2) pregnancy section. In the treatment section, year and indication for treatment, volume of cervix removed, histological results and marginal status of specimen were documented. In the pregnancy section, time interval between treatment and pregnancy, pre-treatment obstetric history, cervical length measurements, cervical suture, gestation and mode of delivery and neonatal outcome were documented. Data were analysed using SPSS. RESULTS: 25 women achieved 47 pregnancies after electrosurgical cone biopsy treatment. Most common indication for cone biopsy was glandular neoplasia accounting for nearly half of the procedures; 21.2% of pregnancies ended in first trimester miscarriages. The preterm delivery rate (<37 weeks) was 19.4%. Volume of cervix excised was significantly greater in women who delivered preterm compared to women who delivered at term (p = 0.028). The rate of preterm delivery was significantly higher in post treatment pregnancies when compared to pregnancies before treatment in the same women (p = 0.02). The preterm delivery in post-treatment pregnancies was not related to the time interval between treatment and pregnancy (p = 0.54). There was no significant difference in miscarriage rates in pre- and post-treatment pregnancies (p = 0.98). CONCLUSION: Electrosurgical cone biopsy of cervix is associated with increased risk of preterm labour that is related to the volume of cervix excised. PMID- 25747955 TI - Omega-3 fatty acid supplementation affects pregnancy outcomes in gestational diabetes: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: This study was designed to assess the effects of omega-3 fatty acid supplementation on inflammatory factors, biomarkers of oxidative stress, and pregnancy outcomes among pregnant women with gestational diabetes (GDM). METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed among 56 women with GDM. Subjects were randomly selected to receive either 1000 mg omega-3 fatty acid supplements (containing 180 mg eicosapentaenoic acid and 120 mg docosahexanoic acid) (n = 27) or a placebo (n = 27) for 6 weeks. Fasting blood samples were taken at study baseline and after 6 weeks of intervention to quantify biochemical variables. Newborn's weight, height, head circumference, Apgar score, and hyperbilirubinemia were determined. RESULTS: At the end of the 6 weeks, taking omega-3 fatty acid significantly decreased serum high-sensitivity C reactive protein (hs-CRP) (change from baseline: -245.1 +/- 1570.5 versus + 913.9 +/- 2329.4 ng/mL, p = 0.03) and plasma malondialdehyde (MDA) concentrations (-0.4 +/- 1.3 versus + 0.6+/-2.3, p = 0.04) compared with the placebo. Supplementation with omega-3 had a low incidence of hyperbilirubinemiain newborns (7.7% versus 33.3%, p = 0.02) and decreased newborns' hospitalization rate (7.7% versus 33.3%, p = 0.02). CONCLUSIONS: Taken together, omega-3 fatty acid supplementation in GDM women had beneficial effects on maternal serum hs-CRP, plasma MDA levels, incidence of newborn's hyperbilirubinemia, and hospitalization. PMID- 25747956 TI - Evaluation of viremia, proviral load and cytokine profile in naturally feline immunodeficiency virus infected cats treated with two different protocols of recombinant feline interferon omega. AB - This study assesses viremia, provirus and blood cytokine profile in naturally FIV infected cats treated with two distinct protocols of interferon omega (rFeIFN omega). Samples from FIV-cats previously submitted to two single-arm studies were used: 7/18 received the licensed/subcutaneous protocol (SC) while 11/18 were treated orally (PO). Viremia, provirus and blood mRNA expression of interleukin (IL)-1, IL-4, IL-6, IL-10, IL-12p40, Interferon-gamma and Tumor Necrosis Factor alpha were monitored by Real-Time qPCR. Concurrent plasma levels of IL-6, IL 12p40 and IL-4 were assessed by ELISA. IL-6 plasma levels decreased in the SC group (p = 0.031). IL-6 mRNA expression (p = 0.037) decreased in the PO group, albeit not sufficiently to change concurrent plasma levels. Neither viremia nor other measured cytokines changed with therapy. Proviral load increased in the SC group (p = 0.031), which can be justified by a clinically irrelevant increase of lymphocyte count. Independently of the protocol, rFeIFN-omega seems to act on innate immunity by reducing pro-inflammatory stimulus. PMID- 25747957 TI - Reaction mechanism for the highly efficient catalytic decomposition of peroxynitrite by the amphipolar iron(III) corrole 1-Fe. AB - The amphipolar iron(III) corrole 1-Fe is one of the most efficient catalysts for the decomposition of peroxynitrite, the toxin involved in numerous diseases. This research focused on the mechanism of that reaction at physiological pH, where peroxynitrite is in equilibrium with its much more reactive conjugated acid, by focusing on the elementary steps involved in the catalytic cycle. Kinetic investigations uncovered the formation of a reaction intermediate in a process that is complete within a few milliseconds (k1 ~ 3 * 10(7) M(-1) s(-1) at 5 degrees C, about 7 orders of magnitude larger than the first order rate constant for the non-catalyzed process). Multiple evidence points towards iron-catalyzed homolytic O-O bond cleavage to form nitrogen dioxide and hydroxo- or oxo-iron(iv) corrole. The iron(iv) intermediate was found to decay via multiple pathways that proceed at similar rates (k2 about 10(6) M(-1) s(-1)): reaction with nitrogen dioxide to form nitrate, nitration of the corrole macrocyclic, and dimerization to binuclear iron(iv) corrole. Catalysis in the presence of substrates affects the decay of the iron intermediate by either oxidative nitration (phenolic substrates) or reduction (ascorbate). A large enough excess of ascorbate accelerates the catalytic decomposition of PN by 1-Fe by orders of magnitude, prevents other decay routes of the iron intermediate, and eliminates nitration products as well. This suggests that the beneficial effect of the iron corrole under the reducing conditions present in most biological media might be even larger than in the purely chemical system. The acquired mechanistic insight is of prime importance for the design of optimally acting catalysts for the fast and safe decomposition of reactive oxygen and nitrogen species. PMID- 25747958 TI - Survival after judicial hanging. AB - Hanging is known not only as a common method of suicide but also as a capital punishment method in some countries. Although several cases have been reported to survive after the attempted suicidal/accidental hanging, to the extent of our knowledge, no modern case of survival after judicial hanging exists. We reported a case of an individual who revived after modern judicial hanging despite being declared dead. The case was admitted with poor clinical presentations and the Glasgow Coma Scale of 6/15. The victim received all the standard supportive intensive care and gained complete clinical recovery. PMID- 25747959 TI - Extracorporeal photopheresis: Focus on therapeutic immunomodulation. PMID- 25747960 TI - Extracorporeal photopheresis for the treatment of Crohn's disease. AB - Small, open-label studies show promising results for ECP in the treatment of steroid-dependent and medically-refractory Crohn's disease. However, proper randomized, sham-controlled trials have not yet been performed. Based on the proposed mechanism of action of ECP, induction of a tolerogenic T cell response, ECP should be assessed in patients with early inflammatory disease rather than those who have progressed to fibrotic or stricturing disease. Randomized, sham controlled trials need to be performed before ECP can be incorporated into standard clinical practice for the treatment of Crohn's disease. PMID- 25747961 TI - Type 1 diabetes and gut microbiota: Friend or foe? AB - Type 1 diabetes is a T cell-mediated autoimmune disease. Environmental factors play an important role in the initiation of the disease in genetically predisposed individuals. With the improved control of infectious disease, the incidence of autoimmune diseases, particularly type 1 diabetes, has dramatically increased in developed countries. Increasing evidence suggests that gut microbiota are involved in the pathogenesis of type 1 diabetes. Here we focus on recent advances in this field and provide a rationale for novel therapeutic strategies targeting gut microbiota for the prevention of type 1 diabetes. PMID- 25747962 TI - Prenatal nicotinic exposure augments cardiorespiratory responses to activation of bronchopulmonary C-fibers. AB - Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 MUg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia. PMID- 25747963 TI - Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells. AB - Because of the many energy-demanding functions they perform and their physical location in the lung, alveolar epithelial type II (ATII) cells have a rapid cellular metabolism and the potential to influence substrate availability and bioenergetics both locally in the lung and throughout the body. A thorough understanding of ATII cell metabolic function in the healthy lung is necessary for determining how metabolic changes may contribute to pulmonary disease pathogenesis; however, lung metabolism is poorly understood at the cellular level. Here, we examine lactate utilization by primary ATII cells and the ATII model cell line, MLE-15, and link lactate consumption directly to mitochondrial ATP generation. ATII cells cultured in lactate undergo mitochondrial respiration at near-maximal levels, two times the rates of those grown in glucose, and oxygen consumption under these conditions is directly linked to mitochondrial ATP generation. When both lactate and glucose are available as metabolic substrate, the presence of lactate alters glucose metabolism in ATII to favor reduced glycolytic function in a dose-dependent manner, suggesting that lactate is used in addition to glucose when both substrates are available. Lactate use by ATII mitochondria is dependent on monocarboxylate transporter (MCT)-mediated import, and ATII cells express MCT1, the isoform that mediates lactate import by cells in other lactate-consuming tissues. The balance of lactate production and consumption may play an important role in the maintenance of healthy lung homeostasis, whereas disruption of lactate consumption by factors that impair mitochondrial metabolism, such as hypoxia, may contribute to lactic acid build-up in disease. PMID- 25747965 TI - The influence of orthographic depth on reading networks in simultaneous biliterate children. AB - Children in bilingual societies often simultaneously acquire reading skills in distinct writing systems that vary in consistency of sound-letter mapping or orthographic depth. To investigate its effect on cortical reading networks in children, we performed functional imaging on 34 simultaneous Hindi-English biliterate children as they read word and nonword stimuli. In contrast to Hindi which is consistent and relies on phonological assembly for both stimuli, English is inconsistent which necessitates lexical retrieval for words, but phonological assembly for nonwords. While children recruited a shared reading network for both languages, factorial analysis revealed stimulus effects (word/nonword) in bilateral frontal, parietal and left angular regions. Subsequent analyses showed that the stimulus effect was significant in English, which has a deep orthography, in comparison to Hindi, which is transparent. Our results provide novel evidence that orthographic depth shapes cortical reading processes during development. PMID- 25747966 TI - Influence of heart rate variability and psychosocial factors on carotid stiffness, elasticity and impedance at menopause. AB - BACKGROUND AND AIMS: The risk for cardiovascular diseases (CVD) increases after menopause. Heart rate variability (HRV), a measure of autonomic control, is a strong predictor of CVD. We undertook this study to test the association of ultrasound indices of early carotid atherosclerosis with HRV, symptoms, hormonal conditions, metabolic state, indicators of stress, and psychosocial factors in women at peri- and postmenopause, registering ambulatory R-R interval monitoring. METHODS: In a cross-sectional design we studied 100 women at peri- and early postmenopause collecting anthropometry, symptoms, stress-related measurements, metabolic variables, cortisol, FSH and estradiol. We evaluated carotid ultrasonographic indices, and HRV was recorded for 4 h calculating time (SDNN, pNN50, rMSSD) and frequency domains (LF, HF, LF/HF) in women according to menopausal stage, estradiol levels, body mass index and waist circumference. RESULTS: Carotid indices were similar in peri- and postmenopausal women. For HRV measurements, SDNN was increased at postmenopause. Women with estradiol levels <109.2 pmol/L had increased intima-media thickness (IMT), resistive index, and systolic diameter. Using multivariate analysis, we found the associations of IMT positively with non-HDL-cholesterol, resistive index positively with LF-HRV, but negatively with effort/reward imbalance, carotid beta stiffness index inversely with estradiol, and arterial distensibility positively with HF-HRV and creatinine concentrations, but negatively with non-HDL-cholesterol. CONCLUSIONS: Carotid thickness was related mainly with lipid alterations. Indices of early carotid damage were related with various components of HRV as a manifestation of autonomic imbalance, indicating CVD risk. Other factors involved were time since last menses and psychological stress. Low creatinine was associated with diminished carotid distensibility. This suggests that estrogen, lifestyle, behavior and autonomic regulation participate in vascular damage. PMID- 25747967 TI - Relapse after allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia: tyrosine kinase inhibitors, donor lymphocyte infusions or both? PMID- 25747964 TI - Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury. AB - Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-alpha-trypsin-inhibitor (IalphaI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IalphaI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca(2+), and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca(2+), blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca(2+) channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. PMID- 25747968 TI - Treatment of patients with secondary central nervous system lymphoma with high dose busulfan/thiotepa-based conditioning and autologous stem cell transplant. AB - Although the survival rates are extremely low for patients with secondary central nervous system lymphoma (SCNSL) treated with conventional chemotherapy and radiotherapy, more encouraging outcomes have recently been reported in small series with high-dose (HD) therapy and autologous stem cell transplant (ASCT). The optimal HD regimen for SCNSL is unknown. Despite reports of thiotepa/busulfan based conditioning for primary CNS lymphoma, very little data exist regarding the use of this regimen for SCNSL. We analyzed 23 patients with SCNSL (median age 62 years) who underwent ASCT at two Alberta centers using thiotepa, busulfan, cyclophosphamide (TBC) in six patients prior to 2011 and rituximab-busulfan, melphalan, thiotepa (R-BuMelTt) in 17 patients after 2011. At a median follow-up of 27.8 months (4.2-113.6), the 2-year actuarial rate of progression-free survival was 76.1%. In conclusion, our results demonstrate encouraging survival outcomes for patients with SCNSL treated with R-BuMelTt and ASCT. PMID- 25747969 TI - B-cell lymphoma with pseudopapillary features, myxoid changes and lack of CD20 expression: a diagnostic pitfall. PMID- 25747970 TI - Catalytic mammalian target of rapamycin inhibitors as antineoplastic agents. AB - The mammalian target of rapamycin (mTOR) pathway is a major therapeutic target in the treatment of hematological malignancies, as it controls cellular events of high importance for regulation of mRNA translation and protein production. Rapalogs, or first-generation mTOR inhibitors, have produced only modest clinical benefits so far. Limitations to rapalogs likely result from the partial inhibition of mTORC1 substrates and lack of effects on mTORC2. Efforts toward the development of agents with more potent and complete inhibitory effects on the mTOR pathway have resulted in the development of catalytic mTOR inhibitors. Key preclinical and early clinical investigations of several catalytic mTOR inhibitors and potential resistance mechanisms to their activities are summarized here. PMID- 25747971 TI - A modified international prognostic index including pretreatment hemoglobin level for early stage extranodal natural killer/T cell lymphoma. AB - In this study, we investigated the prognostic role of pretreatment hemoglobin level in 321 patients with stage I/II extranodal natural killer (NK/T cell lymphoma (ENKTL). Patients with pretreatment hemoglobin level < 120 g/L had significantly inferior progression-free survival (PFS) and overall survival (OS) than those with hemoglobin level >= 120 g/L (p < 0.05). In a multivariate Cox regression model, age, Eastern Cooperative Oncology Group (performance status), lactate dehydrogenase level, Ann Arbor stage and pretreatment hemoglobin level were all independent prognostic factors for PFS and OS (p < 0.05). Using these five parameters, a modified international prognostic index (mIPI) model was constructed. This mIPI could categorize three groups with significantly different PFS and OS (both p < 0.0001) in both the training set and the validation set. In conclusion, this study confirmed the prognostic role of pretreatment hemoglobin level in ENKTL, and a newly modified IPI including pretreatment hemoglobin level could be used to further optimize treatments for patients with stage I/II ENKTL, especially in the era of asparaginase. PMID- 25747972 TI - Clinicopathologic features and management of blastoid variant of mantle cell lymphoma. AB - The blastoid variant of mantle cell lymphoma (MCL), which accounts for less than one-third of MCL, may arise de novo or as a transformation from the classical form of MCL. Blastoid variant, which predominantly involves men in their sixth decade, has frequent extranodal involvement (40-60%), stage IV disease (up to 85%) and central nervous system (CNS) involvement. Diagnosis relies on morphological features and is challenging. Immunophenotyping may display CD23 and CD10 positivity and CD5 negativity in a subset. Genetic analysis demonstrates an increased number of complex genetic alterations. Blastoid variant responds poorly to conventional chemotherapy and has a short duration of response. Although the optimal therapy remains to be established, CNS prophylaxis and the use of aggressive immunochemotherapy followed by autologous stem cell transplant may prolong the remission rate and survival. Further studies are crucial to expand our understanding of this disease entity and improve the clinical outcome. PMID- 25747973 TI - Soluble CD163 as a prognostic biomarker in B-cell chronic lymphocytic leukemia. PMID- 25747974 TI - Reducing the onset of negative affect in adolescents: evaluation of a perfectionism program in a universal prevention setting. AB - OBJECTIVE: The aim of the current study was to evaluate a prevention program targeting unhelpful perfectionism and self-compassion, designed to prevent growth of negative affect (NA). METHOD: Four schools participated in the research, where grade levels were allocated to either the intervention ("Healthy Minds") or the control condition (N = 688 individuals; mean age 14.90 years), and assessments occurred at baseline, post-intervention, and 6- and 12-month follow-up. RESULTS: There were no significant between group differences at post-intervention but at 6 month follow-up the intervention group had significantly lower unhelpful perfectionism, self-criticism and NA than the controls. Only significant between group differences in unhelpful perfectionism were retained at 12-month follow-up (Cohen's d = .24). Examination of the sub-group lower in NA at baseline showed the intervention group was significantly less likely to have elevated NA at 6 month follow-up than controls, indicating a prevention effect. DISCUSSION: The effects obtained in the current study provide support for the utility of a perfectionism intervention for reducing transdiagnostic outcomes, including unhelpful perfectionism, self-judgment, and NA, and preventing the growth of NA. Ways of producing longer terms effects for NA need to be further investigated, as does the impact of the intervention on different types of psychopathology. TRIAL REGISTRATION: ACTRN12614000650695. PMID- 25747975 TI - Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 as important regulators of the pharmacokinetics of substrate drugs. AB - Nobody doubts the importance of organic anion transporting polypeptide (OATP)1B1 and 1B3 in the clinical pharmacokinetics of substrate drugs. Based on the theory of pharmacokinetics, even if a drug is eliminated from the body by extensive metabolism, the rate-determining process of the hepatic intrinsic clearance of OATP substrates is often hepatic uptake. Because of their broad substrate specificities, once the functions of OATP1B1 or OATP1B3 are altered by several kinds of special occasions such as drug-drug interactions (DDI) and genetic polymorphisms of transporter genes, the hepatic clearance of many kinds of structurally-unrelated drugs is expected to be changed. In some cases, these alterations of pharmacokinetics lead to modified pharmacological effects and adverse reactions such as statin-induced myotoxicity and the glucose-lowering effect of anti-diabetes drugs. Thus, appropriate methods with which to quantitatively predict the changes in plasma and tissue concentrations of drugs are needed in the process of drug development. As for DDI, a static model that takes into consideration of the theoretically-maximum unbound inhibitor concentration is often used for the sensitive detection of possible DDI risks and this method has been adopted in several regulatory guidance/guidelines on DDI. Regarding genetic polymorphisms, the effects of SLCO1B1 c.388A>G and c.521T>C on the pharmacokinetics of substrate drugs have been extensively investigated. Even though there are some discrepancies, c.521T>C generally decreased hepatic uptake activity, while c.388A>G tended to slightly increase it. This article briefly summarizes the current status of research on hepatic OATP1B1 and OATP1B3 and the clinical significance of their functions. PMID- 25747976 TI - Rebamipide attenuates 5-Fluorouracil-induced small intestinal mucositis in a mouse model. AB - 5-Fluorouracil (5-FU)-induced intestinal mucositis is one of the most common morbidities in chemotherapy and involves the reactive oxygen species (ROS) system, apoptosis, and inflammatory cytokines. Rebamipide exerts a mucosal protective effect, mediated through several mechanisms. The aim of this study was to evaluate the effects of rebamipide in 5-FU-induced mouse small-intestinal mucositis. BALB/c mice were assigned randomly to four groups; (1) control group (n=10; receiving saline orally for 6 d), (2) rebamipide group (n=10; 150 mg/kg rebamipide for 6 d orally), (3) 5-FU group (n=10; 30 mg/kg 5-FU for 5 d, intraperitoneally (i.p.)), and (4) rebamipide +5-FU group (n=10; 150 mg/kg rebamipide for 6 d orally and 30 mg/kg 5-FU for 5 d, i.p.). Body weights and diarrhea scales were assessed. At day 5, the mice were sacrificed. Small intestinal tissue was used for: (1) hematoxylin and eosin (HE) staining for determination of small intestinal villi height, (2) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, (3) immunohistochemistry for inducible nitric oxide synthase (iNOS), F4/80, and transforming growth factor (TGF)-beta1, (4) measurement of serum and tissue GSH levels, and (5) measurement of serum tumor necrosis factor (TNF)-alpha levels. Rebamipide attenuated the severity of mucosal injury reflected by body weight changes, degrees of diarrhea, and heights of villi. Rebamipide reduced the expression of iNOS and TGF-beta1, apoptosis, macrophage accumulation, serum TNF alpha levels, and prevented reductions in serum and tissue glutathione (GSH) levels by 5-FU administration. These results suggest that rebamipide promotes several mechanisms of mucosal protection and attenuated the 5-FU-induced mucosal injury. In conclusion, administration of rebamipide may have significant protective effects against 5-FU-induced intestinal mucositis. PMID- 25747977 TI - Tacrine, an oral acetylcholinesterase inhibitor, induced hepatic oxidative damage, which was blocked by liquiritigenin through GSK3-beta inhibition. AB - Although the cholinesterase inhibitor tacrine has been successfully used for the treatment of Alzheimer's disease, it is known to have hepatotoxic effects. Liquiritigenin (LQ), an active flavonoid in Glycyrrhizae radix, exerts protective effects against liver damage. This study investigated the toxic effect of tacrine on hepatocytes and the beneficial effect of LQ on tacrine intoxication in vivo and in vitro, and the underlying mechanism involved. In hepatocyte cell lines, tacrine induced cell death and oxidative stress, as indicated by decreases in cell viability and glutathione (GSH) contents, which were blocked by pretreatment with LQ. Fluorescent activated cell sorter (FACS) analysis revealed that LQ inhibited cellular H2O2 production and mitochondrial dysfunction induced by tacrine in HepG2 cells. Furthermore, LQ promoted inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3beta) and prevented decreases in GSK3beta phosphorylation induced by tacrine. In rats treatment with tacrine at 30 mg/kg increased hepatic damage as assessed by blood biochemistry and histopathology. Administration of LQ (10 or 30 mg/kg/d, per os (p.o.)) or the hepatoprotective drug sylimarin (100 mg/kg/d) for 3 d inhibited elevations in alanine aminotransferase, aspartate aminotransferase, and histological changes induced by tacrine. These results show that LQ efficaciously protects the rat liver against tacrine-induced liver damage, and suggest that LQ is a therapeutic candidate for ameliorating the hepatotoxic effects of tacrine. PMID- 25747978 TI - The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice. AB - Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing alpha-smooth muscle actin (alpha-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing alpha-SMA, HSP 47, phospho Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression. PMID- 25747979 TI - Enhanced oral bioavailability of morin administered in mixed micelle formulation with PluronicF127 and Tween80 in rats. AB - To overcome the low oral bioavailability of morin, a mixed micelle formulation with pharmaceutical excipients that facilitate solubilization and modulate P glycoprotein (P-gp) was developed and evaluated in vitro and in vivo rats. Morin loaded mixed micelle formulation with a morin-PluronicF127-Tween80 ratio of 1 : 10 : 0.02 (w/w/w) was prepared by a thin-film hydration method. The solubility, size distribution, drug encapsulation efficiency, and percent drug loading of the formulation were characterized. Subsequently, in vivo pharmacokinetic parameters of morin loaded in a PluronicF127 and Tween80 mixed-micelle formulation were investigated in rats. Absolute bioavailability of morin was dramatically increased by the oral administration of morin-loaded PluronicF127 and Tween80 mixed micelle from 0.4% to 11.2% without changing the systemic clearance and half life. In Caco-2 cells, absorption permeability of morin from the novel formulation was increased 3.6-fold compared with that of morin alone. P-gp inhibition by cyclosporine A (CsA) increased absorptive permeability of morin 2.4 fold but decreased the efflux of morin by 52%, which was consistent with increased plasma concentration of morin in the pretreatment of CsA in rats. The morin formulation inhibited P-gp transport activity by 83.1% at 100 uM as morin concentration. Moreover, morin formulation increased paracellular permeability of Lucifer yellow by 1.6-1.8 fold. In conclusion, enhanced oral bioavailability of morin from morin-loaded PluronicF127 and Tween80 mixed micelle formulation can be attributed to increased intestinal permeation of morin, which was mediated at least by P-gp inhibition and enhanced paracellular route. PMID- 25747980 TI - Pharmacokinetics, tissue distribution, and tentative metabolite identification of sauchinone in mice by microsampling and HPLC-MS/MS methods. AB - Sauchinone, a biologically active lignan found in Saururus chinensis (Saururaceae), exerts various biological activities against jaundice, inflammatory disease, hepatic steatosis, and oxidative injury. Despite its diverse applications, there exists some information about sauchinone's pharmacokinetics but its tissue distribution, metabolism, and tentative metabolites have not been reported yet. Thus we investigated the pharmacokinetics of sauchinone in mice using microsampling and HPLC-MS/MS methods. Sauchinone presented linear pharmacokinetics at intravenous doses 7.5-20 mg/kg and oral doses 20-500 mg/kg. However, the metabolism of sauchinone was saturated and this agent presented nonlinear pharmacokinetics at 50 mg/kg in the intravenous study. At sauchinone 20 mg/kg the F of sauchinone was 7.76% of the oral dose despite that 77.9% of sauchinone was absorbed. This might be due to extensive metabolism of sauchinone in S9 fractions of liver and small intestine. Tentative metabolites of sauchinone by oxidation, dioxidation, methylation, demethylation, dehydrogenation, or bis-glucuronide conjugation were detected in plasma and S9 fractions of liver, intestine, and kidney. The distribution of sauchinone was considerably high (tissue-to-plasma (T/P) ratios, >1) in liver, small intestine, kidney, lung, muscle, fat, or mesentery after intravenous and oral administration and in stomach and large intestine only after oral administration. The protein binding value of sauchinone was 53.0%. These pharmacokinetic data of sauchinone provide an important basis for preclinical applications and experimental methods can be adjusted to evaluate the pharmacokinetics of natural products in mice. PMID- 25747981 TI - Antifibrotic compounds from Liriodendron tulipifera attenuating HSC-T6 proliferation and TNF-alpha production in RAW264.7 cells. AB - The inhibition of hepatic stellate cell (HSC) proliferation has been considered as an effective therapeutic target for the treatment of liver fibrosis. The methanolic extract of Liriodendron tulipifera showed significant inhibitory activity against the proliferation of HSCs. Bioactivity-guided isolation afforded twelve compounds including (-)-sesamin (1), (-)-syringaresinol (2), (+) dihydrodehydrodiconiferyl alcohol (3), salvinal (4), (+)-guaiacylglycerol-8-O-4' dihydroconiferyl ether (5), (+/-)-guaiacylglycerol-8-O-4'-sinapyl alcohol ether (6), tanegool (7), (+)-5,5'-dimethoxy-7-oxolariciresinol (8), 3-hydroxy-4 methoxyacetophenone (9), 4-acetoxymethylphenol (10), (-)-paramicholide (11), and blumenol A (12). Among the compounds isolated, 2, 3 and 4 significantly attenuated the proliferation of the activated HSC-T6 cells. The maximal dose of these compounds, however, showed no cytotoxicity in primary cultured rat hepatocytes. Collagen deposition in the activated HSC-T6 cells was reduced by 2, 3 and 4. Also, the increased production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha induced by lipopolysaccharide was decreased by 3 and 4 in RAW264.7 macrophage cells. Collectively, (-)-syringaresinol (2), (+) dihydrodehydrodiconiferyl alcohol (3), and salvinal (4) isolated from L. tulipifera leaves and twigs exhibited selective antifibrotic activities toward the activated HSCs and suppressed TNF-alpha production in RAW264.7 macrophages. These compounds may be useful candidates for developing therapeutic agents for the prevention and treatment of hepatic fibrosis. PMID- 25747982 TI - Risk factors for ganciclovir-induced thrombocytopenia and leukopenia. AB - Ganciclovir is a nucleoside guanosine analogue that exhibits therapeutic activity against human cytomegalovirus infection, and is primarily excreted via glomerular filtration and active tubular secretion. The adverse effects induced by ganciclovir therapy are generally of a hematological nature and include thrombocytopenia and leukopenia. Low marrow cellularity and elevated serum creatinine have been identified as risk factors for ganciclovir-induced neutropenia. However, the risk factors for thrombocytopenia have yet to be determined. Therefore, this study investigated patients administered ganciclovir to determine the risk factors for thrombocytopenia and leukopenia. Thrombocytopenia occurred in 41 of these patients (30.6%). Multivariate logistic regression analysis identified three independent risk factors for thrombocytopenia: cancer chemotherapy (odds ratio (OR)=3.1), creatinine clearance (<20 mL/min) (OR=12.8), and the ganciclovir dose (>=12 mg/kg/d) (OR=15.1). Leukopenia occurred in 36 patients (28.6%), and white blood cell count (<6000 cells/mm(3)) (OR=3.7) and the ganciclovir dose (>=12 mg/kg/d) (OR=7.8) were identified as risk factors. These results demonstrated that several factors influenced the occurrence of ganciclovir-induced thrombocytopenia and leukopenia, and suggest that special attention should be paid to patients receiving cancer chemotherapy with a low creatinine clearance (<20 mL/min) and high dose (>=12 mg/kg/d) in order to avoid ganciclovir-induced thrombocytopenia. PMID- 25747983 TI - Prevention of postoperative fatigue syndrome in rat model by ginsenoside Rb1 via down-regulation of inflammation along the NMDA receptor pathway in the hippocampus. AB - Postoperative fatigue syndrome (POFS) is a common complication which decelerates recovery after surgery. The present study investigated the anti-fatigue effect of ginsenoside Rb1 (GRb1) through the inflammatory cytokine-mediated N-methyl-D aspartate (NMDA) receptor pathway. A POFS rat model was created by major small intestinal resection and assessed with an open field test. Real-time quantitative polymerase chain reaction, western blot analysis, high performance liquid chromatography and a transmission electron microscopic analysis were used to determine typical biochemical parameters in the hippocampus. Our results showed that POFS rats exhibited fatigue associated with an increased expression of inflammatory cytokines and NMDA receptor 1, higher (kynurenine)/(tryptophan) and (kynurenine)/(kynurenic acid) on postoperative days 1 and 3, and an increased expression of indoleamine 2,3-dioxygenase (IDO) on postoperative day 1. Degenerated neurons were found in the hippocampus of POFS rats. The NMDA receptor antagonist MK801 had a significant effect on central fatigue on postoperative day 1. GRb1 had no effect on IDO or tryptophan metabolism, but exhibited a significant effect on POFS by inhibiting the expression of inflammatory cytokines and NMDA receptor 1. These data suggested that inflammatory cytokines could activate tryptophan metabolism to cause POFS through the NMDA receptor pathway. GRb1 had an anti-fatigue effect on POFS by reducing inflammatory cytokines and NMDA receptors. PMID- 25747984 TI - Involvement of cationic amino acid transporter 1 in L-arginine transport in rat retinal pericytes. AB - Nitric oxide (NO), a known relaxant, is produced in cells from L-arginine (L Arg). Because the relaxation of retinal pericytes alters the microcirculatory hemodynamics, it is important to understand the manner of NO production in retinal pericytes. The purpose of this study was to clarify the molecular mechanism(s) of uptake of L-Arg in retinal pericytes using a conditionally immortalized rat retinal pericyte cell line (TR-rPCT1 cells) which expresses the mRNAs of endothelial NO synthase and inducible NO synthase. L-Arg uptake by TR rPCT1 cells exhibited Na(+)-independence and concentration-dependence with a Km of 28.9 uM. This process was strongly inhibited by substrates of cationic amino acid transporters (CAT), such as L-ornithine and L-lysine. In contrast, L-valine, L-leucine, and L-glutamine, which are substrates of cation/neutral amino acid transport systems, such as system y(+)L, system B(0,+), and system b(0,+), did not strongly inhibit L-Arg uptake by TR-rPCT1 cells. In addition, the expression of mRNA and protein of CAT1 in TR-rPCT1 cells was observed by reverse transcription-polymerase chain reaction and immunoblot analyses. Taking these results into consideration, it appears that CAT1 is involved in L-Arg uptake by retinal pericytes and this is expected to play an important role in the relaxation of retinal pericytes, thereby modulating the microcirculatory hemodynamics in the retina. PMID- 25747986 TI - Efficient delivery to human lung fibroblasts (WI-38) of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor and its inhibitory effect on collagen synthesis in idiopathic pulmonary fibrosis. AB - In the present in vitro study, we assessed the delivery of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor (tbFGF) to lung fibroblasts and investigated the anti-fibrotic effect of the drug. The tbFGF peptide, KRTGQYKLC, was used to modify the surface of liposomes (tbFGF-liposomes). We used the thin-layer evaporation method, followed by sonication, to prepare tbFGF-liposomes containing pirfenidone. The cellular accumulation of tbFGF-liposomes was 1.7-fold greater than that of non-modified liposomes in WI-38 cells used as a model of lung fibroblasts. Confocal laser scanning microscopy showed that tbFGF-liposomes were widely localized in WI-38 cells. The inhibitory effects of pirfenidone incorporated into tbFGF-liposomes on transforming growth factor-beta1 (TGF-beta1)-induced collagen synthesis in WI-38 cells were evaluated by measuring the level of intracellular hydroxyproline, a major component of the protein collagen. Pirfenidone incorporated into tbFGF liposomes at concentrations of 10, 30, and 100 uM significantly decreased the TGF beta1-induced hydroxyproline content in WI-38 cells. The anti-fibrotic effect of pirfenidone incorporated into tbFGF-liposomes was enhanced compared with that of pirfenidone solution. These results indicate that tbFGF-liposomes are a useful drug delivery system of anti-fibrotic drugs to lung fibroblasts for the treatment of idiopathic pulmonary fibrosis. PMID- 25747985 TI - Pharmacological characterization of [trans-5'-(4-amino-7,7-dimethyl-2 trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3' dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate (JTT 553), a novel acyl CoA:diacylglycerol transferase (DGAT) 1 inhibitor. AB - Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the final step in triglyceride (TG) synthesis. This enzyme is considered to be a potential therapeutic target for obesity and diabetes. Here, results of an investigation of the pharmacological effects of JTT-553 [trans-5'-(4-amino-7,7 dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3' dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate, a novel DGAT1 inhibitor, are reported. To measure the inhibitory activity of JTT 553 against DGAT1, TG synthesis using [(14)C]-labeled oleoyl-CoA was evaluated. Similarly, the inhibitory activity of JTT-553 against DGAT2, an isozyme of DGAT1, and acyl-CoA cholesterol acyltransferase (ACAT) 1, which is highly homologous to DGAT1, were evaluated. JTT-553 selectively inhibited human DGAT1 and showed comparable inhibitory effects on the activity of human, rat, and mouse DGAT. In vivo, JTT-553 suppressed plasma TG and chylomicron TG levels after olive oil loading in Sprague-Dawley (SD) rats. JTT-553 also inhibited TG synthesis in epididymal fat after [(14)C] oleic acid injection in C57BL/6J mice. Food intake was evaluated in SD rats fed 3.1%, 13%, or 35% (w/w) fat diets. In rats fed the 35% fat diet, JTT-553 reduced food intake. This reduction of food intake was observed 2 h after feeding, lasted for 24 h, and correlated with dietary fat content. Furthermore, JTT-553 reduced daily food intake and body weight gain in diet-induced obese rats after 4-week repeated administration. JTT-553 exerted multiple effects on intestinal fat absorption, adipose fat synthesis, and food intake, and consequently induced body weight reduction. Therefore, JTT-553 is expected to be an effective novel therapeutic agent for the treatment of obesity. PMID- 25747987 TI - Icariin enhances cytotoxicity of doxorubicin in human multidrug-resistant osteosarcoma cells by inhibition of ABCB1 and down-regulation of the PI3K/Akt pathway. AB - Multidrug resistance is one of the major causes limiting the efficacy of chemotherapeutic agents used to control osteosarcoma. Multidrug resistance protein 1 (MDR1 or ABCB1) was considered to play a critical role in multidrug resistance. Agents from traditional Chinese medicines (TCMs) have great potential to prevent the onset or delay the progression of the carcinogenic process, and also to enhance the efficacy of mainstream antitumor agents. Herein, we investigated the effect and mechanism of icariin in the human osteosarcoma doxorubicin (DOX)-resistant cell line MG-63/DOX. In this study, icariin exhibited significant effects in sensitization of the resistant cancer cells at a concentration non-toxic to doxorubicin. It also increased the intracellular doxorubicin accumulation and retention in MG-63/DOX cells. In addition, an increase in Rh123 accumulation and a decrease in Rh123 efflux were observed in MG 63/DOX cells treated with icariin, indicating a blockage of the activity of MDR1. Furthermore, icariin enhanced the apoptosis induced by doxorubicin and down regulated the expression of MDR1. The mechanism involves the inhibition of phosphatidyl inositol 3-kinase (PI3K)/Akt signaling. In conclusion, icariin possesses a reversal effect on multidrug resistance in MG-63/DOX cells through down-regulation of the MDR1 and the PI3K/Akt pathway, and has the potential to be an adjunct to chemotherapy for osteosarcoma. PMID- 25747988 TI - Pharmacokinetics and brain distribution of tetrahydropalmatine and tetrahydroberberine after oral administration of DA-9701, a new botanical gastroprokinetic agent, in rats. AB - DA-9701, a new botanical gastroprokinetic agent, has potential for the management of delayed gastric emptying in Parkinson's disease if it has no central anti dopaminergic activity. Therefore, we examined the pharmacokinetics of DA-9701 components having dopamine D2 receptor antagonizing activity, tetrahydropalmatine (THP) and tetrahydroberberine (THB), following various oral doses (80-328 mg/kg) of DA-9701. The distribution of THP and THB to the brain and/or other tissues was also evaluated after single or multiple oral administrations of DA-9701. Oral administration of DA-9701 yielded dose-proportional area under the plasma concentration-time curve (AUC0-8 h) and maximum plasma concentration (Cmax) values for THP and THB, indicating linear pharmacokinetics (except for THB at the lowest dose). THP and THB's large tissue-to-plasma concentration ratios indicated considerable tissue distribution. High concentrations of THP and THB in the stomach and small intestine suggest an explanation for DA-9701's potent gastroprokinetic activity. The maximum concentrations of THP and THB in brain following multiple oral DA-9701 for 7 d (150 mg/kg/d) was observed at 30 min after the last oral DA-9701 treatment: 131+/-67.7 ng/g for THP and 6.97+/-4.03 ng/g for THB. Although both THP and THB pass through the blood-brain barrier, as indicated by brain-to-plasma concentration ratios greater than unity (approximately 2-4), oral administration of DA-9701 at the effective dose in humans is not expected to lead to sufficient brain concentrations to exert central dopamine D2 receptor antagonism. PMID- 25747989 TI - Carboxylesterase 1-mediated drug-drug interactions between clopidogrel and simvastatin. AB - Patients with coronary artery disease often receive concurrent treatment with clopidogrel and a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor medication. Accordingly, potential drug-drug interactions associated with the concomitant use of these agents present an area of concern. Both CYP enzymes and carboxylesterase 1 (CES1) are involved in the metabolism of clopidogrel, while CES1 is believed to be the enzyme responsible for the activation of simvastatin. Some in vitro studies have suggested that simvastatin could attenuate clopidogrel activation via inhibiting CYP3A activity. However, these findings have not found support in several recently published clinical investigations. The present study addresses these inconsistencies by exploring the potential role of CES1 in the metabolism of clopidogrel and simvastatin. Our in vitro human liver s9 fraction incubation study demonstrated that simvastatin significantly enhanced the formation of the intermediate metabolite 2-oxo-clopidogrel, and inhibited the CES1-mediated hydrolysis of clopidogrel, 2-oxo-clopidogrel, and the active metabolite. However, the production of the active metabolite remained unchanged. Conversely, clopidogrel was not found to influence the CES1 mediated hydrolysis (activation) of simvastatin. Moreover, we provided evidence that CES1 is not an efficient enzyme for catalyzing simvastatin activation. In summary, the inhibitory effect of simvastatin on the hydrolysis of clopidogrel and its principal metabolites may have offset the influence of simvastatin-mediated inhibition of CYP3A, and permitted the unaltered formation of the clopidogrel active metabolite. These data help explain the conflicting accounts in previous reports regarding clopidogrel and simvastatin interactions by taking into consideration CES1; they suggest that the interactions are unlikely to significantly influence clinical outcomes. PMID- 25747990 TI - Characterization of the enzymatic and structural properties of human D-aspartate oxidase and comparison with those of the rat and mouse enzymes. AB - D-Aspartate (D-Asp), a free D-amino acid found in mammals, plays crucial roles in the neuroendocrine, endocrine, and central nervous systems. Recent studies have implicated D-Asp in the pathophysiology of infertility and N-methyl-D-Asp receptor-related diseases. D-Asp oxidase (DDO), a degradative enzyme that is stereospecific for acidic D-amino acids, is the sole catabolic enzyme acting on D Asp in mammals. Human DDO is considered an attractive therapeutic target, and DDO inhibitors may be potential lead compounds for the development of new drugs against the aforementioned diseases. However, human DDO has not been characterized in detail and, although preclinical studies using experimental rodents are prerequisites for evaluating the in vivo effects of potential inhibitors, the existence of species-specific differences in the properties of human and rodent DDOs is still unclear. Here, the enzymatic activity and characteristics of purified recombinant human DDO were analyzed in detail. The kinetic and inhibitor-binding properties of this enzyme were also compared with those of purified recombinant rat and mouse DDOs. In addition, structural models of human, rat, and mouse DDOs were generated and compared. It was found that the differences among these DDO proteins occur in regions that appear involved in migration of the substrate/product in and out of the active site. In summary, detailed characterization of human DDO was performed and provides useful insights into the use of rats and mice as experimental models for evaluating the in vivo effects of DDO inhibitors. PMID- 25747991 TI - CCL17 production by mouse langerhans cells stimulated with Staphylococcus aureus cell wall components. AB - Patients with atopic dermatitis (AD) show increased numbers of Th2 cells in their acute skin lesions and superficial skin colonization by Staphylococcus aureus. The purpose of this study was to clarify the effect of S. aureus cell wall components on Th2 chemokine production by murine Langerhans cells (LCs). Murine LCs were stimulated with peptidoglycan (PEG) and/or muramyldipeptide (MDP) for 24 or 48 h, and Th1 and Th2 chemokine production was investigated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). PEG-stimulation of LCs induced production of the Th2 chemokine CCL17 and this was enhanced in the presence of interleukin (IL)-4. A low molecular weight PEG fragment, MDP, did not induce CCL17 production by LCs. However, when LCs were stimulated with PEG in combination with MDP, PEG-induced CCL17 production was synergistically enhanced by MDP. Furthermore, PEG- and MDP induced CCL17 production was enhanced to a greater extent in the presence of IL 4. These results suggest that S. aureus colonization in AD patients may enhance the Th2-prone immune response through upregulation of CCL17 production by LCs, which would occur as a result of simultaneous stimulation with PEG and MDP from S. aureus in a Th2 environment. PMID- 25747993 TI - Biotransformation of (-)-epigallocatechin and (-)-gallocatechin by intestinal bacteria involved in isoflavone metabolism. AB - Four isoflavone-metabolizing bacteria were tested for their abilities to degrade (-)-epigallocatechin (EGC) and its isomer (-)-gallocatechin (GC). Biotransformation of both EGC and GC was observed with Adlercreutzia equolifaciens JCM 14793, Asaccharobacter celatus JCM 14811, and Slackia equolifaciens JCM 16059, but not Slackia isoflavoniconvertens JCM 16137. With respect to the degradation of EGC, strain JCM 14793 only catalyzed 4' dehydroxylation to produce 4'-dehydroxylated EGC (7). Strain JCM 14811 mainly produced 7, along with a slight formation of the C ring-cleaving product 1-(3,4,5 trihydroxyphenyl)-3-(2,4,6-trihydroxyphenyl)propan-2-ol (1). Strain JCM 16059 catalyzed only C ring cleavage to form 1. Interestingly, the presence of hydrogen promoted the bioconversion of EGC by these bacteria. In addition, strain JCM 14811 revealed the ability to catalyze 4'-dehydroxylation of 1 to yield 1-(3,5 dihydroxyphenyl)-3-(2,4,6-trihydroxyphenyl)propan-2-ol (2) in the presence of hydrogen. In the case of GC, strain JCM 14793 mainly produced C ring-cleaving product (1) with only a very small amount of 4'-dehydroxylated GC (8), while Strain JCM 14811 only catalyzed 4'-dehydroxylation to form 8. Strain JCM 16059 formed 1. The bioconversion of GC by the three strains was stimulated by hydrogen. Strain JCM 14793 showed the ability to convert 1 into 2 in the presence of hydrogen as did strain JCM 14811. Furthermore, strains JCM 14793 and JCM 14811 were found to have the ability to catalyze p-dehydroxylation of the pyrogallol moiety in the EGC metabolites 4-hydroxy-5-(3,4,5-trihydroxyphenyl)valeric acid (3) and 5-(3,4,5-trihydroxyphenyl)-gamma-valerolactone (4), and this ability was enhanced by the presence of hydrogen. PMID- 25747992 TI - Preventive effects of rapamycin on inflammation and capillary degeneration in a rat model of NMDA-induced retinal injury. AB - Inhibitors of the mammalian target of rapamycin (mTOR) have been shown to protect against neuronal injury, but the mechanisms underlying this effect are not fully understood. The present study aimed to examine the effects of rapamycin, an inhibitor of the mTOR pathway, on inflammation and capillary degeneration in a rat model of N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity. Inflammation and capillary degeneration were evaluated by counting the numbers of CD45-positive leukocytes and Iba1-positive microglia, and by measuring the length of empty basement membrane sleeves, respectively. Marked increases in the numbers of leukocytes and microglia were observed 1 d after intravitreal injection of NMDA (200 nmol), and significant capillary degeneration was observed after 7 d. These NMDA-induced changes were significantly reduced by the simultaneous injection of rapamycin (20 nmol) with NMDA. These results suggest that rapamycin has preventive effects on inflammation and capillary degeneration during retinal injury. PMID- 25747994 TI - Anti-stress effects of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol in immobilized mice. AB - Panax ginseng C.A. MEYER (Araliaceae), which contains ginsenosides as its main components, has been shown to have various biological effects, including anti inflammatory, anxiolytic, anti-stress, and anti-tumor effects. Orally administered ginsenoside Rb1 and Re are metabolized to 20(S)-protopanaxadiol (PPD) and compound K via ginsenoside Rd and 20(S)-protopanaxatriol (PPT) and ginsenoside Rh1 via ginsenoside Rg1 by gut microbiota, respectively. Therefore, we investigated the anti-stress effects of these metabolites, PPD and PPT, by measuring their anxiolytic and anti-inflammatory effects in immobilized mice. Treatment with PPD and PPT prior to immobilization stress increased the time spent in open arms and open arm entries in the elevated plus-maze (EPM) test. The anxiolytic effects of PPD (10 mg/kg) and PPT (10 mg/kg) were comparable to that of buspirone (1 mg/kg). This observed anxiolytic effect of PPD was significantly blocked by flumazenil or bicuculline, and the effect of PPT was blocked by WAY 100635. Treatment with PPD also potently suppressed immobilization stress-induced serum levels of corticosterone and interleukin (IL)-6 by the enzyme-linked immunosorbent assay. However, PPT treatment did not suppress them. Based on these findings, PPD and PPT may exhibit the anxiolytic effect via gamma-aminobutyrateA (GABAA) receptor(s) and serotonergic receptor(s), respectively, and PPD may have an anti-inflammatory effect that is more potent than that of PPT. PMID- 25747995 TI - Quantitative analysis of methylglyoxal, glyoxal and free advanced glycation end products in the plasma of Wistar rats during the oral glucose tolerance test. AB - The purpose of this study was to gain insight into the production behavior of free adducts of advanced glycation end-products (AGEs) in Wistar rats under acute hyperglycemic conditions. Five AGE-free adducts as well as their precursors (i.e., highly reactive carbonyl intermediates of methylglyoxal and glyoxal) in rat plasma were quantitatively determined at greater than nanomolar levels using the liquid chromatography/tandem mass spectrometry method coupled with 2,4,6 trinitrobenzene sulfonate and 2,3-diaminonaphthalene derivatization techniques. An oral glucose (2 g/kg dose) tolerance test to 10-week-old Wistar rats provided evidence that the plasma levels of diabetes-related metabolites did not change acutely within 120 min, irrespective of increasing blood glucose levels. PMID- 25747996 TI - Metabolic syndrome in adolescents with severe mental disorders: Retrospective study from a psychiatry inpatient unit. PMID- 25747998 TI - The Research Registry - answering the call to register every research study involving human participants. PMID- 25747997 TI - The effect of six months of elastic band resistance training, nutritional supplementation or cognitive training on chromosomal damage in institutionalized elderly. AB - Increased DNA and chromosomal damage are linked to aging and age-related diseases like cardiovascular diseases, diabetes or cancer. Physical activity and an optimal status of micro- and macronutrients are known to reduce the incidence of MN, a marker for chromosomal instability and mutagenicity. Once older people reach a certain age they change from a home-living situation to an institutionalized situation, which is often accompanied by malnutrition, depression and inactivity. We conducted the current study to investigate the effect of a six month progressive resistance training (RT), with or without protein and vitamin supplementation (RTS) or cognitive training (CT) only, on chromosomal damage measured by the cytokinesis block micronucleus cytome assay in 97 Austrian institutionalized women and men (65-98years). All three intervention groups demonstrated a tendency of a reduced frequency of cells with MN (-15%) as well as for the total number of MN (-20%), however no significant time-effect was observed. Besides a significant increase in plasma B12 and red blood cell folate status, the six month change of B12 was negatively correlated with the six month change of the MN frequency in the RTS group (r=-0.584, p=0.009). Our results suggest that in this age group either physical or cognitive training may result in similar biochemical changes and therefore enhance resistance against genomic instability. Supplementation with the vitamins B12 and folic acid could contribute to reduced chromosomal damage in institutionalized elderly. PMID- 25747999 TI - Comparison of ferromagnetic induction and bipolar electrosurgery and suction in corticotomies in pig cerebrum. AB - INTRODUCTION: The effects of newer energy-based surgical dissection and coagulation modalities on cerebral tissue have not been investigated. Several instruments have been developed to address the limitations of traditional electrosurgical instruments in the nervous system. We compared the effects of standard bipolar electrocautery and suction (BPS) with those of a new ferromagnetic induction (FMI) device in corticotomies of pig cerebral tissue as assessed by magnetic resonance imaging (MRI) and histological analysis. METHODS: Three adult pigs underwent bilateral corticotomies (3 cm long*1 cm deep) using both FMI and BPS. The acute cerebral tissue edema created by each method was measured on coronal volumetric T2-weighted MRI sequences immediately after surgery. A lateral thermal "damage index" was calculated by dividing the width of the visible T2 tissue edema by the measured depth. The radiographic damage indices with each method were compared statistically. Histological analysis of each incision was conducted to compare the extent of tissue damage. RESULTS: MRI showed that the mean radiographic damage index of each corticotomy was significantly lower with the FMI (0.30 +/- 0.02 (0.28-0.32)) than with the BPS method (0.54 +/- 0.11 (0.42-0.64)) (p = 0.02). Histological analysis suggested a correlation with the radiographic findings as the FMI tissue samples demonstrated less adjacent tissue damage than BPS. CONCLUSIONS: FMI appeared to cause less adjacent tissue damage than the BPS method in pig cerebral tissue based on quantitative radiographic and qualitative histological analysis. Future studies are needed to investigate the clinical implications of energy-based surgical dissection on cerebral tissue. PMID- 25748001 TI - Mechanism of chlorite degradation to chloride and dioxygen by the enzyme chlorite dismutase. AB - Heme b containing chlorite dismutase (Cld) catalyses the conversion of chlorite to chloride and dioxygen which includes an unusual OO bond formation. This review summarizes our knowledge about the interaction of chlorite with heme enzymes and introduces the biological role, phylogeny and structure of functional chlorite dismutases with differences in overall structure and subunit architecture. The paper sums up the available experimental and computational studies on chlorite degradation by water soluble porphyrin complexes as well as a model based on the active site of Cld. Finally, it reports the available biochemical and biophysical data of Clds from different organisms which allow the presentation of a general reaction mechanism. It includes binding of chlorite to ferric Cld followed by subsequent heterolytic OCl bond cleavage leading to the formation of Compound I and hypochlorite, which finally recombine for production of chloride and O2. The role of the Cld-typical distal arginine in catalysis is discussed together with the pH dependence of the reaction and the role of transiently produced hypochlorite in irreversible inactivation of the enzyme. PMID- 25748000 TI - 5-O-Acyl plumbagins inhibit DNA polymerase activity and suppress the inflammatory response. AB - We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase (pol) gamma. In this study, we focused on plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), and chemically synthesized novel plumbagins conjugated with C2:0 to C22:6 fatty acids (5-O-acyl plumbagins). These chemically modified plumbagins displayed enhanced mammalian pol inhibition, with plumbagin conjugated to docosahexaenoic acid (C22:6-acyl plumbagin) exhibiting the strongest inhibition of pol lambda among the ten 5-O-acyl plumbagins synthesized. C22:6-acyl plumbagin selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols or DNA metabolic enzymes tested. The inhibition of pol lambda, a DNA repair/recombination pol, by these compounds was significantly correlated with both their suppression of lipopolysaccharide (LPS) induced tumor necrosis factor-alpha (TNF-alpha) production by mouse RAW264.7 macrophages and the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in the mouse ear. These data indicate that 5-O-acyl plumbagins act as anti inflammatory agents by inhibiting mammalian pol lambda. These results further suggest that C22:6-acyl plumbagin is a promising anti-inflammatory candidate and that acylation could be an effective chemical modification to improve the anti inflammatory activity of vitamin K3 derivatives, such as plumbagin. PMID- 25748002 TI - Quantitative and qualitative assessment of the bovine abortion surveillance system in France. AB - Bovine abortion is the main clinical sign of bovine brucellosis, a disease of which France has been declared officially free since 2005. To ensure the early detection of any brucellosis outbreak, event-driven surveillance relies on the mandatory notification of bovine abortions and the brucellosis testing of aborting cows. However, the under-reporting of abortions appears frequent. Our objectives were to assess the aptitude of the bovine abortion surveillance system to detect each and every bovine abortion and to identify factors influencing the system's effectiveness. We evaluated five attributes defined by the U.S. Centers for Disease Control with a method suited to each attribute: (1) data quality was studied quantitatively and qualitatively, as this factor considerably influences data analysis and results; (2) sensitivity and representativeness were estimated using a unilist capture-recapture approach to quantify the surveillance system's effectiveness; (3) acceptability and simplicity were studied through qualitative interviews of actors in the field, given that the surveillance system relies heavily on abortion notifications by farmers and veterinarians. Our analysis showed that (1) data quality was generally satisfactory even though some errors might be due to actors' lack of awareness of the need to collect accurate data; (2) from 2006 to 2011, the mean annual sensitivity - i.e. the proportion of farmers who reported at least one abortion out of all those who detected such events - was around 34%, but was significantly higher in dairy than beef cattle herds (highlighting a lack of representativeness); (3) overall, the system's low sensitivity was related to its low acceptability and lack of simplicity. This study showed that, in contrast to policy-makers, most farmers and veterinarians perceived the risk of a brucellosis outbreak as negligible. They did not consider sporadic abortions as a suspected case of brucellosis and usually reported abortions only to identify their cause rather than to reject brucellosis. The system proved too complex, especially for beef cattle farmers, as they may fail to detect aborting cows at pasture or have difficulties catching them for sampling. By investigating critical attributes, our evaluation highlighted the surveillance system's strengths and needed improvements. We believe our comprehensive approach can be used to assess other event-driven surveillance systems. In addition, some of our recommendations on increasing the effectiveness of event-driven brucellosis surveillance may be useful in improving the notification rate for suspected cases of other exotic diseases. PMID- 25748003 TI - Virological and serological characterization of vaccinated and non-vaccinated piglet subpopulations coming from vaccinated and non-vaccinated sows. AB - The present study describes the virological and serological profiles of PCV2 vaccinated (V) and non-vaccinated (NV) piglet subpopulations coming from V and NV sows in a PCV2 subclinically infected farm. Four hundred seventy-six piglets born from V or NV sows were further subdivided in a total of four groups: NV sows-NV pigs (NV-NV), NV sows-V pigs (NV-V); V sows-NV pigs (V-NV) and V sows-V pigs (V V). Seventy-five pigs were randomly selected at the beginning of the trial from each group and they were bled at 4, 8, 12, 16, 21 and 25 weeks of age. All animals included in the trial were weighed at 4 and 25 weeks of age and their average daily weight gain (ADWG) was calculated. Serum samples obtained at different time points were used to assess PCV2 infection (viremia) and the level of antibodies by means of immunoperoxidase monolayer assay (IPMA) against this pathogen. IPMA titers (classified in high, medium or low) and PCR results (positive or negative) were analyzed using a multiple correspondence and K-means cluster analysis. According to these tests, animals included in the study were classified into the following four clusters: (1) 93 piglets that were viremic mainly from 12 to 25 weeks of age and with PCV2 antibody titers increasing over time; (2) 75 piglets with late PCV2 infection and seroconversion (later than 16 weeks of age); (3) 26 piglets with high but decreasing PCV2 antibody titers and low percentages of PCV2 PCR positive serum samples; and (4) 105 piglets with medium and high IPMA titers throughout the trial and sporadic PCR positive samples. The defined subpopulations of piglets were observed in all experimental groups (NV-NV, NV-V, V-NV and V-V) although in variable percentages. Thus, animals from clusters 1 and 2 belonged mainly to the NV-NV and V-NV groups and animals from clusters 3 and 4 were distributed mainly into the NV-V and V-V groups. Finally, the ADWG of pigs belonging to clusters 3 and 4 was significantly higher (p=0.02) than that of pigs belonging to clusters 1 and 2. Within each cluster, no statistically significant differences were found in ADWG between treatment groups. PMID- 25748004 TI - Changing practice patterns for breast cancer radiation therapy with clinical pathways: An analysis of hypofractionation in a large, integrated cancer center network. AB - PURPOSE: Hypofractionated whole breast irradiation (HF-WBI) following breast conserving surgery has produced excellent outcomes, but utilization remains limited. We evaluated the impact of a clinical pathway in the adoption of HF-WBI in a large, integrated radiation oncology network. METHODS AND MATERIALS: We identified patients aged >=70 years treated for breast cancer or ductal carcinoma in situ. Patients treated with palliative intent, accelerated partial breast radiation, following mastectomy, or with axillary nodal, supraclavicular, or internal mammary fields were excluded. HF-WBI was defined as <=20 fractions with a dose/fraction >=2.5 Gy. Multivariate analysis identified variables associated with increased HF-WBI utilization. RESULTS: We identified 2426 patients meeting inclusion criteria. HF-WBI utilization increased significantly from 6.5% (22.0% academic, 2.0% community) before pathway modification to 33.8% afterwards (68.5% academic, 25.3% community, P<.001). For academic physicians, the relative risk of HF-WBI utilization was 3.8 following publication of the seminal HF-WBI trial and 10.6 following pathway modification (P < .001). For community physicians, the relative risk of HF-WBI utilization did not significantly change following publication but was 21.0 following pathway modification (P < .001). The increased adoption of HF-WBI saved an estimated $154,000 annually in our network. CONCLUSIONS: We found that our implementation of clinical pathways substantially increased adoption of HF-WBI for breast cancer. We found no significant change in utilization of HF-WBI among community physicians following publication of a seminal trial for HF-WBI until after clinical pathway implementation, which increased the use of HF-WBI by 20-fold. Clinical pathways may be effective in changing practice patterns, disseminating evidence, and realizing health care savings. PMID- 25748005 TI - Safety Profile Assessment: An online tool to gauge safety-critical performance in radiation oncology. AB - PURPOSE: It is challenging for the radiation oncology practitioner to manage and implement the plethora of recently generated recommendations on quality and safety improvement. The online Safety Profile Assessment (SPA) tool uses an easy to-use question-and-answer format to assess safety/quality within a clinic, provide a way to benchmark against peers, and facilitate improvement. This report describes the design and development of the SPA and experience from the first year of use. METHODS: Performance indicators for the SPA were derived from 4 foundations: the Agency for Healthcare Research and Quality, a review of 7 recent authoritative documents specific to radiation oncology, a recent American Association of Physicists in Medicine report on incident learning, and the American College of Radiology-American Society for Radiation Oncology accreditation system as of 2011. After pilot testing, the free-access tool was launched through the American Association of Physicists in Medicine website (http://spa.aapm.org) in July 2013. Questionnaire data were collected to assess the experience of users. RESULTS: The SPA tool consists of 92 indicators designed to probe safety and quality. A clinic's performance is benchmarked against all other responses in the database, and aided by a downloadable log, quality/safety improvement strategies can be developed and tracked over time. At the time this paper was written, 279 individuals had registered, and 107 had completed the SPA. On average, the SPA required 1.3 hours to complete. The majority of respondents to the questionnaire (56%) completed the SPA with a multidisciplinary group of 4 people on average. Respondents noted that the SPA was easy or very easy to use (70%) and that they would definitely or very probably complete it again (63%). CONCLUSIONS: SPA provides a straightforward means of gauging a clinic's performance in key safety-critical areas and has been evaluated favorably by the first cohort of users. The tool has been qualified by the American Board of Radiology (ABR) as meeting the criteria for Practice Quality Improvement requirements of the ABR Maintenance of Certification Program. PMID- 25748006 TI - Dorsal vagal complex of the brainstem: Conformal avoidance to reduce nausea. In regard to Monroe et al. PMID- 25748007 TI - In reply to Wang et al. PMID- 25748008 TI - Kernel eigenspace template matching for detection of lacunar infarcts on MR images. AB - Detection of lacunar infarcts is important because their presence indicates an increased risk of severe cerebral infarction and dementia. However, accurate identification of lacunar infarcts is often difficult for radiologists. Our previous computer-aided detection (CAD) scheme achieved a sensitivity of 96.8% with 0.76 false positives (FPs) per slice. However, further reduction of FPs remained an issue for the clinical application. The purpose of this study is to improve our CAD scheme by using kernel eigenspace template matching. First, we selected the regions of interest (ROIs) around the candidate regions detected in our previous method. A kernel eigenspace was then made by using kernel principal component analysis of the training data set. A test ROI was projected onto the same kernel eigenspace as the training data set. The cross-correlation coefficients between the test ROI and all the training ROIs were calculated on the kernel eigenspace. By comparing the two maxima of coefficients with a lacunar ROI and an FP ROI, the test ROI was classified. By using the proposed method, the quantity of the templates became 1.9% of that in template matching on the real space and 31. 9% of FPs could be eliminated while keeping the same sensitivity; nevertheless 30.3% of FPs were eliminated when we employed the eigenspace template matching under the same condition. Therefore, kernel eigenspace template matching could improve FP rate without a significant reduction in the true positive rate. PMID- 25748009 TI - Validation and analysis of dose distributions in a new and entirely redesigned cobalt-60 stereotactic radiosurgery units. AB - The objective of this study was to evaluate the reproducibility of dose distributions in stereotactic treatment planning throughout Gamma Knife (GK) stereotactic radiosurgery (SRS) procedures in both GK model C and Perfexion (PFX). An originally-developed phantom and a radiochromic film were used for obtaining actual dose distributions. The phantom, with inserted films, was placed on a Leksell skull frame. Computed tomography (CT) was then acquired with a stereotactic localizer box attached to the frame, dose planning was made using the Leksell GammaPlan treatment planning system, and the phantom was ended up as beam delivery on an equal with clinical radiosurgery process. The reproducibility of the dose plan was provided by distance to agreement (DTA) values between planned and irradiated dose distributions calculated by dedicated film analysis software. The DTA values were determined for the isodose lines at 30%, 50%, 70%, and 90% of the maximum dose. In our study, the reproducibility of dose distributions in GK PFX was lower than in GK model C. As the results common to both units, the mean values of middle dose area (50% isodose) were about half the values of high (90% isodose) and low (30% isodose) dose area. Therefore validation of dose distributions is absolutely essential in commissioning of GK PFX. In addition, when risk organs are close to the target, dose prescription should be normalized for middle isodose line. PMID- 25748010 TI - Incident reports related to tasks performed by radiological technologists: an analysis of ten years of incident reports. AB - In the past 10 years at our university hospital, 202 incident reports related to tasks performed by radiological technologists were posted. In order to investigate the causes and trends of these incidents, we classified the incident reports into four groups based on the event content, level of harm caused to the patient, years of experience of the concerned radiological technologist, and relevant departmental section. In the event content group, 'a malfunctioning device' was the most common event (26.2%), whereas the other events were 'wrong examination procedure or therapy' (15.3%), 'patient fall' (10.9%), 'procedure patient mismatch' (8.4%), 'accidental removal of patients' tubes or other intravenous devices' (7.9%), and 'bringing metallic material into the magnetic resonance imaging (MRI) room' (7.4%). In the level of harm caused to the patient group, level one events occurred frequently. Radiological technologists with 6-16 years of experience reported incidents most frequently. With regard to the relevant departmental section where the incidents occurred, departments with the highest number of reports were ranked as follows in descending order: general X ray examination section, MRI section, radiation therapy section, nuclear medicine (NM) section, computed tomography (CT) section, angiography section, and fluoroscopy section. The following events in each corresponding section require careful monitoring: patient fall in the general X-ray examination section and NM section, bringing metallic material into the MRI room, malfunctioning devices in the radiation therapy section, accidental removal of the patient's tubes in the CT section, incorrect handling of the automatic contrast medium injector in the angiography section, and damage of device or article in the fluoroscopy section. PMID- 25748011 TI - 6. Application of the Monte Carlo simulation 3: leakage dose calculation. PMID- 25748012 TI - 4. Diseases of the brain 4: imaging in cerebrovascular diseases. PMID- 25748013 TI - Importance of continuously studying, etc. PMID- 25748014 TI - Dispatch reports to international conferences (held in Japan) in 2014. PMID- 25748015 TI - The Trend of the IEC standard for the safety of medical electrical equipment. PMID- 25748016 TI - [Be cool and practical]. PMID- 25748017 TI - Continuous acidogenesis of sucrose, raffinose and vinasse using mineral kissiris as promoter. AB - The use of kissiris as promoter (culture immobilization carrier) in anaerobic acidogenesis of sucrose, raffinose and vinasse is reported. Initially, the effect of pH (4-8) and fermentation temperature (18-52 degrees C) on the accumulation of low molecular weight organic acids (OAs) during sucrose acidogenesis, was evaluated. The promoting effect of kissiris was confirmed compared to free cells, resulting in 80% increased OAs production. The optimum conditions (pH 8; 37 degrees C) were used during acidogenesis of sucrose/raffinose mixtures. A continuous system was also operated for more than 2 months. When sucrose and sucrose/raffinose mixtures were used, lactic acid type fermentation prevailed, while when vinasse was used, butyric acid type fermentation occurred. Total OAs concentrations were more than 14 g/L and ethanol concentrations were 0.5-1 mL/L. Culture adaptation in vinasse was necessary to avoid poor results. The proposed process is promising for new generation ester-based biofuel production from industrial wastes. PMID- 25748018 TI - Hydrolytic effects of scaffolding proteins CbpB and CbpC on crystalline cellulose mediated by the major cellulolytic complex from Clostridium cellulovorans. AB - The role of the scaffolding proteins, cellulose binding protein B and C (CbpB and CbpC, respectively) were identified in cellulolytic complex (cellulosome) of Clostridium cellulovorans for efficient degradation of cellulose. Recombinant CbpB and CbpC directly anchored to the cell surface of C. cellulovorans. In addition, CbpB and CbpC showed increased hydrolytic activity on crystalline cellulose incubated with exoglucanase S (ExgS) and endoglucanase Z (EngZ) compared with the activity of free enzymes. Moreover, the results showed synergistic effects of crystalline cellulose hydrolytic activity (1.8- to 2.2 fold) when CbpB and CbpC complex with ExgS and EngZ are incubated with cellulolytic complex containing mini-CbpA. The results suggest C. cellulovorans critically uses CbpB and CbpC, which can directly anchor cells for the hydrolysis of cellulosic material with the major cellulosome complex. PMID- 25748020 TI - Improving the quality of papers submitted to dental journals: Transcription of session for editors, associate editors, publishers and others with an interest in scientific publishing held at IADR meeting in Cape Town on Wednesday, 25 June 2014. AB - This satellite symposium was the fourth in a series for editors, publishers, reviewers and all those with an interest in scientific publishing. It was held on Wednesday 25th June 2014 at the IADR International meeting in Cape Town, South Africa. The symposium attracted more than 180 attendees. This symposium placed an emphasis on how the quality of papers submitted to dental journals could be improved. The panel included representation from editors, researchers and publishers from North America, India and the Gulf States. The symposium identified a number of challenges for editors and publishers, including the poor quality of many papers submitted to dental and other scientific journals, plagiarism, attempted duplicate publication and sometimes fraudulent results. Where possible speakers are identified by name. A subsequent symposium was held during the IADR meeting in Boston on March 11th 2015. Involvement open to editors, associate editors, publishers and others with an interest in scientific publishing. PMID- 25748019 TI - IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression. AB - Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL 15. Collectively, the data implicate IL-15 as the master cytokine that induces B 1a cells to mount a mucosal immune response. PMID- 25748021 TI - The glucagon-like peptide 2 receptor is expressed in enteric neurons and not in the epithelium of the intestine. AB - Glucagon-like peptide 2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential in the treatment of intestinal deficiencies. It has recently been approved for the treatment of short bowel syndrome. The effects of GLP-2 are mediated by specific binding of the hormone to the GLP-2 receptor (GLP 2R) which was cloned in 1999. However, consensus about the exact receptor localization in the intestine has never been established. By physical, chemical and enzymatic tissue fragmentation, we were able to divide rat jejunum into different compartments consisting of: (1) epithelium alone, (2) mucosa with lamina propria and epithelium, (3) the external muscle coat including myenteric plexus, (4) a compartment enriched for the myenteric plexus and (5) intestine without epithelium. Expression of Glp2r; chromogranin A; tubulin, beta 3; actin, gamma 2, smooth muscle, enteric and glial fibrillary acidic protein in these isolated tissue fractions was quantified with qRT-PCR. Expression of the Glp2r was confined to compartments containing enteric neurons and receptor expression was absent in the epithelium. Our findings provide evidence for the expression of the GLP-2R in intestinal compartments rich in enteric neurons and, importantly they exclude significant expression in the epithelium of rat jejunal mucosa. PMID- 25748022 TI - Peptidic tools applied to redirect alternative splicing events. AB - Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript yields different mature RNAs leading to the production of protein isoforms with diverse or even antagonistic functions. During splicing events, errors can be caused either by mutations present in the genome or by defects or imbalances in regulatory protein factors. In any case, defects in alternative splicing have been related to several genetic diseases including muscular dystrophy, Alzheimer's disease and cancer from almost every origin. One of the most effective approaches to redirect alternative splicing events has been to attach cell-penetrating peptides to oligonucleotides that can modulate a single splicing event and restore correct gene expression. Here, we summarize how natural existing and bioengineered peptides have been applied over the last few years to regulate alternative splicing and genetic expression. Under different genetic and cellular backgrounds, peptides have been shown to function as potent vehicles for splice correction, and their therapeutic benefits have reached clinical trials and patenting stages, emphasizing the use of regulatory peptides as an exciting therapeutic tool for the treatment of different genetic diseases. PMID- 25748023 TI - Freely designable optical frequency conversion in Raman-resonant four-wave-mixing process. AB - Nonlinear optical processes are governed by the relative-phase relationships among the relevant electromagnetic fields in these processes. In this Report, we describe the physics of arbitrary manipulation of Raman-resonant four-wave-mixing process by artificial control of relative phases. As a typical example, we show freely designable optical-frequency conversions to extreme spectral regions, mid infrared and vacuum-ultraviolet, with near-unity quantum efficiencies. Furthermore, we show that such optical-frequency conversions can be realized by using a surprisingly simple technology where transparent plates are placed in a nonlinear optical medium and their positions and thicknesses are adjusted precisely. In a numerical simulation assuming practically applicable parameters in detail, we demonstrate a single-frequency tunable laser that covers the whole vacuum-ultraviolet spectral range of 120 to 200 nm. PMID- 25748024 TI - High-resolution microbial community succession of microbially induced concrete corrosion in working sanitary manholes. AB - Microbially-induced concrete corrosion in headspaces threatens wastewater infrastructure worldwide. Models for predicting corrosion rates in sewer pipe networks rely largely on information from culture-based investigations. In this study, the succession of microbes associated with corroding concrete was characterized over a one-year monitoring campaign using rRNA sequence-based phylogenetic methods. New concrete specimens were exposed in two highly corrosive manholes (high concentrations of hydrogen sulfide and carbon dioxide gas) on the Colorado Front Range for up to a year. Community succession on corroding surfaces was assessed using Illumina MiSeq sequencing of 16S bacterial rRNA amplicons and Sanger sequencing of 16S universal rRNA clones. Microbial communities associated with corrosion fronts presented distinct succession patterns which converged to markedly low alpha-diversity levels (< 10 taxa) in conjunction with decreasing pH. The microbial community succession pattern observed in this study agreed with culture-based models that implicate acidophilic sulfur-oxidizer Acidithiobacillus spp. in advanced communities, with two notable exceptions. Early communities exposed to alkaline surface pH presented relatively high alpha-diversity, including heterotrophic, nitrogen-fixing, and sulfur-oxidizing genera, and one community exposed to neutral surface pH presented a diverse transition community comprised of less than 20% sulfur-oxidizers. PMID- 25748026 TI - The questions verbal children with autism spectrum disorder encounter in the inclusive preschool classroom. AB - This study investigated questions adults asked to children with autism spectrum disorder in inclusive pre-kindergarten classrooms, and whether child (e.g. autism severity) and setting (i.e. adult-to-child ratio) characteristics were related to questions asked during center-time. Videos of verbal children with autism spectrum disorder (n = 42) were coded based on the following question categories adapted from the work of Massey et al.: management, low cognitive challenging, or cognitively challenging. Results indicated that management questions (mean = 19.97, standard deviation = 12.71) were asked more than less cognitively challenging questions (mean = 14.22, standard deviation = 8.98) and less cognitively challenging questions were asked more than cognitively challenging questions (mean = 10.00, standard deviation = 6.9). Children with higher language levels had a greater likelihood of receiving cognitively challenging questions (odds ratio = 1.025; p = 0.007). Cognitively challenging questions had a greater likelihood of being asked in classrooms with more adults relative to children (odds ratio = 1.176; p = 0.037). The findings present a first step in identifying the questions directed at preschoolers with autism spectrum disorder in inclusive classrooms. PMID- 25748025 TI - Ambient Heat and Sudden Infant Death: A Case-Crossover Study Spanning 30 Years in Montreal, Canada. AB - BACKGROUND: Climate change may lead to more severe and extreme heat waves in the future, but its potential impact on sudden infant death-a leading cause of infant mortality-is unclear. OBJECTIVES: We sought to determine whether risk of sudden infant death syndrome (SIDS) is elevated during hot weather. METHODS: We undertook a case-crossover analysis of all sudden infant deaths during warm periods in metropolitan Montreal, Quebec, Canada, from 1981 through 2010. Our analysis included a total of 196 certified cases of SIDS, including 89 deaths at 1-2 months of age, and 94 at 3-12 months. We estimated associations between maximum outdoor temperatures and SIDS by comparing outdoor temperatures on the day of or day before a SIDS event with temperatures on control days during the same month, using cubic splines to model temperature and adjusting for relative humidity. RESULTS: Maximum daily temperatures of >= 29 degrees C on the same day were associated with 2.78 times greater odds of sudden infant death relative to 20 degrees C (95% CI: 1.64, 4.70). The likelihood of sudden death increased steadily with higher temperature. Associations were stronger for infants 3-12 months of age than for infants 1-2 months of age, with odds ratios of 3.90 (95% CI: 1.87, 8.13) and 1.73 (95% CI: 0.80, 3.73), respectively, for 29 degrees C compared with 20 degrees C on the day of the event. CONCLUSIONS: High ambient temperature may be a novel risk factor for SIDS, especially at >= 3 months of age. Climate change and the higher temperatures that result may account for a potentially greater proportion of sudden infant deaths in the future. PMID- 25748027 TI - Microbial community analysis of anaerobic reactors treating soft drink wastewater. AB - The anaerobic packed-bed (AP) and hybrid packed-bed (HP) reactors containing methanogenic microbial consortia were applied to treat synthetic soft drink wastewater, which contains polyethylene glycol (PEG) and fructose as the primary constituents. The AP and HP reactors achieved high COD removal efficiency (>95%) after 80 and 33 days of the operation, respectively, and operated stably over 2 years. 16S rRNA gene pyrotag analyses on a total of 25 biofilm samples generated 98,057 reads, which were clustered into 2,882 operational taxonomic units (OTUs). Both AP and HP communities were predominated by Bacteroidetes, Chloroflexi, Firmicutes, and candidate phylum KSB3 that may degrade organic compound in wastewater treatment processes. Other OTUs related to uncharacterized Geobacter and Spirochaetes clades and candidate phylum GN04 were also detected at high abundance; however, their relationship to wastewater treatment has remained unclear. In particular, KSB3, GN04, Bacteroidetes, and Chloroflexi are consistently associated with the organic loading rate (OLR) increase to 1.5 g COD/L-d. Interestingly, KSB3 and GN04 dramatically decrease in both reactors after further OLR increase to 2.0 g COD/L-d. These results indicate that OLR strongly influences microbial community composition. This suggests that specific uncultivated taxa may take central roles in COD removal from soft drink wastewater depending on OLR. PMID- 25748029 TI - WHO records slight blip in downward trend in Ebola incidence. PMID- 25748028 TI - Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of epsilon-subunit containing GABA ARs. AB - The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of epsilon-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce epsilon-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in epsilon-subunit-containing GABAARs. PMID- 25748030 TI - Physiological factors contributing to mobility loss over 9 years of follow-up results from the InCHIANTI study. AB - BACKGROUND: Mobility is an essential aspect of everyday life and enables autonomy and participation. Although many risk factors for mobility loss have been previously described, their relative importance and independent contributions to the long-term risk of losing mobility have not been well defined. METHODS: This study is based on 1,013 men and women aged >=65 years enrolled in 1998-2000 and followed for 9 years through 2007-2008 in the population-based InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study. We considered 44 different measures assessed at baseline to explore six subsystems: (i) central nervous system, (ii) peripheral nervous system, (iii) muscles, (iv) bone and joints, (v) energy production and delivery, and (vi) perceptual system. The outcome was incident mobility loss defined as self-report of inability to walk 400 m or climb and descend 10 steps without help from another person. Random survival forest analysis was used to rank the candidate predictors by their importance. RESULTS: The most important physiological markers predicting mobility loss that emerged from the random survival forest modeling were older age among women (81-95 vs 65-68 years, hazard ratio [HR] 9.60 [95% CI 3.35, 27.50]), weaker ankle dorsiflexion strength (lowest vs highest quintile, HR 5.25 [95% CI 2.35, 11.72]), low hip flexion range of motion (lowest vs highest quintile, HR 2.30 [95% CI 1.20, 4.41]), presence of primitive reflexes (yes vs no, HR 1.47 [95% CI 1.03, 2.09]), and tremor (yes vs no, HR 1.91 [95% CI 1.18, 3.07]). CONCLUSION: Prevention of mobility loss with aging should focus on prevention and treatment of neuromuscular impairments. PMID- 25748031 TI - Muscle Quality and Muscle Fat Infiltration in Relation to Incident Mobility Disability and Gait Speed Decline: the Age, Gene/Environment Susceptibility Reykjavik Study. AB - BACKGROUND: Aging is associated with increased risk of reduced mobility. However, data on muscle components in relation to subjective and objective indicators of disability is limited. METHODS: Data were from 2,725 participants (43% men) aged 74.8+/-4.7 years from the AGES-Reykjavik Study. At baseline, maximal isometric thigh strength (dynamometer chair), and midthigh muscle area and muscle fat infiltration were assessed with computed tomography. Usual 6 m gait speed and mobility disability were assessed at baseline and after 5.2+/-0.3 years. Incident mobility disability was defined as having much difficulty or unable to walk 500 m or climb-up 10 steps. A decrease of >=0.1 m/s in gait speed was considered clinically relevant. RESULTS: Greater strength and area were protective for mobility disability risk and gait speed decline. After adjustment for other muscle components, greater strength was independently associated with lower mobility disability risk in women odds ratios (OR) 0.78 (95% CI 0.62, 0.99), and lower decline in gait speed risk among both men OR 0.64 (0.54, 0.76), and women OR 0.72 (0.62, 0.82). Larger muscle area was independently associated with lower mobility disability risk in women OR 0.67 (0.52, 0.87) and lower decline in gait speed risk in men OR 0.74 (0.61, 0.91). CONCLUSIONS: Greater muscle strength and area were independently associated with 15-30% decreased risk of mobility disability in women and gait speed decline in men. Among women, greater muscle strength was also associated with lower risk of gait speed decline. Interventions aimed at maintaining muscle strength and area in old age might delay functional decline. PMID- 25748032 TI - Serum 25-Hydroxyvitamin D, Plasma Klotho, and Lower-Extremity Physical Performance Among Older Adults: Findings From the InCHIANTI Study. AB - BACKGROUND: The hormone klotho is encoded by aging-suppressor gene klotho and has multiple roles, including regulating mineral (calcium and phosphate) homeostasis. Vitamin D also regulates mineral homeostasis and upregulates klotho expression. Klotho positively relates to longevity, upper-extremity strength, and reduced disability in older adults; however, it is unknown whether circulating klotho relates to lower-extremity physical performance or whether the relation of vitamin D with physical performance is mediated by klotho. METHODS: Klotho and 25 hydroxyvitamin D [25(OH)D] were measured in 860 participants aged >= 55 years in Invecchiare in Chianti, "Aging in Chianti" (InCHIANTI), a prospective cohort study comprising Italian adults. Lower-extremity physical performance was measured using the Short Physical Performance Battery, a summary score of balance, chair stand ability, and walking speed. Weighted estimating equations related plasma klotho and serum 25(OH)D concentrations measured at one visit to Short Physical Performance Battery measured longitudinally at multiple visits. RESULTS: Each additional natural log of klotho (pg/mL) was associated with 0.47 higher average Short Physical Performance Battery scores (95% confidence interval: 0.08 to 0.86, p value = .02) after adjustment for covariates, including 25(OH)D. Each natural log of 25(OH)D (ng/mL) was associated with 0.61 higher average Short Physical Performance Battery scores (95% confidence interval: 0.35 to 0.88, p value < .001) after adjustment for covariates, a result that changed little after adjustment for klotho. CONCLUSIONS: Plasma klotho and 25(OH)D both positively related to lower-extremity physical performance. However, the findings did not support the hypothesis that klotho mediates the relation of 25(OH)D with physical performance. PMID- 25748033 TI - Characterization of influenza A (H7N9) viruses isolated from human cases imported into Taiwan. AB - A novel avian influenza A (H7N9) virus causes severe human infections and was first identified in March 2013 in China. The H7N9 virus has exhibited two epidemiological peaks of infection, occurring in week 15 of 2013 and week 5 of 2014. Taiwan, which is geographically adjacent to China, faces a large risk of being affected by this virus. Through extensive surveillance, launched in April 2013, four laboratory-confirmed H7N9 cases imported from China have been identified in Taiwan. The H7N9 virus isolated from imported case 1 in May 2013 (during the first wave) was found to be closest genetically to a virus from wild birds and differed from the prototype virus, A/Anhui/1/2013, in the MP gene. The other three imported cases were detected in December 2013 and April 2014 (during the second wave). The viruses isolated from cases 2 and 4 were similar in the compositions of their 6 internal genes and distinct from A/Anhui/1/2013 in the PB2 and MP genes, whereas the virus isolated from case 3 exhibited a novel reassortment that has not been identified previously and was different from A/Anhui/1/2013 in the PB2, PA and MP genes. The four imported H7N9 viruses share similar antigenicity with A/Anhui/1/2013, and their HA and NA genes grouped together in their respective phylogenies. In contrast with the HA and NA genes, which exhibited a smaller degree of diversity, the internal genes were heterogeneous and provided potential distinctions between transmission sources in terms of both geography and hosts. It is important to strengthen surveillance of influenza and to share viral genetic data in real-time for reducing the threat of rapid and continuing evolution of H7N9 viruses. PMID- 25748034 TI - Normalized MEDx chart coupled with Quality Goal Index for evaluation of analytical quality achievements and quality shortcomings. A novel perspective to its further application. PMID- 25748035 TI - Changes in red blood cell membrane structure in G6PD deficiency: an atomic force microscopy study. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency affects over 400 million people worldwide. The hemolytic anemia in G6PD deficiency is usually triggered by oxidative stress, but the mechanism remains uncertain. We have used atomic force microscopy for studying changes in red blood cell membrane and providing new insights on the mechanism. METHODS: G6PD activity assay and molecular genetic tests were used for molecular diagnosis. AFM was used to investigate alterations in the ultrastructure of G6PD deficient RBC membranes, the influence of different primaquine concentrations, and the protective effects of vitamin C. RESULT: Nine variants were identified from 33 G6PD deficient individuals. AFM imaging and quantitative analysis showed that G6PD deficient erythrocytes became heterogeneous and roughness measurements of erythrocyte membranes are increased. G6PD enzyme activity and different mutations may relate with roughness parameters. Furthermore, primaquine induces an increased roughness and height of erythrocyte membrane. Meanwhile, primaquine induces damages to erythrocytes which could be prevented by vitamin C treatment in normal RBCs but not in G6PD deficient erythrocytes. CONCLUSIONS: Our research may give valuable information about the status of G6PD deficient patients and explore the mechanism of hemolytic anemia. PMID- 25748036 TI - LncRNAs and neoplasia. AB - Long noncoding RNAs are emerging as new mediators of tumorigenesis by virtue of their various functions and their capacity to induce different mechanisms as a result of their wide spectrum of interactions. They play critical roles in a broad range of cellular processes including regulation of gene expression, imprinting, chromatin modification, transcription and posttranslational processing. Expression and activity of lncRNAs are deregulated in several types of human cancer. Impairment of lncRNA activity may affect key components of the cellular gene regulatory networks and is associated with deregulation of a large number of cellular oncogenic pathways. LncRNAs are also being evaluated as diagnostic and prognostic biomarkers and may provide targets for potential therapeutic applications. An improved understanding of the roles played by lncRNAs in cancer will lead to more effective therapeutic strategies. In this review we summarize the current knowledge on lncRNAs and their function as mediators of tumor development. PMID- 25748037 TI - Relationship between serum leptin levels and bone mineral density: a systematic review and meta-analysis. AB - BACKGROUND: The association between leptin and bone mineral density (BMD) is controversial because of conflicting findings from previous studies. METHODS: This meta-analysis aimed to provide an overview of the serum leptin levels and BMD in a healthy population. We reviewed the PubMed, Embase, and Cochrane Library databases until July 2014 for research on the association between leptin levels and BMD in healthy people. RESULTS: We included and analyzed 45 studies in this systematic review and meta-analysis. The pooled correlations between leptin and BMD were analyzed by using the method of the inverse of the variance. Leptin was positively associated with BMD and the bone mineral content (BMC), especially in postmenopausal women (pooled r: 0.13-0.49). Overall, high serum leptin levels were associated with higher BMD levels. CONCLUSIONS: This meta-analysis suggests that serum leptin levels are positively associated with BMD and BMC, especially in postmenopausal women. PMID- 25748038 TI - Autoimmune peripheral neuropathies. AB - Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood-nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides. The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features. Guillain-Barre syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy. Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies. PMID- 25748039 TI - Salivary, blood and plasma nitrite concentrations in periodontal patients and healthy individuals before and after periodontal treatment. AB - BACKGROUND: To date, no study has employed ozone-based reductive chemiluminescence to compare nitrite concentration in the saliva of periodontal disease (PD) and healthy individuals or in the various blood compartments of the same individuals before and after periodontal treatment. We evaluated nitrite concentrations in whole, submandibular, and parotid saliva, as well as in whole blood, erythrocytes, and plasma of healthy volunteers and patients with chronic periodontitis. METHODS: Data obtained for the PD and control groups were compared before and 3 months after periodontal therapy. RESULTS: At baseline, stimulated whole saliva nitrite concentration was lower in PD patients (mean=57.3 +/- 9.8 MUmol/L) as compared with healthy individuals (92.5 +/- 13.6 MUmol/L, P<0.05). PD and periodontal treatment did not affect submandibular or parotid saliva nitrite concentrations. PD patients presented higher baseline whole blood nitrite concentration (238.4 +/- 45.7 MUmol/L) as compared with values recorded 3 months after therapy (141.3 +/- 20.1 nmol/L, P<0.05). PD patients' erythrocytes exhibited higher baseline nitrite concentration (573.1 +/- 97.8 nmol/L) as compared with three months after therapy (298.7 +/- 52.1 nmol/L, P<0.05). Again, PD and PD treatment did not impact plasma nitrite concentration. CONCLUSIONS: PD patients had lower nitrite concentration in whole saliva, and this situation remained unchanged after periodontal treatment. Nevertheless, erythrocytes and whole blood nitrite levels diminished after periodontal treatment. PMID- 25748040 TI - Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications. AB - The cardiac voltage-gated Na(+) channel, Na(V)1.5, is responsible for the upstroke of the action potential in cardiomyocytes and for efficient propagation of the electrical impulse in the myocardium. Even subtle alterations of Na(V)1.5 function, as caused by mutations in its gene SCN5A, may lead to many different arrhythmic phenotypes in carrier patients. In addition, acquired malfunctions of Na(V)1.5 that are secondary to cardiac disorders such as heart failure and cardiomyopathies, may also play significant roles in arrhythmogenesis. While it is clear that the regulation of Na(V)1.5 protein expression and function tightly depends on genetic mechanisms, recent studies have demonstrated that Na(V)1.5 is the target of various post-translational modifications that are pivotal not only in physiological conditions, but also in disease. In this review, we examine the recent literature demonstrating glycosylation, phosphorylation by Protein Kinases A and C, Ca(2+)/Calmodulin-dependent protein Kinase II, Phosphatidylinositol 3 Kinase, Serum- and Glucocorticoid-inducible Kinases, Fyn and Adenosine Monophosphate-activated Protein Kinase, methylation, acetylation, redox modifications, and ubiquitylation of Na(V)1.5. Modern and sensitive mass spectrometry approaches, applied directly to channel proteins that were purified from native cardiac tissues, have enabled the determination of the precise location of post-translational modification sites, thus providing essential information for understanding the mechanistic details of these regulations. The current challenge is first, to understand the roles of these modifications on the expression and the function of Na(V)1.5, and second, to further identify other chemical modifications. It is postulated that the diversity of phenotypes observed with Na(V)1.5-dependent disorders may partially arise from the complex post-translational modifications of channel protein components. PMID- 25748041 TI - Role of vision and mechanoreception in bed bug, Cimex lectularius L. behavior. AB - The role of olfactory cues such as carbon dioxide, pheromones, and kairomones in bed bug, Cimex lectularius L. behavior has been demonstrated. However, the role of vision and mechanoreception in bed bug behavior is poorly understood. We investigated bed bug vision by determining their responses to different colors, vertical objects, and their ability to detect colors and vertical objects under low and complete dark conditions. Results show black and red paper harborages are preferred compared to yellow, green, blue, and white harborages. A bed bug trapping device with a black or red exterior surface was significantly more attractive to bed bugs than that with a white exterior surface. Bed bugs exhibited strong orientation behavior toward vertical objects. The height (15 vs. 30 cm tall) and color (brown vs. black) of the vertical object had no significant effect on orientation behavior of bed bugs. Bed bugs could differentiate color and detect vertical objects at very low background light conditions, but not in complete darkness. Bed bug preference to different substrate textures (mechanoreception) was also explored. Bed bugs preferred dyed tape compared to painted tape, textured painted plastic, and felt. These results revealed that substrate color, presence of vertical objects, and substrate texture affect host seeking and harborage-searching behavior of bed bugs. Bed bugs may use a combination of vision, mechanoreception, and chemoreception to locate hosts and seek harborages. PMID- 25748043 TI - Complete ischemic necrosis of segment IV after radiofrequency ablation with hilar clamping. PMID- 25748042 TI - Arc is a flexible modular protein capable of reversible self-oligomerization. AB - The immediate early gene product Arc (activity-regulated cytoskeleton-associated protein) is posited as a master regulator of long-term synaptic plasticity and memory. However, the physicochemical and structural properties of Arc have not been elucidated. In the present study, we expressed and purified recombinant human Arc (hArc) and performed the first biochemical and biophysical analysis of hArc's structure and stability. Limited proteolysis assays and MS analysis indicate that hArc has two major domains on either side of a central more disordered linker region, consistent with in silico structure predictions. hArc's secondary structure was estimated using CD, and stability was analysed by CD monitored thermal denaturation and differential scanning fluorimetry (DSF). Oligomerization states under different conditions were studied by dynamic light scattering (DLS) and visualized by AFM and EM. Biophysical analyses show that hArc is a modular protein with defined secondary structure and loose tertiary structure. hArc appears to be pyramid-shaped as a monomer and is capable of reversible self-association, forming large soluble oligomers. The N-terminal domain of hArc is highly basic, which may promote interaction with cytoskeletal structures or other polyanionic surfaces, whereas the C-terminal domain is acidic and stabilized by ionic conditions that promote oligomerization. Upon binding of presenilin-1 (PS1) peptide, hArc undergoes a large structural change. A non synonymous genetic variant of hArc (V231G) showed properties similar to the wild type (WT) protein. We conclude that hArc is a flexible multi-domain protein that exists in monomeric and oligomeric forms, compatible with a diverse, hub-like role in plasticity-related processes. PMID- 25748044 TI - [Surgery for gastrinoma: Short and long-term results]. AB - INTRODUCTION: Zollinger-Ellison syndrome (Z-E) is characterized by gastrin secreting tumors, responsible for causing refractory and recurrent peptic ulcers in the gastrointestinal tract. The optimal approach and the extension of tumor resection remains the subject of debate. METHODS: During the period February 2005 and February 2014, 6 patients with Z-E underwent surgery, 4 men and 2 women with a median age 46.8 years (22-61). Two patients were affected with multiple endocrine neoplasia type-1 (MEN-1). Fasting gastrin levels greater than 200pg/ml (NV: <100) was diagnostic. Radiologic imaging to localize the lesion included octreoscan 6/6, computer tomography (CT) 6/6, and endoscopic ultrasonography (EUS) 1/6. RESULTS: The octreoscan was positive in 5 patients. The CT localized the tumor in the pancreas in 2 patients, in the duodenum in 3 patients (1 confirmed by EUS) and between the common bile duct and vena cava in one patient. The laparoscopic approach was used in 4 patients, 2 patients converted to open surgery. The following surgical techniques were performed: 2 pylorus-preserving pancreatico-duodenectomy (PPPD), one spleen-preserving distal pancreatectomy, one duodenal nodular resection, 1 segmental duodenectomy and one extrapancreatic nodular resection. Pathological studies showed lymph nodes metastasis in 2 patients with pancreatic gastrinomas, and in one patient with duodenal gastrinoma. The median follow-up was 76,83 months (5-108) and all patients presented normal fasting gastrin levels. CONCLUSIONS: Surgery may offer a cure in patients with Z-E. The laparoscopic approach remains limited to selected cases. PMID- 25748045 TI - Fresh cadaver, an old surgical model in current general surgery. PMID- 25748046 TI - Bariatric Revision Surgery After POSE. PMID- 25748047 TI - Wilms' tumor 1 (WT1) expression and prognosis in solid cancer patients: a systematic review and meta-analysis. AB - Though proposed as a promising target antigen for cancer immunotherapy, the prognostic value of Wilms' tumor 1 (WT1) in solid tumors remains inconclusive. Here, we report a systematic review and meta-analysis of the association between WT1 expression and prognosis in solid tumors. PubMed, Web of Science and Google Scholar were searched to identify studies exploring the impact of WT1 on clinical outcomes, including overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), relapse/recurrence-free survival (RFS) or progression-free survival (PFS), in solid cancer patients. Hazard ratio (HR) and 95% confidence interval (CI) were applied to assess the strength of these associations. Finally, a total of 29 eligible studies with 4090 patients were identified for qualitative analysis, and 22 studies with 3620 patients were enrolled for quantitative synthesis. Overall, positive expression of WT1 was significantly associated with worse OS (metaHR = 1.48, 95% CI = 1.11-1.97) and DFS/RFS/PFS (metaHR = 2.14, 95% CI = 1.42-3.21). Subgroup analyses showed that WT1 positive expression could independently predict unfavorable DFS/RFS/PFS (metaHR = 1.86, 95%CI = 1.04-3.35). In summary, our study suggests that WT1 may be a potential marker to predict DFS/RFS/PFS in solid tumor patients. Further studies are needed to confirm the role of WT1 expression in clinical practice. PMID- 25748049 TI - GRP78 is implicated in the modulation of tumor aerobic glycolysis by promoting autophagic degradation of IKKbeta. AB - Compared with normal differentiated cells, cancer cells take up much more glucose and metabolize it mainly via aerobic glycolysis. This metabolic phenotype is characterized with high expression of glucose transporters (Gluts) and pyruvate kinase M2 (PKM2). Glucose regulated protein 78 (GRP78) is a glucose-sensing protein and frequently up-regulated in cancer cells, however, whether it is directly implicated in glucose metabolism remains to be elucidated. Here we report that upon glucose deficiency, the induction of GRP78 resulted in enhanced HIF-1alpha transcription, accompanied by a transient increased expression of Glut 1. In addition, GRP78 was likely to facilitate the membrane translocation of Glut 1 via protein-protein interaction. Glucose starvation-stimulated GRP78 also impaired the expression of PKM2 but promoted the expression of mitochondrial pyruvate dehydrogenase A (PDHA) and B (PDHB), resulting in the metabolic shift from glycolysis to the TCA cycle. Interestingly, the inhibition of PKM2 by GRP78 was abrogated when glucose supply was restored, suggesting that GRP78 and PKM2 expressions are adaptable to the nutritional levels in the microenvironment. Further mechanistic study indicated that GRP78 overexpression activated the Class III PI3K-mediated autophagy pathway and induced autophagic degradation of IKKbeta, which caused inactivation of NF-kappaB pathway and subsequently altered the expression of PKM2 and HIF-1alpha. Our study establishes GRP78 and PKM2 as the crucial molecular links between cancer cell glucose metabolism and tumor microenvironment alterations. PMID- 25748048 TI - Association of p75(NTR) and alpha9beta1 integrin modulates NGF-dependent cellular responses. AB - Direct interaction of alpha9beta1 integrin with nerve growth factor (NGF) has been previously reported to induce pro-proliferative and pro-survival activities of non-neuronal cells. We investigated participation of p75(NTR) in alpha9beta1 integrin-dependent cellular response to NGF stimulation. Using selective transfection of glioma cell lines with these receptors, we showed a strong, cation-independent association of alpha9 integrin subunit with p75(NTR) on the cellular membrane by selective immunoprecipitation experiments. The presence of the alpha9/p75(NTR) complex increases NGF-dependent cell adhesion, proliferation and migration. Other integrin subunits including beta1 were not found in complex with p75(NTR). FRET analysis indicated that p75(NTR) and alpha9 integrin subunit are not closely associated through their cytoplasmic domains, most probably because of the molecular interference with other cytoplasmic proteins such as paxillin. Interaction of alpha9beta1 integrin with another ligand, VCAM-1 was not modulated by the p75(NTR). alpha9/p75(NTR) complex elevated NGF-dependent activation of MAPK Erk1/2 arty for integrin that may create active complexes with other types of receptors belonging to the TNF superfamily. PMID- 25748050 TI - Silencing Daxx increases the anti-tumor activity of a TRAIL/shRNA Bcl-xL expressing oncolytic adenovirus through enhanced viral replication and cellular arrest. AB - We previously showed that an increase of cellular Bcl-xL mediates acquired resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and knockdown of Bcl-xL expression greatly sensitized TRAIL-induced cytotoxicity. Here, we show that Daxx downregulation increases the anti-tumorigenic activity through enhancement of viral replication and cellular arrest with combination of TRAIL/shBcl-xL-induced apoptosis. This study was conducted to determine the effect of Daxx downregulation on the anti-tumorigenesis induced by oncolytic adenovirus arming TRAIL or TRAIL/shRNA of Bcl-xL genes. Unlike the enhanced cancer cell death induced by exogenous TRAIL or TRAIL plus shRNA of Bcl-xL, oncolytic adenovirus expressing TRAIL or TRAIL plus shRNA of Bcl-xL did not show much enhanced cancer cell death compared to oncolytic adenovirus itself. On the other hand, enhanced cytotoxic cell death and viral replication was observed after infection with oncolytic adenovirus expressing TRAIL plus shRNA of Bcl-xL and shRNA of Daxx at the same construct. Then we realized that enhanced adenoviral replication through Daxx downregulation was caused by increased adenoviral E1A protein expression and Daxx downregulation also stimulated cellular arrest through p21/p53 accumulation. Taken all together, we have shown here that Daxx downregulation should be essentially needed for the increase of anti-tumor activity through enhancement of viral replication and cellular arrest with the combination of TRAIL/shBcl-xL-induced apoptosis and oncolytic adenovirus. PMID- 25748051 TI - Development of a new PCR-based assay to detect Anaplasmataceae and the first report of Anaplasma phagocytophilum and Anaplasma platys in cattle from Algeria. AB - Bovine anaplasmosis is a hemoparasitic disease considered as a major constraint to cattle production in many countries. This pathology is at least partially caused by Anaplasma phagocytophilum, Anaplasma marginale, Anaplasma centrale, and Anaplasma bovis. The global threat and emergence of these species in animals require the reliable identification of these bacteria in animal samples. In this study, we developed a new qPCR tool targeting the 23S rRNA gene for the detection of Anaplasmataceae bacteria. The primers and probe for the qPCR reaction had 100% specificity and could identify at least A. phagocytophilum, A. marginale, A. centrale, Anaplasma ovis, Anaplasma platys, Ehrlichia canis, Ehrlichia ruminantium, Neorickettisa sennetsu, and Neorickettsia risticii. We used this tool to test samples of bovines from Batna (Algeria), an area from which bovine anaplasmosis have never been reported. We identified three genetic variants of A. phagocytophilum, A. platys and Anaplasma sp. "variant 4". This finding should attract the attention of public authorities to assess the involvement of these pathogens in human and animal health. PMID- 25748052 TI - Practitioner perspectives of implementing check & connect. AB - While there is a growing reserve of evidence-based practices (EBPs) available to practitioners, much can be learned about how to implement EBPs in real-world settings. Evidence of the effects of a widely disseminated student engagement intervention, Check & Connect (C&C), is emerging yet little is known about the implementation of C&C in community-based settings. The purpose of the authors in this study was to examine practitioner attitudes and perspectives related to the C&C intervention and implementation to gain an understanding of core implementation components that facilitated or impeded implementation. A researcher-developed survey instrument was used to assess practitioner attitudes related to the C&C model and implementation among 14 school-based practitioners working in a dropout prevention program. Findings indicate that practitioners were highly positive about the C&C intervention and in their attitudes about implementing EBPs. Benefits of C&C identified by practitioners included increased relationship building with students, tracking students on a consistent and timely basis, and addressing attendance issues as a main focus of treatment. The most common implementation challenges were time constraints, paperwork, and targeting absentee students. These findings contribute to the emerging literature on C&C and the implementation of EBPs in schools and community-based settings. PMID- 25748053 TI - Association of serum phosphorus with subclinical atherosclerosis in chronic kidney disease. Sex makes a difference. AB - BACKGROUND: Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Serum phosphate has been associated to cardiovascular disease in the general population and this effect seems to be different according to sex. In the present study we analyze the effect of phosphate on subclinical atherosclerosis in the NEFRONA population and its effect depending on sex. DESIGN: Carotid ultrasound assessing the presence of plaques was performed by an itinerant team in 1687 CKD patients not in dialysis without previous cardiovascular events. Standard blood test and anthropometrical parameters were also recorded. RESULTS: Multivariate linear regression to model phosphate levels in patients with CKD showed an interaction of sex with age. Thus, among men, serum phosphate levels declined significantly with age almost linearly. Serum phosphate levels in women under the age of 40-45 years overlapped with those in men and then stayed above, showing and overall constant relationship. Multivariate logistic regression analysis showed that higher phosphate levels associated with a higher risk of presenting atheromatous plaque. This risk however was different according to sex. In men, phosphate levels within the normal range associated with an increased risk of subclinical atheromatosis whereas in women this risk only increased with serum levels over the normal range. CONCLUSIONS: This study demonstrates that phosphate levels are associated with the presence of subclinical atheromatosis in a large CKD population. This effect of phosphate on subclinical atheromatosis was different according to sex, suggesting that a recommended serum phosphate levels could be different for male than for female CKD patients. PMID- 25748054 TI - Reply to Letter: "Outcome prediction in postanoxic coma with electroencephalography: the sooner the better". PMID- 25748055 TI - Statistical thermodynamics of irreversible aggregation: the sol-gel transition. AB - Binary aggregation is known to lead, under certain kinetic rules, to the coexistence of two populations, one consisting of finite-size clusters (sol), and one that contains a single cluster that carries a finite fraction of the total mass (giant component or gel). The sol-gel transition is commonly discussed as a phase transition by qualitative analogy to vapor condensation. Here we show that the connection to thermodynamic phase transition is rigorous. We develop the statistical thermodynamics of irreversible binary aggregation in discrete finite systems, obtain the partition function for arbitrary kernel, and show that the emergence of the gel cluster has all the hallmarks of a phase transition, including an unstable van der Waals loop. We demonstrate the theory by presenting the complete pre- and post-gel solution for aggregation with the product kernel. PMID- 25748056 TI - Primer ID Informs Next-Generation Sequencing Platforms and Reveals Preexisting Drug Resistance Mutations in the HIV-1 Reverse Transcriptase Coding Domain. AB - Sequencing of a bulk polymerase chain reaction (PCR) product to identify drug resistance mutations informs antiretroviral therapy selection but has limited sensitivity for minority variants. Alternatively, deep sequencing is capable of detecting minority variants but is subject to sequencing errors and PCR resampling due to low input templates. We screened for resistance mutations among 184 HIV-1-infected, therapy-naive subjects using the 454 sequencing platform to sequence two amplicons spanning HIV-1 reverse transcriptase codons 34-245. Samples from 19 subjects were also analyzed using the MiSeq sequencing platform for comparison. Errors and PCR resampling were addressed by tagging each HIV-1 RNA template copy (i.e., cDNA) with a unique sequence tag (Primer ID), allowing a consensus sequence to be constructed for each original template from resampled sequences. In control reactions, Primer ID reduced 454 and MiSeq errors from 71 to 2.6 and from 24 to 1.2 errors/10,000 nucleotides, respectively. MiSeq also allowed accurate sequencing of codon 65, an important drug resistance position embedded in a homopolymeric run that is poorly resolved by the 454 platform. Excluding homopolymeric positions, 14% of subjects had evidence of >=1 resistance mutation among Primer ID consensus sequences, compared to 2.7% by bulk population sequencing. When calls were restricted to mutations that appeared twice among consensus sequence populations, 6% of subjects had detectable resistance mutations. The use of Primer ID revealed 5-15% template utilization on average, limiting the depth of deep sequencing sampling and revealing sampling variation due to low template utilization. Primer ID addresses important limitations of deep sequencing and produces less biased estimates of low-level resistance mutations in the viral population. PMID- 25748057 TI - Preparation and imaging of rhenium-188 labeled human serum albumin microsphere in orthotopic hepatoma rats. AB - OBJECTIVE: The present study relates to a method for preparing 188Re-labeled human serum albumin microspheres (HSAM) by 188Re(I)-tricarbonyl ion(188Re(OH2)3(CO)3)+). This radioactive particle can be subjected to radioembolization for liver tumor. METHODS: The particle sizes and conformations of HSA microspheres were analyzed by Particle sizes-Malvern mastersizer and Scanning Electron Microscope (SEM). For preparing 188Re(I)-tricarbonyl ion, the 188ReO4- was eluted from a 188W/188Re generator with saline. The radio labeling efficiency was analyzed with high-performance liquid chromatography (HPLC). Amino borane-reduced 188ReO4-was interacted with carbon oxide to form (188Re(OH2)3(CO)3]+). For preparing 188Re-HSA microspheres, the 188Re(I) tricarbonyl ion was added into a vial with HSA microspheres. The in vitro stability was investigated. The rat was injected with 188Re-HSA microspheres via hepatic artery route. Nano-SPECT/CT Imaging was acquired after injection of 188Re HSA microspheres. RESULTS: The shape of HSA microsphere was rough surfaced sphere or oval-shaped. The particle size was distributed between 20 and 35MUm. In the RP HPLC-UV chromatography, the yield of 188Re(I)-tricarbonyl ion was 75-80%. The labeling efficiency of 188Re-HSA microspheres in this method was more than 85%. After incubation, the 188Re(I)-tricarbonyl ion labeled HSA microspheres were found to be stable in vitro in normal saline and rat plasma. The result of Nano SPECT/CT Imaging quantification analysis indicated that the percentage of injection dose %ID was maintained at 95% ID-88% ID from 2 to 72h after injection with 188Re- HSA microspheres. CONCLUSIONS: The method of 188Re(I)-tricarbonyl ion labeled HSA microspheres can proceed with high labeling yield. Furthermore, this method provided a convenient method for radio-labeling of HSA microspheres with 188Re as well as a kit for manufacturing. PMID- 25748059 TI - The distinctive features of Indian malaria parasites. AB - Malaria and factors driving malaria are heterogeneous in India, unlike in other countries, and the epidemiology of malaria therefore is considered 'highly complex'. This complexity is primarily attributed to several unique features of the malaria parasites, mosquito vectors, malaria-susceptible populations, and ecoclimatic variables in India. Recent research on the genetic epidemiology of Indian malaria parasites has been successful in partly unraveling the mysteries underlying these complexities. PMID- 25748058 TI - Elevated AKAP12 in paclitaxel-resistant serous ovarian cancer cells is prognostic and predictive of poor survival in patients. AB - A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression free and overall survival in SOC patients. PMID- 25748060 TI - Clustured regularly interspersed short palindromic repeats (CRISPR) genetic diversity studies as a mean to reconstruct the evolution of the Mycobacterium tuberculosis complex. AB - The natural history of tuberculosis may be tackled by various means, among which the record of molecular scars that have been registered by the Mycobacterium tuberculosis complex (MTBC) genomes transmitted from patient to patient for tens of thousands years and possibly more. Recently discovered polymorphic loci, the CRISPR sequences, are indirect witnesses of the historical phage-bacteria struggle, and may be related to the time when the ancestor of today's tubercle bacilli were environmental bacteria, i.e. before becoming intracellular parasites. In this article, we present what are CRISPRs and try to summarize almost 20 years of research results obtained using the genetic diversity of the CRISPR loci in MTBC as a perspective for studying new models. We show that the study of the diversity of CRISPR sequences, thanks to "spoligotyping", has played a great role in our global understanding of the population structure of MTBC. PMID- 25748061 TI - Cutaneous pseudovasculitis, antiphospholipid syndrome and obstetric misadventure. AB - We present two women with severe obstetric complications from antiphospholipid (aPL) syndrome associated with a rare dermatological manifestation, cutaneous pseudovasculitis. Both of these women developed a rash on the palmar aspect of the hands during the post partum period, with histology consistent with microthrombotic disease, despite anticoagulation. Cutaneous pseudovasculitis appears to be a maternal manifestation of aPL coagulopathy, possibly reflecting the severity of the underlying pregnancy pathology. PMID- 25748062 TI - Erratum. PMID- 25748063 TI - Bioavailability of Micronutrients from Plant Foods: An Update. AB - Deficiencies of iron, zinc, iodine and vitamin A are widespread in the developing countries, poor bioavailability of these micronutrients from plant-based foods being the major reason for their wide prevalence. Diets predominantly vegetarian are composed of components that enhance as well as inhibit mineral bioavailability, the latter being predominant. However, prudent cooking practices and use of ideal combinations of food components can significantly improve micronutrient bioavailability. Household processing such as heat treatment, sprouting, fermentation and malting have been evidenced to enhance the bioavailability of iron and beta-carotene from plant foods. Food acidulants amchur and lime are also shown to enhance the bioavailability of not only iron and zinc, but also of beta-carotene. Recently indentified newer enhancers of micronutrient bioaccessibility include sulphur compound-rich Allium spices-onion and garlic, which also possess antioxidant properties, beta-carotene-rich vegetables-carrot and amaranth, and pungent spices-pepper (both red and black) as well as ginger. Information on the beneficial effect of these dietary compounds on micronutrient bioaccessibility is novel. These food components evidenced to improve the bioavailability of micronutrients are common ingredients of Indian culinary, and probably of other tropical countries. Fruits such as mango and papaya, when consumed in combination with milk, provide significantly higher amounts of bioavailable beta-carotene. Awareness of the beneficial influence of these common dietary ingredients on the bioavailability of micronutrients would help in devising dietary strategies to improve the bioavailability of these vital nutrients. PMID- 25748064 TI - Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population. AB - BACKGROUND: Past studies of blood T-cell phenotyping in patients with atopic dermatitis (AD) have provided controversial results and were mostly performed before the identification of TH9, TH17, and TH22 T-cell populations in human subjects. OBJECTIVE: We sought to quantify TH1, TH2, TH9, TH17, and TH22 T-cell populations and corresponding CD8(+) T-cell subsets in both cutaneous lymphocyte antigen (CLA)-positive and CLA(-) T-cell subsets in patients with AD and control subjects. METHODS: We studied 42 adults with severe AD (mean SCORAD score, 65) and 25 healthy subjects using an 11-color flow cytometric antibody panel. Frequencies of IFN-gamma-, IL-22-, IL-13-, IL-17-, and IL-9-producing CD4(+) and CD8(+) T cells were compared in CLA(-) and CLA(+) populations. RESULTS: We measured increased TH2/TC2/IL-13(+) and TH22/TC22/IL-22(+) populations (P < .1) in patients with severe AD versus control subjects, with significant differences in CLA(+) T-cell numbers (P < .01). A significantly lower frequency of CLA(+) IFN gamma-producing cells was observed in patients with AD, with no significant differences in CLA(-) T-cell numbers. The CLA(+) TH1/TH2 and TC1/TC2 ratio was highly imbalanced in patients with AD (10 vs 3 [P = .005] and 19 vs 7 [P < .001], respectively). Positive correlations were found between frequencies of IL-13- and IL-22-producing CD4(+) and CD8(+) T cells (r = 0.5 and 0.8, respectively; P < .0001), and frequencies of IL-13-producing CLA(+) cells were also correlated with IgE levels and SCORAD scores. Patients with AD with skin infections had higher CD4(+) IL-22(+) and IL-17(+) cell frequencies, which were highly significant among CLA(-) cells (IL-22: 3.7 vs 1.7 [P < .001] and IL-17: 1.7 vs 0.6 [P < .001]), with less significant effects among CLA(+) T cells (IL-22: 11 vs 7.5, P = .04). CONCLUSIONS: Severe AD is accompanied by expansion of skin-homing TH2/TC2 and TH22/TC22 subsets with lower TH1/TC1 frequencies. These data create a critical basis for studying alterations in immune activation in adults and pediatric patients with AD. PMID- 25748065 TI - Exposure to allergen and diesel exhaust particles potentiates secondary allergen specific memory responses, promoting asthma susceptibility. AB - BACKGROUND: Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood. OBJECTIVE: We sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children. METHODS: The effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes. RESULTS: DEP coexposure with HDM resulted in persistent TH2/TH17 CD127(+) effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased TH2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children. CONCLUSION: These findings suggest that DEP exposure results in accumulation of allergen-specific TH2/TH17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma. PMID- 25748066 TI - Insulin resistance, metabolic syndrome, and lung function in US adolescents with and without asthma. AB - BACKGROUND: Obesity increases both the risk of asthma and asthma severity and is a well-known risk factor for insulin resistance and the metabolic syndrome (MS) in children and adolescents. OBJECTIVE: We aimed to examine the association among obesity, insulin sensitivity, MS, and lung function in US adolescents with and without asthma. METHODS: We performed a cross-sectional study of 1429 adolescents aged 12 to 17 years in the 2007-2010 National Health and Nutrition Examination Survey. Adjusted regression was used to assess the relationships among obesity, insulin sensitivity/resistance, MS, and lung function in children with and without asthma. RESULTS: Insulin resistance was negatively associated with FEV1 and forced vital capacity (FVC) in adolescents with and without asthma, whereas MS was associated with lower FEV1/FVC ratios, with a more pronounced decrease found among asthmatic patients; these associations were driven by overweight/obese adolescents. Higher body mass index was associated with a decrease in FEV1/FVC ratios among adolescents with insulin resistance. Compared with healthy participants, adolescents with MS had an approximately 2% decrease in FEV1/FVC ratios, adolescents with asthma had an approximately 6% decrease, and those with MS and asthma had approximately 10% decreased FEV1/FVC ratios (P < .05). CONCLUSION: Insulin resistance and MS are associated with worsened lung function in overweight/obese adolescents. Asthma and MS synergistically decrease lung function, as do obesity and insulin resistance. These factors might contribute to the pathogenesis of asthma severity in obese patients and warrant further investigation. PMID- 25748068 TI - Are the differences in adulthood ill-health across the north-south divide and between Scotland and England also evident in early childhood health indicators? AB - Regional differences in adult morbidity and mortality within England (i.e., north south divide or gradient) and between England and Scotland (i.e., Scottish effect) are only partly explained by adult levels of socioeconomic status or risk factors. This suggests variation in early life, and is supported by the foetal origins and life-course literature which posits that birth outcomes and subsequent, cumulative exposures influence adult health. However, no studies have examined the north-south gradient or Scottish effect in health in the earliest years of life. The aims of the study were: i) to examine health indicators in English and Scottish children at birth and age three to establish whether regional differences exist; and ii) to establish whether observed changes in child health at age three were attributable to birth and/or early life environmental exposures. Respondents included 10,639 biological Caucasian mothers of singleton children recruited to the Millennium Cohort Study (MCS) in the year 2000. Outcome variables were: gestational age and birth weight, and height, body mass index (BMI), and externalising behavioural problems at age three. Region/country was categorised as: South (reference), Midlands, North (England), and Scotland. Respondents provided information on child, maternal, household, and socioeconomic characteristics. Results indicated no significant regional variations for gestational age or birth weight. At age three there was a north south gradient for externalising behaviour and a north-south divide in BMI which attenuated on adjustment. However, a north-south divide in height was not fully explained by adjustment. There was also evidence of a 'Midlands effect', with increased likelihood of shorter stature and behaviour problems. Results showed a Scottish effect for height and BMI in the unadjusted models, and height in the adjusted model, but a decreased likelihood of behaviour problems. Findings indicated no regional differences in health at birth, but some regional variation at age three supports the cumulative life-course model. PMID- 25748069 TI - Enantioselective organocatalytic alkylation of aldehydes and enals driven by the direct photoexcitation of enamines. AB - Disclosed herein is a photo-organocatalytic enantioselective alpha- and gamma alkylation of aldehydes and enals, respectively, with bromomalonates. The chemistry uses a commercially available aminocatalyst and occurs under illumination by a fluorescent light bulb in the absence of any external photoredox catalyst. Mechanistic investigations reveal the previously hidden ability of transiently generated enamines to directly reach an electronically excited state upon light absorption while successively triggering the formation of reactive radical species from the organic halides. At the same time, the ground state chiral enamines provide effective stereochemical induction for the enantioselective alkylation process. PMID- 25748067 TI - Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome. AB - BACKGROUND: DiGeorge syndrome affects more than 3.5 million persons worldwide. Partial DiGeorge syndrome (pDGS), which is characterized by a number of gene deletions in chromosome 22, including the chicken tumor virus number 10 regulator of kinase (Crk)-like (CrkL) gene, is one of the most common genetic disorders in human subjects. To date, the role of natural killer (NK) cells in patients with pDGS remains unclear. OBJECTIVE: We sought to define the effect of pDGS-related Crk haploinsufficiency on NK cell activation and cytotoxic immunological synapse (IS) structure and function. METHODS: Inducible CrkL-silenced NK cells were used to recapitulate the pDGS, CrkL-haploinsufficient phenotype. Findings were validated by using NK cells from patients with actual pDGS. Ultimately, deficits in the function of NK cells from patients with pDGS were restored by lentiviral transduction of CrkL. RESULTS: Silencing of CrkL expression inhibits NK cell function. Specifically, pDGS haploinsufficiency of CrkL inhibits accumulation of activating receptors, polarization of cytolytic machinery and key signaling molecules, and activation of beta2-integrin at the IS. Reintroduction of CrkL protein restores NK cell cytotoxicity. CONCLUSION: CrkL haploinsufficiency causes functional NK deficits in patients with pDGS by disrupting both beta2-integrin activation and activating receptor accumulation at the IS. Our results suggest that NK cell IS quality can directly affect immune status, providing a potential target for diagnosis and therapeutic manipulation in patients with pDGS and in other patients with functional NK cell deficiencies. PMID- 25748071 TI - Oxidative cleavage of allyl ethers by an oxoammonium salt. AB - A method to oxidatively cleave allyl ethers to their corresponding aldehydes mediated by an oxoammonium salt is described. Using a biphasic solvent system and mild heating, cleavage proceeds readily, furnishing a variety of alpha,beta unsaturated aldehydes and ketones. PMID- 25748070 TI - Electronic brachytherapy--current status and future directions. AB - In the past decade, electronic brachytherapy (EB) has emerged as an attractive modality for the treatment of skin lesions and intraoperative partial breast irradiation, as well as finding wider applications in intracavitary and interstitial sites. These miniature X-ray sources, which operate at low kilovoltage energies (<100 kV), have reduced shielding requirements and inherent portability, therefore can be used outside the traditional realms of the radiotherapy department. However, steep dose gradients and increased sensitivity to inhomogeneities challenge accurate dosimetry. Secondly, ease of use does not mitigate the need for close involvement by medical physics experts and consultant oncologists. Finally, further studies are needed to relate the more heterogeneous dose distributions to clinical outcomes. With these provisos, the practical convenience of EB strongly suggests that it will become an established option for selected patients, not only in radiotherapy departments but also in a range of operating theatres and clinics around the world. PMID- 25748072 TI - Triblock peptide-linker-lipid molecular design improves potency of peptide ligands targeting family B G protein-coupled receptors. AB - Two peptide-linker-lipid constructs were designed and prepared which target the parathyroid hormone 1 receptor, a family B G protein-coupled receptor. Both show increased agonist activity in a cell-based assay. The lipid moiety enables the formation of micelle-like nanostructures, which is shown to hinder proteolytic digestion and is expected to reduce renal clearance. PMID- 25748073 TI - Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. AB - OBJECTIVES: To map the current status of head-to-head comparative randomized evidence and to assess whether funding may impact on trial design and results. STUDY DESIGN AND SETTING: From a 50% random sample of the randomized controlled trials (RCTs) published in journals indexed in PubMed during 2011, we selected the trials with >= 100 participants, evaluating the efficacy and safety of drugs, biologics, and medical devices through a head-to-head comparison. RESULTS: We analyzed 319 trials. Overall, 238,386 of the 289,718 randomized subjects (82.3%) were included in the 182 trials funded by companies. Of the 182 industry sponsored trials, only 23 had two industry sponsors and only three involved truly antagonistic comparisons. Industry-sponsored trials were larger, more commonly registered, used more frequently noninferiority/equivalence designs, had higher citation impact, and were more likely to have "favorable" results (superiority or noninferiority/equivalence for the experimental treatment) than nonindustry sponsored trials. Industry funding [odds ratio (OR) 2.8; 95% confidence interval (CI): 1.6, 4.7] and noninferiority/equivalence designs (OR 3.2; 95% CI: 1.5, 6.6), but not sample size, were strongly associated with "favorable" findings. Fifty-five of the 57 (96.5%) industry-funded noninferiority/equivalence trials got desirable "favorable" results. CONCLUSION: The literature of head-to-head RCTs is dominated by the industry. Industry-sponsored comparative assessments systematically yield favorable results for the sponsors, even more so when noninferiority designs are involved. PMID- 25748074 TI - Rasch analysis suggested three unidimensional domains for Affiliate Stigma Scale: additional psychometric evaluation. AB - OBJECTIVES: To examine the psychometrics of the Affiliate Stigma Scale using rigorous psychometric analysis: classical test theory (CTT) (traditional) and Rasch analysis (modern). Differential item functioning (DIF) items were also tested using Rasch analysis. STUDY DESIGN AND SETTING: Caregivers of relatives with mental illness (n = 453; mean age: 53.29 +/- 13.50 years) were recruited from southern Taiwan. Each participant filled out four questionnaires: Affiliate Stigma Scale, Rosenberg Self-Esteem Scale, Beck Anxiety Inventory, and one background information sheet. RESULTS: CTT analyses showed that the Affiliate Stigma Scale had satisfactory internal consistency (alpha = 0.85-0.94) and concurrent validity (Rosenberg Self-Esteem Scale: r = -0.52 to -0.46; Beck Anxiety Inventory: r = 0.27-0.34). Rasch analyses supported the unidimensionality of three domains in the Affiliate Stigma Scale and indicated four DIF items (affect domain: 1; cognitive domain: 3) across gender. CONCLUSION: Our findings, based on rigorous statistical analysis, verified the psychometrics of the Affiliate Stigma Scale and reported its DIF items. We conclude that the three domains of the Affiliate Stigma Scale can be separately used and are suitable for measuring the affiliate stigma of caregivers of relatives with mental illness. PMID- 25748075 TI - Quantitative imaging. PMID- 25748076 TI - Bursts of transcranial electrical stimulation increase arousal in a continuous performance test. AB - Arousal reflects a state of generalised physiological activation, and its key role in cognition and behaviour has been extensively described. The regulation of arousal is controlled by specific nuclei located in the brainstem that contain widely distributed projections to the cortex and form the arousal systems. In humans, arousal has been commonly studied and modulated through behavioural paradigms, whereas in animals, direct electrical stimulation has been used to confirm the important role of these widely distributed structures. Recent evidence suggests that it might be possible to use transcranial electrical stimulation (tES) to non-invasively induce currents in the brainstem regions of the brain. Therefore, we hypothesise that, using a specific electrode arrangement, it might be possible to employ tES to stimulate subcortical-cortical neuromodulatory networks, inducing modulation of general arousal. The aim of the present study was to determine if it is possible to increase arousal during a discriminative reaction times (RTs) task, through the application of tES, to improve the subjects' performance. We developed 3 experiments: Experiment 1 validated the behavioural task, which was an adapted version of the continuous performance test. Experiment 2 aimed to show the task sensitivity to the level of activation. The results confirmed that the task was sensitive enough to reveal modulations of arousal. In Experiment 3, we applied bursts of tES concurrent with the onset of the relevant stimuli of the task to increase the physiological phasic activation of arousal. The skin conductance response was recorded during the experiment in addition to the RTs. The results showed a reduction of RTs and a concurrent increase in skin conductance during the real stimulation condition, which is consistent with a general increase in arousal. In all, these data support the effectiveness of bursts of tES in modulating arousal. PMID- 25748077 TI - Sensorimotor and social aspects of peripersonal space. PMID- 25748078 TI - Dying on the way: the influence of migrational mortality on clines. AB - Migrational mortality is introduced into the classical single-locus model for migration and selection. Genotype-independent migration follows selection, which may be soft or hard. For soft selection, the effect of mortality on the backward migration matrix is the same as in the Malecot model; for hard selection, some neutral results still hold, but some do not. For two diallelic demes, mortality can increase or decrease the stringency of the condition for protecting an allele from loss. In the discrete-space, continuous-time limit, mortality increases the diagonal elements of the migration rate matrix and decreases its off-diagonal elements. Were it not for the same result in the Malecot model, it would be surprising that mortality does not alter the general diffusion limit for multiple alleles, arbitrary multidimensional migration, and arbitrary selection. PMID- 25748079 TI - Prognostic value of vascular invasion in well-differentiated papillary thyroid carcinoma. AB - BACKGROUND: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hurthle cell, and poorly differentiated thyroid carcinomas, but its role in well differentiated papillary thyroid cancer (WDTC) remains unclear. METHODS: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). RESULTS: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naive WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. CONCLUSION: The presence of VI is not an independent predictor of outcome in WDTC. PMID- 25748080 TI - HER2-positive metastatic breast cancer: a changing scenario. AB - Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active. PMID- 25748081 TI - Potential roles of cytokines and chemokines in human intervertebral disc degeneration: interleukin-1 is a master regulator of catabolic processes. AB - OBJECTIVE: These studies investigated cytokine and chemokine receptor profiles in nucleus pulposus (NP) cells, and the effects of receptor stimulation on mRNA levels of extracellular matrix (ECM) components, degrading enzymes and cytokine and chemokine expression. METHOD: Immunohistochemistry (IHC) was performed to localise expression of CD4, CCR1, CXCR1 and CXCR2 in human NP tissue samples. Effects of cytokine and chemokine stimulation was performed to investigate effects related to ECM remodelling and modulation of cytokine and chemokine mRNA expression. RESULTS: IHC identified CD4, CCR1, CXCR1 and CXCR2 expression by NP cells. Differential expression profiles were observed for CD4 and CXCR2 in tissue samples from degenerate and infiltrated IVDs. In vitro stimulations of primary human NP cultures with IL-16, CCL2, CCL3, CCL7 or CXCL8 did not identify any modulatory effects on parameters associated with ECM remodelling or expression of other cytokines and chemokines. Conversely, IL-1 was seen to modulate ECM remodelling and expression of all other cytokines and chemokines investigated. CONCLUSION: This study demonstrates for the first time that NP cells express a number of cytokine and chemokine receptors and thus could respond in an autocrine or paracrine manner to cytokines and chemokines produced by NP cells, particularly during tissue degeneration. However, this study failed to demonstrate regulatory effects on ECM genes and degradative enzymes or other cytokines and chemokines for any target investigated, with the exception of IL-1. This suggests that IL-1 is a master regulator within the IVD and may exert regulatory potential over a plethora of other cytokines and chemokines. PMID- 25748082 TI - Fc-gamma receptors are not involved in cartilage damage during experimental osteoarthritis. AB - OBJECTIVE: Fc-gamma receptors (FcgammaRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcgammaRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcgammaRs may also play a role in osteoarthritis (OA)-related cartilage degradation. METHODS: FcgammaR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental OA was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor gamma-chain-deficient) or inhibitory (FcgammaRIIB-deficient) FcgammaRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover. RESULTS: Expression analyses revealed significant levels for all four types of murine FcgammaRs in mouse chondrocytes and cartilage tissue from newborn and 8 week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcgammaRs did not affect cartilage damage or bone turnover during DMM-induced OA in mice. CONCLUSION: While FcgammaRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcgammaRs do not influence cartilage destruction in experimental OA. This indicates that a certain threshold of inflammation is a prerequisite for FcgammaR-induced cartilage destruction in arthritis. PMID- 25748083 TI - Influence of chopstick size on taste evaluations. AB - This study explored the influence of the length of chopsticks on taste evaluations. Participants (N=78; M age=21.1 yr., SD=3.8) reported a greater liking for their food and higher purchase intentions when using long rather than short chopsticks. Findings also indicated that the long (vs short) chopsticks caused people to slow down when eating, resulting in greater eating duration and a higher number of mouthfuls. The findings of this study provide insights on research into the role of tableware in food intake. PMID- 25748084 TI - Examination of stigmatizing beliefs about depression and stigma-reduction effects of education by using implicit measures. AB - Stigmatizing beliefs about depression have been viewed as a barrier to seeking professional treatments. To reconsider frameworks used in previous research, the present study utilized Brief Implicit Association Tests (BIATs) and examined the following two topics: (i) whether participants tend to hold dangerous beliefs about depression, and (ii) whether stigmatizing beliefs can be reduced through education. Japanese university students (48 women, 82 men; M age=20.2 yr.) voluntarily participated in the study and were randomly assigned to three conditions in which they received different educational texts (biomedical, psychosocial, and bio-psychosocial). Participants completed repeated assessments (baseline, post-education, and 4-wk. follow-up), in which they were administered BIATs measuring beliefs about being weak-willed and dangerousness of people with depression, along with explicit measures of blameworthiness, dangerous beliefs, and of other related variables. BIATs at baseline indicated that the participants did not tend to hold the belief about dangerousness. There was no significant reduction of beliefs about being weak-willed and dangerousness of people with depression, which were measured by BIATs, after reading the educational texts. PMID- 25748085 TI - The effect of grounding the human body on mood. AB - Earthing (grounding) refers to bringing the body in contact with the Earth. Health benefits were previously reported, but no study exists about mood. This study was conducted to assess if Earthing improves mood. 40 adult participants were either grounded or sham-grounded (no grounding) for 1 hr. while relaxing in a comfortable recliner chair equipped with a conductive pillow, mat, and patches connecting them to the ground. This pilot project was double-blinded and the Brief Mood Introspection Scale (comprising 4 mood scales) was used. Pleasant and positive moods statistically significantly improved among grounded-but not sham grounded-participants. It is concluded that the 1-hr. contact with the Earth improved mood more than expected by relaxation alone. More extensive studies are, therefore, warranted. PMID- 25748086 TI - Are sporadic fidgety movements as clinically relevant as is their absence? AB - BACKGROUND: Infants with normal fidgety movements at 3 to 5 months after term are very likely to show neurologically normal development, while the absence of fidgety movements is an early marker for an adverse neurological outcome, mainly cerebral palsy (CP). The clinical significance of so-called sporadic fidgety movements (i.e., fidgety movements occur isolated in a few body parts and are of 1- to 3-second-duration) is not yet known. AIMS: Our objective was to determine whether infants who had developed CP and had sporadic fidgety movements have a better outcome than infants who did not have fidgety movements. STUDY DESIGN: Longitudinal study. Retrospective analysis of prospectively collected data. SUBJECTS: 61 infants who developed CP (46 male, 15 female; 29 infants born preterm; videoed for the assessment of movements and postures at 9 to 16 weeks post-term age). OUTCOME MEASURES: The Gross Motor Function Classification System (GMFCS) was applied at 3 to 5 years of age. RESULTS: There was no difference between children diagnosed with CP who had sporadic fidgety movements at 9 to 16 weeks post-term age (n = 9) and those who never developed fidgety movements (n = 50) with regard to their functional mobility and activity limitation at 3 to 5 years of age. One infant had normal FMs and developed unilateral CP, GMFCS Level I; the remaining infant had abnormal FMs and developed bilateral CP, GMFCS Level II. CONCLUSIONS: There is no evidence that the occurrence of occasional isolated fidgety bursts indicates a milder type of CP. PMID- 25748088 TI - Urocortin 2 in cardiovascular health and disease. AB - Urocortin (Ucn)-2 - corticotropin-releasing hormone receptor 2 signaling has favorable effects in the cardiovascular system, including coronary vasodilatation, with increased coronary blood flow and conductance and augmented cardiac contractility and output, as well as protection against ischemia/reperfusion injury. Indeed, several animal studies have confirmed the salutary therapeutic effects of Ucn-2 in chronic heart failure, with improvements in cardiac performance and animal survival. In addition, recent clinical trials have demonstrated the benefits of Ucn-2 in patients with stable chronic heart failure on optimal medical therapy. PMID- 25748087 TI - Targeting the Spleen Tyrosine Kinase with Fostamatinib as a Strategy against Waldenstrom Macroglobulinemia. AB - PURPOSE: Waldenstrom macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target. EXPERIMENTAL DESIGN: We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells. RESULTS: In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity. CONCLUSIONS: Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG. PMID- 25748089 TI - Comparison of diffusion-weighted imaging and gadoxetic acid-enhanced MR images in the evaluation of hepatocellular carcinoma and hypovascular hepatocellular nodules. AB - PURPOSE: To compare diffusion-weighted imaging (DWI) and gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI) in the evaluation of hepatocellular carcinoma (HCC) and nodules at high risk of HCC transformation. MATERIALS AND METHODS: We evaluated nodules' size, vascular pattern, and signal intensity on hepatobiliary phase images and on DWI of 105 nodules (41 cirrhotic patients). RESULTS: A total of 35/66 HCCs identified on Gd EOB-DTPA MRI showed hyperintensity on DWI. A total of 25/39 nodules (hypovascular and hypointense nodule on hepatobiliary phase images) progressed to HCC (higher risk for nodules >=10mm in size and hyperintense on DWI, P<.05). CONCLUSION: Gd EOB-DTPA MRI demonstrated a significant role in the identification of nodule at higher risk of HCC transformation, and hyperintensity on DWI was associated with progression to HCC. PMID- 25748090 TI - F-18 FDG PET/MRI findings of primary breast lymphoma in two cases: FDG PET/MRI findings of primary breast lymphoma. AB - We present the integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) findings of diffuse large B-cell lymphoma involving the breast in two women. They were admitted with palpable breast masses. PET/MRI revealed high (18)F-fluorodeoxyglucose (FDG) uptake in multinodular enhancing masses without other FDG-avid foci. Diffusion-weighted imaging showed restricted water diffusion and dynamic contrast MRI showed rapid increase and washout kinetics. High FDG accumulation in tumor is related to washout kinetics. We present the usefulness of integrated PET/MRI for lesion characterization and total body staging in breast lymphoma. PMID- 25748091 TI - Adolescent perspectives on the return of individual results in genomic addiction research. AB - This study surveyed all adolescents who were enrolled in behavioral genomic research and provided DNA to a biobank, including 320 patients undergoing treatment for substance and conduct problems (SCPs) and 109 non-SCP controls. Participants selected from three options on the return of individual genomic results (RIR) and rated eight methods of re-contact. Most individuals with SCPs (77.8%) and non-SCP controls (72.5%) wanted RIR involving health or behavioral implications. The majority of individuals with SCPs (67.2%) and non-SCP controls (69.7%) indicated that phone re-contact was 'best', with e-mail (22.5% SCPs, 33.9% non-SCPs) and social networking websites (21.3% SCPs, 20.2% non-SCPs) being viable options. These results suggest a layered approach for RIR: phone calls, followed by e-mails and a secure message to a social networking account. Data from this special and vulnerable population, which includes youth involved in the criminal justice system and substantial minority participation, bring an essential and missing perspective to the discussion of RIR. PMID- 25748092 TI - Catechol-O-methyltransferase genotype and response to Compensatory Cognitive Training in outpatients with schizophrenia. AB - The catechol-O-methyltransferase (COMT) ValMet polymorphism is associated with cognitive functioning in schizophrenia and may predict cognitive training outcomes. This study aimed to explore the contribution of COMT genotype in predicting improvement following Compensatory Cognitive Training (CCT). We conducted mixed factorial analysis of variance to examine COMT genotype as a predictor of response to CCT (i.e. improved cognitive performance) in 41 participants with schizophrenia-spectrum disorders. We also explored the effect of CCT treatment and COMT genotype on psychiatric symptom severity, functional capacity, and subjective quality of life. Met carrier status did not predict CCT treatment outcomes. COMT genotype may exert only modest effects on cognitive training response. Further research with larger samples is needed to establish genetic predictors of response to cognitive training. PMID- 25748093 TI - Visualization of HIV-1 interactions with penile and foreskin epithelia: clues for female-to-male HIV transmission. AB - To gain insight into female-to-male HIV sexual transmission and how male circumcision protects against this mode of transmission, we visualized HIV-1 interactions with foreskin and penile tissues in ex vivo tissue culture and in vivo rhesus macaque models utilizing epifluorescent microscopy. 12 foreskin and 14 cadaveric penile specimens were cultured with R5-tropic photoactivatable (PA) GFP HIV-1 for 4 or 24 hours. Tissue cryosections were immunofluorescently imaged for epithelial and immune cell markers. Images were analyzed for total virions, proportion of penetrators, depth of virion penetration, as well as immune cell counts and depths in the tissue. We visualized individual PA virions breaching penile epithelial surfaces in the explant and macaque model. Using kernel density estimated probabilities of localizing a virion or immune cell at certain tissue depths revealed that interactions between virions and cells were more likely to occur in the inner foreskin or glans penis (from local or cadaveric donors, respectively). Using statistical models to account for repeated measures and zero inflated datasets, we found no difference in total virions visualized at 4 hours between inner and outer foreskins from local donors. At 24 hours, there were more virions in inner as compared to outer foreskin (0.0495 +/- 0.0154 and 0.0171 +/- 0.0038 virions/image, p = 0.001). In the cadaveric specimens, we observed more virions in inner foreskin (0.0507 +/- 0.0079 virions/image) than glans tissue (0.0167 +/- 0.0033 virions/image, p<0.001), but a greater proportion was seen penetrating uncircumcised glans tissue (0.0458 +/- 0.0188 vs. 0.0151 +/- 0.0100 virions/image, p = 0.099) and to significantly greater mean depths (29.162 +/- 3.908 vs. 12.466 +/- 2.985 MUm). Our in vivo macaque model confirmed that virions can breach penile squamous epithelia in a living model. In summary, these results suggest that the inner foreskin and glans epithelia may be important sites for HIV transmission in uncircumcised men. PMID- 25748094 TI - Enantioselective apoptosis induced by individual isomers of bifenthrin in Hep G2 cells. AB - Bifenthrin (BF) has been used in racemate for agricultural purposes against soil insects, leading to increased inputs into soil environments. However, most of the studies about the toxicology research on BF were performed in its racemic form. The aim of the present study was to evaluate the enantiomer-specific cis-BF induced apoptosis and intracellular reactive oxygen species (ROS) generation on human hepatocarcinoma cells (Hep G2). The results of cell viability assay and cytoflow assay indicated an obvious enantioselective hepatocyte toxicity of 1S cis-BF in Hep G2 cells. 1S-cis-BF also induced ROS production, up-regulated Bax protein expression and down-regulated Bcl-2 expression levels. The present study suggested that enantioselective toxicity should be evaluated on currently used chiral pesticides, such as synthetic pyrethroids. PMID- 25748095 TI - Mitogen-activated protein kinase and Akt pathways are involved in 4-n-nonyphenol induced apoptosis in mouse Sertoli TM4 cells. AB - Nonylphenol (NP) is considered an important environmental toxicant, which may disrupt male reproductive system. The aim of this study was to investigate 4-n nonylphenol (4-n-NP) induced apoptosis and its related mechanism in mouse Sertoli cell line, TM4 cells. Our results showed that NP treatment (0.1, 1, 10, 20 and 30 MUM) decreased cell viability and induced apoptosis in the cells, accompanied by alteration of Bcl-2 family mRNA expression, activation of caspases-3, release of Ca(2+), and increase of reactive oxygen species (ROS) generation. Subsequently, it was found that the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in the cells were markedly decreased, and maleic dialdehyde (MDA) content was increased by NP treatment. Then activation of the mitogen-activated protein kinases (MAPKs) pathways and inhibition of Akt pathway were simultaneously detected in NP challenged TM4 cells. Taken together, it was concluded that NP induced cytotoxicity and apoptosis in TM4 cells, and the apoptosis may be mediated via MAPKs and Akt pathways in addition to Ca(2+) release and ROS generation. PMID- 25748096 TI - First-in-human transcatheter tricuspid valve repair in a patient with severely regurgitant tricuspid valve. AB - BACKGROUND: Severe tricuspid regurgitation is associated with poor prognosis; however, there are limited Class I indications for intervention, and high surgical risk patients may go untreated. We report the first-in-human successful transcatheter tricuspid valve repair for severe tricuspid regurgitation. OBJECTIVES: The objective of this study was to show the feasibility of a transcatheter tricuspid annular repair. METHODS: Compassionate-use approval for the procedure was obtained from the regulatory organization in Germany. To perform the transcatheter bicuspidization of the tricuspid valve, the Mitralign system was used to place pledgeted sutures by means of a trans-jugular venous approach. Insulated radiofrequency wires were positioned 2 to 5 mm from the base of the posterior leaflet, 2.6 cm apart. The sutures were drawn together and locked, plicating the posterior annulus. RESULTS: Reconstruction of the 3 dimensional transesophageal echocardiographic dataset at baseline revealed a tricuspid valve annular area of 14.1 cm(2), and effective regurgitant orifice area was 1.35 cm(2). There was a significant reduction in annular area (57%) and effective regurgitant orifice area (53%) measured with 3-dimensional transesophageal echocardiography, at 6.05 cm(2) and 0.63 cm(2), respectively. Hemodynamic parameters also improved with a reduction in right atrial pressure from 22 mm Hg at baseline, to 9 mm Hg and an increase in left ventricular stroke volume from 42 ml at baseline to 72 ml. CONCLUSIONS: Transcatheter tricuspid valve repair could become an effective treatment for high-surgical risk patients who are non-responsive to optimal medical therapy. PMID- 25748097 TI - Transcatheter tricuspid valve intervention: the next frontier. PMID- 25748098 TI - Particulate air pollution and carotid artery stenosis. PMID- 25748099 TI - MRI monitoring of pathological changes in the spinal cord in patients with multiple sclerosis. AB - The spinal cord is a clinically important site that is affected by pathological changes in most patients with multiple sclerosis; however, imaging of the spinal cord with conventional MRI can be difficult. Improvements in MRI provide a major advantage for spinal cord imaging, with better signal-to-noise ratio and improved spatial resolution. Through the use of multiplanar MRI, identification of diffuse and focal changes in the whole spinal cord is now routinely possible. Corroborated by related histopathological analyses, several new techniques, such as magnetisation transfer, diffusion tension imaging, functional MRI, and proton magnetic resonance spectroscopy, can detect non-focal, spinal cord pathological changes in patients with multiple sclerosis. Additionally, functional MRI can reveal changes in the response pattern to sensory stimulation in patients with multiple sclerosis. Through use of these techniques, findings of cord atrophy, intrinsic cord damage, and adaptation are shown to occur largely independently of focal spinal cord lesion load, which emphasises their relevance in depiction of the true burden of disease. Combinations of magnetisation transfer ratio or diffusion tension imaging indices with cord atrophy markers seem to be the most robust and meaningful biomarkers to monitor disease evolution in early multiple sclerosis. PMID- 25748100 TI - Spinal cord pathology in multiple sclerosis. PMID- 25748101 TI - Screening for atrial fibrillation after stroke or TIA. PMID- 25748102 TI - Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. AB - BACKGROUND: Among patients with atrial fibrillation, the risk of stroke is highest for those with a history of stroke; however, oral anticoagulants can lower the risk of recurrent stroke by two-thirds. No consensus has been reached about how atrial fibrillation should be investigated in patients with stroke, and its prevalence after a stroke remains uncertain. We did a systematic review and meta-analysis to estimate the proportion of patients newly diagnosed with atrial fibrillation after four sequential phases of cardiac monitoring after a stroke or transient ischaemic attack. METHODS: We searched PubMed, Embase, and Scopus from 1980 to June 30, 2014. We included studies that provided the number of patients with ischaemic stroke or transient ischaemic attack who were newly diagnosed with atrial fibrillation. We stratified cardiac monitoring methods into four sequential phases of screening: phase 1 (emergency room) consisted of admission electrocardiogram (ECG); phase 2 (in hospital) comprised serial ECG, continuous inpatient ECG monitoring, continuous inpatient cardiac telemetry, and in-hospital Holter monitoring; phase 3 (first ambulatory period) consisted of ambulatory Holter; and phase 4 (second ambulatory period) consisted of mobile cardiac outpatient telemetry, external loop recording, and implantable loop recording. The primary endpoint was the proportion of patients newly diagnosed with atrial fibrillation for each method and each phase, and for the sequential combination of phases. For each method and each phase, we estimated the summary proportion of patients diagnosed with post-stroke atrial fibrillation using random-effects meta analyses. FINDINGS: Our systematic review returned 28,290 studies, of which 50 studies (comprising 11,658 patients) met the criteria for inclusion in the meta analyses. The summary proportion of patients diagnosed with post-stroke atrial fibrillation was 7.7% (95% CI 5.0-10.8) in phase 1, 5.1% (3.8-6.5) in phase 2, 10.7% (5.6-17.2) in phase 3, and 16.9% (13.0-21.2) in phase 4. The overall atrial fibrillation detection yield after all phases of sequential cardiac monitoring was 23.7% (95% CI 17.2-31.0). INTERPRETATION: By sequentially combining cardiac monitoring methods, atrial fibrillation might be newly detected in nearly a quarter of patients with stroke or transient ischaemic attack. The overall proportion of patients with stroke who are known to have atrial fibrillation seems to be higher than previously estimated. Accordingly, more patients could be treated with oral anticoagulants and more stroke recurrences prevented. FUNDING: Heart and Stroke Foundation of Canada, and Natural Science and Engineering Research Council of Canada. PMID- 25748103 TI - Outcomes and resource use of non-small cell lung cancer (NSCLC) patients treated with first-line platinum-based chemotherapy across Europe: FRAME prospective observational study. AB - INTRODUCTION: FRAME was a prospective observational study that captured real world data on patients with advanced or metastatic non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapies as first-line treatment (FLT) across Europe. As previously reported, most patients observed in the study had initiated FLT with either pemetrexed, gemcitabine, vinorelbine or taxanes in combination with a platinum. Baseline patient and disease characteristics including age, performance status, and histology varied (all p<0.01) across cohorts. METHODS: Consenting adult patients initiating FLT for advanced or metastatic NSCLC with platinum-based chemotherapy, with or without a targeted agent, entered the study between April 2009 and February 2011. The choice of FLT was left to physicians' discretion per routine clinical practice. The primary objective was to evaluate overall survival (OS) across platinum-based doublet chemotherapy cohorts and key secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented. RESULTS: Median OS in months was 10.3 across cohorts (n=1524), 10.7 for pemetrexed (n=569), 10.0 for gemcitabine (n=360), 9.1 for taxanes (n=295), and 10.7 for vinorelbine (n=300). For patients with non-squamous NSCLC who received cisplatin (n=616, 40% of total), median OS in months was 10.6 across the cohorts, 11.6 for pemetrexed, 8.4 for gemcitabine, 9.6 for taxanes, and 9.9 for vinorelbine. CONCLUSIONS: FRAME describes real-world treatment patterns and survival for patients initiating FLT for advanced or metastatic NSCLC between 2009 and 2011 across Europe. PMID- 25748105 TI - Organic aerosols associated with the generation of reactive oxygen species (ROS) by water-soluble PM2.5. AB - We compare the relative toxicity of various organic aerosol (OA) components identified by an aerosol mass spectrometer (AMS) based on their ability to generate reactive oxygen species (ROS). Ambient fine aerosols were collected from urban (three in Atlanta, GA and one in Birmingham, AL) and rural (Yorkville, GA and Centerville, AL) sites in the Southeastern United States. The ROS generating capability of the water-soluble fraction of the particles was measured by the dithiothreitol (DTT) assay. Water-soluble PM extracts were further separated into the hydrophobic and hydrophilic fractions using a C-18 column, and both fractions were analyzed for DTT activity and water-soluble metals. Organic aerosol composition was measured at selected sites using a high-resolution time-of-flight AMS. Positive matrix factorization of the AMS spectra resolved the organic aerosol into isoprene-derived OA (Isop_OA), hydrocarbon-like OA (HOA), less oxidized oxygenated OA, (LO-OOA), more-oxidized OOA (MO-OOA), cooking OA (COA), and biomass burning OA (BBOA). The association of the DTT activity of water soluble PM2.5 (WS_DTT) with these factors was investigated by linear regression techniques. BBOA and MO-OOA were most consistently linked with WS_DTT, with intrinsic water-soluble activities of 151 +/- 20 and 36 +/- 22 pmol/min/MUg, respectively. Although less toxic, MO-OOA was most widespread, contributing to WS_DTT activity at all sites and during all seasons. WS_DTT activity was least associated with biogenic secondary organic aerosol. The OA components contributing to WS_DTT were humic-like substances (HULIS), which are abundantly emitted in biomass burning (BBOA) and include highly oxidized OA from multiple sources (MO-OOA). Overall, OA contributed approximately 60% to the WS_DTT activity, with the remaining probably from water-soluble metals, which were mostly associated with the hydrophilic WS_DTT fraction. PMID- 25748106 TI - [Selective laser trabeculoplasty (SLT): our experience in African blacks]. AB - INTRODUCTION: The purpose of our study was to evaluate in the short and medium term, intraocular pressure results after selective laser trabeculoplasty in black patients with chronic open angle glaucoma or isolated ocular hypertension. MATERIALS AND METHODS: We conducted a retrospective study with a mean 12.5-month follow-up in black patients who underwent SLT. Inclusion criteria were: an open iridocorneal angle greater than or equal to Schaeffer grade 3, data recorded and available on trabecular pigmentation, data on SLT parameters available, and intraocular pressure by Goldmann applanation tonometry recorded.A positive result was defined as a post-laser IntraOcular Pressure (IOP) less than 21 mmHg after 1 month follow-up. The main motivation was the reduction of number of eye drops used. Performed first was a treatment of the inferior 180 degrees (3:00-9:00), possibly supplemented by a second session at 15 days or 1 month if a pressure decrease was noted after the first session. IOP results were evaluated prior to SLT, immediately following SLT and then depending on the drop in pressure. Statistical analysis was performed using the EPI.info 7 software. RESULTS: A total of 69 eyes of 40 patients treated with SLT were identified. The mean IOP prior to SLT was 18.3 mmHg +/- 4. Our results showed 90% of patients who positively responded to the treatment (10% failure) with a mean IOP decrease of 2.3 +/- 1 mmHg, that is 13%, by the second week. The mean pressure decrease continued to 4.78 +/- 1 mmHg for patients (30%) in the group treated for 360 degrees , that is 27% in the same period of time. SLT permitted discontinuation of a prostaglandin in 60% (42 cases). Eyes on triple-drug therapy went from 23 before SLT to 5 following SLT (a 26% decline), eyes on two medications went from 32 to 16 (24% decline). In result association tests, only pigmentation of the angle and visual field stage had a statistically significant probability. DISCUSSION: In our experience, SLT is indicated in black patients to potentiate less effective treatments, to reduce the number of drops in order to limit side effects, but also to avoid or delay monotherapy treatment-naive, hypertensive eyes. CONCLUSION: In the short and medium term, SLT brought about an IOP decrease in 90% of black patients, and discontinuation of a prostaglandin in 60% of our patients. In addition, the iridocorneal angle in blacks appears to be less pigmented than previously thought, and a protocol systematically treating 360 degrees seems to provide better results. PMID- 25748104 TI - Murine lung cancer induces generalized T-cell exhaustion. AB - BACKGROUND: Cancer is known to modulate tumor-specific immune responses by establishing a microenvironment that leads to the upregulation of T-cell inhibitory receptors, resulting in the progressive loss of function and eventual death of tumor-specific T-cells. However, the ability of cancer to impact the functionality of the immune system on a systemic level is much less well characterized. Because cancer is known to predispose patients to infectious complications including sepsis, we hypothesized that the presence of cancer alters pathogen-directed immune responses on a systemic level. MATERIALS AND METHODS: We assessed systemic T-cell coinhibitory receptor expression, cytokine production, and apoptosis in mice with established subcutaneous lung cancer tumors and in unmanipulated mice without cancer. RESULTS: Results indicated that the frequencies of programmed death-1-positive, B and T lymphocyte attenuator positive, and 2B4(+) cells in both the CD4(+) and CD8(+) T-cell compartments were increased in mice with localized cancer relative to non-cancer controls, and the frequencies of both CD4(+) and CD8(+) T-cells expressing multiple different inhibitory receptors were increased in cancer animals relative to non-cancer controls. Additionally, 2B4(+)CD8(+) T-cells in cancer mice exhibited reduced interleukin-2 and interferon-gamma, whereas B and T lymphocyte attenuator positive CD8(+) T-cells in cancer mice exhibited reduced interleukin-2 and tumor necrosis factor. Conversely, CD4(+) T-cells in cancer animals demonstrated an increase in the frequency of annexin V(+) apoptotic cells. CONCLUSIONS: Taken together, these data suggest that the presence of cancer induces systemic T-cell exhaustion and generalized immune suppression. PMID- 25748107 TI - Tungsten carbonyl sigma-complexes with charge-compensated nido-carboranyl thioether ligands. AB - Charge-compensated nido-carboranyl thioether ligands [7-MeS-10-Me2S-7,8-C2B9H10] and [7,8-(MeS)2-10-Me2S-7,8-C2B9H9] were prepared and fully characterized. They readily react with labile tungsten carbonyls to give sigma-complexes - mono substituted (CO)5W[7-MeS-10-Me2S-7,8-C2B9H10-kappa(1)-S(1)] and (CO)5W[7,8-(MeS)2 10-Me2S-7,8-C2B9H9-kappa(1)-S(1)] and chelate (CO)4W[7,8-(MeS)2-10-Me2S-7,8 C2B9H9-kappa(2)-S(1),S(2)]. The synthesized metallocomplexes were characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction. The donor ability of the 7-methylsulfide-nido-carborane ligand is not sensitive to introduction of the charge-compensating dimethylsulfonium group. PMID- 25748108 TI - Brief report: Contextual predictors of African American adolescents' ethnic racial identity affirmation-belonging and resistance to peer pressure. AB - The current study examined whether contextual factors (i.e., familial cultural socialization, percentage of same-ethnicity friends in high school, and neighborhood ethnic-racial composition) predicted ethnic-racial identity affirmation-belonging and, in turn, resistance to peer pressure to engage in problem behavior. Participants were 250 African American adolescents (M age = 15.57 years; SD = 1.22). Consistent with ecological theory, findings indicated that familial cultural socialization and percentage of same-ethnicity friends predicted greater ethnic-racial identity affirmation-belonging. Furthermore, consistent with notions from social identity theory, youth who reported higher ethnic-racial identity affirmation-belonging also reported greater resistance to peer pressure. Findings highlight the significance of the family and school context, as well as the importance of ethnic-racial identity affirmation belonging, for African American youths' positive development. PMID- 25748109 TI - Is education the best contraception: the case of teenage pregnancy in England? AB - This paper examines potential explanations for recent declines in teenage pregnancy in England. We estimate panel data models of teenage conception, birth and abortion rates from regions in England. Although point estimates are consistent with the promotion of long acting reversible contraception (LARC) having a negative impact on teenage pregnancy rates, the effects are generally small and statistically insignificant. In contrast, improvements in educational achievement and, to a lesser extent, increases in the non-white proportion of the population are associated with large and statistically significant reductions in teenage pregnancy. PMID- 25748110 TI - Challenging logics of complex intervention trials: community perspectives of a health care improvement intervention in rural Uganda. AB - Health systems in many African countries are failing to provide populations with access to good quality health care. Morbidity and mortality from curable diseases such as malaria remain high. The PRIME trial in Tororo, rural Uganda, designed and tested an intervention to improve care at health centres, with the aim of reducing ill-health due to malaria in surrounding communities. This paper presents the impact and context of this trial from the perspective of community members in the study area. Fieldwork was carried out for a year from the start of the intervention in June 2011, and involved informal observation and discussions as well as 13 focus group discussions with community members, 10 in-depth interviews with local stakeholders, and 162 context descriptions recorded through quarterly interviews with community members, health workers and district officials. Community members observed a small improvement in quality of care at most, but not all, intervention health centres. However, this was diluted by other shortfalls in health services beyond the scope of the intervention. Patients continued to seek care at health centres they considered inadequate as well as positioning themselves and their children to access care through other sources such as research and nongovernmental organization (NGO) projects. These findings point to challenges of designing and delivering interventions within a paradigm that requires factorial (reduced to predictable factors) problem definition with easily actionable and evaluable solutions by small-scale projects. Such requirements mean that interventions often work on the periphery of a health system rather than tackling the murky political and economic realities that shape access to care but are harder to change or evaluate with randomized controlled trials. Highly projectified settings further reduce the ability to genuinely 'control' for different health care access scenarios. We argue for a raised consciousness of how evaluation paradigms impact on intervention choices. PMID- 25748111 TI - Urban environment interventions linked to the promotion of physical activity: a mixed methods study applied to the urban context of Latin America. AB - This study summarizes the evidence from quantitative systematic reviews that assessed the association between urban environment attributes and physical activity. It also documents sociopolitical barriers and facilitators involved in urban interventions linked with active living in the ten most populated urban settings of Latin America. The synthesis of evidence indicates that several attributes of urban environments are associated with physical activity, including land-use mix and cycling infrastructure. The documentary analysis indicated that despite the benefits and opportunities provided by the programs and existing infrastructure in the examined cities, an overall concern is the rising inequality in the coverage and distribution of the initiatives in the region. If these programs and initiatives are to achieve a real population level effect that helps to reduce health disparities, they need to examine their social and spatial distribution within the cities so they can reach underserved populations and develop to their full potential. PMID- 25748112 TI - Non-disclosure of chronic kidney disease in primary care and the limits of instrumental rationality in chronic illness self-management. AB - Early detection of long term conditions is predicated on assumptions that lifestyle changes and medications can be used to reduce or manage the risk of condition progression. However, ambiguity remains about the nature and place of diagnostic disclosure to people in newly recognised or asymptomatic 'pre' conditions such as early stage chronic kidney disease (CKD). The disclosure of a diagnosis is relevant to instigating strategies which rely on actively engaging patients as self-managers of their own care. Whilst primary care routinely records a diagnosis of early stage CKD, little is known about how patients learn about the fact that they have CKD or how they respond to this. This study aimed to explore patients' experiences of disclosure of CKD in primary care settings. A nested qualitative study of participants recruited to a trial of an intervention for CKD patients in Greater Manchester, UK was undertaken. A purposive sample of 26 patients, with a mean age of 72 years (range 59-89, median 71), were interviewed during 2012. Interview transcripts were analysed using constant comparative techniques. Narrative accounts reflected limited or partial disclosure of CKD; often cast in vague terms as "nothing to worry about". How patients described themselves in terms of participation and their tendencies towards 'active' or 'passive' involvement in consultations emerged as important components of narratives around disclosure. The findings illuminate the ways in which diagnosis is oriented in a context where it is possible to meet the requirements for remuneration under a pay for performance system of primary care, whilst apparently not disclosing a label or a diagnosis to patients. This challenges the presumptions inherent in wider health policy objectives that are increasingly built on the notion of responsible patients and the ethos of the active support of self-management for pre-conditions. PMID- 25748113 TI - QTL for fatty acid composition and yield in linseed (Linum usitatissimum L.). AB - KEY MESSAGE: The combined SSR-SNP map and 20 QTL for agronomic and quality traits will assist in marker assisted breeding as well as map-based cloning of key genes in linseed. Flax is an important nutraceutical crop mostly because it is a rich source of omega-3 fatty acids and antioxidant compounds. Canada is the largest producer and exporter of oilseed flax (or linseed), creating a growing need to improve crop productivity and quality. In this study, a genetic map was constructed based on selected 329 single nucleotide polymorphic markers and 362 simple sequence repeat markers using a recombinant inbred line population of 243 individuals from a cross between the Canadian varieties CDC Bethune and Macbeth. The genetic map consisted of 15 linkage groups comprising 691 markers with an average marker density of one marker every 1.9 cM. A total of 20 quantitative trait loci (QTL) were identified corresponding to 14 traits. Three QTL each for oleic acid and stearic acid, two QTL each for linoleic acid and iodine value and one each for palmitic acid, linolenic acid, oil content, seed protein, cell wall, straw weight, thousand seed weight, seeds per boll, yield and days to maturity were identified. The QTL for cell wall, straw weight, seeds per boll, yield and days to maturity all co-located on linkage group 4. Analysis of the candidate gene regions underlying the QTL identified proteins involved in cell wall and fibre synthesis, fatty acid biosynthesis as well as their metabolism and yield component traits. This study provides the foundation for assisting in map-based cloning of the QTL and marker assisted selection of a wide range of quality and agronomic traits in linseed and potentially fibre flax. PMID- 25748114 TI - Development of genic cleavage markers in association with seed glucosinolate content in canola. AB - KEY MESSAGE: The orthologues of Arabidopsis involved in seed glucosinolates metabolism within QTL confidence intervals were identified, and functional markers were developed to facilitate breeding for ultra-low glucosinolates in canola. Further reducing the content of seed glucosinolates will have a positive impact on the seed quality of canola (Brassica napus). In this study 43 quantitative trait loci (QTL) for seed glucosinolate (GSL) content in a low-GSL genetic background were mapped over seven environments in Germany and China in a doubled haploid population from a cross between two low-GSL oilseed rape parents with transgressive segregation. By anchoring these QTL to the reference genomes of B. rapa and B. oleracea, we identified 23 orthologues of Arabidopsis involved in GSL metabolism within the QTL confidence intervals. Sequence polymorphisms between the corresponding coding regions of the parental lines were used to develop cleaved amplified polymorphic site markers for two QTL-linked genes, ISOPROPYLMALATE DEHYDROGENASE1 and ADENOSINE 5'-PHOSPHOSULFATE REDUCTASE 3. The genic cleavage markers were mapped in the DH population into the corresponding intervals of QTL explaining 3.36-6.88 and 4.55-8.67 % of the phenotypic variation for seed GSL, respectively. The markers will facilitate breeding for ultra-low seed GSL content in canola. PMID- 25748115 TI - Mapping the 'breaker' element of the gametocidal locus proximal to a block of sub telomeric heterochromatin on the long arm of chromosome 4S(sh) of Aegilops sharonensis. AB - KEY MESSAGE: The 'breaker' element ( GcB ) of the gametocidal locus derived from Aegilops sharonensis has been mapped to a region proximal to a block of sub telomeric heterochromatin on chromosome 4S (sh) L. The production of alien chromosome addition lines allows the transfer of useful genetic variation into elite wheat varieties from related wild species. However, some wild relatives of wheat, particularly those within the Sitopsis section of the genus Aegilops, possess chromosomes that are transmitted preferentially to the offspring when addition lines are generated. Species within the Sitopsis group possess the S genome, and among these species, Aegilops sharonensis (2n = 14, S(sh)S(sh)) carries the S(sh) genome which is closely related to the D genome of hexaploid wheat. Some S genome chromosomes carry gametocidal loci, which induce severe chromosome breakage in gametes lacking the gametocidal chromosome, and hence, result in gamete abortion. The preferential transmission of gametocidal loci could be exploited in wheat breeding, because linking gametocidal loci with important agronomic traits in elite wheat varieties would ensure retention of these traits through successive generations. In this study, we have mapped the breaker element of the gametocidal locus derived from Ae. sharonensis to the region immediately proximal to a block of sub-telomeric heterochromatin on the long arm of chromosome 4S(sh). PMID- 25748116 TI - CaAP2 transcription factor is a candidate gene for a flowering repressor and a candidate for controlling natural variation of flowering time in Capsicum annuum. AB - KEY MESSAGE: The APETALA2 transcription factor homolog CaAP2 is a candidate gene for a flowering repressor in pepper, as revealed by induced-mutation phenotype, and a candidate underlying a major QTL controlling natural variation in flowering time. To decipher the genetic control of transition to flowering in pepper (Capsicum spp.) and determine the extent of gene function conservation compared to model species, we isolated and characterized several ethyl methanesulfonate (EMS)-induced mutants that vary in their flowering time compared to the wild type. In the present study, we report on the isolation of an early-flowering mutant that flowers after four leaves on the primary stem compared to nine leaves in the wild-type 'Maor'. By genetic mapping and sequencing of putative candidate genes linked to the mutant phenotype, we identified a member of the APETALA2 (AP2) transcription factor family, CaAP2, which was disrupted in the early flowering mutant. CaAP2 is a likely ortholog of AP2 that functions as a repressor of flowering in Arabidopsis. To test whether CaAP2 has an effect on controlling natural variation in the transition to flowering in pepper, we performed QTL mapping for flowering time in a cross between early and late-flowering C. annuum accessions. We identified a major QTL in a region of chromosome 2 in which CaAP2 was the most significant marker, explaining 52 % of the phenotypic variation of the trait. Sequence comparison of the CaAP2 open reading frames in the two parents used for QTL mapping did not reveal significant variation. In contrast, significant differences in expression level of CaAP2 were detected between near isogenic lines that differ for the flowering time QTL, supporting the putative function of CaAP2 as a major repressor of flowering in pepper. PMID- 25748117 TI - Long-term outcome of patients with frequently recurrent non-muscle-invasive bladder carcinoma treated with one perioperative plus four weekly instillations of mitomycin C followed by monthly bacillus Calmette-Guerin (BCG) or alternating BCG and interferon-alpha2b instillations: prospective randomised FinnBladder-4 study. AB - BACKGROUND: Recurrent TaT1 non-muscle-invasive bladder cancer (NMIBC) patients should be treated with immediate instillation of chemotherapy after transurethral resection of bladder tumour followed by instillation therapy. OBJECTIVE: To present long-term results of a study exploring the effect of initial mitomycin C (MMC) instillations followed by two types of immunotherapy for patients with frequently recurring NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Between 1992 and 1996, 236 patients with frequently recurring TaT1 grade 1-2 NMIBC were enrolled in the prospective randomised multicentre FinnBladder-4 study. INTERVENTION: One perioperative plus four weekly instillations of MMC followed by monthly bacillus Calmette-Guerin (BCG) or alternating BCG and interferon (IFN)-alpha2b instillations for up to 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end points were time to first recurrence and time to progression. Secondary end points were disease-specific mortality and overall survival. The principal statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model plus cumulative incidence and Kaplan-Meier analyses. RESULTS AND LIMITATIONS: The median follow-up was 10.3 yr (maximum: 19.8 yr) in the MMC-BCG group and 8.6 yr (maximum: 19.8 yr) in the MMC-BCG/IFN group. The probability of recurrence was significantly lower in the MMC-BCG group than in the MMC-BCG/IFN group (43% vs 78% at 10 yr and 45% vs 80% at 15 yr, respectively; hazard ratio: 2.86; 95% confidence interval, 1.98-4.13; p<0.001). There were no significant differences in the probability of progression, disease free mortality, or overall survival. CONCLUSIONS: Perioperative plus four weekly MMC instillations followed by monthly BCG, instead of alternating BCG and IFN alpha2b instillations, significantly reduce long-term recurrence. PATIENT SUMMARY: We demonstrated in non-muscle-invasive bladder cancer patients with exceptionally frequent recurrences that the risk of long-term recurrence was reduced from 78-80% to 43-45% if one perioperative plus four weekly mitomycin C instillations were followed by monthly bacillus Calmette-Guerin (BCG) instillations for 1 yr instead of alternating instillations of BCG and interferon alpha2b. TRIAL REGISTRATION: The registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1992 and the last randomisation took place in 1996, before the current requirements concerning study registrations were implemented. PMID- 25748118 TI - [Perioperative management of a morbidly obese pregnant patient undergoing cesarean section under general anesthesia - case report]. AB - BACKGROUND AND OBJECTIVES: The increased prevalence of obesity in the general population extends to women of reproductive age. The aim of this study is to report the perioperative management of a morbidly obese pregnant woman, body mass index > 50 kg/m(2), who underwent cesarean section under general anesthesia. CASE REPORT: Pregnant woman in labor, 35 years of age, body mass index 59.8 kg/m(2). Caesarean section was indicated due to the presumed fetal macrosomia. The patient refused spinal anesthesia. She was placed in the ramp position with cushions from back to head to facilitate tracheal intubation. Another cushion was placed on top of the right gluteus to create an angle of approximately 15 degrees to the operating table. Immediately before induction of anesthesia, asepsis was carried out and sterile surgical fields were placed. Anesthesia was induced in rapid sequence, with Sellick maneuver and administration of remifentanil, propofol, and succinilcolina. Intubation was performed using a gum elastic bougie, and anesthesia was maintained with sevoflurane and remifentanil. The interval between skin incision and fetal extraction was 21 minutes, with the use of a Simpson's forceps scoop to assist in the extraction. The patient gave birth to a newborn weighing 4850 g, with Apgar scores of 2 in the 1(st) minute (received positive pressure ventilation by mask for about 2 minutes) and 8 in the 5(th) minute. The patient was extubated uneventfully. Multimodal analgesia and prophylaxis of nausea and vomiting was performed. Mother and newborn were discharged on the 4(th) postoperative day. PMID- 25748119 TI - Psychosocial factors in healthy ageing. PMID- 25748122 TI - New functionalized mercaptoundecahydrododecaborate derivatives for potential application in boron neutron capture therapy: synthesis, characterization and dynamic visualization in cells. AB - A series of mercaptoundecahydrododecaborate (B12H11SH(2-), BSH) bearing mono- and dicarboxyalkyl derivatives was prepared, characterized, and their reactivity towards amidation and esterification in DMF was evaluated. Symmetrical alkylation of BSH was achieved by treatment with primary haloalkyl carboxylic acids in aqueous acetonitrile to produce S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo dodecaborate tetramethylammonium salts. Unsymmetrically substituted sulfonium salts were obtained through a similar treatment of cyanoethylthioether undecahydro-closo-dodecaborate tetramethylammonium salt with haloalkyl carboxylic acid. Selective removal of the remaining cyanoethyl group upon treatment with tetramethylammonium hydroxide yielded S-carboxyalkyl-thioether-undecahydro-closo dodecaborate ditetramethylammonium salts. N,N'-dicyclohexylcarbodiimide (DCC) activated amidation of S,S-bis(carboxyalkyl)sulfonium-undecahydro-closo dodecaborate or S-carboxyalkyl-thioether-undecahydro-closo-dodecaborate tetramethylammonium salts with propargylamine provided the opportunity to install terminal acetylene groups for further conjugation. These compounds acted as powerful building blocks for the synthesis of a broad range of 1,4-disubstituted 1,2,3-triazole products in high yields, utilizing the Cu(I)-mediated click cycloaddition reaction. The synthesis of BSH-lipid with a two-tailed moiety was also achieved, by esterification of S,S-bis(carboxyethyl)sulfoniumundecahydro closo-dodecaborate(1-) tetramethylammonium salt with 1,2-O-distearoyl-sn-3 glycerol, which may prove useful in the liposomal boron delivery system. The bio compatibility of the azide-alkyne click reaction was then utilized by performing this reaction in cell culture. The distribution of BSH in HeLa cells could be visualized by treating the cells first with a BSH-alkyne compound and then with Alexa Fluor 488((r)) azide dye. The BSH-dye conjugate, which did not wash out, revealed the distribution of boron in the HeLa cells. Cytotoxicity assays of these BSH derivatives revealed that the synthesized BSH-conjugated triazoles possessed low cytotoxicity in HeLa cancer cells. Of these compounds, BSH conjugated triazole 15 induced a significant increase in the level of boron accumulation in HeLa cells. PMID- 25748121 TI - Epidemiology of mild traumatic brain injury and neurodegenerative disease. AB - Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury. PMID- 25748123 TI - Docking and binding free energy calculations of sirtuin inhibitors. AB - Sirtuins form a unique and highly conserved class of NAD(+)-dependent lysine deacylases. Among these the human subtypes Sirt1-3 has been implicated in the pathogenesis of numerous diseases such as cancer, metabolic syndromes, viral diseases and neurological disorders. Most of the sirtuin inhibitors that have been identified so far show limited potency and/or isoform selectivity. Here, we introduce a promising method to generate protein-inhibitor complexes of human Sirt1, Sirt2 and Sirt3 by means of ligand docking and molecular dynamics simulations. This method highly reduces the complexity of such applications and can be applied to other protein targets beside sirtuins. To the best of our knowledge, we present the first binding free energy method developed by using a validated data set of sirtuin inhibitors, where both a fair number of compounds (33 thieno[3,2-d]pyrimidine-6-carboxamide derivatives) was developed and tested in the same laboratory and also crystal structures in complex with the enzyme have been reported. A significant correlation between binding free energies derived from MM-GBSA calculations and in vitro data was found for all three sirtuin subtypes. The developed MM-GBSA protocol is computationally inexpensive and can be applied as a post-docking filter in virtual screening to find novel Sirt1-3 inhibitors as well as to prioritize compounds with similar chemical structures for further biological characterization. PMID- 25748120 TI - Current and future implications of basic and translational research on amyloid beta peptide production and removal pathways. AB - Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid beta peptide (Abeta). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Abeta produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Abeta. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Abeta. We also briefly outline how the emerging knowledge about the pathways involved in Abeta generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein". PMID- 25748124 TI - Optimization of low-cost biosurfactant production from agricultural residues through response surface methodology. AB - Biosurfactants are surface-active compounds capable of reducing surface tension and interfacial tension. Biosurfactants are produced by various microorganisms. They are promising replacements for chemical surfactants because of biodegradability, nontoxicity, and their ability to be produced from renewable sources. However, a major obstacle in producing biosurfactants at the industrial level is the lack of cost-effectiveness. In the present study, by using corn steep liquor (CSL) as a low-cost agricultural waste, not only is the production cost reduced but a higher production yield is also achieved. Moreover, a response surface methodology (RSM) approach through the Box-Behnken method was applied to optimize the biosurfactant production level. The results found that biosurfactant production was improved around 2.3 times at optimum condition when the CSL was at a concentration of 1.88 mL/L and yeast extract was reduced to 25 times less than what was used in a basic soybean oil medium (SOM). The predicted and experimental values of responses were in reasonable agreement with each other (Pred-R(2) = 0.86 and adj-R(2) = 0.94). Optimization led to a drop in raw material price per unit of biosurfactant from $47 to $12/kg. Moreover, the biosurfactant product at a concentration of 84 mg/L could lower the surface tension of twice-distilled water from 72 mN/m to less than 28 mN/m and emulsify an equal volume of kerosene by an emulsification index of (E24) 68% in a two-phase mixture. These capabilities made these biosurfactants applicable in microbial enhanced oil recovery (MEOR), hydrocarbon remediation, and all other petroleum industry surfactant applications. PMID- 25748125 TI - Increased frequency of circulating follicular helper T cells in lupus patients is associated with autoantibody production in a CD40L-dependent manner. AB - This study was to determine the frequency of circulating follicular helper T (Tfh) cells in patients with systemic lupus erythematosus (SLE) and investigate the relationship between Tfh cells and autoantibody production. An increased frequency of circulating Tfh cells was found in SLE patients, and there were positive co-relationship between Tfh cells and SLEDAI, serum IgG, Anti-nuclear antibody titers and anti-dsDNA (P=0.0004, 0.0006, 0.0237, 0.0000, respectively). B cells sorted from SLE patients produced more IgG than healthy controls in the presence of autologous CD4(+) T cells. CD4(+) T cells were further sorted into CXCR5(+) and CXCR5(-) cells, and CD4(+)CXCR5(+) T cells helped B cells producing more IgG than CD4(+)CXCR5(-) T cells. Blocking the interaction of T cells and B cells by anti-CD40L but not anti-ICOSL dramatically decreased antibody production in the co-culture system. This study suggests that increased frequency of circulating Tfh cells in SLE patients is associated with excess B-cell help and autoantibody production in a CD40L dependent manner. PMID- 25748126 TI - Synthesis, molecular docking and antitumor activity of novel pyrrolizines with potential as EGFR-TK inhibitors. AB - A new series of pyrrolizine derivatives 4-8c were synthesized, their structures were confirmed by spectral and elemental analyses. Cytotoxic activity of these compounds was evaluated against breast (MCF7), colon (HCT116) and liver (HEPG2) cancer cell lines using sulphorhodamine-B (SRB) assay method. All the tested compounds showed highly potent activity against MCF7 cell line with IC50 range equal 8-194 nM/ml and compound 8c was the best active one (IC50 = 8.6 nM/ml). 8b was the best active compound on both HCT116 and HEPG-2 cancer cell lines; its IC50 is 26.5 and 12.3 nM/ml respectively. Docking studies into ATP binding site of EGFR tyrosine kinase were performed to predict their scores and mode of binding to amino acids, moreover, inhibitory activity of these compounds against EGFR-TKs was evaluated; their inhibitory percent ranged from 40.4 to 97.6, compound 8c and 8b showed inhibitory activity at 97.6% and 88.4% respectively. PMID- 25748127 TI - [A therapeutic approach towards chronic granulomatous disease]. AB - Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID) characterized by the inability of phagocytes to produce reactive oxygen intermediates (ROIs) due to a defect in the NADPH oxidase complex. Recent studies have revealed that ROIs are involved in inflammatory signaling in phagocytes, illuminating the underlying mechanisms of hyper-inflammation in CGD. CGD patients frequently suffer from CGD-associated bowel inflammation, granuloma, and life threatening infections. Based on the discovery of the regulatory function of ROIs in the immune response, therapeutic methods for excessive inflammation focusing on inflammatory cytokines are being developed for CGD. Although hematopoietic stem cell (HSC) transplantation (HSCT) is a curative therapy for CGD, successful transplants greatly depend on HSC source selection and the degree of matching of potential donors. Gene therapy trials for PID have been performed on over 120 patients with no HLA identical donor for HSCT, and have demonstrated clinical benefits. Genotoxicity in HSC gene therapy trials has expanded our knowledge on the mechanisms of vector-associated clonal expansion of gene-modified cells, which will advance gene therapy development using self-inactivating retrovirus and lentivirus vectors. We will discuss the complications of HSCT for CGD. We will then outline the status of gene therapy approaches in the treatment of CGD. PMID- 25748128 TI - [Revertant somatic mosaicism in primary immunodeficiency diseases]. AB - Revertant somatic mosaicism has been described in an increasing number of genetic disorders including primary immunodeficiency diseases. Both back mutations leading to restoration of wild-type sequences and second-site mutations resulting in compensatory changes have been demonstrated in mosaic individuals. Recent studies identifying revertant somatic mosaicism caused by multiple independent genetic changes further support its frequent occurrence in primary immunodeficiency diseases. Revertant mosaicism acquires a particular clinical relevance because it may lead to selective growth advantage of the corrected cells, resulting in improvement of disease symptoms or atypical clinical presentations. This phenomenon also provides us unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. Here we review the recent findings of revertant somatic mosaicism in primary immunodeficiency diseases and discuss its clinical implications. PMID- 25748129 TI - [Management of borderline pulmonary arterial hypertension associated with connective tissue diseases]. AB - The prognosis of connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is so poor that early therapeutic intervention is advisable. Borderline PAH (21-24 mmHg mean pulmonary arterial pressure) is a concept created to distinguish cases that would become definite PAH. It is controversial whether borderline PAH cases with no symptoms should be treated, but therapeutic intervention in the case of borderline PAH is justified when systemic sclerosis (SSc) is in the background, because SSc-associated PAH shows an especially poor prognosis compared to PAH associated with other CTDs, while 42-55% of SSc associated borderline PAH cases become definite PAH within several years. However, cautious attention should be paid when pulmonary vasodilators are administered to SSc-associated PAH cases, because complications caused by SSc such as lung lesions, left heart diseases and pulmonary venous lesions can be obstacles to the success of the therapy. There is very little evidence of the efficacy of therapeutic intervention in borderline PAH. Clinical trials should be planned. PMID- 25748130 TI - [A new mechanism of autoantibody production: antigen presentation of misfolded protein by MHC class II]. AB - Recently a new pathogenic mechanism for autoantibody production was proposed. Misfolded proteins bind to MHC class II in the endoplasmic reticulum and are processed to be presented at the cell surface. Misfolded proteins are not trimmed to peptides, but are presented as they are together with MHC class II molecules. Such misfolded protein/MHC class II complex can stimulate B cells, but not T cells, and will induce autoantibody production. One of such examples is the case of IgG heavy chain (IgGH). HLA class II can bind IgGH and presents it to the cell surface. Such IgGH/HLA class II complex can be recognized by rheumatoid factor. Surprisingly, RA susceptible HLA class II alleles can present IgGH efficiently, but RA resistant HLA class II alleles cannot. Therefore susceptibility to certain autoimmune diseases may be determined by the affinity of misfolded autoantigens to certain HLA class II alleles. Such new autoimmune mechanisms may explain the unexplained autoantibody production mechanisms. PMID- 25748131 TI - [Topics of neuromyelitis optica]. AB - Neuromyelitis optica (NMO) has been revealed the difference in the pathology of multiple sclerosis since the anti-aquaporin 4 (AQP4) antibody associated with NMO has been found. The clinical epidemiological study has been reviewed, NMO-related patient number in Japan is estimated to be about 4400 people. The antibody positive patients against myelin-oligodendrocyte glycoprotein (MOG) are present in anti-AQP4 antibody-negative NMO patients. These patients have a characteristic with high frequency of optic neuritis and good response to therapy. In addition, by research in recent years, a new treatment such as anti-IL-6 therapy or anti complement therapy has been attempted to NMO. PMID- 25748132 TI - [A Uuifying hypothesis for the pathogenesis of systemic sclerosis based on the deficiency of transcription factor Fli1 - the development of a new animal model of systemic sclerosis -]. AB - Systemic sclerosis (SSc) is a multisystem connective tissue disease featured by immune abnormalities, vasculopathy and resultant fibrosis of the skin and various internal organs. Although the pathogenesis of SSc remains incompletely elucidated, it is currently accepted that this disease is caused by the complex interplay between hereditary and environmental factors. The deficiency of transcription factor Fli1, which is epigenetically suppressed in SSc dermal fibroblasts, potentially causes SSc-like phenotypical alteration in various cell types such as fibroblasts, endothelial cells, and macrophages, suggesting that Fli1 is a predisposing factor of SSc. KLF5 is another transcription factor which is suppressed in SSc dermal fibroblasts through an epigenetic mechanism. Importantly, double heterozygous mice for Fli1 and KLF5 develop three cardinal features of SSc, including immune abnormalities, vasculopathy and fibrosis. Therefore, these two transcription factors are likely to be critical predisposing factors regulating the development of SSc. Given that potential disease modifying drugs, bosentan and imatinib, reverse the expression and transcriptional activity of Fli1, the studies on the pathological process of double heterozygous mice and the impact of these transcription factors on various cell types may provide a new clue to further understand the pathogenesis of SSc leading to the development of new therapies. PMID- 25748133 TI - Five-year administration of tocilizumab to a patient with rheumatoid arthritis complicated by severe chronic heart failure. AB - We herein described the long-term administration of tocilizumab (TCZ) to a patient with rheumatoid arthritis (RA) complicated by three vessel coronary artery disease and severe heart failure (HF). A 41-year-old male was admitted to our hospital with exacerbated RA and congestive HF. Cardiac ultrasonography revealed diffuse hypokinesis with a left ventricular ejection fraction (LVEF) of 16.8% and New York Heart Association (NYHA) class III/IV HF. Swelling and tenderness were noted in most of his joints. Methotrexate (MTX) was initiated during his hospitalization and TCZ was introduced 6 months later. Our patient has been treated with MTX and TCZ for five years without any adverse events, and RA and HF have remained stable. Although it may be anecdotal, we suggest that TCZ may be used as a treatment option in patients with RA complicated by severe HF. PMID- 25748134 TI - Atomic scale microstructure and properties of Se-deficient two-dimensional MoSe2. AB - We study the atomic scale microstructure of nonstoichiometric two-dimensional (2D) transition metal dichalcogenide MoSe2-x by employing aberration-corrected high-resolution transmission electron microscopy. We show that a Se-deficit in single layers of MoSe2 grown by molecular beam epitaxy gives rise to a dense network of mirror-twin-boundaries (MTBs) decorating the 2D-grains. With the use of density functional theory calculations, we further demonstrate that MTBs are thermodynamically stable structures in Se-deficient sheets. These line defects host spatially localized states with energies close to the valence band minimum, thus giving rise to enhanced conductance along straight MTBs. However, electronic transport calculations show that the transmission of hole charge carriers across MTBs is strongly suppressed due to band bending effects. We further observe formation of MTBs during in situ removal of Se atoms by the electron beam of the microscope, thus confirming that MTBs appear due to Se-deficit, and not coalescence of individual grains during growth. At a very high local Se-deficit, the 2D sheet becomes unstable and transforms to a nanowire. Our results on Se deficient MoSe2 suggest routes toward engineering the properties of 2D transition metal dichalcogenides by deviations from the stoichiometric composition. PMID- 25748135 TI - The figure-of-nine leg position for anatomic anterior cruciate ligament reconstruction. AB - Anatomic double-bundle anterior cruciate ligament (ACL) reconstruction can restore the function and kinematics of the knee in ACL-deficient patients. Several outside-in drilling systems for accurate femoral tunnel creations have been developed. However, the femoral tunnel creation at the lower position of the intercondylar notch can be difficult in a usual leg position with the knee flexed at 90 degrees without varus stress. This technical note describes that the figure-of-nine leg position provides a better arthroscopic view to safely clean up the ACL femoral footprint located at the lower area of the lateral intercondylar wall. This position is useful to create the optimal femoral tunnels using the outside-in drilling technique, without damaging the lateral meniscus posterior root, lateral tibial eminence, and supplemental fibers that bridge the gap between the lateral meniscus and the ACL tibial insertion. PMID- 25748136 TI - Ventromedial hypothalamic neurons control a defensive emotion state. AB - Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers. PMID- 25748137 TI - Structural dynamics of myosin 5 during processive motion revealed by interferometric scattering microscopy. AB - Myosin 5a is a dual-headed molecular motor that transports cargo along actin filaments. By following the motion of individual heads with interferometric scattering microscopy at nm spatial and ms temporal precision we found that the detached head occupies a loosely fixed position to one side of actin from which it rebinds in a controlled manner while executing a step. Improving the spatial precision to the sub-nm regime provided evidence for an angstrom-level structural transition in the motor domain associated with the power stroke. Simultaneous tracking of both heads revealed that consecutive steps follow identical paths to the same side of actin in a compass-like spinning motion demonstrating a symmetrical walking pattern. These results visualize many of the critical unknown aspects of the stepping mechanism of myosin 5 including head-head coordination, the origin of lever-arm motion and the spatiotemporal dynamics of the translocating head during individual steps. PMID- 25748138 TI - A map of directional genetic interactions in a metazoan cell. AB - Gene-gene interactions shape complex phenotypes and modify the effects of mutations during development and disease. The effects of statistical gene-gene interactions on phenotypes have been used to assign genes to functional modules. However, directional, epistatic interactions, which reflect regulatory relationships between genes, have been challenging to map at large-scale. Here, we used combinatorial RNA interference and automated single-cell phenotyping to generate a large genetic interaction map for 21 phenotypic features of Drosophila cells. We devised a method that combines genetic interactions on multiple phenotypes to reveal directional relationships. This network reconstructed the sequence of protein activities in mitosis. Moreover, it revealed that the Ras pathway interacts with the SWI/SNF chromatin-remodelling complex, an interaction that we show is conserved in human cancer cells. Our study presents a powerful approach for reconstructing directional regulatory networks and provides a resource for the interpretation of functional consequences of genetic alterations. PMID- 25748140 TI - Maternal insulin-like growth factor 1 and 2 differentially affect the renin angiotensin system during pregnancy in the guinea pig. AB - OBJECTIVE: Insulin-like growth factors (IGFs) are known to interact with the renin-angiotensin system (RAS). We previously demonstrated that administration of IGF1 to guinea pigs in early to mid pregnancy promotes placental function and fetal growth in mid to late gestation. Early administration of IGF2 had sustained, but not acute, effects on these parameters and also on placental structural differentiation. Here, we aimed to determine whether the IGFs interact with the placental RAS in early to mid gestation to modulate placental development and increase fetal growth and survival, and if IGF2 binding the IGF2R is implicated in the sustained effects of IGF2 treatment. DESIGN: At day 20 of pregnancy, guinea pigs were infused with 1m g/kg/day of IGF1, IGF2, (Leu27)IGF2 or vehicle for 18days and sacrificed on either day 62 (late pregnancy) or during the infusion period on day 35 (early-mid pregnancy). Placental structure at day 35 was analyzed using morphometric technique and expression of RAS genes in the placenta and placental and plasma renin activity were measured at both time points. RESULTS: Compared with vehicle at day 35 of gestation, IGF1 infusion reduced the total midsagittal cross-sectional area of the placenta (-17%, p = 0.02) and the labyrinth area (-22%, p = 0.014) but did not alter the labyrinth volume nor labyrinth:interlobium ratios. IGF2 treatment did not affect placental structure. IGF1 did not alter placental mRNA for any of the RAS genes quantified at day 35 (AGTR1, ACE, AGT, TGFB1) but increased TGFB1 expression by more than 16 fold (p = 0.005) at day 62. IGF2 increased placental expression of AGTR1 (+88%, p = 0.03) and decreased AGT (-73%, p = 0.01) compared with the vehicle-treated group at day 35, and both IGF2 and (Leu27)IGF2 increased expression of TGFB1 at day 62 by 9-fold (p = 0.016) and 6-fold (p = 0.019) respectively. Both IGFs increased the ratio of active:total placental renin protein (+22% p = 0.026 p = 0.038) compared to vehicle compared to vehicle at day 35 but not 62. At day 62, IGF2-treated mothers showed a marked increase in total plasma renin (+495%) and active renin (+359%) compared to vehicle but decreased the ratio of active to total renin by 41% (p = 0.042). (Leu27)IGF2-treated animals had higher levels of placental active renin (+73%, p = 0.001) and total renin (+71%, p = 0.001) compared with the vehicle control. CONCLUSIONS: The data obtained in the current study suggest the potential for alternate roles for the induction of the RAS after IGF treatment. IGF1 and 2 treatments increase the activation of prorenin to renin in the placenta, possibly due to increased protease activity. In addition, IGF2 treatment in early pregnancy may enhance the maternal adaptation to pregnancy through stimulation of renin in the kidney. The sustained effects on placental differentiation and function after IGF2 treatment suggest therapeutic potential for exogenous administration of IGFs in improving pregnancy outcomes. PMID- 25748139 TI - Importin-beta modulates the permeability of the nuclear pore complex in a Ran dependent manner. AB - Soluble karyopherins of the importin-beta (impbeta) family use RanGTP to transport cargos directionally through the nuclear pore complex (NPC). Whether impbeta or RanGTP regulate the permeability of the NPC itself has been unknown. In this study, we identify a stable pool of impbeta at the NPC. A subpopulation of this pool is rapidly turned-over by RanGTP, likely at Nup153. Impbeta, but not transportin-1 (TRN1), alters the pore's permeability in a Ran-dependent manner, suggesting that impbeta is a functional component of the NPC. Upon reduction of Nup153 levels, inert cargos more readily equilibrate across the NPC yet active transport is impaired. When purified impbeta or TRN1 are mixed with Nup153 in vitro, higher-order, multivalent complexes form. RanGTP dissolves the impbeta*Nup153 complexes but not those of TRN1*Nup153. We propose that impbeta and Nup153 interact at the NPC's nuclear face to form a Ran-regulated mesh that modulates NPC permeability. PMID- 25748141 TI - Venomics, lethality and neutralization of Naja kaouthia (monocled cobra) venoms from three different geographical regions of Southeast Asia. AB - Previous studies showed that venoms of the monocled cobra, Naja kaouthia from Thailand and Malaysia are substantially different in their median lethal doses. The intraspecific venom variations of N. kaouthia, however, have not been fully elucidated. Here we investigated the venom proteomes of N. kaouthia from Malaysia (NK-M), Thailand (NK-T) and Vietnam (NK-V) through reverse-phase HPLC, SDS-PAGE and tandem mass spectrometry. The venom proteins comprise 13 toxin families, with three-finger toxins being the most abundant (63-77%) and the most varied (11-18 isoforms) among the three populations. NK-T has the highest content of neurotoxins (50%, predominantly long neurotoxins), followed by NK-V (29%, predominantly weak neurotoxins and some short neurotoxins), while NK-M has the least (18%, some weak neurotoxins but less short and long neurotoxins). On the other hand, cytotoxins constitute the main bulk of toxins in NK-M and NK-V venoms (up to 45% each), but less in NK-T venom (27%). The three venoms show different lethal potencies that generally reflect the proteomic findings. Despite the proteomic variations, the use of Thai monovalent and Neuro polyvalent antivenoms for N. kaouthia envenomation in the three regions is appropriate as the different venoms were neutralized by the antivenoms albeit at different degrees of effectiveness. BIOLOGICAL SIGNIFICANCE: Biogeographical variations were observed in the venom proteome of monocled cobra (Naja kaouthia) from Malaysia, Thailand and Vietnam. The Thai N. kaouthia venom is particularly rich in long neurotoxins, while the Malaysian and Vietnamese specimens were predominated with cytotoxins. The differentially expressed toxin profile accounts for the discrepancy in the lethal dose of the venom from different populations. Commercially available Thai antivenoms (monovalent and polyvalent) were able to neutralize the three venoms at different effective doses, hence supporting their uses in the three regions. While dose adjustment according to geographical region seems possible, changes to standard recommended dosage should only be made if further study validates that the monocled cobras within a population do not exhibit remarkable inter individual venom variation. PMID- 25748142 TI - Has Proteomics come of age in India? PMID- 25748144 TI - Distinguishing grief from depression during acute recovery from spinal cord injury. AB - OBJECTIVE: To examine whether grief is a psychometrically sound construct that is distinct from depression in individuals who have recently sustained a spinal cord injury (SCI). DESIGN: Cross-sectional survey. SETTING: Inpatient rehabilitation units at 3 geographically diverse, university-affiliated medical centers. PARTICIPANTS: Patients with SCI (N=206) were recruited (163 men [79.1%]). Most patients were non-Hispanic whites (n=175 [85.0%]). Most patients sustained a cervical SCI (n=134 [64.4%]). Various injury etiologies were represented, with the majority being accounted for by falls (n=72 [31.5%]) and vehicle-related accidents (n=69 [33.5%]). The mean time since injury was 53.5+/-40.5 days. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: An adapted version of the 12-item structured clinical interview for Prolonged Grief Disorder was used to assess symptoms of grief, and the Patient Health Questionnaire-9 was used to measure depression. Demographic and injury-related data were also collected. RESULTS: A principal component analysis (with direct oblimin rotation) of the grief measure suggested a 2-component solution. The content of items loading on the separate components suggested 2 subscales: loss (6 items; Cronbach alpha=.810) and trauma (6 items; Cronbach alpha=.823). Follow-up principal component analyses including both grief and depression measures suggested clear differentiation of grief-related loss from depression. The prevalence of clinically significant levels of grief was low (6%), and levels of depression were consistent with previous findings related to inpatient rehabilitation (23.5%). CONCLUSIONS: The items used to assess grief symptoms in patients participating in inpatient rehabilitation for recently sustained SCI appear to capture a psychometrically reliable construct that is distinct from that of depression. Research is needed on the predictive validity of early grief symptoms after SCI and the relation of grief to other psychological constructs over time. PMID- 25748143 TI - Patterns of lymph node metastasis from nasopharyngeal carcinoma based on the 2013 updated consensus guidelines for neck node levels. AB - PURPOSE: To explore patterns of node distribution in nasopharyngeal carcinoma (NPC) based on the 2013 updated guidelines for neck node levels. METHODS AND MATERIALS: We retrospectively reviewed the imaging documents of 3100 cases of newly diagnosed NPC between January 2010 and January 2013. All patients received an MRI scan. The scan range extended from 2 cm above the anterior clinoid process to the inferior margin of the sternal end of the clavicle. All MR images were evaluated by the multi-disciplinary treatment group of NPC. RESULTS: A total of 2679 (86.4%) cases had involved lymph nodes. The detailed distribution was: level Ia 0, level Ib 115 (4.3%), level IIa 1798 (67.1%), level IIb 2341 (87.4%), level III 1184 (44.2%), level IVa 350 (13.1%), level IVb 28 (1.0%), level Va,b 995 (37.1%), level Vc 49 (1.8%), level VI 0, level VIIa 2012 (75.1%), level VIIb 178 (6.6%), level VIII 53 (2.0%), level IX 2, level Xa 2, level Xb 3. Among patients with level VII involvement, only 6 (0.3%) were located at the medial group. Of the patients with level II disease, the upper borders of metastatic nodes in 25.9% cases were beyond the caudal edge of C1. Patients with level VIII, or IX, or X node metastasis were always with extensive ipsilateral lymphadenopathy, and the total number of involved nodes was ?6. There were 35 cases of lymphadenopathy beyond the range of the updated guidelines, located inside the trapezius muscles, but posterior to level V. CONCLUSIONS: This is the first description of nodal spread patterns based on the updated consensus guidelines. Involvement of the retropharyngeal nodes was mainly located at the lateral group, the medial group was rarely seen. The suggested upper border of level II cannot fully cover all the involved level II nodes. The posterior level V border is not enough to cover all level V lymphadenopathies for NPC. PMID- 25748145 TI - Prevalence of myofascial trigger points and diagnostic criteria of different muscles in function of the medial longitudinal arch. AB - OBJECTIVES: To evaluate the reliability of the used diagnostic criteria of latent trigger points (LTrPs) and pressure pain thresholds and to evaluate the prevalence of LTrPs in several muscles of the lower limb in subjects with a lower medial longitudinal arch (MLA) compared with controls. DESIGN: Cross-sectional study. SETTING: University campus. PARTICIPANTS: Subjects with a lower limb MLA (n=82) and controls (n=82) (N=164). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The navicular drop test was used to classify subjects with a lower MLA (>=10mm) and controls (5-9mm). The Simons et al recommended specific diagnostic criteria and pressure pain thresholds were used to evaluate the prevalence of LTrPs in several muscles of the lower limb, which was compared between the 2 groups. The reliability was evaluated using Cohen's kappa and intraclass correlation coefficient. The unpaired Student t test and chi-square test were used to evaluate the difference in the LTrP prevalence between the 2 groups. RESULTS: The intrarater reliability of the navicular drop test and the diagnosis of LTrPs was excellent, with the taut band and tender spot being the most reliable diagnostic criteria. In the lower MLA group, 60 subjects (73%) presented at least 1 LTrP whereas 57 controls (70%) presented at least 1 LTrP. The lower MLA group showed more LTrPs (4.46+/-4.10) than did controls (3.32+/-3.24) (P<.05). There were significantly (P<.05) more subjects with LTrPs in the flexor digitorum longus, tibialis anterior, and vastus medialis in the lower MLA group than in the control group. CONCLUSIONS: LTrPs are common in the lower limb muscles in both controls and subjects with a lower MLA. A lower MLA is associated with a higher prevalence of LTrPs, which are significant in the flexor digitorum longus, tibialis anterior, and vastus medialis. PMID- 25748146 TI - A chitosan-hyaluronan-based hydrogel-hydrocolloid supports in vitro culture and differentiation of human mesenchymal stem/stromal cells. AB - Three-dimensional (3D) cell culture platforms are increasingly utilized due to their ability to more closely mimic the in vivo microenvironment compared to traditional two-dimensional methods. Limitations of currently available 3D materials include lack of cell attachment, long polymerization times, and inclusion of undefined xenobiotics, and cytotoxic cross-linkers. Evaluated here is a unique hydrogel comprised of polyelectrolytic complex (PEC) fibers formed by hyaluronic acid and chitosan (CT). When hydrated with fetal bovine serum containing human mesenchymal stem/stromal cells (hMSCs), a hydrogel with an elastic modulus of 264+/-38 Pa formed in seconds with cells distributed throughout the matrix. Scanning electron microscopy showed a lattice-like meshwork of PEC fibers forming irregular compartments. hMSCs showed 48% viability during the first 24 h, with cell populations thereafter reaching a steady state for 14 days. hMSCs in the matrix were induced to differentiate to chondrogenic, osteogenic, and adipogenic phenotypes. Emergent features, at days 56 and 70, consisted of chondrogenesis on the surface of hydrogels induced to osteogenic and adipogenic phenotypes. Results indicate that this matrix may be useful for tissue engineering and disease modeling applications. PMID- 25748147 TI - Treatment: special conditions. Metabolic syndrome: obesity and the hypertension connection. PMID- 25748148 TI - [Epidemiology of Barrett's cancer in Japan: presents and perspectives]. PMID- 25748149 TI - [Pathogenesis of Barrett's esophageal cancer]. PMID- 25748150 TI - [Endoscopic diagnosis of early Barrett's neoplasia -The present status and future challenges-]. PMID- 25748151 TI - [Histopathologic diagnosis of Barrett's carcinoma -dysplasia and carcinoma and four unique histologic markers of Barrett's esophagus-]. PMID- 25748152 TI - [Impact of gut microbiota on host physiology and pathology]. PMID- 25748153 TI - [A case of MALT lymphoma of the colon, stomach, and small intestine]. AB - An 85-year-old man was diagnosed with mucosa-associated lymphoid tissue (MALT) lymphoma of the colon in 20XX. Although Helicobacter pylori eradication was performed as part of the treatment, it was ineffective. He was followed-up by colonoscopy for 4 years without additional treatment and there was no interval change;however, he was lost to follow-up 6 years after the first visit. Nine years after the initial diagnosis, he presented with new MALT lymphoma lesions in the stomach and small intestine. Genetic analysis showed that a biopsy specimen was positive for API2/MALT1 fusion gene, and IgH rearrangement showed monoclonal banding between colon and stomach. This suggested disseminated monoclonal API2/MALT1-positive MALT lymphoma of the colon, stomach, and small intestine. Careful attention should be paid to the appearance of multiple lesions in MALT lymphoma. PMID- 25748154 TI - [Chemoradiotherapy is effective for primary esophageal adenosquamous cell carcinoma but ineffective for the metastatic adenocarcinoma component]. AB - A 62-year-old man was referred to our hospital with dysphagia. Blood examination revealed significantly elevated serum CA19-9 levels but normal CEA and SCC levels. Imaging uncovered thoracic esophageal cancer with lung and bone metastasis, and subsequent endoscopic biopsy specimens of the primary esophageal tumor showed poorly differentiated squamous cell carcinoma. The patient underwent palliative chemoradiotherapy, but died due to progression of multiple metastases and increasing serum CA19-9 levels. Autopsy revealed adenocarcinoma in multiple metastatic foci, although the squamous component had disappeared in the primary and metastatic lesions. Therefore, we concluded that the adenocarcinoma component of adenosquamous cell carcinoma was refractory to chemoradiotherapy. PMID- 25748155 TI - [Four cases of 5-fluorouracil-related hyperammonemia in patients with large intestinal cancer and multiple liver metastases, including a case of hyperammonemia treated using hemodialysis]. AB - Systemic chemotherapy based on 5-fluorouracil (5-FU) is a standard treatment for unresectable or recurrent large intestinal cancer. Although hyperammonemia is a known side effect of 5-FU that can cause serious pathological conditions, only a few cases have been reported. We describe 4 cases of 5-FU-related hyperammonemia with impairment of consciousness in patients who received 5-FU chemotherapy for large intestinal cancer with multiple liver metastases. Hemodialysis was effective in 1 severe case. There have been no detailed reports on the use of hemodialysis for hyperammonemia caused by 5-FU. Renal dysfunction is considered to be a risk factor for hyperammonemia caused by 5-FU and it is necessary to pay particular attention in patients with renal dysfunction who receive chemotherapy with 5-FU. Here we summarize our cases together with 16 previously reported cases of hyperammonemia caused by 5-FU in Japan. PMID- 25748156 TI - [An autopsy case of penetration of a sigmoid colon diverticulum with septic shock during the treatment of lung cancer-related pain]. AB - A 70-year-old man presented with septic shock and abdominal pain during treatment of pain caused by stage IV lung adenocarcinoma. CT revealed air collection from the retroperitoneum to the muscle around the thigh. Septic shock due to retroperitoneal penetration from the digestive tract was suspected. Despite treatment attempts, the patient died. The autopsy diagnosis was penetration of a sigmoid colon diverticulum under the serosa. When a diverticulum is located near the mesenterium and the size of penetration is small, the air collection rather than fecal matter is likely to extend retroperitoneally. Abdominal pain is little manifest in the penetration in contrast to perforation into abdominal cavity, and the attention is needed. PMID- 25748157 TI - [A case of obstructive jaundice caused by MALT lymphoma of the common bile duct and the papilla of Vater]. AB - We report a rare case of mucosa-associated lymphoid tissue (MALT) lymphoma of the common bile duct and the papilla of Vater. A 66-year-old man was admitted to our hospital with right upper quadrant pain and jaundice. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography showed common bile duct stenosis. Further endoscopy revealed swelling of the papilla of Vater, with erosion at the ileal end. The patient was pathologically diagnosed with MALT lymphoma and treated for Helicobacter pylori eradication, after which the lesions improved. However, 1 year later, the lesions began to enlarge again;thus, he was treated with 6 courses of combination chemotherapy (R-CHOP). After treatment, the tumor and erosion of the papilla of Vater disappeared and the stenosis of the common bile duct improved. PMID- 25748158 TI - [A case of Wilson's disease in an elderly patient initially diagnosed with NASH]. AB - A 62-year-old female was admitted to our hospital for examination of icterus and thrombocytopenia. She had a history of diabetes mellitus (under treatment), and liver cirrhosis was evident on abdominal CT. Because she was clinically obese and had no past history of alcohol consumption, the initial diagnosis was NASH. However, subsequent MRI findings and normal serum transaminase levels were not consistent with this diagnosis. We then performed additional examinations, including liver biopsy, measurements of serum Cu and ceruloplasmin concentrations, and measurement of urinary Cu secretion, which resulted in a diagnosis of Wilson's disease. It is necessary to include Wilson's disease in the differential diagnosis of NASH in cases of unidentified liver disease even among elderly patients. PMID- 25748159 TI - [Overwhelming postsplenectomy infection during combination therapy with interferon ribavirin after living donor liver transplantation for hepatitis C: a case report]. AB - A 60-year old woman was admitted for reintroduction of interferon/ribavirin combination therapy to prevent the recurrence of hepatitis C following living donor liver transplantation (LDLT). She had also undergone splenectomy during LDLT to avoid postoperative pancytopenia due to hypersplenism. However, a few days after reintroduction of the therapy, she developed severe diarrhea and fever that progressed to circulatory and respiratory shock. Blood culture was positive for Streptococcus pneumoniae, leading to a diagnosis of overwhelming postsplenectomy infection (OPSI). Although the patient developed multi-organ failure, she ultimately recovered after intensive care including mechanical ventilation and hemodialysis. Once OPSI is suspected, intensive care should be commenced immediately given the disease' s fulminant clinical course and high mortality. Postoperative prophylaxis with the pneumococcal vaccine needs to be tested in a multi-center study. PMID- 25748160 TI - [A case of freeze-dried gas gangrene antitoxin for the treatment of Clostridium perfringens sepsis]. AB - A 66-year-old man was admitted to our hospital with high fever. We diagnosed a gas-containing liver abscess and performed percutaneous abscess drainage. However, 15 hours after admission, he developed massive intravascular hemolysis and acidosis. Sepsis due to Clostridium perfringens was suspected and we treated the patient intensively with multidisciplinary approaches, including antibiotics, mechanical ventilation, and renal replacement therapy. Furthermore, we administered freeze-dried gas gangrene antitoxin. Despite intensive care, the patient died 43 hours after admission. PMID- 25748161 TI - 3-Anhydro-6-hydroxy-ophiobolin A, a fungal sesterterpene from Bipolaris oryzae induced autophagy and promoted the degradation of alpha-synuclein in PC12 cells. AB - Autophagy is defined as an evolutionarily conserved process responsible for degradation of the cytoplasmic components including protein aggregates via the lysosomal machinery. Increasing evidence has linked defective autophagic degradation of protein aggregates with the pathogenesis of neurodegenerative disorders, and it is suggested that promotion of autophagy is regarded as a potential therapeutic for these diseases including Parkinson's disease (PD). Here we identified, 3-anhydro-6-hydroxy-ophiobolin A (X15-2), an ophiobolin derivative from Bipolaris oryzae that can strongly induce autophagic degradation of alpha synuclein, the major constituent of Lewy bodies. We showed that X15-2 induced autophagy is dependent on both Beclin1 and Beclin2. Knockout of ATG5 by CRISPER/Cas9 prevented X15-2 induced autophagy and degradation of alpha synuclein. Mechanistically, we showed that X15-2 induces ROS and the activation of JNK signaling for the autophagic degradation of alpha-synuclein in PC12 cells. PMID- 25748162 TI - Synthesis and melanogenesis evaluation of 3',4',7-trihydroxyflavanone derivatives and characterization of flavanone-BODIPY. AB - A class of flavanone was found to improve melanogenesis in B16F10 mouse melanoma cell line, but little is known about its target. Herein we described the synthesis and bioevaluation of sixteen 3',4',7-trihydroxyflavanone analogues and further synthesized a novel fluorescent flavanone-BODIPY, which could improve melanogenesis in B16F10 cell line by selectively binding to its endoplasmic reticulum. The fluorescent flavanone-BODIPY was proved to be a valuable probe for studying the localization of intracellular flavanone on living cells. PMID- 25748164 TI - Conformational dynamics of bacterial and human cytoplasmic models of the ribosomal A-site. AB - The aminoacyl-tRNA binding site (A-site) is located in helix 44 of small ribosomal subunit. The mobile adenines 1492 and 1493 (Escherichia coli numbering), forming the A-site bulge, act as a functional switch that ensures mRNA decoding accuracy. Structural data on the oligonucleotide models mimicking the ribosomal A-site with sequences corresponding to bacterial and human cytoplasmic sites confirm that this RNA motif forms also without the ribosome context. We performed all-atom molecular dynamics simulations of these crystallographic A-site models to compare their conformational properties. We found that the human A-site bulge is more internally flexible than the bacterial one and has different base pairing preferences, which result in the overall different shapes of these bulges and cation density distributions. Also, in the human A-site model we observed repetitive destacking of A1492, while A1493 was more stably paired than in the bacterial variant. Based on the dynamics of the A sites we suggest why aminoglycoside antibiotics, which target the bacterial A site, have lower binding affinities and anti-translational activities toward the human variant. PMID- 25748163 TI - LRP5 and plasma cholesterol levels modulate the canonical Wnt pathway in peripheral blood leukocytes. AB - Inflammation is triggered after invasion or injury to restore homeostasis. Although the activation of Wnt/beta-catenin signaling is one of the first molecular responses to cellular damage, its role in inflammation is still unclear. It was our hypothesis that the low-density lipoprotein (LDL) receptor related protein 5 (LRP5) and the canonical Wnt signaling pathway are modulators of inflammatory mechanisms. Wild-type (WT) and LRP5(-/-) mice were fed a hypercholesterolemic (HC) diet to trigger dislipidemia and chronic inflammation. Diets were supplemented with plant sterol esters (PSEs) to induce LDL cholesterol lowering and the reduction of inflammation. HC WT mice showed increased serum cholesterol levels that correlated with increased Lrp5 and Wnt/beta-catenin gene expression while in the HC LRP5(-/-) mice Wnt/beta-catenin pathway was shut down. Functionally, HC induced pro-inflammatory gene expression in LRP5(-/-) mice, suggesting an inhibitory role of the Wnt pathway in inflammation. Dietary PSE administration downregulated serum cholesterol levels in WT and LRP5(-/-) mice. Furthermore, in WT mice PSE increased anti-inflammatory genes expression and inhibited Wnt/beta-catenin activation. Hepatic gene expression of Vldlr, Lrp2 and Lrp6 was increased after HC feeding in WT mice but not in LRP5(-/-) mice, suggesting a role for these receptors in the clearance of plasmatic lipoproteins. Finally, an antiatherogenic role for LRP5 was demonstrated as HC LRP5(-/-) mice developed larger aortic atherosclerotic lesions than WT mice. Our results show an anti-inflammatory, pro-survival role for LRP5 and the Wnt signaling pathway in peripheral blood leukocytes. PMID- 25748166 TI - Neuroendocrine regulation of the stress response in adult zebrafish, Danio rerio. AB - The main objectives of this study were to investigate the dynamics of the cortisol stress response and the underlying molecular regulation in adult zebrafish exposed to acute and long-term stressors that differed in nature, duration and relative intensity. Fish showed a very rapid and prolonged increase in trunk cortisol concentrations, starting at around 15min and returning to basal levels at around 2h following exposure to acute stressors. In addition, acute stress affected significantly brain mRNA expression levels of several genes (corticotropin-releasing factor, crf; pro-opiomelanocortin, pomc; glucocorticoid receptor, gr; MR/GR ratio; prolactin, prl; hypocretin/orexin, hcrt; brain-derived neurotrophic factor, bdnf; c-fos). Exposure of fish to unpredictable relatively low-grade environmental and husbandry stressors (SP-1) did not affect the overall behaviour of fish, as well as trunk cortisol concentrations. Fish exposed to relatively higher-grade long-term stressors (SP-2) showed elevated cortisol levels as well as significant changes in most of gene transcripts. In particular, fish exposed to SP-2 showed statistically significant upregulation in brain gr, mr, prl and hcrt compared to SP-1 and control individuals. The highest mean values of bdnf transcripts were found in SP-2 exposed zebrafish and the lowest in control fish, while an approximately 5 to 6-fold upregulation was observed in c fos mean relative mRNA levels of long-term stress-exposed fish, regardless of stressor intensity, compared to control zebrafish. In conclusion, we developed realistic acute and unpredictable long-term stress protocols, based on husbandry and environmental stressors and physical, chemical, mechanical and social stimuli that fish may experience either in nature or under intensive rearing conditions. PMID- 25748165 TI - Heart ischemia results in connexin43 ubiquitination localized at the intercalated discs. AB - Efficient electric activation and action potential propagation in the heart largely depends on gap junction (GJ) channels, formed by connexins (Cx) localized at the intercalated discs (IDs). Therefore, fine-tuning and maintenance of GJ in cardiomyocytes is essential for normal heart function. Several mechanisms have been implicated in the regulation of the amount of Cx43 at the plasma membrane. Results from our lab demonstrated that Nedd4-mediated ubiquitination of Cx43 signals internalization and degradation of GJ. However, the pathophysiological relevance of this mechanism has never been addressed before. The main objective of this study was to evaluate the involvement of ubiquitination on GJ remodeling, in the ischemic heart. To address this, we used the rat heart Langendorff model and evaluated the ubiquitination profile of Cx43 and its interaction with Nedd4, after 30 min of no-flow ischemia. By confocal microscopy, we show that ischemia induces extensive co-localization of ubiquitin and Nedd4 with Cx43 localized at IDs. Moreover, by subcellular fractionation and co-immunoprecipitation assays, we demonstrate an increased interaction with Nedd4 and ubiquitination of Cx43 localized at IDs. Altogether, these results suggest that ubiquitin is involved in the remodeling of GJ during myocardial ischemia, which requires the recruitment of Nedd4. PMID- 25748167 TI - It takes acid, rather than ice, to freeze glucose. AB - Plasma glucose levels provide the cornerstone of diabetes evaluation. Unfortunately, glucose levels drop in vitro due to glycolysis. Guidelines provide suitable conditions which minimize glycolysis, such as immediate centrifugation or the use of ice/water slurry storage containers. For obvious practical reasons, most laboratories use blood collection tubes containing glycolysis inhibitors. We describe the effect of a variety of commonly used blood collection tubes on in vitro stability of glucose. Furthermore, we looked at the validity of the assumption that glycolytic activity is minimal when blood is kept in an ice/water slurry. Sodium fluoride alone does not reduce in vitro glycolysis in the first 120 minutes after phlebotomy. Addition of citrate almost completely prevented in vitro glycolysis, but showed a positive bias (0.2 mmol/l) compared to control. This is partly due to a small drop in glucose level in control blood, drawn according to the current guidelines. This drop occurs within 15 minutes, in which glycolysis has been described to be minimal and acceptable. NaF-EDTA-citrate based test tubes provide the best pre-analytical condition available. Furthermore, glucose levels are not stable in heparinized blood placed in an ice/water slurry. We strongly advise the use of NaF-EDTA-citrate based test tubes in diabetes research. PMID- 25748168 TI - Hot flush severity during the menopausal transition and early postmenopause: beyond hormones. AB - BACKGROUND: Understanding factors promoting symptom severity is essential to developing innovative symptom management models. AIM: To investigate hot flush severity during the menopausal transition (MT) and early postmenopause and effects of age, MT stages, age of onset of late stage and final menstrual period (FMP), estrogen, follicle stimulating hormone (FSH), cortisol, anxiety, perceived stress, body mass index, smoking, alcohol use and exercise. METHODS: A subset of participants in the Seattle Midlife Women's Health Study (n = 291 with up to 6973 observations) provided data during the late reproductive, early and late MT stages and early postmenopause, including menstrual calendars, annual health questionnaires, and symptom diaries and urine specimens assayed for hormones several times per year. Multilevel modeling with an R program was used to test models accounting for hot flush severity. RESULTS: Hot flush severity persisted through the MT stages and peaked during the late MT stage, diminishing after the second year postmenopause. In individual analyses, hot flush severity was associated with being older, being in the late MT stage or early postmenopause, beginning the late MT stage at a younger age and reporting greater anxiety. In a model including only endocrine factors, hot flush severity was significantly associated with higher FSH and lower estrone levels. An integrated model revealed dominant effects of late MT stage and early postmenopause, with anxiety contributing to hot flush severity. CONCLUSIONS AND IMPLICATIONS: Hot flush severity was affected largely by reproductive aging and anxiety, suggesting symptom management models that modulate anxiety and enhance women's experience of the menopausal transition and early postmenopause. PMID- 25748169 TI - Long-Term Air Pollution Exposure and Blood Pressure in the Sister Study. AB - BACKGROUND: Exposure to air pollution has been consistently associated with cardiovascular morbidity and mortality, but mechanisms remain uncertain. Associations with blood pressure (BP) may help to explain the cardiovascular effects of air pollution. OBJECTIVE: We examined the cross-sectional relationship between long-term (annual average) residential air pollution exposure and BP in the National Institute of Environmental Health Sciences' Sister Study, a large U.S. cohort study investigating risk factors for breast cancer and other outcomes. METHODS: This analysis included 43,629 women 35-76 years of age, enrolled 2003-2009, who had a sister with breast cancer. Geographic information systems contributed to satellite-based nitrogen dioxide (NO2) and fine particulate matter (<= 2.5 MUm; PM2.5) predictions at participant residences at study entry. Generalized additive models were used to examine the relationship between pollutants and measured BP at study entry, adjusting for cardiovascular disease risk factors and including thin plate splines for potential spatial confounding. RESULTS: A 10-MUg/m(3) increase in PM2.5 was associated with 1.4 mmHg higher systolic BP (95% CI: 0.6, 2.3; p < 0.001), 1.0-mmHg higher pulse pressure (95% CI: 0.4, 1.7; p = 0.001), 0.8-mmHg higher mean arterial pressure (95% CI: 0.2, 1.4; p = 0.01), and no significant association with diastolic BP. A 10-ppb increase in NO2 was associated with a 0.4-mmHg (95% CI: 0.2, 0.6; p < 0.001) higher pulse pressure. CONCLUSIONS: Long-term PM2.5 and NO2 exposures were associated with higher blood pressure. On a population scale, such air pollution related increases in blood pressure could, in part, account for the increases in cardiovascular disease morbidity and mortality seen in prior studies. PMID- 25748170 TI - Recombinant Escherichia coli strains with inducible Campylobacter jejuni single domain hemoglobin CHb expression exhibited improved cell growth in bioreactor culture. AB - Maintaining an appropriate concentration of dissolved oxygen in aqueous solution is critical for efficient operation of a bioreactor, requiring sophisticated engineering design and a system of regulation to maximize oxygen transfer from the injected air bubbles to the cells. Bacterial hemoglobins are oxygen-binding proteins that transfer oxygen from the environment to metabolic processes and allow bacteria to grow even under microaerophilic conditions. To improve the oxygen utilization efficiency of cells and overcome the oxygen shortage in bioreactors, the gene coding for the Campylobacter jejuni single domain hemoglobin (CHb) gene was artificially synthesized and functionally expressed under the control of inducible expression promoters PT7 and Pvgh in Escherichia coli. The effects of the recombinants PT7-CHb and Pvgh-CHb on cell growth were evaluated in aerobic shake flasks, anaerobic capped bottles and a 5-L bioreactor, and a pronounced improvement in cell biomass was observed for CHb-expressing cells. To determine the growth curves, CHb gene expression, and CHb oxygen binding capacity of specific recombinants with different promoters, we determined the time course of CHb gene expression in the two recombinants by semi quantitative RT-PCR and CO differential spectrum assays. Based on the growth patterns of the two recombinants in the bioreactor, we proposed different recombinant types with optimal performance under specific culture conditions. PMID- 25748171 TI - Adrenergic receptor beta2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. AB - Stress and its related hormones epinephrine (E) and norepinephrine (NE) play a crucial role in tumor progression. Macrophages in the tumor microenvironment (TME) polarized to M2 is also a vital pathway for tumor deterioration. Here, we explore the underlying role of macrophages in the effect of stress and E promoting breast cancer growth. It was found that the weight and volume of tumor in tumor bearing mice were increased, and dramatically accompanied with the rising E level after chronic stress using social isolation. What is most noteworthy, the number of M2 macrophages inside tumor was up-regulated with it. The effects of E treatment appear to be directly related to the change of M2 phenotype is reproduced in vitro. Moreover, E receptor ADRbeta2 involved in E promoting M2 polarization was comprehended simultaneously. Our results imply psychological stress is influential on specific immune system, more essential for the comprehensive treatment against tumors. PMID- 25748172 TI - Poly(ADP-ribose) protects vascular smooth muscle cells from oxidative DNA damage. AB - Vascular smooth muscle cells (VSMCs) undergo death during atherosclerosis, a widespread cardiovascular disease. Recent studies suggest that oxidative damage occurs in VSMCs and induces atherosclerosis. Here, we analyzed oxidative damage repair in VSMCs and found that VSMCs are hypersensitive to oxidative damage. Further analysis showed that oxidative damage repair in VSMCs is suppressed by a low level of poly (ADP-ribosyl)ation (PARylation), a key post-translational modification in oxidative damage repair. The low level of PARylation is not caused by the lack of PARP-1, the major poly(ADP-ribose) polymerase activated by oxidative damage. Instead, the expression of poly(ADP-ribose) glycohydrolase, PARG, the enzyme hydrolyzing poly(ADP-ribose), is significantly higher in VSMCs than that in the control cells. Using PARG inhibitor to suppress PARG activity facilitates oxidative damage-induced PARylation as well as DNA damage repair. Thus, our study demonstrates a novel molecular mechanism for oxidative damage induced VSMCs death. This study also identifies the use of PARG inhibitors as a potential treatment for atherosclerosis. PMID- 25748173 TI - Protein tyrosine phosphatase PTPRT as a regulator of synaptic formation and neuronal development. AB - PTPRT/RPTPrho is the most recently isolated member of the type IIB receptor-type protein tyrosine phosphatase family and its expression is restricted to the nervous system. PTPRT plays a critical role in regulation of synaptic formation and neuronal development. When PTPRT was overexpressed in hippocampal neurons, synaptic formation and dendritic arborization were induced. On the other hand, knockdown of PTPRT decreased neuronal transmission and attenuated neuronal development. PTPRT strengthened neuronal synapses by forming homophilic trans dimers with each other and heterophilic cis complexes with neuronal adhesion molecules. Fyn tyrosine kinase regulated PTPRT activity through phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT. Phosphorylation induced homophilic cis dimerization of PTPRT and resulted in the inhibition of phosphatase activity. BCR-Rac1 GAP and Syntaxin-binding protein were found as new endogenous substrates of PTPRT in rat brain. PTPRT induced polymerization of actin cytoskeleton that determined the morphologies of dendrites and spines by inhibiting BCR-Rac1 GAP activity. Additionally, PTPRT appeared to regulate neurotransmitter release through reinforcement of interactions between Syntaxin-binding protein and Syntaxin, a SNARE protein. In conclusion, PTPRT regulates synaptic function and neuronal development through interactions with neuronal adhesion molecules and the dephosphorylation of synaptic molecules. PMID- 25748175 TI - Cryopreservation of embryogenic tissues from mature holm oak trees. AB - The development of a vitrification method for cryopreservation of embryogenic lines from mature holm oak (Quercus ilex L.) trees is reported. Globular embryogenic clusters of three embryogenic lines grown on gelled medium, and embryogenic clumps of one line collected from liquid cultures, were used as samples. The effect of both high-sucrose preculture and dehydration by incubation in the PVS2 solution for 30-90 min, on both survival and maintenance of the differentiation ability was evaluated in somatic embryo explants with and without immersion into liquid nitrogen. Growth recovery of the treated samples and ability to differentiate cotyledonary embryos largely depended on genotype. Overall, high growth recovery frequencies on gelled medium and increase of fresh weight in liquid medium were obtained in all the tested lines, also after freezing. However, the differentiation ability of the embryogenic lines was severely hampered following immersion into LN. Two of the embryogenic lines from gelled medium were able to recover the differentiation ability, one not. In the lines with reduced or no differentiation ability, variation in the microsatellite markers was observed when comparing samples taken prior to and after cryopreservation. The best results were achieved in the genotype Q8 in which 80% of explants grown on gelled medium differentiated into cotyledonary embryos following cryopreservation when they were precultured on medium with 0.3M sucrose and then incubated for 30 min in the PVS2 solution. Explants of the same genotype from liquid medium were unable to recover the differentiation ability. A 4-weeks storage period both in liquid nitrogen and in an ultra-low temperature freezer at -80 degrees C was also evaluated with four embryogenic lines from gelled medium using the best vitrification treatment. Growth recovery frequencies of all lines from the two storage systems were very high, but their differentiation ability was completely lost. PMID- 25748174 TI - Chemoprotective effect of taurine on potassium bromate-induced DNA damage, DNA protein cross-linking and oxidative stress in rat intestine. AB - Potassium bromate (KBrO3) is widely used as a food additive and is a major water disinfection by-product. It induces multiple organ toxicity in humans and experimental animals and is a probable human carcinogen. The present study reports the protective effect of dietary antioxidant taurine on KBrO3-induced damage to the rat intestine. Animals were randomly divided into four groups: control, KBrO3 alone, taurine alone and taurine+ KBrO3. Administration of KBrO3 alone led to decrease in the activities of intestinal brush border membrane enzymes while those of antioxidant defence and carbohydrate metabolism were also severely altered. There was increase in DNA damage and DNA-protein cross-linking. Treatment with taurine, prior to administration of KBrO3, resulted in significant attenuation in all these parameters but the administration of taurine alone had no effect. Histological studies supported these biochemical results showing extensive intestinal damage in KBrO3-treated animals and greatly reduced tissue injury in the taurine+ KBrO3 group. These results show that taurine ameliorates bromate induced tissue toxicity and oxidative damage by improving the antioxidant defence, tissue integrity and energy metabolism. Taurine can, therefore, be potentially used as a therapeutic/protective agent against toxicity of KBrO3 and related compounds. PMID- 25748176 TI - The effects of freezing on faecal microbiota as determined using MiSeq sequencing and culture-based investigations. AB - BACKGROUND: High-throughput sequencing has enabled detailed insights into complex microbial environments, including the human gut microbiota. The accuracy of the sequencing data however, is reliant upon appropriate storage of the samples prior to DNA extraction. The aim of this study was to conduct the first MiSeq sequencing investigation into the effects of faecal storage on the microbiota, compared to fresh samples. Culture-based analysis was also completed. METHODS: Seven faecal samples were collected from healthy adults. Samples were separated into fresh (DNA extracted immediately), snap frozen on dry ice and frozen for 7 days at -80 degrees C prior to DNA extraction or samples frozen at -80 degrees C for 7 days before DNA extraction. Sequencing was completed on the Illumina MiSeq platform. Culturing of total aerobes, anaerobes and bifidobacteria was also completed. RESULTS: No significant differences at phylum or family levels between the treatment groups occurred. At genus level only Faecalibacterium and Leuconostoc were significantly different in the fresh samples compared to the snap frozen group (p = 0.0298; p = 0.0330 respectively). Diversity analysis indicated that samples clustered based on the individual donor, rather than by storage group. No significant differences occurred in the culture-based analysis between the fresh, snap or -80 degrees C frozen samples. CONCLUSIONS: Using the MiSeq platform coupled with culture-based analysis, this study highlighted that limited significant changes in microbiota occur following rapid freezing of faecal samples prior to DNA extraction. Thus, rapid freezing of samples prior to DNA extraction and culturing, preserves the integrity of the microbiota. PMID- 25748177 TI - Synergy of Histone-Deacetylase Inhibitor AR-42 with Cisplatin in Bladder Cancer. AB - PURPOSE: Cisplatin based chemotherapy regimens form the basis of systemic bladder cancer treatment, although they show limited response rates and efficacy. Recent molecular analysis of bladder cancer revealed a high incidence of mutations in chromatin regulatory genes, suggesting a therapeutic avenue for histone deacetylase inhibitors. We investigated the ability of the novel histone deacetylase inhibitor AR-42 to synergize with cisplatin in preclinical models of bladder cancer. MATERIALS AND METHODS: We assessed the ability of the pan-histone deacetylase inhibitor AR-42 with and without cisplatin to destroy bladder cancer cells by survival and apoptosis assays in vitro, and by growth and differentiation in an in vivo xenograft model. We also assessed the response to the bladder cancer stem cell population by examining the effect of AR-42 on the CD44(+)CD49f(+) population with and without cisplatin. Synergy was calculated using combination indexes. RESULTS: The AR-42 and cisplatin combination synergistically destroyed bladder cancer cells via apoptosis and it influenced tumor growth and differentiation in vivo. When tested in the CD44(+)CD49f(+) bladder cancer stem cell population, AR-42 showed greater efficacy with and without cisplatin. CONCLUSIONS: AR-42 may be an attractive novel histone deacetylase inhibitor with activity against bladder cancer. Its efficacy in bladder cancer stem cells and synergy with cisplatin warrant further clinical investigation. Our in vitro and animal model studies provide preclinical evidence that AR-42 may be administered in conjunction with cisplatin based chemotherapy to improve the treatment of bladder cancer in patients. PMID- 25748178 TI - Investigation of proposed mechanisms of chemotherapy-induced venous thromboembolism: endothelial cell activation and procoagulant release due to apoptosis. AB - Venous thromboembolism (VTE) during chemotherapy is common, with 7% mortality in metastatic breast cancer (MBC). In a prospective cohort study of patients with breast cancer, we investigated whether vascular endothelial cell activation (VECA), and whether apoptosis, is the cause of chemotherapy-induced VTE. METHODS: Serum markers of VECA, E-selectin (E-sel), vascular cell adhesion molecule 1 (VCAM-1) and d-dimer (fibrin degradation and hypercoagulability marker) were measured prechemotherapy and at 1, 4, and 8 days following chemotherapy. Clinical deep vein thrombosis (DVT) or pulmonary embolism and occult DVT detected by duplex ultrasound imaging were recorded as VTE-positive (VTE+). In patients with MBC, hypercoagulable response to chemotherapy was compared between patients with and without cancer progression. Development of VTE and cancer progression was assessed 3 months following starting chemotherapy. RESULTS: Of the 134 patients, 10 (7.5%) developed VTE (6 [17%] of 36 MBC receiving palliation, 0 of 11 receiving neoadjuvant to downsize tumor, and 4 [5%] of 87 early breast cancer receiving adjuvant chemotherapy, P = .06). Levels of E-sel and VCAM-1 decreased in response to chemotherapy (P < .001) in both VTE+ and patients not developing VTE (VTE-). However, decrease in VECA markers was similar in VTE+ and VTE- patients, implying this is not the cause of VTE. In patients with MBC following chemotherapy, d-dimer (geometric mean) increased by 36% in the 21 patients with MBC responding to chemotherapy but steadily decreased by 11% in the 15 who progressed (day 4, P < .01), implying patients with tumor response (apoptosis) had an early hypercoagulable response. CONCLUSIONS: During chemotherapy for breast cancer, VECA is induced; however, this is not the primary mechanism for VTE. Chemotherapy-induced apoptosis may enhance hypercoagulability and initiate VTE. PMID- 25748179 TI - Government has no plans to end religious slaughter, says minister. PMID- 25748180 TI - Northern Ireland to seek Officially Brucellosis Free status. PMID- 25748181 TI - Warning of potential spring cases of atypical myopathy in horses. PMID- 25748183 TI - Charity's Royal patron visits RVC's Camden hospital. PMID- 25748184 TI - FSA survey puts pressure on retailers to reduce Campylobacter in chickens. PMID- 25748185 TI - Teamwork and the future of practice explored at SPVS/VPMA congress. AB - Effective leadership, strong teamwork and the client journey all formed key themes at this year's congress of the Society of Practising Veterinary Surgeons and the Veterinary Practice Management Association. The congress, the third the two organisations have held jointly, discussed a variety of management topics for vets, practice managers and other members of the veterinary team, with a view to making their practices better places to work in and for clients to visit. PMID- 25748187 TI - Milk drop due to leptospirosis in dairy cows. AB - Leptospiral milk drop in dairy cows. Pseudomonas aeruginosa mastitis in a cow. Systemic pasteurellosis in lambs. Encephalopathy due to water deprivation/salt poisoning suspected in weaned lambs. Biliary cystadenoma in a red deer hind. These are among matters discussed in the disease surveillance report for November 2014 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 25748188 TI - Bacteria involved in acute haemorrhagic diarrhoea syndrome in dogs. PMID- 25748189 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 25748190 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 25748191 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 25748201 TI - A life of cycles. AB - Jonathan Pycock is one of three equine claims consultants with the Veterinary Defence Society. His career in equine reproduction, and lecturing on the same topic, has given him the opportunity to work and travel widely, and ensure his work/life balance stays in sync. PMID- 25748202 TI - Fear of self, doubt and obsessive compulsive symptoms. AB - BACKGROUND AND OBJECTIVES: Following observations in the literature that obsessions often contain or imply negative evaluative information about the self, Aardema et al. (2013) recently developed a measure of feared-self relevant to OCD. The current study aimed to provide further examination of the relevance of such feared self-beliefs to obsessive compulsive processes - in particular whether they partially underlie doubt in OCD-relevant situations. METHOD: Nonclinical participants (N = 463; 291 females; Mage = 25.17, SD = 7.47), were presented with three vignettes, related to washing, checking and non-OCD relevant themes, which assessed doubt through providing alternating sensory and possibility-based information. RESULTS: Higher levels of OCD symptoms and feared self beliefs both significantly predicted both higher baseline levels of doubt and greater fluctuation in levels of doubt in both the contamination and checking scenarios, and to a much lesser extent in the control scenario. Feared-self beliefs did not predict fluctuation in doubt over-and-above OCD symptoms, consistent with a mediation model. LIMITATIONS: The main limitation was the use of a non-clinical sample, although this allowed sufficient participant numbers to test hypotheses. CONCLUSIONS: The findings provided further experimental support for reasoning processes in OCD, and suggested that feared self-beliefs may make individuals vulnerable to experiencing doubt. Additionally, these results suggested that individuals with high OCD symptoms and those with high feared self beliefs are unable to recognise the improbable nature of possibility-based statements. Implications for treatment and theory are discussed. PMID- 25748203 TI - Involvement of mitochondrial pathway of apoptosis in urothelium in ketamine associated urinary dysfunction. AB - BACKGROUND: Long-term use of ketamine results in ketamine-associated urinary dysfunction (KAUD), which is characterized by frequent micturition, urgent urination, urine pain, hematuria, dysuria and urge incontinence. This study aims to examine the effect of ketamine on the urothelium and investigate the underlying mechanisms responsible for KAUD. METHODS: A rat model of KAUD by ketamine injection was developed. Histological changes in bladder tissues were measured by hematoxylin and eosin staining, and apoptosis by the TUNEL assay. Primary bladder epithelial cells were treated with ketamine, and cell proliferation measured by a CellTiter 96 AQ cell proliferation assay, apoptosis assessed by TUNEL assay and levels of apoptosis-related proteins determined by Western blotting. RESULTS: Animals injected with ketamine displayed a decrease in body weight, behavioral signs of addiction, urinary dysfunction and damage to the epithelial layer of the bladder, particularly in the group receiving high-dose ketamine for 3 months. Ketamine increased apoptosis both in bladder tissues and bladder epithelial cells. In addition, ketamine induced the expression of Bax, cytochrome c and capase-3, but inhibited the expression of NF-kappaB and bcl-2. CONCLUSIONS: These results suggest that the mitochondrial pathway of apoptosis in bladder epithelium may contribute to KAUD. PMID- 25748204 TI - Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris. AB - The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients' biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer. PMID- 25748205 TI - Solution structure of the reduced form of human peroxiredoxin-6 elucidated using zero-length chemical cross-linking and homology modelling. AB - Peroxiredoxin-6 (PRDX6) is an unusual member of the peroxiredoxin family of antioxidant enzymes that has only one evolutionarily conserved cysteine. It reduces oxidized lipids and reactive oxygen species (ROS) by oxidation of the active-site cysteine (Cys(47)) to a sulfenic acid, but the mechanism for conversion back to a thiol is not completely understood. Moreover, it has phospholipase A2 (PLA2) activity in addition to its peroxidase activity. Interestingly, some biochemical data are inconsistent with a known high resolution crystal structure of the catalytic intermediate of the protein, and biophysical data indicate that the protein undergoes conformational changes that affect enzyme activity. In order to further elucidate the solution structure of this important enzyme, we used chemical cross-linking coupled with high resolution MS (CX-MS), with an emphasis on zero-length cross-links. Distance constraints from high confidence cross-links were used in homology modelling experiments to determine a solution structure of the reduced form of the protein. This structure was further evaluated using chemical cross-links produced by several homo-bifunctional amine-reactive cross-linking reagents, which helped to confirm the solution structure. The results show that several regions of the reduced version of human PRDX6 are in a substantially different conformation from that shown for the crystal structure of the peroxidase catalytic intermediate. The differences between these two structures are likely to reflect catalysis related conformational changes. These studies also demonstrate that CX-MS using zero-length cross-linking is a powerful strategy for probing protein conformational changes that is complementary to alternative methods such as crystallographic, NMR and biophysical studies. PMID- 25748206 TI - Enamel and Dentin Microhardness and Chemical Composition After Experimental Light activated Bleaching. AB - OBJECTIVES: To evaluate 1) the influence of five bleaching agents (with additional light activation) on enamel and dentin surface microhardness and chemical composition and 2) the remineralizing potential of artificial saliva and amorphous calcium phosphate (ACP). METHODS AND MATERIALS: The study was conducted on 125 human third molars dissected into quarters for separate enamel and dentin measurements. The bleaching process was performed with 38% and 25% hydrogen peroxide (HP) and 30%, 16%, and 10% carbamide peroxide (CP) gels two times for 15 minutes each time. All bleaching gels were tested alone and in combination with ZOOM2, light-emitting diode (LED), organic LED, and femtosecond laser. A total of 25 bleaching combinations (n=10) were evaluated. Microhardness was measured by a Vickers diamond. Chemical analysis was performed using energy-dispersive X-ray spectroscopy. RESULTS: Bleaching agents used in the absence of light activation caused a significant reduction in enamel and dentin surface microhardness (p<0.001), ranging from 8% for 16% CP to 40% for 25% HP. The effects of different light activations were negligible. After two-week treatment with ACP and artificial saliva, maximum deviation from baseline microhardness was just 3%. Such treatment increased the concentrations of calcium, phosphorus, and fluorine. CONCLUSIONS: An increase in peroxide concentration and gel acidity negatively affected microhardness and concentrations of calcium and phosphorus in enamel and dentin. ACP and artificial saliva stimulated the remineralization of hard tissues. PMID- 25748207 TI - One-year Adhesive Bond Durability to Coronal and Radicular Dentin Under Intrapulpal Pressure Simulation. AB - OBJECTIVE: To evaluate the microtensile bond strength (MUTBS) of different adhesives to coronal vs radicular dentin after one year of storage in artificial saliva and under intrapulpal pressure (IPP) simulation. METHODS AND MATERIALS: Roots of 36 freshly extracted premolars were sectioned 5 mm apical to the cemento enamel junction and pulp tissue was removed. Buccal enamel and cementum were trimmed to obtain standardized flat dentin surfaces. Specimens were divided into three groups (n=12/group) according to the adhesive strategies utilized: a two step etch-and-rinse adhesive; a two-step self-etch adhesive; and a single-step self-etch adhesive. Adhesives and resin composite were applied to coronal and radicular dentin while the specimens were subjected to IPP simulation. After curing, specimens were stored in artificial saliva at 37 degrees C in a specially constructed incubator while the IPP was maintained for either 24 hours or one year prior to testing. Bonded specimens were sectioned into sticks with a cross section of 0.8 +/- 0.01 mm(2) and subjected to MUTBS testing. Data were statistically analyzed using multi-way analysis of variance (ANOVA) with repeated measures; one-way ANOVA tests; and Bonferroni post hoc test (p<0.05). Failure modes were determined using a scanning electron microscope at 100* magnification. RESULTS: ANOVA results revealed a statistically significant effect for the adhesive strategy (p<0.001) and storage period (p<0.001) as well as for their interaction (p=0.024) on the MUTBS. However, dentin substrate and its interactions revealed no significant effects. For both dentin substrates, the two step self-etch adhesive revealed statistically significantly higher MUTBS values than did the other two adhesives after 24 hours and one year of storage. After one-year storage, a significant decrease in bond strength values of all tested adhesives occurred with both dentin substrates. Modes of failure were mainly adhesive and mixed. CONCLUSIONS: Adhesives were not sensitive to structural differences between coronal and radicular dentin even after one year of storage under IPP simulation. However, all tested adhesive systems strategies were sensitive to storage. PMID- 25748208 TI - White diet: is it necessary during tooth whitening? AB - Patients are sometimes blamed for a reduced effect of bleaching when they do not adhere to a dentist's prescribed white diet. This study aimed to determine whether a white diet is necessary by evaluating the effects of coffee, tea, wine, and dark fruits on the potential tooth whitening during the bleaching process. Each of the effects of discoloration was categorized as "yes" or "no" based on a patient questionnaire. Data from five published studies were included in the analyses. Outcomes were based on the color change between baseline and the end of bleaching. The relationships between color changes were measured subjectively and objectively. A nonwhite diet was not significantly associated with less tooth whitening, and there was only a weak positive association between tooth whitening and diet for subjects who drank large amounts of coffee/tea. PMID- 25748210 TI - Effect of Thermocycling, Degree of Conversion, and Cavity Configuration on the Bonding Effectiveness of All-in-One Adhesives. AB - The aim of this study was to compare five all-in-one bonding agents with respect to microleakage, microtensile bond strength (MUTBS), degree of conversion (DC) and the impact of cavity configuration. The materials tested were Adper Easy Bond, Clearfil S3 Bond, iBond, Optibond All-in-One, Xeno IV, and Adper Single Bond Plus as a control. The DC of each adhesive was measured on the surfaces of dentin discs (n=5) by attenuated total reflectance Fourier transform infrared spectroscopy. One hundred and forty-four extracted human molars were randomly divided and assigned to one of the five tested adhesives and the control group. The MUTBS to dentin was measured on flat occlusal dentin with and without thermocycling and to the gingival floor dentin of class II cavities (n=8). All specimens were restored with Filtek Z250 resin composite. Class II samples were immersed in a 5% methylene blue dye solution for 24 hours, and microleakage was examined under a stereomicroscope. Micromorphological analysis of demineralized/deproteinized specimens was done using scanning electron microscopy. The DC and microleakage data were statistically analyzed by one-way analysis of variance (ANOVA) and MUTBS data by two-way ANOVA followed by a Bonferroni multiple comparison post hoc test (alpha=0.05) and Weibull distribution survival analysis. The relation between different variables and MUTBS and microleakage was tested by the Pearson correlation coefficient and regression statistics. A moderate direct relation between DC and MUTBS durability was found for all the adhesives tested. Significant wide variations exist among the results obtained for single-bottle adhesives tested regarding their MUTBS and microleakage. Some of the all-in-one materials tested have shown significantly inferior results under a high C-factor or after aging. The use of these materials should be carefully considered. PMID- 25748209 TI - Visual Acuity and Experience with Magnification Devices in Swiss Dental Practices. AB - OBJECTIVES: The aims of the present study in Swiss dental practices were 1) to provide an update on the prevalence of different magnification devices, 2) to examine the relationship between self-assessed and objectively measured visual acuity, and 3) to evaluate the visual performance of dentists in the individually optimized clinical situation of their respective practices. METHODS AND MATERIALS: Sixty-nine dentists from 40 randomly selected private practices (n=20, <40 years; n=49, >=40 years) participated in the study. A questionnaire was provided to evaluate the self-assessed near visual acuity and the experience with magnification devices. The objective near visual acuity was measured under standardized conditions on a negatoscope. The clinical situation, including the use of habitual optical aids, was evaluated with visual tests on a phantom head. RESULTS: A total of 64% of the dentists owned a dental loupe: 45% Galilean loupes, 16% Keplerian loupes, and 3% single lens loupes. In total, 19% of the questioned dentists owned a microscope in addition to the loupes. The correlation between the self-assessed and the objective visual performance of the dentists was weak (Spearman rank correlation coefficient=0.25). In the habitual clinical situation, magnification devices (p=0.03) and the dentist's age (p=0.0012) had a significant influence on the visual performance. CONCLUSIONS: Many dentists were not aware of their visual handicaps. Optical aids such as loupes or microscopes should be used early enough to compensate for individual or age-related visual deficiencies. PMID- 25748211 TI - Microshear Bond Strength of Resin Cements to Lithium Disilicate Substrates as a Function of Surface Preparation. AB - OBJECTIVES: To investigate the effect of hydrofluoric acid (HF) etching, silane solution, and adhesive system application on the microshear bond strength (MUSBS) of lithium disilicate glass-ceramic (LD) to three resin cements. MATERIALS AND METHODS: Circular bonding areas were delimited on the lithium disilicate surfaces using a perforated adhesive tape. Specimens were assigned to 18 subgroups (n=12) according to surface treatment: NT = no treatment; HF = 4.8% HF for 20 seconds; silane solution: (1) no silane; (2) Monobond Plus, a silane/10 methacryloyloxydecyl dihydrogen phosphate solution for 60 seconds; (3) Monobond Plus+ExciTE F DSC, a dual-cure adhesive; and resin cement: (1) Variolink II, a bisphenol A diglycidyl ether dimethacrylate (bis-GMA)-based, hand-mixed, dual cure resin cement; (2) Multilink Automix, a bis-GMA-based, auto-mixed, dual-cure resin cement; (3) RelyX Unicem 2, a self-adhesive, auto-mixed, dual-cure resin cement. Tygon tubes (O=0.8 mm) were used as cylinder matrices for resin cement application. After 24 hours of water storage, the specimens were submitted to the MUSBS test. Mode of failure was evaluated under an optical microscope and classified as adhesive, mixed, cohesive in resin cement, or cohesive in ceramic. Data were statistically analyzed with three-way analysis of variance and Dunnett test (p<0.05). RESULTS: When means were pooled for the factor surface treatment, HF resulted in a significantly higher MUSBS than did NT (p<0.0001). Regarding the use of a silane solution, the mean MUSBS values obtained with Monobond Plus and Monobond Plus+ExciTE F DSC were not significantly different but were higher than those obtained with no silane (p<0.001). Considering the factor resin cement, Variolink II resulted in a significantly higher mean MUSBS than did RelyX Unicem 2 (p<0.03). The mean MUSBS for Multilink Automix was not significantly different from those of Variolink II and RelyX Unicem 2. According to Dunnett post hoc test (p<0.05), there was no significant difference in MUSBS between the different resin cements for HF-etched and silanized (with or without adhesive application) LD surfaces. CONCLUSION: LD may benefit from pretreatment of the inner surface with HF and silanization, regardless of the resin cement used. PMID- 25748212 TI - Fabrication of electrically bistable organic semiconducting/ferroelectric blend films by temperature controlled spin coating. AB - Organic semiconducting/ferroelectric blend films attracted much attention due to their electrical bistability and rectification properties and thereof the potential in resistive memory devices. During film deposition from the blend solution, spinodal decomposition induced phase separation, resulting in discrete semiconducting phase whose electrical property could be modulated by the continuous ferroelectric phase. However, blend films processed by common spin coating method showed extremely rough surfaces, even comparable to the film thickness, which caused large electrical leakage and thus compromised the resistive switching performance. To improve film roughness and thus increase the productivity of these resistive devices, we developed temperature controlled spin coating technique to carefully adjust the phase separation process. Here we reported our experimental results from the blend films of ferroelectric poly(vinylidene fluoride-trifluoroethylene (P(VDF-TrFE)) and semiconducting poly(3-hexylthiophene) (P3HT). We conducted a series of experiments at various deposition temperatures ranging from 20 to 90 degrees C. The resulting films were characterized by AFM, SEM, and VPFM to determine their structure and roughness. Film roughness first decreased and then increased with the increase of deposition temperature. Electrical performance was also characterized and obviously improved insulating property was obtained from the films deposited between 50 and 70 degrees C. By temperature control during film deposition, it is convenient to efficiently fabricate ferroelectric/semiconducting blend films with good electrical bistability. PMID- 25748213 TI - Subjective Age and Changes in Memory in Older Adults. AB - OBJECTIVE: The subjective experience of aging, indexed by how old or young an individual feels, has been related to well-being and health-related outcomes among older adults. The present study examined whether subjective age is associated with memory level and changes, as indexed by measures of immediate and delayed recall. A complementary purpose was to test the mediating role of depressive symptoms and physical activity in the relation between subjective age and memory changes. METHOD: Participants were drawn from three waves of the Health and Retirement Study. Subjective age, baseline memory measures, and covariates were assessed during the 2008 wave (N = 5809), depressive symptoms and physical activity were assessed again in the 2010 wave, and the follow-up memory measures were assessed in the 2012 wave. RESULTS: Regression analyses that included demographic, metabolic, and vascular covariates revealed that a younger subjective age at baseline was associated with better concurrent performance and with slower decline in immediate and delayed recall. Bootstrap procedures indicated that fewer depressive symptoms mediated these associations. Additional analyses revealed that memory level and change were unrelated to changes in subjective age. CONCLUSION: Beyond chronological age, the subjective experience of age is associated with cognitive aging. PMID- 25748214 TI - Depersonalization: physiological or pathological in adolescents? AB - BACKGORUND: This study analyzed the presence of DP symptoms in a sample of both psychiatric patients and normal subjects, addressing the issue of DP symptoms in adolescence. METHODS: A total of 267 subjects (149 patients and 118 healthy controls) aged between 14 and 65 years, were assessed by means of CDS, the SCID-I and the K-SADS. The sample was then divided into two subsamples with a cut-off age of 21 years. RESULTS: As expected CDS score was significantly higher in the patient group compared to the healthy control group. As for the age issue, among patients no statistical difference was found comparing subjects over and under 21 years, whereas in the sample of healthy controls, subjects under 21 years reported CDS scores significantly higher. CONCLUSIONS: While in adults DP symptoms are frequently associated with mental disorders, in adolescents they could be considered as a quasi-physiological phenomenon. PMID- 25748215 TI - Effects of N-glycosylation on protein conformation and dynamics: Protein Data Bank analysis and molecular dynamics simulation study. AB - N-linked glycosylation is one of the most important, chemically complex, and ubiquitous post-translational modifications in all eukaryotes. The N-glycans that are covalently linked to proteins are involved in numerous biological processes. There is considerable interest in developments of general approaches to predict the structural consequences of site-specific glycosylation and to understand how these effects can be exploited in protein design with advantageous properties. In this study, the impacts of N-glycans on protein structure and dynamics are systematically investigated using an integrated computational approach of the Protein Data Bank structure analysis and atomistic molecular dynamics simulations of glycosylated and deglycosylated proteins. Our study reveals that N glycosylation does not induce significant changes in protein structure, but decreases protein dynamics, likely leading to an increase in protein stability. Overall, these results suggest not only a common role of glycosylation in proteins, but also a need for certain proteins to be properly glycosylated to gain their intrinsic dynamic properties. PMID- 25748217 TI - Effect of clearcutting operations on the survival rate of a small mammal. AB - Clearcutting is a common timber harvesting technique that represents a significant and abrupt change in habitat conditions for wildlife living in industrial forests. Most research on this type of impact has focused on comparing populations or communities in mature forests/plantations and the resulting clearcut stands. However, this approach does not separate the effect of changes in habitat attributes from direct mortality produced by the intensive use of heavy machinery required for cutting down trees and dragging them to a road. Because knowing the fate of individuals after a disturbance is important for modelling landscape-scale population dynamics in industrial forests, we conducted a study in South-Central Chile to understand the short-term response to clearcutting operations of the long-haired Akodont (Abrothrix longipillis), a forest specialist mouse. Between 2009 and 2013 we radiotracked a total of 51 adult male Akodonts, before, during and after the clearcutting of the pine plantations in which they lived. A minimum of 52.4% of the individuals died as a direct cause of the timbering operations, being crushed by vehicles or logs during logging operations. Our observations suggest that, instead of fleeing the area, the response of long-haired Akodonts to the approaching machinery is to hide under the forest litter or in burrows, which exposes them to a serious risk of death. The real mortality rate associated to clearcutting may be higher than that estimated by us because of some methodological biases (i.e. individuals with crushed radiotransmitters not recorded) and the fact that additional mortality sources may affect the population in the weeks following logging operations (e.g., higher exposure to predation, effects of site preparation for the new plantation, etc). PMID- 25748216 TI - Mechanisms of azole resistance in Candida albicans clinical isolates from Shanghai, China. AB - This study was undertaken to characterize the mechanism(s) of azole resistance in clinical isolates of Candida albicans collected in Shanghai, China, focusing on the role of efflux pumps, target enzymes of fluconazole (Erg11), respiratory status and the ergosterol biosynthetic pathway. Clinical isolates of C. albicans (n = 30) were collected from 30 different non-HIV-infected patients in four hospitals in Shanghai. All 30 C. albicans isolates were susceptible to amphotericin B and 5-fluorocytosine. Twelve C. albicans isolates showed resistance to at least one type of triazole antifungal. Flow cytometry analysis of rhodamine 6G efflux showed that azole-resistant isolates had greater efflux pump activity, which was consistent with elevated levels of CDR1 and CDR2 genes that code for ABC efflux pumps. However, we did not observe increased expression of ERG11 and MDR1 or respiratory deficiency. Several mutations of ERG11 and TAC1 genes were detected. The F964Y mutation in the TAC1 gene was identified for the first time. Two main sterols, ergosterol and lanosterol, were identified by GC-MS chromatogram, and no missense mutations were found in ERG3. Furthermore, seven amino acid substitutions in ERG11, A114S, Y132H, Y132F, K143Q, K143R, Y257H and G448E were found, by Type II spectral quantitative analysis, to contribute to low affinity binding between Erg11 and fluconazole. PMID- 25748218 TI - Gua Sha a traditional Chinese healing technique that could mimick physical abuse: a potential issue with forensic implications. A case study. AB - Gua Sha (press-stroking) is a traditional Chinese healing technique utilized to combat pain, common cold, heatstroke, and respiratory problems. Patterned ecchymoses may appear due to the action of scraping and scratching repeatedly in a unidirectional manner, with a smooth edge over a lubricated area. They may be very informative, since they, generally, reproduce the shape of the injurious agent. However, many confounding factors can make the identification of the lesions difficult. A case of a 43 year-old Chinese woman, hospitalized for abdominal pain, is reported. An unusual pattern of reddish ecchymoses on the back was present. After a careful investigation, ecchymoses were attributed to Gua Sha. The case demonstrated that clinicians and forensic pathologists should also consider press-stroking, and other similar techniques in adults who present scratch-like marks or ecchymoses on various body districts, even if they have an unusual pattern. PMID- 25748219 TI - Response to the letter by Safak Ekinci et al. PMID- 25748220 TI - Response to the letter by B. Masson. PMID- 25748221 TI - Finite element analysis for evaluating liver tissue damage due to mechanical compression. AB - The development of robotic-assisted minimally invasive surgery (RMIS) has resulted in increased research to improve surgeon training, proficiency and patient safety. Minimizing tissue damage is an essential consideration in RMIS. Various studies have reported the quantified tissue damage resulting from mechanical compression; however, most of them require bench work analysis, which limits their application in clinical conditions of RMIS. We present a new methodology based on nonlinear finite element (FE) analysis that can predict damage degree inside tissue. The effects of the boundary conditions and material property of the FE model on the simulated von Mises stress value and tissue damage were investigated. Four FE models were analyzed: two-dimensional (2D) plane strain model, 2D plane stress model, full three-dimensional (3D) model, and 3D thin membrane model. Nonlinear material properties of liver tissue used in the FEA were derived from previously reported in vivo and in vitro experiments. Our study showed that for integrated von Mises stress and tissue damage computations, the 3D thin membrane model yielded results closest to the full 3D analysis and required only 0.2% of the compute time. The results from 3D thin membrane and the full 3D models fell below plane-strain model and above the plane-stress model. Both stress and necrosis distributions were impacted by the material property of FE models. This study can guide engineers to design surgical instruments to improve patient safety. Additionally it is useful for improving the surgical simulator performance by reflecting more realistic tissue material property and displaying tissue damage severity. PMID- 25748222 TI - EMG burst presence probability: a joint time-frequency representation of muscle activity and its application to onset detection. AB - The purpose of this study was to quantify muscle activity in the time-frequency domain, therefore providing an alternative tool to measure muscle activity. This paper presents a novel method to measure muscle activity by utilizing EMG burst presence probability (EBPP) in the time-frequency domain. The EMG signal is grouped into several Mel-scale subbands, and the logarithmic power sequence is extracted from each subband. Each log-power sequence can be regarded as a dynamic process that transits between the states of EMG burst and non-burst. The hidden Markov model (HMM) was employed to elaborate this dynamic process since HMM is intrinsically advantageous in modeling the temporal correlation of EMG burst/non burst presence. The EBPP was eventually yielded by HMM based on the criterion of maximum likelihood. Our approach achieved comparable performance with the Bonato method. PMID- 25748223 TI - Blood flow reduction of covered small side branches after flow diverter treatment: a computational fluid hemodynamic quantitative analysis. AB - Small side branches related brain infarction remains one of the major concerns for flow-diverter devices. However, among several factors, whether this high profile stent would significantly block blood flow into small side branches remains unclear. The authors quantitatively evaluate blood flow reduction due to the deployment of flow-diverter devices using computational fluid dynamics approach. Thirty one patient-specific anterior inferior cerebellar artery geometries were employed. The flow-diverter device was hypothetically embedded into the basilar trunk, and to cover the anterior inferior cerebellar arteries. The blood flow reduction of each anterior inferior cerebellar artery following flow-diverter device deployment was calculated, with independent validations for both inflow and outflow conditions. Efficient diameters of the anterior inferior cerebellar arteries were calculated to evaluate any correlation with blood flow reduction after flow-diverter devices. The blood flow reduction ratio was shown to be 3.61+/-1.94%. There was moreover no significant difference of either inflow or outflow boundary conditions during the simulation. The results were calculated approximately as a modest linear correlation between the blood flow reduction ratio and the size of anterior anterior inferior cerebellar arteries which had a mean efficient diameter of 1.12+/-0.36 mm (range from 0.31 mm to 1.91 mm), and the R(2) was 0.361. When covered by flow-diverter devices, the mechanical blood flow reduction in anterior inferior cerebellar arteries was found to be low with a maximum value estimated to be less than 8%. Therefore, mechanical blood flow reduction is probably not the leading factor contributing to small side branches related brain infarction. PMID- 25748224 TI - A rational approach to defining principal axes of multidirectional wall shear stress in realistic vascular geometries, with application to the study of the influence of helical flow on wall shear stress directionality in aorta. AB - The distribution of arterial lesions is attributed by the prevalent mechanistic theory to the proatherogenic role played by low and oscillatory wall shear stress (WSS). However, discrepancies observed when comparing WSS distribution with location of regions with lesion prevalence challenge this theory and have recently stimulated the idea that a role in endothelial mechanosensing is played by WSS multidirectionality, which could contribute to explain the observed discrepancies. Here an approach is presented for analyzing the multidirectional nature of WSS in complex vascular geometries. Using an essential geometric attribute of the vessel (its centerline), the local WSS vector is projected along an "axial" direction (aligned with the tangent to the vessel's centerline), and "secondary" direction (orthogonal to centerline's tangent), which is related to secondary flow. The WSS projection scheme is applied: (1) to a realistic computational hemodynamic model of human aorta, with the aim to come up with a plausibility checking regarding its consistency; and (2) to investigate if an aortic hemodynamics characterized by different amount and topology of helical flow (HF) could influence WSS directionality. The projection scheme confirmed its consistency and plausibility in realistic arterial geometries and allowed to get insight into the relationship between aortic intravascular fluid structures and WSS directionality. The findings of this study clearly show the potential of the projection scheme as quantitative tool for an in depth investigation of the WSS multidirectional nature. The proposed approach enriches the arsenal of tools available to study and exploit the role played by local hemodynamics in vascular disease. PMID- 25748226 TI - Intersubtype Genetic Variation of HIV-1 Tat Exon 1. AB - HIV-1 Tat is a regulatory protein that plays a pivotal role in viral transcription and replication. Our study aims to investigate the genetic variation of Tat exon 1 in all subtypes of HIV-1: A, B, C, D, F, G, H, J, and K. We performed phylogenetic, mutation, and selection pressure analyses on a total of 1,179 sequences of different subtypes of HIV-1 Tat obtained from the Los Alamos National Laboratory (LANL). The mean nucleotide divergences (%) among the analyzed sequences of subtypes A, B, C, D, F, G, H, J, and K were 88, 89, 90, 88, 86, 89, 88, 97, and 97, respectively. We revealed that subtype B evolved relatively faster than other subtypes. The second and fifth domains were found comparatively more variable among all subtypes. Site-by-site tests of positive selection revealed that several positions in all subtypes were under significant positive selection. Positively selected sites were found in the acidic domain at positions 3, 4, and 19, in the cysteine-rich domains at positions 24, 29, 32, and 36, in the core domain at position 40, and in the basic domain for the rest of the positions for all subtypes. Positions 58 and 68 in the basic domain were positively selected in subtypes A, B, C and B, C, F, respectively. We also observed high variability within positively selected sites in amino acid positions. Our study findings on HIV-1 Tat genetic variability may contribute to a better understanding of HIV-1 evolution as well as to the development of effective Tat-targeted therapeutics and vaccines. PMID- 25748225 TI - Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits. AB - To examine the therapeutic effect of Src inhibitor on the VEGF mediating vascular hyperpermeability and bone destruction within steroid-associated osteonecrotic lesions in rabbits. Rabbits with high risk for progress to destructive repair in steroid-associated osteonecrosis were selected according to our published protocol. The selected rabbits were systemically administrated with either Anti VEGF antibody (Anti-VEGF Group) or Src inhibitor (Src-Inhibition Group) or VEGF (VEGF-Supplement Group) or a combination of VEGF and Src inhibitor (Supplement &Inhibition Group) or control vehicle (Control Group) for 4 weeks. At 0, 2 and 4 weeks after administration, in vivo dynamic MRI, micro-CT based-angiography, histomorphometry and immunoblotting were employed to evaluate the vascular and skeletal events in different groups. The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group. The angiogenesis was promoted in VEGF-Supplement Group, Src-Inhibition Group and Supplement &Inhibition Group, while the hyperpermeability was inhibited in Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group. The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group. Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis. PMID- 25748227 TI - Regulation of SUMO2 target proteins by the proteasome in human cells exposed to replication stress. AB - In human cells, SUMO2 is predominantly conjugated to target proteins in response to cellular stress. Previous studies suggested that proteins conjugated to SUMO2, but not to SUMO1, could be regulated by the ubiquitin-mediated proteasome system. Hence, we set out to understand the role of the proteasome in determining the fate of proteins conjugated to SUMO2 when cells are treated with DNA replication stress conditions. We conducted a quantitative proteomic analysis in a U2OS cell line stably expressing SUMO2(Q87R) tagged with StrepHA in the presence or absence of epoxomicin (EPOX), a proteasome inhibitor. We identified subgroups of putative SUMO2 targets that were either degraded or stabilized by EPOX upon SUMO2 conjugation in response to replication stress. Interestingly, the subgroup of proteins degraded upon SUMO2 conjugation was enriched in proteins playing roles in DNA damage repair and replication, while the proteins stabilized upon SUMOylation were mainly involved in chromatin maintenance. In addition, we identified 43 SUMOylation sites in target proteins, of which 17 are located in the proximity of phosphorylated residues. Considering that DNA replication stress is a major source of genome instability, which is suggested to drive tumorigenesis and possibly aging, our data will facilitate future functional studies in the fields of DNA metabolism and cancer biology. PMID- 25748228 TI - Synthesis and in vitro and in vivo evaluation of an (18)F-labeled neuropeptide Y analogue for imaging of breast cancer by PET. AB - Imaging of Y1R expression in breast cancer is still a challenging task. Herein, we report a suitable (18)F-labeled high-molecular-weight glycopeptide for imaging of peripheral neuropeptide Y (NPY) Y1 receptor (Y1R)-positive tumors by preclinical small-animal positron emission tomography (PET). The Y1R-preferring NPY [F(7),P(34)]NPY analogue was functionalized with an alkyne-bearing propargylglycine (Pra) in position 4. The corresponding fluoroglycosylated (FGlc) peptide analogue [Pra(4)(FGlc),F(7),P(34)]NPY and its (18)F-labeled analogue were synthesized by click chemistry-based fluoroglycosylation. The radiosynthesis was performed by (18)F-fluoroglycosylation starting from the 2-triflate of the beta mannosylazide and the alkyne peptide [Pra(4),F(7),P(34)]NPY. The radiosynthesis of the(18)F-labeled analogue was optimized using a minimum amount of peptide precursor (40 nmol), proceeding with an overall radiochemical yield of 20-25% (nondecay corrected) in a total synthesis time of 75 min with specific activities of 40-70 GBq/MUmol. In comparison to NPY and [F(7),P(34)]NPY, in vitro Y1R and Y2R activation studies with the cold [Pra(4)(FGlc),F(7),P(34)]NPY on stably transfected COS-7 cells displayed a high potency for the induction of Y1R specific inositol accumulation (pEC50 = 8.5 +/- 0.1), whereas the potency at Y2R was significantly decreased. Internalization studies on stably transfected HEK293 cells confirmed a strong glycopeptide-mediated Y1R internalization and a substantial Y1R subtype selectivity over Y2R. In vitro autoradiography with Y1R positive MCF-7 tumor tissue slices indicated high specific binding of the (18)F labeled glycopeptide, when binding was reduced by 95% ([Pra(4),F(7),P(34)]NPY) and by 86% (BIBP3226 Y1R antagonist) in competition studies. Biodistribution and small-animal PET studies on MCF-7 breast tumor-bearing nude mice revealed radiotracer uptake in the MCF-7 tumor of 1.8%ID/g at 20 min p.i. and 0.7%ID/g at 120 min p.i. (n = 3-4), increasing tumor-to-blood ratios from 1.2 to 2.4, and a tumor retention of 76 +/- 4% (n = 4; 45-90 min p.i.). PET imaging studies with MCF-7 tumor-bearing nude mice demonstrated uptake of the (18)F-labeled glycopeptide in the tumor region at 60 min p.i., whereas only negligible tumor uptake was observed in animals injected with a nonbinding (18)F-labeled glycopeptide pendant as a measure of nonspecific binding. In conclusion, PET imaging experiments with the (18)F-labeled NPY glycopeptide revealed Y1R-specific binding uptake in MCF-7 tumors in vivo together with decreased kidney uptake compared to DOTA-derivatives of this peptide. We consider this glycopeptide to be a potent lead peptide for the design of improved (18)F-glycopeptides with shorter amino acid sequences that would further facilitate PET imaging studies of Y1R positive breast tumors. PMID- 25748229 TI - The state of the art of removal of prion proteins in SD-FFP, by specific prion affinity chromatography and its impact on the hemostatic characteristics of the product. AB - In recent Coimbra' Conference, on the pre-launch of pathogen reduced-FFP for the local clinical use, the question was raised, by the moderator, on the efficacy of the current methodology used for prion removal processes and its influence on the overall quality and safety of the final product. This brief paper put together by speaker of this session and the moderator, as a consensus of opinions, which was largely discussed during Q&A session, to make it available to a large group of readers of transfusion apheresis science, who might be interested to this topic. In short the capacity of the current process of Octaplas to remove prion is in order of 5.6 log10/ID50 reduction based on several animal studies. Moreover the changes in coagulation and inhibitors are within acceptable range and bioequivalent to untreated FFP with no sign of inferiority. This paper describes in brief a technology update on solvent/detergent treated plasma, an alternative to FFP but with increased pathogen safety. The biochemical profile of the final product is comparable with FFP and contains all clinically relevant plasma proteins. Furthermore, Octaplas is a product that, in long term, reduces health care costs. PMID- 25748230 TI - Multilayer-strategy to enhance optimal safety of the blood supply: The role of pathogen inactivation for optimizing recipient safety and helping health care cost containment: Moderator views. AB - This brief paper is based on the Coimbra 'conference presentation by the moderator', prior to the two main lectures on pathogen reduction treatment [PRT] of plasma. Being an educationist and teacher in core and having a great interest to simplify the message convey to conference' participants and readers I decided to maintain the slide format of the presentation. To highlight most effectively the role played by pathogen reduction to supplement the multilayer-strategy already in place, emphasizes were placed by going back to basic focusing on: where we were, where we are now and where we are going!. The unresolved problems of viral safety of blood components and criteria of universal acceptability of PRT are highlighted so is the need for further DDR strategies both in incremental and innovative ways. Finally the issue of who would benefit from implementation of PRT is described based on published data and also providing some visionary foresights for the long term benefits of PRT in both optimizing the safety of blood supply and helping at least in health care containment. I hope this new approach will be useful to readers, providing at least some conceptual and technical supports in understanding the role of PRT in optimizing the safety of blood supply. PMID- 25748231 TI - Extracorporeal photopheresis in prevention and treatment of acute GVHD. AB - Acute graft versus host disease (GVHD), a common complication after allogeneic hematopoietic cell transplantation (HCT), occurs in as many as 70% of recipients of this life saving treatment. Front line therapy for GVHD with corticosteroids will fail in up to 40% of patients, which leads to high morbidity and mortality. Traditional prevention and treatment strategies have focused on reducing alloreactivity, typically with therapy to reduce cytotoxic T-cell function. Emerging evidence exists that promotion of regularly T-cell function, through treatments such as extracorporeal photopheresis, is effective for GVHD treatment and has potential for prevention as well. This review will focus on literature reporting the success of ECP for steroid refractory acute GVHD and the potential for delivery of ECP in the early pre and post-transplant periods that shows promise as a less immunosuppressive strategy to reduce rates of acute GVHD. PMID- 25748232 TI - Extracorporeal photopheresis in heart transplant rejection. AB - Up to 25% of heart transplant recipients develop rejection requiring intervention. While the majority respond to augmentation of immunomodulatory drug therapy, a subset of patients will remain refractory. Extracorporeal photopheresis (ECP) appears particularly useful in the management of select heart transplant recipients at risk of rejection, with recurrent rejection, or rejection associated with hemodynamic compromise. This chapter summarizes the current clinical experience of ECP in heart transplantation. ECP appears to favorably affect both the cellular and humoral arms of the immune response to the allograft and promote a tolerogenic profile. These immunomodulatory effects also appear to decrease development of cardiac allograft vasculopathy. ECP is generally well tolerated with few adverse effects and low infection risk. PMID- 25748233 TI - BUB1-bling over with possibilities. AB - In a new report, Nyati et al. identified a previously undetected participant mediating both canonical signaling, i.e., TGF-beta receptor kinase mediated, and non-canonical signaling, budding uninhibited by benzimidazole 1 (BUB1). PMID- 25748234 TI - A novel NHE1-centered signaling cassette drives epidermal growth factor receptor dependent pancreatic tumor metastasis and is a target for combination therapy. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na(+)/H(+) exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib. PMID- 25748235 TI - Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages. AB - Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs), is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs) or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors), of these three patients in whom both tumors were available (six tumors) and two patients each with only one available tumor (two tumors). Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21), some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor alpha (PDGFRA), and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients. PMID- 25748236 TI - Constitutively active Akt1 cooperates with KRas(G12D) to accelerate in vivo pancreatic tumor onset and progression. AB - BACKGROUND AND AIMS: Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics. Mutation of KRAS is the most frequent early event in pancreatic tumor progression. AKT isoforms are frequently activated in pancreatic cancer, and reports have implicated hyperactivation of AKT1, as well as AKT2, in pancreatic tumor formation. The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer. METHODS: Mice with Akt1 and KRas mutant alleles expressed using the pancreas Pdx promoter were mated to characterize the incidence and frequency of histologic and genetic alterations known to occur commonly in human pancreatic ductal adenocarcinoma. RESULTS: Active Akt1 (Akt1(Myr), containing a myristoylation sequence) cooperated with active mutant KRas(G12D) to accelerate pancreatic carcinoma onset and progression and increase phosphorylation of downstream effectors in the Akt pathway. Mucin and smooth muscle actin expression was found in and around pancreatic intraepithelial neoplasms (PanINs), and accelerated time to metastasis was found in Akt1(Myr)/KRas(G12D) mice. CONCLUSIONS: In contrast to prior reports of pancreatic KRas mutant mice mated with mice deficient for various tumor suppressor genes, which resulted in aggressive disease within a few months of age, Akt1(Myr)/KRas(G12D) mice enabled the study of PanINs and spontaneous pancreatic transformation more characteristic of human pancreatic progression in elderly individuals. The Akt1(Myr)/KRas(G12D) model holds promise for delineating the tumor biology and biomarkers critical for understanding their cooperation in cancer oncogenesis and future targeting in therapeutic strategies. PMID- 25748237 TI - Molecular subtypes of uterine leiomyosarcoma and correlation with clinical outcome. AB - The molecular etiology of uterine leiomyosarcoma (ULMS) is poorly understood, which accounts for the wide disparity in outcomes among women with this disease. We examined and compared the molecular profiles of ULMS and normal myometrium (NL) to identify clinically relevant molecular subtypes. Discovery cases included 29 NL and 23 ULMS specimens. RNA was hybridized to Affymetrix U133A 2.0 transcription microarrays. Differentially expressed genes and pathways were identified using standard methods. Fourteen NL and 44 ULMS independent archival samples were used for external validation. Molecular subgroups were correlated with clinical outcome. Pathway analyses of differentially expressed genes between ULMS and NL samples identified overrepresentation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes (P < 4.4 * 10(-4), Bonferroni corrected), with 84% of the overexpressed genes, including CDC7, CDC20, GTSE1, CCNA2, CCNB1, and CCNB2, participating in cell cycle regulation. Unsupervised clustering of ULMS identified two clades that were reproducibly associated with progression-free (median, 4.0 vs 26.0 months; P = .02; HR, 0.33) and overall (median, 18.2 vs 77.2 months; P = .04; HR, 0.33) survival. Cell cycle genes play a key role in ULMS sarcomagenesis, providing opportunities for therapeutic targeting. Reproducible molecular subtypes associated with clinical outcome may permit individualized adjuvant treatment after clinical trial validation. PMID- 25748239 TI - Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A. AB - Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX 2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 MUm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs. PMID- 25748238 TI - Erlotinib-cisplatin combination inhibits growth and angiogenesis through c-MYC and HIF-1alpha in EGFR-mutated lung cancer in vitro and in vivo. AB - Combination treatment for non-small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose erlotinib-cisplatin combination in NSCLC in vitro and in vivo. In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination erlotinib-cisplatin treatment led to synergistic cell death, but there was minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased vascular endothelial growth factor (VEGF) levels and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through down regulation of the c-MYC/hypoxia inducible factor 1-alpha (HIF-1alpha) pathway. In fact, cell lines with EGFR exon 19 deletions expressed high basal levels of c-MYC and HIF-1alpha and correlate with robust responses to combination treatment. These results suggest that low dose erlotinib-cisplatin combination exhibits its anti-tumor activity by targeting angiogenesis through the modulation of the c MYC/HIF-1alpha/VEGF pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen. PMID- 25748240 TI - Pushing the optical imaging limits of cancer with multi-frequency-band raster scan optoacoustic mesoscopy (RSOM). AB - Angiogenesis is a central cancer hallmark, necessary for supporting tumor growth and metastasis. In vivo imaging of angiogenesis is commonly applied, to understand dynamic processes in cancer development and treatment strategies. However, most radiological modalities today assess angiogenesis based on indirect mechanisms, such as the rate of contrast enhancement after contrast agent administration. We studied the performance of raster-scan optoacoustic mesoscopy (RSOM), to directly reveal the vascular network supporting melanoma growth in vivo, at 50 MHz and 100 MHz, through several millimeters of tumor depth. After comparing the performance at each frequency, we recorded, for the first time, high-resolution images of melanin tumor vasculature development in vivo, over a period of several days. Image validation was provided by means of cryo-slice sections of the same tumor after sacrificing the mice. We show how optoacoustic (photoacoustic) mesoscopy reveals a potentially powerful look into tumor angiogenesis, with properties and features that are markedly different than other radiological modalities. This will facilitate a better understanding of tumor's angiogenesis, and the evaluation of treatment strategies. PMID- 25748241 TI - Successful combination of sunitinib and girentuximab in two renal cell carcinoma animal models: a rationale for combination treatment of patients with advanced RCC. AB - Anti-angiogenic treatment with tyrosine kinase inhibitors (TKI) has lead to an impressive increase in progression-free survival for patients with metastatic RCC (mRCC), but mRCC remains largely incurable. We combined sunitinib, targeting the endothelial cells with Girentuximab (monoclonal antibody cG250, recognizing carbonic anhydrase IX (CAIX) targeting the tumor cells to study the effect of sunitinib on the biodistribution of Girentuximab because combination of modalities targeting tumor vasculature and tumor cells might result in improved effect. Nude mice with human RCC xenografts (NU12, SK-RC-52) were treated orally with 0.8 mg/day sunitinib, or vehicle for 7 to 14 days. Three days before start or cessation of treatment mice were injected i.v. with 0.4 MBq/5 MUg (111)In Girentuximab followed by biodistribution studies. Immunohistochemical analyses were performed to study the tumor vasculature and CAIX expression and to confirm Girentuximab uptake. NU12 appeared to represent a sunitinib sensitive tumor: sunitinib treatment resulted in extensive necrosis and decreased microvessel density (MVD). Accumulation of Girentuximab was significantly decreased when sunitinib treatment preceded the antibody injection but remained unchanged when sunitinib followed Girentuximab injection. Cessation of therapy led to a rapid neovascularization, reminiscent of a tumor flare. SK-RC-52 appeared to represent a sunitinib-resistant tumor: (central) tumor necrosis was minimal and MVD was not affected. Sunitinib treatment resulted in increased Girentuximab uptake, regardless of the sequence of treatment. These data indicate that sunitinib can be combined with Girentuximab. Since these two modalities have different modes of action, this combination might lead to enhanced therapeutic efficacy. PMID- 25748243 TI - Direct immunofluorescence for immunobullous and other skin diseases. AB - A swift glance at ample evidence currently available about the assay clearly illustrates that the development of direct immunofluorescence (DIF), in which direct fluorescent antibodies are utilized to identify the target antigen, has been of immense importance. The immunoreactant deposits have been delineated by the DIF assay in three main locations, including throughout the epidermis, at the dermoepidermal junction (also known as the basement membrane zone) and in and/or around blood vessel walls. DIF testing can be conducted on several specimen sources, which are categorized according to feasibility of collection into invasive (e.g., skin) and non-invasive (e.g., hair). This review was intended to indicate that inspection of immunoreactant deposits via DIF is highly instrumental in diagnosing and monitoring the immunobullous and other diseases of the skin. PMID- 25748242 TI - Oncostatin-M differentially regulates mesenchymal and proneural signature genes in gliomas via STAT3 signaling. AB - Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention. PMID- 25748244 TI - Utilization of Food Processing By-products as Dietary, Functional, and Novel Fiber: A Review. AB - Fast growing food processing industry in most countries across the world, generates huge quantity of by-products, including pomace, hull, husk, pods, peel, shells, seeds, stems, stalks, bran, washings, pulp refuse, press cakes, etc., which have less use and create considerable environmental pollution. With growing interest in health promoting functional foods, the demand of natural bioactives has increased and exploration for new sources is on the way. Many of the food processing industrial by-products are rich sources of dietary, functional, and novel fibers. These by-products can be directly (or after certain modifications for isolation or purification of fiber) used for the manufacture of various foods, i.e. bread, buns, cake, pasta, noodles, biscuit, ice creams, yogurts, cheese, beverages, milk shakes, instant breakfasts, ice tea, juices, sports drinks, wine, powdered drink, fermented milk products, meat products and meat analogues, synthetic meat, etc. A comprehensive literature survey has been carried on this topic to give an overview in the field dietary fiber from food by products. In this article, the developments in the definition of fiber, fiber classification, potential sources of dietary fibers in food processing by products, their uses, functional properties, caloric content, energy values and the labelling regulations have been discussed. PMID- 25748245 TI - Acrosin activity is a good predictor of boar sperm freezability. AB - The main aim of this study was to determine whether acrosin activity could predict boar sperm freezability. For this purpose, we characterized the changes in sperm quality and acrosin activity throughout the cryopreservation procedure of sperm samples from 30 Pietrain boars by analyzing four critical steps: step 1 (extended sperm at 15 degrees C), step 2 (cooled sperm at 5 degrees C), step 3 (30 minutes postthaw), and step 4 (240 minutes postthaw). Freezability ejaculate groups were set on the basis of sperm motility and membrane integrity after freeze-thawing. Results obtained highlighted the low predictive value in terms of freezability of sperm motility and kinematics and sperm membrane integrity, as no differences between good and poor freezability ejaculates were seen before cryopreservation. Significant differences (P < 0.05) between ejaculate groups were observed in the cooling step at 5 degrees C for sperm kinetic parameters, and after thawing for sperm motility and membrane integrity. In contrast, acrosin activity appeared as an indicator of boar sperm freezability because the differences (P < 0.05) between good and poor freezability ejaculates manifested yet in extended samples at 15 degrees C. On the other hand, we also found that variations in sperm kinematics, membrane lipid disorder, intracellular calcium content, acrosome integrity, and acrosin activity throughout the cryopreservation procedure were indicative of a significant damage in spermatozoa during the cooling step in both ejaculate groups. In conclusion, the main finding of our study is that acrosin activity can be used as a reliable predictor of boar sperm freezability because it differs significantly between good and poor freezability ejaculates yet before freeze-thawing procedures took place, i.e., in the refrigeration step at 15 degrees C. PMID- 25748247 TI - Remarkable distinctions in the heat-induced phase transition processes of two poly(2-isopropyl-2-oxazoline)-based mixed aqueous solutions. AB - Detailed phase transition processes of poly(2-isopropyl-2-oxazoline) (PIPOZ)/poly(N-isopropylacrylamide) (PNIPAM) and PIPOZ/poly(N-vinylcaprolactam) (PVCL) mixtures in aqueous solution were investigated by DSC, temperature variable (1)H-NMR, optical microscopy and FT-IR spectroscopy measurements accompanied with two-dimensional correlation spectroscopy (2Dcos) and perturbation correlation moving window (PCMW) analytical methods. Through the comparison of these two systems, it is revealed that PVCL chains can interact with PIPOZ chains directly through the polymer-water-polymer cross-linking hydrogen bonds (C[double bond, length as m-dash]OD-O-DO[double bond, length as m dash]C), which induce their transition process as one. However, in the PIPOZ/PNIPAM mixture, the phase transition of the given component (PNIPAM or PIPOZ) is indirectly affected by the presence of the second component, because the strong hydrogen bonds C[double bond, length as m-dash]OD-N in PNIPAM components forbid the direct connection with PIPOZ, which induces two phase transition processes separately with no liquid-liquid phase separation (LLPS). Additionally, the formation of polymer-water-polymer hydrogen bonds (C[double bond, length as m-dash]OD-O-DO[double bond, length as m-dash]C) is highlighted as the key process in macroscopic LLPS. PMID- 25748246 TI - Effects of acetyl-L-carnitine on lamb oocyte blastocyst rate, ultrastructure, and mitochondrial DNA copy number. AB - Viable lambs can be produced after transfer of in vitro-derived embryos from oocytes harvested from prepubertal lambs. However, this occurs at a much lower efficiency than from adult ewe oocyte donors. The reduced competence of prepubertal oocytes is believed to be due, at least in part, to deficiencies in cytoplasmic maturation. Differences in the cytoplasmic ultrastructure between prepubertal and adult oocytes have been described in the sheep, pig, and cow. Prepubertal lamb oocytes have been shown to have a different distribution of mitochondria and lipid droplets, and less mitochondria and storage vesicles than their adult counterparts. L-carnitine plays a role in supplying energy to the cell by transporting long-chain fatty acids into mitochondria for beta-oxidation to produce ATP. Both L-carnitine and its derivative acetyl-L-carnitine have been reported to increase the blastocyst rate of oocytes from mice, cows, and pigs, treated during IVM. L-carnitine has also been shown to increase mitochondrial biogenesis in adipose cells. Therefore, the aims of this study were to determine if treatment of oocytes from prepubertal lambs with acetyl-L-carnitine during IVM could increase the blastocyst rate and alter mitochondria, vesicle, or lipid droplet number, volume, or distribution. The blastocyst rate was doubled in prepubertal lamb oocytes treated with acetyl-L-carnitine when compared to untreated oocytes (10.0% and 4.6%, respectively; P = 0.028). Light microscopy, scanning electron microscopy, and stereology techniques were used to quantify organelles in untreated and acetyl-L-carnitine-treated lamb oocytes, and quantitative polymerase chain reaction methods were used to measure the mitochondrial DNA copy number. There were no differences in mitochondrial volume, number, or mitochondrial DNA copy number. Acetyl-L-carnitine treatment increased the cytoplasmic volume (P = 0.015) of the oocytes, and there were trends toward an increase in the vesicle volume (P = 0.089) and an altered distribution of lipid droplets (P = 0.076). In conclusion, acetyl-L-carnitine can be used to increase the in vitro blastocyst rate of juvenile oocytes and therefore to improve juvenile in vitro embryo transfer methods. These methods can be used for livestock improvement by increasing the rate of genetic gain. Further work is required to identify the contents of the vesicles and confirm the mode of action of acetyl-L-carnitine in improving oocyte competence. PMID- 25748248 TI - Development of an acid ceramidase activity-based probe. AB - Acid ceramidase is responsible for the ultimate step in the catabolism of (glyco)sphingolipids by hydrolysis of ceramide into sphingosine and free fatty acid. Deficiency in acid ceramidase is the molecular basis of Farber disease. Here we report the synthesis and characterization of an activity-based acid ceramidase probe. PMID- 25748249 TI - Dynamic epithelia of the developing vertebrate face. AB - A segmental series of endoderm-derived pouch and ectoderm-derived cleft epithelia act as signaling centers in the developing face. Their precise morphogenesis is therefore essential for proper patterning of the vertebrate head. Intercellular adhesion and polarity are highly dynamic within developing facial epithelial cells, with signaling from the adjacent mesenchyme controlling both epithelial character and directional migration. Endodermal and ectodermal epithelia fuse to form the primary mouth and gill slits, which involves basement membrane dissolution, cell intercalations, and apoptosis, as well as undergo further morphogenesis to generate the middle ear cavity and glands of the neck. Recent studies of facial epithelia are revealing both core programs of epithelial morphogenesis and insights into the coordinated assembly of the vertebrate head. PMID- 25748250 TI - Watching eyes take shape. AB - Vertebrate eye formation is a multistep process requiring coordinated inductive interactions between neural and non-neural ectoderm and underlying mesendoderm. The induction and shaping of the eyes involves an elaborate cellular choreography characterized by precise changes in cell shape coupled with complex cellular and epithelial movements. Consequently, the forming eye is an excellent model to study the cellular mechanisms underlying complex tissue morphogenesis. Using examples largely drawn from recent studies of optic vesicle formation in zebrafish and in cultured embryonic stem cells, in this short review, we highlight some recent advances in our understanding of the events that shape the vertebrate eye. PMID- 25748251 TI - Regulation of tissue morphodynamics: an important role for actomyosin contractility. AB - Forces arising from contractile actomyosin filaments help shape tissue form during morphogenesis. Developmental events that result from actomyosin contractility include tissue elongation, bending, budding, and collective migration. Here, we highlight recent insights into these morphogenetic processes from the perspective of actomyosin contractility as a key regulator. Emphasis is placed on a range of results obtained through live imaging, culture, and computational methods. Combining these approaches in the future has the potential to generate a robust, quantitative understanding of tissue morphodynamics. PMID- 25748252 TI - Vascular patterning: coordinated signals keep blood vessels on track. AB - The vascular system is a complex, largely stereotyped network of interconnecting and branching vessels. How thousands of vessels form at precise locations is a key question regarding vascular morphogenesis. In order to achieve this defined architecture, the embryo integrates a multitude of attractive and repulsive cues to guide and shape the developing vasculature. This review summarizes recent studies investigating the interactions between endothelial cells and signals from surrounding tissues that pattern the initial blood vessel network. PMID- 25748253 TI - [Quality of conventional release verapamil prescription in patients with arterial hypertension]. AB - OBJECTIVE: To identify patients who were being treated for hypertension with conventional release verapamil (CRV), and to notify the professional responsible for their health care on cardiovascular risk to which they are exposed and achieve a reduction in the number of patients who are treated with this drug. METHODS: A quasi-experimental prospective before and after study without a control group was conducted on 7289 patients diagnosed with hypertension who were on treatment with CRV, between October 1, 2012 and December 31, 2012 in 8 Colombian cities, collected from a database for dispensing medicines. Socio demographic and pharmacological variables were evaluated. A total of 108 educational interventions were performed on those responsible for their health care, and evaluated within three months with the proportion of suspension of the prescriptions of CRV being evaluated. Multivariate analysis was performed using SPSS 22.0. RESULTS: The mean age of patients was 67.9+/-11.8 years (range: 26-96 years), of which 70.6% were men. Withdrawal of treatment with CRV was achieved in a total of 1922 patients (26.3% of users), distributed as follows: 1160 (60.4%) were the presentation of 120mg, while 762 (39.6%) the 80mg. The variable being treated in the city of Medellin (OR: 17.6; 95% CI: 11.949 to 25.924; P<.01) was statistically significantly associated with the replacement of CRV for another antihypertensive. CONCLUSIONS: A relatively moderate adherence to recommendations about the proper use of CRV in hypertensive patients, was found. Intervention programs that reduce inappropriate prescribing of potential risks to patients of insurance companies and cities where the change was not achieved, must be enforced. PMID- 25748254 TI - Hypertensive response to stress: the role of histaminergic H1 and H2 receptors in the medial amygdala. AB - Different brain areas seem to be involved in the cardiovascular responses to stress. The medial amygdala (MeA) has been shown to participate in cardiovascular control, and acute stress activates the MeA to a greater extent than any of the other amygdaloid structures. It has been demonstrated that the brain histaminergic system may be involved in behavioral, autonomic and neuroendocrine responses to stressful situations. The aim of the present study was to investigate the role of the histaminergic receptors H1 and H2 in cardiovascular responses to acute restraint stress. Wistar rats (280-320g) received bilateral injections of cimetidine, mepyramine or saline into the MeA and were submitted to 45min of restraint stress. Mepyramine microinjections at doses of 200, 100 and 50nmol promoted a dose-dependent blockade of the hypertensive response induced by the restraint stress. Cimetidine (200 and 100nmol) promoted a partial blockade of the hypertensive response to stress only at the highest dose administered. Neither drugs altered the typical stress-evoked tachycardiac responses. Furthermore, mepyramine and cimetidine were unable to modify the mean arterial pressure or heart rate of freely moving rats under basal conditions (non-stressed rats). The data suggest that in the MeA the histaminergic H1 receptors appear to be more important than H2 receptors in the hypertensive response to stress. Furthermore, there appears to be no histaminergic tonus in the MeA controlling blood pressure during non-stress conditions. PMID- 25748255 TI - Ovariectomy does not exacerbate the negative effects of sleep deprivation on synaptic plasticity in rats. AB - In our previous work, we found that female rats showed more cognitive impairment than male rats following 72h sleep deprivation (SD). Here, we compared the intact female with ovariectomized (OVX) rats to assess the potential modulatory effects of endogenous female sex hormones against the 48h SD-induced cognitive and synaptic modulations. The multiple platform method was applied for SD induction and spatial performances were determined using Morris water maze (MWM) task. Early longterm potentiation (E-LTP) was evaluated in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess hippocampal BDNF gene and protein expression. To reveal any influence of sleep loss on stress level, we also measured the plasma corticosterone levels of animals. Regardless of reproductive status, SD significantly impaired short-term memory and LTP, but did not significantly change the BDNF expression in the hippocampus. The corticosterone levels were decreased in both intact and OVX female rats following SD. These findings suggest that depletion of female sex steroid hormones does not lead to any heightened responsivity of female animals to the negative effects of SD on cognitive and synaptic functions. PMID- 25748257 TI - Ockham's razor and health care delivery. PMID- 25748258 TI - How do high cost-sharing policies for physician care affect inpatient care use and costs among people with chronic disease? AB - Rapidly rising health care costs continue to be a significant concern in the United States. High cost-sharing strategies thus have been widely used to address rising health care costs. Since high cost-sharing policies can reduce needed care as well as unneeded care use, it raises the concern whether these policies for physician care are a good strategy for controlling costs among chronically ill patients, especially whether utilization and costs in inpatient care will increase in response. This study examined whether high cost sharing in physician care affects inpatient care utilization and costs differently between individuals with and without chronic conditions. Findings from this study will contribute to the insurance benefit design that can control care utilization and save costs of chronically ill individuals. Prior studies suffered from gaps that limit both internal validity and external validity of their findings. This study has its unique contributions by filling these gaps jointly. The study used data from the 2007 Medical Expenditure Panel Survey, a nationally representative sample, with a cross-sectional study design. Instrumental variable technique was used to address the endogeneity between health care utilization and cost-sharing levels. We used negative binomial regression to analyze the count data and generalized linear models for costs data. To account for national survey sampling design, weight and variance were adjusted. The study compared the effects of high cost-sharing policies on inpatient care utilization and costs between individuals with and without chronic conditions to answer the research question. The final study sample consisted of 4523 individuals; among them, 752 had hospitalizations. The multivariate analysis demonstrated consistent patterns. Compared with low cost sharing policies, high cost-sharing policies for physician care were not associated with a greater increase in inpatient care utilization (P = .86 for chronically ill people and P = .67 for healthy people, respectively) and costs (P = .38 for chronically ill people and P = .68 for healthy people, respectively). The sensitivity analysis with a 10% cost-sharing level also generated consistent insignificant results for both chronically ill and healthy groups. Relative to nonchronically ill individuals, chronically ill individuals may increase their utilization and expenditures of inpatient care to a similar extent in response to increased physician care cost sharing. This may be due to cost pressure from inpatient care and short observation window. Although this study did not find evidence that high cost-sharing policies for physician care increase inpatient care differently for individuals with and without chronic conditions, interpretation of this finding should be cautious. It is possible that in the long run, these sick people would demonstrate substantial demands for medical care and there could be a total cost increase for health plans ultimately. Health plans need to be cautious of policies for chronically ill enrollees. PMID- 25748259 TI - Maximizing nurse practitioners' contributions to primary care through organizational changes. AB - The nurse practitioner (NP) workforce represents a considerable supply of primary care providers able to contribute to meeting a growing demand for care. However, organizational barriers hinder their optimal use. This article presents reports from 592 NPs on their roles, organizational support available to them, relationships between NPs and administration, their job satisfaction, and intentions of leaving their jobs. Nurse practitioners reported deficits in organizational context of care, problematic deployment of resources, and unfavorable working relationships with administrators. Addressing these challenges and creating work environments conducive to NP practice are necessary to fully exploit the capacity of the NP workforce. PMID- 25748260 TI - Using feedback to change primary care physician behavior. AB - Recognizing the gap between high-quality care and the care actually provided, health care providers across the country are under increasing institutional and payer pressures to move toward more high-quality care. This pressure is often leveraged through data feedback on provider performance; however, feedback has been shown to have only a variable effect on provider behavior. This study examines the cognitive behavioral factors that influence providers to participate in feedback interventions, and how feedback interventions should be implemented to encourage more provider engagement and participation. PMID- 25748261 TI - Barriers and facilitators to team-based care in the context of primary care transformation. AB - The patient-centered medical home model relies on team-based care for meaningful practice transformation. This article adds to the literature on the importance of teams in primary care by exploring the barriers and facilitators to establishing high functioning teams during a patient-centered medical home transformation process. PMID- 25748262 TI - Perceptions of high-risk patients and their providers on the patient-centered medical home. AB - To explore perceptions of high-risk patients and their practice staff on the patient-centered medical home, we conducted a multisite qualitative study with chronically ill, low-income patients and their primary care practice staff (N = 51). There were 3 key findings. Both patients and staff described a trade-off: timely care from an unfamiliar provider versus delayed access to their personal physician. Staff were enthusiastic about enhancing access through strategies such as online communication, yet high-risk patients viewed these as access barriers. Practices lacked capacity to manage high-risk patients and therefore frequently referred them to the emergency room. PMID- 25748263 TI - Patient-centered medical homes: observable types derived from national recognition assessment scores. AB - The patient-centered medical home (PCMH) is a strategy to transform primary care delivery organizations. However, PCMHs take on many forms and can "look different." To better understand the activities of organizations undertaking this strategy, we sought to identify discernible PCMH types using cluster analyses. From a sample of level 3 National Committee for Quality Assurance PCMHs, We extracted 3 types of PCMHs: information-focused, efficiency-focused, and high scoring. Our findings confirm that the PCMH is not a uniform intervention. Characterizing PCMHs with particular areas of focus has implications for understanding the transformation process, identifying areas for continued practice development, and advancing evaluation of this organizational model. PMID- 25748264 TI - Frontline experiences of a practice redesign to improve self-management of obesity in safety net clinics. AB - Teamlets of physicians and medical assistants may help improve obesity management in primary care settings. We aimed to understand the barriers and facilitators of implementing a teamlet approach to managing obesity in 3 safety net clinics. Key stakeholder interviews (n = 21) were conducted both during early implementation of practice change and 6 months later. Patient surveys (n = 393) examined obese patient activation and health status. Insufficient program resources and limited patient engagement due to external factors were implementation barriers despite fairly high patient activation. Staff members need time and resources to execute new responsibilities to support obesity management in safety net settings. Because of high turnover, multiple supporters may improve sustainability. PMID- 25748265 TI - Public Health Nurses Promoting Healthy Lifestyles (PHeeL-PHiNe): methodology and feasibility. AB - Mother and Child Health Clinics have provided preventive health services in Israel for nearly a century. The Public Health Nurses Promote Healthy Lifestyles Program was developed to assist families in adopting healthy behaviors. The program ran in the Jerusalem District from 2009 to 2011. After piloting, 175 public health nurses received training and interventions took place in 45 clinics serving parents of 167 213 infant and toddlers per year. When evaluation is completed, our hope is to incorporate the program into Mother and Child Health Clinic services regularly provided nationwide, thereby becoming an integral part of the initiative, Healthy Israel 2020. PMID- 25748266 TI - Primary health care access and ambulatory sensitive hospitalizations in New Zealand. AB - Ambulatory sensitive hospitalizations (ASH) are those thought to be preventable by timely and effective primary health care. Better access to primary health care has been associated with lower ASH rates. Funding increases to primary health care in New Zealand beginning in 2001 led to an improvement in access. Analysis of hospitalizations to all New Zealand public hospitals revealed that, for most age groups, ASH rates did not show long-term reductions from 2001 to 2009, while socioeconomic differences in ASH rates widened across this period. We conclude that increasing funding and access to primary health care will not, by itself, reduce ASH rates. PMID- 25748267 TI - Using patient-reported outcomes in routine practice: three novel use cases and implications. AB - Patient-reported outcomes (PROs) can show how patients perceive their illness burden over time. Active use of PROs by clinicians at the point of service can help illuminate the patients' longitudinal changes in outcomes, thereby advancing shared decision making, patient engagement, and self-care. This article offers principles and lessons learned from using PROs and provides 3 case studies to demonstrate how to overcome the challenges in using PROs in routine clinical practice to improve outcomes. These cases demonstrate that it is possible to embed patient-generated data into the flow of care and to track outcomes for improvement and research. PMID- 25748268 TI - Digital health tools for diabetes. AB - Digital health tools are providing patients with easier ways to keep track of their blood glucose levels and other key self-reported data, such as carbohydrates ingested, medication administered, and physical activity. Data are often uploaded into the cloud where physicians and other members of the care team can access them. Clinical studies are beginning to demonstrate efficacy of some of these tools, and Food and Drug Administration approval, when present, provides some much-needed validation. It is anticipated that these tools will continue to evolve and patient acceptance will continue to grow. Physician and care teams will need to familiarize themselves with the tools their patients are using and provide guidance and support for their use. PMID- 25748270 TI - Speeding rod recovery improves temporal resolution in the retina. AB - The temporal resolution of the visual system progressively increases with light intensity. Under scotopic conditions, temporal resolution is relatively poor, and may be limited by both retinal and cortical processes. Rod photoresponses themselves are quite slow because of the slowly deactivating biochemical cascade needed for light transduction. Here, we have used a transgenic mouse line with faster than normal rod phototransduction deactivation (RGS9-overexpressors) to test whether rod signaling to second-order retinal neurons is rate-limited by phototransduction or by other mechanisms. We compared electrical responses of individual wild-type and RGS9-overexpressing (RGS9-ox) rods to steady illumination and found that RGS9-ox rods required 2-fold brighter light for comparable activation, owing to faster G-protein deactivation. When presented with flickering stimuli, RGS9-ox rods showed greater magnitude fluctuations around a given steady-state current amplitude. Likewise, in vivo electroretinography (ERG) and whole-cell recording from OFF-bipolar, rod bipolar, and horizontal cells of RGS9-ox mice displayed larger than normal magnitude flicker responses, demonstrating an improved ability to transmit frequency information across the rod synapse. Slow phototransduction recovery therefore limits synaptic transmission of increments and decrements of light intensity across the first retinal synapse in normal retinas, apparently sacrificing temporal responsiveness for greater overall sensitivity in ambient light. PMID- 25748271 TI - Tablet Computing in Clinical Training of Pediatric Residents. AB - BACKGROUND: Medical residents receive both medical education and clinical skills training. New technologies and pedagogies are being developed to address each of these phases. Our research focuses on the efficacy of an iPad((r)) (Apple, Cupertino, CA) for clinical skills training. MATERIALS AND METHODS: For a period of 3 years, the University of South Florida provided incoming pediatric residents (n=94) with an iPad. At the end of the 3-year program, we surveyed the residents, measuring perceptions and satisfaction of iPad use in clinical training. RESULTS: Sixty percent of the residents responded to the survey. Ninety-three percent reported at least some iPad usage per day on clinical activities. We classified 13 facets of clinical training into three conceptual areas and provided figures detailing iPad use for each facet relative to other facets in the same cluster. The obtaining, management, and display of information are primary uses of iPad applications in clinical training. Finally, we provide information relative to perceived obstacles in clinical training, with weight of the device being the most frequently cited. CONCLUSIONS: The role of graduate medical education is changing with the introduction of new technologies. These technologies can differentially impact the various aspects of residency education and training. Residents reported using an iPad extensively in their clinical training. We argue that in addition to impacting traditional educational strategies, iPads can successfully facilitate aspects of clinical training in medical education. PMID- 25748273 TI - Routine pre- and post-hematopoietic stem cell transplant computed tomography of the abdomen for detecting invasive fungal infection has limited value. AB - The diagnostic utility of obtaining chest and abdomen computed tomography (CT) to evaluate for invasive fungal infection (IFI) before and after hematopoietic stem cell transplant (HSCT) remains unclear. The study was conducted as a quality improvement project. Chest and abdomen CT of patients who underwent an allogeneic HSCT over a 13-month period were reviewed. Scans included those performed pretransplant in all patients and days 0 to 100 post-transplant in selected patients. Sixty-six patients had chest and abdomen CT scans pretransplant. Chest CT was suggestive of IFI in 9 patients (13.6%), including 3 patients with prior history of IFI. After transplant, 37 patients had an initial chest CT and 14 patients an initial abdominal CT. The first chest CT post-transplant was suggestive of IFI in 3 patients; all had an abnormal CT pretransplant. After the initial post-transplant evaluation, 15 patients had 28 additional CT scans of the chest and 12 patients 19 additional CT scans of the abdomen. An abnormal chest CT with proven evidence of IFI was seen in only 1 patient. None of the 99 abdominal CT scans performed pre- or post-transplant had evidence of IFI. There is little benefit in obtaining abdominal CT scans in HSCT patients for detecting IFI either pre- or post-transplant. PMID- 25748272 TI - Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. AB - Cells have evolved a highly integrated network of mechanisms to coordinate cellular survival/death, proliferation, differentiation, and repair with metabolic states. It is therefore not surprising that proteins with canonical roles in cell death/survival also modulate nutrient and energy metabolism and vice versa. The finding that many BCL-2 (B cell lymphoma 2) proteins reside at mitochondria or can translocate to this organelle has long motivated investigation into their involvement in normal mitochondrial physiology and metabolism. These endeavors have led to the discovery of homeostatic roles for BCL-2 proteins beyond apoptosis. We predominantly focus on recent findings that link select BCL-2 proteins to carbon substrate utilization at the level of mitochondrial fuel choice, electron transport, and metabolite import independent of their cell death regulatory function. PMID- 25748274 TI - Concepts in context: Processing mental state concepts with internal or external focus involves different neural systems. AB - According to embodied cognition theories, concepts are contextually situated and grounded in neural systems that produce experiential states. This view predicts that processing mental state concepts recruits neural regions associated with different aspects of experience depending on the context in which people understand a concept. This neuroimaging study tested this prediction using a set of sentences that described emotional (e.g., fear, joy) and nonemotional (e.g., thinking, hunger) mental states with internal focus (i.e., focusing on bodily sensations and introspection) or external focus (i.e., focusing on expression and action). Consistent with our predictions, data suggested that the inferior frontal gyrus, a region associated with action representation, was engaged more by external than internal sentences. By contrast, the ventromedial prefrontal cortex, a region associated with the generation of internal states, was engaged more by internal emotion sentences than external sentence categories. Similar patterns emerged when we examined the relationship between neural activity and independent ratings of sentence focus. Furthermore, ratings of emotion were associated with activation in the medial prefrontal cortex, whereas ratings of activity were associated with activation in the inferior frontal gyrus. These results suggest that mental state concepts are represented in a dynamic way, using context-relevant interoceptive and sensorimotor resources. PMID- 25748275 TI - Syntheses of arnottin I and arnottin II. AB - Short total syntheses of arnottin I and II were accomplished in 5 and 6 steps, respectively. A sesamol-benzyne cycloaddition with a 3-furyl-benzoate followed by regiospecific lactonization provided rapid, large-scale access to the core of arnottin I. Saponification of arnottin I and hypervalent iodide mediated spirocyclization provided an efficient and direct preparation of racemic arnottin II. PMID- 25748276 TI - Bacterial cellulose as a support for the growth of retinal pigment epithelium. AB - The feasibility of bacterial cellulose (BC) as a novel substrate for retinal pigment epithelium (RPE) culture was evaluated. Thin (41.6 +/- 2.2 MUm of average thickness) and heat-dried BC substrates were surface-modified via acetylation and polysaccharide adsorption, using chitosan and carboxymethyl cellulose. All substrates were characterized according to their surface chemistry, wettability, energy, topography, and also regarding their permeability, dimensional stability, mechanical properties, and endotoxin content. Then, their ability to promote RPE cell adhesion and proliferation in vitro was assessed. All surface-modified BC substrates presented similar permeation coefficients with solutes of up to 300 kDa. Acetylation of BC decreased it's swelling and the amount of endotoxins. Surface modification of BC greatly enhanced the adhesion and proliferation of RPE cells. All samples showed similar stress-strain behavior; BC and acetylated BC showed the highest elastic modulus, but the latter exhibited a slightly smaller tensile strength and elongation at break as compared to pristine BC. Although similar proliferation rates were observed among the modified substrates, the acetylated ones showed higher initial cell adhesion. This difference may be mainly due to the moderately hydrophilic surface obtained after acetylation. PMID- 25748277 TI - Dicrocoelium dendriticum found in a Bronze Age cemetery in western Iran in the pre-Persepolis period: The oldest Asian palaeofinding in the present human infection hottest spot region. AB - Dicrocoeliasis of animals and humans is caused by trematode species of the genus Dicrocoelium, mainly Dicrocoelium dendriticum in ruminants of the Holarctic region. D. dendriticum may be considered an old parasite, probably related to the appearance and diversification of Eurasian ovicaprines, occurred 14.7-14.5 million years ago. The oldest palaeoparasitological findings of Dicrocoelium in domestic animals and humans date from more than 5000 years BC in Europe. Eggs of D. dendriticum have been found in a burial of a Bronze Age cemetery (2600-2200 BC) close to Yasuj city, southwestern Iran. This is the oldest finding of D. dendriticum in the Near East, where present human infection reports are more numerous than in other world regions where human dicrocoeliasis is rare and sporadic. This palaeofinding in the Zagros mountainous chain area is of interest by its location close to Persepolis, suggesting a narrow relationship between humans and herbivorous animals in these highlands. Domestic ruminant populations of these highlands were following a repeated contact with those of the western flat lowlands of the Fertile Crescent thanks to annual altitudinal transhumance migrations of the nomadic pastoral tribes with their herds living throughout Zagros Mountains in the several millennium period BC. It is concluded that D. dendriticum spread together with sheep and goats westward throughout Europe from the Fertile Crescent during the 8000-6000 year BC period and somewhat later southward into Africa, both spreads facilitated by the low specificity of that trematode species regarding the snail and ant intermediate hosts. PMID- 25748278 TI - Trypanoxyuris atelis and T. atelophora (Nematoda: Oxyuridae) in wild spider monkeys (Ateles geoffroyi) in tropical rain forest in Mexico: Morphological and molecular evidence. AB - Two species of pinworms, Trypanoxyuris atelis and Trypanoxyuris atelophora were collected from the black-handed spider monkey (Ateles geoffroyi) in several localities across southeastern Mexico, representing the first record for both species in Mexican primates. Identification of pinworm species was based on morphological and molecular data. These pinworms are distinguished from other congeners, and from each other, by the buccal structure, the lateral alae, and the morphology of the oesophagus. Phylogenetic analyses based on sequences of the mitochondrial cytochrome c oxidase subunit 1 gene placed T. atelis as the sister species of Trypanoxyuris minutus, a parasite of the howler monkey Alouatta palliata, and T. atelophora as the sister species of T. microon, a parasite of the night monkey, Aotus azarae. These relationships were supported with high posterior probability values by Bayesian inference. Comparisons of additional pinworm taxa from Neotropical primates are needed to assess oxyurid diversity, and to better understand the evolutionary relationships among these nematodes and their primate hosts. PMID- 25748279 TI - STEREOPSIS AND OPTICAL COHERENCE TOMOGRAPHY FINDINGS AFTER EPIRETINAL MEMBRANE SURGERY. AB - PURPOSE: To evaluate stereopsis in patients undergoing vitrectomy for epiretinal membrane and to investigate the relationship between stereopsis and foveal microstructures. METHODS: This study included 55 eyes of 55 patients who underwent vitrectomy for unilateral epiretinal membrane and 27 age-matched normal subjects. We examined stereopsis using the Titmus Stereo Test, TNO stereotest, and, optical coherence tomography before surgery and 6 months after surgery. Central foveal thickness, central retinal thickness at the parafovea (CRT-3 mm), macular volume, and retinal layer thickness were measured with the optical coherence tomography software and an image-processing program. RESULTS: Epiretinal membrane surgery significantly improved stereopsis in Titmus Stereo Test and in TNO. Stereopsis after surgery was significantly worse than in normal subjects. In stepwise multiple regression analysis, preoperative stereopsis showed a significant association with preoperative CRT-3 mm. Postoperative stereopsis was significantly correlated with postoperative inner nuclear layer thickness. Postoperative Titmus Stereo Test and TNO were significantly related to preoperative CRT-3 mm and preoperative macular volume and inner nuclear layer thickness, respectively. CONCLUSION: Vitrectomy for epiretinal membrane improved stereopsis, albeit not to a normal level. Titmus Stereo Test, a stereotest with a smaller index, was related to CRT-3 mm, whereas TNO with a larger index was correlated with retinal volume of the entire posterior pole and mean inner nuclear layer thickness. PMID- 25748280 TI - THE OMAR STUDY: Comparison of Ozurdex and Triamcinolone Acetonide for Refractory Cystoid Macular Edema in Retinal Vein Occlusion. AB - PURPOSE: To compare the risks and benefits of adding either intravitreal dexamethasone implant (DEX) or preservative-free triamcinolone acetonide (TA) to bevacizumab monotherapy in refractory cystoid macular edema due to retinal vein occlusion. METHODS: This is a multicenter, comparative, interventional, retrospective study that included 74 patients who were initially treated with intravitreal bevacizumab and later received either DEX or TA for the treatment of recalcitrant cystoid macular edema due to retinal vein occlusion. Main outcomes were best-corrected visual acuity, central macular thickness, cost of therapy, frequency of intravitreal injections, and side effects. RESULTS: Thirty-nine patients received TA and 35 patients received DEX injections. Groups were similar in age and gender distribution. Although the mean central macular thickness improved significantly for all groups (P < 0.0001), logMAR best-corrected visual acuity did not change significantly after steroid introduction (P = 0.06). Frequency of any intravitreal injection decreased significantly from 0.66 +/- 0.18 to 0.26 +/- 0.08 injections per month after initiation of steroids (P < 0.0001). This effect was greater in the DEX groups (P < 0.0001). Monthly cost decreased with TA but increased with DEX. CONCLUSION: Adding steroids improved anatomical outcome but did not affect final vision. Injection frequency decreased significantly after adding steroids, more so with DEX. There was no difference between TA and DEX regarding anatomical or functional outcomes or the incidence of side effects. PMID- 25748281 TI - COMPLIANCE WITH THE FACE-DOWN POSITIONING AFTER VITRECTOMY AND GAS TAMPONADE FOR RHEGMATOGENOUS RETINAL DETACHMENTS. AB - PURPOSE: To determine the compliance with the face-down positioning (FDP) of the patients who had undergone vitrectomy and gas tamponade. METHODS: One hundred and twenty-seven patients, 45 females and 82 males, who had undergone primary vitrectomy and gas tamponade for rhegmatogenous retinal detachments were studied. The FDP score was determined as 4 per day for 3 days after the surgery. The patient was given a score of one if the nurse found that the patient was in the FDP and zero if not in the FDP. A perfect FDP score was 12. RESULTS: The mean +/- SD FDP score was 10.2 +/- 1.8 with a range of 3 to 12. Females (10.7 +/- 1.2) scored significantly higher than males (9.9 +/- 2.1) (Mann-Whitney U test: P < 0.05). Patients who scored a perfect 12 were 38 (29.9%; female, 14:31.1%; male 24:29.3%). Low scorers <8 were all males (12:14.6%) and no females (0:0.0%). Age did not seem to be related. Only 1 patient failed to achieve retinal attachment, although she had scored a perfect 12. CONCLUSION: The compliance was considerably varied among patients. Some patients failed nearly or more than half times, and they were mostly males. The significance of the FDP to treat rhegmatogenous retinal detachment needs to be examined in a further investigation. PMID- 25748282 TI - Colocalization error between the scanning laser ophthalmoscope infrared reflectance and optical coherence tomography images of the heidelberg spectralis. AB - PURPOSE: To examine the colocalization error between the infrared reflectance (IR) scanning laser ophthalmoscope (SLO) and spectral domain optical coherence tomography (SD-OCT) images of the Heidelberg Spectralis. METHODS: The IR and corresponding horizontal raster SD-OCT images were compared in 10 healthy volunteers examined with 3 Heidelberg Spectralis + OCT instruments. The center points of retinal vessels selected by random uniform sampling in scanning laser ophthalmoscope-IR images were compared with colocalizing points in corresponding SD-OCT images by two masked readers. The error of colocalization was measured in the SD-OCT image. The point positions were recorded using Cartesian coordinates measured in microns. The error of colocalization was evaluated using a fixed effects generalized least squares regression model with location and instrument as predictor variables. RESULTS: A total of 1,617 points in the IR and SD-OCT images were analyzed, and the mean error of colocalization was 42.2 +/- 32.4 MUm. The Heidelberg Spectralis instrument used was not a significant predictor of colocalization error (P = 0.15). The colocalization errors were negatively correlated with x-coordinate position (P < 0.001). CONCLUSION: There is a mean colocalization error between the IR and SD-OCT images produced by the Heidelberg Spectralis that is on the scale of many features being evaluated in the fundus. The variability in these measurements means the confidence interval for the exact colocalization is much larger. Because of the magnitude and variability of the error, the colocalization feature of the Heidelberg Spectralis should be used as a rough guide, not an absolute determinant. PMID- 25748283 TI - Application of derivative spectrophotometry under orthogonal polynomial at unequal intervals: determination of metronidazole and nystatin in their pharmaceutical mixture. AB - This paper discusses a general method for the use of orthogonal polynomials for unequal intervals (OPUI) to eliminate interferences in two-component spectrophotometric analysis. In this paper, a new approach was developed by using first derivative D1 curve instead of absorbance curve to be convoluted using OPUI method for the determination of metronidazole (MTR) and nystatin (NYS) in their mixture. After applying derivative treatment of the absorption data many maxima and minima points appeared giving characteristic shape for each drug allowing the selection of different number of points for the OPUI method for each drug. This allows the specific and selective determination of each drug in presence of the other and in presence of any matrix interference. The method is particularly useful when the two absorption spectra have considerable overlap. The results obtained are encouraging and suggest that the method can be widely applied to similar problems. PMID- 25748284 TI - Synthesis, photophysical studies, solvatochromic analysis and TDDFT calculations of diazaspiro compounds. AB - Diazaspiro[5.5]undecane-1,3,5,9-tetraones and 3-thioxo-diazaspiro[5.5]undecane 1,5,9-trione have been synthesized via double Michael addition of 1,5-diphenyl 1,4-pentadien-3-one with active methylene heterocycles N,N-dimethyl barbituric acid, barbituric acid and thiobarbituric acid in water:ethanol (1:1) using TBAB as catalyst. The solvent effect on photophysical behavior of these compounds showed that stokes shift increases with increase in polarity of solvents. The solvent effect on the spectral properties has been investigated by using the Lippert-Mataga and Reichardt methods. The solvatochromism is analyzed by linear solvation energy relationship using the new four-parameter Catalan polarity scales. The relative fluorescence quantum yield of these diazaspiro compounds varies in solvents of different polarity. The HOMO and LUMO energies have been calculated by TDDFT (B3LYP/6-311G (d, p)) approach. TDDFT calculations were also used to compare the experimental and theoretical absorption spectra. PMID- 25748285 TI - Thermal oxidation process accelerates degradation of the olive oil mixed with sunflower oil and enables its discrimination using synchronous fluorescence spectroscopy and chemometric analysis. AB - We have investigated the effect of thermal treatment on the discrimination of pure extra virgin olive oil (EVOO) samples from EVOO samples adulterated with sunflower oil. Two groups of samples were used. One group was analyzed at room temperature (25 degrees C) and the other group was thermally treated in a thermostatic water bath at 75 degrees C for 8h, in contact with air and with light exposure, to favor oxidation. All samples were then measured with synchronous fluorescence spectroscopy. Fluorescence spectra were acquired by varying the excitation wavelength in the region from 250 to 720nm. In order to optimize the differences between excitation and emission wavelengths, four constant differential wavelengths, i.e., 20nm, 40nm, 60nm and 80nm, were tried. Partial least-squares discriminant analysis (PLS-DA) was used to discriminate between pure and adulterated oils. It was found that the 20nm difference was the optimal, at which the discrimination models showed the best results. The best PLS DA models were those built with the difference spectra (75-25 degrees C), which were able to discriminate pure from adulterated oils at a 2% level of adulteration. Furthermore, PLS regression models were built to quantify the level of adulteration. Again, the best model was the one built with the difference spectra, with a prediction error of 1.75% of adulteration. PMID- 25748286 TI - Ischemic stroke differential diagnose: spontaneous spinal epidural hematoma can be fatal. PMID- 25748287 TI - Should weakness be subsumed to nonspecific complaints?-Correspondence in response to Bhalla et al. PMID- 25748288 TI - Characterization and distribution of repetitive elements in association with genes in the human genome. AB - Repetitive elements constitute more than 50% of the human genome. Recent studies implied that the complexity of living organisms is not just a direct outcome of a number of coding sequences; the repetitive elements, which do not encode proteins, may also play a significant role. Though scattered studies showed that repetitive elements in the regulatory regions of a gene control gene expression, no systematic survey has been done to report the characterization and distribution of various types of these repetitive elements in the human genome. Sequences from 5' and 3' untranslated regions and upstream and downstream of a gene were downloaded from the Ensembl database. The repetitive elements in the neighboring of each gene were identified and classified using cross-matching implemented in the RepeatMasker. The annotation and distribution of distinct classes of repetitive elements associated with individual gene were collected to characterize genes in association with different types of repetitive elements using systems biology program. We identified a total of 1,068,400 repetitive elements which belong to 37-class families and 1235 subclasses that are associated with 33,761 genes and 57,365 transcripts. In addition, we found that the tandem repeats preferentially locate proximal to the transcription start site (TSS) of genes and the major function of these genes are involved in developmental processes. On the other hand, interspersed repetitive elements showed a tendency to be accumulated at distal region from the TSS and the function of interspersed repeat-containing genes took part in the catabolic/metabolic processes. Results from the distribution analysis were collected and used to construct a gene-based repetitive element database (GBRED; http://www.binfo.ncku.edu.tw/GBRED/index.html). A user-friendly web interface was designed to provide the information of repetitive elements associated with any particular gene(s). This is the first study focusing on the gene-associated repetitive elements in the human genome. Our data showed distinct genes associated with different kinds of repetitive element and implied such combination may shape the function of these genes. Aside from the conventional view of these elements in genome evolution, results from this study offer a systemic review to facilitate exploitation of these elements in genome function. PMID- 25748289 TI - Suicide by injecting lispro insulin with an intravenous cannula. AB - Suicide by injecting insulin is not uncommon both in diabetic and non-diabetic people. The victim usually uses an insulin syringe or a traditional syringe attached to a needle for the injection of insulin, of either animal or synthetic origin. We report a case of suicide by a non-diabetic physician by injecting lispro insulin through an intravenous cannula. To the best of our knowledge, the use of an intravenous cannula for the injection of insulin for suicide is unusual and is rarely reported in the medico-legal literature. PMID- 25748290 TI - Gastro-intestinal ascariasis--an unusual autopsy case report. AB - Ascaris lumbricoides or roundworms' propensity to produce large number of eggs that are resistant to extremes of environmental conditions have made them one of the highly prevalent and geographically well distributed nematodes among poor socio-economic regions throughout the world. We present an unusual case of fatal gastro-intestinal ascariasis where general neglect, and firm and prolonged reliance on traditional healing methods led to aggregation of roundworms to such an extent that otherwise seems improbable in modern times and, hence, is worth reporting. PMID- 25748291 TI - Alternative Therapies as a Substitute for Costly Prescription Medications: Results from the 2011 National Health Interview Survey. AB - PURPOSE: Some researchers have suggested that the popularity of complementary and alternative medicine (CAM) in the United States is due, in part, to the growing cost of conventional medical care. The 2011 National Health Interview Survey is the first population survey that directly asks respondents if they have substituted alternative therapies for prescription medications. The purpose of this study was to estimate the adult prevalence of CAM substitution and to identify factors associated with cost-related CAM use. METHODS: The sample adult core component of the 2011 National Health Interview Survey (N = 33,014) included a number of questions about prescription medication access and use, including "in the past 12 months, did you use alternative therapies to save money?" We used the Behavioral Model of Health Services Use to identify factors associated with the use of alternative therapies among respondents. Multivariate logistic regression models were used to evaluate factors associated with cost-related CAM use. FINDINGS: An estimated 12.3 million adults (5.4% of the population) used alternative therapies to save money in 2011. Women, middle-aged (31-50 years) adults, and residents of the western United States were more likely to engage in CAM substitution, as were smokers, those with activity limitations, and those in fair or poor health. The highest rates of CAM substitution were reported by uninsured adults (11.9%). IMPLICATIONS: A sizable number of adults in the United States use alternative therapies because they are cheaper than prescription medications. The health risks of such CAM substitution can be serious, and the phenomenon merits further investigation. PMID- 25748292 TI - Bringing salivary diagnostics into the 21st century. PMID- 25748293 TI - Pharmacokinetics and tolerability of minodronic acid tablets in healthy Chinese subjects and food and age effects on the pharmacokinetics. AB - PURPOSE: Minodronic acid is a third-generation bisphosphonate being developed for the treatment of osteoporosis. The aim of this study was to evaluate the pharmacokinetic profiles and tolerability of minodronic acid in healthy subjects, as well as to assess the effects of food and age on the pharmacokinetics. METHODS: This single-center, open-label, Phase I study was conducted in 4 parts. In part 1, minodronic acid tablets were administered to young volunteers at doses of 1, 2, and 4 mg. In part 2, after a single dose, young volunteers in the 1-mg dose group received repeated oral doses of minodronic acid once daily for 7 days. In part 3, a single oral dose of minodronic acid 1 mg was administered to elderly volunteers. In part 4, after a washout period of 8 days, volunteers in the 4-mg group received a single dose of 4-mg minodronic acid under fed conditions (administrated 30 minutes before a high-fat breakfast). Plasma samples were collected, and plasma concentrations of minodronic acid were analyzed by using a LC-MS/MS method. Tolerability was assessed throughout the study by physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse events. FINDINGS: Thirty-six young volunteers (mean age, 22.1 years; mean weight, 58.6 kg) and 12 elderly volunteers (mean age, 62.3 years; mean weight, 62.4 kg) were enrolled in the study. After single doses of 1, 2, and 4 mg of minodronic acid, the dose-normalized AUC exhibited dose linearity over the range of 1 to 4 mg in the young subjects. The plasma concentration of minodronic acid reached a steady state on day 7 after oral administration once daily for 7 days, with a mean accumulation ratio of 1.3. After a single dose of minodronic acid 1 mg, plasma Cmax and AUC0-infinity were both 1.8-fold higher compared with those of the young subjects. In the 4-mg dose group, minodronic acid Cmax and AUC0 infinity were reduced by 55% and 72%, respectively, with a high-fat breakfast compared with fasted conditions. No clinically meaningful changes in vital signs, laboratory values, or ECGs were observed. IMPLICATIONS: Single dosing of minodronic acid exhibited linear pharmacokinetics over the range of 1 to 4 mg; there was no accumulation after repeated administration. Food, especially high fat food, reduced the bioavailability of minodronic acid. In addition, the exposure of the drug was increased with age. Minodronic acid seemed to be well tolerated throughout the study. ClinicalTrials.gov Identifier: NCT02295436. PMID- 25748294 TI - The King-Devick test was useful in management of concussion in amateur rugby union and rugby league in New Zealand. AB - AIM: To use the King-Devick (K-D) test in senior amateur rugby union and rugby league players over a domestic competition season to see if it could identify witnessed and unwitnessed episodes of concussion that occurred from participation in competition matches over three years. METHODS: A prospective observational cohort study was conducted on a club level senior amateur rugby union team (n=36 players in 2012 and 35 players in 2013) and a rugby league team (n=33 players in 2014) during competition seasons in New Zealand. All 104 players completed two trials 10min apart of the K-D at the beginning of their competition season. Concussions (witnessed or unwitnessed) were only recorded if they were formally diagnosed by a health practitioner. RESULTS: A total of 52 (8 witnessed; 44 unwitnessed) concussive events were identified over the duration of the study resulting in a concussion injury incidence of 44 (95% CI: 32 to 56) per 1000 match participation hours. There was a six-fold difference between witnessed and unwitnessed concussions recorded. There were observable learning effects observed between the first and the second K-D test baseline testing (50 vs. 45s; z=-8.81; p<0.001). For every 1 point reduction in each of the post-injury SAC components there was a corresponding increase (worsening) of K-D test times post-match for changes in orientation (2.9s), immediate memory (1.8s) concentration (2.8s), delayed recall (2.0s) and SAC total score (1.7s). DISCUSSION: The rate of undetected concussion was higher than detected concussions by using the K-D test routinely following matches. Worsening of the K-D test post-match was associated with reduction in components of the SAC. The appeal of the K-D test is in the rapid, easy manner of its administration and the reliable, objective results it provides to the administrator. The K-D test helped identify cognitive impairment in players without clinically observable symptoms. PMID- 25748295 TI - Autophagic activation may be involved in the mechanism of hesperidin's therapeutic effects on cognitive impairment. PMID- 25748296 TI - The metabolic syndrome in a memory clinic population: relation with clinical profile and prognosis. AB - BACKGROUND: The metabolic syndrome (MetS) refers to a cluster of cardiovascular risk factors that is associated with an increased risk of cognitive impairment and dementia. It is unclear however, if the presence of the MetS is associated with a particular clinical profile or a different prognosis in patients with cognitive complaints or early dementia. OBJECTIVES: To compare 1) the clinical profile and 2) the prognosis of patients attending a memory clinic according to the presence or absence of MetS. DESIGN: Longitudinal cohort. SETTING: Memory clinic. PARTICIPANTS: We included and followed 86 consecutive patients (average age of 66.7 (SD 9.7)) from the Amsterdam Dementia Cohort with an MMSE>22. MEASUREMENTS: Clinical profile (neuropsychological examination, brain MRI, cerebrospinal fluid (CSF) biomarkers, clinical diagnosis) on an initial standardized diagnostic assessment was compared according to MetS status. Progression to dementia was assessed in initially nondemented patients (subjective complaints n=40, mild cognitive impairment n=24, follow-up available in 59). RESULTS: 35 (41%) patients met the MetS criteria. Demographics were similar between patients with or without the MetS. At baseline, diagnosis, cognitive performance, severity of degenerative or vascular abnormalities on MRI, and CSF amyloid and tau levels did not differ between the groups (all p>0.05). Among nondemented patients, however, MetS was associated with worse performance on executive function, attention & speed and visuoconstructive ability (z-scores, p<0.05). During a mean follow-up of 3.4years a similar proportion of patients with (4; 17%) and without (6; 17%) the MetS progressed to dementia (p=0.45). CONCLUSION: Among nondemented patients presenting at a memory clinic MetS was associated with slightly worse cognitive performance (worse on tasks assessing executive functions, visuo-constructive ability, attention & speed), but conversion rate to dementia was not increased. PMID- 25748297 TI - Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. AB - BACKGROUND: A gene expression profile (GEP) test able to accurately identify risk of metastasis for patients with cutaneous melanoma has been clinically validated. OBJECTIVE: We aimed for assessment of the prognostic accuracy of GEP and sentinel lymph node biopsy (SLNB) tests, independently and in combination, in a multicenter cohort of 217 patients. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) was performed to assess the expression of 31 genes from primary melanoma tumors, and SLNB outcome was determined from clinical data. Prognostic accuracy of each test was determined using Kaplan-Meier and Cox regression analysis of disease-free, distant metastasis-free, and overall survivals. RESULTS: GEP outcome was a more significant and better predictor of each end point in univariate and multivariate regression analysis, compared with SLNB (P < .0001 for all). In combination with SLNB, GEP improved prognostication. For patients with a GEP high-risk outcome and a negative SLNB result, Kaplan Meier 5-year disease-free, distant metastasis-free, and overall survivals were 35%, 49%, and 54%, respectively. LIMITATIONS: Within the SLNB-negative cohort of patients, overall risk of metastatic events was higher (~30%) than commonly found in the general population of patients with melanoma. CONCLUSIONS: In this study cohort, GEP was an objective tool that accurately predicted metastatic risk in SLNB-eligible patients. PMID- 25748298 TI - Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy. AB - BACKGROUND: BRAF inhibitors (BRAFi) cause paradoxical activation of the MAPK pathway in keratinocytes resulting in cutaneous squamous cell carcinoma (cuSCC). OBJECTIVE: We sought to examine the clinical factors involved in BRAFi-induced cuSCC development. METHODS: We studied 134 patients with BRAF-mutant metastatic melanoma treated with a BRAFi at Westmead Hospital, Sydney, Australia. Details of cuSCC development and associations with melanoma clinicopathologic features and treatment outcome were examined. RESULTS: In all, 32 (24%) patients developed 110 cuSCC after commencing treatment. In all, 61 (55%) cuSCC developed within the first 3 months. Age was the only independent risk factor for cuSCC development. After 3 months of therapy 4% of patients younger than 40 years developed cuSCC compared with 33% who were older than 60 years, and the hazard ratio of developing a cuSCC increased by 1.7 (95% confidence interval 1.3-2.3) per decade (P < .001). BRAFi cuSCC occurred more often in sun-protected areas (42%) compared with sporadic cuSCC (21%) (P < .001). cuSCC was not associated with progression free survival. LIMITATIONS: The study was from a single center and patients were also at risk of sporadic cuSCC. CONCLUSION: Most BRAFi-induced cuSCC develop within 3 months of BRAFi therapy. The only independent risk factor is increasing age. cuSCC may present in anatomical locations with low ultraviolet exposure such that thorough dermatologic assessment is required. PMID- 25748300 TI - Magnetic resonance spectroscopy detection of high lipid levels in intraaxial tumors without central necrosis: a characteristic of malignant lymphoma. AB - OBJECT: The differentiation of malignant lymphomas from gliomas or malignant gliomas by conventional MRI can be difficult. The authors studied Gd-enhanced MR images to obtain a differential diagnosis between malignant lymphomas and gliomas without central necrosis or cystic changes and investigated the diagnostic value of single-voxel proton MR spectroscopy ((1)H-MRS) using different parameters, including lipid levels. METHODS: This was a retrospective study of patients with primary malignant CNS lymphoma (n = 17) and glioma (n = 122 [Grades I, II, III, and IV in 10, 30, 33, and 49 patients, respectively]) who were treated between 2007 and 2013. The authors focused on 15 patients with homogeneously enhanced primary malignant CNS lymphomas and 7 homogeneously enhanced gliomas. Images of all the included tumors were acquired with (1)H-MRS at 3 T, and the diagnoses were histologically confirmed. RESULTS: Using a short echo time (1)H-MRS, large lipid peaks were observed in all 17 patients with a malignant lymphoma, in 39 patients (79.6%) with a Grade IV glioma, and in 10 patients (30.3%) with a Grade III glioma. A focus on homogeneously enhanced tumors revealed large lipid peaks in 15 malignant lymphomas that were free of central necrosis on Gd-enhanced T1 weighted images. Conversely, in the 7 homogeneously enhanced gliomas (glioblastoma and anaplastic astrocytoma, n = 2 each; anaplastic oligodendroglioma, diffuse astrocytoma, and pilomyxoid astrocytoma, n = 1 each), lipid peaks were small or absent. CONCLUSIONS: Large lipid peaks on (1)H-MRS images of tumors without central necrosis were characteristic of malignant lymphomas. Conversely, small or absent lipid peaks in intraaxial tumors without central necrosis were strongly suggestive of glioma. PMID- 25748301 TI - Effect of graded nerve pressure injuries on motor function. AB - OBJECT: The purpose of this study was to determine the minimum amount of nerve fibers required to maintain normal motor function after nerve injury in rats. METHODS: The authors first confirmed that a common peroneal nerve injury caused more aggravating effects on lower limb motor function than tibial nerve injury, as assessed by the static sciatic index (SSI). Thereafter, rats were subjected to varying degrees of crush injury to the common peroneal nerve. At 48 hours after the injury, motor function was assessed using the SSI and slope-walking ability (with slope angles of 30 degrees and 45 degrees ). The tibialis anterior muscle, a main muscle innervated by the common peroneal nerve, was removed. Muscle sections were co-labeled with neuronal class III beta-tubulin polyclonal antibody to identify the presence of axons and Alexa Fluor 488-conjugated alpha bungarotoxin to identify the presence of motor endplates. RESULTS: The evaluation of neuromuscular innervation showed a correlation between SSI scores and ratios of residual axons (rs = 0.68, p < 0.01), and there was a statistically significant difference between slope-walking ability and ratios of residual axons (p < 0.01). Moreover, the ratios of residual axons in the nerve-crushed rats with normal motor function (SSI above -20) ranged from 36.5% to 88.7%, and those ratios in the success group with slope-walking angles of 30 degrees and 45 degrees ranged from 14.7% to 88.7% and from 39.8% to 88.7%, respectively. CONCLUSIONS: In this study of rodents, less than half of the motor axons were sufficient to maintain normal motor function of the lower limb. PMID- 25748299 TI - Host ESCRT proteins are required for bromovirus RNA replication compartment assembly and function. AB - Positive-strand RNA viruses genome replication invariably is associated with vesicles or other rearranged cellular membranes. Brome mosaic virus (BMV) RNA replication occurs on perinuclear endoplasmic reticulum (ER) membranes in ~70 nm vesicular invaginations (spherules). BMV RNA replication vesicles show multiple parallels with membrane-enveloped, budding retrovirus virions, whose envelopment and release depend on the host ESCRT (endosomal sorting complexes required for transport) membrane-remodeling machinery. We now find that deleting components of the ESCRT pathway results in at least two distinct BMV phenotypes. One group of genes regulate RNA replication and the frequency of viral replication complex formation, but had no effect on spherule size, while a second group of genes regulate RNA replication in a way or ways independent of spherule formation. In particular, deleting SNF7 inhibits BMV RNA replication > 25-fold and abolishes detectable BMV spherule formation, even though the BMV RNA replication proteins accumulate and localize normally on perinuclear ER membranes. Moreover, BMV ESCRT recruitment and spherule assembly depend on different sets of protein-protein interactions from those used by multivesicular body vesicles, HIV-1 virion budding, or tomato bushy stunt virus (TBSV) spherule formation. These and other data demonstrate that BMV requires cellular ESCRT components for proper formation and function of its vesicular RNA replication compartments. The results highlight growing but diverse interactions of ESCRT factors with many viruses and viral processes, and potential value of the ESCRT pathway as a target for broad spectrum antiviral resistance. PMID- 25748302 TI - Letter to the Editor: Improving arteriovenous malformation research and care. PMID- 25748303 TI - Augmented reality-guided neurosurgery: accuracy and intraoperative application of an image projection technique. AB - OBJECT: An augmented reality system has been developed for image-guided neurosurgery to project images with regions of interest onto the patient's head, skull, or brain surface in real time. The aim of this study was to evaluate system accuracy and to perform the first intraoperative application. METHODS: Images of segmented brain tumors in different localizations and sizes were created in 10 cases and were projected to a head phantom using a video projector. Registration was performed using 5 fiducial markers. After each registration, the distance of the 5 fiducial markers from the visualized tumor borders was measured on the virtual image and on the phantom. The difference was considered a projection error. Moreover, the image projection technique was intraoperatively applied in 5 patients and was compared with a standard navigation system. RESULTS: Augmented reality visualization of the tumors succeeded in all cases. The mean time for registration was 3.8 minutes (range 2-7 minutes). The mean projection error was 0.8 +/- 0.25 mm. There were no significant differences in accuracy according to the localization and size of the tumor. Clinical feasibility and reliability of the augmented reality system could be proved intraoperatively in 5 patients (projection error 1.2 +/- 0.54 mm). CONCLUSIONS: The augmented reality system is accurate and reliable for the intraoperative projection of images to the head, skull, and brain surface. The ergonomic advantage of this technique improves the planning of neurosurgical procedures and enables the surgeon to use direct visualization for image-guided neurosurgery. PMID- 25748304 TI - Symptomatic perianeurysmal parenchymal cyst: case illustration. PMID- 25748305 TI - Streamlining deep brain stimulation surgery by reversing the staging order. AB - Deep brain stimulation (DBS) is approved for several clinical indications; however, the sequencing of DBS surgery and the timeline for implementing stimulation therapy are not standardized. In over 140 cases so far, the authors have reversed the sequencing for staged implantation of DBS systems that was conducive to minimizing patient anxiety and discomfort while providing the opportunity to shorten the time between implantation and programming for therapeutic management of symptoms. Stage I was performed with the patient under general anesthesia and consisted of implantation of the pulse generator and lead extensions and placement of the bur holes. Stage II was completed 1-7 days later, using only local anesthesia, and included stereotactic frame-based microelectrode recordings, semi-microstimulation and macrostimulation, and testing and placement of the stimulating electrodes. Stage I lasted approximately 90 minutes, whereas Stage II lasted approximately 230 minutes. All patients tolerated the procedures and received a complete implanted system. Deep brain stimulation therapy was typically initiated on the same day as lead implantation. When sequencing was reversed and bur holes were placed during the first stage while a patient was under general anesthesia, the patient was able to tolerate the second awake stage and was able to begin stimulation therapy within 48 hours of the second stage. PMID- 25748306 TI - Combined noninvasive language mapping by navigated transcranial magnetic stimulation and functional MRI and its comparison with direct cortical stimulation. AB - OBJECT: Repetitive navigated transcranial magnetic stimulation (rTMS) is now increasingly used for preoperative language mapping in patients with lesions in language-related areas of the brain. Yet its correlation with intraoperative direct cortical stimulation (DCS) has to be improved. To increase rTMS's specificity and positive predictive value, the authors aim to provide thresholds for rTMS's positive language areas. Moreover, they propose a protocol for combining rTMS with functional MRI (fMRI) to combine the strength of both methods. METHODS: The authors performed multimodal language mapping in 35 patients with left-sided perisylvian lesions by using rTMS, fMRI, and DCS. The rTMS mappings were conducted with a picture-to-trigger interval (PTI, time between stimulus presentation and stimulation onset) of either 0 or 300 msec. The error rates (ERs; that is, the number of errors per number of stimulations) were calculated for each region of the cortical parcellation system (CPS). Subsequently, the rTMS mappings were analyzed through different error rate thresholds (ERT; that is, the ER at which a CPS region was defined as language positive in terms of rTMS), and the 2-out-of-3 rule (a stimulation site was defined as language positive in terms of rTMS if at least 2 out of 3 stimulations caused an error). As a second step, the authors combined the results of fMRI and rTMS in a predefined protocol of combined noninvasive mapping. To validate this noninvasive protocol, they correlated its results to DCS during awake surgery. RESULTS: The analysis by different rTMS ERTs obtained the highest correlation regarding sensitivity and a low rate of false positives for the ERTs of 15%, 20%, 25%, and the 2-out-of-3 rule. However, when comparing the combined fMRI and rTMS results with DCS, the authors observed an overall specificity of 83%, a positive predictive value of 51%, a sensitivity of 98%, and a negative predictive value of 95%. CONCLUSIONS: In comparison with fMRI, rTMS is a more sensitive but less specific tool for preoperative language mapping than DCS. Moreover, rTMS is most reliable when using ERTs of 15%, 20%, 25%, or the 2-out-of-3 rule and a PTI of 0 msec. Furthermore, the combination of fMRI and rTMS leads to a higher correlation to DCS than both techniques alone, and the presented protocols for combined noninvasive language mapping might play a supportive role in the language-mapping assessment prior to the gold-standard intraoperative DCS. PMID- 25748307 TI - Dr. Arvid Lindau and discovery of von Hippel-Lindau disease. AB - Arvid Lindau, MD, PhD, consolidated the disparate array of benign and malignant visceral and nervous system lesions into the neoplastic syndrome known as von Hippel-Lindau (VHL) disease. Based on this pioneering work, Dr. Lindau was awarded both a Rockefeller fellowship to work in Dr. Harvey Cushing's laboratory in Boston, Massachusetts, and the Lennmalm Prize. While working in Dr. Cushing's laboratory, Dr. Lindau continued his study of CNS hemangioblastomas. His work with Dr. Cushing led to their lifelong friendship and scientific collaboration. In this paper the authors describe Arvid Lindau's pioneering work in nervous system tumor pathology, his relationship to Dr. Cushing, and his role in advancing neurological surgery and research in Europe. PMID- 25748308 TI - Grade 2 meningioma and radiosurgery. AB - OBJECT: World Health Organization Grade 2 meningiomas are aggressive tumors associated with a high recurrence rate leading to repeated surgical procedures, which can seriously worsen a patient's neurological status. Although radiosurgery is an increasingly popular technique, its role in the management of Grade 2 meningiomas has yet to be defined. In this study the authors aimed to evaluate radiosurgery in achieving control of proven tumor progression occurring after resection of Grade 2 meningioma. METHODS: This retrospective study included consecutive patients who, between 2000 and 2012, had undergone radiosurgery for radiologically proven progression of a previously surgically treated Grade 2 meningioma. RESULTS: Twenty-seven patients were eligible for analysis. There were 9 men and 18 women with a mean age of 59 years. The mean radiation dose was 15.2 Gy (range 12-21 Gy), and the mean target volume was 5.4 cm(3) (range 0.194-14.2 cm(3)). Thirty-four radiosurgical procedures were performed in the 27 patients. The mean progression-free survival after radiosurgery was 32.4 months among those with progression in a target irradiated volume and 26.4 months among those with progression in any intracranial meninges. With a mean follow-up of 56.4 months (range 12-108 months), the 12-, 24-, and 36-month actuarial local control rates for all patients were 75%, 52%, and 40%, respectively, and the regional control rates were 75%, 48%, and 33%. A single case of transient hemiparesis completely resolved without sequelae. CONCLUSIONS: Radiosurgery appears to be a safe and effective treatment for the local control of delayed progression after resection of a Grade 2 meningioma. Higher radiation doses similar to those applied for malignant tumors should be recommended when possible. PMID- 25748309 TI - Modeling ozone removal to indoor materials, including the effects of porosity, pore diameter, and thickness. AB - We develop an ozone transport and reaction model to determine reaction probabilities and assess the importance of physical properties such as porosity, pore diameter, and material thickness on reactive uptake of ozone to five materials. The one-dimensional model accounts for molecular diffusion from bulk air to the air-material interface, reaction at the interface, and diffusive transport and reaction through material pore volumes. Material-ozone reaction probabilities that account for internal transport and internal pore area, gamma(ipa), are determined by a minimization of residuals between predicted and experimentally derived ozone concentrations. Values of gamma(ipa) are generally less than effective reaction probabilities (gamma(eff)) determined previously, likely because of the inclusion of diffusion into substrates and reaction with internal surface area (rather than the use of the horizontally projected external material areas). Estimates of gamma(ipa) average 1 * 10(-7), 2 * 10(-7), 4 * 10( 5), 2 * 10(-5), and 4 * 10(-7) for two types of cellulose paper, pervious pavement, Portland cement concrete, and an activated carbon cloth, respectively. The transport and reaction model developed here accounts for observed differences in ozone removal to varying thicknesses of the cellulose paper, and estimates a near constant gamma(ipa) as material thickness increases from 0.02 to 0.16 cm. PMID- 25748310 TI - A guide to prescribing home phototherapy for patients with psoriasis: the appropriate patient, the type of unit, the treatment regimen, and the potential obstacles. AB - BACKGROUND: Ultraviolet B phototherapy is underused because of costs and inconvenience. Home phototherapy may alleviate these issues, but training is spotty, and many physicians are not comfortable prescribing home phototherapy. OBJECTIVE: The purpose of this review is to provide a practical guide for recognizing appropriate patients, prescribing, and dealing with potential obstacles for home phototherapy treatment. METHODS: Current guidelines for treatment of psoriasis were used to describe an appropriate patient for home phototherapy. Current literature and resources from phototherapy providers were reviewed to determine appropriate type of light, unit, treatment regimen, and how to navigate the insurance claim process. RESULTS: Treatment schedules vary based on skin type. Home phototherapy companies provide various units suited for individual situations. Assistance can be used from suppliers to facilitate the process of obtaining a home phototherapy unit and navigating obstacles. LIMITATIONS: Phototherapy treatment varies on an individual basis, so this review serves only as a guide. CONCLUSION: Home phototherapy is a suitable treatment for many patients for whom office-based phototherapy is not accessible. Home phototherapy companies simplify the process by providing assistance for prescribing home light units. PMID- 25748311 TI - Cutaneous manifestations of pediatric granulomatosis with polyangiitis: a clinicopathologic and immunopathologic analysis. AB - BACKGROUND: Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis associated with variable cutaneous manifestations and histopathologic findings. It is less frequent in children than adults and is often positive for cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or proteinase 3-ANCA. OBJECTIVE: We sought to better define and correlate the clinical, histopathologic, and immunopathologic characteristics of cutaneous GPA in pediatric patients. METHODS: We retrospectively reviewed clinical records and cutaneous histopathologic specimens of patients 17 years or younger with cutaneous manifestations of GPA who were seen at our institution from 1990 to 2013. RESULTS: Of the 52 patients identified with GPA, cutaneous involvement occurred in 36.5% and was the initial manifestation of disease in 7.7%. Of the 19 patients with cutaneous involvement, 26.3% developed acneiform and folliculitis-like papules; 84.2% were cytoplasmic ANCA positive; and 78.9% were proteinase 3-ANCA positive. Histopathologic features included leukocytoclastic vasculitis, granulomatous inflammation, acneiform and perifollicular inflammation, granulomatous vasculitis, and palisading granulomas. LIMITATIONS: Our study was limited because of its retrospective design. CONCLUSION: Pediatric patients with cutaneous GPA most commonly have palpable purpura, leukocytoclastic vasculitis, and positive cytoplasmic ANCA or proteinase 3-ANCA serologic results. Cutaneous manifestations and histopathologic findings vary, but acneiform lesions may be a cutaneous manifestation of the disease unique to this age group. PMID- 25748312 TI - Association between tumor necrosis factor inhibitor (TNFi) therapy and changes in C-reactive protein (CRP), blood pressure, and alanine aminotransferase (ALT) among patients with psoriasis, psoriatic arthritis, or rheumatoid arthritis. PMID- 25748313 TI - Clinical, dermoscopic, and histopathologic features of body hair disorders. AB - Dermoscopic examination of hair and scalp, also named "trichoscopy," is an essential tool in diagnosis of hair and scalp diseases. Trichoscopy is fast and noninvasive and can be used to evaluate hair disorders in all body areas. Body hair disorders are uncommon, and most publications on their dermoscopic features are limited to case reports or series. In this review we present the available information on the dermoscopic diagnosis of body hair disorders including keratosis pilaris, trichostasis spinulosa, pili multigemini, circle hairs, rolled hairs, eruptive vellus hair cyst, and ingrown hairs. PMID- 25748314 TI - Expression of prestin in OHCs is reduced in Spag6 gene knockout mice. AB - Sperm-associated antigen 6 (Spag6) gene, which encodes an axonemal protein (SPAG6), ubiquitously expresses in tissue and organs containing ciliated cells. The present work was to investigate whether SPAG6 expressed in cochlear hair cells and, if so, to explore the presumable correlations between prestin and SPAG6. The distribution of SPAG6 in organ of Corti and the morphological features of hair cells in basilar membrane were investigated by immunofluorescent staining. The amount of prestin in Spag6 mutant mice was measured by Western blotting and real-time PCR, respectively. Additionally, co-immunoprecipitation tests were performed to confirm the presumed interaction between prestin and SPAG6. We observed that SPAG6 expressed in the cuticular plate in outer hair cells (OHCs) and prestin in the lateral wall of OHCs that located along with SPAG6 at this site. In comparison to Spag6 +/+ mice, Spag6 -/- mice showed apparent morphological abnormity of OHCs and lower intensity of prestin fluorescence. The expression of prestin in Spag6 -/- mice reduced significantly at both protein and mRNA levels. Moreover, co-immunoprecipitation tests demonstrated the interaction between prestin and SPAG6. Taken together, these data indicate that SPAG6 is indispensible for the stability of OHCs by maintaining the normal expression of prestin, which implies that Spag6 gene is essential for mechanosensory function of OHCs. PMID- 25748315 TI - Pratensein ameliorates beta-amyloid-induced cognitive impairment in rats via reducing oxidative damage and restoring synapse and BDNF levels. AB - This study was designed to investigate the protective effect of pratensein against cognitive impairment induced by amyloid beta (1-42) (Abeta1-42) in rats. Abeta1-42 peptide was injected bilaterally in the hippocampus of rat. Next, pratensein was administered orally for 3 weeks. Our findings demonstrated that treatment with pratensein ameliorated learning and memory deficits in Abeta1-42 rat model of AD. Pratensein treatment significantly attenuated neuronal degeneration and apoptosis in hippocampus. Moreover, the over-expression in IL 1beta and TNF-alpha as well as the extensive astrogliosis and microgliosis in hippocampus induced by Abeta1-42 were significantly reduced following administration of pratensein. Concomitantly, pratensein treatment significantly suppressed the activation of NF-kappaB in hippocampus. In addition, pratensein was able to increase the levels of synaptophysin and brain-derived neurotrophic factor (BDNF). These results indicate that pratensein could significantly ameliorate Abeta1-42-induced spatial learning and memory impairment through reducing neuroinflammation via inhibition of glial activation and NF-kappaB activation, and restoring synapse and BDNF levels, suggesting that administration of pratensein could likely provide a therapeutic approach for AD. PMID- 25748316 TI - Distinct association between the antagonistic jaw muscle activity levels and cardiac activity during chewing and NREM sleep in the freely moving guinea pigs. AB - The aim of this study was to investigate the changes of the association between cardiac activity and the electromyographic (EMG) level of the antagonistic jaw muscles during chewing and NREM sleep in guinea pigs after systemic clonidine injections. Ten animals were prepared for chronic experiments to monitor sleep, cardiac activity and EMG activity of jaw-closing masseter (MAS) and jaw-opening anterior belly of digastric (ADG) muscles. The recordings were made for ten hours with the injections of saline or clonidine (10 MUg/kg, i.p.). Integrated EMG activity of the two muscles and mean heart rate (mHR) were calculated for every 10-s epoch. During the two hours after clonidine injection, the duration of REM sleep and mHR were significantly reduced. During chewing, the high EMG activity level of the two muscles and the activity ratio between the two muscles were not modified although mHR was decreased. During NREM sleep, after clonidine injection, the low EMG activity level at baseline was further decreased by 20-30% in parallel to a decrease of mHR although the heterogeneity of the activity ratio remained unaltered. The results suggest that the maintenance of the activity level for the antagonistic jaw muscles are regulated by the distinct physiological mechanisms reflecting the behavioral states during conscious chewing and unconscious NREM sleep. PMID- 25748317 TI - Effects of haptic supplementation on postural stability in unilateral vestibular loss patients. AB - The effects of haptic supplementation on postural stability during upright standing with vision were investigated in 11 unilateral vestibular loss (UVL) patients and compared to 12 age-marched controls. All the participants were instructed to grip a fixed or mobile stick. In the mobile conditions, the lower extremity of the stick was in contact with a slippery or a rough surface. Postural stability was assessed by the root mean square (RMS) and the velocity of the center of foot pressure (CoP) displacements in both antero-posterior (AP) and medio-lateral (ML) directions. Results showed that RMS was larger in UVL patients than in aged-matched participants in AP direction. However, in the mobile stick conditions, only the rough surface improved postural stability. In addition, RMS was more sensitive to haptic supplementation than CoP velocity. The present study confirms the importance of haptic information in the multi-sensory (re) weighting process underlying postural control in UVL patients. PMID- 25748318 TI - Chronic corticosterone exposure reduces hippocampal astrocyte structural plasticity and induces hippocampal atrophy in mice. AB - Long-term exposure to stress or high glucocorticoid levels significantly reduces hippocampal volume and induces depression-like behavior in rodents; however, the cause of which remains unknown. Increasing evidence shows that astrocytes are the most abundant cells in the central nervous system (CNS). Astrocytes support, nourish, protect, and repair neurons, and these characteristics are closely linked to neuronal activities. This study focused on the effects of corticosterone (CORT) on astrocytes. We probed into the influence of chronic CORT exposure on structural plasticity of astrocytes in hippocampal tissues of male C57BL/6N mice. The number, somal volume, and protrusion length of glial fibrillary acidic protein-positive astrocytes and the hippocampal volume were assayed by immunocytochemistry and quantitative stereological techniques. Results showed that chronic CORT injection induced depression-like behavior in male mice and significantly decreased hippocampal volume, as well as the number of astroctyes, somal volume, and protrusion length in the hippocampus. The reduction in the hippocampal astrocyte structural plasticity may represent the mechanism by which chronic CORT treatment causes hippocampal atrophy and depression-like behavior in male mice. PMID- 25748320 TI - Protection Against Chlamydia trachomatis Infection and Upper Genital Tract Pathological Changes by Vaccine-Promoted Neutralizing Antibodies Directed to the VD4 of the Major Outer Membrane Protein. AB - The VD4 region from the Chlamydia trachomatis major outer membrane protein contains important neutralizing B-cell epitopes of relevance for antibody mediated protection against genital tract infection. We developed a multivalent vaccine construct based on VD4s and their surrounding constant segments from serovars D, E, and F. Adjuvanted with cationic liposomes, this construct promoted strong immune responses to serovar-specific epitopes, the conserved LNPTIAG epitope and neutralized serovars D, E, and F. Vaccinated mice were protected against challenge, with protection defined as reduced bacterial numbers in vagina and prevention of pathological changes in the upper genital tract. Adoptive transfer of serum and T-cell depletion experiments demonstrated a dominant role for antibodies and CD4(+) T cells in the protective immune response. Integrating a multivalent VD4 construct into the sequence of the major outer membrane protein resulted in a protective and broadly neutralizing vaccine. Our findings emphasize the important role of antibodies in protection against Chlamydia trachomatis. PMID- 25748319 TI - Cerebral autoregulation, beta amyloid, and white matter hyperintensities are interrelated. AB - Emerging studies link vascular risk factors and cerebrovascular health to the prevalence and rates of progression in Alzheimer's disease (AD). The brain's ability to maintain constant blood flow across a range of cerebral perfusion pressures, or autoregulation, may both promote and result from small vessel cerebrovascular disease and AD-related amyloid pathology. Here, we examined the relationship among cerebral autoregulation, small vessel cerebrovascular disease, and amyloid deposition in 14 non-demented older adults. Reduced cerebral autoregulation, was associated with increased amyloid deposition and increased white matter hyperintensity volume, which, in turn were positively associated with each other. For the first time in humans, we demonstrate an interrelationship among AD pathology, small vessel cerebrovascular disease, and cerebral autoregulation. Vascular factors and AD pathology are not independent but rather appear to interact. PMID- 25748321 TI - High Soluble CD14 Levels at Primary HIV-1 Infection Predict More Rapid Disease Progression. AB - The soluble CD14 (sCD14) level was found associated with mortality during the chronic phase of human immunodeficiency virus (HIV) infection. Here we assessed its prognostic value in 138 patients with primary HIV infection. Higher sCD14 levels were associated with death, from myocardial infarction, but this was based on 3 deaths only. Among 68 untreated patients, those with higher sCD14 levels had more rapid spontaneous CD4 cell decline during the first 18 months following primary infection. This association persisted after adjustment for age, the CD4 cell count, and HIV viral load at diagnosis. PMID- 25748322 TI - Molecular Epidemiology of Adenovirus Type 21 Respiratory Strains Isolated From US Military Trainees (1996-2014). AB - BACKGROUND: The circulation of human adenovirus type 21 (HAdV21) in the United States has been documented since the 1960s in association with outbreaks of febrile respiratory illness (FRI) in military boot camps and civilian cases of respiratory disease. METHODS: To describe the molecular epidemiology of HAdV21 respiratory infections across the country, 150 clinical respiratory isolates obtained from continuous surveillance of military recruit FRI, and 23 respiratory isolates recovered from pediatric and adult civilian cases of acute respiratory infection were characterized to compile molecular typing data spanning 37 years (1978-2014). RESULTS: Restriction enzyme analysis and genomic sequencing identified 2 clusters of closely related genomic variants readily distinguishable from the prototype and designated 21a-like and 21b-like. A-like variants predominated until 1999. A shift to b-like variants was noticeable by 2007 after a 7-year period (2000-2006) of cocirculation of the 2 genome types. US strains are phylogenetically more closely related to European and Asian strains isolated over the last 4 decades than to the Saudi Arabian prototype strain AV-1645 isolated in 1956. CONCLUSIONS: Knowledge of circulating HAdV21 variants and their epidemic behavior will be of significant value to local and global FRI surveillance efforts. PMID- 25748323 TI - Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis. AB - BACKGROUND: Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA. METHODS: Fifty-one patients were included, 9 with probable/proven IA. We determined quantitative and qualitative reconstitution of polymorphonuclear (PMN), CD4, CD8, and natural killer (NK) cells against Aspergillus fumigatus over 5 time points and compared the values to healthy donors. RESULTS: Absolute CD4 and CD8 cell counts, antigen-specific T-cell responses, and killing capacity of PMN against A. fumigatus were significantly decreased in all patients over 12 months. In patients with probable/proven IA, reactive oxygen species (ROS) production tended to be lower compared to patients without IA, and absolute NK-cell counts remained below 200 cells/uL. Patients with well-controlled IA showed significantly higher ROS production and NK-cell counts compared to patients with poor outcome. CONCLUSIONS: This study highlights the importance of functional PMN, T-cell, and NK-cell immunity for the outcome of IA. Larger multicenter studies should address the potential use of NK-cell counts for the management of antifungal therapy. PMID- 25748324 TI - The Sordid Affair Between Human Herpesvirus and HIV. AB - Both human immunodeficiency virus (HIV) and human herpesvirus (HHV) infections persist lifelong, and almost all individuals infected with HIV are also infected with >=1 HHV. These coinfections are not independent processes or benign. In this review, we discuss how HHVs, and cytomegalovirus in particular, interact with concurrent HIV infection, and we describe the next steps necessary to understand and address these connections. PMID- 25748325 TI - Lung Mucosa Lining Fluid Modification of Mycobacterium tuberculosis to Reprogram Human Neutrophil Killing Mechanisms. AB - We have shown that human alveolar lining fluid (ALF) contains homeostatic hydrolases capable of altering the Mycobacterium tuberculosis cell wall and subsequently its interaction with human macrophages. Neutrophils are also an integral part of the host immune response to M. tuberculosis infection. Here we show that the human lung mucosa influences M. tuberculosis interaction with neutrophils, enhancing the intracellular killing of ALF-exposed M. tuberculosis and up-regulating the expression of tumor necrosis factor and interleukin 8. In contrast, ALF-exposed M. tuberculosis does not induce neutrophil apoptosis or necrosis, degranulation, or release of extracellular traps, and it decreases the oxidative response. These results suggest an important role for the human alveolar mucosa: increasing the innate capacity of the neutrophil to recognize and kill M. tuberculosis by favoring the use of intracellular mechanisms, while at the same time limiting neutrophil extracellular inflammatory responses to minimize their associated tissue damage. PMID- 25748327 TI - Comparing a series of 8-quinolinolato complexes of aluminium, titanium and zinc as initiators for the ring-opening polymerization of rac-lactide. AB - The preparation and characterization of a series of 8-hydroxyquinoline ligands and their complexes with Ti(IV), Al(III) and Zn(II) centres is presented. The complexes are characterized using NMR spectroscopy, elemental analysis and, in some cases, by single crystal X-ray diffraction experiments. The complexes are compared as initiators for the ring-opening polymerization of racemic-lactide; all the complexes show moderate/good rates and high levels of polymerization control. In the case of the titanium or aluminium complexes, moderate iso selectivity is observed (Pi = 0.75), whereas in the case of the zinc complexes, moderate hetero-selectivity is observed (Ps = 0.70). PMID- 25748326 TI - Using Amplicon Deep Sequencing to Detect Genetic Signatures of Plasmodium vivax Relapse. AB - Plasmodium vivax infections often recur due to relapse of hypnozoites from the liver. In malaria-endemic areas, tools to distinguish relapse from reinfection are needed. We applied amplicon deep sequencing to P. vivax isolates from 78 Cambodian volunteers, nearly one-third of whom suffered recurrence at a median of 68 days. Deep sequencing at a highly variable region of the P. vivax merozoite surface protein 1 gene revealed impressive diversity-generating 67 unique haplotypes and detecting on average 3.6 cocirculating parasite clones within individuals, compared to 2.1 clones detected by a combination of 3 microsatellite markers. This diversity enabled a scheme to classify over half of recurrences as probable relapses based on the low probability of reinfection by multiple recurring variants. In areas of high P. vivax diversity, targeted deep sequencing can help detect genetic signatures of relapse, key to evaluating antivivax interventions and achieving a better understanding of relapse-reinfection epidemiology. PMID- 25748328 TI - Lack of the protein tyrosine phosphatase PTPN22 strengthens transplant tolerance to pancreatic islets in mice. AB - AIMS/HYPOTHESIS: Protein tyrosine phosphatase non-receptor 22 (PTPN22) plays a central role in T cell, B cell and innate immune cell signalling. A genetic variation in Ptpn22 is considered a major risk factor for the development of type 1 diabetes and has been the subject of extensive study. While several reports have addressed how Ptpn22 might predispose to autoimmunity, its involvement in other immune-mediated diseases, such as allograft rejection, has not been explored. METHODS: To address a possible function for Ptpn22 in allograft rejection, we used a mouse model of pancreatic islet transplantation. We performed transplant tolerance experiments and determined how PTPN22 shapes tolerance induction and maintenance. RESULTS: Ptpn22 (-/-) recipient mice generate higher numbers of alloreactive T cells after allogeneic pancreatic islet transplantation compared with wild-type (WT) mice, but reject grafts with similar kinetics. This is not only due to their well-documented increase in forkhead box protein P3 (FOXP3)(+) T regulatory (Treg) cells but also to the expansion of T regulatory type 1 (Tr1) cells caused by the lack of PTPN22. In addition, a tolerogenic treatment known to induce transplant tolerance in WT mice via Tr1 cell generation is more effective in Ptpn22 (-/-) mice as a consequence of boosting both Tr1 and FOXP3(+) Treg cells. CONCLUSIONS/INTERPRETATION: A lack of PTPN22 strengthens transplant tolerance to pancreatic islets by expanding both FOXP3(+) Treg and Tr1 cells. These data suggest that targeting PTPN22 could serve to boost transplant tolerance. PMID- 25748329 TI - Metabolomic profiling in the prediction of gestational diabetes mellitus. AB - AIMS/HYPOTHESIS: Metabolomic profiling in populations with impaired glucose tolerance has revealed that branched chain and aromatic amino acids (BCAAs) are predictive of type 2 diabetes. Because gestational diabetes mellitus (GDM) shares pathophysiological similarities with type 2 diabetes, the metabolite profile predictive of type 2 diabetes could potentially identify women who will develop GDM. METHODS: We conducted a nested case-control study of 18- to 40-year-old women who participated in the Massachusetts General Hospital Obstetrical Maternal Study between 1998 and 2007. Participants were enrolled during their first trimester of a singleton pregnancy and fasting serum samples were collected. The women were followed throughout pregnancy and identified as having GDM or normal glucose tolerance (NGT) in the third trimester. Women with GDM (n = 96) were matched to women with NGT (n = 96) by age, BMI, gravidity and parity. Liquid chromatography-mass spectrometry was used to measure the levels of 91 metabolites. RESULTS: Data analyses revealed the following characteristics (mean +/- SD): age 32.8 +/- 4.4 years, BMI 28.3 +/- 5.6 kg/m(2), gravidity 2 +/- 1 and parity 1 +/- 1. Six metabolites (anthranilic acid, alanine, glutamate, creatinine, allantoin and serine) were identified as having significantly different levels between the two groups in conditional logistic regression analyses (p < 0.05). The levels of the BCAAs did not differ significantly between GDM and NGT. CONCLUSIONS/INTERPRETATION: Metabolic markers identified as being predictive of type 2 diabetes may not have the same predictive power for GDM. However, further study in a racially/ethnically diverse population-based cohort is necessary. PMID- 25748330 TI - Animal models for mesiotemporal lobe epilepsy: The end of a misunderstanding? AB - The fact that epilepsy consists in multiple heterogeneous syndromes with different etiologies and different symptoms is insufficiently taken into account in current animal models. This is in particular the case when modeling mesiotemporal lobe epilepsy (MTLE) for which clinical, electrophysiological, histological and pharmacological features have been well described in the clinic but only partially reproduced in most rodent models. In this review, we report the data of our recent survey of european neurologists with expertise in epilepsy. The answers of 82 of them (out of 258) indicated that seizures with mild behavioral signs, hippocampal sclerosis and focal discharges were the three most critical features to be considered when developing an animal model of MTLE. We then examined how these features are reproduced in three different types of animal models of MTLE depending on their induction: (i) generalized convulsive status epilepticus; (ii) hyperthermic seizures in immature animals and (iii) focal status epilepticus. Among them, only rodent models resulting from the induction of a focal status epilepticus appear to present most characteristics of human MTLE. PMID- 25748331 TI - European Academy of Neurology: The first steps. PMID- 25748332 TI - Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the "two-hit" hypothesis. AB - Hippocampal sclerosis (HS) is the most common neuropathological pattern observed in pharmacoresistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy syndrome. However, its pathophysiological mechanisms and neuropathological consequences on seizures remain mostly unresolved. The new international classification of hippocampal sclerosis aims at standardizing its description to allow comparisons between different clinical studies. However, several aspects are not considered in this classification (granule cell dispersion, sprouting, glial modifications...). In this chapter, we discuss these different features associated with hippocampal sclerosis in perspective with the "two-hit" hypothesis and propose mechanisms that could be involved in the modulation of some specific neuropathological aspects like early life stress, hyperthermic seizures, brain lesions or hormonal modifications. PMID- 25748333 TI - The concept of temporal 'plus' epilepsy. AB - The concept of temporal 'plus' epilepsy (T+E) is not new, and a number of observations made by means of intracerebral electrodes have illustrated the complexity of neuronal circuits that involve the temporal lobe. The term T+E was used to unify and better individualize these specific forms of multilobar epilepsies, which are characterized by electroclinical features primarily suggestive of temporal lobe epilepsy, MRI findings that are either unremarkable or show signs of hippocampal sclerosis, and intracranial recordings which demonstrate that seizures arise from a complex epileptogenic network including a combination of brain regions located within the temporal lobe and over closed neighbouring structures such as the orbitofrontal cortex, the insulo-opercular region, and the temporo-parieto-occipital junction. We will review here how the term of T+E has emerged, what it means, and which practical consideration it raises. PMID- 25748334 TI - Rumination is independently associated with poor psychological health: Comparing emotion regulation strategies. AB - OBJECTIVE: Emotion regulation (ER) strategies are related to psychological health, with most work examining reappraisal and suppression. Yet, emerging findings suggest that rumination may have stronger relationships with psychological health, namely depression, than other ER strategies. This paper replicated and extended this work by testing whether rumination was independently associated with a range of poor psychological health risk indicators and outcomes. In addition, it explored whether the reason why rumination is so deleterious to health is because it underlies the stress-health relationship. DESIGN: Participants (n = 218) completed measures online. MAIN OUTCOME MEASURES: Surveys assessed ER strategies (reappraisal, suppression, proactive coping, emotion support seeking, and rumination), health risk indicators (hostility, optimism, self-esteem), health outcomes (depression, poor sleep quality, anxiety) and perceived chronic stress. RESULTS: Multivariate regression analyses revealed rumination as the only ER strategy with a consistent independent effect on all the health risk indicators and outcomes. Bootstrapping analyses revealed indirect effects of perceived chronic stress on all the health variables via rumination. CONCLUSION: Rumination had a deleterious relationship with psychological health, perhaps because rumination underlies the relationship between stress and psychological health. Results have implications for interventions, particularly emphasizing the need to target ruminative thinking after stressful experiences. PMID- 25748335 TI - Vaccine coverage estimation using a computerized vaccination registry with potential underreporting and a seroprevalence study. AB - OBJECTIVE: To develop a method to estimate vaccination coverage using both a computerized vaccine registry with an unknown underreporting rate and a seroprevalence study. A real example of a meningococcal C conjugate vaccine (MCCV) coverage estimation is studied to illustrate the proposed methodology. METHODS: We reviewed the Vaccine Information System of Valencia (Sistema de Informacion Vacunal, SIV) for the MCCV status of 1430 subjects aged 3-29 years as part of a seroprevalence study. When MCCV was not registered in SIV, subjects were classified into three groups (MCCV non-registered, no vaccination records and missing information) depending on the registry of other vaccines. A Bayesian model was developed to ascertain the percentage of MCCV-vaccinated subjects based on the meningococcal C seroprotection levels from the seroprevalence study. RESULTS: The seroprotection levels in subjects with no MCCV registered in SIV (358) were similar to those in subjects with MCCV registered (1072). This indicated a large proportion of vaccinated subjects with no MCCV registered. The estimated vaccine coverage was over 80% in all age groups, except >22 years, where it was 67.6% (95% CI: [54.0-80.4]), which corresponded to those aged over 13 years at the time of the catch-up campaign. An underreporting rate of 23.5 73.4%, depending on the age group, was estimated in those vaccinated in the 2002 catch-up campaign. CONCLUSION: The Bayesian model allowed for a more realistic estimation of MCCV uptake. In this example, we quantified the underreporting of a vaccine registry, especially occurring during a catch-up campaign that occurred at the establishment of the registry. PMID- 25748337 TI - Pleurotus ferulae water extract enhances the maturation and function of murine bone marrow-derived dendritic cells through TLR4 signaling pathway. AB - Dendritic cells (DCs) play important roles in the regulation of immune system, which link innate and adaptive immune responses. Mature DCs produced interleukin (IL)-12 promote optimal type 1 T helper (Th1) cells and cytotoxic T lymphocytes. The extracts of traditional herbal medicines have been shown to enhance immune responses through promoting the maturation and cytokine production of DCs. Here, we investigated the effects of Pleurotus ferulae water extract (PFWE) on the maturation and function of bone marrow-derived DCs (BM-DCs). Upon PFWE treatment, BM-DCs dose-dependently upregulated the expression of CD40, CD80, CD86 and MHC II and increased the production of IL-12, IL-6 and tumor necrosis factor (TNF)-alpha but not for IL-10, which is mediated by TLR4 signaling pathway, at least partially. The production of prostaglandin E2 (PGE2) in BM-DCs was decreased by the treatment of PFWE. Moreover, PFWE treatment decreased the expression of active caspase-3 but increased the expression of CCR7. PFWE treated DCs enhanced the proliferation of allogenic CD8(+) T cells and the capacity of antigen presenting to autologous CD8(+) T cells. The combination of PFWE and CpG-ODN further enhanced the maturation and function of murine BM-DCs. The results showed that PFWE could enhance the maturation and function of DCs through TLR4 signaling pathway and has additive effect when combined with CpG-ODN, suggesting that PFWE alone or combined with CpG-ODN could be used to enhance the immune responses. PMID- 25748336 TI - Helicobacter hepaticus infection in BALB/c mice abolishes subunit-vaccine-induced protection against M. tuberculosis. AB - BCG, the only licensed vaccine against tuberculosis (TB), provides geographically variable protection, an effect ascribed to exposure to environmental mycobacteria (EM). Here we show that altering the intestinal microbiota of mice by early-life infection with the commensal bacterium Helicobacter hepaticus (Hh) increases their susceptibility to challenge with Mycobacterium tuberculosis (Mtb). Furthermore Hh-infected mice immunised parenterally with the recombinant subunit vaccine, human adenovirus type 5 expressing the immunodominant antigen 85A of Mtb (Ad85A), display a reduced lung immune response and protection against Mtb challenge is also reduced. Expression of interleukin 10 (IL10) messenger RNA is increased in the colon of Hh infected mice. Treatment of Hh-infected Ad85A immunised mice with anti-IL10 receptor antibody, following challenge with Mtb, restores the protective effect of the vaccine. These data show for the first time that alteration of the intestinal microbiota by addition of a single commensal organism can profoundly influence protection induced by a TB subunit vaccine via an IL10-dependent mechanism, a result with implications for the deployment of such vaccines in the field. PMID- 25748338 TI - NMR structure and dynamics of Q4D059, a kinetoplastid-specific and conserved protein from Trypanosoma cruzi. AB - Q4D059 (UniProt accession number), is an 86-residue protein from Trypanosoma cruzi, conserved in the related kinetoplastid parasites Trypanosoma brucei and Leishmania major. These pathogens are the causal agents of the neglected diseases: Chagas, sleeping sickness and leishmaniases respectively and had recently their genomes sequenced. Q4D059 shows low sequence similarity with mammal proteins and because of its essentiality demonstrated in T. brucei, it is a potential target for anti-parasitic drugs. The 11 hypothetical proteins homologous to Q4D059 are all uncharacterized proteins of unknown function. Here, the solution structure of Q4D059 was solved by NMR and its backbone dynamics was characterized by (15)N relaxation parameters. The structure is composed by a parallel/anti-parallel three-stranded beta-sheet packed against four helical regions. The structure is well defined by ca. 9 NOEs per residue and a backbone rmsd of 0.50+/-0.05 A for the representative ensemble of 20 lowest-energy structures. The structure is overall rigid except for N-terminal residues A(9) to D(11) at the beginning of beta1, K(38), V(39) at the end of helix H3 with rapid motion in the ps-ns timescale and G(25) (helix H2), I(68) (beta2) and V(78) (loop 3) undergoing internal motion in the MUs-ms timescale. Limited structural similarities were found in protein structures deposited in the PDB, therefore functional inferences based on protein structure information are not clear. Q4D059 adopts a alpha/beta fold that is slightly similar to the ATPase sub-domain IIB of the heat-shock protein 70 (HSP70) and to the N-terminal domain of the ribosomal protein L11. PMID- 25748339 TI - Energy-efficient reconstructions and indoor radon: the impact assessed by CDs/DVDs. AB - Recent modelling suggests that the expense of energy-efficient building reconstructions can be the enhanced indoor radon levels and the related adverse health impact. Here we show that a couple of home-stored CDs/DVDs can be used to check by direct measurements whether a significant change in radon level occurred in the past after building reconstruction. Radon is continuously absorbed in the polycarbonate material of CDs/DVDs and its average concentration can be determined by etching alpha tracks at a certain depth in the disk. With two disks, one bought before and one after the reconstruction, a change in radon concentration can be detected retrospectively. Within a pilot study of 20 rooms in 16 buildings that underwent energy-efficient interventions years in the past, we observed significant increase in radon concentration (at 95% confidence level) in 35% of the cases, and no case with significant decrease. Direct indication of a radon problem emerged after some of the energy-efficient building interventions was observed. The CD/DVD based approach provides a tool for assessment of the effect of different energy-efficient reconstruction approaches on indoor radon in very short terms and could be useful for finding radon-safe energy-efficient options. PMID- 25748340 TI - Surface-deposition and distribution of the radon-decay products indoors. AB - The exposure to radon-decay products is of great concern both in dwellings and workplaces. The model to estimate the lung dose refers to the deposition mechanisms and particle sizes. Unfortunately, most of the dose data available are based on the measurement of radon concentration and the concentration of radon decay products. These combined measurements are widely used in spite of the fact that accurate dose assessments require information on the particle deposition mechanisms and the spatial distribution of radon decay products indoors. Most of the airborne particles and/or radon decay products are deposited onto indoor surfaces, which deposition makes the radon decay products unavailable for inhalation. These deposition processes, if properly known, could be successfully exploited to reduce the exposure to radon decay products. In spite of the importance of the surface deposition of the radon decay products, both for the correct evaluation of the dose and for reducing the exposure; little or no efforts have been made to investigate these deposition processes. Recently, two parallel investigations have been carried out in Rome and at Universidad Nacional Autonoma de Mexico (UNAM) in Mexico City respectively, which address the issue of the surface-deposited radon decay products. Even though these investigations have been carried independently, they complement one another. It is with these considerations in mind that it was decided to report both investigations in the same paper. PMID- 25748342 TI - Observing electron extraction by monolayer graphene using time-resolved surface photoresponse measurements. AB - Graphene is considered a next-generation electrode for indium tin oxide (ITO) free organic photovoltaic devices (OPVs). However, to date, limited numbers of OPVs containing surface-modified graphene electrodes perform as well as ITO-based counterparts, and no devices containing a bare graphene electrode have been reported to yield satisfactory rectification characteristics. In this report, we provide experimental data to learn why. Time-resolved surface photoresponse measurements on templated pentacene-on-graphene films directly reveal that p doped monolayer graphene efficiently extracts electrons, not holes, from photoexcited pentacene. Accordingly, a graphene/pentacene/MoO3 heterojunction displays a large surface photoresponse and, by inference, efficient dissociation of photogenerated excitons, with graphene serving as an electron extraction layer and MoO3 as a hole extraction layer. In contrast, a graphene/pentacene/C60 heterojunction yields a comparatively insignificant surface photoresponse because both graphene and C60 act as competing electron extraction layers. The data presented herein provide experimental insight for future endeavors involving bare graphene as an electrode for organic photovoltaic devices and strongly suggest that p-doped graphene is best considered a cathode for OPVs. PMID- 25748341 TI - Intermittent Pneumatic Compression Enhances Formation of Edema Tissue Fluid Channels in Lymphedema of Lower Limbs. AB - BACKGROUND: In lymphedema, tissue fluid steadily accumulates in the subcutaneous space containing loose connective tissue. We documented previously that deformation of the structure of subcutaneous collagen bundles and fat by excess fluid leads to formation of "lakes" and interconnected channels with irregular shape. Since there is no force that could mobilize and propel stagnant fluid to the regions where lymphatics absorb and contract, this task should be taken over by external massage. The most effective in this respect seems to be the sequential intermittent pneumatic compression (IPC). AIM: The aim of the study was to observe whether IPC would enhance and accelerate formation of tissue fluid channels. METHODS: Together with the Biocompression Systems (Moonachie, NJ), we designed a high pressure intermittent compression device and used in it our therapy protocol for patients with obstructive lymphedema of lower limbs. The study was carried out on 18 patients with lymphedema stages II-IV. The IPC was applied daily for 1-2 hours. The follow up time was 24-36 months. Lymphoscintigraphy and immunohistopathology of tissue biopsies were used for evaluation of channel formation process. RESULTS: The forced fluid flow brought about increase of the area of fluid channels in the thigh and groin, with a decrease in the calf. Concomitantly, with decrease of channel area in the calf, there was a decrease of calf circumference. No new lymphatic collectors were observed. CONCLUSIONS: Compression of limb lymphedema tissues leads to formation of tissue channels as pathways for evacuation of edema fluid. PMID- 25748343 TI - Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma. AB - BACKGROUND: The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients. OBJECTIVE: We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function. METHODS: PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed. RESULTS: Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity. CONCLUSIONS: A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population. PMID- 25748344 TI - Potential analytical interferences and seasonal variability in diethyltoluamide environmental monitoring programs. AB - N,N-diethyl-m-toluamide (DEET), the active component of many insect repellents, is among the most frequently detected compounds in aqueous environments with concentrations reported in the ng L(-1) to MUg L(-1) range. However, DEET is often detected in blanks and reported concentrations differ significantly depending on the analytical technique employed. In addition, relatively sparse data are available regarding the seasonal variability of DEET concentrations in water and there are apparent inconsistencies with expected use patterns. Therefore, the present study investigates potential interferences affecting the detection and quantification of DEET then the geographical and seasonal variations of DEET concentrations. To examine potential analytical interferences, DEET was analyzed in five geographically-diverse wastewater effluents using both gas chromatography and liquid chromatography coupled to mass spectrometric detectors. At times, the concentrations quantified by the employed analytical methods varied significantly. Five compounds with similar molecular weights and structures as DEET were investigated as potential mimics and some were shown to induce an overestimation of DEET. Further experimentation suggested that the solvents used in sample preparation and HPLC analysis are another possible source of interference. Besides potential interferences, the seven-month weekly monitoring of DEET in the primary effluent of a wastewater treatment plant demonstrated a clear seasonal trend with decreasing concentration from summer to winter. These data collectively demonstrate that there are many challenges in the quantification of DEET in complex environmental samples and that co-occurrence of similarly structured substances present in the water sample and/or the solvents used for the analysis could induce analytical bias. PMID- 25748345 TI - Mercury accumulation in hydrothermal vent mollusks from the southern Tonga Arc, southwestern Pacific Ocean. AB - We provide the mercury (Hg) and monomethylmercury (MMHg) levels of the plume water, sulfide ore, sediment, and mollusks located at the hydrothermal vent fields of the southern Tonga Arc, where active volcanism and intense seismic activity occur frequently. Our objectives were: (1) to address the potential release of Hg from hydrothermal fluids and (2) to examine the distribution of Hg and MMHg levels in hydrothermal mollusks (mussels and snails) harboring chemotrophic bacteria. While high concentrations of Hg in the sediment and Hg, As, and Sb in the sulfide ore indicates that their source is likely hydrothermal fluids, the MMHg concentration in the sediment was orders of magnitude lower than the Hg (<0.001%). It suggests that Hg methylation may have not been favorable in the vent field sediment. In addition, Hg concentrations in the mollusks were much higher (10-100 times) than in other hydrothermal vent environments, indicating that organisms located at the Tonga Arc are exposed to exceedingly high Hg levels. While Hg concentration was higher in the gills and digestive glands than in the mantles and residues of snails and mussels, the MMHg concentrations in the gills and digestive glands were orders of magnitude lower (0.004-0.04%) than Hg concentrations. In summary, our results suggest that the release of Hg from the hydrothermal vent fields of the Tonga Arc and subsequent bioaccumulation are substantial, but not for MMHg. PMID- 25748346 TI - Leukodystrophy or genetic leukoencephalopathy? Nature does not make leaps. PMID- 25748347 TI - Mucopolysaccharidosis enzyme production by bone marrow and dental pulp derived human mesenchymal stem cells. AB - Mucopolysaccharidoses (MPS) are inherited metabolic disorders that arise from a complete loss or a reduction in one of eleven specific lysosomal enzymes. MPS children display pathology in multiple cell types leading to tissue and organ failure and early death. Mesenchymal stem cells (MSCs) give rise to many of the cell types affected in MPS, including those that are refractory to current treatment protocols such as hematopoietic stem cell (HSC) based therapy. In this study we compared multiple MPS enzyme production by bone marrow derived (hBM) and dental pulp derived (hDP) MSCs to enzyme production by HSCs. hBM MSCs produce significantly higher levels of MPS I, II, IIIA, IVA, VI and VII enzyme than HSCs, while hDP MSCs produce significantly higher levels of MPS I, IIIA, IVA, VI and VII enzymes. Higher transfection efficiency was observed in MSCs (89%) compared to HSCs (23%) using a lentiviral vector. Over-expression of four different lysosomal enzymes resulted in up to 9303-fold and up to 5559-fold greater levels in MSC cell layer and media respectively. Stable, persistent transduction of MSCs and sustained over-expression of MPS VII enzyme was observed in vitro. Transduction of MSCs did not affect the ability of the cells to differentiate down osteogenic, adipogenic or chondrogenic lineages, but did partially delay differentiation down the non-mesodermal neurogenic lineage. PMID- 25748349 TI - 2014 Presidential Address: The time of our lives. PMID- 25748350 TI - 2014 William Allan Award introduction: Stuart Orkin. PMID- 25748351 TI - 2014 William Allan Award: A hematologist's pursuit of hemoglobin genetics. PMID- 25748352 TI - 2014 Curt Stern Award introduction: Goncalo Abecasis. PMID- 25748353 TI - 2014 Curt Stern Award: Adventures in human genetics. PMID- 25748354 TI - 2014 Curt Stern Award introduction: Mark Daly. PMID- 25748355 TI - 2014 Curt Stern Award: A tryst with genetics. PMID- 25748356 TI - 2014 Victor A. McKusick Leadership Award introduction: David Valle. PMID- 25748357 TI - 2014 Victor A. McKusick Leadership Award. PMID- 25748359 TI - NACK kinesin is required for metaphase chromosome alignment and cytokinesis in the moss Physcomitrella patens. AB - The NACK kinesins (NACK1, NACK2 in tobacco and AtNACK1/HINKEL, AtNACK2/STUD/TETRASPORE in Arabidopsis), members of a plant-specific kinesin-7 family, are required for cytokinesis. Previous studies using tobacco and Arabidopsis cells showed that NACK1 and AtNACK1 at the phragmoplast midzone activate the MAP kinase cascade during the late M phase, which is critical for the cell plate formation. However, the loss-of-function phenotype has not been investigated in details in living cells and the molecular activity of this kinesin remains to be determined. Here, we report the mitotic roles and activity of the NACK kinesins in the moss Physcomitrella patens. When we simultaneously knocked down three PpNACKs by RNA-interference (RNAi) in protonemal cells, we observed a cytokinesis failure following a defect in phragmoplast expansion. In addition, misaligned chromosomes were frequently detected in the pre-anaphase spindle and the anaphase onset was significantly delayed, indicating that PpNACK also plays a role in pre-anaphase. Consistent with the appearance of early and late mitotic phenotypes, endogenous PpNACK was localised to the interpolar microtubule (MT) overlap from prometaphase through telophase. In vitro MT gliding assay and single motor motility assay showed that PpNACK-b is a processive, plus end-directed motor, suggesting that PpNACK is capable of transporting cargoes along the spindle/phragmoplast MT. Our study using Physcomitrella patens demonstrated that PpNACK is an active motor protein and identified unexpected and conserved roles of PpNACK during the mitosis of P. patens. PMID- 25748360 TI - Novel insights into Chk1 regulation by phosphorylation. AB - Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase activated in response to DNA damage or stalled replication, has been considered as the sole regulator of Chk1. Recent progress, however, has led to the identification of additional protein kinases involved in Chk1 phosphorylation, affecting the subcellular localization and binding partners of Chk1. In fact, spatio-temporal regulation of Chk1 is of critical importance not only in the DDR but also in normal cell-cycle progression. In due course, many potent inhibitors targeted to Chk1 have been developed as anticancer agents and some of these inhibitors are currently in clinical trials. In this review, we summarize the current knowledge of Chk1 regulation by phosphorylation. PMID- 25748362 TI - Welcome to the journal of anesthesia history. PMID- 25748363 TI - Names are Important. PMID- 25748361 TI - Structure-specific nucleic acid recognition by L-motifs and their diverse roles in expression and regulation of the genome. AB - The high-mobility group (HMG) domain containing proteins regulate transcription, DNA replication and recombination. They adopt L-shaped folds and are structure specific DNA binding motifs. Here, I define the L-motif super-family that consists of DNA-binding HMG-box proteins and the L-motif of the histone mRNA binding domain of stem-loop binding protein (SLBP). The SLBP L-motif and HMG-box domains adopt similar L-shaped folds with three alpha-helices and two or three small hydrophobic cores that stabilize the overall fold, but have very different and distinct modes of nucleic acid recognition. A comparison of the structure, dynamics, protein-protein and nucleic acid interactions, and regulation by PTMs of the SLBP and the HMG-box L-motifs reveals the versatile and diverse modes by which L-motifs utilize their surfaces for structure-specific recognition of nucleic acids to regulate gene expression. PMID- 25748364 TI - A new name and a new format-same grand tradition of excellence: the journal of anesthesia history. PMID- 25748365 TI - Thoughts on the new journal. PMID- 25748358 TI - Characterization of large structural genetic mosaicism in human autosomes. AB - Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 * 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. PMID- 25748366 TI - To give to the world. PMID- 25748367 TI - C.T. Jackson's Sealed 13 November 1846 Letter to J.B.A.L.L. Elie de Beaumont: Translated (1847), Back-Translated (1861), and Accurately Transcribed for the First Time (2014). AB - Besides the famous London-bound Bigelow-to-Boot letter dated November 28, 1846, the mail bags of the steam paddler Acadia also carried, from Boston to Liverpool, additional correspondence reporting W.T.G. Morton's public demonstration of surgical etherization. Paramount among these other letters was the wax-sealed English language missive of Charles T. Jackson to the French Academy of Science's J.B.A.L.L. Elie de Beaumont, which was dated November 13, 1846. Unfortunately, Jackson made no copy of this original letter. In 1847, Elie de Beaumont published portions of the letter in the French language, extracts that Jackson back translated to English by 1861. The original Jackson-to-Elie de Beaumont letter resurfaced in a Parisian auction (2005) and then a New York sale (2006). Remarkably, this original 13 November 1846 Charles T. Jackson-to-Elie de Beaumont missive-a landmark letter staking Charles T. Jackson's claims over W.T.G. Morton's to discovering etherization-was not transcribed completely and accurately, for publication, until this past year (2014). PMID- 25748368 TI - Toward an understanding of the equality of pain: crawford long and the development of anesthesia in antebellum georgia. AB - Dr. Crawford Long's career illustrates the complicated intersection of science, sympathy, medical experimentation, race, and gender within the history of anesthesia in the United States. Considered by many to be the first physician to administer ether for surgical anesthesia, Long anesthetized a broad cross-section of his rural Georgia society, including white men, white women, and enslaved black children. These initial uses of ether can be considered both a racialized and gendered experiment reflective of contemporary thinking as well as a radical expression of equality in the context of medical development and understandings of pain. Emerging from this examination of Long's practices and writing is the narrative of a well-meaning and time-bound doctor, living amidst the shadows of antebellum plantations and confronted by his diverse patients' experience of pain. PMID- 25748369 TI - Strange Case of Dr. Jekyll and Mr. Hyde-was Robert Louis Stevenson inspired by Horace Wells? AB - It has been suggested that Robert Louis Stevenson's masterpiece Strange Case of Dr. Jekyll and Mr. Hyde derived inspiration from the real-life tragedy of the final days of Connecticut dentist Horace Wells, innovator of the clinical use of the anesthetic properties of nitrous oxide. We examined Stevenson's letters, biographies, and other references in the literature, press, and online to determine whether any factual basis exists for Stevenson to be aware of Wells' life, and also if it played any role in creating the novel's plot. Stevenson was born in Scotland, several years after Wells had committed suicide in New York. Wells' life and death received widespread coverage in the northeastern United States, but there is no evidence that it was printed in newspapers or periodicals in England or Scotland. On the other hand, novelists of the period, psychologists, and the lay public were quite interested in the concept of split personalities and the dual nature of man, so these may have been natural substrates for the novel. There is evidence that Stevenson dreamt about episodes similar to those depicted in his novel. All claims to any relationship between Wells and the novel come from the United States, and none of them are backed by evidence. In the absence of evidence supporting a relationship between the behavior exhibited by Wells during his final days and any inspiration that Stevenson might have derived from it, we conclude that there is insufficient evidence to suggest any relationship between them. PMID- 25748370 TI - Walter sutton: physician, scientist, inventor. AB - Walter S. Sutton (1877-1916) was a physician, scientist, and inventor. Most of the work on Sutton has focused on his recognition that chromosomes carry genetic material and are the basis for Mendelian inheritance. Perhaps less well known is his work on rectal administration of ether. After Sutton's work on genetics, he completed his medical degree in 1907 and began a 2-year surgical fellowship at Roosevelt Hospital, New York City, NY, where he was introduced to the technique of rectal administration of ether. Sutton modified the work of others and documented 100 cases that were reported in his 1910 landmark paper "Anaesthesia by Colonic Absorption of Ether". Sutton had several deaths in his study, but he did not blame the rectal method. He felt that his use of rectal anesthesia was safe when administered appropriately and believed that it offered a distinct advantage over traditional pulmonary ether administration. His indications for its use included (1) head and neck surgery; (2) operations when ether absorption must be minimized due to heart, lung, or kidney problems; and (3) preoperative pulmonary complications. His contraindications included (1) cases involving alimentary tract or weakened colon; (2) laparotomies, except when the peritoneal cavity was not opened; (3) incompetent sphincter or anal fistula; (4) orthopnea; and (5) emergency cases. Sutton wrote the chapter on "Rectal Anesthesia" in one of the first comprehensive textbooks in anesthesia, James Tayloe Gwathmey's Anesthesia. Walter Sutton died of a ruptured appendix in 1916 at age 39. PMID- 25748371 TI - The biogeography of abundant and rare bacterioplankton in the lakes and reservoirs of China. AB - Bacteria play key roles in the ecology of both aquatic and terrestrial ecosystems; however, little is known about their diversity and biogeography, especially in the rare microbial biosphere of inland freshwater ecosystems. Here we investigated aspects of the community ecology and geographical distribution of abundant and rare bacterioplankton using high-throughput sequencing and examined the relative influence of local environmental variables and regional (spatial) factors on their geographical distribution patterns in 42 lakes and reservoirs across China. Our results showed that the geographical patterns of abundant and rare bacterial subcommunities were generally similar, and both of them showed a significant distance-decay relationship. This suggests that the rare bacterial biosphere is not a random assembly, as some authors have assumed, and that its distribution is most likely subject to the same ecological processes that control abundant taxa. However, we identified some differences between the abundant and rare groups as both groups of bacteria showed a significant positive relationship between sites occupancy and abundance, but the abundant bacteria exhibited a weaker distance-decay relationship than the rare bacteria. Our results implied that rare subcommunities were mostly governed by local environmental variables, whereas the abundant subcommunities were mainly affected by regional factors. In addition, both local and regional variables that were significantly related to the spatial variation of abundant bacterial community composition were different to those of rare ones, suggesting that abundant and rare bacteria may have discrepant ecological niches and may play different roles in natural ecosystems. PMID- 25748373 TI - Mannosylerythritol lipids: production and applications. AB - Mannosylerythritol lipids (MELs) are a glycolipid class of biosurfactants produced by a variety yeast and fungal strains that exhibit excellent interfacial and biochemical properties. MEL-producing fungi were identified using an efficient screening method for the glycolipid production and taxonomical classification on the basis of ribosomal RNA sequences. MEL production is limited primarily to the genus Pseudozyma, with significant variability among the MEL structures produced by each species. Outside of Pseudozyma, one recently isolated strain, Ustilago scitaminea, has been shown to exhibit abundant MEL-B production from sugarcane juice. Structural analyses of these compounds suggest a role for MELs in numerous cosmetic applications. MELs act as effective topical moisturizers and can repair damaged hair. Furthermore, these compounds have been shown to exhibit both protective and healing activities, to activate fibroblasts and papilla cells, and to act as natural antioxidants. In this review, we provide a brief summary of MEL research over the past few decades, focusing on the identification of MEL-producing fungi, the structural characterization of MELs, the use of alternative compounds as a primary carbon source, and the use of these compounds in cosmetic applications. PMID- 25748372 TI - Nutraceutical effects of fucoxanthin for obesity and diabetes therapy: a review. AB - Obesity, which results from an imbalance between energy intake and energy expenditure, has become a major health risk factor worldwide, causing numerous and various diseases such as diabetes, hypertension, and cardiovascular diseases. Fucoxanthin, a specific carotenoid in brown algae, has garnered much attention for its anti-obesity and anti-diabetic effects attributable to a unique mechanism. Fucoxanthin induces uncoupling protein 1 (UCP1) expression in white adipose tissue (WAT). That inner membrane mitochondrial protein, UCP1, can dissipate energy through oxidation of fatty acids and heat production. Furthermore, fucoxanthin improves insulin resistance and ameliorates blood glucose levels through down-regulation of adipocytokines related to insulin resistance in WAT and up-regulation of glucose transporter 4 (GLUT4) in skeletal muscle. Algae fucoxanthin is a beneficial compound for the prevention of the metabolic syndrome. PMID- 25748374 TI - Palm oil derived trimethylolpropane triesters synthetic lubricants and usage in industrial metalworking fluid. AB - Trimethylolpropane triesters are biodegradable synthetic lubricant base oil alternative to mineral oils, polyalphaolefins and diesters. These oils can be produced from trimethylolpropane (TMP) and fatty acid methyl esters via chemical or enzymatic catalyzed synthesis methods. In the present study, a commercial palm oil derived winter grade biodiesel (ME18) was evaluated as a viable and sustainable methyl ester source for the synthesis of high oleic trimethylolpropane triesters (HO-TMPTE). ME18 has fatty acid profile containing 86.8% oleic acid, 8.7% linoleic acid with the remaining minor concentration of palmitic acid, stearic acid and linolenic acid. It's high oleic property makes it superior to produce synthetic lubricant base oil that fulfills both the good low temperature property as well as good oxidative stability. The synthetic base oil produced had a viscosity of 44.3 mm(2)/s at 40 degrees C meeting the needs for ISO 46 oils. It also exhibited an excellent viscosity index of 219 that is higher than some other commercial brands of trimethylolpropane trioleate. Properties of base oil such as cloud point, density, acid value, demulsibility and soap content were also examined. The oil was then used in the formulation of tapping oil and appraised in term of adaptability, stability and field test performance. PMID- 25748375 TI - Production of medium chain fatty acid rich mustard oil using packed bed bioreactor. AB - A comparative study was done on the production of different medium chain fatty acid (MCFA) rich mustard oil using a stirred tank batchreactor (STBR) and packed bed bio reactor (PBBR) using three commercially available immobilised lipases viz. Thermomyces lanuginosus, Candida antarctica and Rhizomucor meihe. Three different MCFAs capric, caprylic and lauric acids were incorporated in the mustard oil. Reaction parameters, such as substrate molar ratio, reaction temperature and enzyme concentration were standardized in the STBR and maintained in the PBBR. To provide equal time of residence between the substrate and enzyme in both the reactors for the same amount of substrates, the substrate flow rate in the PBBR was maintainedat 0.27 ml/min. Gas liquid chromatography was used to monitor the incorporation of MCFA in mustard oil. The study showed that the PBBR was more efficient than the STBR in the synthesis of structured lipids with less migration of acyl groups. The physico-chemical parameters of the product along with fatty acid composition in all positions and sn-2 positions were also determined. PMID- 25748376 TI - Removing adsorbed heavy metal ions from sand surfaces via applying interfacial properties of rhamnolipid. AB - In this study, the interfacial properties of biosurfactant rhamnolipid were investigated and were applied to remove adsorbed heavy metal ions from sand surfaces with flushing operations. The surface tension-lowering activity, micelle charge characteristic, and foaming ability of rhamnolipid were identified first. For rhamnolipid in water, the negatively charged characteristic of micelles or aggregates was confirmed and the foaming ability at concentrations higher than 40 mg/L was evaluated. By using the rhamnolipid solutions in a batch washing approach, the potential of applying the interfacial properties of rhamnolipid to remove adsorbed copper ions from sand surfaces was then demonstrated. In rhamnolipid solution flushing operations for sand-packed medium, higher efficiency was found for the removal of adsorbed copper ions with residual type than with inner-sphere interaction type, implying the important role of interaction type between the copper ion and the sand surface in the removal efficiency. In addition, the channeling effect of rhamnolipid solution flow in the sand-packed medium was clearly observed in the solution flushing operations and was responsible for the low removal efficiency with low contact areas between solution and sand. By using rhamnolipid solution with foam to flush the sand packed medium, one could find that the channeling effect of the solution flow was reduced and became less pronounced with the increase in the rhamnolipid concentration, or with the enhanced foaming ability. With the reduced channeling effect in the flushing operations, the removal efficiency for adsorbed copper ions was significantly improved. The results suggested that the foam-enhanced rhamnolipid solution flushing operation was efficient in terms of surfactant usage and operation time. PMID- 25748377 TI - Novel fluorinated gemini surfactants with gamma-butyrolactone segments. AB - In this work, novel gamma-butyrolactone-type monomeric and dimeric (gemini) surfactants with a semifluoroalkyl group [Rf- (CH2)3-; Rf = C4F9, C6F13, C8F17] as the hydrophobic group were successfully synthesized. Dimethyl malonate was dimerized or connected using Br(CH2)sBr (s = 0, 1, 2, 3) to give tetraesters, and they were bis-allylated. Radical addition of fluoroalkyl using Rf-I and an initiator, i.e., 2,2'-azobisisobutyronitrile for C4F9 or di-t-butyl peroxide for C6F13 and C8F17, was perform at high temperature, with prolonged heating, to obtain bis(semifluoroalkyl)-dilactone diesters. These dilactone diesters were hydrolyzed using KOH/EtOH followed by decarboxylation in AcOH to afford gamma butyrolactonetype gemini surfactants. Common 1 + 1 semifluoroalkyl lactone surfactants were synthesized using the same method. Their surfactant properties [critical micelle concentration (CMC), gammaCMC, pC20, GammaCMC, and AG] were investigated by measuring the surface tension of the gamma-hydroxybutyrate form prepared in aqueous tetrabutylammonium hydroxide solution. As expected, the CMC values of the gemini surfactants were more than one order of magnitude smaller than those of the corresponding 1 + 1 surfactants. Other properties also showed the excellent ability of the gemini structure to reduce the surface tension. These surfactants were easily and quantitatively recovered by acidification. The monomeric surfactant was recovered in the gamma-hydroxybutyric acid form, and the gemini surfactant as a mixture of gamma-butyrolactone and gamma-hydroxybutyric acid forms. PMID- 25748378 TI - Dispersion granulation method leveraging pH responsiveness of monoalkyl sulfosuccinate. AB - Monoalkyl sulfosuccinate is an anionic surfactant having two types of hydrophilic groups in one molecule, carboxylic acid group and sulfonic acid group, resulting in three ionization states depending on its pH. In state I, both carboxylic acid and sulfonic acid groups are not ionized; in state II, only sulfonic acid group is ionized; and in state III, both carboxylic acid and sulfonic acid groups are ionized. The ionization state affects the hydrophile-lipophile balance (HLB) of the surfactant, an index of the distribution coefficient of water/oil ratio of the surfactant. The decrease in HLB promotes the adsorption of the surfactant to the oil/water interface and improves the interface activity. State II has high emulsifying property for high interface activity but low water solubility. In contrast, state III has low emulsifying property for low interface activity but high water solubility. We applied the pH responsiveness of monoalkyl sulfosuccinate to the dispersion granulation method to change the state from II to III in a mild range of pH (weak acidity and weak alkalinity). Consequently, we successfully developed a novel dispersion granulation method that decreased the amount of surfactant needed for emulsifying resin solution by employing state II for its high emulsifying property, and we also reduced the amount of surfactant remaining on resin particles after the washing process by employing state III for its high water solubility. PMID- 25748379 TI - Production of high docosahexaenoic acid by Schizochytrium sp. using low-cost raw materials from food industry. AB - The low-cost substrates from food industry, including maize starch hydrolysate and soybean meal hydrolysate, were used to produce docosahexaenoic acid (DHA) by Schizochytrium limacinum OUC88. Glucose derived from maize starch hydrolysate was used as the carbon source and soybean meal hydrolysate as the nitrogen sources. In 10L bioreactor fermentation, by using the soybean meal hydrolysate as the main nitrogen source, the biomass of Schizochytrium limacinum OUC88 reached 85.27 g L( 1), and the yields of DHA was 20.7g L(-1). As a comparison, when yeast extract was used as the main nitrogen source, the yields of biomass and DHA were 68.93 g L(-1) and 13.3 g L(-1), respectively. From the results of this study, these hydrolysates can provide all the nutrients required for high-density cultivation of S. limacinum OUC88 and DHA production, that will improve the economical and competitive efficiency of commercial DHA production. PMID- 25748380 TI - Fatty acid compositions of silver catfish, Pangasius sp. farmed in several rivers of Pahang, Malaysia. AB - Pangasius micronemus (Black Pangasius sp.) and Pangasius nasutus (Fruit Pangasius sp.) are two species of silver catfish widely consumed in Malaysia. The present study evaluated fatty acid profiles of fish muscles in these two Pangasius sp. from different farms and locations to determine which species or location is better in term of lipid quality. The results showed MUFAs (Monounsaturated fatty acid) content was highest (35.0-44.4%) followed by SFA (Saturated fatty acid) [32.0-41.5%] and PUFAs (polyunsaturated fatty acids) [9.3-19.3%]. P. micronemus of Sg. Kanchong displayed higher palmitic acid (SFA; 29.0%) than P. nasutus from Peramu (23.5%). In contrast, oleic acid (MUFA) revealed highest in P. nasutus (38.1%) while lowest in P. micronemus of Sg. Kanchong (29.7%). Additionally, utmost PUFAs belonged to P. micronemus of Sg. Kanchong (19.3%) and lower most in P. nasutus from Peramu (9.3%). P. micronemus presented with a higher EPA (eicosapentaenoic acid) [1.0-1.4%], DHA (Docosahexaenoic acid) [1.7-2.8%] and LA (Linoleic acid) [11.8-12.0%] than P. nasutus (EPA; 0.3%, DHA; 1.0%, LA; 4.8%). However, P. nasutus established higher GLA (gamma-linolenic acid) [0.4%] than P. micronemus (0.04-0.06%). Both Pangasius sp. can be regarded as good supplies of omega-3 and omega-6. Overall, P. micronemus from Sg. Kanchong is the best choice among all for reason high in EPA and DHA. PMID- 25748381 TI - Comparative effects of sesame seeds differing in lignan contents and composition on fatty acid oxidation in rat liver. AB - We compared the physiological activities of sesame seeds rich in lignans from three varieties (Gomazou, Maruhime and Maruemon), and those from a conventional cultivar (Masekin) in rats. The sum of the values of fat-soluble lignans (sesamin and sesamolin) in seeds of Gomazou, Maruhime and Maruemon varieties was approximately double the value in Masekin. Seeds from Maruemon contained fat soluble lignan most exclusively as sesamin while other varieties contained sesamin and sesamolin at about a 2:1 ratio. After a 16 d experiment, sesame seeds, added at 200 g/kg to the experimental diets, increased the activity and mRNA levels of fatty acid oxidation enzymes. Increases were stronger with seeds rich in lignans than with seeds from Masekin. In contrast, sesame seeds lowered the activity and mRNA levels of lipogenic enzymes. However, sesame seeds from all the varieties were comparable in affecting these parameters. Serum triacylglycerol concentrations were lower in rats fed diets containing sesame seeds rich in lignans than in those fed a diet free of sesame seeds or a diet containing seeds from the Masekin variety. Serum malondialdehyde (a marker of lipid peroxidation) was lower in rats fed diets containing sesame seeds rich in lignans than in those fed a sesame seed-free diet or Masekin diet. It is apparent that sesame seeds rich in lignans, irrespective of lignan composition, more profoundly affect hepatic fatty acid oxidation and serum triacylglycerol levels and possibly attenuate oxidative stress. Therefore, consumption of sesame seeds rich in lignans hopefully results in physiological activity to promote health. PMID- 25748382 TI - Analysis and antibacterial activity of Nigella sativa essential oil formulated in microemulsion system. AB - The Essential oil (EO) of Nigella sativa (black cumin) was extracted from the crude oil and the volatile constituents were characterized using gas chromatographic analysis. The EO was formulated in water-based microemulsion system and its antibacterial activity against six pathogenic bacteria was evaluated using the agar well diffusion method. This activity was compared with two other well known biologically active natural and synthetic antimicrobials namely eugenol and Ceftriaxone((r)). Results showed that N. sativa EO microemulsion was highly effective against S. aureus, B. cereus and S. typhimurium even at the lowest tested concentration of that EO in the microemulsion (100.0 MUg/well). Interestingly, the EO microemulsion showed higher antibacterial activity than Ceftriaxone solution against S. typhimurium at 400.0 MUg/well and almost comparable activity against E. coli at 500.0 MUg/well. No activity was detected for the EO microemulsion against L. monocytogenes and P. aeruginosa. Eugenol which was also formulated in microemulsion was less effective than N. sativa EO microemulsion except against P. aeruginosa. The synthetic antibiotic (Ceftriaxone) was effective against most of the six tested bacterial strains. This work is the first report revealing the formulation of N. sativa EO in microemulsion system and investigating its antibacterial activity. The results may offer potential application of that water-based microemulsion in controlling the prevalence of some pathogenic bacteria. PMID- 25748383 TI - Preparation of pH-sensitive anionic liposomes designed for drug delivery system (DDS) application. AB - We prepared pH-sensitive anionic liposomes composed solely of anionic bilayer membrane components that were designed to promote efficient release of entrapped agents in response to acidic pH. The pH-sensitive anionic liposomes showed high dispersion stability at neutral pH, but the fluidity of the bilayer membrane was enhanced in an acidic environment. These liposomes were rather simple and were composed of dimyristoylphosphatidylcholine (DMPC), an anionic bilayer membrane component, and polyoxyethylene sorbitan monostearate (Tween 80). In particular, the present pH-sensitive anionic liposomes showed higher temporal stability than those of conventional DMPC/DPPC liposomes. We found that pHsensitive properties strongly depended on the molecular structure, pKa value, and amount of an incorporated anionic bilayer membrane component, such as sodium oleate (SO), dimyristoylphosphatidylserine (DMPS), or sodium beta-sitosterol sulfate (SS). These results provide an opportunity to manipulate liposomal stability in a pH dependent manner, which could lead to the formulation of a high performance drug delivery system (DDS). PMID- 25748384 TI - Bilirubin, model membranes and serum albumin interaction: The influence of fatty acids. AB - Electronic circular dichroism (ECD), absorption and fluorescence spectroscopy were used to study the enantioselective interactions which involved bilirubin (BR), liposomes, human serum albumin of two different purities, pure (HSA) and non-purified of fatty acids (FA-HSA), and individual fatty acids. The application of the ECD technique to such a complex problem provided a new perspective on the BR binding to liposomes. Our results demonstrated that in the presence of pure HSA, BR preferred to bind to the protein over the liposomes. However, in the presence of FA-HSA, BR significantly bound to the liposomes composed either of DMPC or of sphingomyelin and bound only moderately to the primary and secondary binding sites of FA-HSA even at high BR concentrations. For the DMPC liposomes, even a change of BR conformation upon binding to the primary binding site was observed. The individual saturated fatty acids influenced the BR binding to HSA and liposomes in a similar way as fatty acids from FA-HSA. The unsaturated fatty acids interacted with BR alone and prevented it from interacting with either 99 HSA or the liposomes. In the presence of arachidonic acid, BR interacted enantioselectively with the liposomes and only moderately with 99-HSA. Hence, our results show a substantial impact of the liposomes on the BR binding to HSA. As a consequence of the existence of fatty acids in the blood plasma and in the natural structure of HSA, BR may possibly bind to the cell membranes even though it is normally bound to HSA. PMID- 25748386 TI - Metastasis suppressors Nm23H1 and Nm23H2 differentially regulate neoplastic transformation and tumorigenesis. AB - Nm23H1 and H2 are prototypical metastasis suppressors with diverse functions, but recent studies suggest that they may also regulate tumorigenesis. Here, we employed both cellular and in vivo assays to examine the effect of Nm23H1 and H2 on tumorigenesis induced by oncogenic Ras and/or p53 deficiency. Co-expression of Nm23H1 but not H2 in NIH3T3 cells effectively suppressed neoplastic transformation and tumorigenesis induced by the oncogenic H-Ras G12V mutant. Overexpression of Nm23H1 but not H2 also inhibited tumorigenesis by human cervical cancer HeLa cells with p53 deficiency. However, in human non-small-cell lung carcinoma H1299 cells harboring N-Ras Q61K oncogenic mutation and p53 deletion, overexpression of Nm23H1 did not affect tumorigenesis in nude mice assays, while overexpression of Nm23H2 enhanced tumor growth with elevated expression of the c-Myc proto-oncogene. Collectively, these results suggest that Nm23H1 and H2 have differential abilities to modulate tumorigenesis. PMID- 25748387 TI - MicroRNAs-mediated cell fate in triple negative breast cancers. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function as major modulators of posttranscriptional protein-coding gene expression in diverse biological processes including cell survival, cell cycle arrest, senescence, autophagy, and differentiation. The control of miRNAs plays an important role in cancer initiation and metastasis. Triple negative breast cancer (TNBC) is a distinct breast cancer subtype, which is defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu). Due to its high recurrence rate and poor prognosis, TNBC represents a challenge for breast cancer therapy. In recent years, a large number of microRNAs have been identified to play a crucial role in TNBC and some of them were found to be correlated with worse prognosis of TNBC. Thus, understanding the novel function of miRNAs may allow us to develop promising therapeutic targets for the treatment of TNBC patients. PMID- 25748385 TI - To translate, or not to translate: viral and host mRNA regulation by interferon stimulated genes. AB - Type I interferon (IFN) is one of the first lines of cellular defense against viral pathogens. As a result of IFN signaling, a wide array of IFN-stimulated gene (ISG) products is upregulated to target different stages of the viral life cycle. We review recent findings implicating a subset of ISGs in translational regulation of viral and host mRNAs. Translation inhibition is mediated either by binding to viral RNA or by disrupting physiological interactions or levels of the translation complex components. In addition, many of these ISGs localize to translationally silent cytoplasmic granules, such as stress granules and processing bodies, and intersect with the microRNA (miRNA)-mediated silencing pathway to regulate translation of cellular mRNAs. PMID- 25748388 TI - Trefoil factor 3 (TFF3) enhances the oncogenic characteristics of prostate carcinoma cells and reduces sensitivity to ionising radiation. AB - Trefoil factor 3 (TFF3) is a secreted protein which functions in mucosal repair of the gastrointestinal tract. This is achieved through the combined stimulation of cell migration and prevention of apoptosis and anoikis, thus facilitating repair. Deregulated TFF3 expression at the gene and protein level is implicated in numerous cancers. In prostate cancer TFF3 has previously been reported as a potential biomarker, overexpressed in a subset of primary and metastatic cases. Here we investigated the effect of increased TFF3 expression on prostate cancer cell behaviour. Oncomine analysis demonstrated that TFF3 mRNA expression was upregulated in prostate cancer compared to normal tissue. Forced-expression models were established in the prostate cancer cell lines, DU145 and PC3, by stable transfection of an expression vector containing the TFF3 cDNA. Forced expression of TFF3 significantly increased total cell number and cell viability, cell proliferation and cell survival. In addition, TFF3 enhanced anchorage independent growth, 3-dimensional colony formation, wound healing and cell migration compared to control transfected cell lines. We also observed reduced sensitivity to ionising radiation in stably transfected cell lines. In dose response experiments, forced expression of TFF3 significantly enhanced the regrowth of PC3 cells following ionising radiation compared with control transfected cells. In addition, TFF3 enhanced clonogenic survival of DU145 and PC3 cells. These studies indicate that targeting TFF3 for the treatment of prostate cancer warrants further investigation. PMID- 25748389 TI - A retrospective analysis of allergic reaction severities and minimal eliciting doses for peanut, milk, egg, and soy oral food challenges. AB - Food allergy is a public health concern, affecting up to 6% of children and 2% of adults. The severity of allergic reactions can range from mild to potentially life-threatening. In addition, the minimum amount of protein needed to provoke an allergic reaction in an individual patient (the minimal eliciting dose (MED)) ranges from a few micrograms to several grams. To determine whether a retrospective analysis of published data from oral food challenges could be used to assess the potential relationship between MEDs and reaction severities at the MEDs, a three class (mild, moderate, severe) reaction grading system was developed by integrating previously published reaction grading systems. MEDs and symptoms were collected from food challenge studies and each reaction was graded using the integrated grading system. Peanut allergic patients who experienced severe reactions had significantly higher MEDs and threshold distribution doses than those who experienced mild and moderate reactions. No significant differences in threshold distributions according to the severity grading were found for milk, egg and soy. The relationship between threshold dose distribution and reaction severity based on these grading criteria differed between peanut and other allergens, and severe reactions were found to occur in some patients at low MEDs for all of these food allergens. PMID- 25748390 TI - In vivo quantification of the structural changes of collagens in a melanoma microenvironment with second and third harmonic generation microscopy. AB - Using in vivo second harmonic generation (SHG) and third harmonic generation (THG) microscopies, we tracked the course of collagen remodeling over time in the same melanoma microenvironment within an individual mouse. The corresponding structural and morphological changes were quantitatively analyzed without labeling using an orientation index (OI), the gray level co-occurrence matrix (GLCM) method, and the intensity ratio of THG to SHG (RTHG/SHG). In the early stage of melanoma development, we found that collagen fibers adjacent to a melanoma have increased OI values and SHG intensities. In the late stages, these collagen networks have more directionality and less homogeneity. The corresponding GLCM traces showed oscillation features and the sum of squared fluctuation VarGLCM increased with the tumor sizes. In addition, the THG intensities of the extracellular matrices increased, indicating an enhanced optical inhomogeneity. Multiplying OI, VarGLCM, and RTHG/SHG together, the combinational collagen remodeling (CR) index at 4 weeks post melanoma implantation showed a 400-times higher value than normal ones. These results validate that our quantitative indices of SHG and THG microscopies are sensitive enough to diagnose the collagen remodeling in vivo. We believe these indices have the potential to help the diagnosis of skin cancers in clinical practice. PMID- 25748391 TI - Occupational Exposure to Benzene and Non-Hodgkin Lymphoma in a Population-Based Cohort: The Shanghai Women's Health Study. AB - BACKGROUND: The association between benzene exposure and non-Hodgkin lymphoma (NHL) has been the subject of debate as a result of inconsistent epidemiologic evidence. An International Agency for Research on Cancer (IARC) working group evaluated benzene in 2009 and noted evidence for a positive association between benzene exposure and NHL risk. OBJECTIVE: We evaluated the association between occupational benzene exposure and NHL among 73,087 women enrolled in the prospective population-based Shanghai Women's Health Study. METHODS: Benzene exposure estimates were derived using a previously developed exposure assessment framework that combined ordinal job-exposure matrix intensity ratings with quantitative benzene exposure measurements from an inspection database of Shanghai factories collected between 1954 and 2000. Associations between benzene exposure metrics and NHL (n = 102 cases) were assessed using Cox proportional hazard models, with study follow-up occurring from December 1996 through December 2009. RESULTS: Women ever exposed to benzene had a significantly higher risk of NHL [hazard ratio (HR) = 1.87, 95% CI: 1.19, 2.96]. Compared with unexposed women, significant trends in NHL risk were observed for increasing years of benzene exposure (p(trend) = 0.006) and increasing cumulative exposure levels (p(trend) = 0.005), with the highest duration and cumulative exposure tertiles having a significantly higher association with NHL (HR = 2.07, 95% CI: 1.07, 4.01 and HR = 2.16, 95% CI: 1.17, 3.98, respectively). CONCLUSIONS: Our findings, using a population-based prospective cohort of women with diverse occupational histories, provide additional evidence that occupational exposure to benzene is associated with NHL risk. PMID- 25748392 TI - The influence of rifamycin decontamination on incorporation of autologous onlay bone grafts in rats: A histometric and immunohistochemical evaluation. AB - OBJECTIVE: Although it has been shown that rifamycin is an effective agent for bone graft decontamination, no information exists on the effects of rifamycin decontamination on bone graft incorporation. The aim of this study was to evaluate the influence of rifamycin decontamination on the incorporation of autologous onlay bone grafts quantitatively. DESIGN: In 30 rats, a standardized 5.0-mm-diameter bone graft was harvested from the right mandibular angle, contaminated with saliva, decontaminated with rifamycin solution, and augmented to the left as an onlay graft. Ten animals were sacrificed at 7, 14, and 21 days after surgery. In the control group (10 rats), the onlay grafts were neither contaminated nor decontaminated, and the rats were sacrificed at 21 days after surgery. Histological slides were prepared from each grafted site for both immunohistochemistry analysis (bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) antibodies) and histometric analysis. Images obtained from the graft incorporation area with the light microscope were transferred to a PC, and they were evaluated using Clemex PE 3.5 image analysis software. RESULTS: The grafts were fully incorporated in all specimens. The results showed that rifamycin decontamination has no detrimental effect on graft incorporation and the findings revealed a tendency for earlier revascularization and osteogenesis in the decontamination group. Data were analyzed using variance analysis and Tukey's test. CONCLUSIONS: Rifamycin decontamination has no detrimental effect on autogenous graft incorporation, and it can be used for graft decontamination with confidence. PMID- 25748394 TI - Radiomorphometric indices of mandibular bones in an 18th century population. AB - OBJECTIVE: To estimate four radiomorphometric indices of mandibular bones in an 18th century population sample, and possibly associate the findings with bone mass loss related to sex, age, nutritional habits and pathologies reflecting on the bone. DESIGN: Thirty-six sculls (31 males, 5 females), recovered from the crypt of Pozega Cathedral in Croatia were analyzed. Age estimation was based on tooth wear, and Eichner class was determined according to the number of occlusal supporting zones. The parameters in recording analogue orthopantomographs were set to constant current of 16 mA, exposure time of 14.1s, and voltage between 62 78 kV. Films were processed in an automatic dark chamber processor for 12 min, and digitized at 8-bit, 300 dpi. The thickness of the mandibular cortex was assessed below the mental foramen (MI), at antegonion (AI), at gonion (GI). Qualitative mandibular cortical index (MCI) was assessed. RESULTS: Average values of MI, AI and GI were 3.97 +/- 0.94 mm, 2.98 +/- 0.56 mm, and 1.99 +/- 0.55 mm, respectively. Statistically significant differences between males and females were found for AI right (p=0.014), GI left (p=0.010) and GI average (p=0.006), and were in all cases higher in males. There were no statistically significant differences between age groups for either index (p>0.05). Considering Eichner classification the differences were not significant for MI (p=0.422), AI (p=0.516), and GI (p=0.443), but in Eichner classes II, MCI was significantly higher (p=0.02). CONCLUSION: The obtained data does not suggest generalized malnutrition or calcium, phosphorus and vitamin D deprivation in the historic population studied. PMID- 25748393 TI - Redistribution of Galphas in mouse salivary glands following beta-adrenergic stimulation. AB - OBJECTIVE: Signalling via beta-adrenergic receptors activates heterotrimeric G proteins, which dissociate into alpha and betagamma subunits. In salivary glands, the alpha subunit of Gs stimulates adenylate cyclase, increasing cyclic AMP levels and promoting exocytosis. The goals of this study were to determine Galphas localization in salivary glands and whether it undergoes redistribution upon activation. METHODS: Mouse parotid and submandibular (SMG) glands were fixed with paraformaldehyde and prepared for immunofluorescence labelling with anti Galphas. RESULTS: In unstimulated parotid and SMG acinar cells, Galphas was localized mainly to basolateral membranes. Some parotid acinar cells also exhibited cytoplasmic fluorescence. Isoproterenol (IPR) stimulation resulted in decreased membrane fluorescence and increased cytoplasmic fluorescence, which appeared relatively uniform by 30 min. Beginning about 2 h after IPR, cytoplasmic fluorescence decreased and membrane fluorescence increased, approaching unstimulated levels in SMG acini by 4 h. Some parotid acini exhibited cytoplasmic fluorescence up to 8 h after IPR. The IPR-induced redistribution of Galphas was prevented (SMG) or reduced (parotid) by prior injection of propranolol. Striated duct cells of unstimulated mice exhibited general cytoplasmic fluorescence, which was unchanged after IPR. CONCLUSIONS: Galphas is localized to basolateral membranes of unstimulated salivary acinar cells. Activation of Galphas causes its release from the cell membrane and movement into the cytoplasm. Reassociation of Galphas with the membrane begins about 2 h after stimulation in the SMG, but complete reassociation takes several hours in the parotid gland. The presence of Galphas in striated duct cells suggests a role in signal transduction of secretion and/or electrolyte transport processes. PMID- 25748395 TI - Neck disability is associated with masticatory myofascial pain and regional muscle sensitivity. AB - OBJECTIVE: The primary aims of this study are to compare neck disability in masticatory myofascial pain subjects versus asymptomatic controls, and to evaluate the correlation between neck disability and muscle pain. DESIGN: Two groups composed this case-control study: a symptomatic group comprised of 27 subjects diagnosed with masticatory myofascial pain, as determined by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD), and a control group comprised of 28 asymptomatic subjects. The collected variables were pain intensity (visual analogue scale), pressure pain threshold of the temporomandibular joint, anterior temporalis, masseter, sternocleidomastoid muscle, upper trapezius and Achilles tendon (digital dynamometer, kgf/cm(2)), and neck disability (Neck Disability Index). Statistical analysis included Student's t-test and the Pearson product-moment correlation coefficient (5% significance level and 95% confidence interval). RESULTS: The symptomatic group showed greater neck disability with a mean (SD) of 11.8 (7), as compared with 2.8 (2.4) for the asymptomatic group (p<0.05). A negative correlation was found between neck disability and pressure pain threshold of the anterior temporalis (r=-0.4, 95% CI -0.6 to -0.15, p=0.002), the sternocleidomastoid (r=-0.35, 95% CI -0.56 to -0.09, p=0.007) and the upper trapezius (r=-0.37, 95% CI -0.58 to -0.12, p=0.005). CONCLUSION: Our results reinforced the clinical interconnection between masticatory and cervical structures, insofar as subjects with masticatory myofascial pain reported greater neck disability, which, in turn, was correlated with regional muscle sensitivity. PMID- 25748396 TI - [Promoting medical education reform, cultivating excellent pediatrician]. PMID- 25748397 TI - [Steadily improve the diagnostic and therapeutic level for functional cardiovascular diseases in children]. PMID- 25748398 TI - [Expert consensus for the diagnosis and management of pediatric pulmonary hypertension]. PMID- 25748399 TI - [Expert consensus for the interventional treatment of pediatric congenital heart disease]. PMID- 25748400 TI - [Evaluation of the changes in heart rate during head-up test predicting the efficacy of oral rehydration salts on postural tachycardia syndrome in children]. AB - OBJECTIVE: To predict the therapeutic efficacy of oral rehydration salts (ORS) by quantifying changes in heart rate during the head-up test (HUT) in children with postural tachycardia syndrome (POTS). METHOD: Fifty-four children from Peking University First Hospital during July 2005 to September 2013 were enrolled into POTS group. Twenty healthy children were enrolled in this study as the control group. Children with POTS were treated with ORS and successfully followed up. HUT test was done before and at the end of the treatment. POTS children were further divided into responding group and the non-responding group depending on if the symptom scores were reduced by 50% or greater after the treatment. The heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes during the HUT test were analyzed between the control group and the POTS patients. A receiver operating characteristic (ROC) curve was used to analyze the predictive value of the increase in heart rates (from the supine to upright) and the maximum upright heart rate in 10 minutes after ORS treatment. RESULT: POTS children were 6-17 (11.3 +/- 3.0) years old and the control group children were 10-12 (11.0 +/- 0.8) years old. The changes of the heart rate during the HUT was different between the POTS patients and the controls ((41 +/- 10) vs. (20 +/- 7) beats/min, t = -10.441, P = 0.000) . There was no significant difference between the two groups in the maximum upright heart rate in 10 minutes during the HUT ( (117 +/- 12) vs. (114 +/- 8) beats/min, t = -1.322, P = 0.192) . The symptom scores were reduced compared with those before treatment ((3.2 +/- 1.8) vs. (5.7 +/- 2.0), t = 10.958, P < 0.001) and the heart rate changes from supine to upright were decreased in 30 patients ((33 +/- 11) vs. (41 +/- 11) beats/min, t = 2.956, P = 0.006). Compared with the non-responding group (28 cases), the heart rate change during the HUT test was great in the responding group (26 cases) before treatment ((46 +/- 10) vs. (37 +/- 9) beats/min, t = -3.582, P = 0.001), and the maximum upright heart rate in 10 minutes was also high in the responding group ( (122 +/- 12) vs. (113 +/- 10) beats/min, t = -2.693, P = 0.010). The ROC curve showed that ORS for children with POTS would be predicted to be effective when the pre-treatment increase of heart rate was 41 beats/min (sensitivity 72% and specificity 70%), or when the maximum upright heart rate in 10 minutes was 123 beats/min before treatment (sensitivity 48% specificity 56%). When the two indices were used together, sensitivity was 84% and specificity was 56%. CONCLUSION: The changes in heart rate during the HUT was useful in predicting the response to ORS in children with POTS. PMID- 25748401 TI - [Prospective study on the isolated ventricular septal defect in fetus]. AB - OBJECTIVE: Congenital heart defect is one of the most common birth defects. The isolated ventricular septal defect (VSD) has higher morbidity, and spontaneous closure may occur. Previously many studies about the prognosis of ventricular septal defect in childhood were conducted; in contrast, few studies on evolution and prognosis of ventricular septal defect from fetus to postnatal life have been available. This research aimed to determine the evolution of isolated ventricular septal defect during the period of fetus and postnatal life, and analyze the association between the diameter or location of VSD and the spontaneous closure of VSD. METHOD: All pregnant women seen at the prenatal diagnosis center of the West China Second Hospital were recruited. From June 2011 to June 2014, these participants underwent the fetal 2-dimensional and color Doppler echocardiographic examinations, and the fetuses with isolated VSD were included in the study, and those with other malformations or abnormal chromosome were excluded. This study was a prospective and longitudinal research. These fetuses were followed-up until the VSD closed spontaneously, or were surgically repaired or percutaneously closed. Outcomes of all the cases were recorded. RESULT: There were 234 fetuses with isolated VSD who were recruited in our research cohort. Twelve of 234 lost to follow-up, 5 of 234 were still in uterus. Totally 217 fetuses were followed up. One hundred eighty-nine of 217 (87.1%) cases were delivered. The pregnancies were terminated in 28 of 217 (12.9%) cases. Ten cases died after birth. Of the 179 delivered cases, the rate of VSD spontaneous closure was 45.2% (81/179), the VSD of 49 cases (27.4%, 49/179) spontaneously closed in uterus. The VSD of 17.9% (32/179) cases spontaneously closed after birth and those of 75% (24/32) cases closed in the first year of life. Furthermore, these participants were divided into 3 groups according to the diameter of VSD in fetus. There were 87 cases in <= 2.0 mm group, 51 spontaneously closed (59%, 51/87) and 30 of 84 spontaneously closed (36%, 30/84) in 2.1-5.0 mm group. There were no spontaneous closure in > 5.0 mm group. There was a significant difference in spontaneous closure rate between the 3 groups (chi(2) = 15.200, P = 0.001). Nevertheless, these participants were divided into 2 groups according to the location of VSD in fetus (perimembrane VSD (P-VSD) group and muscular VSD (M-VSD) group). There were 152 cases in P-VSD group, 69 spontaneously closed (45.4%, 69/152) and 12 of 27 spontaneously closed (44%, 12/27) in M-VSD group. There was no significant difference in spontaneous closure between P-VSD and M-VSD (chi(2) = 0.008, P = 0.950). CONCLUSION: There was a high spontaneous closure rate of VSD in the period of late pregnancy. The most of postnatal VSD were spontaneously closed within one year of age. The spontaneous closure rates of fetal VSD with different diameter were different. The spontaneous closure rate of VSD with smaller diameter was higher. PMID- 25748402 TI - [A retrospective analysis of 602 Kawasaki disease cases with electronic data capture system]. AB - OBJECTIVE: To explore the value of electronic data capture (EDC) system in large sample size studies on Kawasaki disease (KD). METHOD: The clinical data of 602 KD cases from 2007 to 2012 admitted to Shanghai Children's Hospital with EDC system connected with hospital information system (HIS) were retrospectively analyzed. Age, gender, acute symptoms, laboratory results, echocardiography, therapy were collected. The differences in parameters were compared between KD with and without coronary artery lesion (CAL). Furthermore, the difference between intravenous immunoglobulin (IVIG) resistant group and sensitive group were compared. Multi-factor logistic regression analyses were used to analyze the risk factors. The sensitivity and specificity of IVIG resistance parameters were detected with receiver operating characteristic curve (ROC) analysis. RESULT: The male to female ratio of KD cases was 1.85: 1. The median age of KD cases was 2.0 years (one month to 11.7 years old); 20.1% cases (121/602) exhibited CAL. Compared with KD without CAL (n = 481), the incidence of bright red cracked lips (71.1% vs. 88.6%, P = 0.001), peeling of the skin of the toes (28.1% vs. 41.6%, P = 0.021) and perianal skin peeling (29.8% vs. 38.9%, P = 0.031) were statistically lower in KD with CAL (n = 121). The incidence of CAL in KD IVIG resistant group was significantly higher than KD IVIG sensitive group (34.6% (9/26) vs.21.3% (112/525), P = 0.05 ). Male ratio (80.8% vs. 63.4%, P = 0.05), time of IVIG ( (6 +/- 2) vs. (8 +/- 5) d, P = 0.009), erythrocyte sedimentation rate(ESR) ( (81 +/- 2) vs. (66 +/- 30) mm/1 h, P = 0.014), C-reactive protein ((107 +/- 51) vs. (87 +/- 52) mg/L, P = 0.017), blood platelet ( (599 +/- 178) vs. (489 +/- 182) *10(9)/L, P = 0.003), hemoglobin ( (96 +/- 13) vs. (102 +/- 19) g/L, P = 0.032) and albumin ((34 +/- 6) vs. (37 +/- 6) g/L, P = 0.020) were significantly different between IVIG resistant group and sensitive group. Logistic regression analysis showed that alanine aminotransferase (ALT) >= 80 U/L was the independent risk factor of IVIG resistance (P = 0.012). C-reactive protein = 104 mg/L (sensitivity 61.5%, specificity 62.7%), ESR = 106 mm/1 h (sensitivity 26.9%, specificity 93.6%) and blood platelet = 187*10(9)/L (sensitivity 76.9%, specificity 53.1%) of KD in acute phase were predictive for IVIG resistance with receiver operate characteristic curve analysis. CONCLUSION: EDC system can acquire KD clinical data quickly and accurately. It is helpful for multicenter retrospective analysis of KD. PMID- 25748403 TI - [Follow up and review of patients with Kawasaki disease complicated with giant coronary artery aneurysms for a decade: a single-institution experience]. AB - OBJECTIVE: To evaluate the prognosis and clinical features of patients with giant coronary artery aneurysm (GCAA) caused by Kawasaki disease (KD). METHOD: KD complicated with GCAA was diagnosed in 55 patients between January 2003 and December 2012 in Guangzhou Women and Children's Medical Center.Of the 55 patients, 48 were studied(43 boys, 5 girls). According to the follow-up time, these patients were divided into four groups: <= 1 year follow-up group, > 1-3 years follow-up group, > 3-5 years follow-up group, and > 5-10 years follow-up group. These patients were investigated at the acute stage, and were followed up respectively at two weeks, one month, three months, six months, and one year after hospitalization and every 3 to 6 months after a year. All patients regularly accepted echocardiography and electrocardiographic examination, while some cases accepted CT coronary angiography (CTA) examination and coronary angiography (CAG) examination to confirm the condition of GCAA. RESULT: (1) The age of 48 patients ranged from 2 months to 10 years. Twenty cases were less than 1 age (42%), 30 cases were under 3 years of age (62%) and follow-up time was (4.0 +/- 3.1) years. Age at endpoint was 1.5 to 19 years, mean (6.8 +/- 4.2) years respectively. (2) In <= 1 year follow-up group, the proportions of no significant changes, retraction, and stenosis were 48%, 48% and 4% respectively. In > 1-3 years follow-up group, the proportions of no significant changes, retraction, and stenosis were 39%, 39% and 22% respectively. In > 3-5 years follow-up group, the proportions of no significant changes, retraction, and stenosis were 30%, 35% and 35% respectively. In > 5-10 years follow-up group, the proportions of no significant changes, retraction, stenosis were 30%, 20% and 50% respectively. Compared with the <= 1 year group, a significant increase in the proportion of coronary artery stenosis occurred at the other three groups.Significant difference in the stenosis rate could be found between the <= 1 year group and the other three groups respectively (chi(2)=6.026, 11.121, 15.652; P=0.019, 0.002, 0.001). (3) The rate of retraction in bilateral GCAA group (20 cases) was lower than unilateral GCAA group (28 cases ); bilateral GCAA group had lower rate than the unilateral group(15% (3/20) vs. 36% (10/28)). There was no significant difference in coronary artery outcome between two groups (P > 0.05) . (4) There were six severe ischemic heart disease in 48 cases including 2 deaths. (5) CTA showed coronary artery wall thickening, mural thrombus and calcification, the CAG could display coronary artery occlusion and recanalization and collateral vessels formation. CONCLUSION: KD complicated with GCAA may occur in infants under one year of age, especially infants under 6 months of age. A significant increase in the proportion of coronary artery stenosis occurred with the follow-up time extended. The proportion of bilateral GCAA patients who had ischemic heart disease and died was higher than the unilateral cases. The combined application of echocardiography, CTA and CAG may greatly help to discover coronary thrombosis, stenosis and occlusion. PMID- 25748404 TI - [SMARCAL1 gene analysis of 2 Chinese Schimke immuno-osseous dysplasia children]. AB - OBJECTIVE: Schimke immuno-osseous dysplasia (SIOD), is an autosomal recessive inherited disease caused by SMARCAL1 (MIM:20606622) mutations, while in about half of the patients no any mutation in SMARCAL1 could be found. This disease involves multiple systems and is characterized by short and dissymmetric stature with spondyloepiphyseal dysplasia, progressive renal failure, lymphopenia with recurrent infections, and hyperpigmented macules. This study aimed to analyze SMARCAL1 gene of 2 unrelated suspected SIOD children, to make definite diagnosis, and find more SMARCAL1 mutation types of Chinese SIOD. METHOD: Two suspected Chinese Han male SIOD children who visited our hospital from 2008 to 2014, aged 3 y 6 m and 7 y 8 m, both were short and had spondyloepiphyseal dysplasia, progressive renal failure, lymphopenia with recurrent infections. After informed consent, they and their parents's DNA were extracted from blood. PCRs for all 16 exons of SMARCAL1 were performed and PCR products were purified by 2% gel electrophoresis and sequenced directly. Pathogenicity of missense variations was confirmed by SIFT and sequencing SMARCAL1 of fifty normal controls. RESULT: (1) Four gene variations were found in the two children: Two reported missense mutations c.1129G>C, p.Glu377Gln and c.1933C>T, p. Arg645Cys. Two splicing mutations c.1334+1G>A and c.2142-1 G>A were detected. (2) c.1129G>C, p.Glu377Gln were reported as a disease-causing mutations before, but it was an single nucleotide polymorphism (SNP) which was found in 15 of 50 normal controls. (3) Two novel splicing mutations were found in this study: c.1334+1G>A and c.2142-1 G>A. CONCLUSION: (1) We detected 3 disease-causing mutations in 2 SIOD children by SMARCAL1 gene analysis, while 2 splicing mutations were novel mutations. (2) c.1129G>C, p.Glu377Gln was a SNP but not a disease-causing mutation at least in Chinese population. PMID- 25748405 TI - [Analysis of pathogenic bacteria and drug resistance in neonatal purulent meningitis]. AB - OBJECTIVE: To study the clinical characteristics, pathogenic bacteria, and antibiotics resistance of neonatal purulent meningitis in order to provide the guide for early diagnosis and appropriate treatment. METHOD: A retrospective review was performed and a total of 112 cases of neonatal purulent meningitis (male 64, female 58) were identified in the neonatal intensive care unit of Yuying Children's Hospital of Wenzhou Medical University seen from January 1, 2004 to December 31, 2013. The clinical information including pathogenic bacterial distribution, drug sensitivity, head imageology and therapeutic outcome were analyzed. Numeration data were shown in ratio and chi square test was applied for group comparison. RESULT: Among 112 cases, 46 were admitted from 2004 to 2008 and 66 from 2009 to 2013, 23 patients were preterm and 89 were term, 20 were early onset (occurring within 3 days of life) and 92 were late onset meningitis (occurring after 3 days of life). In 62 (55.4%) cases the pathogens were Gram-positive bacteria and in 50 (44.6%) were Gram-negative bacteria. The five most frequently isolated pathogens were Escherichia coli (32 cases, 28.6%), coagulase-negative staphylococcus (CNS, 20 cases, 17.9%), Streptococcus (18 cases, 16.1%, Streptococcus agalactiae 15 cases), Enterococci (13 cases, 11.6%), Staphylococcus aureus (9 cases, 8.0%). Comparison of pathogenic bacterial distribution between 2004-2008 and 2009-2013 showed that Gram-positive bacteria accounted for more than 50% in both period. Escherichia coli was the most common bacterium, followed by Streptococcus in last five years which was higher than the first five years (22.7% (15/66) vs. 6.5% (3/46), chi(2) = 5.278, P < 0.05). Klebsiella pneumoniae was more common isolate in preterm infants than in term infants (13.0% (3/23) vs. 1.1% (1/89), chi(2) = 7.540, P < 0.05). Streptococcus (most were Streptococcus agalactiae) was the most common bacteria in early onset meningitis and higher than those in late onset meningitis (35.0% (7/20) vs. 12.0% (11/92), chi(2) = 4.872, P < 0.05). Drug sensitivity tests showed that all the Gram-positive bacterial isolates were sensitive to linezolid. Staphylococci were resistant to penicillin, and most of them were resistant to erythromycin, oxacillin and cefazolin; 77.8%of CNS isolates were methicillin-resistant staphylococcus. No Streptococcus and Enterococcus faecalis was resistant to penicillin. None of enterococci was resistant to vancomycin. Among the Gram negative bacterial isolates, more than 40% of Escherichia coli were resistant to commonly used cephalosporins such as cefuroxime, cefotaxime and ceftazidime, and all of them were sensitive to amikacin, cefoperazone sulbactam and imipenem. Isolates of Klebsiella pneumoniae were all resistant to ampicillin, cefuroxime, cefotaxime and ceftazidime, but none of them was resistant to piperacillin tazobactam and imipenem. Of the 112 patients, 69 were cured, 23 improved, 9 uncured and 11 died. There were 47 cases (42.0%) with poor prognosis, they had abnormal head imageology, severe complications and some cases died, 13 of 18 (72.2%) patients with meningitis caused by Streptococcus died. CONCLUSION: Escherichia coli, CNS and Streptococcus are the predominant pathogens responsible for neonatal purulent meningitis over the past ten years. There were increasing numbers of cases with Streptococcus meningitis which are more common in early onset meningitis with adverse outcome, therefore careful attention should be paid in clinic. Linezolid should be used as a new choice in intractable neonatal purulent meningitis cases caused by gram positive bacteria. PMID- 25748406 TI - [Three Chinese children with Niemann-Pick disease type C with neonatal cholestasis as initial presentation]. AB - OBJECTIVE: To analyze the clinical characteristics of three Chinese cases of Niemann-Pick disease type C patients with neonatal cholestasis as initial presentation, and enhance awareness of Niemann-Pick disease type C among pediatricians. METHOD: Three sporadic cases with confirmed Niemann-Pick disease type C initially presented as neonatal cholestasis were retrospectively reviewed in this study. Their peripheral blood specimens were collected after obtaining informed consent. All exons and the intron-exon boundaries of NPC1 gene were examined by bi-directional sequencing. RESULT: Three patients, 1 female and 2 males, aged from 2 months to 5 years and 10 months, all first complained of jaundice in the neonatal period. Laboratory tests showed total bilirubin and direct bilirubin significantly increased with predominant increase of direct bilirubin. Total bile acid, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were also increased, while high-density lipoprotein cholesterol decreased. All patients were also accompanied by hepatosplenomegaly, with two of them having increased bronchovascular markings in chest X-ray. Two heterozygous changes of NPC1 gene, c.2741G>T +c.3020C>G (p. C914F + p. P1007R), c.2177G>C + c.3734_ 3735delCT (p.R726T + p. P1245RfsX12), and c.2054T>C + c.2128C>T(p.I685T + p.Q710X), were identified in patient 1, 2 and 3, respectively. CONCLUSION: We reported three cases suffered from Niemann-Pick disease type C with initial presentation as neonatal cholestasis in the mainland of China. For newborns with prolonged jaundice in the neonatal period, as well as neonatal cholestasis, hepatosplenomegaly, Niemann-Pick type C should be included in consideration of differential diagnosis. Genetic testing can identify causative mutations for diagnosis. PMID- 25748407 TI - [Acute encephalopathy induced by vaccination in an infant with methylmalonic aciduria cblA]. AB - OBJECTIVE: We report the first case of acute encephalopathy induced by vaccination in an infant with methylmalonic aciduria cblA in China. METHOD: The clinical presentation, blood acylcarnitines analysis, urine organic acids analysis and gene studies of the patient were summarized. RESULT: The proband, a boy, was admitted at the age of 15 months because of recurrent vomiting, acidosis and development delay for 8 months. The previously healthy boy presented vomiting and coma just one hour after hepatitis B vaccination at the age of seven months. Moderate dehydration, electrolyte disturbance and metabolic acidosis had been found. Although his acute metabolic crisis had been corrected soon after intravenous transfusion, psychomotor retardation and recurrent vomiting had been observed. When he was 15 months old, vomiting and lethargy occurred again 3 hours after DTaP vaccination. He was weakened as the illness became worse and got coma with dyspnea 7 days later. He was hospitalized with the suspected diagnosis of viral encephalitis. Blood acylcarnitines analysis, urine organic acids analysis and gene study had been performed for the etiologic investigation.His blood propionylcarnitine (16.3 umol/L vs. normal range 1.0-5.0 umol/L) and propionylcarnitine/free carnitine ratio (0.27 vs. normal range 0.03 to 0.25) increased. Markedly elevated urinary methylmalonic acid (388.21 mmol/mol creatinine vs. normal range 0.2 to 3.6 mmol/mol creatinine) and normal plasma total homocysteine supported the diagnosis of isolated methylmalonic aciduria. Two mutations, c.650 T>A (p.L217X) and c.742 C>T (p.Q248X), were identified in his MMAA gene, confirmed the diagnosis of cblA. Each parent carried one of the two mutations. Progressive clinical and biochemical improvement has been observed after hydroxylcobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine. He is currently 2 years and 7 months old with normal development and general condition. CONCLUSION: A boy with cblA was firstly detected after the acute encephalopathy induced by vaccination in China. It is important to pay more attention to the patients with metabolic crisis or organ damage after vaccination. Metabolic studies are keys to the diagnosis of potential diseases and improve the outcome. PMID- 25748409 TI - [A case of cryoablation for an accessory pathway near the bundle of His in a child]. PMID- 25748408 TI - [Maple syrup urine disease caused by two novel BCKDHB gene mutations in a Chinese neonate]. AB - OBJECTIVE: Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder that is caused by mutations in the subunits of the branched chain alpha ketoacid dehydrogenase (BCKD) complex. This report presents a Han ethnic Chinese newborn infant with the severe classic form of MSUD caused by two novel missense mutations in the BCKDHB gene. METHOD: The clinical and biochemical data of a Chinese neonate with classic form of MSUD were analyzed, and the DNA sequences of BCKDHA, BCKDHB, DBT and DLD genes were investigated for mutations. Then the DNA samples of the proband and the patient's parents were tested with Sanger sequencing. RESULT: The manifestations of this patient were poor feeding, low reaction, and compensatory metabolic acidosis. Tandem mass spectrometry (MS/MS) showed that leucine and valine were significantly higher than normal. Urine gas chromatography-mass spectrometry (GC/MS) showed significant abnormality. Brain CT scan showed white matter changes. We identified two previously unreported mutations in the BCKDHB gene, p.Leu194Phe (c.580 C>T) and p.Ser199Arg (c.597 T>G) in exon 5. Segregation analysis showed that the novel mutation p.Ser199Arg was maternally inherited and the novel mutation p.Leu194Phe was paternally inherited. Neither mutation was found in the 186 alleles of 93 normal Han ethnic Chinese individuals. In human BCKDHB protein crystal structure, the 194th and 199th amino acids changes are likely to affect the spatial structure of the protein. The 194th and 199th amino acid of human BCKDHB protein was conserved among species. PolyPhen protein function prediction indicated that the 194th and 199th amino acid changes were likely to affect protein function. CONCLUSION: Two novel missense mutations were identified in the BCKDHB gene in the Chinese patient with MSUD. PMID- 25748410 TI - [Recent advance in tumor necrosis factor-alpha blockade treatment for Kawasaki disease]. PMID- 25748411 TI - [Advances in the treatment of Alport syndrome]. PMID- 25748413 TI - Prevalence of shingles and its association with PTSD among HIV-infected women in Rwanda. AB - OBJECTIVE: To examine the prevalence of reported shingles in the last 6 months and its association with post-traumatic stress disorder (PTSD), depression and severity of HIV disease in Rwandan women with HIV. SETTINGS: This cross-sectional study was conducted as part of the Rwanda Women's Interassociation Study and Assessment (RWISA), an observational cohort study designed to assess the impact of HIV and residual factors from experiencing rape in the 1994 genocide in Rwandan women. Participants were recruited through grassroots women's associations of people living with HIV infection and clinical care sites for HIV infection. Most participants (58.5%, n=405/692) had PTSD. PARTICIPANTS: This cross-sectional analysis was conducted in 710 HIV-infected women enrolled in RWISA. Inclusion criteria were: age >15 years, informed consent, HIV test, ability to complete the interview in the local language, travel to and from the research site and participate in a baseline outpatient visit, and being naive to antiretroviral therapy at enrolment. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcome of interest was self-reported shingles in the past 6 months. The exposure was PTSD defined using the cross-culturally validated Harvard Trauma Questionnaire. RESULTS: Overall prevalence of reported shingles in the past 6 months was 12.5% (n=89/710). There was an inverse relationship between shingles prevalence and immunological status: 7.6%, 12.3% and 16.7% of women with CD4 >350, 200-350 and <200 cells/uL, respectively, reported singles (p=0.01). In multivariate analysis, PTSD (aOR 1.7; 95% CI 1.02 to 2.89) and low CD4 (aOR 2.4; 95% CI 1.23 to 4.81) were independently associated with reported shingles in the past 6 months. CONCLUSIONS: Our study found a significant independent relationship between PTSD and reported shingles, suggesting that PTSD may be associated with immune compromise that can result in herpes zoster reactivation. Further study is needed. It also confirmed previous findings of a strong relationship between shingles and greater immunosuppression in women with HIV infection. PMID- 25748414 TI - Assessing the validity of respondents' reports of their partners' ages in a rural South African population-based cohort. AB - OBJECTIVES: This study evaluated the validity of using respondents' reports of age disparity in their sexual relationships (perceived disparity), compared to age disparity based on each partner's report of their own date of birth (actual disparity). SETTING: The study was conducted using data from a longitudinal population-based cohort in rural KwaZulu-Natal, South Africa, between 2005 and 2012. PARTICIPANTS: The study used 13,831 reports of partner age disparity within 7337 unique conjugal relationships. 10,012 (72.4%) reports were made by women. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the Lin concordance correlation of perceived and actual age disparities. Secondary outcomes included the sensitivity/specificity of perceived disparities to assess whether the man in the relationship was more than five or more than 10 years older than the woman. RESULTS: Mean relationship age disparity was 6 years. On average, respondents slightly underestimated their partners' ages (male respondents: 0.50 years; female respondents: 0.85 years). Almost three-quarters (72.3%) of age disparity estimates fell within 2 years of the true values, although a small minority of reports were far from correct. The Lin concordance correlation of perceived and actual age disparities (men: rho=0.61; women: rho=0.78), and assessments of whether the man in the relationship was more than five, or more than 10 years older than the woman (sensitivity >60%; specificity >75%), were relatively high. Accuracy was higher for spouses and people living in the same household, but was not affected by relationship duration. CONCLUSIONS: Rural South Africans reported their sexual partners' ages imperfectly, but with less error than in some other African settings. Further research is required to determine how generalisable these findings are. Self-reported data on age disparity in sexual relationships can be used with caution for research, intervention design, and targeting in this and similar settings. PMID- 25748415 TI - Adherence-adjusted estimates of benefits and harms from treatment with amoxicillin for LRTI: secondary analysis of a 12-country randomised placebo controlled trial using randomisation-based efficacy estimators. AB - OBJECTIVES: Estimate the efficacy of amoxicillin for acute uncomplicated lower respiratory-tract infection (LRTI) in primary care and demonstrate the use of randomisation-based efficacy estimators. DESIGN: Secondary analysis of a two-arm individually-randomised placebo-controlled trial. SETTING: Primary care practices in 12 European countries. PARTICIPANTS: Patients aged 18 or older consulting with an acute LRTI in whom pneumonia was not suspected by the clinician. INTERVENTIONS: Amoxicillin (two 500 mg tablets three times a day for 7 days) or matched placebo. MAIN OUTCOME MEASURES: Clinician-rated symptom severity between days 2-4; new/worsening symptoms and presence of side effects at 4-weeks. Adherence was captured using self-report and tablet counts. RESULTS: 2061 participants were randomised to the amoxicillin or placebo group. On average, 88% of the prescribed amoxicillin was taken. The original analysis demonstrated small increases in both benefits and harms from amoxicillin. Minor improvements in the benefits of amoxicillin were observed when an adjustments for adherence were made (mean difference in symptom severity -0.08, 95% CI -0.17 to 0.01, OR for new/worsening symptoms 0.81, 95% CI 0.66 to 0.98) as well as minor increases in harms (OR for side effects 1.32, 95% CI 1.12 to 1.57). CONCLUSIONS: Adherence to amoxicillin was high, and the findings from the original analysis were robust to non-adherence. Participants consulting to primary care with an acute uncomplicated LRTI can on average expect minor improvements in outcome from taking amoxicillin. However, they are also at an increased risk of experiencing side effects. TRIAL REGISTRATION NUMBERS: Eudract-CT 2007-001586-15 and ISRCTN52261229. The trial was registered at EudraCT in 2007 due to an administrative misunderstanding that EudraCT was a suitable registry--which it was not in 2007, but has become since. On discovery of this error, the trial was also registered at ISRCTN (January 2009). Trial procedures did not change between the two registrations. PMID- 25748412 TI - Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development. AB - This review emphasizes how lipids regulate membrane fusion and the proteins involved in three developmental stages: oocyte maturation to the fertilizable egg, fertilization and during first cleavage. Decades of work show that phosphatidic acid (PA) releases intracellular calcium, and recent work shows that the lipid can activate Src tyrosine kinase or phospholipase C during Xenopus fertilization. Numerous reports are summarized to show three levels of increase in lipid second messengers inositol 1,4,5-trisphosphate and sn 1,2-diacylglycerol (DAG) during the three different developmental stages. In addition, possible roles for PA, ceramide, lysophosphatidylcholine, plasmalogens, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 4,5-bisphosphate, membrane microdomains (rafts) and phosphatidylinositol 3,4,5-trisphosphate in regulation of membrane fusion (acrosome reaction, sperm-egg fusion, cortical granule exocytosis), inositol 1,4,5-trisphosphate receptors, and calcium release are discussed. The role of six lipases involved in generating putative lipid second messengers during fertilization is also discussed: phospholipase D, autotaxin, lipin1, sphingomyelinase, phospholipase C, and phospholipase A2. More specifically, proteins involved in developmental events and their regulation through lipid binding to SH3, SH4, PH, PX, or C2 protein domains is emphasized. New models are presented for PA activation of Src (through SH3, SH4 and a unique domain), that this may be why the SH2 domain of PLCgamma is not required for Xenopus fertilization, PA activation of phospholipase C, a role for PA during the calcium wave after fertilization, and that calcium/calmodulin may be responsible for the loss of Src from rafts after fertilization. Also discussed is that the large DAG increase during fertilization derives from phospholipase D production of PA and lipin dephosphorylation to DAG. PMID- 25748416 TI - Psychosocial deprivation in women with gestational diabetes mellitus is associated with poor fetomaternal prognoses: an observational study. AB - OBJECTIVE: To evaluate the prognoses associated with psychosocial deprivation in women with gestational diabetes mellitus (GDM). DESIGN: Observational study considering the 1498 multiethnic women with GDM who gave birth between January 2009 and February 2012. SETTING: Four largest maternity units in the northeastern suburban area of Paris. PARTICIPANTS: The 994 women who completed the Evaluation of Precarity and Inequalities in Health Examination Centers (EPICES) questionnaire. MAIN OUTCOME MEASURE: Main complications of GDM (large infant for gestational age (LGA), shoulder dystocia, caesarean section, pre-eclampsia). RESULTS: Psychosocial deprivation (EPICES score >=30.17) affected 577 women (56%) and was positively associated with overweight/obesity, parity and non-European origin, and negatively associated with family history of diabetes, fruit and vegetable consumption and working status. The psychosocially deprived women were diagnosed with GDM earlier, received insulin treatment during pregnancy more often and were more likely to have LGA infants (15.1% vs 10.6%, OR=1.5 (95% CI 1.02 to 2.2), p<0.05) and shoulder dystocia (3.1% vs 1.2%, OR=2.7 (0.97 to 7.2), p<0.05). In addition to psychosocial deprivation, LGA was associated with greater parity, obesity, history of GDM, ethnicity, excessive gestational weight gain and insulin therapy. A multivariate analysis using these covariates revealed that the EPICES score was independently associated with LGA infants (per 10 units, OR=1.12 (1.03 to 1.20), p<0.01). CONCLUSIONS: In our area, psychosocial deprivation is common in women with GDM and is associated with earlier GDM diagnoses and greater insulin treatment, an increased likelihood of shoulder dystocia and, independently of obesity, gestational weight gain and other confounders with LGA infants. PMID- 25748417 TI - Is the promise of methadone Kenya's solution to managing HIV and addiction? A mixed-method mathematical modelling and qualitative study. AB - BACKGROUND AND OBJECTIVES: Promoted globally as an evidence-based intervention in the prevention of HIV and treatment of heroin addiction among people who inject drugs (PWID), opioid substitution treatment (OST) can help control emerging HIV epidemics among PWID. With implementation in December 2014, Kenya is the third Sub-Saharan African country to have introduced OST. We combine dynamic mathematical modelling with qualitative sociological research to examine the 'promise of methadone' to Kenya. METHODS, SETTING AND PARTICIPANTS: We model the HIV prevention impact of OST in Nairobi, Kenya, at different levels of intervention coverage. We draw on thematic analyses of 109 qualitative interviews with PWID, and 43 with stakeholders, to chart their narratives of expectation in relation to the promise of methadone. RESULTS: The modelled impact of OST shows relatively slight reductions in HIV incidence (5-10%) and prevalence (2-4%) over 5 years at coverage levels (around 10%) anticipated in the planned roll-out of OST. However, there is a higher impact with increased coverage, with 40% coverage producing a 20% reduction in HIV incidence, even when accounting for relatively high sexual transmissions. Qualitative findings emphasise a culture of 'rationed expectation' in relation to access to care and a 'poverty of drug treatment opportunity'. In this context, the promise of methadone may be narrated as a symbol of hope-both for individuals and community-in relation to addiction recovery. CONCLUSIONS: Methadone offers HIV prevention potential, but there is a need to better model the effects of sexual HIV transmission in mediating the impact of OST among PWID in settings characterised by a combination of generalised and concentrated epidemics. We find that individual and community narratives of methadone as hope for recovery coexist with policy narratives positioning methadone primarily in relation to HIV prevention. Our analyses show the value of mixed methods approaches to investigating newly-introduced interventions. PMID- 25748418 TI - Initiation rates of statin therapy for the primary prevention of cardiovascular disease: an assessment of differences between countries of the UK and between regions within England. AB - OBJECTIVES: To investigate the extent to which variation exists in the initiation rate of statin therapy for the primary prevention of cardiovascular disease between countries of the UK and between different regions within England. DESIGN: Cohort study using data from a large UK primary care database. SETTING UK PARTICIPANTS: 4,820,885 individuals from 554 general practices during the period 2004-2012. MAIN OUTCOME MEASURES: Rate of statin therapy initiation per 1000 person-years. RESULTS: Relative to a fixed English rate of 1 initiation per 1000 person-years and accounting for gender, age and social deprivation level, the rate was similar for Scotland at 0.92 (95% CI 0.84 to 1.00) and rates for Northern Ireland and Wales were higher at 1.40 (95% CI 1.20 to 1.62) and 1.18 (95% CI 1.05 to 1.32), respectively. Within England, the regions could be classified into three groups with respect to statin therapy initiation rates (relative to a rate of 1 initiation per 1000 person-years for London): the South Central 0.73 (95% CI 0.64 to 0.83), South West 0.80 (95% CI 0.71 to 0.91), East of England 0.81 (95% CI 0.71 to 0.94) and South East Coast 0.83 (95% CI 0.73 to 0.95); strategic health authorities had similar low rates followed by the East Midlands 0.88 (95% CI 0.73 to 1.05), West Midlands 0.96 (95% CI 0.84 to 1.09), North East 0.96 (95% CI 0.79 to 1.16), Yorkshire and Humber 0.97 (95% CI 0.81 to 1.17) and London strategic health authorities. North West England exhibited the highest rate of statin therapy initiation of 1.16 (95% CI 1.02 to 1.31). CONCLUSIONS: Considerable variation in the rate of statin therapy initiation was observed between the four countries of the UK and between different geographical regions within England. PMID- 25748419 TI - Singular effects of PPAR agonists on nonalcoholic fatty liver disease of diet induced obese mice. AB - AIMS: To assess the effects of peroxisome proliferator-activated receptor (PPAR) agonists on glucose tolerance and hepatic lipid metabolism in diet-induced obese mice. MAIN METHODS: Male C57BL/6 mice received a standard chow diet (SC, 10% energy as lipids) or high-fat diet (HF, 50% energy as lipids) for 10 weeks, after which treatment was initiated, forming the groups: SC group, HF group, HF-BZ group (HF + bezafibrate, pan-PPAR agonist), HF-WY group (HF + WY-14643, PPARalpha agonist) and HF-GW group (HF + GW1929, PPARgamma agonist). Treatments lasted for four weeks. Insulin resistance and liver remodeling were evaluated by biochemical and molecular approaches. KEY FINDINGS: The HF and HF-GW mice were overweight. Conversely, the HF-BZ and HF-WY mice presented with body masses equal to those of the SC mice. All treatments restored insulin sensitivity and blood lipid and adiponectin levels. Hepatic steatosis was prevented in the HF-WY and HF-BZ mice as shown by the elevated mRNA levels of PPARalpha and Carnitine palmitoyl transferase-1a in both groups, which favored enhanced beta-oxidation. Marked decreases in liver triacylglycerol levels confirmed these findings. In contrast, the HF-GW mice exhibited increased PPARgamma and fatty acid translocase/CD136 mRNA levels, contributing to enhanced hepatic lipogenesis. SIGNIFICANCE: The WY14643 and bezafibrate treatments most effectively improved the adverse metabolic and hepatic effects caused by obesity and IR. The results reinforce the central role of PPARalpha, as well as its contrary relationship to PPARgamma in the regulation of metabolic homeostasis and lipolytic pathways in the liver. PMID- 25748420 TI - 20 years of leptin: Role of leptin in cardiomyocyte physiology and physiopathology. AB - Since the discovery of leptin in 1994 by Zhang et al., there have been a number of reports showing its implication in the development of a wide range of cardiovascular diseases. However, there exists some controversy about how leptin can induce or preserve cardiovascular function, as different authors have found contradictory results about leptin beneficial or detrimental effects in leptin deficient/resistant murine models and in wild type tissue and cardiomyocytes. Here, we will focus on the main discoveries about the leptin functions at cardiac level within the last two decades, focusing on its role in cardiac metabolism, remodeling and contractile function. PMID- 25748421 TI - Hair-growth stimulation by conditioned medium from vitamin D3-activated preadipocytes in C57BL/6 mice. AB - AIMS: Recently, immature adipocyte lineage cells have been suggested as a potential hair-growth stimulator. Diverse studies have been attempted to find methods for the preconditioning of immature adipocyte lineage cells. The present study investigates the effect of conditioned medium (CM) from vitamin D3 (Vd3) pre-activated preadipocytes on hair-growth ability. MAIN METHODS: To test the effect of CM from Vd3 pre-activated preadipocytes on hair-growth efficiency in mice, we compared the differences in hair regenerated after injecting CM from mouse preadipocytes pre-activated with or without Vd3. Next, to determine the regulating factors, the VEGF level was measured by ELISA and angiogenesis level was evaluated by IHC. Finally, the signaling mechanism was investigated by inhibitor kinase assay and western blotting. KEY FINDINGS: The CM from Vd3 pre activated preadipocyte injection markedly promoted the ability of hair regeneration in mice. The VEGF levels were increased by Vd3 treatment in vitro and the CM from Vd3 pre-activated preadipocytes significantly increased the angiogenesis in vivo, suggesting the involvement of angiognensis in the hair regeneration induced by CM from pre-activated preadipocytes. In signaling study, Vd3-enhanced VEGF production was reduced by an ERK1/2 inhibitor and the level of ERK1/2 phosphorylation was increased by treatment with Vd3. SIGNIFICANCE: This has been the first report on CM from Vd3 pre-activated preadipocyte displaying stimulatory effects on hair growth via the enhancement of angiogenesis in a hairless-induced C57BL/6 mice. PMID- 25748423 TI - Pharmacological investigations on cross adaptation in mice subjected to stress immobilization. AB - AIMS: The present study was designed to investigate the existence of cross adaptation between immobilization and foot shock stress, and to identify the role of endogenous opioids in cross adaptation. METHODS: Mice were subjected to acute stress using a single episode of immobilization of 2h duration; while stress adaptation was induced by repeated exposures to homotypic stressor for 5 days. To explore the existence of cross adaptation, homotypic stressor was replaced with a heterotypic stressor on the 6th day and foot shocks of 0.5 mA intensity, 1s duration with an interval of 2 min were delivered for 1h. Stress-related behavioral alterations were assessed using the actophotometer, hole board, open field and social interaction tests. KEY FINDINGS: A single exposure of immobilization produced the significant behavioral alterations that were restored on the 5th day following repeated applications of immobilization stress, indicating the development of stress adaptation. Furthermore, acute exposure of foot shock (heterotypic stressor) did not produce the behavioral alterations in immobilization stress adapted animals, indicating the development of cross adaptation. Administration of naloxone abolished the restoration of behavioral changes as a part of adaptive/cross adaptive process in repeated immobilization stress-subjected mice. SIGNIFICANCE: It may be concluded that immobilization stress adapted mice exhibit cross adaptation to foot shock stress, with the possible involvement of opioids as endogenous adaptogenic/cross adaptogenic factors. PMID- 25748422 TI - Upregulation of inorganic pyrophosphatase 1 as a JNK phosphatase in hypothyroid embryonic chick cerebellum. AB - AIM: Thyroid hormones play important roles in vertebrate neuronal development and differentiation. In our previous study, we showed that fetal thyroid dysfunction led to impaired social behaviors of hatchlings on post-hatch day 3, as well as to impaired learning and memory determined by the imprinting preference. However, little is known about the mechanisms underlying the direct adverse effects of fetal thyroid dysfunction on neuronal development. MATERIALS AND METHODS: We used a chick embryo as a fetal model to investigate the effects of prenatal exposure to antithyroid drugs on neuronal development in the chick cerebellum. Methimazole (MMI) at a dose of 20MUmol/egg was administered to eggs on day 14, while the control was given only a vehicle. In order to address the underlying mechanisms of the impaired behavior, proteomic approaches were employed in the chick cerebellum two days after MMI treatment. KEY FINDINGS: In this experiment, we found that inorganic pyrophosphatase 1 (PPA1) was upregulated in the chick cerebellum treated with MMI, and we confirmed this upregulation of PPA1 by Western blot analysis as well as by RT-PCR analysis. Concomitant with the upregulation of PPA1, a marked reduction in JNK activity, as well as of phospho JNK level, was detected in the MMI-treated chick cerebellum. SIGNIFICANCE: Since PPA1 can dephosphorylate JNK, these results suggest that the upregulation of PPA1 during neuronal development in the hypothyroid chick cerebellum may lead to impaired social behaviors as well as to impaired learning and memory via JNK dephosphorylation and inactivation in the chick cerebellum. PMID- 25748424 TI - Role of the MAPK pathway in the observed bystander effect in lymphocytes co cultured with macrophages irradiated with gamma-rays or carbon ions. AB - AIMS: The radiation-induced bystander effect (RIBE) has potential implications in cancer risks from space particle radiation; however, the mechanisms underlying RIBE are unclear. The role of the MAPK pathway in the RIBEs of different linear energy transfer (LET) was investigated. MAIN METHODS: Human macrophage U937 cells were irradiated with gamma-rays or carbon ions and then co-cultured with nonirradiated HMy2.CIR (HMy) lymphocytes for different periods. The activation of MAPK proteins and the generation of intracellular nitric oxide (NO) and reactive oxygen species (ROS) in the irradiated U937 cells were measured. Micronuclei (MN) formation in the HMy cells was applied to evaluate the bystander damage. Some U937 cells were pretreated with different MAPK inhibitors before irradiation. KEY FINDINGS: Additional MN formation was induced in the HMy cells after co-culturing with irradiated U937 cells, and the yield of this bystander MN formation was dependent on the co-culture period with gamma-ray irradiation but remained high after 1h of co-culture with carbon irradiation. Further investigations disclosed that the time response of the RIBEs had a relationship with LET, where ERK played a different role from JNK and p38 in regulating RIBEs by regulating the generation of the bystander signaling factors NO and ROS. SIGNIFICANCE: The finding that the RIBE of high-LET radiation could persist for a much longer period than that of gamma-rays implies that particle radiation during space flight could have a high risk of long-term harmful effects. An appropriate intervention targeting the MAPK pathway may have significant implications in reducing this risk. PMID- 25748425 TI - Expanding imaging capabilities for microfluidics: applicability of darkfield internal reflection illumination (DIRI) to observations in microfluidics. AB - Microfluidics is used increasingly for engineering and biomedical applications due to recent advances in microfabrication technologies. Visualization of bubbles, tracer particles, and cells in a microfluidic device is important for designing a device and analyzing results. However, with conventional methods, it is difficult to observe the channel geometry and such particles simultaneously. To overcome this limitation, we developed a Darkfield Internal Reflection Illumination (DIRI) system that improved the drawbacks of a conventional darkfield illuminator. This study was performed to investigate its utility in the field of microfluidics. The results showed that the developed system could clearly visualize both microbubbles and the channel wall by utilizing brightfield and DIRI illumination simultaneously. The methodology is useful not only for static phenomena, such as clogging, but also for dynamic phenomena, such as the detection of bubbles flowing in a channel. The system was also applied to simultaneous fluorescence and DIRI imaging. Fluorescent tracer beads and channel walls were observed clearly, which may be an advantage for future microparticle image velocimetry (MUPIV) analysis, especially near a wall. Two types of cell stained with different colors, and the channel wall, can be recognized using the combined confocal and DIRI system. Whole-slide imaging was also conducted successfully using this system. The tiling function significantly expands the observing area of microfluidics. The developed system will be useful for a wide variety of engineering and biomedical applications for the growing field of microfluidics. PMID- 25748426 TI - Deconvoluting the composition of low-frequency hepatitis C viral quasispecies: comparison of genotypes and NS3 resistance-associated variants between HCV/HIV coinfected hemophiliacs and HCV monoinfected patients in Japan. AB - Pre-existing low-frequency resistance-associated variants (RAVs) may jeopardize successful sustained virological responses (SVR) to HCV treatment with direct acting antivirals (DAAs). However, the potential impact of low-frequency (~0.1%) mutations, concatenated mutations (haplotypes), and their association with genotypes (Gts) on the treatment outcome has not yet been elucidated, most probably owing to the difficulty in detecting pre-existing minor haplotypes with sufficient length and accuracy. Herein, we characterize a methodological framework based on Illumina MiSeq next-generation sequencing (NGS) coupled with bioinformatics of quasispecies reconstruction (QSR) to realize highly accurate variant calling and genotype-haplotype detection. The core-to-NS3 protease coding sequences in 10 HCV monoinfected patients, 5 of whom had a history of blood transfusion, and 11 HCV/HIV coinfected patients with hemophilia, were studied. Simulation experiments showed that, for minor variants constituting more than 1%, our framework achieved a positive predictive value (PPV) of 100% and sensitivities of 91.7-100% for genotyping and 80.6% for RAV screening. Genotyping analysis indicated the prevalence of dominant Gt1a infection in coinfected patients (6/11 vs 0/10, p = 0.01). For clinical samples, minor genotype overlapping infection was prevalent in HCV/HIV coinfected hemophiliacs (10/11) and patients who experienced whole-blood transfusion (4/5) but none in patients without exposure to blood (0/5). As for RAV screening, the Q80K/R and S122K/R variants were particularly prevalent among minor RAVs observed, detected in 12/21 and 6/21 cases, respectively. Q80K was detected only in coinfected patients, whereas Q80R was predominantly detected in monoinfected patients (1/11 vs 7/10, p < 0.01). Multivariate interdependence analysis revealed the previously unrecognized prevalence of Gt1b-Q80K, in HCV/HIV coinfected hemophiliacs [Odds ratio = 13.4 (3.48-51.9), p < 0.01]. Our study revealed the distinct characteristics of viral quasispecies between the subgroups specified above and the feasibility of NGS and QSR-based genetic deconvolution of pre-existing minor Gts, RAVs, and their interrelationships. PMID- 25748427 TI - MALT1-ubiquitination triggers non-genomic NF-kappaB/IKK signaling upon platelet activation. AB - We have recently shown that IKK complex plays an important non-genomic role in platelet function, i.e., regulates SNARE machinery-dependent membrane fusion. In this connection, it is well known that MALT1, whose activity is modulated by proteasome, plays an important role in the regulation of IKK complex. Therefore, the present studies investigated the mechanism by which IKK signaling is regulated in the context of the platelet proteasome. It was found that platelets express a functional proteasome, and form CARMA/MALT1/Bcl10 (CBM) complex when activated. Using a pharmacological inhibitor, the proteasome was found to regulate platelet function (aggregation, integrin activation, secretion, phosphatidylserine exposure and changes in intracellular calcium). It was also found to regulate thrombogenesis and physiologic hemostasis. We also observed, upon platelet activation, that MALT1 is ubiquitinated, and this coincides with the activation of the IKK/NF-kappaB-signaling pathway. Finally, we observed that the proteasome inhibitor blocks CBM complex formation and the interaction of IKKgamma and MALT1; abrogates SNARE formation, and the association of MALT1 with TAK1 and TAB2, which are upstream of the CBM complex. Thus, our data demonstrate that MALT1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing platelet signals to the NF-kappaB pathway. PMID- 25748428 TI - Multimodal manual therapy vs. pharmacological care for management of tension type headache: A meta-analysis of randomized trials. AB - BACKGROUND: Manual therapies are generally requested by patients with tension type headache. OBJECTIVE: To compare the efficacy of multimodal manual therapy vs. pharmacological care for the management of tension type headache pain by conducting a meta-analysis of randomized controlled trials. METHODS: PubMed, MEDLINE, EMBASE, AMED, CINAHL, EBSCO, Cochrane Database of Systematic Reviews, Cochrane Collaboration Trials Register, PEDro and SCOPUS were searched from their inception until June 2014. All randomized controlled trials comparing any manual therapy vs. medication care for treating tension type headache adults were included. Data were extracted and methodological quality assessed independently by two reviewers. We pooled headache frequency as the main outcome and also intensity and duration. The weighted mean difference between manual therapy and pharmacological care was used to determine effect sizes. RESULTS: Five randomized controlled trials met our inclusion criteria and were included in the meta analysis. Pooled analyses found that manual therapies were more effective than pharmacological care in reducing frequency (weighted mean difference -0.8036, 95% confidence interval -1.66 to -0.44; three trials), intensity (weighted mean difference -0.5974, 95% confidence interval -0.8875 to -0.3073; five trials) and duration (weighted mean difference -0.5558, 95% confidence interval -0.9124 to 0.1992; three trials) of the headache immediately after treatment. No differences were found at longer follow-up for headache intensity (weighted mean difference 0.3498, 95% confidence interval -1.106 to 0.407; three trials). CONCLUSION: Manual therapies were associated with moderate effectiveness at short term, but similar effectiveness at longer follow-up for reducing headache frequency, intensity and duration in tension type headache than pharmacological medical drug care. However, due to the heterogeneity of the interventions, these results should be considered with caution at this stage. PMID- 25748429 TI - Mouse fibroblast L929 cells are less permissive to infection by Nelson Bay orthoreovirus compared to other mammalian cell lines. AB - In recent years, bats have been identified as a natural reservoir for a diverse range of viruses. Nelson Bay orthoreovirus (NBV) was first isolated from the heart blood of a fruit bat (Pteropus poliocephalus) in 1968. While the pathogenesis of NBV remains unknown, other related members of this group have caused acute respiratory disease in humans. Thus the potential for NBV to impact human health appears plausible. Here, to increase our knowledge of NBV, we examined the replication and infectivity of NBV using different mammalian cell lines derived from bat, human, mouse and monkey. All cell lines supported the replication of NBV; however, L929 cells showed a greater than 2 log reduction in virus titre compared with the other cell lines. Furthermore, NBV did not induce major cytopathic effects in the L929 cells, as was observed in other cell lines. Interestingly, the related Pteropine orthoreoviruses, Pulau virus (PulV) and Melaka virus (MelV) were able to replicate to high titres in L929 cells but infection resulted in reduced cytopathic effect. Our study demonstrates a unique virus-host interaction between NBV and L929 cells, where cells effectively control viral infection/replication and limit the formation of syncytia. By elucidating the molecular mechanisms that control this unique relationship, important insights will be made into the biology of this fusogenic virus. PMID- 25748430 TI - Case-control study of platelet glycoprotein receptor Ib and IIb/IIIa expression in patients with acute and chronic cerebrovascular disease. AB - BACKGROUND: Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation. AIMS: To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression. METHODS: This was a case-control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters. RESULTS: GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune cell sub-population counts. C-reactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers. CONCLUSIONS: Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk. PMID- 25748431 TI - Model-based traction force microscopy reveals differential tension in cellular actin bundles. AB - Adherent cells use forces at the cell-substrate interface to sense and respond to the physical properties of their environment. These cell forces can be measured with traction force microscopy which inverts the equations of elasticity theory to calculate them from the deformations of soft polymer substrates. We introduce a new type of traction force microscopy that in contrast to traditional methods uses additional image data for cytoskeleton and adhesion structures and a biophysical model to improve the robustness of the inverse procedure and abolishes the need for regularization. We use this method to demonstrate that ventral stress fibers of U2OS-cells are typically under higher mechanical tension than dorsal stress fibers or transverse arcs. PMID- 25748433 TI - Diversity of maize shoot apical meristem architecture and its relationship to plant morphology. AB - The shoot apical meristem contains a pool of undifferentiated stem cells and controls initiation of all aerial plant organs. In maize (Zea mays), leaves are formed throughout vegetative development; on transition to floral development, the shoot meristem forms the tassel. Due to the regulated balance between stem cell maintenance and organogenesis, the structure and morphology of the shoot meristem are constrained during vegetative development. Previous work identified loci controlling meristem architecture in a recombinant inbred line population. The study presented here expanded on this by investigating shoot apical meristem morphology across a diverse set of maize inbred lines. Crosses of these lines to common parents showed varying phenotypic expression in the F1, with some form of heterosis occasionally observed. An investigation of meristematic growth throughout vegetative development in diverse lines linked the timing of reproductive transition to flowering time. Phenotypic correlations of meristem morphology with adult plant traits showed an association between the meristem and flowering time, leaf shape, and yield traits, revealing links between the control and architecture of undifferentiated and differentiated plant organs. Finally, quantitative trait loci mapping was utilized to map the genetic architecture of these meristem traits in two divergent populations. Control of meristem architecture was mainly population-specific, with 15 total unique loci mapped across the two populations with only one locus identified in both populations. PMID- 25748432 TI - 2-methoxyestradiol induces vasodilation by stimulating NO release via PPARgamma/PI3K/Akt pathway. AB - The endogenous estradiol metabolite 2-methoxyestradiol (2-ME) reduces atherosclerotic lesion formation, while the underlying mechanisms remain obscure. In this work, we investigated the vasodilatory effect of 2-ME and the role of nitric oxide (NO) involved. In vivo studies using noninvasive tail-cuff methods showed that 2-ME decreased blood pressure in Sprague Dawley rats. Furthermore, in vitro studies showed that cumulative addition of 2-ME to the aorta caused a dose- and endothelium-dependent vasodilation. This effect was unaffected by the pretreatment with the pure estrogen receptor antagonist ICI 182,780, but was largely impaired by endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L arginine methyl ester (L-NAME) or by phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (WM). Moreover, 2-ME(10-7 ~10-5 M)enhanced phosphorylation of Akt and eNOS and promoted NO release from cultured human umbilical endothelial cells (HUVECs). These effects were blocked by PI3K inhibitor WM, or by the transfection with Akt specific siRNA, indicating that endothelial Akt/eNOS/NO cascade plays a crucial role in 2-ME-induced vasodilation. The peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA and protein expression were detected in HUVECs and the antagonist GW9662 or the transfection with specific PPARgamma siRNA inhibited 2-ME-induced eNOS and Akt phosphorylation, leading to the impairment of NO production and vasodilation. In conclusion, 2-ME induces vasodilation by stimulating NO release. These actions may be mediated by PPARgamma and the subsequent activation of Akt/eNOS cascade in vascular endothelial cells. PMID- 25748434 TI - Chromatin mediation of a transcriptional memory effect in yeast. AB - Previous studies have described a transcriptional "memory effect," whereby transcript levels of many Abf1-regulated genes in the budding yeast Saccharomyces cerevisiae are undiminished even after Abf1 has dissociated from its regulatory sites. Here we provide additional support for this effect and investigate its molecular basis. We show that the effect is observed in a distinct abf1 ts mutant from that used in earlier studies, demonstrating that it is robust, and use chromatin immunoprecipitation to show that Abf1 association is decreased similarly from memory effect and transcriptionally responsive genes at the restrictive temperature. We also demonstrate that the association of TATA-binding protein and Pol II decreases after the loss of Abf1 binding for transcriptionally responsive genes but not for memory effect genes. Examination of genome-wide nucleosome occupancy data reveals that although transcriptionally responsive genes exhibit increased nucleosome occupancy in abf1 ts yeast, the promoter regions of memory effect targets show no change in abf1 ts mutants, maintaining an open chromatin conformation even after Abf1 eviction. This contrasting behavior reflects different inherent propensity for nucleosome formation between the two classes, driven by the presence of A/T-rich sequences upstream of the Abf1 site in memory effect gene promoters. These sequence-based differences show conservation in closely related fungi and also correlate with different gene expression noise, suggesting a physiological basis for greater access to "memory effect" promoter regions. Thus, our results establish a conserved mechanism underlying a transcriptional memory effect whereby sequences surrounding Abf1 binding sequences affect local nucleosome occupancy following loss of Abf1 binding. Furthermore, these findings demonstrate that sequence-based differences in the propensity for nucleosome occupancy can influence the transcriptional response of genes to an altered regulatory signal. PMID- 25748435 TI - Personalized dentistry meets OMICS and "one health": from Cinderella of healthcare to mainstream? PMID- 25748436 TI - Hypothesis: the sound of the individual metabolic phenotype? Acoustic detection of NMR experiments. AB - We present here an innovative hypothesis and report preliminary evidence that the sound of NMR signals could provide an alternative to the current representation of the individual metabolic fingerprint and supply equally significant information. The NMR spectra of the urine samples provided by four healthy donors were converted into audio signals that were analyzed in two audio experiments by listeners with both musical and non-musical training. The listeners were first asked to cluster the audio signals of two donors on the basis of perceived similarity and then to classify unknown samples after having listened to a set of reference signals. In the clustering experiment, the probability of obtaining the same results by pure chance was 7.04% and 0.05% for non-musicians and musicians, respectively. In the classification experiment, musicians scored 84% accuracy which compared favorably with the 100% accuracy attained by sophisticated pattern recognition methods. The results were further validated and confirmed by analyzing the NMR metabolic profiles belonging to two other different donors. These findings support our hypothesis that the uniqueness of the metabolic phenotype is preserved even when reproduced as audio signal and warrants further consideration and testing in larger study samples. PMID- 25748438 TI - Beta-globin gene haplotypes among cameroonians and review of the global distribution: is there a case for a single sickle mutation origin in Africa? AB - Studies of hemoglobin S haplotypes in African subpopulations have potential implications for patient care and our understanding of genetic factors that have shaped the prevalence of sickle cell disease (SCD). We evaluated HBB gene cluster haplotypes in SCD patients from Cameroon, and reviewed the literature for a global distribution. We reviewed medical records to obtain pertinent socio demographic and clinical features for 610 Cameroonian SCD patients, including hemoglobin electrophoresis and full blood counts. RFLP-PCR was used to determine the HBB gene haplotype on 1082 chromosomes. A systematic review of the current literature was undertaken to catalogue HBB haplotype frequencies in SCD populations around the world. Benin (74%; n = 799) and Cameroon (19%; n = 207) were the most prevalent haplotypes observed among Cameroonian patients. There was no significant association between HBB haplotypes and clinical life events, anthropometric measures, hematological parameters, or fetal hemoglobin (HbF) levels. The literature review of the global haplotype distributions was consistent with known historical migrations of the people of Africa. Previously reported data from Sudan showed a distinctly unusual pattern; all four classical haplotypes were reported, with an exceptionally high proportion of the Senegal, Cameroon, and atypical haplotypes. We did not observe any significant associations between HBB haplotype and SCD disease course in this cohort. Taken together, the data from Cameroon and from the wider literature suggest that a careful reassessment of African HBB haplotypes may shed further light on the evolutionary dynamics of the sickle allele, which could suggest a single origin of the sickle mutation. PMID- 25748437 TI - Comprehensive proteomics analysis of glycosomes from Leishmania donovani. AB - Leishmania donovani is a kinetoplastid protozoan that causes a severe and fatal disease kala-azar, or visceral leishmaniasis. L. donovani infects human host after the phlebotomine sandfly takes a blood meal and resides within the phagolysosome of infected macrophages. Previous studies on host-parasite interactions have not focused on Leishmania organelles and the role that they play in the survival of this parasite within macrophages. Leishmania possess glycosomes that are unique and specialized subcellular microbody organelles. Glycosomes are known to harbor most peroxisomal enzymes and, in addition, they also possess nine glycolytic enzymes. In the present study, we have carried out proteomic profiling using high resolution mass spectrometry of a sucrose density gradient-enriched glycosomal fraction isolated from L. donovani promastigotes. This study resulted in the identification of 4022 unique peptides, leading to the identification of 1355 unique proteins from a preparation enriched in L. donovani glycosomes. Based on protein annotation, 566 (41.8%) were identified as hypothetical proteins with no known function. A majority of the identified proteins are involved in metabolic processes such as carbohydrate, lipid, and nucleic acid metabolism. Our present proteomic analysis is the most comprehensive study to date to map the proteome of L. donovani glycosomes. PMID- 25748439 TI - Translesion polymerase genes polymorphisms and haplotypes influence survival of osteosarcoma patients. AB - Cytotoxic activity of most chemotherapeutic agents is based on their ability to induce DNA damage. Interstrand crosslinks are among the most detrimental forms of DNA damage as both DNA strands are affected. As translesion polymerases participate in their repair, they may be important for response to chemotherapeutic agents that induce such lesions, including commonly used cisplatin. Altered expression of translesion polymerase genes REV1 and REV3L may modify sensitivity to cisplatin. As osteosarcoma patients are commonly treated with cisplatin-based chemotherapy, our aim was to investigate if REV1 and REV3L polymorphisms influence survival of osteosarcoma patients treated with cisplatin based chemotherapy. We determined the genotypes of common functional tag REV1 and REV3L polymorphisms in 66 osteosarcoma patients. Cox regression was used for survival analysis. Carriers of at least one polymorphic REV1 rs3087403 allele had significantly shorter EFS and overall survival (OS) (p = 0.004; HR = 3.79; 95%CI = 1.53-9.35 and p < 0.001; HR = 4.44; 95%CI = 1.92-10.27, respectively). Combination of REV1 rs3087403 and REV3L rs462779 polymorphisms was also significantly associated with shorter OS (ptrend<0.001) and shorter EFS (ptrend = 0.003). The results of this first study on polymorphisms in translesion polymerase genes in osteosarcoma suggest they could help predict outcome of cisplatin-based chemotherapy in osteosarcoma patients. PMID- 25748440 TI - Comparison of the diagnostic accuracy, sensitivity and specificity of four odontological methods for age evaluation in Italian children at the age threshold of 14 years using ROC curves. AB - The age threshold of 14 years is relevant in Italy as the minimum age for criminal responsibility. It is of utmost importance to evaluate the diagnostic accuracy of every odontological method for age evaluation considering the sensitivity, or the ability to estimate the true positive cases, and the specificity, or the ability to estimate the true negative cases. The research aims to compare the specificity and sensitivity of four commonly adopted methods of dental age estimation - Demirjian, Haavikko, Willems and Cameriere - in a sample of Italian children aged between 11 and 16 years, with an age threshold of 14 years, using receiver operating characteristic curves and the area under the curve (AUC). In addition, new decision criteria are developed to increase the accuracy of the methods. Among the four odontological methods for age estimation adopted in the research, the Cameriere method showed the highest AUC in both female and male cohorts. The Cameriere method shows a high degree of accuracy at the age threshold of 14 years. To adopt the Cameriere method to estimate the 14 year age threshold more accurately, however, it is suggested - according to the Youden index - that the decision criterion be set at the lower value of 12.928 for females and 13.258 years for males, obtaining a sensitivity of 85% and specificity of 88% in females, and a sensitivity of 77% and specificity of 92% in males. If a specificity level >90% is needed, the cut-off point should be set at 12.959 years (82% sensitivity) for females. PMID- 25748441 TI - A broad pH range indicator-based spectrophotometric assay for true lipases using tributyrin and tricaprylin. AB - A continuous assay is proposed for the screening of acidic, neutral, or alkaline lipases using microtiter plates, emulsified short- and medium-chain TGs, and a pH indicator. The lipase activity measurement is based on the decrease of the pH indicator optical density due to protonation which is caused by the release of FFAs during the hydrolysis of TGs and thus acidification. Purified lipases with distinct pH optima and an esterase were used to validate the method. The rate of lipolysis was found to be linear with time and proportional to the amount of enzyme added in each case. Specific activities measured with this microplate assay method were lower than those obtained by the pH-stat technique. Nevertheless, the pH-dependent profiles of enzymatic activity were similar with both assays. In addition, the substrate preference of each enzyme tested was not modified and this allowed discriminating lipase and esterase activities using tributyrin (low water solubility) and tricaprylin (not water soluble) as substrates. This continuous lipase assay is compatible with a high sample throughput and can be applied for the screening of lipases and lipase inhibitors from biological samples. PMID- 25748442 TI - Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms. AB - Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 +/- 1 years) and 11 older (O: 71 +/- 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43 degrees C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 +/- 3 vs Y = 96 +/- 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 +/- 6% vs Y = 49 +/- 5, P = 0.03) were attenuated in older participants. 5 MTHF augmented the overall (%CVCmax = 91 +/- 2, P = 0.03) and NO-dependent (%CVCmax = 43 +/- 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1 degrees C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 +/- 8 vs Y = 44 +/- 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 +/- 2 vs Y = 21 +/- 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 +/- 5%, P = 0.001) and NO dependent vasodilatation (20 +/- 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms. PMID- 25748444 TI - Intergenerational programs for persons with dementia: a scoping review. AB - Participation in intergenerational programs can have a positive impact on quality of life and well-being across age groups. We sought to examine the characteristics, goals, and outcomes of intergenerational programs for persons with dementia and children or youth. Six hundred and seventy-nine unique abstracts were identified through a search of 7 medical databases, 16 social science databases, 2 gray literature databases, and other sources. Twenty-seven articles met criteria for review. Articles must have gathered information on program design, goals, outcomes, or participants' perceptions. Overall, 3 themes emerged: program design, outcomes for child or youth participants, and outcomes for persons with dementia. Music, arts-based, and narrative programs were most common. Outcomes include effects on perceptions of aging and dementia, behavior, mood, engagement and sense of self. The use of qualitative and quantitative data, as well as descriptive articles, provided a richer picture of the relational features of intergenerational programs to emerge. The type of program had less of an impact on positive outcomes than if the activity was meaningful for participants and supported shared opportunities for relationship building and growth. The relationship-based skill set and scope of social work practitioners provides opportunity for the development, facilitation, and evaluation of intergenerational programs. The difficulties of establishing best practices due to methodological challenges and implications for further research are presented. PMID- 25748443 TI - Rate perception adapts across the senses: evidence for a unified timing mechanism. AB - The brain constructs a representation of temporal properties of events, such as duration and frequency, but the underlying neural mechanisms are under debate. One open question is whether these mechanisms are unisensory or multisensory. Duration perception studies provide some evidence for a dissociation between auditory and visual timing mechanisms; however, we found active crossmodal interaction between audition and vision for rate perception, even when vision and audition were never stimulated together. After exposure to 5 Hz adaptors, people perceived subsequent test stimuli centered around 4 Hz to be slower, and the reverse after exposure to 3 Hz adaptors. This aftereffect occurred even when the adaptor and test were different modalities that were never presented together. When the discrepancy in rate between adaptor and test increased, the aftereffect was attenuated, indicating that the brain uses narrowly-tuned channels to process rate information. Our results indicate that human timing mechanisms for rate perception are not entirely segregated between modalities and have substantial implications for models of how the brain encodes temporal features. We propose a model of multisensory channels for rate perception, and consider the broader implications of such a model for how the brain encodes timing. PMID- 25748445 TI - Creating social policy to support women's agency in coercive settings: A case study from Uganda. AB - Many emphasise the need for policies that support women's agency in highly coercive settings, and the importance of involving target women in public deliberation to inform policy design. The Ugandan Marriage and Divorce Bill seeks to strengthen women's agency in marriage, but has faced many obstacles, including objections from many women themselves in public consultations. We explore key stakeholders' accounts of the difficulties facing the Bill's progress to date, through focus groups with 24 rural and urban men and women, interviews with 14 gender champions in government, non-governmental organisations and legal sectors, and 25 relevant media and radio reports. Thematic analysis revealed an array of representations of the way the Bill's progress was shaped by the public consultation process, the nature of the Ugandan public sphere, the understanding and manipulation of concepts such as 'culture' and 'custom' in public discourse, the impact of economic inequalities on women's understandings of their gendered interests and low women's trust in the law and the political process. We discuss the complexities of involving highly marginalised women in public debates about gender issues and highlight possible implications for conceptualising agency, gender and social change as tools for gender policy and activism in extreme inequality. PMID- 25748446 TI - DNA base pair resolution measurements using resonance energy transfer efficiency in lanthanide doped nanoparticles. AB - Lanthanide-doped nanoparticles are of considerable interest for biodetection and bioimaging techniques thanks to their unique chemical and optical properties. As a sensitive luminescence material, they can be used as (bio) probes in Forster Resonance Energy Transfer (FRET) where trivalent lanthanide ions (La3+) act as energy donors. In this paper we present an efficient method to transfer ultrasmall (ca. 8 nm) NaYF4 nanoparticles dispersed in organic solvent to an aqueous solution via oxidation of the oleic acid ligand. Nanoparticles were then functionalized with single strand DNA oligomers (ssDNA) by inducing covalent bonds between surface carboxylic groups and a 5' amine modified-ssDNA. Hybridization with the 5' fluorophore (Cy5) modified complementary ssDNA strand demonstrated the specificity of binding and allowed the fine control over the distance between Eu3+ ions doped nanoparticle and the fluorophore by varying the number of the dsDNA base pairs. First, our results confirmed nonradiative resonance energy transfer and demonstrate the dependence of its efficiency on the distance between the donor (Eu3+) and the acceptor (Cy5) with sensitivity at a nanometre scale. PMID- 25748447 TI - Sphingosine-1-phosphate induces the migration of thyroid follicular carcinoma cells through the microRNA-17/PTK6/ERK1/2 pathway. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid known to play a role in tumorigenesis and cancer progression. However, the molecular mechanisms of S1P regulated migration of papillary thyroid cancer cells are still unknown. In this study, we showed that S1P induced PTK6 mRNA and protein expression in two thyroid follicular cancer cell lines (ML-1 and FTC-133). Further studies demonstrated that induced PTK6 and its downstream signal component (ERK1/2) are involved in S1P-induced migration. Upon investigating the mechanisms behind this event, we found that miR-17 inhibited the expression of PTK6 through direct binding to its 3'-UTR. Through overexpression and knockdown studies, we found that miR-17 can significantly inhibit S1P-induced migration in thyroid follicular cancer cells. Interestingly, overexpression or knockdown of PTK6 or ERK1/2 effectively removed the inhibition of S1P-induced migration by miR-17. Furthermore, we showed that S1P decreased miR-17 expression levels. Meanwhile, in papillary thyroid cancers, miR-17 is downregulated and negatively associated with clinical staging, whereas PTK6 is upregulated and positively associated with clinical stages. Collectively, our work defines a novel signaling pathway implicated in the control of thyroid cancer migration. PMID- 25748448 TI - Highly efficient and stable electron injection layer for inverted organic light emitting diodes. AB - A highly efficient and stable electron injection layer (EIL) for inverted organic light-emitting diodes (OLEDs) is developed. A 1 nm-thick Al is deposited between indium tin oxide cathode and commonly used Cs2CO3 EIL, which can significantly improve the stability. The Al may react with evaporated Cs2CO3 and form a much stabler Al-O-Cs complex, avoiding Cs oxidization by air according to X-ray photoemission spectroscopy measurement. When the Al is evaporated after Cs2CO3 layer, although such a Al-O-Cs complex also forms, the inferior electron injection at Al/4,7-diphenyl-1,10-phenanthroline interface leads to a joule heat induced resistance that adversely affects the air stability of the device. It is expected that the developed Al/Cs2CO3 EIL promotes high efficiency and stable active-matrix OLEDs based on n-type thin film transistor. PMID- 25748449 TI - Drosophila S6 Kinase like inhibits neuromuscular junction growth by downregulating the BMP receptor thickveins. AB - Synaptic connections must be precisely controlled to ensure proper neural circuit formation. In Drosophila melanogaster, bone morphogenetic protein (BMP) promotes growth of the neuromuscular junction (NMJ) by binding and activating the BMP ligand receptors wishful thinking (Wit) and thickveins (Tkv) expressed in motor neurons. We report here that an evolutionally conserved, previously uncharacterized member of the S6 kinase (S6K) family S6K like (S6KL) acts as a negative regulator of BMP signaling. S6KL null mutants were viable and fertile but exhibited more satellite boutons, fewer and larger synaptic vesicles, larger spontaneous miniature excitatory junctional potential (mEJP) amplitudes, and reduced synaptic endocytosis at the NMJ terminals. Reducing the gene dose by half of tkv in S6KL mutant background reversed the NMJ overgrowth phenotype. The NMJ phenotypes of S6KL mutants were accompanied by an elevated level of Tkv protein and phosphorylated Mad, an effector of the BMP signaling pathway, in the nervous system. In addition, Tkv physically interacted with S6KL in cultured S2 cells. Furthermore, knockdown of S6KL enhanced Tkv expression, while S6KL overexpression downregulated Tkv in cultured S2 cells. This latter effect was blocked by the proteasome inhibitor MG132. Our results together demonstrate for the first time that S6KL regulates synaptic development and function by facilitating proteasomal degradation of the BMP receptor Tkv. PMID- 25748450 TI - Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD. AB - Cardiac hypertrophy is an adaptive response to pressure, volume stress, and loss of contractile mass from prior infarction. Metabolic changes in cardiac hypertrophy include suppression of fatty acid oxidation and enhancement of glucose utilization, which could result in lipid accumulation in the heart. SIRT3, a mitochondrial NAD+-dependent deacetylase, has been demonstrated to play a crucial role in controlling the acetylation status of many enzymes participating in energy metabolism. However, the role of SIRT3 in the pathogenesis of hypertrophy-related lipid accumulation remains unclear. In this study, hypertrophy-related lipid accumulation was investigated using a mouse cardiac hypertrophy model induced by transverse aortic constriction (TAC). We showed that mice developed heart failure six weeks after TAC. Furthermore, abnormal lipid accumulation and decreased palmitate oxidation rates were observed in the hypertrophic hearts, and these changes were particularly significant in SIRT3-KO mice. We also demonstrated that the short form of SIRT3 was downregulated in wild-type (WT) hypertrophic hearts and that this change was accompanied by a higher acetylation level of long-chain acyl CoA dehydrogenase (LCAD), which is a key enzyme participating in fatty acid oxidation. In addition, SIRT3 may play an essential role in attenuating lipid accumulation in the heart through the deacetylation of LCAD. PMID- 25748451 TI - Characterization of 14-3-3 isoforms expressed in the Echinococcus granulosus pathogenic larval stage. AB - The 14-3-3 protein family of eukaryotic regulators was studied in Echinococcus granulosus, the causative agent of cystic hydatid disease. These proteins mediate important cellular processes in eukaryotes and are expected to play important roles in parasite biology. Six isoforms of E. granulosus 14-3-3 genes and proteins (Eg14-3-3.1-6) were analyzed, and their phylogenetic relationships were established with bona fide 14-3-3 orthologous proteins from eukaryotic species. Eg14-3-3 isoforms with previous evidence of expression (Eg14-3-3.1-4) in E. granulosus pathogenic larval stage (metacestode) were cloned, and recombinant proteins were used for functional studies. These protein isoforms were detected in different components of E. granulosus metacestode, including interface components with the host. The roles that are played by Eg14-3-3 proteins in parasite biology were inferred from the repertoires of interacting proteins with each isoform, as assessed by gel overlay, cross-linking, and affinity chromatography assays. A total of 95 Eg14-3-3 protein ligands were identified by mass spectrometry. Eg14-3-3 isoforms have shared partners (44 proteins), indicating some overlapping functions; however, they also bind exclusive partners (51 proteins), suggesting Eg14-3-3 functional specialization. These ligand repertoires indicate the involvement of Eg14-3-3 proteins in multiple biochemical pathways in the E. granulosus metacestode and note some degree of isoform specialization. PMID- 25748453 TI - Radiopacity measurements of direct and indirect resin composites at different thicknesses using digital image analysis. AB - Radiopacity is an important property of composite materials for clinical diagnosis. For seven direct composites (Aelite LS Posterior, Aelite All-Purpose Body, Quadrant Universal LC, Clearfil Majesty Posterior, Clearfil Majesty Esthetic, Filtek Ultimate Dentin, IPS Empress Direct Dentin) and six indirect composites (Ceromega, Epricord, Estenia C&B, Tescera, Signum Ceramis, Solidex), diskshaped specimens (N=260, n=10 per group) were fabricated for two thicknesses at 1 and 2 mm. Average radiographic density of each composite material was calculated. Radiopacity values of specimens were expressed in equivalent thickness of aluminum using the calibration curve. Data were analyzed using one way and two-way ANOVA, followed by Tukey's HSD test (alpha=0.05). Radiopacity was significantly affected by resin composite type (p<0.05) and thickness (p<0.001). All composites, except Epricord (1.22-1.84), had higher radiopacity values than dentin (1.23-2.24). IPS Empress Direct (5.58-9.38) and Estenia C&B (5.49-9.16) showed significantly higher radiopacity (p<0.05) than the other materials including enamel and dentin. PMID- 25748452 TI - Epidural Electrical Stimulation for Stroke Rehabilitation: Results of the Prospective, Multicenter, Randomized, Single-Blinded Everest Trial. AB - BACKGROUND: This prospective, single-blinded, multicenter study assessed the safety and efficacy of electrical epidural motor cortex stimulation (EECS) in improving upper limb motor function of ischemic stroke patients with moderate to moderately severe hemiparesis. METHODS: Patients >= 4 months poststroke were randomized 2:1 to an investigational (n = 104) or control (n = 60) group, respectively. Investigational patients were implanted (n = 94) with an epidural 6 contact lead perpendicular to the primary motor cortex and a pulse generator. Both groups underwent 6 weeks of rehabilitation, but EECS was delivered to investigational patients during rehabilitation. The primary efficacy endpoint (PE) was defined as attaining a minimum improvement of 4.5 points in the upper extremity Fugl-Meyer (UEFM) scale as well as 0.21 points in the Arm Motor Ability Test (AMAT) 4 weeks postrehabilitation. Follow-up assessments were performed 1, 4, 12, and 24 weeks postrehabilitation. Safety was evaluated by monitoring adverse events (AEs) that occurred between enrollment and the end of rehabilitation. RESULTS: Primary intent-to-treat analysis showed no group differences at 4 weeks, with PE being met by 32% and 29% of investigational and control patients, respectively (P = .36). Repeated-measures secondary analyses revealed no significant treatment group differences in mean UEFM or AMAT scores. However, post hoc comparisons showed that a greater proportion of investigational (39%) than control (15%) patients maintained or achieved PE (P = .003) at 24 weeks postrehabilitation. Investigational group mean AMAT scores also improved significantly (P < .05) when compared to the control group at 24 weeks postrehabilitation. Post hoc analyses also showed that 69% (n = 9/13) of the investigational patients who elicited movement thresholds during stimulation testing met PE at 4 weeks, and mean UEFM and AMAT scores was also significantly higher (P < .05) in this subgroup at the 4-, 12-, and 24-week assessments when compared to the control group. Headache (19%), pain (13%), swelling (7%), and infection (7%) were the most commonly observed implant procedure-related AEs. Overall, there were 11 serious AEs in 9 investigational group patients (7 procedure related, 4 anesthesia related). CONCLUSIONS: The primary analysis pertaining to efficacy of EECS during upper limb motor rehabilitation in chronic stroke patients was negative at 4 weeks postrehabilitation. A better treatment response was observed in a subset of patients eliciting stimulation induced upper limb movements during motor threshold assessments performed prior to each rehabilitation session. Post hoc comparisons indicated treatment effect differences at 24 weeks, with the control group showing significant decline in the combined primary outcome measure relative to the investigational group. These results have the potential to inform future chronic stroke rehabilitation trial design. PMID- 25748454 TI - Influence of various gypsum materials on precision of fit of CAD/CAM-fabricated zirconia copings. AB - The clinical applicability of CAD/CAM-fabricated zirconia copings is tested using working models made from four different highstrength Type IV gypsum materials. Each of the four materials was used to fabricate 15 zirconia copings. Precision of fit was measured with a digital electron microscope using the silicone replica technique. The mean and standard deviation of each reference point were analyzed using the one-way analysis of the variance (ANOVA) and Tukey's honest significant difference (HSD) tests (alpha=0.05). The overall marginal and internal fits of the zirconia copings were as follows: GS (GS: Grey Stone) group: 91.43 MUm, LS (LS: Light green Stone) Group: 87.89 MUm, RS (RS: Red Stone) Group: 88.75 MUm, BS (BS: Beige Stone) Group: 82.78 MUm. There were no significant differences between the mean adaptations of the gypsum varieties (p>0.05). This confirmed that the type of gypsum material used does not determine the precision of fit of a prosthesis. PMID- 25748455 TI - Effect of resin infiltration on enamel surface properties and Streptococcus mutans adhesion to artificial enamel lesions. AB - The aim of this study was to evaluate and compare the effects of resin infiltration and sealant type on enamel surface properties and Streptococcus mutans adhesion to artificial enamel lesions. Artificial enamel lesions were produced on the surfaces of 120 enamel specimens, which were divided into two groups: Group A and Group B (n=60 per group). Each group was further divided into four subgroups (n=15 per subgroup) according to sealant type: Group I Demineralized enamel (control); Group II-Enamel Pro Varnish; Group III-ExciTE F; and Group IV-Icon. In Group A, hardness and surface roughness were evaluated; in Group B, bacterial adhesion was evaluated. Icon application resulted in significantly lower surface roughness and higher hardness than the other subgroups in Group A. In Group B, Enamel Pro Varnish resulted in lowest bacterial adhesion, followed by Icon. This study showed that resin infiltration of enamel lesions could arrest lesion progress. PMID- 25748456 TI - The synthesis and characterization of a novel potassium chloride-fluoridated hydroxyapatite varnish for treating dentin hypersensitivity. AB - Dentin hypersensitivity is treated using materials that occlude the dentinal tubules or release potassium ions that induce nerve desensitization. In this study we formulated a novel varnish containing potassium chloride and fluoridated hydroxyapatite and evaluated its physical properties and cytotoxicity. Potassium ion release from the varnish was measured. Dentin permeability was evaluated by measuring the hydraulic conductance of etched dentin discs treated with the varnish. The direct contact test and MTT assay were performed to evaluate the varnish's cytotoxicity. We found that the varnish released potassium ions over 6 h, and demonstrated a statistically higher reduction in dentin permeability compared to commercial fluoride varnish or control. Dentin disc scanning electron microscopy images demonstrated occluded dentinal tubules in the novel varnish group after brushing. The cytotoxicity tests indicated the varnish was biocompatible with gingival and pulpal fibroblasts. We propose the novel varnish is a potential material for use in hypersensitivity management. PMID- 25748457 TI - Comparison of enamel-bracket bond strength using direct- and indirect-bonding techniques with a self-etching ion releasing S-PRG filler. AB - This in vitro study compared the shear bond strength (SBS) and adhesive remnant index (ARI) of two systems for bonding orthodontic brackets to enamel. The first system involved a self-etching primer (Beauty Ortho Bond, BO) containing surface pre-reacted glass filler. The second involved a primer applied with phosphoric acid etching (Transbond XT, TX). Ninety-six extracted human premolars were divided into eight groups: Group I (TX/direct bonding), Group II (TX/indirect bonding), Group III (BO/direct bonding), and Group IV (BO/indirect bonding). Groups V-VIII were identical to Groups I-IV, respectively, but were also subjected to 1,500 thermal cycles between 5 and 55 degrees C. ARI was scored by binocular microscopy. SBS was analyzed by three-way ANOVA and the Bonferroni test. ARI was analyzed by the chi-squared test. The BO groups showed lower SBS and ARI results than the TX groups. SBS was significantly influenced by the primer material, bonding technique, and thermal cycling. PMID- 25748458 TI - Dimensional changes in stone models simulating full crown preparations with adjacent teeth resulting from long-term immersion of medium-viscosity addition type silicone rubber impressions in disinfectant solutions. AB - If impression materials could be immersed in disinfectant solutions for a longer period, then this form of disinfection would be easier to incorporate into dental preparation procedures. This study investigated the dimensional changes in stone models resulting from immersion of medium-viscosity hydrophilic addition-type silicone rubber impression material in disinfectant solutions for 30 min and 24 h. Impressions of a master die designed to simulate a full crown preparation with adjacent teeth were immersed in 2% glutaraldehyde and 0.55% ortho-phthalaldehyde solutions. The dimensional changes in the mesiodistal and buccolingual dimensions in the stone models were then measured using a three-dimensional coordinate system. It was found that the dimensional changes in the stone models caused by immersion of the impression materials were less than 15 MUm. Immersion in 2% glutaraldehyde or 0.55% ortho-phthalaldehyde for 24 h was as clinically acceptable for medium-viscosity hydrophilic addition-type silicone rubber impressions as immersion for 30 min. PMID- 25748459 TI - Ag-loaded mesoporous bioactive glasses against Enterococcus faecalis biofilm in root canal of human teeth. AB - Ag-loaded mesoporous bioactive glass (Ag-MBG) powders were synthesized and characterized. The ions release of Ag-MBGs in Tris-HCl and the pH stability of simulated body fluids after immersing Ag-MBGs were tested. Root canals were inoculated with Enterococcus faecalis for 4 weeks, and the antibacterial activity of MBGs, Ag-MBGs and calcium hydroxide against E. faecalis biofilm were evaluated. Results showed that Ag-MBGs possessed highly ordered mesoporous structure with silver nanoparticles deposited in the mesopores, which enabled a sustained Ag ions released. The biofilms treated with Ag-MBGs showed a significant structural disruption compared with MBGs. These results indicated that Ag-MBGs possess a potent antibacterial effect against E.faecalis biofilm in root canal, and the antibacterial activity was induced by the release of Ag ions from Ag-MBGs. PMID- 25748460 TI - Microtensile bond strength of a newly developed resin cement to dentin. AB - The purpose of this study was to evaluate the microtensile bond strength (uTBS) of a newly developed resin cement, ECD-89 (ECD, Tokuyama Dental, Tokyo, Japan) to dentin and to observe the interfacial micromorphology by comparing with two commercial resin cements, Multilink Automix (MA, Ivoclar Vivadent AG, Schaan, Liechtenstein) and Panavia F2.0 (PF, Kuraray Noritake Dental, Tokyo, Japan). Flat dentin surfaces of human third molars were exposed using #600 SiC. After application of primer and cement to the dentin surface, each cement was applied and cured with light (light condition) or without light (dark condition). The teeth were sectioned to obtain beams (1 mm*1 mm) after 24 h of water storage. The mean bond strengths and SDs (MPa) were: ECD: 68.6+/-14.9, MA: 39.2+/-18.9, PF: 39.4+/-18.5 and ECD: 54.5+/-22.4, MA: 36.7+/-15.6, PF: 13.4+/-4.46 when cured in light and dark condition, respectively. In both conditions, ECD-89 showed statistically higher uTBS than the others. PMID- 25748461 TI - Influence of monomer content on the viscoelasticity, water sorption and solubility of experimental fluorinated soft lining materials. AB - The influence of monomer content on the viscoelasticity, water sorption and solubility of experimental fluorinated soft lining materials was investigated. Changes in the viscoelastic properties of the materials were also examined after thermal cycling. Four fluorinated soft lining materials containing different amounts of methoxy diethylene glycol methacrylate (MDGMA) and tridecafluorooctyl methacrylate (13FMA) were prepared. The viscoelastic displacement for specimens containing 13FMA was found to be less than that without 13FMA (p<0.05), and the values tended to decrease with increasing 13FMA content. Reduction of the MDGMA content and addition of 13FMA caused a decrease of water sorption and solubility (p<0.05). Thermal cycling was found to affect the viscoelastic deformation of the specimens without 13FMA and those specimens with relatively large amounts of 13FMA.